EA046965B1 - 3-CARBONYLAMINO-5-CYCLOPENTYL-1H-PYRAZOLE COMPOUNDS WITH CDK2 INHIBITORY ACTIVITY - Google Patents

Description

Background to the invention Scope of the invention

The present invention relates to the compounds of formula (I) and their pharmaceutically acceptable salts, to pharmaceutical compositions containing such compounds and salts, and to their use. The compounds, salts and compositions of the present invention may be useful for treating abnormal cell growth, such as cancer, in a subject.

Description of the Prior Art

Cyclin-dependent kinases (CDKs) and related serine/threonine protein kinases are important cellular enzymes that perform critical functions in the regulation of cell division and proliferation. CDKs 1–4, 6, 10, 11 have been reported to play a direct role in cell cycle progression, whereas CDKs 3, 5, and 7–9 may play indirect roles (e.g., through activation of other CDKs, transcriptional regulation, or neuronal functions). CDK catalytic units are activated by binding to regulatory subunits known as cyclins, followed by phosphorylation. Cyclins can be divided into four main classes (G1, G1/S, S and M cyclins), whose expression levels vary at different points in the cell cycle. Cyclin B/CDK1, cyclin A/CDK2, cyclin E/CDK2, cyclin D/CDK4, cyclin D/CDK6 and, in all likelihood, other heterodynes are the most important regulators of cell cycle progression.

CDK2 overexpression is associated with abnormal cell cycle regulation. The cyclin E/CDK2 complex plays an important role in the regulation of G1/S transition, histone biosynthesis and centrosome duplication. Progressive phosphorylation of retinoblastoma (Rb) by the cyclin D/Cdk4/6 complex and the cyclin E/Cdk2 complex releases the G1 transcription factor, E2F, and promotes entry into S phase. Activation of the cyclin A/CDK2 complex during early S phase promotes phosphorylation of endogenous substrates that mediate DNA replication and E2F inactivation to complete S phase (Asghar et al. History and future of targeting cycline-dependent kinases in cancer therapy, Nat. Rev. Drug. 2015; 14(2): 130-146.

Cyclin E, a regulatory cyclin for CDK2, is often overexpressed in cancer. Amplification or overexpression of cyclin E has long been associated with poor outcomes in breast cancer (Keyomarsi et al., Cycline E and survival in patients with breast cancer. N Engl J Med. (2002) 347:1566-75). Cycline E2 (CCNE2) overexpression is associated with endocrine resistance in breast cancer cells, and CDK2 inhibition has been reported to restore responsiveness to tamoxifen or CDK4 inhibitors in tamoxifen-resistant and CCNE2-overexpressing cells (Caldon et al., Cycline E2 overexpression is associated with endocrine resistance but not insensitivity to CDK2 inhibition in human breast cancer cells. Mol Cancer Ther. (2012) 11:1488-99; Herrera-Abreu et al., Early Adaptation and Acquired Resistance to CDK4/6 Inhibition in Estrogen Receptor-Positive Breast Cancer. , Cancer Res. (2016) 76: 2301-2313). Cycline E amplification/overexpression is a mechanism of trastuzumab resistance in HER2+ breast cancer patients, Proc Natl Acad Sci. (2011) 108 : 3761-6). Cyclin E overexpression has also been reported to play a role in basal-like and triple-negative breast cancer (TNBC), as well as inflammatory breast cancer (Elsawaf & Sinn, Triple Negative Breast Cancer: Clinical and Histological Correlations, Breast Care (2011) 6 :273278; Alexander et al., Cycline E overexpression as a biomarker for combination treatment strategies in inflammatory breast cancer, Oncotarget (2017) 8: 14897-14911).

Amplification or overexpression of cyclin E1 (CCNE1) is also associated with poor outcomes in ovarian, gastric, endometrial, and other cancers (Nakayama et al., Gene amplification CCNE1 is related to poor survival and potential therapeutic target in ovarian cancer, Cancer (2010) 116: 2621-34; Etemadmoghadam et al., Resistance to CDK2 inhibitors is Associated with Selection of Polyploid Cells in CCNE1Amplified Ovarian Cancer, Clin Cancer Res (2013) 19: 5960-71; E1-Amplified High-Grade Ovarian Cancer by Cycline-Dependent Kinase 2 and ACT Inhibition, Clin. Cancer Res (2017) 23:1862-1874; CCNE1 copy-number gain and overexpression identify ovarian clear cell carcinoma. with poor prognosis, Modern Pathology (2017) 30: 297–303; Ooi et al., Gene amplification of CCNE1, CCND1, and CDK6 in gastric cancers detected by multiplex ligation-dependent probe amplification and fluorescence in situ hybridization, Hum Pathol. 2017) 61: 58-67; Noske et al., Detection of CCNE1/URI (19ql2) amplification by in situ hybridization is common in high grade and type II endometrial cancer, Oncotarget (2017) 8: 14794–14805).

The small molecule inhibitor dinaciclib (MK-7965) inhibits CDK1, CDK2, CDK5, and CDK9 and is currently in clinical trials for breast and hematologic cancers. Celiciclib (roscovitine or CYC202), which inhibits CDK2, CDK7 and CDK9, has been studied in nasopharyngeal cancer and NSCLC and is currently being studied in combination with sapacitabine in patients with BRCA mutations. CYC065, which inhibits CDK2 and CDK9, is in early-stage clinical trials. Despite significant efforts, there are currently no approved agents that target CDK2 (Cicenas et al. Highlights of Latest Advances in Research on CDK Inhibitors. Cancers, (2014) 6:2224-2242).

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There remains a need to discover CDK inhibitors having novel activity profiles, such as selective CDK2 inhibitors, which may be useful in the treatment of cancer and other proliferative diseases or conditions. In particular, CDK2 inhibitors may be useful in the treatment of tumors with CCNE1 or CCNE2 amplification.

Summary of the invention

The present invention provides in particular the compounds of formula (I) and their pharmaceutically acceptable salts. Such compounds can inhibit the activity of CDKs, including CDK2, thereby exerting biological functions. In some embodiments, the invention provides compounds that are selective for CDK2. Also provided are pharmaceutical compositions and medicaments containing the compounds or salts of the invention, alone or in combination with additional anticancer therapeutic agents.

The present invention also provides, in particular, methods for preparing the compounds, pharmaceutically acceptable salts and compositions of the invention and methods for using them.

In one aspect of the invention there is provided a compound of formula (I)

or a pharmaceutically acceptable salt thereof, where:

R ¹ represents ^1-(5-10 membered heteroaryl) or ^-(Cb-Cn-aryl), wherein said 5-10 membered heteroaryl or C ₆ -C ₁₂ -aryl is optionally substituted by one or more R ⁴ ;

^R2 and ^R3 are independently H, C1-C6-alkyl, C1-C6-fluoroalkyl, ^ ^2- (C3-C7-cycloalkyl) or ^ ^2- (4-7 membered heterocyclyl), wherein each C1- C6 alkyl and C1-C6 fluoroalkyl are optionally substituted with one or more R ⁵ , and each of said C3-C ₇ cycloalkyl and 4-7 membered heterocyclyl is optionally substituted with one or more R ⁶ ; or

R ² and R ³ are taken together with the N atom to which they are attached to form a 4-6 membered heterocyclyl, possibly containing an additional heteroatom selected from O, N(R ⁷ ) and S(O) _q as a ring member wherein said 4-6 membered heterocyclyl is optionally substituted with one or more R ⁸ ;

each L ¹ and L ² independently represents a bond or C1-C ₂ alkylene, optionally substituted by one or more R ⁹ ;

each R ⁴ independently represents F, Cl, OH, CN, NR10R ¹¹ , C1-C4 alkyl, C1-C4 fluoroalkyl, C1-C4 alkoxy, C1-C4 fluoroalkoxy, C3-C8 cycloalkyl, C(O )NR ¹⁰ R ¹¹ , SO2R ¹² , SO(=NH)R ¹² or SO2NR10R ¹¹ , where each C1-C4 alkyl and C1-C ₄ fluoroalkyl is optionally substituted by one or more R ¹³ ;

each R ⁵ independently represents OH, C 1 -C ₄ -alkoxy or NR10R ¹¹ ;

each R ⁶ independently represents F, OH, C1-C4 alkyl, C1-C4 fluoroalkyl, C1-C4 alkoxy, C1-C4 fluoroalkoxy or NR10R ¹¹ , where each C1-C4 alkyl and C1-C ₄ - fluoroalkyl is optionally substituted with one or more R ¹³ ;

R ⁷ represents H, C1- _C4 alkyl or C(O)-C1- _C4 alkyl;

each R ⁸ independently represents F, OH, C1- _C4 alkyl, C1- _C4 alkoxy or CN;

each R ⁹ independently represents F, OH or C1- _C2 alkyl;

R ¹⁰ and R ¹¹ are each independently H or C1- _C4 alkyl;

each R ¹² represents C1- _C4 alkyl or _C3 - _C6 cycloalkyl;

each R ¹³ is independently OH, C1-C ₄ -alkoxy or NR ¹⁴ R ¹⁵ ;

R ¹⁴ and R ¹⁵ are each independently H or C1- _C4 alkyl; and q is 0, 1 or 2.

In another aspect of the invention there is provided a compound of formula (II)

or a pharmaceutically acceptable salt thereof, where:

R ¹ , R ² and R ³ are as defined for formula (I).

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In another aspect of the invention there is provided a compound of formula (III)

R ²

I/O

R ³

or a pharmaceutically acceptable salt thereof, where:

R ¹ , R ² and R ³ are as defined for formula (I).

In another aspect of the invention, there is provided a pharmaceutical composition comprising a compound of the invention according to any of the formulas described herein, or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or excipient. In some embodiments, the pharmaceutical composition contains two or more pharmaceutically acceptable carriers and/or excipients.

The invention also provides therapeutic methods and uses comprising administering a compound of the invention or a pharmaceutically acceptable salt thereof to a subject.

In one aspect of the invention, there is provided a method of treating abnormal cell growth, particularly cancer, in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the invention or a pharmaceutically acceptable salt thereof. The compounds of the invention may be administered as single agents or they may be administered in combination with other anticancer therapeutic agents, in particular standard of care agents appropriate for a particular type of cancer.

In another aspect of the invention, there is provided a method of treating abnormal cell growth, particularly cancer, in a subject in need thereof, comprising administering to the subject an amount of a compound of the invention or a pharmaceutically acceptable salt thereof in combination with an amount of an additional anticancer agent, wherein said amounts together are effective in treating said abnormal cell growth.

In another aspect of the invention, a compound of the invention, or a pharmaceutically acceptable salt thereof, is provided for use in treating a subject in need of such treatment. Some embodiments of the invention provide a compound of the invention, or a pharmaceutically acceptable salt thereof, for use in treating abnormal cell growth, particularly cancer, in a subject.

In another aspect of the invention, there is provided the use of a compound of the invention, or a pharmaceutically acceptable salt thereof, for the treatment of abnormal cell growth, particularly cancer, in a subject.

In another aspect of the invention, there is provided a pharmaceutical composition for use in the treatment of abnormal cell growth, in particular cancer, in a subject in need thereof, comprising a compound of the invention or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or excipient.

In another aspect of the invention, a compound of the invention or a pharmaceutically acceptable salt thereof is provided for use as a drug, in particular a drug for the treatment of abnormal cell growth such as cancer.

Yet another aspect of the invention provides the use of a compound of the invention, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating abnormal cell growth, such as cancer, in a subject.

In another aspect of the invention, there is provided a method of treating a CDK2-mediated disorder in a subject, comprising administering to the subject a compound of the invention or a pharmaceutically acceptable salt thereof in an amount that is effective for treating the disorder, particularly cancer.

Each of the embodiments of the compounds of the present invention described below can be combined with one or more other embodiments of the compounds of the present invention described herein, consistent with the embodiment(s) with which it is combined.

In addition, each of the embodiments described below includes within its scope the pharmaceutically acceptable salts of the compounds of the invention. Accordingly, the phrase or a pharmaceutically acceptable salt thereof includes, in the specification of the invention, all compounds described herein unless expressly stated otherwise.

Brief description of graphic materials

Fig. 1 shows the X-ray structure of a single crystal of (1R,3S)-3-[3-({[3-(methoxymethyl)-1methyl-III-pyrazol-5-yl]carbonyl}amino)-III-pyrazol-5-yl]cyclopentyl- propan-2-ylcarbamate monohydrate (form 1).

Fig. 2 shows the spectrum of DRLP (^^)-3-[3-({[3-(methoxymethyl)-1-methyl-III-pyrazol-5yl]carbonyl}amino)-III-pyrazol-5-yl]cyclopentyl-propan- 2-ylcarbamate monohydrate (form 1).

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Detailed Description of the Invention

The present invention can be better understood by reference to the following detailed description of preferred embodiments of the invention and the examples included therein. It should be understood that the terminology used herein is intended to describe specific embodiments only and is not limiting. It should also be understood that, unless specifically defined herein, terminology used herein has its traditional meaning as known in the art.

As used herein, the singular form includes the plural forms unless otherwise indicated; for example, a substituent includes one or more substituents.

The invention described herein can suitably be practiced in the absence of any element(s) not specifically disclosed herein. Thus, for example, in each instance herein, any of the terms containing, consisting essentially of, and consisting of may be replaced by either of the other two terms.

Alkyl refers to a saturated monovalent aliphatic hydrocarbon radical, including straight-chain and branched groups, having a specifically specified number of carbon atoms. Alkyl substituents usually contain from 1 to 12 carbon atoms (C-C^-alkyl), often from 1 to 8 carbon atoms (C1-C ₈ -alkyl) or even more often from 1 to 6 carbon atoms (Cl-C ₆ -alkyl ), from 1 to 5 carbon atoms (C1-C ₅ -alkyl), from 1 to 4 carbon atoms (C1-C ₄ -alkyl) or from 1 to 2 carbon atoms (C1-C ₂ -alkyl). Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, n-heptyl, n-octyl and the like. Preferred C1- _C4 alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl. Preferred C ₁ -C ₆ alkyl groups include methyl, ethyl, n-propyl, isopropyl, nbutyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl and n-hexyl.

Alkyl groups described herein as optionally substituted may be substituted with one or more substituent groups as further defined in the claims. Such possible substituent groups are independently selected unless otherwise noted. The total number of substituent groups may equal the total number of hydrogen atoms on the alkyl group to the extent that such substitution makes chemical sense. Possibly substituted alkyl groups typically contain from 1 to 6 possible substituents, sometimes from 1 to 5 possible substituents, from 1 to 4 possible substituents, or preferably from 1 to 3 possible substituents.

Exemplary substituent groups on alkyl groups include halogen, -OH, C1- _C4 alkoxy, or ^NRxRy , wherein ^Rx and ^{Ry are} each independently H or C1-C4 alkyl. It will be understood that NR ^x R ^y is used generally herein to refer to amino substituents (eg, NR ¹⁰ R ¹¹ as part of a possible R ⁵ substituent or NR ¹⁴ R ¹⁵ as part of a possible R ¹³ substituent) as defined in the claims. In some cases, substituted alkyl groups are specifically named by reference to the substituent group. For example, haloalkyl refers to an alkyl group having a specific number of carbon atoms, which is substituted with one or more halogen substituents, and typically contains 1-6 carbon atoms, 1-5 carbon atoms, 1-4 carbon atoms, or 1-2 carbon atoms and 1 , 2 or 3 halogen atoms (i.e. C1- _C5 haloalkyl, _C1 - _C4 haloalkyl or C1- _C2 haloalkyl).

More specifically, fluorinated alkyl groups may be specifically referred to as fluoroalkyl groups (eg, C1-C6, C1-C5, C1-C4 or C1- _C2 fluoroalkyl groups), which are typically substituted with 1, 2 or 3 fluorine atoms. For example, C1-C4 _- fluoroalkyl includes trifluoromethyl (-CF3), difluoromethyl (-CF2H), fluoromethyl (-CFH2), difluoroethyl (-CH2CF2H) and the like. Such groups may be further replaced by possible substituent groups, as further described herein. Likewise, alkyl groups substituted by -OH, C1- _C4 -alkoxy or NR ^x R ^y may be referred to as hydroxyalkyl, alkoxyalkyl or aminoalkyl, in each case having the indicated number of carbon atoms.

In some embodiments of the present invention, the alkyl and fluoroalkyl groups are optionally substituted with one or more possible substituents, and preferably 1-4, 1-3 or 1-2 possible substituents.

Alkylene as used herein refers to a divalent hydrocarbon group having a specifically specified number of carbon atoms that can link two other groups together. Such groups may be referred to as, for example, C1- _C6 alkylene, C1- _C4 alkylene, C1- _C2 alkylene, etc. If specifically indicated, the alkylene may also be substituted with other groups and may have one or more degrees of unsaturation (ie, alkenylene or alkylene moiety) or may include rings. The open alkylene valencies do not have to be at opposite ends of the chain. Branched alkylene groups may include -CH(Me)-, -CH ₂ CH(Me)- and -C(Me) ₂ -, which are also included within the term alkylenes. Where an alkylene group is described as optionally substituted, the substituents include those substituents that are described herein. For example, C1- _C2 alkylene may be methylene or ethylene.

Alkoxy refers to the monovalent group -O-alkyl, where the alkyl part has a specific

- 4 046965 specified number of carbon atoms. Alkoxy groups typically contain from 1 to 8 carbon atoms (C1- _C8 alkoxy), or from 1 to 6 carbon atoms (C^C^ alkoxy), or from 1 to 4 carbon atoms (C^C^ alkoxy). For example, C.'i-C'4-alkoxy includes methoxy, ethoxy, isopropoxy, tert-butyloxy (i.e. -OCH3, -OCH2CH3, -OCH(CH3)2, -OC(CH3)3), etc. P. The alkoxy groups may optionally be replaced by one or more halogen atoms, and in particular one or more fluorine atoms, up to the total number of hydrogen atoms present on the alkyl moiety. Such groups are referred to as 'haloalkoxy' groups (or, if fluorinated, then more specifically as 'fluoroalkoxy') having a specified number of carbon atoms and being substituted with one or more halogen substituents. Typically such groups contain 1-6 carbon atoms, preferably 1-4 carbon atoms and sometimes 1-2 carbon atoms and 1, 2 or 3 halogen atoms (i.e. C1- _C6 haloalkoxy, C1- _C4 haloalkoxy or C1-C ₂ -haloalkoxy). More specifically, fluorinated alkyl groups may specifically be referred to as fluoroalkoxy groups, for example C1-C6, C1-C4 or C1- _C2 fluoroalkoxy groups, which are typically substituted with 1, 2 or 3 fluorine atoms. Thus, C1- _C4- fluoroalkoxy includes trifluoromethyloxy (-OCF3), difluoromethyloxy (-OCF2H), fluoromethyloxy (-OCFH2), difluoroethyloxy (-OCH2CF2H), and the like.

Cycloalkyl refers to a non-aromatic saturated carbocyclic ring system containing a specified number of carbon atoms, which may be a monocyclic, spirocyclic, bridged or fused bicyclic or polycyclic ring system that is linked to the parent molecule through a carbon atom of the cycloalkyl ring. Typically, the cycloalkyl groups of the invention contain from 3 to 8 carbon atoms (C ₃ -C ₈ -cycloalkyl), preferably from 3 to 7 carbon atoms (C ₃ -C ₇ -cycloalkyl) or from 3 to 6 carbon atoms (C ₃ -C ₆ -cycloalkyl). Representative examples of cycloalkyl rings include, for example, cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, and the like. Cycloalkyl groups may be optionally substituted, unsubstituted, or substituted with groups that are described herein.

The terms heterocyclyl or heterocyclic can be used interchangeably and refer to a non-aromatic saturated ring system containing a specified number of ring atoms, containing at least one heteroatom selected from N, O and S as a ring member, where the S ring atoms are optionally substituted one or two oxo groups (i.e. S(O)q, where q is 0, 1 or 2), and where the heterocyclic ring is linked to the parent molecule through a ring atom, which may be C or N. If specifically stated, such heterocyclic rings may be partially unsaturated. Heterocyclic rings include rings that are spirocyclic, bridged or fused to one or more other heterocyclic or carbocyclic rings, where such spirocyclic, bridged or fused rings may themselves be saturated, partially unsaturated or aromatic to a degree of unsaturation or aromaticity that makes chemical sense , provided that the point of attachment to the main molecule is an atom of the heterocyclic part of the ring system. Preferably, heterocyclic rings contain from 1 to 4 heteroatoms selected from N, O, and S(O) _q as ring members, and more preferably from 1 to 2 ring heteroatoms, provided that such heterocyclic rings do not contain two adjacent oxygen atoms.

Heterocyclyl groups are unsubstituted or substituted with suitable group substituents as described herein. Such substituents may be present on a heterocyclic ring attached to the main molecule or on a spirocyclic, bridged or fused ring attached thereto. In addition, the N ring atoms are optionally substituted with groups suitable for an amine, such as alkyl, acyl, carbamoyl, sulfonyl, and the like.

Heterocycles typically include 3-8 membered heterocyclyl groups and, more preferably, 4-7 or 4-6 membered heterocyclyl groups as defined herein.

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Illustrative examples of saturated heterocycles include, but are not limited to:

tetrahydro furan (tetrahydrofuranyl) oxirane tiaran (oxiranil) (tiaranil) aziridine oxetane thiatan (aziridinyl) (oxetanil) (tiatanil) azetidine (azetidinyl)

tetrahydrothiophene pyrrolidine tetrahydropyran tetrahydrothiopyran piperidine (tetrahydrothiophenyl) (pyrrolidinyl) (tetrahydropyranyl) (tetrahydrothiopyranyl) (piperidinyl)

1,4-dioxane 1,4-oxathiaranyl morpholine 1,4-dithiane piperazine thiomorpholine (1,4-dioxanyl) (1,4-oxathiaranyl) (morpholinyl) (1,4-dithianyl) (piperazinyl) (thiomorpholinyl)

oxepan tiepan (oxepanil) (tiepanil)

azepane 1,4-dioxepane 1,4-oxathiepanil (azepanil) (1,4-dioxepanil) (1,4-oxathiepanil)

1,4-oxaazepane 1,4-thiazepanyl (1,4-oxazepanil) (1,4-thiazepanil)

1,4-diazepane 1,4-dithiepanyl (1,4-diazepanyl) (1,4-dithiepanyl)

In some embodiments, heterocyclic groups contain 3-8 ring members, including both carbon atoms and non-carbon heteroatoms, and often 4-7 or 4-6 ring members. In some embodiments, substituent groups containing 4-7 membered heterocycles are selected from azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, azepanyl, diazepanyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl and thiomorpholinyl rings, each possibly substituted as described as used herein, to the extent that the substitution makes chemical sense.

In some embodiments of the present invention, the cycloalkyl and heterocyclyl groups are optionally substituted with one or more optional substituents as described herein.

It is clear that no more than two N, O or S atoms are usually bonded in series, except when an oxo group is added to S to form a sulfonyl group, or in the case of certain heteroaromatic rings such as triazole, tetrazole, oxadiazole, thiadiazole, triazine, etc.

Aryl or aromatic refers to an optionally substituted monocyclic or fused bicyclic or polycyclic ring system having known aromaticity characteristics, where at least one ring contains a fully conjugated π electron system. Typically, aryl groups contain from 6 to 20 carbon atoms (^^^aryl) as ring members, preferably from 6 to 14 carbon atoms (C ₆ -C ₁₄ -aryl) or, more preferably, from 6 to 12 carbon atoms (C ₆ -C ₁₂ -aryl). Fused aryl groups may include an aryl ring (eg, a phenyl ring) fused to another aryl or heteroaryl ring, or fused to a saturated or partially unsaturated carbocyclic or heterocyclic ring, provided that the point of attachment to the parent molecule on such fused ring systems is atom of the aromatic part of the ring system. For example, without limitation, aryl groups include phenyl, biphenyl, naphthyl, anthracenyl, phenanthrenyl, indanyl, indenyl and tetrahydronaphthyl. The aryl group is unsubstituted or substituted, as further described herein.

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Likewise, heteroaryl or heteroaromatic refers to monocyclic or fused bicyclic or polycyclic ring systems having known aromaticity characteristics, which contain a specifically specified number of ring atoms as defined above for aryl, which include at least one heteroatom selected from N, O and S , as a ring member in an aromatic ring. Heteroatom inclusion allows aromaticity in 5-membered rings as well as in 6-membered rings. Typically, heteroaryl groups contain from 5 to 12 ring atoms (5-12 membered heteroaryl) and, more preferably, from 5 to 10 ring atoms (5-10 membered heteroaryl). Heteroaryl rings are attached to the main molecule through the ring atom of the heteroaromatic ring, provided that aromaticity is maintained. Thus, 6-membered heteroaryl rings can be attached to the main molecule through a C ring atom, and 5-membered heteroaryl rings can be attached to the main molecule through a C or N ring atom. Heteroaryl groups can also be fused to another aryl or heteroaryl ring, or may be fused to a saturated or partially unsaturated carbocyclic or heterocyclic ring, provided that the point of attachment to the parent molecule on such fused ring systems is an atom of the heteroaromatic portion of the ring system. Examples of unsubstituted heteroaryl groups include, but are not limited to, pyrazole, triazole, isoxazole, oxazole, thiazole, thiadiazole, imidazole, pyridine, pyrazine, indazole, and benzimidazole. Additional heteroaryl groups include pyrrole, furan, thiophene, oxadiazole, tetrazole, pyridazine, pyrimidine, benzofuran, benzothiophene, indole, quinoline, isoquinoline, purine, triazine, naphthyridine and carbazole. In many embodiments, the 5- or 6-membered heteroaryl groups are pyrazole, triazole, isoxazole, oxazole, thiazole, thiadiazole, imidazole, pyridine, or pyrazine rings. The heteroaryl group is unsubstituted or substituted, as further described herein.

Aryl and heteroaryl moieties described herein as optionally substituted may be substituted by one or more independently selected substituent groups unless otherwise indicated. The total number of substituent groups may be equal to the total number of hydrogen atoms on the aryl, heteroaryl or heterocyclyl moiety, to the extent that such substitution makes chemical sense and preserves aromaticity in the case of aryl and heteroaryl rings. Optionally substituted aryl or heteroaryl groups typically contain 1 to 5 possible substituents, sometimes 1 to 4 possible substituents, preferably 1 to 3 possible substituents, or more preferably 1 to 2 possible substituents, as described herein.

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Examples of monocyclic heteroaryl groups include, but are not limited to:

N

N

N

pyrrole (pyrrolyl) furan (furanyl) thiophene (thiophenyl) pyrazole (pyrazolyl) indazole (indazolyl)

isoxazole (isoxazolyl) oxazole (oxazolyl) isothiazole (isothiazolyl) thiazolyl (thiazolyl)

1,2,3-triazole (1,2,3-triazolyl)

N-N

1,3,4-triazole (1,3,4-triazolyl)

-oxa-2,3-diazole (1-oxa-2,3-diazolyl)

-oxa-2,4-diazole (1-oxa-2,4-diazolyl)

-oxa-2,5-diazole (1-oxa-2,5-diazolyl)

S.

.S.

N N

N-N

-oxa-3,4-diazole

-thia-2,3-diiazole (1-oxa-3,4-diazolyl) (1-thia-2,3-diazolyl)

N—'

-thia-2,4-diazole (1-thia-2,4-diazolyl)

-thia-2,5-diazole (1-thia-2,5-diazolyl)

S.

N-N

N.N.

<N

W // N-N

1-thia-3,4-diazole tetrazole (1-thia-3,4-diazolyl) (tetrazolyl) pyridine (pyridinyl) pyridazine (azinyl pyride) pyrimidine (pyrimidinyl)

pyrazine (pyrazinil)

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Illustrative examples of fused ring heteroaryl groups include, but are not limited to:

N benzofuran (benzofuranyl) benzothiophene indole (benzothiophenyl) (indolyl)

N H benzimidazole (benzimidazolyl)

indazole (indazolyl)

pyrrolo[2,3-c]pyridine benzotriazole (benzotriazolyl) pyrrolo[2,3-b]pyridine pyrrolo[3,2-c]pyridine (pyrrolo[2,3-b]pyridinyl) (pyrrolo[2,3-c] ]pyridinyl) (pyrrolo[3,2-c]pyridinyl)

pyrazole [4,3-c] pyridine pyrazolo[3,4-c]pyridine pyrazole [3,4-b] pyridine isoindole (pyrazolo[4,3-c]pyridinyl) (pyrazolo[3,4-c]pyridinyl) (pyrazolo[3,4-b]pyridinyl) (isoindolyl)

indazole purine indolizine imidazo[1,2-a] pyridine imidazo[1,5-a] pyridine (indazolyl) (purinyl) (indolizinyl) (imidazo[1,2-a] pyridinyl) (imidazo[1,5-a] pyridinyl)

pyrazole [1,5-a] pyridine pyrrolo[1,2-b]pyridazine imidazo[1,2-c]pyridine (pyrazole [1,5-a]pyridinyl) (pyrrolo[1,2-b]pyridazinyl) ( imidazo[1,2-c]pyridinyl)

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quinoline (quinolinyl)

cinnoline (cinnolinyl)

quinazoline (quinazolinil)

quinoxaline (quinoxalinyl) isoquinoline (isoquinolinyl)

phthalazine (phthal azinyl)

1,6-naphthyridine (1,6-naphthyridinyl)

1,7-naphthyridine (1,7-naphthyridinyl)

1,8-naphthyridine (1,8-naphthyridinyl)

1,5-naphthyridine (1,5-naphthyridinyl)

2,6-naphthyridine (2,6-inyl naphthyride)

2,7-naphthyridine (2,7-inyl naphthyride)

pyrido[3,2-d]pyrimidine (pyrido[3,2-d]pyrimidinyl) pyrido[4,3-d]pyrimidine (pyrido[4,3-d]pyrimidinyl) pyrido[3,4-d]pyrimidine (pyr ido[3,4-d]pyrimidinyl)

pyrido[2,3-d]pyrimidine (pyrido[2,3-d]pyrimidinyl) pyrido[2,3-b]pyrazine (pyrido[2,3-b]pyrazinyl) pyrido[3,4- b]pyrazine (pyrido[3,4-b]pyrazinyl)

pyrimido [5,4-d] pyrimidine (pyrimido [5,4-d] pyrimidinyl) pyrazine [2,3 -b] pyrazine (pyrazine [2,3 -b] pyrazinyl) pyrimido 14.5 -d | pyrimidine (pyrimido[4,5-d]pyrimidinyl)

Hydroxy belongs to the OH group.

Cyano belongs to the -C=N group.

Unsubstituted amino belongs to the -NH2 group. Where amino is described as substituted or optionally substituted, then the term covers groups of the form -NR ^x R ^y , wherein R ^x and R ^y are each as further described herein. For example, alkylamino refers to the group -NR ^x R ^y , where one of R ^x and R ^y is an alkyl moiety and the other is H, and dialkylamino refers to -NR ^x R ^y , where both R ^x and R ^y are alkyl groups, and these alkyl groups have a specifically specified number of carbon atoms (for example, -NH-C1-C4 alkyl or -N(C ₁ -C ₄ -alkyl) ₂ ). It should be understood that NR ^x R ^y is used generally to refer to amino substituents (eg, NR ¹⁰ R ¹¹ as part of a possible R ⁵ substituent group or NR14R ¹⁵ as part of a possible R ¹³ substituent group) as defined in the claims.

Halogen or halogeno refers to fluorine, chlorine, bromine and iodine (F, Cl, Br, I). Preferably, the halogen is fluorine or chlorine (F or Cl).

Possible or perhaps means that a subsequently described event or circumstance may not necessarily occur, and the description includes cases in which the event or circumstance occurs and cases in which it does not.

The terms optionally substituted and substituted or unsubstituted are used interchangeably to indicate that the particular group being described may have no non-hydrogen substituents (i.e., unsubstituted), or the group may have one or more non-hydrogen substituents. (i.e. substituted). Unless specifically stated otherwise, the total number of substituents that may be present is equal to the number of H atoms present on the unsubstituted form of the group being described. In cases where a possible substituent is attached via a double bond, such as an oxo (=O) substituent, then the group occupies two available valences, so the total number of other substituents that are included is halved. In the case where possible substituents are selected independently from a list of alternatives, then the selected groups are the same or different. From the text of the description of the invention it will be clear that if

- 10 046965 the quality and nature of possible substituent groups will be limited to the extent that such substitutions make chemical sense.

Often, a group described herein as optionally substituted with one or more substituent groups is optionally substituted with 1-4, preferably optionally substituted with 1-3, and more preferably optionally substituted with 1-2 such substituents. An indication herein that a group is optionally substituted by one or more of a list of possible substituents, may be substituted by optionally substituted by 1-4, optionally substituted by 1-3, optionally substituted by 1-2, optionally substituted by one, two, three or four, optionally substituted with one, two or three, or optionally substituted with one or two such possible substituent groups.

In one aspect of the invention there is provided a compound of formula (I) n' R ^{1 n} (I) or a pharmaceutically acceptable salt thereof, wherein:

R1 represents ^1-(5-10 membered heteroaryl) or ^1-(C ₆ -C ₁₂ -aryl), wherein said 5-10 membered heteroaryl or C ₆ -C ₁₂ -aryl is optionally substituted by one or more R ⁴ ;

R ² and R ³ are independently H, C1-C6 alkyl, C1-C6 fluoroalkyl, -L ² -(C3-C ₇ -cycloalkyl) or ^ ² -(4-7 membered heterocyclyl), wherein each C1-C6 alkyl and C1-C6 fluoroalkyl are optionally substituted with one or more R ⁵ , and each of said C3-C ₇ cycloalkyl and 4-7 membered heterocyclyl is optionally substituted with one or more R ⁶ ; or

^R2 and ^R3 are taken together with the N atom to which they are attached to form a 4-6 membered heterocyclyl, possibly containing an additional heteroatom selected from O, N( ^R7 ) and S(O)q as a member rings wherein said 4-6 membered heterocyclyl is optionally substituted with one or more R ;

each L ¹ and L ² independently represents a bond or C1-C ₂ alkylene, optionally substituted by one or more R ⁹ ;

each R ⁴ independently represents F, Cl, OH, CN, NR ¹⁰ R ¹¹ , C1-C4-alkyl, C1-C4-fluoroalkyl, C1-C4-alkoxy, CgCd-fluoroalkoxy, C3-C8-cycloalkyl, C(O )NR ¹⁰ R11, SO2R ¹² , SO(=NH)R ¹² or SO2NR10R ¹¹ , where each C1-C4 alkyl and C1-C ₄ fluoroalkyl is optionally substituted by one or more R ¹³ ;

each R ⁵ independently represents OH, C 1 -C ₄ -alkoxy or NR10R ¹¹ ;

each R ⁶ independently represents F, OH, C1-C4 alkyl, C1-C4 fluoroalkyl, C1-C4 alkoxy, C1-C4 fluoroalkoxy or NR10R ¹¹ , where each C1-C4 alkyl and C1-C ₄ - fluoroalkyl is optionally substituted with one or more R ¹³ ;

R ⁷ represents H, C1- _C4 alkyl or C(O)-C1- _C4 alkyl;

each R ⁸ independently represents F, OH, C1- _C4 alkyl, C1- _C4 alkoxy or CN;

each R ⁹ independently represents F, OH or C1- _C2 alkyl;

R ¹⁰ and R 11 are each independently H or C1-C4 alkyl;

each R ¹² represents C1- _C4 alkyl or _C3 - _C6 cycloalkyl;

each R ¹³ independently represents OH, C1-C ₄ -alkoxy or NR14R ¹⁵ ;

R ¹⁴ and R ¹⁵ are each independently H or C1- _C4 alkyl; and q is 0, 1 or 2.

The compounds of formula (I) are characterized by the syn-reciprocal arrangement of substituent groups at positions 1 and 3 of the cyclopentyl ring. The compounds of formula (I) may be present as a single enantiomer having a syn relative configuration at positions 1 and 3 (i.e. (1R,3S) or (1S,3R)) or as a mixture of syn enantiomeric forms, for example a racemic mixture ( 1R,3S) and (1S,3R).

In compounds of formula (I), R ¹ represents ^1-(5-10 membered heteroaryl) or -L1-(C ₆ -C ₁₂ aryl), wherein said 5-10 membered heteroaryl or C ₆ -C ₁₂ -aryl optionally substituted with one or more R ⁴ .

In some embodiments, R ¹ is a ^1-(5-10 membered heteroaryl), wherein said 510 membered heteroaryl is optionally substituted with one or more R ⁴ . In some such embodiments, said 5-10 membered heteroaryl is pyrazolyl, triazolyl, isoxazolyl, oxazolyl, thiazolyl, thiadiazolyl, imidazolyl, pyridinyl, pyrazinyl, indazolyl, or benzimidazolyl, wherein said 510-membered heteroaryl is optionally substituted with one or more R ⁴ . In some embodiments, said 510-membered heteroaryl is pyrazolyl or triazolyl, optionally substituted with one or more R ⁴ . In specific embodiments, said 5-10 membered heteroaryl is pyrazolyl, optionally substituted with one or more R ⁴ . In other embodiments, said 5-10 membered heteroaryl is triazolyl, optionally substituted with one or more R ⁴ . In other embodiments, said 5-10 membered heteroaryl is isoxazolyl, oxazolyl, thiazolyl, thiadiazolyl, imidazolyl, pyridinyl, pyrazinyl, indazolyl or benzimidazolyl, wherein said 5-10 membered heteroaryl is optionally substituted with one or more R ⁴ . In some embodiments, said 5-10 membered heteroaryl is isoxazolyl or oxazolyl, optionally substituted with one or more R ⁴ .

- 11 046965

In specific embodiments, said 5-10 membered heteroaryl is isoxazolyl, optionally substituted with one or more R ⁴ . In other embodiments, said 5-10 membered heteroaryl is thiazolyl, thiadiazolyl or imidazolyl, wherein said 5-10 membered heteroaryl is optionally substituted with one or more R ⁴ . In still other embodiments, said 5-10 membered heteroaryl is pyridinyl, pyrazinyl, indazolyl or benzimidazolyl, wherein said 5-10 membered heteroaryl is optionally substituted with one or more R ⁴ . In some embodiments of each of the above, said 5-10 membered heteroaryl is optionally substituted with one, two, three or four R ⁴ . In some embodiments of each of the above, said 5-10 membered heteroaryl is optionally substituted with one or two R ⁴ .

In other embodiments, R ¹ is -^-(^-^2^^), wherein said C^-C^-aryl is optionally substituted with one or more R ⁴ . In some such embodiments, said C6-C12 aryl is phenyl, optionally substituted with one or more R ⁴ . In some embodiments of each of the above, said C6-C12 aryl is optionally substituted with one, two, three or four R ⁴ . In some embodiments of each of the above, said C6-C12 aryl is optionally substituted with one or two R ⁴ .

In the compounds of formula (I), L ¹ represents a bond or Ci-C'2-alkylene. optionally substituted with one or more R ⁹ . In some such embodiments, said L ¹ is a bond or C1 -C2 alkylene, optionally substituted with one, two, three or four R ⁹ . In some such embodiments, L ¹ is a bond or ^-^-alkylene, optionally substituted with one or two R ⁹ . In some such embodiments, L ¹ represents a bond, methylene or ethylene. In some such embodiments, L ¹ is a bond or methylene. In some embodiments of each of the above, L ¹ represents a bond. In other embodiments of each of the above, L ¹ is ^-^-alkylene, optionally substituted by one or more R ⁹ . In some such embodiments, said L ¹ is ^-^-alkylene, optionally substituted with one, two, three or four R ⁹ . In some such embodiments, said L ¹ is ^-^-alkylene, optionally substituted with one or two R ⁹ . In some such embodiments, L ¹ is methylene or ethylene (ie -CH2 or -CH2CH2-). In some embodiments, L ¹ is methylene.

In the compounds of formula (I), R2 and ^R3 are independently H, Cj-Cg-alkyl, C1-C6fluoroalkyl, -L2-( _C3 - _C7- cycloalkyl) or -b2-(4-7-membered heterocyclyl), wherein each of said C1-C6 alkyl and C ₁ -C ₆ -fluoroalkyl is optionally substituted with one or more R ⁵ , and each of said ^-^-cycloalkyl and 4-7 membered heterocyclyl is optionally substituted with one or more R ⁶ ; or R2 and ^R3 are taken together with the N atom to which they are attached to form a 4-6 membered heterocyclyl, possibly containing an additional heteroatom selected from O, N( ^R7 ) and S(O)q as a ring member wherein said 4-6 membered heterocyclyl is optionally substituted with one or more R ⁸ .

In some embodiments, R2 and ^R3 are independently H, C1-C6 alkyl, C1-C6 fluoroalkyl, -L2-(C3-C7 cycloalkyl), or -b2-(4-7 membered heterocyclyl), wherein each C1- C6 alkyl and C1-C6 fluoroalkyl are optionally substituted with one or more R ⁵ , and each said C3-C ₇ cycloalkyl and 4-7 membered heterocyclyl is optionally substituted with one or more R ⁶ . In some such embodiments, said ^-^-alkyl and C1-C6-fluoroalkyl are optionally substituted with one, two, three or four R ⁵ , and each said C3-C ₇ -cycloalkyl and 4-7 membered heterocyclyl is optionally substituted with one, two, three or four R ⁶ . In some such embodiments, said ^-^-alkyl and C1-C6-fluoroalkyl are optionally substituted with one or two R ⁵ , and each said C3-C ₇ -cycloalkyl and 4-7 membered heterocyclyl is optionally substituted with one or two R ⁶ .

In some embodiments, R2 and ^R3 are independently H, C1-C6 alkyl, or C1-C6 fluoroalkyl, wherein each of said C1-C6 fluoroalkyl and C1-C6 fluoroalkyl is optionally substituted by one or more ^R5 . In certain such embodiments, each of said C1- _C6 alkyl and _C1 - _C6 fluoroalkyl is optionally substituted with one, two, three or four ^R5 . In some such embodiments, each of said C1-C6 alkyl and C1-C6 fluoroalkyl is optionally substituted with one or two R ⁵ . In specific embodiments, R2 and ^R3 are independently H, ^-^-alkyl or C1-C ₆ -fluoroalkyl. In specific embodiments, R2 is H, and ^R3 is ^-^-alkyl or C1-C6-fluoroalkyl. In specific embodiments, R ² is H, and R ³ is CH3, CH ₂ CH ₃ , CH ₂ CH ₂ CH ₃ , CH(CH ₃ ) ₂ , CH2CH2CH2CH3, CH(CH ₃ )CH2CH ₃ , CH2CH(CH ₃ ) 2 or C(CH ₃ ) ₃ .

In other embodiments, R2 and ^R3 are independently H, -L2-(C3-C7-cycloalkyl) or -L2(4-7 membered heterocyclyl), wherein each of said C3-C7 cycloalkyl and 4-7 membered heterocyclyl is optionally substituted with one or more R ⁶ . In certain such embodiments, R ² is H and R ³ is -L2-(C3-C ₇ -cycloalkyl) or -L2-(4-7 membered heterocyclyl), wherein each is ^-^-cycloalkyl and 4- The 7-membered heterocyclyl is optionally substituted with one or more R ⁶ . In specific embodiments, R2 is H and ^R3 is -L2-( _C3 - _C7cycloalkyl ), wherein said _C3 - _C7cycloalkyl is optionally substituted by one or more ^R6 . In some embodiments of each of the above, each specified ^-^-cycloalkyl and 4-7 membered heterocyclyl is optionally substituted with one, two, three or four R ⁶ . In some embodiments of each of the above, each specified ^-^-cycloalkyl and 4-7 membered heterocyclyl is optionally substituted with one or two R ⁶ . Somehow

- 12 046965 In many such embodiments, each R ⁶ is CH3.

In the compounds of formula (I), L represents a bond or C-C^alkylene, optionally substituted by one or more R ⁹ . In some such embodiments, said L2 is a bond or C/-C2alkylene, optionally substituted with one, two, three or four R ⁹ . In some such embodiments, L is a bond or a C1 -C ₂ alkylene, optionally substituted with one or two R ⁹ . In some such embodiments, L2 is a bond, methylene or ethylene. In some such embodiments, L2 is a bond or methylene. In some embodiments of each of the above, L2 represents a link. In other embodiments of each of the above, L ² is C'rC'2-alkylene. optionally substituted with one or more R ⁹ . In some such embodiments, L2 is C1-C2 alkylene, optionally substituted with one, two, three or four R ⁹ . In some such embodiments, L is C1-C2 alkylene, optionally substituted with one or two ^R9 . In some such embodiments, L2 is methylene or ethylene (ie -CH2 or -CH2CH2-). In some embodiments, L ² is methylene.

In some embodiments, R2 and R3 are taken together with the N atom to which they are attached to form a 4-6 membered heterocyclyl, optionally containing an additional heteroatom selected from O, N( ^R7 ) and S(O)q as a member rings wherein said 4-6 membered heterocyclyl is optionally substituted with one or more R ⁸ and wherein q is 0, 1 or 2. In some such embodiments, said 4-6 membered heterocyclyl is optionally substituted with one, two, three or four R ⁸ . In some such embodiments, said 4-6 membered heterocyclyl is optionally substituted with one or two R ⁸ .

In some such embodiments, R ² and R ³ are taken together with the N atom to which they are attached to form an optionally substituted 4-6 membered heterocyclyl, optionally containing an additional heteroatom selected from O, N(R ⁷ ) and S(O) q, as a ring member, wherein said 4-6 membered heterocyclyl is azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl or thiomorpholinyl, each of which is optionally substituted with one or more R ⁸ . In some such embodiments, R ² and R ³ are taken together with the N atom to which they are attached to form azetidinyl or pyrrolidinyl, each of which is optionally substituted with one or more R ⁸ . In specific embodiments, R ² and R ³ are taken together with the N atom to which they are attached to form azetidinyl, optionally substituted with one or more R ⁸ . In some embodiments of each of the above, the 4-6 membered heterocyclyl is optionally substituted with one, two, three or four R ⁸ . In some embodiments of each of the above, the 4-6 membered heterocyclyl is optionally substituted with one or two R ⁸ . In some such embodiments, each R ⁸ is CH3.

In the compounds of formula (I), each R ⁴ independently represents F, Cl, OH, CN, NR ¹⁰ R ¹¹ , C1-C4 alkyl, C1-C4 fluoroalkyl, C1-C4 alkoxy, C1-C4 fluoroalkoxy, C3 -C8-cycloalkyl, C(O)NR ¹⁰ R ¹¹ , SO2R ¹² , SO(=NH)R ¹² or SO2NR ¹⁰ R ¹¹ , where each C1-C4 alkyl and C1-C4 fluoroalkyl is optionally substituted by one or more R ¹³ . In some embodiments, each R ⁴ is independently a C 1 -C ₄ alkyl or a C 1 -C 4 alkoxy, wherein each C 1 -C 4 alkyl is optionally substituted by one or more R ¹³ . In some such embodiments, each R ¹³ is OCH3. In some embodiments of each of the above, each C1-C4 alkyl and C1-C4 fluoroalkyl is optionally substituted with one, two, three or four R ¹³ . In some embodiments of each of the above, each C 1 -C ₄ -alkyl and C ₁ -C ₄ -fluoroalkyl is optionally substituted with one or two R ¹³ . In specific embodiments, each ^R4 (or ^R4 substituted with ^R13 ) is independently CH3, OCH3, or CH2OCH3.

In the compounds of formula (I), each R ⁵ independently represents OH, C1-C4 alkoxy or NR ¹⁰ R ¹¹ . In some such embodiments, each R ⁵ independently represents OH, OCH3, NH2, \HCH; or K(CH ₃ ) ₂ .

In the compounds of formula (I), each R ⁶ is independently F, OH, C1-C4 alkyl, C1-C4 fluoroalkyl, C1-C4 alkoxy, C1-C4 fluoroalkoxy or NR ¹⁰ R ¹¹ , where each C1-C ₄ is alkyl and C ₁ -C ₄ -fluoroalkyl are optionally substituted with one or more R ¹³ . In some embodiments, each R ⁶ is independently C1-C4 alkyl or C1-C4 alkoxy, wherein each C1-C4 alkyl is optionally substituted by one or more R ¹³ . In some embodiments of each of the above, each C1- _C4 alkyl is optionally substituted with one, two, three or four ^R13 . In some embodiments of each of the above, each C1-C4 alkyl is optionally substituted with one or two R ¹³ . In some such embodiments, R ¹³ is CH3 or OCH3. In specific embodiments, each R ⁶ is independently CH3, OCH3, or CH2OCH3. In specific embodiments, each R ⁶ independently represents CH3.

In the compounds of formula (I), R ⁷ represents H, C1-C4 alkyl or C(O)-C1-C4 alkyl. In some embodiments, R ⁷ is H, CH 3 or C(O)CH ₃ .

In the compounds of formula (I), each R ⁸ is independently F, OH, C1-C4 alkyl, C1-C4 alkoxy, or SA. In particular embodiments, each R ⁸ is independently F, OH, CH3, OCH3, or SA. In specific embodiments, each R ⁸ represents CH ₃ .

In the compounds of formula (I), each R ⁹ independently represents F, OH or C1-C2 alkyl. In some embodiments, R ⁹ is F, OH or CH3. In certain embodiments, R ⁹ is F, OH or CH3. In some embodiments, L ¹ and L ² are a bond or unsubstituted C1-C ₂ alkylene, and R ⁹ is absent.

- 13 046965

In the compounds of formula (I), R ¹⁰ and R ¹¹ are each independently H or C ₁ -C ₄ -alkyl. In specific embodiments, R ¹⁰ and R ¹¹ are each independently H or CH3.

In the compounds of formula (I) each R ¹² represents CrC4 alkyl or C3-C6 cycloalkyl. In specific embodiments, each R ¹² is CH3, CH2CH3, CH2CH ₂ CH3, CH(CH3) ₂ or cyclopropyl.

In the compounds of formula (I), each R ¹³ is independently OH, C1-C4 alkoxy or NR ¹⁴ R ¹⁵ . In specific embodiments, each R ¹³ is independently OH, OCH= or NR ¹⁴ R ¹⁵ where R ¹⁴ and R ¹⁵ are independently H or CH3. In specific embodiments, each R ¹³ is independently OH, OCH3, NH ₂ , NHCH ₃ or N(CH ₃ ) ₂ .

In the compounds of formula (I), R ¹⁴ and R ¹⁵ are each independently H or C ₁ -C ₄ -alkyl. In specific embodiments, R ¹⁴ and R ¹⁵ are independently H or CH3.

In some embodiments, the compound of formula (I) has the absolute stereochemistry shown in formula (II)

R ²

I^N. /ABOUT

R ^{3 Η} / ^Ν -Ν O ip-4 λ 1 ^H (II) or a pharmaceutically acceptable salt thereof, where:

R ¹ , R ² and R ³ are as defined for formula (I).

In some embodiments, the compound of formula (I) has the absolute stereochemistry shown in formula (III)

R ²

or a pharmaceutically acceptable salt thereof, where:

R ¹ , R ² and R ³ are as defined for formula (I).

The compounds of formulas (II) and (III) retain the syn-reciprocity of the substituent groups at positions 1 and 3 of the cyclopentyl ring, but are present as the enantiomer indicated in substantially enantiomerically pure form.

Each of the aspects and embodiments described herein with respect to formula (I) also applies to compounds of formula (II) or (III).

Some embodiments of the invention provide compounds of formula (I), (II) or (III) or pharmaceutically acceptable salts thereof, wherein:

R ¹ represents Y-(5-10 membered heteroaryl), optionally substituted with one or two R ⁴ ;

R ² and R ³ independently represent H, C1-C6 alkyl, ^ ² -(C3-C7 cycloalkyl), wherein said C ₃ C ₇ cycloalkyl is optionally substituted by one R ⁶ ;

L ¹ and L ² are each independently a bond or methylene;

each R ⁴ independently represents F, Cl, OH, CN, NR ¹⁰ R ¹¹ , C1-C4-alkyl, C1-C4-fluoroalkyl, C1-C4-alkoxy, C1-C4-fluoroalkoxy, C3-C8-cycloalkyl, C (O)NR ¹⁰ R ¹¹ , SO2R ¹² , SO(=NH)R ¹² or SO2NR10R ¹¹ , where each C1-C ₄ -alkyl and C1-C ₄ -fluoroalkyl is optionally substituted by one R ¹³ ;

each R6 independently represents F, OH, C1- _C4 -alkyl, C1- _C4 -fluoroalkyl, C1- _C4 -alkoxy, C1C4 _- fluoroalkoxy, or NR10R ¹¹ , where each C1- _C4- alkyl and C1- _C4 -fluoroalkyl is optionally substituted with one R ¹³ ;

R ¹⁰ and R ¹¹ are each independently H or C1- _C4 alkyl;

each R ¹² represents C1- _C4 alkyl or _C3 - _C6 cycloalkyl; and each R ¹³ is independently OH, C1-C ₄ -alkoxy or NR ¹⁴ R ¹⁵ .

Other embodiments of the invention provide compounds of formula (I), (II) or (III) or pharmaceutically acceptable salts thereof, wherein:

R ¹ is an -bc-s-membered heteroaryl) optionally substituted with one or two R ⁴ ;

R ² and R ³ independently represent H, C 1 -C ₆ -alkyl or C ₃ -C ₇ -cycloalkyl, optionally substituted with one C 1 -C ₄ -alkyl;

L ¹ independently represents a bond or methylene; and each R ⁴ independently represents C1- _C4 alkyl, optionally substituted with OH or C1-C4 alkoxy.

Additional embodiments of the invention provide compounds of formula (I), (II) or (III)

- 14 046965 or their pharmaceutically acceptable salts having two or more of the following characteristics:

R ¹ represents -E ¹ -(5-10 membered heteroaryl), wherein said 5-10 membered heteroaryl is optionally substituted by one or more R ⁴ ;

R ² and R ³ independently represent H or C ₁ -Cg-alkyl;

L ¹ represents a bond or GG-alkylene;

each R ⁴ is independently GG-alkyl, wherein each GG-alkyl is optionally substituted by one or more R ¹³ ;

each R ¹³ is independently OH, N-N-alkoxy or NR ¹⁴ R ¹⁵ ; and R ¹⁴ and R ¹⁵ are each independently H or N-N-alkyl.

Some such embodiments of the invention provide compounds of formula (I), (II) or (III), or pharmaceutically acceptable salts thereof, having two or more of the following characteristics:

R ¹ represents -b ¹ -(5-10 membered heteroaryl), optionally substituted by one or more R ⁴ , wherein said 5-10 membered heteroaryl is pyrazolyl;

R ² represents H;

R ³ represents G-Cg-alkyl, preferably GG-alkyl;

L ¹ represents a bond;

each R ⁴ is independently C ₁ -C ₄ alkyl, wherein each C ₁ -C ₄ alkyl is optionally substituted by one or more R ¹³ ;

each R ¹³ is independently OH, OCH ₃ or NR ¹⁴ R ¹⁵ ; and R ¹⁴ and R ¹⁵ are each independently H or CH ₃ .

Other embodiments of the invention provide compounds of formula (I), (II) or (III), or pharmaceutically acceptable salts thereof, having two or more of the following characteristics:

R ¹ represents -b ¹ -(5-10 membered heteroaryl), wherein said 5-10 membered heteroaryl is optionally substituted by one or more R ⁴ ;

R ² and R ³ are independently H or -E ² -(C ₃ -C7-cycloalkyl), wherein said C3-C7 cycloalkyl is optionally substituted by one or more R ⁶ ;

L ¹ represents a bond or GG-alkylene;

L ² represents a bond or GG-alkylene;

each R ⁴ is independently GG-alkyl, wherein each G-Cj-alkyl is optionally substituted by one or more R ¹³ ;

each R ⁶ independently represents F, OH or GG-alkyl;

each R ¹³ is independently OH, GCi-alkoxy or NR ¹⁴ R ¹⁵ ; and R ¹⁴ and R ¹⁵ are each independently H or N-N-alkyl.

Other embodiments of the invention provide compounds of formula (I), (II) or (III), or pharmaceutically acceptable salts thereof, having two or more of the following characteristics:

R ¹ represents -b ¹ -(5-10 membered heteroaryl), optionally substituted by one or more R ⁴ , wherein said 5-10 membered heteroaryl is isoxazolyl;

L ¹ represents GG-alkylene;

R ² represents H;

R ³ represents -L ² -(C ₃ -C ₇ -cycloalkyl), optionally substituted by one or more R ⁶ ;

L ² represents a bond;

each R ⁴ is independently GG-alkyl, wherein each GG-alkyl is optionally substituted by one or more R ¹³ ;

each R ⁶ independently represents F, OH, or N-N-alkyl;

each R ¹³ is independently OH, GCi-alkoxy or NR ¹⁴ R ¹⁵ ; and R ¹⁴ and R ¹⁵ are each independently H or N-N-alkyl.

In another aspect of the invention, there is provided a compound selected from the group consisting of the compounds illustrated in Examples 1-649, inclusive, or pharmaceutically acceptable salts thereof.

- 15 046965

In another aspect of the invention there is provided a compound selected from the group consisting of:

(1R, 35)-3 -(3 - {[(2-methoxypyridin-4-yl)acetyl] amino } - 17/-pyrazol-5 yl)cyclopentylpropylcarbamate;

(1R, 35)-3 -(3 - {[(2-methyl-1,3-thiazol-5 -yl)acetyl]amino } - 17/-pyrazol-5 yl)cyclopentyl-propan-2-ylcarbamate;

(17?,35)-3-(3-{ [(1 -methyl-17/-indazol-5-yl)acetyl] amino}-17/-pyrazol-5yl)cyclopentyl-ethylcarbamate;

(1R, 35)-3-(3-{ [(1 -methyl-1H-1,2,3-triazol-5-yl)carbonyl] amino }-177-pyrazol-5yl)cyclopentyl-(28)-butane -2-ylcarbamate;

(17?,35)-3-(3-{[(5-methyl-1,3-oxazol-2-yl)acetyl]amino}-17/-pyrazol-5yl)cyclopentyl-(1-methylcyclopropyl)carbamate;

(1R, 35)-3 -(3 - {[(5-methoxypyrazin-2-yl)acetyl] amino } - 17(-pyrazol-5 yl)cyclopentyl-(1-methylcyclopropyl)carbamate;

(17?,35)-3-(3-{[(5-methyl-1,2-oxazol-3-yl)acetyl]amino}-17/-pyrazol-5yl)cyclopentyl-(1-methylcyclopropyl)carbamate;

(17?, 35)-3 - [3 -( {[3 -(methoxymethyl)-1 -methyl- 17/-pyrazol-5 -yl] carbonyl } amino)17/-pyrazol-5 -yl] cyclopentyl-( 1-methylcyclopropyl)carbamate;

(lR,3S)-3-[3-({[3 -(methoxymethyl)-1 -methyl-1 H-pyrazol-5 -yl] carbonyl } amino)I H-pyrazol-5-yl] cyclopentyl-[^ )-4,4,4-trifluorobutan-2-yl] carbamate (Isomer A);

(lR,3S)-3-[3-({[3 -(methoxymethyl)-1 -methyl-1 H-pyrazol-5 -yl] carbonyl } amino)I H-pyrazol-5-yl] cyclopentyl-[^ )-4,4,4-trifluorobutan-2-yl] carbamate (Isomer B);

(17?,35)-3-(3-{[(5-methyl-1,3-oxazol-2-yl)acetyl]amino}-17/-pyrazol-5yl)cyclopentyl-ot/?eot-butylcarbamate;

(17?,35)-3-(3-{[(3-methyl-1,2-oxazol-5-yl)acetyl]amino}-17/-pyrazol-5yl)cyclopentyl-2,2-dimethylazetidin-1 -carboxylate;

(17?, 35)-3 - [3 -( {[3 -(methoxymethyl)-1 -methyl- 17/-pyrazol-5-yl] carbonyl } amino)17/-pyrazol-5-yl]cyclopentylpropane -2-ylcarbamate;

(17?, 35)-3 - [3 -( {[3 -(methoxymethyl)-1 -methyl- 17/-pyrazol-5-yl] carbonyl } amino)17/-pyrazol-5-yl]cyclopentyl-( 28)-butan-2-ylcarbamate;

(17?,35)-3-(3-{[(3-methyl-1,2-oxazol-5-yl)acetyl]amino}-1//-pyrazol-5yl)cyclopentyl-(1-methylcyclopropyl)carbamate ;

(17?, 35)-3 - { 3 - [(1,2-oxazol-5 -ylacetyl)amino] - 17/-pyrazol-5 -yl } cyclopentyl(28)-butan-2-ylcarbamate;

(17?, 35)-3 - {3 - [(1,2-oxazol-3-ylacetyl)amino] - 17/-pyrazol-5 -yl} cyclopentyl tert-butplcarbamate; and (17?,35)-3-(3-{[(5-methyl-1,3,4-thiadiazol-2-yl)acetyl]amino}-17/-pyrazol-5yl)cyclopentyl-(1-methylcyclobutyl )carbamate;

or a pharmaceutically acceptable salt thereof.

In another aspect of the invention there is provided a compound selected from the group consisting of:

(1R,3S)-3-[3-({[3-(methoxymethyl)-1-methyl-1H-pyrazol-5-yl]carbonyl}amino)-1H-pyrazol-5yl]cyclopentyl-propan-2-ylcarbamate ; and (1R,3S)-3-[3-({[3-(methoxymethyl)-1-methyl-1H-pyrazol-5-yl]carbonyl}amino)-1H-pyrazol-5yl]cyclopentyl-propane-2- ylcarbamate; or a pharmaceutically acceptable salt thereof.

Another aspect of the invention provides (1R,3S)-3-[3-({[3-(methoxymethyl)-1-methyl-1H-pyrazol-5yl]carbonyl}amino)-III-pyrazol-5-yl]cyclopentyl- propan-2-ylcarbamate or a pharmaceutically acceptable salt thereof.

Another aspect of the invention provides (1R,3S)-3-[3-({[3-(methoxymethyl)-1-methyl-1H-pyrazole-5

- 16 046965 yl]carbonyl}amino)-1H-pyrazol-5-yl]cyclopentyl-propan-2-ylcarbamate in the form of a free base.

Another aspect of the invention provides (4R,3S)-3-[3-(i[3-(methoxymethyl)-1-methyl-111-11irazol-5yl]carbonyl}amino)-1H-pyrazol-5-yl]cyclopentyl- propan-2-ylcarbamate in the form of a pharmaceutically acceptable salt.

Some embodiments of the invention provide (^^)-3-[3-({[3-(methoxymethyl)-1-methyl-Spirazol-5-yl]carbonyl}amino)-III-pyrazol-5-yl]cyclopentylpropane -2-ylcarbamate monohydrate (form 1). In some such embodiments, the monohydrate (Form 1) is characterized by a powder x-ray diffraction (XRD) pattern (2θ) containing:

(a) one, two, three, four, five or more than five peaks selected from the group consisting of the peaks specified in the table. 1, in °2θ±0.2°2θ; (b) one, two, three, four, five or more than five peaks selected from a group consisting of 10.4; 11.7; 12.9; 18.2 and 24.2 in °2θ±0.2°2θ; (c) any two peaks selected from the group consisting of 10.4; 11.7; 12.9; 18.2 and 24.2 in °2θ±0.2°2θ; (d) any three peaks selected from the group consisting of 10.4; 11.7; 12.9; 18.2 and 24.2 in °2θ±0.2°2θ; (e) any four peaks selected from the group consisting of 10.4; 11.7; 12.9; 18.2 and 24.2 in °2θ±0.2°2θ; (e) peaks at 10.4; 11.7; 12.9; 18.2 and 24.2 in °2θ±0.2°2θ; (g) a peak at 10.4 and one, two, three or four peaks selected from the group consisting of 11.7; 12.9; 18.2 and 24.2 in °2θ±0.2°2θ; (h) a peak at 11.7 and one, two, three or four peaks selected from the group consisting of 10.4; 12.9; 18.2 and 24.2 in °2θ±0.2°2θ; (i) a peak at 12.9 and one, two, three or four peaks selected from the group consisting of 10.4; 11.7; 18.2 and 24.2 in °2θ±0.2°2θ; (k) a peak at 18.2 and one, two, three or four peaks selected from the group consisting of 10.4; 11.7; 12.9 and 24.2 in °2θ±0.2°2θ; (k) a peak at 24.2 and one, two, three or four peaks selected from the group consisting of 10.4; 11.7; 12.9 and 18.2 in °2θ±0.2°2θ; or (m) peaks at values of 29, essentially the same as shown in FIG. 2.

Another embodiment of the invention provides (^^)-3-(3-{[(3-methyl-1,2-oxazol-5yl)acetyl]amino}-III-pyrazol-5-yl)cyclopentyl-(1-methylcyclopropyl) carbamate or a pharmaceutically acceptable salt thereof.

Another embodiment of the invention provides (^^)-3-(3-{[(3-methyl-1,2-oxazol-5yl)acetyl]amino}-III-pyrazol-5-yl)cyclopentyl-(1-methylcyclopropyl) carbamate in free base form.

Another embodiment of the invention provides (^^)-3-(3-{[(3-methyl-1,2-oxazol-5yl)acetyl]amino}-III-pyrazol-5-yl)cyclopentyl-(1-methylcyclopropyl) the carbamate in the form of a pharmaceutically acceptable salt.

In a specific embodiment of the invention, a compound is provided having the structure H °· ^ί ? ^ι '\&!/ ^Ν ~!ϊ ft I o

\ ₅ or a pharmaceutically acceptable salt thereof.

In yet another specific embodiment of the invention, there is provided a compound having the structure

or a pharmaceutically acceptable salt thereof.

In preferred embodiments, the compounds of the invention are selective CDK2 inhibitors, i.e. they have a lower inhibition constant (eg Ki or IC ₅₀ ) against CDK2 compared to other enzymatic targets. Emerging evidence suggests that GSK3e inhibition may be associated with the gastrointestinal toxicity that has been observed with some CDK inhibitors. Compounds that are selective inhibitors of CDK2 compared to GSK3e may provide an improved safety profile, improved dosing schedule (eg, by reducing the need for dose reductions or dosing interruptions), and/or increased overall efficacy due to the ability to administer higher doses. the use of a continuous dosing regimen and/or prolongation of the overall treatment time. Likewise, selective CDK2 inhibitors may have a reduced risk of some hematologic toxicities that have been reported to be associated with CDK6 inhibition.

In some embodiments, the compounds of the invention are selective for CDK2 over CDK1. In some such embodiments, the compounds exhibit at least

- 17 046965 at least 10-fold selectivity for CDK2 compared to CDK1. In other embodiments, the compounds exhibit at least 20-fold selectivity for CDK2 over CDK1. In specific embodiments, the compounds exhibit at least 30-fold selectivity for CDK2 over CDK1.

In some embodiments, the compounds of the invention are selective for CDK2 over CDK4 and/or CDK6. In some such embodiments, the compounds exhibit at least 10-fold selectivity for CDK2 over CDK4 and/or CDK6. In other embodiments, the compounds exhibit at least 20-fold selectivity for CDK2 over CDK4 and/or CDK6. In specific embodiments, the compounds exhibit at least 30-fold selectivity for CDK2 over CDK4 and/or CDK6.

In some embodiments, the compounds of the invention are selective for CDK2 over GSK3e. In some such embodiments, the compounds exhibit at least 10-fold selectivity for CDK2 over GSK3e. In other embodiments, the compounds exhibit at least 20-fold selectivity for CDK2 over GSK3e. In specific embodiments, the compounds exhibit at least 30-fold selectivity for CDK2 over GSK3e.

A pharmaceutical composition refers to a mixture of one or more compounds described herein, or pharmaceutically acceptable salts, solvates, hydrates or prodrugs thereof, as the active ingredient and at least one pharmaceutically acceptable carrier or excipient. In some embodiments, the pharmaceutical composition contains two or more pharmaceutically acceptable carriers and/or excipients. In other embodiments, the pharmaceutical composition further comprises at least one additional anticancer therapeutic agent.

In one aspect of the invention there is provided a pharmaceutical composition comprising a compound of the invention or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or excipient. In some embodiments, the pharmaceutical composition contains two or more pharmaceutically acceptable carriers and/or excipients.

In some embodiments, the pharmaceutical composition further comprises at least one additional anticancer therapeutic agent. In some such embodiments, the combination provides an additive, more than additive or synergistic anticancer effect.

The term additive means that the result of the combination of two compounds, components or targeting agents is no greater than the sum of each compound, component or targeting agent individually.

The term synergy or synergistic means that the result of the combination of two compounds, components or targeted agents is greater than the sum of each compound, component or targeted agent individually. This improvement in the treatment of a disease, condition or disorder represents a synergistic effect. A synergistic amount is an amount of a combination of two compounds, components or targeting agents that produces a synergistic effect, as synergistic is defined herein.

When determining the synergistic interaction of one or two components, the optimal range for that effect and the absolute dose ranges of each component for that effect can be uniquely measured by administering the components at different dose ranges and/or dose ratios to patients in need of treatment. However, detection of synergy in in vitro models or in vivo models can predict the effect in humans and other species, and in vitro models or in vivo models exist, as described herein, to measure the synergistic effect. The results of such studies can also be used to predict effective dose and plasma concentration ratio ranges and absolute dose and plasma concentration ratios required in humans and other species, for example, through the use of pharmacokinetic and/or pharmacodynamic methods.

Unless otherwise indicated, all references herein to the compounds of the invention include references to their salts, solvates, hydrates and complexes and to solvates, hydrates and complexes of salts thereof, including polymorphs, stereoisomers and isotopically labeled variants thereof.

The compounds of the invention may exist in the form of pharmaceutically acceptable salts, such as, for example, the acid addition salts and base addition salts of the compounds of one of the formulas provided herein. As used herein, the term pharmaceutically acceptable salt refers to those salts that retain the biological effectiveness and properties of the parent compound. The phrase pharmaceutically acceptable salt(s) as used herein, unless otherwise indicated, covers salts formed by acidic or basic groups that may be present in the compounds of the formulas disclosed herein.

For example, the compounds of the invention, which are basic in nature, are capable of

- 18 046965 form various salts with various inorganic and organic acids. Although such salts should be pharmaceutically acceptable for administration to animals, in practice it is often desirable to first isolate the compound of the present invention from the reaction mixture as a pharmaceutically unacceptable salt and then simply convert the latter back to the free base form by treatment with an alkaline reagent and thereafter convert the last free base into a pharmaceutically acceptable acid addition salt. Acid addition salts of the base compounds of this invention can be prepared by treating the base compound with a substantially equivalent amount of a selected mineral or organic acid in an aqueous solvent environment or in a suitable organic solvent such as methanol or ethanol. After evaporation of the solvent, the target solid salt is obtained. The target acid addition salt can also be precipitated from a solution of the free base in an organic solvent by adding an appropriate mineral or organic acid to the solution.

Acids that can be used to prepare pharmaceutically acceptable acid addition salts of such basic compounds are acids that form non-toxic acid addition salts, i.e. salts containing pharmacologically acceptable anions, such as salts hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate, citrate, acid citrate, tartrate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucuronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate and 1,1'-methylene-bis-(2-hydroxy3-naphthoate) (i.e. pamoate ).

Examples of salts include, but are not limited to, acetate, acrylate, benzenesulfonate, benzoate (such as chlorobenzoate, methyl benzoate, dinitrobenzoate, hydroxybenzoate and methoxybenzoate), bicarbonate, bisulfate, bisulfite, bitartrate, borate, bromide, butine-1,4-dioate, calcium edetate, camsylate, carbonate, chloride, caproate, caprylate, clavulanate, citrate, decanoate, dihydrochloride, dihydrogen phosphate, edetate, edisilate, estolate, esylate, ethyl succinate, formate, fumarate, gluceptate, gluconate, glutamate, glycolate, glycol larsanialate, heptanoate, hexine- 1,6-dioate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, γhydroxybutyrate, iodide, isobutyrate, isothionate, lactate, lactobinate, laurate, malate, maleate, malonate, mandelate, mesylate, metaphosphate, methanesulfonate, methylsulfate, monohydrogen phosphate, mucate, napsylate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, nitrate, oleate, oxalate, pamoate (embonate), palmitate, pantothenate, phenylacetate, phenylbutyrate, phenylpropionate, phthalate, phosphate/diphosphate, polygalacturonate, propanesulfonate, propionate, propiolate, pyrophosphate, pyrosulfate , salicylate, stearate, subacetate, suberate, succinate, sulfate, sulfonate, sulfite, tannate, tartrate, theoclate, tosylate, triethiododo and valerate.

Illustrative examples of suitable salts include organic salts derived from amino acids such as glycine and arginine, ammonia, primary, secondary and tertiary amines and cyclic amines such as piperidine, morpholine and piperazine, and inorganic salts derived from sodium, calcium, potassium, magnesium , manganese, iron, copper, zinc, aluminum and lithium.

The compounds of the invention containing a basic moiety, such as an amino group, can form pharmaceutically acceptable salts with various amino acids in addition to the acids mentioned above.

Alternatively, compounds that are acidic in nature may be capable of forming base salts with various pharmacological cations. Examples of such salts include alkali metal or alkaline earth metal salts, and in particular sodium and potassium salts. All these salts are obtained by generally accepted methods. The chemical bases used as reagents to prepare the pharmaceutically acceptable base addition salts of this invention are those that form non-toxic base addition salts with the acidic compounds described herein. These salts can be prepared by any suitable method, for example by treating the free acid with an inorganic or organic base such as an amine (primary, secondary or tertiary), an alkali metal hydroxide or an alkaline earth metal hydroxide or the like. These salts can also be prepared by treating the corresponding acidic compounds with an aqueous solution containing the desired pharmacologically acceptable cations and then evaporating the resulting solution to dryness, preferably under reduced pressure. Alternatively, they can also be prepared by mixing together solutions of acidic compounds in lower alcohols and the desired alkali metal alkoxide and then evaporating the resulting solution to dryness as above. In any case, it is preferable to use stoichiometric amounts of reagents to ensure completion of the reaction and maximum yields of the desired end product.

Chemical bases that can be used as reagents to prepare pharmaceutically acceptable base salts of compounds of the invention that are acidic in nature are those reagents that form non-toxic base addition salts with such compounds. Such non-toxic base salts include, but are not limited to, those formed from pharmacologically acceptable cations such as alkali metal cations (eg, potassium and sodium) and alkaline earth metal cations (eg, calcium and magnesium), am

- 19 046965 monium salts or water-soluble amine addition salts, such as N-methylglucamine (meglumine), and lower alkanolammonium and other basic salts of pharmaceutically acceptable organic amines.

Hemisalts of acids and bases can also be formed, for example hemisulfate and hemicalcium salts.

For information on suitable salts, see Handbook of Pharmaceutical Salts: Properties, Selection, and Use by Stahl and Wermuth (Wiley-VCH, 2002). Methods for preparing pharmaceutically acceptable salts of the compounds of the invention are known to one skilled in the art.

The salts of the present invention can be prepared by methods known to those skilled in the art. A pharmaceutically acceptable salt of the compound of the invention can be readily prepared by mixing together solutions of the compound and the desired acid or base, as appropriate. The salt may be precipitated from solution and collected by filtration or may be isolated by evaporation of the solvent. The degree of ionization of salt can range from completely ionized to almost non-ionized.

Those skilled in the art will appreciate that the compounds of the invention in free base form having a basic functional group can be converted to acid addition salts by treatment with a stoichiometric excess of a suitable acid. The acid addition salts of the compounds of the invention can be converted back to the corresponding free base by treatment with a stoichiometric excess of a suitable base such as potassium carbonate or sodium hydroxide, typically in the presence of an aqueous solvent and at a temperature of from about 0 to 100°C. The free base form can be isolated by conventional methods such as organic solvent extraction. In addition, the acid addition salts of the compounds of the invention can be interconverted by taking advantage of differences in salt solubility, volatility or acidity of the acids, or by treatment with a suitably loaded ion exchange resin. For example, ion exchange can be accomplished by reacting salts of the compounds of the invention with a small stoichiometric excess of an acid with a pK lower than that of the acid component of the parent salt. This transformation is usually carried out at a temperature from about 0°C to the boiling point of the solvent used as the medium for this procedure. Similar exchanges are possible with base addition salts, usually via an intermediate free base form.

The compounds of the invention may exist in unsolvated form and in solvated forms. When the solvent or water is tightly bound, then the complex will have a well-defined stoichiometry regardless of humidity. However, when the solvent or water is weakly bound, as in channel solvates and hygroscopic compounds, then the water/solvent content will depend on the humidity and drying conditions. In such cases, non-stoichiometry will be the norm. The term solvate is used herein to describe a molecular complex containing a compound of the invention and one or more molecules of a pharmaceutically acceptable solvent, such as ethanol. The term hydrate is used when the solvent is water. Pharmaceutically acceptable solvates according to the invention include hydrates and solvates, wherein the crystallization solvent may be an isotopically labeled solvent, for example D ₂ O, d ₆ -acetone, d ₆ DMS0.

Also included within the scope of the invention are complexes such as clathrates, drug-host inclusion complexes where, unlike the aforementioned solvates, the drug and host are present in stoichiometric or non-stoichiometric amounts. Also covered are drug complexes containing two or more organic and/or inorganic components, which may be present in stoichiometric or non-stoichiometric amounts. The resulting complexes may be ionized, partially ionized, or non-ionized. For information on such complexes, see J Pharm Sci, 64 (8), 1269-1288 by Haleblian (August 1975), the entire contents of which are incorporated herein by reference.

The invention also relates to prodrugs of the compounds of the formulas given herein. Thus, certain derivatives of the compounds of the invention, which themselves may have little or no pharmacological activity, may be converted into the compounds of the invention when administered to a patient, for example by hydrolytic cleavage. Such derivatives are called prodrugs. Additional information on the use of prodrugs can be found in 'Pro-drugs as Novel Delivery Systems, Vol. 14, ACS Symposium Series (T Higuchi and W Stella) and 'Bioreversible Carriers in Drug Design', Pergamon Press, 1987 (ed. E B Roche, American Pharmaceutical Association), the entire contents of which are incorporated herein by reference.

Prodrugs according to the invention can be prepared, for example, by replacing the corresponding functional groups present in the compounds of the invention with certain moieties known to those skilled in the art as progroups, which are described, for example, in Design of Prodrugs by H Bundgaard (Elsevier, 1985), the full contents of which

- 20 046965 is incorporated herein by reference.

Some non-limiting examples of prodrugs according to the invention include:

(1) if the compound contains a carboxylic acid functional group (-COOH), then its ester, for example, replacing hydrogen with (C1- _C8 )alkyl;

(2) if the compound contains an alcohol functional group (-OH), then its ester, for example, replacement of hydrogen (C ₁ -C ₆ ) with an alkanoyloxymethyl or phosphate ester group; and (3) if the compound contains a primary or secondary amine functional group (-NH ₂ or -NHR, where R^H). then its amide, for example, the replacement of one or both hydrogen atoms with a metabolically suitable labile group such as amide, carbamate, urea, phosphonate, sulfonate, etc.

Additional examples of substituent groups in accordance with the above examples and examples of other types of prodrugs can be found in the above-mentioned sources of information. Finally, some of the compounds of the invention may themselves act as prodrugs of other compounds of the invention.

Also included within the scope of the invention are metabolites of the compounds of the formulas described herein, i.e. compounds formed in vivo after drug administration.

In addition to the syn-relationship of substituent groups at positions 1 and 3 of the cyclopentyl ring in formulas (I), (II) and (III), compounds of formulas provided herein may have additional asymmetric carbon atoms as part of the substituent groups defined as R ¹ , R ² and R ³ , or possible substituents attached to these groups. In such additional asymmetric centers, a solid line indicates that all possible stereoisomers at that carbon atom are covered, whereas a solid or dotted wedge indicates that only the illustrated isomer at that stereocenter is covered, unless otherwise indicated. The compounds of the formulas provided herein may include substituent groups containing cis and trans geometric isomers, rotational isomers, atropisomers, conformational isomers and tautomers of the compounds of the invention, including compounds exhibiting more than one type of isomerism.

Also covered are acid addition salts or base addition salts where the counterion is optically active, such as d-lactate or l-lysine, or racemic, such as dl-tartrate or dl-arginine.

When any racemate crystallizes, two different types of crystals are possible. First type: racemic compound (true racemate), mentioned above, where one homogeneous crystal form is formed containing both enantiomers in equimolar amounts. Second type: racemic mixture or conglomerate, where two crystal forms are formed in equimolar quantities, each containing a single enantiomer.

The compounds of the invention may exhibit the phenomenon of tautomerism and structural isomerism. For example, compounds can exist in several tautomeric forms, including enol and imine form, and keto and enamine form, and geometric isomers and mixtures thereof. All such tautomeric forms are included within the scope of the compounds of the invention. Tautomers exist as mixtures of tautomers in solution. In solid form, usually one tautomer predominates. Even though one tautomer may be described, the present invention covers all tautomers of the compounds of the given formulas.

In addition, some compounds of the invention may form atropisomers (eg, substituted biaryls). Atropisomers are conformational stereoisomers that occur when rotation around a single bond in a molecule is prevented or greatly slowed down by steric interactions with other parts of the molecule, and the substituents on both ends of the single bond are asymmetrical. The interconversion of atropisomers is slow enough to allow separation and isolation to occur under predetermined conditions. The energy barrier to thermal racemization may be determined by the steric hindrance of free rotation of one or more bonds forming a chiral axis.

In cases where the compound of the invention contains an alkenyl or alkenylene group, then geometric cis/trans (or Z/E) isomers are possible. Cis/trans isomers can be separated by conventional methods known to those skilled in the art, such as chromatography and fractional crystallization.

Conventional methods for preparing/isolating individual enantiomers include chiral synthesis from a suitable optically pure precursor or resolution of the racemate (or racemate salt or derivative) using, for example, chiral high pressure liquid chromatography (HPLC) or supercritical fluid chromatography (SFC).

Alternatively, the racemate (or racemic precursor) may be reacted with a suitable optically active compound, such as an alcohol, or, in the case where the compound contains an acidic or basic moiety, an acid or base such as tartaric acid or 1-phenylethylamine. The resulting diastereomeric mixture can be separated by chromatography and/or fractional crystallization, and one or both diastereoisomers can be converted to the corresponding pure enantiomer(s) by methods known to those skilled in the art.

- 21 046965

The chiral compounds of the invention (and their chiral precursors) can be obtained in enantiomerically enriched form using chromatography, typically HPLC, on an asymmetric resin with a mobile phase consisting of a hydrocarbon, typically heptane or hexane, containing from 0 to 50% isopropanol, typically 2 to 20%, and 0 to 5% alkylamine, usually 0.1% diethylamine. Concentrating the eluate results in a rich mixture.

Stereoisomeric conglomerates can be separated by standard methods known to those skilled in the art (see, for example, Stereochemistry of Organic Compounds by E. L. Eliel, Wiley, New York, 1994), the full description of which is incorporated herein by reference.

The enantiomeric purity of the compounds described herein can be characterized by the term enantiomeric excess (ee), which indicates the degree to which a sample contains one enantiomer in greater quantity than the other. A racemic mixture has 0% of it, and a completely pure single enantiomer has 100% of it. Likewise, diastereomeric purity can be characterized by the term diastereomeric excess (de). As used herein, enantiomerically pure or substantially enantiomerically pure means that a compound contains one enantiomer of the compound and is substantially free of the opposite enantiomer of the compound. A typical enantiomerically pure compound contains more than about 95 wt% of one enantiomer of the compound and less than about 5 wt% of the opposite enantiomer of the compound, preferably more than about 97 wt% of one enantiomer of the compound and less than about 3 wt% of the opposite enantiomer of the compound, more preferably, more than about 98% by weight of one enantiomer of the compound and less than about 2% by weight of the opposite enantiomer of the compound, and even more preferably more than about 99% by weight of one enantiomer of the compound and less than about 1% by weight of the opposite enantiomer of the compound.

The present invention also covers isotopically labeled compounds that are identical to compounds of one of the following formulas, but in which actually one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number typically found in nature.

The isotope-labeled compounds of the invention can generally be prepared by standard methods known to those skilled in the art, or by methods similar to the methods described herein, using the appropriate isotope-labeled reagent in place of the unlabeled reagent otherwise used.

Examples of isotopes that may be introduced into the compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, such as, but not limited to, ² H, ³ H, ¹³ C, ¹⁴ C, ¹⁵ N, ¹⁸ O, ¹⁷ O, ³¹ P, ³² P, ³⁵ S, ¹⁸ F and ³⁶ Cl. Certain isotope-labeled compounds of the invention, for example compounds into which radioactive isotopes such as ³ H and ¹⁴ C are introduced, are useful for use in drug and/or substrate tissue distribution assays. Tritiated isotopes, i.e. H and carbon-14, i.e. ¹⁴ C are particularly preferred due to their ease of production and detection. In addition, substitution with heavier isotopes such as deuterium, e.g. H may provide some therapeutic benefits due to greater metabolic stability, such as increased in vivo half-life or reduced dosage requirements, and may therefore be preferred in some circumstances. The isotopically labeled compounds of the invention can generally be prepared by the procedures disclosed in the Schemes and/or in the Examples and Preparations below, substituting a labeled reagent for the unlabeled reagent.

The compounds of the invention for pharmaceutical use can be administered as crystalline or amorphous products or mixtures thereof. They can be prepared, for example, in the form of solid masses. powders or films by methods such as precipitation, crystallization, freeze drying, spray drying or evaporative drying. Microwave drying and radiofrequency drying can be used for this purpose.

Therapeutic methods and applications.

The invention also provides therapeutic methods and uses comprising the administration of a compound of the invention or a pharmaceutically acceptable salt thereof, alone or in combination with other therapeutic agents or palliative agents.

In one aspect of the invention, there is provided a method of treating abnormal cell growth in a subject, comprising administering to the subject a therapeutically effective amount of a compound of the invention or a pharmaceutically acceptable salt thereof.

In another aspect of the invention, there is provided a method of treating abnormal cell growth in a subject in need thereof, comprising administering to the subject an amount of a compound of the invention or a pharmaceutically acceptable salt thereof in combination with an amount of an additional therapeutic agent (eg, an anticancer therapeutic agent), wherein said amounts together are effective in the treatment of abnormal cell growth.

In another aspect of the invention, a compound of the invention, or a pharmaceutically acceptable salt thereof, is provided for use in treating abnormal cell growth in a subject.

- 22 046965

A further aspect of the invention provides the use of a compound of the invention or a pharmaceutically acceptable salt thereof for treating abnormal cell growth in a subject.

In another aspect of the invention, there is provided a pharmaceutical composition for use in treating abnormal cell growth in a subject in need thereof, comprising a compound of the invention or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or excipient.

In another aspect of the invention, a compound of the invention or a pharmaceutically acceptable salt thereof is provided for use as a drug, in particular a drug for the treatment of abnormal cell growth.

In yet another aspect of the invention, there is provided the use of a compound of the invention or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of abnormal cell growth in a subject.

In many embodiments of the methods provided herein, the abnormal cell growth is cancer. The compounds of the invention may be administered as single agents or may be administered in combination with other anticancer therapeutic agents, in particular standard agents suitable for a particular cancer.

In some embodiments, the proposed methods result in one or more of the following effects: (1) inhibition of cancer cell proliferation; (2) inhibition of cancer cell invasiveness; (3) inducing apoptosis of cancer cells; (4) inhibition of cancer cell metastasis; or (5) inhibition of angiogenesis.

In another aspect of the invention, there is provided a method of treating a CDK2-mediated disorder in a subject, comprising administering to the subject a compound of the invention or a pharmaceutically acceptable salt thereof in an amount that is effective for treating the disorder, particularly cancer.

In some aspects and embodiments of the compounds, compositions, methods and uses described herein, the compounds of the invention are selective for CDK2 over other CDKs, particularly CDK1. In some embodiments, the compounds of the invention are selective for CDK2 over CDK4 and/or CDK6. In other aspects and embodiments, the compounds of the invention are selective for CDK2 over glycogen synthase kinase 3 beta (GSK3e). The compounds of the invention include compounds of any of the formulas described herein, or pharmaceutically acceptable salts thereof.

In another aspect of the invention, there is provided a method of inhibiting the proliferation of cancer cells in a subject, comprising administering to the subject a compound of the invention, or a pharmaceutically acceptable salt thereof, in an amount effective to inhibit cell proliferation.

In another aspect of the invention, there is provided a method of inhibiting the invasiveness of cancer cells in a subject, comprising administering to the subject a compound of the invention, or a pharmaceutically acceptable salt thereof, in an amount effective to inhibit the invasiveness of the cells.

In another aspect of the invention, there is provided a method of inducing apoptosis of cancer cells in a subject, comprising administering to the subject a compound of the invention or a pharmaceutically acceptable salt thereof in an amount effective to induce apoptosis.

In another aspect of the invention, there is provided a method of inhibiting metastasis of cancer cells in a subject, comprising administering to the subject a compound of the invention, or a pharmaceutically acceptable salt thereof, in an amount effective to inhibit cell metastasis.

In another aspect of the invention, there is provided a method of inhibiting angiogenesis in a subject, comprising administering to the subject a compound of the invention, or a pharmaceutically acceptable salt thereof, in an amount effective to inhibit angiogenesis.

In many embodiments of the methods provided herein, the abnormal cell growth is cancer. In some such embodiments, the cancer is selected from breast cancer, ovarian cancer, bladder cancer, uterine cancer, prostate cancer, lung cancer (including NSCLC (non-small cell lung cancer), SCLC (small cell lung cancer), squamous cell carcinoma or adenocarcinoma), cancer esophagus, head and neck cancer, colorectal cancer, kidney cancer (including RCC (renal cell carcinoma)), liver cancer (including HCC (hepatocellular carcinoma)), pancreatic cancer, stomach cancer (i.e. cancer) and thyroid cancer. In further embodiments of the methods provided herein, the cancer is breast cancer, ovarian cancer, bladder cancer, uterine cancer, prostate cancer, lung cancer, esophageal cancer, liver cancer, pancreatic cancer and stomach cancer.

In other embodiments, the cancer is breast cancer, including, for example, ER-positive/HR-positive breast cancer, HER2-negative breast cancer; ER-positive/HR-positive breast cancer, HER2-positive breast cancer; triple negative breast cancer (TNBC); or inflammatory breast cancer. In some embodiments, the breast cancer is endocrine-resistant breast cancer, trastuzumab-resistant breast cancer, or breast cancer demonstrated

- 23 046965 causing primary or acquired resistance to CDK4/CDK6 inhibition. In some embodiments, the breast cancer is advanced or metastatic breast cancer. In some embodiments of each of the above, breast cancer is characterized by amplification or overexpression of CCNE1 and/or CCNE2.

In some embodiments of the methods provided herein, the abnormal cell growth is a cancer characterized by amplification or overexpression of CCNE1 and/or CCNE2. In some embodiments of the methods provided herein, a subject is identified as having a cancer characterized by amplification or expression of CCNE1 and/or CCNE2.

In some embodiments, the cancer is selected from the group consisting of breast cancer and ovarian cancer. In some such embodiments, the cancer is breast cancer or ovarian cancer characterized by amplification or overexpression of CCNE1 and/or CCNE2. In some such embodiments, the cancer is (a) breast cancer or ovarian cancer; (b) cancer characterized by amplification or overexpression of cyclin E1 (CCNE1) or cyclin E2 (CCNE2); or (c) both (a) and (b). In some embodiments, the cancer is ovarian cancer.

In some embodiments, a compound of the invention is administered as first-line therapy. In other embodiments, a compound of the invention is administered as second (or last) line therapy. In some embodiments, a compound of the invention is administered as second (or last) line therapy followed by treatment with an endocrine therapeutic agent and/or a CDK4/CDK6 inhibitor. In some embodiments, a compound of the invention is administered as second (or last) line therapy followed by treatment with an endocrine therapeutic agent. In some embodiments, a compound of the invention is administered as second (or last) line therapy followed by treatment with a CDK4/CDK6 inhibitor. In some embodiments, a compound of the invention is administered as second (or last) line therapy followed by treatment with an endocrine therapeutic agent, such as an aromatase inhibitor, SERM or SERD. In some embodiments, a compound of the invention is administered as second (or last) line therapy followed by treatment with a CDK4/CDK6 inhibitor. In some embodiments, a compound of the invention is administered as second (or last) line therapy followed by treatment with one or more chemotherapy regimens, including, for example, taxanes or platinum agents. In some embodiments, a compound of the invention is administered as second (or last) line therapy followed by treatment with HER2-targeting agents, such as trastuzumab.

As used herein, an effective dosage or effective amount of a drug, compound or pharmaceutical composition is an amount sufficient to produce a beneficial or desired effect on any one or more symptoms, including biochemical, histological and/or behavioral symptoms, disease, its complications and intermediate pathological phenotypes present during disease development. For therapeutic use, a therapeutically effective amount refers to an amount of a compound to be administered that will alleviate, to some extent, one or more symptoms of the disorder being treated. When referring to cancer treatment, a therapeutically effective amount refers to an amount that has the effect of (1) reducing tumor size, (2) inhibiting (i.e., slowing to some extent, preferably stopping) tumor metastasis, (3) inhibiting to some extent (i.e., slowing to some extent, preferably stopping) tumor growth or tumor invasiveness, (4) reducing to some extent (or preferably eliminating) one or more signs or symptoms associated with cancer, (5) reducing the dose of other drugs needed for treatment disease, and/or (6) enhancing the effect of another drug, and/or (7) delaying the progression of the patient's disease.

An effective dosage may be administered in one or more administrations. For purposes of this invention, an effective dosage of a drug, compound or pharmaceutical composition is an amount sufficient to provide prophylactic or therapeutic treatment, either directly or indirectly. As understood in a clinical context, an effective dosage of a drug, compound or pharmaceutical composition may or may not be achieved in combination with another drug, compound or pharmaceutical composition.

Tumor, as applied to a subject diagnosed with or predisposed to cancer, refers to a malignant or potentially malignant neoplasm or tissue mass of any size and includes primary tumors and secondary neoplasms. A solid tumor is an abnormal growth or mass of tissue that usually does not contain cysts or fluid areas. Examples of solid tumors are sarcomas, carcinomas and lymphomas. Leukemias (blood cancers) do not usually form solid tumors (National Cancer Institute, Dictionary Cancer Therms).

Tumor load or tumor mass refers to the total amount of tumor-like material distributed throughout the body. Tumor burden refers to the total number of cancer cells or the total size of the tumor(s) throughout the body, including lymph nodes and

- 24 046965 bone marrow. Tumor burden can be determined by various methods known in the art, for example using calipers or imaging techniques, such as ultrasound scanning, bone scanning, computed tomography (CT) or magnetic resonance imaging (MRI).

The term tumor size refers to the overall size of the tumor, which can be measured as the length and width of the tumor. Tumor size can be determined by various methods known in the art, such as, for example, by measuring the size of the tumor(s) after removal from the subject, for example using calipers, or imaging techniques, such as bone scanning, ultrasound scanning, CR or MRI.

As used herein, subject refers to a human subject or an animal subject. In some preferred embodiments, the subject is a human.

The term treat or treat cancer as used herein means administering a compound of the present invention to a subject having or diagnosed with cancer to achieve at least one beneficial therapeutic effect, such as, for example, a reduction in the number of cancer cells, a reduction in tumor size, a reduction the rate of infiltration of cancer cells into peripheral organs or reducing the rate of tumor metastasis or tumor growth, reversing, alleviating, inhibiting the progression or preventing the disorder or condition to which such term applies, or one or more symptoms of such disorder or condition. The term treatment as used herein, unless otherwise specified, refers to the act of treatment as treatment as defined immediately above. The term treatment also includes adjuvant and neoadjuvant treatment of a subject.

For purposes of this invention, beneficial or desired clinical results include, without limitation, one or more of the following: decreased proliferation (or delay) of a neoplastic or cancer cell; inhibition of metastasis of neoplastic cells; shrinkage or reduction in tumor size; cancer remission; reduction of symptoms resulting from cancer; increasing the quality of life of cancer sufferers; reducing the dose of other medicines needed to treat cancer; delaying cancer progression; cure cancer; overcoming one or more cancer resistance mechanisms; and/or prolonging the survival of cancer patients. Positive therapeutic effects in cancer can be measured in several ways (see, for example, W. A. Weber, Assessing tumor response to therapy, J. Nucl. Med. 50 Suppl. 1:1S-10S (2009)). For example, regarding tumor growth inhibition (T/C), according to National Cancer Institute (NCI) standards, a T/C less than or equal to 42% represents the minimum level of antitumor activity. T/C <10% is considered a high level of anticancer activity, and T/C (%) = median treated tumor volume/median control tumor volume x 100.

In some embodiments, the treatment achieved by a compound of the invention is determined based on any of the following: partial response (PR), complete response (CR), overall response (OR), progression-free survival (PFS), disease-free survival (DFS) and overall survival (OS). PFS, also referred to as time to tumor progression, measures the length of time during and after treatment that the cancer does not grow, and includes the amount of time that patients experienced CR or PR, as well as the amount of time that patients experienced stable disease (SD). DFS refers to the length of time during and after treatment that patients remain disease-free. OS refers to the increase in survival compared to previously untreated subjects or patients. In some embodiments, the response to a combination of the invention is any of PR, CR, PFS, DFS, OR, or OS, as assessed using Response Evaluation Criteria in Solid Tumors (RECIST) 1.1.

The treatment regimen for a compound of the invention that is effective in treating a cancer patient may vary depending on factors such as the stage of the disease, the age and body weight of the patient, and the ability of the therapy to elicit an anticancer response in the subject. Although the implementation of any aspect of the invention may not be effective in achieving a positive therapeutic effect in every subject, the effect must be so in a statistically significant number of subjects, which is determined in accordance with any statistical test known in the art, such as the Student's t test, chi2-test Mann-Whitney U-test, Kruskal-Wallis test (H-test), Jonckheere-Terpstra test and Wilcoxon test.

The terms treatment regimen, dosing protocol, and dosing regimen are used interchangeably to indicate the dose and schedule of administration of each compound of the invention, alone or in combination with another therapeutic agent.

Attenuation means a decrease or positive change in one or more symptoms after treatment with a combination described herein, compared to no administration of the combination. Relief also covers shortening or decreasing the duration of a symptom.

Abnormal cell growth in this document, unless otherwise stated, refers to the growth of cells

- 25 046965 which occurs independently of normal regulatory mechanisms (eg loss of contact inhibition). Abnormal cell growth may be benign (non-cancerous) or malignant (cancerous).

Abnormal cell growth includes abnormal growth of: (1) tumor cells (tumors) that exhibit increased expression of CDK2; (2) tumors that proliferate when CDK2 is aberrantly activated; (3) tumors characterized by amplification or overexpression of CCNE1 and/or CCNE2; and (4) tumors resistant to endocrine therapy, HER2 antagonists, or CDK4/6 inhibition.

The term additional anti-cancer therapeutic agent as used herein means any one or more than one therapeutic agent, other than a compound of the invention, that is or may be used in the treatment of cancer. In some embodiments, such additional anticancer therapeutic agents include compounds from the following classes: mitotic inhibitors, alkylating agents, antimetabolites, antitumor antibiotics, antiangiogenesis agents, topoisomerase I and II inhibitors, plant alkaloids, hormonal agents and antagonists, growth factor inhibitors, radiation therapy, signal transduction inhibitors, such as protein tyrazine kinase and/or serine/threonine kinase inhibitors, cell cycle inhibitors, biological response modifiers, enzyme inhibitors, antisense oligonucleotides or derivatives of oligonucleotides, cytotoxic agents and immuno-oncology agents, and the like.

In some embodiments, the additional anticancer agent is an endocrine agent such as an aromatase inhibitor, SERD, or SERM.

In other embodiments, a compound of the invention may be administered in combination with a standard agent. In some embodiments, a compound of the invention may be administered in combination with endocrine therapy, for example agents such as letrozole, fulvestrant, tamoxifen, exemestane, or anastrozole. In some embodiments, a compound of the invention may be administered in combination with a chemotherapeutic agent, for example docetaxel, paclitaxel, cisplatin, carboplatin, capecitabine, gemcitabine, or vinorelbine. In other embodiments, a compound of the invention may be administered in combination with an anti-HER2 agent, for example trastuzumab or pertuzumab.

In some embodiments, the additional anti-cancer agent is an anti-angiogenesis agent, including, for example, VEGF inhibitors, VEGFR inhibitors, TIE-2 inhibitors, PDGFR inhibitors, angiopoietin inhibitors, PKCe inhibitors, COX-2 (cyclooxygenase II) inhibitors, integrins (alpha-v /oetp-3). MMP-2 (matrix metalloproteinase 2) inhibitors and MMP9 (matrix metalloproteinase 9) inhibitors. Preferred anti-angiogenesis agents include sunitinib (Sutent™), bevacizumab (Avastin™), axitinib (AG 13736), SU 14813 (Pfizer) and AG 13958 (Pfizer). Additional anti-angiogenesis agents include vatalanib (CGP 79787), sorafenib (Nexavar™), pegaptanib octanodium (Macugen™), vandetanib (Zactima™), PF-0337210 (Pfizer), SU 14843 (Pfizer), AZD 2171 (AstraZeneca), ranibizumab (Lucentis™), Neovastat™ (AE 941), tetrathiomolybdate (Coprexa™), AMG 706 (Amgen), VEGF Trap (AVE 0005), CEP 7055 (Sanofi-Aventis), XL 880 (Exelixis), telatinib (BAY 579352) and CP-868,596 (Pfizer). Other anti-angiogenesis agents include enzastaurin (LY 317615), midostaurin (CGP 41251), perifosine (KRX 0401), teprenone (Selbex™) and UCN 01 (Kyowa Hakko). Other examples of anti-angiogenesis agents include celecoxib (Celebrex™), parecoxib (Dynastat™), deracoxib (SC 59046), lumiracoxib (Preige™), valdecoxib (Bextra™), rofecoxib (Vioxx™), iguratimod (Careram™), IP 751 (Invedus), SC-58125 (Pharmacia) and etoricoxib (Arcoxia™). Additional anti-angiogenesis agents include exisulind (Aptosyn™), salsalate (Amigesic™), diflunisal (Dolobid™), ibuprofen (Motrin™), ketoprofen (Orudis™), nabumetone (Relafen™), piroxicam (Feldene™), naproxen ( Aleve™, Naprosyn™), diclofenac (Voltaren™), indomethacin (Indocin™), sulindac (Clinoril™), tolmetin (Tolectin™), etodolac (Lodine™), ketorolac (Toradol™), and oxaprozin (Daypro™). Additional anti-angiogenesis agents include ABT 510 (Abbott), apratastat (TMI 005), AZD 8955 (AstraZeneca), incyclinide (Metastat™), and PCK 3145 (Procyon). Additional anti-angiogenesis agents include acitretin (Neotigason™), plitidepsin (Aplidine™), cilengtide (EMD 121974), combretastatin A4 (CA4P), fenretinide (4 HPR), halofuginone (Tempostatin™), Panzem™ (2-methoxyestradiol), PF03446962 (Pfizer), rebimastat (BMS 275291), catumaxomab (Removab™), lenalidomide (Revlimid™), squalamine (EVIZON™), thalidomide (Thalidomide™), Ukraine™ (NSC 631570), Vitaxin™ (MEDI 522) and zoledronic acid acid (Zometa™).

In other embodiments, the additional anticancer agent is a so-called signal transduction inhibitor (eg, inhibiting the means by which regulatory molecules that control fundamental processes of cellular growth, differentiation and survival communicate within the cell). Signal transduction inhibitors include small molecules, antibodies, and antisense molecules. Signal transduction inhibitors include, for example, kinase inhibitors (eg, tyrosine kinase inhibitors or serine/threonine kinase inhibitors) and cell cycle inhibitors. More specifically, signal trans inhibitors

- 26 046965 productions include, for example, farnesyl protein transferase inhibitors, EGF inhibitor, ErbB-1 (EGFR), ErbB-2, pan erb, IGF1R inhibitors, MEK, c-Kit inhibitors, FLT-3 inhibitors, KRas inhibitors, PI3 kinase inhibitors, JAK inhibitors, STAT inhibitors, Raf kinase inhibitors, Akt inhibitors, mTOR inhibitor, P70S6 kinase inhibitors, WNT pathway inhibitors and so-called multi-target kinase inhibitors. Additional examples of signal transduction inhibitors that may be used in combination with a compound of the invention and the pharmaceutical composition described herein include BMS 214662 (Bristol-Myers Squibb), lonafarnib (Sarasar™), pelitrexol (AG 2037), matuzumab (EMD 7200), nimotuzumab (TheraCIM h-R3™), panitumumab (Vectibix™), vandetanib (Zactima™), pazopanib (SB 786034), ALT 110 (Alteris Therapeutics), BIBW 2992 (Boehringer Ingelheim) and Cervene™ (TP 38) . Other examples of signal transduction inhibitors include gefitinib (Iressa™), cetuximab (Erbitux™), erlotinib (Tarceva™), trastuzumab (Herceptin™), sunitinib (Sutent™), imatinib (Gleevec™), crizotinib (Pfizer), lorlatinib (Pfizer ), dacomitinib (Pfizer), bosutinib (Pfizer), gedatolisib (Pfizer), canertinib (CI 1033), pertuzumab (Omnitarg™), lapatinib (Tycerb™), pelitinib (EKB 569), miltefosin™, BMS 599626 ( Bristol-Myers Squibb), Lapuleucel-T (Neuvenge™), NeuVax™ (E75 cancer vaccine), Osidem™ (IDM 1), mubritinib (TAK-165), CP-724,714 (Pfizer), panitumumab (Vectibix™), ARRY 142886 (Array Biopharm), everolimus (Certican™), zotarolimus (Endeavor™), temsirolimus (Torisel™), AP 23573 (ARIAD) and VX 680 (Vertex), XL 647 (Exelixis), sorafenib (Nexavar™), LE -AON (Georgetown University) and GI-4000 (Globelmmune). Other signal transduction inhibitors include ABT 751 (Abbott), alvocitib (flavopiridol), BMS 387032 (Bristol Myers), EM 1421 (Erimos), indisulam (E 7070), seliciclib (CYC 200), BIO 112 (Onc Bio), BMS 387032 (Bristol-Myers Squibb), palbociclib (Pfizer), and AG 024322 (Pfizer).

In other embodiments, the additional anticancer agent is a so-called classical antineoplastic agent. Classic antineoplastic agents include, but are not limited to, hormonal modulators such as hormonal, antihormonal, androgen agonist, androgen antagonist and anti-estrogen therapeutic agents, histone deacetylase (HDAC) inhibitors, DNA methyltransferase inhibitors, silencing or gene activation agents, ribonucleases, proteasome agents, inhibitors topoisomerase I, camptothecin derivatives, topoisomerase II inhibitors, alkylating agents, antimetabolites, poly(ADPribose) polymerase-1 (PARP-1) inhibitor (such as talazoparib, olaparib, rucaparib, niraparib, iniparib, veliparib), microtubulin inhibitors, antibiotics, plant-derived spindle structure inhibitors, platinum-coordinated compounds, gene therapeutic agents, antisense oligonucleotides, vascular targeted agents (VTA) and statins. Examples of classical antineoplastic agents used in combination therapy with a compound of the invention, possibly with one or more other agents, include, but are not limited to, glucocorticoids such as dexamethasone, prednisone, prednisolone, methylprednisolone, hydrocortisone and progestins such as medroxyprogesterone, megestrol acetate ( Megace), mifepristone (RU-486), selective estrogen receptor modulators (SERMs; such as tamoxifene, raloxifene, lasofoxifene, amphimoxifene, arzoxifene, bazedoxifene, fispemifene, ormeloxifene, ospemifene, tesmilifene, toremifene, trilostane, and CHF 4227 (Cheisi), selective estrogen receptor downregulators (SERDs; such as fulvestrant), exemestane (Aromasin), anastrozole (Arimidx), atamestane, fadrozole, letrozole (Femara), formestane; gonadotropin-releasing hormone (GnRH; also commonly called luteinizing hormone-releasing hormone) agonists [ LHRH]), such as buserelin (Suprefact), goserelin (Zoladex), leuprorelin (Lupron) and triptorelin (Trelstar), abarelix (Plenaxis), cyproterone, flutamide (Eulexin), megestrol, nilutamide (Nilandron) and osaterone, dutasteride, epristeride , finasteride, Serenoa repens, PHL 00801, abarelix, goserelin, leuprorelin, triptorelin, bicasutamide; antiandrogen agents such as enzalutamide, abiraterone acetate, bicalutamide (Casodex); and their combinations. Other examples of classical antineoplastic agents used in combination with a compound of the invention include, but are not limited to, suberolanilide hydroxamic acid (SAHA, Merck Inc./Aton Pharmaceuticals), depsipeptide (FR901228 or FK228), G2M-777, MC-275, pivaloyloxymethylbutyrate and PXD -101; onconase (ranpirnase), PS-341 (MLN-341), Velcade (bortezonib), 9aminocamptothecin, belotecan, BN-80915 (Roche), camptothecin, diphlomothecan, edotecarin, exatecan (Daiichi), gimatecan, 10-hydroxycamptothecin, irinotecan HCl ( Camptosar), Lurtotecan, Orathecin (Rubitecan, Supergen), SN-38, topotecan, camptothecin, 10-hydroxycamptothecin, 9-aminocamptothecin, irinotecan, SN-38, edotecarin, topotecan, aclarubicin, adriamycin, amonafide, amrubicin, annamycin, daunorubicin, Doksorubicin, Elsomatrutruticin, ethosiside, Idarubicin, Galarubicin, hydroxicarbamide, non -metropolitan, innovantron (mitoxantron), pyrarubicin, picksanthron, pricanin, Rebecamicin, Sobovsan, Tafluposid, Valrubitsin, Zinecard Zoksan), nitrogenous ipit n-oxide, cyclophosphamide, AMD- 473, altretamine, AP-5280, apaziquone, brostallicin, bendamustine, busulfan, carboquone, carmustine, chlorambucil, dacarbazine, estramustine, fotemustine, glufosfamide, ifosfamide, KW2170, lomustine, mafosfamide, mechlorethamine, melphalan, mitobronitol, lactol, mitomycin C, mitoxatron , nimustine, ranimustine, temozolomide, thiotepa and platinum-coordinated alkylating agents

- 27 046965 compounds such as cisplatin, Paraplatin (carboplatin), eptaplatin, lobaplatin, nedaplatin, Eloxatin (oxaliplatin, Sanofi), streptozocin, satrplatin and combinations thereof.

In yet another embodiment, the additional anticancer agent is a so-called dihydrofolate reductase inhibitor (such as methotrexate and NeuTrexin (trimetresate glucuronate)), purine antagonists (such as 6-mercaptopurine riboside, mercaptopurine, 6-thioguanine, cladribine, clofarabine (Clolar), fludarabine, nelarabine and raltitrexed), pyrimidine antagonists (such as 5-fluorouracil (5-FU), Alimta (premetrexed disodium salt, LY231514, MTA), capecitabine (Xeloda™), cytosine arabinoside, Gemzar™ (gemcitabine, Eli Lilly), Tegafur ( UFT Orzel or Uforal and including TS-1 combination of tegafur, hypostat and otostat), doxofluridine, carmofur, cytarabine (including oxphosphate, phosphate stearate, extended release and liposomal forms), enocytabine, 5azacytidine (Vidase), decitabine and ethynylcytidine) and other antimetabolites such as eflornithine, hydroxyurea, leucovorin, nolatrexed (Thymitaq), triapine, trimetrexate, H-(5-[H-(3.4-dihydro-2methyl-4-oxoquinazolin-6-ylmethyl)-N-methylamino]- 2-Thenoyl)-E-glutamic acid, AG-014699 (Pfizer Inc.), ABT-472 (Abbott Laboratories), INO-1001 (Inotek Pharmaceuticals), KU-0687 (KuDOS Pharmaceuticals), and GPI 18180 (Guilford Pharm Inc.) and their combinations.

Other examples of classic antineoplastic cytotoxic agents include, but are not limited to, abraxane (Abraxis BioScience, Inc.), batabulin (Amgen), EPO 906 (Novartis), vinflunine (BristolMyers Squibb Company), actinomycin D, bleomycin, mitomycin C, neocarcinostatin (Zinostatin) , vinblastine, vincristine, vindesine, vinorelbine (Navelbine), docetaxel (Taxotere), ortataxel, paclitaxel (including taxoprexin DHA/paclitaxel conjugate), cisplatin, carboplatin, nedaplatin, oxaliplatin (Eloxatin), satraplatin, camptosar, capecitabine (Xeloda), oxaliplatin (Eloxatin), Taxotere Alitretinoin, Cafosfamide (Telcyta™), DMXAA (Antisoma), Ibandronic Acid, L-Asparaginase, Pegaspargase (Oncaspar™), Efaproxiral (Efaproxyn™ - Radiation Therapy), Bexarotene (Targretin™), Tesmilifene (DPPE, enhances the effectiveness of cytotoxins), Theratope™ (Biomira), tretionin (Vesanoid™), tirapazamine (Trizaone™), motexafin-gadolinium (Xcytrin™) Cotara™ (mAb) and NBI-3001 (Protox Therapeutics), polyglutamate-paclitaxel (Xyotax™ ) and their combinations. Additional examples of classic antineoplastic agents include, but are not limited to, Advexin (ING 201), TNFerade (GeneVec, a compound that expresses TNFalpha in response to radiotherapy), RB94 (Baylor College of Medicine), Genesense (Oblimersen, Genta), Combrestatin A4P (CA4P ), Oxi-4503, AVE-8062, ZD-6126, TZT-1027, atorvastatin (Lipitor, Pfizer Inc.), pravastatin (Pravachol, Bristol-Myers Squibb), lovastatin (Mevacor, Merck Inc.), simvastatin (Zocor, Merck Inc.), fluvastatin (Lescol, Novartis), cerivastatin (Baycol, Bayer), rosuvastatin (Crestor, AstraZeneca), lovostatin, niacin (Advicor, Kos Pharmaceuticals), Caduet, Lipitor, torcetrapib, and combinations thereof.

In other embodiments, the additional anticancer agent is an epigenetic modulator, such as an inhibitor or EZH2, SMARCA4, PBRM1, ARID1A, ARID2, ARID1B, DNMT3A, TET2, MLL1/2/3, NSD1/2, SETD2, BRD4, DOT1L, HKMTsanti, PRMT1- 9, LSD1, UTX, IDH1/2 or BCL6.

In further embodiments, the additional anti-cancer agent is an immunomodulatory agent such as a CTLA-4, PD-1 or PD-L1 inhibitor (eg, pembrolizumab, nivolumab or avelumab), LAG-3, TIM-3, TIGIT, 4-1BB, OX40 , GITR, CD40 or CAR-T cell therapy.

As used herein, cancer refers to any malignant and/or invasive tumor growth caused by abnormal cell growth. Cancer includes solid tumors, named after the type of cells that form them, cancers of the blood, cancer of the bone, or cancer of the lymphatic system. Examples of solid tumors include sarcomas and carcinomas. Types of blood cancer include, but are not limited to, leukemia, lymphoma, and myeloma. Cancer also includes primary cancer, which occurs in a specific area of the body, metastatic cancer, which spreads from the site where it originated to other parts of the body, recurrence of the original primary cancer after remission, and second primary cancer, which is a new primary cancer in the face with a history of previous cancer of a type different from the more recent cancer.

In some embodiments of the methods provided herein, the cancer is selected from the group consisting of breast cancer, ovarian cancer, bladder cancer, uterine cancer, prostate cancer, lung cancer, esophageal cancer, liver cancer, pancreatic cancer, and stomach cancer . In some such embodiments, the cancer is characterized by amplification or overexpression of CCNE1 and/or CCNE2.

Dosage forms and regimens.

Administration of the compounds of the invention can be accomplished by any method that provides delivery of the compounds to the site of action. These routes include oral routes, intraduodenal routes, parenteral injection (including intravenous, subcutaneous, intramuscular, intravascular or infusion), topical and rectal administration.

Dosage regimens may be adjusted to provide the optimal desired response. For example, you can enter a single bolus, you can enter several divided

- 28 046965 doses over time, or the dose can be proportionally reduced or increased if the therapeutic situation requires it. Particularly preferred is the preparation of parenteral compositions in unit dosage form for ease of administration and uniformity of dosage. Unit dosage form as used herein refers to physically discrete units suitable as unitary dosages for mammalian subjects being treated, each unit containing a predetermined amount of active compound calculated to produce the desired therapeutic effect, together with the required pharmaceutical carrier. The detail of the unit dosage forms of the invention is generally dictated by and directly depends on (a) the unique characteristics of the chemotherapeutic agent and the particular therapeutic or prophylactic effect to be achieved, and (b) the limitations inherent in the art of compounding such an active compound for the treatment of susceptible individuals.

Thus, one skilled in the art will be able to appreciate from the description provided herein that the dosage and dosage schedule are adjusted in accordance with methods known in the therapeutic fields. That is, the maximum tolerated dose can be easily determined, and the effective amount to provide detectable therapeutic benefit to the patient can also be determined, as well as the timing requirements for administering each agent to provide detectable therapeutic benefit to the patient. Accordingly, although certain dosages and modes of administration are illustrated by examples herein, these examples do not in any way limit the dose and mode of administration that may be prescribed to a patient when the present invention is practiced.

It should be noted that dosages may vary depending on the type and severity of the condition being treated and may include single or multiple doses. It should also be understood that for any particular subject, specific dosage regimens should be adjusted over time according to the needs of the individual and the professional judgment of the person administering or supervising the administration of the compositions, and that the dosage ranges set forth herein are illustrative and illustrative only. do not limit the scope or practice of the claimed composition. For example, dosages may be adjusted based on pharmacokinetic or pharmacodynamic parameters, which may include clinical effects, such as toxic effects, and/or laboratory values. Thus, the present invention covers dose escalation for an individual patient as determined by one skilled in the art. Determination of suitable dosages and schedules for administration of a chemotherapeutic agent is known in the relevant field and, as would be appreciated by one skilled in the art, is covered by the information disclosed herein.

The amount of a compound of the invention administered will depend on the subject being treated, the severity of the disorder or condition, the rate of administration, the distribution of the compound, and the judgment of the attending physician. However, an effective dosage ranges from about 0.001 to about 100 mg per kg of body weight per day, preferably from about 1 to about 35 mg/kg/day, in a single dose or in divided doses. For a 70 kg person, this amount may be from about 0.05 to about 7 g/day, preferably from about 0.1 to about 2.5 g/day. In some cases, dosage levels below the lower end of the above range may be more than adequate, while in other cases even higher doses can be used without causing any harmful side effects, provided such higher doses are first divided into several smaller doses for administration throughout the day.

Preparation of compositions and routes of administration.

As used herein, a pharmaceutically acceptable carrier refers to a carrier or diluent that does not cause significant irritation to the body and does not abolish the biological activity and properties of the administered compound.

The pharmaceutically acceptable carrier may be a conventional pharmaceutical carrier or excipient. The choice of carrier and/or excipient will largely depend on factors such as the particular mode of administration, the effect of the carrier or excipient on solubility and stability, and the nature of the dosage form.

Suitable pharmaceutical carriers include inert diluents or excipients, water and various organic solvents (such as hydrates and solvates). The pharmaceutical compositions may contain, if desired, additional ingredients such as flavoring agents, binders, excipients and the like. Thus, for oral administration, tablets containing various excipients such as citric acid can be used together with various disintegrants such as starch, alginic acid and some complex silicates, and with binding agents such as sucrose, gelatin and acacia. Examples of excipients include, but are not limited to, calcium carbonate, calcium phosphate, various sugars and types of starch, cellulose derivatives, gelatin, vegetable oils and polyethylene glycols. Additionally, lubricants such as magnesium stearate, sodium lauryl sulfate and talc are often used for tabletting purposes. Solid compositions of this type can also be used in soft and hard gelatin capsules. Non-limiting examples of substances therefore include lactose or milk sugar and high molecular weight polyethylene glycols. If aqueous suspensions or elixirs for feathers are desired

- 29 046965 oral administration of the active compound, they may be combined with various sweeteners or flavoring agents, coloring agents or dyes and, if desired, emulsifiers or suspending agents, together with diluents such as water, ethanol, propylene glycol, glycerin or combinations thereof .

The pharmaceutical composition may be, for example, in a form suitable for oral administration as a tablet, capsule, pill, powder, sustained release preparations, solutions, suspensions, for parenteral injection as a sterile solution, suspension or emulsion, for topical administration as ointment or cream, or for rectal administration in the form of a suppository.

Typical forms for parenteral administration include solutions or suspensions of the active compounds in sterile aqueous solutions, such as aqueous propylene glycol solutions or aqueous dextrose solutions. Such dosage forms may be suitably buffered if desired.

The pharmaceutical composition may be in unit dosage forms suitable for single administration of precise doses.

Pharmaceutical compositions suitable for delivering the compounds of the invention and methods for their preparation will be apparent to those skilled in the art. Such compositions and methods for their preparation can be found, for example, in Remington's Pharmaceutical Sciences, 19th Edition (Mack Publishing Company, 1995), the full description of which is incorporated herein by reference.

The compounds of the invention can be administered orally. Oral administration may involve ingestion so that the compound enters the gastrointestinal tract, or buccal or sublingual administration may be used whereby the compound enters the bloodstream directly from the oral cavity.

Compositions suitable for oral administration include solid forms such as tablets, capsules containing solids, liquids or powders, lozenges (including liquid-filled), chewing gum, multi- and nanoparticles, gels, solid solution, liposomes, films (including mucoadhesive), ovules, sprays and liquid forms.

Liquid forms include suspensions, solutions, syrups and elixirs. Such forms may be used as fillers in soft or hard capsules, and typically contain a carrier, for example water, ethanol, polyethylene glycol, propylene glycol, methylcellulose or a suitable oil, and one or more emulsifiers and/or suspending agents. Liquid forms can also be prepared by diluting a solid, such as from a sachet.

The compounds of the invention can also be used in rapidly dissolving, rapidly disintegrating dosage forms, such as those described in Expert Opinion in Therapeutic Patents, 11 (6), 981-986 by Liang and Chen (2001), the full description of which is incorporated herein by reference .

With respect to tablet dosage forms, depending on the dose, the drug may comprise from 1 to 80% by weight of the dosage form, more typically from 5 to 60% by weight of the dosage form. In addition to the drug, the tablets usually contain a disintegrant. Examples of disintegrants include sodium starch glycolate, sodium carboxymethylcellulose, calcium carboxymethylcellulose, croscarmellose sodium, crospovidone, polyvinylpyrrolidone, methylcellulose, microcrystalline cellulose, lower alkyl-substituted hydroxypropylcellulose, starch, pregelatinized starch and sodium alginate. Typically, the disintegrant constitutes from 1 to 25% by weight, preferably from 5 to 20% by weight of the dosage form.

Binders are typically used to impart cohesive properties to a tablet formulation. Suitable binders include microcrystalline cellulose, gelatin, sugars, polyethylene glycol, natural and synthetic gums, polyvinylpyrrolidone, pregelatinized starch, hydroxypropylcellulose and hydroxypropylmethylcellulose. The tablets may also contain diluents such as lactose (monohydrate, spray-dried monohydrate, anhydrous, etc.), mannitol, xylitol, dextrose, sucrose, sorbitol, microcrystalline cellulose, starch and dibasic calcium phosphate dihydrate.

The tablets may also optionally contain surfactants such as sodium lauryl sulfate and polysorbate 80, and glidants such as silicon dioxide and talc. Surfactants, if present, are typically present in amounts of from 0.2 to 5% by weight of the tablet, and glidants, if present, are typically present in amounts from 0.2 to 1% by weight of the tablet.

The tablets also typically contain lubricants such as magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate, and mixtures of magnesium stearate and sodium lauryl sulfate. Lubricants are typically present in amounts of 0.25 to 10% by weight, preferably 0.5 to 3% by weight, of the tablet.

Other traditional ingredients include antioxidants, coloring agents, flavoring agents, preservatives, and flavor masking agents.

Exemplary tablets contain up to about 80 wt.% drug, from

- 30 046965 about 10% by weight to about 90% by weight binder, from about 0% by weight to about 85% by weight diluent, from about 2% by weight to about 10% by weight disintegrant and from about 0.25 wt.% to about 10 wt.% lubricant.

Tablet mixtures can be compressed directly or by a tablet forming roller. Before tableting, tablet mixtures or portions of mixtures may alternatively be subjected to wet granulation, dry granulation or melt granulation, melt solidification or extrusion. The final preparation may have one or more layers and may or may not be coated or encapsulated.

Tablet preparation is discussed in detail in Pharmaceutical Dosage Forms: Tablets, Vol. 1, by H. Lieberman and L. Lachman, Marcel Dekker, N.Y., N.Y., 1980 (ISBN 0-8247-6918-X), the entire description of which is incorporated herein by reference.

Compositions in solid form for oral administration may be formulated for immediate and/or sustained release. Modified release compositions include delayed, sustained, pulsed, controlled, targeted and programmed release.

Suitable modified release compositions are described in US Pat. No. 6,106,864. Details of other suitable release technologies, such as high-energy dispersions and osmotic and coated particles, can be found in Verma et al, Pharmaceutical Technology On-line, 25(2), 1 -14 (2001). The use of chewing gum to achieve controlled release is described in WO 00/35298. The complete contents of these information sources are incorporated herein by reference.

The compounds of the invention can also be administered directly into the bloodstream, into a muscle or into an internal organ. Suitable routes of parenteral administration include intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrasternal, intracranial, intramuscular and subcutaneous. Suitable devices for parenteral administration include needle (including microneedle) injection devices, needleless injection devices and infusion devices.

Parenteral compositions are typically aqueous solutions that may contain excipients such as salts, carbohydrates and buffering agents (preferably to a pH of 3 to 9), but for some applications they may be more stably prepared as a sterile non-aqueous solution or in in a dried form, which is used in conjunction with a suitable diluent such as sterile pyrogen-free water.

The preparation of parenteral compositions under sterile conditions, for example by lyophilization, can be readily accomplished using standard pharmaceutical techniques known to those skilled in the art.

The solubility of the compounds of the invention used in the preparation of parenteral solutions can be increased using suitable means, such as the inclusion of solubility enhancing agents.

Compositions for parenteral administration can be formulated for immediate and/or modified release. Modified release compositions include delayed, sustained, pulsed, controlled, targeted and programmed release. Thus, the compounds of the invention may be formulated as a solid, semi-solid or thixotropic liquid for administration as an implanted depot providing modified release of the active compound. Examples of such compositions include drug-coated stents and PGLA (glycolic acid-lactic acid copolymer) microspheres.

The compounds of the invention can also be administered topically to the skin or mucous membrane, that is, dermal or transdermal. Typical forms of compositions for this purpose include gels, hydrogels, lotions, solutions, creams, ointments, powders, dressings, foams, films, skin patches, wafers, implants, sponges, fibers, bandages and microemulsions. Liposomes can also be used. Typical carriers include alcohol, water, mineral oil, petrolatum, white petrolatum, glycerin, polyethylene glycol and propylene glycol. Penetration enhancers may be included (see, for example, J Pharm Sci, 88 (10), 955-958 by Finnin and Morgan (October 1999)). Other means of topical administration include delivery by electroporation, iontophoresis, phonophoresis, sonophoresis, and microneedle or needleless (eg, Powderject'™, Bioject™, etc.) injections. Complete descriptions of these information sources are incorporated herein by reference.

Compositions for topical administration can be prepared in immediate and/or modified release form. Modified release compositions include sustained, sustained, pulsed, controlled, targeted and programmed release.

The compounds of the invention can also be administered intranasally or by inhalation, usually in the form of a dry powder (either one compound alone, a mixture, for example a dry mixture with lactose, or

- 31 046965 in the form of a particle of mixed components, for example mixed with phospholipids such as phosphatidylcholine) from a dry powder inhaler or in the form of an aerosol spray from a pressurized container, pump, nebulizer, atomizer (preferably an atomizer using electrohydrodynamics to produce a fine mist) or nebulizer, with or without the use of a suitable propellant such as 1,1,1,2-tetrafluoroethane or 1,1,1,2,3,3,3-heptafluoropropane. For intranasal use, the powder may include a bioadhesive agent such as chitosan or cyclodextrin.

The pressurized container, pump, nebulizer, atomizer or nebulizer contains a solution or suspension of the compound(s) of the invention containing, for example, ethanol, aqueous ethanol or a suitable alternative agent for dispersing, solubilizing or prolonging the release of the active substance, propellant(s) as a solvent and an optional surfactant such as sorbitan trioleate, oleic acid or oligolactic acid.

Before use in a composition in the form of a dry powder or suspension, the drug product is micronized to a size suitable for delivery by inhalation (typically less than 5 microns). This size can be achieved by any suitable comminution method, such as spiral jet milling, fluidized bed jet milling, supercritical fluid treatment to form nanoparticles, high pressure homogenization, or spray drying.

Capsules (made, for example, from gelatin or HPMC (hydroxypropyl methylcellulose)), blisters and cartridges for use in an inhaler or insufflator may contain a powder mixture of a compound of the invention, a suitable powder base such as lactose or starch, and a functional modifier such as 1- leucine, mannitol or magnesium stearate. Lactose may be anhydrous or may be in monohydrate form, preferably monohydrate form. Other suitable excipients include dextran, glucose, maltose, sorbitol, xylitol, fructose, sucrose and trehalose.

A suitable composition in solution form for use in an atomizer using electrohydrodynamics to produce a fine mist may contain from 1 μg to 20 mg of a compound of the invention per actuation, and the actuation volume may vary from 1 μl to 100 μl. A typical composition contains a compound of the invention, propylene glycol, sterile water, ethanol and sodium chloride. Alternative solvents that can be used instead of propylene glycol include glycerin and polyethylene glycol.

Suitable flavoring agents, such as menthol and levomenthol, or sweeteners, such as saccharin or sodium saccharin, can be added to the compositions of the invention intended for inhalation/intranasal administration.

Compositions for inhalation/intranasal administration can be formulated with immediate and/or modified release using, for example, a copolymer of DL-lactic acid-glycolic acid (PGLA). Modified release compositions include sustained, sustained, pulsed, controlled, targeted and programmed release.

In the case of dry powder inhalers and aerosols, the dosage unit is metered through a valve that delivers the metered amount. Dosage units in accordance with the invention are generally selected to administer a metered dose, or zilch, containing the desired amount of a compound of the invention. The total daily dose may be administered as a single dose or, more commonly, in divided doses throughout the day.

The compounds of the invention can be administered rectally or vaginally, for example in the form of a suppository, pessary or enema. Cocoa butter is a traditional suppository base, but other alternative bases that are suitable can be used.

Compositions for rectal/vaginal administration may be formulated for immediate and/or modified release. Modified release compositions include sustained, sustained, pulsed, controlled, targeted and programmed release.

The compounds of the invention can also be administered directly into the eye or ear, typically in the form of drops of a micronized suspension or solution in isotonic, pH-adjusted, sterile saline. Other forms of the composition suitable for administration to the eye or ear include ointments, gels, biodegradable (eg, absorbable gel sponges, collagen) and non-biodegradable (eg, silicone) implants, discs, lenses, and dispersive or vesicular systems such as niosomes or liposomes. A polymer such as cross-linked polyacrylic acid, polyvinyl alcohol, hyaluronic acid, a cellulosic polymer such as hydroxypropyl methylcellulose, hydroxyethylcellulose or methylcellulose, or a heteropolysaccharide polymer such as gelan gum may be included in the formulation along with a preservative such as benzalkonium chloride. Such compositions can also be delivered by iontophoresis.

Compositions for administration to the eye/ear can be prepared for immediate

- 32 046965 and/or modified release. Modified release compositions include sustained, sustained, pulsed, controlled, targeted and programmed release.

Other technologies.

The compounds of the invention may be combined with soluble macromolecular substances, such as cyclodextrin and suitable derivatives thereof or polyethylene glycol-containing polymers, to improve their solubility, dissolution rate, taste masking, bioavailability and/or stability for use in any of the above routes of administration.

Drug-cyclodextrin complexes have been found to be useful in most dosage forms and routes of administration. Both inclusion and non-inclusion complexes can be used. As an alternative to direct complexation with the drug, cyclodextrin can be used as an adjuvant, i.e. as a carrier, diluent or solubilizer. The most commonly used for these purposes are alpha, beta and gamma cyclodextrins, examples of which can be found in international patent application publications WO 91/11172, WO 94/02518 and WO 98/55148, the full descriptions of which are incorporated herein by reference. .

Dosage.

The amount of active compound administered will depend on the subject being treated, the severity of the disorder or condition, the rate of administration, the distribution of the compound, and the judgment of the attending physician. However, an effective dosage typically ranges from about 0.001 to about 100 mg per kg of body weight per day, preferably from about 0.01 to about 35 mg/kg/day, in a single dose or divided doses. For a 70 kg person, this amount may be from about 0.07 to about 7000 mg/day, preferably from about 0.7 to about 2500 mg/day. In some cases, dosage levels below the lower end of the above range may be more than adequate, while in other cases even higher doses can be used without causing any deleterious side effect, with such higher doses usually divided into several smaller doses to be administered at throughout the day.

Composite set.

Since it may be desirable to administer a combination of an active compound, for example for the purpose of treating a particular disease or condition, it is within the scope of the present invention that two or more pharmaceutical compositions, at least one of which contains a compound of the invention, can conventionally be combined in the form of a kit, suitable for co-administration of compositions. Thus, a kit of the invention contains two or more separate pharmaceutical compositions, at least one of which contains a compound of the invention, and a means for separating said compositions, such as a container, a compartmentalized vial or a compartmentalized foil pouch. An example of such a set is the so-called blister pack, used for packaging tablets, capsules, etc.

The kit of the invention is particularly suitable for administering different dosage forms, for example oral and parenteral, for administering individual compositions at different dosage intervals, or for titrating individual compositions against each other. To promote medication adherence, the kit usually contains instructions for administration and may include a reminder sheet.

Combination therapy.

As used herein, the term combination therapy refers to administering a compound of the invention together with at least one additional pharmaceutical or therapeutic agent (eg, an anticancer agent), either sequentially or simultaneously.

As stated above, the compounds of the invention can be used in combination with one or more additional anticancer agents. The effectiveness of the compounds of the invention in some tumors may be enhanced by combination with other approved or investigational cancer therapies, such as radiation therapy, surgery, chemotherapeutic agents, targeted therapies, agents that inhibit other signaling pathways that are dysregulated in tumors, and other immune enhancing agents such as PD-1 antagonists and the like.

When using combination therapy, one or more additional anticancer agents can be administered sequentially or simultaneously with a compound of the invention. In one embodiment, the additional anticancer agent is administered to a mammal (eg, human) prior to administration of a compound of the invention. In another embodiment, the additional anticancer agent is administered to the mammal after administration of a compound of the invention. In another embodiment, the additional anticancer agent is administered to a mammal (eg, human) simultaneously with the administration of a compound of the invention.

The invention also relates to a pharmaceutical composition for the treatment of abnormal cell growth in a mammal, including a human, containing an amount of a compound of the invention as

- 33046965 as defined above (including hydrates, solvates and polymorphs of the said compound or pharmaceutically acceptable salts thereof), in combination with one or more (preferably one to three) anticancer therapeutic agents.

Methods of synthesis.

The compounds of the invention are prepared according to the illustrative procedures set forth herein and modifications thereof known to those skilled in the art.

In the Examples, the following abbreviations are used: Ac means acetyl, AcO or OAc means acetoxy, ACN means acetonitrile, aq. means aqueous, atm means atmosphere(s), BOC, Boc or boc means N-tert-butoxycarbonyl, Bn means benzyl, Bu means butyl, nBu means n-butyl, tBu means tert-butyl, Cbz means benzyloxycarbonyl, DCM (CH2Cl2) means methylene chloride/dichloromethane, de means diastereomeric excess, DEA means diethylamine, DIPEA means diisopropylethylamine, DMA means ^^dimethylacetamide, DMAP means 4-dimethylaminopyridine, DMF means ^^dimethylformamide, DMSO means dimethyl sulfoxide, ee means enantiomeric excess, Et means ethyl, EtOAc means ethyl acetate t , EtOH means ethanol, HATU means 1-[bis(dimethylamino)methylene]-III-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate, HOAc or AcOH means acetic acid, i-Pr or ⁱ Pr means isopropyl, IPA means isopropyl alcohol, Me means methyl, MeOH means methanol, MS means mass spectrometry, MTBE means methyl tert-butyl ether, Ph means phenyl, sat. means saturated, SFC means supercritical fluid chromatography, T3P means propylphosphonic anhydride, TFA means trifluoroacetic acid, THF means tetrahydrofuran, TLC means thin layer chromatography, Rf means retention factor, ~ sign means approximately, rt means retention time, h means hours, min means minutes .

Examples

Preparation of synthetic intermediates.

Intermediate pyrazol-5-yl}carbamate;

intermediate pyrazol-5-yl}carbamate

1:

2:

O.

HE

CH(OCH ₃ ) ₃

TsOH»H ₂ O

MeOH -o pA benzyl-{1-tert-butyl-3-[(1R,3K)-3-hydroxycyclopentyl]-N-benzyl-{1-tert-butyl-3-[(1R,3S)-3-hydroxycyclopentyl 1- 1HCH ₃ CN n-BuLi -o r-D

CAS# 98-78-2

O— (+/-) 1a

THF (+/-) 1b

SG Ό'

_NaHCO3

CH ₃ CN —o o—

TsOH«H ₂ O

Oacetone/H ₂ O

CN

EtOH

Dm ^^^ΝΗ t-BuNHNH ₂ -HCI NaOH

Li(CH ₃ CH ₂ ) ₃ BH THF

Ο O' (+/-) 1е (+/-) ° °' 1d

Two parallel reaction mixtures, each containing a solution of (±)-3-oxocyclopentanecarboxylic acid (CAS#98-78-2, 900 g, 7.02 mol) in methanol (5 L), were each treated at 13°C with trimethyl orthoformate (4, 47 kg, 42.15 mol, 4.62 L) and 4-toluenesulfonic acid monohydrate (26.72 g, 140.5 mmol). The mixtures were stirred at 13°C for 25 hours. Each batch was quenched separately with sat. aq. NaHCO ₃ solution (1 L), then the two batches were combined and concentrated in vacuo to remove most of the methanol. The residue was diluted with ethyl acetate (4 L) and the layers were separated. The aqueous layer was further extracted with ethyl acetate (2x1 L). The combined organic layers were washed with sat. aq. NaCl solution (3x1 L), dried over magnesium sulfate, filtered and concentrated in vacuo to give (±)-methyl-3,3-dimethoxycyclopentanecarboxylate (1a, 2.5 kg, 13.28 mol, 94%) as light yellow oil.

1H NMR (400 MHz, chloroform-d) δ=3.67 (s, 3H), 3.20 (s, 3H), 3.19 (s, 3H), 2.94-2.82 (m, 1H), 2.16-2.00 (m, 2H) , 1.99-1.76 (m, 4H).

A solution of n-butyllithium (3.44 L of 2.5 M solution in hexanes, 8.6 mol) was added to a reactor containing THF (3 L) at -65°C. Anhydrous acetonitrile (453 ml, 353 g, 8.61 mol) was added dropwise enough

- 34 046965 slowly to keep the internal temperature below -55°C. The mixture was stirred for another 1 hour at -65°C. A solution of (±)-methyl-3,3-dimethoxycyclopentanecarboxylate (1a, 810 g, 4.30 mol) in THF (1 L) was then added dropwise slowly enough to maintain the internal temperature below -50°C. After stirring for another hour at -65°C, the reaction mixture was quenched with water (4 L), neutralized with aq. HCl solution (1M) to pH 7 and extracted with ethyl acetate (3x3 L). The combined organic layers were washed with sat. aq. NaCl solution (2x3 L), dried over magnesium sulfate, filtered and concentrated in vacuo to give crude (±)-3-(3,3dimethoxycyclopentyl)-3-oxopropanenitrile (1b, 722 g, 3.66 mol, 85%) in in the form of red oil, which was used without further purification.

Solid sodium hydroxide (131.4 g, 3.29 mol total) was added portionwise to a suspension of tert-butylhydrazine hydrochloride (409.4 g, 3.29 mol) in ethanol (3 L) at 16-25°C. Stirring was continued at 25°C for 1 hour. A solution of crude (±)-3-(3,3-dimethoxycyclopentyl)-3oxopropanenitrile (1b, 540 g, 2.74 mol) in ethanol was added at 25°C, then the mixture was heated to an internal temperature of 75°C and stirred for 30 hours. The reaction mixture was filtered and the filtrate was concentrated in vacuo to give the crude product as a red oil. This product was combined with crude products from three further identically prepared batches (each starting with 540 g of 1b; 2.16 kg, 10.96 mol total for 4 batches) and purified by silica gel chromatography (eluting with 0-35% ethyl acetate in petroleum ether) to give (±)-1-tert-butyl-3-(3,3dimethoxycyclopentyl)-III-pyrazol-5-amine (1c, 1.60 kg, 5.98 mol, 54% yield) as red oil.

¹ H NMR (chloroform-d) δ=5.41 (s, 1H), 3.50 (br. s., 2H), 3.22 (s, 3H), 3.20 (s, 3H), 3.13 (tt, J=7.9, 9 ,6 Hz, 1H), 2.25 (dd, J=8.0, 13.3 Hz, 1H), 2.09-2.00 (m, 1H), 1.99-1.91 (m, 1H), 1.83 (dd, J=10.8, 12 .8 Hz, 2H), 1.781.68 (m, 1H), 1.60 (s, 9H).

Benzyl chloroformate (563.6 ml, 676.3 g, 3.96 mol) was added to a cooled (0-5°C) solution of (±)-1t-butyl-3-(3,3-dimethoxycyclopentyl)-1H-pyrazol- 5-amine (1c, 530 g, 1.98 mol) in acetonitrile (3.5 L). The mixture was stirred at 23°C for 2 hours, and then solid sodium hydrogen carbonate (532.9 g, 6.34 mol) was added in portions. Stirring was continued at 23°C for 26 hours. The resulting suspension was filtered and the filtrate was concentrated in vacuo to give crude (±)-benzyl[1-tert-butyl-3-(3,3-dimethoxycyclopentyl)-III-pyrazole-5 -yl]carbamate (1d, 980 g, 1.98 mol maximum) as a red oil, which was used in the next step without further purification.

A solution of crude (±)-benzyl-[1-tert-butyl-3-(3,3-dimethoxycyclopentyl)-III-pyrazol-5 yl]carbamate (1d, 980 g, 1.98 mol maximum) in acetone (2 L ) and water (2 L) at 18°C were treated with 4-toluenesulfonic acid monohydrate (48.75 g, 256.3 mmol). The mixture was heated to an internal temperature of 60°C for 20 hours. After concentration in vacuo to remove most of the acetone, the aqueous residue was extracted with dichloromethane (3x3 L). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo to a crude red oil. This crude product was combined with crude products from two other identically prepared batches (each obtained from 1.98 mol 1c, 5.94 mol total for 3 batches) and purified by silica gel chromatography (eluting with 0-50% ethyl acetate in petroleum ether) with yielding (±)-benzyl-[1-tert-butyl-3-(3-oxocyclopentyl)-1H-pyrazol-5-yl]carbamate (1e, 1.6 kg) as a yellow solid. This solid was stirred in 10:1 petroleum ether/ethyl acetate (1.5 L) at 20°C for 18 hours. The resulting suspension was filtered, the filter cake was washed with petroleum ether (2x500 ml), and the solid was dried under vacuum with preparing (±)-benzyl-[1-tert-butyl-3-(3-oxocyclopentyl)-1H-pyrazol-5-yl]carbamate (1e, 1.4 kg, 3.9 mol, 66% yield in total for three batches) .

1H NMR (DMSO-d6) δ=9.12 (br. s., 1H), 7.56-7.13 (m, 5H), 6.03 (s, 1H), 5.12 (s, 2H), 3.41-3.27 (m, 1H) , 2.48-2.39 (m, 1H), 2.34-2.10 (m, 4H), 1.98-1.81 (m, 1H), 1.48 (s, 9H).

A solution of (±)-benzyl-[1-tert-butyl-3-(3-oxocyclopentyl)-1H-pyrazol-5-yl]carbamate (1e, 320 g, 0.900 mol) in THF (1.5 L) was degassed under vacuum and purged with dry nitrogen (3 cycles), then cooled to an internal temperature of -65°C. A solution of lithium triethylborohydride (1.0 M in THF, 1.80 L, 1.80 mol) was added dropwise at a rate that maintained the internal temperature below 55°C, then stirring was continued at -65°C for 1.5 h. The reaction mixture was quenched with sat. aq. NaHCO ₃ solution (1.5 l) at a temperature from -40 to -30°C. Hydrogen peroxide (30% aqueous solution, 700 g) was added dropwise to the mixture, maintaining the internal temperature between -10 and 0°C. The mixture was stirred at 10°C for 1 hour, then extracted with ethyl acetate (3x2 L). The combined organic layers were washed with sat. aq. Na ₂ SO ₃ solution (2x1 l) and sat. aq. NaCl solution (2x1 l). The organic phase was dried over magnesium sulfate, filtered and concentrated in vacuo to a crude yellow oil. The crude product from this batch was combined with crude products from three other identically prepared batches (each 0.900 mol 1e, for a total of 3.60 mol) for purification. Prior to chromatography, NMR analysis showed that the combined mixture had proportionally

- 35 046965 cis/trans ratio approximately 3.3:1. The combined crude product was purified twice by chromatography on silica gel, eluting with 0-50% ethyl acetate in dichloromethane) to give (±)-trans-benzyl-[1-tert-butyl-3-(3-hydroxycyclopentyl)-III-pyrazol-5-yl]carbamate (1f, 960 g) as a light yellow solid, which was further purified by trituration as described below.

The previous batch of 1f was obtained from reactions on a smaller scale, starting with a total of 120 g of 1e (0.34 mol). The column product from this batch was combined with the column product from the batch above (which was obtained from 3.60 mol 1e, a total of 3.94 mol 1e used for all combined batches), suspended in a 10:1 mixture of dichloromethane/methanol (1 .5 l) and stirred at 20°C for 16 hours. The suspension was filtered and the filter cake was washed with petroleum ether (2x500 ml). The solid was dried under vacuum to give pure (±)-trans-benzyl-[1t-butyl-3-(3-hydroxycyclopentyl)-N-pyrazol-5-yl]carbamate (1f, 840 g, 2.35 mol, 60 % total yield for all batches combined) as a white solid.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ=9.07 (br. s., 1H), 7.45-7.27 (m, 5H), 5.92 (s, 1H), 5.11 (s, 2H), 4.57 (d , J=4.5 Hz, 1H), 4.21-4.07 (m, 1H), 2.88 (quin, J=8.6 Hz, 1H), 2.24-2.13 (m, 1H), 1.92-1.78 (m, 1H ), 1.78-1.62 (m, 2H), 1.61-1.53 (m, 1H), 1.47 (s, 9H), 1.52-1.43 (m, 1H). MC: 358 [M+H]+.

Enantiomers of (±)-trans-benzyl-[1-tert-butyl-3-(3-hydroxyc,iclopentyl)-III-pyrazol-5yl]carbamate (1f 700 g, 1.96 mol) were separated by chiral SFC.

The product from the first peak to elute (310 g solid) was suspended in methanol/petroleum ether (1:10, 1 L) and stirred at 25°C for 1 hour. The suspension was filtered, the filter was washed with petroleum ether (2x500 ml), and the solid was dried under vacuum to give benzyl-{1-tert-butyl-3-[(1S,3R)-3-hydroxycyclopentyl]-1H-pyrazol-5-yl}carbamate (intermediate 1, 255 g, 713 mmol, 36%, >99% ee) as a white solid.

1H NMR (400 MHz, DMSO-d ₆ ) δ=9.08 (br. s., 1H), 7.58-7.20 (m, 5H), 5.92 (s, 1H), 5.11 (s, 2H), 4.57 (d, J=4.4 Hz, 1H), 4.19-4.09 (m, 1H), 2.88 (quin, J=8.6 Hz, 1H), 2.24-2.13 (m, 1H), 1.91-1.79 (m, 1H) , 1.79-1.61 (m, 2H), 1.61-1.53 (m, 1H), 1.47 (s, 9H), 1.52-1.44 (m, 1H). MC: 358 [M+H] ⁺ . Optical rotation [α]ρ +3.76 (with 1.0, MeOH). Chiral purity: >99% ee, retention time 3.371 min. Chiral SFC analysis was performed on a ChiralPak AD-3 150x4.6 mm i.d. column. (internal diameter), 3 µm, heated to 40°C, eluted with mobile phase CO2 and a gradient of 0-40% methanol + 0.05% DEA over 5.5 min, then hold at 40% for 3 min; flow rate 2.5 ml/min.

The product from the second enantiomer peak (300 g solid) was suspended in methanol/petroleum ether (1:10, 1 L) and stirred at 25°C for 1 hour. The suspension was filtered, the filter was washed with petroleum ether (2x500 ml), and the solid was dried under vacuum to give benzyl-{1-tert-butyl-3-[(^^)-3-hydroxycyt,iclopentyl]-N-pyrazol-5-yl}carbamate (Intermediate 2, 255 g, 713 mmol, 36%, 94% ee) as a white solid.

1H NMR (400 MHz, DMSO-d6) δ=9.08 (br. s., 1H), 7.55-7.19 (m, 5H), 5.92 (s, 1H), 5.11 (s, 2H), 4.57 (d, J =4.4 Hz, 1H), 4.23-4.07 (m, 1H), 2.88 (quin, J=8.7 Hz, 1H), 2.23-2.14 (m, 1H), 1.90-1.79 (m, 1H), 1.77-1.61 (m, 2H), 1.61-1.53 (m, 1H), 1.47 (s, 9H), 1.52-1.44 (m, 1H). MC: 358 [M+H] ⁺ . Optical rotation [a] _D 2.43 (c 1.0, MeOH). Chiral purity: 94% ee, retention time 3.608 min. Chiral SFC analysis was performed on a ChiralPak AD-3 150x4.6 mm ID, 3 µm column, heated to 40°C, eluted with CO2 mobile phase and a gradient of 0-40% methanol + 0.05% DEA in 5.5 min, then hold at 40% for 3 min; flow rate 2.5 ml/min.

A sample of the second enantiomer eluting from the previous batch with [a] _D -3.1 (with 1.1, MeOH) and 96% of it was crystallized from a dichloroethane/pentane mixture. The crystal structure was determined by X-ray crystallography of low molecular weight compounds, which showed (1R,3S) geometry. Absolute stereochemistry (1R,3S) was assigned to intermediate 2 based on its comparative optical rotation and elution order in the analytical method. Intermediate 1, an enantiomer of intermediate 2, was assigned stereochemistry (1S,3R).

Intermediate 3: (5-methyl-1,3-oxazol-2-yl)acetic acid

^sv Intermediate 3

A solution of prop-2-yl-1-amine (25.0 g, 450 mmol) in dichloromethane (500 ml) at 15°C was treated with triethylamine (138 g, 1360 mmol) and DMAP (5.55 g, 45.4 mmol ). The mixture was cooled to 0°C and methyl 3chloro-3-oxopropanoate (74.4 g, 545 mmol) was added dropwise over 30 minutes. Received

- 36 046965 the solution was stirred at 15°C for 16 hours, then left to stand at this temperature for 2 days. The resulting suspension was filtered, the filtrate was concentrated in vacuo, and the residue was purified by chromatography on silica gel (eluting with 60% EtOAc/petroleum ether) to give methyl 3-oxo-3-(prop-2-yn-1-ylamino)propanoate (3 a , 47 g, 67%, 90% pure by NMR) as a light yellow oil.

1H NMR (400 MHz, chloroform-d) δ=7.43 (br s, 1H), 4.09 (dd, J=2.6, 5.3 Hz, 2H), 3.76 (s, 3H), 3.36 (s, 2H), 2.25 (s, 1H).

Two parallel batches were prepared according to the following procedure: A solution of methyl 3-oxo-3-(prop2-yn-1-ylamino)propanoate (3 a, 23.5 g, 151 mmol) in acetonitrile (300 ml) was treated with gold trichloride (2 .50 g, 8.24 mmol) at room temperature (20°C). The resulting mixture was heated to 70°C for 16 h in the dark. The two batches were then combined, filtered to remove catalyst, and the filtrate concentrated to dryness. The residue was purified by chromatography on silica gel (eluting with 40% EtOAc/petroleum ether) to give methyl (5-methyl-1,3-oxazol-2-yl) acetate (3b, 26.5 g, 56.5% for combined batches) as a light yellow oil.

¹ H NMR (400 MHz, chloroform-d) δ=6.68 (d, J=1.0 Hz, 1H), 3.80 (s, 2H), 3.75 (s, 3H), 2.30 (d, J=1.3 Hz, 3H).

A solution of methyl (5-methyl-1,3-oxazol-2-yl) acetate (3b, 26.5 g, 170.8 mmol) in THF (80 ml) and water (20 ml) was treated with lithium hydroxide monohydrate (7 .17 g, 171 mmol) and stirred at room temperature (25°C) for 2 hours. The mixture was concentrated to remove most of the THF, then the residue was diluted with water (25 ml) and extracted with dichloromethane (2x30 ml). The aqueous layer was concentrated to give crude product (ca. 26 g), which was further purified by trituration with EtOAc/MeOH (10/1 v/v) to give (5-methyl-1,3-oxazol-2-yl) acetate lithium (intermediate 3, 21.7 g, 90%) as a light yellow solid.

¹ H NMR (400 MHz, deuterium oxide) δ=6.63 (d, J=1.0 Hz, 1H), 3.59 (s, 2H), 2.22 (d, J=1.0 Hz, 3H).

Intermediate 4: (5-methoxypyrazin-2-yl)lithium acetate

Oh Oh

LiCI _o 1 UN*N ₂ O ₀

H2O _/ DMSO _H2O /THF

4c Intermediate connection 4

A solution of 2,5-dibromopyrazine (30.0 g, 126 mmol) in THF (252 ml) was cooled to 0°C. Sodium methoxide (25 wt.% solution in methanol, 29.0 ml, 27.3 g, 126 mmol) was added dropwise over 18 minutes. The solution was allowed to warm to room temperature and stirred for 37 hours. The suspension was filtered, the flask and filter cake were washed with a small amount of THF, and the filtrate was concentrated in vacuo to give 2-bromo-5-methoxypyrazine (4a, 23.80 g, 100% ) in the form of a solid.

1H NMR (400 MHz, chloroform-d) δ=8.20 (d, J=1.2 Hz, 1H), 8.03 (d, J=1.2 Hz, 1H), 3.97 (s, 3H).

Copper(T) iodide (2.82 g, 14.8 mmol), 2-picolinic acid (3.65 g, 29.6 mmol), cesium carbonate (36.2 g, 111 mmol) and 2- bromo-5-methoxypyrazine (4a, 7.00 g, 37.03 mmol). The flask was again purged with nitrogen, then dry dioxane (250 ml) and dimethyl malonate (22 ml, 192 mmol) were added by syringe. Nitrogen was bubbled through the solution for 10 minutes. The mixture was heated at 100°C for 36 hours. After cooling to room temperature, the suspension was filtered and the filtrate was concentrated to an oil. The solid remaining in the filter cake was suspended in water (150 ml) and the solution was slowly acidified with 4M HCl (approximately 17 ml). This solution was extracted with ethyl acetate (2x150 ml). The ethyl acetate extracts were combined with the crude oil obtained from the filtrate and the whole was washed with sat. aq. NH ₄ Cl solution (50 ml), dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (eluting with 0-50% ethyl acetate in heptane) to give dimethyl (5-methoxypyrazin-2-yl)propanedioate (4b, 5.94 g, 67%) as an oil which solidified on standing.

1H NMR (400 MHz, chloroform-d)) δ=8.23 (d, J=1.3 Hz, 1H), 8.18 (d, J=1.3 Hz, 1H), 4.90 (s, 1H), 3.97 ( s, 3H), 3.79 (s, 6H).

A solution of dimethyl (5-methoxypyrazin-2-yl)propanedioate (4b, 7.30 g, 30.4 mmol) in DMSO (51 ml) and water (3.4 ml) was cooled to 0°C. Solid lithium chloride (5.15 g, 122 mmol) was added and the mixture was heated

- 37 046965 to 100°C for 17 hours. The dark red solution was distributed between ethyl acetate (150 ml) and water (300 ml). The aqueous layer was further extracted with ethyl acetate (3x50 ml). The combined organic phases were washed with half-saturated aq. NaCl solution and sat. aq. NaCl solution, dried over sodium sulfate, filtered and concentrated. The crude product was purified by silica gel chromatography (eluting with 0-60% ethyl acetate in heptane) to give methyl (5-methoxypyrazin-2yl) acetate (4c, 3.86 g, 70%) as an oil.

¹ H NMR (400 MHz, chloroform-d) δ=8.18 (d, J=1.3 Hz, 1H), 8.06 (d, J=1.2 Hz, 1H), 3.96 (s, 3H), 3.79 ( s, 2H), 3.73 (s, 3H).

A suspension of methyl (5-methoxypyrazin-2-yl) acetate (4c, 3.86 g, 21.2 mmol) and lithium hydroxide monohydrate (889 mg, 21.2 mmol) in THF (42 ml) and water (42 ml ) was stirred at 25°C for 14 h. Unreacted ester was still present by LC-MS, so additional lithium hydroxide monohydrate (50 mg, 1.2 mmol) was added and stirring was continued at 25°C for 6 h The conversion was still incomplete, so more lithium hydroxide monohydrate (110 mg, 2.62 mmol; total 1.049 g, 25 mmol) was added and the mixture was heated to 30°C for 2 hours. THF was removed in vacuo. the aqueous residue was lyophilized to dryness to obtain lithium (5methoxypyrazin-2-yl)acetate (intermediate 4, 4.272 g, 115% of theoretical weight 3.71 g) as a mixture with lithium hydroxide.

¹ H NMR (400 MHz, deuterium oxide) δ=8.14 (d, J=1.3 Hz, 1H), 8.01 (d, J=1.2 Hz, 1H), 3.93 (s, 3H), 3.64 (s , 2H).

Intermediate 5: Lithium 3-(methoxymethyl)-1-methyl-III-pyrazole-5-carboxylate

A solution of methanesulfonyl chloride (11.32 g, 98.8 mmol) in dichloromethane (50 ml) was added dropwise to a cooled (0°C) mixture of methyl 3-(hydroxymethyl)-1-methyl-III-pyrazole-5-carboxylate ( CAS# 1208081-25-7, 15.0 g, 88.1 mmol) and diisopropylethylamine (14.8 g, 115 mmol) in dichloromethane (250 ml). The mixture was stirred at 0°C for 45 minutes after completion of addition. The reaction mixture was washed with sat. aq. NH ₄ Cl solution and the organic layer was dried over sodium sulfate, filtered and concentrated to give methyl 1-methyl-3-{[(methylsulfonyl)oxy]methyl}-III-pyrazole-5-carboxylate (5a, 22.6 g, > 99%) as a yellow oil, which was used without further purification.

¹ H NMR (400 MHz, chloroform-d) δ=6.98 (s, 1H), 5.26 (s, 2H), 4.20 (s, 3H), 3.91 (s, 3H), 3.03 (s, 3H).

A solution of methyl 1-methyl-3-{[(methylsulfonyl)oxy]methyl}-III-pyrazole-5-carboxylate (5a, 22.6 g, 91.0 mmol) in methanol (200 ml) at room temperature was treated with solid sodium methoxide (9.84 g, 182 mmol) in small portions. The reaction mixture was heated to 70°C for 30 min. TLC indicated partial hydrolysis of the ester, so for re-esterification, the cloudy mixture was acidified with 4M HCl in ethyl acetate (40 ml, 160 mmol) and heating continued at 70°C for 5 hours. The mixture was concentrated to dryness to give a white solid. This solid was extracted with ethyl acetate/petroleum ether (1/3, 3x200 ml). The combined extracts were concentrated to dryness, then the residual solid was back-extracted with ethyl acetate/petroleum ether (1/3, 100 ml), dried over sodium sulfate, filtered and concentrated to give methyl-3(methoxymethyl)-1-methyl-III-pyrazole-5 -carboxylate (5b, 14.5 g, 86%, 80% purity by NMR) as a light yellow liquid that solidified on standing. Major component only: ¹ H NMR (400 MHz, chloroform-d)) δ=6.83 (s, 1H), 4.45 (s, 2H), 4.16 (s, 3H), 3.88 (s, 3H), 3.39 (s, 3H).

A solution of methyl 3-(methoxymethyl)-1-methyl-III-pyrazole-5-carboxylate (5b, 14.5 g, 78.7 mmol) and lithium hydroxide monohydrate (3.47 g, 82.7 mmol) in THF (150 ml) and water (50 ml) were stirred at room temperature for 16 hours. THF was removed under vacuum and the residue was dissolved in water (100 ml) and extracted with dichloromethane (3x30 ml). Organic layers were discarded. The aqueous layer was concentrated and dried under vacuum to give lithium 3-(methoxymethyl)-1-methyl-N-pyrazole-5-carboxylate (Intermediate 5, 12.85 g, 92%) as a yellow solid.

¹ H NMR (400 MHz^MBO^) δ=6.37 (s, 1H), 4.24 (s, 2H), 4.01 (s, 3H), 3.20 (s, 3H). MS: 171 [M+H]+.

General methods and representative examples.

- 38 046965

Method A.

Example 1: (^^)-3-(3-{[(2-methoxypyridin-4-yl)acetyl1amino}-III-pyrazol-5-yl)cyclopentylpropylcarbamate

ABOUT'

A room temperature solution of benzyl {1-tert-butyl-3-[(1S,3R)-3hydroxycyclopentyl]-1H-pyrazol-5-yl}carbamate (intermediate 1, 5.00 g, 14.0 mmol) and 4-nitrophenylchloroformate (4.23 g, 21.0 mmol) in anhydrous dichloromethane (50 ml) was treated with pyridine (3.40 ml, 42.0 mmol) and 4-(dimethylamino)pyridine (170 mg, 1.4 mmol) . After stirring at room temperature overnight, the solution was concentrated and purified by silica gel chromatography (eluting with 0-100% ethyl acetate in n-heptane) to give (1R,3S)-3-(5{[(benzyloxy)carbonyl]amino}-1 -tert-butyl-III-pyrazol-3-yl)cyclopentyl-4-nitrophenyl carbonate (1A, 7.30 g, 100%) as a solid foam.

1H NMR (400 MHz, chloroform-d) δ=8.24-8.14 (m, 2H), 7.36-7.22 (m, 7H), 6.21 (br. s., 1H), 6.06 (br. s., 1H), 5.25-5.15 (m, 1H), 5.12 (s, 2H), 3.15-2.97 (m, 1H), 2.58-2.47 (m, 1H), 2.09-1.78 (m, 5H), 1.51 (s, 9H). MS: 523 [M+H]+.

A solution of (1R,3S)-3-(5-{ [(benzyloxy)carbonyl]amino }-1-tert-butyl-1-pyrazol-3-yl)cyclopentyl4-nitrophenylcarbonate (1A, 36 g, 69 mmol) in 2 -methyltetrahydrofuran (300 ml) was cooled to 10°C. Diisopropylethylamine (26.7 g, 36 mL, 207 mmol) and propan-1-amine (6.11 g, 8.52 mL, 103 mmol) were added and the solution was stirred at 10°C for 16 h. After concentration to dryness the residue was diluted with ethyl acetate (600 ml), washed with 1M NaOH (4x200 ml) and then saturated. aq. NaCl solution (100 ml). The organic layer was dried over sodium sulfate, filtered and concentrated to give crude benzyl (1-tert-butyl-3-{(1S,3R)-3-[(propylcarbamoyl)oxy]cyclopentyl}-1H-pyrazol-5yl)carbamate ( 1B, 30 g, 98%), which was used without further purification.

A room temperature (20-25°C) suspension of Pd/C (50% H ₂ O, 8 g) and crude benzyl-(1-tert-butyl-3-{(1S,3R)-3-[(propylcarbamoyl) oxy]-cyclopentyl}-1H-pyrazol-5-yl)carbamate (1B, 30 g, 68 mmol) in ethyl acetate (300 ml) and THF (150 ml) was degassed and purged with hydrogen (3 cycles), then stirred at room temperature under a hydrogen atmosphere from a balloon for 16 hours. The suspension was filtered, the filtrate was concentrated in vacuo, and the residue was crystallized from ethyl acetate (50 ml) and petroleum ether (300 ml) to give (1R,3S)-3-(5-amino- 1-tert-butyl-1Hpyrazol-3-yl)cyclopentylpropylcarbamate (1C, 17.65 g, 84%) as a white solid.

1H NMR (400 MHz, DMSO-d ₆ ) δ=7.00 (br t, J=5.6 Hz, 1H), 5.23 (s, 1H), 4.95 (br s, 1H), 4.82-4.58 (m, 2H ), 2.91 (q, J=6.6 Hz, 2H), 2.85-2.73 (m, 1H), 2.37-2.21 (m, 1H), 1.92-1.76 (m, 2H), 1.72-1.52 (m, 3H ), 1.48 (s, 9H), 1.44-1.32 (m, 2H), 0.82 (t, J=7.4 Hz, 3H). MS: 309 [M+H]+. Optical rotation [a]D -4.04 (with 0.89, MeOH). Chiral purity: 98% ee based on chiral analytical SFC.

Cooled (10°C) mixture of (1R,3S)-3-(5-amino-1-tert-butyl-1H-pyrazol-3-yl)cyclopentylpropylcarbamate (1C, 8.65 g, 28.05 mmol), ( 2-methoxypyridin-4-yl)acetic acid (CAS# 464152-383, 5.86 g, 33.7 mmol), diisopropylethylamine (14.7 ml, 84.1 mmol) and propylphosphonic anhydride (T3P®, 50 wt. % solution in EtOAc, 53.5 g, 84.1 mmol) in dichloromethane (250 ml) was stirred for 16 hours. The reaction mixture was quenched with sat. aq. Na ₂ CO ₃ solution (20 ml) and extracted with dichloromethane (100 ml). The organic layer was washed with sat. aq. Na ₂ CO ₃ solution (2x200 ml) and sat. aq. NaCl solution (100 ml), dried over anhydrous sodium sulfate, filtered and concentrated to dryness. For purification, this batch was combined with two other similarly prepared batches,

- 39 046965 obtained from 1.0 g and 8.0 g of 1C (total SM for three batches = 17.65 g, 57.23 mmol 1C). Chromatography on silica gel (eluting with 0-60% EtOAc/petroleum ether) gave (1K_^)-3-(1-tert-butyl-5-{[(2-methoxypyridin-4-yl)acetyl]amino}-III-pyrazole -3-yl)cyclopentylpropylcarbamate (1D, 25 g, 95% yield for combined batches). MS: 458 [M+H]+.

Solution of (1R,3S)-3-(1-tert-butyl-5 - {[(2-methoxypyridin-4-yl)acetyl]amino }-1 I-pyrazol-3 yl)cyclopentylpropylcarbamate (1D, 20, 5 g, 44.8 mmol) in formic acid (50 ml) was stirred at 75°C for 20 hours. For purification, this batch was combined with a smaller batch (prepared from 4.50 g, 9.84 mmol 1D, for a total of 25 .0 g, 54.6 mmol), concentrated to dryness and purified by preparative HPLC [Phenomenex Gemini C18 column 250x50 mmx10 μm; eluting gradiently with water (0.05% ammonium hydroxide v/v) in ACN over 15 min; flow rate 110 ml/min]. Pure (1R,3S)-3-(3-{[(2-methoxypyridin4-yl)acetyl]amino}-1I-pyrazol-5-yl)cyclopentylpropylcarbamate (Example 1, 16.61 g, 76% yield for combined batches) as a pale yellow solid.

¹ AND NMR (400 MHz, chloroform-d)) δ=11.62-9.81 (m, 1I), 9.06 (br s, 1I), 8.06 (d, J=5.3 Hz, 1I), 6.79 (d, J =5.3 Hz, 1I), 6.66 (s, 1I), 6.50 (s, 1I), 5.24-4.94 (m, 2I), 3.88 (s, 3H), 3.58 (s, 2I), 3.19-2.83 ( m, 3H), 2.542.28 (m, 1I), 2.04 (br s, 1I), 1.97-1.70 (m, 4I), 1.54-1.34 (m, 2i), 0.85 (br t, J=7.0 Hz, 3I). MS: 402 [M+H]+. Optical rotation [a] _D +17.1 (c 1.06, MeOH). Chiral purity: 96% according to chiral analytical SFC.

Example 2: (1K_^)-3-(3-['[(2-methyl-1,3-thiazol-5-yl)acetyl]amino}-1I-pyrazol-5-yl)cyclopentylpropan-2-ylcarbamate

Solution of (1R,3S)-3-(5-{ [(benzyloxy)carbonyl] amino }-1 -tert-butyl-1 I-pyrazol-3-yl)cyclopentyl4-nitrophenylcarbonate (1A, 2.00 g, 3. 83 mmol), isopropylamine (294 mg, 4.98 mmol) and diisopropylethylamine (3.33 ml, 19.1 mmol) in THF (20 ml) were stirred at 10°C for 4 hours. After concentration to dryness, the residue was diluted with ethyl acetate ( 100 ml), and the solution was washed with 1M sodium hydroxide (4x50 ml) and sat. aq. NaCl solution (30 ml). The organic layer was dried over sodium sulfate, filtered and concentrated to give crude benzyl-(1-tert-butyl-3-{(1S,3R)-3[(propan-2-ylcarbamoyl)oxy]cyclopentyl}-1I-pyrazole-5 -yl)carbamate (2A, 1.8 g, 100% crude).

A room temperature (10°C) suspension of crude benzyl-(1-tert-butyl-3{(1S,3R)-3-[(propan-2-ylcarbamoyl)oxy]cyclopentyl}-1H-pyrazol-5-yl) carbamate (2A, 1.8 g, 3.83 mmol) and Pd/C (wet, 200 mg) in ethyl acetate (10 ml) and THF (5 ml) were degassed and purged with hydrogen, then stirred under a hydrogen atmosphere from a cylinder at 10 °C for 16 hours. The catalyst was removed by filtration and the filtrate was concentrated to dryness. The residue was purified by preparative HPLC on a Phenomenex Gemini C18 250x50 mmx10 μm column, eluting with a mixture of 25-45% water (0.05% ammonium hydroxide v/v) in acetonitrile. After lyophilization of fractions containing the product, (1R,3S)-3(5-amino-1-tert-butyl-1I-pyrazol-3-yl)cyclopentyl-propan-2-ylcarbamate (2B, 1.0 g, 85 %) as a yellow oil. MS: 309 [M+H]+.

Propylphosphonic anhydride (T3P®, 50 wt.% solution in EtOAc, 457 g, 0.718 mmol) was added to a cooled (0°C) solution of (1K.^)-3-(5-amino-1-tert-butyl-1I- pyrazol-3-yl)cyclopentyl-propan-2ylcarbamate (2B, 80 mg, 0.26 mmol), diisopropylethylamine (92.7 mg, 0.718 mmol) and (2-methyl-1,3thiazol-5-yl)acetic acid ( CAS# 52454-65-6, 45.1 mg, 0.287 mmol) in dichloromethane (3 ml). The mixture was stirred at room temperature (10°C) for 16 hours, then partitioned between dichloromethane (20 ml) and sat. aq. Na ₂ CO ₃ solution (10 ml). The organic layer was washed with sat. aq. NaCl solution (10 ml), dried over sodium sulfate, filtered and concentrated to give crude (1R,3S)-3-(1-tert-butyl-5-{[(2-methyl-1,3-thiazol-5- yl)acetyl] amino }-1 I-pyrazol-3 yl)cyclopentyl-propan-2-ylcarbamate (2C, 120 mg, 100% crude) as a yellow resin.

Crude (^^)-3-(1-tert-butyl-5-{[(2-methyl-1,3-thiazol-5-yl)acetyl]-amino}-1I-pyrazol-3yl)cyclopentyl-propane- 2-ylcarbamate (2C, 120 mg, 0.26 mmol) was dissolved in formic acid (5 ml) and stirred at 75°C for 20 h. Volatiles were removed in vacuo and the residue was purified

- 40 046965 preparative HPLC on an Xtimate C18 150x25 mmx5 µm column, eluting with a mixture of 12-52% water (0.05% ammonium hydroxide v/v) in acetonitrile. After lyophilization of the fraction containing the product, (1K_^)-3-(3-['[(2-methyl-1,3-thiazol-5-yl)acetyl]amino}-1I-pyrazol-5-yl)cyclopentyl was obtained -propan-2ylcarbamate (Example 2, 60.35 mg, 58%) as a white solid.

¹ AND NMR (400 MHz, DMSO-d6) δ=12.10 (s, 1H), 10.58 (s, 1H), 7.41 (s, 1H), 6.95 (br d, J=6.3 Hz, 1H), 6.29 (s, 1H), 4.98 (br s, 1H), 3.81 (s, 2H), 3.57 (br d, J=6.5 Hz, 1H), 3.03 (br s, 1I), 2.59 (s, 3H) , 2.45 (br s, 1H), 2.07-1.81 (m, 2H), 1.78-1.44 (m, 3H), 1.03 (br d, J=6.5 Hz, 6H). MC: 392 [M+H] ⁺ . Chiral purity: 99% ee based on chiral analytical SFC.

Example 3: (1R,3S)-3-(3-{[(1-methyl-1H-indazol-5-yl)acetyl]amino}-1H-pyrazol-5-yl)cyclopentylethylcarbamate

A solution of (1R,3S)-3-(5-{ [(benzyloxy)carbonyl] amino }-1 -tert-butyl-1 I-pyrazol-3-yl)cyclopentyl 4-nitrophenyl carbonate (1A, 2.5 g, 4 .8 mmol) and ethylamine (1.08 g, 23.9 mmol) in THF (20 ml) were stirred at 30°C for 3 hours, concentrated to dryness, and the residue was dissolved in dichloromethane (30 ml). The solution was washed with aq. NaOH solution until the organic layer became colorless (5x5 ml), then washed with water (5 ml) and sat. aq. NaCl solution (5 ml), dried over sodium sulfate, filtered and concentrated to give crude benzyl-(1-Ίret-butyl-3-{(1S,3R)-3[(ethylcarbamoyl)oxy]cyclopentyl}-1I-pyrazol- 5-yl)carbamate (3A, 2.0 g, 97%, >80% purity by LC-MS) as a colorless oil. MS: 429 [M+H] ⁺ , 451 [M+Na] ⁺ .

Crude benzyl-(Gtret-butyl-3-['(A,3C)-3-[(ethylcarbamoyl)oxy]-cyclopentyl}-1I pyrazol-5-yl)carbamate (3A, 2.0 g, 4.7 mmol) was dissolved in ethyl acetate (30 ml) and THF (10 ml), the solution was degassed and 10% Pd/C catalyst (wet, 200 mg) was added. The suspension was stirred under a hydrogen atmosphere from a balloon at room temperature (10°C) for 2 hours. The catalyst was removed by filtration, the filtrate was concentrated to dryness, and the residue was purified by chromatography on silica gel (eluting with 0-60% ethyl acetate in petroleum ether) to give (1R, 3S)-3-(5-Amino-1-tert-butyl-1Hpyrazol-3-yl)cyclopentylethylcarbamate (3B, 1.15 g, 84%) as a light yellow resin that hardened on standing in light yellow solid. MS: 295 [M+H]+.

¹ AND NMR (400 MHz, chloroform-d)) δ=5.43 (s, 1I), 5.13 (br s, 1I), 4.58 (br s, 1I), 3.50 (br s, 2I), 3.313.13 (m , 2I), 2.99 (quin, J=8.5 Hz, 1I), 2.53-2.39 (m, 1I), 2.04-1.96 (m, 1I), 1.95-1.87 (m, 1I), 1.87-1.68 (m , 3I), 1.62 (s, 9I), 1.14 (t, J=7.2 Hz, 3I). Chiral purity: >98% as determined by chiral analytical SFC.

Propylphosphonic anhydride (T3P®, 50 wt.% solution in EtOAc, 0.485 ml, 0.815 mmol) was added to a room temperature (10°C) solution of (1K_^)-3-(5-amino-1-tert-butyl-1I -pyrazol-3yl)cyclopentyl-ethylcarbamate (3B, 80.0 mg, 0.272 mmol), 2-(1-methyl-1I-indazol-5-yl)acetic acid (CAS# 1176749-66-8, 59.1 mg , 0.311 mmol) and diisopropylethylamine (0.142 ml, 0.815 mmol) in dichloromethane (5 ml). The mixture was stirred for 3 hours, then partitioned between dichloromethane (5 ml) and water (3 ml). The organic layer was washed with sat. aq. Na ₂ CO ₃ solution (2x3 ml), sat. aq. NH4C1 solution (2x3 ml), water (2 ml) and sat. aq. NaCl solution (2 ml), then dried over sodium sulfate, filtered and concentrated to give crude (N^)-3-(1-tert-butyl-5{[(1-methyl-1H-indazol-5-yl)acetyl ]amino}-1I-pyrazol-3-yl)cyclopentyl ethylcarbamate (3C, 127 mg, 100% crude) as a light yellow resin. MS: 489 [M+Na] ⁺ .

A solution of crude (1R,3S)-3-(1-tert-butyl-5-{[(1-methyl-1 I-indazol-5-yl)acetyl]amino}-1Ipyrazol-3-yl)cyclopentyl-ethylcarbamate ( 3C, 127 mg, 0.272 mmol) in formic acid (6 ml) was heated at 75°C for 18 hours. The reaction mixture was concentrated to dryness, then purified by preparative HPLC on a DuraShell 150x25 mmx5 μm column, eluting with a mixture of 24-44% water (0 .05% ammonium hydroxide v/v) in acetonitrile. After lyophilization of the product containing fraction, (1R,3S)-3-(3-{[(1methyl-1H-indazol-5-yl)acetyl]amino}-1I-pyrazol-5-yl)cyclopentyl-ethylcarbamate (Example 3 , 52.39 mg, 47%) was obtained as a white solid. MS: 411 [M+H] ⁺ .

Ή NMR (400 MHz, DMSO-d ₆ ) δ=12.05 (br s, 1H), 10.51 (s, 1H), 8.06-7.95 (m, 1H), 7.64 (s, 1H), 7.56 (d, J= 8.5 Hz, 1H), 7.35 (dd, J=1.4, 8.7 Hz, 1H), 7.02 (br t, J=5.5 Hz, 1H), 6.27 (br s, 1I), 4.97 (br s, 1H), 4.04-3.95

- 41 046965 (m, 3H), 3.66 (s, 2H), 3.10-2.85 (m, 3H), 2.43 (td, J=6.9, 14.0 Hz, 1H), 2.04-1.92 (m, 1H), 1.91-1.80 (m, 1H), 1.74-1.49 (m, 3H), 0.97 (t, J=7.2 Hz, 3H). Chiral purity: 99% according to the results of chiral analytical SFC.

Example 4: (1R,3S)-3-(3-{[(1 -methyl-1H-1,2,3-triazol-5-yl)carbonyl] amino }-1 I-pyrazol-5 yl)cyclopentyl- (2S)-butan-2-ylcarbamate

Solution of (1R,3S)-3-(5-{ [(benzyloxy)carbonyl] amino }-1-tert-butyl-1 I-pyrazol-3-yl)cyclopentyl4-nitrophenyl carbonate (1A, 22.0 g, 42. 1 mmol), ^)-(+)-sec-butylamine (4.00 g, 54.7 mmol) and diisopropylethylamine (36.7 ml, 211 mmol) in THF (300 ml) were stirred at 10°C for 16 h. The mixture was concentrated to dryness and the residue was diluted with ethyl acetate (500 ml). The solution was washed with 1M aq., NaOH solution (4x200 ml) and sat. water, NaCl solution (100 ml). The organic layer was dried over sodium sulfate, filtered and concentrated to give crude benzyl-{3-[(1S,3R)-3-{[(2S)butan-2-ylcarbamoyl]oxy}cyclopentyl]-1-tert-butyl-1I -pyrazol-5-yl}carbamate (4A, 18 g, 94%, approximately 80% purity by LC-MS). MS: 479 [M+Na]+.

A room temperature (10°C) solution of crude benzyl-{3-[(1S,3R)-3-{[(2S)butan-2-ylcarbamoyl]oxy}cyclopentyl]-1-tert-butyl-1I-pyrazol- 5-yl}carbamate (4A, 18 g, 39 mmol) in ethyl acetate (200 ml) and THF (100 ml) was degassed and treated with Pd/C catalyst (wet, 5 g). The suspension was stirred under a hydrogen atmosphere from a balloon for 16 hours. The mixture was filtered to remove the catalyst, and the filtrate was concentrated to dryness. For purification, this batch was combined with a second crude batch obtained in the same way from 20 g of 4A (total for both batches: 38 g, 83 mmol), and purified by preparative HPLC on a Phenomenex Gemini C18 250x50 mmx10 µm column, eluting with a mixture of 30-50 % water (0.05% ammonium hydroxide v/v) in acetonitrile. After lyophilization, (^^)-3-(5-amino-1-tert-butyl-1H-pyrazol-3-yl)cyclopentyl-^)-butan-2-ylcarbamate (4B, 20.1 g, 75% for combined parties). MS: 323 [M+H]+.

1H NMR (400 MHz, DMSO-d ₆ ) δ=6.86 (br d, J=8.3 Hz, 1H), 5.22 (s, 1H), 4.94 (br s, 1H), 4.82-4.49 (m, 2H ), 3.46-3.36 (m, 1H), 2.90-2.71 (m, 1H), 2.38-2.24 (m, 1H), 1.91-1.75 (m, 2H), 1.74-1.53 (m, 3H), 1.52-1.46 (m, 9H), 1.43-1.27 (m, 2H), 1.01 (d, J=6.5 Hz, 3H), 0.81 (t, J=7.4 Hz, 3H). Optical rotation [a] _D +4.0 (with 1.3, MeOH). Chiral purity: 98% de based on chiral analytical SFC.

Propylphosphonic anhydride (T3P®, 50 wt.% solution in EtOAc, 592 mg, 0.93 mmol) was added to a cooled (0°C) solution of (1R,3S)-3-(5-amino-1-tert-butyl- 1H-pyrazol-3-yl)cyclopentyl-(2S)-butan2-ylcarbamate (4B, 100 mg, 0.310 mmol), 1-methyl-III-1,2,3-triazole-5-carboxylic acid (CAS# 71636191- 0.59.1 mg, 0.465 mmol) and diisopropylethylamine (120 mg, 0.93 mmol) in dichloromethane (5 ml). The mixture was stirred at 10°C for 18 hours, then washed with sat. aq. Na ₂ CO ₃ solution and sat. aq. NaCl solution, dried over sodium sulfate, filtered and concentrated to give crude (1R,3S)-3-(1-tert-butyl-5-{[(1-methyl-III-1,2,3-triazole-5- yl)carbonyl]amino}-1H-pyrazol-3yl)cyclopentyl-^)-butan-2-ylcarbamate (4C, 130 mg, 97%) as a yellow resin. MS: 432 [M+H] ⁺ , 454 [M+Na] ⁺ .

A solution of crude (1R,3S)-3-(1-tert-butyl-5-{[(1-methyl-1H-1,2,3-triazol-5yl)carbonyl]amino}-1H-pyrazol-3 -yl)cyclopentyl-(2S)-butan-2-ylcarbamate (4C, 130 mg, 0.301 mmol) in formic acid (3 ml) was stirred at 75°C for 6 days. The mixture was concentrated to dryness and the residue was purified by preparative HPLC on a 150 x 25 mm x 5 µm DuraShell column, eluting with 1051% water (0.05% v/v ammonium hydroxide) in acetonitrile. After lyophilization, (1R,3S)-3-(3-{[(1methyl-1H-1,2,3-triazol-5-yl)carbonyl]amino}-1H-pyrazol-5-yl)cyclopentyl-(2S) -Butan-2-ylcarbamate (Example 4, 27.67 mg, 24%) was obtained as a pale yellow solid. MS: 376 [M+H] ⁺ .

1H NMR (400 MHz, DMSO-d ₆ ) δ=12.32 (br s, 1H), 11.14 (s, 1H), 8.46 (s, 1H), 6.90 (br d, J=8.0 Hz, 1H), 6.45 (br s, 1H), 5.00 (br d, J=3.8 Hz, 1H), 4.25 (s, 3H), 3.36 (br s, 2H), 3.29-2.99 (m, 1H), 2.09-2.01 (m, 1H), 1.95-1.84 (m, 1H), 1.81-1.56 (m, 3H), 1.44-1.27 (m, 2H), 1.01 (br d, J=6.5 Hz, 3h), 0.80 ( br t, J=7.4 Hz, 3H). Chiral purity: >98% de based on chiral analytical SFC.

- 42 046965

Example 5: (N^)-3-(3-{[(5-methyl-1,3-oxazol-2-yl)acetyl]amino}-1H-pyrazol-5-yl)cyclopentyl(1-methylcyclopropyl)carbamate

Solution of (1R,3S)-3-(5-{ [(benzyloxy)carbonyl] amino }-1-tert-butyl-1H-pyrazol-3-yl)cyclopentyl4-nitrophenylcarbonate (1A, 9.50 g, 18, 2 mmol), 1-methylcyclopropanamine hydrochloride (2.93 g, 27.2 mmol) and diisopropylethylamine (10.0 ml, 58.2 mmol) in DMF (80 ml) were stirred at 60°C for 2 hours. After cooling to room temperature, the mixture was partitioned between ethyl acetate (300 ml) and water (300 ml). The organic layer was washed with water (2x300 ml), 2M aq. Na ₂ CO ₃ solution (300 ml) and sat. aq. NaCl solution (300 ml), then dried over sodium sulfate, filtered, concentrated and purified by chromatography on silica gel (eluting with 0-100% ethyl acetate in heptane) to give benzyl-{1-tert-butyl-3-[(1S,3R) -3-{[(1-methylcyclopropyl)carbamoyl]oxy}cyclopentyl]-1H-pyrazol-5yl}carbamate (5A, 6.28 g, 76%) as a solid. MS: 455 [M+H]+.

¹ H NMR (400 MHz, chloroform-d) δ=7.45-7.30 (m, 5H), 6.30 (br. s., 1H), 6.10 (br. s., 1H), 5.20 (s, 2H), 5.15 (br. s., 1H), 5.06 (br. s., 1H), 3.08 (quin, J=8.3 Hz, 1H), 2.44 (br. s., 1H), 2.12-1.97 (m, 1H ), 1.96-1.75 (m, 4H), 1.58 (s, 9H), 1.35 (br. s., 3H), 0.74 (br. s., 2H), 0.58 (br. s., 2H).

Mixture of benzyl-{1-tert-butyl-3-[(1S,3R)-3-{[(1-methylcyclopropyl)carbamoyl]-oxy}cyclopentyl]III-pyrazol-5-yl}carbamate (5A, 6.28 g, 13.8 mmol) and 10% Pd/C (620 mg) in methanol (200 ml) were stirred at room temperature (20°C) in a hydrogen atmosphere from a cylinder for 18 hours. The suspension was filtered through a pad of celite to remove the catalyst . The flask and filter bed were washed with additional methanol, then the combined filtrates were concentrated to give (1R,3S)-3-(5-amino-1-tert-butyl-1H-pyrazol-3-yl)cyclopentyl-(1-methylcyclopropyl)carbamate (5B, 4.42 g, 100% crude) as a foamy solid. MS: 321 [M+H] ⁺ .

¹ H NMR (400 MHz, methanol^) δ=5.06 (br. s., 1H), 3.14-2.97 (m, 1H), 2.58-2.37 (m, 1H), 2.14-2.00 (m, 1H), 2.00 -1.69 (m, 4H), 1.69-1.54 (m, 10H), 1.31 (s, 3H), 0.74-0.66 (m, 2H), 0.60-0.53 (m, 2H).

Solution of (N^)-3-(5-amino-1-tert-butyl-III-pyrazol-3-yl)cyclopentyl-(1methylcyclopropyl)carbamate (5B, 4.00 g, 12.5 mmol), (5- lithium methyl 1,3-oxazol-2-yl)acetate (Intermediate 3, 3.52 g, 24.9 mmol), 1-[bis(dimethylamino)methylene]-III-1,2,3-triazolo[ 4,5b]pyridinium hexafluorophosphate 3-oxide (HATU, 14.2 g, 37.3 mmol) and triethylamine (5.30 ml, 38.0 mmol) in DMF (100 ml) were stirred at 60°C for 2 h After cooling to room temperature, the reaction mixture was partitioned between ethyl acetate (200 ml) and water (200 ml). The organic phase was further washed with water (2x200 ml) and sat. aq. NaCl solution (200 ml). The combined aqueous layers were extracted with ethyl acetate (200 ml). The combined organic extracts were dried over sodium sulfate, concentrated and purified by chromatography on silica gel (eluting with 10-100% ethyl acetate in heptane) to give the impurity product (5.50 g solid). This impurity was purified again by chromatography on silica gel (eluting with 100% ethyl acetate) to give pure (1R,3S)-3-(1-tert-butyl-5-{[(5-methyl-1,3-oxazol-2- yl)acetyl]amino}-1H-pyrazol-3yl)cyclopentyl-(1-methylcyclopropyl)carbamate (5C, 4.22 g, 76%) as a solid. MS: 444 [M+H] ⁺ .

1H NMR (400 VllnJDMSOO δ=9.78 (s, 1H), 7.32 (br. s., 1H), 6.78 (d, J=1.1 Hz, 1H), 5.93 (s, 1H), 4.97 (br. s ., 1H), 3.83 (s, 2H), 3.03-2.88 (m, 1H), 2.42-2.30 (m, 1H), 2.27 (d, J=1.1 Hz, 3H), 1.98-1.88 (m, 1H), 1.871.77 (m, 1H), 1.73-1.58 (m, 3H), 1.49 (s, 9H), 1.23 (s, 3H), 0.63-0.56 (m, 2H), 0.50-0.44 (m, 2H).

A solution of (1R,3S)-3-(1-tert-butyl-5-{[(5-methyl-1,3-oxazol-2-yl)acetyl]amino}-1H-pyrazol-3yl)cyclopentyl-(1 α-methylcyclopropyl)carbamate (5C, 4.20 g, 9.47 mmol) in formic acid (50 ml) was stirred at 100°C for 1 hour. After cooling to room temperature, the reaction mixture was concentrated to remove most of the formic acid. The residue was partitioned between ethyl acetate (200 ml) and sodium bicarbonate (200 ml). The aqueous layer was extracted again with ethyl acetate (200 ml). The combined organic extracts were dried over sodium sulfate, filtered and concentrated to dryness. The solid residue was triturated twice with diethyl ether (30 ml) to obtain

- 43 046965 (1R,3S)-3-(3-{ [(5-methyl-1,3-oxazol-2-yl)acetyl] amino }-1 H-pyrazol-5 -yl)cyclopentyl-( 1 methylcyclopropyl )-carbamate (Example 5, 1.93 g, 53%) as a solid. MS: 388 [M+H]+.

¹ H NMR (400 Vllu,DVISO-d„) δ=12.08 (br. s., 1H), 10.59 (br. s., 1H), 7.32 (br. s., 1H), 6.74 (d, J= 1.0 Hz, 1H), 6.27 (br. s., 1H), 4.97 (br. s., 1H), 3.79 (s, 2H), 3.14-2.93 (m, 1H), 2.44 (dd, J= 14.1, 7.0 Hz, 1H), 2.26 (d, J=0.7 Hz, 3H), 1.99 (t, J=3.4 Hz, 1H), 1.93-1.81 (m, 1H), 1.68 (d , J=8.2 Hz, 2H), 1.60-1.46 (m, 1H), 1.22 (s, 3H), 0.58 (br. s., 2H), 0.49-0.42 (m, 2H).

Example 6: (1R,3S)-3-(3-{ [(5-methoxypyrazin-2-yl)acetyl] amino }-1 H-pyrazol-5 -yl)cyclopentyl-(1 methylcyclopropyl)carbamate

Solution of (1R,3S)-3 -(5-amino-1 -tert-butyl-1 H-pyrazol-3 -yl)cyclopentyl-(1 methylcyclopropyl)carbamate (5B, 150.0 mg, 0.468 mmol), (5 -methoxypyrazin-2-yl)lithium acetate (Intermediate 4, 118 mg, 0.702 mmol), diisopropylethylamine (182 mg, 1.40 mmol) and propyl phosphonic anhydride (T3P®, 50 wt.% solution in EtOAc, 447 mg, 0.702 mmol) in dichloromethane (10.0 ml) was stirred at 40°C for 30 hours. The reaction mixture was quenched with sat. aq. NaHCO ₃ solution (8 ml) and extracted with dichloromethane (3x8 ml). The combined organic extracts were washed with sat. aq. NaCl solution (15 ml), concentrated and purified by silica gel chromatography (eluting with 50% ethyl acetate in petroleum ether) to give (^^)-3-(1-tert-butyl-5-{[(5methoxypyrazin-2-yl)acetyl ]amino }-1 H-pyrazol-3 -yl)cyclopentyl-(1-methylcyclopropyl)carbamate (6A, 100 mg, 45%, 81% LC-MS purity) as a light yellow resin. MS: 471 [M+H]+.

(1R,3S)-3-(1-tert-butyl-5 - {[(5-methoxypyrazin-2-yl)acetyl]amino }-1 H-pyrazol-3-yl)cyclopentyl(1-methylcyclopropyl)carbamate ( 6A, 100 mg, 0.213 mmol) was dissolved in formic acid (5 ml) and stirred at 75°C for 16 hours. The solution was concentrated under vacuum and the residue was purified by preparative HPLC on a DuraShell 150x25 mmx5 μm column, eluting with a mixture of 26-46% water (0.05% ammonium hydroxide v/v) in acetonitrile. After lyophilization, (^^)-3-(3-{[(5-methoxypyrazin-2yl)acetyl]amino}-1H-pyrazol-5-yl)cyclopentyl-(1-methylcyclopropyl)carbamate (Example 6, 15.55 mg , 18%) was obtained as a white solid. MS: 415 [M+H]+.

1H NMR (400 MHz, DMSO-d ₆ ) δ=12.07 (br s, 1H), 10.54 (s, 1H), 8.23 (d, J=1.3 Hz, 1H), 8.16 (s, 1H), 7.35 (br s, 1H), 6.26 (br s, 1H), 4.96 (br s, 1H), 3.89 (s, 3H), 3.77 (s, 2H), 3.02 (br d, J=8.5 Hz, 1H ), 2.47-2.39 (m, 1H), 1.97 (br d, J=9.3 Hz, 1H), 1.90-1.80 (m, 1H), 1.72-1.59 (m, 2H), 1.58-1.45 (m, 1H), 1.21 (s, 3H), 0.57 (br s, 2H), 0.48-0.40 (m, 2H). Chiral purity: 99% ee based on chiral analytical SFC.

Example 7: (^^)-3-(3-{[(5-methyl-1,2-oxazol-3-yl)acetyl]amino}-1H-pyrazol-5-yl)cyclopentyl(1-methylcyclopropyl)carbamate

Example 7

Solution of (1R,3S)-3-(5-amino-1-tert-butyl-1H-pyrazol-3-yl)cyclopentyl-(1 methylcyclopropyl)carbamate (5B, 78 mg, 0.24 mmol), (5 -methyl-1,2-oxazol-3-yl)acetic acid (CAS# 57612-87-0, 51.5 mg, 0.365 mmol), diisopropylethylamine (0.130 ml, 0.730 mmol) and propylphosphonic anhydride (T3P®, 50 wt .% solution in EtOAc, 0.435 ml, 0.730 mmol) in dichloromethane (5.0 ml) was stirred at 30-35°C for 18 hours. The solution was washed with sat. aq. NaHCO ₃ solution (5 ml) and sat. aq. NaCl solution (5 ml), dried, filtered and concentrated to give crude (1R,3S)-3-(1-tert-butyl-5-{[(5-methyl-1,2-oxazol-3-yl)acetyl ] amino }-1 H-pyrazole-3

- 44 046965 yl)cyclopentyl-(1-methylcyclopropyl)carbamate (7A, 95 mg, 88%) in the form of a resin. MS: 444 [M+H]+.

Crude (1R,3S)-3-(1 -tert-butyl-5-{ [(5-methyl-1,2-oxazol-3-yl)acetyl]-amino }-1 H-pyrazol3-yl)cyclopentyl- (1-Methylcyclopropyl)carbamate (7A, 95 mg, 0.21 mmol) was dissolved in formic acid (5.0 ml) and heated to 75°C for 15 h. The sample was concentrated to dryness, the residue was dissolved in ethyl acetate (30 ml) , washed with sat. aq. NaHCO ₃ solution (10 ml), dried, filtered and concentrated. The crude product was purified by preparative HPLC on an Agela Durashell C18 150x25 mm, 5 µm column, eluting with a mixture of 18-58% water (with 0.05% ammonium hydroxide) in acetonitrile to give (1R,3S)-3 -(3 - {[ (5-methyl-1,2-oxazol-3 -yl)acetyl]amino}-1 H-pyrazol-5-yl)cyclopentyl-(1 methylcyclopropyl)carbamate (example 7, 39.71 mg, 50%) as beige solid. MS: 388 [M+H]+.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ=12.08 (br s, 1H), 10.59 (s, 1H), 7.34 (br s, 1H), 6.36-6.03 (m, 2H), 4.97 (br s , 1H), 3.64 (s, 2H), 3.15-2.87 (m, 1H), 2.46-2.40 (m, 1H), 2.37 (s, 3H), 1.98 (br d, J=9.0 Hz, 1H) , 1.90-1.81 (m, 1H), 1.77-1.59 (m, 2H), 1.54 (br d, J=8.0 Hz, 1H), 1.22 (s, 3H), 0.58 (br s, 2H), 0.49 -0.43 (m, 2H). Chiral purity: >99% ee based on chiral analytical SFC.

Example 8: (1R,3S)-3-[3-({[3-(methoxymethyl)-1-methyl-1H-pyrazol-5-yl]carbonyl|amino)-1Hpyrazol-5-yl]cyclopentyl-(1 -methylcyclopropyl)carbamate

A solution of (1R,3S)-3-(5-amino-1-tert-butyl-1H-pyrazol-3-yl)cyclopentyl-(1methylcyclopropyl)carbamate (5B, 5.47 g, 17.1 mmol) and 3- (methoxymethyl)-1-methyl-1H-pyrazole-5carboxylic acid (Intermediate 5, 4.36 g, 25.6 mmol) in ethyl acetate (80 ml) was treated with diisopropylethylamine (9.00 ml, 52.4 mmol) and propylphosphonic anhydride (T3P®, 50 wt.% solution in EtOAc, 10.9 g, 10.0 ml, 31.4 mmol) and stirred at room temperature overnight. Since LC-MS indicated that the reaction was incomplete, the mixture was heated to 50°C for 3 h, but LC-MS again showed incomplete conversion. After cooling to room temperature, the solution was partitioned between ethyl acetate (100 ml) and deionized water (200 ml). The organic layer was dried over sodium sulfate, filtered and concentrated. The residue was dissolved in ethyl acetate (80 ml). Additional 3-(methoxymethyl)-1-methyl-1H-pyrazole-5-carboxylic acid (Intermediate 5, 2.90 g, 17.1 mmol), diisopropylethylamine (9.00 mL, 52.4 mmol) and T3P (10.0 ml, 33.6 mmol) and the reaction mixture was stirred at room temperature for 4 hours. The solution was diluted with ethyl acetate (100 ml), washed with water (200 ml), sat. aq. NaHCO ₃ solution (200 ml) and sat. aq. NaCl solution (200 ml); dried over sodium sulfate, filtered and concentrated. The residue was purified by chromatography on silica gel (eluting with a gradient of 0-100% ethyl acetate in heptane) to give (1R,3S)-3-[1-tert-butyl-5-({[3-(methoxymethyl)-1-methyl-1H- pyrazol-5yl]carbonyl}amino)-III-pyrazol-3-yl]cyclopentyl-(1-methylcyclopropyl)carbamate (8A, 4.83 g, 60%) as a foamy solid. MS: 473 [M+H]+.

1H NMR (400 MHz, chloroform-d) δ=7.71 (br. s., 1H), 6.68 (br. s., 1H), 6.23 (br. s., 1H), 5.12 (br. s., 2H ), 4.47 (s, 2H), 4.18 (s, 3H), 3.43 (s, 3H), 3.03-3.16 (m, 1H), 2.41 (br. s., 1H), 1.97-2.11 (m, 1H) , 1.87 (m, J=5.9 Hz, 4H), 1.63 (s, 9H), 1.33 (s, 3H), 0.73 (br. s., 2H), 0.52-0.61 (m, 2H).

Solution of (^^)-3-[1-tert-butyl-5-({[3-(methoxymethyl)-1-methyl-III-pyrazol-5-yl]carbonyl}amino)1H-pyrazol-3-yl] Cyclopentyl (1-methylcyclopropyl)carbamate (8A, 4.77 g, 10.1 mmol) in formic acid (50 ml) was stirred at 100°C for 2 hours. After cooling to room temperature, most of the formic acid was removed under vacuum , and the residue was partitioned between ethyl acetate (200 ml) and sat. aq. NaHCO ₃ solution (200 ml). The aqueous layer was extracted with ethyl acetate (200 ml). The combined organic extracts were dried over sodium sulfate, filtered, concentrated and purified by silica gel chromatography (eluting with 0-10% methanol in ethyl acetate) to give a white solid (3.15 g). This solid was recrystallized from ethyl acetate/heptane to give (1R,3S)-3-[3-({[3-(methoxymethyl)-1-methyl-1H-pyrazol-5yl]carbonyl}amino)-III-pyrazole -5-yl]cyclopentyl-(1-methylcyclopropyl)carbamate (example 8, 2.90 g,

- 45 046965

69%) as a crystalline solid. MS: 417 [M+H]+.

1I NMR (400 MHz, DMSO-d6) δ=12.20 (br. s., 1H), 10.69 (s, 1H), 7.33 (br. s., 1H), 7.11 (s, 1H), 6.41 (br. s., 1H), 4.99 (br. s., 1H), 4.33 (s, 2H), 4.05 (s, 3H), 3.27 (s, 3H), 3.00-3.13 (m, 1H), 2.41-2.49 ( m, 1H), 1.97-2.10 (m, 1H), 1.83-1.95 (m, 1H), 1.72 (br. s., 2h), 1.59 (br. s., 1H), 1.24 (s, 3I), 0.60 (br. s., 2H), 0.47 (br. s., 2H).

Example 9: (1R,3S)-3-[3-({[3-(methoxymethyl)-1-methyl-1I-pyrazol-5-yl]carbonyl}amino)-1Ipyrazol-5-yl]cyclopentyl-G (2£)-4,4,4-trifluorobutan-2-yl]carbamate - Isomer A.

Example 10: (1R,3S)-3-[3-({[3-(methoxymethyl)-1-methyl-1H-pyrazol-5-yl]-carbonyl |amino)-1Ipyrazol-5-yl]cyclopentyl-[ ^)-4,4,4-trifluorobutan-2-yl]carbamate - Isomer B.

A solution of (1R,3S)-3-(5-{ [(benzyloxy)carbonyl] amino }-1 -tert-butyl-1 I-pyrazol-3-yl)cyclopentyl4-nitrophenylcarbonate (1A, 2.5 g, 4, 8 mmol), 4,4,4-trifluorobutan-2-amine (CAS# 37143-52-5, 900 mg, 5.5 mmol) and diisopropylethylamine (4.17 ml, 23.9 mmol) in 2-methyltetrahydrofuran ( 40 ml) and dichloromethane (20 ml) were stirred at 40-50°C for 15 hours. The solvents were removed in vacuo and the residue was partitioned between ethyl acetate (150 ml) and 1 N. water, sodium hydroxide solution (2x50 ml). The organic layer was washed with sat. aq. NaCl solution (60 ml), dried over sodium sulfate, filtered, concentrated and purified by chromatography on silica gel (eluting with 15-30% ethyl acetate in petroleum ether) to give benzyl-{1-tert-butyl-3-[(1S,3R) -3-{[(4,4,4-trifluorobutan-2yl)carbamoyl]oxy}cyclopentyl]-1I-pyrazol-5-yl}carbamate (9A, mixture of diastereomers, 2.0 g, 82%, 79% purity by LC-MS) as a yellow oil. MS: 511 [M+I] ⁺ .

Benzyl-{1-tert-butyl-3-[(1S,3R)-3-{[(4,4,4-trifluorobutan-2-yl)carbamoyl]-oxy}cyclopentyl]-1Ipyrazol-5-yl}carbamate as a mixture of diastereomers (9A, 2.0 g, 3.9 mmol) was dissolved in ethyl acetate (20 ml) and THF (20 ml) and the catalyst 10% Pd/C (50% humidity, 650 mg) was added. The suspension was degassed, filled with hydrogen from a balloon and stirred at 20-25°C in an atmosphere of hydrogen from a balloon for 16 hours. The catalyst was removed by filtration and the filtrate was concentrated to obtain crude (1R,3S)-3-(5-amino-1- tert-butyl-1I-pyrazol-3-yl)cyclopentyl-(4,4,4-trifluorobutan-2yl)carbamate (9B, diastereomer mixture, 1.4 g, 95%, 76% purity by LC-MS ) as a yellow oil. MS: 377 [M+I] ⁺ .

Cooled (0°C) solution of crude (^^)-3-(5-amino-1-tert-butyl-1I-pyrazol-3yl)cyclopentyl-(4,4,4-trifluorobutan-2-yl)carbamate (9B , 225 mg, 0.598 mmol), 3-(methoxymethyl)-1methyl-1I-pyrazole-5-carboxylate (Intermediate 5, 173 mg, 0.897 mmol) and diisopropylethylamine (232 mg, 1.79 mmol) in dichloromethane (10 ml ) were treated with propylphosphonic anhydride (T3P®, 50 wt.% solution in EtOAc, 1.14 g, 1.79 mmol). The mixture was heated to 20°C and stirred for 36 hours, then heated to 40°C for 90 hours. The mixture was partitioned between dichloromethane and semisaturated Na2CO ₃ solution. The organic layer was dried over sodium sulfate, filtered and concentrated to give crude (1K.^)-3-[1-tert-butyl-5-({[3-(methoxymethyl)-1-methyl-1-Ipyrazol-5-yl]carbonyl }amino)-1I-pyrazol-3-yl]cyclopentyl-(4,4,4-trifluorobutan-2-yl)carbamate (9C, mixture of diastereomers, 300 mg, 95%) as a yellow resin. MS: 529 [M+H] ⁺ .

A solution of crude (1R,3S)-3-[1-tert-butyl-5-( {[3 -(methoxymethyl)-1 -methyl-1 I-pyrazol-5 yl]carbonyl}amino)-1I-pyrazol-3 -yl]cyclopentyl-(4,4,4-trifluorobutan-2-yl)carbamate (9C, 300 mg, 0.57 mmol) in formic acid (10 ml) was stirred at 80°C for 2 hours. The mixture was concentrated to dryness, and the residue was purified by preparative HPLC on a DuraShell 150x25 mmx5 μm column, eluting with a mixture of 32% water (0.05% ammonium hydroxide v/v) in acetonitrile. After lyophilization, (1R,3S)-3-[3({[3-(methoxymethyl)-1-methyl-1I-pyrazol-5-yl]carbonyl}amino)-1I-pyrazol-5-yl]cyclopentyl-(4 ,4,4

- 46 046965 trifluorobutan-2-yl)carbamate (9D, mixture of diastereomers, 45 mg, 17%) was obtained as a white solid. MS: 473 [M+H]+.

The diastereomeric mixture 9D was separated by chiral preparative SFC on a PhenomenexAmylose-1 250 mm x 30 mm, 5 µm column, eluting with 40% ethanol (+0.1% NH ₃ H ₂ O) in CO ₂ to obtain the compound of example 9 (Peak 1, 12.26 mg , 27%, 99% de) and the compound of Example 10 (Peak 2, 11.53 mg, 26%, 98% de) as white solids. The absolute stereochemistry of the chiral center in the 4,4,4-trifluorobutan-2yl]carbamate of each molecule was not determined.

Example 9: (1R,3S)-3-[3-({[3 -(methoxymethyl)-1 -methyl-1 H-pyrazol-5-yl]-carbonyl} amino)-1Hpyrazol-5-yl]cyclopentyl- [^)-4,4,4-trifluorobutan-2-yl]carbamate - Isomer A.

¹ H NMR (400 MHz, DMSO-d6) δ=12.25 (br s, 1H), 10.74 (s, 1H), 7.22 (br d, J=8.4 Hz, 1H), 7.12 (s, 1H), 6.43 (br s, 1H), 5.10-4.96 (m, 1H), 4.34 (s, 2H), 4.05 (s, 3H), 3.92-3.79 (m, 1H), 3.27 (s, 3H), 3.17-3.03 (m, 1H), 2.46 (br d, J=6.1 Hz, 1H), 2.43-2.31 (m, 2H), 2.12-1.85 (m, 2H), 1.80-1.57 (m, 3H), 1.13 ( d, J=6.7 Hz, 3H). ¹⁹ F NMR (377 MHz, DMSO-d6) δ=-62.57 (s, 3F). MC: 473 [M+H]+. Optical rotation: [a] _D -2 (with 0.1, MeOH). Chiral purity: 99% de. Chiral SFC/MS analysis was performed on a Chiralpak AD-3 column (150 x 4.6 mm i.d., 3 µm), eluting with 40% ethanol (+0.05% DEA) in CO2, flow rate 2.5 ml/min , at 35°C, with pressure set to 1500 psi. Under these conditions, this peak had a retention time of 3.372 min.

Example 10: (1R,3S)-3-[3-({[3 -(methoxymethyl)-1 -methyl-1 H-pyrazol-5-yl]-carbonyl} amino)-1Hpyrazol-5-yl]cyclopentyl- [^)-4,4,4-trifluorobutan-2-yl]carbamate - Isomer B.

1H NMR (400 MHz, DMSO-d ₆ ) δ=12.25 (br s, 1H), 10.74 (s, 1H), 7.24 (br d, J=8.3 Hz, 1H), 7.12 (s, 1H), 6.42 (br s, 1H), 5.16-4.91 (m, 1H), 4.34 (s, 2H), 4.05 (s, 3H), 3.84 (td, J=7.0, 13.8 Hz, 1H), 3.27 (s , 3H), 3.163.01 (m, 1H), 2.50-2.46 (m, 1H), 2.45-2.29 (m, 2H), 2.12-1.99 (m, 1H), 1.95-1.85 (m, 1H), 1.80 -1.53 (m, 3H), 1.13 (d, J=6.7 Hz, 3H). ¹⁹ F NMR (377 MHz, DMSO-d ₆ ) δ = -62.56 (s, 3F). MC: 473 [M+H]+. Optical rotation: [a] _D +10 (with 0.1, MeOH). Chiral purity: 98% de. Chiral SFC/MS analysis was performed on a Chiralpak AD-3 column (150 x 4.6 mm i.d., 3 µm), eluting with 40% ethanol (+0.05% DEA) in CO2, flow rate 2.5 ml/min , at 35°C, with pressure set to 1500 psi. inch. Under these conditions, this peak had a retention time of 4.123 min.

Method B.

Example 11: (1R,3S)-3-(3-{[(5-methyl-1,3-oxazol-2-yl)acetyl]amino}-1H-pyrazol-5-yl)cyclopentyl tert-butylcarbamate

Benzyl-{1-tert-butyl-3-[(1S,3R)-3-hydroxycyclopentyl]-1 I-pyrazol-5-yl}carbamate (intermediate 1.20 g, 56 mmol) and imidazole (5. 71 g, 83.9 mmol) were dissolved in DMF (200 ml) under ultrasonication. While the solution was at room temperature, tert-butyldimethylsilyl chloride (11.0 g, 72.7 mmol) was added portionwise. After addition was complete, the clear solution was stirred at 25°C for 1 hour. The solvents were removed in vacuo and the residue was partitioned between ethyl acetate (500 ml) and sat. aq. NaCl solution (200 ml). The organic layer was dried over sodium sulfate, filtered and concentrated to give crude benzyl-{1-tert-butyl-3[(1S,3R)-3-{[tert-butyl(dimethyl)silyl]oxy}cyclopentyl]-1H-pyrazole -5-yl}carbamate (11A, 26 g, 99%) as a colorless oil. MS: 472 [M+H]+.

Crude benzyl-{1-tert-butyl-3-[(1S,3R)-3-{[tert-butyl(dimethyl)silyl]oxy}cyclopentyl]

- 47 046965

1H-pyrazol-5-yl}carbamate (11A, 26 g, 55 mmol) was dissolved in ethyl acetate (100 ml) and THF (100 ml). Pd/C (50% humidity, 4 g) was added, the solution was degassed and stirred at 25°C under a hydrogen atmosphere from a balloon for 2 hours. The mixture was then filtered and the filtrate was concentrated in vacuo to give crude 1-tert-butyl -3-[( 1S,3R)-3-{ [tert-butyl(dimethyl)silyl]-oxy}cyclopentyl] N-pyrazol-5-amine (11B, 19 g, >99%) as a light yellow oil . MS: 338 [M+H]+.

Into a room temperature (25°C) solution of crude 1-tert-butyl-3-[(1S,3R)-3{[tert-butyl(dimethyl)silyl]oxy}cyclopentyl]-III-pyrazol-5-amine ( 11B, 5.00 g, 14.8 mmol), lithium (5-methyl1,3-oxazol-2-yl) acetate (intermediate 3, 3.14 g, 21.3 mmol) and diisopropylethylamine (5.74 g , 44.4 mmol) in DMF (150 ml) was added 1-[bis(dimethylamino)methylene]-III-1,2,3triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU, 8.45 g, 22.2 mmol). The mixture was heated to 40°C for 1 hour, then diluted with ethyl acetate (300 ml) and washed successively with water (150 ml) and sat. aq. NaCl solution. The organic layer was dried over sodium sulfate, filtered and concentrated. The residue was purified by chromatography on silica gel (eluting with 30% ethyl acetate in petroleum ether) to give N-{1-tert-butyl-3-[(1S,3R)-3-{[tert-butyl(dimethyl)silyl]oxy}cyclopentyl]-III -pyrazol-5-yl}-2-(5-methyl-1,3-oxazol-2-yl)acetamide (11C, 5.5 g, 81%, 77% purity by LC-MS) as yellow oil. MS: 461 [M+H]+.

A solution of N-{1-tert-butyl-3-[( 1S,3R)-3-{[tert-butyl(dimethyl)silyl]oxy}-cyclopentyl]-1Hpyrazol-5-yl}-2-(5-methyl -1,3-oxazol-2-yl)acetamide (PS, 5.5 g, 11.9 mmol) in formic acid (50 ml) was stirred at 25°C for 14 hours. The solution was concentrated to dryness and light yellow the oily residue was dissolved in methanol (20 ml). To this solution was added a solution of lithium hydroxide monohydrate (2.50 g, 59.7 mmol) in water (10 ml), and the mixture was stirred for 30 minutes at 25°C. The solution was concentrated to dryness. The residue was dissolved in dichloromethane (30 ml), washed with water (10 ml) and sat. aq. NaCl solution (10 ml), dried over sodium sulfate, filtered, concentrated and purified by silica gel chromatography (eluting with 3% methanol in dichloromethane) to give N-{1t-butyl-3-[(1S,3R)-3-hydroxycyclopentyl] -1H-pyrazol-5-yl}-2-(5-methyl-1,3-oxazol-2-yl)acetamide (11D, 3.8 g, 92%, 79% purity by LC-MS) in the form of a light yellow oil. MS: 347 [M+H] ⁺ .

A suspension of N-{1-tert-butyl-3-[( 1S,3R)-3-hydroxycyclopentyl]-III-pyrazol-5-yl}-2-(5-methyl-1,3oxazol-2-yl)acetamide ( 11D, 3.8 g, 11 mmol), DMAP (134 mg, 1.10 mmol), pyridine (2.60 g, 32.9 mmol) and 4-nitrophenylchloroformate (4.42 g, 21.9 mmol) in dichloromethane ( 40 ml) and THF (40 ml) were stirred at 25°C for 2 hours. Solvents were removed under vacuum. The residue was dissolved in ethyl acetate (200 ml), washed with sat. aq. NH ₄ Cl solution (100 ml) and sat. aq. NaCl solution, dried over sodium sulfate, filtered, concentrated and purified by chromatography on silica gel (eluting with 50% ethyl acetate in petroleum ether) to give (^^)-3-(1-tert-butyl-5-{[(5-methyl- 1,3-oxazol-2yl)acetyl]amino}-1H-pyrazol-3-yl)cyclopentyl-4-nitrophenylcarbonate (11E, 5.0 g, 89%, 89% purity by LC-MS) as yellow oil. MS: 512 [M+H]+.

Solution of (1R,3S)-3-(1-tert-butyl-5-{ [(5-methyl-1,3-oxazol-2-yl)acetyl]amino }-III-pyrazol-3 yl)cyclopentyl-4 -nitrophenyl carbonate (11E, 5.0 g, 9.8 mmol) in formic acid (30 ml) was stirred at 75°C for 16 hours. The mixture was concentrated to remove most of the formic acid, then the residue was dissolved in dichloromethane (30 ml) and washed with sat. aq. NaHCO ₃ solution (2x15 ml), water (15 ml) and sat. aq. NaCl solution (15 ml). The organic layer was dried over sodium sulfate, filtered, concentrated and purified by chromatography on silica gel (eluting with 80% ethyl acetate in petroleum ether) to give (^^)-3-(3-{[(5-methyl-1,3-oxazole-2 -yl)acetyl]amino}N-pyrazol^-yl^iclopentyl N-nitrophenyl carbonate (11F, 1.7 g, 38%) as a light yellow solid MS: 456 [M+H]+.

A solution of (1R,3S)-3-(3-{[(5-methyl-1,3-oxazol-2-yl)acetyl]amino}-1H-pyrazol-5-yl)cyclopentyl-4nitrophenylcarbonate (11F, 4, 00 g, 8.78 mmol) and tert-butylamine (6.42 g, 87.8 mmol) in THF (30 ml) were stirred at 25°C for 1 hour. The mixture was concentrated to dryness, the residue was dissolved in dichloromethane (80 ml ), washed with 1M NaOH (2x20 ml) and sat. aq. NaCl solution (20 ml), dried over sodium sulfate, filtered, concentrated and purified by chromatography on silica gel (eluting with 3% methanol in dichloromethane) to give contaminated (^^)-3-(3-{[(5-methyl-1 ,3-oxazol-2ylDcetylPminoGSH-pyrazol^-yl^iclopentyl-tert-butylcarbamate (example 11, 2.3 g, 67%, 73% pure by HPLC) Second batch (^^)-3-(3). -{[(5-methyl-1,3-oxazol-2-yl)acetyl]amino}N-pyrazol^-yl^iclopentyl N-nitrophenyl carbonate (11F, 1.50 g, 3.29 mmol) was dissolved in tert-butylamine (10 ml) and stirred at 40°C for 1 hour. This reaction mixture was concentrated to dryness and the crude product thus obtained was combined with 2.3 g of contaminated product from the first batch above (a total of 12.08 mmol 11F was consumed in both batches) and further purified by preparative HPLC on a Phenomenex Gemimi C18 250x50 mm, 10 µm column, eluting with a mixture of 3-45% water (+0.05% NH4OH) in ACN Pure (^^)-3-(3-{. [(5-methyl-1,3oxazol-2-yl)acetyl]amino}-1H-pyrazol-5-yl)cyclopentyl-tert-butylcarbamate (Example 11, 2.23 g, 47% for combined batches) was prepared in as a white solid.

- 48 046965

1I NMR (400 MHz, DMSO-d ₆ ) δ=12.10 (s, 1H), 10.62 (s, 1H), 6.87-6.63 (m, 2H), 6.29 (d, J=1.8 Hz, 1H), 4.96 (br s, 1H), 3.79 (s, 2H), 3.03 (quin, J=8.6 Hz, 1I), 2.48-2.40 (m, 1H), 2.25 (d, J=1.1 Hz, 3H ), 2.04-1.94 (m, 1H), 1.92-1.80 (m, 1H), 1.75-1.63 (m, 2H), 1.55 (br s, 1H), 1.19 (s, 9H). MC: 390 [M+H]+. Optical rotation [a]D+3.5 (with 0.8, MeOH). Chiral purity: 98% according to chiral analytical SFC.

Example 12: (1R,3S)-3-(3-{[(3 -methyl-1,2-oxazol-5-yl)acetyl] amino }-1 I-pyrazol-5 -yl)cyclopentyl2,2-dimethylazetidine -1-carboxylate

Propylphosphonic anhydride (T3P®, 50 wt.% solution in EtOAc, 4.41 g, 6.93 mmol) was added to a cooled (0°C) solution of 1-tert-butyl-3-[(1 S,3R)-3 -{[tert-butyl(dimethyl)silyl]oxy}cyclonentyl]1I-pyrazol-5-amine (11B, 780 mg, 2.31 mmol), 3-methyl-5-isoxazoleacetic acid (CAS# 19668-85-0 , 489 mg, 3.47 mmol) and diisopropylethylamine (1.23 ml, 6.93 mmol) in dichloromethane (10 ml). The mixture was stirred at 30°C for 1 hour, then partitioned between dichloromethane and semisaturated Na ₂ CO ₃ solution. The organic layer was washed with sat. aq. NaCl solution, dried over sodium sulfate, filtered, concentrated and purified by chromatography on silica gel (eluting with 10-50% ethyl acetate in petroleum ether) to give N-{1-tert-butyl-3-[(1S,3R)-3-{ [tert-butyl(dimethyl)silyl]oxy}cyclopentyl]-1I-pyrazol-5-yl}-2-(3-methyl-1,2-oxazol-5-yl)acetamide (12A, 1.1 g) in in the form of a colorless oil. MS: 461 [M+I] ⁺ .

A solution of N-{1-tert-butyl-3-[(1S,3R)-3-{[tert-butyl(dimethyl)silyl]oxy}-cyclopentyl]-1Ipyrazol-5-yl}-2-(3-methyl -1,2-oxazol-5-yl)acetamide (12A, 1.1 g) in formic acid (15 ml) was stirred at 45°C for 1 hour, then left to stand at room temperature overnight. The mixture was concentrated to dryness, the residue was dissolved in methanol (30 ml) and aqueous NH4OH (10 ml), and the solution was stirred at 20°C for 1 hour. The mixture was concentrated and purified by silica gel chromatography (eluting with 1/10 methanol/dichloromethane) with by preparing N-{1-tert-butyl-3-[(1S,3R)-3hydroxycyclopentyl]-1I-pyrazol-5-yl}-2-(3-methyl-1,2-oxazol-5-yl)acetamide ( 12B, 1.0 g) as a light yellow oil. MS: 347 [M+I] ⁺ .

A solution of N-{1-tert-butyl-3-[(1S,3R)-3-hydroxycyclopentyl]-1I-pyrazol-5-yl}-2-(3-methyl-1,2oxazol-5-yl)acetamide ( 12B, 1.0 g) in dichloromethane (30 ml) and THF (30 ml) was treated with DMAP (70.5 mg, 0.577 mmol), pyridine (1.14 g, 14.4 mmol) and 4-nitrophenylchloroformate (1, 16 g, 5.77 mmol). The resulting suspension was stirred at 20°C for 12 hours. The solvents were removed under vacuum, the residue was dissolved in dichloromethane (30 ml), and the solution was washed successively with sat. aq. NH4C1 solution (15 ml) and sat. aq. NaCl solution (15 ml). The organic layer was dried, concentrated and purified by silica gel chromatography (eluting with 50% ethyl acetate in petroleum ether) to give (1R,3S)-3-(1-tert-butyl-5-{[(3-methyl-1,2-oxazole -5-yl)acetyl]amino}-1 I-pyrazol-3-yl)cyclopentyl4-nitrophenyl carbonate (12C, 1.3 g). MS: 512 [M+H] ⁺ .

Solution of (1R,3S)-3-(1-tert-butyl-5 - {[(3 -methyl-1,2-oxazol-5-yl)acetyl] amino }-1 I-pyrazol-3 yl)cyclopentyl- 4-nitrophenylcarbonate (12C, 1.3 g) in formic acid (20 ml) was heated at 75°C for 16 hours. Most of the formic acid was removed under vacuum, the residue was dissolved in dichloromethane (30 ml), and the solution was washed successively with sat. . aq. NaHCO ₃ solution (2x15 ml), water (15 ml) and sat. aq. NaCl solution (15 ml). The organic layer was dried over sodium sulfate, filtered, concentrated and purified by silica gel chromatography (eluting with 80% ethyl acetate in petroleum ether) to give (^^)-3-(3-{[(3-methyl-1,2-oxazole-5 -yl)acetyl]amino}-1I-pyrazol-5yl)cyclopentyl-4-nitrophenyl carbonate (12D, 850 mg, 81% in 5 steps based on 11B) as a white solid. MS: 456 [M+H] ⁺ .

Solution of (1R,3S)-3-(3-{[(3 -methyl-1,2-oxazol-5 -yl)acetyl]amino }-1 I-pyrazol-5-yl)cyclopentyl-4

- 49 046965 nitrophenyl carbonate (12D, 60 mg, 0.13 mmol), 2,2-dimethylazetidine (CAS# 1086266-55-8, 13.5 mg, 0.158 mmol) and diisopropylethylamine (102 mg, 0.79 mmol) in dichloromethane (1 ml) and 2-methyltetrahydrofuran (1 ml) were stirred at 15°C for 1 hour, then concentrated, and the residue was purified by preparative HPLC (on an Xbridge 150x30 mmx10 μm column, eluting with a mixture of 17-57% water (0.05 % ammonium hydroxide v/v) in acetonitrile). After lyophilization, (^^)-3-(3-{[(3-methyl-1,2-oxazol-5yl)acetyl]amino}-III-pyrazol-5-yl)cyclopentyl-2,2-dimethylazetidin-1- carboxylate (Example 12, 28.21 mg, 53%) was obtained as a white solid. MS: 402 [M+H]+.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ=12.13 (br d, J=8.2 Hz, 1H), 10.62 (br s, 1H), 6.29 (s, 1H), 6.21 (s, 1H) , 5.03-4.91 (m, 1H), 3.82 (s, 2H), 3.71 (br t, J=8.4 Hz, 1H), 3.64 (t, J=7.5 Hz, 1H), 3.12-3.01 ( m, 1H), 2.41 (dt, J=6.7, 15.5 Hz, 1H), 2.19 (s, 3H), 2.04-1.97 (m, 1H), 1.96-1.89 (m, 2H), 1.87-1.79 ( m, 1H), 1.77-1.57 (m, 3H), 1.37-1.27 (m, 6H). Chiral purity: 99% ee based on chiral analytical SFC.

Example 13: (^^)-3-[3-({[3-(methoxymethyl)-1-methyl-III-pyrazol-5-yl]-carbonyl}amino)-Spirazol-5-yl]cyclopentyl-propan- 2-ylcarbamate

Propylphosphonic anhydride (T3P®, 50 wt.% solution in EtOAc, 50.3 g, 79.1 mmol) was added to a room temperature (26°C) solution of 1-tert-butyl-3-[(1S,3R)- 3-{[tert-butyl(dimethyl)silyl]oxy}cyclopentyl]-III-pyrazol-5-amine (11B, 8.90 g, 26.4 mmol), 3(methoxymethyl-N-pyrazole^-lithium carboxylate (intermediate 5, 5.83 g, 34.3 mmol) and diisopropylethylamine (10.2 g, 79.1 mmol) in 2-methyltetrahydrofuran (100.0 ml). The resulting mixture was stirred at this temperature for 18 hours. After concentrating the mixture. the residue was dissolved in dichloromethane (150 ml), and the solution was washed successively with water (2x30 ml), saturated aq. NaHCO ₃ solution (2x30 ml) and saturated aq. NaCl solution (30 ml). filtered and concentrated to give crude Np-tert-butyl-3-[(1S,3R)-3-{[tert-butyl (dimethyl)silyl]oxy}cyclopentyl]-III-pyrazol-5-yl}-3(methoxymethyl)- 1-methyl-III-pyrazole-5-carboxamide (13A, 12.9 g, 100%) as oil MS: 490 [M+H] ⁺ .

Crude N-{1-tert-butyl-3-[(1S,3R)-3-{[tert-butyl(dimethyl)silyl]-oxy}cyclopentyl]-1Hpyrazol-5-yl}-3-(methoxymethyl)- 1-Methyl-III-pyrazole-5-carboxamide (13A, 12.9 g, 26.3 mmol) was dissolved in formic acid (80 ml) and stirred at room temperature (27°C) for 30 minutes. The mixture was concentrated to dryness and the residue was dissolved in methanol (80 ml). A solution of lithium hydroxide monohydrate (3.43 g, 81.8 mmol) in water (15 ml) was added and the mixture was stirred at room temperature (27°C) for 1 hour. The mixture was concentrated to dryness and the residue was purified by silica gel chromatography ( eluting with 0-80% ethyl acetate in petroleum ether) to give N-{1-tert-butyl-3-[(1S,3R)-3hydroxycyclopentyl]-III-pyrazol-5-yl}-3-(methoxymethyl)-1- Methyl-III-pyrazole-5-carboxamide (13B, 8.0 g, 78%) as a yellow gum. MS: 376 [M+H] ⁺ .

A solution of N-{1-tert-butyl-3-[(1S,3R)-3-hydroxycyclopentyl]-1H-pyrazol-5-yl}-3-(methoxymethyl)1-methyl-III-pyrazol-5-carboxamide ( 13B, 8.0 g, 21 mmol) in dichloromethane (80 ml) and THF (80 ml) was treated with DMAP (260 mg, 2.13 mmol), pyridine (5.06 g, 63.9 mmol) and 4-nitrophenylchloroformate (8.59 g, 42.6 mmol). The resulting yellow suspension was stirred at room temperature for 18 hours. The reaction mixture was concentrated to dryness and purified by chromatography on silica gel (eluting with 045% ethyl acetate in petroleum ether) to give (1R,3S)-3-[1-tert-butyl-5-( {[3-(methoxymethyl)-1methyl-III-pyrazol-5-yl]carbonyl}amino)-III-pyrazol-3-yl]cyclopentyl-4-nitrophenylcarbonate (13C, 10.6 g, 92%) as light -brown resin. MS: 541 [M+H] ⁺ .

- 50 046965

Solution ]carboni.1} amino)1H-pyrazol-3-yl]cyclopentyl-4-nitrophenyl carbonate (13C, 10.6 g, 19.6 mmol) in formic acid (80 ml) was stirred at 70°C for 18 hours. The solution was concentrated to dryness. The residue was dissolved in dichloromethane (150 ml) and the solution was neutralized with sat. aq. NaHCO ₃ solution. The organic layer was washed with water (30 ml) and sat. aq. NaCl solution (30 ml), dried over sodium carbonate, filtered and concentrated to give crude (1R,3S)-3-[3-({[3-(methoxymethyl)-1-methyl-1Hpyrazol-5-yl]carbonyl} amino)-1H-pyrazol-5-yl]cyclopentyl-4-nitrophenyl carbonate (13D, 8.5 g, 90%, 86% purity by LC-MS) as a light yellow glass. MS: 485 [M+H]+.

A room temperature (27°C) solution of crude (1R,3S)-3-[3-({[3-(methoxymethyl)1 -methyl-1I Ι-ιshrazo.ι-5-i.ι]carbonyl}amino) -1I Ι-ιshrazo.ι-5-i.ι]cyclopentyl-4-nitrophenyl carbonate (13D, 1.7 g, 3.5 mmol) and 2-propylamine (1.04 g, 17.5 mmol) in THF ( 30 ml) was stirred for 6 hours. The solution was concentrated to dryness and the residue was combined with that from the second batch, which was obtained from 1.7 g, 3.5 mmol 13D (a total of 6.27 mmol 13D was consumed for the two batches combined ) to obtain 3.2 g of crude product. This product was purified by preparative HPLC on a Phenomenex Gemini C18 250 x 50 mm x 10 µm column, eluting with a mixture of 15-45% water (0.05% v/v ammonium hydroxide) in acetonitrile. After lyophilization, (^^)-3-[3-({[3-(methoxymethyl)-1-methyl-1H-pyrazol-5yl]carbonyl}amino)-1H-pyrazol-5-yl]cyclopentyl-propane-2- ylcarbamate (Example 13, 2.06 g, 78%) was obtained as a white crystalline solid, which was determined by elemental analysis to be the monohydrate (Form 1). MS: 405 [M+H] ⁺ .

¹ H NMR (400 MHz, DMSO-d6) δ=12.23 (br s, 1H), 10.73 (br s, 1H), 7.11 (s, 1H), 6.96 (br d, J=7.0 Hz, 1H) , 6.41 (br s, 1H), 5.00 (br s, 1H), 4.33 (s, 2H), 4.04 (s, 3H), 3.57 (qd, J=6.6, 13.4 Hz, 1H), 3.26 (s , 3H), 3.172.96 (m, 1H), 2.48-2.39 (m, 1H), 2.03 (br d, J=6.8 Hz, 1H), 1.95-1.83 (m, 1H), 1.73 (br d , J=8.5 Hz, 2H), 1.61 (br s, 1H), 1.03 (br d, J=6.3 Hz, 6H). Optical rotation [a] _D +4.8 (with 1.0, MeOH). Chiral purity: >99% ee based on chiral analytical SFC. Analysis: Calculated for Ci ₉ H ₂₈ N ₆ O ₄ -H ₂ O: C, 54.02; H, 7.16; N, 19.89. Found: C, 53.94; H, 7.22; N, 19.81. The above white crystalline solid (500 mg) was recrystallized from 9:1 H ₂ O/CH ₃ CN (2 ml) by heating until dissolved and then allowing the resulting solution to stand at room temperature for 18 hours. During this period, larger monohydrate crystals formed (form 1). Single crystal X-ray diffraction of a selected crystal of this substance gave the structure in FIG. 1.

The crystalline solid obtained above as the monohydrate (Form 1) was further characterized by powder x-ray diffraction (XRD).

Devices for X-ray diffraction by powder.

X-ray powder diffraction analysis was carried out using a Bruker AXS D8 Advance diffractometer equipped with a Cu radiation source. Diffracted radiation was detected using a LYNXEYE_EX detector with motorized slits. Both primary and secondary are equipped with 2.5 Soller slits. The X-ray tube voltage and current were set to 40 kV and 40 mA, respectively. Data were collected in a Theta-Theta goniometer with a closed coupled scan at Cu K-alpha wavelengths from 3.0 to 40.0° 2-Theta in 0.01° steps using a scan speed of 1.0 s per step. Samples were prepared by placing them in a silicon low-background sample holder. Data were collected and analyzed using Bruker DIFFRAC Plus software. The XRD data file was not processed before searching for peaks. The peak finding algorithm in EVA software was used to make preliminary peak assignments using a threshold value of 1. To ensure reliability, adjustments were made manually; The results of automated correlations were visually inspected, and peak positions were adjusted to peak maximum. Typically, peaks with relative intensities >3% were selected. Peaks that were not resolved or inconsistent with noise were not selected. Typical USP (United States Pharmacopoeia) peak position uncertainty is up to +/-0.2° 2-Theta (USP941).

The DRLP pattern of the compound of Example 13, Form 1 monohydrate, is shown in FIG. 2. A list of DRLP peaks and relative intensity data for the compound of example 13, form 1 monohydrate, (2Theta °) are presented in table. 1 below.

Table 1

Angle (2-theta°) Relative Angle (2 theta°) Relative

- 51 046965

±0.2°2θ intensity (%) ±0.2°2θ intensity (%) 3.9 19.5% 25.0 25.9% 9.1 18.3% 25.7 8.3% 10.4 96.5% 26.0 10.1% 11.7 64.3% 26.3 15.1% 12.9 41.4% 26.6 8.4% 16.0 15.5% 27.0 5.0% 18.2 100.0% 27.6 21.3% 18.6 14.4% 28.2 31.7% 19.4 38.1% 28.9 5.2% 19.6 20.3% 30.4 6.8% 20.0 10.5% 31.1 7.8% 20.3 20.6% 31.5 9.9% 20.6 43.0% 33.9 11.6% 20.8 26.1% 35.1 3.3% 21.0 23.7% 35.8 3.0% 22.2 20.6% 36.6 7.1% 22.7 3.4% 37.6 3.9% 23.5 22.9% 38.3 5.2% 24.2 64.0%

Example 14: (1R,3S)-3-[3-({ [3-(methoxymethyl)-1 -methyl-1 H-pyrazol-5-yl]-carbonyl } amino)-1Hpyrazol-5-yl]cyclopentyl -(2S)-butan-2-ylcarbamate

A solution of crude (1R,3S)-3-[3-({[3 -(methoxymethyl)-1 -methyl-1 H-pyrazol-5yl]carbonyl}amino)-1H-pyrazol-5-yl]cyclopentyl-4- nitrophenyl carbonate (13D, 5.5 g, 11 mmol), (S)(+)-sec-butylamine (1.49 g, 13.6 mmol) and diisopropylethylamine (4.40 g, 34.1 mmol) in THF ( 100 ml) was stirred at room temperature (30°C) for 18 hours. The reaction mixture was concentrated to dryness, and the residue was purified by preparative HPLC on a Phenomenex Gemini C18 250x50 mmx10 μm column, eluting with a mixture of 25-45% water (0.05% ammonium hydroxide v/v) in acetonitrile to give (1R,3S)-3-[3-({[3-(methoxymethyl)-1-methyl-1H-pyrazol-5-yl]carbonyl}-amino)-1H -pyrazol-5yl]cyclopentyl-(2S)-butan-2-ylcarbamate (Example 14, 3.50 g, 74%) as a light yellow solid. MS: 419 [M+H] ⁺ .

1H NMR (400 MHz, DMSO-d ₆ ) δ=12.23 (br s, 1H), 10.72 (s, 1H), 7.11 (s, 1H), 6.90 (br d, J=8.2 Hz, 1H), 6.42 (br s, 1H), 5.00 (br s, 1H), 4.33 (s, 2H), 4.04 (s, 3H), 3.43-3.37 (m, 1H), 3.26 (s, 3H), 3.14-2.98 ( m, 1H), 2.45 (br s, 1H), 2.08-1.97 (m, 1H), 1.95-1.82 (m, 1H), 1.80-1.68 (m, 2H), 1.67-1.52 (m, 1H), 1.42 -1.26 (m, 2h), 1.00 (d, J=6.5 Hz, 3H), 0.80 (t, J=7.4 Hz, 3H). Optical rotation [a] _D +16.6 (c 2.05, MeOH). Chiral purity: >99% ee based on chiral analytical SFC.

- 52 046965

Example 15: (1R,3S)-3-(3-{[(3 -methyl-1,2-oxazol-5-yl)acetyl] amino }-1 H-pyrazol-5 -yl)cyclopentyl(1-methylcyclopropyl) )carbamate

Example 15

Solution of (1R,3S)-3-(1 -tert-butyl-5 - {[(3 -methyl-1,2-oxazol-5-yl)acetyl] amino }-1 H-pyrazol-3 yl)cyclopentyl- 4-nitrophenylcarbonate (12C, 1.64 g, 3.2 mmol) in DMF (10.7 ml) was treated with 1methylcyclopropan-1-amine hydrochloride (516 mg, 4.8 mmol) and diisopropylethylamine (1.7 ml, 9. 6 mmol). The mixture was stirred under nitrogen for 2 hours at 60°C, then at room temperature overnight. After dilution with ethyl acetate (150 ml), the solution was washed with deionized water (20 ml), 2M aq. Na ₂ CO ₃ solution (20 ml) and sat. aq. NaCl solution (20 ml). The combined aqueous layers were re-extracted with ethyl acetate (30 ml). The combined organic extracts were dried over sodium sulfate, filtered, concentrated and purified by silica gel chromatography (eluting with 0100% ethyl acetate in heptane) to give (^^)-3-(1-tert-butyl-5-{[(3-methyl-1 ,2-oxazol-5yl)acetyl]amino}-III-pyrazol-3-yl)cyclopentyl-(1-methylcyclopropyl)carbamate (15A, 1.58 g, 82%) as an oil.

Solution of (1R,3S)-3-(1-tert-butyl-5 - {[(3 -methyl-1,2-oxazol-5-yl)acetyl] amino }-1 ^pyrazol^ yl)cyclopentyl-(1 α-methylcyclopropyl)carbamate (15A, 1.50 g, 3.4 mmol) in formic acid (10 ml) was heated in an oil bath at 100°C for 1 hour. Most of the formic acid was removed under vacuum. The residue was treated with sat. aq. NaHCO ₃ solution (30 ml), then extracted with ethyl acetate (150 ml, then 50 ml). The combined organic phases were dried over magnesium sulfate, filtered, concentrated and purified by chromatography on silica gel (eluting with 0-40% isopropanol in heptane) to give a white solid (960 mg). This solid was dissolved in acetonitrile (20 ml) and water (10 ml), and the solution was lyophilized overnight to give a white solid (796 mg). The lyophilized material was suspended in ethyl acetate (28 ml), stirred in an oil bath at 60°C for 1 hour and allowed to cool to room temperature with stirring for a further 3 hours. The solid was collected by filtration and dried (50°C, 10 mmHg . art.) to obtain (1R,3S)-3 -(3 -{[(3 -methyl-1,2-oxazol-5-yl)acetyl] amino }-1 H-pyrazol-5-yl)cyclopentyl- (1 methylcyclopropyl)carbamate (Example 15, 565 mg, 41%) as a white solid. MS: 388 [M+H]+.

¹ H NMR (400 MHz, DMSO-d6) δ=12.10 (br s, 1H), 10.61 (s, 1H), 7.34 (br s, 1H), 6.28 (br s, 1H), 6.21 (s, 1H) , 4.97 (br s, 1H), 3.82 (s, 2H), 3.14-2.94 (m, 1H), 2.48-2.39 (m, 1H), 2.20 (s, 3H), 1.99 (s, 1H), 1.93- 1.80 (m, 1H), 1.78-1.60 (m, 2H), 1.54 (br s, 1H), 1.22 (s, 3H), 0.58 (br s, 2H), 0.49-0.42 (m, 2H). Optical rotation [a] _D +10.0° (with 0.2, MeOH).

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Method C.

Example 16: (1R,3S)-3-{3-[(1,2-oxazol-5-ylacetyl)amino]-1I-pyrazol-5-yl}-cyclopentyl-(2S)butan-2-ylcarbamate

Triethylamine (4.7 mL, 33.4 mmol) was added to a suspension of benzyl-{1-tert-butyl-3-[(^,3K)-3hydroxycyclopentyl]-1H-pyrazol-5-yl}carbamate (intermediate 1, 5.97 g, 16.7 mmol) in anhydrous acetonitrile (50 ml). The solution was cooled to 0°C, then N,N'disuccinimidyl carbonate (8.56 g, 33.4 mmol) was added. After stirring at 0°C for 10 min, the cooling bath was removed and the mixture was stirred at room temperature (23°C) for 24 h. LCMS indicated the presence of unreacted starting alcohol, so additional N,N'-disuccinimidyl carbonate (2.36) was added g; total 10.92 g, 42.63 mmol) and triethylamine (2.8 ml; total 7.5 ml, 54 mmol), and stirring was continued at room temperature for another 5 hours. Solvents were removed in vacuo. and the residue was diluted with ethyl acetate (150 ml) and deionized water (100 ml). The resulting emulsion was filtered under vacuum to remove the white solid. The filtrate layers were separated. The filter cake was washed with ethyl acetate (2x100 ml) and the washing liquids were used to further extract the aqueous layer. The combined organic extracts were dried over magnesium sulfate, filtered and concentrated. The residue was purified by chromatography on silica gel (eluting with 20-70% ethyl acetate in heptane) to give benzyl-{1-tert-butyl-3-[(^,3K)-3({[(2,5-dioxopyrrolidin-1-yl) oxy]carbonyl}oxy)cyclopentyl]-III-pyrazol-5-yl}carbamate (16A, 4.5 g, 54%) as a solid.

1I NMR (400 MHz, chloroform-d) δ=7.42-7.34 (m, 5H), 6.24 (br. s., 1H), 6.13 (br. s., 1H), 5.30-5.22 (m, 1H), 5.20 (s, 2H), 3.21-3.12 (m, 1H), 2.82 (s, 4H), 2.57 (ddd, J=6.7, 8.4, 14.8 Hz, 1H), 2.15-2.05 (m, 2H), 2.041.87 (m, 3H), 1.59 (s, 9H). MS: 499 [M+H]+.

A solution of benzyl-{1-tert-butyl-3-[(1S,3R)-3-({[(2,5-dioxopyrrolidin-1-yl)oxy]carbonyl}oxy)cyclopentyl]-1I-pyrazol-5- yl}carbamate (16A, 3.5 g, 7.0 mmol) and 10% Pd/C (1.2 g) in ethyl acetate (150 ml) were stirred under a hydrogen atmosphere from a balloon at room temperature (23°C) for nights. The mixture was filtered through a pad of celite, the filter bed was washed with ethyl acetate (3x30 ml), and the combined filtrates were concentrated to give crude l-[({[(1R,3S)3-(5-amino-1-tert-butyl-1-pyrazole -3-yl)cyclopentyl]oxy}carbonyl)oxy]-pyrrolidine-2,5-dione (16B), which was immediately used in the next step. MS: 365 [M+I] ⁺ .

Crude 1-[({[(1R,3S)-3-(5-amino-1-tert-butyl-1I-pyrazol-3-yl)cyclopentyl]oxy}carbonyl)oxy]pyrrolidine-2,5-dione (16B, 7.0 mmol maximum) was dissolved in DMF (20 ml), 1,2-oxazol-5-ylacetic acid (CAS# 4992-21-6, 1.4 g, 11 mmol) and propylphosphonic anhydride (T3P) were added ®, 11 ml of a 50 wt.% solution in EtOAc, 14 mmol), and the solution was cooled to 0°C under nitrogen. Triethylamine (3.5 mL, 25 mmol) was added dropwise over 10 minutes, slowly enough to maintain the internal temperature below 20°C. The cooling bath was removed and the mixture was stirred at room temperature for 1 hour. The reaction mixture was quenched with sat. aq. NaHCO ₃ solution and extracted with ethyl acetate (3x). The combined organic layers were washed with sat. aq. NaHCO ₃ solution (2x) and sat. aq. NaCl solution (1x), dried over magnesium sulfate, filtered, concentrated and purified by chromatography on silica gel (eluting with 30-100% ethyl acetate

- 54 046965 volume in heptane) to obtain N-(1-tert-butyl-3-{(1S,3R)-3-[(2,5-dioxopyrrolidin-1yl)oxy]cyclopentyl}-1H-pyrazol-5- yl)-2-(1,2-oxazol-5-yl)acetamide (16C, 2.46 g, 74%) as a white foam.

Ή NMR (400 MHz, METHANOL^) δ=8.35 (d, J=1.7 Hz, 1H), 6.42-6.37 (m, 1H), 6.05 (s, 1H), 5.33-5.23 (m, 1H), 3.98 (s, 2H), 3.16 (td, J=8.8, 17.2 Hz, 1H), 2.82 (s, 4H), 2.63-2.51 (m, 1H), 2.16-2.02 (m, 3H), 2.001. 80 (m, 3H), 1.56 (s, 9H). MS: 474 [M+H]+.

A solution of N-(1-tert-butyl-3-{(1S,3R)-3-[(2,5-dioxopyrrolidin-1-yl)oxy]-cyclopentyl}-1Ipyrazol-5-yl)-2-(1 ,2-oxazol-5-yl)acetamide (16C, 158 mg, 0.334 mmol), diisopropylethylamine (0.15 ml, 0.91 mmol) and ^)-(+)-sec-butylamine (50 μl, 0.50 mmol) in dichloromethane (3.5 ml) was stirred at 20°C for 3 hours. The reaction mixture was diluted with dichloromethane (10 ml) and washed with sat. aq. NaHCO ₃ solution (2x3 ml), deionized water (3 ml), sat. aq. NH4Cl solution (3 ml) and sat. aq. NaCl solution (3 ml). The organic layer was dried over magnesium sulfate, filtered and concentrated to dryness to give crude ('1K^)-3-[1-tert-butyl-5-[('1,2-oxazol-5ylacetyl)amino]-1H-pyrazol-3 -yl}cyclopentyl-(2S)-butan-2-ylcarbamate (16D, 115.0 mg, 80%) as a yellow gel.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ=9.79 (s, 1H), 8.50 (d, J=1.7 Hz, 1H), 6.85 (d, J=8.1 Hz, 1H), 6.40 (d, J=1.6 Hz, 1H), 5.93 (s, 1H), 4.97 (br. s., 1H), 3.95 (s, 2H), 3.43-3.33 (m, 1H), 2.95 (quin, J=8.5 Hz, 1H), 2.402.31 (m, 1H), 1.99-1.77 (m, 2H), 1.76-1.57 (m, 3H), 1.47 (s, 9H), 1.39-1.30 (m, 2H), 1.00 (d, J=6.6 Hz, 3H), 0.79 (t, J=7.4 Hz, 3H). MS: 432 [M+H]+.

Crude (1R,3S)-3-{1-tert-butyl-5-[(1,2-oxazol-5-ylacetyl)amino]-1 I-pyrazol-3 yl}cyclopentyl-(2S)-butane-2 β-ylcarbamate (16D, 115.0 mg, 0.2665 mmol) was dissolved in formic acid (6.0 ml) and triethylsilane (1.5 ml) and stirred at 70°C for 18 hours. The layers of the resulting biphasic mixture were separated. The upper triethylsilane layer was discarded. The lower acid layer was concentrated to dryness, dissolved in acetonitrile and concentrated again to dryness. The residue was dried further under vacuum to obtain the crude product as a waxy brown solid (109.9 mg). Acetonitrile (5 ml) was added and the suspension was stirred at room temperature for 1 hour. The resulting precipitate was collected by suction filtration and air-dried to give (^^)-3-{3-[(1,2-oxazol-5- ylacetyl)amino]-1I-pyrazol-5-yl}-cyclopentyl^)-butan-2-ylcarbamate (Example 16, 42.1 mg, 42%) as an off-white solid.

¹ I NMR (400 MHz, DMSO-d ₆ ) 5=12.11 (br. s., 1I), 10.65 (s, 1I), 8.48 (d, J=1.7 Hz, 1I), 6.87 (d, J =8.1 Hz, 1I), 6.37 (d, J=1.5 Hz, 1I), 6.29 (br. s., 1I), 4.98 (br. s., 1I), 3.91 (s, 2I), 3.43-3.33 (m, 1I), 3.11-2.97 (m, 1I), 2.48-2.38 (m, 1I), 2.05-1.94 (m, 1I), 1.94-1.81 (m, 1I), 1.78-1.62 (m , 2I), 1.61-1.50 (m, 1I), 1.41-1.27 (m, 2I), 0.99 (d, J=6.6 Hz, 3I), 0.79 (t, J=7.4 Hz, 3I). MS: 376 [M+H] ⁺ .

Method D

Example 17: (1R,3S)-3-{3-[(1,2-oxazol-3-ylacetyl)amino]-1I-pyrazol-5-yl}-cyclopentyl-tert-butylcarbamate

Solution of (^^)-3-(5-{[(benzyloxy)carbonyl]amino}-1-tert-butyl-1I-pyrazol-3-yl)cyclopentyl4-nitrophenylcarbonate (1A, 5.00 g, 9.57 mmol ) in formic acid (30 ml) was stirred at 75°C for 20 hours. The mixture was concentrated to dryness and the residue was purified by chromatography on silica gel (eluting with 50-70% ethyl acetate in petroleum ether) to give (1R,3S)-3-( 5{[(benzyloxy)carbonyl]amino}-1I-pyrazol-3-yl)cyclopentyl-4-nitrophenyl carbonate (17A, 3.6 g, 81%, 82% purity by LC-MS) as light yellow solid. MS: 467 [M+I]+.

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Mixture of (^^)-3-(5-{[(benzyloxy)carbonyl]amino}-III-pyrazol-3-yl)-cyclopentyl-4nitrophenyl carbonate (17A, 2.2 g, 4.7 mmol) and tert-butylamine (1.38 g, 18.9 mmol) in THF (40 ml) was stirred at room temperature (29°C) for 18 hours. Solvents were removed in vacuo and the residue was purified by chromatography on silica gel (eluting with 0-90% ethyl acetate in petroleum ether) to give benzyl-(3-{(1S,3R)-3-[(tert-butylcarbamoyl)oxy]cyclopentyl}-1H-pyrazol-5-yl)carbamate (17B, 1.5 g, 79%) in the form of light yellow glass. MS: 401 [M+H]+.

Ethyl chloroformate (970 mg, 8.94 mmol) was added in portions to a room temperature (29°C) solution of benzyl-(3-{(^^)-3-[(tert-butylcarbamoyl)oxy]cyclopentyl}-III-pyrazol- 5yl)carbamate (17B, 1.50 g, 3.75 mmol) and diisopropylethylamine (1.45 g, 11.2 mmol) in dichloromethane (30 ml), then the mixture was stirred at room temperature for 18 hours. The solution was washed with sat. . aq. NH4Cl solution (3x5 ml) and sat. aq. NaCl solution (5 ml), dried over sodium sulfate, filtered and concentrated to give crude ethyl 5-{[(benzyloxy)carbonyl]amino}-3{(1S,3R)-3-[(tert-butylcarbamoyl)oxy] cyclopentyl}-1H-pyrazole-1-carboxylate (17C, 2.0 g, >99%) as a light yellow resin, which was used without further purification. MS: 473 [M+H]+.

Crude ethyl-5-{[(benzyloxy)carbonyl]amino}-3-{(1S,3R)-3-[(tert-butylcarbamoyl^xyl-cyclopentyl^-pyrazole-bcarboxylate (17C, 2.0 g, 4.2 mmol, if pure) was dissolved in ethyl acetate (15 ml) and THF (15 ml), 10% Pd/C catalyst (200 mg) was added, degassed and stirred under a hydrogen atmosphere from a cylinder at room temperature (29°C) for 1. .5 hours. The suspension was filtered to remove the catalyst, the filtrate was concentrated to dryness, and the residue was purified by chromatography on silica gel (eluting with 0-100% ethyl acetate in petroleum ether, then 0-30% ethyl acetate in dichloromethane) to give ethyl-5-amino-3- {(1S,3R)-3-[(tert-butylcarbamoyl^xi^iclopentylGH-pyrazole-Hcarboxylate (17D, 900 mg, 63%, 56% from 17A) as a light yellow resin. MS: 339 [M+H]+ .

Solution of ethyl 5-amino-3-{( 1 S,3R)-3-[(tert-butylcarbamoyl)oxy]cyclopentylHS-pyrazole-1 carboxylate (17D, 250 mg, 0.739 mmol), diisopropylethylamine (286 mg, 2. 22 mmol) and 1,2-oxazol-3ylacetic acid (CAS# 57612-86-9, 113 mg, 0.887 mmol) in dichloromethane (10 ml) at room temperature (29°C) were treated with propylphosphonic anhydride (T3P®, 50 wt % solution in EtOAc, 1.41 g, 2.22 mmol), then stirred at room temperature for 6 hours. The solution was diluted with dichloromethane (10 ml), then washed with water (5 ml), sat. aq. NaHCO ₃ solution (2x5 ml), sat. aq. NH4Cl solution (5 ml) and sat. aq. NaCl solution (5 ml). The organic layer was dried over sodium sulfate, filtered and concentrated to give crude ethyl 3-{(1S,3R)-3-[(tert-butylcarbamoyl)oxy]cyclopentyl}-5-[(1,2-oxazol-3-ylacetyl)amino ]-1H-pyrazole-1-carboxylate (17E, 331 mg, 100%) as a brown gum. MS: 448 [M+H]+.

This crude ethyl-3-{(1S,3R)-3-[(tert-butylcarbamoyl)oxy]-cyclopentyl}-5-[(1,2-oxazol-3ylacetyl)amino]-III-pyrazole-1- carboxylate (17E, 331 mg, 0.739 mmol) was dissolved in methanol (5 ml), a solution of lithium hydroxide monohydrate (93.1 mg, 2.22 mmol) in water (1 ml) was added and the mixture was stirred at room temperature (30° C) for 1 hour. The mixture was left to stand overnight, then concentrated to dryness. The residue was dissolved in methanol (3 ml), filtered and the filtrate was purified by preparative HPLC on a YMC-Actus Triart C18 150x30.5 µm column, eluting with a mixture of 20-50% water (0.05% v/v ammonium hydroxide) in acetonitrile. After lyophilization of the fraction containing the product, (1R,3S)-3-{3-[(1,2-oxazol-3-ylacetyl^minoGSH-pyrazol^-yl^iclopentyl-tert-butylcarbamate (Example 17, 74.84 mg, 27 %, 99% ee by chiral analytical SFC) was obtained as a white solid.

1H NMR (500 MHz, DMSO-d6) δ=12.09 (br s, 1H), 10.63 (s, 1H), 8.83 (s, 1H), 6.76 (br s, 1H), 6.53 (s, 1H), 6.29 (s, 1H), 4.96 (br s, 1H), 3.75 (s, 2H), 3.02 (quin, J=8.7 Hz, 1H), 2.47-2.41 (m, 1H), 2.04-1.93 (m, 1H), 1.92-1.79 (m, 1H), 1.78-1.61 (m, 2H), 1.55 (br s, 1H), 1.19 (s, 9H). MC: 376 [M+H]+.

- 56 046965

Method E.

Example 18: (1R,3S)-3-(3-{[(5-methyl-1,3,4-thiadiazol-2-yl)acetyl]amino}-1H-pyrazol-5yl)cyclopentyl-(1-methylcyclobutyl) )carbamate

A solution of benzyl-{1-tert-butyl-3-[(^,31<)-3-({ [(2,5-dioxopyrrolidin-1-yl)oxy]carbonyl}oxy)cyclopentyl]-1H-pyrazole-5 -yl}carbamate (16A, 1.20 g, 2.41 mmol), 1methylcyclobutylamine hydrochloride (CAS# 174886-05-6, 439 mg, 3.61 mmol) and diisopropylethylamine (1.56 g, 12.0 mmol) in THF (15 ml) was stirred at room temperature (32°C) for 18 hours. The mixture was concentrated in vacuo and the residue was dissolved in dichloromethane (25 ml). The solution was washed with water (2x5 ml), sat. aq. NH4Cl solution (5 ml) and sat. aq. NaCl solution (5 ml). The organic layer was dried over sodium sulfate, filtered, and concentrated. The crude product was purified by chromatography on silica gel (eluting with 0-30% ethyl acetate in petroleum ether) to give benzyl-{1-tert-butyl-3-[(1S,3R)-3-{[(1-methylcyclobutyl)carbamoyl]oxy} cyclopentyl]-1H-pyrazol-5yl}carbamate (18A, 920 mg, 82%) as a light yellow resin. MS: 469 [M+H]+.

Benzyl-{1-tert-butyl-3-[(1S,3R)-3-{[(1-methylcyclobutyl)carbamoyl]-oxy}cyclopentyl]-1Hpyrazol-5-yl}carbamate (18A, 920 mg, 1, 96 mmol) was stirred in formic acid (10 ml) at 75°C for 18 hours. Volatiles were removed under vacuum and the residue was partitioned between dichloromethane (20 ml) and sat. aq. NaHCO ₃ solution. The organic layer was dried over sodium sulfate, filtered, concentrated and purified by silica gel chromatography (eluting with 0-80% ethyl acetate in petroleum ether) to give benzyl-{3-[(1S,3R)-3-{[(1-methylcyclobutyl)carbamoyl ]oxy}cyclopentyl]1H-pyrazol-5-yl}carbamate (18B, 500 mg, 62%) as a light yellow resin. MS: 435 [M+Na]+.

Ethyl chloroformate (197 mg, 1.82 mmol) was added portionwise to the benzyl-{3-[(1S,3R)-3-{[(1methylcyclobutyl)carbamoyl]oxy}cyclopentyl]-1H-pyrazol-5-yl}-carbamate solution (18B, 500 mg, 1.21 mmol) and diisopropylethylamine (470 mg, 3.64 mmol) in dichloromethane (15 ml). The mixture was stirred at room temperature (35°C) for 4 hours, then washed with sat. aq. NH4Cl solution (2x5 ml) and sat. aq. NaCl solution (5 ml). The organic layer was dried over sodium sulfate, filtered and concentrated to give crude ethyl 5-{[(benzyloxy)carbonyl]amino}-3-[(1S,3R)-3-{[(1methylcyclobutyl)carbamoyl]oxy}-cyclopentyl] -III-pyrazole-1-carboxylate (18C, 560 mg, 95%, 80% purity by NMR) as a light yellow glass.

¹ H NMR (400 MHz, chloroform-d) δ=9.50 (s, 1H), 7.44-7.32 (m, 5H), 7.33-7.32 (m, 1H), 6.62 (br. s., 1H), 5.22 ( s, 2H), 5.17 (br. s., 1H), 4.51 (q, J=7.0 Hz, 2H), 3.25-3.13 (m, 1H), 2.51-2.30 (m, 2H), 2.14-2.03 (m, 1h), 2.00-1.73 (m, 8H), 1.47 (t, J=7.2 Hz, 4H), 1.44 (s, 3H). MS: 485 [M+H]+; 507 [M+Na]+.

A suspension of crude ethyl 5-{[(benzyloxy)carbonyl]amino}-3-[(1S,3R)-3-{[(1methylcyclobutyl)carbamoyl]oxy}cyclopentyl]-1H-pyrazole-1-carboxylate (18C, 560 mg, 1.16 mmol) and Pd/C catalyst (wet, 50 wt.% 150 mg) in ethyl acetate (10 ml) and THF (10 ml) were degassed, filled with hydrogen, then stirred under a hydrogen atmosphere from a cylinder at room temperature in for 1 hour. The catalyst was removed by filtration and the filtrate was concentrated to give crude ethyl 5-amino-3-[(1S,3R)-3-{[(1-methylcyclobutyl)carbamoyl]oxy}-cyclopentyl]-1H-pyrazol- 1carboxylate (18D, 430 mg, 100% crude) as a light yellow gum. MS: 351 [M+H]+; 373 [M+Na]+.

Crude ethyl 5-amino-3-[(1S,3R)-3-{[(1-methylcyclobutyl)carbamoyl]-oxy}cyclopentyl]1H-pyrazole-1-carboxylate (18D, 100.0 mg, 0.285 mmol) and sodium 2-(5-methyl-1,3,4-thiadiazol-2-yl) acetate

- 57 046965 (CAS# 1909316-87-5, 77.6 mg, 0.428 mmol) was suspended in dichloromethane (10 ml) at room temperature (35°C). Diisopropylethylamine (184 mg, 1.43 mmol) and propylphosphonic anhydride (T3P®, 50 wt% solution in EtOAc, 545 mg, 0.856 mmol) were added and the resulting solution was stirred at 35°C for 3 hours. The reaction mixture was washed with water (3 ml), sat. aq. NH4Cl solution (2x3 ml) and sat. aq. NaCl solution (3 ml). The organic layer was dried over sodium sulfate, filtered and concentrated to give crude ethyl 3-[(1S,3R)-3-{[(1methylcyclobutyl)carbamoyl]oxy}cyclopentyl]-5-{[(5-methyl-1,3 ,4-thiadiazol-2-yl)acetyl]amino}-1Hpyrazole-1-carboxylate (18E, 140 mg, 100% crude) as a light yellow gum. MS: 513 [M+Na].

A mixture of crude ethyl 3-[(1S,3R)-3-{[(1-methylcyclobutyl)carbamoyl]oxy}-cyclopentyl]-5{[(5-methyl-1,3,4-thiadiazol-2-yl) acetyl]amino}-1H-pyrazole-1-carboxylate (18E, 140 mg, 0.285 mmol) and lithium hydroxide monohydrate (35.9 mg, 0.856 mmol) in methanol (5 ml) and water (1 ml) were stirred at room temperature (35°C) for 30 minutes, then left to stand overnight. The suspension was concentrated to about 3 mL, the solid was removed by filtration, and the filtrate was purified by preparative HPLC on a 150 x 25 mm x 5 μm DuraShell column, eluting with a mixture of 27-47% water (0.05% v/v ammonium hydroxide) in acetonitrile. After lyophilization of the product containing fraction, (1R,3S)-3-(3-{[(5-methyl-1,3,4-thiadiazol-2-yl)acetyl]amino}-1H-pyrazol-5-yl) Cyclopentyl (1methylcyclobutyl)carbamate (Example 18, 30.89 mg, 26%, >99% ee by chiral analytical SFC) was obtained as a white solid.

¹ HNMR (500 MHz, DMSO-d6) δ=12.14 (br s, 1H), 10.78 (s, 1H), 7.18 (br s, 1H), 6.30 (br s, 1H), 4.97 (br s, 1H) , 4.19 (s, 2H), 3.13-2.95 (m, 1H), 2.69 (s, 3H), 2.48-2.40 (m, 1H), 2.21 (br s, 2H), 1.99 (br d, J=8, 9 Hz, 1H), 1.92-1.83 (m, 1H), 1.82-1.75 (m, 2H), 1.74-1.63 (m, 4H), 1.57 (br s, 1H), 1.34-1.23 (m, 3H). MC: 419 [M+H] ⁺ .

Additional compounds of the invention have been prepared by modifying the methods illustrated herein. In the presence of chiral starting reagents, compounds were prepared and isolated as single stereoisomers having a known absolute configuration, which is indicated by the symbols (R) and (S) on their structures. Using racemic starting reagents, synthesis was carried out to obtain the compounds as a mixture of diastereomers, and this was then separated into single stereoisomers by suitable chiral preparative HPLC or SFC, and then characterized and tested. In these cases, known stereocenters are represented by wedge-shaped bonds and are designated by the symbols (R) and (S); unknown stereocenters are depicted by solid bonds marked with an asterisk, and an explanation is given in Table. 2. If relative stereochemistry is known, but not absolute stereochemistry, then the structures are depicted with starred wedge bonds without the symbols (R) and/or (S), and an explanation is given in Table. 2.

The selected compounds and their characterizing data are presented in table. 2 below.

table 2

Example No. (Method) Structure; name according to HORAS; stereochemistry; notes LC-MS [M+H] ⁺ Ή NMR (ppm); ⁱ⁹ F NMR (ppm); optical rotation; Chiral HPLC/SFC conditions 19 (A) n 0 ^N 'N O r^N Η (15.3A)-3-(3-{[(2-methoxypyridin-4-yl)acetyl] amino } - 1//-pyrazol-5 yl)cyclopentylpropylcarbamate All stereocenters are known 402.3 'NMR (400 MHz, CHLOROFORM-d) δ = 11.3210.73 (m, 1H), 9.43 (br s, 1H), 8.03 (d, J=5.3 Hz, 1H), 6.77 (d, J=4 ,8 Hz, 1H), 6.65 (s, 1H), 6.47 (br s, 1H), 5.17 (brt, >5.8 Hz, 1H), 5.09 (br s, 1H), 3.86 (s, 3H), 3.57 (s, 2H), 3.11-2.97 (m, 3H), 2.45-2.31 (m, 1H), 2.00 (br d, J=4.8 Hz, 1H), 1.91-1.68 (m, 4H), 1.50- 1.36 (m, 2H), 0.84 (brt, J=7.3 Hz, 3H)

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20 (A) H h (15.37?)-3-{3-[(1,3-thiazol-5ylacetyl)amino]-17/-pyrazol-5yl} cyclopentylpropylcarbamate All stereocenters are known 378.3 Ή NMR (400 MHz, DMSO-d6) δ = 12.10 (s, 1H), 10.62 (s, 1H), 8.97 (s, 1H), 7.73 (s, 1H), 7.04 (br t, J=5.3 Hz, 1H), 6.30 (s, 1H), 5.03-4.95 (m, 1H), 3.92 (s, 2H), 3.11-2.98 (m, 1H), 2.91 (q, J=6.4 Hz, 2H) , 2.47-2.40 (m, 1H), 2.081.95 (m, 1H), 1.94-1.82 (m, 1H), 1.77-1.53 (m, 3H), 1.44-1.31 (m, 2H), 0.81(t, >7.4Hz, 3H) 21 (A) n ^Ο -ΐΧ-.™ ^Η / ^Ν 'Ν ° |^Т° n (15.37?)-3-(3-{[(6-methoxypyridin-3-yl)acetyl] amino } - 177-pyrazole -5 yl)cyclopentylpropylcarbamate All stereocenters are known 402.3 Ή NMR (400 MHz, CHLOROFORM-d) δ = 9.93 (s, 1H), 8.21-8.12 (m, 1H), 8.09 (d, J=2.3 Hz, 1H), 7.56 (dd, J=2.5, 8.5 Hz, 1H), 6.74 (d, J=8.3 Hz, 1H), 6.62-6.49 (m, 1H), 5.21-5.14 (m, 1H), 4.90-4.82 (m, 1H), 3.93 (s, 3H), 3.62 (s, 2H), 3.20-3.01 (m, 3H), 2.46 (ddd, J=6.8, 8.7, 14.9 Hz, 1H), 2.15-2.06(m, 1H), 1.98 -1.76 (m, 4H), 1.56-1.42 (m, 2H), 0.93-0.85 (m, 3H) 22 (A) n ϊ rV h (1S, 3R)-3 -(3 - {[(2-methyl-1,3thiazol-5-yl)acetyl] amino} - 1Hpyrazol-5-yl)cyclopentylpropylcarbamate All stereocenters are known 392.3 'NMR (400 MHz, CHLOROFORM-d) δ = 10.24 (br s, 1H), 8.55 (s, 1H), 7.49 (s, 1H), 6.64-6.50 (m, 1H), 5.22-5.13 (m, 1H ), 4.98-4.87 (m, 1H), 3.88 (s,2H), 3.21-3.00 (m, 3H), 2.68 (s, 3H), 2.57-2.43 (m, 1H), 2.172.04 (m, 1H ), 1.99-1.77 (m, 4H), 1.57-1.41 (m, 2H), 0.90 (t, J=7.4 Hz, 3H)

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23 (A) H /X^N.,0 γ h and rvy- H (15,ZA)-3-(3-{[(2-methyl-SH- benzimide azole-5 - yl)acetyl] amino } - 1//-pyrazole-5 - yl)cyclopentylpropylcarbamate All stereocenters are known 425.3 Ή NMR (400 MHz, DMSO-d6) δ = 12.34-11.82 (m, 2H), 10.46 (br s, 1H), 7.62-7.27 (m, 2H), 7.206.92 (m, 2H), 6.41-6.13 (m, 1H), 5.16-4.78 (m, 1H), 3.63 (s, 2H), 3.11-2.96 (m, 1H), 2.90 (q, J=6.5 Hz, 2H), 2.49-2.36 (m , 4H), 2.051.81 (m, 2H), 1.76-1.50 (m, 3H), 1.44-1.27 (m, 2H), 0.90-0.69 (m, 3H) 24 (A) n /-''Xx-N^O Ο,,ί^χ/Rj 4 ⁿ ~n o Ly n I / (15,3R)-3-(3- {[(3 £)-2,3-dihydro -1 benzofuran-3-ylcarbonyl] amino } - 1/7-pyrazol5 -yl)cyclopentylpropylcarbamate - Isomer A The only stereoisomer; the absolute configuration of the chiral center in dihydrobenzofuran has not been determined 399.3 'H NMR (400 MHz, DMSO-d6) δ = 12.12 (br s, 1H), 10.81 (s, 1H), 7.30 (d, J=7.3 Hz, 1H), 7.14 (t, J=7, 7 Hz, 1H), 7.02 (br t, J=5.6 Hz, 1H), 6.83 (t, J=7.4 Hz, 1H), 6.78 (d, J=8.0 Hz, 1H), 6.28 (s, 1H), 4.98 (br s, 1H), 4.78 (dd, J=6.3, 8.8 Hz, 1H), 4.64 (t, J=9.2 Hz, 1H), 4.45 (dd, J= 6.4, 9.2 Hz, 1H), 3.12-2.96 (m, 1H), 2.89 (q, J=6.7 Hz, 2H), 2.47-2.37 (m, 1H), 2.06-1.94 (m, 1H) , 1.93-1.79 (m, 1H), 1.77-1.62 (m, 2H), 1.60-1.48 (m, 1H), 1.44-1.27 (m, 2H), 0.79(t, J=7.4 Hz, 3H) [a] _D ²⁵ -42.0 (c 0.l,MeOH) Peak 1 of 2: Column: SS WHELK-01 (250 mm x 50 mm, 10 µm); mobile phase: 40% IP A (0.1% NH3.H2O) in CO ₂ ; flow rate: 6.5 ml/min; column temperature 40°C

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25 (A) H /Xz ^N y° / ^N ~ ^N ° /^\ SU Η I / (15,3R)-3-(3-{[(3 £)-2,3-dihydro-1 benzofuran-3-ylcarbonyl] amino } - 1//-pyrazol5 -yl)cyclopentylpropylcarbamate - Isomer B The only stereoisomer; the absolute configuration of the chiral center in dihydrobenzofuran has not been determined 399.3 Ή NMR (400 MHz, DMSO-d6) a = 12.12 (br s, 1H), 10.80 (s, 1H), 7.30 (d, 1=7.5Hz, 1H), 7.14(1, J=7.7 Hz , 1H), 7.03 (br t, J=5.4 Hz, 1H), 6.83 (t, J=7.2 Hz, 1H), 6.78 (d, J=8.0 Hz, 1H), 6.28 (br s, 1H), 4.98 (br s, 1H), 4.78 (dd, J=6.3, 8.8 Hz, 1H), 4.64 (t, J=9.2 Hz, 1H), 4.45 (dd, J=6.3 , 9.3 Hz, 1H), 3.11-2.97 (m, 1H), 2.89 (q, J=6.6 Hz, 2H), 2.48-2.37 (m, 1H), 2.04-1.93 (m, 1H), 1.92-1.79 (m, 1H), 1.76-1.62 (m, 2H), 1.61-1.51 (m, 1H), 1.44-1.29 (m, 2H), 0.80 (t, J=7.4 Hz, 3H) [ a] _D ²⁵ +39.3 (c 0.1, MeOH) Peak 2 of 2: Column: SS WHELK-01 (250 mm x 50 mm, 10 µm); mobile phase: 40% IP A (0.1% NH3.H2O) in CO ₂ ; flow rate: 6.5 ml/min; column temperature 40°C 26 (A) n 'j? /V H (15,3R)-3 -(3 - {[(2-methyl-1,3thiazol-5-yl)acetyl] amino } - 1Hpyrazol-5-yl)cyclopentylpropan-2-ylcarbamate All stereocenters are known 392.3 Ή NMR (400 MHz, DMSO-d6) δ = 12.09 (s, 1H), 10.58 (s, 1H), 7.40 (s, 1H), 6.95 (br d, J=7.8 Hz, 1H), 6.28 ( s, 1H), 4.98 (br s, 1H), 3.81 (s, 2H), 3.65-3.48 (m, 1H), 3.16-2.93 (m, 1H), 2.58 (s, 3H), 2.47-2.37 (m , 1H), 2.05-1.94 (m, 1H), 1.91-1.78 (m, 1H), 1.77-1.63 (m, 2H), 1.55 (brt, 1=13.7Hz, 1H), 1.02 (br d, J =6.3 Hz, 6H)

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27 (IN) n but'-U j? {A h (15.37?)-3-(3-{ [(3.5- difluorophenyl)acetyl] amino }-1Hpyrazol-5-yl)cyclopentyl-(g/is4-hydroxycyclohexyl)carbamate All stereocenters are known; the cyclohexyl ring is meso-N,0cis. 463.4 Ή NMR (400 MHz, DMSO-d6) δ = 12.08 (br s, 1H), 10.57 (s, 1H), 7.15-7.08 (m, 1H), 7.02 (br d, J=6.3 Hz, 2H) , 6.97 (br d, J=7.3 Hz, 1H), 6.27 (br s, 1H), 4.96 (br d, J=l,8 Hz, 1H), 4.31 (br s, 1H), 3.63 (s , 3H), 3.30-3.19 (m, 1H), 3.07-2.96 (m, 1H), 2.46-2.38 (m, 1H), 1.98 (brd, J=8.5 Hz, 1H), 1.91-1.81 (m , 1H), 1.74-1.63 (m, 2H), 1.61-1.48 (m, 5H), 1.41 (br d, J=10.3 Hz, 4H) 28 (IN) n h (15.37?)-3-(3-{ [(3.5- difluorophenyl)acetyl] amino }-\Hpyrazol-5-yl)cyclopentyl(trans-A- hydroxycyclohexyl)carbamate All stereocenters are known; the cyclohexyl ring is meso-N,0trans. 463.4 Ή NMR (400 MHz, DMSO-d6) δ = 12.09 (s, 1H), 10.56 (s, 1H), 7.16-7.07 (m, 1H), 7.06-6.98 (m, 2H), 6.92 (br d, J =7.5 Hz, 1H), 6.27 (s, 1H), 5.01-4.91 (m, 1H), 4.53 (d, J=4.3 Hz, 1H), 3.63 (s, 2H), 3.22-3.13 ( m, 1H), 3.04-2.95 (m, 1H), 2.43-2.37 (m, 1H), 2.011.93 (m, 1H), 1.86 (ddd, J=2.8, 6.7, 9.9 Hz, 1H), 1.81-1.61 (m, 7H), 1.59-1.50 (m, 1H), 1.20-1.07 (m, 4H) 29 (WITH) n n^o = Ο,/^,-ΗΝ-ν o η-Λ I x JI ν Η (15.37?)-3-{3-[(1,2-oxazol-5ylacetyl)amino] - 1//-pyrazol-5yl} cyclopentyl-(2/?)-butan-2ylcarbamate All stereocenters are known 376.2 'NMR (400 MHz, DMSO-d6) δ = 12.13 (s, 1H), 10.66 (s, 1H), 8.49 (d, J=l.5 Hz, 1H), 6.88 (br d, J=8.0 Hz, 1H), 6.38 (s, 1H), 6.30 (s, 1H), 4.99 (br s, 1H),3.92 (s, 2H), 3.39-3.36 (m, 1H), 3.12-2.94 (m, 1H ), 2.49-2.40 (m, 1H), 2.051.95 (m, 1H), 1.94-1.82 (m, 1H), 1.79-1.50 (m, 3H), 1.46-1.27 (m,

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2H), 1.00 (d, J=6.8 Hz, ZN), 0.80 (br t, J=7.4 Hz, ZN) [a] _D ²⁵ +3.6 (s 0.11, MeOH) thirty (WITH) n N^O ^{0 (} GL^ ^H Sk S Ρν n (15.37?)-3-{3-[(1,2-oxazol-5ylacetyl)amino] - 177-pyrazol-5 yl } cyclopentyl-(2 8 )-butan-2ylcarbamate All stereocenters are known 376.2 'H NMR (400 MHz, DMSO-d6) δ = 12.13 (s, 1H), 10.66 (s, 1H), 8.49 (d, J=l.5 Hz, 1H), 6.88 (br d, J=8, 0 Hz, 1H), 6.38 (s, 1H), 6.30 (s, 1H), 4.99 (br s, 1H), 3.92 (s, 2H), 3.36 (d, J=2.8 Hz, 1H), 3.122 .98 (m, 1H), 2.49-2.41 (m, 1H), 2.05-1.95 (m, 1H), 1.94-1.79 (m, 1H), 1.77-1.51 (m, 3H), 1.41-1.29 (m, 2H), 1.00 (d, J=6.5 Hz, ZN), 0.79 (t, J=7.4 Hz, ZN) [a] _D ²⁵ -15.0 (c 0.11, MeOH) 31 (A) n * °^ ^S >\W ^H / ^N 'N ° / hY ,, ^N ^-N (15.37?)-3-(3-{ [(1-methyl-177-1,2,3triazol-5 -yl)carbonyl] amino } 177-pyrazol-5-yl)cyclopentyl-(28)-butan-2-ylcarbamate All stereocenters are known 376.4 'NMR (400 MHz, DMSO-d6) δ = 12.33 (br s, 1H), 11.15 (brs, 1H), 8.46 (s, 1H), 6.91 (brd, J=8.3 Hz, 1H), 6.44 ( s, 1H), 5.00 (br s, 1H), 4.24 (s, 3H), 3.43-3.37 (m, 1H), 3.13-3.01 (m, 1H), 2.492.40 (m, 1H), 2.08-1.98 (m, 1H), 1.96-1.83 (m, 1H), 1.79-1.68 (m, 2H), 1.67-1.56 (m, 1H), 1.40-1.28 (m, 2H), 1.00 (d, J=6, 5 Hz, ZN), 0.81 (t, J=7.3 Hz, ZN) 32 (A) n o*L ^R 2-\ ™ 4 ⁿ ~n O (HA £ ji l| ^χ ν Η (17?, 35)-3 -(3 - {[(3 -methyl-1,2oxazol-5-yl) acetyl] amino } -177pyrazol-5 -yl)cyclopentyl-(2 S)- 390.3 'H NMR (400 MHz, DMSO-d6) δ = 12.12 (s, 1H), 10.64 (s, 1H), 6.89 (br d, J=8.3 Hz, 1H), 6.30 (br s, 1H), 6.22 (s, 1H), 4.99 (br s, 1H), 3.83 (s, 2H), 3.35-3.30 (m, 1H), 3.10-2.99 (m, 1H), 2.48-2.40 (m, 1H), 2.20 (s, 3H), 2.06-1.82

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butan-2-ylcarbamate All stereocenters are known (m, 2H), 1.77-1.51 (m, ZN), 1.411.27 (m, 2H), 1.00 (d, J=6.5 Hz, ZN), 0.80 (t, J=7.4 Hz, ZN ) 33 (A) Η Tl n TGSH. ί Ο Ν X/ UA A // Κ- Η ^ь (ΙΑ,35)-3 -(3 -{[(2-methyl-1,3thiazol-5 -yl)acetyl] amino }-1Hpyrazol-5 -yl) cyclopentyl-(2 S)butan-2-ylcarbamate All stereocenters are known 406.2 'H NMR (400 MHz, DMSO-d6) δ = 12.08 (s, 1H), 10.56 (s, 1H), 7.41 (s, 1H), 6.86 (br d, J=8.0 Hz, 1H), 6.29 (br s, 1H), 4.99 (br s, 1H), 3.82 (s, 2H), 3.34 (br s, 1H), 3.12-2.97 (m, 1H), 2.59 (s, 3H), 2.48-2.39 ( m, 1H), 2.05-1.95 (m, 1H), 1.94-1.82 (m, 1H), 1.77-1.65 (m, 2H), 1.63-1.52 (m, 1H), 1.431.27 (m, 2H), 1.00 (d, J=6.5 Hz, ZN), 0.80 (t, J=7.4 Hz, ZN) 34 (A) n ^ο 'Χ\Χ ^ν ~ν 9 Η (1A,35)-3-(3-{[(5-methylpyrazin2-yl)acetyl] amino } - 1//-pyrazol5 -yl)cyclopentyl-(2 8) -butan-2ylcarbamate All stereocenters are known 401.4 DNMR (400 MHz, DMSO-d6) δ = 12.08 (br s, 1H), 10.60 (s, 1H), 8.47 (d, J=13.6 Hz, 2H), 6.88 (br d, J=8.3 Hz, 1H), 6.28 (s, 1H), 4.99 (br s, 1H), 3.83 (s, 2H), 3.423.37 (m, 1H), 3.11-2.97 (m, 1H), 2.47 (s, 3H ), 2.45 (br d, J=6.0 Hz, 1H), 2.07-1.80 (m, 2H), 1.78-1.49 (m, 3H), 1.40-1.26 (m, 2H), 0.99 (d, J= 6.5 Hz, ZN), 0.78 (t, J=7.3 Hz, ZN) 35 (A) n °ТЯТлХГ n (1A,35)-3-(3-{[(6-methylpyridin3 -yl)acetyl] amino } - 1//-pyrazol5 -yl)cyclopentyl-(2 8)-butan-2ylcarbamate All stereocenters are known 400.4 'H NMR (400 MHz, DMSO-d6) δ = 12.06 (s, 1H), 10.54 (s, 1H), 8.34 (d, J=2.0 Hz, 1H), 7.58 (dd, J=2.3, 8 ,0 Hz, 1H), 7.18 (d, J=8.0 Hz, 1H), 6.86 (br d, 3=8.0Hz, 1H), 6.27 (s, 1H), 4.97 (br s, 1H), 3.56 (s, 2H), 3.34-3.31 (m, 1H), 3.102.93 (m, 1H), 2.47-2.39 (m, 4H),

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2.03-1.93 (m, 1H), 1.91-1.80 (w, 1H), 1.75-1.61 (m, 2H), 1.60-1.50 (m, 1H), 1.32 (td, J=7.1, 11.1 Hz, 2H ), 0.99 (d, J=6.5 Hz, ZN), 0.78 (t, J=7.4 Hz, ZN) 36 (A) H * 0 βΛ Ly H (17?,35)-3-{3-[(1,3-thiazol-5- ylacetyl)amino] - 1//-pyrazol-5 yl } cyclopentyl-(2 8)-butan-2ylcarbamate All stereocenters are known 392.3 Ή NMR (400 MHz, DMSO-d6) δ = 12.11 (br s, 1H), 10.63 (s, 1H), 8.97 (s, 1H), 7.73 (s, 1H), 6.88 (br d, J=8, 3 Hz, 1H), 6.30 (br s, 1H), 4.99 (br s, 1H), 4.05-3.79 (m, 2H), 3.36-3.31 (m, 1H), 3.12-2.98 (m, 1H), 2.49 -2.41 (m, 1H), 2.071.81 (m, 2H), 1.77-1.52 (m, 3H), 1.42-1.26 (m, 2H), 1.00 (d, J=6.5 Hz,ZN), 0.79 (t, J=7.4 Hz, ZN) 37 (A) n n (17?,35)-3-(3-{[(2methoxypyridin-4yl)acetyl] amino } -1//-pyrazol-5 yl)cyclopentyl-(28)-butan-2ylcarbamate All stereocenters are known 416.3 Ή NMR (400 MHz, DMSO-d6) δ =12.09 (s, 1H), 10.58 (s, 1H), 8.08 (d, J=5.3 Hz, 1H), 6.98-6.81 (m, 2H), 6.74 (s, 1H), 6.28 (br s, 1H), 4.98 (br s, 1H), 3.83 (s, 3H), 3.59 (s, 2H), 3.35 (br s, 1H), 3.102.96 (m, 1H), 2.49-2.40 (m, 1H), 2.04-1.81 (m, 2H), 1.78-1.52 (m, 3H), 1.42-1.25 (m, 2H), 1.00 (d, J=6.5 Hz, ZN), 0.79 (t, J=7.4 Hz, ZN) 38 (A) n '—Г η (17?,35)-3-{3- [(phenylacetyl)amino]-Spirazol-5-yl } cyclopentyl-(2 S)butan-2-ylcarbamate 385.4 ¹ H NMR (400 MHz, DMSO-d6) δ = 12.06 (s, 1H), 10.51 (br s, 1H), 7.34-7.27 (m, 4H), 7.27-7.20 (m, 1H), 6.87 (brd, J=8.3 Hz, 1H), 6.29 (br s, 1H), 4.98 (br s, 1H), 3.58 (s, 2H), 3.36-3.30 (m, 1H), 3.09-2.96 (m, 1H) , 2.45 (td,

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All stereocenters are known J=7.2, 14.0 Hz, 1H), 2.05-1.80 (m, 2H), 1.77-1.50 (m, ZN), 1.401.26 (m, 2H), 1.00 (d, J=6.5 Hz, ZN), 0.79 (t, J=7.4 Hz, ZN) 39 (A) Η Ν^,Ο * ⁰ ·&- _Β Λ/ ^Ν τ й Art Η (17?,35)-3-{3- [([ 1,2,4]triazolo[ 1,5- ά]pyrimidine-6 -ylacetyl)amino] 1//-pyrazol-5 -yl } cyclopentyl(28)-butan-2-ylcarbamate All stereocenters are known 427.2 Ή NMR (400 MHz, DMSO-d6) δ = 12.11 (br s, 1H), 10.66 (s, 1H), 9.33 (d, J=2.0 Hz, 1H), 8.84 (d, J=2.3 Hz, 1H), 8.71-8.56 (m, 1H), 6.94-6.72 (m, 1H), 6.28 (br s, 1H), 4.98 (br s, 1H), 3.86 (s, 2H), 3.42 (br d , J=4.8 Hz, 1H), 3.152.91 (m, 1H), 2.48-2.39 (m, 1H), 2.07-1.80 (m, 2H), 1.78-1.50 (m, 3H), 1.45- 1.22 (m, 2H), 1.060.89 (m, 3H), 0.85-0.68 (m, 3H) 40 (A) n ^ο *βΓχ«> ^Η / ^Ν ~Ν O ji XL II ⁿ o=s^ a (17?,35)-3-[3-({[2-(ethyl sulfonyl)phenyl] acetyl} amino) - 1//-pyrazol-5-yl]cyclopentyl-(28)-butan-2ylcarbamate All stereocenters are known 477.3 'NMR (400 MHz, DMSO-d6) δ = 12.09 (br s, 1H), 10.59 (s, 1H), 8.04-7.85 (m, 1H), 7.70 (dt, J=1.1, 7.5 Hz, 1H ), 7.59-7.48 (m, 2H), 6.87 (br d, J=8.3 Hz, 1H), 6.26 (br s, 1H), 4.98 (br s, 1H), 4.17 (s, 2H), 3.37 -3.29 (m, 3H), 3.10-2.96 (m, 1H), 2.49-2.39 (m, 1H), 2.07-1.79 (m, 2H), 1.77-1.48 (m, 3H), 1.42- 1.24 (m, 2H), 1.12 (t, J=7.4 Hz, ZN), 0.99 (br d, J=6.5 Hz, ZN), 0.78 (t, J=7.4 Hz, ZN) 41 (A) N /-4¾ N^O 9 / n O- (17?, 35)-3 -(3 - {[(3 -methoxy-1 - 405.3 'n NMR (400 MHz, DMSO-d6) δ = 12.24 (s, 1H), 10.66 (s, 1H), 6.89 (br d, J=8.3 Hz, 1H), 6.59 (s, 1H), 6.42 (br s, 1H), 5.00 (brd, J=4,l Hz, 1H), 3.94 (s, 3H), 3.78

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methyl-1//-pyrazol-5yl)carbonyl] amino } - 1/7-pyrazol5 -yl)cyclopentyl-(2 8)-butan-2ylcarbamate All stereocenters are known (s, ZN), 3.43-3.36 (m, 1H), 3.133.02 (m, 1H), 2.56-2.52 (m, 1H), 2.09-1.99 (m, 1H), 1.97-1.86 (w, 1H) , 1.80-1.69 (m, 2H), 1.67-1.57 (m, 1H), 1.43-1.31 (m, 2H), 1.01 (d, J=6.6 Hz, ZN), 0.81 (t, J=7, 4 Hz, ZN) 42 (A) H ^ο *β-χ^ ^Ν 'ϊι n / Η (17?, 35)-3-(3-{[(1 -methyl-1Hpyrazol-5-yl)carbonyl] amino } 1/7-pyrazol-5- yl)cyclopentyl(28)-butan-2-ylcarbamate All stereocenters are known 375.3 Ή NMR (400 MHz, DMSO-d6) δ = 11.39 (s, 1H), 9.88 (s, 1H), 6.64 (d, 1=1.9Hz, 1H), 6.31 (s, 1H), 6.05 (br d , J=8.3 Hz, 1H), 5.59 (br s, 1H), 4.16 (brs, 1H), 3.24 (s, 3H), 2.61-2.54 (m, 1H), 2.32-2.18 (m, 1H) , 1.72-1.68 (m, 1H), 1.271.14 (m, 1H), 1.12-1.00 (m, 1H), 0.97-0.84 (m, 2H), 0.82-0.72 (m, 1H), 0.58-0.44 ( m, 2H), 0.16 (d, J=6.6 Hz, ZN), -0.04 (t, J=7.4 Hz, ZN) 43 (A) n 1 AA,ν ^H (17?,35)-3-{3-[([1,3]thiazolo[4,5-b~\pyridin-7-ylcarbonyl)amino] 1/7-pyrazol-5 - yl } cyclopentyl(28)-butan-2-ylcarbamate All stereocenters are known 429.3 Ή NMR (400 MHz, DMSO-d6) δ = 12.40 (s, 1H), 11.49 (br s, 1H), 9.81 (s, 1H), 8.93 (d, J=5.0 Hz, 1H), 8.37 ( d, J=5.0 Hz, 1H), 6.92 (br d, J=8.3 Hz, 1H), 6.56 (br s, 1H), 5.03 (br s, 1H), 3.34-3.31 (m, 1H ), 3.20-3.08 (m, 1H), 2.48 (brs, 1H), 2.12-2.03 (m, 1H), 1.97-1.85 (m, 1H), 1.77 (br d, J=9.8 Hz, 2H) , 1.66 (brt, J=14.l Hz, 1H), 1.44-1.30 (m, 2H), 1.02 (d, J=6.8 Hz, ZN), 0.81 (t, J=7.4 Hz, ZN )

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44 (A) H ./43-NO I O43^/ _S) ^h , ⁿ ~n o ^'Ύ' ⁰ ' Y N2-< Jj· K r I] ^H o=s— II 0 (17?,35)-3- [3-({[4-methoxy-2(methyl sulfonyl)phenyl] acetyl } -amino)-III-pyrazol-5-yl]cyclopentyl-(28)-butan-2ylcarbamate All stereocenters are known 493.4 Ή NMR (400 MHz, DMSO-d6) δ = 12.06 (br s, 1H), 10.53 (br s, 1H), 7.45-7.38 (m, 2H), 7.25 (dd, J=2.6, 8.4 Hz, 1H), 6.86 (br d, J=8.0 Hz, 1H), 6.25 (br s, 1H), 4.97 (br s, 1H), 4.08 (s, 2H), 3.83 (s, 3H), 3.37 ( brs, 1H), 3.28 (s, 3H), 3.08-2.95 (m, 1H), 2.45-2.37 (m, 1H), 2.03-1.93 (m, 1H), 1.911.80 (m, 1H), 1.76- 1.62 (m, 2H), 1.59-1.48 (m, 1H), 1.38-1.26 (m, 2H), 0.98 (br d, J=6.5 Hz, 3H), 0.77 (br t, J=7.3 Hz, 3H) 45 (A) n o ^γ ⁿ ο4- II 0 (17?,35)-3-[3-({[4-methyl-2- (methyl sulfonyl)φ enyl] acetyl } -amino)- 1//-pyrazole-5 - yl]cyclopentyl-(28)-butan-2ylcarbamate All stereocenters are known 477.1 'Η NMR (400 MHz, DMSO-d6) δ = 12.08 (s, 1H), 10.56 (s, 1H), 7.77 (s, 1H), 7.49 (d, J=6.5 Hz, 1H), 7.38 ( d, J=7.8 Hz, 1H), 6.88 (br d, J=8.5 Hz, 1H), 6.26(s, 1H), 4.98 (br s, 1H), 4.13 (s, 2H), 3.313 .23 (m, 4H), 3.11-2.96 (m, 1H), 2.48-2.44 (m, 1H), 2.39 (s, 3H), 1.99 (brd, J=8.3 Hz, 1H), 1.931.83 (m, 1H), 1.76-1.63 (m, 2H), 1.62-1.50 (m, 1H), 1.33 (br dd, J=6.9, 11.2 Hz, 2H), 0.99 (d, J=6.5 Hz, 3H), 0.78 (t, J=7.3 Hz, 3H) 46 (A) n/43-O (17?,3S)-3-(3-{[(3- methylimidazo[1,2-/>]pyridazin- 6-yl)acetyl] amino } -1 Η- p irasol- 440.4 Ή NMR (400 MHz, CHLOROFORM-d) δ = 10.72 (br s, 1H), 10.11 (br s, 1H), 7.84 (d, J=9.3 Hz, 1H), 7.56 (d, J=0, 7 Hz, 1H), 7.07 (d, J=9.3 Hz, 1H), 6.62 (br s, 1H), 5.17 (brs, 1H), 4.66

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5 -yl)cyclopentyl-(2 8)-butan-2ylcarbamate All stereocenters are known (br d, J=7.9 Hz, 1H), 3.91 (s, 2H), 3.65-3.53 (m, 1H), 3.19 (quin, J=8.2 Hz, 1H), 2.56-2.43 (m, 4H), 2.18-2.06 (m, 1H), 1.98-1.84 (m, 4H), 1.47-1.34 (m, 2H), 1.15-1.01 (m, 3H), 0.85 (t, J=7.4 Hz, 3H) 47 (A) n ^η / ^ν ~ ^ν o \Ρζ—/ η π 1 /> Η (17?,35)-3-(3-{[(2-methylimidazo[1,2-/>]pyridazin6-yl)acetyl] amino } - 177-pyrazol 5 -yl)cyclopentyl-(2 8)-butan-2ylcarbamate All stereocenters are known 440.4 Ή NMR (400 MHz, DMSO-d6) δ = 12.11 (br s, 1H), 10.69 (s, 1H), 7.99 (s, 1H), 7.93 (d, J=9.3 Hz, 1H), 7.15 ( d, J=9.3 Hz, 1H), 6.87 (br d, J=8.3 Hz, 1H), 6.29 (br s, 1H), 4.98 (br s, 1H), 3.87 (s, 2H), 3.38 (br s, 1H), 3.10-2.97 (m, 1H), 2.48-2.40 (m, 1H), 2.38 (s, 3H), 2.06-1.80 (m, 2H), 1.78-1.49 (m, 3H) , 1.42-1.24 (m, 2H), 0.99 (br d, J=6.5 Hz, 3H), 0.78 (br t, J=7.3 Hz, 3H) 48 (A) n * ABOUT Η (17?, 35)-3 -(3 - {[(1 -methyl-177- ind azol-5 -yl)acetyl] amino } -177pyrazol-5 -yl)cyclopentyl-(2 S)butan-2-ylcarbamate All stereocenters are known 439.4 Ή NMR (400 MHz, DMSO-d6) δ = 12.05 (br s, 1H), 10.51 (br s, 1H), 7.99 (s, 1H), 7.65 (s, 1H), 7.56 (br d, J=8 ,5 Hz, 1H), 7.35 (br d, J=8.5 Hz, 1H), 6.86 (br d, J=8.0 Hz, 1H), 6.28 (br s, 1H), 4.97 (br s, 1H), 4.01 (s, 3H), 3.67 (s, 2H), 3.30 (br s, 1H), 3.11-2.92 (m, 1H), 2.46-2.37 (m, 1H), 2.041.91 (m, 1H ), 1.85(br d, J=5.8 Hz, 1H), 1.76-1.61 (m, 2H), 1.54 (br s, 1H), 1.43-1.15 (m, 2H), 0.98 (br d, J= 6.5 Hz, 3H), 0.77 (br t, J=7.2 Hz, 3H)

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49 (A) H x^CHE-N^jO ^ο γΛ«7 ^Ν 'Ν J P Lv ^H o=s-nh ₂ O (17?,35)-3-(3-{[(2-sulfamoylphenyl)acetyl] amino } - 1//-pyrazol-5 - yl)cyclopentyl-(28)-butan-2ylcarbamate All stereocenters are known 463.8 Ή NMR (400 MHz, DMSO-d6) δ = 12.25-11.99 (m, 1H), 10.6710.42 (m, 1H), 7.91 (brd, J=6.6 Hz, 1H), 7.56 (brd, J= 6.0 Hz, 1H), 7.46 (br s, 4H), 6.88 (br d, J=6.l Hz, 1H), 6.28 (br s, 1H), 4.98 (br s, 1H), 4.12 (br s, 2H), 3.47-3.42 (m, 1H), 3.03 (br s, 1H), 2.46-2.39 (m, 1H), 1.98 (br s, 1H), 1.87 (brs, 1H), 1.69 (brs, 2H), 1.56 (br s, 1H), 1.34 (br s, 2H), 0.99 (br s, 3H), 0.79 (br s, 3H) 50 (A) H \ Ν^Ο Ό ^th oХ o (17?,36)-3-[3-({[5-methoxy-2-(methyl sulfonyl)phenyl] acetyl } -amino)-1//-pyrazole-5 - yl]cyclopentyl-(28)-butan-2ylcarbamate All stereocenters are known 492.9 'NMR (400 MHz, DMSO-d6) δ = 12.08 (s, 1H), 10.56 (s, 1H), 7.89 (d, J=8.5 Hz, 1H), 7.17-6.99 (m, 2H), 6.87 (br d, J=7.8 Hz, 1H), 6.27 (s, 1H), 4.97 (br s, 1H), 4.13 (s, 2H), 3.84 (s, 3H), 3.39 (br s, 1H) , 3.22 (s, 2H), 3.27-3.15 (m, 1H), 3.08-2.99 (m, 1H), 2.44 (br d, J=6.5 Hz, 1H), 2.08-1.79 (m, 2H), 1.78-1.47 (m, 3H), 1.42-1.24 (m, 2H), 0.99 (br d, J=6.5 Hz, 3H), 0.82-0.73 (m, 1H), 0.78 (br t, J=7 .4 Hz, 2H) 51 (A) n n X/ (17?,35)-3-[3-({[1-(2methoxyethyl)-1//-pyrazol-5yl]carbonyl} amino)-1//-pyrazol5 -yl]cyclopentyl-(2 8 )-butane-2- 419.3 'Η NMR (400 MHz, DMSO-d6) δ = 12.24 (br s, 1H), 10.74 (br s, 1H), 7.52 (s, 1H), 7.12 (br s, 1H), 6.90 (br d, J =8.0 Hz, 1H), 6.42 (br s, 1H), 5.00 (brs, 1H), 4.69 (brt, J=5.6 Hz, 2H), 3.66 (br t, J=5.6 Hz, 2H), 3.46 (br s, 1H), 3.18 (s,

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ylcarbamate All stereocenters are known ZN), 3.12-3.00 (m, 1H), 2.46-2.36 (m, 1H), 2.03 (br d, J=7.0 Hz, 1H), 1.94-1.82 (m, 1H), 1.79-1.68 (m , 2H), 1.65-1.55 (m, 1H), 1.441.22 (m, 2H), 1.00 (br d, J=6.5 Hz, 3H), 0.80 (t, J=7.3 Hz, 3H) 52 (A) n/4¾. Ν-ψ>Ο OH ⁿ o=s=o 1 (17?,35)-3-[3-({[2-hydroxy-5(methylsulfonyl)pyridin-4yl] acetyl } amino)- 1//-pyrazole -5 yl]cyclopentyl-(28)-butan-2ylcarbamate All stereocenters are known 479.9 Ή NMR (400 MHz, DMSO-d6) δ = 12.52-11.80 (m, 2H), 10.60 (s, 1H), 7.94 (s, 1H), 6.89 (br d, J=8.3 Hz, 1H), 6.37 (s, 1H), 6.27 (br s, 1H), 4.98 (br s, 1H), 3.89 (s, 2H), 3.39 (br s, 1H), 3.25 (s, 3H), 3.09-2.98 (m , 1H), 2.49-2.41 (m, 1H), 2.09-1.95 (m, 1H), 1.87 (br d, J=8.3 Hz, 1H), 1.78-1.64 (m, 2H), 1.63-1.50 ( m, 1H), 1.34 (br dd, J=6.9, 11.4 Hz, 2H), 1.00 (d, J=6.8 Hz, 3H), 0.79 (t, J=7.4 Hz, 3H) 53 (A) n he Η (17?,3S)-3-[3-({[l-(2hydroxyethyl)-1//-pyrazol-5yl]carbonyl } amino)-1//-pyrazol5 -yl]cyclopentyl-(2 8)-butane -2ylcarbamate All stereocenters are known 405.3 Ή NMR (400 MHz, DMSO-d6) δ = 12.25 (s, 1H), 10.76 (s, 1H), 7.51 (d, 1=1.8Hz, 1H), 7.11 (d, J=l.8 Hz, 1H), 6.92 (br d, J=8.0 Hz, 1H), 6.44 (s, 1H), 5.01 (br s, 1H), 4.87 (t, J=5.5 Hz, 1H), 4.58 (t , J=6.3 Hz, 2H), 3.70 (q, J=5.9 Hz, 2H), 3.44-3.37 (m, 1H), 3.133.02 (m, 1H), 2.50-2.44 (m, 1H ), 2.07-1.99 (m, 1H), 1.96-1.85 (m, 1H), 1.80-1.70 (m, 2H), 1.67-1.56 (m, 1H), 1.41-1.30 (m, 2H), 1.01 (d , J=6.8 Hz, 3H), 0.81 (t, J=7.4 Hz, 3H)

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54 (A) H H (17?, 35)-3 -(3 - {[(1 -methyl-177- ind azol-5 -yl)acetyl] amino } -177pyrazol-5-yl)cyclopentylpropylcarbamate All stereocenters are known 425.4 Ή NMR (400 MHz, DMSO-d6) δ = 12.05 (br s, 1H), 10.51 (br s, 1H), 7.99 (s, 1H), 7.64 (s, 1H), 7.56 (d, J=8, 8 Hz, 1H), 7.35 (d, J=8.3 Hz, 1H), 7.03 (br s, 1H), 6.27 (br s, 1H), 4.97 (br s, 1H), 4.01 (s, 3H) , 3.66 (s, 2H), 3.092.95 (m, 1H), 2.88 (q, J=6.6 Hz, 2H), 2.44-2.35 (m, 1H), 1.97 (br d, J=8.0 Hz, 1H), 1.91-1.78 (m, 1H), 1.74-1.61 (m, 2H), 1.54 (br s, 1H), 1.42-1.29 (m, 2H), 0.79 (t, J=7.4 Hz , 3H) 55 (A) n \.N^O ί About ΓΥ/Ν n (17?, 35)-3 -(3 - {[(1 -methyl-177- indazol-5-yl)acetyl] amino } -177pyrazol-5-yl)cyclopentyl- propan-2-ylcarbamate All stereocenters are known 425.4 'H NMR (400 MHz, DMSO-d6) δ = 12.13 (br s, 1H), 10.53 (s, 1H), 8.00 (s, 1H), 7.66 (s, 1H), 7.56 (d, J=8, 5 Hz, 1H), 7.37 (dd, J=1.4, 8.7 Hz, 1H), 6.93 (br d, J=7.8 Hz, 1H), 6.28 (s, 1H), 4.98 (br s, 1H ), 4.06-3.99 (m, 3H), 3.68 (s, 2H), 3.61-3.54 (m, 1H), 3.09-2.97 (m, 1H), 2.44 (td, J=7.2, 13.9 Hz, 1H ), 2.05-1.93 (m, 1H), 1.91-1.81 (m, 1H), 1.75-1.63 (m, 2H), 1.611.50 (m, 1H), 1.08-0.96 (m, 6H) 56 (A) ⁿ η \ζ ^Ν ^ ⁰ 1 L· ^Η , ^Ν ~ ^Ν ? \ / N ^H '-o (17?, 35)-3 -(3 - {[(3^)-2,3-dihydro-1 benzofuran-3-ylcarbonyl] amino } - 177-pyrazol5 -yl)cyclopentyl- propan-2ylcarbamate - Isomer A 399.3 'H NMR (400 MHz, DMSO-d6) δ = 12.12 (br s, 1H), 10.81 (s, 1H), 7.30 (d, >7.5 Hz, 1H), 7.14 (t, J=7.5 Hz , 1H), 6.93 (br d, J=7.5 Hz, 1H), 6.87-6.74 (m, 2H), 6.29 (br s, 1H), 4.98 (br s, 1H), 4.79 (dd, J= 6.1, 8.7 Hz, 1H), 4.65 (t, J=9.2 Hz, 1H), 4.46 (dd, J=6.1,

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The only stereoisomer; the absolute configuration of the chiral center in dihydrobenzofuran has not been determined 9.4 Hz, 1H), 3.56 (br dd, J=6.8, 13.3 Hz, 1H), 3.04 (brd, J=7.5 Hz, 1H), 2.48-2.38 (m, 1H), 2.071. 79 (m, 2H), 1.77-1.49 (m, 3H), 1.02 (br d, >5.8Hz, 6H) [a] _D ²⁵ -50 (c 0.12, MeOH) Peak 1 of 2: Column: Chiralpak AD-3 150 x 4.6 mm i.d., 3 µm; mobile phase: 40% IPA (0.05% DEA) in CCE; flow rate: 2.5 ml/min; column temperature 35°C 57 (A) \ / ⁿ 1-0 (1R,3S)~3 -(3 - {[(3 £)-2,3-dihydro-1 benzofuran-3-ylcarbonyl] amino } - 177-pyrazol5 -yl)cyclopentyl-propan- 2ylcarbamate - Isomer B The only stereoisomer; the absolute configuration of the chiral center in dihydrobenzofuran has not been determined 399.3 Ή NMR (400 MHz, DMSO-d6) δ = 12.12 (br s, 1H), 10.81 (s, 1H), 7.30 (d, J=7.3 Hz, 1H), 7.14 (t, J=7.8 Hz, 1H), 6.93 (br d, J=8.3 Hz, 1H), 6.87-6.74 (m, 2H), 6.29 (br s, 1H), 4.98 (br s, 1H), 4.79 (dd, J =6.0, 8.8 Hz, 1H), 4.65 (t, J=9.0 Hz, 1H), 4.46 (dd, J=6.4, 9.4 Hz, 1H), 3.65-3.47 (m, 1H), 3.04 (br d, 1=8.0Hz, 1H), 2.44 (br d, J=7.0 Hz, 1H), 2.08-1.80 (m, 2H), 1.79-1.47 (m, 3H), 1.11-0.88 ( m, 6H) [a] _D ²⁵ -47 (c 0.4, MeOH) Peak 2 of 2: Column: Chiralpak AD-3 150 x 4.6 mm i.d., 3 µm; mobile phase: 40% IPA (0.05% DEA) in CO2; flow rate: 2.5 ml/min; column temperature 35°C

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58 (IN) 1 ijX Η (17?,35)-3-(3-{[(2- methoxypyridine-4- yl)acetyl] amino } - 177-pyrazol-5 yl)cyclopentyl-methyl(propan-2yl)carbamate All stereocenters are known 416.4 Ή NMR (400 MHz, DMSO-d6) δ = 12.09 (br s, 1H), 10.56 (s, 1H), 8.07 (d, J=5.3 Hz, 1H), 6.91 (dd, J=1.3, 5 ,3 Hz, 1H), 6.74 (s, 1H), 6.29 (br s, 1H), 5.01 (br s, 1H), 4.37-4.01 (m, 1H), 3.89-3.79 (m, 3H), 3.58 ( s, 2H), 3.16-2.98 (m, 1H), 2.61 (br s, 3H), 2.46-2.26 (m, 1H), 2.05-1.94 (m, 1H), 1.931.81 (m, 1H), 1.79 -1.60 (m, 3H), 0.99 (br d, J=6.5 Hz, 6H) 59 (IN) 1 Η (17?,35)-3-(3-{[(6methoxypyridin-3yl)acetyl]amino} - 177-pyrazol-5yl)cyclopentyl-methyl(propan-2yl)carbamate All stereocenters are known 416.3 Ή NMR (400 MHz, DMSO-d6) δ = 12.07 (br s, 1H), 10.52 (s, 1H), 8.06 (d, J=2.3 Hz, 1H), 7.63 (dd, J=2.5, 8 .5 Hz, 1H), 6.77 (d, J=8.5 Hz, 1H), 6.28 (br s, 1H), 5.01 (br s, 1H), 4.31-4.00 (m, 1H), 3.853.77 ( m, 3H), 3.53 (s, 2H), 3.08 (quin, J=7.9 Hz, 1H), 2.61 (br s, 3H), 2.44-2.33 (m, 1H), 2.05-1.96 (m, 1H ), 1.93-1.81 (m, 1H), 1.791.61 (m, 3H), 0.99 (br d, J=6.6 Hz, 6H) 60 (A) N Τι/у рЦ. Ji J| _/N H (17?, 35)-3 -(3 - {[(1 -methyl-177pyrazol-4-yl)acetyl] amino } -177pyrazol-5-yl)cyclopentylpropan-2-ylcarbamate All stereocenters are known 375.3 Ή NMR (400 MHz, DMSO-d6) δ = 12.04 (br s, 1H), 10.35 (br s, 1H), 7.54 (s, 1H), 7.29 (s, 1H), 6.95 (br d, J=7 ,6 Hz, 1H), 6.29 (br s, 1H), 4.98 (br s, 1H), 3.78 (s, 3H), 3.57 (br dd, J=6.7, 13.4 Hz, 1H), 3.39 (s , 2H), 3.11-2.97 (m, 1H), 2.48-2.38 (m, 1H), 2.09-1.79 (m, 2H), 1.78-1.50 (m, 3H), 1.02 (br d, J=6.5 Hz, 6H)

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61 (IN) n/x LE Al I °*CA/si ^H , ^N ~N 0 πΝ y N2LZ Ji J| _/N H (17?, 35)-3 -(3 - {[(1 -methyl-177pyrazol-4-yl)acetyl] amino }-1Hpyrazol-5-yl)cyclopentyl-(2methylbutan-2-yl)carbamate All stereocenters are known [M+Na]+ 424.8 Ή NMR (400 MHz, DMSO-d6) δ = 12.03 (br s, 1H), 10.34 (s, 1H), 7.53 (s, 1H), 7.28 (s, 1H), 6.62 (br s, 1H), 6.27 (br s, 1H), 4.95 (br s, 1H), 3.77 (s, 3H), 3.38 (br s, 2H), 3.10-2.91 (m, 1H), 2.47-2.37 (m, 1H), 2.04- 1.93 (m, 1H), 1.91-1.78 (m, 1H), 1.76-1.62 (m, 2H), 1.56 (br d, J=7.5 Hz, 3H), 1.13 (s, 6H), 0.74 (t , J=7.4 Hz, 3H) 62 (IN) n /χ,Ν^Ο L_/ AA _N AA _O η (17?,35)-3-(3-{[(5-methyl-1,3-oxazol-2-yl)acetyl] amino} -177pyrazol- 5-yl)cyclopentyl-(2methylbutan-2-yl)carbamate All stereocenters are known 404.4 Ή NMR (400 MHz, DMSO-d6) δ = 12.10 (br s, 1H), 10.62 (s, 1H), 6.74 (d, J=l, 1 Hz, 1H), 6.62 (br s, 1H), 6.28 (s, 1H), 4.95 (br s, 1H), 3.79 (s, 2H), 3.03(quin, J=8.6 Hz, 1H), 2.47-2.40 (m, 1H), 2.25 (d, J= 0.9 Hz, 3H), 2.04-1.94 (m, 1H), 1.92-1.82 (m, 1H), 1.74-1.64 (m, 2H), 1.56 (q, J=7.2 Hz, 3H), 1.13 (s, 6H), 0.73 (t, >7.5Hz, 3H) 63 (A) n ^F XX^X*, ^N x^0 ^F F 1 ^o *6L\/ _S1 ^H / ^N ~N 0 N'Q ι /AL DA/ Η (17?, 35)-3-{3-[(1 ,2-oxazole-Zylacetyl)amino] - 177-pyrazol-5- Ηπ}φΐκποπεΗΤΗΠ-[(2ξ)-4,4,4trifluorobutan-2-yl] carbamate - Isomer A The only stereoisomer; the absolute configuration of the chiral center in 4,4,4trifluorobutan-2-yl] carbamate is not 430.2 'H NMR (400 MHz, DMSO-d6) δ = 12.12 (s, 1H), 10.65 (br s, 1H), 8.83 (s, 1H), 7.19 (br d, J=8.3 Hz, 1H), 6.53 (s, 1H), 6.29 (br s, 1H), 4.99 (br d, J=2.5 Hz, 1H), 3.893.78 (m, 1H), 3.75 (s, 2H), 3.092.97 ( m, 1H), 2.45-2.29 (m, 3H), 2.04-1.95 (m, 1H), 1.92-1.84 (m, 1H), 1.77-1.63 (m, 2H), 1.61-1.52 (m, 1H), 1.10 (br d, J=6.5 Hz, 3H) [a] _D ²⁰ -2.85 (c 0.117, MeOH) Peak 1 of 2: Column: Xtimate

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determined C18 150 x 25 mm x 5 microns; mobile phase: 22 to 52% CH ₃ CN in water (0.05% ammonium hydroxide v/v); flow rate: 25 ml/min 64 (A) Η ^F F 1 °«6Γ\«ι ^Η / ^Ν ~Ν 0 N'Q ίγ \ΡΖ^Ζ η and and \ Τ A Η (1R, 35)-3-{3-[(1,2-oxazol- Zylacetyl)amino] - 177-pyrazol-5ππ}ιιπκποπ6Ητππ-[(2ξ)-4,4,4trifluorobutan-2-yl] carbamate Isomer B Single stereoisomer; the absolute configuration of the chiral center in 4,4,4trifluorobutan-2-yl] carbamate was not determined 430.4 'H NMR (400 MHz, DMSO-d6) δ = 12.11 (s, 1H), 10.63 (s, 1H), 8.83 (d, J=l,0 Hz, 1H), 7.20 (br d, J=8, 0 Hz, 1H), 6.53 (s, 1H), 6.29 (s, 1H), 5.04-4.95 (m, 1H), 3.843.77 (m, 1H), 3.75 (s, 2H), 3.072.98 (m , 1H), 2.46-2.32 (m, 3H), 2.04-1.95 (m, 1H), 1.94-1.84 (m, 1H), 1.77-1.64 (m, 2H), 1.61-1.50 (m, 1H), 1.11 (br d, J=6.8 Hz, 3H) [a] _D ²⁵ +8.12 (c 0.197, MeOH) Peak 2 of 2: Column: Xtimate Cl8 150 x 25 mm x 5 µm; mobile phase: 22 to 52% CH ₃ CN in water (0.05% ammonium hydroxide v/v); flow rate: 25 ml/min 65 (A) n I ^F °4^\(-sJ- ^N ~N ° NN H (17?, 35)-3 -(3 - {[(1-methyl-177pyrazol-3-yl)acetyl] amino } - 1Hpyrazol-5 -yl)cyclopentyl-[(2ξ)4,4,4-trifluorobutan-2yl]carbamate - Isomer A The only stereoisomer; the absolute configuration of the chiral center is 4,4,4-. 443.3 'H NMR (400 MHz, DMSO-d6) δ = 12.04 (s, 1H), 10.35 (s, 1H), 7.55 (d, J=2.0 Hz, 1H), 7.19 (br d, J=8, 3 Hz, 1H), 6.29 (s, 1H), 6.10 (d, J=2.3 Hz, 1H), 4.99 (br d, J=2.0 Hz, 1H), 3.88-3.79 (m, 1H) , 3.76 (s, 3H), 3.52 (s, 2H), 3.072.98 (m, 1H), 2.48-2.30 (m, 3H), 2.05-1.95 (m, 1H), 1.92-1.83 (m, 1H) , 1.77-1.63 (m, 2H), 1.61-1.52 (m, 1H), 1.10 (d, J=6.5 Hz, 3H)

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trifluorobutan-2-yl] carbamate was not determined [a] _D ²⁵ -3.56 (s 0.15, MeOH) Peak 1 of 2: Column: Chiralpak AD-3 150 x 4.6 mm x 3 µm; mobile phase: 40% EtOH (0.05% DEA) in CO ₂ ; flow rate: 2.5 ml/min 66 (A) n F ¹ HM- _N ο Ν'* ¹ . y xsLZ H K j] λ Η (ΙΑ, 35)-3 -(3 - {[(1 -methyl-1Ηpyrazol-3 -yl)acetyl] amino } -1Hpyrazol-5 -yl)cyclopentyl- [(2ξ)4 ,4,4-trifluorobutan-2yl]carbamate - Isomer B The only stereoisomer; the absolute configuration of the chiral center in 4,4,4trifluorobutan-2-yl] carbamate was not determined 443.3 'H NMR (400 MHz, DMSO-d6) δ = 12.04 (br dd, J=5.9, 9.4 Hz, 1H), 10.36 (br s, 1H), 7.55 (d, J=2.0 Hz, 1H ), 7.24-7.16 (m, 1H), 6.31-6.22 (m, 1H), 6.10 (d, J=2.0 Hz, 1H), 5.04-4.94 (m, 1H), 3.863.78 (m, 1H ), 3.76 (s, 3H), 3.52 (s, 2H), 3.08-2.97 (m, 1H), 2.472.29 (m, 3H), 2.05-1.94 (m, 1H), 1.93-1.83 (m, 1H ), 1.77-1.62 (m, 2H), 1.60-1.49 (m, 1H), 1.11 (d, J=6.5 Hz, ZN) [a] _D ²⁵ +2.73 (c 0.22, MeOH) ; Peak 2 of 2: Column: Chiralpak AD-3 150 x 4.6 mm x 3 µm; mobile phase: 40% EtOH (0.05% DEA) in CO ₂ ; flow rate: 2.5 ml/min 67 (A) n ^F F 1 HN-N O ^N Xf'° H (lA,35)-3-(3-{[(5methoxypyrazin-2-yl)acetyl] amino } - 17/-pyrazol-5 yl)cyclopentyl-[^ )-4,4,4trifluorobutan-2-yl] carbamate Isomer A 471.3 'H NMR (400 MHz, DMSO-d6) δ = 12.07 (s, 1H), 10.54 (s, 1H), 8.23 (d, J=l,3 Hz, 1H), 8.16 (s, 1H), 7.17 ( brd, J=8.3 Hz, 1H), 6.27 (s, 1H), 5.02-4.95 (m, 1H), 3.89 (s, 3H), 3.85-3.79 (m, 1H), 3.77 (s, 2H) , 3.07-2.99 (m, 1H), 2.47-2.29 (m, 3H), 2.03-1.94 (m, 1H), 1.91-1.83 (m, 1H), 1.73-1.62

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The only stereoisomer; the absolute configuration of the chiral center in 4,4,4trifluorobutan-2-yl] carbamate was not determined (m, 2H), 1.60-1.52 (m, 1H), 1.121.07 (w, ZI) [a] _D ²⁵ -1.67 (c 0.12, MeOH); Peak 1 of 2: Column: Chiralpak AD-3 150 x 4.6 mm x 3 µm; Mobile phase: 40% IPA (0.05% DEA) in CO2, Flow rate: 2.5 ml/min 68 (A) n ^F F 1 Ο Η (17?,3S)-3-(3-{[(5methoxypyrazin-2yl)acetyl] amino } - 1//-pyrazol-5 Ηπ)πΗκποπεΗΤΗΠ-[(2ξ)-4,4, 4trifluorobutan-2-yl] carbamate Isomer B Single stereoisomer; the absolute configuration of the chiral center in 4,4,4trifluorobutan-2-yl] carbamate was not determined 471.3 Ή NMR (400 MHz, DMSO-d6) δ = 12.07 (s, 1H), 10.54 (s, 1H), 8.22 (d, 1=1.0Hz, 1H), 8.16 (s, 1H), 7.19 (brd, J=8.5 Hz, 1H), 6.27 (s, 1H), 5.05-4.94 (m, 1H), 3.89 (s, 3H), 3.85-3.78 (m, 1H), 3.77 (s, 2H), 3.02 (dt, J=1.3, 8.3 Hz, 1H), 2.47-2.30 (m, 3H), 2.041.93 (m, 1H), 1.91-1.83 (m, 1H), 1.73-1.62 (m, 2H) , 1.58-1.48 (m, 1H), 1.14-1.07 (m, 3H) [a] _D ²⁵ +6.67 (c 0.11, MeOH); Peak 2 of 2: Column: Chiralpak AD-3 150 x 4.6 mm x 3 µm; Mobile phase: 40% IPA (0.05% DEA) in CO2, Flow rate: 2.5 ml/min 69 (A) n R/χ^,Ν^,Ο ^F F 1 ⁰ h (17?,30)-3-(3-{[(6-methylpyridin3 -yl)carbonyl] amino } -\Hpyrazol-5 -yl)cyclopentyl- [(2ξ)4,4,4-trifluorobutane-2- 440.3 'H NMR (400 MHz, DMSO-d6) a = 12.23 (s, 1H), 10.87 (s, 1H), 8.99 (d, J=l,8 Hz, 1H), 8.20 (dd, J=2.3, 8 ,0 Hz, 1H), 7.36 (d, J=7.8 Hz, 1H), 7.22 (br d, 1=8.3Hz, 1H), 6.46 (s, 1H), 5.02 (br d, >5.5 Hz, 1H), 3.90-3.77 (m, 1H), 3.14-3.01 (m, 1H), 2.53 (s, ZN), 2.49-2.44

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yl]carbamate - Isomer A The only stereoisomer; the absolute configuration of the chiral center in 4,4,4trifluorobutan-2-yl] carbamate was not determined (m, 1H), 2.43-2.31 (m, 2H), 2.081.99 (m, 1H), 1.96-1.84 (m, 1H), 1.78-1.69 (m, 2H), 1.67-1.57 (w, 1H) , 1.12 (d, J=6.5 Hz, ZI) [a] _D ²⁵ -2 (s 0.1, MeOH) Peak 1 of 2: Column: ChiralPak AD-3 150 x 4.6 mm x 3 µm; Gradient: 40% IP A (0.1% ethanolamine) in CO ₂ ; flow rate: 2.5 ml/min; column temperature 40°C 70 (A) n ^F F °«β!-Χ«> ^Η / ^Ν ~Ν O '—/ ^H (17?,35)-3-(3-{[(6-methylpyridin3 -yl)carbonyl] amino } - \Hpyrazol- 5 -yl)cyclopentyl-[(2ξ)4,4,4-trifluorobutan-2yl]carbamate - Isomer B Single stereoisomer; the absolute configuration of the chiral center in 4,4,4trifluorobutan-2-yl] carbamate was not determined 440.4 Ή NMR (400 MHz, DMSO-d6) δ = 12.23 (s, 1H), 10.87 (s, 1H), 8.99 (d, J=l,8 Hz, 1H), 8.20 (dd, J=2.3, 8, 0 Hz, 1H), 7.36 (d, J=8.3 Hz, 1H), 7.23 (br d, 1=8.5Hz, 1H), 6.46 (s, 1H), 5.02 (br d, J=5.0 Hz, 1H), 3.83 (td, J=7.0, 14.2 Hz, 1H), 3.15-3.01 (m, 1H), 2.53 (s, 3H), 2.47 (br s, 1H), 2.45-2.29 (m , 2H), 2.04 (br d, J=7.8 Hz, 1H), 1.96-1.85 (m, 1H), 1.80-1.67 (m, 2H), 1.66-1.55 (m, 1H), 1.13 (d, J=6.5 Hz, 3H) [a] _D ²⁵ +8 (c 0.1, MeOH) Peak 2 of 2: Column: ChiralPak AD-3 150 x 4.6 mm x 3 µm; Gradient: 40% IP A (0.1% ethanolamine) in CO ₂ ; flow rate: 2.5 ml/min; column temperature 40°C

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71 (IN) n f^x* n^o ^F F 1 0«0\/s) ^H / ^N ~N o P Y p-4 XXX n H (17?, 35)-3 -(3 - {[(3 -methyl -1,2oxazol-5 -yl)acetyl] amino } - 1Hpyrazol-5 -yl)cyclopentyl-[(2ξ)4,4,4-trifluorobutan-2yl]carbamate - Isomer A Single stereoisomer; the absolute configuration of the chiral center in 4,4,4trifluorobutan-2-yl] carbamate was not determined 444.3 Ή NMR (400 MHz, DMSO-d6) δ = 12.14 (s, 1H), 10.64 (s, 1H), 7.18 (d, J=8.5 Hz, 1H), 6.29 (br s, 1H), 6.22 ( s, 1H), 5.06-4.93 (m, 1H), 3.94-3.69 (m, 3H), 3.14-2.93 (m, 1H), 2.48-2.29 (m, 3H), 2.20 (s, 3H), 2.07- 1.80 (m, 2H), 1.771.52 (m, 3H), 1.12 (d, J=6.8 Hz, ZN) [a] _D ²⁵ -1.0 (c 0.2, MeOH) Peak 1 of 2: Column : SS WHELK-01 (250 mm x 50 mm, 10 µm); mobile phase: 35% IP A (0.1% NH ₃ .H ₂ O) in CO ₂ ; flow rate: 7 ml/min; column temperature 40°C 72 (IN) n F^-v· Ν^Ο ^F f 1 ^ο «6Α«> ^Η / ^Ν ~ν ο φ ρ-4 XXX ν η (17?, 35)-3 -(3 - {[(3 -methyl-1 ,2oxazol-5 -yl)acetyl] amino } - 1Hpyrazol-5 -yl)cyclopentyl-[(2ξ)4,4,4-trifluorobutan-2yl]carbamate - Isomer B Single stereoisomer; the absolute configuration of the chiral center in 4,4,4trifluorobutan-2-yl] carbamate was not determined 444.3 Ή NMR (400 MHz, DMSO-d6) δ = 12.13 (br s, 1H), 10.64 (s, 1H), 7.20 (d, J=8.5 Hz, 1H), 6.28 (s, 1H), 6.22 ( s, 1H), 5.07-4.90 (m, 1H), 3.89-3.77 (m, 3H), 3.13-2.98 (m, 1H), 2.48-2.26 (m, 3H), 2.20 (s, 3H), 2.06- 1.83 (m, 2H), 1.791.51 (m, 3H), 1.12 (d, J=6.5 Hz, ZN) [a] _D ²⁵ +1.0 (c 0.2, MeOH) Peak 2 of 2 : Column: SS WHELK-01 (250 mm x 50 mm, 10 µm); mobile phase: 35% IP A (0.1% NH ₃ .H2O) in CO ₂ ; flow rate: 7 ml/min; column temperature 40°C

- 80 046965

73 (IN) n ^F F 1 °4ST\(S?/ ^N 'N o ΙΑΜΧ» Η (1A,35)-3-(3-{[(5-methylpyrazin2-yl)acetyl] amino} - 177-pyrazol5 -yl)cyclopentyl - [(2ξ)-4,4,4trifluorobutan-2-yl]carbamate Isomer A The only stereoisomer; the absolute configuration of the chiral center in 4,4,4trifluorobutan-2-yl]carbamate was not determined. 455.4 Ή NMR (400 MHz, DMSO-d6) δ =12.09 (br s, 1H), 10.64-10.53 (m, 1H), 8.50-8.42 (m, 2H), 7.18 (d, J=8.3 Hz, 1H ), 6.27 (br s, 1H), 5.02-4.94 (m, 1H), 3.85-3.78 (m, 3H), 3.07-2.96 (m, 1H), 2.46 (s, 3H), 2.44-2.26 (m, 3H), 2.03-1.95 (m, 1H), 1.91-1.82 (m, 1H), 1.721.62 (m, 2H), 1.57 (dt, J=5.0, 9.0 Hz, 1H), 1.09 (d, J=6.8 Hz, ZN) [a] _D ²⁵ -1.82° (c 0.11, MeOH) Peak 1 of 2; Column: Chiralpak AD-3 50x 3 mm x 3 µm; mobile phase: 40% EtOH (0.05% DEA) in CO ₂ ; flow rate: 2 ml/min; column temperature 40°C 74 (IN) n F^XX^-IM^O ^F F 1 O N^^y H (17?,35)-3-(3-{[(5-methylpyrazin2-yl)acetyl] amino} - 177-pyrazol5-yl) cyclopentyl-[(2ξ)-4,4,4trifluorobutan-2-yl] carbamate Isomer B Single stereoisomer; the absolute configuration of the chiral center in 4,4,4trifluorobutan-2-yl] carbamate was not determined 455.4 'H NMR (400 MHz, DMSO-d6) δ =12.09 (s, 1H), 10.60 (s, 1H), 8.46 (d, J=13.6 Hz, 2H), 7.20 (br d, J=8, 3 Hz, 1H), 6.27 (s, 1H), 5.02-4.94 (m, 1H), 3.84-3.76 (m, 3H), 3.02 (quin, J=8.4 Hz, 1H), 2.46 (s, 3H ), 2.45-2.25 (m, 3H), 2.03-1.94 (m, 1H), 1.92-1.83 (m, 1H), 1.75-1.63 (m, 2H), 1.60-1.49 (m, 1H), 1.10 (d , J=6.8 Hz, ZN) [a] _D ²⁵ +6.67 (c 0.12, MeOH) Peak 2 of 2; Column: Chiralpak AD-3 50x 3 mm x 3 µm; mobile phase: 40% EtOH (0.05% DEA) in CO ₂ ; flow rate: 2 ml/min; temperature

- 81 046965

columns 40°C 75 (IN) n ^Ff TXijXi Η (17?,35)-3-(3-{[(6-methylpyridin3 -yl)acetyl] amino } - 1//-pyrazol5 -yl)cyclopentyl-[(2ξ)-4,4,4trifluorobutane -2-yl]carbamate Isomer A Single stereoisomer; the absolute configuration of the chiral center in 4,4,4trifluorobutan-2-yl] carbamate was not determined 454.4 Ή NMR (400 MHz, DMSO-d6) δ = 12.17-11.90 (m, 1H), 10.6210.49 (m, 1H), 8.35 (d, J=2.0 Hz, 1H), 7.58 (dd, J= 2.1, 7.9 Hz, 1H), 7.22-7.13 (m, 2H), 6.25 (s, 1H), 5.02-4.94 (m, 1H), 3.87-3.76 (m, 1H), 3.57 (s, 2H) , 3.08-2.96 (m, 1H), 2.46-2.28 (m, 6H), 2.03-1.93 (m, 1H), 1.92-1.81 (m, 1H), 1.761.61 (m, 2H), 1.55 (dt, J=4.8, 9.3 Hz, 1H), 1.10 (d, J=6.8 Hz, ZH) [a] _D ²⁵ +4.44 (c 0.120, MeOH) Peak 1 of 2: Column: SS WHELK- 01 (250 mm x 50 mm, 10 µm); mobile phase: 35% EtOH (0.1% NH3.H2O) in CO ₂ ; flow rate: 7 ml/min; column temperature 40°C 76 (IN) n ^f >X ⁴ y' ⁿ 'X° ^FF °4s-^X/ ⁿ ~n ο χχ Η (17?,35)-3-(3-{[(6-methylpyridin3 -yl)acetyl ] amino } - 1//-pyrazol5-yl) cyclopentyl-[(2ξ)-4,4,4trifluorobutan-2-yl] carbamate Isomer B Single stereoisomer; the absolute configuration of the chiral center in 4,4,4trifluorobutan-2-yl] carbamate was not determined 454.4 Ή NMR (400 MHz, DMSO-d6) δ = 12.25-11.76 (m, 1H), 10.7310.48 (m, 1H), 8.35 (s, 1H), 7.627.54 (m, 1H), 7.18 (br d , J=8.0 Hz, 2H), 6.29-6.21 (m, 1H), 5.054.91 (m, 1H), 3.88-3.75 (m, 1H), 3.57 (s, 2H), 3.08-2.94 (m , 1H), 2.45-2.25 (m, 6H), 2.06-1.93 (m, 1H), 1.91-1.83 (m, 1H), 1.76-1.61 (m, 2H), 1.59-1.48 (m, 1H), 1.151 .06 (m, 3H) [a] _D ²⁵ +5.56 (c 0.108, MeOH) Peak 2 of 2: Column: SS WHELK-01 (250 mm x 50 mm,

- 82 046965

10 µm); mobile phase: 35% EtOH (0.1% NH3.H2O) in CO ₂ ; flow rate: 7 ml/min; column temperature 40°C 77 (IN) n ^ρ >Ι^Α ^Ν 'γ> ^{ο F} F 1 °«iS^«i ^H / ^N ~N 0 A'N yWji K G jf H (lA,3S)-3-(3-{[(2methoxypyridinium 4yl)acetyl] amino } - 1//-pyrazol-5 yl)cyclopentyl-[^)-4,4,4trifluorobutan-2-yl] carbamate Isomer A Single stereoisomer; the absolute configuration of the chiral center in 4,4,4trifluorobutan-2-yl] carbamate was not determined 470.4 Ή NMR (400 MHz, DMSO-d6) δ = 12.10 (br s, 1H), 10.59 (s, 1H), 8.08 (d, J=5.3 Hz, 1H), 7.17 (br d, J=8, 5 Hz, 1H), 6.92 (dd, J=1.3, 5.3 Hz, 1H), 6.74 (s,lH), 6.27 (s, 1H), 5.07-4.92 (m, 1H), 3.90-3.76 (m , 4H), 3.59 (s, 2H), 3.11-2.97 (m, 1H), 2.48-2.27 (m, 3H), 2.051.94 (m, 1H), 1.92-1.80 (m, 1H), 1.75-1.52 (m, 3H), 1.11 (d, J=6.8 Hz, ZN) [a] _D ²⁵ +2.98 (c 0.134, MeOH) Peak 1 of 2: Column: SS WHELK-01 (250 mm x 50 mm, 10 µm); mobile phase: 35% IP A (0.1% NH3.H2O) in CO ₂ ; flow rate: 6.5 ml/min; column temperature 40°C 78 (IN) n ^ι= >ρ ^χχ γ ^Ν γ ^{ο FF} o Η (17?,3S)-3-(3-{[(2methoxypyridin-4-yl)acetyl] amino } - 1//-pyrazol-5 yl)cyclopentyl- [^)-4,4,4trifluorobutan-2-yl] carbamate Isomer B Single stereoisomer; absolute configuration 470.4 Ή NMR (400 MHz, DMSO-d6) δ = 12.10 (br s, 1H), 10.59 (s, 1H), 8.08 (d, J=5.0 Hz, 1H), 7.19 (br d, J=8, 5 Hz, 1H), 6.98-6.88 (m, 1H), 6.74 (s, 1H), 6.27 (s, 1H), 5.00 (br s, 1H), 3.91-3.75 (m, 4H), 3.59 (s, 2H), 3.12-2.97 (m, 1H), 2.49-2.27 (m, 3H), 2.07-1.80 (m, 2H), 1.771.62 (m, 2H), 1.61-1.49 (m, 1H), 1.12 ( d, 1=6.8Hz, ZN) [a] _D ²⁵ +8.0 (c 0.1, MeOH)

- 83 046965

chiral center in 4,4,4trifluorobutan-2-yl] carbamate was not determined Peak 2 of 2: Column: SS WHELK-O1 (250 mm x 50 mm, 10 µm); mobile phase: 35% IP A (0.1% NH3.H2O) in CO ₂ ; flow rate: 6.5 ml/min; column temperature 40°C 79 (IN) n ^F F 1 O fi^N ΎΤ-ζΛ l Η (17?,35)-3 -(3 -{[(2-methyl-1,3thiazol-5 -yl)acetyl] amino } -1/7pyrazol-5 -yl)cyclopentyl-[(2 ξ)4,4,4-trifluorobutan-2yl]carbamate - Isomer A Single stereoisomer; the absolute configuration of the chiral center in 4,4,4trifluorobutan-2-yl] carbamate was not determined 460.2 Ή NMR (400 MHz, DMSO-d6) δ = 12.10 (br s, 1H), 10.58 (s, 1H), 7.40 (s, 1H), 7.18 (br d, J=8.5 Hz, 1H), 6.27 (br s, 1H), 4.99 (br s, 1H), 3.86-3.73 (m, 3H), 3.10-2.95 (m, 1H), 2.58 (s, 3H), 2.47-2.28 (m, 3H), 2.04 -1.95 (m, 1H), 1.921.81 (m, 1H), 1.75-1.63 (m, 2H), 1.61-1.52 (m, 1H), 1.11 (d, J=6.8 Hz, 3H) ¹⁹ F NMR (376 MHz, DMSO-d6) δ = -62.57 (br s, 3F); [a] _D ²⁵ +3 (c 0.2, MeOH) Peak 1 of 2: Column: SS WHELK-01 (250 mm x 50 mm, 10 µm); mobile phase: 35% EtOH (0.1% NH3.H2O) in CO ₂ ; flow rate: 7 ml/min; column temperature 40°C 80 (IN) n ^f >| ^x ^ ⁴ y' ⁿ 'Y ^{>o F} F 1 o tPMa l___L>~~ H (17?,35)-3 -(3 -{[(2-methyl-1,3-thiazol-5-yl)acetyl ] amino } -1/7pyrazol-5-yl)cyclopentyl-[(2 ξ)- 4,4,4-trifluorobutan-2yl]carbamate - Isomer B 460.3 'H NMR (400 MHz, DMSO-d6) δ = 12.09 (br s, 1H), 10.58 (s, 1H), 7.40 (s, 1H), 7.19 (d, J=8.3 Hz, 1H), 6.27 (s, 1H), 4.99 (br s, 1H), 3.87-3.79 (m, 3H), 3.08- 2.97 (m, 1H), 2.58 (s, 3H), 2.47-2.28 (m, 3H), 2.04- 1.95 (m, 1H), 1.93-1.82 (m, 1H), 1.76-1.62 (m, 2H), 1.60-

- 84 046965

The only stereoisomer; the absolute configuration of the chiral center in 4,4,4trifluorobutan-2-yl]carbamate was not determined 1.49 (m, 1H), 1.12 (d, J=6.8 Hz, 3H) ¹⁹ F NMR (376 MHz, DMSO-d6) δ = -62.55 (br s, 3F); [a] _D ²⁵ +12 (c 0.2, MeOH) Peak 2 of 2: Column: SS WHELK-01 (250 mm x 50 mm, 10 µm); mobile phase: 35% EtOH (0.1% NH3H2O) in CO ₂ ; flow rate: 7 ml/min; column temperature 40°C 81 (A) n ^F >| ^X ^V' ^N 'Y ^>OFF fl ϊίA— Η (17?,35)-3-(3-{[(5-methyl-1,3oxazol-2-yl)acetyl] amino } -\Ηpyrazol-5 - yl)cyclopentyl-[(2ξ)4,4,4-trifluorobutan-2yl]carbamate - Isomer A Single stereoisomer; the absolute configuration of the chiral center in 4,4,4-trifluorobutan-2-yl]carbamate was not determined 444.3 Ή NMR (400 MHz, DMSO-d6) δ = 12.12 (s, 1H), 10.62 (br s, 1H), 7.18 (br d, J=8.6 Hz, 1H), 6.74 (s, 1H), 6.28 (br s, 1H), 4.99 (br d, J=2.0 Hz, 1H), 3.83 (br d, J=6.2 Hz, 1H), 3.79 (s, 2H), 3.08-2.98 (m, 1H), 2.46-2.32 (m, 3H), 2.25 (s, 3H), 2.04-1.95 (m, 1H), 1.931.83 (m, 1H), 1.74-1.54 (m, 3H), 1.10 (brd, 1=6.6Hz, 3H) [a] _D ²⁵ -1.91 (c 0.115, MeOH) Peak 1 of 2: Column: Chiralpak AD-3 150 x 4.6 mm i.d., 3 µm; mobile phase: 40% EtOH (0.05% DEA) in CO ₂ ; flow rate: 2.5 ml/min; column temperature 35°C 82 (A) n Υγ'-γΝ'γί ^{0 FF} °γ\ΐ( ^Ν 'ΐ] Η ΐίΎη (17?,36)-3-(3-{[(5-methyl-1,3oxazol-2-yl)acetyl] amino }-1Η- 444.3 Ή NMR (400 MHz, DMSO-d6) δ = 12.11 (s, 1H), 10.62 (br s, 1H), 7.20 (br d, >8.3 Hz, 1H), 6.74 (d, J=l,l Hz, 1H), 6.28 (br s, 1H), 5.05-4.94 (m, 1H), 3.88-3.80 (m,

- 85 046965

pyrazol-5 -yl)cyclopentyl-[(2ξ)4,4,4-trifluorobutan-2yl]carbamate - Isomer B Single stereoisomer; the absolute configuration of the chiral center in 4,4,4trifluorobutan-2-yl] carbamate was not determined 1H), 3.79 (s, 2H), 3.09-2.99 (w, 1H), 2.47-2.31 (w, ZI), 2.25 (d, J=l,0 Hz, ZI), 2.06-1.95 (m, 1H) , 1.95-1.85 (m, 1H), 1.75-1.64 (w, 2H), 1.61-1.51 (m, 1H), 1.11 (d, J=6.7 Hz, ZI) [a] _D ²⁵ +1.74 (c 0.115, MeOH) Peak 2 of 2: Column: Chiralpak AD-3 150 x 4.6 mm i.d., 3 µm; mobile phase: 40% EtOH (0.05% DEA) in CO ₂ ; flow rate: 2.5 ml/min; column temperature 35°C 83 (A) n ^F F 1 O4S- HIM-N 0 itN f NSLZ to l| } H (17?,35)-3-{3-[(1,3-oxazol-5ylacetyl)amino] - 1//-pyrazole-5Ηπ}ρπκποπεΗΤΗπ-[(2ξ)-4,4,4trifluorobutane-2- yl]carbamate Isomer A Single stereoisomer; the absolute configuration of the chiral center in 4,4,4trifluorobutan-2-yl] carbamate was not determined 430.4 'H NMR (400 MHz, DMSO-d6) δ = 12.09 (s, 1H), 10.56 (s, 1H), 8.25 (s, 1H), 7.17 (br d, J=8.2 Hz, 1H), 7.00 (s, 1H), 6.28 (s, 1H), 5.05-4.94 (m, 1H), 3.89-3.80 (m, 1H), 3.78 (s, 2H), 3.09-3.00 (m, 1H), 2.46-2.34 (m, 3H), 2.00 (br d, J=9.3 Hz, 1H), 1.88 (dt, J=2.9, 6.5 Hz, 1H), 1.75-1.64 (m, 2H), 1.62-1.53 ( m, 1H), 1.11 (d, J=6.7 Hz, 3H) [a] _D ²⁵ -1.82 (c 0.11, MeOH) Peak 1 of 2: Column: Chiralpak AD-3 150 x 4, 6 mm x 3 µm; mobile phase: 40% EtOH (0.05% DEA) in CO ₂ ; flow rate: 2.5 ml/min; column temperature 35°C

- 86 046965

84 (A) H ^F F 1 ^ο «β>\«) ^Η / ^Ν ~Ν O r/N γ γ-ζ J? X II) C-U H (17?,35)-3-{3-[(1,3-oxazol-5ylacetyl)amino] - 1//-pyrazole-5Ηπ}φΐκποπεΗΤΗπ-[(2ξ)-4,4 ,4trifluorobutan-2-yl] carbamate Isomer B Single stereoisomer; the absolute configuration of the chiral center in 4,4,4trifluorobutan-2-yl] carbamate was not determined 430.4 Ή NMR (400 MHz, DMSO-d6) δ = 12.09 (br s, 1H), 10.56 (s, 1H), 8.25 (s, 1H), 7.18 (br d, J=8.8 Hz, 1H), 7.00 (s, 1H), 6.28 (br s, 1H), 5.00 (br d, J=2.0 Hz, 1H), 3.873.79 (m, 1H), 3.78 (s, 2H), 3.03 (br t, J=8.7 Hz, 1H), 2.47-2.34 (m, 3H), 2.05-1.96 (m, 1H), 1.89 (ddd, J=2.9, 6.6, 9.7 Hz, 1H), 1.75-1.64 ( m, 2H), 1.61-1.50 (m, 1H), 1.12 (brd, J=6.6 Hz, 3H) [a] _D ²⁵ +8.60 (c 0.31, MeOH) Peak 2 of 2: Column : Chiralpak AD-3 150 x 4.6 mm x 3 µm; mobile phase: 40% EtOH (0.05% DEA) in CO ₂ ; flow rate: 2.5 ml/min; column temperature 35°C 85 (A) n ^ρ '>< ^χχ γ ^Ν γ ^{>ο F} F 1 °«6Γχ«> ^Η / ^Ν ~Ν Ο γ X JI Ν Η (17?,35)-3-{3-[(1,2-oxazol- 5ylacetyl)amino] - 1//-pyrazol-5 yl}cyclopentyl-[(2 ξ)-4,4,4trifluorobutan-2-yl] carbamate Isomer A Single stereoisomer; the absolute configuration of the chiral center in 4,4,4trifluorobutan-2-yl] carbamate was not determined 430.3 Ή NMR (400 MHz, DMSO-d6) δ = 12.14 (s, 1H), 10.68 (s, 1H), 8.49 (d, J=l.5 Hz, 1H), 7.20 (d, J=8.5 Hz , 1H), 6.37 (s, 1H), 6.29 (s, 1H), 5.00 (br s, 1H), 3.91 (s, 2H), 3.82 (td, J=7.1, 13.7 Hz, 1H), 3.10 -2.98 (m, 1H), 2.48-2.28 (m, 3H), 2.06-1.95 (m, 1H), 1.951.83 (m, 1H), 1.77-1.52 (m, 3H), 1.10 (d, 1= 6.8 Hz, 3H) [a] _D ²⁵ -4 (c 0.1, MeOH) Peak 1 of 2; Column: Chiralpak AD-3 150 x 4.6 mm i.d., 3 µm; mobile phase: 40% EtOH (0.05% DEA) in CO ₂ ; speed

- 87 046965

flow: 2.5 ml/min; column temperature 35°C 86 (A) H Τ/χ'.ΝγΟ ^F F । °4SLx«> ^H / ^N ~n o t уЦХ X JL ⁿ АУ ^n^'O h (1А,35)-3-{3-[(1,2-oxazol-5ylacetyl)amino] - 1//- pyrazol-5 yl}cyclopentyl-[(2 ξ)-4,4,4trifluorobutan-2-yl] carbamate Isomer B Single stereoisomer; the absolute configuration of the chiral center in 4,4,4trifluorobutan-2-yl] carbamate was not determined 430.4 Ή NMR (400 MHz, DMSO-d6) δ = 12.14 (s, 1H), 10.67 (s, 1H), 8.49 (d, J=l.5 Hz, 1H), 7.21 (br d, J=8.5 Hz, 1H), 6.37 (s, 1H), 6.29 (s, 1H), 5.00 (br s, 1H), 3.91 (s, 2H), 3.87-3.77 (m, 1H), 3.08-2.98 (m, 1H ), 2.47-2.27 (m, 3H), 2.00 (brd, J=8.3 Hz, 1H), 1.94-1.83 (m, 1H), 1.75-1.63 (m, 2H), 1.601.48 (m, 1H ), 1.11 (d, J=6.5 Hz, 3H) [a] _D ²⁵ +12 (c 0.l,MeOH) Peak 2 of 2; Column: Chiralpak AD-3 150 x 4.6 mm i.d., 3 µm; mobile phase: 40% EtOH (0.05% DEA) in CCE; flow rate: 2.5 ml/min; column temperature 35°C 87 (A) n ^F F 1 °4S^4S1 ^H , ^N ~N O n L/ (17?,3S)-3-[3-({[l-(2methoxyethyl)-1//-pyrazol-5yl]carbonyl } amino) - 1//-pyrazol5 -yl] cy clopentyl-[(2ξ)-4,4,4trifluorobutan-2-yl] carbamate Isomer A Single stereoisomer; the absolute configuration of the chiral center in 4,4,4trifluorobutan-2-yl] carbamate is not 473.4 'H NMR (400 MHz, DMSO-d6) δ =12.26 (d, J=l.5 Hz, 1H), 10.75 (s, 1H), 7.51 (d, 1=1.8Hz, 1H), 7.22 (br d, J=8.5 Hz, 1H), 7.13 (d, J=l,8 Hz, 1H), 6.42 (s, 1H), 5.064.97 (m, 1H), 4.69 (t, J=5, 6 Hz, 2H), 3.84 (quind, J=6.7, 13.7 Hz, 1H), 3.66 (t, J=5.6 Hz, 2H), 3.18 (s, 3H), 3.13-3.02 (m, 1H ), 2.472.30 (m, 3H), 2.08-1.99 (m, 1H), 1.96-1.84 (m, 1H), 1.78-1.69 (m, 2H), 1.63 (ddd, J=4.5, 9.3, 13, 8 Hz, 1H), 1.12 (d, J=6.8 Hz, 3H)

- 88 046965

determined [a] _D ²⁵ -7.27 (s 0.11, MeOH) Peak 1 of 2: Column: ChiralPak AD-3 150 x 4.6 mm i.d., 3 µm; mobile phase: 40% EtOH (0.1% ethanolamine) in CO ₂ ; flow rate: 2.5 ml/min; column temperature 40°C 88 (A) Η ^F Y^Y ^N Y° o- ^F F । °«i5A\4si ^H , ^N ''N O h M ^N (17?,3S)-3-[3-({[l-(2methoxyethyl)-1//-pyrazol-5yl]carbonyl } amino)- 1 //-pyrazol5 -yl] cyclopentyl-[(2ξ)-4,4,4trifluorobutan-2-yl] carbamate Isomer B Single stereoisomer; the absolute configuration of the chiral center in 4,4,4trifluorobutan-2-yl] carbamate was not determined 473.3 Ή NMR (400 MHz, DMSO-d6) δ =12.26 (s, 1H), 10.75 (s, 1H), 7.51 (d, J=2.0 Hz, 1H), 7.23 (br d, J=8.3 Hz, 1H), 7.13 (d, J=l,8 Hz, 1H), 6.42 (s, 1H), 5.01 (brd, J=4.5 Hz, 1H), 4.69 (t, J=5.6 Hz , 2H), 3.83 (td, J=7.1, 13.6 Hz, 1H), 3.66 (t, J=5.6 Hz, 2H), 3.18 (s, 3H), 3.14-3.00 (m, 1H), 2.492.25 (m, 3H), 2.09-1.98 (m, 1H), 1.98-1.83 (m, 1H), 1.81-1.67 (m, 2H), 1.65-1.53 (m, 1H), 1.12 (d, J =6.5 Hz, 3H) [a] _D ²⁵ +7.22 (c 0.12, MeOH); Peak 2 of 2: Column: ChiralPak AD-3 150 x 4.6 mm i.d., 3 µm; mobile phase: 40% EtOH (0.1% ethanolamine) in CO ₂ ; flow rate: 2.5 ml/min Column temperature 40°C 89 (A) 1 ^F f 1 °4SL\«) ^H / ^N ~n o VW y K II > H (17?,35)-3-{3-[(1,2-oxazol-5ylacetyl)amino] - 177-pyrazol- 5 - yl}cyclopentyl methyl[(2 £)- 444.3 'H NMR (400 MHz, DMSO-d6) δ = 12.13 (br s, 1H), 10.65 (s, 1H), 8.48 (d, J=l.5 Hz, 1H), 6.36 (s, 1H), 6.30 (s, 1H), 5.00 (br s, 1H), 4.52-4.31 (m, 1H), 3.90 (s, 2H), 3.13-3.01 (m, 1H), 2.68-2.56 (m,

- 89 046965

4,4,4-trifluorobutan-2yl]carbamate - Isomer A Single stereoisomer; the absolute configuration of the chiral center in 4,4,4trifluorobutan-2-yl] carbamate was not determined 4H), 2.45-2.30 (w, 2H), 2.01 (br d, >7.8 Hz, 1H), 1.88 (brd, J=5.8 Hz, 1H), 1.79-1.62 (w, ZI), 1.10 ( d, >7.0Hz, SI) [a] _D ²⁵ -U (s 0.1, MeOH) Peak 1 of 2: Column: Chiralpak AD-3 150 x 4.6 mm i.d., 3 µm; mobile phase: 40% EtOH (0.05% DEA) in CO ₂ ; flow rate: 2.5 ml/min; column temperature 35°C 90 (A) 1 F^/,Ν^,Ο ^F F 1 °«(5^S) ^H / ^N ~N ο π X Ji Ν Η (17?,35)-3-{3-[(1,2-oxazol- 5ylacetyl)amino] - 1//-pyrazol-5 yl}cyclopentyl methyl[(2 ξ)4,4,4-trifluorobutan-2yl]carbamate - Isomer B The only stereoisomer; the absolute configuration of the chiral center in 4,4,4trifluorobutan-2-yl] carbamate was not determined 444.3 Ή NMR (400 MHz, DMSO-d6) δ = 12.13 (br s, 1H), 10.65 (s, 1H), 8.48 (d, J=l.5 Hz, 1H), 6.36 (s, 1H), 6.30 ( s, 1H), 5.04 (brd, J=9.8 Hz, 1H), 4.42 (br s, 1H), 3.90 (s, 2H), 3.08 (br t, J=7.9 Hz, 1H), 2.65 (s, 3H), 2.62-2.53 (m, 1H), 2.45-2.38 (m, 1H), 2.38-2.24 (m, 1H), 2.01 (brd, J=7.5 Hz, 1H), 1.86 (br d, J=4.8 Hz, 1H), 1.78-1.57 (m, 3H), 1.10 (br dd, J=6.9, 15.2 Hz, 3H) [a] _D ²⁵ -4 (s 0.1, MeOH) Peak 2 of 2: Column: Chiralpak AD-3 150 x 4.6 mm i.d., 3 µm; mobile phase: 40% EtOH (0.05% DEA) in CO ₂ ; flow rate: 2.5 ml/min; column temperature 35°C

- 90 046965

91 (IN) n F^/^(S),N^O ^F F * ΗΙΜ-Ν O h ' ,, ^N /N~N (17?,35)-3-(3-{[(1-methyl-177-1 ,2,3triazol-5-yl)carbonyl] amino ) 177-pyrazol-5-yl)cyclopentyl[(28)-4,4,4-trifluorobutan-2yl]carbamate All stereocenters are known 430.2 Ή NMR (400 MHz, DMSO-d6) δ = 12.31 (br. s., 1H), 11.12 (s, 1H), 8.46 (s, 1H), 7.21 (d, J=8.4 Hz, 1H), 6.44 (br. s., 1H), 5.02 (br. s., 1H), 4.24 (s, 3H), 3.92-3.75 (m, 1H), 3.15-3.00 (m, 1H), 2.47-2.24 (m , 3H), 2.04 (d, J=7.8 Hz, 1H), 1.89 (d, 1=5.4 Hz, 1H), 1.73 (t, J=8.l Hz, 2H), 1.60 (br s. , 1H), 1.13 (d, 1=6.6Hz, 3H) ¹⁹ F NMR (376 MHz, DMSO-d6) δ = -62.58 (s, 3F) 92 (A) n F'i / ^h F * Ο^\«, ^Η / ^Ν ~Ν O iT ^N > I K || _/N H (17?, 35)-3 -(3 - {[(1-methyl-177pyrazol-4-yl)acetyl] amino)-177-pyrazol-5-yl)cyclopentyl- [(2 S)4, 4,4-trifluorobutan-2-yl]carbamate All stereocenters are known 443.4 Ή NMR (400 MHz, METHANOLd4)d7.54 (s, 1H), 7.42 (s, 1H), 6.35 (br. s., 1H), 5.09 (br. s., 1H), 3.89-4.02 (m, 1H), 3.86 (s, 3H), 3.53 (s, 2H), 3.07-3.22 (m, 1H), 2.45-2.54 (m, 1H), 2.17-2.44 (m, 2H), 2.10 (d, J= 6.97 Hz, 1H), 1.72-2.01 (m, 4H), 1.21 (d, J=6.60 Hz, 3H) [a] _D ²² +10.0 (c 0.3, MeOH) 93 (A) n ^FF * ϊ Η (17?,35)-3 -(3 -{[(4-methyl-1,3-oxazol-2-yl)acetyl] amino )-177pyrazol-5 -yl)cyclopentyl-[(2 S)4,4,4-trifluorobutan-2-yl]carbamate All stereocenters are known 444.1 'NMR (400 MHz, DMSO-d6) δ = 12.12 (s, 1H), 10.63 (s, 1H), 7.71 (s, 1H), 7.21 (br d, J=8.3 Hz, 1H), 6.28 ( s, 1H), 4.99 (br s, 1H), 3.86-3.81 (m, 1H), 3.80 (s, 2H), 3.08-2.99 (m, 1H), 2.47-2.34 (m, 3H), 2.05 (d , J=l,0 Hz, 3H), 2.00 (brd, J=8.3 Hz, 1H), 1.88 (br s, 1H), 1.69 (br dd, J=10.8, 15.6 Hz, 2H), 1.55 (br s, 1H), 1.11 (d, J=6.8 Hz, 3H)

- 91 046965

[a] _D ²⁵ +12.41 (with 0.145, MeOH); 94 (A) Η ^FF θΧ+ΧΧιι H / L/hL _y Al h lX ^N o— (1R, 35)-3 -(3 - {[(3-methoxy-1 methyl-1//-pyrazol-5yl)carbonyl] amino } - 17/-pyrazol5 -yl)cyclopentyl-[(2 S)-4,4,4trifluorobutan-2-yl]carbamate All stereocenters are known 459.3 'H NMR (500MHz, DMSO-d6) δ =12.25 (s, 1H), 10.66 (s, 1H), 7.22 (br d, J=8.4 Hz, 1H), 6.58 (s, 1H), 6.41 ( s, 1H), 5.01 (br s, 1H), 3.93 (s, 3H), 3.83 (td, J=6.9, 13.9 Hz, 1H), 3.77 (s, 3H), 3.12-3.03 (m, 1H ), 2.54-2.51 (m, 1H), 2.442.29 (m, 2H), 2.08-1.99 (m, 1H), 1.94-1.84 (m, 1H), 1.79-1.66 (m, 2H), 1.64-1.54 (m, 1H), 1.12 (d, J=6.7 Hz, ZN) 95 (IN) n ^{FF /x} 9 ηΧ-- Η (17?,35)-3-(3-{[(5-methyl-1,3oxazol-2-yl)acetyl] amino }-1Ηpyrazol-5-yl)cyclopentyl (4 ,4,4trifluoro-2-methylbutan-2yl)carbamate All stereocenters are known 458.4 Ή NMR (400 MHz, DMSO-d6) δ = 12.10 (s, 1H), 10.62 (s, 1H), 7.12 (br s, 1H), 6.74 (d, J=l,3 Hz, 1H), 6.29 ( d, J=2.0 Hz, 1H), 4.98 (br s, 1H), 3.79 (s, 2H), 3.11-2.95 (m, 1H), 2.79-2.61 (m, 2H), 2.482.41 (m , 1H), 2.25 (d, J=l,0 Hz, ZN), 2.04-1.95 (m, 1H), 1.92-1.82 (m, 1H), 1.75-1.62 (m, 2H), 1.55 (br s, 1H), 1.27 (s, 6H) 96 (IN) n ^F °-χ\Χ/ ^Ν ~Ν o Ly ν< _Ν ΑΛ _ο Η (17?,35)-3-(3-{[(5-methyl-1,3-oxazol-2-yl)acetyl] amino }-1Hpyrazol-5 -yl)cyclopentyl-[(2^)4,4-difluorobutan-2-yl] carbamate - Isomer A Single stereoisomer; absolute configuration of the chiral center in 4,4- 426.3 X NMR (400 MHz, DMSO-d6) δ = 12.11 (s, 1H), 10.61 (s, 1H), 7.12 (br d, J=8.3 Hz, 1H), 6.74 (d, J=l,0 Hz, 1H), 6.29 (s, 1H), 6.185.84 (m, 1H), 4.99 (br s, 1H), 3.79 (s, 2H), 3.73-3.60 (m, 1H), 3.10-2.98 (m , 1H), 2.48-2.39 (m, 1H), 2.25 (d, J=l,0 Hz, ZN), 2.061.82 (m, 4H), 1.78-1.51 (m, 3H), 1.07 (d, > 6.8 Hz, ZN) [a] _D ²⁵ -4 (c 0.1, MeOH)

- 92 046965

difluorobutan-2-yl] carbamate was not determined Peak 1 of 2: Column: Chiralpak AD-3 50x 3 mm x 3 µm; mobile phase: 40% EtOH (0.05% DEA) in CO ₂ ; flow rate: 2 ml/min; column temperature 40°C 97 (IN) n Η (1A,35)-3-(3-{[(5-methyl-1,3oxazol-2-yl)acetyl] amino }-1Hpyrazol-5-yl)cyclopentyl-[(2^)4,4-difluorobutan- 2-yl]carbamate Isomer B The only stereoisomer, the absolute configuration of the chiral center in 4,4difluorobutan-2-yl] carbamate was not determined 426.3 Ή NMR (400 MHz, DMSO-d6) δ = 12.11 (s, 1H), 10.61 (s, 1H), 7.13 (br d, J=8.3 Hz, 1H), 6.74 (d, J=l.0 Hz, 1H), 6.29 (d, J=l.5 Hz, 1H), 6.18-5.83 (m, 1H), 4.99 (br s, 1H), 3.79 (s, 2H), 3.72-3.59 (m, 1H ), 3.11-2.97 (m, 1H), 2.48-2.39 (m, 1H), 2.25 (d, J=l,3 Hz, ZN), 2.06-1.81 (m, 4H), 1.78-1.52 (m, 3H ), 1.08 (br d, J=6.8 Hz, ZN) [a] _D ²⁵ +18(c 0.1, MeOH) Peak 2 of 2: Column: Chiralpak AD-3 50x 3 mm x 3 µm; mobile phase: 40% EtOH (0.05% DEA) in CO ₂ ; flow rate: 2 ml/min; column temperature 40°C 98 (IN) n F ⁰ ί^ ^Ν Η (17?,3S)-3-(3-{[(2-methoxypyridin-4-yl)acetyl] amino } - 1//-pyrazol-5 yl)cyclopentyl-[(2^ )-4,4difluorobutan-2-yl] carbamate - Isomer A Single stereoisomer; 452.4 Ή NMR (400 MHz, DMSO-d6) δ = 12.09 (s, 1H), 10.57 (s, 1H), 8.07 (d, J=5.0 Hz, 1H), 7.11 (br d, J=8.0 Hz, 1H), 6.91 (dd, J=l.l, 5.1 Hz, 1H), 6.73 (s, 1H), 6.27 (s, 1H), 6.18-5.83 (m, 1H), 4.98 (br s, 1H ), 3.82 (s, 3H), 3.74-3.63 (m, 1H), 3.58 (s, 2H), 3.08-2.96 (m, 1H), 2.48-2.39 (m, 1H), 2.04-1.80 (m, 4H ), 1.77-1.49 (m, 3H), 1.07

- 93 046965

the absolute configuration of the chiral center in 4,4difluorobutan-2-yl]carbamate was not determined (br d, J=6.8 Hz, SI) [a] _D ²⁵ -4° (s 0.1, MeOH) Peak 1 of 2: Column: Chiralpak AD-3 150 x 4.6 mm i.d. , 3 µm; mobile phase: 40% EtOH (0.05% DEA) in CO2; flow rate: 2.5 ml/min; column temperature 35°C 99 (IN) n Fy-γΝ^Ο F। Ο^^χχ,^Ν-Ν O ί^Ν —ΆΑθ/ Η (17?,3S)-3-(3-{[(2methoxypyridin-4yl)acetyl] amino } - 1//-pyrazol-5 yl)cyclopentyl-[(2£)-4,4difluorobutan-2-yl] carbamate Isomer B The only stereoisomer; the absolute configuration of the chiral center in 4,4difluorobutan-2-yl]carbamate was not determined 452.3 Ή NMR (400 MHz, DMSO-d6) δ = 12.09 (s, 1H), 10.57 (s, 1H), 8.07 (d, J=5.3 Hz, 1H), 7.12 (br d, J=8.0 Hz, 1H), 6.91 (dd, J=ll, 5.1 Hz, 1H), 6.73 (s, 1H), 6.28 (s, 1H), 6.17-5.84 (m, 1H), 4.99 (br s, 1H ), 3.82 (s, 3H), 3.67 (td, J=6.8, 13.4 Hz, 1H), 3.58 (s, 2H), 3.09-2.96 (m, 1H), 2.47-2.38 (m, 1H), 2.05-1.80 (m, 4H), 1.76-1.51 (m, 3H), 1.07 (br d, J=6.8 Hz, 3H) [a] _D ²⁵ +18(c 0.1, MeOH) Peak 2 from 2: Column: Chiralpak AD-3 150 x 4.6 mm i.d., 3 µm; mobile phase: 40% EtOH (0.05% DEA) in CO2; flow rate: 2.5 ml/min; column temperature 35°C 100 (IN) n θ i^n Ly Η (17?,3S)-3-(3-{[(2- methoxypyridine-4- yl)acetyl] amino } - 1//-pyrazol-5 yl)cyclopentyl-[(20)-1- 420.3 Ή NMR (400 MHz, DMSO-d6) δ = 12.08 (br s, 1H), 10.57 (s, 1H), 8.07 (d, J=5.5 Hz, 1H), 7.15 (br d, J=7, 9 Hz, 1H), 6.91 (dd, J=1.3, 5.3 Hz, 1H), 6.73 (s, 1H), 6.27 (br s, 1H), 4.99 (br s, 1H), 4.30 (br d, J=5.5 Hz, 1H), 4.18 (br d, J=5.5

- 94 046965

fluoropropan-2-yl]carbamate All stereocenters are known Hz, 1H), 3.83 (s, 3H), 3.80-3.67 (m, 1H), 3.58 (s, 2H), 3.09-2.96 (m, 1H), 2.48-2.39 (m, 1H), 2.031.94 ( m, 1H), 1.92-1.82 (m, 1H), 1.75-1.63 (m, 2H), 1.62-1.52 (w, 1H), 1.02 (br d, J=6.7 Hz, ZN) 101 (IN) I n ΛβΝ ,O 'WY G ^ο Χν Ly -Α/ν Η (1Α,35)-3-(3-{[(2-methoxypyridin-4-yl)acetyl] amino } - 1//-pyrazole-5 yl)cyclopentyl-[(25,ZA)-3-fluorobutan-2-yl]carbamate All stereocenters are known 434.4 'H NMR (400 MHz, DMSO-d6) δ = 12.09 (s, 1H), 10.58 (s, 1H), 8.08 (d, J=5.3 Hz, 1H), 7.17 (br d, J=8, 6 Hz, 1H), 6.92 (dd, J=1.2, 5.2 Hz, 1H), 6.74 (s, 1H), 6.28 (d, J=l,5 Hz, 1H), 4.99 (br d, J= l.8 Hz, 1H), 4.66-4.30 (m, 1H), 3.83 (s, 3H), 3.66-3.48 (m, 3H), 3.162.93 (m, 1H), 2.48-2.42 (m, 1H) , 2.08-1.81 (m, 2H), 1.78-1.48 (m, 3H), 1.31-1.09 (m, 3H), 1.04 (br d, J=6.6 Hz, ZN) 102 (IN) n Fy^N^O ^F FO«gi^ys;J/ ^N ~N Ο ι^Ν n (1A,35)-3-(3-{[(2-methoxypyridin-4-yl)acetyl] amino } - 1//-pyrazol-5 yl)cyclopentyl-(3,3,3 trifluoropropyl)carbamate All stereocenters are known 456.3 DNMR (400 MHz, DMSO-d6) δ = 12.10 (s, 1H), 10.59 (s, 1H), 8.07 (d, J=5.0 Hz, 1H), 7.28 (t, J=5.8 Hz, 1H), 6.91 (d, J=5.3 Hz, 1H), 6.73 (s, 1H), 6.27 (s, 1H), 4.99 (br s, 1H), 3.82 (s, 3H), 3.58 (s, 2H), 3.23-3.15 (m, 2H), 3.082.97 (m, 1H), 2.47-2.34 (m, 3H), 2.03-1.94 (m, 1H), 1.91-1.82 (m, 1H), 1.75- 1.63 (m, 2H), 1.61-1.51 (m, 1H) 103 (IN) n F^/χ^Ν^Ο ^F f og^, hn-n o , ITUxi n L/ '—o \ 459.3 'H NMR (400 MHz, DMSO-d6) δ = 12.25 (d, J=l,3 Hz, 1H), 10.74 (s, 1H), 7.31 (brt, J=5.5 Hz, 1H), 7.13 ( s, 1H), 6.43 (s, 1H), 5.15-

- 95 046965

(17?, 35)-3 - [3 -( {[3 -(methoxymethyl)1 -methyl- 1//-pyrazol-5 yl]carbonyl } amino)- 1//-pyrazol5 -yl ] ring opentyl-( 3,3,3trifluoropropyl)carbamate All stereocenters are known 4.92 (m, 1H), 4.34 (s, 2H), 4.05 (s, ZN), 3.27 (s, ZN), 3.25-3.17 (w, 2H), 3.15-3.03 (m, 1H), 2.492.32 ( w, ZN), 2.13-1.84 (m, 2N), 1.82-1.57 (w, ZN) 104 (IN) A n N^O I/n iQ \ (17?, 35)-3 - [3 -( {[3 -(methoxymethyl)- 1 -methyl- 1//-pyrazole-5 - yl]carbonyl } amino)- 1//-pyrazol5 -yl] cyclopentyl- [(1S)-1 cyclopropylethyl] carbamate All stereocenters are known 431.4 Ή NMR (500 MHz, DMSO-d6) δ = 12.23 (s, 1H), 10.73 (s, 1H), 7.12 (s, 1H), 7.02 (br d, J=8,l Hz, 1H), 6.43 (s , 1H), 4.99 (br s, 1H), 4.33 (s, 2H), 4.05 (s, 3H), 3.26 (s, 3H), 3.13-3.02 (m, 1H), 3.02-2.93 (m, 1H) , 2.52 (brd, 1=1.7Hz, 1H), 2.10-1.99 (m, 1H), 1.95-1.84 (m, 1H), 1.73 (brd, J=7.6 Hz, 2H), 1.61 (br s , 1H), 1.08 (d, J=6.7 Hz, ZN), 0.81 (br d, J=7.8 Hz, 1H), 0.40-0.28 (m, 2H), 0.24 (br dd, J=4.2 , 8.8 Hz, 1H), 0.09 (qd, J=4.8, 9.3 Hz, 1H) 105 (IN) A n A-o \ (17?, 35)-3 - [3 -( {[3 -(methoxymethyl)- 1 -methyl- 1//-pyrazole-5 - yl]carbonyl } amino)- 1//-pyrazol5 -yl] cyclopentyl-[(17?)-1 cyclopropylethyl] carbamate All stereocenters are known 431.4 'NMR (400 MHz, DMSO-d6) δ = 12.23 (s, 1H), 10.85-10.66 (m, 1H), 7.12 (s, 1H), 7.02 (brd, J=8,l Hz, 1H), 6.42 (br s, 1H), 5.00 (br s, 1H), 4.33 (s, 2H), 4.05 (s, 3H), 3.26 (s, 3H), 3.14-2.88 (m, 2H), 2.48-2.38 (m , 1H), 2.02 (td, J=7.3, 15.1 Hz, 1H), 1.951.84 (m, 1H), 1.82-1.69 (m, 2H), 1.61 (br s, 1H), 1.12-1.03 ( m, 3H), 0.89-0.72 (m, 1H), 0.42-0.19 (m, 3H), 0.14-0.00 (m, 1H)

- 96 046965

106 (IN) △xg^N^O । 1 O^gHN'N o nAT° 1/LA H (17?,35)-3-(3-{[(5- methoxypyrazine-2- yl)acetyl] amino } - 177-pyrazol-5 yl)cyclopentyl-[( 1S)-1 cyclopropylethyl] carbamate All stereocenters are known 429.3 Ή NMR (500 MHz, DMSO-d6) δ = 12.07 (br s, 1H), 10.54 (s, 1H), 8.23 (s, 1H), 8.16 (s, 1H), 7.00 (br d, J=8.4 Hz, 1H), 6.28 (s, 1H), 4.96 (br s, 1H), 3.89 (s, 3H), 3.77 (s, 2H), 3.08-2.92 (m, 2H), 2.472.39 (m, 1H ), 1.98 (br d, J=8.7 Hz, 1H), 1.93-1.82 (m, 1H), 1.751.62 (m, 2H), 1.55 (br s, 1H), 1.07 (br d, J= 6.4 Hz, 3H), 0.77 (br s, 1H), 0.34 (br d, J=4.0 Hz, 1H), 0.31-0.25 (m, 1H), 0.22 (br d, J=4.6 Hz, 1H), 0.11-0.00 (m, 1H) 107 (D) n χ,Ν^Ο /Ί [ |_| i? 9 O ^N 1/ Vk JI 1 v H (17?, 35)-3 -(3 - {[(3-methyl-1,2oxazol-5-yl)acetyl] amino } -177pyrazol-5-yl)cyclopentyl- m/tem-butylcarbamate All stereocenters are known 389.9 'NMR (400 MHz, DMSO-d6) δ = 12.12 (br s, 1H), 10.68-10.62 (m, 1H), 6.78 (br s, 1H), 6.29 (br s, 1H), 6.22 (s, 1H ), 4.96 (br d, J=2.3 Hz, 1H), 3.82 (s, 2H), 3.112.95 (m, 1H), 2.47-2.41 (m, 1H), 2.20 (s, 3H), 2.04 -1.95 (m, 1H), 1.92-1.83 (m, 1H), 1.68 (brt, J=8.l Hz, 2H), 1.60-1.50 (m, 1H), 1.19 (s, 9H) 108 (D) n x^N^O Ά g n °TW7 o o-N 1/ \>Jk L 1 \\ νΆΑ/ n (17?,35)-3-{3-[(1,2-oxazol-5- ylacetyl)amino] - 177-pyrazol-5 yl}cyclopeutyl-tert-butylcarbamate All stereocenters are known 376.4 'NMR (400 MHz, DMSO-d6) δ = 12.12 (br s, 1H), 10.67 (s, 1H), 8.49 (s, 1H), 6.77 (br s, 1H), 6.37 (s, 1H), 6.29 (s, 1H), 4.96 (br s, 1H), 3.91 (s, 2H), 3.03 (quin, J=8.5 Hz, 1H), 2.47-2.42 (m, 1H), 2.03-1.94 (m, 1H), 1.93-1.80 (m, 1H), 1.74-1.60 (m, 2H), 1.55 (br s, 1H), 1.19 (s, 9H) [a] _D ²⁵ +8.20 (s 0.13, MeOH);

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109 (D) Η \,Ν^0 SU Η (17?,35)-3-(3-{[(5- methoxypyrazine-2- yl)acetyl] amino } -1 R-p irazol-5 yl)cyclopentyl-ot/?eotbutylcarbamate All stereocenters are known M+Na ⁺ 438.9 Τι NMR (400 MHz, DMSO-d6) δ = 12.06 (br s, 1H), 10.56 (s, 1H), 8.23 (s, 1H), 8.16 (s, 1H), 6.76 (br s, 1H), 6.26 (br s, 1H), 4.95 (br s, 1H), 3.89 (s, 3H), 3.77 (s, 2H), 3.01 (br t, J=8.2 Hz, 1H), 2.472.40 (m, 1H), 2.01-1.83 (m, 2H), 1.74-1.62 (m, 2H), 1.54 (br s, 1H), 1.18 (s, 9H) BY (D) n •I 1 / ^ο *βΗ\/ςι4 ^Ν ~Ν O N-CH y N2LZ J? K j] _/N Η (17?,35)-3-(3-{[(2-methyl-2R-1,2,3triazol-4-yl)acetyl]amino}-\Hpyrazol-5-yl)cyclopentyl /rsot-butyl carbamate All stereocenters are known 390.4 'NMR (500 MHz, DMSO-d6) δ = 12.07 (br s, 1H), 10.53 (br s, 1H), 7.59 (s, 1H), 6.77 (br s, 1H), 6.28 (br s, 1H), 4.95 (br s, 1H), 4.08 (s, 3H), 3.68 (s, 2H), 3.072.96 (m, 1H), 2.47-2.42 (m, 1H), 2.02-1.94 (m, 1H), 1.91 -1.81 (m, 1H), 1.75-1.61 (m, 2H), 1.54 (br s, 1H), 1.19 (s, 9H) 111 (IN) n °* ^£ X'\2U ^N X I / Χ/χ-'Κ.,Α.ν n '—o \ (17?, 35)-3 - [3 -( {[3 -(methoxymethyl)1 - methyl-1R-pyrazol-5 -yl]carbonyl } amino)-1R-pyrazol5 -yl ] ring opentyl-t/?eobutylcarbamate All stereocenters are known 419.4 'H NMR (400 MHz, DMSO-d6) δ =12.23 (s, 1H), 10.74 (s, 1H), 7.12 (s, 1H), 6.79 (br s, 1H), 6.42 (d, J=l, 5 Hz, 1H), 4.98 (br s, 1H), 4.33 (s, 2H), 4.05 (s, 3H), 3.26 (s, 3H), 3.11-3.00 (m, 1H), 2.49-2.41 (m, 1H), 2.06-1.97 (m, 1H), 1.941.82 (m, 1H), 1.77-1.67 (m, 2H), 1.60 (br s, 1H), 1.21 (s, 9H) 112 (IN) N y \ / y N2LZ And y 1| _/N n (17?, 35)-3 -(3 - {[(1 -methyl- Iff- M+Na ⁺ 410.9 'H NMR (400 MHz, DMSO-d6) δ = 12.03 (br s, 1H), 10.35 (br s, 1H), 7.53 (s, 1H), 7.28 (s, 1H), 6.77 (br s, 1H) , 6.28 (br s, 1H),

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pyrazol-4-yl)acetyl] amino }-1Hpyrazol-5-yl)cyclopentyl/7?/?e/7?-butyl carbamate All stereocenters are known 4.95 (br s, 1H), 3.77 (s, 3H), 3.38 (s, 2H), 3.08-2.93 (m, 1H), 2.44 (br s, 1H), 2.05-1.93 (m, 1H), 1.86 ( br s, 1H), 1.75-1.61 (t, 2H), 1.54 (br s, 1H), 1.19 (s, 9H) FROM (IN) n 0*0 ™ ^H / ^N ~ ^N ° ίΓ^\ Yyu jl XA - H (17?,35)-3 -(3 -{[(2-methyl-1,3thiazol-5-yl)acetyl] amino } - 1Hpyrazol-5-yl)cyclopentyl/7?/7e/7?-butyl carbamate All stereocenters are known 406.4 Ή NMR (400 MHz, DMSO-d6) a = 12.09 (s, 1H), 10.58 (s, 1H), 7.40 (s, 1H), 6.77 (br s, 1H), 6.28 (s, 1H), 4.95 ( br d, J=2.5 Hz, 1H), 3.81 (s, 2H), 3.07-2.97 (m, 1H), 2.58 (s, 3H), 2.47-2.40 (m, 1H), 2.01-1.93 (m , 1H), 1.91-1.82 (m, 1H), 1.73-1.63 (m, 2H), 1.55 (br t, J=13.2 Hz, 1H), 1.19 (s, 9H) 114 (IN) n \.ν^ο 'j? ί Η (17?,35)-3-(3-{[(6- methoxypyr idine-3 - yl)acetyl] amino } - 17/-pyrazol-5 yl)cyclopentyl-/7?/7e/7?- butylcarbamate All stereocenters are known 416.4 'NMR (400 MHz, DMSO-d6) δ =12.06 (s, 1H), 10.53 (s, 1H), 8.06 (d, J=2.0 Hz, 1H), 7.62 (dd, J=2.3, 8, 5 Hz, 1H), 6.77 (d, J=8.5 Hz, 2H), 6.27 (d, J=l.5 Hz, 1H), 4.99-4.90 (m, 1H), 3.81 (s, 3H), 3.52 (s, 2H), 3.05-2.96 (m, 1H), 2.44 (td, J=7.3, 14.1 Hz, 1H), 2.01-1.91 (m, 1H), 1.89-1.80 (m, 1H), 1.73-1.61 (m, 2H), 1.58-1.48 (m, 1H), 1.18 (s, 9H) 115 (D) n \.M^O ^o 4SL\/ ₄₁ ^H / ^N ~n o YMZ ϊ ϊ II Η (17?,35)-3-(3 -{[(4-chloropyridin-2yl)acetyl] amino } - 17/ -pyrazol-5 yl)cyclopentyl tert-butylcarbamate All stereocenters are known 420.3 'NMR (400 MHz, DMSO-d6) δ = 12.04 (br s, 1H), 10.67-10.48 (m, 1H), 8.46 (d, J=5.3 Hz, 1H), 7.58-7.48 (m, 1H ), 7.42 (dd, J=2.0, 5.3 Hz, 1H), 6.73 (br s, 1H), 6.34-6.22 (m, 1H), 4.96 (br s, 1H), 3.83 (s, 2H), 3.11-2.95 (m, 1H), 2.48-2.38 (m, 1H), 2.04-1.94

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(m, 1H), 1.92-1.80 (m, 1H), 1.751.62 (m, 2H), 1.55 (br s, 1H), 1.19 (s, 9H) 116 (IN) 1 ⁿ γΎ ^ν Ά° O O Π-Ν 1 lChA. A. N (17?,35)-3 -(3 -{[(2-methyl-1,3thiazol-5 -yl)acetyl]amino } -177pyrazol-5 -yl)cyclopentyl-(1 methylcyclopentyl)carbamate All stereocenters known 432.3 'H NMR (400 MHz, DMSO-d6) δ = 12.08 (br s, 1H), 10.56 (s, 1H), 7.40 (s, 1H), 6.82 (br s, 1H), 6.28 (br s, 1H) , 4.95 (br s, 1H), 3.80 (s, 2H), 3.10-2.94 (m, 1H), 2.58 (s, 3H), 2.47-2.38 (m, 1H), 2.04-1.79 (m, 4H), 1.68 (brt, 1=7.7Hz, 2H), 1.63-1.48 (m, 5H), 1.42 (br dd, J=6.3, 11.8 Hz, 2H), 1.24 (s, 3H) 117 (IN) 1 ⁿ ΓΛ ^Ν Υ° About j? ρ _Ν H (17?,35)-3-{3-[(1,2-oxazol-5ylacetyl)amino] - 177-pyrazol-5yl}cyclopentyl-(1 - methylcyclopentyl)carbamate All stereocenters are known 402.1 'NMR (400 MHz, DMSO-d6) δ = 12.11 (br s, 1H), 10.65 (br s, 1H), 8.48 (s, 1H), 6.83 (br s, 1H), 6.37 (s, 1H), 6.29 (br s, 1H), 4.96 (br s, 1H), 3.91 (s, 2H), 3.10-2.96 (m, 1H), 2.46-2.40 (m, 1H), 2.061.80 (m, 4H), 1.69 (br s, 2H), 1.55 (brd, 1=14.7Hz, 5H), 1.41 (br s, 2H), 1.25 (s, 3H) 118 (IN) 1 ⁿ Λ ^Ν γ° VA ^ο Ν-γ η (17?,35)-3-(3-{[(5-methyl-1,3oxazol-2-yl)acetyl] amino } -177pyrazol-5 -yl) cyclopentyl-(1 methylcyclobutyl)carbamate All stereocenters are known 402.3 'NMR (400 MHz, DMSO-d6) δ = 12.10 (br s, 1H), 10.62 (s, 1H), 7.16 (br s, 1H), 6.74 (d, J=l,l Hz, 1H), 6.29 (s, 1H), 4.97 (br s, 1H), 3.79 (s, 2H), 3.11-2.97 (m, 1H), 2.45-2.41 (m, 1H), 2.25 (d, J=l,0 Hz, 5H), 2.03-1.95 (m, 1H), 1.921.84 (m, 1H), 1.83-1.76 (m, 2H), 1.74-1.63 (m, 4H), 1.56 (br s, 1H), 1.30 (s , 3H)

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119 (IN) 1 ⁿ AV / O rN Y X2LZ χ γ l| _/Ν Η (17?, 35)-3 -(3 - {[(1 -methyl-177pyrazol-4-yl)acetyl] amino } -177pyrazol-5-yl)cyclopentyl-(1 methylcyclobutyl)carbamate All stereocenters are known M+Na ⁺ 422.9 ΉΉΜΡ (400 MHz, DMSO-d6) δ = 12.03 (br s, 1H), 10.35 (br s, 1H), 7.53 (s, 1H), 7.28 (s, 1H), 7.17 (br s, 1H), 6.29 (br s, 1H), 4.97 (br s, 1H), 3.77 (s, 3H), 3.38 (br s, 2H), 3.09-2.95 (m, 1H), 2.43 (br s, 1H), 2.20 (br s, 2H), 1.98 (br d, J=6.5 Hz, 1H), 1.921.75 (m, 3H), 1.70 (br d, J=8.3 Hz, 4H), 1.56 (br s, 1H ), 1.30 (s, 3H) 120 (IN) Q j? lA H (17?, 35)-3-(3-{ [(3.5- difluorophenyl )acetyl] amino } -177pyrazol-5 -yl)cyclopentyl-[(3 ξ)3-methyltetrahydrofuran-3 yl]carbamate - Isomer A Single stereoisomer; the absolute configuration of the chiral center in methyltetrahydrofuran has not been determined M+Na ⁺ 470.9 ΉΉΜΡ (400 MHz, CHLOROFORM-d) δ = 8.23 (br s, 1H), 6.87 (br d, J=5.9 Hz, 2H), 6.75 (dt, J=2.2, 8.9 Hz, 1H), 6.52 (br s, 1H), 5.28 (br s, 1H), 5.16 (br s, 1H), 4.02-3.85 (m, 3H), 3.67 (s, 2H), 3.57 (d, J=9.0 Hz , 1H), 3.17 (quin, J=8.0 Hz, 1H), 2.42 (br s, 1H), 2.32-2.19 (m, 1H), 2.16-2.02 (m, 1H), 1.98-1.79 (m, 5H), 1.47 (s, 3H) [a] _D ²⁵ +16.67 (s 0.2, MeOH) Peak 1 of 2: Column: Chiralpak IC-3 150 x 4.6 mm i.d., 3 µm ; mobile phase: 40% IPA (0.05% DEA) in CO ₂ ; flow rate: 2.5 ml/min; column temperature 35°C 121 (IN) V j? χΊ Ay A+ _n Az4A _f h (17?.35)-3-(3-{ [(3.5- M+Na ⁺ 470.9 'NMR (400 MHz, CHLOROFORM-d) δ = 8.16 (br s, 1H), 6.87 (br d, J=6.0 Hz, 2H), 6.50 (br s, 1H), 5.17 (br s, 1H) ,

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difluorophenyl)acetyl] amino }-1Hpyrazol-5 -yl)cyclopentyl-[(3 ξ)3-methyltetrahydrofuran-3 yl]carbamate - Isomer B Single stereoisomer; the absolute configuration of the chiral center in methyltetrahydrofuran has not been determined 5.29-5.10 (m, 1H), 4.00-3.84 (w,ZN), 3.67 (s, 2H), 3.57 (d, J=9.0 Hz, 1H), 3.62-3.52 (m, 1H), 3.17 ( quin, J=7.9 Hz, 1H), 2.43 (br s, 1H), 2.24 (br d, J=6.6 Hz, 1H), 2.16-2.04 (m, 1H), 1.98-1.78 (m, 5H), 1.48 (s, 3H) [a] _D ²⁰ +12 (s 0.2, MeOH) Peak 2 of 2: Column: Chiralpak IC-3 150 x 4.6 mm i.d., 3 µm; mobile phase: 40% IPA (0.05% DEA) in CO ₂ ; flow rate: 2.5 ml/min; column temperature 35°C 122 (IN) rV ^N V° $ LJ n (1R,35)-3-(3-{[(6-methoxypyridin-3-yl)acetyl] amino } - 1//-pyrazol-5 yl)cyclopentyl-[(3 ^ )-3methyltetrahydrofuran-3 yl]carbamate - Isomer A The only stereoisomer; the absolute configuration of the chiral center in methyltetrahydrofuran has not been determined 444.4 Ή NMR (400 MHz, DMSO-d6) δ = 12.07 (br s, 1H), 10.53 (s, 1H), 8.06 (d, J=2.1 Hz, 1H), 7.63 (dd, J=2.4, 8 .5 Hz, 1H), 7.22 (br s, 1H), 6.77 (d, J=8.4 Hz, 1H), 6.27 (brs, 1H), 4.97 (br s, 1H), 3.873.78 (m, 4H), 3.72 (t, J=7.1 Hz, 2H), 3.53 (s, 2H), 3.42 (d, J=8.6 Hz, 1H), 3.02 (brt, J=8.l Hz, 1H ), 2.48-2.39 (m, 1H), 2.19-2.08 (m, 1H), 2.04-1.93 (m, 1H), 1.921.82 (m, 1H), 1.79-1.62 (m, 3H), 1.56 (brs , 1H), 1.30 (s, 3H) [a] _D ²⁰ +17 (s 0.2, MeOH) Peak 1 of 2: Column: Chiralpak AD-3 150 x 4.6 mm i.d., 3 µm; mobile phase: 40% IPA (0.05% DEA) in CO ₂ ; flow rate: 2.5 ml/min;

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column temperature 35°C. 123 (IN) 1 ⁿ r-\ ^N V° n (17?,3S)-3-(3-{[(6methoxypyridin-3 yl)acetyl] amino } - 1//-pyrazol-5 yl)cyclopentyl-[(3 ξ )-3methyltetrahydrofuran-3 yl]carbamate - Isomer B The only stereoisomer; the absolute configuration of the chiral center in methyltetrahydrofuran has not been determined 444.4 Ή NMR (400 MHz, CHLOROFORM-d) δ = 8 16 (br s, 1H), 8.09 (s, 1H), 7.62-7.50 (m, 1H), 6.75 (d, J=8.6 Hz, 1H) , 6.49 (s, 1H), 5.16 (br s, 2H), 4.04-3.83 (m, 6H), 3.62 (s, 2H), 3.57 (d, J=9.0 Hz, 1H), 3.23-3.09 ( m, 1H), 2.44 (br d, J=7.1 Hz, 1H), 2.24 (br d, J=5.4 Hz, 1H), 2.12 (br s, 1H), 1.95-1.80 (m, 5H ), 1.47 (s, 3H) [a] _D ²⁰ +H (s 0.2, MeOH) Peak 2 of 2: Column: Chiralpak AD-3 150 x 4.6 mm i.d., 3 µm; mobile phase: 40% IPA (0.05% DEA) in CO ₂ ; flow rate: 2.5 ml/min; column temperature 35°C 124 (A) 1 ⁿ n (17?,3S)-3-{3[(phenylacetyl)amino]-Spirazol-5-yl}cyclopentyl-[(3^)3-methyltetrahydrofuran-3yl]carbamate - Isomer A Single stereoisomer; the absolute configuration of the chiral center in methyltetrahydrofuran has not been determined 413.3 Ή NMR (400 MHz, DMSO-d6) δ = 12.06 (s, 1H), 10.52 (s, 1H), 7.30 (d, J=4.3 Hz, 4H), 7.23 (qd, J=4.2, 8, 3 Hz, 2H), 6.28 (s, 1H), 4.97 (br s, 1H), 3.81 (br d, J=8.5 Hz, 1H), 3.75-3.68 (m, 2H), 3.57 (s, 2H ), 3.41 (d, J=8.5 Hz, 1H), 3.07-2.95 (m, 1H), 2.48-2.40 (m, 1H), 2.18-2.09 (m, 1H), 2.03-1.93 (m, 1H ), 1.92-1.81 (m, 1H), 1.771.62 (m, 3H), 1.61-1.49 (m, 1H), 1.30 (s, 3H) Peak 1 of 2: Column: ChiralPak AD-3 150 x 4.6 mm i.d., 3 µm; Gradient: 40% IPA (0.05%

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DEA) in COg; flow rate: 2.5 ml/min; column temperature 40°C 125 (A) 1 ^H H (17?,3S)-3-{3[(phenylacetyl)amino]-177pyrazol-5-yl}cyclopentyl-[(3£)3-methyltetrahydrofuran-3yl]carbamate - Isomer B The only stereoisomer; the absolute configuration of the chiral center in methyltetrahydrofuran has not been determined 413.4 Ή NMR (400 MHz, DMSO-d6) δ = 12.06 (br s, 1H), 10.52 (s, 1H), 7.38-7.13 (m, 6H), 6.28 (br s, 1H), 4.97 (br s, 1H ), 3.80 (br d, J=8.3 Hz, 1H), 3.71 (brt, J=7.0 Hz, 2H), 3.57 (s, 2H), 3.42 (d, J=8.5 Hz, 1H ), 3.07-2.95 (m, 1H), 2.48-2.40 (m, 1H), 2.14 (br d, J=6.5 Hz, 1H), 1.98 (br d, J=8.3 Hz, 1H), 1.91-1.81 (m, 1H), 1.771.62 (m, 3H), 1.55 (br s, 1H), 1.30 (s, 3H) Peak 2 of 2: Column: ChiralPak AD-3 150 x 4.6 mm i.d., 3 µm; Gradient: 40% IPA (0.05% DEA) in CO2; flow rate: 2.5 ml/min; column temperature 40°C 126 (D) O 5 XY-o ⁷ n (17?,35)-3-(3-{[(2-methoxy-1,3thiazol-5-yl)acetyl] amino } -1/7pyrazol-5-yl)cyclopentyl-[ (3 ξ)3 -methyltetrahydrofuran-3 yl]carbamate - Isomer A Single stereoisomer; the absolute configuration of the chiral center in methyltetrahydrofuran is not 450.3 Ή NMR (500 MHz, DMSO-d6) δ = 12.10 (br s, 1H), 10.58 (s, 1H), 7.24 (br s, 1H), 6.96 (s, 1H), 6.30 (br s, 1H), 4.98 (br s, 1H), 3.96 (s, 3H), 3.81 (br d, >7.6Hz, 1H), 3.76-3.68 (m, 4H), 3.42 (d, J=8.5 Hz, 1H), 3.08 -2.97 (m, 1H), 2.482.42 (m, 1H), 2.19-2.10 (m, 1H), 1.99 (br d, J=9.5 Hz, 1H), 1.87 (br dd, J=6.4, 10.1 Hz, 1H), 1.77-1.64 (m, 3H), 1.57 (br s, 1H), 1.31 (s, 3H)

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determined [a] _D ²⁵ +4 (s 0.1, MeOH) Peak 1 of 2: Column: Chiralpak IC-3 150 x 4.6 mm i.d., 3 µm; mobile phase: 40% IPA (0.05% DEA) in CO ₂ ; flow rate: 2.5 ml/min; column temperature 35°C 127 (D) Q°L/ H (17?,35)-3-(3-{[(2-methoxy-1,3thiazol-5 -yl)acetyl] amino }-1Hpyrazol-5 -yl)cyclopentyl-[(3 £)3-methyltetrahydrofuran- 3 yl]carbamate - Isomer B The only stereoisomer; the absolute configuration of the chiral center in methyltetrahydrofuran has not been determined 450.3 Ή NMR (500 MHz, DMSO-d6) δ = 12.11 (br s, 1H), 10.58 (s, 1H), 7.24 (br s, 1H), 6.96 (s, 1H), 6.30 (s, 1H), 4.98 ( br s, 1H), 3.96 (s, 3H), 3.80 (br d, 1=7.6Hz, 1H), 3.75-3.67 (m, 4H), 3.42 (d, J=8.5 Hz, 1H), 3.08 -2.98 (m, 1H), 2.482.42 (m, 1H), 2.20-2.12 (m, 1H), 1.99 (brd, J=9.3 Hz, 1H), 1.911.83 (m, 1H), 1.78 -1.64 (m, 3H), 1.56 (br s, 1H), 1.31 (s, 3H) [a] _D ²⁵ +6 (c 0.1, MeOH) Peak 2 of 2: Column: Chiralpak IC-3 150 x 4.6 mm i.d., 3 µm; mobile phase: 40% IPA (0.05% DEA) in CO ₂ ; flow rate: 2.5 ml/min; column temperature 35°C 128 (A) n ^H / ^N 'N o (HA γ y—C H K II ν n (17?,35)-3-{3-[(1,2-oxazol-5ylacetyl)amino] - 1//-pyrazole-5 - yl}cyclopentyl-( 1 - methylcyclopropyl)carbamate All stereocenters are known 374.4 'H NMR (400 MHz, DMSO-d6) δ = 12.11 (br s, 1H), 10.65 (s, 1H), 8.48 (s, 1H), 7.34 (br s, 1H), 6.37 (s, 1H), 6.28 (br s, 1H), 4.97 (br s, 1H), 3.91 (s, 2H), 3.14-2.96 (m, 1H), 2.46-2.41 (m, 1H), 1.98 (br d, J=8, 8 Hz, 1H), 1.92-1.79 (m, 1H), 1.72-1.59 (m, 2H), 1.53 (br

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s, 1Н), 1.22 (s, ЗН), 0.58 (br s, 2Н), 0.50-0.41 (m, 2Н) 129 (A) 1 ^H L ^N y° H (17?,35)-3-(3-{[(4-chloropyridin-2yl)acetyl] amino } - 1//-pyrazol-5 yl)cyclopentyl-(1 methylcyclopropyl)carbamate All stereocenters are known 418.4 Ή NMR (400 MHz, DMSO-d6) δ = 12.07 (br s, 1H), 10.56 (br s, 1H), 8.46 (d, J=5.4 Hz, 1H), 7.52 (d, J=1, 8 Hz, 1H), 7.42 (d, J=5.5 Hz, 1H), 7.33 (br s, 1H), 6.27 (br s, 1H), 4.96 (br s, 1H), 3.83 (s, 2H) , 3.02 (br d, J=8.4 Hz, 1H), 2.48-2.39 (m, 1H), 1.97 (br d, J=8.l Hz, 1H), 1.91-1.80 (m, 1H), 1.74 -1.57 (m, 2H), 1.57-1.47 (m, 1H), 1.22 (s, 3H), 0.57 (br s, 2H), 0.50-0.43 (m, 2H) 130 (A) 1 ⁿ X ^N y° P ^F °Ovs) ^H / ^N ~N O y ^N 3r^F if4JL XX JI Η (17?,3S)-3-[3-({[5-(trifluoromethyl)pyrazin-2yl] acetyl } amino)-1//-pyrazol-5 yl]cyclopentyl-(1methylcyclopropyl)carbamate All stereocenters are known 453.3 ¹ NMR (500 MHz, DMSO-d6) δ = 12.11 (br s, 1H), 10.72 (s, 1H), 9.12 (s, 1H), 8.86 (s, 1H), 7.34 (s, 1H), 6.40-6.15 (m, 1H), 5.10-4.85 (m, 1H), 4.06 (s, 2H), 3.07-2.97 (m, 1H), 2.48-2.40 (m, 1H), 1.97 (brd, J=8.l Hz , 1H), 1.91-1.81 (m, 1H), 1.72-1.57 (m, 2H), 1.52 (br s, 1H), 1.21 (s, 3H), 0.56 (br s, 2H), 0.47-0.41 (m , 2H) 131 (A) 1 ^{n Ν} γ° °<Χβ!< ^Ν 'ί{ n ϊΉΓ n (17?,3X)-3-(3-{[(4-chloro-5-methylpyridin-2-yl)acetyl] amino } - 1 //-pyrazol-5 - yl)cyclopentyl-( 1 - methylcyclopropyl)carbamate All stereocenters are known 432.3 'NMR (400 MHz, DMSO-d6) δ = 12.05 (br s, 1H), 10.52 (s, 1H), 8.41 (s, 1H), 7.47 (s, 1H), 7.33 (br s, 1H), 6.26 (br s, 1H), 4.96 (br s, 1H), 3.77 (s, 2H), 3.02 (br d, J=8.0 Hz, 1H), 2.46-2.37 (m, 1H), 2.32-2.25 ( m, 3H), 1.97 (brd, J=8.8 Hz, 1H), 1.90-1.77 (m, 1H), 1.77-1.58 (m, 2H), 1.57-1.44 (m,

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1Н), 1.21 (s, ЗН), 0.57 (br s, 2Н), 0.48-0.40 (m, 2Н) 132 (A) 1 ^N L· ^Ν γ° ι—/ H (17?,35)-3-{3-[(1,5-naphthyridin-2ylacetyl)amino]-177-pyrazol-5 yl}cyclopentyl-(1 methylcyclopropyl)carbamate All stereocenters are known 435.3 Ή NMR (400 MHz, DMSO-d6) δ = 12.09 (br s, 1H), 10.69 (s, 1H), 8.97 (d, J=4.5 Hz, 1H), 8.37 (dd, J=5.4, 8 ,4 Hz, 2H), 7.81-7.74 (m, 2H), 7.33 (br s, 1H), 6.28 (br s, 1H), 4.95 (br s, 1H), 4.07 (s, 2H), 3.01 (br s, 1H), 2.43-2.37 (m, 1H), 1.97 (br d, J=7.5 Hz, 1H), 1.92-1.80 (m, 1H), 1.65 (br s, 2H), 1.52 (br s , 1H), 1.21 (s, 3H), 0.56 (br s, 2H), 0.43 (br s, 2H) 133 (A) ^Ο *ί5Αν«) ^Η / ^Ν ~Ν O (ΤΑ yLZ J[ Ji 'n h (17?, 35)-3 -(3 - {[(3 -methyl-1,2oxazol-5 -yl)acetyl] amino } -177pyrazol-5-yl)cyclopentyl-2,2dimethylpiperidine-1 carboxylate All stereocenters are known 430.4 'NMR (400 MHz, DMSO-d6) δ = 12.13 (br s, 1H), 10.62 (s, 1H), 6.29 (br s, 1H), 6.21 (s, 1H), 5.024.95 (m, 1H) , 3.82 (s, 2H), 3.30 (br d, J=3.8 Hz, 2H), 3.07 (quin, J=8.2 Hz, 1H), 2.44-2.37 (m, 1H), 2.19 (s, 3H), 2.05-1.97 (m, 1H), 1.90-1.82 (m, 1H), 1.78-1.68 (m, 2H), 1.64 (dt, J=4.3, 8.9 Hz, 1H), 1.47 (s, 6H), 1.31 (s, 6H) 134 (IN) °*CAv«i ^H / ^N 'N O /HA y X2LZ ji X JI 'n n (17?, 35)-3 -(3 - {[(3 -methyl-1,2-oxazol-5-yl) acetyl] amino } -177pyrazol-5-yl)cyclopentyl-2,2dimethylpyrrolidine-1 - carboxylate All stereocenters are known 416.4 'n NMR (400 MHz, DMSO-d6) δ = 12.24-12.02 (m, 1H), 10.62 (s, 1H), 6.30 (br s, 1H), 6.22 (s, 1H), 5.09-4.94 (m, 1H), 3.83 (s, 2H), 3.35-3.26 (m, 2H), 3.09 (br d, J=8.0 Hz, 1H), 2.48-2.33 (m, 1H), 2.20 (s, 3H), 2.08-1.97 (m, 1H), 1.94-1.81 (m, 1H), 1.80-1.61 (m, 7H), 1.33-1.22 (m, 6H)

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135 (A) Ο^βΓχ/ςι^'Ν 0 N'Q y N2LZ K j] 5 H (17?,35)-3-{3-[(1,2-oxazol-3ylacetyl)amino]-177-pyrazol-5 yl}cyclopentyl-2,2- dimethylpyrrolidine-1 carboxylate All stereocenters are known 402.2 'H NMR (400 MHz, DMSO-d6, Т=80С) δ = 11.90 (br s, 1H), 10.30 (br s, 1H), 8.76 (d, J=l,8 Hz, 1H), 6.51 (d , J=l,5 Hz, 1H), 6.28 (br s, 1H), 5.04 (br s, 1H), 3.77 (s,2H), 3.34 (brt, J=6.5 Hz, 2H), 3.14 ( br d, J=3.3 Hz, 1H), 2.46 (br s, 1H), 2.11-1.98 (m, 1H), 1.96-1.86 (m, 1H), 1.84-1.62 (m, 7H), 1.31 ( s, 6H) 136 (A) \^N^O [ / ^ο *βΓχ/ς> ^Η / ^Ν 'Ν About Ν-Ν y NSLZ J? K jO Η (17?, 35)-3 -(3 - {[(1 -methyl-177pyrrolidine-3-yl)acetyl] amino } -1/7pyrazol-5-yl)cyclopentyl-2,2dimethylpyrrolidine-1 carboxylate All stereocenters are known 415.2 'NMR (400 MHz, DMSO-d6) δ = 12.22-11.91 (m, 1H), 10.35 (br s, 1H), 7.54 (s, 1H), 7.29 (s, 1H), 6.30 (br s, 1H) , 5.15-4.85 (m, 1H), 3.78 (s, 3H), 3.33-3.21 (m, 3H), 3.06 (br d, J=6.5 Hz, 1H), 2.44-2.32 (m, 1H), 2.00 (br d, J=6.8 Hz, 1H), 1.94-1.58 (m, 9H), 1.37-1.21 (m, 6H) 137 (A) ^< 0n^-O n (17?,35)-3-{3- [([1,2,4]triazolo[1,5-a]pyrimidin-6-ylacetyl)amino] 177-pyrazol-5 -yl } cyclopentyl-2,2-dimethylpyrrolidine-1 carboxylate All stereocenters are known 453.2 'NMR (400 MHz, DMSO-d6) δ = 12.11 (br s, 1H), 10.66 (s, 1H), 9.33 (d, J=2.0 Hz, 1H), 8.84 (d, J=2.3 Hz, 1H), 8.66 (s, 1H), 6.29 (br s, 1H), 5.13-4.89(m, 1H), 3.85 (s, 2H), 3.33-3.29 (m, 1H), 3.26 (brt, J =6.l Hz, 1H), 3.13-3.02 (m, 1H), 2.44-2.32 (m, 1H), 2.061.96 (m, 1H), 1.93-1.82 (m, 1H), 1.80-1.57 (m , 7H), 1.35-1.19 (m, 6H)

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138 (A) Ly H (17?,35)-3-{3-[(1,3-oxazol-5- ylacetyl)amino]-17/-p irazol-5 yl}cyclopentyl-2,2- dimethylpyrrolidine-1 carboxylate All stereocenters are known 402.3 'H NMR (400 MHz, DMSO-d6) δ = 12.23-12.01 (m, 1H), 10.57 (s, 1H), 8.26 (s, 1H), 6.99 (s, 1H), 6.29 (br s, 1H) , 5.12-4.87 (m, 1H), 3.77 (s, 2H), 3.32-3.25 (m, 2H), 3.06 (br d, J=7.0 Hz, 1H), 2.45-2.35 (m, 1H), 2.01 (br s, 1H), 1.85 (br s, 1H), 1.81-1.58 (m, 7H), 1.34-1.21 (m, 6H) 139 (A) O^\, _S) H ^N -N O fi-N Y i ji II - FU H (17?,35)-3 -(3 -{[(2-methyl-1,3-thiazol-5-yl) acetyl] amino} - 1Hpyrazol-5 -yl)cyclopentyl-(2 S)- 2-methylpyrrolidine-1 carboxylate All stereocenters are known 418.4 'NMR (400 MHz, DMSO-d6) δ = 12.11 (br s, 1H), 10.58 (s, 1H), 7.41 (s, 1H), 6.30 (s, 1H), 5.02 (br s, 1H), 3.81 (s, 3H), 3.24 (br s, 2H), 3.13-3.02 (m, 1H), 2.59 (s, 3H), 2.45-2.36 (m, 1H), 2.06-1.97 (m, 1H), 1.95- 1.59 (m, 7H), 1.48 (br s, 1H), 1.14-0.98 (m, 3H) 140 (A) X^N^O 1 / °*£ΓΑ/ςι ^Η / ^Ν ~Ν O Ν'Ν y N2LZ K j] \ n (17?, 35)-3 -(3 - {[(1 -methyl-\Hpyrazole -3 -yl)acetyl] amino } - 1Hpyrazol-5 -yl)cyclopentyl-(2 S)2-methylpyrrolidine-1 carboxylate All stereocenters are known 401.3 'NMR (400 MHz, DMSO-d6) δ = 12.05 (br s, 1H), 10.35 (br s, 1H), 7.54 (s, 1H), 7.29 (s, 1H), 6.29 (br s, 1H), 5.01 (brs, 1H), 3.78 (s, 4H), 3.38-3.34 (m, 2H), 3.24 (br s, 2H), 3.07 (quin, J=8.2 Hz, 1H), 2.42 (br d, J=8.3 Hz, 1H), 2.12-1.58 (m, 8H), 1.49 (br s, 1H), 1.13-0.98 (m, 3H)

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141 (A) yA!·' Η (lR,3S)-3-{3- [([ 1,2,4]triazolo[ 1,5- a] pyrimidin-6-ylacetyl) amino] 177-pyrazol-5 -yl } cyclopentyl(28)-2-methylpyrrolidin-1- carboxylate All stereocenters are known 438.9 'H NMR (400 MHz, DMSO-d6) δ = 12.11 (br s, 1H), 10.65 (s, 1H), 9.33 (s, 1H), 8.84 (d, J=2.0 Hz, 1H), 8.66 (s, 1H), 6.30 (s, 1H), 5.01 (br s, 1H), 3.90-3.68(m, 3H), 3.29-3.15 (m, 2H), 3.14-3.02 (m, 1H), 2.44- 2.36 (m, 1H), 2.01 (br d, J=9.0 Hz, 1H), 1.95-1.58 (m, 7H), 1.45 (br s, 1H), 1.13-0.94 (m, 3H) 142 (IN) 9 ΥΊ AU ⁿ - s=o II O (17?,35)-3-[3-({[2- (methyl sulfonyl)phenyl] acetyl } amino)-1//-pyrazol-5 - yl]cyclopentyl -2,2-dimethyl azetidine-1-carboxylate All stereocenters are known 475.4 'NMR (400 MHz, DMSO-d6) δ = 12.10 (brd, J=7.0 Hz, 1H), 10.59 (br s, 1H), 7.96 (dd, J=1.3, 8.0 Hz, 1H), 7.72-7.64 (m, 1H), 7.58-7.52 (m, 1H), 7.50 (d, J=7.5 Hz, 1H), 6.27 (s, 1H), 5.04-4.91 (m, 1H), 4.18 ( s, 2H), 3.69 (brt, J=8.3 Hz, 1H), 3.63 (t, J=7.7 Hz, 1H), 3.28 (s, 3H), 3.06 (br d, J=8.5 Hz, 1H), 2.48-2.34 (m, 1H), 2.04-1.96 (m, 1H), 1.96-1.79 (m, 3H), 1.77-1.56 (m, 3H), 1.37-1.25 (m, 6H) 143 (IN) Cn^o θ'ΥγγΧ J А АУ A>A _n x— ⁿ —s=o II O (15.37?)-3-[3-({[2- (methyl sulfonyl)phenyl] acetyl } amino) - 1//-pyrazol-5 - yl]cyclopentyl-2,2- 475.4 'H NMR (400 MHz, DMSO-d6) δ = 12.09 (br d, J=8.0 Hz, 1H), 10.58 (br s, 1H), 7.96 (dd, J=1.1, 7.9 Hz, 1H ), 7.71-7.64 (m, 1H), 7.57-7.52 (m, 1H), 7.50 (d, J=7.8 Hz, 1H), 6.27 (s, 1H), 5.02-4.90 (m, 1H), 4.18 (s, 2H), 3.69 (brt, J=7.8 Hz, 1H), 3.63 (t, J=7.7 Hz, 1H), 3.28 (s, 3H), 3.11-3.00 (m,

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dimethyl azetidine-1-carboxylate All stereocenters are known 1H), 2.46-2.32 (m, 1H), 2.04-1.96 (m, 1H), 1.94-1.88 (m, 2H), 1.871.79 (m, 1H), 1.76-1.65 (m, 2H), 1.64- 1.55 (m, 1H), 1.34 (d, J=5.8 Hz, ZN), 1.28 (d, >9.5Hz, ZN) 144 (IN) UAA _n AXn Η (17?,3S)-3-(3-{[(6-methoxypyridin-3-yl)acetyl] amino } - 1//-pyrazol-5 yl)cyclopentyl-2,2-dimethyl azetidine -1-carboxylate All stereocenters are known 428.3 Ή NMR (400 MHz, DMSO-d6) δ = 12.07 (br s, 1H), 10.51 (br s, 1H), 8.06 (br s, 1H), 7.62 (dd, J=2.4, 8.4 Hz, 1H ), 6.76 (br d, J=8.5 Hz, 1H), 6.27 (br s, 1H), 5.07-4.85 (m, 1H), 3.87-3.77 (m, 3H), 3.73-3.59 (m, 2H ), 3.52 (br s, 2H), 3.04 (br s, 1H), 2.46-2.32 (m, 1H), 1.99 (br s, 1H), 1.961.88 (m, 2H), 1.84 (br s, 1H ), 1.76-1.54 (m, 3H), 1.37-1.25 (m, 6H) 145 (IN) W'WXn fl ΓΥ ^Οχ · Η (15.37?)-3-(3-{[(6methoxypyridin-3 yl)acetyl] amino } - 1//-pyrazol-5 yl)cyclopentyl-2,2dimethyl azetidin-1 -carboxylate All stereocenters are known 428.4 Ή NMR (400 MHz, DMSO-d6) δ = 12.07 (br d, J=7.0 Hz, 1H), 10.51 (br s, 1H), 8.06 (d, J=2.0 Hz, 1H), 7.62 (dd, J=2.5, 8.5 Hz, 1H), 6.77 (d, J=8.3 Hz, 1H), 6.28 (br s, 1H), 5.06-4.90 (m, 1H), 3.81 (s, 3H), 3.72-3.66 (m, 1H), 3.63 (t, >7.7Hz, 1H), 3.52 (s, 2H), 3.10-2.99 (m, 1H), 2.45-2.32 (m, 1H), 2.05 -1.96 (m, 1H), 1.951.89 (m, 2H), 1.87-1.77 (m, 1H), 1.76-1.65 (m, 2H), 1.62 (br dd, J=4.9, 9.2 Hz, 1H ), 1.34 (d, J=5.8 Hz, ZN), 1.28 (d, J=8.3 Hz, ZN)

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146 (IN) Η (17?,35)-3-(3-{[(2- methoxypyridine-4- yl)acetyl] amino } - 1//-pyrazole-5 - yl)cyclopentyl-2,2- dimethyl azetidine-1-carboxylate All stereocenters are known 428.4 Ή NMR (400 MHz, DMSO-d6) δ = 12.09 (br d, J=7.3 Hz, 1H), 10.57 (br s, 1H), 8.07 (d, J=5.3 Hz, 1H), 6.91 (d, J=4.3 Hz, 1H), 6.73 (s, 1H), 6.28 (br s, 1H), 5.084.86 (m, 1H), 3.82 (s, 3H), 3.743.54 (m, 4H), 3.06 (br d, J=7.3 Hz, 1H), 2.46-2.34 (m, 1H), 2.051.78 (m, 4H), 1.77-1.55 (m, 3H), 1.41-1.21 (m , 6H) 147 (IN) ^ο γλΧ ^Ν 'Ν and H (17?,35)-3-(3-{[(5-methyl-1,3oxazol-2-yl)acetyl] amino } -\Hpyrazol-5-yl)cyclopentyl-2, 2dimethyl azetidine-1-carboxylate All stereocenters are known 402.3 Ή NMR (400 MHz, DMSO-d6) δ = 12.13 (br s, 1H), 10.61 (br s, 1H), 6.74 (s, 1H), 6.28 (br s, 1H), 4.98 (br d, J= 19.1 Hz, 1H), 3.79 (s, 2H), 3.70 (br d, >6.8 Hz, 1H), 3.64 (br t, J=7.4 Hz, 1H), 3.07 (br d, J=6 ,8 Hz, 1H), 2.42 (br s, 1H), 2.25 (s, 3H), 2.12-1.81 (m, 4H), 1.79-1.52 (m, 3H), 1.45-1.22 (m, 6H) 148 (IN) 1 / ⁰ *CXffi> ^H / ^N 'N O ιτ-Ν ϊ II _Z N n (17?, 35)-3 -(3 - {[(1 -methyl-17/pyrazol-4-yl)acetyl] amino } - 1Hpyrazol-5-yl)cyclopentyl-2,2dimethyl azetidine-1-carboxylate All stereocenters are known 401.4 Ή NMR (400 MHz, DMSO-d6) δ = 12.02 (br d, J=2.2 Hz, 1H), 10.34 (s, 1H), 7.53 (s, 1H), 7.28 (s, 1H), 6.27 ( s, 1H), 5.04-4.90 (m, 1H), 3.77 (s, 3H), 3.72 (dt, J=3.2, 7.5 Hz, 1H), 3.64 (t, J=7.5 Hz, 1H) , 3.38 (s, 2H), 3.10-2.98 (m, 1H), 2.42 (dt, J=8.0, 15.1 Hz, 1H), 2.04-1.97 (m, 1H), 1.96-1.90 (m, 2H) , 1.89-1.79 (m, 1H), 1.771.66 (m, 2H), 1.65-1.56 (m, 1H), 1.38-1.28 (m, 6H)

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149 (IN) o ^and θΤΥΥνΥν n (17?,35)-3-(3-{[(2-methoxypyridin-4-yl)acetyl] amino } - 17/-pyrazol-5 yl)cyclopentyl-(28,45)-2, 4dimethyl azetidine-1-carboxylate All stereocenters are known 428.3 Ή NMR (400 MHz, DMSO-d6) δ = 12.09 (s, 1H), 10.57 (s, 1H), 8.07 (d, J=5.3 Hz, 1H), 6.91 (dd, J=1.3, 5, 3 Hz, 1H), 6.73 (s, 1H), 6.27 (s, 1H), 4.99-4.91 (m, 1H), 4.22-4.11 (m, 2H), 3.82 (s, 3H), 3.58 (s, 2H ), 3.08-2.98 (m, 1H), 2.45-2.37 (m, 1H), 1.99 (br d, J=8.5 Hz, 1H), 1.85 (t, J=6.7 Hz, ZN), 1.76 -1.64 (m, 2H), 1.59 (dt, J=4.4, 9.0 Hz, 1H), 1.28 (d, J=6.0 Hz, ZN), 1.20 (d, J=6.3 Hz, ZN ) 150 (IN) VN^O /fS) χ / °4S--\rs> ^H / ^N 'N O V Ж 1 1 l ' ^N Η (17?, 35)-3 -(3 - {[(3 -methyl-1, 2oxazol-5-yl)acetyl]amino} - 1Hpyrazol-5-yl)cyclopentyl(28.45)-2,4-dimethylazetidin-1 carboxylate All stereocenters are known 401.9 'H NMR (400 MHz, DMSO-d6) δ = 12.13 (s, 1H), 10.62 (s, 1H), 6.29 (d, 1=1.8Hz, 1H), 6.21 (s, 1H), 5.02-4.95 (m, 1H), 4.25-4.15 (m, 2H), 3.82 (s, 2H), 3.06 (br s, 1H), 2.41 (br d, J=7.8 Hz, 1H), 2.19 (s, 3H ), 2.00 (br d, J=8.5 Hz, 1H), 1.87 (t, J=6.7 Hz, ZN), 1.761.65 (m, 2H), 1.59 (brs, 1H), 1.30-1.21 (m, 6H) 151 (IN) Η (17?,35)-3-(3-{[(6- methox ypir idin-3 - yl)acetyl] amino } - 17/-pyrazol-5 yl)cyclopentyl-^)-2- methylazetidine-1-carboxylate - Isomer A The only stereoisomer; 414.3 'NMR (400 MHz, DMSO-d6) δ = 12.08 (br s, 1H), 10.54 (br s, 1H), 8.06 (d, J=2.0 Hz, 1H), 7.63 (dd, J=2.4, 8.4 Hz, 1H), 6.78 (d, J=8.5 Hz, 1H), 6.28 (br s, 1H), 5.06-4.88 (m, 1H), 4.30-4.14 (m, 1H), 3.82 ( s, 3H), 3.72 (brt, J=7.3 Hz, 2H), 3.53 (s, 2H), 3.06 (quin, J=8.2 Hz, 1H), 2.43-2.34 (m, 1H), 2.29 -2.18(m, 1H), 2.041.94 (m, 1H), 1.92-1.80 (m, 1H),

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absolute configuration of the chiral center in 2- methylazetidine was not determined 1.78-1.58 (m, 4H), 1.24 (br s, 3H) [a] _D ²⁵ +15.0 (c 0.12, MeOH) Peak 1 of 2 Column: Chiralpak AD-3 50x 3 mm x 3 µm; mobile phase: 40% EtOH (0.05% DEA) in CO ₂ ; flow rate: 2 ml/min; column temperature 40°C 152 (IN) o |PT° ^x Η (17?,35)-3-(3-{[(6methoxypyridin-3 yl)acetyl] amino } - 1//-pyrazol-5 yl)cyclopentyl-(A)-2methylazetidin-1 -carboxylate Isomer B Single stereoisomer; the absolute configuration of the chiral center in 2methylazetidine was not determined 414.3 Ή NMR (400 MHz, DMSO-d6) δ = 12.08 (br s, 1H), 10.54 (br s, 1H), 8.07 (d, J=l,8 Hz, 1H), 7.63 (dd, J=2.3, 8.5 Hz, 1H), 6.78 (d, J=8.3 Hz, 1H), 6.28 (br s, 1H), 4.98 (br s, 1H), 4.20 (br d, J=7.0 Hz, 1H), 3.82 (s, 3H), 3.72 (br s, 2H), 3.53 (s, 2H), 3.06 (brt, J=8.3 Hz, 1H), 2.39 (br dd, J=6.8, 14, 1 Hz, 1H), 2.22 (br d, J=7.8 Hz, 1H), 2.06-1.94 (m, 1H), 1.911.80 (m, 1H), 1.75-1.57 (m, 4H), 1.24 ( br s, 3H) [a] _D ²⁵ -21.15° (c 0.104, MeOH) Peak 2 of 2 Column: Chiralpak AD-3 50x 3 mm x 3 µm; mobile phase: 40% EtOH (0.05% DEA) in CO ₂ ; flow rate: 2 ml/min; column temperature 40°C 153 (IN) ίϊ S? '—/αΑ _ν ΑΑΑ _ο η 1 (LR,35)-3-(3-{[(2- 414.3 Ή NMR (400 MHz, DMSO-d6) δ = 12.10 (br s, 1H), 10.58 (s, 1H), 8.07 (d, J=5.3 Hz, 1H), 6.91 (dd, J=1.0, 5 ,3 Hz, 1H), 6.74 (s, 1H), 6.28 (br s, 1H), 5.06-4.89 (m,

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methoxypyridin-4yl)acetyl] amino } - 1//-pyrazole-5 Ηπ)ιΐΗΐοιοπ6ΗΤΗπ-(2ξ)-2methylazetidine-1-carboxylate Isomer A The only stereoisomer; the absolute configuration of the chiral center in 2methylazetidine was not determined 1Н), 4.30-4.15 (m, 1Н), 3.83 (s, ЗН), 3.71 (br t, J=7.5 Hz, 2Н), 3.58 (s, 2Н), 3.06 (quin, J=8.3 Hz, 1H), 2.44-2.35 (m, 1H), 2.28-2.16 (m, 1H), 2.05-1.95 (m, 1H), 1.911.80 (m, 1H), 1.78-1.56 (m, 4H), 1.24 (br s, 3H) [a] _D ²⁵ +17.40 (c 0.1, MeOH) Peak 1 of 2: Column: Chiralpak AD-3 50x 3 mm x 3 µm; mobile phase: 40% EtOH (0.05% DEA) in CO ₂ ; flow rate: 2 ml/min; column temperature 40°C 154 (IN) _Ν -Χχ+χθ η I (lA,3S)-3-(3-{[(2methoxypyridin-4-yl)acetyl] amino } - 1//-pyrazole-5 Ηπ)ρΗκποπ6ΗΤΗπ-(2ξ)-2methylazetidine-1 -carboxylate Isomer B Single stereoisomer; the absolute configuration of the chiral center in 2methylazetidine was not determined 414.3 'H NMR (400 MHz, DMSO-d6) δ = 12.10 (br s, 1H), 10.59 (s, 1H), 8.07 (d, J=5.3 Hz, 1H), 6.91 (dd, J=1.0, 5.3 Hz, 1H), 6.74 (s, 1H), 6.28 (br s, 1H), 4.98 (br s, 1H), 4.26-4.12 (m, 1H), 3.83 (s, 3H), 3.72 (br s, 2H), 3.58 (s, 2H), 3.07 (quin, J=8.1 Hz, 1H), 2.43-2.33 (m, 1H), 2.29-2.16 (m, 1H), 2.051.94 (m, 1H), 1.92-1.78 (m, 1H), 1.76-1.57 (m, 4H), 1.24 (br d, J=4.3 Hz, ZN) [a] _D ²⁵ -33.15 (s 0.1, MeOH) Peak 2 of 2: Column: Chiralpak AD-3 50x 3 mm x 3 µm; mobile phase: 40% EtOH (0.05% DEA) in CO ₂ ; flow rate: 2 ml/min; column temperature 40°C

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155 (IN) * Υν^Ο ^o tKLYOY Η (17?,3S)-3-(3-{[(2methoxypyridin-4-yl)acetyl] amino} -1 //-pyrazol-5 yl)cyclopentyl-(27?*, 35*)-3cyano-2-methylazetidine-1 carboxylate - Isomer A The only stereoisomer; the methyl and cyano groups on the azetidine ring are in the trans position, but the absolute stereochemistry of these groups has not been determined 439.4 Ή NMR (400 MHz, DMSO-d6) δ = 12.09 (s, 1H), 10.58 (s, 1H), 8.07 (d, J=5.3 Hz, 1H), 6.91 (dd, J=1.3, 5, 3 Hz, 1H), 6.74 (s, 1H), 6.29 (s, 1H), 5.04-4.95 (m, 1H), 4.41 (quin, J=6.3 Hz, 1H), 4.023.88 (m, 2H ), 3.82 (s, 3H), 3.58 (s, 2H), 3.39-3.34 (m, 1H), 3.07 (brt, >8.0Hz, 1H), 2.39 (td, J=7.3, 14.4 Hz, 1H), 1.99 (brd, J=7.8 Hz, 1H), 1.93-1.83 (m, 1H), 1.80-1.59 (m, 3H), 1.33 (brd, J=4.0 Hz, 3H) [[ a] _D ²⁵ -10(c 0.1, MeOH) Peak 1 of 2: Column: Chiralpak AD-3 50x 3 mm i.d., 3 µm; mobile phase: 40% EtOH (0.05% DEA) in CO ₂ ; flow rate: 2 ml/min; column temperature 40°C 156 (IN) Yn^o Η (17?,3S)-3-(3-{[(2methoxypyridin-4yl)acetyl] amino } - 1//-pyrazol-5 yl)cyclopentyl-(27?*,35*)-3cyano-2-methylazetidine -1 carboxylate - Isomer B The only stereoisomer; the methyl and cyano groups on the azetidine ring are in the trans position, but 439.4 'H NMR (400 MHz, DMSO-d6) δ = 12.10 (br s, 1H), 10.59 (s, 1H), 8.07 (d, J=5.3 Hz, 1H), 6.92 (dd, J=1.3, 5.3 Hz, 1H), 6.74 (s, 1H), 6.29 (brs, 1H), 5.01 (brs, 1H), 4.40 (quin, J=6.3 Hz, 1H), 4.053.90 (m, 2H ), 3.82 (s, 3H), 3.58 (s, 2H), 3.33-3.26 (m, 1H), 3.07 (brt, 1=8.2Hz, 1H), 2.43-2.31 (m, 1H), 2.00 (q , J=7.7 Hz, 1H), 1.91-1.81 (m, 1H), 1.80-1.62 (m, 3H), 1.33 (brd, J=6.0 Hz, 3H) [a] _D ²⁵ -8 ( c 0.1, MeOH)

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the absolute stereochemistry of these groups was not determined Peak 2 of 2: Column: Chiralpak AD-3 50x 3 mm i.d., 3 µm; mobile phase: 40% EtOH (0.05% DEA) in CO ₂ ; flow rate: 2 ml/min; column temperature 40°C 157 (IN) Nx' ? Vn^o LJ n (1/?,35)-3-(3-{[(6methoxypyridin-3 yl)acetyl] amino } -1//-pyrazol-5 yl)cyclopentyl-(28 *,3/?*)- 3cyano-2-methylazetidine-1 carboxylate - Isomer A Single stereoisomer; the methyl and cyano groups on the azetidine ring are in the trans position, but the absolute stereochemistry of these groups has not been determined 439.4 Ή NMR (400 MHz, DMSO-d6) δ = 12.08 (s, 1H), 10.54 (s, 1H), 8.06 (d, J=2.0 Hz, 1H), 7.63 (dd, J=2.4, 8, 4 Hz, 1H), 6.77 (d, J=8.5 Hz, 1H), 6.28 (br s, 1H), 5.01 (br s, 1H), 4.40 (quin, J=6.3 Hz, 1H), 4.04-3.88 (m, 2H), 3.81 (s, 3H), 3.53 (s, 2H), 3.34-3.28 (m, 1H), 3.07 (quin, J=8.2 Hz, 1H), 2.422.32 ( m, 1H), 2.04-1.95 (m, 1H), 1.90-1.80 (m, 1H), 1.80-1.60 (m, 3H), 1.32 (br d, J=5.8 Hz, 3H) [a] _D ²⁵ -8 (c 0.1, MeOH) Peak 1 of 2: Column: Chiralpak IC-3 150 x 4.6 mm i.d., 3 µm; mobile phase: 40% IPA (0.05% DEA) in CO ₂ ; flow rate: 2.5 ml/min; column temperature 35°C 158 (IN) Nx. at TachLOA n (17?,35)-3-(3-{[(6- methoxypyr idine-3 - yl)acetyl] amino } -1//-pyrazol-5 yl)cyclopentyl-(28 *,3/?*)-3cyano-2-methylazetidine-1 - 439.4 'H NMR (400 MHz, DMSO-d6) δ = 12.08 (s, 1H), 10.53 (s, 1H), 8.06 (d, J=2.3 Hz, 1H), 7.63 (dd, J=2.4, 8 ,4 Hz, 1H), 6.77 (d, J=8.5 Hz, 1H), 6.28 (s, 1H), 5.04-4.94 (m, 1H), 4.41 (quin, J=6.3 Hz, 1H) , 4.02-3.87 (m, 2H), 3.81 (s, 3H), 3.52 (s, 2H), 3.39-3.35 (m,

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carboxylate - Isomer B The only stereoisomer; the methyl and cyano groups on the azetidine ring are in the trans position, but the absolute stereochemistry of these groups has not been determined 1H), 3.06 (quin, J=8.0 Hz, 1H), 2.44-2.34 (m, 1H), 1.99 (br d, J=7.5 Hz, 1H), 1.90-1.81 (m, 1H), 1.80-1.56 (m, 3H), 1.32 (br s, 3H) [a] _D ²⁵ -10 (c 0.1, MeOH) Peak 2 of 2: Column: Chiralpak IC-3 150 x 4.6 mm h. d., 3 µm; mobile phase: 40% IPA (0.05% DEA) in CO ₂ ; flow rate: 2.5 ml/min; column temperature 35°C 159 (IN) , r t * Vn^o °«©-Χ«) ^Η / ^Ν ~ ^ν θ irt Ji JL Ji >— H (17?,35)-3 -(3 -{[(2-methyl-1,3- thiazol-5-yl)acetyl]amino}-1Hpyrazol-5-yl)cyclopentyl-(2S*, 37?*)-3-cyano-2-methylazetidine-1-carboxylate - Isomer A Single stereoisomer; the methyl and cyano groups on the azetidine ring are in the trans position, but the absolute stereochemistry of these groups has not been determined 429.3 Ή NMR (400 MHz, DMSO-d6) δ = 12.11 (s, 1H), 10.60 (s, 1H), 7.40 (s, 1H), 6.31 (s, 1H), 5.02 (br s, 1H), 4.41 ( quin, J=6.2 Hz, 1H), 4.09-3.87 (m, 2H), 3.81 (s, 2H), 3.39-3.35 (m, 1H), 3.08 (quin, J=8.3 Hz, 1H) , 2.58 (s, 3H), 2.432.31 (m, 1H), 2.04-1.96 (m, 1H), 1.92-1.82 (m, 1H), 1.79-1.61 (m, 3H), 1.34 (br d, J =6.0 Hz, 3H) [a] _D ²⁵ -6 (c 0.1, MeOH) Peak 1 of 2: Column: Chiralpak IC-3 150 x 4.6 mm i.d., 3 µm; mobile phase: 40% IPA (0.05% DEA) in CO ₂ ; flow rate: 2.5 ml/min; column temperature 35°C 160 (IN) V * Vn^o ^ο «βΓχ«) ^Η / ^Ν ~ ^{Ν 0} γΊ Υ Ρ-Ζ ΐί Η EV X^N-^^x^S Η (17?,35)-3 -(3 -{[(2 -methyl-1,3- 429.3 'H NMR (400 MHz, DMSO-d6) δ = 12.11 (s, 1H), 10.59 (s, 1H), 7.40 (s, 1H), 6.30 (br s, 1H), 5.064.95 (m, 1H) , 4.42 (quin, J=6.3 Hz, 1H), 4.04-3.89 (m, 2H), 3.80

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thiazol-5-yl)acetyl]amino}-1Hpyrazol-5-yl)cyclopentyl(2 S *, 3R *)-3 -cyano-2 - methylazetidine-1-carboxylate Isomer B The only stereoisomer; the methyl and cyano groups on the azetidine ring are in the trans position, but the absolute stereochemistry of these groups has not been determined (s, 2H), 3.40-3.35 (m, 1H), 3.08 (quin, J=8.3 Hz, 1H), 2.58 (s, ZI), 2.40 (td, J=7.3, 14.4 Hz, 1H ), 2.00 (br d, J=7.8 Hz, 1H), 1.91-1.82 (m, 1H), 1.81-1.60 (m, 3H), 1.40-1.39 (m, 1H), 1.34 (br d, J =5.3 Hz, 2H) [a] _D ²⁵ -10 (c 0.1, MeOH) Peak 2 of 2: Column: Chiralpak IC-3 150 x 4.6 mm i.d., 3 µm; mobile phase: 40% IPA (0.05% DEA) in CO ₂ ; flow rate: 2.5 ml/min; column temperature 35°C 161 (IN) ' Vn^o J l-/ X\zA/ Η (17?,3S)-3-{3- [(phenylacetyl)amino]-Spirazol-5-yl}cyclopentyl- (2 S *, 3 R *)-3 -cyano-2 - methylazetidine-1-carboxylate - Isomer A The only stereoisomer; methyl and cyano groups on are in the trans position on the azetidine ring, but the absolute stereochemistry of these groups has not been determined 408.3 Ή NMR (400 MHz, DMSO-d6) δ =12.06 (s, 1H), 10.50 (s, 1H), 7.34-7.21 (m, 5H), 6.29 (s, 1H), 4.99 (br d, J=2 ,8 Hz, 1H), 4.41 (quin, J=6.2 Hz, 1H), 4.02-3.88 (m, 2H), 3.57 (s, 2H), 3.40-3.35 (m, 1H), 3.06 (quin, J=8.2 Hz, 1H), 2.47-2.32 (m, 1H), 1.99 (br d, J=7.0 Hz, 1H), 1.89-1.80 (m, 1H), 1.79-1.59 (m, 3H ), 1.32 (br s, 3H) [a] _D ²⁵ -16.3 (c 0.11, MeOH) Peak 1 of 2: Column: Chiralpak AD-3 50 x 4.6 mm i.d., 3 µm : Mobile phase: 40% EtOH (0.05% DEA) in CO ₂ ; flow rate: 4 ml/min; column temperature 40°C

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162 (IN) —G ♦ Η (1A,35)-3-{3- [(phenylacetyl)amino]-Spirazol-5-yl}cyclopentyl- (2 S *, FOR *)-3 -cyano-2 - methylazetidine-1-carboxylate - Isomer B The only stereoisomer; methyl and cyano groups on are in the trans position on the azetidine ring, but the absolute stereochemistry of these groups has not been determined 408.3 Ή NMR (400 MHz, DMSO-d6) δ =12.06 (s, 1H), 10.51 (s, 1H), 7.33-7.21 (m, 5H), 6.29 (s, 1H), 5.01 (br s, 1H), 4.40 (quin, J=6.3 Hz, 1H), 4.03-3.88 (m, 2H), 3.57 (s, 2H), 3.32-3.24 (m, 1H), 3.07 (quin, J=8.3 Hz, 1H), 2.47-2.33 (m, 1H), 1.99 (brd, J=7.5 Hz, 1H), 1.93-1.79 (m, 1H), 1.79-1.60 (m, 3H), 1.32 (br d, J =5.8 Hz, 3N) [a] _D ²⁵ -7.27 (c 0.12, MeOH) Peak 2 of 2: Column: Chiralpak AD-3 50 x 4.6 mm i.d., 3 µm: Mobile phase : 40% EtOH (0.05% DEA) in CO ₂ ; flow rate: 4 ml/min; column temperature 40°C

Additional compounds of the invention have been prepared by modifying the methods illustrated herein and are shown in Table 1. 3.

Table 3_______________________________________________________________________________

Example No. Structure lx-ms [M+N] ⁺ Name according to HORAS 163 |_| ^ ^ν υ°^. ^η λ S ¹ ° ⁴ well 361.3 (15.3 A)-3 -(3 - {[(1 -methyl-1Hpyrazole-5- yl)carbonyl] amino } - 1Hpyrazol-5 -yl)cyclopentylpropylcarbamate 164 |_| U 361.4 (1A,35)-3-(3-{[(1-methyl-1Hpyrazole-5- yl)carbonyl] amino } - 1Hpyrazol-5 -yl)cyclopentylpropylcarbamate

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165 |_| χ^ ^Ν γ°γ^, ^Η / ^Ν 'Ν o jNH Η 361.2 (15.37?)-3-{3-[(17/-imidazol-4ylacetyl)amino]-177-pyrazol5-yl}cyclopentylpropylcarbamate 166 |_| o SU ν+ _Ν Α/+/ Η 362.3 (15.37?)-3-{3-[(1,3-oxazol-5ylacetyl)amino]-17/-pyrazol5-yl}cyclopentylpropylcarbamate 167 |_| /^^ ^Ν γ°4^γΑ ^Ν ~Ν o o-γ o SU ΧΆνΑ^/А/ η 362.1 (17?,35)-3-{3-[(1,3-oxazol-5-ylacetyl)amino]-177-pyrazol- 5-yl}cyclopentylpropylcarbamate 168 |_| ΗΝ-ν ο Ο'Ν o '—/ >A _n A^A/ Η 362.3 (15.37?)-3-{3-[(1,2-oxazol-5- ylacetyl)amino]-177-pyrazol- 5-yl}cyclopentylpropylcarbamate 169 |_| ^Χ/ ^Ν γ°*β%γδγ ^Ν ~Ν ⁰ °Λ Η 362.3 (17?, 35)-3 - {3 - [(1,2-oxazol-5 ylacetyl) amino]-177-pyrazol- 5-yl}cyclopentylpropylcarbamate 170 |_| ^^ ^Ν γ ^Ο γΑ^ ^Η / ^Ν 'Ν J 0 SU ^Η ys 372.3 (15.37?)-3-(3-{[(2methylpyridin-4yl)carbonyl] amino } - 1Hpyrazol-5 -yl)cyclopentylpropylcarbamate 171 |_| ^^ ^Ν γ ^ο γγ^γ1 j? ffj] Ο '--/ + ^L Y ^L UA Η 372.3 (15.37?)-3 - { 3 - [(pyridin-2ylacetyl)amino]-III-pyrazol- 5-yl}cyclopentylpropylcarbamate

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172 |_| ^^ ^Ν γ ^ο γγ?η ^Η Λ X / ° ^x h jQ 375.3 (1S, 3R)-3 -(3 - {[(1,3-dimethylIII-pyrazol-5yl)carbonyl] amino } - 1Hpyrazol-5-yl)cyclopentylpropylcarbamate 173 |_| /'-vV-b·? 9 / II /\·_Α Ak _,N h 11? 375.3 (17?,35)-3-(3-{[(1,3-dimethyl- Sh-pyrazole-5- yl)carbonyl] amino } - 1Hpyrazol-5 -yl)cyclopentylpropylcarbamate 174 |_| ^Ύ ^Ο Τ^<1 S ] ⁰ Η p \ 375.3 (15,3R)-3 -(3 - {[(1,3-dimethyl1R-pyrazol-4yl)carbonyl] amino } - 1Hpyrazol-5-yl)cyclopentylpropylcarbamate 175 -^γθΫγγ ~W j? o 1—J ^ΑΎ-Α^/Ύ h 376.4 (15,3R)-3 -(3 - {[(2-methyl-1,3oxazol-5-yl)acetyl] amino } Ш-pyrazol-5yl)cyclopentylpropylcarbamate 176 |_| - ^/ ^ ^Ν γ°Χγγ X j? X>—H 376.0 (17?,35)-3 -(3 -{[(2-methyl-1,3oxazol-5-yl)acetyl] amino } 17/-pyrazol-5yl)cyclopentylpropylcarbamate 177 |_| O,/^™HN-n j 0'1 o Ly νχΑΆ/ H 376.4 (15.37?)-3-(3-{[(3-methyl-1,2oxazol-5-yl)acetyl] amino } 17/-pyrazol-5yl)cyclopentylpropylcarbamate

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178 |_| q ₀ -N Y TPA Λ AY H 376.0 (17?, 35)-3 -(3 - {[(3 -methyl-1,2oxazol-5 -yl)acetyl] amino } 17/-pyrazol-5yl)cyclopentylpropylcarbamate 179 |_| O*^\, _s) H ⁿ ~ _N o Y i rA XAX, ^N O SU _N H 378.09 (17?,35)-3-{3-[(1,3-thiazol-5- ylacetyl)amino]-177-pyrazol- 5 -yl}cyclopentylpropylcarbamate 180 |_| , ^h . ⁿ ~n o i y rT'VL l A o Cy ^h Lc 386.3 (15.37?)-3-(3-{[(2,6dimethylpyridin-3yl)carbonyl] amino } -1/7pyrazol-5-yl)cyclopentylpropylcarbamate 181 |_| ^\/ ^N \/ ^O *6Ars> ^H / ^N ~N О I X ΎΎ4α a1 о %у ν ν ^Η ΚΛ 386.4 (17?,35)-3-(3-{[(2,6dimethylpyridin-3yl)carbonyl]amino} -1/7pyrazol-5-yl)cyclopentylpropylcarbamate 182 χ^Νγ°4ΑΑ ^Ν ~Ν Ο o cy ^Η 11 A A'tU 388.4 (15.37?)-3-(3-{[(6- methoxypyridin-3 yl)carbonyl] amino } -1/7pyrazol-5 -yl)cyclopentylpropylcarbamate 183 o SU ^'^Ν'ητί'Α ^Η IL A νΆ 388.4 (17?,35)-3-(3-{[(6- methoxypyridin-3 yl)carbonyl] amino } -1/7pyrazol-5 -yl)cyclopentylpropylcarbamate

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184 ο Ly ^Η Μ 388.2 (15.37?)-3-(3-{[(2methoxypyridin-4yl)carbonyl] amino } - 1Ηpyrazol-5 -yl)cyclopentylpropylcarbamate 185 Η 392.1 (17?,35)-3 -(3 -{[(2-methyl-1,3thiazol-5-yl)acetyl] amino } 177-pyrazol-5yl)cyclopentylpropylcarbamate 186 1 ΧΎ°^ ο Ly Ky^ _N >4~y<> _N > Η 402.3 (15.37?)-3-(3-{[(5methoxypyridin-2yl)acetyl] amino }-1Hpyrazol-5 -yl)cyclopentylpropylcarbamate 187 ϊ ΧΎ° Η 402.3 (17?,35)-3-(3-{[(5- methoxypyridine-2- yl)acetyl] amino }-1Hpyrazol-5 -yl)cyclopentylpropylcarbamate 188 ο Υγθ^ Η 402.3 (17?,35)-3-(3-{[(6- methoxypyridin-3 yl)acetyl] amino }-1Hpyrazol-5 -yl)cyclopentylpropylcarbamate 189 ^V°XX ^R u χ X XU-X O Gu —^S Η 408.1 (15.37?)-3 -(3 - {[(2-methoxy-1,3thiazol-5 -yl)acetyl] amino } 177-pyrazol-5yl)cyclopentylpropylcarbamate

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190 j? rW O 1—/ H 408.1 (17?,35)-3-(3-{[(2-methoxy-1,3thiazol-5-yl)acetyl] amino } Ш-pyrazol-5yl)cyclopentylpropylcarbamate 191 H /—\ /^ ⁿ ^°z,(S^^HN~n o £Nj> o Ly _N A— H 411.3 (15.37?)-3-{3-[(imidazo[1,2a]pyrid in-2-ylacetyl)amino]III-pyrazol-5yl}cyclopentylpropylcarbamate 192 N 0D5)_. HN~m Y pCh1 f jT) H 413.3 (15.37?)-3-(3-{[(55)-5- (d imetilamino)-6,7-dihydro5/-cyclopenta[b]pyridin-2yl]amino} - 1//-pyrazol-5 yl)cyclopentylpropylcarbamate 193 o'''''^Υθ'ί^Χ'ϊ Ϊ fj o CHU ⁿ OH 418.2 (15.37?)-3-(3-{[(5-hydroxy-2methoxypyridin-4yl)acetyl] amino }-1Hpyrazol-5 -yl)cyclopentylpropylcarbamate 194 /^Νγ°4^Α ^Ν ~Ν Ο ι^Ν ⁿ OH 418.2 (15.37?)-3 -(3 - {[(3 -hydroxy-2methoxypyridin-4yl)acetyl] amino }-1Hpyrazol-5 -yl)cyclopentylpropylcarbamate

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195 Η 1/JL s ΗL? 418.4 (17?,35)-3-{3-[({1-[2- (d imethylamino)ethyl] - \Hpyrazole-5- yl } carbonyl)amino] - 1Hpyrazol-5 -yl } cyclopentylpropylcarbamate 196 ^ΞΕ ο /—9$ Κΐ V ζ. \ 1 / ^ζ ΙΖ \=ο ”-Ο ο=/ 428.1 (17?,35)-3-{3-[(1,3-benzothiazol7-ylacetyl)amino]-\Hpyrazol-5-yl} cyclopentylpropylcarbamate 197 ^^γ ^ο '^4)Η/ ^Ν γ 2 χΥ ο CHU xU+k+Ch/Ch/ n ο ^^νη ₂ 430.4 (15.37?)-3-[3-({[2-(2- aminoethoxy)phenyl] acetyl } amino)-1//-pyrazol-5yl ] cyclopentylpropylcarbamate 198 ' ^χχ ^^γ ^ο ' ^,ί ^Υ- ^Η < ^Ν 'ϊ S ΓΥ°^ ^ΝΗ2 o 4/ 4Χ _Ν >4/4/ η [M+Naf 452.2 (15.37?)-3-[3-({[4-(2aminoethoxy)phenyl] acetyl } amino)-1//-pyrazol-5yl ] cyclopentylpropylcarbamate 199 Η z ^s > //Ν Ο,γ ΗΝ^Ν ο _Ν γ И π \гчХ X JL ^Ν \о chu χ-Ύ ^/ \^''~-/ Η 431.3 (15.37?)-3-(3-{[(3methylimidazo[2.1 />][1,3]thiazol-6yl)acetyl] amino }-1Hpyrazol-5 -yl)cyclopentylpropylcarbamate

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200 „ ΗΝ~ _ν q _Ν χ ΪΓ π \ 1 L/A Ο Ν — Η 445.2 (15.37?)-3-(3-{ [(2,3dimethylimidazo[2,1 />][1,3]thiazol-6yl)acetyl] amino }-1Hpyrazol-5 -yl)cyclopentylpropylcarbamate 201 |_| /^ ^Ν γ°ΫΥ4χ A jf) ο L~y ^Η O=S=NH 1 448.2 (17?,35)-3-[3-({[2< methylsulfonimidoyl)phenyl] acetyl } amino)- 1Hpyrazol-5 -yl] cyclopentylpropylcarbamate - Isomer A 202 |_| OU; ^H O=S=NH 1 448.2 (17?,35)-3-[3-({[2< methylsulfonimidoyl)phenyl] acetyl } amino)- 1Hpyrazol-5 -yl] cyclopentylpropylcarbamate - Isomer B 203 |_| ^ ^N Y°^<1 ϊ jO o ^H o=s=o 1 449.3 (15.37?)-3-[3-({[2- (methylsulfonyl)phenyl]acetyl }amino)-1//-pyrazol-5 yl]cyclopentylpropylcarbamate 204 |_| ^H o=s=o nh ₂ 449.9 (17?,35)-3-(3-{[(2sulfamoylphenyl)acetyl]amino } - 1//-pyrazol-5 yl)cyclopentylpropylcarbamate 205 |_| '^ ⁿ y°'?yhX I /Ί O L-U ΑΎ<\/γΑ ^H o=s=o 463.4 (17?,35)-3-[3-({[2- (ethylsulfonyl)phenyl]acetyl }amino)-1//-pyrazol-5 yl]cyclopentylpropylcarbamate

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206 ⁿ o=s=o 1 463.4 (17?,35)-3-[3-({[5-methyl-2(methylsulfonyl)phenyl]acetyl } amino)-1//-pyrazol-5 yl] cyclopentylpropylcarbamate 207 |_| ο eV ^H o=s=o 1 463.4 (17?,35)-3-[3-({[4-methyl-2(methylsulfonyl)phenyl]acetyl } amino)-1//-pyrazol-5 yl] cyclopentylpropylcarbamate 208 'J} o A o EV ^H o=s=o 1 464.3 (17?,35)-3-[3-({[2-methyl-5(methylsulfonyl)pyridin-4yl] acetyl } amino)-1Hpyrazol-5 -yl] cyclopentylpropylcarbamate 209 /=\ ° / / \ II / \\ /)—ω-ζ // II I ^λ —K o ^ο= λ ΖΙ ζ=\ / \ Ζ^^Ζ ^Ζ 1 90—' ο 463.8 (17?,35)-3-[3-({[2(methylsulfamoyl)phenyl] acetyl } amino)-1Hpyrazol-5 -yl]cyclopentyl- propylcarbamate 210 |_| '^ ^ν υ ^ο *?Ύ47 λ jf) o Εν +A _N AVy ^Η o=s=o Λ 475.4 (17?,35)-3-[3-({[2- (cyclopropylsulfonyl)phenyl]acetyl}amino)-1Hpyrazol-5-yl]cyclopentylpropylcarbamate 211 /=V° J ^λ —< ο ⁴ ο=( ΖΤ ζ=\ 1 \ Ζ ΛΖ ¹ 1 ' O 477.3 (17?,35)-3-[3-({[2-(propan-2yl sulfonyl)phenyl] acetyl } amino)-1//-pyrazol-5yl ] cyclopentylpropylcarbamate

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212 S ΓΎ°' o SU +^+ _Ν -Ά/ΑΑ η „ J, _η o=s=o 1 479.3 (17?,35)-3-[3-({[4-methoxy-2(methylsulfonyl)phenyl]acetyl} amino)-1/7-pyrazol-5 yl]cyclopentylpropylcarbamate 213 o'' H 1 Ο Α=Υ o AU ^Η o=s=o 1 479.1 (17?,35)-3-[3-({[5-methoxy-2(methylsulfonyl)phenyl]acetyl} amino)-1//-pyrazol-5 yl] cyclopentylpropylcarbamate 214 \ _/ ^ζ =\ θ 4λ \ ° ^ο= \ ΖΙ ζ=< / \ όο—' ο 480.3 (17?,35)-3-[3-({[2-methoxy-5(methylsulfonyl)pyridin-4yl] acetyl } amino)-1Hpyrazol-5 -yl] cyclopentylpropylcarbamate 215 Η .. ______, ' ^χ ^ ^Ν γ ^Ο ΥγΐΧχ ^Η j? £|| ° o A/ Χ^ν+ΑΑΑΑ ^Η o=s=o 1 493.3 (17?,35)-3-[5-({[4- (methoxymethyl)-2- (methylsulfonyl)phenyl]acetyl }amino)-1//-pyrazol-3 yl]cyclopentylpropylcarbamate 216 |_| ___ΗΝ-ν Ο γ₽ ^ν , AT Υ INL Α L Ν- F O +U Η 429.3 (17?, 35)-3 -(3 - {[(1 -methyl-177pyrazol-4-yl)acetyl] amino } 177-pyrazol-5- yl)cycle opentyl-(3,3,3trifluoropropyl)carbamate 217 |_| F^/χ,Ν___О «еь-,_. ΗΝ-Ν ο f^N f< γ ύύ4α and λ ν- Η 430.4 (17?,35)-3-(3-{[(2-methyl-2771,2,3-triazol-4-yl)acetyl] amino } - 1/7-pyrazol-5yl) ring opentyl-(3, 3,3trifluoropropyl)carbamate

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218 |_| ^F F O '—Ά/ H 430.4 (1^,35)-3-(3-{[(5-methyl-1,3oxazol-2-yl)acetyl] amino } III-pyrazol-5- yl)cycle opentyl-(3,3,3trifluoropropyl)carbamate 219 |_| ___·Ο«β/,_ΗΝ- _Ν q _F < Y ПЧ1 l l > H 432.3 (17?,35)-3-{3-[(1,3-thiazol-2- ylacetyl)amino]-1 /7-pyrazol5 -yl } cyclopentyl-(3,3,3trifluoropropyl)carbamate 220 ^F F O '—/ H 441.3 (17?,35)-3-(3-{[(5- methylpyrazin-2-yl)acetyl] amino } - 1//-pyrazol-5 - yl)cycle opentyl-(3,3,3trifluoropropyl)carbamate 221 |_| i 13— ^F F O EV У\АА/ Η 446.3 (17?,35)-3-(3-{[(5-methyl-1,3thiazol-2-yl)acetyl] amino } Ш-pyrazol-5- yl)cycle opentyl-(3,3,3trifluoropropyl)carbamate 222 ^f y^^y°'3Y4~1 1 1V ^{4 F} F O L<^ ⁴ N ^zW4/ ^N^ Η 457.4 (17?,35)-3-(3-{[(5- methoxypyrazin-2-yl)acetyl] amino } - 1//-pyrazol-5- yl)cycle opentyl-(3,3,3trifluoropropyl)carbamate 223 _f h Y pCha a A Yq F O Ж/ \ H 462.1 (1^,35)-3-(3-{[(5-methoxy-1,3thiazol-2-yl)acetyl] amino } III-pyrazol-5- yl)cycle opentyl-(3,3,3trifluoropropyl)carbamate

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224 \ /=\ ° \ / \ II O—<\ /)— W— \\ // II '—K o ^o= \ ΖΞ IZ i- 533.3 (17?, 35)-3-[3-({ [5-methoxy-2(methylsulfonyl)phenyl]acetyl } amino)-1/7-pyrazol-5 yl]cyclopentyl-(3,3,3 trifluoropropyl)carbamate 225 ζ0 ^Ν γ ^ο γΥ/ ^Ν 'Ν o O'N h 403.9 (17?, 35)-3 - {3 - [(1,2-oxazol-5 ylacetyl)amino]-1/7-pyrazol5 -yl}cyclopentyldipropylcarbamate 226 |_| ^ ⁿ ^°^-\«Y ^N 'N ο ON Η 347.9 (17?, 35)-3 - {3 - [(1,2-oxazol-5 ylacetyl) amino]-1/7-pyrazol- 5 -yl}cyclopentylethylcarbamate 227 |_| about su η 372.3 (17?,35)-3-(3-{[(6methylpyridin-3yl)acetyl]amino} -1/7pyrazol-5-yl)cyclopentylethylcarbamate 228 ^γ°γγ^Υ j? GT' η 375.1 (17?,35)-3-(3-{[(4- fluoroenyl)acetyl ] amino } 177-pyrazole-5- yl)cyclopentyl ethyl carbamate 229 u 1XV 0 C~/ Η 378.3 (17?,35)-3 -(3 -{[(2-methyl-1,3thiazol-5-yl)acetyl] amino } 177-pyrazol-5- yl)cyclopentyl ethyl carbamate 230 Η 387.3 (17?,35)-3-(3-{[(4- methoxyphenyl)acetyl] amino } 177-pyrazole-5- yl)cyclopentyl ethyl carbamate

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231 O '-/ Η 388.2 (17?,35)-3-(3-{[(6methoxypyridin-3 yl)acetyl] amino } - \Hpyrazol-5 -yl)cyclopentylethylcarbamate 232 |_| H 388.2 (17?,35)-3-(3-{[(2methoxypyridin-4yl)acetyl ] amino } -1Hpyrazol-5-yl)cyclopentylethylcarbamate 233 F h 1 0 J'S H 393.1 (17?,35)-3-(3-{[(3.5- difluorophenyl)acetyl] amino } 1R-pyrazole-5- yl)cyclopentyl ethyl carbamate 234 CO /=( » o=( ZI Z=< / \ ^X 1 gj— o IZ ) 414.3 (17?,35)-3-{3-[(1,3-benzothiazol4-ylacetyl)amino]-177pyrazol-5-yl} cyclopentylethylcarbamate 235 ( ZI °4 o /—V? λΐ <zz \ / / ^z IZ \=o Js 0= ⁷ 413.8 (17?,35)-3-{3-[(1,3-benzothiazol7-ylacetyl)amino]-\Hpyrazol-5-yl} cyclopentylethylcarbamate 236 X/NJWsHJ Ο O' ^N H 361.9 (17?, 35)-3 - { 3 - [(1,2-oxazol-5 ylacetyl) amino] - 177-pyrazol5 -yl} cyclopentylethyl (methyl) carbamate 237 ( Z— °=( p ,—\§ ll /z Z \ / / ^Z IZ v° И 386.3 (17?,35)-3-(3-{[(6methylpyridin-3yl)acetyl ] amino } -177pyrazol-5-yl)cyclopentylethyl(methyl)carbamate

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238 1 IiT o X/H 389.3 (17?,35)-3-(3-{[(4- fluoroenyl)acetyl ] amino } 17/-pyrazol-5yl)cyclopentylethyl(methyl)carbamate 239 j? jr ^N yo X/ X'nXX's H 392.3 (17?,35)-3 -(3 -{[(2-methyl-1,3thiazol-5-yl)acetyl] amino } 17/-pyrazol-5yl)cyclopentylethyl(methyl)carbamate 240 / ^: O -z ) 401.3 (17?,35)-3-(3-{[(4methoxyphenyl)acetyl] amino } 17/-pyrazol-5yl)cyclopentylethyl(methyl)carbamate 241 (_ °=< p ¢1 IZ o \ 402.3 (15.37?)-3-(3-{[(2- methoxypyridine-4- yl)acetyl] amino }-1Hpyrazol-5 -yl)cyclopentylethyl(methyl)carbamate 242 XytXXxCv H 402.3 (17?,35)-3-(3-{[(2methoxypyridin-4yl)acetyl] amino }-1Hpyrazol-5 -yl)cyclopentylethyl(methyl)carbamate 243 4. n O,(S). HN~n ο γ (XX 1 ? Г F o X/ +·^^ _Ν +ΧΧ>Χ n 402.3 (15.37?)-3-(3-{[(6- methoxypyridin-3 yl)acetyl]amino}-1Hpyrazol-5 -yl)cyclopentylethyl(methyl)carbamate

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244 y χ ΓΎ° ^χ o I—/ U+ts+UCH/ Η 402.3 (17?,35)-3-(3-{[(6methoxypyridin-3yl)acetyl]amino}-1Hpyrazol-5-yl)cyclopentylethyl(methyl)carbamate 245 ( Ζ— Μ ο /— ζζ ζ \ / / ^Ζ ΖΕΖ ^=°^_ 407.3 (17?,35)-3-(3-{[(3,5difluorophenyl)acetyl] amino } 1R-pyrazol-5yl)cyclopentylethyl(methyl)carbamate 246 F _{Η f} A^n^O4^hn~n ο ο-ν ο SU ν+ _Ν Λ^4/ Η 384.0 (17?,35)-3-{3-[(1,2-oxazol-5ylacetyl)amino]-177-pyrazol5 -yl} cyclopentyl-(2,2difluoroethyl)carbamate 247 ^Ly gp<chаa Η 408.3 (17?,35)-3-(3-{[(6methylpyridin-3yl)acetyl]amino}-1Hpyrazol-5-yl)cyclopentyl(2,2-difluoroethyl)carbamate 248 0 jpy ^F o SU Η 411.1 (17?,35)-3-(3-{[(4- fluoroenyl)acetyl ] amino } 177-pyrazol-5yl)cyclopentyl-(2,2difluoroethyl)carbamate 249 _f A/N^O^Y^~N 0 Π'Ν^ 0 GV C- ^A ' _N - ^A x/<S Η 414.1 (17?,35)-3 -(3 -{[(2-methyl-1,3thiazol-5-yl)acetyl] amino } 177-pyrazol-5- yl)cyclopentyl-(2,2difluoroethyl)carbamate

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250 j? ίΎ°^ o 1—/ V^n-A/Y Η 423.2 (1Α,35)-3-(3-{[(4- methoxyphenyl)acetyl] amino } - Sh-pyrazole-5- yl)cyclopentyl-(2,2- difluoroethyl)carbamate 251 ^Ζ °4 o ί o\ 424.2 (1A,35)-3-(3-{[(2methoxypyridin-4yl)acetyl] amino }-1Hpyrazol-5 -yl)cyclopentyl(2,2-difluoroethyl)carbamate 252 Λγ*ΧΧ ο j* ^N y°Η 424.2 (1A,35)-3-(3-{[(6methoxypyridin-3 yl)acetyl] amino }-1Hpyrazol-5 -yl)cyclopentyl(2,2-difluoroethyl)carbamate 253 ^Λ γ·χχχΑ Η 429.1 (1A,35)-3-(3-{[(3,5difluorophenyl)acetyl] amino } Ш-pyrazol-5yl)cyclopentyl-(2,2difluoroethyl)carbamate 254 ? /Λ. o X ^x χ-^ν'-Χ-'Χ Η 432.3 (1 A,35)-3 -(3 -{[(2-methyl-1,3thiazol-5-yl)acetyl] amino } Sh-pyrazol-5yl)cyclopentyl-(2,2,2trifluoroethyl)carbamate 255 \Ο : ζτ i ο ζζ 442.2 (1A,35)-3-(3-{[(2methoxypyridin-4yl)acetyl] amino} - 1Hpyrazol-5 -yl)cyclopentyl(2,2,2-trifluoroethyl)carbamate

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256 / ^N jL a Jl η 374.3 (17?,35)-3-(3-{[(6- methoxypyridin-3 yl)acetyl] amino } -1/7pyrazol-5 -yl)cyclopentyl methylcarbamate 257 H ₂ N^,O,,fsy-. _fR ΗΜ-Ν ο jA^N n 360.2 (15.37?)-3-(3-{[(2methoxypyridin-4yl)acetyl] amino }-1Hpyrazol-5 -yl)cyclopentylcarbamate 258 |_| ' ⁴ ^^ ^Ν Υ ^0/ ' ⁽ ί%-< ^Ν 'ι ϊ ί > ο Chu ν+ _Ν Α/4/ Η 376.2 (15.37?)-3-{3-[(1,2-oxazol-5- ylacetyl)amino]- l/7-pyrazol- 5-yl}cyclopentylbutylcarbamate 259 |_| \-/\χ ^Ν γ ^ο 43^Λ ^Ν ~Ν Ο Ο'Ν ο L/xA _n -As/4/ Η 376.1 (17?, 35)-3 - {3 - [(1,2-oxazole-5 - ylacetyl)amino]- l/7-pyrazol- 5-yl}cyclopentylbutylcarbamate 260 |_| 'γ ^Ν γ°ΥΎ5ϊ ? ¹ 1 ο LY χ- ^>χ ν'4' ^ν \ η Π // ^~Ν 361.4 (17?, 35)-3 -(3 - {[(1 -methyl- 1Nimide azol-5yl)carbonyl] amino } -1/7pyrazol-5 -yl)cyclopentylpropan-2-ylcarbamate 261 |_| γ ^Ν γ°'<?44,Τ7 2 ' ⁰ ηΛ ^~Ν 362.4 (15.37?)-3 -(3 - {[(1 -methyl-1/71,2,3-triazol-5yl)carbonyl] amino } -1/7pyrazol-5 -yl)cyclopentylpropan-2-ylcarbamate

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262 |_| f? /ht ^; ' ^N 362.3 (17?, 35)-3 -(3 - {[(1 -methyl- 1H1,2,3-triazol-5yl)carbonyl] amino } - 1Hpyrazol-5 -yl)cyclopentylpropan-2-ylcarbamate 263 |_| Ύ ^Ν Υ°ΫΥ4Ίί ϊ ?' ^N > 1 o E-/ H 362.3 (15.37?)-3-{3-[(1,2-oxazol-5ylacetyl)amino]-1 /7-pyrazol5 -yl} cyclopentyl-propan-2ylcarbamate 264 |_| V ^N Y°TY4'i ϊ jA 1 О EV H 372.3 (15.37?)-3-{3-[(pyridin-2ylacetyl)amino]-1 /7-pyrazol5 -yl} cyclopentyl-propan-2ylcarbamate 265 |_| H 372.2 (17?, 35)-3 - { 3 - [(pyridin-2ylacetyl)amino]-1 /7-pyrazol5 -yl } cyclopentyl-propan-2ylcarbamate 266 |_| Χ^Ν^Ο,^α» HN- _no TY (/41 XL n—- H 375.3 (15.37?)-3 -(3 - {[(1 -methyl- 1Hpyrazol-4-yl)acetyl] amino } 17/-pyrazol-5- yl)cyclopentyl-propan-2ylcarbamate 267 H / HN~ _{no N} -N YY \ YY X ii ji z> । About EV H 375.3 (17?, 35)-3 -(3 - {[(1 -methyl- 1Hpyrazol-3 -yl)acetyl] amino} 17/-pyrazol-5- yl)cyclopentyl-propan-2ylcarbamate

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268 |_| \ _/ N _4Z O,® _Aw| HN-. _N o nQ 1 Y \ X x?— H 376.4 (15.37?)-3-(3-{[(5-methyl-1,2oxazol-3-yl)acetyl] amino } 17/-pyrazol-5- yl)cyclopentyl-propan-2ylcarbamate 269 |_| , _s . HN- _non -0 1 y uHx λ aY- 1 0 </ N H 376.3 (17?,35)-3-(3-{[(5-methyl-1,2oxazol-3-yl)acetyl] amino } 17/-pyrazol-5- yl)cyclopentyl-propan-2ylcarbamate 270 |_| Ύ ^Ν Υ°ΤΤ<χ I GU। o X/ +x-> _N >»-- ₀ H 376.4 (15.37?)-3 -(3 - {[(5 -methyl-1,3oxazol-2-yl)acetyl] amino } 17/-pyrazol-5- yl)cyclopentyl-propan-2ylcarbamate 271 |_| hn~ _{n 0 ν} -λ 1 V TAX l l l ¹ 0 Ly N 0 H 376.4 (17?,35)-3-(3-{[(5-methyl-1,3oxazol-2-yl)acetyl] amino } 17/-pyrazol-5- yl)cyclopentyl-propan-2ylcarbamate 272 Α^γθΑγΧγΤ j? 1 Ο Ά Αχ> _Ν >ΑχΧ< _ο Η 376.4 (17?,35)-3 -(3 -{[(4-methyl-1,3oxazol-2-yl)acetyl] amino } 17/-pyrazol-5- yl)cyclopentyl-propan-2ylcarbamate 273 |_| YXYCUUY H 392.3 (17?,35)-3-(3-{[(5-methyl-1,3thiazol-2-yl)acetyl] amino } 17/-pyrazol-5- yl)cyclopentyl-propan-2ylcarbamate

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274 j? jjX i o L/ Η 392.3 (17?,35)-3 -(3 -{[(4-methyl-1,3thiazol-2-yl)acetyl] amino } 177-pyrazol-5- yl)cyclopentyl-propan-2ylcarbamate 275 ΎΥτΥΛγσ ⁰ ' Η 401.3 (17?,35)-3-(3-{[(4- methoxyphenyl)acetyl] amino } 177-pyrazole-5- yl)cyclopentyl-propan-2ylcarbamate 276 |_| ΎΥΥ<4λΛν Η 402.3 (17?,35)-3-(3-{[(2methoxypyridin-4yl)acetyl] amino }-1Hpyrazol-5 -yl)cyclopentylpropan-2-ylcarbamate 277 γ ^Ν γ°Αγγγ 9 /4°^ 1 ο Λ/ ^ΎΎκ Η 403.4 (17?,35)-3-(3-{[(5methoxypyrazin-2yl)acetyl] amino }-1Hpyrazol-5 -yl)cyclopentylpropan-2-ylcarbamate 278 Η? 'ν ^Ν Υ°* ^ί τΑΛ? ^Ν 'ϊι η 1 Η (ί/ 405.3 (17?,35)-3-[3-({[1-(2methoxyethyl)-1//-pyrazol-5-yl]carbonyl} amino)-1Hpyrazol-5-yl]cyclopentylpropan-2-ylcarbamate 279 F η 1 ·γ ^Ν γ°γ4βΤγ ο jA 1 ο W 5γ><Α/\ η 407.4 (17?,35)-3-(3-{[(3.5- difluorophenyl)acetyl] amino } 177-pyrazole-5- yl)cyclopentyl-propan-2ylcarbamate

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280 Υυ ^ο ϋΥΓ1 χ xVo ^z Η 408.3 (17?,35)-3-(3-{[(5-methoxy-1,3thiazol-2-yl)acetyl] amino } Ш-pyrazol-5yl)cyclopentyl-propan-2ylcarbamate 281 ^ ^N Y°* ^£ rYrfj' j? Gu/ Η 408.3 (17?,35)-3-(3-{[(2-methoxy-1,3thiazol-5-yl)acetyl] amino } Ш-pyrazol-5yl)cyclopentyl-propan-2ylcarbamate 282 9 χγ 1 ο Ι-У Η 419.9 (17?,35)-3-(3-{[(5-chloro-6methylpyridin-2yl)acetyl] amino }-1Hpyrazol-5 -yl)cyclopentylpropan-2-ylcarbamate 283 Υυ°5Υ<χ χ jfl ^Η Ν=/ 428.4 (17?,35)-3-{3-[(1,3-benzothiazol4-ylacetyl)amino]-\Hpyrazol-5-yl} cyclopentylpropan-2-ylcarbamate 284 /=Α θ' ο=( ζτ ΖΥ / \ ^ΙΖ \<^ Η όή—' ο >ο _ 427.8 (17?,35)-3-{3-[(1,3-benzothiazol7-yl acetyl) amino] -\Hpyrazol-5 -yl} cyclopentylpropan-2-ylcarbamate 285 (X Υ5Υ? γ ? Α* 1 ο X/ ⁿ y 432.5 (1R,35)-3-(3-{[(2.5- dimethoxypyridine-4- yl)acetyl] amino }-1Hpyrazol-5 -yl)cyclopentylpropan-2-ylcarbamate

- 140 046965

286 U- U_ o ^z \ ^o= \ ZI i o _ 440.3 (17?,35)-3-[3-({[5- (trifluoromethyl)pyridin-2yl] acetyl } amino)- 1Hpyrazol-5 -yl] cyclopentylpropan-2-ylcarbamate 287 Υ^γ ^ο * ^ί Χγ^Υ fl i ^N Y ^kp 1 o AC η 441.1 (17?,35)-3-[3-({[5- (trifluoromethyl)pyrazine-2- yl] acetyl } amino) - 1Hpyrazol-5 -yl] cyclopentylpropan-2-ylcarbamate 288 cA ΎΥΤΥΧΥό ^H o=s=o 1 479.3 (17?,35)-3-[3-({ [5-methoxy-2(methylsulfonyl)phenyl]acetyl } amino)-1//-pyrazol-5 yl]cyclopentyl-propan-2ylcarbamate 289 \ , _with HN~ _{n o} qN t Υ ι gХа X XX— Η 390.3 (17?,35)-3-(3-{[(3-methyl-1,2oxazol-5-yl)acetyl] amino } Ш-pyrazol-5yl)cyclopentyl- methyl(propan-2-yl)carbamate 290 5 ϊΛ— 1 ο AU Η 390.3 (17?,35)-3-(3-{ [(5-methyl-1,3oxazol-2-yl)acetyl] amino } 177-pyrazol-5- yl)cyclopentyl- methyl(propan-2-yl)carbamate 291 УХ'ТХХъф ^Η o=s=o 1 533.3 (17?,35)-3-[3-({ [5-methoxy-2(methylsulfonyl)phenyl]acety l}amino)-1//-pyrazol-5yl]cyclopentyl-[(2^)-1,1 ,1trifluoropropan-2-yl] carbamate - Isomer A

- 141 046965

292 o /—\b \ / / ^z IZ v° o )—< and // Vk —ω—С V- o ο ^λ — ^{f 4} 533.3 (17?,35)-3-[3-({[5-methoxy-2(methylsulfonyl)phenyl]acetyl} amino)-1//-pyrazol-5 yl]cyclopentyl-[(2£)-1, 1,1trifluoropropan-2-yl] carbamate - Isomer B 293 |_| zY|A Li ⁰ h li > 376.2 (17?, 35)-3 -(3 - {[(1 -methyl-1771,2,3-triazol-5- yl)carbonyl] amino } -1/7pyrazol-5 -yl)cyclopentylot/?eot-butyl carbamate 294 D ^o= \ ZI z=\ / \ I ^x * ©— o IZ ?v 386.4 (17?,35)-3-{3-[(pyridin-2ylacetyl)amino]-1/7-pyrazol5 -yl } ring opentyl-t/?eotbutylcarbamate 295 |_| H ⁿ -- _N 0 N-° AY ΎΥ4A A AX' 1 o С/ N H 390.4 (17?,35)-3-(3-{[(5-methyl-1,2oxazol-3-yl)acetyl] amino } 17/-pyrazol-5yl)cyclopentyl-t/?eotbutylcarbamate 296 |_| x>n^q^saAAn ° °l _ Η 390.4 (17?,35)-3 -(3 -{[(4-methyl-1,3oxazol-2-yl)acetyl] amino } 1//-pyrazol-5-yl)cyclopentyl /??/?<?/ ??-butyl carbamate 297 |_| \ziAO45As .ην- _ν ο Ν=\ Α ν YTAa a nA i O SU η 390.1 (17?, 35)-3-(3-{ [(4-methyl-1H1,2,3-triazol-1yl)acetyl] amino }-1Hpyrazol-5 -yl)cyclopentyl tert-butyp carbamate

- 142 046965

298 |_| hn- _non -n < y YXa aa y H 391.4 (17?,35)-3-(3-{ [(5-methyl-1,3,4oxadiazol-2- yl)acetyl] amino }-1Hpyrazol-5 -yl)cyclopentyl tert-butyl l carbamate 299 x'j'tys.uiX H 401.4 (17?,35)-3-(3-{[(5methylpyrazin-2yl)acetyl]amino}-1Hpyrazol-5-yl)cyclopentyl tert-butyl carbamate 300 Y ^N Y°XY ^s XAA XX 1 О С/ —Ам H 404.3 (17?,35)-3-(3-{[(5fluoropyridin-2yl)acetyl] amino }-1Hpyrazol-5 -yl)cyclopentyl tert-butyl carbamate 301 |_| \z ⁿ x-0 _< 0 ₄ ™HM-n o and YYMa aa J ^H F 404.4 (17?,35)-3-(3-{[(3fluoropyridin-2yl)acetyl] amino }-1Hpyrazol-5 -yl)cyclopentyl tert-butyl carbamate 302 |_| γ ^Ν γ ^ο <ΜΥ O ! ⁷⁷ BL? 0— 405.3 (17?, 35)-3 -(3 - {[(3-methoxy-1 methyl- 17/-pyrazol-5yl)carbonyl] amino } - 1Hpyrazol-5 -yl)cyclopentyl/7?rs'/7?- buty l carbamate 303 |_| Α ^Ν γ°ΫΑ4Ίί ϊ ΓΥl o '—/ΑγΥΥ Η 406.2 (17?,35)-3-(3-{[(5-methyl-1,3thiazol-2-yl)acetyl] amino } 177-pyrazol-5- Il)cyclopentyl-777/?v777butylcarbamate

- 143 046965

304 |_| J JT ^S ^ 1 o X/ η 406.0 (17?,35)-3 -(3 -{[(2-methyl-1,3thiazol-4-yl)acetyl] amino } 17/-pyrazol-5- yl)cyclopentyl-/7?/?c77?butylcarbamate 305 |_| HN-n o NN and Y TgChl l l ¹ o X/ s Η 407.4 (17?,35)-3-(3-{ [(5-methyl-1,3,4thiadiazol-2- yl)acetyl] amino }-1Hpyrazol-5 -yl)cyclopentyl/7?/7c77?-butyl l carbamate 306 ΥγθΫγΤΚ J £/Х<1 1 о 1—/Х\ХХы x n 416.4 (17?,35)-3-(3-{[(2- cyclopropyl-1,3-oxazol-4yl)acetyl]amino}-1Hpyrazol-5-yl)cyclopentyl/7?/7c77?-butyl l carbamate 307 |_| 9 l^il And J ΙΧ^Λ _Ν ^ΜγΝ ⁿ <x 416.3 (17?,35)-3-(3-{[(2methoxypyridin-3 yl)acetyl] amino }-1Hpyrazol-5 -yl)cyclopentyl/7?/7c77?-butyl carbamate 308 О' n / \/ ^ν \/ ^ο *(3Χ« ₁ ^Η / ^Ν ~ν o X 4 X iХ lХ n X/ 419.4 (17?,35)-3-[3-({[1-(2- methoxyethyl)- 1//-pyrazol-5 yl]carbonyl } amino)- 1Hpyrazol-5 -yl] cyclopentyl/7?/7c77?-butyl carbamate 309 N / ,hn- _n about ggCh and Y TTCha λ 1 about X/ NY ⁿ 419.4 (17?, 35)-3 -(3 - {[(3-methoxy-1 methyl- 1//-pyrazol-4yl)acetyl] amino }-1Hpyrazol-5 -yl)cyclopentyl/7?/7c77?-buty l carbamate

- 144 046965

310 Χ/Ν ΟΛλ ΗΝ^ _{o N} ^ ^CI AY lAA AAJ H 420.3 (17?,35)-3-(3-{[(5chloropyridin-2yl)acetyl] amino } - 1Hpyrazol-5 -yl)cyclopentyl/7?/7<?/7?-butyl carbamate 311 |_| N ,S) ^H / ^N ~N on^\ A TAA Vo H 422.3 (17?,35)-3-(3-{[(5-methoxy-1,3thiazol-2-yl)acetyl] amino} 177-pyrazol-5- IL)CYCLOPENTYL-/77/7<?/77butylcarbamate 312 νγ·^'| ? gt ^C| 1 o A'^^Ν'ΑΑ' _Ν ^ΐ> \ Η 433.9 (17?,35)-3-(3-{[(5-chloro-6methylpyridin-2yl)acetyl] amino }-1Hpyrazol-5 -yl)cyclopentyl/tgret-butylcarbamate 313 |_| γΑγθ^γγΑγ ° ^N Y[ 1 o A/ A^AAA, ^H Cl 433.9 (17?, 35)-3 -(3 - {[(3-chloro-4methylpyridin-2yl)acetyl] amino } -177pyrazol-5 -yl)cyclopentyl/tgret-butylcarbamate 314 |_| 1 o AA _n aaA ^{f H} F 436.4 (1Х35)-3-[3-({[4- (difluoromethyl)pyridin-2yl] acetyl } amino)-177pyrazol-5 -yl] cyclopentyl/tgret-butylcarbamate 315 o' γ _γ °γγγ aJ0 ⁿ i o k/ n ^H X 446.4 (17?,35)-3-(3-{[(2.5- dimethoxypyridin-4yl)acetyl]amino}-177pyrazol-5-yl)cyclopentyl/tgret-butylcarbamate

- 145 046965

316 |_| Ο ^N<! S 1 o AC ^Η V ^F 454.4 (17?,35)-3-[3-({[4- (trifluoromethyl)pyridine-2- yl] acetyl } amino) - 1Hpyrazol-5 -yl] cyclopentyl tert-butyl carbamate 317 GGTZH.bA Η 455.4 (17?,35)-3-[3-({[5- (trifluoromethyl)pyrazine-2- yl] acetyl } amino) - 1Hpyrazol-5 -yl] cyclopentyl tert-butyl carbamate 318 Η ^F \ / \xN O^R^, _s) ^H , ^N ~N ο r^N У-F А π ι ji and L ,ν—/ ¹ O ¹ —/ Ν ν' Η 458.1 (17?, 35)-3-[3-({ [2-(2,2,2trifluoroethyl)-2//-1,2,3triazol-4-yl] acetyl } amino)17/-pyrazol-5- yl] opevgyl-tert-butylcarbamate cycle 319 o' Χτ ^ο ΤΥα _ν Υ0 ^Η o=s=o 1 493.4 (17?,35)-3-[3-({[5-methoxy-2(methylsulfonyl)phenyl]acetyl } amino)-1//-pyrazol-5 yl] opevgyl-tert-butylcarbamate ring 320 |_| /chYa N HN~ _no IY Y74a a _ • O !-U N h A' 375.3 (17?, 35)-3 -(3 - {[(1 -methyl- 1Hpyrazole-4- yl)carbonyl] amino } - 1Hpyrazol-5 -yl)cyclopentyl(28)-butan-2-ylcarbamate 321 |_| ^/ Y^ ⁿ v°*^ssl/ ⁿ ' ^{n 0} 1 I D 1 / 'αΎ JL ¹ O +A η H // ^-N 375.3 (17?, 35)-3 -(3 - {[(1 -methyl- 1Nimide azol-5- yl)carbonyl] amino } - 1Hpyrazol-5 -yl)cyclopentyl(28)-butan-2-ylcarbamate

- 146 046965

322 |_| j °l = about η 376.2 (17?, 35)-3 - {3 - [(1,2-oxazol-5 ylacetyl) amino] - 177-pyrazol- 5 -yl } cyclopentyl-(27?)-butan2-ylcarbamate 323 |_| , _ς ΗΝ-ν ο nQ Τ Υ TuCha A AJ Η 376.2 (17?, 35)-3 - {3 - [(1,2-oxazol-3 ylacetyl)amino] - 177-pyrazol5 -yl } cyclopentyl-(2 8)-butan2-ylcarbamate 324 |_| /^^ ^Ν ·γ°4ί5γβ^ ^Ν ~Ν ο 1 Ο '— ^Η L 1 Ν^ 386.3 (17?,35)-3-(3-{[(6- methylpyr idine-3 - yl)carbonyl] amino } - 1Hpyrazol-5 -yl)cyclopentyl(28)-butan-2-ylcarbamate 325 Η!!>! Ν f ν°ΤΥ4 ϊ ϊ ί 1 ι o Ly^-Ύ^ΥΥχτ Η 387.3 (17?, 35)-3 - { 3 - [(pyrazin-2 ylacetyl)amino] - 177-pyrazol- 5 -yl } cyclopentyl-(2 8)-butan2-ylcarbamate 326 Η to Τ Υ CLOUD Λ ΑΫ • Ο +-/ Ν Η 389.3 (17?, 35)-3 -(3 - {[(1 -methyl-177pyrazol-5-yl)acetyl] amino } 177-pyrazol-5- yl)cyclopentyl-(2 8)-butan-2ylcarbamate 327 |_| /^ ^Ν χ^θ«ί5Α«) ^Η / ^Ν ~ν ο φΝ γ γ YW JI X υν- Η 389.3 (17?, 35)-3 -(3 - {[(1 -methyl-177pyrazol-4-yl)acetyl] amino} 177-pyrazol-5- yl)cyclopentyl-(2 8)-butan-2ylcarbamate

- 147 046965

328 |_| ts)2/N~N o γγ Η 389.4 (17?, 35)-3 -(3 - {[(1 -methyl-\Hpyrazol-3-yl)acetyl] amino } 177-pyrazol-5- yl)cyclopentyl-(2 8)-butan-2ylcarbamate 329 |_| ^ ^ν Υ°Ϋ^Η ^ν ~ν o h \ 389.4 (17?, 35)-3 -(3 - {[(1 -methyl- 1Nimide azol-5 -yl)acetyl]amino } 177-pyrazol-5yl)cyclopentyl-(2 8)-butan-2ylcarbamate 330 |_| /Ai-N___O4S-X/s> ^H / ^N ~N O r^N IYV ji L n— ¹ O H 390.3 (17?,35)-3-(3-{[(2-methyl-277- 1,2,3-triazole-4- yl)acetyl] amino } - 1Hpyrazol-5 -yl)cyclopentyl(28)-butan-2-ylcarbamate 331 3 ZI Z=< 1 \ Sil ¢3--' ABOUT >° IZ 390.3 (17?, 35)-3 -(3 - {[(1 -methyl- 1H1,2,3-triazol-4yl)acetyl] amino } - 1Hpyrazol-5 -yl)cyclopentyl(28)-butan-2-ylcarbamate 332 |_| HN- _{N on} -O 1 Y |Yal and iiU~ ¹ O *—/ N — N 390.3 (17?,35)-3-(3-{[(5-methyl-1,2- oxazol-3 -yl)acetyl] amino } 177-pyrazol-5- yl)cyclopentyl-(2 8)-butan-2ylcarbamate 333 |_| o 4S—- 1 o Ly^5x _N AY _o n 390.3 (17?,35)-3-(3-{[(5-methyl-1,3oxazol-2-yl)acetyl] amino} 177-pyrazol-5- yl)cyclopentyl-(2 8)-butan-2ylcarbamate

- 148 046965

334 |_| ,HN~ _non -N T p TUCHL XI U— H 391.4 (17?,35)-3-(3-{ [(5-methyl-1,3,4oxadiazol-2- yl)acetyl]amino)-177pyrazol-5-yl)cyclopentyl(28)-butan-2-ylcarbamate 335 ύπαυα H 400.4 (17?,35)-3-(3-{[(2- methylpyridin-4yl)acetyl]amino)-177pyrazol-5-yl)cyclopentyl(28)-butan-2-ylcarbamate 336 ZI °c o /—\2 Xi /7 Z. \ 1 / ^z IZ c // ^z 401.2 (17?,35)-3-(3-{[(6- methylpyrazin-2yl)acetyl]amino)-17/pyrazol-5-yl)cyclopentyl(28)-butan-2-ylcarbamate 337 |_| yvet-N^.O^BX-sJN-N o r=4 _N i o GV H \ 403.4 (17?,35)-3 -(3 -{[(1,5-dimethyl17/-pyrazole-4- yl)acetyl] amino )-17/pyrazol-5 -yl)cyclopentyl(28)-butan-2-ylcarbamate 338 H to /^®'Ν _χ .Ο«β!χ _Χ ,_.ΗΝ~ _Ν θ nN TY YMa a a>- * O GV H 403.4 (17?,35)-3-(3-{[(1,3-dimethyl17/-pyrazole-5- yl)acetyl] amino )-17/pyrazol-5 -yl)cyclopentyl(28)-butan-2-ylcarbamate 339 ^VSfN O^gv^/s )H,N~ _N O f=N / TY ΎΎΚ1 AX NZ * O GV X^^N — n' H 404.1 (17?,35)-3-(3-{[(2-ethyl-277- 1,2,3-triazole-4- yl)acetyl] amino )-17/pyrazol-5 -yl)cyclopentyl(28)-butan-2-ylcarbamate

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340 N h _o Xq ι Y ТгЧХ X JL/ ⁿ * 0 X ^x H \ 404.4 (1R, 35)-3 -(3 -{[(3,5-dimethyl1,2-oxazol-4- yl)acetyl] amino }-1Hpyrazol-5 -yl)cyclopentyl(28)-butan-2-ylcarbamate 341 |_| 1 o '——Ύ H 406.3 (1A,35)-3-(3-{[(5-methyl-1,3thiazol-2-yl)acetyl] amino } 1//-pyrazol-5yl)cyclopentyl-(2 8)-butan-2ylcarbamate 342 ΎγΐΥΥχΥ H 406.2 (1 A,35)-3 -(3 -{[(4-methyl-1,3thiazol-5-yl)acetyl] amino } 1//-pyrazol-5yl)cyclopentyl-(2 8)-butan-2ylcarbamate 343 |_| χΧ^ ^Ν γ°γχΧ ^Ν 'Ν J I o X ^x Х'лХ'л Η 406.2 (1 A,35)-3 -(3 -{[(4-methyl-1,3thiazol-2-yl)acetyl] amino } 1//-pyrazol-5yl)cyclopentyl-(2 8)-butan-2ylcarbamate 344 |_| /NS-ΝγΟΛ^ΗΝ-Ν O N'N I Π T / ^- xJE JL X /— • O XV N — s H 407.3 (1A,35)-3-(3-{ [(5-methyl-1,3,4thiadiazol-2- yl)acetyl] amino }-1Hpyrazol-5 -yl)cyclopentyl(28)-butan-2-ylcarbamate 345 |_| -Χ ^ν υ°ΧΧ ^ν ~ ^ν ° IJI/VVJy <k 416.4 (1A,35)-3-(3-{[(2methoxypyridin-3 yl)acetyl] amino} - IHpyrazol-5 -yl)cyclopentyl(28)-butan-2-ylcarbamate

- 150 046965

346 /ΧΝ Οχ. ΗΝ-Μ _ο Τ Υ Ύυϋλ X 1 J * Ο ¹ -f _Ν Η 416.3 (17?,35)-3-(3-{[(6methoxypyridin-3 yl)acetyl] amino } -\Ηpyrazol-5 -yl)cyclopentyl(28)-butan-2-ylcarbamate 347 1 o Η 417.1 (17?,35)-3-(3-{[(5methoxypyrazin-2yl)acetyl] amino } -\Hpyrazol-5 -yl)cyclopentyl(28)-butan-2-ylcarbamate 348 Η 417.3 (17?,35)-3-(3-{[(6methoxypyrazin-2yl)acetyl] amino } -\Hpyrazol-5 -yl)cyclopentyl(28)-butan-2-ylcarbamate 349 ^S> N^O^S^/sjHN'N □ ρ=Ν γ Ύ \ gAk l L ν—Ζ 1 ο L-U \ Η 417.3 (17?,35)-3-[3-({[1-(propan-2yl)-17/-pyrazol-4- yl] acetyl } amino)- 1Hpyrazol-5 -yl] cyclopentyl(28)-butan-2-ylcarbamate 350 |_| ___Ο«ί2Χ ΗΝ-ν ο Ν=Ν / i Υ ΙγΑΛ Λ L/U Η 418.2 (17?,35)-3-[3-({[1-(propan-2yl)- 1H-1,2,3-triazol-4yl] acetyl } amino)- 1Hpyrazol-5 -yl] cyclopentyl(28) -butan-2-ylcarbamate 351 Η / Χ^®-Ν^ _χ Ο _< βγ,_,ΗΝ-. _{Ν ο} Τ Υ ΤΊΗλ X Α/ ^{Ν Η} ο^ 419.4 (17?, 35)-3 -(3 - {[(3-methoxy-1 methyl- 1//-pyrazol-4yl)acetyl] amino } - 1Hpyrazol-5 -yl)cyclopentyl(28)-butane-2- ylcarbamate

- 151 046965

352 χ Yy_ * ο LV Η 420.3 (17?,35)-3-(3-{[(2,4-dimethyl1,3-thiazol-5- yl)acetyl] amino } -\Hpyrazol-5 -yl)cyclopentyl(28)-butan-2-ylcarbamate 353 |_| /Υ-Ν ΟΛα^ην-ν ο ν\ ι Υ ΤΤΎ λ lu-o *οEV\ Η 422.4 (17?,35)-3-(3-{[(5-methoxy-1,3thiazol-2-yl)acetyl] amino } 17/-pyrazol-5- yl)cyclopentyl-(2 8)-butan-2ylcarbamate 354 Η , ^Ν =\ ^ ^Ν γ ^Ο γΝ2ΐ!/ ^Ν 'ΐί J νΥ * ο EV Ύ _Ν Α/4/ η 426.3 (17?,35)-3-{3-[(imidazo[1,2- a] pyrimidine-2- ylacetyl)amino]-1 /7-pyrazol- 5 -yl } cyclopentyl-(2 8)-butan2-ylcarbamate 355 Η χ-νρ-ΝγΟ+ί^χΥΫ'-Ν Ο Γ ^Ν χ3 Η 431.3 (17?,35)-3-{3-[(imidazo[2,1- th][1,3]thiazole-6- ylacetyl)amino]-1 /7-pyrazol- 5 -yl } cyclopentyl-(2 8)-butan2-ylcarbamate 356 Η ^/ Y ^N Y°* ⁱ rY(av ^J ~ ^{NH 0} / 1 D 1 / \Vx Jk Ν * Ο Ύ Ίΐ \1 n ιΙν ^Ν 432.2 (17?,35)-3-{5-[({1-[2- (d ymethylamino)ethyl] - 1H- pyrazole-5- yl } carbonyl)amino] - 1H- pyrazol-3-yl } cyclopentyl(28)-butan-2-ylcarbamate

- 152 046965

357 n /—\ χ-χ®-Ν___„.ΗΝ- _ν ο --Ν /)— Τ π ι A 1 X L Χ ^{Ν 1} Ο ¹ —/ Η 440.4 (17?,35)-3-(3-{[(7- methylimidazo[1,2- ά]pyrimidin-2 yl)acetyl] amino )-1//pyrazol-5 -yl)cyclopentyl(28)-butan-2-ylcarbamate 358 Ο'' Η X Ν γ- ⁰ Ax(sJ ^N ~N ^ο Τ| ^Η X 446.4 (17?,35)-3-(3-{[(2.5- dimethoxypyridine-4- yl)acetyl] amino } - 1Hpyrazol-5 -yl)cyclopentyl(28)-butan-2-ylcarbamate 359 Η / ^5χ Ζ /-/¾ Ν___Ο«β>. ,_.ΗΝ~ _{ν ο Ν} χ ιΤ γ Υ γγ-ζ X K ? Ν'Ν Η 446.3 (17?,35)-3-(3-{[(2methylimidazo[2,1 Z>] [1,3,4]thiadiazol-6yl)acetyl] amino } - 1Hpyrazol-5 -yl)cyclopentyl(28)- butan-2-ylcarbamate 360 Η Ρ /-/¾ Ν___0/5^ , _ς , ΗΝ~ _{ν ο} ι τ Cloud λ λ J Η 454.4 (17?,35)-3-[3-({[5- (trifluoromethyl)pyridin-2yl] acetyl } amino)-\Hpyrazol-5 -yl] cyclopentyl(28)-butan-2-ylcarbamate 361 ΖΖ ί / ο 454.4 (17?,35)-3-(3-{ [(2-methyl-1 - oxo-2,3-dihydro-1H- isoind ol-4-yl)acetyl] amino } 177-pyrazol-5- yl)cyclopentyl-(2 8)-butan-2ylcarbamate

- 153 046965

362 AggZZhu 455.1 (17?,35)-3-[3-({[6- (trifluoromethyl)pyrazin-2yl] acetyl } amino)- 1Hpyrazol-5 -yl] cyclopentyl(28)-butan-2-ylcarbamate 363 O ί ^Ν γ ^Ι<Ρ η 455.3 (17?,35)-3-[3-({[5- (trifluoromethyl)pyrazine-2- yl] acetyl } amino)- 1Hpyrazol-5 -yl] cyclopentyl(28)-butan-2-ylcarbamate 364 0 η 11 ΗΝ- _{Ν ο} /γ ⁴ Ν ^Ζ Τ Υ ΥΥΗα λ Λ J ¹ Η 456.3 (17?,35)-3-[3-({[4- (dimethylcarbamoyl)phenyl] acetyl } amino)-1Hpyrazol-5 -yl] cyclopentyl(28)-butan-2-ylcarbamate 365 |_| /-45- ^Ν χ/θ «64\« ην~ _{ν ο} Τ Υ \ ΥΑλ XX ^Ν — ¹ Ο η 1 fX ^f 457.4 (17?,35)-3-[3-({[1-methyl-5(trifluoromethyl)-1 R-p-yrazol-4yl] acetyl} amino)-1H-pyrazol-5-yl] cyclopentyl(28)-butane -2-ylcarbamate 366 |_| /Χ^Ν___.043^χ ΗΝ-ν 0 Ν=4 Τ Υ ΎτΑλ Λ Α/ ^Ν ~λ * Ο '—У Ν—\ Η _F y 458.1 (17?,35)-3-[3-({[1-(2,2,2trifluoroethyl)-177-1,2,3triazol-4-yl] acetyl } amino)177-pyrazol-5- yl]cyclopentyl-(28)-butan-2ylcarbamate

- 154 046965

367 H χΑΧ. ^Υ ^Ν γ°γγιγΧ χ Κ'Ν 1 Q 1--/ H 460.4 (17?,35)-3-(3-{[(2ethylimidazo[2,1 Ζ>] [1,3,4]thiadiazol-6yl)acetyl] amino } -\Ηpyrazol-5 -yl)cyclopentyl(28) -butan-2-ylcarbamate 368 |_| 1 o L/YA _n A/y η 1 HN=S=O 1 462.3 (17?,35)-3-[3-({ [2-(^methylsulfonimidoyl)phenyl] acetyl } amino)-177pyrazol-5 -yl] cyclopentyl(28)-butan-2-ylcarbamate - Isomer A 369 |_| 1 ochu ^N HN=S=O 1 462.3 (17?,35)-3-[3-({ [2-(^methylsulfonimidoyl)phenyl] acetyl } amino)-177pyrazol-5 -yl] cyclopentyl(28)-butan-2-ylcarbamate - Isomer B 370 |_| ^z γ Y Yp^XXL l| • about ChU ^H o=s=o 1 463.4 (17?,35)-3-[3-({[2- (methylsulfonyl)phenyl]acetyl}amino)-177-pyrazol-5yl]cyclopentyl-(28)-butan-2ylcarbamate 371 ΖΙ °4 ο /—γ5 1^2 \ / / ^ζ ΙΖ ν° Ο )---< ¹¹ #Α —ω—(' υ— II \__/ Ο ^χ —' 477.3 (17?,35)-3-[3-({[5-methyl-2(methylsulfonyl)phenyl]acetyl} amino)-177-pyrazol-5 yl]cyclopentyl-(28)-butan-2ylcarbamate

- 155 046965

372 J YA * ο Ay ^H o=s=o 1 477.3 (1A35)-3-[3-({[3-methyl-2(methylsulfonyl)phenyl]acetyl } amino)-1//-pyrazol-5 yl]cyclopentyl-(28)-butan-2ylcarbamate 373 Yy°W(| ο Y 1 o Ay ААу>А/А> ^Η o=s=o 1 478.4 (17?,35)-3-[3-({[2-methyl-5(methylsulfonyl)pyridin-4yl] acetyl } amino)- 1/7pyrazol-5 -yl] cyclopentyl- (28)-butan-2-ylcarbamate 374 |_| /^-Ν^ΟΛ,-.ΗΝ-ν _o IY ΥΎΚα α χJ ^H o=s=o HN ₄ 477.9 (17?,35)-3-[3-({[2- (methylsulfamoyl)phenyl] acetyl } amino)- 1//-pyrazol-5 yl]cyclopentyl-(28)-butan-2ylcarbamate 375 ° A * o A/ ^H o=s=o 1 494.4 (17?,35)-3-[3-({[2-methoxy-5(methylsulfonyl)pyridin-4yl] acetyl } amino)-Iffpyrazol-5 -yl] cyclopentyl(28)-butan-2-ylcarbamate 376 /^®- ^Ν γ°4^γ)Α ^Ν ~ ^Ν Η 0 YY^° 1 O <У Χ~ _Ν Α^/γ H „ J. „ o=s=o 1 507.3 (17?,35)-3-[5-({[4- (methoxymethyl)-2- (methylsulfonyl)phenyl]acetyl } amino)-1//-pyrazol-3 yl]cyclopentyl-(28)-butan-2ylcarbamate 377 /4 ^s 4Y/O4SL\«i ^H / ^N ~n o ^x nY / γ Y ΎΎΧα l al * O ¹ —/ N — ^{u n} o=s=o 516.3 (17?,35)-3-[3-({[1-methyl-3(methylsulfonyl)- 1//-indol2-yl] acetyl } amino)- Iffpyrazol-5 -yl] cyclopentyl(28)-butan- 2-ylcarbamate

- 156 046965

378 |_| ^F γ Y YW JI 1 L ^N ~ * o SU χ-Ά H 393.3 (17?, 35)-3 -(3 - {[(1 -methyl-177pyrazol-4-yl)acetyl] amino } 177-pyrazol-5- yl)cyclopentyl-[(25)-1fluoropropan-2-yl]carbamate 379 ^f A^y°5Ak'i ϊ ΐΛ— * o A χ'Ά'Ύ-'Ά h 394.4 (17?,35)-3-(3-{[(5-methyl-1,3oxazol-2-yl)acetyl] amino } 177-pyrazol-5- yl)cyclopentyl-[(25)-1fluoropropan-2-yl]carbamate 380 f H Αγ ^Ν γ°γΑ4Α Λ Χ ^Ν ' ^Ν ~ η 407.3 (17?, 35)-3 -(3 - {[(1 -methyl-177pyrazol-4-yl)acetyl] amino } 177-pyrazol-5- yl)cyclopentyl-[(25.37?)-3 fluorobutan-2-yl]carbamate 381 F Η Υγ ^Ν γ°ΫΑ4Υ I Α ^Ν ν~ * ο Α ν+ _Ν ΑΑ/ Η 407.3 (17?, 35)-3 -(3 - {[(1 -methyl-177pyrazol-4-yl)acetyl] amino } 177-pyrazol-5- yl)cycle opentyl-[(25*, 3 5* )-3 fluorobutan-2-yl]carbamate Isomer A 382 F Η Υγ ^Ν γ°ΫΑ<Χ I rV * ο Α +ΎΛΥ4/ Η 407.4 (17?, 35)-3 -(3 - {[(1 -methyl-177pyrazol-4-yl)acetyl] amino } 177-pyrazol-5- yl)cycle opentyl-[(25*,35*)-3 fluorobutan-2-yl]carbamate - Isomer B

- 157 046965

383 I Η j? jry_ * o A/ η 408.3 (17?,35)-3-(3-{[(5-methyl-1,3oxazol-2-yl)acetyl] amino} 1/7-pyrazol-5- yl)cyclopentyl-[(25,3R)-3 fluorobutan-2-yl]carbamate 384 YYVYACv Η 434.4 (17?,35)-3-(3-{[(2methoxypyridin-4yl)acetyl] amino } - 1Hpyrazol-5 -yl)cyclopentyl[(25*,35*)-3-fluorobutan-2yl]carbamate - Isomer A 385 Al°WY Η 434.4 (17?,35)-3-(3-{[(2- methoxypyridine-4- yl)acetyl] amino } - 1Hpyrazol-5 -yl)cyclopentyl[(25*,35*)-3-fluorobutan-2yl]carbamate - Isomer B 386 Ρ^ΛΝ___°45A _isi ^H , ^N ~N Ο f=N Υ γ γ YW ji υ L ν— F ¹ Ο L—/ Η 425.4 (17?, 35)-3 -(3 - {[(1-methyl-1/7pyrazol-4-yl)acetyl] amino } 177-pyrazol-5- yl)cyclopentyl-[(2^)-4,4difluorobutan-2-yl]carbamate Isomer A 387 ^F ^^AN^/O«i5A«> ^H / ^N ~N ο f=n Υύ υ ΎΎ4α Α Α/ ^ν ~ Η 425.4 (17?, 35)-3 -(3 - {[(1 -methyl-1/7pyrazol-4-yl)acetyl] amino } 1/7-pyrazol-5- yl)cyclopentyl-[(2^)-4,4difluorobutan-2-yl]carbamate Isomer B

- 158 046965

388 ΖΙ ο /— J<x <7 ζ \ 1 ιζ \=ο ^ζ \ 436.4 (17?,35)-3-(3-{[(6- methylpyridin-3 yl)acetyl] amino } -\Ηpyrazol-5 -yl)cyclopentyl[(2^)-3,3-difluorobutan-2yl]carbamate - Isomer A 389 1 o ХУ V\AzV η 436.4 (17?,35)-3-(3-{[(6methylpyridin-3yl)acetyl] amino } -\Hpyrazol-5 -yl)cyclopentyl[(2^)-3,3-difluorobutan-2yl]carbamate - Isomer B 390 ΧχγθΫγΥΥ ° jA ι ο '—/ HuHA Η 442.4 (17?,35)-3 -(3 -{[(2-methyl-1,3thiazol-5-yl)acetyl] amino } 17/-pyrazol-5- yl)cyclopentyl-[(2^)-3,3difluorobutan-2-yl] carbamate - Isomer A 391 ^γ ^Η γ°4Χγ!Τ'Ν 0 1 o X/ X'nXXs η 442.2 (17?,35)-3 -(3 -{[(2-methyl-1,3thiazol-5-yl)acetyl] amino } 17/-pyrazol-5- yl)cyclopentyl-[(2^)-3,3difluorobutan-2-yl] carbamate - Isomer B 392 F. F Η XytXXXCv Η 452.3 (17?,35)-3-(3-{[(2methoxypyridin-4yl)acetyl]amino)-17/pyrazol-5-yl)cyclopentyl[(2^)-3,3-difluorobutan-2yl]carbamate - Isomer A

- 159 046965

393 E F h About jJ'N 1 o +-/ '^N'A/Y'q/ Η 452.3 (17?,35)-3-(3-{ [(2- methoxypyridin-4yl)acetyl] amino } -\Hpyrazol-5 -yl)cyclopentyl[(2/)-3,3-difluorobutan-2yl]carbamate - Isomer B 394 H / ^f \-^©-N ₄ .o«(5^ _x . _s ην~ _{ν ο r} N _F YY Y ТЯд Al/ Η 443.4 (17?, 35)-3 -(3 - {[(1 -methyl- 1Hpyrazol-4-yl)acetyl] amino } 177-pyrazol-5- yl)cyclopentyl-[(27?)-4,4,4trifluorobutan-2-yl] carbamate 395 |_| ^ρ γ^^ ^Ν γ°«^!γ5>2^ ^Ι ~ρ ° °Λ _ ^F F ^Ξ O Η 444.3 (17?,35)-3 -(3 -{[(4-methyl-1,3oxazol-2-yl)acetyl] amino } 177-pyrazol-5- yl)cyclopentyl-[(27?)-4,4,4trifluorobutan-2-yl] carbamate 396 _P F _H Υύ-Ν Ο^ ^H / ^N ~ ⁿ ° ^F YY ijHa X LX H 444.3 (17?, 35)-3 -(3 - {[(3 -methyl-1,2oxazol-5 -yl)acetyl] amino} 177-pyrazol-5- yl)cyclopentyl-[(2/)-1,1,1trifluorobutan-2-yl] carbamate Isomer A 397 _P F Sn^o^.,.. hn~ _noo -n ^F YY TgChl X XX— J o ¹ —/ X-^ _N H 444.3 (17?, 35)-3 -(3 - {[(3-methyl-1,2oxazol-5-yl)acetyl] amino } 177-pyrazol-5- yl)cyclopentyl-[(2/)-1,1,1trifluorobutan-2-yl] carbamate Isomer B

- 160 046965

398 >=z V? ^o= \ ZI Z=< / \ ZA* - o IZ A 454.4 (17?,35)-3-(3-{[(6methylpyridin-3yl)acetyl]amino}-1Ηpyrazol-5-yl)cyclopentyl[(2^)-1,1,1-trifluorobutan-2yl]carbamate - Isomer A 399 H 454.4 (17?,35)-3-(3-{[(6- methylpyr idine-3 - yl)acetyl]amino}-1Hpyrazol-5-yl)cyclopentyl[(2^)-1,1,1-trifluorobutan-2yl]carbamate - Isomer B 400 ._ hn~ _n o r^N Yr TY VM1 γ L n- H \ 457.4 (17?,35)-3 -(3 -{[(1,5-dimethyl1R-pyrazol-4- yl)acetyl] amino } - 1Hpyrazol-5 -yl)cyclopentyl[^)-4,4,4-trifluorobutan-2yl]carbamate - Isomer A 401 φ/φ,Ν___Ο.£/, _ς ΗΝ- _Ν ο pN _F Y Υ Y PCH1 XA/ ⁿ ~ F ¹ O ¹ --' Η \ 457.4 (17?,35)-3 -(3 -{[(1,5-dimethyl1R-pyrazol-4- yl)acetyl] amino } - 1Hpyrazol-5 -yl)cyclopentyl[^)-4,4,4-trifluorobutan-2yl]carbamate - Isomer B 402 Η oimPC F/γγ ΧΑΥF 459.3 (17?, 35)-3 -(3 - {[(3-methoxy-1 methyl- 17/-pyrazol-5yl)carbonyl] amino } - 1Hpyrazol-5 -yl)cyclopentyl[(27?)-4,4 ,4-trifluorobutan-2yl]carbamate

- 161 046965

403 fΑγ ^N γ°Υγιγ γ 9 _ J o Su Η 460.4 (17?,35)-3 -(3 -{[(2-methyl-1,3thiazol-5-yl)acetyl] amino } 17/-pyrazol-5- yl)cyclopentyl-[(2T)-1,1,1trifluorobutan-2-yl] carbamate Isomer A 404 ρΑγΝ _γ θγγ^-Ν Ο £^ J O Su A _N » _S Η 460.4 (17?,35)-3 -(3 -{[(2-methyl-1,3thiazol-5-yl)acetyl] amino } 17/-pyrazol-5- yl)cyclopentyl-[(2T)-1,1,1trifluorobutan-2-yl] carbamate Isomer B 405 Υτθγγχγχγ Η 470.3 (17?,35)-3-(3-{[(2methoxypyridin-4yl)acetyl] amino } -1/7pyrazol-5 -yl)cyclopentyl[(2^)-1,1,1-trifluorobutan-2yl]carbamate - Isomer A 406 A^ OAli ^η , ^ν ~ν ο An А t waa Η 470.3 (17?,35)-3-(3-{[(2methoxypyridin-4yl)acetyl] amino } -1/7pyrazol-5 -yl)cyclopentyl[(2£)-1,1,1-trifluorobutan-2yl]carbamate - Isomer B 407 |_| ___O«i3^A ^N ~N O r=N , ΑΎ Y ιγΪΑ A A/l F ¹ O A —^ ⁷ \ H 471.3 (17?,35)-3-[3-({[1-(propan-2yl)-1/7-pyrazol-4- yl]acetyl}amino)-1/7pyrazol-5-yl]cyclopentyl[^)-4,4,4-trifluorobutan-2yl]carbamate - Isomer A

- 162 046965

408 Η 471.3 (1A,35)-3-[3-({[1-(propan-2yl)-17/-pyrazol-4- yl] acetyl } amino) - 1Hpyrazol-5 -yl] cyclopentyl[(2ξ)-4,4,4-τρπφτορ6γτΒΗ-2yl]carbamate - Isomer B 409 Η ^ρ υΧ ^ν υ°Χο'νη 0 У F'i 1 Π I Chapter XN F O 486.5 (1A,35)-3-{5-[({1-[2- (d ymethylamino)ethyl] - 1H- pyrazole-5- yl } carbonyl)amino] - 1Hpyrazol-3 -yl } cyclopentyl[(2ξ)-4,4,4-τρπφτορ6γτΒΗ-2yl]carbamate - Isomer A 410 H ^{ρ υΥ ν} υ ^ο Χρυ'νη O X F'i | fl I /\Д XN F Ο 486.5 (1A,35)-3-{5-[({1-[2- (d imethylamino)ethyl] - 1Hpyrazole-5- yl } carbonyl)amino] - 1Hpyrazol-3 -yl } cyclopentyl[(2ξ)-4,4,4-τρπφτορ6γτΒΗ-2yl]carbamate - Isomer B 411 ΑγΧαγΗΝ-Ν o _t fH I P I /y Jk X F 0 444.2 (1A,35)-3-(3-{[(1 -methyl-1H1,2,3-triazol-5- yl)carbonyl] amino } - 1Hpyrazol-5 -yl)cyclopentylmethyl[(2£)-4,4,4- trifluorobutan-2-yl] carbamate Isomer A

- 163 046965

412 η / fH I AND I / A F 0 ; _n 444.2 (17?, 35)-3 -(3 - {[(1 -methyl-1/71,2,3-triazol-5yl)carbonyl] amino } -1/7pyrazol-5 -yl)cyclopentylmethyl[(2£) -4,4,4- trifluorobutan-2-yl] carbamate Isomer B 413 YyU___°«i3^ ™ ^H / ^N ~N O g==Ч _F V y Y ΎΎ4χ AA/ ⁿ ~ F ¹ O '--/ H 457.4 (17?, 35)-3 -(3 - {[(1 -methyl-177pyrazol-4-yl)acetyl] amino } 1/7-pyrazol-5- yl)cyclopentyl-methyl[(2£)4,4,4-trifluorobutan-2yl]carbamate - Isomer A 414 Ρχ/Υ,Ν___<W\, _S1 ^H , ^N ~N O r==N FX J l/HA AA/ ^N F ¹ O +U H 457.4 (17?, 35)-3 -(3 - {[(1 -methyl-177pyrazol-4-yl)acetyl] amino } 1/7-pyrazol-5- yl)cyclopentyl-methyl[(2£)4,4,4-trifluorobutan-2yl]carbamate - Isomer B 415 ~ H ΥΥ ^Ν γ°Ύγ'| j? ?d about su V+n+x/V Η 390.3 (17?, 35)-3 - {3 - [(1,2-oxazol-5 ylacetyl) amino] -1 H-pyrazol5 -yl } cyclopentyl-[(25)-2methylbutyl] carbamate 416 - H ^Α ^ν υ°ϋΥ4'1 χ XVо L-У Η 404.3 (17?,35)-3 -(3 -{[(2-methyl-1,3oxazol-5-yl)acetyl] amino } 1/7-pyrazol-5- yl)cyclopentyl-[(25)-2methylbutyl]carbamate

- 164 046965

417 - H γΑ ^Ν γ°ΥγΑγ 9 χ ^Ν γ_ ο I—/ YY Η 420.3 (17?,35)-3 -(3 -{[(2-methyl-1,3thiazol-5-yl)acetyl] amino } 1H-pyrazol-5yl)cyclopentyl-[(25)-2methylbutyl] carbamate 418 1 n Ν γ°4^γ^γ ~~Ν ° °Α ο ι—/AHAL/ Η 390.0 (17?, 35)-3 - {3 - [(1,2-oxazol-5-ylacetyl)amino]-1 /U-pyrazol5 -yl} cyclopentyl-(2,2dimethylpropyl)carbamate 419 |_| ^γθΤΥΚΑ l l? ο Λ/ '-'Ά Η 374.3 (17?, 35)-3 - {3 - [(1,2-oxazol-3-ylacetyl)amino]-1/U-pyrazol5-yl} ring opentyl-(1 methylcyclopropyl)carbamate 420 SZhSh Η 384.3 (17?, 35)-3 - { 3 - [(pyr idin-2 ylacetyl) amino]-1 /U-pyrazol5 -yl } ring opentyl-(1 methylcyclopropyl)carbamate 421 Η / Χγ ^Ν γ°ΤΑΛχ Λ A? Η 387.3 (17?, 35)-3 -(3 - {[(1 -methyl-\Npyrazol-3-yl)acetyl] amino } 1/U-pyrazol-5yl)cyclopentyl-(1 methylcyclopropyl)carbamate 422 |_| >Χγ°γγί ^Ν Υ £ ?Ύο IJAA _n AA|/ Η 388.4 (17?,35)-3 -(3 -{[(4-methyl-1,3oxazol-2-yl)acetyl] amino } 1/U-pyrazol-5yl)cyclopentyl-(1 methylcyclopropyl)carbamate 423 |_| χ Ν OJR)^ HN-ы ο r—S ><γ TUCHL ί Jo Ο ’—/ Η 390.3 (17?,35)-3-{3-[(1,3-thiazol-4ylacetyl)amino]-1/U-pyrazol5 -yl} ring opentyl-(1 methylcyclopropyl)carbamate

- 165 046965

424 |_| >ς ^Ν γ°ΫΎ4А A aX Η 398.3 (17?,35)-3-(3-{[(5methylpyridin-2yl)acetyl] amino }-1Hpyrazol-5 -yl)cyclopentyl-(1 methylcyclopropyl)carbamate 425 |_| j? jO about chu χΑ\ _Ν >\Υ^>\ Η 398.4 (17?,35)-3-(3-{[(4methylpyridin-2yl)acetyl] amino }-1Hpyrazol-5 -yl)cyclopentyl-(1 methylcyclopropyl)carbamate 426 |_| >χ ^ν Υ ^ο Τ^4α α ii o CHU χ-^ _Ν ^Χ^ _Ν ^ Η 398.4 (17?,35)-3-(3-{[(6methylpyridin-2yl)acetyl] amino }-1Hpyrazol-5 -yl)cyclopentyl-(1 methylcyclopropyl)carbamate 427 |_| 4 ^N r ^o YYY5y°n 398.4 (17?,35)-3-(3-{[(3methylpyridin-2yl)acetyl] amino }-1Hpyrazol-5 -yl)cyclopentyl-(1 methylcyclopropyl)carbamate 428 USHU Η 399.4 (17?,35)-3-(3-{[(5methylpyrazin-2yl)acetyl] amino }-1Hpyrazol-5 -yl)cyclopentyl-(1 methylcyclopropyl)carbamate 429 |_| a dP o CHU ⁿ ί 402.3 (17?,35)-3-(3-{[(3fluoropyridin-2yl)acetyl] amino }-1Hpyrazol-5 -yl)cyclopentyl-(1 methylcyclopropyl)carbamate

- 166 046965

430 Ηρ Η 402.3 (17?,35)-3-(3-{[(5fluoropyridin-2yl)acetyl] amino }-1Ηpyrazol-5 -yl)cyclopentyl-(1 methylcyclopropyl)carbamate 431 |_| [χ^γθ^Κ^'χ ο ο ...... Η 404.3 (17?,35)-3 -(3 -{[(2-methyl-1,3thiazol-4-yl)acetyl] amino } 177-pyrazol-5yl)cyclopentyl-( 1 - methylcyclopropyl)carbamate 432 |_| Ο^γθΫγ^'χ ° Γ°>-<ι Η 414.3 (17?,35)-3-(3-{[(2cyclopropyl-1,3-oxazol-4yl)acetyl] amino }-1Hpyrazol-5 -yl)cyclopentyl-(1 methylcyclopropyl)carbamate 433 AiuAaLA Η 414.3 (17?,35)-3-(3-{[(5methoxypyridin-2yl)acetyl] amino }-1Hpyrazol-5 -yl)cyclopentyl-(1 methylcyclopropyl)carbamate 434 ixYtxYVX Η 414.3 (17?,35)-3-(3-{[(6methoxypyridin-2yl)acetyl] amino }-1Hpyrazol-5 -yl)cyclopentyl-(1 methylcyclopropyl)carbamate 435 ⁿ J 416.4 (17?, 35)-3-(3-{[(3-fluoro-bmethylpyridin-2yl)acetyl] amino }-1Hpyrazol-5 -yl)cyclopentyl-(1 methylcyclopropyl)carbamate

- 167 046965

436 1 X ^N nV Η 416.1 (1/?,35)-3-[3-({[1-(propan-2yl)-1/7-1,2,3-triazol-4yl] acetyl } amino)-1/7pyrazol-5 -yl ]cyclopentyl-(1 methylcyclopropyl)carbamate 437 Η _____ pi >ς ^Ν γ°<ΥβΐΤχ ο JjfV Η 418.4 (1/?,35)-3-(3-{[(5- chloropyridine-2- yl)acetyl] amino } -1/7- pyrazol-5-yl)cyclopentyl-(1 methylcyclopropyl)carbamate 438 |_| >γ ^Ν γ ^ο ΫΎ41 χ ΥΥ Ο EV ^Η CI 432.3 (1/?,35)-3-(3-{[(3-chloro-5methylpyridin-2- yl)acetyl] amino } -1/7pyrazol-5 -yl)cyclopentyl-(1 methylcyclopropyl)carbamate 439 >Χυ°ΤΥΥλ λ αΎ°' ο EV +Α _Ν Λχγ Η 1 432.3 (1/?,35)-3-(3-{[(5-chloro-3methylpyridin-2- yl)acetyl] amino } -1/7pyrazol-5 -yl)cyclopentyl-(1 methylcyclopropyl)carbamate 440 ><?γ ^ο Τγγ'ϊ χ ΧΎ°' η 432.3 (1/?,35)-3-(3-{[(5-chloro-4methylpyridin-2- yl)acetyl] amino } -1/7pyrazol-5 -yl)cyclopentyl-(1 methylcyclopropyl)carbamate 441 |_| [Χ^ΥθΫΥΥχ χ P ^Η CI 432.3 (1/?, 35)-3 -(3 - {[(3-chloro-4methylpyridin-2yl)acetyl] amino } -1/7pyrazol-5 -yl)cyclopentyl-(1 methylcyclopropyl)carbamate

- 168 046965

442 p i—Φ zz z \ / / ^z IZ 5=ow o 432.3 (1A35)-3-(3-{[(5-chloro-6methylpyridin-2yl)acetyl] amino } -1/7pyrazol-5 -yl)cyclopentyl-(1 methylcyclopropyl)carbamate 443 ΑγθΤΥΑ1 I jfl f 0 LX ^H F 434.4 (17?,35)-3-[3-({[4- (difluoromethyl)pyridine-2- yl] acetyl } amino) - 1Hpyrazol-5 -yl] cyclopentyl-( 1 methylcyclopropyl) carbamate 444 >Υγ ^ο 5Α4Χ A jfl F 0 Lx ^H i ^F 452.4 (17?,35)-3-[3-({[4- (trifluoromethyl)pyridine-2- yl] acetyl } amino) - 1Hpyrazol-5 -yl] cyclopentyl-( 1 methylcyclopropyl) carbamate 445 H > [ΑγθΑγκχ a Ij ^f o L^z V+jj+XX H 452.4 (17?,35)-3-[3-({[5- (trifluoromethyl)pyridine-2- yl] acetyl } amino) - 1Hpyrazol-5 -yl] cyclopentyl-( 1 methylcyclopropyl) carbamate 446 HV [>Αγ ^Ο γ-ΑΤ~Ν O JAn.A ^F o LX Υ+Ν ^Λ — H 456.0 (17?,35)-3-[3-({[1-(2,2,2trifluoroethyl)-177-1,2,3triazol-4-yl] acetyl } amino)1//-pyrazol-5yl]cyclopentyl -( 1 - methylcyclopropyl)carbamate 447 (A χ”τ ^ο ΤΑΧ _Ν Αχ0 ^H o=s=o 1 491.4 (17?,35)-3-[3-({[5-methoxy-2(methylsulfonyl)phenyl]acetyl}amino)-1//-pyrazol-5- yl]cyclopentyl-(1 methylcyclopropyl)carbamate

- 169 046965

448 ϊ ΉΛ— ο —Αθ Η 402.3 (1 R,3S)-3-(3-{ [(5-methyl-1,3oxazol-2-yl)acetyl] amino } Ш-pyrazol-5yl)cyclopentyl-(1 ethylcyclopropyl)carbamate 449 Α ί ^Ν χ Ο А/ Η 413.4 (17?,35)-3-(3-{[(5methylpyrazin-2yl)acetyl] amino }-1Hpyrazol-5 -yl)cyclopentyl-(1 ethylcyclopropyl)carbamate 450 ^Ν Υ° Υγχ Υ χ ί Υ Η 429.3 (17?,35)-3-(3-{[(5methoxypyrazin-2yl)acetyl] amino }-1Hpyrazol-5 -yl)cyclopentyl-(1 ethylcyclopropyl)carbamate 451 |_| ^F '~X^ ⁿ x/°«(SL\«> ^H / ^N 'N ο Ν'° _F Y △ Υ ΥΥ4A Α F Ο <-У Η 442.4 (1R, 35)-3 - {3 - [(1,2-oxazol-3-ylacetyl)amino]-17/-pyrazol5-yl} cyclopentyl-[1-(2,2,2trifluoroethyl)cyclopropyl] carbamate 452 ?' ο τζ ί· 452.1 (17?,35)-3-(3-{[(6- methylpyr idine-3 - yl)carbonyl] amino } - 1Hpyrazol-5 -yl)cyclopentyl- [ 1 - (2,2,2-trifluoroethyl)cyclopropyl]carbamate

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453 |_| F^/-\.N___Ο45^, _ς ΗΝ~Ν ο O'N F< △ Y Cloud AA?— F O LJ H 456.3 (1R, 35)-3 -(3 - {[(3-methyl-1,2oxazol-5-yl)acetyl] amino } Ш-pyrazol-5yl)cyclopentyl-[ 1 -(2,2,2trifluoroethyl)cyclopropyl] carbamate 454 ^f YA^Y°TY4T p ^F f Ak _o Ly h 456.1 (17?,35)-3-(3-{[(5-methyl-1,3oxazol-2-yl)acetyl] amino } Ш-pyrazol-5yl)cyclopentyl-[ 1 -(2,2,2trifluoroethyl)cyclopropyl ] carbamate 455 x X ^N X ^F F О '—/ Ά+ _ν ^Λ — H 467.3 (17?,35)-3-(3-{[(5- methylpyrazine-2- yl)acetyl] amino }-1Hpyrazol-5 -yl)cyclopentyl-[1 (2,2,2-trifluoroethyl)cyclopropyl] carbamate 456 J ZI p /—v? </ z \ / / ^z zz £ M o / 483.3 (17?,35)-3-(3-{[(5- methoxypyrazine-2- yl)acetyl] amino }-1Hpyrazol-5 -yl)cyclopentyl-[1 (2,2,2-trifluoroethyl)cyclopropyl] carbamate 457 ^F F O +-0 \ 485.4 (17?,35)-3-[3-({[3(methoxymethyl)-1 -methyl-1Hpyrazol-5-yl]carbonyl}amino)-177-pyrazol-5yl]cyclopentyl-[1 -(2,2 ,2trifluoroethyl)cyclopropyl]carbamate

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458 ο Ο'Ν X Ο MXAH—XY Η 374.3 (17?, 35)-3 - {3 - [(1,2-oxazole-5 - ylacetyl)amino]- 1//-pyrazol- 5-yl}cyclopentylcyclobutylcarbamate 459 <Χ^γ°γχβ^γ fl Γ ^Ν γ_ ο УУ X _n XA _o η 403.4 (17?,35)-3-(3-{ [(5-methyl-1,3,4oxadiazol-2- yl)acetyl] amino }-1Hpyrazol-5 -yl)cyclopentyl-(1 methylcyclobutyl)carbamate 460 |_| Ζγ/ ^Ν γ ^Ο *^ΧΧ/ ^Ν --Ν Ο Ο-Ν \_J Ο ΜΧΑνΧΧ ⁷ Η 387.9 (17?, 35)-3 - {3 - [(1,2-oxazol-5 ylacetyl) amino]- 17/-pyrazol- 5-yl}cyclopentylcyclopentylcarbamate 461 ΐ Η 0 Ο-Ν \—J o Η 402.3 (17?, 35)-3 - {3 - [(1,2-oxazol-5 ylacetyl)amino]-177-pyrazol5 -yl } cyclopentyl-[( 17?,25)-2methylcyclopentyl] carbamate 462 /^'^γθΫχβχΧ' χ jT ^N y~ \-J o УУ A+ _n AA _O η 416.3 (17?,35)-3 -(3 -{[(2-methyl-1,3oxazol-5-yl)acetyl] amino } 177-pyrazol-5- yl)cyclopentyl-[(17?,25)-2methylcyclopentyl]carbamate 463 <^'Βγ°γγ^χ χ ГУ- VJ о УУ A>^ _n >4x< _s Η 432.3 (17?,35)-3 -(3 -{[(2-methyl-1,3thiazol-5-yl)acetyl] amino} 177-pyrazol-5- yl)cyclopentyl-[(17?,25)-2methylcyclopentyl]carbamate

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464 1 |_| VJ o АУ SA _n >A^A _s η 432.3 (17?,35)-3 -(3 -{[(2-methyl-1,3thiazol-5-yl)acetyl] amino } 177-pyrazol-5- yl)cyclopentyl-[(15.27?)-2methylcyclopentyl] carbamate 465 Λ |_| J?Λ o m+HAUCH/ Η 374.3 (17?, 35)-3 - {3 - [(1,2-oxazole-5 - ylacetyl)amino]- l/7-pyrazol- 5-yl}cyclopentyl- (cyclopropylmethyl)carbamate 466 /\ Η ^AgJ-N^Oy^.-.HN-N 0 Ν'°> Τ V pChl a ¹ 0 ¹ —/ Ν Η 388.4 (17?, 35)-3 - {3 - [(1,2-oxazol-3 ylacetyl)amino]-l/7-pyrazol5 -yl } ring opentyl-[(1S)-1 cyclopropylethyl] carbamate 467 (S,Η.Ν-Μ 0 NQ V Υ CLOUD AA? = 0 ¹ -f N H 388.2 (17?, 35)-3 - {3 - [(1,2-oxazol-3 ylacetyl)amino]-1 /7-pyrazol- 5 -yl } cyclopentyl-[( 17?)-1 cyclopropylethyl] carbamate 468 /\ H _{o O} -N I y u4a aaY • O Uy N H 402.3 (17?, 35)-3 -(3 - {[(3-methyl-1,2oxazol-5-yl)acetyl] amino } 177-pyrazol-5yl)cyclopentyl-[( 1S)-1 cyclopropylethyl] carbamate 469 ^Ζ Α®'Ν_,Ο«β^ _χ ._.ΗΝ- _{Ν o O} -N ύ y YY4a aay H 402.3 (17?, 35)-3 -(3 - {[(3 -methyl-1,2oxazol-5 -yl)acetyl] amino} 177-pyrazol-5- yl)cyclopentyl-[(17?)-1 cyclopropylethyl] carbamate

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470 ^^γθΫγχΥ 9 /G * Ο XY Η 413.4 (17?,35)-3-(3-{[(5methylpyrazin-2-yl)acetyl] amino } - 1//-pyrazol-5 yl)cyclopentyl-[( 1S)-1 cyclopropylethyl] carbamate 471 Α&ν ολλ,,ην-ν ο < ^Ν >Χ ύ V ΎχΗа l Λ 2 - Ο L-/ Ν— Ν Η 413.4 (17?,35)-3-(3-{[(5- methylpyrazin-2-yl)acetyl] amino } - 1//-pyrazol-5 yl)cyclopentyl-[(17?)-1 cyclopropylethyl] carbamate 472 γργ/^ΗΝ-γ _ο ΑΥ”'' = ο Χ/^χΧ'νΑ—Υ Η 429.3 (17?,35)-3-(3-{[(5- methoxypyrazin-2-yl)acetyl] amino } - 1//-pyrazol-5 yl)cyclopentyl-[(17?)-1 cyclopropylethyl] carbamate 473 |_| θ£γ°*ΑΧ2ίγ γ 9 A A o X/ Χ'νΧΧΧ η 404.3 (17?, 35)-3 - {3 - [(1,2-oxazol-5 ylacetyl)amino] - 177-pyrazol5 -yl } cyclopentyl-[(3 £)-3 methyltetrahydrofuran-3 yl]carbamate - Isomer A 474 3 ζχ Ζ=Λ 1 \ Ζ ΖΖ ¹ 1 m, — Ο >° £ ο—' 404.3 (17?, 35)-3 - {3 - [(1,2-oxazol-5 ylacetyl) amino] - 1//-pyrazol5 -yl } cyclopentyl-[(3 £)-3 methyltetrahydrofuran-3 yl]carbamate - Isomer B 475 ^ο ϋχΎ ^ο ΫΥχ Ύ 5 ТУХ ⁷ О X/ Χ ^χ Ν ^> Χ ^Λ Ο ^/ Η 418.4 (15.37?)-3 -(3 - {[(5 -methyl-1,3oxazol-2-yl)acetyl] amino } 17/-pyrazol-5yl)cyclopentyl-[(3 ξ)-3 methyltetrahydrofuran-3 yl]carbamate - Isomer A

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476 ο Ay 5\ΑΛ _Ο ⁷ Η 418.4 (15,3R)-3 -(3 - {[(5 -methyl-1,3oxazol-2-yl)acetyl] amino } 177-pyrazol-5yl)cyclopentyl-[(3 /)-3 methyltetrahydrofuran-3 yl] carbamate - Isomer B 477 Ο^τ°ΤΥ4'ίί ϊ 13ο Ly LAAY/ Η 418.4 (17?,35)-3-(3-{[(5-methyl-1,3oxazol-2-yl)acetyl] amino } 177-pyrazol-5- yl)cyclopentyl-[(3 /)-3 methyltetrahydrofuran-3 yl]carbamate - Isomer A 478 ^< l3<?y ^o *?^ak ⁿ 'jl u 13— ο Ly ΑΆ _ν >ΥΆ _ο Η 418.4 (17?,35)-3-(3-{[(5-methyl-1,3oxazol-2-yl)acetyl] amino } 177-pyrazol-5yl)cyclopentyl-[(3 /)-3 methyltetrahydrofuran-3 yl ]carbamate - Isomer B 479 |_| ?3< ^Ν ν' ^ο * ^ί ?Α?Λ[ ^Ν 'Ν 0 , ΥΑ D I Υ3Α ΑΧ η \Q ο— 433.4 (17?, 35)-3 -(3 - {[(3-methoxy-1 methyl-17/-pyrazol-5yl)carbonyl] amino } - 1Hpyrazol-5-yl)cyclopentyl[(zo-zmethyltetrahydrofuran-3yl] carbamate - Isomer A

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480 |_| ?> ^N v ^O4 ?xs2 ^N '!fi? i ^h Ly ^N o— 433.4 (17?, 35)-3 -(3 - {[(3-methoxy-1 methyl-17/-pyrazol-5yl)carbonyl] amino } - 1Hpyrazol-5-yl)cyclopentyl[(zo-zmethyltetrahydrofuran-3yl] carbamate - Isomer B 481 ΟΧΥ°ΫΎ4 AA XVо su a _n » _s H 434.3 (17?,35)-3 -(3 -{[(2-methyl-1,3thiazol-5-yl)acetyl] amino } 177-pyrazol-5yl)cyclopentyl-[(3 ξ)-3 methyltetrahydrofuran-3 yl ]carbamate - Isomer A 482 |_| Οα ^ν υ°ϋΎ4a a Xy o SU Oy -A Η 434.3 (17?,35)-3 -(3 -{[(2-methyl-1,3thiazol-5-yl)acetyl] amino } 17/-pyrazol-5yl)cyclopentyl-[(3 ξ)-3 methyltetrahydrofuran-3 yl]carbamate - Isomer B 483 ΑγθΌξΐ I GA o ¹ ~U Η 442.9 (17?,35)-3-(3-{[(4- methoxyphenyl)acetyl] amino } 177-pyrazole-5- yl)cyclopentyl-[(3 ξ)-3 methyltetrahydrofuran-3 yl]carbamate - Isomer A 484 αυααι λ γα Η 442.9 (17?,35)-3-(3-{[(4- methoxyphenyl)acetyl] amino } 177-pyrazole-5- yl)cyclopentyl-[(3 ξ)-3 methyltetrahydrofuran-3 yl]carbamate - Isomer B

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485 a GU ⁴ O A/N 445.4 (17?,35)-3-(3-{[(5methoxypyrazin-2yl)acetyl] amino } -1/7pyrazol-5 -yl)cyclopentyl[(30-3- methyltetrahydrofuran-3 yl]carbamate - Isomer A 486 °OYy°YYAa a jTX ⁴ n 445.4 (17?,35)-3-(3-{[(5methoxypyrazin-2yl)acetyl] amino } -1/7pyrazol-5 -yl)cyclopentyl[(30-3- methyltetrahydrofuran-3 yl]carbamate - Isomer B 487 _μ ΗΝ-Ν O 1 Ν DELZHchyU, \\ A Zh ?ΆΎ \ γΑγ ν γΧ- ό Η Μ '—o \ 447.5 (17?,35)-3-[3-({[3- (methoxymethyl)-1-methyl-1/7pyrazole-5- yl]carbonyl} amino)-1/7pyrazol-5-yl]cyclopentyl[(3^)-3-methyl- tetrahydrofuran-3yl]carbamate - Isomer A 488 с< Ζ^ J Ζ ·γ ^Ο= \ ΖΙ ζ=\ ι \ Ζ ^Χ 1 §1 — Ο X ο—' 447.5 (17?,35)-3-[3-({[3- (methoxymethyl)-1-methyl-1/7pyrazole-5- yl]carbonyl}amino)-1/7pyrazol-5-yl]cyclopentyl[(3^)-3-methyl- tetrahydrofuran-3yl]carbamate - Isomer B

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489 ο Γ°\ n X/ 455.4 (1A,35)-3-(3-{ [(30-2,3dihydro-1-benzofuran-3-acetyl] amino } - 1/7-pyrazol 5 -yl)cyclopentyl-[(3 0-3 methyltetrahydrofuran-3 yl]carbamate - Isomer A 490 ?^V'°*?>\(S) ^I 1 ^N ' ^N ° Г°\ X ^х П I УХА Лт X. о С.У ^nXX 1 n X/ 455.4 (1A,35)-3-(3-{ [(30-2,3dihydro-1-benzofuran-3-acetyl] amino } - 1/7-pyrazol 5 -yl)cyclopentyl-[(3 0-3 methyltetrahydrofuran-3 yl]carbamate - Isomer B 491 Ο^χΝγθ-^βΤΤί Ϊ TV °n X/ 455.4 (1A,35)-3-(3-{ [(30-2,3dihydro-1-benzofuran-3-acetyl] amino} - 1/7-pyrazol 5 -yl)cyclopentyl- [(3 0-3 methyltetrahydrofuran-3 yl]carbamate - Isomer C 492 oX^-'WmY! η ·Γ°κ, Ο<ύ CLOUDS+Xn, ° n X/ 455.4 (1A,35)-3-(3-{ [(30-2,3dihydro-1-benzofuran-3-acetyl] amino } - 1/7-pyrazol 5 -yl)cyclopentyl-[(3 0-3 methyltetrahydrofuran-3 yl]carbamate - Isomer D 493 9 ' ΖΖ °ts o ί ΤΖ s ^ζ \\ 483.3 (1A,35)-3-[3-({[5(trifluoromethyl)pyrazin-2yl] acetyl } amino)-\Hpyrazol-5 -yl]cyclopentyl[(30-3- methyltetrahydrofuran-3 yl]carbamate - Isomer A

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494 Η 483.3 (17?,35)-3-[3-({[5(trifluoromethyl)pyrazin-2yl] acetyl } amino)- 1Hpyrazol-5 -yl]cyclopentyl[(zo-z- methyltetrahydrofuran-3 yl]carbamate - Isomer B 495 1 LL. Z Lil o=\ ZI Z^< /Λ 6 O—' 485.4 (17?,35)-3-[3-({[1-methyl-5(trifluoromethyl)-1 R-p-yrazol-4yl] acetyl} amino)-1H-pyrazol-5-yl] cyclopentyl[(zo-zmethyltetrahydrofuran -Zyl]carbamate - Isomer A 496 /—° 9 ' ZI °4 o /----- li /7 Z. \ 1 / ^z iz ^=° 9-Д1 z ^m 1 485.4 (17?,35)-3-[3-({[1-methyl-5(methyl trifluoro)-1 R-p-irazol-4yl] acetyl } amino)- 1-R-pyrazol-5-yl] cyclopentyl[(zo-zmethyltetrahydrofuran -Zyl]carbamate - Isomer B 497 Q x-'E \ ZI °4P fl zz 5 o \ 444.2 (15.37?)-3-(3-{[(2methoxypyridin-4yl)acetyl] amino } - 1Napyrazol-5 -yl)cyclopentyl[(25)-tetrahydrofuran-2ylmethyl] carbamate

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498 uo _n 1 ^-^V°TYAa X Χχ O GV VX _N Ay4A _F Η 449.3 (15.37?)-3-(3-{ [(3,5difluorophenyl)acetyl] amino } 1R-pyrazol-5yl)cyclopentyl-[(27?)tetrahydrofuran-2ylmethyl] carbamate 499 уо Η ϊ ν'-^ΝγΟ'^Μ,^'Χ χ jA ο G.V. Η 449.3 (15.37?)-3-(3-{[(3,5difluorophenyl)acetyl] amino } 1R-pyrazol-5yl)cyclopentyl-[(25)tetrahydrofuran-2ylmethyl] carbamate 500 Α Α XV O. J O 1—f +GX _n XVyXs H 434.3 (15.37?)-3 -(3 - {[(2-methyl-1,3thiazol-5-yl)acetyl] amino } 1R-pyrazol-5yl)cyclopentyl-tetrahydro2R-pyran-4-ylcarbamate 501 <Yy°'T^Aa a XY°^ o^J o *—/ xy-UxX ⁷ Η 443.3 (15.37?)-3-(3-{[(4methoxyphenyl)acetyl] amino } 1R-pyrazol-5yl)cyclopentyl-tetrahydro2R-pyran-4-ylcarbamate 502 Αγ ^Κ γ ^ο γγιγ'χ χ ΧΥ° o^J ο Gv ^У^х/х/ H 443.3 (17?,35)-3-(3-{[(4methoxyphenyl)acetyl] amino } 1R-pyrazol-5yl)cyclopentyl-tetrahydro2R-pyran-4-ylcarbamate

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503 , _R ;ΗΝ~ν _ο Η 444.3 (15.37?)-3-(3-{[(2methoxypyridin-4yl)acetyl] amino } - 1Hpyrazol-5 -yl)cyclopentyltetrahydro-27/-pyran-4ylcarbamate 504 |_| Υγ ^Ν γΟγΗΝ~Ν ° o. J o Υ/ΧΧν'^ΧΧχ H 444.3 (17?,35)-3-(3-{[(2- methoxypyridin-4yl)acetyl]amino}-1Hpyrazol-5-yl)cyclopentyltetrahydro-27/-pyran-4ylcarbamate 505 F hl γγ ^Ν γ°ΤΥΑχ 1 JAL oY O LX —XAp H 449.4 (17?,35)-3-(3-{[(3.5- difluorophenyl)acetyl] amino } 177-pyrazole-5- yl)cyclopentyl-tetrahydro2//-pyran-4-ylcarbamate 506 ^Α ^Ν γ°γΑγΥ ° jA oX o Cy χ-'-'Ύ'-χχ·'-/ H 431.3 (17?, 35)-3 -(3 - {[(1 -methyl-177pyrazol-4-yl)acetyl] amino } 177-pyrazol-5- yl)cyclopentyl-(4methyltetrahydro-277-pyran-4yl)carbamate 507 H / ^/Ν Ο,^κ hn- _{n 0 n} -N g Y YrU aa? oX O Cy H 431.4 (17?, 35)-3 -(3 - {[(1 -methyl-1Hpyrazol-3-yl)acetyl] amino } 177-pyrazol-5yl)cyclopentyl-(4- methyltetrahydro-277-pyran-4yl)carbamate

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508 ι^γ°γγί ^Ν a J χΥcxJ o E-/ Η 432.3 (1A,35)-3-(3-{[(5-methyl-1,3oxazol-2-yl)acetyl] amino } Sh-pyrazol-5yl)cyclopentyl-(4methyltetrahydro-2//-pyran-4yl)carbamate 509 A A XU-o ⁷ CL J O '—f +% ⁷ %% ⁷ Η [M+Na] ⁺ 486.0 (1A,35)-3-(3-{[(2-methoxy-1,3thiazol-5-yl)acetyl] amino } III-pyrazol-5yl)cyclopentyl-(4- methyltetrahydro-2//-pyran-4yl)carbamate 510 ^Υγ ^ο γγ?,,ζΥ J Gu. ογλ,, _ζ about EU YnAVs 448.2 (15.37?)-3 -(3 - {[(2-methyl-1,3thiazol-5-yl)acetyl] amino } Ш-pyrazol-5- yl)cyclopentyl-[(35*,47?*)-3methyltetrahydro-2//-pyran-4yl]carbamate - Isomer A 511 γγ ^Ν γ°γ\α?Χ j? G y OW, 0 EU 448.2 (15.37?)-3 -(3 - {[(2-methyl-1,3thiazol-5-yl)acetyl] amino } Ш-pyrazol-5- yl)cyclopentyl-[(35*,47?*)-3methyltetrahydro-2//-pyran-4yl]carbamate - Isomer B 512 H ΗΝ- _{ν o} γ ϊΎ4ϊ XA a o EU X^ _N H 458.3 (15.37?)-3-(3-{[(2methoxypyridin-4yl)acetyl] amino }-1Hpyrazol-5 -yl)cyclopentyl(tetrahydro-2R-pyran-4ylmethyl)carbamate

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513 PZI P 0 IZ Jo hu 463.4 (15.37?)-3-(3-{ [(3,5difluorophenyl)acetyl] amino } 1R-pyrazole-5- yl)cyclopentyl-(tetrahydro2R-pyran-4-ylmethyl)carbamate 514 J ⁴ ] _H >F ΑγογΥ'Ν j? if J ^F o AU h 496.4 (15,3R)-3-[3-({[6(trifluoromethyl)pyraidin-3yl] acetyl } amino)-1Hpyrazol-5 -yl]cyclopentyl(tetrahydro-2R-pyran-4ylmethyl)carbamate 515 F 1 1 h JL А^°ж ⁿ Л j? Du Η 463.4 (15.37?)-3-(3-{[(3,5difluorophenyl)acetyl] amino } 1R-pyrazol-5yl)cyclopentyl-[(3 £)tetrahydro-2R-iran-3 ylmethyl] carbamate - Isomer A 516 j? jAjL Η 463.3 (15.37?)-3-(3-{[(3,5difluorophenyl)acetyl] amino } 1R-pyrazol-5yl)cyclopentyl-[(3 £)tetrahydro-2R-iran-3 ylmethyl] carbamate - Isomer B 517 |_| ΥΥΥΑζΧΟ Η 401.4 (17?,35)-3-{5[(phenylacetyl)amino] - 1Hpyrazol-3-yl} cyclopentyl[(25)-1-methoxypropan-2yl]carbamate

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518 |_| \Υ ^Ν γ ^ο ΎΧ 9 1 ⁷⁷ H o— 421.4 (17?, 35)-3 -(3 - {[(3-methoxy-1 methyl- 17/-pyrazol-5yl)carbonyl] amino } - 1Hpyrazol-5-yl)cyclopentyl[(25)-1 - methoxypropan- 2 yl]carbamate 519 ΧΎθΎπΙ i χΎ Η 432.3 (17?,35)-3-(3-{[(6methoxypyridin-3 yl)acetyl] amino }-1Hpyrazol-5 -yl)cyclopentyl[(25)-1 - methoxypropan-2 yl]carbamate 520 ^4σ Ί ^κ ϊ ^ο τΛΐ ι GA * ο Ay '^ν'Α-Ύ Η 433.4 (17?,35)-3-(3-{[(5- methoxypyrazin-2yl)acetyl] amino } -177pyrazol-5 -yl)cyclopentyl[(25)-1 - methoxypropan-2 yl]carbamate 521 9 / 1 D 1 / \A ΓΓ ^ν ⁷⁷ Η Aq \ 435.4 (17?,35)-3-[5-({[3- (methoxymethyl)-1-methyl-1Hpyrazole-5- yl]carbonyl } amino)-1Hpyrazol-3-yl]cyclopentyl[(25)-1-methoxypropan-2yl]carbamate 522 |_| 1 GU-O 1 ο Ay А^LUу _χ Η 438.3 (17?,35)-3-(3-{ [(5-methoxy-1,3thiazol-2-yl)acetyl] amino } 1//-pyrazol-5- yl)cyclopentyl-[(25)-1methoxypropan-2-yl] carbamate

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523 Η 471.3 (17?,35)-3-[3-({[5(trifluoromethyl)pyrazin-2yl] acetyl } amino)-\Hpyrazol-5 -yl]cyclopentyl[(25)-1 - methoxypropan-2 yl]carbamate 524 BUT. 1 n <Υ ^Ν γΟ4%-γχ~Ν Ο O'N_ H 420.0 (17?, 35)-3 -(3 - {[(3-methyl-1,2oxazol-5-yl)acetyl] amino } 177-pyrazol-5- yl)cyclopentyl-[(2^)-2(hydroxymethyl)butyl] carbamate - Isomer A 525 H.O. J-YN'-CUW-yg HN- _N Q _O -N \ Y VY4.A Λ ΑΛ- Ι o N H 420.1 (17?, 35)-3 -(3 - {[(3-methyl-1,2oxazol-5-yl)acetyl] amino } 177-pyrazol-5- yl)cyclopentyl-[(2^)-2(hydroxymethyl)butyl] carbamate - Isomer B 526 H.O. x gy_ i o chU 4+ _Ν +—A Η 420.1 (17?,35)-3 -(3 -{[(2-methyl-1,3oxazol-5-yl)acetyl] amino } 177-pyrazol-5- yl)cyclopentyl-[(2^)-2(hydroxymethyl)butyl] carbamate - Isomer A 527 But. 1 n ο f ^Ν γ_ ¹ o CHU chul/u, n 420.0 (17?,35)-3 -(3 -{[(2-methyl-1,3oxazol-5-yl)acetyl] amino } 177-pyrazol-5- yl)cyclopentyl-[(2^)-2(hydroxymethyl)butyl] carbamate - Isomer B

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528 BUT- a Xx 1 about EV H 436.1 (17?,35)-3 -(3 -{[(2-methyl-1,3thiazol-5-yl)acetyl] amino } 17/-pyrazol-5- yl)cyclopentyl-[(2£)-2(hydroxymethyl)butyl] carbamate - Isomer A 529 HO- a a XУ- ¹ o Ey +^ ⁴ N'»'s H 436.1 (17?,35)-3-(3-{ [(2-methyl-1,3thiazol-5-yl)acetyl] amino } 17/-pyrazol-5- yl)cyclopentyl-[(2£)-2(hydroxymethyl)butyl] carbamate - Isomer B 530 HO- Ρ^νθΎγΑΑ A ΧΤ°^ Η 445.4 (17?,35)-3-(3-{[(4- methoxyphenyl)acetyl] amino } 17/-pyrazole-5- yl)cyclopentyl-[(2£)-2(hydroxymethyl)butyl] carbamate - Isomer A 531 ΗΟ- ρΑΝγθγγ^'Ν O HA ⁰ 1 ο EV +++n—+>> Η 445.4 (17?,35)-3-(3-{[(4- methoxyphenyl)acetyl] amino } 17/-pyrazole-5- yl)cyclopentyl-[(2£)-2(hydroxymethyl)butyl] carbamate - Isomer B 532 ΗΟ- [ΑΝγΟ^γΑ^'-Ν O AG° 1 o EV E+ _n AAz ⁿ H 446.2 (17?,35)-3-(3-{[(6methoxypyridin-3 yl)acetyl] amino }-1Hpyrazol-5 -yl)cyclopentyl[(20-2(hydroxymethyl)butyl] carbamate - Isomer A

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533 But. 1 o Lv A-+ _n >O^n Η 446.2 (17?,35)-3-(3-{[(6methoxypyridin-3 yl)acetyl] amino }-1Ηpyrazol-5 -yl)cyclopentyl[(20-2(hydroxymethyl)butyl] carbamate - Isomer B 534 but γΧ^Υθγγγ ¹ '·^ ° 1 O '— Η 446.2 (17?,35)-3-(3-{[(2methoxypyridin-4yl)acetyl] amino }-1Hpyrazol-5 -yl)cyclopentyl[(20-2(hydroxymethyl)butyl] carbamate - Isomer A 535 \ ο ζχ ζ=\ / \ Ζ ijO--' ABOUT >° χζ -X 446.2 (17?,35)-3-(3-{[(2methoxypyridin-4yl)acetyl] amino }-1Hpyrazol-5 -yl)cyclopentyl[(20-2(hydroxymethyl)butyl] carbamate - Isomer B 536 H.O. F ^Ν γθργγ χ l J^X 1 ο 1—J A+fjANv+F Η 451.2 (17?,35)-3-(3-{[(3,5difluorophenyl)acetyl] amino } 1R-pyrazol-5yl)cyclopentyl-[(2/)-2(hydroxymethyl)butyl] carbamate - Isomer A

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537 HO, F 1 |_| 1 Α ^Ν γ°ΑΑ 9 jA 1 o SU V+ _n A» _f η 451.2 (17?,35)-3-(3-{[(3.5- difluorophenyl)acetyl] amino } 177-pyrazole-5- yl)cyclopentyl-[(2T)-2(hydroxymethyl)butyl] carbamate - Isomer B 538 F 1 n X HoAX ^N ^°«£\fsjJ/ ^N ~N ° JAI o 1U^s _m suchA _R n 437.3 (17?,35)-3-(3-{[(3.5- difluorophenyl)acetyl] amino } 177-pyrazole-5- yl)cyclopentyl-[(2£)-3hydroxy-2-methylpropyl] carbamate - Isomer A 539 F ⁿ °^tjlA n 437.3 (17?,35)-3-(3-{[(3.5- difluorophenyl)acetyl] amino } 177-pyrazole-5- yl)cyclopentyl-[(2£)-3hydroxy-2-methylpropyl] carbamate - Isomer B 540 he O £y o X/ VX _n AyA/ n 431.3 (17?,35)-3-(3-{[(4- methoxyphenyl)acetyl] amino } 177-pyrazole-5- yl)cyclopentyl-[(2£)-2hydroxybutyl]carbamate - Isomer A 541 He Ау£А'| O O o Su n 431.3 (17?,35)-3-(3-{[(4- methoxyphenyl)acetyl] amino } 177-pyrazole-5- yl)cyclopentyl-[(2£)-2hydroxybutyl]carbamate - Isomer B

- 188 046965

542 OH ϊ λXX OU/ Η 437.3 (17?,35)-3-(3-{[(3,5difluorophenyl)acetyl] amino } III-pyrazol-5yl)cyclopentyl-[(2^)-2hydroxybutyl] carbamate Isomer A 543 OH ί ^^ ^Ν γ ^ο Τγχχ γ Α Η 437.3 (1A,35)-3-(3-{[(3,5difluorophenyl)acetyl] amino } III-pyrazol-5yl)cyclopentyl-[(2^)-2hydroxybutyl] carbamate Isomer B 544 /^ΝγΟ,γΗΝ-Ν _ο ηοΧΧ ° Ο'νγΧΑΧ 442.4 (15,ZA)-3-(3-{[(2methylpyridin-4yl)acetyl] amino }-1Hpyrazol-5 -yl)cyclopentyl(g/g/c-4-hydroxycyclohexyl)carbamate 545 <Ύ ^η υ ^ο, ΤΎ ^? ·4χ X ΓΧ Js. J O 1st--'th 442.4 (15.37?)-3-(3-{[(6- methylpyr idine-3 - yl)acetyl] amino }-1Hpyrazol-5 -yl)cyclopentyl(g/g/c-4-hydroxycyclohexyl)carbamate 546 /γγθγ\w ^hn ~n o 442.4 (15.37?)-3-(3-{[(5methylpyridin-2yl)acetyl] amino }-1Hpyrazol-5 -yl)cyclopentyl(g/g/c-4-hydroxycyclohexyl)carbamate

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547 ΗΝ~ν _ο ί^Ν HO'-U ο LZ''V4A>U\ 442.4 (15.37?)-3-(3-{[(2methylpyridin-4yl)acetyl] amino }-1Hpyrazol-5 -yl)cyclopentyl(trans-Ahydroxycyclohexyl)carbamate 548 °fV -L J O '—-/ HO 442.4 (15.37?)-3-(3-{[(6methylpyridin-3yl)acetyl] amino }-1Hpyrazol-5 -yl)cyclopentyl(trans-Ahydroxycyclohexyl)carbamate 549 |_| Ο^Υθ'ΤΎχΊί 2 _v4 .LJ o '—-/ kg — HO Y 442.4 (15.37?)-3-(3-{[(5methylpyridin-2yl)acetyl] amino }-1Hpyrazol-5 -yl)cyclopentyl(trans-Ahydroxycyclohexyl)carbamate 550 ^ΎΎθ'ΤΥ’ΑΑ a £>- 448.4 (15.37?)-3 -(3 - {[(2-methyl-1,3thiazol-5-yl)acetyl] amino } Ш-pyrazol-5yl)cyclopentyl-(g/is-4hydroxycyclohexyl)carbamate

- 190 046965

551 I £>~~ knife θ A 448.4 (15.35)-3 -(3 - {[(2-methyl-1,3thiazol-5-yl)acetyl] amino } 1R-pyrazol-5yl)cyclopentyl-(from/?ans-4hydroxycyclohexyl)carbamate 552 |_| ΗΝ-ν O Α ^Ν G T P \ r'vl 11 XI, _BUT A> ° 458.3 (15.37?)-3-(3-{[(2methoxypyridin-4yl)acetyl] amino }-1Hpyrazol-5 -yl)cyclopentyl(g/is-4-hydroxycyclohexyl)carbamate 553 X ъ ZZ ° h r i ZZ 5 O / 458.4 (15.37?)-3-(3-{[(6methoxypyridin-3 yl)acetyl] amino }-1Hpyrazol-5 -yl)cyclopentyl(g/is-4-hydroxycyclohexyl)carbamate 554 J O '—/ +>X N A—X/ nsA^ th 458.4 (15.37?)-3-(3-{[(5methoxypyridin-2yl)acetyl] amino }-1Hpyrazol-5 -yl)cyclopentyl(g/is-4-hydroxycyclohexyl)carbamate 555 X Q Q ZZ °h R :^Y I ΧΖ 5 ABOUT \ 458.3 (15.37?)-3-(3-{[(2methoxypyridin-4yl)acetyl] amino }-1Hpyrazol-5 -yl)cyclopentyl(trans-Ahydroxycyclohexyl)carbamate

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556 z Q Q zz p zz about / 458.3 (15,3Α)-3-(3-{[(6methoxypyridin-3 yl)acetyl] amino }-1Hpyrazol-5 -yl)cyclopentyl(trans-Ahydroxycyclohexyl)carbamate 557 «)Η/ ^Ν 'Ν O CHH' ⁰ '' .LJ o i·—/ -AA NO' 4/ N 458.3 (15,ZA)-3-(3-{[(5methoxypyridin-2yl)acetyl] amino }-1Hpyrazol-5 -yl)cyclopentyl(trans-Ahydroxycyclohexyl)carbamate 558 <γγ°γγ. ^Η / ^Ν γ S ί^Ί ΗΟ»Χ J O I—/ —АУ i Η 441.3 (15,ZA)-3-{3[(phenylacetyl)amino]-1Hpyrazol-5-yl} cyclopentyl(g/is-4-hydroxy-4methylcyclohexyl)carbamate 559 <υ ^κ υ°Υυ ^η <υ ι Π ηο'Ύ J ο А/ / Η 441.3 (15,ZA)-3-{3[(phenylacetyl)amino]-1Hpyrazol-5-yl} cyclopentyl(/7?/A///c-4-hydroxy-4methylcyclohexyl)carbamate 560 j? lTY ^F HO-k J o 1—/ ^X »N^'—AU ί Η 459.3 (15,FOR)-3-(3-{[(4- fluoroenyl)acetyl ] amino } - Sh-pyrazole-5- yl)cyclopentyl-(g/is-4- hydroxy-4- methylcyclohexyl)carbamate

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561 γΥγθ'ΥΥΥ 9 YY ^F ns AJ o SU AA _N 4AA%A / Η 459.3 (15.37?)-3-(3-{[(4- fluoroenyl)acetyl ] amino } 177-pyrazole-5- yl)cyclopentyl-(from/?sh/s-4hydroxy-4- methylcyclohexyl)carbamate 562 |_| γγ ^Ν γ ^ο 'Χγ.7 ^Ν Υ 9 JfV no-A J o su <·' H 462.3 (15.37?)-3 -(3 - {[(2-methyl-1,3thiazol-5-yl)acetyl] amino } 177-pyrazol-5- yl)cyclopentyl-(g/is-4hydroxy-4- methylcyclohexyl)carbamate 563 γγγ ^ο 'ΥΥ ^Ν γ 9 fV. hoA J o A/ ✓ Η 462.3 (15.37?)-3 -(3 - {[(2-methyl-1,3thiazol-5-yl)acetyl] amino } 177-pyrazol-5- yl)cyclopentyl-(/??/l7//s-4hydroxy-4- methylcyclohexyl)carbamate 564 /o 3 ζχ ¢3= d xz 7. o X 471.3 (15.37?)-3-(3-{[(4methoxyphenyl) acetyl] amino } 177-pyrazol-5- yl)cyclopentyl-(g/is-4hydroxy-4- methylcyclohexyl)carbamate 565 / ABOUT 3 zx i5 X 6 >=° xz y o X 471.3 (15.37?)-3-(3-{[(4- methoxyphenyl) acetyl] amino } 177-pyrazole-5- yl)cyclopentyl-(A/l7//s-4- hydroxy-4- methylcyclohexyl)carbamate

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566 / o 3 ζτ Ζ=\ 1 \ ^Ζ 1 c£j—' Ο ΙΖ 7 ο ζ 471.3 (17?,35)-3-(3-{[(4methoxyphenyl)acetyl] amino } Sh-pyrazol-5yl)cyclopentyl-(g/is-4hydroxy-4methylcyclohexyl)carbamate 567 / Ο 3 ζτ Ζ==\ / \ τ'ν φ—' ο τζ t> ο τ 471.3 (17?,35)-3-(3-{[(4methoxyphenyl)acetyl] amino } W-pyrazol-5yl)cyclopentyl-(from/?w/s-4hydroxy-4methylcyclohexyl)carbamate 568 τ Ο 6 ζτ °4 o A-3 τζ 5 Ο \ 472.4 (15.37?)-3-(3-{[(2methoxypyridin-4yl)acetyl] amino }-1Hpyrazol-5 -yl)cyclopentyl(g/is-4-hydroxy-4methylcyclohexyl)carbamate 569 ^Χ ο 3 ζτ ίξχ '6' τζ t> ο τ 472.4 (15.37?)-3-(3-{[(2methoxypyridin-4yl)acetyl] amino }-1Hpyrazol-5 -yl)cyclopentyl(from/?w/s-4-hydroxy-4methylcyclohexyl)carbamate 570 τ ο 6 ζτ °4 Ρ Ξ3 τζ 3 ο / 472.4 (15.37?)-3-(3-{[(6methoxypyridin-3 yl)acetyl] amino }-1Hpyrazol-5 -yl)cyclopentyl(g/is-4-hydroxy-4methylcyclohexyl)carbamate

- 194 046965

571 a. A ΗΟ'Ά J O '—' / Η 472.4 (15.37?)-3-(3-{[(6methoxypyridin-3 yl)acetyl] amino }-1Hpyrazol-5 -yl)cyclopentyl(from/?w/s-4-hydroxy-4methylcyclohexyl)carbamate 572 F n 1 <γ ^Ν γ°ΫΎΚ AA £1 no-k J o SU f H 477.3 (17?,35)-3-(3-{[(3,5difluorophenyl)acetyl] amino } 1R-pyrazol-5yl)cyclopentyl-(g/is-4hydroxy-4methylcyclohexyl)carbamate 573 I o A ZI °4 o /—vb /ZZ \ 1 / ^z iz ^=° yj” ⁴¹ 477.3 (17?,35)-3-(3-{[(3,5difluorophenyl)acetyl] amino } 1R-pyrazol-5yl)cyclopentyl-(from/?w/s-4hydroxy-4methylcyclohexyl)carbamate 574 ZI o ; IZ Co ll-p 437.3 (17?,35)-3-(3-{[(3.5- difluorophenyl)acetyl] amino } 1R-pyrazole-5- yl)cyclopentyl-(2-hydroxy2-methylpropyl)carbamate 575 HO,, F 'V \ H 1 A _z n γθ/ ⁵ Α)Η, ^Ν 'Ν О rAj, о SU Vx _n AAA _f Η 449.3 (15.37?)-3-(3-{[(3,5difluorophenyl)acetyl] amino } 1R-pyrazol-5yl)cyclopentyl-[(g/is-3 hydroxycyclobutyl)methyl] carbamate

- 195 046965

576 but,,__ ^F O jA o SU +-++GT— Η 449.4 (15.37?)-3-(3-{ [(3,5difluorophenyl)acetyl]amino } 1R-pyrazole-5- yl)cyclopentyl-[(from/?sh/s-3hydroxycyclobutyl)methyl] carbamate 577 ^ΗΟ *\—λ L ^f ΧΛΑγΟ,, ₍ 3^ΗΝ-Ν ο jA ο Ly H 482.3 (15.37?)-3-[3-({[6(trifluoromethyl)pyridin-3yl] acetyl } amino)-1Hpyrazol-5 -yl]cyclopentyl[(trans-3hydroxycyclobutyl)methyl] carbamate 578 F ΗΟχ^ _? Λ^Ν _γ Ο„^ΗΝ-Ν o A o '—/ AL^AZHAR Η 449.3 (15.37?)-3-(3-{[(3.5- difluorophenyl)acetyl] amino } 1R-pyrazole-5- yl)cyclopentyl-{[(17?,27?)-2(hydroxymethyl)- cyclopropyl] methyl } carbamate 579 F HoA^ _Y °,yW?-N O jA o A/ A- _n AAxA _f h 449.3 (15.37?)-3-(3-{[(3,5difluorophenyl)acetyl] amino } 1R-pyrazol-5-yl)cyclopentyl {[(15.25)-2-(hydroxymethyl)cyclopropyl] methyl } carbamate 580 Λ η μ J> O £ Xf o А/ cA _n AAA h 482.3 (15.37?)-3-[3-({[6(trifluoromethyl)pyridin-3 yl] acetyl } amino)-1Hpyrazol-5 -yl] cyclopentyl{[(15.25)-2-(hydroxymethyl) cyclopropyl] methyl } carbamate

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581 0 Χν γ _h Υ/ΑΝγΟ,^/^ΗΝ-Ν 0 r^N h 499.2 (15.37?)-3-(3-{[(2methoxypyridin-4yl)acetyl]amino(-1/7pyrazol-5-yl)cyclopentyl[(1-acetylpiperidin-4yl)methyl]carbamate 582 0 । h A 4^ ^Ν γ°(γΑ/-Ν o A, n 504.3 (15.37?)-3-(3-{[(3.5- difluorophenyl)acetyl]amino (1/7-pyrazole-5- yl)cyclopentyl-[(1acetylpiperidin-4yl)methyl]carbamate 583 ZI ζ< gS—> o' IZ 492.1 (15.37?)-3-(3-{[(3.5- difluorophenyl)acetyl] amino } 1/7-pyrazole-5- yl)cyclopentyl-{[(2^)-4methyl-5-oxomorpholin-2yl]methyl (carbamate - Isomer A 584 i ZI —'o' IZ 492.0 (15.37?)-3-(3-{[(3.5- difluorophenyl)acetyl] amino } 1/7-pyrazole-5- yl)cyclopentyl-{[(2^)-4methyl-5-oxomorpholin-2yl]methyl (carbamate - Isomer B 585 Cn hn- _no Z® Y TZhl A n 0 4/ γ\ η [1 // A 372.9 (17?, 35)-3 -(3 - {[(1 -methyl-1/7imide azol-5- yl)carbonyl] amino (-1/7pyrazol-5 -yl)cyclopentyl(2 8)-2-methylazetidine-1 carboxylate

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586 0 / ⁰ Η ί > 374.3 (17?, 35)-3-(3- {[(1 -methyl-1771,2,3-triazol-5- yl)carbonyl] amino } -177pyrazol-5 -yl)cyclopentyl(2 8)-2-methylazetidine-1 carboxylate 587 , _s ΗΝ- _ν ο γ=Ν π YWX XL Ν— ' about AU А'х'хУа/ Η 386.9 (17?, 35)-3 -(3 - {[(1 -methyl-177pyrazol-4-yl)acetyl] amino } 177-pyrazol-5- yl)cyclopentyl-(27?)-2methylazetidine-1-carboxylate 588 l ΧΑ ο SU ' 408.9 (17?, 35)-3 -(3 - {[(1 -methyl-177pyrazol-4-yl)acetyl] amino } 177-pyrazol-5- yl)cyclopentyl-(2S)-2methylazetidine-1-carboxylate 589 .^Ν γ°4Χ\ ₍ sJ/ ^N Ν Ο Ο'Ν__ ο Ay Aa _n AAV Η 388.4 (17?, 35)-3 -(3 - {[(3-methyl-1,2oxazol-5-yl)acetyl] amino } 177-pyrazol-5- yl)cyclopentyl-(2G)-2methylazetidine-1-carboxylate - Isomer A 590 ^ ⁿ y°^A _(S J, ⁿ ~-n ο ο-ν_ ο Ay ΑχΑ _Ν /Α/Α/...... Η 388.4 (17?, 35)-3 -(3 - {[(3-methyl-1,2oxazol-5-yl)acetyl] amino } 177-pyrazol-5- yl)cyclopentyl-(2G)-2methylazetidine-1-carboxylate - Isomer B

- 198 046965

591 /-Ytrn-uy Η 399.3 (17?,3S)-3-(3-{[(5methylpyrazin-2yl)acetyl] amino }-1Hpyrazol-5 -yl)cyclopentyl(2 8)-2-methylazetidin-1 carboxylate 592 \ \ z^ °4 p /— J<z /7 Z\ 1 / ^Z IZ c: zz y // o / 415.4 (17?,35)-3-(3-{[(5methoxypyrazin-2yl)acetyl] amino } - 1Hpyrazol-5 -yl)cyclopentyl(2 8)-2-methylazetidin-1 carboxylate 593 GL 0 V-Ν O^l hn^n o X .'(R) γ Y \2LZ n II / '° 417.3 (17?,35)-3-[3-({[1-(2methoxyethyl)- 1//-pyrazol-5 yl]carbonyl } amino)- 1Hpyrazol-5 -yl] cyclopentyl(2/?)-2- methyl azetide in-1 carboxylate 594 O' Χτθγγξχ »° / ⁰ L ^N 417.3 (17?,35)-3-[3-({[1-(2methoxyethyl)- 1//-pyrazol-5 yl]carbonyl } amino)- 1Hpyrazol-5 -yl]cyclopentyl(2 8)-2-methylazetidine -1 carboxylate 595 Xy°YA1 a 1 ⁰ S l» ^N +-0 \ 417.3 (17?,35)-3-[3-({[3- (methoxymethyl)-1-methyl-1Hpyrazole-5- yl]carbonyl}amino)-1Hpyrazol-5-yl]cyclopentyl(2 8)-2-methylazetidine-1 carboxylate

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596 L' 430.4 (1Α,35)-3-{3-[({1-[2- (d imethylamino)ethyl] - 1Ηpyrazole-5- yl } carbonyl)amino] - 1Hpyrazol-5 -yl } cyclopentyl(2 8)-2-methylazetidine-1 carboxylate 597 ~ N Ο O-N__ o —-X/ H 402.3 (17?,35)-3-(3-{[(3-methyl-1,2oxazol-5-yl)acetyl] amino } Ш-pyrazol-5yl)cyclopentyl-(2|+)-2ethyl azetidin-1-carboxylate Isomer A 598 .Ji γ'θ+ΒΕχ _fS J/ ^N ~ N Ο ON Η 402.3 Isomer IN 599 γΡ ^Ν γ ^Ο 5Υβν ^Ν Υ jj ΉΛ- Η 402.1 (17?,35)-3-(3-{ [(5-methyl-1,3oxazol-2-yl)acetyl] amino } III-pyrazol-5yl)cyclopentyl-(2^)-2ethyl azetidin-1-carboxylate Isomer A 600 Α^ ^ν υ°ϋΎ41 J ΉΛη 402.1 (17?,35)-3-(3-{ [(5-methyl-1,3oxazol-2-yl)acetyl] amino} 1R-pyrazol-5yl)cyclopentyl-(2^)-2ethyl azetidin-1-carboxylate Isomer IN

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601 Η 413.3 (17?,35)-3-(3-{[(5- methylpyrazin-2yl)acetyl]amino}-1Ηpyrazol-5-yl)cyclopentyl2,2-dimethylazetidine-1 carboxylate 602 γ ^χ o 1—ν=$ χ ζ \ / / ^ζ ΙΖ C ^ζ \\ // ο / 429.3 (17?,35)-3-(3-{[(5- methoxypyrazine-2- yl)acetyl] amino }-1Hpyrazol-5 -yl)cyclopentyl2,2-dimethylazetidine-1 carboxylate 603 An^O4^xx _(S J. ⁿ ~n ο Ο' ^Ν λ_ Η 416.3 (17?, 35)-3 -(3 - {[(3-methyl-1,2oxazol-5-yl)acetyl] amino } 177-pyrazol-5- yl)cyclopentyl-(^)-2-ethyl-2methylazetidine-1-carboxylate - Isomer A 604 yp ^N Y°5A4 ^N AS ϊΛ— [ about сУ У\АА/ Η 416.4 (17?, 35)-3 -(3 - {[(3-methyl-1,2oxazol-5-yl)acetyl] amino } 177-pyrazol-5- yl)cyclopentyl-(^)-2-ethyl-2methylazetidine-1-carboxylate - Isomer B 605 χ-γ) >-Ν _χ χΟ^χχ« ₎ ^Η _/ ^Ν '·Ν 0 r=N Υ ΎγΑλ χ L ν~ Η 401.4 (17?, 35)-3 -(3 - {[(1 -methyl-177pyrazol-4-yl)acetyl] amino } 177-pyrazol-5- yl)cyclopentyl-(28.45)-2,4dimethylazetidine-1 carboxylate

- 201 046965

606 CN O,ffiK ^H / ^N ~ ^N 0 N4 γ YJHji XX y— ο SU H 402.1 (17?,35)-3-(3-{[(5-methyl-1,3oxazol-2-yl)acetyl] amino } 1/7-pyrazol-5- yl)cyclopentyl-(28.45)-2,4dimethylazetidine-1 carboxylate 607 \-\ ^(R> HAAs) ^H / ^N 'N 0 O'N /yu T । LC X JLVо Су o^ _n OOy/ H 402.3 (17?, 35)-3 -(3 - {[(3 -methyl-1,2oxazol-5-yl)acetyl] amino } 1/7-pyrazol-5- yl)cyclopentyl-(27?,45)-2,4dimethylazetidine-1 carboxylate 608 Mr. A way H 413.3 (17?,35)-3-(3-{[(5- methylpyrazin-2yl)acetyl] amino } -\Hpyrazol-5 -yl)cyclopentyl(28,45)-2,4-dimethylase etidine1-carboxylate 609 CH _I SSu H 428.3 (17?,35)-3-(3-{[(2methoxypyridin-4yl)acetyl]amino}-177pyrazol-5-yl)cyclopentyl(27?,47?)-2,4-dimethylase etidine1-carboxylate 610 An o^a, _s hn~ _no UуС /&> YIXXJ o su h 429.3 (17?,35)-3-(3-{[(5- methoxypyrazin-2yl)acetyl]amino}-1/7pyrazol-5-yl)cyclopentyl(2S,45)-2,4-dimethylase etidine1-carboxylate

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611 Ln^OJS). hn~ _n q A _n /go Y Гу4 ϊ ϊ l| T H 430.3 (15.37?)-3-(3-{[(2methoxypyridin-4yl)acetyl] amino } - 1Hpyrazol-5 -yl)cyclopentyl(27?.35)-3-hydroxy-2methylazetidin-1-carboxylate 612 NOD4TS /vtAAbCvH 430.4 (17?,35)-3-(3-{[(2methoxypyridin-4yl)acetyl] amino } - 1Hpyrazol-5-yl)cyclopentyl(2 S, 37?)-3-hydroxy-2methylazetidine-1-carboxylate 613 ^H0 *SA YrWAbCY H 430.4 (17?,35)-3-(3-{[(2methoxypyridin-4yl)acetyl] amino } - 1Hpyrazol-5-yl)cyclopentyl(27?,35)-3-hydroxy-2methylazetidin-1-carboxylate 614 NOD4TS Cn o,,®^ hn~ _no jy(\ AY LCHa a Lj H 430.4 (15.37?)-3-(3-{[(6methoxypyridin-3 yl)acetyl] amino } - 1Hpyrazol-5 -yl)cyclopentyl(2 S, 37?)-3 -hydroxy-2methylazetidine-1-carboxylate 615 NOD4TS Cn 0»S^, _s . HN- _n o /у° ^h Y YrY A AJ H 430.4 (17?,35)-3-(3-{[(6methoxypyridin-3 yl)acetyl] amino } - 1Hpyrazol-5 -yl)cyclopentyl(2 S, 37?)-3-hydroxy-2methylazetidine-1-carboxylate

- 203 046965

616 ^Η0 <% Τν ολ, ην~ _{ν ο} γ γ°\ Υ Υ Ж ϊ К L 1] ' Ο ¹ —'+/χ-^4>>4 Η 430.4 (17?,35)-3-(3-{[(6methoxypyridin-3 yl)acetyl] amino }-1Ηpyrazol-5 -yl)cyclopentyl(27?,35)-3-hydroxy-2methylazetidin-1-carboxylate 617 BUT,,(CHC 7 γ ^Ν γ°γγχ χ χ JOL ο +У Η 435.0 (17?,35)-3-(3-{[(3.5- difluorophenyl)acetyl] amino } Ш-pyrazole-5- yl)cycle opentyl-(2 S, 37?)-3 hydroxy-2-methyl azetide in-1 carboxylate 618 ^Ο/,ίγ Cn o^g)^, _s ΗΝ- _{Ν ο ο} -ν /7s; γ γ^ ΥΥυ j ϊ )—- Η 418.4 (17?, 35)-3 -(3 - {[(3-methyl-1,2oxazol-5-yl)acetyl] amino } 177-pyrazol-5- yl)cycle opentyl-(2 S, 37?)-3 methoxy-2-methyl azetide in-1 carboxylate 619 ^,ο,/γ λγγ<ι _Ν χα _ο Η 443.9 (17?,35)-3-(3-{[(2methoxypyridin-4yl)acetyl]amino}-177pyrazol-5-yl)cyclopentyl(2 S, 37?)-3-methoxy-2methylazetidine-1-carboxylate 620 ΧγγγίςγΟΧ Η 444.3 (17?,35)-3-(3-{[(6methoxypyridin-3 yl)acetyl] amino } - 1Hpyrazol-5-yl)cyclopentyl(27?,35)-3-methoxy-2methylazetidin-1-carboxylate

- 204 046965

621 /0, ,(RK Atjlhg Η 443.9 (17?,35)-3-(3-{[(6methoxypyridin-3yl)acetyl]amino } - 1Hpyrazol-5-yl)cyclopentyl(2S,3R)-3-methoxy-2methylazetidine-1-carboxylate 622 A Α ^Ν χζΌ»61-χ®> ^η /Ν~ _Ν ο ο-ν Y \ /41 X ο Gy Η 418.3 (17?, 35)-3 -(3 - {[(3-methyl-1,2oxazol-5-yl)acetyl] amino } 177-pyrazol-5- yl)cycle opentyl-(2 S, 37?)-3 - hydroxy-2,3- dimethylazetidine-1 carboxylate 623 Ά ην- _{ν ο} ν γ ΤΥ4Χ XXV- Η 434.3 (17?,35)-3 -(3 -{[(2-methyl-1,3thiazol-5-yl)acetyl] amino } 177-pyrazol-5- yl)cycle opentyl-(2 S, 37?)-3 hydroxy-2,3dimethylazetidine-1 carboxylate 624 γ y NO/,(5^ ΗΝ- _{ν ο} γ^ _Ν /S γ γ X Λ A Η 444.3 (15.37?)-3-(3-{[(2methoxypyridin-4yl)acetyl] amino } - 1Hpyrazol-5 -yl)cyclopentyl(2 S, 37?)-3 -hydroxy-2,3 dimethylazetidine-1 carboxylate

- 205 046965

625 UN___Ο«β/,_.ΗΝ- _Ν ο Α> γ pChl λ Λα / ο ¹ —/ Ν — Ο Η 444.3 (15,35)-3-(3-{[(2methoxypyridin-4yl)acetyl] amino } -\Ηpyrazol-5 -yl)cyclopentyl(2 S, 35)-3 -hydroxy-2,3 dimethylazetidine-1 carboxylate 626 F ~Υν ο,β/ ην- _{ν ο} ΥΆ'· Α Υ O-vL l AJ Η 444.3 (15,35)-3-(3-{[(6methoxypyridin-3 yl)acetyl] amino } -\Hpyrazol-5 -yl)cyclopentyl(2 S, 35)-3 -hydroxy-2,3 dimethylazetidine-1 carboxylate 627 Ж ~Υν ^η , ^ν ~ν ο fV' υ ΥτΛα aAJ 0 X/ Ν Η 444.3 (15.35)-3-(3-{[(6- methoxypyridin-3 yl)acetyl] amino } -\Hpyrazol-5 -yl)cyclopentyl(2 S, 35)-3 -hydroxy-2,3 dimethylazetidine-1 carboxylate 628 Υ ^Ν ΑΑ\Υ/ ^Ν 'Ν 0 NQ I< ^s > Υ TgChl I l! Η 388.1 (15.35)-3 - {3 - [(1,2-oxazol-3-ylacetyl)amino]-1 /7-pyrazol5 -yl } cyclopentyl-(2 S)-2methylpyrrolidine-1 carboxylate 629 Cn (\ «u , _S) ^η / ^ν ' ^ν ° Γ λ I< ^s > Υ ТгЧх X Λ > * ο ¹ -/ η 388.1 (15.35)-3-{3-[(1,3-oxazol-5ylacetyl)amino]-177-pyrazol5 -yl} cyclopentyl-(2 S)-2methylpyrrolidin-1 carboxylate

- 206 046965

630 9tTYal.1Х1 Η 398.3 (17?, 35)-3 - { 3 - [(pyr idin-2 ylacetyl) amino]-177-pyrazol5 -yl } cyclopentyl-(2 S)-2methylpyrrolidine-1 carboxylate 631 Λη / V- ⁿ x/°*O\/si ^H / ^N ''N 0 hl-* ¹ . ns> Υ TrAX X XJ> Η 401.4 (17?, 35)-3 -(3 - {[(1 -methyl-177pyrazol-3-yl)acetyl] amino } 177-pyrazol-5- yl)cyclopentyl-(2 S)-2methylpyrrolidine-1 carboxylate 632 ν-Ν Ο^κγ ^ΗΝ ~Ν _ο θ-Ν Υ ιΜα XX A * ο A/ ^Χ -Ύ /χ/χ/ Η 402.3 (17?, 35)-3 -(3 - {[(3 -methyl-1,2oxazol-5-yl)acetyl] amino } 1/7-pyrazol-5- yl)cyclopentyl-(2 S)-2methylpyrrolidine-1 carboxylate 633 ΥΝΥ^Χ/.ς ΗΝ- _{ν ο ο} -Ν Υ 1 YA 1 Λ to Υ - O SU Η 401.9 (17?, 35)-3 -(3 - {[(3-methyl-1,2oxazol-5-yl)acetyl] amino } 177-pyrazol-5- yl)cyclopentyl-(27?)-2methylpyrrolidine-1 carboxylate 634 νΝ Ο,ρκ ^η . ^ν --ν ο Ν'° _κ ϊν Υ \ γ-4 JL 11 L λ— ¹ Ο cy Η 402.1 (17?,35)-3-(3-{[(5-methyl-1,2oxazol-3-yl)acetyl] amino } 177-pyrazol-5yl)cyclopentyl-(2 S)-2methylpyrrolidin-1 carboxylate

- 207 046965

635 VN O^gu „ hm- _n ο ο-λ pl Υ TgCh 1 χ X >' o U~/ n 402.1 (17?,35)-3-(3-{ [(5-methyl-1,3oxazol-2-yl)acetyl] amino } 177-pyrazol-5- yl)cyclopentyl-(2 S)-2methylpyrrolidine-1 carboxylate 636 V ^N \z°»(Sa«i ^H / ^N 'N O NX I< ^S) Y TJ ALL/ ¹ o U-/ n 402.3 (17?,35)-3 -(3 -{[(4-methyl-1,3oxazol-2-yl)acetyl] amino } 177-pyrazol-5- yl)cyclopentyl-(2 S)-2methylpyrrolidine-1 carboxylate 637 V ^N \z°XiS) ^H / ^N 'N 0 NA p> Y \ aCh X LA/ ¹ o L—/ n 418.4 (17?,35)-3 -(3 -{[(4-methyl-1,3thiazol-2-yl)acetyl] amino } 177-pyrazol-5yl)cyclopentyl-(2 S)-2methylpyrrolidin-1 carboxylate 638 ysjy VN O45Y ην- _{ν о ο} -ν ρΥ \ аЦх Α 1 ΑΧ • о yy Η 416.3 (17?, 35)-3 -(3 - {[(3-methyl-1,2oxazol-5-yl)acetyl] amino } 177-pyrazol-5yl)cyclopentyl-(2 S, 55)-2,5 dimethylpyrrolidine -1 carboxylate 639 '3 ζτ Ζ=< / \ Ζ^ /Υ ^Χ 1 ¢0— Ο \ χ° Ύ—-ζ 415.4 (17?,3S)-3-(3-{[(l -methyl-1Hpyrazol-3-yl)acetyl] amino } 177-pyrazol-5yl)cyclopentyl-2,2dimethylpyrrolidin-1 carboxylate

- 208 046965

640 γ ^Ν γ°'Χ\βγ ¹ '^ ° °Υ_ 1 ο Χ/ΑΑ^^Α—Χζ Η 415.9 (1R, 35)-3 -(3 - {[(3-methyl-1,2oxazol-5-yl)acetyl] amino } Ш-pyrazol-5yl)cyclopentyl-(2 S)-2methylpiperidin-1 carboxylate 641 CgPI γ°*Χ\Υ ^Ν ~Ν Ο Ο' ^ν = o X ^x Χ _Ν ΧΧ/ Η 416.4 (17?, 35)-3 -(3 - {[(3 -methyl-1,2oxazol-5 -yl)acetyl] amino } 17/-pyrazol-5- yl)cyclopentyl-(27?)-2methylpiperidine-1 carboxylate 642 °γ Ο Ο-Ν__ * o X ^x Ά _Ν ΑΑ/ Η 418.4 (17?, 35)-3 -(3 - {[(3-methyl-1,2oxazol-5-yl)acetyl] amino } 17/-pyrazol-5yl)cyclopentyl-(35)-3 methylmorpholine-4carboxylate 643 °γ Xn^O4S^-\, _s) ^h , ⁿ ~N Ο Ο'Ν ύ υ xChl λ α>— = ο '—/ Ν Η 418.4 (17?, 35)-3 -(3 - {[(3 -methyl-1,2oxazol-5 -yl)acetyl] amino } 17/-pyrazol-5- yl)cyclopentyl-(37?)-3 methylmorpholine-4carboxylate 644 /^° / Ζ—' °γ ρ /—С® ζ^ζ \ / / ^ζ ΙΖ 449.2 (17?,35)-3-(3-{[(3.5- difluorophenyl)acetyl] amino } 17/-pyrazole-5- yl)cyclopentyl-(35)-3 methylmorpholine-4- carboxylate

- 209 046965

645 Υν ΟΛα,,,ΗΝ- _ν o Ύ Y CLOUD λ ΧΛ = o GV x^n Xx X^ F Η 449.2 (17?,35)-3-(3-{ [(3.5- difluorophenyl)acetyl] amino } 177-pyrazole-5- yl)cyclopentyl-(37?)-3 methylmorpholine-4- carboxylate 646 °Ά A ^N xV>4SG\rs> ^H / ^N ~N O / IY tPM AA • O XV N - S H 450.1 (17?,35)-3-(3-{[(2-methoxy-1,3thiazol-5-yl)acetyl] amino } 177-pyrazol-5yl)cyclopentyl-(35)-3 methylmorpholine-4carboxylate 647 O _T °-<syr-N o rt _o / = o Gv -A H 450.3 (17?,35)-3-(3-{[(2-methoxy-1,3thiazol-5-yl)acetyl] amino } 177-pyrazol-5yl)cyclopentyl-(37?)-3 methylmorpholine-4carboxylate 648 ?Άτ 4¾ N ° °'A_ 1 o LA+C _n AA/ H 432.3 (17?, 35)-3 -(3 - {[(3-methyl-1,2oxazol-5-yl)acetyl] amino } 177-pyrazol-5- yl)cyclopentyl-(35.55)-3,5dimethylmorpholine-4carboxylate 649 4 ^Ν γ°<Αβν ^Ν Υ ° on /\ LjA _n AA/ H 432.3 (17?, 35)-3 -(3 - {[(3-methyl-1,2oxazol-5-yl)acetyl] amino } 177-pyrazol-5- yl)cycle opentyl-3,3 dimethylmorpholine-4carboxylate

Biochemical tests.

Full-length mobility shift assay of the CDK2/Cyclin E1 complex.

The purpose of the CDK2^ukhuh E1 assay is to evaluate the inhibitory effects (% inhibition, Kiapp (apparent inhibition constant) and Ki (inhibition constant) values) of small molecule inhibitors using a fluorescence-based microfluidic mobility shift assay. CDK2^ukhuh E1 full length catalyzes the production of ADP (adenosine diphosphate) from ATP (adenosine triphosphate), which transfers phosphoryl to the substrate peptide FLPeptide-18 (5-FAM-QSPKKG-CONH2) (SEQ ID NO: 1) (CPC Scientific, Sunnyvale, CA). The mobility shift assay electrophoretically separates fluorescently labeled peptides (substrate and phosphorylated product) following a kinase reaction. Both substrate and product are measured and the ratio of the two is used to obtain the % conversion of substrate to product using the LabChip EZ Reader. Wild-type OP^/wild-type full-length Cyclin E1 enzyme complex was produced independently (baculovirus expression, LJIC-2080/LJIC-2103) and phosphorylated with the GOIU/Cyclin H1/Mat1 enzyme complex with a CDK2:CDK7 ratio of 50:1 (concentration in mg/ml ) in the presence of 10 mM MgCl ₂ and 5 mM ATP at room temperature for one hour. Typical reactions

- 210 046965 reaction solutions (final reaction volume 50 μl) contained 2% DMSO (± inhibitor), 4 mM MgCl ₂ , 1 mM DTT (dithiothreitol), 150 μM ATP (ATP Km (Michaelis constant) = 67.4 μM), 0.005% Tween-20, 3 μM FL-Peptide-18 and 0.36 nM (catalytically competent active site) phosphorylated wild-type full-length C.'OK2/Cyclin E1 enzyme complex in 25 mM HEPES buffer at pH 7.15. The assay was initiated by the addition of ATP after a fifteen-minute pre-incubation of the enzyme and inhibitor at room temperature in the reaction mixture. The reaction was stopped after 45 min at room temperature by adding 50 μl of 80 mM EDTA, pH 7.5. The Ki value was determined from fitting the data to the Morrison tight binding competitive inhibition equation with enzyme concentration as a variable of ^1.2 .

GSK3beta (GSK3e) mobility shift assay.

The purpose of the GSK3 β assay is to evaluate the inhibitory effect (% inhibition, K _iapp and Ki values) of small molecule inhibitors using a fluorescence-based microfluidic mobility shift assay. GSK3e catalyzes the production of ADP from ATP, which transfers phosphoryl to the substrate peptide FL-Peptide-15 (5-FAM-KRREILSRRPpSYR-COOH, CPC Scientific, Sunnyvale, CA) (SEQ ID NO: 2). The mobility shift assay electrophoretically separates fluorescently labeled peptides (substrate and phosphorylated product) following a kinase reaction. Both substrate and product are measured and the ratio of the two is used to obtain the % conversion of substrate to product using the LabChip EZ Reader. Active GSK3e (H350L) was purchased from Upstate/Millipore. Typical reaction solutions (final reaction volume 50 µl) contained 2% DMSO (± inhibitor), 4 mM MgCl ₂ , 1 mM DTT, 40 µM ATP (ATP Km=9.43 µM), 0.005% Tween-20, 2 µM FL -Peptide-15 and 0.6 nM GSK3e in 25 mM HEPES buffer at pH 7.5. The assay was initiated by the addition of ATP after a 15-min pre-incubation of the enzyme and inhibitor at room temperature in the reaction mixture. The reaction was stopped after 30 min at room temperature by adding 50 μl of 80 mM EDTA. The Ki value was determined from fitting the data to Morrison's tight-binding competitive inhibition equation with enzyme concentration as the variable (see Morrison, JF (1969) Kinetics of reversible inhibition of enzyme-catalysed reactions by tight-binding inhibitors, Biochimica et biophysica acta 185 , 269-286; Murphy, DJ (2004) Determination of accurate KI values for tight-binding enzyme inhibitors: an in silico study of experimental error and assay design, Analytical biochemistry 327, 61-67).

Mobility shift assay of the CDK4/Cyclin D1 complex.

The purpose of the COK4/Cyclin Dj assay is to evaluate the inhibitory effect (% inhibition, K _iapp and Ki values) of small molecule inhibitors using a fluorescence-based microfluidic mobility shift assay. CDK4/Cyclin D ₃ catalyzes the production of ADP from ATP, which transfers phosphoryl to the substrate peptide 5-FAM-Dyrktide (5-FAMRRRFRPASPLRGPPK) (SEQ ID NO: 3). The mobility shift assay electrophoretically separates fluorescently labeled peptides (substrate and phosphorylated product) following a kinase reaction. Both substrate and product are measured and the ratio of the two is used to obtain the % conversion of substrate to product using the LabChip EZ Reader. Typical reaction solutions contained 2% DMSO (± inhibitor), 10 mM MgCl ₂ , 1 mM DTT, 3.5 mM ATP, 0.005% TW-20, 3 μM 5FAM-Dyrktide, 3 nM (active sites) activated CDK4/Cyclin D1 in 40 mM HEPES buffer at pH 7.5.

Determinations of Ki inhibitors of the activated CDK4/Cyclin D1 complex (2007 E1/2008 +PO4) were initiated by the addition of ATP (final reaction volume 50 μl) after an eighteen-minute pre-incubation of enzyme and inhibitor at 22°C in the reaction mixture. The reaction was stopped after 195 min by adding 50 μl of 30 mM EDTA. Ki was determined from a plot of fractional velocity versus inhibitor concentration fitted to the Morrison equation with enzyme concentration as a variable.

Mobility shift assay of the CDK6/Cyclin D ₃ complex.

The purpose of the CDK6/Cyclin D ₃ assay is to evaluate the inhibitory effect (% inhibition, K _iapp and Ki values) of small molecule inhibitors using a fluorescence-based microfluidic mobility shift assay. CDK6/Cyclin D ₃ catalyzes the production of ADP from ATP, which transfers phosphoryl to the substrate peptide 5-FAM-Dyrktide (5-FAMRRRFRPASPLRGPPK) (SEQ ID NO: 3). The mobility shift assay electrophoretically separates fluorescently labeled peptides (substrate and phosphorylated product) following a kinase reaction. Both substrate and product are measured and the ratio of the two is used to obtain the % conversion of substrate to product using the LabChip EZ Reader. Typical reaction solutions contained 2% DMSO (± inhibitor), 2% glycerol, 10 mM MgCl ₂ , 1 mM DTT, 3.5 mM ATP, 0.005% Tween 20 (TW-20), 3 μM 5-FAM-Dyrktide, 4 nM (active sites) of activated CDK6/Cyclin D ₃ complex in 40 mM HEPES buffer at pH 7.5.

Ki determinations of activated CDK4 inhibitors/Cyclin D ₃ (LJIC-2009G1/2010 +PO4) were initiated by adding ATP (final reaction volume 50 μl) after an eighteen-minute pre-treatment.

- 211 046965 careful incubation of the enzyme and inhibitor at 22°C in the reaction mixture. The reaction was stopped after 95 min by adding 50 μl of 30 mM EDTA. Ki was determined from a plot of fractional velocity versus inhibitor concentration fitted to the Morrison equation with enzyme concentration as a variable.

To approximate the tight binding inhibition data obtained from the CDK4 and CDK6 mobility shift assays, equations and principles are taken from Morrison, J. F. (1969) Kinetics of reversible inhibition of enzyme-catalysed reactions by tight-binding inhibitors, Biochimica et biophysica acta 185 , 269-286; and Murphy, D. J. (2004) and Determination of accurate Ki values for tight-binding enzyme inhibitors: an in silico study of experimental error and assay design, Analytical biochemistry 327, 61-67.

Biological activity data.

Biological activity data for representative compounds of the invention are given in table. 4 below.

__________________Table 4_________________

Example No. SPK2/Cyclin Εχ Ki (nM) GSK3p Ki (nM) 1 0.55 26.18 2 0.31 40.43 3 0.34 10.04 4 0.10 109.99 5 0.40 39.40 6 0.38 32.29 7 0.61 8 0.50 666.56 9 1.14 >95.31 10 0.25 100.53 AND 0.32 36.21 12 0.13 4.86 13 1.16 537.81 14 0.27 293.53 15 0.17 29.30 16 0.37 51.67 17 0.33 65.76 18 0.17 19 0.17 20.83 20 0.21 27.85 21 0.25 4.20 22 0.23 >190.72 23 ο,ιι 2.45

- 212 046965

24 0.26 20.55 25 2.70 135.07 26 0.21 13.69 27 0.24 3.57 28 0.18 4.50 29 0.16 19.73 thirty 0.16 20.55 31 0.16 45.12 32 0.36 35.67 33 0.17 26.35 34 0.33 31.21 35 0.22 12.49 36 0.17 21.26 37 0.19 23.39 38 0.18 69.70 39 0.14 23.95 40 0.24 64.47 41 0.20 342.89 42 0.05 34.42 43 0.04 45.43 44 0.21 47.75 45 ο,ιι 61.35 46 0.18 20.56 47 ο,ιι 10.16 48 0.17 9.58 49 0.19 50 0.17 116.87 51 0.20 54.01 52 0.20 10.91 53 0.10 45.70 54 0.24 9.25 55 0.10 10.37

- 213 046965

56 0.25 42.81 57 3.54 58 0.21 9.86 59 0.15 2.89 60 0.33 92.52 61 ο,ιι 42.27 62 0.21 24.01 63 1.25 64 0.14 18.73 65 2.21 66 0.17 17.88 67 1.50 68 0.36 16.30 69 4.26 70 0.35 31.34 71 ι,οι 33.82 72 0.15 12.81 73 2.31 74 0.30 13.21 75 0.26 9.59 76 0.10 4.96 77 0.39 19.72 78 0.15 8.90 79 0.54 16.46 80 0.15 8.85 81 1.48 32.94 82 0.19 12.61 83 0.69 33.29 84 0.10 12.03 85 1.06 86 0.25 12.89 87 1.32

- 214 046965

88 0.15 89 0.85 90 0.23 2.36 91 0.09 28.14 92 0.10 16.59 93 0.22 7.64 94 0.15 95 0.25 32.23 96 2.05 97 0.39 18.00 98 0.33 21.59 99 0.09 100 0.43 41.69 101 0.28 20.91 102 0.39 9.90 103 1.37 >47.63 104 0.17 >47.63 105 0.47 >47.63 106 0.76 107 0.19 27.09 108 0.15 38.75 109 0.68 39.20 110 0.29 111 0.38 771.75 112 0.15 40.19 FROM 0.16 11.10 114 0.19 5.65 115 0.23 116 0.13 8.86 117 0.14 15.91 118 0.22 17.78 119 0.13 19.28

- 215 046965

120 0.09 34.89 121 0.08 19.36 122 0.22 12.73 123 0.13 8.87 124 0.19 80.65 125 0.34 126 0.27 26.56 127 0.23 20.12 128 0.15 55.36 129 0.20 31.57 130 0.25 131 0.20 132 0.19 133 0D1 7.00 134 0.12 7.12 135 0.19 11.72 136 0.22 8.22 137 0.09 6.07 138 0.23 7.06 139 0.21 8.48 140 0.19 15.27 141 0.08 5.75 142 0.22 17.74 143 0.25 15.82 144 0.10 1.26 145 0.12 0.95 146 0.07 3.47 147 0.25 6.87 148 0.24 5.57 149 0.06 5.58 150 0.25 8.35 151 0.15 3.89

- 216 046965

152 1.06 153 0.22 9.15 154 1.77 155 0.13 1.63 156 2.21 157 1.86 158 0.17 0.78 159 3.63 160 0.15 1.72 161 0.15 5.93 162 3.01 163 0.32 16.64 164 0.72 44.74 165 2.28 166 0.40 24.29 167 1.40 33.85 168 0.36 25.84 169 1.63 29.63 170 1.37 >190.72 171 1.73 18.22 172 1.20 101.69 173 2.29 >190.72 174 3.00 >95.33 175 0.82 39.66 176 2.50 46.08 177 0.43 19.04 178 ι,ιο 21.38 179 0.54 13.50 180 0.81 >95.33 181 3.91 >190.72 182 0.82 90.62 183 3.68 >95.33

- 217 046965

184 1.35 >95.33 185 0.71 13.02 186 1.03 9.64 187 4.59 23.93 188 0.44 9.32 189 0.38 11.41 190 0.81 26.12 191 3.33 192 0.70 >190.72 193 0.41 194 0.80 195 4.39 196 1.44 197 0.49 >190.72 198 0.28 52.14 199 3.45 200 2.87 201 1.91 202 1.85 203 0.29 34.19 204 1.13 205 0.76 97.69 206 1.22 >95.33 207 0.66 208 3.18 209 1.21 210 3.80 211 4.87 212 0.67 77.19 213 0.32 183.00 214 0.37 131.31 215 1.26

- 218 046965

216 0.86 28.16 217 2.22 218 2.09 30.64 219 3.81 220 3.26 221 1.73 222 2.93 223 2.33 224 0.31 225 2.67 226 3.72 131.65 227 1.21 18.92 228 1.84 229 2.06 230 1.55 48.59 231 1.18 15.57 232 1.54 34.13 233 0.85 43.44 234 4.11 235 2.33 236 3.16 237 0.64 5.23 238 1.13 14.73 239 1.15 9.44 240 0.73 16.08 241 1.04 13.36 242 0.81 9.70 243 0.75 5.35 244 0.57 3.70 245 0.53 19.18 246 3.29 247 1.36 12.15

- 219 046965

248 2.41 249 2.32 250 1.62 27.37 251 1.83 252 1.39 10.56 253 1.26 28.80 254 2.17 255 1.69 256 2.58 257 4.20 258 0.74 10.69 259 0.68 17.38 260 2.89 261 1.00 121.36 262 0.64 >47.63 263 0.52 31.91 264 1.83 265 1.91 266 0.39 32.63 267 3.02 268 0.97 269 1.68 270 0.86 39.88 271 1.57 272 2.63 40.85 273 3.08 274 2.62 275 0.49 53.15 276 0.64 33.09 277 0.98 278 0.52 56.69 279 0.32 53.18

- 220 046965

280 2.12 281 0.33 24.42 282 2.34 283 4.60 284 0.60 285 3.97 286 4.14 287 2.26 288 0.39 289 0.49 10.63 290 1.45 291 0.43 >47.63 292 0.86 293 0.85 >95.31 294 0.62 31.97 295 0.38 56.13 296 0.30 297 1.17 298 0.68 72.02 299 0.26 29.89 300 0.65 301 0.55 302 0.50 303 0.33 304 1.41 305 0.52 306 1.09 307 0.73 308 0.30 89.06 309 1.55 310 0.69 311 0.36

- 221 046965

312 0.43 313 0.63 314 0.41 40.58 315 0.65 132.72 316 1.30 317 0.26 45.99 318 0.53 319 0.39 123.24 320 2.95 321 0.63 >190.68 322 0.93 81.21 323 1.07 74.13 324 0.54 94.28 325 0.81 54.02 326 1.17 72.42 327 0.44 57.75 328 1.77 329 1.02 107.07 330 0.55 85.98 331 1.49 332 1.05 61.28 333 0.41 63.16 334 1.60 335 0.41 23.86 336 0.39 53.47 337 0.58 94.93 338 1.58 94.40 339 0.66 340 2.24 341 0.64 342 0.74 40.03 343 0.77 26.14

- 222 046965

344 0.58 345 2.66 346 0.26 10.74 347 0.37 45.60 348 0.59 54.15 349 0.40 57.31 350 3.45 351 2.77 352 0.82 58.42 353 0.50 29.47 354 3.74 355 1.13 18.13 356 0.67 148.05 357 4.08 358 1.65 359 0.39 28.46 360 1.46 361 0.94 25.61 362 0.84 363 0.35 52.03 364 0.82 59.92 365 2.08 366 1.79 367 0.27 23.52 368 0.41 369 0.84 370 0.28 50.81 371 0.32 160.53 372 0.85 114.62 373 0.47 74.30 374 0.32 10.83 375 0.31 115.98

- 223 046965

376 0.40 99.35 377 1.14 378 0.83 379 3.05 380 0.63 381 3.11 382 0.77 74.18 383 1.34 43.17 384 1.24 385 0.52 25.86 386 0.66 45.93 387 0.30 388 2.34 36.88 389 0.83 18.31 390 3.74 391 1.38 37.96 392 3.14 393 0.97 34.05 394 0.42 42.71 395 1.43 396 2.10 139.07 397 1.87 155.22 398 0.65 44.11 399 0.47 68.80 400 1.29 401 0.34 32.95 402 1.54 403 1.76 76.11 404 1.38 84.27 405 1.37 97.90 406 1.81 73.33 407 1.16

- 224 046965

408 0.29 17.91 409 4.15 410 0.42 55.54 411 2.58 412 0.19 413 0.44 14.69 414 0.42 3.44 415 1.48 26.45 416 2.27 417 0.81 12.56 418 2.69 419 0.36 420 0.54 421 0.94 422 0.55 423 0.60 424 0.51 14.40 425 1.05 426 0.53 17.04 427 1.78 428 0.40 30.11 429 1.15 430 1.14 431 1.19 432 1.25 433 0.50 17.12 434 0.48 39.83 435 1.49 436 3.30 437 0.51 15.87 438 2.50 439 2.37

- 225 046965

440 1.47 441 1.42 442 0.37 443 0.36 444 1.41 445 0.60 446 1.70 447 0.36 >47.63 448 0.29 449 0.39 450 0.38 451 0.46 452 0.51 453 0.29 454 0.48 455 0.47 21.28 456 0.38 457 0.38 458 3.07 459 0.32 460 1.62 39.91 461 1.75 462 1.74 463 0.55 28.32 464 2.63 465 1.95 466 1.02 467 1.20 468 0.35 469 0.31 470 0.83 471 1.43

- 226 046965

472 1.17 473 0.36 66.25 474 0.44 475 0.83 23.95 476 0.45 30.89 477 1.04 59.19 478 1.13 479 0.89 480 2.01 481 0.53 44.64 482 0.55 36.16 483 0.32 484 0.32 30.32 485 1.41 486 1.46 487 0.67 >47.63 488 1.40 489 3.71 490 3.68 491 3.87 492 2.39 493 0.98 156.95 494 1.02 53.29 495 1.79 496 2.25 497 4.38 498 4.28 499 2.55 500 2.36 501 1.43 12.54 502 3.71 503 2.13

- 227 046965

504 3.64 505 1.60 506 0.76 77.63 507 3.69 508 1.46 509 0.50 30.23 510 0.19 13.98 511 1.52 4.74 512 3.20 513 3.19 514 2.78 515 1.25 11.30 516 3.24 517 1.29 518 1.43 519 0.56 520 2.88 521 1.95 522 3.05 523 2.49 524 1.69 10.88 525 1.24 7.01 526 3.95 527 2.63 528 1.11 3.60 529 0.73 3.92 530 2.03 531 1.51 532 0.89 2.97 533 0.77 1.41 534 0.85 4.63 535 1.21 3.80

- 228 046965

536 2.07 537 1.34 10.73 538 2.72 539 2.35 540 2.65 541 1.85 542 2.41 543 1.96 544 0.54 1.96 545 0.39 2.20 546 1.85 3.51 547 0.61 3.62 548 0.39 2.10 549 0.90 3.24 550 0.36 3.12 551 0.34 2.94 552 0.29 2.41 553 0.41 1.90 554 1.76 5.11 555 0.37 3.58 556 0.46 1.85 557 ι,οι 2.60 558 0.41 18.59 559 1.44 8.58 560 0.60 9.84 561 1.80 562 0.43 4.85 563 1.80 4.35 564 0.37 10.07 565 1.24 4.07 566 0.79 37.61 567 1.61

- 229 046965

568 0.41 5.12 569 1.25 4.31 570 0.35 3.29 571 1.08 2.28 572 0.37 24.23 573 0.83 14.08 574 4.07 575 2.28 576 1.99 577 3.36 578 3.64 579 2.41 580 3.38 581 2.62 582 2.23 583 2.71 584 3.84 585 2.57 586 0.88 51.55 587 2.77 588 0.75 589 0.59 18.16 590 2.86 591 1.67 592 2.27 593 2.21 594 0.62 14.35 595 1.52 596 1.75 597 0.54 20.86 598 0.78 16.39 599 1.38

- 230 046965

600 2.12 601 0.39 7.32 602 0.30 603 0.07 13.82 604 0.08 5.00 605 0.32 9.89 606 0.63 11.50 607 1.90 608 1.11 609 4.81 610 1.04 611 1.67 13.94 612 0.45 8.01 613 2.98 614 1.66 6.58 615 1.99 616 0.28 4.05 617 0.27 7.18 618 0.78 8.57 619 0.42 5.75 620 3.91 621 0.36 2.77 622 4.00 623 1.17 6.31 624 4.18 16.26 625 0.45 4.97 626 4.73 627 0.51 2.76 628 0.92 20.77 629 0.40 10.58 630 1.43 631 1.12 11.78

- 231 046965

632 0.36 12.67 633 2D1 634 0.99 14.37 635 0.53 16.29 636 0.83 637 1.47 638 0.28 14.94 639 0.47 6.34 640 0.48 13.27 641 0.59 14.45 642 1.37 10.33 643 1.84 644 0.33 8.71 645 0.37 7.23 646 1.03 5.18 647 1.08 3.39 648 0.47 12.25 649 0.31 9.20

Additional data on biological activity for selected compounds are given in table. 5 below.

Table 5

Example No. Biochemical analysis Ki (nM) 13 CDKl/cyclin A ₂ 110 13 SPK4/cyclin Di 238 13 SPKb/cyclin D ₃ 465 13 CDK9 177 15 CDKl/cyclin A ₂ 16.4 15 SOK4/cyclin Di 26.6 15 SOKb/cyclin D ₃ 58.6 15 CDK9 6.3

All publications and patent applications cited in this specification are hereby incorporated by reference in their entirety. It will be apparent to one skilled in the art that certain substitutions and modifications may be made without departing from the spirit or scope of the appended claims.

Sequence listing <110> Pfizer Inc.

Behenna, Douglas C

Freeman-Cook, Kevin D

Hoffman, Robert L Nagata, Asako Ninkovic, Sacha Sutton, Scott C <120> 3-CARBONYLAMINO-5-CYCLOPENTYL-1H-PYRAZOLE COMPOUNDS WITH CDK2 INHIBITORY ACTIVITY <130> PC72484A

- 232 046965 <160> 3 <170> PatentIn version 3.5 <210> 1 <211> 6 <212> PRT <213> Artificial <220>

<223> Synthetic construction <220>

<221> MISC_FEATURE <222> (1)..(1) <223> 5-FAM-labeled glutamine <220>

<221> MISC_FEATURE <222> (6)..(6) <223> Glycine carboxamide <400> 1

Gln Ser Pro Lys Lys Gly

5 <210> 2 <211> 10 <212> PRT <213> Artificial <220>

<223> Synthetic construction <220>

<221> MISC_FEATURE <222> (1)..(1) <223> 5-FAM-labeled lysine <220>

<221> MISC_FEATURE <222> (11)..(11) <223> serine phosphorylated <400> 2

Lys Arg Arg Glu Ile Leu Ser Arg Arg Pro 1 5 10 <210> 3 <211> 15 <212> PRT <213> Artificial <220>

<223> Synthetic construction

- 233 -

Claims (17)

<220> <221> MISC_FEATURE <222> (1)..(1) <223> 5-1 ^; AM1-labeled arginine <400> 3 Arg Arg Arg Phe Arg Pro Ala Ser Pro Leu Arg Gly Pro Pro Lys 1 5 10 15 CLAIM 1. Compound of formula (I) or a pharmaceutically acceptable salt or hydrate thereof; Where R ¹ represents an -L3-10-membered heteroaryl containing at least one heteroatom selected from N, O and S as a ring member) or -L ¹ -(C ₆ -C ₁₂ -aryl), where the specified 5 -10-membered heteroaryl or C ₆ -C12-aryl is optionally substituted with one or more R ⁴ ; R ² and R ³ independently represent H, C1-C6-alkyl, C1-C6-fluoroalkyl, -,2-(C3-C7-cycloalkyl) or -1,2-(4-7-1 ^- membered heterocyclyl containing at least one heteroatom selected from N, O and S as a ring member), wherein each said C1-C6 alkyl and C1-C ₆ fluoroalkyl is optionally substituted with one or more R ⁵ and each said C ₃ -C ₇ -cycloalkyl and 4-7 membered heterocyclyl are optionally substituted with one or more R ⁶ ; or R ² and R ³ are taken together with the N atom to which they are attached to form a 4-6 membered heterocyclyl, possibly containing an additional heteroatom selected from O, N(R ⁷ ) and S(O)q as a ring member wherein said 4-6 membered heterocyclyl is optionally substituted with one or more R ⁸ ; each L ¹ and L ² independently represents a bond or C1-C ₂ alkylene, optionally substituted by one or more R ⁹ ; each R ⁴ independently represents F, Cl, OH, CN, NR ¹⁰ R ¹¹ , C1-C4-alkyl, C1-C4-fluoroalkyl, C1-C4-alkoxy, CrC4-fluoroalkoxy, C3A-cycloalkyl, C(O)NR ¹⁰ R11, SO2R ¹² , SO(=NH)R ¹² or SO2NR10R ¹¹ , where each C1-C4 alkyl and C1-C ₄ fluoroalkyl is optionally substituted by one or more R ¹³ ; each R ⁵ independently represents OH, C 1 -C ₄ -alkoxy or NR10R ¹¹ ; each R ⁶ is independently F, OH, C1-C4 alkyl, C1-C4 fluoroalkyl, C1-C4 alkoxy, C1C4 fluoroalkoxy, or NR10R ¹¹ , wherein each C1-C4 alkyl and C1- _C4 fluoroalkyl are optional substituted with one or more R ¹³ ; R ⁷ represents H, C1- _C4 alkyl or C(O)-C1- _C4 alkyl; each R ⁸ independently represents F, OH, C1-C4 alkyl, C1- _C4 alkoxy or GN; each R ⁹ independently represents F, OH or C ₁ -C ₂ -alkyl; R ¹⁰ and R ¹¹ are each independently H or C1- _C4 alkyl; each R ¹² represents C1- _C4 alkyl or _C3 - _C6 cycloalkyl; each R ¹³ independently represents OH, C1-C ₄ -alkoxy or NR14R ¹⁵ ; R ¹⁴ and R ¹⁵ are each independently H or C1- _C4 alkyl; and q is 0, 1 or 2. 2. A compound according to claim 1, having formula (II) or a pharmaceutically acceptable salt or hydrate thereof. - 234 046965 3. A compound according to claim 1, having formula (III) R ² I or a pharmaceutically acceptable salt or hydrate thereof. 4. A compound according to any one of claims 1-3 or a pharmaceutically acceptable salt or hydrate thereof, where R ¹ represents an A-(5-10 membered heteroaryl containing at least one heteroatom selected from N, O and S, in as a ring member), wherein said 5-10 membered heteroaryl is optionally substituted with one or more R ⁴ . 5. A compound according to claim 4 or a pharmaceutically acceptable salt or hydrate thereof, wherein said 5-10 membered heteroaryl is pyrazolyl, triazolyl, isoxazolyl, oxazolyl, thiazolyl, thiadiazolyl, imidazolyl, pyridinyl, pyrazinyl, indazolyl or benzimidazolyl, wherein said 5-10 membered heteroaryl heteroaryl is optionally substituted with one or more R ⁴ . 6. A compound according to claim 5 or a pharmaceutically acceptable salt or hydrate thereof, wherein said 5-10 membered heteroaryl is pyrazolyl, optionally substituted with one or more R ⁴ . 7. A compound according to claim 5 or a pharmaceutically acceptable salt or hydrate thereof, wherein said 5-10 membered heteroaryl is isoxazolyl, optionally substituted with one or more R ⁴ . 8. A compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt or hydrate thereof, wherein L ¹ represents a bond or methylene. 9. A compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt or hydrate thereof, wherein each R ⁴ is independently a C ₁ -C ₄ alkyl or a C ₁ -C ₄ alkoxy, wherein each R ₁ -C ₄ - alkyl is optionally substituted with one or more R ¹³ . 10. A compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt or hydrate thereof, wherein R ² represents H and R ³ represents C ₁ -C ₆ -alkyl. 11. A compound according to any one of claims 1 to 9 or a pharmaceutically acceptable salt or hydrate thereof, wherein R ² represents H and R ³ represents A ² -(C ₃ -C ₇ -cycloalkyl), wherein said C ₃ -C _{The 7} -cycloalkyl is optionally substituted with one or more R ⁶ . 12. A compound according to claim 11 or a pharmaceutically acceptable salt or hydrate thereof, wherein L ² represents a bond or methylene. 13. A compound according to claim 1, selected from the group consisting of: (^^)-3-[3-({[3-(methoxymethyl)-1-methyl-III-pyrazol-5-yl]carbonyl}amino)-III-pyrazol-5yl]cyclopentyl-propan-2-ylcarbamate; and (1R,3S)-3-(3-{[(3 -methyl-1,2-oxazol-5 -yl)acetyl] amino }-1 H-pyrazol-5 -yl)cyclopentyl-(1 methylcyclopropyl)carbamate . 14. A compound having a structure or its hydrate. 15. Hydrate (^^)-3-[3-({[3-(methoxymethyl)-1-methyl-III-pyrazol-5-yl]carbonyl}amino)-III-pyrazol-5-yl]cyclopentylpropane -2-ylcarbamate. 16. A compound that is (^^)-3-[3-({[3-(methoxymethyl)-1-methyl-Spirazol-5-yl]carbonyl}amino)-1H-pyrazol-5-yl]cyclopentyl monohydrate -propan-2-ylcarbamate, having the structure 17. A compound having a structure - 235 -