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WO2024173572A1 - INHIBITION DE L'INTÉGRINE α Vβ8 - Google Patents

INHIBITION DE L'INTÉGRINE α Vβ8 Download PDF

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Publication number
WO2024173572A1
WO2024173572A1 PCT/US2024/015824 US2024015824W WO2024173572A1 WO 2024173572 A1 WO2024173572 A1 WO 2024173572A1 US 2024015824 W US2024015824 W US 2024015824W WO 2024173572 A1 WO2024173572 A1 WO 2024173572A1
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WO
WIPO (PCT)
Prior art keywords
compound
pharmaceutically acceptable
acceptable salt
tert
mmol
Prior art date
Application number
PCT/US2024/015824
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English (en)
Inventor
Dawn TROAST
Kerim Babaoglu
Alex BUCKMELTER
Matthew BURSAVICH
Katherine CHONG
Donghui Cui
James Dowling
Bryce Harrison
Fu-Yang Lin
Blaise Lippa
Thomas Andrew MCTEAGUE
Qi Qiao
Inese ŠMUKSTE
Cheng Zhong
Steven ALBANESE
Aleksey GERASYUTO
Jiaye GUO
Eugene Hickey
Daigo Inoyama
Ana NEGRI
Mats Svensson
Original Assignee
Morphic Therapeutic, Inc.
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Filing date
Publication date
Application filed by Morphic Therapeutic, Inc. filed Critical Morphic Therapeutic, Inc.
Publication of WO2024173572A1 publication Critical patent/WO2024173572A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • TGF- ⁇ 1 and 3 The major function of ⁇ v ⁇ 8 is activation of growth factor TGF- ⁇ 1 and 3.
  • the TGF- ⁇ s are biosynthesized and stored in tissues as latent forms.
  • the TGF- ⁇ homodimer is kept latent by association with its dimeric prodomain (pro-TGF- ⁇ ).
  • the prodomain-derived homodimer prevents TGF- ⁇ from binding TGF- ⁇ receptor and is called latency-associated peptide (LAP).
  • LAP latency-associated peptide
  • the latent TGF- ⁇ complex is stored in the extracellular matrix or on the cell surface for subsequent, integrin-dependent activation.
  • TGF- ⁇ is a pleiotropic cytokine mediating multiple biological process including development and homeostasis.
  • TGF- ⁇ is a key player in cell growth, differentiation, and apoptosis. It regulates extracellular matrix (ECM) production contributing to tissue repair processes.
  • ECM extracellular matrix
  • TGF- ⁇ Homeostatic role of TGF- ⁇ on immunity is critical to prevent excessive inflammatory responses and essential for maintaining tolerance to self- antigens to prevent autoimmunity.
  • TGF- ⁇ is ubiquitously expressed it activity needs to be tightly regulated and when exacerbated lead to disease states. Dysregulation of TGF- ⁇ signaling is involved in multiple disorders, especially cancer and fibrosis.
  • the TGF- ⁇ pathway has been implicated in many human neoplastic diseases, including solid and hematopoietic tumors.
  • TGF- ⁇ acts as a tumor suppressor; however, in tumor cells, TGF- ⁇ loses its anti-proliferative response and promotes cancer progression.
  • the TGF- ⁇ -promoted tumorigenesis is mainly driven by downregulation of anti-tumor immunity.
  • the immunosuppressive effect leads to tumor immune tolerance.
  • TGF- ⁇ facilitates epithelial to mesenchymal transition (EMT) and angiogenesis to increase tumor invasiveness.
  • EMT epithelial to mesenchymal transition
  • the integrin avb8 expression in cancers correlates with TGF- ⁇ activity. It modulates inflammatory phenotype of the APCs and Tregs, the main cell types fundamental for T/NK cell driven anti-tumor activity.
  • the ⁇ v ⁇ 8 integrin locally activates TGF- ⁇ to regulate cross-talk between APCs and effector cells to skew immunity from inflammation to tolerance.
  • the invention features a compound of Formula (I), or a pharmaceutically acceptable salt thereof: wherein: h is optionally substituted with 1 to 6 R 4 ; each of R 1a , R 1b , R 1c , R 1d , R 1e , and R 1f is independently H, C 1-4 alkyl, halogen, C 1- 4 alkyloxy, OH, C 1-4 alkyl-OH, C 1-4 alkyl-C 1-4 alkyloxy, C 1-4 alkyloxy-C 1-4 alkyloxy, CF 3 , CHF 2 , CH 2 F, CN, NO 2 , NR a R b or C 1-4 alkyl-NR a R b , R 2 is H, C1-4al
  • the invention features a compound of Formula (I), or a pharmaceutically acceptable salt thereof: wherein: h is optionally substituted with 1 to 6 R 4 ; each of R 1a , R 1b , R 1c , R 1d , R 1e , and R 1f is independently H, C1-4alkyl, halogen, C1- 4 alkyloxy, OH, C 1-4 alkyl-OH, C 1-4 alkyl-C 1-4 alkyloxy, C 1-4 alkyloxy-C 1-4 alkyloxy, CF 3 , CHF 2 , CH 2 F, CN, NO 2 , NR a R b or C 1-4 alkyl-NR a R b , R 2 is H, C 1-4 alkyl or C 3-5 cycloalkyl, each of C 1-4 alkyl and C 3-5 cycloalkyl is optionally substituted with 1 to 4 R 5 ; R 3a is cyano, halogen, C1-4al
  • m is 0 and each of R 1a , R 1c , R 1d , R 1e and R 1f is independently H; and R 1b is H or methoxy.
  • L is optionally substituted with 1 to 2 R 4 ; and each R 4 is independently H, methyl, F, CF3, CHF2 or CH2F.
  • R 2 is C 1-4 alkyl.
  • R 3c is H, and R 3e is H.
  • R 3a is OMe.
  • R 3b is F.
  • R 3d is C1-4alkyl.
  • each of R 1a , R 1b , R 1c , R 1d , R 1e , and R 1f is independently H
  • R 2 is C 1-4 alkyl or cyclopropyl, and each of C 1-4 alkyl is optionally substituted with 1 to 4 R 5
  • R 3a is OMe
  • R 3b is F
  • R 3c is H or F
  • R 3d is C 1-4 alkyl, C 3-5 cycloalkyl, or 4-6-membered heterocycloalkyl, each of which is optionally substituted with 1 to 4 R 6
  • R 3e is H
  • each R 4 is independently F or CH3
  • each R 5 is independently cyclopropyl, C1-4alkyloxy, F, CF3, CHF2, CH2F, OCF3, OCHF2 or OCH 2 F
  • n is 0, 1 or 2
  • m is 0.
  • the compound has a structure according to Formula (III), pharmaceutically acceptable salt thereof.
  • the carbon marked by the asterisk has the (R)-configuration.
  • the carbon marked by the asterisk has the (S)-configuration.
  • the Q ring i [0021] In embodiments, each of R 1c , R 1d , and R 1e is independently H. [0022] In embodiments, each R 1a is independently H. [0023] In embodiments, each R 1b is independently H. [0024] In embodiments, each R 1b is independently OMe.
  • each of R 1c and R 1d is independently H.
  • each of R 1a , R 1b and R 1f is independently H.
  • R 2 is C1-4alkyl.
  • R 2 is methyl.
  • R 2 is ethyl.
  • R 2 is cyclopropyl.
  • R 3a is C1-4alkyl. [0035] In embodiments, R 3a is ethyl.
  • R 3a is methyl. [0037] In embodiments, R 3a is CN. [0038] In embodiments, R 3a is halogen. [0039] In embodiments, R 3a is Cl. [0040] In embodiments, R 3a is F. [0041] In embodiments, R 3a is C 1-4 alkyl optionally substituted with one or more halogen. [0042] In embodiments, R 3a is C 1-4 alkyl optionally substituted with one or more F. [0043] In embodiments, R 3a is methyl optionally substituted with one or more F. [0044] In embodiments, R 3a is C1-4alkyloxy.
  • R 3a is OMe, OEt, OCF3, OCHF2 or OCH2F. [0046] In embodiments, R 3a is OMe. [0047] In embodiments, R 3b is F. [0048] In embodiments, R 3c is H. [0049] In embodiments, R 3d is C1-4alkyl. [0050] In embodiments, R 3d is C3-5cycloalkyl. [0051] In embodiments, R 3d is oxetanyl, tetrahydrofuranyl, tetrahydro-2H-pyranyl, morpholinyl or piperazinyl-C 1-4 alkyl.
  • R 3d is C 6 cyckoalkyl optionally substituted with 1 to 4 R 6 .
  • R 3d is C 3-6 cyckoalkyl optionally substituted with 1 to 4 R 6 .
  • R 3d is iso-propyl.
  • R 3e is H.
  • each R 4 is independently methyl.
  • each R 4 is independently F.
  • each R 4 is independently CF 3 , CHF 2 or CH 2 F.
  • each R 4 is independently H.
  • each R 5 is independently C1-4alkyl. [0061] In embodiments, each R 5 is independently C3-5cycloalkyl. [0062] In embodiments, each R 5 is independently C1-4alkyloxy. [0063] In embodiments, each R 5 is independently C 3-5 cycloalkoxy. [0064] In embodiments, each R 5 is independently F, CF 3 , CHF 2 , CH 2 F, OCF 3 , OCHF 2 or OCH 2 F. [0065] In embodiments, each R 5 is independently H. [0066] In embodiments, each R 6 is independently H. [0067] In embodiments, each R 6 is independently C1-4alkyl.
  • each R 6 is independently C2-4alkenyl. [0069] In embodiments, each R 6 is independently C3-5cycloalkyl. [0070] In embodiments, each R 6 is independently C 1-4 alkyloxy. [0071] In embodiments, each R 6 is independently C 3-5 cycloalkoxy. [0072] In embodiments, each R 6 is independently F, CF 3 , CHF 2 , CH 2 F, OCF 3 , OCHF 2 , OCH2F or OH. [0073] In embodiments, each R 6 is independently a 5-6-membered heteroaryl. [0074] In embodiments, each R 6 is independently H. [0075] In embodiments, each R 7 is independently methyl or F.
  • n is 0. [0077] In embodiments, n is 1. [0078] In embodiments, n is 2. [0079] In embodiments, m is 0. [0080] In embodiments, a compound has a structure according to Formula (II), pharmaceutically acceptable salt thereof. [0081] In embodiments, a compound has a structure according to Formula (IIA), pharmaceutically acceptable salt thereof. [0082] In embodiments, a compound has a structure according to Formula (IIB), pharmaceutically acceptable salt thereof. [0083] In embodiments, a compound has a structure according to Formula (III), pharmaceutically acceptable salt thereof. [0084] In embodiments, a compound has a structure according to Formula (IIIA), pharmaceutically acceptable salt thereof.
  • a compound has a structure according to Formula (IIIB), pharmaceutically acceptable salt thereof.
  • a compound has a structure according to Formula (IV), pharmaceutically acceptable salt thereof.
  • a compound has a structure according to Formula (IVA), pharmaceutically acceptable salt thereof.
  • a compound has a structure according to Formula (IVB), pharmaceutically acceptable salt thereof.
  • a compound has a structure according to Formula (V), pharmaceutically acceptable salt thereof.
  • a compound has a structure according to Formula (VA), pharmaceutically acceptable salt thereof.
  • a compound has a structure according to Formula (VB), pharmaceutically acceptable salt thereof.
  • a compound has a structure according to Formula (VI), pharmaceutically acceptable salt thereof.
  • the carbon marked by the asterisk has the (R)-configuration.
  • the carbon marked by the asterisk has the (S)-configuration.
  • R 2 is C 1-4 alkyl optionally substituted with 1 or 2 R 5 .
  • R 2 is –CH 3 , -CH 2 CH 3 , -CH(CH 3 ) 2 , -C(CH 3 ) 3 , -CH2CH(CH3)2, -CH2CF3, -(CH2)2CF3, -CHF2, -CH2CHF2, -(CH2)2CHF2, -(CH 2 ) 2 OCH 3 , -(CH 2 ) 2 O-(cyclopropyl), -(CH 2 ) 2 OCF 3 , -(CH 2 ) 2 C(OCH 3 )(CH 3 )CH 3 , or cyclopropyl.
  • R 2 is –CH3.
  • R 3c is H. [0099] In embodiments, R 3c is F. [0100] In embodiments, R 3b is F. [0101] In embodiments, R 3d is isopropyl. [0102] In embodiments, L is unsubstituted . [0103] In embodiments, L is substituted by 1 or 2 R 5 . [0104] In embodiments, each R 5 is independently selected from -CH3, -CH2F, and –F. [0105] In embodiments, L is unsubstituted . [0106] In embodiments, the compound is selected from any compound described in Table 1, or a pharmaceutically acceptable salt thereof. [0107] In embodiments, the compound is selected from the group consisting of:
  • a compound of Formula (I) is pharmaceutically acceptable salt thereof.
  • a compound is Compound 1A, or a pharmaceutically acceptable salt thereof.
  • a compound is Compound 1B, or a pharmaceutically acceptable salt thereof.
  • a compound of Formula (I) is salt thereof.
  • a compound is Compound 7A, or a pharmaceutically acceptable salt thereof.
  • a compound is Compound 7B, or a pharmaceutically acceptable salt thereof.
  • a compound of Formula (I) is salt thereof.
  • a compound is Compound 8A, or a pharmaceutically acceptable salt thereof.
  • a compound is Compound 8B, or a pharmaceutically acceptable salt thereof.
  • a compound of Formula (I) is pharmaceutically acceptable salt thereof.
  • a compound is Compound 18A, or a pharmaceutically acceptable salt thereof.
  • a compound is Compound 18B, or a pharmaceutically acceptable salt thereof.
  • a compound of Formula (I) is pharmaceutically acceptable salt thereof.
  • a compound is Compound 28A, or a pharmaceutically acceptable salt thereof.
  • a compound is Compound 28B, or a pharmaceutically acceptable salt thereof.
  • a compound of Formula (I) is pharmaceutically acceptable salt thereof.
  • a compound is Compound 30A, or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound 30B, or a pharmaceutically acceptable salt thereof.
  • a compound of Formula (I) is pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound 100A, or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound 100B, or a pharmaceutically acceptable salt thereof.
  • a compound of Formula (I) is pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound 101A, or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound 101B, or a pharmaceutically acceptable salt thereof.
  • a compound of Formula (I) is pharmaceutically acceptable salt thereof.
  • a compound is Compound 102A, or a pharmaceutically acceptable salt thereof.
  • a compound is Compound 102B, or a pharmaceutically acceptable salt thereof.
  • a compound of Formula (I) is pharmaceutically acceptable salt thereof.
  • a compound is Compound 103A, or a pharmaceutically acceptable salt thereof.
  • a compound is Compound 103B, or a pharmaceutically acceptable salt thereof.
  • a compound of Formula (I) is pharmaceutically acceptable salt thereof.
  • a compound is Compound 110A, or a pharmaceutically acceptable salt thereof.
  • a compound is Compound 110B, or a pharmaceutically acceptable salt thereof.
  • a compound is Compound 110C, or a pharmaceutically acceptable salt thereof.
  • a compound is Compound 110D, or a pharmaceutically acceptable salt thereof.
  • a compound of Formula (I) is pharmaceutically acceptable salt thereof.
  • a compound is Compound 112A, or a pharmaceutically acceptable salt thereof.
  • a compound is Compound 112B, or a pharmaceutically acceptable salt thereof.
  • a compound of Formula (I) is salt thereof.
  • a compound is Compound 113A, or a pharmaceutically acceptable salt thereof.
  • a compound is Compound 113B, or a pharmaceutically acceptable salt thereof.
  • a compound of Formula (I) is pharmaceutically acceptable salt thereof.
  • a compound is Compound 114A, or a pharmaceutically acceptable salt thereof.
  • a compound is Compound 114B, or a pharmaceutically acceptable salt thereof.
  • a compound of Formula (I) is pharmaceutically acceptable salt thereof.
  • a compound is Compound 117A, or a pharmaceutically acceptable salt thereof.
  • a compound is Compound 117B, or a pharmaceutically acceptable salt thereof.
  • a compound is Compound 117C, or a pharmaceutically acceptable salt thereof.
  • a compound is Compound 117D, or a pharmaceutically acceptable salt thereof.
  • a compound of Formula (I) is pharmaceutically acceptable salt thereof.
  • a compound is Compound 127A, or a pharmaceutically acceptable salt thereof.
  • a compound is Compound 127B, or a pharmaceutically acceptable salt thereof.
  • a compound of Formula (I) is pharmaceutically acceptable salt thereof.
  • a compound is Compound 128A, or a pharmaceutically acceptable salt thereof.
  • a compound is Compound 128B, or a pharmaceutically acceptable salt thereof.
  • a compound of Formula (I) is pharmaceutically acceptable salt thereof.
  • a compound is Compound 131A, or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound 131B, or a pharmaceutically acceptable salt thereof. [0126] In embodiments, a compound of Formula (I) is pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound 135A, or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound 135B, or a pharmaceutically acceptable salt thereof. [0127] In another aspect, the invention features a method of inhibiting avb8 integrin in a patient, the method comprising administering to the patient in need thereof a therapeutically effective amount of any compound described herein, or a pharmaceutically acceptable salt thereof.
  • the method is for treating a solid tumor in a patient in need thereof.
  • the invention features a method of treating solid tumor in a patient, the method comprising administering to the patient in need thereof (a) a therapeutically effective amount of any compound described herein, or a pharmaceutically acceptable salt thereof, and (b) a therapeutically effective amount of a second active agent.
  • the solid tumor is selected from: anal cancer, bile duct cancer, bladder cancer, breast cancer, cervical cancer, colorectal cancer, endometrial cancer, esophageal cancer, fallopian tube cancer, gastric cancer, glioma liver cancer, lung cancer, melanoma, nasopharyngeal carcinoma, neuroblastoma, osteosarcoma, ovarian cancer, pancreatic cancer, primary peritoneal carcinoma, prostate cancer, renal cell carcinoma, skin cancer, squamous cell carcinoma of the head and neck (SCCHN), testicular cancer, urothelial carcinoma, and uterine cancer.
  • anal cancer bile duct cancer, bladder cancer, breast cancer, cervical cancer, colorectal cancer, endometrial cancer, esophageal cancer, fallopian tube cancer, gastric cancer, glioma liver cancer, lung cancer, melanoma, nasopharyngeal carcinoma, neuroblastoma, osteosarcoma, ovarian cancer
  • the solid tumor is selected from: breast cancer, squamous cell carcinoma of the head and neck (SCCHN), renal cell carcinoma, ovarian cancer, gastric cancer, esophageal cancer, lung cancer, pancreatic cancer, bile duct cancer, endometrial cancer, melanoma, and urothelial carcinoma.
  • the second active agent is an immune checkpoint inhibitor (e.g., an anti-PD-1 or an anti-PD-L1 therapy).
  • an immune checkpoint inhibitor is selected from: nivolumab, pembrolizumab, cemiplimab, dostarlimab, atezolizumab, avelumab, and durvalumab.
  • the term “or” as used herein shall only be interpreted as indicating exclusive alternatives (i.e., “one or the other but not both”) when preceded by terms of exclusivity, such as “either,” “one of,” “only one of,” or “exactly one of.” “Consisting essentially of,” when used in the claims, shall have its ordinary meaning as used in the field of patent law. [0137] As used herein in the specification and in the claims, the phrase “at least one,” in reference to a list of one or more elements, should be understood to mean at least one element selected from any one or more of the elements in the list of elements, but not necessarily including at least one of each and every element specifically listed within the list of elements and not excluding any combinations of elements in the list of elements.
  • At least one of A and B can refer, in one embodiment, to at least one, optionally including more than one, A, with no B present (and optionally including elements other than B); in another embodiment, to at least one, optionally including more than one, B, with no A present (and optionally including elements other than A); in yet another embodiment, to at least one, optionally including more than one, A, and at least one, optionally including more than one, B (and optionally including other elements); etc.
  • compositions of the present invention may exist in particular geometric or stereoisomeric forms.
  • polymers of the present invention may also be optically active.
  • the present invention contemplates all such compounds, including cis- and trans-isomers, R- and S-enantiomers, diastereomers, (d)-isomers, (l)-isomers, the racemic mixtures thereof, and other mixtures thereof, as falling within the scope of the invention.
  • asymmetric carbon atoms may be present in a substituent such as an alkyl group. All such isomers, as well as mixtures thereof, are intended to be included in this invention. [0141] If, for instance, a particular enantiomer of compound of the present invention is desired, it may be prepared by asymmetric synthesis, or by derivation with a chiral auxiliary, where the resulting diastereomeric mixture is separated and the auxiliary group cleaved to provide the pure desired enantiomers.
  • diastereomeric salts are formed with an appropriate optically-active acid or base, followed by resolution of the diastereomers thus formed by fractional crystallization or chromatographic means well known in the art, and subsequent recovery of the pure enantiomers.
  • Structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds produced by the replacement of a hydrogen with deuterium or tritium, or of a carbon with a 13 C- or 14 C-enriched carbon are within the scope of this invention.
  • ⁇ v ⁇ 8 means a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material, involved in carrying or transporting the subject chemical from one organ or portion of the body, to another organ or portion of the body.
  • a pharmaceutically acceptable material, composition or vehicle such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material, involved in carrying or transporting the subject chemical from one organ or portion of the body, to another organ or portion of the body.
  • Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of the formulation, not injurious to the patient, and substantially non- pyrogenic.
  • materials which can serve as pharmaceutically acceptable carriers include: (1) sugars, such as lactose, glucose, and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose, and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol, and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, such as magnesium hydroxide and aluminum hydroxide; (15) alg
  • compositions of the present invention are non-pyrogenic, i.e., do not induce significant temperature elevations when administered to a patient.
  • pharmaceutically acceptable salts refers to the relatively non-toxic, inorganic and organic acid addition salts of the compound(s). These salts can be prepared in situ during the final isolation and purification of the compound(s), or by separately reacting a purified compound(s) in its free base form with a suitable organic or inorganic acid, and isolating the salt thus formed.
  • Representative salts include the hydrobromide, hydrochloride, sulfate, bisulfate, phosphate, nitrate, acetate, valerate, oleate, palmitate, stearate, laurate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthylate, mesylate, glucoheptonate, lactobionate, and laurylsulphonate salts, and the like.
  • sulfate bisulfate
  • phosphate nitrate
  • acetate valerate
  • oleate palmitate
  • stearate laurate
  • benzoate lactate
  • phosphate tosylate
  • citrate maleate
  • fumarate succinate
  • tartrate naphthylate
  • mesylate glucoheptonate
  • lactobionate lactobionate
  • laurylsulphonate salts and the like.
  • the compounds useful in the methods of the present invention may contain one or more acidic functional groups and, thus, are capable of forming pharmaceutically acceptable salts with pharmaceutically acceptable bases.
  • pharmaceutically acceptable salts refers to the relatively non-toxic inorganic and organic base addition salts of a compound(s). These salts can likewise be prepared in situ during the final isolation and purification of the compound(s), or by separately reacting the purified compound(s) in its free acid form with a suitable base, such as the hydroxide, carbonate, or bicarbonate of a pharmaceutically acceptable metal cation, with ammonia, or with a pharmaceutically acceptable organic primary, secondary, or tertiary amine.
  • Representative alkali or alkaline earth salts include the lithium, sodium, potassium, calcium, magnesium, and aluminum salts, and the like.
  • Representative organic amines useful for the formation of base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, and the like (see, for example, Berge et al., supra).
  • a “therapeutically effective amount” (or “effective amount”) of a compound with respect to use in treatment refers to an amount of the compound in a preparation which, when administered as part of a desired dosage regimen (to a mammal, preferably a human) alleviates a symptom, ameliorates a condition, or slows the onset of disease conditions according to clinically acceptable standards for the disorder or condition to be treated or the cosmetic purpose, e.g., at a reasonable benefit/risk ratio applicable to any medical treatment.
  • the term “prophylactic or therapeutic” treatment is art-recognized and includes administration to the host of one or more of the subject compositions.
  • the treatment is prophylactic, (i.e., it protects the host against developing the unwanted condition), whereas if it is administered after manifestation of the unwanted condition, the treatment is therapeutic, (i.e., it is intended to diminish, ameliorate, or stabilize the existing unwanted condition or side effects thereof).
  • the term “patient” refers to a mammal in need of a particular treatment.
  • a patient is a primate, canine, feline, or equine.
  • a patient is a human.
  • a term e.g., alkyl or aryl
  • prefix roots e.g., alk- or ar-
  • affixing the suffix “-ene” to a group indicates the group is a divalent moiety, e.g., arylene is the divalent moiety of aryl
  • heteroarylene is the divalent moiety of heteroaryl
  • heterocycloalkylene is the divalent moiety of heterocycloalkyl.
  • an aliphatic chain comprises the classes of alkyl, alkenyl and alkynyl defined below.
  • a straight aliphatic chain is limited to unbranched carbon chain moieties.
  • the term “aliphatic group” refers to a straight chain, branched-chain, or cyclic aliphatic hydrocarbon group and includes saturated and unsaturated aliphatic groups, such as an alkyl group, an alkenyl group, or an alkynyl group.
  • Alkyl refers to a fully saturated cyclic or acyclic, branched or unbranched carbon chain moiety having the number of carbon atoms specified, or 1 up to 30 carbon atoms if no specification is made.
  • alkyl of 1 to 8 carbon atoms refers to moieties such as methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, and octyl, and those moieties which are positional isomers of these moieties.
  • Alkyl of 10 to 30 carbon atoms includes decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl, eicosyl, heneicosyl, docosyl, tricosyl and tetracosyl.
  • a straight chain or branched chain alkyl has 30 or fewer carbon atoms in its backbone (e.g., C 1 -C 30 for straight chains, C 3 -C 30 for branched chains), and more preferably 20 or fewer.
  • Alkyl goups may be substituted or unsubstituted.
  • the term “alkylene” refers to an alkyl group having the specified number of carbons, for example from 2 to 12 carbon atoms, that contains two points of attachment to the rest of the compound on its longest carbon chain.
  • alkylene groups include methylene -(CH 2 )-, ethylene -(CH 2 CH 2 )-, n-propylene -(CH 2 CH 2 CH 2 )-, isopropylene -(CH2CH(CH3))-, and the like.
  • Alkylene groups can be cyclic or acyclic, branched or unbranched carbon chain moiety, and may be optionally substituted with one or more substituents.
  • "Cycloalkyl” means mono- or bicyclic or bridged or spirocyclic, or polycyclic saturated carbocyclic rings, each having from 3 to 12 carbon atoms. Likewise, preferred cycloalkyls have from 3-10 carbon atoms in their ring structure, and more preferably have 3-6 carbons in the ring structure. Cycloalkyl groups may be substituted or unsubstituted.
  • Exemplary cycloalkyl groups include cyclopropyl (C3), cyclobutyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cycloheptyl(C7), and cyclooctyl (C8).
  • lower alkyl means an alkyl group, as defined above, but having from one to ten carbons, more preferably from one to six carbon atoms in its backbone structure such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl.
  • lower alkenyl and “lower alkynyl” have similar chain lengths.
  • preferred alkyl groups are lower alkyls.
  • a substituent designated herein as alkyl is a lower alkyl.
  • aryl as used herein includes 3- to 12-membered substituted or unsubstituted single-ring aromatic groups in which each atom of the ring is carbon (i.e., carbocyclic aryl) or where one or more atoms are heteroatoms (i.e., heteroaryl).
  • aryl groups include 5- to 12-membered rings, more preferably 6- to 10-membered rings
  • aryl also includes polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjoining rings wherein at least one of the rings is aromatic, e.g., the other cyclic rings can be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and/or heterocyclyls.
  • Carbocyclic aryl groups include benzene, naphthalene, phenanthrene, phenol, aniline, and the like.
  • Heteroaryl groups include substituted or unsubstituted aromatic 3- to 12-membered ring structures, more preferably 5- to 12-membered rings, more preferably 5- to 10- membered rings, whose ring structures include one to four heteroatoms.
  • Heteroaryl groups include, for example, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, triazole, pyrazole, pyridine, pyrazine, pyridazine and pyrimidine, and the like.
  • Aryl and heteroaryl can be monocyclic, bicyclic, or polycyclic.
  • halo means halogen and includes, for example, and without being limited thereto, fluoro, chloro, bromo, iodo and the like, in both radioactive and non-radioactive forms. In a preferred embodiment, halo is selected from the group consisting of fluoro, chloro and bromo.
  • heterocyclyl or “heterocyclic group” refer to 3- to 12-membered ring structures, more preferably 5- to 12-membered rings, more preferably 5- to 10-membered rings, whose ring structures include one to four heteroatoms.
  • Heterocycles can be monocyclic, bicyclic, spirocyclic, or polycyclic.
  • Heterocyclyl groups include, for example, thiophene, thianthrene, furan, pyran, isobenzofuran, chromene, xanthene, phenoxathiin, pyrrole, imidazole, pyrazole, isothiazole, isoxazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indole, indazole, purine, quinolizine, isoquinoline, quinoline, phthalazine, naphthyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine, pyrimidine, phenanthroline, phenazine, phenarsazin
  • the heterocyclic ring can be substituted at one or more positions with such substituents as described above, as for example, halogen, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, amino, nitro, sulfhydryl, imino, amido, phosphate, phosphonate, phosphinate, carbonyl, carboxyl, silyl, sulfamoyl, sulfinyl, ether, alkylthio, sulfonyl, ketone, aldehyde, ester, a heterocyclyl, an aromatic or heteroaromatic moiety, -CF 3 , -CN, and the like.
  • substituents as described above, as for example, halogen, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, amino, nitro, sulfhydryl, imino
  • heterocycloalkyl is a non-aromatic heterocyclyl wherein at least one atom is a heteroatom such as, but not limited to, nitrogen, oxygen, sulfur, or phosphorus, and the remaining atoms are carbon.
  • heterocycloalkyl groups are pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidino, morpholino, thiomorpholino, thioxanyl, piperazinyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl, diazepinyl, thiazepinyl, 1,2,3,6-tetrahydropyridinyl, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, 2H- pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolanyl, pyrazolinyl, dithiany
  • the heterocycloalkyl group can be substituted or unsubstituted as recited, e.g., for heterocyclyls as described herein.
  • the term “carbonyl” is art-recognized and includes such moieties as can be represented by the formula: [0161] wherein X’ is a bond or represents an oxygen or a sulfur, and R 15 represents a hydrogen, an alkyl, an alkenyl, -(CH 2 ) m -R 10 or a pharmaceutically acceptable salt, R 16 represents a hydrogen, an alkyl, an alkenyl or -(CH 2 ) m -R 10 , where m and R 10 are as defined above.
  • X’ is an oxygen and R15 or R16 is not hydrogen
  • the formula represents an “ester.”
  • X’ is an oxygen, and R15 is as defined above, the moiety is referred to herein as a carboxyl group, and particularly when R15 is a hydrogen, the formula represents a “carboxylic acid”.
  • R 16 is a hydrogen
  • the formula represents a “formate.”
  • X’ is a bond, and R 15 is not hydrogen
  • the above formula represents a “ketone” group.
  • X’ is a bond, and R 15 is a hydrogen
  • the above formula represents an “aldehyde” group.
  • substituted is contemplated to include all permissible substituents of organic compounds.
  • permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and nonaromatic substituents of organic compounds.
  • Illustrative substituents include, for example, those described herein above, and for example substituted with one or more substituents selected from alkyl, cycloalkyl, heterocyclylakyl, halogen, OH, OMe, C(H)F 2 , C(F)H 2 , CF 3 , C(H) 2 CF 3 , SF 5 , CHFCH2amine, CH2amine, and CN.
  • the permissible substituents can be one or more and the same or different for appropriate organic compounds.
  • the heteroatoms such as nitrogen may have hydrogen substituents and/or any permissible substituents of organic compounds described herein which satisfy the valences of the heteroatoms.
  • substitution or “substituted with” includes the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound, e.g., which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc.
  • nitro means -NO 2
  • halogen designates - F, -Cl, -Br, or -I
  • hydroxyl means -OH
  • cyano means –CN;
  • prodrug encompasses compounds that, under physiological conditions, are converted into therapeutically active agents.
  • a common method for making a prodrug is to include selected moieties that are hydrolyzed under physiological conditions to reveal the desired molecule.
  • the prodrug is converted by an enzymatic activity of the host animal. Accordingly, prodrugs include compounds that are transformed in vivo to yield a disclosed compound or any other pharmaceutically acceptable form of the compound.
  • a prodrug may be inactive when administered to a subject but may be converted in vivo to an active compound, for example, by hydrolysis. See, e.g., Bundgard, H., Design of Prodrugs (1985), pp.7-9, 21-24 (Elsevier, Amsterdam). A discussion of prodrugs is provided in Higuchi, T., et al., “Pro-drugs as Novel Delivery Systems,” A.C.S. Symposium Series, Vol.14, and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated in full by reference herein.
  • Prodrugs can typically be prepared using well known methods, such as those described in Burger's Medicinal Chemistry and Drug Discovery, 172-178, 949-982 (Manfred E. Wolff ed., 5th ed., 1995), and Design of Prodrugs (H. Bundgaard ed., Elselvier, New York, 1985).
  • the term “prodrug” is also meant to include any covalently bonded carriers, which release the active compound in vivo when such prodrug is administered to a subject.
  • Prodrugs of compounds described herein may be prepared by modifying functional groups present in the active compound in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to provide a compound described herein (i.e., the parent active compound).
  • Prodrugs include compounds wherein a hydroxy, amino or mercapto group is bonded to any group that, when the prodrug of the active compound is administered to a subject, cleaves to form a free hydroxy, free amino or free mercapto group, respectively.
  • Examples of prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of an alcohol or acetamide, formamide and benzamide derivatives of an amine functional group in the active compound and the like.
  • prodrugs include compounds that comprise —NO, — NO 2 , —ONO, or —ONO 2 moieties.
  • the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 67th Ed., 1986-87, inside cover.
  • Exemplary Compounds of the Invention This disclosure relates to novel chemical compounds and methods useful for inhibiting ⁇ v ⁇ 8 integrin.
  • Exemplary formulas and compounds are described herein. Also provided herein are exemplary embodiments of structural features which may be present in any formula described herein. Any exemplary embodiment of a structural feature may occur in combination with any other exemplary structural feature described herein.
  • any description of a formula or compound also includes any pharmaceutically acceptable forms of the compound, including but not limited to any pharmaceutically acceptable salts, hydrates, solvates, isomers, polymorphs, prodrugs, and isotopically labeled derivatives of disclosed formulas and compounds.
  • a compound described herein is a selective inhibitor of ⁇ v ⁇ 8 integrin.
  • a compound described herein selectively inhibits ⁇ v ⁇ 8 integrin over, e.g., ⁇ v ⁇ 6 integrin (e.g., a selectivity of at least about 10 ⁇ , 50 ⁇ , 100 ⁇ , or 1000 ⁇ as measured according to an assay (e.g., fluorescence polarization assay)).
  • an assay e.g., fluorescence polarization assay
  • the invention features a compound of Formula (I), or a pharmaceutically acceptable salt thereof: wherein: h is optionally substituted with 1 to 6 R 4 ; each of R 1a , R 1b , R 1c , R 1d , R 1e , and R 1f is independently H, C 1-4 alkyl, halogen, C 1- 4 alkyloxy, OH, C 1-4 alkyl-OH, C 1-4 alkyl-C 1-4 alkyloxy, C 1-4 alkyloxy-C 1-4 alkyloxy, CF 3 , CHF 2 , CH2F, CN, NO2, NRaRb or C1-4alkyl-NRaRb, R 2 is H, C1-4alkyl or C3-5cycloalkyl, each of C1-4alkyl and C3-5cycloalkyl is optionally substituted with 1 to 4 R 5 ; R 3a is C 1-4 alkyloxy, C 3-5 cycloalkoxy, CF 3
  • the invention features a compound of Formula (I), or a pharmaceutically acceptable salt thereof: wherein: to 6 R 4 ; each of R 1a , R 1b , R 1c , R 1d , R 1e , and R 1f is independently H, C 1-4 alkyl, halogen, C 1- 4 alkyloxy, OH, C 1-4 alkyl-OH, C 1-4 alkyl-C 1-4 alkyloxy, C 1-4 alkyloxy-C 1-4 alkyloxy, CF 3 , CHF 2 , CH2F, CN, NO2, NRaRb or C1-4alkyl-NRaRb, R 2 is H, C1-4alkyl or C3-5cycloalkyl, each of C1-4alkyl and C3-5cycloalkyl is optionally substituted with 1 to 4 R 5 ; R 3a is cyano, halogen, C 1-4 alkyl, C 1-4 alkyloxy, C 3-5 cycloalkoxy,
  • the invention features a compound of Formula (I), or a pharmaceutically acceptable salt thereof: wherein: h is optionally substituted with 1 to 6 R 4 ; each of R 1a , R 1b , R 1c , R 1d , R 1e , and R 1f is independently H, C 1-4 alkyl, halogen, C 1- 4 alkyloxy, OH, C 1-4 alkyl-OH, C 1-4 alkyl-C 1-4 alkyloxy, C 1-4 alkyloxy-C 1-4 alkyloxy, CF 3 , CHF 2 , CH 2 F, CN, NO 2 , NR a R b or C 1-4 alkyl-NR a R b , R 2 is H, C1-4alkyl or C3-5cycloalkyl, each of C1-4alkyl and C3-5cycloalkyl is optionally substituted with 1 to 4 R 5 ; R 3a is cyano, halogen, or C1-4alkyl; R 3
  • the Q ring i wherein R 1c1 and R 1c2 are each independently selected from R 1c ; R 1d1 and R 1d2 are each independently selected from R 1d ; and R1e1 and R1e2 are each independently selected from R1e. [0176] In embodiments, each of R1c1, R1c2, R1d1, R1d2, R1e1 and R1e2 are each independently H. [0177] In embodiments, the Q ring i . [0178] In embodiments, each of R 1c , R 1d , and R 1e is independently H. [0179] In embodiments, each R 1a is independently H. [0180] In embodiments, each R 1b is independently H.
  • each R 1b is independently OMe.
  • the Q ring i are each independently selected from R 1c ; and R 1d1 and R 1d2 are each independently selected from R 1d .
  • each of R1c1, R1c2, R1d1, and R1d2 are each independently H.
  • the Q ring i . is independently H.
  • each of R 1a , R 1b and R 1f is independently H. [0190] In embodiments, . [0191] In embodiments, . [0192] In embodiments, . [0193] In embodiments, . [0194] In embodiments, L is , wherein R4a, R4b, R4c and R4d are each independently an R 4 . [0195] In embodiments, wherein R4a is C1-4alkyl, and R4b, R4c and R 4d are each independently H. [0196] In embodiments, L is , wherein R 4a is methyl, and R 4b , R 4c and R 4d are each independently H.
  • L is , wherein R4a and R4b are each independently C 1-4 alkyl, and R 4c and R 4d are each independently H. [0198] In embodiments, L is , wherein R 4a and R 4b are each independently methyl, and R 4c and R 4d are each independently H. [0199] In embodiments, L i , wherein R 4c is halogen, and R 4a , R 4b and R 4d are each independently H. [0200] In embodiments, L i , wherein R 4c is F, and R 4a , R 4b and R 4d are each independently H.
  • L i wherein R 4a and R 4b are each independently H, and R 4c and R 4d are each independently halogen.
  • L is , wherein R 4a and R 4b are each independently H, and R 4c and R 4d are each independently F.
  • R 2 is C 1-4 alkyl.
  • R 2 is methyl.
  • R 2 is ethyl.
  • R 2 is cyclopropyl.
  • R 3a is C1-4alkyloxy.
  • R 3a is OMe, OEt, OCF3, OCHF2 or OCH2F.
  • R 3a is OMe.
  • R 3a is -CN.
  • R 3a is halogen.
  • R 3a is Cl.
  • R 3a is C1-4alkyl.
  • R 3a is methyl.
  • R 3a is ethyl.
  • R 3b is F.
  • R 3c is H.
  • R 3d is C 1-4 alkyl.
  • R 3d is C3-5cycloalkyl.
  • R 3d is oxetanyl, tetrahydrofuranyl, tetrahydro-2H-pyranyl, morpholinyl or piperazinyl-C 1-4 alkyl.
  • R 3d is iso-propyl.
  • R 3e is H.
  • each R 4 is independently methyl.
  • each R 4 is independently F. [0231] In embodiments, each R 4 is independently CF 3 , CHF 2 or CH 2 F. [0232] In embodiments, each R 4 is independently H. [0233] In embodiments, each R 5 is independently C1-4alkyl. [0234] In embodiments, each R 5 is independently C3-5cycloalkyl. [0235] In embodiments, each R 5 is independently C1-4alkyloxy. [0236] In embodiments, each R 5 is independently C 3-5 cycloalkoxy. [0237] In embodiments, each R 5 is independently F, CF 3 , CHF 2 , CH 2 F, OCF 3 , OCHF 2 or OCH 2 F.
  • each R 5 is independently H.
  • each R 6 is independently C1-4alkyl, C2-4alkenyl, C3-5cycloalkyl, C1- 4alkyloxy, C3-5cycloalkoxy, F, CF3, CHF2, CH2F, OCF3, OCHF2, OCH2F, OH, 5-6-membered heteroaryl, or NR a R b .
  • each R 6 is independently H.
  • each R 6 is independently C 1-4 alkyl.
  • each R 6 is independently C2-4alkenyl.
  • each R 6 is independently C3-5cycloalkyl.
  • each R 6 is independently C1-4alkyloxy. [0245] In embodiments, each R 6 is independently C 3-5 cycloalkoxy. [0246] In embodiments, each R 6 is independently F, CF 3 , CHF 2 , CH 2 F, OCF 3 , OCHF 2 , OCH 2 F or OH. [0247] In embodiments, each R 6 is independently a 5-6-membered heteroaryl. [0248] In embodiments, each R 6 is independently H. [0249] In embodiments, each R 7 is independently methyl or F. [0250] In embodiments, n is 0. [0251] In embodiments, n is 1. [0252] In embodiments, n is 2.
  • R 2 is independently C1-4alkyl (e.g., methyl, ethyl, or cyclopropyl);
  • R 3a is independently C1-4alkyloxy (e.g., OMe or OEt), OCF3, OCHF2, or OCH2F;
  • R 3b is independently F;
  • R 3c is independently H;
  • R 3d is independently C 1-4 alkyl (e.g., isopropyl), C 3-5 cycloalkyl, oxetanyl, tetrahydrofuranyl, tetrahydro-2H-pyranyl, morpholinyl or piperazinyl-C1-4alkyl;
  • R 3e is independently H;
  • each R 4 is independently H, CH3, F, CF3, CHF2, or CH2F;
  • each R 5 is independently, H, C 1-4 alkyl, C
  • R 3a is OMe, R 3b is F, and/or R 3d is iso-propyl.
  • R 3a is OMe and R 3b is F.
  • R 3a is OMe and R 3d is iso-propyl.
  • R 3b is F and R 3d is iso-propyl.
  • R 3a is OMe, R 3b is F, and R 3d is iso-propyl.
  • each of R 1c 1d 1e , R , and R is independently H; each R 1a is independently H; and/or each R 1b is independently H or OMe.
  • 1c 1d each of R and R is independently H; and/or each of R 1a , R 1b and R 1f is independently H.
  • Formulas (II)-(VI) [0264]
  • a compound has a structure according to Formula (II), pharmaceutically acceptable salt thereof, wherein L, R 1b , R 2 , R 3a , R 3b , R 3c , R 3d , and R 3e are according to any embodiments described herein.
  • a compound has a structure according to Formula (IIA), pharmaceutically acceptable salt thereof, wherein L, R 1b , R 2 , R 3c , and R 3d are according to any embodiments described herein.
  • a compound has a structure according to Formula (IIB), pharmaceutically acceptable salt thereof, wherein L, R 1b , R 2 , R 3b , and R 3c are according to any embodiments described herein.
  • a compound has a structure according to Formula (III), pharmaceutically acceptable salt thereof, wherein L, R 1b , R 2 , R 3a , R 3b , R 3c , R 3d , and R 3e are according to any embodiments described herein.
  • a compound has a structure according to Formula (IIIA), pharmaceutically acceptable salt thereof, wherein L, R 1b , R 2 , R 3c , and R 3d are according to any embodiments described herein.
  • a compound has a structure according to Formula (IIIB), pharmaceutically acceptable salt thereof, wherein L, R 1b , R 2 , R 3b , and R 3c are according to any embodiments described herein.
  • a compound has a structure according to Formula (IV), pharmaceutically acceptable salt thereof, wherein L, R 2 , R 3a , R 3b , R 3c , R 3d , and R 3e are according to any embodiments described herein.
  • a compound has a structure according to Formula (IVA), pharmaceutically acceptable salt thereof, wherein L, R 2 , R 3c , and R 3d are according to any embodiments described herein.
  • a compound has a structure according to Formula (IVB), thereof, wherein L, R 2 , R 3b , and R 3c are according to any embodiments described herein.
  • a compound has a structure according to Formula (V), pharmaceutically acceptable salt thereof, wherein L, R 2 , R 3a , R 3b , R 3c , R 3d , and R 3e are according to any embodiments described herein.
  • a compound has a structure according to Formula (VA), pharmaceutically acceptable salt thereof, wherein L, R 2 , R 3c , and R 3d are according to any embodiments described herein.
  • a compound has a structure according to Formula (VB), thereof, wherein L, R 2 , R 3b , and R 3c are according to any embodiments described herein.
  • a compound has a structure according to Formula (VI), pharmaceutically acceptable salt thereof, wherein R 2 , R 3a , R 3b and R 3d are according to any embodiments described herein.
  • a compound has a structure according to Formula (VI), pharmaceutically acceptable salt thereof, wherein R 2 is methyl, R 3a is methoxy and R 3b and R 3d are according to any embodiments described herein.
  • a compound has a structure according to Formula (VI), pharmaceutically acceptable salt thereof, wherein R 2 is methyl, R 3a is methoxy, R 3b is F and R 3d is according to any embodiments described herein.
  • the carbon marked by the asterisk has the (R)-configuration.
  • the carbon marked by the asterisk has the (S)-configuration.
  • R 2 is C1-4alkyl optionally substituted with 1 or 2 R 5 .
  • R 2 is –CH 3 , -CH 2 CH 3 , -CH(CH 3 ) 2 , -C(CH 3 ) 3 , -CH 2 CH(CH 3 ) 2 , -CH 2 CF 3 , -(CH 2 ) 2 CF 3 , -CHF 2 , -CH 2 CHF 2 , -(CH 2 ) 2 CHF 2 , -(CH 2 ) 2 OCH 3 , -(CH 2 ) 2 O-(cyclopropyl), -(CH 2 ) 2 OCF 3 , -(CH 2 ) 2 C(OCH 3 )(CH 3 )CH 3 , or cyclopropyl.
  • R 2 is –CH3.
  • R 3c is H.
  • R 3c is F.
  • R 3b is F.
  • R 3d is isopropyl.
  • L is unsubstituted .
  • L is substituted by 1 or 2 R 5 .
  • each R 5 is independently selected from -CH3, -CH2F, and –F.
  • L is unsubstituted .
  • the compound is selected from any compound described in Table 1, or a pharmaceutically acceptable salt thereof.
  • L is optionally substituted with 1 to 6 R 4 .
  • L is unsubstituted.
  • L is substituted with 1 to 6 R 4 .
  • L is substituted with 1, 2, or 3 R 4 .
  • L is substituted with 1 R 4 .
  • L is substituted with 2 R 4 .
  • L is substituted with 3 R 4 .
  • L is substituted with 4 R 4 .
  • L is substituted with 5 R 4 .
  • L is substituted with 6 R 4 .
  • L is optionally substituted with 1 to 6 R 4 .
  • L is unsubstituted.
  • L is substituted with 1 to 6 R 4 .
  • L is substituted with 1, 2, or 3 R 4 .
  • L is substituted with 1 R 4 .
  • L is substituted with 2 R 4 .
  • L is substituted with 3 R 4 .
  • L is substituted with 4 R 4 .
  • L is substituted with 5 R 4 .
  • L is substituted with 6 R 4 .
  • R 2 is H.
  • R 2 is C1-4alkyl optionally substituted with 1 to 4 R 5 .
  • R 2 is unsubstituted C 1-4 alkyl.
  • R 2 is C 1-4 alkyl substituted with 1 to 4 R 5 .
  • R 2 is C 1-4 alkyl substituted with 1 R 5 .
  • R 2 is C 1-4 alkyl substituted with 2 R 5 .
  • R 2 is C 1-4 alkyl substituted with 3 R 5 .
  • R 2 is C1-4alkyl substituted with 4 R 5 .
  • R 2 is C3-5cycloalkyl optionally substituted with 1 to 4 R 5 .
  • R 2 is unsubstituted C3-5cycloalkyl. In embodiments, R 2 is C3-5cycloalkyl substituted with 1 to 4 R 5 . In embodiments, R 2 is C 3-5 cycloalkyl substituted with 1 R 5 . In embodiments, R 2 is C 3-5 cycloalkyl substituted with 2 R 5 . In embodiments, R 2 is C 3-5 cycloalkyl substituted with 3 R 5 . In embodiments, R 2 is C 3-5 cycloalkyl substituted with 4 R 5 . [0299] In embodiments, R 2 is C1-4alkyl (e.g., methyl, ethyl, or cyclopropyl).
  • R 2 is C1-4alkyl (e.g., methyl, ethyl, or cyclopropyl).
  • R 3a is -CN. [0301] In embodiments, R 3a is halogen. [0302] In embodiments, R 3a is Cl. [0303] In embodiments, R 3a is C 1-4 alkyl. [0304] In embodiments, R 3a is methyl. [0305] In embodiments, R 3a is ethyl. [0306] In embodiments, R 3a is C1-4alkyloxy. [0307] In embodiments, R 3a is C3-5cycloalkoxy. [0308] In embodiments, R 3a is CF 3 . [0309] In embodiments, R 3a is CHF 2 . [0310] In embodiments, R 3a is CH 2 F.
  • R 3a is OCF3. [0312] In embodiments, R 3a is OCHF2. [0313] In embodiments, R 3a is OCH2F. [0314] In embodiments, R 3a is C 1-4 alkyloxy (e.g., OMe or OEt), OCF 3 , OCHF 2 , or OCH 2 F. In embodiments, R 3a is OMe. [0315] In embodiments, R 3b is H. [0316] In embodiments, R 3b is halogen (e.g., F). [0317] In embodiments, R 3b is CF3. [0318] In embodiments, R 3b is CN. [0319] In embodiments, R 3c is H.
  • R 3c is F. [0321] In embodiments, R 3c is CN. [0322] In embodiments, R 3c is C1-4alkyl. [0323] In embodiments, R 3d is H. [0324] In embodiments, R 3d is C1-4alkyl optionally substituted with 1 to 4 R 6 . In embodiments, R 3d is unsubstituted C 1-4 alkyl. In embodiments, R 3d is C 1-4 alkyl substituted with 1 to 4 R 6 . In embodiments, R 3d is C 1-4 alkyl substituted with 1 R 6 . In embodiments, R 3d is C 1-4 alkyl substituted with 2 R 6 .
  • R 3d is C 1-4 alkyl substituted with 3 R 6 . In embodiments, R 3d is C1-4alkyl substituted with 4 R 6 . [0325] In embodiments, R 3d is C 3-5 cycloalkyl optionally substituted with 1 to 4 R 6 . In embodiments, R 3d is unsubstituted C 3-5 cycloalkyl. In embodiments, R 3d is C 3-5 cycloalkyl substituted with 1 to 4 R 6 . In embodiments, R 3d is C3-5cycloalkyl substituted with 1 R 6 . In embodiments, R 3d is C3-5cycloalkyl substituted with 2 R 6 .
  • R 3d is C3-5cycloalkyl substituted with 3 R 6 . In embodiments, R 3d is C3-5cycloalkyl substituted with 4 R 6 . [0326] In embodiments, R 3d is C 3-6 cycloalkyl optionally substituted with 1 to 4 R 6 . In embodiments, R 3d is unsubstituted C 3-6 cycloalkyl. In embodiments, R 3d is C 3-6 cycloalkyl substituted with 1 to 4 R 6 . In embodiments, R 3d is C 3-6 cycloalkyl substituted with 1 R 6 . In embodiments, R 3d is C3-6 cycloalkyl substituted with 2 R 6 .
  • R 3d is C3-6cycloalkyl substituted with 3 R 6 . In embodiments, R 3d is C3-6cycloalkyl substituted with 4 R 6 . [0327] In embodiments, R 3d is 4-6-membered heterocycloalkyl optionally substituted with 1 to 4 R 6 . In embodiments, R 3d is unsubstituted 4-6-membered heterocycloalkyl. In embodiments, R 3d is 4-6-membered heterocycloalkyl substituted with 1 to 4 R 6 . In embodiments, R 3d is 4-6- membered heterocycloalkyl substituted with 1 R 6 .
  • R 3d is 4-6-membered heterocycloalkyl substituted with 2 R 6 . In embodiments, R 3d is 4-6-membered heterocycloalkyl substituted with 3 R 6 . In embodiments, R 3d is 4-6-membered heterocycloalkyl substituted with 4 R 6 . [0328] In embodiments, R 3d is C 1-4 alkyl (e.g., isopropyl), C 3-6 cycloalkyl, oxetanyl, tetrahydrofuranyl, tetrahydro-2H-pyranyl, morpholinyl or piperazinyl-C 1-4 alkyl. [0329] In embodiments, R 3e is H.
  • R 3e is F.
  • R 4 is independently H.
  • R 4 is independently C1-4alkyl.
  • R 4 is independently halogen.
  • R 4 is independently CF 3 .
  • R 4 is independently CHF 2 .
  • R 4 is independently CH2F.
  • R 4 is independently cyclopropyl.
  • two geminal R 4 groups together form a spiro-cyclopropyl.
  • each R 4 is independently H, CH 3 , F, CF 3 , CHF 2 , or CH 2 F.
  • R 5 is independently H. [0341] In embodiments, R 5 is independently C1-4alkyl. [0342] In embodiments, R 5 is independently C3-5cycloalkyl. [0343] In embodiments, R 5 is independently C1-4alkyloxy. [0344] In embodiments, R 5 is independently C 3-5 cycloalkoxy. [0345] In embodiments, R 5 is independently F. [0346] In embodiments, R 5 is independently CF 3 . [0347] In embodiments, R 5 is independently CHF2. [0348] In embodiments, R 5 is independently CH2F.
  • R 5 is independently OCF3. [0350] In embodiments, R 5 is independently OCHF 2 . [0351] In embodiments, R 5 is independently OCH 2 F. [0352] In embodiments, each R 5 is independently, H, C 1-4 alkyl, C 3-5 cycloalkyl, C 1-4 alkyloxy, F, CF3, CHF2, CH2F, OCF3, OCHF2 or OCH2F. [0353] In embodiments, R 6 is independently H. [0354] In embodiments, R 6 is independently C1-4alkyl. [0355] In embodiments, R 6 is independently C 2-4 alkenyl. [0356] In embodiments, R 6 is independently C 3-5 cycloalkyl.
  • R 6 is independently C 1-4 alkyloxy. [0358] In embodiments, R 6 is independently C3-5cycloalkoxy. [0359] In embodiments, R 6 is independently F. [0360] In embodiments, R 6 is independently CF3. [0361] In embodiments, R 6 is independently CHF 2 . [0362] In embodiments, R 6 is independently CH 2 F. [0363] In embodiments, R 6 is independently OCF 3 . [0364] In embodiments, R 6 is independently OCHF 2 . [0365] In embodiments, R 6 is independently OCH 2 F. [0366] In embodiments, R 6 is independently OH. [0367] In embodiments, R 6 is independently 5-6-membered heteroaryl.
  • R 6 is independently NRaRb.
  • R 7 is independently C 1-4 alkyl.
  • R 7 is F.
  • R 7 is CH 3 or F.
  • Ra is independently hydrogen.
  • Ra is independently C1-4alkyl.
  • Ra is independently C3-5cycloalkyl.
  • R b is independently hydrogen.
  • R b is independently C 1-4 alkyl.
  • R b is independently C 3-5 cycloalkyl.
  • Ra and Rb together with the nitrogen atom to which they are attached, form a saturated or unsaturated heterocyclic ring containing from three to seven ring atoms, wherein said ring may optionally contain additional one or two heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur and may be optionally substituted by from one to three groups which may be the same or different selected from the group consisting of F, C 1 - 4 alkyl, phenyl and benzyl.
  • Ra and Rb, together with the nitrogen atom to which they are attached form a saturated heterocyclic ring.
  • said heterocyclic ring is unsubstituted.
  • said heterocyclic ring is substituted by 1, 2 or 3 groups independently selected from the group consisting of F, C 1 - 4 alkyl, phenyl and benzyl. In embodiments, said heterocyclic ring does not contain additional one or two heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur. In embodiments, said heterocyclic ring contains additional one or two heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur. [0380] In embodiments, R a and R b , together with the nitrogen atom to which they are attached, form an unsaturated heterocyclic ring. In embodiments, said heterocyclic ring is unsubstituted.
  • said heterocyclic ring is substituted by 1, 2 or 3 groups independently selected from the group consisting of F, C1-4alkyl, phenyl and benzyl. In embodiments, said heterocyclic ring does not contain additional one or two heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur. In embodiments, said heterocyclic ring contains additional one or two heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur. [0381] In embodiments, n is 0. [0382] In embodiments, n is 1. [0383] In embodiments, n is 2. [0384] In embodiments, m is 0. [0385] In embodiments, m is 1. [0386] In embodiments, m is 2.
  • R 1a is independently H. In embodiments, R 1a is independently C1- 4 alkyl. In embodiments, R 1a is independently halogen. In embodiments, R 1a is independently C 1- 4 alkyloxy. In embodiments, R 1a is independently OH. In embodiments, R 1a is independently C 1- 4 alkyl-OH. In embodiments, R 1a is independently C 1-4 alkyl-C 1-4 alkyloxy. In embodiments, R 1a is independently C1-4alkyloxy-C1-4alkyloxy. In embodiments, R 1a is independently CF3.
  • R 1a is independently CHF2. In embodiments, R 1a is independently CH2F. In embodiments, R 1a is independently CN. In embodiments, R 1a is independently NO2. In embodiments, R 1a is independently NR a R b . In embodiments, R 1a is independently C 1-4 alkyl- NR a R b . [0390] In embodiments, R 1b is independently H. In embodiments, R 1b is independently C 1- 4 alkyl. In embodiments, R 1b is independently halogen. In embodiments, R 1b is independently C 1- 4alkyloxy. In embodiments, R 1b is independently OH. In embodiments, R 1b is independently C1- 4alkyl-OH.
  • R 1b is independently C1-4alkyl-C1-4alkyloxy. In embodiments, R 1b is independently C1-4alkyloxy-C1-4alkyloxy. In embodiments, R 1b is independently CF3. In embodiments, R 1b is independently CHF 2 . In embodiments, R 1b is independently CH 2 F. In embodiments, R 1b is independently CN. In embodiments, R 1b is independently NO 2 . In embodiments, R 1b is independently NR a R b . In embodiments, R 1b is independently C 1-4 alkyl- NRaRb. [0391] In embodiments, R 1c is independently H. In embodiments, R 1c is independently C1- 4alkyl.
  • R 1c is independently halogen. In embodiments, R 1c is independently C1- 4 alkyloxy. In embodiments, R 1c is independently OH. In embodiments, R 1c is independently C 1- 4 alkyl-OH. In embodiments, R 1c is independently C 1-4 alkyl-C 1-4 alkyloxy. In embodiments, R 1c is independently C 1-4 alkyloxy-C 1-4 alkyloxy. In embodiments, R 1c is independently CF 3 . In embodiments, R 1c is independently CHF2. In embodiments, R 1c is independently CH2F. In embodiments, R 1c is independently CN. In embodiments, R 1c is independently NO2. In embodiments, R 1c is independently NRaRb.
  • R 1c is independently C1-4alkyl- NR a R b .
  • R 1d is independently H. In embodiments, R 1d is independently C 1- 4 alkyl. In embodiments, R 1d is independently halogen. In embodiments, R 1d is independently C 1- 4alkyloxy. In embodiments, R 1d is independently OH. In embodiments, R 1d is independently C1- 4alkyl-OH. In embodiments, R 1d is independently C1-4alkyl-C1-4alkyloxy. In embodiments, R 1d is independently C1-4alkyloxy-C1-4alkyloxy. In embodiments, R 1d is independently CF3. In embodiments, R 1d is independently CHF 2 .
  • R 1d is independently CH 2 F. In embodiments, R 1d is independently CN. In embodiments, R 1d is independently NO 2 . In embodiments, R 1d is independently NR a R b . In embodiments, R 1d is independently C 1-4 alkyl- NRaRb. [0393] In embodiments, R 1e is independently H. In embodiments, R 1e is independently C1- 4alkyl. In embodiments, R 1e is independently halogen. In embodiments, R 1e is independently C1- 4 alkyloxy. In embodiments, R 1e is independently OH. In embodiments, R 1e is independently C 1- 4 alkyl-OH.
  • R 1e is independently C 1-4 alkyl-C 1-4 alkyloxy. In embodiments, R 1e is independently C 1-4 alkyloxy-C 1-4 alkyloxy. In embodiments, R 1e is independently CF 3 . In embodiments, R 1e is independently CHF2. In embodiments, R 1e is independently CH2F. In embodiments, R 1e is independently CN. In embodiments, R 1e is independently NO 2 . In embodiments, R 1e is independently NR a R b . In embodiments, R 1e is independently C 1-4 alkyl- NRaRb. [0394] In embodiments, R 1f is independently H. In embodiments, R 1f is independently C1- 4alkyl.
  • R 1f is independently halogen. In embodiments, R 1f is independently C1- 4 alkyloxy. In embodiments, R 1f is independently OH. In embodiments, R 1f is independently C 1- 4 alkyl-OH. In embodiments, R 1f is independently C 1-4 alkyl-C 1-4 alkyloxy. In embodiments, R 1f is independently C 1-4 alkyloxy-C 1-4 alkyloxy. In embodiments, R 1f is independently CF 3 . In embodiments, R 1f is independently CHF2. In embodiments, R 1f is independently CH2F. In embodiments, R 1f is independently CN. In embodiments, R 1f is independently NO2. In embodiments, R 1f is independently NRaRb.
  • R 1f is independently C1-4alkyl- NR a R b .
  • each of R 1c , R 1d , and R 1e is independently H; each R 1a is independently H; and/or each R 1b is is independently H or OMe.
  • each of R 1a , R 1b , R 1c , R 1d , and R 1e is H.
  • each of R 1a , R 1b , R 1d , and R 1e is H.
  • each of R 1c and R 1d is H; and/or each of each R 1a , R 1b , and R 1f is independently H.
  • each of R 1a , R 1b , R 1c , R 1d , and R 1f is H.
  • each of R 1a , R 1c , R 1d , and R 1f is H.
  • Exemplary Compounds include those described in Table 1 herein and pharmaceutically acceptable salts thereof.
  • a compound may be used as a mixture of stereoisomers (e.g., a mixture of diastereomers or a mixture of enantiomers).
  • a stereochemically enriched composition comprising a compound described herein (e.g., a composition of a compound is substantially free of any other stereoisomer of that compound).
  • a compound described herein e.g., a composition of a compound is substantially free of any other stereoisomer of that compound.
  • a compound is Compound 1A, or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound 1B, or a pharmaceutically acceptable salt thereof. [0405] In embodiments, a compound i (Compound 2A/2B), or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound 2A, or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound 2B, or a pharmaceutically acceptable salt thereof. [0406] In embodiments, a compound i (Compound 3A/3B), or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound 3A, or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound 3B, or a pharmaceutically acceptable salt thereof.
  • a compound i (Compound 4A/4B), or a pharmaceutically acceptable salt thereof.
  • a compound is Compound 4A, or a pharmaceutically acceptable salt thereof.
  • a compound is Compound 4B, or a pharmaceutically acceptable salt thereof.
  • a compound i (Compound 5A/5B), or a pharmaceutically acceptable salt thereof.
  • a compound is Compound 5A, or a pharmaceutically acceptable salt thereof.
  • a compound is Compound 5B, or a pharmaceutically acceptable salt thereof.
  • a compound i (Compound 6A/6B), or a pharmaceutically acceptable salt thereof.
  • a compound is Compound 6A, or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound 6B, or a pharmaceutically acceptable salt thereof. [0410] In embodiments, a compound i (Compound 7A/7B), or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound 7A, or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound 7B, or a pharmaceutically acceptable salt thereof. [0411] In embodiments, a compound (Compound 8A/8B), or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound 8A, or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound 8B, or a pharmaceutically acceptable salt thereof.
  • a compound (Compound 9A/9B), or a pharmaceutically acceptable salt thereof.
  • a compound is Compound 9A, or a pharmaceutically acceptable salt thereof.
  • a compound is Compound 9B, or a pharmaceutically acceptable salt thereof.
  • a compound i (Compound 10A/10B), or a pharmaceutically acceptable salt thereof.
  • a compound is Compound 10A, or a pharmaceutically acceptable salt thereof.
  • a compound is Compound 10B, or a pharmaceutically acceptable salt thereof.
  • a compound is Compound 10B, or a pharmaceutically acceptable salt thereof.
  • a compound i (Compound 11A/11B), or a pharmaceutically acceptable salt thereof.
  • a compound is Compound 11A, or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound 11B, or a pharmaceutically acceptable salt thereof. [0415] In embodiments, a compound (Compound 12A/12B), or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound 12A, or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound 12B, or a pharmaceutically acceptable salt thereof. [0416] In embodiments, a compound (Compound 13A/13B), or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound 13A, or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound 13B, or a pharmaceutically acceptable salt thereof.
  • a compound (Compound 14A/14B), or a pharmaceutically acceptable salt thereof.
  • a compound is Compound 14A, or a pharmaceutically acceptable salt thereof.
  • a compound is Compound 14B, or a pharmaceutically acceptable salt thereof.
  • a compound (Compound 15A/15B), or a pharmaceutically acceptable salt thereof.
  • a compound is Compound 15A, or a pharmaceutically acceptable salt thereof.
  • a compound is Compound 15B, or a pharmaceutically acceptable salt thereof.
  • a compound (Compound 16A/16B), or a pharmaceutically acceptable salt thereof.
  • a compound is Compound 16A, or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound 16B, or a pharmaceutically acceptable salt thereof. [0420] In embodiments, a compound (Compound 17A/17B), or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound 17A, or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound 17B, or a pharmaceutically acceptable salt thereof. [0421] In embodiments, a compound (Compound 18A/18B), or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound 18A, or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound 18B, or a pharmaceutically acceptable salt thereof.
  • a compound i (Compound 18C/18D), or a pharmaceutically acceptable salt thereof.
  • a compound is Compound 18C, or a pharmaceutically acceptable salt thereof.
  • a compound is Compound 18D, or a pharmaceutically acceptable salt thereof.
  • a compound is (Compound 19A/19B), or a pharmaceutically acceptable salt thereof.
  • a compound is Compound 19A, or a pharmaceutically acceptable salt thereof.
  • a compound is Compound 19B, or a pharmaceutically acceptable salt thereof.
  • a compound (Compound 19C/19D), or a pharmaceutically acceptable salt thereof is a pharmaceutically acceptable salt thereof.
  • a compound is Compound 19C, or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound 19D, or a pharmaceutically acceptable salt thereof.
  • a compound i (Compound 22A/22B), or a pharmaceutically acceptable salt thereof.
  • a compound is Compound 22A, or a pharmaceutically acceptable salt thereof.
  • a compound is Compound 22B, or a pharmaceutically acceptable salt thereof.
  • a compound i (Compound 23A/23B), or a pharmaceutically acceptable salt thereof.
  • a compound is Compound 23A, or a pharmaceutically acceptable salt thereof.
  • a compound is Compound 23B, or a pharmaceutically acceptable salt thereof.
  • a compound (Compound 24A/24B), or a pharmaceutically acceptable salt thereof.
  • a compound is Compound 24A, or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound 24B, or a pharmaceutically acceptable salt thereof. [0430] In embodiments, a compound i (Compound 25A/25B), or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound 25A, or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound 25B, or a pharmaceutically acceptable salt thereof. [0431] In embodiments, a compound (Compound 25C/25D), or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound 25C, or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound 25D, or a pharmaceutically acceptable salt thereof.
  • a compound is Compound 26A, or a pharmaceutically acceptable salt thereof.
  • a compound is Compound 26B, or a pharmaceutically acceptable salt thereof.
  • Compound 26C/26D or a pharmaceutically acceptable salt thereof.
  • a compound is Compound 26C, or a pharmaceutically acceptable salt thereof.
  • a compound is Compound 26D, or a pharmaceutically acceptable salt thereof.
  • a compound is Compound 27A/27B, or a pharmaceutically acceptable salt thereof.
  • a compound is Compound 27A, or a pharmaceutically acceptable salt thereof.
  • a compound is Compound 27B, or a pharmaceutically acceptable salt thereof.
  • a compound (Compound 28A/28B), or a pharmaceutically acceptable salt thereof.
  • a compound is Compound 28A, or a pharmaceutically acceptable salt thereof.
  • a compound is Compound 28B, or a pharmaceutically acceptable salt thereof.
  • a compound i (Compound 29A/29B), or a pharmaceutically acceptable salt thereof.
  • a compound is Compound 29A, or a pharmaceutically acceptable salt thereof.
  • a compound is Compound 29B, or a pharmaceutically acceptable salt thereof.
  • a compound i (Compound 30A/30B), or a pharmaceutically acceptable salt thereof.
  • a compound is Compound 30A, or a pharmaceutically acceptable salt thereof.
  • a compound is Compound 30B, or a pharmaceutically acceptable salt thereof.
  • Compound 31A/31B or a pharmaceutically acceptable salt thereof.
  • a compound is Compound 31A, or a pharmaceutically acceptable salt thereof.
  • a compound is Compound 31B, or a pharmaceutically acceptable salt thereof.
  • a compound i (Compound 32A/32B), or a pharmaceutically acceptable salt thereof.
  • a compound is Compound 32A, or a pharmaceutically acceptable salt thereof.
  • a compound is Compound 32B, or a pharmaceutically acceptable salt thereof.
  • a compound i Compound 33A/33B
  • a pharmaceutically acceptable salt thereof In embodiments, a compound is Compound 33A, or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound 33B, or a pharmaceutically acceptable salt thereof.
  • a compound In embodiments, a compound (Compound 34A/34B), or a pharmaceutically acceptable salt thereof.
  • a compound is Compound 34A, or a pharmaceutically acceptable salt thereof.
  • a compound is Compound 34B, or a pharmaceutically acceptable salt thereof.
  • a compound (Compound 35A/35B), or a pharmaceutically acceptable salt thereof In embodiments, a compound is Compound 35A, or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound 35B, or a pharmaceutically acceptable salt thereof. [0443] In embodiments, a compound (Compound 100A/100B), or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound 100A, or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound 100B, or a pharmaceutically acceptable salt thereof. [0444] In embodiments, a compound (Compound 101A/101B), or a pharmaceutically acceptable salt thereof.
  • a compound is Compound 101A, or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound 101B, or a pharmaceutically acceptable salt thereof. [0445] In embodiments, a compound (Compound 102A/102B), or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound 102A, or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound 102B, or a pharmaceutically acceptable salt thereof. [0446] In embodiments, a compound i (Compound 103A/103B), or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound 103A, or a pharmaceutically acceptable salt thereof.
  • a compound is Compound 103B, or a pharmaceutically acceptable salt thereof.
  • a compound is Compound 104A, or a pharmaceutically acceptable salt thereof.
  • a compound is Compound 104B, or a pharmaceutically acceptable salt thereof.
  • a compound (Compound 105A/105B), or a pharmaceutically acceptable salt thereof.
  • a compound is Compound 105A, or a pharmaceutically acceptable salt thereof.
  • a compound is Compound 105B, or a pharmaceutically acceptable salt thereof.
  • a compound (Compound 106A/106B), or a pharmaceutically acceptable salt thereof.
  • a compound is Compound 106A, or a pharmaceutically acceptable salt thereof.
  • a compound is Compound 106B, or a pharmaceutically acceptable salt thereof.
  • a compound is Compound 107A/107B, or a pharmaceutically acceptable salt thereof.
  • a compound is Compound 107B, or a pharmaceutically acceptable salt thereof.
  • a compound i Compound 108A/108B
  • a compound is Compound 108A, or a pharmaceutically acceptable salt thereof.
  • a compound is Compound 108B, or a pharmaceutically acceptable salt thereof.
  • a compound is Compound 109A, or a pharmaceutically acceptable salt thereof.
  • a compound is Compound 109B, or a pharmaceutically acceptable salt thereof.
  • a compound is Compound 109B, or a pharmaceutically acceptable salt thereof.
  • a compound is Compound 110A, or a pharmaceutically acceptable salt thereof.
  • a compound is Compound 110B, or a pharmaceutically acceptable salt thereof.
  • a compound is Compound 110C, or a pharmaceutically acceptable salt thereof.
  • a compound is Compound 110D, or a pharmaceutically acceptable salt thereof.
  • a compound i (Compound 111A/111B), or a pharmaceutically acceptable salt thereof.
  • a compound is Compound 111A, or a pharmaceutically acceptable salt thereof.
  • a compound is Compound 111B, or a pharmaceutically acceptable salt thereof.
  • a compound (Compound 112A/112B), or a pharmaceutically acceptable salt thereof.
  • a compound is Compound 112A, or a pharmaceutically acceptable salt thereof.
  • a compound is Compound 112B, or a pharmaceutically acceptable salt thereof.
  • a compound is Compound 112B, or a pharmaceutically acceptable salt thereof.
  • a compound (Compound 113A/113B), or a pharmaceutically acceptable salt thereof.
  • a compound is Compound 113A, or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound 113B, or a pharmaceutically acceptable salt thereof. [0457] In embodiments, a compound (Compound 114A/114B), or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound 114A, or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound 114B, or a pharmaceutically acceptable salt thereof. [0458] In embodiments, a compound (Compound 115A/115B), or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound 115A, or a pharmaceutically acceptable salt thereof.
  • a compound is Compound 115B, or a pharmaceutically acceptable salt thereof.
  • a compound is (Compound 116A/116B), or a pharmaceutically acceptable salt thereof.
  • a compound is Compound 116A, or a pharmaceutically acceptable salt thereof.
  • a compound is Compound 116B, or a pharmaceutically acceptable salt thereof.
  • a compound i (Compound 117A/117B/117C/117D), or a pharmaceutically acceptable salt thereof.
  • a compound is Compound 117A, or a pharmaceutically acceptable salt thereof.
  • a compound is Compound 117B, or a pharmaceutically acceptable salt thereof.
  • a compound is Compound 117C, or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound 117D, or a pharmaceutically acceptable salt thereof.
  • a compound i Compound 118A/118B
  • a pharmaceutically acceptable salt thereof In embodiments, a compound is Compound 118A, or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound 118B, or a pharmaceutically acceptable salt thereof.
  • a compound i Compound 119A/119B
  • a compound is Compound 119A, or a pharmaceutically acceptable salt thereof.
  • a compound is Compound 119B, or a pharmaceutically acceptable salt thereof.
  • [0463] (Compound 120A/120B), or a pharmaceutically acceptable salt thereof.
  • a compound is Compound 120A, or a pharmaceutically acceptable salt thereof.
  • a compound is Compound 120B, or a pharmaceutically acceptable salt thereof.
  • a compound i (Compound 121A/121B), or a pharmaceutically acceptable salt thereof.
  • a compound is Compound 121A, or a pharmaceutically acceptable salt thereof.
  • a compound is Compound 121B, or a pharmaceutically acceptable salt thereof.
  • a compound i (Compound 122A/122B), or a pharmaceutically acceptable salt thereof.
  • a compound is Compound 122A, or a pharmaceutically acceptable salt thereof.
  • a compound is Compound 122B, or a pharmaceutically acceptable salt thereof.
  • a compound i (Compound 123A/123B), or a pharmaceutically acceptable salt thereof.
  • a compound is Compound 123A, or a pharmaceutically acceptable salt thereof.
  • a compound is Compound 123B, or a pharmaceutically acceptable salt thereof.
  • a compound (Compound 124A/124B), or a pharmaceutically acceptable salt thereof.
  • a compound is Compound 124A, or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound 124B, or a pharmaceutically acceptable salt thereof. [0468] In embodiments, a compound (Compound 125A/125B), or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound 125A, or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound 125B, or a pharmaceutically acceptable salt thereof. [0469] In embodiments, a compound is (Compound 126A/126B), or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound 126A, or a pharmaceutically acceptable salt thereof.
  • a compound is Compound 126B, or a pharmaceutically acceptable salt thereof.
  • a compound i Compound 127A/127B), or a pharmaceutically acceptable salt thereof.
  • a compound is Compound 127A, or a pharmaceutically acceptable salt thereof.
  • a compound is Compound 127B, or a pharmaceutically acceptable salt thereof.
  • a compound i Compound 128A/128B
  • a pharmaceutically acceptable salt thereof In embodiments, a compound is Compound 128A, or a pharmaceutically acceptable salt thereof.
  • a compound is Compound 128B, or a pharmaceutically acceptable salt thereof.
  • a compound (Compound 129A/129B), or a pharmaceutically acceptable salt thereof.
  • a compound is Compound 129A, or a pharmaceutically acceptable salt thereof.
  • a compound is Compound 129B, or a pharmaceutically acceptable salt thereof.
  • a compound i (Compound 130A/130B), or a pharmaceutically acceptable salt thereof.
  • a compound is Compound 130A, or a pharmaceutically acceptable salt thereof.
  • a compound is Compound 130B, or a pharmaceutically acceptable salt thereof.
  • a compound is Compound 130B, or a pharmaceutically acceptable salt thereof.
  • a compound i (Compound 131A/131B), or a pharmaceutically acceptable salt thereof.
  • a compound is Compound 131A, or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound 131B, or a pharmaceutically acceptable salt thereof. [0475] In embodiments, a compound (Compound 132A/132B), or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound 132A, or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound 132B, or a pharmaceutically acceptable salt thereof. [0476] In embodiments, a compound (Compound 133A/133B), or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound 133A, or a pharmaceutically acceptable salt thereof.
  • a compound is Compound 133B, or a pharmaceutically acceptable salt thereof.
  • a compound is Compound 134A, or a pharmaceutically acceptable salt thereof.
  • a compound is Compound 134B, or a pharmaceutically acceptable salt thereof.
  • a compound is Compound 135A, or a pharmaceutically acceptable salt thereof.
  • a compound is Compound 135B, or a pharmaceutically acceptable salt thereof.
  • a compound i (Compound 136A/136B), or a pharmaceutically acceptable salt thereof.
  • a compound is Compound 136A, or a pharmaceutically acceptable salt thereof.
  • a compound is Compound 136B, or a pharmaceutically acceptable salt thereof.
  • a compound i (Compound 137A/137B), or a pharmaceutically acceptable salt thereof.
  • a compound is Compound 137A, or a pharmaceutically acceptable salt thereof.
  • a compound is Compound 137B, or a pharmaceutically acceptable salt thereof.
  • a compound i (Compound 138A/138B), or a pharmaceutically acceptable salt thereof.
  • a compound is Compound 138A, or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound 138B, or a pharmaceutically acceptable salt thereof. [0482] In embodiments, a compound is pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound 139A, or a pharmaceutically acceptable salt thereof. In embodiments, a compound is 139B, or a pharmaceutically acceptable salt thereof. [0483] In embodiments, a compound i (Compound 140A/140B) , or a pharmaceutically acceptable salt thereof. In embodiments, a compound is Compound 140A, or a pharmaceutically acceptable salt thereof. In embodiments, a compound is 140B, or a pharmaceutically acceptable salt thereof.
  • Compounds described herein can comprise atoms that exhibit their natural isotopic abundances, or one or more of the atoms may be artificially enriched in a particular isotope having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number predominately found in nature.
  • isotopologue refers to a species that has the same chemical structure and formula as a specific compound provided herein, with the exception of the positions of isotopic substitution and/or level of isotopic enrichment at one or more positions, e.g., hydrogen vs. deuterium.
  • the present invention is meant to include all suitable isotopic variations of the compounds of the compounds described herein.
  • H isotopic forms of hydrogen
  • different isotopic forms of hydrogen (H) include protium ( 1 H), deuterium ( 2 H), and tritium ( 3 H), as well as compositions enriched in isotopologues of any compound described herein.
  • one or more of the hydrogens of the compounds described herein is replaced by a deuterium.
  • a position is designated as “H” or “hydrogen”, the position is understood to have hydrogen at its natural abundance isotopic composition.
  • the position is understood to have deuterium at an abundance that is at least 3340 times greater than the natural abundance of deuterium, which is 0.015% (i.e., the term “ 2 H” or “deuterium” indicates at least 50.1% incorporation of deuterium). Accordingly, the invention also features compositions enriched in deuterated compounds.
  • compositions of any compound provided herein may have an isotopic enrichment factor for each deuterium present at a site designated as a potential site of deuteration on the compound of at least 3500 (52.5% deuterium incorporation), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation).
  • compositions Compounds described herein (e.g., compounds of any one of Formulas (I)-(VI)) or pharmaceutically acceptable salts thereof can be formulated in various pharmaceutical compositions.
  • a compound described herein e.g., a compound of Formula (I) (including compounds of Formulas (II)-(VI) and any compound of Table 1 as provided herein), as well as pharmaceutically acceptable salts thereof, may be the active pharmaceutical ingredient (API) combined with one or more other ingredients to form a drug substance pharmaceutical composition.
  • the drug substance (DS) pharmaceutical composition can comprise the API (e.g., a compound of Formula (I) or pharmaceutically acceptable salt thereof) and one or more pharmaceutically acceptable carriers, diluents, and/or excipients.
  • the carrier(s), diluent(s) or excipient(s) can be selected to be compatible with the other ingredients of the formulation and appropriately safe and effective for an intended therapy.
  • a desired weight concentration of a compound described herein (e.g., a compound of Formula (I)) or a pharmaceutically acceptable salt thereof as the active pharmaceutical ingredient (API) can be combined with the other inactive ingredients to form a drug substance (DS) in a formulation batch.
  • Pharmaceutically acceptable compositions can be formulated for administration by an appropriate route, for example by the oral delivery (including as a capsule or tablet) in unit dosage forms. Such compositions may be prepared by bringing into association the active pharmaceutical ingredient (API) comprising a compound of Formula (I) with the carrier(s) or excipient(s).
  • the invention provides a pharmaceutical composition formulated for oral delivery of an ⁇ 4 ⁇ 7 integrin integrin inhibitor, the composition comprising the ⁇ 4 ⁇ 7 integrin inhibitor compound described herein (e.g., a compound of any one of Formulas (I)- (VI) such as any compound of Table 1, or a pharmaceutically acceptable salt thereof) as an API and a pharmaceutically acceptable carrier formulated for oral therapeutic administration of the ⁇ 4 ⁇ 7 integrin inhibitor compound.
  • the invention provides a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof as the active pharmaceutical ingredient (API).
  • the invention provides a pharmaceutical composition comprising a compound of Formula (II), or a pharmaceutically acceptable salt thereof as the active pharmaceutical ingredient (API).
  • the invention provides a pharmaceutical composition comprising a compound of Formula (IIA), or a pharmaceutically acceptable salt thereof as the active pharmaceutical ingredient (API).
  • the invention provides a pharmaceutical composition comprising a compound of Formula (IIB), or a pharmaceutically acceptable salt thereof as the active pharmaceutical ingredient (API).
  • the invention provides a pharmaceutical composition comprising a compound of Formula (III), or a pharmaceutically acceptable salt thereof as the active pharmaceutical ingredient (API).
  • the invention provides a pharmaceutical composition comprising a compound of Formula (IIIA), or a pharmaceutically acceptable salt thereof as the active pharmaceutical ingredient (API).
  • the invention provides a pharmaceutical composition comprising a compound of Formula (IIIB), or a pharmaceutically acceptable salt thereof as the active pharmaceutical ingredient (API).
  • the invention provides a pharmaceutical composition comprising a compound of Formula (IV), or a pharmaceutically acceptable salt thereof as the active pharmaceutical ingredient (API).
  • the invention provides a pharmaceutical composition comprising a compound of Formula (IVA), or a pharmaceutically acceptable salt thereof as the active pharmaceutical ingredient (API).
  • the invention provides a pharmaceutical composition comprising a compound of Formula (IVB), or a pharmaceutically acceptable salt thereof as the active pharmaceutical ingredient (API).
  • the invention provides a pharmaceutical composition comprising a compound of Formula (V), or a pharmaceutically acceptable salt thereof as the active pharmaceutical ingredient (API).
  • the invention provides a pharmaceutical composition comprising a compound of Formula (VA), or a pharmaceutically acceptable salt thereof as the active pharmaceutical ingredient (API).
  • the invention provides a pharmaceutical composition comprising a compound of Formula (VB), or a pharmaceutically acceptable salt thereof as the active pharmaceutical ingredient (API).
  • the invention provides a pharmaceutical composition comprising a compound of Formula (VI), or a pharmaceutically acceptable salt thereof as the active pharmaceutical ingredient (API).
  • the invention provides a pharmaceutical composition comprising a compound of Table 1, or a pharmaceutically acceptable salt thereof as the active pharmaceutical ingredient (API).
  • Pharmaceutically acceptable compositions comprising a compound described herein (e.g., a compound of Formula (I)) or a pharmaceutically acceptable salt thereof can be prepared by various procedures.
  • the compounds of Formula (I) can be formulated with suitable excipients, diluents, or carriers, and formed into tablets, or capsules, and other suitable dosage forms.
  • compositions can be provided in unit dose forms containing a predetermined amount of API comprising a compound described herein (e.g., a compound of Formula (I)) or a pharmaceutically acceptable salt thereof per unit dose.
  • a unit may contain, a desired amount of a compound (e.g., a compound of the Formula (I)) or pharmaceutically acceptable salt thereof, depending on the condition being treated, the route of administration and the age, weight and condition of the patient.
  • Such unit doses may therefore be administered at a desired dose interval.
  • concentration of active compound in the drug composition will depend on various applicable parameters and considerations such as the absorption, inactivation and excretion rates of the drug as well as other factors known to those of skill in the art.
  • dosage values will also vary with the severity of the condition to be alleviated. It is to be further understood that for any particular subject, specific dosage regimens should be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the compositions, and that the concentration ranges set forth herein are exemplary only and are not intended to limit the scope or practice of the claimed composition.
  • the active ingredient can be administered at once, or can be divided into a number of smaller doses to be administered at varying intervals of time.
  • the mode of administration of the active compound is oral.
  • Oral compositions will generally include an inert diluent or an edible carrier. They can be enclosed in gelatin capsules or compressed into tablets.
  • the active compound can be incorporated with excipients and used in the form of tablets, troches or capsules.
  • Pharmaceutically compatible binding agents, and/or adjuvant materials can be included as part of the composition.
  • Pharmaceutical compositions comprising a compound described herein (e.g., a compound of Formula (I)) or a pharmaceutically acceptable salt thereof formulated for oral delivery can be prepared in a unit dosage form, such as a capsule at a desired dosage strength (e.g., of the compound of Formula (I) or a pharmaceutically acceptable salt thereof).
  • the oral drug components can be combined with any oral, non-toxic, pharmaceutically acceptable inert carrier such as ethanol, glycerol, water and the like.
  • a compound described herein e.g., a compound of Formula (I)
  • a pharmaceutically acceptable salt thereof can be combined with an oral, non-toxic, pharmaceutically acceptable, inert carrier.
  • excipients, diluents, and carriers that are suitable for such formulations include the following: fillers and extenders such as starch, and sugars; and binding agents such as cellulose derivatives.
  • suitable binders, lubricants, disintegrating agents and coloring agents can also be incorporated into the mixture.
  • suitable binders include starch, natural sugars, natural and synthetic gums, and the like. Lubricants and/or glidants can be used in these dosage forms.
  • the tablets, pills, capsules, troches and the like can contain any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel or corn starch; a lubricant such as magnesium stearate or Sterotes; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring.
  • a binder such as microcrystalline cellulose, gum tragacanth or gelatin
  • an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel or corn starch
  • a lubricant such as magnesium stearate or Sterotes
  • a glidant such as colloidal silicon dioxide
  • a sweetening agent such
  • the dosage unit form When the dosage unit form is a capsule, it can contain, in addition to material of the above type, a liquid carrier such as a fatty oil.
  • unit dosage forms can contain various other materials that modify the physical form of the dosage unit, for example, coatings of sugar, or other enteric agents.
  • the compound can be administered as a component of an elixir, suspension, syrup, wafer, or the like.
  • a syrup can contain, in addition to the active compound(s), sucrose or sweetener as a sweetening agent and certain preservatives, dyes and colorings and flavors.
  • the compounds can be formulated as solutions appropriate for parenteral administration, for example, by intramuscular, subcutaneous or intravenous routes.
  • a compound described herein e.g., a compound of Formula (I)
  • a pharmaceutically acceptable salt thereof can be dissolved in a suitable buffer.
  • a pharmaceutical composition comprising a desired concentration of a compound described herein (e.g., a compound of Formula (I)) or a pharmaceutically acceptable salt thereof can be formulated as an injectable drug solution in (useful, e.g., in preclinical animal studies).
  • Exemplary Therapeutic Methods Compounds described herein can be useful for the treatment of various diseases and disorders that benefit from antagonizing the integrin ⁇ v ⁇ 8 .
  • inhibiting the integrin ⁇ v ⁇ 8 -driven TGF ⁇ activation is proposed to reverse tumor tolerance and enhance anti-tumor T/NK cell responses.
  • ⁇ v ⁇ 8 inhibition can enhance outcomes in checkpoint inhibitors regimens or reverse checkpoint inhibitor resistance.
  • a compound described herein can modulate an anti-tumor immune response (e.g., in checkpoint-inhibitor resistant tumors).
  • the invention features a method of inhibiting ⁇ v ⁇ 8 integrin in a patient, said method comprising administering to a patient in need thereof a therapeutically effective amount of a compound described herein (e.g., a compound of any one of Formulas (I)- (VI) such as any compound of Table 1) or a pharmaceutically acceptable salt thereof.
  • a compound described herein e.g., a compound of any one of Formulas (I)- (VI) such as any compound of Table 1
  • a pharmaceutically acceptable salt thereof e.g., a compound of any one of Formulas (I)- (VI) such as any compound of Table 1
  • the invention features a method of treating a cancer (e.g., a solid tumor) in a patient, said method comprising administering to a patient in need thereof a therapeutically effective amount of a compound described herein (e.g., a compound of any one of Formulas (I)-(VI) such as any compound of Table 1) or a pharmaceutically acceptable salt thereof.
  • a method further comprises administration of a therapeutically effective amount of a second active agent.
  • Solid Tumors [0513] In embodiments, administration of a compound described herein (e.g., a compound of any one of Formulas (I)-(VI) such as any compound of Table 1) or a pharmaceutically acceptable salt thereof can be useful for treating a solid tumor in a patient in need thereof, optionally in combination with one or more additional therapies (e.g., a second active agent).
  • a solid tumor is resistant to one or more previous lines of therapy (e.g., a solid tumor is a treatment-resistant tumor). In embodiments, a solid tumor is resistant to immune checkpoint therapy.
  • a cancer is a solid tumor such as fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma, endotheliosarcoma, lymphangiosarcoma, lymphangioendotheliosarcoma, synovioma, mesothelioma, Ewing’s tumor, leiomyosarcoma, rhabdomyosarcoma, osteosarcoma, colon cancer, colorectal cancer, kidney cancer, pancreatic cancer, bone cancer, breast cancer, ovarian cancer, prostate cancer, esophageal cancer, stomach cancer, oral cancer, nasal cancer, throat cancer, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinomas, cystadenocarcinoma,
  • a solid tumor is an advanced stage solid tumor (e.g., a locally advanced solid tumor).
  • a solid tumor is a metastatic solid tumor.
  • a cancer e.g., solid tumor
  • SCCHN squamous cell carcinoma of the head and neck
  • a cancer e.g., solid tumor
  • a cancer is breast cancer, squamous cell carcinoma of the head and neck (SCCHN), renal cell carcinoma, ovarian cancer, gastric cancer, esophageal cancer, lung cancer, pancreatic cancer, bile duct cancer, endometrial cancer, melanoma, or urothelial carcinoma.
  • a cancer e.g., a solid tumor
  • a cancer is advanced (e.g., locally advanced).
  • a cancer e.g., a solid tumor
  • a cancer is metastatic.
  • a cancer is anal cancer.
  • a cancer e.g., solid tumor
  • a cancer is bile duct cancer (cholangiocarcinoma).
  • a cancer e.g., solid tumor
  • bladder cancer e.g., bladder cancer.
  • a cancer e.g., solid tumor
  • breast cancer e.g., solid tumor
  • a cancer e.g., solid tumor
  • cervical cancer e.g., solid tumor
  • colorectal cancer ectal cancer.
  • a cancer e.g., solid tumor
  • a cancer e.g., solid tumor
  • a cancer is endometrial cancer.
  • a cancer e.g., solid tumor
  • an esophageal cancer is adenocarcinoma. In embodiments, an esophageal cancer is squamous cell carcinoma.
  • a cancer e.g., solid tumor
  • a cancer is fallopian tube cancer.
  • a cancer e.g., solid tumor
  • gastric cancer e.g., gastric cancer.
  • a cancer e.g., solid tumor
  • a cancer e.g., solid tumor
  • glioma e.g., solid tumor
  • a cancer (e.g., solid tumor) is liver cancer. In embodiments, a liver cancer is hepatocellular carcinoma.
  • a cancer e.g., solid tumor
  • lung cancer e.g., adenocarcinoma.
  • a cancer squamous cell carcinoma.
  • a cancer e.g., solid tumor
  • a cancer e.g., solid tumor
  • gastric cancer e.g., gastric cancer.
  • a lung cancer is squamous cell carcinoma of the lung.
  • a lung cancer is non small cell lung cancer (NSCLC).
  • NSCLC non small cell lung cancer
  • a cancer e.g., solid tumor
  • a cancer e.g., solid tumor
  • a cancer e.g., solid tumor
  • a cancer is neuroblastoma.
  • a cancer e.g., solid tumor
  • osteosarcoma is osteosarcoma.
  • a cancer e.g., solid tumor
  • a cancer e.g., solid tumor
  • a cancer is pancreatic cancer.
  • a cancer e.g., solid tumor
  • a cancer is primary peritoneal carcinoma.
  • a cancer e.g., solid tumor
  • prostate cancer e.g., a cancer (e.g., solid tumor)
  • a cancer e.g., solid tumor
  • RCC renal cell carcinoma
  • a renal cell carcinoma is clear cell renal cell carcinoma (ccRCC).
  • a renal cell carcinoma is papillary renal cell carcinoma (PRCC).
  • a cancer e.g., solid tumor
  • skin cancer e.g., skin cancer.
  • a skin cancer is cutaneous squamous cell carcinoma (CSCC). In embodiments, a skin cancer is basal cell carcinoma (BCC).
  • a cancer e.g., solid tumor
  • SCCHN head and neck
  • a cancer e.g., solid tumor
  • SCCHN head and neck
  • a cancer e.g., solid tumor
  • a cancer e.g., solid tumor
  • SCCHN head and neck
  • a cancer e.g., solid tumor
  • a cancer is testicular cancer.
  • a cancer e.g., solid tumor
  • a cancer is urothelial carcinoma.
  • a cancer e.g., solid tumor
  • a patient has a cancer (e.g., a solid tumor such as those described herein) that is therapy resistant.
  • a therapy resistant cancer e.g., a solid tumor
  • checkpoint resistant e.g., a therapy resistant cancer (e.g., a solid tumor)
  • a therapy resistant cancer e.g., a solid tumor
  • is resistant to an anti-PD-1 or anti-PD-L1 therapy collectively, a PD-(L)1 resistant cancer.
  • a compound described herein e.g., a compound of any one of Formulas (I)-(VI) such as any compound of Table 1 or a pharmaceutically acceptable salt thereof, may be used in combination therapies.
  • administration of a compound or pharmaceutically acceptable salt described herein enhances response to one or more additional therapies (e.g., a second active agent).
  • administration of a compound or pharmaceutically acceptable salt described herein can improve response to additional therapy (e.g., a second active agent).
  • a compound or pharmaceutically acceptable salt described herein may be administered in combination with one or more additional therapies (e.g., a second active agent) in the treatment of certain diseases and disorders.
  • a compound or pharmaceutically acceptable salt described herein may be administered in combination with an immunotherapy.
  • an immunotherapy is a cancer immunotherapy.
  • a cancer immunotherapy is an immune checkpoint therapy (e.g., therapy comprising administration of an immune checkpoint inihbitor).
  • a cancer immunotherapy is a cellular immunotherapy such as adoptive T cell transfer therapy (e.g., Chimeric Antigen Receptor (CAR) T cell therapy, CAR natural killer (NK) cell therapy, tumor infiltrating lymphocyte (TIL) therapy, or endogenous T cell (ETC) therapy).
  • adoptive T cell transfer therapy e.g., Chimeric Antigen Receptor (CAR) T cell therapy, CAR natural killer (NK) cell therapy, tumor infiltrating lymphocyte (TIL) therapy, or endogenous T cell (ETC) therapy.
  • a cancer immunotherapy is a cancer vaccine.
  • a cancer immunotherapy is monoclonal antibody therapy (e.g., an antibody useful for immune checkpoint therapy such as those described herein).
  • a cancer immunotherapy is cytokine therapy (e.g., interferon or interleukin therapy).
  • cytokine therapy e.g., interferon or interleukin therapy.
  • a compound or pharmaceutically acceptable salt described herein is administered with a second active agent to a patient in need thereof for the treatment of a solid tumor (e.g., as described herein).
  • a second active agent is an immune checkpoint inhibitor.
  • an immune checkpoint inhibitor targets PD-1 (e.g., inhibition via anti-PD-1, anti- PD-L1, or anti-PD-L2 therapies), CTLA-4, TIM-3, TIGIT, LAGs (e.g., LAG-3), CEACAM (e.g., CEACAM-1, -3 and/or -5), VISTA, BTLA, LAIR1, CD160, 2B4, CD80, CD86, B7-H3 (CD276), B7-H4 (VTCN1), HVEM (TNFRSF14 or CD270), KIR, A2aR, MHC class I, MHC class II, GALS, adenosine, TGFR (e.g., TGFR beta), B7-H1, B7-H4 (VTCN1), OX-40, CD137, CD40, IDO, or CSF-1/CSF-1R.
  • PD-1 e.g., inhibition via anti-PD-1, anti- PD-L1, or anti-PD-L2 therapies
  • a checkpoint inhibitor is a small molecule, a nucleic acid, a polypeptide (e.g., an antibody), a carbohydrate, a lipid, a metal, a toxin, or a binding agent.
  • a checkpoint inhibitor is an antibody, an antibody conjugate, or an antigen-binding fragment thereof.
  • an immune checkpoint inhibitor is an agent that inhibits PD-1, TIM- 3, CTLA-4, LAG-3, TIGIT, IDO or CSF-1/CSF-1R.
  • an immune checkpoint inhibitor is selected from: pembrolizumab (Keytruda®), nivolumab (Opdivo®), cemiplimab (Libtayo®), dostarlimab (Jemperli®), atezolizumab (Tecentriq®), avelumab (Bavencio®), durvalumab (Imfinzi®), ipilimumab (Yervoy®), and relatlimab, as well as biosimilars thereof.
  • a second active agent is an anti-PD-1 therapy or an anti-PD-L1 therapy (collectively referred to as anti-PD(L)-1 therapy).
  • an anti-PD(L)-1 therapy is selected from the group consisting of: pembrolizumab, nivolumab, cemiplimab, dostarlimab, atezolizumab, avelumab, durvalumab, PDR001, Cemiplimab, BGB-A317, LY3300054, BI 754091, IBI308, INCSHR-1210, JNJ-63723283, JS-001, MEDI0680 (AMP-514), MGA-012, PF-06801591, CX-072, FAZ053, and PD-L1 millamolecule, as well as biosimilars thereof.
  • an anti-PD(L)-1 therapy is selected from atezolizumab, avelumab, BGB-A317, BI 754091, CX-072, durvalumab, FAZ053, IBI308, INCSHR-1210, JNJ-63723283, JS-001, MEDI-0680, MGA-012, nivolumab, PDR001, pembrolizumab, PF-06801591, cemiplimab, dostarlimab, any of the antibodies disclosed in WO2014/179664, as well as biosimilarsthereof.
  • an anti-PD(L)-1 therapy is selected from the group consisting of BGB-A317, BI 754091, CX-072, FAZ053, IBI308, INCSHR-1210, JNJ-63723283, JS-001, LY3300054, MEDI-0680, MGA-012, nivolumab, PD-L1 millamolecule, PDR001, pembrolizumab, PF-06801591, cemiplimab, and dostarlimab, as well as biosimilars thereof.
  • an anti-PD(L)-1 therapy is selected from pembrolizumab, nivolumab, atezolizumab, durvalumab, avelumab, dostarlimab, PDR-001, tislelizumab (BGB- A317), cemiplimab (REGN2810), LY-3300054, JNJ-63723283, MGA012, BI-754091, IBI-308, camrelizumab (HR-301210), BCD-100, JS-001, CX-072, BGB-A333, AMP-514 (MEDI-0680), AGEN-2034, CS1001, Sym-021, SHR-1316, PF-06801591, LZM009, KN-035, AB122, genolimzumab (CBT-501), FAZ-053, CK-301, AK 104, GLS-010, JTX-4014, SHR-1210, AMP-
  • an anti-PD(L)-1 therapy is selected from durvalumab, atezolizumab, avelumab, BGB-A333, SHR-1316, FAZ-053, CK-301, and PD-L1 millamolecule, or derivatives thereof.
  • an anti-PD(L)-1 therapy is selected from nivolumab, pembrolizumab, cemiplimab, dostarlimab, atezolizumab, avelumab, and durvalumab.
  • an anti-PD(L)-1 therapy is selected from nivolumab, pembrolizumab, cemiplimab, and dostarlimab.
  • an anti-PD(L)-1 therapy is selected from atezolizumab, avelumab, and durvalumab.
  • a second active agent is an anti-CTLA-4 therapy.
  • an anti-CTLA-4 therapy is ipilimumab.
  • a second active agent is an anti-LAG-3 therapy.
  • an anti-LAG-3 therapy is selected from: LAG525 (IMP701), REGN3767 (R3767), BI 754,091, tebotelimab (MGD013), eftilagimod alpha (IMP321), TSR-033, and FS118.
  • a second active agent is an anti-TIM-3 therapy.
  • an anti-TIM-3 therapy is selected from: MBG453, Sym023, and TSR-022.
  • a second active agent is an anti-CSF-1/R therapy.
  • an anti-CSF-1/R therapy is selected from: lacnotuzumab (MCS110), LY3022855, SNDX-6352, emactuzumab (RG7155), and pexidartinib (PLX3397).
  • a second active agent is an anti-TIGIT therapy.
  • an anti-TIGIT therapy is selected from: BMS-986207, ociperlimab, tiragolumab, vibostolimab, domvanalimab, EOS448, COM902, and AGEN307.
  • a second active agent is an anti-CEACAM therapy.
  • an anti-TIGIT therapy is selected from: CM24 and NEO-201.
  • HNMR instrumental information [0569] Proton nuclear magnetic resonance (NMR) spectra were obtained on either Bruker or Varian spectrometers at 400 MHz. Spectra are given in ppm (d) and coupling constants, J, are reported in Hertz. Tetramethylsilane (TMS) was used as an internal standard. LCMS instrumental information and analysis method: [0570] Mass spectra were collected using an Agilent 6120 Single Quad Mass Spectrometer (ESI).
  • ESI Agilent 6120 Single Quad Mass Spectrometer
  • Method A Column: Kinetex C182.1 x 50 mm, 5 um; Flow rate 1.0 mL/min; Mobile phase A: water with 0.04% TFA, Mobile phase B: acetonitrile with 0.02% trifluoroacetic acid; Gradient: 5% B from 0-0.40 min, then a gradient of 5-95% B over 2.60 min, then hold on 95% B for 1.00 min, then 95-5% B over 0.01 min.
  • Method B Column: Xbridge C182.1 x 50 mm column (5 um particles); Flow rate 0.8 mL/min; Mobile phase A: water with 10 mM NH 4 HCO 3 ; Mobile phase B: acetonitrile; Gradient: 5% B from 0-0.40 min, then a gradient of 5-95% B from 0.40-3.40 min, then hold 95% B for 0.45 min, then 95-5% B over 0.01 min.
  • Preparative Chiral HPLC method Instruments: Gilson-281 semi preparative HPLC system; UV: Gilson-156 UV [0593] Conditions: Mobile Phase A: n-heptane; Mobile Phase B: ethanol with 0.1% ammonium hydroxide (or 2-propanol with 0.1% ammonium hydroxide, or ethanol with 0.1% TFA, or 2-propanol with 0.1% TFA).
  • Step 2 tert-butyl 7-(5-((tert-butyldiphenylsilyl)oxy)pentyl)-3,4-dihydro-1,8-naphthyridine- 1(2H)-carboxylate [0610] To a solution of tert-butyl(pent-4-en-1-yloxy)diphenylsilane (18.11 g, 55.82 mmol) in THF (60 mL) was added 9-BBN (0.5 M in THF, 163.73 mL), the reaction was stirred at 30 °C for 12 h.
  • Step 3 tert-butyl 7-(5-hydroxypentyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxylate [0611] To a solution of tert-butyl 7-(5-((tert-butyldiphenylsilyl)oxy)pentyl)-3,4-dihydro-1,8- naphthyridine-1(2H)-carboxylate (11 g, 19.68 mmol) in THF (400 mL) was added TBAF (1 M in THF, 78.74 mL), the mixture was stirred at 50 °C for 16 h.
  • Step 4 tert-butyl 7-(5-oxopentyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxylate [0612] To a solution of oxalyl dichloride (11.88 g, 93.63 mmol, 8.20 mL) in DCM (80 mL) was added DMSO (7.32 g, 93.63 mmol, 7.32 mL) at -70 °C, after stirred at -70 °C for 10 min, a solution of compound 5 (10 g, 31.21 mmol) in DCM (20 mL) was added dropwise at -70 °C.
  • tert-butyl 7-(5-oxopentyl)-3,4-dihydro-1,8-naphthyridine- 1(2H)-carboxylate (6.5 g, 20.41 mmol, 65.41% yield) was obtained as a yellow oil.
  • Step 2 tert-butyl (R)-3-((2,2,2-trifluoroethyl)amino)pyrrolidine-1-carboxylate
  • BH3 ⁇ THF 1 M in THF, 32.95 mL
  • Step 4 (R)-N-(5-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)pentyl)-N-(2,2,2- trifluoroethyl)pyrrolidin-3-amine [0616] To a solution of tert-butyl (R)-7-(5-((1-(tert-butoxycarbonyl)pyrrolidin-3-yl)(2,2,2- trifluoroethyl)amino)pentyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxylate (400 mg, 700.91 umol) in MeOH (3 mL) was added HCl/MeOH (4 M, 6 mL) and the mixture was stirred at 25 °C for 12 h.
  • Step 2 phenyl (E)-2-(5-hydroxypent-2-en-1-yl)-1,8-naphthyridine-1(2H)-carboxylate [0618] (1,3-Bis(2,4,6-trimethylphenyl)-2- imidazolidinylidene)dichloro(phenylmethylene)(tricyclohexylphosphine)ruthenium (1.45 g, 1.71 mmol) was added to a solution of phenyl 2-allyl-1,8-naphthyridine-1(2H)-carboxylate (10 g, 34.21 mmol) and but-3-en-1-ol (12.33 g, 171.04 mmol, 14.72 mL) in DCM (200 mL) at 25 °C.
  • Step 3 Mixture of phenyl 2-(5-hydroxypentyl)-3,4-dihydro-1,8-naphthyridine-1(2H)- carboxylate and methyl 2-(5-hydroxypentyl)-3,4-dihydro-1,8-naphthyridine-1(2H)- carboxylate [0619] To a suspension of Pd/C (3 g, 10 wt% loading) in MeOH (300 mL) was added phenyl (E)-2-(5-hydroxypent-2-en-1-yl)-1,8-naphthyridine-1(2H)-carboxylate (9.5 g, 28.24 mmol) under argon atmosphere.
  • Step 4 methyl 2-(5-hydroxypentyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxylate [0620] To a solution of a mixture of phenyl 2-(5-hydroxypentyl)-3,4-dihydro-1,8- naphthyridine-1(2H)-carboxylate and methyl 2-(5-hydroxypentyl)-3,4-dihydro-1,8-naphthyridine- 1(2H)-carboxylate (8 g, 23.50 mmol) in MeOH (80 mL) was added sodium methoxide (2.54 g, 47.00 mmol) and the mixture was stirred at 25 °C for 16 h.
  • Step 5 methyl 2-(5-bromopentyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxylate
  • THF tetrachromomethane
  • Step 6 methyl 2-(5-(((R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl)(methyl)amino)pentyl)-3,4- dihydro-1,8-naphthyridine-1(2H)-carboxylate [0622] To a solution of methyl 2-(5-bromopentyl)-3,4-dihydro-1,8-naphthyridine-1(2H)- carboxylate (4.9 g, 8.33 mmol, 58% purity), tert-butyl (R)-3-(methylamino)pyrrolidine-1- carboxylate (1.7 g, 8.49 mmol) in toluene (40 mL) was added a solution of NaOH (3.33 g, 83.28 mmol) in water (40 mL) and tetrabutylammonium bromide (TBAB) (268.48 mg, 832.84 umol).
  • Racemic tert-butyl (3R)-3-(methyl(5-(1,2,3,4-tetrahydro-1,8-naphthyridin-2- yl)pentyl)amino)pyrrolidine-1-carboxylate (2.1 g, 5.22 mmol) was separated by SFC (column: Regis (S, S) Whelk-O1 (250 mm x 25 mm x 10 um); mobile phase: [0.1% NH3water IPA]; B%: 45%-45%, 5 min) to give two peaks: [0625] Peak 1, arbitrarily assigned as tert-butyl (R)-3-(methyl(5-((S)-1,2,3,4-tetrahydro-1,8- naphthyridin-2-yl)pentyl)amino)pyrrolidine-1-carboxylate (800 mg, 1.99 mmol, 76.19% yield) was obtained as a yellow oil.
  • Step 8 (R)-N-methyl-N-(5-((S)-1,2,3,4-tetrahydro-1,8-naphthyridin-2-yl)pentyl)pyrrolidin- 3-amine
  • R tert-butyl
  • R -3-(methyl(5-((S)-1,2,3,4-tetrahydro-1,8-naphthyridin-2- yl)pentyl)amino)pyrrolidine-1-carboxylate (800 mg, 1.99 mmol) in HCl/MeOH (4 M, 20 mL) was stirred at 50 °C for 16 h then was concentrated in vacuum.
  • Step 2 tert-butyl (R)-7-(5-((1-(tert-butoxycarbonyl)pyrrolidin-3-yl)(2,2- difluoroethyl)amino)pentyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxylate [0630] To a solution of tert-butyl (R)-7-(5-((1-(tert-butoxycarbonyl)pyrrolidin-3- yl)amino)pentyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxylate (1.25 g, 2.56 mmol) and 2,2- difluoroethyl trifluoromethanesulfonate (1.64 g, 7.67 mmol) in DMF (10 mL) was added TEA (1.04 g, 10.23 mmol, 1.42 mL
  • Step 3 (R)-N-(2,2-difluoroethyl)-N-(5-(5,6,7,8-tetrahydro-1,8-naphthyridin-2- yl)pentyl)pyrrolidin-3-amine
  • R tert-butyl
  • R-7-(5-((1-(tert-butoxycarbonyl)pyrrolidin-3-yl)(2,2- difluoroethyl)amino)pentyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxylate 300 mg, 542.79 umol
  • HCl/MeOH 4 M, 10 mL
  • Step 2 tert-butyl (R)-7-(5-((1-(tert-butoxycarbonyl)pyrrolidin-3-yl)(3-methoxy-3- methylbutyl)amino)pentyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxylate [0633] To a solution of tert-butyl (R)-7-(5-((1-(tert-butoxycarbonyl)pyrrolidin-3- yl)amino)pentyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxylate (880.37 mg, 1.80 mmol) and sodium triacetoxyborohydride (1.15 g, 5.40 mmol) in DCM (14 mL) was added 3-methoxy-3- methylbutanal (837.08 mg, 7.21 mmol) at 25 o C.
  • Step 2 phenyl 2-(6-hydroxyhexyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxylate [0636] To a stirred mixture of Pd/C (3 g, 10 wt% loading) in MeOH (350 mL) was added phenyl (E)-2-(6-hydroxyhex-2-en-1-yl)-1,8-naphthyridine-1(2H)-carboxylate (12.5 g, 35.67 mmol) under argon atmosphere. The suspension was degassed and purged with hydrogen for 3 times. The mixture was stirred under hydrogen (50 psi) at 50 °C for 16 h.
  • Step 3 phenyl 2-(6-bromohexyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxylate
  • phenyl 2-(6-hydroxyhexyl)-3,4-dihydro-1,8-naphthyridine-1(2H)- carboxylate 8.2 g, 23.13 mmol
  • triphenylphosphine 9.04 g, 34.47 mmol
  • tetrabromomethane 11.51 g, 34.70 mmol
  • Step 5 tert-butyl (3R)-3-(methyl(6-(1,2,3,4-tetrahydro-1,8-naphthyridin-2- yl)hexyl)amino)pyrrolidine-1-carboxylate
  • phenyl 2-(6-(((R)-1-(tert-butoxycarbonyl)pyrrolidin-3- yl)(methyl)amino)hexyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxylate (3.8 g, 7.08 mmol) in THF (40 mL) was added t-BuOK (1.19 g, 10.62 mmol) at 0 °C.
  • Peak 2 arbitrarily assigned as tert-butyl (R)-3-(methyl(6-((R)-1,2,3,4-tetrahydro-1,8- naphthyridin-2-yl)hexyl)amino)pyrrolidine-1-carboxylate (520 mg, 1.25 mmol, 47.3% yield) was obtained as a white solid.
  • SFC: Rt 2.720 min, 98.84%.
  • Step 6 (R)-N-methyl-N-(6-((S)-1,2,3,4-tetrahydro-1,8-naphthyridin-2-yl)hexyl)pyrrolidin-3- amine
  • tert-butyl (R)-3-(methyl(6-((S)-1,2,3,4-tetrahydro-1,8-naphthyridin-2- yl)hexyl)amino)pyrrolidine-1-carboxylate 500 mg, 1.20 mmol
  • HCl/MeOH 4 M, 9.62 mL
  • Step 2 ethyl 2-(4-((tert-butyldiphenylsilyl)oxy)but-1-yn-1-yl)-1,8-naphthyridine-1(2H)- carboxylate
  • i-PrMgCl ⁇ LiCl 1.3 M, 500.92 mL
  • Step 3 ethyl 2-(4-((tert-butyldiphenylsilyl)oxy)butyl)-3,4-dihydro-1,8-naphthyridine-1(2H)- carboxylate [0647] To a suspension of Pd/C (7 g, 10 wt% loading) in EtOH (50 mL) was added a solution of ethyl 2-(4-((tert-butyldiphenylsilyl)oxy)but-1-yn-1-yl)-1,8-naphthyridine-1(2H)- carboxylate (25 g, 48.95 mmol) in THF (50 mL) and EtOH (450 mL) under argon at 20 o C.
  • the mixture was stirred at 25 °C for 12 h.
  • the reaction mixture (three parallel reactions) was quenched by aqueous HCl (1.0 L, 1 M) and extracted with petroleum ether (500 mL).
  • the aqueous phase was added aqueous NaHCO 3 and adjusted the pH of the reaction solution to 6-7 and extracted with ethyl acetate (500 mL x 3), the combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue.
  • the crude product was triturated with ethyl acetate at 25 °C for 0.5 h.
  • Step 7 ethyl 2-(4-(((R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl)(methyl)amino)butyl)-3,4- dihydro-1,8-naphthyridine-1(2H)-carboxylate [0650] To a solution of ethyl 2-(4-bromobutyl)-3,4-dihydro-1,8-naphthyridine-1(2H)- carboxylate (4 g, 11.72 mmol), tert-butyl (R)-3-(methylamino)pyrrolidine-1-carboxylate (2.35 g, 11.72 mmol) in DMF (40 mL) was added DIEA (6.41 g, 49.58 mmol, 8.64 mL).
  • Step 8 tert-butyl (3R)-3-(methyl(4-(1,2,3,4-tetrahydro-1,8-naphthyridin-2- yl)butyl)amino)pyrrolidine-1-carboxylate [0651] To a solution of ethyl 2-(4-(((R)-1-(tert-butoxycarbonyl)pyrrolidin-3- yl)(methyl)amino)butyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxylate (3.64 g, 7.90 mmol) in dioxane (20 mL) was added aqueous NaOH (6 M, 20 mL) and the mixture was stirred at 100 °C for 32 h.
  • tert-butyl (3R)-3-(methyl(4-(1,2,3,4-tetrahydro-1,8-naphthyridin-2- yl)butyl)amino)pyrrolidine-1-carboxylate (2.8 g, 7.21 mmol) was separated by SFC (column: Regis (S,S) Whelk-O1 (250 mm x 25 mm, 10 um); mobile phase: [0.1% NH 3 water IPA]; B%: 40%-40%, 6 min).
  • Peak 1 arbitrarily assigned as tert-butyl (R)-3-(methyl(4-((S)-1,2,3,4-tetrahydro-1,8- naphthyridin-2-yl)butyl)amino)pyrrolidine-1-carboxylate (1.1 g, 2.83 mmol, 78.6% yield) was obtained as a yellow oil.
  • SFC: Rt 2.438 min, 98.66%.
  • Peak 2 arbitrarily assigned as tert-butyl (R)-3-(methyl(4-((R)-1,2,3,4-tetrahydro-1,8- naphthyridin-2-yl)butyl)amino)pyrrolidine-1-carboxylate (880 mg, 2.26 mmol, 62.9% yield) was obtained as a yellow oil.
  • SFC: R t 2.640 min, 98.46%.
  • Step 9 (R)-N-methyl-N-(4-((S)-1,2,3,4-tetrahydro-1,8-naphthyridin-2-yl)butyl)pyrrolidin-3- amine [0655] To a solution of tert-butyl (R)-3-(methyl(4-((S)-1,2,3,4-tetrahydro-1,8-naphthyridin- 2-yl)butyl)amino)pyrrolidine-1-carboxylate (300 mg, 772.11 umol) in DCM (4 mL) was added TFA (2 mL), the mixture was stirred at 25 °C for 16 h. The mixture was concentrated to give crude residue.
  • Step 2 tert-butyl (R)-7-(5-((1-(tert-butoxycarbonyl)pyrrolidin-3- yl)(isopropyl)amino)pentyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxylate
  • tert-butyl (R)-3-(isopropylamino)pyrrolidine-1-carboxylate (1.43 g, 6.28 mmol) and sodium triacetoxyborohydride (2.00 g, 9.42 mmol) in DCM (20 mL) was added a solution of tert-butyl 7-(5-oxopentyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxylate (1 g, 3.14 mmol) in DCM (10 mL) dropwise at 25 o C.
  • Step 3 (R)-N-isopropyl-N-(5-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)pentyl)pyrrolidin-3- amine
  • R tert-butyl
  • Step 2 tert-butyl (R)-7-(5-((1-(tert-butoxycarbonyl)pyrrolidin-3-yl)(3,3,3- trifluoropropyl)amino)pentyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxylate [0661] To a solution of tert-butyl 7-(5-oxopentyl)-3,4-dihydro-1,8-naphthyridine-1(2H)- carboxylate tert-butyl 7-(5-oxopentyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxylate (806.45 mg, 2.53 mmol) and tert-butyl (R)-3-((3,3,3-trifluoropropyl)amino)pyrrolidine-1-carboxylate (650 mg, 2.
  • Step 3 (R)-N-(5-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)pentyl)-N-(3,3,3- trifluoropropyl)pyrrolidin-3-amine
  • R tert-butyl
  • Step 2 tert-butyl 7-(bromoethynyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxylate
  • NBS (344.51 mg, 1.94 mmol) was added portion wise to a solution of tert-butyl 7- ethynyl-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxylate (0.5 g, 1.94 mmol), DBU (294.67 mg, 1.94 mmol, 291.76 uL) in acetonitrile (5 mL) at 20 °C. The mixture was stirred for 1 h at 20 °C.
  • the reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with brine (50 mL), dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to give a residue.
  • the residue was purified by flash silica gel chromatography (ISCO ®; 25 g SepaFlash ® Silica Flash Column, Eluent of 0 ⁇ 50% Ethyl acetate/Petroleum ether gradient @ 100 mL/min).
  • Step 3 tert-butyl (R)-7-(5-((1-(tert-butoxycarbonyl)pyrrolidin-3-yl)(methyl)amino)-5- methylhexa-1,3-diyn-1-yl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxylate [0665] A mixture of tert-butyl 7-(bromoethynyl)-3,4-dihydro-1,8-naphthyridine-1(2H)- carboxylate (0.65 g, 1.93 mmol), tert-butyl (R)-3-(methyl(2-methylbut-3-yn-2- yl)amino)pyrrolidine-1-carboxylate (564.81 mg, 2.12 mmol), CuI (36.71 mg, 192.76 umol), K 2 CO 3 (532.82 mg, 3.86 mmol) in MeOH (10
  • the reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue.
  • the residue was purified by flash silica gel chromatography (ISCO ®; 25 g SepaFlash ® Silica Flash Column, Eluent of 0 ⁇ 100% Ethyl acetate/Petroleum ether gradient @ 100 mL/min).
  • the reaction mixture was diluted with water (150 mL) and extracted with ethyl acetate (100 mL x 3). The combined organic layers were washed with brine (150 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue.
  • the residue was purified by flash silica gel chromatography (ISCO®; 80 g SepaFlash® Silica Flash Column, Eluent of 0 ⁇ 100% Ethyl acetate/Petroleum ether gradient @ 200 mL/min).
  • tert-butyl (R)-3-((2-((tert- butyldimethylsilyl)oxy)ethyl)amino)pyrrolidine-1-carboxylate (10 g, 29.02 mmol, 54.06% yield) was obtained as a yellow oil.
  • Step 2 tert-butyl (R)-3-(((benzyloxy)carbonyl)(2-((tert- butyldimethylsilyl)oxy)ethyl)amino)pyrrolidine-1-carboxylate
  • TEA 2.3 mmol
  • benzyl chloroformate 7.08 g, 41.50 mmol, 5.90 mL
  • tert-butyl (R)-3-(((benzyloxy)carbonyl)(2-((tert- butyldimethylsilyl)oxy)ethyl)amino)pyrrolidine-1-carboxylate (10 g, 20.89 mmol, 65.44% yield) was obtained as colorless oil.
  • Step 3 tert-butyl (R)-3-(((benzyloxy)carbonyl)(2-hydroxyethyl)amino)pyrrolidine-1- carboxylate
  • tert-butyl (R)-3-(((benzyloxy)carbonyl)(2-((tert- butyldimethylsilyl)oxy)ethyl)amino)pyrrolidine-1-carboxylate 8.8 g, 18.38 mmol
  • THF 100 mL
  • TBAF 1 M in THF, 22.06 mL
  • Step 4 tert-butyl (R)-3-(((benzyloxy)carbonyl)(2- (trifluoromethoxy)ethyl)amino)pyrrolidine-1-carboxylate
  • tert-butyl (R)-3-(((benzyloxy)carbonyl)(2- hydroxyethyl)amino)pyrrolidine-1-carboxylate (1 g, 2.74 mmol) were added successively in a nitrogen-filled glovebox.
  • Step 6 tert-butyl (R)-7-(5-((1-(tert-butoxycarbonyl)pyrrolidin-3-yl)(2- (trifluoromethoxy)ethyl)amino)pentyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxylate [0673] To a solution of tert-butyl 7-(5-oxopentyl)-3,4-dihydro-1,8-naphthyridine-1(2H)- carboxylate (578.50 mg, 1.94 mmol), sodium triacetoxyborohydride (865.31 mg, 4.08 mmol) in DCM (10 mL) was added tert-butyl (R)-3-((2-(trifluoromethoxy)ethyl)amino)pyrrolidine-1- carboxylate (650 mg, 2.04 mmol) at 0 °C and the mixture was stir
  • tert-butyl (R)-7-(5-((1- (tert-butoxycarbonyl)pyrrolidin-3-yl)(2-(trifluoromethoxy)ethyl)amino)pentyl)-3,4-dihydro-1,8- naphthyridine-1(2H)-carboxylate 600 mg, 998.82 umol, 48.93% yield was obtained as a yellow oil.
  • Step 3 tert-butyl 7-(5-((3,3-difluoropropyl)amino)pentyl)-3,4-dihydro-1,8-naphthyridine- 1(2H)-carboxylate
  • a solution of 3,3-difluoropropan-1-amine hydrochloride (1.5 g, 11.40 mmol, HCl) in THF (10 mL) was free-based by basic resin and filtered.
  • Step 4 tert-butyl 7-(5-((1-(tert-butoxycarbonyl)pyrrolidin-3-yl)(3,3- difluoropropyl)amino)pentyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxylate [0678] To a solution of tert-butyl 7-(5-((3,3-difluoropropyl)amino)pentyl)-3,4-dihydro-1,8- naphthyridine-1(2H)-carboxylate (730 mg, 1.84 mmol) in DCM (25 mL) was added tert-butyl 3- oxopyrrolidine-1-carboxylate (1.82 g, 9.85 mmol) and sodium triacetoxyborohydride (1.17 g, 5.51 mmol).
  • the mixture was stirred at 25 °C for 16 h.
  • the resulting mixture was extracted with ethyl acetate (15 mL x 2).
  • the combined organic layers were washed with brine (30 mL), dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to give a residue.
  • the crude product was purified by prep-HPLC (column: Welch Xtimate C18250 x 70 mm x 10 um; mobile phase: A water (NH4HCO310 mmol/L), B acetonitrile 55%-85%, 20 min; Flow Rate (25 mL/min) to give tert-butyl 7-(5-((1-(tert-butoxycarbonyl)pyrrolidin-3-yl)(3,3- difluoropropyl)amino)pentyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxylate (480 mg, 846.98 umol, 46.12% yield) as a yellow oil which was separated by SFC (column: DAICEL CHIRALPAK IG (250 mm x 30 mm, 10 um); mobile phase: [0.1% NH3water MeOH]; B%: 25%- 25%, 7 min.) to give two peaks
  • Peak 1 arbitrarily assigned as tert-butyl (S)-7-(5-((1-(tert-butoxycarbonyl)pyrrolidin- 3-yl)(3,3-difluoropropyl)amino)pentyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxylate (240 mg, 423.49 umol, 82.76% yield) obtained as a white solid.
  • SFC: Rt 4.641 min, 100.00%.
  • Step 2 tert-butyl 7-((R)-5-(((S)-tert-butylsulfinyl)amino)-6,6-difluoro-6- (phenylsulfonyl)hexyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxylate [0684] To a solution of tert-butyl (S,E)-7-(5-((tert-butylsulfinyl)imino)pentyl)-3,4-dihydro- 1,8-naphthyridine-1(2H)-carboxylate (1.62 g, 3.84 mmol), ((difluoromethyl)sulfonyl)benzene (723.99 mg, 3.77 mmol, 536.29 uL) in THF (40 mL) was added LiHMDS (1 M, 4.52 mL) dropwise at
  • Step 3 tert-butyl 7-((R)-5-(((S)-tert-butylsulfinyl)(methyl)amino)-6,6-difluoro-6- (phenylsulfonyl)hexyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxylate [0685] To a solution of tert-butyl 7-((R)-5-(((S)-tert-butylsulfinyl)amino)-6,6-difluoro-6- (phenylsulfonyl)hexyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxylate (1.64 g, 2.67 mmol) in THF (30 mL) was added NaH (160.30 mg, 4.01 mmol, 60% purity) at 0 °C and the mixture was stir
  • Step 4 tert-butyl 7-((R)-5-(((S)-tert-butylsulfinyl)(methyl)amino)-6,6-difluorohexyl)-3,4- dihydro-1,8-naphthyridine-1(2H)-carboxylate [0686] To a solution of tert-butyl 7-((R)-5-(((S)-tert-butylsulfinyl)(methyl)amino)-6,6- difluoro-6-(phenylsulfonyl)hexyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxylate (1.3 g, 2.07 mmol) in DMF (40 mL) was added 20 mL HOAc/NaOAc (1:1, 8 M) buffer solution, Mg (1.71 g, 70.36 mmol) in portions and the
  • Step 5 (R)-1,1-difluoro-N-methyl-6-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)hexan-2- amine
  • tert-butyl 7-((R)-5-(((S)-tert-butylsulfinyl)(methyl)amino)-6,6- difluorohexyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxylate 1.5 g, 3.08 mmol
  • HCl/MeOH 4 M, 20 mL
  • Peak 1 arbitrarily assigned as tert-butyl (S)-3-(((R)-1,1-difluoro-6-(5,6,7,8- tetrahydro-1,8-naphthyridin-2-yl)hexan-2-yl)(methyl)amino)pyrrolidine-1-carboxylate (190 mg, 419.82 umol, 29.74% yield) was obtained as a yellow oil.
  • SFC: R t 1.020 min, 100%.
  • Peak 2 arbitrarily assigned as tert-butyl (R)-3-(((R)-1,1-difluoro-6-(5,6,7,8- tetrahydro-1,8-naphthyridin-2-yl)hexan-2-yl)(methyl)amino)pyrrolidine-1-carboxylate (240 mg, 530.29 umol, 37.57% yield) was obtained as a yellow oil.
  • SFC: R t 1.109 min, 98.42%.
  • Step 7 (S)-N-((R)-1,1-difluoro-6-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)hexan-2-yl)-N- methylpyrrolidin-3-amine
  • a solution of tert-butyl (S)-3-(((R)-1,1-difluoro-6-(5,6,7,8-tetrahydro-1,8- naphthyridin-2-yl)hexan-2-yl)(methyl)amino)pyrrolidine-1-carboxylate (170 mg, 375.62 umol) in HCl/MeOH (4 M, 10 mL) was stirred at 20 °C for 16 h.
  • Step 2 tert-butyl 7-(5-(((2S,3S)-1-(tert-butoxycarbonyl)-2-methylpyrrolidin-3- yl)(methyl)amino)pentyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxylate and tert-butyl 7-(5-(((2R,3R)-1-(tert-butoxycarbonyl)-2-methylpyrrolidin-3-yl)(methyl)amino)pentyl)-3,4- dihydro-1,8-naphthyridine-1(2H)-carboxylate [0694] A mixture of rel-tert-butyl 7-(5-(((2R,3R)-1-(tert-butoxycarbonyl)-2- methylpyrrolidin-3-yl)amino)pentyl)-3,4-dihydro-1,8-na
  • the aqueous phase was extracted with DCM (20 mL x 3).
  • the combined organic phase was washed with brine (20 mL), dried with anhydrous Na 2 SO 4 , filtered and concentrated in vacuum.
  • Peak 2 arbitrarily assigned as tert-butyl 7-(5-(((2R,3R)-1-(tert-butoxycarbonyl)-2- methylpyrrolidin-3-yl)(methyl)amino)pentyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxylate (0.4 g, 766.30 umol, 65.99% yield, 98.99% purity) was obtained as a yellow oil.
  • SFC: Rt 4.420 min, 100.00%.
  • Step 3 (2S,3S)-N,2-dimethyl-N-(5-(5,6,7,8-tetrahydro-1,8-naphthyridin-2- yl)pentyl)pyrrolidin-3-amine
  • tert-butyl 7-(5-(((2S,3S)-1-(tert-butoxycarbonyl)-2-methylpyrrolidin- 3-yl)(methyl)amino)pentyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxylate 600 mg, 1.16 mmol
  • HCl/MeOH 4 M, 10 mL
  • Step 2 tert-butyl (R)-3-(ethyl(pent-4-en-1-yl)amino)pyrrolidine-1-carboxylate
  • Step 3 tert-butyl (R)-7-(5-((1-(tert-butoxycarbonyl)pyrrolidin-3-yl)(ethyl)amino)pentyl)- 3,4-dihydro-1,8-naphthyridine-1(2H)-carboxylate [0701] A solution of tert-butyl (R)-3-(ethyl(pent-4-en-1-yl)amino)pyrrolidine-1-carboxylate (1.6 g, 5.7 mmol) was added to 9-BBN (22.8 mL, 11.4 mmol, 0.5 N in THF) under nitrogen atmosphere.
  • Step 4 (R)-N-ethyl-N-(5-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)pentyl)pyrrolidin-3- amine
  • TFA (2 mL) was added to a soluion of tert-butyl (R)-7-(5-((1-(tert- butoxycarbonyl)pyrrolidin-3-yl)(ethyl)amino)pentyl)-3,4-dihydro-1,8-naphthyridine-1(2H)- carboxylate (2.2 g, 4.3 mmol) in 8 mL of DCM.
  • Step 2 tert-butyl (R)-3-((5-(4-methoxy-1,8-naphthyridin-2- yl)pentyl)(methyl)amino)pyrrolidine-1-carboxylate
  • a solution of tert-butyl (R)-3-(methyl(pent-4-en-1-yl)amino)pyrrolidine-1- carboxylate (1.22 g, 4.56 mmol) was added to 9-BBN (18.2 mL, 9.1 mmol, 0.5 N in THF) under nitrogen atmosphere.
  • Step 3 tert-butyl (R)-3-((5-(4-methoxy-5,6,7,8-tetrahydro-1,8-naphthyridin-2- yl)pentyl)(methyl)amino)pyrrolidine-1-carboxylate
  • Step 4 (R)-N-(5-(4-methoxy-5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)pentyl)-N- methylpyrrolidin-3-amine
  • TFA 2 mL
  • tert-butyl (R)-3-((5-(4-methoxy-5,6,7,8- tetrahydro-1,8-naphthyridin-2-yl)pentyl)(methyl)amino)pyrrolidine-1-carboxylate (1.08 g, 2.5 mmol) in 8 mL of DCM.
  • the mixture was stirred at room temperature for 4 h and concentrated.
  • reaction mixture was stirred at 50°C for 2 h, then cooled to ambient temperature, added 2-chloro-4-methoxy-1,8-naphthyridine (1.32 g, 4.9 mmol), Pd(OAc)2 (46 mg, 0.205 mmol), PCy3 (115 mg, 0.41 mmol) and KOH (681 mg, 12.3 mmol).
  • 2-chloro-4-methoxy-1,8-naphthyridine 1.32 g, 4.9 mmol
  • Pd(OAc)2 46 mg, 0.205 mmol
  • PCy3 115 mg, 0.41 mmol
  • KOH 681 mg, 12.3 mmol
  • Step 2 (R)-N-methyl-N-(5-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)pentyl)pyrrolidin-3- amine
  • R tert-butyl
  • R-7-(5-((1-(tert-butoxycarbonyl)pyrrolidin-3- yl)(methyl)amino)pentyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxylate (1.38 g, 2.7 mmol) and TFA (20 mL) in DCM (20 mL) was stirred at RT for 16 h.
  • Step 2 tert-butyl (R)-7-(5-((1-(tert-butoxycarbonyl)pyrrolidin-3-yl)(2- methoxyethyl)amino)pentyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxylate
  • a solution of tert-butyl (R)-3-((2-methoxyethyl)(pent-4-en-1-yl)amino)pyrrolidine-1- carboxylate (1.5 g, 4.8 mmol) was added to 9-BBN (19.2 mL, 9.6 mmol, 0.5 N in THF) under nitrogen atmosphere.
  • Step 3 (R)-N-(2-methoxyethyl)-N-(5-(5,6,7,8-tetrahydro-1,8-naphthyridin-2- yl)pentyl)pyrrolidin-3-amine [0711] TFA (2 mL) was added to a soluion of tert-butyl (R)-7-(5-((1-(tert- butoxycarbonyl)pyrrolidin-3-yl)(2-methoxyethyl)amino)pentyl)-3,4-dihydro-1,8-naphthyridine- 1(2H)-carboxylate (2.2 g, 4.0 mmol) in 8 mL of DCM.
  • Step 2 tert-butyl (R)-7-(5-((1-(tert-butoxycarbonyl)pyrrolidin-3- yl)(cyclopropyl)amino)pentyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxylate [0713] A solution of ert-butyl (R)-3-(cyclopropyl(pent-4-en-1-yl)amino)pyrrolidine-1- carboxylate (1.46 g, 5 mmol) was added to 9-BBN (20 mL, 10 mmol, 0.5 N in THF) under nitrogen atmosphere.
  • Step 3 (R)-N-cyclopropyl-N-(5-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)pentyl)pyrrolidin- 3-amine
  • HCl/dioxane (3 mL, 4N in dioxane) was added to a soluion of tert-butyl (R)-7-(5-((1- (tert-butoxycarbonyl)pyrrolidin-3-yl)(cyclopropyl)amino)pentyl)-3,4-dihydro-1,8-naphthyridine- 1(2H)-carboxylate (0.9 g, 1.7 mmol) in 6 mL of MeOH.
  • Step 2 tert-butyl 7-(2-ethoxy-2-oxoethyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxylate
  • a mixture of ethyl 2-(1,8-naphthyridin-2-yl)acetate as a pale yellow solid (5.7 g, 26.4 mmol) and Pd/C (570 mg, 10 wt% loading) in MeOH (50 mL) was stirred at room temperature under hydrogen overnight. The mixture was filtered and the filtrate was concentrated in vacuo. The residue was dissolved in dioxane (50 mL), then added Boc2O (17.3 g, 79.2 mmol).
  • Step 3 tert-butyl 7-(2-hydroxyethyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxylate [0717] To a solution of tert-butyl 7-(2-ethoxy-2-oxoethyl)-3,4-dihydro-1,8-naphthyridine- 1(2H)-carboxylate (1.6 g, 4.99 mmol) in THF (20 mL) and EtOH (4 mL) at 0 °C, was added a solution of lithium borohydride in THF (1M, 10 mL, 10 mmol) dropwise. The reaction was stirred at ambient temperature for 15 h.
  • Step 4 tert-butyl 7-(2-(allyloxy)ethyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxylate [0718] To a solution of tert-butyl 7-(2-hydroxyethyl)-3,4-dihydro-1,8-naphthyridine-1(2H)- carboxylate (1.3 g, 4.67 mmol) in n-heptane (20 mL) was added sodium hydroxide 50% solution in water (10 mL, 62.4 mmol), tetrabutylammonium bromide (74 mg, 0.23 mmol) and 3- bromoprop-1-ene (1.13 g, 9.34 mmol).
  • the mixture was heated at 80 °C for 2 h. Then the reaction mixture was cooled to ambient temperature, ethyl acetate (100 mL) and water (100 mL) were added. The organic phase was separated and the aqueous phase was extracted with ethyl acetate (50 mL x2). The combined organic layer was dried over Na2SO4, filtered.
  • Step 5 tert-butyl 7-(2-(2-oxoethoxy)ethyl)-3,4-dihydro-1,8-naphthyridine-1(2H)- carboxylate
  • tert-butyl 7-(2-(allyloxy)ethyl)-3,4-dihydro-1,8-naphthyridine-1(2H)- carboxylate 890 mg, 2.80 mmol
  • sodium periodate 1.5 g, 7.0 mmol
  • potassium osmate 11 mg, 0.03 mmol
  • Step 6 tert-butyl (R)-7-(2-(2-((1-(tert-butoxycarbonyl)pyrrolidin-3- yl)(methyl)amino)ethoxy)ethyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxylate
  • Sodium cyanoborohydride (461 mg, 7.32 mmol) was added to a stirred mixture of tert-butyl 7-(2-(2-oxoethoxy)ethyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxylate (780 mg, 2.44 mmol) and tert-butyl (R)-3-(methylamino)pyrrolidine-1-carboxylate (488 mg, 2.44 mmol) in MeOH (20 mL) at room temperature.
  • Step 3 tert-butyl (R)-7-(5-((1-(tert-butoxycarbonyl)pyrrolidin-3-yl)(2- cyclopropoxyethyl)amino)pentyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxylate
  • a solution of tert-butyl (R)-3-((2-cyclopropoxyethyl)(pent-4-en-1- yl)amino)pyrrolidine-1-carboxylate (760 mg, 2.25 mmol) was added to 9-BBN (9 mL, 4.5 mmol, 0.5 N in THF) under nitrogen atmosphere.
  • Step 4 (R)-N-(2-cyclopropoxyethyl)-N-(5-(5,6,7,8-tetrahydro-1,8-naphthyridin-2- yl)pentyl)pyrrolidin-3-amine
  • TFA (3 mL) was added to a soluion of tert-butyl (R)-7-(5-((1-(tert- butoxycarbonyl)pyrrolidin-3-yl)(2-cyclopropoxyethyl)amino)pentyl)-3,4-dihydro-1,8- naphthyridine-1(2H)-carboxylate (370 mg, 0.65 mmol) in 3 mL of DCM.
  • Step 2 tert-butyl (R)-7-(2-(2-((1-(tert-butoxycarbonyl)pyrrolidin-3- yl)(isobutyl)amino)ethoxy)ethyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxylate [0727] To a solution of tert-butyl (R)-7-(2-(2-((1-(tert-butoxycarbonyl)pyrrolidin-3- yl)amino)ethoxy)ethyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxylate (600 mg, 1.22 mmol) and isobutyraldehyde (176 mg, 2.44 mmol) in DCM (20 ml), was added sodium triacetoxyborohydride (517 mg, 2.44
  • Step 2 tert-butyl 7-(5-(((R)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl)(methyl)amino)hexyl)- 3,4-dihydro-1,8-naphthyridine-1(2H)-carboxylate [0730] To a solution of tert-butyl (3R)-3-(hex-5-en-2-yl(methyl)amino)pyrrolidine-1- carboxylate (650 mg, 2.3 mmol) in THF (dry, 5 mL) under argon, was added 9-BBN (0.5 M in THF, 9.2 mL, 4.6 mmol).
  • reaction mixture was stirred at 50°C for 2 h, then cooled to ambient temperature, added 2-chloro-4-methoxy-1,8-naphthyridine (618 mg, 2.3 mmol), Pd(OAc) 2 (27 mg, 0.12 mmol), PCy 3 (67 mg, 0.24 mmol) and KOH (386 mg, 6.9 mmol).
  • 2-chloro-4-methoxy-1,8-naphthyridine 618 mg, 2.3 mmol
  • Pd(OAc) 2 27 mg, 0.12 mmol
  • PCy 3 67 mg, 0.24 mmol
  • KOH 386 mg, 6.9 mmol
  • Step 2 tert-butyl (S)-7-(5-((1-(tert-butoxycarbonyl)pyrrolidin-3-yl)(methyl)amino)pentyl)- 3,4-dihydro-1,8-naphthyridine-1(2H)-carboxylate [0733] To a solution of tert-butyl (S)-3-(methyl(pent-4-en-1-yl)amino)pyrrolidine-1- carboxylate (1.9 g, 7.1 mmol) in THF (dry, 10 mL) under argon, was added 9-BBN (0.5 M in THF, 28.4 mL, 14.2 mmol).
  • reaction mixture was stirred at 50°C for 2 h, then cooled to ambient temperature, added 2-chloro-4-methoxy-1,8-naphthyridine (2.28 g, 8.5 mmol), Pd(OAc)2 (80 mg, 0.35 mmol), PCy 3 (199 mg, 0.71 mmol) and KOH (1.18 g, 21.3 mmol).
  • 2-chloro-4-methoxy-1,8-naphthyridine 2.28 g, 8.5 mmol
  • Pd(OAc)2 80 mg, 0.35 mmol
  • PCy 3 199 mg, 0.71 mmol
  • KOH 1.18 g, 21.3 mmol
  • Step 2 tert-butyl (R)-(1-benzylpyrrolidin-3-yl)(pent-4-en-1-yl)carbamate
  • (R)-1-benzyl-N-(pent-4-en-1-yl)pyrrolidin-3-amine 900 mg, 3.69 mmol
  • DIEA 952 mg, 7.38 mmol
  • Boc2O 1.6 g, 7.38 mmol
  • Step 3 tert-butyl (R)-7-(5-((1-benzylpyrrolidin-3-yl)(tert-butoxycarbonyl)amino)pentyl)- 3,4-dihydro-1,8-naphthyridine-1(2H)-carboxylate [0737] To a solution of tert-butyl (R)-(1-benzylpyrrolidin-3-yl)(pent-4-en-1-yl)carbamate (855 mg, 2.48 mmol) in THF (dry, 10 mL) under argon, was added 9-BBN (0.5 M in THF, 10 mL, 5 mmol).
  • reaction mixture was stirred at 50°C for 2 h, then cooled to ambient temperature, added 2-chloro-4-methoxy-1,8-naphthyridine (667 mg, 2.48 mmol), Pd(OAc)2 (27 mg, 0.12 mmol), PCy3 (70 mg, 0.25 mmol) and KOH (417 mg, 7.44 mmol).
  • 2-chloro-4-methoxy-1,8-naphthyridine 667 mg, 2.48 mmol
  • Pd(OAc)2 27 mg, 0.12 mmol
  • PCy3 70 mg, 0.25 mmol
  • KOH 417 mg, 7.44 mmol
  • Step 4 tert-butyl (R)-7-(5-((tert-butoxycarbonyl)(pyrrolidin-3-yl)amino)pentyl)-3,4- dihydro-1,8-naphthyridine-1(2H)-carboxylate
  • Step 2 tert-butyl 7-(4-((tert-butyldiphenylsilyl)oxy)butyl)-3,4-dihydro-1,8-naphthyridine- 1(2H)-carboxylate
  • a mixture of (but-3-en-1-yloxy)(tert-butyl)diphenylsilane (3 g, 9.66 mmol) in THF (30 mL) was added 9-BBN (0.5 M in THF, 38.65 mL) in one portion at 0 °C under N2 and stirred at 50 °C for 2 h.
  • Step 3 tert-butyl 7-(4-hydroxybutyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxylate [0741] To a solution of tert-butyl 7-(4-((tert-butyldiphenylsilyl)oxy)butyl)-3,4-dihydro-1,8- naphthyridine-1(2H)-carboxylate (31 g, 56.90 mmol) in THF (300 mL) was added TBAF (1 M in THF, 170.71 mL). The mixture was stirred at 50 °C for 16 h. The reaction was concentrated in vacuum.
  • Step 4 tert-butyl 7-(4-oxobutyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxylate [0742] To a solution of oxalyl chloride (4.97 g, 39.16 mmol, 3.43 mL) in DCM (80 mL) was added DMSO (4.59 g, 58.75 mmol, 4.59 mL) at -70 °C, after stirred at -70 °C for 10 min, then a solution of tert-butyl 7-(4-hydroxybutyl)-3,4-dihydro-2H-1,8-naphthyridine-1-carboxylate (6 g, 19.58 mmol) in DCM (15 mL) was added at -70 °C, after stirred at -70 °C for 0.5 h, Et3N (11.89 g, 117.49 mmol,
  • Step 5 (S)-tert-butyl 7-(4-((1-(tert-butoxycarbonyl)pyrrolidin-3-yl)(methyl)amino)butyl)- 3,4-dihydro-1,8-naphthyridine-1(2H)-carboxylate
  • Step 2 (R)-N-methyl-N-(4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)butyl)pyrrolidin-3- amine
  • tert-butyl 7-[4-[[(3R)-1-tert-butoxycarbonylpyrrolidin-3-yl]-methyl- amino] butyl]-3,4-dihydro-2H-1,8-naphthyridine-1-carboxylate 0.6 g, 1.23 mmol
  • MeOH 3 mL
  • HCl/MeOH 4 M, 15 mL
  • Step 2 tert-butyl (R)-3-(tert-butyl(pent-4-en-1-yl)amino)pyrrolidine-1-carboxylate
  • tert-butyl (R)-3-(tert-butylamino)pyrrolidine-1-carboxylate 2.4 g, 9.4 mmol
  • 1-bromo-2-methoxyethane 2.2 g, 15 mmol
  • DIPEA 2.58 g, 20 mmol
  • Step 3 tert-butyl (R)-7-(5-((1-(tert-butoxycarbonyl)pyrrolidin-3-yl)(tert- butyl)amino)pentyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxylate [0749] A solution of tert-butyl (R)-3-(tert-butyl(pent-4-en-1-yl)amino)pyrrolidine-1- carboxylate (380 mg, 1.23 mmol) was added to 9-BBN (4.9 mL, 2.46 mmol, 0.5 N in THF) under N2 atmosphere.
  • Step 4 (R)-N-(tert-butyl)-N-(5-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)pentyl)pyrrolidin- 3-amine
  • tert-butyl (R)-7-(5-((1-(tert-butoxycarbonyl)pyrrolidin-3-yl)(tert-butyl)amino)pentyl)- 3,4-dihydro-1,8-naphthyridine-1(2H)-carboxylate (416 mg, 0.76 mmol) was added to a solution of HCl/dioxane (2 mL, 4N).
  • Step 3 tert-butyl (R)-3-((2,2-difluoropent-4-en-1-yl)(methyl)amino)pyrrolidine-1- carboxylate
  • 2,2-difluoropent-4-en-1-yl trifluoromethanesulfonate 700 mg, 2.74 mmol
  • tert-butyl (R)-3-(methylamino)pyrrolidine-1-carboxylate 1.1 g, 5.5 mmol
  • Step 4 tert-butyl (R)-7-(5-((1-(tert-butoxycarbonyl)pyrrolidin-3-yl)(methyl)amino)-4,4- difluoropentyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxylate
  • a solution of tert-butyl (R)-3-((2,2-difluoropent-4-en-1- yl)(methyl)amino)pyrrolidine-1-carboxylate (380 mg, 1.25 mmol) was added to 9-BBN (5 mL, 2.5 mmol, 0.5 N in THF) under N2 atmosphere.
  • Step 5 (R)-N-(2,2-difluoro-5-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)pentyl)-N- methylpyrrolidin-3-amine
  • HCl/dioxane (1.63 mL, 6.4 mmol, 4N) was added to a solution of tert-butyl (R)-7-(5- ((1-(tert-butoxycarbonyl)pyrrolidin-3-yl)(methyl)amino)-4,4-difluoropentyl)-3,4-dihydro-1,8- naphthyridine-1(2H)-carboxylate (360 mg, 0.65 mmol) in 1 mL of DCM.
  • Step 2 benzyl (R)-pyrrolidin-3-yl(5-(5,6,7,8-tetrahydro-1,8-naphthyridin-2- yl)pentyl)carbamate
  • the mixture was cooled to 25 °C and partitioned between ethyl acetate (150 mL) and water (200 mL).
  • the aqueous phase was extracted with ethyl acetate (150 mL x 3).
  • the combined organic phase was washed with brine (150 mL), dried with anhydrous Na2SO4, filtered and concentrated in vacuum.
  • the mixture was filtered and the filtrate was concentrated under reduced pressure.
  • the mixture was purified by MPLC (Biotage ®; 40 g SepaFlash ® Silica Flash Column, Eluent of 0 ⁇ 1% ethyl acetate/petroleum ether gradient @ 120 mL/min) to give 1,4- difluoro-2-isopropyl-5-methoxybenzene (1.9 g, 10.20 mmol, 78.4% yield) as colorless oil.
  • Step 2 1-(3-bromo-5-fluoro-4-methoxyphenyl)ethan-1-one [0763] To a solution of 1-(3-bromo-5-fluoro-4-hydroxyphenyl)ethan-1-one (37.5 g, 160.92 mmol) in DMF (450 mL) was added K2CO3 (55.60 g, 402.30 mmol) at 0 °C.
  • Step 3 1-bromo-5-(1,1-difluoroethyl)-3-fluoro-2-methoxybenzene
  • 1-(3-bromo-5-fluoro-4-methoxyphenyl)ethan-1-one (2 g, 8.10 mmol) was added dropwise to (bis-(2-methoxyethyl)amino)sulfur trifluoride (10.10 g, 45.65 mmol, 10 mL) at 0°C.
  • the mixture was stirred at 60 °C for 16 h.
  • the reactions were poured into ice saturated NaHCO3 (400 mL) slowly and extracted with ethyl acetate (100 mL x 3).
  • Step 4 tert-butyl 2-(5-(1,1-difluoroethyl)-3-fluoro-2-methoxyphenyl)acetate
  • Step 5 tert-butyl 2-bromo-2-(5-(1,1-difluoroethyl)-3-fluoro-2-methoxyphenyl)acetate
  • tert-butyl 2-(5-(1,1-difluoroethyl)-3-fluoro-2-methoxyphenyl)acetate 1.5 g, 4.93 mmol
  • LiHMDS LiHMDS (1 M in THF, 7.39 mL
  • TMSCl (803.29 mg, 7.39 mmol, 938.42 uL) was added. After stirred at -70 °C for 0.5 h, a solution of NBS (2.63 g, 14.79 mmol) in THF (30 mL) was added dropwise. The reaction was stirred at - 70 °C for 1 h. Then the reaction was quenched with aqueous NH 4 Cl (20 mL) and extracted with ethyl acetate (20 mL x 2). The combined organic phase was washed with brine (30 mL), dried with anhydrous Na2SO4, filtered and concentrated in vacuum.
  • Step 3 (3-fluoro-2-methoxy-5-(1-methylcyclopropyl)phenyl)boronic acid
  • 1-bromo-3-fluoro-2-methoxy-5-(1-methylcyclopropyl)benzene 400 mg, 1.54 mmol
  • triisopropyl borate 435.49 mg, 2.32 mmol, 532.39 uL
  • THF 10 mL
  • n-butyllithium 2.5 M, 926.23 uL
  • Step 2 1-bromo-3-fluoro-2-methoxy-5-(trifluoromethyl)benzene [0775] To a solution of 2-bromo-6-fluoro-4-(trifluoromethyl)phenol (2.73 g, 10.54 mmol) in DMF (30 mL) was added K 2 CO 3 (3.64 g, 26.35 mmol) at 25 °C. Iodomethane (2.99 g, 21.08 mmol, 1.31 mL) was added dropwise slowly into the reaction. The mixture was stirred at 25 °C for 16 h. The reaction mixture was quenched with water (60 mL), extracted with ethyl acetate (20 ml x 3).
  • Step 3 tert-butyl 2-(3-fluoro-2-methoxy-5-(trifluoromethyl)phenyl)acetate
  • 1-bromo-3-fluoro-2-methoxy-5-(trifluoromethyl)benzene (1 g, 3.66 mmol) in THF (10 mL) was added bis(tri-tert-butylphosphine)palladium(0) (374.37 mg, 732.54 umol) and (2-(tert-butoxy)-2-oxoethyl)zinc(II) bromide (1 M in THF, 20 mL) at 25 °C.
  • the mixture was stirred at 70 °C for 16 h under nitrogen atmosphere.
  • the reaction mixture was quenched with water (50 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue.
  • the residue was purified by flash silica gel chromatography (ISCO ®; 80 g Sepa Flash ® Silica Flash Column, Eluent of 0 ⁇ 20% Ethyl acetate/Petroleum ether gradient @ 100 mL/min) to give 1-bromo-3-fluoro-5-iodo-2-methoxybenzene (28 g, 84.61 mmol, 96.38% yield) as a yellow oil.
  • Step 2 4-(3-bromo-5-fluoro-4-methoxyphenyl)tetrahydro-2H-pyran-4-ol
  • i-PrMgBr (2 M, 11.33 mL) was added dropwise to a solution of 1-bromo-3-fluoro-5- iodo-2-methoxybenzene (5 g, 15.11 mmol) in THF (100 mL) at 0 °C. The mixture was stirred for 1 h at 0 °C and then cooled to -78 °C.
  • Step 4 (3-fluoro-2-methoxy-5-(4-methyltetrahydro-2H-pyran-4-yl)phenyl)boronic acid [0781]
  • n-Butyllithium 2.5 M, 990.00 uL was added dropwise to a solution of triisopropyl borate (930.95 mg, 4.95 mmol, 1.14 mL) and 4-(3-bromo-5-fluoro-4-methoxyphenyl)-4- methyltetrahydro-2H-pyran (0.5 g, 1.65 mmol) in THF (10 mL) at -78 °C under nitrogen. The resulting mixture was stirred for 1 h at -78 °C and 1 h at 20 °C.
  • the residue was purified by flash silica gel chromatography (ISCO ®; 20 g Sepa Flash ® Silica Flash Column, Eluent of 0 ⁇ 100% THF/Petroleum ether gradient @ 100 mL/min).
  • Step 3 (S)-(3-fluoro-2-methoxy-5-(1-methoxypropan-2-yl)phenyl)boronic acid [0787] To a solution of (S)-1-bromo-3-fluoro-2-methoxy-5-(1-methoxypropan-2-yl)benzene (450 mg, 1.62 mmol) and 2-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-5,5-dimethyl-1,3,2- dioxaborinane (1.10 g, 4.87 mmol) in dioxane (6 mL) was added PCy 3 (68.30 mg, 243.57 umol), Pd(dba) 2 (140.05 mg, 243.57 umol) and KOAc (318.72 mg, 3.25 mmol), the reaction was stirred at 90 °C for 16 h under nitrogen.
  • Step 2 (R)-2-(3-fluoro-2-methoxy-5-(1-methoxypropan-2-yl)phenyl)-4,4,5,5-tetramethyl- 1,3,2-dioxaborolane [0789] To a solution of (R)-1-bromo-3-fluoro-2-methoxy-5-(1-methoxypropan-2-yl)benzene (400 mg, 1.44 mmol) in dioxane (8 mL) was added KOAc (283.31 mg, 2.89 mmol), bis(pinacolato)diboron (733.06 mg, 2.89 mmol), Pd(dba) 2 (165.99 mg, 288.67 umol) and PCy 3 (80.95 mg, 288.67 umol).
  • Step 2 1-bromo-3-fluoro-5-iodo-2-methoxybenzene
  • NIS 11.52 g, 51.21 mmol
  • H2SO4 4 mL
  • Water 500 mL
  • ethyl acetate 300 mL x 2
  • Step 3 (3-bromo-5-fluoro-4-methoxyphenyl)(cyclopropyl)methanone [0794] To a solution of 1-bromo-3-fluoro-5-iodo-2-methoxybenzene (15 g, 45.33 mmol) in THF (150 mL) was added isopropylmagnesium chloride (1.3 M, 41.84 mL) at 0 °C, after stirred at 0 °C for 0.5 h, a solution of N-methoxy-N-methylcyclopropanecarboxamide (14.64 g, 113.32 mmol) in THF (10 mL) was added at 0 °C, then the reaction was stirred at 0 °C for 1.5 h.
  • isopropylmagnesium chloride 1.3 M, 41.84 mL
  • N-methoxy-N-methylcyclopropanecarboxamide 14.64 g, 113.32 mmol
  • Step 4 1-bromo-5-(cyclopropyldifluoromethyl)-3-fluoro-2-methoxybenzene [0795] To a solution of (3-bromo-5-fluoro-4-methoxyphenyl)(cyclopropyl)methanone (5 g, 18.31 mmol) in (bis-(2-methoxyethyl)amino)sulfur trifluoride (30.30 g, 136.95 mmol, 30.00 mL) was added EtOH (84.34 mg, 1.83 mmol) at 0 °C, the reaction was stirred at 60 °C for 72 h.
  • Step 5 tert-butyl 2-(5-(cyclopropyldifluoromethyl)-3-fluoro-2-methoxyphenyl)acetate
  • 1-bromo-5-(cyclopropyldifluoromethyl)-3-fluoro-2-methoxybenzene 0.5 g, 1.69 mmol
  • bis(tri-tert-butylphosphine)palladium(0) 17.18 mg, 338.87 umol
  • Step 6 tert-butyl 2-bromo-2-(5-(cyclopropyldifluoromethyl)-3-fluoro-2- methoxyphenyl)acetate
  • tert-butyl 2-(5-(cyclopropyldifluoromethyl)-3-fluoro-2- methoxyphenyl)acetate 0.5 g, 1.51 mmol
  • LiHMDS Li, 2.27 mL
  • TMSCl (246.66 mg, 2.27 mmol, 288.15 uL) was added and the resulting mixture was stirred at -78 °C for 0.5 h.
  • Step 2 3-bromo-5-fluoro-4-methoxybenzaldehyde [0799] To a solution of 3-bromo-5-fluoro-4-hydroxybenzaldehyde (37.5 g, 160.92 mmol) in DMF (450 mL) was added K 2 CO 3 (55.60 g, 402.30 mmol) at 0 °C. The mixture was stirred at 0 °C for 0.5 h. Iodomethane (45.68 g, 321.84 mmol, 20.04 mL) was slowly dropwise added into the reaction at 0 ⁇ 5 o C. The mixture was stirred at 25 °C for 15.5 h.
  • Step 3 1-bromo-5-(2,2-difluorovinyl)-3-fluoro-2-methoxybenzene
  • triphenylphosphine 13.51 g, 51.49 mmol
  • KI 5.70 g, 34.33 mmol
  • 3- bromo-5-fluoro-4-methoxybenzaldehyde (4 g, 17.16 mmol) in acetonitrile (30 mL) was stirred for 0.5 h, then methyl 2,2-difluoro-2-(fluorosulfonyl)acetate (6.60 g, 34.33 mmol, 4.37 mL) was added slowly over a period 1 h.
  • Step 4 1-bromo-3-fluoro-2-methoxy-5-(2,2,2-trifluoroethyl)benzene
  • 1-bromo-5-(2,2-difluorovinyl)-3-fluoro-2-methoxybenzene 2.4 g, 8.99 mmol
  • water 1.2 mL
  • DMA 24 mL
  • KF 1.57 g, 26.96 mmol, 631.61 uL
  • 18-crown-6 (1.19 g, 4.49 mmol
  • Step 5 2-(3-fluoro-2-methoxy-5-(2,2,2-trifluoroethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2- dioxaborolane [0802] To a solution of 1-bromo-3-fluoro-2-methoxy-5-(2,2,2-trifluoroethyl)benzene (500 mg, 1.74 mmol) in dioxane (5 mL) was added bis(pinacolato)diboron (884.66 mg, 3.48 mmol) and Pd(dba)2 (200.32 mg, 348.37 umol) and PCy3 (97.69 mg, 348.37 umol) and KOAc (341.90 mg, 3.48 mmol).
  • oxetan-3-one (2.18 g, 30.22 mmol) was added to the reaction mixture and the mixture was stirred for 1 h at -78 °C and 1 h at 25 °C.
  • the reaction mixture was quenched with aqueous NH4Cl (50 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue.
  • Step 2 (3-fluoro-5-(3-hydroxyoxetan-3-yl)-2-methoxyphenyl)boronic acid
  • 3-(3-bromo-5-fluoro-4-methoxyphenyl)oxetan-3-ol (1 g, 3.61 mmol)
  • 5,5,5',5'-tetramethyl-2,2'-bi(1,3,2-dioxaborinane) (2.45 g, 10.83 mmol) in dioxane (50 mL) was added Pd(dba)2 (294.72 mg, 360.90 umol) and KOAc (708.39 mg, 7.22 mmol).
  • Step 2 1-bromo-2-ethoxy-3-fluoro-5-(prop-1-en-2-yl)benzene [0806] To a solution of 1-(3-bromo-4-ethoxy-5-fluorophenyl)ethan-1-one (7.46 g, 28.57 mmol) in THF (100 mL) was added methyltriphenylphosphonium bromide (20.41 g, 57.15 mmol) and t-BuOK (6.41 g, 57.15 mmol), the mixture was stirred at 25 °C for 16 h. Water (100 mL) was added, the mixture was extracted with ethyl acetate (100 mL x 2).
  • Step 3 1-bromo-2-ethoxy-3-fluoro-5-isopropylbenzene [0807] To a solution of 1-bromo-2-ethoxy-3-fluoro-5-(prop-1-en-2-yl)benzene (5.4 g, 20.84 mmol) in THF (80 mL) was added Pd/C (2.5 g, 5 wt% loading) under hydrogen (15 psi), the mixture was stirred at 25 °C for 16 h. The reaction mixture was filtered and concentrated in vacuum to get a residue. 1-bromo-2-ethoxy-3-fluoro-5-isopropylbenzene (4.8 g, crude) was obtained as brown oil.
  • Step 4 (2-ethoxy-3-fluoro-5-isopropylphenyl)boronic acid
  • n-Butyllithium 2.5 M, 3.45 mL was added dropwise to a solution of 1-bromo-2- ethoxy-3-fluoro-5-isopropylbenzene (1.5 g, 5.74 mmol) and triisopropyl borate (1.62 g, 8.62 mmol, 1.98 mL) in THF (35 mL) at -78 °C under nitrogen. The resulting mixture was stirred for 1 h at -78 °C and 1 h at 25 °C.
  • Step 2 2-bromo-6-fluoro-4-isopropylphenol
  • boron tribromide 11.86 g, 47.35 mmol, 4.56 mL
  • the reaction was stirred at 25 °C for 2 h.
  • the mixture was poured into ice water (70 mL) and stirred for 0.5 h, then the mixture was extracted with dichloromethane (50 mL x 2), the organic layer was combined and concentrated.
  • Step 3 1-bromo-2-(difluoromethoxy)-3-fluoro-5-isopropylbenzene
  • 2-bromo-6-fluoro-4-isopropylphenol (1 g, 4.29 mmol) in DMF (10 mL) was added sodium chlorodifluoroacetate (3.27 g, 21.45 mmol), Cs2CO3 (4.19 g, 12.87 mmol) and water (2 mL), the mixture was stirred at 100 °C for 12 h. Water (20 mL) was added, the mixture was extracted with ethyl acetate (10 mL x 2).
  • Step 4 2-(2-(difluoromethoxy)-3-fluoro-5-isopropylphenyl)-5,5-dimethyl-1,3,2- dioxaborinane
  • 1-bromo-2-(difluoromethoxy)-3-fluoro-5-isopropylbenzene 590 mg, 2.08 mmol
  • dioxane 15 mL
  • Pd(dba)2 119.84 mg, 208.42 umol
  • PCy3 87.67 mg, 312.63 umol
  • KOAc 613.64 mg, 6.25 mmol
  • the combined organic layers were washed with brine (100 mL), dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to give a residue which was purified by flash silica gel chromatography (ISCO®; 25 g SepaFlash® Silica Flash Column, Eluent of 0 ⁇ 50% Acetone/Petroleum ether gradient @ 100 mL/min) to afford (3-fluoro-5-isopropyl-2- methoxyphenyl)boronic acid (1.8 g, 8.49 mmol, 83.91% yield) as a yellow oil.
  • Step 2 1-bromo-3-fluoro-5-isopropyl-2-(trifluoromethoxy)benzene
  • 1-bromo-2-(bromodifluoromethoxy)-3-fluoro-5-isopropylbenzene (1 g, 2.76 mmol) in DCE (10 mL)
  • silver tetrafluoroborate 2.15 g, 11.05 mmol
  • Step 3 (3-fluoro-5-isopropyl-2-(trifluoromethoxy)phenyl)boronic acid
  • Step 2 methyl 2-(5-bromo-3-fluoro-2-(trifluoromethyl)phenyl)acetate
  • DMSO dimethyl 2-(5-bromo-3-fluoro-2-(trifluoromethyl)phenyl)malonate
  • LiCl 937.43 mg, 22.11 mmol
  • Step 3 methyl 2-(3-fluoro-5-(prop-1-en-2-yl)-2-(trifluoromethyl)phenyl)acetate
  • methyl 2-(5-bromo-3-fluoro-2-(trifluoromethyl)phenyl)acetate 2.4 g, 7.62 mmol
  • 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (3.84 g, 22.85 mmol)
  • dioxane 30 mL
  • water 0.3 mL
  • Cs2CO3 7.45 g, 22.85 mmol
  • Pd(dppf)Cl2.CH2Cl2 622.08 mg, 761.76 umol
  • Step 4 methyl 2-(3-fluoro-5-isopropyl-2-(trifluoromethyl)phenyl)acetate
  • methyl 2-(3-fluoro-5-(prop-1-en-2-yl)-2- (trifluoromethyl)phenyl)acetate 1.6 g, 5.79 mmol
  • Pd/C 0.8 g, 5 wt% loading
  • the reaction was stirred at 25 °C for 12 h under hydrogen (15 psi). After the reaction, the mixture was filtered and concentrated to give the crude product.
  • Step 5 methyl 2-bromo-2-(3-fluoro-5-isopropyl-2-(trifluoromethyl)phenyl)acetate
  • methyl 2-(3-fluoro-5-isopropyl-2-(trifluoromethyl)phenyl)acetate 200 mg, 718.80 umol
  • LiHMDS Li, 1.08 mL
  • TMSCl (117.14 mg, 1.08 mmol, 136.84 uL) was added at -78 °C, the mixture was stirred at -78 °C for 0.33 h.
  • a solution of NBS (383.80 mg, 2.16 mmol) in THF (2 mL) was added at -78 °C, the resulting mixture was stirred at 25 °C for 0.5 h.
  • the mixture was quenched by water (10 mL), exacted by ethyl acetate (10 mL x 3). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, concentrated under reduced pressure to give a residue.
  • Step 2 3-(3-bromo-5-fluoro-4-methoxyphenyl)-3-methyloxetane
  • Step 2a i-PrMgBr (2 M, 12.03 mL) was added to a solution of 1-bromo-3-fluoro-5- iodo-2-methoxybenzene (7.96 g, 24.06 mmol) in THF (36 mL) at 0 °C under nitrogen. The mixture was stirred for 0.25 h at 0 °C and then treated with zinc dibromide (5.42 g, 24.06 mmol) at 0 °C. The resulting mixture was stirred for 0.5 h at 0 °C to afford the zinc reagent.
  • Step 2b 4,5,6,7-tetrachloro-1,3-dioxoisoindolin-2-yl 3-methyloxetane-3-carboxylate (3.2 g, 8.02 mmol) was dissolved in 1,3-dimethyl-2-imidazolidinone (48 mL) under nitrogen. Then nickel (II) (E)-2, 2, 6, 6-tetramethyl-5-oxohept-3-en-3-olate (682.05 mg, 1.60 mmol) and zinc dibromide (1.81 g, 8.02 mmol) was added at 0 °C and the mixture was stirred for 0.25 h.
  • Step 3 (3-fluoro-2-methoxy-5-(3-methyloxetan-3-yl)phenyl)boronic acid [0825] To the mixture of 3-(3-bromo-5-fluoro-4-methoxyphenyl)-3-methyloxetane (500 mg, 1.82 mmol) and 5,5,5',5'-tetramethyl-2,2'-bi(1,3,2-dioxaborinane) (1.23 g, 5.45 mmol) in dioxane (5 mL) was added Pd(dppf)Cl2.CH2Cl2 (148.42 mg, 181.74 umol) and KOAc (356.73 mg, 3.63 mmol) under nitrogen.
  • the mixture was stirred at 90 °C for 16 h under nitrogen.
  • the reaction mixture was concentrated under reduced pressure to remove solvent.
  • the mixture was further purified by pre-HPLC (column: Waters Xbridge BEH C18100 x 30 mm x 10 um; mobile phase: A water (NH4HCO310 mmol/L), B acetonitrile 10%-40%, 8 min; Flow Rate (25 mL/min).
  • Step 2 2-(3-bromo-5-fluoro-4-methoxyphenyl)propan-2-ol [0827] To a solution of methyl 3-bromo-5-fluoro-4-methoxybenzoate (2 g, 7.63 mmol) in THF (15 mL) was added MeMgBr (1M in THF, 15 mL,15 mmol) at 0 °C and stirred at ambient temperature for 4 h. The reaction mixture was quenched with water (30 mL), and extracted with ethyl acetate (3x 30 mL).
  • Step 3 1-bromo-3-fluoro-2-methoxy-5-(2-methoxypropan-2-yl)benzene
  • 2-(3-bromo-5-fluoro-4-methoxyphenyl)propan-2-ol 1.5 g, 5.72 mmol
  • NaH 344 mg, 8.59 mmol
  • MeI 1.2 g, 8.59 mmol
  • the mixture was quenched with aqueous NH4Cl (30 mL) and extracted with ethyl acetate (3x 30mL).
  • Step 4 ethyl 2-(3-fluoro-2-methoxy-5-(2-methoxypropan-2-yl)phenyl)acetate
  • 1-bromo-3-fluoro-2-methoxy-5-(2-methoxypropan-2-yl)benzene 690 mg, 2.5 mmol
  • Pd 2 (dba) 3 92 mg, 0.125 mmol
  • Q-Phos 115 mg, 0.125 mmol
  • Step 5 ethyl 2-bromo-2-(3-fluoro-2-methoxy-5-(2-methoxypropan-2-yl)phenyl)acetate
  • ethyl 2-(3-fluoro-2-methoxy-5-(2-methoxypropan-2- yl)phenyl)acetate was added lithium diisopropylamide solution 2.0 M in THF/hexanes (5.0 mL, 10.0 mmol) dropwise.
  • reaction mixture was stirred at -50°C for 15 min, then added a solution of 1-(3-bromo-5-fluoro-4- methoxyphenyl)ethan-1-one (1.25 g, 5.1 mmol) in anhydrous DCM (10 mL) dropwise.
  • the reaction mixture was warmed to ambient temperature slowly, then stirred at ambient temperature overnight.
  • the reaction was quenched with water (20 mL) and extracted with DCM (2 x 20 mL).
  • Step 2 ethyl 2-(5-(tert-butyl)-3-fluoro-2-methoxyphenyl)acetate
  • N-(tert-butyl)-3-fluoro-2-methoxyphenyl)acetate To a mixture of 1-bromo-5-(tert-butyl)-3-fluoro-2-methoxybenzene (1.26 g, 4.83 mmol), Q-Phos (171 mg, 0.24 mmol) and Pd2(dba)3 (249 mg, 0.24 mmol) in THF (10 mL) was added (2-ethoxy-2-oxoethyl)zinc(II) bromide (1 M in THF, 14.4 mL, 14.4 mmol) at RT under argon.
  • Step 3 ethyl 2-bromo-2-(5-(tert-butyl)-3-fluoro-2-methoxyphenyl)acetate
  • ethyl 2-(5-(tert-butyl)-3-fluoro-2-methoxyphenyl)acetate 1.19 g, 4.44 mmol
  • THF 20 mL
  • lithium diisopropylamide solution 2.0 M in THF/hexanes 5.6 mL, 11.2 mmol
  • Step 2 ethyl 2-(3-fluoro-5-isopropyl-2-methoxyphenyl)acetate
  • a mixture of ethyl 2-(3-fluoro-2-methoxy-5-(prop-1-en-2-yl)phenyl)acetate (7.9 g, 31.1 mmol), and Pd/C (0.79 g, 10 wt% loading) in ethyl acetate (100 mL) was stirred at 25 °C under hydrogen for 16 h.
  • Step 3 ethyl 2-bromo-2-(3-fluoro-5-isopropyl-2-methoxyphenyl)acetate
  • ethyl 2-(3-fluoro-5-isopropyl-2-methoxyphenyl)acetate 7. g, 28.7 mmol
  • lithium diisopropylamide solution 2.0 M in THF/hexanes 35.9 mL, 71.8 mmol
  • the reaction mixture was poured into water (500 mL) slowly and the pH of the mixture was adjusted to 8 with aqueous NaOH (2M), the resulting mixture was extracted with dichloromethane (500 mL x 3), the combined organic layers were dried over Na2SO4, concentrated under reduced pressure to give a residue.
  • the residue was purified by flash silica gel chromatography (Biotage®; 330 g SepaFlash® Silica Flash Column, Eluent of 0 ⁇ 10% Ethyl acetate/Petroleum ether gradient @ 200 mL/min) to give 1-bromo-3-fluoro-5-isopropyl-benzene (79 g, 363.92 mmol, 82.43% yield) as white oil.
  • Step 3 1-(2-bromo-6-fluoro-4-isopropylphenyl) ethanol
  • Step 4 1-bromo-2-ethyl-3-fluoro-5-isopropylbenzene [0840] To a solution of 1-(2-bromo-6-fluoro-4-isopropyl-phenyl) ethanol (1.8 g, 6.89 mmol) in DCM (20 mL) was added Et3SiH (1.60 g, 13.79 mmol, 2.20 mL) and TFA (4.72 g, 41.36 mmol, 3.06 mL). The mixture was stirred at 40 °C for 16 h. The reaction was quenched by ice water (40 mL) slowly, extracted with ethyl acetate (40 mL x 2).
  • Step 2 1-bromo-3,4-difluoro-5-iodo-2-methoxybenzene
  • a mixture of 6-bromo-2,3-difluorophenol (6.0 g, 28.9 mmol), KI (7.18 g, 43.3 mmol) and I2 (10.99 g, 43.3 mmol) in H2O (30 mL) was stirred at 0°C for 10 min, then added a solution of NaOH (2.3g, 57.7 mmol) in H 2 O (30mL) at 0°C. The mixture was stirred at room temperature for 8 hours, then diluted with aq. HCl (1N) and extracted with EtOAc.
  • Step 3 4-(5-bromo-2,3-difluoro-4-methoxyphenyl)tetrahydro-2H-pyran-4-ol
  • 1-bromo-3,4-difluoro-5-iodo-2-methoxybenzene (6.8 g, 19.5 mmol) in THF (40 mL) at -78°C, was added i-PrMgCl solution 2.0 M in THF (19 mL, 38 mmol) dropwise.
  • Step 4 4-(5-bromo-2,3-difluoro-4-methoxyphenyl)-4-methyltetrahydro-2H-pyran [0845] To a solution of TiCl4 (2.19 g, 11.6 mmol) in DCM (30 mL) at -55°C, was added Me2Zn (1M in hexanes, 11.6 mL,11.6 mmol) dropwise.
  • Step 5 ethyl 2-(3,4-difluoro-2-methoxy-5-(4-methyltetrahydro-2H-pyran-4- yl)phenyl)acetate
  • 4-(5-bromo-2,3-difluoro-4-methoxyphenyl)-4-methyltetrahydro-2H- pyran 360 mg, 1.12 mmol
  • Q-phos 43 mg, 0.23 mmol
  • Pd2(dba)3 55 mg, 0.23 mmol
  • 2-ethoxy-2-oxoethyl)zinc(II) bromide (1 M in THF, 4.8 mL).
  • Step 6 ethyl 2-bromo-2-(3,4-difluoro-2-methoxy-5-(4-methyltetrahydro-2H-pyran-4- yl)phenyl)acetate
  • ethyl 2-(3,4-difluoro-2-methoxy-5-(4-methyltetrahydro-2H-pyran-4- yl)phenyl)acetate 260 mg, 0.79 mmol
  • THF 20 mL
  • hexanes 0.8 mL, 1.6 mmol
  • Step 2 ethyl 2-(3,4-difluoro-2-methoxyphenyl)acetate
  • 1-bromo-3,4-difluoro-2-methoxybenzene (490 mg, 2.2 mmol)
  • Pd2(dba)3 101 mg, 0.05 mmol
  • Q-phos 80 mg, 0.05 mmol
  • THF 5 mL
  • 2- tert-butoxy-2-oxoethyl)zinc(II) bromide solution 1 M in THF (7.0 mL, 7.0 mmol) at rt under Ar was stirred at 60°C for 2 hours.
  • Step 3 ethyl 2-(5-bromo-3,4-difluoro-2-methoxyphenyl)acetate
  • HOAc 0.5 mL
  • H2SO4 0.15 mL
  • NBS 98 mg, 0.55 mmol
  • Step 4 ethyl 2-(5-cyclopropyl-3,4-difluoro-2-methoxyphenyl)acetate
  • Step 5 ethyl 2-bromo-2-(5-cyclopropyl-3,4-difluoro-2-methoxyphenyl)acetate
  • ethyl 2-(5-cyclopropyl-3,4-difluoro-2-methoxyphenyl)acetate 120 mg, 0.44 mmol
  • lithium diisopropylamide solution 2.0 M in THF/hexanes 0.6 mL, 1.2 mmol
  • Step 2 methyl 2-(3-bromo-5-fluoro-4-hydroxyphenyl)acetate
  • NBS 5.2 g, 29.22 mmol
  • K2CO3 3.54 g, 25.64 mmol
  • Step 3 methyl 2-(3-bromo-5-fluoro-4-methoxyphenyl)acetate
  • MeI 4.9 g, 34.7 mmol
  • K2CO3 6.4 g, 46.2 mmol
  • the reaction mixture was stirred at rt overnight.
  • the reaction mixture was diluted with H2O (50 mL) and extracted with EtOAc (3x 100 mL). The combined organic layer was washed with brine, dried over Na2SO4, filtered and concentrated in vacuo.
  • Step 4 methyl 2-(3-bromo-5-fluoro-4-methoxyphenyl)-4-((tert- butyldimethylsilyl)oxy)butanoate [0856] To a solution of methyl 2-(3-bromo-5-fluoro-4-methoxyphenyl)acetate (3 g, 10.83 mmol) in THF (30 mL) at -78°C, was added lithium diisopropylamide solution 2.0 M in THF/hexanes (8.1 mL, 16.2 mmol) dropwise.
  • Step 5 3-(3-bromo-5-fluoro-4-methoxyphenyl)-5-((tert-butyldimethylsilyl)oxy)-2- methylpentan-2-ol
  • MeMgBr 3N in THF, 8.5 mL, 25.5 mmol
  • the mixture was stirred at room temperature for 18 hours, then quenched with aq.
  • Step 6 3-(3-bromo-5-fluoro-4-methoxyphenyl)-2,2-dimethyltetrahydrofuran [0858] 3-(3-bromo-5-fluoro-4-methoxyphenyl)-5-((tert-butyldimethylsilyl)oxy)-2- methylpentan-2-ol (472 mg, 1.5 mmol) was treated with TBAF (1M in THF, 10 mL) at rt for 4 hours, then added MsCl (422 mg, 3.7 mmol) and TEA (522 mg, 5.2 mmol). The reaction mixture was stirred at rt for 18 hours.
  • Step 7 ethyl 2-(5-(2,2-dimethyltetrahydrofuran-3-yl)-3-fluoro-2-methoxyphenyl)acetate
  • 3-(3-bromo-5-fluoro-4-methoxyphenyl)-2,2-dimethyltetrahydrofuran (443 mg, 1.5 mmol)
  • Q-phos(53 mg, 0.075 mmol) and Pd 2 (dba) 3 69 mg, 0.075 mmol
  • 2 (dba) 3 69 mg, 0.075 mmol) in THF (10 mL)
  • (2-ethoxy-2-oxoethyl)zinc(II) bromide (1 M in THF, 4.4 mL).
  • Step 8 ethyl 2-bromo-2-(5-(2,2-dimethyltetrahydrofuran-3-yl)-3-fluoro-2- methoxyphenyl)acetate
  • ethyl 2-(5-(2,2-dimethyltetrahydrofuran-3-yl)-3-fluoro-2- methoxyphenyl)acetate 415 mg, 1.3 mmol
  • THF 10 mL
  • Li diisopropylamide solution 2.0 M in THF/hexanes 1.5 mL, 3.0 mmol
  • Step 2 ethyl 2-(2-fluoro-6-methoxy-3-(prop-1-en-2-yl)phenyl)acetate
  • Step 3 ethyl 2-(2-fluoro-3-isopropyl-6-methoxyphenyl)acetate
  • a mixture of ethyl 2-(2-fluoro-6-methoxy-3-(prop-1-en-2-yl)phenyl)acetate (780 mg, 3.10 mmol) and Pd/C (78 mg, 10%) in EtOH (30 mL) was stirred at 25 °C under H2 for 16 hours. Then the solid was removed by filtration and the filtrate was concentrated in vacuo to give the desired product ethyl 2-(2-fluoro-3-isopropyl-6-methoxyphenyl)acetate (750 mg, 2.95 mmol) as a light yellow oil.
  • Step 4 ethyl 2-bromo-2-(2-fluoro-3-isopropyl-6-methoxyphenyl)acetate
  • ethyl ethyl 2-(2-fluoro-3-isopropyl-6-methoxyphenyl)acetate 750 mg, 2.95 mmol
  • THF 20 mL
  • lithium diisopropylamide solution 2.0 M in THF/hexanes 3.6 mL, 7.2 mmol
  • Step 2 ethyl 2-(5-bromo-3-fluoro-2-methoxyphenyl)acetate
  • NBS 6.6 g, 36.9 mmol
  • HOAc a solution of ethyl 2-(3-fluoro-2- methoxyphenyl)acetate (7.1 g, 33.5 mmol) in HOAc (55 mL) and concentrated H2SO4 (9 mL) at 0 °C.
  • the mixture was stirred at 0 °C for 5 hours, quenched with water (20 mL) and extracted with EtOAc (20 mL x3).
  • Step 3 ethyl 2-(5-(2,5-dihydrofuran-2-yl)-3-fluoro-2-methoxyphenyl)acetate
  • Step 4 ethyl 2-(3-fluoro-2-methoxy-5-(tetrahydrofuran-2-yl)phenyl)acetate
  • Step 5 ethyl 2-bromo-2-(3-fluoro-2-methoxy-5-((R)-tetrahydrofuran-2-yl)phenyl)acetate
  • LDA 1.2 mL, 2.3 mmol, 2N in THF
  • TMSCl 250 mg, 2.3 mmol
  • Step 2 ethyl 2-bromo-2-(5-cyclopropyl-3-fluoro-2-methoxyphenyl)acetate
  • LDA 2.3 mL, 4.6 mmol, 2N in THF
  • TMSCl 500 mg, 4.6 mmol
  • NBS 819 mg, 4.6 mmol
  • Step 2 ethyl 2-(2-methoxy-3-(trifluoromethyl)phenyl)acetate
  • (2-ethoxy-2-oxoethyl)zinc(II) bromide (15 mL, 15 mmol, 1 N in THF) was added to a solution of 1-bromo-2-methoxy-3-(trifluoromethyl)benzene (1.28 g, 5 mmol), Pd2(dba)3 (73 mg, 0.08 mmol) and Q-phos (57 mg, 0.08 mmol) in 15 mL of THF under argon atmosphere.
  • Step 3 ethyl 2-(5-bromo-2-methoxy-3-(trifluoromethyl)phenyl)acetate
  • NBS (427 mg, 2.4 mmol) was added to a solution of ethyl 2-(2-methoxy-3- (trifluoromethyl)phenyl)acetate (524 mg, 2 mmol) in HOAc (4 mL) and concentrated H2SO4 (2 mL) at 0 °C.
  • HOAc 4 mL
  • H2SO4 2 mL
  • the mixture was stirred at room temperature for 4 hours, quenched with water ( 10 mL) and extracted with EtOAc (10 mLx3).
  • Step 4 ethyl 2-(2-methoxy-5-(prop-1-en-2-yl)-3-(trifluoromethyl)phenyl)acetate
  • K 2 CO 3 (830 mg, 6 mmol) and Pd(dppf)Cl2 (110 mg, 0.15 mmol) in 15 mL of dioxane and 3 mL of H2O was stirred at 90 °C for 2 hours.
  • Step 5 ethyl 2-(5-isopropyl-2-methoxy-3-(trifluoromethyl)phenyl)acetate
  • Step 6 ethyl 2-bromo-2-(5-isopropyl-2-methoxy-3-(trifluoromethyl)phenyl)acetate
  • LDA 1.6 mL, 3.2 mmol, 2N in THF
  • TMSCl 348 mg, 3.2 mmol
  • NBS 570 mg, 3.2 mmol
  • Step 2 ethyl 2-(5-bromo-3-chloro-2-methoxyphenyl)acetate
  • NBS 85 mg, 0.48 mmol
  • HOAc 3 mL
  • H 2 SO 4 0.5 mL
  • the mixture was stirred at 0 °C for 4 hours, quenched water (10 mL) and extracted with EtOAc (10 mLx3).
  • Step 3 ethyl 2-(3-chloro-2-methoxy-5-(prop-1-en-2-yl)phenyl)acetate
  • Step 4 ethyl 2-(3-chloro-5-isopropyl-2-methoxyphenyl)acetate
  • Step 5 ethyl 2-bromo-2-(3-chloro-5-isopropyl-2-methoxyphenyl)acetate
  • LDA 5.4 mL, 2.7 mmol, 2N in THF
  • TMSCl 583 mg, 5.4 mmol
  • NBS 961 mg, 5.4 mmol
  • Step 2 ethyl 2-(3-fluoro-2-methoxy-5-(2-methylprop-1-en-1-yl)phenyl)acetate
  • K 2 CO 3 (940 mg, 6.8 mmol)
  • Pd(dppf)Cl 2 124 mg, 0.17 mmol
  • Step 3 ethyl 2-(3-fluoro-5-isobutyl-2-methoxyphenyl)acetate
  • Step 4 ethyl 2-bromo-2-(3-fluoro-5-isobutyl-2-methoxyphenyl)acetate
  • LDA 3.9 mL, 7.8 mmol, 2N in THF
  • TMSCl 836 mg, 7.8 mmol
  • NBS 1.5 g, 7.8 mmol
  • Step 2 ethyl 2-bromo-2-(3-fluoro-5-(2-hydroxypropan-2-yl)-2-methoxyphenyl)acetate
  • ethyl 2-(3-fluoro-5-(2-hydroxypropan-2-yl)-2-methoxyphenyl)acetate 500 mg, 1.85 mmol
  • THF 10 mL
  • lithium diisopropylamide solution 2.0 M in THF/hexanes 1.9 mL, 3.8 mmol
  • Step 2 1-(3-bromo-5-fluoro-4-methoxyphenyl)cyclohexan-1-ol
  • Step 3 1-(3-bromo-5-fluoro-4-methoxyphenyl)cyclohexan-1-ol
  • Step 4 ethyl 2-(3-fluoro-2-methoxy-5-(1-methoxycyclohexyl)phenyl)acetate
  • 1-bromo-3-fluoro-2-methoxy-5-(1-methoxycyclohexyl)benzene 750 mg, 2.37 mmol
  • Pd2(dba)3 92 mg, 0.125 mmol
  • Q-phos 115 mg, 0.125 mmol
  • Step 5 ethyl 2-bromo-2-(3-fluoro-2-methoxy-5-(1-methoxycyclohexyl)phenyl)acetate
  • ethyl 2-(3-fluoro-2-methoxy-5-(1-methoxycyclohexyl)phenyl)acetate 510 mg, 1.57 mmol
  • THF 15 mL
  • -78°C lithium diisopropylamide solution 2.0 M in THF/hexanes (1.5 mL, 3.0 mmol) dropwise.
  • Step 3 2-(3-bromo-5-fluoro-4-methoxyphenyl)-2-methyltetrahydro-2H-pyran [0899] To a solution of 5-(3-bromo-5-fluoro-4-methoxyphenyl)hexane-1,5-diol (430 mg, 1.34 mmol) and Et3N (271 mg, 2.68 mmol) in THF (10 mL) at 0 °C, was added MsCl (230 mg, 2.01mmol). The reaction mixture was stirred at rt for 2 hours, then added H2O (10 mL), and extracted with EtOAc (3x 20 mL).
  • Step 4 ethyl 2-(3-fluoro-2-methoxy-5-(2-methyltetrahydro-2H-pyran-2-yl)phenyl)acetate
  • 2-(3-bromo-5-fluoro-4-methoxyphenyl)-2-methyltetrahydro-2H- pyran (298 mg, 0.98 mmol)
  • Pd2(dba)3 56 mg, 0.05 mmol
  • Q-phos 38 mg, 0.05 mmol
  • Step 5 ethyl 2-bromo-2-(3-fluoro-2-methoxy-5-(2-methyltetrahydro-2H-pyran-2- yl)phenyl)acetate
  • ethyl 2-(3-fluoro-2-methoxy-5-(2-methyltetrahydro-2H-pyran-2- yl)phenyl)acetate 250 mg, 0.81 mmol
  • THF 10 mL
  • hexanes 0.8 mL, 1.6 mmol
  • Step 2 4-(3-bromo-5-fluoro-4-methoxyphenyl)tetrahydro-2H-pyran-4-ol
  • 1-bromo-3-fluoro-5-iodo-2-methoxybenzene 500 mg, 1.51 mmol
  • THF dry, 20 mL
  • iso-propylmagnesium chloride 1.0 M, 1.8 mL, 1.8 mmol
  • the reaction was stirred at 0°C for 1 hour, then a solution of tetrahydro-4H-pyran-4-one (180 mg, 1.8 mmol) in THF (5 mL) was added dropwise.
  • Step 3 4-(3-bromo-5-fluoro-4-methoxyphenyl)-4-methyltetrahydro-2H-pyran [0904] To a solution of TiCl 4 (3.60 g, 18.8 mmol) in DCM (30 mL) at -55°C, was added Me2Zn (1M in hexanes, 19 mL,19 mmol) dropwise. The reaction was stirred at -78°C for 1 hour, then 4-(3-bromo-5-fluoro-4-methoxyphenyl)tetrahydro-2H-pyran-4-ol (2.28 g, 7.47 mmol) in THF (10 mL) was added at -78 °C.
  • Step 4 ethyl 2-(3-fluoro-2-methoxy-5-(4-methyltetrahydro-2H-pyran-4-yl)phenyl)acetate
  • 4-(3-bromo-5-fluoro-4-methoxyphenyl)-4-methyltetrahydro-2H- pyran 660 mg, 2.18 mmol
  • Q-phos 80 mg, 0.11 mmol
  • Pd2(dba)3 100 mg, 0.11 mmol
  • 2-ethoxy-2-oxoethyl)zinc(II) bromide (1 M in THF, 8.8 mL).
  • Step 5 ethyl 2-bromo-2-(3-fluoro-2-methoxy-5-(4-methyltetrahydro-2H-pyran-4- yl)phenyl)acetate
  • ethyl 2-(3-fluoro-2-methoxy-5-(4-methyltetrahydro-2H-pyran-4- yl)phenyl)acetate 550 mg, 1.77 mmol
  • THF 20 mL
  • 4.4 mmol lithium diisopropylamide solution 2.0 M in THF/hexanes
  • Step 2 1-(3-bromo-5-fluoro-4-methoxyphenyl)ethan-1-one [0908] A mixture of 1-(3-bromo-5-fluoro-4-hydroxyphenyl)ethan-1-one (12.1 g, 52.16 mmol), Methyl iodide (11.1 g, 78.24 mmol) and K2CO3 (14.4 g, 104.32 mmol) in DMF (100 mL) were stirred at rt for 16 hours. Water (500 mL) was added, the mixture was extracted with EtOAc (2x 200 mL).
  • Step 3 1-bromo-5-ethyl-3-fluoro-2-methoxybenzene
  • a solution of 1-(3-bromo-5-fluoro-4-methoxyphenyl)ethan-1-one (4.92 g, 20 mmol) in DCM (50 mL) was cooled to 0°C, added TFA (13.68 g, 120 mmol) and stirred at 0°C for 10 min, then Et3SiH (13.92 g, 120 mmol) was added and the reaction mixture was stirred at 0°C for 30min. The mixture was quenched with sat.NaHCO3 solution (100 mL), then extracted with DCM (3 ⁇ 50mL).
  • Step 4 ethyl 2-(5-ethyl-3-fluoro-2-methoxyphenyl)acetate
  • Pd2(dba)3 512 mg, 0.56 mmol
  • Q-phos 409 mg, 0.56 mmol
  • THF 50 mL
  • the reaction was stirred at 60°C for 2 hours.
  • Step 5 ethyl 2-bromo-2-(5-ethyl-3-fluoro-2-methoxyphenyl)acetate
  • ethyl 2-(5-ethyl-3-fluoro-2-methoxyphenyl)acetate 3.92 g, 16.33 mmol
  • lithium diisopropylamide solution 2.0 M in THF/hexanes (16.3 mL, 32.6 mmol) dropwise.

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Abstract

La présente invention concerne de nouveaux composés chimiques et des méthodes utiles pour inhiber l'intégrine αvβ8, y compris des composés selon la formule (I) et des sels pharmaceutiquement acceptables de ceux-ci.
PCT/US2024/015824 2023-02-14 2024-02-14 INHIBITION DE L'INTÉGRINE α Vβ8 WO2024173572A1 (fr)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014179664A2 (fr) 2013-05-02 2014-11-06 Anaptysbio, Inc. Anticorps dirigés contre la protéine de mort programmée 1 (pd-1)
US20180244648A1 (en) * 2017-02-28 2018-08-30 Lazuli, Inc. Inhibitors of (alpha-v)(beta-6) integrin
WO2020047239A1 (fr) * 2018-08-29 2020-03-05 Morphic Therapeutic, Inc. INHIBITION DE L'INTÉGRINE ανβ6

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014179664A2 (fr) 2013-05-02 2014-11-06 Anaptysbio, Inc. Anticorps dirigés contre la protéine de mort programmée 1 (pd-1)
US20180244648A1 (en) * 2017-02-28 2018-08-30 Lazuli, Inc. Inhibitors of (alpha-v)(beta-6) integrin
WO2020047239A1 (fr) * 2018-08-29 2020-03-05 Morphic Therapeutic, Inc. INHIBITION DE L'INTÉGRINE ανβ6

Non-Patent Citations (6)

* Cited by examiner, † Cited by third party
Title
"Bioreversible Carriers in Drug Design", 1987, AMERICAN PHARMACEUTICAL ASSOCIATION AND PERGAMON PRESS
"Burger's Medicinal Chemistry and Drug Discovery", vol. 172-178, article "Periodic Table of the Elements", pages: 1986 - 982
BERGE ET AL.: "Pharmaceutical Salts", J. PHARM. SCI, vol. 66, 1977, pages 1 - 19, XP002675560, DOI: 10.1002/jps.2600660104
BUNDGARD, H: "Design of Prodrugs", 1985, ELSELVIER, pages: 7 - 9,21-24
HIGUCHI, T ET AL.: "A. C S. Symposium Series", vol. 14, article "Pro-drugs as Novel Delivery Systems"
UNITED STATES PATENT OFFICE MANUAL OF PATENT EXAMINING PROCEDURES

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