OA18225A

OA18225A - Aminopyrimidinyl compounds as Jak inhibitors.

Info

Publication number: OA18225A
Application number: OA1201700051
Authority: OA
Inventors: Ariamala Gopalsamy; Betsy PIERCE; Li Xing; Eddine Saiah; John I Trujillo; Jean-Baptiste Telliez; Ivan Viktorovich Efremov; Zhao-Kui Wan; Andrew Fensome; Liying Zhang; Brian S. GERSTENBERGER
Original assignee: Pfizer Inc.
Priority date: 2014-08-21
Filing date: 2015-08-07
Publication date: 2018-09-04

Abstract

A compound compound having the structure:

Description

AMINOPYRIMIDINYL COMPOUNDS

FIELD OF THE INVENTION

The présent invention provides pharmaceutically active aminopyrimidinyl compounds and analogues. Such compounds are useful for inhibiting Janus Kinase (JAK). This invention also is directed to compositions comprising methods for making such compounds, and methods for treating and preventing conditions mediated by JAK.

BACKGROUND OFTHE INVENTION

Protein kinases are familles of enzymes that catalyze the phosphorylation of spécifie residues in proteins, broadly classified into tyrosine and serine/threonine kinases. Inappropriate kinase activity, arising from mutation, over-expression, or inappropriate régulation, dys-regulation or de-regulation, as well as over- or under-production of growth factors or cytokines has been implicated in many diseases, including but not limited to cancer, cardiovascular diseases, allergies, asthma and other respiratory diseases, autoimmune diseases, inflammatory diseases, bone diseases, metabolic disorders, and neurological and neurodegenerative disorders such as Alzheimer's disease. Inappropriate kinase activity triggers a variety of biological cellular responses relating to cell growth, cell différentiation, cell function, survival, apoptosis, and cell mobility implicated in the aforementioned and related diseases.

Thus, protein kinases hâve emerged as an important class of enzymes as targets for therapeutic intervention. In particular, the JAK famiiy of cellular protein tyrosine kinases (JAK1, JAK2, JAK3, and Tyk2) play a central rôle in cytokine signaling (Kisseieva et al., Gene, 2002, 285, 1; Yamaoka et al. Genome Biology 2004, 5, 253)). Upon binding to their receptors, cytokines activate JAK which then phosphorylate the cytokine receptor, thereby creating docking sites for signaling molécules, notably, members of the signal transducer and activator of transcription (STAT) famiiy that ultimateiy lead to gene expression. Numerous cytokines are known to activate the JAK famiiy. These cytokines include, the interferon (IFN) famiiy (IFN-alpha, IFN-beta, IFN-omega, Limitin, IFN-gamma, IL-10, IL-19, IL-20, IL-22), the gp130 famiiy (IL-6, IL-11, OSM, LIF, CNTF, NNT-1/BSF-3, G-CSF, ΟΤΙ, Leptin, IL-12, IL-23), gamma C famiiy (IL-2, IL-7, TSLP, IL-9, IL-15, IL-21, IL-4, IL-13), IL-3 famiiy 30 (IL-3, IL-5, GM-CSF), single chain famiiy (EPO, GH, PRL, TPO), receptor tyrosine kinases (EGF,

PDGF, CSF-1, HGF), and G-protein coupled receptors (AT1).

There remains a need for new compounds that effectively and selectively inhibit spécifie JAK enzymes: TYK2 and JAK1 in particular. TYK2 is a JAK kinase famiiy member, and is important in the signaling ofthe type I interferons (IFNa, INFb) IL-6, IL-10, IL-12 and IL-23 (Liang, Y. et al., Expert 35 Opinion on Therapeutic Targets, 18, 5, 571-580 (2014)). As such, TYK2 signais with other members of the JAK kinase famiiy in the following combinations: TYK2/JAK1, TYK2/JAK2, TYK2/JAK1/JAK2. TYK2 has been shown to be important in the différentiation and function of multiple cell types important in inflammatory disease and autoimmune disease including natural killer cells, B cells, and T helper cell types. Aberrant TYK2 expression is associated with multiple autoimmune or 40 inflammatory conditions. JAK1 is a member of the Janus famiiy of protein kinases composed of JAK1,

JAK2, JAK3 and TYK2. JAK1 is expressed to various levels in ail tissues. Many cytokine receptors signal through pairs of JAK kinases in the following combinations: JAK1/JAK2, JAK1/JAK3, JAK1/TYK2, JAK2/TYK2 or JAK2/JAK2. JAK1 is the most broadly paired JAK kinase in this context and is required for signaling by γ-common (IL-2Ry) cytokine receptors, IL-6 receptor family, Type I, Il and III receptor families and IL-10 receptor family. Animal studies hâve shown that JAK1 is required for the development, function and homeostasis of the immune system. Modulation of immune activity through inhibition of JAK1 kinase activity can prove useful in the treatment of various immune disorders (Murray, P.J., J. Immunol., 178, 2623-2629 (2007); Kisseleva, T., et al., Gene, 285, 1-24 (2002); O'Shea, J. J., et al., Cell, 109 (suppl.), S121-S131 (2002)) while avoiding JAK2 dépendent erythropoietin (EPO) and thrombopoietin (TPO) signaling (Neubauer H., et al., Cell, 93(3), 397-409 (1998); Parganas E., étal., Cell, 93(3), 385-95 (1998)).

SUMMARY OF THE INVENTION

The présent invention provides a compound of formula I having the structure:

Ri \

(CH₂)_y

A

n or a pharmaceutically acceptable sait thereof, wherein X is N or CR, where R is hydrogen, deuterium, C1-C4 alkyl, C1-C4 alkoxy, C3-C6 cycloalkyl, aryl, heteroaryl, aryl(Ci-C6 alkyl), CN, amino, alkylamino, dialkylamino, CF3, or hydroxyl;

A is selected from the group consisting of a bond, C=O, -SO2--, -(C=0)NRo-, and — (CR_aRb)_Q-, where Ro is H or C1-C4 alkyl, and R_a and Rb are independently hydrogen, deuterium, C1-C6 alkyl, C3-C6 cycloalkyl, aryl, aryI(Ci-Cs alkyl), heteroaryl, (Ci-Ce alkyl)heteroaryl, heteroaryl(Ci-Ce alkyl), and heterocyclic(Ci-C6 alkyl);

A' is selected from the group consisting of a bond, C=O, --SO2--, --(C=0)NRo', -- NRo'(C=0)--, and -(CRa'Rb')q--, where Ro' is H or C1-C4 alkyl, and R_a' and Rb' are independently hydrogen, deuterium, C1-C6 alkyl, C3-C6 cycloalkyl, aryl, aryl(Ci-C6 alkyl), heteroaryl, (C1-C6 alkyl)heteroaryl, heteroaryl(Ci-C6 alkyl), and heterocyclic(Ci-C6 alkyl);

Z is -(ΟΗ2)λ- or a bond, where one or more methylene units are optionally substituted by one or more C1-C3 alkyl, CN, OH, methoxy, or halo, and where said alkyl may be substituted by one or more fluorine atoms;

Ri and Ri' are independently selected from the group consisting of hydrogen, deuterium, C1C₄ alkyl, C3-C6 cycloalkyl, aryl, heteroaryl, aryl(Ci-C6 alkyl), CN, amino, alkylamino, dialkylamino, fluoroalkyl, alkoxy, heteroaryl(Ci-C6 alkyl), heterocyclic and heterocyclic(Ci-C6 alkyl), wherein said alkyl, aryl, cycloalkyl, heterocyclic, or heteroaryl is further optionally substituted with one or more substituents selected from the group consisting of C1-C6 alkyl, halo, CN, hydroxy, methoxy, amino, C1-C4 alkyl amino, di(Ci-C₄ alkyl)amino, CF3, --SO2-(Ci-C6 alkyl), and C3-C6 cycloalkyl;

R2 is selected from the group consisting of hydrogen, deuterium, C1-C6 alkyl, C3-C6 cycloalkyl, halo, and cyano, where said alkyl may be substituted by one or more fluorine atoms;

R3 is selected from the group consisting of hydrogen, deuterium, and amino;

R₄ is monocyclic or bicyclic aryl or monocyclic or bicyclic heteroaryl wherein said aryl or heteroaryl is optionally substituted with one or more substituents selected from the group consisting of C1-C6 alkyl, heterocycloalkyl, halo, CN, hydroxy, --CO2H, C1-C6 alkoxy, amino, -N(Ci-Ce alkyl) (CO)(Ci-Ce alkyl), -NH(CO)(Ci-Ce alkyl), -(CO)NH_Z, -(CO)NH(Ci-C_e alkyl), -(CO)N(Ci-Ce alkyl)2, --(C1-C6 alkyl)amino, --N(Ci-C6 alkyl)2, -SO2-(Ci-C6 alkyl), --(SO)NH2, and C3-C6 cycloalkyl, where said alkyl, cycloalkyl, alkoxy, or heterocycloalkyl may be substituted by one or more Ci-Ce alkyl, halo, CN, OH, alkoxy, amino, --CO2H, -(CO)NH2, -(CO)NH(Ci-C6 alkyl), or --(CO)N(Ci-Ce alkyl)2, and where said alkyl may be further substituted by one or more fluorine atoms;

Rs is independently selected from the group consisting of hydrogen, C1-C6 alkyl, Ci-Ce alkoxy, and hydroxyl;

h is 1, 2 or 3; j and k are independently 0, 1, 2, or 3; m and n are independently 0, 1 or 2; and, <7 is 0,1 or 2.

In other aspects, the présent invention also provides:

pharmaceutical compositions which comprise a pharmaceutically acceptable carrier and a compound of formula I; methods for treating conditions or disorders including myositis, vasculitis, pemphigus, Crohn’s disease, lupus, nephritis, psoriasis, multiple sclerosis, major dépréssion disorder, allergy, asthma, Sjogren’s disease, dry eye syndrome, transplant rejection, cancer, inflammatory bowel disease, septic shock, cardiopulmonary dysfunction, vitiligo, alopecia, acute respiratory disease, ankylosing spondylitis, autoimmune hepatitis, primary sclerosing cholangitis, primary biliary cirrhosis, Alzheimer’s disease, or cachexia by administering to a subject in need a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable sait thereof;

methods for treating conditions or disorders including atopie dermatitis, eczema, psoriasis, scleroderma, lupus, pruritus, other pruritic conditions, allergie reactions including allergie dermatitis in mammal, horse allergie diseases including bite hypersensitivity, summer eczema, sweet itch in horses, heaves, inflammatory airway disease, récurrent airway obstruction, airway hyperresponsiveness, and chronic obstruction pulmonary disease by administering to a mammal in need a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable sait thereof; and, methods for the préparation of compounds ofthe présent invention.

The présent invention will be further understood from the following description given by way of example only. The présent invention is directed to a class of aminopyrimidine dérivatives. In particular, the présent invention is directed to aminopyrimidine compounds useful as inhibitors of JAK, and particularly TYK2 and JAK1. While the présent invention is not so limited, an appréciation of various aspects ofthe invention will be gained through the following discussion and the examples.

The term “alkyl”, alone or in combination, means an acyclic, saturated hydrocarbon group of the formula C_nH2n+i which may be linear or branched. Examples of such groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyi, tert-butyl, pentyl, iso-amyl and hexyl. Unless otherwise specified, an alkyl group comprises from 1 to 6 carbon atoms. The carbon atom content of alkyl and various other hydrocarbon-containing moieties is indicated by a prefix designating a lower and upper number of carbon atoms in the moiety, that is, the prefix Ci-Cj indicates a moiety of the integer i to the integer j carbon atoms, inclusive. Thus, for example, C1-C6 alkyl refers to alkyl of one to six carbon atoms, inclusive.

The term “hydroxy,” as used herein, means an OH group. The term “heterocyclic refers to a saturated or partially saturated (i.e., non aromatic) heterocycle which contains five to ten ring atoms where one or more, preferably, one, two or three ring atoms, are heteratom(s) selected from N, O and S, the remaining being carbon, and which may be attached via a ring nitrogen atom or a ring carbon atom. Equally, when substituted, the substituent may be located on a ring nitrogen atom (if the substituent is joined through a carbon atom) or a ring carbon atom (in ail cases). Spécifie examples include oxiranyl, aziridinyl, oxetanyl, azetidinyl, tetrahydrofuranyl, pyrrolidinyl, tetrahydropyranyl, piperidinyl, 1,4-dioxanyl, morphoiinyl, piperazinyl, azepanyl, oxepanyl, oxazepanyl and diazepinyl.

The term “aryl” refers to an aromatic monocyclic or bicyclic hydrocarbon containing six to ten ring carbon atoms which may be attached via one of the ring carbon atoms. Equally, when substituted, the substituent may be located on a ring carbon atom. Spécifie examples include, but are not limited to, phenyl, toluyl, xylyi, trimethylphenyl, and naphthyl. Examples of aryl substituents include, but are not limited to, alkyl, hydroxyl, halo, nitrile, alkoxy, trifluoromethyl, carboxamido, SO2Me, benzyl, and substituted benzyl.

The term “heteroaryl” refers to a monovalent aromatic monocyclic or bicyclic heterocycle of five to ten ring atoms where one or more, preferably, one, two or three ring atoms, are heteratom(s) selected from N, O, and S, the remaining being carbon, and which may be attached via a ring carbon atom or a ring nitrogen atom with an appropriate valency. Equally, when substituted, the substituent may be located on a ring carbon atom or a ring nitrogen atom with an appropriate valency. Spécifie examples include, but are not limited to, thienyl, furanyl, pyrrolyl, pyrazolyl, imidazoiyl, oxazoiyl, isoxazolyl, thiazolyl, isothiazolyi, triazolyl, oxadiazolyl, thiadiazolyi, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl and pyrazinyl. The term cycloalkyl means a monocyclic, saturated hydrocarbon group of the formula C_nH2n-i. Examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. Unless otherwise specified, a cycloalkyl group comprises from 3 to 8 carbon atoms.

The terms “halo” and “halogen” refer to fluoride (F), chloride (Cl), bromide (Br) or iodide (I).

The term mammai refers to human, livestock or companion animais.

The term “companion animal” or “companion animais” refers to animais kept as pets or household animal. Examples of companion animais include dogs, cats, and rodents including hamsters, guinea pigs, gerbils and the like, rabbits, ferrets and birds.

The term “livestock” refers to animais reared or raised in an agricultural setting to make products such as food or fiber, or for its labor. In some embodiments, livestock are suitable for consumption by mammals, for example humans. Examples of livestock animais include cattle, goats, horses, pigs, sheep, including lambs, and rabbits, as well as birds, such as chickens, ducks and turkeys.

The term “treating” or “treatment” means an alleviation of symptoms associated with a disease, disorder or condition, or hait of further progression or worsening of those symptoms. Depending on the disease and condition of the patient, the term “treatment” as used herein may include one or more of curative, palliative and prophylactic treatment. Treatment can also include administering a pharmaceutical formulation of the présent invention in combination with other thérapies.

The term therapeutically-effective indicates the capability of an agent to prevent, or improve the severity of, the disorder, while avoiding adverse side effects typically associated with alternative thérapies. The phrase therapeutically-effective is to be understood to be équivalent to the phrase effective for the treatment, prévention, or amelioration, and both are intended to qualify the amount of each agent for use in the combination therapy which will achieve the goal of improvement in the severity of cancer, cardiovascular disease, or pain and inflammation and the frequency of incidence over treatment of each agent by itself, while avoiding adverse side effects typically associated with alternative thérapies.

“Pharmaceutically acceptable” means suitable for use in mammals, companion animais or livestock animais.

If substituents are described as being “independently selected” from a group, each substituent is selected independent of the other. Each substituent therefore may be identical to or different from the other substituent(s).

DETAILED DESCRIPTION OF THE INVENTION

The présent invention is related to novel compounds which are TYK2 and JAK1 modulators useful for the treatment of diseases and conditions associated with dysrégulation of TYK2 and JAK1. The présent invention further provides pharmaceutical compositions comprising such JAK enzyme modulators as well as methods of treating and/or preventing such diseases and conditions. Accordingly, the présent invention provides a compound of formula I having the structure:

^R1 \ (CH₂)j

or a pharmaceutically acceptable sait thereof, wherein X is N or CR, where R is hydrogen, deuterium, C1-C4 alkyl, C1-C4 alkoxy, C3-C6 cycloalkyl, aryl, heteroaryl, aryl(Ci-C6 alkyl), CN, amino, alkylamino, dialkylamino, CF3, or hydroxyl;

A is selected from the group consisting of a bond, C=O, -SO2--, --(C=0)NRo--, and -(CRaRb)₉-, where Ro is H or C1-C4 alkyl, and R_a and Rb are independently hydrogen, deuterium, C1-C6 alkyl, C3-C6 cycloalkyl, aryl, aryl(Ci-C6 alkyl), heteroaryl, (Ci-Ce alkyl)heteroaryl, heteroaryl(Ci-C6 alkyl), and heterocyclic(Ci-C6 alkyl);

A' is selected from the group consisting of a bond, C=O, --SO2--, -(C=0)NRo', -- NRo'(C=0)-, and -(CRa'RbV-, where Ro' is H or C1-C4 alkyl, and R_a' and Rb' are independently hydrogen, deuterium, Ci-Ce alkyl, C3-C6 cycloalkyl, aryl, aryl(Ci-Ce alkyl), heteroaryl, (Ci-Ce alkyl)heteroaryl, heteroaryl(Ci-C6 alkyl), and heterocyclic(Ci-C6 alkyl);

Z is --(CH2)/)-- or a bond, where one or more methylene units are optionally substituted by one or more C1-C3 alkyl, CN, OH, methoxy, or halo, and where said alkyl may be substituted by one or more fluorine atoms;

Ri and Ri' are independently selected from the group consisting of hydrogen, deuterium, C1C4 alkyl, C3-C6 cycloalkyl, aryl, heteroaryl, aryl(Ci-C6 alkyl), CN, amino, alkylamino, dialkylamino, fluoroalkyl, alkoxy, heteroaryl(Ci-C6 alkyl), and heterocyclic(Ci-C6 alkyl), wherein said alkyl, aryl, cycloalkyl, heterocyclic, or heteroaryl is further optionally substituted with one or more substituents selected from the group consisting of Ci-Ce alkyl, halo, CN, hydroxy, methoxy, amino, C1-C4 alkyl amino, di(Ci-C4 alkyl)amino, CF3, -SO2-(Ci-C6 alkyl), and C3-C6 cycloalkyl;

R3 is selected from the group consisting of hydrogen, deuterium, and amino;

R4 is monocyclic or bicyclic aryl or monocyclic or bicyclic heteroaryl wherein said aryl or heteroaryl is optionally substituted with one or more substituents selected from the group consisting of Ci-Ce alkyl, heterocycloalkyl, halo, CN, hydroxy, -CO2H, C1-C6 alkoxy, amino, -N(Ci-C6 alkyl)(CO)(Ci-C₆ alkyl), -NH(CO)(Ci-C₆ alkyl), -(CO)NH_Z, -(CO)NH(Ci-C₆ alkyl), -(CO)N(Ci-C₆alkyl)2, --(C1-C6 alkyl)amino, --N(Ci-C6 alkyl)2, --SC>2-(Ci-C6 alkyl), --(SO)NH2, and C3-C6 cycloalkyl, where said alkyl, cycloalkyl, alkoxy, or heterocycloalkyl may be substituted by one or more C1-C6 alkyl, halo, CN, OH, alkoxy, amino, -CO₂H, _(CO)NH₂, -(CO)NH(Ci-C₆ alkyl), or -(CO)N(Ci-Ce alkyl)2, and where said alkyl may be further substituted by one or more fluorine atoms;

Rs is independently selected from the group consisting of hydrogen, Ci-Ce alkyl, Ci-Ce alkoxy, and hydroxyl;

h is 1, 2 or 3; j and k are independently 0,1,2, or 3; m and n are independently 0, 1 or 2; and, q is 0, 1 or 2.

The invention also provides a compound having the structure:

or a pharmaceutically acceptable sait thereof, wherein

Xis N;

A is selected from the group consisting of a bond, C=O, -SO2--, --(C=0)NRo~-, and (CRaRb)q--, where Ro is H or C1-C4 alkyl, and R_a and Rb are independently hydrogen, deuterium, C1-C6 alkyl, C3-C6 cycloalkyl, aryl, aryl(Ci-C6 alkyl), heteroaryl, (C1-C6 alkyl)heteroaryl, heteroaryl(Ci-C6 alkyl), and heterocyclic(Ci-C6 alkyl);

Ri is selected from the group consisting of hydrogen, deuterium, C1-C4 alkyl, C3-C6 cycloalkyl, aryl, heteroaryl, aryl(Ci-C6 alkyl), CN, amino, alkylamino, dialkylamino, fluoroalkyl, alkoxy, heteroaryl(Ci-C6 alkyl), and heterocyclic(Ci-C6 alkyl), wherein said alkyl, aryl, cycloalkyl, heterocyclic, or heteroaryl is further optionally substituted with one or more substituents selected from the group consisting of Ci - C6 alkyl, halo, CN, hydroxy, methoxy, amino, C1-C4 alkyl amino, di(Ci-C4 alkyl)amino, CF3, --SO₂-(Ci-Ce alkyl), and C3-C6 cycloalkyl;

R3 is selected from the group consisting of hydrogen and deuterium;

R4 is monocyclic or bicyclic aryl or monocyclic or bicyclic heteroaryl wherein said aryl or heteroaryl is optionally substituted with one or more substituents selected from the group consisting of C1-C6 alkyl, heterocycloalkyl, halo, CN, hydroxy, --CO2H, C1-C6 alkoxy, amino, -N(Ci-C6 alkyl)(CO)(Ci-C_B alkyl), -NH(CO)(Ci-C₆ alkyl), -(CO)NH₂, -(CO)NH(Ci-Ce alkyl), -(CO)N(Ci-Cs alkyl)2, --(C1-C6 alkyl)amino, -N(Ci-C6 alkyl)2, --SO₂-(Ci-C6 alkyl), -(SO)NH2, and C3-C6 cycloalkyl,

where said alkyl, cycloalkyl, alkoxy, or heterocycloalkyl may be substituted by one or more C1-C6 alkyl, halo, CN, OH, alkoxy, amino, --CO2H, --(CO)NH2, --(CO)NH(Ci-C6 alkyl), or --(CO)N(Ci-C6 alkyl)2, and where said alkyl may be further substituted by one or more fluorine atoms;

h is 1, j is 1,2, or 3; and, q is 0,1 or 2.

The invention further provides a compound having the structure:

or a pharmaceutically acceptable sait thereof, wherein

Xis N;

A is selected from the group consisting of a bond, C=O, --SO2--, -(C=0)NRo--, and (CRaRb)q-, where Ro is H or C1-C4 alkyl, and R_a and Rb are independently hydrogen, deuterium, C1-C6 alkyl, C3-C6 cycloalkyl, aryl, aryl(Ci-C6 alkyl), heteroaryl, (C1-C6 alkyl)heteroaryl, heteroaryI(Ci-C6 alkyl), and heterocyclic(Ci-C6 alkyl);

Ri is selected from the group consisting of hydrogen, deuterium, C1-C4 alkyl, C3-C6 cycloalkyl, aryl, heteroaryl, aryl(Ci-C6 alkyl), CN, amino, alkylamino, dialkylamino, fluoroalkyl, alkoxy, heteroaryl(Ci-C6 alkyl), and heterocyclic(Ci-C6 alkyl), wherein said alkyl, aryl, cycloalkyl, heterocyclic, or heteroaryl is further optionally substituted with one or more substituents selected from the group consisting of C1-C6 alkyl, halo, CN, hydroxy, methoxy, amino, C1-C4 alkyl amino, di(Ci-C4 alkyi)amino, CF3, --SO2-(Ci-C6 alkyl), and C3-C6 cycloalkyl;

R3 is selected from the group consisting of hydrogen and deuterium;

R4 is monocyclic or bicyclic aryl or monocyclic or bicyclic heteroaryl wherein said aryl or heteroaryl is optionally substituted with one or more substituents selected from the group consisting of 25 Ci-Ce alkyl, heterocycloalkyl, halo, CN, hydroxy, -CO2H, Ci-Ce alkoxy, amino, -N(Ci-C6 alkyl)(CO)(Ci-C₆ alkyl), -NH(CO)(Ci-C₆ alkyl), -(CO)NH₂, -(CO)NH(Ci-Ce alkyl), -(CO)N(Ci-Ce alkyl)2, --(C1-C6 alkyl)amino, --N(Ci-C6 alkyl)2, --SC>2-(Ci-C6 alkyl), -(SO)NH2, and C3-C6 cycloalkyl, where said alkyl, cycloalkyl, alkoxy, or heterocycloalkyl may be substituted by one or more Ci-Ce alkyl, halo, CN, OH, alkoxy, amino, -CO2H, -(CO)NH₂, -(CO)NH(Ci-Ce alkyl), or -(CO)N(Ci-Ce 30 alkyl)2, and where said alkyl may be further substituted by one or more fluorine atoms;

Rs is selected from the group consisting of hydrogen, C1-C6 alkyl, C1-C6 alkoxy, and hydroxy!; j is 0,1,2, or 3; and, q is 0, 1 or 2.

The invention also provides a compound having the structure:

or a pharmaceutically acceptable sait thereof, wherein

A' is selected from the group consisting of a bond, C=O, --SO2-, --(C=0)NRo', -- NRo'(C=0)-, and --(CRa'Rb')q-, where Ro' is H or C1-C4 alkyl, and R_a' and Rb' are independently hydrogen, deuterium, C1-C6 alkyl, C3-C6 cycloalkyl, aryl, aryl(Ci-C6 alkyl), heteroaryl, (C1-C6 alkyl)heteroaryl, heteroaryI(Ci-C6 alkyl), and heterocyclicfCi-Cs alkyl);

RT is selected from the group consisting of hydrogen, deuterium, C1-C4 alkyl, C3-C6 cycloalkyl, aryl, heteroaryl, aryl(Ci-Cs alkyl), CN, amino, alkylamino, dialkylamino, fluoroalkyl, alkoxy, heteroarylfCi-Ce alkyl), and heterocyclic(Ci-C6 alkyl), wherein said alkyl, aryl, cycloalkyl, heterocyclic, or heteroaryl is further optionally substituted with one or more substituents selected from the group consisting of C1-C6 alkyl, halo, CN, hydroxy, methoxy, amino, C1-C4 alkyl amino, di(Ci-C4 alkyl)amino, CF3, --SO2-(Ci-C6 alkyl), and C3-C6 cycloalkyl;

R2 is selected from the group consisting of hydrogen, deuterium, Ci-Cs alkyl, C3-C6 cycloalkyl, halo, and cyano, where said alkyl may be substituted by one or more fluorine atoms;

R3 is selected from the group consisting of hydrogen and deuterium;

R4 is monocyclic or bicyclic aryl or monocyciic or bicyclic heteroaryl wherein said aryl or heteroaryl is optionally substituted with one or more substituents selected from the group consisting of C1-C6 alkyl, heterocycloalkyl, halo, CN, hydroxy, -CO2H, C1-C6 alkoxy, amino, --N(Ci-C6 alkyl)(CO)(Ci-Ce alkyl), -NH(CO)(Ci-C₆ alkyl), -(CO)NH_Z, -(CO)NH(Ci-C₆ alkyl), -(CO)N(Ci-C₆alkyl)2, --(C1-C6 alkyl)amino, --N(Ci-Ce alkyl)2, -SO2-(Ci-C6 alkyl), --(SO)NH2, and C3-C6 cycloalkyl, where said alkyl, cycloalkyl, alkoxy, or heterocycloalkyl may be substituted by one or more C1-C6 alkyl, halo, CN, OH, alkoxy, amino, -CO2H, -(CO)NH_Z, ~(CO)NH(Ci-C₆ alkyl), or -(CO)N(Ci-C₆alkyl)2, and where said alkyl may be further substituted by one or more fluorine atoms;

R7 and Rs are independently hydrogen, C1-C4 alkyl, aryl, heteroaryl, (aryl)Ci-C6 alkyl, (heteroaryl)Ci-C6 alkyl, (heterocyclic)Ci-Cs alkyl, (C1-C6 alkyl)aryl, (Ci-Ce alkyl)heteroaryl, or (C1-C6 alkyl)heterocyclic, wherein said alkyl is further optionally substituted with one or more substituents selected from the group consisting of halo, hydroxy, methoxy, amino, CF3, and C3-C6 cycloalkyl;

k is 0,1,2, or 3; m and n are both 1 ; and, q is 0, 1 or 2.

In certain embodiments, the invention provides a compound selected from the group consisting of:

[(1S)-2,2-difluorocyclopropyI]{(1R,5S)-3-[2-({5-fluoro-6-[(3S)-3-hydroxypyrrolidin-1-yi]pyridin-

3- yl}amino)pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]oct-8-yl}methanone;

(1R,5S)-N-ethyl-3-[2-(1,2-thiazol-4-ylamino)pyrimidin-4-yl]-3,8-diazabicycIo[3.2.1]octane-8carboxamide;

4- {(1R,5S)-8-[(2,2-difluorocyclopropyl)methyl]-3,8-diazabicycIo[3.2.1]oct-3-yl}-N-(1H-pyrazol-

4- yl)pyrimidin-2-amine;

(1R,5S)-3-(2-{[5-chloro-6-(methylcarbamoyl)pyridin-3-yl]amino}pyrimidin-4-yl)-N-ethyl-3,810 diazabicyclo[3.2.1]octane-8-carboxamide;

cyclopropyl[(1R,5S)-3-(2-{[1-(2-hydroxyethyl)-1H-pyrazol-4-yl]amino}pyrimidin-4-yl)-3,8diazabicyclo[3.2.1 ]oct-8-yl]methanone;

N-(1-methyi-1H-pyrazol-4-yl)-4-{(1R,5S)-8-[1-(methylsulfonyl)azetidin-3-yl]-3,8diazabicyclo[3.2.1]oct-3-yl}pyrimidin-2-amine;

4-({4-[(1R,5S)-8-{[(1S)-2,2-difluorocycIopropyl]carbonyi}-3,8-diazabicyclo[3.2.1]oct-3yl]pyrimidin-2-yl}amino)-N,6-dimethylpyridine-2-carboxamide;

5- ({4-[(1R,5S)-8-{[(1R,2S)-2-fluorocyclopropyl]carbonyl}-3,8-diazabicyclo[3.2.1]oct-3yl]pyrimidin-2-yl}amino)-N,3-dimethylpyridine-2-carboxamide;

cyclopropyl[(1R,5S)-3-{2-[(1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-3,820 diazabicycio[3.2.1]oct-8-yl]methanone;

3-{(1R,5S)-3-[2-(1H-pyrazol-4-ylamino)pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]oct-8yljbutanenitrile;

5-({4-[(1R,5S)-8-(cyclopropylcarbonyl)-3,8-diazabicyclo[3.2.1]oct-3-yl]pyrimidin-2-yl}amino)-Nethyl-3-methyIpyridine-2-carboxamide;

3-[(1R,5S)-3-[2-[(1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-3,8-diazabicyclo[3.2.1]oct-8yljbutanenitrile;

5-({4-[(1R,5S)-8-(cyclopropylcarbonyl)-3,8-diazabicyclo[3.2.1]oct-3-yl]pyrimidin-2-yl}amino)-3methylpyridine-2-carboxamide;

(1R,5S)-N-ethyl-3-(2-{[5-fluoro-6-(methyIcarbamoyI)pyridin-3-yi]amino}pyrimidin-4-yl)-3,830 diazabicyclo[3.2.1]octane-8-carboxamide;

3-chIoro-5-({4-[(1R,5S)-8-(cycIopropylcarbonyl)-3,8-diazabicyclo[3.2.1]oct-3-yl]pyrimidin-2yl}amino)-N-methylpyridine-2-carboxamide;

(1R,5S)-3-{2-[(1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-N-(propan-2-yl)-3,8diazabicyclo[3.2.1]octane-8-carboxamide;

(3,3-difluorocyclobutyl)[(1R,5S)-3-{2-[(1-methyl-'1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-3,8diazabicyclo[3.2.1]oct-8-yl]methanone;

1-({(1R,5S)-3-[2-(1H-pyrazol-4-ylamino)pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]oct-8yl}methyl)cyclopropanecarbonitrile;

3-[(1R,5S)-3-{2-[(1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-ylJ-3,8-diazabicyclo[3.2.1]oct-8- yljbutanenitrile;

(1 S,2R)-2-{[(1 R,5S)-3-{2-[(1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-3,8diazabicyclo[3.2.1]oct-8-yl]carbonyl}cyclopropanecarbonitrile;

(1 R,2S)-2-{[(1 R,5S)-3-{2-[(1-methyl-1 H-pyrazol-4-yl)amino]pyrimidin-4-yl}-3,8diazabicyclo[3.2.1]oct-8-yI]carbonyl}cyclopropanecarbonitrile;

[(1R,2R)-2-fluorocyclopropyl][(1R,5S)-3-{2-[(1-methy!-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-

3.8- diazabicyclo[3.2.1]oct-8-yl]methanone;

[(1R,2R)-2-fluorocyclopropyl][(1R,5S)-3-{2-[(1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-

3.8- diazabicyclo[3.2.1]oct-8-yl]methanone (1R,5S)-3-{2-[(1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-3,8-diazabicyclo[3.2.1]octane8-carboxamide;

(1R,5S)-3-{2-[(1-methyl-1 H-pyrazol-4-yl)amino]pyrimidin-4-yl}-N-[5-(trifluoromethyl)pyridin-2yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxamide;

N,3-dimethyl-5-[(4-{(1R,5S)-8-[(3-methyloxetan-3-yl)methyl]-3,8-diazabicyclo[3.2.1]oct-3yl}pyrimidin-2-yl)amino]pyridine-2-carboxamide;

{3-[(1R,5S)-3-{2-[(1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-3,8-diazabicycIo[3.2.1]oct-8yl]-1-(methylsulfonyl)azetidin-3-yl}acetonitriIe;

4- ({4-[8-(cyanoacetyl)-3,8-diazabicyclo[3.2.1]oct-3-yl]pyrimidin-2-yl}amino)-N-ethylbenzamide; (1R,5S)-N-(cyanomethyl)-3-{2-[(1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-3,8- diazabicycIo[3.2.1]octane-8-carboxamide;

5- ({4-[(1R,5S)-8-{[(1S,2R)-2-fluorocyclopropyl]carbonyl}-3,8-diazabicyclo[3.2.1]oct-3yl]pyrimidin-2-yl}amino)-N,3-dimethylpyridine-2-carboxannide;

5-({4-[(1R,5S)-8-(cis-3-cyanocyclobutyl)-3,8-diazabicyclo[3.2.1]oct-3-yl]pyrimidin-2-yl}amino)N,3-dimethylpyridine-2-carboxamide;

5-({4-[(1R,5S)-8-{[(1S)-2,2-difluorocyclopropyl]carbonyl}-3,8-diazabicyclo[3.2.1]oct-3yl]pyrimidin-2-yl}amino)-3-fluoropyridine-2-carboxamide

5-({4-[(1R,5S)-8-{[(1R)-2,2-difluorocyclopropyl]methyI}-3,8-diazabicyclo[3.2.1]oct-3yl]pyrimidin-2-yl}amino)-N,3-dimethylpyridine-2-carboxamide;

N,3-dimethyl-5-({4-[(1R,5S)-8-(1,2-oxazol-5-ylmethyI)-3,8-diazabicyclo[3.2.1]oct-3yl]pyrimidin-2-yI}amino)pyridine-2-carboxamide;

2- [5-({4-[(1R,5S)-8-{[(1S)-2,2-difluorocyclopropyl]carbonyl}-3,8-diazabicyclo[3.2.1]oct-3- yl]pyrimidin-2-yl}amino)pyridin-2-yl]-2-methylpropanenitrile;

3- {(1R,5S)-3-[2-(1H-pyrazol-4-ylamino)pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]oct-8yljpropanenitrile;

(1R,5S)-N-ethyl-3-[2-(1H-pyrazol-4-ylamino)pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8carboxamide;

4- [(1R,5S)-8-{[(1S)-2,2-difluorocyclopropyl]methyl}-3,8-diazabicyclo[3.2.1]oct-3-yl]-N-(1methyl-1H-pyrazol-4-yl)pyrimidin-2-amine;

[(1S)-2,2-difluorocyclopropyl][(1R,5S)-3-(2-{[5-fluoro-6-(2-hydroxyethyl)pyridin-3yI]amino}pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]oct-8-yl]methanone;

[(1S)-2,2-difluorocyclopropyl][(1R,5S)-3-(2-{[5-fluoro-6-(3-hydroxyazetidin-1-yl)pyridin-3yl]amino}pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]oct-8-yl]methanone;

[(1R,5S)-3-(2-{[5-chloro-6-(2-hydroxyethoxy)pyridin-3-yl]amino}pyrimidin-4-yl)-3,8diazabicyclo[3.2.1]oct-8-yl][(1S)-2,2-difluorocyclopropyl]methanone;

{3-[(1R,5S)-3-{2-[(1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-3,8-diazabicyclo[3.2.1]oct-8yl]oxetan-3-yl}acetonitrile;

[(1R,5S)-3-(2-{[5-chloro-6-(2-hydroxyethyI)pyridin-3-yl]amino}pyrimidin-4-yl)-3,8diazabicyclo[3.2.1]oct-8-yl][(1S)-2,2-difluorocyclopropyl]methanone;

2- [(1R,5S)-3-{2-[(1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-3,8-diazabicyclo[3.2.1]oct-8yl]pyridine-4-carbonitrile;

3- [(1R,5S)-3-{2-[(1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-3,8-diazabicyclo[3.2.1]oct-8yljcyclobutanecarbonitrile;

2-[(1R,5S)-3-{2-[(1-methyl-1 H-pyrazol-4-yl)amino]pyrimidin-4-yl}-3,8-diazabicycIo[3.2.1]oct-8- yl]-1,3-oxazole-5-carbonitriIe;

(1R,5S)-N-(2-cyanoethyI)-3-{2-[(1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-3,8diazabicyclo[3.2.1]octane-8-carboxamide;

N-(1-methyl-1H-pyrazol-4-yl)-4-[(1R,5S)-8-(1,2-oxazol-4-ylmethyl)-3,8-diazabicyclo[3.2.1]oct-

3-yl]pyrimidin-2-amine;

4- ({4-[(1R,5S)-8-{[(1S)-2,2-difluorocyclopropyl]carbonyl}-3,8-diazabicyclo[3.2.1]oct-3yl]pyrimidin-2-yl}amino)-6-(hydroxymethyl)-N-methylpyridine-2-carboxamide;

(1-fluorocyclopropyl)[(1R,5S)-3-{2-[(1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-3,8diazabicyclo[3.2.1 ]oct-8-yl]methanone;

N-(1-methyl-1H-pyrazol-4-yl)-4-[(1R,5S)-8-(1,3-thiazol-2-ylmethyl)-3,8-diazabicyclo[3.2.1]oct-

3-yl]pyrimidin-2-amine;

cyclopropyl{(1R,5S)-3-[2-(1,2-thiazol-4-ylamino)pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]oct-8yljmethanone;

[(1S)-2,2-difluorocyclopropyl]{(1R,5S)-3-[2-({5-fluoro-6-[(3R)-3-hydroxypyrrolidin-1-yl]pyridin-

3-yl}amino)pyrimidin-4-yl]-3,8-diazabicycIo[3.2.1]oct-8-yl}methanone;

5- ({4-[(1R,5S)-8-{[(1S)-2,2-difluorocyclopropyl]methyl}-3,8-diazabicyclo[3.2.1]oct-3yl]pyrimidin-2-yl}amino)-N,3-dimethyIpyridine-2-carboxamide;

4- [(1R,5S)-8-{[(1R)-2,2-difluorocycIopropyI]methyl}-3,8-diazabicyclo[3.2.1]oct-3-yl]-N-(1methyl-1H-pyrazol-4-yl)pyrimidin-2-amine;

6- ({4-[(1R,5S)-8-(cyclopropylcarbonyl)-3,8-diazabicyclo[3.2.1]oct-3-yl]-5-fluoropyrimidin-2yl}amino)imidazo[1,2-a]pyridine-2-carboxamide;

5- ({4-[(1R,5S)-8-(cyclopropylcarbonyl)-3,8-diazabicyclo[3.2.1]oct-3-yl]-5-fluoropyrimidin-2yl}amino)pyridine-2-sulfonamide;

5-({4-[(1R,5S)-8-(trans-3-cyanocyclobutyI)-3,8-diazabicyclo[3.2.1]oct-3-yl]pyrimidin-2yl}amino)-N,3-dimethylpyridine-2-carboxamide;

1,2-oxazol-5-yl{(1R,5S)-3-[2-(1H-pyrazol-4-ylamino)pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]oct8-yl}methanone;

N-(1-methyl-1H-pyrazol-4-yl)-4-[(1R,5S)-8-(methylsulfonyl)-3,8-diazabicyclo[3.2.1]oct-3yl]pyrimidin-2-amine;

(15.25) -2-{[(1R,5S)-3-{2-[(1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-3,8diazabicyclo[3.2.1]oct-8-yl]methyl}cyclopropanecarbonitrile;

3- ({4-[(1R,5S)-8-(cyclopropylcarbonyI)-3,8-diazabicyclo[3.2.1]oct-3-yl]-5-fluoropyrimidin-2yl}amino)-N-propyl-1H-pyrazole-5-carboxamide;

(1 S,2S)-2-{[(1 R,5S)-3-{2-[(1-methyl-1 H-pyrazol-4-yl)amino]pyrimidin-4-yl}-3,8diazabicycIo[3.2.1]oct-8-yl]methyl}cyclopropanecarbonitrile;

cyclopropyl{(1R,5S)-3-[5-fluoro-2-(pyridazin-4-ylamino)pyrimidin-4-yl]-3,8diazabicyclo[3.2.1]oct-8-yl}methanone;

4- ({4-[6-(2,2-difluoropropanoyl)-3,6-diazabicyclo[3.1.1]hept-3-yl]-5-fluoropyrimidin-2-yl}amino)-

N-ethyl-2-methylbenzamide;

(15.25) -2-cyano-N-[(1S,5R,6R)-3-(2-{[6-(2-hydroxyethoxy)pyridin-3-yl]amino}-5methylpyrimidin-4-yl)-6-methyl-3-azabicyclo[3.1.0]hex-1-yl]cyclopropanecarboxamide;

N-[(1S,5R)-3-(5-chloro-2-{[1-(2-hydroxyethyI)-1H-pyrazoI-4-yi]amino}pyrimidin-4-yl)-3azabicyclo[3.1.0]hex-1-yl]cyclopropanecarboxamide;

(1 S)-2,2-difluoro-N-[(1 S,5R,6R)-3-(5-fluoro-2-{[1-(oxetan-3-yl)-1 H-pyrazol-4yl]amino}pyrimidin-4-yl)-6-methyl-3-azabicyclo[3.1.0]hex-1-yl]cyclopropanecarboxamide;

(1 S)-2,2-difluoro-N-[(1 S,5S)-3-{5-fluoro-2-[(1 -methyl-1 H-pyrazol-4-yl)amino]pyrimidin-4-yl}-5(hydroxymethyl)-3-azabicyclo[3.1.0]hex-1-yl]cyclopropanecarboxamide;

N-{(1S,5R,6R)-3-[5-fluoro-2-({6-[(2S)-1-hydroxypropan-2-yl]pyridin-3-yl}amino)pyrimidin-4-yl]-

6-methyl-3-azabicyclo[3.1.0]hex-1-yl}cyclopropanecarboxamide;

5- [(4-{(1S,5R,6R)-1-[(cyclopropylcarbonyl)amino]-6-methyl-3-azabicyclo[3.1.0]hex-3-yl}-5- fluoropyrimidin-2-yl)amino]-N,3-dimethylpyridine-2-carboxamide;

N-{(1S,5R,6R)-3-[2-({5-chloro-6-[(1R)-1-hydroxyethyl]pyridin-3-yl}amino)-5-fluoropyrimidin-4yl]-6-methyl-3-azabicyclo[3.1.0]hex-1-yl}cyclopropanecarboxamide;

(1 R)-2,2-difluoro-N-[(1 R,5S,6S)-3-{5-fiuoro-2-[(1-methyl-1 H-pyrazol-4-yl)amino]pyrimidin-4yl}-6-methyl-3-azabicyclo[3.1.0]hex-1-yl]cyclopropanecarboxamide;

5-[(4-{(1 R,5S,6S)-1-[(cycIopropylcarbonyl)amino]-6-methyl-3-azabicycIo[3.1.0]hex-3-yl}-5fluoropyrimidin-2-yl)amino]-N,3-dimethylpyridine-2-carboxamide;

N-[(1 R,5S)-3-(5-chloro-2-{[1 -(2-hydroxyethyl)-1 H-pyrazoI-4-yl]amino}pyrimidin-4-yl)-3azabicyclo[3.1.0]hex-1-yl]cyclopropanecarboxamide; and, (1S)-2,2-difluoro-N-[(1R,5S,6S)-3-{5-fluoro-2-[(1-methyi-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-

6-methyl-3-azabicyclo[3.1.0]hex-1-yl]cyclopropanecarboxamide;

or, a pharmaceutically acceptable sait thereof.

In certain other embodiments, the invention provides a compound selected from the group consisting of:

N-ethyl-4-({5-fluoro-4-[6-(2-fluoro-2-methylpropanoyl)-3,6-diazabicyclo[3.1.1]hept-3yl]pyrimidin-2-yl}amino)-2-methyIbenzamide;

N-ethyl-2-methyl-4.-({4-[6-(trifluoroacetyl)-3,6-diazabicyclo[3.1.1]hept-3-yl]pyrimidin-2yl}amino)benzamide; and,

4-({4-[6-(2,2-difluoropropanoyl)-3,6-diazabicyclo[3.1.1]hept-3-yl]pyrimidin-2-yl}amino)-Nethylbenzamide;

or, a pharmaceutically acceptable sait thereof.

In yet other embodiments, the invention provides a compound selected from the group consisting of:

4- ({4-[8-(cyclopropyIcarbonyl)-3,8-diazabicycIo[3.2.1]oct-3-yl]-5-fluoropyrimidin-2-yl}amino)-Nethylbenzamide;

N-ethyl-4-({5-fluoro-4-[8-(trifIuoroacetyl)-3,8-diazabicyclo[3.2.1]oct-3-yl]pyrimidin-2-yl}amino)-

2- methylbenzamide;

(1R,5S)-3-(2-{[5-methyI-6-(methylcarbamoyl)pyridin-3-yl]amino}pyrimidin-4-yl)-N-(2,2,2trifluoroethyl)-3,8-diazabicycIo[3.2.1]octane-8-carboxamide;

(1R,5S)-N-(cyanomethyl)-3-(2-{[5-methyl-6-(methylcarbamoyl)pyridin-3-yl]amino}pyrimidin-415 yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxamide;

5- ({4-[(1 R,5S)-8-{[(1 S)-2,2-difluorocyclopropyl]carbonyl]-3,8-diazabicyclo[3.2.1]oct-3yl]pyrimidin-2-yl}amino)-N,3-dimethylpyridine-2-carboxamide;

tert-butyl 3-(2-{[4-(ethylcarbamoyl)-3-methylphenyl]amino}-5-fluoropyrimidin-4-yi)-3,8diazabicyclo[3.2.1]octane-8-carboxylate;

5-({4-[(1 R,5S)-8-{[(1 R,2R)-2-cyanocyclopropyl]carbonyl}-3,8-diazabicyclo[3.2.1]oct-3yl]pyrimidin-2-yl}amino)-N,3-dimethylpyridine-2-carboxamide;

3-chloro-5-({4-[(1R,5S)-8-{[(1S)-2,2-difluorocyclopropyI]carbonyl}-3,8-diazabicyclo[3.2.1]oct-3yl]pyrimidin-2-yl}amino)-N-methylpyridine-2-carboxamide;

N-(1-methyl-1 H-pyrazol-4-yl)-4-[(1 R,5S)-8-(1,2-thiazol-5-ylmethyl)-3,8-diazabicycio[3.2.1]oct25 3-yl]pyrimidin-2-amine;

5-({4-[(1 R,5S)-8-{[(1 S)-2,2-difluorocyclopropyl]carbonyl}-3,8-diazabicyclo[3.2.1]oct-3yl]pyrimidin-2-yl}amino)-3-methylpyridine-2-carboxamide;

[(1S)-2,2-difluorocyclopropyl]{(1R,5S)-3-[2-({6-[(2S)-1-hydroxypropan-2-yl]pyridin-3yl}amino)pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]oct-8-yl}methanone;

3-chloro-5-({4-[(1R,5S)-8-{[(1R,2R)-2-cyanocyclopropyl]carbonyl}-3,8-diazabicyclo[3.2.1]oct-

3- yl]pyrimidin-2-yl}amino)-N-methylpyridine-2-carboxamide;

[(1S)-2,2-difluorocyclopropyl][(1R,5S)-3-(2-{[5-fluoro-6-(hydroxymethyl)pyridin-3yl]amino}pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]oct-8-yI]methanone;

5-[(4-{(1R,5S)-8-[(2,2-difluorocyclopropyl)carbonyl]-3,8-diazabicyclo[3.2.1]oct-3-yl}pyrimidin-235 yl)amino]-3-methyIpyridine-2-carboxamide;

5-({4-[(1R,5S)-8-(cyclopropylcarbonyl)-3,8-diazabicyclo[3.2.1]oct-3-yl]pyrimidin-2-yl}amino)N,3-dimethylpyridine-2-carboxamide;

(1R,5S)-N-ethyl-3-(2-{[5-methyl-6-(methylcarbamoyl)pyridin-3-yl]amino}pyrimidin-4-yl)-3,8diazabicyclo[3.2.1 ]octane-8-carboxamide;

[(1S)-2,2-difluorocyclopropyl]{(1R,5S)-3-[2-({6-[(2R)-1-hydroxypropan-2-yl]pyridin-3yl}amino)pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]oct-8-yl}methanone;

N-(1-methyl-1H-pyrazol-4-yl)-4-[(1R,5S)-8-(1,2-oxazol-5-ylmethyl)-3,8-diazabicyclo[3.2.1]oct-

3-yl]pyrimidin-2-amine;

cyclopropyl{(1R,5S)-3-[2-(1H-pyrazol-4-ylamino)pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]oct-8yljmethanone;

5-({4-[(1R,5S)-8-{[(1R,2R)-2-cyanocyclopropyl]carbonyl}-3,8-diazabicyclo[3.2.1]oct-3yl]pyrimidin-2-yl}amino)-3-fluoro-N-methylpyridine-2-carboxamide;

[(1 R)-2,2-difluorocyclopropyl]{(1 R, 5S)-3-[2-(1 H-pyrazol-4-ylamino)pyrimidin-4-yl]-3,8diazabicyclo[3.2.1]oct-8-yl}methanone; and,

5-((4-((1 R,5S)-8-{[(1R)-2,2-difluorocyclopropyl]carbonyl}-3,8-diazabicyclo[3.2.1]oct-3yl]pyrimidin-2-yl}amino)-3-fluoro-N-methylpyridine-2-carboxamide;

or, a pharmaceutically acceptable sait thereof.

In other embodiments, the invention provides a compound selected from the group consisting of:

(1R)-2,2-difluoro-N-[(1 S,5R,6R)-3-{5-fluoro-2-[(1-methyl-1 H-pyrazol-4-yl)amino]pyrimidin-4yl}-6-methyl-3-azabicyclo[3.1.0]hex-1-yl]cyclopropanecarboxamide;

N-{(1S,5R,6R)-3-[5-fIuoro-2-((6-[(2R)-1-hydroxypropan-2-yl]pyridin-3-yl}amino)pyrimidin-4-yl]-

6-methyl-3-azabicyclo[3.1.0]hex-1-yl}cyclopropanecarboxamide;

N-[(1S,5R,6R)-3-(2-{[5-chloro-6-(hydroxymethyl)pyridin-3-yl]amino}-5-fluoropyrimidin-4-yl)-6methyl-3-azabicyclo[3.1.0]hex-1-yl]cyclopropanecarboxamide; and,

N-[(1S,5R,6R)-3-(5-fluoro-2-{[6-(2-hydroxyethyl)pyridin-3-yl]amino}pyrimidin-4-yl)-6-methyl-3azabicyclo[3.1.0]hex-1-yl]cyclopropanecarboxamide;

or, a pharmaceutically acceptable sait thereof.

In one embodiment, the invention provides a compound which is [(1S)-2,2-difluorocyclopropyl]{(1R,5S)-3-[2-(1H-pyrazol-4-ylamino)pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]oct-8-yl}methanone; or, a pharmaceutically acceptable sait thereof.

In another embodiment, the invention provides a compound which is [(1S)-2,2-difluorocyclopropyl][(1R,5S)-3-{2-[(1-methy!-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-3,8-diazabicyclo[3.2.1]oct-8yljmethanone; or, a pharmaceutically acceptable sait thereof.

In yet another embodiment, the invention provides a compound which is 5-((4-((1 R, 5S)-8{[(1S)-2,2-difluorocyclopropyl]carbonyl}-3,8-diazabicycIo[3.2.1]oct-3-yl]pyrimidin-2-yl}amino)-3-fluoroN-methylpyridine-2-carboxamide; or, a pharmaceutically acceptable sait thereof.

In another embodiment, the invention provides a compound which is (1R,5S)-N-ethyl-3-{2-[(1methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-3,8-diazabicyclo[3.2.1]octane-8-carboxamide; or, a pharmaceutically acceptable sait thereof.

In one embodiment, the invention provides a compound which is [(1 R)-2,2-difluorocyclopropyl][(1 R,5S)-3-{2-[(1-methyI-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-3,8-diazabicycio[3.2.1]oct-8yl]methanone; or, a pharmaceutically acceptable sait thereof.

In another embodiment, the invention provides a compound which is (1S)-2,2-difluoro-N[(1S,5R,6R)-3-{5-fluoro-2-[(1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-6-methyl-3azabicyclo[3.1.0]hex-1-yl]cyclopropanecarboxamide, or, a pharmaceutically acceptable sait thereof.

In a certain other embodiment, the invention provides a compound which is (1 R,2R)-2-cyano5 N-[(1 S,5R,6R)-3-{5-fluoro-2-[(1-methyl-1 H-pyrazol-4-yl)amino]pyrimidin-4-yl}-6-methyl-3azabicyclo[3.1.0]hex-1-yl]cyclopropanecarboxamide or, a pharmaceutically acceptable sait thereof.

In one embodiment, the invention provides a compound which is (1R,2R)-2-cyano-N-[(1S,5S)-

3-{5-fluoro-2-[(1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-5-(hydroxymethyl)-3azabicyclo[3.1.0]hex-1-yl]cyciopropanecarboxamide; or, a pharmaceutically acceptable sait thereof.

In another embodiment, the invention provides a compound which is (1R,2R)-2-{[(1R,5S)-3{2-[(1-ethyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-3,8-diazabicyclo[3.2.1]oct-8yljcarbonyljcyclopropanecarbonitrile; or, a pharmaceutically acceptable sait thereof.

In a certain other embodiment, the invention provides a compound which is 4-{(1R,5S)-8[(2,2-difluorocyclopropyl)methyl]-3,8-diazabicyclo[3.2.1]oct-3-yl}-N-(1H-pyrazol-4-yl)pyrimidin-2-amine; 15 or, a pharmaceutically acceptable sait thereof.

The invention further provides a pharmaceutical or a veterinary composition comprising a compound of formula 1, or a pharmaceutically acceptable sait thereof, and a pharmaceutically acceptable carrier.

The invention also provides a method for treating or preventing a disorder or condition 20 selected from inflammation, autoimmune disease, neuroinflammation, arthritis, rheumatoid arthritis, spondyloarthropathies, systemic lupus erythematous, lupus nephritis, arthritis, osteoarthritis, gouty arthritis, pain, fever, pulmonary sarcoisosis, silicosis, cardiovascular disease, atherosclerosis, myocardial infarction, thrombosis, congestive heart failure and cardiac reperfusion injury, cardiomyopathy, stroke, ischaemia, reperfusion injury, brain edema, brain trauma, 25 neurodegeneration, liver disease, inflammatory bowel disease, Crohn’s disease, ulcerative colitis, nephritis, retinitis, retinopathy, macular degeneration, glaucoma, diabètes (type 1 and type 2), diabetic neuropathy, viral and bacterial infection, myalgia, endotoxic shock, toxic shock syndrome, autoimmune disease, osteoporosis, multiple sclerosis, endometriosis, menstrual cramps, vaginitis, candidiasis, cancer, fibrosis, obesity, muscular dystrophy, polymyositis, dermatomyositis, autoimmune 30 hepatitis, primary biliary cirrhosis, primary sclerosing cholangitis, vitiligo, alopecia, Alzheimer’s disease, skin flushing, eczema, psoriasis, atopie dermatitis and sunburn, comprising administering to the subject a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable sait thereof, or a pharmaceutically acceptable solvaté of said compound or sait.

In certain embodiments, the invention provides the method above wherein the compound is selected from the group consisting of:

4-({4-[8-(cycIopropylcarbonyl)-3,8-diazabicyclo[3.2.1]oct-3-yl]-5-fluoropyrimidin-2-yl}amino)-Nethylbenzamide;

N-ethyl-4-({5-fluoro-4-[8-(trifluoroacetyl)-3,8-diazabicyclo[3.2.1]oct-3-yl]pyrimidin-2-yl}amino)-

2-methylbenzamide;

(1R,5S)-3-(2-{[5-methyl-6-(methylcarbamoyl)pyridin-3-yl]amino}pyrimidin-4-yl)-N-(2,2,2trifluoroethyl)-3,8-diazabicyclo[3.2.1]octane-8-carboxamide;

(1R,5S)-N-(cyanomethyl)-3-(2-{[5-methyl-6-(methylcarbamoyl)pyridin-3-yl]amino}pyrimidin-4yI)-3,8-diazabicyclo[3.2.1]octane-8-carboxamide;

⁵ 5-({4-[(1 R,5S)-8-{[(1 S)-2,2-difluorocyclopropyl]carbonyl}-3,8-diazabicyclo[3.2.1]oct-3yl]pyrimidin-2-yl}amino)-N,3-dimethylpyridine-2-carboxamide;

tert-butyl 3-(2-{[4-(ethylcarbamoyl)-3-methylphenyl]amino}-5-fluoropyrimidin-4-yI)-3,8diazabicyclo[3.2.1 ]octane-8-carboxylate;

5-({4-[(1R,5S)-8-{[(1R,2R)-2-cyanocyclopropyl]carbonyl}-3,8-diazabicyclo[3.2.1]oct-3- yl]pyrimidin-2-yl}amino)-N,3-dimethylpyridine-2-carboxamide;

3-chloro-5-({4-[(1 R,5S)-8-{[(1 S)-2,2-difluorocyclopropyl]carbonyl}-3,8-diazabicyclo[3.2.1]oct-3yI]pyrimidin-2-yl}amino)-N-methyIpyridine-2-carboxamide;

N-(1-methyl-1H-pyrazol-4-yl)-4-[(1R,5S)-8-(1,2-thiazol-5-ylmethyl)-3,8-diazabicyclo[3.2.1]oct3-yl]pyrimidin-2-amine;

5-({4-[(1 R, 5S)-8-{[(1 S)-2,2-difluorocyclopropyl]carbonyl}-3,8-diazabicyclo[3.2.1]oct-3yl]pyrimidin-2-yl}amino)-3-methylpyridine-2-carboxamide;

3-chloro-5-({4-[(1R,5S)-8-{[(1R,2R)-2-cyanocyclopropyl]carbonyl}-3,8-diazabicycIo[3.2.1]oct20 3-yl]pyrimidin-2-yl}amino)-N-methylpyridine-2-carboxamide;

[(1S)-2,2-difluorocyclopropyl][(1R,5S)-3-(2-{[5-fluoro-6-(hydroxymethyl)pyridin-3yl]amino}pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]oct-8-yl]methanone;

5-[(4-{(1R,5S)-8-[(2,2-difluorocyclopropyl)carbonyl]-3,8-diazabicyclo[3.2.1]oct-3-yl}pyrimidin-2yI)amino]-3-methyIpyridine-2-carboxamide;

5-({4-[(1R,5S)-8-(cyclopropylcarbQnyl)-3,8-diazabicyclo[3.2.1]oct-3-yl]pyrimidin-2-yl}amino)N,3-dimethylpyridine-2-carboxamide;

(1R,5S)-N-ethyl-3-(2-{[5-methyl-6-(methylcarbamoyl)pyridin-3-yI]amino}pyrimidin-4-yl)-3,8diazabicycIo[3.2.1]octane-8-carboxamide;

[(1S)-2,2-difluorocyclopropyl]{(1R,5S)-3-[2-({6-[(2R)-1-hydroxypropan-2-yl]pyridin-330 yI}amino)pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]oct-8-yl}methanone;

N-(1 -methyl-1 H-pyrazol-4-yl)-4-[(1 R,5S)-8-(1,2-oxazol-5-ylmethyl)-3,8-diazabicycIo[3.2.1 ]oct3-yl]pyrimidin-2-amine;

cycIopropyI{(1R,5S)-3-[2-(1H-pyrazol-4-ylamino)pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]oct-8yQmethanone;

5-({4-[(1 R, 5S)-8-{[(1 R,2R)-2-cyanocyclopropyl]carbonyl}-3,8-diazabicyclo[3.2.1]oct-3yl]pyrimidin-2-yl}amino)-3-fluoro-N-methylpyridine-2-carboxamide;

[(1 R)-2,2-difluorocyclopropyl]{(1 R,5S)-3-[2-(1 H-pyrazol-4-ylamino)pyrimidin-4-yl]-3,8diazabicyclo[3.2.1 ]oct-8-yl}methanone;

5-({4-[(1 R,5S)-8-{[(1 R)-2,2-difluorocyclopropyl]carbonyl}-3,8-diazabicyclo[3.2.1]oct-340 yl]pyrimidin-2-yl}amino)-3-fluoro-N-methylpyridine-2-carboxamide;

N-ethyl-4-({5-fluoro-4-[6-(2-fluoro-2-methylpropanoyl)-3,6-diazabicyclo[3.1.1]hept-3yl]pyrimidin-2-yl}amino)-2-methylbenzamide;

(1 R)-2,2-difluoro-N-[(1 S,5R,6R)-3-{5-fluoro-2-[(1 -methyl-1 H-pyrazol-4-yl)amino]pyrimidin-4yl}-6-methyl-3-azabicyclo[3.1.0]hex-1-yl]cyclopropanecarboxamide;

N-ethyl-2-methyl-4-({4-[6-(trifluoroacetyl)-3,6-diazabicyclo[3.1.1]hept-3-yl]pyrimidin-2yl}amino)benzamide;

4- ({4-[6-(cyclopropylcarbonyl)-3,6-diazabicyclo[3.1.1]hept-3-yl]pyrimidin-2-yl}amino)-N-ethyl2-methylbenzamide;

N-{(1S,5R,6R)-3-[5-fluoro-2-({6-[(2R)-1-hydroxypropan-2-yl]pyridin-3-yl}amino)pyrimidin-4-yI]-

6-methyl-3-azabicyclo[3.1.0]hex-1-yl}cyclopropanecarboxamide;

or, a pharmaceutically acceptable sait thereof.

In certain other embodiments, the invention provides a method for treating or preventing psoriasis, vitiligo, alopecia, or atopie dermatitis by administering to a mammal in need a therapeutically effective amount of a compound selected from the group consisting of:

[(1 S)-2,2-difluorocyclopropyl]{(1 R,5S)-3-[2-(1 H-pyrazoI-4-ylamino)pyrimidin-4-yl]-3,8diazabicyclo[3.2.1]oct-8-yl}methanone;

[(1 S)-2,2-difluorocyclopropyl][(1 R,5S)-3-{2-[(1 -methyl-1 H-pyrazol-4-yl)amino]pyrimidin-4-yl}-

3.8- diazabicyclo[3.2.1 ]oct-8-yl]methanone;

5- ({4-[(1R,5S)-8-{[(1S)-2,2-difluorocyclopropyl]carbonyI}-3,8-diazabicyclo[3.2.1]oct-3yl]pyrimidin-2-yl}amino)-3-fluoro-N-methylpyridine-2-carboxamide;

(1R,5S)-N-ethyl-3-{2-[(1-methyI-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-3,8diazabicyclo[3.2.1]octane-8-carboxamide;

[(1 R)-2,2-difluorocyclopropyl][(1 R,5S)-3-{2-[(1 -methyl-1 H-pyrazol-4-yl)amino]pyrimidin-4-yl}-

3.8- diazabicyclo[3.2.1]oct-8-yl]methanone;

(1 S)-2,2-difluoro-N-[(1 S,5R,6R)-3-{5-fluoro-2-[(1-methyl-1 H-pyrazol-4-yl)amino]pyrimidin-4yl}-6-methyl-3-azabicyclo[3.1.0]hex-1-yl]cyclopropanecarboxamide;

(1 R, 2R)-2-cyano-N-[(1 S, 5R,6R)-3-{5-fluoro-2-[(1 -methyl-1 H-pyrazol-4-yl)amino]pyrimidin-4yl}-6-methyl-3-azabicyclo[3.1.0]hex-1-yI]cyclopropanecarboxamide;

(1 R,2R)-2-cyano-N-[(1 S,5S)-3-{5-fluoro-2-[(1-methyl-1 H-pyrazol-4-yl)amino]pyrimidin-4-yl}-5(hydroxymethyl)-3-azabicyclo[3.1.0]hex-1-yl]cyclopropanecarboxamide;

(1R,2R)-2-{[(1R,5S)-3-{2-[(1-ethyl-1H-pyrazoI-4-yl)amino]pyrimidin-4-yl}-3,8diazabicyclo[3.2.1]oct-8-yl]carbonyl}cyclopropanecarbonitrile; and,

4-{(1R,5S)-8-[(2,2-difIuorocyclopropyl)methyl]-3,8-diazabicyclo[3.2.1]oct-3-yl}-N-(1H-pyrazol-

4-yl)pyrimidin-2-amine;

or, a pharmaceutically acceptable sait thereof.

In other embodiments, the invention provides a method for treating or preventing systemic lupus erythematosus or lupus nephritis by administering to a mammal in need a therapeutically effective amount of a compound selected from the group consisting of:

[(1 S)-2,2-difluorocyclopropyl]{(1 R,5S)-3-[2-(1 H-pyrazol-4-ylamino)pyrimidin-4-yl]-3,8diazabicyclo[3.2.1 ]oct-8-yl}methanone;

[(1S)-2,2-difluorocyclopropyl][(1 R,5S)-3-{2-[(1-methyl-1 H-pyrazol-4-yl)amino]pyrimidin-4-yl}-

3,8-diazabicyclo[3.2.1]oct-8-yl]methanone;

5-({4-[(1R,5S)-8-{[(1S)-2,2-difluorocyclopropyl]carbonyl}-3,8-diazabicyclo[3.2.1]oct-3- yl]pyrimidin-2-yl}amino)-3-fIuoro-N-methylpyridine-2-carboxamide;

(1 R,5S)-N-ethyl-3-{2-[(1-methyl-1H-pyrazol-4-yt)amino]pyrimidin-4-yl}-3,8diazabicyclo[3.2.1]octane-8-carboxamide;

[(1R)-2,2-difluorocyclopropyI][(1R,5S)-3-{2-[(1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-

3,8-diazabicyclo[3.2.1]oct-8-yl]methanone;

(1R,2R)-2-cyano-N-[(1S,5R,6R)-3-{5-fluoro-2-[(1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4yl}-6-methyl-3-azabicyclo[3.1.0]hex-1-yl]cyclopropanecarboxamide;

(1 R,2R)-2-cyano-N-[(1 S, 5S)-3-{5-fluoro-2-[(1-methyl-1 H-pyrazol-4-yl)amino]pyrimidin-4-yl}-520 (hydroxymethyl)-3-azabicyclo[3.1.0]hex-1-yl]cyclopropanecarboxamide;

(1 R,2R)-2-{[(1 R,5S)-3-{2-[(1 -ethyl-1 H-pyrazol-4-yl)amino]pyrimidin-4-yl}-3,8diazabicyclo[3.2.1]oct-8-yl]carbonyl}cyclopropanecarbonitrile; and,

4- {(1R,5S)-8-[(2,2-difluorocyclopropyl)methyl]-3,8-diazabicyclo[3.2.1]oct-3-yl}-N-(1H-pyrazoI4-yl)pyrimidin-2-amine;

or, a pharmaceutically acceptable sait thereof.

In other embodiments, the invention provides a method for treating or preventing primary biliary cirrhosis, autoimmune hepatitis, primary sclerosing cholangitis by administering to a mammal in need a therapeutically effective amount of a compound selected from the group consisting of:

[(1 S)-2,2-difluorocyclopropyl]{(1 R,5S)-3-[2-(1 H-pyrazol-4-ylamino)pyrimidin-4-yl]-3,830 diazabicyclo[3.2.1]oct-8-yl}methanone;

3,8-diazabicyclo[3.2.1]oct-8-yl]methanone;

5- ({4-[(1R,5S)-8-{[(1S)-2,2-difluorocyclopropyl]carbonyl}-3,8-diazabicyclo[3.2.1]oct-3yl]pyrimidin-2-yl}amino)-3-fluoro-N-methylpyridine-2-carboxamide;

(1 R, 5S)-N-ethyl-3-{2-[(1 -methyl-1 H-pyrazol-4-yl)amino]pyrimidin-4-yl}-3,8diazabicyclo[3.2.1]octane-8-carboxamide;

[(1R)-2,2-difluorocyclopropyl][(1 R,5S)-3-{2-[(1-methyl-1 H-pyrazol-4-yl)amino]pyrimidin-4-yl}-

3,8-diazabicyclo[3.2.1]oct-8-yl]methanone;

(1S)-2,2-difluoro-N-[(1S,5R,6R)-3-{5-fIuoro-2-[(1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-440 yl}-6-methyl-3-azabicyclo[3.1.0]hex-1 -yljcyclopropanecarboxamide;

(1 R,2R)-2-cyano-N-[(1 S,5R,6R)-3-{5-f!uoro-2-[(1-methyl-1 H-pyrazoI-4-yl)amino]pyrimidin-4yl}-6-methyl-3-azabicyclo[3.1.0]hex-1-yl]cyclopropanecarboxamide;

(1R,2R)-2-cyano-N-[(1S,5S)-3-{5-fluoro-2-[(1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-5(hydroxymethyl)-3-azabicyclo[3.1.0]hex-1-yl]cyclopropanecarboxamide;

(1 R,2R)-2-{[(1 R,5S)-3-{2-[(1-ethyl-1 H-pyrazol-4-yl)amino]pyrimidin-4-yl}-3,8diazabicyclo[3.2.1]oct-8-yl]carbonyI}cyclopropanecarbonitriIe; and,

4- {(1R,5S)-8-[(2,2-difIuorocyclopropyi)methyl]-3,8-diazabicyclo[3.2.1]oct-3-yl}-N-(1 H-pyrazol4-yl)pyrimidin-2-amine;

or, a pharmaceutically acceptable sait thereof.

In certain other embodiments, the invention provides a method for treating or preventing inflammatory bowel disease, Crohn’s disease, or ulcerative colitis by administering to a mammal in need a therapeuticaliy effective amount of a compound selected from the group consisting of: [(1S)-2,2-difluorocyclopropyl]{(1R,5S)-3-[2-(1H-pyrazoi-4-ylamino)pyrimidin-4-yl]-3,8diazabicyclo[3.2.1 ]oct-8-yl}methanone;

[(1S)-2,2-difluorocycIopropyl][(1R,5S)-3-{2-[(1-methyl-1H-pyrazoi-4-yl)amino]pyrimidin-4-yl}-

3,8-diazabicyclo[3.2.1]oct-8-yl]methanone;

(1R,5S)-N-ethyl-3-{2-[(1-methyl-1H-pyrazoi-4-yl)amino]pyrimidin-4-yl}-3,820 diazabicyclo[3.2.1]octane-8-carboxamide; [(1R)-2,2-difIuorocyclopropyl][(1R,5S)-3-{2-[(1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-

3,8-diazabicyclo[3.2.1]oct-8-yl]methanone;

(1 S)-2,2-difluoro-N-[(1 S,5R,6R)-3-{5-fluoro-2-[(1-methyi-1 H-pyrazol-4-yl)amino]pyrimidin-4yl}-6-methyl-3-azabicyclo[3.1.0]hex-1-yl]cyclopropanecarboxamide;

(1R,2R)-2-cyano-N-[(1 S,5R,6R)-3-{5-fluoro-2-[(1-methyl-1 H-pyrazol-4-yl)amino]pyrimidin-4yl}-6-methyl-3-azabicyclo[3.1.0]hex-1-yl]cyclopropanecarboxamide;

(1R,2R)-2-cyano-N-[(1S,5S)-3-{5-fluoro-2-[(1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-5(hydroxymethyl)-3-azabicyclo[3.1.0]hex-1-yi]cyclopropanecarboxamide;

(1 R,2R)-2-{[(1 R,5S)-3-{2-[(1 -ethyl-1 H-pyrazol-4-yl)amino]pyrimidin-4-yl}-3,830 diazabicyclo[3.2.1 ]oct-8-yl]carbonyl}cyciopropanecarbonitrile; and,

4-{(1 R,5S)-8-[(2,2-difluorocyclopropyl)methyl]-3,8-diazabicyclo[3.2.1]oct-3-yl}-N-(1H-pyrazol4-yl)pyrimidin-2-amine;

or, a pharmaceutically acceptable sait thereof.

In other embodiments, the invention provides a method for treating or preventing multiple sclerosis by administering to a mammal in need a therapeuticaliy effective amount of a compound selected from the group consisting of:

[(1 S)-2,2-difluorocyclopropyl]{(1 R,5S)-3-[2-(1 H-pyrazol-4-ylamino)pyrimidin-4-yl]-3,8diazabicyclo[3.2.1]oct-8-yl}methanone;

[(1S)-2,2-difluorocyclopropyl][(1R,5S)-3-{2-[(1-methyI-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}40 3,8-diazabicyclo[3.2.1]oct-8-yl]methanone;

5-({4-[(1R,5S)-8-{[(1S)-2,2-difluorocyclopropyl]carbonyl}-3,8-diazabicyclo[3.2.1]oct-3yl]pyrimidin-2-yl}amino)-3-fluoro-N-methylpyridine-2-carboxamide;

(1R,5S)-N-ethyl-3-{2-[(1-methyl-1H-pyrazoi-4-yl)amino]pyrimidin-4-yl}-3,8diazabicyclo[3.2.1]octane-8-carboxamide;

[(1 R)-2,2-difluorocyclopropyl][(1 R,5S)-3-{2-[(1-methyl-1 H-pyrazol-4-yl)amino]pyrimidin-4-yl}-

3,8-diazabicyclo[3.2.1]oct-8-yl]methanone;

(1S)-2,2-difluoro-N-[(1S,5R,6R)-3-{5-fluoro-2-[(1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4yl}-6-methyl-3-azabicyclo[3.1.0]hex-1-yl]cyclopropanecarboxamide;

(1 R,2R)-2-cyano-N-[(1 S,5R,6R)-3-{5-fluoro-2-[(1-methyl-1 H-pyrazoi-4-yl)amino]pyrimidin-410 yl}-6-methyI-3-azabicyclo[3.1.0]hex-1-yl]cyclopropanecarboxamide; (1R,2R)-2-cyano-N-[(1S,5S)-3-{5-fluoro-2-[(1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-5(hydroxymethy!)-3-azabicyclo[3.1.0]hex-1-yl]cyclopropanecarboxamide;

(1 R,2R)-2-{[(1 R,5S)-3-{2-[(1 -ethyl-1 H-pyrazol-4-yl)amino]pyrimidin-4-yl}-3,8diazabicyclo[3.2.1]oct-8-yl]carbonyI}cyclopropanecarbonitrile; and,

4-{(1R,5S)-8-[(2,2-difluorocyclopropyl)methyl]-3,8-diazabicyclo[3.2.1]oct-3-yl}-N-(1H-pyrazol4-yl)pyrimidin-2-amine;

or, a pharmaceutically acceptable sait thereof.

The invention further provides a method of treating or preventing a disorder or condition selected from acute myeloid leukemia, T cell acute lymphoblastic leukemia, multiple myeloma, pancreatic cancer, brain tumors, gliomas including astrocytoma, oligodendroglioma, and glioblastoma, acute CNS trauma including traumatic brain injury, encephalitis, stroke, and spinal cord injury, epilepsy, seizures, PD, ALS, frontotemporal lobe dementia, and with neuropsychiatrie disorders including schizophrenia, bipolar disorder, dépréssion, treatment résistant dépréssion, PTSD, anxiety, and auto-antibodies mediated encéphalopathies, comprising the step of administering to a subject an effective amount of a composition comprising a compound of formula I, or a pharmaceutically acceptable sait thereof, or a pharmaceutically acceptable solvaté of said compound or sait.

The invention also provides a method of treating a disease or condition for which a JAK inhibitor is indicated, in a subject in need of such treatment, comprising administering to the subject a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable sait 30 thereof, or a pharmaceutically acceptable solvaté of said compound or sait.

In certain embodiments, the therapeutically effective amount used in accord with the method is from 0.01 mg/kg of body weight/day to 100 mg/kg of body weight/day. In certain other embodiments, the therapeutically effective amount used in accord with the method is wherein the therapeutically effective amount is from 0.1 mg/kg of body weight/day to 10 mg/kg of body weight/day.

Compounds of the invention that hâve the same molecular formula but differ in the nature or sequence of bonding of their atoms or the arrangement of their atoms in space are termed isomers. Isomers that differ in the arrangement of their atoms in space are termed stereoisomers. It will be appreciated by those skilled in the art that the compound of formula I can exist as cis- and transachiral diastereomers.

Included within the scope of the described compounds are all isomers (e.g., cis-, trans-, or diastereomers) of the compounds described herein alone as well as any mixtures. All of these forms, including enantiomers, diastereomers, cis, trans, syn, anti, solvatés (including hydrates), tautomers, and mixtures thereof, are included in the described compounds. Stereoisomeric mixtures, e.g., 5 mixtures of diastereomers, can be separated into their corresponding isomers in a known manner by means of suitable séparation methods. Diastereomeric mixtures for example may be separated into their individual diastereomers by means of fractionated crystallization, chromatography, solvent distribution, and similar procedures. This séparation may take place either at the level of one of the starting compounds or in a compound of formula I itself. Enantiomers may be separated through the 10 formation of diastereomeric salts, for example by sait formation with an enantiomer-pure chiral acid, or by means of chromatography, for example by HPLC, using chromatographie substrates with chiral ligands. The présent invention includes all pharmaceutically acceptable isotopically-labelled compounds of formula I wherein one or more atoms are replaced by atoms having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number which 15 prédominâtes in nature.

Examples of isotopes suitable for inclusion in the compounds ofthe invention include isotopes of hydrogen, such as ²H and ³H, carbon, such as ¹¹C, ¹³C and ¹⁴C, chlorine, such as ³⁶CI, fluorine, such as ¹⁸F, iodine, such as ¹²³l and ¹²⁵l, nitrogen, such as ¹³N and ¹⁵N, oxygen, such as ¹⁵O, ¹⁷O and ¹⁸O, phosphorus, such as ³²P, and sulphur, such as ³⁵S.

Certain isotopically-labelled compounds of formula I, for example, those incorporating a radioactive isotope, are useful in drug and/or substrate tissue distribution studies. The radioactive isotopes tritium, i.e., ³H, and carbon-14, i.e., ¹⁴C, are particularly useful for this purpose in view of their ease of incorporation and ready means of détection.

Substitution with heavier isotopes such as deuterium, i.e., ²H, may afford certain therapeutic 25 advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements, and hence may be preferred in some circumstances. Substitution with positron emitting isotopes, such as ¹¹C, ¹⁸F, ¹⁵O and ¹³N, can be useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy. Isotopically-labeled compounds of formula I can generally be prepared by conventional techniques known to those skilled 30 in the art or by processes analogous to those described in the accompanying Examples and Préparations using an appropriate isotopically-labeled reagent in place of the non-Iabeled reagent previously employed.

In therapeutic use for treating disorders in a mammal, a compound ofthe présent invention or its pharmaceutical compositions can be administered orally, parenteraily, topically, rectally, 35 transmucosaily, or intestinally. Parentéral administrations include indirect injections to generate a systemic effect or direct injections to the afflicted area. Topical administrations include the treatment of skin or organs readily accessible by local application, for example, eyes or ears. it also includes transdermal delivery to generate a systemic effect The rectal administration includes the form of suppositories. The preferred routes of administration are oral and parentéral.

Pharmaceutically acceptable salts of the compounds of formula I include the acid addition and base salts thereof. Suitable acid addition salts are formed from acids which form non-toxic salts. Examples include the acetate, adipate, aspartate, benzoate, besylate, bicarbonate/carbonate, bisulfate/sulfate, borate, camsylate, citrate, cyclamate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hibenzate, hydrochloride/chloride, hydrobromide/bromide, hydroiodide/iodide, isethionate, lactate, malate, maleate, malonate, mesylate, methylsulfate, naphthylate, 2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate/hydrogen phosphate/dihydrogen phosphate, pyroglutamate, saccharate, stéarate, succinate, tannate, tartrate, tosylate, trifluoroacetate and xinofoate salts.

Suitable base salts are formed from bases which form non-toxic salts. Examples include the aluminium, arginine, benzathine, calcium, choiine, diethylamine, diolamine, glycine, lysine, magnésium, meglumine, olamine, potassium, sodium, tromethamine and zinc salts.

Hemisalts of acids and bases may also be formed, for example, hemisulfate and hemicalcium salts. For a review on suitable salts, see Handbook of Pharmaceutical Salts: Properties, Sélection, and Use by Stahl and Wermuth (Wiley-VCH, 2002).

Pharmaceutically acceptable salts of compounds of formula I may be prepared, respectively, by one or more of three methods: (i) by reacting the compound of formula I with the desired acid or base; (ii) by removing an acid- or base-labile protecting group from a suitable precursor of the compound of formula I or by ring-opening a suitable cyclic precursor, for example, a lactone or lactam, using the desired acid or base; or (iii) by converting one sait of the compound of formula I to another by reaction with an appropriate acid or base or by means of a suitable ion exchange column. Ail three reactions are typically carried out in solution. The resulting sait may precipitate out and be collected by filtration or may be recovered by évaporation of the solvent. The degree of ionization in the resulting sait may vary from completely ionized to almost non-ionized.

Pharmaceutical compositions of the présent invention may be manufactured by methods well known in the art, e.g., by means of conventional mixing, dissolving, granulation, dragee-making, levigating, emulsifying, encapsulating, entrapping, lyophilizing processes or spray drying.

Pharmaceutical compositions for use in accordance with the présent invention may be formulated in conventional manner using one or more pharmaceutically acceptable carriers comprising excipients and auxiliaries, which facilitate processing of the active compound into préparations, which can be used pharmaceutically. Proper formulation is dépendent upon the route of administration chosen. Pharmaceutically acceptable excipients and carriers are generally known to those skilled in the art and are thus included in the instant invention. Such excipients and carriers are described, for example, in Remington’s Pharmaceutical Sciences, Mack Pub. Co., New Jersey (1991). The formulations of the invention can be designed to be short-acting, fast-releasing, long-acting, and sustained-releasing. Thus, the pharmaceutical formulations can also be formulated for controlled release or for slow release.

Pharmaceutical compositions suitable for use in the présent invention include compositions wherein the active ingrédients are contained in an amount sufficient to achieve the intended purpose, i.e., control or the treatment of disorders or diseases. More specifically, a therapeutically effective amount means an amount of compound effective to prevent, alleviate or ameliorate symptoms/signs of disease or prolong the survival ofthe subject being treated.

The quantity of active component, which is the compound of this invention, in the pharmaceutical composition and unit dosage form thereof, may be varied or adjusted widely depending upon the manner of administration, the potency of the particular compound and the desired concentration. Détermination of a therapeutically effective amount is well within the capability of those skilled in the art. Generally, the quantity of active component will range between 0.01% to 99% by weight of the composition.

Generally, a therapeutically effective amount of dosage of active component will be in the range of about 0.01 to about 100 mg/kg of body weight/day, preferably about 0.1 to about 10 mg/kg of body weight/day, more preferably about 0.3 to 3 mg/kg of body weight/day, even more preferably about 0.3 to 1.5 mg/kg of body weight/day It is to be understood that the dosages may vary depending upon the requirements of each subject and the severity of the disorders or diseases being treated.

The desired dose may conveniently be presented in a single dose or as divided doses administered at appropriate intervals, for example, as two, three, four or more sub-doses per day. The sub-dose itself may be further divided, e.g., into a number of discrète loosely spaced administrations; such as multiple inhalations from an insufflator or by application of a plurality of drops into the eye.

Also, it is to be understood that the initial dosage administered may be increased beyond the above upper level in order to rapidly achieve the desired plasma concentration. On the other hand, the initial dosage may be smaller than the optimum and the daily dosage may be progressively increased during the course of treatment depending on the particular situation. If desired, the daily dose may also be divided into multiple doses for administration, e.g., two to four times per day.

Compounds of the présent invention are directed to aminopyrimidinyl compounds useful as Janus Kinase inhibitors (JAK-i). They are useful as therapeutic agents in connection with the treating or preventing a disorder or condition selected from rheumatoid arthritis, myositis, vasculitis, pemphigus, Crohn’s disease, ulcerative colitis, Alzheimer’s disease, lupus, nephritis, psoriasis, atopie dermatitis, autoimmune thyroid disorders, multiple sclerosis, major dépréssion disorder, allergy, asthma, Sjogren’s disease, dry eye syndrome, organ transplant rejection, xeno transplantation, Type I diabètes and complications from diabètes, cancer, leukemia, T cell acute lymphoblastic leukemia, aduItT cell leukemia activated B-cell like, diffuse large B cell lymphoma, inflammatory bowel disease, septic shock, cardiopulmonary dysfunction, chronic pulmonary obstructive disorder, acute respiratory disease, cachexia, and other indications where immunosuppression/immunomodulation would be désirable, comprising the step of administering to a subject an effective amount of a compound of the invention.

There are substantial needs for safe and efficacious agents to control disorders related to JAK, such as atopie dermatitis, both in human and animais. The market for treating atopie dermatitis in animais is currently dominated by corticosteroids, which cause distressing and undesirable side effects in animais, specifically in companion animais such as dogs. Antihistamines are also used, but are poorly effective. A canine formulation of cyclosporine (ATOPICA™) is currently being marketed

for atopie dermatitis, but is expensive and has a slow onset of efficacy. In addition, there are Gl toleration issues with ATOPICA™. Compounds of the présent invention are JAK inhibitors with sélective efficacy against JAK1. These compounds are expected to provide an alternative to steroid usage and provide resolution of chronic pruritus and inflammation that would either persist in atopie 5 dermatitis or slowly regress following removal of allergen or causative agent, such as fleas in fleaallergic dermatitis.

The présent invention also provides any of the uses, methods or compositions as defined above wherein the compound of formula I, or pharmaceutically acceptable sait thereof, or pharmaceutically acceptable solvaté of said compound or sait, is used in combination with another 10 pharmacologically active compound, particularly one of the functionally-defined classes or spécifie compounds listed below. These agents may be administered as part of the same or separate dosage forms, via the same or different routes of administration, and on the same or different administration schedules according to standard pharmaceutical practice known to one skilled in the art.

Suitable agents for use in combination therapy with a compound of formula I, or pharmaceutically acceptable sait thereof, or pharmaceutically acceptable solvaté of said compound or sait, particularly in the treatment of respiratory disease, include: a 5-lipoxygenase activating protein (FLAP) antagonist; a leukotriene antagonist (LTRA) such as an antagonist of LTB4, LTC4, LTD4, LTE4, CysLTi or CysLT2, e.g., montelukast or zafirlukast; a histamine receptor antagonist, such as a histamine type 1 receptor antagonist or a histamine type 2 receptor antagonist, e.g., loratidine, fexofenadine, desloratidine, levocetirizine, methapyrilene or cetirizine; an a1 -adrenoceptor agonist or an a2-adrenoceptor agonist, e.g., phenylephrine, methoxamine, oxymetazoline or methyinorephrine; a muscarinic M3 receptor antagonist, e.g. tiotropium or ipratropium; a dual muscarinic M3 receptor antagononist/p2 agonist; a PDE inhibitor, such as a PDE3 inhibitor, a PDE4 inhibitor or a PDE5 inhibitor, e.g., theophylline, sildenafil, vardenafil, tadaiafil, ibudilast, cilomilast or roflumilast; sodium cromoglycate or sodium nedocromil; a cyclooxygenase (COX) inhibitor, such as a non-selective inhibitor (e.g., aspirin or ibuprofen) or a sélective inhibitor (e.g. ceiecoxib or valdecoxib); a glucocorticosteroid, e.g., fluticasone, mometasone, dexamethasone, prednisolone, budesonide, ciclesonide or beclamethasone; an anti-inflammatory monoclonal antibody, e.g., infliximab, adalimumab, tanezumab, ranibizumab, bevacizumab or mepolizumab; a β2 agonist, e.g., salmeterol, albuterol, salbutamol, fenoterol or formoterol, particularly a Iong-acting β2 agonist; an intigrin antagonist, e.g., natalizumab; an adhesion molécule inhibitor, such as a VLA-4 antagonist; a kinin B1 or B2 receptor antagonist; an immunosuppressive agent, such as an inhibitor ofthe IgE pathway (e.g., omalizumab) or cyclosporine; a matrix metalloprotease (MMP) inhibitor, such as an inhibitor of MMP-9 or MMP-12; a tachykinin NK1, NK2 or NK3 receptor antagonist; a protease inhibitor, such as an inhibitor of elastase, chymase or catheopsin G; an adenosine A2a receptor agonist; an adenosine A2b receptor antagonist; a urokinase inhibitor; a dopamine receptor agonist (e.g., ropinirole), particularly a dopamine D2 receptor agonist (e.g., bromocriptine); a modulator of the NFkB pathway, such as an IKK inhibitor; a further modulator of a cytokine signalling pathway such as an inhibitor of JAK kinase, syk kinase, p38 kinase, SPHK-1 kinase, Rho kinase, EGF-R or MK-2; a mucolytic, mucokinetic or anti-tussive agent; an antibiotic; an antiviral agent; a vaccine; a chemokine; an épithélial sodium

channel (ENaC) blocker or Epithelial sodium channel (ENaC) inhibitor; a nucléotide receptor agonist, such as a P2Y2 agonist; a thromboxane inhibitor; niacin; a 5-lipoxygenase (5-LO) inhibitor, e.g., Zileuton; an adhesion factor, such as VLAM, ICAM or ELAM; a CRTH2 receptor (DP2) antagonist; a prostaglandin D2 receptor (DP1) antagonist; a haematopoietic prostaglandin D2 synthase (HPGDS) 5 inhibitor; interferon-β; a soluble human TNF receptor, e.g., Etanercept; a HDAC inhibitor; a phosphoinositotide 3-kinase gamma (PI3Ky) inhibitor; a phosphoinositide 3-kinase delta (PI3KÔ) inhibitor; a CXCR-1 or a CXCR-2 receptor antagonist; an IRAK-4 inhibitor; and, a TLR-4 or TLR-9 inhibitor, including the pharmaceutically acceptable salts of the specifically named compounds and the pharmaceutically acceptable solvatés of said specifically named compounds and salts.

Accordingly, the invention provides methods of treating or preventing a disease, condition or disorder associated with JAK in a subject, such as a human or non-human mammal, comprising administering an effective amount of one or more compounds described herein to the subject. Suitable subjects that can be treated include domestic or wild animais, companion animais, such as dogs, cats, horses and the like; livestock including, cows and other ruminants, pigs, poultry, rabbits 15 and the like; primates, for example monkeys, such as rhésus monkeys and cynomolgus (also known as crab-eating or long-tailed) monkeys, marmosets, tamarins, chimpanzees, macaques and the like; and rodents, such as rats, mice, gerbils, guinea pigs and the like. In one embodiment, the compound is administered in a pharmaceutically acceptable form, optionally in a pharmaceutically acceptable carrier.

Conditions in which sélective targeting of the JAK pathway or modulation of the JAK kinases, particularly JAK1, are contemplated to be therapeutically useful include, arthritis, asthma, autoimmune diseases, cancers or tumors, diabètes, certain eye diseases, disorders or conditions, inflammation, intestinal inflammations, allergies or conditions, neurodegenerative diseases, psoriasis, and transplant rejection. Conditions which can benefit from sélective inhibition of JAK1 are discussed in 25 greater detail below.

Accordingly, the compound of formula I or its pharmaceutically acceptable salts, and pharmaceutical compositions thereof can be used to treat a variety of conditions or diseases such as the following:

Arthritis, including rheumatoid arthritis, juvénile arthritis, and psoriatic arthritis;

Autoimmune diseases or disorders, including those designated as single organ or single celltype autoimmune disorders, for example Hashimoto's thyroiditis, autoimmune hemolytic anémia, autoimmune atrophie gastritis of pernicious anémia, autoimmune encephalomyelitis, autoimmune orchitis, Goodpasture's disease, autoimmune thrombocytopenia, sympathetic ophthalmia, myasthenia gravis, Graves' disease, primary biliary cirrhosis, chronic aggressive hepatitis, ulcerative colitis and membranous glomerulopathy, those designated as involving systemic autoimmune disorder, for example systemic lupus erythematosis, rheumatoid arthritis, Sjogren's syndrome, Reiter's syndrome, polymyositis-dermatomyositis, systemic sclerosis, polyarteritis nodosa, multiple sclerosis and bullous pemphigoid, and additional autoimmune diseases, which can be O-cell (humoral) based or T-cell based, including Cogan's syndrome, ankylosing spondylitis, Wegener's granulomatosis, autoimmune 40 alopecia, Type I or juvénile onset diabètes, or thyroiditis;

PC72027

Cancers or tumors, including alimentary/gastrointestinal tract cancer, colon cancer, liver cancer, skin cancer including mast cell tumor and squamous cell carcinoma, breast and mammary cancer, ovarian cancer, prostate cancer, lymphoma, leukemia, including acute myelogenous leukemia and chronic myelogenous leukemia, kidney cancer, lung cancer, muscle cancer, bone cancer, bladder cancer, brain cancer, melanoma including oral and metastatic melanoma, Kaposi's sarcoma, myelomas including multiple myeloma, myeloproliferative disorders, proliférative diabetic retinopathy, or angiogenic-associated disorders including solid tumors;

Diabètes, including Type I diabètes or complications from diabètes;

Eye diseases, disorders or conditions including autoimmune diseases of the eye, keratoconjunctivitis, vernal conjunctivitis, uveitis including uveitis associated with Behcet's disease and lens-induced uveitis, keratitis, herpetic keratitis, conical keratitis, corneal épithélial dystrophy, keratoleukoma, ocular premphigus, Mooren's ulcer, scleritis, Grave's ophthalmopathy, Vogt-KoyanagiHarada syndrome, keratoconjunctivitis sicca (dry eye), phlyctenule, iridocyclitis, sarcoidosis, endocrine ophthalmopathy, sympathetic ophthalmitis, allergie conjunctivitis, or ocular neovascularization;

Intestinal inflammations, allergies or conditions including Crohn’s disease and/or ulcerative colitis, inflammatory bowel disease, celiac diseases, proctitis, éosinophilie gastroenteritis, or mastocytosis;

Neurodegenerative diseases including motor neuron disease, Alzheimer's disease, Parkinson’s disease, amyotrophie latéral sclerosis, Huntington’s disease, cérébral ischemia, or neurodegenerative disease caused by traumatic injury, strike, glutamate neurotoxicity or hypoxia; ischemic/reperfusion injury in stroke, myocardial ischemica, rénal ischemia, heart attacks, cardiac hypertrophy, atherosclerosis and arteriosclerosis, organ hypoxia, or platelet aggregation;

Skin diseases, conditions or disorders including atopie dermatitis, eczema, psoriasis, scleroderma, pruritus or other pruritic conditions, vitiligo, alopecia;

Allergie reactions including allergie dermatitis in mammal (including horse allergie diseases such as bite hypersensitivity), summer eczema, sweet itch in horses, heaves, inflammatory airway disease, récurrent airway obstruction, airway hyper-responsiveness, or chronic obstruction pulmonary disease;

Asthma and other obstructive airways diseases, including chronic or inveterate asthma, late asthma, bronchitis, bronchial asthma, allergie asthma, intrinsic asthma, extrinsic asthma, or dust asthma;

Transplant rejection, including pancréas islet transplant rejection, bone marrow transplant rejection, graft-versus-host disease, organ and cell transplant rejection such as bone marrow, cartilage, cornea, heart, intervertébral dise, islet, kidney, limb, liver, lung, muscle, myoblast, nerve, pancréas, skin, small intestine, or trachea, or xeno transplantation.

Chemical Synthesis

The following schemes and written descriptions provide general details regarding the préparation of the compounds of the invention.

The compounds of the invention may be prepared by any method known in the art for the préparation of compounds of analogous structure. In particular, the compounds of the invention can be prepared by the procedures described by reference to the schemes that follow, or by the spécifie methods described in the examples, or by similar processes to either.

The skilled person will appreciate that the experimental conditions set forth in the schemes that follow are illustrative of suitable conditions for effecting the transformations shown, and that it may be necessary or désirable to vary the précisé conditions employed for the préparation of compounds of formula (I).

In addition, the skilled person will appreciate that it may be necessary or désirable at any stage in the synthesis of compounds of the invention to protect one or more sensitive groups, so as to prevent undesirable side reactions. In particular, it may be necessary or désirable to protect amino or carboxylic acid groups. The protecting groups used in the préparation of the compounds of the invention may be used in conventional manner. See, for example, those described in Protective Groups in Organic Synthesis by Theodora W. Greene and Peter G. M. Wuts, 3rd édition, (John Wiley and Sons, 1999), in particular chapters 7 (“Protection for the Amino Group”) and 5 (“Protection for the Carboxyl Group”), incorporated herein by reference, which also describes methods for the removal of such groups.

Ail of the dérivatives of formula I can be prepared by the procedures described in the general methods presented below or by routine modifications thereof. The présent invention also encompasses any one or more of these processes for preparing the dérivatives of formula (I), in addition to any novel intermediates used therein. The person skilled in the art will appreciate that the following reactions may be heated thermally or under microwave irradiation.

It will be further appreciated that it may be necessary or désirable to carry out the transformations in a different order from that described in the schemes, or to modify one or more of the transformations, to provide the desired compound of the invention.

According to a first process, compounds of formula (IA) may be prepared from compounds of formulae (VI) and (V), as illustrated by Scheme 1.

(III) (II) (ΙΑ)

Scheme 1

Wherein PG is tert-butoxycarbonyl; X is chloro, hydroxyl, a suitable leaving group or a suitable anhydride; Z = (CH_z)_ft; A is -N(C=O)R°-;

Compounds of formulae (VI), (V), (VIII) and (VII) are commercially available or may be synthesized by those skilled in the art according to the literature or préparations described herein. Compounds of formula (IA) may be separated into the respective enantiomers via chiral séparation of the racemate as required. Wherein R⁴ contains a protecting group such as tert-butoxycarbonyl or tosyl, suitable deprotection conditions may be employed as necessary. Preferred conditions comprise 4M HCI in dioxane or 5N NaOH in dioxane.

Compounds of formula (IA) may be prepared from compounds of formula (II) according to process step (iv), a nucleophilic substitution reaction with compounds of formula (VII) under either Buchwald-Hartwig cross coupling conditions or mediated by acid and high températures. Typical Buchwald-Hartwig conditions comprise a suitable palladium catalyst with a suitable chelating phosphine ligand with an inorganic base in a suitable organic solvent at elevated températures either thermally or under microwave irradiation. Preferred conditions comprise tris(dibenzylideneacetone)dipalladium (0) and 2-dicyclohexyiphosphino-2',4',6'-triisopropylbiphenyl or xantphos or RuPHOS palladium (II) phenethylamine chloride with sodium tert-butoxide or potassium phosphate or césium carbonate in tert-amyl alcohol or DMSO at from 120-140°C under microwave irradiation. Typical acidic conditions comprise a suitable inorganic acid in a suitable alcoholic solvent at elevated températures either thermally or under microwave irradiation. Preferred conditions comprise concentrated hydrochloric acid in /so-propanol at 140°C under microwave irradiation.

Compounds of formula (II) may be prepared from compounds of formula (III) according to process step (iii), an amide bond formation reaction with compounds of formula (VIII), wherein X may be chloro, hydroxyl, a suitable leaving group or anhydride. Wherein compounds of formula (VIII) are acid chlorides, preferred conditions comprise triethylamine in DCM at room température. Wherein compounds of formula (VIII) are carboxylic acids, activation of the carboxylic acid using a suitable inorganic base and a suitable coupling agent is employed. Preferred conditions comprise DIPEA or triethylamine with HATU in DCM or DMF at room température. Wherein compounds of formula (VIII) are anhydrides, preferred conditions comprise stirring in DCM at room température. Wherein compounds of formula (VII) contain suitable leaving groups such as para-chlorophenoxy, preferred conditions comprise DIPEA in dioxane at reflux.

Compounds of formula (III) may be prepared from compounds of formula (IV) according to process step (ii) a deprotection reaction mediated by either an inorganic or organic acid in a suitable organic solvent. Preferred conditions comprise hydrochloric acid or THF in dioxane or DCM. Compounds of formula (IV) may be prepared from compounds of formulae (V) and (VI) according to process step (i), an aromatic nucleophilic substitution reaction in the presence of an inorganic base. Preferred conditions comprise triethylamine in methanol at from 0°C to room température.

According to a second process, compounds of formula (IA) may be prepared from compounds of formula (IV) as illustrated by Scheme 2

Scheme 2

Wherein PG is tert-butoxycarbonyl; X is chloro, hydroxyl, a suitable leaving group or a suitable anhydride; Z = (CH₂)/>; A is -N(C=O)R⁰-.

Compounds of formula (IV) may be prepared as described in Scheme 1.

Compounds of formulae (VIII) and (Vil) are commercially available or may be synthesized by those skilled in the art according to the literature or préparations described herein. Compounds of formula (IA) may be prepared from compounds of formula (IV) by reversing the steps shown in Scheme 1. Compounds of formula (IA) may be prepared from compounds of formulae (XI) and (VIII) according to process step (iii), an amide bond formation reaction as described in Scheme 1.

Compounds of formula (XI) may be prepared from compounds of formula (IV) according to process steps (iv) and (ii), a nucleophilic substitution reaction with compounds of formula (VII) under either Buchwald-Hartwig cross coupling conditions or mediated by acid and high températures followed by a deprotection reaction mediated by either an inorganic or organic acid as described in Scheme 1. Alternatively the deprotection occurs in situ during process step (iv).

According to a third process, compounds of formula (IA) may be prepared from compounds of formula (XI) as illustrated by Scheme 3.

ê ' N	0 A i R° H/R (X)
^rA.	R°
Αλ 4 R³ N NHR⁴	^or A
	(XII)
(XI)
	^or r°'^lg

(IA) (vii)

(XIH)

Scheme 3

Wherein A is NR°; Z = (CH2)/,; LG is leaving group such as chloro, bromo, iodo, tosylate, mesylate.

Compounds of formula (XI) may be prepared as described in Scheme 1. Compounds of formula (X), (XII) and (XIII) are commercially available or may be synthesized by those skilled in the art according to the literature or préparations described herein. Compounds of formula (IA) may be prepared from compounds of formula (XI) according to either process step (v), a reductive amination reaction with aldéhydes or ketones of formula (X) or process step (vi), a Michael addition reaction with conjugated alkenes of formula (XII) or process step (vii), an alkylation reaction with compounds of formula (XIII). Preferred conditions for the reductive amination comprise sodium triacetoxyborohydride or sodium cyanoborohydride in MeOH either with or without an inorganic base and an inorganic acid; such as triethylamine and acetic acid. Preferred conditions for the Michael addition comprise stirring compounds of formula (XI) with conjugated alkenes of formula (XII) in éthanol atfrom 0-140°C either thermally or under microwave irradiation. Preferred conditions for the alkylation reaction comprise stirring compounds of formula (XI) with compounds of formula (XIII) that contain a suitable leaving group for alkylation with an inorganic base such as sodium carbonate with a catalyst such as tertbutylammonium iodide.

According to a fourth process, compounds of formula (IA) may be prepared from compounds of formula (XI) as illustrated by Scheme 4.

Scheme 4

Wherein A is NR°, Z = (CH2)/,; wherein R° is heteroaryl; Hal is fluoro, chloro, bromo, iodo.

Compounds of formula (XI) may be prepared as described in Scheme 1. Compounds of formula (XIV) are commercially available or may be synthesized by those skilled in the art according to the literature or préparations described herein. Compounds of formula (IA) may be prepared from compounds of formula (XI) according to process step (iv) an a nucleophilic substitution reaction with compounds of formula (XIV) under either Buchwald-Hartwig cross coupling conditions as described in Scheme 1 or mediated by base and high températures. Preferred conditions mediated by base and high températures comprise triethylamine in isopropanol at 160°C under microwave irradiation.

According to a fifth process, compounds of formula (IA) may be prepared from compounds of formula (XI) as illustrated by Scheme 5.

Wherein A is NSO2R⁰; Z = (CH2)/>.

Compounds of formula (XI) may be prepared as described in Scheme 1. Compounds of formula (XV) are commercially available or may be synthesized by those skilled in the art according to the literature or préparations described herein. Compounds of formula (IA) may be prepared from compounds of formula (XI) according to process step (viii) a sulfonamide formation reaction with compounds of formula (XV). Preferred conditions comprise triethylamine in DCM at room température.

According to a sixth process, compounds of formula (IA) may be prepared from compounds of formula (XI) as illustrated by Scheme 6.

or

O=C=NR° (XVI)

(XI)

Scheme 6

Wherein A is -N(C=O)NHR⁰-; Z = (CH₂)/>..

Compounds of formula (XI) may be prepared as described in Scheme 1. Compounds of formula (XVI) and (XVII) are commercially available or may be synthesized by those skilled in the art according to the literature or préparations described herein.

Compounds of formula (IA) may be prepared from compounds of formula (XI) according to process step (ix), a urea formation reaction with isocyanates of formula (XVI) or imidazoureas of formula (XVII). Preferred conditions comprise triethylamine in DCM at températures from -50°C to room température.

According to a seventh process, compounds of formula (IA) may also be interconverted to other compounds of formula (IA) as illustrated below in Scheme 7.

Scheme 7

Wherein Z = (CH₂)ft.. ·

Compounds of formula (lAi) may be prepared as for compounds of formula (IA) as described in Schemes 1-5. Compounds of formula (lAii) may be prepared from compounds of formula (lAi) according to process steps (ii) and (viii), a deprotection step followed by a suifonamide formation reaction as described in Schemes 1 and 5. According to an eighth process, compounds of formula (lAiv) may also be interconverted to other compounds of formula (lAiii) as illustrated below in Scheme 8.

Scheme 8

Wherein Z = (CLL)/;..

Compounds of formula (lAiv) may be prepared as for compounds of formula (IA) as described in Schemes 1-5. Compounds of formula (lAiii) may be prepared from compounds of formula (lAiv) according to process step (x), a déhydration reaction via a primary carboxamide. Preferred conditions comprise 7M ammonia in methanol at elevated températures of 90°C followed by déhydration with TFAA.

According to a ninth process, compounds of formula (IB) may be prepared from compounds of formula (XXIII) as illustrated by Scheme 9.

(XVIII)

(XXIII)

(ü). (i)

(xxi)

(XIX)

Scheme 9

Wherein R^x is H or Methyl, R^y is H or CH2OH, PG¹ is tert-butoxycarbonyl; PG² is benzyl; X is chloro, hydroxyl, a suitable leaving group or a suitable anhydride.

Compounds of formula (XXIII), (VI), (XVIII) and (VII) are commercially available or may be synthesized by those skilled in the art according to the literature or préparations described herein. Compounds of formula (IB) may be separated into the respective enantiomers via chiral séparation of the racemate as required. Compounds of formula (IB) may be prepared from compounds of formula (XIX) and (VII) according to process step (iv) a nucleophilic substitution reaction with compounds of formula (VII) under either Buchwald-Hartwig cross coupling conditions or mediated by acid and high températures as described in Scheme 1.

Compounds of formula (IB) may also be prepared from compounds of formula (XX) and (XVIII) according to process step (iii) an acylation reaction as described in Scheme 1. Compounds of formula (XIX) may be prepared from compounds of formula (XXI) and (VI) according to process steps (ii) and (i), a deprotection reaction followed by an aromatic nucleophilic substitution reaction as described in Scheme 1. and as illustrated by Scheme 10. Compounds of formula (XIX) may be prepared from compounds of formula (XXIII) and (XVIII) according to process step (iii), an amide bond formation reaction as described in Scheme 1.

According to a tenth process, compounds of formula (IB) may be prepared from compounds of formula (XXIII) as illustrated by Scheme 10.

(VI)

R^x

(XXII) (ü). (M

H2NR4

Scheme 10

Wherein R^x is H or Methyl, R* is H or CH2OH, PG¹ is tert-butoxycarbonyl; PG² is benzyl; X is chloro, hydroxyl, a suitable leaving group or a suitable anhydride. Compounds of formula (XX) may be prepared from compounds of formula (XXII) and (VII) according to process steps (ii) and (iv), a deprotection reaction and a nucleophilic substitution reaction with compounds of formula (VII) under either Buchwald-Hartwig cross coupling conditions or mediated by acid and high températures as described in Scheme 1. Deprotection may also occur during the process of reaction step (iv).

Compounds of formula (XXII) may be prepared from compounds of formula (XXIV) and (VI) according to process step (i) an aromatic nucleophilic substitution reaction as described in Scheme 1. Compounds of formula (XXIV) may be prepared from compounds of formula (XXIII) according to reaction steps (xi) and (xii), suitable deprotection and protection steps as necessary. Preferred protection conditions comprise di-tert-butyl dicarbonate with triethylamine at room température followed by deprotection of an orthogonal protecting group under hydrogénation over a métal catalyst. Preferred conditions comprise hydrogénation at 50psi at room température over palladium hydroxide.

According to a eleventh process, Compounds of formula (IA) may be prepared from compounds of formulae (XXX) and (VIII), as illustrated by Scheme 11.

Scheme 11

Wherein PG is tert-butoxycarbonyl; LG is a leaving group such as chloro, bromo, iodo, tosylate, mesylate; W is a hydroxyl or thiolether; X is chloro, hydroxyl, a suitable leaving group or a suitable anhydride; Z = (ΟΗ2)λ; A is --N(C=O)R⁰-;

Compounds of formula (XXX), (XXVII), and (VII) are commercially available or may be synthesized by those skilled in the art according to the iiterature or préparations described herein, Compounds of formula (IA) may be prepared from compounds of formula (XXV) and (VII) according to process (iii), an amide bond formation reaction as described in Scheme 1.

Compounds of formula (XXV) can be prepared from compounds of formula (XXVIII) and (XXVII) according to process (iv), a nucleophiiic substitution reaction as described in Scheme 1.

Compounds of formula (XXVIII) can be prepared from compounds of formula (XXIX) according to process (xiii), halogénation mediated by phosphoryi halides. Typical conditions comprise of reaction of a phoshoryl halide with or without additional solvent at room température or heated. Preferred conditions for conversion of an alcohol to halide comprise of phosphoryi chloride and heated to reflux.

Compound of formula (XXIX) can be prepared from compounds of formula (XXX) and (VII) according to process (ii), a nucleophiiic substitution reaction as described in Scheme 1.

In executing the synthesis of the compounds of the invention, one skilled in the art will recognize the need to sample and assay reaction mixtures prior to work up in order to monitor the progress of reactions and décidé whether the reaction should be continued or whether it is ready to be worked up to obtain the desired product. Common methods for assaying reaction mixtures include thin-layer chromatography (TLC), liquid chromatography/mass spectroscopy (LCMS), and nuclear magnetic résonance (NMR).

One skilled in the art will also recognize that the compounds of the invention may be prepared as mixtures of diastereomers or géométrie isomers (e.g., cis and trans substitution on a cycloalkane ring). These isomers can be separated by standard chromatographie techniques, such as normal phase chromatography on silica gel, reverse phase préparative high pressure liquid chromatography

or supercritical fluid chromatography. One skilled in the art will also recognize that some compounds of the invention are chiral and thus may be prepared as racemic or scalemic mixtures of enantiomers. Several methods are available and are well known to those skilled in the art for the séparation of enantiomers. A preferred method for the routine séparation enantiomers is supercritical fluid 5 chromatography employing a chiral stationary phase.

EXPERIMENTAL SECTION

Except where otherwise noted, reactions were run under an atmosphère of nitrogen. Chromatography on silica gel was carried out using 250-400 mesh silica gel using pressurized nitrogen (-10-15 psi) to drive solvent through the column (“flash chromatography”). Where indicated, 10 solutions and reaction mixtures were concentrated by rotary évaporation under vacuum.

¹H and ¹⁹F Nuclear magnetic résonance (NMR) spectra were in ail cases consistent with the proposed structures. Characteristic chemical shifts (δ) are given in parts-per-million downfield from tetramethylsilane (for ¹H-NMR) and upfield from trichlorofluoromethane (for ¹⁹F NMR) using conventional abbreviations for désignation of major peaks: e.g., s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br, broad. The following abbreviations hâve been used for common solvents: CDCh, deuterochloroform; d6-DMSO, deuterodimethylsulfoxide; and CD3OD, deuteromethanol. Where appropriate, tautomers may be recorded within the NMR data; and some exchangeable protons may not be visible. Mass spectra, MS (m/z), were recorded using either electrospray ionization (ESI) or atmospheric pressure chemical ionization (APCI). Where relevant and unless otherwise stated the m/z data provided are for isotopes ¹⁹F, ³⁵CI, ⁷⁹Br and ¹²⁷l.

The nomenclature in this patent is written as described by IUPAC (International Union of Pure and Applied Chemistry and using ACD/Name Version 12 (Toronto, Canada) to generate names.

In the non-limiting Examples and Préparations that are set out later in the description, and in the aforementioned Schemes, the following the abbreviations, définitions and analytical procedures 25 may be referred to:

CDI is carbonyl di-imidazole;

DBU is diazabicyclo[5.4.0]undec-7-ene;

DCC is N,N’-dicyclohexylcarbodiimide;

DCM is dichloromethane; methylene chloride;

DEAD is diethylazodicarboxylate;

DIPEA/DlEAis N-ethyldiisopropylamine, N,N-diisopropylethylamine;

DMA is dimethylacetamide;

DMAP is dimethylaminopyridine;

DPPP is 1,3-bis(diphenylphosphino)propane;

EDCI-HCI is 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride;

ee is enantiomeric excess;

HATU is 1-[Bis(dimethylamino)methylene]-1/7-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate;

HOBt is hydroxybenzotriazole;

LCMS is liquid chromatography mass spectrometry (Rt = rétention time);

Pd₂(dba)3 is trisdibenzylideneacetonedipalladium;

Pd(dppf)CI2 is 1,1-bis(diphenylphosphino)ferrocene-palladium(ll)dichloride;

RuPHOS is 2-Dicyclohexylphosphino-2',6'-diisopropoxybiphenyi;

TBDMS is tertbutyldimethylsilyl;

TLC is thin layer chromatography;

Xantphos/Xphos is 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene.

GCMS Conditions

Column: 12m x 0.2mm, HP-1 Methyl Siloxane, 0.33pm film, 1.0ml/min column flow

Method: 7.6min: Initial Oven Temp 105°C; 0.1 min hold; 30°C/min ramp to 300°C endpoint at 7.6min or 7.6min: Initial Oven Temp 60°C; 0.1 min hold; 40°C/min ramp to 320°C endpoint at 7.6min or 5.1min: Initial Oven Temp 40°C; 0.1min hold; 30°C/min ramp to 150°C endpoint at 5.1min

GC Inlet Parameters: Front Iniet, Split 30:1, He, 8psi pressure, 250°C Injecter, 33.9ml/min total flow 15

MSD Tune: 230°C Source Temp, 150°C Quad Temp, 280°C Aux2 Temp

Injection Volume: 1.0 pL

System Components: Agilent 5890 GC Oven with Agitent 5973 Mass Sélective Detector

LCMS Conditions

Acid: Waters Acquity HSS T3, 2.1mmx50mm, C18,1.7pm; Column Température 60°C

Base: Waters Acquity UPLC BEH, 2.1mmx50mm, C18,1.8pm; Column Température 60°C

Mobile Phase: A: 0.1% formic acid in water (v/v); Mobile phase B: 0.1% formic acid in acetonitrile (v/v).

Mobile Phase A: 0.1% ammonia in water (v/v); Mobile phase B: 0.1% ammonia in acetonitrile (v/v) Gradient Profiles:

1.5 min Run: Initial conditions: A-95%:B-5%; hold at initial from 0.0-0.1min; Linear Ramp to A-5%:B95% over 0.1-1.0min; hold at A-5%:B-95% from 1.0-1.1min; return to initial conditions 1.1-1.5min ¹H and ¹⁹F Nuclear magnetic résonance (NMR) spectra were in ail cases consistent with the proposed structures. Characteristic chemical shifts (δ) are given in parts-per-million downfield from tetramethylsilane (for ¹H-NMR) and upfield from trichloro-fluoro-methane (for ¹⁹F NMR) using conventional abbreviations for désignation of major peaks: e.g., s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br, broad. The following abbreviations hâve been used for common solvents:

CDCI3, deuterochloroform; d6-DMSO, deuterodimethylsulphoxide; and CD3OD, deuteromethanol.

Where appropriate, tautomers may be recorded within the NMR data; and some exchangeable protons may not be visible.

Mass spectra, MS (m/z), were recorded using either eiectrospray ionisation (ESI) or atmospheric pressure chemical ionisation (APCI). Where relevant and unless otherwise stated the m/z data provided are for isotopes ¹⁹F, ^{30 * * * * 35 * * * * 40}CI, ⁷⁹Br and ¹²⁷l. Where préparative TLC or silica gei chromatography has been used, one skilled in the art may choose any combination of solvents to purify the desired compound.

Purification methods (PM)

The compounds of the Examples were purified according to one of the Purification Methods (PM) referred to below unless otherwise described:

Purification Method A: Préparative HPLC using [Agella venusil ASB C18 150x21.2mmx5pm, from 16% MeCN in water (0.225% formic acid) to 36% MeCN in water (0.225% formic acid)]

Purification Method B: Préparative HPLC using [Phenomenex Gemini C18 250x21.2mmx8um or 150mmx25mmx5pm; from 16-55% MeCN in water (0.1% ammonia) to 36-60% MeCN in water (0.1% ammonia)]

Purification Method C: [YMC -Actus Triart C18 150x30pm, from 24% MeCN in water (0.1 % ammonia) to 44% MeCN in water (0.1 % ammonia)]

Purification Mçthod D: Préparative HPLC using [Phenomenex Gemini C18 250x21.2mmx8pm, from 25% MeCN in water (ammonia pH=10) to 45% MeCN in water (ammonia pH=10)] followed by chiral chromatography using AS 250x25mm I.D. 20 μΜ column, with supercritical CO2: EtOH or IPA (0.05% aqueous ammonia) 70:30 atfrom 50-80 mL/min

Purification Method E: Préparative HPLC using [Phenomenex Gemini C18 250x21.2mmx8pm, from 25% MeCN in water (0.225% ammonia) to 45% MeCN in water (0.225% ammonia) followed by chiral chromatography using AD 250mmx30mmx20pm column with mobile phase A: supercritical CO2 and mobile phase B MeOH with 0.1% ammonia A:B 50:50 at 180 mL/min

Purification Method F: Silica gel column chromatography eluting with 100% DCM to 12% MeOH with 1% NH4OH.

Purification Method G: Silica gel column chromatography eluting with 97:2:1 DCM:MeOH:NH3 followed by préparative HPLC.

Purification Method H: Préparative HPLC using Column: Waters XBridge C18 19mmx100mm, 5μ; Mobile phase A: 0.03% ammonium hydroxide in water (v/v); Mobile phase B: 0.03% ammonium hydroxide in acetonitrile (v/v); from 5-20% B to 40-100% B at 25 mL/min flow rate.

Purification Method I: Préparative HPLC using Column: Waters Sunfire C18 19mmx100mm, 5μ; Mobile phase A: 0.05% TFA in water (v/v); Mobile phase B: 0.05% TFA in acetonitrile (v/v); from 20% B to 40% B at 6.75 minutes, then to 100% B at 7 minutes at 30 mL/min flow rate.

Spécifie Rotation

Spécifie rotations based on the équation [a] = (100-a)/(l-c) and are reported as unitless numbers where the concentration c is in g/100 mL and the path length I is in decimeters. The units of the spécifie rotation, (deg-mL)/(g-dm), are implicit and are not included with the reported value.

Library Protocol 1

A 0.2M solution of ((1R,5S)-3-(2-chloro-5-fiuoropyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8yl)(cyclopropyl)methanone (Préparation 27, 500 pl, 100 pmol) in tert-amyl alcohol was added to amines of formula (R⁴NH2) (150 pmol) followed by sodium tert-butoxide (200 pmol), Pd2(dba)3 (2 pmol) and XPhos (2 pmol) under nitrogen. The reactions were heated to 140°C under microwave irradiation for 40 minutes. The reactions were cooled, concentrated in vacuo and purified using préparative HPLC.

Préparative HPLC

Purification Method 1 (PM1): Phenomenex Gemini C18, 250x21.2mmx8pm; Acetonitrile-ammonium hydroxide; Flow rate 30 mL/min; Gradient time 8 mins.

Purification Method 2 (PM2): DIKMA Diamonsil C18 200mmx20mmx5pm; MeCN-water (0.225% formic acid); Flow rate 35 mL/min; Gradient time 9 mins.

LCMS Method:

Column: XBridge C18 2.1mmx50mmx5pm

Mobile Phase A: 0.05% ammonium hydroxide in water

Mobile phase B: 100% MeCN

Gradient: 5% B to 100% B at 3.40 minutes then back to 5% B at4.21 minutes.

Flow rate: 0.8 mL/min

The compounds of the Examples in the table below were prepared from ((1R,5S)-3-(2-chloro-5fluoropyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)(cyclopropyl)methanone (Préparation 27) and the appropriate amine according to Library Protocol 1.

Ex	Name	SM/Data/HPLC Organic gradient
1	cyciopropyl{(1R,5S)-3-[5-fluoro-2(pyridazin-4-ylamino)pyrimidin-4yl]-3,8-diazabicyclo[3.2.1]oct-8yljmethanone	Pyridazin-4-amine Rt = 2.31 minutes MS m/z 370 [M+H]⁺17-47% organic in PM 1.

2	3-({4-[(1R,5S)-8- (cyclopropylcarbonyl)-3,8diazabicyclo[3.2.1]oct-3-yl]-5fluoropyrimidin-2-yl}amino)-Npropyl-1 H-pyrazoIe-5carboxamide	5-amino-1 H-pyrazole-3-carboxyIic acid propylamide (Préparation 83). Rt = 2.45 minutes MS m/z 443 [M+H]⁺11-41% organic in PM 2.
3	6-({4-[(1R,5S)-8- (cyclopropylcarbonyl)-3,8diazabicyclo[3.2.1]oct-3-yl]-5fluoropyrimidin-2yl}amino)imidazo[1,2-a]pyridine-2carboxamide	7-amino-imidazo[1,2-a]pyridine-2-carboxylic acid amide(Preparation 86). Rt = 2.22 minutes MS m/z 451 [M+H]⁺10-40% organic in PM 2.
4	5-({4-[(1 R,5S)-8- (cyc!opropylcarbonyl)-3,8diazabicyclo[3.2.1]oct-3-yl]-5fluoropyrimidin-2yl}amino)pyridine-2-sulfonamide	2-(methylsulfonyl)-pyridin-4-amine Rt = 2.35 minutes MS m/z 448 [M+H]⁺ 13-53% organic in PM 1.

Example 5 (1R,5S)-N-ethvl-3-[2-(1H-pvrazol-4-vlamino)pvrimidin-4-vll-3,8-diazabicvclo[3.2.11octane-8carboxamide

To a solution of (1R,5S)-3-(2-chloropyrimidin-4-yi)-N-ethyl-3,8-diazabicyclo[3.2.1]octane-8carboxamide (Préparation 29, 184 mg, 0.624 mmol) and tert-butyl 4-amino-1H-pyrazole-1carboxylate (PCT Publication No. WO2012022681, 126 mg, 0.686 mmol) in DMA (8 mL) was added CS2CO3 (405.6 mg, 1.248 mmol), Pd(OAc)2 (28 mg, 0.124 mmol) and xantphos (72 mg, 0.124 mmol). The reaction was purged with nitrogen for 3 minutes before heating to 120°C under microwave irradiation for 1 hour. The reaction was concentrated in vacuo and purified by silica gel column chromatography eluting with 10% MeOH in DCM followed by préparative HPLC (Purification Method B) to afford the title compound (81 mg, 38%).

¹H NMR (400MHz, DMSO-de): δ ppm 1.02 (t, 3H), 1.58 (d, 2H), 1.77 (d, 2H), 2.96-3.11 (m, 4H) 3.794.09 (m, 2H), 4.34 (br s, 2H), 6.07 (d, 1H), 6.67 (t, 1H), 7.49-7.94 (m, 3H), 8.82 (br s, 1H), 12.35 (br s, 1H). MS m/z 343 [M+H]⁺

Example 6

5-((44(1 R.5S)-8-(cvclopropvlcarbonvl)-3,8-diazabicvclo[3.2.1loct-3-vllpvrimidin-2-vl}amino)-N,3dimethvlpyridine-2-carboxamide

To a solution of 5-((4-((1 R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyrimidin-2-yl)amino)-N,3dimethylpicolinamide hydrochloride (Préparation 1, 77 mg, 0.220 mmol) and triethylamine (133 mg, 1.32 mmol) in DCM (10 mL) was added cyclopropanecarbonyl chloride (27 mg, 0.26 mmol) dropwise. The reaction was stirred at room température for 1 hour before concentrating in vacuo. The residue was purified using préparative HPLC to afford the title compound (48 mg, 52%).

¹H NMR (400MHz, DMSO-de): δ ppm 0.60-0.85 (m, 4H), 1.53-2.07 (m, 5H), 2.56 (s, 3H), 2.75 (d, 3H), 2.95-3.04 (m, 1H), 3.04-3.15 (m, 1H), 3.96-4.26 (m, 2H), 4.55-4.67 (m, 1H), 4.73-4.85 (m, 1H), 6.2818225

6.37 (m, 1H), 7.99-8.11 (m, 2H), 8.39-8.47 (m, 1H), 8.74-8.81 (m, 1H), 9.52 (s, 1H). MS m/z 444 [M+Na]⁺

Examples 7 and 8 r(1S)-2,2-difluorocvclopropvl1R1R.5S)-3-(2-r(1-methvl-1H-pvrazol-4-vl)aminolpyrimidin-4-vl}-3,85 diazabicyclo[3.2.T|oct-8-vl1methanone and r(1R)-2,2-difluorocvclopropvni(1R,5S)-3-(2-[(1-methvl-1Hpvrazol-4-vl)amino1pvrimidin-4-vl}-3,8-diazabicycloi3.2.1loct-8-vl1methanone

To a solution of (S)-2,2-difluorocyclopropane-1-carboxylic acid (Préparation 68, 318 mg, 2.61mmol) in DCM (20 mL) was added 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-N-(1-methyl-1H-pyrazol-4yl)pyrimidin-2-amine hydrochloride (Préparation 19, 700 mg, 2.17 mmol), HATU (1.02 g, 2.61 mmol 10 and DIPEA (0.76 mL, 4.34 mmol) and the reaction was stirred at room température for 18 hours. The reaction was diluted with DCM and saturated aqueous ammonium chloride solution. The organic layer was separated, washed with further ammonium chloride solution and concentrated in vacuo. The residue was purified using silica gel column chromatography eluting with 0-12% MeOH and 1% NH4OH in DCM. The residue was dissolved in DCM and further washed with saturated aqueous 15 ammonium chloride solution three times. The organic layer was collected, concentrated in vacuo and dried to afford the title compound (500 mg, 60%).

The title compound and its enantiomer may also be prepared according to the same method using racemic 2,2-difluorocyclopropane-1-carboxylic acid with additional chiral séparation of the enantiomers after purification using the method below to afford:

Peak 1: Example 7:

[(1S)-2,2-difluorocyclopropyl][(1R,5S)-3-{2-[(1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-3,8diazabicyclo[3.2.1 ]oct-8-yl]methanone ¹H NMR (400MHz, DMSO-de): δ ppm 1.58-2.06 (m, 6H), 2.82-3.27 (m, 3H), 3.80 (s, 3 H), 4.14 (br s, 2H), 4.55-4.74 (m, 2H), 6.07-6.19 (m, 1H), 7.44 (s, 1H), 7.74 (brs, 1H), 7.93 (d, 1H), 8.90 (brs, 1H).

MS m/z 390 [M+H]⁺; [cc]_D ²⁰ 50.1 (c 1.27, EtOH)

Peak 2: Example 8:

[(1R)-2,2-difluorocyclopropyl][(1R,5S)-3-{2-[(1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-3,8diazabicyclo[3.2.1]oct-8-yl]methanone ¹H NMR (400MHz, DMSO-d_B): δ ppm 1.58-2.06 (m, 6H), 2.82-3.27 (m, 3H), 3.80 (s, 3 H), 4.14 (br s, 30 2H), 4.55-4.74 (m, 2H), 6.07-6.19 (m, 1 H), 7.44 (s, 1 H), 7.74 (br s, 1 H), 7.93 (d, 1 H), 8.90 (br s, 1 H).

MS m/z 390 [M+H]⁺; [oc]d²⁰ -51 (c 0.66, EtOH)

Example 7 may also be prepared according to the following method:

To a solution of (S)-2,2-difluorocyclopropane-1-carboxylic acid (Préparation 68, 18.1 g, 35.33 mmol),

4-((1 R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-N-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-amine hydrochloride (Préparation 19, 11 g, 40 mmol) and DIPEA (41.7 mL, 246 mmol) in DMF (60 mL) was added T3P (102 mL, 176 mmol) and the reaction was stirred at room température for 1.5 hours. The reaction was quenched by the addition of saturated aqueous NaHCO3 solution until pH 6 and concentrated in vacuo. The residue was dissolved in DCM and washed with saturated aqueous NaHCO3 solution followed by water. The organic layer was collected, dried over sodium sulfate and concentrated in vacuo. The residue was purified using silica gel column chromatography eluting with

0-15% MeOH in DCM with 1% ammonia followed by chiral préparation using Chiral Tech OD-H 250mmx21.2mm, 5μ, using mobile phase A 75% CO2 and mobile phase B 25% MeOH at a flow rate of 80 mL/min.

Example 9

4-(f4-r8-(cvclopropvlcarbonvl)-3.8-diazabicvclor3.2.1loct-3-vl1-5-fluoropyrimidin-2-vl|amino)-Nethylbenzamide

To a solution of 4-((4-((1 R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-fluoropyrimidin-2-yl)amino)-Nethylbenzamide hydrochloride (Préparation 24, 50 mg, 0.14 mmol) in DCM (5 mL) was added triethylamine (0.1 mL, 0.7 mmol), HATU (50 mg, 0.135 mmol) and cyclopropanecarboxylic acid (15 mg, 0.17 mmol). The reaction was stirred at room température for 18 hours before purification directly using silica gel column chromatography eluting with 0-10% MeOH in DCM to afford the title compound. ¹H NMR (400MHz, CDCh): δ ppm 0.78 (br s, 2H), 1.00 (d, 2H), 1.21 (t, 3H), 1.61-1.75 (m, 1H), 1.79 (d, 1H), 1.83-1.97 (m, 2H), 2.05 (d, 2H), 3.25 (dd, 2H) 3.36-3.53 (m, 2H), 4.16 (d, 1H), 4.28 (d,1H), 4.52 (d, 1H), 4.74 (brs, 1H), 6.28 (t, 1H), 7.37 (s, 1H), 7.53 (d, 2H), 7.70 (d, 2H), 7.85 (d, 1H). MS m/z 439 [M+H]⁺

Example 10

3-chloro-5-((4-r(1 R, 5S)-8-([ ( 1 S)-2,2-difluorocyclopropvl1carbonvl)-3,8-diazabicyclor3.2.1 loct-3vllpyrimidin-2-vl)amino)-N-methvlpvridine-2-carboxamide

The title compound was prepared according to the method described for Example 9 using 5-((4((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyrimidin-2-yl)amino)-3-chloro-N-methylpicolinamide hydrochloride (Préparation 5) and (S)-2,2-difluorocyclopropane-1-carboxylic acid (Préparation 68). The residue was purified by préparative HPLC followed by chiral chromatography as described below: Préparative HPLC: DIKMA Diamonsil(2) C18 200 x 20mm x 5pm

Mobile phase: from 10% MeCN in water (0.225% formic acid) to 60% MeCN in water (0.225% formic acid)

Préparative chiral chromatography: Chiralpak AD 250x30mm l.D.IOpm

Mobile phase: Supercritical CO2:MeOH (0.1% aqueous ammonia) 55:45;

Flow rate: 50 mL/min ¹H NMR (400MHz, DMSO-de): δ ppm 1.61-2.03 (m, 6H), 2.75 (d, 3H), 2.92-3.10 (m, 2H), 3.18-3.26 (m, 1H), 4.15 (br s, 2H), 4.58-4.76 (m, 2H), 6.40 (dd, 1H), 8.05-8.14 (m, 1H), 8.44 (d, 2H), 8.81 (dd, 1H), 9.77 (d, 1H). MS m/z 478 [M+H]⁺

Examples 11 and 12

K1S)-2.2-difluorocvclopropvllK1R.5S)-3-r2-((6-K2R)-1-hvdroxvpropan-2-vl1pvridin-3vl)amino)pvrimidin-4-vl1-3,8-diazabicvclo[3.2.1loct-8-yl)methanone and ((i(1S)-2.2-difluorocvcloDropvlK(1R.5S)-3-r2-({6-r(2S)-1-hvdroxypropan-2-vnpvridin-3vl}amino)pvrimidin-4-vn-3.8-diazabicvclo[3.2.11oct-8-vl}methanone

The title compounds were prepared according to the method described by Example 9 using racemic 2-(5-((4-((1 R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyrimidin-2-yl)amino)pyridin-2-yl)propan-1-ol hydrochloride (Préparation 2) and (S)-2,2-difluorocyclopropane-1-carboxylic acid (Préparation 68).

The residue was purified using préparative HPLC followed by enantiomeric séparation using chiral chromatography as described below:

Préparative HPLC: Kromasil Eternity XT C18 250x21.2x1 Opm

Mobile phase: from 16% MeCN in water (Ammonia pH=10) to 36% MeCN in water (Ammonia pH=10); 5 Flow Rate: 30 mL/min

Préparative chiral chromatography: Chiralpak AD 250x30mm I.D.IOpm

Mobile phase: Supercritical CO2:IPA (aqueous ammonia) 55:45; Flow rate: 70 mL/min

First eluting compound was arbitrarily assigned as: Example 11:

¹H NMR (400MHz, DMSO-de): δ ppm 1.19 (d, 3H), 1.61 - 2.07 (m, 6H), 2.83-3.06 (m, 3H), 3.24 (brs, 10 2H), 3.43-3.53 (m, 1H), 3.62 (m,1H), 4.18 (br s, 2H), 4.50-4.81 (m, 3H), 6.27 (m, 1H), 7.15 (d, 1H),

7.93-8.11 (m, 2H), 8.74 (brs, 1H) , 9.19 (s, 1H). MS m/z445 [M+H]⁺

Second eluting compound was arbitrarily assigned as: Example 12 ¹H NMR (400MHz, DMSO-de): δ ppm 1.18 (d, 3H), 1.60-2.07 (m, 7H), 2.83-3.04 (m, 3H), 3.25 (dd,

1H), 3.44-3.52 (m, 1 H), 3.57-3.66 (m, 1 H), 4.13 (br s, 2H), 4.52-4.79 (m, 3H), 6.27 (dd, 1H), 7.15 15 (d, 1H), 7.93-8.09 (m, 2H), 8.74 (d,1H), 9.19 (s, 1H). MS m/z 445 [M+H]⁺

The following Examples were prepared according to the method described for Example 9 using the appropriate acid and amine as described. Purification details are as described or referred to below:

Example No.	Structure/name	Starting Materials	Data
13	4-({4-[(1R,5S)-8(cyanoacetyl)-3,8diazabicyclo[3.2.1 ]oct-3yl]pyrimidin-2-yl}amino)-Nethylbenzamide	Cyanoacetic acid and 4-((4((1 R,5S)-3,8diazabicyclo[3.2.1]octan-3yl)pyrimidin-2-yl)amino)-Nethylbenzamide hydrochloride (Préparation 4).	Rt = 1.76 minutes MS m/z 420 [M+H]⁺Purification Method H.
14	5-({4-[(1R,5S)-8- (cyclopropyicarbonyl)-3,8diazabicyclo[3.2.1]oct-3yl]pyrimidin-2-yl}amino)-Nethyl-3-methylpyridine-2carboxamide	Cyclopropanecarboxylic acid and 5-((4-((1 R,5S)-3,8diazabicyclo[3.2.1]octan-3yl)pyrimidin-2-yl)amino)-Nethyl-3-methyipicolinamide hydrochloride (Préparation 3)·	¹H NMR (400MHz, MeOHdfr: δ ppm 0.87-0.97 (m, 4H), 1.26 (t, 3H), 1.77-2.15 (m, 5H), 2.65 (s, 3H), 3.40 (m, 2H), 3.45 (m, 2H), 4.07 (m, 1H), 4.56 (m, 1H), 4.85 (m, 2H), 6.69 (d, 1H), 7.87 (br s, 1H), 7.90 (d, 1H), 8.69 (brs, 1H). MS m/z 436 [M+H]⁺PM A.

15	5-({4-[(1R,5S)-8(cyclopropylcarbonyl)-3,8diazabicyclo[3.2.1]oct-3yl]pyrimidin-2-yl}amino)-3methylpyridine-2carboxamide	Cyclopropanecarboxylic acid and 5-((4-((1 R,5S)-3,8diazabicyclo[3.2.1]octan-3yl)pyrimidin-2-yl)amino)-3methylpicolinamide hydrochloride (Préparation 18).	¹H NMR (400MHz, MeOHd4): δ ppm 0.86-0.98 (m, 4H), 1.78-2.13 (m, 5H), 2.62 (s, 3H), 3.11-3.35 (m, 3H), 4.41-4.49 (br s, 1H), 4.75-4.81 (m, 2H), 6.296.30 (m, 1H), 8.00-8.01 (m, 2H), 8.75-8.76 (m, 1H). MS m/z 408 [M+H]⁺PM B.
16	cyclopropyl[(1 R,5S)-3-(2{[1-(2-hydroxyethyl)-1Hpyrazol-4yl]amino}pyrimidin-4-yl)3,8-diazabicyclo[3.2.1]oct8-yl]methanone	Cyclopropanecarboxylic acid and 2-(4-((4-((1 R,5S)3,8-diazabicyclo[3.2.1]octan-3-yl)pyrimidin2-yl)amino)-1H-pyrazol-1yl)ethan-1-ol hydrochloride (Préparation 20).	¹H NMR (400MHz, MeOHd4): δ ppm 0.89-0.97 (m, 5H), 1.77-2.10 (m, 6H), 3.07-3.18 (m, 2H), 3.87 (t, 2H), 4.19 (t, 2H), 4.72-4.77 (m, 2H), 6.12 (d, 1H), 7.52 (s, 1 H), 7.86 -7.89 (m, 2H). MS m/z 384 [M+H]⁺PM C.
17	1,2-oxazol-5-yl{(1 R,5S)-3[2-(1 H-pyrazol-4ylamino)pyrimidin-4-yl]-3,8diazabicyclo[3.2.1]oct-8yljmethanone	4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-N(1 l2-pyrazol-4-yl)pyrimidin2-amine hydrochloride (Préparation 22) and isoxazole-5-carboxyüc acid.	¹H NMR (400MHz, DMSOde): δ ppm 1.56-2.39 (m, 4H), 2.96-3.22 (m, 2H), 4.01-4.37 (m, 2H), 4.614.96 (m, 2H), 6.04-6.20 (m, 1H), 7.10 (d,1H), 7.427.84 (m, 2H), 7.87-8.04 (m, 1H), 8.77-8.82 (m, 1H), 8.83-8.94 (m, 1H), 12.19-12.48 (m, 1H), MS m/z 367 [M+H]⁺PM B.
18	[(1R,5S)-3-(2-{[5-chloro-6- (2-hydroxyethyl)pyridin-3yl]amino}pyrimidin-4-yl)- 3,8-diazabicyclo[3.2.1 Joct8-yl][(1S)-2,2difluorocyclopropyljmethan one	2-(5-((4-((1 R, 5S)-3,8diazabicyclo[3.2.1 ]octan-3yl)pyrimidin-2-yl)amino)-3chloropyridin-2-yl)ethan-1 ol hydrochloride (Préparation 6) and (S)2,2-difluorocyclopropane-1 carboxylic acid (Préparation 68).	¹H NMR (400MHz, MeOHd4): δ ppm 1.75-2.07 (m, 6H), 3.00-3.07 (m, 1H), 3.11 (s, 2H), 3.81-3.95 (m, 2H), 4.09-4.41 (m, 2H), 4.58-4.83 (m, 4H), 6.236.34 (m, 1H), 7.92-8.06 (m, 1H), 8.24- 8.35 (m, 1H), 8.61-8.72 (m, 1H). MS m/z 465 [M+H]⁺PM D.
19	[(1S)-2,2- difluorocyclopropyl][(1 R,5S) -3-(2-{[5-fluoro-6-(2hydroxyethyl)pyridin-3yl]amino}pyrimidin-4-yl)3,8-diazabicyclo[3.2.1 ]oct8-yl]methanone	2-(5-((4-((1 R,5S)-3,8diazabicyclo[3.2.1]octan-3yl)pyrimidin-2-yl)amino)-3fluoropyridin-2-yl)ethan-1-ol hydrochloride (Préparation 7) and (S)-2,2- difluorocyclopropane-1carboxylic acid (Préparation 68).	¹H NMR (400MHz, MeOHd4): δ ppm 1.58-2.07 (m, 1H), 2.81-2.89 (m, 1H), 2.90-3.26 (m, 2H), 3.623.73 (m, 1H), 3.98-4.32 (m, 1H), 4.53-4.78 (m, 2H), 6.25-6.37 (m, 1H), 8.00-8.15 (m, 2H), 8.548.67 (m, 1H), 9.46 (s, 1H). MS m/z 449 [M+H]⁺PM D.

20	[(1S)-2,2difluorocyclopropyl]{(1 R,5S) -3-[2-({5-fluoro-6-[(3S)-3hydroxypyrrolidin-1yl]pyridin-3yl}amino)pyrimidin-4-yl]3,8-diazabicyclo[3.2.1]oct8-yl}methanone	(S)-1-(5-((4-((1R,5S)-3,8diazabicyclo[3.2.1]octan-3yl)pyrimidin-2-yl)amino)-3fluoropyridin-2-yl)pyrrolidin3-ol (Préparation 8) and (S)-2,2-difluorocyclopropane-1-carboxylic acid (Préparation 68).	¹H NMR (400MHz, DMSOd6): δ ppm 1.58-2.07 (m, 1H), 2.81-2.89 (m, 1H), 2.90-3.26 (m, 2H), 3.623.73 (m, 1H), 3.98-4.32 (m, 1H), 4.53-4.78 (m, 2H), 6.25-6.37 (m, 1H), 8.00-8.15 (m, 2H), 8.548.67 (m, 1H), 9.46 (s, 1H). MS m/z 490 [M+H]⁺PM B.
21	[(1S)-2,2- difluorocyclopropyl]{(1 R,5S) -3-[2-({5-fluoro-6-[(3R)-3hydroxypyrrolidin-1yl]pyridin-3yl}amino)pyrimidin-4-yl]3,8-diazabicyclo[3.2.1]oct8-yl}methanone	(R) -1 -(5-((4-((1 R,5S)-3,8diazabicyclo[3.2.1]octan-3yl)pyrimidin-2-yl)amino)-3fluoropyridin-2-yl)pyrrolidin- 3-ol (Préparation 9) and (S) -2,2-difluorocyclopropane-1-carboxylic acid (Préparation 68).	¹H NMR (400MHz, DMSOd6): δ ppm 1.59-2.06 (m, 8H), 2.82-3.03 (m, 2H), 3.10- 3.29 (m, 2H), 3.483.67 (m, 3H), 4.00-4.37 (m, 3H), 4.59-4.74 (m, 2H), 4.85-4.94 (m, 1H), 6.16-6.27 (m, 1H), 7.787.89 (m, 1H), 7.95 (s, 1H), 8.11- 8.22 (m, 1H), 8.909.03 (m, 1H). MS m/z 490 [M+H]⁺PM B.
22	[(1S)-2,2- difluorocyclopropyl][(1 R,5S) -3-(2-{[5-fluoro-6-(3hydroxyazetidin-1- yl)pyridin-3yljamino}pyrimidin-4-yl)3,8-diazabicyclo[3.2.1]oct8-yl]methanone	1-(5-((4-((1 R, 5S)-3,8diazabicyclo[3.2.1]octan-3yl)pyrimidin-2-yl)amino)-3fluoropyridin-2-yl)azetidin3-oI (Préparation 10) and (S)-2,2-difluorocycIopropane-1-carboxylic acid (Préparation 68).	¹H NMR (400MHz, DMSOδε): δ ppm 1.70-2.20 (m, 6H), 2.91-3.25 (m, 3H), 3.81-3.93 (m, 2H), 4.084.24 (m, 1H), 4.24-4.38 (m, 3H), 4.53-4.79 (m, 5H), 6.14-6.26 (m, 1H), 7.64-7.77 (m, 1H), 7.867.97 (m, 1H), 8.08-8.19 (m, 1H). MS m/z 476 [M+H]⁺PM D.
23	[(1 R,5S)-3-(2-{[5-chloro-6(2-hydroxyethoxy)pyridin-3yl]amino}pyrimidin-4-yl)3,8-diazabicyclo[3.2.1]oct8-yl][(1S)-2,2difluorocyclopropyl]methan one	2-((5-((4-((1 R,5S)-3,8diazabicyclo[3.2.1 ]octan-3yl)pyrimidin-2-yl)amino)-3chloropyridin-2-yl)oxy)ethan-1-ol hydrochloride (Préparation 11) and (S)2,2-difluorocyclopropane-1 carboxylic acid (Préparation 68).	¹H NMR (400MHz, DMSOδε): δ ppm 1.61-2.02 (m, 6H), 2.87-3.14 (m, 2H), 3.21-3.29 (m, 1H), 3.673.77 (m, 1H), 3.87-4.27 (m, 2H), 4.27-4.32 (m, 2H), 4.55-4.73 (m, 2H), 4.79-4.88 (m, 1H), 6.216.32 (m, 1H), 7.94-8.05 (m, 1H), 8.22-8.41 (m, 2H), 9.12-9.24 (m, 1H). MS m/z 481 [M+H]⁺PM B.

24	(1 R,2R)-2-{[(1 R,5S)-3-{2[(1 -ethyl-1 H-pyrazol-4yl)amino]pyrimidin-4-yl}3,8-diazabicyclo[3.2.1]oct8yl]carbonyl}cyclopropaneca rbonitrile	(1 R,2R)-2-cyanocyclopropane-1-carboxylic acid (Préparation 72) and 4((1 R,5S)-3,8-diazabicyclo[3.2.1 ]octan-3-yl)-N-(1 ethyl-1 H-pyrazol-4yl)pyrimidin-2-amine hydrochloride (Préparation 23).	¹H NMR (400MHz, DMSOd_B): δ ppm 1.33 (t, 3H), 1.42 (m, 1H), 1.63-1.81 (m, 3H), 1.80-2.10 (m, 2H), 2.88-3.15 (m, 4H), 4.07 (m, 2H), 4.04-4.09 (m, 2H), 4.60 (s, 1H), 4.85 (s, 1H), 6.11 (m, 1H), 7.45 (s, 1H), 7.75 (s, 1H), 7.92 (d, 1H), 8.86 (s, 1H). MS m/z 393 [M+H]⁺PM B (RT = 8.31 min).
25	[(1S)-2,2- difluorocyclopropyl][(1 R,5S) -3-(2-{[5-fluoro-6(hydroxymethyl)pyridin-3yl]amino}pyrimidin-4-yl)3,8-diazabicyclo[3.2.1 ]oct8-yl]methanone	(5-((4-((1 R,5S)-3,8-diazabicyclo[3.2.1 ]octan-3-yl)pyrimidin-2-yl)amino)-3-fluoropyridin-2-yl)methanol hydrochloride (Préparation 12) and (S)-2,2- difluorocyclopropane-1 carboxylic acid (Préparation 68).	¹H NMR (400MHz, DMSOd6): δ ppm 1.57-2.08 (m, 7H), 2.95 (d, 1H), 3.03 (d, 1H), 4.15 (br s, 2H), 4.50 (s, 2H), 4.59-4.76 (m, 2H), 5.15 (br s, 1H), 6.34 (m, 1H), 8.06 (d, 1H), 8.12 (d, 1H), 8.62 (d, 1H), 9.56 (br s, 1H). MS m/z 435 [M+H]⁺PM B.
26	2- [5-({4-[(1R,5S)-8-{[(1S)2,2- difluorocyclopropyl]carbonyl }-3,8-diazabicyclo[3.2.1 ]oct- 3- yl]pyrimidin-2yl}amino)pyridin-2-yl]-2methylpropanenitrile	2-(5-((4-((1 R,5S)-3,8diazabicyclo[3.2.1]octan-3yl)pyrimidin-2-yl)amino)pyridin-2-yl)-2-methylpropanenitrile hydrochloride (Préparation 13) and (S)2,2-difluorocyclopropane-1carboxylic acid (Préparation 68).	¹H NMR (400MHz, DMSOde): δ ppm 1.67-1.884 (m, 11 H), 2.92-2.95 (m, 2H), 3.20-3.28 (m, 2H), 4.20 (m, 2H), 4.65 (m, 2H), 6.29-6.32 (m, 1H), 7.477.50 (m ,1H), 8.01-8.03 (m, 1H), 8.24-8.26 (m, 1H), 8.81 (br s, 1H), 9.41 (s, 1H). MS m/z 454 [M+H]⁺PM B.
27	5-({4-[(1 R,5S)-8-{[(1 R,2R)2cyanocycloprapyljcarbonyl} -3,8-diazabicyclo[3.2.1 ]oct3-yl]pyrimidin-2-yl}amino)3-fluoro-N-methylpyridine2-carboxamide	5-((4-((1 R,5S)-3,8diazabicyclo[3.2.1]octan-3yI)pyrimidin-2-yl)amino)-3fluoro-N-methylpicolinamide hydrochloride (Préparation 14) and (1 R,2R)-2-cyanocyclopropane-1-carboxylic acid (Préparation 72).	¹H NMR (400MHz, DMSOδε): δ ppm 1.35 (m, 2H), 1.65 (m, 1H), 1.75 (m, 2H), 2.09 (m, 2H), 2.76 (m, 3H), 2.94-3.08 (m, 3H), 4.15 (m, 2H), 4.61 (m, 1H), 4.88 (m, 1H), 6.40-6.43 (m, 1H), 8.08-8.10 (m, 1H), 8.28 (m, 1H), 8.43-8.44 (m, 1H), 8.69 (s, 1H), 9.89 (s,1H). MS m/z 452 [M+H]⁺PM B.

28	5-({4-[(1 R,5S)-8-{[(1 R)-2,2difluorocyclopropyljcarbonyl }-3,8-diazabicycio[3.2.1]oct3-yl]pyrimidin-2-yl}amino)3-fluoro-N-methylpyridine2-carboxamide	Racemic 2,2-difluoro- cyclopropane-1-carboxylic acid and 5-((4-((1 R,5S)-3,8diazabi-cyclo[3.2.1]octan-3yl)pyrimidin-2-yl)amino)-3fluoro-N-methylpicolinamide hydrochloride (Préparation 14) with séparation of the enantiomers as described above in PM E.	¹H NMR (400MHz, DMSOd6): δ ppm 1.60-2.00 (m, 6H), 2.75-2.76 (m, 3H), 2.95-3.05 (m, 2H), 3.25 (m, 1H), 4.20 (m, 2H), 4.65 (m, 2H), 6.40 (m, 1H), 8.09-8.11 (m, 1H), 8.208.30 (m, 1H), 8.40 (m, 1H), 8.69 (s, 1H), 9.89 (s, 1H). SFC Rt = 5.05 minutes
29	5-((4-[(1R,5S)-8-([(1S)-2,2difluorocyclopropyljcarbonyl }-3,8-diazabicyclo[3.2.1]oct3-yl]pyrimidin-2-yl}amino)3-fiuoro-N-methylpyridine2-carboxamide	Racemic 2,2-difluoro- cyclopropane-1 -carboxylic acid and 5-((4-((1 R,5S)-3,8diazabi-cyclo[3.2.1]octan-3yl)pyrimidin-2-yl)amino)-3fluoro-N-methylpicolinamide hydrochloride (Préparation 14) with séparation of the enantiomers as described above in PM E.	¹H NMR (400MHz, DMSOd6): δ ppm 1.60-2.05 (m, 6H), 2.75-2.76 (m, 3H), 2.95-2.98 (m, 2H), 3.19 (m, 1H), 4.20 (m, 2H), 4.63-4.73 (m, 1H), 6.396.43 (m, 1H), 8.09-8.11 (m, 1H), 8.24-8.27 (m, 1H), 8.43 (m, 1H), 8.69 (s, 1 H), 9.89 (s, 1H). MS m/z 462 [M+H]⁺SFC Rt = 5.51 minutes
30	3-chloro-5-((4-[(1R,5S)-8(cyclopropylcarbonyl)-3,8diazabicyclo[3.2.1]oct-3yl]pyrimidin-2-yl}amino)-Nmethylpyridine-2carboxamide	5-((4-((1 R,5S)-3,8-diazabicyclo[3.2.1 ]octan-3yl)pyrimidin-2-yl)amino)-3chioro-N-methylpicolinamide hydrochloride (Préparation 5) and cyclopropanecarboxylic acid.	¹H NMR (400MHz, DMSOde): δ ppm 0.78 (d, 4H), 1.57-1.89 (m, 3H), 2.03 (br s, 2H), 2.76 (d, 3H), 3.003.16 (m, 2H), 4.05 (s, 2H), 4.62 (brs, 1H), 4.79 (br s, 1H), 6.39 (d, 1H), 8.08 (d, 1H), 8.45 (s, 2H), 8.82 (d, 1H), 9.77 (s, 1H). MS m/z 442 [M+H]⁺PM B.
31	3-chloro-5-((4-[(1R,5S)-8{[(1R,2R)-2cyanocyclopropyl]carbonyl} -3,8-diazabicyclo[3.2.1]oct3-yl]pyrimidin-2-yl}amino)N-methylpyridine-2carboxamide	5-((4-((1 R,5S)-3,8diazabicyclo[3.2.1]octan-3yl)pyrimidin-2-yl)amino)-3chloro-N-methylpicoIinamide hydrochloride (Préparation 5) and (1R,2R)-2cyanocyclopropane-1 carboxylic acid (Préparation 72).	¹H NMR (400MHz, DMSOd6): δ ppm 1.21 (t, 1H), 1.30-1.47 (m, 2H), 1.64 (d, 1H), 1.68-1.88 (m, 2H), 1.90-2.14 (m, 2H), 2.73 (d, 3H), 2.84-2.96 (m, 1H), 2.97-3.22 (m, 2H), 4.12 (br s, 2H), 4.60 (d, 1H), 4.87 (br s, 1H), 6.39 (t, 1H), 8.07 (dd, 1H), 8.43 (br s, 2H), 8.80 (d, 1H), 9.77 (s, 1H). MS m/z 467 [M+H]⁺PM B.

32	5-({4-[(1 R,5S)-8-{[(1 R,2R)2cyanocyclopropyl]carbonyl} -3,8-diazabicycIo[3.2.1]oct3-yl]pyrimidin-2-yl}amino)N,3-dimethylpyridine-2carboxamide	5-((4-((1 R,5S)-3,8- diazabicyclo[3.2.1]octan-3yl)pyrimidin-2-yl)amino)N,3-dimethylpicolinamide hydrochloride (Préparation 1) and (1 R,2R)-2-cyanocyclopropane-1-carboxylic acid (Préparation 72).	¹H NMR (400MHz, DMSOde): δ ppm 1.29-1.51 (m, 2H), 1.55-2.16 (m, 5H), 2.56 (s, 3H), 2.75 (d, 3H), 2.89-3.12 (m, 3H), 4.13 (br s, 2H), 4.61 (d, 1H), 4.89 (br s, 1H), 6.35 (t, 1H), 8.02-8.10 (m, 2H), 8.45 (d, 1H), 8.77 (s, 1H), 9.56 (s, 1H). MS m/z 447 [M+H]⁺PM B.
33	5-((4-((1 R,5S)-8-((S)-2,2difluorocyclopropane-1 carbonyl)-3,8diazabicyclo[3.2.1 ]octan-3yl)pyrimidin-2-yl)amino)N,3-dimethylpicolinamide	5-((4-((1 R,5S)-3,8diazabicyclo[3.2.1]octan-3yl)pyrimidin-2-yl)amino)N,3-dimethylpicolinamide hydrochloride (Préparation 1) and racemic 2,2- difluorocyclopropane-1carboxylic acid with séparation of the isomers using PM D Peak 2 arbitrarily assign as title compound.	¹H NMR (400MHz, DMSOde): δ ppm 1.67-1.88 (m, 6H), 2.57 (d, 3H), 2.76 (d, 3H), 2.95-3.06 (m, 2H), 3.21-3.24 (m, 1H), 4.644.72 (m, 2H), 6.32-6.36 (m, 1H), 8.064 (d, 2H), 8.43 (s, 1H), 8.77 (d, 1H), 9.54 (s, 1H). MS m/z 458 [M+H]⁺
34	5-[(4-{(1R,5S)-8-[(2,2difluorocyclopropyl)carbony IJ-3,8diazabicyclo[3.2.1]oct-3y I} py ri m idin-2-yl) am i n o]-3 methylpyridine-2carboxamide	Racemic 2,2-difluoro- cyclopropane-1 -carboxylic acid and 5-((4-((1 R,5S)-3,8diaza-bicyclo[3.2.1]octan-3yl)pyrimidin-2-yl)amino)-3methylpicolinamide hydrochloride (Préparation 26).	¹H NMR (400MHz, DMSOd6): δ ppm 1.85-2.03 (m, 6H), 2.57 (s, 3H), 2.98 (d, 1 H), 3.07-3.28 (m, 3H), 4.08-4.36 (m, 2H), 4.624.75 (m, 2H), 6.34-6.38 (m, 1H), 7.20 (s, 1H), 7.84 (s, 1H), 8.07-8.10 (m, 2H), 8.74-8.78 (m, 1H), 9.54 (s, 1H). MS m/z 444 [M+H]⁺PM B.
35	5-({4-[(1 R,5S)-8-{[(1 S)-2,2difluorocyclopropyl]carbonyl }-3,8-diazabicyclo[3.2.1]oct3-yl]pyrimidin-2-yl}amino)3-methylpyridine-2carboxamide	(S)-2,2-difluorocyclopropane-1-carboxylic acid (Préparation 70) and 5-((4((1 R,5S)-3,8diazabicyclo[3.2.1 ]octan-3yl)pyrimidin-2-yl)amino)-3methylpicolinamide hydrochloride (Préparation 26).	¹H NMR (400MHz, DMSOd6): δ ppm 1.85-2.03 (m, 6H), 2.57 (s, 3H), 2.98 (d, 1 H), 3.07-3.28 (m, 3H), 4.08-4.36 (m, 2H), 4.624.75 (m, 2H), 6.34-6.38 (m, 1H), 7.20 (s, 1H), 7.84 (s, 1H), 8.07-8.10 (m, 2H), 8.74-8.78 (m, 1H), 9.54 (s, 1H). Rt = 0.55 minutes; MS m/z 444 [M+H]⁺ PM F.

36	cyclopropyl[(1 R,5S)-3-{2[(1 -methyl-1 H-pyrazol-4yl)amino]pyrimidin-4-yI}3,8-diazabicyclo[3.2.1 ]oct8-yl]methanone	4-((1R,5S)-3,8-diazabicyclo[3.2.1 ]octan-3-yl)-N(1-methyl-1 H-pyrazol-4yl)pyrimidin-2-amine hydrochloride (Préparation 26) and Cyclopropylcarboxylic acid.	¹H NMR (400MHz, CDCh): δ ppm 0.78 (m, 4H), 0.901.00 (m, 2H), 1.60-2.05 (m,4H), 3.10 (m, 1H), 3.80 (s, 1H), 3.90 (m, 1H), 4.10 (m, 1 H), 4.50 (m, 1H), 4.80 (m, 1H), 5.80 (d, 1H), 7.20 (d, 1H), 7.40 (s, 1H), 7.60 (brs, 1H), 7.90 (m, 1H). Rt = 0.59 minutes MS m/z 354 [M+H]⁺PM F.
37	(1S,2R)-2-{[(1R,5S)-3-{2[(1-methyl-1 H-pyrazol-4yl)am ino]pyrimidin-4-yl}3,8-diazabicyclo[3.2.1 Joct8yl]carbonyl}cyclopropaneca rbonitrile	4-((1R,5S)-3,8-diazabicyclo[3.2.1 ]octan-3-yl)-N(1-methyl-1 H-pyrazol-4yl)pyrimidin-2-amine hydrochloride (Préparation 19) and (1S,2R)-2- cyanocyclopropane-1carboxylic acid (J. Med. Chem. (2013), 56 (11), 4521-4536).	¹H NMR (400MHz, MeOHd4): δ ppm 1.40-1.50 (m, 1H), 1.70-2.20 (m, 6H), 2.60-2.70 (m, 1H), 3.103.30 (m, 2H), 3.35 (s, 3H), 4.10-4.40 (br m, 2H), 4.80 (m, 2H), 6.70 (m, 1H), 7.55 (s, 1H), 7.80 (s, 1H), 7.90 (m, 1H). LCMS Rt = 0.50 minutes MS m/z 379 [M+H]⁺PM F.
38	(1R,2S)-2-{[(1R,5S)-3-{2[(1 -methyl-1 H-pyrazol-4yl)amino]pyrimidin-4-yl}3,8-diazabicyclo[3.2.1]oct8yl]carbonyl}cyclopropaneca rbonitrile	4-((1 R,5S)-3,8-diazabicyclo[3.2.1 ]octan-3-yl)-N(1-methyl-1 H-pyrazoI-4yl)pyrimidin-2-amine hydrochloride (Préparation 19) and (1R,2S)-2- cyanocyclopropane-1 carboxylic acid (J. Med. Chem. (2013) ,56 (11), 4521-4536).	¹H NMR (400MHz, MeOHd4): δ ppm 1.40-1.50 (m, 1H), 1.70-2.20 (m, 6H), 2.60-2.70 (m, 1H), 3.103.30 (m, 2H), 3.35 (s, 3H), 4.10-4.40 (br m, 2H), 4.80 (m, 2H), 6.70 (m, 1 H), 7.55 (s, 1H), 7.80 (s, 1H), 7.90 (m, 1H). LCMS Rt = 0.49 minutes MS m/z 379 [M+H]⁺PM F.
39	(3,3- difluorocyclobutyl)[(1 R,5S)- 3- {2-[(1-methyl-1 H-pyrazol- 4- yI)amino]pyrimidin-4-yl}3,8-diazabicyclo[3.2.1]oct8-yl]methanone	4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-N(1-methyl-1 H-pyrazol-4yl)pyrimidin-2-amine hydrochloride (Préparation 19) and 3,3-difluoro- cyclobutanecarboxylic acid.	¹H NMR (400MHz, CDCh): δ ppm 1.70-2.00 (m, 4H), 2.70-3.00 (m, 4H), 3.003.18 (m, 2H), 3.25-3.40 (m, 2H), 3.80 (s, 3H), 4.054.35 (br m, 2H), 4.40 (m, 1H), 4.75 (m, 1H), 6.10 (m, 1H), 7.50 (m, 1H), 7.75 (m, 1H), 7.90 (m, 1H). LCMS Rt = 0.65 minutes MS m/z 404 [M+H]⁺ PM F.
40	4-({4-[(1R,5S)-8-{[(1S)-2,2difluorocyclopropyl]carbonyl }-3,8-diazabicyclo[3.2.1]oct3-yl]pyrimidin-2-yl}amino)N,6-dimethylpyridine-2carboxamide	4-((4-((1 R, 5S)-3,8diazabicyclo[3.2.1 ]octan-3yl)pyrimidin-2-yl)amino)N,6-dimethylpicolinamide (Préparation 16) and (S)2,2-difluorocyclopropane-1carboxylic acid (Préparation 68).	Rt = 2.43 minutes MS m/z 458 [M+H]⁺PM G.

41

4-((4-((1 R,5S)-8-{[(1S)-2,2difluorocyclopropyl]carbonyl }-3,8-diazabicyclo[3.2.1]oct3-yl]pyrimidin-2-yl}amino)6-(hydroxymethyl)-Nmethylpyridine-2carboxamide

4-((4-((1 R,5S)-3,8diazabicyclo[3.2.1 ]octan-3yi)pyrimidin-2-yl)amino)-6(hydroxymethyl)-Nmethylpicoiinamide hydrochloride (Préparation 17) and (S)-2,2- difluorocyclopropane-1 carboxylic acid (Préparation 68).

Rt = 1.59 minutes MS m/z 474 [M+H]⁺PM G.

Examples 42 and 43 r(1R,2R)-2-fluorocyclopropvll[(1R,5S)-3-{2-f(1-methvl-1H-pvrazol-4-vl)aminolpvrimidin-4-yl}-3,8diazabicvclor3.2.11oct-8-vllmethanone and r(1S,2S)-2-fluorocvclopropvllf(1R,5S)-3-{2-F(1-methvl-1HPVrazol-4-vl)aminolpvrimidin-4-vl}-3,8-diazabicvclof3.2.1loct-8-vnmethanone

The title compounds were prepared according to the method described for Example 9 using 4((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-N-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-amine hydrochloride (Préparation 19) and cis-racemic (1 S,2S)-2-fluorocyclopropane-1-carboxylic acid (PCT Publication No. W02005095322). The cis-racemic title compound was separated into its enantiomers using chiral chromatography as described below:

Column: IB 21mmx250mmx5pm, Mobile phase A: CO2; Mobile phase B: 0.2% Ammonium hydroxide in MeOH; 80:20 A/B; 15 minutes hold; flow rate 65 mL/min.

¹H NMR (400MHz, MeOH-d₄): δ ppm 1.10-1.20 (m, 1H), 1.70-2.30 (m, 6H), 3.10-3.25 (m, 3H), 3.85 (s, 3H), 4.10-4.40 (br m, 2H), 4.75-5.00 (m, 2H), 6.15 (m, 1H), 7.55 (s, 1H), 7.80 (m, 1H), 7.90 (m, 1H). LCMS Rt = 0.50 minutes; MS m/z 372 [M+H]⁺

Examples 44 and 45

5-({4-f(1R,5S)-8~iT(1R,2S)-2-fluorocvclopropvncarbonvl)-3.8-diazabicyclor3.2.11oct-3-vllpyrimidin-2vl}amino)-N,3-dimethvlpyridine-2-carboxamide and 5-({4-f(1R,5S)-8-ffî1S,2R)-2fluorocvclopropvl1carbonvD-3,8-diazabicvclo[3.2.11oct-3-vnpvrimidin-2-vl}amino)-N,3-dimethvlpyridine2-carboxamide

The title compounds were prepared according to the method described for Example 9 using 5-((4((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyrimidin-2-yl)amino)-N,3-dimethylpicolinamide hydrochloride (Préparation 1) and trans-racemic (1 S,2S)-2-fluorocyclopropane-1-carboxylic acid (PCT Publication No. W02005095322). The trans-racemic title compound was separated into its enantiomers using chiral chromatography as described below:

Column: Lux-celIulose-3; 250mmx21.2mm, 5μ; Mobile phase A: 75% CO2, mobile phase B: MeOH, flow rate 80 mL/min.

First eluting isomer: Rt = 6.06 minutes; Second eluting isomer: Rt = 6.40 minutes ¹H NMR (400MHz, MeOH-d₄): δ ppm 1.30-1.40 (m, 1H), 1.40-1.60 (m, 1H), 1.80-1.90 (m, 1H), 1.902.05 (m, 1H), 2.10-2.40 (m, 1H), 2.50-2.60 (m, 1H), 3.10-3.40 (m, 4H), 4.10-4.40 (brm, 2H), 4.70-5.00 (m, 2H), 6.30 (m, 1H), 8.00 (m, 2H), 8.80 (brs, 1H). MS m/z440 [M+H]⁺

Example 46 (1-fluorocvclopropvl)[(1R,5S)-3-{2-r(1-methvl-1H-pyrazol-4-vl)aminolpvrimidin-4-yl}-3,8diazabicvclo[3.2.11oct-8-vllmethanone

To a solution of 4-((1 R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-N-(1-methyl-1 H-pyrazol-4-yl)pyrimidin-2amine hydrochloride (Préparation 19,100 mg, 0.311 mmol) in dioxane (10 mL) was added DIEA (401 mg, 3.11 mmol) and racemic 4-chlorophenyl-1-fluorocyclopropane-1-carboxylate (Eur. Pat. Appl. 533013, 80 mg, 0.373 mmol). The reaction mixture was heated to reflux for 18 hours. The reaction was concentrated in vacuo and purified using préparative HPLC to afford the title compound as a yellow solid as the hemiformate sait (37 mg, 32%).

Préparative HPLC using Phenomenex Synergi C18 150mmx30mmx4pm; from 5% MeCN in water (0.225%FA) to 25% MeCN in water (0.225%FA). ¹H NMR (400MHz, DMSO-de): δ ppm 1.27-1.32 (m, 4H), 1.69 (m, 2H), 1.90 (m, 2H), 3.04-3.07 (m, 2H), 3.18 (s, 3H), 4.13 (m, 2H), 4.72 (m, 2H), 6.11 (d, 1H), 7.42 (s, 1H), 7.92 (d, 1H), 8.87 (s, 1H). MS m/z 372 [M+H]⁺

Example 47 (1R,5S)-N-(2-cvanoethvl)-3-{2-f(1-methvl-1H-pvrazol-4-vl)aminolpvrimidin-4-yl)-3,8diazabicvclor3.2.1loctane-8-carboxamide

To a solution of 4-((1 R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-N-(1-methyl-1 H-pyrazol-4-yl)pyrimidin-2amine hydrochloride (Préparation 19, 50 mg, 0.175 mmol) in DCM (10 mL) was added triethylamine (53 mg, 0.525 mmol) and N-(2-cyanoethyl)-1 H-imidazole-1 -carboxamide (Préparation 78, 0.35 mmol) and the reaction was stirred at room température for 3 hours. The reaction was concentrated in vacuo and purified using préparative HPLC (Purification Method B) to afford the title compound (31 mg, 47%). ¹H NMR (400MHz, DMSO-de): δ ppm 1.59-1.61 (m, 2H), 1.80-1.82 (m, 2H), 2.66 (t, 2H), 3.02 (m, 4H), 3.28-3.29 (m, 2H), 3.78 (s, 3H), 3.97 (brs, 2H), 4.36 (s, 2H), 6.10 (d, 1H), 7.14 (m, 1H), 7.43 (s, 1H), 7.72 (s, 1H), 7.90 (d, 1H), 8.84 (s, 1H). MS m/z 382 [M+H]⁺

Example 48 (1R,5S)-3~(2-r(1-methvl-1H-pvrazol-4-vl)amino1pvrimidin-4-vl}-N-[5-(trifluoromethvl)pvridin-2-vl1-3.8diazabicvclor3.2.11octane-8-carboxamide

The title compound was prepared according to the method described for Example 47 using phenyl[4(trifluoromethyl)pyridine-2-yl]carbamate (PCT Publication No. WO2010006938) at 50°C and purified using préparative HPLC (Purification Method B). ¹H NMR (400MHz, MeOH-d4): δ ppm 1.80-1.83 (m, 2H), 2.02 (m, 2H), 3.20-3.23 (m, 2H), 3.85 (s, 3H), 4.17 (br m, 2H), 4.64 (m, 2H), 6.14 (d, 1H), 7.51 (s, 1H), 7.75 (s, 1H), 7.87 (d, 1H), 7.95-7.98 (m, 1H), 8.08 (d, 1H), 8.54 (s, 1H). MS m/z 474 [M+H]⁺

Example 49 cvclopropvlf(1R,5S)-3-i2-(1H-pvrazol-4-vlamino)pvrimidin-4-vl1-3,8-diazabicvclof3.2.1loct-8vllmethanone

To a solution of ((1R,5S)-3-(2-chloropyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)(cyclopropyl)methanone (Préparation 28, 100mg, 0.342mmol) and 1-H-pyrazol-4-amine (100 mg, 0.54 mmol) in iPrOH (5 mL) was added cHCI (2 drops) and the reaction was heated to 140°C under microwave irradiation for 1 hour. The reaction was cooled, concentrated in vacuo and purified by siiica gel column chromatography eluting with 5% MeOH in DCM followed by préparative HPLC (Purification Method B) to afford the title compound (34 mg, 29%).

¹H NMR (400MHz, DMSO-de): δ ppm 0.77 (br s, 4H), 1.63 (br s, 1H), 1.74 (br s, 2H), 2.01 (d, 2H), 2.94-3.10 (m, 2H), 3.87-4.27 (m, 2H), 4.53-4.84 (m, 2H), 6.10 (d, 1H), 7.53 (br s, 1H), 7.78 (br s, 1H), 7.92 (d, 1 H), 8.86 (br s, 1 H), 12.36 (br s, 1 H). MS m/z 340 [M+H]⁺

Example 50 and 51 ((1R,5S)-3-(2-((1H-Pvrazol-4-vl)amino)pvrimidin-4-vl)-3.8-diazabicvclo(3.2.11octan-8-vl)((R)-2,2difluorocyclopropvDmethanone and ((1R,5S)-3-(2-((1H-Pvrazol-4-vl)amino)pyrimidin-4-vl)-3,8diazabicvclor3.2.11octan-8-vl)((S)-2.2-difluorocvclopropyl)methanone

The title compounds were prepared according to the method described for Example 49 using racemic ((1R,5S)-3-(2-chIoropyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)(2,2-difluorocyclopropyl)methanone (Préparation 30) and tert-butyl 4-amino-1H-pyrazoIe-1 -carboxylate. The enantiomers were purified using préparative HPLC (Purification Method B) followed by séparation using chiral chromatography: Chiral préparative HPLC: Column AD 250mmx30mm I. D. 20pm; Mobile phase: supercritical CC^/MeOH (0.05% ammonia, 55/45 at 80 mL/min.

Example 50: ((1R,5S)-3-(2-((1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-3,8-diazabi-cyclo[3.2.1]octan-8yl)((R)-2,2-difluorocycIopropyl)methanone (25 mg, 11%).

¹H NMR (400MHz, DMSO-de): δ ppm 1.60-2.04 (m, 5H), 2.84-2.96 (m, 1H), 2.96-3.17 (m, 1H), 3.183.32 (m, 2H), 3.97-4.40 (m, 2H), 4.54-4.76 (m, 2H), 6.05-6.22 (m, 1H), 7.43-7.86 (m, 2H), 7.89-8.01 (m, 1H), 8.84-9.05 (m, 1H), 12.32-12.51 (m, 1H). MS m/z 376 [M+H]⁺

Example 51: ((1R,5S)-3-(2-((1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8yl)((S)-2,2-difIuorocyclopropyl)methanone (23 mg, 10%).

¹H NMR (400MHz, DMSO-de): δ ppm 1.59-2.05 (m, 5H), 2.86-2.95 (m, 1H), 2.96-3.16 (m, 1H), 3.163.32 (m, 2H), 3.93-4.40 (m, 2H), 4.54-4.77 (m, 2H), 6.04-6.21 (m, 1H), 7.41-7.86 (m, 2H), 7.87-8.00 (m, 1H), 8.79-9.00 (m, 1H), 12.27-12.43 (m, 1H). MS m/z 376 [M+H]⁺Example 51 may also be prepared according to the following method:

To a solution of (S)-2,2-difluorocyclopropane-1-carboxylic acid (Préparation 68, 28 mg, 0.227 mmol), 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-N-(1l2-pyrazoI-4-yl)pyrimidin-2-amine hydrochloride (Préparation 22, 56 mg, 0.21 mmol) and DIPEA (0.22 mL, 1.24 mmol) in dichioromethane (3 mL) and DMF (1 mL) was added HATU (97 mg, 0.25 mmol) and the reaction was stirred at room température for 18 hours. The reaction was concentrated in vacuo. The residue was purified using silica gel column chromatography eluting with 0-20% MeOH in DCM to afford the title compound (26 mg, 34%).

Example 52 cvclopropvl((1R.5S)-3-[2-(1,2-thiazol-4-vlamino)pvrimidin-4-vn-3,8-diazabicvclor3.2.11oct-8yllmethanone

The title compound was prepared according to the method described for Example 49 using 4isothiasolamine.

Préparative HPLC: Column: Phenomenex Gemini C18 250 x 21.2mm x 8pm

Mobile phase: from 3% MeCN in water (0.225% formic acid) to 23% MeCN in water (0.225% formic acid); Flow Rate: 30 mL/min. ¹H NMR (400MHz, DMSO-d6): δ ppm 0.70-0.77 (m, 4H), 1.61-1.81 (m, 3H), 1.99-2.00 (m, 2H), 2.97-3.00 (m, 1H), 3.07-3.10 (m, 1H), 4.11 (s, 2H), 4.62 (s, 1H), 4.77 (s, 1H), 6.24 (d, 1H), 8.00 (d, 1H), 8.59 (s, 1H), 8.76 (s, 1H), 9.71 (s, 1H). MS m/z 357 [M+H]⁺

Example 53

N,3-dimethvl-5-((4-K1R,5S)-8-(1,2-oxazol-5-vlmethvl)-3,8-diazabicvclor3.2.1loct-3-vllpvrimidin-2vl}amino)pyridine-2-carboxamide

To a solution of N-(2,2,2-trifluoroethyl)-1H-imidazole-1-carboxamide (Préparation 82) and

5-((4-((1 R, 5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyrimidin-2-yl)amino)-N,3-dimethylpicolinamide hydrochloride (Préparation 1, 50 mg, 0.12 mmol) and 5-isoxazolecarboxaldehyde (32 mg, 0.33 mmol) in MeCN (1 mL) was added sodium triacetoxyborohydride (76 mg, 0.35 mmol) and the reaction was stirred at room température for 1.5 hours. The reaction was quenched by the addition of saturated aqueous NaHCO3 solution and extracted into EtOAc three times. The organic layer was collected, dried over magnésium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with 0-10% MeOH in DCM followed by trituration with diethylether to afford the title compound (30 mg, 59%). LCMS Rt = 0.69 minutes; MS m/z 435 [M+H]⁺

Example 54

N, 3-dimethvl-5-r(4-{(1R,5S)-8-r(3-methvloxetan-3-vl)methvl1-3,8-diazabicvclof3.2.11oct-3-vl}pvrimidin2-yl)aminolpyridine-2-carboxamide

The title compound may be prepared according to the method described for Example 53 using 3methyloxetane-3-carbaldehyde with DIPEA in THF/DMSO. Purified using préparative HPLC. Préparative HPLC: DIKMA Diamonsil(2) C18 200 x20mm x 5pm

Mobile phase: from 0-27% MeCN in water (0.225%FA); 35 mL/min flow rate. Rt = 1.95 minutes; MS m/z 438 [M+H]⁺

Example 55

N-(1-methvl-1H-pvrazol-4-vl)-4-iï1R,5S)-8-(1,2-thiazol-5-vlmethvl)-3.8-diazabicvclof3.2.1loct-3vllpyrimidin-2-amine

To a solution of 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-N-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2amine hydrochloride (Préparation 19, 100 mg, 0.351 mmol) and 5-isothiazolecarboxaldehyde (55 mg,

O. 49 mmol) in MeOH (10 mL) was added triethylamine (71 mg, 0.70 mmol) and acetic acid (3 drops).The solution was stirred at room température for 3 hours before the addition of sodium cyanoborohydride (44 mg, 0.702 mmol) at 0°C. The reaction was stirred at room température for 18 hours. The solution was concentrated in vacuo and purified by préparative HPLC (Purification Method B) to afford the title compound (26.2 mg, 20%). ¹H NMR (400MHz, DMSO-de): δ ppm 1.57 (d, 2H), 1.96 (br s, 2H), 3.06 (d, 2H), 3.77 (s, 9H), 6.06 (d, 1H), 7.28 (s, 1H), 7.42 (s, 1H), 7.74 (br s, 1H), 7.90 (d, 1H), 8.49 (d, 1H), 8.83 (brs, 1H). MS m/z 383 [M+H]⁺

The following Examples were prepared according to the method described for Example 55 using 4((1R,5S)-3,8-diazabicycIo[3.2.1]octan-3-yl)-N-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-amine hydrochloride (Préparation 19) and the appropriate aldéhyde or ketone. Where necessary the imine

formation was carried out at elevated températures of 95°C in toluene with camphorsulfonic acid, or triethylamine and acetic acid were omitted. Purification methods are as described or referred to below:

Example No.	Name	SM/Data
56	N-(1 -methyl-1 H-pyrazoi-4yl)-4-[(1 R,5S)-8-(1,2oxazoi-5-ylmethyl)-3,8diazabicycio[3.2.1 ]oct-3yl]pyrimidin-2-amine	5-isoxazolecarboxaldehyde ¹H NMR (400MHz, DMSO-de): δ ppm 1.54 (d, 2H), 1.912.03 (m, 2H), 3.03 (d, 2H), 3.66-4.05 (m, 7H), 6.05 (d, 1H), 6.47 (s, 1H), 7.41 (s, 1H), 7.72 (br s, 1H), 7.88 (d, 1H), 8.52 (d, 1H), 8.83 (brs, 1H). MS m/z 337 [M+H]⁺ PM B.
57	N-(1 -methyl-1 H-pyrazol-4yl)-4-[(1R,5S)-8-(1,3thiazol-2-ylmethyl)-3,8diazabicyclo[3.2.1]oct-3yl]pyrimidin-2-amine	2-thiazolecarboxaldehyde ¹H NMR (400MHz, DMSO-ds): δ ppm 1.57 (d, 2H), 1.902.03 (m, 2H), 3.06 (d, 2H), 3.41 (br s, 2H), 3.76 (s, 3H), 3.84-4.15 (m, 4H), 6.06 (d, 1H), 7.41 (s, 1H), 7.64 (d, 1H), 7.74 (d, 2H), 7.89 (d, 1H), 8.83 (brs, 1H). MS m/z 383 [M+H]⁺ PM B.
58	N-(1 -methyl-1 H-pyrazol-4yl)-4-[(1 R,5S)-8-(1,2oxazol-4-ylmethyl)-3,8diazabicyclo[3.2.1]oct-3yl]pyrimidin-2-amine	4-isoxazolecarboxaidehyde ¹H NMR (400MHz, DMSO-de): δ ppm 1.52 (d, 2H), 1.96 (d, 2H), 3.02 (d, 2H), 3.43-3.47 (m, 4H), 3.76 (s, 5H), 6.03 (d, 1H), 7.41 (s, 1H), 7.72 (br s, 1H), 7.87 (d, 1H), 8.02 (s, 1H), 8.31 (s, 1H), 8.78 (brs, 1H). MS m/z 367 [M+H]⁺ PM B.
59	Cis and trans 3-[(1 R,5S)-3{2-[(1 -methyl-1 H-pyrazol-4yI)amino]pyrimidin-4-yl}-3,8diazabicyclo[3.2.1]oct-8yl]cyclobutanecarbonitrile	3-oxo-cyclobutanecarbonitrile and isolated as the cis/trans mixture. LCMS Rt = 0.63 minutes MS m/z 365 [M+H]⁺ ¹H NMR (400MHz, MeOH-d₄): δ ppm 1.70 (m, 2H), 1.90 (m, 2H), 2.35 (m, 1H), 2.40 (m, 1H), 2.50 (m, 1H), 2.60 (m, 1H), 3.00 (m, 1H), 3.10-3.20 (m, 3H), 3.25-3.45 (m, 5H), 4.00-4.15 (br m, 2H), 6.10 (m, 1H), 7.55 (d, 1H), 7.80 (s, 1 H), 7.90 (d, 1H).

Example 60

N-(1-methvl-1H-pvrazol-4-vl)-4-((1R,5S)-8-ri-(methvlsulfonvl)azetidin-3-vl1-3,8-diazabicvclor3.2.1loct5 3-vl)pyrimidin-2-amine

To a solution of tert-butyl 3-((1 R,5S)-3-(2-((1 -methyl-1 H-pyrazol-4-yl)amino)pyrimidin-4-yl)-3,8diazabicycIo[3.2.1]octan-8-yl)azetidine-1-carboxylate (Préparation 135, 51 mg,0.12 mmol) in DCM (1 mL) was added 4N HCl in dioxane (2 mL) and the reaction was stirred at room température for 2 hours. The reaction was concentrated in vacuo and dissolved in DCM (1 mL). DIPEA (61 μΙ, 0.348 10 mmol) followed by methanesulfonyl chloride (10 μΙ, 0.128 mmol) and the reaction was stirred at room température for 30 minutes. The réaction was quenched by the addition of water, concentrated in vacuo and purified using silica gel column chromatography eluting with 0-10% MeOH (1% ammonia) in DCM followed by préparative HPLC (Purification Method H). Rt = 1.18 minutes; MS m/z 419 [M+H]⁺

Examples 61 and 62

54(44(1 R.5S')-84cis-3-cvanocvclobutvl)-3.8-diazabicvclor3.2.1'|oct-3-vnpvrimidin-2-vl}amino)-N,3dimethvlpyridine-2-carboxamide and 54(44(1R,5S)-84trans-3-cvanocvclobutvl)-3,8diazabicvclo[3.2.11oct-3-vllpvrimidin-2-vl}amino)-N,3-dimethvlpvridine-2-carboxamide

The title compounds were prepared using the method described for Example 55 using 3-oxo5 cyclobutanecarbonitrile and 5-((4-((1 R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyrimidin-2-yl)amino)N,3-dimethylpicoIinamide hydrochloride (Préparation 1). The isomers were separated using chiral chromatography as described below:

Column: Lux Cellulose-4 250mmx21.2mmx5pm; Mobile phase A: Heptanes; Mobile phase B: Ethanol; from 50:50 A:B to 100% B at 10 minutes then back to 50:50 A:B at 12.5 minutes. Flow rate: 27.0 10 mL/min. First eluting compound was arbitrarily assigned as Example 61: Rt = 8.45 minutes, MS m/z

433 [M+H]⁺

Second eluting isomer was arbitrarily assigned as Example 62: Rt = 9.35 minutes, MS m/z 433 [M+H]⁺

Examples 63 and 64

4-r(1R,5S)-8-(r(1R)-2,2-difluorocvclopropvl1methvl}-3,8-diazabicvclo[3.2.1loct-3-vll-N-(1-methvl-1 HPVrazol-4-vl)pyrimidin-2-amine and 44(1 R,5S)-8-(K1 S)-2,2-difluorocvclopropyl1methvl}-3,8diazabicvclo[3.2.11oct-3-vll-N-(1-methvl-1H-pvrazol-4-vl)pvrimidin-2-amine

To a solution of 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-N-(1-methyl-1H-pyrazol-4-yI)pyrimidin-2amine hydrochloride (Préparation 19, 32 mg, 11 mmol) and racemic (2,2-difluorocyclopropyl)methyl

4-methylbenzenesulfonate (PCT Publication No. WO20130908375, 30 mg, 12 mmol) in MeCN (3 mL) was added sodium carbonate (18 mg, 17 mmol) and tert-butylammonium iodide (6 mg, 17 mmol) and the reaction was stirred at 60°C for 42 hours. The reaction was cooled and concentrated in vacuo.

The residue was partitioned between DCM and saturated aqueous ammonium chloride solution. The organic layer was collected and purified using silica gel column chromatography eluting with 0-10% 25 MeOH (1% ammonia) in DCM. The residue was dissolved in DCM and washed with ammonium chloride three times before concentrating in vacuo. The residue was then dissolved in EtOAc and washed with saturated aqueous NaHCO3 solution, water, brine, and concentrated in vacuo to afford the racemic title compound that was separated into the two enantiomers using chiral chromatography as described below:

Column: OJ-H 21mmx250mmx5p, Mobile phase A: CO2; Mobile phase B: MeOH (0.2% ammonium hydroxide) using 90%A and 10% B, Hold for 10 minutes, flow rate 75 mL/min.

¹H NMR (400MHz, MeOH-d₄): δ ppm 1.20-1.30 (m, 1H), 1.50-2.05 (m, 6H), 2.50 (m, 1H), 2.75 (m,

1H), 3.15-3.20 (m, 3H), 3.50 (m, 1H), 3.90 (s, 3H), 4.00 (m, 2H), 6.10 (m, 1H), 7.50 (d, 1H), 7.78 (s, 1H), 7.85 (d, 1H). LCMS Rt = 0.71 minutes; MS m/z 376 [M+H]⁺

Examples 65 and 66

44(1R.5S)-8-ffî1S)-2,2-difluorocvclopropvllmethvD-3,8-diazabicvclor3.2.T|oct-3-vll-N41H-pvrazol-4vl)pyrimidin-2-amine and 44(1 R,5S)-8-([(1 R)-2.2-difluorocvclopropyl1methvl}-3,8diazabicvclor3.2.1loct-3-vl1-N41H-pvrazol-4-vl)pyrimidin-2-amine

The title compounds were prepared according to the method described for Examples 63 and 64 40 using racemic (2,2-difluorocyclopropyl)methyl 4-methylbenzenesulfonate (PCT Publication No.

WO20130908375) and 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-N-(1-tosyl-1H-pyrazol-4yl)pyrimidin-2-amine (Préparation 15). The residue was dissolved in DCM (1 mL) and treated with 4N HCl in dioxane (1 mL) and stirred at room température for 18 hours. MeOH (1 mL) was added and the reaction continued for a further 18 hours. The reaction was concentrated in vacuo, eiuted through a 5 carbonate cartridge and separated into enantiomers using chiral chromatography as described below:

Column: AD-H 21mmx250mmx5p, Mobile phase A: CO2; Mobile phase B: MeOH (0.2% ammonium hydroxide) using 75%A and 25% B, Hold for 8 minutes, flow rate 75 mL/min.

First eluting isomer: Rt = 5.74 minutes, Example 66; Second eluting isomer: Rt = 6.44 minutes, Example 67

Examples 67 and 68

5-((4-r(1R,5S)-8-(r(1S)-2,2-difluorocvclopropvl1methvl)-3,8-diazabicvclo|'3.2.1loct-3-vllpvrimidin-2vl)amino)-N.3-dimethvlpyridine-2-carboxamide and 5-((4-1(1 R,5S)-8-ffî1 R)-2,215 difluorocvclopropvl1methvl}-3,8-diazabicvclor3.2.1loct-3-vllpvrimidin-2-vl}amino)-N.3-dimethvlpvridine2-carboxamide

The title compounds were prepared according to the method described for Examples 63 and 64 using 5-((4-((1 R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyrimidin-2-yl)amino)-N,3-dimethylpicolinamide hydrochloride (Préparation 1).

The racemate was separated into two enantiomers using chiral chromatography as described below:

Column: Chiral Tech OJ-H; 500mmx21.2mm, 5μ; Mobile phase A 70% CO2, 30% MeOH (0.2% ammonia), flow rate 80 mL/min.

First eluting compound was arbitrarily assigned as Example 67: Rt = 6.09 minutes, MS m/z 444 [M+H]⁺

Second eluting compound was arbitrarily assigned as Example 68: Rt = 6.21 minutes, MS m/z 444 [M+H]⁺

Examples 69 and 70 (1S,2S)-2-{r(1R,5S)-3~[2-r(1-methvl-1H-pvrazol-4-vl)aminolpvrimidin-4-vl)-3,8-diazabicvclor3.2.11oct-8vllmethvDcyclopropanecarbonitrile and (1S,2S)-2-IT(1R,5S)-3~[2-r(1-methvl-1H-pvrazol-430 vl)aminolpvrimidin-4-vl}-3.8-diazabicvcloi3.2.11oct-8-vl1methvl)cvclopropanecarbonitrile

The title compounds were prepared according to the method described for Examples 63 and 64 using (2-cyanocyclopropyl)methyl 4-methylbenzenesulfonate (Acta Pharmaceutica Suecica (1972), 9 (5), 491-498). The residue was separated into the two enantiomers using chiral chromatography as described below: Column: OD-H 21mmx250mmx5p, Mobile phase A: CO2; Mobile phase B: EtOH 35 (0.2% ammonium hydroxide) using 70%A and 30% B, Hold for 7 minutes, flow rate 75 mL/min.

¹H NMR (400MHz, MeOH-d₄): δ ppm 1.05-1.10 (m, 1H), 1.30 (m, 1H), 1.50-1.55 (m, 1H), 1.70 (m, 3H), 2.00 (m, 2H), 3.15-3.40 (m, 4H), 3.50 (m, 1H), 3.80 (s, 3H), 4.00 (br m, 2H), 4.80 (m, 1H), 6.10 (m, 1H), 7.55 (d, 1H), 7.75 (s, 1H), 7.90 (m, 1H). MS m/z 365 [M+H]⁺

Example 71

1-(1(1 R,5S)-342-(1H-pvrazol-4-vlamino)pvrimidin-4-vn-3,8-diazabicvclor3.2.1loct-8vllmethvDcvclopropanecarbonitrile

The title compound was prepared according to the method described for Example 55 using 4((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-N-(1-tosyI-1H-pyrazol-4-yl)pyrimidin-2-amine (Préparation 15) and 1-formylcyclopropane-1-carbonitrile (PCT Publication No. W02009005675). The residue (5 mg, 0.011 mmol) was dissolved in MeOH (0.5 mL) and 5N NaOH (aq) (220 pi) was added with stirring for 1 hour. The reaction was concentrated in vacuo, azeotroped with DCM and purified using préparative HPLC (Purification Method H). Rt = 1.06 minutes; MS m/z 351 [M+H]⁺

Example 72

N-ethvl-4-({5-fluoro-4-[8-(trifluoroacetvl)-3,8-diazabicvclo[3.2.11oct-3-vl1pvrimidin-2-vl}amino)-2methylbenzamide

To a solution of 4-((4-((1 R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-5-fluoropyrimidin-2-yl)amino)-Nethyl-2-methylbenzamide hydrochloride (Préparation 25, 30 mg, 0.08 mmol) in DCM (5 mL) was added TFAA (5 drops) and the reaction stirred at room température for 18 hours. The reaction was purified directly by silica gel column chromatography eluting with 0-10% MeOH in DCM followed by préparative HPLC (Purification Method I). Rt = 2.22 minutes; MS m/z 481 [M+H]⁺

Example 73 tert tert-butvl 3-(2-{r4-(ethvlcarbamovl)-3-methvlphenvl1aminol-5-fluoropyrimidin-4-vl)-3,8diazabicvclo(3.2.1loctane-8-carboxvlate

The title compound was prepared according to the method described for Préparation 24 Step 1 using 4-amino-N-ethyl-2-methyl-benzamide (PCT Publication No. W02006109846). ¹H NMR (400MHz, DMSO-de): δ ppm 1.13 (t, 3H), 1.44-1.49 (m, 9H), 1.74 (d, 2H), 1.89 (brs, 2H), 2.35 (s, 3H), 3.18-3.28 (m, 4H), 4.16 (d, 2H), 4.26 (brs, 2H), 7.29 (d, 1H), 7.51-7.55 (m, 1H), 7.56 (s, 1H), 8.03-8.09 (m, 2H), 9.30 (s, 1H).

Example 74 (1R,5S)-N-ethvl-3-[2-(1,2-thiazol-4-vlamino)pvrimidin-4-yll-3,8-diazabicvclo[3.2.11octane-8carboxamide

To a solution of N-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyrimidin-2-yl)isothiazol-4-amine hydrochloride (Préparation 21, 100 mg, 0.27 mmol) in DCM (10 mL) was added triethylamine (84 mg, 0.83 mmol) and the solution was cooled to 0°C. Isocyanatoethane (21.7 mg, 0.306 mmol) was added and the reaction was stirred at room température for 18 hours. The reaction was concentrated in vacuo and purified directly by Préparative HPLC (Purification Method B) to afford the title compound (29 mg, 29%). Préparative HPLC: Column: Phenomenex Gemini C18 250 x 21.2mm x 24pm

Mobile phase: from 29% MeCN in water (Ammonia pH=10) to 39% MeCN in water (Ammonia pH=10); Flow Rate: 30 mL/min. ¹H NMR (400MHz, DMSO-de): δ ppm 1.021 (t, 3H), 1.58-1.59 (m, 2H), 1.77 (m, 2H), 3.01-3.08 (m, 4H), 3.96 (m, 2H), 4.35 (s, 2H), 6.23 (d, 1H), 6.67-6.69 (m, 1H), 7.98 (d, 1H), 8.59 (s, 1 H), 8.75 (s, 1H), 9.68 (s, 1 H). MS m/z 382 [M+Na]⁺

Example 75 (1R,5S)-3-(2-([5-chloro-6-(methvlcarbamovl)pvridin-3-vllamino)pvrimidin-4-yl)-N-ethvl-3,8diazabicvclor3.2.1loctane-8-carboxamide

The title compound was prepared according to the method described for Example 74 using 5-((4((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyrimidin-2-yl)amino)-3-chloro-N-methylpicolinamide hydrochloride (Préparation 5) and isocyanatoethane. The residue was purified using préparative HPLC as described below: Préparative HPLC: DIKMA Diamonsil(2) C18 200 x 20mm x 5pm

Mobile phase: from 10% MeCN in water (0.225% formic acid) to 30% MeCN in water (0.225% formic acid). ¹H NMR (400MHz, DMSO-de): δ ppm 1.02 (t, 3H), 1.53-1.63 (m, 2H), 1.74-1.84 (m, 2H), 2.75 (d, 3H), 3.03-3.12 (m, 4H), 3.96 (brs, 2H), 4.37 (brs, 2H), 6.36 (d, 1H), 6.72 (t, 1H), 8.05 (d, 1H), 8.45 (d, 2H), 8.80 (d,1H), 9.74 (s, 1H). MS m/z 445 [M+H]⁺

Example 76 (1R,5S)-3-{2-K1-methvl-1H-pvrazol-4-vl)aminolpvrimidin-4-yl}-3,8-diazabicvclor3.2.1]octane-8carboxamide

To a solution of 4-((1 R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-N-(1-methyl-1 H-pyrazol-4-yi)pyrimidin-2amine hydrochloride (Préparation 19, 30 mg, 0.09 mmol) and sodium isocyanate (14 mg, 0.21 mmol) in DCM (0.3 mL) was added acetic acid (11μΙ, 0.186 mmol) and the reaction was stirred at room température for 18 hours. The reaction was concentrated in vacuo and purified by reverse phase silica gel column chromatography eluting with 5-50% MeCN in 0.1% aqueous ammonia followed by trituration with MeOH and diethylether to afford the title compound (26 mg, 85%).

¹H NMR (400MHz, MeOH-d₄): δ ppm 1.70 (m, 2H), 1.90 (m, 2H), 3.10 (m, 2H), 3.90 (s, 3H), 4.00-4.15 (br m, 2H), 4.40 (m, 2H), 6.10 (m, 1 H), 7.50 (s, 1 H), 7.75 (s, 1 H), 7.85 (m, 1 H).

LCMS Rt = 0.50 minutes; MS m/z 329 [M+H]⁺

Example 77

N-(1-methvl-1H-pvrazol-4-yl)-4-i(1R.5S)-8-(methvlsulfonvl)-3.8-diazabicvcloi3.2.T|oct-3-vl1pvrimidin-2amine

To a solution of 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-N-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2amine hydrochloride (Préparation 19, 100 mg, 0.31 mmol) in DCM (30 mL) at 10°C was added triethylamine (350 mg, 3.46 mmol) followed by MsCI (280 mg, 2.44 mmol). The reaction was stirred at room température for 1 hour. The reaction was washed with water (10 mL) and the organic layer was concentrated in vacuo and purified using préparative HPLC (Purification Method B) to afford the title compound (70 mg, 62%). ¹H NMR (400MHz, DMSO-de): δ ppm 1.55-1.70 (m, 2H), 1.85-2.01 (m, 2H), 3.04 (s, 5H), 3.78 (s, 3H), 3.95-4.21 (m, 2H), 4.23-4.36 (m, 2H), 6.02-6.17 (m, 1H), 7.41 (s, 1H), 7.657.80 (m, 1H), 7.85-7.97 (m, 1H), 8.79-8.95 (m, 1H). MS m/z 364 [M+H]Example 78

2-[(1R,5S)-3-{2-r(1-methvl-1H-pvrazol-4-vl)aminolpvrimidin-4-vl)-3,8-diazabicyclor3.2.1loct-8-vl1-1,3- oxazole-5-carbonitrile

A solution of ethyl 2-((1R,5S)-3-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-3,8diazabicyclo[3.2.1]octan-8-yI)oxazole-5-carboxylate (Préparation 136, 200 mg, 0.47 mmol) in 7M NH3/MeOH (50 mL) was heated to 90°C in a sealed vessel for 18 hours.. The reaction was concentrated in vacuo and dissolved in DCM (20 mL). Triethylamine (6 mL) followed by TFAA (3 mL) was added and the reaction was stirred at room température for 18 hours. The solution was washed with saturated aqueous NaHCO3 solution, and concentrated in vacuo. The residue was purified by Préparative HPLC (Purification Method B) to afford the title compound (46 mg, 26%).

¹H NMR (400MHz, DMSO-de): δ ppm 1.73 (d, 2H), 1.97-2.01 (m, 2H), 3.16 (d, 2H), 3.79 (s, 3H), 4.044.24 (m, 2H), 4.55 (br s, 2H), 6.14 (d, 1H), 7.42 (s, 1H), 7.75 (br s, 1H), 7.92 (d, 1H), 8.04 (s, 1H),

8.98 (br s, 1 H). MS m/z 378 [M+H]⁺ PM B HATU

Example 79

3-{(1 R.5S)-3-[2-(1H-pvrazol-4-vlamino)pvrimidin-4-vl1-3,8-diazabicyclor3.2.1'|oct-8-vl}Dropanenitrile

To a solution of 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-N-(1l2-pyrazol-4-yl)pyrimidin-2-amine hydrochloride (Préparation 22, 83 mg, 0.308 mmol) and triethylamine (622 mg, 6.16 mmol) in EtOH (10 mL) at 0°C was added acrylonitrile (270 mg, 5.09 mmol) dropwise. The reaction was stirred at room température for 18 hours before concentrating in vacuo. The residue was purified by préparative HPLC (Purification Method B) to afford the title compound as a white solid (45 mg, 44%).

¹H NMR (400MHz, DMSO-de): δ ppm 1.43-1.57 (m, 2H), 1.75-1.91 (m, 2H), 2.56-2.71 (m, 4H), 2.923.05 (m, 2H), 3.37-3.43 (m, 3H), 3.64-4.06 (m, 1H), 6.03 (d,1 H), 7.41-7.61 (m, 1H), 7.64-7.79 (m, 1H),

7.87 (d, 1H), 8.72-8.87 (m, 1H), 12.33 (brs, 1H). MS m/z325 [M+H]⁺

Examples 80 and 81

3-r(1R,5S)-3-{2-r(1-methvl-1H-pvrazol-4-vl)aminolpvrimidin-4-vl)-3.8-diazabicycloF3.2.1loct-8yllbutanenitrile and 3-r(1R,5S)-3-{2-r(1-methvl-1H-pvrazol-4-vl)aminolpyrimidin-4-vl}-3,8diazabicvclor3.2.11oct-8-vllbutanenitrile

The title compound was prepared according to the method described for Example 80 using 4((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-N-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-amine hydrochloride (Préparation 19) and E/Z-but-2-enenitrile at 100°C in a sealed vessel. The residue was purified using silica gel column chromatography eluting with 5% MeCN in 0.1% aqueous ammonia to 40% MeCN in 0.1% aqueous ammonia followed by chiral séparation using a Chiraltech OJ-H

250mmx10mmx5pm column; with mobile phase A: 70% CO2 and mobile phase B: 30% EtOH with 0.2% ammonia; flow rate 15 mL/min.

First eluting compound was arbitrarily assigned as Example 80: Peak 1 Rt = 6.69 minutes; LCMS Rt = 0.63 minutes MS m/z 353 [M+H]⁺

Second eluting compound was arbitrarily assigned as Example 81: Peak 2 Rt = 6.95 minutes and is 35 Example 81 ; LCMS Rt = 0.63 minutes; MS m/z 353 [M+H]⁺

Example 82

3~iï1R.5S)-3-i2-(1H-pvrazol-4-vlamino)pyrimidin-4-vri-3,8-diazabicvclor3.2.11oct-8-vl}butanenitrile

The title compound was prepared according to the method described for Example 79 using 4((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-N-(1l2-pyrazol-4-yl)pyrimidin-2-amine hydrochloride (Préparation 22) and E/Z-but-2-enenitrile at 140°C under microwave irradiation for 8 hours. The

residue was purified using reverse phase siiica gel column chromatography eluting with from 5-75% MeCN (0.1% ammonia) in water.

¹H NMR (400MHz, DMSO-ds): δ ppm 0.50 (d, 3H), 0.90 (m, 2H), 1.00-1.20 (m, 2H), 2.10 (m, 1H), 2.30-2.40 (m, 2H), 2.80 (m, 2H), 3.00-3.40 (br m, 2H), 4.00 (m, 2H), 5.25 (m, 1H), 6.90 (m, 2H), 7.05 (m, 1 H). LCMS Rt = 0.59 minutes; MS m/z 339 [M+H]⁺

Example 83 (3-F(1R,5S)-3-(2-[(1-methvl-1H-pvrazol-4-vl)aminolpvrimidin-4-vl)-3.8-diazabicycloF3.2.11oct-8-vll-1(methvlsulfonvl)azetidin-3-vll·acetonίtrίle

The title compound was prepared according to the method described for Example 77 using 2-(310 ((1R,5S)-3-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octan-8yl)azetidin-3-yl)acetonitrile hydrochloride (Example 84) and DIPEA. The residue was purified using siiica gel column chromatography eluting with 10% MeOH (with 1% ammonia) in DCM.

¹H NMR (400MHz, MeOH-d₄): δ ppm 1.75-1.90 (m, 4H), 3.05 (s, 3H), 3.20 (m, 2H), 3.30 (m, 2H), 3.40 (s, 3H), 3.80 (m, 2H), 3.85 (m, 2H), 4.00-4.20 (m, 4H), 6.10 (m, 1H), 7.55 (d, 1H), 7.78 (s, 1H), 7.90 (d, 1 H). LCMS Rt = 0.52 minutes; MS m/z 458 [M+H]⁺

Example 84 (3-[(1R,5S)-3-{2-r(1-methvl-1H-pvrazol-4-vl)amino1pvrimidin-4-vl}-3,8-diazabicyclo[3.2.1loct-8vlloxetan-3-vBacetonitrile

The title compound was prepared according to the method described for Préparation 135 using 2-(320 oxetanylidene)acetonitrile at 85°C for 5 days. The reaction was cooled and purified using Préparative HPLC (Purification Method H). LCMS Rt = 1.50 minutes; MS m/z 381 [M+H]⁺

Example 85 ((1R,5S)-N-(cvanomethvl)-3-f2-r(1-methvl-1H-pvrazol-4-vl)aminolpyrimidin-4-vl)-3.8diazabicyclor3.2.1loctane-8-carboxamide

To a solution of 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-N-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2amine hydrochloride (Préparation 19, 26 mg, 0.08 mmol) and N-(cyanomethyl)carbamoylimidazole (Préparation 79, 14 mg, 0.09 mmol) in EtOH (0.8 mL) was added triethylamine (110 pl, 0.082 mmol) in a sealed vessel and the reaction was heated to 60°C for 2 hours. Further N(cyanomethyl)carbamoylimidazole (2 mg, 0.01 mmol) was added and the reaction continued heating for 2 hours before concentrating in vacuo. The residue was dissolved in DCM (10 mL) and washed with brine, dried over magnésium sulfate and concentrated in vacuo. The residue was purified using siiica gel column chromatography eluting with 0-10% MeOH in DCM to afford the title compound as a white solid (21 mg, 70%). ¹H NMR (400MHz, MeOH-d₄): δ ppm 1.78 (m, 2H), 2.00 (m, 2H), 3.15 (m, 4H), 3.88 (d, 3H), 4.00-4.15 (m, 2H), 4.43 (m, 2H), 6.10 (m, 1H), 7.55 (m, 1H), 7.75 (m, 1H), 7.90 (m,

1 H). MS m/z 368 [M+H]⁺

Example 86 (1R,5S)-N-ethvl-3-{2-r(1-methvl-1H-pvrazol-4-vl)aminolpyrimidin-4-vl}-3,8-diazabicvclor3.2.Tloctane-8carboxamide

The title compound was prepared according to Example 85 using N-ethyl-1H-imidazole-140 carboxamide (Préparation 80, 24 mg, 0.17 mmol) and 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)18225

N-(1-methyl-1 H-pyrazol-4-yl)pyrimidin-2-amine hydrochloride (Préparation 19, 50 mg, 0.16 mmol). The residue was purified using silica gel column chromatography eluting with 0-10% MeOH in DCM to afford the title compound as a white solid (41 mg, 74%).¹H NMR (400MHz, DMSO-d6): δ ppm 1.00 (m, 3H), 1.55 (m, 2H), 1.75 (m, 2H), 3.10 (m, 3H), 3.18 (m, 3 H) 3.80 (s, 3H), 4.00 (m, 1H), 4.10 (m, 1H), 4.40 (m, 2H), 6.10 (m, 1H), 6.67 (t, 1H), 7.45 (s, 1H), 7.73 (br s, 1H), 7.91 (d, 1H), 8.82 (s, 1H). LCMS Rt = 0.58 minutes; MS m/z 357 [M+H]⁺

Example 87 (IR.SSI-N-ethvl-S-fë-FS-fluoro-e-fmethvlcarbamovDpvridin-S-vllaminoIpyrimidin^-vD-S.Sdiazabicycloi3.2.11octane-8-carboxamide

The title compound was prepared according to Example 85 using N-ethyl-1H-imidazole-1carboxamide (Préparation 80) and 5-((4-((1 R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyrimidin-2yl)amino)-3-fluoro-N-methylpicolinamide hydrochloride (Préparation 14) without triethylamine as base. ¹H NMR (400MHz, DMSO-de): δ ppm 1.04 (t, 3H), 1.60 (q, 2H), 1.81 (d, 2H), 2.78 (d, 3H), 2.933.14 (m, 4H), 3.18 (d, 2H), 4.39 (br s, 2H), 6.39 (d,1 H), 6.71 (t, 1H), 8.07 (d, 1H), 8.27 (d, 1H), 8.42 (d,1 H), 8.71 (s, 1H), 9.85 (s, 1H). MS m/z 429 [M+H]⁺

Example 88 (1R.5S)-3-{2-r(1-methvl-1H-pvrazol-4-vl)aminolpvrimidin-4-yl)-N-(propan-2-vl)-3,8diazabicvclo[3.2.11octane-8-carboxamide

The title compound was prepared according to the method described for Example 85 using NisopropyI-1H-imidazole-1-carboxamide (Préparation 81) and 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan3-yl)-N-(1-methyl-1 H-pyrazol-4-yl)pyrimidin-2-amine hydrochloride (Préparation 19). Following chromatography the residue was dissolved in DCM, precipitated by the addition of diethylether and filtered. LCMS Rt = 0.61 minutes; MS m/z 371 [M+H]⁺

Example 89 (1 R,5S)-3-(2-(r5-methvl-6-(methvlcarbamovl)pyridin-3-vllamino)pvrimidin-4-vl)-N-(2,2,2-trifluoroethvl)3,8-diazabicyclo[3.2.11octane-8-carboxamide

The title compound was prepared according to the method described for Example 85 using 5-((4((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyrimidin-2-yl)amino)-N,3-dimethylpicolinamide hydrochloride (Préparation 1). The residue was purified using silica gel column chromatography eluting with 0-20% MeOH (1% ammonia) in DCM. ¹H NMR (400MHz, MeOH-d4): δ ppm 1.80 (m, 2H), 2.00 (m, 2H), 2.60 (s, 3H), 2.95 (s, 3H), 3.40 (m, 2H), 3.90-4.00 (m, 2H), 4.15 (br m, 2H), 4.50 (m, 2H), 6.30 (m, 1H), 8.00 (m, 2H), 8.75 (m, 1H). LCMS Rt = 0.56 minutes; MS m/z 479 [M+H]⁺

Example 90 (1R,5S)-N-(cvanomethvl)-3-(2-(i5-methvl-6-(methvlcarbamovl)pvridin-3-vl1amino)pyrimidin-4-vl)-3.8diazabicvclo[3.2· 11octane-8-carboxamide

The title compound was prepared according to the method described for Example 85 using 5-((4((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyrimidin-2-yl)amino)-N,3-dimethylpicolinamide hydrochloride (Préparation 1) and N-(cyanomethyI)-1H-imidazoIe-1-carboxamide (Préparation 78). The residue was purified using silica gel column chromatography eluting with 0-20% MeOH (1% ammonia) in DCM. ¹H NMR (400MHz, MeOH-d₄): δ ppm 1.80 (m, 2H), 2.00 (m, 2H), 2.65 (s, 3H),

2.95 (s, 3H), 3.20 (m, 2H), 4.20 (m, 4H), 4.50 (m, 2H), 6.30 (m, 1H), 8.00 (m, 2H), 8.70 (s, 1H). LCMS Rt = 0.50 min; MS m/z 436 [M+H]⁺

Example 91 (1R,5S)-N-ethvl-3-(2~iï5-methvl-6-(methvlcarbamovl)pvridin-3-vllamino}pvrimidin-4-vl)-3,8diazabicycloF3.2.1loctane-8-carboxamide

The title compound was prepared according to the method described for Example 85 using 5-((4((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)pyrimidin-2-yl)amino)-N,3-dimethylpicolinamide hydrochloride (Préparation 1) and N-ethyl-1H-imidazole-1-carboxamide (Préparation 79). Following chromatography the title compound was further purified using Préparative HPLC (Purification Method H). Rt = 1.69 minutes; MS m/z 425 [M+HJExample 92

2-Γ(1 R,5S)-3~[2-r(1-methyl-1 H-pvrazol-4-vl)aminolpvrimidin-4-vl)-3,8-diazabicyclor3.2.11oct-8vllPvridine-4-carbonitrile

To a solution of 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-N-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2amine hydrochloride (Préparation 19, 51 mg, 0.16 mmol) in iPrOH (1.5 mL) was added 4-cyano-2chloropyridine (45 mg, 0.32 mmol) and triethylamine (100 pl, 0.68 mmol). The reaction was heated to 160°C under microwave irradiation for 13 hours. The reaction was cooled, concentrated in vacuo and purified using reverse phase silica gel column chromatography eluting with 5-100% MeCN in 0.1% aqueous ammonia to afford the title compound. ¹H NMR (400MHz, CDCL): δ ppm 1.70 (m, 2H), 1.90 (m, 2H), 3.10 (m, 2H), 3.70 (s, 3H), 3.80-3.90 (br m, 2H), 4.50 (m, 2H), 5.75 (d, 1H), 6.50 (br s, 1H), 6.60-6.70 (m, 2H), 7.35 (s, 1H), 7.50 (s, 1H), 7.80 (d, 1H), 8.15 (m, 1H). LCMS Rt = 0.74 minutes; MS m/z 388 [M+H]⁺

Examples 93 and 94 (1 S)-2,2-difluoro-N-lï1S,5R,6R)-3-{5-fluoro-2-[ï1-methvl-1H-pvrazol-4-vl)aminolpyrimidin-4-vl}-6methvl-3-azabicyclo[3.1 .Olhex-l-yncvclopropanecarboxamide and (1 R)-2,2-difluoro-N-r(1S,5R,6R)-3{5-fluoro-2-r(1-methvl-1H-pvrazol-4-vl)aminolpvrimidin-4-vl}-6-methvl-3-azabicycloi3.1.01hex-1vncyclopropanecarboxamide _To a solution of (1S,5R,6R)-3-(5-fluoro-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-6-methyl3-azabicyclo[3.1.0]hexan-1-amine hydrochloride (Préparation 90, 148 mg, 0.15 mmol) in DMA (1 mL) and DCM (1 mL) was added racemic 2,2-difluorocyclopropane-1-carboxylic acid (51 mg, 0.42 mmol), HATU (188 mg, 0.49 mmol) and DIPEA (279 pl, 0.54 mmol) and the reaction was stirred at room température for 18 hours. The reaction was concentrated in vacuo and partitioned between EtOAc and water. The organic layer was collected, dried and concentrated in vacuo. The residue was purified using silica gel column chromatography eluting with from DCM to 91:8:1 DCM:MeOH:ammonia to afford the racemic title compound. The racemate was separated using chiral chromatography using ChiralTech AD-H column (250mmx21.2mmx5um); mobile phase A: 80% CO2; mobile phase B: 20% MeOH with 0.2% ammonia. The residue for each enantiomer may be purified further by recrystallization from MeOH.

Peak 2 Rt = 5.89 minutes Example 93:

¹H NMR (400MHz, MeOH-d₄): δ ppm 1.05-1.10 (m, 3H), 1.36-1.43 (m, 1H), 1.73-1.82 (m, 1H), 1.861.90 (m, 1H), 1.98-2.06 (m, 1H), 2.45-2.53 (m, 1H), 3.75-3.83 (m, 2H), 3.86 (s, 3H), 4.10 (m, 2H), 7.50 (s, 1 H), 7.76 (d, 1H), 7.80 (s, 1H).

LCMS Rt = 0.57 minutes; MS m/z 408 [M+H]⁺

Peak 1 Rt = 3.90 minutes Example 94:

¹H NMR (400MHz, MeOH-d₄): δ ppm 1.05-1.10 (m, 3H), 1.40 (m, 1H), 1.75 (m, 1H), 1.80 (m, 1H), 2.00 (m, 1H), 2.50 (m, 1H), 3.60-3.80 (m, 5H), 4.10 (m, 2H), 7.50 (s, 1H), 7.80 (m, 2H).

LCMS Rt = 0.57 minutes; MS m/z 408 [M+H]⁺; [a]_D ²⁰ = 16.8 (c 1.095, MeOH)

Example 95 (1R,2R)-2-cvano-N-r(1S,5R,6R)-3-{5-fluoro-2-F(1-methvl-1H-pvrazol-4-vl)aminolpyrimidin-4-vl}-615 methvl-3-azabicvcloF3.1.0lhex-1-vl]cvclopropanecarboxamide

The title compound was prepared according to the method described for Example 93 using (1 R,2R)2-cyanocyclopropane-1-carboxylate (Préparation 72).

¹H NMR (400MHz, DMSO-de): δ ppm 0.90 (m, 3H), 1.25-1.35 (m, 4H), 1.45 (m, 1H), 1.80 (m, 1H), 2.00 (m, 1H), 2.20 (m, 1H), 3.60-3.80 (m, 3H), 3.90 (m, 2H), 7.40 (s, 1H), 7.70 (s, 1H), 7.90 (d, 1H),

9.00 (br s, 1 H), 9.10 (s, 1 H).MS m/z 397 [M+H]⁺; [ct]_D ²⁰ = -113.3 (c 0.965, EtOH)

The following Examples were prepared according to the method described for Example 93 using the appropriate acid and amine as described. Purification details are as described or referred to below: Purification Method A: Purified using préparative HPLC: Column: Diol, 250mmx21.2mmx5pm;

mobile phase A: heptanes; mobile phase B: éthanol; from 50% B to 100% B at 10 minutes then retum to 50% B at 12 minutes; Flow rate 27 mL/min.

Analyticai LCMS: Phenomenex Luna C18; 150mmx3mmx5pm, mobile phase A: 0.1% formic acid in water, mobile phase B: 0.1% formic acid in acetonitrile from 5% B to 100% B at 10 minutes then return to 5% B at 12.5 minutes. Flow rate 0.75 mL/min.

Purification Method B: Silica gel column chromatography eluting with 97:2:1 DCM:MeOH:NH4OH. Purification Method C: Préparative HPLC using [Phenomenex Gemini C18 250x21.2mmx8pm or 150mmx25mmx5pm; from 16-55% MeCN in water (0.1% ammonia) to 36-60% MeCN in water (0.1% ammonia)]

Ex. No.	Structure/name	Starting Materials	Data
96	(1S)-2,2-difluoro-N- [(1 R,5S,6S)-3-{5-fluoro-2-[(1methyl-1 H-pyrazol-4yl)amino]pyrimidin-4-yl}-6methyl-3-azabicyclo[3.1,0]hex1 -yl]cyclopropanecarboxamide	(1R,5S,6S)-3-(5-fluoro-2((1-methyl-1 H-pyrazoI-4yl)amino)pyrimidin-4-yl)-6methyl-3-azabicyclo[3.1.0]hexan-1-amine hydrochloride (Préparation 91) and (S)-2,2-difluorocyclopropane-1 -carboxylic acid (Préparation 68).	LCMS Rt = 0.50 minutes MS m/z 408 [M+H]⁺[a]_D ²⁰ = 0 (c 1.095, EtOH) ¹H NMR (400MHz, DMSOds): δ ppm 0.90 (m, 5H), 1.30 (m, 1H), 1.70-2.00 (m, 3H), 2.40 (m, 1H), 3.60-3.80 (m, 5H), 7.40 (s, 1H), 7.70 (s, 1H), 7.90 (m, 1H), 8.90-9.00 (m,2H). PM B.
97	(1R)-2,2-difluoro-N- [(1 R,5S,6S)-3-{5-fluoro-2-[(1methyl-1 H-pyrazol-4yI)amino]pyrimidin-4-yl}-6methyl-3-azabicyclo[3.1,0]hex1 -yljcyclopropanecarboxamide	(1R,5S,6S)-3-(5-fluoro-2((1 -methyl-1 H-pyrazol-4yl)amino)pyrimidin-4-yl)-6methyl-3-azabicyclo[3.1.0]hexan-1-amine hydrochloride (Préparation 91) and (R)-2,2-difluorocyclopropane-1-carboxylic acid (Préparation 69).	LCMS Rt = 0.50 minutes MS m/z 408 [M+H]⁺[a]_D ²⁰ = -7.1 (c 1.095, EtOH) ¹H NMR (400MHz, DMSOδθ): δ ppm 0.90 (m, 5H), 1.30 (m, 1H), 1.70-2.00 (m, 3H), 2.40 (m, 1H), 3.60-4.00 (m, 5H), 7.40 (s, 1H), 7.70 (s, 1H), 7.90 (m, 1H), 8.90-9.00 (m, 2H). PM B.
98	(1 S,2S)-2-cyano-N- [(1 S,5R,6R)-3-(2-{[6-(2hydroxyethoxy) pyridin-3yl]amino}-5-methyIpyrimidin-4yl)-6-methyl-3azabicyclo[3.1,0]hex-1yljcyclopropanecarboxamide	2-((5-((4-((1 S, 5R, 6R)-1amino-6-methyl-3azabicyclo[3.1.0]hexan-3yl)-5-methylpyrimidin-2yl)amino)pyridin-2yl)oxy)ethan-1-ol (Préparation 92) and (1S.2S)-2-cyanocyclopropane-1 -carboxylic acid (Préparation 73).	Rt = 5.64 minutes MS m/z 450 [M+H]⁺PM A.
99	(1S)-2,2-difluoro-N- [(1 S,5R,6R)-3-(5-fluoro-2-{[1(oxetan-3-yl)-1 H-pyrazol-4yl]amino}pyrimidin-4-yl)-6methyl-3-azabicycIo[3.1.0]hex- 1 -yl]cyclopropanecarboxamide	(1S,5R,6R)-3-(5-fiuoro-2((1-(oxetan-3-yl)-1 Hpyrazol-4yl)amino)pyrimidin-4-yl)-6methyl-3- azabicyclo[3.1,0]hexan-1amine (Préparation 93) and (S)-2,2- difluorocyclopropane-1carboxylic acid (Préparation 68).	¹H NMR (400MHz, MeOHd₄): δ ppm 1.03 (d, 3H), 1.31-1.40 (m, 1H), 1.711.89 (m, 2H), 1.99 (dt, 1H), 2.41-2.53 (m, 1H), 3.733.85 (m, 2H), 4.08 (dd, 2H), 4.95-5.09 (m, 4H), 5.48 (m, 1 H), 7.63 (s, 1 H), 7.75 (d, 1H), 8.04 (s, 1H). MS m/z 450 [M+H]⁺PM C.

Examples 100 and 101

5-r(4-{(1S,5R,6R)-1-[(cvclopropvlcarbonvl)amino1-6-methvl-3-azabicvclor3.1.0lhex-3-yl)-5 fluoropvrimidin-2-vl)aminol-N.3-dimethvlpvridine-2-carboxamide and 5-F(4-!ï1 R,5S,6S)-15

Kcvclopropvlcarbonvl)aminol-6-methvl-3-azabicvclo[3.1.01hex-3-yl}-5-fluoropvrimidin-2-vl)amino1-N,3dimethylpyridine-2-carboxamide

The title compounds were prepared according to the method described for Example 5 using transracemic N-(3-(2-chloro-5-fluoropyrimidin-4-yl)-6-methyl-3-azabicyclo[3.1.0]hexan-1-yl)cyclopropanecarboxamide (Préparation 95) and 5-amino-N,3-dimethylpicolinamide (Préparation 38). The residue was purified and separated in enantiomers by chiral chromatography: Chiral column: Lux Celiuiose-4, 250mmx21.2mmx5pm, mobile phase A: supercritical CO2, mobile phase B: Methanol, A:B 65:35; flow rate 80 mL/min. First eluting isomer: Example 100; Second eluting isomer: Example 101.

MS m/z 440 [M+H]⁺

Example 102

N-[(1S.5R,6R)-3-(5-fluoro-2-{[6-(2-hvdroxvethvl)pvridin-3-vllamino)pvrimidin-4-vl)-6-methvl-3azabicvclor3.1.01hex-1-vncyclopropanecarboxamide

The title compound was prepared according to the method described for Example 5 using N((1S,5R,6R)-3-(2-chioro-5-fluoropyrimidin-4-yl)-6-methyl-3-azabicyclo[3.1.0]hexan-1yl)cyclopropanecarboxamide (Préparation 95) and 2-(5-aminopyridin-2-yl)ethan-1-ol (Preparation116). The residue was purified by silica gel column chromatography eluting with 10% MeOH in DCM followed by préparative HPLC (Purification Method B). ¹H NMR (400MHz, DMSOd₆): δ ppm 0.64-0.66 (m, 4H), 0.90 (d, 3H), 1.24-1.28 (m, 1H), 1.49 (m, 1H), 1.76-1.77 (m, 1H), 2.762.80 (m, 2H), 3.39 (s, 1H), 3.64-3.70 (m, 4H), 3.87-3.88 (m, 1H), 4.59-4.61 (m, 1H), 7.13 (d, 1H), 7.94 (d, 1H), 7.97 (d, 1H), 8.71 (s, 1H), 8.74 (s, 1H), 9.20 (s,1H). MS m/z 413 [M-H]Examples 103 and 104

N N-((1S.5R,6R)-3-i5-fluoro-2-((6-[(2R)-1-hvdroxvpropan-2-vllpvridin-3-vl}amino)pvrimidin-4-yll-6methvl-3-azabicvclor3.1.01hex-1-vl)cvclopropanecarboxamide and N-((1S.5R,6R)-3-r5-fluoro-2-((6[(2S)-1-hvdroxvpropan-2-vllpvridin-3-vl}amino)pvrimidin-4-vll-6-methvl-3-azabicycloi3.1.0lhex-1vDcvclopropanecarboxamide

The title compounds were prepared according to the method described for Example 5 using N((1S,5R,6R)-3-(2-chloro-5-fluoropyrimidin-4-yl)-6-methyl-3-azabicyclo[3.1.0]hexan-1yl)cyclopropanecarboxamide (Préparation 95) and racemic-2-(5-aminopyridin-2-yl)propan-1-ol (Préparation 40). The residue was purified using silica gel column chromatography eluting with 10% MeOH in DCM followed by préparative HPLC (Préparation Method B). The racemate was separated into its enantiomers using chiral chromatography:

Chiral column: Chiralpak IC, 250mmx30mmx5pm, mobile phase A: supercritical CO2, mobile phase B: IPA (0.1% ammonia), A:B 60:40; flow rate 70 mL/min.

First eluting isomer was arbitrarily assigned as Example 103;

¹H NMR (400MHz, MeOH-d₄): δ ppm 0.76-0.86 (m, 4H), 1.00-1.02 (m, 3H), 1.28-1.38 (m, 4H), 1.54 (m, 1H), 1.76-1.83 (m, 1H), 3.00-3.05 (m, 1H), 3.66-3.80 (m, 4H), 4.03-4.05 (m, 2H), 7.23 -7.27 (d, 1H), 7.80-7.81 (d, 1H), 8.04-8.05 (d, 1H), 8.84 (s, 1H). MS m/z 449 [M+Na]⁺, 99.2% ee.

Second eluting isomer was arbitrarily assigned as Example 104;

¹H NMR (400MHz, MeOH-ch): δ ppm ¹H NMR (400MHz, MeOH-d₄): δ ppm 0.76-0.86 (m, 4H), 1.001.02 (m, 3H), 1.28-1.38 (m, 4H), 1.54 (m, 1H), 1.76-1.83 (m, 1H), 3.00-3.05 (m, 1H), 3.66-3.80 (m, 4H), 4.03-4.05 (m, 2H), 7.23 -7.27 (d, 1H), 7.80-7.81 (d, 1H), 8.04-8.05 (d, 1H), 8.84 (s, 1H).

MS m/z 449 [M+Na]⁺, 94% ee.

Example 105

N-i(1S.5R,6R)-3-(2-(r5-chloro-6-(hvdroxvmethvl)pvridin-3-vllamino)-5-fluoropyrimidin-4-vl)-6-methvl-3azabicvclo[3.1.01hex-1-vncyclopropanecarboxamide

The title compound was prepared according to the method described for Example 5 using N((1S,5R,6R)-3-(2-chloro-5-fluoropyrimidin-4-yl)-6-methyl-3-azabicyclo[3.1.0]hexan-1yl)cyclopropanecarboxamide (Préparation 95) and (5-amino-3-chloropyridin-2-yl)methanol (Préparation 122). The residue was purified using silica gel column chromatography eluting with 30% petroleum ether in EtOAc followed by préparative HPLC (Purification Method B).

¹H NMR (400MHz, MeOH-d₄): δ ppm 0.76-0.78 (m, 2H), 0.86 (m, 2H), 1.01-1.03 (m, 3H), 1.35-1.37 (m, 1H), 1.53 (m, 1H), 1.82 (m, 1H), 3.75-3.78 (m, 2H), 4.04 (m, 2H), 4.72 (s, 2H), 7.85 (m, 1H), 8.45 (s, 1H), 8.65 (s, 1H). MS m/z 433 [M+H]⁺

Example 106

N-iï 1 S,5R,6R)-3-i2-((5-chloro-6-r(1 R)-1 -hvdroxvethvnpvridin-3-vnamino)-5-fluoropvrimidin-4-vl1-6methvl-3-azabicvclor3.1.01hex-1-yl}cyclopropanecarboxamide

To a solution of tert-butyl ((1S,5R,6R)-3-(2-((5-chloro-6-((S)-1-hydroxyethyl)pyridin-3-yl)amino)-5fluoropyrimidin-4-yl)-6-methyl-3-azabicyclo[3.1.0]hexan-1-yl)carbamate (Préparation 138 350 mg, 0.718 mmol) in MeOH (10 mL) was added 4M HCl in dioxane (10 mL, 4M) dropwise. The solution was stirred at room température for 1 hour before concentrating in vacuo. The residue (54 mg, 0.143 mmol) was dissolved in DMF (10 mL) and treated with triethylamine (86 mg, 0.85 mmol) cyclopropanecarboxylic acid (24 mg, 0.28 mmol) and HATU (86 mg, 0.23 mmol). The reaction was stirred at room température for 18 hours. The réaction was concentrated in vacuo and purified directly using préparative HPLC (Purification Method B) to afford the title compound (38 mg, 58%).

¹H NMR (400MHz, DMSO-de): δ ppm 0.62-0.73 (m, 3H), 0.93 (s, 2H), 1.16-1.21 (m, 1H), 1.24-1.31 (m, 1H), 1.37 (d, 2H), 1.46-1.56 (m, 1H), 1.72-1.85 (m, 1H), 3.06-3.15 (m, 1H), 3.58-3.76 (m, 1H), 3.86-3.97 (m, 1H), 4.97-5.08 (m, 1H), 7.98-8.05 (m, 1H), 8.29-8.40 (m, 1H), 8.69-8.79 (m, 2H), 9.509.60 (m, 1H). MS m/z 447 [M+H]⁺

Examples 107 and 108

N-r(1S,5R)-3-(5-chloro-2-iT1-(2-hvdroxvethvl)-1H-pvrazol-4-vl1amino}pyrimidin-4-vl)-3azabicvclof3.1.01hex-1-vl1cvclopropanecarboxamide and N-F(1R.5S)-3-(5-chloro-2-(ri-(2hvdroxvethvl)-1H-pvrazol-4-vllamino}pvrimidin-4-vl)-3-azabicyclor3.1.01hex-1vncyclopropanecarboxamide

The racemic title compound was prepared according to the method described for Example 49 using racemic-N-(3-(2,5-dichloropyrimidin-4-yl)-3-azabicyclo[3.1.0]hexan-1-yi)cyclopropanecarboxamide (Préparation 98) and 4-amino-1 H-pyrazole-1 -éthanol.

The racemate was separated into its enantiomers using préparative chiral chromatography as described below:

Chiral column: Chiralpak Ad 250mmx30mm I.D. 20pm; Mobile phase: supercritical CO2:EtOH (0.2% ammonia) 45:55; Flow rate: 80 mL/min

First eluting isomer: Example 107;

¹H NMR (400MHz, MeOH-d₄): δ ppm 0.76-0.79 (m, 3H), 0.86-0.87 (m, 2H), 1.10 (m, 1H), 1.28 (m, 1H), 1.54 (m, 1H), 1.76 (m, 1H), 3.73 (m, 1H), 3.87 (m, 2H), 3.91-3.94 (m, 1H), 4.16 (m, 3H), 4.474.49 (m, 1H), 7.52 (s, 1H), 7.81 (s, 1H), 7.87 (s, 1H). MS m/z 404 [M+H]⁺

Second eluting isomer: Example 108;

Example 109 (1S)-2,2-difluoro-N-[(1S,5S)-3T5-fluoro-2-[(1-methyl-1 H-pvrazol-4-yl)amino1pvrimidin-4-vl)-5(hvdroxvmethvl)-3-azabicvclor3.1.0lhex-1-vllcyclopropanecarboxamide

The title compound was prepared according to the method described for Example 49 using (S)-N((1S,5S)-3-(2-chloro-5-fluoropyrimidin-4-yl)-5-(hydroxymethyl)-3-azabicyclo[3.1.0]hexan-1-yl)-2,2difluorocyclopropane-1-carboxamide (Préparation 88) and 1-methyi-1H-pyrazol-4-ylamine at 85°C.

The residue was purified using silica gel column chromatography eluting with 0-5% MeOH in DCM.

¹H NMR (400MHz, MeOH-d₄): δ ppm 1.78-1.88 (m, 1H), 2.00-2.10 (m, 1H), 2.55-2.65 (m, 1H), 3.70 (m, 1H), 3.70 (m, 1H), 3.90 (s, 3H), 3.95-4.00 (m, 1H), 4.10-4.20 (m, 1H), 7.50 (s, 1H), 7.80 (s, 2H). MS m/z 424 [M+H]⁺

Example 110 (1R,2R)-2-cvano-N-[(1S.5S)-3-{5-fluoro-2-r(1-methvl-1H-pvrazol-4-vl)aminolpyrimidin-4-vl}-5(hydroxvmethvl)-3-azabicvcloF3.1.0lhex-1-vllcyclopropanecarboxamide

The title compound was prepared according to the method described by Example 109 using racemic(1R,2R)-N-(3-(2-chloro-5-fluoropyrimidin-4-yl)-5-(hydroxymethyl)-3-azabicyclo[3.1.0]hexan-1-yl)-2cyanocyclopropane-1-carboxamide (Préparation 89). The racemate was separated into its enantiomers using chiral chromatography as described below:

¹H NMR (400MHz, DMSO-de): δ ppm 1.05 (d, 1H), 1.13 (m, 1H), 1.50 (m, 2H), 2.02 (m, 1H), 2.33 (m, 1H), 3.60-3.79 (m, 4H), 3.87 (s, 3H), 3.98 (m, 1H), 4.09 (m, 1 H), 4.16 (m, 1H), 7.54 (s, 1H), 7.77-7.78 (m, 2H).

Column: Cellulose-3 21mmx250mmx5pm; Mobile phase A: CO2, Mobile phase B: MeOH; 90:10 A:B; hold for 10 minutes; 65 mL/min. Peak 2; Rt = 7.08 minutes, MS m/z 413 [M+H]⁺

Example 111

4-((4-i6-(2.2-difluoropropanovl)-3,6-diazabicyclo|3.1.11hept-3-vl1-5-fluoropvrimidin-2-vl}amino)-N-ethvl2-methylbenzamide

To a solution of 4-((4-(3,6-diazabicyclo[3.1.1]heptan-3-yl)-5-fluoropyrimidin-2-yl)amino)-N-ethyl-2methylbenzamide (Préparation 126, 25 mg, 0.067 mmol) in DCM (5 mL) was added 2,2difluoropropanoic acid (7 mg, 0.067 mmol), HATU (25 mg, 0.066 mmol) and triethylamine (0.03 mL, 0.2 mmol). The reaction was stirred at room température for 1 hour. The reaction was diluted with water, the organic phase collected through a phase séparation cartridge and concentrated in vacuo.

The residue was purified using préparative HPLC (Method 1, 5% B to 50% B in 8.5 min, to 100% B in 9 min, hold at 100% B to 10 min) to afford the title compound.

Préparative HPLC conditions

Method 1: Waters Sunfire C18 19x500 mm, 5μ, Mobile Phase A: 0.05% TFA in water; Mobile Phase 5 B: 0.05% TFA in Acetonitrile. Flow rate 25 mL/min.

Method 2: Waters Sunfire C18 19x500 mm, 5μ, Mobile Phase A: 0.05% Formic acid in water; Mobile Phase B: 0.05% Formic acid in Acetonitrile. Flow rate 25 mL/min.

LCMS QC conditions:

Column: Waters Atlantis dC18 4.6x50mm, 5μ

Modifier: TFA 0.05%

Gradient: 95% water:5% MeCN linear to 5% water:95% MeCN over 4 minutes, hold for 1 minute to 5 minutes. Flow rate: 2 mL/min

MS mode: ESI+; scan range 160-650 Da ¹H NMR (400MHz, DMSO-de): δ ppm 1.15 (t, 3H), 1.77-1.88 (m, 4H), 2.37 (s, 3H), 2.86 (q, 1H), 3.2315 3.30 (m, 2H), 4.02-4.09 (m, 2H), 4.09-4.19 (m, 2H), 4.65 (br s, 1 H), 4.92 (br s, 1 H), 7.31 (d, 1 H), 7.60 (brs, 2H), 8.05-8.12 (m, 2H), 9.36 (s, 1H). LCMS Rt = 1.96 minutes; MS m/z463 [M+HJExample 112

N-ethvl-4-({5-fluoro-4-f6-(2-fluoro-2-methvlpropanovl)-3,6-diazabicvclof3.1.nhept-3-vllpyrimidin-2vl1amino)-2-methvlbenzamide

The title compound was prepared, purified and analysed as described for Example 111 using 2fluoro-2-methylpropanoic acid and 4-((4-(3,6-diazabicyclo[3.1.1]heptan-3-yl)-5-fluoropyrimidin-2yl)amino)-N-ethyl-2-methylbenzamide (Préparation 126).

Prep. HPLC Method 1, 10% B to 50% B in 8.5 min, to 100% B in 9 min, hold at 100% B to 10 min.

¹H NMR (400MHz, DMSO-de): δ ppm 1.13 (t, 3H), 1.38-1.49 (m, 3H), 1.52-1.61 (m, 3H), 1.74 (d, 1H),

2.35 (s, 3H), 2.77 (q, 1H), 3.20-3.28 (m, 2H), 3.94 (d, 1H), 4.02 (d, 1H), 4.06-4.13 (m, 1H), 4.17 (d,

H), 4.52 (brs, 1H), 4.82 (brs, 1 H), 7.28 (d, 1H), 7.54-7.63 (m, 2H), 8.05 (d, 2H), 9.31 (s, 1H). LCMS Rt = 1.95 minutes; MS m/z 459 [M+H]⁺

Example 113

4-({4-[6-(cvclopropvlcarbonvl)-3,6-diazabicvcloi3.1.1lhept-3-vllpvrimidin-2-vl)amino)-N-ethvl-2methylbenzamide

The title compound was prepared, purified and analysed as described for Example 111 using cyclopropanecarboxylic acid and tert-butyl 3-(2-chIoropyrimidin-4-yl)-3,6-diazabicyclo[3.1.1]heptanes6-carboxylate hydrochloride (Préparation 128).

Préparative HPLC Method 2, 5% B to 100% B in 8.5 min, hold at 100% B to 10 min.

LCMS Rt = 1.57 minutes; MS m/z 421 [M+H]⁺

Example 114

4-({4-Γ6-(2,2-δίΑυοΓθΡΓθΡ3ηονΙ)-3.6-άί3Ζ3όίονοΙοΓ3·1·11ΐΊ6Ρί-3-νΙΐρνΐΊΓηΐόίη-2-ν1}3ΠΊίηο)-Νethylbenzamide

The title compound was prepared, purified and analysed as described for Example 115 using 2,2difluoropropanoic acid and 4-((4-3,6-diazabicyclo[3.1.1 ]heptan-3-yl)pyrimidin-2-yl)amino-Nethylbenzamide hydrochloride (Préparation 127).

Prep. HPLC Method 1,10% B to 60% B in 8.5 min, to 100% B in 9 min, hold at 100% B to 10 min.

¹H NMR (400MHz, DMSO-ds): δ ppm 1.17 (t, 3H), 1.76-1.88 (m, 4H), 2.87-2.95 (m, 1H), 3.28-3.37 (m, 2H), 3.84-4.14 (m, 4H), 4.70 (br s, 1H), 4.97 (br s, 1H), 6.51 (d, 1H), 7.75-7.83 (m, 2H), 7.91 (br s, 2H), 8.14 (d, 1H), 8.42 (brs, 1H), 10.48 (brs, 1H). LCMS Rt= 1.93 minutes; MS m/z431 [M+H]⁺

Example 115

N-ethvl-2-methvl-4-({4-|6-(trifluoroacetvl)-3.6-diazabicvclor3.1.1lhept-3-vllpvrimidin-2vllaminolbenzamide

To a solution of 4-((4-(3,6-diazabicyclo[3.1.1]heptan-3-yI)pyrimidin-2-yI)amino)-N-ethyl-2methylbenzamide hydrochloride (Préparation 128, 30 mg, 0.077 mmol) in DCM (5 mL) was added triethylamine (0.1 mL, 0.7 mmol) followed by TFAA (2 drops). The reaction was stirred at room température for 2 hours, concentrated in vacuo and purified and analysed using préparative HPLC (Method 2, 5% B to 100% B in 8.5 min, hold at 100% B to 10 min) as described for Example 111 to afford the title compound. LCMS Rt = 1.76 minutes; MS m/z 449 [M+H]⁺

Example 116

N-ethvl-4-((5-fluoro-4-i6-(trifluoroacetvl)-3,6-diazabicvcloi3.1.1lhept-3-vllpvrimidin-2-vl)amino)-2methylbenzamide

A solution of 1-(3-(2-chloro-5-fluoropyrimidin-4-yi)-3,6-diazabicyclo[3.1,1]heptan-6-yI)-2,2,2trifluoroethan-1-one (Préparation 129, 100 mg, 0.31 mmol) and 4-amino-N-ethyl-2-methylbenzamide (PCT Publication No. W02006109846) in isopropanol (3 mL) was treated with 1 drop of cHCI and heated to 140°C for 40 minutes under microwave irradiation. The reaction was cooled, concentrated in vacuo and taken on directly to the next step.

Example 117

5-({4-r(1R,5S)-8-{[(1S)-2,2-Difluorocvclopropvl1carbonvl}-3,8-diazabicvclof3.2.1loct-3-vl1pvrimidin-2vl}amino)-3-fluoropyridine-2-carboxamide

To a solution of Préparation 144 (280 mg, 0.815 mmol) and Préparation 68 (129 mg, 1.06 mmol) in DMF (30 mL) was added TEA (330 mg, 3.26 mmol) and HATU (372 mg, 0.979 mmol) at 0 °C. The mixture was stirred at room température (10 °C) for 18 h. The solution was concentrated and purified by Préparative HPLC

Préparative HPLC conditions

Phenomenex Synergi C18 150x30mm, 4μ, Mobile Phase A: acetonitrile; Mobile Phase B: water (adjusted to pH 10 with ammonia). Flow Rate: 35 mL/min. LCMS: (M+1 =447.9, M+23=469.9)

The racemate was separated using chiral chromatography using Chiralpal AS-H column (150mmx4.6mmx5um); mobile phase A: 5% CO2to 40%; mobile phase B: MeOH with 0.05% DEA to

provide the title compound (143 mg, 39%) at Rt =8.12 minutes. LCMS Rt = 0.73 minutes, MS m/z 448.1 [M+H] ¹H NMR (400MHz, DMSO-d6): δ ppm 1.58-2.10 (m, 6H), 2.93-3.28 (m, 3H), 4.04-4.33 (m, 2H), 4.574.78 (m, 2H), 6.41 (dd, 1H), 7.37 (br. s., 1H), 7.80 (br. s., 1H), 8.10 (dd, 1H), 8.27 (m, 1H), 8.67 (d,

1 H), 9.88 (s, 1 H).

Préparation 1

5-((4-((1 R,5S)-3,8-Diazabicyclor3.2.11octan-3-vl)pvrimidin-2-vl)amino)-N.3-dimethylpicolinamide hydrochloride

Step 1

To tert-butyl (1R,5S)-3-(2-chloropyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Préparation 34, 500 mg, 1.54 mmol) and 5-amino-N,3-dimethylpicolinamide (Préparation 38, 458 mg, 2.78 mmol) in DMA (20 mL) was added césium carbonate (1 g, 3.08 mmol), xantphos (178 mg, 0.31 mmol) and palladium acetate (69 mg, 0.31 mmol). The reaction was purged with nitrogen for 1 minute before heating to 130°C under microwave irradiation for 1 hour. The reaction was cooled, filtered and concentrated in vacuo. The residue was purified using silica gel column chromatography eluting with 50-80% EtOAc in petroleum ether.

Step 2

The resulting solid was dissolved in DCM (20 mL) and treated with 4M HCl in dioxane (20 mL) and the reaction was stirred at room température for 2 hours. The reaction was concentrated in vacuo to afford the title compound as the hydrochloride sait. ¹H NMR (400MHz, DMSO-d6): δ ppm 1.67-1.83 (m, 2H), 1.90-2.06 (m, 2H), 2.58 (s, 3H), 2.78 (br s, 3H), 3.59-3.72 (m, 2H), 4.16-4.27 (m, 4H), 6.666.77 (m, 1H), 7.88 (br s, 1H), 8.17 (d, 1H), 8.46-8.60 (m, 1H), 8.66 (br s, 1H), 9.61-9.75 (m, 1H), 10.03-10.16 (m, 1H), 11.09 (brs, 1H).

MS m/z 354 [M+H]⁺

The following préparations were prepared according to the method described by Préparation 1 using tert-butyl (1R,5S)-3-(2-chloropyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Préparation 34) and the appropriate amine as described below. The compounds were isolated as the hydrochloride salts unless otherwise specified.

Deprotection Method B: The Boc-protected intermediate was dissolved in DCM, treated with TFA and stirred at room température for 18 hours. The reaction was basified to pH=10 by the addition of triethylamine. The solution was concentrated in vacuo and purified by silica gel column chromatography eluting with 10% MeOH in EtOAc or 96:3:1 DCM:MeOH:NH3.

Deprotection Method C: The Boc-protected intermediate was dissolved in DCM, treated with TFA and stirred at room température for 1.5 hours. The reaction was concentrated in vacuo, dissolved in MeOH and eluted through a carbonate cartridge to afford the free parent.

Préparation number	Structure	Name	SM/Data
2	H ê N Me A /N. A. /OH rf^N 1^ Y H	Racemic 2-(5-((4- ((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3yl)pyrimidin-2-yl)amino)pyridin-2-yl)propan-1-ol hydrochloride	Racemic 2-(5-aminopyridin2-yl)propan-1-ol (Préparation 40). Taken on directly to the next step.
3	H ô N 0 ÎI^N T A⁶ \..<A /AA\ N N Me H	5-((4-((1 R,5S)-3,8diazabicyclo[3.2.1 Joctan3-yl)pyrimidin-2-yl)amino)N-ethyl-3-methylpicolinamide hydrochloride	5-amino-N-ethyl-3methylpicolinamide (Préparation 42). Taken on directly to the next step.
4	H ê N 0 ifA ^AN^Me A A - H	4-((4-((1 R,5S)-3,8diazabicyclo[3.2.1]octan3-yI)pyrimidin-2-yl)amino)N-ethylbenzamide hydrochloride	4-amino-N-ethyl benzamide. Taken on directly to the next step.
5	H ô N 0 A /*K A. „Me aAO H	5-((4-((1 R,5S)-3,8diazabicyclo[3.2.1]octan3-yl)pyrimidin-2-yl)amino)3-chloro-Nmethylpicolinamide hydrochloride	5-amino-3-chloro-Nmethylpicolinamide (Préparation 39).Taken on directly to the next step.
6	è àzc H	2- (5-((4-((1 R,5S)-3,8diazabicyclo[3.2.1 joctan- 3- yl)pyrimidin-2-yl)amino)3-chIoropyridin-2-yl)ethan1-oi hydrochloride	2-(5-amino-3-chloropyridin2-yl)ethan-1-ol (Préparation 45). Taken on directly to the next step.
7	H û N cur H	2- (5-((4-((1 R,5S)-3,8diazabicyclo[3.2.1 Joctan- 3- yl)pyrimidin-2-yl)amino)3-fluoropyridin-2-yl)ethan1 -ol hydrochloride	2-(5-amino-3-fluoropyridin2-yl)ethan-1-oI (Préparation 46). Taken on directly to the next step.

8	Δ Λ ό ^ΑνΔΑρ Η	(S)-1-(5-((4-((1 R,5S)-3,8diazabicyclo[3.2.1 Joctan3-yl)pyrimidin-2-yl)amino)3-fluoropyridin-2yI)pyrrolidin-3-ol hydrochloride	(S)-1-(5-amino-3fluoropyridin-2-yl)pyrrolidin3-ol (Préparation 47). Taken on directly to the next step.
9	A .°Η Α_ν ζγθ Η	(R)-1-(5-((4-((1R,5S)-3,8diazabicyclo[3.2.1]octan3-yi)pyrimidin-2-yl)amino)3-fiuoropyridin-2yl)pyrrolidin-3-ol hydrochloride	(R)-1-(5-amino-3fluoropyridin-2-yl)pyrrolidin3-ol (Préparation 48). Taken on directly to the next step.
10	Η Û γ λτ^οη ΟΛΧ Η	1-(5-((4-((1 R,5S)-3,8diazabicyclo[3.2.1]octan3-yl)pyrimidin-2-yl)amino)3-fluoropyridin-2yl)azetidin-3-ol hydrochloride	1 -(5-amino-3-fluoropyridin2-yl)azetidin-3-ol (Préparation 49). Taken on directly to the next step.
11	Η Ô Ν Αν Αγ°·^0Η Η	2- ((5-((4-((1 R,5S)-3,8diazabicyclo[3.2.1 Joctan- 3- yl)pyrimidin-2-yl)amino)3-chloropyridin-2yl)oxy)ethan-1-ol hydrochloride	2-((5-amino-3-chloropyridin2-yl)oxy)ethan-1-ol (Préparation 50). Taken on directly to the next step.
12	Η Ô Ν Αν Αγ^οΗ AnAA_fΗ	(5-((4-((1 R,5S)-3,8diazabicyclo[3.2.1]octan3-yl)pyrimidin-2-yl)amino)3-fluoropyridin-2yl)methanol hydrochloride	5-amino-3-fluoro-2-pyridine methanol (PCT Publication No. W02013013815) Taken on directly to the next step.
13	Η ê Ν Me Me Αν γ^ΝγΑ·ΟΝ IZ.-U Η	2- (5-((4-((1 R,5S)-3,8diazabicyclo[3.2.1]octan- 3- yl)pyrimidin-2yi)amino)pyridin-2-yl)-2methylpropanenitrile	2-)5-aminopyridin-2-yl)-2methylpropanenitrile and using deprotection method B.

14	H ê N O A /N. A „Me H	5-((4-((1 R,5S)-3,8diazabicyclo[3.2.1]octan3-yl)pyrimidin-2-yl)amino)3-fluoro-Nmethylpicolinamide hydrochloride	5-amino-3-fluoro-Nmethylpicolinamide (Préparation 51).
15	H Y YY /A < A Az N N H	4-((1R,5S)-3,8diazabicyclo[3.2.1 Joctan3-yl)-N-(1-tosyl-1Hpyrazol-4-yl) pyrimidin-2amine	1-[(4-methylphenyl)sulfonyl]1H-pyrazol-4-amine (PCT Publication No. WO 2011106114). Deprotection method C. LCMS Rt = 0.73 minutes MS m/z 426 [M+H]⁺
16	H û N Me (A_n A UXv N N AA Me H II O	4-((4-((1 R,5S)-3,8diazabicyclo[3.2.1 Joctan3-yl)pyrimidin-2-yl)amino)N,6-dimethylpicolinamide	4-amino-N,6dimethylpicolinamide (Préparation 44). Deprotection method B. LCMS Rt = 0.39 minutes MS m/z 354 [M+H]⁺
17	é _r ( A AAA N N AA ^xMe H II O	4-((4-((1 R,5S)-3,8diazabicyclo[3.2.1 Joctan3-yl)pyrimidin-2-yl)amino)6-(hydroxymethyl)-Nmethyipicolinamide hydrochloride	4-amino-6-(hydroxymethyl)N-methylpicolinamide hydrochloride (Préparation 125). Taken on directly to the next step.

Préparation 18

5-((4-((1 R,5S)-3,8-Diazabicvclor3.2.1loctan-3-vl)pvrimidin-2-vl)amino)-3-methylpicolinamide hydrochloride

The title compound was prepared according to the method described for Préparation 1 Step 1. Following the Buchwald step the intermediate was heated with ammonia in methanol to 90°C in a sealed vessel. The reaction was cooled and concentrated in vacuo before deprotection with HCl as described.

Préparation 19

4-((1 R,5S)-3,8-Diazabicvclor3.2.11octan-3-vl)-N-(1-methvl-1H-Dvrazol-4-vl)pyrimidin-2-amine hydrochloride

A solution of tert-butyl (1R,5S)-3-(2-chloropyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Préparation 34, 2.25 g, 6.93 mmol) and 1-methyl-1 H-pyrazol-4-ylamine hydrochloride (1.02 g, 7.62 mmol) in iPrOH (30 mL) was heated to 140°C under microwave irradiation for 1 hour. The reaction was concentrated in vacuo to afford the title compound as the hydrochloride sait (2.2 g, 99%). ¹H NMR (400MHz, MeOH-d₄): δ ppm 1.97-2.02 (m, 2H), 2.19-2.20 (m, 2H), 3.48-3.51 (m, 1 H), 3.72-3.78 (m, 1 H), 3.98 (s, 3 H), 4.20-4.31 (m, 3H), 6.67 (d, 1H), 7.81 (s, 1H), 7.86 (m, 2H). MS m/z 286 [M+H]⁺

Préparation 20

2-(4-((4-((1 R,5S)-3,8-Diazabicvcloi3.2.1]octan-3-yl)pvrimidin-2-vl)amino)-1H-pvrazol-1-yl)ethan-1-ol hydrochloride

To a solution of tert-butyl (1R,5S)-3-(2-chloropyrimidin-4-yl)-3,8-diazabicycIo[3.2.1]octane-85 carboxylate (Préparation 34, 200 mg, 0.617 mmol) and 4-amino-1H-pyrazole-1 -éthanol (134 mg,

0.74 mmol) in (PrOH (10 mL) was added 3 drops of concentrated HCl at room température. The reaction was heated to 140°C under microwave irradiation for 40 minutes. The reaction was concentrated in vacuo to afford the title compound and taken on directly to the next step as the hydrochloride sait.

The following préparations were prepared according to the method described by Préparation 20 using tert-butyl (1R,5S)-3-(2-chloropyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Préparation 34) and the appropriate amine as described below. The compounds were isolated as the hydrochloride salts.

Préparation number	Structure	Name	SM/Data
21	H $ H	N-(4-((1R,5S)-3,8diazabicyclo[3.2.1]octan-3yl)pyrimidin-2-yl)isothiazol-4amine hydrochloride	MS m/z 289 [M+H]⁺ 4-isothiazolamine
22	H 0 H	4-((1R,5S)-3,8- diazabicyclo[3.2.1 ]octan-3yl)-N-(1l2-pyrazol-4yl)pyrimidin-2-amine hydrochloride	tert-butyl 4-amino-1 H- pyrazole-1-carboxylate (PCT Publication No. WO 2012022681).
23	H ô > /—Me H	4-((1 R,5S)-3,8diazabicyclo[3.2.1 ]octan-3y l)-N-(1 -ethyl-1 H-pyrazol-4yl)pyrimidin-2-amine hydrochloride	MS m/z 300 [M+H]⁺ 1-ethyl-1 H-pyrazol-4-amine

Préparation 24

4-((4-((1 R,5S)-3,8-Diazabicvclo[3.2.1loctan-3-vl)-5-fluoropvrimidin-2-yl)amino)-N-ethvlbenzamide hydrochloride

Step 1

To a solution of tert-butyl (1R,5S)-3-(2-chloro-5-fluoropyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8carboxylate (Préparation 35, 0.5 g, 1.5 mmol)in dioxane (5 mL) was added 4-amino-N-ethyl benzamide (0.26 g, 1.6 mmol), RuPHOS palladium (II) phenethylamine chloride (0.1 g, 0.1 mmol) and sodium tert-butoxide (0.15 g, 1.5 mmol). The reaction was heated to 120°C under microwave irradiation for 25 minutes. The reaction was cooled and eluted through a solid phase extraction cartridge. The filtrate was purified using silica gel column chromatography eiuting with 0-20% MeOH in DCM to afford boc-protected intermediate (0.65 g, 95%).

¹H NMR (400MHz, DMSO-de): δ ppm 1.07 (t, 3H), 1.37-1.41 (m, 9H), 1.67 (d, 2H), 1.78-1.86 (m, 2H), 3.13-3.18 (m, 2H), 3.18-3.26 (m, 2H), 4.07-4.13 (m, 2H), 4.20 (br s, 2H), 7.65-7.69 (m, 2H), 7.69-7.74 (m, 2H), 8.02 (d,1H), 8.19 (t, 1H), 9.43 (s, 1H).

Step 2

The intermediate was dissolved in DCM (5 mL) and MeOH (2 mL) and treated with 4M HCl in dioxane. The reaction was stirred at room température for 18 hours before concentrating in vacuo to afford the title compound as the hydrochloride sait.

Préparation 25

4-((4-((1 R.5S)-3,8-Diazabicvclo[3.2.11octan-3-vl)-5-fluoropyrimidin-2-vl)amino)-N-ethvl-2methylbenzamide hydrochloride tert-Butyl (1R,5S)-3-(2-((4-(ethyIcarbamoyl)-3-methylphenyl)amino)-5-fluoropyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Example 74) was dissolved in DCM (5 mL) and MeOH (2 mL) and treated with 4M HCl in dioxane. The reaction was stirred at room température for 18 hours before concentrating in vacuo to afford the title compound as the hydrochloride sait.

Préparation 26

5-((4-((1 R,5S)-3,8-Diazabicvclor3.2.11octan-3-vl)pyrimidin-2-vl)amino)-3-methvlpicolinamide hydrochloride

A solution of tert-butyl (1R,5S)-3-(2-((6-(ethoxycarbonyl)-5-methylpyridin-3-yl)amino)pyrimidin-4-yi)3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Préparation 33, 100 mg, 0.214 mmol) in NH3/MeOH (15 mL) was heated to 90°C in a seaied vessel for 18 hours. The solution was concentrated in vacuo and the residue was treated with 4M HCI/dioxane (20 mL) and stirred at room température for 2 hours. solution was concentrated in vacuo to afford the title compound as the hydrochloride sait.

Préparation 27 ((1R.5S)-3-(2-Chloro-5-fluoropvrimidin-4-vl)-3,8-diazabicvcloi3.2.11octan-8-vl)(cvclopropvl)methanone To a suspension of (1R,5S)-3-(2-chloro-5-fluoropyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane (Préparation 31, 4 g, 11.7 mmol), cyclopropanecarboxylic acid (2 g, 23.4 mmol) and triethylamine (3.5 g, 35.1 mmol) in DMF (40 mL) was added HATU (5.33 g, 14 mmol) at room température. After

the addition, the reaction was stirred at room température for 30 minutes. The reaction was concentrated in vacuo and purified by siiica gel column chromatography eluting with 20% petroleum ether in EtOAc to afford the title compound (2.5 g, 70%). ¹H NMR (400MHz, CDCI3): δ ppm 0.80-0.86 (m, 2H), 1.01-1.05 (m, 2H), 1.66-2.09 (m, 5H), 3.29-3.34 (m, 2H), 4.23-4.26 (m, 1H), 4.37-4.40 (m, 5 1H), 4.53-4.52 (m, 1H), 4.77-4.78 (m, 1H), 7.94-7.95 (m, 1H). MS m/z 311 [M+H]⁺

Préparation 28 ((1R,5S)-3-(2-Chloropvrimidin-4-vl)-3.8-diazabicvclor3.2.11octan-8-vl)(cvclopropyl)methanone

To a solution of (1R,5S)-3-(2-chloropyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane (Préparation 32, 3.5 g, 15.57 mmol) in DCM (20 mL) was added triethylamine (7.86 g, 78 mmol) and cyclopropanecarbonyl chloride (3.26 g, 31 mmol) at room température. The reaction was stirred at room température for 1 hour. The reaction was washed with saturated aqueous NaHCC>3 solution (100 mL). The organic layer was collected, dried, concentrated in vacuo and purified by siiica gel column chromatography eluting with 10% MeOH in to afford the title compound (2.5 g, 55%).

MS m/z 293 [M+H]⁺

Préparation 29 (1R.5S)-3-(2-ChloroDvrimidin-4-vl)-N-ethvl-3,8-diazabicyclor3.2.11octane-8-carboxamide

To a solution of (1R,5S)-3-(2-chloropyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane_(Preparation 32, 170 mg, 0.6173mmol) in DCM (20 mL) was added triethylamine (125 mg, 1.23 mmol) followed by isocyanatoethane (175.4 mg, 2.47 mmol) at 0°C. The reaction was stirred at room température for 1 hour before concentrating in vacuo and purifying with siiica gel column chromatography eluting with 20% petroleum ether in EtOAc to afford the title compound (184 mg, 100%). MS m/z 296 [M+H]⁺

Préparation 30

Racemic ((1R,5S)-3-(2-Chloropvrimidin-4-vl)-3,8-diazabicvcloi3.2.11octan-8-vl)(2,2difluorocvclopropvDmethanone

The title compound was prepared according to the method described for Préparation 27 using racemic 2,2-difluorocyclopropane-1-carboxylic acid. MS m/z 329 [M+H]⁺

Preparation31 (1R,5S)-3-(2-Chloro-5-fluoropyrimidin-4-vl)-3.8-diazabicvclo[3.2.1loctane

The title compound was prepared according to the method described for Préparation 25 using tert30 butyl (1R,5S)-3-(2-chloro-5-fluoropyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Préparation 35).

Préparation 32 (1R,5S)-3-(2-Chloropvrimidin-4-vl)-3,8-diazabicvclof3.2.1loctane

The title compound was prepared according to the method described for Préparation 125 using tert35 butyl (1R,5S)-3-(2-chloropyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Préparation 34) in dioxane.

Préparation 33 tert-Butyl (1R,5S)-3-(2-((6-(ethoxvcarbonvl)-5-methvlpyridin-3-vl)amino)pvrimidin-4-vl)-3,8diazabicvclof3.2.1loctane-8-carboxvlate

The title compound was prepared according to the method described for Préparation 1 Step 1 using tert-butyl (1R,5S)-3-(2-chIoropyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Préparation 34) and ethyl-5-amino-3-methylpicolinate (Préparation 41). MS m/z 469 [M+H]⁺

Préparation 34 tert-Butvl (1R,5S)-3-(2-chloropvrimidin-4-vl)-3,8-diazabicvclo[3.2.1loctane-8-carboxylate

To a solution of tert-butyl (1R,5S)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Préparation 36, 11 g, mmol) in MeOH (500 mL) was added 2,4-dichloropyrimidine (8.4 g, 57 mmol) and TEA (6.7 g, 66 mmol) at 0°C. The reaction was stirred at room température for 18 hours before concentrating in vacuo. The residue was purified by silica gel column chromatography eluting with 20% EtOAc in petroleum ether to afford the title compound as a white solid (12 g, 71%).

¹H NMR (400MHz, CDCh): δ ppm 1.48 (s, 9H), 1.63-1.74 (m, 2H), 1.97 (br s, 2H), 3.18 (br s, 2H), 3.38-3.74 (m, 1 H), 4.36 (br s, 3H), 6.35 (d, 1 H), 8.06 (d, 1 H). MS m/z 325 [M+H]⁺

Préparation 35 tert-Butvl (1R,5S)-3-(2-chloro-5-fluoropvrimidin-4-vl)-3,8-diazabicvclo[3.2.1loctane-8-carboxylate

The title compound was prepared according to the method described for Préparation 36 using 2,4dichloro-5-fluoropyrimidine. The residue was purified by silica gel column chromatography eluting with 0-100% EtOAc in heptanes. ¹H NMR (400MHz, DMSO-ds): δ ppm 1.38 (s, 9H), 1.62 (d, 2H,) 1.761.84 (m, 2H), 3.16 (d, 2H), 4.08 (d, 2H), 4.15-4.22 (m, 2H), 8.17 (d, 1H).

Préparation 36 tert-Butvl (1 R.5S)-3,8-diazabicvclor3.2.11octane-8-carboxvlate

A solution of tert-butyl (1R,5S)-3-benzyl-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Préparation 37, 19 g, 63 mmol) in methanol (500 mL) was hydrogenated over palladium on carbon (4 g) at 50 psi at room température for 18 hours. The reaction was filtered and the filtrate was concentrated in vacuo to afford the title compound as a white solid (13.2 g, 99%).

¹H NMR (400MHz, MeOH-d₄): δ ppm 1.49 (s, 9H), 1.85-2.02 (m, 4H), 2.65 (d, 2H), 2.90 (d, 2H), 4.08 (brs, 2H).

Préparation 37 tert-Butvl (1R.5S)-3-benzvl-3,8-diazabicvcloF3.2.noctane-8-carboxviate

A solution of (1R,5S)-3-benzyl-3,8-diazabicyclo[3.2.1]octane (20 g, 99 mmol), ditertbutyldicarboxylate (21 g, 97 mmol) and triethylamine (10 g, 99 mmol) in DCM (500 mL) was stirred at room température for 18 hours. The reaction was concentrated in vacuo and purified by silica gel column chromatography eluting with 1% EtOAc in petroleum ether to afford the title compound (19 g, 64%).

Préparation 38

5-Amino-N,3-dimethvlpicolinamide

Ethyl 5-amino-3-methylpicolinate (Préparation 41, 500 mg, 2.78 mmol) was dissolved in ethanolic methylamine (30%, 50 mL) and the solution was heated to 100°C in a sealed vessel for 18 hours. The reaction was cooled, concentrated in vacuo and used directly in the next reaction.

Préparation 39

5-Amino-3-chloro-N-methylpicolinamide

The title compound was prepared according to the method described for Préparation 38 using 5amino-3-chloro-2-pyridinecarboxylic acid methyl ester.

Préparation 40

Racemic 2-(5-Sminopvridin-2-vl)propan-1-ol

To a solution of LÎAIH4 (1.16 g, 30.7 mmol) in THF (15 mL) cooled to 0°C was added racemic methyl 2-(5-aminopyridin-2-yl)propanoate (Préparation 43, 850 mg, 4.72 mmol). The reaction was stirred at room température for 2 hours before quenching with Na2SO₄.1 OH2O. The reaction was filtered and the filtrate was concentrated in vacuo to afford the title compound (0.72 g, 100%).

¹H NMR (400MHz, CDCh): δ ppm 1.28 (d, 3H), 2.94-3.01 (m, 1H), 3.62 (br s, 1H), 3.78 (m, 1H), 3.853.93 (m, 1H), 6.99 (d, 2H), 8.00 (m, 1H).

Préparation 41

Ethyl 5-amino-3-methvlpicolinate

A solution of ethyl 3-methyl-5-nitropicolinate (Préparation 53, 28 g, 133 mmol) in éthanol (600 mL) was degassed with argon for 15 minutes. 10% palladium on carbon (12 g) was added and the reaction was hydrogenated under an atmosphère of hydrogen at room température for 18 hours. The reaction was filtered through a pad of celite and washed with éthanol. The filtrate was concentrated in vacuo and the residue purified by silica gel column chromatography eluting with 0-2% methanol in DCM followed by trituration in hexane to afford the title compound (22 g, 92%).

¹H NMR (400MHz, CDCh): δ ppm 1.39 (t, 3H), 3.99 (brs, 2H), 4.38 (q, 2H), 6.76 (d, 1H), 7.98 (d, 1H).

The following préparations were prepared according to the method described by Préparation 41 using the appropriate nitro intermediate as described. The purification method was as described or referred to below:

Purification Method 1 (PM1): Silica gel column chromatography eluting with 25% petroleum ether in

EtOAc.

Préparation number	Structure	Name	SM/Data
42	O £P Me H₂N^AY-_Me	5-amino-N-ethyl-3methylpicolinamide	N-ethyl-3-methyl-5nitropicolinamide (Préparation 52). PM1. ¹H NMR (400MHz, CDCh): δ ppm 1.07 (t, 3H), 2.50 (s, 3H), 3.21 (m, 2H), 5.76 (br s, 2H), 6.71 (d, 1H), 7.75 (d, 1H), 8.24 (t, 1H). MS m/z 180 [M+H]⁺

43	Me ,Ν,Α,ΟΜβ Y Y ° H₂N	Racemic methyl 2-(5aminopyridin-2yi)propanoate	Racemic methyl 2-(5- nitropyridin-2-yl)propanoate (Préparation 54) in methanol. Taken on directly to the next step.
44	Me A H₂N Y ^Me O	4-amino-N,6dimethylpicolinamide	N,6-dimethyl-4nitropicolinamide (Préparation 56). ¹H NMR (400MHz, MeOH-d₄): δ ppm 2.35 (s, 3H), 2.90 (s, 3H), 6.50 (d, 1H), 7.05 (d, 1H).

Préparation 45

2-(5-Amino-3-chloropyridin-2-yl)ethan-1-ol

To a solution of methyl 2-(3-chIoro-5-nitropyridin-2-yl)acetate (Préparation 58, 4.6 g, 20 mmol) in EtOH/hLO (50 mL/20 mL) was added ammonium chloride (20 g, 374 mmol) and Fe (8 g,143 mmol).

The reaction was stirred at room température for 3 hours before filtering and concentrating in vacuo. The residue was purified using silica gel column chromatography, dissolved in THF (50 mL) and added dropwise to a solution of L1AIH4 (2.3 g, 55 mmol) in THF (50 mL) at 0°C. The reaction was stirred at room température for 3 hours before quenching with Na2SO4.10H2O at 0°C. The mixture was filtered and the filtrate was concentrated in vacuo to afford the title compound as a yellow solid (1.3 g, 46%). MS m/z 173 [M+H]⁺

Préparation 46

2-(5-Amino-3-fluoropvridin-2-yl)ethan-1-ol

The title compound was prepared according to the method described for Préparation 45, 57 and 58 using 2-chloro-3-fluoro-5-nitropyridine. MS m/z 157 [M+H]⁺

Préparation 47 (S)-1-(5-Amino-3-fluoropvridin-2-vl)pyrrolidin-3-ol

To a solution of (S)-1-(3-fluoro-5-nitropyridin-2-yl)pyrrolidin-3-ol (Préparation 59, 250 mg, 1.10 mmol) in EtOH/H2O (5 mL/2 mL) was added ammonium chloride (233 mg, 4.40 mmol) and Fe (123 mg, 2.20 mmol). The reaction was stirred at 80°C for 30 minutes before filtering and concentrating in vacuo.

The residue was purified using silica gel column chromatography eluting with 10-100% EtOAc in petroleum ether to afford the title compound (80 mg, 36%).

The following préparations were prepared according to the method described by Préparation 47 using the appropriate nitro intermediate as described. The purification method was as described or 25 referred to below:

Préparation number	Structure	Name	SM/Data
48	OH /NyO	(R)-1-(5-amino-3fluoropyridin-2-yl)pyrrolidin-3ol	(R)-1-(3-fluoro-5n itropy ri di n-2-y I) pyrrolidin-3ol (Préparation 60). Taken on directly to the next step.
49	r/^0H Η₂Ν^>Χχ'^/Τ	1-(5-amino-3-fluoropyridin-2- yl)azetidin-3-ol	1 -(3-fluoro-5-nitropyridin-2yl)azetidin-3-ol (Préparation 61). Taken on directly to the next step.
50	i^ + r'''^0/,OH h,AA_ci	2-((5-amino-3-chloropyridin- 2-yl)oxy)ethan-1-ol	2-((3-chloro-5-nitropyridin-2yl)oxy)ethan-1-ol (Préparation 62). Taken on directly to the next step.

Préparation 51

5-Amino-3-fluoro-N-methylpicolinamide

To a solution of 5-((di-[tert-butoxycarbonyl])amino)-3-fluoropicolinic acid (Préparation 65, 750 mg, 2.11 mmol) in DMF (20 mL) was added triethylamine (3.2 g, 31.65 mmol), HATU (1.2g , 3.17 mmol) and MeNhk.HCI (1.5 g, 22.4 mmol) at 0°C. The reaction was stirred at room température for 18 hours then concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with 33% petroleum ether in EtOAc and dissolving in MeOH (20 mL). To the solution was added 4M

HCl in MeOH (30 mL) and the reaction was stirred at room température for 18 hours before concentrating in vacuo. The residue was dissolved in MeOH (20 mL) and adjusted to pH 10 by adding 10 1M aqueous NaHCO3 solution. The mixture was concentrated in vacuo and added to 10:1

DCM:MeOH (100mL) and stirred at room température for 30 minutes. The mixture was filtered and the filtrate was concentrated in vacuo to afford the title compound as a yellow solid (480mg, 80%).

¹H NMR (400MHz, DMSO-ds): δ ppm 2.70-2.71 (d, 3H), 6.25 (s, 2H), 6.67-6.71 (dd, 1H), 7.75 (s, 1H), 8.20 (s, 1H).

Préparation 52

N-Ethvl-3-methyl-5-nitropicolinamide

The title compound was prepared according to the method described for Préparation 41 using ethyl 3-methyl-5-nitropicolinate (Préparation 53) and ethylamine at 70°C.

¹H NMR (400MHz, CDCi₃): δ ppm 1.28 (t, 3H), 2.87 (s, 3H), 3.49 (q, 2H), 7.97 (brs, 1H), 8.37 (d, 1H), 20 9.17 (d,1H).

Préparation 53

Ethyl 3-methvl-5-nitropicolinate

Sulfuric acid (150 mL) was added slowly to éthanol (600 mL) slowly at 0°C. To this solution was added 2-cyano-3-methyl-5-nitropyridine (15 g, 92 mmol) portion-wise and the reaction heated to reflux for 65 hours. The reaction was cooled, poured into ice-water and extracted into EtOAc. The organic layer was collected and the aqueous further washed with EtOAc. The organic extracts were combined, washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified using silica gel column chromatography eluting with 0-30% DCM in hexanes to afford the title compound (8.5 g, 44%). ¹H NMR (400MHz, CDCh): δ ppm 1.44 (t, 3H), 2.67 (s, 3H), 4.50 (q, 2H), 8.39 (d, 1H), 9.29 (d, 1H).

Préparation 54

Racemic Methyl 2-(5-nitropyridin-2-vl)propanoate

A solution of racemic 1 -(tert-butyl) 3-methyl 2-methyl-2-(5-nitropyridin-2-yl)malonate (Préparation 55, 1.6 g, 5.15 mmol) and TFA (15 mL) in DCM (50 mL) was stirred at room température for 18 hours. The reaction was concentrated in vacuo and treated with triethylamine before purifying directly by silica gel column chromatography eluting with 25% EtOAc in petroleum ether to afford the title compound (0.99 g, 91%). ¹H NMR (400MHz, CDCb): δ ppm 1.61 (d, 3H), 3.72 (s, 3H), 4.10-4.30 (m, 1H), 7.51 (d, 1H), 8.46 (dd, 1H), 9.38 (d, 1H).

Préparation 55

Racemic l-(tert-Butyl) 3-methyl 2-methvl-2-(5-nitropyridin-2-yl)malonate

To a solution of 1-(tert-butyl) 3-methyl 2-(5-nitropyridin-2-yl)malonate (PCT Publication No. WO 2007042299, 1.9 g, 6.41 mmol) in DMF (50 mL) was added césium carbonate (4.18 g, 13 mmol) at 0°C. The reaction was stirred at room température for 10 minutes before the addition of Mel (3.64 g, 25.7 mmol) and stirring at room température for 3 hours. The reaction was added water (40 mL)at 10°C and then extracted with EtOAc three times (3 x50 mL ). The organic layers were combined, concentrated in vacuo and purified by silica gel column chromatography eluting with 25% EtOAc in pentane to afford the title compound (1.6 g, 80%). ¹H NMR (400MHz, CDCI3): δ ppm 1.47 (s, 9H), 1.89 (s, 3H), 3.80 (s, 3H), 7.71 (d, 1H), 8.47 (m, 1H), 9.35 (d, 1H).

Préparation 56

N,6-Dimethvl-4-nitropicolinamide

To a solution of 6-methyl-4-nitro-2-pyridinecarboxylic acid (2 g, 10 mmol) in THF (50 mL) was added HOBt (1.77 g, 13.1 mmol), EDCI.HCI (2.30 g, 12 mmol), DIPEA (1.90 mL, 10.9 mmol) and methylamine (5.46 mL, 10.9 mmol). The reaction was stirred at room température for 15 minutes followed by reflux for 30 minutes. The reaction was poured into saturated aqueous NaHCO3 solution and extracted into EtOAc. The organic layer was collected dried over sodium sulfate and concentrated in vacuo. The residue was purified using silica gel column chromatography to afford the title compound.

Préparation 57

Methyl 2-(3-chloro-5-nitropyridin-2-vl)acetate

To a solution of 1-(tert-butyl) 3-methyl 2-(3-chloro-5-nitropyridin-2-yl)maionate (Préparation 58, 6.6 g, 20 mmol) in DCM (100 mL) was added TFA (100 mL) and the reaction was stirred at room température for 20 hours. The reaction was concentrated in vacuo to afford the title compound as the trifluoroacetate sait (6.8 g,100%).

Préparation 58 l-(tert-Butyl) 3-methvl 2-(3-chloro-5-nitropvridin-2-yl)malonate

To a solution of NaH (6 g, 150 mmol) in DMF(30 mL) was added tert-butylmethylmalonate (5 g, 28.7 mmol) slowly. The mixture was stirred at room température for 30 minutes before the addition of 2,3dichloro-5-nitropyridine (5 g, 26 mmol) dropwise. The reaction was stirred at room température for 2 hours. The reaction was concentrated in vacuo and purified by silica gel column chromatography to get afford the title compound (6.6 g, 77%) as red oil.

Préparation 59 (S)-1-(3-Fluoro-5-nitropvridin-2-vl)pyrrolidin-3-oi

To a mixture of NaH (227 mg, 5.68 mmol, 60%) in DME (30 mL) was added (S)-pyrrolidin-3-ol (494 mg, 5.68 mmol) and the reaction was stirred at room température for 1 hour. A solution of 2-chloro-4fIuoro-5-nitropyridine (250 mg, 1.42 mmol) in DME (10 mL) was added at 10°C and stirred at room température for 1 hour. The reaction was quenched with water (30 mL) and extracted with EtOAc (100 mL x 2). The organic layers were combined, concentrated in vacuo and purified by silica gel column chromatography eluting with 0-50% EtOAc in petroleum ether to afford the title compound (250 mg, 77%) as yellow solid.

The following préparations were prepared according to the method described by Préparation 59 using the appropriate fluoropyridine as described.

Préparation number	Structure	Name	SM/Data
60	pH O₂N^T	(R)-1-(3-fluoro-5-nitropyridin- 2-yl)pyrrolidin-3-ol	(R)-pyrrolidin-3-ol. ¹H NMR (400MHz, DMSOds): δ ppm 1.82-2.05 (m, 2H), 3.58-3.92 (m, 4H), 4.34-4.44 (m, 1H), 5.09 (d, 1H), 8.16 (dd, 1H), 8.84 (dd, 1H).
61	N N-J OgN-^^^F	1 -(3-fluoro-5-nitropyridin-2- yl)azetidin-3-ol	Azetidinol. ¹H NMR (400MHz, DMSOde): δ ppm 3.98-4.09 (m, 2H), 4.47-4.55 (m, 2H), 4.58-4.69 (m, 2H), 5.87 (d, 1H), 8.13-8.21 (m, 1H), 8.75-8.88 (m, 1H).
62	/fk f T ^0HO₂N'^<x'^/OI	2-((3-chloro-5-nitropyridin-2- yl)oxy)ethan-1-ol	Ethane-1,2-diol. Taken on directly to the next step.

Préparation 63

Methyl 4-((tert-butoxvcarbonvl)amino)-6-(hvdroxvmethyl)picolinate

To a solution of dimethyl 4-((tert-butoxycarbonyl)amino)pyridine-2,6-dicarboxylate (Préparation 64, 300 mg, 0.967 mmol), in DCM (2 mL) and MeOH (1 mL) at 0°C was added sodium borohydride (38 mg, 0.966 mmol). The reaction was stirred at this température for 30 minutes, further sodium borohydride (17 mg, 0.483 mmol) was added and the reaction stirred at room température for 18

hours. The reaction was quenched by the addition of 1:1 brine:water and extracted into EtOAc five times. The organic layers were combined, dried over sodium sulfate and concentrated in vacuo to afford the title compound as a white solid (232 mg, 85%). MS m/z 281 [M-H]·

Préparation 64

Dimethyl 4-((tert-butoxycarbonvl)amino)pyridine-2,6-dicarboxylate

To a solution of dimethyl 4-bromopyridine-2,6-dicarboxylate (2.4 g, 8.76 mmol) in dioxane (30 mL) was added tert-butylcarbamate (1.13 g, 9.63 mmol), Pd2(dba)3 (246 mg, 0.263 mmol), xantphos (207 mg, 0.350 mmol) and césium carbonate (5.7 g, 17.5 mmol). The reaction was degassed with argon and heated to 85°C for 18 hours. The reaction was cooled, concentrated in vacuo and purified using silica gel column chromatography eluting with 20% EtOAc in heptanes to afford the title compound (1.2 g, 44%). ’H NMR (400MHz, CDCL): δ ppm 1.55 (s, 9H), 4.05 (s, 6H), 7.30 (d, 1H), 8.35 (d, 1H).

Préparation 65

5-((di-[tert-Butoxvcarbonvl1)amino)-3-fluoropicolinic acid

To a solution of ethyl 5-((di-[tert-butoxycarbonyl])amino)-3-fluoropicolinate (Préparation 66, 3.3 g, 8.59 mmol) in THF:water (46 mL,15:8) was added LiOH (0.72 g, 17.12 mmol) at room température. The reaction was stirred at room température for 4 hours. The reaction was acidified to pH 3 by the addition of citric acid at 0°C and extracted with ethyl acetate (50 mL x 2). The combined organic layers were concentrated in vacuo to afford the title compound as a white solid (2.6 g, 86%).

MS m/z 357 [M+HJPréparation 66

Ethyl 5-((di-itert-butoxvcarbonyl1)amino)-3-fluoropicolinate

To a solution of di-[tert-butyl carbamate]-(6-bromo-5-fluoropyridin-3-yl) (Préparation 67, 3.7 g, 9.46 mmol) in éthanol (100 mL) was added Pd(OAc)2 (1.6 g, 7.53 mmol), DPPP (3.12 g, 7.56 mmol) and triethylamine (5.4 g, 53.46 mmol). The reaction was heated to 60°C under an atmosphère of carbon monoxide at 50psi for 18 hours. The reaction was filtered and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with 10% EtOAc in petroleum ether to afford the title compound (3.3 g, 90%).

Préparation 67 di-ltert-Butyl carbamate1-(6-bromo-5-fluoropyridin-3-vl)

To a solution of 6-bromo-5-fluoro-3-pyridinamine (2.6 g, 13.6mmol) in THF (100 mL) was added ditertbutyldicarbonate (8.81 g, 40.8 mmol), DIPEA (5.26 g, 40.8 mmol) and DMAP (83.2 mg, 0.68 mmol) at room température. The reaction was heated to reflux for 4 hours. The reaction was concentrated in vacuo and purified by silica gel column chromatography eluting with 10% EtOAc in petroleum ether to afford the title compound that was taken on directly to the next step (3.7 g, 56%).

Préparation 68 (S)-2,2-Difluorocyclopropane-1-carboxvlic acid

To a solution of (S)-l-phenylethyl (S)-2,2-difluorocyclopropane-1-carboxylate (Préparation 70, 3.67 g, 16.2 mmol) in MeOH (48 mL) was added 1N NaOH (48 mL, 48 mmol) and the reaction was stirred at room température for 1.5 hours. The reaction was concentrated in vacuo, acidified to pH=5.8 using 12N HCl (aq) and extracted into nBuOH. The organic layer was collected and concentrated in vacuo

to afford the title compound (1.5 g, 76%). ¹H NMR (400MHz, DMSO-de): δ ppm 1.90 (m, 2H), 2.65 (m, 1H).

Préparation 69 (R)-2,2-Difluorocyclopropane-1-carboxylic acid

The title compound was prepared according to the method described for Préparation 68 using (S)-1 phenylethyl(R)-2,2-difluorocyclopropane-1-carboxylate (Préparation 71).

Préparations 70 and 71 (S)-1-Phenvlethyl(S)-2,2-difluorocvclopropane-1-carboxylate and (S)-1-phenylethvl(R)-2,2difluorocvclopropane-1-carboxvlate

To a solution of 2,2-difluoro-cyclopropanecarboxylic acid (4.02 g, 33 mmol) in DCM (140 mL) was added DCC (8.16 g, 39 mmol) followed by DMAP (403 mg, 3.30 mmol) and the reaction was stirred for 10 minutes. (S)-1-phenylethan-1-ol (4.83 g, 39 mmol) was added and the reaction stirred at room température for 72 hours. The reaction was filtered, concentrated in vacuo and purified using silica gel column chromatography eluting with 0-5% EtOAc to afford the title compounds as a mixture of diastereomers. The diastereomers were separated using chromatography as described below: Kromasil Silica 10um, 4.6x250mm; run time 14 minutes; 1.0 mL/min; eluting with 3% MTBE in heptanes.

Peak 1: Rt = 5.34 minutes; (S)-1-phenylethyl(S)-2,2-difluorocyclopropane-1-carboxylate (Préparation 70). ¹H NMR (400MHz, CDCh): δ ppm 1.61 (d, 3H), 1.74-1.79 (m, 1H), 2.06-2.12 (m, 1H), 2.45-2.53 (m, 1 H), 5.95-6.00 (m, 1 H), 7.33-7.42 (m, 5H).

Peak 2: Rt = 6.22 minutes; (S)-1-phenylethyl(R)-2,2-difluorocyclopropane-1-carboxylate (Préparation 71). ¹H NMR (400MHz, CDCh): δ ppm 1.61 (d, 3H), 1.74-1.79 (m, 1H), 2.06-2.12 (m, 1H), 2.45-2.53 (m, 1H), 5.95-6.00 (m, 1H), 7.33-7.42 (m, 5H).

Préparation 72 (1 R,2R)-2-Cvanocyclopropane-1-carboxylic acid

To a solution of benzyl (1 R,2R)-2-cyanocyclopropane-1-carboxylate (Préparation 74, 100 mg, 0.5 mmol) in anhydrous THF (10 mL) was added wet Pd/C (10 mg). The reaction was degassed, then stirred at room température under a balloon of hydrogen for 1 hour. The reaction was filtered and the 30 filtrate concentrated in vacuo to afford the title compound as a white solid that was used directly in the next step (56 mg, 100%).

Préparation 73 (1S,2S)-2-Cyanocyclopropane-1-carboxylic acid

The title compound was prepared according to the method described for Préparation 72 using benzyl 35 (1 S,2S)-2-cyanocyclopropane-1-carboxylate (Préparation 75).

Préparations 74 and 75

Benzvl(1R.2R)-2-Cvanocyclopropane-1-carboxylate and Benzvl(1S,2S)-2-Cyanocyclopropane-1carboxylate

To a solution of trans-racemic ethyl 2-cyanocyclopropane-1-carboxylate (Préparation 77, 24.7 g, 0.17 mol) in THF (400 mL) and water (200 mL) was added lithium hydroxide (14.9 g, 0.35 mol) and the reaction was stirred at room température for 2 hours. The reaction was diluted with water (20 mL) and extracted with DCM (2x30 mL). The aqueous layer was acidified to pH 2 with 1M HCl and extracted into EtOAc three times (3x400 mL). The combined organic layers were washed with brine, dried over sodium sulfate and concentrated in vacuo.The residue was recrystallized from ether to afford the carboxylic acid. To a portion of the acid (8 g, 0.072 mol) in DMF (150 mL) was added césium carbonate (25.8 g, 0.35 mol) followed by benzyl bromide (13.6 g, 0.08 mol) and the reaction was stirred at room température for 18 hours. The reaction was diluted with water (300 mL) and extracted with EtOAc three times (3x400 mL). The combined organic layers were washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with 10-70% EtOAc in petroleum ether to afford the title compound as the trans-racemate (13.6 g, 94%).

The trans-racemate was separated by chiral chromatography as described below:

Column: OD 300mmx50mmx10pm.

Mobile phase: A: Supercritical CO2, B: EtOH(0.1%NH3H2O), A:B = 90:10; Flow rate: 180mL/min Preperation 74: Benzyl (1 S,2S)-2-cyanocyclopropane-1-carboxylate (5.80 g, 43%)

Peak 1, Rt = 3.61 minutes; ¹H NMR (400MHz, CDCh): δ ppm 1.50-1.56 (m, 2H), 1.96-1.99 (m, 1H),

2.29- 2.32 (m, 1H), 5.16 (s, 2H), 7.35-7.41 (m, 5H).

Preperation 75: Benzyl (1R,2R)-2-cyanocyclopropane-1-carboxylate (5.82 g, 43%)

Peak 2, Rt = 3.87 minutes; ¹H NMR (400MHz, CDCh): δ ppm 1.50-1.56 (m, 2H), 1.96-1.98 (m, 1H),

2.30- 2.32 (m, 1H), 5.16 (s, 2H), 7.35-7.41 (m, 5H).

Préparations 76 and 77 cis-racemic and trans-racemic Ethyl 2-cvanocyclopropane-1-carboxvlate

Acrylonitrile (70 g, 1.32 mol) was stirred under reflux as ethyl diazoacetate (70 g, 0.614 mol) was added portion wise over period of 2.5 hours. After completion of the addition, the mixture was stirred at reflux for an additional 1.5 hours, before removing the excess acrylonitrile by distillation. The reaction was then heated to 125-130°C and maintained there until nitrogen évolution ceased and the reaction was heated to 160-170°C for 1 hour before cooling to room température under nitrogen. The reaction was distiiled under vacuum and the product purified by silica gel column chromatography eluting with 10-50% EtOAc in petroleum ether afford trans-racemic ethyl 2-cyanocyclopropane-1carboxylate as the first eluting compound (24 g, 28%) and cis-racemic ethyl 2-cyanocyclopropane-1carboxylate as the second eluting compound (17 g, 20%).

Préparation 76;

¹H NMR (400MHz, CDCh): δ ppm 1.30 (m, 3H), 1.42 (m, 1H), 1.67 (m, 1H), 1.82 (m, 1H), 2.10 (m,

H), 4.23 (m,2H)

Préparation 77;

¹H NMR (400MHz, CDCh): δ ppm 1.28 (m, 3H), 1.42 (m, 1H), 1.66 (m, 1H), 1.82 (m, 1H), 2.10 (m,

1H), 4.23 (m, 2H); MS m/z 140 [M+H]⁺

Préparation 78

N-(2-Cyanoethyl)-1 H-imidazole-1-carboxamide

To a solution of CDI (250 mg, 1.56 mmol) and triethylamine (236 mg, 2.34 mmol) in anhydrous THF (15 mL) was added a solution of 2-cyanoethylamine (100 mg, 0.78 mmol) in anhydrous THF (5 mL) at 0°C and the reaction was stirred at room température for 18 hours The reaction was concentrated in vacuo and purified by silica gel column chromatography eluting with EtOAc to afford the title compound as a colourless oil (44 mg, 34%). ¹H NMR (400MHz, CDCh): δ ppm 2.79 (t, 2H), 3.47 (q, 2H), 7.12 (s, 1 H), 7.50 (s, 1 H), 7.66 (brs, 1H), 8.39 (s, 1H).

Préparation 79

N-(Cyanomethvl)-1 H-imidazole-1-carboxamide

To a solution of aminoacetonitrile bisulfate (436 mg, 2.75 mmol) and 1,1'-carbonyldiimidazole (500 mg, 3.0 mmol) in acetonitrile (3 mL) was added N,N-dimethylformamide (1 mL) and the reaction stirred at room température in a sealed vessel for 18 hours. The residue was concentrated in vacuo, taken up in DCM and filtered. The filtrate was purified using silica gel column chromatography eluting with 0-10% MeOH in DCM to afford the title compound.

¹H NMR (400MHz, CDCh): δ ppm 3.50 (s, 2H), 7.18 (d, 1H), 7.30 (d, 1H), 7.75 (s, 1H).

Préparation 80

N-Ethvl-1 H-imidazole-1 -carboxamide

Ethylamine hydrochloride (1.78 g, 21 mmol) and CDI (4.20 g, 25 mmol) was stirred at room température in MeCN (20 mL) for 3 hours. The reaction was diluted with DCM, filtered and concentrated in vacuo. The residue was further diluted with DCM, filtered, and purified using silica gel column chromatography eluting with 0-10% MeOH in DCM to afford the title compound.

¹H NMR (400MHz, CDCh): δ ppm 1.88 (t, 3H), 3.50 (m, 2H), 6.35 (br s, 1H), 7.10 (d, 1H), 7.40 (d, 1 H), 8.20 (s, 1H).

Préparation 81

N-lsopropyl-1 H-imidazole-1 -carboxamide

The title compound was prepared according to the method described for Préparation 80 using isopropylamine hydrochloride with DMF (1 mL). The residue was suspended in EtOAc, filtered, the filtrate washed with brine, concentrated in vacuo and taken directly on to the next step.

¹H NMR (400MHz, CDCh): δ ppm 1.20 (m, 6H), 4.10 (m, 1H), 6.95 (s, 1H), 7.50 (d, 1H), 7.80 (d, 1H), 7.80 (m, 1H), 8.20 (d, 1H).

Préparation 82

N-(2.2,2-Trifluoroethvl)-1 H-imidazole-1-carboxamide

The title compound was prepared according to the method described for Préparation 80 using 2,2,2trifiuoroethan-1-amine hydrochloride with DMF. ¹H NMR (400MHz, CDCh): δ ppm 4.00 (m, 2H), 7.00 (d, 1H), 7.60 (d, 1H), 8.25 (s, 1H), 9.00 (brs, 1H).

Préparation 83

5-Amino-N-propyl-1 H-pyrazole-3-carboxamide hydrochloride

A solution of 1-(tert-butyl) 3-ethyl 5-amino-1H-pyrazole-1,3-dicarboxylate (Préparation 84, 7.5 g, 29 mmol) in propylamine (40 mL) was heated to reflux for 48 hours. The reaction was cooled, concentrated in vacuo and dissolved in DCM (20 mL). 4N HCl in dioxane (20 mL) was added and the reaction stirred at room température for 2 hours. The resulting solid was filtered, washed with tertbutyl ether and dried. The solid was recrystaliised from 2:1 EtOAc: I PA with decolourising charcoal to afford the title compound as the hydrochloride sait (5.1 g, 85%).

¹H NMR (400MHz, MeOH-d₄): δ ppm 0.95 (t, 3H), 1.60 (m, 2H), 3.30 (m, 4H), 5.90 (brs, 1H).

Préparation 84

1-(tert-Butvl) 3-ethyl 5-amino-1H-pyrazole-1,3-dicarboxvlate

To a solution of tert-butyl (Z)-2-(1-cyano-2-ethoxy-2-oxoethylidene)hydrazine-1-carboxylate (Préparation 85, 10.5 g, 41 mmol) in acetonitrile (150 mL) was added triethylamine (17.4 mL, 123 mmol) and the reaction was stirred at room température for 3 hours. The reaction was concentrated in vacuo and purified using silica gel column chromatography eluting with from 20-80% EtOAc in heptanes.

<H NMR (400MHz, CDCIs): δ ppm 1.40 (t, 3H), 1.60 (s, 9H), 4.40 (q, 2H), 5.40 (brs, 2H), 5.95 (s, 1H).

Préparation 85 tert-Butvl (Z)-2-(1-cvano-2-ethoxv-2-oxoethvlidene)hvdrazine-1-carboxylate

To a solution of sodium ethylate (21% solution in EtOH, 51 mL, 137 mmol) in diethylether (30 mL) was added a solution of diethyl oxalate (20 g, 140 mmol) in diethylether (80 mL) dropwise over 15 minutes at 0°C followed by stirring at this température for 1 hour. Acetonitrile (7.15 mL, 137 mmol) was added slowly and the reaction stirred at room température for 18 hours. The resulting precipitate was filtered, washed with 1:1 ether:ethanol and dried under vacuum. The solid (8.7 g, 53 mmol) was dissolved in éthanol (25 mL) and acetic acid (3.2 g, 53 mmol) and cooled to 0°C. tert-Butyl hydrazinecarboxylate (7.75 g, 59 mmol) was added and the reaction stirred at 0°C for 1 hour followed by room température for 18 hours. The reaction was concentrated in vacuo and partitioned between EtOAc and saturated aqueous sodium carbonate solution. The organic layer was collected, dried over sodium sulfate and concentrated in vacuo to afford the title compound as an orange solid (10.5 g, 77%).

Préparation 86

6-Aminoimidazori,2-alpyridine-2-carboxamide

To a solution of ethyl 6-aminoimidazo[1,2-a]pyridine-2-carboxyiate (Préparation 87, 2 g, 0.0074mol) in MeOH (30 mL) was added ammonia (3 g, 0,044 mol) and the reaction was heated to 100°C in a sealed vessel for 24 hours. The reaction was cooled and concentrated in vacuo to afford the title compound (1.9 g, 90%).

Préparation 87

Ethyl 6-aminoimidazo[1,2-alpyridine-2-carboxylate

To a solution of 2-amino-5-bromopyridine (5 g, 0.029 mol) in éthanol (180 mL) was added ethyl 3bromo-2-oxopropanoate (5.64 g, 0.029 mol) and NaHCCh (4.86 g, 0.058 mol) and the reaction was heated to reflux for 18 hours. The reaction was cooled, concentrated in vacuo and partitioned between EtOAc and saturated aqueous sodium carbonate solution. The organic layer was collected, washed with brine, dried over magnésium sulfate and concentrated in vacuo. The residue was purified using silica gel column chromatpgraphy eluting with 30% EtOAc in petroleum ether to afford the title compound (4.2 g, 45%).

Préparation 88 (S)-N-((1S,5S)-3-(2-Chloro-5-fluoropvrimidin-4-vl)-5-(hvdroxvmethvl)-3-azabicycloi3.1.01hexan-1-vl)2,2-difluorocyclopropane-1-carboxamide

The title compound was prepared according to the method described for Préparation 27 using racemic-(5-amino-3-(2-chloro-5-fluoropyrimidin-4-yl)-3-azabicycio[3.1.0]hexan-1-yl)methanol (Préparation 99) and (S)-2,2-difluorocyclopropane-1-carboxylic acid (Préparation 68) with DIPEA in DCM. The racemic residue was purified using silica gel column chromatography eluting with 50-100% EtOAc in heptanes. The second, more polar eluting isomer was collected as the title compound.

MS m/z 363 [M+H]⁺

Préparation 89

Racemic-H R,2R)-N-('3-('2-Chloro-5-fluoropvrimidin-4-yl)-5-(^,hvdroxvmethvl)-3-azabicyclof3.1.0lhexan1-yl)-2-cvanocyclopropane-1-carboxamide

The racemic title compound was prepared according to the method described for Préparation 27 using racemic-(5-amino-3-(2-chloro-5-fluoropyrimidin-4-yl)-3-azabicyclo[3.1.0]hexan-1-yl)methanol (Préparation 99) and (1R,2R)-2-cyanocyclopropane-1-carboxylic acid (Préparation 72) with DIPEA in DCM. The residue was purified using silica gel column chromatography eluting with 50-100% EtOAc in heptanes. MS m/z 352 [M+H]⁺

Préparation 90 (1S,5R,6R')-3-(5-Fluoro-2-((1-methvl-1H-pvrazol-4-yhamino]pvrimidin-4-yl')-6-methvl-3azabicyclo[3.1 .OIhexan-1-amine hydrochloride

To a solution of tert-butyl ((1S,5R,6R)-3-(2-chloro-5-fluoropyrimidin-4-yl)-6-methyl-3-azabicyclo[3.1.0]hexan-1-yl)carbamate (Préparation 94, 1 g, 2.91 mmol) in isopropanol_(10 mL) was added 1methyl-1H-pyrazol-4-yIamine hydrochloride (506 mg, 3.79 mmol) and the reaction was heated to 140°C under microwave irradiation for 1 hour. The resulting solid was filtered and dried to afford the title compound as the hydrochloride sait (991 mg, 86%). MS m/z 304 [M+H]⁺

The following préparations were prepared according to the method described by Préparation 90 or Préparation 1 using the appropriate halide and the appropriate amine as described below. The compounds were isolated as the hydrochloride salts unless otherwise specified.

Deprotection Method B: The Boc-protected intermediate was dissolved in DCM, treated with TFA and stirred at room température for 18 hours. The reaction was basified to pH=10 by the addition of triethylamine. The solution was concentrated in vacuo and purified by silica gel column chromatography eluting with 10% MeOH in DCM.

Préparation number	Structure	Name	SM/Data
91		Me			(1R,5S,6S)-3-(5-fluoro-2-	tert-butyl ((1 R,5S,6S)-3-(2-
		i			((1-methyl-1 H-pyrazol-4-	chloro-5-fluoropyrimidin-4-
	H₂N	..A..	H		yl)amino)pyrimidin-4-yI)-6-	yl)-6-methyl-3-
				methyl-3-	azabicyclo[3.1,0]hexan-1-
		V i			azabicyclo[3.1.0]hexan-1-	yl)carbamate (Préparation
			Me	amine hydrochloride	96) and 1-methyl-1H-
		A		A		pyrazol-4-ylamine
			JAn		hydrochloride.
			''N' H	AA		MS m/z 304 [M+HJ-
92		Me			2-((5-((4-((1S,5R,6R)-1-	tert-butyl ((1S,5R,6R)-3-(2-
		Â			amino-6-methyl-3-	chloro-5-methylpyrimidin-4-
	h₂n-	AA	H		azabicyclo[3.1.0]hexan-3-	yl)-6-methyl-3-
		/ \		yl)-5-methylpyrimidin-2-	azabicyclo[3.1,0]hexan-1-
		V I			yl)amino)pyridin-2-	yl)carbamate (Préparation
	Me_x		Γ^ΝΤ°Ί	yl)oxy)ethan-1-ol	97) and 2-[(5-amino-2pyridinyl)oxy]-ethanol. Taken on directly to the next
Ά
		TT	H			step.
93		Me			(1S,5R,6R)-3-(5-fluoro-2-	tert-butyl ((1 R,5S,6S)-3-(2-
					((1-(oxetan-3-yl)-1 H-	chloro-5-fluoropyrimidin-4-
	h₂n-	V-H		pyrazol-4-	yl)-6-methyl-3-
					yl)am ino)pyrim idin-4-yl)-6-	azabicyclo[3.1.0]hexan-1-
		N			methyl-3-	yl)carbamate (Préparation
	R			r=N	azabicyclo[3.1,0]hexan-1-	96) and 1-(oxetan-3-yl)-1H-
		A N		amine	pyrazol-4-amine
		AA	N H	^/^N A°		(Préparation 123) with
		N			deprotection method B.

Préparation 94 tert-Butyl ((1S,5R,6R)-3-(2-chloro-5-fluoropvrimidin-4-vl)-6-methvl-3-azabicyclo[3.1.01hexan-1vljcarbamate

To a solution of tert-butyl ((1S,5R,6R)-6-methyl-3-azabicyclo[3.1.0]hexan-1-yl)carbamate (Préparation 101, 1.8 g, 8.50 mmol) and triethylamine (1.7 g, 16.8 mmol) in MeOH (100 mL) was added 2,4-dichloro-5-fluoropyrimidine (1.5 g, 9.03 mmol), and the reaction was stirred at room température for 18 hours. The reaction was concentrated in vacuo and purified directly using silica gel column chromatography eluting with 20% EtOAc in petroleum ether to afford the title compound as a white solid (2 g, 69%). ¹H NMR (400MHz, DMSO-de): δ ppm 0.98 (d, 3H), 1.39 (m, 1H), 1.45 (br s,

9H), 1.80 (m, 1H), 3.67-4.17 (m, 4H), 5.05 (m, 1H), 7.86 (d, 1H). MS m/z 343 [M+H]⁺ Chiral

Analytical Column: Chiralpak AD-3 150mmx4.6 mm I.D., 3 pm; Rétention Time: 3.83 minutes; 100% ee. Mobile phase: Methanol (0.05% Ethanolamine) in CO2 from 5% to 40%, Flow rate: 2.5 mL/min

Préparation 95 and 95A

N-((1S.5R.6R)-3-(2-Chloro-5-fluoropvrimidin-4-vl)-6-methyl-3-azabicyclor3.1.01hexan-115 vDcyclopropanecarboxamide and N-((1 R.5S,6S)-3-(2-chloro-5-fluoropvrimidin-4-vl)-6-methvl-3azabicvcloi3.1.01hexan-1-vl)cvclopropanecarboxamide

The title compounds were prepared as a trans-racemic mixture according to the method described by Préparation 94 using trans-racemic-6-methyl-3-azabicyclo[3.1.0]hexan-1-yl)cyclopropanecarboxamide (Préparation 102). GCMS Rt = 5.91 minutes MS m/z 310 [M] N-((1S,5R,6R)-3-(2-chloro-5-fluoropyrimidin-4-yl)-6-methyl-3-azabicyclo[3.1.0]hexan-1yl)cyclopropanecarboxamide may also be prepared as the single enantiomer according to the methods described by Préparations 94 and 102 using N-((1S,5R,6R)-3-benzyi-6-methyl-3azabicycio[3.1.0]hexan-1-yl)cyclopropanecarboxamide (Préparation 107A).

Préparation 96 tert-Butyl ((1R,5S.6S)-3-(2-chloro-5-fluoropvrimidin-4-vl)-6-methvl-3-azabicvclo[3.1.0lhexan-1vDcarbamate

The title compound was prepared according to the methods described for Préparations 105, 101 and 94 using (1R,5S,6S)-3-benzyl-6-methyl-3-azabicyclo[3.1.0]hexan-1-amine (Préparation 110).

Préparation 97 tert-Butvl ((1S,5R,6R)-3-(2-chloro-5-methvlpyrimidin-4-vl)-6-methyl-3-azabicyclo[3.1.0lhexan-1vDcarbamate

The title compound was prepared according to the method described for Préparation 94 using tertbutyl ((1S,5R,6R)-6-methyl-3-azabicyclo[3.1.0]hexan-1-yl)carbamate (Préparation 101) and 2,4dichloro-5-methylpyrimidine. LCMS Rt = 0.90 minutes; MS m/z 339 [M+H]⁺

Préparation 98

Racemic-N-(3-(2,5-Dichloropvrimidin-4-vl)-3-azabicvcloi3.1.0lhexan-1-vl)cyclopropanecarboxamide The title compound was prepared according to the method described for Préparation 94 using racemic-N-(3-azabicyclo[3.1.0]hexan-1-yl)cyclopropanecarboxamide (Préparation 103) and 2,4,5trichloropyrimidine. The residue was purified using silica gel column chromatography eluting with 10% MeOH in DCM.

Préparation 99

Racemic-(5-Amino-3-(2-chloro-5-fluoropvrimidin-4-vl)-3-azabicvclor3.1.0lhexan-1-vl)methanol

To a solution of racemic-tert-butyl (5-(((tert-butyldimethylsilyl)oxy)methyl)-3-(2-chloro-5fluoropyrimidin-4-yl)-3-azabicyclo[3.1.0]hexan-1-yl)carbamate (Préparation 100, 1.25 g, 2.64 mmol) in DCM (25 mL) was added TFA (5 mL) and the reaction was stirred at 0°C for 30 minutes followed by room température for 3 hours. The reaction was quenched with saturated aqueous NaHCO3 solution, basified to pH = 12 with solid NaOH and extracted into DCM. The organic layer was collected, dried over sodium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with 0-5% MeOH in DCM to afford the title compound (200 mg, 30%).

LCMS Rt = 0.49 minutes; MS m/z 261 [M³⁷CI+H]⁺

Préparation 100

Racemic-tert-Butyl (5-(((tert-butvldimethvlsilvDoxv)methvl)-3-(2-chloro-5-fluoropvrimidin-4-vl)-3azabicyclor3.1.01hexan-1-vDcarbamate

The title compound was prepared according to the method described for Préparation 94 using racemic-tert-butyl (5-(((tert-butyldimethylsilyl)oxy)methyl)-3-azabicyclo[3.1.0]hexan-1-yl)carbamate (Préparation 104) and 2,4-dichloro-5-fluoropyrimidine. MS m/z 473 [M+H]⁺

Préparation 101 tert-Butyl ((1S,5R,6R)-6-methvl-3-azabicvclof3.1.0lhexan-1-vl)carbamate

To a solution of tert-butyl ((1S,5R,6R)-3-benzyl-6-methyl-3-azabicyclo[3.1.0]hexan-1-yl)carbamate (Préparation 105, 3.4 g, 0.326 mmol) in MeOH (200 mL) was added Pd(OH)2 (20%, 3 g) and the 5 reaction was hydrogenated under 50 psi of hydrogen at room température for 2 days. The reaction was filtered and concentrated in vacuo to afford the title compound give (2.3 g, 100%).

The following préparations were prepared according to the method described by Préparation 101 or

Préparation 1 using the appropriate benzyl protected intermediate as described below:

Préparation number	Structure	Name	SM/Data
102	/P	Me		N-((1S,5R,6R)-6-methyl-	GCMS Rt = 3.64 minutes
	N-	Â		3-azabicyclo[3.1 .OJhexan-	MS m/z 181 [M]
	-A	—H	1-yl)cyclopropane-	Trans-racemic 3-benzyl-6-
	H	/	carboxamide and N-	methyl-3-azabi-
		V H		((1 R,5S,6S)-6-methyl-3-	cyclo[3.1.0]hexan-1-
			azabi-cyclo[3.1.0]hexan-	yl)cyclopropanecarboxamid
	n	Me		1-yl)cyclopropane-	e (Préparation 107).
	0-4 N· H	N^X H	·· H	carboxamide	Isolated as the transracemic mixture.
103	/P			Racemic-N-(3-azabi-	Racemic-N-(3-benzyl-3-
	OH N-	A		cyclo[3.1.0]hexan-1-	azabicyclo[3.1.0]hexan-1-
	-A	—H	yl)cyclo-	yl)cyclopropanecarboxamid
	H	V H	propanecarboxam ide	e (Préparation 108) with Pd/C. Taken on directly to the next step.

104		A		Racemic-tert-butyl (5-	Racemic-tert-butyl (3-ben-
	BocNH—Y	A-	Λ OTBDMS	(((tert-butyldimethyl-	zyl-5-(((tert-butyldimeth-
	7		silyl)oxy)methyl)-3-	y(silyl)oxy)methyl)-3-
		F H	azabicyclo[3.1.0]hexan-1-	azabicyclo[3.1,0]hexan-1-
			yl)carbamate	yl)carbamate (Préparation 106). Taken on directly to the next step.

Préparation 105 tert-Butyl ((1S,5R,6R)-3-benzvl-6-methyl-3-azabicvctof3.1.0lhexan-1-vl)carbamate

To a solution of (1S,5R,6R)-3-benzyl-6-methyl-3-azabicyclo[3.1.0]hexan-1-amine (Préparation 109, 2.5 g, 0.0123 mol) and triethylamine (2.5 g, 0.0247 mmol) in DCM (50 mL) was added ditertbutyldicarbonate (2.6 g, 0.0130 mmol) and the reaction was stirred at room température for 18 15 hours. The reaction was filtered and the filtrate was purified directly by silica gel column chromatography eluting with 10% EtOAc in petroleum ether to afford the title compound as a yellow oil (3.4 g, 91%).

Préparation 106

Racemic-tert-Butyl (3-benzvl-5-(((tert-butvldimethvlsilvl)oxy)methvl)-3-azabicycloF3.1.01hexan-1vDcarbamate

The title compound was prepared according to the method described for Préparation 105 using racemic-3-benzyl-5-(((tert-butyldimethylsilyi)oxy)methyl)-3-azabicyclo[3.1.0]hexan-1-amine (Préparation 111) in TBME. MS m/z 433 [M+H]⁺

Préparation 107

N-((1S.5R.6R)-3-Benzvl-6-methvl-3-azabicycloF3.1.01hexan-1-vl)cyclopropanecarboxamide and N((1R,5S,6S)-3-benzvI-6-methyl-3-azabicvclo[3.1.0lhexan-1-yl)cyclopropanecarboxamide

To a solution of trans-racemic-3-benzyl-6-methyl-3-azabicyclo[3.1.0]hexan-1-amine (Préparations 109 and 110, 700 mg, 3.46 mmol) in DCM (15 mL) was added DIPEA (1.20 mL, 6.92 mmol) followed by cyclopropylcarbonyl chloride (362 mg, 3.46 mmol) and the reaction was stirred at room température for 2 hours. The reaction was concentrated in vacuo and purified directly using silica gel column chromatography eluting with 10-100% EtOAc in heptanes to afford the trans-racemic mixture of the title compounds (400 mg, 43%).

N-((1S,5R,6R)-3-benzyl-6-methyl-3-azabicyclo[3.1.0]hexan-1-yl)cyclopropanecarboxamide may also be prepared as the single enantiomer according to this préparation using (1S,5R,6R)-3-benzyl-6methyl-3-azabicyclo[3.1.0]hexan-1-amine (Préparation 667C).

Préparation 108

Racemic-N-(3-Benzvl-3-azabicvclor3.1.0lhexan-1-vl)cvclopropanecarboxamide

The title compound was prepared according to the method described by Préparation 107 using racemic-3-benzyl-3-azabicyclo[3.1.0]hexan-1 -amine (Tetrahedron L., (2003), 44 (12), 2485-2487) and triethylamine with cyclopropylcarbonyl chloride. The residue was purified directly using silica gel column chromatography eluting with 10% MeOH in DCM.

Préparations 109 and 110 (1S,5R.6R)-3-Benzyl-6-methvl-3-azabicvclor3.1.01hexan-1-amine and (1R,5S,6S)-3-benzyl-6-methyl3-azabicvcloi3.1.0lhexan-1-amine

To a solution of (Z)-2-(benzyl(but-2-en-1-yl)amino)acetonitrile (Préparation 112, 64 g, 0.32 mol) in anhydrous THF (2 L) under nitrogen was added Ti(O'Pr)4 (300 g, 1.05 mol) followed by cyclohexylmagnesium chloride (2M solution in ether, 800 mL, 1.6 mol) dropwise at 20-30°C over 1.5 hours. The reaction was then stirred at room température for 2 hours. The reaction was quenched by the addition of 10% aqueous NaOH (1 L) and stirred for 1 hour before filtering and concentrating in vacuo. The residue was dissolved in DCM (6 L), washed with water (2 L), dried over sodium sulfate and concentrated in vauco. The residue was purified using silica gel column chromatography eluting with 10% MeOH in DCM to afford the trans-racemic mixture ofthe title compounds (827 g, 36%).

¹H NMR (400MHz, CDCh): δ ppm 1.07-1.08 (m, 1H), 1.18-1.21 (m, 1H), 1.25-1.28 (d, 3H), 2.54-2.56 (d, 1H), 2.76-2.81 (m, 2H), 3.05-3.07 (d, 1H), 3.55 (s, 2H), 7.21-7.31 (m, 5H). MS m/z 203 [M+H]⁺The trans-racemic compound may be separated into its enantiomers using chiral chromatography as described below:

Φ

Chiral column: IC 300mmx50mmx10pm; Mobile phase: A: Supercritical CO2, B: MeOH (with 0.1% aqueous ammonia), A:B = 75:25 at 200 mL/min

Chiral LCMS QC:

Chiralpak Pheno Lux Cellulose-2; 150mmx4.6mm I.D. 5pm; mobile phase MeOH (0.05% 5 ethanolamine) in CO2 from 5-60%; flow rate 3 mL/min.

(1 R,5S,6S)-3-Benzyi-6-methyl-3-azabicyclo[3.1.0]hexan-1 -amine

First eluting isomer: Rt = 6.78 minutes, 89.9% ee. ¹H NMR (400MHz, CDCh): δ ppm 1.08-1.11 (m, 1H), 1.16-1.22 (m, 1H), 1.26 (m, 3H) 2.54 (d, 1H), 2.70-2.84 (m, 2H), 3.05 (d, 1H), 3.59 (s, 2H), 7.237.30 (m, 5H).

(1S,5R,6R)-3-Benzyl-6-methyI-3-azabicyclo[3.1.0]hexan-1-amine

Second eluting isomer: Rt = 6.10 minutes, 99.4% ee. ¹H NMR (400MHz, CDCI3): δ ppm 1.05-1.13 (m, 1H), 1.20 (m,1H), 1.26 (m, 3H), 2.53 (m, 1H), 2.71-2.84 (m, 2H), 3.05 (d, 1H), 3.58 (s, 2H), 7.25-7.30 (m, 5H).

Préparation 111

Racemic-3-Benzvl-5-(((tert-butvldimethvlsilyl)oxy)methvl)-3-azabicvcloF3.1.01hexan-1-amine

The title compound was prepared according to the method described for Préparations 109 and 110 using 2-(benzyJ(2-(((tert-butyldimethylsilyl)oxy)methyl)allyl)amino)acetonitrile (Préparation 114).

Préparation 112 (Z)-2-(Benzvl(but-2-en-1-vl)amino)acetonitrile

To a solution of 2-(benzyl(but-2-yn-1-yl)amino)acetonitrile (Préparation 113, 100 g, 0.5 mol) in MeOH (2000 mL) was added Lindlar catalyst (10 g) and the reaction was stirred at 30°C under a balloon of hydrogen for 24 hours. The reaction was filtered and concentrated in vacuo to afford the title compound. ¹H NMR (400MHz, CDCh): δ ppm 1.72-1.74 (m, 3H), 3.26-3.27 (m, 2H), 3.45 (s, 2H), 3.69 (s, 2H), 5.45-5.48 (m, 1H), 5.73-5.77 (m, 1H), 7.29-7.39 (m, 5H).

Préparation 113

2-(Benzvl(but-2-vn-1-vl)amino)acetonitrile

To a solution of 2-(benzylamino)acetonitrile (Préparation 115, 666 g, 4.56 mol) in MeCN (11 L) was added 1-bromobut-2-yne (600 g, 4.51 mol) and potassium carbonate (1365 g, 14 mol) and the reaction was heated to 40°C for 18 hours. The reaction was filtered, concentrated in vacuo and 30 purified using silica gel column chromatography eluting with 3-10% EtOAc in petroleum ether to afford the title compound as a yellow oil (700 g, 77%). ¹H NMR (400MHz, CDCh): δ ppm 1.72-1.74 (m, 3H), 3.25-3.27 (d, 2H), 3.45 (s, 2H), 3.69 (s, 2H), 7.29-7.39 (m, 5H).

Préparation 114

2-(Benzyl(2-(((tert-butvldimethvlsilvl)oxv)methvl)allyl)amino)acetonitrile

The title compound was prepared according to the method described by Préparation 113 using ((2(bromomethyl)allyl)oxy)(tert-butyl)dimethylsilane and 2-(benzylamino)acetonitrile (Préparation 115) at 75°C for 6 hours. ¹H NMR (400MHz, CDCh): δ ppm 0.00 (s, 6H), 0.80 (s, 9H), 3.15 (s, 2H), 3.35 (s, 2H), 3.60 (s, 2H), 4.10 (s, 2H), 5.10 (m, 1H), 5.20 (m, 1H), 7.20-7.40 (m, 5H).

Préparation 115

2-(Benzylamino)acetonitrile

To a solution of benzylamine (1250 g, 11.68 mol) and DIPEA (2878 g, 22.31 mol) in acetonitrile (13 L) was added 2-bromoacetonitrile (1340 g, 11.17 mol) and the reaction was stirred at room température for 3 hours. The reaction was concentrated in vacuo and dissolved in DCM (2.5 L). The solution was washed with water (1.5 L x 2), concentrated in vacuo and purified using silica gel column chromatography eluting with 10-30% EtOAc in petroleum ether (1600 g, 94%).

¹H NMR (400MHz, CDCh): δ ppm 3.57 (s, 2H), 3.94 (s, 2H), 7.35-7.37 (m, 5H).

Préparation 116

2-(5-Aminopyridin-2-vl)ethan-1-ol

The title compound was prepared according to the method described for Préparation 40 using methyl 2-(5-aminopyridin-2-yl)acetate (PCT Publication No. W02007042299).

¹H NMR (400MHz, MeOH-d₄): δ ppm 2.80-2.85 (t, 2H), 3.80 (t, 2H), 7.05 (m, 2H), 7.90 (s, 1H).

Préparation 117

Racemic-1-(5-Amino-3-chloropyridin-2-vl)ethan-1-ol

To a suspension of racemic-tert-butyl (5-chloro-6-(1-hydroxyethyl)pyridin-3-yl)carbamate (Préparation 118, 2.2 g , 8 mmol) in MeOH (50 mL) was added HCI/dioxane (4M, 30 mL) at 0°C. The reaction was stirred at room température for 18 hours before concentrating in vacuo to afford the title compound as the hydrochloride sait, which was taken on directly to the next step (2.2 g, 100%).

Préparation 118

Racemic-tert-Butyl (5-chloro-6-(1-hvdroxvethvl)pyridin-3-vl)carbamate

To a suspension of di-tert-butyl (6-acetyl-5-chloropyridin-3-yl)carbamate (Préparation 119, 2.33 g , 6.7 mmol) in MeOH (50 mL) was added sodium borohydride (656 mg, 17.25 mmol) at 0°C. The reaction was stirred at room température for 3 hours before being quenched by the addition of water and extracted with EtOAc (3 x 50 mL). The combined organic layers were concentrated in vacuo to afford the title compound as a white solid (2 g, 85%). MS m/z 372 [M+H]⁺

Préparation 119 tert-Butyl (6-acetvl-5-chloropyridin-3-vl)carbamate

To a suspension of di-tert-butyl (5-chloro-6-(methoxy(methyl)carbamoyl)pyridin-3-yI)carbamate (Préparation 120, 2.1 g, 6.7mmol) in THF (150 mL) was added MeMgCI (2.2 mL,3mol/L) dropwise at -30°C. The reaction was stirred at room température for 3 hours before quenching with the addition of water. The reaction was extracted into EtOAc (3 x 50 mL) and concentrated in vacuo to afford the title compound as a white solid (2.3 g, 77%). MS m/z 271 [M+H]⁺

Préparation 120

Di-tert-Butvl (5-chloro-6-(methoxy(methvl)carbamovl)pvridin-3-vl)carbamate

To a solution of methyl 5-((di-tert-butoxycarbonyl)amino)-3-chloropicoiinate (Préparation 121, 2 g, 5.18 mmol) in THF/H2O (100 mL/50 mL) was added LiOH (435 mg, 10.36 mmol) at 0°C and stirred at room température for 2 hours. The reaction was adjusted pH=2 with citric acid and extracted with EtOAc (3 x 100 mL). The combined organic layers were dried over sodium sulfate and concentrated in vacuo. The residue (1.35 g, 3.6 mmol) was dissolved in DCM (100 mL) and treated with N,O18225

dimethylhydroxylamine hydrochloride (423 mg, 4.3 mmol), triethylamine (1.1 g, 11 mmol) and HATU (1.65 g, 4.3 mmol) at 0°C. The reaction was stirred at room température for 3 hours. The reaction was concentrated in vacuo and purified directly using silica gel column chromatography eluting with 30% EtOAc in petroleum ether to afford the title compound (1.4 g, 94%). MS m/z 416 [M+H]⁺

Préparation 121

Methyl 5-((di-tert-butoxvcarbonvl)amino)-3-chloropicolinate

To a solution of methyl 5-amino-3-chloropicolinate (1.42 g, 7.63 mmol) and di-tert-butyidicarbonate (4.7 g, 18.8 mmol) in THF (150 mL) was added DIPEA (2.95 g, 22.87 mmol followed by DMAP (47 mg, 0.38 mmol). The reaction was heated to 70°C for 3 hours. The reaction was concentrated in vacuo and purified by silica gel column chromatography eluting with 30% EtOAc in petroleum ether to afford the title compound (2.5 g, 85%). MS m/z 387 [M+H]⁺

Préparation 122 (5-Amino-3-chloropyridin-2-vl)methanol

The title compound was prepared according to the method described for Préparation 40 using methyl 5-amino-3-chloropicolinate. The residue was purified using silica gel column chromatography eluting with 30% petroleum ether on EtOAc. ¹H NMR (400MHz, DMSO-ds): δ ppm 4.42-4.44 (d, 2H), 4.88 (t, 1H), 5.57 (brs, 2H), 6.97 (s, 1H), 7.83 (s, 1H).

Préparation 123

-( Oxetan-3-vl)-1 H-pyrazol-4-amine

To a solution of 4-nitro-1-(oxetan-3-yl)-1 H-pyrazole (Préparation 124, 119 mg, 0.70 mmol) in MeOH (20 mL) was added wet Pd/C (30 mg) and the reaction was hydrogenated under a balloon of hydrogen at room température for 2 hours. The reaction was filtered and the filtrate concentrated in vacuo to afford the title compound (100 mg, 100%).

Préparation 124

4-Nitro-1-(oxetan-3-vl)-1H-pyrazole

To a solution of 4-nitro-1 H-pyrazole (0.3 g, 2.66 mmol) and 3-iodo-oxetane (1.47 g, 7.99 mmol) in DMF (13 mL) was added césium carbonate (1.7g, 5.23 mmol) and the reaction was heated to 100°C for 18 hours. The reaction was concentrated in vacuo and purified by silica gel column chromatography eluting with EtOAc to afford the title compound (380 mg, 86%).

¹H NMR (400MHz, MeOH-d4): δ ppm 5.02 (br s, 4H), 5.61 (br s, 1 H), 8.24 (br s, 1 H), 8.68 (br s, 1 H).

Préparation 125

4-Amino-6-(hvdroxymethvl)-N-methvlpicolinamide

Methyl 4-((tert-butoxycarbonyl)amino)-6-(hydroxymethyl)picolinate (Préparation 63, 220 mg, 0.78 mmol) in 2M methylamine in MeOH (4 mL) was heated to 60°C for 18 hours. The reaction was cooled and the resulting solid filtered, dried, and dissolved in DCM (4 mL). To the solution was added MeOH (1 mL) followed by 4M HCl in dioxane (3 mL) and the reaction was stirred at room température for 4 hours. The resulting solid was filtered and dried to afford the title compound as the hydrochloride sait (75 mg, 40% over 2 steps). LCMS Rt = 0.16 minutes; MS m/z 182 [M+H]⁺

Préparation 126

4-((4-(3,6-DiazabicvcloF3.1.11heptan-3-vl)-5-fluoropyrimidin-2-vl)amino)-N-ethvl-2-methvlbenzamide To a solution of N-ethyI-4-((5-fluoro-4-(6-(2,2,2-trifluoroacetyl)-3,6-diazabicyclo[3.1.1]heptan-3yl)pyrimidin-2-yI)amino)-2-methylbenzamide (Example 121, 100 mg, 0.21 mmol) in MeOH (5 mL) was added 1M NaOH (aq) (2 mL) and the reaction was stirred at 50°C for 1 hour. The reaction was concentrated in vacuo and partitioned between DCM and water. The organic phase was collected through a phase séparation cartridge and concentrated in vacuo to afford the title compound that was used directly in the next reaction.

Préparation 127

4-(^,(4-(3.6-Diazabicvcloi3.1.1lheptan-3-vl)pvrimidin-2-vl)amino)-N-ethvlbenzamide hydrochloride

To a solution of 4-((4-chioropyrimidin-2-yl)amino)-N-ethylbenzamide (Préparation 132, 1.2 g, 4.3 mmol) and tert-butyl 3,6-diazabicycIo[3.1.1]heptanes-6-carboxylate (900 mg, 5 mmol) in THF (20 mL) was added triethylamine (2 mL, 10 mmol) and the reaction was heated to 50°C for 18 hours. The réaction was cooled and purified directly using silica gel column chromatography eluting with 0-20% MeOH in DCM. The residue was dissolved in 1:1 MeOHOCM (10 mL) and treated with 4M HCl in dioxane (5 mL). The reaction was stirred at room température for 18 hours before concentrating in vacuo. The resulting solid was collected as the hydrochloride sait of the title compound (1.5 g, quant). MS m/z 339 [M+H]⁺

Préparation 128

4-((4-(3.6-Diazabicyclo|^,3.1.1lheptan-3-vl)pyrimidin-2-vl)amino)-N-ethvl-2-methylbenzamide hydrochloride

To a solution of tert-butyl 3-(2-chloropyrimidin-4-yl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxylate (Préparation 131, 100 mg, 0.3 mmol) and 4-amino-N-ethyl-2-methylbenzamide (PCT Publication No. W02006109846, 60 mg, 0.34 mmol) in dioxane (3 mL) was added sodium tert-butoxide (35 mg, 0.36 mmol) and RuPHOS (25 mg, 0.034 mmol). The reaction was heated to 140°C under microwave irradiation for 25 minutes. The reaction was cooled, filtered and purified directly using silica gel column chromatography eluting with 0-20% MeOH in DCM. The residue was dissolved in DCM (5 mL) and treated with 4M HCl in dioxane with a few drops of MeOH to enable a solution. The reaction was stirred at room température for 18 hours and concentrated in vacuo to afford the title compound as the hydrochloride sait that was used directly in the next reaction.

Préparation 129

1-(3-(2-Chloro-5-fluoropvrimidin-4-vl)-3,6-diazabicvclo[3.1.1lheptan-6-vl)-2,2,2-trifluoroethan-1-one

To a solution of tert-butyl 3-(2-chloro-5-fluoropyrimidin-4-yl)-3,6-diazabicyclo[3.1.1]heptane-6carboxylate (Préparation 130, 200 mg, 0.61 mmol) in DCM (5 mL) was added 4M HCl in dioxane (4 mL) and the reaction was stirred at room température to ensure removal of the tert-butoxycarbonyl protecting group. The reaction was concentrated in vacuo, dissolved in DCM (5 mL), treated with TFAA (0.1 mL) and stirred at room température for 18 hours. The reaction was concentrated in vacuo and the residue partitioned between DCM and water. The organic layer was collected through a phase séparation cartridge and concentrated in vacuo to afford the title compound that was taken directly on to the next step. MS m/z 325 [M+H]⁺

Préparation 130 tert-Butyl 3-(2-chloro-5-fluoropvrimidin-4-vl)-3,6-diazabicvcloi3.1.1]heptane-6-carboxvlate

To a solution of 5-fIuoro-2,4-dichloropyrimidine (0.85 g, 5.1 mmol) in MeOH (15 mL) was added tertbutyl 3,6-diazabicyclo[3.1.1]heptanes-6-carboxylate (1 g, 5 mmol) followed by triethylamine (3 mL, 20 mmol) and the reaction was stirred at room température for 18 hours. The resulting precipitate was filtered, washed with MeOH and dried to afford the title compound as a white solid (1.46 g, 88%).

¹H NMR (400MHz, DMSO-de): δ ppm 1.28 (s, 9H), 1.48 (d, 1H), 2.48-2.53 (m, 1H), 3.70 (br s, 2H), 4.03-4.19 (m, 4H), 8.88 (d, 1H). MS m/z 329 [M+H]⁺

Préparation 131 tert-butyl 3-(2-chloropyrimidin-4-vl)-3,6-diazabicyclof3.1.1]heptane-6-carboxvlate

The title compound was prepared according to the method described for Préparation 130 using 2,4dichloropyrimidine and tert-butyl 3,6-diazabicyclo[3.1.1]heptanes-6-carboxylate. The residue was purified using siiica gel column chromatography eluting with 0-100% EtOAc in heptanes.

¹H NMR (400MHz, DMSO-de): δ ppm 1.24 (s, 9H), 1.44 (d, 1H), 2.48-2.56 (m, 1H), 3.42 (m, 2H), 3.83 (brs, 1H), 3.92-4.04 (m, 1H), 4.15 (d, 2H), 6.70 (brd, 1H), 8.09 (d, 1H). MS m/z 311 [M+H]⁺

Preparation 132

4-((4-Chloropyrimidin-2-vl)amino)-N-ethvlbenzamide

To a solution of 4-((4-chloropyrimidin-2-yl)amino)benzoic acid (Préparation 133, 1 g, 4 mmol) in DCM (20 mL) was added ethylamine (4.4 mL, 8.81 mmol) followed by HATU (1.71 g, 4.4 mmol) and triethylamine (1.23 mL, 8.81 mmol). The reaction was stirred at room température for 30 minutes before being poured into water. The organic layer was separated, dried over sodium sulfate and concentrated in vacuo. The residue was purified using siiica gel column chromatography eluting with 0-100% EtOAc in heptanes to afford the title compound (1 g, 90%).

¹H NMR (400MHz, DMSO-de): δ ppm 1.05 (t, 3H), 3.20-3.30 (m, 2H), 7.00 (m, 1H), 7.70 (m, 4H), 8.30 (t, 1H), 8.45 (s, 1H), 10.25 (brs, 1H). MS m/z 277 [M+H]⁺

Préparation 133

4-((4-Chloropvrimidin-2-vl)amino)benzoic acid

A mixture of 4-((4-hydroxypyrimidin-2-yl)amino)benzoic acid (Préparation 134, 5 g, 21.6 mmol) and POCh was heated to reflux for 6 hours and then cooled to room température and concentrated in vacuo. The residue was poured into ice-water and the resulting solid was collected by filtration and dried to afford the title compound that was taken on directly to the next step.

Préparation 134

4-((4-Hvdroxypvrimidin-2-vl)amino)benzoic acid

To a solution of 4-hydroxy-2-methylthiopyrimidine (5 g, 35.17 mmol) in diethylene glycol dimethyl ether (20 mL) was added 4-aminobenzoic acid (5.79 g, 42.2 mmol) and the reaction was heated to reflux for 18 hours. The reaction was cooled to room température and the resulting solid was filtered, washed with ether and dried to afford the title compound (6.5 g, 35.17 mmol). A sample was purified and analysed using préparative HPLC as described for Example 116 (Method 1, 5% B to 100% B in 9 min, hold at 100% B to 10 min) to obtain the following data. The remainder was taken directly on to the next step. LCMS Rt = 1.37 minutes; MS m/z 232 [M+H]⁺

Préparation 135

2-(3-((1 R.5S)-3-(2-((1-Methvl-1H-pvrazol-4-vl)amino)pvrimidin-4-vl)-3.8-diazabicvclo(3.2.11octan-8vl)azetidin-3-yl)acetonitrile hydrochloride

To a solution of 1-Boc-3-(cyanomethylene)azetidine (PCT Publication No. WO2013043964, 60 mg, 0.308 mmol) and 4-((1 R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-N-(1-methyI-1 H-pyrazol-4-yl)pyrimidin2-amine hydrochloride (Préparation 19, 83 mg, 0.257 mol) in MeCN (1 mL) and EtOH (1 mL) was added DBU (77 pl, 0.514 mmol) and the reaction was heated to 90°C for 24 hours. Further 4((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-N-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-amine hydrochloride (Préparation 19, 3eq) was added and the reaction continued heating at 90°C for 72 hours. The reaction was cooled, concentrated in vacuo and purified using silica gel column chromatography eluting with 0-10% MeOH (with 1% ammonia). The residue was dissolved in DCM (1 mL) and treated with 4M HCl in dioxane (1 mL). The reaction was stirred at room température for 1 hour before concentrating in vacuo to afford the title compound as the hydrochloride sait.

LCMS Rt = 0.38 minutes; MS m/z 380 [M+H]⁺

Préparation 136

Ethyl 2-((1R,5S)-3-(2-((1-methvl-1H-pvrazol-4-vl)amino)pvrimidin-4-vl)-3,8-diazabicvclor3.2.11octan-8yl)oxazole-5-carboxvlate

A mixture of 4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-N-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2amine hydrochloride (Préparation 19, 300 mg, 0.614 mmol), ethyl-2-chloro-1,3-oxazole-5-carboxylate (300 mg, 1.71 mmol), potassium phosphate (163 mg, 0.613 mmol), X-phos (60 mg, 0.126 mmol) and Pd2(dba)3 (60 mg, 0.065 mmol) in DMSO (20 mL) was purged with nitrogen for 1 minutes. The reaction was heated to 130°C for 30 minutes under microwave irradiation. The reaction was filtered, concentrated in vacuo and purified by silica gel column chromatography 0-20% MeOH in DCM to afford the title compound (200 mg, 76%). MS m/z 425 [M+H]⁺

Préparation 137 and 138 tert-Butvl ((1S.5R,6R)-3-(2-((5-chloro-6-((R)-1-hvdroxvethvl)pvridin-3-vl)amino)-5-fluoropyrimidin-4-vl)6-methvl-3-azabicyclo[3.1.0]hexan-1-vl)carbamate and tert-Butvl ((1S,5R,6R)-3-(2-((5-chloro-6-((S)1-hvdroxvethvl)pvridin-3-vl)amino)-5-fluoropvrimidin-4-vl)-6-methvl-3-azabicyclo[3.1.0lhexan-1vDcarbamate

To a solution of racemic-1-(5-amino-3-chloropyridin-2-y()ethan-1-ol (Préparation 117, 100 mg, 0.58 mmol), tert-butyl ((1 S,5R,6R)-3-(2-chloro-5-fluoropyrimidin-4-yl)-6-methyI-3-azabicyclo[3.1,0]hexan-1yl)carbamate (Préparation 94, 187 mg,0.46 mmol) and CS2CO3 (375 mg, 1.16 mmol) in DMA (5 mL) was added Pd(OAc)2 (25 mg, 0.93 mmol) and xantphos (65 mg, 0.93 mmol ) under nitrogen. The reaction was heated to 110°C under microwave irradiation for 1 hour. The reaction was concentrated in vacuo and purified directly using silica gel column chromatography eluting with 50% EtOAc in petroleum ether followed by préparative HPLC to afford the racemic title compound. The racemate was separated into its enantiomers by préparative chiral chromatography as described below: Column: Chiralpak AS-3 150x4.6mm I.D. 3pm

Mobile phase: Ethanol (0.05% DEA) in CO2 from 5% to 40%; Flow rate: 2.5mL/min

First eluting enantiomer:

100

Example 137: tert-Butyl ((1S,5R,6R)-3-(2-((5-chloro-6-((R)-1-hydroxyethyl)pyridin-3-yl)amino)-5fluoropyrimidin-4-yl)-6-methyl-3-azabicyclo[3.1.0]hexan-1-yl)carbamate. ¹H NMR (400MHz, DMSOd₆): δ ppm 0.88-0.90 (m, 3H), 1.20-1.30 (m, 1H), 1.40 (m, 12H), 1.75 (m, 1H), 3.60 (m, 2H), 3.90 (m, 2H), 5.00 (m, 2H), 7.55 (brs, 1H), 8.00 (m, 1H), 8.35 (brs, 1H), 8.75 (brs, 1H), 9.55 (s, 1H). MS m/z 479 [M+H]⁺; 100% ee.

Second eluting isomer:

Example 138: tert-Butyl ((1 S,5R,6R)-3-(2-((5-chloro-6-((S)-1-hydroxyethyl)pyridin-3-yl)amino)-5fluoropyrimidin-4-yl)-6-methyl-3-azabicyclo[3.1.0]hexan-1-yl)carbamate. ¹H NMR (400MHz, DMSOde): δ ppm 0.88-0.90 (m, 3H), 1.20-1.30 (m, 1H), 1.35-1.39 (m, 12H), 1.75 (m, 1H), 3.60 (m, 2H), 3.90 (m, 2H), 5.00 (m, 2H), 7.55 (br s, 1 H), 8.00 (m, 1 H), 8.38 (br s, 1 H), 8.71 (br s, 1 H), 9.57 (s, 1 H). MS m/z 479 [M+H]⁺; 100% ee.

Préparation 139 tert-butyl (6-chloro-5-fluoropyridin-3-yl)carbamate

To a solution of 5-bromo-2-chloro-3-fluoropyridine (62.5 g, 297 mmol x 4), Xantphos (38.4 g, 327.8 mmol x 4), and CS2CO3 (6.87 g, 11.9 mmol x 4) in dioxane (2 L x 4) was added Pd2(dpa)3 (10.8 g, 11.9 mmol x 4). The mixture was heated to 85 °C overnight. The reactions were combined than filtered. The filtrate was purified by silica gel column chromatography eluting with 5% EtOAc in petroleum ether to afford the title compound (170 g, 58%). ¹H NMR (400MHz, CDCI3): δ ppm 1.53 (s, 9 H), 6.78 (br. s., 1 H), 7.99 (d, 1 H), 8.05 (d, 1 H)

Préparation 140

Methyl 5-((tert-butoxvcarbonvl)amino)-3-fluoropicolinate

To a solution of tert-butyl (6-chloro-5-fluoropyridin-3-yl)carbamate (Préparation 139, 43.3 g, 175.67 mmol x 3), DPPP (14.46 g, 35.1 mmol x 3), TEA (124.1 g, 1.228 moi x 3) in MeOH (600 mL x 3) was added Pd(OAc)2 (7.88 g, 35.1 mmol x 3). The mixture was stirred at 50psi of CO at 60 °C for 36 hrs. The reaction mixtures were combined, filtered and the filtrated was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with 10% EtOAc in petroleum ether to afford the title compound (33.7 g, 71 %). ¹H NMR (400MHz, CDCI3): δ ppm 1.53 (s, 9 H) 3.99 (s, 3 H) 7.06 (br. s., 1 H) 8.13 (d, 1 H) 8.24 (s, 1 H)

Préparation 141

6-chloro-5-fluoropyridin-3-amine hydrochloride

A mixture of methyl 5-((tert-butoxycarbonyl)amino)-3-fluoropicolinate (Préparation 140, 1.50 g, 5.55 mmol) in 1 N HCI/dioxane (70 mL, 4 M) was stirred at room température (10 °C) for 16 hours. The mixture was concentrated in vacuo to afford the title compound (1.1 g, 100%), which was used in the next step without further purification.

Préparation 142 tert-butvl-3-(2-((5-fluoro-6-(methoxycarbonvl)pvridin-3-vl)amino)pyrimidin-4-yl)-3,8diazabicvclof3.2.noctane-8-carboxylate

To a mixture of 6-chloro-5-fluoropyridin-3-amine hydrochloride (Préparation 141, 500 mg, 1.54 mmol), tert-butyl (1R,5S)-3-(2-chloropyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Préparation 34, 314 mg, 1.85 mmol) and CS2CO3 (1000 mg, 3.08 mmol) in DMA (15 mL) was added

Xantphos (178 mg, 0.308 mmol) and Pd(OAc)2 (69.1 mg, 0.308 mmol) at room température (10 °C). The mixture was bubbled with N2 for 3 min. The vial was sealed and then treated with microwave irradiation at 120 °C for 1 h. The mixture was concentrated and purified by column chromatography on silica gel 25% EtOAc in petroleum ether to 75% EtOAc in petroleum ether to give the title compound 5 (296 mg, 42%). LCMS Rt = 0.70 minutes; MS m/z 459 [M+H]

Préparation 143 tert-butvl-3-(2-((6-carbamovl-5-fluoropvridin-3-vl)amino)pvrimidin-4-vl)-3,8-diazabicvcloi3.2.1loctane8-carboxylate

A solution of tert-butyl-3-(2-((5-fluoro-6-(methoxycarbonyl)pyridin-3-yl)amino)pyrimidin-4-yl)-3,810 diazabicyclo[3.2.1]octane-8-carboxylate (Préparation 142, 400 mg, 0.11 mmol) in NH3/MeOH (80 mL,

M) was stirred at 100 °C in a 100 mL sealed tube for 8 h. The solution was concentrated in vacuo to afford the title compound (270 mg, 72%), which was used in the next step without further purification. LCMS Rt = 0.67 minutes; MS m/z 444 [M+H]

Préparation 144

5-((4-(3,8-diazabicvclo[3.2.11octan-3-vl)pvrimidin-2-vl)amino)-3-fluoropicolinamide hydrochloride

To a mixture of Préparation 143 (250 mg, 0.564 mmol) in THF (10 mL) was added HCI/dioxane (20 mL, 4 M) at 0 oC. The mixture was stirred at room température (10 oC) for 3 h. TLC (DCM:MeOH=10:1) showed some of the starting material was still remained. The solution was concentrated in vacuo to afford the title compound (300 mg, yield: 100%), which was taken to the next 20 step directly.

Biological Evaluation

Compounds of the invention were evaluated by in vitro methods to détermine their respective ability to inhibit the JAK kinases (TYK2, JAK1, JAK2, JAK3).

Assay Format

The human JAK inhibitory activity was determined by using a microfluidic assay to monitor phosphorylation of a synthetic peptide by the recombinant human kinase domain of each of the four 30 members of the JAK family, JAK1, JAK2, JAK3 and TYK2. Reaction mixtures contained 1 μΜ of a fluorescentiy labeled synthetic peptide, a concentration less than the apparent Km, and 1 mM ATP.

Each assay condition was optimized for enzyme concentration and room température incubation time to obtain a conversion rate of 20% to 30% phosphorylated peptide product. Reactions were terminated by the addition of stop buffer containing EDTA. Utilizing the LabChip 3000 mobility shift 35 technology (Caliper Life Science), each assay reaction was sampled to détermine the level of phosphorylation. This technology is separation-based, allowing direct détection of fluorescentiy labeled substrates and products. Séparations are controlled by a combination of vacuum pressure and electric field strength optimized for each peptide substrate.

Assay Protocol

JAK Caliper Enzyme Assay at 1mM ATP

Compounds were added to a 384-well plate. Reaction mixtures contained 10 mM HEPES, pH 7.4,10 mM MgCb, 0.01% BSA, 0.0005% Tween 20, 1 mM ATP and 1 μΜ peptide substrate. The JAK1 and

TYK2 assays contained 1 μΜ of the IRStide peptide (5FAM-KKSRGDYMTMQID) and the JAK2 and JAK3 assays contained 1 μΜ ofthe JAKtide peptide (FITC-KGGEEEEYFELVKK). The assays were initiated by the addition of 20 nM JAK1,1 nM JAK2,1 nM JAK or 1 nM TYK2 enzyme and were incubated at room température for three hours for JAK1,60 minutes for JAK2, 75 minutes for JAK3 or 135 minutes for TYK2. Enzyme concentrations and incubation times were optimized for each new enzyme preps and were modified slightly over time to ensure 20% to 30% phosphorylation. The assays were stopped with 15 pL of 180 mM HEPES, pH 7.4, 20 mM EDTA, and 0.2% Coating Reagent 3. The assay plates were placed on a Caliper Life Science LC3000 instrument, and each well was sampled using appropriate séparation conditions to measure the unphosphorylated and phosphorylated peptide.

Data Analysis

The data was collected using the HTS Well Analyzer software from Caliper Life Sciences. The data output for data analysis is the percent product converted calculated on peak height (Equation 1).

Equation 1 : % product converted = 100*((product)/(product + substrate))

The percent effect at each compound concentration was calculated based on the positive and 20 négative control well contained within each assay plate (Equation 2). The positive control wells contained a saturating concentration of a control compound that produced a level of phosphorylation comparable to background (i.e., completely inhibited JAK1, JAK2, JAK3 or TYK2). The négative control wells contained DMSO alone (at the same concentration as the compound wells) that was used to set the baseline activity in the assay (i.e., uninhibited JAK1, JAK2, JAK3 or TYK2).

Equation 2: % effect = 100*((sample well - négative control)/(positive control-negative control))

The percent effect was plotted against the compound concentration compound. An unconstrained sigmoid curve was fitted using a 4 parameter logistic model and the compound concentration required for 50% inhibition (IC50) was determined (Equation 3).

Equation 3: y = ((max - min)/(1 + ((x/ICso)^As))) + min

Where max is the maximum asymptote (complété inhibition), min is the minimum asymptote (no inhibition) and s is the slope factor. ICso values are reported in nM for each compound:

103

Ex. No.	Structure	ICso (nM)
TYK2	JAK1	JAK2	JAK3
1	V ô N aAn U/U N N H	1098	2730	>10000	>10000
2	V a i °Ή A A A AA	432	1547	4721	>10000
3	A° ê N Aⁿ ΑλΑ H	128	215	1974	>10000
4	V Ô N 0_n 1 H',⁰ ^FA« /V^s> VA H	176	659	2885	>10000
5	H °^/^N\x'^Meû N An k A A^nhN N H	41	41	477	>10000

104

6	V $ 0 A aA î\| C NHMe H	36	337	754	>10000
7	X/O ’Ί^ e Ar 1 /^Μθ H	23	17	77	6494
8	V 6 I Me A_N	702	842	3148	>10000
9	V G » ^FAn ri^i:X7r'N^/X'Me IaAJ ^hN N H	4	20	112	1661
10	y ô N 0 À ,hL A „Me rf^N C T N IaAA ^h N N ^^ CI H	22	171	367	>10000

105

11	Υ· ê N Me An AAAJ H	40	139	141	>10000
12	X_fo ô,rY H	28	79	80	>10000
13	°^CN ê N 0 Va-V ^h H	12	41	199	>10000
14	A e o il ^N r^vA^Me Iaajl ^h H	79	757	745	>10000
15	°A 0 AXA H	84	588	855	>10000
16	Y⁷¹ Θ A N p=\ ^-₀H N N H	66	150	421	>10000

106

17	$ A H	242	684	3375	>10000
18	F F V ê H	62	352	331	>10000
19	X, άχχ· H	52	463	402	>10000
20	ç © d Cl AI H	58	314	346	>10000
21	F F v ώ γ ό ùlXX N N F H	95	622	434	>10000
22	F F V e ÎaZï N N F H	55	490	312	>10000

107

23	F F V e An Uy°^oH	58	258	498	>10000
24	ÇN °A û N /—Me r^N CW N N H	32	13	67	4987
25	F F L Θ [An AU™ VAX H	34	317	468	>10000
26	F F A ô N Me Me ΑΥΐΝ Au	25	60	192	>10000
27	CN A° e » Jj. ,N. JQ ^Me uâA N N F H	61	78	640	>10000
28	F F A e , X JQ ^Me (aXA H	736	1371	8152	>10000

108

29	F F Y 9 . A /N. Jk ^Me AXA Y N F H	31	131	487	>10000
30	V ô N 0 Xs / A Xk A^e ÎaXa ⁹ A n ^^ CI H	97	1156	2126	>10000
31	CN A° 0 0 /L /N. JL ^Me ÔAÛù N N ^^ CI H	32	78	401	>10000
32	CN A e » 1 JL ^Me A^N A >r N ÎaAA ^h N N Me H	17	28	140	>10000
33	'/· û N II 1 Xk xMe ôkZx ^K N N Me H	15	62	116	9276
34	U û N 0 An /Ah₂L <>k N N Me H	36	152	377	>10000

109

35	'0 fi άχΰ H	23	170	337	>10000
36	V e N An IL A A/^N~^MeN N H	76	199	684	>10000
37	r/'v/ e N An IL A ΛΛ^μ<:N N H	250	467	1398	8306
38	„..Δ o NC “F ô N An H J X.z^N~Me H	427	707	2328	>10000
39	ê N Av- H	136	305	1171	>10000
40	F F A e „ ^h s	70	369	189	>10000

110

41	F F V 0 _r» ^H s	84	201	279	>10000
42	ô ï /^Me îiA 1Γ^Νχl A Ay ^A A H	437	717	2459	>10000
43	F À /O ô ^N 1 Me AA H	474	902	2842	>10000
44	A φ e A rA“' An^A H	72	475	854	>10000
45	Y 0 0 A x A“· ΑΆθ H	17	46	100	7402

111

46	ô A- H	84	173	526	4158
47	H CK .N. Y CN ô N .. i Me A· H	65	42	262	>10000
48	H Ck.N.zx ,N^ nL A. Λ f Me CMÏ- H	964	300	2508	>10000
49	°A Θ A- H	49	77	614	>10000
50	A ô Υγ Υ^Νχ \|\| JL / nh H	436	478	3418	>10000

112

51	X e Ν ίι ^Ν rA \|\| 1 \| ΝΗ Η	11	13	97	8611
52	°Α Ô Ν ίι ^Ν Γ\ Η	93	172	1241	>10000
53	A Ô Ν 0 A A _xMe ΙαΧΓ Ν Ν Me Η	24	226	375	>10000
54	0 Q Ô Ν 0 A Jk „Me ÎaZa ^Η Ν Ν Me Η	8	19	29	4292
55	A ô Ν .. 1 Me ά.Χ'· Η	23	35	221	8615

113

56	Ο, ô N ? Me Q·» H	41	110	394	>10000
57	fl A ê N ? Me àU- H	89	294	1069	>10000
58	ô N ,, \| M, Αχ- H	73	267	821	>10000
59	CN i Ô H	62	78	236	8798
60	9' -Me 0 I Me H	70	36	159	>10000

114

61	CN Φ θ ₀ J. ,Ν^ JL /-Me ιι ( Ίι H	18	31	44	4083
62	CN fi N 0 /L JL ,Me A X 1 ” H θ	224	1021	1387	>10000
63	A ô ΙΨ „ I Me (A1> H	125	303	856	>10000
64	X û N „ I Me uA H	41	95	320	>10000
65	X. A Y N ^N A H	22	35	223	>10000

115

66	e Λ r“ IA JLz H	65	106	655	>10000
67	K ό άχά“ H	108	418	973	>10000
68	C N 0 A aA La aa ^H H	22	85	188	>10000
69	CN A, é N „ I Me VAA> H	811	1098	5703	>10000
70	ÇN Θ N I Me CaA H	261	259	1541	>10000

116

71	^Ν^>Δ 0 άΑ Η	152	153	453	>10000
72	ê Ν 0 ΙαΛΙ ^η Ν Ν Me Η	6	81	151	411
73	<\Α> Me Ν Μθ^Μ® Η Ν 0 ^FX^N ΑΑΑΥ'^Μθ 1 λ ΛΑ ^ΗΝ N^^Me Η	17	260	170	1771
74	Η O^N^^Me e ά.χ> Η	65	67	691	>10000
75	Η °γ^Ν^^Μθ Ô Ν 0 Αχ /Νχ Αχ yMe Y T Ν ΙλΑΑ ^ηΝ Ν CI Η	66	462	1289	>10000
76	ΟγΝΗ₂ Ô Ν Αν Υ^νχ Η A Js^yN—Me Η	662	537	1476	>10000

77	°\\ _xMe ê ï ^Me ii Y A IL A JA N N H	256	380	653	>10000
78	NC OyN ô N An H J J^z^N~Me H	63	68	461	>10000
79	CN S ô N (i ï r^s H	34	38	406	8425
80	CN ^Me^J ê N An A' H J kz^Me H	79	190	436	>10000
81	CN Me^J û N An H J L N—Me H	199	405	603	>10000
82	CN Me^J e άχ- H	79	135	473	>10000

118

83	°\ _.Me 0'? ê N ilX jZ/ⁿ~^mbN N H	11	7	21	1239
84	^ncA û N il ^N A \|l J L .N—Me H	62	141	155	>10000
85	H ⁰<Y^N\/^CNô N An Iq A A/^N~^Me N N H	16	13	67	2477
86	H O^N^^Me ô N Aⁿ A l! aL U N—Me H	71	104	538	>10000
87	H O^N^Me ô àxU H	93	337	1787	>10000
88	^ο·^χΝ^,Μβ ,Ν_χ Me θ N An lA²'''⁷ H	110	165	894	>10000

119

89	H θγΜ*, Ô N 0 A, Jk „Me rf^N f V N IaXA ^hN N Me H	9	10	65	4426
90	H O^N^-CN û V 0 A .N. ^Me UUÛU N N Me H	14	17	76	4168
91	H O^N^Me Ô N 0 A /N. A. ^Me Iaâa ^hN N Me H	39	183	513	>10000
92	^NCp e U F=\ H ,1 .N—Me N tl H	62	52	264	6564
93	F F*-A 0 Me u......< HN^-/ V-H i Me ^FVA A uU	28	41	652	4267
94	F F-~J 0 Me Λ. - HN-y—ÿ-H \| Me Ua _r< k A Az	56	113	1132	4023

120

95	NC \ O Me i>.....< Λ N—AA—H ^HO N ? Me H	35	11	228	255
96	_F F \/ 0 Me >.....< λ Ν...ΖΛ...Η ^HO N \| Me Ή H	924	684	2676	>10000
97	p F \7 0 Me Μ· λ N-AA··· H Y - H	588	672	1883	9970
98	„ 0 Me nZ ^-À-h S^-2 Me. A A. .0. i Γ ΊΓ Ί aAn^+AcY H	19	13	147	2599
99	_F F \/ O Me “À V ^F-yA A' k A ΑΆθ N N 'S H	26	65	391	4937
100	. ,0 Me Λ - HN—/ \ ^H >r o R J\ JL χΜθ ζι X JL ^H^N N H	97	965	4253	>10000
101	0 Me k hn-ν..ΖΧ..πη \r o F·. J\ JA JL xMe >^n A Ar ^N L. A XX Me H	663	1881	2908	>10000

121

102	0 Me ^HV aA SA h	m	252	2076	6872	>10000
	. c	Me
	M	A
	N	—/ \—H
	H	V		Me
103		I		:	150	1738	3465	>10000
	Γ S.	Ύν V,	XA
		H
	0	Me
		A
	HN-	Y
		v		Me
104		Y A H	/A	A^oh	86	1150	3127	>10000
	1	U
	0	Me
	i>-(	λ
	HN-	A-^h
105		Y			152	1569	6100	>10000
	S		f Y	A
	1	A' H	Ul	'Cl
	N H	Me -À-H V 1		OH A
106	F_x	.ht	229	2297	9412	>10000
		A'N	Y	X Me
		V» H	A>	Y
	A
	Ό
107	^CIY	1			21	19	177	1883
	A_N	p=^N
	1		JAn-
		N N H		Ah
	A	A
	HN·	A
108	A	v 1			675	323	1491	3964
	An	r==^N
	1		O-
		-N N^x		Ah

122

109	Α _ΛAjA J Me A A k A AZ N N	51	211	2337	>10000
110	W Λ ^NC H 0 ^λ°^Η 1 Me ’ /j r-l( k A JJ» N N H	58	29	455	928
111	Αγ·° ô ^N il	56	1691	2214	4867
112	::V Ô ^N il VAA..^K H	21	4068	3037	>10000
113	V G Ç\AX.^H H	82	8584	7865	>10000
114	fy³ O AcA H	62	955	1855	>10000

123

115	A 0 H	64	3790	3309	>10000
116	A H	20	1469	1911	9819
117	'A- G o ixc*	32	114	452	>10000

2. Selected compounds were assessed for their ability to inhibit interferon alpha signalling in a human whole blood flow cytometry assay. Intereron alpha signais through TYK2 and JAK1.

Human whole blood INFa induced STAT3 phosphorylation Assay

Test articles were prepared as 30 mM stocks in DMSO. A 11-point 2.5 dilution sériés was created in DMSO with a top concentration of 5 mM. Further dilution was done by adding 4 pL ofthe above test article solutions into 96 pL of PBS with a top concentration of 200 pM. Human whole blood was collected from healthy donors via vein puncture into Vacutainer collection tubes containing sodium heparin (Catalog No. 366480; Becton Dickinson, Franklin Lakes, NJ). Blood was warmed to 37°C prior to use. Human whole blood was aliquoted (90 pL/well) in 96-well, deep-well, V-bottom plates and treated with compounds at 11 different concentrations (0.2% DMSO final) at 37°C for 60 minutes. This was followed by a challenge with IFNa (5 pL/well; final, 5000 U/MI) for 15 minutes. Samples were treated with warm 1X Lyse/Fix buffer (700 pL/well) to terminate activation and further incubated at 37°C for 20 minutes to lyse red blood cells. Plates were centrifuged at 300 x g for 5 minutes, supernatant was aspirated, and cells were washed with 800 μ!_ per well of staining buffer. The washed cell pellets were resuspended with 350 pL per well of pre-chilled 90% methanol, and incubated on ice for 30 minutes. After the removal of 90% methanol, cells were washed once with staining buffer (800 pL/well). Cell pellets were resuspended in staining buffer containing antipSTAT3-AlexaFluor647 (1 to 150 dilution, 150 pL/well), and incubated at room température in the dark overnight

124

ΊΪ

Samples were transferred to 96-well U-bottom plates and flow cytométrie analysis was performed on a FACSCalibur, FACSCanto or LSRFortessa equipped with a HTS plate loader (BD Biosciences). The lymphocyte population was gated for histogram analysis of pSTAT3. Background fluorescence was defined using unstimulated cells and a gâte was placed at the foot of the peak to 5 include -0.5% gated population. The histogram statistical analysis was performed using CelIQuest™

Pro version 5.2.1 (BD Biosciences), FACSDiva version 6.2 (BD Biosciences) or FlowJo version 7.6.1 (Ashland, OR) software. Relative fluorescence unit (RFU), which measures the level of phospho

STAT3, was calculated by multiplying the percent positive population and its mean fluorescence. Data from 11 compound concentrations (singlicate at each concentration) was normalized as a percentage of control based on the formula: % of Control = 100 x (A - B)/(C - B) where A is the RFU from wells containing compound and cytokine, B is the RFU from wells without cytokine and compound (minimum fluorescence) and C is the RFU from wells containing only cytokine (maximum fluorescence). Inhibition curves and IC50 values were determined using the Prism version 5 software (GraphPad, La Jolla, CA).

Example Number	HWB IFN alpha IC50 (nM)
5	105
6	232
7	30
10	439
11	134
12	88
14	287
15	534
18	338
19	238
20	458
21	731
22	410
23	428
24	43
25	229
26	247
27	139
29	118
30	653
31	284
32	115

125

33	122
35	90
36	119
44	562
45	110
46	209
49	85
51	20
53	287
55	168
56	78
57	338
58	158
59	84
60	103
61	135
64	71
65	60
66	187
74	213
75	751
79	65
80	112
83	85
84	156
85	120
86	116
87	582
89	118
90	247
91	195
93	191
95	87
98	246
109	507
110	146
112	775
113	939
114	166
115	234

126

Claims

What is claimed is:

1. A compound having the structure:

Ri \ (CH₂)_y or a pharmaceutically acceptable sait thereof, wherein X is N or CR, where R is hydrogen, deuterium, C1-C4 alkyl, C1-C4 alkoxy, C3-C6 cycloalkyl, aryl, heteroaryl, aryl(Ci-C6 alkyl), CN, amino, alkylamino, dialkylamino, CF3, or hydroxyl;

A is selected from the group consisting of a bond, C=O, --SO2-, --(C=0)NRo--, and --(CR_aRb)q-, where Ro is H or C1-C4 alkyl, and R_a and Rb are independently hydrogen, deuterium, Ci-Ce alkyl, C3Ce cycloalkyl, aryl, aryl(Ci-C6 alkyl), heteroaryl, (C1-C6 alkyi)heteroaryl, heteroaryl(Ci-Ce alkyl), and heterocyclic(Ci-C6 alkyl);

A' is selected from the group consisting of a bond, C=O, --SO2--, ~(C=0)NRo', -- NRo'(C=0)--, and -(CR_a'Rb%-, where Ro' is H or C1-C4 alkyl, and R_a' and Rb' are independently hydrogen, deuterium, C1-C6 alkyl, C3-C6 cycloalkyl, aryl, aryl(Ci-C6 alkyl), heteroaryl, (C1-C6 alkyl)heteroaryl, heteroaryl(Ci-Ce alkyl), and heterocyclic(Ci-C6 alkyl);

Z is -(CH₂)/r- or a bond, where one or more methyiene units are optionally substituted by one or more C1-C3 alkyl, CN, OH, methoxy, or halo, and where said alkyl may be substituted by one or more fluorine atoms ;

Ri and Ri' are independently selected from the group consisting of hydrogen, deuterium, C1-C4 alkyl, C3-C6 cycloalkyl, aryl, heteroaryl, aryl(Ci-C6 alkyl), CN, amino, alkylamino, dialkylamino, alkoxy, heteroaryl(Ci-C6 alkyl), and heterocyclic(Ci-C6 alkyl), wherein said alkyl, aryl, cycloalkyl, heterocyclic, or heteroaryl is further optionally substituted with one or more substituents selected from the group consisting of C1-C6 alkyl, halo, CN, hydroxy, methoxy, amino, C1-C4 alkyl amino, di(Ci-C4 alkyl)amino, CF3, -SO₂-(Ci-C6 alkyl), and C3-C6 cycloalkyl;

R2 is selected from the group consisting of hydrogen, deuterium, Ci-Ce alkyl, C3-C6 cycloalkyl, halo, and cyano, where said alkyl may be substituted by one or more fluorine atoms;

R3 is selected from the group consisting of hydrogen, deuterium, and amino;

127

P

R4 is monocyclic or bicyclic aryl or monocyclic or bicyclic heteroaryl wherein said aryl or heteroaryl is optionally substituted with one or more substituents selected from the group consisting of C1-C5 alkyl, heterocycloalkyl, halo, CN, hydroxy, --CO2H, C1-C6 alkoxy, amino, -N(Ci-C6alkyl)(CO)(CiCe alkyl), -NH(CO)(Ci-C₆ alkyl), -(CO)NH₂, ~(CO)NH(Ci-C₆ alkyl), ~(CO)N(Ci-C₆ alkyl)₂, -(Ci-Ce 5 alkyl)amino, -N(Ci-C6 alkyl)2, --SO2-(Ci-C6 alkyl), --(SO)NH2, and C3-C6 cycloalkyl, where said alkyl, cycloalkyl, alkoxy, or heterocycloalkyl may be substituted by one or more C1-C6 alkyl, halo, CN, OH, alkoxy, amino, -CO2H, -(CO)NH2, --(CO)NH(Ci-C6 alkyl), or --(CO)N(Ci-C6 alkyl)2, and where said alkyl may be further substituted by one or more fluorine atoms;

Rs is independently selected from the group consisting of hydrogen, C1-C6 alkyl, Ci-Ce alkoxy, 10 and hydroxyl;

h is 1, 2 or 3; J and k are independently 0, 1, 2, or 3; m and n are independently 0,1 or 2;

and, gis 0,1 or2.
2. The compound of claim 1 having the structure:

or a pharmaceutically acceptable sait thereof, wherein

XisN;

A is selected from the group consisting of a bond, C=O, --SO2--, -(C=0)NRo--, and -(CRaRbjq20 -, where Ro is H or C1-C4 alkyl, and R_a and Rb are independently hydrogen, deuterium, C1-C6 alkyl, C3C6 cycloalkyl, aryl, aryl(Ci-C6 alkyl), heteroaryl, (Ci-Ce alkyl)heteroaryl, heteroaryl(Ci-C6 alkyl), and heterocyclic(Ci-C6 alkyl);

Ri is selected from the group consisting of hydrogen, deuterium, C1-C4 alkyl, C3-C6 cycloalkyl, aryl, heteroaryl, aryl(Ci-C6 alkyl), CN, amino, alkylamino, dialkylamino, fluoroalkyl, alkoxy, 25 heteroaryl(C1-C6 alkyl), heterocyclic and heterocycIic(Ci-C6 alkyl), wherein said alkyl, aryl, cycloalkyl, heterocyclic, or heteroaryl is further optionally substituted with one or more substituents selected from the group consisting of C1-C6 alkyl, halo, CN, hydroxy, methoxy, amino, C1-C4 alkyl amino, di(Ci-C4 alkyl)amino, CF3, -SO2-(Ci-C6 alkyl), and C3-C6 cycloalkyl;

R2 is selected from the group consisting of hydrogen, deuterium, Ci-Ce alkyl, C3-C6 cycloalkyl, 30 halo, and cyano, where said alkyl may be substituted by one or more fluorine atoms;

128

Y'

R3 is selected from the group consisting of hydrogen and deuterium;

R₄ is monocyclic or bicyclic aryl or monocyclic or bicyclic heteroaryl wherein said aryl or heteroaryl is optionally substituted with one or more substituents selected from the group consisting of C1-C6 alkyl, heterocycloalkyl, halo, CN, hydroxy, --CO2H, C1-C6 alkoxy, amino, -N(Ci-C6 alkyl)(CO)(Ci5 C₆ alkyl), -NH(CO)(Ci-Ce alkyl), -(CO)NH₂, -(CO)NH(Ci-Ce alkyl), -(CO)N(Ci-C₆ alkyl)₂, -(Ci-Ce alkyl)amino, -N(Ci-Ce alkyl)₂, --SO₂-(Ci-Ce alkyl), -(SO)NH₂, and C3-C6 cycloalkyl, where said alkyl, cycloalkyl, alkoxy, or heterocycloalkyl may be substituted by one or more C1-C6 alkyl, halo, CN, OH, alkoxy, amino, -CO₂H, -(CO)NH₂, --(CO)NH(Ci-C6 alkyl), or -(CO)N(Ci-C6 alkyl)₂, and where said alkyl may be further substituted by one or more fluorine atoms;

10 Λis 1,2or 3;/is 0,1, 2, or3; and, gis 0,1 or2.

Rs is independently selected from the group consisting of hydrogen, C1-C6 alkyl, Ci-Ce alkoxy, and hydroxyl;

15 3. The compound of claim 1 having the structure:

or a pharmaceutically acceptable sait thereof, wherein

Xis N;

20 A is selected from the group consisting of a bond, C=O, --SO₂--, -(C=0)NRo--, and -(CRaRb)q-, where Ro is H or C1-C4 alkyl, and R_a and Rb are independently hydrogen, deuterium, C1-C6 alkyl, C3C6 cycloalkyl, aryl, aryl(Ci-C6 alkyl), heteroaryl, (C1-C6 aikyl)heteroaryl, heteroaryl(Ci-C6 alkyl), and heterocyclic(Ci-C6 alkyl);

Ri is selected from the group consisting of hydrogen, deuterium, C1-C4 alkyl, C3-C6 cycloalkyl,

25 aryl, heteroaryl, aryl(Ci-C6 alkyl), CN, amino, alkylamino, dialkylamino, fluoroalkyl, alkoxy, heteroaryl(Ci-C6 alkyl), heterocyclic and heterocyclic(Ci-C6 alkyl), wherein said alkyl, aryl, cycloalkyl, heterocyclic, or heteroaryl is further optionally substituted with one or more substituents selected from the group consisting of Ci - Οθ alkyl, halo, CN, hydroxy, methoxy, amino, C1-C4 alkyl amino, di(Ci-C4 alkyl)amino, CF3, --SO₂-(Ci-C6 alkyl), and C3-C6 cycloalkyl;

30 R₂ is selected from the group consisting of hydrogen, deuterium, Ci-Ce alkyl, C3-C6 cycloalkyl, halo, and cyano, where said alkyl may be substituted by one or more fluorine atoms;

129

V

R3 is selected from the group consisting of hydrogen and deuterium;

R4 is monocyclic or bicyclic aryl or monocyclic or bicyclic heteroaryl wherein said aryl or heteroaryl is optionally substituted with one or more substituents selected from the group consisting of C1-C6 alkyl, heterocycloalkyl, halo, CN, hydroxy, --CO2H, C1-C6 alkoxy, amino, -N(Ci-C6alkyl)(CO)(Ci5 C₆ alkyl), -NH(CO)(Ci-C₆ alkyl), ~(CO)NH_Z, -(CO)NH(Ci-C₆ alkyl), -(CO)N(Ci-C₆ alkyl)₂, --(Ci-C₆alkyl)amino, --N(Ci-Ce alkyl)2, -SO2-(Ci-C6 alkyl), -(SO)NH2, and C3-C6 cycloalkyl, where said alkyl, cycloalkyl, alkoxy, or heterocycloalkyl may be substituted by one or more Ci-Ce alkyl, halo, CN, OH, alkoxy, amino, -CO2H, -(CO)NH2, --(CO)NH(Ci-C6 alkyl), or --(CO)N(Ci-C6 alkyl)2, and where said alkyl may be further substituted by one or more fluorine atoms;Rs is selected from the group consisting

10 of hydrogen, C1-C6 alkyl, Ci-Ce alkoxy, and hydroxyl; j is 0, 1, 2, or 3; and, q is 0, 1 or 2.

Rs is independently selected from the group consisting of hydrogen, C1-C6 alkyl, Ci-Ce alkoxy, and hydroxyl;

15 4. The compound of claim 1 having the structure:

or a pharmaceutically acceptable sait thereof, wherein

A' is selected from the group consisting of a bond, C=O, -SO2--, ,--(C=0)NRo', -- NRo'(C=0)--,

20 and --(CR_a'Rb')_Q--, where Ro' is H or C1-C4 alkyl, and R_a' and Rb' are independently hydrogen, deuterium, Ci-Ce alkyl, C3-C6 cycloalkyl, aryl, aryl(Ci-C6 alkyl), heteroaryl, (Ci-Ce alkyl)heteroaryl, heteroaryl(Ci-C6 alkyl), and heterocyclic(Ci-C6 alkyl);

RT is selected from the group consisting of hydrogen, deuterium, C1-C4 alkyl, C3-C6 cycloalkyl, aryl, heteroaryl, aryl(Ci-C6 alkyl), CN, amino, alkylamino, dialkylamino, fluoroalkyl, alkoxy, 25 heteroaryl(Ci-C6 alkyl), hetrocyclic and heterocyclic(Ci-C6 alkyl), wherein said alkyl, aryl, cycloalkyl, heterocyclic, or heteroaryl is further optionally substituted with one or more substituents selected from the group consisting of C1-C6 alkyl, halo, CN, hydroxy, methoxy, amino, C1-C4 alkyl amino, di(Ci-C4 alkyl)amino, CF3, --SO2-(Ci-C6 alkyl), and C3-C6 cycloalkyl;

R2 is selected from the group consisting of hydrogen, deuterium, C1-C6 alkyl, C3-C6 cycloalkyl, 30 halo, and cyano, where said alkyl may be substituted by one or more fluorine atoms;

130

R3 is selected from the group consisting of hydrogen and deuterium;

R₄ is monocyclic or bicyclic aryl or monocyclic or bicyclic heteroaryl wherein said aryl or heteroaryl is optionally substituted with one or more substituents selected from the group consisting of Ci-Ce alkyl, heterocycloalkyl, halo, CN, hydroxy, --CO2H, C1-C6 alkoxy, amino, -N(Ci-C6alkyl)(CO)(CiCe alkyl), -NH(CO)(Ci-Ce alkyl), -(CO)NH₂, -(CO)NH(Ci-Ce alkyl), -(CO)N(Ci-C₆ alkyl)₂, -(Ci-C₆alkyl)amino, --N(Ci-Ce alkyl)2, -SO2-(Ci-C6 alkyl), -(SO)NH2, and C3-C6 cycloalkyl, where said alkyl, cycloalkyl, alkoxy, or heterocycloalkyl may be substituted by one or more Ci-Ce alkyl, halo, CN, OH, alkoxy, amino, -CO2H, -(CO)NH2, --(CO)NH(Ci-C6 alkyl), or --(CO)N(Ci-C6 alkyl)2, and where said alkyl may be further substituted by one or more fluorine atoms;

Rs is independently selected from the group consisting of hydrogen, Ci-Ce alkyl, C1-C6 alkoxy, and hydroxyl;

R7 and Re are independently hydrogen, Ci-C₄ alkyl, aryl, heteroaryl, (aryi)Ci-C6 alkyl, (heteroaryl)Ci-C6 alkyl, (heterocyclic)Ci-C6 alkyl, (C1-C6 alkyl)aryl, (Ci-Ce alkyl)heteroaryl, or (Ci-Ce alkyl)heterocyclic, wherein said alkyl is further optionally substituted with one or more substituents selected from the group consisting of halo, hydroxy, methoxy, amino, CF3, and C3-C6 cycloalkyl;

k is 0, 1,2, or 3; m and n are both 1 ; and, q is 0,1 or 2.

5. A compound of claim 1 selected from the group consisting of: [(1S)-2,2-difluorocyclopropyl]{(1R,5S)-3-[2-({5-fluoro-6-[(3S)-3-hydroxypyrrolidin-1-yl]pyridin-
3- yl}amino)pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]oct-8-yl}methanone;

(1R,5S)-N-ethyl-3-[2-(1,2-thiazol-4-ylamino)pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8carboxamide;
4-{(1R,5S)-8-[(2,2-difluorocyclopropyl)methyl]-3,8-diazabicyclo[3.2.1]oct-3-yl}-N-(1H-pyrazol-

4- yi)pyrimidin-2-amine;

(1R,5S)-3-(2-{[5-chloro-6-(methylcarbamoyl)pyridin-3-yl]amino}pyrimidin-4-yl)-N-ethyl-3,8diazabicyclo[3.2.1]octane-8-carboxamide;

cyclopropyl[(1R,5S)-3-(2-{[1-(2-hydroxyethyl)-1H-pyrazol-4-yl]amino}pyrimidin-4-yl)-3,8diazabicyclo[3.2.1]oct-8-yl]methanone;

N-(1-methyl-1H-pyrazol-4-yl)-4-{(1R,5S)-8-[1-(methylsulfonyl)azetidin-3-yl]-3,8diazabicyclo[3.2.1]oct-3-yl}pyrimidin-2-amine;

4- ({4-[(1R,5S)-8-{[(1S)-2,2-difluorocyclopropyl]carbonyl}-3,8-diazabicyclo[3.2.1]oct-3yl]pyrimidin-2-yl}amino)-N,6-dimethylpyridine-2-carboxamide;
5- ({4-[(1R,5S)-8-{[(1R,2S)-2-fluorocyclopropyl]carbonyl}-3,8-diazabicyclo[3.2.1]oct-3yl]pyrimidin-2-yl}amino)-N,3-dimethylpyridine-2-carboxamide;

cyclopropyl[(1R,5S)-3-{2-[(1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-3,8diazabicyclo[3.2.1 ]oct-8-yl]methanone;

3-{(1R,5S)-3-[2-(1H-pyrazol-4-ylamino)pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]oct-8yljbutanenitrile;

5-({4-[(1R,5S)-8-(cyclopropyIcarbonyl)-3,8-diazabicyclo[3.2.1]oct-3-yl]pyrimidin-2-yl}amino)-Nethyl-3-methylpyridine-2-carboxamide;

131

3-[(1R,5S)-3-{2-[(1-methyI-1H-pyrazol-4-yl)amino]pynrnidin-4-yl}-3,8-diazabicyclo[3.2.1]oct-8yl]butanenitrile;

5-({4-[(1R,5S)-8-(cycIopropylcarbonyl)-3,8-diazabicyclo[3.2.1]oct-3-yl]pyrimidin-2-yl}amino)-3methylpyridine-2-carboxamide;

(1R,5S)-N-ethyl-3-(2-{[5-fluoro-6-(methylcarbamoyl)pyridin-3-yl]amino}pyrimidin-4-yl)-3,8diazabicyclo[3.2.1 ]octane-8-carboxamide;

3-chloro-5-({4-[(1R,5S)-8-(cycIopropylcarbonyl)-3,8-diazabicyclo[3.2.1]oct-3-yl]pyrimidin-2yl}amino)-N-methylpyridine-2-carboxamide;

(1R,5S)-3-{2-[(1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-N-(propan-2-yl)-3,8diazabicyclo[3.2.1 ]octane-8-carboxamide;

(3,3-difluorocyclobutyl)[(1R,5S)-3-{2-[(1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-3,8diazabicyclo[3.2.1]oct-8-yl]methanone;

1-({(1 R, 5S)-3-[2-(1H-pyrazol-4-ylamino)pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]oct-8yl}methyl)cyclopropanecarbonitrile;

3- [(1 R, 5S)-3-{2-[(1 -methyl-1 H-pyrazol-4-yl)amino]pyrimidin-4-yl}-3,8-diazabicyclo[3.2.1]oct-8yl]butanenitrile;

(1S,2R)-2-{[(1R,5S)-3-{2-[(1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-3,8diazabicyclo[3.2.1]oct-8-yl]carbonyl}cyclopropanecarbonitrile;

(1R,2S)-2-{[(1R,5S)-3-{2-[(1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-3,8diazabicyclo[3.2.1]oct-8-yl]carbonyl}cyclopropanecarbonitriIe;

[(1 R,2R)-2-fluorocyclopropyl][(1R,5S)-3-{2-[(1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}3,8-diazabicyclo[3.2.1]oct-8-yl]methanone;

[(1R,2R)-2-fluorocyclopropyl][(1R,5S)-3-{2-[(1-methyl-1H-pyrazol-4-yl)aminQ]pyrimidin-4-yl}3,8-diazabicyclo[3.2.1]oct-8-yl]methanone;

(1R,5S)-3-{2-[(1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-3,8-diazabicycIo[3.2.1]octane8-carboxamide;

(1 R,5S)-3-{2-[(1-methyl-1 H-pyrazol-4-yl)amino]pyrimidin-4-yl}-N-[5-(trifluoromethyl)pyridin-2yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxamide;

N,3-dimethyl-5-[(4-{(1R,5S)-8-[(3-methyloxetan-3-yI)methyl]-3,8-diazabicyclo[3.2.1]oct-3yl}pyrimidin-2-yI)amino]pyridine-2-carboxamide;

{3-[(1R,5S)-3-{2-[(1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-3,8-diazabicyclo[3.2.1]Qct-8yI]-1-(methylsulfonyl)azetidin-3-yl}acetonitrile;

4- ({4-[8-(cyanoacetyl)-3,8-diazabicyclo[3.2.1]oct-3-yl]pyrimidin-2-yl}amino)-N-ethyIbenzamide; (1R,5S)-N-(cyanomethyl)-3-{2-[(1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-3,8- diazabicyclo[3.2.1]octane-8-carboxamide;

5- ({4-[(1R,5S)-8-{[(1S,2R)-2-fluorocyclopropyl]carbonyl}-3,8-diazabicyclo[3.2.1]oct-3yl]pyrimidin-2-yl}amino)-N,3-dimethylpyridine-2-carboxamide;

5-({4-[(1R,5S)-8-(cis-3-cyanocyclobutyl)-3,8-diazabicyclo[3.2.1]oct-3-yl]pyrimidin-2-yl}amino)N,3-dimethylpyridine-2-carboxamide;

132

5-({4-[(1 R,5S)-8-{[(1R)-2,2-difluorocyclopropyl]methyl}-3,8-diazabicyclo[3.2.1]oct-3yl]pyrimidin-2-yl}amino)-N,3-dimethylpyridine-2-carboxamide;

N,3-dimethyl-5-({4-[(1R,5S)-8-(1,2-oxazol-5-ylmethyl)-3,8-diazabicyclo[3.2.1]oct-3yI]pyrimidin-2-yl}amino)pyridine-2-carboxamide;

2- [5-({4-[(1 R,5S)-8-{[(1 S)-2,2-difluorocyclopropyl]carbonyl}-3,8-diazabicyclo[3.2.1]oct-3- yl]pyrimidin-2-yl}amino)pyridin-2-yI]-2-methylpropanenitrile;

3- {(1R,5S)-3-[2-(1H-pyrazol-4-ylamino)pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]oct-8yl}propanenitrile;

(1R,5S)-N-ethyl-3-[2-(1H-pyrazol-4-ylamino)pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]octane-8carboxamide;

4- [(1R,5S)-8-{[(1S)-2,2-difluorocyclopropyl]methyl}-3,8-diazabicyclo[3.2.1]oct-3-yl]-N-(1methyl-1H-pyrazol-4-yl)pyrimidin-2-amine;

[(1S)-2,2-difluorocyclopropyl][(1R,5S)-3-(2-{[5-fluoro-6-(2-hydroxyethyl)pyridin-3yl]amino}pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]oct-8-yl]methanone;

[(1 S)-2,2-difluorocycIopropyl][(1 R,5S)-3-(2-{[5-fluoro-6-(3-hydroxyazetidin-1 -y I) py ridi n-3yl]amino}pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]oct-8-yl]methanone; · [(1R,5S)-3-(2-{[5-chloro-6-(2-hydroxyethoxy)pyridin-3-yl]amino}pyrimidin-4-yl)-3,8diazabicyclo[3.2.1]oct-8-yl][(1S)-2,2-difluorocyclopropyl]methanone;

{3-[(1R,5S)-3-{2-[(1-methyI-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-3,8-diazabicyclo[3.2.1]oct-8yl]oxetan-3-yl}acetonitrile;

[(1R,5S)-3-(2-{[5-chloro-6-(2-hydroxyethyl)pyridin-3-yl]amino}pyrimidin-4-yl)-3,8diazabicyclo[3.2.1]oct-8-yl][(1S)-2,2-difluorocyclopropyl]methanone;

2- [(1R,5S)-3-{2-[(1-methyl-1 H-pyrazol-4-yl)amino]pyrimidin-4-yl}-3,8-diazabicyclo[3.2.1]oct-8yl]pyridine-4-carbonitrile;

3- [(1R,5S)-3-{2-[(1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-3,8-diazabicyclo[3.2.1]oct-8yljcyclobutanecarbonitrile;

2-[(1R,5S)-3-{2-[(1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-3,8-diazabicycIo[3.2.1]oct-8yl]-1,3-oxazole-5-carbonitrile;

(1R,5S)-N-(2-cyanoethyl)-3-{2-[(1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-3,8diazabicycIo[3.2.1]octane-8-carboxamide;

N-(1-methyl-1H-pyrazol-4-yl)-4-[(1R,5S)-8-(1,2-oxazol-4-ylmethyl)-3,8-diazabicyclo[3.2.1]oct3-yl]pyrimidin-2-amine;

4- ({4-[(1R,5S)-8-{[(1S)-2,2-difluorocyclopropyl]carbonyl}-3,8-diazabicyclo[3.2.1]oct-3yl]pyrimidin-2-yl}amino)-6-(hydroxymethyI)-N-methylpyridine-2-carboxamide;

(1-fluorocycIopropyl)[(1R,5S)-3-{2-[(1-methyI-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-3,8diazabicycIo[3.2.1]oct-8-y!]methanone;

N-(1-methyl-1H-pyrazol-4-yI)-4-[(1R,5S)-8-(1,3-thiazol-2-ylmethyl)-3,8-diazabicyclo[3.2.1]oct3-yl]pyrimidin-2-amine;

cyclopropyl{(1R,5S)-3-[2-(1,2-thiazol-4-yIamino)pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]oct-8yl}methanone;

133 [(1S)-2,2-difluorocyclopropyl]{(1R,5S)-3-[2-({5-fluoro-6-[(3R)-3-hydroxypyrrolidin-1-yl]pyridin3-yl}amino)pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]oct-8-yl}methanone;

5- ({4-[(1R,5S)-8-{[(1S)-2,2-difluorocyclopropyl]methyl}-3,8-diazabicycIo[3.2.1]oct-3yl]pyrimidin-2-yI}amino)-N,3-dimethylpyridine-2-carboxamide;

4- [(1R,5S)-8-{[(1R)-2,2-difluorocycIopropyl]methyl}-3,8-diazabicyclo[3.2.1]oct-3-yl]-N-(1methyl-1H-pyrazol-4-yl)pyrimidin-2-amine;
6- ({4-[(1R_t5S)-8-(cyclopropyIcarbonyl)-3,8-diazabicyclo[3.2.1]oct-3-yl]-5-fluoropyrimidin-2yl}amino)imidazo[1,2-a]pyridine-2-carboxamide;

5- ({4-[(1R,5S)-8-(cyclopropylcarbonyI)-3,8-diazabicyclo[3.2.1]oct-3-yl]-5-fluoropyrimidin-2y!}amino)pyridine-2-sulfonamide;

5-({4-[(1R,5S)-8-(trans-3-cyanocyclobutyl)-3,8-diazabicyclo[3.2.1]oct-3-yI]pyrimidin-2yl}amino)-N,3-dimethylpyridine-2-carboxamide;

1,2-oxazol-5-yl{(1R,5S)-3-[2-(1H-pyrazol-4-ylamino)pyrimidin-4-yl]-3,8-diazabicycIo[3.2.1]oct8-yl}methanone;

N-(1 -methyl-1 H-pyrazol-4-yl)-4-[(1 R, 5S)-8-(methylsulfonyl)-3,8-diazabicyclo[3.2.1]oct-3yl]pyrimidin-2-amine;

(15.25) -2-{[(1R,5S)-3-{2-[(1-methy!-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-3,8diazabicycIo[3.2.1]oct-8-yI]methyl}cyclopropanecarbonitrile;

3- ({4-[(1R,5S)-8-(cyclopropylcarbonyl)-3,8-diazabicyclo[3.2.1]oct-3-yl]-5-fluoropyrimidin-2yl}amino)-N-propyl-1H-pyrazole-5-carboxamide;

(15.25) -2-{[(1R,5S)-3-{2-[(1-methyI-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-3,8diazabicyclo[3.2.1]oct-8-yl]methyl}cyclopropanecarbonitrile;

cyclopropyl{(1R,5S)-3-[5-fluoro-2-(pyridazin-4-yIamino)pyrimidin-4-yl]-3,8diazabicyclo[3.2.1]oct-8-yl}methanone;

4- ({4-[6-(2,2-difluoropropanoyl)-3,6-diazabicyclo[3.1.1]hept-3-yl]-5-fluoropyrimidin-2-yl}amino)N-ethyl-2-methylbenzamide;

(15.25) -2-cyano-N-[(1S,5R,6R)-3-(2-{[6-(2-hydroxyethoxy)pyridin-3-yl]amino}-5methylpyrimidin-4-yl)-6-methyl-3-azabicycIo[3.1.0]hex-1-yl]cyclopropanecarboxamide;

N-[(1S,5R)-3-(5-chloro-2-{[1-(2-hydroxyethyl)-1H-pyrazol-4-yl]amino}pyrimidin-4-yI)-3azabicyclo[3.1.0]hex-1-yl]cyclopropanecarboxamide;

(1S)-2,2-difluoro-N-[(1S,5R,6R)-3-(5-fIuoro-2-{[1-(oxetan-3-yl)-1H-pyrazol-4yl]amino}pyrimidin-4-yl)-6-methyl-3-azabicyclo[3.1.0]hex-1-yl]cyclopropanecarboxamide;

(1S)-2,2-difluoro-N-[(1S,5S)-3-{5-fluoro-2-[(1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-5(hydroxymethyI)-3-azabicyclo[3.1.0]hex-1-yl]cyclopropanecarboxamide;

N-{(1S,5R,6R)-3-[5-fluoro-2-({6-[(2S)-1-hydroxypropan-2-yl]pyridin-3-yl}amino)pyrimidin-4-yl]-

6-methyl-3-azabicyclo[3.1.0]hex-1-yl}cyclopropanecarboxamide;

5- [(4-{(1S,5R,6R)-1-[(cyclopropylcarbonyl)amino]-6-methyl-3-azabicyclo[3.1.0]hex-3-yl}-5fluoropyrimidin-2-yl)amino]-N,3-dimethylpyridine-2-carboxamide;

N-{(1S,5R,6R)-3-[2-({5-chloro-6-[(1R)-1-hydroxyethyl]pyridin-3-yl}amino)-5-fluoropyrimidin-4yl]-6-methyl-3-azabicyclo[3.1.0]hex-1-yl}cyclopropanecarboxamide;

134

X l

(1 R)-2,2-dif luoro-N-[(1 R,5S,6S)-3-{5-fluoro-2-[(1-methyl-1 H-pyrazol-4-yl)amino]pyrimidin-4yl}-6-methyl-3-azabicyclo[3.1.0]hex-1-yl]cyclopropanecarboxamide;

5-[(4-{(1R,5S,6S)-1-[(cyclopropylcarbonyl)amino]-6-methyl-3-azabicyclo[3.1.0]hex-3-yl}-5fluoropyrimidin-2-yl)amino]-N,3-dimethylpyridine-2-carboxamide;

5 N-[(1 R,5S)-3-(5-chloro-2-{[1 -(2-hydroxyethyl)-1 H-pyrazol-4-yl]amino}pyrimidin-4-yl)-3azabicyclo[3.1.0]hex-1-yl]cyclopropanecarboxamide; N-{(1 S,5R,6R)-3-[5-fluoro-2-({6-[(2R)-1hydroxypropan-2-yl]pyridin-3-yl}amino)pyrimidin-4-yl]-6-methy!-3-azabicyclo[3.1.0]hex-1yljcyclopropanecarboxamide; and,(1 S)-2,2-difluoro-N-[(1 R,5S,6S)-3-{5-fluoro-2-[(1-methyl-1 Hpyrazol-4-yl)amino]pyrimidin-4-yl}-6-methyl-3-azabicyclo[3.1.0]hex-1-yl]cycIopropanecarboxamide;

10 or, a pharmaceutically acceptable sait thereof.

6. A compound of claim 2, selected from the group consisting of: N-ethyl-4-({5-fluoro-4-[6-(2-fluoro-2-methylpropanoyl)-3,6-diazabicyclo[3.1.1]hept-3-yl]pyrimidin-2yl}amino)-2-methyibenzamide; N-ethyI-4-({5-fIuoro-4-[6-(trifluoroacetyl)-3,6-diazabicyclo[3.1.1]hept-3-

15 yl]pyrimidin-2-yl}amino)-2-methylbenzamide; N-ethyl-2-methyl-4-({4-[6-(trifluoroacetyl)-3,6diazabicyclo[3.1.1]hept-3-yl]pyrimidin-2-yl}amino)benzamide; 4-({4-[6-(cyclopropylcarbonyl)-3,6diazabicycIo[3.1.1]hept-3-yl]pyrimidin-2-yl}amino)-N-ethyi-2-methylbenzamide; and, 4-({4-[6-(2,2difluoropropanoyl)-3,6-diazabicyclo[3.1.1]hept-3-yl]pyrimidin-2-yi}amino)-N-ethylbenzamide;

or, a pharmaceutically acceptable sait thereof.
7. A compound of claim 3, selected from the group consisting of:

4- ({4-[8-(cyclopropylcarbonyl)-3,8-diazabicyclo[3.2.1]oct-3-yl]-5-fluoropyrimidin-2-yl}amino)-Nethylbenzamide;

N-ethyl-4-({5-fluoro-4-[8-(trifluoroacetyI)-3,8-diazabicyclo[3.2.1]oct-3-yl]pyrimidin-2-yl}amino)25 2-methylbenzamide;

(1R,5S)-3-(2-{[5-methyl-6-(methylcarbamoyl)pyridin-3-yl]amino}pyrimidin-4-yl)-N-(2,2,2trif I uoroethy !)-3,8-diazabicyclo[3.2.1 ]octane-8-carboxamide; (1R,5S)-N-(cyanomethyl)-3-(2-{[5-methyl-6-(methylcarbamoyl)pyridin-3-yl]amino}pyrimidin-4yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxamide;

30 5-({4-[(1 R,5S)-8-{[(1 S)-2,2-difluorocycIopropyl]carbonyi}-3,8-diazabicyclo[3.2.1]oct-3yl]pyrimidin-2-yl}amino)-N,3-dimethylpyridine-2-carboxamide;

tert-butyl 3-(2-{[4-(ethylcarbamoyl)-3-methylphenyI]amino}-5-fluoropyrimidin-4-yi)-3,8diazabicyclo[3.2.1]octane-8-carboxylate;

5- ({4-[(1R,5S)-8-{[(1R,2R)-2-cyanocyciopropyl]carbonyl}-3,8-diazabicyclo[3.2.1]oct-3-

35 yl]pyrimidin-2-yl}amino)-N,3-dimethylpyridine-2-carboxamide;

3-chloro-5-({4-[(1R,5S)-8-{[(1 S)-2,2-difluorocyclopropyl]carbonyl}-3,8-diazabicyclo[3.2.1]oct-3yl]pyrimidin-2-yl}amino)-N-methylpyridine-2-carboxamide;

N-(1-methyl-1H-pyrazol-4-yl)-4-[(1R,5S)-8-(1,2-thiazol-5-ylmethyl)-3,8-diazabicycIo[3.2.1]oct-3yl]pyrimidin-2-amine;

[(1 S)-2,2-difluorocyclopropyl]{(1 R,5S)-3-[2-({6-[(2S)-1-hydroxypropan-2-yl]pyridin-3yl}amino)pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]oct-8-yl}methanone;

3-chloro-5-({4-[(1R,5S)-8-{[(1R,2R)-2-cyanocyclopropyl]carbonyl}-3,8-diazabicycIo[3.2.1]oct3-yl]pyrimidin-2-yl}amino)-N-methylpyridine-2-carboxamide;

5 [(1 S)-2,2-difluorocyclopropyl][(1 R,5S)-3-(2-{[5-fluoro-6-(hydroxymethyl)pyridin-3yl]amino}pyrimidin-4-yl)-3,8-diazabicyclo[3.2.1]oct-8-yl]methanone;

5-[(4-{(1R,5S)-8-[(2,2-difluorocyclopropyl)carbonyl]-3,8-diazabicyclo[3.2.1]oct-3-yl}pyrimidin-2yl)amino]-3-methylpyridine-2-carboxamide;

5-({4-[(1R,5S)-8-(cyclopropylcarbonyl)-3,8-diazabicyclo[3.2.1]oct-3-yl]pyrimidin-2-yl}amino)10 N,3-dimethylpyridine-2-carboxamide; (1R,5S)-N-ethyl-3-(2-{[5-methyl-6-(methylcarbamoyl)pyridin-3-yl]amino}pyrimidin-4-yl)-3,8diazabicyclo[3.2.1]octane-8-carboxamide;

[(1S)-2,2-difluorocyclopropyl]{(1R,5S)-3-[2-({6-[(2R)-1-hydroxypropan-2-yl]pyridin-3yl}amino)pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]oct-8-yl}methanone;

15 N-(1-methyl-1 H-pyrazol-4-yl)-4-[(1 R,5S)-8-(1,2-oxazol-5-ylmethyl)-3,8-diazabicyclo[3.2.1]oct3-yl]pyrimidin-2-amine; cyclopropyI{(1R,5S)-3-[2-(1H-pyrazol-4-ylamino)pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]oct-8yljmethanone;

5-({4-[(1R,5S)-8-{[(1R,2R)-2-cyanocyclopropyl]carbonyl}-3,8-diazabicyclo[3.2.1]oct-320 yl]pyrimidin-2-yl}amino)-3-fluoro-N-methylpyridine-2-carboxamide;

[(1 R)-2,2-difluorocyclopropyl]{(1 R,5S)-3-[2-(1 H-pyrazol-4-ylamino)pyrimidin-4-yl]-3,8diazabicyclo[3.2.1]oct-8-yl}methanone; and,

5-({4-[(1R,5S)-8-{[(1R)-2,2-difluorocyclopropyl]carbonyl}-3,8-diazabicyclo[3.2.1]oct-3yl]pyrimidin-2-yl}amino)-3-fIuoro-N-methylpyridine-2-carboxamide;

25 or, a pharmaceutically acceptable sait thereof.
8. A compound of claim 4, selected from the group consisting of:

(1 R)-2,2-difluoro-N-[(1 S,5R,6R)-3-{5-fluoro-2-[(1-methyl-1 H-pyrazol-4-yl)amino]pyrimidin-4yi}-6-methyl-3-azabicyclo[3.1.0]hex-1-yl]cyclopropanecarboxamide;

30 N-[(1S,5R,6R)-3-(2-{[5-chloro-6-(hydroxymethyl)pyridin-3-yl]amino}-5-fluoropyrimidin-4-yl)-6methyl-3-azabicyclo[3.1.0]hex-1-yl]cyclopropanecarboxamide; and,

N-[(1S,5R,6R)-3-(5-fluoro-2-{[6-(2-hydroxyethyl)pyridin-3-yl]amino}pyrimidin-4-yl)-6-methyl-3azabicyclo[3.1.0]hex-1-yl]cyclopropanecarboxamide;

or, a pharmaceutically acceptable sait thereof.
9. A compound of claim 1, where the compound is [(1 S)-2,2-difluorocyclo- propyl]{(1R,5S)-3-[2-(1 H-pyrazoi-4-ylamino)pyrimidin-4-yl]-3,8-diazabicyclo[3.2.1]oct-8-yl]methanone; or, a pharmaceutically acceptable sait thereof.

136
10. A compound of claim 1, where the compound is [(1S)-2,2-difluorocyclopropyl][(1R,5S)-3-{2-[(1-methyl-1H-pyrazol-4-yl)amino]pyrimidin-4-yl}-3,8-diazabicyclo[3.2.1]oct-8yl]methanone; or, a pharmaceutically acceptable sait thereof.

5
11. A compound of claim 1, wherein the compound is 5-({4-[(1 R,5S)-8-{[(1S)-2,2difluorocyclopropyl]carbonyl}-3,8-diazabicyclo[3.2.1]oct-3-yl]pyrimidin-2-yl}amino)-3-fIuoro-Nmethylpyridine-2-carboxamide; or, a pharmaceutically acceptable sait thereof.
12. A compound of claim 1, wherein the compound is (1 R,5S)-N-ethyl-3-{2-[(1 -methyl-1 H10 pyrazol-4-yI)amino]pyrimidin-4-yl}-3,8-diazabicyclo[3.2.1]octane-8-carboxamide; or, a pharmaceutically acceptable sait thereof.
13. A pharmaceutical or a veterinary composition comprising a compound of claim 1, or a pharmaceutically acceptable sait thereof, and a pharmaceutically acceptable carrier.
14. A therapeuticaliy effective amount of a compound of claim 1, or a pharmaceutically acceptable sait thereof, or a pharmaceutically acceptable solvaté of said compound or sait for use in a method of treating or preventing a disorder or condition selected from inflammation, autoimmune disease, neuroinflammation, arthritis, rheumatoid arthritis, spondyloarthropathies, systemic lupus

20 erythematous, lupus nephritis, arthritis, osteoarthritis, gouty arthritis, pain, fever, pulmonary sarcoisosis, silicosis, cardiovascular disease, atherosclerosis, myocardial infarction, thrombosis, congestive heart failure and cardiac reperfusion injury, cardiomyopathy, stroke, ischaemia, reperfusion injury, brain edema, brain trauma, neurodegeneration, liver disease, inflammatory bowel disease, Crohn’s disease, ulcerative colitis, nephritis, retinitis, retinopathy, macular degeneration, glaucoma, diabètes (type 1 and 25 type 2), diabetic neuropathy, viral and bacterial infection, myalgia, endotoxic shock, toxic shock syndrome, autoimmune disease, osteoporosis, multiple sclerosis, endometriosis, menstrual cramps, vaginitis, candidiasis, cancer, fibrosis, obesity, muscular dystrophy, polymyositis, dermatomyositis, autoimmune hepatitis, primary biliary cirrhosis, primary sclerosing cholangitis, vitiligo, alopecia, Aizheimer’s disease, skin flushing, eczema, psoriasis, atopie dermatitis and sunburn.
15. A compound of claim 1, or a pharmaceutically acceptable sait thereof, or a pharmaceutically acceptable solvaté of said compound or sait for use in a method of treating or preventing a disorder or condition selected from acute myeloid leukemia, T cell acute lymphoblastic leukemia, multiple myeloma, pancreatic cancer, brain tumors, gliomas including astrocytoma,

35 oligodendroglioma, and glioblastoma, acute CNS trauma including traumatic brain injury, encephalitis, stroke, and spinal cord injury, epilepsy, seizures, PD, ALS, fronto-temporal lobe dementia, and with neuropsychiatrie disorders including schizophrenia, bipolar disorder, dépréssion, treatment résistant dépréssion, PTSD, anxiety, and auto-antibodies mediated encéphalopathies.