Heterocyclic SIK inhibitors

Abstract

Compounds of formula (I): or pharmaceutically acceptable salts thereof as SIK inhibitors wherein A1 and A2 are independently O or S; x is selected from CH2, CD2, NR3, O and S, wherein R3 is selected from hydrogen, C1-C4 linear or branched alkyl, halogenated (C1-C4) linear or branched alkyl and hydroxyl (C1-C4) linear or branched alkyl; y and Z are selected from C and N, when Y is C, Z is N, and when Y is N, Z is C; r1 and R2 are independently selected from the group consisting of hydrogen, deuterium, C1-C4 linear or branched alkyl, and the like; or C1-C2 alkyl substituted by a C3-C5 cycloalkyl ring; or they together form a C3-C6 cycloalkyl ring; or if X is CH2 or CD2, R1 and R2 are independently selected from the group consisting of hydrogen, deuterium, halogen, hydroxyl, C1-C4 linear or branched alkyl, and the like; r4 is selected from hydrogen, deuterium, cyano, halogen, (C1-C3) alkoxy and the like; r5 is selected from hydrogen, deuterium, halogen, C1-C3 alkoxy, amino, (C1-C4 linear or branched alkyl) amino and the like; r6 is selected from hydrogen, deuterium, halogen and CO2R7, wherein R7 is selected from H, C1-C4 straight-chain or branched-chain alkyl and the like; r8 is selected from hydrogen, deuterium and C1-C3 straight chain or branched chain alkyl; r9 is selected from a C1-C3 straight chain or branched chain alkyl group and a halogenated (C1-C3) straight chain or branched chain alkyl group; and n and m are independently selected from 0, 1, and 2. The invention also relates to pharmaceutical compositions thereof and methods of treatment using the same.

Description

Technical Field

[0001] The present invention relates to novel salt-inducible kinase (SIK) inhibitors, pharmaceutical compositions comprising such compounds and their use as medicaments. More particularly, the present invention provides novel SIK inhibitors useful for the treatment and prevention of intestinal disorders and ulcerative colitis. Background Art

[0002] Protein kinases are a family of enzymes that catalyze the phosphorylation of the hydroxyl side chains of serine, threonine or tyrosine amino acids of their protein substrates. The resulting phosphorylated substrates play a physiological role in controlling cellular functions, including cell signaling, metabolism, differentiation, motility, survival, proliferation and apoptosis. Poor control of kinase function has been associated with a wide range of inflammatory, autoimmune, allergic, fibrotic, neoplastic and metabolic diseases. Therapeutic agents that inhibit protein kinases have been a successful and effective approach to treating disease.

[0003] Three closely related salt-inducible kinase (SIK) isoforms have been identified: SIK1, SIK2 and SIK3. SIK1 was identified in 1999 (Wang, FEBS Lett. (1999) 453, 135-139), followed by close homologs SIK2 and SIK3 (Horike, J. Biol. Chem. (2003) 278 18440-18447; Katoh, Molecular and Cellular Endocrinology (2004) 217, 109-112). These serine-threonine kinases belong to the AMP-activated protein kinase (AMPK) subfamily and are widely expressed in all cell types and tissues.

[0004] The characterized substrates of SIK are the second class histone deacetylases (HDAC4, HDAC5, HDAC7 and HDAC9) and the transcriptional coactivators (CRTC2, CRTC3) regulated by the cyclic AMP response element binding protein (CREB). SIK kinase phosphorylates these proteins and causes their nuclear export and cytoplasmic localization by binding to 14-3-3s proteins (Berdeaux, Nature Medicine (2007) 13 597-603; Henriksson (2015) J. Cell Sci. 128 472-486; Clark, Proc. Natl. Acad. Sci. USA (2012) 109 16986-16991). Inactivation or inhibition of SIK kinase causes its translocation to the nucleus (Ozanne, Biochemical Journal (2015) 465, 271-279). Once translocated to the nucleus, class 2 HDAC molecules inhibit gene expression, including proinflammatory cytokines, chemokines, and other proteins involved in signal transduction and immune responses. Thus, inhibition of SIK has been shown to cause a reduction in proinflammatory molecules such as TNF-α, IL-6, IL-12, GM-CSF, IL-13, CCL2, CCL3, CCL4, and CCL24 (Ozanne, supra; Darling, Biochem. J. (2017) 474 521-537; Darling, J. Biol. Chem. (2021) 296 100428), which are key contributors to the pathology of inflammatory diseases.

[0005] Nuclear translocation of the CRTC transcriptional coactivator causes activation of the transcription factor CREB and induction of CREB-regulated gene expression (including cytokine IL-10). IL-10 is an anti-inflammatory cytokine whose immunomodulatory effects are crucial in regulating immune responses and their disease-associated defects (Saraiva, Journal of Experimental Medicine (2020) 217 ​​e20190418). Pharmacological inhibition or gene excision of SIK kinase activity has been shown to induce IL-10 (Clark, supra; Sundberg, PNAS (2014) 111 (34) 12468-73; Ozanne, supra; Darling, supra).

[0006] Inhibition of SIK kinases has been shown to result in a concomitant downregulation of pro-inflammatory molecules and induction of anti-inflammatory molecules. Thus, inhibition of SIK may result in suppression of inflammation and promotion of an immune tolerogenic, anti-inflammatory phenotype; these factors make the SIK family of kinases targets for disease intervention, including inflammatory bowel disease, rheumatoid arthritis, psoriasis, vitiligo, and other immune disorders.

[0007] Despite advances in therapeutics, patients with these diseases still suffer from debilitating symptoms and may have difficulty managing their disease with current treatment options and standards of care. Patients may not achieve deep, long-term remission, or they may relapse or experience adverse events or become refractory to current therapies over time. Therefore, there is a significant unmet medical need for additional effective therapies for the treatment of these diseases. Summary of the invention

[0008] The present invention provides a compound having a structure of formula I:

[0009]

[0010] or a pharmaceutically acceptable salt thereof, wherein

[0011] A1 and A2 are independently O or S;

[0012] X is selected from CH2, CD2, NR3, O and S, wherein R3 is selected from hydrogen, C1-C4 straight chain or branched alkyl, halogenated (C1-C4) straight chain or branched alkyl and hydroxy (C1-C4) straight chain or branched alkyl;

[0013] Y and Z are selected from C and N, wherein when Y is C, then Z is N, and when Y is N, then Z is C;

[0014] R1 and R2 are independently selected from hydrogen, deuterium, C1-C4 straight or branched alkyl, halo (C1-C4) straight or branched alkyl, hydroxy (C1-C4) straight or branched alkyl, cyano (C1-C4) straight or branched alkyl and C1-C3 alkoxy (C1-C4) straight or branched alkyl; or C1-C2 alkyl substituted with a C3-C5 cycloalkyl ring; or joined together to form a C3-C6 cycloalkyl ring; or If X is CH2 or CD2, R1 and R2 are independently selected from hydrogen, deuterium, halogen, hydroxyl, C1-C4 straight or branched alkyl, halo(C1-C4) straight or branched alkyl, hydroxyl(C1-C4) straight or branched alkyl, cyano(C1-C4) straight or branched alkyl and C1-C3 alkoxy(C1-C4) straight or branched alkyl, and C1-C2 alkyl substituted with a C3-C5 cycloalkyl ring;

[0015] R4 is selected from hydrogen, deuterium, cyano, halogen, (C1-C3) alkoxy, halo (C1-C3) alkoxy, mercapto substituted by C1-C3 alkyl, C1-C4 straight or branched alkyl, halo (C1-C4) straight or branched alkyl and hydroxy (C1-C4) straight or branched alkyl;

[0016] R5 is selected from hydrogen, deuterium, halogen, C1-C3 alkoxy, amino, (C1-C4 straight chain or branched alkyl)amino, di(C1-C4 straight chain or branched alkyl)amino, (4-6 membered) heterocyclyl, C1-C4 straight chain or branched alkyl, halo(C1-C4) straight chain or branched alkyl and hydroxy(C1-C4) straight chain or branched alkyl;

[0017] R6 is selected from hydrogen, deuterium, halogen, C1-C4 straight or branched alkoxy, CONH2, C1-C4 straight or branched alkyl, halo (C1-C4) straight or branched alkyl, hydroxy (C1-C4) straight or branched alkyl and CO2R7, wherein R7 is selected from H and C1-C4 straight or branched alkyl;

[0018] R8 is selected from hydrogen, deuterium and C1-C3 straight or branched alkyl;

[0019] R9 is selected from C1-C3 straight or branched alkyl and halogenated (C1-C3) straight or branched alkyl; and

[0020] n and m are independently selected from 0, 1 and 2.

[0021] In other aspects, the present invention also provides:

[0022] A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of formula I or a pharmaceutically acceptable salt thereof.

[0023] In other aspects, the present invention also provides methods for treating conditions or disorders comprising:

[0024] Arthritis, including rheumatoid arthritis, juvenile arthritis, and psoriatic arthritis;

[0025] Autoimmune or inflammatory diseases or conditions, including Hashimoto's thyroiditis, autoimmune hemolytic anemia, autoimmune atrophic gastritis of pernicious anemia, autoimmune encephalomyelitis, autoimmune orchitis, Goodpasture's disease, autoimmune thrombocytopenia, sympathetic ophthalmia, myasthenia gravis, Graves' disease, primary biliary cirrhosis, autoimmune hepatitis, primary sclerosing cholangitis, chronic invasive hepatitis, nonalcoholic fatty liver disease, nonalcoholic steatosis, ulcerative colitis and membranous glomerulopathy, systemic lupus erythematosus, rheumatoid arthritis, psoriatic arthritis, Sjogren's syndrome, Reiter's syndrome, syndrome), polymyositis, dermatomyositis, type I interferonopathies (including Aicardi-Goutières syndrome and other Mendelian diseases with overexpression of type I interferons), systemic sclerosis, polyarteritis nodosa, multiple sclerosis, relapsing-remitting multiple sclerosis, primary progressive multiple sclerosis, secondary progressive multiple sclerosis, and bullous pemphigoid, as well as additional autoimmune diseases, which may be O-cell (humoral) or T-cell based, including Cogan's syndrome, ankylosing spondylitis, Wegener's granulomatosis, autoimmune alopecia, type I or juvenile-onset diabetes mellitus, or thyroiditis;

[0026] Cancer or tumors, including digestive tract / gastrointestinal cancer, colon cancer, liver cancer, skin cancer (including mast cell tumor and squamous cell carcinoma), breast cancer and breast cancer, ovarian cancer, prostate cancer, lymphoma, leukemia (including acute myeloid leukemia and chronic myeloid leukemia), kidney cancer, lung cancer, muscle cancer, bone cancer, bladder cancer, brain cancer, melanoma (including oral and metastatic melanoma), Kaposi's sarcoma, myeloma (including multiple myeloma), myeloproliferative disease, proliferative diabetic retinopathy, or angiogenesis-related disorders (including solid tumors);

[0027] Diabetes, including type 1 diabetes or complications of diabetes;

[0028] ocular disease, illness or condition, including autoimmune disease of the eye, keratoconjunctivitis, vernal conjunctivitis, uveitis (including uveitis associated with Behcet's disease and lens-induced uveitis), keratitis, herpetic keratitis, keratoconus, corneal epithelial nutritional atrophy, corneal leukoma, ocular pemphigus, Mooren's ulcer, scleritis, Grave's ophthalmopathy, Vogt-Koyanagi-Harada syndrome, keratoconjunctivitis sicca (dry eyes), vesicles, iridocyclitis, sarcoidosis, endocrine eye disease, sympathetic ophthalmia, allergic conjunctivitis or ocular neovascularization;

[0029] Inflammatory bowel disease, including Crohn's disease, ulcerative colitis, inflammatory bowel disease, celiac disease, proctitis, eosinophilic gastroenteritis, or mastocytosis;

[0030] Neurodegenerative diseases, including motor neuron disease, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, cerebral ischemia or neurodegenerative diseases caused by traumatic injury, impact, glutamate neurotoxicity or hypoxia; stroke, myocardial ischemia, renal ischemia, heart attack, cardiac hypertrophy, atherosclerosis and arteriosclerosis, ischemic / reperfusion injury of organ hypoxia or platelet aggregation;

[0031] Skin diseases, conditions or disorders, including atopic dermatitis, hand dermatitis, contact dermatitis, allergic contact dermatitis, irritant contact dermatitis, neurodermatitis, perioral dermatitis, stasis dermatitis, dyshidrotic eczema, xerotic dermatitis, nummular dermatitis, seborrheic dermatitis, eyelid dermatitis, diaper dermatitis, dermatomyositis, lichen planus, lichen sclerosis, alopecia areata, vitiligo, rosacea, epidermolysis bullosa, keratosis pilaris, pityriasis alba, pemphigus, labia vaginitis, acne, chronic spontaneous urticaria, chronic idiopathic urticaria, chronic physical urticaria, Vogt-Koyanagi-Harada disease, Sutton's nevus / nevus nevus / nevi), post-inflammatory hypopigmentation, senile vitiligo, chemical / drug-induced vitiligo, cutaneous lupus erythematosus, discoid lupus, palmoplantar pustulosis, pemphigoid, Sweet's syndrome, suppurative hidradenitis, psoriasis, plaque psoriasis, pustular psoriasis, nail psoriasis, flexural psoriasis, guttate psoriasis, psoriatic arthritis, erythrodermic psoriasis, or inverse psoriasis;

[0032] Allergic reactions, including mammalian allergic dermatitis (including equine allergic diseases such as bite hypersensitivity), summer eczema, equine sweet itch, equine panting, inflammatory airway disease, recurrent airway obstruction, airway hyperreactivity, or chronic obstructive pulmonary disease;

[0033] Asthma and other obstructive airway diseases, including chronic or refractory asthma, late-onset asthma, bronchitis, bronchial asthma, allergic asthma, intrinsic asthma, exogenous asthma or dust-induced asthma; and

[0034] Transplant rejection, including islet transplant rejection, bone marrow transplant rejection, graft-versus-host disease, organ and cell transplant rejection, such as bone marrow, cartilage, cornea, heart, intervertebral disc, islet, kidney, limb, liver, lung, muscle, myoblast, nerve, pancreas, skin, small intestine or trachea, or xenotransplantation.

[0035] The present invention will be further understood from the following description given for the purpose of example only. The present invention relates to a class of benzonitrile derivatives. In particular, the present invention relates to benzonitrile compounds suitable for use as SIK inhibitors. Various aspects of the present invention will be understood through the following discussion and examples, but the present invention is not limited thereto.

[0036] The terms "isolated" and "in isolated form" with respect to a compound mean that the compound or its salt refers to the physical state of the compound after separation from a synthetic process, such as from a reaction mixture. Thus, the terms "isolated" and "in isolated form" with respect to a compound refer to the physical state of the compound after it is obtained from a purification process or a process described in the present application or well known to those skilled in the art (e.g., chromatography, recrystallization, and the like), and its purity is sufficient to be characterized by standard analytical techniques described in the present application or well known to those skilled in the art. As an example, the purification techniques disclosed in the present application (e.g., LC-MS and LC-MS / MS techniques) produce isolated forms of the compounds of the present invention. It is expected that such separation and purification techniques will produce a product purity containing at least about 70% by weight, at least about 80% by weight, at least about 90% by weight, at least about 95% by weight, at least about 97% by weight, or at least about 99% by weight of the compound or its salt.

[0037] The term "subject" refers to a mammal, such as a human, livestock, or companion animal. "Patient," "individual," or "subject," used interchangeably, is a mammal, more preferably a human.

[0038] The term "companion animal" or "companion animal" refers to an animal that is kept as a pet or domestic animal. Examples of companion animals include dogs, cats, and rodents, including hamsters, guinea pigs, gerbils, and the like, rabbits, ferrets, and birds.

[0039] The term "livestock" refers to animals raised or cultivated in an agricultural environment to produce products such as food or fiber or to obtain their labor. In some embodiments, livestock are suitable for consumption by mammals (e.g., humans). Examples of livestock animals include cattle, goats, horses, pigs, sheep (including lambs) and rabbits, as well as poultry, such as chickens, ducks and turkeys.

[0040] Unless otherwise defined herein, scientific and technical terms used in connection with the present invention shall have the meanings that are commonly understood by one of ordinary skill in the art.

[0041] If substituents are described as being "independently selected" from a group, each substituent is selected independently of the other substituents. Thus each substituent may be the same as or different from the other substituents.

[0042] Unless otherwise indicated, the term "treat" as used in this application means to reverse, alleviate, inhibit the progression of, delay the progression of, delay the onset of, or prevent the disease or condition or one or more symptoms of the disease or condition to which the term applies, or one or more symptoms of the disease or condition. Unless otherwise indicated, the term "treat" as used in this application refers to the act of treating as defined immediately above.

[0043] The term "selective" when used in this application to describe a functionally defined receptor ligand or enzyme inhibitor means selectivity for the defined receptor or enzyme subtype compared to other receptors or enzyme subtypes in the same family. For example, a selective SIK inhibitor is a compound that inhibits a SIK enzyme subtype more effectively than any other SIK enzyme subtype. Such selectivity is at least 2-fold (as measured using a conventional binding assay), or at least 10-fold in another embodiment, or at least 100-fold in yet another embodiment.

[0044] The term "therapeutically effective" refers to the ability of an agent to prevent a condition or reduce the severity of a condition. The phrase "therapeutically effective" should be understood to be equivalent to the phrase "effective for treatment, prevention or improvement", and both are intended to qualify the amount of an agent that will achieve the goal of alleviating the severity and frequency of cancer, cardiovascular disease, or pain and inflammation compared to the treatment of each agent itself.

[0045] "Pharmaceutically acceptable" means suitable for use with the subject.

[0046] As used throughout this specification and the appended claims, the following terms have the following meanings:

[0047] As used herein, the term "C1-C3 straight or branched chain alkyl" means a straight or branched hydrocarbon chain containing 1 to 3 carbon atoms. Representative examples of C1-C3 straight or branched chain alkyl include methyl, ethyl, n-propyl and isopropyl.

[0048] As used in this application, the term "C1-C4 straight or branched alkyl" means a straight or branched hydrocarbon chain containing 1 to 4 carbon atoms. Representative examples of C1-C4 straight or branched alkyl include, but are not limited to, methyl, ethyl, n-propyl, n-butyl, isobutyl and isopropyl.

[0049] As used in this application, the term "halo (C1-C3) straight or branched chain alkyl" means at least one halogen as defined herein attached to the parent molecular moiety via a (C1-C3) straight or branched chain alkyl as defined herein. Representative examples of halo (C1-C3) straight or branched chain alkyl include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl and 2,2-difluoropropyl.

[0050] As used herein, the term "halo (C1-C4) straight or branched chain alkyl" means at least one halogen as defined herein attached to the parent molecular moiety via a (C1-C4) straight or branched chain alkyl as defined herein. Representative examples of halo (C1-C4) straight or branched chain alkyl include, but are not limited to, fluoromethyl, chloromethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, and pentafluoroethyl.

[0051] As used in this application, the term "cyano (C1-C4) straight or branched chain alkyl" means at least one cyano or nitrile group as defined herein attached to the parent molecular moiety via a (C1-C4) straight or branched chain alkyl as defined herein. Representative examples of cyano (C1-C4) straight or branched chain alkyl include, but are not limited to, cyanomethyl, 2-cyanoethyl, 3-cyanopropyl and 4-cyanobutyl.

[0052] As used herein, the term "hydroxy (C1-C4) straight or branched chain alkyl" means at least one hydroxyl group as defined herein is attached to the parent molecular moiety via a (C1-C4) straight or branched chain alkyl group as defined herein. Representative examples of hydroxy (C1-C4) straight or branched chain alkyl groups include, but are not limited to, hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl, 2,3-dihydroxypropyl, and 3,4-dihydroxybutyl.

[0053] As used herein, the term "C1-C3 alkoxy (C1-C4) straight or branched alkyl" means at least one C1-C3 alkoxy group, as defined herein, attached to the parent molecular moiety via a (C1-C4) straight or branched alkyl group, as defined herein. Representative examples of C1-C3 alkoxy (C1-C4) straight or branched alkyl groups include, but are not limited to, 2-methoxyethyl, 2-methoxypropyl, 3-methoxypropyl, 2-ethoxyethyl, and 3,4-dimethoxybutyl.

[0054] As used in this application, the term "halo (C1-C3) alkoxy" means at least one halogen as defined herein attached to the parent molecular moiety via a (C1-C3) alkoxy group as defined herein. Representative examples of halo (C1-C3) alkoxy include, but are not limited to, fluoromethoxy, difluoromethoxy, trifluoromethoxy and 2-fluoroethoxy.

[0055] As used herein, the term "C1-C3 alkoxy" means a (C1-C3) alkoxy group, as defined herein, attached to the parent molecular moiety through an oxygen atom. Representative examples of (C1-C3) alkoxy include methoxy, ethoxy, propoxy and 2-propoxy.

[0056] As used herein, the term "C1-C4 straight or branched chain alkoxy" means a C1-C4 straight or branched chain alkyl group as defined herein attached to the parent molecular moiety via an oxygen atom. Representative examples of C1-C4 straight or branched chain alkoxy groups include methoxy, ethoxy, propoxy, 2-propoxy, and butoxy.

[0057] As used herein, the term "thiol substituted with C1-C3 alkyl" means a C1-C3 alkyl group, as defined herein, attached to the parent molecular moiety through a sulfur atom. Representative examples of C1-C3 alkylthio groups include methylthio, ethylthio, propylthio and 2-propylthio.

[0058] As used herein, the term "(C3-C5)cycloalkyl" means a saturated cyclic hydrocarbon group containing 3 to 5 carbons, and examples of (C3-C5)cycloalkyl include cyclopropyl, cyclobutyl and cyclopentyl.

[0059] As used herein, the term "(C3-C6)cycloalkyl" means a saturated cyclic hydrocarbon group containing 3 to 6 carbons, and examples of (C3-C6)cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

[0060] As used herein, the term "(C1-C4 straight chain or branched chain alkyl)amino" means a (C1-C4 straight chain or branched chain alkyl)amino group attached to the parent molecular moiety through a nitrogen atom. Representative examples of (C1-C4 straight chain or branched chain alkyl)amino groups include, but are not limited to, methylamino, ethylamino, propylamino, 2-propylamino, and butylamino groups.

[0061] As used herein, the term "di(C1-C4 straight or branched alkyl)amino" means a di(C1-C4 straight or branched alkyl)amino group attached to the parent molecular moiety via a nitrogen atom. Representative examples of di(C1-C4 straight or branched alkyl)amino groups include, but are not limited to, dimethylamino, ethylmethylamino, diethylamino, methylpropylamino, 2-propylmethylamino, and butylmethylamino.

[0062] As used in this application, the term "(4-6 membered) heterocyclyl" or "heterocycle" means a 4, 5 or 6 membered ring containing at least one heteroatom independently selected from the group consisting of O, N and S. The 4 membered ring contains 1 heteroatom selected from the group consisting of O, N and S; the 5 and 6 membered rings contain one or two heteroatoms selected from the group consisting of O, N and S. The heterocycle is attached to the parent molecular moiety via any carbon atom or any nitrogen atom contained in the heterocycle. Representative examples of heterocycles include, but are not limited to, azetidinyl, morpholinyl, piperazinyl, piperidinyl, pyranyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, thiomorpholinyl and thiopyranyl.

[0063] As used in the present application, the term "C1-C2 alkyl" means a methyl group or an ethyl group.

[0064] As used in this application, the term "amino" means a -NH2 group.

[0065] As used in this application, the term "cyano" or "nitrile" refers to a -CN group.

[0066] As used in this application, the term "halo" or "halogen" means -Cl, -Br, -I or -F.

[0067] As used in this application, the term "hydroxy" or "hydroxyl" means -OH. DETAILED DESCRIPTION

[0068] The present invention relates to novel compounds which are SIK modulators useful for treating diseases and conditions associated with dysregulation of SIK (particularly SIK1, SIK2 and SIK3). The present invention further provides pharmaceutical compositions comprising such SIK enzyme modulators and methods for treating and / or preventing such diseases and conditions.

[0069] According to a first aspect of the present invention, there is provided a compound of formula I:

[0070]

[0071] or a pharmaceutically acceptable salt thereof, wherein

[0072] A1 and A2 are independently O or S;

[0073] X is selected from CH2, CD2, NR3, O and S, wherein R3 is selected from hydrogen, C1-C4 straight chain or branched alkyl, halogenated (C1-C4) straight chain or branched alkyl and hydroxy (C1-C4) straight chain or branched alkyl;

[0074] Y and Z are selected from C and N, wherein when Y is C, then Z is N, and when Y is N, then Z is C;

[0075] R1 and R2 are independently selected from hydrogen, deuterium, C1-C4 straight or branched alkyl, halo (C1-C4) straight or branched alkyl, hydroxy (C1-C4) straight or branched alkyl, cyano (C1-C4) straight or branched alkyl and C1-C3 alkoxy (C1-C4) straight or branched alkyl; or C1-C2 alkyl substituted with a C3-C5 cycloalkyl ring; or joined together to form a C3-C6 cycloalkyl ring; or If X is CH2 or CD2, R1 and R2 are independently selected from hydrogen, deuterium, halogen, hydroxyl, C1-C4 straight or branched alkyl, halo(C1-C4) straight or branched alkyl, hydroxyl(C1-C4) straight or branched alkyl, cyano(C1-C4) straight or branched alkyl and C1-C3 alkoxy(C1-C4) straight or branched alkyl, and C1-C2 alkyl substituted with a C3-C5 cycloalkyl ring;

[0076] R4 is selected from hydrogen, deuterium, cyano, halogen, (C1-C3) alkoxy, halo (C1-C3) alkoxy, mercapto substituted by C1-C3 alkyl, C1-C4 straight or branched alkyl, halo (C1-C4) straight or branched alkyl and hydroxy (C1-C4) straight or branched alkyl;

[0077] R5 is selected from hydrogen, deuterium, halogen, C1-C3 alkoxy, amino, (C1-C4 straight chain or branched alkyl)amino, di(C1-C4 straight chain or branched alkyl)amino, (4-6 membered) heterocyclyl, C1-C4 straight chain or branched alkyl, halo(C1-C4) straight chain or branched alkyl and hydroxy(C1-C4) straight chain or branched alkyl;

[0078] R6 is selected from hydrogen, deuterium, halogen, C1-C4 straight or branched alkoxy, CONH2, C1-C4 straight or branched alkyl, halo (C1-C4) straight or branched alkyl, hydroxy (C1-C4) straight or branched alkyl and CO2R7, wherein R7 is selected from H and C1-C4 straight or branched alkyl;

[0079] R8 is selected from hydrogen, deuterium and C1-C3 straight or branched alkyl;

[0080] R9 is selected from C1-C3 straight or branched alkyl and halogenated (C1-C3) straight or branched alkyl; and

[0081] n and m are independently selected from 0, 1 and 2.

[0082] Described below are a number of embodiments (E) of this first aspect of the invention, wherein for convenience, E1 is identical to the aforementioned embodiments.

[0083] E1. A compound of formula I as defined above, or a pharmaceutically acceptable salt thereof.

[0084] E2. The compound according to E1, wherein A1 is O, or a pharmaceutically acceptable salt thereof.

[0085] E3. The compound according to E1, wherein A2 is O or S, or a pharmaceutically acceptable salt thereof.

[0086] E4. The compound according to E1, or a pharmaceutically acceptable salt thereof, wherein R1 and R2 are independently selected from ethyl, methyl and H.

[0087] E5. The compound according to E1, or a pharmaceutically acceptable salt thereof, wherein R4 is cyano or methoxy.

[0088] E6. The compound according to E1, wherein R5 is H, or a pharmaceutically acceptable salt thereof.

[0089] E7. The compound according to E1, or a pharmaceutically acceptable salt thereof, wherein R5 is azetidinyl, pyrrolidinyl or dimethylamino.

[0090] E8. The compound according to E1, wherein R6 is H, or a pharmaceutically acceptable salt thereof.

[0091] E9. The compound according to E1, wherein R8 is H, or a pharmaceutically acceptable salt thereof.

[0092] E10. The compound according to E1, or a pharmaceutically acceptable salt thereof, wherein R9 is methyl.

[0093] E11. The compound according to E1, or a pharmaceutically acceptable salt thereof, wherein X is CH2.

[0094] E12. The compound according to E1, wherein X is O, or a pharmaceutically acceptable salt thereof.

[0095] E13. The compound according to E1, wherein m is 0 and n is 1, or a pharmaceutically acceptable salt thereof.

[0096] E14. The compound according to E1, or a pharmaceutically acceptable salt thereof, wherein m is 1 and n is 1.

[0097] E15. A compound of formula IA having the following structure:

[0098]

[0099] or a pharmaceutically acceptable salt thereof, wherein

[0100] A1 and A2 are independently O or S;

[0101] X is selected from CH2, CD2, NR3, O and S, wherein R3 is selected from hydrogen, C1-C4 straight chain or branched alkyl, halogenated (C1-C4) straight chain or branched alkyl and hydroxy (C1-C4) straight chain or branched alkyl;

[0102] R1 and R2 are independently selected from hydrogen, deuterium, C1-C4 straight or branched alkyl, halo (C1-C4) straight or branched alkyl, hydroxy (C1-C4) straight or branched alkyl, cyano (C1-C4) straight or branched alkyl and C1-C3 alkoxy (C1-C4) straight or branched alkyl; or C1-C2 alkyl substituted with a C3-C5 cycloalkyl ring; or joined together to form a C3-C6 cycloalkyl ring; or If X is CH2 or CD2, R1 and R2 are independently selected from hydrogen, deuterium, halogen, hydroxyl, C1-C4 straight or branched alkyl, halo(C1-C4) straight or branched alkyl, hydroxyl(C1-C4) straight or branched alkyl, cyano(C1-C4) straight or branched alkyl and C1-C3 alkoxy(C1-C4) straight or branched alkyl, and C1-C2 alkyl substituted with a C3-C5 cycloalkyl ring;

[0103] R4 is selected from hydrogen, deuterium, cyano, halogen, (C1-C3) alkoxy, halo (C1-C3) alkoxy, mercapto substituted by C1-C3 alkyl, C1-C4 straight or branched alkyl, halo (C1-C4) straight or branched alkyl and hydroxy (C1-C4) straight or branched alkyl;

[0104] R5 is selected from hydrogen, deuterium, halogen, C1-C3 alkoxy, amino, (C1-C4 straight chain or branched alkyl)amino, di(C1-C4 straight chain or branched alkyl)amino, (4-6 membered) heterocyclyl, C1-C4 straight chain or branched alkyl, halo(C1-C4) straight chain or branched alkyl and hydroxy(C1-C4) straight chain or branched alkyl;

[0105] R6 is selected from hydrogen, deuterium, halogen, C1-C4 straight or branched alkoxy, CONH2, C1-C4 straight or branched alkyl, halo (C1-C4) straight or branched alkyl, hydroxy (C1-C4) straight or branched alkyl and CO2R7, wherein R7 is selected from H and C1-C4 straight or branched alkyl;

[0106] R8 is selected from hydrogen, deuterium and C1-C3 straight or branched alkyl;

[0107] R9 is selected from C1-C3 straight or branched alkyl and halogenated (C1-C3) straight or branched alkyl; and

[0108] n and m are independently selected from 0, 1 and 2.

[0109] E16. The compound according to E15, wherein A1 is O, or a pharmaceutically acceptable salt thereof.

[0110] E17. The compound according to E15, wherein A2 is O or S, or a pharmaceutically acceptable salt thereof.

[0111] E18. The compound according to E15, or a pharmaceutically acceptable salt thereof, wherein R1 and R2 are independently selected from ethyl, methyl and H.

[0112] E19. The compound according to E15, or a pharmaceutically acceptable salt thereof, wherein R4 is cyano or methoxy.

[0113] E20. The compound according to E15, wherein R5 is H, or a pharmaceutically acceptable salt thereof.

[0114] E21. The compound according to E15, or a pharmaceutically acceptable salt thereof, wherein R5 is azetidinyl, pyrrolidinyl or dimethylamino.

[0115] E22. The compound according to E15, wherein R6 is H, or a pharmaceutically acceptable salt thereof.

[0116] E23. The compound according to E15, wherein R8 is H, or a pharmaceutically acceptable salt thereof.

[0117] E24. The compound according to E15, or a pharmaceutically acceptable salt thereof, wherein R9 is methyl.

[0118] E25. The compound according to E15, or a pharmaceutically acceptable salt thereof, wherein X is CH2.

[0119] E26. The compound according to E15, wherein X is O, or a pharmaceutically acceptable salt thereof.

[0120] E27. The compound according to E15, or a pharmaceutically acceptable salt thereof, wherein m is 0 and n is 1.

[0121] E28. The compound according to E15, or a pharmaceutically acceptable salt thereof, wherein m is 1 and n is 1.

[0122] E29. A compound of formula IB having the following structure:

[0123]

[0124] or a pharmaceutically acceptable salt thereof, wherein

[0125] A1 and A2 are independently O or S;

[0126] X is selected from CH2, CD2, NR3, O and S, wherein R3 is selected from hydrogen, C1-C4 straight chain or branched alkyl, halogenated (C1-C4) straight chain or branched alkyl and hydroxy (C1-C4) straight chain or branched alkyl;

[0127] R1 and R2 are independently selected from hydrogen, deuterium, C1-C4 straight or branched alkyl, halo (C1-C4) straight or branched alkyl, hydroxy (C1-C4) straight or branched alkyl, cyano (C1-C4) straight or branched alkyl and C1-C3 alkoxy (C1-C4) straight or branched alkyl; or C1-C2 alkyl substituted with a C3-C5 cycloalkyl ring; or joined together to form a C3-C6 cycloalkyl ring; or If X is CH2 or CD2, R1 and R2 are independently selected from hydrogen, deuterium, halogen, hydroxyl, C1-C4 straight or branched alkyl, halo(C1-C4) straight or branched alkyl, hydroxyl(C1-C4) straight or branched alkyl, cyano(C1-C4) straight or branched alkyl and C1-C3 alkoxy(C1-C4) straight or branched alkyl, and C1-C2 alkyl substituted with a C3-C5 cycloalkyl ring;

[0128] R4 is selected from hydrogen, deuterium, cyano, halogen, (C1-C3) alkoxy, halo (C1-C3) alkoxy, mercapto substituted by C1-C3 alkyl, C1-C4 straight or branched alkyl, halo (C1-C4) straight or branched alkyl and hydroxy (C1-C4) straight or branched alkyl;

[0129] R5 is selected from hydrogen, deuterium, halogen, C1-C3 alkoxy, amino, (C1-C4 straight chain or branched alkyl)amino, di(C1-C4 straight chain or branched alkyl)amino, (4-6 membered) heterocyclyl, C1-C4 straight chain or branched alkyl, halo(C1-C4) straight chain or branched alkyl and hydroxy(C1-C4) straight chain or branched alkyl;

[0130] R6 is selected from hydrogen, deuterium, halogen, C1-C4 straight or branched alkoxy, CONH2, C1-C4 straight or branched alkyl, halo (C1-C4) straight or branched alkyl, hydroxy (C1-C4) straight or branched alkyl and CO2R7, wherein R7 is selected from H and C1-C4 straight or branched alkyl;

[0131] R8 is selected from hydrogen, deuterium and C1-C3 straight or branched alkyl;

[0132] R9 is selected from C1-C3 straight or branched alkyl and halogenated (C1-C3) straight or branched alkyl; and

[0133] n and m are independently selected from 0, 1 and 2.

[0134] E30. The compound according to E29, or a pharmaceutically acceptable salt thereof, wherein A1 is O.

[0135] E31. The compound according to E29, or a pharmaceutically acceptable salt thereof, wherein A2 is O or S.

[0136] E32. The compound according to E29, or a pharmaceutically acceptable salt thereof, wherein R1 and R2 are independently selected from ethyl, methyl and H.

[0137] E33. The compound according to E29, or a pharmaceutically acceptable salt thereof, wherein R4 is cyano or methoxy.

[0138] E34. The compound according to E29, wherein R5 is H, or a pharmaceutically acceptable salt thereof.

[0139] E35. The compound according to E29, wherein R6 is H, or a pharmaceutically acceptable salt thereof.

[0140] E36. The compound according to E29, wherein R8 is H, or a pharmaceutically acceptable salt thereof.

[0141] E37. The compound according to E29, or a pharmaceutically acceptable salt thereof, wherein R9 is methyl.

[0142] E38. The compound according to E29, or a pharmaceutically acceptable salt thereof, wherein X is CH2.

[0143] E39. The compound according to E29, or a pharmaceutically acceptable salt thereof, wherein m is 0 and n is 1.

[0144] E40. The compound according to E29, or a pharmaceutically acceptable salt thereof, wherein m is 1 and n is 1.

[0145] E41. A compound according to E1, selected from the group consisting of:

[0146] 2-((1-aminocyclopentyl)methoxy)-4-(5-methoxyimidazo[1,2-a]pyridin-3-yl)-6-(methylthio)benzonitrile;

[0147] 2-(((1S,2R)-1-amino-2-ethylcyclopentyl)methoxy)-6-methoxy-4-(5-methoxyimidazo[1,2-a]pyridin-3-yl)benzonitrile;

[0148] 2-(((1R,2S)-1-amino-2-ethylcyclopentyl)methoxy)-6-methoxy-4-(5-methoxyimidazo[1,2-a]pyridin-3-yl)benzonitrile;

[0149] 2-((1-amino-3-ethylcyclopentyl)methoxy)-6-methoxy-4-(5-methoxyimidazo[1,2-a]pyridin-3-yl)benzonitrile;

[0150] 2-(((1R,3R)-1-amino-3-ethylcyclopentyl)methoxy)-6-methoxy-4-(5-methoxyimidazo[1,2-a]pyridin-3-yl)benzonitrile;

[0151] 2-(((1S,3S)-1-amino-3-ethylcyclopentyl)methoxy)-6-methoxy-4-(5-methoxyimidazo[1,2-a]pyridin-3-yl)benzonitrile;

[0152] 2-(((1R,3S)-1-amino-3-ethylcyclopentyl)methoxy)-6-methoxy-4-(5-methoxyimidazo[1,2-a]pyridin-3-yl)benzonitrile;

[0153] 2-(((1S,3R)-1-amino-3-ethylcyclopentyl)methoxy)-6-methoxy-4-(5-methoxyimidazo[1,2-a]pyridin-3-yl)benzonitrile;

[0154] 2-(((1S,2S)-1-amino-2-ethylcyclopentyl)methoxy)-6-methoxy-4-(5-methoxyimidazo[1,2-a]pyridin-3-yl)benzonitrile;

[0155] 2-(((1R,2R)-1-amino-2-ethylcyclopentyl)methoxy)-6-methoxy-4-(5-methoxyimidazo[1,2-a]pyridin-3-yl)benzonitrile;

[0156] 3-(3-(((1S,2R)-1-amino-2-ethylcyclopentyl)methoxy)-4-cyano-5-(methylthio)phenyl)imidazo[1,2-a]pyridine-5-carbonitrile;

[0157] 3-(3-(((1R,2S)-1-amino-2-ethylcyclopentyl)methoxy)-4-cyano-5-(methylthio)phenyl)imidazo[1,2-a]pyridine-5-carbonitrile;

[0158] 2-((1-amino-2-ethylcyclopentyl)methoxy)-4-(5-methoxyimidazo[1,2-a]pyridin-3-yl)-6-(methylthio)benzonitrile;

[0159] 2-(((1S,2R)-1-amino-2-ethylcyclopentyl)methoxy)-4-(5-methoxyimidazo[1,2-a]pyridin-3-yl)-6-(methylthio)benzonitrile;

[0160] 2-(((1R,2S)-1-amino-2-ethylcyclopentyl)methoxy)-4-(5-methoxyimidazo[1,2-a]pyridin-3-yl)-6-(methylthio)benzonitrile;

[0161] 2-(((2S,3R)-3-amino-2-ethyltetrahydrofuran-3-yl)methoxy)-4-(5-methoxyimidazo[1,2-a]pyridin-3-yl)-6-(methylthio)benzonitrile;

[0162] 2-(((2R,3R)-3-amino-2-ethyltetrahydrofuran-3-yl)methoxy)-4-(5-methoxyimidazo[1,2-a]pyridin-3-yl)-6-(methylthio)benzonitrile;

[0163] 2-(((2R,3S)-3-amino-2-ethyltetrahydrofuran-3-yl)methoxy)-4-(5-methoxyimidazo[1,2-a]pyridin-3-yl)-6-(methylthio)-benzonitrile;

[0164] 2-(((2S,3S)-3-amino-2-ethyltetrahydrofuran-3-yl)methoxy)-4-(5-methoxyimidazo[1,2-a]pyridin-3-yl)-6-(methylthio)benzonitrile;

[0165] (R)-3-(3-((1-amino-3,3-difluorocyclopentyl)methoxy)-4-cyano-5-(methylthio)phenyl)imidazo[1,2-a]pyridine-5-carbonitrile;

[0166] (S)-3-(3-((1-amino-3,3-difluorocyclopentyl)methoxy)-4-cyano-5-(methylthio)phenyl)imidazo[1,2-a]pyridine-5-carbonitrile;

[0167] (R)-2-((1-amino-3,3-difluorocyclopentyl)methoxy)-4-(5-methoxyimidazo[1,2-a]pyridin-3-yl)-6-(methylthio)benzonitrile;

[0168] (S)-2-((1-amino-3,3-difluorocyclopentyl)methoxy)-4-(5-methoxyimidazo[1,2-a]pyridin-3-yl)-6-(methylthio)benzonitrile;

[0169] (R)-3-(3-((1-amino-3,3-dimethylcyclohexyl)methoxy)-4-cyano-5-(methylthio)phenyl)imidazo[1,2-a]pyridine-5-carbonitrile;

[0170] (S)-3-(3-((1-amino-3,3-dimethylcyclohexyl)methoxy)-4-cyano-5-(methylthio)phenyl)imidazo[1,2-a]pyridine-5-carbonitrile;

[0171] 2-(((1R,3R)-1-amino-3-ethylcyclohexyl)methoxy)-6-methoxy-4-(5-methoxyimidazo[1,2-a]pyridin-3-yl)benzonitrile;

[0172] 2-(((1S,3S)-1-amino-3-ethylcyclohexyl)methoxy)-6-methoxy-4-(5-methoxyimidazo[1,2-a]pyridin-3-yl)benzonitrile;

[0173] 3-(3-(((1S,3S)-1-amino-3-ethylcyclohexyl)methoxy)-4-cyano-5-(methylthio)phenyl)imidazo[1,2-a]pyridine-5-carbonitrile;

[0174] 3-(3-(((1R,3R)-1-amino-3-ethylcyclohexyl)methoxy)-4-cyano-5-(methylthio)phenyl)imidazo[1,2-a]pyridine-5-carbonitrile;

[0175] (S)-2-((1-aminospiro[4.4]nonan-1-yl)methoxy)-6-methoxy-4-(5-methoxyimidazo[1,2-a]pyridin-3-yl)benzonitrile;

[0176] (R)-2-((1-aminospiro[4.4]nonan-1-yl)methoxy)-6-methoxy-4-(5-methoxyimidazo[1,2-a]pyridin-3-yl)benzonitrile;

[0177] (S)-2-((3-amino-1-(2,2,2-trifluoroethyl)piperidin-3-yl)methoxy)-6-methoxy-4-(5-methoxyimidazo[1,2-a]pyridin-3-yl)benzonitrile;

[0178] (R)-2-((3-amino-1-(2,2,2-trifluoroethyl)piperidin-3-yl)methoxy)-6-methoxy-4-(5-methoxyimidazo[1,2-a]pyridin-3-yl)benzonitrile;

[0179] (R)-2-((3-aminotetrahydrothiophen-3-yl)methoxy)-4-(imidazo[1,2-a]pyridin-3-yl)-6-(methylthio)benzonitrile;

[0180] (S)-2-((3-aminotetrahydrothiophen-3-yl)methoxy)-4-(imidazo[1,2-a]pyridin-3-yl)-6-(methylthio)benzonitrile;

[0181] (R)-2-((3-aminotetrahydrofuran-3-yl)methoxy)-4-(5-methoxyimidazo[1,2-a]pyridin-3-yl)-6-(methylthio)benzonitrile;

[0182] (S)-2-((3-aminotetrahydrofuran-3-yl)methoxy)-4-(5-methoxyimidazo[1,2-a]pyridin-3-yl)-6-(methylthio)benzonitrile;

[0183] (R)-2-((1-amino-3,3-difluorocyclopentyl)methoxy)-4-(imidazo[1,2-a]pyridin-3-yl)-6-(methylthio)benzonitrile;

[0184] (S)-2-((1-amino-3,3-difluorocyclopentyl)methoxy)-4-(imidazo[1,2-a]pyridin-3-yl)-6-(methylthio)benzonitrile;

[0185] (R)-3-(3-((3-aminotetrahydrothiophen-3-yl)methoxy)-4-cyano-5-(methylthio)phenyl)imidazo[1,2-a]pyridine-5-carbonitrile;

[0186] (S)-3-(3-((3-aminotetrahydrothiophen-3-yl)methoxy)-4-cyano-5-(methylthio)phenyl)imidazo[1,2-a]pyridine-5-carbonitrile;

[0187] 2-((1-aminocyclohexyl)methoxy)-4-(5-methoxyimidazo[1,2-a]pyridin-3-yl)-6-(methylthio)benzonitrile;

[0188] (R)-2-((3-aminotetrahydrothiophen-3-yl)methoxy)-4-(5-methoxyimidazo[1,2-a]pyridin-3-yl)-6-(methylthio)benzonitrile;

[0189] (S)-2-((3-aminotetrahydrothiophen-3-yl)methoxy)-4-(5-methoxyimidazo[1,2-a]pyridin-3-yl)-6-(methylthio)benzonitrile;

[0190] 2-(((1S)-1-amino-3-(methoxymethyl)cyclohexyl)methoxy)-4-(imidazo[1,2-a]pyridin-3-yl)-6-(methylthio)benzonitrile;

[0191] 2-(((1R)-1-amino-3-(methoxymethyl)-cyclohexyl)methoxy)-4-(imidazo[1,2-a]pyridin-3-yl)-6-(methylthio)benzonitrile;

[0192] 2-(((1S,2S)-1-amino-2-(cyclopropylmethyl)cyclopentyl)methoxy)-6-methoxy-4-(5-methoxyimidazo[1,2-a]pyridin-3-yl)benzonitrile;

[0193] 2-(((1R,2R)-1-amino-2-(cyclopropylmethyl)cyclopentyl)methoxy)-6-methoxy-4-(5-methoxyimidazo[1,2-a]pyridin-3-yl)benzonitrile;

[0194] 2-(((1S,2R)-1-amino-2-(cyclopropylmethyl)cyclopentyl)methoxy)-6-methoxy-4-(5-methoxyimidazo[1,2-a]pyridin-3-yl)benzonitrile;

[0195] 2-(((1R,2S)-1-amino-2-(cyclopropylmethyl)cyclopentyl)methoxy)-6-methoxy-4-(5-methoxyimidazo[1,2-a]pyridin-3-yl)benzonitrile;

[0196] 2-(((1S,3S)-1-amino-3-(trifluoromethyl)cyclohexyl)methoxy)-4-(imidazo[1,2-a]pyridin-3-yl)-6-(methylthio)benzonitrile;

[0197] 2-(((1R,3R)-1-amino-3-(trifluoromethyl)cyclohexyl)methoxy)-4-(imidazo[1,2-a]pyridin-3-yl)-6-(methylthio)benzonitrile;

[0198] 2-(((1R,3S)-1-amino-3-(trifluoromethyl)cyclohexyl)methoxy)-4-(imidazo[1,2-a]pyridin-3-yl)-6-(methylthio)benzonitrile;

[0199] 2-(((1S,3R)-1-amino-3-(trifluoromethyl)cyclohexyl)methoxy)-4-(imidazo[1,2-a]pyridin-3-yl)-6-(methylthio)benzonitrile;

[0200] 3-(3-((1-aminocyclohexyl)methoxy)-4-cyano-5-(methylthio)phenyl)imidazo[1,2-a]pyridine-5-carbonitrile;

[0201] 3-(3-((1-aminocyclopentyl)methoxy)-4-cyano-5-(methylthio)phenyl)imidazo[1,2-a]pyridine-5-carbonitrile;

[0202] 3-(3-((1-aminocyclopentyl)methoxy)-4-cyano-5-(methylthio)phenyl)pyrazolo[1,5-a]pyridine-4-carbonitrile;

[0203] 3-(3-((1-aminocyclopentyl)methoxy)-4-cyano-5-(methylthio)phenyl)-5-cyanoimidazolo[1,2-a]pyridine-7-carboxylic acid ethyl ester;

[0204] 3-(3-((1-aminocyclopentyl)methoxy)-4-cyano-5-(methylthio)phenyl)-6-methoxyimidazo[1,2-a]pyridine-5-carbonitrile;

[0205] 3-(3-((1-aminocyclopentyl)methoxy)-4-cyano-5-(methylthio)phenyl)-7-methylimidazo[1,2-a]pyridine-5-carbonitrile;

[0206] 3-(3-((1-aminocyclopentyl)methoxy)-4-cyano-5-(methylthio)phenyl)-6-(dimethylamino)imidazo[1,2-a]pyridine-5-carbonitrile;

[0207] 3-(3-((1-aminocyclopentyl)methoxy)-4-cyano-5-(methylthio)phenyl)-6-ethylimidazo[1,2-a]pyridine-5-carbonitrile;

[0208] 3-(3-((1-aminocyclopentyl)methoxy)-4-cyano-5-(methylthio)phenyl)-6-methylimidazo[1,2-a]pyridine-5-carbonitrile;

[0209] 3-(3-((1-aminocyclopentyl)methoxy)-4-cyano-5-(methylthio)phenyl)-7-chloroimidazo[1,2-a]pyridine-5-carbonitrile;

[0210] 3-(3-((1-aminocyclohexyl)methoxy)-4-cyano-5-(methylthio)phenyl)pyrazolo[1,5-a]pyridine-4-carbonitrile;

[0211] 6-amino-3-(3-((1-aminocyclopentyl)methoxy)-4-cyano-5-(methylthio)phenyl)imidazo[1,2-a]pyridine-5-carbonitrile;

[0212] 3-(3-((1-aminocyclopentyl)methoxy)-4-cyano-5-(methylthio)phenyl)-6-(azetidin-1-yl)imidazo[1,2-a]pyridine-5-carbonitrile;

[0213] 3-(3-((1-aminocyclopentyl)methoxy)-4-cyano-5-(methylthio)phenyl)-6-(pyrrolidin-1-yl)imidazo[1,2-a]pyridine-5-carbonitrile;

[0214] 3-(3-((1-aminocyclopentyl)methoxy)-4-cyano-5-methoxyphenyl)-6-(dimethylamino)imidazo[1,2-a]pyridine-5-carbonitrile;

[0215] 3-(3-((1-aminocyclohexyl)methoxy)-4-cyano-5-(methylthio)phenyl)-6-methoxyimidazo[1,2-a]pyridine-5-carbonitrile;

[0216] 3-(3-((1-aminocyclopentyl)methoxy)-4-cyano-5-(methylthio)phenyl)-7-methoxyimidazo[1,2-a]pyridine-5-carbonitrile;

[0217] 3-(3-((1-aminocyclohexyl)methoxy)-4-cyano-5-(methylthio)phenyl)-7-methoxyimidazo[1,2-a]pyridine-5-carbonitrile;

[0218] 3-(3-((1-aminocyclohexyl)methoxy)-4-cyano-5-methoxyphenyl)-7-methoxyimidazo[1,2-a]pyridine-5-carbonitrile; and

[0219] 3-(3-((1-aminocyclopentyl)methoxy)-4-cyano-5-(methylthio)phenyl)-6-(methylamino)imidazo[1,2-a]pyridine-5-carbonitrile;

[0220] or a pharmaceutically acceptable salt thereof.

[0221] E42. A compound according to E1, selected from the group consisting of:

[0222] 3-(3-((1-aminocyclohexyl))methoxy)-4-cyano-5-(methylthio)phenyl)imidazo[1,2-a]pyridine-5-carbonitrile;

[0223] 2-(((1S,2R)-1-amino-2-ethylcyclopentyl)methoxy)-6-methoxy-4-(5-methoxyimidazo[1,2-a]pyridin-3-yl)benzonitrile;

[0224] 2-(((2S,3R)-3-amino-2-ethyltetrahydrofuran-3-yl)methoxy)-4-(5-methoxyimidazo[1,2-a]pyridin-3-yl)-6-(methylthio)benzonitrile;

[0225] 3-(3-(((1S,2R)-1-amino-2-ethylcyclopentyl)methoxy)-4-cyano-5-(methylthio)phenyl)imidazo[1,2-a]pyridine-5-carbonitrile; and

[0226] 3-(3-((1-aminocyclopentyl)methoxy)-4-cyano-5-(methylthio)phenyl)-6-(dimethylamino)imidazo[1,2-a]pyridine-5-carbonitrile; or a pharmaceutically acceptable salt thereof.

[0227] E43. 3-(3-((1-aminocyclohexyl)methoxy)-4-cyano-5-(methylthio)phenyl)imidazo[1,2-a]pyridine-5-carbonitrile; or a pharmaceutically acceptable salt thereof.

[0228] E44. 2-(((1S,2R)-1-amino-2-ethylcyclopentyl)methoxy)-6-methoxy-4-(5-methoxyimidazo[1,2-a]pyridin-3-yl)benzonitrile; or a pharmaceutically acceptable salt thereof.

[0229] E45. 2-(((2S,3R)-3-amino-2-ethyltetrahydrofuran-3-yl)methoxy)-4-(5-methoxyimidazo[1,2-a]pyridin-3-yl)-6-(methylthio)benzonitrile; or a pharmaceutically acceptable salt thereof.

[0230] E46. 3-(3-(((1S,2R)-1-amino-2-ethylcyclopentyl)methoxy)-4-cyano-5-(methylthio)phenyl)imidazo[1,2-a]pyridine-5-carbonitrile; or a pharmaceutically acceptable salt thereof.

[0231] E47. 3-(3-((1-aminocyclopentyl)methoxy)-4-cyano-5-(methylthio)phenyl)-6-(dimethylamino)imidazo[1,2-a]pyridine-5-carbonitrile; or a pharmaceutically acceptable salt thereof.

[0232] E48. A pharmaceutical composition comprising a compound according to any one of E1 to E47 or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable solvate of the compound or salt and a pharmaceutically acceptable excipient.

[0233] E49. A method for treating a disease or condition selected from inflammation, autoimmune disease, neuroinflammation, arthritis, rheumatoid arthritis, spondyloarthropathies, systemic lupus erythematosus, lupus nephritis, osteoarthritis, gouty arthritis, pain, fever, pulmonary sarcoidosis, silicosis, cardiovascular disease, atherosclerosis, myocardial infarction, thrombosis, congestive heart failure and cardiac reperfusion injury, cardiomyopathy, stroke, ischemia, reperfusion injury, cerebral edema, brain damage, neurodegeneration, liver disease, inflammatory bowel disease, Crohn's disease, ulcerative colitis, nephritis, retinitis, retinopathy, macular degeneration, glaucoma, diabetes (type 1 and type 2), diabetic neuropathy, viral and bacterial infections, myalgia, endotoxin shock, toxic shock syndrome, osteoporosis, multiple sclerosis, endometriosis, dysmenorrhea, vaginitis, candidiasis , gastrointestinal cancer, cancer, fibrosis, obesity, muscular dystrophy, polymyositis, dermatomyositis, autoimmune hepatitis, primary biliary cirrhosis, primary sclerosing cholangitis, vitiligo, Alzheimer's disease, skin flushing, eczema, psoriasis, atopic dermatitis, sunburn, keloids, hypertrophic scars, rheumatic diseases, urticaria, discoid lupus, cutaneous lupus, central nervous system lupus, psoriatic arthritis, asthma, allergic asthma, type I interferonopathy (including Aicardi-Gautiers syndrome and other Mendelian diseases with overexpression of type I interferons), primary progressive multiple sclerosis, relapsing remitting multiple sclerosis, nonalcoholic fatty liver disease, nonalcoholic steatosis, scleroderma, alopecia areata, scarring alopecia, prurigo, prurigo nodularis, CPUO, lichen diseases, lichen planus, Steven's Johnson syndrome (Steven's Johnson's syndrome), spondylosis, myositis, vasculitis, pemphigus, lupus, major depression, allergy, dry eye syndrome, transplant rejection, cancer, septic shock, cardiopulmonary dysfunction, acute respiratory disease, ankylosing spondylitis, cachexia, chronic graft-versus-host disease, acute graft-versus-host disease, steatorrhea, idiopathic thrombocytopenic thrombotic purpura, thrombotic thrombocytopenic purpura, myasthenia gravis, Sjogren's syndrome, epidermal hyperplasia, cartilage inflammation, bone degradation, juvenile arthritis, juvenile rheumatoid arthritis, oligoarticular juvenile rheumatoid arthritis, polyarticular juvenile rheumatoid arthritis, systemic onset juvenile rheumatoid arthritis, juvenile ankylosing spondylitis, juvenile enteropathic arthritis, juvenile Reiter's syndromeSyndrome, SEA syndrome, juvenile dermatomyositis, juvenile psoriatic arthritis, juvenile scleroderma, juvenile systemic lupus erythematosus, juvenile vasculitis, oligoarticular rheumatoid arthritis, polyarticular rheumatoid arthritis, systemic onset rheumatoid arthritis, enteropathic arthritis, reactive arthritis, Reiter's syndrome, myositis, polymyositis, dermatomyositis, polyarteritis nodosa, Wegener's granulomatosis, arteritis, polymyalgia rheumatica, sarcoidosis, cirrhosis, primary biliary cirrhosis, sclerosing cholangitis, dermatitis, Still's disease, chronic obstructive pulmonary disease, Guillain-Barre disease, Graves' disease, Addison's disease, Raynaud's phenomenon phenomenon), psoriatic epidermal hyperplasia, plaque psoriasis, guttate psoriasis, inverse psoriasis, pustular psoriasis, erythrodermic psoriasis, immune disorders associated with or caused by pathogenic lymphocyte activity, non-infectious uveitis, Behcet's disease and Vogt-Koyage-Harada syndrome, the method comprising administering to a subject in need thereof a compound according to any one of E1 to E47 or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of the compound or salt.

[0234] E50. A method for treating inflammatory bowel disease, Crohn's disease, ulcerative colitis or gastrointestinal cancer, comprising administering to a subject a compound according to any one of E1 to E47 or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of the compound or salt.

[0235] E51. The method according to E49, wherein the compound is selected from the group consisting of:

[0236] 3-(3-((1-aminocyclohexyl)methoxy)-4-cyano-5-(methylthio)phenyl)imidazo[1,2-a]pyridine-5-carbonitrile;

[0237] 2-(((1S,2R)-1-amino-2-ethylcyclopentyl)methoxy)-6-methoxy-4-(5-methoxyimidazo[1,2-a]pyridin-3-yl)benzonitrile;

[0238] 2-(((2S,3R)-3-amino-2-ethyltetrahydrofuran-3-yl)methoxy)-4-(5-methoxyimidazo[1,2-a]pyridin-3-yl)-6-(methylthio)benzonitrile;

[0239] 3-(3-(((1S,2R)-1-amino-2-ethylcyclopentyl)methoxy)-4-cyano-5-(methylthio)phenyl)imidazo[1,2-a]pyridine-5-carbonitrile; and

[0240] 3-(3-((1-aminocyclopentyl)methoxy)-4-cyano-5-(methylthio)phenyl)-6-(dimethylamino)imidazo[1,2-a]pyridine-5-carbonitrile;

[0241] or a pharmaceutically acceptable salt thereof.

[0242] E52. Use of a compound according to any one of E1 to E47 for the preparation of a medicament for the treatment of a disorder for which a SIK inhibitor is indicated.

[0243] E53. Use of a compound according to any one of E1 to E47 for the preparation of a medicament for the treatment of inflammatory bowel disease, Crohn's disease, ulcerative colitis or gastrointestinal cancer.

[0244] E54. A compound according to any one of E1 to E47 for use in the treatment of a disorder for which a SIK inhibitor is indicated.

[0245] Compounds of the invention that have the same molecular formula but differ in the nature or order of bonding of their atoms or the arrangement of their atoms in space are referred to as "isomers". Isomers that differ in the spatial arrangement of their atoms are referred to as "stereoisomers". These stereoisomers are "R" or "S", depending on the configuration of the substituents around the chiral carbon atom. The terms "R" and "S" used in this application are configurations as defined in IUPAC 1974 Recommendations for Section E, Fundamental Stereochemistry, Pure Appl. Chem., 1976, 45: 13-30. An enantiomer of the invention indicated by (R), (S) or * is substantially free of the other enantiomer. "Substantially free" means an enantiomeric excess greater than about 90%, preferably greater than about 95%, and more preferably greater than about 99%. In the context of enantiomeric excess, the term "about" means ±1.0%. The symbol * indicates that the chiral carbon atom is either (R) or (S) stereochemistry, depending on the configuration of substituents around the chiral carbon atom. The present invention encompasses various stereoisomers and mixtures thereof that are specifically included within the scope of the present invention. Stereoisomers include enantiomers and mixtures of enantiomers. Individual stereoisomers of the compounds of the present invention may be prepared synthetically from commercially available starting materials containing asymmetric or chiral centers or by preparing racemic mixtures followed by resolution as is well known to those of ordinary skill in the art. These resolution methods include, but are not limited to: (1) attaching a chiral auxiliary to the enantiomeric mixture, separating the resulting diastereomeric mixture by recrystallization or chromatography, and liberating the optically pure product from the auxiliary; or (2) directly separating the optical enantiomer mixture on a chiral chromatography column. Compounds of the invention not indicated as (R), (S) or * may exist as racemates (i.e., 50% (R) and 50% (S)) or as mixtures of two enantiomers in which one enantiomer is in excess. For example, an enantiomeric mixture may include 51% (R) enantiomer and 49% (S) enantiomer or vice versa, or any combination of (R) and (S) other than a racemic mixture of 50% (R) and 50% (S).

[0246] Included within the scope of the compounds are all isomers (e.g., cis, trans, or diastereomers) of the individual compounds described in the present application, as well as any mixtures. The compounds include all of these forms, including enantiomers, diastereomers, cis, trans, cis-side, trans-side, solvates (including hydrates), tautomers, and mixtures thereof. Stereoisomers (e.g., diastereomeric mixtures) can be separated into their corresponding isomers in a known manner by means of suitable separation methods. For example, diastereomeric mixtures can be separated into their individual diastereomers by means of fractional crystallization, chromatography, solvent distribution, and similar procedures. This separation can occur at the level of one of the starting compounds or in the compounds of formula I, IA, or IB themselves. Enantiomers can be separated via the formation of diastereomeric salts (e.g., salt formation with enantiomerically pure chiral acids) or by means of chromatography (e.g., HPLC), using chromatographic substrates with chiral ligands. The present invention includes all pharmaceutically acceptable isotopically labeled compounds of Formula I, IA or IB, or pharmaceutically acceptable salts thereof, wherein one or more atoms are replaced by an atom having the same atomic number but an atomic mass or mass number different from the atomic mass or mass number predominant in nature.

[0247] Examples of suitable isotopes for inclusion in the compounds of the present invention include isotopes of hydrogen such as 2 H and 3 H; isotopes of carbon, such as 11 C. 13 C and 14 C; isotopes of chlorine, such as 36 Cl; isotopes of fluorine, such as 18 F; isotopes of iodine, such as 123 I and 125 I; isotopes of nitrogen, such as 13 N and 15 N; isotopes of oxygen, such as 15 O. 17 O and 18 O; isotopes of phosphorus, such as 32 P; and isotopes of sulfur, such as 35 S.

[0248] Certain isotopically-labeled compounds of Formula I, IA or IB or pharmaceutically acceptable salts thereof, for example those into which a radioactive isotope is incorporated, are useful in drug and / or substrate tissue distribution studies. 3 H) and carbon-14 (i.e. 14 C) is particularly suitable for this purpose due to its ease of incorporation and ready detection means.

[0249] Deuterium (i.e. 2Substitution with heavier isotopes of H) may afford certain therapeutic 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. Positron emitting isotopes such as 11 C. 18 F. 15 O and 13 N) substitution may be useful in positron emission tomography (PET) studies to examine substrate receptor occupancy. Isotopically labeled compounds of Formula I, IA or IB can generally be prepared by conventional techniques known to those skilled in the art, or by methods analogous to those described in the accompanying Examples and Preparations, using an isotopically labeled appropriate reagent in place of the non-labeled reagent previously employed.

[0250] In some embodiments, the present invention provides deuterium-labeled (or deuterated) compounds and salts, wherein the chemical formulas and variables of such compounds and salts are each and independently as described in the present application. "Deuterated" means that at least one atom in the compound is deuterium, and its abundance is greater than the natural abundance of deuterium (usually about 0.015%). Those skilled in the art recognize that in compounds with hydrogen atoms, the hydrogen atoms actually represent a mixture of H and D, of which about 0.015% is D. The concentration of deuterium incorporated into the deuterium-labeled compounds and salts of the present invention can be defined by the deuterium enrichment factor.

[0251] As used in this application, "deuterium enrichment factor" means the ratio between the abundance of deuterium and the natural abundance of deuterium, each relative to the abundance of hydrogen. In certain embodiments, the deuterium enrichment factor for an atomic position designated as having deuterium is typically at least 1000 (15% deuterium incorporation), at least 2000 (30% deuterium incorporation), at least 3000 (45% deuterium incorporation), at least 3500 (52.5% deuterium incorporation), at least 3500 (52.5% deuterium incorporation at each designated deuterium atom), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium incorporation), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99% deuterium incorporation). (99.5 % deuterium incorporated).

[0252] It will be appreciated that under physiological conditions one or more deuteriums may be exchanged for hydrogen.

[0253] In some embodiments, the present disclosure provides deuterated compounds of Formula I to replace previously employed unlabeled reagents, or pharmaceutically acceptable salts thereof.

[0254] In some embodiments, R1 is selected from CH3, CH2D, CHD2 and CD3.

[0255] In some embodiments, the deuterium compound of Formula I is selected from any one of the compounds described in the Examples section.

[0256] In some embodiments, metabolically labile sites in the compounds of the invention are deuterated.

[0257] Isotopically labeled compounds of the invention can generally be prepared by conventional techniques known to those skilled in the art, or by methods analogous to those described in the accompanying Examples and Preparations, using isotopically labeled appropriate reagents in place of the unlabeled reagents previously employed. It is also well recognized in the art that some variation in natural isotopic abundance may exist in synthetic compounds, which may depend on the source of the synthetic material used in the synthetic compound.

[0258] Deuterium enrichment of the compounds provided herein can be determined using conventional analytical methods known to those of ordinary skill in the art, including mass spectrometry, nuclear magnetic resonance spectroscopy, and crystallography.

[0259] Pharmaceutically acceptable solvates according to the invention include those wherein the solvent of crystallization may be isotopically substituted, for example D2O, d6-acetone, d6-DMSO.

[0260] In therapeutic use for treating mammalian conditions, the compounds of the invention or their pharmaceutical compositions may be administered orally, parenterally, topically, rectally, transmucosally or intestinally. Parenteral administration includes indirect injection or direct injection into the affected area to produce systemic effects. Topical administration includes treatment of skin or organs (e.g., eyes or ears) that are easily accessible by topical application. It also includes transdermal delivery to produce systemic effects. Rectal administration includes suppository forms. Preferred routes of administration are oral and parenteral administration.

[0261] Pharmaceutically acceptable salts of the compounds of formula I, IA or IB include acid addition salts and base salts thereof. Suitable acid addition salts are formed from acids which form non-toxic salts. Examples include acetate, adipate, aspartate, benzoate, benzenesulfonate, bicarbonate / carbonate, bisulfate / sulfate, borate, camphorsulfonate, citrate, cyclamate, edisylate, ethanesulfonate, formate, fumarate, glucoheptonate, gluconate, glucuronate, hexafluorophosphate, hyaluronate, hydrochloride / chloride, hydrobromide / bromide, hydroiodide / iodide, isethionate, lactate, malate, maleate, malonate, methanesulfonate, methylsulfate, naphthalene dicarboxylate, 2-naphthalenesulfonate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate / hydrogenphosphate / dihydrogenphosphate, pyroglutamate, glucarate, stearate, succinate, tannate, tartrate, toluenesulfonate, trifluoroacetate, and hydroxynaphthoate.

[0262] Suitable base salts are formed from bases which form non-toxic salts. Examples include aluminum, arginine, benzylethylenediamine, calcium, choline, diethylamine, diethanolamine, glycine, lysine, magnesium, meglumine, ethanolamine, potassium, sodium, tromethamine, and zinc salts.

[0263] Hemi-salts of acids and bases, such as hemisulphate and hemicalcium salts, can also be formed. For a review of suitable salts, see Stahl and Wermuth, Handbook of Pharmaceutical Salts: Properties, Selection, and Use (Wiley-VCH, 2002).

[0264] Pharmaceutically acceptable salts of compounds of formula I, IA or IB can be prepared by one or more of three methods, respectively: (i) reacting a compound of formula I, IA or IB with a desired acid; (ii) removing an acid- or base-labile protecting group from a suitable precursor of a compound of formula I, IA or IB, or ring-opening a suitable ring precursor (e.g., a lactone or lactam) using a desired acid or base; or (iii) converting one salt of a compound of formula I, IA or IB into another salt by reaction with an appropriate acid or base or by passing through a suitable ion exchange column. All three reactions are typically performed in solution. The resulting salt can be precipitated and collected by filtration, or can be recovered by evaporating the solvent. The degree of ionization of the resulting salt can vary from fully ionized to almost non-ionized.

[0265] The present invention also includes the following embodiments:

[0266] A compound I, IA or IB as defined in any of the embodiments described in this application, or a pharmaceutically acceptable salt thereof, for use as a medicament;

[0267] A compound of I, IA or IB as defined in any of the embodiments described herein, or a pharmaceutically acceptable salt thereof, for use in treating a disease or condition selected from the group consisting of inflammation, autoimmune disease, neuroinflammation, arthritis, rheumatoid arthritis, spondyloarthropathies, systemic lupus erythematosus, lupus nephritis, osteoarthritis, gouty arthritis, pain, fever, pulmonary sarcoidosis, silicosis, cardiovascular disease, atherosclerosis, myocardial infarction, thrombosis, congestive heart failure and cardiac reperfusion injury, cardiomyopathy, stroke, ischemia, reperfusion injury, cerebral edema, brain damage, neurodegeneration, liver disease, inflammatory bowel disease, Crohn's disease, ulcerative colitis, nephritis, retinitis, retinopathy, macular degeneration, glaucoma, diabetes (type 1 and 2), diabetic neuropathy, viral and bacterial infections, myalgia, endotoxin shock, toxic shock syndrome, osteoporosis, multiple sclerosis, endometriosis, dysmenorrhea, vaginitis, candidiasis, cancer, fibrosis, obesity, muscular dystrophy, polymyositis, dermatomyositis, autoimmune hepatitis, primary biliary cirrhosis, primary sclerosing cholangitis, vitiligo, Alzheimer's disease, skin erythema, eczema, psoriasis, atopic dermatitis, sunburn, keloids, hypertrophic scars, rheumatic diseases, urticaria, discoid lupus, cutaneous lupus, central nervous system lupus, psoriatic arthritis, asthma, allergic asthma, type I interferon pathology (including Icardi-Gautiers syndrome and type I interferon overexpression) Other Mendelian diseases), primary progressive multiple sclerosis, relapsing-remitting multiple sclerosis, nonalcoholic fatty liver disease, nonalcoholic fatty hepatitis, scleroderma, alopecia areata, alopecia myositis cicatrix, vasculitis, pemphigus, lupus, major depression, allergy, dry eye syndrome, transplant rejection, cancer, septic shock, cardiopulmonary dysfunction, acute respiratory disease, adhesive spondylitis, cachexia, chronic graft-versus-host disease, acute graft-versus-host disease, steatorrhea, idiopathic thrombocytopenic thrombotic purpura, thrombotic thrombocytopenic purpura, myasthenia gravis, Sjögren's syndrome, epidermal hyperplasia, cartilage inflammation, bone degradation, juvenile arthritis, juvenile rheumatoid arthritis, oligoarticular juvenile rheumatoid arthritis , polyarticular juvenile rheumatoid arthritis, systemic onset juvenile rheumatoid arthritis, juvenile adhesive spondylitis, juvenile enteropathic arthritis, juvenile Reiter's syndrome, SEA syndrome, juvenile dermatomyositis, juvenile psoriatic arthritis, juvenile scleroderma, juvenile systemic lupus erythematosus, juvenile vasculitis, oligoarticular rheumatoid arthritis, polyarticular rheumatoid arthritis, systemic onset rheumatoid arthritis, enteropathic arthritis, reactive arthritis, Reiter's syndrome, myositis, polymyositis, dermatomyositis, polyarteritis nodosa, Wegener's granulomatosis, arteritis, polymyalgia rheumatica, sarcoidosis, sclerosis, primary biliary sclerosis, sclerosing cholangitis, dermatitis, Still's disease, chronic obstructive pulmonary disease,Guillain-Barré disease, Graves' disease, Addison's disease, Raynaud's phenomenon, psoriatic epidermal hyperplasia, plaque psoriasis, guttate psoriasis, inverse psoriasis, pustular psoriasis, erythrodermic psoriasis, immune disorders associated with or caused by pathogenic lymphocyte activity, non-infectious uveitis, Behcet's disease, and Vogt-Koyage-Harada syndrome;

[0268] A method of treating a disease for which a SIK 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, IA or IB as defined in any of the embodiments described herein, or a pharmaceutically acceptable salt thereof;

[0269] Use of a compound of formula I, IA or IB as defined in any of the embodiments described herein, or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for treating a disease or condition for which a SIK inhibitor is indicated;

[0270] A compound of formula I, IA or IB as defined in any of the embodiments described in the present application, or a pharmaceutically acceptable salt thereof, for use in treating a disease or condition for which a SIK inhibitor is indicated;

[0271] A pharmaceutical composition for treating a disease or condition for which a SIK inhibitor is indicated, comprising a compound of formula I, IA or IB as defined in any of the embodiments described herein or a pharmaceutically acceptable salt thereof.

[0272] The invention also provides any of the uses, methods or compositions as defined above, wherein a compound of formula I, IA or IB or a pharmaceutically acceptable salt thereof is used in combination with another pharmacologically active compound, in particular one of the functionally defined classes or specific compounds listed below. These agents may be administered according to standard pharmaceutical practice known to those skilled in the art, as part of the same or separate dosage forms, via the same or different routes of administration and according to the same or different administration regimens.

[0273] Suitable agents for use in combination therapy with a compound of Formula I, IA or IB, or a pharmaceutically acceptable salt thereof: sulfasalazine, mesalazine, prednisone, azathioprine, infliximab, adalimumab, belimumab, becertolizumab, natalizumab, vedolizumab, hydrocortisone, budesonide, cyclosporin, tacrolimus, fexofenadine, 6-mercaptopurine, methotrexate, ursodeoxycholic acid, obeticholic acid acid, antihistamines, rifampin, prednisone, methotrexate, azathioprine, cyclophosphamide, hydroxychloroquine, mofetil, sodium mycophenolate, tacrolimus, leflunomide, chloroquine and quinacrine, thalidomide, rituxan, NSAIDs, solumedrol, depomedrol, and dexamethasone.

[0274] Other suitable agents for use in combination therapy with a compound of Formula I, IA or IB, or a pharmaceutically acceptable salt thereof, include: a 5-lipoxygenase activating protein (FLAP) antagonist; a leukotriene antagonist (LTRA), such as an LTB4, LTC4, LTD4, LTE4, CysLT1 or CysLT2 antagonist, for example, montelukast or zafirlukast; a histamine receptor antagonist, such as a histamine type 1 receptor antagonist or a histamine type 2 receptor antagonist, for example, loratidine, fexofenadine, desloratidine, levocetirizine, methapyrilene or cetirizine; an alpha 1-adrenergic receptor agonist or an alpha 2-adrenergic receptor agonist; agonists, such as phenylephrine, methoxamine, oxymetazoline or methylnorephrine; muscarinic M3 receptor antagonists, such as tiotropium or ipratropium; dual muscarinic M3 receptor antagonists / β2 agonists; PDE inhibitors, such as PDE3 inhibitors, PDE4 inhibitors or PDE5 inhibitors, such as theophylline, sildenafil, vardenafil, tadalafil, ibudilast, cilomilast or roflumilast; sodium cromoglycate cromoglycate or sodium nedocromil; cyclooxygenase (COX) inhibitors, such as non-selective inhibitors (e.g., aspirin or ibuprofen) or selective inhibitors (e.g., celecoxib or valdecoxib); glucocorticosteroids, such as fluticasone, mometasone, dexamethasone, prednisolone, budesonide, ciclesonide, or beclamethasone;Anti-inflammatory monoclonal antibodies, such as infliximab, adalimumab, tanezumab, ranibizumab, bevacizumab or mepolizumab; beta-2 agonists, such as salmeterol, albuterol, salbutamol, fenoterol or formoterol, especially long-acting beta-2 agonists; integrative antagonists, such as natalizumab; adhesion molecule inhibitors, such as VLA-4 antagonists; kinin B1 or B2 receptor antagonists; immunosuppressants, such as inhibitors of the IgE pathway (e.g. omalizumab) or cyclosporine; matrix metalloproteinase (MMP) inhibitors, such as inhibitors of MMP-9 or MMP-12; tachykinin NK1, NK2 or NK3 receptor antagonists; protease inhibitors, such as inhibitors of elastase, chymosin or cathepsin G; adenosine A; 2a Adenosine A receptor agonist 2b receptor antagonists; urokinase inhibitors; dopamine receptor agonists (e.g. ropinirole), in particular dopamine D2 receptor agonists (e.g. bromocriptine); modulators of the NFκB pathway, such as IKK inhibitors; another modulator of the cytokine signaling pathway, such as inhibitors of syk kinase, p38 kinase, SPHK-1 kinase, Rho kinase, EGF-R or MK-2; mucolytics, mucodynamics or antitussives; antibiotics; antivirals; vaccinia; chemokines; epithelial sodium channel (ENaC) blockers Or epithelial sodium channel (ENaC) inhibitors; nucleotide receptor agonists, such as P2Y2 agonists; thrombin inhibitors; nicotinic acid; 5-lipoxygenase (5-LO) inhibitors, such as Zileuton; adhesion factors, such as VLAM, ICAM or ELAM; CRTH2 receptor (DP2) antagonists; prostaglandin D2 receptor (DP1) antagonists; hematopoietic prostaglandin D2 synthase (HPGDS) inhibitors; interferon-β; human soluble TNF receptors, such as Etanercept; HDAC inhibitors; phosphoinositide 3-kinase gamma (PI3Kγ) inhibitors; phosphoinositide 3-kinase delta (PI3Kδ) inhibitors; CXCR-1 or CXCR-2 receptor antagonists; IRAK-4 inhibitors; and TLR-4 or TLR-9 inhibitors, including pharmaceutically acceptable salts of the specifically mentioned compounds. The agent can be administered together with another active agent, wherein the second active agent can be administered orally or topically.

[0275] Thus, the present invention provides a method for treating or preventing a disease, condition or disorder associated with SIK in a subject (such as a human or non-human mammal), comprising administering to a subject in need thereof an effective amount of one or more compounds described herein. Conditions for which selective targeting of the SIK pathway or modulation of SIK kinase is considered therapeutically useful include, among others, arthritis, asthma, autoimmune diseases, cancer or tumors, diabetes, certain eye diseases, diseases or conditions, inflammation, intestinal inflammation, allergies or conditions, neurodegenerative diseases, psoriasis, and transplant rejection.

[0276] One way to implement the present invention is to administer a compound of formula I, IA or IB in the form of a prodrug. Therefore, certain derivatives of compounds of formula I, IA or IB that are hardly pharmacologically active in themselves can be converted into compounds of formula I, IA or IB with desired activity, for example, by hydrolytic cleavage, especially hydrolytic cleavage promoted by esterase or peptidase, when administered in vivo or on the body. Such derivatives are referred to as "prodrugs". Other information on the use of prodrugs can be found in 'Pro-drugs as Novel Delivery Systems', Vol. 14, ACS Symposium Series (T. Higuchi and W. Stella) and 'Bioreversible Carriers in Drug Design', Pergamon Press, 1987 (EB Roche, American Pharmaceutical Association). Reference may also be made to Nature Reviews / Drug Discovery, 2008, 7, 355 and Current Opinion in Drug Discovery and Development, 2007, 10,550.

[0277] Prodrugs according to the invention may be generated, for example, by replacing appropriate functional groups present in compounds of formula I, IA or IB with certain moieties known to the skilled person as "promoieties", for example as described in 'Design of Prodrugs' by H. Bundgaard (Elsevier, 1985).

[0278] Therefore, the prodrugs of the present invention are (a) ester or amide derivatives of a hydroxy group in a compound of Formula I, IA or IB; (b) ester, carbonate, carbamate, phosphate or ether derivatives of a hydroxy group in a compound of Formula I, IA or IB; (c) amide, imine, carbamate or amine derivatives of an amino group in a compound of Formula I, IA or IB; (d) oxime or imine derivatives of a carbonyl group in a compound of Formula I, IA or IB.

[0279] Some specific examples of prodrugs according to the present invention include:

[0280] (i) wherein the compound of formula I, IA or IB contains a hydroxyl functional group;

[0281] (ii) wherein the compound of formula I, IA or IB contains an alcohol function (-OH) and the prodrug is an ester thereof, such as a compound wherein the hydrogen of the alcohol function of the compound of formula I, IA or IB is replaced by -CO(C1-C8 alkyl) (e.g. methylcarbonyl) or the alcohol is esterified by an amino acid;

[0282] (iii) wherein the compound of formula I, IA or IB contains an alcohol functional group (-OH) and the prodrug is an ether thereof, such as a compound wherein the hydrogen of the alcohol functional group of the compound of formula I, IA or IB is replaced by (C1-C8 alkyl)C(=O)OCH2 or -CH2OP(=O)(OH)2;

[0283] (iv) wherein the compound of formula I, IA or IB contains an alcohol functional group (-OH) and the prodrug is a phosphate ester thereof, such as wherein the hydrogen of the alcohol functional group of the compound of formula I, IA or IB is substituted by -P(=O)(OH)2 or -P(=O)(ONa)2 or -P(=O)(O - )2Ca 2+ Displaced compounds;

[0284] (v) wherein the compound of formula I, IA or IB contains a secondary amino functional group (-NHR, where R ≠ H), and the prodrug is an amide thereof, for example wherein, as the case may be, one or both hydrogen atoms of the amino functional group of the compound of formula I, IA or IB are (C1-C 10 ) Compounds in which the alkanoyl group is replaced by -COCH2NH2 or the amino group is derived from an amino acid;

[0285] (vi) wherein the compound of formula I, IA or IB contains a secondary amino function (-NH2 or -NHR, wherein R ≠ H) and the prodrug is an amine thereof, for example a compound wherein, as the case may be, one or both hydrogens of the amino function of the compound of formula I, IA or IB are replaced by -CH2OP(=O)(OH)2.

[0286] Reference to a compound of Formula I, IA or IB includes the compound itself and prodrugs thereof. The present invention includes such compounds of Formula I, IA or IB and pharmaceutically acceptable salts of such compounds.

[0287] Also included within the scope of the present invention are active metabolites of compounds of formula I, IA or IB, i.e. compounds formed in vivo after administration of the drug, usually by oxidation or dealkylation. Some examples of metabolites according to the present invention include

[0288] (i) wherein the compound of formula I, IA or IB contains a methylene group and the metabolite is its hydroxymethylene derivative (-CH2- -> -CHOH):

[0289] (ii) wherein the compound of formula I, IA or IB contains a tertiary amino group and the metabolite is a secondary amino derivative thereof (-NRR ' -> -NHR or -NHR ' );as well as

[0290] (iii) wherein the compound of formula I, IA or IB contains a secondary amino group and the metabolite is a primary derivative thereof (-NHR ->-NH2).

[0291] In another embodiment, the present invention provides a pharmaceutical composition or formulation comprising a therapeutically effective amount of a compound of the present invention and a pharmaceutically acceptable diluent or carrier. The pharmaceutical composition or formulation of the present invention can be administered to humans and other mammals in the form of topical, oral, parenteral, intracisternal, intravaginal, intraperitoneal, buccal mucosa, oral spray, nasal spray, rectal suppository or liposomes.

[0292] Typical pharmaceutical compositions or preparations are prepared by mixing the compounds of the present invention and carriers or diluents. Suitable carriers and diluents include, for example, carbohydrates, waxes, water-soluble and / or swellable polymers, hydrophilic or hydrophobic substances, gelatin, oils, solvents, water and the like. The specific carrier or diluent used will depend on the manner and purpose of applying the compounds of the present invention. Suitable aqueous solvents include water, ethanol, propylene glycol, polyethylene glycol (e.g., PEG400, PEG300), etc. and mixtures thereof. The preparation may also include one or more buffers, stabilizers, surfactants, wetting agents, lubricants, emulsifiers, suspending agents, preservatives, antioxidants, light-shielding agents, slip agents, processing aids, colorants, sweeteners, aromatics, flavoring agents, and other known additives that make the drug (i.e., the compound of the present invention or its pharmaceutical composition) exquisitely presented or contribute to the manufacture of a pharmaceutical product (i.e., for the preparation of a medicament).

[0293] The formulation can be prepared using conventional dissolution and mixing procedures. For example, the main bulk drug (i.e., the compound of the present invention or a stable form of the compound (e.g., complexed with a cyclodextrin derivative or other known complexing agent)) is dissolved in a suitable solvent in the presence of one or more of the above-mentioned carriers. The dissolution rate of poorly water-soluble compounds can be enhanced by using spray-dried dispersions, such as those described in the following documents: Takeuchi, H. et al., "Enhancement of the dissolution rate of a poorly water-soluble drug (tolbutamide) by a spray-drying solvent deposition method and disintegrants", J. Pharm. Pharmacol., 39, 769-773 (1987); and EP0901786 B1 (US2002 / 009494), which is incorporated herein by reference. The compounds of the present invention are generally formulated into pharmaceutical dosage forms to provide drugs that can be easily controlled in dosage and to provide patients with delicate and easy-to-handle products.

[0294] Depending on the method for administering the drug, the pharmaceutical composition or preparation for administration can be packaged in a variety of ways. Generally speaking, the product for distribution includes a container of appropriate form in which the pharmaceutical preparation is stored. Suitable containers include materials such as bottles (plastic and glass), pouches, ampoules, plastic bags, metal cylinders and similar substances. The container may also include an anti-misopening assembly to prevent the contents of the package from being obtained rashly. In addition, the container is attached with a label describing the contents of the container. The label may also include appropriate warnings.

[0295] The term "pharmaceutically acceptable carrier" refers to a carrier medium that suitably delivers an effective amount of an active agent as defined herein, does not interfere with the effectiveness of the biological activity of the active agent, and is sufficiently nontoxic to the host or patient. Representative carriers include water, oils, vegetable and mineral, cream bases, emulsion bases, ointment bases, and the like. These bases include suspending agents, thickening agents, penetration enhancers, and the like. Additional information about carriers can be found in Remington: The Science and Practice of Pharmacy, 21st edition, Lippincott, Williams & Wilkins (2005), which is incorporated herein by reference. Other examples of substances that can serve as pharmaceutically acceptable carriers are: sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethylcellulose, ethylcellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; carriers such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols such as propylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffers such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethanol and phosphate buffer solutions and other nontoxic compatible lubricants such as sodium lauryl sulfate and magnesium stearate, and colorants, release agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the composition according to the judgment of the formulator.

[0296] The term "pharmaceutically acceptable topical carrier" refers to a pharmaceutically acceptable carrier as described above that is suitable for topical application. Inactive liquid or cream media that are capable of suspending or dissolving the active agent and that have non-toxic and non-inflammatory properties when applied to the skin, nails, hair, claws or hooves are examples of pharmaceutically acceptable topical carriers. This term is particularly intended to also encompass carrier substances approved for use in topical cosmetics.

[0297] The term "topical application" refers to applying a pharmaceutical agent to the outer surface of the skin, nail, hair, claw or hoof so that the agent passes over the outer surface of the skin, nail, hair, claw or hoof and enters the subcutaneous tissue. Topical application includes applying the composition to intact skin, nail, hair, claw or hoof, or to a broken, untreated or open wound of the skin, nail, hair, claw or hoof. Topical application of a pharmaceutical agent may result in limited distribution of the agent to the skin and surrounding tissues, or may cause systemic distribution of the agent as the agent is removed from the treatment area by the bloodstream.

[0298] Dosage forms for topical or transdermal administration of the compounds of the invention include ointments, pastes, creams, emulsions, gels, powders, solutions, sprays, inhalants or patches. The active ingredient is mixed with a pharmaceutically acceptable carrier and any desired preservatives or buffers that may be required under aseptic conditions. Volatile compounds may need to be mixed with specific formulations or with specific encapsulated materials to ensure proper dose delivery. In addition, compounds of the invention with poor human skin permeability may require one or more permeability enhancers, and compounds that are rapidly absorbed through the skin may need to be formulated with absorption retardants or barriers.

[0299] In addition to the active compounds of the present invention, ointments, pastes, creams, emulsions, gels, powders and solutions for topical application may contain pharmaceutically acceptable carriers such as animal and vegetable fats, oils, waxes, paraffins, starches, tragacanth, cellulose derivatives, polyethylene glycols, polysilicone, bentonite, silicic acid, talc, zinc oxide, preservatives, antioxidants, fragrances, emulsifiers, dyes, inert fillers, anti-irritants, viscosity enhancers, fragrances, sunscreens, antioxidants, gelling agents, stabilizers, surfactants, emollients, colorants, preservatives, buffers, penetration enhancers or mixtures thereof. Topical carriers should not interfere with the effective biological activity of the active agent and will not be harmful to epithelial cells or their functions.

[0300] The term "permeability enhancer" or "penetration enhancer" refers to the increase in the permeability of a drug to the skin, nail, hair, claw or hoof, thereby increasing the rate at which the drug penetrates through the skin, nail, hair, claw or hoof. The penetration enhancement achieved by using such enhancers can be observed, for example, by measuring the diffusion rate of the drug through the skin, nail, hair, claw or hoof of an animal or human using a diffusion cell device. Merritt et al. Diffusion Apparatus for SkinPenetration, J of Controlled Release, 1 (1984) pp. 161-162 describe diffusion cells. The term "permeation enhancer" or "penetration enhancer" means an agent or mixture of agents used alone or in combination to increase the permeability of a drug to the skin, nail, hair or hoof.

[0301] The term "transdermal delivery" refers to the diffusion of agents through the barriers of skin, nails, hair, claws or hooves caused by topical application of the composition or other applications. The stratum corneum acts as a barrier and very few pharmaceutical agents can penetrate intact skin. In contrast, the surface layer and dermis can be penetrated by a variety of solutes and therefore, the drug is more easily absorbed through the skin, nails, hair, claws or hooves that are worn or otherwise stripped of the stratum corneum to expose the surface layer. Transdermal delivery includes injection or other delivery via any part of the skin, nails, hair, claws or hooves or mucous membranes, and absorption or penetration via the residual part. Absorption via intact skin, nails, hair, claws or hooves can be enhanced by placing the active agent in a pharmaceutically acceptable appropriate medium before being applied to the skin, nails, hair, claws or hooves. Passive topical application can be composed of directly applying the active agent to the treatment site, and applying an emollient or a penetration enhancer. As used in this application, transdermal delivery is intended to include delivery by penetration or through the integument (ie, skin, nail, hair, claw, or hoof).

[0302] Powders and sprays may contain, in addition to the compounds of this invention, lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances. Sprays may additionally contain customary propellants such as chlorofluorohydrocarbons.

[0303] Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In such solid dosage forms, the active compound is mixed with at least one pharmaceutically acceptable inert carrier, such as sodium citrate or calcium phosphate and / or a) fillers or bulking agents, such as starch, lactose, sucrose, glucose, mannitol and salicylic acid; b) binders, such as carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and acacia; c) humectants, such as glycerol; d) disintegrators, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates and sodium carbonate; e) solution retardants, such as paraffin; f) absorption promoters, such as quaternary ammonium compounds; g) wetting agents, such as cetyl alcohol and glyceryl monostearate; h) adsorbents, such as kaolin and bentonite; and i) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents.

[0304] Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.

[0305] Solid dosage forms of tablets, dragees, capsules, pills and granules may be prepared with coatings and shells, such as enteric coatings and other coatings well known in the art of pharmaceutical formulation. They may optionally contain opacifying agents and may also be of a composition that releases the active ingredient only or preferentially in a certain part of the intestinal tract in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes.

[0306] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active compound, the liquid dosage form may contain: inert diluents commonly used in the art, such as water or other solvents; solubilizers and emulsifiers, such as ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (especially cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil and sesame oil), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycol and fatty acid esters of sorbitan and mixtures thereof.

[0307] Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

[0308] As used in this application, the term "parenteral" refers to a mode of administration, which includes intravenous, intramuscular, intraperitoneal, intrasternal, subcutaneous, intraarticular injection and infusion. The pharmaceutical composition for parenteral injection includes a pharmaceutically acceptable sterile aqueous solution or non-aqueous solution, dispersion, suspension or emulsion, and a sterile powder for reconstitution into a sterile injectable solution or dispersion. Examples of suitable aqueous and non-aqueous carriers, diluents, solvents or media include water, ethanol, polyols (propylene glycol, polyethylene glycol, glycerol and similar alcohols), suitable mixtures thereof, vegetable oils (such as olive oil) and injectable organic esters, such as ethyl oleate. For example, by using a coating (such as lecithin), in the case of a dispersion, by maintaining the desired particle size, and by using a surfactant to maintain appropriate fluidity.

[0309] Injectable depot forms are made by forming microencapsulated matrices of the drug in biodegradable polymers such as polylactide-polyglycolide. Depending on the ratio of drug to polymer and the nature of the particular polymer employed, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by encapsulating the drug in liposomes or microemulsions that are compatible with body tissues.

[0310] The injectable formulations can be sterilized, for example, by filtration through a bacteria-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.

[0311] Suitable dispersants or wetting agents and suspending agents can be used to prepare injectable preparations (e.g., sterile injectable aqueous or oily suspensions). Sterile injectable preparations can also be sterile injectable solutions, suspensions, or emulsions present in parenterally acceptable nontoxic diluents or solvents, such as solutions present in 1,3-butanediol. Among acceptable media and solvents, water, Ringer's solution, USP, and isotonic sodium chloride solutions can be used. In addition, sterile non-volatile oils are conventionally used as solvents or suspension media. For this purpose, any mild non-volatile oil can be used, including synthetic monoglycerides or diglycerides. In addition, fatty acids, such as oleic acid, are used to prepare injectables.

[0312] Pharmaceutical compositions or formulations for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds of the present invention with a suitable non-irritating carrier such as cocoa butter, polyethylene glycol or a suppository wax which is solid at ambient temperature but liquid at body temperature and therefore melts in the rectal or vaginal cavity and releases the active compound.

[0313] The compounds of the present invention can also be administered in the form of liposomes. Liposomes are generally derived from phospholipids or other lipid substances and are formed by single or multilamellar hydrated liquid crystals dispersed in an aqueous medium. Any non-toxic, physiologically acceptable and metabolizable lipid capable of forming liposomes can be used. In addition to the compounds of the present invention, the compositions of the present invention in the form of liposomes may contain stabilizers, preservatives and the like. Preferred lipids are natural and synthetic phospholipids and phosphatidylcholines (lecithins) used alone or together. Methods for forming liposomes are known in the art. See, for example, Prescott, Methods in Cell Biology, Volume XIV, Academic Press, New York, NY (1976), page 33 and subsequent pages.

[0314] The pharmaceutical composition or preparation of the present invention may also contain adjuvants, such as preservatives, wetting agents, emulsifiers and dispersants. Protection against the action of microorganisms may be ensured by various antibacterial or antifungal agents (e.g., parabens, chlorobutanol, phenol, sorbic acid and the like). It may also be desirable to include isotonic agents, such as sugars, sodium chloride and the like. Prolonged absorption of injectable pharmaceutical forms may be achieved by the use of agents that delay absorption (e.g., aluminum monostearate and gelatin).

[0315] The pharmaceutical composition or preparation of the present invention may be a suspension. In addition to the active compound, the suspension may also contain suspending agents such as ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar, tragacanth and mixtures thereof.

[0316] Pharmaceutical compositions also include solvates and hydrates of the compounds of the present invention. The term "solvate" refers to a molecular complex of a compound represented by Formula I, IA or IB (including pharmaceutically acceptable salts thereof) and one or more solvent molecules. Such solvent molecules are commonly used in the pharmaceutical field and are known to be harmless to the recipient, such as water, ethanol, ethylene glycol, (S)-propylene glycol, (R)-propylene glycol and the like. The term "hydrate" refers to a complex in which the solvent molecule is water. Solvates and / or hydrates are preferably present in crystalline form. Other solvents can be used as intermediate solvates to prepare more desirable solvates. Intermediate solvents include, but are not limited to, methanol, methyl tert-butyl ether, ethyl acetate, methyl acetate, 1,4-butynediol and the like.

[0317] The actual dosage level of the active ingredient in the pharmaceutical composition of the present invention can be varied to obtain an amount of active compound that is effective to achieve the desired therapeutic response of a particular patient, composition, and mode of administration. The selected dosage level will depend on the activity of the particular compound, the route of administration, the severity of the morbidity being treated, and the morbidity and previous medical history of the patient being treated. However, it is within the skill of the art to start administering the compound at a level lower than that required to achieve the desired therapeutic effect, and gradually increase the dosage until the desired effect is achieved.

[0318] The total daily dose of the compounds of the invention administered to humans or lower animals may be in the range of about 0.000001 to about 10 mg / kg / day. For the purpose of oral administration, a more preferred dose may be in the range of about 0.001 to about 1 mg / kg / day. For topical administration, a more preferred dose may be in the range of 0.00001 mg / kg / day to about 5 mg / kg / day. If desired, for the purpose of administration, the effective daily dose may be divided into multiple doses, such as two to four separate doses per day.

[0319] Synthesis method

[0320] The following flow and written description provide general details about preparing the compounds of the present invention. The compounds of the present invention can be prepared by any method known in the art for preparing compounds with similar structures. In particular, the compounds of the present invention can be prepared by the procedures described in the following flow, or by the specific methods described in the examples or by methods similar thereto.

[0321] It will be appreciated by those skilled in the art that the experimental conditions set forth in the schemes below are illustrative of conditions suitable for achieving the indicated transformations and that it may be necessary or desirable to vary the precise conditions used to prepare compounds of Formula I, IA or IB.

[0322] In addition, it will be appreciated by those skilled in the art that it may be necessary or desirable to protect one or more sensitive groups at any stage of the synthesis of the compounds of the present invention in order to prevent undesired side reactions. In particular, it may be necessary or desirable to protect amino or carboxylic acid groups. The protecting groups used to prepare the compounds of the present invention can be used in a conventional manner. See, for example, Greene's Protective Groups in Organic Synthesis by Theodora W Greene and Peter GM Wuts, the third edition (John Wiley and Sons, 1999), in particular, those protecting groups described in Chapter 7 ("Protection for the Amino Group") and Chapter 5 ("Protection for the Carboxyl Group"), which are incorporated herein by reference, and which also describe methods for removing such groups.

[0323] All derivatives of formula I can be prepared by the procedures described in the general methods presented below or by conventional variations thereof. The present invention also encompasses any one or more of these methods for preparing derivatives of formula I, IA or IB (except any novel intermediates used therein). It will be appreciated by those skilled in the art that the following reactants can be heated thermally or under microwave irradiation. It will also be appreciated that it may be necessary or desirable to transform in an order different from that described in the flow, or to modify one or more transformations, to obtain the desired compounds of the present invention.

[0324] Those skilled in the art will also recognize that some of the compounds of the present invention possess chirality and can therefore be prepared as racemic or achiral mixtures of enantiomers. Several methods of separating enantiomers are available and well known to those skilled in the art. A preferred method for conventionally separating enantiomers is supercritical fluid chromatography using a chiral stationary phase.

[0325] Reaction Scheme IA and Reaction Scheme IB outline general procedures for the synthesis of intermediates that can be used to provide compounds of the invention having formula (I). R' and R" represent chemical groups described within the scope of the claims; Boc = tert-butyloxycarbonyl; PG = protecting group. One skilled in the art will recognize that Reaction Scheme IA and Reaction Scheme IB can depict the synthesis of racemic compounds, and that these routes can be adapted to synthesize either enantiomer of the compound of formula (I).

[0326] Reaction Scheme IA

[0327]

[0328] Reaction Scheme IB

[0329]

[0330] The intermediate 1,2-amino alcohol of structure (1) where A1=O is well known in the chemical literature, with many derivatives commercially available and many synthetic methods reported. For chiral amino alcohol intermediates (1), methods for synthesizing racemic compounds and enantiomerically enriched compounds are known. Amino alcohol intermediates (1) are easily prepared from α-amino acids (1c), which are also widely commercially available and well reported in the literature. For example, the preparation and transformation of intermediates of structure (1c) to (1) are described in Chem. Revs 1996, 96, 835, J. Med. Chem. 2020, 63, 10188; J. Org. Chem. 2013, 78, 12726; Tetrahedron 1994, 50, 1539, Chem. Revs 2007, 107, 4584. The preparation of amino acids (1c) from ketones (1a) is described in Chemical Reviews 2017, 117, 13757; Molecules 2021, 26, 1707. The use of N-protecting groups, including tert-butoxycarbonyl (Boc), is described in TW Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, New York, 1991.

[0331] It is well known that amino acid intermediate (1c) can be converted to amino alcohol intermediate (1) wherein A1=O and R8=H by direct addition of a suitable hydride source (preferably lithium aluminum hydride). Alternatively, amino acid intermediate (1c) can be treated with an anhydrous alcohol solvent and an acid (preferably methanol and hydrogen chloride) to give intermediate ester (1f), wherein preferably R=methyl, followed by reduction with a suitable hydride source (preferably lithium aluminum hydride or lithium borohydride) to give amino alcohol intermediate (1). In the case of R8=alkyl, α-amino acid intermediate (1c) can be converted to N-protected derivative intermediate (1g), wherein PG=a suitable protecting group, preferably tert-butoxycarbonyl, followed by conversion to amide derivative intermediate (1h) suitable for selective addition of a suitable R8 group. Nucleophilic addition of a suitable alkyl organometallic reagent (preferably a Grignard reagent or an organolithium reagent) can provide ketone intermediate (1i). Reduction of the ketone intermediate (1i) with a hydride reagent (preferably sodium borohydride or lithium borohydride) can yield an N-protected 1,2-amino alcohol intermediate (1j). When PG = tert-butoxycarbonyl, preferably trifluoroacetic acid or hydrochloric acid is used to cleave the N-protecting group to yield the amino alcohol intermediate (1). The amino alcohol intermediate (1) can also be readily converted to an N-protected 1,2-amino alcohol intermediate (1j) by standard methods; preferably, by reaction with di-tert-butyl dicarbonate, PG = tert-butoxycarbonyl.

[0332] Alternatively, amino acid intermediates (1c) that are not commercially available or unknown in the literature can be synthesized from appropriate ketone starting material intermediates (1a). The conversion of ketone intermediates (1a) to aminonitrile intermediates (1b) and then to amino acid intermediates (1c) via the Strecker reaction is well known in the literature. Ketones (1a) can be treated with an ammonia source such as ammonium chloride and / or ammonium hydroxide and a cyanide source, preferably sodium or potassium cyanide or trimethylsilyl cyanide, in a protic solvent such as water or methanol to give aminonitrile intermediates (1b). Aminonitrile intermediates (1b) can be hydrolyzed to amino acid intermediates (1c) by aqueous acid (preferably hydrochloric acid or sulfuric acid) and heating. An alternative route to convert ketone intermediates (1a) to amino acid intermediates (1c) is treatment with a cyanide source (preferably sodium or potassium cyanide, or trimethylsilyl cyanide) and ammonium carbonate to give hydantoin intermediates (1d). Some hydantoin intermediates (1d) can be directly cleaved to amino acid intermediates (1c) by treatment with a strong aqueous base (preferably potassium hydroxide or barium hydroxide) and heating, or by treatment with a strong acid (such as hydrobromic acid in phosphoric acid) and heating. Alternatively, the hydantoin intermediate (1d) can first be activated for hydrolysis by treatment with di-tert-butyl dicarbonate to give intermediate (1e), followed by treatment with a strong aqueous base (preferably potassium hydroxide) to give the amino acid intermediate (1c).

[0333] Intermediate 1,2-aminothiols of structure (1) where A1=S are well known in the chemical literature, many derivatives of which are commercially available and many synthetic methods have been reported. Similar to established synthetic methods, such as those described in Synlett 2000, 908, J. Med. Chem. 2014, 57, 5748, Eur. J. Org. Chem. 2019, 7432, aminothiol intermediates (1) where A1=S or corresponding N-protected aminothiol intermediates (1k) can be easily prepared from amino alcohol intermediates (1) where A1=O or corresponding N-protected amino alcohol intermediates (1j).

[0334] The conversion of the N-protected amino alcohol intermediate (1j) to the N-protected aminothiol intermediate (1k) is achieved by activating the ethanol for displacement by a suitable sulfur-derived nucleophile, followed by protective group or oxidation state manipulation of the sulfur derivative to obtain the aminothiol intermediate (1k). For example, activation of the ethanol can be achieved by a combination of triphenylphosphine and N-bromosuccinimide or by a combination of methanesulfonyl chloride and triethylamine. The activated ethanol is reacted with a sulfur-derived nucleophile such as potassium thioacetate or benzylthiol or p-methoxybenzylthiol and a base such as potassium tert-butoxide or sodium hydride, followed by deprotection of the protected thiol to obtain the N-protected aminothiol intermediate (1k). When PG = tert-butoxycarbonyl, preferably cleavage of the N-protecting group with trifluoroacetic acid or hydrochloric acid can obtain the aminothiol intermediate (1), wherein A1 = S.

[0335] Reaction Scheme II outlines the general procedure for the synthesis of intermediates that can be used to provide compounds of the invention having formula (I). R' and R" represent chemical groups described in the claims; Boc = tert-butyloxycarbonyl. The conversion of commercially available intermediate (2a) to intermediate (2) can be carried out by well-documented conditions for sequential SNAr reactions and borylation. There are also well-documented examples of converting intermediate (2b) to intermediate (3b) by sequential SNAr reactions with intermediate (1) and introduction of N-protecting groups, or by SNAr reactions with N-protected intermediates (1j / 1k) and borylation to produce intermediate (3). For example, SNAr reactions with appropriate nucleophiles are described in US20140142102; J. Org. Chem. 1983, 48, 3341; J. Heterocyclic Chem. 1988, 25, 1173; Org. Proc. Res. & Dev. 2021, 25, 2351; Org. Proc. Res. & Dev. 2019, 23, 783; WO201912991; Org. Prep. Proc. Int. 2022, 34, 405; Tetrahedron 2013, 69, 1663. Aromatic bromides can be borated as described in WO2011061168, WO2014140078 to convert intermediate (2b) to intermediate (2) or intermediate (3b) to intermediate (3). The use of N-protecting groups (including tert-butyloxycarbonyl (Boc)) is described in TW Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, New York, 1991.

[0336] Reaction Scheme II

[0337]

[0338] Conversion of intermediate (2a) to (2b) can be readily achieved by reaction with a suitable nucleophile such as ethanol or thiol in the presence of a suitable base such as sodium hydride, or with a metal salt of ethanol or thiol (preferably sodium methoxide or sodium methylthiolate) in a suitable solvent (preferably methanol or tetrahydrofuran) at a temperature preferably between 0 and 25° C. Intermediate (2b) can be borylated to give intermediate (2) under standard palladium catalyzed reaction conditions in a suitable solvent (such as dioxane) using a catalyst such as [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), a base (such as potassium acetate) and a borylation agent (such as bis(pinacolato)diboron) at a temperature preferably between 80 and 110° C. Alternatively, intermediate (2b) can be reacted with an amino alcohol or aminothiol intermediate (1) under basic conditions in a suitable solvent, preferably potassium bis(trimethylsilyl)amide in tetrahydrofuran or sodium tert-butoxide in tert-butanol, to give intermediate (3a). Intermediate (3a) can be N-protected by reaction with di-tert-butyl dicarbonate, preferably tert-butyl carbamate, to give intermediate (3b). Alternatively, intermediate (2b) can be reacted with an N-protected amino alcohol intermediate (1j) (preferably, wherein the N-protecting group is tert-butoxycarbonyl (Boc)) and a suitable base (such as potassium bis(trimethylsilyl)amide or sodium tert-butoxide) to give intermediate (3b). Alternatively, intermediate (2b) can be reacted with an N-protected aminothiol intermediate (1k) (preferably, wherein the N-protecting group is tert-butoxycarbonyl (Boc)) and a suitable base (such as sodium carbonate or potassium carbonate) to give intermediate (3b). Intermediate (3b) can be borylated to give intermediate (3) under standard palladium catalyzed reaction conditions using a catalyst such as [1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloride, a base such as potassium acetate and a borylation agent such as bis(pinacolato)diboron in a suitable solvent such as dioxane at a temperature preferably between 80 and 110°C.

[0339] Reaction Scheme IIIA and Reaction Scheme IIIB outline the general procedures for the synthesis of compounds of the present invention having formula (I). R' and R" represent chemical groups described in the claims; Boc = tert-butyloxycarbonyl; hal represents halogen, preferably bromine or iodine. Intermediates (4b) and (4e) have many commercially available derivatives. Alternatively, the preparation of substituted pyrazolopyridines (such as intermediate (4b)) via precursor pyridine intermediates (4a) and the preparation of substituted imidazopyridines (such as intermediate (4e)) via precursor pyridine intermediates (4d) are described in the chemical literature. For example, pyrazolopyridine intermediates (4b) and (4c) can be prepared in analogy to the procedures in J. Med. Chem. 2015, 58, 8713; WO2014078802. Imidazolopyridine intermediates (4e) and (4c) can be prepared in analogy to Bioorg. Med. Chem. 2020, 28, 115775; J. Med. Chem. 2015, 58, 8713; WO2019105886. Those skilled in the art will recognize that when R4, R5 or R6 = halogen on intermediate (4b) or intermediate (4e), such halogen can be converted to other substituents via standard methods. For example, the conversion of R5 = bromine in intermediate (4b) or intermediate (4e) to R5 = (substituted) amino can be achieved similarly to the procedures described in WO2015108490, WO2020150626, WO2021140122, WO2014078802. The reaction of intermediate (4c) with alkyl borate intermediate (2) to obtain intermediate (4f), or the reaction of intermediate (4c) with intermediate (3) to obtain intermediate (4g) can be described in Bioorg. Med. Chem. 2020, 28, 115775; J. Med. Chem. 2015,58, 8713; WO2019105886. The preparation of the compound of formula (I) by reaction of intermediate (4f) with intermediate (1) can be similar to the procedures described in Organic Process Research & Development 2021, 25, 2351; Organic Process Research & Development 2019, 23, 783; Tetrahedron 2013, 69,1663; Journal of Organic Chemistry 1983, 48, 3341.Alternatively, similar to the procedures in Tetrahedron 2013, 69, 1663; Organic Preparations and Procedures International 2002, 34, 405; WO2019212991, intermediate (4f) can be reacted with N-protected amino alcohol intermediate (1j) or N-protected aminothiol intermediate (1k) to obtain intermediate (4g). Alternatively, as described in TW Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, New York, 1991, the compound of formula I can be prepared from intermediate (4g) by cleavage of the N-tert-butoxycarbonyl (Boc) group.

[0340] Reaction Scheme IIIA

[0341]

[0342] Reaction Scheme IIIB

[0343]

[0344] The pyrazolopyridine intermediate (4b) or the imidazopyridine intermediate (4e) can be reacted with a halogenating agent (preferably a brominating agent such as N-bromosuccinimide, or an iodinating agent such as N-iodosuccinimide) to give the intermediate (4c). In a suitable solvent (such as aqueous dioxane or N,N-dimethylformamide), using a catalyst (such as bis(triphenylphosphine)palladium(II) dichloride or [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride), a base (such as potassium carbonate or trisphosphate) The intermediate (4c) is subjected to a palladium-catalyzed reaction with a hydrocarbon borate intermediate (2) or a hydrocarbon borate intermediate (3) at an appropriate temperature (preferably between 80 and 110° C.) to obtain an intermediate (4f) or an intermediate (4g), respectively. The intermediate (4f) can be reacted with an amino alcohol or aminothiol intermediate (1) under basic conditions in a suitable solvent, preferably potassium bis(trimethylsilyl)amide in tetrahydrofuran or sodium tert-butoxide in tert-butanol, to obtain a compound of formula (I). Alternatively, the intermediate (4c) is subjected to a palladium-catalyzed reaction with a hydrocarbon borate intermediate (2) or a hydrocarbon borate intermediate (3) at an appropriate temperature (preferably between 80 and 110° C.) to obtain an intermediate (4f) or an intermediate (4g), respectively. Intermediate (4f) can be reacted with an N-protected amino alcohol intermediate (1j) (preferably, wherein the N-protecting group is tert-butoxycarbonyl (Boc)) and a suitable base (such as potassium bis(trimethylsilyl)amide or sodium tert-butoxide) to give intermediate (4g). Alternatively, intermediate (4f) can be reacted with an N-protected aminothiol intermediate (1k) (preferably, wherein the N-protecting group is tert-butoxycarbonyl (Boc)) and a suitable base (such as sodium carbonate or potassium carbonate) to give intermediate (4g). Intermediate (4 g) can be treated with an acid, preferably trifluoroacetic acid or hydrogen chloride, to give a compound of formula (I). The chiral compound of formula (I) can be separated into individual stereoisomers by chromatography using a chiral stationary phase to separate the racemic and / or diastereomeric compounds of formula (I). Alternatively, a chiral precursor, such as intermediate (3a), intermediate (3b) or intermediate (4g), can be separated into individual stereoisomers by chromatography using a chiral stationary phase, followed by conversion of each stereoisomer into a compound of formula (I).

[0345] Reaction Scheme IV outlines an alternative general procedure for the synthesis of compounds of the invention having formula (I) wherein Y=C and Z=N. R' and R" represent chemical groups described in the claims; Boc = tert-butyloxycarbonyl. Vinyl ether intermediate (5) can be prepared under conditions similar to those described in the following documents: WO2021013864; WO2019148132; Tetrahedron Lett 2000, 41, 4579; Tetrahedron Lett 1999, 40, 6193; Chem. Biol.&Drug Design 2015, 86, 180; J. Amer. Chem. Soc. 2011, 133, 32; Org. Lett 2013,15, 1838; J. Amer. Chem. Soc. 2018, 140, 126; Org. Lett. 2002, 4, 4399. Intermediate (5) can be reacted with 2-aminopyridine intermediate (4d) under conditions similar to those described in WO2021013864, WO2019148132 to obtain intermediate (4g). Compounds of formula (IA) can be prepared from intermediate (4g) by cleavage of the N-tert-butoxycarbonyl (Boc) group, as described in TW Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, New York, 1991.

[0346] Reaction Scheme IV

[0347]

[0348] Intermediate (5) can be prepared by a palladium-catalyzed reaction of bromide intermediate (3b) with a suitable coupling partner (preferably [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) and (E)-2-(2-ethoxyvinyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane) in the presence of a base such as tripotassium phosphate in a suitable solvent such as aqueous dioxane at a temperature preferably between 80 and 110°C. Intermediate (5) and intermediate (4d) can be reacted in the presence of an oxidant (preferably N-bromosuccinimide) to form a catalytic reaction. The intermediate (4g) is prepared by cyclization in a suitable solvent such as aqueous dioxane. The intermediate (4g) can be treated with an acid, preferably trifluoroacetic acid or hydrogen chloride, to give the compound of formula (IA). The chiral compound of formula (IA) can be separated into individual stereoisomers by chromatography using a chiral stationary phase to separate the racemic and / or diastereomeric compounds of formula (IA). Alternatively, a chiral precursor such as intermediate (4g) can be separated into individual stereoisomers by chromatography using a chiral stationary phase, followed by conversion of each stereoisomer into a compound of formula (IA).

[0349] Preparation examples and embodiments

[0350] The following non-limiting preparation examples and examples illustrate the preparation of the compounds and salts of the present invention. In the following examples and preparation examples, and in the foregoing processes, the following abbreviations, definitions and analytical procedures may be mentioned. Other abbreviations common in the art may also be used. The compounds of the present invention are named using ChemDraw Professional™ version 20 (Perkin Elmer) or given names consistent with IUPAC nomenclature.

[0351] 1 H nuclear magnetic resonance (NMR) spectra are consistent with the proposed structure in all cases. Characteristic chemical shifts (δ) are given in parts per million downfield from tetramethylsilane, with conventional abbreviations used to indicate major peaks: for example, s, singlet; d, doublet; t, triplet; q, quartet; quin, quintet; m, multiplet; br, broad. The following abbreviations are used for common NMR solvents: CD3CN, deuterated acetonitrile; CDCl3, deuterated chloroform; DMSO-d6, deuterated dimethyl sulfoxide; and MeOD, deuterated methanol. Where appropriate, tautomers may be recorded in the NMR data; and some exchangeable protons may not be visible. Some resonances in the NMR spectrum appear as complex multiplets because the isolate is a mixture of two conformers.

[0352] Mass spectra were recorded using electron impact ionization (EI), electrospray ionization (ESI), or atmospheric pressure chemical ionization (APCI). The observed ions are reported as MS m / z and may be compound [M] +、Compound plus proton [M+H] + or compound plus sodium ion [M+Na] + In some cases, the observed ions may be only fragment ions, reported as [M+H-(fragment loss)] + When relevant, the reported ions are designated as chloride ( 35 Cl and / or 37 Cl), bromine ( 79 Br and / or 81 Br) and Sn( 120 Sn) isotopes.

[0353] Where TLC, chromatography or HPLC has been used to purify compounds, one skilled in the art may select any appropriate solvent or combination of solvents to purify the desired compound. Unless otherwise indicated, chromatography separations (excluding HPLC) were performed using silica gel adsorbents.

[0354] Unless otherwise specified, all reactions are carried out under nitrogen or argon atmosphere using continuous stirring. In some cases, before starting the reaction, the reactants are purged with nitrogen or argon. In these cases, nitrogen or argon is bubbled through the liquid phase of the mixture for approximately a specified time. The solvent used is commercial anhydrous grade. All starting materials are commercially available products. In some cases, starting materials are prepared according to reported literature procedures. It will be apparent to those skilled in the art that the term "concentrated" as used in this application generally refers to implementing solvent evaporation under reduced pressure, typically accomplished by using a rotary evaporator.

[0355] Chemical structures were named using ChemDraw Professional 20.

[0356] abbreviation

[0357] B2(pin)2: Bis(pinacolyl)diboron

[0358] Boc2O: di-tert-butyl dicarbonate

[0359] CH3CN: Acetonitrile

[0360] CDCl3: deuterated chloroform

[0361] DCM: dichloromethane

[0362] DMF: N,N-dimethylformamide

[0363] DMSO: dimethyl sulfoxide

[0364] DMSO-d6: hexadeuterated dimethyl sulfoxide

[0365] Et2O: ether

[0366] EtOAc: Ethyl acetate

[0367] EtOH: ethanol

[0368] HOAc: acetic acid

[0369] HPLC: High Performance Liquid Chromatography

[0370] iPr2NEt: N,N-diisopropylethylamine

[0371] iPrOH: 2-propanol

[0372] KHMDS: Potassium bis(trimethylsilyl)amide

[0373] KOAc: Potassium acetate

[0374] h: hours

[0375] M: molar concentration

[0376] Me2NH: dimethylamine

[0377] MeOH: Methanol

[0378] MeOD: deuterated methanol

[0379] MeTHF: 2-methyl-tetrahydrofuran

[0380] mg: milligram

[0381] min: minutes

[0382] mL: milliliters

[0383] mmol: millimole

[0384] MS: mass spectrometry, (M): molecular mass

[0385] MsOH: Methanesulfonic acid

[0386] MTBE: Methyl tert-butyl ether

[0387] N: Standard

[0388] NaHMDS: Sodium bis(trimethylsilyl)amide

[0389] NaOMe: Sodium Methanol

[0390] NaOtBu: Sodium tert-butoxide

[0391] NBS: N-bromosuccinimide

[0392] NIS: N-iodosuccinimide

[0393] NMR: nuclear magnetic resonance; s, singlet; d, doublet; t, triplet; q, quartet; quin, quintet; m, multiplet; br s, broad singlet; app, apparent

[0394] PdCl2(dppf)-DCM: [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane

[0395] PdCl2(dppf): [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II)

[0396] Pd(OAc)2: Palladium(II) acetate

[0397] Pd(PPh3)2Cl2: Bis(triphenylphosphine)palladium(II) dichloride

[0398] PE: Petroleum ether

[0399] SFC: Supercritical Fluid Chromatography

[0400] TFA: trifluoroacetic acid

[0401] THF: Tetrahydrofuran

[0402] TMSCN: trimethylsilyl cyanide

[0403] UPLC: Ultra-Performance Liquid Chromatography

[0404] Xantphos: 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene

[0405] XPhos: 2-Dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl

[0406] XPhos-G3-Palladacycle: (2-Dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate

[0407] Preparation Example A

[0408] 4-Bromo-2-fluoro-6-methoxybenzonitrile. A solution of NaOMe in MeOH (5.4 M, 688 mL, 3.72 mol) was added to a solution of 4-bromo-2,6-difluorobenzonitrile (900 g, 4.13 mol) in MeOH (3.81 L) at 0°C, and the reaction was stirred for 60 h at 0°C. H2O (2.61 L) was added, and the resulting mixture was stirred at 25°C for 2 h, then the solid was collected by filtration and dried to give 4-bromo-2-fluoro-6-methoxybenzonitrile (894 g). 1H NMR (400 MHz, CDCl3) δ 7.00 (dd, 1H), 6.94 (app t, 1H), 3.95 (s, 3H).

[0409] Preparation Example B

[0410] 4-Bromo-2-fluoro-6-(methylthio)benzonitrile. CH3SNa (6.21 g, 88.6 mol) was slowly added to a solution of 4-bromo-2,6-difluorobenzonitrile (20.0 g, 91.7 mmol) in THF (300 mL) at 0°C. The resulting mixture was slowly warmed to 15°C and stirred for 3 days, then diluted with aqueous NH4Cl and extracted with EtOAc (3×). The combined organics were washed with brine (2×), dried over Na2SO4, filtered and concentrated. The resulting residue was purified by silica gel chromatography (4% to 95% EtOAc / PE) to give 4-bromo-2-fluoro-6-(methylthio)benzonitrile (18.3 g) as a white solid. 1 H NMR (400MHz, DMSO-d6) δ 7.68 (dd, 1H), 7.48 (d, 1H), 2.67 (s, 3H).

[0411] Preparation Example C

[0412] 2-Fluoro-6-(methylthio)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile. PdCl2(dppf) (1.19 g, 1.63 mmol) was added to a solution of 4-bromo-2-fluoro-6-(methylthio)benzonitrile (8.00 g, 32.5 mmol), B2(pin)2 (8.25 g, 32.5 mmol) and KOAc (7.98 g, 81.3 mmol) in dioxane (140 mL) under N2. The resulting mixture was stirred at 90 °C for 16 h and then concentrated. The resulting residue was purified by silica gel chromatography to give 2-fluoro-6-(methylthio)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile (6.5 g) as a yellow solid. 1 H NMR (400 MHz, CDCl3) δ 7.44 (s, 1H), 7.33 (d, 1H), 2.61 (s, 3H), 1.35 (s, 12H).

[0413] Preparation Example D

[0414] 2-Fluoro-4-(5-methoxyimidazo[1,2-a]pyridin-3-yl)-6-(methylthio)benzonitrile. A solution of dioxane (100 mL) and H2O (10 mL) was bubbled with N2 for 10 min and then charged into a flask containing K3PO4 (22.2 g, 105 mmol), 3-bromo-5-methoxyimidazo[1,2-a]pyridine (10.0 g, 42.0 mmol), 2-fluoro-6-(methylthio)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile (12.9 g, 43.9 mmol) and PdCl2(dppf)-DCM (1.76 g, 2.09 mmol) under N2 atmosphere. The resulting mixture was heated at 80°C for 20 h and then concentrated to remove dioxane. Dilute with water and filter the resulting suspension.The collected solid was purified by silica gel chromatography (2% to 10% MeOH / DCM) to give 2-fluoro-4-(5-methoxyimidazo[1,2-a]pyridin-3-yl)-6-(methylthio)benzonitrile (6.30 g). 1 H NMR (400 MHz, CDCl3) δ 7.62 (s, 1H), 7.37 (dd, 1H), 7.30 (dd, 1H), 7.12 (d, 1H), 7.00 (dd, 1H), 6.16 (dd, 1H), 3.93 (s, 3H), 2.60 (s, 3H). MS (M+H) + 314.0.

[0415] Example 1

[0416]

[0417] 2-((1-aminocyclopentyl)methoxy)-4-(5-methoxyimidazo[1,2-a]pyridin-3-yl)-6-(methylthio)benzonitrile. A solution of NaHMDS in THF (1.0 M, 26.8 mL, 26.8 mmol) was added dropwise to a solution of 2-fluoro-4-(5-methoxyimidazo[1,2-a]pyridin-3-yl)-6-(methylthio)benzonitrile (6.00 g, 19 mmol) and (1-aminocyclopentyl)methanol (2.67 g, 23.2 mmol) in THF (12 mL). The resulting mixture was stirred at ambient temperature for 16 hours. Aqueous phosphate buffer (pH 7, 100 mL) was added and the resulting mixture was concentrated to remove THF, followed by extraction with MeTHF (3×). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated. Silica gel chromatography (50% MeOH-DCM) afforded 2-((1-aminocyclopentyl)methoxy)-4-(5-methoxyimidazo[1,2-a]pyridin-3-yl)-6-(methylthio)benzonitrile (3.4 g) as a solid. 1 H NMR (600 MHz, DMSO-d6) δ 7.76 (s, 1H), 7.39 (dd, 1H), 7.29 (d, 1H), 7.08 (s, 1H), 7.05 (s, 1H), 6.45 (d, 1H), 3.99 (s, 2H), 3.93(s, 3H), 2.61 (s, 3H), 1.82-1.72 (m, 2H), 1.72-1.55 (m, 4H), 1.48-1.41 (m,2H).MS (M+H) + 409.4.

[0418] The following examples were synthesized by analogous procedures and starting materials as described for 2-((1-aminocyclopentyl)methoxy)-4-(5-methoxyimidazo[1,2-a]pyridin-3-yl)-6-(methylthio)benzonitrile.

[0419] Example 2

[0420]

[0421] 2-(((1S,2R)-1-amino-2-ethylcyclopentyl)methoxy)-6-methoxy-4-(5-methoxyimidazo[1,2-a]pyridin-3-yl)benzonitrile and 2-(((1R,2S)-1-amino-2-ethylcyclopentyl)methoxy)-6-methoxy-4-(5-methoxyimidazo[1,2-a]pyridin-3-yl)benzonitrile. Synthesized from 1-amino-2-ethylcyclopentane-1-carboxylic acid (Tetrahedron: Asymmetry 2000, 11, 3231-3252). The enantiomers were separated by chiral SFC (absolute stereochemistry was not determined): Chiral SFC: Phenomenex-Cellulose-2, 100 mm × 4.6 mm, 3 µ; A: CO2, B: 0.05% diethylamine / EtOH 60:40 A:B, 2.8 mL / min, 35°C; retention time, 3.5 min (peak 1), 4.7 min (peak 2). 2B Peak 1: 1 H NMR (400 MHz, MeOD) δ 7.62 (s, 1H), 7.43 (dd, 1H), 7.26 (d, 1H), 6.84(app s, 2H), 6.41 (d, 1H), 4.01 (s, 2H), 3.97 (s, 3H), 3.96 (s, 3H), 2.1-1.9(m, 2H), 1.9-1.7 (m, 3H), 1.7-1.6 (m, 2H), 1.6-1.4 (m, 1H), 1.4-1.2 (m, 1H),0.97 (t, 3H). MS (M+H) + 421.4. Enantiomeric ratio 100:0. 2A Peak 2: 1 H NMR (400 MHz, MeOD)δ 7.62 (s, 1H), 7.43 (dd, 1H), 7.26 (d, 1H), 6.84 (s, 1H), 6.84 (s, 1H), 6.41(d, 1H), 4.01 (s, 2H), 3.97 (s, 3H), 3.96 (s, 3H), 2.1-1.9 (m, 2H), 1.9-1.6(m, 5H), 1.6-1.4 (m, 1H), 1.3-1.2 (m, 1H), 0.97 (t, 3H), MS (M+H) + 421.4. Enantiomeric ratio 1:99.

[0422] Example 3

[0423]

[0424] 2-((1-amino-3-ethylcyclopentyl)methoxy)-6-methoxy-4-(5-methoxyimidazo[1,2-a]pyridin-3-yl)benzonitrile (racemic, cis / trans mixture). Synthesized from (1-amino-3-ethylcyclopentyl)methanol. 1 H NMR (400 MHz, MeOD) δ 7.63-7.62 (m, 1H), 7.45-7.41 (m, 1H), 7.27-7.25 (m, 1H), 6.87-6.83 (m, 2H), 6.42-6.40 (m, 1H), 4.04-3.91 (m, 8H), 2.21-2.10 (m, 1H),2.04-1.77 (m, 3H), 1.75-1.54 (m, 1H), 1.53-1.17 (m, 4H), 0.97-0.89 (m, 3H).MS (M+H) + 421.4.

[0425] Example 4

[0426]

[0427] 2-(((1R,3R)-1-amino-3-ethylcyclopentyl)methoxy)-6-methoxy-4-(5-methoxyimidazo[1,2-a]pyridin-3-yl)benzonitrile hydrochloride and 2-(((1S,3S)-1-amino-3-ethylcyclopentyl)methoxy)-6-methoxy-4-(5-methoxyimidazo[1,2-a]pyridin-3-yl)benzonitrile hydrochloride and 2-(((1R,3S)-1-amino-3-ethylcyclopentyl)methoxy)-6-methoxy-4-(5-methoxyimidazo[1,2-a]pyridin-3-yl)benzonitrile hydrochloride and 2-(((1S,3R)-1-amino-3-ethylcyclopentyl)methoxy)-6-methoxy-4-(5-methoxyimidazo[1,2-a]pyridin-3-yl)benzonitrile hydrochloride. Prepared from 2-((1-amino-3-ethylcyclopentyl)methoxy)-6-methoxy-4-(5-methoxyimidazo[1,2-a]pyridin-3-yl)benzonitrile (racemic, cis / trans mixture) by N-Boc protection (Boc2O, Na2CO3, H2O-THF) to give tert-butyl (1-((2-cyano-3-methoxy-5-(5-methoxyimidazo[1,2-a]pyridin-3-yl)phenoxy)methyl)-3-ethylcyclopentyl)carbamate, followed by separation of the stereoisomers by chiral SFC, followed by deprotection of the N-Boc group. Four individual stereoisomers of tert-butyl (1-((2-cyano-3-methoxy-5-(5-methoxyimidazo[1,2-a]pyridin-3-yl)phenoxy)methyl)-3-ethylcyclopentyl)carbamate were separated by chiral SFC: Chiralpak AD-3 150 mm × 4.6 mm, 3µ; A: CO2, B: 0.05% diethylamine / iPrOH; gradient: 5% to 40% B over 4 min, then 40% B; 2.5 mL / min. Intermediate stereoisomer 1, retention time 4.6 min; intermediate stereoisomer 2, retention time 4.9 min; intermediate stereoisomer 3, retention time 5.3 min; intermediate stereoisomer 4, retention time 5.5 min. The isolated individual intermediate stereoisomers (25 mg each) were then treated independently with 2M aqueous HCl (2 mL) and MeOH (1 mL) for 16 h to afford, after lyophilization, the individual stereoisomers of 2-((1-amino-3-ethylcyclopentyl)methoxy)-6-methoxy-4-(5-methoxyimidazo[1,2-a]pyridin-3-yl)benzonitrile as the hydrochloride salt (absolute stereochemistry not determined).

[0428] Chiral SFC of separated stereoisomers of 2-((1-amino-3-ethylcyclopentyl)methoxy)-6-methoxy-4-(5-methoxyimidazo[1,2-a]pyridin-3-yl)benzonitrile: Phenomenex-Cellulose-4, 100 mm×4.6 mm, 3 µ; A: CO2, B: 0.05% diethylamine / MeOH, 60:40 A:B, 2.8 mL / min, 40°C; retention time, 2.62 min (4A), 2.97 min (4B), 2.71 min (4C), 3.49 min (4D). 4A (from intermediate stereoisomer 1): 1 HNMR (400 MHz, DMSO-d6) δ 8.59 (br s, 3H), 8.32 (s, 1H), 8.02-7.96 (m, 1H), 7.61 (d, 1H), 7.14 (s, 1H), 7.13 (s, 1H), 6.99 (d, 1H), 4.27 (s, 2H), 4.03(s, 3H), 3.94 (s, 3H), 2.20-2.00 (m, 3H), 2.00-1.90 (m, 1H), 1.89-1.79 (m,1H), 1.49 (dd, 1H), 1.40-1.29 (m, 3H), 0.87 (t, 3H). MS (M+H) + 421.4. Stereochemical purity by chiral SFC >99%. 4B (from intermediate stereoisomer 3): 1 H NMR (400 MHz, DMSO-d6) δ 8.61(br s, 3H), 8.34 (s, 1H), 8.04-7.97 (m, 1H), 7.62 (d, 1H), 7.15 (br s, 1H),7.14 (br s, 1H), 7.00 (d, 1H), 4.27 (s, 2H), 4.03 (s, 3H), 3.94 (s, 3H), 2.22-2.00 (m, 3H), 1.99-1.79 (m, 2H), 1.49 (dd, 1H), 1.41-1.28 (m, 3H), 0.87(t, 3H). MS (M+H) + 421.4. Stereochemical purity by chiral SFC >99%. 4C (from intermediate stereoisomer 2): 1H NMR (400 MHz, DMSO-d6) δ 8.61 (br s, 3H), 8.32 (s, 1H), 7.99 (t, 1H), 7.61 (d, 1H), 7.15 (s, 1H), 7.14 (s, 1H), 6.99 (d, 1H), 4.23 (m, 2H), 4.03(s, 3H), 3.94 (s, 3H), 2.20 (m, 1H), 2.01-1.78 (m, 4H), 1.56-1.33 (m, 4H),0.87 (t, 3H). MS (M+H) + 421.4. Stereochemical purity by chiral SFC >99%. 4D (from intermediate stereoisomer 4): 1 H NMR (400 MHz, DMSO-d6) δ 8.61 (br s, 3H), 8.32 (s, 1H), 7.99 (t,1H), 7.61 (d, 1H), 7.15 (s, 1H), 7.14 (s, 1H), 6.99 (d, 1H), 4.24 MS (M+H) + 421.4. Stereochemical purity by chiral SFC >97%.

[0429] Example 5

[0430]

[0431] 2-(((1S,2S)-1-amino-2-ethylcyclopentyl)methoxy)-6-methoxy-4-(5-methoxyimidazo[1,2-a]pyridin-3-yl)benzonitrile and 2-(((1R,2R)-1-amino-2-ethylcyclopentyl)methoxy)-6-methoxy-4-(5-methoxyimidazo[1,2-a]pyridin-3-yl)benzonitrile. Synthesized from 1-amino-2-ethylcyclopentane-1-carboxylic acid (Tetrahedron: Asymmetry 2000, 11, 3231-3252). The enantiomers were separated by chiral SFC (absolute stereochemistry was not determined): Chiral SFC: Phenomenex-Cellulose-2, 100 mm × 4.6 mm, 3 µ; A: CO2, B: 0.05% diethylamine / EtOH 60:40 A:B, 2.8 mL / min, 35°C; retention time, 3.99 min (peak 1), 6.64 min (peak 2). 5A Peak 1: 1 H NMR (400 MHz, MeOD) δ 7.63 (s, 1H), 7.48-7.41 (m, 1H), 7.26(d, 1H), 6.86 (s, 1H), 6.86 (s, 1H), 6.42 (d, 1H), 4.07-3.99 (m, 2H), 3.97(s, 6H), 2.13-1.96 (m, 2H), 1.82-1.65 (m, 5H), 1.53-1.42 (m, 1H), 1.23-1.10(m, 1H), 0.96 (t, 3H). MS (M+H) + 421.4. Enantiomer ratio 100:0. 5B Peak 2: 1 H NMR 1 H NMR (400 MHz, MeOD) δ 7.63 (s, 1H), 7.46-7.41 (m, 1H), 7.26 (d, 1H), 6.86 (s, 1H), 6.86 (s, 1H), 6.42 (d, 1H), 4.06-3.99 (m, 2H), 3.97 (s, 6H), 2.13-1.95(m, 2H), 1.81-1.64 (m, 5H), 1.55-1.41 (m, 1H), 1.23-1.10 (m, 1H), 0.96 (t,3H). MS (M+H) + 421.4. Enantiomeric ratio 0.8:99.2.

[0432] Example 6

[0433]

[0434] 3-(3-(((1S,2R)-1-amino-2-ethylcyclopentyl)methoxy)-4-cyano-5-(methylthio)phenyl)imidazo[1,2-a]pyridine-5-carbonitrile and 3-(3-(((1R,2S)-1-amino-2-ethylcyclopentyl)methoxy)-4-cyano-5-(methylthio)phenyl)imidazo[1,2-a]pyridine-5-carbonitrile. Synthesized from 1-amino-2-ethylcyclopentane-1-carboxylic acid (Tetrahedron: Asymmetry 2000, 11, 3231-3252). The enantiomers were separated by chiral SFC (absolute stereochemistry was not determined): Chiral SFC: Phenomenex-Cellulose-2, 100 mm × 4.6 mm, 3 µ; A: CO2, B: 0.05% diethylamine / EtOH 50:50 A:B, 2.8 mL / min, 35°C; retention time, 2.32 min (peak 1), 3.09 min (peak 2). 6A Peak 1: 1 H NMR (400 MHz, CDCl3) δ 8.02 (d 1H), 7.82 (s, 1H), 7.49 (d, 1H), 7.33 (dd, 1H), 6.96 (s, 1H), 6.84 (s, 1H), 4.02-3.93 (m, 2H), 2.59 (s, 3H),2.08-1.74 (m, 6H), 1.53-1.42 (m, 2H), 1.33-1.22 (m, 1H), 1.01-0.94 (m, 3H).MS (M+H) + 432.3. The enantiomeric ratio is 99.6:0.4. 6B Peak 2: 1 H NMR (400 MHz, CDCl3) δ 8.02(d, 1H), 7.82 (s, 1H), 7.49 (d, 1H), 7.36-7.29 (m, 1H), 6.96 (s, 1H), 6.84(s, 1H), 4.04-3.93 (m, 2H), 2.59 (s, 3H), 2.06-1.73 (m, 5H), 1.52-1.40 (m,2H), 1.35-1.20 (m, 2H), 0.96 (t, 3H). MS (M+H) + 432.3. The enantiomeric ratio is 0.7:99.3.

[0435] Example 7

[0436]

[0437] 3-(3-(((1S,2R)-1-amino-2-ethylcyclopentyl)methoxy)-4-cyano-5-(methylthio)phenyl)imidazo[1,2-a]pyridine-5-carbonitrile and 3-(3-(((1R,2S)-1-amino-2-ethylcyclopentyl)methoxy)-4-cyano-5-(methylthio)phenyl)imidazo[1,2-a]pyridine-5-carbonitrile (racemate). Synthesized from 1-amino-2-ethylcyclopentane-1-carboxylic acid (Tetrahedron: Asymmetry 2000, 11, 3231-3252). 1 H NMR (400 MHz, MeOD) δ 8.00(dd, 1H), 7.88 (s, 1H), 7.72 (dd, 1H), 7.48 (dd, 1H), 7.21 (s, 1H), 7.20 (s,1H), 4.10-4.05 (m, 2H), 2.61 (s, 3H), 2.09-1.92 (m, 2H), 1.88-1.71 (m, 3H), 1.70-1.60 (m, 2H), 1.54-1.42 (m, 1H), 1.34-1.20 (m, 1H), 1.02-0.93 (m, 3H).MS (M+H) + 432.3.

[0438] Example 8

[0439]

[0440] 2-((1-amino-2-ethylcyclopentyl)methoxy)-4-(5-methoxyimidazo[1,2-a]pyridin-3-yl)-6-(methylthio)benzonitrile (racemic cis / trans mixture). Synthesized from 1-amino-2-ethylcyclopentane-1-carboxylic acid (Tetrahedron: Asymmetry 2000, 11, 3231-3252). 1H NMR (400 MHz, MeOD) δ 7.66-7.63 (m, 1H), 7.47-7.40 (m, 1H), 7.29-7.24 (m, 1H), 7.08-7.01 (m, 2H), 6.46-6.39 (m, 1H), 4.07-3.99 (m, 2H), 3.96 (s, 3H), 2.59 (s, 3H), 2.12-1.94 (m,2H), 1.83-1.62 (m, 5H), 1.54-1.40 (m, 1H), 1.23-1.10 (m, 1H), 1.00-0.92 (m,3H). MS (M+H) + 437.3.

[0441] Example 9

[0442]

[0443] 2-(((1S,2R)-1-amino-2-ethylcyclopentyl)methoxy)-4-(5-methoxyimidazo[1,2-a]pyridin-3-yl)-6-(methylthio)benzonitrile and 2-(((1R,2S)-1-amino-2-ethylcyclopentyl)methoxy)-4-(5-methoxyimidazo[1,2-a]pyridin-3-yl)-6-(methylthio)benzonitrile (racemate). Synthesized from 1-amino-2-ethylcyclopentane-1-carboxylic acid (Tetrahedron: Asymmetry 2000, 11, 3231-3252). 1 H NMR (400 MHz, MeOD) δ7.64 (s, 1H), 7.44 (dd, 1H), 7.28 (d, 1H), 7.06 (s, 1H), 7.03 (s, 1H), 6.42(d, 1H), 4.03 (s, 2H), 3.97 (s, 3H), 2.60 (s, 3H), 2.09-1.93 (m, 2H), 1.89-1.72 (m, 3H), 1.70-1.59 (m, 2H), 1.56-1.42 (m, 1H), 1.34-1.22 (m, 1H), 1.03-0.95 (m, 3H). MS (M+H) + 437.3.

[0444] Example 10

[0445]

[0446] 2-(((1S,2R)-1-amino-2-ethylcyclopentyl)methoxy)-4-(5-methoxyimidazo[1,2-a]pyridin-3-yl)-6-(methylthio)benzonitrile and 2-(((1R,2S)-1-amino-2-ethylcyclopentyl)methoxy)-4-(5-methoxyimidazo[1,2-a]pyridin-3-yl)-6-(methylthio)benzonitrile. Synthesized from 1-amino-2-ethylcyclopentane-1-carboxylic acid (Tetrahedron: Asymmetry 2000, 11, 3231-3252). The enantiomers were separated by chiral SFC (absolute stereochemistry was not determined): Chiral SFC: Phenomenex-Cellulose-2, 100 mm × 4.6 mm, 3 µ; A: CO2, B: 0.05% diethylamine / EtOH 60:40 A:B, 2.8 mL / min, 35°C; retention time, 4.43 min (peak 1), 6.27 min (peak 2). 10A Peak 1: 1 H NMR (400 MHz, MeOD) δ 7.64 (s, 1H), 7.48-7.41 (m, 1H), 7.27(d, 1H), 7.06 (s, 1H), 7.02 (s, 1H), 6.42 (d, 1H), 4.02 (s, 2H), 3.97 (s,3H), 2.60 (s, 3H), 2.08-1.91 (m, 2H), 1.86-1.72 (m, 3H), 1.69-1.60 (m, 2H), 1.54-1.42 (m, 1H), 1.33-1.21 (m, 1H), 1.02-0.94 (m, 3H). MS (M+H) + 437.4. Enantiomeric ratio 99.8:0.2. 10B Peak 2: 1 H NMR (400 MHz, MeOD) δ 7.64 (s, 1H), 7.44 (dd,1H), 7.27 (d, 1H), 7.05 (s, 1H), 7.02 (s, 1H), 6.42 (d, 1H), 4.02 (s, 2H), 3.96 (s, 3H), 2.59 (s, 3H), 2.07-1.91 (m, 2H), 1.86-1.72 (m, 3H), 1.69-1.58(m, 2H), 1.53-1.42 (m, 1H), 1.32-1.20 (m, 1H), 1.01-0.94 (m, 3H). MS (M+H) +437.4. Enantiomeric ratio 0.3:99.7.

[0447] Embodiment 11

[0448]

[0449] 2-(((2S,3R)-3-amino-2-ethyltetrahydrofuran-3-yl)methoxy)-4-(5-methoxyimidazo[1,2-a]pyridin-3-yl)-6-(methylthio)benzonitrile, 2-(((2R,3R)-3-amino-2-ethyltetrahydrofuran-3-yl)methoxy)-4-(5-methoxyimidazo[1,2-a]pyridin-3-yl)-6-(methylthio)benzonitrile and 2 -(((2R,3S)-3-amino-2-ethyltetrahydrofuran-3-yl)methoxy)-4-(5-methoxyimidazo[1,2-a]pyridin-3-yl)-6-(methylthio)-benzonitrile and 2-(((2S,3S)-3-amino-2-ethyltetrahydrofuran-3-yl)methoxy)-4-(5-methoxyimidazo[1,2-a]pyridin-3-yl)-6-(methylthio)benzonitrile. Synthesized from propionaldehyde similar to Beilstein Journal of Organic Chemistry 2009,5, No. 5. doi:10.3762 / bjoc.5.5. Diastereomers and enantiomers were separated by chiral SFC (absolute stereochemistry was not determined): Chiral SFC: Chiralpak IG-3, 50 mm×4.6 mm, 3 µ; A: CO2, B: 0.05% diethylamine / MeOH, 60:40 A:B, 4 mL / min, 40°C; retention time: 1.69 min (peak 1), 2.05 min (peak 2), 2.78 min (peak 3), 3.84 min (peak 4). 11A Peak 1: 1 H NMR (400 MHz, DMSO-d6) δ7.76 (s,1H), 7.43-7.37 (m, 1H), 7.32-7.27 (m, 1H), 7.09 (s, 1H), 7.07 (s, 1H), 6.45(d, 1H), 4.08 (s, 2H), 3.94 (s, 3H), 3.87 (q, 1H), 3.68-3.59 (m, 1H), 3.48(dd, 1H), 2.61 (s, 3H), 2.14-2.04 (m, 1H), 1.79-1.70 (m, 1H), 1.68-1.56 (m,2H), 1.54-1.40 (m, 1H), 0.94 (t, 3H). MS (M+H)+ 439.4. Stereoisomers ratio: 99.47:0:0.15:0.39. 11B Peak 2: 1 H NMR (400 MHz, DMSO-d6) δ 7.78 (s, 1H), 7.43-7.38 (m, 1H),7.34-7.28 (m, 1H), 7.18 (s, 1H), 7.08 (s, 1H), 6.46 (d, 1H), 4.10-4.00 (m,2H), 3.94 (s, 3H), 3.83-3.76 (m, 2H), 3.40-3.37 (m, 1H, partially obscured by residual solvent), 2.62 (s, 3H), 2.12-2.03 (m, 1H), 1.85-1.76 (m, 3H), 1.67-1.56 (m, 1H),1.38-1.28 (m, 1H), 0.93 (t, 3H). MS (M+H) + 439.4. Stereoisomers ratio: 1.56:98.44:0:0. 11C peak 3: 1 H NMR (400 MHz, DMSO-d6) δ 7.77 (s, 1H), 7.43-7.37 (m, 1H), 7.32-7.27(m, 1H), 7.10 (s, 1H), 7.08 (s, 1H), 6.46 (d, 1H), 4.09 (s, 2H), 3.94 (s,3H), 3.91-3.84 (m, 1H), 3.68-3.60 (m, 1H), 3.48 (dd, 1H), 2.61 (s, 3H), 2.14-2.04 (m, 1H), 1.79-1.71 (m, 1H), 1.69-1.56 (m, 2H), 1.54-1.42 (m, 1H), 0.95(t, 3H). MS (M+H) + 439.4. Stereoisomers ratio: 0.25:1.06:98.57:0.12. 11D peak 4: 1H NMR (400 MHz, DMSO-d6) δ 7.78 (s, 1H), 7.43-7.37 (m, 1H), 7.33-7.27 (m, 1H), 7.18 (s, 1H), 7.07 (s, 1H), 6.46 (d, 1H), 4.10-4.00 (m, 2H), 3.94 (s, 3H), 3.83-3.75 (m, 2H), 3.37 (m, 1H, partially obscured by residual solvent), 2.62 (s, 3H), 2.11-2.01 (m,1H), 1.86-1.75 (m, 3H), 1.67-1.56 (m, 1H), 1.38-1.27 (m, 1H), 0.93 (t, 3H).MS (M+H) + 439.4. Stereoisomers ratio: 0.03:0.14:1.20:98.62.

[0450] Example 12

[0451]

[0452] (R)-3-(3-((1-amino-3,3-difluorocyclopentyl)methoxy)-4-cyano-5-(methylthio)phenyl)imidazo[1,2-a]pyridine-5-carbonitrile and (S)-3-(3-((1-amino-3,3-difluorocyclopentyl)methoxy)-4-cyano-5-(methylthio)phenyl)imidazo[1,2-a]pyridine-5-carbonitrile (racemate). 1 H NMR (400 MHz, CDCl3) δ 8.03 (d,1H), 7.83 (s, 1H), 7.50 (d, 1H), 7.34 (dd, 1H), 7.00 (s, 1H), 6.84 (s, 1H), 4.02 (s, 2H), 2.6 (s, 3H), 2.5-2.3 (m, 2H), 2.3-2.2 (m, 2H), 2.2-2.1 (m, 1H),1.9-1.8 (m, 3H). MS (M+H) + 440.1.

[0453] Example 13

[0454]

[0455] (R)-2-((1-amino-3,3-difluorocyclopentyl)methoxy)-4-(5-methoxyimidazo[1,2-a]pyridin-3-yl)-6-(methylthio)benzonitrile and (S)-2-((1-amino-3,3-difluorocyclopentyl)methoxy)-4-(5-methoxyimidazo[1,2-a]pyridin-3-yl)-6-(methylthio)benzonitrile. Enantiomers were separated by chiral SFC (absolute stereochemistry not determined): Chiral SFC: Chiralpak IG-3, 50 mm × 4.6 mm, 3 µ; A: CO2, B: 0.05% diethylamine / MeOH 60:40A:B, 4 mL / min, 35°C; retention time, 1.13 min (peak 1), 2.58 min (peak 2). 13A value 1: 1 H NMR (400MHz, MeOD) δ 7.63 (s, 1H), 7.43 (dd, 1H), 7.29-7.24 (m, 1H), 7.08 (s, 1H), 7.03 (s, 1H), 6.41 (d, 1H), 4.04 (s, 2H), 3.95 (s, 3H), 2.59 (s, 3H), 2.52-2.35 (m, 2H), 2.33-2.19 (m, 1H), 2.18-2.07 (m, 2H), 1.90-1.80 (m, 1H). MS (M+H) + 445.2. Enantiomer ratio: 100:0. 13B Peak 2: 1 H NMR (400 MHz, MeOD) δ 7.65 (s, 1H),7.46 (dd, 1H), 7.28 (d, 1H), 7.13 (s, 1H), 7.07 (s, 1H), 6.44 (d, 1H), 4.17(s, 2H), 3.96 (s, 3H), 2.61 (s, 3H), 2.46-2.23 (m, 5H), 2.06-1.97 (m, 1H). MS(M+H) + 445.3. Enantiomer ratio: 99.9:0.1.

[0456] Embodiment 14

[0457]

[0458] (R)-3-(3-((1-amino-3,3-dimethylcyclohexyl)methoxy)-4-cyano-5-(methylthio)phenyl)imidazo[1,2-a]pyridine-5-carbonitrile and (S)-3-(3-((1-amino-3,3-dimethylcyclohexyl)methoxy)-4-cyano-5-(methylthio)phenyl)imidazo[1,2-a]pyridine-5-carbonitrile (racemate). 1 H NMR (400 MHz, DMSO-d6) δ 8.12(d, 1H), 7.98 (s, 1H), 7.88 (d, 1H), 7.50-7.43 (m, 1H), 7.30 (s, 1H), 7.25(s, 1H), 3.89-3.78 (m, 2H), 2.62 (s, 3H), 1.85-1.73 (m, 1H), 1.47-1.21 (m,7H), 1.12 (s, 3H), 0.86 (s, 3H).MS (M+H) + 446.3.

[0459] Embodiment 15

[0460]

[0461] (R)-3-(3-((1-amino-3,3-dimethylcyclohexyl)methoxy)-4-cyano-5-(methylthio)phenyl)imidazo[1,2-a]pyridine-5-carbonitrile and (S)-3-(3-((1-amino-3,3-dimethylcyclohexyl)methoxy)-4-cyano-5-(methylthio)phenyl)imidazo[1,2-a]pyridine-5-carbonitrile. Enantiomers were separated by chiral SFC (absolute stereochemistry not determined): Chiral SFC: Phenomenex-Cellulose-4, 100 mm × 4.6 mm, 3 µ; A: CO2, B: 0.05% diethylamine / EtOH 50:50 A:B, 2.8 mL / min, 40°C; retention time, 1.65 min (peak 1), 1.97 min (peak 2). 15A Peak 1: 1H NMR (400 MHz, MeOD) δ 8.01 (dd, 1H), 7.89 (s, 1H), 7.73 (dd, 1H), 7.49(dd, 1H), 7.21 (s, 1H), 7.20 (s, 1H), 4.06-3.95 (m, 2H), 2.63 (s, 3H), 1.81-1.70 (m, 1H), 1.70-1.62 (m, 2H), 1.62-1.51 (m, 2H), 1.43-1.34 (m, 2H), 1.34-1.25 (m, 1H), 1.09 (s, 3H), 0.95 (s, 3H). MS (M+H) + 446.3. Enantiomer ratio: 100:0. 15B Peak 2: 1 H NMR (400 MHz, MeOD) δ 8.00 (dd, 1H), 7.88 (s, 1H), 7.74-7.69 (m,1H), 7.48 (dd, 1H), 7.20 (s, 1H), 7.19 (s, 1H), 4.05-3.90 (m, 2H), 2.61 (s,3H), 1.79-1.71 (m, 1H), 1.69-1.60 (m, 2H), 1.60-1.50 (m, 2H), 1.42-1.33 (m,2H), 1.32-1.24 (m, 1H), 1.08 (s, 3H), 0.94 (s, 3H). MS (M+H) + 446.3. Enantiomeric ratio: 0:100.

[0462] Example 16

[0463]

[0464] 2-(((1R,3R)-1-amino-3-ethylcyclohexyl)methoxy)-6-methoxy-4-(5-methoxyimidazo[1,2-a]pyridin-3-yl)benzonitrile and 2-(((1S,3S)-1-amino-3-ethylcyclohexyl)methoxy)-6-methoxy-4-(5-methoxyimidazo[1,2-a]pyridin-3-yl)benzonitrile (racemate). Synthesized from 3-ethylcyclohexan-1-one by a procedure analogous to Tetrahedron 2015, 71, 2409-2420. 1H NMR (400 MHz, MeOD) δ 7.61(s, 1H), 7.42 (dd, 1H), 7.25 (dd, 1H), 6.83 (s, 1H), 6.82 (s, 1H), 6.40 (d,1H), 3.96 (s, 3H), 3.95 (s, 3H), 3.87 (s, 2H), 1.87-1.62 (m, 4H), 1.62-1.41(m, 3H), 1.27 (m, 2H), 1.13 (t, 1H), 0.92 (t, 3H), 0.86 (m, 1H).MS (M+H) + 435.5.

[0465] Embodiment 17

[0466]

[0467] 2-(((1R,3R)-1-amino-3-ethylcyclohexyl)methoxy)-6-methoxy-4-(5-methoxyimidazo[1,2-a]pyridin-3-yl)benzonitrile and 2-(((1S,3S)-1-amino-3-ethylcyclohexyl)methoxy)-6-methoxy-4-(5-methoxyimidazo[1,2-a]pyridin-3-yl)benzonitrile. Synthesized from 3-ethylcyclohexan-1-one by a procedure analogous to Tetrahedron 2015, 71, 2409-2420. The enantiomers were separated by chiral HPLC (absolute stereochemistry was not determined): Chiral HPLC: ChiralPak IG, 50 mm × 4.6 mm, 3 µ; A: 0.1% diethylamine / hexane, B: 0.05% diethylamine / ethanol, 60:40 A:B, 1 mL / min, 35°C; retention time, 5.0 min (peak 1), 6.2 min (peak 2). 17A Peak 1: 1 H NMR (400 MHz, MeOD) δ 7.62 (s, 1H), 7.43 (dd, 1H), 7.26 (dd,1H), 6.84 (s, 1H), 6.82 (s, 1H), 6.40 (d, 1H), 3.96 (s, 3H), 3.95 (s, 3H),3.87 (s, 2H), 1.89-1.42 (m, 7H), 1.33-1.19 (m, 3H), 1.14 (t, 1H), 0.93 (t,3H), 0.88 (m, 1H). MS (M+H) + 435.3. The enantiomeric ratio is 98.8:1.2. 17B Peak 2:1 H NMR (400MHz, MeOD) δ 7.62 (s, 1H), 7.43 (dd, 1H), 7.26 (dd, 1H), 6.84 (s, 1H), 6.82(s, 1H), 6.41 (d, 1H), 3.96 (s, 3H), 3.95 (s, 3H), 3.87 (s, 2H), 1.90-1.42(m, 7H), 1.33-1.20 (m, 2H), 1.14 (t, 1H), 0.93 (t, 3H), 0.89 (m, 1H). MS (M+H) + 435.3. The enantiomeric ratio is 0.4:99.6.

[0468] Embodiment 18

[0469]

[0470] 3-(3-(((1S,3S)-1-amino-3-ethylcyclohexyl)methoxy)-4-cyano-5-(methylthio)phenyl)imidazo[1,2-a]pyridine-5-carbonitrile and 3-(3-(((1R,3R)-1-amino-3-ethylcyclohexyl)methoxy)-4-cyano-5-(methylthio)phenyl)imidazo[1,2-a]pyridine-5-carbonitrile (racemate). Synthesized from 3-ethylcyclohexane-1-one by a procedure analogous to Tetrahedron 2015, 71, 2409-2420. 1 H NMR (400 MHz, MeOD) δ8.02-7.97 (m, 1H), 7.88 (s, 1H), 7.72 (d, 1H), 7.48 (dd, 1H), 7.20 (s, 1H),7.18 (s, 1H), 3.93 (s, 2H), 2.62 (s, 3H), 1.86-1.78 (m, 1H), 1.77-1.63 (m,4H), 1.62-1.43 (m, 2H), 1.34-1.21 (m, 2H), 1.18-1.08 (m, 1H), 0.93 (t, 3H),0.90-0.78 (m, 1H). MS (M+H) + 446.3.

[0471] Embodiment 19

[0472]

[0473] 3-(3-(((1S,3S)-1-amino-3-ethylcyclohexyl)methoxy)-4-cyano-5-(methylthio)phenyl)imidazo[1,2-a]pyridine-5-carbonitrile and 3-(3-(((1R,3R)-1-amino-3-ethylcyclohexyl)methoxy)-4-cyano-5-(methylthio)-phenyl)imidazo[1,2-a]pyridine-5-carbonitrile. Synthesized from 3-ethylcyclohexane-1-one by a procedure analogous to Tetrahedron 2015, 71, 2409-2420. The enantiomers were separated by chiral SFC (absolute stereochemistry was not determined): Chiral SFC: Chiralpak IG-3, 150 mm × 4.6 mm, 3 µ; A: CO2, B: 0.05% diethylamine / iPrOH; Gradient: 5% to 40% B over 4 min and hold for 2 min, 2.5 mL / min, 35 °C; Retention time 4.98 min (peak 1), 5.28 min (peak 2). 19A Peak 1: 1 H NMR (400 MHz, MeOD) δ 8.00 (dd, 1H), 7.89 (s,1H), 7.73 (dd, 1H), 7.49 (dd, 1H), 7.21 (s, 1H), 7.18 (s, 1H), 3.93 (s, 2H), 2.62 (s, 3H), 1.87-1.78 (m, 1H), 1.78-1.64 (m, 4H), 1.62-1.42 (m, 2H), 1.33-1.22 (m, 2H), 1.17-1.09 (m, 1H), 0.93 (t, 3H), 0.90-0.80 (m, 1H). MS (M+H) + 446.3. Enantiomer ratio: 99.1:0.90. 19B Peak 2: 1 H NMR (400 MHz, MeOD) δ 8.00 (dd, 1H),7.89 (s, 1H), 7.75-7.70 (m, 1H), 7.49 (dd, 1H), 7.20 (s, 1H), 7.18 (s, 1H),3.93 (s, 2H), 2.62 (s, 3H), 1.87-1.78 (m, 1H), 1.78-1.64 (m, 4H), 1.61-1.44(m, 2H), 1.34-1.21 (m, 2H), 1.19-1.08 (m, 1H), 0.93 (t, 3H), 0.90-0.79 (m,1H). MS (M+H) +446.3. The enantiomeric ratio is 1.65:98.35.

[0474] Embodiment 20

[0475]

[0476] (S)-2-((1-aminospiro[4.4]nonan-1-yl)methoxy)-6-methoxy-4-(5-methoxyimidazo[1,2-a]pyridin-3-yl)benzonitrile and (R)-2-((1-aminospiro[4.4]nonan-1-yl)methoxy)-6-methoxy-4-(5-methoxyimidazo[1,2-a]pyridin-3-yl)benzonitrile. Enantiomers were separated by chiral SFC (absolute stereochemistry not determined): Chiral SFC: Phenomenex-Cellulose-2, 150 mm × 4.6 mm, 5 µ; A: CO2, B: 0.05% diethylamine / EtOH 40:60 A:B, 2.5 mL / min, 35°C; retention time, 2.86 min (peak 1), 4.42 min (peak 2). 20A Peak 1: 1 H NMR (400 MHz, MeOD) δ 7.63 (s, 1H), 7.43 (dd, 1H), 7.26 (d, 1H), 6.85 (s,1H), 6.85 (s, 1H), 6.41 (d, 1H), 4.21-4.02 (m, 2H), 3.96 (s, 3H), 3.96 (s,3H), 2.12-2.00 (m, 1H), 1.98-1.89 (m, 1H), 1.85-1.75 (m, 2H), 1.74-1.59 (m,8H), 1.54-1.44 (m, 1H), 1.41-1.32 (m, 1H). MS (M+H) + 447.3. Enantiomer ratio: 99.35:0.65. 20B Peak 2: 1H NMR (400 MHz, MeOD) δ 7.63 (s, 1H), 7.45-7.40 (m, 1H), 7.25 (d, 1H), 6.85 (s, 1H), 6.84 (s, 1H), 6.40 (d, 1H), 4.18-4.03 (m, 2H),3.96 (s, 3H), 3.96 (s, 3H), 2.09-2.00 (m, 1H), 1.97-1.89 (m, 1H), 1.87-1.77(m, 2H), 1.74-1.59 (m, 8H), 1.52-1.44 (m, 1H), 1.39-1.31 (m, 1H). MS (M+H) + 447.4. Enantiomeric ratio: 0.5:99.5.

[0477] Embodiment 21

[0478]

[0479] (S)-2-((3-amino-1-(2,2,2-trifluoroethyl)piperidin-3-yl)methoxy)-6-methoxy-4-(5-methoxyimidazo[1,2-a]pyridin-3-yl)benzonitrile and (R)-2-((3-amino-1-(2,2,2-trifluoroethyl)piperidin-3-yl)methoxy)-6-methoxy-4-(5-methoxyimidazo[1,2-a]pyridin-3-yl)benzonitrile. Synthesized from (3-amino-1-(2,2,2-trifluoroethyl)piperidin-3-yl)methanol. The enantiomers were separated by chiral SFC (absolute stereochemistry was not determined): Chiral SFC: Chiralpak IG-3, 100 mm × 4.6 mm, 3 µ; A: CO2, B: 0.05% diethylamine / EtOH 60:40 A:B, 2.5 mL / min, 40°C; retention time, 2.03 min (peak 1), 2.70 min (peak 2). 21A Peak 1: 1H NMR (400MHz, DMSO-d6) δ 7.74 (s, 1H), 7.43-7.36 (m, 1H), 7.32-7.27 (m, 1H), 6.90 (s,1H), 6.89 (s, 1H), 6.45 (d, 1H), 4.16-4.09 (m, 1H), 3.95-3.89 (m, 7H), 3.22-3.10 (m, 2H), 2.75 (d, 1H), 2.61-2.54 (m, 2H), 2.40 (d, 1H), 1.70-1.50 (m,3H), 1.39-1.28 (m, 1H). MS (M+H) + 490.4. Enantiomeric ratio is 100:0. 21B Peak 2: 1 H NMR(400 MHz, DMSO-d6) δ 7.74 (s, 1H), 7.39 (dd, 1H), 7.31-7.27 (m, 1H), 6.90 (s,1H), 6.89 (s, 1H), 6.45 (d, 1H), 4.15-4.09 (m, 1H), 3.95-3.90 (m, 7H), 3.20-3.11 (m, 2H), 2.75 (d, 1H), 2.60-2.54 (m, 2H), 2.40 (d, 1H), 1.69-1.50 (m,3H), 1.38-1.28 (m, 1H). MS (M+H) + 490.4. The enantiomeric ratio is 0.6:99.4.

[0480] Embodiment 22

[0481]

[0482] (R)-2-((3-aminotetrahydrothiophen-3-yl)methoxy)-4-(imidazo[1,2-a]pyridin-3-yl)-6-(methylthio)benzonitrile and (S)-2-((3-aminotetrahydrothiophen-3-yl)methoxy)-4-(imidazo[1,2-a]pyridin-3-yl)-6-(methylthio)benzonitrile (racemate). 1H NMR (400 MHz, MeOD) δ 8.67 (d, 1H), 7.90 (s,1H), 7.67 (d, 1H), 7.44 (dd, 1H), 7.27-7.20 (m, 2H), 7.07 (dd, 1H), 4.33 (appq, 2H), 3.05-2.82 (m, 4H), 2.65 (s, 3H), 2.22-2.12 (m, 2H).MS (M+H) + 397.2.

[0483] Embodiment 23

[0484]

[0485] (R)-2-((3-aminotetrahydrothiophen-3-yl)methoxy)-4-(imidazo[1,2-a]pyridin-3-yl)-6-(methylthio)benzonitrile and (S)-2-((3-aminotetrahydrothiophen-3-yl)methoxy)-4-(imidazo[1,2-a]pyridin-3-yl)-6-(methylthio)benzonitrile. Enantiomers were separated by chiral HPLC (absolute stereochemistry not determined): Chiral HPLC: ChiralPak IE, 100 mm × 4.6 mm, 3 µ; A: 0.1% diethylamine / hexane, B: 0.1% diethylamine / ethanol, 20:80A:B, 1 mL / min, 35°C; retention time, 5.9 min (peak 1), 7.0 min (peak 2). 23A Peak 1: 1 H NMR (400MHz, MeOD) δ 8.66 (d, 1H), 7.89 (s, 1H), 7.66 (d, 1H), 7.44 (dd, 1H), 7.24-7.19 (m, 2H), 7.07 (dd, 1H), 4.32-4.19 (m, 2H), 3.12-3.01 (m, 2H), 2.99-2.89(m, 1H), 2.75 (d, 1H), 2.65 (s, 3H), 2.20-2.00 (m, 2H).MS (M+H) +397.4. The enantiomeric ratio is 100:0. 23B Peak 2: 1H NMR (400 MHz, MeOD) δ 8.67 (d, 1H), 7.89 (s, 1H), 7.67 (d, 1H), 7.44 (m, 1H), 7.25-7.19 (m, 2H), 7.07 (m, 1H), 4.33-4.19 (m,2H), 3.11-3.02 (m, 2H), 2.99-2.90 (m, 1H), 2.76 (d, 1H), 2.65 (s, 3H), 2.19-2.02 (m, 2H). MS (M+H) + 397.2. The enantiomeric ratio is 0.4:99.6.

[0486] Embodiment 24

[0487]

[0488] (R)-2-((3-aminotetrahydrofuran-3-yl)methoxy)-4-(5-methoxyimidazo[1,2-a]pyridin-3-yl)-6-(methylthio)benzonitrile and (S)-2-((3-aminotetrahydrofuran-3-yl)methoxy)-4-(5-methoxyimidazo[1,2-a]pyridin-3-yl)-6-(methylthio)benzonitrile. Enantiomers were separated by chiral SFC (absolute stereochemistry not determined): Chiral SFC: Lux Amylose 1, 4.6 mm × 100 mm, 5 µ; A: 0.2% NH4OH / MeOH, B: CO2, 40:60A:B, 1.5 mL / min, 120 bar, room temperature; retention time, 2.47 min (peak 1), 2.57 min (peak 2). 24A Peak 1: MS (M+Na) + 433.3.24B Peak 2: MS (M+Na) + 433.3.

[0489] Embodiment 25

[0490]

[0491] (R)-2-((1-amino-3,3-difluorocyclopentyl)methoxy)-4-(imidazo[1,2-a]pyridin-3-yl)-6-(methylthio)benzonitrile and (S)-2-((1-amino-3,3-difluorocyclopentyl)methoxy)-4-(imidazo[1,2-a]pyridin-3-yl)-6-(methylthio)benzonitrile (racemate). The compound was purified by preparative HPLC. MS (M+H) + 415.4.

[0492] Embodiment 26

[0493]

[0494] (R)-2-((1-amino-3,3-difluorocyclopentyl)methoxy)-4-(imidazo[1,2-a]pyridin-3-yl)-6-(methylthio)benzonitrile and (S)-2-((1-amino-3,3-difluorocyclopentyl)methoxy)-4-(imidazo[1,2-a]pyridin-3-yl)-6-(methylthio)benzonitrile. Enantiomers were separated by chiral SFC (absolute stereochemistry not determined): Chiral SFC: Chiralpak IG-3, 4.6 mm × 50 mm, 3 µ; A: CO2, B: 0.05% diethylamine / MeOH 60:40 A:B, 4 mL / min, 1500 psi, 35°C; retention time, 1.82 min (peak 1), 2.49 min (peak 2). 26B Peak 1: MS (M+H) + 415.2. Enantiomeric ratio 100:0. 26A Peak 2: MS (M+H) + 415.2. Enantiomeric ratio 0.4:99.6.

[0495] Embodiment 27

[0496]

[0497] (R)-3-(3-((3-aminotetrahydrothiophen-3-yl)methoxy)-4-cyano-5-(methylthio)phenyl)imidazo[1,2-a]pyridine-5-carbonitrile and (S)-3-(3-((3-aminotetrahydrothiophen-3-yl)methoxy)-4-cyano-5-(methylthio)phenyl)imidazo[1,2-a]pyridine-5-carbonitrile (racemic). The compound was purified by preparative HPLC. MS (M+H) + 422.2.

[0498] Embodiment 28

[0499]

[0500] (R)-3-(3-((3-aminotetrahydrothiophen-3-yl)methoxy)-4-cyano-5-(methylthio)phenyl)imidazo[1,2-a]pyridine-5-carbonitrile and (S)-3-(3-((3-aminotetrahydrothiophen-3-yl)methoxy)-4-cyano-5-(methylthio)phenyl)imidazo[1,2-a]pyridine-5-carbonitrile. The enantiomers of the intermediate (R)-tert-butyl (3-((2-cyano-5-(5-cyanoimidazolo[1,2-a]pyridin-3-yl)-3-(methylthio)phenoxy)methyl)tetrahydrothiophen-3-yl)carbamate and (S)-tert-butyl (3-((2-cyano-5-(5-cyanoimidazolo[1,2-a]pyridin-3-yl)-3)-(methylthio)phenoxy)methyl)tetrahydrothiophen-3-yl)carbamate were separated by chiral SFC (absolute stereochemistry not determined). Chiral SFC: ChiralTech AD-H 250 mm×30.0 mm, 5 µ; A: CO2; B: EtOH (0.2% 7N NH3 / MeOH). Gradient: 95% A:5% B for 0.5 min, then linear to 20% A and 80% B at 5.5 min and hold; 3 mL / min. Intermediate enantiomer 1, retention time 4.7 min; intermediate enantiomer 2, retention time 4.9 min. The separated individual intermediate enantiomers were then converted independently to (R)-3-(3-((3-aminotetrahydrothiophen-3-yl)methoxy)-4-cyano-5-(methylthio)phenyl)imidazo[1,2-a]pyridine-5-carbonitrile and (S)-3-(3-((3-aminotetrahydrothiophen-3-yl)methoxy)-4-cyano-5-(methylthio)phenyl)imidazo[1,2-a]pyridine-5-carbonitrile (absolute stereochemistry not determined). HPLC: Atlantis dC18 4.6×50 mm 5 µ; A: 0.05% TFA / H2O, B: 0.05% TFA / CH3CN; 95:5 A:B to 5:95 A:B in 4 min; 2 mL / min. 28A Enantiomer 1 (derived from Intermediate Enantiomer 1), retention time 1.88 min. MS (M+H) + 422.2. 28B enantiomer 2 (derived from intermediate enantiomer 2), retention time 1.87 min; MS (M+H) + 422.2.

[0501] Embodiment 29

[0502]

[0503] 2-((1-aminocyclohexyl)methoxy)-4-(5-methoxyimidazo[1,2-a]pyridin-3-yl)-6(methylthio)benzonitrile. 1 H NMR (400 MHz, CDCl3) δ 7.59 (s, 1H), 7.38-7.25 (m, 2H), 6.91 (s,1H), 6.77 (d, 1H), 6.13 (d, 1H), 3.90 (s, 3H), 3.85 (s, 2H), 2.55 (s, 3H),1.68-1.47 (m, 10H).MS (M+H) + 423.5.

[0504] Embodiment 30

[0505]

[0506] (R)-2-((3-aminotetrahydrothiophen-3-yl)methoxy)-4-(5-methoxyimidazo[1,2-a]pyridin-3-yl)-6-(methylthio)benzonitrile and (S)-2-((3-aminotetrahydrothiophen-3-yl)methoxy)-4-(5-methoxyimidazo[1,2-a]pyridin-3-yl)-6-(methylthio)benzonitrile. Enantiomers (absolute stereochemistry undetermined; separated by chiral chromatography): Chiral SFC: ChiralTech OX-H 100 mm × 4.6 mm, 3 µ; A: CO2, B: MeOH + 0.2% TFA; 5:95 A:B to 30:70 A:B over 2.5 min, then hold. 30A Peak 1: retention time 2.47 min; MS (M+H) + 427.3. 30B peak 2, retention time 2.63 min; MS (M+H) + 427.3.

[0507] Embodiment 31

[0508]

[0509] 2-(((1S)-1-amino-3-(methoxymethyl)cyclohexyl)methoxy)-4-(imidazo[1,2-a]pyridin-3-yl)-6-(methylthio)benzonitrile and 2-(((1R)-1-amino-3-(methoxymethyl)-cyclohexyl)methoxy)-4-(imidazo[1,2-a]pyridin-3-yl)-6-(methylthio)benzonitrile (mixture of diastereomers). 1H NMR (400 MHz, MeOD) δ 8.66 (d, 1H), 7.89 (s, 1H), 7.67 (d, 1H), 7.45 (m, 1H), 7.21 (d, 1H), 7.17 (d, 1H), 7.08 (m, 1H), 3.96 (s, 2H), 3.33 (s, 3H), 3.30-3.20 (m, 2H), 2.65 (s, 3H), 2.10-1.96 (m, 1H), 1.86-1.67 (m, 5H), 1.58-1.46 (m, 1H), 1.25(t, 1H), 1.05-0.90 (m, 1H).MS (M+H) + 437.2.

[0510] Embodiment 32

[0511]

[0512] 2-(((1S,2S)-1-amino-2-(cyclopropylmethyl)cyclopentyl)methoxy)-6-methoxy-4-(5-methoxyimidazo[1,2-a]pyridin-3-yl)benzonitrile and 2-(((1R,2R)-1-amino-2-(cyclopropylmethyl)cyclopentyl)methoxy)-6-methoxy-4-(5-methoxyimidazo[1,2-a]pyridin-3-yl)benzonitrile (cis enantiomer); 2-(((1S,2R)-1-amino-2-(cyclopropylmethyl)cyclopentyl)methoxy)-6-methoxy-4-(5-methoxyimidazo[1,2-a]pyridin-3-yl)benzonitrile and 2-(((1R,2S)-1-amino-2-(cyclopropylmethyl)cyclopentyl)methoxy)-6-methoxy-4-(5-methoxyimidazo[1,2-a]pyridin-3-yl)benzonitrile (trans enantiomer). The stereoisomers were separated by chiral SFC (absolute stereochemistry not determined). Chiral SFC: Chiralpak IC-3, 4.6 mm×100 mm, 3 µ; A: CO2, B: 0.05% iPr2NEt / EtOH, 50:50 A:B, 2.8 mL / min, 1500 psi, 35°C; retention times are 3.72 min (peak 1), 4.55 min (peak 2), 5.62 min (peak 3), 6.01 min (peak 4). 32A Peak 1 (cis): 1H NMR (400MHz, MeOD) δ 7.63 (s, 1H), 7.44 (dd, 1H), 7.27 (dd, 1H), 6.85 (app s, 2H), 6.42 (d, 1H), 4.02 (s, 2H), 3.97 (s, 3H), 3.97 (s, 3H), 2.18-1.75 (m, 4H), 1.71-1.53 ​​(m, 3H), 1.51-1.40 (m, 1H), 1.39-1.26 (m, 1H), 0.80-0.64 (m, 1H), 0.52-0.32 (m, 2H), 0.17-0.08 (m, 1H), 0.00 (m, 1H). MS (M+H) + 447.4. Stereoisomers ratio 100:0:0:0. 32B Peak 2 (trans): 1 H NMR (400 MHz, MeOD) δ 7.64 (s, 1H), 7.45 (dd,1H), 7.28 (d, 1H), 6.87 (app s, 2H), 6.43 (d, 1H), 4.07-3.99 (m, 2H), 3.97(app s, 6H), 2.25-2.11 (m, 1H), 2.07-1.96 (m, 2H), 1.86-1.69 (m, 2H), 1.67-1.55 (m, 1H), 1.50-1.41 (m, 1H), 1.32-1.19 (m, 1H), 0.96-0.83 (m, 1H), 0.79-0.67 (m, 1H), 0.52-0.37 (m, 2H), 0.17-0.01 (m, 2H). MS(M+H) + 447.3. Stereoisomers ratio 5.0:95.0:0:0. 32C peak 3 (cis): 1H NMR (400 MHz, MeOD) δ 7.63 (s, 1H), 7.44(dd, 1H), 7.27 (dd, 1H), 6.85 (s, 1H), 6.85 (s, 1H), 6.42 (d, 1H), 4.02 (s,2H), 3.97 (s, 3H), 3.97 (s, 3H), 2.17-2.08 (m, 1H), 2.06-1.98 (m, 1H), 1.98-1.91 (m, 1H), 1.89-1.76 (m, 1H), 1.70-1.53 ​​(m, 3H), 1.51-1.41 (m, 1H), 1.39-1.27 (m, 1H), 0.79-0.67 (m, 1H), 0.51-0.35 (m, 2H), 0.17-0.09 (m, 1H), 0.0(m, 1H).MS (M+H) + 447.3. Stereoisomers ratio 0:0:100:0. 32D peak 4 (trans): 1 H NMR (400 MHz, MeOD) δ 7.65 (s, 1H), 7.45 (dd, 1H), 7.31-7.24 (m, 1H), 6.89 (app s, 2H), 6.43 (d, 1H), 4.11-4.03 (m, 2H), 3.97 (app s, 6H), 2.26-2.15 (m, 1H), 2.11-2.01 (m, 2H), 1.86-1.72 (m, 2H), 1.69-1.55 (m, 1H), 1.51-1.42 (m, 1H), 1.39-1.22 (m, 1H), 0.97-0.87 (m, 1H), 0.79-0.68 (m, 1H), 0.54-0.38 (m, 2H), 0.16-0.00 (m, 2H). MS(M+H) + 447.3. The stereoisomer ratio is 0:0:0.9:99.1.

[0513] Embodiment 33

[0514]

[0515] 2-(((1S,3S)-1-amino-3-(trifluoromethyl)cyclohexyl)methoxy)-4-(imidazo[1,2-a]pyridin-3-yl)-6-(methylthio)benzonitrile and 2-(((1R,3R)-1-amino-3-(trifluoromethyl)cyclohexyl)methoxy)-4-(imidazo[1,2-a]pyridin-3-yl)-6-(methylthio)benzonitrile (racemic trans); and 2-(((1R,3S)-1-amino-3-(trifluoromethyl)cyclohexyl)methoxy)-4-(imidazo[1,2-a]pyridin-3-yl)-6-(methylthio)benzonitrile and 2-(((1S,3R)-1-amino-3-(trifluoromethyl)cyclohexyl)methoxy)-4-(imidazo[1,2-a]pyridin-3-yl)-6-(methylthio)benzonitrile (racemic cis). The diastereoisomers were separated by HPLC. 33A racemic trans: 1 H NMR (400 MHz, DMSO-d6) δ 8.79-8.70 (m, 1H), 8.01 (s, 1H), 7.71-7.64 (m, 1H), 7.38 (m, 1H), 7.22(d, 1H), 7.20 (d, 1H), 7.03 (m, 1H), 3.98 (s, 2H), 2.66 (s, 3H), 1.89-1.68(m, 3H), 1.65-1.38 (m, 5H), 1.21-1.07 (m, 1H). MS(M+H) + 461.3.33B racemate (cis form): 1 H NMR (400 MHz, DMSO-d6) δ 8.81-8.69 (m, 1H), 8.01 (s, 1H), 7.72 (d, 1H), 7.38 (m, 1H), 7.31 (d, 1H), 7.20 (d, 1H), 7.05 (m, 1H), 4.15 (s, 2H), 2.66 (s, 3H), 2.06-1.98 (m, 1H), 1.89-1.62 (m, 4H), 1.54-1.38 (m, 1H), 1.32-1.09 (m, 3H). MS(M+H) + 461.3

[0516] Preparation E

[0517] 3-iodopyrazolo[1,5-a]pyridine-4-carbonitrile. N-iodosuccinimide (443 mg, 1.97 mmol) was added to a solution of pyrazolo[1,5-a]pyridine-4-carbonitrile (282 mg, 1.97 mmol) in MeCN (10 mL). The resulting mixture was stirred for 2 h, and then the solid was collected by filtration to give 3-iodopyrazolo[1,5-a]pyridine-4-carbonitrile (530 mg). 1 HNMR (400 MHz, DMSO) δ 9.10 (dd, 1H), 8.33 (s, 1H), 8.04 (dd, 1H), 7.08 (t,1H). MS(M+H) + 269.9.

[0518] Preparation F

[0519] 3-Iodoimidazo[1,2-a]pyridine-5-carbonitrile. NIS (1184 g, 5.26 mol) was added to a solution of imidazo[1,2-a]pyridine-5-carbonitrile (579.5 g, 4.05 mol) in DMF (5.795 L), followed by purging the reaction vessel with 2 cycles of vacuum and N2 gas. The mixture was heated at 65-75°C for 0.5 h, then cooled to 15-20°C and added with aqueous Na2SO3 solution (10.3 wt%, 5.795 L). After stirring for 0.5 h, the solids were collected by filtration and rinsed with H2O. The collected solids were dissolved in dioxane (11.59 L) at 60-70°C, then the resulting solution was cooled to 20-25°C, H2O (11.59 L) was added, and the mixture was stirred for another 0.5 h. The solid was collected and dried to give 3-iodoimidazo[1,2-a]pyridine-5-carbonitrile (932 g). 1 H NMR (400 MHz, DMSO-d6) δ 8.01 (dd, 1H), 7.89 (s, 1H), 7.86 (dd, 1H), 7.36 (dd, 1H). MS(M+H) + 269.9

[0520] Preparation G

[0521] 2-((1-aminocyclohexyl)methoxy)-4-bromo-6-(methylthio)benzonitrile. A solution of KHMDS in THF (1 M, 754 mL, 754 mmol) was added dropwise to a solution of 4-bromo-2-fluoro-6-(methylthio)-benzonitrile (186 g, 754 mmol) and (1-aminocyclohexyl)methanol (104 g, 754 mmol) in THF (1.856 L) at 10 °C under N2 atmosphere. The resulting mixture was stirred at 25 °C for 9 h and then added to 25% aqueous NH4Cl. The mixture was extracted with EtOAc, and the organic layer was concentrated. The residue was purified by silica gel chromatography (10:1 DCM:MeOH) to give 2-((1-aminocyclohexyl)methoxy)-4-bromo-6-(methylthio)benzonitrile (165 g). 1 H NMR (400 MHz, CDCl3) δ 6.98 (s, 1H), 6.95 (s, 1H), 3.95 (s, 2H), 2.56 (s, 3H), 1.72-1.39 (m, 10H). MS (M+H) + 357.0

[0522] Preparation of H

[0523] Tert-butyl (1-((5-bromo-2-cyano-3-(methylthio)phenoxy)methyl)cyclohexyl)-carbamate. BocO (94.6 g, 433 mmol) was added to a solution of 2-((1-aminocyclohexyl)methoxy)-4-bromo-6-(methylthio)benzonitrile (140 g, 394 mmol) in THF (1.68 L) and EtOH (0.28 L) at 15 °C. The mixture was stirred for 40 h and then concentrated. The residue was concentrated from EtOAc (2×) and then treated with EtOAc (0.70 L) and stirred at 20 °C for 1 h. The resulting solids were collected, rinsed with EtOAc, and combined with solids from another reaction performed under similar conditions (from 280 g 2-((1-aminocyclohexyl)methoxy)-4-bromo-6-(methylthio)benzo-nitrile and 189 g BocO). The combined solids were dried to give tert-butyl (1-((5-bromo-2-cyano-3-(methylthio)phenoxy)methyl)cyclohexyl)carbamate (493 g) as a solid. 1H NMR (400 MHz, DMSO-d6) δ 7.27 (s, 1H), 7.13 (s, 1H), 6.44 (br s,1H), 4.22 (s, 2H), 2.59 (s, 3H), 2.02 (m, 2H), 1.44 (m, 7H), 1.34 (s, 9H),1.21 (m, 1H). MS (M+H) + 457.2

[0524] Preparation I

[0525] tert-Butyl (1-((2-cyano-3-(methylthio)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)methyl)cyclohexyl)carbamate. PdCl2(dppf)-DCM (17.9 g, 22.0 mmol) was added to a mixture of tert-butyl (1-((5-bromo-2-cyano-3-(methylthio)phenoxy)methyl)-cyclohexyl)carbamate (200 g, 439 mmol), B2(pin)2 (134 g, 527 mmol) and KOAc (129 g, 1.32 mol) in dioxane (2.20 L) at 20 °C. The reaction mixture was purged with N2 and then stirred at 100 °C for 18 h. The mixture was concentrated and then suspended in MeTHF-DCM (3.0 L each). The mixture was filtered through Celite™ and the filtrate was washed with water. The organic layer was concentrated, and the residue was suspended in heptane (1.0 L) and the resulting mixture was stirred for 1 h at 20 ° C. The solid was collected by filtration, rinsed with heptane, and then purified by silica gel chromatography (10: 1 to 3: 1 heptane: EtOAc) to obtain (1-((2-cyano-3-(methylthio)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)methyl)cyclohexyl)-carbamic acid tert-butyl ester (166 g). 1 H NMR (400 MHz, DMSO-d6) δ 7.13 (s, 1H), 7.09 (s, 1H), 6.42(br s, 1H), 4.22 (s, 2H), 2.58 (s, 3H), 2.09-1.97 (m, 2H), 1.62-1.39 (m, 7H),1.32 (s, 9H), 1.31 (s, 12H), 1.26-1.10 (m, 1H). MS (M+H) + 503.2.

[0526] Preparation J

[0527] tert-Butyl (1-((2-cyano-5-(5-cyanoimidazolo[1,2-a]pyridin-3-yl)-3-(methylthio)phenoxy)methyl)cyclohexyl)carbamate. Dioxane (23.35 mL) and H2O (7.75 mL) were added to a solid mixture of 3-iodoimidazo[1,2-a]pyridine-5-carbonitrile (2.50 g, 9.29 mmol), tert-butyl (1-((2-cyano-3-(methylthio)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)methyl)cyclohexyl)carbamate (4.90 g, 9.76 mmol) and K3PO4 (5.92 g, 27.9 mmol). The reaction vessel was purged with 4 cycles of vacuum and N2 gas, and then Pd(PPh3)2Cl2 (65 mg, 0.093 mmol) was added. The reaction vessel was purged with 3 cycles of vacuum and N2 gas, and then heated in a heating block at 95°C for 17 h, then cooled to ambient temperature. The mixture was diluted with MeTHF (24 mL) and H2O (7 mL), then N-acetylcysteine ​​(758 mg, 4.65 mmol) was added, and the resulting mixture was vigorously stirred at 65°C for 1 h. The layers were separated, and the aqueous layer was further extracted with MeTHF (2 × 12 mL). The combined organics were washed with 75% saturated brine solution (12 mL), then dried over Na2SO4, filtered through Celite™, and concentrated. The resulting solid was suspended in 1-chlorobutane (69 mL) and the mixture was heated at 65°C for 4 h, then cooled to ambient temperature and stirred for 18 h. The solid was collected and dried to give tert-butyl (1-((2-cyano-5-(5-cyanoimidazolo[1,2-a]pyridin-3-yl)-3-(methylthio)phenoxy)methyl)cyclohexyl)carbamate (4.83 g) as a light yellow solid contaminated with 1-chlorobutane and pinacol which was used in the next step without further purification. 1 H NMR (400 MHz, DMSO-d6) δ 8.12 (d, 1H), 7.99 (s, 1H), 7.89(d, 1H), 7.47 (dd, 1H), 7.33 (s, 1H), 7.27 (s, 1H), 6.49 (br s, 1H), 4.26 (s,2H), 2.63 (s, 3H), 2.06 (m, 2H), 1.58-1.43 (m, 7H), 1.30 (s, 9H), 1.24 (m,1H). MS (M+H) + 518.3.

[0528] Embodiment 34

[0529]

[0530] 3-(3-((1-aminocyclohexyl)methoxy)-4-cyano-5-(methylthio)phenyl)imidazo[1,2-a]pyridine-5-carbonitrile. HCl solution (4 M in dioxane, 21.0 mL, 84.4 mmol) was added to a solution of tert-butyl (1-((2-cyano-5-(5-cyanoimidazolo[1,2-a]pyridin-3-yl)-3-(methylthio)phenoxy)methyl)cyclohexyl)carbamate (4.82 g, 8.44 mmol) in MeOH (42.2 mL) at 0° C. over a period of 5 min. The mixture was warmed to ambient temperature and stirred for 16 h. The mixture was concentrated and the resulting solid was suspended in 10% 2-butanol-DCM (25 mL) followed by the addition of H 2 O (20 mL). Concentrated aqueous ammonium hydroxide solution (2 mL) was added and the biphasic mixture was stirred for 20 min. The layers were separated and the aqueous layer was extracted with 10% 2-butanol-DCM (2 × 10 mL). The combined organics were dried over Na2SO4, filtered and concentrated. The resulting solid was suspended in 10% H2O-EtOH and the mixture was heated at 60 °C for 3 h, then stirred at ambient temperature for 19 h. The solid was collected by filtration and dried to give 3-(3-((1-aminocyclohexyl)methoxy)-4-cyano-5-(methylthio)phenyl)imidazo[1,2-a]pyridine-5-carbonitrile (3.07 g) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ 8.11 (d, 1H), 7.98 (s, 1H), 7.88 (d, 1H), 7.46 (dd,1H), 7.33 (s, 1H),7.25 (s, 1H), 3.92 (s, 2H), 2.62 (s, 3H), 1.70-1.32 (m, 9H), 1.29-1.17 (m,1H). MS (M+H) + 418.1.

[0531] The following examples were synthesized by analogous procedures and starting materials as described for 3-(3-((1-aminocyclohexyl)methoxy)-4-cyano-5-(methylthio)phenyl)imidazo[1,2-a]pyridine-5-carbonitrile.

[0532] Embodiment 35

[0533]

[0534] 3-(3-((1-aminocyclohexyl)methoxy)-4-cyano-5-(methylthio)phenyl)pyrazolo[1,5-a]pyridine-4-carbonitrile. 1 H NMR (400 MHz, MeOD) δ 8.93 (dd, 1H), 8.37 (s, 1H), 7.91-7.97 (m,1H), 7.15 (app d, 2H), 7.10 (t, 1H), 4.11 (s, 2H), 2.65 (s, 3H), 1.45-1.80(m, 10H).MS (M+H) + 418.4.

[0535] Embodiment 36

[0536]

[0537] 3-(3-((1-aminocyclopentyl)methoxy)-4-cyano-5-(methylthio)phenyl)imidazo[1,2-a]pyridine-5-carbonitrile. 1 H NMR (400 MHz, DMSO-d6) δ 8.11 (d, 1H), 7.98 (s, 1H), 7.88 (d, 1H), 7.46 (dd, 1H), 7.32 (s, 1H), 7.26 (s, 1H), 4.01 (s, 2H), 2.62 (s, 3H), 1.81-1.54 (m, 6H), 1.45 (t, 2H). MS (M+H) + 404.2.

[0538] Embodiment 37

[0539]

[0540] 3-(3-((1-aminocyclopentyl)methoxy)-4-cyano-5-(methylthio)phenyl)pyrazolo[1,5-a]pyridine-4-carbonitrile. 1 H NMR (400 MHz, MeOD) δ 8.93 (d, 1H), 8.36 (s, 1H), 7.93 (d, 1H), 7.19-7.03 (m, 3H), 4.11 (s, 2H), 2.65 (s, 3H), 1.92-1.83 (m, 5H), 1.79-1.70(m, 2H), 1.64 (m, 2H). MS (M+H) + 404.3.

[0541] Embodiment 38

[0542]

[0543] Ethyl 3-(3-((1-aminocyclopentyl)methoxy)-4-cyano-5-(methylthio)phenyl)-5-cyanoimidazolo[1,2-a]pyridine-7-carboxylate. Synthesized from ethyl 5-cyanoimidazolo[1,2-a]pyridine-7-carboxylate. Ethyl 5-cyanoimidazolo[1,2-a]pyridine-7-carboxylate was prepared from 7-bromoimidazo[1,2-a]pyridine-5-carbonitrile via Pd-catalyzed carbonylation. 1 H NMR (400 MHz, MeOD) δ 8.58 (d, 1H), 8.16 (d, 1H), 8.06 (s, 1H), 7.25 (s, 1H), 7.24 (s, 1H), 4.47 (q, 2H), 4.08 (s, 2H), 2.63 (s, 3H), 1.93-1.81 (m, 4H), 1.77-1.69 (m, 2H), 1.69-1.60 (m, 2H), 1.44 (t, 3H). MS (M+H) + 476.3.

[0544] Preparation of K

[0545] (E)-tert-Butyl (1-((2-cyano-5-(2-ethoxyvinyl)-3-(methylthio)phenoxy)methyl)-cyclopentyl)carbamate. Tert-butyl (1-((5-bromo-2-cyano-3-(methylthio)phenoxy)methyl)cyclopentyl)carbamate was synthesized by a procedure similar to that of tert-butyl (1-((5-bromo-2-cyano-3-(methylthio)phenoxy)methyl)-cyclohexyl)carbamate. To a solution of tert-butyl (1-((5-bromo-2-cyano-3-(methylthio)phenoxy)methyl)cyclopentyl)carbamate (4.4 g, 8.0 mmol) and (E)-2-(2-ethoxyvinyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.9 g, 9.57 mmol) in dioxane (50 mL) and water (5 mL) was added K3PO4 (5.08 g, 23.9 mmol) and Pd(dppf)Cl2-DCM. The reaction was stirred at 90 °C under N2 atmosphere for 2. The reaction was cooled to room temperature and partitioned between EtOAc (150 mL) and H2O (20 mL). The organic phase was dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified via silica gel chromatography (0-12% EtOAc / PE) to give tert-butyl (E)-(1-((2-cyano-5-(2-ethoxyvinyl)-3-(methylthio)phenoxy)methyl)cyclopentyl)carbamate (3.1 g).1 H NMR (400 MHz, DMSO-d6) δ 7.57 (d, 1H), 6.89 (s, 1H), 6.84 (s, 1H), 6.80 (br s, 1H), 5.86 (d, 1H), 4.20 (s, 2H), 3.94(q, 2H), 2.54 (s, 3H), 1.97-1.86 (m, 2H), 1.77-1.57 (m, 6H), 1.34 (s, 9H),1.26 (t, 3H). MS (M+H-Boc) + 333.3.

[0546] Embodiment 39

[0547]

[0548] 3-(3-((1-aminocyclopentyl)methoxy)-4-cyano-5-(methylthio)phenyl)-6-methoxyimidazo[1,2-a]pyridine-5-carbonitrile. To a solution of tert-butyl (E)-(1-((2-cyano-5-(2-ethoxyvinyl)-3-(methylthio)phenoxy)methyl)cyclopentyl)carbamate (100 mg, 0.231 mmol) in dioxane (2.0 mL) and H2O (1.0 mL) at 15°C was added NBS (45.3 mg, 0.254 mmol). The mixture was stirred at 15°C for 50 min. 6-amino-3-methoxy-2-pyridinecarbonitrile (34.5 mg, 0.231 mmol) was added thereto and the reaction was stirred at 100°C for 16 h. The reaction was concentrated and purified via preparative HPLC (12 mg obtained). HPLC: Boston Prime C18, 150 mm×30 mm, 5 µ; A: H2O (0.2% NH4OH), B: CH3CN; Gradient: 19% to 59% B over 9 min, then 100% B; 25 mL / min. 1 H NMR (400 MHz, DMSO-d6) δ 8.12 (d, 1H), 7.91 (s, 1H), 7.60 (d, 1H), 7.24(s, 1H), 7.19 (s, 1H), 4.05 (s, 3H), 4.00 (s, 2H), 2.61 (s, 3H), 1.79-1.71(m, 2H), 1.71-1.56 (m, 4H), 1.50-1.40 (m, 2H).MS (M+H) + 434.3.

[0549] The following examples were synthesized by analogous procedures and starting materials as described for 3-(3-((1-aminocyclopentyl)methoxy)-4-cyano-5-(methylthio)phenyl)-6-methoxyimidazo[1,2-a]pyridine-5-carbonitrile.

[0550] Embodiment 40

[0551]

[0552] 3-(3-((1-aminocyclopentyl)methoxy)-4-cyano-5-(methylthio)phenyl)-6-methylimidazo[1,2-a]pyridine-5-carbonitrile. 1 H NMR (400 MHz, DMSO-d6) δ 8.02 (d, 1H), 7.91 (s, 1H), 7.44 (d,1H), 7.29 (s, 1H), 7.22 (s, 1H), 4.00 (s, 2H), 2.62 (s, 3H), 2.54 (s, 3H), 1.8-1.7 (m, 2H), 1.7-1.6 (m, 6H), 1.5-1.4 (m, 2H). MS(M+H) + 418.4.

[0553] Embodiment 41

[0554]

[0555] 3-(3-((1-aminocyclopentyl)methoxy)-4-cyano-5-(methylthio)phenyl)-7-methylimidazo[1,2-a]pyridine-5-carbonitrile. 1 H NMR (400 MHz, DMSO-d6) δ 7.90 (br s, 1H), 7.89 (br s, 1H), 7.80 (s, 1H), 7.29 (s, 1H), 7.23 (s, 1H), 4.01 (s, 2H), 2.62 (s, 3H), 2.43(s, 3H), 1.8-1.5 (m, 8H), 1.5-1.4 (m, 2H). MS (M+H) + 418.4.

[0556] Embodiment 42

[0557]

[0558] 3-(3-((1-aminocyclopentyl)methoxy)-4-cyano-5-(methylthio)phenyl)-7-chloroimidazo[1,2-a]pyridine-5-carbonitrile. 1 H NMR (400 MHz, MeOD) δ 8.07 (d, 1H), 7.89 (s, 1H), 7.84 (d,1H), 7.21 (s, 1H), 7.21 (s, 1H), 4.06 (s, 2H), 2.61 (s, 3H), 1.92-1.81 (m,4H), 1.77-1.68 (m, 2H), 1.68-1.59 (m, 2H). MS (M+H) + 438.1.

[0559] Embodiment 44

[0560]

[0561] 3-(3-((1-aminocyclopentyl)methoxy)-4-cyano-5-(methylthio)phenyl)-6-ethylimidazo[1,2-a]pyridine-5-carbonitrile. Synthesized similarly to 6-amino-3-methylpyridinecarbonitrile (WO2018071794) from 6-amino-3-bromopyridinecarbonitrile and triethylborane. 1 H NMR (400 MHz, CDCl3) δ 7.91 (d, 1H), 7.74 (s, 1H),7.24 (d, 1H), 6.95 (d, 1H), 6.84 (d, 1H), 4.00 (s, 2H), 2.96-2.85 (m, 2H),2.58 (s, 3H), 2.01-1.74 (m, 4H), 1.74-1.61 (m, 4H), 1.34 (t, 3H).MS (M+H) + 432.3.

[0562] Embodiment 45

[0563]

[0564] 6-amino-3-(3-((1-aminocyclopentyl)methoxy)-4-cyano-5-(methylthio)phenyl)imidazo[1,2-a]pyridine-5-carbonitrile. 1H NMR (400 MHz, DMSO-d6) δ 7.75 (d, 1H), 7.66 (s, 1H), 7.17 (s,1H), 7.11 (s, 1H), 7.01 (d, 1H), 6.54 (s, 2H), 4.02 (s, 2H), 2.63 (s, 3H).MS(M+H) + 419.1.

[0565] Embodiment 46

[0566]

[0567] 3-(3-((1-aminocyclopentyl)methoxy)-4-cyano-5-(methylthio)phenyl)-6-(azetidin-1-yl)imidazo[1,2-a]pyridine-5-carbonitrile. 1 H NMR (500 MHz, MeOD) δ 7.68 (d, 1H), 7.64 (s,1H), 7.12 (s, 1H), 7.09 (s, 1H), 6.92 (d, 1H), 4.31 (t, 4H), 4.06 (s, 2H), 2.63 (s, 3H), 2.46 (quin, 2H), 1.82-1.90 (m, 4H), 1.70-1.78 (m, 2H), 1.63 (brdd, 2H). MS(M+H) + 459.3.

[0568] Embodiment 47

[0569]

[0570] 3-(3-((1-aminocyclopentyl)methoxy)-4-cyano-5-(methylthio)phenyl)-6-(pyrrolidin-1-yl)imidazo[1,2-a]pyridine-5-carbonitrile. 1 H NMR (400 MHz, MeOD) δ 7.64-7.70 (m, 2H), 7.29 (d,1H), 7.15 (s, 1H), 7.12 (s, 1H), 4.07 (s, 2H), 3.62-3.69 (m, 4H), 2.64 (s,3H), 2.04-2.11 (m, 4H), 1.81-1.92 (m, 4H), 1.60-1.78 (m, 4H). MS(M+H) + 473.1.

[0571] Embodiment 48

[0572]

[0573] 3-(3-((1-aminocyclopentyl)methoxy)-4-cyano-5-methoxyphenyl)-6-(dimethylamino)imidazo[1,2-a]pyridine-5-carbonitrile. 1 H NMR (400 MHz, DMSO-d6) δ 7.84 (d, 1H), 7.81 (s, 1H), 7.38 (d, 1H), 7.05 (app d, 2H), 4.01 (s, 2H), 3.96 (s, 3H), 3.16 (s, 6H),1.40-1.85 (m, 8H). MS(M+H) + 431.2.

[0574] Embodiment 49

[0575]

[0576] 3-(3-((1-aminocyclohexyl)methoxy)-4-cyano-5-(methylthio)phenyl)-6-methoxyimidazo[1,2-a]pyridine-5-carbonitrile. 1 H NMR (400 MHz, MeOD) δ 7.98 (d, 1H), 7.83 (s, 1H), 7.59 (d,1H), 7.16 (app d, 2H), 4.10 (s, 3H), 4.04 (s, 2H), 2.62 (s, 3H), 1.61-1.77(m, 4H), 1.40-1.60(m, 6H). MS(M+H) + 448.4.

[0577] Embodiment 50

[0578]

[0579] 3-(3-((1-aminocyclopentyl)methoxy)-4-cyano-5-(methylthio)phenyl)-7-methoxyimidazo[1,2-a]pyridine-5-carbonitrile. 1H NMR (400 MHz, MeOD) δ 7.70 (s, 1H), 7.49 (d, 1H), 7.32 (d,1H), 7.18 (app d, 2H), 4.07 (s, 2H), 3.97 (s, 3H), 2.62 (s, 3H), 1.82-1.91(m, 4H), 1.60-1.77(m, 4H). MS(M+H) + 434.3.

[0580] Embodiment 51

[0581]

[0582] 3-(3-((1-aminocyclohexyl)methoxy)-4-cyano-5-(methylthio)phenyl)-7-methoxyimidazo[1,2-a]pyridine-5-carbonitrile. 1 H NMR (400 MHz, MeOD) δ 7.70 (s, 1H), 7.49 (d, 1H), 7.32 (d,1H), 7.19 (s, 1H), 7.18 (s, 1H), 4.04 (s, 2H), 3.98 (s, 3H), 2.62 (s, 3H),1.62-1.79 (m, 4H), 1.49-1.60 (m, 6H). MS (M+H) + 448.4.

[0583] Embodiment 52

[0584]

[0585] 3-(3-((1-aminocyclohexyl)methoxy)-4-cyano-5-methoxyphenyl)-7-methoxyimidazo[1,2-a]pyridine-5-carbonitrile. 1 H NMR (400 MHz, MeOD) δ 7.68 (s, 1H), 7.45 (d, 1H), 7.28 (d,1H), 6.99 (s, 1H), 6.97 (s, 1H), 4.02 (s, 2H), 3.98 (s, 3H), 3.96 (s, 3H),1.60-1.75 (m, 4H), 1.49-1.58 (m, 6H). MS (M+H) + 432.3.

[0586] Preparation of L

[0587] 2-((1-aminocyclopentyl)methoxy)-4-bromo-6-(methylthio)benzonitrile. A solution of KHMDS in THF (1 M, 1.0 L, 1.00 mol) was added dropwise to a solution of 4-bromo-2-fluoro-6-(methylthio)benzonitrile (240 g, 975 mmol) and (1-aminocyclopentyl)methanol (101 g, 878 mmol) in THF (2.5 L) at 10 °C. The mixture was stirred at 25 °C for 1 hour. Five reactions of this scale were poured together into saturated aqueous NH4Cl solution (1 L) and stirred for 10 min. The aqueous phase was extracted with EtOAc (3×1.5 mL). The combined organic phases were washed with brine (2×1.5 L), dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel chromatography (10:1 EtOAc:MeOH) to give 2-((1-aminocyclopentyl)methoxy)-4-bromo-6-(methylthio)benzonitrile (700 g) as a brown solid. 1 H NMR (400 MHz, DMSO-d6) δ 7.27 (d,1 H), 7.15 (d, 1H), 3.98 (s, 2H), 2.60 (s, 3H,) 1.69-1.82 (m, 2H), 1.56-1.68(m, 4H), 1.39-1.50 (m, 2H).

[0588] Preparation of M

[0589] To a solution of 2-((1-aminocyclopentyl)methoxy)-4-bromo-6-(methylthio)benzonitrile (347 g, 1.02 mol) in THF (2.9 L) and EtOH (580 mL) was added BocO (444 g, 2.03 mol). The mixture was stirred at 20 °C for 12 hours. The two reactions of this scale were combined and concentrated. The crude product was triturated with petroleum ether (1 L) at 25 °C for 2 h to give tert-butyl (1-((5-bromo-2-cyano-3-(methylthio)phenoxy)methyl)cyclopentyl)carbamate (820 g) as a brown solid which was used without further purification. 1 H NMR (400 MHz, CDCl3) δ 6.94 (d, 1H), 6.92 (d, 1H), 4.73 (br s, 1H), 4.24 (s, 2H), 2.54 (s, 3H), 1.85-2.00 (m, 4H), 1.67-1.84 (m,4H,) 1.40 (s, 9H).

[0590] Preparation of N

[0591] tert-Butyl (1-((2-cyano-3-(methylthio)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)methyl)cyclopentyl)carbamate. To a suspension of tert-butyl (1-((5-bromo-2-cyano-3-(methylthio)phenoxy)methyl)cyclopentyl)carbamate (205 g, 464 mmol) and B2Pin2 (130 g, 511 mmol) in MeTHF (3 L) at 25° C. were added KOAc (137 g, 1.39 mol), XPhos (11.1 g, 23.2 mmol) and Pd(OAc)2 (2.61 g, 11.6 mmol) sequentially. The mixture was stirred at 90° C. under N2 for 3.5 h. The mixture was cooled to 20 °C, diluted with DCM (3 L), and filtered through celite. The filtrate was washed sequentially with H2O (3 L) and brine (1.5 L), dried over MgSO4, filtered, and concentrated. The crude products of four reactions of this scale were combined and triturated with petroleum ether (5 mL / g crude product) at 25 °C for 1 h to give (1-((2-cyano-3-(methylthio)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)methyl)cyclopentyl)carbamate (800 g) as a grey solid. 1 H NMR (400 MHz, CDCl3) δ 7.25 (s, 1H), 7.13 (s, 1H), 4.79 (br s, 1H), 4.25 (s, 2H), 2.59 (s,3H), 1.86-2.02 (m, 4H), 1.66-1.84 (m, 4H), 1.38 (s, 9H), 1.35 (s, 12H).

[0592] Preparation of O

[0593] 3-(Dimethylamino)picolinonitrile. To 3-fluoropicolinonitrile (10 g, 82 mmol) was added MeNH solution (40% in H2O, 31.1 mL, 246 mmol) dropwise at 0°C over 3 min. The reaction was stirred at room temperature for 90 min, then diluted with H2O and EtOAc. The layers were separated, and the organics were washed with H2O (2×30 mL), and the combined aqueous layers were then extracted with EtOAc (3×30 mL). The combined organics were dried over MgSO4, filtered, and concentrated to give 3-(dimethylamino)picolinonitrile (11.2 g) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.09 (app t, 1H), 7.49 (app d, 2H), 3.05 (s, 6H). MS (M+H) + 148.4.

[0594] Preparation of P

[0595] 6-Bromo-3-(dimethylamino)picolinonitrile. A solution of 3-(dimethylamino)picolinonitrile (11.2 g, 76.3 mmol) and NBS (14.9 g, 83.9 mmol) in CH3CN (231 mL) was stirred at room temperature for 15 h. The mixture was concentrated and the resulting residue was partitioned between EtOAc (100 mL) and aqueous NaOH (1 N, 100 mL). The aqueous layer was extracted with EtOAc (3×50 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated to give 6-bromo-3-(dimethylamino)picolinonitrile (17.1 g) as a yellow solid. 1 H NMR (400 MHz, DMSO-d6) δ 7.65 (d, 1H), 7.45 (d, 1H), 3.10 (s, 6H). MS (M+H) + 226.0 / 228.0.

[0596] Preparation of Q

[0597] Tert-butyl (6-cyano-5-(dimethylamino)pyridin-2-yl)carbamate. Dioxane (180 mL) was added to a mixture of 6-bromo-3-(dimethylamino)picolinonitrile (12.3 g, 54.4 mmol), tert-butyl carbamate (7.05 g, 60.2 mmol), Pd(OAc)2 (70.7 mg, 0.315 mmol), Xantphos (271 mg, 0.469 mmol), and Cs2CO3 (47.9 g, 147 mmol), and the mixture was bubbled with N2 for 15 min, then heated at 100 °C for 22 h. The mixture was cooled to room temperature and partitioned between H2O (300 mL) and EtOAc (300 mL). The aqueous layer was extracted with EtOAc (4×225 mL). The organic layers were combined, dried over anhydrous Na2SO4, filtered, and concentrated. The resulting residue was dissolved in EtOAc (200 mL) and the solution was filtered through celite. The filtrate was concentrated, diluted with Et2O (65 mL), and sonicated to a free-flowing mixture. Heptane (80 mL) was added and the resulting mixture was stirred for 21 h. The solid was collected and dried in vacuo to give tert-butyl (6-cyano-5-(dimethylamino)pyridin-2-yl)carbamate (12.1 g) as a beige solid. 1 H NMR (400 MHz, CDCl3) δ8.03 (d, 1H), 7.32 (d, 1H), 7.10 (br s, 1H), 3.03 (s, 6H), 1.52 (s, 9H).

[0598] Preparation of R

[0599] 6-amino-3-(dimethylamino)picolinonitrile. EtOAc (190 mL) was added to a mixture of tert-butyl (6-cyano-5-(dimethylamino)pyridin-2-yl)carbamate (9.95 g, 37.9 mmol) and p-toluenesulfonic acid monohydrate (14.4 g, 75.8 mmol), and the mixture was stirred at 70 °C for 24 h. The suspension was then cooled to room temperature, and the solids were collected and dried in vacuo. The solids were then diluted with DCM (200 mL) and saturated aqueous NaHCO3 solution (200 mL), and the mixture was stirred for 30 min. The layers were then separated and the aqueous layer was extracted with EtOAc (3×100 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated to give 6-amino-3-(dimethylamino)picolinonitrile (5.51 g) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 7.44 (d, 1H), 6.71 (d, 1H), 6.08 (s, 2H), 2.72 (s, 6H).

[0600] Preparation of S

[0601] 6-amino-3-(dimethylamino)picolinonitrile p-toluenesulfonate. A mixture of 6-amino-3-(dimethylamino)picolinonitrile (5.51 g, 34.0 mmol) and p-toluenesulfonic acid monohydrate (7.75 g, 40.8 mmol) in EtOAc (170 mL) was stirred at room temperature for 18 h. The suspension was filtered, and the collected solid was washed with Et2O (50 mL) and then dried in vacuo to give 6-amino-3-(dimethylamino)picolinonitrile-p-toluenesulfonate (11.4 g) as a yellow solid. 1 H NMR (400 MHz, DMSO-d6) δ 7.45-7.53 (m, 3H), 7.11 (d, 2H), 6.75 (d, 1H), 2.76 (s, 6H), 2.29 (s, 3H).

[0602] Preparation of T

[0603] 6-(Dimethylamino)imidazo[1,2-a]pyridine-5-carbonitrile. To 6-amino-3-(dimethylamino)pyridinecarbonitrile p-toluenesulfonate (11.2 g, 33.5 mmol) and NaHCO3 (5.62 g, 66.9 mmol) was added i-PrOH (200 mL). Chloroacetaldehyde solution (55% in H2O, 19.6 mL, 134 mmol) was added dropwise and the mixture was stirred at 80 °C for 3 h. The mixture was concentrated and EtOAc (100 mL) was added to the residue. The organic layer was washed with saturated aqueous Na2CO3 solution (3×50 mL). The organic layer was dried over Na2SO4, filtered and concentrated. The residue was passed through a plug of silica gel with 1:1 heptane-EtOAc (500 mL). The silica was then washed with 9:1 DCM-MeOH (750 mL) and the filtrate was concentrated to give 6-(dimethylamino)imidazo[1,2-a]pyridine-5-carbonitrile (6.2 g) as a yellow solid. 1 H NMR (500 MHz, DMSO-d6) δ 7.83 (app s,1H), 7.74 (d, 1H), 7.59 (d, 1H), 7.22 (d, 1H), 3.16 (s, 6H).

[0604] Preparation of U

[0605] 6-(Dimethylamino)-3-iodoimidazo[1,2-a]pyridine-5-carbonitrile. To 6-(dimethylamino)imidazo[1,2-a]pyridine-5-carbonitrile (6.2 g, 33 mmol) and NIS (8.99 g, 40.0 mmol) was added CH3CN (166 mL). The mixture was stirred at room temperature for 65 h and then concentrated to approximately half of the original volume. The suspension was filtered and the solid was washed with cold CH3CN (2×15 mL) to give 6-(dimethylamino)-3-iodoimidazo[1,2-a]pyridine-5-carbonitrile (9.7 g) as a yellow solid. 1 H NMR (400 MHz, DMSO-d6) δ 7.72 (d, 1H), 7.64 (s, 1H), 7.29 (d, 1H), 3.11 (s, 6H).

[0606] Preparation of V

[0607] Tert-butyl (1-((2-cyano-5-(5-cyano-6-(dimethylamino)imidazo[1,2-a]pyridin-3-yl)-3-(methylthio)phenoxy)methyl)cyclopentyl)carbamate. MeTHF (940 mL) and H2O (230 mL) were added to a mixture of 6-(dimethylamino)-3-iodoimidazo[1,2-a]pyridine-5-carbonitrile (29.5 g, 94.6 mmol), tert-butyl (1-((2-cyano-3-(methylthio)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)methyl)cyclopentyl)carbamate (47.1 g, 96.5 mmol), K3PO4 (62.1 g, 284 mmol), and Pd(PPh3)2Cl2 (3.39 g, 4.73 mmol) under N2. The resulting solution was bubbled with N2 for 10 min and then heated at 80°C for 52 h. The mixture was cooled to room temperature and then diluted with H2O (100 mL). The solid was collected by filtration and dried in vacuo. The solid was dissolved in DCM (200 mL) and celite (30 g) was added. The mixture was stirred for 20 min and then filtered through a pad of celite, rinsing with DCM (3×50 mL). The filtrate was concentrated to give tert-butyl (1-((2-cyano-5-(5-cyano-6-(dimethylamino)imidazo[1,2-a]pyridin-3-yl)-3-(methylthio)phenoxy)methyl)cyclopentyl)-carbamate (41.5 g) as a yellow solid. 1H NMR(400 MHz, DMSO-d6) δ 7.86 (s, 1H), 7.84 (d, 1H), 7.38 (d, 1H), 7.22 (s, 1H), 7.18 (s, 1H), 6.82 (br s, 1H), 4.34 (br s, 2H), 3.16 (s, 6H), 2.64 (s, 3H), 1.88-1.98 (m, 2H), 1.70-1.81 (m, 2H), 1.56-1.69 (m, 4H), 1.27 (s, 9H). MS(M+H) + 547.5.

[0608] Embodiment 43

[0609]

[0610] 3-(3-((1-aminocyclopentyl)methoxy)-4-cyano-5-(methylthio)phenyl)-6-(dimethylamino)imidazo[1,2-a]pyridine-5-carbonitrile. Acetyl chloride (0.680 mL, 9.53 mmol) was added to EtOH (5.56 mL) and the mixture was heated at 50° C. for 30 min. The resulting solution was added in one portion to tert-butyl (1-((2-cyano-5-(5-cyano-6-(dimethylamino)imidazo[1,2-a]pyridin-3-yl)-3-(methylthio)phenoxy)-methyl)cyclopentyl)carbamate (521 mg, 0.953 mmol) and the mixture was stirred at 50° C. under N2 for 4 h. The mixture was concentrated and the resulting residue was diluted with DCM (30 mL) and saturated aqueous Na2CO3 solution (30 mL). The biphasic mixture was stirred for 15 min and the organic layer was collected. The aqueous layer was extracted with DCM (2×15 mL) and the combined organics were dried over Na 2 SO 4 , filtered and concentrated to give 3-(3-((1-aminocyclopentyl)methoxy)-4-cyano-5-(methylthio)phenyl)-6-(dimethylamino)imidazo[1,2-a]pyridine-5-carbonitrile (426 mg) as a yellow solid. 1 H NMR (400 MHz, MeOD) δ 7.73 (app t, 2H), 7.41 (d, 1H), 7.17 (s, 1H), 7.15 (s, 1H), 4.07 (s, 2H), 3.22 (s, 6H), 2.64 (s, 3H), 1.82-1.91 (m, 4H), 1.70-1.77 (m, 2H), 1.58-1.67 (m, 2H).MS (M+H) +447.3.

[0611] Preparation of W

[0612] Tert-butyl (5-cyanoimidazolo[1,2-a]pyridin-6-yl)(methyl)carbamate. To 6-bromoimidazo[1,2-a]pyridine-5-carbonitrile (565 mg, 2.54 mmol), cesium carbonate (2.49 g, 7.63 mmol) and XPhos-G3-Palladacycle (241 mg, 0.254 mmol) were added toluene (25.4 mL) and tert-butyl methylcarbamate (567 mg, 4.33 mmol). The mixture was degassed with N2 for 5 min and heated at 100 °C under N2 atmosphere. After 22 h, the sample was cooled to room temperature and diluted with EtOAc (10 mL). The mixture was washed with brine (3×10 mL), and the organic layer was dried over MgSO4, filtered and concentrated. The residue was purified via silica gel chromatography (0% to 100% EtOAc-heptane) to give tert-butyl (5-cyanoimidazolo[1,2-a]pyridin-6-yl)(methyl)carbamate (292 mg). 1 H NMR (400 MHz, DMSO-d6) δ8.18 (s, 1H), 8.02 (d, 1H), 7.86 (s, 1H), 7.45 (d, 1H), 3.23 (s, 3H), 1.39 (s, 9H).

[0613] Preparation X

[0614] 6-(Methylamino)imidazo[1,2-a]pyridine-5-carbonitrile. To a solution of tert-butyl (5-cyanoimidazo[1,2-a]pyridin-6-yl)(methyl)carbamate (400 mg, 1.47 mmol) in DCM (7.34 mL) was added TFA (95.9 mmol, 7.34 mL) at 0°C. The reactants were stirred at 0°C for 2 h and then concentrated. The solid was partitioned between EtOAc (10 mL) and saturated aqueous NaHCO3. The aqueous layer was extracted with EtOAc (3×10 mL). The combined organics were dried over MgSO4, filtered and concentrated. The residue was purified by silica gel chromatography (0% to 20% MeOH-DCM) to give 6-(methylamino)imidazo[1,2-a]pyridine-5-carbonitrile (234 mg). 1 H NMR (400 MHz, DMSO-d6) δ 7.75 (s, 1H), 7.70 (d,1H), 7.54 (d, 1H), 6.97 (d, 1H), 2.96 (d, 3H).MS (M+H)+ 172.9.

[0615] Preparation of Y

[0616] 3-iodo-6-(methylamino)imidazo[1,2-a]pyridine-5-carbonitrile. CH3CN (5.63 mL) was added to 6-(methylamino)imidazo[1,2-a]pyridine-5-carbonitrile (223 mg, 1.30 mmol) and NIS (350 mg, 1.55 mmol), and the resulting mixture was stirred at room temperature for 20 h. The mixture was filtered to collect the solid, which was washed with cold CH3CN (2×10 mL) and then dried in vacuo to give 3-iodo-6-(methylamino)imidazo[1,2-a]pyridine-5-carbonitrile (311 mg) as a yellow solid. 1 H NMR (400 MHz, DMSO-d6) δ 7.72 (d, 1H), 7.57 (s, 1H), 7.07 (d,1H), 6.50-6.55 (m, 1H), 2.92 (d, 3H). MS (M+H) + 299.1.

[0617] The following examples were synthesized by analogous procedures and starting materials as described for 3-(3-((1-aminocyclohexyl)methoxy)-4-cyano-5-(methylthio)phenyl)imidazo[1,2-a]pyridine-5-carbonitrile.

[0618] Embodiment 53

[0619]

[0620] 3-(3-((1-aminocyclopentyl)methoxy)-4-cyano-5-(methylthio)phenyl)-6-(methylamino)imidazo[1,2-a]pyridine-5-carbonitrile. 1 H NMR (400 MHz, DMSO-d6) δ 7.84 (d, 1H), 7.72 (s, 1H),7.17 (s, 1H), 7.14 (d, 1H), 7.12 (s, 1H), 6.61-6.68 (m, 1H), 4.02 (s, 2H),2.93 (d, 3H), 2.63 (s, 3H). MS (M+H) +433.4. HPLC: Waters X-bridge BEH ShieldRP 18, 2.1 × 100 mm 2.5 µ; A: 0.1% MsOH / H2O, B: 0.1% MsOH / CH3CN; gradient: 5% to 100% B in 8.2 min; 0.5 mL / min, 45°C; retention time 1.96 min.

[0621] Preparation of Z

[0622]

[0136] 2-Fluoro-6-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile. A flask containing a mixture of 4-bromo-2-fluoro-6-methoxybenzonitrile (256 g, 1.11 mol), B(pin)2 (339 g, 1.34 mol) and KOAc (328 g, 3.34 mol) in dioxane (3 L) was purged with N2 (3x) at 25 °C. PdCl2(dppf) (24.4 g, 33.3 mmol) was added and the resulting mixture was purged with N2 (3x) then heated at 90 °C for 16 h. The mixture was cooled to 25 °C and concentrated. The resulting residue was diluted with H2O (10 L) and EtOAc (10 L). The mixture was filtered to remove insoluble solids then the layers were separated. The aqueous layer was further extracted with EtOAc (3 L). The combined organics were dried over Na2SO4, filtered and concentrated. This crude product and the crude products from two additional reactions performed on the same scale were combined and purified by silica gel chromatography (20: 1 to 5: 1 petroleum ether-EtOAc). The fractions containing the desired product (approximately 3 L) were combined and a suspension was formed; the slurry was further diluted with petroleum ether (2 L) and the resulting suspension was stirred at 25 ° C for 30 min. The solid was collected by filtration to obtain 2-fluoro-6-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile (765 g) as a white solid. 1 H NMR (400 MHz, CDCl3) δ 7.17 (d, 1H), 7.13 (s, 1H), 3.98 (s, 3H), 1.34 (s, 12H).

[0623] Preparation of AA

[0624] 2-Fluoro-6-methoxy-4-(5-methoxyimidazo[1,2-a]pyridin-3-yl)benzonitrile. A flask containing a mixture of 3-bromo-5-methoxyimidazo[1,2-a]pyridine (260 g, 1.15 mol), 2-fluoro-6-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile (380.7 g, 1.37 mol) and K3PO4 (729.1 g, 3.44 mol) in dioxane (2.6 L) and H2O (0.31 L) was purged with N2 (3×) at 20°C. PdCl2(dppf) (25.1 g, 34.3 mmol) was added and the resulting mixture was purged with N2 (3×) and then heated at 90°C for 16 h. The mixture was cooled to 20 ° C and combined with material from another reaction performed on the same scale. The combined mixture was concentrated and the resulting residue was diluted with DCM-MeOH (10: 1, 20 L) and H2O (10 L). Insoluble solids were removed by filtration, then the layers were separated, and the aqueous solution was extracted with DCM (5 L). The combined organics were dried over Na2SO4, filtered and concentrated. The resulting residue was purified by silica gel chromatography (10: 0 to 10: 1 DCM-MeOH). The fractions containing the desired product (about 6 L) were combined and a suspension was formed. The solid was collected by filtration and rinsed with MTBE to obtain 2-fluoro-6-methoxy-4-(5-methoxyimidazo[1,2-a]pyridin-3-yl)benzonitrile (399 g) as a yellow solid. 1 H NMR (400 MHz, CDCl3) δ 7.61 (s,1H), 7.37-7.35 (m, 1H), 7.32-7.27 (m, 1H), 6.87-6.79 (m, 2H), 6.16 (dd, 1H), 3.97 (s, 3H), 3.93 (s, 3H). MS(M+H) + 297.9.

[0625] Preparation of AB

[0626] (5S,6R)-6-ethyl-1,3-diazaspiro[4.4]nonane-2,4-dione and (5R,6S)-6-ethyl-1,3-diazaspiro[4.4]nonane-2,4-dione) (racemate). KF (1.93 kg, 33.9 mol), TMSCN (873 g, 8.80 mol) and ammonium carbonate (1.595 kg) were added sequentially to racemic 2-ethylcyclopentan-1-one (759 g, 6.77 mol) in HO (7.60 L) and 2,2,2-trifluoroethanol (7.60 L), and the resulting mixture was stirred at 80 °C for 16 h. The mixture was then concentrated and the resulting solid was dried to give a mixture of (5S,6R)-6-ethyl-1,3-diazaspiro[4.4]nonane-2,4-dione / (5R,6S)-6-ethyl-1,3-diazaspiro[4.4]nonane-2,4-dione) (cis racemate) and (5S,6S)-6-ethyl-1,3-diazaspiro[4.4]nonane-2,4-dione / (5R,6R)-6-ethyl-1,3-diazaspiro[4.4]nonane-2,4-dione) (trans racemate) as a solid (985 g). UPLC: Cortecs C18, 100 mm×4.6 mm, 2.7 μ; A: 0.05% TFA-H2O, B: 0.05% TFA-CH3CN; gradient: 10% to 65% B over 5 min, 65% B for 2 min; 1 mL / min; 40°C; 210 nM; retention time, cis racemate (2.7 min), trans racemate (2.9 min); cis:trans 88:12.

[0627] Preparation of AC

[0628] (5S,6R)-6-Ethyl-1,3-diazaspiro[4.4]nonane-2,4-dione and (5R,6S)-6-Ethyl-1,3-diazaspiro[4.4]nonane-2,4-dione (racemate). A mixture of (5S,6R)-6-ethyl-1,3-diazaspiro[4.4]nonane-2,4-dione / (5R,6S)-6-ethyl-1,3-diazaspiro[4.4]nonane-2,4-dione (cis racemate) and (5S,6S)-6-ethyl-1,3-diazaspiro[4.4]nonane-2,4-dione / (5R,6R)-6-ethyl-1,3-diazaspiro[4.4]nonane-2,4-dione (trans racemate) (>83:17 cis:trans, 1194 g, 5.98 mol) in HOAc (2.626 L) was stirred at 40 °C for 10 min. min, then the mixture was seeded with a sample of the cis-racemic (5S,6R)-6-ethyl-1,3-diazaspiro[4.4]nonane-2,4-dione. The mixture was cooled to 20°C, then diluted with H2O (2.00 L), and the resulting mixture was stirred at 20°C for 16 h. The solids were collected by filtration, rinsed with H2O (1 L), and then dried to give cis-racemic (5S,6R)-6-ethyl-1,3-diazaspiro[4.4]nonane-2,4-dione (795 g). UPLC: Waters Acquity UPLC BEH C8, 2.1×100 mm, 1.7 µ; A: 0.1% TFA-H2O, B: 0.1% TFA-CH3CN; gradient: 10% to 95% B over 5 min, 95% B for 3 min; 0.4 mL / min; 40°C; 210 nM; retention time, cis racemate (2.5 min), trans racemate (2.6 min); cis:trans 95:5.

[0629] Preparation of AD

[0630] (1S,2R)-1-amino-2-ethylcyclopentane-1-carboxylic acid hydrobromide and (1R,2S)-1-amino-2-ethylcyclopentane-1-carboxylic acid hydrobromide (racemate). Hydrobromic acid (48 wt % in H2O, 400 mL) and phosphoric acid (85 wt % in H2O, 50 mL) were added sequentially to racemic (5S,6R)-6-ethyl-1,3-diazaspiro[4.4]nonane-2,4-dione / (5R,6S)-6-ethyl-1,3-diazaspiro[4.4]nonane-2,4-dione (50 g, 270 mmol), and the resulting mixture was heated at 135°C for 72 h. The mixture was then cooled to 0°C and stirred at this temperature for 2 h. The resulting solid was collected by filtration and dried at 45 °C for 20 h to give racemic (1R,2S)-1-amino-2-ethylcyclopentane-1-carboxylic acid hydrobromide / (1S,2R)-1-amino-2-ethylcyclopentane-1-carboxylic acid hydrobromide (65 g). Quantification of the isolated material 1 H NMR analysis showed 52.8 wt % 1-amino-2-ethylcyclopentane-1-carboxylic acid. 1 H NMR (400 MHz, MeOD) δ 2.53-2.35(m, 2H), 2.25-2.09 (m, 1H), 2.02-1.83 (m, 3H), 1.59-1.40 (m, 2H), 1.36-1.25(m, 1H), 0.99 (t, 3H).

[0631] Preparation of AE

[0632] (1S,2R)-1-amino-2-ethylcyclopentane-1-carboxylic acid methyl ester and (1R,2S)-1-amino-2-ethylcyclopentane-1-carboxylic acid methyl ester (racemate). Thionyl chloride (111 g, 933 mmol) was added dropwise to MeOH (864 mL) at 0°C, and the resulting solution was stirred at 20°C for 30 min. Racemic (1R,2S)-1-amino-2-ethylcyclopentane-1-carboxylic acid / (1S,2R)-1-amino-2-ethylcyclopentane-1-carboxylic acid hydrobromide (62 g, quantitatively 11-Amino-2-ethylcyclopentane-1-carboxylic acid (32.7 g, 179 mmol) at 52.8 wt % by H NMR analysis) was added, and the resulting mixture was stirred at 50 °C for 16 h. The mixture was concentrated to a volume of about 0.16 L, then diluted twice with MTBE (0.2 L) and concentrated to about 0.16 L. H2O (0.1 L) was added and the aqueous layer was collected. To the aqueous layer was added MTBE (0.16 L) and the pH was adjusted to about 8 by adding aqueous Na2CO3 solution (15 wt %) at 0 °C. The mixture was then stirred at 25 °C for 1 h. The layers were separated, and the aqueous solution was further extracted with MTBE (4×0.16 L). The combined organics were washed with brine (16 mL) and then concentrated to afford racemic (1R,2S)-methyl 1-amino-2-ethylcyclopentane-1-carboxylate (29 g) as an oil. 1 H NMR (400 MHz, MeOD) δ 3.71 (s, 3H), 2.25-2.18 (m, 1H), 2.15-2.07 (m, 1H), 2.01-1.91 (m, 1H), 1.89-1.60 (m, 3H), 1.53-1.20 (m, 3H),0.89 (t, 3H).

[0633] Preparation of AF

[0634] (1S,2R)-1-amino-2-ethylcyclopentane-1-carboxylic acid methyl ester. CES E-2 enzyme (AmanoEnzyme USA, product number SUNDV-R&D1 CES E-2 (chiral), 6.25 g) was dissolved in potassium phosphate buffer (0.2 M, 932 mL) at pH 7 at 20°C. A solution of racemic (1R,2S)-1-amino-2-ethylcyclopentane-1-carboxylic acid methyl ester / (1S,2R)-1-amino-2-ethylcyclopentane-1-carboxylic acid methyl ester (31.1 g, 181 mmol) in CH3CN (90 mL, plus 13 mL rinse) was added over 5 min. After stirring for 22 h, Celite™ (62 g) was added and the mixture was stirred for 5 min. MeTHF (932 mL) was added and the resulting mixture was stirred for 45 min. The mixture was then filtered through a pad of celite (62 g, pre-washed with H2O), rinsed sequentially with H2O and MeTHF (125 mL each). The filtrate layers were separated, and the aqueous solution was adjusted to about pH 7.8 by the addition of aqueous NaOH (1 N, 19 mL), then further extracted with MeTHF (932 mL). The organic layer and emulsion were filtered through a pad of celite (31 g, pre-washed with H2O), then the combined organics were dried over MgSO4, filtered, and concentrated. The resulting residue was dissolved in DCM (150 mL), dried over MgSO4, filtered, and concentrated to give (1S,2R)-1-amino-2-ethylcyclopentane-1-carboxylic acid methyl ester (12.3 g) as an oil. 1H NMR (400 MHz, MeOD) δ 3.71 (s, 3H),2.26-2.18 (m, 1H), 2.16-2.07 (m, 1H), 2.00-1.92 (m, 1H), 1.86-1.62 (m, 3H),1.53-1.19 (m, 3H), 0.89 (t, 3H). Chiral SFC for analysis of cis enantiomers: ChiralPak IG, 250 mm × 4.6 mm, 5 µ; A: CO2, B: [MeOH + 0.2% NH3 (7 N in MeOH)]; gradient: 10% B for 5 min, 10% to 60% B over 3.5 min; 3 mL / min; 40 °C; 120 bar; 210 nM; MS detection based on total ion counts of (M) = 171; retention times, (1S,2R)-methyl 1-amino-2-ethylcyclopentane-1-carboxylate (3.6 min), methyl (1R,2S)-methyl 1-amino-2-ethylcyclopentane-1-carboxylate (3.4 min); (1S,2R)-isomer:(1R,2S)-isomer >98:2 based on MS total ion counts. Chiral SFC method for detection of all 4 stereoisomers: ChiralTech IG, 250 mm × 4.6 mm, 5 µ; 85:15 CO2:[MeOH + 0.2% NH3 (7N in MeOH)], 4.0 mL / min; 40 °C; 120 bar; 210 nM; retention times, (1S,2R)-methyl 1-amino-2-ethylcyclopentane-1-carboxylate (2.7 min), methyl (1R,2S)-methyl 1-amino-2-ethylcyclopentane-1-carboxylate (2.4 min), both enantiomers of trans-methyl 1-amino-2-ethylcyclopentane-1-carboxylate (2.0 min and 3.6 min, absolute stereochemistry not assigned).

[0635] Preparation of AG

[0636] ((1S,2R)-1-amino-2-ethylcyclopentyl)methanol. A solution of (1S,2R)-1-amino-2-ethylcyclopentane-1-carboxylic acid methyl ester (7.13 g, 41.6 mmol) in THF (167 mL) was added dropwise to a solution of LiBH4 in THF (2.0 M, 100 mL, 200 mmol) over 20 min. The resulting solution was heated at 59 °C for 18 h. The mixture was then cooled to 0 °C and MeOH (200 mL) was slowly added, and the resulting solution was stirred for 1.5 h, causing a precipitate to form. The suspension was concentrated to remove the solvent, and the resulting solid was dissolved in aqueous KOH (20 wt %, 150 mL) and the solution was stirred at ambient temperature for 3 days. The solution was extracted with MeTHF (3 x 100 mL), and the combined organics were washed with brine (200 mL), dried over Na2SO4, filtered, and concentrated to give crude ((1S,2R)-1-amino-2-ethylcyclopentyl)methanol (5.57 g) as an oil. This material was combined with another 2.84 g portion of crude (1S,2R)-1-amino-2-ethylcyclopentyl)methanol from a similar reaction, and the combined material was purified by silica gel chromatography (0% to 20% DCM-MeOH containing 2% aqueous NH4OH (25 wt%)) to give ((1S,2R)-1-amino-2-ethylcyclopentyl)methanol (5.01 g) as an oil. 1 H NMR (400 MHz, MeOD) δ3.39 (m, 2H), 1.98-1.88 (m, 1H), 1.86-1.65 (m, 2H), 1.62-1.32 (m, 5H), 1.24-1.05 (m, 1H), 0.94 (t, 3H).

[0637] Example 2A, Alternative Procedure

[0638]

[0639] 2-(((1S,2R)-1-amino-2-ethylcyclopentyl)methoxy)-6-methoxy-4-(5-methoxyimidazo[1,2-a]pyridin-3-yl)benzonitrile. To 2-fluoro-6-methoxy-4-(5-methoxyimidazo[1,2-a]pyridin-3-yl)benzonitrile (4.58 g, 15.4 mmol) was added a solution of ((1S,2R)-1-amino-2-ethylcyclopentyl)methanol (3.09 g, 21.6 mmol) in THF (20 mL, plus 30 mL rinse). A solution of NaOtBu in THF (2 M, 23.1 mL, 46.2 mmol) was added dropwise to maintain the internal reaction temperature at 21 to 23 °C, and the resulting mixture was stirred at this temperature for 22 h. The mixture was cooled to 5 °C, then H2O (40 mL) was added and the resulting mixture was stirred for 10 min. Several more portions of H2O and EtOAc (40 mL each) were added, then the mixture was concentrated to remove THF. The layers were separated, and the aqueous solution was further extracted with EtOAc (3×100 mL). The combined organics were washed with H2O, dried over Na2SO4, filtered and concentrated to give a solid foam (6.9 g). This sample was combined with another batch derived from a similar reaction to give a total of 8.5 g of crude material. The combined solid foam was suspended in MTBE (100 mL) and heated to an internal temperature of 55 °C for 4 h, then kept at an internal temperature of 40 °C for 40 min, and seeded with a sample of 2-(((1S,2R)-1-amino-2-ethylcyclopentyl)methoxy)-6-methoxy-4-(5-methoxyimidazo[1,2-a]pyridin-3-yl)benzonitrile, then kept at 21 °C for 4 days. The solid was collected by filtration to give 2-(((1S,2R)-1-amino-2-ethylcyclopentyl)methoxy)-6-methoxy-4-(5-methoxyimidazo[1,2-a]pyridin-3-yl)benzonitrile (7.6 g) as a brown solid. 1 H NMR (400 MHz, DMSO-d6) δ 7.74 (s, 1H), 7.39 (dd, 1H), 7.29 (d, 1H), 6.89 (s, 1H), 6.88 (s, 1H), 6.45 (d, 1H), 3.96 (s, 2H), 3.95 (s, 3H), 3.93 (s, 3H), 1.89-1.10 (m, 9H), 0.87 (t, 3H). MS (M+H) +421.4. Chiral SFC: Chiral Technologies OZ-H, 250 mm × 4.6 mm, 5 µ; A: CO2, B: 0.2% isopropylamine / EtOH; gradient: 5% B for 0.5 min, then 5% to 80% B for 5 min, then 80% B; 3.0 mL / min; 40 °C; 120 bar; 210 nM and MS detection; retention time, 2-(((1S,2R)-1-amino-2-ethylcyclopentyl)methoxy)-6-methoxy-4-(5-methoxyimidazo[1,2-a]pyridin-3-yl)benzonitrile (2A, 6.0 min), 2-(((1R,2S)-1-amino-2-ethylcyclopentyl)methoxy)-6-methoxy-4-(5-methoxyimidazo[1,2-a]pyridin-3-yl)benzonitrile (2B, 5.6 min), two enantiomers of trans-2-((1-amino-2-ethylcyclopentyl)methoxy)-6-methoxy-4-(5-methoxyimidazo[1,2-a]pyridin-3-yl)benzonitrile (5.7 min and 6.3 min); stereochemical purity >98%.

[0640] Biology Program

[0641] Enzyme analysis: Pan SIK MS IC50 analysis

[0642] Salt-induced kinase (SIK) activity is determined by measuring the effect of the test substance on the activity of the appropriate SIK enzyme to phosphorylate its corresponding substrate. Substrate peptides AQT0868, AQT0252, and AQT0508 were engineered by AssayQuant to be specific for their corresponding enzymes SIK 1, SIK 2, and SIK 3, respectively. The phosphorylated substrate products produced by the kinase reaction are detected by LCMS / MS, and the area under the peak curve is correlated with the kinase activity. Prior to starting the analysis, an assay ready plate (ARP) containing 0.15 μL of compound in a dose response format (10 μM diluted 4-fold to 9.5 pM) was thawed at room temperature for 20 to 30 minutes. The plate was spun at 1000 rpm for 30 seconds to ensure that the compound was at the bottom of the well before removing the foil cover. 0.15 μL of HPE (assay standard) and ZPE (DMSO) were added to the ARP using an HP D300 dispenser. The plate was spun again at 1000 rpm for 30 seconds. Using the Multidrop Combi and the designated small volume cartridge, add 20 µL of 1.25X enzyme (one disc each for SIK 1, SIK 2, and SIK 3) with 1 mM ATP in reaction buffer (reagent grade water, 50 mM Hepes pH 7.5, 0.5 mM EGTA, 10 mM MgCl2, 0.01% Brij-35, 1% glycerol, 0.01% BSA, 1 mM TCEP). The disc was spun at 1000 rpm for 30 seconds. The disc was then sealed and incubated at room temperature for 10 minutes. After incubation, 5 µL of 5X peptide reagent was added to initiate the kinase reaction using the Multidrop Combi and the designated small volume cartridge. The disc was spun at 1000 rpm for 30 seconds. The disc was then sealed and incubated at room temperature for 90 minutes. The assay was terminated by adding 5 µL of 120 mM EDTA (20 mM final concentration) using the Multidrop Combi and the designated small volume cartridge. The plate was spun at 1000 rpm for 30 seconds. 10 µl of the final reaction mixture from each of the three separate enzyme plates was transferred via Platemate Plus to the corresponding identical 96-well deep-well plate containing 70 µl of water / methanol (85 / 15%) for multiplexed MS detection (total volume 100 µl).

[0643] Use idbs data analysis software tool Activity Base (ABase), the area ratio unit data reported is associated with compound, batch and dosage information, the quality of the data is assessed, and the inhibition percentage of each hole is calculated.Evaluate the data of each maximum effect / HPE and minimum effect / ZPE control hole, and exclude outliers from all other calculations.Then calculate the mean value and standard deviation of HPE and ZPE of each dish, and Z '.Use average ZPE and HPE control as 0% and 100% activity respectively, compound data are converted into percentage effect.

[0644] Cytokine analysis: SIK macrophage analysis

[0645] Cytokine activity was determined by measuring the effect of the test substances on the inhibitory release of the cytokine TNFα and the incremental release of the cytokine IL10 from human monocyte-derived macrophages (human macrophages) stimulated with lipopolysaccharide (LPS). For analysis, human macrophages (CGPS group Pfizer Groton, CT) were removed from cryopreservation, rapidly thawed at 37°C, diluted in thawing medium (OptiMEM-Gibco medium, 10% heat-inactivated fetal bovine serum (HIFBS)), and then centrifuged at 200×g for 10 minutes. The resulting cell pellet was resuspended in assay medium (OptiMEM-Gibco medium, 0.5% HIFBS) to a concentration of approximately 0.56×10 6Cells / mL were added and 45 µL of this cell suspension (approximately 25,000 cells) were added to each well of a 384-well cell culture microtiter plate (Greiner) containing 0.05 µL of different concentrations of the test compound. After approximately 60 minutes in an incubator at 37°C in a humidified atmosphere with 5% carbon dioxide, the cells were stimulated by adding 5 µL of LPS (10 ng / mL; Sigma) and the assay plate was returned to an incubator at 37°C in a humidified atmosphere with 5% carbon dioxide for 4 hours. The final assay conditions were approximately 25,000 human macrophages per well in assay medium containing 1 ng / mL LPS and the test compound at the specified final concentration (approximately 10 µM by 4-fold dilution to 38 pM). The final concentration of DMSO in the assay was approximately 0.1%. After 4 hours, the assay plate was removed from the incubator and centrifuged at 1500 rpm for 10 minutes. Subsequently, a portion of the obtained cell supernatant was used to determine the amount of IL-10 and TNFα in each well. Human IL-10 and TNFα HTRF assay kits (Perkin Elmer) were used to measure cytokines according to the manufacturer's assay protocol. The concentration of the tested compound and the resulting effect value were plotted, and the compound concentration required for 50% effect (IC50) was determined using a four-parameter logarithmic dose-response equation (IL10 data analysis used E-WorkBook, and TNFα data analysis used Activity base of IDBusiness Solutions Ltd.).

[0646] Table 1

Claims

1. A compound of formula I having the following structure: or a pharmaceutically acceptable salt thereof, wherein A1 and A2 are independently O or S; X is selected from CH2, CD2, NR3, O and S, wherein R3 is selected from hydrogen, C1-C4 straight chain or branched alkyl, halogenated (C1-C4) straight chain or branched alkyl and hydroxy (C1-C4) straight chain or branched alkyl; Y and Z are selected from C and N, wherein when Y is C, then Z is N, and when Y is N, then Z is C; R1 and R2 are independently selected from hydrogen, deuterium, C1-C4 straight or branched alkyl, halo (C1-C4) straight or branched alkyl, hydroxy (C1-C4) straight or branched alkyl, cyano (C1-C4) straight or branched alkyl and C1-C3 alkoxy (C1-C4) straight or branched alkyl; or C1-C2 alkyl substituted with a C3-C5 cycloalkyl ring; or joined together to form a C3-C6 cycloalkyl ring; or If X is CH2 or CD2, R1 and R2 are independently selected from hydrogen, deuterium, halogen, hydroxyl, C1-C4 straight or branched alkyl, halo(C1-C4) straight or branched alkyl, hydroxyl(C1-C4) straight or branched alkyl, cyano(C1-C4) straight or branched alkyl and C1-C3 alkoxy(C1-C4) straight or branched alkyl, and C1-C2 alkyl substituted with a C3-C5 cycloalkyl ring; R4 is selected from hydrogen, deuterium, cyano, halogen, (C1-C3) alkoxy, halo (C1-C3) alkoxy, mercapto substituted by C1-C3 alkyl, C1-C4 straight or branched alkyl, halo (C1-C4) straight or branched alkyl and hydroxy (C1-C4) straight or branched alkyl; R5 is selected from hydrogen, deuterium, halogen, C1-C3 alkoxy, amino, (C1-C4 straight chain or branched alkyl)amino, di(C1-C4 straight chain or branched alkyl)amino, (4-6 membered) heterocyclyl, C1-C4 straight chain or branched alkyl, halo(C1-C4) straight chain or branched alkyl and hydroxy(C1-C4) straight chain or branched alkyl; R6 is selected from hydrogen, deuterium, halogen, C1-C4 straight or branched alkoxy, CONH2, C1-C4 straight or branched alkyl, halo (C1-C4) straight or branched alkyl, hydroxy (C1-C4) straight or branched alkyl and CO2R7, wherein R7 is selected from H and C1-C4 straight or branched alkyl; R8 is selected from hydrogen, deuterium and C1-C3 straight or branched alkyl; R9 is selected from C1-C3 straight or branched alkyl and halogenated (C1-C3) straight or branched alkyl; and n and m are independently selected from 0, 1 and 2.

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein A1 is O.

3. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein A2 is O or S.

4. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R1 and R2 are independently selected from ethyl, methyl and H.

5. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R4 is cyano or methoxy.

6. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R5 is H.

7. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R5 is azetidinyl, pyrrolidinyl or dimethylamino.

8. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R6 is H.

9. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R8 is H.

10. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R9 is methyl.

11. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein X is CH2.

12. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein X is O.

13. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein m is 0 and n is 1.

14. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein m is 1 and n is 1.

15. A compound of formula IA having the following structure: or a pharmaceutically acceptable salt thereof, wherein A1 and A2 are independently O or S; X is selected from CH2, CD2, NR3, O and S, wherein R3 is selected from hydrogen, C1-C4 straight chain or branched alkyl, halogenated (C1-C4) straight chain or branched alkyl and hydroxy (C1-C4) straight chain or branched alkyl; R1 and R2 are independently selected from hydrogen, deuterium, C1-C4 straight or branched alkyl, halo (C1-C4) straight or branched alkyl, hydroxy (C1-C4) straight or branched alkyl, cyano (C1-C4) straight or branched alkyl and C1-C3 alkoxy (C1-C4) straight or branched alkyl; or C1-C2 alkyl substituted with a C3-C5 cycloalkyl ring; or joined together to form a C3-C6 cycloalkyl ring; or If X is CH2 or CD2, R1 and R2 are independently selected from hydrogen, deuterium, halogen, hydroxyl, C1-C4 straight or branched alkyl, halo(C1-C4) straight or branched alkyl, hydroxyl(C1-C4) straight or branched alkyl, cyano(C1-C4) straight or branched alkyl and C1-C3 alkoxy(C1-C4) straight or branched alkyl, and C1-C2 alkyl substituted with a C3-C5 cycloalkyl ring; R4 is selected from hydrogen, deuterium, cyano, halogen, (C1-C3) alkoxy, halo (C1-C3) alkoxy, mercapto substituted by C1-C3 alkyl, C1-C4 straight or branched alkyl, halo (C1-C4) straight or branched alkyl and hydroxy (C1-C4) straight or branched alkyl; R5 is selected from hydrogen, deuterium, halogen, C1-C3 alkoxy, amino, (C1-C4 straight chain or branched alkyl)amino, di(C1-C4 straight chain or branched alkyl)amino, (4-6 membered) heterocyclyl, C1-C4 straight chain or branched alkyl, halo(C1-C4) straight chain or branched alkyl and hydroxy(C1-C4) straight chain or branched alkyl; R6 is selected from hydrogen, deuterium, halogen, C1-C4 straight or branched alkoxy, CONH2, C1-C4 straight or branched alkyl, halo (C1-C4) straight or branched alkyl, hydroxy (C1-C4) straight or branched alkyl and CO2R7, wherein R7 is selected from H and C1-C4 straight or branched alkyl; R8 is selected from hydrogen, deuterium and C1-C3 straight or branched alkyl; R9 is selected from C1-C3 straight or branched alkyl and halogenated (C1-C3) straight or branched alkyl; and n and m are independently selected from 0, 1 and 2.

16. The compound according to claim 15 or a pharmaceutically acceptable salt thereof, wherein A1 is O.

17. The compound of claim 15 or a pharmaceutically acceptable salt thereof, wherein A2 is O or S.

18. The compound of claim 15 or a pharmaceutically acceptable salt thereof, wherein R1 and R2 are independently selected from ethyl, methyl and H.

19. The compound according to claim 15 or a pharmaceutically acceptable salt thereof, wherein R4 is cyano or methoxy.

20. The compound of claim 15, or a pharmaceutically acceptable salt thereof, wherein R5 is H.

21. The compound of claim 15 or a pharmaceutically acceptable salt thereof, wherein R5 is azetidinyl, pyrrolidinyl or dimethylamino.

22. The compound of claim 15 or a pharmaceutically acceptable salt thereof, wherein R6 is H.

23. The compound of claim 15 or a pharmaceutically acceptable salt thereof, wherein R8 is H.

24. The compound of claim 15 or a pharmaceutically acceptable salt thereof, wherein R9 is methyl.

25. The compound of claim 15, or a pharmaceutically acceptable salt thereof, wherein X is CH2.

26. The compound of claim 15, or a pharmaceutically acceptable salt thereof, wherein X is O.

27. The compound of claim 15, or a pharmaceutically acceptable salt thereof, wherein m is 0 and n is 1.

28. The compound of claim 15, or a pharmaceutically acceptable salt thereof, wherein m is 1 and n is 1.

29. A compound of formula IB having the following structure: or a pharmaceutically acceptable salt thereof, wherein A1 and A2 are independently O or S; X is selected from CH2, CD2, NR3, O and S, wherein R3 is selected from hydrogen, C1-C4 straight chain or branched alkyl, halogenated (C1-C4) straight chain or branched alkyl and hydroxy (C1-C4) straight chain or branched alkyl; R1 and R2 are independently selected from hydrogen, deuterium, C1-C4 straight or branched alkyl, halo (C1-C4) straight or branched alkyl, hydroxy (C1-C4) straight or branched alkyl, cyano (C1-C4) straight or branched alkyl and C1-C3 alkoxy (C1-C4) straight or branched alkyl; or C1-C2 alkyl substituted with a C3-C5 cycloalkyl ring; or joined together to form a C3-C6 cycloalkyl ring; or If X is CH2 or CD2, R1 and R2 are independently selected from hydrogen, deuterium, halogen, hydroxyl, C1-C4 straight or branched alkyl, halo(C1-C4) straight or branched alkyl, hydroxyl(C1-C4) straight or branched alkyl, cyano(C1-C4) straight or branched alkyl and C1-C3 alkoxy(C1-C4) straight or branched alkyl, and C1-C2 alkyl substituted with a C3-C5 cycloalkyl ring; R4 is selected from hydrogen, deuterium, cyano, halogen, (C1-C3) alkoxy, halo (C1-C3) alkoxy, mercapto substituted by C1-C3 alkyl, C1-C4 straight or branched alkyl, halo (C1-C4) straight or branched alkyl and hydroxy (C1-C4) straight or branched alkyl; R5 is selected from hydrogen, deuterium, halogen, C1-C3 alkoxy, amino, (C1-C4 straight chain or branched alkyl)amino, di(C1-C4 straight chain or branched alkyl)amino, (4-6 membered) heterocyclyl, C1-C4 straight chain or branched alkyl, halo(C1-C4) straight chain or branched alkyl and hydroxy(C1-C4) straight chain or branched alkyl; R6 is selected from hydrogen, deuterium, halogen, C1-C4 straight or branched alkoxy, CONH2, C1-C4 straight or branched alkyl, halo (C1-C4) straight or branched alkyl, hydroxy (C1-C4) straight or branched alkyl and CO2R7, wherein R7 is selected from H and C1-C4 straight or branched alkyl; R8 is selected from hydrogen, deuterium and C1-C3 straight or branched alkyl; R9 is selected from C1-C3 straight or branched alkyl and halogenated (C1-C3) straight or branched alkyl; and n and m are independently selected from 0, 1 and 2.

30. The compound of claim 29 or a pharmaceutically acceptable salt thereof, wherein A1 is O.

31. The compound of claim 29 or a pharmaceutically acceptable salt thereof, wherein A2 is O or S.

32. The compound of claim 29 or a pharmaceutically acceptable salt thereof, wherein R1 and R2 are both H.

33. The compound of claim 29 or a pharmaceutically acceptable salt thereof, wherein R4 is cyano.

34. The compound of claim 29, or a pharmaceutically acceptable salt thereof, wherein R5 is H.

35. The compound of claim 29 or a pharmaceutically acceptable salt thereof, wherein R6 is H.

36. The compound of claim 29 or a pharmaceutically acceptable salt thereof, wherein R8 is H.

37. The compound of claim 29 or a pharmaceutically acceptable salt thereof, wherein R9 is methyl.

38. The compound of claim 29, or a pharmaceutically acceptable salt thereof, wherein X is CH2.

39. The compound of claim 29, or a pharmaceutically acceptable salt thereof, wherein m is 0 and n is 1.

40. The compound of claim 29, or a pharmaceutically acceptable salt thereof, wherein m is 1 and n is 1.

41. The compound of claim 1 or a pharmaceutically acceptable salt thereof, the compound being selected from the group consisting of: 2-((1-aminocyclopentyl)methoxy)-4-(5-methoxyimidazo[1,2-a]pyridin-3-yl)-6-(methylthio)benzonitrile; 2-(((1S,2R)-1-amino-2-ethylcyclopentyl)methoxy)-6-methoxy-4-(5-methoxyimidazo[1,2-a]pyridin-3-yl)benzonitrile; 2-(((1R,2S)-1-amino-2-ethylcyclopentyl)methoxy)-6-methoxy-4-(5-methoxyimidazo[1,2-a]pyridin-3-yl)benzonitrile; 2-((1-amino-3-ethylcyclopentyl)methoxy)-6-methoxy-4-(5-methoxyimidazo[1,2-a]pyridin-3-yl)benzonitrile; 2-(((1R,3R)-1-amino-3-ethylcyclopentyl)methoxy)-6-methoxy-4-(5-methoxyimidazo[1,2-a]pyridin-3-yl)benzonitrile; 2-(((1S,3S)-1-amino-3-ethylcyclopentyl)methoxy)-6-methoxy-4-(5-methoxyimidazo[1,2-a]pyridin-3-yl)benzonitrile; 2-(((1R,3S)-1-amino-3-ethylcyclopentyl)methoxy)-6-methoxy-4-(5-methoxyimidazo[1,2-a]pyridin-3-yl)benzonitrile; 2-(((1S,3R)-1-amino-3-ethylcyclopentyl)methoxy)-6-methoxy-4-(5-methoxyimidazo[1,2-a]pyridin-3-yl)benzonitrile; 2-(((1S,2S)-1-amino-2-ethylcyclopentyl)methoxy)-6-methoxy-4-(5-methoxyimidazo[1,2-a]pyridin-3-yl)benzonitrile; 2-(((1R,2R)-1-amino-2-ethylcyclopentyl)methoxy)-6-methoxy-4-(5-methoxyimidazo[1,2-a]pyridin-3-yl)benzonitrile; 3-(3-(((1S,2R)-1-amino-2-ethylcyclopentyl)methoxy)-4-cyano-5-(methylthio)phenyl)imidazo[1,2-a]pyridine-5-carbonitrile; 3-(3-(((1R,2S)-1-amino-2-ethylcyclopentyl)methoxy)-4-cyano-5-(methylthio)phenyl)imidazo[1,2-a]pyridine-5-carbonitrile; 2-((1-amino-2-ethylcyclopentyl)methoxy)-4-(5-methoxyimidazo[1,2-a]pyridin-3-yl)-6-(methylthio)benzonitrile; 2-(((1S,2R)-1-amino-2-ethylcyclopentyl)methoxy)-4-(5-methoxyimidazo[1,2-a]pyridin-3-yl)-6-(methylthio)benzonitrile; 2-(((1R,2S)-1-amino-2-ethylcyclopentyl)methoxy)-4-(5-methoxyimidazo[1,2-a]pyridin-3-yl)-6-(methylthio)benzonitrile; 2-(((2S,3R)-3-amino-2-ethyltetrahydrofuran-3-yl)methoxy)-4-(5-methoxyimidazo[1,2-a]pyridin-3-yl)-6-(methylthio)benzonitrile; 2-(((2R,3R)-3-amino-2-ethyltetrahydrofuran-3-yl)methoxy)-4-(5-methoxyimidazo[1,2-a]pyridin-3-yl)-6-(methylthio)benzonitrile; 2-(((2R,3S)-3-amino-2-ethyltetrahydrofuran-3-yl)methoxy)-4-(5-methoxyimidazo[1,2-a]pyridin-3-yl)-6-(methylthio)-benzonitrile; 2-(((2S,3S)-3-amino-2-ethyltetrahydrofuran-3-yl)methoxy)-4-(5-methoxyimidazo[1,2-a]pyridin-3-yl)-6-(methylthio)benzonitrile; (R)-3-(3-((1-amino-3,3-difluorocyclopentyl)methoxy)-4-cyano-5-(methylthio)phenyl)imidazo[1,2-a]pyridine-5-carbonitrile; (S)-3-(3-((1-amino-3,3-difluorocyclopentyl)methoxy)-4-cyano-5-(methylthio)phenyl)imidazo[1,2-a]pyridine-5-carbonitrile; (R)-2-((1-amino-3,3-difluorocyclopentyl)methoxy)-4-(5-methoxyimidazo[1,2-a]pyridin-3-yl)-6-(methylthio)benzonitrile; (S)-2-((1-amino-3,3-difluorocyclopentyl)methoxy)-4-(5-methoxyimidazo[1,2-a]pyridin-3-yl)-6-(methylthio)benzonitrile; (R)-3-(3-((1-amino-3,3-dimethylcyclohexyl)methoxy)-4-cyano-5-(methylthio)phenyl)imidazo[1,2-a]pyridine-5-carbonitrile; (S)-3-(3-((1-amino-3,3-dimethylcyclohexyl)methoxy)-4-cyano-5-(methylthio)phenyl)imidazo[1,2-a]pyridine-5-carbonitrile; 2-(((1R,3R)-1-amino-3-ethylcyclohexyl)methoxy)-6-methoxy-4-(5-methoxyimidazo[1,2-a]pyridin-3-yl)benzonitrile; 2-(((1S,3S)-1-amino-3-ethylcyclohexyl)methoxy)-6-methoxy-4-(5-methoxyimidazo[1,2-a]pyridin-3-yl)benzonitrile; 3-(3-(((1S,3S)-1-amino-3-ethylcyclohexyl)methoxy)-4-cyano-5-(methylthio)phenyl)imidazo[1,2-a]pyridine-5-carbonitrile; 3-(3-(((1R,3R)-1-amino-3-ethylcyclohexyl)methoxy)-4-cyano-5-(methylthio)phenyl)imidazo[1,2-a]pyridine-5-carbonitrile; (S)-2-((1-aminospiro[4.4]nonan-1-yl)methoxy)-6-methoxy-4-(5-methoxyimidazo[1,2-a]pyridin-3-yl)benzonitrile; (R)-2-((1-aminospiro[4.4]nonan-1-yl)methoxy)-6-methoxy-4-(5-methoxyimidazo[1,2-a]pyridin-3-yl)benzonitrile; (S)-2-((3-amino-1-(2,2,2-trifluoroethyl)piperidin-3-yl)methoxy)-6-methoxy-4-(5-methoxyimidazo[1,2-a]pyridin-3-yl)benzonitrile; (R)-2-((3-amino-1-(2,2,2-trifluoroethyl)piperidin-3-yl)methoxy)-6-methoxy-4-(5-methoxyimidazo[1,2-a]pyridin-3-yl)benzonitrile; (R)-2-((3-aminotetrahydrothiophen-3-yl)methoxy)-4-(imidazo[1,2-a]pyridin-3-yl)-6-(methylthio)benzonitrile; (S)-2-((3-aminotetrahydrothiophen-3-yl)methoxy)-4-(imidazo[1,2-a]pyridin-3-yl)-6-(methylthio)benzonitrile; (R)-2-((3-aminotetrahydrofuran-3-yl)methoxy)-4-(5-methoxyimidazo[1,2-a]pyridin-3-yl)-6-(methylthio)benzonitrile; (S)-2-((3-aminotetrahydrofuran-3-yl)methoxy)-4-(5-methoxyimidazo[1,2-a]pyridin-3-yl)-6-(methylthio)benzonitrile; (R)-2-((1-amino-3,3-difluorocyclopentyl)methoxy)-4-(imidazo[1,2-a]pyridin-3-yl)-6-(methylthio)benzonitrile; (S)-2-((1-amino-3,3-difluorocyclopentyl)methoxy)-4-(imidazo[1,2-a]pyridin-3-yl)-6-(methylthio)benzonitrile; (R)-3-(3-((3-aminotetrahydrothiophen-3-yl)methoxy)-4-cyano-5-(methylthio)phenyl)imidazo[1,2-a]pyridine-5-carbonitrile; (S)-3-(3-((3-aminotetrahydrothiophen-3-yl)methoxy)-4-cyano-5-(methylthio)phenyl)imidazo[1,2-a]pyridine-5-carbonitrile; 2-((1-aminocyclohexyl)methoxy)-4-(5-methoxyimidazo[1,2-a]pyridin-3-yl)-6-(methylthio)benzonitrile; (R)-2-((3-aminotetrahydrothiophen-3-yl)methoxy)-4-(5-methoxyimidazo[1,2-a]pyridin-3-yl)-6-(methylthio)benzonitrile; (S)-2-((3-aminotetrahydrothiophen-3-yl)methoxy)-4-(5-methoxyimidazo[1,2-a]pyridin-3-yl)-6-(methylthio)benzonitrile; 2-(((1S)-1-amino-3-(methoxymethyl)cyclohexyl)methoxy)-4-(imidazo[1,2-a]pyridin-3-yl)-6-(methylthio)benzonitrile; 2-(((1R)-1-amino-3-(methoxymethyl)-cyclohexyl)methoxy)-4-(imidazo[1,2-a]pyridin-3-yl)-6-(methylthio)benzonitrile; 2-(((1S,2S)-1-amino-2-(cyclopropylmethyl)cyclopentyl)methoxy)-6-methoxy-4-(5-methoxyimidazo[1,2-a]pyridin-3-yl)benzonitrile; 2-(((1R,2R)-1-amino-2-(cyclopropylmethyl)cyclopentyl)methoxy)-6-methoxy-4-(5-methoxyimidazo[1,2-a]pyridin-3-yl)benzonitrile; 2-(((1S,2R)-1-amino-2-(cyclopropylmethyl)cyclopentyl)methoxy)-6-methoxy-4-(5-methoxyimidazo[1,2-a]pyridin-3-yl)benzonitrile; 2-(((1R,2S)-1-amino-2-(cyclopropylmethyl)cyclopentyl)methoxy)-6-methoxy-4-(5-methoxyimidazo[1,2-a]pyridin-3-yl)benzonitrile; 2-(((1S,3S)-1-amino-3-(trifluoromethyl)cyclohexyl)methoxy)-4-(imidazo[1,2-a]pyridin-3-yl)-6-(methylthio)benzonitrile; 2-(((1R,3R)-1-amino-3-(trifluoromethyl)cyclohexyl)methoxy)-4-(imidazo[1,2-a]pyridin-3-yl)-6-(methylthio)benzonitrile; 2-(((1R,3S)-1-amino-3-(trifluoromethyl)cyclohexyl)methoxy)-4-(imidazo[1,2-a]pyridin-3-yl)-6-(methylthio)benzonitrile; 2-(((1S,3R)-1-amino-3-(trifluoromethyl)cyclohexyl)methoxy)-4-(imidazo[1,2-a]pyridin-3-yl)-6-(methylthio)benzonitrile; 3-(3-((1-aminocyclohexyl)methoxy)-4-cyano-5-(methylthio)phenyl)imidazo[1,2-a]pyridine-5-carbonitrile; 3-(3-((1-aminocyclopentyl)methoxy)-4-cyano-5-(methylthio)phenyl)imidazo[1,2-a]pyridine-5-carbonitrile; 3-(3-((1-aminocyclopentyl)methoxy)-4-cyano-5-(methylthio)phenyl)pyrazolo[1,5-a]pyridine-4-carbonitrile; 3-(3-((1-aminocyclopentyl)methoxy)-4-cyano-5-(methylthio)phenyl)-5-cyanoimidazolo[1,2-a]pyridine-7-carboxylic acid ethyl ester; 3-(3-((1-aminocyclopentyl)methoxy)-4-cyano-5-(methylthio)phenyl)-6-methoxyimidazo[1,2-a]pyridine-5-carbonitrile; 3-(3-((1-aminocyclopentyl)methoxy)-4-cyano-5-(methylthio)phenyl)-7-methylimidazo[1,2-a]pyridine-5-carbonitrile; 3-(3-((1-aminocyclopentyl)methoxy)-4-cyano-5-(methylthio)phenyl)-6-(dimethylamino)imidazo[1,2-a]pyridine-5-carbonitrile; 3-(3-((1-aminocyclopentyl)methoxy)-4-cyano-5-(methylthio)phenyl)-6-ethylimidazo[1,2-a]pyridine-5-carbonitrile; 3-(3-((1-aminocyclopentyl)methoxy)-4-cyano-5-(methylthio)phenyl)-6-methylimidazo[1,2-a]pyridine-5-carbonitrile; 3-(3-((1-aminocyclopentyl)methoxy)-4-cyano-5-(methylthio)phenyl)-7-chloroimidazo[1,2-a]pyridine-5-carbonitrile; 3-(3-((1-aminocyclohexyl)methoxy)-4-cyano-5-(methylthio)phenyl)pyrazolo[1,5-a]pyridine-4-carbonitrile; 6-amino-3-(3-((1-aminocyclopentyl)methoxy)-4-cyano-5-(methylthio)phenyl)imidazo[1,2-a]pyridine-5-carbonitrile; 3-(3-((1-aminocyclopentyl)methoxy)-4-cyano-5-(methylthio)phenyl)-6-(azetidin-1-yl)imidazo[1,2-a]pyridine-5-carbonitrile; 3-(3-((1-aminocyclopentyl)methoxy)-4-cyano-5-(methylthio)phenyl)-6-(pyrrolidin-1-yl)imidazo[1,2-a]pyridine-5-carbonitrile; 3-(3-((1-aminocyclopentyl)methoxy)-4-cyano-5-methoxyphenyl)-6-(dimethylamino)imidazo[1,2-a]pyridine-5-carbonitrile; 3-(3-((1-aminocyclohexyl)methoxy)-4-cyano-5-(methylthio)phenyl)-6-methoxyimidazo[1,2-a]pyridine-5-carbonitrile; 3-(3-((1-aminocyclopentyl)methoxy)-4-cyano-5-(methylthio)phenyl)-7-methoxyimidazo[1,2-a]pyridine-5-carbonitrile; 3-(3-((1-aminocyclohexyl)methoxy)-4-cyano-5-(methylthio)phenyl)-7-methoxyimidazo[1,2-a]pyridine-5-carbonitrile; 3-(3-((1-aminocyclohexyl)methoxy)-4-cyano-5-methoxyphenyl)-7-methoxyimidazo[1,2-a]pyridine-5-carbonitrile; and 3-(3-((1-aminocyclopentyl)methoxy)-4-cyano-5-(methylthio)phenyl)-6-(methylamino)imidazo[1,2-a]pyridine-5-carbonitrile.

42. The compound of claim 1 or a pharmaceutically acceptable salt thereof, the compound being selected from the group consisting of: 3-(3-((1-aminocyclohexyl))methoxy)-4-cyano-5-(methylthio)phenyl)imidazo[1,2-a]pyridine-5-carbonitrile; 2-(((1S,2R)-1-amino-2-ethylcyclopentyl)methoxy)-6-methoxy-4-(5-methoxyimidazo[1,2-a]pyridin-3-yl)benzonitrile; 2-(((2S,3R)-3-amino-2-ethyltetrahydrofuran-3-yl)methoxy)-4-(5-methoxyimidazo[1,2-a]pyridin-3-yl)-6-(methylthio)benzonitrile; 3-(3-(((1S,2R)-1-amino-2-ethylcyclopentyl)methoxy)-4-cyano-5-(methylthio)phenyl)imidazo[1,2-a]pyridine-5-carbonitrile; and 3-(3-((1-aminocyclopentyl)methoxy)-4-cyano-5-(methylthio)phenyl)-6-(dimethylamino)imidazo[1,2-a]pyridine-5-carbonitrile.

43. 3-(3-((1-aminocyclohexyl)methoxy)-4-cyano-5-(methylthio)phenyl)imidazo[1,2-a]pyridine-5-carbonitrile; or a pharmaceutically acceptable salt thereof.

44. 2-(((1S,2R)-1-amino-2-ethylcyclopentyl)methoxy)-6-methoxy-4-(5-methoxyimidazo[1,2-a]pyridin-3-yl)benzonitrile; or a pharmaceutically acceptable salt thereof.

45. 2-(((2S,3R)-3-amino-2-ethyltetrahydrofuran-3-yl)methoxy)-4-(5-methoxyimidazo[1,2-a]pyridin-3-yl)-6-(methylthio)benzonitrile; or a pharmaceutically acceptable salt thereof.

46. ​​3-(3-(((1S,2R)-1-amino-2-ethylcyclopentyl)methoxy)-4-cyano-5-(methylthio)phenyl)imidazo[1,2-a]pyridine-5-carbonitrile; or a pharmaceutically acceptable salt thereof.

47. 3-(3-((1-aminocyclopentyl)methoxy)-4-cyano-5-(methylthio)phenyl)-6-(dimethylamino)imidazo[1,2-a]pyridine-5-carbonitrile; or a pharmaceutically acceptable salt thereof.

48. A pharmaceutical composition comprising the compound according to claim 1 or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable solvate of the compound or salt, and a pharmaceutically acceptable excipient.

49. A method of treating a disease or condition selected from inflammation, autoimmune disease, neuroinflammation, arthritis, rheumatoid arthritis, spondyloarthropathies, systemic lupus erythematosus, lupus nephritis, osteoarthritis, gouty arthritis, pain, fever, pulmonary sarcoidosis, silicosis, cardiovascular disease, atherosclerosis, myocardial infarction, thrombosis, congestive heart failure and cardiac reperfusion injury, cardiomyopathy, stroke, ischemia, reperfusion injury, cerebral edema, brain injury, neurodegeneration, liver disease, inflammatory bowel disease, Crohn's disease, ulcerative colitis, nephritis, retinitis, retinopathy, macular degeneration, glaucoma, diabetes (type 1 and type 2), diabetic neuropathy, viral and bacterial infections, myalgia, endotoxin shock, toxic shock Klebsiella pneumoniae, osteoporosis, multiple sclerosis, endometriosis, dysmenorrhea, vaginitis, candidiasis, cancer, gastrointestinal cancer, fibrosis, obesity, muscular dystrophy, polymyositis, dermatomyositis, autoimmune hepatitis, primary biliary cirrhosis, primary sclerosing cholangitis, vitiligo, Alzheimer's disease, skin flushing, eczema, psoriasis, atopic dermatitis, sunburn, keloids, hypertrophic scars, rheumatic diseases, urticaria, discoid lupus, cutaneous lupus, central nervous system lupus, psoriatic arthritis, asthma, allergic asthma, type I interferon lesions including Icardi-Gautiers syndrome and other Mendelian diseases with overexpression of type I interferons, primary progressive multiple sclerosis, relapsing remitting multiple sclerosis, nonalcoholic fatty liver disease, nonalcoholic fatty liver disease, scleroderma, alopecia areata, scarring alopecia, prurigo, prurigo nodularis, CPUO, lichen diseases, lichen planus, Steven Johnson syndrome, spondylosis, myositis, vasculitis, pemphigus, lupus, severe depression, allergy, dry eye syndrome, transplant rejection, cancer, septic shock, cardiopulmonary dysfunction, acute respiratory disease, adhesive spondylitis, cachexia, chronic graft-versus-host disease, acute graft-versus-host disease, steatorrhea, idiopathic thrombocytopenic thrombotic purpura, thrombotic thrombocytopenic purpura, myasthenia gravis, Sjögren's syndrome, epidermal hyperplasia, cartilage inflammation, bone degradation, juvenile arthritis, juvenile rheumatoid arthritis, oligoarticular juvenile rheumatoid arthritis Inflammation, polyarticular juvenile rheumatoid arthritis, systemic onset juvenile rheumatoid arthritis, juvenile adhesive spondylitis, juvenile enteropathic arthritis, juvenile Reiter's syndrome, SEA syndrome, juvenile dermatomyositis, juvenile psoriatic arthritis, juvenile scleroderma, juvenile systemic lupus erythematosus, juvenile vasculitis, oligoarticular rheumatoid arthritis, polyarticular rheumatoid arthritis, systemic onset rheumatoid arthritis, enteropathic arthritis, reactive arthritis, Reiter's syndrome, myositis, polymyositis, dermatomyositis, polyarteritis nodosa, Wegener's granulomatosis, arteritis, polymyalgia rheumatica, sarcoidosis, sclerosis, primary biliary sclerosis, sclerosing cholangitis, dermatitis, Still's disease, chronic obstructive pulmonary disease,Guillain-Barre disease, Graves' disease, Addison's disease, Raynaud's phenomenon, psoriatic epidermal hyperplasia, plaque psoriasis, guttate psoriasis, inverse psoriasis, pustular psoriasis, erythrodermic psoriasis, immune disorders associated with or caused by the activity of pathogenic lymphocytes, non-infectious uveitis, Behcet's disease and Vogt-Koyage-Harada syndrome, the method comprising administering to a subject in need thereof a compound according to any one of claims 1 to 47 or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable solvate of the compound or salt.

50. A method of treating inflammatory bowel disease, Crohn's disease, ulcerative colitis or gastrointestinal cancer, the method comprising administering to a subject in need thereof a compound according to any one of claims 1 to 47 or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of said compound or salt.

51. The method of claim 49, wherein the compound is selected from the group consisting of: 3-(3-((1-aminocyclohexyl)methoxy)-4-cyano-5-(methylthio)phenyl)imidazo[1,2-a]pyridine-5-carbonitrile; 2-(((1S,2R)-1-amino-2-ethylcyclopentyl)methoxy)-6-methoxy-4-(5-methoxyimidazo[1,2-a]pyridin-3-yl)benzonitrile; 2-(((2S,3R)-3-amino-2-ethyltetrahydrofuran-3-yl)methoxy)-4-(5-methoxyimidazo[1,2-a]pyridin-3-yl)-6-(methylthio)benzonitrile; 3-(3-(((1S,2R)-1-amino-2-ethylcyclopentyl)methoxy)-4-cyano-5-(methylthio)phenyl)imidazo[1,2-a]pyridine-5-carbonitrile; and 3-(3-((1-aminocyclopentyl)methoxy)-4-cyano-5-(methylthio)phenyl)-6-(dimethylamino)imidazo[1,2-a]pyridine-5-carbonitrile; or a pharmaceutically acceptable salt thereof.

52. Use of a compound according to any one of claims 1 to 47 for the preparation of a medicament for the treatment of a condition for which a SIK inhibitor is indicated.

53. Use of a compound according to any one of claims 1 to 47 or in the preparation of a medicament for the treatment of inflammatory bowel disease, Crohn's disease, ulcerative colitis or gastrointestinal cancer.

54. A compound according to any one of claims 1 to 47 for use in the treatment of a condition for which a SIK inhibitor is indicated.

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