Compounds and pharmaceutical compositions thereof for the treatment of diseases

Abstract

The present invention discloses compounds according to Formula (I) wherein X1, X2, Y, R1, L1, R 2, R 3, Cy and the subscript n are as defined herein. The present invention relates to compounds, methods for their production, pharmaceutical compositions comprising the same, and methods of treatment using the same, for the prophylaxis and / or treatment of inflammatory diseases, autoinflammatory diseases, autoimmune diseases, proliferative diseases, fibrotic diseases, transplant rejection, diseases involving impairment of cartilage turnover, congenital cartilage malformation, diseases involving impairment of bone turnover, diseases associated with hypersecretion of IL-6, diseases associated with hypersecretion of TNFα, interferons, IL-12, IL-17 and / or IL-23, respiratory diseases, endocrine diseases, metabolic diseases, cardiovascular diseases, dermatological diseases, and / or abnormal angiogenesis associated diseases by administering a compound of the invention.

Description

COMPOUNDS AND PHARMACEUTICAL COMPOSITIONS THEREOF FOR THETREATMENT OF DISEASESFIELD OF THE INVENTION

[0001] The present invention relates to compounds, methods for the production of the compounds of the invention, pharmaceutical compositions comprising the compounds of the invention, uses and methods for the prophylaxis and / or treatment of inflammatory diseases, autoinflammatory diseases, autoimmune diseases, proliferative diseases, fibrotic diseases, transplant rejection, diseases involving impairment of cartilage turnover, congenital cartilage malformation, diseases involving impairment of bone turnover, diseases associated with hypersecretion of IL-6, diseases associated with hypersecretion of TNFa, interferons, IL-12, IL-17 and / or IL-23, respiratory diseases, endocrine diseases, metabolic diseases, cardiovascular diseases, dermatological diseases, and / or abnormal angiogenesis associated diseases by administering the compounds of the invention. In particular, the compounds of the invention may inhibit Salt-Inducible Kinases (“SIK” kinases).BACKGROUND OF THE INVENTION

[0002] Protein kinases belong to a large family of structurally related enzymes which are responsible for the control of a wide variety of cellular signal transduction processes. In particular, they have been shown to be key regulators in cellular functions including for example proliferation, metabolism, and apoptosis. Consequently, defective control of protein phosphorylation which leads to uncontrolled signaling is involved in a number of diseases, including for example, inflammation, allergies, cancer, autoimmune diseases, CNS disorders, and angiogenesis.

[0003] In healthy individuals inflammation is self-limiting, and resolution is controlled by the release of anti-inflammatory mediators and cytokines, such as interleukin- 10 (IL- 10), produced by “suppressive” or “regulatory” cells, which are produced as part of a negative feedback loop.

[0004] During the process of inflammation, an initial pro -inflammatory response is followed by a pro resolution response which turns the inflammation off after the insult has been resolved, leading to the reduction of pro-inflammatory cytokines such as TNFa and IL-12, coupled with increased levels of antiinflammatory cytokines such as IL-10 and TGF-J3, resulting in the generation of a so-called tolerogenic environment.

[0005] Salt-Inducible Kinases (SIKs) are a family of serine / threonine kinases widely expressed in the body, and involved in particular in cellular energy homeostasis. Three SIK isoforms have been identified, named SIK1 (also referred as SNFl-Like Kinase (SNF1LK) or Myocardial SNFl-Like Kinase (MSK)), SIK2 (SNF1LK2 or KIAA0781) and SIK3 (KIAA0999) (Katoh et al. 2004).

[0006] The SIKs play a number of roles in different cell types . They have been found to phosphorylate a number of substrates including CREB-responsive transcriptional co-activator (CRTC) proteins and histone de-acetylase (HDAC) proteins, thereby regulating the transcription of a number of different genes. HDAC and CRTC proteins control the phenotype of activated macrophages by reducing the proinflammatorycytokine secretion (TNFa and IL-12) and increase the production of anti-inflammatory cytokines like IL- 10 (Clark et al. 2012; Ozanne et al. 2015).

[0007] The regulation of ALK5 by SIK1 (Yu et al. 2013), the identification of the SIK2 gene as a risk locus for primary sclerosing cholangitis (Liu et al. 2013), and the modulation by SIKs of gene expression induced by TGF-J3 of factors implicated in the pathology of fibrosis such as plasminogen activator inhibitor 1 (PAI-1) (Hutchinson et al. 2020) suggest a role for SIK proteins in fibrotic diseases. SIK2 and SIK3 have recently been identified to play a role in inflammation through the secretion of high levels of antiinflammatory cytokines, in particular IL- 10, and very low levels of pro -inflammatory cytokines such as TNFa upon inhibition of their kinase activity (Darling et al. 2017; Darling et al. 2021).

[0008] A role for SIK2 in T helper (Th) 1 cell differentiation has been described through the regulation of IFNy and IL- 12 signaling, suggesting SIK2 may be an interesting target for inflammatory diseases (Y ao et al. 2013).

[0009] SIK1 has recently been shown to be involved in skeletal muscle sensitivity in obese mice, and may be an interesting target to prevent type II diabetes (Nixon et al. 2016), and diabetic nephropathy (Hsu et al. 2020).

[0010] Recently, it has also been shown that like PTH (parathyroid hormone), small molecule SIK inhibitors cause decreased phosphorylation and increased nuclear translocation ofHDAC4 / 5 and CRTC2. Treatment with the small molecule SIK inhibitor YKL-05 -099 increased bone formation and bone mass in mice (Wein et al. 2016), confirming the relevance of SIK inhibition in the treatment of bone turnover diseases (Nishimori et al. 2019; Sato et al. 2022).

[0011] Inducible knock-out or mutation of SIK isoforms and pharmacological inhibition in mice and in human embryonic stem cell-derived kidney organoids led to induction of Cyp27bl expression and 1,25 - vitamin D synthesis. Thus, SIK isoforms, in particular SIK2 and SIK3, modulate renal 1,25-vitamin D production downstream of PTH (Y oon et al. 2023), which could be beneficial for the treatment of chronic kidney disease-mineral bone disorder (CKD-MBD).

[0012] Furthermore, it was shown that inhibition of SIK2 after oxygen-glucose deprivation enhances neuron survival (Sasaki et al. 2011) or promotes melanogenesis in melanoma cells (Kumagai et al. 2011). In this context, since therapeutic strategies are needed to modulate the cellular stress response, such as during ischaemia and post reperfusion of tissue, in the chronic phase of cardiac remodeling, in diabetes and neurodegenerative conditions, the rapid inhibition or degradation of the SIK proteins, following multiple kinds of stresses, makes them interesting targets in inflammatory, cardiac or metabolic diseases and neurodegenerative disorders. SIK inhibition might also have application in cosmetology or pigmentation- related diseases to induce melanogenesis (Mujahid et al. 2017).

[0013] Besides the pivotal function in cellular energy homeostasis, the SIK proteins have also been involved in the regulation of the cell cycle. Higher expression of SIK2 significantly correlated with poor survival in patients with high-grade serous ovarian cancers (Ahmed et al. 2010), moreover, expression of SIK3 was elevated in ovarian cancers, particularly in the serous subtype and at later stages (Charoenfuprasert et al. 2011). Therefore SIK inhibition may be useful in the treatment of cancer.

[0014] Despite great advances over the past two decades in the treatments of patients affected by autoimmune disorders based on antibodies targeting pro -inflammatory cytokines, such as anti-TNFa, a significant proportion of patients do not respond to these therapies or experience serious adverse events such as opportunistic infections. Therefore a large unmet medical need still exists for the treatment of these diseases, and new agents for the prophylaxis and / or treatment of the above mentioned diseases are required.SEQUENCE LISTING

[0015] SEQ ID 1: AMARA peptide (Kaneca Eurogentec S.A.).

[0016] SEQ ID 2: SIK3 FL Gst-TEV-HsSIK3 (Uniprot# Q9Y2K2-5, amino acids 59-1321)-Thr-6His protein.SUMMARY OF THE INVENTION

[0017] The present invention is based on the identification of novel compounds, and their use in the prophylaxis and / or treatment of inflammatory diseases, autoinflammatory diseases, autoimmune diseases, proliferative diseases, fibrotic diseases, transplant rejection, diseases involving impairment of cartilage turnover, congenital cartilage malformation, diseases involving impairment of bone turnover, diseases associated with hypersecretion of IL-6, diseases associated with hypersecretion of TNFa, interferons, IL- 12, IL- 17 and / or IL-23, respiratory diseases, endocrine diseases, metabolic diseases, cardiovascular diseases, dermatological diseases, and / or abnormal angiogenesis associated diseases. In particular, the compounds of the invention may be SIK inhibitors, and more particularly SIK2 and / or SIK3 inhibitors . The present invention also provides methods for the production of these compounds, pharmaceutical compositions comprising these compounds and methods for the prophylaxis and / or treatment of inflammatory diseases, autoinflammatory diseases, autoimmune diseases, proliferative diseases, fibrotic diseases, transplant rejection, diseases involving impairment of cartilage turnover, congenital cartilage malformation, diseases involving impairment of bone turnover, diseases associated with hypersecretion of IL-6, diseases associated with hypersecretion of TNFa, interferons, IL-12, IL-17 and / or IL-23, respiratory diseases, endocrine diseases, metabolic diseases, cardiovascular diseases, dermatological diseases, and / or abnormal angiogenesis associated diseases by administering the compounds of the invention.

[0018] Accordingly, in a first aspect of the invention, the compounds of the invention are provided having a Formula I:whereinone of Xi and X2is N and the other is C;Y is CH orN;Provided that- when Xi is C, X2is N, and Y is N, then R2is not -NR3aR3\ or- -Li R1is not -OH, -Me, -OMe, -CH2CH2OH, or -NMe2;Li is absent,C1-6 alkylenyl,LIA,-C1-6 alkylenyl-LiA-, or-LIA-CI-6 alkylenyl-;LIA is -O-, -N Rxl-, -C(=O)-, -C(=O)O-, -C(=O)NRx1-, -NRxlC(=O)-, -NRxlC(=O)O-, S(=O), S(=O)2, - NHS(=O)2NRX1-, -S(=O)2NRX1-, -NRX1S(=O)2-, -P(=O) RX1;Rxlis H, or C1-6 alkyl optionally substituted with one or more independently selected halo;R1isC1-6 alkyl optionally substituted with one or more groups independently selected from =0 and R7, C3-7 cycloalkyl optionally substituted with one or more groups independently selected from =0 and R7, polycyclic fused, spiro or bridged C4-10 cycloalkyl optionally substituted with one or more groups independently selected from =0 and R7,4-7 membered heterocycloalkyl comprising one or more heteroatoms independently selected from O, S, N, P, and B, which heterocycloalkyl is optionally substituted with one or more groups selected from =0 and R7, polycyclic fused, spiro or bridged 6-10 membered heterocycloalkyl comprising one or more heteroatoms independently selected from O, S, N, P, and B, which heterocycloalkyl is optionally substituted with one or more groups selected from =0 and R7,Phenyl optionally substituted with one or more groups independently selected from R7,5-7 membered heteroaryl comprising one or more heteroatoms independently selected from O, S, and N, which heteroaryl is optionally substituted with one or more groups independently selected from R7, andpolycyclic fused 8-10 membered heteroaryl comprising one or more heteroatoms independently selected from O, S, and N, which heteroaryl is optionally substituted with one or more groups independently selected from R7;Each R7is independently selected from halo,- -CN,-LVA-R7A, and-Ci-6 alkylenyl-L7A-R7A;L7Ais absent, -O-, -NRx2-, -C(=O)-, -C(=O)O-, -C(=O)NRx2-, -NRx2C(=O)-, -NRx2C(=O)O-, -S(=O), -S(=O)2, -NHS(=O)2NRX2-, -S(=O)2NRX2-, -NRX2S(=O)2-, or -P(=O) Rx2;Rx2is H, or Ci-6 alkyl optionally substituted with one or more independently selected halo;R7Ais- HCi-4 alkyl optionally substituted with one or more independently selected =0, halo, CN, or OH, C3-7 cycloalkyl optionally substituted with one or more groups independently selected from =0, halo, CN, or OH, or4-7 membered heterocycloalkyl comprising one or more heteroatoms independently selected from O, S, N, P, and B, which heterocycloalkyl is optionally substituted with one or more groups selected from =0, halo, CN, or OH;R2is- H,C1-4 alkyl optionally substituted with one or more independently selected halo, or- -NR2aR2b;Each R2aand R2bis independently selected from H, C1-4 alkyl optionally substituted with one or more independently selected halo, or phenyl;Each R3is independently selected from halo, CN, and C1-4 alkyl optionally substituted with one or more independently selected halo;The subscript n is 0, 1, 2 or 3;Cy is a 8-10 membered bicyclic heteroaryl comprising one or more heteroatoms independently selected from N, O, and S, which heteroaryl is optionally substituted with one or more independently selected R4;Each R4is independently selected from: halo,CN, and-L4A-R4A; orTwo R4groups together with the atoms to which they are attached may form together a fused 4-7 membered heterocycloalkyl comprising one or more heteroatoms independently selected from O, S, N, P, and B, which heterocycloalkyl is optionally substituted with one or more groups selected from =0, halo, CN, or OH;L4Ais absent, -O-, -NRx4-, -C(=O)-, -C(=O)O-, -C(=0)NRx4-, -NRx4C(=0)-, -NRx4C(=0)0-, -S(=O), =S(=O)2, -NHS(=O)2NRX4-, -S(=O)2NRX4-, -NRX4S(=O)2-, or -P(=O)Rx4;Rx4is H, or Ci-6 alkyl optionally substituted with one or more independently selected halo;Each R4Ais independently selected from:- H,Ci-6 alkyl optionally substituted with one or more groups independently selected from =0 and R5, C3-7 cycloalkyl optionally substituted with one or more groups independently selected from =0 and R5, polycyclic fused, spiro or bridged C4-10 cycloalkyl optionally substituted with one or more groups independently selected from =0 and R5,4-7 membered heterocycloalkyl comprising one or more heteroatoms independently selected from O, S, N, P, and B, which heterocycloalkyl is optionally substituted with one or more groups selected from =0 and R5, polycyclic fused, spiro or bridged 6-10 membered heterocycloalkyl comprising one or more heteroatoms independently selected from O, S, N, P, and B, which heterocycloalkyl is optionally substituted with one or more groups selected from =0 and R5,Phenyl optionally substituted with one or more groups independently selected from R5, and5-7 membered heteroaryl comprising one or more heteroatoms independently selected from O, S, and N, which heteroaryl is optionally substituted with one or more groups independently selected from R5;Each R5is independently selected from: halo,CN, and- -L5A-R5A;L5Ais absent, -O-, -NRx5-, -C(=O)-, -C(=O)O-, -C(=O)NRx5-, -NRx5C(=O)-, -NRx5C(=O)O-, -S(=O), -S(=O)2, -NHS(=O)2NRX5-, -S(=O)2NRX5-, -NRX5S(=O)2-, or -P(=O)Rx5;Rx5is H, or Ci-6 alkyl optionally substituted with one or more independently selected halo;Each R5Ais independently selected from:- H,Ci-6 alkyl optionally substituted with one or more groups independently selected from =0 and R6, C3-7 cycloalkyl optionally substituted with one or more groups independently selected from =0 and R6,4-7 membered heterocycloalkyl comprising one or more heteroatoms independently selected from O, S, N, P, and B, which heterocycloalkyl is optionally substituted with one or more groups selected from =0 and R6,Phenyl optionally substituted with one or more groups independently selected from R6, and5-7 membered heteroaryl comprising one or more heteroatoms independently selected from O, S, and N, which heteroaryl is optionally substituted with one or more groups independently selected from R6;Each R6is independently selected from: halo,- CN,- -OH,C1-6 alkyl optionally substituted with one or more independently selected halo, andC1-6 alkoxy optionally substituted with one or more halo.

[0019] In a particular aspect, the compounds of the invention are provided for use in the prophylaxis and / or treatment of inflammatory diseases, autoinflammatory diseases, autoimmune diseases, proliferative diseases, fibrotic diseases, transplant rejection, diseases involving impairment of cartilage turnover, congenital cartilage malformation, diseases involving impairment of bone turnover, diseases associated with hypersecretion of IL-6, diseases associated with hypersecretion of TNFa, interferons, IL-12, IL-17 and / or IL-23, respiratory diseases, endocrine diseases, metabolic diseases, cardiovascular diseases, dermatological diseases, and / or abnormal angiogenesis associated diseases .

[0020] Furthermore, the compounds of the invention exhibit potent inhibition against SIKs, particularly SIK2 and SIK3, more particularly SIK3, which may result in a tolerogenic therapy (z.e., reduction of pro- inflammatory cytokines such as TNFa and IL- 12, coupled with increased levels of anti-inflammatory cytokines such as IL-10 and TGF-J3). Particularly, the compounds of the invention exhibit enhanced inhibition of SIK3, with improved selectivity over SIK1 and SIK2.

[0021] In a further aspect, the present invention provides pharmaceutical compositions comprising a compound of the invention, and a pharmaceutical carrier, excipient or diluent. In a particular aspect, thepharmaceutical composition may additionally comprise further therapeutically active ingredients suitable for use in combination with the compounds of the invention. In a more particular aspect, the further therapeutically active ingredient is an agent for the treatment of inflammatory diseases, autoinflammatory diseases, autoimmune diseases, proliferative diseases, fibrotic diseases, transplant rejection, diseases involving impairment of cartilage turnover, congenital cartilage malformation, diseases involving impairment of bone turnover, diseases associated with hypersecretion of IL-6, diseases associated with hypersecretion of TNFa, interferons, IL-12, IL-17 and / or IL-23, respiratory diseases, endocrine diseases, metabolic diseases, cardiovascular diseases, dermatological diseases, and / or abnormal angiogenesis associated diseases.

[0022] Moreover, the compounds of the invention, useful in the pharmaceutical compositions and treatment methods disclosed herein, are pharmaceutically acceptable as prepared and used.

[0023] In a further aspect of the invention, this invention provides a method of treating a mammal, in particular humans, afflicted with a condition selected from among those listed herein, and particularly inflammatory diseases, autoinflammatory diseases, autoimmune diseases, proliferative diseases, fibrotic diseases, transplant rejection, diseases involving impairment of cartilage turnover, congenital cartilage malformation, diseases involving impairment of bone turnover, diseases associated with hypersecretion of IL-6, diseases associated with hypersecretion of TNFa, interferons, IL-12, IL-17 and / or IL-23, respiratory diseases, endocrine diseases, metabolic diseases, cardiovascular diseases, dermatological diseases, and / or abnormal angiogenesis associated diseases, which method comprises administering an effective amount of the pharmaceutical composition or compounds of the invention as described herein.

[0024] The present invention also provides pharmaceutical compositions comprising a compound of the invention, and a suitable pharmaceutical carrier, excipient or diluent for use in medicine . In a particular aspect, the pharmaceutical composition is for use in the prophylaxis and / or treatment of inflammatory diseases, autoinflammatory diseases, autoimmune diseases, proliferative diseases, fibrotic diseases, transplant rejection, diseases involving impairment of cartilage turnover, congenital cartilage malformation, diseases involving impairment of bone turnover, diseases associated with hypersecretion of IL-6, diseases associated with hypersecretion of TNFa, interferons, IL-12, IL-17 and / or IL-23, respiratory diseases, endocrine diseases, metabolic diseases, cardiovascular diseases, dermatological diseases, and / or abnormal angiogenesis associated diseases.

[0025] In additional aspects, this invention provides methods for synthesizing the compounds of the invention, with representative synthetic protocols and pathways disclosed later on herein.

[0026] Other objects and advantages will become apparent to those skilled in the art from a consideration of the ensuing detailed description.

[0027] It will be appreciated that compounds of the invention may be metabolized to yield biologically active metabolites.DETAILED DESCRIPTION OF THE INVENTIONDefinitions

[0028] The following terms are intended to have the meanings presented therewith below and are useful in understanding the description and intended scope of the present invention.

[0029] When describing the invention, which may include compounds, pharmaceutical compositions containing such compounds and methods of using such compounds and compositions, the following terms, if present, have the following meanings unless otherwise indicated. It should also be understood that when described herein any of the moieties defined forth below may be substituted with a variety of substituents, and that the respective definitions are intended to include such substituted moieties within their scope as set out below. Unless otherwise stated, the term “substituted” is to be defined as set out below. It should be further understood that the terms “groups” and “radicals” can be considered interchangeable when used herein.

[0030] The articles ‘a’ and ‘an’ may be used herein to refer to one or to more than one (i.e. at least one) of the grammatical objects of the article. By way of example ‘an analogue’ means one analogue or more than one analogue.

[0031] ‘Alkyl’ means straight or branched aliphatic hydrocarbon having the specified number of carbon atoms. Particular alkyl groups have 1 to 6 carbon atoms or 1 to 4 carbon atoms. Branched means that one or more alkyl groups such as methyl, ethyl or propyl is attached to a linear alkyl chain. Particular alkyl groups are methyl (-CH3), ethyl (-CH2-CH3), w-propyl (-CH2-CH2-CH3), isopropyl (-CH(CH3)2), w-butyl (- CH2-CH2-CH2-CH3), tert-butyl (-€(043)3), sec-butyl (-Q^CPbj-CPhCTh), isobutyl (-CH2-CH(CH3)2), n- pentyl (-CH2-CH2-CH2-CH2-CH3), w-hcxyl (-CH2-CH2-CH2-CH2-CH2-CH3), and 1,2 -dimethylbutyl (- CHCH3)-C(CH3)H2-CH2-CH3). Particular alkyl groups have between 1 and 4 carbon atoms.

[0032] ‘Alkenyl’ refers to monovalent olefinically (unsaturated) hydrocarbon groups with the number of carbon atoms specified. Particular alkenyl has 2 to 8 carbon atoms, and more particularly, from 2 to 6 carbon atoms, which can be straight-chained or branched and having at least 1 and particularly from 1 to 2 sites of olefinic unsaturation. Particular alkenyl groups include ethenyl (-C UCH2). w-propcnyl (-C H2C UCH2). isopropenyl (-C(CH3)=CH2) and the like.

[0033] ‘Alkylene’ refers to divalent alkene radical groups having the number of carbon atoms specified, in particular having 1 to 6 carbon atoms and more particularly 1 to 4 carbon atoms which can be straight- chained or branched. This term is exemplified by groups such as methylene (-CH2-), ethylene (-CH2-CH2- ), or -CH(CH3)- and the like.

[0034] ‘Alkynylene’ refers to divalent alkyne radical groups having the number of carbon atoms and the number of triple bonds specified, in particular 2 to 6 carbon atoms and more particularly 2 to 4 carbon atoms which can be straight-chained or branched. This term is exemplified by groups such as -C=C-, -CH2- C=C-, and -C(CH3)H-C=CH-.

[0035] ‘Alkoxy’ refers to the group O-alkyl, where the alkyl group has the number of carbon atoms specified. In particular the term refers to the group -O-Ci e alkyl. Particular alkoxy groups are methoxy,ethoxy, w-propoxy. isopropoxy, w-butoxy. tert-butoxy, isobutoxy, scc-butoxy. w-pcntoxy. w-hcxoxy. and 1,2-dimethylbutoxy. Particular alkoxy groups are lower alkoxy, i.e. with between 1 and 6 carbon atoms. Further particular alkoxy groups have between 1 and 4 carbon atoms.

[0036] ‘ Amino’ refers to the radical -NH2.

[0037] ‘Aryl’ refers to a monovalent aromatic hydrocarbon group derived by the removal of one hydrogen atom from a single carbon atom of a parent aromatic ring system. In particular aryl refers to an aromatic ring structure, monocyclic or fused polycyclic, with the number of ring atoms specified. Specifically, the term includes groups that include from 6 to 10 ring members. Particular aryl groups include phenyl, and naphthyl.

[0038] ‘Cycloalkyl ’refers to a non-aromatic hydrocarbyl ring structure, monocyclic, fused polycyclic, bridged polycyclic, or spirocyclic, with the number of ring atoms specified. A cycloalkyl may have from 3 to 12 carbon atoms, in particular from 3 to 10, and more particularly from 3 to 7 carbon atoms. Such cycloalkyl groups include, by way of example, single ring structures such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.

[0039] ‘Cyano’ refers to the radical -CN.

[0040] ‘Halo’ or ‘halogen’ refers to fluoro (F), chloro (Cl), bromo (Br) and iodo (I). Particular halo groups are either fluoro or chloro.

[0041] As used herein, term ‘polycyclic’ refers to chemical groups featuring several closed rings of atoms. In particular it refers to groups featuring two, three or four rings of atoms, more particularly two or three rings of atoms, most particularly two rings of atoms.

[0042] ‘Hetero’ when used to describe a compound or a group present on a compound means that one or more carbon atoms in the compound or group have been replaced by a nitrogen, oxygen, or sulfur heteroatom. Hetero may be applied to any of the hydrocarbyl groups described above such as alkyl, e.g. heteroalkyl, cycloalkyl, e.g. heterocycloalkyl, aryl, e.g. heteroaryl, and the like having from 1 to 4, and particularly from 1 to 3 heteroatoms, more typically 1 or 2 heteroatoms, for example a single heteroatom.

[0043] ‘Heteroaryl’ means an aromatic ring structure, monocyclic or fused polycyclic, that includes one or more heteroatoms independently selected from O, N and S and the number of ring atoms specified. In particular, the aromatic ring structure may have from 5 to 9 ring members. The heteroaryl group can be, for example, a five membered or six membered monocyclic ring or a fused bicyclic structure formed from fused five and six membered rings or two fused six membered rings or, by way of a further example, two fused five membered rings. Each ring may contain up to four heteroatoms typically selected from nitrogen, sulfur and oxygen. Typically the heteroaryl ring will contain up to 4 heteroatoms, more typically up to 3 heteroatoms, more usually up to 2, for example a single heteroatom. In particular, the heteroaryl ring contains at least one ring nitrogen atom. The nitrogen atoms in the heteroaryl rings can be basic, as in the case of an imidazole or pyridine, or essentially non -basic as in the case of an indole or pyrrole nitrogen. In general the number of basic nitrogen atoms present in the heteroaryl group, including any amino group substituents of the ring, will be less than five.

[0044] Examples of five membered monocyclic heteroaryl groups include but are not limited to pyrrolyl, furanyl, thiophenyl, imidazolyl, furazanyl, oxazolyl, oxadiazolyl, oxatriazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, triazolyl and tetrazolyl groups.

[0045] Examples of six membered monocyclic heteroaryl groups include but are not limited to pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl and triazinyl.

[0046] Particular examples of bicyclic heteroaryl groups containing a five membered ring fused to another five-membered ring include but are not limited to imidazothiazolyl and imidazoimidazolyl.

[0047] Particular examples of bicyclic heteroaryl groups containing a six membered ring fused to a five membered ring include but are not limited to benzofuranyl, benzothiophenyl, benzoimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzoisothiazolyl, isobenzofuranyl, indolyl, isoindolyl, indolizinyl, purinyl (e.g. adenine, guanine), indazolyl, pyrazolopyrimidinyl, triazolopyrimidinyl, and pyrazolopyridinyl groups.

[0048] Particular examples of bicyclic heteroaryl groups containing two fused six membered rings include but are not limited to quinolinyl, isoquinolinyl, pyridopyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, phthalazinyl, naphthyridinyl, and pteridinyl groups. Particular heteroaryl groups are those derived from thiophenyl, pyrrolyl, benzothiophenyl, benzofuranyl, indolyl, pyridinyl, quinolinyl, imidazolyl, oxazolyl and pyrazinyl.

[0049] Examples of representative heteroaryls include the following:wherein each Y is selected from >C=O, NH, O and S.

[0050] ‘Heterocycloalkyl’ means a non-aromatic fully or partially saturated ring structure, monocyclic, fused polycyclic, spirocyclic, or bridged polycyclic, that includes one or more heteroatoms independently selected from O, N, P and S and the number of ring atoms specified. The heterocycloalkyl ring structure may have from 4 to 12 ring members, in particular from 4 to 10 ring members and more particularly from 4 to 7 ring members. Each ring may contain up to four heteroatoms typically selected from nitrogen, phosphorus, sulfur and oxygen. Typically the heterocycloalkyl ring will contain up to 4 heteroatoms, more typically up to 3 heteroatoms, more usually up to 2, for example a single heteroatom. When partially saturated, the heterocycloalkyl may contain one or two double bonds, and more particularly one double bond. Examples of heterocyclic rings include, but are not limited to azetidinyl, oxetanyl, thietanyl, pyrrolidinyl (e.g. 1-pyrrolidinyl, 2-pyrrolidinyl and 3-pyrrolidinyl), tetrahydrofuranyl (e.g. 1- tetrahydrofuranyl, 2 -tetrahydrofuranyl and 3 -tetrahydrofuranyl), tetrahydrothiophenyl (e.g. 1- tetrahydrothiophenyl, 2-tetrahydrothiophenyl and 3 -tetrahydrothiophenyl), piperidinyl (e.g. 1-piperidinyl, 2-piperidinyl, 3 -piperidinyl and 4-piperidinyl), tetrahydropyranyl (e.g. 4-tetrahydropyranyl),tetrahydrothiopyranyl (e.g. 4-tetrahydrothiopyranyl), morpholinyl, thiomorpholinyl, dioxanyl, or piperazinyl.

[0051] Particular examples of monocyclic rings are shown in the following illustrative examples:wherein each W and Y is independently selected from -CH2-, -NH-, -O-, P, and -S-.

[0052] Particular examples of monocyclic rings comprising one double bond are shown in the following illustrative examples:wherein each W and Y is independently selected from -CH2-, -NH-, P, -O- and -S-.

[0053] Particular examples of fused bicyclic rings are shown in the following illustrative examples:wherein each W and Y is independently selected from -CH2-, -NH-, P, -O- and -S-.

[0054] Particular examples of bridged bicyclic rings are shown in the following illustrative examples:wherein each W and Y is independently selected from -CH2-, -NH-, P, -O- and -S-.

[0055] Particular examples of spirocyclic rings are shown in the following illustrative examples:wherein each Y is selected from -CH2-, -NH-, P, -O- and -S-.

[0056] ‘Hydroxyl’ refers to the radical -OH.

[0057] ‘ Oxo’ refers to the radical =0.

[0058] ‘ Substituted’ refers to a group in which one or more hydrogen atoms are each independently replaced with the same or different substituent(s).

[0059] ‘Sulfo’ or ‘sulfonic acid’ refers to a radical such as -SO3H.

[0060] ‘ Thiol’ refers to the group -SH.

[0061] As used herein, term ‘substituted with one or more’ refers to one to four substituents. In particular, it refers to one to three substituents. More particularly, it refers to one or two substituents. Most particularly, it refers to one substituent.

[0062] One having ordinary skill in the art of organic synthesis will recognize that the maximum number of heteroatoms in a stable, chemically feasible heterocyclic ring, whether it is aromatic or non-aromatic, is determined by the size of the ring, the degree of unsaturation and the valence of the heteroatoms. In general, a heterocyclic ring may have one to four heteroatoms so long as the heteroaromatic ring is chemically feasible and stable.

[0063] ‘Pharmaceutically acceptable’ means approved or approvable by a regulatory agency of the Federal or a state government or the corresponding agency in countries other than the United States, or that is listed in the U.S. Pharmacopoeia or other generally recognized pharmacopoeia for use in animals, and more particularly, in humans.

[0064] ‘Pharmaceutically acceptable salt’ refers to a salt of a compound of the invention that is pharmaceutically acceptable and that retains the biological activity of the given compound, and which are is not biologically or otherwise undesirable. In particular, such salts may be inorganic or organic acid addition salts and base addition salts. For example, pharmaceutically acceptable salts are described in Handbook of Pharmaceutical Salts: Properties, Selection, and Use (Stahl & Wermuth 2011). The salts can be prepared in situ during the final isolation and purification of the compounds described herein or separately, e.g., by reacting the free base group with a suitable inorganic or organic acid. The compounds of the invention may have ionizable groups so as to be capable of preparation as pharmaceutically acceptable salts. These salts may be acid addition salts involving inorganic or organic acids or the salts may, in the case of acidic forms of the compounds of the invention be prepared from inorganic or organic bases. Frequently, the compounds are prepared or used as pharmaceutically acceptable salts prepared as addition products of pharmaceutically acceptable acids or bases. Suitable pharmaceutically acceptable acids and bases are well known in the art, such as, e.g., hydrochloric acid for forming acid addition salts, and such as, e.g., sodium hydroxide for forming basic salts. The term ‘pharmaceutically acceptable cation’ refers to an acceptable cationic counter-ion of an acidic functional group. Such cations are exemplified by sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium cations, and the like.

[0065] ‘Pharmaceutically acceptable vehicle’ refers to a diluent, adjuvant, excipient, or carrier with which a compound of the invention is administered.

[0066] ‘Prodrugs’ refers to compounds, including derivatives of the compounds of the invention, which have cleavable groups and become by solvolysis or under physiological conditions the compounds of the invention which are pharmaceutically active in vivo. Such examples include, but are not limited to, choline ester derivatives and the like, N-alkylmorpholine esters and the like.

[0067] ‘ Solvate’ refers to forms of the compound that are associated with a solvent, usually by a solvolysis reaction. This physical association includes hydrogen bonding. Conventional solvents include water, EtOH, acetic acid and the like. The compounds of the invention may be prepared e.g. in crystalline form and may be solvated or hydrated. Suitable solvates include pharmaceutically acceptable solvates, such as hydrates, and further include both stoichiometric solvates and non -stoichiometric solvates. In certain instances, the solvate will be capable of isolation, for example when one or more solvent molecules are incorporated inthe crystal lattice of the crystalline solid. ‘Solvate’ encompasses both solution -phase and isolable solvates. Representative solvates include hydrates, ethanolates and methanolates.

[0068] ‘Subject’ includes humans. The terms ‘human’, ‘patient’ and ‘subject’ are used interchangeably herein.

[0069] ‘ Effective amount’ means the amount of a compound of the invention that, when administered to a subject for treating a disease, is sufficient to effect such treatment for the disease. The “effective amount” can vary depending on the compound, the disease and its severity, and the age, weight, etc., of the subject to be treated.

[0070] ‘Preventing’ or ‘prevention’ refers to a reduction in risk of acquiring or developing a disease or disorder (i.e. causing at least one of the clinical symptoms of the disease not to develop in a subject that may be exposed to a disease-causing agent, or predisposed to the disease in advance of disease onset.

[0071] The term ‘prophylaxis’ is related to ‘prevention’, and refers to a measure or procedure the purpose of which is to prevent, rather than to treat or cure a disease. Non-limiting examples of prophylactic measures may include the administration of vaccines; the administration of low molecular weight heparin to hospital patients at risk for thrombosis due, for example, to immobilization; and the administration of an anti- malarial agent such as chloroquine, in advance of a visit to a geographical region where malaria is endemic or the risk of contracting malaria is high.

[0072] ‘Treating’ or ‘treatment’ of any disease or disorder refers, in one embodiment, to ameliorating the disease or disorder (z. e. arresting the disease or reducing the manifestation, extent or severity of at least one of the clinical symptoms thereof). In another embodiment ‘treating’ or ‘treatment’ refers to ameliorating at least one physical parameter, which may not be discernible by the subject. In yet another embodiment, ‘treating’ or ‘treatment’ refers to modulating the disease or disorder, either physically, (e.g. stabilization of a discernible symptom), physiologically, (e.g. stabilization of a physical parameter), or both. In a further embodiment, “treating” or “treatment” relates to slowing the progression of the disease.

[0073] As used herein the term ‘inflammatory disease(s)’ refers to the group of conditions including, rheumatoid arthritis, osteoarthritis, juvenile idiopathic arthritis, psoriasis, psoriatic arthritis, ankylosing spondylitis, allergic airway disease (e.g. asthma, rhinitis), chronic obstructive pulmonary disease (COPD), inflammatory bowel diseases (e.g. Crohn’s disease, ulcerative colitis), endotoxin-driven disease states (e.g. complications after bypass surgery, acute kidney injury (AKI), Alport syndrome or chronic endotoxin states contributing to e.g. chronic cardiac failure), and related diseases involving cartilage, such as that of the joints. Particularly the term refers to rheumatoid arthritis, psoriasis, psoriatic arthritis, ankylosing spondylitis and inflammatory bowel diseases. More particularly the term refers to rheumatoid arthritis and inflammatory bowel diseases.

[0074] As used herein the term ‘autoinflammatory diseases(s)’ refers to the group of diseases including cryopyrin-associated periodic syndromes (CAPS), familial Mediterranean fever (FMF) and tumor necrosis factor receptor-associated periodic syndrome (TRAPS), Behcet’s disease, systemic -onset juvenile idiopathic arthritis (SJIA), or Still’s disease.

[0075] As used herein the term ‘autoimmune disease(s)’ refers to the group of diseases including obstructive airways disease, including conditions such as COPD, asthma (e.g. intrinsic asthma, extrinsic asthma, dust asthma, infantile asthma) particularly chronic or inveterate asthma (for example late asthma and airway hyperresponsiveness), bronchitis, including bronchial asthma, systemic lupus erythematosus (SLE), cutaneous lupus erythematosus, lupus nephritis, dermatomyositis, autoimmune liver diseases (e.g. autoimmune hepatitis, primary sclerosing cholangitis, and primary biliary cirrhosis), Sjogren’s syndrome, multiple sclerosis, psoriasis, dry eye disease, type I diabetes mellitus and complications associated therewith, atopic eczema (atopic dermatitis), thyroiditis (Hashimoto’s and autoimmune thyroiditis), pemphigus vulgaris, contact dermatitis and further eczematous dermatitis, inflammatory bowel disease (e.g. Crohn's disease and ulcerative colitis), atherosclerosis, type I diabetic kidney disease, anti-GBM (Goodpasture’s) disease, IgA nephropathy (Berger’s disease), focal segmental glomerulosclerosis, or thin basement membrane disease and amyotrophic lateral sclerosis. Particularly, the term refers to COPD, asthma, systemic lupus erythematosus (SLE), cutaneous lupus erythematosus, lupus nephritis, Sjogren’s syndrome, psoriasis, dry eye disease, and inflammatory bowel disease.

[0076] As used herein the term ‘proliferative disease(s)’ refers to conditions such as cancer (e.g. uterine leiomyosarcoma or prostate cancer), myeloproliferative disorders (e.g. polycythemia vera, essential thrombocytosis and myelofibrosis), leukemia (e.g. acute myeloid leukemia, acute and chronic lymphoblastic leukemia), multiple myeloma, psoriasis, restenosis, scleroderma or fibrosis. In particular, the term refers to psoriasis, scleroderma and fibrosis.

[0077] As used herein, the term ‘cancer’ refers to a malignant or benign growth of cells in skin or in body organs, for example but without limitation, breast, prostate, lung, kidney, pancreas, stomach or bowel. A cancer tends to infiltrate into adjacent tissue and spread (metastasize) to distant organs, for example to bone, liver, lung or the brain. As used herein the term cancer includes both metastatic tumor cell types (such as but not limited to, melanoma, lymphoma, leukemia, fibrosarcoma, rhabdomyosarcoma, and mastocytoma) and types of tissue carcinoma (such as but not limited to, colorectal cancer, prostate cancer, small cell lung cancer and non-small cell lung cancer, breast cancer, pancreatic cancer, bladder cancer, renal cancer, gastric cancer, glioblastoma, primary liver cancer, ovarian cancer, and uterine leiomyosarcoma). In particular, the term ‘cancer’ refers to acute lymphoblastic leukemia, acute myeloid leukemia, adrenocortical carcinoma, anal cancer, appendix cancer, astrocytomas, atypical teratoid / rhabdoid tumor, basal cell carcinoma, bile duct cancer, bladder cancer, bone cancer (osteosarcoma and malignant fibrous histiocytoma), brain stem glioma, brain tumors, brain and spinal cord tumors, breast cancer, bronchial tumors, Burkitt lymphoma, cervical cancer, chronic lymphocytic leukemia, chronic myelogenous leukemia, colon cancer, colorectal cancer, craniopharyngioma, cutaneous T-cell lymphoma, embryonal tumors, endometrial cancer, ependymoblastoma, ependymoma, esophageal cancer, Ewing sarcoma family of tumors, eye cancer, retinoblastoma, gallbladder cancer, gastric (stomach) cancer, gastrointestinal carcinoid tumor, gastrointestinal stromal tumor (GIST), gastrointestinal stromal cell tumor, germ cell tumor, glioma, hairy cell leukemia, head and neck cancer, hepatocellular (liver) cancer, hypopharyngeal cancer, intraocular melanoma, islet cell tumors (endocrine pancreas), Kaposi’s sarcoma, kidney cancer, Langerhans cellhistiocytosis, laryngeal cancer, leukemia, hairy cell leukemia, liver cancer, non-small cell lung cancer, small cell lung cancer, cutaneous T-cell lymphoma, Hodgkin lymphoma, non-Hodgkin lymphoma, lymphoma, Waldenstrom macroglobulinemia, medulloblastoma, medulloepithelioma, melanoma, mesothelioma, mouth cancer, myeloid leukemia, multiple myeloma, nasopharyngeal cancer, neuroblastoma, oral cancer, oropharyngeal cancer, osteosarcoma, malignant fibrous histiocytoma of bone, ovarian cancer, ovarian epithelial cancer, ovarian germ cell tumor, ovarian low malignant potential tumor, pancreatic cancer, papillomatosis, parathyroid cancer, penile cancer, pharyngeal cancer, pineal parenchymal tumors of intermediate differentiation, pineoblastoma and supratentorial primitive neuroectodermal tumors, pituitary tumor, plasma cell neoplasm / multiple myeloma, pleuropulmonary blastoma, primary central nervous system lymphoma, prostate cancer, rectal cancer, renal cell (kidney) cancer, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, sarcoma, Ewing sarcoma family of tumors, sarcoma, Sezary syndrome, skin cancer, small cell lung cancer, small intestine cancer, soft tissue sarcoma, squamous cell carcinoma, stomach (gastric) cancer, supratentorial primitive neuroectodermal tumors, testicular cancer, throat cancer, thymoma and thymic carcinoma, thyroid cancer, urethral cancer, uterine cancer, uterine sarcoma, vaginal cancer, vulvar cancer, and Wilms tumor.

[0078] As used herein the term ‘leukemia’ refers to neoplastic diseases of the blood and blood forming organs. Such diseases can cause bone marrow and immune system dysfunction, which renders the host highly susceptible to infection and bleeding. In particular the term leukemia refers to acute myeloid leukemia (AML), and acute lymphoblastic leukemia (ALL) and chronic lymphoblastic leukemia (CLL).

[0079] As used herein the term ‘fibrotic disease(s)’ refers to diseases characterized by excessive scarring due to excessive production, deposition, and contraction of extracellular matrix, and that are associated with the abnormal accumulation of cells and / or fibronectin and / or collagen and / or increased fibroblast recruitment and include but are not limited to fibrosis of individual organs or tissues such as the heart, kidney, liver, joints, lung, pleural tissue, peritoneal tissue, skin, cornea, retina, musculoskeletal and digestive tract. In particular, the term fibrotic diseases refers to idiopathic pulmonary fibrosis (IPE); cystic fibrosis, other diffuse parenchymal lung diseases of different etiologies including iatrogenic drug-induced fibrosis, occupational and / or environmental induced fibrosis, granulomatous diseases (sarcoidosis, hypersensitivity pneumonia), collagen vascular disease, alveolar proteinosis, Langerhans cell granulomatosis, lymphangioleiomyomatosis, inherited diseases (Hermansky-Pudlak syndrome, tuberous sclerosis, neurofibromatosis, metabolic storage diseases, familial interstitial lung disease); radiation induced fibrosis; chronic obstructive pulmonary disease (COPD); scleroderma; bleomycin induced pulmonary fibrosis; chronic asthma; silicosis; asbestos induced pulmonary fibrosis; acute respiratory distress syndrome (ARDS); kidney fibrosis, autosomal dominant polycystic kidney disease, tubulointerstitium fibrosis; glomerular nephritis; diabetic nephropathy, focal segmental glomerular sclerosis; IgA nephropathy; hypertension; Alport syndrome; gut fibrosis; liver fibrosis; cirrhosis; alcohol induced liver fibrosis; toxic / drug induced liver fibrosis; hemochromatosis; nonalcoholic steatohepatitis (NASH); biliary duct injury; primary biliary cirrhosis; infection induced liver fibrosis; viral induced liver fibrosis; and autoimmune hepatitis; comeal scarring; hypertrophic scarring; Dupuytren’s disease, keloids,cutaneous fibrosis; cutaneous scleroderma; systemic sclerosis, spinal cord injury / fibrosis; myelofibrosis; Duchenne muscular dystrophy (DMD) associated musculoskeletal fibrosis, vascular restenosis; atherosclerosis; arteriosclerosis; Wegener's granulomatosis; Peyronie's disease, or chronic lymphocytic. More particularly, the term ‘fibrotic diseases’ refers to idiopathic pulmonary fibrosis (IPF), radiation induced fibrosis, nonalcoholic steatohepatitis (NASH), scleroderma, bleomycin induced pulmonary fibrosis, cutaneous scleroderma, kidney fibrosis and systemic sclerosis.

[0080] As used herein the term ‘transplant rejection’ refers to the acute or chronic rejection of cells, tissue or solid organ allo- or xenografts of e.g. pancreatic islets, stem cells, bone marrow, skin, muscle, comeal tissue, neuronal tissue, heart, lung, combined heart-lung, kidney, liver, bowel, pancreas, trachea or esophagus, or graft-versus-host disease (GvHD). More particularly the term refers to graft-versus-host disease (GvHD).

[0081] As used herein the term ‘diseases involving impairment of cartilage turnover’ includes conditions such as osteoarthritis, psoriatic arthritis, juvenile rheumatoid arthritis, gouty arthritis, septic or infectious arthritis, reactive arthritis, reflex sympathetic dystrophy, algodystrophy, Tietze syndrome or costal chondritis, fibromyalgia, osteochondritis, neurogenic or neuropathic arthritis, arthropathy, endemic forms of arthritis like osteoarthritis deformans endemica, Mseleni joint disease and Handigodu disease; degeneration resulting from fibromyalgia, systemic lupus erythematosus, scleroderma and ankylosing spondylitis.

[0082] As used herein the term ‘congenital cartilage malformation(s)’ includes conditions such as hereditary chondrolysis, chondrodysplasias and pseudo chondrodysplasias, in particular, but without limitation, microtia, anotia, metaphyseal chondrodysplasia, and related disorders.

[0083] As used herein the term ‘diseases involving impairment of bone turnover’ includes conditions such as osteoporosis (including postmenopausal osteoporosis, male osteoporosis, glucocorticosteroid induced osteoporosis and juvenile osteoporosis), osteoporosis caused through neoplastic bone marrow disorders, osteopenia, hormone deficiency (vitamin D deficiency, male and female hypogonadism), hormone excess (hyperprolactinemia, excess glucocorticoid, hyperthyroidism, hyperparathyroidism), Paget's disease, osteoarthritis, renal bone disease, osteogenesis imperfecta, hypophosphatasia and chronic kidney disease mineral bone disorders (CKD-MBD).

[0084] As used herein the term ‘disease(s) associated with hypersecretion of IL-6’ includes conditions such as Castleman’s disease, multiple myeloma, psoriasis, Kaposi’s sarcoma and / or mesangial proliferative glomerulonephritis.

[0085] As used herein the term ‘disease(s) associated with hypersecretion of TNFa, interferons, IL-12, IL- 17 and / or IL-23 includes conditions such as systemic and cutaneous lupus erythematosus, lupus nephritis, dermatomyositis, Sjogren’s syndrome, psoriasis, rheumatoid arthritis, psoriatic arthritis, multiple sclerosis, Down syndrome, ulcerative colitis, spondyloarthropathies (particularly ankylosing spondylitis) and / or Crohn’s disease.

[0086] As used herein, the term ‘respiratory disease(s)’ refers to diseases affecting the organs that are involved in breathing, such as the nose, throat, larynx, eustachian tubes, trachea, bronchi, lungs, relatedmuscles (e.g., diaphragm and intercostals), and nerves. In particular, examples of respiratory diseases include asthma, adult respiratory distress syndrome and allergic (extrinsic) asthma, non-allergic (intrinsic) asthma, acute severe asthma, chronic asthma, clinical asthma, nocturnal asthma, allergen-induced asthma, aspirin-sensitive asthma, exercise-induced asthma, isocapnic hyperventilation, child onset asthma, adultonset asthma, cough-variant asthma, occupational asthma, steroid-resistant asthma, seasonal asthma, seasonal allergic rhinitis, perennial allergic rhinitis, chronic obstructive pulmonary disease (COPD), including chronic bronchitis or emphysema, pulmonary hypertension, interstitial lung fibrosis and / or airway inflammation, cystic fibrosis, and hypoxia.

[0087] As used herein the term ‘endocrine diseases’ refers to disorders of the endocrine system and hormonal secretion. In particular, the term refers to hypothyroidism, congenital adrenal hyperplasia, diseases of the parathyroid gland, diabetes mellitus, diseases of the adrenal glands (including Cushing’s syndrome and Addison’s disease), and ovarian dysfunction (including polycystic ovary syndrome).

[0088] As used herein the term ‘metabolic diseases’ refers to disorders that disrupt normal metabolism, the process of converting food to energy on a cellular level. Metabolic diseases affect the ability to perform critical biochemical reactions that involve the processing or transport of proteins (amino acids), carbohydrates (sugars and starches), or lipids (fatty acids). In particular, the term refers to cystic fibrosis, phenylketonuria (PKU), diabetes, hyperlipidemia, gout, type II diabetic kidney disease and rickets. In more particular, the term refers to obesity and / or type II diabetes.

[0089] As used herein the term ‘cardiovascular disease(s)’ refers to diseases affecting the heart or blood vessels or both. In particular, cardiovascular disease includes arrhythmia (atrial or ventricular or both); atherosclerosis and its sequelae; angina; cardiac rhythm disturbances; myocardial ischemia; myocardial infarction; cardiac or vascular aneurysm; vasculitis (e.g., giant cell arteritis (GCA), retinal vasculitis, rheumatoid vasculitis), stroke; peripheral obstructive arteriopathy of a limb, an organ, or a tissue; reperfusion injury following ischemia of the brain, heart, kidney or other organ or tissue; endotoxic, surgical, or traumatic shock; hypertension, valvular heart disease, heart failure, abnormal blood pressure; vasoconstriction (including that associated with migraines); vascular abnormality, inflammation, or insufficiency limited to a single organ or tissue. More particularly, cardiovascular disease refers to atherosclerosis or giant cell arteritis.

[0090] As used herein the term ‘dermatological disease(s)’ refers to a skin disorder. In particular, dermatological disorders include proliferative or inflammatory disorders of the skin such as atopic dermatitis, bullous disorders, collagenoses, psoriasis, psoriatic lesions, dermatitis, contact dermatitis, eczema, vitiligo, pruritus, scleroderma, wound healing, scarring, hypertrophic scarring, keloids, Kawasaki disease, rosacea, Sjogren-Larsson syndrome, or urticaria. More particularly, the term dermatological disorders refers to psoriasis, psoriatic lesions, scleroderma, and vitiligo.

[0091] As used herein the term ‘abnormal angiogenesis associated disease(s)’ refers to diseases caused by the dysregulation of the processes mediating angiogenesis. In particular, abnormal angiogenesis associated disease refers to atherosclerosis, hypertension, tumor growth, inflammation, rheumatoid arthritis, wet -form macular degeneration, choroidal neovascularization, retinal neovascularization, and diabetic retinopathy.

[0092] ‘Compound(s) of the invention’, and equivalent expressions, are meant to embrace compounds of the Formula(e) as herein described, which expression includes the pharmaceutically acceptable salts, and the solvates, e.g. hydrates, and the solvates of the pharmaceutically acceptable salts where the context so permits. Similarly, reference to intermediates, whether or not they themselves are claimed, is meant to embrace their salts, and solvates, where the context so permits .

[0093] When ranges are referred to herein, for example but without limitation, Ci-s alkyl, the citation of a range should be considered a representation of each member of said range.

[0094] Other derivatives of the compounds of this invention have activity in both their acid and acid derivative forms, but in the acid sensitive form often offers advantages of solubility, tissue compatibility, or delayed release in the mammalian organism (Bundgaard 1985). Prodrugs include acid derivatives well known to practitioners of the art, such as, for example, esters prepared by reaction of the parent acid with a suitable alcohol, or amides prepared by reaction of the parent acid compound with a substituted or unsubstituted amine, or acid anhydrides, or mixed anhydrides. Simple aliphatic or aromatic esters, amides and anhydrides derived from acidic groups pendant on the compounds of this invention are particularly useful prodrugs. In some cases it is desirable to prepare double ester type prodrugs such as (acyloxy)alkyl esters or ((alkoxycarbonyl)oxy)alkylesters. Particular such prodrugs are the Ci-s alkyl, C2-8 alkenyl, Ce-io optionally substituted aryl, and (C6-io aryl)-(Ci-4 alkyl) esters of the compounds of the invention.

[0095] The present disclosure includes all isotopic forms of the compounds of the invention provided herein, whether in a form (i) wherein all atoms of a given atomic number have a mass number (or mixture of mass numbers) which predominates in nature (referred to herein as the “natural isotopic form”) or (ii) wherein one or more atoms are replaced by atoms having the same atomic number, but a mass number different from the mass number of atoms which predominates in nature (referred to herein as an “unnatural variant isotopic form”). It is understood that an atom may naturally exists as a mixture of mass numbers. The term “unnatural variant isotopic form” also includes embodiments in which the proportion of an atom of given atomic number having a mass number found less commonly in nature (referred to herein as an “uncommon isotope”) has been increased relative to that which is naturally occurring e.g. to the level of >20%, >50%, >75%, >90%, >95% or> 99% by number of the atoms of that atomic number (the latter embodiment referred to as an "isotopically enriched variant form"). The term “unnatural variant isotopic form” also includes embodiments in which the proportion of an uncommon isotope has been reduced relative to that which is naturally occurring. Isotopic forms may include radioactive forms (i.e. they incorporate radioisotopes) and non-radioactive forms. Radioactive forms will typically be isotopically enriched variant forms.

[0096] An unnatural variant isotopic form of a compound may thus contain one or more artificial or uncommon isotopes such as deuterium (2H or D), carbon-11 (nC), carbon-13 (13C), carbon-14 (14C), nitrogen-13 (13N), nitrogen-15 (15N), oxygen-15 (15O), oxygen-17 (17O), oxygen-18 (18O), phosphorus-32 (32P), sulfur-35 (35S), chlorine-36 (36C1), chlorine-37 (37C1), fluorine-18 (18F) iodine-123 (123I), iodine-125 (125I) in one or more atoms or may contain an increased proportion of said isotopes as compared with the proportion that predominates in nature in one or more atoms.

[0097] Unnatural variant isotopic forms comprising radioisotopes may, for example, be used for drug and / or substrate tissue distribution studies. The radioactive isotopes tritium, i.e.3H, and carbon- 14, i.e.14C, are particularly useful for this purpose in view of their ease of incorporation and ready means of detection. Unnatural variant isotopic forms which incorporate deuterium i.e.2H or D 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. Further, unnatural variant isotopic forms may be prepared which incorporate positron emitting isotopes, such asnC,18F,15O and13N, and would be useful in Positron Emission Tomography (PET) studies for examining substrate receptor occupancy.

[0098] It is also to be understood that compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or the arrangement of their atoms in space are termed ‘isomers’. Isomers that differ in the arrangement of their atoms in space are termed ‘stereoisomers’.

[0099] Stereoisomers that are not mirror images of one another are termed ‘diastereomers’ and those that are non-superimposable mirror images of each other are termed ‘enantiomers’ . When a compound has an asymmetric center, for example, it is bonded to four different groups, a pair of enantiomers is possible. An enantiomer can be characterized by the absolute configuration of its asymmetric center and is described by the R- and S-sequencing rules of Cahn, Ingold and Prelog, or by the manner in which the molecule rotates the plane of polarized light and designated as dextrorotatory or levorotatory (i.e. as (+) or (-)-isomers respectively). A chiral compound can exist as either individual enantiomer or as a mixture thereof. A mixture containing equal proportions of the enantiomers is called a ‘racemic mixture’.

[0100] ‘ Tautomers’ refer to compounds that are interchangeable forms of a particular compound structure, and that vary in the displacement of hydrogen atoms and electrons. Thus, two structures may be in equilibrium through the movement of 7i electrons and an atom (usually H). For example, enols and ketones are tautomers because they are rapidly interconverted by treatment with either acid or base. Another example of tautomerism is the aci- and nitro- forms of phenylnitromethane that are likewise formed by treatment with acid or base.

[0101] Tautomeric forms may be relevant to the attainment of the optimal chemical reactivity and biological activity of a compound of interest.

[0102] The compounds of the invention may possess one or more asymmetric centers; such compounds can therefore be produced as individual (R)- or (S)- stereoisomers or as mixtures thereof.

[0103] Unless indicated otherwise, the description or naming of a particular compound in the specification and claims is intended to include both individual enantiomers and mixtures, racemic or otherwise, thereof. The methods for the determination of stereochemistry and the separation of stereoisomers are well-known in the art.THE INVENTION

[0104] The present invention is based on the identification of novel compounds, and their use in the prophylaxis and / or treatment of inflammatory diseases, autoinflammatory diseases, autoimmune diseases,proliferative diseases, fibrotic diseases, transplant rejection, diseases involving impairment of cartilage turnover, congenital cartilage malformation, diseases involving impairment of bone turnover, diseases associated with hypersecretion of IL-6, diseases associated with hypersecretion of TNFa, interferons, IL- 12, IL- 17 and / or IL-23, respiratory diseases, endocrine diseases, metabolic diseases, cardiovascular diseases, dermatological diseases, and / or abnormal angiogenesis associated diseases. In particular, the compounds of the invention may be SIK inhibitors, and more particularly SIK2 and / or SIK3 inhibitors.

[0105] The present invention also provides methods for the production of these compounds, pharmaceutical compositions comprising these compounds and methods for the prophylaxis and / or treatment of inflammatory diseases, autoinflammatory diseases, autoimmune diseases, proliferative diseases, fibrotic diseases, transplant rejection, diseases involving impairment of cartilage turnover, congenital cartilage malformation, diseases involving impairment of bone turnover, diseases associated with hypersecretion of IL-6, diseases associated with hypersecretion of TNFa, interferons, IL-12, IL-17 and / or IL-23, respiratory diseases, endocrine diseases, metabolic diseases, cardiovascular diseases, dermatological diseases, and / or abnormal angiogenesis associated diseases by administering the compounds of the invention.

[0106] Accordingly, in a first aspect of the invention, the compounds of the invention are provided having a Formula I:wherein one of Xi and X2is N and the other is C;Y is CH orN;Provided that- when Xi is C, X2is N, and Y is N, then R2is not -NR3aR3\ or- -Li R1is not -OH, -Me, -OMe, -CH2CH2OH, or -NMe2; absent,C1-6 alkylenyl,LIA,-C1-6 alkylenyl-LiA-, or-LIA-CI-6 alkylenyl-;LIA is -O-, -NRx1-, -C(=O)-, -C(=O)O-, -C(=O)NRx1-, -NRxlC(=O)-, -NRxlC(=O)O-, S(=O), S(=O)2, - NHS(=O)2NRX1-, -S(=O)2NRX1-, -NRX1S(=O)2-, -P(=O) RX1;Rxlis H, or Ci-6 alkyl optionally substituted with one or more independently selected halo;R1isCi-6 alkyl optionally substituted with one or more groups independently selected from =0 and R7,C3-7 cycloalkyl optionally substituted with one or more groups independently selected from =0 and R7, polycyclic fused, spiro or bridged C4-10 cycloalkyl optionally substituted with one or more groups independently selected from =0 and R7,4-7 membered heterocycloalkyl comprising one or more heteroatoms independently selected from O, S, N, P, and B, which heterocycloalkyl is optionally substituted with one or more groups selected from =0 and R7, polycyclic fused, spiro or bridged 6-10 membered heterocycloalkyl comprising one or more heteroatoms independently selected from O, S, N, P, and B, which heterocycloalkyl is optionally substituted with one or more groups selected from =0 and R7,Phenyl optionally substituted with one or more groups independently selected from R7,5-7 membered heteroaryl comprising one or more heteroatoms independently selected from O, S, and N, which heteroaryl is optionally substituted with one or more groups independently selected from R7, and polycyclic fused 8-10 membered heteroaryl comprising one or more heteroatoms independently selected from O, S, and N, which heteroaryl is optionally substituted with one or more groups independently selected from R7;Each R7is independently selected from halo,- -CN,-L2A-R7A, and-C1-6 alkylenyl-L7A-R7A;L7Ais absent, -O-, -NRx2-, -C(=O)-, -C(=O)O-, -C(=0)NRx2-, -NRx2C(=0)-, -NRx2C(=0)0-, -S(=O), -S(=O)2, -NHS(=O)2NRX2-, -S(=O)2NRX2-, -NRX2S(=O)2-, or -P(=O) Rx2;Rx2is H, or Ci-6 alkyl optionally substituted with one or more independently selected halo;R7Ais- HCi-4 alkyl optionally substituted with one or more independently selected =0, halo, CN, or OH, C3-7 cycloalkyl optionally substituted with one or more groups independently selected from =0, halo, CN, or OH, or4-7 membered heterocycloalkyl comprising one or more heteroatoms independently selected from O, S, N, P, and B, which heterocycloalkyl is optionally substituted with one or more groups selected from =0, halo, CN, or OH;R2is- H,C1-4 alkyl optionally substituted with one or more independently selected halo, or- -NR2aR2b;Each R2aand R2bis independently selected from H, C1-4 alkyl optionally substituted with one or more independently selected halo, or phenyl;Each R3is independently selected from halo, CN, and C1-4 alkyl optionally substituted with one or more independently selected halo;The subscript n is 0, 1, 2 or 3;Cy is a 8-10 membered bicyclic heteroaryl comprising one or more heteroatoms independently selected from N, O, and S, which heteroaryl is optionally substituted with one or more independently selected R4;Each R4is independently selected from: halo, CN, and -L4A-R4A; orTwo R4groups together with the atoms to which they are attached may form together a fused 4-7 membered heterocycloalkyl comprising one or more heteroatoms independently selected from O, S, N, P, and B, which heterocycloalkyl is optionally substituted with one or more groups selected from =0, halo, CN, or OH;L4Ais absent, -O-, -NRx4-, -C(=O)-, -C(=O)O-, -C(=0)NRx4-, -NRx4C(=0)-, -NRx4C(=0)0-, -S(=O), =S(=O)2, -NHS(=O)2NRX4-, -S(=O)2NRX4-, -NRX4S(=O)2-, or -P(=O)Rx4;Rx4is H, or Ci-6 alkyl optionally substituted with one or more independently selected halo;Each R4Ais independently selected from:- H,Ci-6 alkyl optionally substituted with one or more groups independently selected from =0 and R5,C3-7 cycloalkyl optionally substituted with one or more groups independently selected from =0 and R5, polycyclic fused, spiro or bridged C4-10 cycloalkyl optionally substituted with one or more groups independently selected from =0 and R5,4-7 membered heterocycloalkyl comprising one or more heteroatoms independently selected from O, S, N, P, and B, which heterocycloalkyl is optionally substituted with one or more groups selected from =0 and R5, polycyclic fused, spiro or bridged 6-10 membered heterocycloalkyl comprising one or more heteroatoms independently selected from O, S, N, P, and B, which heterocycloalkyl is optionally substituted with one or more groups selected from =0 and R5,Phenyl optionally substituted with one or more groups independently selected from R5, and5-7 membered heteroaryl comprising one or more heteroatoms independently selected from O, S, and N, which heteroaryl is optionally substituted with one or more groups independently selected from R5;Each R5is independently selected from: halo,CN, and- -L5A-R5A;L5Ais absent, -O-, -NRx5-, -C(=O)-, -C(=O)O-, -C(=0)NRx5-, -NRx5C(=0)-, -NRx5C(=0)0-, -S(=O), -S(=O)2, -NHS(=O)2NRX5-, -S(=O)2NRX5-, -NRX5S(=O)2-, or -P(=O)Rx5;Rx5is H, or C1-6 alkyl optionally substituted with one or more independently selected halo;Each R5Ais independently selected from:- H,C1-6 alkyl optionally substituted with one or more groups independently selected from =0 and R6, C3-7 cycloalkyl optionally substituted with one or more groups independently selected from =0 and R6,4-7 membered heterocycloalkyl comprising one or more heteroatoms independently selected from O, S, N, P, and B, which heterocycloalkyl is optionally substituted with one or more groups selected from =0 and R6,Phenyl optionally substituted with one or more groups independently selected from R6, and5-7 membered heteroaryl comprising one or more heteroatoms independently selected from O, S, and N, which heteroaryl is optionally substituted with one or more groups independently selected from R6;Each R6is independently selected from: halo,- CN,- -OH,Ci-6 alkyl optionally substituted with one or more independently selected halo, andCi-6 alkoxy optionally substituted with one or more halo.

[0107] In another aspect of the invention, the compounds of the invention are provided having a Formula I wherein one of Xi and X2is N and the other is C;Y is CH orN;Provided that- when Xi is C, X2is N, and Y is N, then R2is not -NR3aR3\ or- -Li R1is not -OH, -Me, -OMe, -CH2CH2OH, or -NMe2;Li is absent,C1-6 alkylenyl,LIA,-C1-6 alkylenyl-LiA-, or-LIA-CI-6 alkylenyl-;LIA is -O-, -NRx1-, -C(=O)-, -C(=O)O-, -C(=O)NRx1-, -NRxlC(=O)-, -NRxlC(=O)O-, S(=O), S(=O)2, - NHS(=O)2NRX1-, -S(=O)2NRX1-, -NRX1S(=O)2-, -P(=O)RX1;Rxlis H, or C1-6 alkyl optionally substituted with one or more independently selected halo;R1isC1-6 alkyl optionally substituted with one or more groups independently selected from =0 and R7,C3-7 cycloalkyl optionally substituted with one or more groups independently selected from =0 and R7, polycyclic fused, spiro or bridged C4-10 cycloalkyl optionally substituted with one or more groups independently selected from =0 and R7,4-7 membered heterocycloalkyl comprising one or more heteroatoms independently selected from O, S, N, P, and B, which heterocycloalkyl is optionally substituted with one or more groups selected from =0 and R7, polycyclic fused, spiro or bridged 6-10 membered heterocycloalkyl comprising one or more heteroatoms independently selected from O, S, N, P, and B, which heterocycloalkyl is optionally substituted with one or more groups selected from =0 and R7,Phenyl optionally substituted with one or more groups independently selected from R7,5-7 membered heteroaryl comprising one or more heteroatoms independently selected from O, S, and N, which heteroaryl is optionally substituted with one or more groups independently selected from R7, and polycyclic fused 8-10 membered heteroaryl comprising one or more heteroatoms independently selected from O, S, and N, which heteroaryl is optionally substituted with one or more groups independently selected from R7;Each R7is independently selected from halo,- -CN,-LVA-R7A, and-Ci-6 alkylenyl-L7A-R7A;L7Ais absent, -O-, -NRx2-, -C(=O)-, -C(=O)O-, -C(=O)NRx2-, -NRx2C(=O)-, -NRx2C(=O)O-, -S(=O), -S(=O)2, -NHS(=O)2NRX2-, -S(=O)2NRX2-, -NRX2S(=O)2-, or -P(=O) Rx2;Rx2is H, or Ci-6 alkyl optionally substituted with one or more independently selected halo;R7Ais- HCi-4 alkyl optionally substituted with one or more independently selected =0, halo, CN, or OH,C3-7 cycloalkyl optionally substituted with one or more groups independently selected from =0, halo, CN, or OH, or4-7 membered heterocycloalkyl comprising one or more heteroatoms independently selected from O, S, N, P, and B, which heterocycloalkyl is optionally substituted with one or more groups selected from =0, halo, CN, or OH;R2isH,C1-4 alkyl optionally substituted with one or more independently selected halo, or -NR2aR2b;Each R2aand R2bis independently selected from H, Ci-4 alkyl optionally substituted with one or more independently selected halo, or phenyl;Each R3is independently selected from halo, CN, and Ci-4 alkyl optionally substituted with one or more independently selected halo;The subscript n is 0, 1, 2 or 3;Cy is a 8-10 membered bicyclic heteroaryl comprising one or more heteroatoms independently selected from N, O, and S, which heteroaryl is optionally substituted with one or more independently selected R4;Each R4is independently selected from: halo, CN, and- -L4A-R4A;L4Ais absent, -O-, -NRx4-, -C(=O)-, -C(=O)O-, -C(=O)NRx4-, -NRx4C(=O)-, -NRx4C(=O)O-, -S(=O), =S(=O)2, -NHS(=O)2NRX4-, -S(=O)2NRX4-, -NRX4S(=O)2-, or -P(=O)Rx4;Rx4is H, or Ci-6 alkyl optionally substituted with one or more independently selected halo;Each R4Ais independently selected from:- H,Ci-6 alkyl optionally substituted with one or more groups independently selected from =0 and R5, C3-7 cycloalkyl optionally substituted with one or more groups independently selected from =0 andR5, polycyclic fused, spiro or bridged C4-10 cycloalkyl optionally substituted with one or more groups independently selected from =0 and R5,4-7 membered heterocycloalkyl comprising one or more heteroatoms independently selected from O, S, N, P, and B, which heterocycloalkyl is optionally substituted with one or more groups selected from =0 and R5, polycyclic fused, spiro or bridged 6-10 membered heterocycloalkyl comprising one or more heteroatoms independently selected from O, S, N, P, and B, which heterocycloalkyl is optionally substituted with one or more groups selected from =0 and R5,Phenyl optionally substituted with one or more groups independently selected from R5, and5-7 membered heteroaryl comprising one or more heteroatoms independently selected from O, S, and N, which heteroaryl is optionally substituted with one or more groups independently selected from R5;Each R5is independently selected from: halo,CN, and- -L5A-R5A;L5Ais absent, -O-, -NRx5-, -C(=O)-, -C(=O)O-, -C(=O)NRx5-, -NRx5C(=O)-, -NRx5C(=O)O-, -S(=O), -S(=O)2, -NHS(=O)2NRX5-, -S(=O)2NRX5-, -NRX5S(=O)2-, or -P(=O)Rx5;Rx5is H, or Ci-6 alkyl optionally substituted with one or more independently selected halo;Each R5Ais independently selected from:- H,Ci-6 alkyl optionally substituted with one or more groups independently selected from =0 and R6,C3-7 cycloalkyl optionally substituted with one or more groups independently selected from =0 and R6,4-7 membered heterocycloalkyl comprising one or more heteroatoms independently selected from O, S, N, P, and B, which heterocycloalkyl is optionally substituted with one or more groups selected from =0 and R6,Phenyl optionally substituted with one or more groups independently selected from R6, and5-7 membered heteroaryl comprising one or more heteroatoms independently selected from O, S, and N, which heteroaryl is optionally substituted with one or more groups independently selected from R6;Each R6is independently selected from: halo,- CN,- -OH,C1-6 alkyl optionally substituted with one or more independently selected halo, andC1-6 alkoxy optionally substituted with one or more halo .

[0108] In one embodiment, the compound of the invention is according to Formula I, wherein the subscript n is 1, 2, or 3. In a particular embodiment, the subscript n is 1 or 2. In a most particular embodiment, the subscript n is i.

[0109] In one embodiment, the compound of the invention is according to Formula I, wherein each R3is independently selected from F, Cl, CN, -CH3, and -CF3.

[0110] In one embodiment, the compound of the invention is according to Formula I, wherein the subscript n is 0.[OlH] In one embodiment, the compound of the invention is according to Formula II:wherein R1, L1, R2, Y, Xi, X2 and Cy are as defined for Formula I.

[0112] In one embodiment, the compound of the invention is according to Formula I or II, wherein Y is CR3. In a particular embodiment, R3is selected from F, Cl, CN, -CH3, and -CF3.

[0113] In one embodiment, the compound of the invention is according to Formula I or II, wherein Y is CH.

[0114] In one embodiment, the compound of the invention is according to Formula I or II, wherein Y is N.

[0115] In one embodiment, the compound of the invention is according to Formula Illa, Illb, IIIc, Illd, Ille or Illf:wherein R1, L1, R2, R3, and Cy are as defined for Formula I.

[0116] In one embodiment, the compound of the invention is according to any one of Formulae I -Illf, wherein R2is H.

[0117] In one embodiment, the compound of the invention is according to any one of Formulae I- Illf, wherein R2is C1.4 alkyl optionally substituted with one or more independently selected halo. In a particular embodiment, R2is -CH3, -CH2CH3, or -CF3.

[0118] In one embodiment, the compound of the invention is according to any one of Formulae I- Illf, wherein R2is -NR2aR2b, wherein each R2aand R2bis independently selected from H and C1-4 alkyl optionally substituted with one or more independently selected halo. In one embodiment, R2is -NH2, -NHCH3, - N(CH3)2.

[0119] In one embodiment, the compound of the invention is according to Formulae IVa, IVb, IVc, IVd,IVe or IVf:wherein R1, L1, R2, and Cy are as defined for Formula I,

[0120] In one embodiment, the compound of the invention is according to Formula Ille, Illf, IVe, or IVf, wherein R3is selected from F, Cl, CN, -CH3, and -CF3.

[0121] In one embodiment, the compound of the invention is according to any one of Formula I-IVf, wherein Li is absent, CH2-, -CH2CH2-, LIA, -CH2-LIA-, -CH2CH2-LIA, -LIA-CH2-. or -LIA-CH2CH2-. In particular embodiment, Li is absent, -CH2-, -CH2CH2-, -O-, -NH-, -C(=O)NH-, -S(O)2-, -S(O)2NH-, - NHS(O)2NH-, -NHS(O)2- or -CH2CH2-O-. In a more particular embodiment, Li is absent, -O-, or -NH-.

[0122] In one embodiment, the compound of the invention is according to any one of Formula I-IVf, wherein R1is Ci-6 alkyl optionally substituted with one or more groups independently selected from =0 and R7. In a particular embodiment, R1is Ci-6 alkyl optionally substituted with one, two or three groups independently selected from =0 and R7. In a more particular embodiment, R1is Ci-e alkyl optionally substituted with one or two groups independently selected from =0 and R7. In a particular embodiment, R1is Ci-6 alkyl optionally substituted with one group selected from =0 and R7.

[0123] In one embodiment, the compound of the invention is according to any one of Formula I-IVf, wherein R1is -CH,. -CFFCFfi, -CH(CH3)2, -C(CH3)2CH2CH3, -CH(CH3)CH(CH3)2, each of which is optionally substituted with one or more groups independently selected from =0 and R7. In a particular embodiment, R1is -CH3, -CH2CH3, -CH(CH3)2, -C(CH3)2CH2CH3, -CH(CH3)CH(CH3)2, each of which is optionally substituted with one, two or three groups independently selected from =0 and R7. In a more particular embodiment, R1is -CH3, -CH2CH3, -CH(CH3)2, -C(CH3)2CH2CH3, -CH(CH3)CH(CH3)2, each of which is optionally substituted with one or two groups independently selected from =0 and R7. In a particular embodiment, R1is -CH3, -CH2CH3, -CH(CH3)2, -C(CH3)2CH2CH3, -CH(CH3)CH(CH3)2, each of which is optionally substituted with one group selected from =0 and R7.

[0124] In one embodiment, the compound of the invention is according to any one of Formula I-IVf, wherein R1is C3-7 cycloalkyl optionally substituted with one or more groups independently selected from =0 and R7. In a particular embodiment, R1is C3-7 cycloalkyl optionally substituted with one, two or three groups independently selected from =0 and R7. In a more particular embodiment, R1is C3-7 cycloalkyl optionally substituted with one or two groups independently selected from =0 and R7. In a particular embodiment, R1is C3-7 cycloalkyl optionally substituted with one group selected from =0 and R7.

[0125] In one embodiment, the compound of the invention is according to any one of Formula I-IVf, wherein R1is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, each of which is optionally substituted with one or more groups independently selected from =0 and R7. In a particular embodiment, R1is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, each of which is optionally substituted with one, two or three groups independently selected from =0 and R7. In a more particular embodiment, R1is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, each of which is optionally substituted with one or two groups independently selected from =0 and R7. In a particular embodiment, R1is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, each of which is optionally substituted with one group selected from =0 and R7.

[0126] In one embodiment, the compound of the invention is according to any one of Formula I-IVf, wherein R1is 4-7 membered heterocycloalkyl comprising one or more heteroatoms independently selected from O, S, N, P, and B, which heterocycloalkyl is optionally substituted with one or more groups independently selected from =0 and R7. In a particular embodiment, R1is 4-7 membered heterocycloalkyl comprising one or more heteroatoms independently selected from O, S, N, P, and B, which heterocycloalkyl is optionally substituted with one, two or three independently selected R7. In a more particular embodiment, R1is 4-7 membered heterocycloalkyl comprising one or more heteroatoms independently selected from O, S, N, P, and B, which heterocycloalkyl is optionally substituted with one or two independently selected R7. In a particular embodiment, R1is 4-7 membered heterocycloalkyl comprising one or more heteroatoms independently selected from O, S, N, P, and B, which heterocycloalkyl is optionally substituted with one group selected from =0 and R7.

[0127] In one embodiment, the compound of the invention is according to any one of Formula I-IVf, wherein R1is oxetanyl, tetrahydrofuranyl, pyrrolidinyl, tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, phosphinanyl, or azaphosphinazyl, each of which is optionally substituted with one or more groups independently selected from =0 and R7. In a particular embodiment, R1is oxetanyl, tetrahydrofuranyl, pyrrolidinyl, tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, phosphinanyl, or azaphosphinazyl, each of which is optionally substituted with one, two or three groups independently selected from =0 and R7. In a more particular embodiment, R1is oxetanyl, tetrahydrofuranyl, pyrrolidinyl, tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, phosphinanyl, or azaphosphinazyl, each of which is optionally substituted with one or two groups independently selected from =0 and R7. In a particular embodiment, R1is oxetanyl, tetrahydrofuranyl, pyrrolidinyl, tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, phosphinanyl, or azaphosphinazyl, each of which is optionally substituted with one group selected from =0 and R7.

[0128] In one embodiment, the compound of the invention is according to any one of Formula I-IVf, wherein R1is polycyclic fused, spiro or bridged 6-10 membered heterocycloalkyl comprising one or more heteroatoms independently selected from O, S, N, P, and B, which heterocycloalkyl is optionally substituted with one or more groups selected from =0 and R7. In a particular embodiment, R1is polycyclic fused, spiro or bridged 6-10 membered heterocycloalkyl comprising one or more heteroatoms independently selected from O, S, N, P, and B, which heterocycloalkyl is optionally substituted with one, two or three independently selected R7. In a more particular embodiment, R1is polycyclic fused, spiro or bridged 6-10membered heterocycloalkyl comprising one or more heteroatoms independently selected from O, S, N, P, and B, which heterocycloalkyl is optionally substituted with one or two independently selected R7. In a particular embodiment, R1is polycyclic fused, spiro or bridged 6-10 membered heterocycloalkyl comprising one or more heteroatoms independently selected from O, S, N, P, and B, which heterocycloalkyl is optionally substituted with one group selected from =0 and R7.

[0129] In one embodiment, the compound of the invention is according to any one of Formula I-IVf, wherein R1is oxaspiroheptanyl, diazaspirononanyl, oxazaspirodecanyl, or octahydropyrrolo[3,4- c]pyrrolyl, each of which is optionally substituted with one or more groups independently selected from =0 and R7. In a particular embodiment, R1is oxaspiroheptanyl, diazaspirononanyl, oxazaspirodecanyl, or octahydropyrrolo[3,4-c]pyrrolyl, each of which is optionally substituted with one, two or three groups independently selected from =0 and R7. In a more particular embodiment, R1is oxaspiroheptanyl, diazaspirononanyl, oxazaspirodecanyl, or octahydropyrrolo[3,4-c]pyrrolyl, each of which is optionally substituted with one or two groups independently selected from =0 and R7. In a particular embodiment, R1is oxaspiroheptanyl, diazaspirononanyl, oxazaspirodecanyl, or octahydropyrrolo[3,4-c]pyrrolyl, each of which is optionally substituted with one group selected from =0 and R7.

[0130] In one embodiment, the compound of the invention is according to any one of Formula I-IVf, wherein R1is phenyl optionally substituted with one or more groups independently selected from R7. In a particular embodiment, R1is phenyl optionally substituted with one, two or three independently selected R7. In a more particular embodiment, R1is phenyl optionally substituted with one or two independently selected R7. In a particular embodiment, R1is phenyl optionally substituted with one group selected R7.

[0131] In one embodiment, the compound of the invention is according to any one of Formula I-IVf, wherein R1is 5-7 membered heteroaryl comprising one or more heteroatoms independently selected from O, S, and N, which heteroaryl is optionally substituted with one or more groups independently selected from R7. In a particular embodiment, R1is 5-7 membered heteroaryl comprising one or more heteroatoms independently selected from O, S, and N, which heteroaryl is optionally substituted with one, two or three independently selected R7. In a more particular embodiment, R1is 5-7 membered heteroaryl comprising one or more heteroatoms independently selected from O, S, and N, which heteroaryl is optionally substituted with one or two independently selected R7. In a particular embodiment, R1is 5-7 membered heteroaryl comprising one or more heteroatoms independently selected from O, S, and N, which heteroaryl is optionally substituted with one group selected R7.

[0132] In one embodiment, the compound of the invention is according to any one of Formula I-IVf, wherein R1is furanyl, thienyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, thioxazolyl, pyridinyl, pyrimidinyl, or pyrazinyl, each of which is optionally substituted with one or more groups independently selected from R7. In a particular embodiment, R1is furanyl, thienyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, thioxazolyl, pyridinyl, pyrimidinyl, or pyrazinyl, each of which is optionally substituted with one, two or three independently selected R7. In a more particular embodiment, R1is furanyl, thienyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, thioxazolyl, pyridinyl, pyrimidinyl, or pyrazinyl, each of which is optionally substituted with one or two independently selected R7. In a particular embodiment, R1is furanyl, thienyl,pyrazolyl, imidazolyl, triazolyl, oxazolyl, thioxazolyl, pyridinyl, pyrimidinyl, or pyrazinyl, each of which is optionally substituted with one group selected R7.

[0133] In one embodiment, -Li-R1is:wherein * is the attachment point.

[0134] In one embodiment, the compound of the invention is according to any one of Formula I-IVf, wherein one or more independently selected R7is -L7A-R7A, -CH2-L7A-R7A, or wherein L7A is absent, O, - NH-, -S(=O)2-, -S(=O)2NH-, -S(=O)2NCH3-, -NHS(=O)2-, -C(=O)-, -C(=O)NH-, -P(=O)CH3-, -NHC(=O)-, or -NHC(=O)O-, and R7Ais as defined for Formula I.

[0135] In one embodiment, the compound of the invention is according to any one of Formula I-IVf, wherein R7Ais H.

[0136] In one embodiment, the compound of the invention is according to any one of Formula I-IVf, wherein R7Ais Ci-6 alkyl optionally substituted with one or more groups independently selected from =0, halo, CN, or OH. In a particular embodiment, R7Ais Ci-6 alkyl optionally substituted with one, two or three groups independently selected from =0, halo, CN, or OH. In a more particular embodiment, R7Ais Ci-6 alkyl optionally substituted with one or two groups independently selected from =0, halo, CN, or OH. In a particular embodiment, R7Ais Ci-6 alkyl optionally substituted with one group selected from =0, halo, CN, or OH.

[0137] In one embodiment, the compound of the invention is according to any one of Formula I-IVf, wherein R7Ais -CH3, -CH2CH3, -CH(CH3)2, -C(CH3)2CH2CH3, -CH(CH3)CH(CH3)2, each of which is optionally substituted with one or more groups independently selected from =0, halo, CN, or OH. In a particular embodiment, R7Ais -CH3, -CH2CH3, -CH(CH3)2, -C(CH3)2CH2CH3, -CH(CH3)CH(CH3)2, each of which is optionally substituted with one, two or three groups independently selected from =0, halo, CN, or OH. In a more particular embodiment, R7Ais -CH3, -CH2CH3, -CH(CH3)2, -C(CH3)2CH2CH3, - CH(CH3)CH(CH3)2, each of which is optionally substituted with one or two groups independently selected from =0, halo, CN, or OH. In a particular embodiment, R7Ais -CH3, -CH2CH3, -CH(CH3)2, - C(CH3)2CH2CH3, -CH(CH3)CH(CH3)2, each of which is optionally substituted with one group selected from =0, halo, CN, or OH.

[0138] In one embodiment, the compound of the invention is according to any one of Formula I-IVf, wherein R7Ais C3.7cycloalkyl optionally substituted with one or more groups independently selected from =0, halo, CN, or OH. In a particular embodiment, R7Ais C3.7cycloalkyl optionally substituted with one, two or three groups independently selected from =0, halo, CN, or OH. In a more particular embodiment, R7Ais C3.7cycloalkyl optionally substituted with one or two groups independently selected from =0, halo, CN, or OH. In a particular embodiment, R7Ais C3.7cycloalkyl optionally substituted with one group selected from =0, halo, CN, or OH.

[0139] In one embodiment, the compound of the invention is according to any one of Formula I-IVf, wherein R7Ais cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, each of which is optionally substituted with one or more groups independently selected from =0, halo, CN, or OH. In a particular embodiment, R7Ais cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, each of which is optionally substituted with one, two or three groups independently selected from =0, halo, CN, or OH. In a more particular embodiment, R7Ais cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, each of which is optionally substituted with one or two groups independently selected from =0, halo, CN, or OH. In a particular embodiment, R7Ais cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, each of which is optionally substituted with one group selected from =0, halo, CN, or OH.

[0140] In one embodiment, the compound of the invention is according to any one of Formula I-IVf, wherein R7Ais 4-7 membered heterocycloalkyl comprising one or more heteroatoms independently selected from O, S, N, P, and B, which heterocycloalkyl is optionally substituted with one or more groups independently selected from =0, halo, CN, or OH. In a particular embodiment, R7Ais 4-7 membered heterocycloalkyl comprising one or more heteroatoms independently selected from O, S, N, P, and B, which heterocycloalkyl is optionally substituted with one, two or three independently selected R7AA. In a more particular embodiment, R7Ais 4-7 membered heterocycloalkyl comprising one or more heteroatoms independently selected from O, S, N, P, and B, which heterocycloalkyl is optionally substituted with one or two independently selected R7AA. In a particular embodiment, R7Ais 4-7 membered heterocycloalkyl comprising one or more heteroatoms independently selected from O, S, N, P, and B, which heterocycloalkyl is optionally substituted with one group selected from =0, halo, CN, or OH.

[0141] In one embodiment, the compound of the invention is according to any one of Formula I-IVf, wherein R7Ais oxetanyl, tetrahydrofuranyl, pyrrolidinyl, tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, phosphinanyl, or azaphosphinazyl, each of which is optionally substituted with one or more groups independently selected from =0, halo, CN, or OH. In a particular embodiment, R7Ais oxetanyl, tetrahydrofuranyl, pyrrolidinyl, tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, phosphinanyl, or azaphosphinazyl, each of which is optionally substituted with one, two or three groups independently selected from =0, halo, CN, or OH. In a more particular embodiment, R7Ais oxetanyl, tetrahydrofuranyl, pyrrolidinyl, tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, phosphinanyl, or azaphosphinazyl, each of which is optionally substituted with one or two groups independently selected from =0, halo, CN, or OH. In a particular embodiment, R7Ais oxetanyl, tetrahydrofuranyl, pyrrolidinyl, tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, phosphinanyl, or azaphosphinazyl, each of which is optionally substituted with one group selected from =0, halo, CN, or OH.

[0142] In one embodiment, the compound of the invention is according to any one of Formula I-IVf, wherein one or more R7is independently selected from -CHs, -CH2CH3, -CF3, -CH2CF3, -C(CH3)3, -OH, - P(=O)(CH3)2, -C(=0)CH3, -NHC(=0)CF3, -NHC(=O)OC(CH3)3, -S(=O)2CH3, C(=0)NH2, -NH2, - NHCH2CF3, and oxetanyl.

[0143] In one embodiment, the compound of the invention is according to any one of Formula I-IVf, wherein -Li-R1is selected from:wherein * is the attachment point.

[0144] In one embodiment, the compound of the invention is according to any one of Formula I-IVf, wherein -Li-R1iswherein * is the attachment point.

[0145] In one embodiment, the compound of the invention is according to any one of Formula I-IVf, wherein -Li-R1is:wherein * is the attachment point.

[0146] In one embodiment, the compound of the invention is according to any one of Formulae I-IVf wherein Cy is a imidazothiazolyl, imidazooxazolyl, benzoimidazolyl, benzoxazolyl, oxazolopyridinyl,benzothiazolyl, thiazolopyridinyl, indazolyl, indolyl, pyrrolopyridinyl, imidazopyridinyl, pyrazolopyridine, quinolinyl, isoquinolinyl , each of which is optionally substituted with one or more independently selected R4. In a particular embodiment, Cy is a benzoimidazolyl, benzoxazolyl, oxazolopyridinyl, benzothiazolyl, thiazolopyridinyl, indazolyl, indolyl, pyrrolopyridinyl, imidazopyridinyl, pyrazolopyridine, quinolinyl, isoquinolinyl, each of which is optionally substituted with one, two, three or four independently selected R4.

[0147] In one embodiment, the compound of the invention is according to any one of Formulae I-IVf wherein Cy is a benzoimidazolyl, benzoxazolyl, oxazolopyridinyl, benzothiazolyl, thiazolopyridinyl, indazolyl, indolyl, pyrrolopyridinyl, imidazopyridinyl, pyrazolopyridine, quinolinyl, isoquinolinyl , each of which is optionally substituted with one or more independently selected R4. In a particular embodiment, Cy is a benzoimidazolyl, benzoxazolyl, oxazolopyridinyl, benzothiazolyl, thiazolopyridinyl, indazolyl, indolyl, pyrrolopyridinyl, imidazopyridinyl, pyrazolopyridine, quinolinyl, isoquinolinyl, each of which is optionally substituted with one, two, three or four independently selected R4.

[0148] In one embodiment, the compound of the invention is according to any one of Formulae I-IVf wherein Cy is a benzoimidazolyl optionally substituted with one or more independently selected R4. In a particular embodiment, Cy is a benzoimidazolyl optionally substituted with one, two, three or four independently selected R4.

[0149] In one embodiment, the compound of the invention is according to any one of Formulae I-IVf wherein Cy is selected fromeach of which is optionally substituted with one or more independently selected R4group, and wherein each R4is as defined for Formula I, and * represents the attachment point.

[0150] In one embodiment, the compound of the invention is according to any one of Formulae I-IVf wherein Cy is selected from:each of which is optionally substituted with one or more independently selected R4group, and wherein each R4is as defined for Formula I, and * represents the attachment point.

[0151] In one embodiment, one or more independently selected R4is halo. In a particular embodiment, one or more independently selected R4is selected from F, Cl, or Br.

[0152] In one embodiment, one or more independently selected R4is CN.

[0153] In one embodiment, one or more independently selected R4is -L4A-R4A. In a particular embodiment, I A is selected from absent, O, -NH-, -C(=O), -C(=O)O- or -C(=O)NH-.

[0154] In one embodiment, one or more independently selected R4is -L4A-R4A. In a particular embodiment, R4Ais H.

[0155] In one embodiment, one or more independently selected R4is -L4A-R4A. In a particular embodiment, R4Ais Ci-6 alkyl optionally substituted with one or more groups independently selected from =0 and R5. In a particular embodiment, R4Ais -CHs, -CH2CH3, -CH(CHs)2, or -C(CH3)3, each of which is optionally substituted with one or more groups independently selected from =0 and R5.

[0156] In one embodiment, one or more independently selected R4is -L4A-R4A. In a particular embodiment, R4Ais C3-7 cycloalkyl optionally substituted with one or more groups independently selected from =0 and R5. In a particular embodiment, R4Ais cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, each of which is optionally substituted with one or more groups independently selected from =0 and R5.

[0157] In one embodiment, one or more independently selected R4is -L4A-R4A. In a particular embodiment, R4Ais polycyclic fused, spiro or bridged C4-10 cycloalkyl optionally substituted with one or more groups independently selected from =0 and R5. In a particular embodiment, R4Ais bicyclopentanyl or spiroheptanyl, each of which is optionally substituted with one or more groups independently selected from =0 and R5.

[0158] In one embodiment, one or more independently selected R4is -L4A-R4A. In a particular embodiment, R4Ais 4-7 membered heterocycloalkyl comprising one or more heteroatoms independently selected from O, S, N, P, and B, which heterocycloalkyl is optionally substituted with one or more groups independently selected from =0 and R5. In a particular embodiment, R4Ais oxetanyl, tetrahydrofuranyl, pyrrolidinyl, tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, phosphinanyl, or azaphosphinazyl, each of which is optionally substituted with one or more groups independently selected from =0 and R5.

[0159] In one embodiment, one or more independently selected R4is -L4A-R4A. In a particular embodiment, R4Ais 6-10 membered heterocycloalkyl comprising one or more heteroatoms independently selected from O, S, N, P, and B, which heterocycloalkyl is optionally substituted with one or more groups independently selected from =0 and R5.

[0160] In one embodiment, one or more independently selected R4is -L4A-R4A. In a particular embodiment, R4Ais phenyl optionally substituted with one or more groups independently selected from R5.

[0161] In one embodiment, one or more independently selected R4is -L4A-R4A. In a particular embodiment, R4Ais 5-7 membered heteroaryl comprising one or more heteroatoms independently selected from O, S, and N, which heteroaryl is optionally substituted with one or more groups independently selected from R5. In a particular embodiment, R4Ais furanyl, thienyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, thioxazolyl, pyridinyl, pyrimidinyl, or pyrazinyl, each of which is optionally substituted with one or more groups independently selected from R5.

[0162] In one embodiment two R4groups together with the atoms to which they are attached may form together a fused 4-7 membered heterocycloalkyl comprising one or more heteroatoms independently selected from O, S, N, P, and B, which heterocycloalkyl is optionally substituted with one or more groups selected from =0, halo, CN, or OH;

[0163] In one embodiment, one or more independently selected R5is halo. In a particular embodiment, one or more independently selected R5is selected from F, Cl and Br.

[0164] In one embodiment, one or more independently selected R5is CN.

[0165] In one embodiment, one or more independently selected R5is -L5A-R5A. In a particular embodiment, L5Ais absent, O, -NH-, -NHC(=O)-, -C(=O)NH-, -NHC(=O)- or -S(=O)2.

[0166] In one embodiment, one or more independently selected R5is -L5A-R5A. In a particular embodiment, R5Ais H.

[0167] In one embodiment, one or more independently selected R5is -OH.

[0168] In one embodiment, one or more independently selected R5is -L5A-R5A. In a particular embodiment, R5Ais Ci-6 alkyl optionally substituted with one or more groups independently selected from R6. In a particular embodiment, one or more independently selected R5Ais selected from -CH,. -CH2CH3, - CH(CHS)2, or -C(CH3)3, each of which is optionally substituted with one or more groups independently selected from R6.

[0169] In one embodiment, one or more independently selected R5is -O-R5A. In a particular embodiment, R5Ais C1-6 alkyl optionally substituted with one or more groups independently selected from R6. In a particular embodiment, one or more independently selected R5Ais selected from -OCH3, -OCH2CH3, -OCH(CH3)2, or -OC(CH3)3, each of which is optionally substituted with one or more groups independently selected from R6.

[0170] In one embodiment, one or more independently selected R5is -L5A-R5A. In a particular embodiment, R5Ais C3-7 cycloalkyl optionally substituted with one or more groups independently selected from R6. In a particular embodiment, one or more independently selected R5Ais selected from cyclopropyl, cyclobutyl,cyclopentyl or cyclohexyl, each of which is optionally substituted with one or more groups independently selected from R6.

[0171] In one embodiment, one or more independently selected R5is -L5A-R5A. In a particular embodiment, LSA is absent, and R5Ais C3-7 cycloalkyl optionally substituted with one or more groups independently selected from R6. In a particular embodiment, one or more independently selected R5Ais selected from cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, each of which is optionally substituted with one or more groups independently selected from R6.

[0172] In one embodiment, one or more independently selected R5is -L5A-R5A. In a particular embodiment, R5Ais 4-7 membered heterocycloalkyl comprising one or more heteroatoms independently selected from O, S, N, P, and B, which heterocycloalkyl is optionally substituted with one or more groups independently selected from R6. In a particular embodiment, R5Ais oxetanyl, tetrahydrofuranyl, pyrrolidinyl, tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, phosphinanyl, or azaphosphinazyl, each of which is optionally substituted with one or more groups independently selected from R6.

[0173] In one embodiment, one or more independently selected R5is -L5A-R5A. In a particular embodiment, LSA is absent, and R5Ais 4-7 membered heterocycloalkyl comprising one or more heteroatoms independently selected from O, S, N, P, and B, which heterocycloalkyl is optionally substituted with one or more groups independently selected from R6. In a particular embodiment, R5Ais oxetanyl, tetrahydrofuranyl, pyrrolidinyl, tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, phosphinanyl, or azaphosphinazyl, each of which is optionally substituted with one or more groups independently selected from R6.

[0174] In one embodiment, one or more independently selected R5is -L5A-R5A. In a particular embodiment, R5Ais phenyl optionally substituted with one or more groups independently selected from R6.

[0175] In one embodiment, one or more independently selected R5is -L5A-R5A. In a particular embodiment, LSA is absent, and R5Ais phenyl optionally substituted with one or more groups independently selected from R6.

[0176] In one embodiment, one or more independently selected R5is -L5A-R5A. In a particular embodiment, R5Ais membered 5-7 heteroaryl comprising one or more heteroatoms independently selected from O, S, and N, which heteroaryl is optionally substituted with one or more groups independently selected from R6. In a particular embodiment, R5is furanyl, thienyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, thioxazolyl, pyridinyl, pyrimidinyl, or pyrazinyl, each of which is optionally substituted with one or more groups independently selected from R6.

[0177] In one embodiment, one or more independently selected R5is -L5A-R5A. In a particular embodiment, LSA is absent, and R5Ais membered 5-7 heteroaryl comprising one or more heteroatoms independently selected from O, S, and N, which heteroaryl is optionally substituted with one or more groups independently selected from R6. In a particular embodiment, R5is furanyl, thienyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, thioxazolyl, pyridinyl, pyrimidinyl, or pyrazinyl, each of which is optionally substituted with one or more groups independently selected from R6.

[0178] In one embodiment, one or more independently selected R6is F, Cl, CN, OH, -CH3, -CF3, -CHF2, -CH2CH3, CH2CF3, -OCH3, -OCF3, -OCHF2, -OCH2CH3, or -OCH2CF3.

[0179] In one embodiment, each R4is independently selected from: F, Cl, CN, OH, -CH3, -CF3, -CHF2, - CH2CH3, -CHFCH3, -CH(OH)CH2CH3, -CH2CH(CH3)2, -C(CH3)3, -CH2CF3, -CH2OH, -CH(CH3)CH2OH, -C(CH3)2CH2OH, -C(CH3)2CH2NH2, -0CH3, -0CF3, -OCHF2, -OCH2CH3, -OCH2CF3, cyclopropyl, cyclobutyl, cyclopentyl, -C(=O)OH, -C(=O)OCH3, -C(=O)OCH2CH3, -C(=O)OC(CH3)3, -C(=O)NH2, - NH2, -NHCH3, -NHCH2CH3, -NHCH2CF3,

[0180] In one embodiment, the compound of the invention is according to any one of Formulae I-IVf wherein Cy is:wherein each R4bl, R4b2, and R4b3is independently as defined for R4in Formula I, and* represents the attachment point.

[0181] In one embodiment, one or more independently selected R4bl, R4b2, and R4b3is halo. In a particular embodiment, one or more independently selected R4bl, R4b2, and R4b3is selected from F, Cl, or Br.

[0182] In one embodiment, one or more independently selected R4bl, R4b2, and R4b3is CN.

[0183] In one embodiment, one or more independently selected R4bl, R4b2, and R4b3is -L,4A-R4AIn a particular embodiment, I A is selected from absent, O, -NH-, -C(=O), -C(=O)O- or -C(=O)NH-.

[0184] In one embodiment, one or more independently selected R4bl, R4b2, and R4b3is -L,4A-R4AIn a particular embodiment, R4Ais H.

[0185] In one embodiment, one or more independently selected R4bl, R4b2, and R4b3is -L,4A-R4AIn a particular embodiment, R4Ais Ci-6 alkyl optionally substituted with one or more groups independently selected from =0 and R5. In a particular embodiment, R4Ais -CHs, -CH2CH3, -CH(CHs)2, or -C(CH3)3, each of which is optionally substituted with one or more groups independently selected from =0 and R5.

[0186] In one embodiment, one or more independently selected R4bl, R4b2, and R4b3is -L,4A-R4AIn a particular embodiment, R4Ais C3-7 cycloalkyl optionally substituted with one or more groups independently selected from =0 and R5. In a particular embodiment, R4Ais cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, each of which is optionally substituted with one or more groups independently selected from =0 and R5.

[0187] In one embodiment, one or more independently selected R4bl, R4b2, and R4b3is -L4A-R4AIn a particular embodiment, R4Ais polycyclic fused, spiro or bridged C4-10 cycloalkyl optionally substituted with one or more groups independently selected from =0 and R5. In a particular embodiment, R4Aisbicyclopentanyl or spiroheptanyl, each of which is optionally substituted with one or more groups independently selected from =0 and R5.

[0188] In one embodiment, one or more independently selected R4bl, R4b2, and R4b3is -L,4A-R4AIn a particular embodiment, R4Ais 4-7 membered heterocycloalkyl comprising one or more heteroatoms independently selected from O, S, N, P, and B, which heterocycloalkyl is optionally substituted with one or more groups independently selected from =0 and R5. In a particular embodiment, R4Ais oxetanyl, tetrahydrofuranyl, pyrrolidinyl, tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, phosphinanyl, or azaphosphinazyl, each of which is optionally substituted with one or more groups independently selected from =0 and R5.

[0189] In one embodiment, one or more independently selected R4bl, R4b2, and R4b3is -L,4A-R4AIn a particular embodiment, R4Ais 6-10 membered heterocycloalkyl comprising one or more heteroatoms independently selected from O, S, N, P, and B, which heterocycloalkyl is optionally substituted with one or more groups independently selected from =0 and R5.

[0190] In one embodiment, one or more independently selected R4bl, R4b2, and R4b3is -L,4A-R4AIn a particular embodiment, R4Ais phenyl optionally substituted with one or more groups independently selected from R5.

[0191] In one embodiment, one or more independently selected R4bl, R4b2, and R4b3is -L,4A-R4AIn a particular embodiment, R4Ais 5-7 membered heteroaryl comprising one or more heteroatoms independently selected from O, S, and N, which heteroaryl is optionally substituted with one or more groups independently selected from R5. In a particular embodiment, R4Ais furanyl, thienyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, thioxazolyl, pyridinyl, pyrimidinyl, or pyrazinyl, each of which is optionally substituted with one or more groups independently selected from R5.

[0192] In one embodiment, one or more independently selected R5is halo. In a particular embodiment, one or more independently selected R5is selected from F, Cl and Br.

[0193] In one embodiment, one or more independently selected R5is CN.

[0194] In one embodiment, one or more independently selected R5is -L5A-R5A. In a particular embodiment, L5Ais absent, O, -NH-, -NHC(=O)-, -C(=O)NH-, -NHC(=O)- or -S(=O)2.

[0195] In one embodiment, one or more independently selected R5is -L5A-R5A. In a particular embodiment, R5Ais H.

[0196] In one embodiment, one or more independently selected R5is -OH.

[0197] In one embodiment, one or more independently selected R5is -L5A-R5A. In a particular embodiment, R5Ais Ci-6 alkyl optionally substituted with one or more groups independently selected from R6. In a particular embodiment, one or more independently selected R5Ais selected from -CH,. -CH2CH3, - CH(CHS)2, or -C(CH3)3, each of which is optionally substituted with one or more groups independently selected from R6.

[0198] In one embodiment, one or more independently selected R5is -O-R5A. In a particular embodiment, R5Ais C1-6 alkyl optionally substituted with one or more groups independently selected from R6. In a particular embodiment, one or more independently selected R5Ais selected from -OCH3,-OCH2CH3, -OCH(CHS)2, or -OC(CH3)3, each of which is optionally substituted with one or more groups independently selected from R6.

[0199] In one embodiment, one or more independently selected R5is -L5A-R5A. In a particular embodiment, R5Ais C3.7 cycloalkyl optionally substituted with one or more groups independently selected from R6. In a particular embodiment, one or more independently selected R5Ais selected from cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, each of which is optionally substituted with one or more groups independently selected from R6.

[0200] In one embodiment, one or more independently selected R5is -L5A-R5A. In a particular embodiment, LSA is absent, and R5Ais C3.7 cycloalkyl optionally substituted with one or more groups independently selected from R6. In a particular embodiment, one or more independently selected R5Ais selected from cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, each of which is optionally substituted with one or more groups independently selected from R6.

[0201] In one embodiment, one or more independently selected R5is -L5A-R5A. In a particular embodiment, R5Ais 4-7 membered heterocycloalkyl comprising one or more heteroatoms independently selected from O, S, N, P, and B, which heterocycloalkyl is optionally substituted with one or more groups independently selected from R6. In a particular embodiment, R5Ais oxetanyl, tetrahydrofuranyl, pyrrolidinyl, tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, phosphinanyl, or azaphosphinazyl, each of which is optionally substituted with one or more groups independently selected from R6.

[0202] In one embodiment, one or more independently selected R5is -L5A-R5A. In a particular embodiment, LSA is absent, and R5Ais 4-7 membered heterocycloalkyl comprising one or more heteroatoms independently selected from O, S, N, P, and B, which heterocycloalkyl is optionally substituted with one or more groups independently selected from R6. In a particular embodiment, R5Ais oxetanyl, tetrahydrofuranyl, pyrrolidinyl, tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, phosphinanyl, or azaphosphinazyl, each of which is optionally substituted with one or more groups independently selected from R6.

[0203] In one embodiment, one or more independently selected R5is -L5A-R5A. In a particular embodiment, R5Ais phenyl optionally substituted with one or more groups independently selected from R6.

[0204] In one embodiment, one or more independently selected R5is -L5A-R5A. In a particular embodiment, L5 A is absent, and R5Ais phenyl optionally substituted with one or more groups independently selected from R6.

[0205] In one embodiment, one or more independently selected R5is -L5A-R5A. In a particular embodiment, R5Ais membered 5-7 heteroaryl comprising one or more heteroatoms independently selected from O, S, and N, which heteroaryl is optionally substituted with one or more groups independently selected from R6. In a particular embodiment, R5is furanyl, thienyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, thioxazolyl, pyridinyl, pyrimidinyl, or pyrazinyl, each of which is optionally substituted with one or more groups independently selected from R6.

[0206] In one embodiment, one or more independently selected R5is -L5A-R5A. In a particular embodiment, LSA is absent, and R5Ais membered 5-7 heteroaryl comprising one or more heteroatoms independently selected from O, S, and N, which heteroaryl is optionally substituted with one or more groups independently selected from R6. In a particular embodiment, R5is furanyl, thienyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, thioxazolyl, pyridinyl, pyrimidinyl, or pyrazinyl, each of which is optionally substituted with one or more groups independently selected from R6.

[0207] In one embodiment, one or more independently selected R6is F, Cl, CN, OH, -CHs, -CFs, -CHF2, -CH2CH3, CH2CF3, -OCH3, -OCF3, -OCHF2, -OCH2CH3, or -OCH2CF3.

[0208] In one embodiment, each R4bl, R4b2, and R4b3is independently selected from: F, Cl, CN, OH, -CH3, -CF3, -CHF2, -CH2CH3, -CHFCH3, -CH(OH)CH2CH3, -CH2CH(CH3)2, -C(CH3)3, -CH2CF3, -CH2OH, - CH(CH3)CH2OH, -C(CH3)2CH2OH, -C(CH3)2CH2NH2, -0CH3, -0CF3, -OCHF2, -OCH2CH3, -OCH2CF3, cyclopropyl, cyclobutyl, cyclopentyl, -C(=O)OH, -C(=O)OCH3, -C(=O)OCH2CH3, -C(=O)OC(CH3)3, -C(=O)NH2, -NH2. -NHCH3 -NHCH2CH3 -NHCH2CF3wherein * is the attachment point.

[0210] In one embodiment, Cy is selected fromwherein * is the attachment point.

[0211] In one embodiment, Cy is selected fromwherein * is the attachment point.In one embodiment, Cy is selected fromwherein * is the attachment point.

[0212] In one embodiment, Cy is selected fromwherein * is the attachment point.

[0213] In one embodiment, Cy is selected fromwherein * is the attachment point.

[0214] In one embodiment, Cy is selected from

[0215] In one embodiment, the compound of the invention is selected from the compounds disclosed in table III herein.

[0216] In one embodiment, a compound of the invention is provided in a natural isotopic form.

[0217] In one embodiment, a compound of the invention is provided in an unnatural variant isotopic form.In a specific embodiment, the unnatural variant isotopic form is a form in which deuterium (z. e.2H or D) is incorporated where hydrogen is specified in the chemical structure in one or more atoms of a compound of the invention. In one embodiment, the atoms of the compounds of the invention are in an isotopic form which is not radioactive. In one embodiment, one or more atoms of the compounds of the invention are in an isotopic form which is radioactive. Suitably radioactive isotopes are stable isotopes. Suitably, the unnatural variant isotopic form is a pharmaceutically acceptable form.

[0218] In one embodiment, a compound of the invention is provided whereby a single atom of the compound exists in an unnatural variant isotopic form. In another embodiment, a compound of the invention is provided whereby two or more atoms exist in an unnatural variant isotopic form.

[0219] Unnatural isotopic variant forms can generally be prepared by conventional techniques known to those skilled in the art or by processes described herein e.g. processes analogous to those described in the accompanying Examples for preparing natural isotopic forms. Thus, unnatural isotopic variant forms could be prepared by using appropriate isotopically variant (or labelled) reagents in place of the normal reagents employed in the illustrative example as examples.

[0220] In one aspect a compound of the invention according to any one of the embodiments herein described is present as the free base.

[0221] In one aspect a compound of the invention according to any one of the embodiments herein described is a pharmaceutically acceptable salt.

[0222] In one aspect a compound of the invention according to any one of the embodiments herein described is a solvate of the compound.

[0223] In one aspect a compound of the invention according to any one of the embodiments herein described is a solvate of a pharmaceutically acceptable salt of a compound.

[0224] While specified groups for each embodiment have generally been listed above separately, a compound of the invention includes one in which several or each embodiment in the above Formula, as well as other formulae presented herein, is selected from one or more of particular members or groups designated respectively, for each variable. Therefore, this invention is intended to include all combinations of such embodiments within its scope.

[0225] While specified groups for each embodiment have generally been listed above separately, a compound of the invention may be one for which one or more variables (for example, R groups) is selected from one or more embodiments according to any of the Formula(e) listed above. Therefore, the present invention is intended to include all combinations of variables from any of the disclosed embodiments within its scope.

[0226] Alternatively, the exclusion of one or more of the specified variables from a group or an embodiment, or combinations thereof is also contemplated by the present invention.

[0227] In certain aspects, the present invention provides prodrugs and derivatives of the compounds according to the formulae above. Prodrugs are derivatives of the compounds of the invention, which have metabolically cleavable groups and become by solvolysis or under physiological conditions the compounds of the invention, which are pharmaceutically active, in vivo . Such examples include, but are not limited to, choline ester derivatives and the like, A-alkylmorpholine esters and the like.

[0228] Other derivatives of the compounds of this invention have activity in both their acid and acid derivative forms, but the acid sensitive form often offers advantages of solubility, tissue compatibility, or delayed release in the mammalian organism (Bundgaard 1985). Prodrugs include acid derivatives well known to practitioners of the art, such as, for example, esters prepared by reaction of the parent acid with a suitable alcohol, or amides prepared by reaction of the parent acid compound with a substituted orunsubstituted amine, or acid anhydrides, or mixed anhydrides . Simple aliphatic or aromatic esters, amides and anhydrides derived from acidic groups pendant on the compounds of this invention are preferred prodrugs. In some cases it is desirable to prepare double ester type prodrugs such as (acyloxy)alkyl esters or ((alkoxy carbonyl)oxy)alkylesters. Particularly useful are the Ci to Cs alkyl, C2-C8 alkenyl, aryl, C7-C12 substituted aryl, and C7-C12 arylalkyl esters of the compounds of the invention.PHARMACEUTICAL COMPOSITIONS

[0229] When employed as a pharmaceutical, a compound of the invention is typically administered in the form of a pharmaceutical composition. Such compositions can be prepared in a manner well known in the pharmaceutical art and comprise at least one active compound of the invention according to Formula I. Generally, a compound of the invention is administered in a pharmaceutically effective amount. The amount of compound of the invention actually administered will typically be determined by a physician, in the light of the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound of the invention administered, the age, weight, and response of the individual patient, the severity of the patient’s symptoms, and the like.

[0230] In one embodiment, the present invention provides pharmaceutical compositions comprising a compound of the invention and another therapeutic agent.

[0231] In one embodiment, the present invention provides pharmaceutical compositions comprising a compound of the invention and another therapeutic agent, which other therapeutic agent is an inflammatory diseases, autoinflammatory diseases, autoimmune diseases, proliferative diseases, fibrotic diseases, transplant rejection, diseases involving impairment of cartilage turnover, congenital cartilage malformation, diseases involving impairment of bone turnover, diseases associated with hypersecretion of IL-6, diseases associated with hypersecretion of TNFa, interferons, IL-12, IL-17 and / or IL-23, respiratory diseases, endocrine diseases, metabolic diseases, cardiovascular diseases, dermatological diseases, and / or abnormal angiogenesis associated diseases treatment agent.

[0232] In one embodiment, the present invention provides pharmaceutical compositions comprising a compound of the invention and another therapeutic agent, which other therapeutic agent is an inflammatory diseases treatment agent. In particular, the term inflammatory diseases refers to rheumatoid arthritis, psoriasis, psoriatic arthritis, ankylosing spondylitis and inflammatory bowel diseases. More particularly, the term refers to rheumatoid arthritis and inflammatory bowel diseases.

[0233] In one embodiment, the present invention provides pharmaceutical compositions comprising a compound of the invention and another therapeutic agent, which other therapeutic agent is an autoinflammatory diseases treatment agent. In particular, the term autoinflammatory diseases refers to cryopyrin-associated periodic syndromes (CAPS), familial mediterranean fever (FMF) and tumor necrosis factor receptor-associated periodic syndrome (TRAPS), Behcet’s disease, systemic-onset juvenile idiopathic arthritis (SJIA) or Still’s disease. More particularly, the term refers to CAPS, FMF, TRAPS and Still’s disease.

[0234] In one embodiment, the present invention provides pharmaceutical compositions comprising a compound of the invention and another therapeutic agent, which other therapeutic agent is an autoimmune diseases treatment agent. Particularly, the term autoimmune diseases refers to COPD, asthma, systemic lupus erythematosus (SLE), cutaneous lupus erythematosus, lupus nephritis, Sjogren’s syndrome, psoriasis, dry eye disease, and inflammatory bowel disease. More particularly, the term refers to COPD, asthma, systemic lupus erythematosus, and inflammatory bowel disease.

[0235] In one embodiment, the present invention provides pharmaceutical compositions comprising a compound of the invention and another therapeutic agent, which other therapeutic agent is a proliferative diseases treatment agent. In particular, the term proliferative diseases refers to cancer, myeloproliferative disorders, leukemia, multiple myeloma, psoriasis, restenosis, scleroderma or fibrosis. In particular, the term refers to psoriasis, scleroderma, and fibrosis.

[0236] In one embodiment, the present invention provides pharmaceutical compositions comprising a compound of the invention and another therapeutic agent, which other therapeutic agent is a fibrotic diseases treatment agent. In particular, the term fibrotic diseases refers to idiopathic pulmonary fibrosis (IPF), radiation induced fibrosis, nonalcoholic steatohepatitis (NASH), scleroderma, bleomycin induced pulmonary fibrosis, cutaneous scleroderma, and systemic sclerosis.

[0237] In one embodiment, the present invention provides pharmaceutical compositions comprising a compound of the invention and another therapeutic agent, which other therapeutic agent is a transplant rejection treatment agent. In particular, the term transplant rejection refers to acute or chronic rejection of cells, tissue or solid organ allo- or xenografts of e.g. pancreatic islets, stem cells, bone marrow, skin, muscle, comeal tissue, neuronal tissue, heart, lung, combined heart -lung, kidney, liver, bowel, pancreas, trachea or esophagus, or graft-versus-host disease. More particularly, the term refers to graft-versus-host disease.

[0238] In one embodiment, the present invention provides pharmaceutical compositions comprising a compound of the invention and another therapeutic agent, which other therapeutic agent is a disease involving impairment of cartilage turnover treatment agent. In particular, the term diseases involving impairment of cartilage turnover refers to osteoarthritis, psoriatic arthritis, juvenile rheumatoid arthritis, gouty arthritis, septic or infectious arthritis, reactive arthritis, reflex sympathetic dystrophy, algodystrophy, Tietze syndrome or costal chondritis, fibromyalgia, osteochondritis, neurogenic or neuropathic arthritis, arthropathy, endemic forms of arthritis like osteoarthritis deformans endemica, Mseleni disease and Handigodu disease; degeneration resulting from fibromyalgia, systemic lupus erythematosus, scleroderma and ankylosing spondylitis. More particularly, the term refers to osteoarthritis, psoriatic arthritis, juvenile rheumatoid arthritis, systemic lupus erythematosus, scleroderma and ankylosing spondylitis.

[0239] In one embodiment, the present invention provides pharmaceutical compositions comprising a compound of the invention and another therapeutic agent, which other therapeutic agent is a congenital cartilage malformation treatment agent. In particular, the term congenital cartilage malformation refers to hereditary chondrolysis, chondrodysplasias and pseudochondrodysplasias, microtia, anotia, metaphyseal chondrodysplasia. More particularly, the term refers to microtia, anotia, metaphyseal chondrodysplasia.

[0240] In one embodiment, the present invention provides pharmaceutical compositions comprising a compound of the invention and another therapeutic agent, which other therapeutic agent is a diseases involving impairment of bone turnover treatment agent. In particular, the term diseases involving impairment of bone turnover refers to osteoporosis, osteopenia, hormone deficiency, hormone excess, Paget's disease, osteoarthritis, renal bone disease, osteogenesis imperfecta, and hypophosphatasia. More particularly, the term refers to osteoporosis.

[0241] In one embodiment, the present invention provides pharmaceutical compositions comprising a compound of the invention and another therapeutic agent, which other therapeutic agent is a diseases associated with hypersecretion of IL-6 treatment agent. In particular, the term diseases associated with hypersecretion of IL-6 refers to Castleman’s disease, multiple myeloma, psoriasis, Kaposi’s sarcoma and / or mesangial proliferative glomerulonephritis.

[0242] In one embodiment, the present invention provides pharmaceutical compositions comprising a compound of the invention and another therapeutic agent, which other therapeutic agent is a diseases associated with hypersecretion of TNFa, interferons, IL-12, IL-17 and / or IL-23 treatment agent. In particular, the term diseases associated with hypersecretion of TNFa, interferons, IL-12, IL-17 and / or IL-23 refers to systemic and cutaneous lupus erythematosus, lupus nephritis, dermatomyositis, Sjogren’s syndrome, psoriasis, rheumatoid arthritis, psoriatic arthritis, multiple sclerosis, Down syndrome, ulcerative colitis, spondyloarthropathies (particularly ankylosing spondylitis) and / or Crohn’s disease. More particularly, the term refers to Sjogren’s syndrome, psoriasis, rheumatoid arthritis, psoriatic arthritis, multiple sclerosis, Down syndrome, ulcerative colitis, ankylosing spondylitis and / or Crohn’s disease.

[0243] In one embodiment, the present invention provides pharmaceutical compositions comprising a compound of the invention and another therapeutic agent, which other therapeutic agent is a respiratory diseases treatment agent. In particular, the term respiratory diseases refers to asthma, adult respiratory distress syndrome, isocapnic hyperventilation, seasonal asthma, seasonal allergic rhinitis, perennial allergic rhinitis, chronic obstructive pulmonary disease, emphysema, pulmonary hypertension, interstitial lung fibrosis, cystic fibrosis, or hypoxia. More particularly, the term refers to pulmonary hypertension or interstitial lung fibrosis.

[0244] In one embodiment, the present invention provides pharmaceutical compositions comprising a compound of the invention and another therapeutic agent, which other therapeutic agent is an endocrine diseases treatment agent. In particular, the term endocrine diseases refers to hypothyroidism, congenital adrenal hyperplasia, diseases of the parathyroid gland, diabetes mellitus, diseases of the adrenal glands, Cushing’s syndrome and Addison’s disease, ovarian dysfunction polycystic ovary syndrome.

[0245] In one embodiment, the present invention provides pharmaceutical compositions comprising a compound of the invention and another therapeutic agent, which other therapeutic agent is a metabolic diseases treatment agent. In particular, the term metabolic diseases refers to cystic fibrosis, phenylketonuria (PKU), diabetes, hyperlipidemia, gout, type II diabetic kidney disease and rickets. More particularly, the term refers to obesity and / or type II diabetes .

[0246] In one embodiment, the present invention provides pharmaceutical compositions comprising a compound of the invention and another therapeutic agent, which other therapeutic agent is a cardiovascular diseases treatment agent. In particular, the term cardiovascular diseases refers to arrhythmia (atrial or ventricular or both); atherosclerosis and its sequelae; angina; cardiac rhythm disturbances; myocardial ischemia; myocardial infarction; cardiac or vascular aneurysm; vasculitis, stroke; peripheral obstructive arteriopathy of a limb, an organ, or a tissue; reperfusion injury following ischemia of the brain, heart, kidney or other organ or tissue; endotoxic, surgical, or traumatic shock; hypertension, valvular heart disease, heart failure, abnormal blood pressure; vasoconstriction (including that associated with migraines); vascular abnormality, inflammation, or insufficiency limited to a single organ or tissue. More particularly, the term refers to atherosclerosis or giant cell arteritis.

[0247] In one embodiment, the present invention provides pharmaceutical compositions comprising a compound of the invention and another therapeutic agent, which other therapeutic agent is a dermatological diseases treatment agent. In particular, the term dermatological diseases refers to atopic dermatitis, bullous disorders, collagenoses, psoriasis, psoriatic lesions, dermatitis, contact dermatitis, eczema, vitiligo, pruritus, scleroderma, wound healing, scarring, hypertrophic scarring, keloids, Kawasaki disease, rosacea, Sjogren- Larsson syndrome, or urticaria. More particularly, the term refers to a psoriasis, psoriatic lesions, scleroderma, and vitiligo.

[0248] In one embodiment, the present invention provides pharmaceutical compositions comprising a compound of the invention and another therapeutic agent, which other therapeutic agent is an abnormal angiogenesis associated diseases treatment agent. In particular, the term abnormal angiogenesis associated diseases refers to atherosclerosis, hypertension, tumor growth, inflammation, rheumatoid arthritis, wetform macular degeneration, choroidal neovascularization, retinal neovascularization, and diabetic retinopathy. More particularly, the term refers to atherosclerosis, hypertension, or diabetic retinopathy.

[0249] The pharmaceutical compositions of this invention can be administered by a variety of routes including oral, rectal, transdermal, subcutaneous, intra-articular, intravenous, intramuscular, and intranasal. Depending on the intended route of delivery, a compound of the invention is preferably formulated as either injectable or oral compositions or as salves, as lotions or as patches all for transdermal administration.

[0250] The compositions for oral administration can take the form of bulk liquid solutions or suspensions, or bulk powders. More commonly, however, the compositions are presented in unit dosage forms to facilitate accurate dosing. The term ‘unit dosage forms’ refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient, vehicle or carrier. Typical unit dosage forms include prefdled, premeasured ampules or syringes of the liquid compositions or pills, tablets, capsules or the like in the case of solid compositions . In such compositions, the compound of the invention according to Formula I is usually a minor component (from about 0. 1 to about 50% by weight or preferably from about 1 to about 40% by weight) with the remainder being various vehicles or carriers and processing aids helpful for forming the desired dosing form.

[0251] Liquid forms suitable for oral administration may include a suitable aqueous or non-aqueous vehicle with buffers, suspending and dispensing agents, colorants, flavors and the like . Solid forms may include, for example, any of the following ingredients, or compound of the inventions of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or com starch; a lubricant such as magnesium stearate; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint or orange flavoring.

[0252] Injectable compositions are typically based upon injectable sterile saline or phosphate -buffered saline or other injectable carriers known in the art. As before, the active compound of the invention according to Formula I in such compositions is typically a minor component, often being from about 0.05 to 10% by weight with the remainder being the injectable carrier and the like.

[0253] Transdermal compositions are typically formulated as a topical ointment or cream containing the active ingredient(s), generally in an amount ranging from about 0.01 to about 20% by weight, preferably from about 0.1 to about 20% by weight, preferably from about 0.1 to about 10% by weight, and more preferably from about 0.5 to about 15% by weight. When formulated as an ointment, the active ingredients will typically be combined with either a paraffinic or a water-miscible ointment base. Alternatively, the active ingredients may be formulated in a cream with, for example an oil-in-water cream base. Such transdermal formulations are well-known in the art and generally include additional ingredients to enhance the dermal penetration or stability of the active ingredients or the formulation. All such known transdermal formulations and ingredients are included within the scope of this invention.

[0254] A compound of the invention can also be administered by a transdermal device. Accordingly, transdermal administration can be accomplished using a patch either of the reservoir or porous membrane type, or of a solid matrix variety.

[0255] The above-described components for orally administrable, injectable or topically administrable compositions are merely representative. Other materials as well as processing techniques and the like are set forth in Part 8 of Remington’s Pharmaceutical Sciences, 17th edition, 1985, Mack Publishing Company, Easton, Pennsylvania, which is incorporated herein by reference.

[0256] A compound of the invention can also be administered in sustained release forms or from sustained release drug delivery systems. A description of representative sustained release materials can be found in Remington’s Pharmaceutical Sciences (Remington & Gennaro 1985).

[0257] The following formulation examples illustrate representative pharmaceutical compositions that may be prepared in accordance with this invention. The present invention, however, is not limited to the following pharmaceutical compositions.Formulation 1 - Tablets

[0258] A compound of the invention according to Formula I may be admixed as a dry powder with a dry gelatin binder in an approximate 1:2 weight ratio. A minor amount of magnesium stearate may be added asa lubricant. The mixture may be formed into 240-270 mg tablets (80-90 mg of active compound of the invention according to Formula I per tablet) in a tablet press.Formulation 2 - Capsules

[0259] A compound of the invention according to Formula I may be admixed as a dry powder with a starch diluent in an approximate 1: 1 weight ratio. The mixture may be fdled into 250 mg capsules (125 mg of active compound of the invention according to Formula I per capsule).Formulation 3 - Liquid

[0260] A compound of the invention according to Formula I (125 mg), may be admixed with sucrose (1.75 g) and xanthan gum (4 mg) and the resultant mixture may be blended, passed through a No. 10 mesh U.S. sieve, and then mixed with a previously made solution of microcrystalline cellulose and sodium carboxymethyl cellulose (11:89, 50 mg) in water. Sodium benzoate (10 mg), flavor, and color may be diluted with water and added with stirring. Sufficient water may then be added with stirring. Further sufficient water may be then added to produce a total volume of 5 mL.Formulation 4 - Tablets

[0261] A compound of the invention according to Formula I may be admixed as a dry powder with a dry gelatin binder in an approximate 1:2 weight ratio. A minor amount of magnesium stearate may be added as a lubricant. The mixture may be formed into 450-900 mg tablets (150-300 mg of active compound of the invention according to Formula I) in a tablet press.Formulation 5 - Injection

[0262] A compound of the invention according to Formula I may be dissolved or suspended in a buffered sterile saline injectable aqueous medium to a concentration of approximately 5 mg / mL.Formulation 6 - Topical

[0263] Stearyl alcohol (250 g) and a white petrolatum (250 g) may be melted at about 75 °C and then a mixture of a compound of the invention according to Formula I (50 g) methylparaben (0.25 g), propylparaben (0.15 g), sodium lauryl sulfate (10 g), and propylene glycol (120 g) dissolved in water (about 370 g) may be added and the resulting mixture may be stirred until it congeals.METHODS OF TREATMENT

[0264] In one embodiment, the present invention provides compounds of the invention, or pharmaceutical compositions comprising a compound of the invention, for use in medicine .

[0265] In one embodiment, the present invention provides compounds of the invention or pharmaceutical compositions comprising a compound of the invention, for use in the prophylaxis and / or treatment of inflammatory diseases, autoinflammatory diseases, autoimmune diseases, proliferative diseases, fibrotic diseases, transplant rejection, diseases involving impairment of cartilage turnover, congenital cartilagemalformation, diseases involving impairment of bone turnover, diseases associated with hypersecretion of IL-6, diseases associated with hypersecretion of TNFa, interferons, IL-12, IL-17 and / or IL-23, respiratory diseases, endocrine diseases, metabolic diseases, cardiovascular diseases, dermatological diseases, and / or abnormal angiogenesis associated diseases.

[0266] In another embodiment, the present invention provides the use of compounds of the invention or pharmaceutical compositions comprising a compound of the invention in the manufacture of a medicament for the prophylaxis and / or treatment of inflammatory diseases, autoinflammatory diseases, autoimmune diseases, proliferative diseases, fibrotic diseases, transplant rejection, diseases involving impairment of cartilage turnover, congenital cartilage malformation, diseases involving impairment of bone turnover, diseases associated with hypersecretion of IL-6, diseases associated with hypersecretion of TNFa, interferons, IL-12, IL-17 and / or IL-23, respiratory diseases, endocrine diseases, metabolic diseases, cardiovascular diseases, dermatological diseases, and / or abnormal angiogenesis associated diseases.

[0267] In additional methods of treatment aspects, this invention provides methods of prophylaxis and / or treatment of a mammal afflicted with inflammatory diseases, autoinflammatory diseases, autoimmune diseases, proliferative diseases, fibrotic diseases, transplant rejection, diseases involving impairment of cartilage turnover, congenital cartilage malformation, diseases involving impairment of bone turnover, diseases associated with hypersecretion of IL-6, diseases associated with hypersecretion of TNFa, interferons, IL-12, IL-17 and / or IL-23, respiratory diseases, endocrine diseases, metabolic diseases, cardiovascular diseases, dermatological diseases, and / or abnormal angiogenesis associated diseases, which methods comprise the administration of an effective amount of a compound of the invention or one or more of the pharmaceutical compositions herein described for the treatment or prophylaxis of said conditions.

[0268] In one embodiment, the present invention provides compounds of the invention or pharmaceutical compositions comprising a compound of the invention, for use in the prophylaxis and / or treatment of inflammatory diseases. In particular, the term inflammatory diseases refers to rheumatoid arthritis, psoriasis, psoriatic arthritis, ankylosing spondylitis and inflammatory bowel diseases. More particularly, the term refers to rheumatoid arthritis and inflammatory bowel diseases.

[0269] In another embodiment, the present invention provides the use of compounds of the invention or pharmaceutical compositions comprising a compound of the invention in the manufacture of a medicament for the prophylaxis and / or treatment of inflammatory diseases. In particular, the term inflammatory diseases refers to rheumatoid arthritis, psoriasis, psoriatic arthritis, ankylosing spondylitis and inflammatory bowel diseases. More particularly, the term refers to rheumatoid arthritis and inflammatory bowel diseases.

[0270] In additional methods of treatment aspects, this invention provides methods of prophylaxis and / or treatment of a mammal afflicted with inflammatory diseases, which methods comprise the administration of an effective amount of a compound of the invention or one or more of the pharmaceutical compositions herein described for the treatment or prophylaxis of said condition. In particular, the term inflammatory diseases refers to rheumatoid arthritis, psoriasis, psoriatic arthritis, ankylosing spondylitis and inflammatory bowel diseases. More particularly, the term refers to rheumatoid arthritis and inflammatory bowel diseases.

[0271] In one embodiment, the present invention provides compounds of the invention or pharmaceutical compositions comprising a compound of the invention, for use in the prophylaxis and / or treatment of autoinflammatory diseases. In particular, the term autoinflammatory diseases refers to cryopyrin-associated periodic syndromes (CAPS), familial mediterranean fever (FMF) and tumor necrosis factor receptor- associated periodic syndrome (TRAPS), Behcet’s disease, systemic -onset juvenile idiopathic arthritis (SJIA) or Still’s disease. More particularly, the term refers to CAPS, FMF, TRAPS and Still’s disease.

[0272] In another embodiment, the present invention provides the use of compounds of the invention or pharmaceutical compositions comprising a compound of the invention in the manufacture of a medicament for the prophylaxis and / or treatment of autoinflammatory diseases. In particular, the term autoinflammatory diseases refers to cryopyrin-associated periodic syndromes (CAPS), familial mediterranean fever (FMF) and tumor necrosis factor receptor-associated periodic syndrome (TRAPS), Behcet’s disease, systemiconsetjuvenile idiopathic arthritis (SJIA) or Still’s disease. More particularly, the term refers to CAPS, FMF, TRAPS and Still’s disease.

[0273] In additional methods of treatment aspects, this invention provides methods of prophylaxis and / or treatment of a mammal afflicted with autoinflammatory diseases, which methods comprise the administration of an effective amount of a compound of the invention or one or more of the pharmaceutical compositions herein described for the treatment or prophylaxis of said condition. In particular, the term autoinflammatory diseases refers to cryopyrin-associated periodic syndromes (CAPS), familial mediterranean fever (FMF) and tumor necrosis factor receptor-associated periodic syndrome (TRAPS), Behcet’s disease, systemic-onset juvenile idiopathic arthritis (SJIA) or Still’s disease. More particularly, the term refers to CAPS, FMF, TRAPS and Still’s disease.

[0274] In one embodiment, the present invention provides compounds of the invention or pharmaceutical compositions comprising a compound of the invention, for use in the prophylaxis and / or treatment of autoimmune diseases. Particularly, the term autoimmune diseases refers to COPD, asthma, systemic lupus erythematosus (SLE), cutaneous lupus erythematosus, lupus nephritis, Sjogren’s syndrome, psoriasis, dry eye disease, and inflammatory bowel disease. More particularly, the term refers to COPD, asthma, systemic lupus erythematosus, and inflammatory bowel disease.

[0275] In another embodiment, the present invention provides the use of compounds of the invention or pharmaceutical compositions comprising a compound of the invention in the manufacture of a medicament for the prophylaxis and / or treatment of autoimmune diseases . Particularly, the term autoimmune diseases refers to COPD, asthma, systemic lupus erythematosus (SLE), cutaneous lupus erythematosus, lupus nephritis, Sjogren’s syndrome, psoriasis, dry eye disease, and inflammatory bowel disease. More particularly, the term refers to COPD, asthma, systemic lupus erythematosus, and inflammatory bowel disease.

[0276] In additional methods of treatment aspects, this invention provides methods of prophylaxis and / or treatment of a mammal afflicted with autoimmune diseases, which methods comprise the administration of an effective amount of a compound of the invention or one or more of the pharmaceutical compositions herein described for the treatment or prophylaxis of said condition. Particularly, the term autoimmunediseases refers to COPD, asthma, systemic lupus erythematosus (SLE), cutaneous lupus erythematosus, lupus nephritis, Sjogren’s syndrome, psoriasis, dry eye disease, and inflammatory bowel disease. More particularly, the term refers to COPD, asthma, systemic lupus erythematosus, and inflammatory bowel disease.

[0277] In one embodiment, the present invention provides compounds of the invention or pharmaceutical compositions comprising a compound of the invention, for use in the prophylaxis and / or treatment of proliferative diseases. In particular, the term proliferative diseases refers to cancer, myeloproliferative disorders, leukemia, multiple myeloma, psoriasis, restenosis, scleroderma or fibrosis. In particular, the term refers to psoriasis, scleroderma, and fibrosis.

[0278] In another embodiment, the present invention provides the use of compounds of the invention or pharmaceutical compositions comprising a compound of the invention in the manufacture of a medicament for the prophylaxis and / or treatment of proliferative diseases. In particular, the term proliferative diseases refers to cancer, myeloproliferative disorders, leukemia, multiple myeloma, psoriasis, restenosis, scleroderma or fibrosis. In particular, the term refers to psoriasis, scleroderma, and fibrosis.

[0279] In additional methods of treatment aspects, this invention provides methods of prophylaxis and / or treatment of a mammal afflicted with proliferative diseases, which methods comprise the administration of an effective amount of a compound of the invention or one or more of the pharmaceutical compositions herein described for the treatment or prophylaxis of said condition. In particular, the term proliferative diseases refers to cancer, myeloproliferative disorders, leukemia, multiple myeloma, psoriasis, restenosis, scleroderma or fibrosis. In particular, the term refers to psoriasis, scleroderma, and fibrosis.

[0280] In one embodiment, the present invention provides compounds of the invention or pharmaceutical compositions comprising a compound of the invention, for use in the prophylaxis and / or treatment of fibrotic diseases. In particular, the term fibrotic diseases refers to idiopathic pulmonary fibrosis (IPF), radiation induced fibrosis, nonalcoholic steatohepatitis (NASH), scleroderma, bleomycin induced pulmonary fibrosis, cutaneous scleroderma, and systemic sclerosis.

[0281] In another embodiment, the present invention provides the use of compounds of the invention or pharmaceutical compositions comprising a compound of the invention in the manufacture of a medicament for the prophylaxis and / or treatment of fibrotic diseases. In particular, the term fibrotic diseases refers to idiopathic pulmonary fibrosis (IPF), radiation induced fibrosis, nonalcoholic steatohepatitis (NASH), scleroderma, bleomycin induced pulmonary fibrosis, cutaneous scleroderma, and systemic sclerosis.

[0282] In additional methods of treatment aspects, this invention provides methods of prophylaxis and / or treatment of a mammal afflicted with fibrotic diseases, which methods comprise the administration of an effective amount of a compound of the invention or one or more of the pharmaceutical compositions herein described for the treatment or prophylaxis of said condition. In particular, the term fibrotic diseases refers to idiopathic pulmonary fibrosis (IPF), radiation induced fibrosis, nonalcoholic steatohepatitis (NASH), scleroderma, bleomycin induced pulmonary fibrosis, cutaneous scleroderma, and systemic sclerosis.

[0283] In one embodiment, the present invention provides compounds of the invention or pharmaceutical compositions comprising a compound of the invention, for use in the prophylaxis and / or treatment oftransplant rejection. In particular, the term transplant rejection refers to acute or chronic rejection of cells, tissue or solid organ allo- or xenografts of e.g. pancreatic islets, stem cells, bone marrow, skin, muscle, comeal tissue, neuronal tissue, heart, lung, combined heart -lung, kidney, liver, bowel, pancreas, trachea or esophagus, or graft-versus-host disease. More particularly, the term refers to graft-versus-host disease.

[0284] In another embodiment, the present invention provides the use of compounds of the invention or pharmaceutical compositions comprising a compound of the invention in the manufacture of a medicament for the prophylaxis and / or treatment of transplant rejection. In particular, the term transplant rejection refers to acute or chronic rejection of cells, tissue or solid organ allo- or xenografts of e.g. pancreatic islets, stem cells, bone marrow, skin, muscle, comeal tissue, neuronal tissue, heart, lung, combined heart -lung, kidney, liver, bowel, pancreas, trachea or esophagus, or graft-versus-host disease. More particularly, the term refers to graft-versus-host disease.

[0285] In additional methods of treatment aspects, this invention provides methods of prophylaxis and / or treatment of a mammal afflicted with transplant rejection, which methods comprise the administration of an effective amount of a compound of the invention or one or more of the pharmaceutical compositions herein described for the treatment or prophylaxis of said condition. In particular, the term transplant rejection refers to acute or chronic rejection of cells, tissue or solid organ allo- or xenografts of e.g. pancreatic islets, stem cells, bone marrow, skin, muscle, comeal tissue, neuronal tissue, heart, lung, combined heart-lung, kidney, liver, bowel, pancreas, trachea or esophagus, or graft-versus-host disease. More particularly, the term refers to graft-versus-host disease.

[0286] In one embodiment, the present invention provides compounds of the invention or pharmaceutical compositions comprising a compound of the invention, for use in the prophylaxis and / or treatment of diseases involving impairment of cartilage turnover. In particular, the term diseases involving impairment of cartilage turnover refers to osteoarthritis, psoriatic arthritis juvenile rheumatoid arthritis, gouty arthritis, septic or infectious arthritis, reactive arthritis, reflex sympathetic dystrophy, algodystrophy, Tietze syndrome or costal chondritis, fibromyalgia, osteochondritis, neurogenic or neuropathic arthritis, arthropathy, endemic forms of arthritis like osteoarthritis deformans endemica, Mseleni disease and Handigodu disease; degeneration resulting from fibromyalgia, systemic lupus erythematosus, scleroderma and ankylosing spondylitis. More particularly, the term refers to osteoarthritis, psoriatic arthritis, juvenile rheumatoid arthritis, systemic lupus erythematosus, scleroderma and ankylosing spondylitis.

[0287] In another embodiment, the present invention provides the use of compounds of the invention or pharmaceutical compositions comprising a compound of the invention in the manufacture of a medicament for the prophylaxis and / or treatment of diseases involving impairment of cartilage turnover. In particular, the term diseases involving impairment of cartilage turnover refers to osteoarthritis, psoriatic arthritis, juvenile rheumatoid arthritis, gouty arthritis, septic or infectious arthritis, reactive arthritis, reflex sympathetic dystrophy, algodystrophy, Tietze syndrome or costal chondritis, fibromyalgia, osteochondritis, neurogenic or neuropathic arthritis, arthropathy, endemic forms of arthritis like osteoarthritis deformans endemica, Mseleni disease and Handigodu disease; degeneration resulting from fibromyalgia, systemic lupus erythematosus, scleroderma and ankylosing spondylitis. More particularly, the term refers toosteoarthritis, psoriatic arthritis, juvenile rheumatoid arthritis, systemic lupus erythematosus, scleroderma and ankylosing spondylitis.

[0288] In additional methods of treatment aspects, this invention provides methods of prophylaxis and / or treatment of a mammal afflicted with diseases involving impairment of cartilage turnover, which methods comprise the administration of an effective amount of a compound of the invention or one or more of the pharmaceutical compositions herein described for the treatment or prophylaxis of said condition. In particular, the term diseases involving impairment of cartilage turnover refers to osteoarthritis, psoriatic arthritis, juvenile rheumatoid arthritis, gouty arthritis, septic or infectious arthritis, reactive arthritis, reflex sympathetic dystrophy, algodystrophy, Tietze syndrome or costal chondritis, fibromyalgia, osteochondritis, neurogenic or neuropathic arthritis, arthropathy, endemic forms of arthritis like osteoarthritis deformans endemica, Mseleni disease and Handigodu disease; degeneration resulting from fibromyalgia, systemic lupus erythematosus, scleroderma and ankylosing spondylitis. More particularly, the term refers to osteoarthritis, psoriatic arthritis, juvenile rheumatoid arthritis, systemic lupus erythematosus, scleroderma and ankylosing spondylitis.

[0289] In one embodiment, the present invention provides compounds of the invention or pharmaceutical compositions comprising a compound of the invention, for use in the prophylaxis and / or treatment of congenital cartilage malformation. In particular, the term congenital cartilage malformation refers to hereditary chondrolysis, chondrodysplasias and pseudochondrodysplasias, microtia, anotia, metaphyseal chondrodysplasia. More particularly, the term refers to microtia, anotia, metaphyseal chondrodysplasia.

[0290] In another embodiment, the present invention provides the use of compounds of the invention or pharmaceutical compositions comprising a compound of the invention in the manufacture of a medicament for the prophylaxis and / or treatment of congenital cartilage malformation. In particular, the term congenital cartilage malformation refers to hereditary chondrolysis, chondrodysplasias and pseudochondrodysplasias, microtia, anotia, metaphyseal chondrodysplasia. More particularly, the term refers to microtia, anotia, metaphyseal chondrodysplasia.

[0291] In additional methods of treatment aspects, this invention provides methods of prophylaxis and / or treatment of a mammal afflicted with congenital cartilage malformation, which methods comprise the administration of an effective amount of a compound of the invention or one or more of the pharmaceutical compositions herein described for the treatment or prophylaxis of said condition. In particular, the term congenital cartilage malformation refers to hereditary chondrolysis, chondrodysplasias and pseudochondrodysplasias, microtia, anotia, metaphyseal chondrodysplasia. More particularly, the term refers to microtia, anotia, metaphyseal chondrodysplasia.

[0292] In one embodiment, the present invention provides compounds of the invention or pharmaceutical compositions comprising a compound of the invention, for use in the prophylaxis and / or treatment of diseases involving impairment of bone turnover. In particular, the term diseases involving impairment of bone turnover refers to osteoporosis, osteopenia, hormone deficiency, hormone excess, Paget's disease, osteoarthritis, renal bone disease, osteogenesis imperfecta, and hypophosphatasia. More particularly, the term refers to osteoporosis.

[0293] In another embodiment, the present invention provides the use of compounds of the invention or pharmaceutical compositions comprising a compound of the invention in the manufacture of a medicament for the prophylaxis and / or treatment of diseases involving impairment of bone turnover. In particular, the term diseases involving impairment of bone turnover refers to osteoporosis, osteopenia, hormone deficiency, hormone excess, Paget's disease, osteoarthritis, renal bone disease, osteogenesis imperfecta, and hypophosphatasia. More particularly, the term refers to osteoporosis.

[0294] In additional methods of treatment aspects, this invention provides methods of prophylaxis and / or treatment of a mammal afflicted with diseases involving impairment of bone turnover, which methods comprise the administration of an effective amount of a compound of the invention or one or more of the pharmaceutical compositions herein described for the treatment or prophylaxis of said condition. In particular, the term diseases involving impairment of bone turnover refers to osteoporosis, osteopenia, hormone deficiency, hormone excess, Paget's disease, osteoarthritis, renal bone disease, osteogenesis imperfecta, and hypophosphatasia. More particularly, the term refers to osteoporosis.

[0295] In one embodiment, the present invention provides compounds of the invention or pharmaceutical compositions comprising a compound of the invention, for use in the prophylaxis and / or treatment of diseases associated with hypersecretion of IL-6. In particular, the term diseases associated with hypersecretion of IL-6 refers to Castleman’s disease, multiple myeloma, psoriasis, Kaposi’s sarcoma and / or mesangial proliferative glomerulonephritis.

[0296] In another embodiment, the present invention provides the use of compounds of the invention or pharmaceutical compositions comprising a compound of the invention in the manufacture of a medicament for the prophylaxis and / or treatment of diseases associated with hypersecretion of IL-6. In particular, the term diseases associated with hypersecretion of IL-6 refers to Castleman’s disease, multiple myeloma, psoriasis, Kaposi’s sarcoma and / or mesangial proliferative glomerulonephritis.

[0297] In additional methods of treatment aspects, this invention provides methods of prophylaxis and / or treatment of a mammal afflicted with diseases associated with hypersecretion of IL-6, which methods comprise the administration of an effective amount of a compound of the invention or one or more of the pharmaceutical compositions herein described for the treatment or prophylaxis of said condition. In particular, the term diseases associated with hypersecretion of IL-6 refers to Castleman’s disease, multiple myeloma, psoriasis, Kaposi’s sarcoma and / or mesangial proliferative glomerulonephritis.

[0298] In one embodiment, the present invention provides compounds of the invention or pharmaceutical compositions comprising a compound of the invention, for use in the prophylaxis and / or treatment of diseases associated with hypersecretion of TNFa, interferons, IL-12, IL-17 and / or IL-23. In particular, the term diseases associated with hypersecretion of TNFa, interferons, IL-12, IL-17 and / or IL-23 refers to systemic and cutaneous lupus erythematosus, lupus nephritis, dermatomyositis, Sjogren’s syndrome, psoriasis, rheumatoid arthritis, psoriatic arthritis, multiple sclerosis, Down syndrome, ulcerative colitis, and / or Crohn’s disease. More particularly, the term refers to Sjogren’s syndrome, psoriasis, rheumatoid arthritis, psoriatic arthritis, multiple sclerosis, Down syndrome, ulcerative colitis, and / or Crohn’s disease.

[0299] In another embodiment, the present invention provides the use of compounds of the invention or pharmaceutical compositions comprising a compound of the invention in the manufacture of a medicament for the prophylaxis and / or treatment of diseases associated with hypersecretion ofTNFa, interferons, IL-12, IL- 17 and / or IL-23. In particular, the term diseases associated with hypersecretion of TNFa, interferons, IL-12, IL-17 and / or IL-23 refers to systemic and cutaneous lupus erythematosus, lupus nephritis, dermatomyositis, Sjogren’s syndrome, psoriasis, rheumatoid arthritis, psoriatic arthritis, multiple sclerosis, Down syndrome, ulcerative colitis, and / or Crohn’s disease. More particularly, the term refers to Sjogren’s syndrome, psoriasis, rheumatoid arthritis, psoriatic arthritis, multiple sclerosis, Down syndrome, ulcerative colitis, and / or Crohn’s disease.

[0300] In additional methods of treatment aspects, this invention provides methods of prophylaxis and / or treatment of a mammal afflicted with diseases associated with hypersecretion of TNFa, interferons, IL-12, IL- 17 and / or IL-23, which methods comprise the administration of an effective amount of a compound of the invention or one or more of the pharmaceutical compositions herein described for the treatment or prophylaxis of said condition. In particular, the term diseases associated with hypersecretion of TNFa, interferons, IL- 12, IL- 17 and / or IL-23 refers to systemic and cutaneous lupus erythematosus, lupus nephritis, dermatomyositis, Sjogren’s syndrome, psoriasis, rheumatoid arthritis, psoriatic arthritis, multiple sclerosis, Down syndrome, ulcerative colitis, and / or Crohn’s disease. More particularly, the term refers to Sjogren’s syndrome, psoriasis, rheumatoid arthritis, psoriatic arthritis, multiple sclerosis, Down syndrome, ulcerative colitis, and / or Crohn’s disease.

[0301] In one embodiment, the present invention provides compounds of the invention or pharmaceutical compositions comprising a compound of the invention, for use in the prophylaxis and / or treatment of respiratory diseases. In particular, the term respiratory diseases refers to asthma, adult respiratory distress syndrome, isocapnic hyperventilation, seasonal asthma, seasonal allergic rhinitis, perennial allergic rhinitis, chronic obstructive pulmonary disease, emphysema, pulmonary hypertension, interstitial lung fibrosis, cystic fibrosis, or hypoxia. More particularly, the term refers to pulmonary hypertension or interstitial lung fibrosis.

[0302] In another embodiment, the present invention provides the use of compounds of the invention or pharmaceutical compositions comprising a compound of the invention in the manufacture of a medicament for the prophylaxis and / or treatment of respiratory diseases. In particular, the term respiratory diseases refers to asthma, adult respiratory distress syndrome, isocapnic hyperventilation, seasonal asthma, seasonal allergic rhinitis, perennial allergic rhinitis, chronic obstructive pulmonary disease, emphysema, pulmonary hypertension, interstitial lung fibrosis, cystic fibrosis, or hypoxia. More particularly, the term refers to pulmonary hypertension or interstitial lung fibrosis.

[0303] In additional methods of treatment aspects, this invention provides methods of prophylaxis and / or treatment of a mammal afflicted with respiratory diseases, which methods comprise the administration of an effective amount of a compound of the invention or one or more of the pharmaceutical compositions herein described for the treatment or prophylaxis of said condition. In particular, the term respiratory diseases refers to asthma, adult respiratory distress syndrome, isocapnic hyperventilation, seasonal asthma,seasonal allergic rhinitis, perennial allergic rhinitis, chronic obstructive pulmonary disease, emphysema, pulmonary hypertension, interstitial lung fibrosis, cystic fibrosis, or hypoxia. More particularly, the term refers to pulmonary hypertension or interstitial lung fibrosis.

[0304] In one embodiment, the present invention provides compounds of the invention or pharmaceutical compositions comprising a compound of the invention, for use in the prophylaxis and / or treatment of endocrine diseases. In particular, the term endocrine diseases refers to hypothyroidism, congenital adrenal hyperplasia, diseases of the parathyroid gland, diabetes mellitus, diseases of the adrenal glands, Cushing’s syndrome and Addison’s disease, ovarian dysfunction polycystic ovary syndrome.

[0305] In another embodiment, the present invention provides the use of compounds of the invention or pharmaceutical compositions comprising a compound of the invention in the manufacture of a medicament for the prophylaxis and / or treatment of endocrine diseases. In particular, the term endocrine diseases refers to hypothyroidism, congenital adrenal hyperplasia, diseases of the parathyroid gland, diabetes mellitus, diseases of the adrenal glands, Cushing’s syndrome and Addison’s disease, ovarian dysfunction polycystic ovary syndrome.

[0306] In additional methods of treatment aspects, this invention provides methods of prophylaxis and / or treatment of a mammal afflicted with endocrine diseases, which methods comprise the administration of an effective amount of a compound of the invention or one or more of the pharmaceutical compositions herein described for the treatment or prophylaxis of said condition. In particular, the term endocrine diseases refers to hypothyroidism, congenital adrenal hyperplasia, diseases of the parathyroid gland, diabetes mellitus, diseases of the adrenal glands, Cushing’s syndrome and Addison’s disease, ovarian dysfunction polycystic ovary syndrome.

[0307] In one embodiment, the present invention provides compounds of the invention or pharmaceutical compositions comprising a compound of the invention, for use in the prophylaxis and / or treatment of metabolic diseases. In particular, the term metabolic diseases refers to cystic fibrosis, phenylketonuria (PKU), diabetes, hyperlipidemia, gout, type II diabetic kidney disease and rickets. More particularly, the term refers to obesity and / or type II diabetes.

[0308] In another embodiment, the present invention provides the use of compounds of the invention or pharmaceutical compositions comprising a compound of the invention in the manufacture of a medicament for the prophylaxis and / or treatment of metabolic diseases. In particular, the term metabolic diseases refers to cystic fibrosis, phenylketonuria (PKU), diabetes, hyperlipidemia, gout, type II diabetic kidney disease and rickets. More particularly, the term refers to obesity and / or type II diabetes.

[0309] In additional methods of treatment aspects, this invention provides methods of prophylaxis and / or treatment of a mammal afflicted with metabolic diseases, which methods comprise the administration of an effective amount of a compound of the invention or one or more of the pharmaceutical compositions herein described for the treatment or prophylaxis of said condition. In particular, the term metabolic diseases refers to cystic fibrosis, phenylketonuria (PKU), diabetes, hyperlipidemia, gout, type II diabetic kidney disease and rickets. More particularly, the term refers to obesity and / or type II diabetes.

[0310] In one embodiment, the present invention provides compounds of the invention or pharmaceutical compositions comprising a compound of the invention, for use in the prophylaxis and / or treatment of cardiovascular diseases. In particular, the term cardiovascular diseases refers to arrhythmia (atrial or ventricular or both); atherosclerosis and its sequelae; angina; cardiac rhythm disturbances; myocardial ischemia; myocardial infarction; cardiac or vascular aneurysm; vasculitis, stroke; peripheral obstructive arteriopathy of a limb, an organ, or a tissue; reperfusion injury following ischemia of the brain, heart, kidney or other organ or tissue; endotoxic, surgical, or traumatic shock; hypertension, valvular heart disease, heart failure, abnormal blood pressure; vasoconstriction (including that associated with migraines); vascular abnormality, inflammation, or insufficiency limited to a single organ or tissue. More particularly, the term refers to atherosclerosis or giant cell arteritis.

[0311] In another embodiment, the present invention provides the use of compounds of the invention or pharmaceutical compositions comprising a compound of the invention in the manufacture of a medicament for the prophylaxis and / or treatment of cardiovascular diseases. In particular, the term cardiovascular diseases refers to arrhythmia (atrial or ventricular or both); atherosclerosis and its sequelae; angina; cardiac rhythm disturbances; myocardial ischemia; myocardial infarction; cardiac or vascular aneurysm; vasculitis, stroke; peripheral obstructive arteriopathy of a limb, an organ, or a tissue; reperfusion injury following ischemia of the brain, heart, kidney or other organ or tissue; endotoxic, surgical, or traumatic shock; hypertension, valvular heart disease, heart failure, abnormal blood pressure; vasoconstriction (including that associated with migraines); vascular abnormality, inflammation, or insufficiency limited to a single organ or tissue. More particularly, the term refers to atherosclerosis or giant cell arteritis.

[0312] In additional methods of treatment aspects, this invention provides methods of prophylaxis and / or treatment of a mammal afflicted with cardiovascular diseases, which methods comprise the administration of an effective amount of a compound of the invention or one or more of the pharmaceutical compositions herein described for the treatment or prophylaxis of said condition. In particular, the term cardiovascular diseases refers to arrhythmia (atrial or ventricular or both); atherosclerosis and its sequelae; angina; cardiac rhythm disturbances; myocardial ischemia; myocardial infarction; cardiac or vascular aneurysm; vasculitis, stroke; peripheral obstructive arteriopathy of a limb, an organ, or a tissue; reperfusion injury following ischemia of the brain, heart, kidney or other organ or tissue; endotoxic, surgical, or traumatic shock; hypertension, valvular heart disease, heart failure, abnormal blood pressure; vasoconstriction (including that associated with migraines); vascular abnormality, inflammation, or insufficiency limited to a single organ or tissue. More particularly, the term refers to atherosclerosis or giant cell arteritis.

[0313] In one embodiment, the present invention provides compounds of the invention or pharmaceutical compositions comprising a compound of the invention, for use in the prophylaxis and / or treatment of dermatological diseases. In particular, the term dermatological diseases refers to atopic dermatitis, bullous disorders, collagenoses, psoriasis, psoriatic lesions, dermatitis, contact dermatitis, eczema, vitiligo, pruritus, scleroderma, wound healing, scarring, hypertrophic scarring, keloids, Kawasaki disease, rosacea, Sjogren- Larsson syndrome, or urticaria. More particularly, the term refers to psoriasis, psoriatic lesions, scleroderma, and vitiligo.

[0314] In another embodiment, the present invention provides the use of compounds of the invention or pharmaceutical compositions comprising a compound of the invention in the manufacture of a medicament for the prophylaxis and / or treatment of dermatological diseases. In particular, the term dermatological diseases refers to atopic dermatitis, bullous disorders, collagenoses, psoriasis, psoriatic lesions, dermatitis, contact dermatitis, eczema, vitiligo, pruritus, scleroderma, wound healing, scarring, hypertrophic scarring, keloids, Kawasaki disease, rosacea, Sjogren -Larsson syndrome, or urticaria. More particularly, the term refers to psoriasis, psoriatic lesions, scleroderma, and vitiligo.

[0315] In additional methods of treatment aspects, this invention provides methods of prophylaxis and / or treatment of a mammal afflicted with dermatological diseases, which methods comprise the administration of an effective amount of a compound of the invention or one or more of the pharmaceutical compositions herein described for the treatment or prophylaxis of said condition. In particular, the term dermatological diseases refers to atopic dermatitis, bullous disorders, collagenoses, psoriasis, psoriatic lesions, dermatitis, contact dermatitis, eczema, vitiligo, pruritus, scleroderma, wound healing, scarring, hypertrophic scarring, keloids, Kawasaki disease, rosacea, Sjogren -Larsson syndrome, or urticaria. More particularly, the term refers to psoriasis, psoriatic lesions, scleroderma, and vitiligo.

[0316] In one embodiment, the present invention provides compounds of the invention or pharmaceutical compositions comprising a compound of the invention, for use in the prophylaxis and / or treatment of abnormal angiogenesis associated diseases. In particular, the term abnormal angiogenesis associated diseases refers to atherosclerosis, hypertension, tumor growth, inflammation, rheumatoid arthritis, wetform macular degeneration, choroidal neovascularization, retinal neovascularization, and diabetic retinopathy. More particularly, the term refers to atherosclerosis, hypertension, or diabetic retinopathy.

[0317] In another embodiment, the present invention provides the use of compounds of the invention or pharmaceutical compositions comprising a compound of the invention in the manufacture of a medicament for the prophylaxis and / or treatment of abnormal angiogenesis associated diseases. In particular, the term abnormal angiogenesis associated diseases refers to atherosclerosis, hypertension, tumor growth, inflammation, rheumatoid arthritis, wet-form macular degeneration, choroidal neovascularization, retinal neovascularization, and diabetic retinopathy. More particularly, the term refers to atherosclerosis, hypertension, or diabetic retinopathy.

[0318] In additional methods of treatment aspects, this invention provides methods of prophylaxis and / or treatment of a mammal afflicted with abnormal angiogenesis associated diseases, which methods comprise the administration of an effective amount of a compound of the invention or one or more of the pharmaceutical compositions herein described for the treatment or prophylaxis of said condition. In particular, the term abnormal angiogenesis associated diseases refers to atherosclerosis, hypertension, tumor growth, inflammation, rheumatoid arthritis, wet-form macular degeneration, choroidal neovascularization, retinal neovascularization, and diabetic retinopathy. More particularly, the term refers to atherosclerosis, hypertension, or diabetic retinopathy.

[0319] Injection dose levels range from about 0.1 mg / kg / h to at least 10 mg / kg / h, all for from about 1 to about 120 h and especially 24 to 96 h. A preloading bolus of from about 0.1 mg / kg to about 10 mg / kg ormore may also be administered to achieve adequate steady state levels . The maximum total dose is not titled to exceed about 1 g / day for a 40 to 80 kg human patient.

[0320] For the prophylaxis and / or treatment of long-term conditions, such as degenerative conditions, the regimen for treatment usually stretches over many months or years so oral dosing is preferred for patient convenience and tolerance. With oral dosing, one to four (1-4) regular doses daily, especially one to three (1-3) regular doses daily, typically one to two (1-2) regular doses daily, and most typically one (1) regular dose daily are representative regimens. Alternatively for long lasting effect drugs, with oral dosing, once every other week, once weekly, and once a day are representative regimens . In particular, dosage regimen can be every 1-14 days, more particularly 1-10 days, even more particularly 1-7 days, and most particularly 1-3 days.

[0321] Using these dosing patterns, each dose provides from about 1 to about 1000 mg of a compound of the invention, with particular doses each providing from about 10 to about 500 mg and especially about 30 to about 250 mg.

[0322] Transdermal doses are generally selected to provide similar or lower blood levels than are achieved using injection doses.

[0323] When used to prevent the onset of a condition, a compound of the invention will be administered to a patient at risk for developing the condition, typically on the advice and under the supervision of a physician, at the dosage levels described above. Patients at risk for developing a particular condition generally include those that have a family history of the condition, or those who have been identified by genetic testing or screening to be particularly susceptible to developing the condition.

[0324] A compound of the invention can be administered as the sole active agent or it can be administered in combination with other therapeutic agents, including other compound of the inventions that demonstrate the same or a similar therapeutic activity and that are determined to be safe and efficacious for such combined administration. In a specific embodiment, co-administration of two (or more) agents allows for significantly lower doses of each to be used, thereby reducing the side effects seen.

[0325] In one embodiment, a compound of the invention or a pharmaceutical composition comprising a compound of the invention is administered as a medicament. In a specific embodiment, said pharmaceutical composition additionally comprises a further active ingredient.

[0326] In one embodiment, a compound of the invention is co -administered with another therapeutic agent for the treatment and / or prophylaxis of a disease involving inflammation, particular agents include, but are not limited to, immunoregulatory agents e.g. azathioprine, corticosteroids (e.g. prednisolone or dexamethasone), cyclophosphamide, cyclosporin A, tacrolimus, my cophenolate mofetil, muromonab-CD3 (OKT3, e.g. Orthocolone®), ATG, aspirin, acetaminophen, ibuprofen, naproxen, and piroxicam.

[0327] In one embodiment, a compound of the invention is co -administered with another therapeutic agent for the treatment and / or prophylaxis of arthritis (e.g. rheumatoid arthritis), particular agents include but are not limited to analgesics, non-steroidal anti-inflammatory drugs (NSAIDS), steroids, synthetic DMARDS (for example but without limitation methotrexate, leflunomide, sulfasalazine, auranofin, sodium aurothiomalate, penicillamine, chloroquine, hydroxychloroquine, azathioprine, JAK inhibitors (forexample tofacitinib, baricitinib, Upadacitinib, ruxolitinib, or filgotinib), fostamatinib, and cyclosporin), and biological DMARDS (for example but without limitation infliximab, etanercept, adalimumab, rituximab, and abatacept).

[0328] In one embodiment, a compound of the invention is co -administered with another therapeutic agent for the treatment and / or prophylaxis of proliferative disorders, particular agents include but are not limited to: methotrexate, leucovorin, adriamycin, prednisone, bleomycin, cyclophosphamide, 5 -fluorouracil, paclitaxel, docetaxel, vincristine, vinblastine, vinorelbine, doxorubicin, tamoxifen, toremifene, megestrol acetate, anastrozole, goserelin, anti-HER2 monoclonal antibody (e.g. Herceptin®), capecitabine, raloxifene hydrochloride, EGFR inhibitors (e.g. Iressa®, Tarceva®, Erbitux®), VEGF inhibitors (e.g. Avastin®), proteasome inhibitors (e.g. Velcade®), Glivec® and hsp90 inhibitors (e.g. 17-AAG). Additionally, the compound of the invention according to Formula I may be administered in combination with other therapies including, but not limited to, radiotherapy or surgery. In a specific embodiment the proliferative disorder is selected from cancer, myeloproliferative disease or leukemia.

[0329] In one embodiment, a compound of the invention is co -administered with another therapeutic agent for the treatment and / or prophylaxis of autoimmune diseases, particular agents include but are not limited to: glucocorticoids, cytostatic agents (e.g. purine analogs), alkylating agents, (e.g. nitrogen mustards (cyclophosphamide), nitrosoureas, platinum compound of the inventions, and others), antimetabolites (e.g. methotrexate, azathioprine and mercaptopurine), cytotoxic antibiotics (e.g. dactinomycin anthracy clines, mitomycin C, bleomycin, and mithramycin), antibodies (e.g. anti-CD20, anti-CD25 or anti-CD3 (OTK3) monoclonal antibodies, Atgam® and Thymoglobuline®), cyclosporin, tacrolimus, rapamycin (sirolimus), interferons (e.g. IFN-|3), TNF binding proteins (e.g. infliximab, etanercept, or adalimumab), mycophenolate, fmgolimod and myriocin.

[0330] In one embodiment, a compound of the invention is co -administered with another therapeutic agent for the treatment and / or prophylaxis of transplant rejection, particular agents include but are not limited to: calcineurin inhibitors (e.g. cyclosporin or tacrolimus (FK506)), mTOR inhibitors (e.g. sirolimus, everolimus), anti-proliferatives (e.g. azathioprine, mycophenolic acid), corticosteroids (e.g. prednisolone, hydrocortisone), antibodies (e.g. monoclonal anti-IL-2Ra receptor antibodies, basiliximab, daclizumab), polyclonal anti-T-cell antibodies (e.g. anti-thymocyte globulin (ATG), anti -lymphocyte globulin (ALG)).

[0331] In one embodiment, a compound of the invention is co -administered with another therapeutic agent for the treatment and / or prophylaxis of asthma and / or rhinitis and / or COPD, particular agents include but are not limited to: beta2-adrenoceptor agonists (e.g. salbutamol, levalbuterol, terbutaline and bitolterol), epinephrine (inhaled or tablets), anticholinergics (e.g. ipratropium bromide), glucocorticoids (oral or inhaled), long-acting [32-agonists (e.g. salmeterol, formoterol, bambuterol, and sustained -release oral albuterol), combinations of inhaled steroids and long-acting bronchodilators (e.g. fluticasone / salmeterol, budesonide / formoterol), leukotriene antagonists and synthesis inhibitors (e.g. montelukast, zafirlukast and zileuton), inhibitors of mediator release (e.g. cromoglycate and ketotifen), biological regulators of IgE response (e.g. omalizumab), antihistamines (e.g. cetirizine, cinnarizine, fexofenadine) and vasoconstrictors (e.g. oxymethazoline, xylomethazoline, nafazoline and tramazoline) .

[0332] Additionally, a compound of the invention may be administered in combination with emergency therapies for asthma and / or COPD, such therapies include oxygen or heliox administration, nebulized salbutamol or terbutaline (optionally combined with an anticholinergic (e.g. ipratropium), systemic steroids (oral or intravenous, e.g. prednisone, prednisolone, methylprednisolone, dexamethasone, or hydrocortisone), intravenous salbutamol, non-specific beta-agonists, injected or inhaled (e.g. epinephrine, isoetharine, isoproterenol, metaproterenol), anticholinergics (IV or nebulized, e.g. glycopyrrolate, atropine, ipratropium), methylxanthines (theophylline, aminophylline, bamiphylline), inhalation anesthetics that have a bronchodilatory effect (e.g. isoflurane, halothane, enflurane), ketamine and intravenous magnesium sulfate.

[0333] In one embodiment, a compound of the invention is co -administered with another therapeutic agent for the treatment and / or prophylaxis of inflammatory bowel disease (IBD), particular agents include but are not limited to: glucocorticoids (e.g. prednisone, budesonide) synthetic disease modifying, immunomodulatory agents (e.g. methotrexate, leflunomide, sulfasalazine, mesalazine, azathioprine, 6- mercaptopurine and cyclosporin) and biological disease modifying, immunomodulatory agents (infliximab, adalimumab, rituximab, and abatacept).

[0334] In one embodiment, a compound of the invention is co -administered with another therapeutic agent for the treatment and / or prophylaxis of SLE, particular agents include but are not limited to: human monoclonal antibodies (belimumab (Benlysta®)), Disease -modifying antirheumatic drugs (DMARDs) such as antimalarials (e.g. hydroxychloroquine), immunosuppressants (e.g. methotrexate and azathioprine), cyclophosphamide and mycophenolic acid, immunosuppressive drugs and analgesics, such as nonsteroidal anti-inflammatory drugs, opiates (e.g. dextropropoxyphene and co-codamol), opioids (e.g. hydrocodone, oxycodone, MS Contin, or methadone) and the fentanyl duragesic transdermal patch.

[0335] In one embodiment, a compound of the invention is co -administered with another therapeutic agent for the treatment and / or prophylaxis of psoriasis, particular agents include but are not limited to: topical treatments such as bath solutions, moisturizers, medicated creams and ointments containing coal tar, dithranol (anthralin), corticosteroids like desoximetasone (Topicort®), fluocinonide, vitamin D3 analogues (for example, calcipotriol), argan oil and retinoids (etretinate, acitretin, tazarotene), systemic treatments such as methotrexate, cyclosporine, retinoids, tioguanine, hydroxyurea, sulfasalazine, mycophenolate mofetil, azathioprine, tacrolimus, fumaric acid esters or biologies such as Amevive®, Enbrel®, Humira®, Remicade®, Raptiva® and ustekinumab (an IL-12 and IL-23 blocker). Additionally, a compound of the invention may be administered in combination with other therapies including, but not limited to phototherapy, or photochemotherapy (e.g. psoralen and ultraviolet A phototherapy (PUVA)).

[0336] In one embodiment, a compound of the invention is co -administered with another therapeutic agent for the treatment and / or prophylaxis of allergic reaction, particular agents include but are not limited to: antihistamines (e.g. cetirizine, diphenhydramine, fexofenadine, levocetirizine), glucocorticoids (e.g. prednisone, betamethasone, beclomethasone, dexamethasone), epinephrine, theophylline or anti- leukotrienes (e.g. montelukast or zafirlukast), anti-cholinergics and decongestants.

[0337] By co-administration is included any means of delivering two or more therapeutic agents to the patient as part of the same treatment regime, as will be apparent to the skilled person. Whilst the two or more agents may be administered simultaneously in a single formulation, i. e. as a single pharmaceutical composition, this is not essential. The agents may be administered in different formulations and at different times.CHEMICAL SYNTHETIC PROCEDURESGeneral

[0338] The compound of the invention can be prepared from readily available starting materials using the following general methods and procedures. It will be appreciated that where typical or preferred process conditions (i.e. reaction temperatures, times, mole ratios of reactants, solvents, pressures, etc.) are given, other process conditions can also be used unless otherwise stated. Optimum reaction conditions may vary with the particular reactants or solvent used, but such conditions can be determined by one skilled in the art by routine optimization procedures.

[0339] Additionally, as will be apparent to those skilled in the art, conventional protecting groups may be necessary to prevent certain functional groups from undergoing undesired reactions. The choice of a suitable protecting group for a particular functional group as well as suitable conditions for protection and deprotection are well known in the art (Wuts & Greene 2006).

[0340] The following methods are presented with details as to the preparation of a compound of the invention as defined hereinabove and the comparative examples. A compound of the invention may be prepared from known or commercially available starting materials and reagents by one skilled in the art of organic synthesis.

[0341] All reagents are of commercial grade and are used as received without further purification, unless otherwise stated. Commercially available anhydrous solvents are used for reactions conducted under inert atmosphere. Reagent grade solvents are used in all other cases, unless otherwise specified. Column chromatography is performed on silica gel 60 (35-70 pm) or with Biotage® SNAP KP-NH, Biotage® SNAP Ultra, or Interchim® PuriFlash® Si HC flash or Sfar HC chromatography cartridges (FSUS-0443-0100). Thin layer chromatography is carried out using pre-coated silica gel F-254 plates (thickness 0.25 mm). Biotage® ISOLUTE® phase separators (e.g, Cat# 120-1907-E) are used for aqueous phase separation. ’H NMR spectra are recorded on a Bruker DPX 400 NMR spectrometer (400 MHz), a Bruker Avance 300 NMR spectrometer (300 MHz), or a Bruker Avance III HD NMR spectrometer (400 MHz). Chemical shifts (5) for ’H NMR spectra are reported in parts per million (ppm) relative to tetramethylsilane (5 0.00) or the appropriate residual solvent peak, e.g. CHCL (5 7.27), as internal reference. Multiplicities are given as singlet (s), doublet (d), triplet (t), quartet (q), quintet (quin), multiplet (m) and broad (br). Electrospray MS spectra are obtained on a Waters Acquity H-Class or I-Class UPLC system coupled to a UV PDA detector and to a Waters SQD, SQD2 or QDa mass spectrometer.

[0342] Analytical LCMS methods: Acid 2 min mode; Column Acquity UPLC BEH C18 column, 2.1x30mm, 1.7pm particles size from waters; Mobile phase A Water +0.1% formic acid; Mobile phase BAcetonitrile +0.1% formic acid - Acid 3 min mode; Column Acquity UPLC BEH C18 column, 2. 1x50mm, 1.7pm particles size from Waters; Mobile Phase A Water +0.1% formic acid; Mobile phase B Acetonitrile +0.1% formic acid; Basic 3 min mode; Column Acquity UPLC BEH C18 column, 2.1x50mm, 1.7pm particles size from Waters; Mobile phase A Water +0.05% ammoniac; Mobile phase B Acetonitrile +0.05% ammoniac; Flow rate 0.8 mL / min; UV detection 210 to 400 nm, Ionisation mode Positive and negative Electrospray. Preparative LCMS methods: Column XBridge Prep C18, 30* 100mm, 5pm particles size from Waters Mobile phases for acid method A Phase Al : Water + 0.1% Formic acid Phase Bl : ACN + 0.1% Formic acid Mobile phases for basic method B Phase A2 : Water + 0.1% NFLOH Phase B2 : ACN + 0.1% NH4OH Elution gradient Optimal focused gradient Elution gradient Optimal focused gradient Flow rate 50 mL / min UV detection 210 to 400 nm ELSD detection Gas pressure 35psi Drift tube temperature 50°C Gain 10 Make up 1 mL / min, MeOH+0. 1% Formic acid Ionisation mode Positive and negative Electrospray. SFC analyses are performed on a Waters Acquity UPC2system coupled to a Acquity UV PDA detector and a Acquity QDa mass detector. Screened chiral columns : Chiralcel OJ-H 5pm, 4.6mm ID x 150mm L, Chiralpak IJ-H 5pm, 4.6mm ID x 150mm L, Chiralpak IA 5pm, 4.6mm ID x 150mm L, Chiralpak IG 5pm, 4.6mm ID x 150mm L, Chiralpak IBN-5 5pm, 4.6mm ID x 150mm L, Chiralpak IH 5pm 4.6mm ID x 250mm L, Lux Cellulose-1 5pm, 4.6mm ID x 150mm L, Lux Cellulose-4 5pm, 4.6mm ID x 150mm L, Lux i-Cellulose-5 5pm, 4.6mm ID x 150mm L. Screened methods are using CCF / cosoIvcnt gradients with ethanol, acetonitrile, methanol or isopropanol as cosolvent. SFC purifications are performed on a Pic Solution Prep 100 system coupled to a UV detector, using same columns in dimension 5 pm, 20mmID x 150mm L and same co-solvent.

[0343] NH4OH. Microwave heating is performed with a Biotage® Initiator or Anton Paar® Monowave 400.Table I. List of abbreviations used in the experimental section:Example 1. Illustrative intermediates preparation1.1. Int i

[0344] In a 15 L single jacketed process reactor equipped with mechanical stirring (200 rpm) and baffle, were charged DMF (3.5 L, 8V) and Int 57 (430 g, 1,712 mmol, 1 eq.). The resulting solution was stirred 10 min at RT then cooled down to 0°C. A solution of Int 58 (490 g, 1763 mmol, 1.03 eq.) in DMF (860 mL, 2V) was slowly added over 1.3 h while maintaining the process temperature between 0 and 2°C. Over the course of the addition, the stirring was increased to 275 rpm. Following the addition, the reaction mixture was stirred for a further 3 h at 0°C. The reaction mixture was quenched by slow addition (approx. 45 min) of aq. K2CO3 10% (1.075 L, 2.5V) while maintaining the process temperature below 5°C. Water (2.2 L, 5V) and EtOAc (4.4L, 10V) were added in 3 portions each, alternating between the two liquids. The jacket temperature was set to 22°C and the biphasic mixture was stirred for 5 min at 275 rpm. The layers were separated and the aqueous layer extracted with EtOAc (2x 1.1 L, 2x2.5V), the organic layers were combined, washed with aq. K2CO3 10% (860 mL, 2V), aq. LiCl 10% (1.7 L, 4V), water (1.3 L, 3V) and aq. NaCl 10% (860 mL, 2V); and concentrated under vacuum to afford ethyl (2S)-2-(3-bromopyrazolo[l,5- a]pyridin-6-yl)oxypropanoate .

[0345] ’H NMR (400 MHz, DMSO-de) 5 8.45 (dd, 1H), 8.05 (s, 1H), 7.53 (dd, 1H), 7.22 (dd, 1H), 5.12 (q, 1H), 4.16 (qd, 2H), 1.54 (d, 3H), 1.18 (t, 3H).

[0346] In a 15 L single jacketed process reactor equipped with mechanical stirring (200 rpm) and baffle, were charged ethyl (2S)-2-(3-bromopyrazolo[l,5-a]pyridin-6-yl)oxypropanoate (432 g, 1170 mmol, 1 eq.) and 2-MeTHF (4.3 L, 10V). The resulting solution was cooled to 0°C. A solution of MeMgBr (3.4 M in 2- MeTHF, 1 L, 3400 mmol, 2.9 eq.) was slowly added over 1.25 h while maintaining the process temperature between 0 and 2°C. Following the addition, the reaction mixture was stirred for a further 30 min at this temperature. The jacket temperature was set at -15 °C and the reaction mixture was quenched by slow addition over 55 min of aq. HC1 1 M (5.5 L, 5500 mmol, IV) while maintaining the process temperature below 10°C, with the jacket temperature set to warm to 30°C over 30 min after addition of 3.5 L of HC1. The stirring was set to 250 rpm and the biphasic mixture was stirred 30 min, with jacket temperature set at 30°C for 20 min, then cooled down to 23°C. The layers were separated, and the aqueous layer was extracted with 2-MeTHF (4V). The organic layers were combined, washed with aq. NaHCOs 10% (2V), brine (3V), filtered over cellulose and concentrated under vacuum to give Int 1 (3S)-3-(3-bromopyrazolo[l,5-a]pyridin- 6-yl)oxy-2 -methyl -butan-2 -ol .

[0347] ’H NMR (400 MHz, DMSO-de) 5 8.49 (dd, 1H), 8.02 (s, 1H), 7.53 - 7.42 (m, 1H), 7.18 (dd, 1H), 4.54 (s, 1H), 4.19 (q, 1H), 1.22 (d, 3H), 1.18 (s, 3H), 1.16 (s, 3H)1.2. Int 2

[0348] A pvial was charged with 6-bromo-3-iodopyrazolo[l,5-a]pyrimidine (1 eq., 300 mg, 0.93 mmol) , 4-fluoro-2 -methyl- 1 -(propan-2 -yl)-6-(4, 4,5,5 -tetramethyl- 1 ,3, 2-dioxaborolan-2 -yl)- 1H- 1 ,3 -benzodiazole (1 eq., 294.703 mg, 0.93 mmol) , CS2CO3 (2 eq., 603.52 mg, 1.85 mmol), Pd(dppf)C12'DCM (0.1 eq., 75.63 mg, 0.093 mmol), and degassed with Argon. Anhydrous degassed (bubbling Nitrogen for 15min) dioxane (7.103 mb) and water (1.42 mb) were added at RT and reaction mixture was degassed through vacuum / Argon cycles 4 times, kept under Argon atmosphere. Then reaction mixture was heated at reflux under argon atmosphere for 18 h. The reaction mixture was filtered through a pad of celite and solid was rinsed with EtOAc, the filtrate was washed twice with water, and with brine, dried over anhydrous MgSCh, filtered and concentrated under vacuum. The crude residue was then purified by column chromatography (Sfar HC 25g, elution with DCM / MeOH 100 to 94 / 6 in 50CV) to afford Int 2 6 -bromo-3-(4-fluoro-l -isopropyl -2- methyl-lH-benzo[d]imidazol-6-yl)pyrazolo[l,5-a]pyrimidine (34 mg).

[0349] LCMS: MW (calcd): 388.2; m / z MW (obsd): 388.1 - 390.0 (M+H).1.3. Int 3

[0350] A lOOmL round botom flask was charged with Int4 (1 eq., 2.4 g, 8 mmol), 4,4,5,5-tetraethyl-2- (4,4,5,5-tetraethyl-l,3,2-dioxaborolan-2-yl)-l,3,2-dioxaborolane (1.5 eq., 4.39 g, 11.99 mmol) and degassed with Argon. Anhydrous degassed (bubbling Nitrogen for 15min) dioxane (24 mL) was added at RT and reaction mixture was degassed through vacuum / Argon cycles 4 times, kept under Argon atmosphere (balloon), reaction mixture was stirred at 85-90°C (preheated oil bath) under argon atmosphere for 5 min then KOPiv (3 eq., 3.36 g, 23.99 mmol) and XPhosPdG4 (0.065 eq., 0.45 g, 0.52 mmol) were added, reaction mixture was degassed through vacuum / Argon cycles 3 times, kept under Argon atmosphere (balloon) and stirred at 85-90°C for 6h. The reaction mixture was cooled down to rt, diluted with AcOEt. The resulting suspension was filtered on a sintered disc funnel grade 4. Solids were washed with AcOEt (3 times) until a colorless filtrate was obtained. The combined filtrates were washed with water, brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was purified in normal phase chromatography (SiO2 20 pm 100 g, loading DCM, gradient Hept / EtOAc 100:0 to 50:50 in 15 CV) to afford (S)-2-methyl-3-((3-(4,4,5,5-tetraethyl-l,3,2-dioxaborolan-2-yl)pyrazolo[l,5-a]pyrimidin-6- yl)oxy)butan-2-ol Int 3(1.71 g).

[0351] LCMS: MW (calcd): 403.3; m / z MW (obsd): 404.4 (M+H).1.4. Int 41.4.1. Step A: methyl (2S)-2-pyrazolo[l,5-a]pyrimidin-6-yloxypropanoate

[0352] In a round botom flask, to a solution of potassium pyrazolo[l,5-a]pyrimidin-6-olate (4.0 g, 23 mmol, 1.0 eq.) in DMF (32 mL) at 0°C was added a solution of Int 59 (6.6 g, 25 mmol, 1.1 eq.) in DMF (8.0 mL). The reaction mixture was stirred at 0°C for 1 h. The reaction mixture was quenched by slow addition of aq. K2CO3 10%. Water and EtOAc were then added, and the layers were separated. The aqueous layer was extracted with EtOAc (four times), the organic layers were combined, washed with aq. LiCl 10% (twice), NaCl 10%, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude was purified by flash chromatography with a Biotage® Sfar HC 100 g cartridge, eluting with heptane / EtOAc 100 / 0 to 0 / 100 to afford methyl (2S)-2-pyrazolo[l,5-a]pyrimidin-6-yloxypropanoate.

[0353] LCMS: MW (calcd): 221.0; m / z MW (obsd): 221.8 (M+H)1.4.2. Step B: methyl (2S)-2-(3-bromopyrazolo[l,5-a]pyrimidin-6-yl)oxypropanoate

[0354] In a round botom flask, to a solution of methyl (2S)-2-pyrazolo[I,5-a]pyrimidin-6- yloxypropanoate (2.4 g, 11 mmol, 1.0 eq.) in ACN (48 mL) at 0°C was added NBS (2.1 g, 1.0 mL, 12 mmol, l. leq.). The reaction mixture was stirred at RT for 45 min. The mixture was diluted in DCM and the organic layer was washed with aq. NaHCCE 5%, brine, dried over Na2SC>4, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography with a Biotage® Sfar HC 100 g cartridge (CAT N# FSUS-0443-0100), eluting with heptane / EtOAc 100 / 0 to 75 / 25 to afford methyl (2S)-2-(3-bromopyrazolo[I,5-a]pyrimidin-6-yl)oxypropanoate.

[0355] LCMS: MW (calcd): 299.0; m / z MW (obsd): 299.7 / 301.7 (M+H)

[0356] ’H NMR (400 MHz, CD3OD) 5 8.62 (d, 1H), 8.51 (d, 1H), 8.06 (s, 1H), 5.02 (q, 1H), 3.78 (s, 3H), 1.66 (d, 3H)1.4.3. Step C: (3S)-3-(3-bromopyrazolo[l,5-a]pyrimidin-6-yl)oxy-2-methyl-butan-2-ol

[0357] In a round botom flask, to a suspension of methyl (2S)-2-(3-bromopyrazolo[l,5-a]pyrimidin-6- yl)oxypropanoate (3100 mg, 10 mmol, 1.0 eq.) at 0°C in 2-MeTHF (31 mL) was added dropwise a methylmagnesium bromide solution (3.0 mol / L in 2-MeTHF; 10 mL, 31 mmol, 3.0 eq.). The reaction mixture was stirred at 0°C for 15 min. The mixture was then quenched with hydrochloric acid (1 mol / L) in water (36 mL, 36 mmol, 3.5eq.) and extracted with 2-MeTHF (twice). The yellow organic layer was washed with water, brine, dried over Na2SC>4, filtered and concentrated under reduced pressure. The crude was purified by flash chromatography with a Biotage® Sfar HC 100 g cartridge, eluting with heptane / EtOAc 100 / 0 to 0 / 100 to afford Int 4 (3S)-3-(3-bromopyrazolo[l,5-a]pyrimidin-6-yl)oxy-2-methyl-butan-2-ol, with a measured enantiomeric excess of 84%.

[0358] SFC Chiral preparative purification done on Column Lux Cellulose-1, 150 x 21.2mm, 5pm; CO2 back pressure : 100 bar; Co-solvent : Ethanol; Flowrate : 60mL / min; Mode : Isocratic; %Co-Solvent : 10%; Detection : UV at 238nm; Temperature : 40°C. Second eluting compound recovered with a measured enantiomeric excess of >99.2%.

[0359] LCMS: MW (calcd): 299.0; m / z MW (obsd): 299.8 / 301.8 (M+H)1.5. Int 5

[0360] In a vial was introduced 6-bromo-4-fluoro-3-methyl-lH-indazole (1 eq., 249 mg, 1.087 mmol), 2- bromopropane (2 eq., 267.409 mg, 204.13 pL, 2.17 mmol), KOH (1.5 eq., 91.49 mg, 1.63 mmol) in EtOH (4,000 pL) and the mixture was heated to 70°C for 18 h. The reaction mixture was filtered, concentrated and purified by normal phase chromatography (SiO2 40-63 pm 10 g, loading DCM, gradient Heptane / EtOAc 100:0 to 50:50 to afford 6-bromo-3-(4-fluoro-l-isopropyl-2-methyl-lH-benzo[d]imidazol- 6-yl)pyrazolo[l,5-a]pyrimidine Int 5 (162 mg).

[0361] LCMS: MW (calcd): 271.1; m / z MW (obsd): 271.1 - 273.1 (M+H).1.6. Int 6

[0362] In a vial was introduced 6-Bromo-4-methoxy-lH-indazole (1 eq., 200 mg, 0.88 mmol), 2- bromopropane (2 eq., 216.67 mg, 165.4 pL, 1.76 mmol), KOH (1.5 eq., 74.13 mg, 1.32 mmol) in EtOH (4,000 pL) and the mixture was heated to 70°C for 18 h. The reaction mixture was fdtered, concentrated and purified by normal phase chromatography (SiO2 40-63 pm 10 g, loading DCM, gradient Heptane / EtOAc 100:0 to 50:50 in 10 CV to afford 6-bromo-l-isopropyl-4-methoxy-lH-indazole Int 6(88 mg).

[0363] LCMS: MW (calcd): 269.1; m / z MW (obsd): 269.1 - 271.1 (M+H).1.7. Int 71.7.1. Step A: 5-bromo-3-fluoro-N-isopropyl-2-nitroaniline + )— NH N O' ' 6'

[0364] A 500 ml round bottom flask was charged at RT under Air with 5-bromo-l,3-difluoro-2- nitrobenzene 98% (1 eq., 10 g, 42.019 mmol) and DMSO (100 mb). To the resulting solution was added Isopropylamine (1 eq., 2.48 g, 3.6 mb, 42.019 mmol) and the reaction mixture was stirred at RT over weekend. The reaction mixture was cooled down (ice water / bath) and hydrolysed with 60 mb of NaHCOs sat. The resulting suspension was vigorously stirred at 0°C for 15min, then filtered on a sintered disc funnel grade 4. The orange solid was washed with water (3 times) and dried in vacuo and then vigorously triturated in 26mL of isobutanol. The suspension was filtered on a sintered disc funnel grade 4. The yellow / orange solid was washed / triturated with isobutanol (twice 2*5mL) and dried in vacuo. The resulting solid wastaken up in DCM (116 mb) and the resulting suspension was filtered on a sintered disc funnel grade 4. Solids were washed with DCM (twice 2*30mL) and the filtrate was concentrated in vacuo to afford 5- bromo-3-fluoro-N-isopropyl-2 -nitroaniline (7.42 g).

[0365] LCMS: MW (calcd): 277. 1; m / z MW (obsd): 277.0 - 279. 1 (M+H).1. 7.2. Step B: 5-bromo-3-f / uoro-Nl -isopropylbenzene- 1,2-diamine

[0366] In a round botom flask, to a stirred solution 5-bromo-3-fluoro-N-isopropyl-2 -nitroaniline (1 eq., 1 g, 3.609 mmol) in EtOH (10 m ) and water (3.33 m ) and NH4CI (5 eq., 0.97 g, 18.044 mmol) at 80°C was added be (5.27 eq., 1.062 g, 19.019 mmol). The mixture was stirred at 80°C for 30min. The reaction mixture was cooled down to rt, diluted with AcOEt. The resulting suspension was filtered on a sintered disc funnel grade 4. Solids were washed with AcOEt (3 times) until a colorless filtrate was obtained. The combined filtrates were washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The crude residue was purified by chromatography SiO2, AGELA 40 g, 40 - 60pm, dry loading (crude dissolved in DCM), biotage Isolera, Q=30mL / min, gradient Hept / EtO Ac 100:0 to 85: 15 in 15 CV. To afford 5 -bromo- 3 -fluoro-Nl -isopropylbenzene- 1,2-diamine. (861 mg, 97% yield).

[0367] LCMS: MW (calcd): 247. 1; m / z MW (obsd): 247. 1 - 249. 1 (M+H).1.7.3. Step C: (R)-l-(6-bromo-4-fluoro-l-isopropyl-lH-benzo[d]imidazol-2-yl)-2,2,2-

[0368] In an open vial, under air, a mixture of 5-bromo-3-fluoro-Nl-isopropylbenzene-l,2-diamine (1 eq., 100 mg, 0.405 mmol) and (R)-(-)-3,3,3-Trifluoro-2-hydroxypropanoic acid (10 eq., 582.93 mg, 4.047 mmol) was stirred at 80°C in dioxane (1 mb) over night. After evaporation, the crude was purified by Normal phase chromatography (SiCE 20 pm 10 g, loading DCM, gradient Heptane / EtOAc 100:0 to 50:50 in 15 CV. The tubes containing product were evaporated to afford (R)-l-(6-bromo-4-fluoro-l -isopropyl - lH-benzo[d]imidazol-2-yl)-2,2,2-trifluoroethan-l-ol Int 7(108 mg, 75% yield), ee: 94%. Chiral SFC; Chiralpak IA, 150 x 4.6mm, 5pm ; CO2 back pressure : 1500psi; Detection : PDA and MS; Co-solvent : Ethanol; Flowrate : 3mL / min; Mode : Gradient; Temperature : 40°C.

[0369] LCMS: MW (calcd): 355.1; m / z MW (obsd): 355.1 - 357.1 (M+H).1.8. Int 8

[0370] A screw vial cap was charged at RT under nitrogen, 3-bromopyrazolo[l,5-a]pyrimidin-6-ol (1 eq.,120 mg, 0.56 mmol) and 3,3-dimethylbutan-2-yl 4-methylbenzenesulfonate (1.5 eq., 215.608 mg, 0.84 mmol), with anhydrous DMSO (3 mL). To the mixture was added at RT K2CO3 (3 eq., 232.47 mg, 1.68 mmol). The mixture was stirred at 100°C over the weekend. 3,3-dimethylbutan-2-yl 4- methylbenzenesulfonate (0.75 eq., 108 mg, 0.42 mmol) was added at RT to the mixture then the reaction was stirred at 100°C. The mixture was cooled to RT and water was added to the mixture, EtOAc was added, and extraction was done, organic layer was recovered and dried over MgSO4, filtered, concentrated under vacuum and directly purified on Agela 12g irregular column, Silica deposit, eluted with gradient 0 to 100% ethyl acetate in heptane (10CV) (Biotage Isolera One device). The product fraction was evaporated to dryness to afford 3-bromo-6-((3,3-dimethylbutan-2-yl)oxy)pyrazolo[l,5-a]pyrimidine Int 8 (35 mg).

[0371] LCMS: MW (calcd): 298.2; m / z MW (obsd): 298.1 - 300.1 (M+H).1.9. Int 91.9.1. Step A: 5-bromo-3-fluoro-N-isopropyl-2-nitroaniline

[0372] In a sealed tube, under air, a mixture of 5-Bromo-l,3-difluoro-2 -nitrobenzene (1 eq., 400 mg, 1.68 mmol), 2,2,2-Trifluoroethylamine hydrochloride (1 eq., 227.76 mg, 1.68 mmol) and DIPEA (1.25 eq., 271.54 mg, 0.37 mL, 2.101 mmol) was dissolved in DMF (7 mL). The reaction mixture was stirred at 80°C for 21 h. Water and EtOAc were added. The organic layer was washed with water, brine, dried over anhydrous Na2SO4, fdtered and evaporated. The crude was purified in reverse phase chromatography (Cl 8 40 pm 60 g, loading DMSO, gradient water (formic acid 0.1%) / MeCN (formic acid 0.1%) 100:0 to 20:80 in 15 CV) to afford 5-bromo-3-fhioro-2-nitro-N-(2,2,2-trifluoroethyl)aniline (257 mg)

[0373] LCMS: MW (calcd): 317.0; m / z MW (obsd): 315.2 - 317.1 (M-H).1.9.2. Step B: 5-bromo-3-fluoro-Nl-(2,2,2-trifluoroethyl)benzene-l,2-diamine

[0374] In a round bottom flask, to a stirred solution of 5-bromo-3-fluoro-2-nitro-N-(2,2,2- trifluoroethyl)aniline (1 eq., 247 mg, 0.78 mmol) in MeOH (2.52 mL) and water (0.75 mL) was added NH4CI (5 eq., 208.37 mg, 3.9 mmol) followed by Fe (5 eq., 217.54 mg, 3.9 mmol) at RT and at 60°C for 3 h. The mixture was cooled to RT and filtered on a pad of celite. The solid was washed with EtOAc. The filtrate was concentrated, then the residue was taken up in EtOAc and washed with water. The aqueous layer was extracted with EtOAc (2x), and the combined organic layer were dried over anhydrous Na2SO4,filtered and concentrated under vacuo afford 5-bromo-3-fluoro-Nl-(2,2,2-trifluoroethyl)benzene-l,2- diamine (224 mg).

[0375] LCMS: MW (calcd): 287.1; m / z MW (obsd): 287.0 - 289.0 (M+H).1.9.3. Step C: 5-bromo-3- luoro-Nl-(2,2,2-tri luoroethyl)benzene-l,2-diamine

[0376] In a sealed tube, under air, a mixture of 5-bromo-3-fhioro-Nl-(2,2,2-trifluoroethyl)benzene-l,2- diamine (1 eq., 140 mg, 0.49 mmol) and L-(+)-Lactic acid 95% (10 eq., 439.32 mg, 0.37 mb, 4.88 mmol) was stirred at 80°C for 29 h and at 115°C for 18 h. The reaction mixture was directly purified by preparative LC-MS method A to afford a mixture of (S)-l-(6-bromo-4-fluoro-l-(2,2,2-trifhioroethyl)-lH- benzo [d]imidazol-2-yl)ethan- 1 -ol and (R)- 1 -(6-bromo-4-fluoro- 1 -(2,2,2-trifluoroethyl)- 1H- benzo[d]imidazol-2-yl)ethan-l-ol, Int 9 (10 mg, 6% yield, ee% 41.1). Chiral SFC; Chiralpak IA, 150 x 4.6mm, 5pm ; CO2 back pressure : 1500psi; Detection : PDA and MS; Co-solvent : Methanol; Flowrate : 3mL / min; Mode : Gradient; Temperature : 40°C.

[0377] LCMS: MW (calcd): 341.1; m / z MW (obsd): 341.1 - 343.1 (M+H).1.10. Int 10

[0378] In a sealed tube, under air, 3-bromopyrazolo[l,5-a]pyrimidin-6-ol (1 eq., 100 mg, 0.47 mmol),CAS# 185399-66-0 (1 eq., 47.72 mg, 0.47 mmol) and CMBP CAS# 157141-27-0 (2 eq., 0.93 mL, 0.93 mmol) were dissolved in toluene (3 mL). The reaction mixture was stirred at 90°C for additional 22 h. CSOIYAI_0443RM1 (Pl 36%, 0.53min, MH+ 298.1, acid 2min). DCM and water were added, and the biphasic solution was fdtered on a Biotage ISOLUTE phase separator. The organic layer was collected and concentrated in vacuo .The crude residue was purified in normal phase chromatography (SiO2 20 pm 25 g, loading DCM, gradient DCM / MeOH 90: 10 in 15 CV) to afford a mixture of (lS,3R)-3-((3- bromopyrazolo [1,5 -a]pyrimidin-6-yl)oxy)cyclopentan- 1 -ol and (lR,3S)-3-((3 -bromopyrazolo [1,5- a]pyrimidin-6-yl)oxy)cyclopentan-l-ol, Int 10 (30 mg).

[0379] LCMS: MW (calcd): 298.1; m / z MW (obsd): 298.0 - 300.0 (M+H).1.11. Int 111.11.1. Step A: 6-bromo-l-isopropyl-4-methoxy-2-methyl-lH-benzo[d]imidazole

[0380] The reaction was performed in a sealed vial under micro wave irradiation and split in 3 vials.

[0381] To a stirred solution of 6-bromo-4-fluoro-2-methyl-l-(propan-2-yl)-lH-l,3-benzodiazole (1 eq., 600 mg, 2.21 mmol) in MeOH (9 mL) was added MeONa (5 eq., 2391.033 mg, 2.53 mL, 11.065 mmol) atRT. The reaction mixture was stirred at 150°C for 2H under microwave irradiation. The reaction mixture was evaporated to dryness. Water and DCM were added and the reaction mixture was fdtered over a phase separator. The organic layer was concentrated under vacuum. The crude material was then purified by column chromatography (Sfar HC 25g, elution with DCM / MeOH (3 / 1) 100 to 97 / 3 over 20CV ) to afford 6-bromo-l-isopropyl-4-methoxy-2-methyl-lH-benzo[d]imidazole Int51 (532 mg).

[0382] LCMS: MW (calcd): 283.2; m / z MW (obsd): 283.1 - 285.1 (M+H).1.11.2. Step B: 6-bromo-l-isopropyl-2-methyl-lH-benzo[d]imidazol-4-ol

[0383] In a round bottom flask with dry solvent and under inert atmosphere, to a stirred solution of 6- bromo-l-isopropyl-4-methoxy-2-methyl-lH-benzo[d]imidazole (1 eq., 530 mg, 1.87 mmol) in DCM (16.74 mL) was added BBr3 (3 eq., 5.62 mb, 5.62 mmol) at 0°C. The reaction mixture was stirred at RT overnight. BBr3 (3 eq., 5.62 mL, 5.62 mmol) was added and the reaction mixture was stirred at RT for 6 h. The reaction mixture was cooled to 0°C, quenched by addition of MeOH and evaporated to dryness after SiC>2 addition. The crude material was then purified by column chromatography (Sfar HC 25g, elution with DCM / MeOH (3 / 1) 100 to 95 / 5 over 20 CV ) to afford 6-bromo-l-isopropyl-2-methyl-lH- benzo[d]imidazol-4-ol (503.6 mg).

[0384] LCMS: MW (calcd): 269.1; m / z MW (obsd): 269.0 - 271.0 (M+H).

[0385] Step C: 6-bromo-4-(difluoromethoxy)-l-isopropyl-2-methyl-lH-benzo[d]imidazole

[0386] In a sealed vial under argon atmosphere, to a stirred solution of 6-bromo-l-isopropyl-2-methyl-lH- benzo[d]imidazol-4-ol (1 eq., 50 mg, 0.19 mmol) and K2CO3 (2 eq., 51 .35 mg, 0.37 mmol) in DMF (1.61 mL) was added CClF2COONa (2 eq., 56.65 mg, 0.37 mmol) at RT. The reaction mixture stirred at 100°C for 3 h. Water was added and the reaction mixture was extracted twice with EtOAc. The combined organic layer was dried over Na2SC>4, filtered and evaporated to dryness. The crude material was then purified by column chromatography (Sfar HC 10g, elution with DCM / AcOEt-EtOH (3 / 1) 100 to 50 / 50 over 20 CV ) to afford 6-bromo-4-(difhioromethoxy)-l-isopropyl-2-methyl-lH-benzo[d]imidazole, Int 11(15 mg).

[0387] LCMS: MW (calcd): 319.1; m / z MW (obsd): 319.2 - 321.2 (M+H).1.12. Int 12

[0388] In a sealed tube, under air, a mixture of 2-({3-bromopyrazolo[l,5-a]pyrimidin-6-yl}oxy)-2- methylpropanamide (1 eq., 100 mg, 0.47 mmol), 2-bromo-2-methylpropanamide (1 eq., 77.57 mg, 0.47 mmol) and K2CO3 (1 eq., 64.58 mg, 0.47 mmol) in DMF (0.72 mL) was stirred at RT for 21 h at 70°C. The mixture was filtered and purified by reverse phase chromatography (Cl 8 40 pm 60 g, loading MeOH, gradient water (formic acid 0.1%) / MeCN (formic acid 0.1%) 100:0 to 0: 100 in 15 CV and purified by preparative LC-MS method B to afford 2-((3-bromopyrazolo[l,5-a]pyrimidin-6-yl)oxy)-2- methylpropanamide Int 12 (12 mg).

[0389] LCMS: MW (calcd): 299.1; m / z MW (obsd): 299.1 - 301.1 (M+H).1.13. Int 131.13.1. Step A: 5-bromo-N-cyclopentyl-3-fluoro-2-nitroaniline

[0390] In a sealed tube, under air, a mixture of 5-Bromo-l,3-difluoro-2-nitrobenzene (1 eq., 4 g, 16.808 mmol), CS2CO3 (1.2 eq., 6.57 g, 20. 17 mmol) were dissolved in DMSO (35 mb). At 0°C, cyclopentanamine 95% (0.9 eq., 1.29 g, 1.5 mL, 15.13 mmol) was added slowly and the reaction mixture was stirred at RT for 26 h. EtOAc, and water were added. The organic layer was washed with water (x 3) and brine (x 2). The combined organic layer was dried over anhydrous Na2SC>4, filtered and concentrated. The crude was purified in normal phase chromatography (SiC>220 pm 100 g, loading DCM, gradient Heptane / EtOAc 100:0 to 50:50 in 15 CV) to afford 5-bromo-N-cyclopentyl-3-fluoro-2-nitroaniline (3.3 g).

[0391] LCMS: MW (calcd): 303.1; m / z MW (obsd): 303.1 - 305.1 (M+H). In a round bottom flask, to a stirred solution of -bromo-N-cyclopentyl-3-fluoro-2-nitroaniline (1 eq., 1.22 g, 4.025 mmol) in MeOH (13 mL) and water (3.9 mL) was added NH4CI (5 eq., 1.076 g, 20. 12 mmol) followed by Fe (5 eq., 1.12 g, 20.12 mmol) at RT. The mixture was stirred at 60°C for 5 h and was cooled to RT, filtered on a pad of celite. The solid was washed with EtOAc. The filtrate was concentrated, then the residue was taken up in EtOAc and washed with water. The aqueous layer was extracted with EtOAc (2x) and the combined organic layer were dried over anhydrous Na2SO4, filtered, concentrated under vacuo and purified in normal phase chromatography (SiO2 20 pm 50 g, loading DCM, gradient Hept / EtOAc 100:0 to 90: 10 in 15 CV) to afford 5-bromo-Nl-cyclopentyl-3-fluorobenzene-l,2-diamine (713 mg).1.13.2. Step B: 5-bromo-Nl-cyclopentyl-3-fluorobenzene-l,2-diamine

[0392] In a round bottom flask, to a stirred solution of -bromo-N-cyclopentyl-3-fluoro-2-nitroaniline (1 eq., 1.22 g, 4.025 mmol) in MeOH (13 mL) and water (3.9 mL) was added NH4CI (5 eq., 1.076 g, 20.12 mmol) followed by Fe (5 eq., 1. 12 g, 20. 12 mmol) at RT. The mixture was stirred at 60°C for 5 h and was cooled to RT, filtered on a pad of celite. The solid was washed with EtOAc. The filtrate was concentrated, then the residue was taken up in EtOAc and washed with water. The aqueous layer was extracted with EtOAc (2x) and the combined organic layer were dried over anhydrous Na2SO4, filtered, concentrated under vacuo and purified in normal phase chromatography (SiO2 20 pm 50 g, loading DCM, gradient Hept / EtOAc 100:0 to 90: 10 in 15 CV) to afford 5-bromo-Nl-cyclopentyl-3-fluorobenzene-l,2-diamine (713 mg).

[0393] LCMS: MW (calcd): 273.2; m / z MW (obsd): 273.1 - 275.1 (M+H).1.14. Step C: 5-bromo-Nl-cyclopentyl-3-fluorobenzene-l,2-diamine

[0394] In atube, under air, amixture of 5-bromo-Nl-cyclopentyl-3-fluorobenzene-l,2-diamine (1 eq., 100 mg, 0.37 mmol) and L-(+)-Lactic acid 95% (10 eq., 329.78 mg, 0.27 mL, 3.66 mmol) was stirred at 80°Cfor 7 h. The reaction mixture was directly purified in preparative LCMS method A to afford (S)-l-(6- bromo-l-cyclopentyl-4-fluoro-lH-benzo[d]imidazol-2-yl)ethan-l-ol Int 13 (61 mg).

[0395] LCMS: MW (calcd): 327.2; m / z MW (obsd): 327.1 - 329.1 (M+H).1.15. Int 141.15.1. Step A: 5-bromo-N-(tert-butyl)-3-fluoro-2-nitroaniline

[0396] In a sealed tube, under air, a mixture of 5-Bromo-l,3-difluoro-2 -nitrobenzene (1 eq., 200 mg, 0.84 mmol) was dissolved in DMSO (1.7 mb). 2-Amino-2 -methylpropane hydrochloride 97% (1 eq., 92.105 mg, 0.84 mmol) and cesium carbonate (3 eq., 821.43 mg, 2.52 mmol) were added and the reaction mixture was stirred at 40°C for 2.5h. EtOAc and water were added. The aqueous layer was extracted with EtOAc (x3), and the combined organic layer was washed with brine (x2). The organic layer was dried over anhydrous Na2SC>4, fdtered, concentrated and purified in normal phase chromatography (SiCE 20 pm 12 g, loading DCM, gradient Hept / EtOAc 100:0 to 90: 10 in 15 CV) and purified in reverse phase chromatography (C18 40 pm 60 g, loading DMSO, gradient water (formic acid 0.1%) / MeCN (formic acid 0.1%) 100:0 to 0: 100 in 15 CV) to afford 5-bromo-N-(tert-butyl)-3-fluoro-2 -nitroaniline (140 mg).

[0397] ’H NMR (400 MHz, DMSO) 5 7.08 (s, 1H), 7.06 (t, J = 1.8 Hz, 1H), 6.96 (dd, J = 11.1, 1.9 Hz, 1H), 1.41 (s, 9H).1.15.2. Step B: (R)-6-bromo-l-(tert-butyl)-2-(l-((tert-butyldimethylsilyl)oxy)ethyl)-4-fluoro- lH-benzo[d]imidazole

[0398] In a sealed tube, under air, a mixture of 5-bromo-N-(tert-butyl)-3-fluoro-2-nitroaniline (1 eq., 60 mg, 0.206 mmol) and (2R)-2-[(tert-butyldimethylsilyl)oxy]propanal 95% (2 eq., 77.63 mg, 0.41 mmol) was dissolved in DMSO (0.6 mb) and EtOH (2.4 mb). Then, Na2S2O4 (5 eq., 179.41 mg, 1.031 mmol) was added and the reaction mixture was stirred at 80°C for 22h. EtOAc and water were added. The aqueous layer was extracted with EtOAc (x3), and the combined organic layer was washed with water and brine. The organic layer was dried over anhydrous Na2SO4, filtered and concentrated under vacuum. The crude was purified in normal phase chromatography (SiO2 20 pm 5 g, loading DCM, gradient Hept / EtOAc 100:0 to 90: 10 in 15 CV) to afford (R)-6-bromo-l-(tert-butyl)-2-(l-((tert-butyldimethylsilyl)oxy)ethyl)-4-fluoro- lH-benzo[d] imidazole (27 mg).

[0399] LCMS: MW (calcd): 429.4; m / z MW (obsd): 429.3 - 431.3 (M+H).1.16. Step C: (R)-l-(6-bromo-l-(tert-butyl)-4-fluoro-lH-benzo[d]imidazol-2-yl)ethan-l-ol

[0400] In a sealed tube, under air, (R)-6-bromo-l-(tert-butyl)-2-(l-((tert-butyldimethylsilyl)oxy)ethyl)-4- fluoro-lH-benzo[d]imidazole (1 eq., 21 mg, 0.049 mmol) was dissolved in THF (0.5 mb). TBAF (IM inTHF) (1.5 eq., 0.073 mL, 0.073 mmol) was added and the reaction mixture was stirred at RT for 4.5 h. The reaction mixture was diluted in DCM and water. The biphasic mixture was fdtered on a Biotage ISOLUTE phase separator. The organic phase was collected and evaporated under reduced pressure to afford (R)-l- (6-bromo-l-(tert-butyl)-4-fluoro-lH-benzo[d]imidazol-2-yl)ethan-l-ol Int 14 (15.4 mg).

[0401] LCMS: MW (calcd): 315.2; m / z MW (obsd): 315.1 - 317.1 (M+H).1.17. Int 15

[0402] Intl5 (R)-l-(6-bromo-l-cyclopentyl-4-fluoro-lH-benzo[d]imidazol-2-yl)ethan-l-ol was prepared according to the method used for Intl3.

[0403] LCMS: MW (calcd): 327.2; m / z MW (obsd): 327.1 - 329.1 (M+H).1.18. Int 16

[0404] Int 16, (R)-l-(6-bromo-l-(tert-butyl)-4-fluoro-lH-benzo[d]imidazol-2-yl)ethan-l-ol was prepared according to the method used for Int 14.

[0405] LCMS: MW (calcd): 315.2; m / z MW (obsd): 315.1 - 317.1 (M+H).

[0406] Int 171.18.1. Step A: 5-bromo-3-chloro-N-isopropyl-2-nitroaniline

[0407] In a sealed tube, under air, a mixture of 5-bromo-l-chloro-3-fluoro-2-nitrobenzene (1 eq., 1.018 g, 4 mmol), 2-propanamine (1 eq., 0.24 g, 0.34 mL, 4 mmol), CS2CO3 (1.2 eq., 1.56 g, 4.8 mmol) and DMSO (7. 102 mL) was stirred at RT for 2 h. EtOAc and water were added. The organic layer was washed with brine, dried (MgSCL), fdtered, evaporated to give 5-bromo-3-chloro-N-isopropyl-2-nitroaniline (1.17 g).

[0408] LCMS: MW (calcd): 293.5; m / z MW (obsd): 295.5 - 297.5 (M+H).1.18.2. Step B: 5-bromo-3-chloro-Nl-isopropylbenzene-l,2-diamine

[0409] In a sealed tube, under air, a mixture of 5-bromo-3-chloro-N-isopropyl-2 -nitroaniline (1 eq., 1170 mg, 3.99 mmol) in MeOH (13.25 mL) , water (3.87 mL), and NH4CI (5 eq., 1065.97 mg, 19.93 mmol) andFe (5 eq., 1112.905 mg, 19.93 mmol) was stirred at 60°C for 2 h. The mixture was filtered on a cellite pad (rinsed with EtOAc, concentrated then EtOAc and water were added. The organic layer was washed with brine, dried (MgSCE), filtered, evaporated to afford 5-bromo-3-chloro-Nl-isopropylbenzene-l,2-diamine (l g).

[0410] LCMS: MW (calcd): 263.5; m / z MW (obsd): 263.1 - 265.0 (M+H).1.18.3. Step C: 5-bromo-3-chloro-Nl-isopropylbenzene-l,2-diamine

[0411] In a sealed tube, under air, a mixture of 5-bromo-3-chloro-Nl-isopropylbenzene-l,2-diamine (1 eq., 100 mg, 0.38 mmol), triethyl orthoacetate (20 eq., 1231.059 mg, 1.39 mb, 7.59 mmol) was stirred at 150°C for 1 h, cooled at RT and directly purified by normal phase chromatography (SiC>2 50 pm 20 g, loading DCM, gradient Heptane / EtOAc 100:0 to 50:50 in 10 CV) to afford 6 -bromo-4-chloro-l -isopropyl - 2-methyl-lH-benzo[d]imidazole Int 17 (58 mg, 53% yield).

[0412] LCMS: MW (calcd): 287.6; m / z MW (obsd): 287.0 - 289.0 (M+H).

[0413] Int 18

[0414] Intl8, 6-bromo-4-chloro-l-cyclopentyl-2-methyl-lH-benzo[d]imidazole was prepared according to the method used for Int 17.

[0415] LCMS: MW (calcd): 313.6; m / z MW (obsd): 313.1 - 315.0 (M+H).1.19. Int 19

[0416] To a stirred solution of intermediate prepared (Int 51, step A) 6-bromo-l -isopropyl -4-methoxy-2- methyl-lH-benzo[d]imidazole (1 eq., 190 mg, 0.67 mmol) in DCM (6 mL) was added BBr3 (3 eq., 2.013 mL, 2.013 mmol) at 0°C. The reaction mixture was stirred at RT for 18 h. More BBr3 (3 eq., 2.013 mL, 2.013 mmol) was added and the reaction mixture was stirred at RT 18 h. The reaction mixture was cooled to 0°C, quenched by addition of MeOH and evaporated to dryness after SiCL addition. The residue was purified on a 10g Sfar HC column (Biotage), eluted with gradient 0-4% MeOH in DCM (Biotage Isolera One device) to afford 6-bromo-l-isopropyl-2-methyl-lH-benzo[d]imidazol-4-ol (152 mg).

[0417] LCMS: MW (calcd): 269.1; m / z MW (obsd): 269.1 - 271.1 (M+H).1.20. Int 20

[0418] A sealed tube was charged with Int36 (1 eq., 55 mg, 0.16 mmol), 4,4,5,5-tetraethyl-2-(4,4,5,5- tetraethyl-l,3,2-dioxaborolan-2-yl)-l,3,2-dioxaborolane CAS#2247367-07-l (1.5 eq., 89.049 mg, 0.24 mmol) and degassed with Argon. Anhydrous degassed (bubbling Nitrogen for 15min) dioxane (0.49 mL) was added at RT and reaction mixture was degassed through vacuum / Argon cycles 4 times, kept under Argon atmosphere (balloon), reaction mixture was stirred at 85-90°C (preheated oil bath) under argon atmosphere for 5 min then Potassium 2-ethylhexanoate (3 eq., 88.67 mg, 0.49 mmol) and PdC12dppf.dcm (0.5 eq., 66.201 mg, 0.081 mmol) were added, reaction mixture was degassed through vacuum / Argon cycles 3 times, kept under Argon atmosphere (balloon) and stirred at 85-90°C for 4 h. The mixture was evaporated and purified by Normal phase chromatography (SiC>2 50 pm 25 g, loading DCM, gradient Heptane / EtOAc 100:0 to 0: 100 in 15 CV ) The tubes containing product were evaporated to afford (S)-l- (l-cyclopentyl-4-methoxy-6-(4,4,5,5-tetraethyl-l,3,2-dioxaborolan-2-yl)-lH-benzo[d]imidazol-2- yl)ethan-l-ol Int 20 (45 mg).

[0419] LCMS: MW (calcd): 442.4; m / z MW (obsd): 443.5 (M+H).1.21. Int 211.22. Step A: ethyl 3-((3-bromopyrazolo[l,5-a]pyrimidin-6-yl)oxy)-2,2-dimethylbutanoate

[0420] A 25 ml round bottom flask in 0°C was charged under nitrogen, Ethyl 3 -hydroxy-2, 2- dimethylbutanoate (1 eq., 1.77 g, 11.048 mmol) and DMAP (0.05 eq., 0.067 g, 0.55 mmol), with pyridine (17.41 mL) . To the mixture was added tosyl chloride (1.5 eq., 3.16 g, 16.57 mmol) The mixture was warmed up to RT and stirred at 65°C for 4 h, at RT for 48 h and at 90°C for 1 h. The mixture was cooled to RT and water was added to the mixture and the mixture was extracted with EtOAc. The organic layer was recovered, dried over anhydrous Na2SC>4, concentrated under vacuum and directly purified by normal phase chromatography (SiCE 50 pm 25 g, loading DCM, gradient Heptane / EtOAc 100:0 to 50:50 in 10 CV ) to afford ethyl 2,2-dimethyl-3-[(4-methylbenzenesulfonyl)oxy]butanoate (2.77 g, 80% yield). A portion of the intermediate obtained (2 eq., 293.802 mg, 0.93 mmol) was charged into a screw vial cap at RT under nitrogen with 3-bromopyrazolo[l,5-a]pyrimidin-6-ol (2 eq., 293.802 mg, 0.93 mmol), with anhydrous DMSO (2 mL). The mixture was warmed up to 100°C and stirred at 100°C for 3 h. At RT, was added K2CO3 (1.5 eq., 96.86 mg, 0.7009 mmol) and again ethyl 2,2-dimethyl-3-[(4- methylbenzenesulfonyl)oxy]butanoate (1 eq., 146.901 mg, 0.47 mmol) and the mixture was warmed up to 100°C and was stirred at 100°C for 2 h. The mixture was cooled to RT and water was added to the mixture, EtOAc was added and extraction was done, organic layer was recovered and dried over MgSO4, filtered, concentrated under vacuum and purified by normal phase chromatography (SiO2 50 pm Biotage HP 5 g, loading DCM, gradient Heptane / EtOAc 100:0 to 50:50 in 10 CV ) to afford ethyl 3-((3-bromopyrazolo[l,5- a]pyrimidin-6-yl)oxy)-2,2-dimethylbutanoate (85 mg).

[0421] LCMS: MW (calcd): 356.2; m / z MW (obsd): 356.1 - 358.0 (M+H).1.22.1. Step B: 5-(3-((3-bromopyrazolo[l,5-a]pyrimidin-6-yl)oxy)-2-methylbutan-2-yl)-3- methyl-l,2,4-oxadiazole

[0422] A 2-5 ml screw vial cap was charged under nitrogen at RT ethyl 3-((3-bromopyrazolo[l,5- a]pyrimidin-6-yl)oxy)-2,2-dimethylbutanoate (1 eq., 85 mg, 0.24 mmol) and Acetamidoxime 97% (2 eq., 35.35 mg, 0.48 mmol) with anhydrous DMF (8.5 mL). To the mixture was slowly added by portion NaH (1.5 eq., 14.32 mg, 0.36 mmol). The mixture was stirred at RT for 0.5 h. To the mixture was added at RT HATU (1.5 eq., 136.096 mg, 0.36 mmol) and DIPEA (3 eq., 92.52 mg, 0.12 mL, 0.72 mmol) and Acetamidoxime 97% (2 eq., 35.35 mg, 0.48 mmol). The mixture was warmed up to 100°C and stirred at 100°C and at RT for 48 h. To the mixture were added water and EtOAc, aqueous layer was extracted with EtOAc. The organic layer was recovered, concentrated under vacuum and directly purified by normal phase chromatography (SiCE 5 g, loading DCM, gradient DCM / (EtOAc / MeOH 3: 1) from 100:0 to 90: 10 to afford 5-(3-((3-bromopyrazolo[l,5-a]pyrimidin-6-yl)oxy)-2-methylbutan-2-yl)-3-methyl-l,2,4-oxadiazole Int21 (47 mg)

[0423] LCMS: MW (calcd): 366.2; m / z MW (obsd): 366.2 - 368.2 (M+H).1.23. Int 221.23.1. Step A: 6-((6-(trifluoromethyl)pyridazin-3-yl)oxy)pyrazolo[l,5-a]pyrimidine

[0424] In a sealed tube, under nitrogen, a mixture of pyrazolo[l,5-a]pyrimidin-6-ol (1 eq., 100 mg, 0.74 mmol), 3-chloro-6-(trifhioromethyl)pyridazine (1.5 eq., 202.62 mg, 1.11 mmol), K3PO4 (2 eq., 314.17 mg, 1.48 mmol) and tbu Brett Phos Pd G3 (0.1 eq., 63.23 mg, 0.074 mmol) in DMSO (2.63 mL) was purged with nitrogen and stirred at 100°C for 2 h. The mixture was filtered, evaporated and purified by reverse phase chromatography (C18 25pm 12 g, loading DMSO , water (formic acid 0.1%) / MeCN (formic acid 0.1%) 100:0 to 0: 100 in 15 CV ) to afford 6-((6-(trifluoromethyl)pyridazin-3-yl)oxy)pyrazolo[l,5- a]pyrimidine (107 mg).

[0425] LCMS: MW (calcd): 281.2; m / z MW (obsd): 282.2 (M+H).1.23.2. Step B: 3-bromo-6-((6-(trifluoromethyl)pyridazin-3-yl)oxy)pyrazolo[l,5-a]pyrimidine

[0426] In a round bottom flask, under air, a mixture of 6-((6-(trifluoromethyl)pyridazin-3- yl)oxy)pyrazolo[l,5-a]pyrimidine (1 eq., 107 mg, 0.38 mmol), NBS (1 eq., 67.73 mg, 0.38 mmol), and DMF (1.47 mL) was stirred at RT for 1 h. EtOAc and water were added. The organic layer was washed with brine, dried (MgSO4), filtered, evaporated to afford 3-bromo-6-((6-(trifluoromethyl)pyridazin-3- yl)oxy)pyrazolo[l,5-a]pyrimidine (170 mg).

[0427] LCMS: MW (calcd): 360.1; m / z MW (obsd): 360.1 - 362.1(M+H).1.23.3. Step C: 3-(4,4,5,5-tetraethyl-l,3,2-dioxaborolan-2-yl)-6-((6-(tri luoromethyl)pyridazin- 3-yl)oxy)pyrazolo[l,5-a]pyrimidine

[0428] In a sealed tube under nitrogen a mixture of 3-bromo-6-((6-(trifluoromethyl)pyridazin-3- yl)oxy)pyrazolo[l,5-a]pyrimidine (1 eq., 160 mg, 0.36 mmol), 4,4,5,5-tetraethyl-2-(4,4,5,5-tetraethyl- l,3,2-dioxaborolan-2-yl)-l,3,2-dioxaborolane (1.5 eq., 195.23 mg, 0.53 mmol) and degassed with nitrogen. Anhydrous degassed (bubbling Nitrogen for 15min) dioxane (3.2 mL) was added at RT and reaction mixture was degassed through vacuum / nitrogen cycles 4 times. Potassium pivalate (3 eq., 149.53 mg, 1.066 mmol) and XPhosPdG4 (0.065 eq., 19.88 mg, 0.023 mmol) were added, reaction mixture was degassed through vacuum / nitrogen cycles 3 times, kept under nitrogen atmosphere and stirred at 85°C for 1 h. EtOAc and water were added. The organic layer was washed with brine, dried (MgSCh), fdtered, evaporated and purified by Normal phase chromatography (SiCh 20 pm 25 g, loading DCM, gradient Heptane / EtOAc 100:0 to 50:50 in 10 CV ) to afford 3-(4,4,5,5-tetraethyl-l,3,2-dioxaborolan-2-yl)-6-((6- (trifluoromethyl)pyridazin-3-yl)oxy)pyrazolo[l,5-a]pyrimidine Int 22 (55 mg).

[0429] LCMS: MW (calcd): 463.3; m / z MW (obsd): 464.5 (M+H).1.24. Int 231.24.1. Step A: N-(5-bromo-3-fluoro-2-nitrophenyl)-l-methyl-lH-pyrazol-4-amine

[0430] In a round-bottom flask, 5-bromo-l,3-difluoro-2-nitrobenzene (1.5 eq., 300 mg, 1.26 mmol), 1- methyl-lH-pyrazol-4-amine (1 eq., 81.62 mg, 0.84 mmol) and CS2CO3 (2 eq., 547.62 mg, 1.68 mmol) were dissolved in DMSO (10 mL) and stirred at 70°C for 2.5 h. The reaction mixture was diluted in DCM and Water. The biphasic mixture was filtered on a BIOTAGE isolute phase separator and the organic layer was collected and evaporated under reduced pressure to afford a red wax that was purified by reverse phase preparative LC (Sfar Silica Gel C18 Duo 30 pm 12 g, liquid loading (DMSO), mobile phase gradient: Water + 0.1% NH4OH 20% / MeCN + 0.1 % NH4OH 20% from 70:30 to 20:80 over 10 CV) to afford The fractions containing compound were combined and evaporated in vacuo to afford N-(5-bromo-3-fluoro-2- nitrophenyl)-l -methyl- lH-pyrazol-4-amine (172 mg).

[0431] LCMS: MW (calcd): 315.1; m / z MW (obsd): 315.1 - 317.1 (M+H).1.24.2. Step B: 5-bromo-3-fluoro-Nl-(l-methyl-lH-pyrazol-4-yl)benzene-l,2-diamine

[0432] In a round-bottom flask, to a stirred solution of N-(5-bromo-3-fluoro-2-nitrophenyl)-l-methyl-lH- pyrazol-4-amine (1 eq., 172 mg, 0.55 mmol) in MeOH (1.82 mL) and water (0.53 mL) was added NH4CI (5 eq., 145.99 mg, 2.73 mmol) followed by Le (5 eq., 152.42 mg, 2.73 mmol). The reaction mixture was stirred at 60°C for 5 h. The mixture was cooled to rt, diluted with EtOAc and filtered on a Celite Pad. The solid was washed with EtOAc and the filtrate was concentrated to afford a dark red wax that was purifiedby normal phase preparative LC (Biotage Sfar Silica Gel HC D 20 pm 10 g, liquid loading (DCM), mobile phase gradient: heptane / (EtOAc / EtOH 3: 1) 100:0 to 60:40 over 2 CV then isocratic for 1 CV then 60:40 to 40:60 over 10 CV) to afford 5-bromo-3-fluoro-Nl-(l-methyl-lH-pyrazol-4-yl)benzene-l,2-diamine (124 mg).

[0433] LCMS: MW (calcd): 285.1; m / z MW (obsd): 285.0 - 287.1 (M+H).1.24.3. Step C: (S)-l-(6-bromo-4-fluoro-l-(l-methyl-lH-pyrazol-4-yl)-lH-benzo[d]imidazol-2- yl)ethan-l-ol

[0434] In a tube, under air, a mixture of 5-bromo-3-fluoro-Nl-(l-methyl-lH-pyrazol-4-yl)benzene-l,2- diamine (0.5 eq., 72 mg, 0. 12 mmol) and L(+)-lactic acid (16.49 eq., 360 mg, 0.3 mb, 4 mmol) were stirred at 80°C for 48 h. DMSO was added and the mixture was directly purified by Preparative LCMS method A to afford (S)- 1 -(6-bromo-4-fluoro- 1 -( 1 -methyl- lH-pyrazol-4-yl)- IH-benzo [d]imidazol-2-yl)ethan- 1 -ol Int 23(15 mg).

[0435] LCMS: MW (calcd): 339.2; m / z MW (obsd): 339.1 - 341.1 (M+H).1.25. Int 24

[0436] Int 24, (R)-l-(6-bromo-4-fluoro-l-(l -methyl- lH-pyrazol-4-yl)-lH-benzo[d]imidazol-2-yl)ethan- l-ol was prepared according to the method used for Int 23.

[0437] LCMS: MW (calcd): 339.2; m / z MW (obsd): 339.1 - 341.1 (M+H).1.26. Int 251.26.1. Step A: 5-bromo-N-cyclobutyl-3-fluoro-2-nitroaniline

[0438] In a round-bottom flask, 5-bromo-l,3-difluoro-2 -nitrobenzene (1.5 eq., 300 mg, 1.26 mmol) and cyclobutylamine (1 eq., 59.77 mg, 0.072 mL, 0.84 mmol) were dissolved in DMSO (10 mL) and stirred at RT for 4.5 h. The reaction mixture was diluted in DCM and water and filtered on a BIOTAGE isolute phase separator. The organic layer was collected, evaporated under reduced pressure and evaporated to afford an orange wax was purified by reverse phase preparative LC (Sfar Silica Gel C18 Duo 30 pm 12 g, liquid loading (DMSO), mobile phase gradient: Water + 0.1% NH4OH 20% / MeCN + 0.1% NH4OH 20% from 50:50 to 0: 100 over 10 CV). The fractions containing compound were combined and evaporated in vacuo to give 5-bromo-N-cyclobutyl-3-fluoro-2 -nitroaniline (252 mg).

[0439] LCMS: MW (calcd): 289.1; m / z MW (obsd): 289.1 - 291.1 (M+H).1.26.2. Step B: 5-bromo-Nl-cyclobutyl-3-fluorobenzene-l,2-diamine

[0440] In a round-botom flask, to a stirred solution of 5-bromo-N-cyclobutyl-3-fluoro-2-nitroaniline (1 eq., 252 mg, 0.87 mmol) in MeOH (2.9 mb) and water (0.85 mb) was added NH4CI (5 eq., 233. 13 mg, 4.36 mmol) followed by Fe (5 eq., 243.39 mg, 4.36 mmol). The reaction mixture was stirred at 60°C for 3h.p

[0441] The mixture was cooled to rt, diluted with EtOAc and filtered on a Celite Pad. The solid was washed with EtOAc and the filtrate was concentrated to afford a pale wax that was purified by normal phase preparative LC (Biotage Sfar Silica Gel HC D 20 pm 10 g, liquid loading (DCM), mobile phase gradient: heptane / EtOAc 100:0 to 70:30 over 7 CV then isocratic for 3 CV). Fractions containing product were collected and solvent removed under reduced pressure to afford 5-bromo-Nl-cyclobutyl-3-fluorobenzene- 1,2-diamine (148 mg).

[0442] LCMS: MW (calcd): 259.1; m / z MW (obsd): 259.1 - 261.1 (M+H).1.26.3. Step C: (S)-l-(6-bromo-l-cyclobutyl-4-fluoro-lH-benzo[d]imidazol-2-yl)ethan-l-ol

[0443] In a tube, under air, a mixture of 5-bromo-Nl-cyclobutyl-3-fluorobenzene-l,2-diamine (1 eq., 74 mg, 0.29 mmol) and L(+)-lactic acid (10 eq., 257.24 mg, 0.21 mL, 2.86 mmol) was stirred at 80°C for 18 h. DCM was added and the mixture was directly purified by normal phase preparative LC (Biotage Sfar Silica Gel HC D 20 pm 5 g, liquid loading (DCM), mobile phase gradient: heptane / EtOAc 100 / 0 to 50 / 50 over 3 CV then isocratic for 2 CV then 50 / 50 to 0 / 100 for 7 CV) and was purified by preparative LCMS method B to afford (S)-l-(6-bromo-l-cyclobutyl-4-fluoro-lH-benzo[d]imidazol-2-yl)ethan-l-ol Int 25 (28.4 mg)

[0444] LCMS: MW (calcd): 313.2; m / z MW (obsd): 313.2 - 315.2 (M+H).1.27. Int 26

[0445] Int 26, (R)-l-(6-bromo-l-cyclobutyl-4-fluoro-lH-benzo[d]imidazol-2-yl)ethan-l-ol was prepared according to the method used for Int 25.

[0446] LCMS: MW (calcd): 313.2; m / z MW (obsd): 313.2 - 315.2 (M+H).1.28. Int 27

[0447] In a sealed tube, under air, 3-bromopyrazolo[l,5-a]pyrimidin-6-ol (1 eq., 100 mg, 0.47 mmol), (lS,4S)-4-Hydroxy-l -methylcyclohexane- 1 -carbonitrile (1 eq., 65.039 mg, 0.47 mmol) and CMBP CAS#157141-27-0 (2 eq., 0.93 mL, 0.93 mmol) were dissolved in toluene (3 mL). The reaction mixturewas stirred at 90°C for 72 h. DCM and water were added and the biphasic solution was filtered on a Biotage ISOLUTE phase separator. The organic layer was collected, concentrated under vacuo and purified twice by normal phase chromatography (SiO2 20 pm 10 g, loading DCM, gradient DCM / MeOH 100:0 to 95:05 in 15 CV) and in normal phase chromatography (SiO2 20 pm 10 g, loading DCM, gradient Hept / EtOAC 100:0 to 0: 100 in 15 CV) to afford (lr,4r)-4-((3-bromopyrazolo[l,5-a]pyrimidin-6-yl)oxy)-l- methylcyclohexane-1 -carbonitrile Int 27 (78 mg).

[0448] LCMS: MW (calcd): 335.2; m / z MW (obsd): 335.1 - 337.1 (M+H).1.29. Int 281.29.1. Step A: (R)-N-(5-bromo-3-fluoro-2-nitrophenyl)tetrahydrofuran-3-amine

[0449] In a sealed tube, under air, a mixture of 5 -Bromo- 1,3 -difluoro -2 -nitrobenzene (1 eq., 500 mg, 2.101 mmol), (3R)-oxolan-3 -amine hydrochloride (1 eq., 259.63 mg, 2.101 mmol) and DiPEA (1.25 eq., 339.43 mg, 0.46 mL, 2.63 mmol) was dissolved in DMF (8.75 mL). The reaction mixture was stirred at 80°C for 4 h. EtOAc and water were added. The organic layer was washed with brine, dried (MgSCL), fdtered, evaporated and purified by Normal phase chromatography (SiCE 20 pm 50 g, loading DCM, gradient Heptane / EtOAc 100:0 to 75:25 in 10 CV ) to afford (R)-N-(5-bromo-3-fluoro-2- nitrophenyl)tetrahydrofuran-3-amine (476 mg, 74% yield).

[0450] LCMS: MW (calcd): 305.1; m / z MW (obsd): 305.1 - 307.1 (M+H).1.29.2. Step B: (R)-5-bromo-3-fluoro-Nl-(tetrahydrofuran-3-yl)benzene-l,2-diamine

[0451] In a sealed tube, under air, a mixture of (R)-N-(5-bromo-3-fluoro-2-nitrophenyl)tetrahydrofuran- 3-amine (1 eq., 476 mg, 1.56 mmol) in MeOH (5.19 mL) , water (1.51 mL), and NH4CI (5 eq., 417.26 mg, 7.801 mmol) and Fe (5 eq., 435.63 mg, 7.801 mmol) was stirred at 60°C for 2 h. The mixture was filtered on a cellite pad (rinced with EtOAc, concentrated then EtOAc and water were added. The organic layer was washed with brine, dried (MgSO4), filtered, evaporated to afford (R)-5-bromo-3-fluoro-Nl- (tetrahydrofuran-3-yl)benzene-l,2-diamine (430 mg.)

[0452] LCMS: MW (calcd): 275.1; m / z MW (obsd): 275.1 - 277.1 (M+H).1.29.3. Step C: (S)-l-(6-bromo-4-fluoro-l-((R)-tetrahydrofuran-3-yl)-lH-benzo[d]imidazol-2- yl)ethan-l-ol

[0453] In a sealed tube, under air, a mixture of (R)-5-bromo-3-fluoro-Nl-(tetrahydrofuran-3-yl)benzene- 1,2-diamine (1 eq., 210 mg, 0.76 mmol), L(+)-lactic acid (50 eq., 3437.83 mg, 2.84 mL, 38.17 mmol) was stirred at 80°C for 18 h. DCM was added and the mixture was purified twice by normal phase chromatography (SiO2 20 pm 25 g, loading DCM, gradient Heptane / EtOAc 50:50 to 0: 100 in 10 CV then 100% EtOAc for 5 CV) and by reverse phase chromatography (Cl 8 40 pm 60 g, loading MeCN, gradientwater (formic acid 0. l%) / MeCN (formic acid 0.1%) 100:0 to 0: 100 in 10 CV ) to afford (S)-l-(6-bromo-4- fluoro- 1 -((R)-tetrahydrofuran-3-yl)- IH-benzo [d]imidazol-2-yl)ethan- 1 -ol (74 mg)

[0454] LCMS: MW (calcd): 329.2; m / z MW (obsd): 329.2 - 331.2 (M+H).1.30. Int 29

[0455] Int 29, (R)- 1 -(6-bromo-4-fluoro- 1 -((R)-tetrahydrofuran-3-yl)- lH-benzo[d]imidazol-2-yl)ethan- 1 - ol was prepared according to the method used for Int 28.

[0456] LCMS: MW (calcd): 329.2; m / z MW (obsd): 329.2 - 331.2 (M+H).1.31. Int 30

[0457] Int30, (S)- 1 -(6-bromo-4-fluoro- 1 -((S)-tetrahydrofuran-3 -yl)- IH-benzo [d]imidazol-2-yl)ethan- 1 -ol was prepared according to the method used for Int 28 and Int 29.

[0458] LCMS: MW (calcd): 329.2; m / z MW (obsd): 329.2 - 331.2 (M+H).1.32. Int 31

[0459] Int31 , (R)- 1 -(6-bromo-4-fluoro- 1 -((S)-tetrahydrofuran-3-yl)- lH-benzo[d]imidazol-2-yl)ethan- 1 - ol was prepared according to the method used for Int28, 29 and 30.

[0460] LCMS: MW (calcd): 329.2; m / z MW (obsd): 329.2 - 331.2 (M+H).1.33. Int 321.33.1. Step A: 3,5-dichloro-6-cyclobutylpyrazolo[l,5-a]pyrimidine

[0461] In a round-bottom flask under nitrogen, 3,5-dichloro-6-iodopyrazolo[l,5-a]pyrimidine (1 eq., 2.29 g, 7.29 mmol) and Di-p-iodobis(tri-t-butylphosphino)dipalladium(I) (0.1 eq., 0.64 g, 0.73 mmol) weredegassed by 3 cycles vacuum / nitrogen, dissolved in dry Toluene (30 mL) and cooled at 0°C. At this temperature, bromo(cyclobutyl)zinc (0.5 M in THE) (1.7 eq., 24.8 mL, 12.4 mmol) was added and the reaction mixture was stirred at 0°C for 25 min. Water and EtOAc were added. The aqueous layer was extracted with EtOAc. Combined organic layer was washed with brine, dried (MgSO4), filtered, evaporated and purified by normal phase chromatography (Sfar Silica Gel HC D 20 pm, 50 g Biotage, dry loading (Celite), mobile phase gradient: Heptanes / EtOAc 100 / 0 to 90 / 10 for 3 CV then isocratic for 3 CV then 90 / 10 to 80 / 20 for 4 CV then isocratic for 4 CV). The residue that was triturated in MeCN and filtered. The filtrate was evaporated under reduced pressure to afford 3,5-dichloro-6-cyclobutylpyrazolo[l,5- a]pyrimidine (404 mg).

[0462] LCMS: MW (calcd): 242. 1; m / z MW (obsd): 242. 1 - 244. 1 (M+H).1.33.2. Step B: 3-ch loro-6-cyclobutyl-N-methylpyrazolo[ 1, 5-a]pyrimidin -5-amin e

[0463] In a sealed tube, under air, a mixture of 3,5-dichloro-6-cyclobutylpyrazolo[l,5-a]pyrimidine (1 eq., 400 mg, 1.65 mmol), MeNH2 2M in THF (10 eq., 8.26 mb, 16.52 mmol), dioxane (7.039 mb) was stirred at 60°C for 4 h. The mixture was evaporated and purified by normal phase chromatography (SiC>2 20 pm 25 g, loading DCM, gradient Heptane / EtOAc 100:0 to 0: 100 in 15 CV then 100% EtOAc for 5 CV) to afford 3-chloro-6-cyclobutyl-N-methylpyrazolo[l,5-a]pyrimidin-5-amine Int 32 (318 mg).

[0464] LCMS: MW (calcd): 236.7; m / z MW (obsd): 237.1 - 239.2 (M+H).1.34. Int 331.34.1. Step A: 7-(benzyloxy)imidazo[l,2-b]pyridazine

[0465] In a sealed tube, under air, a mixture of 5-(benzyloxy)pyridazin-3-amine (1 eq., 1000 mg, 4.97 mmol), 2-chloroacetaldehyde 50% in H2O (10 eq., 7802.056 mg, 7.802 mL, 49.69 mmol), NaHCOs (2 eq., 834.93 mg, 9.94 mmol), and isopropanol (10 mL) was stirred at 90°C for 1 h. EtOAc and water were added. The organic layer was washed with brine, dried (MgSO4), filtered, evaporated and purified by Normal phase chromatography (SiO2 20 pm 50 g, loading DCM, gradient Heptane / EtOAc 100:0 to 0: 100 in 10 CV then 100% EtOAc for 5 CV) to afford 7-(benzyloxy)imidazo[l,2-b]pyridazine (778 mg).

[0466] LCMS: MW (calcd): 225.2; m / z MW (obsd): 226.3 (M+H).1.34.2. Step B: imidazo[l,2-b]pyridazin-7-ol

[0467] In a round bottom flask , under air and at 0°C Trifluoromethanesulfonic acid (3 eq., 1554.99 mg, 0.92 mL, 10.36 mmol) was added to a solution of 7-(benzyloxy)imidazo[l,2-b]pyridazine (1 eq., 778 mg, 3.45 mmol) in DCM (11.74 mL). The mixture was stirred at 0°C for 1 h. Water (10 mL) was added, the mixture was neutralized to pH 7 with NH4OH aq. 20%. Purification by reverse phase chromatography (Cl 8 40 pm 120 g, loading MeOH, gradient water (formic acid 0. l%) / MeCN (formic acid 0.1%) 100:0 to 70:30 in 15 CV ) afford imidazo[l,2-b]pyridazin-7-ol (451 mg).

[0468] LCMS: MW (calcd): 135.1; m / z MW (obsd): 136.0 (M+H).1.34.3. Step C: 7-((6-methylpyridazin-3-yl)oxy)imidazo[l,2-b]pyridazine

[0469] In a sealed vial, under nitrogen, a mixture of imidazo[l,2-b]pyridazin-7-ol (1 eq., 200 mg, 1.48 mmol), 3-chloro-6-methylpyridazine (2 eq., 380.56 mg, 2.96 mmol), K3PO4 (2 eq., 628.35 mg, 2.96 mmol), tBuBrettPhos Pd G3 (0.1 eq., 126.47 mg, 0.15 mmol)and DMSO (2.48 mL) was purged with nitrogen and stirred at 100°C for 2 h. The mixture was filtered and purified by reverse phase chromatography (Cl 8 40 pm 120 g, loading DMSO / H2O, gradient water (formic acid 0.1%) / MeCN (formic acid 0.1%) 100:0 to 50:50 in 10 CV ) to afford 7-((6-methylpyridazin-3-yl)oxy)imidazo[l,2-b]pyridazine (192 mg, 57% yield).

[0470] LCMS: MW (calcd): 227.2; m / z MW (obsd): 228.1 (M+H).

[0471] Step D: 3 -bromo-7 -((6-methylpyridazin-3 -yl)oxy)imidazo [ 1 ,2-b]pyridazine

[0472] In a round bottom flask, under air, a mixture of 7-((6-methylpyridazin-3-yl)oxy)imidazo[l,2- b]pyridazine (1 eq., 190 mg, 0.84 mmol), NBS (1 eq., 148.83 mg, 0.84 mmol), and DMF (3.23 mL) was stirred at RT for 1 h. EtOAc and water were added. The organic layer was washed with brine (3x), dried (MgSCL), filtered, evaporated to afford 3-bromo-7-((6-methylpyridazin-3-yl)oxy)imidazo[l,2- b]pyridazine Int 33 (255 mg, quantitative yield).

[0473] LCMS: MW (calcd): 306.1; m / z MW (obsd): 306.1 - 308.1 (M+H).1.35. Int 341.35.1. Step A: 2-methyl-2-(6-methylpyridin-3-yl)propyl 4-methylbenzenesulfonate

[0474] A 25 ml round bottom flask was charged at RT under nitrogen, 2-methyl-2-(6-methylpyridin-3- yl)propan-l-ol (1 eq., I l l mg, 0.67 mmol) with pyridine (2 mL). To the mixture was added at RT tosyl chloride (1.2 eq., 153.68 mg, 0.806 mmol) . The mixture was stirred at RT for 20 h. To the mixture was added water and extraction with EtOAc was done, organic layer was dried over anhydrous Na2SO4, filtered, concentrated under vacuum and directly purified by Normal phase chromatography SiO2 Biotage HP sfar 10 g loading DCM, gradient DCM 100% (3CV), DCM / (EtOAc / EtOH (3 / 1)) 100 to 90 / 10 (10CV) to afford 2-methyl-2-(6-methylpyridin-3-yl)propyl 4-methylbenzenesulfonate (68 mg).

[0475] LCMS: MW (calcd): 319.4; m / z MW (obsd): 320.3 (M+H).1.35.2. Step B: 3-bromo-6-(2-methyl-2-(6-methylpyridin-3-yl)propoxy)pyrazolo[l,5- a]pyrimidine

[0476] In a sealed tube, under air, 2-methyl-2-(6-methylpyridin-3-yl)propyl 4-methylbenzenesulfonate (1 eq., 58.07 mg, 0.27 mmol) and 3-bromopyrazolo[l,5-a]pyrimidin-6-ol (1.5 eq., 130 mg, 0.407 mmol) were dissolved in DMF (1.3 mL). To the mixture was added K2CO3 (3 eq., 112.5 mg, 0.81 mmol) and the mixture was stirred at 90°C for 22 h. Water and EtOAc were added, and the organic layer was washed with water and brine. The combined organic layer was dried over anhydrous MgSO4, filtered and evaporated. Thecrude was purified in normal phase chromatography (SiO2 20 pm 5 g, liquid loading, gradient DCM / (EtOAc / EtOH 3: 1) 100:0 to 90: 10 in 15 CV) to afford 3 -bromo-6-(2 -methyl -2-(6-methylpyridin-3 - yl)propoxy)pyrazolo[l,5-a]pyrimidine Int 34(32 mg).

[0477] LCMS: MW (calcd): 361.2; m / z MW (obsd): 361.0 - 363.0 (M+H).1.36. Int 35

[0478] Int 35, (R)-l-(6-bromo-l-cyclopentyl-4-methoxy-lH-benzo[d]imidazol-2-yl)ethan-l-ol was prepared according to the method used for Int 36.

[0479] LCMS: MW (calcd): 315.2; m / z MW (obsd): 315.2 - 317.2 (M+H).1.37. Int 361.37.1. Step A: 5-bromo-N-cyclopentyl-3-methoxy-2-nitroaniline

[0480] In a sealed tube, under air, a mixture of 5-bromo-l-fluoro-3-methoxy-2 -nitrobenzene (1 eq., 1 g, 4 mmol), cyclopentanamine (1 eq., 0.34 g, 0.4 mL, 4 mmol), cesium carbonate (1.2 eq., 1.56 g, 4.8 mmol) and DMSO (7.102 mL) was stirred at RT for 2 h. EtOAc and water were added. The organic layer was washed with brine, dried (MgSO4), filtered, evaporated and purified by Normal phase chromatography (SiO2 20 pm 50 g, loading DCM, gradient Heptane / EtOAc 100:0 to 0: 100 in 10 CV ) to afford 5-bromo- N-cyclopentyl-3-methoxy-2 -nitroaniline (1.26 g).

[0481] LCMS: MW (calcd): 315.2; m / z MW (obsd): 315.2 - 317.2 (M+H).1.37.2. Step B: 5-bromo-Nl-cyclopentyl-3-methoxybenzene-l,2-diamine

[0482] In a sealed tube, under air, a mixture of 5-bromo-N-cyclopentyl-3-methoxy-2-nitroaniline (1 eq., 1.26 g, 4 mmol) in MeOH (13.29 mb) , water (3.88 mb), and NH4CI (5 eq., 1.069 g, 19.99 mmol) and Fe (5 eq., 1.12 g, 19.99 mmol) was stirred at 60°C for 2 h. The mixture was fdtered on a cellite pad (rinced with EtOAc, concentrated then EtOAc and water were added. The organic layer was washed with brine, dried (MgSCE), fdtered, evaporated and purified by Normal phase chromatography (SiCE 20 pm 25 g, loading DCM, gradient Heptane / EtOAc 100:0 to 0: 100 in 15 CV ) to afford 5-bromo-Nl-cyclopentyl-3- methoxybenzene-l,2-diamine (794 mg).

[0483] LCMS: MW (calcd): 285.2; m / z MW (obsd): 285.1 - 287.1 (M+H).1.37.3. Step C: (S)-l-(6-bromo-l-cyclopentyl-4-methoxy-lH-benzo[d]imidazol-2-yl)ethan-l-ol

[0484] In a sealed tube, under air, a mixture of 5-bromo-Nl-cyclopentyl-3-methoxybenzene-l,2-diamine (1 eq., 120 mg, 0.42 mmol), L(+)-lactic acid (9.57 eq., 362.7 mg, 300 pL, 4.027 mmol) was stirred at 80°C for 18 h. DCM was added and the mixture was purified by Normal phase chromatography (SiO2 20 pm 25 g, loading DCM, gradient Heptane / EtOAc 50:50 to 0: 100 in 10 CV then 100% EtOAc for 5 CV) to afford (S)-l-(6-bromo-l-cyclopentyl-4-methoxy-lH-benzo[d]imidazol-2-yl)ethan-l-ol Int 36 (118 mg).

[0485] LCMS: MW (calcd): 339.2; m / z MW (obsd): 339.2 - 341.1 (M+H).1.38. Int 37

[0486] In a sealed vial under argon atmosphere, to a stirred solution of 6-bromo-4-fluoro-2-methyl-lH- benzo[d] imidazole (1 eq., 64 mg, 0.28 mmol) and KF (2 eq., 32.47 mg, 0.56 mmol) in acetonitrile (1.38 mb) was added diethyl (bromodifluoromethyl)phosphonate (1.1 eq., 82.066 mg, 0.2 mb, 0.307 mmol) at RT. The reaction mixture stirred at RT for 18 h.The reaction mixture was evaporated to dryness after SiC>2 addition. The residue was purified twice on a 10g Star HC column (Biotage), eluted with gradient 0-1% MeOH in DCM (Biotage Isolera One device) and on a 12g C18 column (Biotage), eluted with gradient 0- 100% [ACN / 0.1% NH4OH] in [H2O / 0.1% NH4OH](Biotage Isolera One device to afford 6-bromo-l- (difluoromethyl)-4-fluoro-2-methyl-lH-benzo[d]imidazole Int 37 (42 mg).

[0487] LCMS: MW (calcd): 279.1; m / z MW (obsd): 279.3 - 281.3 (M+H).1.39. Int 381.39.1. Step A: ethyl 6-bromo-4-fluoro-l-isopropyl-lH-benzo[d]imidazole-2-carboxylate

[0488] To a solution of 5-bromo-3-fluoro-Nl-isopropylbenzene-l,2-diamine (see Int7, step B)(l eq., 560 mg, 2.27 mmol) and ethyl 2-oxoacetate (2 eq., 1542.35 mg, 4.53 mmol) in EtOH (18.67 mL) was added AcOH (2 eq., 272.18 mg, 0.26 mL, 4.53 mmol). The reaction mixture was stirred at 80°C for 20 h. The reaction mixture was concentrated under vacuum and purified by column chromatography (Sfar HC 25g, elution with Heptane / AcOEt 100 to 70 / 30 over 40 CV) to afford ethyl 6-bromo-4-fluoro-l-isopropyl-lH- benzo[d]imidazole-2 -carboxylate (117.9 mg).

[0489] LCMS: MW (calcd): 329.2; m / z MW (obsd): 329.1 - 331.1 (M+H).1.39.2. Step B: 6-bromo-4- luoro-l-isopropyl-lH-benzo[d]imidazole-2-carboxamide

[0490] A pvial was charged with ethyl 6-bromo-4-fluoro-l-isopropyl-lH-benzo[d]imidazole-2- carboxylate (1 eq., 24 mg, 0.073 mmol) and NH3 in MeOH (172.81 eq., 1.8 mL, 12.6 mmol) and then sealed. The reaction mixture was stirred at 85°C for 18 h. The reaction mixture was concentrated under vacuum to afford 6-bromo-4-fluoro-l-isopropyl-lH-benzo[d]imidazole-2-carboxamide Int 38 (19 mg).

[0491] LCMS: MW (calcd): 300.1; m / z MW (obsd): 300.0 - 302.1 (M+H).1.40. Int 39

[0492] To a solution of ethyl 6-bromo-4-fluoro-l-isopropyl-lH-benzo[d]imidazole-2-carboxylate (1 eq., 20 mg, 0.0608 mmol) Int 38, step A and anhydrous Et20 (0.33 mb) in a 10 ml round bottom flask under Nitrogen to 0°C was added dropwise a solution of MeMgBr (3M Et2OEt2O) (3 eq., 0.0608 mL, 0. 18 mmol). The reaction mixture was warmed to room temperature and stirred for 20 h. The reaction mixture was hydrolyzed at 0°C with a saturated solution of ammonium Chloride stirred at RT for 5 min. The mixture was extracted with EtOAc. Organic layer was washed with twice with a saturated solution of ammonium Chloride, brine, dried over anhydrous MgSO4, filtered and concentrated under vacuum then purified by column chromatography (Sfar HC 5g, elution with Heptane / AcOEt-EtOH 100 to50 / 50 in 30CV) to afford 2-(6-bromo-4-fluoro-l-isopropyl-lH-benzo[d]imidazol-2-yl)propan-2-ol Int 39 (11 mg)

[0493] LCMS: MW (calcd): 315.2; m / z MW (obsd): 315.1 - 317.1 (M+H).1.41. Int 40

[0494] A pwave vial was charged with 5-bromo-3-fluoro-Nl-isopropylbenzene-l,2-diamine (see Int 7, step B) (1 eq., 100 mg, 0.405 mmol) and L(+)-lactic acid (8.4 eq., 306.201 mg, 3.4 mmol). The mixture was stirred at 80°C for 18 h. The reaction mixture was concentrated, then the residue was taken up in EtOAc (lOmL) and water (lOmL), the aqueous layer was extracted with EtOAc (3* lOmL). The combined organic layer were washed with water (5 ml) then with brine (5ml), dried over anhydrous Na2SO4, filtered and concentrated under vacuum and purified twice by column chromatography (SiO2, Claricep Flash Spherical Silica, Spherical, 20pm, 40g, loading in DCM, biotage Isolera,Q=40mL / min, eluent : Hept / (AcOEtEtOH 3 : 1) gradient 100 / 0 (1CV), 100 / 0 to 70 / 30 (30CV) and purified by preparative LCMS method A to afford (S)-l-(6-bromo-4-fluoro-l-isopropyl-lH-benzo[d]imidazol-2-yl)ethan-l-ol Int 40 (75 mg).

[0495] LCMS: MW (calcd): 301.2; m / z MW (obsd): 301.1 - 303.1 (M+H).1.42. Int 41

[0496] Int 41, (R)-l-(6-bromo-4-fluoro-l-isopropyl-lH-benzo[d]imidazol-2-yl)ethan-l-ol was prepared from Int 7, step B according to the method used for Int 36.

[0497] LCMS: MW (calcd): 301.2; m / z MW (obsd): 301.1 - 303.1 (M+H).1.43. Int 42 and 43

[0498] In a screw cap vial under argon atmosphere, to a stirred solution of 6-bromo-2-methyl-lH-l,3- benzodiazole (1 eq., 200 mg, 0.95 mmol) CAS#1964-77-8 and KF (2 eq., 110.104 mg, 1.9 mmol) in acetonitrile (5 mb) was added diethyl (bromodifhroromethyl)phosphonate (1.2 eq., 303.62 mg, 0.202 mb, 1.14 mmol) at RT. The reaction mixture stirred at RT for 4 h. The reaction mixture was evaporated to dryness after SiCL / ClS addition. The residue was purified on a 12g C18 column (Biotage), eluted with gradient 0-100% [ACN / 0.1% Formic acid] in [H2O / 0.1% Formic acid) (Biotage Isolera One device). The product fraction was evaporated to dryness to afford a mixture of 2 regioisomers which were separated by preparative SFC to afford Int 43, 6-bromo-l-(difluoromethyl)-2-methyl-lH-benzo[d]imidazole (70 mg) first eluting compound and Int 42, 5-bromo-l-(difluoromethyl)-2-methyl-lH-benzo[d]imidazole (62 mg) second eluting compound

[0499] Int 42: LCMS: MW (calcd): 261.1; m / z MW (obsd): 261.1 - 263.1 (M+H).

[0500] Int 43: LCMS: MW (calcd): 261.1; m / z MW (obsd): 261.1 - 263.1 (M+H).

[0501] SFC chiral separation: Column : Chiralpak IG, 150 x 4.6mm, 5pm; CO2 back pressure : 1500psi; Detection : PDA and MS; Co-solvent : Ethanol; %Co-Solvent: 10%; Mode: Isocratic; Flowrate: 3mL / min1.44. Int 44

[0502] In a screw cap vial under argon atmosphere, to a stirred solution of 6-bromo-lH-l,3-benzodiazole CAS#4887-88-l (1 eq., 50 mg, 0.25 mmol) and KF (2 eq., 29.49 mg, 0.508 mmol) in acetonitrile (2 mb) was added ethyl bromodifluoroacetate (1.1 eq., 56.66 mg, 0.036 mb, 0.28 mmol) at RT. The reaction mixture stirred at RT for 67 h. The reaction mixture was evaporated to dryness after SiCL addition and purified on a 10g Sfar HC column (Biotage), eluted with gradient 0-2% MeOH in DCM (Biotage IsoleraOne device) to afford Int44 as a mixture of regioisomers 5 -bromo- 1 -(difluoromethyl)- 1H- benzofd] imidazole and 6-bromo-l-(difhioromethyl)-lH-benzo[d]imidazole Int 44 (20 mg).

[0503] LCMS: MW (calcd): 247.0; m / z MW (obsd): 246.9 - 248.7 (M+H).1.45. Int 45

[0504] A pwave vial was charged with 5-bromo-3-fluoro-N-isopropyl-2 -nitroaniline (Int 7, step A) (1 eq., 100 mg, 0.36 mmol), l,4-dioxane-2,5-diol (1.2 eq., 52.013 mg, 0.43 mmol) and Na2S2O4 (5 eq., 314.15 mg, 1.804 mmol) in a mixture of water (1 mb) and EtOH (4 m ) at RT. The mixture was stirred at 80°C for 24 h. The reaction mixturereaction mixture was concentrated, then the residue was taken up in EtOAc (lOmL) and water (lOmL), the aqueous layer was extracted with EtOAc (3* 10mL). The combined organic layer were washed with water (5 ml) then with brine (5ml), dried over anhydrous Na2SO4, fdtered and concentrated under vacuum and directly purified by column chromatography (Sfar HC 10g, elution with Heptane / EtOAc 100 to 30 / 70 over 30CV then isocratic for 5 CV) to afford (6 -bromo-4-fluoro-l -isopropyl - lH-benzo[d]imidazol-2-yl)methanol Int 45 (51 mg).

[0505] LCMS: MW (calcd): 287.1; m / z MW (obsd): 287.0 - 289.0 (M+H).1.46. Int 46

[0506] To the sealed vial was charged with 2-{3-bromopyrazolo[l,5-a]pyridin-6-yl}-2- methylpropanenitrile (WO2020 / 239658, 2020, Al) (1 eq., 150 mg, 0.57 mmol), 4, 4, 5, 5 -tetraethyl -2- (4,4,5,5-tetraethyl-l,3,2-dioxaborolan-2-yl)-l,3,2-dioxaborolane (1.5 eq., 311.92 mg, 0.85 mmol) and degassed with Argon. Anhydrous degassed (bubbling Nitrogen for 15min) dioxane (1.705 mb) was added at RT and reaction mixture was degassed through vacuum / Argon cycles 4 times, kept under Argon atmosphere. Potassium pivalate (3 eq., 238.902 mg, 1.704 mmol) and XPhosPdG4 (0.065 eq., 31.76 mg, 0.037 mmol) were added at RT. The reaction mixture was degassed through vacuum / Argon cycles 3 times, kept under Argon atmosphere and stirred at 85-90°C for 2 h. The reaction mixture was cooled to RT and diluted with AcOEt. The resulting suspension was filtered on a pad of celite. Solids were washed with AcOEt (4 times) until a yellow filtrate was obtained. The combined filtrates were washed with water, brine, dried over Na2SC>4, filtered and concentrated in vacuo. The residue was purified twice on a 12g Cl 8 column (Biotage), eluted with gradient 0-100% [ACN / 0. 1% acid formic] in [H2O / 0.1% acid formic] (Biotage IsoleraOne device) to afford 2-methyl-2-(3-(4,4,5,5-tetraethyl-l,3,2-dioxaborolan-2-yl)pyrazolo[l,5-a]pyridin-6- yl)propanenitrile Int 46 (5 Img).

[0507] LCMS: MW (calcd): 367.3; m / z MW (obsd): 368.5 (M+H).1.47. Int 47

[0508] In a sealed vial under microwave irradiation, to a stirred solution of 6 -bromo- 1 -cyclopentyl -4- fluoro-2-methyl-lH-l,3-benzodiazole CAS#1231930-36-l (1 eq., 150 mg, 0.505 mmol) in MeOH (2 mL) was added MeONa (5 eq., 545.38 mg, 0.84 mL, 2.52 mmol) at RT. The reaction mixture was stirred at 150°C for 3 h. The reaction mixture was evaporated to dryness. Water and DCM were added and the reaction mixture was filtered over a phase separator. The organic layer was evaporated to dryness and the residue was purified on a 10g Star HC column (Biotage), eluted with gradient 0-3% MeOH in DCM (Biotage Isolera One device) to afford 6-bromo-l-cyclopentyl-4-methoxy-2-methyl-lH-benzo[d]imidazole Int 47 (128 mg).

[0509] LCMS: MW (calcd): 309.2; m / z MW (obsd): 309.1 - 311.1 (M+H).1.48. Int 48

[0510] In a sealed vial under microwave irradiation, to a stirred solution of 6 -bromo-4-fluoro-2 -methyl- 1- (propan-2-yl)-lH-l,3-benzodiazole CAS#1231930-33-8 (1 eq., 50 mg, 0.18 mmol) in EtOH (2 mL) was added NaOEt (5 eq., 298.79 mg, 0.34 mL, 0.92 mmol) at RT. The reaction mixture was stirred at 150°C for 2 h. The reaction mixture was evaporated to dryness after SiCE addition. The residue was purified on a 10g Sfar HC column (Biotage), eluted with gradient 0-2% MeOH in DCM (Biotage Isolera One device) to afford 6-bromo-l-cyclopentyl-4-ethoxy-2-methyl-lH-benzo[d]imidazole Int 48(53 mg).

[0511] LCMS: MW (calcd): 297.2; m / z MW (obsd): 297.3 - 299.2 (M+H).1.49. Int 49

[0512] In a sealed vial under argon atmosphere, to a stirred solution of Int 3 (1 eq., 100 mg, 0.25 mmol) and 5 -bromo-2-fluoro-3 -methoxybenzonitrile CAS#1898131-10-6 (1 eq., 57.034 mg, 0.25 mmol) indioxane (1.6 mL) were added at RT K3PO4 (2 eq., 105.26 mg, 0.5 mmol) in water (0.47 mL). The reaction mixture was degassed with argon for 5 minutes. SPhosPdG4 (0.1 eq., 19.69 mg, 0.025 mmol) was then added and the reaction mixture was stirred at 100°C for 2 h. The reaction mixture was cooled down to rt, diluted with EtOAc. The resulting suspension was fdtered on celite. The fdtrate was concentrated in vacuo. The residue was purified over silica gel (SiOH, 25 pm, 12 g select spherical silica column (Btichi), dry loading (silica)) eluted with gradient 0-2% MeOH in DCM (Biotage Isolera One device). The product fraction was evaporated to dryness to afford (S)-2-fluoro-5-(6-((3-hydroxy-3-methylbutan-2- yl)oxy)pyrazolo[l,5-a]pyrimidin-3-yl)-3-methoxybenzonitrile Int 49 (46 mg).

[0513] LCMS: MW (calcd): 370.4; m / z MW (obsd): 371.3 (M+H).1.50. Int 50

[0514] In a sealed vial under argon atmosphere, to a stirred solution of Int4 (1 eq., 100 mg, 0.33 mmol) and (3-cyano-4-fhiorophenyl)boronic acid CAS#214210-21-6 (1 eq., 54.95 mg, 0.33 mmol) in dioxane (2.15 mL) were added at RT K3PO4 (2 eq., 141.44 mg, 0.67 mmol) in water (0.64 mL). The reaction mixture was degassed with argon for 5 minutes. SPhosPdG4 (0.1 eq., 26.46 mg, 0.033 mmol) was then added and the reaction mixture was stirred at 100°C for 2 h. The reaction mixture was cooled down to rt, diluted with EtOAc. The resulting suspension was filtered on celite. The filtrate was concentrated in vacuo and purified over silica gel (SiOH, 25 pm, 12 g select spherical silica column (Btichi), dry loading (silica)) eluted with gradient 0-2% MeOH in DCM (Biotage Isolera One device) to afford (S) -2 -fluoro-5-(6-((3 -hydroxy-3 - methylbutan-2-yl)oxy)pyrazolo[l,5-a]pyrimidin-3-yl)benzonitrile Int 50 (71 mg).

[0515] LCMS: MW (calcd): 340.4; m / z MW (obsd): 341.3 (M+H).1.51. Int 51

[0516] 6-bromo-l-isopropyl-4-methoxy-2-methyl-lH-benzo[d]imidazole Int 51 was prepared according to the method described in Int 11, step A.

[0517] LCMS: MW (calcd): 283.2; m / z MW (obsd): 283.1 - 285.1 (M+H).1.52. Int 52

[0518] Step A:

[0519] In a sealed vial, to a stirred solution of 5-bromo-lH-benzimidazole CAS# 4887-88-1 (1 eq., 183.24 mg, 0.93 mmol) and DHP (3 eq., 234.69 mg, 0.26 mb, 2.79 mmol) in THF (4 mb) was added at RT APTS monohydrate (0.1 eq., 17.69 mg, 0.093 mmol). The reaction mixture was stirred at 80°C for 72 h. The reaction mixture was evaporated to dryness and the residue was purified on a 10g Star HC column (Biotage), eluted with gradient 0-2% MeOH in DCM (Biotage Isolera One device) to afford a mixture of regioisomers 5-bromo-l-(tetrahydro-2H-pyran-2-yl)-lH-benzo[d]imidazole and 6-bromo-l-(tetrahydro- 2H-pyran-2-yl)-lH-benzo[d]imidazole (114 mg).

[0520] ’H NMR (400 MHz, DMSO) 5 8.45 (d, 1H), 7.90 (dd, 1H), 7.64 (dd, 1H), 7.39 (ddd, 1H), 5.69 (ddd, 1H), 3.97 (ddt, 1H), 3.82 - 3.68 (m, 1H), 2.18 (dddd, 1H), 2.05 - 1.93 (m, 2H), 1.81 - 1.69 (m, 1H), 1.72 - 1.55 (m, 2H).

[0521] Step B:

[0522] In a sealed vial under argon atmosphere, to a stirred solution of a regioisomers mixture from step A (0.5 eq., 28.2 mg, 0.1003 mmol) and Int 3 (1 eq., 80.9 mg, 0.2006 mmol) in dioxane (2 mb) was added CS2CO3 (2 eq., 130.701 mg, 0.401 mmol) in water (0.2 mb) at RT. The reaction mixture was degassed with argon for 5 minutes. Pd(dppf)C12'DCM (0.05 eq., 8.19 mg, 0.01 mmol) was then added and the reaction mixture was stirred at 100°C for 3 h. The reaction mixture was evaporated to dryness. DCM was added and the mixture was fdtered over a pad of Celite. The fdtrate was evaporated to dryness. The residue was purified on a 12g C18 column (Biotage), eluted with gradient 0-100% [ACN / 0.1% Formic acid] in [H2O / 0.1% Formic acid (Biotage Isolera One device). The product fraction was evaporated to dryness to afford a mixture of 5-bromo-l-(tetrahydro-2H-pyran-2-yl)-lH-benzo[d]imidazole and 6-bromo-l- (tetrahydro-2H-pyran-2-yl)-lH-benzo[d]imidazole Int 52 (24 mg).

[0523] LCMS: MW (calcd): 421.5; m / z MW (obsd): 422.3 (M+H) and LCMS: MW (calcd): 421.5; m / z MW (obsd): 422.3 (M+H).1.53. Int 53

[0524] In a sealed vial with anhydrous solvent and under argon atmosphere, to a stirred solution of 8- bromo-2 -chloroquinoline CAS#163485-86-7 (1 eq., 42.38 mg, 0.17 mmol) and 4-N-Boc-aminopiperidine (1 eq., 35 mg, 0. 17 mmol) in toluene (1 mL) was added K2CO3 (2 eq., 48.304 mg, 0.35 mmol). The reaction mixture was degassed with argon for 5 minutes. BINAP (0.1 eq., 10.88 mg, 0.017 mmol) was added and the reaction mixture was stirred at 80°C for 2 h, at 100°C for 16 h. The reaction mixture was evaporated to dryness and purified on a 10g Sfar HC column (Biotage), eluted with gradient 0-2% MeOH in DCM (Biotage Isolera One device) to afford tert-butyl (l-(8-bromoquinolin-2-yl)piperidin-4-yl)carbamate Int 53 (30 mg).

[0525] LCMS: MW (calcd): 406.3; m / z MW (obsd): 406.3 - 408.3 (M+H)1.54. Int 54 and Int 55

[0526] In a sealed vial, under nitrogen, a mixture of pyrazolo[l,5-a]pyrimidin-6-amine (1 eq., 1000 mg,7.45 mmol), 2,2,3-trimethyloxirane (3.3 eq., 2118.97 mg, 24.601 mmol), lithium perchlorate (10 eq., 7931.15 mg, 74.55 mmol) and MeCN (20 mL) was stirred at 100°C for 24 h. The mixture was fdtered, concentrated and purified by Reverse phase chromatography (Cl 8 30 pm 120 g, loading water / MeCN, gradient water (0.1% formic acid) / MeCN (0.1% formic acid) 100:0 to 50:50 in 10 CV ) to afford 3-((3- bromopyrazolo[l,5-a]pyrimidin-6-yl)amino)-3-methylbutan-2-ol, Int 54, first eluting compound (RT=0.40 min, LC-MS acid method) 242 mg and 3-((3-bromopyrazolo[l,5-a]pyrimidin-6-yl)amino)-2-methylbutan-2-ol, Int 55, second eluting compound(RT=0.44 min, LC-MS acid method) 371 mg

[0527] Int54, LCMS: MW (calcd): 220.3; m / z MW (obsd): 221.2 (M+H)Int55, LCMS: MW (calcd): 220.3; m / z MW (obsd): 221.2 (M+H)1.55. Int 561.55.1. Step A

[0528] To a suspension of 6-bromopyrazolo[l,5-a]pyridine (CAS# 1264193-11-4; 148 g, 751.15 mmol, 1 eq.) and bis(pinacol)diborane (209.82 g, 826.26 mmol, 1.1 eq.) in 2-MeTHF (1.5 L) were added Pd(OAc)2 (4.22 g, 18.78 mmol, 0.025 eq.), KOAc (221.15 g, 2.25 mol, 3 eq.) and XPhos (17.90 g, 37.56 mmol, 0.05 eq.) at 25°C. The suspension was degassed and purged with nitrogen three times and stirred at 90°C under nitrogen for 12 h. The reaction mixture was cooled down to 25°C, diluted with DCM (1.5 L), filtered through a thin layer of celite. The mother liquor was extracted with DCM (2 L) and H2O (2 L), dried with MgSC , filtered, and the filtrate was concentrated under vacuum. The crude product was purified by silicagel chromatography (eluting with EtOAc / petroleum ether 12 / 88) to give 6-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)pyrazolo [ 1 ,5 -a]pyridine .

[0529] LCMS: MW (calcd): 401.2; m / z MW (obsd): 162.9 (M+H of corresponding boronic acid)

[0530] ’H NMR (400 MHz, CDC13): 5 8.79 (d, 1H), 7.90 (d, 1H), 7.41 (dd, 1H), 7.28 (dd, 1H), 6.40 (d, 1H), 1.28 (s, 12H)1.55.2. Step B

[0531] To a solution of 6-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyrazolo[l,5-a]pyridine (173 g, 708.74 mmol, 1 eq.) in ACN (1.6 L) was added NBS (126.14 g, 708.74 mmol, 1 eq.), and the mixture was stirred at 25 °C for 12 h. The reaction mixture was diluted with EtOAc (2 L) at 25 °C, washed with H2O (1 L) and brine (1 L), and the organic phase was dried over anhydrous MgSCE, fdtered and concentrated under vacuum to give 3-bromopyrazolo-6-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyrazolo[l,5-a]pyridine.

[0532] ’H NMR: (400 MHz, CDCh): 5 8.74 (s, 1 H), 7.89 (s, 1H), 7.39 (s, 2 H), 1.28 (s, 12 H)1.55.3. Step C

[0533] To a solution of 3-bromopyrazolo-6-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyrazolo[l,5- a]pyridine (142 g, 439.64 mmol, 1 eq.) in THF (1.25 L) was added dropwise NaOH (2 M in water, 659.46 mb, 3 eq.) and H2O2 (168.63 g, 1.49 mol, 142.90 mb, 30% w / w in H2O, 3.38 eq.) at 0°C. The reaction was stirred at 0-5°C for 2 h. The mixture was quenched with 10% Na2SOs (2 L) and stirred at 25°C for 2 h, then checked by potassium iodide starch paper. The mixture was acidified with 2N HC1 to pH 5, filtered and concentrated under reduced pressure to give product. The crude product was purified by column chromatography on silica gel (eluting with DCM / THF 9 / 1 to 7 / 3) and further purified by SFC (column: Daicel CHIRALPAK IG (250 mm L * 50 mm ID, 10 pm); CO2 back pressure: 100 bar; co-solvent: 0.1% NH4OH in EtOH; flowrate: 220 mL / min; mode: isocratic 15%; temperature: 40°C) to give Int 56.

[0534] 'HNMR: (400 MHz, DMSO-de): 5 9.85 (s, 1H), 8.15 (dd, 1H), 7.95 (s, 1H), 7.46 (d, 1H), 7.10 (dd, 1H)1.56. Int 57

[0535] In a 15 L single jacketed process reactor equipped with mechanical stirring (200 rpm) and baffle, were charged THF (8.5 L, 17V) and Int 56 (500 g, 2347 mmol, 1.0 eq.). The reaction mixture was stirred for 10 min at RT, until full dissolution of substrate, then cooled down to 11 °C. t-BuOK (85 g, 742 mmol, 0.32 eq.) was added. When the reaction temperature reached 15°C the jacket temperature was increased from 5 °C to 10°C and the stirring was increased to 250 rpm. When the reaction temperature reached 12 °C, additional tBuOK (170 g, 1484 mmol, 0.64 eq.) was added. Following the addition of the base, a thick suspension formed rapidly. The jacket temperature was set at 22°C and the stirring increased to 300 rpm. The reaction mixture was stirred for one further hour after reaching a temperature of 20°C. The reactionmixture was filtered on a sintered funnel, the solid was washed with THF (3 V), triturated with MTBE (3 V), then filtered and collected. The resulting solid was dried under vacuum (3 days at 35 °C, then one day at RT) to afford Int 57.

[0536] ’H NMR (400 MHz, DMSO-de) 5 7.39 (s, 1H), 7.21 (d, 1H), 6.90 (d, 1H), 6.59 (dd, 1H)1.57. Int 58

[0537] In a 15 L single jacketed process reactor equipped with mechanical stirring (200 rpm) and baffle were charged DCM (4 L, 6.7V) and 4-methylbenzenesulfonyl chloride (873 g, 4571 mmol, 0.9 eq.). Then 4-dimethylaminopyridine (73 g, 598 mmol, 0.2 eq.) was added. DCM (1.5 L, 2.5V) was used to rinse the containers and funnels and was added to the reaction mixture. The reaction mixture was cooled down to0°C and ethyl (R)-(+) lactate (CAS# 7699-00-5; 600 g, 5079 mmol, 1.00 eq.) was added in one portion. DCM (0.5 L, 0.8V) was used to rinse the containers and funnels used and added to the reaction mixture. Triethylamine (1.42 L, 10200 mmol, 2.01 eq.) was added dropwise, while maintaining reaction temperature below 5°C. The reaction mixture was stirred (250 rpm) at 0°C for a further 1.5 h. HC1 2N (3.7 L, 6V) was slowly added under cooling, maintaining reaction temperature below 5 °C, until pH reached 2-3. The layers were separated, and the organic layer washed with water (2 L, 3 V) and 10% NaCl in water (2 L, 3 V), then concentrated under vacuum to give 1.228 kg of crude product. The crude product was purified by flash chromatography using heptane / EtOAc 100 / 0 to 70 / 30 as eluting system to afford Int 58.

[0538] ’H NMR (400 MHz, DMSO-de) 5 7.85 - 7.77 (m, 2H), 7.53 - 7.45 (m, 2H), 4.99 (q, 1H), 4.05 (qd, 2H), 2.43 (s, 3H), 1.38 (d, 3H), 1.12 (t, 3H)1.58. Int 59

[0539] In a 5 L reactor equipped with baffles and under nitrogen atmosphere, triethylamine (250.32 mb, 182.24 g, 1800.87 mmol, 2 eq.) was added to a solution of methyl (R)-(+)-lactate (CAS# 17392-83-5; 93.74 g, 86 mb, 900.44 mmol, 1 eq.), tosyl chloride (163.076 g, 855.42 mmol, 0.95 eq.) and DMAP (20 g, 163.705 mmol, 0.18 eq.) in DCM (1000 mb) cooled at -5°C (jacket temperature). The addition lasted 1 h with reaction temperature kept under 7°C. The reaction mixture was then stirred at 0-5°C for 2.2 h. HC1 2 M (500 mb, 6V) was added until pH <4 while keeping the the reaction mixture temperature below 10°C. The organic phase was washed with water (500 mb, 5V) and a 10% aqueous NaCl solution (300 mb, 3V). The organic phase was concentrated and purified by chromatography on silica gel (eluting with heptane / EtOAc 100 / 0 to 70 / 30) to afford Int 59.1.59. Int 60

[0540] In a sealed tube, under nitrogen, 6-Bromo-4-fluoro-l-isopropyl-2-methyl-lh-benzo[d]imidazole CAS#1231930-33-8 (1 eq., 100 mg, 0.37 mmol), 4,4,5,5-tetraethyl-2-(4,4,5,5-tetraethyl-l,3,2- dioxaborolan-2-yl)-l,3,2-dioxaborolane (1.5 eq., 202.57 mg, 0.55 mmol), potassium pivalate (3 eq., 155. 15 mg, 1.106 mmol) and XPhosPdG4 (0.065 eq., 20.63 mg, 0.024 mmol) were dissolved in dioxane (1.107 mb). This mixture was degassed with nitrogen for 5 min. Then, the reaction mixture was degassed through vacuum / nitrogen cycles 3 times, kept under nitrogen atmosphere. The reaction mixture was stirred at 85°C for 1.5 h. The reaction mixture was fdtered on a pad of celite, evaporated and purified in normal phase chromatography (SiC>2 20 pm 25 g, loading DCM, gradient Hept / EtOAc 100:0 to 50:50 in 10 CV then 50:50 for 5 CV) to afford Int 60(113 mg).

[0541] LCMS: MW (calcd): 374.3; m / z MW (obsd): 375.3 (M+H).1.60. Int 61

[0542] In a round bottom flask, a mixture of Int 54 (1 eq., 242 mg, 1.099 mmol), NBS (1 eq., 195.54 mg, 1.099 mmol), and DMF (4.25 mL) was stirred at 0°C for 1 h. EtOAc and water were added. The organic layer was washed with brine, dried (MgSCE), filtered, evaporated and purified by reverse phase chromatography (C18 30 pm 120 g, loading DMSO, gradient water (0.1% formic acid) / MeCN (formic acid 0.1%) 100:0 to 50:50 in 15 CV) to afford Int 61 (60 mg).

[0543] LCMS: MW (calcd): 299.2; m / z MW (obsd): 299.2 - 301.2 (M+H).1.61. Int 62

[0544] In a round bottom flask, a mixture of Int 55 (1 eq., 371 mg, 1.68 mmol), NBS (1 eq., 299.77 mg, 1.68 mmol), and DMF (6.51 mL) was stirred at 0 °C for 1 h. EtOAc and water were added. The organic layer was washed with brine, dried (MgSO4), filtered, evaporated and purified by reverse phase chromatography (C18 30 pm 120 g, loading DMSO, gradient water (0.1% formic acid) / MeCN (formic acid 0.1%) 100:0 to 50:50 in 15 CV) to afford Int 62 (197 mg).

[0545] LCMS: MW (calcd): 299.2; m / z MW (obsd): 299.2 - 301.2 (M+H).1.62. Int 63

[0546] In a RBF, under air, a mixture of Cpd 128 (1 eq., 875 mg, 2.061 mmol), TFA (10 eq., 2350.408 mg, 1.53 mL, 20.61 mmol) and DCM (10 mL) was stirred at rt for 6 h. The reaction mixture was directly evaporated and the crude was purified by reverse phase chromatography (Cl 8 40 pm 60 g, loading DMSO, gradient water (formic acid 0.1%) / MeCN (formic acid 0.1%) 100:0 to 55:45 in 15 CV) and was purified in reverse phase chromatography (Biotage C18 40 pm 30 g, loading DMSO, gradient water (+ 0.1% NH4OH 20%) / MeCN (+ 0.1% NH4OH 20%) 100:0 to 50:50 in 15 CV) to afford Int 63 (280 mg)

[0547] LCMS: MW (calcd): 324.3; m / z MW (obsd): 325.2 (M+H).1.63. Int 64

[0548] A lOOmL RBF was charged with Int 40 (1 eq., 1 g, 3.32 mmol), 4,4,4',4',5,5,5',5'-Octaethyl-2,2'- bi(l,3,2-dioxaborolane) (1.5 eq., 1.82 g, 4.98 mmol) and degassed with Argon. Anhydrous degassed (bubbling Nitrogen for 15min) 1,4-dioxane (20 mL) was added at rt and reaction mixture was degassed through vacuum / Argon cycles 4 times, kept under Argon atmosphere (balloon), reaction mixture was stirred at 85-90°C (preheated oil bath) under argon atmosphere for 10 min then potassium 2,2- dimethylpropanoate (3 eq., 1.4 g, 9.96 mmol) and XPhosPdG4 (0.065 eq., 0.19 g, 0.22 mmol) were added, reaction mixture was degassed through vacuum / Argon cycles 3 times, kept under Argon atmosphere (balloon) and stirred at 85-90°C for 2 h. The reaction mixture was cooled down to rt, diluted with AcOEt.The resulting suspension was filtered on a sintered disc funnel grade 4. Solids were washed with AcOEt (3 times) until a colorless filtrate was obtained. The combined filtrates were washed with water, brine, dried over MgSO4, filtered and concentrated in vacuo. The crude residue was purified by chromatography SiO2, sfar 100G (20pm), loading in DCM, biotage Isolera, Q=60mL / min, eluent Hept / AcOEt, gradient 100 / 0 (1CV), 100 / 0 to 60 / 40 (20CV), 60 / 40 (5CV), to afford Int 64 (1 .02 g).

[0549] LCMS: MW (calcd): 404.3; m / z MW (obsd): 405.3 (M+H).1.64. Int 661.64.1. Step A

[0550] A solution of CAS#2177297-22-0 (1 eq., 1 g, 4.047 mmol) and ethyl 3 -ethoxy-3 -iminopropionate hydrochloride (1.5 eq., 1.19 g, 6.07 mmol) in MeOH (10 mL) was heated at 60 °C for 2 h. The mixture was cooled to RT, water was added and the aqueous layer was extracted with DCM using a phase separator. The organics layers were concentrated under vacuo. The residue was purified on a 40g Agela Silica-CS (Phenomenex), eluted with gradient n-heptane / EtOAc (100 / 0, 60 / 40 to 0 / 100) (Biotage Isolera One device) to afford ethyl 2-(6-bromo-4-fluoro-l-isopropyl-lH-benzo[d]imidazol-2-yl)acetate Int 69(1.3 g).

[0551] LCMS: MW (calcd): 343.2; m / z MW (obsd): 341.0 - 343.0 (M-H).1.64.2. Step B

[0552] To a stirred solution of Int 3 (1 eq., 470.087 mg, 1.17 mmol) and ethyl 2-(6-bromo-4-fluoro-l- isopropyl-lH-benzo[d]imidazol-2-yl)acetate (1 eq., 400 mg, 1.17 mmol) in dioxane (7.32 mb) was added dropwise at RT NaHCOs (2 eq., 195.82 mg, 2.33 mmol) in water (1.83 mL). The reaction mixture was degassed with argon for 5 minutes. RuPHOS PdG4 (0. 1 eq., 99. 12 mg, 0. 12 mmol) was then added and the reaction mixture was stirred at 80°C for 1 h. The reaction mixture was filtered through a pad of celite and solid was rinsed with EtOAc, the filtrate was concentrated under vacuo. The crude was purified on a 20g Agela Silica-CS (Phenomenex), eluted with gradient 0-2% MeOH in DCM (Biotage Isolera One device) to afford ethyl (S)-2-(4-fhioro-6-(6-((3-hydroxy-3-methylbutan-2-yl)oxy)pyrazolo[l,5-a]pyrimidin-3-yl)-l- isopropyl-lH-benzo[d]imidazol-2-yl)acetate (573 mg).

[0553] ’H NMR (400 MHz, DMSO) 5 8.99 (d, J = 2.7 Hz, 1H), 8.78 (s, 1H), 8.62 (d, J = 2.7 Hz, 1H), 8.26 (d, J = 1.3 Hz, 1H), 7.83 (dd, J = 12.6, 1.2 Hz, 1H), 4.73 (h, J = 6.8 Hz, 1H), 4.62 (s, 1H), 4.30 (q, J = 6.2 Hz, 1H), 4.19 (s, 2H), 4.16 (q, J = 7.1 Hz, 2H), 1.64 (s, 3H), 1.62 (s, 3H), 1.27 (d, J = 6.2 Hz, 3H), 1.25 - 1.16 (m, 9H).1.64.3. Step C

[0554] To a solution of ethyl (S)-2-(4-fluoro-6-(6-((3-hydroxy-3-methylbutan-2-yl)oxy)pyrazolo[l,5- a]pyrimidin-3-yl)-l-isopropyl-lH-benzo[d]imidazol-2-yl)acetate (1 eq., 573 mg, 1.19 mmol) in MeOH (16.43 mL) was added a solution ofNaOH (1 M in H2O) (10 eq., 5.93 mL, 11.85 mmol) atRT. The reaction mixture was stirred at 60 °C for 1.5 h. The mixture was cooled to RT and acidified with HC1 2N (pH ~ 5). The aqueous layer was extracted with EtOAc. The combined organics layers was dried over Na2SO4, filtered and concentrated under vacuo. The crude was purified on a 12g C18 column (Biotage), eluted withgradient 0-100% [ACN / 0.1% formic acid] in [H2O / 0.1% formic acid](Biotage Isolera One device), to afford Int 66 (164 mg).

[0555] ’H NMR (400 MHz, DMSO) 5 8.98 (d, J = 2.7 Hz, IH), 8.75 (s, IH), 8.61 (d, J = 2.7 Hz, IH), 8.18 (d, J = 1.3 Hz, IH), 7.79 (dd, J = 12.6, 1.3 Hz, IH), 4.78 (h, J = 7.4 Hz, IH), 4.62 (s, IH), 4.29 (q, J = 6.2 Hz, IH), 2.58 (s, 2H), 1.62 (d, J = 6.9 Hz, 6H), 1.27 (d, J = 6.2 Hz, 3H), 1.20 (d, J = 10.2 Hz, 6H).1.65. Int 671.65.1. Step A

[0556] In a sealed tube, under N2, Morpholin-3-one 97% (1 eq., 127.45 mg, 1.26 mmol) was dissolved in THF (0.3 mb). At 0°C, NaH (1.5 eq., 45.38 mg, 1.89 mmol) was added and the reaction mixture was stirred at rt for Ih. 5-Bromo-l,3-difluoro-2 -nitrobenzene 98% (1 eq., 300 mg, 1.26 mmol) in THF (0.3 mb) was added dropwise and the reaction mixture was stirred at rt for 3 h. EtOAc and water were added. The organic layer was washed with water, brine, dried over anhydrous Na2SO4, filtered, evaporated and purified in reverse phase chromatography (Biotage C18 40 pm 30 g, loading DMSO, gradient water (formic acid 0.1%) / MeCN (formic acid 0.1%) 100:0 to 40:60 in 15 CV) to afford 4-(5-bromo-3-fluoro-2- nitrophenyl)morpholin-3-one (189 mg).

[0557] ECMS: MW (calcd): 319.1; m / z MW (obsd): 319.0 - 321.0 (M+H).1.65.2. Step B

[0558] In a sealed tube, to a stirred solution of 4-(5-bromo-3-fluoro-2-nitrophenyl)morpholin-3-one (1 eq., 185 mg, 0.58 mmol) in EtOH (2.67 m ) and water (0.56 m ) was added NH4CI (5 eq., 155.062 mg, 2.9 mmol) followed by be (5 eq., 161.89 mg, 2.9 mmol) at RT. The mixture was stirred at 60°C for 1.5 h. The mixture was cooled to RT, and fdtered on a pad of celite. The solid was washed with EtOAc. The fdtrate was concentrated, then the residue was taken up in EtOAc and washed with water. The aqueous layer was extracted with EtOAc (2x) and the combined organic layer were dried over anhydrous Na2SO4, filtered, concentrated under vacuo and the crude was purified in reverse phase chromatography (Biotage C 18 40 pm 12 g, loading DMSO, gradient water (+ 0.1% HCOOH) / MeCN (+ 0.1% HCOOH) 100:0 to 50:50 in 15 CV) to afford 4-(2-amino-5-bromo-3-fluorophenyl)morpholin-3-one (70 mg).

[0559] LCMS: MW (calcd): 289.1; m / z MW (obsd): 289.0 - 291.0 (M+H).1.65.3. Step C

[0560] In a sealed tube, under air, 4-(2-amino-5-bromo-3-fhrorophenyl)morpholin-3-one (1 eq., 65 mg, 0.22 mmol) was dissolved in toluene (2 mb) and AcOH (10 eq., 135.016 mg, 0.13 mb, 2.25 mmol) was added. The reaction mixture was stirred at 110°C for 2 h. The reaction mixture was evaporated and the crude was purified in normal phase chromatography (irregular SiOH 40-60 pm 60 A 4 g Claricep Agela, liquid loading (DCM), gradient Hept / EtOAc 100:0 to 0: 100 in 10CV) to afford Int 67 (32 mg).

[0561] LCMS: MW (calcd): 271.1; m / z MW (obsd): 270.9 - 272.9 (M+H).1.66. Int 681.66.1. Step A

[0562] In a sealed tube, a mixture of 6-(benzyloxy)-3-bromopyrazolo[l,5-a]pyrimidine CAS#2750708- 07-5 (1 eq., 500 mg, 1.64 mmol), 4-fluoro-2-methyl-l-(propan-2-yl)-6-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)-lH-l,3-benzodiazole CAS#1231930-37-2 (1 eq., 523.102 mg, 1.64 mmol) , CS2CO3 (2 eq., 1071.26 mg, 3.29 mmol), PdC12dppf.dcm (0.1 eq., 134.25 mg, 0.16 mmol), dioxane (9.48 mb) and water (2.37 mL) was degassed with N2 and stirred at 80 °C for 2 h. EtOAc and water were added. The organic layer of the fdtrate was separated and washed with brine, dried (MgSCh), fdtered, evaporated then triturated with isopropanol, fdtered and washed with isopropanol and dried on the frit to afford 6- (benzyloxy)-3-(4-fluoro-l-isopropyl-2-methyl-lH-benzo[d]imidazol-6-yl)pyrazolo[l,5-a]pyrimidine (457 mg).

[0563] LCMS: MW (calcd): 415.5; m / z MW (obsd): 416.3 (M+H).1.66.2. Step B

[0564] In a RBF, under air and at 0 °C Trifluoromethanesulfonic acid (6 eq., 990.42 mg, 0.59 mL, 6.6 mmol) was added to a solution of 6-(benzyloxy)-3-(4-fluoro-l-isopropyl-2-methyl-lH-benzo[d]imidazol- 6-yl)pyrazolo[l,5-a]pyrimidin (1 eq., 457 mg, 1.1 mmol) in DCM (3.74 mL). The mixture was stirred at 0 °C for 1 h. Water (30 mL) was added and the reaction mixture was stirred at rt for 3 h. A precipitate was formed and was fdtered to afford Int 68 (357 mg).

[0565] LCMS: MW (calcd): 325.3; m / z MW (obsd): 326.2 (M+H).1.67. Int 69

[0566] In a sealed tube, under air, a mixture of 5-bromo-3-fluoro-N-isopropyl-2-nitroandine CAS#2177297-28-6 (1 eq., 50 mg, 0.18 mmol) and oxetane-3-carbaldehyde (2 eq., 31.069 mg, 0.36 mmol) was dissolved in DMSO (0.53 mL) and ethanol (2.101 mL). Then, disodium sulfinatosulfinate (5 eq., 157.077 mg, 0.902 mmol) was added and the reaction mixture was stirred at 80°C for 19 h. EtOAc and water were added to the mixture. The aqueous layer was extracted with EtOAc (x3) and the combined organic layer was washed with water and brine. The organic layer was dried over anhydrous Na2SO4,I l l filtered and concentrated under vacuum. The crude material was then purified by column chromatography (Sfar HC 5g, elution with DCM / MeOH 100 to 96 / 4 over 25 CV ) to afford Int 69

[0567] LCMS: MW (calcd): 313.2; m / z MW (obsd): 313.0 - 314.9 (M+H).1.68. Int 70

[0568] A 25 ml flask was charged at RT under nitrogen with 3-bromopyrazolo[l,5-a]pyrimidine-6- carboxylic acid CAS#1273577-71-1 (1 eq., 50 mg, 0.207 mmol), 3-amino-3-methylbutan-2-ol (1.5 eq., 31.97 mg, 0.31 mmol), DIPEA (1.5 eq., 40.051 mg, 0.054 mL, 0.31 mmol) and HATU (1.5 eq., 117.83 mg, 0.31 mmol) with anhydrous DMF (2.5 mL). The mixture was stirred at RT overnight. EtOAc and water were added to the mixture. Extraction with EtOAc and organic layer was dried over Na2SO4 and filtered. The crude material was then purified by column chromatography (Sfar HC 10g, elution with DCM / MeOH 100 to 93 / 78 over 30 CV ) to afford Int 70 (55.4 mg).

[0569] LCMS: MW (calcd): 313.2; m / z MW (obsd): 313.1 - 315.1 (M+H).1.69. Int 71

[0570] Same conditions used for Int 70 afforded Int 71.

[0571] LCMS: MW (calcd): 313.2; m / z MW (obsd): 313.1 - 315.1 (M+H).1. 70. Int 72

[0572] Same conditions used for Int 70 afforded Int 72.

[0573] LCMS: MW (calcd): 285.1; m / z MW (obsd): 285.0 - 287.0 (M+H).1. 71. Int 731. 71.1. Step A

[0574] A 25 ml RBF was charged under nitrogen, with 3-hydroxy-2,2-dimethylbutanenitrile (1 eq., 500 mg, 4.42 mmol), DMAP (0.05 eq., 26.99 mg, 0.22 mmol), and pyridine (4.54 mb) at 0°C. To the mixture was added tosyl chloride (1.5 eq., 1263.52 mg, 6.63 mmol). The mixture was warmed up to RT and stirred at RT. The reaction mixture was stirred at RT overnight. The reaction mixture was concentrated under vacuum, the obtained residue was diluted with water and extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous MgSCE, filtered and concentrated under vacuum. The crude material was then purified by column chromatography (Sfar HC 25g, elution with Heptane / AcOEt 100 to 40 / 60 in 25CV) to afford 3-cyano-3-methylbutan-2-yl 4-methylbenzenesulfonate (1.08 g).

[0575] 1H NMR (400 MHz, DMSO) 5 7.89 - 7.81 (m, 2H), 7.54 - 7.46 (m, 2H), 4.64 (q, J = 6.3 Hz, 1H), 2.43 (s, 3H), 1.27 - 1.23 (m, 6H), 1.18 (s, 3H)1. 71.2. Step B

[0576] A screw vial cap was charged at RT under nitrogen, 3-bromopyrazolo[l,5-a]pyrimidin-6-ol CAS#1314893-97-4 (1 eq., 50 mg, 0.23 mmol) and 3-cyano-3-methylbutan-2-yl 4-methylbenzenesulfonate (3 eq., 187.37 mg, 0.7009 mmol), with anhydrous DMSO (1.52 mb). To the mixture was added at RT K2CO3 (3 eq., 96.86 mg, 0.7009 mmol). The mixture was warmed up to 100°C and stirred at 100°C overnight. Water was added to the reaction mixture and the mixture was extracted twice with EtOAc. The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under vacuum and directly purified by column chromatography (Sfar HC 10g, elution with Heptane / AcOEt 100 to 50 / 50 in 30CV) to afford Int 73(47.1 mg).

[0577] LCMS: MW (calcd): 309.2; m / z MW (obsd): 309.0 - 311.0 (M+H).1. 71.3. Int 74

[0578] A 25 mb RBF under nitrogen was charged with 3-bromopyrazolo[l,5-a]pyrimidine-6-carboxylic acid CAS#1273577-71-1 (1 eq., 80 mg, 0.33 mmol) NH4C1 (10 eq., 176.803 mg, 0.12 mL, 3.305 mmol) with anhydrous DMF (1 mL) and to the mixture was added HATU (1.5 eq., 188.52 mg, 0.5 mmol) DIPEA (1.5 eq., 64.081 mg, 0.086 mL, 0.5 mmol) The mixture was stirred at RT for 48 h. EtOAc and water were added to the mixture. Extraction with EtOAc and organic layer was dried over Na2SO4, filtered to afford Int 74.

[0579] LCMS: MW (calcd): 241.0; m / z MW (obsd): 240.9 - 243.0 (M+H).1. 72. Int 75

[0580] A screw vial cap was charged 5-bromo-3-fluoro-Nl-isopropylbenzene-l,2-diamine CAS#2177297-22-0 (1 eq., 75 mg, 0.304 mmol) and Cyclopropylcarboxylic acid 99% (10 eq., 261.29 mg, 0.24 mb, 3.035 mmol). To the mixture was added Eaton's Reagent (3.4 eq., 392.12 mg, 0.25 mb, 1.032 mmol) .The mixture was warmed up to 100°C and stirred at 100°C for 16 h. EtOAc and water were added to the mixture. Extraction with EtOAc and organic layer was dried over Na2SO4, filtered and directly purified by flash chromatography phenomenex 12g 20 pm, DCM 100% (3CV) DCM / (EtOAc / EtOH (3 / 1)) 100 to 90 / 10 (10CV) to afford Int 75 (45 mg).

[0581] LCMS: MW (calcd): 297.2; m / z MW (obsd): 297.0 - 299.0 (M+H).1. 73. Int 761.73.1. Step A

[0582] In a vial, a mixture of 5-Bromo-l,3-difluoro-2 -nitrobenzene 98% (1 eq., 700 mg, 2.94 mmol) was dissolved in DMSO (5.95 mb). (3-Aminobicyclo[l. l.l]pentan-l-yl)methanol hydrochloride 98% (1 eq., 440.081 mg, 2.94 mmol) and CS2CO3 (3 eq., 2875.019 mg, 8.82 mmol) were added and the reaction mixture was stirred at 40°C for 1 h. 12mL of water and 8mL of DCM were added to the mixture. The organic layer was evaporated under reduced pressure and was directly purified by normal phase chromatography (irregular SiOH 40-60 pm 20 g Claricep Agela, liquid loading (DCM), gradient Hept / EtOAc 0: 100 in 15CV then 5CV at 100%) to afford (3-((5-bromo-3-fhioro-2-nitrophenyl)amino)bicyclo[l. l. l]pentan-l- yl)methanol (810 mg).

[0583] LCMS: MW (calcd): 331.1; m / z MW (obsd): 329.0 - 331.0 (M-H).1. 73.2. Step B

[0584] In a RBF, to a stirred solution of (3-((5-bromo-3-fluoro-2-nitrophenyl)amino)bicyclo[l . 1. l]pentan- l-yl)methanol (1 eq., 810 mg, 2.45 mmol) in EtOH (28.89 m ) and water (9.25 m ) and NH4CI (5 eq., 654.206 mg, 12.23 mmol) at 80°C was added Fe (5.27 eq., 719.89 mg, 12.89 mmol). The mixture was stirred at 80°C for 1.5 h. The reaction mixture was cooled down to rt, fdtered on a celite pad and purified in Normal phase chromatography (SiO2 biotage KP-NH 11 g, loading DCM, gradient Heptane / EtOAc 100:0 to 50:50 in 15 CV. The tubes containing product were evaporated to afford (3-((2-amino-5-bromo- 3-fhrorophenyl)amino)bicyclo[l. l. l]pentan-l-yl)methanol (372 mg).

[0585] ECMS: MW (calcd): 301.2; m / z MW (obsd): 300.9 - 302.9 (M+H).1.73.3. Step C

[0586] In a sealed tube, under air, triethyl orthoacetate (15 eq., 1357.48 mg, 1533.87 microb, 8.37 mmol), AcOH (20 eq., 669.99 mg, 639.307 microL, 11.16 mmol) and (3-((2-amino-5-bromo-3- fluorophenyl)amino)bicyclo[l. l. l]pentan-l-yl)methanol (1 eq., 168 mg, 0.56 mmol) were stirred at 120°Cin dioxane (3069.5 microL) for 1 h. The crude filtered and purified by LCMS : PrepB_50mL_40-55_8min. to afford Int 76 (70 mg).

[0587] LCMS: MW (calcd): 325.2; m / z MW (obsd): 324.9 - 326.9 (M+H).1. 74. Int 771.74.1. Step A

[0588] A 100 ml round bottom flask was charged at RT under Air with 5-Bromo-l,3-difluoro-2- nitrobenzene 98% (1 eq., 700 mg, 2.94 mmol) in EtOH (35 mb). To the resulting solution was added bicyclofl. l. l]pentan-2-amine;Hydrochloride (1 eq., 351.75 mg, 2.94 mmol), TEA (1 eq., 297.64 mg, 0.409 mb, 2.94 mmol) and the reaction mixture was stirred at 70°C overnight. Solvent removed and the crude was purified in Normal phase chromatography (SiO2 40-63 pm 40 g, loading DCM, gradient Heptane / EtOAc 100:0 to 50:50 in 15 CV to afford N-(5-bromo-3-fluoro-2- nitrophenyl)bicyclo[l. l. l]pentan-2 -amine (687 mg).

[0589] LCMS: MW (calcd): 301.1; m / z MW (obsd): 301.0 - 303.0 (M+H).1.74.2. Step B

[0590] In a RBF, to a stirred solution ofN-(5-bromo-3-fluoro-2-nitrophenyl)bicyclo[l . 1. l]pentan-2-amine (1 eq., 687 mg, 2.28 mmol) in EtOH (26.95 m ) and water (8.62 m ) and NH4CI (5 eq., 610.19 mg, 11.408 mmol) at 80°C was added Fe (5.27 eq., 671.46 mg, 12.024 mmol). The mixture was stirred at 80°C for 1.5 h. The reaction mixture was cooled down to rt, fdtered on a celite pad and purified in Normal phase chromatography (SiO2 biotage KP-NH 28 g, loading DCM, gradient Heptane / EtOAc 100:0 to 50:50 in 15 CV to afford Nl-(bicyclo[l. l. l]pentan-2-yl)-5-bromo-3-fluorobenzene-l,2-diamine (292 mg).

[0591] ECMS: MW (calcd): 271.1; m / z MW (obsd): 272.0 - 273.0 (M+H).1.74.3. Step CIn a sealed tube, under air, triethyl orthoacetate (15 eq., 224.38 mg, 253.53 microb, 1.38 mmol), AcOH (20 eq., 110.74 mg, 105.67 microL, 1.84 mmol) and N 1 -(bicyclo [1.1.1 ]pentan -2 -yl)-5-bromo-3- fluorobenzene-l,2-diamine (1 eq., 25 mg, 0.092 mmol) were stirred at 140°C in dioxane (500 microL) overnight. The reaction mixture was evaporated and purified in normal phase chromatography (irregular SiOH 40-60 pm 60 A 4 g Claricep Agela, liquid loading (DCM), gradient Hept / EtOAc 0: 100 in 15CV then 5CV at 100%) to afford Int 77 (8 mg).

[0592] LCMS: MW (calcd): 295.2; m / z MW (obsd): 295.2 - 297.2 (M+H).1. 75. Int 781. 75.1. Step AA 50 ml round botom flask was charged at RT under Air with 5-bromo-l,3-difluoro-2 -nitrobenzene (1 eq., 500 mg, 2.101 mmol) in ethanol (25 mL). To the resulting solution was added tert -butyl N-(2-amino- 2-methylpropyl)carbamate (1 eq., 395.55 mg, 2.101 mmol) and the reaction mixture was stirred at 70°C for 72 h. The reaction mixture was evaporated under reduced pressure to afford a red / orange liquid that was directly purified by reverse phase BiotageSfar C18 30 g, dry loading , mobile phase gradient 0 to 100% [ACN / 0. 1% NH4OH] in [H2O / 0. 1%NH4OH] (10CV)(Biotage Isolera One device) to afford tertbutyl (2-((5-bromo-3-fluoro-2-nitrophenyl)amino)-2-methylpropyl)carbamate (532 mg).

[0593] LCMS: MW (calcd): 406.2; m / z MW (obsd): 406.1 - 408.1 (M+H).1. 75.2. Step B

[0594] In a round-botom flask, to a stirred solution of tert-butyl (2-((5-bromo-3-fluoro-2- nitrophenyl)amino)-2-methylpropyl)carbamate (1 eq., 532 mg, 1.31 mmol) in EtOH (4 mL) and water (2 mL) was added ammonium chloride (5 eq., 350.23 mg, 6.55 mmol) followed by iron (5 eq., 365.65 mg, 6.55 mmol). The reaction mixture was stirred at 70 °C for 1 h. The mixture was cooled to rt, diluted with EtOAc and filtered on a Celite Pad. The solid was washed with EtOAc and the filtrate was concentrated and was purified by reverse phase Biotage Sfar C 18 30 g, dry loading , mobile phase gradient 0 to 100% [ACN / 0. 1% NH4OH] in [H2O / 0.1%NH4OH] (10CV)(Biotage Isolera One device) to afford tert -butyl (2- ((2-amino-5 -bromo-3 -fluorophenyl)amino)-2-methylpropyl)carbamate (394 mg) .

[0595] LCMS: MW (calcd): 376.3; m / z MW (obsd): 376.2 - 378.2 (M+H).1. 75.3. Step C

[0596] In a screw vial was solubilized tert-butyl (2-((2-amino-5-bromo-3-fluorophenyl)amino)-2- methylpropyl)carbamate (1 eq., 150 mg, 0.4 mmol) in AcOH (4.5 mL). The reaction mixture was stirred at 120°C overnight. The mixture was cooled to rt and concentrated and treated with ammonia 4N in MeOH (ImL). The crude was purified by reverse phase Biotage Sfar Amino 11g, dry loading , mobile phase gradient 0 to 10% MeOH in DCM (10CV)(Biotage Isolera One device) to afford Int 78 (42 mg).

[0597] LCMS: MW (calcd): 400.3; m / z MW (obsd): 400.1 - 402.0 (M+H).1. 76. Int 79To a stirred solution of 3-bromopyrazolo[l,5-a]pyrimidin-6-ol CAS#1314893-97-4 (1 eq., 100 mg, 0.47 mmol) and l-(3-Hydroxypyrrolidin-l-yl)ethan-l-one 96% (2 eq., 120.7 mg, 0.93 mmol) in toluene (3.33 mL) was added CMBP CAS#157141-27-0 (3 eq., 338.32 mg, 0.37 mL, 1.402 mmol). The reaction mixture was stirred at 90°C for 2 h. Water was added to the reaction mixture. The two phases were separated and the aqueous layer was extracted twice with EtOAc. The combined organic layers were dried over MgSCL, fdtered, evaporated and purified on Agela 20g (loading in DCM) irregular column, Q= 18mL / min, eluted with Heptane / (AcOEt : EtOH 3 : 1) gradient 100 / 0 (1CV), 100 / 0 to 0 / 100 (20 CV), 0 / 100 (10CV) to afford Int 79 (118 mg).

[0598] LCMS: MW (calcd): 325.2; m / z MW (obsd): 325.0 - 327.0 (M+H).1. 77. Int 80A screw vial cap was charged in isopropanol (1 mL), 5-bromo-3-fluoro-Nl-isopropylbenzene-l,2- diamine CAS#2177297-22-0 (1 eq., 70 mg, 0.28 mmol) and l,3-Bis(tert-butoxycarbonyl)-2-methyl-2- thiopseudourea (1.5 eq., 123.39 mg, 0.42 mmol). To the mixture was added APTS (0.1 eq., 4.88 mg, 0.0046 mL, 0.028 mmol) and the mixture was warmed up to 80°C and stirred at 80°C for 20 min. Water was added to the mixture and mixture was stirred at RT for 1 h. A precipitate was formed and was fdtered to afford Int 80 (66 mg).

[0599] LCMS: MW (calcd): 372.2; m / z MW (obsd): 372.1 - 374.1 (M+H).1. 78. Int 811.78.1. Step AIn a vial, a mixture of 5-Bromo-l,3-difluoro-2-nitrobenzene 98% (1 eq., 500 mg, 2.101 mmol) was dissolved in DMSO (4.25 mL). tert-butyl N-(3-aminocyclobutyl)carbamate (1 eq., 391.31 mg, 2.101 mmol) and CS2CO3 (3 eq., 2053.58 mg, 6.303 mmol) were added and the reaction mixture was stirred at 40°C for 2 h. The reaction mixture was filtered, the solid was washed with DCM and the filtrate was evaporated under reduced pressure to afford a red / orange liquid that was directly purified by reverse phase Biotage Sfar C18 30 g, dry loading , mobile phase gradient 0 to 100% [ACN / 0. 1% NH4OH] in[H2O / 0. 1%NH4OH] (10CV)(Biotage Isolera One device) to afford a mixture of tert-butyl ((ls,3s)-3-((5- bromo-3-fluoro-2-nitrophenyl)amino)cyclobutyl)carbamate and tert-butyl ((lr,3r)-3-((5-bromo-3-fluoro-2-nitrophenyl)amino)cyclobutyl)carbamate (745 mg).

[0600] LCMS: MW (calcd): 404.2; m / z MW (obsd): 404.1 - 406.1 (M+H).1. 78.2. Step BIn a round-bottom flask, to a stirred solution of a mixture of a mixture of tert-butyl ((ls,3s)-3-((5-bromo-3-fluoro-2-nitrophenyl)amino)cyclobutyl)carbamate and tert-butyl ((lr,3r)-3-((5-bromo-3-fluoro-2- nitrophenyl)amino)cyclobutyl)carbamate (1 eq., 745 mg, 1.84 mmol) in EtOH (5 m ) and water (2 m ) was added NH4CI (5 eq., 492.906 mg, 9.21 mmol) followed by be (5 eq., 514.607 mg, 9.21 mmol). The reaction mixture was stirred at 70 °C for 2 h. The mixture was cooled to rt, diluted with EtOAc and filtered on a Celite Pad. The solid was washed with EtOAc and the filtrate was concentrated. The crude was purified by reverse phase Biotage Sfar C18 12 g, dry loading , mobile phase gradient 10 to 100% [ACN / 0. 1% NH40H] in [H2O / 0. 1%NH4OH] (10CV)(Biotage Isolera One device) and purified by normal phase chromatography on Agela 20g irregular column, dry deposit, eluted with gradient 30-100% ethyl acetate in n-Heptane (Biotage Isolera One device) to afford a mixture of tert-butyl ((ls,3s)-3-((2- amino-5 -bromo-3 -fluorophenyl)amino)cyclobutyl)carbamate and tert-butyl ((lr,3r)-3-((2-amino-5- bromo-3-fluorophenyl)amino)cyclobutyl)carbamate (275 mg).

[0601] LCMS: MW (calcd): 374.2; m / z MW (obsd): 374.1 - 376.1 (M+H).1. 78.3. Step CIn a screw vial was solubilized a mixture of tert-butyl ((ls,3s)-3-((2-amino-5-bromo-3- fluorophenyl)amino)cyclobutyl)carbamate and tert-butyl ((lr,3r)-3-((2-amino-5-bromo-3- fhiorophenyl)amino)cyclobutyl)carbamate (1 eq., 149.2 mg, 0.4 mmol) in acetic acid (4.5 mb). The reaction mixture was stirred at 120°C overnight. The mixture was cooled to rt and concentrated and treated with ammonia 4N in MeOH (2mL).The crude was purified by reverse phase Biotage Sfar Amino 11g, dry loading , mobile phase gradient 0 to 10% MeOH in DCM (10CV)(Biotage Isolera One device) to afford Int 81 (101 mg).

[0602] LCMS: MW (calcd): 340.2; m / z MW (obsd): 340.1 - 342.1 (M+H).1. 79. Int 821. 79.1. Step AIn an open tube (without screw cap), under air, a mixture of 5 -Bromo-3 -fluorobenzene- 1,2-diamine 99% (1 eq., 500 mg, 2.44 mmol) and (2R)-2-hydroxypropanoic acid (10 eq., 2196.703 mg, 1.69 mb, 24.39 mmol) was stirred at 80 °C for 16 h. After cooling down to rt, the reaction mixture was dissolved inMeOH (25 mb) and THF (25 mb). NaOH (2M in water) (15 eq., 18.29 mb, 36.58 mmol) was added and the reaction mixture was stirred at rt for 2 h. The reaction mixture was neutralized with HC1 aq. (2M) then with NaHCOs sat. aq. until pH = 8 and evaporated under reduced pressure and was triturated in MeCN, fdtered and the fdtrate was evaporated under reduced pressure to afford (R)-l-(5-bromo-7-fluoro-lH- benzo[d]imidazol-2-yl)ethan-l-ol (561 mg).

[0603] LCMS: MW (calcd): 259.1; m / z MW (obsd): 259.0 - 261.0 (M+H).1. 79.2. Step B

[0604] In a tube, (R)-l-(5-bromo-7-fluoro-lH-benzo[d]imidazol-2-yl)ethan-l-ol (1 eq., 100 mg, 0.39 mmol), Cyclopropylboronic acid 98% (2 eq., 66.31 mg, 0.77 mmol), Na2COs (2 eq., 81.82 mg, 0.77 mmol), Cu(OAc)2 (1 eq., 70.108 mg, 0.39 mmol) and 2,2' -bipyridine (1 eq., 60.29 mg, 0.39 mmol) were dissolved in air-purged toluene (4 mb) and DMSO (0.25 mb) (for the solubility), briefly sonicated and stirred under air at 70 °C for 16 h. After cooling down to rt, the reaction mixture was diluted with DCM and NaHCOs aq. sat. The biphasic layer was filtered on a BIOTAGE isolute phase separator. The organic layer was collected and evaporated to afford a residue that was purified by reverse phase preparative LC (Sfar Silica Gel C18 Duo 30 pm 6 g, liquid loading (DMSO), mobile phase gradient: Water + 0.1% NH4OH 20% / MeCN + 0.1% NH4OH 20% from 90: 10 to 30:70 over 10 CV then isocratic for 3 CV then 30:70 to 0: 100 over 3 CV) to afford Int 82 (12 mg).

[0605] LCMS: MW (calcd): 299.1; m / z MW (obsd): 299.0 - 301.0 (M+H).1.80. Int 83The same method as for Int 82 was used to obtain Int 83 starting from (2S)-2-hydroxypropanoic acid.

[0606] LCMS: MW (calcd): 299.1; m / z MW (obsd): 299.0 - 301.0 (M+H).1.81. Int 841.81.1. Step A

[0607] In a sealed tube, under N2, a mixture of 6-Bromopyrazolo[l,5-a]pyridine (1 eq., 150 mg, 0.76 mmol), 3, 3 -Difluoroazetidine HC1 97% (2.5 eq., 246.52 mg, 1.903 mmol), CS2CO3 (4 eq., 992.17 mg, 3.045 mmol), XantPhos Pd G3 (0.1 eq., 72.2 mg, 0.076 mmol) and xantphos (0.1 eq., 44.05 mg, 0.076 mmol) in dioxane (7 mb) was degassed with N2 for 5min. Then, the reaction mixture was degassed through vacuum / N2 cycles 3 times, kept under N2 atmosphere. The reaction mixture was stirred at 90°C for 16 h. The reaction mixture was directly filtered, evaporated and was purified in reverse phase chromatography (Cl 840 pm 12 g, loading DMSO, gradient water (+ 0.1% HCOOH) / MeCN (+ 0.1% HCOOH) 100:0 to 40:60 in 15 CV) to afford 6-(3,3-difluoroazetidin-l-yl)pyrazolo[l,5-a]pyridine (112 mg).

[0608] LCMS: MW (calcd): 209.2; m / z MW (obsd): 210.1(M+H).1.81.2. Step B

[0609] In a sealed tube, under air, 6-(3,3-difluoroazetidin-l-yl)pyrazolo[l,5-a]pyridine (1 eq., 100 mg, 0.48 mmol) was added in N,N-dimethylformamide (1.85 mL). Then at 0°C, NBS (0.9 eq., 76.57 mg, 0.43 mmol) was added and the reaction mixture was stirred at 0°C for 1 h. NBS (0.5 eq., 42.54 mg, 0.24 mmol) was added and the reaction mixture was stirred at 0°C for additional 1 h. EtOAc and water were added. The o...

Claims

CLAIMS1. A compound according to Formula I:wherein one of Xi and X2is N and the other is C;Y is CH or N;Provided that- when Xi is C, X2is N, and Y is N, then R2is not -NR3aR3\ or- -Li R1is not -OH, -Me, -OMe, -CH2CH2OH, or -NMe2;Li is absent,Ci -e alkylenyl,LIA,-CI -e alkylenyl-LiA-, or-LIA-CI-6 alkylenyl-;LIA is -O-, -NRx1-, -C(=O)-, -C(=O)O-, -C(=O)NRx1-, -NRxlC(=O)-, -NRxlC(=O)O-, S(=O), -S(=O)2-, - NHS(=O)2NRX1-, -S(=O)2NRX1-, -NRX1S(=O)2-, -P(=O) RX1;Rxlis H, or C1-6 alkyl optionally substituted with one or more independently selected halo;R1isCi -e alkyl optionally substituted with one or more groups independently selected from =0 and R7, C3-7 cycloalkyl optionally substituted with one or more groups independently selected from =0 and R7, polycyclic fused, spiro or bridged C4-10 cycloalkyl optionally substituted with one or more groups independently selected from =0 and R7,4-7 membered heterocycloalkyl comprising one or more heteroatoms independently selected from O, S, N, P, and B, which heterocycloalkyl is optionally substituted with one or more groups selected from =0 and R7, polycyclic fused, spiro or bridged 6-10 membered heterocycloalkyl comprising one or more heteroatoms independently selected from O, S, N, P, and B, which heterocycloalkyl is optionally substituted with one or more groups selected from =0 and R7,Phenyl optionally substituted with one or more groups independently selected from R7,5-7 membered heteroaryl comprising one or more heteroatoms independently selected from O, S, and N, which heteroaryl is optionally substituted with one or more groups independently selected from R7, and polycyclic fused 8-10 membered heteroaryl comprising one or more heteroatoms independently selected from O, S, and N, which heteroaryl is optionally substituted with one or more groups independently selected from R7;Each R7is independently selected from halo,- -CN,-L7A-R7A, and-Ci-6 alkylenyl-L7A-R7A;L7Ais absent, -O-, -NRx2-, -C(=O)-, -C(=O)O-, -C(=0)NRx2-, -NRx2C(=0)-, -NRx2C(=0)0-, -S(=O), -S(=O)2-, -NHS(=O)2NRX2-, -S(=O)2NRX2-, -NRX2S(=O)2-, or -P(=O) Rx2;Rx2is H, or Ci-6 alkyl optionally substituted with one or more independently selected halo;R7Ais- HCi .4 alkyl optionally substituted with one or more independently selected =0, halo, CN, or OH, C2-7cycloalkyl optionally substituted with one or more groups independently selected from =0, halo, CN, or OH, or4-7 membered heterocycloalkyl comprising one or more heteroatoms independently selected from O, S, N, P, and B, which heterocycloalkyl is optionally substituted with one or more groups selected from =0, halo, CN, or OH;R2isH,Ci .4 alkyl optionally substituted with one or more independently selected halo, or -NR2aR2b;Each R2aand R2bis independently selected from H, C1-4 alkyl optionally substituted with one or more independently selected halo, or phenyl;Each R3is independently selected from halo, CN, and C1.4 alkyl optionally substituted with one or more independently selected halo;The subscript n is 0, 1, 2 or 3;Cy is a 8-10 membered bicyclic heteroaryl comprising one or more heteroatoms independently selected from N, O, and S, which heteroaryl is optionally substituted with one or more independently selected R4;Each R4is independently selected from: halo, CN, and -L4A-R4A; orTwo R4groups together with the atoms to which they are attached may form together a fused 4-7 membered heterocycloalkyl comprising one or more heteroatoms independently selected from O, S, N, P, and B, which heterocycloalkyl is optionally substituted with one or more groups selected from =0, halo, CN, or OH;L4Ais absent, -O-, -NRx4-, -C(=O)-, -C(=O)O-, -C(=O)NRx4-, -NRx4C(=O)-, -NRx4C(=O)O-, -S(=O), =S(=O)2, -NHS(=O)2NRX4-, -S(=O)2NRX4-, -NRX4S(=O)2-, or -P(=O)Rx4;Rx4is H, or Ci-6 alkyl optionally substituted with one or more independently selected halo;Each R4Ais independently selected from:- H,C1-6 alkyl optionally substituted with one or more groups independently selected from =0 and R5, C3-7 cycloalkyl optionally substituted with one or more groups independently selected from =0 andR5, polycyclic fused, spiro or bridged C4-10 cycloalkyl optionally substituted with one or more groups independently selected from =0 and R5,4-7 membered heterocycloalkyl comprising one or more heteroatoms independently selected from O, S, N, P, and B, which heterocycloalkyl is optionally substituted with one or more groups selected from =0 and R5, polycyclic fused, spiro or bridged 6-10 membered heterocycloalkyl comprising one or more heteroatoms independently selected from O, S, N, P, and B, which heterocycloalkyl is optionally substituted with one or more groups selected from =0 and R5,Phenyl optionally substituted with one or more groups independently selected from R5, and5-7 membered heteroaryl comprising one or more heteroatoms independently selected from O, S, and N, which heteroaryl is optionally substituted with one or more groups independently selected from R5;Each R5is independently selected from: halo,CN, and- -L5A-R5A;L5Ais absent, -O-, -NRx5-, -C(=O)-, -C(=O)O-, -C(=O)NRx5-, -NRx5C(=O)-, -NRx5C(=O)O-, -S(=O), -S(=O)2, -NHS(=O)2NRX5-, -S(=O)2NRX5-, -NRX5S(=O)2-, or -P(=O)Rx5;Rx5is H, or Ci-6 alkyl optionally substituted with one or more independently selected halo;Each R5Ais independently selected from:- H,Ci -e alkyl optionally substituted with one or more groups independently selected from =0 and R6, C3-7 cycloalkyl optionally substituted with one or more groups independently selected from =0 and R6,4-7 membered heterocycloalkyl comprising one or more heteroatoms independently selected from O, S, N, P, and B, which heterocycloalkyl is optionally substituted with one or more groups selected from =0 and R6,Phenyl optionally substituted with one or more groups independently selected from R6, and5-7 membered heteroaryl comprising one or more heteroatoms independently selected from O, S, and N, which heteroaryl is optionally substituted with one or more groups independently selected from R6;Each R6is independently selected from: halo,- CN,- -OH,Ci -e alkyl optionally substituted with one or more independently selected halo, and Ci -e alkoxy optionally substituted with one or more halo; or a pharmaceutically acceptable salt, solvate, or solvate of a pharmaceutically acceptable salt thereof.

2. A compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein R2is H.

3. A compound or a pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein the compound is according to any one of Formulae IVa, IVb, IVc, IVd, IVe or IVf:

4. A compound or a pharmaceutically acceptable salt thereof according to claim 3, wherein the compound is according to Formula IVe or IVf, wherein R3is selected from F, Cl, CN, -CH3, and -CF3.

5. A compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 -4, wherein Li is absent, -CH2-, -CH2CH2-, -O-, -NH-, -C(=O)NH-, -S(O)2-, -S(O)2NH-, -NHS(O)2NH-, -NHS(O)2- or -CH2CH2-O-.

6. A compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 -4, wherein R1is -CH3, -CH2CH3, -CH(CH3)2, -C(CH3)2CH2CH3, -CH(CH3)CH(CH3)2, each of which is optionally substituted with one or more groups independently selected from =0 and R7.

7. A compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 -4, wherein R1is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, each of which is optionally substituted with one or more groups independently selected from =0 and R7.

8. A compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 -4, wherein R1is oxetanyl, tetrahydrofuranyl, pyrrolidinyl, tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, phosphinanyl, or azaphosphinazyl, each of which is optionally substituted with one, two or three groups independently selected from =0 and R7.

9. A compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 -4, wherein R1is furanyl, thienyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, thioxazolyl, pyridinyl, pyrimidinyl, or pyrazinyl, each of which is optionally substituted with one, two or three independently selected R7.

10. A compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 -4, wherein -Li-R1is:wherein * is the attachment point.

11. A compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 -9, wherein Cy is selected fromeach of which is optionally substituted with one or more independently selected R4group, and wherein each R4is as defined for Formula I, and * represents the attachment point.

12. A compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 -9, wherein each R4is independently selected from F, Cl, CN, OH, -CHs, -CFs, -CHF2, -CH2CH3, -CHFCH3, - CH(OH)CH2CH3, -CH2CH(CH3)2, -C(CH3)3, -CH2CF3, -CH2OH, -CH(CH3)CH2OH, -C(CH3)2CH2OH, -C(CH3)2CH2NH2, -OCH3, -OCF3, -OCHF2, -OCH2CH3, -OCH2CF3, cyclopropyl, cyclobutyl, cyclopentyl, -C(=O)OH, -C(=O)OCH3, -C(=O)OCH2CH3, -C(=O)OC(CH3)3, -C(=O)NH2, -NH2, -, wherein * is the attachment point.

13. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a pharmaceutically effective amount of a compound, a pharmaceutically acceptable salt, a solvate, or a solvate of a pharmaceutically acceptable salt thereof according to any one of claims 1-12.

14. A compound, a pharmaceutically acceptable salt, a solvate, or a solvate of a pharmaceutically acceptable salt thereof, according to any one of claims 1-12, or a pharmaceutical composition according to claim 13 for use in medicine.

15. A compound, a pharmaceutically acceptable salt, a solvate, or a solvate of a pharmaceutically acceptable salt thereof, according to any one of claims 1-12, or a pharmaceutical composition accordingto claim 13 for use in the prophylaxis and / or treatment of inflammatory diseases, autoinflammatory diseases, autoimmune diseases, proliferative diseases, fibrotic diseases, transplant rejection, diseases involving impairment of cartilage turnover, congenital cartilage malformation, diseases involving impairment of bone turnover, diseases associated with hypersecretion of IL-6, diseases associated with hypersecretion of TNFa, interferons, IL-12, IL-17 and / or IL-23, respiratory diseases, endocrine diseases, metabolic diseases, cardiovascular diseases, dermatological diseases, and / or abnormal angiogenesis associated diseases.

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