Heterocyclic compounds as SIK inhibitors

Abstract

The present invention discloses compounds according to Formula (I): wherein W, Y1, Y2, Y3, Z, X1, X2, RA, R1, R2a and R3 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 THE TREATMENT 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)l 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 of HDAC4 / 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 (Yoon 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:IwhereinW is N or CH;one of Xi and X2 is N and the other one is C, with the proviso that when W is CH, X2 is not N;R1is H or -P(=O)(OH)2;RAis- H,Ci -4 alkyl optionally substituted with one or more independently selected halo,- -NRB1RB2; andEach RB1and RB2is independently selected from H, C1-4 alkyl optionally substituted with one or more independently selected halo, or phenyl,Yi is selected from N and CR2b;Each Y2 and Y3 is independently selected from N and CH provided that Y2, and Y3, are not simultaneously N,R3is5-6 membered heteroaryl comprising one or more independently selected N, O, or S heteroatoms optionally substituted with one or more independently selectedo halo,o -OH,o -NH2,o Ci -4 alkyl optionally substituted with one or more independently selected halo, or o C1-4 alkyl optionally substituted with one or more independently selected halo, or - -C(=O)Z, or- -CN;Z is- -NH2,- -NH-L-R3a,- -NH-R3a,- '-linkcd 4-7 membered heterocycloalkyl further comprising zero, one, or two additional heteroatoms independently selected from N, O, P or S, optionally substituted with one or more independently selected R7groups,- '-l inked 5-12 membered bicyclic fused, bridged or spiro heterocycloalkyl, further comprising zero, one, or two additional independently selected N, O, P or S heteroatoms, optionally comprising one or more double bonds, which heterocycloalkyl is optionally substituted with one or more groups independently selected from R7; or- -NR3b-, wherein the N atom and R2atogether with the atoms onto which they are attached form a fused 5-6 membered heterocycloalkenyl comprising one or two double bonds;R2aand R2bare independently selected from- halo,- C1-4 alkyl,- C1-4 alkoxy optionally substituted with one or more independently selected halo or C1-4 alkoxy, and- -NR6aR6b;L is- S(0)2, or- Ci-4 alkylenyl optionally substituted with one or more independently selected halo;R3ais- Ci-6 alkyl optionally substituted with one or more independently selected R8,- C3-7 cycloalkyl optionally substituted with one or more groups independently selected from =0 and R8, - 5-12 membered bicyclic fused, bridged or spiro cycloalkyl, optionally comprising one or more double bonds, which heterocycloalkyl is optionally substituted with one or more groups independently selected from =0 and R8;- 4-7 membered monocyclic heterocycloalkyl, comprising one or more independently selected N, O, P or S heteroatoms, optionally substituted with one or more groups independently selected from =0 and R8, or- 5-12 membered bicyclic fused, bridged or spiro heterocycloalkyl, comprising one or more independently selected N, O, P or S heteroatoms, optionally comprising one or more double bonds, which heterocycloalkyl is optionally substituted with one or more groups independently selected from =0 and R8;- 5-6 membered heteroaryl comprising one or more independently selected N, O, or S heteroatoms optionally substituted with one or more independently selected R8;R3bis selected from H, C3-7 cycloalkyl and C1-6 alkyl optionally substituted with one or more independently selected halo or -CN;each R6aand R6bis independently selected from H and C1-4 alkyl;each R7is independently selected from =0, -OH, -CN, and C1-4 alkyl optionally substituted with one or more independently selected halo or -CN;each R8is independently selected from- halo,- -CN,- -OH,- -NH2,- C1-6 alkyl optionally substituted with one or more independently selected halo, CN or OH, and - C1-6 alkoxy optionally substituted with one or more independently selected halo, CN or OH, provided that the compound is not:- 2-(difhioromethoxy)-N-[(lR,2S)-2-fhiorocyclopropyl]-4-[6-[(2S)-3-hydroxy-3-methylbutan-2- yl] oxypyrazolo [ 1 ,5 -a]pyrimidin-3 -yl] -6-methoxybenzamide- 2-(difhioromethoxy)-N-[(lR,2S)-2-fhiorocyclopropyl]-4-[7-[(2S)-3-hydroxy-3-methylbutan-2- yl] oxyimidazo [1,2 -b]pyridazin-3 -yl] -6-methoxybenzamide- 2-(difhioromethoxy)-N-[(lR,2S)-2-fhiorocyclopropyl]-4-[7-(3-hydroxy-3-methylbutan-2- yl)oxyimidazo[l,2-b]pyridazin-3-yl]-6-methoxybenzamide- 2-(difluoromethoxy)-N-[(lR,2S)-2-fluorocyclopropyl]-4-[6-(3-hydroxy-3-methylbutan-2- yl)oxypyrazolo [ 1 ,5 -a]pyrimidin-3 -y 1] -6-methoxybenzamide- [(3S)-3-[3-[3-(difluoromethoxy)-4-[[(lR,2S)-2-fluorocyclopropyl]carbamoyl]-5- methoxyphenyl]imidazo[ l,2-b]pyridazin-7-yl]oxy-2-methylbutan-2-yl] dihydrogen phosphate - [(3S)-3-[3-[3-(difluoromethoxy)-4-[[(lR,2S)-2-fluorocyclopropyl]carbamoyl]-5- methoxyphenyl]pyrazolo[l,5-a]pyrimidin-6-yl]oxy-2-methylbutan-2-yl] dihydrogen phosphate - 2-(difluoromethoxy)-N-[(lR,2S)-2-fluorocyclopropyl]-4-[7-[(2S)-3-hydroxy-3-methylbutan-2- yl] oxy-6-methylimidazo [ 1 ,2-b]pyridazin-3 -yl] -6-methoxybenzamide- 2-(difluoromethoxy)-N-[(lR,2S)-2-fluorocyclopropyl]-4-[6-[(2R)-3-hydroxy-3-methylbutan-2- yl] oxypyrazolo [ 1 ,5 -a]pyrimidin-3 -yl] -6-methoxybenzamide- [(3S)-3-[3-[3-(difluoromethoxy)-4-[[(lR,2S)-2-fluorocyclopropyl]carbamoyl]-5-methoxyphenyl]-6- methylimidazo [ 1 ,2-b]pyridazin-7 -yl] oxy-2 -methylbutan-2-yl] dihydrogen phosphate- 2-(difluoromethoxy)-N-[(lR,2S)-2-fluorocyclopropyl]-4-[6-[(2S*)-3-hydroxy-3-methylbutan-2- yl] oxy-5 -methylpyrazolo [1,5 -a]pyrimidin-3 -yl] -6-methoxybenzamide- 2-(difluoromethoxy)-N-[(lR,2S)-2-fluorocyclopropyl]-4-[6-[(2R*)-3-hydroxy-3-methylbutan-2- yl] oxy-5 -methylpyrazolo [1,5 -a]pyrimidin-3 -yl] -6-methoxybenzamide- 2-(difluoromethoxy)-4-(5-(dimethylamino)-6-(((R*)-3-hydroxy-3-methylbutan-2- yl)oxy)pyrazolo[l,5-a]pyrimidin-3-yl)-N-((lR,2S)-2-fluorocyclopropyl)-6-methoxybenzamide - 2-(difluoromethoxy)-4-(5-(dimethylamino)-6-(((S*)-3-hydroxy-3-methylbutan-2- yl)oxy)pyrazolo[l,5-a]pyrimidin-3-yl)-N-((lR,2S)-2-fluorocyclopropyl)-6-methoxybenzamide - 2-(difluoromethoxy)-4-(5-ethyl-6-(((R*)-3-hydroxy-3-methylbutan-2-yl)oxy)pyrazolo[l,5- a]pyrimidin-3-yl)-N-((lR,2S)-2-fluorocyclopropyl)-6-methoxybenzamide- 2-(difluoromethoxy)-4-(5-ethyl-6-(((S*)-3-hydroxy-3-methylbutan-2-yl)oxy)pyrazolo[l,5- a]pyrimidin-3-yl)-N-((lR,2S)-2-fluorocyclopropyl)-6-methoxybenzamide- 2-(difluoromethoxy)-4-(5-(difluoromethyl)-6-(((R*)-3-hydroxy-3-methylbutan-2- yl)oxy)pyrazolo[l,5-a]pyrimidin-3-yl)-N-((lR,2S)-2-fluorocyclopropyl)-6-methoxybenzamide - 2-(difluoromethoxy)-4-(5-(difluoromethyl)-6-(((S*)-3-hydroxy-3-methylbutan-2- yl)oxy)pyrazolo[l,5-a]pyrimidin-3-yl)-N-((lR,2S)-2-fluorocyclopropyl)-6-methoxybenzamide - 4-(5 -(benzylamino)-6-((3 -hydroxy-3 -methylbutan-2-yl)oxy)pyrazolo [ 1 ,5 -a]pyrimidin-3 -yl)-2- (difluoromethoxy)-N-((lR,2S)-2-fluorocyclopropyl)-6-methoxybenzamide- 4-(5-amino-6-((3-hydroxy-3-methylbutan-2-yl)oxy)pyrazolo[l,5-a]pyrimidin-3-yl)-2- (difluoromethoxy)-N-((lR,2S)-2-fluorocyclopropyl)-6-methoxybenzamide- 4-(5-(benzyl(methyl)amino)-6-((3-hydroxy-3-methylbutan-2-yl)oxy)pyrazolo[l,5-a]pyrimidin-3-yl)- 2-(difluoromethoxy)-N-((lR,2S)-2-fluorocyclopropyl)-6-methoxybenzamide- 2-(difluoromethoxy)-N-((lR,2S)-2-fluorocyclopropyl)-4-(6-(((R*)-3-hydroxy-3-methylbutan-2- yl)oxy)-5-(methylamino)pyrazolo[l,5-a]pyrimidin-3-yl)-6-methoxybenzamide, or- 2-(difluoromethoxy)-N-((lR,2S)-2-fluorocyclopropyl)-4-(6-(((S*)-3-hydroxy-3-methylbutan-2- yl)oxy)-5 -(methylamino)pyrazolo [ 1 ,5 -a]pyrimidin-3 -yl)-6-methoxybenzamide .

[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] Additionally, the compounds of the invention may exhibit a low human pregnane X receptor (PXR, NR1I2) activation liability and therefore a more stable metabolic profde and reduced risk of harmful drugdrug interaction.

[0022] Certain compounds according to the invention may also exhibit one or more benefits including, inter alia, advantageous levels of biological activity which may be useful in the prophylaxis and / or treatment of one or more disease, improved safety characteristics (e.g. relating to hERG inhibition, drugdrug interaction (DDI) or CYP-interaction characteristics, etc.), improved selectivity for one or more disease-associated biological target (e.g. reduced off-target effects, etc.), improved pharmacokinetic properties (e.g. relating to dosing, solubility, absorption, etc.), improved pharmacodynamic properties (e.g. relating to permeability, efflux, etc.) or superior properties for use as pharmaceutical active ingredients alone or in pharmaceutical compositions (e.g. stability), or advantageous physico-chemical properties useful in the manufacturability of such aforementioned pharmaceutical compositions.

[0023] 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, the pharmaceutical 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.

[0024] Moreover, the compounds of the invention, useful in the pharmaceutical compositions and treatment methods disclosed herein, are pharmaceutically acceptable as prepared and used.

[0025] 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.

[0026] 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.

[0027] In additional aspects, this invention provides methods for synthesizing the compounds of the invention, with representative synthetic protocols and pathways disclosed later on herein.

[0028] Other objects and advantages will become apparent to those skilled in the art from a consideration of the ensuing detailed description.

[0029] It will be appreciated that compounds of the invention may be metabolized to yield biologically active metabolites.DETAILED DESCRIPTION OF THE INVENTIONDefinitions

[0030] 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.

[0031] 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 befurther understood that the terms “groups” and “radicals” can be considered interchangeable when used herein.

[0032] 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.

[0033] ‘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 (-C(CH3)3), sec-butyl (-CH(CH3)-CH2CH3), isobutyl (-CH2-CH(CH3)2), w-pcntyl (-CH2-CH2-CH2-CH2-CH3), w-hcxyl (-CH2-CH2-CH2-CH2-CH2-CH3), and 1,2-dimethylbutyl (-CH(CH3)-CH(CH3)-CH2-CH3). Particular alkyl groups have between 1 and 4 carbon atoms.

[0034] ‘ Substituted’ refers to a group in which one or more hydrogen atoms are each independently replaced with the same or different substituent(s).

[0035] 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.

[0036] ‘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.

[0037] ‘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.

[0038] ‘Pharmaceutically acceptable vehicle’ refers to a diluent, adjuvant, excipient or carrier with which a compound of the invention is administered.

[0039] ‘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.

[0040] ‘ 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 in the crystal lattice of the crystalline solid. ‘Solvate’ encompasses both solution-phase and isolable solvates. Representative solvates include hydrates, ethanolates and methanolates.

[0041] ‘Subject’ includes humans. The terms ‘human’, ‘patient’ and ‘subject’ are used interchangeably herein.

[0042] ‘ 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.

[0043] ‘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.

[0044] 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.

[0045] ‘Treating’ or ‘treatment’ of any disease or disorder refers, in one embodiment, to ameliorating the disease or disorder (i.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.

[0046] As used herein the term ‘inflammatory disease(s)’ refers to the group of conditions including, rheumatoid arthritis, osteoarthritis, juvenile idiopathic arthritis, psoriasis, psoriatic arthritis, ankylosingspondylitis, 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.

[0047] 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.

[0048] 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.

[0049] 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.

[0050] 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 cancertends 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, theterm ‘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 cell histiocytosis, 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.

[0051] 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).

[0052] 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.

[0053] 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).

[0054] 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.

[0055] 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.

[0056] 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).

[0057] 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 .

[0058] 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.

[0059] 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, related muscles (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.

[0060] 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).

[0061] 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.

[0062] 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, orinsufficiency limited to a single organ or tissue. More particularly, cardiovascular disease refers to atherosclerosis or giant cell arteritis.

[0063] 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.

[0064] 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.

[0065] ‘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.

[0066] 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.

[0067] 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 know 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-ioaryl)-(Ci-4 alkyl) esters of the compounds of the invention.

[0068] 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.

[0069] 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.

[0070] 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.

[0071] 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’.

[0072] 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’.

[0073] ‘ 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.

[0074] Tautomeric forms may be relevant to the attainment of the optimal chemical reactivity and biological activity of a compound of interest.

[0075] 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.

[0076] 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

[0077] 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.

[0078] 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.

[0079] Accordingly, in a first aspect of the invention, the compounds of the invention are provided having a Formula I:RAWwhereinW is N or CH;one of Xi and X2 is N and the other one is C, with the proviso that when W is CH, X2 is not N;R1is H or -P(=O)(OH)2;RAis- H,Ci -4 alkyl optionally substituted with one or more independently selected halo,- -NRB1RB2; andEach RB1and RB2is independently selected from H, C1-4 alkyl optionally substituted with one or more independently selected halo, or phenyl,Yi is selected from N and CR2b;Each Y2and Y3 is independently selected from N and CH provided that Y2, and Y3, are not simultaneously N,R3is5-6 membered heteroaryl comprising one or more independently selected N, O, or S heteroatoms optionally substituted with one or more independently selectedo halo,o -OH,o -NH2,o Ci -4 alkyl optionally substituted with one or more independently selected halo, or o Ci -4 alkyl optionally substituted with one or more independently selected halo, or - -C(=O)Z, or- -CN;Z is- -NH2,- -NH-L-R3a,- -NH-R3a,- '-linkcd 4-7 membered heterocycloalkyl further comprising zero, one, or two additional heteroatoms independently selected from N, O, P or S, optionally substituted with one or more independently selected R7groups,- '-l inked 5-12 membered bicyclic fused, bridged or spiro heterocycloalkyl, further comprising zero, one, or two additional independently selected N, O, P or S heteroatoms, optionally comprising one or more double bonds, which heterocycloalkyl is optionally substituted with one or more groups independently selected from R7; or- -NR3b-, wherein the N atom and R2atogether with the atoms onto which they are attached form a fused 5-6 membered heterocycloalkenyl comprising one or two double bonds;R2aand R2bare independently selected from- halo,- C1-4 alkyl,- C1-4 alkoxy optionally substituted with one or more independently selected halo or C1-4 alkoxy, and - -NR6aR6b;L is- S(0)2, or- Ci-4 alkylenyl optionally substituted with one or more independently selected halo;R3ais- Ci-6 alkyl optionally substituted with one or more independently selected R8,- C3-7 cycloalkyl optionally substituted with one or more groups independently selected from =0 and R8, - 5-12 membered bicyclic fused, bridged or spiro cycloalkyl, optionally comprising one or more double bonds, which heterocycloalkyl is optionally substituted with one or more groups independently selected from =0 and R8;- 4-7 membered monocyclic heterocycloalkyl, comprising one or more independently selected N, O, P or S heteroatoms, optionally substituted with one or more groups independently selected from =0 and R8, or- 5-12 membered bicyclic fused, bridged or spiro heterocycloalkyl, comprising one or more independently selected N, O, P or S heteroatoms, optionally comprising one or more double bonds, which heterocycloalkyl is optionally substituted with one or more groups independently selected from =0 and R8;- 5-6 membered heteroaryl comprising one or more independently selected N, O, or S heteroatoms optionally substituted with one or more independently selected R8;R3bis selected from H, C3-7 cycloalkyl and C1-6 alkyl optionally substituted with one or more independently selected halo or -CN;each R6aand R6bis independently selected from H and C1-4 alkyl;each R7is independently selected from =0, -OH, -CN, and C1-4 alkyl optionally substituted with one or more independently selected halo or -CN;each R8is independently selected from- halo,- -CN,- -OH,- -NH2,- C1-6 alkyl optionally substituted with one or more independently selected halo, CN or OH, and - C1-6 alkoxy optionally substituted with one or more independently selected halo, CN or OH, provided that the compound is not:- 2-(difhioromethoxy)-N-[(lR,2S)-2-fhiorocyclopropyl]-4-[6-[(2S)-3-hydroxy-3-methylbutan-2- yl] oxypyrazolo [ 1 ,5 -a]pyrimidin-3 -yl] -6-methoxybenzamide- 2-(difhioromethoxy)-N-[(lR,2S)-2-fhiorocyclopropyl]-4-[7-[(2S)-3-hydroxy-3-methylbutan-2- yl] oxyimidazo [1,2 -b]pyridazin-3 -yl] -6-methoxybenzamide- 2-(difhioromethoxy)-N-[(lR,2S)-2-fhiorocyclopropyl]-4-[7-(3-hydroxy-3-methylbutan-2- yl)oxyimidazo[l,2-b]pyridazin-3-yl]-6-methoxybenzamide- 2-(difluoromethoxy)-N-[(lR,2S)-2-fluorocyclopropyl]-4-[6-(3-hydroxy-3-methylbutan-2- yl)oxypyrazolo [ 1 ,5 -a]pyrimidin-3 -y 1] -6-methoxybenzamide- [(3S)-3-[3-[3-(difluoromethoxy)-4-[[(lR,2S)-2-fluorocyclopropyl]carbamoyl]-5- methoxyphenyl]imidazo[ l,2-b]pyridazin-7-yl]oxy-2-methylbutan-2-yl] dihydrogen phosphate - [(3S)-3-[3-[3-(difluoromethoxy)-4-[[(lR,2S)-2-fluorocyclopropyl]carbamoyl]-5- methoxyphenyl]pyrazolo[l,5-a]pyrimidin-6-yl]oxy-2-methylbutan-2-yl] dihydrogen phosphate - 2-(difluoromethoxy)-N-[(lR,2S)-2-fluorocyclopropyl]-4-[7-[(2S)-3-hydroxy-3-methylbutan-2- yl] oxy-6-methylimidazo [ 1 ,2-b]pyridazin-3 -yl] -6-methoxybenzamide- 2-(difluoromethoxy)-N-[(lR,2S)-2-fluorocyclopropyl]-4-[6-[(2R)-3-hydroxy-3-methylbutan-2- yl] oxypyrazolo [ 1 ,5 -a]pyrimidin-3 -yl] -6-methoxybenzamide- [(3S)-3-[3-[3-(difluoromethoxy)-4-[[(lR,2S)-2-fluorocyclopropyl]carbamoyl]-5-methoxyphenyl]-6- methylimidazo [ 1 ,2-b]pyridazin-7 -yl] oxy-2 -methylbutan-2-yl] dihydrogen phosphate- 2-(difluoromethoxy)-N-[(lR,2S)-2-fluorocyclopropyl]-4-[6-[(2S*)-3-hydroxy-3-methylbutan-2- yl] oxy-5 -methylpyrazolo [1,5 -a]pyrimidin-3 -yl] -6-methoxybenzamide- 2-(difluoromethoxy)-N-[(lR,2S)-2-fluorocyclopropyl]-4-[6-[(2R*)-3-hydroxy-3-methylbutan-2- yl] oxy-5 -methylpyrazolo [1,5 -a]pyrimidin-3 -yl] -6-methoxybenzamide- 2-(difluoromethoxy)-4-(5-(dimethylamino)-6-(((R*)-3-hydroxy-3-methylbutan-2- yl)oxy)pyrazolo[l,5-a]pyrimidin-3-yl)-N-((lR,2S)-2-fluorocyclopropyl)-6-methoxybenzamide - 2-(difluoromethoxy)-4-(5-(dimethylamino)-6-(((S*)-3-hydroxy-3-methylbutan-2- yl)oxy)pyrazolo[l,5-a]pyrimidin-3-yl)-N-((lR,2S)-2-fluorocyclopropyl)-6-methoxybenzamide - 2-(difluoromethoxy)-4-(5-ethyl-6-(((R*)-3-hydroxy-3-methylbutan-2-yl)oxy)pyrazolo[l,5- a]pyrimidin-3-yl)-N-((lR,2S)-2-fluorocyclopropyl)-6-methoxybenzamide- 2-(difluoromethoxy)-4-(5-ethyl-6-(((S*)-3-hydroxy-3-methylbutan-2-yl)oxy)pyrazolo[l,5- a]pyrimidin-3-yl)-N-((lR,2S)-2-fluorocyclopropyl)-6-methoxybenzamide- 2-(difluoromethoxy)-4-(5-(difluoromethyl)-6-(((R*)-3-hydroxy-3-methylbutan-2- yl)oxy)pyrazolo[l,5-a]pyrimidin-3-yl)-N-((lR,2S)-2-fluorocyclopropyl)-6-methoxybenzamide - 2-(difluoromethoxy)-4-(5-(difluoromethyl)-6-(((S*)-3-hydroxy-3-methylbutan-2- yl)oxy)pyrazolo[l,5-a]pyrimidin-3-yl)-N-((lR,2S)-2-fluorocyclopropyl)-6-methoxybenzamide - 4-(5 -(benzylamino)-6-((3 -hydroxy-3 -methylbutan-2-yl)oxy)pyrazolo [ 1 ,5 -a]pyrimidin-3 -yl)-2- (difluoromethoxy)-N-((lR,2S)-2-fluorocyclopropyl)-6-methoxybenzamide- 4-(5-amino-6-((3-hydroxy-3-methylbutan-2-yl)oxy)pyrazolo[l,5-a]pyrimidin-3-yl)-2- (difluoromethoxy)-N-((lR,2S)-2-fluorocyclopropyl)-6-methoxybenzamide- 4-(5-(benzyl(methyl)amino)-6-((3-hydroxy-3-methylbutan-2-yl)oxy)pyrazolo[l,5-a]pyrimidin-3-yl)- 2-(difluoromethoxy)-N-((lR,2S)-2-fluorocyclopropyl)-6-methoxybenzamide- 2-(difluoromethoxy)-N-((lR,2S)-2-fluorocyclopropyl)-4-(6-(((R*)-3-hydroxy-3-methylbutan-2- yl)oxy)-5-(methylamino)pyrazolo[l,5-a]pyrimidin-3-yl)-6-methoxybenzamide, or- 2-(difluoromethoxy)-N-((lR,2S)-2-fhiorocyclopropyl)-4-(6-(((S*)-3-hydroxy-3-methylbutan-2- yl)oxy)-5 -(methylamino)pyrazolo [ 1 ,5 -a]pyrimidin-3 -yl)-6-methoxybenzamide .

[0080] In one embodiment, the compound of the invention is according to Formula I, wherein RAis H.

[0081] In one embodiment, the compound of the invention is according to Formula I, wherein RAis Ci-4 alkyl. In a particular embodiment, RAis -CHs, -CH2CH3, or -CH(CHs)2. In a more particular embodiment, RAis -CH3 or -CH2CH3. In a further more particular embodiment RAis -CH3.

[0082] In one embodiment, the compound of the invention is according to Formula I, wherein RAis C1-4 alkyl substituted with one or more independently selected halo. In a particular embodiment, RAis -CH3, -CH2CH3, or -CH( 013)2, each of which is substituted with one or more independently selected halo. In a particular embodiment, RAis -CH3, -CH2CH3, or -CH( 013)2, each of which is substituted with one or more independently selected F. In a more particular embodiment, RAis -CH3 or -CH2CH3, each of which is substituted with one or more independently selected F. In a further more particular embodiment RAis -CHF2, or -CF3.

[0083] In one embodiment, the compound of the invention is according to Formula I, wherein RAis -NRB1RB2, wherein RB1and RB2are as previously defined. In a particular embodiment, RAis -NRB1RB2, and each RB1and RB2is independently selected from H, -CH3, -CH2CH3, and -CFFPhcnyl. In more particular embodiment, RAis -NH2, -NHCH3, -NH2, -N(CH3)2, -NH(CH2Phenyl), or -NCH3(CH2Phenyl).

[0084] In one embodiment, the compound of the invention is according to Formula I, wherein R3is -CN.

[0085] In one embodiment, the compound of the invention is according to Formula I, wherein R3is heteroaryl. In a particular embodiment, R3is selected frompoint of attachment.

[0086] In one embodiment, the compound of the invention is according to Formula II, whereinwherein R1, R2a, Z, W, Xi, X2, Yi, Y2, and Y3, are as described above.

[0087] In one embodiment, the compound of the invention is according to Formula II, wherein Z is -NR3b-, wherein the N atom and R2atogether with the atoms onto which they are attached form a fused 5-6 membered heterocycloalkenyl comprising one or two double bonds, and R3bis as previously described. In a particular embodiment, Z is -NR3b-, wherein the N atom and R2atogether with the atoms onto which they are attached form a fused 3-pyrroline, 1,2-dihydropyridine, or 1,2,3,6-tetrahydropyridine. In a more particular embodiment, Z is -NR3b-, wherein the N atom and R2atogether with the atoms onto which they are attached form a fused 1,2,3,6-tetrahydropyridine.

[0088] In one embodiment, the compound of the invention is according to Formula Illa, Illb, or IIIc:Illa Illb IIIc wherein R1, R3b, W, Xi, X2, Yi, Y2, and Y3, are as described above.

[0089] In one embodiment, the compound of the invention is according to any one of Formulae Illa-IIIc, wherein R3bis H.

[0090] In one embodiment, the compound of the invention is according to any one of Formulae Illa-IIIc, wherein R3bis C3-7 cycloalkyl. In a particular embodiment, R3bis cyclopropyl, cyclobutyl, or cyclopentyl. In a more particular embodiment, R3bis cyclopropyl.

[0091] In one embodiment, the compound of the invention is according to any one of Formulae Illa-IIIc, wherein R3bis C1-6 alkyl. In a particular embodiment, R3bis -CH3, -CH2CH3, -CH2CH2CH3, -CH( 013)2, or -C(Ql3)3. In a more particular embodiment, R3bis -CH2CH3.

[0092] In one embodiment, the compound of the invention is according to any one of Formulae Illa-IIIc, wherein R3bis C1-6 alkyl substituted with one or more independently selected halo or -CN. In a particular embodiment, R3bis -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, or -C(CH3)3, each of which is substituted with one or more independently selected halo or -CN. In another particular embodiment, R3bis C1-6 alkyl substituted with one, two, or three independently selected halo or -CN. In yet another particular embodiment, R3bis C1-6 alkyl substituted with one or more independently selected F, Cl, or -CN. In a more particular embodiment, R3bis -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, or -C(CH3)3, each of which is substituted with one, two, or three independently selected halo or -CN. In another more particular embodiment, R3bis C1-6 alkyl substituted with one, two, or three independently selected F, Cl, or -CN. In yet another more particular embodiment, R3bis -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, or -C(CH3)3, each of which is substituted with one or more independently selected F, Cl, or -CN. In a further more particular embodiment, R3bis -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, or -C(CH3)3, each of which is substituted with one, two, or three independently selected F, Cl, or -CN. In another further more particular embodiment, R3bis -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, or -C(CH3)3, each of which is substitutedwith one or more F or -CN. In yet another further more particular embodiment, R3bis Ci-6 alkyl substituted with one, two, or three independently selected F or -CN. In a most particular embodiment, R3bis -CH2CH3 substituted with one, two, or three F. In another most particular embodiment, R3bis -CH2-CN. In a further most particular embodiment, R3bis -CH2CF3.

[0093] In one embodiment, the compound of the invention is according to any one of Formulae I-IIIc, wherein Y2 is N, and Y3 is CH.

[0094] In one embodiment, the compound of the invention is according to any one of Formulae I-IIIc, wherein Y2 is CH, and Y3 is N.

[0095] In one embodiment, the compound of the invention is according to any one of Formulae I-IIIc, wherein Y2 and Y3 are CH.

[0096] In one embodiment, the compound of the invention is according to any one of Formulae I-IIIc, wherein Yi is N.

[0097] In one embodiment, the compound of the invention is according to any one of Formulae I-IIIc, wherein Yi is CR2b, and R2bis halo. In a particular embodiment, R2bis F, Cl, or Br. In a more particular embodiment, R2bis F.

[0098] In one embodiment, the compound of the invention is according to any one of Formulae I-IIIc, wherein Y 1 is CR2b, and R2bis C1-4 alkyl. In a particular embodiment, R2bis -CH3, -CH2CH3, or -CH(CH3)2. In a more particular embodiment, R2bis -CH3.

[0099] In one embodiment, the compound of the invention is according to any one of Formulae I-IIIc, wherein Y 1 is CR2b, and R2bis C1-4 alkoxy. In a particular embodiment, R2bis -O-CH3, -O-CH2CH3, or -O-CH(CH3)2. In a more particular embodiment, R2bis -O-CH3 or -O-CH2CH3. In a most particular embodiment, R2bis -O-CH3.

[0100] In one embodiment, the compound of the invention is according to any one of Formulae I-III, wherein Y 1 is CR2b, and R2bis C1-4 alkoxy substituted with one or more independently selected halo or C1.4 alkoxy. In a particular embodiment, R2bis -O-CH3, -O-CH2CH3, or -O-CH(CH3)2, each of which is substituted with one or more independently selected halo or C1-4 alkoxy. In another particular embodiment, R2bis C1-4 alkoxy substituted with one, two, or three independently selected halo or C1.4 alkoxy. In yet another particular embodiment, R2bis C1.4 alkoxy substituted with one or more independently selected F, Cl, Br, -O-CH3, -O-CH2CH3, or -O-CH(CH3)2. In a more particular embodiment, R2bis -O-CH3, -O-CH2CH3, or -O-CH(CH3)2, each of which is substituted with one, two, or three independently selected halo or C1-4 alkoxy. In another more particular embodiment, R2bis C1-4 alkoxy substituted with one, two, or three independently selected F, Cl, Br, -O-CH3, -O-CH2CH3, or -O-CH(CH3)2. In a further more particular embodiment, R2bis -O-CH3, substituted with one, two, or three independently selected halo. In another further more particular embodiment, R2bis -O-CH2CH3, substituted with one, two, or three independently selected halo or C1-4 alkoxy. In a most particular embodiment, R2bis -O-CHF2 or -O-CH2CH2-O-CH2CH3.

[0101] In one embodiment, the compound of the invention is according to any one of Formulae I-IIIc, wherein Yi is CR2b, and R2bis -NR6aR6b, and R6aand R6bare independently selected from H and C1.4 alkyl.In a particular embodiment, R6aand R6bare both H. In another particular embodiment, one of R6aand R6bis H, and the other is C1-4 alkyl. In yet another particular embodiment, R6aand R6bare both C1-4 alkyl. In a more particular embodiment, one of R6aand R6bis H, and the other is -CH3, -CH2CH3, or -CH(CH3)2. In another more particular embodiment, R6aand R6bare -CH3, -CH2CH3, or -CH( 0^3)2. In a most particular embodiment, one of R6aand R6bis H, and the other is -CH3.

[0102] In one embodiment, the compound of the invention is according to Formula IVa or IVb, whereinIVa IVbwherein R1, R2a, R2b, W, Xi, X2, and Z, are as described above.

[0103] In one embodiment, the compound of the invention is according to Formula I, II, IVa, or IVb, wherein R2ais halo. In a particular embodiment, R2ais F, Cl, or Br. In a more particular embodiment, R2ais F.

[0104] In one embodiment, the compound of the invention is according to Formula I, II, IVa, or IVb, wherein R2ais C1.4 alkyl. In a particular embodiment, R2ais -CH3, -CH2CH3, or -CH(CH3)2. In a more particular embodiment, R2ais -CH3.

[0105] In one embodiment, the compound of the invention is according to Formula I, II, IVa, or IVb, wherein R2ais C1.4 alkoxy. In a particular embodiment, R2ais -O-CH3, -O-CH2CH3, or -O-CH( 0^3)2. In a more particular embodiment, R2ais -O-CH3 or -O-CH2CH3. In a most particular embodiment, R2ais -O-CH3.

[0106] In one embodiment, the compound of the invention is according to Formula I, II, IVa, or IVb, wherein R2ais C1-4 alkoxy substituted with one or more independently selected halo or C1-4 alkoxy. In a particular embodiment, R2ais -O-CH3, -O-CH2CH3, or -O-CH( 0^3)2, each of which is substituted with one or more independently selected halo or C1-4 alkoxy. In another particular embodiment, R2ais C1.4 alkoxy substituted with one, two, or three independently selected halo or C1-4 alkoxy. In yet another particular embodiment, R2ais C1.4 alkoxy substituted with one or more independently selected F, Cl, Br, -O-CH3, -O-CH2CH3, or -O-CH(CH3)2. In a more particular embodiment, R2ais -O-CH3, -O-CH2CH3, or -O-CH( 013)2, each of which is substituted with one, two, or three independently selected halo or C1.4 alkoxy. In another more particular embodiment, R2ais C1.4 alkoxy substituted with one, two, or three independently selected F, Cl, Br, -O-CH3, -O-CH2CH3, or -O-CH(CH3)2. In a further more particular embodiment, R2ais -O-CH3, substituted with one, two, or three independently selected halo. In another further more particular embodiment, R2ais -O-CH2CH3, substituted with one, two, or three independently selected halo or C1-4 alkoxy. In a most particular embodiment, R2ais -O-CHF2 or -O-CH2CH2-O-CH2CH3.

[0107] In one embodiment, the compound of the invention is according to Formula I, II, IVa, or IVb, wherein R2ais -NR6aR6b, and R6aand R6bare independently selected from H and C1-4 alkyl. In a particular embodiment, R6aand R6bare both H. In another particular embodiment, one of R6aand R6bis H, and the other is C1.4 alkyl. In yet another particular embodiment, R6aand R6bare both C1-4 alkyl. In a more particular embodiment, one of R6aand R6bis H, and the other is -CH3, -CH2CH3, or -CH(CH3)2. In another more particular embodiment, R6aand R6bare independently -CH3, -CH2CH3, or -CH(CH3)2. In a most particular embodiment, one of R6aand R6bis H, and the other is -CH3.

[0108] In one embodiment, the compound of the invention is according to any one of Formulae IVa, wherein R2bis H.

[0109] In one embodiment, the compound of the invention is according to any one of Formulae IVa, wherein R2bis halo. In a particular embodiment, R2bis F, Cl, or Br. In a more particular embodiment, R2bis F.

[0110] In one embodiment, the compound of the invention is according to any one of Formulae IVa, wherein R2bis C1.4 alkyl. In a particular embodiment, R2bis -CH3, -CH2CH3, or -CH( 013)2. In a more particular embodiment, R2bis -CH3.[OlH] In one embodiment, the compound of the invention is according to any one of Formulae IVa, wherein R2bis C1-4 alkoxy. In a particular embodiment, R2bis -O-CH3, -O-CH2CH3, or -O-CH(CH3)2. In a more particular embodiment, R2bis -O-CH3 or -O-CH2CH3. In a most particular embodiment, R2bis -O-CH3.

[0112] In one embodiment, the compound of the invention is according to any one of Formulae IVa, wherein R2bis C1-4 alkoxy substituted with one or more independently selected halo or C1-4 alkoxy. In a particular embodiment, R2bis -O-CH3, -O-CH2CH3, or -O-CH( 013)2, each of which is substituted with one or more independently selected halo or C1-4 alkoxy. In another particular embodiment, R2bis C1-4 alkoxy substituted with one, two, or three independently selected halo or C1-4 alkoxy. In yet another particular embodiment, R2bis C1-4 alkoxy substituted with one or more independently selected F, Cl, Br, -O-CH3, -O-CH2CH3, or -O-CH(CH3)2. In a more particular embodiment, R2bis -O-CH3, -O-CH2CH3, or -O-CH( 013)2, each of which is substituted with one, two, or three independently selected halo or C1.4 alkoxy. In another more particular embodiment, R2bis C1-4 alkoxy substituted with one, two, or three independently selected F, Cl, Br, -O-CH3, -O-CH2CH3, or -O-CH(CH3)2. In a further more particular embodiment, R2bis -O-CH3, substituted with one, two, or three independently selected halo. In another further more particular embodiment, R2bis -O-CH2CH3, substituted with one, two, or three independently selected halo or C1-4 alkoxy. In a most particular embodiment, R2bis -O-CHF2 or -O-CH2CH2-O-CH2CH3.

[0113] In one embodiment, the compound of the invention is according to any one of Formulae IVa, wherein R2bis -NR6aR6b, and R6aand R6bare independently selected from H and C1-4 alkyl. In a particular embodiment, R6aand R6bare both H. In another particular embodiment, one of R6aand R6bis H, and the other is C1-4 alkyl. In yet another particular embodiment, R6aand R6bare both C1.4 alkyl. In a more particular embodiment, one of R6aand R6bis H, and the other is -CH3, -CH2CH3, or -CH(CH3)2. In another moreparticular embodiment, R6aand R6bare -CH3, -CH2CH3, or -CH(CH3)2. In a most particular embodiment, one of R6aand R6bis H, and the other is -CH3.

[0114] In one embodiment, the compound of the invention is according to any one of Formulae I-IVb, wherein W is N, Xi is N and X2 is C.

[0115] In one embodiment, the compound of the invention is according to any one of Formulae I-IVb, wherein W is N, Xi is C and X2 is N.

[0116] In one embodiment, the compound of the invention is according to any one of Formulae I-IVb, wherein W is CH, Xi is N and X2 is C.

[0117] In one embodiment, the compound of the invention is according to Formula Va, Vb, Vc, Vd, Ve or Vf:Ve Vfwherein R1and Z are as defined for formula I.

[0118] In one embodiment, the compound of the invention is according to any one of Formulae I, II, IVa-Vf, wherein Z is '-linkcd 4-7 membered heterocycloalkyl further comprising zero, one, or two additional heteroatoms independently selected from N, O, P or S. In a particular embodiment, Z is azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, or piperazinyl. In a more particular embodiment, Z is azetidinyl.

[0119] In one embodiment, the compound of the invention is according to any one of Formulae I, II, IVa-Vf, wherein Z is '-linkcd 4-7 membered heterocycloalkyl further comprising zero, one, or two additional heteroatoms independently selected from N, O, P or S, substituted with one or more independently selected R7groups. In a particular embodiment, Z is azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, or piperazinyl, each of which is substituted with one or more independently selected R7groups. In another particular embodiment, Z is V-1 inked 4-7 membered heterocycloalkyl further comprising zero, one, or two additional heteroatoms independently selected from N, O, P or S, substituted with one, two, or three independently selected R7groups. In a more particular embodiment, Z is azetidinyl substituted with one or more independently selected R7groups. In another more particular embodiment, Z is azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, or piperazinyl, each of which is substituted with one, two, or three independently selected R7groups. In yet another more particular embodiment, Z is N-linked 4-7 membered heterocycloalkyl further comprising zero, one, or two additional heteroatoms independently selected from N, O, P or S, substituted with one or two independently selected R7group. In a further more particular embodiment, Z is azetidinyl substituted with one, two, or three independently selected R7groups. In another further more particular embodiment, Z is azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, or piperazinyl, each of which is substituted with one or two independently selected R7groups. In a most particular embodiment, Z is azetidinyl substituted with one or two independently selected R7groups.

[0120] In one embodiment, the compound of the invention is according to any one of Formulae I, II, IVa-Vf, wherein Z is V-linked 4-7 membered heterocycloalkyl further comprising zero, one, or two additional heteroatoms independently selected from N, O, P or S, substituted with one or more independently selected R7groups, and R7is -OH, -CN, or Ci-4 alkyl. In a particular embodiment, R7is =0, -OH, -CN, -CHs, -CH2CH3, or -CH(CHS)2. In a more particular embodiment, R7is -OH or -CN.

[0121] In one embodiment, the compound of the invention is according to any one of Formulae I, II, IVa-Vf, wherein Z is N-linked 4-7 membered heterocycloalkyl further comprising zero, one, or two additional heteroatoms independently selected from N, O, P or S, substituted with one or more independently selected R7groups, and R7is C1.4 alkyl substituted with one or more independently selected halo or -CN. In a particular embodiment, R7is -CH3, -CH2CH3, or -CH(CH3)2, each of which is substituted with one or more independently selected halo or -CN. In another particular embodiment, R7is C1-4 alkyl substituted with one, two, or three independently selected halo or -CN. In yet another particular embodiment, R7is C1-4 alkyl substituted with one or more F, Cl, Br, or -CN. In a more particular embodiment, R7is -CH3 substituted with one or more independently selected halo or -CN. In another more particular embodiment, R7is -CH3, -CH2CH3, or -CH(CH3)2, each of which is substituted with one, two, or three independently selected halo or -CN. In yet another more particular embodiment, R7is -CH3, -CH2CH3, or -CH( 013)2, each of which is substituted with one or more independently selected F, Cl, Br, or -CN. In yet another more particular embodiment, R7is C1-4 alkyl substituted with one, two, or three independently selected F, Cl, Br, or -CN. In a further more particular embodiment, R7is -CH3 substituted with one, two, or three independently selected halo or -CN. In another further more particular embodiment, R7is -CH3 substituted with one ormore , two, or three independently selected F, Cl, Br, or -CN. In a most particular embodiment, R7is -CH3 substituted with one, two, or three independently selected F or -CN.

[0122] In one embodiment, the compound of the invention is according to any one of Formulae I, II, IVa-Vf, wherein Z is -linked 5-12 membered bicyclic fused, bridged or spiro heterocycloalkyl further comprising zero, one, or two additional heteroatoms independently selected from N, O, P or S. In a particular embodiment, Z is azaspirohexanyl azaspiroheptanyl, or azaspirohexanyl.

[0123] In one embodiment, the compound of the invention is according to any one of Formulae I, II, IVa-Vf, wherein Z is -linked 5-12 membered bicyclic fused, bridged or spiro heterocycloalkyl further comprising zero, one, or two additional heteroatoms independently selected from N, O, P or S, substituted with one or more independently selected R7groups. In a particular embodiment, Z is azaspirohexanyl azaspiroheptanyl, or azaspirohexanyl, each of which is substituted with one or more independently selected R7groups. In another particular embodiment, Z is '-linkcd 5-12 membered bicyclic fused, bridged or spiro heterocycloalkyl further comprising zero, one, or two additional heteroatoms independently selected from N, O, P or S, substituted with one, two, orthree independently selected R7groups. In another more particular embodiment, Z is azaspirohexanyl azaspiroheptanyl, or azaspirohexanyl, each of which is substituted with one, two, or three independently selected R7groups. In yet another more particular embodiment, Z is N-linked 5-12 membered bicyclic fused, bridged or spiro heterocycloalkyl further comprising zero, one, or two additional heteroatoms independently selected from N, O, P or S, substituted with one or two independently selected R7group. In another further more particular embodiment, Z is azaspirohexanyl azaspiroheptanyl, or azaspirohexanyl, each of which is substituted with one or two independently selected R7groups. In a most particular embodiment, Z is azetidinyl substituted with one or two independently selected R7groups.

[0124] In one embodiment, the compound of the invention is according to any one of Formulae I, II, IVa-Vf, wherein Z is '-linkcd 5-12 membered bicyclic fused, bridged or spiro heterocycloalkyl further comprising zero, one, or two additional heteroatoms independently selected from N, O, P or S, substituted with one or more independently selected R7groups, and R7is -OH, -CN, or C1-4 alkyl. In a particular embodiment, R7is -OH, -CN, -CH3, -CH2CH3, or -CH(CH3)2. In a more particular embodiment, R7is -OH or -CN.

[0125] In one embodiment, the compound of the invention is according to any one of Formulae I, II, IVa-Vf, wherein Z is '-linkcd 5-12 membered bicyclic fused, bridged or spiro heterocycloalkyl further comprising zero, one, or two additional heteroatoms independently selected from N, O, P or S, substituted with one or more independently selected R7groups, and R7is C1-4 alkyl substituted with one or more independently selected halo or -CN. In a particular embodiment, R7is -CH3, -CH2CH3, or -CH( 013)2, each of which is substituted with one or more independently selected halo or -CN. In another particular embodiment, R7is C1.4 alkyl substituted with one, two, orthree independently selected halo or -CN. In yet another particular embodiment, R7is C1.4 alkyl substituted with one or more F, Cl, Br, or -CN. In a more particular embodiment, R7is -CH3 substituted with one or more independently selected halo or -CN. In another more particular embodiment, R7is -CH3, -CH2CH3, or -CH( 013)2, each of which is substitutedwith one, two, or three independently selected halo or -CN. In yet another more particular embodiment, R7is -CH3, -CH2CH3, or -CH(CHS)2, each of which is substituted with one or more independently selected F, Cl, Br, or -CN. In yet another more particular embodiment, R7is C1-4 alkyl substituted with one, two, or three independently selected F, Cl, Br, or -CN. In a further more particular embodiment, R7is -CH3 substituted with one, two, or three independently selected halo or -CN. In another further more particular embodiment, R7is -CH3 substituted with one or more , two, or three independently selected F, Cl, Br, or -CN. In a most particular embodiment, R7is -CH3 substituted with one, two, or three independently selected F or -CN.

[0126] In one embodiment, the compound of the invention is according to any one of Formulae I, II, IVa-Vf, wherein Z is selected from

[0127] In one embodiment, the compound of the invention is according to any one of Formulae I, II, IVa- Vf, wherein Z is -NH2.

[0128] In one embodiment, the compound of the invention is according to any one of Formulae I, II, IVa- Vf, wherein Z is -NH-L-R3a, and R3ais as defined for Formula I or II. in a particular embodiment, Z is -NH-CH2-R3a.

[0129] In one embodiment, the compound of the invention is according to any one of Formulae I, II, IVa- Vf, wherein Z is -NH-R3a, and R3ais as defined for formula I.

[0130] In one embodiment, the compound of the invention is according to Formula Via, VIb, Vic, Vid, Vie or VIf, whereinVie VIfWherein R1and Z are as defined for formula I.

[0131] In one embodiment, the compound of the invention is according to any one of Formulae I, II, IVa-Vlf, wherein R3ais Ci-6 alkyl. In a particular embodiment, R3ais -CHs, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, -CH2CH(CH3)2, -C(CH3)3, -CH(CH3)CH2CH3, or -CH(CH3)CH(CH3)2. In a more particular embodiment, R3ais -CH3, -CH2CH3, -CH2CH2CH3, -CH( 013)2, or -CH2CH( 013)2. In a most particular embodiment, R3ais -CH2CH3.

[0132] In one embodiment, the compound of the invention is according to any one of Formulae I, II, IVa-Vlf, wherein Z is -NHR3a, and R3ais C1-6 alkyl substituted with one or more independently selected R8. In a particular embodiment, R3ais -CH3, -CH2CH3, -CH2CH2CH3, -CH( 013)2, or -C(CH3)3, each of which is substituted with one or more independently selected R8. In another particular embodiment, R3ais C1-6 alkyl substituted with one, two, or three independently selected R8. In a more particular embodiment, R3ais -CH3, -CH2CH3, -CH2CH2CH3, -CH(CH3)2, or -C(CH3)3, each of which is substituted with one, two, or three independently selected R8.

[0133] In one embodiment, the compound of the invention is according to any one of Formulae I, II, IVa-Vlf, wherein R3ais C3-7 cycloalkyl. In a particular embodiment, R3ais cyclopropyl, cyclobutyl, or cyclopentyl. In a more particular embodiment, R3ais cyclopropyl.

[0134] In one embodiment, the compound of the invention is according to any one of Formulae I, II, IVa-Vlf, wherein R3ais C3-7 cycloalkyl substituted with one or more groups independently selected from =0 and R8. In a particular embodiment, R3ais cyclopropyl, cyclobutyl, or cyclopentyl, each of which is with one or more groups independently selected from =0 and R8. In another particular embodiment, R3ais C3-7 cycloalkyl substituted with one, two, or three groups independently selected from =0 and R8. In a more particular embodiment, R3ais cyclopropyl, cyclobutyl, or cyclopentyl, each of which is substituted with one, two, or three groups independently selected from =0 and R8. In a more particular embodiment, R3ais C3-7 cycloalkyl substituted with one, or two groups independently selected from =0 and R8. In a more particular embodiment, R3ais cyclopropyl, cyclobutyl, or cyclopentyl, each of which is substituted with one, or two groups independently selected from =0 and R8.

[0135] In one embodiment, the compound of the invention is according to any one of Formulae I, II, IVa-Vlf, wherein R3ais 5-12 membered bicyclic fused, bridged or spiro cycloalkyl. In a particular embodiment, R3ais spiropentanyl, spirohetanyl or bicyclohexanyl.

[0136] In one embodiment, the compound of the invention is according to any one of Formulae I, II, IVa-Vlf, wherein R3ais 5-12 membered bicyclic fused, bridged or spiro cycloalkyl substituted with one or moregroups independently selected from =0 and R8. In a particular embodiment, R3ais spiropentanyl, spirohetanyl or bicyclohexanyl, each of which is with one or more groups independently selected from =0 and R8. In another particular embodiment, R3ais 5-12 membered bicyclic fused, bridged or spiro cycloalkyl substituted with one, two, or three groups independently selected from =0 and R8. In a more particular embodiment, R3ais spiropentanyl, spirohetanyl or bicyclohexanyl, each of which is substituted with one, two, or three groups independently selected from =0 and R8. In a more particular embodiment, R3ais 5-12 membered bicyclic fused, bridged or spiro cycloalkyl substituted with one, or two groups independently selected from =0 and R8. In a more particular embodiment, R3ais spiropentanyl, spirohetanyl or bicyclohexanyl, each of which is substituted with one, or two groups independently selected from =0 and R8.

[0137] In one embodiment, the compound of the invention is according to any one of Formulae I, II, IVa-Vlf, wherein R3ais 4-7 membered monocyclic heterocycloalkyl, comprising one or more independently selected N, O, P or S heteroatoms. In a particular embodiment, R3ais azetidinyl, oxetanyl, tetrahydrofuranyl, pyrrolidinyl, tetrahydropyranyl, piperidinyl, morpholinyl, thiomorpholinyl, or piperazinyl.

[0138] In one embodiment, the compound of the invention is according to any one of Formulae I, II, IVa-Vlf, wherein R3ais 4-7 membered monocyclic heterocycloalkyl, comprising one or more independently selected N, O, P or S heteroatoms substituted with one or more groups independently selected from =0 and R8. In a particular embodiment, R3ais azetidinyl, oxetanyl, tetrahydrofuranyl, pyrrolidinyl, tetrahydropyranyl, piperidinyl, morpholinyl, thiomorpholinyl, or piperazinyl, each of which is with one or more groups independently selected from =0 and R8. In another particular embodiment, R3ais 4-7 membered monocyclic heterocycloalkyl, comprising one or more independently selected N, O, P or S heteroatoms substituted with one, two, or three groups independently selected from =0 and R8. In a more particular embodiment, R3ais azetidinyl, oxetanyl, tetrahydrofuranyl, pyrrolidinyl, tetrahydropyranyl, piperidinyl, morpholinyl, thiomorpholinyl, or piperazinyl, each of which is substituted with one, two, or three groups independently selected from =0 and R8. In a more particular embodiment, R3ais 4-7 membered monocyclic heterocycloalkyl, comprising one or more independently selected N, O, P or S heteroatoms substituted with one, or two groups independently selected from =0 and R8. In a more particular embodiment, R3ais azetidinyl, oxetanyl, tetrahydrofuranyl, pyrrolidinyl, tetrahydropyranyl, piperidinyl, morpholinyl, thiomorpholinyl, or piperazinyl, each of which is substituted with one, or two groups independently selected from =0 and R8.

[0139] In one embodiment, the compound of the invention is according to any one of Formulae I, II, IVa-Vlf, wherein R3ais 5-12 membered bicyclic fused, bridged or spiro heterocycloalkyl, comprising one or more independently selected N, O, P or S heteroatoms. In a particular embodiment, R3ais azaspirohexanyl azaspiroheptanyl, or azaspirohexanyl.

[0140] In one embodiment, the compound of the invention is according to any one of Formulae I, II, IVa-Vlf, wherein R3ais 5-12 membered bicyclic fused, bridged or spiro heterocycloalkyl, comprising one or more independently selected N, O, P or S heteroatoms substituted with one or more groups independently selected from =0 and R8. In a particular embodiment, R3ais azaspirohexanyl azaspiroheptanyl, orazaspirohexanyl, each of which is with one or more groups independently selected from =0 and R8. In another particular embodiment, R3ais 5-12 membered bicyclic fused, bridged or spiro heterocycloalkyl, comprising one or more independently selected N, O, P or S heteroatoms substituted with one, two, or three groups independently selected from =0 and R8. In a more particular embodiment, R3ais azaspirohexanyl azaspiroheptanyl, or azaspirohexanyl, each of which is substituted with one, two, or three groups independently selected from =0 and R8. In a more particular embodiment, R3a5-12 membered bicyclic fused, bridged or spiro heterocycloalkyl, comprising one or more independently selected N, O, P or S heteroatoms substituted with one, or two groups independently selected from =0 and R8. In a more particular embodiment, R3ais azaspirohexanyl azaspiroheptanyl, or azaspirohexanyl, each of which is substituted with one, or two groups independently selected from =0 and R8.

[0141] In one embodiment, the compound of the invention is according to any one of Formulae I, II, IVa-Vlf, wherein R3ais 5-6 membered heteroaryl comprising one or more independently selected N, O, or S heteroatoms. In a particular embodiment, R3ais pyrazolyl, imidazolyl, oxadiazolyl, thiazolyl, thiadiazolyl, pyridinyl, pyrimidinyl, or pyrazinyl.

[0142] In one embodiment, the compound of the invention is according to any one of Formulae I, II, IVa-Vlf, wherein R3ais 5-6 membered heteroaryl comprising one or more independently selected N, O, or S heteroatoms, substituted with one or more independently selected R8. In a particular embodiment, R3ais pyrazolyl, imidazolyl, oxadiazolyl, thiazolyl, thiadiazolyl, pyridinyl, pyrimidinyl, or pyrazinyl, each of which is substituted with one or more independently selected R8. In another particular embodiment, R3ais 5-6 membered heteroaryl comprising one or more independently selected N, O, or S heteroatoms, substituted with one, two, or three independently selected R8. In a more particular embodiment, R3ais pyrazolyl, imidazolyl, oxadiazolyl, thiazolyl, thiadiazolyl, pyridinyl, pyrimidinyl, or pyrazinyl, each of which is substituted with one, two, or three independently selected R8. In a more particular embodiment, R3ais 5-6 membered heteroaryl comprising one or more independently selected N, O, or S heteroatoms, substituted with one, or two independently selected from R8. In a more particular embodiment, R3ais pyrazolyl, imidazolyl, oxadiazolyl, thiazolyl, thiadiazolyl, pyridinyl, pyrimidinyl, or pyrazinyl, each of which is substituted with one, or two independently selected R8.

[0143] In one embodiment, the compound of the invention is according to any one of Formulae I, II, IVa-Vlf, wherein each R8is independently selected from F, Cl, CN, OH, NH2, -CH3, -CH2CH3,-CH(CHs)2, -O-CH3, -O-CH2CH3, or -O-CH(CH3)2, -CHF2, -CF3, -CH2CF3, -CH2CN, -CH20H,

[0144] In one embodiment, the compound of the invention is according to any one of Formulae I, II, IVa-Vlf, wherein R3ais selected from:wherein * represents the point of attachment.

[0145] In one embodiment, the compound of the invention is according to any one of Formulae I-VIf, wherein R1is H.In one embodiment, the compound of the invention is according to Formula I, wherein the compound is selected from the illustrative compounds described in Table IV herein.

[0146] In one embodiment, a compound of the invention is provided in a natural isotopic form.

[0147] 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 (i.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.

[0148] 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.

[0149] 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.

[0150] In one aspect a compound of the invention according to any one of the embodiments herein described is present as the free base.

[0151] In one aspect a compound of the invention according to any one of the embodiments herein described is a pharmaceutically acceptable salt.

[0152] In one aspect a compound of the invention according to any one of the embodiments herein described is a solvate of the compound.

[0153] 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.

[0154] 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.

[0155] 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.

[0156] 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.

[0157] 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.

[0158] 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 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 preferred prodrugs. In some cases it is desirable to prepare double ester type prodrugs such as (acyloxy)alkyl esters or ((alkoxycarbonyl)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

[0159] 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.

[0160] In one embodiment, the present invention provides pharmaceutical compositions comprising a compound of the invention and another therapeutic agent.

[0161] 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.

[0162] 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.

[0163] 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.

[0164] 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.

[0165] 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.

[0166] 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.

[0167] 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, corneal 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.

[0168] 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.

[0169] 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.

[0170] 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.

[0171] 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.

[0172] 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.

[0173] 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.

[0174] 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.

[0175] 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.

[0176] 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.

[0177] 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.

[0178] 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.

[0179] 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.

[0180] 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 prefilled, 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.

[0181] 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.

[0182] 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.

[0183] 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.

[0184] 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.

[0185] 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.

[0186] 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).

[0187] 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

[0188] 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 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

[0189] 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 filled into 250 mg capsules (125 mg of active compound of the invention according to Formula I per capsule).Formulation 3 - Liquid

[0190] A compound of the invention according to Formula I (125 mg), maybe 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

[0191] 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

[0192] 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

[0193] 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

[0194] In one embodiment, the present invention provides compounds of the invention, or pharmaceutical compositions comprising a compound of the invention, for use in medicine.

[0195] 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 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.

[0196] 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.

[0197] 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.

[0198] 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.

[0199] 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 medicamentfor 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.

[0200] 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.

[0201] 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.

[0202] 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.

[0203] 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.

[0204] 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.

[0205] 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.

[0206] 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 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.

[0207] 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.

[0208] 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.

[0209] 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.

[0210] 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.

[0211] 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 medicamentfor 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.

[0212] 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.

[0213] 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 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, corneal 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.

[0214] 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.

[0215] 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.

[0216] 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, sclerodermaand ankylosing spondylitis. More particularly, the term refers to osteoarthritis, psoriatic arthritis juvenile rheumatoid arthritis, systemic lupus erythematosus, scleroderma and ankylosing spondylitis.

[0217] 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 to osteoarthritis, psoriatic arthritis, juvenile rheumatoid arthritis, systemic lupus erythematosus, scleroderma and ankylosing spondylitis.

[0218] 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.

[0219] 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.

[0220] 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.

[0221] 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 theadministration 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.

[0222] 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.

[0223] 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.

[0224] 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.

[0225] 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.

[0226] 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.

[0227] 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. Inparticular, 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.

[0228] 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.

[0229] 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 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.

[0230] 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.

[0231] 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.

[0232] 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 medicamentfor 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.

[0233] 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.

[0234] 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.

[0235] 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.

[0236] 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.

[0237] 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.

[0238] 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 medicamentfor 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.

[0239] 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.

[0240] 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.

[0241] 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.

[0242] 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 (includingthat 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.

[0243] 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.

[0244] 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.

[0245] 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.

[0246] 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.

[0247] 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.

[0248] 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.

[0249] 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 or more 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.

[0250] 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.

[0251] 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.

[0252] Transdermal doses are generally selected to provide similar or lower blood levels than are achieved using injection doses.

[0253] 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.

[0254] 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.

[0255] 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.

[0256] 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, mycophenolate mofetil, muromonab-CD3 (OKT3, e.g. Orthocolone®), ATG, aspirin, acetaminophen, ibuprofen, naproxen, and piroxicam.

[0257] 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, auranofm, sodium aurothiomalate, penicillamine, chloroquine, hydroxychloroquine, azathioprine, JAK inhibitors (for example tofacitinib, baricitinib, Upadacitinib, ruxolitinib, or filgotinib), fostamatinib, and cyclosporin), and biological DMARDS (for example but without limitation infliximab, etanercept, adalimumab, rituximab, and abatacept).

[0258] 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.

[0259] 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-J3), TNF binding proteins (e.g. infliximab, etanercept, or adalimumab), mycophenolate, fmgolimod and myriocin.

[0260] 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 -proliferative s (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)).

[0261] 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 / sahneterol, 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) .

[0262] 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.

[0263] 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).

[0264] 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.

[0265] 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, mycophenolatemofetil, 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)).

[0266] 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 antileukotrienes (e.g. montelukast or zafirlukast), anti-cholinergics and decongestants.

[0267] 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

[0268] 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.

[0269] 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).

[0270] 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.

[0271] 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 chromatography cartridges. 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 ona 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 (50.00) or the appropriate residual solvent peak, e.g. CHCI3 (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. Columns used: Waters Acquity UPLC BEH C18 1.7 pm, 2.1 mm ID x 30 / 50 mm L; Waters Acquity UPLC CSH C18 1.7 pm, 2.1 mm ID x 100 mm L; Waters Acquity UPLC CSH PhenylHexyl 1.7 pm, 2.1 mm ID x 100 mm L; Waters Acquity UPLC HSS PPP 1.8 pm, 2.1 mm ID x 100 mm L. The methods are using ACN / water or MeOH / water gradients with either 0.1% formic acid in both mobile phases or 0.05% NH3 in both mobile phases. Preparative HPLC is performed on a Waters AutoPurification system with UV and MS detection using Waters XBridge BEH C18 OBD 30 mm ID x 100 mm L columns and ACN / water gradients with either 0.1% formic acid in both mobile phases or 0.1% NH4OH in both mobile phases. Microwave heating is performed with a Biotage® Initiator.Table I. List of abbreviations used in the experimental section:Abbreviation Definition Abbreviation Definition ACN acetonitrile DSS dextran sodium sulfate AcOH acetic acid dt doublet of triplets ANOVA analysis of variance DTT dithiothreitol aq. aqueous ethylenediaminetetraaceti EDTAc acid ATP adenosine 5 '-triphosphateenzyme-linked b.i.d. bis in die (twice a day) ELISAimmunosorbent assay bis(pinacolato)diboronB2pin2eq- equivalent (CAS# 73183-34-3)Enantiomeric excess BUN blood urea nitrogen % e.e.percentage Cpd compoundEtOAc ethyl acetate d doubletEt2O diethyl ether DCM dichloromethaneEtOH ethanol dd doublet of doubletsh hour DMF dimethylformamide high-performance liquid HPLC DMSO dimethylsulfoxide chromatography 1 , 1 '-bis(diphenylphos i.n. intranasal dppf phino)ferrocene Int intermediate (CAS# 12150-46-8)i.p. intraperitonealAbbreviation Definition Abbreviation Definition (1,5 -cyclooctadiene) [1,1 '-bis(diphenylphos [Ir(OCH3)(methoxy)iridium(I)dimer phino)ferrocene] dichlorop (COD)]2(CAS# 12148-71-9) Pd(dppf)Cl2DCM alladium(II) complex with i.v. intravenous dichloromethane liquid chromatography(CAS# 95464-05-4) LCMSmass spectrometry PIN percentage inhibition LPS lipopolysaccharide p.o. per os m multiplet PPm parts-per-million 2-MeTHF 2-methyltetrahydrofuran q quartet MeOH methanol q.d. quaque die (once a day) min minute 2-dicyclohexylphosphino- 2',6'-diisopropoxy-l,l'- mmol millimole RuPhosbiphenyl MS mass spectrometry(CAS# 787618-22-8) MTBE methyl tert-butyl etherRT room temperature Mtd methods singlet MW molecular weightsat. saturated molecular weightMW (calcd) sc subcutaneous calculatedSEM standard error of the mean molecular weightMW (obsd)observed sept. septetN-ter N-terminal supercritical fluid SFCchromatography NA not availableSM starting material NBS JV-bromosuccinimidet triplet NCS JV-chlorosuccinimide / -BuOH tert-butanol NIS JV-iodosuccinimidet-BuOK potassium tert-butoxide tris(dibenzylideneacetone)Pd2(dba)3dipalladium(O) td triplet of doublets (CAS# 51364-51-3) THF tetrahydrofuran Pd / C palladium on carbon 2-dicyclohexylphosphino- [1,1 '-bis(diphenylphos 2',4',6'-triisopropyl-l,l'- XPhosphino)ferrocene] dichloro biphenyl Pd(dppf)Cl2palladium(II) (CAS# 564483-18-7)(CAS# 72287-26-4)Abbreviation Definition* next to R or / and Sstereochemistry indicatorsR*means that theS*stereochemistry has beenarbitrarily assignedSYNTHETIC PREPARATION OF THE COMPOUNDS OF THE INVENTIONExample 1. Preparation of intermediates toward illustrative compounds of the invention 1.1. Int 51.1.1. Step AA round bottomed flask (100 mb) was charged with Int 4 (1 eq., 4012 mg, 13.37 mmol), CAS#2563897-58-3 (1.2 eq., 6402 mg, 16 mmol), PdCl2(dppf).DCM (0.094 eq., 1033 mg, 1.26 mmol), K3PO4(3.15 eq., 8936 mg, 42.098 mmol), and a degassed mixture of dioxane (30 mb) and water (10 mb), equipped with a reflux condenser, sealed with an oil bubbler under a N2atmosphere and heated to 110 °C. After 1 hour, heating ceased. The mixture was combined with CHCh (250 mb), n-BuOH (25 mb) and H2O (250 mb) in a separatory funnel and agitated. The organic phase was collected, washed with brine (50 mb) and dried over MgSCft. After filtration, volatiles were removed from the filtrate via rotary evaporation. The residue was charged onto a column of silica gel (350 g) and eluted with a gradient of CH2Cl2 / EtOAc (1:0 to 0: 1). Product containing fractions (85-120) were pooled, and the solvent was removed via rotary evaporation to give tert-butyl (S)-2-(difluoromethoxy)-4-(6-((3-hydroxy-3-methylbutan-2-yl)oxy)pyrazolo [ 1 ,5 -a]pyrimidin-3 -yl)-6-methoxybenzoate (5760 mg) .

[0272] LCMS: MW (calcd): 493.5; m / z MW (obsd): 494.5 (M+H).1.1.2. Step B

[0273] Tert-butyl (S)-2-(difluoromethoxy)-4-(6-((3-hydroxy-3-methylbutan-2-yl)oxy)pyrazolo[l,5-a]pyrimidin-3-yl)-6-methoxybenzoate (750 mg, 1.52 mmol) in solution in dioxane (4 m ). Hydrogen chloride 4N in dioxane (3.75 m , 15 mmol) was added. The reaction mixture was stirred at RT for 36 h. The reaction mixture was concentrated to dryness to afford Int 5 (716 mg) hydrochloride salt.LCMS: MW (calcd): 437.4; m / z MW (obsd): 438.4 (M+H).1.2. Int 6

[0274] Int 6 was prepared as for Int 5 starting from (S)- lactate CAS# 687-47-81.3. Int 7

[0275] A round bottomed flask (25 mL) was charged with Int 5 (1 eq., 214.2 mg, 0.45 mmol), 1,1'-carbonyldiimidazole (2.44 eq., 178.9 mg, 1.103 mmol) and dry acetonitrile (8 mL) and sealed with a septum for 17 h. The mixture was combined with CHCL (50 mL), an aqueous KH2PO4 / K2HPO4 buffer (pH 7, IM, 25 mL) and H2O (25 mL) in a separatory funnel and stirred. The organic phase was collected, washed with brine (50 mL) and dried over MgSCL. After filtration, volatiles were removed from the filtrate via rotary evaporation. The residue was charged onto a column of silica gel (25 g) and eluted with a gradient of CTLCh / iPrOH (1:0 to 9: 1). Product containing fractions (38-45) were pooled, and the solvent was removed via rotary evaporation to give Int 7 (219 mg).1.4. Int 8

[0276] A vial was charged with (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 eq., 120 mg, 0.3 mmol), 2-bromo-5-iodo-l,3-dimethoxybenzene (1.1 eq., 112 mg, 0.33 mmol), SPHOS PdG4 (0.1 eq., 24 mg, 0.03 mmol), K3PO4 (2 eq., 126 mg, 0.6 mmol), and degassed with Argon. Anhydrous degassed (bubbling Nitrogen for 15min) dioxane (3 mL) and water (0.7 mL) were added at rt and RM was degassed through vacuum / Argon cycles 4 times, kept under Argon atmosphere. Then RM was heated at 60°C (preheated oil bath >60°C) under argon atmosphere. After hour, he 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 MgSCfi. filtered and concentrated under vaccum. The crude material was then purified by column chromatography (Sfar HC 25g, elution with DCM / AcOEt-EtOH (3 / 1) 100 to 98 / 2 over 5 cv then isocratic for 5 CV then 98 / 2 to 95 / 5 over 7 CV then isocratic for 8 CV ) to give (S)-3-((3-(4-bromo-3,5-dimethoxyphenyl)pyrazolo[l,5-a]pyrimidin-6-yl)oxy)-2-methylbutan-2-ol. Int 8 (72 mg).

[0277] MW (calcd):436.3 m / z MW (obsd):436.3-438.3 (M+l)1.5. Int 91.5.1. Step A

[0278] A round botomed flask was charged with diisopropylamine (1.11 eq., 13.7 mL, 96.94 mmol) and dry THF (100 mL) and sealed with a septum. The flask was evacuated and refilled with Nitrogen twice and left under an atmosphere of nitrogen. The flask was cooled in a dry ice / EtOH bath at -78 °C, and n-BuLi (1.10 eq., 38.5 mL, 96.25 mmol) was added to the cold solution. After 10 minutes, a dry THF (10 mL) solution of 2,4-difluoropyridine CAS#34941-90-7 (1 eq., 10.0 g, 87.0 mmol) was added via syringe. After 20 minutes, a dry THF solution (55 mL) of Boc2O (1.2 eq., 22.8 mL, 107 mmol) was added via an addition funnel over a period of 15 minutes. The dry ice / EtOH bath was removed and the reaction mixture was left under stirring at rt overnight. An aqueous KH2PO4 / K2HPO4 buffer (pH 7, IM, 200 mL) was added. The mixture was combined with EtOAc (500 mL) and water (300 mL) in a separatory funnel and agitated. The organic phase was collected, washed with brine (500 mL) and dried over MgSO4. After filtration, volatiles were removed from the filtrate via rotary evaporation. The residue was charged onto a column of silica gel (350 g) and eluted with a gradient of heptane / EtOAc (1 :0 to 9: 1). Fractions containing product were pooled, and the solvent was removed via rotary evaporation to give tert-butyl 2,4-difluoronicotinate (14,22 g) .

[0279] LCMS: MW (ealed): 215.2; m / z MW (obsd): 216.1 (M+H).1.5.2. Step B

[0280] A round botomed flask was charged with potassium tert-butoxide (3.1 eq., 9.70 g, 86.4 mmol) and dry methanol (100 mL) and sealed with a septum. The flask was evacuated and refilled with nitrogen twice then the flask was cooled to -78 °C with a dry ice / ethanol bath. After 15 minutes, a methanol solution (6 mL) of tert-butyl 2,4-difluoronicotinate (1 eq., 6.0 g, 27.9 mmol) was added. After 5 minutes, the cold bath was removed. The flask was equipped with a reflux condenser, sealed with an oil bubbler and heated to 65 °C overnight. The mixture was allowed to cool to room temperature. The mixture was combined with EtOAc (500 mL), an aqueous KH2PO4 / K2HPO4 buffer (pH 7, IM, 350 mL) and water (150 mL) in a separatory funnel and agitated. The organic phase was collected, washed with water (500 mL) and brine (250 mL) and dried over MgSCL. After filtration, volatiles were removed from the filtrate via rotary evaporation. The residue was charged onto a column of silica gel (350 g) and eluted with a gradient of heptane / EtOAc (1:0 to 3:2). Fractions containing product were pooled, and the solvent was removed via rotary evaporation to give tert-butyl 2,4-dimethoxynicotinate (5.65 g).

[0281] LCMS: MW (ealed): 239.3; m / z MW (obsd): 240.3 (M+H).1.5.3. Step C

[0282] A round botomed flask was charged with (l,5-Cyclooctadiene)(methoxy)iridium(I) dimer (0.05 eq., 0.77 g, 1.16 mmol), 3,4,7,8-tetramethyl-l,10-phenanthroline (0.1 eq., 0.55 g, 2.33 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 (1.4 eq., 12.0 g, 32.77 mmol), and a solution of tert-butyl 2,4-dimethoxynicotinate (1 eq., 5.56 g, 23.2 mmol) in degassed heptane (100 mL), equipped with a reflux condenser, sealed with an oil bubbler under an atmosphere of nitrogen, and heated to 80 °C for 4 hours. The mixture was allowed to cool to room temperature and volatiles were removed via rotary evaporation. The crude reaction mixture was charged onto a column of silica gel (750 g) and eluted with a gradient of heptane / EtOAc (1:0 to 0:1). Fractions containing product were pooled, and the solvent was removed via rotary evaporation to give tert-butyl 2,4-dimethoxy-6-(4,4,5,5-tetraethyl-l,3,2-dioxaborolan-2-yl)nicotinate (6.36 g) .

[0283] LCMS: MW (ealed): 421.3; m / z MW (obsd): 422.5 (M+H).1.5.4. StepD

[0284] A round botomed flask was charged with (3S)-3-({3-bromopyrazolo[l,5-a]pyrimidin-6-yl}oxy)-2-methylbutan-2-ol Int 4 (1 eq., 1.49 g, 4.98 mmol), tert-butyl 2,4-dimethoxy-6-(4,4,5,5-tetraethyl-l,3,2-dioxaborolan-2-yl)nicotinate (1 eq., 2.26 g, 4.82 mmol), SPhosPdG4 (0.05 eq., 0.197 g, 0.25 mmol), potassium phosphate (2.1 eq., 2.18 g, 10.3 mmol), toluene (20 mL) and water (2 mL). The mixture was degassed by bubbling a stream of nitrogen through the mixture. The flask was equipped with a reflux condenser, sealed with an oil bubbler under a nitrogen atmosphere and heated at 110 °C for 1 hour. The mixture was allowed to cool to room temperature. The mixture was combined with CHCL (250 mL), n-BuOH (25 mL) and an aqueous KH2PO4 / K2HPO4 buffer (pH 7, IM, 250 mL) in a separatory funnel and agitated. The organic phase was collected, washed with water (250 mL) and brine (250 mL) and dried over MgSC After filtration, volatiles were removed from the filtrate via rotary evaporation. The residue was charged onto a column of silica gel ( 100 g) and eluted with a gradient of DCM / EtOAc ( 1 : 0 to 3 : 2) . Fractions containing product were pooled, and the solvent was removed via rotary evaporation to give tert-butyl (S)-6-(6-((3 -hydroxy-3 -methylbutan-2-yl)oxy)pyrazolo [1,5 -a]pyrimidin-3 -yl)-2,4-dimethoxynicotinate (2.03 g) •

[0285] LCMS: MW (ealed): 458.5; m / z MW (obsd): 459.5 (M+H).1.6. StepE

[0286] A round botomed flask was charged with tert-butyl (S)-6-(6-((3-hydroxy-3-methylbutan-2-yl)oxy)pyrazolo[l,5-a]pyrimidin-3-yl)-2,4-dimethoxynicotinate (1 eq., 2 g, 4.43 mmol) and dry dichloromethane (10 mL) and sealed with an oil bubbler. The resulting solution was cooled in an ice bath. Trifluoroacetic acid (30 eq., 10 mL, 135 mmol) was added to the cold solution. The reaction mixture was stirred at rt for 24h. Volatiles were removed via rotary evaporation. The residue was dissolved in DCM (20 mL), and then volatiles were removed via rotary evaporation to give (S)-6-(6-((3-hydroxy-3-methylbutan-2-yl)oxy)pyrazolo[l,5-a]pyrimidin-3-yl)-2,4-dimethoxynicotinic acid-2, 2, 2-trifluoroacetic acid salt Int 9 (2.28 g) .

[0287] LCMS: MW (calcd): 402.4; m / z MW (obsd): 403.4 (M+H).1.7. Int i

[0288] Step A: 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 RM was stirred for a further 3 h at 0 °C. The RM 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 (2x1.1 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 .

[0289] ’HNMR (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).

[0290] Step B: 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 RM was stirred for a further 30 min at this temperature. The jacket temperature was set at -15 °C and the RM 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 ofHCl.lM. 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. NaHCO; 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 .

[0291] ’HNMR (400 MHz, DMSO-de) 58.49 (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)1.8. Int 3

[0292] A lOOmL RBF was charged with Int 4 (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 RM was degassed through vacuum / Argon cycles 4 times, kept under Argon atmosphere (balloon). RM 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. RM was degassed through vacuum / Argon cycles 3 times, kept under Argon atmosphere (balloon) and stirred at 85-90°C for 6h. The RM was cooled down to rt, diluted with AcOEt. The resulting suspension was fdtered 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).

[0293] LCMS: MW (calcd): 403.3; m / z MW (obsd): 404.4 (M+H).1.9. Int 4Int 41.9.1. Step A

[0294] In a round bottom 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 RM was stirred at 0 °C for 1 h. The RM 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 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 methyl (2S)-2-pyrazolo[l,5-a]pyrimidin-6-yloxypropanoate.

[0295] LCMS: MW (calcd): 221.0; m / z MW (obsd): 221.8 (M+H)1.9.2. Step B

[0296] In a round botom flask, to a solution of methyl (2S)-2-pyrazolo[l,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 RM was stirred at RT for 45 min. The mixture was diluted in DCM and the organic layer was washed with aq. NaHCOs 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 [1,5 -a]pyrimidin-6-yl)oxypropanoate .

[0297] LCMS: MW (calcd): 299.0; m / z MW (obsd): 299.7 / 301.7 (M+H)

[0298] 'HNMR (400 MHz, CD3OD) 58.62 (d, 1H), 8.51 (d, 1H), 8.06 (s, 1H), 5.02 (q, 1H), 3.78 (s, 3H), 1.66 (d, 3H)

[0299] Step CIn 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 RM 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.,

[0300] 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%.

[0301] LCMS: MW (calcd): 299.0; m / z MW (obsd): 299.8 / 301.8 (M+H)1.10. Int 58

[0302] 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 RM. The RM was cooled down to 0°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 RM. Triethylamine (1.42 L, 10200 mmol, 2.01 eq.) was added dropwise, while maintaining reaction temperature below 5 °C. The RM 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, 3V) and 10% NaCl in water (2 L, 3V), then concentrated under vacuum to give 1.228 kg ofcrude product. The crude product was purified by flash chromatography using heptane / EtOAc 100 / 0 to 70 / 30 as eluting system to afford Int 58.

[0303] 1H NMR (400 MHz, DMSO-de) 57.85 - 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).1.11. Int 561.11.1. Step A

[0304] 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 N2 three times and stirred at 90 °C under N2 for 12 h. The RM 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 MgSCL, filtered, and the filtrate was concentrated under vacuum. The crude product was purified by silica gel 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 .

[0305] LCMS: MW (calcd): 401.2; m / z MW (obsd): 162.9 (M+H of corresponding boronic acid)

[0306] 'HNMR (400 MHz, CDCL): 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)1.11.2. Step B

[0307] 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 RM was diluted with EtOAc (2 L) at 25 °C, washed with H2O (I L) and brine (1 L), and the organic phase was dried over anhydrous MgSCL, fdtered and concentrated under vacuum to give 3 -bromopyrazolo-6-(4, 4, 5 ,5 -tetramethyl- 1 ,3 ,2-dioxaborolan-2-yl)pyrazolo [ 1 ,5 -a]pyridine .

[0308] 'HNMR: (400 MHz, CDCL): 58.74 (s, 1 H), 7.89 (s, 1H), 7.39 (s, 2 H), 1.28 (s, 12 H)1.11.3. Step C

[0309] 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 mL, 3 eq.) and H2O2 (168.63 g, 1.49 mol, 142.90 mL, 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 columnchromatography 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.

[0310] 'H NMR: (400 MHz, DMSO-de): 59.85 (s, 1H), 8.15 (dd, 1H), 7.95 (s, 1H), 7.46 (d, 1H), 7.10 (dd, 1H)1.12. Int 57

[0311] In a 15 E single jacketed process reactor equipped with mechanical stirring (200 rpm) and baffle, were charged THF (8.5 E, 17V) and Int 56 (500 g, 2347 mmol, 1.0 eq.). The RM 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 RM was stirred for one further hour after reaching a temperature of 20 °C. The RM was filtered on a sintered funnel, the solid was washed with THF (3V), triturated with MTBE (3V), 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.

[0312] 'H NMR (400 MHz, DMSO-de) 57.39 (s, 1H), 7.21 (d, 1H), 6.90 (d, 1H), 6.59 (dd, 1H) 1.13. Int 59

[0313] In a 5 L reactor equipped with baffles and under N2 atmosphere, triethylamine (250.32 m , 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 m , 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 RM was then stirred at 0-5 °C for 2.2 h. HC12 M (500 mb, 6V) was added until pH <4 while keeping the the RM 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 59.1.14. Int 7

[0314] A reactor (50 mL) was charged with Int 5 (1 eq., 503.9 mg, 1.063 mmol), 1,1 '-carbonyldiimidazole (2.51 eq., 433.1 mg, 2.67 mmol) and dry acetonitrile (20 mL) and sealed with a septum. After 16 hours, LC-MS analysis showed complete conversion. The mixture was combined with CHC13 (100 mL), an aqueous KH2PO4 / K2HPO4 buffer (pH 7, IM, 50 mL) and H2O (50 mL) in a separatory funnel and agitated. The organic phase was collected, washed with brine (100 mL) and dried over MgSC After filtration, volatiles were removed from the filtrate via rotary evaporation. The residue was charged onto a column of silica gel (25 g) and eluted with a gradient of C tLC L / iPrOH (1 :0 to 9: 1) to afford Int 7 (503 mg).

[0315] MW (calcd):487.5 m / z MW (obsd):488.3 (M+l)1.15. Int 8

[0316] A vial was charged with (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 eq., 120 mg, 0.3 mmol), 2-bromo-5-iodo-l,3-dimethoxybenzene (1.1 eq., 112 mg, 0.33 mmol), SPHOS PdG4 (0.1 eq., 24 mg, 0.03 mmol), K3PO4 (2 eq., 126 mg, 0.6 mmol), and degassed with Argon. Anhydrous degassed (bubbling Nitrogen for 15min) dioxane (3 mL) and water (0.7 mL) were added at rt and RM was degassed through vacuum / Argon cycles 4 times, kept under Argon atmosphere. Then RM was heated at 60°C (preheated oil bath >60°C) under argon atmosphere. After 1H, he reaction mixture was filtered through a pad of celite and solid was rinced with EtOAc, the filtrate was washed twice with water, and with brine, dried over anhydrous MgSCL, filtered and concentrated under vaccum to afford an yellow oil. The crude material was then purified by column chromatography (Sfar HC 25g, elution with DCM / AcOEt-EtOH (3 / 1) 100 to 98 / 2 over 5 cv then isocratic for 5 CV then 98 / 2 to 95 / 5 over 7 CV then isocratic for 8 CV ) to give (S)-3-((3-(4-bromo-3,5-dimethoxyphenyl)pyrazolo[l,5-a]pyrimidin-6-yl)oxy)-2-methylbutan-2-ol Int 8 (72 mg).

[0317] MW (calcd):436.3 m / z MW (obsd):436.3-438.3 (M+H)1.16. Int 91.16.1. Step A

[0318] A round botomed flask was charged with diisopropylamine (1.11 eq., 13.7 mL, 96.94 mmol) and dry THF (100 mL) and sealed with a septum. The flask was evacuated and refilled with Nitrogen twice and left under an atmosphere of nitrogen. The flask was cooled in a dry ice / EtOH bath at -78 °C, and n-BuLi (1.10 eq., 38.5 mL, 96.25 mmol) was added to the cold solution. After 10 minutes, a dry THF (10 mL) solution of 2,4-difluoropyridine CAS#34941-90-7 (1 eq., 10.0 g, 87.0 mmol) was added via syringe. After 20 minutes, a dry THF solution (55 mL) of Boc2O (1.2 eq., 22.8 mL, 107 mmol) was added via an addition funnel over a period of 15 minutes. The dry ice / EtOH bath was removed and the reaction mixture was left under stirring at rt overnight. An aqueous KH2PO4 / K2HPO4 buffer (pH 7, IM, 200 mL) was added. The mixture was combined with EtOAc (500 mL) and water (300 mL) in a separatory funnel and agitated. The organic phase was collected, washed with brine (500 mL) and dried over MgSCft. After filtration, volatiles were removed from the filtrate via rotary evaporation. The residue was charged onto a column of silica gel (350 g) and eluted with a gradient of heptane / EtOAc (1 :0 to 9: 1). Fractions containing product were pooled, and the solvent was removed via rotary evaporation to give tert-butyl 2,4-difluoronicotinate (14,22 g).

[0319] LCMS: MW (calcd): 215.2; m / z MW (obsd): 216.1 (M+H).1.16.2. Step B

[0320] A round botomed flask was charged with potassium tert-butoxide (3.1 eq., 9.70 g, 86.4 mmol) and dry methanol (100 mL) and sealed with a septum. The flask was evacuated and refilled with nitrogen twice then the flask was cooled to -78 °C with a dry ice / ethanol bath. After 15 minutes, a methanol solution (6 mL) of tert-butyl 2,4-difluoronicotinate (1 eq., 6.0 g, 27.9 mmol) was added. After 5 minutes, the cold bath was removed. The flask was equipped with a reflux condenser, sealed with an oil bubbler and heated to 65 °C overnight. The mixture was allowed to cool to room temperature. The mixture was combined with EtOAc (500 mL), an aqueous KH2PO4 / K2HPO4 buffer (pH 7, IM, 350 mL) and water (150 mL) in a separatory funnel and agitated. The organic phase was collected, washed with water (500 mL) and brine (250 mL) and dried over MgSO4. After filtration, volatiles were removed from the filtrate via rotary evaporation. The residue was charged onto a column of silica gel (350 g) and eluted with a gradient of heptane / EtOAc (1:0 to 3:2). Fractions containing product were pooled, and the solvent was removed via rotary evaporation to give tert-butyl 2,4-dimethoxynicotinate (5.65 g).

[0321] LCMS: MW (calcd): 239.3; m / z MW (obsd): 240.3 (M+H).1.16.3. Step C

[0322] A round botomed flask was charged with (l,5-Cyclooctadiene)(methoxy)iridium(I) dimer (0.05 eq., 0.77 g, 1.16 mmol), 3,4,7,8-tetramethyl-l,10-phenanthroline (0.1 eq., 0.55 g, 2.33 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 (1.4 eq., 12.0 g, 32.77 mmol), and a solution of tert-butyl 2,4-dimethoxynicotinate (1 eq., 5.56 g, 23.2 mmol) in degassed heptane (100 mL), equipped with a reflux condenser, sealed with an oil bubbler under an atmosphere of nitrogen, and heated to 80 °C for 4 hours. The mixture was allowed to cool to room temperature and volatiles were removed via rotary evaporation. The crude reaction mixture was chargedonto a column of silica gel (750 g) and eluted with a gradient of heptane / EtOAc (1:0 to 0:1). Fractions containing product were pooled, and the solvent was removed via rotary evaporation to give tert-butyl 2,4-dimethoxy-6-(4,4, 5 ,5 -tetraethyl- 1 ,3 ,2-dioxaborolan-2-yl)nicotinate (6.36 g).

[0323] LCMS: MW (calcd): 421.3; m / z MW (obsd): 422.5 (M+H).1.16.4. StepD

[0324] A round bottomed flask was charged with (3S)-3-({3-bromopyrazolo[l,5-a]pyrimidin-6-yl}oxy)-2-methylbutan-2-ol Int 4 (1 eq., 1.49 g, 4.98 mmol), tert-butyl 2,4-dimethoxy-6-(4,4,5,5-tetraethyl-l,3,2-dioxaborolan-2-yl)nicotinate (1 eq., 2.26 g, 4.82 mmol), SPhosPdG4 (0.05 eq., 0.197 g, 0.25 mmol), potassium phosphate (2.1 eq., 2.18 g, 10.3 mmol), toluene (20 mb) and water (2 mb). The mixture was degassed by bubbling a stream of nitrogen through the mixture. The flask was equipped with a reflux condenser, sealed with an oil bubbler under a nitrogen atmosphere and heated at 110 °C for 1 hour. The mixture was allowed to cool to room temperature. The mixture was combined with CHC13 (250 mb), n-BuOH (25 mb) and an aqueous KH2PO4 / K2HPO4 buffer (pH 7, IM, 250 mb) in a separatory funnel and agitated. The organic phase was collected, washed with water (250 mb) and brine (250 mb) and dried over MgSC After filtration, volatiles were removed from the filtrate via rotary evaporation. The residue was charged onto a column of silica gel ( 100 g) and eluted with a gradient of DCM / EtOAc ( 1 : 0 to 3 : 2) . Fractions containing product were pooled, and the solvent was removed via rotary evaporation to give tert-butyl (S)-6-(6-((3 -hydroxy-3 -methylbutan-2-yl)oxy)pyrazolo [ 1 ,5 -a]pyrimidin-3 -yl)-2,4-dimethoxynicotinate (2.03 g)-

[0325] LCMS: MW (calcd): 458.5; m / z MW (obsd): 459.5 (M+H).1.16.5. Step E

[0326] A round bottomed flask was charged with tert-butyl (S)-6-(6-((3-hydroxy-3-methylbutan-2-yl)oxy)pyrazolo[l,5-a]pyrimidin-3-yl)-2,4-dimethoxynicotinate (1 eq., 2 g, 4.43 mmol) and dry dichloromethane (10 mb) and sealed with an oil bubbler. The resulting solution was cooled in an ice bath. Trifluoroacetic acid (30 eq., 10 mb, 135 mmol) was added to the cold solution. The reaction mixture was stirred at rt for 24h. Volatiles were removed via rotary evaporation. The residue was dissolved in DCM (20 mb), and then volatiles were removed via rotary evaporation to give (S)-6-(6-((3-hydroxy-3-methylbutan-2-yl)oxy)pyrazolo[l,5-a]pyrimidin-3-yl)-2,4-dimethoxynicotinic acid-2, 2, 2-trifluoroacetic acid salt Int 9 (2.28 g).

[0327] LCMS: MW (calcd): 402.4; m / z MW (obsd): 403.4 (M+H).1.17. Int 10Int 10 was prepared as for Int 5 using Int 1 and Int 2Example 2. Preparation of illustrative compounds of the invention.1. Compound 212.1.1. Step A

[0328] A RBF was charged with 6-bromo-8-methoxyisoquinoline (1 eq., 8 g, 33.6 mmol), 2,2,2-trifluoroethyl trifluoromethanesulfonate (1.05 eq., 4.5 mL, 35.3 mmol), acetonitrile (80 mL) and stirred at 80 °C for 2 days. The RM was left cooling down to rt, concentrated then reslurried in MTBE (5V, 85mL) at 0°C (cooled with an ice-bath). The suspension was left warmed to rt under stirring over the week-end.

[0329] Product was sticked on the flask so it was sonicated, MTBE (5V) was added and the suspension was left under vigorous stirring at rt. Red suspension was filtered and washed with MTBE. The obtained cake was dried under vacuum at 45°C, solubilized with EtOAc (50 mL) / MeOH (20 mL), then filtered on SiC>2 cake (30g) rinced with DCM and concentrated under reduced pressure to give 6-bromo-8-methoxy-2-(2,2,2-trifluoroethyl)isoquinolin-2-ium trifluoromethane sulfonate (7.7 g).

[0330] LCMS: MW (calcd): 319.9; m / z MW (obsd): 319.7- 321.7 (M+H).2.1.2. Step B

[0331] A rbf was charged with 6-bromo-8-methoxy-2-(2,2,2-trifluoroethyl)isoquinolin-2-ium trifluoromethane sulfonate (1 eq., 6.2 g, 13.2 mmol), anhydrous THF (60 mL), urea hydrogen peroxide (1.3 eq., 1.6 g, 17.14 mmol) and dbu (1.4 eq., 2.8 mL, 18.46 mmol). The RM was heated to 40 °C for 3h. Heating was stopped and RM was left cooled down to rt. Na2SOs 10% sol (30mL) was added to the RM then MTBE (50mL) was added. Aqueous layer was extracted with MTBE (20mL). Organic layers were combined, washed with NaCl 10% sol (30mL) and concentrated under reduced pressure and purified by column chromatography on SiO2 (cl 00g, dry loading (solubilization in THF)) using heptane / THF [100:0 to 70:30] as eluting system. Fractions with product were combined and concentrated under reduced pressure to give 6-bromo-8-methoxy-2-(2,2,2-trifluoroethyl)isoquinolin-l(2H)-one (2.55g).

[0332] LCMS: MW (calcd): 336.11; m / z MW (obsd): 336.0-338.1 (M+H).2.1.3. Step C

[0333] In a sealed tube under N2, 6-bromo-8-methoxy-2-(2,2,2-trifluoroethyl)isoquinolin-l(2H)-one (1 eq., 20 mg, 0.06 mmol) and SelectFluor (2 eq., 42 mg, 0.12 mmol) were degassed by 3 cycles vacuum / N2 then dissolved in dry MeCN (0.6 mL). The reaction mixture was stirred at 60 °C for 2.5 h The reaction mixture was cooled down to rt, evaporated to dryness and the obtained residue was purified by PrepLCMS (PrepA_50mL_55-70_8min). Fractions containing product were collected and solvent removed under reduced pressure to give 6-bromo-3,4,4-trifluoro-8-methoxy-2-(2,2,2-trifluoroethyl)-3,4-dihydroisoquinolin-l(2H)-one (4 mg).

[0334] LCMS: MW (calcd): 392.09; m / z MW (obsd): 392.2,- 394.1 (M+H).2.1.4. StepD

[0335] In a sealed tube, 4,4,5,5-tetraethyl-2-(4,4,5,5-tetraethyl-l,3,2-dioxaborolan-2-yl)-l,3,2-dioxaborolane (1.5 eq., 5.6 mg, 0.015 mmol), 6-bromo-3,4,4-trifluoro-8-methoxy-2-(2,2,2-trifluoroethyl)-3,4-dihydroisoquinolin-l(2H)-one (1 eq., 4 mg, 0.0102 mmol), potassium pivalate (2.8 eq., 4 mg, 0.028 mmol) and XPhos Pd G4 (0.06 eq., 0.5 mg, 0.0006 mmol) were degassed by 3 cycles vacuum / N2 and dissolved in dioxane (0.14 mb). The heterogenous reaction mixture was degassed by N2 bubbling for 5 min and stirred at 80°C for 1 h After cooling down to rt, the reaction mixture was diluted with EtOAc, filtered and the filtrate was evaporated under reduced pressure to afford 3,4,4-trifluoro-8-methoxy-6-(4,4,5,5-tetraethyl-l,3,2-dioxaborolan-2-yl)-2-(2,2,2-trifluoroethyl)-3,4-dihydroisoquinolin-l(2H)-one (5 mg) that was used without further purification.

[0336] LCMS: MW (calcd): 495.3; m / z MW (obsd): 496.4 (M+H).2.1.5. Step E

[0337] In a sealed tube, (S)-3-((3-bromopyrazolo[l,5-a]pyridin-6-yl)oxy)-2-methylbutan-2-ol (Int-1) (1.034 eq., 3.12 mg, 0.0104 mmol), 3,4,4-trifluoro-8-methoxy-6-(4,4,5,5-tetraethyl-l,3,2-dioxaborolan-2-yl)-2-(2,2,2-trifluoroethyl)-3,4-dihydroisoquinolin-l(2H)-one (1 eq., 5 mg, 0.0101 mmol), K3PO4 (2.99 eq., 6.4 mg, 0.0302 mmol) and SPhos Pd G4 (0.099 eq., 0.8 mg, 0.001 mmol) were dissolved in water (0.02 mL) and dioxane (0.1 mL). The reaction mixture was degassed by N2 bubbling for 10 min and heated at 70 °C for 60 min. After being cooled down to rt, the reaction mixture was diluted with EtOAc, filtered on a Celite pad and the filtrate was evaporated under reduced pressure and purified by PrepHPLC (PrepA_50mL_55-70_8min). Fractions containing product were collected and solvent removed under reduced pressure to give (S)-3,4,4-trifluoro-6-{6-[(S)-2-hydroxy-l,2-dimethylpropoxy]-l,7a-diaza-3-indenyl}-8-methoxy-2-(2,2,2-trifluoroethyl)-3,4-dihydro-l(2H)-isoquinolinone (1.6 mg) Cpd 21

[0338] LCMS: MW (calcd): 531.5; m / z MW (obsd): 532.5 (M+H)..2. Compound 322.2.1. Step A

[0339] A round bottomed flask was charged with (S)-6-(6-((3-hydroxy-3-methylbutan-2-yl)oxy)pyrazolo[l,5-a]pyrimidin-3-yl)-2,4-dimethoxynicotinic acid-2, 2, 2-trifluoroacetic acid salt Int 5 (1 eq., 80 mg, 0.15 mmol), HATU (1.5 eq., 88 mg, 0.23 mmol), dry DMF (2 mL) and diisopropylethylamine (10 eq., 0.27 mL, 1.55 mmol) and sealed with a septum. After 30 minutes, tert -butyl N-[(lR,2S)-2-aminocyclobutyl] carbamate CAS#1932344-68-7 (1 eq., 28.85 mg, 0.15 mmol) was added and the reaction mixture was stirred at rt for 64 hours. The mixture was combined with CHCL (50 mL), n-butanol (5 mL) and an aqueous KH2PO4 / K2HPO4 buffer (pH 7, IM, 50 mL) and agitated. The organic phase was collected, washed with water (3 x 50 mL) and brine (50 mL) and dried over MgSCfi. After filtration, volatiles were removed from the filtrate via rotary evaporation. The residue was charged onto a column of silica gel (25 g) and eluted with a gradient of CfLCL / McOH (1:0 to 9: 1). Fractions containing product were pooled, and the solvent was removed via rotary evaporation to give tert-butyl ((lR,2S)-2-(6-(6-(((S)-3-hydroxy-3-methylbutan-2-yl)oxy)pyrazolo[l,5-a]pyrimidin-3-yl)-2,4-dimethoxynicotinamido)cyclobutyl)carbamate (57 mg).

[0340] LCMS: MW (calcd): 570.7; m / z MW (obsd): 571.4 (M+H).2.2.2. StepB

[0341] A round botomed flask was charged with tert-butyl ((lR,2S)-2-(6-(6-(((S)-3-hydroxy-3-methylbutan-2-yl)oxy)pyrazolo[l,5-a]pyrimidin-3-yl)-2,4-dimethoxynicotinamido)cyclobutyl)carbamate (1 eq., 52 mg, 0.091 mmol) and dichloromethane (4 mL) and sealed with an oil bubbler. To the resulting solution was added trifluoroacetic acid (590 eq., 4 mL, 53.85 mmol). After 16 hours, the volatiles were removed via rotary evaporation. The mixture was combined with CHCL (50 mL), n-BuOH (5 mL) and an aqueous l^COs / NaHCOs buffer (pH 10, 0.57M, 50 mL) in a separatory funnel and agitated. The organic phase was collected, washed with brine (50 mL) and dried over MgSCL. After filtration, volatiles were removed from the filtrate via rotary evaporation. The residue was charged onto a column of silica gel (10 g) and eluted with a gradient of CfLCL / McOH ( 1 : 0 to 7: 3) . Fractions containing product were pooled, and the solvent was removed via rotary evaporation to give N-((lS,2R)-2-aminocyclobutyl)-6-(6-(((S)-3-hydroxy-3-methylbutan-2-yl)oxy)pyrazolo[l,5-a]pyrimidin-3-yl)-2,4-dimethoxynicotinamide Cpd 32 (25 mg).

[0342] LCMS: MW (calcd): 470.5; m / z MW (obsd): 471.5 (M+H).2.2.3. Compound 442.2.4. Step A

[0343] A vial was charged with (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 eq., 120 mg, 0.3 mmol), 2-bromo-5-iodo-l,3-dimethoxybenzene (1.1 eq., 112 mg, 0.33 mmol), SPHOS PdG4 (0.1 eq., 24 mg, 0.03 mmol), K3PO4 (2 eq., 126 mg, 0.6 mmol), and degassed with Argon. Anhydrous degassed (bubbling Nitrogen for 15min) dioxane (3 mL) and water (0.7 mL) were added at rt and RM was degassed through vacuum / Argon cycles 4 times,kept under Argon atmosphere. Then RM was heated at 60°C (preheated oil bath >60°C) under argon atmosphere. After 1H, he reaction mixture was filtered through a pad of celite and solid was rinced with EtOAc, the filtrate was washed twice with water, and with brine, dried over anhydrous MgSCL, filtered and concentrated under vaccum to afford a yellow oil. The crude material was then purified by column chromatography (Sfar HC 25g, elution with DCM / AcOEt-EtOH (3 / 1) 100 to 98 / 2 over 5 cv then isocratic for 5 CV then 98 / 2 to 95 / 5 over 7 CV then isocratic for 8 CV ) to give (S)-3-((3-(4-bromo-3,5-dimethoxyphenyl)pyrazolo[l,5-a]pyrimidin-6-yl)oxy)-2-methylbutan-2-ol. (72 mg)

[0344] MW (calcd):436.3 m / z MW (obsd):436.3-438.3 (M+l)2.2.5. Step B

[0345] A vial was charged with give (S)-3-((3-(4-bromo-3,5-dimethoxyphenyl)pyrazolo[l,5-a]pyrimidin-6-yl)oxy)-2-methylbutan-2-ol. (1 eq., 80 mg, 0.18 mmol), tert-butyl N-[5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l,3-thiazol-2-yl]carbamate (1.1 eq., 65.8 mg, 0.202 mmol), XPhosPdG3 (0.1 eq., 15.5 mg, 0.018 mmol), K3PO4 (2 eq., 77.8 mg, 0.37 mmol), and degassed with Argon. Anhydrous degassed (bubbling Nitrogen for 15min) dioxane (1.8 mL) and water (0.5 mL) were added at rt and RM was degassed through vacuum / Argon cycles 4 times, kept under Argon atmosphere.

[0346] Then RM was heated at 80°C (preheated oil bath >80°C) under argon atmosphere. After 1H, 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 MgSO4, filtered and concentrated under vaccum to afford an yellow oil. The crude material was then purified by column chromatography (Claricep 12g, elution with DCM / AcOEt-EtOH (3 / 1) 100 to 60 / 40 over 20 CV)) to give tert-butyl (S)-(5-(4-(6-((3-hydroxy-3-methylbutan-2-yl)oxy)pyrazolo[l,5-a]pyrimidin-3-yl)-2,6-dimethoxyphenyl)thiazol-2-yl)carbamate. (33 mg)

[0347] MW (calcd):555.6 m / z MW (obsd): 556.2 (M+l)2.2.6. Step C

[0348] A RBF was charged under nitrogen with give tert-butyl (S)-(5-(4-(6-((3-hydroxy-3-methylbutan-2-yl)oxy)pyrazolo[l,5-a]pyrimidin-3-yl)-2,6-dimethoxyphenyl)thiazol-2-yl)carbamate (1 eq., 25 mg, 0.045 mmol) and HC14N dioxane (10 eq., 0.11 mL, 0.45 mmol) in DCM (0.303 mL). Then RM was stirred at RT for 70h. To the reaction mixture 10 ml of a K2CO3 solutionl0% mass and 10 ml of water was added and mixture was stirred to RT for 10 min. The resulting mixture was extracted with DCM (10ml), the two phases were separated and the aqueous phase was further extracted with DCM (2 times* 10 mL). The combined organic phase was washed with brine, dried over MgSC and concentrated under reducedpressure to afford the desired compound (S)-3-{3-[4-(2-amino-l,3-thiazol-5-yl)-3,5-dimethoxyphenyl]- l,4,7a-triaza-6-indenyloxy}-2-methyl-2-butanol. (19 mg, Cpd 44)

[0349] MW (calc) 455.5 m / z MW (obsd): 456.4 (M+l)2.3. Compound 46Same method used as for Cpd 44 starting from tert-butyl (3-bromopyridin-2-yl)carbamate CAS# 149489- .4. Compound 59.5. Step A

[0350] In a sealed tube under N2, 4,4,5,5-tetraethyl-2-(4,4,5,5-tetraethyl-l,3,2-dioxaborolan-2-yl)-l,3,2-dioxaborolane (1.5 eq., 556 mg, 1.52 mmol), (S)-3-((3-(4-bromo-3,5-dimethoxyphenyl)pyrazolo[l,5-a]pyrimidin-6-yl)oxy)-2-methylbutan-2-ol. (1 eq., 442 mg, 1.013 mmol), palladium diacetate (0.1 eq., 22.7 mg, 0.101 mmol), tris(4-methoxy-3,5-dimethylphenyl)phosphane (0.2 eq., 88 mg, 0.203 mmol) and cesium carbonate (3 eq., 990 mg, 3.04 mmol) were dissolved in degassed EtOAc (5 mb). The reaction mixture was degassed by N2 bubbling for 5 min and stirred at 80 °C for 1.5 The mixture was filtered through on a pad of celite washed with EtOAc. The filtrate was evaporated under reduced pressure to afford a brown was that was purified by normal phase preparative LC (Sfar Silica Gel HC D 20 pm, 25 g Biotage, liquid loading (DCM), mobile phase gradient: Heptanes / (EtOAc / EtOH 3:1) 100 / 0 to 60 / 40 over 3 CV then 60 / 40 to 40 / 60 over 8 CV). Fractions containing product were collected and solvent removed under reduced pressure to give (S)-3-((3-(3,5-dimethoxy-4-(4,4,5,5-tetraethyl-l,3,2-dioxaborolan-2-yl)phenyl)pyrazolo[l,5-a]pyrimidin-6-yl)oxy)-2-methylbutan-2-ol (648.2 mg).

[0351] MW (calc) 539.48m / z MW (obsd): 540.6 (M+l).6. Step B

[0352] In a sealed tube, 5-bromo-l,3-dimethyl-l,2,3,4-tetrahydropyrimidine-2,4-dione (1.5 eq., 22 mg, 0.101 mmol), (S)-3-((3-(3,5-dimethoxy-4-(4,4,5,5-tetraethyl-l,3,2-dioxaborolan-2-yl)phenyl)pyrazolo[l,5-a]pyrimidin-6-yl)oxy)-2-methylbutan-2-ol (1 eq., 50 mg, 0.068 mmol), K3PO4 (3 eq., 43 mg, 0.203 mmol) was charged and degassed with Argon . Anhydrous degassed (bubbling Nitrogen for 15min) Dioxane (0.7 mb) and water (0.2 mb) were added at rt and RM was degassed through vacuum / Argon cycles 4 times, kept under Argon atmosphere (balloon). XPhos Pd G3 (0.1 eq., 5.7 mg, 0.0068 mmol) was added. RM was degassed through vacuum / Argon cycles 3 times, kept under Argon atmosphere (balloon) and stirred at 90°C overnight. The reaction mixture was cooled down to rt, diluted with EtOAc and filtered on a Celite Pad. The filtrate was evaporated under reduced pressure. The crude sample wasdissolved in DMSO and submited to preparative purification. The crude product was then purified by HPLC PREP in acid method (PrepA_50mL_35-50_8min) to give 5-(4-{6-[(S)-2-hydroxy-l,2-dimethylpropoxy] - 1 ,4,7a-triaza-3-indenyl} -2,6-dimethoxyphenyl)- 1 ,3 -dimethyl -2, 4( 1H,3H)-pyrimidinedione (17 mg) Cpd 59.

[0353] MW (calcd):495.5 m / z MW (obsd): 496.0 (M+l)Compound 62

[0354] A round botomed flask was charged with (S)-6-(6-((3-hydroxy-3-methylbutan-2-yl)oxy)pyrazolo[l,5-a]pyrimidin-3-yl)-2,4-dimethoxynicotinic acid-2, 2, 2-trifluoroacetic acid salt Int 9 (1 eq., 40 mg, 0.077 mmol), HATU (1.5 eq., 44 mg, 0.12 mmol), dry DMF (1 mL) and diisopropylethylamine (10 eq., 0.13 mL, 0.77 mmol) and sealed with a septum. After 30 minutes, (lR,2S)-2-fluorocyclopropan-1-amine; 4 -methylbenzene -1 -sulfonic acid CAS# 143062-84-4 (2 eq., 39 mg, 0.16 mmol) was added and the reaction mixture was stirred at rt for 18 hours. The mixture was combined with CHC13 (10 mL), n-butanol (1 mL) and an aqueous KH2PO4 / K2HPO4 buffer (pH 7, IM, 10 mL) and agitated. The organic phase was collected, and volatiles were removed via rotary evaporation. The residue was charged onto a column of silica gel (10 g) and eluted with a gradient of CtLCL / McOH (1:0 to 9:1). Fractions containing product were pooled, and the solvent was removed via rotary evaporation to give N-[(lR,2S)-2-fluorocyclopropyl] -6- { 6 - [ ( S ) -2 -hydroxy- 1 ,2-dimethylpropoxy] - 1 ,4,7a-triaza-3 -indenyl } -2,4-dimethoxynicotinamide (20 mg) Cpd 62.

[0355] LCMS: MW (calcd): 459.4; m / z MW (obsd): 460.4 (M+H)..7. Compound 1172.7.1. Step A

[0356] In a sealed tube, 4-bromo-l-(oxan-2-yl)-lH-pyrazole (1.5 eq., 19.9 mg, 0.086 mmol), (S)-3-((3-(3,5-dimethoxy-4-(4,4,5,5-tetraethyl-l,3,2-dioxaborolan-2-yl)phenyl)pyrazolo[l,5-a]pyrimidin-6-yl)oxy)-2-methylbutan-2-ol Int 8 (1 eq., 42.4 mg, 0.057 mmol), K3PO4 (3 eq., 36.5 mg, 0.17 mmol) and XPhos Pd G3 (0.1 eq., 4.9 mg, 0.0057 mmol) were dissolved in Dioxane (0.6 mL) and water (0.14 mL). The reaction mixture was degassed by N2 bubbling for 2 min and heated at 90 °C for 2 h. The reaction mixture was cooled down to rt, diluted with EtOAc and filtered on a Celite Pad. The filtrate was evaporated underreduced pressure and directly purified by PrepHPLC (PrepB_50mL_45-65_8min). Fractions containing product were collected and solvent removed under reduced pressure to give (3S)-3-((3-(3,5-dimethoxy-4-(l-(tetrahydro-2H-pyran-2-yl)-lH-pyrazol-4-yl)phenyl)pyrazolo[l,5-a]pyrimidin-6-yl)oxy)-2-methylbutan-2-ol (11.7 mg) .

[0357] MW (calcd): 507.59 m / z MW (obsd): 508.4 (M+l)2.7.2. Step B

[0358] In a tube, (3S)-3-((3-(3,5-dimethoxy-4-(l-(tetrahydro-2H-pyran-2-yl)-lH-pyrazol-4-yl)phenyl)pyrazolo[l,5-a]pyrimidin-6-yl)oxy)-2-methylbutan-2-ol (1 eq., 10 mg, 0.02 mmol) was dissolved in 0.5 mb of HC1 (4M in dioxane) and stirred for 4 h at rt. Then, DCM (1 mb) was added and additional 0.5 mb of HC1 (4M in dioxane) was added. The reaction mixture was stirred at rt overnight. The reaction mixture was evaporated to dryness and taken-up in TFA (0.5 mb) and DCM (1 mb) and stirred at rt over 2 days. The reaction mixture was evaporated to dryness and the obtained yellow residue 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% NFUOH 20% / MeCN + 0.1% NH40H 20% from 90: 10 to 0: 100 over 10 CV). The fractions containing compound were combined and evaporated in vacuo to give (S)-3-((3-(3,5-dimethoxy-4-(lH-pyrazol-4-yl)phenyl)pyrazolo[l,5-a]pyrimidin-6-yl)oxy)-2-methylbutan-2-ol (4.3 mg) Cpd 117.

[0359] MW (calcd): 423.5 m / z MW (obsd): 424.4 (M+l).8. Compound 130HOA^O^N,N~~oyT V~NH0C TZ y-FF

[0360] A round bottomed flask was charged with (S)-6-(6-((3-hydroxy-3-methylbutan-2-yl)oxy)pyrazolo[l,5-a]pyrimidin-3-yl)-2,4-dimethoxynicotinic acid-2, 2, 2-trifluoroacetic acid salt Int 5 (1 eq., 40 mg, 0.077 mmol), HATU (1.5 eq., 44 mg, 0.12 mmol), dry DMF (1 mb) and diisopropylethylamine (10 eq., 0.13 mb, 0.77 mmol) and sealed with a septum. After 30 minutes, (2S)-l,l,l-trifluoropropan-2-amine hydrochloride CAS# 125278-10-6 (2.5 eq., 29 mg, 0.2 mmol) was added and the reaction mixture was stirred at rt for 15 hours. The mixture was combined with CHCh (10 mb), n-butanol (1 mb) and an aqueous KH2PO4 / K2HPO4 buffer (pH 7, IM, 10 mb) and agitated. The organic phase was collected, and volatiles were removed via rotary evaporation. The residue was purified via preparative LC-MS (PrepA_50mL_45-60_8min) to give N-[(S)-2,2,2-trifluoro-l-methylethyl]-6-{6-[(S)-2-hydroxy-l,2-dimethylpropoxy]-l,4,7a-triaza-3-indenyl}-2,4-dimethoxynicotinamide (27 mg) Cpd 130.

[0361] LCMS: MW (calcd): 497.5; m / z MW (obsd): 498.4 (M+H)..9. Compound 131

[0362] A round botomed flask was charged with (S)-6-(6-((3-hydroxy-3-methylbutan-2-yl)oxy)pyrazolo[l,5-a]pyrimidin-3-yl)-2,4-dimethoxynicotinic acid-2, 2, 2-trifluoroacetic acid salt Int 5 (1 eq., 40 mg, 0.077 mmol), HATU (1.5 eq., 44 mg, 0.12 mmol), dry DMF (1 mL) and diisopropylethylamine (10 eq., 0.13 mL, 0.77 mmol) and sealed with a septum. After 30 minutes, (lR,2R)-2-fluorocyclopropan-1-amine hydrochloride CAS# 1314933-35-1 (2.1 eq., 18 mg, 0.16 mmol) was added and the reaction mixture was stirred at rt for 15 hours. The mixture was combined with CHCL (10 mL), n-butanol (1 mL) and an aqueous KH2PO4 / K2HPO4 buffer (pH 7, IM, 10 mL) and agitated. The organic phase was collected, and volatiles were removed via rotary evaporation. The residue was purified via preparative LC-MS (PrepA_50mL_35-50_8min) to give N-[(lR,2R)-2-fluorocyclopropyl]-6-{6-[(S)-2-hydroxy-l,2-dimethylpropoxy]-l,4,7a-triaza-3-indenyl}-2,4-dimethoxynicotinamide (14 mg) Cpd 131.

[0363] LCMS: MW (calcd): 459.5; m / z MW (obsd): 460.4 (M+H).

[0364] 1H NMR (400 MHz, DMSO) 59.07 (d, J= 2.7 Hz, 1H), 8.70 (s, 1H), 8.68 (d, J= 2.7 Hz, 1H), 8.23 (dd, J= 4.4, 1.9 Hz, 1H), 7.75 (s, 1H), 4.64 (dddd, J= 62.7, 6.8, 3.2, 1.3 Hz, 1H), 4.62 (s, 1H), 4.31 (q, J= 6.2 Hz, 1H), 3.94 (s, 3H), 3.89 (s, 3H), 3.22 - 3.08 (m, 1H), 1.35 (dddd, J= 24.3, 10.6, 7.8, 3.2 Hz, 1H), 1.27 (d, J = 6.3 Hz, 3H), 1.20 (s, 3H), 1.18 (s, 3H), 0.92 (ddt,J= 11.9, 7.4, 6.2 Hz, 1H)..10. Compound 132

[0365] A round botomed flask was charged with (S)-6-(6-((3-hydroxy-3-methylbutan-2-yl)oxy)pyrazolo[l,5-a]pyrimidin-3-yl)-2,4-dimethoxynicotinic acid-2, 2, 2-trifluoroacetic acid salt Int 5 (1 eq., 40 mg, 0.077 mmol), HATU (1.5 eq., 44 mg, 0.12 mmol), dry DMF (1 mL) and diisopropylethylamine (10 eq., 0.13 mL, 0.77 mmol) and sealed with a septum. After 30 minutes, (R,R)-l,2-diaminocyclohexane CAS# 20439-47-8 (6.9 eq., 0.064 mL, 0.53 mmol) was added and the reaction mixture was stirred at rt for 15 hours. The mixture was combined with CHCL (10 mL), n-butanol (1 mL) and an aqueous KH2PO4 / K2HPO4 buffer (pH 7, IM, 10 mL) and agitated. The organic phase was collected, and volatiles were removed via rotary evaporation. The residue was purified via preparative LC-MS (PrepA_50mL_25-40_8min) to give N-[rel-(lR,2R)-2-aminocyclohexyl]-6-{6-[(S)-2-hydroxy-l,2-dimethylpropoxy]-l,4,7a-triaza-3-indenyl}-2,4-dimethoxynicotinamide (10 mg) Cpd 132.

[0366] LCMS: MW (calcd): 498.6; m / z MW (obsd): 499.4 (M+H).

[0367] ’HNMR (400 MHz, DMSO) 59.09 (d, J= 2.7 Hz, 1H), 8.73 (s, 1H), 8.68 (d, J= 2.7 Hz, 1H), 8.15 - 8.06 (m, 1H), 7.80 (s, 1H), 7.70 (s, 2H), 4.62 (s, 1H), 4.32 (q, J= 6.2 Hz, 1H), 3.97 (s, 3H), 3.92 (s, 3H), 3.88 - 3.77 (m, 1H), 3.04 - 2.91 (m, 1H), 2.08 - 1.90 (m, 2H), 1.71 (d, J= 7.5 Hz, 2H), 1.49 - 1.23 (m, 4H), 1.27 (d, J= 6.3 Hz, 3H), 1.21 (s, 3H), 1.18 (s, 3H).2.10.1. Compound 172

[0368] A round botomed flask was charged with (S)-6-(6-((3-hydroxy-3-methylbutan-2-yl)oxy)pyrazolo[l,5-a]pyrimidin-3-yl)-2,4-dimethoxynicotinic acid-2, 2, 2-trifluoroacetic acid salt Int 5 (1 eq., 40 mg, 0.077 mmol), HATU (1.5 eq., 44 mg, 0.12 mmol) , dry DMF (1 mb) and diisopropylethylamine (10 eq., 0.13 mL, 0.77 mmol) and sealed with a septum. After 30 minutes, 3 -fluoroazetidine hydrochloride CAS# 617718-46-4 (2 eq., 17.28 mg, 0.15 mmol) was added and the reaction mixture was stirred at rt for 64 hours. The mixture was combined with CHCL (10 mL), n-butanol (1 mL) and an aqueous KH2PO4 / K2HPO4 buffer (pH 7, IM, 10 mL) and agitated. The organic phase was collected, and volatiles were removed via rotary evaporation. The residue was charged onto a column of silica gel (25 g) and eluted with a gradient of CFLCL / McOH (1:0 to 20: 1). fractions containing product were pooled, and the solvent was removed via rotary evaporation to give (3-fluoro-l-azetidinyl)(6-{6-[(S)-2-hydroxy-l,2-dimethylpropoxy]-l,4,7a-triaza-3-indenyl}-2,4-dimethoxy-3-pyridyl)methanone (30 mg) Cpd 172.

[0369] LCMS: MW (calcd): 459.5; m / z MW (obsd): 460.5 (M+H).

[0370] ’HNMR (400 MHz, CDCh) 58.72 (s, 1H), 8.52 (d, J= 2.7 Hz, 1H), 8.40 (d, J= 2.7 Hz, 1H), 7.80 (s, 1H), 5.50 - 5.23 (m, 1H), 4.55 - 4.41 (m, 1H), 4.36 - 4.07 (m, 4H), 4.05 (s, 3H), 4.00 (s, 3H), 2.14 (s, 1H), 1.38 - 1.32 (m, 9H)..11. Compound 173, 174, 175, 176, 212, 213, 214, 215, 215, 217.

[0371] Same method used as Compound 172.12. Compound 1822.12.1. Step A

[0372] A round botomed flask was charged with diisopropylamine (1.11 eq., 13.7 mL, 96.94 mmol) and dry THF (100 mL) and sealed with a septum. The flask was evacuated and refilled with Nitrogen twice and left under an atmosphere of nitrogen. The flask was cooled in a dry ice / EtOH bath at -78 °C, and n-BuLi (1.10 eq., 38.5 mL, 96.25 mmol) was added to the cold solution. After 10 minutes, a dry THF (10 mL) solution of 2,4-difluoropyridine CAS#34941-90-7 (1 eq., 10.01 g, 87.02 mmol) was added via syringe. After 20 minutes, a dry THF solution (55 mL) of BOC2O (1.23 eq., 23.30 g, 22.84 mL, 106.76 mmol) was added via an addition funnel over a period of 15 minutes. The dry ice / EtOH bath was removed and the reaction mixture was left under stirring at rt overnight. An aqueous KH2PO4 / K2HPO4 buffer (pH 7, IM, 200 mL) was added. The mixture was combined with EtOAc (500 mL) and water (300 mL) in a separatory funnel and agitated. The organic phase was collected, washed with brine (500 mL) and dried over MgSC After filtration, volatiles were removed from the filtrate via rotary evaporation. The residue was charged onto a column of silica gel (350 g) and eluted with a gradient of heptane / EtOAc (1:0 to 9:1). Fractions containing product were pooled, and the solvent was removed via rotary evaporation to give tert-butyl 2,4-difluoronicotinate (14,22 g).

[0373] LCMS: MW (calcd): 215.2; m / z MW (obsd): 216.1 (M+H)..13. Step B

[0374] A round botomed flask was charged potassium tert-butoxide (1.30 eq., 1.7 g, 15.2 mmol) and dry THF (50 mL) and sealed with a septum. The flask was evacuated and refilled with nitrogen twice and was left under an atmosphere of nitrogen. The reaction mixture was cooled in a dry ice / EtOH bath at -78 °C. To the cold solution was added a dry THF solution (4 mL) of benzyl alcohol CAS#100-51-6 (1.31 eq., 1.6 mL, 15.2 mmol). A THF solution (4 mL) of tert-butyl 2,4-difluoronicotinate (1 eq., 2.5 g, 11.6 mmol) was added dropwise via syringe pump over a period of 15 minutes. After 20 minutes the flask was transferred to a cryostat bath at -40 °C. After 3.5 hours the cryostat bath was raised to -20 °C. After 16 hours, acetic acid (2 mL) was added, and the cold bath was removed. The mixture was combined with EtOAc (250 mL), an aqueous KH2PO4 / K2HPO4 buffer (pH 7, IM, 80 mL) and water (170 mL) in a separatory funnel and agitated. The organic phase was collected, washed with brine (250 mL) and dried over MgSO4. Afterfiltration, volatiles were removed from the filtrate via rotary evaporation. The residue was charged onto a column of silica gel (100 g) and eluted with a gradient of heptane / EtO Ac (1:0 to 1:1). Fractions containing product were pooled, and the solvent was removed via rotary evaporation to give tert-butyl 4-(benzyloxy)-2 -fluoronicotinate (1.6 g). The impure fractions of product were pooled, and the solvent was removed via rotary evaporation. The residue was charged onto a column of silica gel (100 g) and eluted with a gradient of hcptanc / CFECF (1:0 to 0: 1). Fraction containing product were pooled, and the solvent was removed via rotary evaporation to give tert-butyl 4-(benzyloxy)-2 -fluoronicotinate (1 g) . The two batches of tert-butyl 4-(benzyloxy)-2-fluoronicotinate were combined to give tert-butyl 4-(benzyloxy)-2-fluoronicotinate (2.6 g)-

[0375] LCMS: MW (calcd): 303.3; m / z MW (obsd): 304.1 (M+H).2.13.1. Step C

[0376] A round bottomed flask was charged with potassium tert-butoxide (1.52 eq., 1.48 g, 13.2 mmol) and dry methanol (8 m ), sealed with a septum and cooled in an ice bath. To the cold solution was added a MeOH solution (4 m ) of tert-butyl 4-(benzyloxy)-2 -fluoronicotinate (1 eq., 2.6 g, 8.67 mmol), and the cold bath was removed. After 3 hours, the mixture was combined with EtOAc (250 mb) and an aqueous KH2PO4 / K2HPO4 buffer (pH 7, IM, 250 mb) in a separatory funnel and agitated. The organic phase was collected, washed with brine (250 mb) and dried over MgSC After filtration, volatiles were removed from the filtrate via rotary evaporation. The residue was charged onto a column of silica gel (200 g) and eluted with a gradient of heptane / EtO Ac (1:0 to 3:2). Fractions containing product were pooled, and the solvent was removed via rotary evaporation to give tert-butyl 4-(benzyloxy)-2 -methoxynicotinate (2.18 g) .

[0377] ECMS: MW (calcd): 315.4; m / z MW (obsd): 316.1 (M+H).2.13.2. StepD

[0378] A round bottomed flask was charged with tert-butyl 4-(benzyloxy)-2-methoxynicotinate (1 eq., 2 g, 6.55 mmol), palladium hydroxide (0.05 eq., 457 mg, 0.33 mmol) and methanol (20 mb) and sealed with a septum. The round bottomed flask was evacuated and refilled with Hydrogen twice and was left under an atmosphere of hydrogen. After 71 hours, the mixture was filtered through a plug of celite. Volatiles were removed from the filtrate via rotary evaporation to give tert-butyl 4-hydroxy-2 -methoxynicotinate (1.5 g) .

[0379] ECMS: MW (calcd): 225.2; m / z MW (obsd): 226.3 (M+H).2.13.3. StepE

[0380] A round bottomed flask was charged with tert-butyl 4-hydroxy-2 -methoxynicotinate (1 eq., 1.5 g, 6.65 mmol) and acetonitrile (30 mb), sealed with a septum and cooled in a cryostat bath at -30 °C. After 15 minutes, the solution had partially solidified. A solution of potassium hydroxide (16.1 eq., 6 g, 107 mmol) in water (20 mb) was added which melted all of the solid in the flask. After 15 minutes, diethyl (bromodifluoromethyl)phosphonate CAS#65094-22-6 (4 eq., 4.7 mb, 26.5 mmol) was added. After 30 minutes, the cyrostat bath was removed. The reaction mixture was stirred at rt for 17 h. The mixture was combined with EtOAc (150 mb) and water (250 mb) in a separatory funnel and agitated. The organic phasewas collected, washed with brine (250 mL) and dried over MgSCL. After fdtration, volatiles were removed from the filtrate via rotary evaporation. The residue was charged onto a column of silica gel (100 g) and eluted with a gradient of heptane / EtOAc (1:0 to 7:3). Fractions containing product were pooled, and the solvent was removed via rotary evaporation to give tert-butyl 4-(difluoromethoxy)-2 -methoxynicotinate (1-l g) .

[0381] LCMS: MW (calcd): 275.3; m / z MW (obsd): 276.2 (M+H).2.13.4. Step F

[0382] A round bottomed flask was charged with tert-butyl 4-(difluoromethoxy)-2 -methoxynicotinate (1 eq., 937 mg, 3.41 mmol), (l,5-Cyclooctadiene)(methoxy)iridium(I) dimer (0.05 eq., 113 mg, 0.17 mmol), 3,4,7,8-tetramethyl-l,10-phenanthroline (0.1 eq., 80.5 mg, 0.34 mmol), 4,4,5,5-tetraethyl-2-(4,4,5,5-tetraethyl-l,3,2-dioxaborolan-2-yl)-l,3,2-dioxaborolane CAS# 2247367-07-1 (1.5 eq., 1.87 g, 5.11 mmol) and degassed heptane (10 mL), equipped with a reflux condenser, sealed with an oil bubbler under an atmosphere of nitrogen and heated to 80 °C for 18 hours. The mixture was allowed to cool to room temperature and volatiles were removed via rotary evaporation. The crude reaction mixture was charged onto a column of silica gel (100 g) and eluted with a gradient of heptane / EtOAc (1:0 to 3:1). Fractions containing product were pooled, and the solvent was removed via rotary evaporation to give tert-butyl 4-(difluoromethoxy)-2-methoxy-6-(4,4,5,5-tetraethyl-l,3,2-dioxaborolan-2-yl)nicotinate as impure viscous pale brown oil. The impure product was charged onto a column of Sfar amino Duo D silica gel (220 g) and eluted with a gradient of heptane / acetone (1:0 to 2:3). Fractions containing product were pooled and the solvent was removed via rotary evaporation to give tert-butyl 4-(difluoromethoxy)-2-methoxy-6-(4, 4,5,5-tetraethyl-l,3,2-dioxaborolan-2-yl)nicotinate (382 mg) .

[0383] LCMS: MW (calcd): 457.3; m / z MW (obsd): 458.3 (M+H)..14. Step G

[0384] A round bottomed flask was charged with (3S)-3-({3-bromopyrazolo[l,5-a]pyrimidin-6-yl}oxy)-2-methylbutan-2-ol Int-4 (1 eq., 128 mg, 0.42 mmol), tert-butyl 4-(difluoromethoxy)-2-methoxy-6-(4,4,5,5-tetraethyl-l,3,2-dioxaborolan-2-yl)nicotinate (1 eq., 191 mg, 0.42 mmol), SPhosPdG4 (0.05 eq., 17 mg, 0.021 mmol), potassium phosphate (2 eq., 178 mg, 0.84 mmol), toluene (2 mL) and water (0.2 mL), degassed by bubbling nitrogen through the mixture, sealed with a crimped cap under a nitrogen atmosphere and heated at 110 °C. After 3 hours, the mixture was allowed to cool to room temperature. The mixture was combined with CHCL (50 mL), n-BuOH (5 mL), and water (50 mL) in a separatory funnel and agitated. The organic phase was collected, washed with brine (50 mL) and dried over MgSC After fdtration, volatiles were removed from the fdtrate via rotary evaporation. The residue was charged onto a column of silica gel (25 g) and eluted with a gradient of QLCL / EtOAc ( 1 : 0 to 1 : 1 ) . Fractions containing product were pooled, and the solvent was removed via rotary evaporation to give tert-butyl (S)-4-(difluoromethoxy)-6-(6-((3 -hydroxy-3 -methylbutan-2-yl)oxy)pyrazolo [ 1 ,5 -a]pyrimidin-3 -yl)-2 -methoxynicotinate (127 mg) .

[0385] LCMS: MW (calcd): 494.5; m / z MW (obsd): 495.4 (M+H).2.14.1. Step H

[0386] A round botomed flask was charged with tert-butyl (S)-4-(difluoromethoxy)-6-(6-((3-hydroxy-3-methylbutan-2-yl)oxy)pyrazolo[l,5-a]pyrimidin-3-yl)-2-methoxynicotinate (1 eq., 127 mg, 0.26 mmol) and dry dioxane (4 mL). The resulting solution was cooled in an ice bath, and then hydrogen chloride in dioxane (62 eq., 4 mL, 16 mmol) was added. After 5 minutes, the cold bath was removed. After 1 hour, the volatiles were removed via rotary evaporation. The residue was dissolved in DCM, and then volatiles were removed via rotary evaporation to give (S)-4-(difluoromethoxy)-6-(6-((3-hydroxy-3-methylbutan-2-yl)oxy)pyrazolo[l,5-a]pyrimidin-3-yl)-2 -methoxynicotinic acid hydrochloride salt (111 mg) .

[0387] LCMS: MW (calcd): 438.4; m / z MW (obsd): 439.3 (M+H)..15. Step I

[0388] A round botomed flask was charged with (S)-4-(difluoromethoxy)-6-(6-((3-hydroxy-3-methylbutan-2-yl)oxy)pyrazolo[l,5-a]pyrimidin-3-yl)-2-methoxynicotinic acid hydrochloride salt (1 eq., 106 mg, 0.22 mmol), HATU (1.5 eq., 127 mg, 0.33 mmol), dry DMF (2.7 mL) and diisopropylethylamine (10 eq., 0.4 mL, 2.3 mmol) and sealed with a septum. After 30 minutes, (lR,2S)-2-fluorocyclopropan-l-amine; 4-methylbenzene-l -sulfonic acid CAS# 143062-84-4 (2 eq., 110 mg, 0.45 mmol) was added and the reaction mixture was stirred at rt for 4 hours. The mixture was combined with CHCL (50 mL), n-butanol (5 mL) and an aqueous KH2PO4 / K2HPO4 buffer (pH 7, IM, 50 mL) and agitated. The organic phase was collected, washed with H2O (3 x 50 mL) and brine (50 mL) and dried over MgSCL. After filtration, volatiles were removed from the filtrate via rotary evaporation. The residue was charged onto a column of silica gel (25 g) and eluted with a gradient of CtLCL / EtOAc (1 :0 to 0: 1). Fractions containing product were pooled, and the solvent was removed via rotary evaporation to give 4-(difluoromethoxy)-N-((lR,2S)-2-fluorocyclopropyl)-6-(6-(((S)-3-hydroxy-3-methylbutan-2-yl)oxy)pyrazolo[l,5-a]pyrimidin-3-yl)-2-methoxynicotinamide (84 mg) Cpd 182.

[0389] LCMS: MW (calcd): 495.5; m / z MW (obsd): 496.3 (M+H).Compound 1922.15.1. Step A

[0390] A round botomed flask was charged with diisopropylamine (1.11 eq., 13.7 mL, 96.94 mmol) and dry THF (100 mL) and sealed with a septum. The flask was evacuated and refilled with Nitrogen twice andleft under an atmosphere of nitrogen. The flask was cooled in a dry ice / EtOH bath at -78 °C, and n-BuLi (1.10 eq., 38.5 mL, 96.25 mmol) was added to the cold solution. After 10 minutes, a dry THF (10 mL) solution of 2,4-difluoropyridine CAS#34941-90-7 (1 eq., 10.01 g, 87.02 mmol) was added via syringe. After 20 minutes, a dry THF solution (55 mL) of Boc2O (1.23 eq., 23.30 g, 22.84 mL, 106.76 mmol) was added via an addition funnel over a period of 15 minutes. The dry ice / EtOH bath was removed and the reaction mixture was left under stirring at rt overnight. An aqueous KH2PO4 / K2HPO4 buffer (pH 7, IM, 200 mL) was added. The mixture was combined with EtOAc (500 mL) and water (300 mL) in a separatory funnel and agitated. The organic phase was collected, washed with brine (500 mL) and dried over MgSC After filtration, volatiles were removed from the filtrate via rotary evaporation. The residue was charged onto a column of silica gel (350 g) and eluted with a gradient of heptane / EtOAc (1:0 to 9:1). Fractions containing product were pooled, and the solvent was removed via rotary evaporation to give tert-butyl 2,4-difluoronicotinate (14,22 g) .

[0391] LCMS: MW (calcd): 215.2; m / z MW (obsd): 216.1 (M+H).2.15.2. Step B

[0392] A round bottomed flask was charged with potassium tert-butoxide (1.49 eq., 2.35 g, 20.94 mmol) and dry methanol (60 mL), sealed with a septum and cooled to -78 °C with a dry ice / ethanol bath. To the cooled solution was added a methanol solution (6 mL) of tert-butyl 2,4-difluoronicotinate (1 eq., 3.02 g, 14.02 mmol). After 10 minutes, the flask was transferred to a cryostat bath at -40 °C. The mixture was stirred at -40 °C for 20 h. The cryostat bath was raised to -20 °C. The mixture was stirred at -20 °C for 17 h. Acetic acid (2 mL) was added to the reaction mixture, and the cold bath was removed. The mixture was combined with EtOAc (250 mL), an aqueous KH2PO4 / K2HPO4 buffer (pH 7, IM, 80 mL) and H2O (170 mL) in a separatory funnel and agitated. The organic phase was collected, washed with brine (250 mL) and dried over MgSO4. After filtration, volatiles were removed from the filtrate via rotary evaporation. The residue was charged onto a column of silica gel (100 g) and eluted with a gradient of heptane / EtOAc (1:0 to 3:2). Fractions containing product were pooled, and the solvent was removed via rotary evaporation to give tert-butyl 2-fluoro-4-methoxynicotinate (2.80 g) as colorless oil.

[0393] LCMS: MW (calcd): 227.2; m / z MW (obsd): 228.2 (M+H).2.15.3. Step C

[0394] A round bottomed flask was charged with potassium tert-butoxide (1.30 eq., 1.24 g, 11.05 mmol) and dry THF (18 mL) and sealed with a septum. To the solution was added a dry THF solution (4 mL) of benzyl alcohol CAS#100-51-6 (1.22 eq., 1.08 mL, 10.38 mmol). After 10 minutes, a dry THF solution (4 mL) of tert-butyl 2-fluoro-4-methoxynicotinate (1 eq., 1.93 g, 8.48 mmol) was added. The flask was equipped with a reflux condenser, sealed with an oil bubbler and heated to 65 °C. The mixture was stirred at 65 °C for 16 h. The flask was allowed to cool to room temperature. The mixture was combined with EtOAc (100 mL), an aqueous KH2PO4 / K2HPO4 buffer (pH 7, IM, 40 mL) and water (60 mL) in a separatory funnel and agitated. The organic phase was collected, washed with brine (100 mL) and dried over MgSO4. After filtration, volatiles were removed from the filtrate via rotary evaporation. The residue was chargedonto a column of silica gel (100 g) and eluted with a gradient of heptane / EtOAc (1:0 to 7:3). Fractions containing product were pooled, and the solvent was removed via rotary evaporation to give tert-butyl 2-(benzyloxy)-4-methoxynicotinate (2.41 g) as colorless oil.

[0395] LCMS: MW (calcd): 315.4; m / z MW (obsd): 316.1 (M+H).2.15.4. StepD

[0396] A round bottomed flask was charged with tert-butyl 2-(benzyloxy)-4-methoxynicotinate (1 eq., 2.41 g, 7.63 mmol), palladium hydroxide (0.049 eq., 526 mg, 0.37 mmol) and methanol (40 mb) and sealed with a septum. The round bottomed flask was evacuated and refdled with Hydrogen twice and was left under an atmosphere of hydrogen. The reaction mixture was stirred for 17 h. The mixture was filtered through a plug of celite. Volatiles were removed from the filtrate via rotary evaporation to give tert-butyl 2-hydroxy-4-methoxynicotinate (1.72 g) .

[0397] LCMS: MW (calcd): 225.2; m / z MW (obsd): 170.1 (M+H-tBu).2.15.5. StepE

[0398] A round bottomed flask was charged with tert-butyl 2-hydroxy-4-methoxynicotinate (1 eq., 1.31 mg, 5.82 mmol) and acetonitrile (50 mL). The flask was cooled in an ice bath and a solution of potassium hydroxide (18.0 eq., 5.88 g, 105 mmol) in water (25 mL) was added. The flask was sealed with a septum and cooled in a cryostat bath at -20 °C. After 15 minutes, diethyl (bromodifluoromethyl)phosphonate CAS#65094-22-6 (5.80 eq., 6 mL, 33.8 mmol) was added. The reaction mixture was stirred for 6 hours. The cryostat bath was removed. The mixture was combined with EtOAc (100 mL) and H2O (100 mL) in a separatory funnel and agitated. The organic phase was collected, washed with brine (100 mL) and dried over MgSCL. After filtration, volatiles were removed from the filtrate via rotary evaporation. The residue was charged onto a column of silica gel (100 g) and eluted with a gradient of heptane / EtOAc (1:0 to 2:3). Fractions containing product were pooled, and the solvent was removed via rotary evaporation. The residue was charged onto a column of KP -amino phase (55 g) and eluted with a gradient of heptane / EtOAc (1:0 to 3:2). Fractions containing product were pooled, and the solvent was removed via rotary evaporation to give tert-butyl 2-(difluoromethoxy)-4-methoxynicotinate (510 mg) .

[0399] LCMS: MW (calcd): 275.3; m / z MW (obsd): 276.2 (M+H)..16. Step F

[0400] A round bottomed flask was charged with tert-butyl 2-(difluoromethoxy)-4-methoxynicotinate (1 eq., 500 mg, 1.82 mmol), (l,5-Cyclooctadiene)(methoxy)iridium(I) dimer (0.05 eq., 60 mg, 0.0908 mmol), 3,4,7,8-tetramethyl-l,10-phenanthroline (0.1 eq., 43 mg, 0.18 mmol), 4,4,5,5-tetraethyl-2-(4,4,5,5-tetraethyl-l,3,2-dioxaborolan-2-yl)-l,3,2-dioxaborolane CAS# 2247367-07-1 (1.1 eq., 731.65 mg, 2 mmol), and degassed heptane (10 mL), equipped with a reflux condenser, sealed with an oil bubbler under an atmosphere of nitrogen, and heated to 80 °C for 16 h. The mixture was allowed to cool to room temperature and volatiles were removed via rotary evaporation. The crude reaction mixture was charged onto a column of silica gel (100 g) and eluted with a gradient of heptane / EtOAc (1:0 to 1:1). Fractionscontaining product were pooled, and the solvent was removed via rotary evaporation to give tert-butyl 2-(difluoromethoxy)-4-methoxy-6-(4,4,5,5-tetraethyl-l,3,2-dioxaborolan-2-yl)nicotinate (125 mg) .

[0401] LCMS: MW (calcd): 457.3; m / z MW (obsd): 458.5 (M+H).2.16.1. Step G

[0402] A round bottomed flask was charged with (3S)-3-({3-bromopyrazolo[l,5-a]pyrimidin-6-yl}oxy)-2-methylbutan-2-ol Int 4 (1.036 eq., 81.2 mg, 0.27 mmol), tert-butyl 2-(difluoromethoxy)-4-methoxy-6-(4,4,5,5-tetraethyl-l,3,2-dioxaborolan-2-yl)nicotinate (1 eq., 117 mg, 0.26 mmol), SPhosPdG4 (0.059 eq., 12 mg, 0.015 mmol), potassium phosphate (2.15 eq., 117 mg, 0.55 mmol), toluene (2 mb) and water (0.2 mb), degassed by bubbling N2 through the mixture, sealed with a crimped cap under a nitrogen atmosphere and heated at 110 °C. The reaction mixture was stirred for 1 h. The mixture was allowed to cool to room temperature. The mixture was combined with CHCI3 (50 mb), n-BuOH (5 mb), and H2O (50 mb) in a separatory funnel and agitated. The organic phase was collected, washed with brine (50 mb) and dried over MgSC After filtration, volatiles were removed from the filtrate via rotary evaporation. The residue was charged onto a column of silica gel (25 g) and eluted with a gradient of CTLCL / EtOAc (1:0 to 1:1). Fractions containing product were pooled, and the solvent was removed via rotary evaporation to give tert-butyl (S)-2-(difluoromethoxy)-6-(6-((3-hydroxy-3-methylbutan-2-yl)oxy)pyrazolo[l,5-a]pyrimidin-3-yl)-4-methoxynicotinate (81 mg) .

[0403] LCMS: MW (calcd): 494.5; m / z MW (obsd): 495.4 (M+H).2.16.2. Step H

[0404] A round bottomed flask was charged with tert-butyl (S)-2-(difluoromethoxy)-6-(6-((3-hydroxy-3-methylbutan-2-yl)oxy)pyrazolo[l,5-a]pyrimidin-3-yl)-4-methoxynicotinate (1 eq., 81 mg, 0.16 mmol) and dry dioxane (4 mb). To the resulting solution was added hydrogen chloride in dioxane (4 mb, 16 mmol). The mixture was stirred for 16 h. Volatiles were removed via rotary evaporation. The residue was dissolved in DCM, and then volatiles were removed via rotary evaporation to give (S)-2-(difluoromethoxy)-6-(6-((3-hydroxy-3-methylbutan-2-yl)oxy)pyrazolo[l,5-a]pyrimidin-3-yl)-4-methoxynicotinic acid hydrochloride salt (78 mg)

[0405] LCMS : MW (calcd) : 438.1 ; m / z MW (obsd) : 439.3 (M+H) .2.16.3. Step I

[0406] A round bottomed flask was charged with (S)-2-(difluoromethoxy)-6-(6-((3-hydroxy-3-methylbutan-2-yl)oxy)pyrazolo[l,5-a]pyrimidin-3-yl)-4-methoxynicotinic acid hydrochloride salt (1 eq., 78 mg, 0.16 mmol), HATU (1.5 eq., 93.33 mg, 0.25 mmol), dry DMF (2 mb) and diisopropylethylamine (10.5 eq., 0.3 mb, 1.72 mmol) and sealed with a septum. After 15 minutes, (lR,2S)-2-fluorocyclopropan-1-amine; 4-methylbenzene-l -sulfonic acid CAS# 143062-84-4 (2 eq., 81 mg, 0.33 mmol) was added. The reaction mixture was stirred for 16 h. The mixture was combined with CHCL (50 mb), n-butanol (5 mb) and an aqueous KH2PO4 / K2HPO4 buffer (pH 7, IM, 50 mb) and agitated. The organic phase was collected, washed with H2O (3 x 50 mb) and brine (50 mb) and dried over MgSCL. After filtration, volatiles wereremoved from the filtrate via rotary evaporation. The residue was charged onto a column of silica gel (25 g) and eluted with a gradient of CFECE / EtOAc (1:0 to 0: 1). Fractions containing product were pooled, and the solvent was removed via rotary evaporation to give 2-(difluoromethoxy)-N-((lR,2S)-2-fhiorocyclopropyl)-6-(6-(((S)-3-hydroxy-3-methylbutan-2-yl)oxy)pyrazolo[l,5-a]pyrimidin-3-yl)-4-methoxynicotinamide (29 mg) Cpd 192.

[0407] LCMS: MW (calcd): 495.5; m / z MW (obsd): 496.3 (M+H).

[0408] A vial was charged under nitrogen with 2-bromo-3-fluoro-6-methylpyridine (1.5 eq., 23.6 mg, 0.12 mmol), (S)-3-((3-(3,5-dimethoxy-4-(4,4,5,5-tetraethyl-l,3,2-dioxaborolan-2-yl)phenyl)pyrazolo[l,5-a]pyrimidin-6-yl)oxy)-2-methylbutan-2-ol Int 8(1 eq., 58 mg, 0.083 mmol) and K3PO4 (2 eq., 35 mg, 0.17 mmol) in water (0.17 mb) and dioxane (0.67 mb). To the RM was added SPHOS PdG4 (0.1 eq., 6.6 mg, 0.0083 mmol) Then RM was heated at 80°C for 1 hour. The mixture was filtered through on a pad of celite, rinsed with EtOAc. To the mixture was added water. The mixture was extracted with EtOAc . Organic layer was washed with water and brine, dried over anhydrous MgSO4, filtered, concentrated under vacuo and directly purified (Column: Silica HP 10 g ( deposit in DCM ) gradient: DCM / ((EtOAc / EtOH 3 / 1)) 100 to 90 / 10 (20 CV)to afford (S)-3-{3-[4-(3-fluoro-6-methyl-2-pyridyl)-3,5-dimethoxyphenyl]-l,4,7a-triaza-6-indenyloxy} -2 -methyl -2 -butanol (18.1 mg) Cpd 210.

[0409] MW (calcd): 466.5 m / z MW (obsd): 466.9 (M+l).17. Compound 2182.17.1. Step A

[0410] The reaction was performed in a round bottom flask with anhydrous solvent. To a stirred solution of 4-bromo-2,6-dimethoxybenzoic acid (1 eq., 250 mg, 0.96 mmol in DCM were added at RT HATU (1 eq., 364 mg, 0.96 mmol) and DIEA (3 eq., 0.5 mL, 2.87 mmol). The reaction mixture was stirred at RT for 5 minutes and hydrazine monohydrochloride (3 eq., 197 mg, 2.87 mmol) was added. The reaction mixture was stirred at RT overnight. The precipitate was filtered and the filtrate was purified on a 28g Sfar Amino column, eluted with gradient 0-2% MeOH in CH2Q2. The product fraction was evaporated to dryness to afford 4-bromo-2,6-dimethoxybenzohydrazide (190 mg) .

[0411] MW (calcd): 275.1 m / z MW (obsd): 275.0-277.3 (M+l)2.17.2. Step B

[0412] The reaction was performed in a sealed vial with anhydrous solvent. To a stirred solution of 4-bromo-2,6-dimethoxybenzohydrazide (1 eq., 90 mg, 0.33 mmol) and triethyl orthopropionate (1.1 eq., 0.072 mb, 0.36 mmol EtOH (3 m ) was added at RT NH4CI (3 eq., 0.035 m , 0.98 mmol). The reaction mixture was stirred at 100°C overnight. The reaction mixture was evaporated to dryness. The residue was purified on a 10g Star Amino column, eluted with 0-3% MeOH in CTECf.Thc product fraction was evaporated to dryness to afford 2-(4-bromo-2,6-dimethoxyphenyl)-5-ethyl-l,3,4-oxadiazole (66 mg) .

[0413] MW (calcd): 313.15 m / z MW (obsd): 313.1-315.1 (M+l)2.17.3. Step C

[0414] The reaction was performed in a sealed vial under argon atmosphere. To a stirred solution of 2-(4-bromo-2,6-dimethoxyphenyl)-5-ethyl-l,3,4-oxadiazole (1 eq., 66 mg, 0.21 mmol) and (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 eq. ,86 mg, 0.21 mmol) in dioxane (3 mb) was added CS2CO3 (2 eq., 137 mg, 0.42 mmol) in water (0.3 mb) at RT. The reaction mixture was degassed with argon for 5 minutes. Pd(dppf)C12 • DCM (0.05 eq., 8.6 mg, 0.0105 mmol) was then added and the reaction mixture was stirred at 100°C overnight. The reaction mixture was evaporated to dryness. The residue was purified on a 11g Star Amino column, eluted with 0-1% MeOH in CH2CI2. Then by C18 column 12g, eluted with gradient 0-100% [ACN / 0.1% formic acid] in [H2O / 0.1% Formic acid]. The product fraction was evaporated to dryness to afford (S)-3-{3-[4-(5-ethyl-l,3,4-oxadiazol-2-yl)-3,5-dimethoxyphenyl]-l,4,7a-triaza-6-indenyloxy}-2-methyl-2-butanol (45 mg) Cpd 218.

[0415] MW (calcd): 453.5 m / z MW (obsd): 454.3 (M+l)Compound 2192.17.4. Step A

[0416] The reaction was performed in a round bottom flask with anhydrous solvent. To a stirred solution of 4-bromo-2,6-dimethoxybenzoic acid (1 eq., 250 mg, 0.96 mmol) in DMF (3 mb) were added at 0°C HATU (1 eq., 364 mg, 0.96 mmol) and DIEA (2 eq., 0.33 mb, 1.92 mmol). The reaction mixture was stirred at RT for 5 minutes and acethydrazide (1 eq., 71 mg, 0.96 mmol) was added. The reaction mixture was stirred at RT for 72H. Water was added to the reaction mixture. The solid was filtered. The aqueous layer was extracted twice with EtOAc. The combined organic layer was dried over Na2SC>4, filtered and evaporated to dryness. The residue was purified on a 25g Star HC column, eluted with gradient 0-3% MeOH in CH2CI2. The product fraction was evaporated to dryness to afford N'-acetyl-4-bromo-2,6-dimethoxybenzohydrazide (222 mg) .

[0417] MW (calcd): 317.14 m / z MW (obsd): 316.9-318.9 (M+l)2.17.5. Step B

[0418] The reaction was performed in a round bottom flask with anhydrous solvent. To a stirred solution of N'-acetyl-4-bromo-2,6-dimethoxybenzohydrazide (1 eq., 160 mg, 0.505 mmol) in THF (4 mb) was added at RT burgess reagent (1.5 eq., 180 mg, 0.76 mmol). The reaction mixture was stirred at 80°C for 2H. Water was added to the reaction mixture. The aqueous layer was extracted twice with EtOAc. The combined organic layer was dried overNa2SC>4, filtered and evaporated to dryness. The residue was purified on a 10g Star HC column, eluted with gradient 0-2% MeOH in CH2CI2. The product fraction was evaporated to dryness to afford 2-(4-bromo-2,6-dimethoxyphenyl)-5-methyl-l,3,4-oxadiazole (112 mg) .

[0419] MW (calcd): 299.12 m / z MW (obsd): 299.4-301.6 (M+l)2.17.6. Step C

[0420] The reaction was performed in a sealed vial under argon atmosphere.To a stirred solution of 2-(4-bromo-2,6-dimethoxyphenyl)-5-methyl-l,3,4-oxadiazole (1 eq., 28 mg, 0.094 mmol) and (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 4 (1.1 eq., 41 mg, 0.103 mmol) in dioxane (1.5 m ) was added CS2CO3 (2 eq., 61 mg, 0.19 mmol) in water (0.15 m ) at RT. The reaction mixture was degassed with argon for 5 minutes. Pd(dppf)C12 • DCM (0.05 eq., 3.8 mg, 0.0047 mmol) was then added and the reaction mixture was stirred at 100°C overnight. The reaction mixture was evaporated to dryness. The residue was purified on a 11g Star Amino column, eluted with 0-1% MeOH in CH2CI2. Then purified on a 12g C18 column, eluted with gradient 0-100% [ACN / 0.1% Formic acid] in [H2O / 0.1% Formic acid]. The product fraction was evaporated to dryness to (S)-3-{3-[3,5-dimethoxy-4-(5 -methyl- 1 ,3 ,4-oxadiazol-2-yl)phenyl] - 1 ,4,7a-triaza-6-indenyloxy } -2 -methyl -2 -butanol (18 mg) Cpd 219.

[0421] MW (calcd): 439.47 m / z MW (obsd): 440.2 (M+l).18. Compound 2232.18.1. Step A

[0422] A RBF was charged at RT under nitrogen with NaH (1.5 eq., 64.7 mg, 1.62 mmol) and (lr,4r)-cyclohexane-l,4-diol (1.5 eq., 188 mg, 1.62 mmol) in DMSO (5 mb) and 4-bromo-2-fluoro-6-methylbenzonitrile (1.34 eq., 310 mg, 1.45 mmol) was added. Then RM was heated at 60°C for 40 h. The mixture was cooled down to RT. To the mixture was added water. The mixture was extracted with EtOAc. Organic layer was washed with water and brine, dried over anhydrous MgSO4, filtered, concentrated under vacuo and directly purified (Column: Silica HP 25 g ( deposit in DCM ); Gradient: Hept 100% (3CV) thenHept / EtOAc 100 to 50 / 50) to afford 4-bromo-2-(((lr,4r)-4-hydroxycyclohexyl)oxy)-6-methylbenzonitrile (48.4 mg)

[0423] MW (calcd): 310.2 m / z MW (obsd): 310.0-311.2 (M+l)2.18.2. Step B

[0424] A screw vial cap was charged under nitrogen with (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 eq., 60 mg, 0.13 mmol), 4-bromo-2-(((lr,4r)-4-hydroxycyclohexyl)oxy)-6-methylbenzonitrile (1.2 eq., 47 mg, 0.15 mmol) and K3PO4 (2 eq., 54 mg, 0.25 mmol) in water (0.6 mL)and dioxane (2.4 mb). To the RM was added SPHOS PdG4 (0.1 eq., 10 mg, 0.013 mmol) Then RM was heated at 60°C for 45 min.The mixture was fdtered through on a pad of celite, rinsed with EtOAc. To the mixture was added water. The mixture was extracted with EtOAc . Organic layer was washed with water and brine, dried over anhydrous MgSO4, fdtered, concentrated under vacuo and directly purified by HPLC preparative to give Cpd 223 (8.7 mg).

[0425] MW (calcd): 450.5 m / z MW (obsd): 451.5 (M+l).19. Compound 237

[0426] Int 4 (1 eq., 65 mg, 0.22 mmol), 2,6-dimethoxy-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)benzonitrile CAS#482628-05-7 (1.3 eq., 81.4 mg, 0.28 mmol), RuPhos (0.1 eq., 10.105 mg, 0.022 mmol), Pd(OAc)2 (0.05 eq., 1.79 mg, 0.0108 mmol) and Na2COs (3 eq., 68.86 mg, 0.65 mmol) in dioxane (2 mL) and water (0.5 mL) in a sealed vial. The RM is purged under vacuum then under N2 (2 cycles). The RM was stirred at 90°C 2.5 h. At RT, water and EtOAc were added. The mixture was extracted with EtOAc. The organic layers were gathered and dried over anhydrous MgSO4. The crude was purified by PrepHPLC (PrepB_50mL_45-65_8min) to afford Cpd 237 (32 mg).

[0427] LCMS: MW (calcd): 382.4; m / z MW (obsd): 3835.3 (M+H).20. Compound 241

[0428] A 2-5mL Biotage microwave vial was charged with 5-bromo-7-methoxy-2-(2,2,2-trifhioroethyl)isoindolin-l-one CAS# 3038864-93-3 (1 eq., 36 mg, 0.11 mmol), Int 3 (1.2 eq., 53.76 mg, 0.13 mmol), SPhosPdG4 (0.1 eq., 8.82 mg, 0.011 mmol), K3PO4 (2 eq., 47.16 mg, 0.22 mmol), and degassed with Argon. Anhydrous degassed (bubbling Nitrogen for 15min) water (0.21 mL) and dioxane(0.709 mL) were added at rt and RM was degassed through vacuum / Argon cycles 4 times, kept under Argon atmosphere (balloon). RM was stirred at 55 °C (preheated oil bath) under argon atmosphere . for 15 min. The RM was cooled down to RT and reloaded with Int 3 (0.75 eq., 33.601 mg, 0.083 mmol) in solution in dioxane (0.35 mL) and SPhosPdG4 (0.1 eq., 8.82 mg, 0.011 mmol). RM was purged with argon and heated to 55°C for 1 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 brine, dried over MgSO4, filtered and concentrated in vacuo and purified by chromatography SiO2, eluent (DCM / MeOH 90 / 10) and repurified by reverse phase chromatography, SNAP Cl 8 25g, loading in DMSO, biotage Isolera, eluent water / ACN (+0.1 % formic acid) gradient 100 / 0 (3CV), 100 / 0 to 50 / 50 (20CV), 50 / 50 (5CV) to afford Cpd 241(28 mg).

[0429] LCMS: MW (calcd): 464.4; m / z MW (obsd): 465.3 (M+H)2.21. Compound 285o

[0430] To a solution of Int 5 (1 eq., 100 mg, 0.21 mmol) and methanesulfonamide (2.49 eq., 50 mg, 0.53 mmol) in DCM (2 mL) were added EDC1 (1.2 eq., 48.55 mg, 0.25 mmol), DMAP (0.2 eq., 5.16 mg, 0.042 mmol) and then DIPEA (3 eq., 81.83 mg, 0.11 mL, 0.63 mmol). The reaction mixture was stirred at room temperature for 6 h. Methanesulfonamide (2 eq., 40.15 mg, 0.42 mmol), EDC1 (1.2 eq., 48.55 mg, 0.25 mmol) and DIPEA (3 eq., 81.83 mg, 0.11 mL, 0.63 mmol) were added into the mixture, and reaction was stirred at room temperature for 66 h. The reaction was poured into HC1 IN (5 mL) and extracted with DCM (3 * 2 mL). The combined organic layers were dried and concentrated under reduce pressure and the crude residue was purified by LC-MS PrepA_50mL_40-55_8min to afford Cpd 285 (10 mg).

[0002] MW (calcd): 514.5 m / z MW (obsd): 515.1 (M+l)2.22. General methods for amide compounds synthesisMethod A

[0431] The reactions were monitored by LC-MS and stirred for 1 to 64 h. Solvents were DCM, DMF or DMSO. Mono Boc protected diamines were used and Boc protecting group was removed as described forCpd 32 step B. Flash Chromatography and LCMS prep purification methods were used. Prep Chiral SFC purification method were used in case of separation of diastereoisomers or, and enantiomers.Illustrative example with Compound 13

[0432] A 25 ml flask was charged at RT under nitrogen Int 5 (1 eq., 40 mg, 0.084 mmol), 2-(5- chloropyridin-2-yl)-2,2-difluoroethan-l -amine hydrochloride (1.5 eq., 29.002 mg, 0.13 mmol), TEA (4 eq., 34.17 mg, 0.047 mL, 0.34 mmol) and HATU (1.5 eq., 48.15 mg, 0.13 mmol) with anhydrous DCM (0.62 mL). The mixture was stirred at RT for 72 h. The solvent was evaporated at 50°C under nitrogen flow. The crude sample was dissolved in DMSO and purified by HPLC PREP in acid method (PrepA_50mL_50- 65_8min) to give the desired compound.Method B

[0433] The reactions were monitored by LC-MS and stirred for 15 to 47 h. Mono Boc protected diamines were used and Boc protecting group was removed as described for Cpd 32 step B. Flash Chromatography and LCMS prep purification methods were used. Prep Chiral SFC purification method were used in case of separation of diastereoisomers or, and enantiomers.Illustrative example with compound 50

[0434] A pressure reactor (12 mL) was charged with 5 -fluoro- 1 -methyl- lH-pyrazol-4-amine; trifluoroacetic acid (1.96 eq., 28 mg, 0.12 mmol), dry DCM (1 mL) and DIEA (5.22 eq., 42 mg, 0.057 mL, 0.32 mmol). To the resulting solution was added the solution of Int 7 (1 eq., 2 mL, 0.062 mmol) in CH2Q2 (2 mL), and the reactor was sealed with a crimped cap. The reactor was heated to 80 °C for 15 h. The mixture was combined with CHC13 (10 mL), n-butanol (1 mL) and an aqueous KH2PO4 / K2HPO4 buffer (pH 7, IM, 10 mL) and agitated. The organic phase was collected, and volatiles were removed via rotary evaporation. The residue was purified via preparative LC-MS (PrepA_50mL_35-50_8min) to give Cpd 50 (17 mg).Method C

[0435] The reactions were monitored by LC-MS and stirred for 2 to 90 h. The reaction was stirred at RT to 80°C when no conversion is observed at RT. Mono Boc protected diamines were used and Boc protecting group was removed as described for Cpd 32 step B. Flash Chromatography and LCMS prep purification methods were used. Prep Chiral SFC purification method was used in case of separation of diastereoisomers or, and enantiomers.Illustrative example with compound 4

[0436] A reactor (12 mb) was charged with Int 5 (1 eq., 30.1 mg, 0.064 mmol), l-(4-amino-5-chloro-lH-pyrazol-l-yl)-2-methylpropan-2-ol (2.6 eq., 31.3 mg, 0.17 mmol), 1 -methylimidazole (9.99 eq., 52.1 mg, 0.0506 mb, 0.63 mmol) and acetonitrile (1 mb) and sealed with a septum. After 5 minutes, TCFH, [Chloro(dimethylamino)methylene]dimethylammonium hexafluorophosphate (1.25 eq., 22.2 mg, 0.079 mmol) was added and the RM was stirred at RT for 17 hours. The mixture was combined with CHC13 (10 mb), n-butanol (1 mb) and an aqueous KH2PO4 / K2HPO4 buffer (pH 7, IM, 10 mb) and agitated. The organic phase was collected, and volatiles were removed via rotary evaporation. The residue was purified via preparative LC-MS (PrepA_50mL_35-50_8min) to give Cpd 4 (20.5 mg).Table II. Methods used for amide compounds synthesisPrep Chiral SFC Cpd# Method Solvent Purification methodmethod Second eluting Cpd 1 DMF PrepB_50mL_50-65_8min Chiralpak IA, 150 x A21mm, 5pm., Ethanol + 0,l%DEA, isocratic 2 A DMF PrepA_50mL_50-65_8min - FC, (Cl 8 30 pm, water (0.1% formic3 A DMF - acid) / MeCN (0.1% formic acid4 C Acetonitrile PrepA_50mL_50-65_8min - 5 C Acetonitrile PrepA_50mL_50-65_8min - 6 c Acetonitrile PrepA_50mL_50-65_8min - 7 A DCM FC, DCM / EtOAc 70 / 30 to 20 / 80 - 8 A DCM FC, DCM / EtOAc 70 / 30 to 20 / 80 - 9 A DCM FC, DCM / EtOAc 70 / 30 to 20 / 80 - 10 A DCM FC, DCM / EtOAc 70 / 30 to 20 / 80 - 11 C Acetonitrile PrepA_50mL_50-65_8min -Prep Chiral SFC Cpd# Method Solvent Purification methodmethod 12 C Acetonitrile PrepA_50mL_50-65_8min - 13 A DCM PrepA_50mL_50-65_8min - First eluting Cpd Lux FC, DCM / (EtOAc / EtOH (3 / 1) 10014 C Acetonitrile Cellulose-4, 150 x to 90 / 10 21.2mm, 5 pm, EtOH, isocratic 15% Second eluting Cpd FC, DCM / (EtOAc / EtOH (3 / 1) 10015 C Acetonitrile Lux Cellulose-4, 150 x to 90 / 10 21.2mm, 5 pm, EtOH, isocratic 15% Second eluting, Chiralpak IA, 150 x 21mm, 5 pm with 16 B DCM FC, DCM / EtOAc (1:0 to 0:1)Guard of 50 x 21mm, 5 pm, EtOH, isocratic 15% First eluting, Chiralpak IA, 150 x 17 21mm, 5 pm with B DCM FC, DCM / EtOAc (1:0 to 0:1)Guard of 50 x 21mm, 5 pm, EtOH, isocratic 15% Second eluting, Lux i- 18 DCM FC ,DCM / (DCM : MeOH 90 : 10) Cellulose-5, 150 x A21.2mm, 5 pm, iPrOH 30% isocratic First eluting, Lux i- Cellulose-5, 150 x 19 DCM FC ,DCM / (DCM : MeOH 90 : 10) A21.2mm, 5 pm, iPrOH 30% isocratic First FC: (DCM : MeOH 90 : 10),20 DCM Second FC: DCM / AcOEt-EtOH (3- - A1) then Hept / (AcOEtEtOH 3 :1)22 DCM PrepA_50mL_50-65_8min - A23 DCM PrepA_50mL_50-65_8min - A24 DCM PrepA_50mL_50-65_8min - ASecond eluting, Lux FC, DCM / (EtOAc / EtOH 3 / 1) 100Cellulose-4, 150 x 25 DCM Ato 90 / 10 21.2mm, 5 pm, EtOH,Isocratic 34% First eluting, Lux FC, DCM / (EtOAc / EtOH 3 / 1) 100Cellulose-4, 150 x 26 DCM Ato 90 / 10 21.2mm, 5 pm, EtOH,Isocratic 34% 27 DCM PrepA_50mL_50-65_8min - B28 DCM PrepA_50mL_50-65_8min - B31 DCM FC, DCM / iPrOH (1:0 to 3:1) - BPrep Chiral SFC Cpd# Method Solvent Purification methodmethod First eluting, Lux 33 PrepA_50mL_50-65_8min Cellulose-4, 150 x A DMSO21.2mm, 5 pm, EtOH isocratic 20% Second eluting, Lux 34 Cellulose-4, 150 x A DMSO PrepA_50mL_50-65_8min21.2mm, 5 pm, EtOH isocratic 20% 35 DCM PrepA_50mL_50-65_8min - A36 DCM PrepA_50mL_50-65_8min - A37 DCM PrepA_50mL_50-65_8min - A38 DCM PrepA_50mL_50-65_8min - A39 DCM PrepA_50mL_50-65_8min - A40 DCM PrepA_50mL_50-65_8min - A41 DCM PrepA_50mL_50-65_8min - AFirst eluting, Chiralpak IC 20x250 42 PrepA_50mL_50-65_8min DMSO A mm, Mobile phase:CO2 / (ACN + 0,3%iPrNH2) 70 / , 30 Second eluting, Chiralpak IC 20x250 43 PrepA_50mL_50-65_8min DMSO A mm, Mobile phase:CO2 / (ACN + 0,3%iPrNH2) 70 / , 30 47 DCM PrepA_50mL_50-65_8min - B48 DCM PrepA_50mL_50-65_8min - B49 DCM PrepA_50mL_50-65_8min - B50 DCM PrepA_50mL_50-65_8min - B51 DCM PrepA_50mL_50-65_8min - B52 DCM PrepA_50mL_50-65_8min - B53 DCM PrepA_50mL_50-65_8min - B54 PrepA_50mL_50-65_8min DMSO - A55 DCM PrepA_50mL_50-65_8min - B56 DCM PrepA_50mL_50-65_8min - B57 DCM PrepA_50mL_50-65_8min - B58 DMF PrepA_50mL_50-65_8min - A60 DCM FC, DCM / EtOAc (1:0 to 0:1). - B61 DMF PrepA_50mL_50-65_8min - A63 DCM PrepA_50mL_50-65_8min - A64 DCM PrepA_50mL_50-65_8min - APrep Chiral SFC Cpd# Method Solvent Purification methodmethod 65 A DMSO PrepA_50mL_50-65_8min - 68 A DCM PrepB_50mL_50-65_8min - 69 A DCM PrepB_50mL_50-65_8min - 70 A DMF PrepB_50mL_50-65_8min - 71 A DMF PrepB_50mL_50-65_8min - 72 A DMF PrepB_50mL_50-65_8min - 73 A DMF PrepB_50mL_50-65_8min - 74 A DMF PrepB_50mL_50-65_8min - 75 A DMF PrepB_50mL_50-65_8min - 76 A DMF PrepB_50mL_50-65_8min - 77 A DMF PrepA_50mL_50-65_8min - 78 A DMF PrepA_50mL_50-65_8min - 79 A DMF PrepB_50mL_50-65_8min - 80 A DMF PrepA_50mL_50-65_8min - 81 A DMF PrepA_50mL_50-65_8min - 82 A DMF PrepA_50mL_50-65_8min - 83 A DMF PrepA_50mL_50-65_8min - 84 A DMF PrepA_50mL_50-65_8min - 85 A DMF PrepA_50mL_50-65_8min - Second eluting, FC, DCM / AcOEt-EtOH (3-1) 100 to Chiralpak AD-H 89 A DMF 20x250 mm, Mobile 30 / 70phase: CO2 / MeOH 75 / 25 Second eluting, FC, DCM / AcOEt-EtOH (3-1) 100 to Chiralpak AD-H 90 DMF A 20x250 mm, Mobile 30 / 70phase: CO2 / MeOH 75 / 25 91 C Acetonitrile PrepB_50mL_50-65_8min B - 95 A DMSO PrepB_50mL_50-65_8min - Second eluting, Chiralpak IA, 150 x 21mm, 5 pm with 96 A DMSO PrepA_50mL_50-65_8minGuard of 50 x 21mm, 5 pm, EtOH isocratic 30% First eluting, Chiralpak IA, 150 x 97 21mm, 5 pm with A DMSO PrepA_50mL_50-65_8minGuard of 50 x 21mm, 5 pm, EtOH isocratic 30%Prep Chiral SFC Cpd# Method Solvent Purification methodmethod 98 A DMSO PrepA_50mL_50-65_8min - 99 A DMSO PrepA_50mL_50-65_8min - FC, DCM / (EtOAc / EtOH 3 / 1) 100100 A DCM - to 50 / 50101 A DMF FC, DCM / MeOH (1:0 to 9:1). - 102 A DMF FC, DCM / MeOH (1:0 to 9:1). - First eluting, (Lux i- Cellulose-5, 150 x 103 A DCM PrepA_50mL_50-65_8min 21.2mm, 5 pm, CO2 / EtOH 70 / 30). first eluting Second eluting, (Lux i- Cellulose-5, 150 x 104 A DCM PrepA_50mL_50-65_8min 21.2mm, 5 pm, CO2 / EtOH 70 / 30). first eluting 105 A DCM PrepA_50mL_50-65_8min - 106 A DCM PrepA_50mL_50-65_8min - 107 A DCM PrepB_50mL_50-65_8min - Second eluting, Lux FC, DCM / AcOEt-EtOH (3: 1) 100 to108 A DCM Cellulose- 1, 150 x 0 / 100 21.2mm, 5 pm, EtOH isocratic 25% 109 A DCM PrepB_50mL_50-65_8min - 110 A DCM PrepB_50mL_50-65_8min - 111 A DCM PrepB_50mL_50-65_8min - 112 A DCM PrepA_50mL_50-65_8min - 113 A DMF PrepA_50mL_50-65_8min - 114 A DMF PrepA_50mL_50-65_8min - 115 A DMF PrepB_50mL_50-65_8min - 116 A DMF PrepA_50mL_50-65_8min - 118 A DCM No purification - 119 A DCM PrepA_50mL_50-65_8min - FC, (DCM:MeOH 90: 10) 100 / 0 to120 A DMSO - 60 / 40121 A DCM PrepA_50mL_50-65_8min - 122 A DCM PrepA_50mL_50-65_8min - 123 A DCM PrepA_50mL_50-65_8min - 124 A DCM PrepA_50mL_50-65_8min - 125 A DCM PrepA_50mL_50-65_8min -Prep Chiral SFC Cpd# Method Solvent Purification methodmethod First eluting, Lux FC, DCM / AcOEt-EtOH (3-1) 100 toCellulose- 1, 150 x 126 A DCM0 / 100 21.2mm, 5 pm, EtOH isocratic 25% Second eluting, Lux i- 127 Cellulose-5, 150 x A DCM PrepB_50mL_50-65_8min21.2mm, 5 pm, EtOH, isocratic 35% First eluting, Lux i- Cellulose-5, 150 x 128 DCM PrepB_50mL_50-65_8min A21.2mm, 5 pm, EtOH, isocratic 35% 133 DMF PrepA_50mL_50-65_8min - A134 DMF PrepA_50mL_50-65_8min - A135 DMF PrepA_50mL_50-65_8min - A136 DMF PrepA_50mL_50-65_8min - A137 DMF PrepA_50mL_50-65_8min - A138 DMF PrepA_50mL_50-65_8min - A141 DCM PrepA_50mL_50-65_8min - A142 DCM PrepA_50mL_50-65_8min - A146 DCM PrepA_50mL_50-65_8min - A147 PrepA_50mL_50-65_8min DMSO - ASecond eluting, Lux FC, DCM / ((EtOAc / EtOH 3 / 1))Cellulose-4, 150 x 148 DCM A21.2mm, 5 pm, EtOH, 100 to 80 / 20isocratic 20% First eluting, Lux FC, DCM / ((EtOAc / EtOH 3 / 1))Cellulose-4, 150 x 149 DCM A21.2mm, 5 pm, EtOH, 100 to 80 / 20isocratic 20% 150 DCM PrepA_50mL_50-65_8min - A151 PrepA_50mL_50-65_8min Acetonitrile - C157 DCM PrepA_50mL_50-65_8min - A158 PrepB_50mL_50-65_8min Acetonitrile - C159 DCM PrepA_50mL_50-65_8min - A160 DCM PrepA_50mL_50-65_8min - A161 DCM PrepA_50mL_50-65_8min - A162 DCM PrepA_50mL_50-65_8min - A163 DCM PrepA_50mL_50-65_8min - A164 DCM PrepA_50mL_50-65_8min - A165 DCM PrepA_50mL_50-65_8min - A166 DCM PrepA_50mL_50-65_8min - APrep Chiral SFC Cpd# Method Solvent Purification methodmethod 167 A DCM PrepA_50mL_50-65_8min - 168 A DCM PrepA_50mL_50-65_8min - 169 A DCM PrepA_50mL_50-65_8min - 177 A DCM PrepB_50mL_50-65_8min - 178 A DCM PrepA_50mL_50-65_8min - 179 A DCM PrepB_50mL_50-65_8min - First eluting, Lux i- 183 DCM PrepB_50mL_50-65_8min Cellulose-5, 150 x A21.2mm, 5 pm, EtOH, isocratic 35% 184 A DCM PrepA_50mL_50-65_8min186 A DCM PrepA_50mL_50-65_8min - 187 A DCM PrepA_50mL_50-65_8min - 188 A DMSO PrepA_50mL_50-65_8min - FC, DCM / EtOAc-EtOH(3:l) 100 to189 A DCM - 70 / 30190 A DCM Prep B - 191 C Acetonitrile PrepA_50mL_50-65_8min - 194 A DCM Prep B - FC, DCM / (EtOAc / EtOH (3 / 1)) 100First eluting. to 90 / 10 and FC, DCM / 195 A DCM Chiralpak IA, 150 x (EtOAc / EtOH (3 / 1)) 100 to 90 / 10 4.6mm, 5pm, EtOH,45% isocratic after boc cleavage196 DCM PrepA_50mL_50-65_8min - A197 A DCM PrepA_50mL_50-65_8min - 198 A DCM PrepB_50mL_50-65_8min - 199 A DCM PrepB_50mL_50-65_8min - Second eluting, Lux i- 200 Cellulose-5, 150 x A DCM PrepB_50mL_50-65_8min21.2mm, 5 pm, EtOH, isocratic 35% 202 DCM PrepB_50mL_50-65_8min - AFirst eluting, Chiralpak IA, 150 x 21mm, 5 pm with 203 DCM PrepA_50mL_50-65_8min AGuard of 50 x 21mm, 5pm, MeOH+ 0.1%DEA, gradientPrep Chiral SFC Cpd# Method Solvent Purification methodmethod Second eluting, Chiralpak IA, 150 x I204 o I DCM PrepA_50mL_50-65_8min 21mm, 5 pm with o AGuard of 50 x 21mm, o 5pm, MeOH+ o 0.1%DEA, gradient 205 A 5 <;DCM PrepB_50mL_50-65_8min - 206 A DCM PrepA_50mL_50-65_8min - J207 DC \ / A M X o- PrepB_50mL_50-65_8min - 209 A DCM ° V1PrepB_50mL_50-65_8min -Table III. Intermediates used towards the compounds of the invention.SM = Starting Material, Mtd = Method, MS Mes’d = Measured mass, NA = not measuredInt# Structure SM MW MS Mes’dInt 57 299.11H°'V'QA + 299.1Br Int 58 301.1O-B F. WO2020 / 239658, 2020, Al2 / F400.2 401.4\ / ° CAS# 2563897-58-3— o \-o° )v3 Int4 403.3 404.4Int 57 300.04 + 300.1Br Int 59 302.05 Ex 437.4 438.4Int# Structure SM MW MS Mes’d6 o IO -n -n Ex 437.4 438.4 / o° / = o yO= O OJ> oHO^Q 212.9 56 CAS#1264193-11-4 212.0bW J oBr 214.9 o57 ° V ° A 212.9Int56 249.9Br 214.9 58 A .o, JO CAS#7699-00-5 272.1 272.8° I 1' / 0 x 059 CAS#17392-83-5 258.1 258.8< AJ7 A ° " Int 5 487.5 488.3OHOA o oY°Y^N'\7^ 436.3 8 To Int 4 436.3X 438.2M~~~° BrQ / 9 Ex 402.4 403.4Int 110 436.4 437.4Int 2Int# Structure SM MW MS Mes’d11 I Int 8 539.5 540.6o ob°ry >.— < oo _ ,\ / / °VT1Table IV. Illustrative compou Z -nn Ids of the invention.SM = Starting Material, Mtd = Method, MS Mes’d = Mesured massDescribed above = Synthesis described above in Example 2 SectionGen = may be prepared using methods described herein and general methods of the artCp MS Structure Name SM MW d# Mes’d N-((lS,2R)-2- M LL aminocyclohexyl)-2- fJ " (difluoromethoxy ) -4 - (6 - 1* (((S)-3-hydroxy-3- Int 5 533.6 534.3 methylbutan-2- Wy z"oyl)oxy)pyrazolo[l,5- z V a]pyrimidin-3-yl)-6- p o* °o o methoxy benzamide7^ 2 - (difluoromethoxy ) -4 - [6- 7 7^^ X [(lS)-2-hydroxy-l,2- dimethyl- 2 propoxy ]pyrazolo [1,5- Int 10 479.2 480.3 a]pyridin-3-yl]-N,6- dimethoxy -N -methy 1- benz amide2 - (difluoromethoxy ) -4 - [6- [(lS)-2-hydroxy-l,2- dimethyl- 3 propoxy ]pyrazolo [1,5- Int 5 436.4 437.3 a]pyrimidin-3-yl]-6- methoxy -benzamideN-[5-chloro-l-(2-hydroxy-2- methyl-propyl)pyrazol-4-yl]- 2 - (difluoromethoxy ) -4 - [6- 4 [(lS)-2-hydroxy-l,2- Int 5 609.0 609.5 dimethyl- propoxy ]pyrazolo [1,5- a]pyrimidin-3-yl]-6-methoxy -benzamideCp MS Structure Name SM MW d# Mes’d N-(3 -chloro- 1 -methyl- pyrazol-4-yl)-2- (difhioromethoxy )-4- [6- X Xo o [(lS)-2-hydroxy-l,2- 5 dimethyl- Int 5 550.9 551.4 propoxy ]pyrazolo [1,5- o o a]pyrimidin-3-yl]-6- methoxy -benzamide0 'bb^^rrrr o o N-(5-chloro-l-methyl- pyrazol-4-yl)-2- (difluoromethoxy ) -4 - [6 - F ° °yynn[(lS)-2-hydroxy-l,2- 6 550.9dimethyl- Int 5 551.4 propoxy ]pyrazolo [1,5- a]pyrimidin-3-yl]-6- methoxy -benz amide2 - (difluoromethoxy ) -N- [(lS,2S)-2- fluorocy clopropy 1] -4- [6- [(lS)-2-hydroxy-l,2- 7 495.4 dimethyl Int 5 494.5Tv7° - ^ j z ^X propoxy ]pyraA4-oDA “ zolo [1,5- “■a]pyrimidin-3-yl]-6- methoxy -benzamideAv <p CAAA t50 <° 2 - (difluoromethoxy ) -N- P[(lR,2R)-2- u o o o fluorocy clopropy 1] -4- [6- J . [(lS)-2-hydroxy-l,2- 8 495.4 Int 5 7^ 494.5 dimethyl- 0propoxy ]pyrazolo [1,5- a]pyrimidin-3-yl]-6- methoxy -benzamide2 - (difluoromethoxy ) -N- [(lS,2S)-2- fluorocy clopropy 1] -4- [6- [(lR)-2-hydroxy-l,2- 9 495.4 Int 6 494.5 dimethyl- propoxy ]pyrazolo [1,5- a]pyrimidin-3-yl]-6- methoxy -benzamide2 - (difluoromethoxy ) -N- [(lR,2R)-2- fluorocy clopropy 1] -4- [6- [(lR)-2-hydroxy-l,2- 10 495.4 Int 6 494.5 dimethyl- propoxy ]pyrazolo [1,5- a]pyrimidin-3-yl]-6- methoxy -benzamideCp MS Structure Name SM MW d# Mes’d 2 - (difluoromethoxy ) -N- (4 - fluoro- 1 H-pyrazol-5-y l)-4- 521.4 [6-[(lS)-2-hydroxy-l,2- X X X dimethyl- (M+H) 11 propoxy ]pyrazolo [1,5- Int 5 520.5a]pyrimidin-3-yl]-6- 519.4 (M- o O o methoxy -benzamideH) 00 ' 'b °Yv 2 - (difluoromethoxy ) -N- (3 - / z z. , fhioro-2-pyridyl)-4-[6-[(l S)- Cf °1y- 2 -hydroxy- 1 ,2-dimethyl- 00' r r propoxy ]pyrazolo [1,5- 12 a]pyrimidin-3-yl]-6- Int 5 531.5 532.4 methoxy -benzamideHOA^O^N,NN-[2-(5-chloro-2-pyridyl)- 2,2-difhioro-ethyl]-2- "Nk, 1 (difluoromethoxy ) -4 - [6 - [(lS)-2-hydroxy-l,2- ip- dimethyl- M-H 13 -o / \ 0JP- O propoxy ]pyrazolo [1,5- Int 5 612.0 ^TLLF 610.4 a]pyrimidin-3-yl]-6- Z=^N methoxy -benzamide 612.4 WClo2 - (difluoromethoxy )-N- [(lR*,3R*)-2,2-difluoro-3- methyl-cyclopropyl]-4-[6- [(lS)-2-hydroxy-l,2- 14* dimethyl- Int 5 526.5 527.3 propoxy ]pyrazolo [1,5- a]pyrimidin-3-yl]-6- methoxy -benzamide2 - (difluoromethoxy )-N- [(lS*,3S*)-2,2-difhioro-3- methyl-cyclopropyl]-4-[6- [(lS)-2-hydroxy-l,2- 15* dimethyl- Int 5 526.5 527.3 propoxy ]pyrazolo [1,5- a]pyrimidin-3-yl]-6- methoxy -benzamideN-[(lS*)-2,2- difluorocy clopenty 1] -2- "AX-Jf(difluoromethoxy ) -4 - [6 - [(lS)-2-hydroxy-l,2- 16* dimethyl- Int 7 540.5 541.4F propoxy ]pyrazolo [1,5- a]pyrimidin-3-yl]-6- d^~Fmethoxy -benzamideCp MS Structure Name SM MW d# Mes’d N-[(lR*)-2,2- difluorocy clopenty 1] -2- (difhioromethoxy )-4- [6- I X X X o [(lS)-2-hydroxy-l,2- 17* dimethyl- Int7 540.5 541.4"' G o propoxy ]pyrazolo [1,5- oX C a]pyrimidin-3-yl]-6- methoxy -benzamided / £Zy0 / ' o4Sfn o^^iyyQfv V y 2 - (difluoromethoxy ) -4 - [6- y / ><= , .Y1°\= / [(lS)-2-hydroxy-l,2- "H < Z— dimethyl- ° 0^ ° Y V^T1y propoxy ]pyrazolo [1,5- 18* Va]pyrimidin-3-yl]-6- Int 5 558.5 559.4 methoxy-N-[(l S*,2S*)-2- (trifluoromethyl)cyclobutyl]benzamide2 - (difluoromethoxy ) -4 - [6- [(lS)-2-hydroxy-l,2- dimethyl- propoxy ]pyrazolo [1,5- 19* a]pyrimidin-3-yl]-6- Int 5 558.5 559.4 methoxy-N- [( 1 R*,2R*)-2- (trifluoromethyl)cyclobutyl]7 benzamidemethyl 2-[2- o o p' (difluoromethoxy ) -4 - [6 - [(lS)-2-hydroxy-l,2- 7^ dimethyl- X X 7^20 propoxy ]pyrazolo [1,5- Int 5 574.5 575.4 a]pyrimidin-3-yl]-6- methoxy -benzoyl] -2- azaspiro [3.3]heptane-7 - carboxylate3,4,4-tnfluoro-6-[6-[(l S)-2- hydroxy- 1 ,2-dimethyl- Described21 propoxy ]pyrazolo [1,5- 531.4 531.4 a] py ridin- 3 -y 1] - 8 -methoxy - above2-(2,2,2-trifhioroethyl)-3H- isoquinolin-l-one[2 - (difluoromethoxy ) -4 - [6 - [(lS)-2-hydroxy-l,2- dimethyl- propoxy ]pyrazolo [1,5- 22 a]pyrimidin-3-yl]-6- Int 5 570.6 571.7 methoxy-pheny 1] -[3 - [(4- methy Ipyrazol- 1 - y l)methyl] azetidin- 1 -yl]methanoneCp MS Structure Name SM MWd# Mes’d 2 - (difluoromethoxy ) -4 - [6- [(lS)-2-hydroxy-l,2- dimethyl- T Z z X X propoxy ]pyrazolo [1,5- 583.3 23 O£L ^ ^ / — a]pyrimidin-3-yl]-6- Int 5 584.5o o o o methoxy-N-[[3- (M-H) o (trifluoromethy 1)- 1 H- s^ pyrazol-4- 0 ' zyllmethyllbenzamideXJ^TCVA 2 - (difluoromethoxy ) -4 - [6- i r [(lS)-2-hydroxy-l,2- T O V"T °zJZ ■n °i1Y'T'''y-n F- <\"\ dimethyl- %x / o 6 -n o X T Z propoxy ]pyrazolo [1,5- 24 a]pyrimidin-3-yl]-6- Int 5 598.5 599.7 methoxy-N-[[l-methyl-5- (trifluoromethyl)pyrazol-4- yl]methyl]benzamide2 - (difluoromethoxy ) -4 - [6- [(lS)-2-hydroxy-l,2- dimethyl- 5* X propoxy ]pyrazolo [1,5- Int 5 506.5 507.4< ° a]pyrimidin-3-yl]-N- jQ? i-. [(lS*,2R*)-2- (hydroxymethyl)cyclopropylyW z^ 1-6-methoxy -benz amide2 - (difluoromethoxy ) -4 - [6- p ' [(lS)-2-hydroxy-l,2- o o dimethyl- 6* propoxy ]pyrazolo [1,5- Int 5 506.5 507.4 X X 7 7^^ a]pyrimidin-3-yl]-N- [(lR*,2S*)-2- (hydroxymethyl)cyclopropyl]-6-methoxy -benz amide2 - (difluoromethoxy )-N- [(lS,2R)-2- hydroxy cyclohexyl] -4- [6- [(lS)-2-hydroxy-l,2- 27 dimethyl- Int 7 534.5 535.4 propoxy ]pyrazolo [1,5- a]pyrimidin-3-yl]-6- methoxy -benzamide2 - (difluoromethoxy )-N- [(lS,2R)-2- hydroxy cyclobutyl] -4- [6- 28 [(lS)-2-hydroxy-l,2- In 7 506.5 507.4 dimethyl- propoxy ]pyrazolo [1,5- a]pyrimidin-3-yl]-6- methoxy -benzamide(3S)-3-[3-[4-(6,7-dihydro- 5H-pyrazolo[5,l- b][l,3]oxazin-3-yl)-3,5- 29 dimethoxy- Int 8 479.5 480.3 pheny l]py razolo [1,5- a]pyrimidin-6-yl]oxy-2- methyl-butan-2-olCp MS Structure Name SM MWd# Mes’d (3S)-3-[3-[3,5-dimethoxy-4- (1 -methylimidazol-2- 437.7 yl)phenyl]pyrazolo[l,5- 30 X X M- o ' a]pyrimidin-6-yl]oxy-2- Int 8 437.5 H methyl-butan-2-ol 436.0 p o? / 1 Vz (3S)-3-[3-[3,5-dimethoxy-4- (3-methoxy-l -methyl- pyrazol-4- 31- l \" Y'p ox yl)phenyl]pyrazolo[l,5- A a]pyrimidin-6-yl]oxy-2- Int 8 467.5 468.7"HX mo oI I methyl-butan-2-ol2 - (difluoromethoxy ) -4 - [6- [(lS)-2-hydroxy-l,2- dimethyl- propoxy ]pyrazolo [1,5- a]pyrimidin-3-yl]-N- [(lS,2R)-2- CMM C32- I (hydroxymethyl)cyclopropylz 505.4 ]-6-methoxy-benzamide and Int 5 506.5A ppo x 2 - (difluoromethoxy ) -4 - [6- (M-H) zx^Z-^ 2° [(lS)- y AH-? 2-hydroxy-l,2- rVVodimethyl- yz2propoxy ]pyrazolo [1,5- p p p o o V* ' ' ° a]pyrimidin-3-yl]-N- o o o [(lS,2R)-2- (hydroxymethyl)cyclopropyl7QX X X Xo 7^^^ X^ ” - "" 1-6-methoxy -benz amideN-[(lR,6R)-6-amino-2,2- difluoro-cyclohexyl]-2- (difluoromethoxy ) -4 - [6 - [(lS)-2-hydroxy-l,2- 31 dimethyl- Int 7 569.6 570.4 propoxy ]pyrazolo [1,5- a]pyrimidin-3-yl]-6- methoxy -benzamideN-[(lS,2R)-2- aminocyclobutyl]-6-[6- [(lS)-2-hydroxy-l,2- 32 dimethyl- Desc’d 570.7 571.4 propoxy ]pyrazolo [1,5- a]pyrimidin-3-yl]-2,4- dimethoxy -pyridine-3 - carboxamide2 - (difluoromethoxy ) -N- [(lS*,2R*)-2- (difluoromethyl)cyclopropyl]-4-[6-[(lS)-2-hydroxy-l,2- 3* dimethyl- Int 5 526.5 527.5 propoxy ]pyrazolo [1,5- a]pyrimidin-3-yl]-6- methoxy -benzamideCp MS Structure Name SM MWd# Mes’d 2 - (difluoromethoxy ) -N- [(lR*,2S*)-2- (difluoromethyl)cyclopropylZE I ZE ]-4-[6-[(lS)-2-hydroxy-l,2- 4* o ^dimethyl- Int 5 526.5 527.5 o propoxy ]pyrazolo [1,5- o o a]pyrimidin-3-yl]-6- methoxy -benzamide}d <JA ° / N- [( 1 S)- 1 -cyclopropylethyl] - Jv 2 - (difluoromethoxy ) -4 - [6-1' V ° °y"zy-n^, Z [(lS)-2-hydroxy-l,2- 35 rTy u dimethyl- Int 5 504.5 505.3 propoxy ]pyrazolo [1,5- a]pyrimidin-3-yl]-6- methoxy -benzamideN-[(1R)-1- cyclopropylethyl]-2- (difluoromethoxy ) -4 - [6 - 36 [(lS)-2-hydroxy-l,2- Int 5 504.5 505.3 dimethyl- propoxy ]pyrazolo [1,5- j a]pyrimidin-3-yl]-6- methoxy -benzamide2 - (difluoromethoxy ) -N- (2 ,2 - ° ° difluoro -2 -pheny 1 -ethy 1) -4 - Vg t [6-[(lS)-2-hydroxy-l,2- p* ° dimethyl- o o o V 575.3 37 propoxy ]pyrazolo [1,5- Int 5 576.5a]pyrimidin-3-yl]-6- (M-H) 7^ methoxy -benzamideI T I 7 7^^2 - (difluoromethoxy ) -N- [2 ,2 - difluoro-2-(2-pyridyl)ethyl]- 4-[6-[(lS)-2-hydroxy-l,2- dimethyl- 576.3 38 propoxy ]pyrazolo [1,5- Int 5 577.5a]pyrimidin-3-yl]-6- (M-H) methoxy -benzamide2-(difhioromethoxy)-N-[(l - fluorocy clobuty l)methy 1] -4- [6-[(lS)-2-hydroxy-l,2- 39 dimethyl- Int 5 522.5 523.6 propoxy ]pyrazolo [1,5- a]pyrimidin-3-yl]-6- methoxy -benzamideCp MS Structure Name SM MW d# Mes’d N-(cyclobutylmethyl)-2- (difhioromethoxy )-4- [6- [(lS)-2-hydroxy-l,2- 4 X X0 X p 3: \ dimethyl- ^Z_ Int 5 504.5 505.8 propoxy ]pyrazolo [1,5- 0 a]pyrimidin-3-yl]-6- o methoxy -benzamided - , / ^ / C W o [3-(l,l-difluoro-2-hydroxy- ethyl)azetidin-l-yl]-[2- (difluoromethoxy ) -4 - [6 - 41 [(lS)-2-hydroxy-l,2- 77 Int 5 556.5 557.4 °r o X dimethyl- propoxy ]pyrazolo [1,5- a]pyrimidin-3-yl]-6- methoxy-phenyllmethanone2 - (difluoromethoxy ) -N- [(lR*,2R*)-2- (difluoromethyl)cyclopropyl]-4-[6-[(lS)-2-hydroxy-l,2- 2* dimethyl- Int 5 526.5 527.5CM propoxy ]pyrazolo [1,5- ^> U_u-U" a]pyrimidin-3-yl]-6- A) “- methoxy -benzamideHO2 - (difluoromethoxy ) -N- A^O^N-^WN z° [(lS*,2S*)-2- (difluoromethyl)cyclopropylVz\L io o ]-4-[6-[(lS)-2-hydroxy-l,2- 3* dp- dimethyl- Int 5 526.5 527.5 propoxy ]pyrazolo [1,5- I 7^ a]pyrimidin-3-yl]-6- F methoxy -benzamide(3S)-3-[3-[4-(2- aminothiazol-5-yl)-3,5- dimethoxy- pheny l]py razolo [1,5- Described44 a]pyrimidin-6-yl]oxy-2- 455.5 456.4 abovemethyl-butan-2-ol2 - (difluoromethoxy ) -4 - [6- [(lS)-2-hydroxy-l,2- dimethyl- propoxy ]pyrazolo [1,5- a]pyrimidin-3-yl]-6- m ethoxy -N-(2-methy 1-6,7 - dihydro-5H- 45 cyclopenta[b]pyridin-5- Int 5 567.6 568.4 yl)benzamideCp MS Structure Name SM MW d# Mes’d (3S)-3-[3-[4-(2-amino-3- pyridyl) -3 ,5 -dimethoxy - pheny l]py razolo [1,5- CAS# 149446 X Ip ^ a]pyrimidin-6-yl]oxy-2- 449.5 450.3 methyl-butan-2-ol 89-04-3o oN-[(lS)-2,2- 0 ' difluorocy clohexy 1] -2- (difluoromethoxy ) -4 - [6 - [(lS)-2-hydroxy-l,2- 47 V V"" dimethyl- Int7 554.5 555.3 propoxy ]pyrazolo [1,5- a]pyrimidin-3-yl]-6- methoxy -benzamideHON-[(lR)-2,2- ^Y°Y^N'N difluorocy clohexy 1] -2- "NL E (difluoromethoxy ) -4 - [6 - [(lS)-2-hydroxy-l,2- 48 dimethyl- Int7 554.5 555.3 o I propoxy ]pyrazolo [1,5- a]pyrimidin-3-yl]-6- °vsA “°\Xmethoxy -benzamidevtC zV^F / pP t0(I2 - (difluoromethoxy ) -4 - [6- [(lS)-2-hydroxy-l,2- o V oz° dimethyl- o49 propoxy ]pyrazolo [1,5- 7^ Int7 520.5 521.5 a]pyrimidin-3-yl]-N-[[l- I 7 7^^ I(hydroxymethyl)cyclopropyl]methyl]-6-methoxy- benz amide2 - (difluoromethoxy ) -N- (5 - fluoro- 1 -methy l-pyrazol-4- y l)-4- [6- [( 1 S)-2-hydroxy- 1 ,2-dimethyl- 50 propoxy ]pyrazolo [1,5- Int7 534.5 535.3 a]pyrimidin-3-yl]-6- methoxy -benzamide2 - (difluoromethoxy ) -N- (3 - fluoro- 1 -methy l-pyrazol-4- y l)-4- [6- [( 1 S)-2-hydroxy- 1 ,2-dimethyl- 51 propoxy ]pyrazolo [1,5- Int7 534.5 535.4 a]pyrimidin-3-yl]-6- methoxy -benzamideCp MS Structure Name SM MW d# Mes’d 2 - (difluoromethoxy ) -4 - [6- [(lS)-2-hydroxy-l,2- dimethyl- X Xp ^ propoxy ]pyrazolo [1,5- 52 a]pyrimidin-3-yl]-6- Int7 528.5 529.4 methoxy-N-(3- o o methylpyrazin-2- yl)benzamidec '2 - (difluoromethoxy ) -4 - [6- Pc . 1 [(lS)-2-hydroxy-l,2- A Xr °*v^. y-" o-z o [z-- dimethyl- propoxy ]pyrazolo [1,5- 53 a]pyrimidin-3-yl]-6- Int7 517.5 518.4 methoxy-N-(4- methylisoxazol-3- yl)benzamide2 - (difluoromethoxy ) -N- [(lS,2R)-2-HOA^O^N,N (difluoromethyl)cyclopropyl]-4-[6-[(lS)-2-hydroxy-l,2- k,F\ dimethyl- 0-0^ propoxy ]pyrazolo [1,5- "c / [ p ikx^~~NH a]pyrimidin-3-yl]-6- 0°1methoxy -benzamide54 f Z O- AND“W HFInt 5 526.5 527.52 - (difluoromethoxy ) -N- V po o [(lR,2S)-2-F\ (difluoromethyl)cyclopropyleV- 7 7X^^ ]-4-[6-[(lS)-2-hydroxy-l,2- X '~~O / \^-~NH dimethyl- 0 1k F propoxy ]pyrazolo [1,5- F a]pyrimidin-3-yl]-6- methoxy -benzamide2 - (difluoromethoxy ) -N- (2 , 3 - dimethylimidazol-4-yl)-4-[6- [(lS)-2-hydroxy-l,2- dimethyl- 55 propoxy ]pyrazolo [1,5- Int7 530.5 531.4 a]pyrimidin-3-yl]-6- methoxy -benzamide2 - (difluoromethoxy ) -N- (4 , 5 - dimethylisoxazol-3-yl)-4-[6- [(lS)-2-hydroxy-l,2- dimethyl- 56 propoxy ]pyrazolo [1,5- Int 7 531.5 532.4 a]pyrimidin-3-yl]-6- methoxy -benzamideIllCp MS Structure Name SM MW d# Mes’d 2 - (difluoromethoxy ) -4 - [6- [(lS)-2-hydroxy-l,2- dimethyl- z z z Ippp ^ ^ propoxy ]pyrazolo [1,5- 57 \ a]pyrimidin-3-yl]-6- Int 7 517.5 518.4 methoxy-N-(3-methyltriazol- o o o o 4-yl)benzamide0 ’ '0W V k \>> ° Pv^ □00>c « , 2 - (difluoromethoxy ) -N- (3 ,5 - — N2^5 / dimethylimidazol-4-yl)-4-[6- ^ O y'y °-\ [(lS)-2-hydroxy-l,2- / dimethyl- 58 propoxy ]pyrazolo [1,5- Int 5 530.5 531.4 a]pyrimidin-3-yl]-6- methoxy -benzamide5-[4-[6-[(lS)-2 -hydroxy-1, 2- dimethyl- propoxy ]pyrazolo [1,5- a]pyrimidin-3-yl]-2,6- Described59 dim ethoxy -phenyl] -1,3- 495.5 496.0 dimethyl-pyrimidine-2,4- above? AA "“ dione1p4 zo o 2 - (difluoromethoxy ) -4 - [6- [(lS)-2-hydroxy-l,2- 7^ dimethyl- z z propoxy ]pyrazolo [1,5- 60 a]pyrimidin-3-yl]-6- Int 7 526.5 527.4 methoxy-N-(o- tolyl)benz amide2,5-diazaspiro[3.5]nonan-2- y 1 - [2 - (difluoromethoxy ) -4 - [6-[(lS)-2-hydroxy-l,2- 61 dimethyl- Int 5 545.6 546.5 propoxy ]pyrazolo [1,5- a]pyrimidin-3-yl]-6- methoxy-phenyl]methanoneN-[(lR,2S)-2- fluorocy clopropy 1] -6- [6- [(lS)-2-hydroxy-l,2- dimethyl- Described62 propoxy ]pyrazolo [1,5- 459.5 459.48 abovea]pyrimidin-3-yl]-2,4- dimethoxy -pyridine-3 - carboxamideCp MS Structure Name SM MWd# Mes’d 2 - [ 1 - [2 - (difluoromethoxy) -4 - [6-[(lS)-2-hydroxy-l,2- dimethyl- 532.3 63 z z Io propoxy ]pyrazolo [1,5- Int 5 533.5 a]pyrimidin-3-yl]-6- (M-H) o o methoxy -benzoy 1] - 3 -fluoro - o azetidin-3 -y 1] acetonitrile[2 - (difluoromethoxy ) -4 - [6 - [(lS)-2-hydroxy-l,2- S dvdimethyl- propoxy ]pyrazolo [1,5- 64 a]pyrimidin-3-yl]-6- Int 5 545.5 546.3I z methoxy -pheny 1] - (7 -methy 1- 5-oxa-2,6- diazaspiro[3.4]oct-6-en-2- yl)methanone2 - (difluoromethoxy )-N- [(3S,4S)-3- fluorotetrahy dropyran-4-y 1] - 4-[6-[(lS)-2-hydroxy-l,2- 65 dimethyl- Int 5 538.5 539.5 propoxy ]pyrazolo [1,5- J u_ d a]pyrimidin-3-yl]-6- CS iSO- “■ "''S V ‘‘■' methoxy -benzamideti’vA\ ? Cz~ ' [(3aR,6aS)-2,3,3a,4,6,6a- hexahy dro- 1 H-py rrolo [3,4- p V V 'zc]pyrrol-5-yl]-[2- o o o(difluoromethoxy ) -4 - [6 - 68 [(lS)-2-hydroxy-l,2- Int 5 531.5 532.2 z z z 7^ dimethyl- propoxy ]pyrazolo [1,5- a]pyrimidin-3-yl]-6- methoxy -pheny l]methanoneN- [( 1 S,2S)-1 -aminoindan-2- yl]-2-(difluoromethoxy)-4- [6-[(lS)-2-hydroxy-l,2- dimethyl- propoxy ]pyrazolo [1,5- 69 a]pyrimidin-3-yl]-6- Cpd 92 567.6 568.5 methoxy -benzamide2 - (difluoromethoxy ) -4 - [6- [(lS)-2-hydroxy-l,2- dimethyl- propoxy ]pyrazolo [1,5- 70 a]pyrimidin-3-yl]-6- Int 5 517.5 518.5 methoxy-N-(3- methylisoxazol-4- yl)benzamideCp MS Structure Name SM MW d# Mes’d 2 - (difluoromethoxy ) -4 - [6- [(lS)-2-hydroxy-l,2- dimethyl- X X I00 ^ ^ propoxy ]pyrazolo [1,5- 71 a] py rimidin - 3 -y 1] -N- [2 - (2 - Int 5 560.5 561.50 hy droxy ethy 1) - 5 -methy 1 - 0 o pyrazol-3-yl]-6-methoxy- benz amidedj / jj y .j y I °T oxx^ °AJv- 2-(difhroromethoxy)-N-[l - ^ Szw(difluoromethy 1) - 5 -methy 1 - ^ V 1 fV Z-n°-ny try- pyrazol-4-yl]-4-[6-[(lS)-2- « / hy droxy- 1 ,2-dimethyl- 72 propoxy ]pyrazolo [1,5- Int 5 566.5 567.5 a]pyrimidin-3-yl]-6- methoxy -benzamide2 - (difluoromethoxy ) -4 - [6- [(lS)-2-hydroxy-l,2- dimethyl- propoxy ]pyrazolo [1,5- 73 a]pyrimidin-3-yl]-6- Int 5 544.6 545.6J rZSSj x “■^■' methoxy-N-[2-(3- methylimidazol-4-0yl)ethyl]benzamidep ' 2 - (difluoromethoxy ) -4 - [6- 0 o[(lS)-2-hydroxy-l,2- dimethyl- X X00^^ ” ” "* propoxy ]pyrazolo [1,5- 74 a]pyrimidin-3-yl]-6- Int 5 544.6 545.6 methoxy-N-[2-(l- methylimidazol-4- yl)ethyl]benzamideH02 - (difluoromethoxy ) -4 - [6- Jr ' °v [(lS)-2-hydroxy-l,2- f^N\ p dimethyl- 75 S NA< / —O\=0-^}0N_ propoxy ]pyrazolo [1,5- Int 5 554.6 555.50 ' — \f-( >=\ a]pyrimidin-3-yl]-6-f\J methoxy-N-(3- phenylpropyl)benzamide2 - (difluoromethoxy ) -N- [2 - (3 -fluoropheny l)ethy 1] -4 - [6 - [(lS)-2-hydroxy-l,2- dimethyl- 76 propoxy ]pyrazolo [1,5- Int 5 558.6 559.6 a]pyrimidin-3-yl]-6- methoxy -benzamideCp MS Structure Name SM MW d# Mes’d 2 - (difluoromethoxy ) -N- (3 ,5 - dimethylisoxazol-4-yl)-4-[6- [(lS)-2-hydroxy-l,2- z z z zO N^ dimethyl- 77 propoxy ]pyrazolo [1,5- Int 5 531.5 532.5 o o a]pyrimidin-3-yl]-6- o o methoxy -benzamideSpfi i • 2 - (difluoromethoxy ) -4 - [6- [(lS)-2-hydroxy-l,2- S>°s «r y dimethyl- 6 ’ propoxy ]pyrazolo [1,5- 78 a]pyrimidin-3-yl]-6- Int 5 516.5 517.5 methoxy-N-(3- methylimidazol-4- yl)benzamidetert-butyl 2- [2- (difluoromethoxy ) -4 - [6 - [(lS)-2-hydroxy-l,2- dimethyl- 79 646.6'" 64 propoxy ]pyrazolo [1,5- Int 5 645.7a]pyrimidin-3-yl]-6- ~°7 ifAO methoxy-benzoyl]-2,5- diazaspiro[3.5]nonane-5- Vi i ° carboxylatetert-butyl 2- [2- po (difluoromethoxy ) -4 - [6 - [(lS)-2-hydroxy-l,2- dimethyl- 80 z 7^propoxy ]pyrazolo [1,5- Int 5 532.5 533.5 a]pyrimidin-3-yl]-6- methoxy-benzoyl]-2,5- diazaspiro[3.5]nonane-5- carboxylate[2 - (difluoromethoxy ) -4 - [6 - [(lS)-2-hydroxy-l,2- dimethyl- 81 propoxy ]pyrazolo [1,5- Int 5 532.5 533.5 a]pyrimidin-3-yl]-6- methoxy-phenyl]-(5-oxa-2- azaspiro[3.4]octan-2- yl)methanone[2 - (difluoromethoxy ) -4 - [6 - [(lS)-2-hydroxy-l,2- dimethyl- 82 propoxy ]pyrazolo [1,5- Int 5 546.6 547.4 a]pyrimidin-3-yl]-6- methoxy-phenyl]-(6-oxa-2- azaspiro [3.5]nonan-2-yl)methanoneCp MS Structure Name SM MW d# Mes’d[2 - (difluoromethoxy ) -4 - [6 - [(lS)-2-hydroxy-l,2- dimethyl- 83 z z I00 ^ ^ propoxy ]pyrazolo [1,5- Int 5 546.6 547.4 a]pyrimidin-3-yl]-6- 00 methoxy-phenyl]-(5-oxa-2- 0 azaspiro [3.5]nonan-2- yl)methanone0 ' 2-azaspiro[3.5]nonan-2-yl- SV v [2 - (difluoromethoxy ) -4 - [6 - blv ° " <y"X\z ys-m[(lS)-2-hydroxy-l,2- 84 p e dimethyl- Int 5 544.6 545.4°x0XOZ z- propoxy ]pyrazolo [1,5- a]pyrimidin-3-yl]-6- methoxy-phenyl]methanone2-azaspiro[3.4]octan-2-yl-[2- (difluoromethoxy ) -4 - [6 - [(lS)-2-hydroxy-l,2- 85 dimethyl- Int 5 530.6 531.5 propoxy ]pyrazolo [1,5- a]pyrimidin-3-yl]-6- methoxy-phenyl]methanone%^CO- 6-[6-[(lS)-2-hydroxy-l,2- dimethyl- if propoxy ]pyrazolo [1,5- vi^ cAX Z° a]pyrimidin-3-yl]-N- 86 isoxazol-3-y 1-2,4- Gen 468.5 469.4 p ' dimethoxy -pyridine-3 - 0 o 0carboxamide77 7^^^T I2 - (difluoromethoxy ) -4 - [6- [(lS)-2-hydroxy-l,2- dimethyl- 89* propoxy ]pyrazolo [1,5- Int 5 506.5 507.2 a]pyrimidin-3-yl]-N- [(lS*,2S*)-2- (hydroxymethyl)cyclopropyl]-6-methoxy -benz amide2 - (difluoromethoxy ) -4 - [6- [(lS)-2-hydroxy-l,2- dimethyl- 90 propoxy ]pyrazolo [1,5- Int 5 506.5 507.2 a]pyrimidin-3-yl]-N- [(lR,2R)-2- (hydroxymethyl)cyclopropyl]-6-methoxy -benz amide2 - (difluoromethoxy ) -4 - [6- [(lS)-2-hydroxy-l,2- dimethyl- propoxy ]pyrazolo [1,5- a]pyrimidin-3-yl]-N- 91 imidazo[l,2-a]pyridin-2-yl- Int 5 552.5 553.56-methoxy -benzamideCp MS Structure Name SM MW d# Mes’d tert-butyl N- [( 1 S,2S)-2- [[2- (difhioromethoxy )-4- [6- [(lS)-2-hydroxy-l,2- I I X dimethyl- propoxy ]pyrazolo [1,5- 92 a]pyrimidin-3-yl]-6- Int 5 567.6 568.5O o o methoxy- benzoyl]amino]indan-l -1yl]carbamate0 lx .np Q- . 2 - (difluoromethoxy )-N- Ay,. 02 $ / * 0 °y- [(3R,4R)-3- A* F fluorotetrahy dropyran-4-y 1] - 4-[6-[(lS)-2-hydroxy-l,2- 95 OA~Fdimethyl- Int 5 538.5 539.5-o7V propoxy ]pyrazolo [1,5- o <Z~N -.Ha]pyrimidin-3-yl]-6- F,... / \ methoxy -benzamide^-o7N-((S)-2,2- difluorocyclobutyl)-2- (difluoromethoxy ) -4 - (6 - 96 A JA (((S)-3-hydroxy-3- Int 5 526.5 527.5 methylbutan-2- yl)oxy)pyrazolo[l,5- a]pyrimidin-3-yl)-6- gA' methoxy benzamideAo o N-((R)-2,2- difluorocyclobutyl)-2- (difluoromethoxy ) -4 - (6 - X X 77^^(((S)-3-hydroxy-3- 97 methylbutan-2- Int 5 526.5 527.5 yl)oxy)pyrazolo[l,5- a]pyrimidin-3-yl)-6- methoxy benzamide2 - (difluoromethoxy ) -N- ((lS,2R)-2- fluorocyclopentyl)-4-(6- (((S)-3-hydroxy-3- 98 methylbutan-2- Int 5 522.5 523.4 yl)oxy)pyrazolo[l,5- a]pyrimidin-3-yl)-6- methoxy benzamideethyl (IS, 2S)-2-(2- (difluoromethoxy ) -4 - (6 - (((S)-3-hydroxy-3- 99 methylbutan-2- Int 5 576.6 577.6 yl)oxy)pyrazolo[l,5- a]pyrimidin-3-yl)-6- methoxybenzamido)cy elopentane- 1 -carboxylateCp MS Structure Name SM MW d# Mes’d 2 - (difluoromethoxy ) -N- ((ls,3R)-3- fluorocyclobutyl)-4-(6-(((S)- z z zop ^ 3 -hydroxy - 3 -methy Ibutan -2 - 100 yl)oxy)pyrazolo[l,5- Int 5 508.5 509.3 a]pyrimidin-3-yl)-6- o o o methoxy benzamideWJy p ( S) -2 - (difluoromethoxy ) -4 - (6-((3-hydroxy-3- y?y t4y ° v-r =- methylbutan-2-zO yl)oxy)pyrazolo[l,5- 101 a]pyrimidin-3-yl)-6- Int 5 516.5 517.4 methoxy-N-( 1 -methyl- 1 H- imidazol-2-yl)benzamide( S) -2 - (difluoromethoxy ) -N- (5-(difluoromethyl)- 1 - methy 1-1 H-pyrazol-4-y l)-4- (6-((3-hydroxy-3- 102 / ,x fi-• methylbutan-2- Int 5 566.5 567.3^J_4. y ° yl)oxy)pyrazolo[l,5- a]pyrimidin-3-yl)-6- methoxy benzamidey y2 - (difluoromethoxy ) -N- v P ((lR,5S,6s)-3,3-dioxido-3- o o othiabicyclo[3.1 ,0]hexan-6- yl)-4-(6-(((S)-3-hydroxy-3- z 7 7^z z ^^ methylbutan-2- 103 yl)oxy)pyrazolo[l,5- Int 5 566.6 567.2 a]pyrimidin-3-yl)-6- methoxy benzamide2 - (difluoromethoxy ) -N- ((lR,5S,6r)-3,3-dioxido-3- thiabicyclo[3.1 ,0]hexan-6- yl)-4-(6-(((S)-3-hydroxy-3- methylbutan-2- 104 567.2 yl)oxy)pyrazolo[l,5- Int 5 566.6 a]pyrimidin-3-yl)-6- methoxy benzamide2 - (difluoromethoxy ) -N- ((lS,2S)-2-hydroxy-2- methylcyclopentyl)-4-(6- (((S)-3-hydroxy-3- 105 methylbutan-2- Int 5 534.6 535.7 yl)oxy)pyrazolo[l,5- a]pyrimidin-3-yl)-6- methoxy benzamideCp MS Structure Name SM MW d# Mes’d ( S) - (2 - (difluoromethoxy ) -4 - (6-((3-hydroxy-3- methylbutan-2- yl)oxy)pyrazolo[l,5- 106 ^ ^a]pyrimidin-3-yl)-6- Int 5 546.6 547.6 methoxyphenyl)(6-hydroxy- 6 -methyl -2- azaspiro [3.3]heptan-2- jj y yl)methanone2^" / 2 - (difluoromethoxy ) -4 - (6- (((S)-3-hydroxy-3- QCr v methylbutan-2- F yl)oxy)pyrazolo[l,5- 107 a]pyrimidin-3-yl)-6- Int 5 502.5 503.6 methoxy-N- (spiro [2.2]pentan- 1 - yl)benzamide2 - (difluoromethoxy )-N-((S)- 4 , 4 -difluorotetrahy dro -2H- pyran-3-yl)-4-(6-(((S)-3- hydroxy-3-methylbutan-2- 108 7" yl)oxy)pyrazolo[l,5- Int 5 556.5 557.6 a]pyrimidin-3-yl)-6- 9 i / ) ^ methoxy benzamideHoj (S)-N-((5-oxa-6- o o azaspiro[3.4]oct-6-en-7- "N\L F(yl)methyl)-2- 109 7 (difluoromethoxy)-4-(6-((3- Int 5 559.6 560.4 X X 7^^■~~oz\ hydroxy-3-methylbutan-2- yl)oxy)pyrazolo[l,5- N-0 r"' a]pyrimidin-3-yl)-6- methoxy benzamide2 - (difluoromethoxy ) -4 - (6- (((S)-3-hydroxy-3- methylbutan-2- yl)oxy)pyrazolo[l,5- 110 a]pyrimidin-3-yl)-N- Int 5 536.5 537.4((3R,4S)-3- hydroxytetrahydro-2H- pyran-4-yl)-6- methoxy benzamide2 - (difluoromethoxy ) -4 - (6- (((S)-3-hydroxy-3- methylbutan-2- yl)oxy)pyrazolo[l,5- 111 a]pyrimidin-3-yl)-N- Int 5 536.5 537.4((3R,4R)-3- hydroxytetrahydro-2H- pyran-4-yl)-6-methoxy benzamideCp MS Structure Name SM MW d# Mes’d 2 - (difluoromethoxy ) -N- ((3R,4S)-3-fluorotetrahydro- 2H-pyran-4-yl)-4-(6-(((S)-3- z I I I hydroxy-3-methylbutan-2- 112 p o ^yl)oxy)pyrazolo[l,5- Int 5 538.5 539.4 o o a]pyrimidin-3-yl)-6- o o methoxy benzamide0 ’ 'bVP °Jr o^P v 1 (S)-2-(difluoromethoxy)-N- y-n (l,3-dimethyl-lH-pyrazol-5- ° °1yK yl)-4-(6-((3-hydroxy-3- methylbutan-2- 113 yl)oxy)pyrazolo[l,5- Int 5 530.5 531.4 a]pyrimidin-3-yl)-6- methoxy benzamide(S)-2-(difluoromethoxy)-N- (l,4-dimethyl-lH-pyrazol-3- yl)-4-(6-((3-hydroxy-3- methylbutan-2- 114 yl)oxy)pyrazolo[l,5- Int 5 530.5 531.5 a]pyrimidin-3-yl)-6- methoxy benzamide5 ^°o (S)-N-(5-cyclopropyl-l- methyl-lH-pyrazol-4-yl)-2- (difluoromethoxy)-4-(6-((3- z 7^ hydroxy-3-methylbutan-2- 115 yl)oxy)pyrazolo[l,5- Int 5 556.6 557.4 a]pyrimidin-3-yl)-6- methoxy benzamide( S) -2 - (difluoromethoxy ) -N- ( 1 ,5-dimethy 1- 1 H-pyrazol-4- yl)-4-(6-((3-hydroxy-3- methylbutan-2- 116 yl)oxy)pyrazolo[l,5- Int 5 530.5 531.5 a]pyrimidin-3-yl)-6- methoxy benzamideHoJ (S)-3-((3-(3,5-dimethoxy-4- >Y °Y^N'\ (lH-pyrazol-4- yl)phenyl)pyrazolo[l ,5- a]pyrimidin-6-yl)oxy)-2- Described117 424.4Qv methylbutan-2-ol 423.4above"-o y^N'NHCp MS Structure Name SM MWd# Mes’d 2 - (difluoromethoxy ) -N- ((lR,5S)-3,3-dioxido-3- thiabicyclo[3.1 ,0]hexan-6- X XO x^ XF\ yl)-4-(6-(((S)-3-hydroxy-3- 118 z= / ~° methylbutan-2- ~~o \ yl)oxy)pyrazol Int 5 566.6 567.5 <Z~NH o[l,5- O o a]pyrimidin-3-yl)-6- ° K methoxy benzamide°Gw 2^- / / / 7 o. 0 °— T JQ” °* C\ oy. -n 2 - (difluoromethoxy ) -4 - (6- Xzr 'Z^Ox- (((S)-3-hydroxy-3- / n z X -,methylbutan-2- yl)oxy)pyrazolo[l,5- 119 a]pyrimidin-3-yl)-6- Int 5 531.6 532.5 methoxy-N-((lR,5S,6s)-3- methyl-3- azabicyclo[3.1 ,0]hexan-6- yl)benzamide[2 - (difluoromethoxy ) -4 - [6 - ro I [(lS)-2-hydroxy-l,2- / / O■ dimethyl- J A propoxy ]pyrazolo [1,5- 120 9 A " a]pyrimidin-3-yl]-6- Int 5 518.5 519.3 methoxy-pheny 1] -[( 1R,5S)- 6-hydroxy-3- p ' azabicyclo[3.1 ,0]hexan-3- 0 o o Vzyllmethanone2 - (difluoromethoxy ) -N- O^ ~ "I I X 7^ [(5,5-dimethyl-4H-isoxazol- 3-yl)methyl]-4-[6-[(lS)-2- 121 hydroxy- 1 ,2-dimethyl- Int 5 547.6 548.9 propoxy ]pyrazolo [1,5- a]pyrimidin-3-yl]-6- methoxy -benzamide2 - (difluoromethoxy ) -4 - [6- [(lS)-2-hydroxy-l,2- dimethyl- propoxy ]pyrazolo [1,5- 535.3 122 a]pyrimidin-3-yl]-N- Int 5 536.5(M-H) [(3S,4R)-3- hy droxy tetrahy dropy ran -4 - yl]-6-methoxy -benzamide2 - (difluoromethoxy ) -4 - [6- [(lS)-2-hydroxy-l,2- dimethyl- propoxy ]pyrazolo [1,5- 123 a]pyrimidin-3-yl]-N- Int 5 536.5 537.4[(3S,4S)-3- hy droxy tetrahy dropy ran -4 - yl]-6-methoxy -benzamideCp MS Structure Name SM MWd# Mes’d 2 - (difluoromethoxy )-N- [(3S,4R)-3- fluorotetrahy dropyran-4-y 1] - I I I 4-[6-[(lS)-2-hydroxy-l,2- 124 dimethyl- Int 5 538.5 539.3 propoxy ]pyrazolo [1,5- o o o a]pyrimidin-3-yl]-6- methoxy -benzamidebV \CrV / A o 2 - (difluoromethoxy ) -4 - [6- Tlr°j° °^ < [(lS)-2-hydroxy-l,2- 6 " dimethyl- C^r" y °’ °K-\“n\ x 516.3 125 propoxy ]pyrazolo [1,5- Int 5 517.5a]pyrimidin-3-yl]-N- (M-H) (isoxazol-4-ylmethyl)-6- methoxy -benzamide2 - (difluoromethoxy ) -N- [(3R)-4,4- difluorotetrahy dropyran-3 - y 1] -4- [6- [( 1 S)-2-hydroxy- 537.3 126 Pz' 1 ,2-dimethyl- Int 5 538.5propoxy ]pyrazolo [1,5- (M-H) a]pyrimidin-3-yl]-6- methoxy -benzamideH?W tert-butyl N-[(7S*)-2-[2- p 'N(difluoromethoxy ) -4 - [6 - o [(lS)-2-hydroxy-l,2- 127 "N\L 1 dimethyl- 7^ CKo^ propoxy ]pyrazolo [1,5- * T Int 5 631.7 632.4"o'' \ - a]pyrimidin-3-yl]-6- o^<\>methoxy -benzoyl] -2- azaspiro [3.3]heptan-7 - 0 yl]carbamatetert-butyl N-[(7R*)-2-[2- (difluoromethoxy ) -4 - [6 - [(lS)-2-hydroxy-l,2- 128 dimethyl- propoxy ]pyrazolo [1,5- Int 5 631.7 632.4 *a]pyrimidin-3-yl]-6- methoxy -benzoyl] -2- azaspiro [3.3]heptan-7 - yl]carbamate6-[6-[(lS)-2-hydroxy-l,2-H0^Y°Y^NA dimethyl- SI''”5 / propoxy ]pyrazolo [1,5- a]pyrimidin-3-yl]-2,4- Described130 fl- / dimethoxy-N-[(l S)-2,2,2- 497.5 498.4 abovetrifluoro- 1 -methy 1-Fethyl]pyridine-3- / f F-F carboxamideCp MS Structure Name SM MW d# Mes’d N-[(lR,2R)-2- fluorocy clopropy 1] -6- [6- [(lS)-2-hydroxy-l,2- X X Describedpp ^ ^ dimethyl- 131 prop 459.5 460.4oxy ]pyrazolo [1,5- abovea]pyrimidin-3-yl]-2,4- O odimethoxy -pyridine-3 - carboxamide0 '°GYV N-[(lR,2R)-2-$ °r aminocyclohexyl]-6-[6- [(lS)-2-hydroxy-l,2- °y-n_Described dimethyl- Co 132 499.4 498...

Claims

1. CLAIMSwhereinW is N or CH;one of Xi and X2 is N and the other one is C, with the proviso that when W is CH, X2 is not N;R1is H or -P(=O)(OH)2;RAis- H,Ci -4 alkyl optionally substituted with one or more independently selected halo,- -NRB1RB2; andEach RB1and RB2is independently selected from H, C1-4 alkyl optionally substituted with one or more independently selected halo, or phenyl,Yi is selected from N and CR2b;Each Y2 and Y3 is independently selected from N and CH provided that Y2, and Y3, are not simultaneously N,R3is5-6 membered heteroaryl comprising one or more independently selected N, O, or S heteroatoms optionally substituted with one or more independently selectedo halo,o -OH,o -NH2,o Ci -4 alkyl optionally substituted with one or more independently selected halo, or Ci -4 alkyl optionally substituted with one or more independently selected halo, or- -C(=O)Z, or- -CN;Z is- -NH2,- -NH-L-R3a,- -NH-R3a,- -linked 4-7 membered heterocycloalkyl further comprising zero, one, or two additional heteroatoms independently selected from N, O, P or S, optionally substituted with one or more independently selected R7groups,- '-l inked 5-12 membered bicyclic fused, bridged or spiro heterocycloalkyl, further comprising zero, one, or two additional independently selected N, O, P or S heteroatoms, optionally comprising one or more double bonds, which heterocycloalkyl is optionally substituted with one or more groups independently selected from R7; or- -NR3b-, wherein the N atom and R2atogether with the atoms onto which they are attached form a fused 5-6 membered heterocycloalkenyl comprising one or two double bonds;R2aand R2bare independently selected from- halo,- Ci-4 alkyl,- Ci-4 alkoxy optionally substituted with one or more independently selected halo or Ci-4 alkoxy, and - -NR6aR6b;L is- S(O)2, or- Ci-4 alkylenyl optionally substituted with one or more independently selected halo;R3ais- Ci-6 alkyl optionally substituted with one or more independently selected R8,- C3-7 cycloalkyl optionally substituted with one or more groups independently selected from =0 and R8, - 5-12 membered bicyclic fused, bridged or spiro cycloalkyl, optionally comprising one or more double bonds, which heterocycloalkyl is optionally substituted with one or more groups independently selected from =0 and R8;- 4-7 membered monocyclic heterocycloalkyl, comprising one or more independently selected N, O, P or S heteroatoms, optionally substituted with one or more groups independently selected from =0 and R8, or- 5-12 membered bicyclic fused, bridged or spiro heterocycloalkyl, comprising one or more independently selected N, O, P or S heteroatoms, optionally comprising one or more double bonds, which heterocycloalkyl is optionally substituted with one or more groups independently selected from =0 and R8;- 5-6 membered heteroaryl comprising one or more independently selected N, O, or S heteroatoms optionally substituted with one or more independently selected R8;R3bis selected from H, C3-7 cycloalkyl and C1-6 alkyl optionally substituted with one or more independently selected halo or -CN;each R6aand R6bis independently selected from H and C1-4 alkyl;each R7is independently selected from =0, -OH, -CN, and C1-4 alkyl optionally substituted with one or more independently selected halo or -CN;each R8is independently selected from- halo,- -CN,- -OH,- -NH2,- Ci-6 alkyl optionally substituted with one or more independently selected halo, CN or OH, and - Ci-6 alkoxy optionally substituted with one or more independently selected halo, CN or OH, provided that the compound is not:- 2-(difluoromethoxy)-N-[(lR,2S)-2-fluorocyclopropyl]-4-[6-[(2S)-3-hydroxy-3-methylbutan-2- yl] oxypyrazolo [ 1 ,5 -a]pyrimidin-3 -yl] -6-methoxybenzamide- 2-(difluoromethoxy)-N-[(lR,2S)-2-fluorocyclopropyl]-4-[7-[(2S)-3-hydroxy-3-methylbutan-2- yl] oxyimidazo [1,2 -b]pyridazin-3 -yl] -6-methoxybenzamide- 2-(difluoromethoxy)-N-[(lR,2S)-2-fluorocyclopropyl]-4-[7-(3-hydroxy-3-methylbutan-2- yl)oxyimidazo[l,2-b]pyridazin-3-yl]-6-methoxybenzamide- 2-(difluoromethoxy)-N-[(lR,2S)-2-fluorocyclopropyl]-4-[6-(3-hydroxy-3-methylbutan-2- yl)oxypyrazolo [ 1 ,5 -a]pyrimidin-3 -yl] -6-methoxybenzamide- [(3S)-3-[3-[3-(difluoromethoxy)-4-[[(lR,2S)-2-fluorocyclopropyl]carbamoyl]-5- methoxyphenyl] imidazo[ l,2-b]pyridazin-7-yl]oxy-2-methylbutan-2-yl] dihydrogen phosphate - [(3S)-3-[3-[3-(difluoromethoxy)-4-[[(lR,2S)-2-fluorocyclopropyl]carbamoyl]-5- methoxyphenyl]pyrazolo[l,5-a]pyrimidin-6-yl]oxy-2-methylbutan-2-yl] dihydrogen phosphate - 2-(difluoromethoxy)-N-[(lR,2S)-2-fluorocyclopropyl]-4-[7-[(2S)-3-hydroxy-3-methylbutan-2- yl] oxy-6-methylimidazo [ 1 ,2-b]pyridazin-3 -yl] -6-methoxybenzamide- 2-(difluoromethoxy)-N-[(lR,2S)-2-fluorocyclopropyl]-4-[6-[(2R)-3-hydroxy-3-methylbutan-2- yl] oxypyrazolo [ 1 ,5 -a]pyrimidin-3 -yl] -6-methoxybenzamide- [(3S)-3-[3-[3-(difluoromethoxy)-4-[[(lR,2S)-2-fluorocyclopropyl]carbamoyl]-5-methoxyphenyl]-6- methylimidazo [ 1 ,2-b]pyridazin-7 -yl] oxy-2 -methylbutan-2-yl] dihydrogen phosphate- 2-(difluoromethoxy)-N-[(lR,2S)-2-fluorocyclopropyl]-4-[6-[(2S*)-3-hydroxy-3-methylbutan-2- yl] oxy-5 -methylpyrazolo [1,5 -a]pyrimidin-3 -yl] -6-methoxybenzamide- 2-(difluoromethoxy)-N-[(lR,2S)-2-fluorocyclopropyl]-4-[6-[(2R*)-3-hydroxy-3-methylbutan-2- yl] oxy-5 -methylpyrazolo [1,5 -a]pyrimidin-3 -yl] -6-methoxybenzamide- 2-(difluoromethoxy)-4-(5-(dimethylamino)-6-(((R*)-3-hydroxy-3-methylbutan-2- yl)oxy)pyrazolo[l,5-a]pyrimidin-3-yl)-N-((lR,2S)-2-fluorocyclopropyl)-6-methoxybenzamide - 2-(difluoromethoxy)-4-(5-(dimethylamino)-6-(((S*)-3-hydroxy-3-methylbutan-2- yl)oxy)pyrazolo[l,5-a]pyrimidin-3-yl)-N-((lR,2S)-2-fluorocyclopropyl)-6-methoxybenzamide - 2-(difluoromethoxy)-4-(5-ethyl-6-(((R*)-3-hydroxy-3-methylbutan-2-yl)oxy)pyrazolo[l,5- a]pyrimidin-3-yl)-N-((lR,2S)-2-fluorocyclopropyl)-6-methoxybenzamide- 2-(difluoromethoxy)-4-(5-ethyl-6-(((S*)-3-hydroxy-3-methylbutan-2-yl)oxy)pyrazolo[l,5- a]pyrimidin-3-yl)-N-((lR,2S)-2-fluorocyclopropyl)-6-methoxybenzamide- 2-(difluoromethoxy)-4-(5-(difluoromethyl)-6-(((R*)-3-hydroxy-3-methylbutan-2- yl)oxy)pyrazolo[l,5-a]pyrimidin-3-yl)-N-((lR,2S)-2-fluorocyclopropyl)-6-methoxybenzamide - 2-(difluoromethoxy)-4-(5-(difluoromethyl)-6-(((S*)-3-hydroxy-3-methylbutan-2- yl)oxy)pyrazolo[l,5-a]pyrimidin-3-yl)-N-((lR,2S)-2-fluorocyclopropyl)-6-methoxybenzamide - 4-(5 -(benzylamino)-6-((3 -hydroxy-3 -methylbutan-2-yl)oxy)pyrazolo [ 1 ,5 -a]pyrimidin-3 -yl)-2- (difluoromethoxy)-N-((lR,2S)-2-fluorocyclopropyl)-6-methoxybenzamide- 4-(5-amino-6-((3-hydroxy-3-methylbutan-2-yl)oxy)pyrazolo[l,5-a]pyrimidin-3-yl)-2- (difluoromethoxy)-N-((lR,2S)-2-fluorocyclopropyl)-6-methoxybenzamide- 4-(5-(benzyl(methyl)amino)-6-((3-hydroxy-3-methylbutan-2-yl)oxy)pyrazolo[l,5-a]pyrimidin-3-yl)- 2-(difluoromethoxy)-N-((lR,2S)-2-fluorocyclopropyl)-6-methoxybenzamide- 2-(difluoromethoxy)-N-((lR,2S)-2-fluorocyclopropyl)-4-(6-(((R*)-3-hydroxy-3-methylbutan-2- yl)oxy)-5-(methylamino)pyrazolo[l,5-a]pyrimidin-3-yl)-6-methoxybenzamide, or- 2-(difluoromethoxy)-N-((lR,2S)-2-fluorocyclopropyl)-4-(6-(((S*)-3-hydroxy-3-methylbutan-2- yl)oxy)-5 -(methylamino)pyrazolo [ 1 ,5 -a]pyrimidin-3 -yl)-6-methoxybenzamide ;or a pharmaceutically acceptable salt, solvate, solvate of a pharmaceutically acceptable salt or a prodrug thereof.

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

3. A compound or pharmaceutically acceptable salt thereof, according to claim 1, wherein Y2 is CH, and Y3is N.

4. A compound or pharmaceutically acceptable salt thereof, according to claim 1, wherein Yi is N.

5. A compound or pharmaceutically acceptable salt thereof, according to claim 1, wherein the compound is according to Formula IVa or IVb :IVa IVb6. A compound or pharmaceutically acceptable salt thereof, according to any one of claims 1-5, wherein R2ais -CH3, -CH2CH3, or -CH(CH3)2, -O-CH3, -O-CH2CH3,-O-CH(CH3)2, -O-CHF2or -O-CH2CH2-O-CH2CH3.

7. A compound or pharmaceutically acceptable salt thereof, according to any one of claims 1 -6, wherein CR2band R2bis C1-4 alkoxy.

8. A compound or pharmaceutically acceptable salt thereof, according to claim 1, wherein the compound is according Formula Va, Vb, Vc, Vd, Ve or Vf:Vc VdVe Vf9. A compound or pharmaceutically acceptable salt thereof, according to any one of claims 1 -8, wherein Z is selected from10. A compound or pharmaceutically acceptable salt thereof, according to any one of claims 1 -8, wherein Z is -NH-R3a.

11. A compound or pharmaceutically acceptable salt thereof, according to claim 9, wherein R3ais selected from:51012. The compound, pharmaceutically acceptable salt, solvate, or solvate of a pharmaceutically acceptable salt thereof according to any one of claims 1-8, wherein R1is H.

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 according to 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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