LPARl is the first high-affinty receptor identified for lysophosphatidic acids (LP A), which are small bioactive glycerophospholipids. LPA-mediated LPARl activation implicates numerous cellular responses including cell proliferation, migration, and survival. Particularly, the LPA-LPARl pathway may contribute to the development of non-alcoholic steatohepatitis (NASH), which is a liver disease characterized by fat deposits, inflammation and tissue damage. NASH progression leads to the accumulation of scarring, or fibrosis, in the liver. If further advanced, NASH can cause cirrhosis and portal hypertension. About 2-5 percent of adult Americans and up to 20 percent of those who are obese may suffer from NASH. Beyond fibrosis and cirrhosis, NASH may progress to hepatocellular carcinoma and liver failure.

It has been suggested that inhibition of LPARl may be useful in treating

inflammation, fibrosis, and other LPARl -mediated diseases or disorders. For example, U.S. Patent No. 9,272,990 discloses LPAR antagonists for treating fibrosis.

PCT Publication No. WO 2017/086430 discloses an a halogen-substitued thiophene compound as LPARl antagonsist for the treatment and/or prophylaxis of NASH.

There is an unmet need for LPARl antagonist compounds that may be useful for treating NASH as well as other LPARl -mediated diseases or disorders. Thus, the present invention provides compounds which display potent and selective LPARl antagonist activities in vitro, as well as efficacy in an animal model of liver inflammation and fibrosis. Further, the present invention provides ester prodrug of such LPARl antagonist compounds. Particularly, the present invention provides a compound of Formula I

wherein,

X1 and X2 are each independently CH or N, and X3 is C-R2 or N, provided that when X1 is CH, then X2 is CH and X3 is C-R2, and provided that when X1 is N, then no more than one of X2 and X3 may be N;

Y1 and Y2 are CH or N, provided that only one of Y1 or Y2 may be N;

RMs

isopropyl,

isobutyl,

t-butyl,

2-hydroxyprop-2-yl,

cyclopropyl,

cyclopropyloxy,

t-butyl oxy,

cyclobutyloxy,

3,3-difluorocyclobutyloxy,

2-fluoroprop-2-yl,

1, 1-difluoroethyl,

trifluorom ethyl,

isopropyl oxy, or

2-methoxyprop-2-yl;

R2 is H or fluoro;

R3 is H, halogen, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 alkoxymethyl, CF3, cyanomethyl or cyano;

R4 is H, halogen, C1-C3 alkyl, CF3 or cyano;

R5 is H, methyl, ethyl, propyl, isopropyl, or cyclopropyl; or

a pharmaceutically acceptable salt thereof.

In one embodiment, X1 is N.

In one embodiment, X1 is CH.

In one embodiment, Y1 is CH.

In one embodiment, R1 is isopropyl.

In one embodiment, R1 is cyclopropyl oxy.

In one embodiment, R3 is H, methyl, methoxymethyl, cyanomethyl or cyano.

In one embodiment, R4 is H, methyl, CF3, or cyano.

In one embodiment, R5 is H.

In another embodiment, a compound of the present invention is any one of the compounds of the examples, or a pharmaceutically acceptable salt thereof.

In another aspect of the present invention there is provided a pharmaceutical composition, comprising a compound of Formula I, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier, diluent, or excipient. This aspect of the invention also provides a pharmaceutical composition for treating NASH in a mammal, particularly a human, comprising a compound of Formula I, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients, carriers, or diluents. Furthermore, this aspect of the present invention provides a pharmaceutical composition for treating fibrosis in a mammal, particularly a human, as for example pulmonary fibrosis, liver fibrosis, kidney fibrosis, heart fibrosis or skin fibrosis, comprising a compound of Formula I, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients, carriers, or diluents. Furthermore, this aspect of the present invention provides a pharmaceutical composition for treating inflammatory diseases in a mammal, particularly a human, as for example chronic respiratory disease, chronic

obstructive pulmonary disease (COPD), multiple sclerosis, rheumatoid arthritis,

osteoarthritis, psoriasis, systemic lupus erythematosus, scleroderma, Sjorgen's syndrome, ulcerative colitis and Crohn's disease, comprising a compound of Formula I, or a

pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients, carriers, or diluents.

In another aspect of the present invention there is provided a method of treating NASH in a mammal, particularly a human, comprising administering to a mammal in need of such treatment an effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof.

In one embodiment of this aspect of the present invention provides a method of treating fibrosis in a mammal, particularly a human, as for example pulmonary fibrosis, liver fibrosis, kidney fibrosis, heart fibrosis or skin fibrosis, comprising administering to a mammal in need of such treatment an effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof.

In another embodiment of this aspect of the present invention provides a method of treating treating inflammatory diseases in a mammal, particularly a human, as for example chronic respiratory disease, chronic obstructive pulmonary disease (COPD), multiple sclerosis, rheumatoid arthritis, osteoarthritis, psoriasis, systemic lupus erythematosus, scleroderma, Sjorgen's syndrome, ulcerative colitis and Crohn's disease, comprising administering to a mammal in need of such treatment an effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof.

In another aspect of the present invention there is provided a compound of Formula I, or a pharmaceutically acceptable salt thereof for use in therapy. Within this aspect, the invention provides a compound of Formula I, or a pharmaceutically acceptable salt thereof, for use in the treatment of NASH in a mammal, particularly a human. The present invention also provides a compound of Formula I, or a pharmaceutically acceptable salt thereof, for use in the treatment of fibrosis in a mammal, particularly a human, as for example pulmonary fibrosis, liver fibrosis, kidney fibrosis, heart fibrosis or skin fibrosis. The present invention also provides a compound of Formula I, or a pharmaceutically acceptable salt thereof, for use in the treatment of inflammatory diseases in a mammal, particularly a human. In an embodiment of this aspect of the invention said inflammatory disease is selected from the group consisting of, but not limited to, chronic respiratory disease, chronic obstructive pulmonary disease (COPD), multiple sclerosis, rheumatoid arthritis, osteoarthritis, psoriasis, systemic lupus erythematosus, scleroderma, Sjorgen's syndrome, ulcerative colitis and Crohn's disease

Another aspect of the present invention provides the use of a compound of Formula I, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of NASH in a mammal.

Another aspect of the present invention provides the use of a compound of Formula I, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of fibrosis in a mammal.

A further aspect of the present invention provides the use of a compound of Formula I, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of inflammatory diseases in a mammal. In an embodiment of this aspect of the invention said inflammatory disease is selected from the group consisting of, but not limited to, chronic respiratory disease, chronic obstructive pulmonary disease (COPD), multiple sclerosis, rheumatoid arthritis, osteoarthritis, psoriasis, systemic lupus erythematosus, scleroderma, Sjorgen's syndrome, ulcerative colitis and Crohn's disease.

As used herein, the term "effective amount" or "therapeutically effective amount" of a compound refers to an amount, or a dosage, which is effective in treating a disorder or a disease, such as NASH, fibrosis, inflammatory diseases, other LP ARl -mediated diseases or disorders as described herein. The attending diagnostician, as one skilled in the art, can readily determine an effective amount by the use of conventional techniques and by observing results obtained under analogous circumstances. In determining the effective amount or dose of a compound, a number of factors are considered, including but not limited

to, the compound to be administered; the co-administration of other agents, if used; the species of mammal; its size, age, and general health; the degree of involvement or the severity of the disorder; the response of the individual patient; the mode of administration; the bioavailability characteristics of the preparation administered; the dose regimen selected; the use of other concomitant medication; and other relevant circumstances.

The terms "treatment" and "treating" as used herein are intended to refer to all processes wherein there may be a slowing, interrupting, arresting, controlling, or stopping of the progression of an existing disorder and/or symptoms thereof, but does not necessarily indicate a total elimination of all symptoms.

The term "pharmaceutically acceptable carrier, diluent, or excipients" means that the carrier, diluent, and excipients are pharmaceutically compatible with the other ingredients of the composition. In a particular embodiment, the pharmaceutical compositions are formulated as a tablet or capsule for oral administration. The tablet or capsule can include a compound of the present invention in an amount effective to treat fibrosis, inflammatory diseases, NASH, other LP AR1 -mediated diseases or disorders.

As used herein, the term "fibrosis" refers to the formation or presence of excessive connective tissue in an organ or tissue. Fibrosis may occur as a repair or replacement response to a stimulus such as tissue injury or inflammation. A hallmark of fibrosis is the production of excessive extracellular matrix. The normal physiological response to injury results in the deposition of connective tissue as part of the healing process, but this connective tissue deposition may persist and become pathological, altering the architecture and function of the tissue. In exemplary embodiments, the fibrosis is pulmonary fibrosis, liver fibrosis, kidney fibrosis, heart fibrosis, or skin fibrosis.

While it is possible to administer compounds employed in the methods of this invention directly without any formulation, the compounds are usually administered in the form of pharmaceutical compositions comprising the compound of Formula I, or a pharmaceutically acceptable salt thereof, as an active ingredient and at least one

pharmaceutically acceptable carrier, diluent and/or excipient. These compositions can be

administered by a variety of routes including oral, sublingual, nasal, subcutaneous, intravenous, and intramuscular. Such pharmaceutical compositions and processes for preparing them are well known in the art. See, e.g., Remington: The Science and Practice of Pharmacy (University of the Sciences in Philadelphia, ed., 21st ed., Lippincott Williams & Wilkins Co., 2005).

Compounds of Formula I are generally effective over a wide dosage range. For example, dosages per day normally fall within the range of about 0.2 mg/kg to about 15 mg/kg, more usually from about 0.7 mg/kg to about 7.5 mg/kg, and as for example about 1.5 mg/kg of body weight. In some instances dosage levels below the lower limit of the aforesaid range may be more than adequate, while in other cases still larger doses may be employed without causing any harmful side effect, and therefore the above dosage ranges are not intended to limit the scope of the invention in any way. It may also be advantageous to administer the daily dose in parts over the course of each day (e.g. ½ dose twice a day or 1/3 dose three times a day). It will be understood that the amount of the compound actually administered will 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 or compounds administered, the age, weight, and response of the individual patient, and the severity of the patient's symptoms.

The compositions are preferably formulated in a unit dosage form, each dosage containing from about 20 to about 2000 mg, more usually about 50 to about 500 mg, as for example about 200 mg of the active ingredient. The term "unit dosage form" 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 at least one suitable pharmaceutically acceptable carrier, diluent and/or excipient.

Compounds of this invention have basic and acidic moieties, and accordingly react with a number of organic and inorganic acids and bases to form pharmaceutically acceptable salts. Pharmaceutically acceptable salts of the compound of the present invention are

contemplated within the scope of the present application. The term "pharmaceutically acceptable salt" as used herein, refers to any salt of the compound of the invention that is substantially non-toxic to living organisms. Such pharmaceutically acceptable salts and common methodology for preparing them are well known in the art. See, e.g., P. Stahl, et al., HANDBOOK OF PHARMACEUTICAL SALTS: PROPERTIES, SELECTION AND USE, (VCHA/Wiley-VCH, 2008); and S.M. Berge, et al, "Pharmaceutical Salts", Journal of Pharmaceutical Sciences, Vol 66, No. 1, January 1977.

Abbreviations used herein are defined as follows:

"Brine" means saturated NaCl.

"BSA" means bovine serum albumin

"DAST" means diethylaminosulfur trifluoride

"DCM" means dichloromethane.

"DMF" means n ,n-dimethylformamide

"DMSO" means dimethyl sulfoxide (perdeuterated [ d6] if for NMR).

"EtOAc" means ethyl acetate.

"FLIPR" means fluorescence imaging plate reader.

"HBSS" means Hank's Buffered Salt Solution.

"HEPES" means 4-(2-hydroxyethyl)-l-piperazine ethanesulfonic acid.

"HPLC" means high pressure liquid chromatography,

"hr." or "h" means hour or hours.

"IC50" means the concentration at which 50% of the maximum inhibition is achieved. "LCMS" means liquid chromatography mass spectrometry.

"MeOH" means methanol.

"MS" means mass spectroscopy or mass spectrum.

"MTBE" means methyl tert-butyl ether.

"PE" means petroleum ether solvent.

"THF" means tetrahydrofuran.

A compound of Formula I may be prepared by processes known in the chemical arts or by a novel process described herein. A process for the preparation of a compound of Formula I and novel intermediates for the manufacture of a compound of Formula I, provide further features of the invention and are illustrated by the following procedures.

Generally, a compound of Formula I may be prepared from a compound of Formula II (Scheme 1). More specifically, a compound of Formula II is reacted with a compound of Formula III in the presence of a suitable transition metal catalysis such as

tris(dibenylideneacetone)dipalladium and a base such as cesium carbonate in a suitable solvent to provide a compound of Formula I. Suitable solvents include dioxane. A compound of Formula III may be prepared by methods known in the chemical arts as well as methods provided in the Preparations and Examples.

Alternatively, a compound of Formula I may be prepared from a compound of Formula IV (Scheme 1). More specifically, a compound of Formula IV is reacted with a suitable R1 -boron reagent compound in the presence of a suitable transition metal catalysis such as tris(dibenylideneacetone)dipalladium and a base such as cesium carbonate in a suitable solvent to provide a compound of Formula I. Suitable solvents include dioxane. A suitable R1 -boron reagent compound may be prepared by methods known in the chemical arts as well as methods provided in the Preparations and Examples.

It is understood that certain functional groups employed during the preparation of a compound of Formula I may act as precursors to groups ultimately encompassed in a compound of Formula I. Such groups are known in the chemical arts and may be disclosed in the Preparations and Examples. For instance, the R5-0-(C=0)- group of a compound of Formula I may be acquired through chemical transformation a suitable precursor group such as cyano (-CN).

Scheme 1

Alternatively, a compound of Formula I may be prepared from a compound of Formula V and a compound of Formula VI (Scheme 2). More specifically, a compound of Formula VI is first reacted with bis(pinacolato)diboron in the presence of a suitable transition metal catalyst such as [l,l '-bis(diphenylphosphino) ferrocene]dichloropalladium in a suitable solvent such as dioxane to provide an intermediate pinacolatoboron compound which is further reacted compound of Formula V in the presence of a base such as sodium carbonate to provide a compound of Formula I. A compound of Formula V or a compound of Formula VI may be prepared by methods known in the chemical arts as well as methods provided in the Preparations and Examples.

Scheme 2

As shown in Scheme 3, compounds of Formula II may be prepared by reacting a compound of Formula VIII with a pinacolatoboron compound of Formula VII in the presence of a suitable transition metal catalysis such as

[l, -bis(diphenylphosphino)ferrocene]dichloropalladium and a suitable base such as sodium carbonate in a suitable solvent. Suitable solvents include dioxane.

It is understood reacting groups suitable for coupling methods are known in the chemical arts as well as disclosed in the Preparations and Examples. For instance, the pinacolatoboron reacting group of a compound of Formula VII may be substituted with alternative coupling groups such as tributylstannyl.

Alternatively, a compound of Formula II may be prepared from a compound of Formula IX (Scheme 3). More specifically, a compound of Formula IX is reacted with 4-bromo-2-methyl-pyrazol-3-amine in the presence of a suitable transition metal catalysis such as tris(dibenylideneacetone)dipalladium and a base such as cesium carbonate in a suitable solvent to provide a compound of Formula II. Suitable solvents include dioxane.

A compound of Formula VII, Formula VIII or Formula IX may be prepared by methods known in the chemical arts as well as methods provided in the Preparations and Examples.

Preparation 1 : 2-chloro-6-(cyclopropoxy)pyrazine

Add sodium hydride (1.36 g, 34.1 mmol, 60 mass%) to cyclopropanol (1.00 g, 17.0 mmol) in tetrahydrofuran (10 mL) at 0 °C, and the reaction mixture is stirred at 20 °C for 30 min. Then 2, 6-dichloropyrazine (2.57 g, 17.0 mmol) is added and the mixture is stirred at 20 °C for 12 h. The reaction mixture is poured into saturated H4CI (30 mL). The resulting mixture is extracted with EtOAc (30 mL x 3). The combined organic phases are washed with water (30 mL), brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated to afford title compound (2.50 g, 81.7%) as a white solid. LCMS (m/z): 170.9 [M+H]+.

Preparation 2: 2-chloro-6-(l, l-difluoroethyl)pyrazine

1. Synthesis of 1 -(6-chloropyrazin-2- l)ethanone

Add 2, 6-dichloropyrazine (3.00 g, 20.1 mmol) and tetrakis(triphenylphosphine) palladium (2.33 g, 2.01 mmol) to tributyl(l-ethoxyvinyl)stannane (8.08 g, 22.2 mmol) in anhydrous toluene (100 mL) under N2 atmosphere. Then the mixture is stirred at 100 °C under N2 atmosphere for 16 hrs. After cooling to room temperature, the mixture is poured into a mixture of sat. KF aq. (300 mL) and MTBE/EtOAc (1/1, 200 mL) and stirred for 1 h. The solids are filtered on celite and washed with MTBE/EtOAc (1/1, 150 mL x 2). The filtrate is separated. The aqueous layer is extracted with EtOAc (200 mL). The combined organic layer is concentrated under reduced pressure. The residue is taken up in acetone (200 mL) and treated with 1 N HC1 aq. (120 mL), stirred at 10-15 °C for 1 h. The mixture is concentrated under reduced pressure to remove most acetone, and the residue is extracted with MTBE/EtOAc (1/1, 100 mL x 3). The combined organic layer is washed with sat. NaHCCb (150 mL x 2), brine (150 mL x 2), dried over anhydrous Na2S04, filtered, concentrated under reduced pressure, the residue is purified by column chromatography on silica gel eluting with 0-10% EtOAc in PE to afford title compound (1.0 g, 31.4%) as a

yellow solid.

¾ MR (400 MHz, CDCh): δ = 9.14 (s, 1H), 8.80 (s, 1H), 2.74 (s, 3H).

2. Synthesis of 2-chloro-6-(l,l-difluoroeth l)pyrazine

Add diethylaminosulfur trifluoride (2.81 g, 17.2 mmol) to l-(6-chloropyrazin-2-yl)ethanone (540 mg, 1.15 mmol) in dichloromethane (30 mL) at 0 °C and the solution is stirred at 15 °C for 12 h. The reaction mixture is poured into ice water (30 mL), and aq. Na2C03 (10% mass in water) is added dropwise to adjust pH = 8. The reaction mixture is diluted with 30mL water and extracted with DCM (40 mL x 3). The organic layer is dried over Na2S04, filtered and concentrated under reduced pressure to afford crude product (800 mg) as yellow oil. The crude product is purified by column chromatography on silica gel eluting with 0-30% EA in PE to give title compound (385 mg, 90 mass%, 56.3%) as a yellow oil.

¾ MR (400 MHz, CDCh): δ = 8.86 (s, 1H), 8.71 (s, 1H), 2.05 (t, J= 18.4 Hz, 3H).

Preparation 3 : 2-chloro-6- l-fluoro-l -methyl-ethyl )pyrazine

1. Synthesis of 2-(6-chloropyrazin-2- l)propan-2-ol

Add methyl 6-chloropyrazine-2-carboxylate (20.0 g, 116 mmol) in THF (100 mL) to methylmagnesium bromide (3.0 mol/L) in diethyl ether (120 g, 348 mmol, 3.0 mol/L) at 0 °C and the mixture is stirred at this temperature for 2 h. The reaction is quenched with 1.0 M HC1 solution (100 mL) and extracted with EtOAc (100 mL x 3). The combined organic layers are washed with brine (100 mL), dried over anhydrous sodium sulfate, concentrated to afford a yellow oil. The yellow oil is purified by column chromatography on silica gel eluting with 0-30% EA in PE to afford title compound (3.80 g, 18.0%) as brown oil. LCMS (m/z): 172.8 [M+H]+.

2. Synthesis of 2-chloro-6-(l-fluoro-l-meth l-ethyl)pyrazine

Add DAST (6.74 g, 41.8 mmol) to 2-(6-chloropyrazin-2-yl)propan-2-ol (3.80 g, 20.9 mmol) in CH2CI2 (30 mL) at 0 °C, then the reaction mixture is stirred at 0 °C for 1 h. The reaction is quenched with water (20 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers are washed with sat. NaHCCb (20 mL), 1 M HC1 (20 mL) and brine (30 mL), and dried over anhydrous sodium sulfate and to afford a yellow oil. The crude product was purified column chromatography on silica gel eluting with 0-30% EA in PE to afford title compound (3.40 g, 84%) as yellow oil. LCMS (m/z): 174.9 [M+H]+.

¾ MR (400 MHz, CDCh) δ = 8.75 (s, 1H), 8.53 (s, 1H), 1.76 (d, J= 22.4 Hz, 6H)

Preparation 4: 2-chloro-6-iso ropoxy-pyrazine

Add sodium hydride in oil (1.07 g, 26.8 mmol, 60 mass%) to propan-2-ol (0.807 g, 13.4 mmol) in THF ( 20 mL) at 0 °C and the mixture is stirred for 20 min at this temperature Then 2,6-dichloropyrazine (2.00 g, 13.4 mmol) is added and the mixture is stirred at 20 °C for 18 hours. The reaction mixture is poured into a saturated H4CI solution (100 mL) and extracted with EtOAc (50 mL x 2). The combined organic layers are washed with brine, dried over sodium sulfate and concentrated to afford the title compound (2.20 g, 85.4%) as brown oil.

¾ MR (400 MHz, CDC13) δ = 7.93 (s, 1H), 7.88 (s, 1H), 5.25-5.04(m, 1H), 1.21 (d, J= 6.4 Hz, 6H).

Pre aration 5: 2-chloro-6-isopropyl-pyrazine

Step A

1. Synthesis of 2-chloro-6-isopropenyl-pyrazine

Add 2-isopropenyl-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (6.00 g, 35.4 mmol), [l, l'-bis(diphenylphosphino)ferrocene] dichloropalladium(II) (1.32 g, 1.77 mmol) and sodium carbonate (9.37 g, 88.4 mmol) to 2,6-dichloropyrazine (10.6 g, 70.7 mmol) in 1,4-dioxane (80 mL) and water (20 mL) to under N2. The mixture is stirred at 100 °C for 6 hours.. The solid is filtered off. The mixture is diluted with water (100 mL) and extracted with EtOAc (200 mL x 3). The combined organic layers are washed with brine (300 mL), dried over anhydrous Na2S04, filtered and evaporated to afford the crude product. The crude product is purified by column chromatography on silica gel eluting with 0-50% EtOAc in PE to afford title compound (3.0 g, 54.9% Yield) as colorless oil.

¾ MR (400 MHz, CDCh,) δ = 8.65 (s, 1H), 8.45 (s, 1H), 6.02 (s, 1H), 5.47 (s, 1H), 2.21 (s, 3H).

2. Synthesis of 2-chloro-6-isopropyl-pyrazine

Add palladium on activated carbon (500 mg, 10 mass%) to 2-chloro-6-isopropenyl-pyrazine (5.00 g, 19.4 mmol, 60 mass%) in ethyl acetate (40 mL) under N2. It is stirred at 20 °C under molecular hydrogen (15 psi) for 12 hours. The solid is filtered off. The mixture is evaporated to afford the crude. The residue is purified by flash chromatography eluting with petroleum ether: EtOAc (3 : 1) to afford title compound (1.56 g, 45% Yield) as colorless oil. LCMS (m/z): 156.8 [M+H]+.

¾ NMR: (400MHz, CDCb) δ = 8.42 (s, 1H), 8.38 (s, 1H), 3.14-3.05 (m, 1H), 1.34 (d, J = 7.2 Hz, 6H).

Preparation 6: 2-tert-butox -6-chloro-pyrazine

Add 2,6-dichloropyrazine (2.0 g, 13 mmol) in THF ( 20 mL) to potassium tert-butoxide (1.0 g, 8.8 mmol) at 0 °C, the reaction mixture is stirred at 0 °C for 20 min, then the reaction mixture is stirred at 20 °C for 18 hours. The reaction mixture is poured into a saturated H4C1 solution (100 mL) and extracted with EtOAc (50 mL x 2). The combined organic layers are washed with brine, dried over sodium sulfate and concentrated. The residue is purified by flash chromatography eluting with petroleum ether: EtOAc (3 : 1) to afford title compound (2.18 g, 86%) as white solid. LCMS (m/z): 131.2 [M-CH2=C(CH3)2+H]+.

Preparation 7: 2-chloro-6-(cyclobutoxy)pyrazine

Add cyclobutanol (2.00 g, 17.0 mmol) to sodium hydride (0.5 g, 19.8 mmol, 60 mass%) in tetrahydrofuran (20 mL) at 0 °C and the reaction mixture is stirred at 20 °C for 30 min. then 2,6-dichloropyrazine (2.0 g, 13.0 mmol) is added and the mixture is stirred at 20 °C for 12 h. The reaction mixture is poured into saturated H4CI (30 mL). The result mixture is extracted with EtOAc (30 mL x 3). The combined organic phases are washed with water (30 mL), brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated to afford title compound (2.1 g, 87%) as a white solid. LCMS (m/z): 185.2 [M+H]+.

Preparation 8: 2-chloro-6-(3, 3-difluorocyclobutoxy)pyrazine

Add 3,3-difluorocyclobutanol (2.00 g, 17.0 mmol) to sodium hydride (0.5 g, 19.8 mmol, 60 mass%) in tetrahydrofuran (20 mL) at 0 °C, then the mixture is stirred at 20 °C for 30 min, 2,6-dichloropyrazine (2.0 g, 13.0 mmol) is added and the mixture is stirred at 20 °C for 12 h. The reaction mixture is poured into saturated H4CI (30 mL). The result mixture is extracted with EtOAc (30 mL x 3). The combined organic phases are washed with water (30 mL), brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated to afford the title compound (2.4 g, 85%). LCMS (m/z): 221.1 [M+H]+.

Preparation 9: 2-chloro-6-(l-methoxy-l-methyl-ethyl)pyrazine

Step B

1. Synthesis of 2-(6-chloropyrazin-2-yl)propan-2-ol

Add methylmagnesium bromide (3 mol/L) in ether (28.7 mL, 86.1 mmol, 3 mol/L) to a solution of methyl 6-chloropyrazine-2-carboxylate (5.00 g, 28.7 mmol) in tetrahydrofuran (40 mL) at 0 °C and the mixture is stirred at 0 °C for 2 hours. The reaction is quenched with 1.0 M HC1 solution (50 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers are washed with brine (30 mL), dried over anhydrous sodium sulfate, concentrated to afford a yellow oil. The yellow oil was purified by flash chromatography eluting with petroleum ether/ EtOAc (3 : 1) to afford title compound (600 mg, 11.5%) as brown oil.

2. Synthesis of 2-chloro-6-(l-m ethoxy-1 -methyl-ethyl )pyrazine

Add sodium hydride (0.0792 g, 1.98 mmol, 60 mass%) to a solution of 2-(6-chloropyrazin-2-yl)propan-2-ol (180 mg, 0.991 mmol) in DMF (1 mL) at 0 °C, and the mixture is stirred for 30 min, then iodomethane (0.213 g, 1.49 mmol) is added to the solution and the mixture is stirred at 20 °C for 2 h. The reaction is quenched with water (20 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers are washed with brine (30 mL), dried over anhydrous sodium sulfate and concentrated to afford title compound (150 mg, 77.1%) as brown oil.

¾ MR (400 MHz, CDCb) δ = 8.75 (s, 1H), 8.48 (s, 1H), 3.25 (s, 3H), 1.57 (s, 6H).

Preparation 10: 4-(5-bromo-2-pyridyl)-2-methyl-pyrazol-3 -amine

1. Synthesis of (E)-2-(5-bromo-2-pyridyl)-3-ethoxy-prop-2-enenitrile

Add 2-(5-bromo-2-pyridyl)acetonitrile (5.00 g, 25.1 mmol) in triethyl orthoformate (30 mL) to acetic anhydride (7.93 g ,75.4 mmol) and the mixture is stirred at 125 °C for 36 h. The reaction mixture is concentrated to afford the title compound (5.6 g, 88%) as a brown crude without further purification for next step. LCMS (m/z): 253.1 [M+H]+.

2. Synthesis of 4-(5-bromo-2-pyridyl)-2-methyl-pyrazol-3 -amine

Add (E)-2-(5-bromo-2-pyridyl)-3-ethoxy-prop-2-enenitrile(5.5 g, 21.8 mmol) in ethanol (10 mL) to methylhydrazine (10 mL). The reaction mixture is heated to 100 °C and stirred for 3 hours. Then the reaction mixture is concentrated and purified by flash chromatography eluting with petroleum ether: EtOAc (3 : 1) to afford title compound (3.15 g, 57.1%). LCMS (m/z): 254.8/256.8 [M+H, Br79/Br81]+.

Preparation 11 : N-[4-(5-bromo-2-pyridyl)-2-methyl-pyrazol-3-yll-6-isopropoxy-pyrazin-2-amine

Add sodium hydride (0.585 g, 14.6 mmol, 60 mass%) to a solution of 4-(5-bromo-2-pyridyl)-2-methyl-pyrazol-3-amine (1.30 g, 4.88 mmol) in DMF (15 mL). The reaction mixture is heated to 50 °C and then 2-chloro-6-isopropoxy-pyrazine (0.975 g, 5.37 mmol) is added. The reaction mixture is stirred at 50 °C for 3 hours. The reaction mixture is poured into ammonium chloride solution (20 ml) and extracted with EtOAc (30 mL x 2). The combined organic layers are washed with brine (20 mL x 2), dried over sodium sulfate and concentrated to afford the crude. The residue is purified by column chromatography (0-80% EA in PE) to give title compound (1.20 g, 60.0%) as a yellow oil. LCMS (m/z): 389.0/390.8 [M+H, Br79/Br81]+.

Example 1A Methyl l-[4-[6-[5-[(6-tert-butoxypyrazin-2-yl)amino]-l-methyl-pyrazol-4-yl]-3 -pyri dyl ] phenyl ] cy cl opropanecarb oxyl ate

1. Synthesis of methyl l-[4-[6-(5-amino-l-methyl-pyrazol-4-yl)-3- pyri dyl ] phenyl ] cy cl opropanecarb oxyl ate

Add 4-(5-bromo-2-pyridyl)-2-methyl-pyrazol-3-amine (0.9 g, 3.56 mmol %), sodium carbonate (0.754 g , 7.11 mmol), l-[4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl]cyclopropanecarboxylate (1.19 g ,3.73 mmol) in in 1,4-dioxane (10.0 mL) and water (2 mL) to [l, -bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.266 g, 0.356 mmol) under N2. Then the reaction mixture is stirred at 100 °C for 4 h under N2. The reaction mixture is concentrated to give a black solid, which is purified by flash chromatography eluting with EtOAc: CH2CI2 (1 : 1) to afford title compound (1.1 g, 89.2%) as a brown solid. LCMS (m/z): 348.9 [M+H]+.

2. Synthesis of methyl l-[4-[6-[5-[(6-tert-butoxypyrazin-2-yl)amino]-l-methyl-pyrazol- 4-yl ] -3 -pyri dyl ] phenyl ] cy cl oprop anecarb oxyl ate

Add tris(dibenzylideneacetone)dipalladium (116 mg, 0.123 mmol) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (110 mg, 0.185 mmol) to a solution of methyl l-[4-[6-(5-amino-l-methyl-pyrazol-4-yl)-3-pyridyl]phenyl]cyclopropanecarboxylate (430 mg, 1.23 mmol), 2-tert-butoxy-6-chloro-pyrazine (254 mg, 1.23 mmol) and cesium carbonate (1.21 g, 3.7 mmol) in 02-free 1,4-dioxane (4 mL) at 25 °C. The mixture is then stirred at 100 °C for 6 hr. The mixture is filtered through a pad of silica gel and the filtrate is concentrated. The residue is purified by flash chromatograph eluting with PE/EtOAc (1 : 1) to afford the title compound (160 mg, 25%). LCMS (m/z): 499.3 [M+H]+.

Example IB l-[4-[6-[5-[(6-tert-butoxypyrazin-2-yl)amino]-l -methyl -pyrazol-4-yl]-3-pyri dyl ] phenyl ] cy cl opropanecarb oxyli c aci d

Add lithium hydroxide monohydrate (200 mg, 8.1 mmol) to methyl l-[4-[6-[5-[(6-tert-butoxypyrazin-2-yl)amino]-l-methyl-pyrazol-4-yl]-3-pyridyl]phenyl]

cyclopropanecarboxylate (160 mg, 0.32 mmol) in MeOH (3 mL) and water (3 mL). The resulting mixture is stirred for 12 hours 25 °C. The mixture is concentrated and diluted with water (5 mL). The mixture is acidified with HC1 (1M) to pH = 4-6. The mixture is extracted with DCM (5 mL x 5). The combined organic phases are washed with brine (10 mL), concentrated, purified by prep-HPLC [Column SunFire C18, 5μπι, 30x100 mm Condition: water (0.1%FA)-ACN Begin B 29 End B 44 Gradient Time(min) 10 100%B Hold Time(min) 9.0 FlowRate(ml/min) 30 ] to afford the title compound (100 mg, 64%) as yellow solid. LCMS (m/z): 485.3 [M+H]+.

¾ MR (500MHz, DMSO-d6) δ 9.15 (s, 1H), 8.80 (s, 1H), 8.08 (s, 1H), 7.98 (m, 1H), 7.76 (s, 1H), 7.83 (s, 1H), 7.60-7.57 (m, 3H), 7.54 (s, 1H), 7.43-7.40 (m, 3H), 3.67 (s, 3H), 1.48 (m, 2H), 1.23 - 1.23 (s, 9H), 1.15 (m, 2H).

Example 2A Methyl l-[4-[6-[5-[[6-(cyclobutoxy)pyrazin-2-yl]amino]-l-methyl-pyrazol-4-yl ] -3 -pyri dyl ] phenyl ] cy cl opropanecarb oxyl ate

Under 02 free condition, add tris(dibenzylideneacetone)dipalladium (116 mg, 0.123 mmol) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (110 mg, 0.185 mmol) to the 1,4-dioxane (4 mL) solution of methyl l-[4-[6-(5-amino-l-methyl-pyrazol-4-yl)-3-pyridyl]phenyl]cyclopropane carboxylate (430 mg, 1.23 mmol) (prepared according to

Example 1A), 2-chloro-6-(cyclobutoxy)pyrazine (250 mg, 1.36 mmol) and cesium carbonate (1.21 g, 3.7 mmol)), stirred at 100 °C for 6 hr. The mixture is filtered through a pad of silica gel (200-300 mush) and the filtrate is concentrated. The residue is purified by flash chromatograph eluting with petroleum ether: EtOAc (1 : 1) to afford the title compound (260 mg, 41%). LCMS (m/z): 497.3 [M+H]+.

Example 2B l-[4-[6-[5-[[6-(cyclobutoxy)pyrazin-2-yl]amino]-l-methyl-pyrazol-4-yl]-3-pyri dyl ] phenyl ] cy cl opropanecarb ox li c aci d

Add lithium hydroxide monohydrate (200 mg, 8.1 mmol) to a solution of methyl 1- [4-[6-[5-[[6-(cyclobutoxy)pyrazin-2-yl]amino]-l-methyl-pyrazol-4-yl]-3-

pyridyl]phenyl]cyclopropanecarboxylate (260 mg, 0.51 mmol) in MeOH (3 mL) and water (3 mL) and the mixture is stirred for 12 hours 25 °C. The mixture is concentrated and diluted with water (5 mL). The mixture is acidified with HC1 (1M) to pH = 4-6. The mixture is extracted with DCM (5 mL x 5). The combined organic phases are washed with brine (10 mL), concentrated and then purified by prep-HPLC [Column SunFire CI 8, 5μπι, 30x100 mm Condition: water (0.1%FA)-ACN Begin B 29 End B 44 Gradient Time (min) 10 100%B Hold Time (min) 8.5 FlowRate (ml/min) 30] to afford the title compound (50 mg, 23%) as yellow solid. LCMS (m/z): 483.3 [M+H]+.

¾ MR (500MHz, DMSO-d6) δ 9.32 (s, 1H), 8.80 (s, 1H), 8.80 (s, 1H), 8.08 (s, 1H), 8.00 (m, 1H), 7.79 (s, 1H), 7.63-7.57 (m, 3H), 7.54 (s, 1H), 7.41 (m, 2H), 4.63 (m, 1H) 3.68 (s, 3H), 2.11 (m,2H), 2.02 (m, 2H). 1.68 (m, 1H), 1.49 (m, 1H), 1.46 (m, 2H), 1.14 (m, 2H).

Example 3A Methyl l-[4-[6-[5-[[6-(cyclopropoxy)pyrazin-2-yl]amino]-l-methyl-pyrazol-4-yl]-5-fluoro-3-pyridyl]phenyl]cyclopropanecarboxylate

1. Synthesis of 2-(5-chloro-3-fluoro-2-pyridyl)acetonitrile

Add n-butyllithium in hexanes (110 g, 381 mmol, 2.5 mol/L) to a solution of acetonitrile (17.2 g, 419 mmol) in anhydrous THF (50 mL)at -78 °C under nitrogen. The mixture is stirred at -78 °C for 30 min. Then added with a solution of 5-chloro-2,3-difluoro-pyridine (60.0 g, 381 mmol) in THF (100 mL) and the mixture is stirred at -78 °C for 2 h. The reaction mixture is warmed to 20 °C and stirred for 1 h. The reaction mixture is quenched with sat. H4CI (300 mL). The reaction mixture is extracted with EtOAc (200 mL x 3). The combined organic phases are washed with water (100 mL), brine (100 mL), concentrated to afford a yellow residue, which is purified by column chromatography on silica gel eluting with PE:EtOAc (10: 1) to afford title compound 2-(5-chloro-3-fluoro-2-pyridyl)acetonitrile (20.0 g, 30.8%) as a yellow oil. LCMS (m/z): 170.8 [M+H]+.

2. Synthesis of (Z)-2-(5-chloro-3-fluoro-2-pyridyl)-3-ethoxy-prop-2-enenitrile

Add 2-(5-chloro-3-fluoro-2-pyridyl)acetonitrile (20.0 g, 117 mmol) in acetic anhydride (47.9 g, 469 mmol) to triethyl orthoformate (100 mL) and the mixture is stirred at 125 °C for 36 h. The reaction mixture is concentrated to afford title compound (Z)-2-(5-chloro-3-fluoro-2-pyridyl)-3-ethoxy-prop-2-enenitrile (45.7 g, 117 mmol, 58 mass%, 99.5%) as a brown oil. it is used for the next step directly without further purification. LCMS (m/z): 226.9 [M+H]+.

3. Synthesis of 4-(5-chloro-3-fluoro-2-pyridyl)-2-methyl-pyrazol-3 -amine

Add methylhydrazine (40.4 g, 351 mmol, 40 mass%) to a solution of 2-(5-chloro-3-fluoro-2-pyridyl)-3-ethoxy-prop-2-enenitrile (45.7 g, 117 mmol, 58mass%) in ethanol (100 mL), and the reaction mixture is stirred at 100 °C for 3 h. The reaction mixture is

concentrated and purified by column chromatography on silica gel eluting with PE:EtOAc (1 : 1) to afford title (5.50 g, 19.7%) as a brown solid. LCMS (m/z): 226.9 [M+H]+.

4. Synthesis of methyl l-[4-[6-(5-amino-l-methyl-pyrazol-4-yl)-5-fluoro-3- pyri dyl ] phenyl ] cy cl opropanecarb oxylate

Add Pd2(dba)3 (0.576 g, 0.629 mmol) and tricyclohexylphosphine (0.184 g, 0.629 mmol) to sodium carbonate (1.33 g, 12.6 mmol), methyl, l-[4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl]cyclopropane carboxylate (1.55 g, 4.61 mmol, 90 mass%) and 4-(5-chloro-3-fluoro-2-pyridyl)-2-methyl-pyrazol-3-amine (1.00 g, 4.19 mmol) in 1,4-dioxane (16 mL) and water (4 mL), then the reaction mixture is stirred at 90 °C for 1 h under nitrogen. The reaction mixture is concentrated to afford a black residue, which is purified by column chromatography on silica gel eluting with PE:EtOAc (2:3) to afford title (1.20 g, 74.2%) as a brown solid. LCMS (m/z): 367.1 [M+H]+.

5. Synthesis of methyl l-[4-[6-[5-[[6-(cyclopropoxy)pyrazin-2-yl]amino]-l-methyl- pyrazol-4-yl]-5-fluoro-3- ridyl]phenyl]cyclopropanecarboxylate

Add Pd2(dba)3 (0.107 g, 0.117 mmol) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.0675 g, 0.117 mmol) to a solution of methyl l-[4-[6-(5-amino-l-methyl-pyrazol-4-yl)-5-fluoro-3-pyridyl]phenyl]cyclopropanecarboxylate (300 mg, 0.778 mmol), 2-chloro-6-(cyclopropoxy)pyrazine (0.168 g, 0.933 mmol) and cesium carbonate (0.760 g, 2.33 mmol) in 1,4-dioxane (3 mL), then the reaction mixture is stirred at 90 °C for 1 h under nitrogen. The reaction mixture is concentrated and purified by column

chromatography on silica gel eluting with PE:EtOAc (1 :2) to afford title compound (320 mg, 87 %mass, 71.5%) as a yellow solid. LCMS (m/z): 501.2 [M+H]+.

Example 3B l-[4-[6-[5-[[6-(cyclopropoxy)pyrazin-2-yl]amino]-l-methyl-pyrazol-4-yl]-5-fluoro-3 -pyri dyl ] phenyl ] cy cl o ropanecarb oxyli c aci d; hy drochl ori de

Add lithium hydroxide hydrate (0.0461 g, 1.04 mmol) to a solution of methyl l-[4-[6-[5-[[6-(cyclopropoxy)pyrazin-2-yl]amino]-l-methyl-pyrazol-4-yl]-5-fluoro-3-pyridyl]phenyl]cyclopropanecarboxylate ( 300 mg, 0.521 mmol, 87 mass%) in methanol (1 mL) and water (1 mL), and the mixture is stirred at 60 °C for 1 h. then the reaction mixture is acidified by IN HCl to pH = 6 and removed the solvent.The crude product is purified by prep-HPLC [column: YMC-ActusTriart C18 150 x 30mm x 5μιη, condition: 55-85%B (A: water/ 0.05% HCl, B: CH3CN), flow rate: 25 mL/min] and lyophilized to afford title compound (153.0 mg, 55.3%) as a yellow solid. LCMS (m/z): 487.1 [M+H]+.

¾ NMR (400MHz, CD3OD) δ = 8.65 (s, 1H), 8.00 (d, J = 2.0 Hz, 1H), 7.95 (br d, J = 12.0 Hz, 1H), 7.83 (s, 1H), 7.63 (d, J = 8.0 Hz, 2H), 7.60 (s, 1H), 7.49 (d, J = 8.0 Hz, 2H), 3.99 -3.92 (m, 1H), 3.86 (s, 3H), 1.64 - 1.58 (m, 2H), 1.25 - 1.20 (m, 2H), 0.70 - 0.58 (m, 4H).

Example 4A Methyl l-[4-[5-fluoro-6-[5-[[6-(l-fluoro-l-methyl-ethyl)pyrazin-2-yl]amino]-l-methyl-pyrazol-4-yl]-3-pyridyl]phenyl]cyclopropanecarboxylate

Add cesium carbonate (1.18 g, 3.63 mmol) and Pd2(dba)3 (85.7 mg, 0.0907 mmol) to methyl l-[4-[6-(5-amino-l -methyl -pyrazol-4-yl)-5-fluoro-3-pyridyl]phenyl]

cyclopropanecarboxylate (350 mg, 0.907 mmol) (prepared according to Example 3 A), 2-chloro-6-(l-fluoro-l-methyl-ethyl)pyrazine (220 mg, 1.13 mmol, 90 mass%) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (81.0 mg, 0.136 mmol) in 1,4-dioxane (5 mL) under N2. The mixture is stirred at 100 °C for 12 hours. The reaction is quenched with water (20 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers are washed with brine (30 mL), dried over anhydrous sodium sulfate and concentrated to afford crude product. The residue is purified by column chromatography eluting with 0-80% EtOAc in PE to afford title product (350 mg, 60 mass%, 45.9%) as brown oil. LCMS (m/z): 505.1 [M+H]+.

Example 4B l-[4-[5-fluoro-6-[5-[[6-(l-fluoro-l-methyl-ethyl)pyrazin-2-yl]amino]-l-methyl-pyrazol-4-yl]-3-pyrid l]phenyl]cyclopropanecarboxylic acid hydrochloride

Add lithium hydroxide hydrate (53.5 mg, 1.25 mmol) to methyl l-[4-[5-fluoro-6-[5-[[6- (1-fluoro-l -methyl -ethyl)pyrazin-2-yl]amino]-l -methyl-pyrazol-4-yl]-3-pyridyl]phenyl]cyclopropanecarboxylate (350 mg, 0.416 mmol, 60 mass%) in

tetrahydrofuran (5 mL) and water (0.5 mL). The reaction is stirred at 50 °C for 14 hours. The mixture is adjusted to pH=5-6 with 1 N HCl, extracted with EtOAc (40 mL x 3). The combined organic layers are washed with brine (30 mL), dried over Na2S04, filtered and concentrated. The crude product is purified by prep-HPLC [Column YMC-Actus Triart CI 8 100 x 30mm x 5μιη Condition: water (0.05%HC1)-ACN Begin B 50 End B 80 Gradient Time(min) 9.5 100%B Hold Time(min) 2.5 FlowRate(ml/min) 25 ] to afford the title product (116 mg, 51.6%) as a yellow solid. LCMS (m/z): 491.1 [M+H]+.

¾ MR (400 MHz, MeOD): 5 = 8.71 (d, J= 1.6 Hz, 1H), 8.25 (s, 1H), 8.20 (dd, J= 11.6, 2.0 Hz, 1H), 8.14 (s, 1H), 8.07 (d, J= 2.0 Hz, 1H), 7.67 (d, J= 8.4 Hz, 2H), 7.53 (d, J= 8.4 Hz, 2H), 3.89 (s, 3H), 1.68-1.61 (m, 2H), 1.44 (d, J= 22.0 Hz, 6H), 1.29-1.22 (m, 2H).

Example 5A Methyl l-[4-[6-[5-[[6-(3,3-difluorocyclobutoxy)pyrazin-2-yl]amino]-l-methyl-pyrazol-4-yl]-3-pyridyl]phenyl]cyclopropanecarboxylate

Add tris(dibenzylideneacetone)dipalladium (116 mg, 0.123 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (110 mg, 0.185 mmol) ) and cesium carbonate (1.21 g, 3.7 mmol) to a solution of methyl l-[4-[6-(5-amino-l-methyl-pyrazol-4-yl)-3-pyridyl]phenyl]cyclopropanecarboxylate (530 mg, 1.52 mmol) (prepared according to Example 1A) and 2-chloro-6-(cyclobutoxy)pyrazine (250 mg, 1.36 mmol) in 02-free 1,4-dioxane (4 mL) at 25 °C. The mixture is stirred at 100 °C for 6 hr. The mixture is filtered through a pad of silica gel (200-300 mush) and the filtrate is concentrated. The residue is purified by flash chromatograph eluting with petroleum ether: EtOAc (1 : 1) to afford the title compound (260 mg, 41%). LCMS (m/z): 497.3 [M+H]+.

Example 5B l-[4-[6-[5-[[6-(3,3-difluorocyclobutoxy)pyrazin-2-yl]amino]-l-methyl-pyrazol -4-yl] -3 -pyri dyl ] phenyl] cy cl oprop anecarb oxyli c aci d

Add lithium hydroxide monohydrate (200 mg, 8.1 mmol) to a solution of methyl 1-[4-[6-[5-[[6-(3,3-difluorocyclobutoxy)pyrazin-2-yl]amino]-l-methyl-pyrazol-4-yl]-3-pyridyl]phenyl]cyclopropanecarboxylate (260 mg, 0.51 mmol) in MeOH (3 mL) and water (3 mL). The resulting mixture is stirred for 12 hours 25 °C. The mixture is concentrated and diluted with water (5 mL). The mixture is acidified with HC1 (1M) to pH = 4-6 and extracted with DCM (5 mL x 5). The combined organic phases are washed with brine (10 mL), concentrated, and purified by prep-HPLC [Column SunFire C18, 5μπι, 30x100 mm

Condition: water (0.1%FA)-ACN Begin B 29 End B 44 Gradient Time(min) 10 100%B Hold Time(min) 8.5 FlowRate(ml/min) 30 ] to afford the title compound (50 mg, 23%) as yellow solid. LCMS (m/z): 483.3 [M+H]+.

¾ MR (500MHz, DMSO-d6) δ = 9.41 (s, 1H), 8.79 (m, 1H), 8.80 (s, 1H), 8.10 (s, 1H), 7.99 (m, 1H), 7.86 (s, 1H), 7.63-7.58 (m, 4H), 7.43 (m, 2H), 4.61 (m, 1H) 3.69 (s, 3H), 2.79 (m,2H), 2.57 (m, 2H). 1.45 (m,2H), 1.14 (m, 2H).

Example 6A Methyl l-[4-[6-[5-[[6-(l-methoxy-l-methyl-ethyl)pyrazin-2-yl]amino]-l-methyl-pyrazol-4-yl]-3-pyridyl]phenyl]cyclopropanecarboxylate

Add tris(dibenzylideneacetone)dipalladium (0.0384 g, 0.0407 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.0364 g, 0.0611 mmol) and cesium carbonate (0.398 g, 1.22 mmol) to a solution of methyl l-[4-[6-(5-amino-l-methyl-pyrazol-4-yl)-3-pyridyl]phenyl]cyclopropanecarboxylate (0.142 g, 0.387 mmol), 2-chloro-6-(l-methoxy-l-methyl-ethyl)pyrazine (80.0 mg, 0.407 mmol) in 1,4-dioxane (4 mL) under N2. The mixture is stirred at 100 °C for 4 hours. The reaction is quenched with water (20 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers are washed with brine (30 mL), dried over anhydrous sodium sulfate and concentrated to afford crude. The residue is purified by flash chromatography eluting with petroleum ether/ EtOAc (1 :5) to afford title compound (90 mg, 44.3%) as brown oil. LCMS (m/z): 521.1 [M+Na]+.

Example 6B l-[4-[6-[5-[[6-(l-methoxy-l-methyl-ethyl)pyrazin-2-yl]amino]-l-methyl-pyrazol-4-yl]-3-pyridyl]phenyl]cyclopropanecarboxylic acid;hydrochloride

Add lithium hydroxide (11.4 mg, 0.271 mmol) to a solution of methyl l-[4-[6-[5-[[6-(1 -methoxy- 1 -methyl-ethyl )pyrazin-2-yl]amino]- 1 -methyl -pyrazol-4-yl]-3-pyridyl]phenyl]cyclopropanecarboxylate (90 mg, 0.181 mmol) in tetrahydrofuran (4 mL) and water (4 mL) at room temprature. The mixture is stirred at 60 °C for 2 hours. The mixture is extracted with EtOAc (lOmL x 3) and the aqueous is adjusted to pH=5-7 with HC1 (1M). The mixture is extracted with EtOAc (30mL x 3). The combined organic layers are washed with brine (30mL), dried over anhydrous Na2S04, filtered and evaporated to afford the crude. It is purified by pre-HPLC [Column Boston Green ODS 150*30, 5 μπι, Condition water

(0.05%HC1)-ACN Begin B 35 End B 65 Gradient Time(min) 3 100%B Hold Time(min) 1.66 FlowRate(ml/min) 25] to afford title compound (44.1 mg, 45.3%) as a yellow solid. LCMS (m/z): 485.2 [M+H]+.

¾ MR (DMSO-d6, 400 MHz) δ = 9.99 (s, 1H), 8.85 (s, 1H), 8.43 (d, J= 7.2 Hz, 1H), 8.27 (d, J= 4.4 Hz, 2H), 8.09 (s, 1H), 7.81 (d, J= 8.4 Hz, 1H), 7.68 (d, J= 8.4 Hz, 2H), 7.46 (d, J = 8.0 Hz, 2H), 3.78 (s, 3H), 2.92 (s, 3H), 1.52-1.45 (m, 2H), 1.22-1.09 (m, 2H), 1.09 (s, 6H).

Example 7A Ethyl l-[4-[6-[5-[(6-isopropoxypyrazin-2-yl)amino]-l -methyl -pyrazol-4-yl]-3 -pyridyl] -2-methyl -phenyl] cyclopropanecarboxylate

1. Synthesis of ethyl 2-(4-bromo-2-methyl-phenyl)acetate

Add sulfuric acid (3.68 g, 2 mL) to a mixture of 2-(4-bromo-2-methyl-phenyl)acetic acid (2.00 g, 8.73 mmol) in ethanol (20 mL), then the reaction mixture is stirred at 80 °C for 2 h. The reaction mixture is cooled to 20 °C and poured into water (100 mL). The resulting mixture is neutralized by sat. Na2C03 to pH = 8. The mixture is extracted with EtOAc (30 mL x 3). The combined organic phases are washed with water (20 mL) and brine (20 mL), dried over anhydrous sodium sulfate, concentrated to afford title compound (2.30 g, 97.3%) as a yellow oil.

¾ MR (400MHz, CHLOROFORM-d) δ = 7.34 (s, 1H), 7.29 (dd, J= 2.0, 8.4 Hz, 1H), 7.07 (d, J= 8.4 Hz, 1H), 4.16 (q, J= 7.2 Hz, 2H), 3.58 (s, 2H), 2.30 (s, 3H), 1.25 (t, J= 7.2 Hz, 3H)

2. Synthesis of ethyl l-(4-bromo-2-methyl-phenyl)cyclopropanecarboxylate

Add sodium hydride (60 mass%) in oil (0.296 g, 7.39 mmol, 60 mass%) to a mixture of ethyl 2-(4-bromo-2-methyl-phenyl)acetate (1.00 g, 3.69 mmol) in DMF (5 mL). The mixture is stirred at 20 °C for 0.5 h, then 1,2-dibromoethane (0.764 g, 4.06 mmol) is added and stirred at 20 °C for 2 h. The reaction mixture is quenched with sat. H4C1 (10 mL). The result mixture is extracted with EtOAc (10 mL x 3). The combined organic phases are washed with water (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated, then purified by column chromatography on silica gel eluting with PE:EtOAc (10 : 1) to afford title

compound (100 mg, 9.08%) as a colorless oil.

¾ MR (400MHz, CDCb) δ = 7.32 (d, J= 1.6 Hz, 1H), 7.27 (dd, J = 1.6, 8.4 Hz, 1H), 7.10 (d, J= 8.4 Hz, 1H), 4.10 (q, J= 7.2 Hz, 2H), 2.30 (s, 3H), 1.70 - 1.65 (m, 2H), 1.16 (t, J = 7.2 Hz, 3H), 1.14 - 1.09 (m, 2H)

3. Synthesis of ethyl l-[4-[6-[5-[(6-isopropoxypyrazin-2-yl)amino]-l-methyl-pyrazol-4- yl ] -3 -pyri dyl ] -2-m ethyl -phenyl ] cy cloprop anecarb oxyl ate

Add Pd(dppf)Cl2 (0.0225 g, 0.0302 mmol) and potassium acetate (0.0916 g, 0.906 mmol) to a solution of ethyl l-(4-bromo-2-methyl-phenyl)cyclopropanecarboxylate (90.0 mg, 0.302 mmol), bis(pinacolato)diboron (0.0861 g, 0.332 mmol) in 1,4-dioxane (0.5 mL), then the reaction mixture is stirred at 90 °C for 1 h under nitrogen. N-[4-(5-bromo-2-pyridyl)-2-methyl-pyrazol-3-yl]-6-isopropoxy-pyrazin-2-amine (0.136 g, 0.332 mmol), sodium carbonate (0.0960 g, 0.906 mmol) and water (0.1 mL) is added to above solution and stirred at 90 °C for 1 h under nitrogen. The reaction mixture is concentrated to afford a black residue, which is purified by column chromatography on silica gel eluting with PE:EtOAc (1 : 1) to afford title compound (90 mg, 58.0%) as a yellow oil. LCMS (m/z): 513.2 [M+H]+.

Example 7B l-[4-[6-[5-[(6-isopropoxypyrazin-2-yl)amino]-l -methyl -pyrazol-4-yl]-3-pyridyl]-2-methyl-phenyl]cyclopropanecarboxylic acid;hydrochloride

Add lithium hydroxide hydrate (0.0137 g, 0.323 mmol) to a mixture of ethyl l-[4-[6-[5-[(6-isopropoxypyrazin-2-yl)amino]-l-methyl-pyrazol-4-yl]-3-pyridyl]-2-methyl-phenyljcyclopropanecarboxylate (90 mg, 0.162 mmol) in methanol (1 mL) and water (1 mL), then the reaction mixture is stirred at 60 °C for 2 h. The reaction mixture is acidified by 1 N HC1 to pH = 6 and extracted with EtOAc (30 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated. The crude product is purified by prep-HPLC [column: YMC-ActusTriart C18 150 x 30mm x 5μιη, condition: 30-60%B (A: water/ 0.05% HC1, B:

CH3CN), flow rate: 25 mL/min] and lyophilized to afford title compound (17.9 mg, 20.5%) as a yellow solid. LCMS (m/z): 485.2 [M+H]+.

¾ MR (400MHz, CD3OD) δ = 8.90 (d, J= 2.0 Hz, 1H), 8.71 (dd, J= 2.0, 8.8 Hz, 1H), 8.27 (s, 1H), 8.11 (d, J= 8.8 Hz, 1H), 7.81 (br s, 1H), 7.62 - 7.57 (m, 2H), 7.54 (dd, J= 2.0, 8.0 Hz, 1H), 7.44 (d, J= 8.0 Hz, 1H), 4.78 - 4.67 (m, 1H), 3.87 (s, 3H), 2.46 (s, 3H), 1.74 -1.66 (m, 2H), 1.25 - 1.17 (m, 2H), 1.12 (d, J = 6.4 Hz, 6H).

Example 8A Ethyl l-[4-[6-[5-[[6-(cyclopropoxy)pyrazin-2-yl]amino]-l-methyl-pyrazol-4-yl]-3-pyridyl]-2-(trifluoromethyl)phenyl]cyclopropanecarboxylate

1. Synthesis of 2-[4-bromo-2-(trifluoromethyl)phenyl]acetic acid

Add hydrochloric acid (2 mL, 12 M) to a solution of 2-[4-bromo-2-(trifluoromethyl)phenyl]acetonitrile (600 mg, 2.25 mmol) in acetic acid (2 mL), the mixture is stirred at 100 °C for 2 h under nitrogen. The reaction mixture is concentrated to afford title compound (600 mg, 89.5%) as colorless oil.

¾ MR (400MHz, CDCb) δ = 7.82 (d, J= 1.6 Hz, 1H), 7.67 (dd, J = 1.6, 8.4 Hz, 1H), 7.29 (s, 1H), 3.83 (s, 2H).

2. Synthesis of ethyl 2-[4-bromo-2-(trifluoromethyl)phenyl]acetate

Add sulfuric acid (3.68 g, 2 mL) to a solution of 2-[4-bromo-2- (trifluoromethyl)phenyl]acetic acid (600 mg, 2.0 mmol) in ethanol (10 mL), the mixture is stirred at 80 °C for 3 h under nitrogen. The reaction mixture is diluted with water (20 mL) and extracted with EtOAc (20 mL x 2). The combined organic layers are washed with sat. NaHCCb (20 mL), brine (20 mL x 2), dried over sodium sulfate and concentrated to afford title compound (600 mg, 91.0%) as colorless oil.

¾ NMR (400MHz, CDCb) δ = 7.80 (d, J= 1.6 Hz, 1H), 7.66 (dd, J = 1.6, 8.0 Hz, 1H), 7.28 (d, J= 9.2 Hz, 1H), 4.17 (q, J = 7.2 Hz, 2H), 3.77 (s, 2H), 1.25 (t, J= 7.2 Hz, 3H).

3. Synthesis of ethyl l-[4-bromo-2-(trifluoromethyl)phenyl]cyclopropane carboxylate

Add sodium hydride in paraffin oil (0.148 g, 3.69 mmol, 60 mass%) to a solution of ethyl 2-[4-bromo-2-(trifluoromethyl)phenyl]acetate (550 mg, 1.68 mmol) in DMF (5 mL), then the mixture is heated to 50 °C for 1 hour. 1, 2-dibromoethane (0.335 g, 1.76 mmol) is added and the reaction is stirred at 50 °C for 2 hours. The reaction is quenched with saturated H4CI solution (30 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers are washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue is purified by flash chromatography eluting with petroleum ether/ EtOAc (20: 1) to afford the crude. The crude is purified by pre-HPLC [column: Boston Green ODS 150 x 30, 5μιη. condition: 35-65%B (A:water(0.05%HCl), B:ACN), flow rate: 25 mL/min] to afford title compound (0.150 g, 25.2%) as colorless oil. LCMS (m/z):

336.9/338.8 [M+H, Br79/Br81]+.

¾ MR (400MHz, CDCb) δ = 7.78 (d, J= 2.0 Hz, 1H), 7.63 (dd, J = 1.6, 8.4 Hz, 1H), 7.34 (d, J = 8.4 Hz, 1H), 4.13 - 3.96 (m, 2H), 1.65-1.58 (m, 2H), 1.33 - 1.19 (m, 2H), 1.12 (t, J = 7.2 Hz, 3H).

4. Synthesis of ethyl l-[4-[6-(5-amino-l-methyl-pyrazol-4-yl)-3-pyridyl]-2- (trifluoromethyl) phenyljcyclopropanecarboxylate

Add Pd(dppf)Cl2 (0.0316 g, 0.0423 mmol) and potassium acetate (0.128 g, 1.27 mmol) to a solution of ethyl l-[4-bromo-2-(trifluoromethyl)phenyl]cyclopropanecarboxylate (150 mg, 0.423 mmol), bis(pinacolato)diboron (0.120 g, 0.465 mmol) in 1,4-dioxane (4 mL), then the reaction mixture is stirred at 90 °C for 1 h under nitrogen. Then 4-(5-bromo-2-pyridyl)-2-methyl-pyrazol-3-amine (0.124 g, 0.465 mmol), sodium carbonate (0.134 g, 1.27 mmol) and water (1 mL) is added to above solution and stirred at 90 °C for 1 h under nitrogen. The reaction mixture is concentrated to afford a black residue, which is purified by column chromatography on silica gel eluting with PE:EtOAc (1 : 1) to afford title compound (140 mg, 77.6%) as a yellow oil. LCMS (m/z): 431.1 [M+H]+.

5. Synthesis of ethyl l-[4-[6-[5-[[6-(cyclopropoxy)pyrazin-2-yl]amino]-l-methyl- pyrazol-4-yl]-3-pyrid l]-2-(trifluoromethyl)phenyl]cyclopropanecarboxylate

Add tris(dibenzylideneacetone)dipalladium (0.0300 g, 0.0328 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.0190 g, 0.0328 mmol) and cesium carbonate (0.320 g, 0.984 mmol) to a mixture of ethyl l-[4-[6-(5-amino-l -methyl -pyrazol-4-yl)-3-pyridyl]-2-(trifluoromethyl)phenyl]cyclopropanecarboxylate (140 mg, 0.328 mmol), 2-chloro-6-(cyclopropoxy)pyrazine (0.0706 g, 0.393 mmol) in 1,4-dioxane (5 mL), then the reaction mixture is stirred at 95 °C for 2 h under nitrogen. The reaction mixture is concentrated and purified by column chromatography on silica gel eluting with PE:EtOAc (4: 1) to afford title compound (133 mg, 72.0%) as a yellow solid. LCMS (m/z): 565.1

[M+H]+.

Example 8B l-[4-[6-[5-[[6-(cyclopropoxy)pyrazin-2-yl]amino]-l-methyl-pyrazol-4-yl]-3-pyridyl]-2-(trifluoromethyl)phenyl]cyclopropanecarboxylic acid;hydrochloride

Add lithium hydroxide hydrate (0.0187 g, 0.446 mmol) to a mixture of ethyl l-[4-[6-[5-[[6-(cyclopropoxy)pyrazin-2-yl]amino]-l-methyl-pyrazol-4-yl]-3-pyridyl]-2-(trifluoromethyl)phenyl]cyclopropanecarboxylate (133 mg, 0.223 mmol) in methanol (2 mL) and water (2 mL), then the reaction mixture is stirred at 60 °C for 1 h. The reaction mixture is acidified by IN HCl to pH = 6, then purified by prep-HPLC [column: YMC-Actus Triart C18 150*30ιηιη*5μιη, condition: 40-70%B (A: water/ 0.05% HCl, B: CH3CN), flow rate: 25 mL/min] and lyophilized to afford title compound (34.4 mg, 25.3%) as a white solid. LCMS (m/z): 537.0 [M+H]+.

¾ NMR (400MHz, CD3OD) δ = 9.01 (d, J= 2.0 Hz, 1H), 8.76 (dd, J= 2.4, 8.8 Hz, 1H), 8.27 (s, 1H), 8.15 (d, J= 8.4 Hz, 1H), 8.09 (s, 1H), 8.00 (dd, J= 1.6, 8.0 Hz, 1H), 7.92 (s, 1H), 7.77 (d, J= 8.0 Hz, 1H), 7.70 (s, 1H), 3.91 - 3.84 (m, 4H), 1.97 - 1.54 (m, 2H), 1.54 -1.08 (m, 2H), 0.65 - 0.55 (m, 4H)

Example 9A Ethyl l-[2-cyano-4-[6-[5-[[6-(cyclopropoxy)pyrazin-2-yl]amino]-l-methyl-pyrazol-4-yl]-3-pyridyl]phenyl]cyclopropanecarboxylate

1. Synthesis of 2-(4-bromo-2-cyano- henyl)acetate

Add chlorotrimethylsilane (0.233 g, 2.10 mmol) to a mixture of zinc (2.55 g, 39.0 mmol) in tetrahydrofuran (20 mL) at 15 °C. The mixture is stirred for 15 min and then a solution of ethyl bromoacetate (5.11 g, 30.0 mmol) in tetrahydrofuran (10 mL) is added dropwise. The reaction is heated to 40 °C for 30 min. The mixture is cooled to 20 °C and the supernatant liquid is used as title compound bromo-(2-ethoxy-2-oxo-ethyl)zinc (30 mmol, 1 mol/L, 100%) in the next step directly. Add bromo-(2-ethoxy-2-oxo-ethyl)zinc (15.4 mL, 15.4 mmol, 1 mol/L) to a mixture of 5-bromo-2-iodo-benzonitrile (4.00 g, 12.9 mmol), bis(dibenzylideneacetone)palladium (0.187 g, 0.322 mmol,) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.188 g, 0.322 mmol) in tetrahydrofuran (10 mL) under nitrogen. The reaction is heated to 65 °C for 12 hours. The reaction is quenched with saturated H4CI solution (30 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers are washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue is purified by flash chromatography eluting with petroleum ether/EtOAc (10: 1) to the title compound (0.520 g, 14.3%) as a light grey solid.

¾ MR (400MHz, CDCb) δ = 7.80 (d, J = 2.0 Hz, 1H), 7.70 (dd, J = 2.0, 8.4 Hz, 1H), 7.32 (d, J = 8.0 Hz, 1H), 4.21 (q, J = 7.2 Hz, 2H), 3.84 (s, 2H), 1.29 (t, J = 7.2 Hz, 3H).

2. Synthesis of ethyl l-(4-bromo-2-cyano-phenyl)cyclopropanecarboxylate

Add sodium hydride in paraffin oil (0.162 g, 4.05 mmol, 60 mass%) to a solution of ethyl 2-(4-bromo-2-cyano-phenyl)acetate (0.520 g, 1.84 mmol) in DMF (10 mL), and the mixture is heated to 50 °C for 1 hour. Then 1,2-dibromoethane (0.367 g, 1.93 mmol) is added and the reaction is stirred at 50 °C for 3 hours. The reaction is quenched with saturated H4CI solution (30 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers are washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered and

concentrated. The residue is purified by flash chromatography eluting with petroleum ether/ EtOAc (20: 1) to afford title compound (0.370 g, 64.9%) as a grey solid.

¾ NMR (400MHz, CDCb) δ = 7.79 (d, J = 2.0 Hz, 1H), 7.67 (dd, J = 2.0, 8.4 Hz, 1H), 7.28 (d, J = 8.4 Hz, 1H), 4.14 (q, J = 7.2 Hz, 2H), 1.85 - 1.79 (m, 2H), 1.29 - 1.24 (m, 2H), 1.20 (t, J = 7.2 Hz, 3H).

3. Synthesis of ethyl l-[4-[6-(5-amino-l-methyl-pyrazol-4-yl)-3-pyridyl]-2-cyano- phenyljcyclopropanecarboxylate

Add [l,l'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.0482 g, 0.0646 mmol) to a mixture of ethyl l-(4-bromo-2-cyano-phenyl)cyclopropanecarboxylate (200 mg, 0.646 mmol), bis(pinacolato)diboron (0.184 g, 0.711 mmol) and potassium acetate (0.196 g, 1.94 mmol) in 1,4-dioxane (4 mL), then the reaction mixture is stirred at 90 °C for 1 h under nitrogen. Then 4-(5-bromo-2-pyridyl)-2-methyl-pyrazol-3-amine (0.189 g, 0.711 mmol), sodium carbonate (0.205 g, 1.94 mmol) and water (1 mL) are added to above solution and stirred at 90 °C for 1 h under nitrogen. The reaction mixture is concentrated to afford a black residue, which is purified by column chromatography on silica gel eluting with PE:EtOAc (1 : 1) to afford title compound (230 mg, 87.3%) as a yellow solid. LCMS (m/z): 388.1

[M+H]+.

¾ NMR (400MHz, CDCb) δ = 8.68 (d, J= 2.4 Hz, 1H), 7.86 (d, J= 1.6 Hz, 1H), 7.80 (dd, J = 2.4, 8.4 Hz, 1H), 7.76 - 7.71 (m, 2H), 7.49 (dd, J= 1.6, 8.4 Hz, 2H), 5.62 (br s, 2H), 4.17 (q, J= 7.2 Hz, 2H), 3.71 (s, 3H), 1.88 - 1.81 (m, 2H), 1.36 - 1.30 (m, 2H), 1.22 (t, J= 7.2 Hz, 3H).

4. Synthesis of ethyl l-[2-cyano-4-[6-[5-[[6-(cyclopropoxy)pyrazin-2-yl]amino]-l- methyl-pyrazol-4-yl]-3-pyridyl]phenyl]cyclopropanecarboxylate

Add tris(dibenzylideneacetone)dipalladium(0) (0.0695 g, 0.0736 mmol) and 4,5- bis(diphenylphosphino)-9,9-dimethylxanthene (0.0434 g, 0.0736 mmol) to a mixture of ethyl l-[4-[6-(5-amino-l-methyl-pyrazol-4-yl)-3-pyridyl]-2-cyano- phenyljcyclopropanecarboxylate (200 mg, 0.490 mmol), 2-chloro-6-(cyclopropoxy)pyrazine (0.106 g, 0.589 mmol) and cesium carbonate (0.479 g, 1.47 mmol,) in 1,4-dioxane (5 mL, then the reaction mixture is stirred at 95 °C for 2 h under nitrogen. The reaction mixture is concentrated to afford a black residue, which is purified by column chromatography on silica gel eluting with PE:EtOAc (1 :4) to afford title compound (200 mg, 63 mass%, 49.3%) as a yellow solid. LCMS (m/z): 522.1 [M+H]+.

Example 9B l-[2-cyano-4-[6-[5-[[6-(cyclopropoxy)pyrazin-2-yl]amino]-l -methyl -pyrazol- 4- l]-3-pyridyl]phenyl]cyclopropanecarboxylic acid;hydrochloride

cyano-4-[6-[5-[[6-(cyclopropoxy)pyrazin-2-yl]amino]-l -methyl -pyrazol-4-yl]-3- pyridyl]phenyl]cyclopropanecarboxylate (200 mg, 0.242 mmol, 63 mass%) in methanol (2

mL) and water (2 mL, then the reaction mixture is stirred at 60 °C for 1 h. The reaction mixture is acidified by IN HCl to pH = 6 and is concentrated. Then purified by prep-HPLC [column: YMC -Actus Triart C 18 150 x 30mm x 5μιη, condition: 35-65%B (A: water/ 0.05% HCl, B: CH3CN), flow rate: 25 mL/min] and lyophilized to afford title compound (49.6 mg, 92.44 mass%, 35.8%) as a yellow solid. LCMS (m/z): 494.1 [M+H]+.

¾ NMR (400MHz, CDCb) δ = 9.02 (s, 1H), 8.77 (d, J= 7.2 Hz, 1H), 8.28 (s, 1H), 8.22 (s, 1H), 8.18 (d, J = 8.4 Hz, 1H), 8.05 (d, J= 7.2 Hz, 1H), 7.96 (s, 1H), 7.79 - 7.67 (m, 2H), 3.99 - 3.80 (m, 4H), 1.86 - 1.75 (m, 2H), 1.45 - 1.34 (m, 2H), 0.71 - 0.54 (m, 4H).

Example 10A Methyl l-[4-[6-[5-[[6-(cyclopropoxy)pyrazin-2-yl]amino]-l-methyl-pyrazol-4-yl ] -3 -pyri dyl ] phenyl ] cy cl oprop anecarb oxyl ate

Add methyl l -[4-[6-(5-amino-l-methyl-pyrazol-4-yl)-3-pyridyl]phenyl]cyclo propanecarboxylate (530 mg, 1.377 mmol) (prepared according to Example 1A), 2-chloro-6-(cyclopropoxy)pyrazine (300 mg, 1.758 mmol) and cesium carbonate (1.0 g, 3.1 mmol) in C -free 1,4-dioxane (10 mL) to tris(dibenzylideneacetone)dipalladium (300 mg, 0.33 mmol) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (280 mg, 0.483 mmol) at 25 °C. The mixture is then stirred at 100 °C for 6 hr. The mixture is filtered through a pad of silica gel (200-300 mush) and the filtrate is concentrated. The residue is purified by flash chromatograph eluting with petroleum ether: EtOAc (1 : 1) to afford the title compound (300 mg, 45.2%) as light yellow oil. LCMS (m/z): 483.2 [M+H]+.

Example 10B l-[4-[6-[5-[[6-(cyclopropoxy)pyrazin-2-yl]amino]-l-methyl-pyrazol-4-yl]-3-pyri dyl ] phenyl ] cy cl opropanecarb ox li c acid

Add methyl l-[4-[6-[5-[[6-(cyclopropoxy)pyrazin-2-yl]amino]-l-methyl-pyrazol-4-yl]-3-pyridyl]phenyl]cyclopropanecarboxylate (300 mg, 0.621 mmol) in THF (4 mL) and water (2 mL) to lithium hydroxide monohydrate (200 mg, 8.1 mmol). The resulting mixture is stirred for 12 hours 25 °C. The mixture is concentrated and diluted with water (5 mL). The mixture is acidified with HC1 (1M) to pH = 4-6. The mixture is extracted with DCM (5 mL x 5). The combined organic phases are washed with brine (10 mL), concentrated, purified by prep-HPLC [Column SunFire C18, 5μιη, 30x100 mm Condition: water (0.1%FA)-ACN Begin B 29 End B 44 Gradient Time (min) 10 100%B Hold Time(min) 7.5

FlowRate(ml/min) 30 ] to afford the title compound (50 mg, 42.1%) as yellow solid. LCMS (m/z): 469.2 [M+H]+.

¾ MR (500MHz, DMSO-d6) δ 9.41 (s, 1H), 8.80 (d, J = 2.0 Hz, 1H), 8.10-7.98 (M,2H), 7.81 (s, 1H), 7.68 (s, 1H), 7.62-7.60 (m, 3H), 3.94 (m, 1H), 3.70 (s, 3H), 1.45 (m, 2H), 1.13 (m, 2H), 0.60 (d, J= 6.0 Hz, 4H).

Example 11A Methyl l-[4-[5-fluoro-6-[5-[(6-isopropoxypyrazin-2-yl)amino]-l-methyl-pyrazol-4-yl]-3-pyridyl]phenyl]cyclopropanecarboxylate

Add tris(dibenzylideneacetone)dipalladium (0.0712 g, 0.0778 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.0450 g, 0.0778 mmol) and cesium carbonate (0.507 g, 3 1.56 mmol) to a solution of methyl l-[4-[6-(5-amino-l-methyl-pyrazol-4-yl)-5-fluoro-3-pyridyl]phenyl] cyclopropanecarboxylate (200 mg, 0.519 mmol) (prepared according to Example 3 A), 2-chloro-6-isopropoxy-pyrazine (0.1 13 g, 0.622 mmol) in 1,4-dioxane (3 mL), then the reaction mixture is stirred at 90 °C for 1 h under nitrogen. The reaction mixture is concentrated and purified by column chromatography on silica gel eluting with PE:EtOAc (1 :2) to afford title compound (130 mg, 49.9%) as a yellow solid. LCMS (m/z): 503.2 [M+H]+.

Example 11B l-[4-[5-fluoro-6-[5-[(6-isopropoxypyrazin-2-yl)amino]-l -methyl -pyrazol -4-yl]-3-pyridyl]phenyl]cyclopro anecarboxylic acid;hydrochloride

Add hydroxide lithium hydrate (0.0217 g, 0.517 mmol) to a mixture of methyl l -[4-[5-fluoro-6-[5-[(6-isopropoxypyrazin-2-yl)amino]-l-methyl-pyrazol-4-yl]-3-

pyridyl]phenyl]cyclopropanecarboxylate (200 mg, 0.259 mmol, 65 mass%) in methanol (1 mL) and water (1 mL) was added, then the reaction mixture is stirred at 60 °C for 1 h. The reaction mixture was acidified by IN HCl to pH = 6. The result mixture is concentrated and purified by prep-HPLC [column: YMC-ActusTriart C18 150 x 30mm x 5μπι, condition: 48-78%B (A: water/ 0.05% HCl, B: CH3CN), flow rate: 25 mL/min] and lyophilized to afford title compound (101.6 mg, 99.69 mass%, 74.6%) as a yellow solid. LCMS (m/z): 489.1

[M+H]+.

¾ NMR (400MHz, CDC13) δ = 8.60 (s, 1H), 8.00 (d, J= 2.8 Hz, 1H), 7.84 (dd, J= 2.0, 12.0 Hz, 1H), 7.69 (s, 1H), 7.60 (d, J= 8.4 Hz, 2H), 7.47 (d, J= 8.4 Hz, 2H), 7.45 (br s, 1H), 4.86 - 4.83 (m, 1H), 3.84 (s, 3H), 1.63 - 1.59 (m, 2H), 1.25 - 1.20 (m, 2H), 1.16 (d, J= 6.4 Hz, 6H)

Example 12A Methyl l-[4-[6-[5-[[6-(l,l-difluoroethyl)pyrazin-2-yl]amino]-l-methyl-pyrazol-4-yl]-3-pyridyl]phenyl]cyclopropanecarboxylate

Add to tris(dibenzylideneacetone)dipalladium (0.103 g, 0.109 mmol) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.0976 g, 0.164 mmol) to methyl l-[4-[6-(5-amino-l-methyl-pyrazol-4-yl)-3-pyridyl]phenyl]cyclopropanecarboxylate (0.400, 1.09 mmol) (prepared according to Example 1A), 2-chloro-6-(l,l-difluoroethyl)pyrazine (0.325 g, 1.64 mmol, 90 mass%) and cesium carbonate (1.42 g, 4.36 mmol) in 1,4-dioxane (8 mL) under N2. The mixture is stirred at 100 °C for 12 hours. The mixture is diluted with water (40 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers are washed

with brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue is purified by column chromatography on silica gel EtOAc : PE(1 : 1) to afford title (361mg, 68.1%). LCMS (m/z): 491.1 [M+H]+.

Example 12B l-[4-[6-[5-[[6-(l, l-difluoroethyl)pyrazin-2-yl]amino]-l-methyl-pyrazol-4-yl]-3-pyridyl]phenyl]cyclopropanecarboxylic acid;hydrochloride

Add lithium hydroxide hydrate (91.0 mg, 2.12 mmol) to a solution of methyl l-[4-[6-[5-[[6-(l, l-difluoroethyl)pyrazin-2-yl]amino]-l-methyl-pyrazol-4-yl]-3-pyridyl]phenyl]cyclopropanecarboxylate (360 mg, 0.706 mmol) in tetrahydrofuran (5 mL) and water (0.5 mL). The reaction is stirred at 50 °C for 14 hours. The mixture is adjusted to pH = 5-6 with 1 N HC1, extracted with EtOAc (40 mL x 3). The combined organic layers are washed with brine (30 mL), dried over Na2S04, filtered and concentrated. The crude product is purified by prep-HPLC [Column YMC-Actus Triart C 18 100 x 30mm x 5μπι Condition: water (0.05%HC1)-ACN Begin B 30 End B 60 Gradient Time(min) 9.5 100%B Hold

Time(min) 2.5 FlowRate(ml/min) 25 ] to afford title compound (80.0 mg, 21.0%) as a yellow solid. LCMS (m/z): 477.0 [M+H]+.

¾ MR (400 MHz, DMSO-d6) δ = 10.06 (br s, 1H), 8.78 (s, 1H), 8.43 (s, 1H), 8.23-8.16 (m, 3H), 7.73 (d, J= 8.4 Hz, 1H), 7.65 (d, J= 8.4 Hz, 2 H), 7.44 (d, J= 8.0 Hz, 2H), 3.75 (s, 3H), 1.65 (t, J= 18.8 Hz, 3H), 1.50-1.43 (m, 2H), 1.23-1.15 (m, 2H).

Example 13A Methyl l-[4-[6-[5-[[6-(l-fluoro-l-methyl-ethyl)pyrazin-2-yl]amino]-l-methyl-pyrazol-4-yl]-3-pyridyl]phenyl]cyclopropanecarboxylate

Add Pd2(dba)3 (1.10 g, 1.20 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (1.04 g, 1.80 mmol) and cesium carbonate (9.80 g, 30.1 mmol) to 2-chloro-6-(l-fluoro-l-methyl-ethyl)pyrazine (2.50 g, 12.0 mmol, 84 mass%), methyl l-[4-[6-(5-amino-l-methyl-pyrazol-4-yl)-3-pyridyl]phenyl]cyclopropanecarboxylate (4.19 g, 10.8 mmol, 90 mass%) (Prepared according to Example 1 A) in 1,4-dioxane (60 mL), then the reaction mixture is stirred at 100 °C for 5 h under nitrogen. The reaction mixture is concentrated to afford a black residue, which is purified by column chromatography on silica gel eluting with PE/EtOAc(l : 1) to afford the title compound (3.10 g, 50.3%) as yellow solid. LCMS (m/z): 487.2 [M+H]+.

Example 13B l-[4-[6-[5-[[6-(l-fluoro-l -methyl-ethyl )pyrazin-2-yl]amino]- 1 -methyl -pyrazol-4-yl]-3-pyridyl]phenyl]cyclopropanecarboxylic acid;hydrochloride

Add lithium hydroxide hydrate (0.750 g, 17.9 mmol) to methyl l -[4-[6-[5-[[6-(l-fluoro- 1 -methyl-ethyl)pyrazin-2-yl]amino]- 1 -methyl -pyrazol-4-yl]-3-pyridyl]phenyl]cyclopropanecarboxylate (6.10 g, 1 1.9 mmol) in THF (30 mL) and water (30 mL), then the reaction mixture is stirred at 60 °C for 1 h. The aqueous is acidified by IN HCl to pH = 6, then extracted with EtOAc (60 mL x 3), the combined organic phases are concentrated to afford crude product. The crude product is purified by prep-HPLC [column: Phenomenexluna CI 8 250 x 50mm x 10 μιη, condition: 20-45%B (A: water/ 0.05% HCl, B: CH3CN), flow rate: 25 mL/min] and lyophilized to afford title compound (2.7380 g, 37.8%) as a yellow solid. LCMS (m/z): 473.1 [M+H]+.

¾ NMR (400MHz, CD3OD) δ = 8.88 (d, J= 2.0 Hz, 1H), 8.67 (dd, J= 2.4, 8.8 Hz, 1H), 8.36 - 8.28 (m, 1H), 8.26 - 8.22 (m, 1H), 8.19 (s, 1H), 8.12 - 8.05 (m, 1H), 7.71 (d, J= 8.4 Hz, 2H), 7.56 (d, J= 8.4 Hz, 2H), 3.91 - 3.85 (m, 3H), 1.67 - 1.62 (m, 2H), 1.40 - 1.29 (m, 5H), 1.27 - 1.22 (m, 2H), 1.19 (s, 1H)

Example 14A methyl l-[4-[6-[5-[(6-isopropylpyrazin-2-yl)amino]-l-methyl-pyrazol-4-yl]-3- pyridyl]-3-(methoxymethyl)phenyl]cyclopropanecarboxylate 1. Synthesis of ethyl 2-(4-bromo-3 -methyl -phenyl)acetate

Add sulfuric acid (9.2 g, 5 mL) to a mixture of 2-(4-bromo-3-methyl-phenyl)acetic acid ( 5.00 g, 20.7 mmol) in ethanol (50 mL) and the reaction is heated to 80 °C for 3 hours. The mixture is cooled to 20 °C and poured into saturated NaHC03 solution (30 mL). The mixture is extracted with EtOAc (30 mL x 3). The combined organic layers are washed with brine (30 mL), dried over anhydrous sodium sulfate and concentrated to afford title

compound (5.30 g, 94.4%) as colorless oil.

¾ NMR (400MHz, CDCb) δ = 7.48 (d, J = 8.0 Hz, 1H), 7.16 (s, 1H), 6.98 (dd, J = 2.0, 8.0 Hz, 1H), 4.16 (q, J = 7.2 Hz, 2H), 3.54 (s, 2H), 2.39 (s, 3H), 1.26 (t, J = 7.2 Hz, 3H).

2. Synthesis of ethyl l-(4-bromo-3-methyl-phenyl)cyclopropanecarboxylate

Add NaH (1.63 g, 40.6 mmol, 60 mass%) to a mixture of ethyl 2-(4-bromo-3 -methyl -phenyl)acetate (5.00 g, 18.5 mmol) in DMF (50 mL) at 20 °C and the mixture is stirred at 50 °C for 1 hour. Then 1, 2-dibromoethane (3.68 g, 19.4 mmol) is added and the reaction is stirred at 50 °C for 12 hours. The reaction is quenched with saturated NH4C1 solution (30 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers are washed with brine (30 mL), dried over anhydrous sodium sulfate and concentrated. The residue is purified by flash chromatography eluting with petroleum ether/ EtOAc (50: 1) to afford the title compound (550 mg, 9.99%) as colorless oil.

¾ NMR (400MHz, CDCb) δ = 7.46 (d, J = 8.4 Hz, 1H), 7.21 (d, J = 2.0 Hz, 1H), 7.03 (dd, J = 2.0, 8.4 Hz, 1H), 4.11 (q, J = 7.2 Hz, 2H), 2.39 (s, 3H), 1.63 - 1.56 (m, 2H), 1.22 - 1.11 (m, 5H).

3. Synthesis of ethyl l-[4-bromo-3-(bromomethyl)phenyl]cyclopropanecarboxylate

Add NBS (0.369 g, 2.03 mmol) and 2,2'-azobis(2-methylpropionitrile) (31.0 mg, 184 mmol) in carbon tetrachloride (10 mL) to a mixture of ethyl l-(4-bromo-3 -methyl

phenyl)cyclopropanecarboxylate (550 mg, 1.84 mmol) in carbon tetrachloride (10 mL) and the mixture is heated to 70 °C for 12 hours. The mixture is diluted with water (20 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers are washed with brine (30 mL), dried over anhydrous sodium sulfate and concentrated. The residue is purified by flash chromatography eluting with petroleum ether/ EtOAc (20: 1) to afford the title compound (500 mg, 71.1%) as colorless oil.

¾ NMR (400MHz, CDCb) δ = 7.51 (d, J = 8.4 Hz, 1H), 7.44 (d, J = 2.0 Hz, 1H), 7.16 (dd, J = 2.0, 8.4 Hz, 1H), 4.59 (s, 2H), 4.10 (q, J = 7.2 Hz, 2H), 1.65 - 1.60 (m, 2H), 1.21 - 1.13 (m, 5H).

4. Synthesis of methyl l-[4-bromo-3-(methoxymethyl)phenyl]cyclopropane carboxylate

Add sodium methoxide (0.0515 g, 0.944 mmol) to a solution of ethyl l-[4-bromo-3-(bromomethyl)phenyl]cyclopropanecarboxylate (300 mg, 0.787 mmol) in methanol (5 mL) at 20 °C and the reaction is stirred at 50 °C for 2 hours. The mixture is diluted with water (20 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers are washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue is purified by flash chromatography eluting with petroleum ether/ EtOAc (20: 1) to afford the title compound (200 mg, 80.7%) as colorless oil.

¾ NMR (400MHz, CDCb) δ = 7.48 (d, J = 8.0 Hz, 1H), 7.44 (d, J = 1.6 Hz, 1H), 7.14 (dd, J = 2.0, 8.0 Hz, 1H), 4.51 (s, 2H), 3.63 (s, 3H), 3.49 (s, 3H), 1.65 - 1.58 (m, 2H), 1.22 - 1.14 (m, 2H).

5. Synthesis of N-[4-(5-bromo-2-pyridyl)-2-methyl-pyrazol-3-yl]-6-isopropyl-pyrazin- 2-amine

Add sodium hydride in oil (1.26 g, 31.5 mmol, 60 mass%) to a suspension of 4-(5-bromo-2-pyridyl)-2 -methyl -pyrazol-3 -amine (1.68 g, 6.31 mmol) in DMF (8 mL). The reaction mixture is heated to 50 °C and then 2-chloro-6-isopropyl-pyrazine (1.12 g, 6.94 mmol) is added. The reaction mixture is stirred at 50 °C for 1 hour. The reaction mixture is poured into saturated ammonium chloride solution (20 mL) and extracted with EtOAc (30 mL*2). The combined organic layers are washed with brine (20 mL x 2), dried over sodium sulfate and filtered and concentrated to afford the residue. The residue is purified by column chromatography on silica gel (0-30% EtOAc in PE) to afford title compound (850 mg, 34.3%) as a yellow solid. LCMS (m/z): 373.0 [M+H]+.

6. Synthesis of methyl l-[4-[6-[5-[(6-isopropylpyrazin-2-yl)amino]-l-methyl-pyrazol-4- yl ] -3 -pyri dyl ] -3 -(methox m ethyl)phenyl ] cy cl opropanecarb oxyl ate

Add [l,l'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.0356 g, 0.0476 mmol) to a mixture of methyl l-[4-bromo-3-(methoxymethyl)phenyl]cyclo

propanecarboxylate (150 mg, 0.476 mmol), bis(pinacolato)diboron (0.128 g, 0.500 mmol) and potassium acetate (0.142 g, 1.43 mmol) in 1,4-dioxane (5 mL) under nitrogen. The

reaction is heated to 100 °C for 1 hour. The mixture is cooled to 20 °C and then N-[4-(5-bromo-2-pyridyl)-2-methyl-pyrazol-3-yl]-6-isopropyl-pyrazin-2-amine (0.196 g, 0.500 mmol), [l,l'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.0356 g, 0.0476 mmol), sodium carbonate (0.153 g, 1.43 mmol) and water (0.5 mL) are added under nitrogen. The reaction is heated to 100 °C for 12 hours. The mixture is diluted with EtOAc (30 mL) and the solid is filtered off. The filtrate is diluted with water (30 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers are washed with brine (30 mL), dried over anhydrous sodium sulfate and concentrated. The residue is purified by flash chromatography eluting with petroleum ether/ EtOAc (1 :2) to afford title compound (153 mg, 62.7%) as yellow oil. LCMS (m/z): 513.3 [M+H]+.

¾ MR (400MHz, CDCb) δ = 9.38 (s, 1H), 8.54 (d, J = 1.6 Hz, 1H), 8.07 (s, 1H), 7.98 (s, 1H), 7.92 (s, 1H), 7.74 (dd, J = 2.0, 8.0 Hz, 1H), 7.54 (d, J = 8.4 Hz, 1H), 7.51 (d, J = 1.6 Hz, 1H), 7.38 (dd, J = 2.0, 8.0 Hz, 1H), 7.25 (d, J = 7.6 Hz, 1H), 4.31 (s, 2H), 3.87 (s, 3H), 3.66 (s, 3H), 3.37 (s, 3H), 3.00 - 2.92 (m, 1H), 1.68 - 1.63 (m, 2H), 1.27 - 1.25 (m, 8H).

Example 14B l-[4-[6-[5-[(6-isopropylpyrazin-2-yl)amino]-l-methyl-pyrazol-4-yl]-3-pyridyl]-3-(methoxymethyl)phenyl]cyclopropanecarboxylic acid;hydrochloride

Add lithium hydroxide hydrate (0.0380 g, 0.895 mmol) to a mixture of methyl l-[4-[6-[5-[(6-isopropylpyrazin-2-yl)amino]-l-methyl-pyrazol-4-yl]-3-pyridyl]-3- (methoxymethyl)phenyl]cyclopropanecarboxylate (0.170 g, 0.298 mmol, 90 mass%) in THF (3 mL) and water (0.5 mL) and the mixture is heated to 50 °C for 12 hours. The mixture is adjusted pH to 5-6 with l .OM HCl solution and the mixture is extracted with EtOAc (30 mL x 3). The combined organic layers are washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The mixture is purified by prep-HPLC (column: YMC-Actus Triart C18 100 x 30mm x 5μιη, Gradient: 32-62% B (A = water/0.05% HCl, B= acetonitrile), Flow rate: 25 mL/min). The desired fractions are lyophilized to afford title compound (59.5 mg, 36.9%) as a white solid. LCMS (m/z): 499.1 [M+H]+.

¾ MR (400MHz, DMSO-d6) δ = 10.09 (br s, 1H), 8.64 (br s, 1H), 8.36 (br s, 1H), 8.31 -8.19 (m, 2H), 7.97 - 7.80 (m, 2H), 7.50 (br s, 1H), 7.42 (br d, J = 7.2 Hz, 1H), 7.30 (d, J = 8.0 Hz, 1H), 4.27 (br s, 2H), 3.78 (br s, 3H), 3.22 (s, 3H), 2.77 - 2.63 (m, 1H), 1.56 - 1.42 (m, 2H), 1.24 - 1.09 (m, 2H), 0.93 (d, J = 6.4 Hz, 6H).

Example 15A Ethyl l-[3-(cyanomethyl)-4-[6-[5-[(6-isopropylpyrazin-2-yl)amino]-l -methyl-pyrazol-4-yl]-3-pyridyl]phenyl]cyclopropanecarboxylate

1. Synthesis of ethyl l-[4-bromo-3-(cyanomethyl)phenyl]cyclopropanecarboxylate

Add trimethylsilyl cyanide (0.0637 g, 0.630 mmol) and tetrabutyl ammonium fluoride (1.0 mol/L) in THF (0.63 mL, 0.630 mmol, 1.0 mol/L) to a solution of ethyl l-[4-bromo-3-(bromomethyl)phenyl]cyclopropanecarboxylate (0.200 g, 0.525 mmol) (prepared according to Example 14A) in THF (5 mL), and the reaction is stirred at 20 °C for 3 hours. The mixture is diluted with water (20 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers are washed with brine (30 mL), dried over anhydrous sodium sulfate and concentrated. The residue is purified by flash chromatography eluting with petroleum ether/ EtOAc (20: 1) to afford title compound (100 mg, 58.7%) as colorless oil.

¾ NMR (400MHz, CDCb) δ = 7.54 (d, J = 8.4 Hz, 1H), 7.51 (d, J = 2.0 Hz, 1H), 7.21 (dd,

J = 2.0, 8.4 Hz, 1H), 4.1 1 (q, J = 7.2 Hz, 2H), 3.84 (s, 2H), 1.69 - 1.61 (m, 2H), 1.24 - 1.14 (m, 5H).

2. Synthesis of ethyl l-[3-(cyanomethyl)-4-[6-[5-[(6-isopropylpyrazin-2-yl)amino]-l- methyl -pyrazol -4-yl ] -3 - ri dyl ] phenyl ] cy cl opropanecarb oxyl ate

Add Pd(dppf)Cl2 (0.023 g, 0.031 mmol) potassium acetate (0.0917 g, 0.925 mmol) to a mixture of ethyl l-[4-bromo-3-(cyanomethyl)phenyl]cyclopropanecarboxylate (0.100 g, 0.308 mmol), bis(pinacolato)diboron (0.083 g, 0.324 mmol) and potassium acetate (0.0917 g, 0.925 mmol) in 1,4-dioxane (3 mL) under nitrogen. The reaction is heated to 100 °C for 3 hours. The mixture is cooled to 20 °C and then N-[4-(5-bromo-2-pyridyl)-2-methyl-pyrazol-3-yl]-6-isopropyl-pyrazin-2-amine (0.127 g, 0.324 mmol) (prepared according to Example 14A), Pd(dppf)Cl2 (0.0230 g, 0.0308 mmol), sodium carbonate (0.0990 g, 0.925 mmol) and water (0.3 mL) are added. The reaction is heated to 100 °C for 3 hours. The solid is filtered off and the filtrate was diluted with water (20 mL). The mixture is extracted with EtOAc (30 mL x 3). The combined organic layers ware washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue is purified by flash chromatography eluting with petroleum ether/ EtOAc (1 :2) to afford title compound (81.0 mg, 50.4%) as a light yellow solid. LCMS (m/z): 522.1 [M+H]+.

Example 15B l-[3-(cyanomethyl)-4-[6-[5-[(6-isopropylpyrazin-2-yl)amino]-l-methyl-pyrazol-4-yl]-3-pyridyl]phenyl]cyclopropanecarboxylic acid;hydrochloride

Add lithium hydroxide hydrate (0.0079 g, 0.186 mmol) to a mixture of ethyl l-[3-(cyanomethyl)-4-[6-[5-[(6-isopropylpyrazin-2-yl)amino]-l-methyl-pyrazol-4-yl]-3-pyridyl]phenyl]cyclopropanecarboxylate (90.0 mg, 0.155 mmol, 90 mass%) in THF (2 mL) and water (0.2 mL) and the mixture is heated to 50 °C for 12 hours. The mixture is adjusted pH to 5-6 with 1.0M HCl solution and the mixture is extracted with EtOAc (30 mL x 3). The combined organic layers are washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The mixture is purified by prep-HPLC (column: YMC-Actus Triart C18 100 x 30mm x 5μιη, Gradient: 35-65% B (A = water/0.05% HCl, B= acetonitrile), Flow rate: 25mL/min). The desired fractions were lyophilized to afford title compound (27.6 mg, 33.2%) as a white solid. LCMS (m/z): 494.1 [M+H]+.

¾ MR (400MHz, DMSO-d6) δ = 9.91 (br s, 1H), 8.62 (d, J = 1.6 Hz, 1H), 8.30 (s, 1H), 8.20 - 8.12 (m, 2H), 7.92 (s, 1H), 7.88 (d, J = 8.4 Hz, 1H), 7.53 (s, 1H), 7.43 (dd, J = 1.6, 8.0 Hz, 1H), 7.27 (d, J = 7.6 Hz, 1H), 4.00 (s, 2H), 3.75 (s, 3H), 2.81 - 2.70 (m, 1H), 1.57 - 1.45 (m, 2H), 1.24 - 1.14 (m, 2H), 0.98 (d, J = 6.8 Hz, 6H).

Example 16A Ethyl l-[3-cyano-4-[6-[5-[(6-isopropylpyrazin-2-yl)amino]-l-methyl-pyrazol-4-yl ] -3 -pyri dyl ] phenyl ] cy cl oprop anecarb oxyl ate; hy drochl ori de

1. Synthesis of ethyl 2-(4-bromo-3-cyano-phenyl)acetate

Add bromo-(2-ethoxy-2-oxo-ethyl)zinc (2.97 g, 12.7 mmol) (prepared according to Example 9A) to a mixture of 2-bromo-5-iodo-benzonitrile (2.60 g, 8.44 mmol),

bis(dibenzylideneacetone)palladium (0.121 g, 0.211 mmol) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.122 g, 0.211 mmol) in THF (20 mL), then the reaction mixture is stirred at 65 °C for 1 h under nitrogen. The reaction mixture is quenched with water (10 mL). The result mixture is extracted with EtOAc (10 mL x 3). The combined organic phases are washed with water (10 mL), concentrated to afford a black residue, which is purified by column chromatography on silica gel eluting with PE:EtOAc (20: 1) to afford the title compound (1.00 g, 42.0% Yield) as a yellow solid.

¾ MR (400MHz, CDCb) δ = 7.65 (d, J= 8.4 Hz, 1H), 7.60 (d, J= 2.0 Hz, 1H), 7.39 (dd, J = 2.0, 8.4 Hz, 1H), 4.18 (q, J= 7.2 Hz, 2H), 3.61 (s, 2H), 1.28 (t, J= 7.2 Hz, 3H)

2. Synthesis of ethyl l-(4-bromo-3-cyano-phenyl)cyclopropanecarboxylate

Add sodium hydride in oil (0.142 g, 3.54 mmol, 60 mass%) to a solution of ethyl 2- (4-bromo-3-cyano-phenyl)acetate (500 mg, 1.77 mmol) in DMF (5 mL), the mixture is stirred at 20 °C for 1 h, then 1,2-dibromoethane (0.333 g, 1.77 mmol) is added to above solution and stirred at 20 °C for 2 h. The reaction mixture is quenched with MeOH (5 mL), diluted with EtOAc (20 mL). The result mixture is washed with water (10 mL x 2), concentrated to afford a light yellow residue, which is purified by column chromatography on silica gel eluting with PE:EtOAc (20 : 1) to afford title compound (260 mg, 47.4%) as a yellow solid.

¾ MR (400MHz, CHLOROFORM-d) δ = 7.68 - 7.58 (m, 2H), 7.44 (dd, J = 2.0, 8.4 Hz, 1H), 4.11 (q, J= 7.2 Hz, 2H), 1.70 - 1.65 (m, 2H), 1.21 - 1.15 (m, 5H)

3. Synthesis of ethyl l-[4-[6-(5-amino-l-methyl-pyrazol-4-yl)-3-pyridyl]-3-cyano- phenyljcyclopropanecarboxylate

Add [l,l'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.0482 g, 0.0646 mmol) to a solution of ethyl l-(4-bromo-3-cyano-phenyl)cyclopropanecarboxylate (200 mg, 0.646 mmol), 4,4,5, 5-tetramethyl-2-(4,4,5,5-tetramethyl-l,3-dioxolan-2-yl)-l, 3,2-dioxaborolane (0.182 g, 0.711 mmol) and potassium acetate (0.190 g, 1.94 mmol) in 1,4-dioxane (4 mL), then the reaction mixture is stirred at 90 °C for 1 h under nitrogen. The reaction mixture is cooled to 20 °C, then 4-(5-bromo-2-pyridyl)-2-methyl-pyrazol-3-amine (0.189 g, 0.711 mmol), sodium carbonate (0.205 g, 1.94 mmol) and water (1 mL) are added to above solution and stirred at 90 °C for 1 h under nitrogen. The reaction mixture is concentrated to afford a black residue, which is purified by column chromatography on silica gel eluting with EtOAc to afford title compound (130 mg, 46.7%) as a yellow oil. LCMS (m/z): 388.1 [M+H]+.

4. Synthesis of ethyl l-[3-cyano-4-[6-[5-[(6-isopropylpyrazin-2-yl)amino]-l-methyl- pyrazol-4-yl]-3-pyridyl]phenyl]cyclopropanecarboxylate;hydrochloride

Add tris(dibenzylideneacetone)dipalladium (0.0277 g, 0.0302 mmol) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.0262 g, 0.0453 mmol) to a suspensions of ethyl l-[4-[6-(5-amino-l-methyl-pyrazol-4-yl)-3-pyridyl]-3-cyano-phenyl]cyclopro-panecarboxylate (130 mg, 0.302 mmol), 2-chloro-6-isopropyl-pyrazine (0.0585 g, 0.362 mmol) and cesium carbonate (0.295 g, 0.906 mmol) in 1,4-dioxane (5 mL), then the reaction mixture is stirred at 100 °C for 3 h under nitrogen. The reaction mixture is concentrated to afford a black residue, which is purified by column chromatography on silica gel eluting with EtOAc to afford crude product, which is purified by prep-HPLC [column: YMC-ActusTriart C18 150 x 30mm x 5μιη, condition: 45-75%B (A: water/ 0.05% HC1, B: CH3CN), flow rate: 25 mL/min] to afford title compound (60.0 mg, 35.1%) as a yellow solid. LCMS (m/z): 508.2 [M+H]+.

Example 16B l-[3-cyano-4-[6-[5-[(6-isopropylpyrazin-2-yl)amino]-l-methyl-pyrazol-4-yl]-3-pyridyl]phenyl]cyclopropanecarboxylic acid;hydrochloride

Add lithium hydroxide hydrate (4.4 mg, 0.106 mmol) to a solution of ethyl l-[3-cyano-4-[6-[5-[(6-isopropylpyrazin-2-yl)amino]-l-methyl-pyrazol-4-yl]-3-pyridyl]phenyl]cyclopropanecarboxylate;hydrochloride (60.0 mg, 0.106 mmol) in methanol (1 mL) and water (1 mL), then the reaction mixture is stirred at 60 °C for 1 h. The reaction mixture is diluted with water (10 mL), acidified by IN HC1 to pH =4. The precipitate is filtered and dried over vacuo to afford the title compound (29.5 mg, 96.9 mass%, 52.3%) as a white solid. LCMS (m/z): 480.1 [M+H]+.

!H NMR (400MHz, CDCb) δ = 8.65 (s, 1H), 8.10 (s, 1H), 8.02 (s, 1H), 7.92 (d, J= 8.0 Hz, 1H), 7.85 (s, 2H), 7.74 (d, J= 8.0 Hz, 1H), 7.67 (d, J= 8.0 Hz, 1H), 7.53 (d, J= 8.0 Hz, 1H), 3.80 (s, 3H), 2.89 - 2.80 (m, 1H), 1.67 - 1.60 (m, 2H), 1.28 - 1.20 (m, 2H), 1.10 (d, 7= 7.2 Hz, 6H)

Example 17 l-[4-[4-[5-[(6-isobutylpyrazin-2-yl)amino]-l -methyl -pyrazol -4-yl ] phenyl ] phenyl ] cy cl opropanecarb oxyli c aci d

1. Synthesis of methyl l-(4-bromophenyl)cyclopropanecarboxylate

Add l-(4-bromophenyl)cyclopropanecarboxylic acid (10.0 g, 41.5 mmol) in DMF (50.0 mL, 646 mmol) to potassium carbonate (11.5 g., 83.0 mmol) and iodomethane (11.7 g, 83.0 mmol). Then the reaction mixture is stirred at 20 °C for 0.5 h. the reaction mixture is added with water (50 mL) and the result mixture is extracted with EtOAc (50 mL x3), then the combined organic phases is washed with water (30 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated to give the title compound (10.0 g, 94.5%) as a colorless oil. LCMS (m/z): 254.8/256.8 [M+H, Br79/Br81]+.

Synthesis of methyl l-[4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phi propanecarb oxyl ate

Add methyl l-(4-bromophenyl)cyclopropanecarboxylate (10.0 g, 39.2 mmol) and 4,4,5, 5-tetramethyl-2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l,3,2-dioxaborolane (10.5 g., 41.2 mmol) in dioxane (50.0 mL) to potassium acetate (18.9 g, 137 mmol) and [Ι,Γ-bis(diphenylphosphino)ferrocene]dichloropalladium (2.9 g, 3.92 mmol). Then the reaction mixture is stirred at 100 °C for 2 h under N2. To the reaction mixture is added water (50 mL) and EtOAc (100 mL). The solution is separated and the aqueous is extracted with EtOAc (50 mL x 3). The combined organic phases are washed with brine (50 mL x 2), water (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give the title compound (10.0 g, 84.4%) as a white solid. LCMS (m/z): 303.1 [M+H]+.

3. Synthesis of methyl l-[4-(4-bromophenyl)phenyl]cyclopropanecarboxylate

Add l-[4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl]cyclo

propanecarboxylate (10.0 g, 33.1 mmol), l-bromo-4-iodo-benzene (10.5g, 34.7 mmol) in dioxane (50.0 mL) and water (10.0 mL) to potassium carbonate (9.1 g., 66.2 mmol) and [Ι,Γ-bis(diphenylphosphino)ferrocene]dichloropalladium (2.4 g, 3.31 mmol). The reaction mixture is stirred at 100 °C for 2 h under N2. The reaction mixture is concentrated to give a black solid, which was purified by column chromatography (PE:EtOAc = 10: 1) to give the title compound (10.0 g, 91.2%) as a white solid,

¾ MR (400MHz, CDCb) δ = 7.56-7.40 (m, 8H), 3.65 (s, 3H), 1.64 (m, 2H), 1.22 (m, 2H).

4. Synthesis of methyl l-[4-[4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl )phenyl ] phenyl ] cy cl opropanecarb oxyl ate

Add methyl l-[4-(4-bromophenyl)phenyl]cyclopropanecarboxylate (10.0 g, 30.2 mmol), 4,4,5, 5-tetramethyl-2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l,3,2-dioxaborolane (8.1 g, 31.7 mmol,) in 1,4-dioxane (50.0 mL) to potassium acetate (14.6 g, 106 mmol) and [l, l'-bis(diphenylphosphino)ferrocene]dichloropalladium (2.2 g, 3.02 mmol). Then the reaction mixture is stirred at 100 °C for 2 h under N2. The reaction mixture is concentrated to give a black solid. The black solid is purified by column chromatography (PE:EtOAc = 10: 1) to give the title compound (8.00 g, 70.0%) as a light yellow solid.

¾ MR (400MHz, CDCb) δ = 7.87 (m, 2H), 7.61-7.57 (m, 4H), 7.41 (m, 2H), 3.65 (s, 3H), 1.64 (m, 2H), 1.22 (m, 2H).

5. Synthesis of methyl l-[4-[4-(5-amino-l-methyl-pyrazol-4- yl )phenyl ] phenyl ] cy cl opropanecarb oxylate

Add l-[4-[4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)phenyl]phi

cyclopropanecarboxylate (2.00 g, 5.29 mmol), 4-bromo-2-methyl-pyrazol-3-amine

( 1.1 g, 6.34 mmol), tetrakis(triphenylphosphine)palladium (0.60 g, 0.529 mmol) in ethanol (4.00 mL), toluene (20.0 mL) and water (3.00 mL) to sodium carbonate (2.3 g, 21.1 mmol). The mixture is stirred at 110 °C for 4 h under N2. The reaction mixture is concentrated to give a yellow residue. The residue is purified by column chromatography (DCM:MeOH = 10: 1) to give the title compound (1.12 g, 61.0%) as a yellow solid. LCMS (m/z): 347.9

[M+H]+.

6. Synthesis of l-[4-[4-[5-[(6-chloropyrazin-2-yl)amino]-l -methyl -pyrazol -4- yl ] phenyl ] phenyl ] cy cl opropanecarb oxyli c aci d

Add sodium hydride (60 mass%) in oil (0.131 g, 3.28 mmol, 60 mass%) to the solution of methyl l-[4-[4-(5-amino-l-methyl-pyrazol-4-yl)phenyl]phenyl]cyclopropanecarboxylate (300 mg, 0.820 mmol) in DMF (3 mL). The reaction mixture is heated to 50 °C and then 2, 6-dichloropyrazine (0.123 g, 0.820 mmol) is added. The reaction mixture is stirred at 50 °C for 2 hours. The reaction mixture is poured into ammonium chloride solution (50 ml) and extracted with EtOAc (50 mL x 2). The combined organic layers are washed with brine (40 mL x 3), dried over sodium sulfate, filtered and concentrated to afford the crude product. The crude product is purified by prep-HPLC (column: Phenomenex Gemini 150*25mm* 10 μπι, Gradient: 36-66% B (A = water/0.05% HC1, B = acetontrile), Flow rate: 25mL/min) to afford the title product (75.0 mg, 20.8%) as a yellow solid. LCMS (m/z) 446.0 [M+H]+.

WE CLAIMS

1. A compound of the formula

wherein,

X1 and X2 are each independently CH or N, and X3 is C-R2 or N, provided that when X1 is CH, then X2 is CH and X3 is C-R2, and provided that when X1 is N, then no more than one of X2 and X3 may be N;

Y1 and Y2 are CH or N, provided that only one of Y1 or Y2 may be N;

R s

isopropyl,

isobutyl,

t-butyl,

2-hydroxyprop-2-yl,

cyclopropyl,

cyclopropyloxy,

t-butyl oxy,

cyclobutyloxy,

3 ,3 -difluorocyclobutyloxy,

2-fluoroprop-2-yl,

1, 1-difluoroethyl,

trifluoromethyl,

isopropyloxy, or

2-methoxyprop-2-yl;

R2 is H or fluoro;

R3 is H, halogen, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 alkoxymethyl, CF3, cyanomethyl or cyano;

R4 is H, halogen, C1-C3 alkyl, CF3 or cyano;

R5 is H, methyl, ethyl, propyl, isopropyl, or cyclopropyl; or

a pharmaceutically acceptable salt thereof.

2. The compound according to Claim 1, wherein X1 is N, or a pharmaceutically acceptable salt thereof.

3. The compound according to Claim 1, wherein X1 is CH, or a pharmaceutically acceptable salt thereof

4. The compound according to any one of Claims 1-3, wherein Y1 is CH, or a pharmaceutically acceptable salt thereof.

5. The compound according to any one of Claims 1-4, wherein R1 is isopropyl, or a pharmaceutically acceptable salt thereof.

6. The compound according to any one of Claims 1-4, wherein R1 is

cyclopropyloxy, or a pharmaceutically acceptable salt thereof.

7. The compound according to any one of Claims 1-6, wherein R5 is hydrogen, or a pharmaceutically acceptable salt thereof.

8. The compound according to Claim 1, which is:

l-[4-[6-[5-[(6-tert-butoxypyrazin-2-yl)amino]-l-methyl-pyrazol-4-yl]-3-pyri dyl ] phenyl ] cy cl opropanecarb oxyli c aci d,

l-[4-[6-[5-[[6-(cyclobutoxy)pyrazin-2-yl]amino]-l-methyl-pyrazol-4-yl]-3-pyri dyl ] phenyl ] cy cl opropanecarb oxyli c aci d,

l-[4-[6-[5-[[6-(cyclopropoxy)pyrazin-2-yl]amino]-l-methyl-pyrazol-4-yl]-5-fluoro-3 pyri dyl ] phenyl ] cy cl opropanecarb oxyli c aci d,

l-[4-[5-fluoro-6-[5-[[6-(l-fluoro-l-methyl-ethyl)pyrazin-2-yl]amino]-l -methyl-pyrazol-4-yl]-3-pyridyl]phenyl]cyclopropanecarboxylic acid,

l-[4-[6-[5-[[6-(3,3-difluorocyclobutoxy)pyrazin-2-yl]amino]-l-methyl-pyrazol-4-yl]-3 -pyri dyl ] phenyl ] cy cl opropanecarb oxyli c aci d,

l-[4-[6-[5-[[6-(l-methoxy-l-methyl-ethyl)pyrazin-2-yl]amino]-l-methyl-pyrazol-4-yl]-3-pyridyl]phenyl]cyclopropanecarboxylic acid,

l-[4-[6-[5-[(6-isopropoxypyrazin-2-yl)amino]-l-methyl-pyrazol-4-yl]-3-pyridyl]-2-methyl -phenyl ] cy cl oprop anecarb oxyli c aci d,

1- [4-[6-[5-[[6-(cyclopropoxy)pyrazin-2-yl]amino]-l-methyl-pyrazol-4-yl]-3-pyridyl]

2- (trifluoromethyl)phenyl]cyclopropanecarboxylic acid,

l-[2-cyano-4-[6-[5-[[6-(cyclopropoxy)pyrazin-2-yl]amino]-l-methyl-pyrazol-4-yl]-3 pyri dyl ] phenyl ] cy cl opropanecarb oxyli c aci d,

l-[4-[6-[5-[[6-(cyclopropoxy)pyrazin-2-yl]amino]-l-methyl-pyrazol-4-yl]-3-pyri dyl ] phenyl ] cy cl opropanecarb oxyli c aci d,

l-[4-[5-fluoro-6-[5-[(6-isopropoxypyrazin-2-yl)amino]-l-methyl-pyrazol-4-yl]-3-pyri dyl ] phenyl ] cy cl opropanecarb oxyli c aci d,

l-[4-[6-[5-[[6-(l,l-difluoroethyl)pyrazin-2-yl]amino]-l-methyl-pyrazol-4-yl]-3-pyri dyl ] phenyl ] cy cl opropanecarb oxyli c aci d,

l-[4-[6-[5-[[6-(l-fluoro-l -methyl-ethyl )pyrazin-2-yl]amino]-l -methyl -pyrazol-4-yl]-3 -pyri dyl ] phenyl ] cy cl opropanecarb oxyli c aci d,

l-[4-[6-[5-[(6-isopropylpyrazin-2-yl)amino]-l-methyl-pyrazol-4-yl]-3-pyridyl]-3-(methoxymethyl)phenyl]cyclopropanecarboxylic acid,

1 - [3 -(cyanomethyl)-4- [6-[5 - [(6-i sopropylpyrazin-2-yl)amino] - 1 -m ethyl -pyrazol-4-yl]-3-pyridyl]phenyl]cyclopropanecarboxylic acid,

l-[3-cyano-4-[6-[5-[(6-isopropylpyrazin-2-yl)amino]-l-methyl-pyrazol-4-yl]-3-pyri dyl ] phenyl ] cy cl opropanecarb oxyli c aci d,

l-[4-[4-[5-[(6-isobutylpyrazin-2-yl)amino]-l -methyl -pyrazol -4-yl ] phenyl ] phenyl ] cy cl opropanecarb oxyli c acid,

l-[4-[2-[5-[(6-isopropylpyrazin-2-yl)amino]-l-methyl-pyrazol-4-yl]pyrimidin-5-yl ] phenyl ] cy cl oprop anecarb oxyli c aci d,

l-[4-[5-[5-[(6-isopropylpyrazin-2-yl)amino]-l-methyl-pyrazol-4-yl]pyrazin-2-yl ] phenyl ] cy cl oprop anecarb oxyli c aci d,

l-[4-[6-[5-[(6-isopropoxypyrazin-2-yl)amino]-l-methyl-pyrazol-4-yl]-3-pyri dyl ] phenyl ] cy cl opropanecarb oxyli c aci d,

l-[4-[6-[l-methyl-5-[[6-(trifluoromethyl)pyrazin-2-yl]amino]pyrazol-4-yl]-3-pyri dyl ] phenyl ] cy cl opropanecarb oxyli c aci d,

l-[4-[6-[5-[(6-isopropylpyrazin-2-yl)amino]-l-methyl-pyrazol-4-yl]-3-pyridyl]-3-methyl -phenyl ] cy cl oprop anecarb oxyli c aci d,

Ammonia; l-[5-[6-[5-[(6-isopropylpyrazin-2-yl)amino]-l-methyl-pyrazol-4-yl]-3-pyridyl]-2-pyridyl]cyclopropanecarboxylic acid,

l-[6-[6-[5-[(6-isopropylpyrazin-2-yl)amino]-l-methyl-pyrazol-4-yl]-3-pyridyl]-3-pyridyl]cyclopropanecarboxylic acid,

Ammonium l-[4-[4-[5-[(6-cyclopropylpyrazin-2-yl)amino]-l -methyl -pyrazol -4-yl ] phenyl ] phenyl ] cy cl opropanecarb oxylate,

l-[4-[4-[5-[(6-isopropylpyrazin-2-yl)amino]-l-methyl-pyrazol-4-yl]phenyl]phenyl]cyclopropanecarboxylic acid, or

l-[4-[6-[5-[(6-isopropylpyrazin-2-yl)amino]-l-methyl-pyrazol-4-yl]-3-pyri dyl ] phenyl ] cy cl opropanecarb oxyli c aci d;

or a pharmaceutically acceptable salt thereof.

9. The compound of Claim 1 which is, l-[4-[6-[5-[(6-isopropylpyrazin-2-yl)amino]-l-methyl-pyrazol-4-yl]-3-pyridyl]phenyl]cyclopropanecarboxylic acid, or a pharmaceutically acceptable salt thereof.

10. The compound of Claim 1 which is, l-[4-[4-[5-[(6-isopropylpyrazin-2-yl)amino]-l-methyl-pyrazol-4-yl]phenyl]phenyl]cyclopropanecarboxylic acid, or a pharmaceutically acceptable salt thereof.

11. A pharmaceutical composition, comprising a compound according to any one of Claims 1 to 10, or a pharmaceutically acceptable salt thereof, and at least one

pharmaceutically acceptable carrier, diluent, or excipient.

12. A method for treating nonalcoholic steatohepatitis (NASH), comprising administering to a mammal in need thereof, an effective amount of a compound of the formula

wherein,

X1 and X2 are each independently CH or N, and X3 is C-R2 or N, provided that when X1 is CH, then X2 is CH and X3 is C-R2, and provided that when X1 is N, then no more than one of X2 and X3 may be N;

Y1 and Y2 are CH or N, provided that only one of Y1 or Y2 may be N;

R s

isopropyl,

isobutyl,

t-butyl,

2-hydroxyprop-2-yl,

cyclopropyl,

cyclopropyloxy,

t-butyloxy,

cyclobutyloxy,

3 , 3 -di fluorocy cl obutyl oxy ,

2-fluoroprop-2-yl,

1, 1-difluoroethyl,

trifluoromethyl,

isopropyloxy, or

2-methoxyprop-2-yl;

R2 is H or fluoro;

R3 is H, halogen, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 alkoxymethyl, CF3, cyanomethyl or cyano;

R4 is H, halogen, C1-C3 alkyl, CF3 or cyano;

R5 is H, methyl, ethyl, propyl, isopropyl, or cyclopropyl; or a pharmaceutically acceptable salt thereof.

13. A method for treating fibrosis, comprising administering to a mammal thereof, an effective amount of a compound of the formula

wherein,

X1 and X2 are each independently CH or N, and X3 is C-R2 or N, provided that when X1 is CH, then X2 is CH and X3 is C-R2, and provided that when X1 is N, then no more than one of X2 and X3 may be N;

Y1 and Y2 are CH or N, provided that only one of Y1 or Y2 may be N;

R s

isopropyl,

isobutyl,

t-butyl,

2-hydroxyprop-2-yl,

cyclopropyl,

cyclopropyloxy,

t-butyl oxy,

cyclobutyloxy,

3 , 3 -difluorocy cl obutyl oxy,

2-fluoroprop-2-yl,

1, 1-difluoroethyl,

trifluorom ethyl,

isopropyloxy, or

2-methoxyprop-2-yl;

R2 is H or fluoro;

R3 is H, halogen, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 alkoxymethyl, CF3, cyanomethyl or cyano;

R4 is H, halogen, C1-C3 alkyl, CF3 or cyano;

R5 is H, methyl, ethyl, propyl, isopropyl, or cyclopropyl; or

a pharmaceutically acceptable salt thereof.

14. The method according to Claims 12 or 13, wherein the mammal is a human.

15. A compound according to any one of Claims 1 to 10, or a pharmaceutically acceptable salt thereof, for use in therapy.

16. A compound according to any one of Claims 1 to 10, or a pharmaceutically acceptable salt thereof, for use in the treatment of NASH.

17. A compound according to any one of Claims 1 to 10, or a pharmaceutically acceptable salt thereof, for use in the treatment of fibrosis.