BTK inhibitors

Abstract

Compounds of formula (I) JPEG2024544530000174.jpg5299, or a pharma- ceutically acceptable salt thereof, is provided, wherein the variables in formula (I) are as defined herein, as well as methods of use and preparation thereof.

Description

[Technical field]

[0001] Related Applications This application claims the benefit under 35 U.S.C. §119(e) of the filing date of U.S. Provisional Application No. 63 / 278,718, filed November 12, 2021, the entire contents of which are incorporated herein by reference.

[0002] Provided are certain agents that inhibit Bruton's tyrosine kinase (Btk), as well as methods for making and using such agents. [Background technology]

[0003] Protein kinases are a large multigene family of over 500 proteins that play important roles in the development and treatment of many human diseases in oncology, neurology and immunology.

[0004] Tec kinases are non-receptor tyrosine kinases that consist of five members (Tec (tyrosine kinase expressed in hepatocellular carcinoma), Btk (Bruton's tyrosine kinase), Itk (interleukin-2 (IL-2)-inducible T cell kinase, also known as Emt or Tsk), Rlk (resting lymphocyte kinase, also known as Txk), and Bmx (myeloid tyrosine kinase gene on chromosome X, also known as Etk)) and are expressed primarily in hematopoietic cells. However, expression of Bmx and Tec has been detected in endothelial cells and hepatocytes. Tec kinases (Itk, Rlk, and Tec) are expressed in T cells and are all activated downstream of the T cell receptor (TCR). Btk is a downstream mediator of B cell receptor (BCR) signaling involved in regulating B cell activation, proliferation, and differentiation. More specifically, Btk contains a PH domain that binds phosphatidylinositol (3,4,5)-triphosphate (PIP3). Binding of PIP3 induces Btk to phosphorylate phospholipase C (PLCy), which hydrolyzes PIP2 to generate two second messengers, inositol triphosphate (IP3) and diacylglycerol (DAG), which activate the protein kinase PKC, which in turn induces further B cell signaling. Mutations that impair Btk enzymatic activity result in the primary immunodeficiency disorder XLA syndrome (X-linked agammaglobulinemia). Given that Tec kinase plays an important role in both B and T cell signaling, it is a valuable target for autoimmune diseases.

[0005] Given the important role Btk plays in B cell signaling, there is a great need in the art for effective inhibitors of Btk. Summary of the Invention

[0006] One aspect of the present disclosure is a compound of formula (I) [ka] or a pharma- ceutically acceptable salt thereof, X 0 is N and X 1 is C and X 2 is N and X 4 is N or X 0 is CR 0 and X 1 is C and X 2 is N and X 4 is N or X 0 is CR 0 and X 1 is N and X 2 is C and X 4 is N or X 0 is CR 0 and X 1 is N and X 2 is C and X 4 is CH or X 0 is CR 0 and X 1 is C and X 2 is N and X 4 is CH, R 0 is H, halo, -CH3, halomethyl, cyclopropyl, or CN; Het is phenyl, 5-6 membered heteroaryl, or N-(C-C alkyl)pyridonyl; R 1 is H or C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C3-C6 cycloalkyl, or a 4-7 membered monocyclic oxygen-containing heterocycle; X 3 does not exist or is -S-, -SO2-, CR 3a R 3b , -C(=O)-, or -(C=O)-NH-*, where * is R 2 indicates the point of attachment to R 3a and R 3b are each independently H or halo; R 3a and R 3b At least one of them is not H, X 3 However, it does not exist or -S-, -SO2-, CR3a R 3b , or -(C=O)-NH-*, R 2 is connected to X via a ring carbon atom 3 a 4-12 membered monocyclic or bicyclic nitrogen-containing heterocycle bonded to X via a ring nitrogen atom ("C-linked"); 3 ("N-linked") 8-12 membered bicyclic nitrogen-containing heterocycle, 4-7 membered monocyclic oxygen-containing heterocycle, phenyl, or 3-12 membered monocyclic or bicyclic carbocyclyl bonded to R 2 The 4- to 7-membered monocyclic oxygen-containing heterocycle, the phenyl, and the 3- to 12-membered monocyclic or bicyclic carbocyclyl are each represented by R 4 and further substituted with a group represented by R 10 and R 2 The C-linked 4-12 membered monocyclic or bicyclic nitrogen-containing heterocycle represented by R 5 and further R 10 and R 2 The N-linked 8-12 membered bicyclic nitrogen-containing heterocycle represented by R 5 and further R 10 and optionally substituted with one or two groups represented by X 3 If does not exist, R 2 may be represented by formula (A): [ka] X 3 is -C(=O)-, R2 is linked to X via a ring nitrogen atom 3 ("N-linked") 4-12 membered monocyclic or bicyclic nitrogen-containing heterocycle, 4-7 membered monocyclic oxygen-containing heterocycle, phenyl, or 3-12 membered monocyclic or bicyclic carbocyclyl bonded to R 2 The 4- to 7-membered monocyclic oxygen-containing heterocycle, the phenyl, and the 3- to 12-membered monocyclic or bicyclic carbocyclyl are each represented by R 4and further substituted with a group represented by R 10 and R 2 The N-linked 4-12 membered monocyclic or bicyclic nitrogen-containing heterocycle represented by R 4 and further R 10 and optionally substituted with one or two groups represented by [ka] [ka] R 6 is H, C1-C3 alkyl, C1-C3 haloalkyl, N(R a )2, or CH2N(R a )2, and each R a are independently H or methyl; R 6’ is H, C1-C3 alkyl, or C1-C3 haloalkyl; R 7 is H, C1-C2 alkyl, or C1-C2 fluoroalkyl; Each R 10 are independently F or C 1~3 is alkyl, R 11 is H or N(R 12 )2, Each R 12 are independently H or C1-C3 alkyl; R 13 is CN or F, n is 0 or 1, p is 1 or 2; q is 1 or 2.

[0007] In a second aspect, the present disclosure provides a pharmaceutical composition comprising at least one compound described herein, or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable excipient.

[0008] In a third aspect, the present disclosure provides a method for treating a disease responsive to inhibition of Bruton's tyrosine kinase (Btk) in a subject, the method comprising administering to the subject an effective amount of at least one compound described herein or a pharma- ceutically acceptable salt thereof.

[0009] The disclosure also includes the use of at least one compound described herein, or a pharma- ceutically acceptable salt thereof, in the manufacture of a medicament for treating a disease that responds to inhibition of Btk.Also provided is a compound described herein, or a pharma- ceutically acceptable salt thereof, for use in treating a disease that responds to inhibition of Btk.

[0010] Other features or advantages will become apparent from the following detailed description of several embodiments, and from the appended claims. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0011] The compounds described herein or their pharma- ceutically acceptable salts may have activity as Btk modulators. In particular, the compounds described herein or their pharma- ceutically acceptable salts may be Btk inhibitors.

[0012] I. Definition The term "alkyl" as used herein refers to a fully saturated branched or unbranched hydrocarbon moiety. In some embodiments, an alkyl contains 1-20 carbon atoms, 1-10 carbon atoms, 1-8 carbon atoms, 1-6 carbon atoms, or 1-4 carbon atoms. In some embodiments, an alkyl contains 6-20 carbon atoms. Representative examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, or n-hexyl.

[0013] "Alkenyl" refers to an unsaturated hydrocarbon group, which may be straight or branched, having at least one carbon-carbon double bond. In some embodiments, an alkenyl group has 2-20 carbon atoms, 2-10 carbon atoms, or 2-6 carbon atoms. An alkenyl group may contain one, two, or three carbon-carbon double bonds, or more. Examples of alkenyl groups include ethenyl, n-propenyl, isopropenyl, n-but-2-enyl, n-hex-3-enyl, and the like.

[0014] "Alkynyl" refers to an unsaturated hydrocarbon group, which may be straight or branched, having at least one carbon-carbon triple bond. In some embodiments, the alkynyl group preferably has 2-20 carbon atoms, 2-10 carbon atoms, or 2-6 carbon atoms. The alkynyl group may contain one, two, or three carbon-carbon triple bonds, or more. Examples of alkynyl groups include ethynyl, n-propynyl, n-but-2-ynyl, n-hex-3-ynyl, and the like.

[0015] As used herein, the term "alkoxy" refers to a fully saturated branched or unbranched alkyl moiety attached through an oxygen bridge (i.e., --O--C 1~4 Alkyl group, where C 1~4 Alkyl refers to an alkyl group as defined herein. Representative examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy, tert-butoxy, and the like. In some embodiments, alkoxy groups have about 1-4 carbons, more preferably about 1-2 carbons.

[0016] The term "aryl" as used herein is defined to include all-carbon monocyclic or fused-ring polycyclic groups (i.e., rings which share adjacent pairs of carbon atoms) having a completely conjugated pi-electron system. Aryl groups may have 6, 8, 9, or 10 carbon atoms in the ring(s). In some embodiments, aryl groups may have 6 or 10 carbon atoms in the ring(s). For example, "(C6-C 10 The term "aryl" refers to an aromatic group containing 6 to 10 carbon atoms, such as phenyl, naphthyl, tetrahydronaphthyl, anthracenyl, indanyl, etc. An aryl group having 6 carbon atoms in the ring(s) may be optionally substituted with 1 to 5 suitable substituents.

[0017] In some embodiments, the number of carbon atoms in a group is indicated herein by the prefix "C x~xx " or "C x ~c xx " where x and xx are integers. For example, "C 1~4 "Alkyl" or "C1-C4 alkyl" is an alkyl group having from 1 to 4 carbon atoms.

[0018] The terms "carbocyclyl," "carbocycle," or "carbocyclic ring" as used herein refer to a saturated or partially unsaturated monocyclic or bicyclic (e.g., fused, bridged, or spiro ring systems) ring system of 4 to 12 ring members that are all carbon. The term "carbocyclyl" encompasses cycloalkyl and cycloalkenyl groups.

[0019] In one embodiment, the carbocyclyl is a 3- to 7-membered monocyclic carbocyclyl. Exemplary 3- to 7-membered monocyclic carbocyclyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopropenyl, cyclobutenyl, cyclopenentyl, cyclohexenyl, cycloheptenyl, cyclobutadienyl, cyclopentadienyl, cyclohexadienyl, cycloheptadienyl, phenyl, and cycloheptatrienyl.

[0020] In one embodiment, the carbocyclyl is a 7-10 membered bicyclic carbocyclyl. Exemplary 7-10 membered bicyclic carbocyclyls include, but are not limited to, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.1]heptenyl, 6,6-dimethylbicyclo[3.1.1]heptyl, 2,6,6-trimethylbicyclo[3.1.1]heptyl, spiro[3.3]heptanyl, spiro[2.5]octanyl, spiro[2.2]pentanyl, spiro[3.3]heptanyl, bicyclo[3.3.0]octanyl, bicyclo[2.2.2]octanyl, bicyclo[3.3.1]nonanyl, bicyclo[3.3.2]decanyl, decalinyl, naphthyl, and indanyl.

[0021] Fused bicyclic carbocyclyls are fused 4- to 7-membered carbocyclyls with 3- to 7-membered non-aromatic carbocyclyls. Examples include decahydronaphthalene, octahydro-1H-indene, octahydropentalene, decahydroazulene, decahydro-1H-annulene, bicyclo[4.2.0]octane, and bicyclo[3.2.0]heptane.

[0022] A bridged bicyclic carbocyclyl is composed of a 5- to 7-membered nonaromatic carbocyclyl and a 5- to 7-membered aromatic carbocyclyl that share three ring atoms. Examples of bridged bicyclic carbocycles include bicyclo[2.2.1]heptanyl, bicyclo[3.2.1]octanyl, and bicyclo[3.3.1]nonanyl.

[0023] "Cycloalkyl" refers to a fully saturated monocyclic hydrocarbon group of 3 to 7 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cyclopentyl. "Cycloalkenyl" refers to an unsaturated non-aromatic monocyclic hydrocarbon group of 3 to 7 carbon atoms, such as cyclopentenyl, cyclohexenyl, and cyclopentenyl. The term "cycloalkyl" encompasses fully saturated monocyclic or bicyclic or spiro-type hydrocarbon groups of 3 to 7 carbon atoms, 3 to 6 carbon atoms, or 5 to 7 carbon atoms. In some embodiments, the cycloalkyl is a 3-6 membered monocyclic cycloalkyl.

[0024] "Halogen" or "halo" can be fluoro, chloro, bromo or iodo.

[0025] The term "haloalkyl" or "halo-substituted alkyl" refers to an alkyl group having at least one halogen substitution.

[0026] "Haloalkoxy" refers to a haloalkyl group that is attached to another moiety through an oxygen atom such as, but not limited to, -OCHCF2 or -OCF3.

[0027] "Heteroaryl" refers to a 5-6 membered aromatic monocyclic ring system having 1-4 heteroatoms independently selected from O, S, and N, where N may be oxidized (e.g., N(O)) or quaternized, and S may be oxidized to sulfoxide and sulfone. Examples of 5-6 membered monocyclic heteroaryls include, but are not limited to, pyrrolyl, furanyl, thiophenyl (or thienyl), imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, furazanyl, oxadiazolyl, thiadiazolyl, dithiazolyl, triazolyl, tetrazolyl, pyridinyl, pyranyl, thiopyranyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazinyl, thiazinyl, dioxinyl, dithiinyl, oxathianyl, triazinyl, tetrazinyl, and the like. In one embodiment, the heteroaryl is a 5 membered heteroaryl. Examples of 5-membered heteroaryls include, but are not limited to, pyrazolyl, oxazolyl, isoxazolyl, 1,2,3-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,3-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, and tetrazolyl.

[0028] The terms "heterocyclyl" and "heterocycle" refer to a saturated or partially unsaturated monocyclic or bicyclic (e.g., fused, bridged, or spiro) ring system having 3-12 ring members, at least one of which is a heteroatom and up to four (e.g., 1, 2, 3, or 4) of which may be heteroatoms, where the heteroatoms are independently selected from O, S, and N, where C may be oxidized (e.g., C(O)), N may be oxidized (e.g., N(O)) or quaternized, and S may be oxidized to sulfoxide and sulfone. In some embodiments, a heterocyclyl is a 4-6 membered, 4-7 membered, or 3-7 membered monocyclic heterocycle. In some embodiments, a heterocyclyl is a 7-12 membered bicyclic heterocycle, which may be a fused, bridged, or spiro bicyclic heterocycle. In some embodiments, a bicyclic heterocycle can include a non-aromatic heterocycle fused to a heteroaromatic ring.

[0029] Examples of monocyclic heterocycles include, but are not limited to, oxatanyl, thietanyl, azetedinyl, pyrrolidinyl, tetrahydrofuranyl, thiolanyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, dioxolanyl, dithiolanyl, oxathiolanyl, piperidinyl, tetrahydropyranyl, thianyl, piperazinyl, morpholinyl, thiomorpholinyl, dioxanyl, dithianyl, trioxanyl, trithianyl, azepanyl, oxepanyl, thiepanyl, dihydrofuranyl, imidazolinyl, and dihydropyranyl.

[0030] Examples of bicyclic heterocycles include, but are not limited to, 9-azabicyclo[3.3.1]nonanyl, 2-azabicyclo[2.2.2]octanyl, 8-azabicyclo[3.2.1]octanyl, 2,7-diazaspiro[4.4]nonane, octahydrocyclopenta[c]pyrrolyl, octahydro-1H-pyrrolo[3,4-c]pyridine, and the like.

[0031] A "fused ring system" is an 8-12 membered (ring atom) ring with two rings sharing two adjacent ring atoms. A fused bicyclic heterocycle is a 4-7 membered heterocycle fused with a 4-7 membered heterocycle or a 3-7 membered carbocyclyl. A fused bicyclic heterocyclyl may be a 4-7 membered heterocycle fused with a 5-6 membered heteroaryl. Examples include cyclopentapyrrolidinyl, cyclopentapiperidinyl, cyclopentazapanyl, cyclohexapyrrolidinyl, cyclohexapiperidinyl, cyclohexaazapanyl, cycloheptapyrrolidinyl, cycloheptapiperidinyl, cycloheptaazapanyl, pyrrolopyrrolidinyl, pyrrolopiperidinyl, pyrroloazapanyl, furanopyrrolidinyl, furanopiperidinyl, furanoazapanyl, pyranopyrrolidinyl, pyranopiperidinyl, pyranoazapanyl, dihydropyrrolo[3,4-d]thiazoyl, and the like.

[0032] A "bridged bicyclic ring system" (also referred to herein as "bridged bicyclic" or "bridged ring system") is a ring that is 7-10 membered (ring atoms) and has two rings that share three adjacent ring atoms. A bridged bicyclic heterocycle is composed of a 5-7 membered heterocycle and a 5-7 membered heterocycle or a 5-7 membered carbocycle that share three ring atoms. Examples of nitrogen-containing bridged bicycles include azabicyclo[2.2.1]heptanyl, azabicyclo[3.2.1]octanyl, azabicyclo[3.3.1]nonanyl, diazabicyclo[2.2.1]heptanyl, diazabicyclo[3.2.1]octanyl, and diazabicyclo[3.3.1]nonanyl. Examples of oxygen-containing bridged bicycles include oxobicyclo[2.2.1]heptanyl, oxobicyclo[3.2.1]octanyl, oxobicyclo[3.3.1]nonanyl, oxazabicyclo[2.2.1]heptanyl, oxazabicyclo[3.2.1]octanyl, and oxazabicyclo[3.3.1]nonanyl.

[0033] A "spiro ring system" (also referred to herein as "spiro ring") is an 8-12 membered (ring atom) ring with two rings sharing one ring atom. A spiro bicyclic heterocycle is composed of a 4-7 membered heterocycle and a 4-7 membered heterocycle or a 4-7 membered non-aromatic carbocycle, which share one atom. Examples of 8-12 membered nitrogen-containing spiro ring systems include 3,4-azabicyclooctanyl, 4,4-azabicyclononanyl, 3,5-azabicyclononanyl, 3,6-azabicyclodecanyl, 4,5-azabicyclodecanyl, 3,7-azabicycloundecanyl, 4,6-azabicycloundecanyl, and 5,5-azabicycloundecanyl. Examples of 8-12 membered oxygen-containing spiro ring systems include 3,4-oxobicyclooctanyl, 4,4-oxobicyclononanyl, 3,5-oxobicyclononanyl, 3,6-oxobicyclodecanyl, 4,5-oxobicyclodecanyl, 3,7-oxobicycloundecanyl, 4,6-oxobicycloundecanyl and 5,5-oxobicycloundecanyl.

[0034] Examples of 4-12 membered nitrogen-containing heterocycles include pyrrolidinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, azepanyl, oxepanyl, imidazolinyl, cyclopentapyrrolidinyl, cyclopentapiperidinyl, cyclopentaazapanyl, cyclohexapyrrolidinyl, cyclohexapyrrolidinyl, cyclohexaazapanyl, cycloheptapyrrolidinyl, cycloheptapyrrolidinyl, cycloheptaazapanyl, pyrrolopyrrolidinyl, pyrrolopiperidinyl, pyrroloazapanyl, furanopiperidinyl, Examples of the azabicyclooctanyl include furanoazapanyl, pyranopyrrolidinyl, pyranopiperidinyl, pyranoazapanyl, azabicyclo[2.2.1]heptanyl, azabicyclo[3.2.1]octanyl, azabicyclo[3.3.1]nonanyl, diazabicyclo[2.2.1]heptanyl, diazabicyclo[3.2.1]octanyl, diazabicyclo[3.3.1]nonanyl, 3,4-azabicyclooctanyl, 4,4-azabicyclononanyl, 3,5-azabicyclononanyl, 3,6-azabicyclodecanyl, 4,5-azabicyclodecanyl, 3,7-azabicycloundecanyl, 4,6-azabicycloundecanyl, and 5,5-azabicycloundecanyl. Examples of 4-7 membered nitrogen-containing heterocycles (which may contain one ring oxygen atom or one ring sulfur atom) include pyrrolidinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, azepanyl, oxepanyl and imidazolinyl.

[0035] Examples of 4- to 7-membered oxygen-containing heterocycles include oxetanyl, tetrahydrofuranyl, oxazolidinyl, isoxazolidinyl, dioxolanyl, oxathiolanyl, tetrahydropyranyl, morpholinyl, dioxanyl, oxepanyl, dihydrofuranyl, and dihydropyranyl.

[0036] The suffix "yl" added to the end of a chemical name indicates that the specified moiety is attached to the molecule at one point. The suffix "ene" added to the end of a chemical name indicates that the specified moiety is attached to the molecule at two points. Examples include azetidinylene, pyrrolidinylene, piperidinylene, azapanylene, or oxyazapanylene, which indicate that the azetidine, pyrrolidine, piperidine, azapane, or oxyazapane is attached to the rest of the compound at two points.

[0037] A nitrogen-containing heterocycle is "N-substituted" if a ring nitrogen atom is substituted.

[0038] The term "oxo" refers to the diradical =O.

[0039] When the compounds described herein are sufficiently basic or acidic to form stable non-toxic acid salts or base salts, it may be appropriate to prepare and administer the compounds as pharmaceutically acceptable salts. Examples of pharmaceutically acceptable salts are organic acid addition salts formed with acids that form physiologically acceptable anions (e.g., tosylate, methanesulfonate, acetate, citrate, malonate, tartrate, succinate, benzoate, ascorbate, α-ketoglutarate, or α-glycerophosphate). Inorganic salts can also be formed, including hydrochloride, sulfate, nitrate, bicarbonate, and carbonate.

[0040] Pharmaceutically acceptable salts can be obtained using standard procedures well known in the art, for example, by reacting a sufficiently basic compound, such as an amine, with a suitable acid that provides a physiologically acceptable anion. Alkali metal (e.g., sodium, potassium, or lithium) or alkaline earth metal (e.g., calcium) salts of carboxylic acids can also be formed.

[0041] Pharmaceutically acceptable base addition salts can be prepared from inorganic and organic bases. Salts from inorganic bases can include, but are not limited to, sodium salts, potassium salts, lithium salts, ammonium salts, calcium salts, or magnesium salts. Salts derived from organic bases include, for example, alkylamines, dialkylamines, trialkylamines, substituted alkylamines, di(substituted alkyl)amines, tri(substituted alkyl)amines, alkenylamines, dialkenylamines, trialkenylamines, substituted alkenylamines, di(substituted alkenyl)amines, tri(substituted alkenyl)amines, cycloalkylamines, di(cycloalkyl)amines, tri(cycloalkyl)amines, substituted cycloalkylamines, disubstituted cycloalkylamines, trisubstituted cycloalkylamines, cycloalkenylamines, di(cycloalkenyl)amines, tri(cycloalkenyl)amines, substituted cycloalkenylamines, disubstituted cycloalkenylamines, tri ... These include, but are not limited to, salts of primary, secondary or tertiary amines, such as substituted cycloalkenylamines, arylamines, diarylamines, triarylamines, heteroarylamines, diheteroarylamines, triheteroarylamines, heterocycloalkylamines, diheterocycloalkylamines, triheterocycloalkylamines, or mixed diamines and triamines, where at least two of the substituents of the amine may be different and may be alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, heteroaryl, or heterocycloalkyl, etc. Also included are amines where two or three of the substituents, taken together with the amino nitrogen, form a heterocycloalkyl or heteroaryl group.Non-limiting examples of amines include isopropylamine, trimethylamine, diethylamine, tri(isopropyl)amine, tri(n-propyl)amine, ethanolamine, 2-dimethylaminoethanol, trimethamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, N-alkylglucamines, theobromine, purine, piperazine, piperidine, morpholine, N-ethylpiperidine, etc. Other carboxylic acid derivatives may be useful, such as carboxylic acid amides, including carboxamides, lower alkyl carboxamides, or dialkyl carboxamides, etc.

[0042] The compounds described herein or their pharma- ceutically acceptable salts may contain one or more asymmetric centers in the molecule. Any structure that does not specify stereochemistry according to the present disclosure should be understood to include all of the various stereoisomers (e.g., diastereomers and enantiomers) in pure or substantially pure form, as well as mixtures thereof (such as racemic mixtures or enantiomerically enriched mixtures). Methods for preparing such optically active forms (e.g., resolution of racemates by recrystallization techniques, synthesis from optically active starting materials, by chiral synthesis, or chromatographic separation using chiral stationary phases) are well known in the art.

[0043] When a particular stereoisomer of a compound is designated by name or structure, the stereochemical purity of the compound is at least 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 97%, 99%, 99.5% or 99.9%. "Stereochemical purity" means the percent by weight of the desired stereoisomer based on the combined weight of all stereoisomers.

[0044] When a particular enantiomer of a compound is designated by name or structure, the stereochemical purity of the compound is at least 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 97%, 99%, 99.5% or 99.9%. "Stereochemical purity" means the percent by weight of the desired enantiomer based on the combined weight of all stereoisomers.

[0045] When the stereochemistry of a disclosed compound is named or depicted by structure, and the named or depicted structure encompasses more than one stereoisomer (e.g., isomeric pairs), it is to be understood that one of the encompassed stereoisomers or any mixture of the encompassed stereoisomers is included. Furthermore, the stereoisomeric purity of the named or depicted stereoisomer is to be understood to be at least 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 97%, 99%, 99.5% or 99.9%. Stereoisomeric purity is expressed as a percentage by weight of the desired stereoisomer encompassed by the name or structure relative to the total weight of all stereoisomers.

[0046] Where a disclosed compound is named or depicted in a structure without indicating stereochemistry and the compound has one chiral center, the name or structure should be understood to encompass one enantiomer of the compound in pure or substantially pure form, and mixtures thereof, including racemic mixtures of the compounds and mixtures in which one enantiomer is enriched relative to its corresponding optical isomer.

[0047] Where a disclosed compound is named or depicted in a structure without indicating stereochemistry, and for example, the compound has at least two chiral centers, the name or structure should be understood to encompass one stereoisomer in pure or substantially pure form, as well as mixtures thereof, including mixtures of stereoisomers and mixtures of stereoisomers in which one or more stereoisomers are enriched relative to the other(s).

[0048] The compounds of the present disclosure may exist in tautomeric forms and tautomeric mixtures, and each individual tautomer is contemplated. Additionally, some compounds may exhibit polymorphism.

[0049] In one embodiment, the present invention provides a compound disclosed herein that is deuterated, where any or more positions occupied by hydrogen can contain deuterium at a concentration above the natural abundance of deuterium. For example, one or more hydrogen atoms are replaced with deuterium at an abundance at least 3340 times greater than the natural abundance of deuterium, which is 0.015% (i.e., at least 50.1% deuterium incorporation), or at least 3500 times (52.5% deuterium incorporation at each designated deuterium atom), at least 4000 times (60% deuterium incorporation), at least 4500 times (67.5% deuterium incorporation), at least 5000 times (75% deuterium), at least 5500 times (82.5% deuterium incorporation), at least 6000 times (90% deuterium incorporation), at least 6333.3 times (95% deuterium incorporation), at least 6466.7 times (97% deuterium incorporation), at least 6600 times (99% deuterium incorporation), or at least 6633.3 times (99.5% deuterium incorporation) greater than the natural abundance of deuterium, which is 0.015%. In one embodiment, hydrogen is present at its natural abundance at all positions. The compounds described herein, or pharma- ceutically acceptable salts thereof, may exist in tautomeric forms and tautomeric mixtures, and each individual tautomer is also contemplated.

[0050] II. Compounds of the Disclosure In a first embodiment, the compound of the present disclosure is represented by formula (I) or a pharma- ceutically acceptable salt thereof, wherein the variables are as defined above. [ka]

[0051] In a second embodiment of the present disclosure, for a compound of formula (I) or a pharma- ceutically acceptable salt thereof, R 11is H, and the other symbols are as described in the first embodiment.

[0052] In a third embodiment of the present disclosure, the compound is represented by one of the following formulas: [ka] or a pharma- ceutically acceptable salt thereof, and the other symbols are as described in the first embodiment.

[0053] In a fourth embodiment of the present disclosure, the compound is represented by one of the following formulas: [ka] or a pharma- ceutically acceptable salt thereof, wherein R 3a and R 3b are each independently H or halo; R 3a and R 3b At least one of these is not H, and the other symbols are as described in the first embodiment.

[0054] In a fifth embodiment of the present disclosure, for a compound of formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII) or (IX), or a pharma- ceutically acceptable salt thereof, R 0 is H, Cl, F or -CH3, R 3a and R 3b are each F, and the other symbols are as described in the first, second, third or fourth embodiment.

[0055] In a sixth embodiment of the present disclosure, for a compound of formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII) or (IX), or a pharma- ceutically acceptable salt thereof, X 3 does not exist or is -S-, -SO2-, CR 3a R 3b or -(C=O)-NH-*, where R 2 is connected to X via a ring carbon atom 3a 4-9 membered monocyclic or bicyclic nitrogen-containing heterocycle bonded to X via a ring nitrogen atom ("C-linked"); 3 ("N-linked") 8-9 membered bicyclic nitrogen-containing heterocycle, phenyl, or 4-6 membered monocyclic carbocyclyl bonded to R 2 The phenyl and the 4- to 6-membered monocyclic carbocyclyl are each represented by R 4 and further substituted with a group represented by R 10 and R 2 The C-bonded 4-9 membered monocyclic or bicyclic nitrogen-containing heterocycle represented by R 5 and further R 10 and R 2 The N-linked 8-9 membered bicyclic nitrogen-containing heterocycle represented by R 5 and further R 10 and the other symbols are as described in the first, second, fourth or fifth embodiment.

[0056] In a seventh embodiment of the present disclosure, for a compound of formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII) or (IX), or a pharma- ceutically acceptable salt thereof, R 2 is selected from cyclobutanyl, cyclopentanyl, cyclohexanyl, and phenyl, each of which is R 4 and further substituted with a group represented by R 10 or R 2 is selected from azepanyl, azetidinyl, 9-azabicyclo[3.3.1]nonanyl, 2-azabicyclo[2.2.2]octanyl, 8-azabicyclo[3.2.1]octanyl, 2,7-diazaspiro[4.4]nonane, octahydrocyclopenta[c]pyrrolyl, octahydro-1H-pyrrolo[3,4-c]pyridine, piperidinyl, tetrahydropyridinyl, and pyrrolidinyl, each of which is selected from R 5and further R 10 and the other symbols are as described in the sixth embodiment.

[0057] In an eighth embodiment of the present disclosure, for a compound of formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII) or (IX), or a pharma- ceutically acceptable salt thereof, R 2 is selected from the following: [ka] In the formula, m is 0, 1 or 2; [ka] X 3 or a bond to ring A, and the other symbols are as described in the sixth embodiment.

[0058] In a ninth embodiment of the present disclosure, for a compound of formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII) or (IX), or a pharma- ceutically acceptable salt thereof, R 2 is selected from the following: [ka] During the ceremony, [ka] X 3 or a bond to ring A, and the other symbols are as described in the sixth embodiment.

[0059] In a tenth embodiment of the present disclosure, the compound is represented by the formula: [ka] or a pharma- ceutically acceptable salt thereof, and the other symbols are as described in the first embodiment.

[0060] In an eleventh embodiment of the present disclosure, for a compound of formula (X), or a pharma- ceutically acceptable salt thereof, R 2 is connected to X via a ring nitrogen atom 3 ("N-linked") 4- to 7-membered monocyclic nitrogen-containing heterocycle or 4- to 6-membered monocyclic carbocyclyl bonded to R 2 The 4- to 6-membered monocyclic carbocyclyl represented by the formula: 4 and further substituted with a group represented by R 10 and R 2 The N-bonded 4- to 7-membered monocyclic nitrogen-containing heterocycle represented by R 4 and is C-substituted with a group represented by R10 and the other symbols are as described in the tenth embodiment.

[0061] In a twelfth embodiment of the present disclosure, for a compound of formula (X) or a pharma- ceutically acceptable salt thereof, R 2 is selected from the following: [ka] In the formula, m is 0, 1 or 2; [ka] represents the bond to C(O)-ring A, and the other symbols are as described in the tenth or eleventh embodiment.

[0062] In a thirteenth embodiment of the present disclosure, for a compound of formula (X) or a pharma- ceutically acceptable salt thereof, R 2 is selected from the following: [ka] During the ceremony, [ka] represents a bond to the C(O)-ring A, and the other symbols are as described in the tenth or eleventh embodiment.

[0063] In a fourteenth embodiment of the present disclosure, for a compound of formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX) or (X), or a pharma- ceutically acceptable salt thereof, each R 10 is independently F, -CH or -CHCH, and the other symbols are as described in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh or twelfth embodiment.

[0064] In a fifteenth embodiment of the present disclosure, for a compound of formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX) or (X), or a pharma- ceutically acceptable salt thereof, [ka] and R 6 is H or -CF3, R 6′ is -CH3, R 7 is H, -CH3 or -CH2CH3, n is 0 or 1, [ka] is R 2 and the other symbols are as described in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth or fourteenth embodiment.

[0065] In a sixteenth embodiment of the present disclosure, for compounds of formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX) or (X), or a pharma- ceutically acceptable salt thereof, Het is a 5-membered heteroaryl, and the other symbols are as described in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth or sixteenth embodiment.

[0066] In a seventeenth embodiment of the present disclosure, for compounds of formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX) or (X), or a pharma- ceutically acceptable salt thereof, Het is pyrazolyl and the other symbols are as described in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth or fifteenth embodiment.

[0067] In an eighteenth embodiment of the present disclosure, for a compound of formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX) or (X), or a pharma- ceutically acceptable salt thereof, Het is [ka] where: [ka] represents a bond to ring A, and the other symbols are as described in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth or fifteenth embodiment.

[0068] In a nineteenth embodiment of the present disclosure, for a compound of formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX) or (X), or a pharma- ceutically acceptable salt thereof, Het is [ka] where: [ka] represents a bond to ring A, and the other symbols are as described in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth or fifteenth embodiment.

[0069] In a twentieth embodiment of the present disclosure, for a compound of formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX) or (X), or a pharma- ceutically acceptable salt thereof, R 1 is C1-C3 alkyl, C1-C3 haloalkyl, or C3-C6 cycloalkyl, and the other symbols are as described in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, or nineteenth embodiment.

[0070] In a twenty-first embodiment of the present disclosure, for a compound of formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX) or (X), or a pharma- ceutically acceptable salt thereof, R 1 is -CH3, -CF3, cyclopropyl, or cyclobutyl, and other symbols are as described in the twentieth embodiment.

[0071] In a twenty-second embodiment of the present disclosure, the compound is represented by one of the following formulas: [ka] or a pharma- ceutically acceptable salt thereof, wherein R 0 is H, F, or -CH3, and R 1 is -CH3, cyclopropyl, or cyclobutyl, and R 2a is R 5 and further R 10 via a ring carbon atom which may be substituted with one or two groups represented by 3 ("C-linked") 6-9 membered monocyclic or bicyclic nitrogen-containing heterocycle bonded to R 2b is R 5 and further R 10 via a ring carbon atom which may be substituted with one or two groups represented by 3 ("C-linked") 4-6 membered monocyclic nitrogen-containing heterocycle bonded to R 2c is R4 and further substituted with a group represented by R 10 C which may be substituted with one or two groups represented by 3~6 cycloalkyl, R 2d teeth, R5 and further R 10 via a ring carbon atom which may be substituted with one or two groups represented by 3 ("C-linked") 4- to 7-membered monocyclic nitrogen-containing heterocycle, or R4 and further substituted with a group represented by R 10 C which may be substituted with one or two groups represented by 3~6 is cycloalkyl, [ka]

[0072] In a twenty-third embodiment of the present disclosure, for a compound of formula (XI), (XII), (XIII) or (XIV), or a pharma- ceutically acceptable salt thereof, R 2a is 8-azabicyclo[3.2.1]octanyl, octahydrocyclopenta[c]pyrrolyl, or piperidinyl, each of which is R 5 and further R 10 and R 2b is azetidinyl or pyrrolidinyl, each of which is R 5 and further R 10 and R 2c is R 4 and further substituted with a group represented by R 10 and R is a cyclopentyl optionally substituted with one or two groups represented by 2d is R 5 and further R 10 or R 4and further substituted with a group represented by R 10 and the other symbols are as described in the twenty-second embodiment.

[0073] In a twenty-fourth embodiment of the present disclosure, for a compound of formula (XI), (XII), (XIII) or (XIV), or a pharma- ceutically acceptable salt thereof, [ka] m is 0, 1 or 2; [ka] X 3 or a bond to ring A, and the other symbols are as described in the twenty-second embodiment.

[0074] In a twenty-fifth embodiment of the present disclosure, for a compound of formula (XI), (XII), (XIII) or (XIV), or a pharma- ceutically acceptable salt thereof, [ka] R 10 is -CH3 or -CH2CH3, [ka] isX 3 or a bond to ring A, and the other symbols are as described in the twenty-second embodiment.

[0075] Neutral forms and pharma- ceutically acceptable salts of the compounds disclosed in the examples are also included in the present invention.

[0076] III. Pharmaceutical Compositions and Methods of Use Another embodiment is a pharmaceutical composition comprising at least one compound described herein, or a pharma- ceutically acceptable salt thereof, and at least one pharma- ceutically acceptable excipient and / or carrier.

[0077] The compounds described herein, or pharma- ceutically acceptable salts thereof, can be used to decrease the activity of Btk or to affect the properties and / or behavior of Btk (e.g., stability, phosphorylation, kinase activity, interaction with other proteins, etc.).

[0078] In some embodiments, the present invention provides methods of reducing Btk enzymatic activity. In some embodiments, such methods comprise contacting Btk with an effective amount of a Btk inhibitor. Thus, the present invention further provides methods of inhibiting Btk enzymatic activity by contacting Btk with a Btk inhibitor of the present invention.

[0079] One embodiment of the invention includes a method of treating a disease responsive to inhibition of Btk in a subject, the method comprising administering to the subject an effective amount of at least one compound described herein, or a pharma- ceutically acceptable salt thereof.

[0080] The term "diseases responsive to inhibition of Btk" includes, for example, autoimmune diseases, inflammatory diseases, and cancer. In one embodiment, the present invention provides a method of treating autoimmune diseases, inflammatory diseases, and cancer in a subject in need of treatment, comprising administering to the subject an effective amount of at least one compound described herein, or a pharma- ceutically acceptable salt thereof.

[0081] The term "autoimmune disease" includes diseases or disorders involving an inappropriate immune response to natural antigens, such as acute disseminated encephalomyelitis (ADEM), Addison's disease, alopecia areata, antiphospholipid syndrome (APS), autoimmune hemolytic anemia, autoimmune hepatitis, bullous pemphigoid (BP), celiac disease, dermatomyositis, type 1 diabetes, Goodpasture's syndrome, Graves' disease, Guillain-Barre syndrome (GBS), Hashimoto's disease, idiopathic thrombocytopenic purpura, lupus erythematosus, mixed connective tissue disease, multiple sclerosis, myasthenia gravis, pemphigus vulgaris, pernicious anemia, polymyositis, primary biliary cirrhosis, Sjogren's syndrome, temporal arteritis, rheumatoid arthritis, systemic lupus erythematosus, and Wegener's granulomatosis.

[0082] The term "inflammatory disease" includes diseases or disorders involving acute or chronic inflammation, such as allergies, asthma, prostatitis, glomerulonephritis, pelvic inflammatory disease (PID), inflammatory bowel disease (IBD, e.g., Crohn's disease, ulcerative colitis), reperfusion injury, rheumatoid arthritis, atopic dermatitis, transplant rejection, and vasculitis. In some embodiments, the invention provides methods of treating rheumatoid arthritis or lupus. In some embodiments, the invention provides methods of treating multiple sclerosis.

[0083] The term "cancer" includes diseases or disorders involving abnormal growth and / or proliferation of cells, such as glioma, thyroid cancer, breast cancer, lung cancer (e.g., small cell lung cancer, non-small cell lung cancer), gastric cancer, gastrointestinal stromal tumors, pancreatic cancer, bile duct cancer, ovarian cancer, endometrial cancer, prostate cancer, renal cell carcinoma, lymphoma (e.g., anaplastic large cell lymphoma), leukemia (e.g., acute myeloid leukemia, T-cell leukemia, chronic lymphocytic leukemia), multiple myeloma, malignant mesothelioma, malignant melanoma, and colon cancer (e.g., microsatellite instability-high colon carcinoma). In some embodiments, the invention provides methods of treating leukemia or lymphoma.

[0084] As used herein, the terms "subject" and "patient" may be used interchangeably and refer to a mammal in need of treatment, such as companion animals (e.g., dogs, cats, etc.), farm animals (e.g., cows, pigs, horses, sheep, goats, etc.), and laboratory animals (e.g., rats, mice, guinea pigs, etc.). Typically, the subject is a human in need of treatment.

[0085] The term "treating" or "treatment" as used herein refers to obtaining a desired pharmacological and / or physiological effect. The effect may be an effect of restoring health, including partially or substantially achieving one or more of the following results: partially or completely reducing the extent of a disease, disorder or syndrome, alleviating or ameliorating clinical symptoms or indicators associated with a disease, or slowing, inhibiting or reducing the likelihood of progression of a disease, disorder or syndrome.

[0086] An effective dose of a compound provided herein, or a pharma- ceutically acceptable salt thereof, to be administered to a subject can be from 10 μg to 500 mg.

[0087] Administering the compound described herein or its pharmaceutically acceptable salt to a mammal includes any suitable delivery method.Administering the compound described herein or its pharmaceutically acceptable salt to a mammal includes administering the compound described herein or its pharmaceutically acceptable salt to a mammal topically, enterally, parenterally, transdermally, transmucosally, by inhalation, intracisternally, epidurally, intravaginally, intravenously, intramuscularly, subcutaneously, intradermally, or intravitreally.Administering the compound described herein or its pharmaceutically acceptable salt to a mammal also includes administering the compound metabolized to the compound described herein in or on the body of the mammal topically, enterally, parenterally, transdermally, transmucosally, by inhalation, intracisternally, epidurally, intravaginally, intravenously, intramuscularly, subcutaneously, intradermally, or intravitreally to a mammal.

[0088] Thus, the compounds described herein or pharma- ceutically acceptable salts thereof may be administered systemically, e.g., orally, in combination with a pharma- ceutically acceptable vehicle, such as an inert diluent or an assimilable edible carrier. They may be enclosed in hard or soft shell gelatin capsules, compressed into tablets, or directly combined with the food of the patient's diet. For therapeutic oral administration, the compounds described herein or pharma- ceutically acceptable salts thereof may be combined with one or more excipients and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, or wafers, and the like. Such compositions and preparations should contain at least about 0.1% of the active compound. The percentage of the compositions and preparations may, of course, be varied and may conveniently be from about 2 to about 60% of the weight of a given unit dosage form. The amount of active compound in such therapeutically useful compositions may be such that an effective dosage level will be obtained.

[0089] The tablets, troches, pills, capsules, etc. may contain: a binder such as tragacanth, acacia, corn starch or gelatin; an excipient such as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch, alginic acid, and the like; a lubricant such as magnesium stearate; or a sweetening or flavoring agent such as sucrose, fructose, lactose, or aspartame.

[0090] The active compound may be administered intravenously or intraperitoneally by infusion or injection. Solutions of the active compound or its salts can be prepared in water, optionally mixed with a nontoxic surfactant.

[0091] Exemplary pharmaceutical dosage forms for injection or infusion can include sterile aqueous solutions or dispersions or sterile powders containing the active ingredient suitable for the extemporaneous preparation of sterile injectable or infusible solutions or dispersions. In all cases, the ultimate dosage form should be sterile, fluid and stable under the conditions of manufacture and storage.

[0092] Sterile injectable solutions can be prepared by incorporating the active compound in the required amount in a suitable solvent together with various other ingredients mentioned above as required, followed by filtration sterilization. In the case of sterile powders for preparing sterile injectable solutions, the preferred preparation method can be vacuum drying and freeze-drying, which can produce a powder of the active ingredient and any desired additional ingredient from a previously sterile-filtered solution.

[0093] Exemplary solid carriers can include finely divided solids such as talc, clay, microcrystalline cellulose, silica, alumina, etc. Useful liquid carriers include water, alcohols or glycols or mixtures of water and alcohols / glycols, in which the compounds described herein or pharma- ceutically acceptable salts thereof can be dissolved or dispersed at effective concentrations, optionally with the use of nontoxic surfactants.

[0094] Useful dosages of the compounds described herein or their pharma- ceutically acceptable salts can be determined by comparing their in vitro activity and in vivo activity in animal models. Methods for the extrapolation of effective dosages in mice, and other animals, to humans are known in the art; see, for example, U.S. Patent No. 4,938,949, which is incorporated by reference in its entirety.

[0095] The amount of the compound described herein or its pharma- ceutically acceptable salt required for use in therapy may vary not only depending on the particular salt selected, but also on the route of administration, the nature of the disease being treated, and the age and condition of the patient, and may ultimately be left to the discretion of the attending physician or clinician. Generally, however, the dosage may range from about 0.1 to about 10 mg / kg body weight per day.

[0096] The compounds described herein, or pharma- ceutically acceptable salts thereof, can be conveniently administered in unit dosage form, for example, containing 0.01 to 10 mg, or 0.05 to 1 mg, of active ingredient per unit dosage form, in some embodiments, dosages of 5 mg / kg or less may be suitable.

[0097] The desired dose may conveniently be presented in a single dose or as divided doses administered at appropriate intervals.

[0098] The disclosed method may include a kit, which includes a compound described herein or a pharma- ceutically acceptable salt thereof and an instructional material that can explain administering the compound described herein or a pharma- ceutically acceptable salt thereof or a composition comprising the compound described herein or a pharma- ceutically acceptable salt thereof to a cell or a subject. This should be understood to include other embodiments of the kit known to those skilled in the art, such as a kit that includes a solvent (e.g., sterile) for dissolving or suspending the compound described herein or a pharma- ceutically acceptable salt thereof or composition before administering the compound described herein or a pharma- ceutically acceptable salt thereof or composition to a cell or a subject. In some embodiments, the subject may be a human. EXAMPLES

[0099] The invention is illustrated by the following examples, which are not intended to be limiting. IV. Working Examples A. Abbreviations and Acronyms Abbreviations and acronyms used herein include the following: ABPR: Automatic back pressure regulator Ac2O: acetic anhydride ACN: Acetonitrile Aq.: Water-based Ar: Argon Bn: Benzyl Boc: tert-butoxycarbonyl Boc2O: Di-tert-butyl dicarbonate BPin: Pinacolatoboron (BPin)2 or B2pin2: Bis(pinacolato)diboron, i.e., 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi-1,3,2-dioxaborolane br: Broad t-BuOH: tert-butanol n-BuLi: n-butyl lithium ℃: Celsius degree CHCl3: Chloroform CDCl3: Deuterochloroform CDI: 1,1'-carbonyldiimidazole CO2: Carbon dioxide Cs2CO3: Cesium carbonate CsF: Cesium fluoride CuI: Copper iodide δ: chemical shift d: doublet dd: double doublet ddd: Double doublet of doublets DCM: dichloromethane DIEA or DIPEA: N-ethyldiisopropylamine or N,N-diisopropylethylamine DEA: Diethylamine deg: degree Dess-Martin Periodinane or DMP: 1,1,1-tris(acetyloxy)-1,1-dihydro-1,2-benziodoxol-3-(1H)-one DIAD: Diisopropyl azodicarboxylate DABCO: 1,4-diazabicyclo[2.2.2]octane DABAL-Me3: Adduct of trimethylaluminum and DABCO DME: 1,2-dimethoxyethane DMF: N,N-dimethylformamide DMP: DMSO: Dimethyl sulfoxide DMSO-d6: Hexadeuterodimethylsulfoxide DPPA: Diphenylphosphoryl azide Et: Ethyl Et 2O :ether EtOH: Ethanol EA or EtOAc: Ethyl acetate Eq.:Equivalent g: grams h: time HATu: O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate HE: Heptane HBr: Hydrogen bromide HCl: Hydrochloric acid HCO2H:Formic acid Hept: Heptane HFIP: Hexafluoroisopropanol 1 H NMR: Proton nuclear magnetic resonance H2O: Water H2SO4: Sulfuric acid HMPA: hexamethylphosphoramide HPLC: High Pressure Liquid Chromatography Hz: Hertz IPA or iPrOH: Isopropanol J: Coupling constant K2CO3: Potassium carbonate kg: kilogram KHMDS: Potassium hexamethyldisilazide KOAc: Potassium acetate KOH: Potassium hydroxide KOt-Bu: Potassium tert-butoxide K3PO4: Potassium phosphate K4Fe(CN)6·3H2O: Potassium hexacyanoferrate(II) trihydrate L: Liters LCMS: Liquid Chromatography Mass Spectrometry LG: Leaving group m:Multiplet M: mole MBPR: Manual back pressure regulator Me: Methyl MeB(OH)2: Methylboronic acid MeCN: Acetonitrile MeOH: Methanol MeOH-d4: Deuteromethanol mg: milligram MgSO4: Magnesium sulfate MHz: Megahertz mins: minutes mL: milliliter mmol: millimolar MMPNO: Methylmorpholine N-oxide mol: mole MS m / z: mass spectrum peak N2: Nitrogen NaOt-Bu: Sodium tert-butoxide NaH: Sodium hydride NaHCO3: Sodium bicarbonate NaHMDS: Sodium hexamethyldisilylazide NaOH: Sodium hydroxide Na2S2O3: Sodium thiosulfate Na2SO4: Sodium sulfate NEt3: Triethylamine NFSI: N-fluorobenzenesulfonimide NH3: Ammonia NH4Cl: Ammonium chloride NH4OH: Ammonium hydroxide NH4OAc: Ammonium acetate NIS: N-iodosuccinimide OsO4: Osmium tetroxide P(cy)3: Tricyclohexylphosphine Pd2(dba)3: Tris(dibenzylideneacetone)dipalladium(0) Pd(dppf)Cl2: [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) Pd(dppf)Cl2·DCM: [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex Pd(dtbpf)Cl2: [1,1'-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II) Pd(t-Bu3P)2: Bis(tri-tert-butylphosphine)palladium(0) PE: Petroleum ether PEPPSI-IPr or Pd-PEPPSI-IPr: [1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene](3-chloropyridyl)palladium(II) dichloride PG: Protecting group Ph: Phenyl POCl3: Phosphoryl chloride Pyr: Pyridine q:Quartet Rf: Retardation factor Rt: retention time rt or RT: room temperature Rh(OAc)2 dimer: Rhodium(II) acetate dimer RuPhos: 2-dicyclohexylphosphino-2',6'-diisopropoxybiphenyl s: singlet sat.: saturation SCX: Strong cation exchange SFC: Supercritical Fluid Chromatography SiO2: Silicon dioxide Si-SPE: Silica solid phase extraction SPE: solid phase extraction t: triplet td: Triple doublet t-BuONa: Sodium tert-butoxide TEA: Triethylamine TFA: Trifluoroacetic acid TfO: Trifluoromethanesulfonic anhydride THF: tetrahydrofuran TLC: Thin Layer Chromatography TsNHNH2: p-Toluenesulfonylhydrazide T3P: Propane phosphonic anhydride μL: microliter μmol: micromolar μW: Microwave v / v: volume per volume XPhos: 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl Xphos G3: (2-dichlorohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl) [2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate tBuXPhos Pd G3: [(2-di-tert-butylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)-2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate

[0100] B. Experiment Example 1: 1-[(3aS,6aR)-5-[6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrol-2-yl]prop-2-en-1-one [ka] 1. Preparation of tert-butyl 5-(trifluoromethylsulfonyloxy)-3,3a,6,6a-tetrahydro-1H-cyclopenta[c]pyrrole-2-carboxylate [ka] A solution of tert-butyl 5-oxo-1,3,3a,4,6,6a-hexahydrocyclopenta[c]pyrrole-2-carboxylate (1.61 g, 7.15 mmol) in THF (20 mL) was cooled to -78 °C and [bis(trimethylsilyl)amino]potassium (1 M, 7.58 mL) was added dropwise. After stirring at 0 °C for 2 h, 1,1,1-trifluoro-N-phenyl-N-(trifluoromethylsulfonyl)methanesulfonamide (3.83 g, 10.72 mmol) was added in one pot. The mixture was allowed to warm to room temperature overnight. Aqueous NH4Cl (sat) was added and extracted with EA. The organic layer was dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (EA / Hept, 0-100%) to give tert-butyl 5-(trifluoromethylsulfonyloxy)-3,3a,6,6a-tetrahydro-1H-cyclopenta[c]pyrrole-2-carboxylate (2.2 g, 6.16 mmol, 86% yield) as a colorless oil. LCMS (ESI+): m / z C 13 H 19 Calculated for FNOS[M+H]+ 358.1; found 358.1, Rt=0.98 min. 1 H NMR(400 MHz,CDCl3,δ):5.58(d,J=1.5Hz,1H),3.63-3.80(m,1H),3.47-3.59(m,1H),3.40(qd,J=5.2,2.4Hz,2H),3.16(br s,1H),2.85-3.00(m,2H),2.40(br d,J=14.8Hz,1H),1.41-1.48(m,9H)

[0101] 2. Preparation of tert-butyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,3a,6,6a-tetrahydro-1H-cyclopenta[c]pyrrole-2-carboxylate [ka] To a solution of tert-butyl 5-(trifluoromethylsulfonyloxy)-3,3a,6,6a-tetrahydro-1H-cyclopenta[c]pyrrole-2-carboxylate (606 mg, 1.70 mmol) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (861.28 mg, 3.39 mmol) in dioxane was added Pd(dppf)Cl2·DCM (138.49 mg, 169.58 umol) and KOAc (499.29 mg, 5.09 mmol). The mixture was stirred at 90 °C under N2 for 12 h. After filtration through Celite, the reaction mixture was concentrated under vacuum to give the crude product, which was purified by silica gel column chromatography (PE / EA=7 / 3) to give tert-butyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,3a,6,6a-tetrahydro-1H-cyclopenta[c]pyrrole-2-carboxylate (386 mg, 1.15 mmol, 68% yield) as a colorless oil. LCMS (ESI+): m / z C 13 H 23 BNO2[M+H-C5H8O2] + Calculated for 236.2; Found 236.3, Rt=1.02 min. 1 H NMR(400MHz,CDCl3,δ):6.33(s,1H),3.57-3.67(m,1H),3.47-3.54(m,1H),3.41-3.46(m,1H),3.34-3.40(m,1H), 2.93-2.98(m,1H),2.83-2.92(m,1H),2.57-2.70(m,1H),2.28-2.44(m,1H),1.42-1.46(m,9H),1.27-1.28(m,12H)

[0102] 3. Preparation of tert-butyl 5-[6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl]-3,3a,6,6a-tetrahydro-1H-cyclopenta[c]pyrrole-2-carboxylate [ka] 4-Chloro-6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazine (200 mg, 855.96 umol), tert-butyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,3a,6,6a-tetrahydro-1H-cyclopenta[c]pyrrole-2-carboxylate (401.74 mg, 1.20 mmol), K2CO3 (354.91 mg, 2.57 mmol), and tetrakis(triphenylphosphine)palladium(0) (197.82 mg, 171.19 umol) were degassed in water (1 mL) and dioxane (6 mL) and cooled to 95°C. o C for 16 h. After cooling to room temperature, the mixture was diluted with EtOAc and filtered through Celite. The concentrated residue was purified by silica gel column chromatography (DCM / EtOAc 0-100%) to give tert-butyl 5-[6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl]-3,3a,6,6a-tetrahydro-1H-cyclopenta[c]pyrrole-2-carboxylate (309 mg, 760.19 umol, 89% yield) as a white solid. LCMS (ESI+): m / z C 22 H 27 N6O2[M+H] + Calculated for 407.2; Found for 407.3, Rt=0.82 min. 1 H NMR(400MHz,CDCl3,δ):8.42-8.47(m,1H),7.97-8.15(m,1H),7.91(d,J=7.4Hz,2H),6.90(d,J=2.0Hz,1 H),6.67(s,1H),3.99(s,3H),3.53-3.78(m,4H),3.14-3.31(m,2H),3.01-3.14(m,2H),1.42-1.50(m,9H)

[0103] 4. Preparation of 4-(1,2,3,3a,6,6a-hexahydrocyclopenta[c]pyrrol-5-yl)-6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazine [ka] To tert-butyl 5-[6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl]-3,3a,6,6a-tetrahydro-1H-cyclopenta[c]pyrrole-2-carboxylate (309 mg, 760.19 umol) in DCM (4 mL) was added TFA (86.68 mg, 760.19 umol, 58.21 uL) and stirred at room temperature for 1 hour. LCMS (ESI+): m / z C 17 H 19 N6[M+H] + Calculated for 307.2; found 307.1, Rt = 0.44 min. The crude product was concentrated and used directly in the next step.

[0104] 5. Preparation of 4-[(3aS,6aR)-1,2,3,3a,4,5,6,6a-octahydrocyclopenta[c]pyrrol-5-yl)-6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazine [ka] To 4-(1,2,3,3a,6,6a-hexahydrocyclopenta[c]pyrrol-5-yl)-6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazine (0.78 g, 1.71 mmol, trifluoromethanesulfonic acid) in MeOH (10 mL) was added Pd(OH)2 / C (120.00 mg, 170.89 μmol, 20% purity) and stirred at room temperature under H2 at 60 psi for 2 days. After filtration through Celite, the concentrated residue 4-[(3aS,6aR)-1,2,3,3a,4,5,6,6a-octahydrocyclopenta[c]pyrrol-5-yl]-6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazine (392 mg, 928.02 umol, 54% yield, TFA salt) was used directly in the next step. LCMS (ESI+): m / z C 17 H 21 N6[M+H] + Calculated value 309.2; Measured value 309.2, Rt = 0.44 min

[0105] 6. Preparation of 1-[(3aS,6aR)-5-[6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrol-2-yl]prop-2-en-1-one [ka] To 4-[(3aS,6aR)-1,2,3,3a,4,5,6,6a-octahydrocyclopenta[c]pyrrol-5-yl]-6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazine (392 mg, 928.02 umol, TFA) in DCM (5 mL) was added TEA (187.81 mg, 1.86 mmol, 258.70 uL) and stirred for 5 minutes. o After cooling to C, acryloyl chloride (100.79 mg, 1.11 mmol, 90.48 uL) was added and stirred for 3 min. The reaction was quenched with saturated aqueous NHCO3 and extracted with DCM. The organic layer was dried over Na2SO4, and the concentrated residue was purified by silica gel column chromatography (EtOAc. / MeOH 0-15%) to obtain 1-[(3aS,6aR)-5-[6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrol-2-yl]prop-2-en-1-one (62.2 mg, 166.47 μmol, 18% yield, 97% purity) as peak 2. LCMS (ESI+): m / z C20 H 23 NO[M+H] + Calculated for 363.2; Found 363.2, Rt=0.63 min. 1H NMR(400MHz,CDCl3,δ):8.42(s,1H),7.95(d,J=2.51Hz,1H),7.92(s,1H),7.87(s,1H),6.72(dd,J=0.88,2.38Hz,1H), 6.51-6.37(m,2H),5.69(dd,1H,J=2.5,10.0Hz),3.99(s,3H),3.85-3.76(m,4H),3.64(dd,1H,J=4.4,10.7Hz),3.01-2.84(m,2H),2.47(br t,1H,J=7.9Hz),2.43(br t,1H,J=7.8Hz),2.17-2.01(m,2H)

[0106] Example 2: 1-[(3aS,6aR)-5-[6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrol-2-yl]prop-2-en-1-one [ka] 1-[(3aS,6aR)-5-[6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrol-2-yl]prop-2-en-1-one was isolated as a white solid along with Example 1 as peak 1 (20 mg, 52.42 umol, 6% yield, 95% purity). LCMS (ESI+): m / z C 20 H 23 NO[M+H] + Calculated for 363.2; Found 363.2, Rt=0.61 min. 1 H NMR(400MHz,CDCl3,δ):8.41(s,1H),7.94(brs,1H),7.89(s,1H),7.87(s,1H),6.70(brs,1H),6.52-6.37(m,2 H),5.71-5.68(m,1H),3.97(s,3H),3.87-3.48(m,5H),3.07-2.98(m,2H),2.53-2.41(m,2H),2.07-1.99(m,2H)

[0107] Example 3.1-[5-[6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrol-2-yl]prop-2-en-1-one [ka] 1. Preparation of tert-butyl 5-[6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl]-3,3a,6,6a-tetrahydro-1H-cyclopenta[c]pyrrole-2-carboxylate [ka] [6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl]trifluoromethanesulfonate (300 mg, 866.34 umol), tert-butyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,3a,6,6a-tetrahydro-1H-cyclopenta[c]pyrrole-2-carboxylate (435.65 mg, 1.30 mmol), KCO 3( 359.21 mg, 2.60 mmol), tetrakis(triphenylphosphine)palladium(0) (100.11 mg, 86.63 umol) were degassed in water (1 mL) and dioxane (6 mL) and o C for 16 h. After cooling to room temperature, the mixture was diluted with EtOAc and filtered through Celite. The concentrated residue was purified by silica gel column chromatography (DCM / EtOAc 0-100%) to give tert-butyl 5-[6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl]-3,3a,6,6a-tetrahydro-1H-cyclopenta[c]pyrrole-2-carboxylate (290 mg, 715.18 umol, 83% yield) as a white solid. LCMS (ESI+): m / z C 23 H 28 N5O2[M+H] + Calculated value 406.2; Measured value 406.2, Rt = 0.85 min

[0108] 2. Preparation of 4-(1,2,3,3a,6,6a-hexahydrocyclopenta[c]pyrrol-5-yl)-6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyridine [ka] To tert-butyl 5-[6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl]-3,3a,6,6a-tetrahydro-1H-cyclopenta[c]pyrrole-2-carboxylate (290 mg, 715.18 umol) in DCM (4 mL) was added TFA (744.50 mg, 6.53 mmol, 0.5 mL) and stirred at room temperature for 1 h. LCMS (ESI+): m / z C 18 H 20 N5[M+H] + Calculated for 306.2; found 306.2, Rt = 0.52 min. The crude product was concentrated and used directly in the next step.

[0109] 3. Preparation of 4-[(3aS,6aR)-1,2,3,3a,4,5,6,6a-octahydrocyclopenta[c]pyrrol-5-yl)-6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyridine [ka] Pd(OH)2 / C (132.27 mg, 188.36 umol, 20% purity) was added to 4-(1,2,3,3a,6,6a-hexahydrocyclopenta[c]pyrrol-5-yl)-6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyridine (790 mg, 1.88 mmol, TFA) in MeOH (10 mL) and stirred at room temperature under H2 at 60 psi for 2 days. After filtration through Celite, the concentrated residue 4-[(3aS,6aR)-1,2,3,3a,4,5,6,6a-octahydrocyclopenta[c]pyrrol-5-yl]-6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyridine (0.35 g, 765.08 umol, 41% yield, TFA) was used directly in the next step. LCMS(ESI+):m / z C 18H 22 N5[M+H] + Calculated value 308.2; Measured value 308.1, Rt = 0.51 min

[0110] 4. Preparation of 1-[5-[6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrol-2-yl]prop-2-en-1-one [ka] To 4-(1,2,3,3a,4,5,6,6a-octahydrocyclopenta[c]pyrrol-5-yl)-6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyridine (350 mg, 830.54 umol, TFA) in DCM (5 mL) was added TEA (168.08 mg, 1.66 mmol, 231.52 uL) and stirred for 5 minutes. o After cooling to C, acryloyl chloride (90.21 mg, 996.64 umol, 80.97 uL) was added and stirred for 3 minutes. The reaction was quenched with saturated aqueous NaHCO3 and extracted with DCM. The organic layer was dried over Na2SO4, and the concentrated residue was purified by silica gel column chromatography (EtOAc / MeOH 0-50%) to give 1-[5-[6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrol-2-yl]prop-2-en-1-one (89 mg, 233.93 umol, 28% yield, 95% purity). LCMS (ESI+): m / z C 21 H 24 NO[M+H] + Calculated for 362.2; Found 362.2, Rt=0.62 min. 1H NMR(400MHz,CDCl3,δ):8.82(br s,1H),7.99(br s,1H),7.71-7.84(m,2H),7.20-7.25(m,1H),6.60(br s,1H),6.38-6.53(m,2H),5.70-5.74(m,1H),3.96-4.03(m,3H),3.75(br d,J=6.0Hz,3H),3.61(br s,1H),3.39-3.56(m,1H),2.95(br s,2H),2.42-2.63(m,2H),2.34(br s,2H)

[0111] Example 4.1-[4-[6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl]-1-piperidyl]prop-2-en-1-one [ka] 1. Preparation of tert-butyl 4-[6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl]-3,6-dihydro-2H-pyridine-1-carboxylate [ka] 4-Chloro-6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazine (214 mg, 915.87 umol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylate (424.79 mg, 1.37 mmol), K2CO3 (379.75 mg, 2.75 mmol), and tetrakis(triphenylphosphine)palladium(0) (211.67 mg, 183.17 umol) were degassed in 1,2-dimethoxyethane (5 mL) and water (1 mL) and the mixture was cooled to 95°C. oC for 16 h. After cooling to room temperature, the mixture was diluted with EtOAc and filtered through Celite. The concentrated residue was purified by silica gel column chromatography (DCM / EtOAc 0-100%) to give tert-butyl 4-[6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl]-3,6-dihydro-2H-pyridine-1-carboxylate (144 mg, 378.51 μmol, 41% yield) as a white solid. LCMS (ESI+): m / z C 20 H 25 N6O2[M+H] + Calculated value 381.2; Measured value 381.2, Rt = 0.83 min

[0112] 2. Preparation of tert-butyl 4-[6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl]piperidine-1-carboxylate [ka] To a flask of Pd(OH)2 / C (53.16 mg, 75.70 umol, 20% purity) was added a solution of tert-butyl 4-[6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl]-3,6-dihydro-2H-pyridine-1-carboxylate (144 mg, 378.51 umol) in MeOH (5 mL). The mixture was stirred under 50 bar H2 for 16 hours. LCMS: Rt=0.88 min, m / z 384.2. After filtration through Celite, the concentrated residue tert-butyl 4-[6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl]piperidine-1-carboxylate (143 mg, 373.90 umol, 99% yield) was used as is. LCMS (ESI+): m / z C 20 H 27 N6O2[M+H] + Calculated value 383.2; Measured value 383.2, Rt = 0.83 min

[0113] 3. Preparation of 6-(1-methylpyrazol-4-yl)-4-(4-piperidyl)pyrazolo[1,5-a]pyrazine [ka] To tert-butyl 4-[6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl]piperidine-1-carboxylate (143 mg, 373.90 umol) in DCM was added TFA (42.63 mg, 373.90 umol, 28.63 uL) and stirred for 1 h. After concentration, the crude residue was used directly in the next step. LCMS (ESI+): m / z C 15 H 19 N6[M+H] + Calculated value 283.2; Measured value 283.1, Rt = 0.47 min

[0114] 4. Preparation of 1-[4-[6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl]-1-piperidyl]prop-2-en-1-one [ka] To 6-(1-methylpyrazol-4-yl)-4-(4-piperidyl)pyrazolo[1,5-a]pyrazine (269 mg, 678.67 umol, TFA salt) in DCM (4 mL) was added TEA (137.35 mg, 1.36 mmol, 189.19 uL) and stirred for 5 minutes. o After cooling to C, acryloyl chloride (73.71 mg, 814.40 umol, 66.17 uL) was added and stirred for 3 min. The reaction was quenched with saturated aqueous NaHCO3 and extracted with DCM. The organic layer was dried over Na2SO4, and the concentrated residue was purified by silica gel column chromatography (EtOAc / MeOH 0-15%), followed by preparative HPLC to give 1-[4-[6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl]-1-piperidyl]prop-2-en-1-one (38.7 mg, 109.29 umol, 16% yield, 95% purity) as a white solid. LCMS (ESI+): m / z C 18 H 21 NO[M+H] + Calculated for 337.2; Found 337.1, Rt=0.58 min. 1H NMR(400MHz,CDCl3,δ):8.45-8.47(m,1H),7.99-8.01(m,1H),7.96-7.99(m ,1H),7.89-7.91(m,1H),6.78-6.81(m,1H),6.62-6.70(m,1H),6.30-6.38(m ,1H),5.71-5.76(m,1H),4.79-4.92(m,1H),4.17-4.26(m,1H),4.00(s,3H) ,3.42-3.53(m,1H),3.29-3.40(m,1H),2.93-3.02(m,1H),2.06-2.11(m,4H)

[0115] Example 5.1-[3-[6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl]-1-piperidyl]prop-2-en-1-one [ka] 1. Preparation of benzyl 5-[6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl]-3,4-dihydro-2H-pyridine-1-carboxylate [ka] 4-Chloro-6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazine (238 mg, 1.02 mmol), benzyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydro-2H-pyridine-1-carboxylate (524.41 mg, 1.53 mmol), K2CO3 (422.34 mg, 3.06 mmol), and tetrakis(triphenylphosphine)palladium(0) (235.41 mg, 203.72 umol) were degassed in water (1 mL) and dioxane (5 mL) and diluted with 95% water. oC for 16 h. After cooling to room temperature, the mixture was diluted with EtOAc and filtered through Celite. The concentrated residue was purified by silica gel column chromatography (DCM / EtOAc 0-100%) to give benzyl 5-[6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl]-3,4-dihydro-2H-pyridine-1-carboxylate (363 mg, 875.84 umol, 85.99% yield) as a white solid. LCMS (ESI+): m / z C 23 H 23 N6O2[M+H] + Calculated value 415.2; Measured value 415.1, Rt = 0.84 min

[0116] 2. Preparation of 6-(1-methylpyrazol-4-yl)-4-(3-piperidyl)pyrazolo[1,5-a]pyrazine [ka] To benzyl 5-[6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl]-3,4-dihydro-2H-pyridine-1-carboxylate (363 mg, 875.84 umol) in THF (10 mL) was added Pd(OH)2 / C (123.00 mg, 875.84 umol) and stirred under H2 for 2 days. After filtration through Celite, the concentrated residue was used directly in the next step. LCMS (ESI+): m / z C 15 H 19 N6[M+H] + Calculated value 283.2; Measured value 283.0, Rt = 0.49 min

[0117] 3. Preparation of 1-[3-[6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl]-1-piperidyl]prop-2-en-1-one [ka] To 6-(1-methylpyrazol-4-yl)-4-(3-piperidyl)pyrazolo[1,5-a]pyrazine (126 mg, 446.27 umol) in DCM (4 mL) was added TEA (90.32 mg, 892.53 umol, 124.40 uL) and stirred for 5 minutes. o After cooling to C, acryloyl chloride (48.47 mg, 535.52 umol, 43.51 uL) was added and stirred for 3 min. The reaction was quenched with saturated aqueous NaHCO3 and extracted with DCM. The organic layer was dried over Na2SO4, and the concentrated residue was purified by silica gel column chromatography (EtOAc / MeOH 0-15%) to give 1-[3-[6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl]-1-piperidyl]prop-2-en-1-one (18.3 mg, 53.31 umol, 12% yield, 98% purity) as a white solid. LCMS (ESI+): m / z C 18 H 21 N6 O [M+H] + Calculated for 337.2; Found 337.1, Rt=0.58 min. 1 H NMR(400MHz,CDCl3,d):8.49-8.43(m,1H),8.01-7.89(m,3H),6.95-6.79(m,1H),6.72-6.59(m,1H),6.39-6.27(m,1H),5.79-5.66(m,1H),5.0 3-4.83(m,1H),4.74-4.58(m,1H),4.03(s,3H),3.38-3.17(m,2H),2.3 4-2.20(m,2H),2.16-2.06(m,1H),2.00-1.93(m,1H),1.80-1.68(m,1H)

[0118] Example 6. 1-[4-[6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl]azepan-1-yl]prop-2-en-1-one [ka] 1. Preparation of tert-butyl 4-oxoazepane-1-carboxylate [ka] To tert-butyl 4-hydroxyazepane-1-carboxylate (300 mg, 1.39 mmol) in DCM (10 mL) was added Dess-Martin periodinane (886.55 mg, 2.09 mmol) and stirred at room temperature for 16 h. After filtration through Celite, the concentrated residue was purified by silica gel column chromatography (HE / EA 0-100%) to give tert-butyl 4-oxoazepane-1-carboxylate (297 mg, 1.39 mmol, yield 99.94%) as an oil. 1 H NMR(400MHz,CDCl3,d):3.50-3.66(m,4H),2.55-2.73(m,4H),1.73-1.86(m,2H),1.46(s,9H)

[0119] 2. Preparation of tert-butyl 5-(trifluoromethylsulfonyloxy)-2,3,4,7-tetrahydroazepine-1-carboxylate [ka] tert-Butyl 4-oxoazepane-1-carboxylate (297 mg, 1.39 mmol) was cooled to -78 °C and [bis(trimethylsilyl)amino] potassium (1 M, 1.48 mL) was added dropwise to it. After stirring at 0 °C for 2 h, 1,1,1-trifluoro-N-phenyl-N-(trifluoromethylsulfonyl)methanesulfonamide (746.25 mg, 2.09 mmol) was added in one pot. The mixture was allowed to warm to room temperature overnight. NH4Cl (sat) was added and extracted with EA. The organic layer was dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (EA / Hept (0-100%)) to give tert-butyl 5-(trifluoromethylsulfonyloxy)-2,3,4,7-tetrahydroazepine-1-carboxylate (404 mg, 1.17 mmol, 84% yield) as a colorless oil.

[0120] 3. Preparation of tert-butyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3,4,7-tetrahydroazepine-1-carboxylate [ka] To a solution of tert-butyl 5-(trifluoromethylsulfonyloxy)-2,3,4,7-tetrahydroazepine-1-carboxylate (404 mg, 1.17 mmol) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (594.15 mg, 2.34 mmol) in dioxane (5 mL) was added KOAc (344.44 mg, 3.51 mmol) and Pd(dppf)Cl2DCM (95.54 mg, 116.99 umol). The mixture was stirred at 90 °C under N2 for 12 h. After filtration through Celite, the reaction mixture was concentrated in vacuo to give the crude product, which was purified by silica gel column chromatography (PE / EA=7 / 3) to give tert-butyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3,4,7-tetrahydroazepine-1-carboxylate (550 mg) as a white solid.

[0121] 4. Preparation of tert-butyl 5-[6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl]-2,3,4,7-tetrahydroazepine-1-carboxylate [ka] 4-Chloro-6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazine (263.45 mg, 1.13 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohept-3-ene-1-carboxylate (545 mg, 1.69 mmol), K2CO3 (467.50 mg, 3.38 mmol), and tetrakis(triphenylphosphine)palladium(0) (260.58 mg, 225.50 umol) were degassed in water (1 mL) and dioxane (5 mL) and diluted with 95% water. o C for 16 h. After cooling to room temperature, the mixture was diluted with EtOAc and filtered through Celite. The concentrated residue was purified by silica gel column chromatography (DCM / EtOAc 0-100%) to give tert-butyl 5-[6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl]-2,3,4,7-tetrahydroazepine-1-carboxylate (404 mg, 1.02 mmol, 91% yield) as an oil. LCMS (ESI+): m / z C 21 H 27 N6O2[M+H] + Calculated value 395.2; Measured value 395.2, Rt = 0.83 min

[0122] 5. Preparation of tert-butyl 4-[6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl]azepane-1-carboxylate [ka] To a flask of Pd(OH)2 / C (71.92 mg, 102.42 umol, 20% purity) was added a solution of tert-butyl 5-[6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl]-2,3,4,7-tetrahydroazepine-1-carboxylate (404 mg, 1.02 mmol) in THF (5 mL). The mixture was stirred under 50 bar H2 for 16 h. After filtration through Celite, the concentrated residue tert-butyl 4-[6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl]azepane-1-carboxylate (315 mg, 794.48 umol, 78% yield) was used as is. LCMS (ESI+): m / z C 21 H 29 N6O2[M+H] + Calculated value 397.2; Found value 397.3, Rt = 0.86 min

[0123] 6. Preparation of 4-(azepan-4-yl)-6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazine [ka] To tert-butyl 4-[6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl]azepane-1-carboxylate (315 mg, 794.48 umol) in DCM (3 mL) was added TFA (744.50 mg, 6.53 mmol, 0.5 mL) and stirred for 16 h. After concentration, the crude residue 4-(azepan-4-yl)-6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazine (342 mg, TFA salt) was used directly in the next step. LCMS (ESI+): m / z C 16 H 21 N6[M+H] + Calculated value 297.2; Found value 297.1, Rt = 0.48 min

[0124] 7. Preparation of 1-[4-[6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl]azepan-1-yl]prop-2-en-1-one [ka] To a solution of 4-(azepan-4-yl)-6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazine (342 mg, 833.35 umol, TFA salt) in DCM (4 mL) was added TEA (168.65 mg, 1.67 mmol, 232.30 uL) and stirred for 5 minutes. o After cooling to C, acryloyl chloride (90.51 mg, 1.00 mmol, 81.25 uL) was added and stirred for 3 min. The reaction was quenched with saturated aqueous NaHCO3 and extracted with DCM. The organic layer was dried over Na2SO4, and the concentrated residue was purified by silica gel column chromatography (EtOAc / MeOH 0-15%), followed by preparative HPLC to give 1-[4-[6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl]azepan-1-yl]prop-2-en-1-one (17.2 mg, 46.63 umol, 5.6% yield, 95% purity) as a white solid. LCMS (ESI+): m / z C 19 H 23 NO[M+H] + Calculated for 351.1; Found 351.1, Rt=0.58 min. 1 H NMR(400MHz CDCl3,d):8.47-8.54(m,1H),8.26-8.34(m,1H),8.04(s,1H),7.88-7.92(m,1H),6.79-6.92(m,1H),6.62- 6.70(m,1H),6.41-6.47(m,1H),5.72-5.78(m,1H),3.99-4.03(m,3H),3.63-3.86(m,4H),1.82-2.33(m,7H)

[0125] Example 7. 1-[4-[3-Fluoro-6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl]-1-piperidyl]prop-2-en-1-one [ka] 1. Preparation of tert-butyl 4-(6-chloro-3-fluoro-pyrazolo[1,5-a]pyrazin-4-yl)-3,6-dihydro-2H-pyridine-1-carboxylate [ka] 4,6-Dichloro-3-fluoro-pyrazolo[1,5-a]pyrazine (200 mg, 970.85 umol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylate (300.20 mg, 970.85 umol), K2CO3 (402.54 mg, 2.91 mmol), and tetrakis(triphenylphosphine)palladium(0) (112.19 mg, 97.09 umol) were degassed in water (0.3 mL) and dioxane (2 mL) and 95% ethanol was added. o After heating at C for 16 hours and cooling to room temperature, the mixture was diluted with EtOAc and filtered through Celite. The concentrated residue was purified by silica gel column chromatography (DCM / EtOAc 0-100%) to give tert-butyl 4-(6-chloro-3-fluoro-pyrazolo[1,5-a]pyrazin-4-yl)-3,6-dihydro-2H-pyridine-1-carboxylate (246 mg, 697.30 umol, 72% yield) as a white solid. LCMS (ESI+): m / z C 11 H 11 ClFN4[M+H-Boc] + Calculated value 253.1; Measured value 253.0, Rt = 0.96 min

[0126] 2. Preparation of tert-butyl 4-[3-fluoro-6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl]-3,6-dihydro-2H-pyridine-1-carboxylate [ka] tert-Butyl 4-(6-chloro-3-fluoro-pyrazolo[1,5-a]pyrazin-4-yl)-3,6-dihydro-2H-pyridine-1-carboxylate (246 mg, 697.30 umol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (217.62 mg, 1.05 mmol), Pd(dppf)Cl2CH2Cl2 (56.94 mg, 69.73 umol), K2CO3 (289.12 mg, 2.09 mmol) were degassed in dioxane (2 mL) and water (0.3 mL) and cooled to 95 °C. o C for 16 h. After cooling to room temperature, the mixture was filtered through Celite and concentrated. The residue was purified by silica gel column chromatography (HE / EA 0-100%) to give tert-butyl 4-[3-fluoro-6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl]-3,6-dihydro-2H-pyridine-1-carboxylate (236 mg, 592.32 umol, 85% yield) as a pale yellow gel. LCMS (ESI+): m / z C 20 H 24 FN6O2[M+H] + Calculated value 399.2; Found value 399.2, Rt = 0.86 min

[0127] 3. Preparation of 3-fluoro-6-(1-methylpyrazol-4-yl)-4-(1,2,3,6-tetrahydropyridin-4-yl)pyrazolo[1,5-a]pyrazine [ka] To tert-butyl 4-[3-fluoro-6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl]-3,6-dihydro-2H-pyridine-1-carboxylate (236 mg, 592.32 umol) in DCM (3 mL) was added TFA (744.50 mg, 6.53 mmol, 0.5 mL) and stirred for 16 h. After concentration, the crude residue was used directly in the next step. LCMS (ESI+): m / z C 15 H 16 FN6[M+H] +Calculated value 299.2; Measured value 299.0, Rt = 0.53 min

[0128] 4. Preparation of 3-fluoro-6-(1-methylpyrazol-4-yl)-4-(4-piperidyl)pyrazolo[1,5-a]pyrazine [ka] To a flask of Pd(OH)2 / C (187.33 mg, 266.77 umol, 20% purity) was added a solution of 3-fluoro-6-(1-methylpyrazol-4-yl)-4-(1,2,3,6-tetrahydropyridin-4-yl)pyrazolo[1,5-a]pyrazine (550 mg, 1.33 mmol, TFA) in MeOH (5 mL). The mixture was stirred under H2 for 16 h. After filtration and concentration, the crude product was used directly in the next step. LCMS (ESI+): m / z C 15 H 18 FN6[M+H] + Calculated value 301.2; Measured value 301.1, Rt = 0.48 min

[0129] 5. Preparation of 1-[4-[3-fluoro-6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl]-1-piperidyl]prop-2-en-1-one [ka] To 3-fluoro-6-(1-methylpyrazol-4-yl)-4-(4-piperidyl)pyrazolo[1,5-a]pyrazine (233 mg, 775.80 umol, TFA salt) in DCM (5 mL) was added TEA (157.01 mg, 1.55 mmol, 216.26 uL) and stirred for 5 minutes. oAfter cooling to C, acryloyl chloride (84.26 mg, 930.97 umol, 75.64 uL) was added and stirred for 3 min. The reaction was quenched with saturated aqueous NaHCO3 and extracted with DCM. The organic layer was dried over Na2SO4, and the concentrated residue was purified by silica gel column chromatography (EtOAc / MeOH 0-15%), followed by preparative HPLC to give 1-[4-[3-fluoro-6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl]-1-piperidyl]prop-2-en-1-one (36 mg, 96.51 umol, 12% yield, 95% purity) as a white solid. LCMS (ESI+): m / z C 18 FH 20 NO[M+H] + Calculated for 355.2; Found 355.1, Rt=0.63 min. 1 H NMR(400MHz,CDCl3,d):8.09-8.36(m,2H),7.91-8.02(m,1H),7.79-7.88(m,1H),6.60-6.74(m,1H),6.29-6 .41(m,1H),5.69-5.79(m,1H),3.88-4.14(m,3H),3.48-3.62(m,1H),3.02-3.29(m,2H),1.87-2.16(m,6H). 19 F NMR(376MHz,CDCl3,d):-171.56(s,1F)

[0130] Example 8. 1-[4-[6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl]-1-piperidyl]prop-2-en-1-one [ka] 1. Preparation of [6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl]trifluoromethanesulfonate [ka] Pyridine (147.70 mg, 1.87 mmol, 151.02 uL) and trifluoromethanesulfonic anhydride (316.09 mg, 1.12 mmol, 188.48 uL) were added to 6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-ol (200 mg, 933.61 umol) in DCM (4 mL) and stirred at room temperature for 16 hours. After concentration, the residue was purified by silica gel column chromatography (EA / HE 0-100%) to give [6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl]trifluoromethanesulfonate (219 mg, 632.43 umol, 68% yield) as a white solid. LCMS (ESI+): m / z C 12 H 10 F3N4O3S[M+H] + Calculated value 347.0; Measured value 347.0, Rt = 0.79 min

[0131] 2. Preparation of tert-butyl 4-[6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl]-3,6-dihydro-2H-pyridine-1-carboxylate [ka] [6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl]trifluoromethanesulfonate (219 mg, 632.43 umol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylate (195.55 mg, 632.43 umol), K2CO3 (262.22 mg, 1.90 mmol), and tetrakis(triphenylphosphine)palladium(0) (73.08 mg, 63.24 umol) were degassed in water (0.3 mL) and dioxane (2 mL) and diluted with 95% water. oC for 16 h. After cooling to room temperature, the mixture was diluted with EtOAc and filtered through Celite. The concentrated residue was purified by silica gel column chromatography (EtOAc / DCM 0-100%) to give tert-butyl 4-[6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl]-3,6-dihydro-2H-pyridine-1-carboxylate (235 mg, 619.31 umol, 98% yield) as a gel. LCMS (ESI+): m / z C 21 H 26 N5O2[M+H] + Calculated value 380.2; Measured value 380.2, Rt=0.82

[0132] 3. Preparation of 6-(1-methylpyrazol-4-yl)-4-(1,2,3,6-tetrahydropyridin-4-yl)pyrazolo[1,5-a]pyridine [ka] To tert-butyl 4-[6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl]-3,6-dihydro-2H-pyridine-1-carboxylate (235 mg, 619.31 umol) in DCM (3 mL) was added TFA (744.50 mg, 6.53 mmol, 0.5 mL) and stirred at room temperature for 1 h. The crude product was concentrated and used directly in the next step. LCMS (ESI+): m / z C 16 H 18 N5[M+H] + Calculated value 280.2; Measured value 280.0, Rt = 0.50 min

[0133] 4. Preparation of 6-(1-methylpyrazol-4-yl)-4-(4-piperidyl)pyrazolo[1,5-a]pyridine [ka] To 6-(1-methylpyrazol-4-yl)-4-(1,2,3,6-tetrahydropyridin-4-yl)pyrazolo[1,5-a]pyridine (657 mg, 2.35 mmol) in MeOH (6 mL) was added Pd(OH)2 / C (165.16 mg, 235.20 umol, 20% purity) and stirred at room temperature under H2 for 16 hours. After filtration through Celite, the concentrated residue was used directly in the next step. LCMS (ESI+): m / z C 16 H 20 N5[M+H] + Calculated value 282.2; Measured value 282.1, Rt = 0.48 min

[0134] 5. Preparation of 1-[4-[6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl]-1-piperidyl]prop-2-en-1-one [ka] To 6-(1-methylpyrazol-4-yl)-4-(4-piperidyl)pyrazolo[1,5-a]pyridine (249 mg, 629.78 umol, TFA salt) in DCM (5 mL) was added TEA (127.45 mg, 1.26 mmol, 175.56 uL) and stirred for 5 minutes. o After cooling to C, acryloyl chloride (68.40 mg, 755.73 umol, 61.40 uL) was added and stirred for 3 min. The reaction was quenched with saturated aqueous NaHCO3 and extracted with DCM. The organic layer was dried over Na2SO4, and the concentrated residue was purified by silica gel column chromatography (EtOAc / MeOH 0-15%), followed by preparative HPLC to give 1-[4-[6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl]-1-piperidyl]prop-2-en-1-one (82 mg, 244.48 umol, 39% yield) as a white solid. LCMS (ESI+): m / z C 19 H 22 NO[M+H] + Calculated for 336.2; Found 336.1, Rt=0.57 min. 1H NMR(400MHz,CDCl3,d):8.56(s,1H),7.95(d,J=2.3Hz,1H),7.75(d,J=0.8Hz,1H ),7.55-7.69(m,1H),7.05(s,1H),6.59-6.74(m,1H),6.56(dd,J=0.9,2.38Hz,1H ),6.34(dd,J=2.0,16.82Hz,1H),5.74(dd,J=1.8,10.5Hz,1H),4.86-5.03(m,1H ),4.13-4.31(m,1H),3.98(s,3H),3.22-3.37(m,1H),2.97-3.22(m,1H),2.82(br s,1H),2.07-2.16(m,2H),1.80(br s,2H)

[0135] Example 9. 1-[4-[3-Methyl-6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl]-1-piperidyl]prop-2-en-1-one [ka] 1. Preparation of tert-butyl 4-(6-chloro-3-methyl-pyrazolo[1,5-a]pyrazin-4-yl)-3,6-dihydro-2H-pyridine-1-carboxylate [ka] 4,6-Dichloro-3-methyl-pyrazolo[1,5-a]pyrazine (200 mg, 989.90 umol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylate (306.09 mg, 989.90 umol), K2CO3 (410.44 mg, 2.97 mmol), and tetrakis(triphenylphosphine)palladium(0) (114.39 mg, 98.99 umol) were degassed in water (0.3 mL) and dioxane (2 mL) and cooled to 95 °C. oC for 16 h. After cooling to room temperature, the mixture was diluted with EtOAc and filtered through Celite. The concentrated residue was purified by silica gel column chromatography (EtOAc / DCM 0-100%) to give tert-butyl 4-(6-chloro-3-methyl-pyrazolo[1,5-a]pyrazin-4-yl)-3,6-dihydro-2H-pyridine-1-carboxylate (281 mg, 805.56 umol, 82% yield) as a gel. LCMS (ESI+): m / z C 17 H 22 ClN4O2[M+H] + Calculated value 349.1; Measured value 349.0, Rt = 0.94 min

[0136] 2. Preparation of tert-butyl 4-[3-methyl-6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl]-3,6-dihydro-2H-pyridine-1-carboxylate [ka] tert-Butyl 4-(6-chloro-3-methyl-pyrazolo[1,5-a]pyrazin-4-yl)-3,6-dihydro-2H-pyridine-1-carboxylate (281 mg, 805.56 umol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (251.41 mg, 1.21 mmol), Pd(dppf)Cl2CH2Cl2 (65.79 mg, 80.56 umol), K2CO3 (334.01 mg, 2.42 mmol) were degassed in dioxane (2 mL) and water (0.3 mL) and cooled to 95°C. o C for 16 h. After cooling to room temperature, the mixture was filtered through Celite and concentrated. The residue was purified by silica gel column chromatography (HE / EA 0-100%) to give tert-butyl 4-[3-methyl-6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl]-3,6-dihydro-2H-pyridine-1-carboxylate (325 mg, 823.89 umol, 102% yield) as a pale yellow gel. LCMS (ESI+): m / z C 21 H 27 N6O2[M+H]+ Calculated value 395.2; Measured value 395.3, Rt = 0.85 min

[0137] 3. Preparation of 3-methyl-6-(1-methylpyrazol-4-yl)-4-(1,2,3,6-tetrahydropyridin-4-yl)pyrazolo[1,5-a]pyrazine [ka] To tert-butyl 4-[3-methyl-6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl]-3,6-dihydro-2H-pyridine-1-carboxylate (325 mg, 823.89 umol) in DCM (2 mL) was added TFA (744.50 mg, 6.53 mmol, 0.5 mL) and stirred for 16 h. After concentration, the crude residue was used directly in the next step. LCMS (ESI+): m / z C 16 H 19 N6[M+H] + Calculated value 295.2; Found value 295.1, Rt = 0.49 min

[0138] 4. Preparation of 3-methyl-6-(1-methylpyrazol-4-yl)-4-(4-piperidyl)pyrazolo[1,5-a]pyrazine [ka] 3-Methyl-6-(1-methylpyrazol-4-yl)-4-(1,2,3,6-tetrahydropyridin-4-yl)pyrazolo[1,5-a]pyrazine (690 mg, 1.69 mmol, TFA salt) in MeOH (6 mL) was added with Pd(OH)2 / C (118.64 mg, 168.96 umol, 20% purity) and stirred under H2 at 60 psi for 16 h. After filtration through Celite, the concentrated residue was used directly in the next step. LCMS (ESI+): m / z C 16 H 21 N6[M+H] + Calculated value 297.2; Found value 297.2, Rt = 0.41 min

[0139] 5. Preparation of 1-[4-[3-methyl-6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl]-1-piperidyl]prop-2-en-1-one [ka] To 3-methyl-6-(1-methylpyrazol-4-yl)-4-(4-piperidyl)pyrazolo[1,5-a]pyrazine (226 mg, 762.56 umol) in DCM (4 mL) was added TEA (154.33 mg, 1.53 mmol, 212.57 uL) and stirred for 5 minutes. o After cooling to C, acryloyl chloride (82.82 mg, 915.08 umol, 74.35 uL) was added and stirred for 3 min. The reaction was quenched with saturated aqueous NaHCO3 and extracted with DCM. The organic layer was dried over Na2SO4, and the concentrated residue was purified by silica gel column chromatography (EtOAc / MeOH 0-15%), followed by preparative HPLC to give 1-[4-[3-methyl-6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl]-1-piperidyl]prop-2-en-1-one (26.5 mg, 75.62 umol, 9.9% yield) as a white solid. LCMS (ESI+): m / z C 19 H 23 NO[M+H] + Calculated for 351.2; Found for 351.1, Rt=0.61 min. 1 H NMR(400MHz,CDCl3,d):8.34-8.37(m,1H),7.88-7.90(m,1H),7.86-7.88(m, 1H),7.76-7.78(m,1H),6.63-6.71(m,1H),6.31-6.37(m,1H),5.72-5.76(m,1 H),4.79-4.89(m,1H),4.17-4.26(m,1H),3.98-4.00(m,3H),3.50-3.58(m,1H ),3.28-3.37(m,1H),2.90-3.00(m,1H),2.53-2.56(m,3H),2.02-2.12(m,4H)

[0140] Example 10. 1-[4-[3-Methyl-6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl]-3,6-dihydro-2H-pyridin-1-yl]prop-2-en-1-one [ka] 1-[4-[3-methyl-6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl]-3,6-dihydro-2H-pyridin-1-yl]prop-2-en-1-one (20 mg, 54.53 umol, 95% purity) was isolated as a white solid by-product of Example 9. LCMS (ESI+): m / z C 19 H 21 NO[M+H] + Calculated for 349.2; Found 349.2, Rt=0.57 min. 1 H NMR(400MHz,CDCl3,d):8.41-8.47(m,1H),7.97-8.05(m,1H),7.87-7.92(m,1H),7.81-7.84(m,1H),6.62-6.76(m,1H),6.33- 6.43(m,1H),6.01-6.15(m,1H),5.75-5.83(m,1H),4.35-4.50(m,2H),3.88-4.09(m,5H),2.77-2.92(m,2H),2.29-2.37(m,3H)

[0141] Example 11. 1-[3-[6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl]-8-azabicyclo[3.2.1]octan-8-yl]prop-2-en-1-one [ka] 1. Preparation of tert-butyl 3-(trifluoromethylsulfonyloxy)-8-azabicyclo[3.2.1]oct-2-ene-8-carboxylate [ka] tert-Butyl 3-oxo-8-azabicyclo[3.2.1]octane-8-carboxylate (300 mg, 1.33 mmol) was cooled to -78 °C and [bis(trimethylsilyl)amino]potassium (1 M, 1.41 mL) was added dropwise. After stirring at 0 °C for 2 h, 1,1,1-trifluoro-N-phenyl-N-(trifluoromethylsulfonyl)methanesulfonamide (713.60 mg, 2.00 mmol) was added in one pot. The mixture was allowed to warm to room temperature overnight. NH4Cl (sat) was added and extracted with EA. The organic layer was dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (EA / Hept (0-100%)) to obtain tert-butyl 3-(trifluoromethylsulfonyloxy)-8-azabicyclo[3.2.1]oct-2-ene-8-carboxylate (473 mg, 1.32 mmol, yield 99%) as a colorless oil.

[0142] 2. Preparation of tert-butyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-8-azabicyclo[3.2.1]oct-2-ene-8-carboxylate [ka] To a solution of tert-butyl 3-(trifluoromethylsulfonyloxy)-8-azabicyclo[3.2.1]oct-2-ene-8-carboxylate (573 mg, 1.60 mmol) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (814.38 mg, 3.21 mmol) in dioxane (5 mL) was added Pd(dppf)Cl2DCM (130.95 mg, 160.35 μmol) and KOAc (472.10 mg, 4.81 mmol). The mixture was stirred at 90 °C under N2 for 12 h. After filtration through Celite, the reaction mixture was concentrated in vacuo to give the crude product, which was purified by silica gel column chromatography (PE / EA=7 / 3) to give tert-butyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-8-azabicyclo[3.2.1]oct-2-ene-8-carboxylate (372 mg, 1.11 mmol, 69% yield) as a colorless oil.

[0143] 3. Preparation of tert-butyl 3-[6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl]-8-azabicyclo[3.2.1]oct-2-ene-8-carboxylate [ka] 4-Chloro-6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazine (200 mg, 855.96 umol), tert-butyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-8-azabicyclo[3.2.1]oct-2-ene-8-carboxylate (430.43 mg, 1.28 mmol), K2CO3 (354.91 mg, 2.57 mmol), and tetrakis(triphenylphosphine)palladium(0) (197.82 mg, 171.19 umol) were degassed in water (0.5 mL) and dioxane (3 mL) and the mixture was cooled to 95°C. oC for 16 h. After cooling to room temperature, the mixture was diluted with EtOAc and filtered through Celite. The concentrated residue was purified by silica gel column chromatography (EtOAc / DCM 0-100%) to give tert-butyl 3-[6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl]-8-azabicyclo[3.2.1]oct-2-ene-8-carboxylate (372 mg, 915.17 umol, 106% yield) as a white solid. LCMS (ESI+): m / z C 22 H 27 N6O2[M+H] + Calculated value 407.2; Found value 407.3, Rt = 0.99 min

[0144] 4. Preparation of 4-(8-azabicyclo[3.2.1]oct-2-en-3-yl)-6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazine [ka] To tert-butyl 3-[6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl]-8-azabicyclo[3.2.1]oct-2-ene-8-carboxylate (376 mg, 925.01 umol) in DCM was added TFA (105.47 mg, 925.01 umol, 70.83 uL) and stirred at room temperature for 1 hour. The crude product was concentrated and used directly in the next step. LCMS (ESI+): m / z C 17 H 19 N6[M+H] + Calculated value 307.2; Measured value 307.1, Rt = 0.64 min

[0145] 5. Preparation of 4-(8-azabicyclo[3.2.1]octan-3-yl)-6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazine [ka] 4-(8-azabicyclo[3.2.1]oct-2-en-3-yl)-6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazine (481 mg, 1.57 mmol) in MeOH (6 mL) was added with Pd(OH)2 / C (220.49 mg, 314.01 umol, 20% purity) and stirred at room temperature under H2 at 60 psi for 16 hours. After filtration through Celite, the concentrated residue was used directly in the next step. LCMS (ESI+): m / z C 17 H 21 N6[M+H] + Calculated value 309.2; Measured value 309.1, Rt = 0.47 min

[0146] 6. Preparation of 1-[3-[6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl]-8-azabicyclo[3.2.1]octan-8-yl]prop-2-en-1-one [ka] To 4-(8-azabicyclo[3.2.1]octan-3-yl)-6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazine (446 mg, 1.06 mmol, TFA) in DCM (5 mL) was added TEA (214.20 mg, 2.12 mmol, 295.04 uL) and stirred for 5 minutes. o After cooling to C, acryloyl chloride (114.95 mg, 1.27 mmol, 103.19 uL) was added and stirred for 3 min. The reaction was quenched with saturated aqueous NaHCO3 and extracted with DCM. The organic layer was dried over Na2SO4, and the concentrated residue was purified by silica gel column chromatography (EtOAc / MeOH 0-15%), followed by preparative HPLC to give 1-[3-[6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl]-8-azabicyclo[3.2.1]octan-8-yl]prop-2-en-1-one (45.3 mg, 118.74 umol, 11% yield, 95% purity) as a white solid. LCMS (ESI+): m / z C 20 H 23 NO[M+H] +Calculated for 363.2; Found 363.2, Rt=0.60 min. 1 H NMR(400MHz,CDCl3,d):8.44-8.47(m,1H),7.99-8.06(m,1H),7.92-7.98(m,1H),7.86-7.90(m,1H),6.64-6.77(m,1H),6 .55-6.63(m,1H),6.43-6.51(m,1H),5.72-5.80(m,1H),4.82-5.00(m,1H),4.42-4.58(m,1H),3.98-4.04(m,3H),3.92(br s,1H),1.86-3.00(m,8H)

[0147] Example 12. 1-[2-Methyl-4-[6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl]-1-piperidyl]prop-2-en-1-one [ka] 1-[2-Methyl-4-[6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl]-1-piperidyl]prop-2-en-1-one was prepared in a similar manner to Example 1, starting instead with tert-butyl 2-methyl-4-oxo-piperidine-1-carboxylate. Weight: 22.6 mg, 95% pure as a white solid. LCMS (ESI+): m / z C 19 H 23 NO[M+H] + Calculated for 351.2; Found for 351.1, Rt=0.61 min. 1 H NMR(400MHz,CDCl3,d):8.43-8.47(m,1H),7.96-8.01(m,1H),7.87-7.93(m,2H),6.71-6.79(m,1H),6 .60-6.69(m,1H),6.37-6.44(m,1H),5.70-5.77(m,1H),4.20-4.56(m,2H),3.98-4.03(m,3H),3.49(br s,1H),3.33-3.43(m,1H),2.19-2.34(m,2H),2.02-2.14(m,2H),1.16-1.28(m,3H)

[0148] Example 13. 1-[3-[6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl]-9-azabicyclo[3.3.1]nonan-9-yl]prop-2-en-1-one [ka] 1-[3-[6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl]-9-azabicyclo[3.3.1]nonan-9-yl]prop-2-en-1-one was prepared in a similar manner to Example 1, starting instead with tert-butyl 3-oxo-9-azabicyclo[3.3.1]nonane-9-carboxylate. Weight: 96 mg, 95% pure as a white solid. LCMS (ESI+): m / z C 21 H 25 NO[M+H] + Calculated for 377.2; Found for 377.3, Rt=0.66 min. 1 H NMR(400MHz,CDCl3,d):8.43(s,1H),7.84-8.01(m,3H),6.72-6.80(m,1H),6.59-6.72(m,1H),6.30-6.42(m,1H),5.67-5.79(m,1H), 5.04-5.24(m,1H),4.35-4.54(m,1H),3.96-4.02(m,3H),2.98-3.13(m,1H),2.32-2.53(m,2H),1.85-2.21(m,4H),1.55-1.84(m,4H)

[0149] Example 14. 1-[5-[6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl]-2-azabicyclo[2.2.2]octan-2-yl]prop-2-en-1-one [ka] 1-[5-[6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl]-2-azabicyclo[2.2.2]octan-2-yl]prop-2-en-1-one was prepared in a similar manner to Example 1, starting instead from tert-butyl 5-oxo-2-azabicyclo[2.2.2]octane-2-carboxylate. Weight: 4.9 mg, 95% pure as a white solid. LCMS (ESI+): m / z C 20 H 23 NO[M+H] + Calculated for 363.2; Found 363.2, Rt=0.62 min. 1 H NMR(400MHz, CDCl3, δ):8.44-8.51(m,1H),7.85-8.04(m,3H),6.68-6.76(m,1H),6.54-6.67(m,1H),6.34-6.49(m,1H),5.57-5 .75(m,1H),4.17-4.24(m,1H),3.99-4.04(m,3H),3.53-3.85(m,2H),2.14-3.00(m,3H),1.44-1.97(m,5H)

[0150] Example 15. 1-[3-Methyl-4-[6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl]-1-piperidyl]prop-2-en-1-one [ka] 1-[3-Methyl-4-[6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl]-1-piperidyl]prop-2-en-1-one was prepared in a similar manner to Example 1, starting instead with tert-butyl 3-methyl-4-oxo-piperidine-1-carboxylate. Weight: 51 mg, 95% pure as a white solid. LCMS (ESI+): m / z C 19 H 23 NO[M+H] + Calculated for 351.2; Found for 351.1, Rt=0.61 min. 1H NMR(400MHz,CDCl3,δ):8.45-8.48(m,1H),7.97-8.00(m,1H),7.86-7.96(m,2H),6.75-6.79(m,1H),6.58-6.71(m,1H),6.31- 6.39(m,1H),5.69-5.77(m,1H),3.99-4.02(m,3H),3.03-3.71(m,4H),2.25-2.68(m,3H),1.87-1.96(m,1H),0.75-0.85(m,3H)

[0151] Examples 16 to 19 [ka] 1. Preparation of Rac-3-(methylamino)cyclopentan-1-ol [ka] To rac-tert-butyl(3-oxocyclopentyl)carbamate (3 g, 15.06 mmol, 1 equiv.) in THF (100 mL) was added LAH (1.14 g, 30.11 mmol, 2 equiv.) under N2 at 0 °C. The mixture was then heated to 70 °C and stirred at 70 °C for 2.5 h. TLC (PE / EtOAc = 1 / 1) showed complete consumption of starting material and a new more polar spot was detected. Water (5 mL) was added dropwise and Na2SO4 (3 g) was added to the mixture. The mixture was filtered and the filtrate was concentrated to give rac-3-(methylamino)cyclopentan-1-ol (1.7 g, crude) as a colorless oil. 1 H NMR:(400MHz,CDCl3)δ=4.37-4.14(m,1H),3.24-3.08(m,1H),2.32(d,J=5.6Hz, 3H),2.06-1.91(m,1H),1.88-1.72(m,2H),1.65-1.46(m,2H),1.39-1.26(m,1H)

[0152] 2. Preparation of rac-tert-butyl(3-hydroxycyclopentyl)(methyl)carbamate [ka] rac-3-(Methylamino)cyclopentan-1-ol (1.7 g, 14.76 mmol, 1 equiv), DIEA (3.82 g, 29.52 mmol, 5.14 mL, 2 equiv) and Boc2O (6.44 g, 29.52 mmol, 2 equiv) were stirred in DCM (50 mL) at 20° C. for 12 h. TLC (PE / EtOAc=1 / 1) showed complete consumption of starting material and a new, less polar spot was detected. LCMS showed the desired mass was detected. Water (30 mL) was added and the mixture was extracted with DCM (60 mL×3). The organics were dried over Na2SO4, filtered and concentrated to give the crude product, which was purified by silica gel column chromatography eluting with EtOAc in PE (0%-50%-80%) to give rac-tert-butyl(3-hydroxycyclopentyl)(methyl)carbamate (2.8 g, 13.01 mmol, 88.11% yield) as a colorless oil. LCMS: (M+H + -56:160.1), 1 H NMR:(400MHz,CDCl3)δ=4.78-4.31(m,1H),4.26-4.13(m,1H),2.84-2.68(m,3H),1.90-1.73(m,4H),1.64-1.54(m,2H),1.47-1.41(m,9H)

[0153] 3. Preparation of rac-tert-butyl methyl (3-oxocyclopentyl)carbamate [ka] To a mixture of rac-tert-butyl(3-hydroxycyclopentyl)(methyl)carbamate (2.8 g, 13.01 mmol, 1 equiv.) in DCM (10 mL) was added DMP (8.27 g, 19.51 mmol, 1.5 equiv.) under N2 at 20 °C. The mixture was stirred at 20 °C for 16 h. A large amount of white solid separated. TLC (PE / EtOAc = 3 / 1) showed complete consumption of starting material and a new less polar spot was detected. The mixture was filtered and the filtrate was washed with water (30 mL x 2), brine (30 mL), dried over Na2SO4 and filtered. The filtrate was concentrated to give the crude product, which was purified by silica gel column chromatography eluting with EtOAc in PE (0% to 30%) to give rac-tert-butyl methyl(3-oxocyclopentyl)carbamate (2.3 g, 10.78 mmol, 82.92% yield) as a colorless oil. 1 H NMR:(400MHz,CDCl3)δ=4.69(s,1H),2.77(s,3H),2.47-2.33(m,2H),2.28-2.14(m,3H),1.99-1.91(m,1H),1.45(s,9H)

[0154] 4. Preparation of rac-tert-butyl (Z)-methyl(3-(2-tosylhydrazinylidene)cyclopentyl)carbamate [ka] To a solution of rac-tert-butyl methyl(3-oxocyclopentyl)carbamate (1 g, 4.69 mmol, 1 equiv.) in MeOH (10 mL) was added TsNHNH2 (873.21 mg, 4.69 mmol, 1 equiv.) at 20° C. The mixture was stirred at 20° C. for 40 min. LCMS showed complete consumption of starting material with a major peak of desired mass. The solvent was removed below 25° C. to give crude rac-tert-butyl (Z)-methyl(3-(2-tosylhydrazinylidene)cyclopentyl)carbamate (1.7 g, crude product) as a colorless oil. LCMS: (M+H + :326.1)

[0155] 5. Preparation of rac-tert-butyl methyl (3-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine-4-carbonyl)cyclopentyl)carbamate [ka] To a solution of rac-tert-butyl (Z)-methyl(3-(2-tosylhydrazinylidene)cyclopentyl)carbamate (1.7 g, 4.46 mmol, 1 equiv.) in dioxane (30 mL) was added Cs2CO3 (4.36 g, 13.37 mmol, 3 equiv.) at 20 °C. Compound 6 (1.62 g, 7.13 mmol, 1.6 equiv.) was then added slowly to the mixture at 20 °C. The mixture was stirred at 110 °C under N2 for 16 h. LCMS showed several peaks, including the peak of the desired mass. The solvent was removed to give the crude product, which was purified by silica gel column chromatography eluting with EtOAc in PE (0%-50%-100%) to give rac-tert-butyl methyl (3-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine-4-carbonyl)cyclopentyl)carbamate (302 mg, 0.604 mmol, 13.57% yield, 85% purity) as a colorless oil. LCMS: (M+H + :425.2), 1 H NMR:(500MHz,CDCl3)δ=8.73-8.69(m,1H),8.14-8.11(m,1H),8.00-7.92(m,2H),7.46-7.44(m,1H),4.63-4.35(m,2H),4.17- 4.09(m,1H),4.03-4.00(m,3H),3.86-3.73(m,1H),2.86-2.78(m,3H),2.23-2.14(m,1H),1.99-1.84(m,3H),1.49-1.47(m,9H)

[0156] 6. Preparation of rac-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)(3-(methylamino)cyclopentyl)methanone hydrochloride [ka] To a mixture of rac-tert-butyl methyl (3-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine-4-carbonyl)cyclopentyl)carbamate (302 mg, 0.711 mmol, 1 equiv) in DCM (1 mL) was added HCl in EtOAc (4M, 6 mL). The mixture was stirred at 25° C. for 1 h. LCMS showed complete consumption of starting material and a peak of desired mass was detected. The reaction mixture was concentrated to give rac-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)(3-(methylamino)cyclopentyl)methanone hydrochloride (230 mg, 0.709 mmol, 99.66% yield) as a yellow solid which was used directly in the next step. LCMS: (M+H + :325.1)

[0157] 7. Preparation of rac-N-methyl-N-(3-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine-4-carbonyl)cyclopentyl)acrylamide [ka] To a mixture of rac-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)(3-(methylamino)cyclopentyl)methanone hydrochloride (230 mg, 0.709 mmol, 1 equiv.) and DIEA (274.92 mg, 2.13 mmol, 3 equiv.) in DCM (15 mL) was added compound 9 (64.17 mg, 0.709 mmol, 1 equiv.) at 0 °C. The mixture was stirred at 0 °C for 2 min. LCMS showed complete consumption of starting material and a peak of the desired mass was detected. MeOH (1 mL) was added dropwise. The resulting mixture was stirred at 25 °C for 10 min. The solvent was removed to give the crude product, which was purified by preparative HPLC (column: Welch Xtimate C18 150x25mmx5um, conditions: water (NH4HCO3)-ACN, start B35, end B55, gradient time (min) 12, 100% B hold time (min) 2, flow rate (mL / min) 25) to give rac-N-methyl-N-(3-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine-4-carbonyl)cyclopentyl)acrylamide (200mg, 0.528mmol, 74.54% yield) as a white solid. LCMS: (M+H + :379.1)

[0158] 8. General procedure for the isolation of N-methyl-N-(3-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine-4-carbonyl)cyclopentyl)acrylamide [ka] N-methyl-N-(3-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine-4-carbonyl)cyclopentyl)acrylamide (120 mg, 0.305 mmol, 1 equiv.) as a diastereomeric mixture was separated by SFC (column: DAICEL CHIRALPAK IG (250 mm x 30 mm, 10 um), conditions: 0.1% NH3H2O ​​MeOH, start B 55%, end B 55%, gradient time (min), 100% B retention time (min), flow rate (mL / min) 80) to give Example 16 (15.2 mg, Rt = 2.256 min) as a yellow solid, a mixture of Example 17 and Example 18 (40 mg) as a yellow solid, and impure Example 19 (17 mg). The mixture of Example 17 and Example 18 (40 mg) was further separated by SFC (column: DAICEL CHIRALPAK IG (250 mm × 30 mm, 10 μm), conditions: 0.1% NH3H2O ​​EtOH, start B 60%, end B 60%, gradient time (min), 100% B retention time (min), flow rate (mL / min) 80) to obtain Example 17 (11.6 mg, Rt = 2.437 min) as a yellow solid and Example 18 (12.6 mg, Rt = 2.409 min) as a yellow solid. Impure Example 19 (17 mg) was further purified by preparative HPLC (Column: Waters Xbridge BEH C18 100x25mmx5um, Conditions: Water (FA)-ACN, Start B 20, End B 40, Gradient time (min) 12, 100% B hold time (min) 2, Flow rate (mL / min) 25) to give Example 19 (11.6 mg, Rt=2.630 min) as a yellow solid.

[0159] Spectra of Example 16: [ka] LCMS: (M+H + :379.3), HPLC: (purity: 100%), SFC: (ee:96.64%), 1H NMR: (500MHz,メタノール-d4)δ=8.96(s,1H),8.14(s,1H),8.06(s,1H),7.99(s ,1H),7.32(d,J=1.5Hz,1H),6.80-6.59(m,1H),6.09(t,J=17.5Hz,1H ),5.66-5.63(m,1H),4.99-4.88(m,0.5H),4.57-4.46(m,1.5H),3.93 -3.86(m,3H),3.04-2.85(m,3H),2.29-2.09(m,2H),2.06-1.74(m,4H)

[0160] Example 17 of this article:

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[0161] Example 18:

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[0162] Spectra of Example 19: [ka] LCMS: (M+H + :379.3), HPLC: (purity: 100%), SFC: (purity: 97.26%), 1 H NMR: (500MHz, methanol-d4)δ=8.94(s,1H),8.13(s,1H),8.05(d,J=2.0Hz,1H), 7.97(s,1H),7.31(s,1H),6.86-6.59(m,1H),6.11(t,J=18.5Hz,1H),5.66-5 .63(m,1H),5.12-4.99(m,0.5H),4.66-4.54(m,0.5H),4.42(d,J=5.5Hz,1H) ,3.94-3.83(m,3H),3.04-2.82(m,3H),2.18-2.00(m,2H),1.99-1.63(m,4H)

[0163] Examples 20 to 23 [ka] 1. Preparation of rac-methyl 3-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)cyclopent-3-ene-1-carboxylate [ka] A mixture of 4-chloro-6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazine (1 g, 4.28 mmol, 1.00 equiv), methylcyclopent-3-ene-1-carboxylate (971.83 mg, 7.70 mmol, 1.80 equiv), Pd(dba)2 (246.09 mg, 427.98 μmol, 0.10 equiv), XPhos (306.04 mg, 641.97 μmol, 0.15 equiv) and N,N-dicyclohexylmethylamine (1.67 g, 8.56 mmol, 2.00 equiv) in dioxane (24 mL) was bubbled with N2 for 1 min. The mixture was then stirred at 100 °C for 16 h. LCMS showed complete consumption of starting material with a major peak of the desired mass. The mixture was cooled to 15° C., the solvent was removed and the residue was purified by silica gel column chromatography eluting with EtOAc in PE (0% to 50% to 100%) to give rac-methyl 3-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)cyclopent-3-ene-1-carboxylate (1.3 g, 93.94% yield) as an orange oil. LCMS: (M+H + :324.3), 1 H NMR: (400MHz, methanol-d4) δ = 8.61 (s, 1H), 8.07 (s, 1H), 7.98-7.94 (m, 2H), 6.92-6.86 (m, 1H), 6.09-5.94 (m, 1H), 4.10-3.91 (m, 6H), 3.74-3.70 (m, 3H), 3.11-3.06 (m, 1H), 2.68-2.66 (m, 1H)

[0164] 2. Preparation of rac-methyl 3-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)cyclopentane-1-carboxylate [ka] To a solution of rac-methyl 3-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)cyclopent-3-ene-1-carboxylate (700.00 mg, 2.16 mmol, 1.00 equiv) in MeOH (60 mL) was added Pd / C (230.38 mg, 216.48 μmol, 10% purity, 0.10 equiv) at 20° C. The mixture was stirred with H2 at 20° C. and 15 psi for 8 h. LCMS showed complete consumption of starting material with a major peak of the desired mass. The reaction mixture was filtered and concentrated in vacuo to give crude rac-methyl 3-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)cyclopentane-1-carboxylate (540 mg, crude), which was used directly in the next step. LCMS: (M+H + :326.1)

[0165] 3. Preparation of rac-3-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)cyclopentane-1-carboxylic acid [ka] To a solution of rac-methyl 3-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)cyclopentane-1-carboxylate (1.00 g, 3.07 mmol, 1.00 equiv) in MeOH (30 mL) and water (10 mL) was added NaOH (147.52 mg, 3.69 mmol, 1.20 equiv) at 25 °C. The reaction mixture was stirred at 25 °C for 8 h. LCMS showed that the starting material was consumed. The reaction mixture was adjusted to pH = 5-6 by addition of HCl (2 M, 2 mL) at 25 °C. The crude product was concentrated under vacuum to give crude rac-3-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)cyclopentane-1-carboxylic acid (950 mg, crude) as a yellow solid. LCMS: (M+H + :312.1)

[0166] 4. Preparation of rac-N-methyl-3-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)cyclopentane-1-carboxamide [ka] To a solution of rac-3-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)cyclopentane-1-carboxylic acid (950 mg, 3.05 mmol, 1.00 equiv) in DCM (40 mL) was added DIEA (1.18 g, 9.15 mmol, 3.00 equiv) at 25° C. The mixture was stirred at 25° C. for 10 min. Compound 7 (247.22 mg, 3.66 mmol, hydrochloride salt, 1.20 equiv) and HAtu (1.40 g, 3.66 mmol, 1.20 equiv) were then added at 25° C. The reaction mixture was stirred at 25° C. for 1 h. LCMS showed complete consumption of starting material with a major peak of the desired mass. The reaction mixture was concentrated to give the crude product, which was purified by silica gel column chromatography eluting with EtOAc in PE (0% to 100%) to give rac-N-methyl-3-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)cyclopentane-1-carboxamide (900 mg, 90.93% yield) as a yellow oil. LCMS: (M+H + :325.2), 1 H NMR (400MHz, methanol-d4) δ = 8.62 (s, 1H), 8.15-8.12 (m, 1H), 7.99-7.95 (m, 2H), 6.94-6.92 (m, 1H), 3.93 (s, 3H), 3.74-3.69 (m, 1H), 2.95 (s, 1H), 2.74-2.72 (m, 3H), 2.36-2.11 (m, 6H)

[0167] 5. Preparation of rac-N-methyl-1-(3-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)cyclopentyl)methanamine [ka] To a solution of rac-N-methyl-3-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)cyclopentane-1-carboxamide (200 mg, 616.56 μmol, 1.00 equiv) in THF (10 mL) was added BH3·THF (1 M, 3.08 mL, 5.00 equiv) at 0 °C. The ice bath was removed and the reaction mixture was stirred at 35 °C for 2 h. LCMS showed complete consumption of starting material with a major peak of the desired mass. The reaction mixture was quenched by the addition of MeOH (3 mL). The mixture was concentrated to give crude rac-N-methyl-1-(3-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)cyclopentyl)methanamine (130.00 mg, crude product), which was used directly in the next step. LCMS: (M+H + :311.2)

[0168] 6. Preparation of rac-tert-butyl methyl ((3-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)cyclopentyl)methyl)carbamate [ka] To a mixture of rac-N-methyl-1-(3-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)cyclopentyl)methanamine (130 mg, 418.82 μmol, 1.00 equiv) in MeOH (15 mL) was added DIEA (162.38 mg, 1.26 mmol, 3.00 equiv). The reaction mixture was stirred at 25° C. for 10 min. Then Boc2O (137.11 mg, 628.23 μmol, 1.50 equiv) was added at 25° C. The reaction mixture was stirred at 25° C. for 10 min. LCMS showed the starting material was consumed and a peak of the desired mass was detected. The solvent was removed to give the crude product, which was purified by silica gel column chromatography eluting with EtOAc in PE (0% to 100%) to give rac-tert-butyl methyl ((3-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)cyclopentyl)methyl)carbamate (130 mg, 75.61% yield) as a yellow oil. LCMS: (M+H + :411.3), 1 H NMR: (400MHz, methanol-d4)δ=8.62(s,1H),8.11(s,1H),8.00-7.96(m,2H),6.91(s,1H),3.94-3.93(m,3H) ),3.81(s,2H),2.88(s,3H),2.60-2.46(m,1H),2.25-2.16(m,4H),1.91-1.73(m,3H),1.45-1.43(m,9H)

[0169] 7. Preparation of rac-N-methyl-1-(3-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)cyclopentyl)methanamine hydrochloride [ka] To a solution of rac-tert-butyl methyl((3-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)cyclopentyl)methyl)carbamate (280 mg, 682.08 μmol, 1.0 equiv) in DCM (10 mL) was added HCl / EA (4M, 10 mL) at 20° C. and the reaction was stirred at 20° C. for 30 min. LCMS showed complete consumption of starting material and a peak of the desired mass was detected. The mixture was concentrated under vacuum to give rac-N-methyl-1-(3-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)cyclopentyl)methanamine hydrochloride (220 mg, crude) as a yellow oil. LCMS: (M+H + :311.3) [ka]

[0170] 8. Preparation of rac-N-methyl-N-((3-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)cyclopentyl)methyl)acrylamide To a mixture of rac-N-methyl-1-(3-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)cyclopentyl)methanamine hydrochloride (220 mg, 708.77 μmol, 1.0 equiv) and DIPEA (183.20 mg, 1.42 mmol, 2.0 equiv) in DCM (20 mL) was added compound 12 (70.56 mg, 779.65 μmol, 1.1 equiv) at 0 °C. The mixture was stirred at 0 °C for 10 min. LCMS showed that the starting material was completely consumed. MeOH (3 mL) was added dropwise. The reaction mixture was concentrated to give rac-N-methyl-N-((3-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)cyclopentyl)methyl)acrylamide (220 mg, crude) as a yellow oil. LCMS: (M+H + :365.3) [ka]

[0171] 9. General procedure for the isolation of rac-N-methyl-N-((3-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)cyclopentyl)methyl)acrylamide rac-N-methyl-N-((3-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)cyclopentyl)methyl)acrylamide (220.00 mg, 603.66 μmol, 1.0 equiv.) was purified by SFC (column: DAICEL CHIRALPAK AD (250 mm x 30 mm, 10 μm), condition: 0.1% NH3HO) Separation with ETOH, start B 45%, end B 45%, flow rate (mL / min) 70) afforded N-methyl-N-((3-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)cyclopentyl)methyl)acrylamide as a mixture of two isomers (100 mg, 45.45% yield) as a yellow solid, Example 22 (45.8 mg, 19.68% yield) as a yellow solid, and Example 23 (42.7 mg, 18.85% yield) as a yellow solid. [ka]

[0172] 10. General procedure for the isolation of rac-N-methyl-N-((3-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)cyclopentyl)methyl)acrylamide N-methyl-N-((3-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)cyclopentyl)methyl)acrylamide (100.00 mg, 274.39 μmol, 1.0 equivalents) as a mixture of two isomers was separated by SFC (column: Phenomenex-Cellulose-2 (250 mm x 30 mm, 10 μm), conditions: 0.1% NH3H2O ​​ETOH, start B45, end B45, flow rate (mL / min) 80) to obtain Example 20 (33.4 mg, yield 33.40%) as a yellow solid and Example 21 (35.8 mg, yield 35.80%) as a yellow solid.

[0173] Spectra of Example 20: [ka] LCMS: (M+H + :365.2), HPLC:(purity:100.00%), SFC:(ee:100.00%), 1 H NMR: (400MHz, methanol-d4)δ=8.62(d,J=4.4Hz,1H),8.11(d,J=8.4Hz,1H),8.04-7.91(m,2H),6.96-6.72(m,2H),6.31-6.19(m,1H),5.80-5.69(m,1H) ),3.95(s,3H),3.89-3.80(m,1H),3.71-3.39(m,2H),3.18-3.03(m,3H),2 .66-2.51(m,1H),2.38-2.00(m,4H),1.91-1.80(m,1H),1.59-1.43(m,1H)

[0174] Spectra of Example 21: [ka] LCMS: (M+H + :365.2), HPLC:(purity:100.00%), SFC:(ee:100.00%), 1H NMR:(500MHz,メタノール-d4)δ=8.84(d,J=3.5Hz,1H),.42-8.16(m,3H),7.16-6.89(m,2H),6.43-6.31(m,1H),5.96-5.74(m,1H),4.1 7-4.09(m,3H),4.00-3.69(m,3H),3.36-3.17(m,3H),2.77-2.67(m,1H),2.48-2.32(m,3H),2.16-2.04(m,2H),1.88-1.73(m,1H)

[0175] Example 22:

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[0176] Example 23:

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[0177] Examples 24 to 27 [ka] 1. Preparation of rac-tert-butyl (3-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)cyclohex-2-en-1-yl)carbamate [ka] A mixture of 4-chloro-6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazine (300.00 mg, 1.28 mmol, 1.0 equiv), rac-tert-butyl (R)-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-2-en-1-yl)carbamate (700.00 mg, 1.30 mmol, 1.0 equiv), K2CO3 (532.36 mg, 3.85 mmol, 3.0 equiv), Pd(dtbpf)Cl2 (83.68 mg, 128.39 μmol, 0.1 equiv) in dioxane (10 mL) / water (2 mL) was sparged with N2 for 1 min and the reaction was stirred at 90 °C for 2 h. LCMS showed complete consumption of starting material. The reaction mixture was concentrated to give a crude product, which was purified by silica gel column chromatography (PE to PE / EA=1 / 1 to EA) to give rac-tert-butyl (R)-(3-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)cyclohex-2-en-1-yl)carbamate (350.00 mg, 62.19% yield) as a yellow solid. LCMS: (M+H + :395.7)

[0178] 2. Preparation of rac-tert-butyl ((1R,3S)-3-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)cyclohexyl)carbamate [ka] To a mixture of rac-tert-butyl (R)-(3-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)cyclohex-2-en-1-yl)carbamate (610.00 mg, 1.55 mmol, 1.0 equiv) in MeOH (30 mL) was added Pd / C (700.00 mg, 6.58 mmol) at 15 °C. The reaction was stirred at 50 °C under H2 (50 Psi) for 24 h. LCMS showed complete consumption of starting material and a peak of the desired mass was detected. The mixture was filtered to remove Pd / C and concentrated in vacuo to remove MeOH to give rac-tert-butyl ((1R,3S)-3-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)cyclohexyl)carbamate (550.00 mg, crude) as a yellow oil. LCMS: (M+H + :397.2)

[0179] 3. Preparation of rac-tert-butyl methyl (3-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)cyclohexyl)carbamate [ka] To a solution of rac-tert-butyl ((1R,3S)-3-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)cyclohexyl)carbamate (600.00 mg, 1.51 mmol, 1.0 equiv) in DMF (10 mL) was added NaH (181.60 mg, 4.54 mmol, 60% purity, 3.0 equiv) at 0 °C. The reaction mixture was stirred at 0 °C for 30 min. Then, CHI (644.39 mg, 4.54 mmol, 3.0 equiv) was added to the mixture at 0 °C. The mixture was stirred at 20 °C for 6 h. LCMS showed that the desired mass was detected and the starting material was completely consumed. The reaction mixture was quenched by adding MeOH (5 mL). The reaction mixture was removed to give the crude product, which was purified by preparative HPLC (column: Waters Xbridge BEH C18 Purification using a column (100x25mmx5μm, conditions: water (0.225% FA)-ACN, start B38, end B68, gradient time (min) 12, 100% B hold time (min) 2, flow rate (mL / min) 25) gave rac-cis-tert-butyl methyl (3-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)cyclohexyl)carbamate (200mg, 26.40% yield) as a white solid and rac-trans-tert-butyl methyl (3-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)cyclohexyl)carbamate (150mg, 22.94% yield) as a white solid. rac-cis-tert-butyl methyl (3-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)cyclohexyl)carbamate: LCMS: (M+H + :411.8), rac-trans-tert-butyl methyl (3-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)cyclohexyl)carbamate: LCMS: (M+H + :411.8).

[0180] 4. Preparation of rac-trans-N-methyl-3-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)cyclohexan-1-amine hydrochloride [ka] To a solution of rac-trans-tert-butyl methyl((3-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)cyclohexyl)carbamate (150.00 mg, 365.40 μmol, 1.0 equiv) in DCM (2 mL) was added HCl / EA (4M, 15.00 mL) at 20° C. and the reaction was stirred at 20° C. for 30 min. LCMS showed complete consumption of starting material and a peak of the desired mass was detected. The mixture was concentrated under vacuum to give rac-trans-N-methyl-3-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)cyclohexan-1-amine hydrochloride (90.00 mg, crude) as a yellow oil. LCMS: (M+H) + :311.3)

[0181] 5. Preparation of rac-trans-N-methyl-N-(3-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)cyclohexyl)acrylamide [ka] To a mixture of rac-trans-N-methyl-3-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)cyclohexan-1-amine hydrochloride (90.00 mg, 289.95 μmol, 1.0 equiv.) and DIPEA (74.95 mg, 579.90 μmol, 2.0 equiv.) in DCM (6 mL) was added compound 7 (30 mg, 331.46 μmol, 1.14 equiv.) at 0° C. The mixture was stirred at 0° C. for 10 min. LCMS showed that the starting material was completely consumed. MeOH (3 mL) was added dropwise. The reaction mixture was concentrated to give rac-trans-N-methyl-N-(3-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)cyclohexyl)acrylamide (100.00 mg, crude product) as a yellow oil. LCMS: (M+H + :365.2)

[0182] 6. Isolation of rac-trans-N-methyl-N-(3-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)cyclohexyl)acrylamide [ka] rac-trans-N-methyl-N-(3-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)cyclohexyl)acrylamide (100.00 mg, 274.39 μmol, 1.0 equivalent) was separated by SFC (column: Phenomenex-Cellulose-2 (250 mm x 30 mm, 10 μm), conditions: 0.1% NH3H2O ​​ETOH, start B40, end B40, flow rate (mL / min) 80), and Example 24 (41.1 mg, yield 40.15%) was obtained as a yellow solid, and Example 25 (47.1 mg, yield 47.10%) was obtained as a yellow solid.

[0183] Spectra of Example 24: [ka] LCMS: (M+H +:365.2), HPLC: (purity: 97.70%), SFC (purity: 94.99%), 1 H NMR: (400MHz, methanol-d4)δ=8.68-8.62(m,1H),8.13-7.92(m,2H),6.95-6.68(m,2H),6.28-6.12(m, 1H),5.84-5.70(m,1H),5.46-5.05(m,1H),4.17-3.75(m,4H),3.11-2.82(m,3H),2.40-1.41(m,9H)

[0184] Spectra of Example 25: [ka] LCMS: (M+H + :365.3), HPLC: (purity: 100.00%), SFC: (purity: 99.52%), 1 H NMR: (400MHz, methanol-d4)δ=8.71-8.61(m,1H),8.16-7.95(m,2H),6.98-6.70(m,2H),6.28-6.14(m, 1H),5.84-5.70(m,1H),5.46-5.05(m,1H),4.11-3.72(m,4H),3.13-2.86(m,3H),2.33-1.49(m,9H)

[0185] 7. Preparation of rac-cis-N-methyl-3-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)cyclohexan-1-amine hydrochloride [ka] To a mixture of rac-cis-tert-butyl methyl(3-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)cyclohexyl)carbamate (200 mg, 0.487 mmol, 1.0 equiv) in DCM (2 mL) was added HCl in EtOAc (4 M, 8.00 mL). The mixture was stirred at 25° C. for 1 h. LCMS showed complete consumption of starting material and a peak of the desired mass was detected. The reaction mixture was concentrated to give rac-cis-N-methyl-3-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)cyclohexan-1-amine hydrochloride (120 mg, crude) as a yellow solid which was used directly in the next step. LCMS: (M+H + :311.2)

[0186] 8. Preparation of rac-cis-N-methyl-N-(3-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)cyclohexyl)acrylamide [ka] To a mixture of rac-cis-N-methyl-3-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)cyclohexan-1-amine hydrochloride (120 mg, 0.386 mmol, 1.0 equiv.) and DIPEA (149.90 mg, 1.16 mmol, 3.0 equiv.) in DCM (10 mL) was added acryloyl chloride (38.49 mg, 0.425 mmol, 1.0 equiv.) at 0 °C. The mixture was stirred at 0 °C for 2 min. LCMS showed complete consumption of starting material and a peak of the desired mass was detected. MeOH (1 mL) was added dropwise. The resulting mixture was stirred at 25 °C for 10 min. The solvent was removed to give crude rac-cis-N-methyl-N-(3-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)cyclohexyl)acrylamide (102 mg, crude) as a yellow oil. LCMS: (M+H + :365.2)

[0187] 9. Isolation of cis-N-methyl-N-(3-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)cyclohexyl)acrylamide [ka] rac-cis-N-methyl-N-(3-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)cyclohexyl)acrylamide (102 mg, 0.280 mmol, 1.0 equivalent) was separated by SFC (column: DAICEL CHIRALPAK IG (250 mm x 30 mm, 10 μm), conditions: 0.1% NH3H2O ​​EtOH, start B50%, end B50%, gradient time (min), 100% B retention time (min), flow rate (mL / min) 80), and Example 26 (37.2 mg, yield 36.47%) was obtained as a white solid, and Example 27 (33.4 mg, yield 32.75%) was obtained as a pale yellow solid.

[0188] Spectra of Example 26: [ka] LCMS: (M+H + :365.2), SFC: (ee:99.57%), HPLC: (purity: 100%), 1 H NMR: (400MHz, methanol-d4)δ=8.64(d,J=4.0Hz,1H),8.14(s,1H),8.05-7.92(m,2H),6.99(s,1H),6.93-6.66(m,1H),6.23-6.16(m,1H) ,5.74(d,J=10.8Hz,1H),4.41-4.39(m,1H),3.95(s,3H),3.41-3.38(m,1H),3.09-2.91(m,3H),2.32-1.89(m,4H),1.86-1.61(m,4H)

[0189] Spectra of Example 27: [ka] LCMS: (M+H+ :365.3), SFC: (ee:98.44%), HPLC: (purity: 100%), 1 H NMR: (400MHz, methanol-d4)δ=8.65(d,J=4.0Hz,1H),8.15(s,1H),8.05-7.92(m,2H),6.99(s,1H),6.93-6.66(m,1H),6.23-6.16(m,1H) ,5.74(d,J=10.8Hz,1H),4.41-4.39(m,1H),3.95(s,3H),3.41-3.38(m,1H),3.09-2.91(m,3H),2.32-1.89(m,4H),1.86-1.61(m,4H)

[0190] Example 28. N-(3-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)phenyl)acrylamide [ka] 1. Preparation of 6-(1-methyl-1H-pyrazol-4-yl)-4-(3-nitrophenyl)pyrazolo[1,5-a]pyrazine [ka] An 8 mL vial was charged with 4-chloro-6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazine (150 mg, 641.97 umol), (3-nitrophenyl)boronic acid (215 mg, 1.29 mmol), Pd(dppf)Cl2 (15 mg, 20.50 umol), K2CO3 (250 mg, 1.81 mmol), and EtOH (3 mL), sealed and heated at 85° C. for 2 hours. Analysis by LCMS then showed complete consumption of starting material. The reaction was cooled to room temperature.

[0191] The reaction mixture was diluted with 5 mL of EtOH and stirred at 40° C. for 30 minutes, then filtered through a 0.2 um syringe filter. The filtrate was analyzed by LCMS, which showed that it contained only traces of the desired product. The EtOH filtrate was discarded. 10 mL of DCM was added to the remaining solid to completely dissolve all material. The DCM filtrate was concentrated to give the desired product 6-(1-methylpyrazol-4-yl)-4-(3-nitrophenyl)pyrazolo[1,5-a]pyrazine (300 mg, 936.61 umol, 145.90% yield) as a tan solid. LCMS: (M+H + :321.1), 1 H NMR(500MHz,DMSO-d6)δ ppm 8.86(t,J=1.83Hz,1H)8.59(dd,J=7.94,1.22Hz,1H)8.42-8.47(m,1H)8.37(s,1H )8.27(d,J=2.44Hz,1H)8.14(s,1H)7.92(s,1H)7.25(d,J=2.44Hz,1H)3.92(s,3H)

[0192] 2. Preparation of 3-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)aniline [ka] To a 30 mL vial containing 6-(1-methylpyrazol-4-yl)-4-(3-nitrophenyl)pyrazolo[1,5-a]pyrazine (200 mg, 624.40 umol) was added Pd(OH)2 / C (125 mg, 178.02 umol, 20% purity) followed by 3:1 EtOAc:EtOH (8 mL). The mixture was purged with H2 for 15 min and then stirred at 40 °C under a H2 balloon for 1 h. The reaction was analyzed by LCMS, which confirmed complete conversion to the desired product. The H2 balloon was removed.

[0193] The reaction was filtered through Celite and washed with 25 mL of 3:1 EtOAc:EtOH. The filtrate was concentrated to dryness to give a pale yellow solid 3-[6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl]aniline (175 mg, 602.78 umol, 96.54% yield). LCMS: (M+H + :291.1), 1 H NMR(500MHz,DMSO-d6)δ ppm 9.09(d,J=1.22Hz,1H)8.31(s,1H)8.17(d,J=2.44Hz,1H)8.10(s,1H)7.36(t,J=1.83Hz,1H)7 .24(d,J=14.04Hz,2H)7.09(dd,J=2.44,1.22Hz,1H)6.74-6.79(m,1H)5.35(s,2H)3.91(s,3H)

[0194] 3. Preparation of N-(3-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)phenyl)acrylamide [ka] To a 30 mL vial containing 3-[6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl]aniline (175 mg, 602.78 umol) was added DCM (5 mL) and DIPEA (148.40 mg, 1.15 mmol, 200 uL) and stirred at room temperature for 5 minutes. The mixture was cooled in a dry ice / acetone bath for 10 minutes, then acryloyl chloride (54.56 mg, 602.78 umol, 48.97 uL) was added. The reaction was allowed to warm to room temperature and stirred for an additional 15 minutes.

[0195] The reaction was purified by silica gel column chromatography (12 g, heptane to 3:1 EtOAc:EtOH). The desired fractions were collected and concentrated to give N-[3-[6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl]phenyl]prop-2-enamide (180 mg, 512.24 umol, 84.98% yield, 98% purity) as a white solid. LCMS: (M+H + :345.1),1 H NMR(600MHz,DMSO-d6)δ ppm 10.39(s,1H)9.15(s,1H)8.50-8.59(m,1H)8.30-8.37(m,1H)8.19-8.26(m,1H)8.09-8.14(m,1H)7.81-7.93 (m,2H)7.52-7.64(m,1H)7.15-7.24(m,1H)6.44-6.54(m,1H)6.29-6.39(m,1H)5.76-5.87(m,1H)3.93(s,3H)

[0196] Example 29. N-Methyl-N-(3-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)phenyl)acrylamide [ka] To a 30 mL vial containing N-[3-[6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl]phenyl]prop-2-enamide (130 mg, 377.50 umol) was added THF (5 mL) and iodomethane (130 mg, 915.89 umol, 57.02 uL) and stirred at room temperature for 5 minutes, followed by dropwise addition of potassium tert-butoxide (1M, 750 uL). The reaction was stirred for 15 minutes and then analyzed by LCMS, which showed complete conversion to the desired product. The reaction was diluted with 10 mL of water and extracted with 3x10 mL of EtOAc. The combined organic layers were concentrated to dryness and then purified by silica gel column chromatography (12 g, heptane to 3:1 EtOAc:EtOH). The desired fractions were collected and concentrated to give a yellow foamy solid, N-methyl-N-[3-[6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl]phenyl]prop-2-enamide (105 mg, 287.11 umol, 76.06% yield, 98% purity). LCMS: (M+H + :359.1), 1H NMR(500MHz,DMSO-d6)δ ppm 9.19(s,1H)8.35(s,1H)8.22(d,J=2.44Hz,1H)8.13(s,2H)8.00(s,1H)7.7 0(t,J=7.94Hz,1H)7.50-7.56(m,1H)7.17(dd,J=2.44,1.22Hz,1H)6.21(br s,2H)5.59-5.68(m,1H)3.91(s,3H)3.35-3.39(m,3H)

[0197] Examples 30 and 31: (R)-1-(4-((6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)thio)azepan-1-yl)prop-2-en-1-one and (S)-1-(4-((6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)thio)azepan-1-yl)prop-2-en-1-one [ka] 1. Synthesis of tert-butyl 4-((methylsulfonyl)oxy)azepane-1-carboxylate [ka] TEA (201 mg, 1.99 mmol) was added dropwise to tert-butyl 4-hydroxyazepane-1-carboxylate (214 mg, 0.994 mmol) in ice-cold DCM (9.5 mL) under N2. To this was added MsCl (168 mg, 1.47 mmol) at 0 °C and the resulting solution was stirred at 0 °C for 2 h. The mixture was quenched with water (10 mL) and the mixture was extracted with DCM (20 mL x 3). The combined organics were washed with brine (10 mL), dried (MgSO4) and evaporated to dryness under vacuum to give tert-butyl 4-((methylsulfonyl)oxy)azepane-1-carboxylate (0.326 g, yield: 112%) as a colorless oil. ESI-MS (M+Na) + :316.0

[0198] 2. Synthesis of tert-butyl 4-(acetylthio)azepane-1-carboxylate [ka] To a solution of tert-butyl 4-((methylsulfonyl)oxy)azepane-1-carboxylate (0.163 g, 0.52 mmol) in DMF (5.5 mL) at room temperature was added potassium thioacetate (112 mg, 0.980 mmol) and the mixture was stirred at 80 °C under nitrogen overnight. The mixture was quenched with water (10 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine, dried (Na2SO4) and concentrated in vacuo. The residue was purified by silica gel chromatography (0-100% EtOAc in heptane) to give tert-butyl 4-(acetylthio)azepane-1-carboxylate (0.105 g, yield: 74%) as an orange oil. ESI-MS (M+Na) + :296.1

[0199] 3. Synthesis of tert-butyl 4-mercaptoazepane-1-carboxylate [ka] To a solution of tert-butyl 4-(acetylthio)azepane-1-carboxylate (0.104 g, 379 μmol) in MeOH (6 mL) at room temperature was added sodium methoxide (120 uL, 0.52 mmol, 4.37 M) and the mixture was stirred at room temperature under nitrogen for 1 h. The mixture was diluted with water (10 mL) and extracted with EtOAc (20 mL x 3). The combined organics were washed with saturated sodium chloride solution, dried (Na2SO4) and evaporated to dryness in vacuo to give tert-butyl 4-mercaptoazepane-1-carboxylate (83 mg, yield: 95%) as an orange oil. 1 H NMR (400MHz,CDCl3)δ 3.47-3.62(m,1H),3.15-3.47(m,3H),3.00-3.13(m,1H),1.58-2.19(m,7H),1.47(s,9H)

[0200] 4. Synthesis of tert-butyl 4-((6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)thio)azepane-1-carboxylate [ka] To a stirred solution (0 °C) of tert-butyl 4-mercaptoazepane-1-carboxylate (83 mg, 0.360 mmol) in THF (5 mL), sodium hydride (43 mg, 1.1 mmol, 60% purity) was added and the mixture was stirred at 0 °C for 0.5 h, after which 4-chloro-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine (101 mg, 0.433 mmol) was added and the resulting mixture was stirred at room temperature for 2 h. The reaction was quenched by the addition of water (2 mL) and extracted with EtOAc (3 × 5 mL). The combined organics were washed with saturated sodium chloride solution, dried (Na2SO4) and evaporated to dryness under vacuum. The residue was purified twice by silica gel chromatography, first using 0-100% 3:1 EtOAc-EtOH in heptane as eluent and then 0-10% MeOH in methylene chloride as eluent. The material was further purified by reversed-phase HPLC (Waters XSelect CSH C18, 5 μm, 50 mm × 100 mm column, mobile phase HO (A) and MeCN (B), 10-90% B gradient (final 0.1% TFA v / v % modifier), flow rate 30 mL / min) to give tert-butyl 4-((6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)thio)azepane-1-carboxylate (76 mg, yield: 49%) as a colorless oil. ESI-MS (M+H) + :429.2

[0201] 5. Synthesis of 4-(azepan-4-ylthio)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine [ka] TFA (60 mg, 530 μmol, 40 uL) was added to a solution of tert-butyl 4-((6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)thio)azepane-1-carboxylate (76 mg, 0.180 mmol) in HFIPA (1 mL) and the solution was stirred at room temperature for 1 h. The reaction mixture was evaporated to dryness, diluted with DCM and washed with saturated sodium bicarbonate solution. The aqueous solution was re-extracted with a mixture of CHCl3 / IPA (8 / 1 v / v ratio, 3 times). The combined organics were dried (MgSO4) and evaporated to dryness under vacuum to give 4-(azepan-4-ylthio)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine (52 mg, yield: 90%) as a colorless film, which was used without further purification. ESI-MS (M+H) + :329.1

[0202] 6. Synthesis of (R)-1-(4-((6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)thio)azepan-1-yl)prop-2-en-1-one and (S)-1-(4-((6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)thio)azepan-1-yl)prop-2-en-1-one [ka] To a 20 mL vial containing 4-(azepan-4-ylthio)-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine (52 mg, 0.160 mmol) was added DCM (1 mL) followed by triethylamine (80 mg, 0.79 mmol). The mixture was stirred at room temperature for 5 min and then cooled to 0°C. Acryloyl chloride (21 mg, 0.240 mmol) was added dropwise and the reaction was allowed to warm slowly to room temperature. After stirring at room temperature for 1 h, the reaction mixture was diluted with DCM and washed with saturated sodium bicarbonate solution. The organic layer was collected. The aqueous layer was re-extracted 2xDCM. The combined organics were dried (MgSO4) and evaporated to dryness under vacuum to give a pale yellow film. This material was purified by silica gel chromatography (0 to 100% 3:1 EtOAc-EtOH in heptane) to give racemic 1-(4-((6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)thio)azepan-1-yl)prop-2-en-1-one (30 mg, yield: 49%) as a colorless film. 1-(4-((6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)thio)azepan-1-yl)prop-2-en-1-one (25 mg) was separated by chiral SFC (CHIRALPAK AD-H 30x250mm, 5um, 45% MeOH, no modifier in CO2, flow rate: 100mL / min, ABPR 120 bar, MBPR 40 psi, column temperature 40°C) to give the following products: *Peak 1: E1 of Example 30 (8.6 mg, 34%) 1H NMR (400 MHz, methanol-d4) δ 8.55 (s, 1H), 8.08-8.18 (m, 1H), 7.99 (s, 1H), 7.94 (t, J = 2.01 Hz, 1H), 6.82 (ddd, J = 10.54, 15.18, 16.69 Hz, 1H), 6.72-6.75 (m, 1H), 6.30 (ddd, J = 2.01, 11.29, 16.82 Hz, 1H ),5.78(ddd,J=2.01,10.54,16.56Hz,1H),4.25-4.45(m,1H),3.98(d,J=4.27Hz,3H),3.83-3.93 (m,1H),3.57-3.83(m,3H),2.37-2.55(m,1H),2.17-2.28(m,1H),1.88-2.17(m,4H),ESI-MS(M+H) + :383.1 *Peak 2: E2 of Example 31 (9.2 mg, 37%) 1H NMR (400 MHz, methanol-d4) δ 8.55 (s, 1H), 8.09-8.17 (m, 1H), 7.99 (s, 1H), 7.94 (t, J = 2.01 Hz, 1H), 6.82 (ddd, J = 10.54, 15.12, 16.75 Hz, 1H), 6.72-6.76 (m, 1H), 6.31 (ddd, J = 2.01, 11.11, 16.75 Hz, 1H ),5.78(ddd,J=2.13,10.54,16.69Hz,1H),4.26-4.45(m,1H),3.98(d,J=4.27Hz,3H),3.83-3.93 (m,1H),3.56-3.83(m,3H),2.39-2.54(m,1H),2.18-2.28(m,1H),1.87-2.18(m,4H),ESI-MS(M+H) + :383.1

[0203] D. In Vitro Assays In vitro BTK kinase assay: Btk-polyGAT-LS assay The purpose of the BTK in vitro assay is to determine the potency of compounds against BTK by measuring the IC50. Inhibition by compounds is measured by monitoring the amount of phosphorylation of a fluorescein-labeled polyGAT peptide (Invitrogen PV3611) in the presence of active BTK enzyme (Upstate 14-552), ATP, and inhibitors. BTK kinase reactions were performed in black 96-well plates (costar 3694). In a typical assay, a 24 pL aliquot of ATP / peptide master mix (final concentrations; ATP 10 μM, polyGAT 100 nM) in kinase buffer (10 mM Tris-HCl pH 7.5, 10 mM MgCl2, 200 μM Na3PO4, 5 mM DTT, 0.01% Triton X-100, and 0.2 mg / ml casein) is added to each well. Next, 1 pL of 4X, 40X compound titration in 100% DMSO solvent is added, followed by 15 uL of BTK enzyme mix in 1X kinase buffer (final concentration 0.25 nM). The assay is incubated for 30 minutes and then stopped with 28 pL of 50 mM EDTA solution. An aliquot (5 uL) of the kinase reaction is transferred to a low volume white 384-well plate (Coming3674) and 5 pL of 2X detection buffer (Invitrogen PV3574, containing 4 nM Tb-PY20 antibody, Invitrogen PV3552) is added. The plate is covered and incubated for 45 minutes at room temperature. Time resolved fluorescence (TRF) is measured with a Molecular Devices M5 (excitation 332 nm, emission 488 nm, fluorescein emission 518 nm). IC50 values ​​are determined by four parameter fitting using 100% enzyme activity measured from the DMSO control and 0% activity measured from the EDTA control.

[0204] Table 1 shows the activity of selected exemplary compounds of the present invention in the in vitro Btk kinase assay, where each compound number corresponds to an example number in Examples 1 to 31. "†" indicates an IC value of >1 μM and <10 μM. 50 "††" indicates IC greater than 10 nM and less than 1 μM 50 (10nM <MIC 50≤ 1μM). "†††" indicates IC greater than 1nM and less than 10nM. 50 (1nM <IC 50 ≦10 nM). "††††" indicates an IC50 of less than 1 nM. [Table 1]

[0205] In vitro whole blood CD69 assay Human heparinized venous blood from healthy donors was dispensed into 96-well plates and serial dilutions of formula I compound in DMSO or drug-free DMSO were added thereto. The final concentration of DMSO in all wells was 0.1%. The plates were incubated at 37°C for 30 min. Drug-containing samples were stimulated with 0.1 μg / mL mouse anti-human IgD dextran (1A62) or 20 μg / mL polyclonal rabbit F(ab')2 anti-human IgD. Phosphate-buffered saline (PBS) was added to the negative control unstimulated samples and the plates were incubated overnight (18-22 h) at 37°C. Cells were stained with fluorochrome-conjugated anti-CD19 and anti-CD69 antibodies. After removing red blood cells by hypotonic lysis using lysis / fixation solution and fixing the remaining cells, they were analyzed by flow cytometry. CD19+ B cells were gated and analyzed for CD69 expression. The percentage of B cells expressing CD69 was plotted against the log10 of drug concentration and a best-fit curve (variable Hill slope) was generated to obtain IC50 values. Table 2 shows the activity of selected exemplary compounds of the present invention in the in vitro whole blood CD69 assay, with each compound number corresponding to an Example number shown in Examples 1-31 herein. "†" indicates an IC of greater than 10 μM. 50 "††" indicates a value greater than 1 μM and less than 10 μM (1 μM <IC 50 IC ≦10μM 50 "†††" indicates IC less than 1 μM 50 Represents. [Table 2]

Claims

1. Compounds represented by formula (I) 【Chemistry 1】 or a pharmaceutically acceptable salt thereof, wherein: X ０ is N and X １ is C and X ２ is N and X ４ is N or X ０ is CR ０ and X １ is C and X ２ is N and X ４ is N or X ０ is CR ０ and X １ is N and X ２ is C and X ４ is N or X ０ is CR ０ and X １ is N and X ２ is C and X ４ is CH or X ０ is CR ０ and X １ is C and X ２ is N and X ４ is CH, R ０ is H, halo, -CH ３ , halomethyl, cyclopropyl, or CN; Het is phenyl, 5- to 6-membered heteroaryl, or N—(C １ -C4 alkyl)pyridonyl, R １ is H or C １ ~C ３ Alkyl, C １ ~C ３ Alkoxy, C １ ~C ３ Haloalkyl, C ３ ~C ６ cycloalkyl, or a 4- to 7-membered monocyclic oxygen-containing heterocycle; X ３ is not present, -S-, -SO ２ -, CR ３ａ R ３ｂ , —C(═O)—, or —(C═O)—NH—*, where * is R ２ indicates the point of attachment to R ３ａ and R ３ｂ are each independently H or halo, and R ３ａ and R ３ｂ At least one of them is not H, X ３ However, it does not exist, -S-, -SO ２ -, CR ３ａ R ３ｂ or -(C=O)-NH-*, R ２ is connected to X via a ring carbon atom ３ a ("C-linked") 4-12 membered monocyclic or bicyclic nitrogen-containing heterocycle bonded to X through a ring nitrogen atom; ３ ("N-linked") 8-12 membered bicyclic nitrogen-containing heterocycle, 4-7 membered monocyclic oxygen-containing heterocycle, phenyl, or 3-12 membered monocyclic or bicyclic carbocyclyl bonded to R ２ The 4- to 7-membered monocyclic oxygen-containing heterocycle, the phenyl, and the 3- to 12-membered monocyclic or bicyclic carbocyclyl are each represented by R ４ and further substituted with a group represented by R １０ and R ２ The C-linked 4- to 12-membered monocyclic or bicyclic nitrogen-containing heterocycle represented by R ５ and further R １０ and R ２ The N-linked 8- to 12-membered bicyclic nitrogen-containing heterocycle represented by R ５ and further R １０ and optionally substituted with one or two groups represented by X ３ If there is no ２ may be represented by formula (A): 【Chemistry 2】 X ３ is —C(═O)—, R 2 is connected to X via a ring nitrogen atom ３ ("N-linked") 4-12 membered monocyclic or bicyclic nitrogen-containing heterocycle, 4-7 membered monocyclic oxygen-containing heterocycle, phenyl, or 3-12 membered monocyclic or bicyclic carbocyclyl bonded to R ２ The 4- to 7-membered monocyclic oxygen-containing heterocycle, the phenyl, and the 3- to 12-membered monocyclic or bicyclic carbocyclyl are each represented by R ４ and further substituted with a group represented by R １０ and R ２ The N-linked 4- to 12-membered monocyclic or bicyclic nitrogen-containing heterocycle represented by R ４ and further R １０ and optionally substituted with one or two groups represented by 【Transformation 3】 【Chemistry 4】 R ６ is H, C １ ~C ３ Alkyl, C １ ~C ３ Haloalkyl, N(R ａ ) ２ , or C.H. ２ N (R ａ ) ２ and each R ａ are independently H or methyl; R ６’ is H, C １ ~C ３ Alkyl, or C １ ~C ３ is haloalkyl, R ７ is H, C １ ~C ２ Alkyl, or C １ ~ Ｃ２ is a fluoroalkyl; Each R １０ are independently F or C １～３ is alkyl, R １１ is H or N(R １２ ) ２ and Each R １２ are independently H or C １ ~C ３ is alkyl, R １３ is CN or F, n is 0 or 1; p is 1 or 2; The compound or a pharmaceutically acceptable salt thereof, wherein q is 1 or 2.

2. R １１ is H, or a pharmaceutically acceptable salt thereof.

3. The compound has the formula: 【Transformation 5】 wherein R 3a and R 3b are each independently H or halo, and at least one of R 3a and R 3b is not H; or a pharmaceutically acceptable salt thereof.

4. R ０ is H, Cl, F, or -CH ３ and R ３ａ and R ３ｂ and each are F, or a pharmaceutically acceptable salt thereof.

5. (i) R ２ is selected from cyclobutanyl, cyclopentanyl, cyclohexanyl, and phenyl, each of which is R ４ and further substituted with a group represented by R １０ and optionally substituted with one or two groups represented by (ii) R ２ is selected from azepanyl, azetidinyl, 9-azabicyclo[3.3.1]nonanyl, 2-azabicyclo[2.2.2]octanyl, 8-azabicyclo[3.2.1]octanyl, 2,7-diazaspiro[4.4]nonane, octahydrocyclopenta[c]pyrrolyl, octahydro-1H-pyrrolo[3,4-c]pyridine, piperidinyl, tetrahydropyridinyl, and pyrrolidinyl, each of which is selected from R ５ and further R １０ and optionally substituted with one or two groups represented by (iii) R 2 is 【Transformation 6】 is selected from wherein m is 0, 1 or 2; 【Transformation 7】 represents a bond to X 3 or ring A, or (iv) R 2 is 【Transformation 8】 is selected from: 【Chemistry 9】 represents a bond to X 3 or ring A; 2. The compound of claim 1 or a pharmaceutically acceptable salt thereof.

6. The compound has the formula 【Chemistry 10】 2. The compound according to claim 1, wherein:

7. (i) R ２ is connected to X via a ring nitrogen atom ３ and 4-6 membered monocyclic carbocyclyl ("N-linked") bonded to R ２ The 4- to 6-membered monocyclic carbocyclyl represented by ４ and further substituted with a group represented by R １０ and R ２ The N-linked 4- to 7-membered monocyclic nitrogen-containing heterocycle represented by R ４ and further R １０ and optionally substituted with one or two groups represented by (ii) R 2 is 【Chemistry 11】 wherein m is 0, 1 or 2; 【Chemistry 12】 represents the bond to the C(O)-ring A, or (iii) R 2 is 【Chemistry 13】 is selected from: 【Chemistry 14】 represents the bond to the C(O)-ring A, 7. The compound of claim 6 or a pharmaceutically acceptable salt thereof.

8. Each R １０ are independently F, —CH ３ , or -CH ２ CH ３ 8. The compound of claim 7, wherein: 【Request Item 9】 【Chemistry 15】 【Chemistry 16】 R ６ is H or -CF 3 and R ６′ is -CH ３ and R ７ is H, -CH ３ , or -CH ２ CH ３ and n is 0 or 1; 【Chemistry 17】 is R ２ 5. The compound of claim 1, wherein the compound represents a bond to:

10. Het is a 5-membered heteroaryl; Preferably, (i) Het is pyrazolyl; (ii) Het is [Chemistry 18] During the ceremony, 【Chemistry 19】 represents a bond to ring A, or (iii) Het is 【Chemistry 20】 During the ceremony, 【Chemistry 21】 represents a bond to A, The compound according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof.

11. R １ is C １ ~C ３ Alkyl, C １ ~C ３ haloalkyl, or C ３ ~C ６ The compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein R 1 is cycloalkyl, preferably R 1 is -CH 3 , -CF 3 , cyclopropyl, or cyclobutyl.

12. The compound has the formula 【Chemistry 22】 wherein: R ０ is H, F, or -CH ３ and R １ is -CH ３ , cyclopropyl, or cyclobutyl; R ２ａ is R ５ and further R １０ and X via a ring carbon atom which may be substituted with one or two groups represented by ３ ("C-linked") 6-9 membered monocyclic or bicyclic nitrogen-containing heterocycle bonded to R ２ｂ is connected to X via a ring carbon atom ３ ("C-linked") 4-6 membered monocyclic nitrogen-containing heterocycle bonded to The ring carbon atoms are R ５ and N-substituted with a group represented by Furthermore, R １０ and optionally substituted with one or two groups represented by R ２ｃ is R ４ and further substituted with a group represented by R １０ C optionally substituted with one or two groups represented by ３～６ is cycloalkyl, R ２ｄ is R ５ and further R １０ and X via a ring carbon atom which may be substituted with one or two groups represented by ３ a ("C-linked") 4- to 7-membered monocyclic nitrogen-containing heterocycle bonded to R ４ and further substituted with a group represented by R １０ C optionally substituted with one or two groups represented by ３～６ is cycloalkyl, 【Chemistry 23】 R ６ is H or -CF ３ 2. The compound of claim 1, wherein:

13. R ２ａ is 8-azabicyclo[3.2.1]octanyl, octahydrocyclopenta[c]pyrrolyl, or piperidinyl, each of which is R ５ and further R １０ and optionally substituted with one or two groups represented by R ２ｂ is azetidinyl or pyrrolidinyl, each of which is R ５ and further R １０ and optionally substituted with one or two groups represented by R ２ｃ is R ４ and further substituted with a group represented by R １０ and cyclopentyl optionally substituted with one or two groups represented by R ２ｄ is R ５ and further R １０ or R ４ and further substituted with a group represented by R １０ 13. The compound of claim 12, wherein R is 1 or 2; or a pharmaceutically acceptable salt thereof. 【Request Item 14】 【Chemistry 24】 wherein m is 0, 1 or 2; 【Chemistry 25】 is X ３ or a bond to ring A. The compound of claim 12, or a pharmaceutically acceptable salt thereof. 【Request Item 15】 【Chemistry 26】 In the formula, R １０ is -CH ３ or -CH ２ CH ３ and 【Chemistry 27】 is X ３ or a bond to ring A. The compound of claim 12, or a pharmaceutically acceptable salt thereof.

16. A pharmaceutical composition comprising the compound according to any one of claims 1 to 8 and 12 to 15 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

17. 17. The pharmaceutical composition of claim 16, for use in a method for treating a disease in a subject that responds to inhibition of Bruton's tyrosine kinase, said method comprising administering to said subject an effective amount of said pharmaceutical composition.

18. 18. The pharmaceutical composition of claim 17, wherein the disease is an autoimmune disease, atopic dermatitis, leukemia, or lymphoma.

19. 19. The pharmaceutical composition of claim 18, wherein the autoimmune disease is rheumatoid arthritis, systemic lupus erythematosus, or multiple sclerosis.

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