Pyrazolo[1,5-A]pyrazine derivatives as BTK inhibitors

Abstract

Compounds of formula (I'): TIFF2023549360000758.tif5974 or a pharmaceutically acceptable salt thereof, wherein the variables are as defined herein; and methods of using and making same.

Description

Technical Field

[0001] Cross - reference to Related Applications This application claims the benefit of the filing date of U.S. Provisional Application No. 63 / 113,515, filed on November 13, 2020, under 35 U.S.C. § 119(e), the entire content of which is incorporated herein by reference.

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

Background Art

[0003] Protein kinases are a large multigene family consisting of more than 500 proteins that play important roles in the development and treatment of many human diseases in oncology, neurology, and immunology. Tec kinases are non-receptor tyrosine kinases consisting of five members (Tec (tyrosine kinase expressed in hepatocellular carcinoma), Btk (Bruton's tyrosine kinase), Itk (interleukin-2 (IL-2)-induced T cell kinase; also known as Emt or Tsk), Rlk (resting lymphocyte kinase; also known as Txk), and Bmx (bone marrow tyrosine kinase gene on the X chromosome; also known as Etk)), which are mainly expressed in hematopoietic cells, although 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 the regulation of B cell activation, proliferation, and differentiation. More specifically, Btk contains a PH domain that binds to phosphatidylinositol (3,4,5)-trisphosphate (PIP3). Binding of PIP3 induces Btk to phosphorylate phospholipase C (PLCγ), whereby PIP2 is hydrolyzed to generate the two secondary messengers inositol trisphosphate (IP3) and diacylglycerol (DAG), which activate protein kinase PKC, which in turn induces further B cell signaling. Mutations that disrupt Btk enzyme activity result in the primary immunodeficiency disorder XLA syndrome (X-linked agammaglobulinemia). Given the important role of Tec kinases in signaling in both B cells and T cells, Tec kinases are a target of interest in the case of autoimmune disorders.

[0004] Therefore, effective inhibitors of Btk are greatly needed in the art. SUMMARY OF THE INVENTION

[0005] One embodiment of the present invention is a compound represented by formula (I’):

Chemical formula

[0006] Another embodiment of the present invention is a compound of formula (I): [Chemical formula] or a pharmaceutically acceptable salt thereof, wherein

[0007] Het is phenyl, 5- to 6-membered heteroaryl or N-(C1-C3 alkyl)pyridonyl,

[0008] X 0 is N, X 1 is C, X 2 is N, X 4 is N, or X 0 is CR 0 and X 1 is C, X 2 is N, X 4 is N, or X 0 is CR 0 and X 1 is N, X 2 is C, X 4 is N, or X 0 is CR 0 and X 1 is N, X 2 is C, X 4 is CH, or X 0 is CR 0 and X 1 is C, X 2 is N, X 4 is CH,

[0009] R 0 is H, halo, methyl, halomethyl, cyclopropyl or CN,

[0010] R 1 is H or C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl or a 4- to 7-membered monocyclic oxygen-containing heterocycle,

[0011] X 3 is absent, CH2, CH2CH2, O, O-CH2*, NH or NH-CH2*, where "*" indicates the point of attachment to R 2 and

[0012] X 3 is absent, or when it is CH2 or CH2CH2, R 2 is a 4- to 12-member monocyclic or bicyclic nitrogen-containing heterocyclic ring that is bonded to the bicyclic core or X 3 through a ring nitrogen atom ("N-bonded"), and when X 3 is CH2, CH2CH2, O, O-CH2*, or NH-CH2*, R 2 is a 4- to 12-member monocyclic or bicyclic nitrogen-containing heterocyclic ring, a 4- to 7-member monocyclic oxygen-containing heterocyclic ring, or a 3- to 12-member monocyclic or bicyclic carbocyclic ring that is bonded to X 3 through a ring carbon atom ("C-bonded"),

[0013] R 2 The N-bonded 4- to 12-member monocyclic or bicyclic nitrogen-containing heterocyclic ring, 4- to 7-member oxygen-containing heterocyclic ring, and 3- to 12-member monocyclic or bicyclic carbocyclic ring represented by R 4 is substituted with a group represented by R 10 and optionally further substituted with one or two groups represented by R

[0014] The C-bonded 4- to 12-member monocyclic or bicyclic nitrogen-containing heterocyclic ring is N-substituted with a group represented by R 5 and optionally further substituted with one or two groups represented by R 10 R 4 is

Chemical formula

Chemical formula

[0015] Each R 6 is independently H, C1-C3 alkyl, C1-C3 haloalkyl, N(R a )2 or CH2N(R​a )2, where each R a These are independently H or methyl,

[0016] Each R 6’ These are independently H, C1-C3 alkyl or C1-C3 haloalkyl,

[0017] Each R 7 These are independently H, C1-C2 alkyl or C1-C2 fluoroalkyl,

[0018] Each R 10 is F or methyl,

[0019] R 11 is H or N(R 12 )2. Or, R 11 is H or NH2,

[0020] Each R 12 These are independently H or C1-C3 alkyl, or R 12 is H or NH2,

[0021] R 13 is CN or F,

[0022] Each n is independently either 0 or 1.

[0023] Each p is independently either 1 or 2.

[0024] q is either 1 or 2.

[0025] The present invention also provides a pharmaceutical composition comprising at least one compound described herein or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

[0026] Another embodiment of the present invention is a method for treating a Btk inhibition-responsive disorder in a subject, comprising administering an effective amount of at least one compound described herein or a pharmaceutically acceptable salt thereof to the subject.

[0027] The present invention also comprises the use of at least one compound described herein or a pharmaceutically acceptable salt thereof for the manufacture of a pharmaceutical for the treatment of a disorder responsive to Btk inhibition. Furthermore, compounds described herein or pharmaceutically acceptable salts thereof are also provided for use in the treatment of a disorder responsive to Btk inhibition.

[0028] Other features or advantages will become apparent from the detailed description of some embodiments below and from the appended claims. [Modes for carrying out the invention]

[0029] The compounds described herein or their pharmaceutically acceptable salts may have activity as Btk modulators. In particular, the compounds described herein or their pharmaceutically acceptable salts may be Btk inhibitors.

[0030] In the first embodiment, the compound of the present invention is represented by formula (I') or a pharmaceutically acceptable salt thereof, wherein the variable group is as described above.

[0031] In a second embodiment, the compound of the present invention is represented by formula (I) or a pharmaceutically acceptable salt thereof, wherein the variable group is as described above.

[0032] In the third embodiment, for a compound of formula (I') or (I), or a pharmaceutically acceptable salt thereof, R 11 This is H or NH2, and the remaining variable group is as described in the first or second embodiment.

[0033] In the fourth embodiment, the compound of the present invention is of formula (II): [ka] It is represented by or a pharmaceutically acceptable salt thereof. The variable group in formula (II) is as described for formula (I') or (I) as described in the first or second embodiment.

[0034] In the fifth embodiment, the compound of the present invention is represented by formula (I'), (I), or (II), or a pharmaceutically acceptable salt thereof, wherein (R) in formula (I'), (I), and (II) 1 ) q -Het- is, [ka] Selected from the above. The remaining variable groups in formulas (I), (I'), and (II) are as described in any one of the first to fourth embodiments.

[0035] In the sixth embodiment, the compound of the present invention is of formula (III): [ka] It is represented by or a pharmaceutically acceptable salt thereof. The variable group in formula (III) is as described for formula (I') or (I) as described in the first or second embodiment.

[0036] In the seventh embodiment, the compound of the present invention is represented by formula (I'), (I), (II), or (III), or a pharmaceutically acceptable salt thereof, where X 0 is N, and X 1 C is X 2 is N, and X 4 Is it N, or X 0 CH is X 1 C is X 2 is N, and X 4 Is it N, or X 0 CH is X1 is N, and X 2 C is X 4 Is it N, or X 0 CR 0 X 1 is N, and X 2 C is X 4 Is CH or X 0 CH is X 1 C is X 2 is N, and X 4 CH is X 3 is absent, O, O-CH2*, NH or NH-CH2*, where "*" is R 2 It shows the connection point to X 3 If R is absent, 2 This is a bicyclic core or X via a ring nitrogen atom. 3 A 4-12 member monocyclic or bicyclic nitrogen-containing heterocycle that is bonded to ("N-bonded") X 3 If R is O, O-CH2*, or NH-CH2*, 2 X is formed via the ring carbon atoms. 3 A 4-12 member monocyclic or bicyclic nitrogen-containing heterocycle, a 4-7 member monocyclic oxygen-containing heterocycle, or a 3-12 member monocyclic or bicyclic carbocyclyl is bonded to ("C bonded") R 2 The nitrogen-containing 4-12 member monocyclic or bicyclic heterocycles, 4-7 member monocyclic oxygen-containing heterocycles, and 3-12 member monocyclic or bicyclic carbon rings represented by R 4 Substituted with a base represented by, and optionally, R 10 A 4-12 member monocyclic or bicyclic nitrogen-containing heterocycle, further substituted with one or two groups represented by and bonded by C, is R 5 N is substituted with a group represented by, and optionally R 10 It is further substituted with one or two groups represented by , and the remaining variable groups are as described for formulas (I'), (I), (II), and (III) described in any one of the first to sixth embodiments.

[0037] In the eighth embodiment, the compound of the present invention is of formula (IV), (V), (VI), (VII), or (VIII): [ka] The salt is represented by or any of the pharmaceutically acceptable salts described above, where the variable group is as described in any one of the first to seventh embodiments.

[0038] In the ninth embodiment, the compound of the present invention is represented by any one of the formulas (I'), (I), (II), (III), (IV), (V), (VI), (VII), and (VIII), or a pharmaceutically acceptable salt thereof, where X 3 It is a bond, R 2 R is a 4-12 member monocyclic or bicyclic nitrogen-containing heterocycle bonded to a bicyclic core via a ring nitrogen atom, 2 A monocyclic or bicyclic 4-12 member nitrogen-containing heterocycle represented by R 4 Substituted with a base represented by, and optionally, R 10 It is further substituted with a group represented by R. 2 It is a 4-7 member monocyclic nitrogen-containing heterocycle bonded to a bicyclic core via a ring nitrogen atom, and R 2 A 4- to 7-membered monocyclic nitrogen-containing heterocycle represented by R 4 Substituted with a base represented by, and optionally, R 10 The remaining variable groups are as described for any one of the first to eighth embodiments of formula (I'), (I), (II), (III), (IV), (V), (VI), (VII), or (VIII).

[0039] In the tenth embodiment, the compound of the present invention is represented by any one of the formulas (I'), (I), (II), (III), (IV), (V), (VI), (VII), and (VIII), or a pharmaceutically acceptable salt thereof, where X 3 It is a bond, R 2It is a 7-10 member bicyclic nitrogen-containing heterocycle bonded to a bicyclic core via a ring nitrogen atom, and R 2 A 7-10 membered bicyclic nitrogen-containing heterocycle represented by R 4 Substituted with a base represented by, and optionally, R 10 It is further substituted with one or two groups represented by , and the remaining variable groups are as described in any one of the first to ninth embodiments.

[0040] In the eleventh embodiment, the compound of the present invention is represented by any one of the formulas (I'), (I), (II), (III), (IV), (V), (VI), (VII), and (VIII), or a pharmaceutically acceptable salt thereof, where R 2 A 7-10 membered bicyclic nitrogen-containing heterocycle represented by R 4 Substituted with a base represented by, and optionally, R 10 Azaspiro[2.4]heptanylene further substituted with the group represented by , the remaining variable group being as described in any one of the first to tenth embodiments.

[0041] In the twelfth embodiment, the compound of the present invention is represented by any one of (I'), (I), (II), (III), (IV), (V), (VI), (VII), and (VIII), or a pharmaceutically acceptable salt thereof, where X 3 It is a bond, R 2 It is a 4-7 member monocyclic nitrogen-containing heterocycle bonded to a bicyclic core via a ring nitrogen atom, and R 2 A 4- to 7-membered monocyclic nitrogen-containing heterocycle represented by R 4 Substituted with a base represented by, and optionally, R 10 The group is further substituted with the group represented by , and the remaining variable group is as described in any one of the first to ninth embodiments.

[0042] In the 13th embodiment, the compound of the present invention is represented by any one of (I'), (I), (II), (III), (IV), (V), (VI), (VII), and (VIII), or a pharmaceutically acceptable salt thereof, where R 2 The 4- to 7-membered monocyclic or bicyclic nitrogen-containing heterocycles represented by are azetidinylene, pyrrolinedinylene, piperidylene, azapanylene, or oxazapanylene, each of which is R 4 Substituted with a base represented by, and optionally, R 10 The group is further substituted with the group represented by , and the remaining variable group is as described in any one of the first to ninth embodiments.

[0043] In the fourteenth embodiment, the compounds of the present invention are of formula (IX), (X), (XI), (XII), (XIII), or (XIV): [ka] A salt represented by or any of the pharmaceutically acceptable salts described above, where the variable group is as described in the 13th embodiment.

[0044] In the fifteenth embodiment, the compound of the present invention is represented by any one of the formulas (I'), (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), or (XIV), where R 6 and R 6 ' is independently H, CH3 or CH2Cl, p is 2, and the remaining variable groups are as described in any one of the 1st to 14th embodiments.

[0045] In the sixteenth embodiment, the compound of the present invention is represented by any one of the formulas (I'), (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), or (XIV), where R 4These are CH2NHC(O)C≡CH, CH2NHC(O)CH=CH2, N(CH3)C(O)C≡CH, NHC(O)CH=CH2, NHC(O)C≡CH, or NHC(O)CH=CHCH2Cl, and the remaining variable groups are as described in any one of the first to fifteenth embodiments.

[0046] In the 17th embodiment, the compound of the present invention is represented by any one of the formulas (I'), (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), or (XIV), where R 4 These are CH2NHC(O)C≡CH, CH2NHC(O)CH=CH2, N(CH3)C(O)C≡CH, or CH2NR 7 The molecule is C(O)CH=CHCH2Cl, and the remaining variable groups are as described in any one of the first to fifteenth embodiments.

[0047] In the 18th embodiment, the compound of the present invention is represented by any one of the formulas (I'), (I), (II), (III), (IV), (V), (VI), (VII), or (VIII), where X 3 These are O, O-CH2*, O-CH2CH2*, NH, NH-CH2*, N(CH3), or CH2N(CH3)-*, and R 2 X is formed via the ring carbon atoms. 3 A 4- to 12-membered monocyclic or bicyclic nitrogen-containing heterocycle that is bonded to ("carbon-bonded") is R 5 N is substituted with a group represented by, and optionally R 10 It is further substituted with 1 to 3 groups represented by , and the remaining variable groups are as described in any one of the first to eighth embodiments.

[0048] In the 19th embodiment, the compound of the present invention is represented by any one of the formulas (I'), (I), (II), (III), (IV), (V), (VI), (VII), or (VIII), where X 3R is O, O-CH2*, NH or NH-CH2*, 2 X is formed via the ring carbon atoms. 3 A 4-12 member nitrogen-containing heterocycle that is bonded to ("carbon-bonded") is R 5 N is substituted with a group represented by, and optionally R 10 The group is further substituted with the group represented by , and the remaining variable group is as described in any one of the first to eighth embodiments.

[0049] In the 20th embodiment, the compound of the present invention is represented by any one of the formulas (I'), (I), (II), (III), (IV), (V), (VI), (VII), or (VIII), X 3 The group is O or O-CH2*, and the remaining variable groups are as described in any one of the first to eighth, eighteenth, and nineteenth embodiments.

[0050] In the 21st embodiment, the compound of the present invention is represented by one of the formulas (I'), (I), (II), (III), (IV), (V), (VI), (VII), or (VIII), where R 2 The 4-12 member nitrogen-containing heterocycles with carbon bonds represented by are 4-7 member monocyclic heterocycles containing one ring oxygen or one ring sulfur atom of any choice, 6-10 member fused bicycles, 8-12 member spirocycles, or 7-10 member bridging bicycles, and R 2 A 4-12 member nitrogen-containing heterocycle with carbon bonds, represented by R 5 N is substituted with a group represented by, and optionally R 10 The group is further substituted with the group represented by , and the remaining variable group is as described in the first to eighth and eighteenth to twentieth embodiments.

[0051] In the 22nd embodiment, the compound of the present invention is represented by one of the formulas (I'), (I), (II), (III), (IV), (V), (VI), (VII), or (VIII), where R 2The 4-12 member nitrogen-containing heterocycles with carbon bonds represented by are azaspiro[3.3]heptanylene, azaspiro[3.5]nonanylene, azaspiro[4.4]nonanylene, azaspiro[3.4]octanylene, azetidinylene, pyrrolinedinylene, piperidinylene, azapanylene, diazepanylene, morpholinylene, octahydrocyclopenta[c]pyrrolylene, oxazapanylene, azabicyclo[3.2.0]hepta Nylene, azabicyclo[2.2.1]heptanylene, azabicyclo[3.1.1]heptanylene, azabicyclo[3.2.1]octanylene, azabicyclo[4.2.0]octanylene, azatricyclo[4.1.1.03,7]octylene, azabicyclo[3.2.0]heptanylene, azabicyclo[2.1.1]heptanylene, azabicyclo[2.1.1]hexanylene, azabicyclo[3.1.0]hexanylene, 2λ 2 - azaspiro[3.4]octylene or octahydrocyclopenta[c]pyrolene, R 2 A 4-12 member nitrogen-containing heterocycle with carbon bonds, represented by R 5 N is substituted with a group represented by, and optionally R 10 It is further substituted with one or two groups represented by , and the remaining variable groups are as described in any one of the first to eighth and eighteenth to twenty-first embodiments. 2 Examples of 4- to 12-membered nitrogen-containing heterocycles represented by the following are: [ka] [ka] The following are listed, and in the formula, "**" represents X 3 The connection point to is indicated by "***", and R 5 The connection point to R is shown, where R 2 Each group represented by can be optionally selected as R 10 It is further substituted by 1 to 3 groups represented by .

[0052] In the 23rd embodiment, the compound of the present invention is represented by one of the formulas (I'), (I), (II), (III), (IV), (V), (VI), (VII), or (VIII), and R 2 The 4-12 member nitrogen-containing heterocycles with carbon bonds represented by are azetidinylene, pyrrolinedinylene, piperidylene, azapanylene, oxazapanylene, azabicyclo[3.2.1]octanylene, and azatricyclo[4.1.1.0 3,7 Octylene, azabicyclo[3.2.0]heptanylene, azabicyclo[3.1.0]hexanylene, 2λ 2 -Azaspiro[3.4]octylene or octahydrocyclopenta[c]pyrolene, R 2 A 4-12 member nitrogen-containing heterocycle with carbon bonds, represented by R 5 N is substituted with a group represented by, and optionally R 10 It is further substituted with one or two groups represented by , and the remaining variable groups are as described in any one of the first to eighth and eighteenth to twenty-first embodiments. 2 Examples of 4- to 12-membered nitrogen-containing heterocycles represented by the following are: [ka] R is one example. 2 A nitrogen-containing heterocycle represented by R can be optionally selected. 10 Further replaced by, "**" becomes X 3 The connection point to is indicated by "***", and R 5 The connection point to R is shown, where R 2 Each group represented by can be optionally selected as R 10 It is further substituted with one or two bases represented by .

[0053] In the 24th embodiment, the compound of the present invention is represented by one of the formulas (I'), (I), (II), (III), (IV), (V), (VI), (VII), or (VIII), where X 3 R is connected to 2The stereochemical configuration of the ring carbon atoms in a 4-12 member nitrogen-containing heterocycle bonded by C is R. Alternatively, X 3 R is connected to 2 The stereochemical configuration of the ring carbon atoms in the 4- to 12-membered nitrogen-containing heterocycles bonded by the formula is S. The remaining variable groups in formula (I'), (I), (II), (III), (IV), (V), (VI), (VII), or (VIII) are as described in any one of the first to eighth and eighteenth to twenty-third embodiments.

[0054] In the 25th embodiment, the compound of the present invention is represented by any one of the formulas (I'), (I), (II), (III), (IV), (V), (VI), (VII), or (VIII), where R 6 and R 6’ The group is independently H, CH3, or CH2Cl, p is 2, and the remaining variable group is as described in any one of the first to eighth and eighteenth to twenty-fourth embodiments.

[0055] In the 26th embodiment, the compound of the present invention is represented by any one of the formulas (I'), (I), (II), (III), (IV), (V), (VI), (VII), or (VIII), where R 5 are SO2CH=CH2, SO2CH=CHCH3, SO2CH=CHCH2Cl, SO2C≡CH, SO2C≡CCH3, SO2C≡CCH2Cl, COCH=CH2, COCH= CHCH3, COCH=CHCH2Cl, CO-C≡CH, CO-C≡CCH3, CO-C≡CCH2Cl, COCF=CH2, COCF=CHCH3, COCF=CHCH2Cl, [ka] The remaining variable groups are as described in the first to eighth and eighteenth to twenty-fifth embodiments.

[0056] In the 27th embodiment, the compound of the present invention is represented by any one of the formulas (I'), (I), (II), (III), (IV), (V), (VI), (VII), or (VIII), where R 5 These are SO2CH=CH2, SO2CH=CHCH3, SO2CH=CHCH2Cl, SO2C≡CH, SO2C≡CCH3, SO2C≡CCH2Cl, COCH=CH2, COCH=CHCH3, COCH=CHCH2Cl, CO-C≡CH, CO-C≡CCH3, or CO-C≡CCH2Cl. Alternatively, R 5 These are SO2CH=CH2, SO2CH=CHCH3, COCH=CH2, COCH=CHCH2Cl, CO-C≡CH, or CO-C≡CCH3. The remaining variable groups in formulas (I'), (I), (II), (III), (IV), (V), (VI), (VII), or (VIII) are as described in any one of the first to eighth and eighteenth to twenty-fifth embodiments.

[0057] In the 28th embodiment, the compound of the present invention is represented by one of the formulas (I'), (I), (II), (III), (IV), (V), (VI), (VII), or (VIII), where X 3 R is O, O-CH2*, NH or NH-CH2*, 2 R is a 3-12 member monocyclic or bicyclic carbocyrill, a 4-7 member monocyclic or bicyclic oxygen-containing heterocyclic or 5-6 member heteroaryl, 2 3-12 member monocyclic or bicyclic carbon rings, 4-7 member monocyclic or bicyclic oxygen-containing heterocyclic rings, and 5-6 member heteroaryls represented by R 4 Substituted with a base represented by, and optionally, R 10 It is further substituted with 1 to 3 groups represented by , and the remaining variable groups are as described in any one of the first to eighth embodiments.

[0058] In the 29th embodiment, the compound of the present invention is represented by one of the formulas (I'), (I), (II), (III), (IV), (V), (VI), (VII), or (VIII), where X3 R is O, O-CH2*, NH or NH-CH2*, 2 R is a 4-7 member monocyclic or bicyclic oxygen-containing heterocyclic or a 5-6 member heteroaryl, 2 4-7 member monocyclic or bicyclic oxygen-containing heterocyclic rings and 5-6 member heteroaryls represented by R 4 Substituted with a base represented by, and optionally, R 10 It is further substituted with 1 to 3 groups represented by , and the remaining variable groups are as described in any one of the first to eighth embodiments.

[0059] In the 30th embodiment, the compound of the present invention is represented by one of the formulas (I'), (I), (II), (III), (IV), (V), (VI), (VII), or (VIII), where R 2 The 4- to 7-membered monocyclic or bicyclic oxygen-containing heterocycles represented by are oxabicyclo[3.1.1]heptanylene or tetrahydro-2H-pyranylene, respectively, R 4 Substituted with a base represented by, and optionally, R 10 Further substituted with one or two groups represented by R, the 5-6 member heteroaryl is R 4 Substituted with a base represented by, and optionally, R 10 A pyridinylene further substituted with 1 to 3 groups represented by , the remaining variable groups as described in any one of the first to eighth and twenty-nine embodiments.

[0060] In the 31st embodiment, the compound of the present invention is represented by any one of the formulas (I'), (I), (II), (III), (IV), (V), (VI), (VII), or (VIII), where R 2 teeth, [ka] Selected from, Each is R 4 Substituted with a base represented by, and optionally, R 10It is further substituted with one or two groups represented by , and the remaining variable groups are as described in any one of the first to eighth and twenty-nine embodiments.

[0061] In the 32nd embodiment, the compound of the present invention is represented by one of the formulas (I'), (I), (II), (III), (IV), (V), (VI), (VII), or (VIII), where X 3 R is O, O-CH2*, NH or NH-CH2*, 2 R is a monocyclic or bicyclic carbocyclyl with 3 to 12 members. 2 A monocyclic or bicyclic carbon ring with 3 to 12 members represented by R 4 Substituted with a base represented by, and optionally, R 10 It is further substituted with one or two groups represented by , and the remaining variable groups are as described in any one of the first to eighth embodiments. Or, X 3 is O or O-CH2*. In another alternative, X 3 is O. The remaining variable groups in formulas (I'), (I), (II), (III), (IV), (V), (VI), (VII), or (VIII) are as described in any one of the first to eighth embodiments.

[0062] In the 33rd embodiment, the compound of the present invention is represented by one of the formulas (I'), (I), (II), (III), (IV), (V), (VI), (VII), or (VIII), where R 2 R is phenylene, C3-C7 cycloalkylene or C6-C9 bicyclic saturated carbon ring, 2 Phenylene, C3-C7 cycloalkylenes, and C6-C9 bicyclic saturated carbon rings represented by R 4 Substituted with a base represented by, and optionally, R 10 It is further substituted with one or two groups represented by , and the remaining variable groups are as described in any one of the first to eighth and twenty-eighth embodiments.

[0063] In the 34th embodiment, the compound of the present invention is represented by one of the formulas (I'), (I), (II), (III), (IV), (V), (VI), (VII), or (VIII), where R 2 R 4 Substituted with a base represented by, and optionally, R 10 Phenylene or C4-C7 cycloalkylene further substituted with one or two groups represented by , the remaining variable groups being as described in any one of the first to eighth, thirty-second and thirty-third embodiments.

[0064] In the 35th embodiment, the compound of the present invention is represented by one of the formulas (I'), (I), (II), (III), (IV), (V), (VI), (VII), or (VIII), where X 3 is O, and the remaining variable groups are as described in any one of the first to eighth and twenty-eighth embodiments.

[0065] In the 36th embodiment, the compound of the present invention is represented by one of the formulas (I'), (I), (II), (III), (IV), (V), (VI), (VII), or (VIII), where R 2 These are phenylene, cyclobutylene, cyclohexylene, cyclopentylene, cyclopropylene, bicyclo[3.3.1]heptylene, bicyclo[2.2.1]heptanylene, bicyclo[4.1.0]heptanylene, or bicyclo[2.1.1]hexanylene, each of which is R 4 Substituted with a base represented by, and optionally, R 10 It is further substituted with one or two groups represented by , and the remaining variable groups are as described in any one of the first to eighth and thirty-second to thirty-fifth embodiments.

[0066] In the 37th embodiment, the compound of the present invention is represented by one of the formulas (I'), (I), (II), (III), (IV), (V), (VI), (VII), or (VIII), where R 2 R 4Substituted with a base represented by, and optionally, R 10 Phenylene, cyclobutylene, cyclohexylene, or bicyclo[3.3.1]heptylene further substituted with one or two groups represented by , the remaining variable groups being as described in the 1st to 8th and 32nd to 35th embodiments.

[0067] In the 38th embodiment, the compound of the present invention is represented by one of the formulas (I'), (I), (II), (III), (IV), (V), (VI), (VII), or (VIII), where R 2 teeth, [ka] And in the formula, "**" is X 3 The connection point to is indicated by "***", and R 4 The connection point to R is shown, where R 2 The base represented by R can be chosen at will. 10 It is further substituted with one or two groups represented by . The remaining variable groups in formula (I'), (I), (II), (III), (IV), (V), (VI), (VII), or (VIII) are as described in the 1st to 8th and 32nd to 35th embodiments.

[0068] In the 39th embodiment, the compound of the present invention is represented by any one of the formulas (I'), (I), (II), (III), (IV), (V), (VI), (VII), or (VIII), where R 2 teeth, [ka] And here, R 2 The base represented by R can be chosen at will. 10 It is substituted with one or two groups represented by , and the remaining variable groups are as described in any one of the first to eighth or thirty-second to thirty-fifth embodiments.

[0069] In the 40th embodiment, the compound of the present invention is represented by one of the formulas (I'), (I), (II), (III), (IV), (V), (VI), (VII), or (VIII), where R 6 and R 6 ' is independently H, CN, CH3, CH2Cl, CF3, cyclopropyl or CH2N(R a ) and the remaining variable groups are as described in any one of the first to eighth and thirty-two to thirteenth embodiments.

[0070] In the 41st embodiment, the compound of the present invention is represented by any one of the formulas (I'), (I), (II), (III), (IV), (V), (VI), (VII), or (VIII), where R a The group is independently selected from -CH3 and cyclopropyl, and the remaining variable group is as described in any one of the first to eighth and thirty-second to forty-second embodiments.

[0071] In the 42nd embodiment, the compound of the present invention is represented by one of the formulas (I'), (I), (II), (III), (IV), (V), (VI), (VII), or (VIII), where R 6 and R 6’ These are independently H, CH3, or CH2Cl, and the remaining variable group is as described in any one of the first to eighth and thirty-second to thirteenth embodiments.

[0072] In the 43rd embodiment, the compound of the present invention is represented by one of the formulas (I'), (I), (II), (III), (IV), (V), (VI), (VII), or (VIII), where R 4are NHC(O)CH=CH2, N(CH3)C(O)CH=CH2, NHC(O)CH=CHCH3, N(CH3)C(O)CH=CHCH3, N(CH3)C(O)CH=CHCN, NHC(O)C≡CH, N(CH3)C(O)C≡CH, N (H)C(O)C≡CCH3, N(CH3)C(O)C≡CCH3, N(CH2CH2F)C(O)CH=CH2, N(CH2CH2F)C(O)CH=CHCH3, N(CH2CH2F)C(O)C≡CH, N(CH2CH2F)C(O)C≡CC H3, CH2N(CH3)C(O)CH=CH2, N(CH2CHF2)C(O)CH=CH2, N(CH3)C(O)CH=CHCH2Cl, NHC(O)CH=CHCF3, N(CH3)C(O)CH=CHCF3, NHC(O)C≡C-cyclopropyl, NHC(O)CH=CHCH2N(CH3)-cyclobutyl, N(CH2CHF2)C(O)CH=CHCH2N(CH3)2, N(cyclopropyl)C(O)CH=CH2, N(CH3)C(O)CH2Cl, N(CH3)CH2CN, [ka] The formula is CH2NHC(O)CH=CH2 or CH(CH3)NHC(O)CH=CH2. The remaining variable groups in formula (I'), (I), (II), (III), (IV), (V), (VI), (VII), or (VIII) are as described in any one of the first to eighth and thirty-second to forty-first embodiments.

[0073] In the 44th embodiment, the compound of the present invention is represented by any one of the formulas (I'), (I), (II), (III), (IV), (V), (VI), (VII), or (VIII), R 4 These are NHCOCH=CH2, N(CH3)COCH=CH2, NHCOCH=CHCH3, N(CH3)COCH=CHCH3, N(H)COC≡CH, N(CH3)COC≡CH, N(H)COC≡CCH3, N(CH3)COC≡CCH3, N(CH2CH2F)COCH=CH2, N(CH2CH2F)COCH=CHCH3, N(CH2CH2F)COC≡CH or N(CH2CH2F)COC≡CCH3. Alternatively, R4 is NHC(O)C≡CH 、 The groups are NHC(O)C≡CCH3, NHC(O)CH=CH2, N(CH3)COCH=CH2, N(CH3)COC≡CCH3, or N(CH2CH2F)COCH=CH2. The remaining variable groups in formulas (I'), (I), (II), (III), (IV), (V), (VI), (VII), or (VIII) are as described in any one of the first to eighth and thirty-second to forty-second embodiments.

[0074] In the 45th embodiment, the compound of the present invention is represented by one of the formulas (I'), (I), (II), (III), (IV), (V), (VI), (VII), or (VIII), where X 3 R is connected to 2 The stereochemical configuration of the ring carbon atoms in a 3- to 12-membered carbon ring bonded by the given symbol is R. Alternatively, X 3 R is connected to 2 The stereochemical configuration of the ring carbon atoms in the 3- to 12-membered carbon rings represented by is S. The remaining variable groups in formula (I'), (I), (II), (III), (IV), (V), (VI), (VII), or (VIII) are as described in any one of embodiments 1 to 8 and 32 to 44.

[0075] In the 46th embodiment, the compound of the present invention is represented by any one of the formulas (I'), (I), (II), (III), (IV), (V), (VI), (VII), or (VIII), where X 3 and R 4 This is the orientation of trans. Or, X 3 and R 4 This is the cis orientation. The remaining variable groups in formula (I'), (I), (II), (III), (IV), (V), (VI), (VII), or (VIII) are as described in any one of the first to eighth and thirty-second to forty-fourth embodiments.

[0076] In the 47th embodiment, the compound of the present invention is represented by any one of the formulas (I'), (I), (II), (III), (IV), (V), (VI), (VII), or (VIII), where X 3 It is O-CH2CH2*, and R 2 R 4 Substituted with a base represented by, and optionally, R 10 A C1-C3 alkyl group further substituted with one or two groups represented by R 2 X is absent, 3 R 4 It is directly connected to. The remaining variable groups in formulas (I'), (I), (II), (III), (IV), (V), (VI), (VII), or (VIII) are as described in the first to eighth embodiments.

[0077] In the 48th embodiment, the compound of the present invention is represented by one of the formulas (I'), (I), (II), (III), (IV), (V), (VI), (VII), or (VIII), where R 2 The is selected from **-CH2-*** and **-CH2CH(CH3)-***, where "**" is X 3 The symbol "***" represents the connection point to R 4 This represents a bonding point to . The remaining variable groups in formula (I'), (I), (II), (III), (IV), (V), (VI), (VII), or (VIII) are as described in any one of the first to eighth and forty-seventh embodiments.

[0078] In the 49th embodiment, the compound of the present invention is represented by one of the formulas (I'), (I), (II), (III), (IV), (V), (VI), (VII), or (VIII), where R 4 The group is N(CH3)C(O)CH=CH2, and the remaining variable groups are as described in any one of the first to eighth, forty-seventh, and forty-eighth embodiments.

[0079] In the 50th embodiment, the compound of the present invention is represented by any one of the formulas (I'), (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), or (XIV), where R 1 is H or a C1-C3 alkyl, a C1-C3 fluoroalkyl, or a 4-7 membered monocyclic oxygen-containing heterocycle. Alternatively, R 1 is H, CH3, CH(CH3)2, CHF2, oxetanyl, or tetrahydrofuranyl. The remaining variable groups in formula (I'), (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), or (XIV) are as described in any one of the 1st to 49th embodiments.

[0080] In the 51st embodiment, the compound of the present invention is represented by any one of the formulas (I'), (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), or (XIV), where R 1 The variable group is H, CH3, CH(CH3)2, CHF2, CF3, oxetanyl, or tetrahydrofuranyl, and the remaining variable group is as described in any one of the 1st to 49th embodiments.

[0081] In the 52nd embodiment, the compound of the present invention is represented by any one of the formulas (I'), (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), or (XIV), where R 0 The variable group is H, F, CN, CH3, CF3, cyclopropyl, or phenyl, and the remaining variable group is as described in any one of the first to fifty-one embodiments.

[0082] In the 53rd embodiment, the compound of the present invention is represented by any one of the formulas (I'), (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), or (XIV), where R 0 The group is H, F, CN, CH3, or CF3, and the remaining variable group is as described in any one of the first to fifty-one embodiments.

[0083] In the 54th embodiment, the compound of the present invention is represented by any one of the formulas (I'), (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), or (XIV), where R 7 The group is selected from H, CH3, CH2CH3, CH2CHF2, and cyclopropyl, and the remaining variable group is as described in any one of the first to fifty-three embodiments.

[0084] In the 55th embodiment, the compound of the present invention is represented by any one of the formulas (I'), (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), or (XIV), where R 8 is H or CH3, and the remaining variable groups are as described in any one of the first to fifty-fourth embodiments.

[0085] In the 56th embodiment, the compound of the present invention is represented by any one of the formulas (I'), (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), or (XIV), where R 10 is F, Cl, CH3 or cyclopropyl, and the remaining variable group in formula (I'), (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), or (XIV) is as described in any one of the first to fifth embodiments.

[0086] In the 57th embodiment, the compound of the present invention is represented by any one of the formulas (I'), (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), or (XIV), where R 14 The first is Cl, and the remaining variable groups are as described in any one of the first to fifty-sixth embodiments.

[0087] In the 58th embodiment, the compound is given by the following formula: [ka] It is represented by or a pharmaceutically acceptable salt thereof, where R 0 is H, halo, or cyclopropyl, and X 3 is O or O-CH2*, and R 2 R is a 4-7 member monocyclic or bicyclic saturated carbocyclyl, 2 Saturated carbocyclyls of 4-7 member monocyclic or bicyclic forms represented by R 4 Substituted with a group represented by , and optionally one or two R 10 It is further replaced by R 2 X is formed via the ring carbon atoms. 3 A 7-9 member bicyclic nitrogen-containing heterocycle that is bonded to ("carbon-bonded") is R 5 Substituted with a group represented by , and optionally one or two R 10 Further substitutions are made with R 4 N(R) 7 )C(O)C≡CCH3、N(R 7 )C(O)CH=CH2, and R 5 C(O)CH=CH2, and R 7 is H, C1-C2 alkyl, or C1-C2 haloalkyl, and R 10 It is a C1-C3 alkyl group.

[0088] In the 59th embodiment, the compound of the present invention is represented by formula (XV), where X 3 is O, and the remaining variable groups in formula (XV) are as described in Embodiment 58.

[0089] In the 60th embodiment, the compound of the present invention is represented by formula (XV), where R 2 is cyclobutylene, cyclohexylene, cyclopentylene, or bicyclo[2.1.1]hexanylene, each of which is R 4 Substituted with a group represented by, and optionally one or two R 10 It is further substituted with. The remaining variable groups in formula (XV) are as described in the 58th or 59th embodiment.

[0090] In the 61st embodiment, the compound of the present invention is represented by formula (XV), where R 2 teeth, [ka] And here, R 2 The base represented by R can be chosen at will. 10 It is further substituted with one or two groups represented by . The remaining variable groups in formula (XV) are as described in the 58th or 59th embodiment.

[0091] In the 62nd embodiment, the compound of the present invention is represented by formula (XV), where R 2 These are azabicyclo[3.2.1]octanylene, azabicyclo[3.1.1]heptanylene, or azabicyclo[3.2.0]heptanylene, each of which is R 5 Substituted with a group represented by, and optionally one or two R 10 It is further substituted with. The remaining variable groups in formula (XV) are as described in the 58th or 59th embodiment.

[0092] In the 63rd embodiment, the compound of the present invention is represented by formula (XV), In the formula, R 2 teeth, [ka] And here, "**" is X 3 The connection point to is indicated by "***", and R 5 It shows the connection point to R 2 Each group represented by can be optionally selected as R 10 It is further substituted with one or two groups represented by . The remaining variable groups in formula (XV) are as described in any one of embodiments 58 to 62.

[0093] In the 64th embodiment, the compound of the present invention is represented by formula (XV), where R 7 is H, CH3, or CH2CHF2. The remaining variable groups in formula (XV) are as described in one of embodiments 58 to 63.

[0094] In the 65th embodiment, the compound of the present invention is represented by formula (XV), where R 10 is CH3. The remaining variable groups in formula (XV) are as described in any one of embodiments 58 to 64.

[0095] The present invention also includes both neutral forms and pharmaceutically acceptable salts of the compounds disclosed as examples.

[0096] As used herein, the term "alkyl" refers to a fully saturated branched or unbranched hydrocarbon moiety. Unless otherwise specified, alkyls contain 1 to 6 carbon atoms or 1 to 3 carbon atoms. Typical examples of alkyls 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.

[0097] As used herein, the term “alkoxy” refers to a fully saturated branched or unbranched alkyl moiety linked via oxygen crosslinking (i.e., --O--C). 1-4 Alkyl alkyl group, where C 1-4 Alkyl is as defined herein. Typical examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy, and tert-butoxy. In some embodiments, the alkoxy group has about 1 to 4 carbon atoms, more preferably about 1 to 2 carbon atoms.

[0098] The number of carbon atoms in the group is, in this specification, "C x-xx This is explicitly indicated by the prefix ", where x and xx are integers. For example, "C 1-3 "Alkyl" refers to an alkyl group that has 1 to 3 carbon atoms.

[0099] "Halogen" or "halo" can be fluoro, chloro, bromo, or iodine.

[0100] The term "haloalkyl" or "halo-substituted alkyl" refers to an alkyl group having at least one halogen substitution. The term "fluoroalkyl" or "fluoro-substituted alkyl" refers to an alkyl group having at least one fluorine substitution.

[0101] A “heterocyclyl” or “heterocycle” is defined as a saturated or partially unsaturated monocyclic or bicyclic (e.g., fused, bridging, or spirocyclic) ring system having 4 to 12 ring members, of which at least one is a heteroatom, and up to four (e.g., 1, 2, 3, or 4) may be heteroatoms, where the heteroatoms are independently selected from O, S, and N, C may be oxidized (e.g., C(O)), N may be oxidized (e.g., N(O)) or quaternized, and S may optionally be oxidized to sulfoxides and sulfones. In some embodiments, if a “heterocyclyl” or “heterocycle” described herein contains both N and O, then that “heterocyclyl” or “heterocycle” is considered an N-containing heterocycle.

[0102] 4- to 12-membered heterocyclils may be 4- to 7-membered monocyclic heterocyclils, or 7- to 12-membered bicyclic heterocyclils that are condensed, cross-linked, or spiro. Examples of 4- to 7-membered monocyclic heterocyclils include, but are not limited to, oxetanil, thietanil, azetedinil, pyrrolidinil, tetrahydrofuranil, thiolanil, imidazolidinil, pyrazolidinil, oxazolidinil, isoxazolidinil, thiazolidinil, isothiazolidinil, dioxolanil, dithiolanil, oxathiolanil, piperidinil, tetrahydropyranil, thianil, piperazinil, morpholinil, thiomorpholinil, dioxanil, dithianil, trioxanil, trithianil, azepanil, oxepanil, thiepanil, dihydrofuranil, imidazolinil, and dihydropyranil.

[0103] A "condensed ring system" has 8 to 12 members (ring atoms) and two rings sharing two adjacent ring atoms. A condensed bicyclic heterocyclyl has a 4 to 7-membered heterocyclyl or a 4 to 7-membered heterocyclyl condensed with a 3 to 7-membered non-aromatic carbocyclyl. Examples include cyclopentapyrrolidinyl, cyclopentapiperidinyl, cyclopentaazapanil, cyclohexapyrrolidinyl, cyclohexapiperidinyl, cyclohexaazapanil, cycloheptapyrrolidinyl, cycloheptapiperidinyl, cycloheptaazapanil, pyrrolopyrrolidinyl, pyrrolopiperidinyl, pyrroroazapanil, furanopyrrolidinyl, furanopiperidinyl, furanoazapanil, pyranopyrrolidinyl, pyranopiperidinyl, and pyranoazapanil.

[0104] A "bridged bicyclic ring system" (also referred to herein as "bridged bicyclic") has 7 to 10 members (ring atoms) and comprises two rings sharing three adjacent ring atoms. Bridged bicyclic heterocyclils include 5 to 7-membered heterocyclils or 5 to 7-membered non-aromatic carbocyclils sharing three ring atoms. Examples of nitrogen-containing bridged bicyclics include azabicyclo[2.2.1]hepantil, azabicyclo[3.2.1]octanyl, azabicyclo[3.3.1]nonanyl, diazabicyclo[2.2.1]hepantil, diazabicyclo[3.2.1]octanyl, and diazabicyclo[3.3.1]nonanyl. Examples of oxygen-containing crosslinked birings include oxobicyclo[2.2.1]hepantil, oxobicyclo[3.2.1]octanyl, oxobicyclo[3.3.1]nonanyl, oxa-azabicyclo[2.2.1]hepantil, oxa-azabicyclo[3.2.1]octanyl, and oxa-azabicyclo[3.3.1]nonanyl.

[0105] A "spirocycle" (also referred to herein as a "spirocycle") has 8 to 12 members (ring atoms) and comprises two rings sharing one ring atom. Spiro-bicyclic heterocyclils include 4 to 7-membered heterocyclils or 4 to 7-membered non-aromatic carbocyclils sharing one atom. Examples of 8 to 12 nitrogen-containing spirocycles include 3,4-azabicyclooctanyl, 4,4-azabicyclononanyl, 3,5-azabicyclononanyl, 3,6-azabicyclodecanyl, 4,5-azabicyclodecanyl, 3,7-azabicycloundenyl, 4,6-azabicycloundenyl, and 5,5-azabicycloundenyl. Examples of oxygen-containing spiro ring systems 8-12 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.

[0106] Examples of 4-12 member nitrogen-containing heterocycles include pyrrolidinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, azepanil, oxepanil, imidazolinyl, cyclopentapyrrolidinyl, cyclopentapiperidinyl, cyclopentazapanil, cyclohexapyrrolidinyl, cyclohexapyrrolidinyl, cyclohexazapanil, cycloheptapyrrolidinyl, cycloheptapyrrolidinyl, cycloheptazapanil, pyrrolopyrrolidinyl, pyrrolopiperidinyl, pyrroroazapanil, furanopiperidinyl. Examples include furanoazapanil, pyranopyrrolidinil, pyranopiperidinil, pyranoazapanil, azabicyclo[2.2.1]hepantil, azabicyclo[3.2.1]octanil, azabicyclo[3.3.1]nonanil, diazabicyclo[2.2.1]hepantil, diazabicyclo[3.2.1]octanil, diazabicyclo[3.3.1]nonanil, 3,4-azabicyclooctanil, 4,4-azabicyclononanil, 3,5-azabicyclononanil, 3,6-azabicyclodecanil, 4,5-azabicyclodecanil, 3,7-azabicycloundenyl, 4,6-azabicycloundenyl, and 5,5-azabicycloundenyl. Examples of 4-7 member nitrogen-containing heterocycles (containing one ring oxygen or one ring sulfur atom by choice) include pyrrolidinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, azepanyl, oxepanyl, and imidazolinyl.

[0107] Examples of 4- to 7-membered oxygen-containing heterocycles include oxetanyl, tetrahydrofuranyl, oxazolidinyl, isoxazolidinyl, dioxolanyl, oxathiolanyl, tetrahydropyranyl, morpholinyl, dioxanyl, oxepanyl, dihydrofuranyl, and dihydropyranyl.

[0108] A "heteroaryl" refers to an aromatic 5-6 member monocyclic ring system having 1-4 heteroatoms independently selected from O, N, and S, where N may be oxidized (e.g., N(O)) or quaternized, and S may be optionally oxidized to sulfoxides and sulfones. Examples of 5-6 member monocyclic heteroaryls include, but are not limited to, pyrrolyl, furanyl, thiophenyl (or thienyl), imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, flazanyl, oxadiazolyl, thiadiazolyl, dithiazolyl, triazolyl, tetrazolyl, pyridinyl, pyranyl, thiopyranyl, pyrazinyl, pyrimidinyl, pyridadinyl, oxazinyl, thiadinyl, dioxynyl, dithiynyl, oxathianyl, triazinyl, and tetradinyl. In one embodiment, the heteroaryl is a 5-member heteroaryl. Examples of five-membered heteroaryls include, but are not limited to, pyrazolyl, oxazolyl, isoxazolyl, 1,2,3-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,4-oxadizolyl, 1,2,3-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, and tetrazolyl.

[0109] A "carbocyclyl" refers to a saturated or partially unsaturated monocyclic or bicyclic (e.g., fused, bridging, or spirocyclic) ring system having 4 to 12 ring members, all of which are carbon atoms. The term "carbocyclyl" encompasses cycloalkyl groups, cycloalkenyl groups, and aromatic groups (i.e., aryl groups). A "cycloalkyl" refers to a fully saturated monocyclic hydrocarbon group with 3 to 7 carbon atoms, including cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cyclopentyl. A "cycloalkenyl" refers to an unsaturated non-aromatic monocyclic hydrocarbon group with 3 to 7 carbon atoms, including cyclopentenyl, cyclohexenyl, and cyclopentenyl. An example of an aromatic carbocyclyl group is phenyl.

[0110] Condensed bicyclic carbocyclyls have a 4-7 membered carbocyclyl condensed with a 3-7 membered non-aromatic carbocyclyl. Examples include decahydronaphthalene, octahydro-1H-indene, octahydropentalene, decahydroazulene, decahydro-1H-annelene, bicyclo[4.2.0]octane, and bicyclo[3.2.0]heptane.

[0111] Bridged bicyclic carbocyclyls include 5-7 member non-aromatic carbocyclyls sharing 3 ring atoms with 5-7 member non-aromatic carbocyclyls. Examples of bridged bicyclic carbocyclyls include bicyclo[2.2.1]hepantil, bicyclo[3.2.1]octanyl, and bicyclo[3.3.1]nonanyl.

[0112] The suffix "-yl" added to the end of a chemical name indicates that the specified part is attached to the molecule by one point. The suffix "-ene" added to the end of a chemical name indicates that the specified part is attached to the molecule by two points. Examples include azetidinylene, pyrrolinedinylene, piperidinylene, azapanylene, or oxazapanylene, which indicate that azetidine, pyrrolidine, piperidine, azapan, or oxazapan are attached to the rest of the compound by two points.

[0113] In the context of nitrogen-containing heterocycles, "nitrogen-bonded to a bicyclic core" means that the nitrogen-containing heterocycle is bonded to the core via its ring nitrogen atoms. [ka] This means that it is bonded to the core. In the context of nitrogen-containing heterocycles or carbocycles, "C bonded to a bicyclic core" means that the nitrogen-containing heterocycle or carbocycle is bonded to the core via the ring carbon atoms. [ka] This means that they are joined together.

[0114] When a nitrogen atom in the ring is substituted, the nitrogen-containing heterocycle is called "N-substituted".

[0115] If a compound provided herein is sufficiently basic or acidic to form a stable, non-toxic acidic or basic salt, preparation and administration of the compound as a pharmaceutically acceptable salt may be appropriate. Examples of pharmaceutically acceptable salts include organic acid addition salts formed with acids that form physiologically acceptable anions, such as tosylates, methanesulfons, acetates, citrates, malons, tartrates, succinates, benzoates, ascorbicates, α-ketoglutarates, or α-glycerophosphates. Inorganic salts may also be formed, including hydrochlorides, sulfates, nitrates, bicarbonates, and carbonates.

[0116] Pharmaceutically acceptable salts may be obtained by reacting a sufficiently basic compound, such as an amine, with a suitable acid that yields a physiologically acceptable anion, using standard procedures well known in the art. Alkali metal (e.g., sodium, potassium, or lithium) or alkaline earth metal (e.g., calcium) salts of carboxylic acids can also be produced.

[0117] pharmaceutically acceptable base addition salts can be prepared from inorganic and organic bases. Examples of salts from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, or magnesium salts. Examples of salts derived from organic bases include 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, trisubstituted cycloalkenylamines. Examples include, but are not limited to, salts of primary, secondary, or tertiary amines such as chloroalkenylamines, arylamines, diarylamines, triarylamines, heteroarylamines, diheteroarylamines, triheteroarylamines, heterocycloalkylamines, diheterocycloalkylamines, triheterocycloalkylamines, or mixed diamines and triamines, wherein at least two 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. Also included are amines in which two or three substituents combine with an amino nitrogen to 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, trimamine, lysine, arginine, histidine, caffeine, procaine, hydravamin, choline, betaine, ethylenediamine, glucosamine, N-alkylglucamine, theobromine, purine, piperazine, piperidine, morpholine, or N-ethylpiperidine. Carboxylic acid amides, including other carboxylic acid derivatives such as carboxamides, lower alkylcarboxamides, or dialkylcarboxamides, may also be useful.

[0118] The compounds described herein or their pharmaceutically acceptable salts may contain one or more chiral centers within the molecule. According to this disclosure, any structure not specifying stereochemistry shall be understood to include all of the various stereoisomers (e.g., diastereomers and enantiomers) in their pure or substantially pure forms, as well as mixtures thereof (e.g., racemic mixtures or mixtures with enantiomers concentrated). Methods for preparing such optically active compounds (e.g., recrystallization techniques for racemic solutions, synthesis from optically active starting materials, chiral synthesis, or chromatographic separation using a chiral stationary phase) are well known in the art.

[0119] If a specific stereoisomer of a compound is indicated by name or structure, the stereochemical purity of that compound is at least 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 97%, 99%, 99.5%, or 99.9%. "Stereochemical purity" means the weight percentage of the desired stereoisomer relative to the total weight of all stereoisomers.

[0120] If a specific enantiomer of a compound is indicated by name or structure, the stereochemical purity of that compound is at least 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 97%, 99%, 99.5%, or 99.9%. "Stereochemical purity" means the weight percentage of the desired enantiomer relative to the total weight of all stereoisomers.

[0121] If the stereochemistry of a disclosed compound is named or described by structure, and the named or described structure encompasses multiple stereoisomers (e.g., diastereomer pairs), it is understood that it may contain one of the encompassed stereoisomers or any mixture of the encompassed stereoisomers. Furthermore, it is understood that the stereoisomer purity of the named or described stereoisomer is at least 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 97%, 99%, 99.5%, or 99.9%. Stereoisomer purity means a weight percentage of the total weight of all stereoisomers of the desired stereoisomer encompassed by its name or structure.

[0122] If a disclosed compound is named or described structurally without indicating stereochemistry, and the compound has one chiral center, it should be understood that the name or structure may include one enantiomer of the compound in its pure or substantially pure form, and mixtures thereof (such as racemic mixtures of the compound, and mixtures in which one enantiomer is concentrated compared to its corresponding optical isomer).

[0123] If a disclosed compound is named or described structurally without indicating stereochemistry, and for example, if the compound has at least two chiral centers, it should be understood that its name or structure may encompass one stereoisomer in a pure or substantially pure form, and mixtures thereof (such as mixtures of stereoisomers, and mixtures of stereoisomers in which one or more stereoisomers are concentrated compared to other stereoisomers).

[0124] The disclosed compounds may exist as tautomers, and mixtures and individual tautomers are also intended. Furthermore, some compounds may exhibit polymorphism.

[0125] In one embodiment, the present invention provides a deuterated compound disclosed herein, in which any or more positions occupied by hydrogen may include enrichment by deuterium exceeding 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 is introduced), at least 3500 times (52.5% deuterium is introduced in each specified deuterium atom), at least 4000 times (60% deuterium is introduced), at least 4500 times (67.5% deuterium is introduced), at least 5000 times (75% deuterium), at least 5500 times (82.5% deuterium is introduced), at least 6000 times (90% deuterium is introduced), at least 6333.3 times (95% deuterium is introduced), at least 6466.7 times (97% deuterium is introduced), at least 6600 times (99% deuterium is introduced), or at least 6633.3 times (99.5% deuterium is introduced) greater than the natural abundance of deuterium. In one embodiment, hydrogen is present at all positions in its natural abundance. The compounds described herein or their pharmaceutically acceptable salts may exist as tautomers, and mixtures and separate tautomers are also intended.

[0126] Another embodiment is a pharmaceutical composition comprising at least one compound described herein or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable carrier.

[0127] The compounds described herein or their pharmaceutically acceptable salts may be used to reduce the activity of Btk or to otherwise affect the properties and / or behavior of Btk, such as stability, phosphorylation, kinase activity, and interactions with other proteins.

[0128] In some embodiments, the present invention provides a method for reducing Btk enzyme activity. In some embodiments, such a method involves contacting Btk with an effective amount of a Btk inhibitor. Thus, the present invention further provides a method for inhibiting Btk enzyme activity by contacting Btk with the Btk inhibitor of the present invention.

[0129] One embodiment of the present invention includes a method for treating a Btk inhibition-responsive disorder in a subject, comprising administering an effective amount of at least one compound described herein or a pharmaceutically acceptable salt thereof to the subject.

[0130] In one embodiment, the present invention provides a method for treating autoimmune disorders, inflammatory diseases, and cancer in a subject in need thereof, comprising administering an effective amount of at least one compound described herein or a pharmaceutically acceptable salt thereof to the subject.

[0131] The term "autoimmune disorder" includes diseases or disorders that involve an inadequate 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, diabetes mellitus type 1, Goodpasture syndrome, Graves' disease, Guillain-Barré 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, Sjögren's syndrome, temporal arteritis, and Wegener's granulomatosis. 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, transplant rejection, and vasculitis. In some embodiments, the present invention provides a method for treating rheumatoid arthritis or lupus. In some embodiments, the present invention provides a method for treating multiple sclerosis.

[0132] 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, cholangiocarcinoma, 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., high microsatellite instability colorectal cancer). In some embodiments, the present invention provides methods for treating leukemia or lymphoma.

[0133] As used herein, the terms “subject” and “patient” may be used interchangeably and refer to mammals in need of treatment, such as companion animals (e.g., dogs, cats, etc.), livestock (e.g., cows, pigs, horses, sheep, goats, etc.), and laboratory animals (e.g., rats, mice, guinea pigs, etc.). Typically, the subject is a human being in need of treatment.

[0134] As used herein, the terms “to treat” or “treatment” mean to obtain a desired pharmacological and / or physiological effect. An effect may be therapeutic and this includes partially or substantially achieving one or more of the following results: partially or completely reducing the degree of a disease, disorder or syndrome; relieving or improving a clinical symptom or indicator associated with the disorder; or delaying, inhibiting or reducing the likelihood of progression of a disease, disorder or syndrome.

[0135] The effective dose of the compound provided herein, or a pharmaceutically acceptable salt thereof, administered to the subject may range from 10 μg to 500 mg.

[0136] Administration of the compounds described herein, or pharmaceutically acceptable salts thereof, to mammals includes any preferred method of delivery. Administration of the compounds described herein, or pharmaceutically acceptable salts thereof, to mammals includes administering the compounds described herein, or pharmaceutically acceptable salts thereof, to mammals topically, enterally, parenterally, percutaneously, transmucosally, by inhalation, into the cisterna magna, epidurally, vaginally, intravenously, intramuscularly, subcutaneously, intradermally, or intravitreously, to mammals. Administration of the compounds described herein, or pharmaceutically acceptable salts thereof, to mammals includes administering the compounds, or pharmaceutically acceptable salts thereof, which are metabolized to the compounds described herein in or on the surface of the mammal, to mammals topically, enterally, parenterally, percutaneously, transmucosally, by inhalation, into the cisterna magna, epidurally, vaginally, intravenously, intramuscularly, subcutaneously, intradermally, or intravitreously, to mammals.

[0137] Therefore, the compounds described herein or pharmaceutically acceptable salts thereof may be administered systemically, for example, orally, in combination with a pharmaceutically acceptable vehicle such as an inert diluent or an assimilated food carrier. They may be encapsulated in hard-shell or soft-shell gelatin capsules, compressed into tablets, or directly combined with patient food. For therapeutic oral administration, the compounds described herein or pharmaceutically acceptable salts thereof may be used in combination with one or more excipients in the form of ingestible tablets, buccal tablets, lozenges, capsules, elixirs, suspensions, syrups, or wafers. 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, vary and, conveniently, may be about 2 to about 60% of the weight of a given unit dosage form. The amount of the active compound in such therapeutically useful compositions may be such that an effective dose level is obtained.

[0138] Tablets, lozenges, pills, capsules, etc. may contain: binders such as tragacanth, acacia, corn starch, or gelatin; excipients such as dicalcium phosphate; disintegrants such as corn starch, potato starch, or alginic acid; lubricants such as magnesium stearate; or sweeteners or flavorings such as sucrose, fructose, lactose, or aspartum.

[0139] The active compound may be administered intravenously or intraperitoneally by injection or infusion. Solutions of the active compound or its salt can be prepared by mixing it in water with an optional non-toxic surfactant.

[0140] Examples of pharmaceutical dosage forms for injection or infusion include sterile aqueous solutions, dispersions, or sterile powders containing an active ingredient suitable for immediate preparation as a sterile injection or infusion solution or dispersion. In all cases, the final dosage form should be sterile, fluid, and stable under manufacturing and storage conditions.

[0141] Sterile injectable solutions can be prepared by combining the required amount of active compound in a suitable solvent with the other components listed above in various ways, and then sterilizing by filtration as needed. For sterile powders used in the preparation of sterile injectable solutions, preferred preparation methods may be vacuum drying and freeze-drying, which allow for obtaining a powder of the active component with any additional desired components added, which may have been previously contained in a sterile filtered solution.

[0142] Examples of solid carriers include pulverized solids such as talc, clay, microcrystalline cellulose, silica, and alumina. Useful liquid carriers include water, alcohol or glycol, or blends of water and alcohol / glycol, in which the compounds described herein or their pharmaceutically acceptable salts can be dissolved or dispersed at an effective level using optionally non-toxic surfactants.

[0143] Useful doses of the compounds described herein or their pharmaceutically acceptable salts can be determined by comparing their in vitro activity and in vivo activity in animal models. Methods for extrapolating effective doses 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 in whole by reference.

[0144] The amount of the compound or a pharmaceutically acceptable salt described herein required for therapeutic use varies not only depending on the specific salt selected, but also on the route of administration, the nature of the condition being treated, and the patient's age and condition, and is ultimately left to the judgment of the attending physician or clinician. However, generally, the dose may range from approximately 0.1 to approximately 10 mg / kg body weight per day.

[0145] The compounds described herein or pharmaceutically acceptable salts thereof can, for convenience, be administered in unit dosage forms containing, for example, 0.01 to 10 mg or 0.05 to 1 mg of the active ingredient per unit dosage form. In some embodiments, doses of 5 mg / kg or less may be preferred.

[0146] The desired dose may, for convenience, be presented as a single dose or as divided doses administered at appropriate intervals.

[0147] The methods of this disclosure may include kits that include instructional materials capable of demonstrating the administration of the compounds described herein or pharmaceutically acceptable salts thereof, and compositions comprising the compounds described herein or pharmaceutically acceptable salts thereof, to cells or subjects. This should be interpreted as including other embodiments of kits known to those skilled in the art, such as kits that include a solvent (e.g., sterile) for dissolving or suspending the compounds described herein or pharmaceutically acceptable salts thereof or compositions before administration to cells or subjects. In some embodiments, the subjects may be human. [Examples]

[0148] The present invention is illustrated by the following embodiments, but is not intended to be limiting. The abbreviations and acronyms used herein include the following: ABPR stands for Automatic Back Pressure Adjustment System. Ac2O means acetic anhydride. ACN stands for acetonitrile. Aq. means aqueous solution. Ar stands for argon. Bn stands for benzyl. Boc means tert-butoxycarbonyl. Boc2O stands for di-tert-butyl dicarbonate. BPin stands for pineacolatoboron. B2pin2 stands for bispinacolate diborone. br means broad. t-BuOH stands for tert-butanol. n-BuLi means n-butyllithium. °C stands for degrees Celsius. CHCl3 means chloroform. CDCl3 stands for deuterochloroform. CO2 means carbon dioxide. Cs2CO3 means cesium carbonate. CsF stands for cesium fluoride. CuI stands for copper iodide. δ stands for chemical shift. d means double line. dd means double double lines. ddd means double double double line, DCM stands for dichloromethane. DIEA or DIPEA means N-ethyldiisopropylamine or N,N-diisopropylethylamine. DEA stands for diethylamine. "Deg" means degree. DIAD stands for diisopropyl azodicarboxylate. DME stands for 1,2-dimethoxyethane. DMF stands for N,N-dimethylformamide. DMSO stands for dimethyl sulfoxide. DMSO-d6 stands for hexaduterodimethyl sulfoxide. DPPA stands for diphenylphosphoryl azide. Et stands for ethyl. Et2O means ether. EtOH means ethanol. RINKAN means ethyl acetate. Eq. means equivalent. g stands for grams. h stands for time. HATU stands for O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate. HBr stands for hydrogen bromide. HCl means hydrochloric acid. HCO2H means formic acid. Hept means heptane. HFIP stands for hexafluoroisopropanol. 1 1H NMR stands for Proton Nuclear Magnetic Resonance. H2O means water. H2SO4 means sulfuric acid. HMPA stands for hexamethylphosphoramide. HPLC stands for High-Performance Liquid Chromatography. Hz stands for Hertz. IPA or iPrOH means isopropanol. J represents the coupling constant. K2CO3 means potassium carbonate. kg means kilogram. KHMDS stands for potassium hexamethyldisilazide. KOAc stands for potassium acetate. KOH stands for potassium hydroxide. KOt-Bu means potassium tert-butoxide. K3PO4 means tripotassium phosphate. K4Fe(CN)6·3H2O means potassium hexacyanoiron(II) trihydrate. L stands for liter. LCMS stands for Liquid Chromatography Mass Spectrometry. m means multiple lines. M stands for mole. MBPR stands for Manual Back Pressure Adjuster. Me means methyl. MeB(OH)2 stands for methylboronic acid. MeCN stands for acetonitrile. MeOH means methanol. MeOH-d4 means deuteromethanol. mg means milligrams. MgSO4 means magnesium sulfate. MHz stands for megahertz. "Mins" means minutes. mL means milliliter. "Millimol" means millimoles. MMPNO stands for methylmorpholine N-oxide. mol means mole. MS m / z stands for Mass Spectral Peak. N2 means nitrogen. NaOt-Bu means sodium tert-butoxide. NaH stands for sodium hydride. NaHCO3 means sodium bicarbonate. NaHMDS stands for sodium hexamethyldisilyl azide. NaIO4 means sodium periodate. NaOH stands for sodium hydroxide. Na2S2O3 means sodium thiosulfate. Na2SO4 means sodium sulfate. NEt3 stands for triethylamine. NFSI stands for N-fluorobenzenesulfonimide. NH3 means ammonia. NH4Cl means ammonium chloride. NH4OH is ammonium hydroxide. NH4OAc is ammonium acetate. NIS stands for N-iodosuccinimide. OsO4 stands for osmium tetroxide. P(cy)3 stands for tricyclohexylphosphine. Pd2(dba)3 means Tris(dibenzylideneacetone)dipalladium(0). Pd(dppf)Cl2 means [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II), Pd(dtbpf)Cl2 means [1,1'-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II), PEPPSI-IPr or Pd-PEPPSI-IPr means [1,3-bis(2,6-diisopropylphenyl)imidazole-2-ylidene](3-chloropyridyl)palladium(II) dichloride. Ph stands for phenyl. POCl3 stands for phosphoryl chloride. Pyr means pyridine. q means quadruple lines. Rf represents the delay coefficient. Rt stands for retention time. RT stands for room temperature. RuPhos stands for 2-dicyclohexylphosphino-2',6'-diisopropoxybiphenyl. s means a single line. sat. means saturation. SCX stands for Strong Cation Exchange. SFC stands for supercritical fluid chromatography. SiO2 means silicon dioxide. Si-SPE stands for silica solid-phase extraction. t means triple line. td means triple double lines. t-BuONa means sodium tert-butoxide. TEA stands for triethylamine. TFA stands for trifluoroacetic acid. THF stands for tetrahydrofuran. TLC stands for Thin-Layer Chromatography. T3P stands for propanephosphonic anhydride. μL means microliter. μmol means micromoles. μW stands for microwave. v / v represents the volume per unit volume. Xphos stands for 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl. Xphos G3 means (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II)methanesulfonate.

[0149] [ka] Synthesis of 1-(1-methyl-1H-pyrazole-4-yl)ethane-1-one (2). [ka] A mixture of 1-methyl-1H-pyrazole (50.0 g, 1 equivalent, 609 mmol) and acetic anhydride (112 g, 104 mL, 1.8 equivalents, 1.10 mol) was mixed with sulfuric acid (4.78 g, 2.61 mL, 0.08 equivalents, 48.7 mmol) at room temperature. The mixture was heated at 150 °C for 7 hours and then cooled to room temperature overnight. The reaction mixture was poured onto ice, and the pH of the resulting solution was adjusted to 10 with 20% NaOH aqueous solution. The solution was then extracted with DCM, and the organic phase was dried over sodium sulfate and concentrated. This yielded 1-(1-methyl-1H-pyrazole-4-yl)ethane-1-one (36.8 g, yield 49%). 1 H NMR (300 MHz, CDCl3) d 7.80-7.96 (m, 2H), 3.91 (s, 3H), 2.39 (s, 3H).

[0150] Synthesis of 2-bromo-1-(1-methyl-1H-pyrazole-4-yl)ethane-1-one (3). [ka] In a round-bottom flask, 1-(1-methyl-1H-pyrazole-4-yl)ethane-1-one (36.8 g, 1 equivalent, 296 mmol) was dissolved in dichloromethane (700 mL). Ethanol (175 mL) and pyridinium tribromide (94.7 g, 1 equivalent, 296 mmol) were added gradually at 15°C. The mixture was stirred overnight from 0°C to room temperature. The mixture was confirmed by TLC (heptane: SiO4 4:6) and HPLC. After the addition was complete, the reaction was quenched with water. The layers were separated, the organic phase was dried over sodium sulfate, and concentrated to obtain the product as a brown solid. The solid was suspended in a mixture of DCM and heptane, heated to 50°C, and then cooled again to room temperature. The product was precipitated and isolated by filtration (28.8 g). Further solid precipitated from the mother liquor (7.43 g). A total of 36.2 g (60% yield) of the title product was isolated as a brown solid. ESI-MS (M+H) + : 205.1.

[0151] Synthesis of diethyl=1-(2-(1-methyl-1H-pyrazole-4-yl)-2-oxoethyl)-1H-pyrazole-3,5-dicarboxylate (5). [ka] In a round-bottom flask, 2-bromo-1-(1-methyl-1H-pyrazole-4-yl)ethane-1-one (60.6 g, 1 equivalent, 298 mmol) was dissolved in DMF (900 mL), and 1H-pyrazole-3,5-dicarboxylate diethyl (69.6 g, 1.1 equivalents, 328 mmol) and cesium carbonate (126 g, 1.30 equivalents, 388 mmol) were added. The reaction mixture was stirred overnight at room temperature. The reaction mixture was diluted with water and extracted with DCM. The organic layer was dried over sodium sulfate and concentrated. The crude product was suspended in heptane:toluene 1:1 (50-100 mL) and filtered. The solid was washed once with toluene and once with heptane to obtain the product (68.5 g) as a white solid. The mother liquor was concentrated and purified by column chromatography (120g silica, heptane:siRNA gradient 0-100%) to obtain a separate fraction of the product (9.7g). A total of 78.2g (78% yield) of the product was isolated as a white solid. ESI-MS (M+H) + : 335.2.

[0152] Synthesis of ethyl=4-hydroxy-6-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyrazine-2-carboxylate (6). [ka] Diethyl-1-(2-(1-methyl-1H-pyrazole-4-yl)-2-oxoethyl)-1H-pyrazole-3,5-dicarboxylate (15.0 g, 1 equivalent, 44.9 mmol), ethanol (150 mL), and ammonium acetate (10.4 g, 3.0 equivalents, 135 mmol) were placed in a Berghoff reaction vessel. The mixture was heated at 130°C for 24 hours, after which complete conversion was observed by HPLC (samples were taken after the reactor was cooled again to room temperature). The reaction mixture was filtered off, washed with water, and air-dried to obtain the product (11.8 g, 92%) as a white solid. This reaction was carried out in batches with a total of 78.2 g of starting material to obtain a total of 66.6 g of product (yield 92%). ESI-MS (M+H) + : 288.3.

[0153] Synthesis of 4-hydroxy-6-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyrazine-2-carboxylic acid (7). [ka] In a round-bottom flask, ethyl-4-hydroxy-6-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyrazine-2-carboxylate (66.6 g, 1.0 equivalent, 232 mmol) was suspended in methanol (1.2 L), and 1 M sodium hydroxide (27.9 g, 696 mL, 3.0 equivalents, 696 mmol) was added at room temperature. The mixture was stirred overnight at room temperature. The mixture was acidified to pH 2 with concentrated HCl and then filtered (filtration was very slow and difficult). The solid was washed with MeOH, transferred to a round-bottom flask, and stripped with acetonitrile. The resulting product was found to be a mixture of the methyl ester and salt (92.8 g, max 232 mmol). The solid was divided into two and subjected to repeated hydrolysis. In a round-bottom flask, methyl-4-hydroxy-6-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyrazine-2-carboxylate (46.0 g, 1.0 equivalent, 116 mmol) was suspended in methanol (1.2 L), and 13.9 g, 348 mL, 3.0 equivalents, 348 mmol, 1 M sodium hydroxide (13.9 g, 348 mL, 3.0 equivalents, 348 mmol) and 10 ml of water were added at room temperature. The mixture was stirred overnight at room temperature. The mixture was neutralized to pH 7 with concentrated HCl and then filtered (filtration was still difficult). The solid was washed with acetonitrile and dioxane, transferred to a round-bottom flask, and stripped with acetonitrile to obtain batch 1 of 4-hydroxy-6-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyrazine-2-carboxylic acid containing a large amount of salt (71.0 g, max 116 mmol, batch 1). The same procedure was repeated for the methyl ester of the second batch. In this case, the reaction mixture was acidified to pH 5 once the conversion was complete. This yielded 4-hydroxy-6-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyrazine-2-carboxylic acid (60.0 g, max 116 mmol, batch 1) containing many salts. ESI-MS (MH) +: 258.0.

[0154] Synthesis of 6-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4-ol (8). [ka] Preheated sulfolane (0.24 kg, 0.19 L, 30 equivalents, 2.0 mol) was placed in a three-necked flask and heated to 50°C. Then, 4-hydroxy-6-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyrazine-2-carboxylic acid (41.8 g, 1.0 equivalent, 68 mmol) and a few drops of concentrated sulfuric acid were added little by little. The reaction mixture was heated to 350°C (external heating, gentle reflux of sulfolane), and the transformation was checked every hour. After 4 hours, the reaction mixture was cooled to room temperature, diluted with DCM, and purified by filtration through a short plug of silica eluted with 3 L of heptane (fr1), 6 L of heptane:HCl 1:1 (fr2-3), 6 L of HCl (fr4-5), 4 L of DCM (fr6), and 6 L of DCM:MeOH 9:1 (fr7-8). The product (containing by-product 8a) (2.88 g, 20%) was isolated from fr7 as a brown solid. ESI-MS (MH) + : 214.1.

[0155] Synthesis of 4-chloro-6-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyrazine. [ka] In a round-bottom flask, 6-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4-ol (2.88 g, 1.0 equivalent, 13.4 mmol) was suspended in POCl3 (32.8 g, 19.9 mL, 16 equivalents, 214 mmol), and the reaction mixture was heated overnight at 80°C. The mixture was diluted with acetonitrile, concentrated, and the residue was suspended in DCM. The mixture was washed with saturated NaHCO3 and brine, dried over sodium sulfate, and concentrated. The crude product was purified by column chromatography (DCM: HCl / NEt 35% gradient 0-25%) to obtain the product (1.35 g, 43%) as a yellow solid. ESI-MS (M+H) + : 234.0.

[0156] [ka] Synthesis of 7-chloro-5-(methylthio)imidazo[1,2-c]pyrimidine hydrochloride (11). [ka] In a round-bottom flask, 6-chloro-2-(methylthio)pyrimidine-4-amine (150 g, 1 equivalent, 854 mmol) was dissolved in 1,4-dioxane (300 mL), and 2-chloroacetaldehyde (220 g, 0.18 L, 1.5 equivalents, 1.28 mol) was added. The mixture was stirred at 100°C. After 2 hours, a solid precipitated in the reaction mixture, and after 3 hours, the reaction products were examined by HPLC, indicating completion of the conversion. The reaction mixture was cooled to room temperature overnight. The suspension was cooled to 0°C, and the solid was filtered off to obtain the product (151 g, 75%) as a yellow solid. ESI-MS (M+H) + : 200.1.

[0157] Synthesis of 7-chloroimidazo[1,2-c]pyrimidine-5(6H)-one(12). [ka] In a three-necked flask, 7-chloro-5-(methylthio)imidazo[1,2-c]pyrimidine hydrochloride (52.2 g, 1 equivalent, 221 mmol) was suspended in MeOH (200 mL). A solution of potassium hydroxide (55.9 g, 4.5 equivalents, 996 mmol) in water (520 mL) was slowly added. The reaction mixture was heated under reflux for 3 hours and then confirmed by HPLC-MS. The starting material disappeared. The reaction mixture was cooled to room temperature overnight. The mixture was acidified to pH 6 with 1 M HCl, and the resulting suspension was filtered. The solid was washed with MeOH, then transferred to a round-bottom flask, suspended in ACN, and then concentrated. The product, 7-chloroimidazo[1,2-c]pyrimidine-5(6H)-one (28.55 g, 76%), was obtained in pure form as a white solid. ESI-MS (M+H) + : 170.1.

[0158] Synthesis of 7-(1-methyl-1H-pyrazole-4-yl)imidazo[1,2-c]pyrimidine-5(6H)-one(13). [ka] In a three-necked flask, 7-chloroimidazo[1,2-c]pyrimidine-5(6H)-one (40.0 g, 1 equivalent, 236 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (73.6 g, 1.5 equivalents, 354 mmol), and X-phos (11.2 g, 0.10 equivalents, 23.6 mmol) were dissolved in 2-propanol (1.8 L), and 2M potassium phosphate aqueous solution (150 g, 0.35 L, 3.0 equivalents, 708 mmol) was added. The mixture was purged with N2 for 15 minutes, then Pd2(dba)3 (10.8 g, 0.05 equivalents, 11.8 mmol) was added, and the mixture was refluxed overnight. HPLC-MS analysis of the reaction products indicated that the conversion was nearly complete. Pd2(dba)3 (5.0 g) and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (25.0 g) were added, and the mixture was refluxed overnight. HPLC-MS showed complete conversion. The reaction mixture was filtered to remove the palladium residue. The organic solvent was evaporated, and the residue was partitioned into water and a 1:1 mixture of heptane:siRNA. A white solid precipitated in both the organic and aqueous layers. The mixture was filtered off. The solid was washed with water, ethyl acetate, and acetonitrile, and dried under vacuum to obtain the product (32.8 g). The filtrate layers were separated. The organic phase was discarded, and the aqueous layer was cooled on an ice bath. The solution was treated with concentrated HCl while stirring to adjust the pH to 6. The resulting fine precipitate was collected, washed with H2O and Et2O, and dried under vacuum to obtain a separate amount of product (9.0 g). A total of 41.8 g (82%) of the product was obtained as a yellowish solid. ESI-MS (M+H) + : 215.0.

[0159] Synthesis of 5-chloro-7-(1-methyl-1H-pyrazole-4-yl)imidazo[1,2-c]pyrimidine. [ka] 7-(1-methyl-1H-pyrazole-4-yl)imidazo[1,2-c]pyrimidine-5(6H)-one (41.8 g, 1 equivalent, 194 mmol), anhydrous DCM (300 mL), and DIPEA (126 g, 0.17 L, 5 equivalents, 971 mmol) were placed in a round-bottom flask. After 5 minutes, the mixture was cooled to 0°C, and POCl3 (89.3 g, 54.1 mL, 3 equivalents, 583 mmol) was added dropwise over 5 minutes. The mixture was allowed to return to room temperature, diluted with DCM (150 mL), and then stirred at room temperature for 24 hours. The suspension was diluted with hexane, and the solid was recovered by filtration (66.0 g). The recovered solid was suspended in DCM:DIPEA (5:1, 500 mL). The mixture was stirred for 30 minutes, then saturated aqueous solution of NaHCO3 was added, and the mixture was stirred for 1 hour. The mixture was filtered with Celite, then the layers were separated, and the aqueous layer was extracted three times with DCM. The organic layer was dried over sodium sulfate and concentrated. The product 5-chloro-7-(1-methyl-1H-pyrazole-4-yl)imidazo[1,2-c]pyrimidine (22.5 g, 50%) was obtained as a yellow solid. ESI-MS (M+H) + : 234.0.

[0160] [ka] Synthesis of 4-methoxy-6-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyridine [ka] To a solution of 6-bromo-4-methoxypyrazolo[1,5-a]pyridine (8.0 g, 35 mmol) and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (8.8 g, 42 mmol) in water (30 mL) and dioxane (150 mL), K2CO3 (9.74 g, 70.5 mmol) and Pd(dppf)Cl2 (1.29 g, 1.76 mmol) were added, and the reaction mixture was stirred at 90°C under N2 for 2 hours. The reaction mixture was diluted with H2O (80 mL) and extracted with ELISA (100 mL x 2). The combined organic phase was dried over Na2SO4 and filtered. The filtrate was concentrated under vacuum, and the residue was purified by column chromatography (PE / HCl=1 / 1-0 / 1) on silica gel to obtain 4-methoxy-6-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyridine (8.0 g) as a white solid. ¹H NMR (400 MHz, CDCl3) δ: 8.27 (s, 1H), 7.86 (d, J=1.6 Hz, 1H), 7.74 (s, 1H), 7.61 (s, 1H), 6.62 (s, 1H), 6.47 (s, 1H), 4.00 (s, 3H), 3.97 (s, 3H)

[0161] Synthesis of 1,6-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyridine-4-ol [ka] A solution of 4-methoxy-6-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyridine (15 g, 65.7 mmol) in an aqueous HBr solution (100 mL, 48%) was stirred at 120°C for 48 hours. The reaction mixture was concentrated under vacuum, and the residue was quenched with saturated NaHCO3 to pH 8 and extracted with siRNA (3 × 80 mL). The combined organic layers were dried over Na2SO4 and filtered. The filtrate was concentrated to obtain the crude product, which was purified by column chromatography on silica gel (DCM / MeOH = 20 / 1-10 / 1) to obtain 6-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyridine-4-ol (13.0 g, yield 92%) as a gray solid. LCMS m / z = 215.0 (M+H)+

[0162] 2. Synthesis of 6-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyridine-4-yl=trifluoromethanesulfonate [ka] To a solution of 6-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyridine-4-ol (40 g, 136 mmol) in THF (600 mL), DIPEA (87.58 g, 678 mmol) and N-phenyl-bis(trifluoromethanesulfonimide) (72.63 g, 203 mmol) were added, and the reaction mixture was stirred at 20°C for 20 hours. The reaction mixture was diluted with H2O (500 mL) and extracted with siRNA (3 × 350 mL). The combined organic layers were dried over Na2SO4 and filtered. The filtrate was concentrated under vacuum, and the crude product was purified by column chromatography (PE / siRNA = 20 / 1-1 / 1) on silica gel to obtain 6-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyridine-4-yl=trifluoromethanesulfonate (32.0 g, yield 68%) as a yellow solid, and 10 g of crude product was obtained. LCMS m / z = 347.1 (M+H)+

[0163] C. Synthesis of Examples 1-236 Example 1: 1-[4-[6-(1-methylpyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl]oxy-1-piperidyl]propa-2-in-1-one. [ka]

[0164] Synthesis of tert-butyl=4-[6-(1-methylpyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl]oxypiperidine-1-carboxylate [ka] A solution of tert-butyl 4-hydroxypiperidine-1-carboxylate (664 mg, 3.30 mmol) in anhydrous DMF (10 mL) was cooled in an ice bath. Then, sodium hydride (396 mg, 9.90 mmol, 60% purity) was added in four portions with stirring. Stirring in the ice bath was continued for 45 minutes, during which time a pale yellow suspension was formed. To this mixture, 4-chloro-6-(1-methylpyrazole-4-yl)pyrazolo[1,5-a]pyrazine (701 mg, 3.00 mmol) was added in one dose, and the mixture instantly turned brownish-orange. Stirring was continued overnight at room temperature. The mixture was diluted with ELISA, and then water was carefully added. The mixture was transferred to a separatory funnel and the phases were separated. The aqueous phase was extracted again with ELISA, and the combined organic phase was washed with brine, dried over Na2SO4, filtered, and evaporated under vacuum. The residual material was purified using a 10g Si-SPE column (Rt=0.18, heptane / ethylacetate=1 / 1) to obtain tert-butyl=4-[6-(1-methylpyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl]oxypiperidine-1-carboxylate (1.30g, yield 98%, purity 90%) as a sticky yellow rubbery substance. LCMS: m / z = 399.0 (M+H + ).

[0165] Synthesis of 6-(1-methylpyrazole-4-yl)-4-(4-piperidyloxy)pyrazolo[1,5-a]pyrazine [ka] To a solution of tert-butyl=4-[6-(1-methylpyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl]oxypiperidine-1-carboxylate (1.17 g, 2.94 mmol) in DCM (5 mL), TFA (6.70 g, 58.8 mmol, 4.5 mL) was added at room temperature while stirring. Stirring was continued overnight. The mixture was diluted with MeOH, and the product was purified by elution with 2 M NH3-MeOH on a 10 g SCX column to obtain 6-(1-methylpyrazole-4-yl)-4-(4-piperidyloxy)pyrazolo[1,5-a]pyrazine (890 mg, yield 96%, purity 95%) as a pale yellow solid. LCMS: m / z = 299.0 (M+H + ).

[0166] Synthesis of 1-[4-[6-(1-methylpyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl]oxy-1-piperidyl]propa-2-in-1-one [ka] DIPEA (26 mg, 201 μmol, 35 μL) was added at room temperature with stirring to a solution of 6-(1-methylpyrazole-4-yl)-4-(4-piperidyloxy)pyrazolo[1,5-a]pyrazine (30 mg, 101 μmol) in DMF (1 mL) and propiolic acid (7.0 mg, 101 μmol, 6 μL). Then, T3P (128 mg, 201 μmol, 50% purity) was added with stirring. Stirring was continued overnight. The mixture was diluted with ethyl acetate and washed with water. The organic phase was dried over Na2SO4, filtered, and the filtrate was evaporated to dryness. This substance was dissolved in DMSO, filtered through a syringe filter, and purified by preparative HPLC (Waters XSelect CSH C18, 5 μm, 19 mm × 100 mm column, mobile phase H2O (A) and MeCN (B), and gradient 5-50% B (0.2% NH4OH final v / v% modifier), flow rate 30 mL / min) to obtain 1-[4-[6-(1-methylpyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl]oxy-1-piperidyl]propa-2-in-1-one (12.6 mg, purity 95%, yield 34%) as a white solid. LCMS: m / z = 351.0 (M+H + ). 1 H NMR (500 MHz, DMSO-d6) δ 8.76 (s, 1H), 8.20 (s, 1H), 7.98-8.04 (m, 2H), 6.83-6.92 (m, 1H), 5.55-5.69 (m, 1H), 4.57 (s, 1H), 3.95-4.06 (m, 1H), 3.88 (s, 3H), 3.72-3.86 (m, 2H), 3.50-3.61 (m, 1H), 2.12-2.20 (m, 1H), 2.02-2.11 (m, 1H), 1.82-1.91 (m, 1H), 1.73-1.81 (m, 1H).

[0167] Example 2: 1-(4-((6-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl)oxy)piperidine-1-yl)propa-2-en-1-one [ka]

[0168] 6-(1-methylpyrazole-4-yl)-4-(4-piperidyloxy)pyrazolo[1,5-a]pyrazine (30 mg, 101 μmol) and THF (1 mL) were placed in a 20 mL screw-top vial. Then, acryloyl chloride (12 μL, 151 μmol) was added with stirring, and a milky white suspension was instantly formed. Next, triethylamine (28 μL, 201 μmol) was added with stirring. After stirring at room temperature for 5 minutes, the volatile substances were evaporated, leaving a white solid. This substance was dissolved in DMSO, filtered through a syringe filter, and purified by preparative HPLC (Waters XSelect CSH C18, 5 μm, 19 mm × 100 mm column, mobile phase H2O (A) and MeCN (B), and gradient 5-50% B (0.2% NH4OH final v / v% modifier), flow rate 30 mL / min) to obtain 1-(4-((6-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl)oxy)piperidine-1-yl)propa-2-en-1-one (24.9 mg, purity 95%, yield 67%) as a white solid. LCMS: m / z = 353.0 (M+H + ). 1 H NMR (500 MHz, DMSO-d6) δ 8.75 (d, J =1.22Hz,1H),8.21(s,1H),8.01-8.03(m,2H),6.86-6.88(m,1H),6.83-6.90(m,1H),6.12(brdd,J = 2.44, 16.48 Hz, 1H), 5.67-5.73 (m, 1H), 5.60 (ddd, J =3.97,7.63,11.60Hz,1H),3.85-3.97(m,2H),3.89(s,3H),3.39-3.69(m,2H),1.98-2.21(m,2H), 1.59-1.91 (m, 2H).

[0169] Example 3: 6-(1-methyl-1H-pyrazole-4-yl)-4-((1-(vinylsulfonyl)piperidine-4-yl)oxy)pyrazolo[1,5-a]pyrazine [ka]

[0170] 6-(1-methyl-1H-pyrazole-4-yl)-4-((1-(vinylsulfonyl)piperidine-4-yl)oxy)pyrazolo[1,5-a]pyrazine was prepared in the same manner as in Example 2, except that acryloyl chloride was replaced with 2-chloroethane-sulfonyl chloride. The substance was purified by preparative HPLC (Waters XSelect CSH C18, 5 μm, 19 mm × 100 mm column, mobile phase H2O(A) and MeCN(B) and gradient 5-55% B (0.2% NH4OH final v / v% modifier), flow rate 30 mL / min) to obtain 6-(1-methyl-1H-pyrazole-4-yl)-4-((1-(vinylsulfonyl)piperidine-4-yl)oxy)pyrazolo[1,5-a]pyrazine (4.9 mg, purity 95%, yield 12%) as a white solid. LCMS: m / z = 389.0 (M+H + ). 1 H NMR (500 MHz, DMSO-d6) δ 8.75 (d, J =1.22Hz,1H),8.20(s,1H),8.02(d,J = 2.44 Hz, 1H), 8.01 (s, 1H), 6.89 (dd, J =10.38,16.48Hz,1H),6.85(d,J = 3.05 Hz, 1H), 6.20 (d, J =9.77Hz,1H),6.16(d,J = 17.09 Hz, 1H), 5.49 (ddd, J =3.66,7.63,11.29Hz,1H),3.88(s,3H),3.37-3.54(m,2H),3.18(m,2H),2.10-2.24(m,2H),1.79-1.96(m,2H).

[0171] Example 4: (R)-1-(3-((6-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl)oxy)piperidine-1-yl)propa-2-en-1-one [ka]

[0172] (R)-1-(3-((6-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl)oxy)piperidine-1-yl)propa-2-en-1-one was prepared in the same manner as in Example 2, except that it was started with (R)-tert-butyl=3-hydroxypiperidine-1-carboxylate. The substance was purified by preparative HPLC (Waters XSelect CSH C18, 5 μm, 19 mm × 100 mm column, mobile phase H2O (A) and MeCN (B), and gradient 5-50% B (0.2% NH4OH final v / v% modifier), flow rate 30 mL / min) to obtain (R)-1-(3-((6-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl)oxy)piperidine-1-yl)propa-2-en-1-one (23.1 mg, purity 95%, yield 67%) as a white powder. LCMS: m / z = 353.0 (M+H + ). 1 HNMR(500MHz,DMSO-d6) δ 8.76 (s, 1H), 8.28-8.33 (m, 1H), 8.14-8.22 (m, 1H), 7.97-8.03 (m, 1H), 6.67-6.77 (m, 1H), 6.52-6.97 (m, 1H), 5.92-6.15 (m, 1H), 5.42-5.74 (m, 1H), 5.19-5.40 (m, 1H), 3.88 (s, 3H), 3.59-4.27 (m, 4H), 1.47-2.22 (m, 4H).

[0173] Example 5: (R)-6-(1-methyl-1H-pyrazole-4-yl)-4-((1-(vinylsulfonyl)piperidine-3-yl)oxy)pyrazolo[1,5-a]pyrazine [ka]

[0174] (R)-6-(1-methyl-1H-pyrazole-4-yl)-4-((1-(vinylsulfonyl)piperidine-3-yl)oxy)pyrazolo[1,5-a]pyrazine was prepared in the same manner as in Example 3, except that it was started with (R)-tert-butyl=3-hydroxypiperidine-1-carboxylate. The substance was purified by preparative HPLC (Waters XSelect CSH C18, 5 μm, 19 mm × 100 mm column, mobile phase H2O (A) and MeCN (B), and gradient 5-55% B (0.2% NH4OH final v / v% modifier), flow rate 30 mL / min) to obtain (R)-6-(1-methyl-1H-pyrazole-4-yl)-4-((1-(vinylsulfonyl)piperidine-3-yl)oxy)pyrazolo[1,5-a]pyrazine (8.9 mg, purity 95%, yield 22%) as a white powder. LCMS: m / z = 389.0 (M+H + ). 1 H NMR (500 MHz, DMSO-d6) δ 8.78 (s, 1H), 8.21 (s, 1H), 8.03 (d, J =1.83Hz,1H),8.02(s,1H),6.84(d,J = 2.44 Hz, 1H), 6.78-6.88 (m, 1H), 6.11 (s, 1H), 6.08 (d, J =6.10Hz,1H),5.38(ddd,J = 3.66, 7.17, 10.53 Hz, 1H), 3.88 (s, 3H), 3.74 (br dd, J =3.66,12.21Hz,1H),3.46(brd, J = 18.31 Hz, 1H), 3.21-3.29 (m, 1H), 3.11 (ddd, J =3.36,8.09,11.75Hz,1H),2.05(ddd,J = 3.66, 8.39, 12.36 Hz, 1H), 1.89-1.98 (m, 1H), 1.79-1.88 (m, 1H), 1.71 (tdd, J =4.04,8.47,17.01Hz,1H).

[0175] Example 6: (S)-6-(1-methyl-1H-pyrazole-4-yl)-4-((1-(vinylsulfonyl)piperidine-3-yl)oxy)pyrazolo[1,5-a]pyrazine [ka]

[0176] (S)-6-(1-methyl-1H-pyrazole-4-yl)-4-((1-(vinylsulfonyl)piperidine-3-yl)oxy)pyrazolo[1,5-a]pyrazine was prepared in the same manner as in Example 3, except that the starter was (S)-tert-butyl=3-hydroxypiperidine-1-carboxylate. The substance was purified by preparative HPLC (Waters XSelect CSH C18, 5 μm, 19 mm × 100 mm column, mobile phase H2O(A) and MeCN(B) and gradient 5-55% B (0.2% NH4OH final v / v% modifier), flow rate 30 mL / min) to obtain (S)-6-(1-methyl-1H-pyrazole-4-yl)-4-((1-(vinylsulfonyl)piperidine-3-yl)oxy)pyrazolo[1,5-a]pyrazine (8.0 mg, purity 95%, yield 18%). LCMS: m / z = 389.0 (M+H + ). 1 H NMR (500 MHz, DMSO-d6) δ 8.78 (s, 1H), 8.21 (s, 1H), 8.03 (d, J =1.83Hz,1H),8.02(s,1H),6.84(d,J = 2.44 Hz, 1H), 6.79-6.86 (m, 1H), 6.11 (s, 1H), 6.08 (d, J =6.10Hz,1H),5.38(tt,J = 3.59, 7.10 Hz, 1H), 3.88 (s, 3H), 3.74 (dd, J =3.36,11.90Hz,1H),3.48(brs, 1H), 3.21-3.29 (m, 1H), 3.11 (ddd, J =3.36,8.09,11.75Hz,1H),2.05(ddd,J = 3.97, 8.24, 12.21 Hz, 1H), 1.89-1.98 (m, 1H), 1.80-1.89 (m, 1H), 1.65-1.76 (m, 1H).

[0177] Example 7: (R)-1-(3-((6-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl)oxy)piperidine-1-yl)propa-2-in-1-one [ka]

[0178] Synthesis of (R)-tert-butyl=3-[6-(1-methylpyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl]oxypiperidine-1-carboxylate [ka] A solution of (R)-tert-butyl=3-hydroxypiperidine-1-carboxylate (221 mg, 1.10 mmol) in anhydrous DMF (3 mL) was cooled in an ice bath. Then, sodium hydride (132 mg, 3.30 mmol, 60% purity) was added in two batches with stirring. Stirring in the ice bath was continued for 45 minutes, during which time a pale yellow suspension was formed. To this mixture, 4-chloro-6-(1-methylpyrazole-4-yl)pyrazolo[1,5-a]pyrazine (234 mg, 1.00 mmol) was added in one batch, and the mixture instantly turned orange-brown. Stirring was continued overnight at room temperature. The mixture was diluted with ELISA, and then water was carefully added. The mixture was transferred to a separatory funnel and the phases were separated. The aqueous phase was extracted again with ELISA, and the combined organic phase was washed with brine, dried over Na2SO4, filtered, and evaporated under vacuum. The residual material was purified using a 10g Si-SPE column (Rt=0.22, heptane / ethylacetate=1 / 1) to obtain (R)-tert-butyl=3-[6-(1-methylpyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl]oxypiperidine-1-carboxylate (390 mg, yield 88%, purity 90%) as a colorless, viscous, rubbery substance. LCMS: m / z = 399.0 (M+H + ).

[0179] Synthesis of (R)-6-(1-methylpyrazole-4-yl)-4-(3-piperidyloxy)pyrazolo[1,5-a]pyrazine [ka] To a solution of (R)-tert-butyl=3-[6-(1-methylpyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl]oxypiperidine-1-carboxylate (390 mg, 979 μmol) in anhydrous DCM (3 mL), TFA (2.23 g, 19.58 mmol, 1.50 mL) was added at room temperature with stirring. After stirring overnight at room temperature, the mixture was diluted with MeOH, and the product was purified by elution with 2 M NH3-MeOH on a 5 g SCX column to obtain (R)-6-(1-methylpyrazole-4-yl)-4-(3-piperidyloxy)pyrazolo[1,5-a]pyrazine (270 mg, yield 88%, purity 95%) as a colorless, rubbery substance. LCMS: m / z = 299.0 (M+H + ).

[0180] Synthesis of (R)-1-(3-((6-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl)oxy)piperidine-1-yl)propa-2-in-1-one [ka] To a solution of (R)-6-(1-methylpyrazole-4-yl)-4-(3-piperidyloxy)pyrazolo[1,5-a]pyrazine (30 mg, 101 μmol) in DMF (1 mL), propiolic acid (7.0 mg, 101 μmol, 6 μL), followed by DIPEA (26 mg, 201 μmol, 35 μL), was added at room temperature with stirring. Then, T3P (128 mg, 201 μmol, 50% purity) was added with stirring. Stirring at room temperature was continued overnight. The mixture was diluted with ethyl acetate and washed with water. The organic phase was dried over Na2SO4 and filtered. The filtrate was evaporated under vacuum, and the residual material was redissolved in DMSO. The substance was purified by preparative HPLC (Waters XSelect CSH C18, 5 μm, 19 mm × 100 mm column, mobile phase H2O (A) and MeCN (B), and gradient 5-50% B (0.2% NH4OH final v / v% modifier), flow rate 30 mL / min) to obtain (R)-1-(3-((6-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl)oxy)piperidine-1-yl)propa-2-in-1-one (20.6 mg, purity 95%, yield 55%) as a white powder. LCMS: m / z = 350.1 (M+H + ). 1 HNMR(500MHz,DMSO-d6)δ8.75-8.77(m,1H),8.02(d,J = 1.83 Hz, 1H), 8.00-8.27 (m, 2H), 6.76-6.77 (m, 1H), 5.26-5.49 (m, 1H), 4.13-4.61 (m, 1H), 3.90-4.33 (m, 1H), 3.88 (s, 3H), 3.70-3.84 (m, 1H), 3.44-3.62 (m, 1H), 3.15-3.30 (m, 1H), 1.53-2.18 (m, 4H).

[0181] Example 8: (Z)-4-chloro-1-(4-((6-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl)oxy)piperidine-1-yl)buta-2-en-1-one [ka]

[0182] Synthesis of (Z)-4-chloro-1-(4-((6-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl)oxy)piperidine-1-yl)buta-2-en-1-one [ka] 6-(1-methylpyrazole-4-yl)-4-(4-piperidyloxy)pyrazolo[1,5-a]pyrazine (30 mg, 100 μmol) and DMF (1 mL) were placed in a 20 mL screw-top vial. (Z)-4-chlorobuta-2-enoic acid (15.5 mg, 120 μmol) was then added with stirring, and a milky white suspension was instantly formed. HATU (57.7 mg, 150 μmol) was then added, and the mixture was stirred at room temperature for 5 minutes. DIPEA (35 μL, 201 μmol) was then added with stirring. Stirring at room temperature was continued overnight. The mixture was diluted with ELISA and washed with water. The organic phase was dried over Na2SO4 and filtered. The filtrate was evaporated under vacuum, and the residual material was dissolved in DMSO. Purification by preparative HPLC (Waters XSelect CSH C18, 5 μm, 19 mm × 100 mm column, mobile phase H2O (A) and MeCN (B), and gradient 5-55% B (0.2% NH4OH final v / v% modifier), flow rate 30 mL / min) yielded (Z)-4-chloro-1-(4-((6-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl)oxy)piperidine-1-yl)buta-2-en-1-one (17.8 mg, purity 95%, yield 42%) as a white powder. LCMS: m / z = 400.1. 1H NMR (500 MHz, DMSO-d6) δ 8.76 (s, 1H), 8.21 (s, 1H), 8.00-8.03 (m, 2H), 6.88 (d, J =1.22Hz,1H),6.84-6.87(m,1H),6.65-6.72(m,1H),5.61(ddd,J = 3.66, 7.48, 11.44 Hz, 1H), 4.38 (dd, J =1.22,6.71Hz,2H),3.89(s,3H),3.44-3.69(m,4H),2.00-2.17(m,2H),1.67-1.86(m,2H).

[0183] Example 9: 1-(3-((6-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl)oxy)azetidine-1-yl)propa-2-en-1-one [ka]

[0184] Synthesis of tert-butyl=3-[6-(1-methylpyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl]oxyazetidine-1-carboxylate [ka] A solution of tert-butyl=3-hydroxyazetidine-1-carboxylate (191 mg, 1.10 mmol) in anhydrous DMF (3 mL) was cooled in an ice bath. Then, sodium hydride (132 mg, 3.30 mmol, 60% purity) was added in two batches with stirring. Stirring in the ice bath was continued for 45 minutes, during which time a pale yellow suspension was formed. To this mixture, 4-chloro-6-(1-methylpyrazole-4-yl)pyrazolo[1,5-a]pyrazine (234 mg, 1.00 mmol) was added in one batch, and the mixture instantly turned orange-brown. Stirring was continued overnight at room temperature. The mixture was diluted with ELISA, and then water was carefully added. The mixture was transferred to a separatory funnel and the phases were separated. The aqueous phase was extracted again with ELISA, and the combined organic phase was washed with brine, dried over Na2SO4, filtered, and evaporated under vacuum. The residual material was purified using a 10g Si-SPE column (Rt=0.0.18, heptane / ethylacetate=1 / 1) to obtain tert-butyl=3-[6-(1-methylpyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl]oxyazetidine-1-carboxylate (380mg, yield 97%, purity 95%) as a colorless, viscous, rubbery substance. ESI-MS (M+H) + : 371.0.

[0185] Synthesis of 4-(azetidine-3-yloxy)-6-(1-methylpyrazole-4-yl)pyrazolo[1,5-a]pyrazine [ka] To a solution of tert-butyl=3-[6-(1-methylpyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl]oxyazetidine-1-carboxylate (380 mg, 1.03 mmol) in DCM (5 mL), TFA (2.34 g, 20.5 mmol, 1.57 mL) was added at room temperature while stirring. Stirring was continued overnight. The mixture was diluted with MeOH, and the product was purified by elution with 2 M NH3-MeOH on a 10 g SCX column to obtain 4-(azetidine-3-yloxy)-6-(1-methylpyrazole-4-yl)pyrazolo[1,5-a]pyrazine (250 mg, yield 85%, purity 95%) as a white solid. ESI-MS (M+H) + : 271.0.

[0186] Synthesis of 1-(3-((6-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl)oxy)azetidine-1-yl)propa-2-en-1-one [ka] 1-(3-((6-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl)oxy)azetidine-1-yl)propa-2-en-1-one was prepared in the same manner as in Example 2. The substance was purified by preparative HPLC (Waters XSelect CSH C18, 5 μm, 19 mm × 100 mm column, mobile phase H2O (A) and MeCN (B), and gradient 5-45% B (0.2% NH4OH final v / v% modifier), flow rate 30 mL / min) to obtain 1-(3-((6-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl)oxy)azetidine-1-yl)propa-2-en-1-one (20 mg, purity 95%, yield 64%) as a white powder. LCMS: m / z = 325.0. 1H NMR (500 MHz, DMSO-d6) δ 8.82 (s, 1H), 8.24 (s, 1H), 8.06 (d, J =2.44Hz,1H),8.03(s,1H),6.90-6.92(m,1H),6.38(dd,J = 10.38, 17.09 Hz, 1H), 6.11-6.17 (m, 1H), 5.70 (dd, J =2.44,10.38Hz,1H),5.62(tt,J = 4.27, 6.71 Hz, 1H), 4.83 (br dd, J =6.71,9.16Hz,1H),4.52(brdd,J = 7.02, 11.29Hz, 1H), 4.37 (br dd, J =3.66,9.77Hz,1H),4.08(brdd,J = 3.66, 11.60 Hz, 1H), 3.89 (s, 3H).

[0187] Example 10: (Z)-6-(1-methyl-1H-pyrazole-4-yl)-4-((1-(propa-1-en-1-ylsulfonyl)azetidine-3-yl)oxy)pyrazolo[1,5-a]pyrazine [ka]

[0188] (Z)-6-(1-methyl-1H-pyrazole-4-yl)-4-((1-(propa-1-en-1-ylsulfonyl)azetidine-3-yl)oxy)pyrazolo[1,5-a]pyrazine was prepared in the same manner as in Example 9, except that (Z)-propa-1-en-1-sulfonyl chloride was used instead of acryloyl chloride. The substance was purified by preparative HPLC (Waters XSelect CSH C18, 5 μm, 19 mm × 100 mm column, mobile phase H2O (A) and MeCN (B), and gradient 5-55% B (0.2% NH4OH final v / v% modifier), flow rate 30 mL / min) to obtain (Z)-6-(1-methyl-1H-pyrazole-4-yl)-4-((1-(propa-1-en-1-ylsulfonyl)azetidine-3-yl)oxy)pyrazolo[1,5-a]pyrazine (10 mg, purity 95%, yield 28%) as a beige solid. LCMS: m / z = 374.0. 1 H NMR (500 MHz, DMSO-d6) δ 8.82 (s, 1H), 8.23-8.27 (s, 1H), 8.06 (d, J =2.44Hz,1H),7.98-8.04(s,1H),6.87-6.92(m,1H),6.72-6.84(m,2H),5.4 2-5.56(m,1H),4.31-4.45(m,2H),3.92-4.04(m,2H),3.88(s,3H),1.95(d,J = 4.88 Hz, 3H).

[0189] Example 11: (R)-1-(3-((6-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl)oxy)pyrrolidine-1-yl)propa-2-en-1-one [ka]

[0190] Synthesis of tert-butyl=(3R)-3-[6-(1-methylpyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl]oxypyrrolidine-1-carboxylate [ka] A solution of tert-butyl(3R)-3-hydroxypyrrolidine-1-carboxylate (193 mg, 1.03 mmol) in anhydrous DMF (3 mL) was cooled in an ice bath. Then, sodium hydride (136 mg, 3.40 mmol, 60% purity) was added in four portions with stirring. Stirring in the ice bath was continued for 45 minutes, during which time a pale yellow suspension was formed. To this mixture, 4-chloro-6-(1-methylpyrazole-4-yl)pyrazolo[1,5-a]pyrazine (240 mg, 1.03 mmol) was added in one portion, and the mixture instantly turned orange-brown. Stirring was continued overnight at room temperature. The mixture was diluted with ELISA, and then water was carefully added. The mixture was transferred to a separatory funnel and the phases were separated. The aqueous phase was extracted again with ELISA, and the combined organic phase was washed with brine, dried over Na2SO4, filtered, and evaporated under vacuum. The residual substance was purified using a 10g Si-SPE column with heptane / ethyl acetate at a ratio of 1 / 1 to obtain tert-butyl=(3R)-3-[6-(1-methylpyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl]oxypyrrolidine-1-carboxylate (345 mg, yield 83%, purity 95%) as a sticky, colorless, rubbery substance. Further drying of this substance yielded a sticky, white, foamy substance. ESI-MS (M+H)+: 395.0.

[0191] Synthesis of 6-(1-methylpyrazole-4-yl)-4-[(3R)-pyrrolidine-3-yl]oxypyrazolo[1,5-a]pyrazine [ka] To a solution of tert-butyl=(3R)-3-[6-(1-methylpyrazole-4-yl)pyrazole[1,5-a]pyrazine-4-yl]oxypyrrolidine-1-carboxylate (326 mg, 849 μmol) in DCM (5 mL), TFA (1.93 g, 17 mmol, 1.30 mL) was added at room temperature while stirring. Stirring was continued overnight. The mixture was diluted with MeOH, and the product was purified by elution with 2 M NH3-MeOH on a 10 g SCX column to obtain 6-(1-methylpyrazole-4-yl)-4-[(3R)-pyrrolidine-3-yl]oxypyrazole[1,5-a]pyrazine (230 mg, yield 91%, purity 95%) as a sticky, pale yellow, rubbery substance. ESI-MS (M+H)+: 285.0.

[0192] Synthesis of (R)-1-(3-((6-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl)oxy)pyrrolidine-1-yl)propa-2-en-1-one [ka] (R)-1-(3-((6-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl)oxy)pyrrolidine-1-yl)propa-2-en-1-one was prepared in the same manner as in Example 2. The substance was purified by preparative HPLC (Waters XSelect CSH C18, 5 μm, 19 mm × 100 mm column, mobile phase H2O (A) and MeCN (B), and gradient 5-45% B (0.2% NH4OH final v / v% modifier), flow rate 30 mL / min) to obtain (R)-1-(3-((6-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl)oxy)pyrrolidine-1-yl)propa-2-en-1-one (27.9 mg, purity 95%, yield 74%) as a white solid. ESI-MS (M+H)+: 339.0. 1H NMR (500 MHz, DMSO-d6) δ 8.78 (s, 1H), 8.21-8.26 (m, 1H), 8.03 (d, J =1.83Hz,1H),8.00-8.02(m,1H),6.84(brd, J = 1.22 Hz, 1H), 6.54-6.69 (m, 1H), 6.12-6.20 (m, 1H), 5.81-5.94 (m, 1H), 5.64-5.73 (m, 1H), 3.89 (s, 3H), 3.82-4.11 (m, 1H), 3.65-3.78 (m, 1H), 3.43-3.59 (m, 2H), 2.19-2.47 (m, 2H).

[0193] Example 12: (R)-6-(1-methyl-1H-pyrazole-4-yl)-4-((1-(vinylsulfonyl)pyrrolidine-3-yl)oxy)pyrazolo[1,5-a]pyrazine [ka]

[0194] (R)-6-(1-methyl-1H-pyrazole-4-yl)-4-((1-(vinylsulfonyl)pyrrolidine-3-yl)oxy)pyrazolo[1,5-a]pyrazine was prepared in the same manner as in Example 11, except that acryloyl chloride was replaced with 2-chloroethane-sulfonyl chloride. The substance was purified by preparative HPLC (Waters XSelect CSH C18, 5 μm, 19 mm × 100 mm column, mobile phase H2O (A) and MeCN (B), and gradient 5-50% B (0.2% NH4OH final v / v% modifier), flow rate 30 mL / min) to obtain (R)-6-(1-methyl-1H-pyrazole-4-yl)-4-((1-(vinylsulfonyl)pyrrolidine-3-yl)oxy)pyrazolo[1,5-a]pyrazine (6.6 mg, purity 95%, yield 16%) as a white solid. ESI-MS (M+H)+: 375.0. 1H NMR (500 MHz, DMSO-d6) δ 8.78 (s, 1H), 8.22 (s, 1H), 8.03 (d, J =2.44Hz,1H),8.00-8.02(m,1H),6.92(dd,J = 10.38, 16.48 Hz, 1H), 6.85-6.86 (m, 1H), 6.07-6.12 (m, 1H), 6.05 (d, J =9.77Hz,1H),5.78-5.84(m,1H),3.88(s,3H),3.39-3.75(m,4H),2.20-2.39(m,2H).

[0195] Example 13: (R)-1-(3-((6-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl)oxy)pyrrolidine-1-yl)propa-2-in-1-one [ka]

[0196] (R)-1-(3-((6-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl)oxy)pyrrolidine-1-yl)propa-2-in-1-one was prepared in the same manner as in Example 1. The substance was purified by preparative HPLC (Waters XSelect CSH C18, 5 μm, 19 mm × 100 mm column, mobile phase H2O (A) and MeCN (B), and gradient 5-45% B (0.2% NH4OH final v / v% modifier), flow rate 30 mL / min) to obtain (R)-1-(3-((6-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl)oxy)pyrrolidine-1-yl)propa-2-in-1-one (18.2 mg, purity 95%, yield 51%) as a white solid. ESI-MS (M+H)+: 337.0. 1H NMR (500 MHz, DMSO-d6) δ 8.77-8.81 (m, 1H), 8.21-8.26 (m, 1H), 8.00-8.06 (m, 2H), 6.86 (d, J =2.44Hz,1H),5.81-5.91(m,1H),4.43-4.58(m,1H),3.86-3.91(m,1H),3.86(s,3H),3.40-3.71(m,3H),2.20-2.47(m,2H).

[0197] Example 14: (S)-1-(3-(((6-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl)oxy)methyl)piperidine-1-yl)propa-2-en-1-one [ka]

[0198] Synthesis of tert-butyl=(3S)-3-[[6-(1-methylpyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl]oxymethyl]piperidine-1-carboxylate [ka] A solution of tert-butyl=(3S)-3-(hydroxymethyl)piperidine-1-carboxylate (222 mg, 1.03 mmol) in anhydrous DMF (3 mL) was cooled in an ice bath. Then, sodium hydride (136 mg, 3.40 mmol, 60% purity) was added in four portions with stirring. Stirring in the ice bath was continued for 45 minutes, during which time a pale yellow suspension was formed. To this mixture, 4-chloro-6-(1-methylpyrazole-4-yl)pyrazolo[1,5-a]pyrazine (240 mg, 1.03 mmol) was added in one dose, and the mixture instantly turned orange-brown. Stirring was continued overnight at room temperature. The mixture was diluted with ELISA, and then water was carefully added. The mixture was transferred to a separatory funnel and the phases were separated. The aqueous phase was extracted again with ELISA, and the combined organic phase was washed with brine, dried over Na2SO4, filtered, and evaporated under vacuum. The residual substance was purified using a 10g Si-SPE column (Rt=0.1, heptane / ethylacetate=2 / 1) to obtain tert-butyl(3S)-3-[[6-(1-methylpyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl]oxymethyl]piperidine-1-carboxylate (386 mg, yield 86%, purity 95%) as an off-white solid. ESI-MS (M+H)+: 413.0.

[0199] Synthesis of 6-(1-methylpyrazole-4-yl)-4-[[(3S)-3-piperidyl]methoxy]pyrazolo[1,5-a]pyrazine [ka] To a solution of tert-butyl=(3S)-3-[[6-(1-methylpyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl]oxymethyl]piperidine-1-carboxylate (404 mg, 978 μmol) in DCM (5 mL), TFA (2.23 g, 19.6 mmol, 1.50 mL) was added at room temperature while stirring. Stirring was continued overnight. The mixture was diluted with MeOH, and the product was purified by elution with 2 M NH3-MeOH on a 10 g SCX column to obtain 6-(1-methylpyrazole-4-yl)-4-[[(3S)-3-piperidyl]methoxy]pyrazolo[1,5-a]pyrazine (240 mg, yield 75%, purity 95%) as a pale yellow, sticky, rubbery substance. Further drying of this substance resulted in the formation of a white, foamy substance. ESI-MS (M+H)+: 313.0.

[0200] Synthesis of (S)-1-(3-(((6-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl)oxy)methyl)piperidine-1-yl)propa-2-en-1-one [ka] (S)-1-(3-(((6-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl)oxy)methyl)piperidine-1-yl)propa-2-en-1-one was prepared in the same manner as in Example 2. The substance was purified by preparative HPLC (Waters XSelect CSH C18, 5 μm, 19 mm × 100 mm column, mobile phase H2O (A) and MeCN (B), and gradient 5-50% B (0.2% NH4OH final v / v% modifier), flow rate 30 mL / min) to obtain (S)-1-(3-(((6-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl)oxy)methyl)piperidine-1-yl)propa-2-en-1-one (10.6 mg, purity 95%, yield 28%) as a white powder. ESI-MS (M+H)+: 367.0. 1H NMR (500 MHz, DMSO-d6) δ 8.76 (s, 1H), 8.21 (br s, 1H), 8.03 (d, J =2.44Hz,1H),8.01(s,1H),6.85-6.92(m,1H),6.77-6.84(m,1H),5.96-6.10(m,1H),5.54-5.67(m,1H),4.41-4. 50(m,2H),3.90-4.13(m,1H),3.89(s,3H),2.89-3.29(m,3H),1.88-2.07(m,2H),1.73(s,1H),1.35-1.57(m,2H).

[0201] Example 15: (S)-6-(1-methyl-1H-pyrazole-4-yl)-4-((1-(vinylsulfonyl)piperidine-3-yl)methoxy)pyrazolo[1,5-a]pyrazine [ka]

[0202] (S)-6-(1-methyl-1H-pyrazole-4-yl)-4-((1-(vinylsulfonyl)piperidine-3-yl)methoxy)pyrazolo[1,5-a]pyrazine was prepared in the same manner as in Example 14, except that acryloyl chloride was replaced with 2-chloroethanesulfonyl chloride. The substance was purified by preparative HPLC (Waters SunFire Prep C18, 5 μm, OBD 19 mm × 100 mm column, mobile phase H2O (A) and MeCN (B), and gradient 5-55% B (0.1% TFA final v / v% modifier), flow rate 30 mL / min) to obtain (S)-6-(1-methyl-1H-pyrazole-4-yl)-4-((1-(vinylsulfonyl)piperidine-3-yl)methoxy)pyrazolo[1,5-a]pyrazine (8.0 mg, purity 95%, yield 19%) as a beige solid. ESI-MS (M+H)+: 403.0. 1H NMR (500 MHz, DMSO-d6) δ 8.77 (s, 1H), 8.21 (s, 1H), 8.03 (d, J =2.44Hz,1H),8.01(s,1H),6.84(d,J = 3.05 Hz, 1H), 6.76-6.84 (m, 1H), 6.13 (d, J =9.77Hz,1H),6.09(d,J = 16.48 Hz, 1H), 4.42-4.52 (m, 2H), 3.89 (s, 3H), 3.63 (br dd, J =3.66,11.60Hz,1H),3.38-3.55(m,2H),2.59-2.74(m,1H),2.12-2.28(m,1H),1.84-1.95(m,1H),1.79(td,J = 3.66, 13.43 Hz, 1H), 1.50-1.64 (m, 1H), 1.18-1.38 (m, 1H).

[0203] Example 16: (S)-1-(3-(((6-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl)oxy)methyl)piperidine-1-yl)propa-2-in-1-one [ka]

[0204] (S)-1-(3-(((6-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl)oxy)methyl)piperidine-1-yl)propa-2-in-1-one was prepared in the same manner as in Example 1. The substance was purified by preparative HPLC (Waters XSelect CSH C18, 5 μm, 19 mm × 100 mm column, mobile phase H2O (A) and MeCN (B), and gradient 5-55% B (0.2% NH4OH final v / v% modifier), flow rate 30 mL / min) to obtain (S)-1-(3-(((6-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl)oxy)methyl)piperidine-1-yl)propa-2-in-1-one (24.8 mg, purity 95%, yield 68%) as a white solid. ESI-MS (M+H)+: 365.0. 1H NMR (500 MHz, DMSO-d6) δ 8.74-8.78 (m, 1H), 8.21 (s, 1H), 7.96-8.07 (m, 2H), 6.78-6.90 (m, 1H), 4.52-4.55 (m, 1H), 4.27-4.51 (m, 2H), 4.01-4.17 (m, 1H), 3.89 (s, 3H), 3.22-3.32 (m, 1H), 2.78-2.98 (m, 2H), 1.98-2.21 (m, 1H), 1.88-1.95 (m, 1H), 1.67-1.83 (m, 1H), 1.28-1.55 (m, 2H).

[0205] Example 17: (R,E)-6-(1-methyl-1H-pyrazole-4-yl)-4-((1-(propa-1-en-1-ylsulfonyl)piperidine-3-yl)oxy)pyrazolo[1,5-a]pyrazine [ka]

[0206] 1. Synthesis of (R,E)-6-(1-methyl-1H-pyrazole-4-yl)-4-((1-(propa-1-en-1-ylsulfonyl)piperidine-3-yl)oxy)pyrazolo[1,5-a]pyrazine [ka] 6-(1-methylpyrazole-4-yl)-4-[[(3R)-3-piperidyl]oxy]pyrazolo[1,5-a]pyrazine (125 mg, 419 μmol), DCM (2.1 mL), N-ethyl-N-isopropyl-propan-2-amine (162 mg, 1.26 mmol, 220 μL), and (E)-propa-1-en-1-sulfonyl chloride (88 mg, 628 μmol, 66 μL) were added to the vial in that order. The vial was stirred overnight at room temperature. The reaction mixture was diluted with water, passed through a phase separator, and concentrated. The substance was dissolved in 2.5 mL of DMSO and passed through a syringe filter. The substance was purified by reverse-phase HPLC (Waters XSelect CSH C18, 5 μm, 19 mm × 100 mm column, mobile phase H2O (A) and MeCN (B), and gradient 5-60% B (0.2% NH4OH final v / v% modifier), flow rate 30 mL / min) to obtain 6-(1-methylpyrazole-4-yl)-4-[[(3R)-1-[(E)-propa-1-enyl]sulfonyl-3-piperidyl]oxy]pyrazolo[1,5-a]pyrazine (55 mg, yield: 30%) as an off-white solid. ESI-MS (M+H) + : 403.1. 1 H NMR (500 MHz, DMSO-d6) δ 8.78 (s, 1H), 8.21 (s, 1H), 7.99-8.06 (m, 1H), 6.84 (dd, J =1.22,2.44Hz,1H),6.61(brd, J = 6.71 Hz, 1H), 6.46-6.54 (m, 1H), 5.38 (td, J =3.89,7.48Hz,1H),3.88(s,3H),3.72(brdd,J = 3.36, 11.90 Hz, 1H), 3.12-3.28 (m, 2H), 3.05 (ddd, J =3.36,8.09,11.75Hz,1H),2.02-2.08(m,1H),1.90-1.98(m,2H),1.85(dd,J = 1.83, 6.71 Hz, 3H), 1.71 (ddd, J =4.58,8.55,13.12Hz,2H).

[0207] Example 18: 1-(4-(((6-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl)amino)methyl)piperidine-1-yl)propa-2-en-1-one [ka]

[0208] 1. Synthesis of tert-butyl=4-(((6-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl)amino)methyl)piperidine-1-carboxylate [ka] To a suspension of 4-chloro-6-(1-methylpyrazole-4-yl)pyrazolo[1,5-a]pyrazine (500 mg, 2.14 mmol) and tert-butyl=4-(aminomethyl)piperidine-1-carboxylate (504 mg, 2.35 mmol, 500 μL) in DMF (7.13 mL), Hünig base (553 mg, 4.28 mmol, 750 μL) was added. The reaction mixture was heated to 70°C and stirred overnight. The reaction mixture was concentrated and purified by column chromatography (40 g silica column, 0-100% HCl:heptane gradient elution) to obtain tert-butyl=4-[[[6-(1-methylpyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl]amino]methyl]piperidine-1-carboxylate (398 mg, yield: 45%) as a brown solid. ESI-MS (M+H) + : 412.2.

[0209] 2. Synthesis of 6-(1-methyl-1H-pyrazole-4-yl)-N-(piperidine-4-ylmethyl)pyrazolo[1,5-a]pyrazine-4-amine [ka] 397 mg, 965 μmol of tert-butyl=4-[[[6-(1-methylpyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl]amino]methyl]piperidine-1-carboxylate was dissolved in 4.8 mL of dimethylcellulose (DCM). 1.10 g, 9.65 mmol, 738 μL of TFA was added, and the reaction mixture was stirred overnight at room temperature. The reaction mixture was concentrated, diluted with DCM, and carefully quenched with saturated sodium bicarbonate solution. The aqueous layer was washed twice with DCM, then diluted with saturated ammonium hydroxide solution, and extracted twice with ethyl acetate. The combined ethyl acetate layers were washed with brine, dried over magnesium sulfate, filtered, and concentrated to obtain 6-(1-methylpyrazole-4-yl)-N-(4-piperidylmethyl)pyrazolo[1,5-a]pyrazine-4-amine (300 mg, yield: 100%) as a pale yellow oily solid. ESI-MS (M+H) + : 312.1.

[0210] 3. Synthesis of 1-(4-(((6-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl)amino)methyl)piperidine-1-yl)propa-2-en-1-one [ka] A vial containing 6-(1-methylpyrazole-4-yl)-N-(4-piperidylmethyl)pyrazolo[1,5-a]pyrazine-4-amine (75 mg, 241 μmol) was mixed with DCM (2.4 mL) and TEA (73 mg, 725 μmol, 100 μL), and the mixture was then placed on a dry ice / acetone bath for 10 minutes. Acryloyl chloride (28 mg, 313 μmol, 26 μL) was added dropwise to the solution. The reaction mixture was stirred for 10 minutes. The reaction mixture was diluted with water and passed through a phase separator. The aqueous layer was extracted by DCM, the combined organic layer was concentrated and dissolved in DMSO, and purified by reverse-phase HPLC (Waters XSelect CSH C18, 5 μm, 19 mm × 100 mm column, mobile phase H2O (A) and MeCN (B), and gradient 5-35% B (0.2% NH4OH final v / v% modifier), flow rate 30 mL / min) to obtain 1-[4-[[[6-(1-methylpyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl]amino]methyl]-1-piperidyl]propa-2-en-1-one (35 mg, yield: 39%) as a yellow solid. ESI-MS (M+H) + : 366.2. 1 H NMR (500 MHz, DMSO-d6) δ 8.27 (s, 1H), 8.09 (s, 1H), 7.92 (s, 1H), 7.84 (d, J =2.44Hz,1H),7.64(brt, J = 5.49 Hz, 1H), 6.93-6.97 (m, 1H), 6.80 (br dd, J =10.68,16.79Hz,1H),6.07(brdd,J = 2.44, 17.09 Hz, 1H), 5.61-5.68 (m, 1H), 4.42 (br d, J =12.21Hz,1H),4.06(brd, J = 12.82 Hz, 1H), 3.87 (s, 3H), 3.40-3.50 (m, 1H), 2.97-3.10 (m, 1H), 2.59-2.67 (m, 1H), 1.99 (ddd, J =3.97,7.17,10.83Hz,2H),1.81(brd, J = 13.43 Hz, 2H), 1.06-1.22 (m, 2H).

[0211] Example 19: 6-(1-methyl-1H-pyrazole-4-yl)-N-((1-(vinylsulfonyl)piperidine-4-yl)methyl)pyrazolo[1,5-a]pyrazine-4-amine [ka]

[0212] Synthesis of 1,6-(1-methyl-1H-pyrazole-4-yl)-N-((1-(vinylsulfonyl)piperidine-4-yl)methyl)pyrazolo[1,5-a]pyrazine-4-amine [ka] 6-(1-methylpyrazole-4-yl)-N-(4-piperidylmethyl)pyrazolo[1,5-a]pyrazine-4-amine (75 mg, 241 μmol) was placed in a vial, to which DCM (2.4 mL), DMF (200 μL), and TEA (73 mg, 725 μmol, 100 μL) were added, and the mixture was then placed on a dry ice / acetone bath for 10 minutes. Ethenesulfonyl chloride (40 mg, 313 μmol, 28 μL) was added dropwise to this solution. The reaction mixture was warmed to room temperature and stirred overnight. The reaction mixture was diluted with water and passed through a phase separator. The aqueous layer was extracted by DCM, the combined organic layer was concentrated and dissolved in DMSO, and purified by reverse-phase HPLC (Waters XSelect CSH C18, 5 μm, 19 mm × 100 mm column, mobile phase H2O (A) and MeCN (B), and gradient 5-40% B (0.2% NH4OH final v / v% modifier), flow rate 30 mL / min) to obtain 6-(1-methylpyrazole-4-yl)-N-[(1-vinylsulfonyl-4-piperidyl)methyl]pyrazolo-[1,5-a]pyrazine-4-amine (19 mg, yield: 20%) as a yellow solid. ESI-MS (M+H) + : 402.2. 1H NMR (500 MHz, DMSO-d6) δ 8.27 (s, 1H), 8.09 (s, 1H), 7.92 (s, 1H), 7.82-7.86 (m, 1H), 7.66 (br t, J =5.80Hz,1H),6.93-6.96(m,1H),6.78(dd,J = 9.77, 16.48 Hz, 1H), 6.06-6.15 (m, 2H), 3.87 (s, 3H), 3.55 (br d, J =11.60Hz,2H),2.57-2.65(m,4H),1.85(brd, J = 11.60Hz, 3H), 1.25-1.35 (m, 2H).

[0213] Example 20: N-[1-[6-(1-methylpyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl]-3-piperidyl]propa-2-enamide [ka]

[0214] Synthesis of tert-butyl=N-[1-[6-(1-methylpyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl]-3-piperidyl]carbamate [ka] To a solution of 4-chloro-6-(1-methylpyrazole-4-yl)pyrazolo[1,5-a]pyrazine (300 mg, 1.28 mmol) in t-BuOH (5.1 mL), N-ethyl-N-isopropyl-propan-2-amine (249 mg, 1.93 mmol, 336 μL) and tert-butyl=N-(3-piperidyl)carbamate (264 mg, 1.32 mmol) were added in that order. The reaction mixture was stirred overnight at 80°C. The substance was concentrated and the process proceeded as a crude product (assumed yield 100%). LCMS m / z = 398.0. (M+H)+.

[0215] Synthesis of 1-[6-(1-methylpyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl]piperidine-3-amine hydrochloride [ka] To a solution of tert-butyl=N-[1-[6-(1-methylpyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl]-3-piperidyl]carbamate (509 mg, 1.28 mmol) in dioxane (6.4 mL), HCl (4 M, 1.92 mL) was added. The mixture was stirred overnight at room temperature. The solid was precipitated, filtered off, and washed with ethyl acetate. The solid was air-dried to obtain 1-[6-(1-methylpyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl]piperidine-3-amine hydrochloride (500 mg, 94% yield) as a brown solid. The solid was estimated to have a purity of 80%.

[0216] Synthesis of N-[1-[6-(1-methylpyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl]-3-piperidyl]propa-2-enamide [ka] To a solution of 1-[6-(1-methylpyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl]piperidine-3-amine hydrochloride (75 mg, 180 μmol) in DCM (1.8 mL), N-ethyl-N-isopropyl-propan-2-amine (93 mg, 719 μmol, 126 μL) and propa-2-enoyl chloride (18 mg, 198 μmol, 16 μL) were added in that order. The reaction mixture was stirred overnight at room temperature. The substance was concentrated and purified by reverse-phase purification (column: Waters XSelect CSH Prep C18 5um OBD 19 × 100 mm; conditions: 5-45% acetonitrile / 0.1% v / v ammonium carbonate / water; flow rate: 30 mL / min) to obtain 30.5 mg (yield 49%). LCMS m / z = 352.2 (M+H)+. 1H NMR (500 MHz, DMSO-d6) δ ppm 1.19 - 1.30 (m, 1 H) 1.53 - 1.69 (m, 2 H) 1.81 - 2.01 (m, 2 H) 3.06 (dd, J =12.82,9.77Hz,1 H) 3.23 - 3.27 (m, 1 H) 3.87 (s, 3 H) 3.91 - 3.97 (m, 1 H) 4.22 - 4.47 (m, 2 H) 5.57 - 5.66 (m, 1 H) 6.18 (s, 1 H) 6.23 - 6.34 (m, 1 H) 7.06 (d, J =2.44Hz,1 H) 7.89 - 8.03 (m, 1 H) 8.19 - 8.27 (m, 2 H) 8.40 - 8.53 (m, 1 H).

[0217] Example 21: N-[1-[6-(1-methylpyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl]-3-piperidyl]propa-2-inamide [ka]

[0218] Synthesis of N-[1-[6-(1-methylpyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl]-3-piperidyl]prop-2-inamide [ka] To a solution of 1-[6-(1-methylpyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl]piperidine-3-amine hydrochloride (75 mg, 180 μmol) in DCM (1.5 mL), N-ethyl-N-isopropyl-propan-2-amine (86 mg, 669 μmol, 117 μL) and HATU (68 mg, 178 μmol) were added in that order. The reaction mixture was stirred for 15 minutes, then propa-2-ic acid (15 mg, 216 μmol, 13 μL) was added, and the resulting mixture was stirred overnight at room temperature. The substance was concentrated and purified by reverse-phase purification (column: Waters XSelect CSH Prep C18 5um OBD 19 × 100 mm; conditions: 5-45% acetonitrile / 0.1% v / v ammonium carbonate / water; flow rate: 30 mL / min) to obtain 14.8 mg (yield 24%). LCMS m / z = 350.1 (M+H)+. 1 H NMR (500 MHz, DMSO-d6) δ ppm 1.22 - 1.43 (m, 1 H) 1.51 - 1.68 (m, 2 H) 1.78 - 1.99 (m, 2 H) 3.04 (dd, J =12.82,9.16Hz,1 H) 3.18 - 3.26 (m, 1 H) 3.87 (s, 3 H) 3.90 - 3.99 (m, 1 H) 4.22 - 4.41 (m, 2 H) 6.96 (d, J =1.83Hz,1 H) 7.90 - 8.07 (m, 1 H) 8.20 (s, 1 H) 8.44 - 8.56 (m, 1 H) 8.92 (d, J (=7.32Hz, 1 H). One proton signal is shielded by residual water in the deuterated solvent.

[0219] Example 22: 4-Chloro-N-[1-[6-(1-methylpyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl]-3-piperidyl]buta-2-enamide [ka]

[0220] Synthesis of 4-chloro-N-[1-[6-(1-methylpyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl]-3-piperidyl]buta-2-enamide [ka] To a solution of 1-[6-(1-methylpyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl]piperidine-3-amine hydrochloride (75 mg, 180 μmol) in DCM (1.5 mL), N-ethyl-N-isopropyl-propan-2-amine (86 mg, 669 μmol, 117 μL) and HATU (68 mg, 178 μmol) were added in that order. The reaction mixture was stirred for 15 minutes, then 4-chlorobuta-2-enoic acid (26 mg, 216 μmol) was added, and the resulting mixture was stirred overnight at room temperature. The substance was concentrated and purified by reverse-phase purification (column: Waters XSelect CSH Prep C18 5um OBD 19 × 100 mm; conditions: 5-55% acetonitrile / 0.1% v / v ammonium carbonate / water; flow rate: 30 mL / min) to obtain 5.7 mg (yield 8%). LCMS m / z = 400.2 (M+H)+. 1 H NMR (500MHz, DMSO-d6) δ: 8.51 - 8.43 (m, 1H), 8.30 (d, J = 7.3 Hz, 1H), 8.25 - 8.17 (m, 1H), 8.02 - 7.89 (m, 1H), 7.09 - 6.98 (m, 1H), 6.75 (td, J = 6.1, 14.6 Hz, 1H), 6.31 - 6.19 (m, 1H), 4.37 (dd, J = 1.2, 6.1 Hz, 3H), 4.32 - 4.19 (m, 1H), 4.02 - 3.91 (m, 1H), 3.87 (s, 3H), 3.31 - 3.22 (m, 1H), 3.15 - 3.00 (m, 1H), 2.03 - 1.90 (m, 1H), 1.86 (br d, J = 3.1 Hz, 1H), 1.70 - 1.54 (m, 2H), 1.33 - 1.17 (m, 1H).

[0221] Example 23: N-methyl-N-[1-[7-(1-methylpyrazole-4-yl)imidazo[1,2-c]pyrimidine-5-yl]-3-piperidyl]prop-2-inamide [ka]

[0222] Synthesis of tert-butyl=N-methyl-N-[1-[7-(1-methylpyrazole-4-yl)imidazo[1,2-c]pyrimidine-5-yl]-3-piperidyl]carbamate [ka] To a solution of 5-chloro-7-(1-methylpyrazole-4-yl)imidazo[1,2-c]pyrimidine (1.00 g, 4.28 mmol) in t-BuOH (8.6 mL), N-ethyl-N-isopropyl-propan-2-amine (830 mg, 6.42 mmol, 1.1 mL) and tert-butyl=N-methyl-N-(3-piperidyl)carbamate (945 mg, 4.41 mmol) were added in that order. The reaction mixture was stirred overnight at 80°C. The substance was concentrated and the process proceeded as a crude product (expected yield 100%). LCMS m / z = 412.0 (M+H)+.

[0223] Synthesis of N-methyl-1-[7-(1-methylpyrazole-4-yl)imidazo[1,2-c]pyrimidine-5-yl]piperidine-3-amine hydrochloride [ka] To a solution of tert-butyl=N-methyl-N-[1-[7-(1-methylpyrazole-4-yl)imidazo[1,2-c]pyrimidine-5-yl]-3-piperidyl]carbamate (1.76 g, 4.28 mmol) in dioxane (8.56 mL), HCl (4 M, 6.42 mL) was added. The mixture was stirred overnight at room temperature. The solid was allowed to precipitate overnight, filtered off, and washed with SiO2. The solid was air-dried to obtain N-methyl-1-[7-(1-methylpyrazole-4-yl)imidazo[1,2-c]pyrimidine-5-yl]piperidine-3-amine hydrochloride (1.94 g, 3.90 mmol, yield 91%) as an off-white solid. The solid was estimated to have a purity of 70%. LCMS m / z = 312.1 (M+H)+.

[0224] Synthesis of N-methyl-N-[1-[7-(1-methylpyrazole-4-yl)imidazo[1,2-c]pyrimidine-5-yl]-3-piperidyl]prop-2-inamide [ka] To a solution of N-methyl-1-[7-(1-methylpyrazole-4-yl)imidazo[1,2-c]pyrimidine-5-yl]piperidine-3-amine hydrochloride (100 mg, 201 μmol) in DCM (1 mL), N-ethyl-N-isopropyl-propan-2-amine (130 mg, 1.01 mmol, 176 μL) and propa-2-ic acid (18 mg, 262 μmol, 16 μL) were added in that order. Then, HATU (100 mg, 262 μmol) was added to the vial, and the resulting mixture was stirred overnight at room temperature. The substance was concentrated and purified by reverse-phase purification (column: Waters XSelect CSH Prep C18 5um OBD 19×100mm; conditions: 5-45% acetonitrile / 0.1% v / v ammonium carbonate / water; flow rate: 30 mL / min) to obtain 33.4 mg (yield 46%). LCMS m / z = 364.3 (M+H)+.

[0225] Example 24: N-methyl-N-[1-[6-(1-methylpyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl]-3-piperidyl]prop-2-inamide [ka]

[0226] Synthesis of tert-butyl=N-methyl-N-[1-[6-(1-methylpyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl]-3-piperidyl]carbamate [ka] To a solution of 4-chloro-6-(1-methylpyrazole-4-yl)pyrazolo[1,5-a]pyrazine (400 mg, 1.71 mmol) in t-BuOH (3.42 mL), N-ethyl-N-isopropyl-propan-2-amine (332 mg, 2.57 mmol, 448 μL) and tert-butyl=N-methyl-N-(3-piperidyl)carbamate (378 mg, 1.76 mmol) were added in that order. The vial was stirred overnight at 80°C. The substance was concentrated and the process proceeded as a crude product (assumed yield 100%). LCMS m / z = 412.1 (M+H)+.

[0227] Synthesis of N-methyl-1-[6-(1-methylpyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl]piperidine-3-amine hydrochloride [ka] To a solution of tert-butyl=N-methyl-N-[1-[6-(1-methylpyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl]-3-piperidyl]carbamate (704 mg, 1.71 mmol) in dioxane (8.6 mL), HCl (4 M, 2.57 mL) was added. The mixture was stirred overnight at room temperature. The solid was allowed to precipitate overnight, filtered off, and washed with ethyl acetate. The solid was air-dried to obtain N-methyl-1-[6-(1-methylpyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl]piperidine-3-amine hydrochloride (651 mg, yield 88%) as an off-white solid. The solid was estimated to have a purity of 80%. LCMS m / z = 312.1 (M+H)+.

[0228] Synthesis of N-methyl-N-[1-[6-(1-methylpyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl]-3-piperidyl]prop-2-inamide [ka] To a solution of 1N-methyl-1-[6-(1-methylpyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl]piperidine-3-amine hydrochloride (100 mg, 230 μmol) in DCM (1 mL), propa-2-ic acid (21 mg, 299 μmol, 18 μL), N-ethyl-N-isopropyl-propan-2-amine (86 mg, 669 μmol, 117 μL) and HATU (114 mg, 299 μmol) were added in that order. The reaction mixture was stirred overnight at room temperature. The substance was concentrated and purified by reverse-phase purification (column: Waters XSelect CSH Prep C18 5um OBD 19 × 100 mm; conditions: 5-50% acetonitrile / 0.1% v / v ammonium carbonate / water; flow rate: 30 mL / min) to obtain 1.9 mg (yield 2%). LCMS m / z = 364.2 (M+H)+. 1H NMR (500 MHz, DMSO-d6) δ ppm 1.59 - 1.75 (m, 1 H) 1.78 - 2.05 (m, 4 H) 2.90 (s, 2 H), 2.99 - 3.11 (m, 1 H) 3.14 - 3.18 (m, 1 H) 3.87 (d, J =1.83Hz,3 H) 4.29 - 4.56 (m, 4 H) 6.95 (d, J =2.44Hz,1 H) 7.90 - 8.04 (m, 2 H) 8.17 (d, J =17.70Hz,1 H) 8.46 - 8.59 (m, 1 H).

[0229] Example 25: N-((1-(6-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl)piperidine-3-yl)methyl)propiolamide [ka]

[0230] Synthesis of tert-butyl=N-[[1-[6-(1-methylpyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl]-3-piperidyl]methyl]carbamate [ka] A suspension of tert-butyl=N-(3-piperidylmethyl)carbamate (229 mg, 1.07 mmol), 4-chloro-6-(1-methylpyrazole-4-yl)pyrazolo[1,5-a]pyrazine (250 mg, 1.07 mmol), and DIPEA (277 mg, 2.14 mmol, 374 μL) in isopropanol (4 mL) was heated under reflux for 17 hours. The reaction mixture was cooled to room temperature and concentrated under vacuum. The residue was taken in SiO2 and washed with water and brine. The organic layer was dried (MgSO4), filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography (0-100% SiO2 / heptane). tert-butyl=N-[[1-[6-(1-methylpyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl]-3-piperidyl]methyl]carbamate (379 mg, yield 86%) was obtained as a pale yellow solid. LCMS: m / z = 412.3 (M+H)+. 1 H NMR (500 MHz, Chloroform-d)δ ppm 8.09 (s, 1 H), 7.82 - 7.96 (m, 3 H), 6.69 (br s, 1 H), 4.81 (br s, 1 H), 4.38 (br d, J =13.4Hz,2 H), 3.98 (s, 3 H), 3.29 (br t, J =11.0Hz,1 H), 3.15 (br s, 2 H), 3.09 (br dd, J =12.8,9.8Hz,1 H), 1.95 (br d, J =12.2Hz,2 H), 1.87 (dt, J =13.4,3.7Hz,1 H), 1.68 - 1.78 (m, 1H), 1.45 - 1.53 (m,9 H), 1.33 - 1.42 (m,1 H).

[0231] Synthesis of [1-[6-(1-methylpyrazole-4-yl)pyrrolo[2,1-f][1,2,4]triazine-4-yl]-3-piperidyl]methanamine (hydrochloride) [ka] A solution of tert-butyl=N-[[1-[6-(1-methylpyrazole-4-yl)pyrrolo[2,1-f][1,2,4]triazine-4-yl]-3-piperidyl]methyl]carbamate (150 mg, 365 μmol) in anhydrous methanol (1 mL) was treated with hydrochloric acid (4 M solution in dioxane, 1 mL). The resulting mixture was stirred at room temperature for 1 hour and concentrated under vacuum. [1-[6-(1-methylpyrazole-4-yl)pyrrolo[2,1-f][1,2,4]triazine-4-yl]-3-piperidyl]methanamine hydrochloride was obtained as an off-white solid. LCMS: m / z = 312.3 (M+H)+.

[0232] Synthesis of N-[[1-[6-(1-methylpyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl]-3-piperidyl]methyl]prop-2-inamide [ka] Crude [1-[6-(1-methylpyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl]-3-piperidyl]methanamine hydrochloride (50 mg, 161 μmol) was suspended in anhydrous DMF (1 mL) at 0°C under a nitrogen atmosphere. DIPEA (62 mg, 482 μmol, 84 μL), followed by propa-2-ic acid (17 mg, 241 μmol, 15 μL) and T3P (204 mg, 321 μmol, 217 μL, 50% in DMF) were added. The resulting solution was stirred at room temperature for 1 hour, quenched with saturated sodium bicarbonate solution, and extracted with phenylethylamine. The organic layer was washed with water and brine, dried (MgSO4), filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography (0-10% MeOH / DCM). N-[[1-[6-(1-methylpyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl]-3-piperidyl]methyl]propa-2-inamide (42.8 mg, yield 66%, purity 90%) was obtained as an orange oil. LCMS: m / z = 364.2 (M+H)+. 1H NMR (500 MHz, Chloroform-d)δ ppm 8.07 (s, 1 H), 7.83 - 7.88 (m, 2 H), 7.79 - 7.83 (m, 1 H), 6.65 (d, J =2.4Hz,1 H), 6.45 (br s, 1 H), 4.16 - 4.25 (m, 2 H), 3.94 - 3.98 (m, 3 H), 3.44 - 3.52 (m, 1 H), 3.35 - 3.44 (m, 1 H), 3.28 - 3.35 (m, 1 H), 3.20 - 3.27 (m, 1 H), 2.80 - 2.84 (m, 1 H), 2.08 (quind, J =9.0,9.0,9.0,9.0,3.7Hz,1 H), 1.91 - 2.00 (m, 1 H), 1.78 - 1.86 (m, 1 H), 1.61 - 1.78 (m,1 H), 1.38 - 1.50 (m, 1 H).

[0233] Example 26: (S)-N-((1-(6-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl)piperidine-2-yl)methyl)propiolamamide and (R)-N-((1-(6-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl)piperidine-2-yl)methyl)propiolamamide [ka]

[0234] Synthesis of tert-butyl=N-[[1-[6-(1-methylpyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl]-2-piperidyl]methyl]carbamate [ka] A suspension of tert-butyl=N-(2-piperidylmethyl)carbamate (302 mg, 1.41 mmol), 4-chloro-6-(1-methylpyrazole-4-yl)pyrazolo[1,5-a]pyrazine (300 mg, 1.28 mmol), and cesium carbonate (1.25 g, 3.84 mmol) in dioxane (5 mL) was sparged with nitrogen for 5 minutes. RuPhos (119 mg, 256 μmol) and Pd2(dba)3 (117 mg, 128 μmol) were added, and the resulting mixture was heated overnight under reflux. Additional tert-butyl=N-(2-piperidylmethyl)carbamate (302 mg, 1.41 mmol), RuPhos (119 mg, 256 μmol), and Pd2(dba)3 (117 mg, 128 μmol) were added, and heating was continued for a further 24 hours. Next, the reaction mixture was cooled to room temperature, filtered through Celite, rinsed with ethyl acetate, and the filtrate was concentrated under vacuum. The residue was purified by silica gel chromatography (0-100% ethyl acetate / heptane). Tert-butyl=N-[[1-[6-(1-methylpyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl]-2-piperidyl]methyl]carbamate (267 mg, yield 51%) was obtained as a yellow foam. LCMS: m / z = 412.3 (M+H)+. 1 H NMR (400 MHz, Chloroform-d)δ ppm 8.09 (s, 1 H), 7.82 - 7.95 (m, 3 H), 6.69 (br s, 1 H), 5.96 (br s, 1 H), 4.90 (br s, 1 H), 4.29 - 4.42 (m, 1 H), 3.99 (s, 3 H), 3.85 (br t, J =11.8Hz,1 H), 3.35 (br d, J =13.6Hz,2 H), 1.71 - 1.92 (m, 6 H), 1.35 (s,9 H).

[0235] Synthesis of [1-[6-(1-methylpyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl]-2-piperidyl]methanamine (hydrochloride) [ka] A suspension of tert-butyl=N-[[1-[6-(1-methylpyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl]-2-piperidyl]methyl]carbamate (150 mg, 365 μmol) in anhydrous methanol (1 mL) was treated with hydrochloric acid (4 M solution in dioxane, 1 mL), and the resulting solution was stirred at room temperature for 2 hours. A solid was formed, and the reaction mixture was concentrated under vacuum, and the residue was used directly. [1-[6-(1-methylpyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl]-2-piperidyl]methanamine hydrochloride was obtained as a pale yellow solid. Quantitative yield assumed. LCMS: m / z = 312.2 (M+H)+.

[0236] Synthesis of N-[[1-[6-(1-methylpyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl]-2-piperidyl]methyl]prop-2-inamide [ka] To a suspension of crude [1-[6-(1-methylpyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl]-2-piperidyl]methanamine hydrochloride (50 mg, 161 μmol) in anhydrous DMF (1 mL) at 0°C under nitrogen, DIPEA (62 mg, 482 μmol, 84 μL), followed by propa-2-ic acid (17 mg, 241 μmol, 15 μL) and T3P (204 mg, 321 μmol, 217 μL, 50% in DMF). The resulting solution was stirred at room temperature for 1 hour, quenched with saturated sodium bicarbonate solution, and extracted with ethyl acetate. The organic layer was washed with water and brine, dried, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography (0-10% MeOH / DCM), and the product was further purified by preparative TLC (7% MeOH / DCM). N-[[1-[6-(1-methylpyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl]-2-piperidyl]methyl]propa-2-inamide (20 mg, yield 33%, purity 95%) was obtained as a brown solid. LCMS: m / z = 364.2 (M+H)+. 1H NMR (400 MHz, Chloroform-d)δ ppm 8.56 (br s, 1 H), 8.07 - 8.14 (m, 1 H), 7.89 (d, J =2.3Hz,1 H), 7.84 (s, 2 H), 6.67 (d, J =2.0Hz,1 H), 4.90 - 5.02 (m, 1 H), 4.31 (br d, J =13.8Hz,1 H), 4.05 - 4.19 (m, 1 H), 3.92 - 4.00 (m, 3 H), 3.42 - 3.52 (m, 1 H), 3.36 (br s, 1 H), 2.54 (s, 1 H), 1.73 - 1.96 (m,6 H).

[0237] Chiral SFC purification (using a CHIRALPAK AD-H 30×250mm, 5um column; method: 30% MeOH (no modifier) / CO2 (flow rate: 100 mL / min, ABPR 120 bar, MBPR 40 psi, column temperature 40°C)) yielded enantiomer E1 (first eluting peak, 7.9 mg, 100% ee). Rf = 3.76 min. Enantiomer E2 (second eluting peak, 7.8 mg, 95.90% ee). Rf = 4.43 min.

[0238] Example 27: N-[[1-[6-(1-methylpyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl]-2-piperidyl]methyl]propa-2-enamide [ka]

[0239] Crude [1-[6-(1-methylpyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl]-2-piperidyl]methanamine hydrochloride (60 mg, 193 μmol) was suspended in anhydrous THF (1 mL) under nitrogen at 0°C. DIPEA (75 mg, 578 μmol, 101 μL) was added, followed by propa-2-enoyl chloride (26 mg, 289 μmol, 24 μL). The resulting suspension was stirred at 0°C for 10 minutes, quenched with saturated sodium bicarbonate solution, and extracted with ethyl acetate. The organic layer was washed with brine, dried (MgSO4), filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography (0-10% MeOH / DCM) and further purified by preparative TLC (93:7 DCM / MeOH). N-[[1-[6-(1-methylpyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl]-2-piperidyl]methyl]propa-2-enamide (13.2 mg, yield 18%, purity 95%) was obtained as a brownish foam. LCMS: m / z = 366.1 (M+H)+. 1 H NMR (400 MHz, Chloroform-d)δ ppm 8.09 (s, 1 H), 7.86 - 7.90 (m, 1 H), 7.83 - 7.86 (m, 1 H), 7.78 (s, 1 H), 7.70-7.90 (br s, 1H), 6.67 (d, J =2.0Hz,1 H), 6.08 (dd, J =17.1,1.3Hz,1 H), 5.79 (dd, J =17.1,10.3Hz,1 H), 5.43 (dd, J =10.4,1.4Hz,1 H), 4.98 - 5.08 (m, 1 H), 4.27 - 4.40 (m, 1 H), 4.08 - 4.22 (m, 1 H), 3.93 - 4.00 (m,3 H), 3.44 - 3.53 (m,1 H), 3.28 - 3.44 (m, 1 H), 1.72 - 1.96 (m,6 H).

[0240] Example 28: (R)-6-(1-methyl-1H-pyrazole-4-yl)-4-((1-(vinylsulfonyl)azepan-4-yl)oxy)pyrazolo[1,5-a]pyrazine [ka]

[0241] 1. Synthesis of tert-butyl=(R)-4-((6-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl)oxy)azepan-1-carboxylate [ka] A solution of tert-butyl=4-hydroxyazepan-1-carboxylate (710 mg, 3.30 mmol) in anhydrous DMF (10 mL) was cooled in an ice bath. Then, sodium hydride (396 mg, 9.90 mmol, 60% purity) was added in four portions with stirring. Stirring in the ice bath was continued for 45 minutes, during which a pale yellow suspension was formed. To this mixture, 4-chloro-6-(1-methylpyrazole-4-yl)pyrazolo[1,5-a]pyrazine (700 mg, 3.00 mmol) was added in one portion. Stirring was continued overnight at room temperature. The mixture was diluted with ethyl acetate, and then water was carefully added. The mixture was transferred to a separatory funnel and the phases were separated. The aqueous phase was extracted again with ethyl acetate, and the combined organic phase was washed with brine, dried over Na2SO4, filtered, and concentrated. The residual material was purified on a 10 g silica column with 50% heptane / ethyl acetate to obtain tert-butyl=4-[6-(1-methylpyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl]oxyazepan-1-carboxylate (1.30 g, yield: 95%) as a sticky, pale yellow, rubbery substance. The racemic substance was separated by chiral SFC purification (CHIRALPAK AD-H 30×250mm, 5um, 25% IPA + 0.1% DEA / CO2, flow rate: 100 mL / min, ABPR 120 bar, MBPR 60 psi, column temperature 40°C) to obtain (S)-tert-butyl=4-[6-(1-methylpyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl]oxyazepan-1-carboxylate (first eluted peak) (389 mg, yield: 63%) and (R)-tert-butyl4-[6-(1-methylpyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl]oxyazepan-1-carboxylate (second eluted peak) (407 mg, yield: 66%) as off-white solids. The absolute stereochemistry of the products in these two peaks was later confirmed using commercially available chiral tert-butyl=(4S)-hydroxyazepane-1-carboxylate, and the compound was synthesized that matched the first eluted peak in the analytical data. ESI-MS (M+H) + : 413.2.

[0242] 2. Synthesis of (R)-4-(azepan-4-yloxy)-6-(1-methylpyrazole-4-yl)pyrazolo[1,5-a]pyrazine [ka] To a solution of tert-butyl(4R)-[6-(1-methylpyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl]oxyazepan-1-carboxylate (407 mg, 987 μmol) in DCM (3 mL), TFA (2.25 g, 19.7 mmol, 1.51 mL) was added at room temperature with stirring. After stirring overnight, the mixture was dissolved in MeOH, and the desired product was purified by elution with 2 M NH3-MeOH on a 5 g SCX column to obtain 4-(azepan-4-yloxy)-6-(1-methylpyrazole-4-yl)pyrazolo[1,5-a]pyrazine (250 mg, yield: 77% yield) as a white solid. ESI-MS (M+H) + : 313.2.

[0243] 3. Synthesis of (R)-6-(1-methyl-1H-pyrazole-4-yl)-N-((1-(vinylsulfonyl)piperidine-4-yl)methyl)pyrazolo[1,5-a]pyrazine-4-amine [ka] When 2-chloroethanesulfonyl chloride (31 mg, 192 μmol, 20 μL) was added to a solution of (4R)-(azepan-4-yloxy)-6-(1-methylpyrazole-4-yl)pyrazolo[1,5-a]pyrazine (30 mg, 96 μmol) in THF (1 mL), a precipitate formed instantaneously. Then, TEA (39 mg, 384 μmol, 53 μL) was added at room temperature while stirring. After stirring overnight, volatile substances were removed, and the residue was redissolved in DMSO. Purification by reverse-phase HPLC (Waters XSelect CSH C18, 5 μm, 19 mm × 100 mm column, mobile phase H2O (A) and MeCN (B), and gradient 5-60% B (0.2% NH4OH final v / v% modifier), flow rate 30 mL / min) yielded (R)-6-(1-methylpyrazole-4-yl)-4-(1-vinylsulfonylazepan-4-yl)oxy-pyrazolo[1,5-a]pyrazine (11 mg, yield: 26%) as a yellow oil. ESI-MS (M+H) + : 403.2. 1 H NMR (500 MHz, DMSO-d6) δ 8.74 (s, 1H), 8.19 (s, 1H), 7.98-8.03 (m, 1H), 6.79-6.94 (m, 2H), 6.05-6.11 (m, 2H), 5.57 (tt, J =3.66,7.63Hz,1H),3.88(s,3H),3.40-3.67(m,2H),3.33-3.38(m,2H),3.21-3.31( m,1H),2.17-2.27(m,1H),1.99-2.10(m,3H),1.89-1.99(m,1H),1.68-1.83(m,1H).

[0244] Example 29: (R)-1-(4-((6-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl)oxy)azepan-1-yl)propa-2-en-1-one [ka]

[0245] 1. Synthesis of (R)-1-(4-((6-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl)oxy)azepan-1-yl)propa-2-en-1-one [ka] When propa-2-enoyl chloride (17 mg, 192 μmol, 16 μL) was added to a solution of (4R)-(azepan-4-yloxy)-6-(1-methylpyrazole-4-yl)pyrazolo[1,5-a]pyrazine (30 mg, 96 μmol) in THF (1 mL), a precipitate formed instantaneously. Then, TEA (19 mg, 192 μmol, 27 μL) was added at room temperature while stirring. After stirring overnight, volatile substances were removed, and the residual material was redissolved in DMSO. Purification by reverse-phase HPLC (Waters XSelect CSH C18, 5 μm, 19 mm × 100 mm column, mobile phase H2O (A) and MeCN (B), and gradient 5-50% B (0.2% NH4OH final v / v% modifier), flow rate 30 mL / min) yielded (R)-1-(4-((6-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl)oxy)azepan-1-yl)propa-2-en-1-one (9 mg, yield: 23%) as a clear oil. ESI-MS (M+H) + : 367.2. 1 H NMR (500 MHz, DMSO-d6) δ 8.73 (s, 1H), 8.18 (d, J =18.92Hz,1H),7.98-8.03(m,1H),6.76-6.87(m,2H),6.18(ddd,J = 2.44, 3.66, 16.48 Hz, 1H), 5.65-5.75 (m, 1H), 5.45-5.58 (m, 1H), 3.88 (d, J =1.83Hz,3H),3.56-3.79(m,4H),2.71-2.92(m,1H),2.17-2.26(m,1H),1.99-2.10(m,2H),1.84-1.98(m,2H),1.63-1.82(m,1H).

[0246] Example 30: (R)-1-(4-((6-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl)oxy)azepan-1-yl)propa-2-in-1-one [ka]

[0247] 1. Synthesis of (R)-1-(4-((6-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl)oxy)azepan-1-yl)propa-2-in-1-one [ka] To a solution of (4R)-(azepan-4-yloxy)-6-(1-methylpyrazole-4-yl)pyrazolo[1,5-a]pyrazine (30 mg, 96 μmol) in DMF (1 mL), propiolic acid (13 mg, 192 μmol, 12 μL), followed by DIPEA (25 mg, 192 μmol, 34 μL), was added at room temperature with stirring. After stirring at room temperature for 5 minutes, T3P (122 mg, 192 μmol, 50% purity) was added dropwise with stirring. After stirring for a further 3 hours at room temperature, the mixture was diluted with ethyl acetate and washed with water. The organic phase was dried over sodium sulfate, filtered, and evaporated. The residual white solid was redissolved in DMSO and purified by reverse-phase HPLC (Waters XSelect CSH C18, 5 μm, 19 mm × 100 mm column, mobile phase H2O (A) and MeCN (B), and gradient 5-55% B (0.2% NH4OH final v / v% modifier), flow rate 30 mL / min) to obtain (R)-1-(4-((6-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl)oxy)azepan-1-yl)propa-2-in-1-one (24 mg, yield: 48%) as a white solid. ESI-MS (M+H) + : 365.2. 1H NMR (500 MHz, DMSO-d6)δ8.70-8.81(m,1H),8.19(d,J = 3.66 Hz, 1H), 7.95-8.08 (m, 2H), 6.74-6.88 (m, 1H), 5.45-5.63 (m, 1H), 3.88 (s, 3H), 3.75-3.84 (m, 2H), 3.48-3.66 (m, 2H), 2.19-2.29 (m, 1H), 2.10-2.20 (m, 1H), 1.85-2.09 (m, 4H), 1.67-1.84 (m, 1H).

[0248] Example 31: (S)-1-(4-((6-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl)oxy)azepan-1-yl)propa-2-in-1-one [ka]

[0249] 1. Synthesis of (S)-4-(azepan-4-yloxy)-6-(1-methylpyrazole-4-yl)pyrazolo[1,5-a]pyrazine [ka] To a solution of tert-butyl=(4S)-4-[6-(1-methylpyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl]oxyazepan-1-carboxylate (389 mg, 944 μmol) in DCM (3 mL), TFA (2.15 g, 18.9 mmol, 1.44 mL) was added at room temperature with stirring. After stirring overnight, the mixture was dissolved in MeOH, and the desired product was eluted and purified on a 5 g SCX column with 2 M NH3-MeOH to obtain 4-[(4S)-azepan-4-yl]oxy-6-(1-methylpyrazole-4-yl)pyrazolo[1,5-a]pyrazine (170 mg, yield: 55%) as a white solid. ESI-MS (M+H) + : 313.2.

[0250] 2. Synthesis of (S)-1-(4-((6-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl)oxy)azepan-1-yl)propa-2-in-1-one [ka] To a solution of (4S)-(azepan-4-yloxy)-6-(1-methylpyrazole-4-yl)pyrazolo[1,5-a]pyrazine (30 mg, 96 μmol) in DMF (1 mL), propiolic acid (13 mg, 192 μmol, 12 μL), followed by DIPEA (25 mg, 192 μmol, 34 μL), was added at room temperature with stirring. After stirring at room temperature for 5 minutes, T3P (122 mg, 192 μmol, 50% purity) was added dropwise with stirring. After stirring for a further 3 hours at room temperature, the mixture was diluted with ethyl acetate and washed with water. The organic phase was dried over sodium sulfate, filtered, and evaporated. The residual white solid was redissolved in DMSO and purified by reverse-phase HPLC (Waters XSelect CSH C18, 5 μm, 19 mm × 100 mm column, mobile phase H2O (A) and MeCN (B), and gradient 5-55% B (0.2% NH4OH final v / v% modifier), flow rate 30 mL / min) to obtain (S)-1-(4-((6-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl)oxy)azepan-1-yl)propa-2-in-1-one (18 mg, yield: 48%) as a yellow solid. ESI-MS (M+H) + : 365.2. 1 H NMR (500 MHz, DMSO-d6)δ8.74(d,J = 3.05 Hz, 1H), 8.19 (d, J = 3.66 Hz, 1H), 7.98-8.05 (m, 2H), 6.79-6.87 (m, 1H), 5.46-5.64 (m, 1H), 3.88 (s, 3H), 3.75-3.84 (m, 2H), 3.50-3.67 (m, 2H), 2.12-2.29 (m, 2H), 1.87-2.11 (m, 4H), 1.67-1.84 (m, 1H).

[0251] Example 32: (S)-1-(4-((6-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl)oxy)azepan-1-yl)propa-2-en-1-one [ka]

[0252] 1. Synthesis of (S)-1-(4-((6-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl)oxy)azepan-1-yl)propa-2-en-1-one [ka] When propa-2-enoyl chloride (17 mg, 192 μmol, 16 μL) was added to a solution of (S)-4-(azepan-4-yloxy)-6-(1-methylpyrazole-4-yl)pyrazolo[1,5-a]pyrazine (30 mg, 96 μmol) in THF (1 mL), a precipitate formed instantaneously. Then, TEA (19 mg, 192 μmol, 27 μL) was added at room temperature while stirring. After stirring overnight, volatile substances were removed, and the residue was redissolved in DMSO. Purification by reverse-phase HPLC (Waters XSelect CSH C18, 5 μm, 19 mm × 100 mm column, mobile phase H2O (A) and MeCN (B), and gradient 5-50% B (0.2% NH4OH final v / v% modifier), flow rate 30 mL / min) yielded (S)-1-(4-((6-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl)oxy)azepan-1-yl)propa-2-en-1-one (25 mg, yield: 67%) as a clear oil. ESI-MS (M+H) + : 367.2. 1H NMR (500 MHz, DMSO-d6) δ 8.73 (d, J =1.22Hz,1H),8.18(d,J = 18.92 Hz, 1H), 7.96-8.02 (m, 2H), 6.76-6.87 (m, 2H), 6.18 (ddd, J =2.44,3.66,16.48Hz,1H),5.66-5.72(m,1H),5.45-5.58(m,1H),3.88(d,J = 1.83 Hz, 3H), 3.55-3.79 (m, 4H), 2.18-2.25 (m, 1H), 1.99-2.07 (m, 2H), 1.85-1.98 (m, 2H), 1.69-1.79 (m, 1H).

[0253] Example 33: (S)-6-(1-methyl-1H-pyrazole-4-yl)-4-((1-(vinylsulfonyl)azepan-4-yl)oxy)pyrazolo[1,5-a]pyrazine [ka]

[0254] Synthesis of (S)-6-(1-methyl-1H-pyrazole-4-yl)-N-((1-(vinylsulfonyl)piperidine-4-yl)methyl)pyrazolo[1,5-a]pyrazine-4-amine [ka]

[0255] When 2-chloroethanesulfonyl chloride (31 mg, 192 μmol, 20 μL) was added to a solution of 4-(azepan-4-yloxy)-6-(1-methylpyrazole-4-yl)pyrazolo[1,5-a]pyrazine (30 mg, 96 μmol) in THF (1 mL), a precipitate formed instantaneously. Then, TEA (39 mg, 384 μmol, 53 μL) was added at room temperature while stirring. After stirring overnight, volatile substances were removed, and the residue was redissolved in DMSO. Purification by reverse-phase HPLC (Waters XSelect CSH C18, 5 μm, 19 mm × 100 mm column, mobile phase H2O (A) and MeCN (B), and gradient 5-60% B (0.2% NH4OH final v / v% modifier), flow rate 30 mL / min) yielded (S)-6-(1-methylpyrazole-4-yl)-4-(1-vinylsulfonylazepan-4-yl)oxy-pyrazolo[1,5-a]pyrazine (7 mg, yield: 16%) as a yellow oil. ESI-MS (M+H) + : 403.2. 1 H NMR (500 MHz, DMSO-d6) δ 8.74 (s, 1H), 8.19 (s, 1H), 7.98-8.04 (m, 2H), 6.82-6.91 (m, 2H), 6.09 (d, J =16.48Hz,1H),6.06(d,J = 10.38 Hz, 1H), 5.57 (tt, J =3.66,7.63Hz,1H),3.88(s,3H),3.43-3.52(m,1H),2.17-2.25(m,1H),2.00-2.09(m,4H),1.88-1.98(m,2H),1.69-1.82(m,2H).

[0256] Example 34: (S) or (R)-1-(4-((7-(1-methyl-1H-pyrazole-4-yl)imidazo[1,2-c]pyrimidine-5-yl)oxy)azepan-1-yl)propa-2-en-1-one [ka]

[0257] 1. Synthesis of tert-butyl=(R) and (S)-4-((7-(1-methyl-1H-pyrazole-4-yl)imidazo[1,2-c]pyrimidine-5-yl)oxy)azepan-1-carboxylate [ka] A solution of tert-butyl=4-hydroxyazepan-1-carboxylate (355 mg, 1.65 mmol) in anhydrous DMF (5 mL) was cooled in an ice bath. Then, sodium hydride (198 mg, 4.95 mmol, 60% purity) was added in four portions with stirring. Stirring in the ice bath was continued for 45 minutes, during which a pale yellow suspension was formed. To this mixture, 5-chloro-7-(1-methylpyrazole-4-yl)imidazo[1,2-c]pyrimidine (350 mg, 1.50 mmol) was added in one portion. Stirring was continued overnight at room temperature. The mixture was diluted with ethyl acetate, and then water was carefully added. The mixture was transferred to a separatory funnel and the phases were separated. The aqueous phase was extracted again with ethyl acetate, and the combined organic phase was washed with brine, dried over Na2SO4, filtered, and concentrated. The residual material was purified on a 10 g silica column with 50% heptane / ethyl acetate to obtain tert-butyl=4-[7-(1-methylpyrazole-4-yl)imidazo[1,2-c]pyrimidine-5-yl]oxyazepan-1-carboxylate (520 mg, yield: 84%) as a sticky, pale yellow, rubbery substance. 450 mg of the racemic material was separated by chiral SFC purification (CHIRALPAK AD-H 30 × 250 mm, 5 μm, 30% IPA + 0.1% DEA / CO2, flow rate: 100 mL / min, ABPR 120 bar, MBPR 60 psi, column temperature 40 °C) to obtain two products as off-white solids, with the first eluting peak (E1) Peak 1 (172 mg, yield: 76%) and the second eluting peak (E2) Peak 2 (171 mg, yield: 76%). ESI-MS (M+H) + 413.3. The absolute stereochemistry of the products at each peak could not be assigned.

[0258] 2. Synthesis of (R) or (S)-5-(azepan-4-yloxy)-7-(1-methyl-1H-pyrazole-4-yl)imidazo[1,2-c]pyrimidine [ka] To a solution of tert-butyl=(4R) or (4S)-4-[7-(1-methylpyrazole-4-yl)imidazo[1,2-c]pyrimidine-5-yl]oxyazepan-1-carboxylate (172 mg, 416 μmol) in DCM (3 mL), TFA (949 mg, 8.33 mmol, 637 μL) was added at room temperature with stirring. After stirring overnight, the reaction mixture was dissolved in MeOH, and the desired product was eluted and purified on a 10 g SCX column with 2 M NH3-MeOH to obtain 5-[(4R) or (4S)-azepan-4-yl]oxy-7-(1-methylpyrazole-4-yl)imidazo[1,2-c]pyrimidine (95 mg, yield: 69%) as a white solid. ESI-MS (M+H) + : 313.2.

[0259] 3. Synthesis of (R) or (S)-1-(4-((7-(1-methyl-1H-pyrazole-4-yl)imidazo[1,2-c]pyrimidine-5-yl)oxy)azepan-1-yl)propa-2-en-1-one [ka] When propa-2-enoyl chloride (17 mg, 192 μmol, 16 μL) was added to a solution of E3 5-(4R) or (4S)-(azepan-4-yloxy)-7-(1-methylpyrazole-4-yl)imidazo[1,2-c]pyrimidine (30 mg, 96 μmol) (single enantiomer; chirality arbitrarily assigned) in THF (1 mL), a precipitate formed instantaneously. Then, TEA (19 mg, 192 μmol, 27 μL) was added at room temperature with stirring. After stirring overnight, volatile substances were removed, and the residue was redissolved in DMSO. Purification by reverse-phase HPLC (Waters XSelect CSH C18, 5 μm, 19 mm × 100 mm column, mobile phase H2O (A) and MeCN (B), and gradient 5-35% B (0.2% NH4OH final v / v% modifier), flow rate 30 mL / min) yielded (R)- or (S)-1-(4-((7-(1-methyl-1H-pyrazole-4-yl)imidazo[1,2-c]pyrimidine-5-yl)oxy)azepan-1-yl)propa-2-en-1-one (17 mg, yield: 45%) as a clear oil. ESI-MS (M+H) + : 367.2. 1 H NMR (500 MHz, DMSO-d6) δ 8.25 (d, J =12.82Hz,1H),8.04(d,J = 3.66 Hz, 1H), 7.70 (s, 1H), 7.50 (t, J =1.53Hz,1H),7.44(s,1H),6.82(ddd,J = 8.55, 10.38, 16.48 Hz, 1H), 6.17 (dd, J =2.44,16.48Hz,1H),5.69(dt,J = 2.44, 10.38 Hz, 1H), 5.50-5.64 (m, 1H), 3.89 (d, J =1.22Hz,3H),3.75-3.84(m,1H),3.59-3.72(m,3H),2.21(dq,J = 3.05, 7.32 Hz, 1H), 2.06-2.17 (m, 2H), 1.87-2.01 (m, 2H), 1.70-1.82 (m, 1H).

[0260] Example 35: (S) or (R)-1-(4-((7-(1-methyl-1H-pyrazole-4-yl)imidazo[1,2-c]pyrimidine-5-yl)oxy)azepan-1-yl)propa-2-in-1-one [ka]

[0261] Synthesis of (R) or (S) 1-(4-((7-(1-methyl-1H-pyrazole-4-yl)imidazo[1,2-c]pyrimidine-5-yl)oxy)azepan-1-yl)propa-2-in-1-one [ka] To a solution of E3 5-(4R)- or (4S)-(azepan-4-yloxy)-7-(1-methylpyrazole-4-yl)imidazo[1,2-c]pyrimidine (30 mg, 96 μmol) in DMF (1 mL), propiolic acid (13 mg, 192 μmol, 12 μL), followed by DIPEA (25 mg, 192 μmol, 34 μL), was added at room temperature with stirring. After stirring at room temperature for 5 minutes, T3P (122 mg, 192 μmol, 50% purity) was added dropwise with stirring. After stirring for a further 3 hours at room temperature, the mixture was diluted with ethyl acetate and washed with water. The organic phase was dried over Na2SO4, filtered, and concentrated. The residual white solid was redissolved in DMSO and purified by reverse-phase HPLC (Waters XSelect CSH C18, 5 μm, 19 mm × 100 mm column, mobile phase H2O (A) and MeCN (B), and gradient 5-40% B (0.2% NH4OH final v / v% modifier), flow rate 30 mL / min) to obtain (R) or (S)-1-(4-((7-(1-methyl-1H-pyrazole-4-yl)imidazo[1,2-c]pyrimidine-5-yl)oxy)azepan-1-yl)propa-2-in-1-one (2 mg, yield: 5%) as a yellow oil. ESI-MS (M+H) + : 365.2. 1H NMR (500 MHz, DMSO-d6) δ 8.26 (d, J =2.44Hz,1H),8.05(d,J = 4.27 Hz, 1H), 7.73 (d, J =11.60Hz,1H),7.52(t,J = 1.53 Hz, 1H), 7.46 (d, J =2.44Hz,1H),5.55-5.67(m,1H),4.53(d,J = 17.70 Hz, 1H), 3.89 (s, 3H), 3.78-3.82 (m, 1H), 3.53-3.72 (m, 2H), 3.40-3.52 (m, 1H), 2.21-2.28 (m, 1H), 2.07-2.19 (m, 2H), 1.91-2.06 (m, 2H), 1.72-1.89 (m, 1H).

[0262] Example 36: (R)-or (S)-7-(1-methyl-1H-pyrazole-4-yl)-5-((1-(vinylsulfonyl)azepan-4-yl)oxy)imidazo[1,2-c]pyrimidine [ka]

[0263] Synthesis of (R)-or (S)-7-(1-methyl-1H-pyrazole-4-yl)-5-((1-(vinylsulfonyl)azepan-4-yl)oxy)imidazo[1,2-c]pyrimidine [ka] When 2-chloroethanesulfonyl chloride (31 mg, 192 μmol, 20 μL) was added to a solution of E3 5-(4R)- or (4S)-(azepan-4-yloxy)-7-(1-methylpyrazole-4-yl)imidazo[1,2-c]pyrimidine (30 mg, 96 μmol) in THF (1 mL), a precipitate formed instantaneously. Then, TEA (39 mg, 384 μmol, 53 μL) was added at room temperature with stirring. After stirring overnight, volatile substances were removed, and the residue was redissolved in DMSO. Purification by reverse-phase HPLC (Waters XSelect CSH C18, 5 μm, 19 mm × 100 mm column, mobile phase H2O (A) and MeCN (B), and gradient 5-40% B (0.2% NH4OH final v / v% modifier), flow rate 30 mL / min) yielded (R)- or (S)-7-(1-methyl-1H-pyrazole-4-yl)-5-((1-(vinylsulfonyl)azepan-4-yl)oxy)imidazo[1,2-c]pyrimidine (2 mg, yield: 4%) as a yellow solid. ESI-MS (M+H) + : 403.2.

[0264] Example 37: (R)-or (S)-1-(4-((7-(1-methyl-1H-pyrazole-4-yl)imidazo[1,2-c]pyrimidine-5-yl)oxy)azepan-1-yl)propa-2-in-1-one [ka]

[0265] 1. Synthesis of (R) or (S)-5-(azepan-4-yloxy)-7-(1-methyl-1H-pyrazole-4-yl)imidazo[1,2-c]pyrimidine [ka] To a solution of tert-butyl=(4R) or (4S)-4-[7-(1-methylpyrazole-4-yl)imidazo[1,2-c]pyrimidine-5-yl]oxyazepan-1-carboxylate (172 mg, 416 μmol) in DCM (3 mL), TFA (949 mg, 8.33 mmol, 637 μL) was added at room temperature with stirring. After stirring overnight, the reaction mixture was dissolved in MeOH, and the desired product was eluted and purified on a 10 g SCX column with 2 M NH3-MeOH to obtain 5-[(4R) or (4S)-azepan-4-yl]oxy-7-(1-methylpyrazole-4-yl)imidazo[1,2-c]pyrimidine (95 mg, yield: 69%) as a white solid. ESI-MS (M+H) + : 313.2.

[0266] 2. Synthesis of (R) or (S)-1-(4-((7-(1-methyl-1H-pyrazole-4-yl)imidazo[1,2-c]pyrimidine-5-yl)oxy)azepan-1-yl)propa-2-in-1-one [ka] To a solution of E4 5-[(4R)-or (4S)-azepan-4-yl]oxy-7-(1-methylpyrazole-4-yl)imidazo[1,2-c]pyrimidine (30 mg, 96 μmol) in DMF (1 mL), propiolic acid (13 mg, 192 μmol, 12 μL), followed by DIPEA (25 mg, 192 μmol, 34 μL), was added at room temperature with stirring. After stirring at room temperature for 5 minutes, T3P (122 mg, 192 μmol, 50% purity) was added dropwise with stirring. After stirring for a further 3 hours at room temperature, the mixture was diluted with ethyl acetate and washed with water. The organic phase was dried over Na2SO4, filtered, and concentrated. The residual white solid was redissolved in DMSO and purified by reverse-phase HPLC (Waters XSelect CSH C18, 5 μm, 19 mm × 100 mm column, mobile phase H2O (A) and MeCN (B), and gradient 5-40% B (0.2% NH4OH final v / v% modifier), flow rate 30 mL / min) to obtain (R)- or (S)-1-(4-((7-(1-methyl-1H-pyrazole-4-yl)imidazo[1,2-c]pyrimidine-5-yl)oxy)azepan-1-yl)propa-2-in-1-one (1 mg, yield: 3%) as a clear oil. ESI-MS (M+H) + : 365.2.

[0267] Example 38: (R)-or (S)-1-(4-((7-(1-methyl-1H-pyrazole-4-yl)imidazo[1,2-c]pyrimidine-5-yl)oxy)azepan-1-yl)propa-2-en-1-one [ka]

[0268] 1. Synthesis of (R)- or (S)-1-(4-((7-(1-methyl-1H-pyrazole-4-yl)imidazo[1,2-c]pyrimidine-5-yl)oxy)azepan-1-yl)propa-2-en-1-one [ka] When propa-2-enoyl chloride (19 mg, 207 μmol, 17 μL) was added to a solution of E4 5-[(4R)-or (4S)-azepan-4-yl]oxy-7-(1-methylpyrazole-4-yl)imidazo[1,2-c]pyrimidine (32 mg, 104 μmol) in THF (1 mL), a precipitate formed instantaneously. Then, TEA (21 mg, 207 μmol, 29 μL) was added at room temperature while stirring. After stirring overnight, volatile substances were removed, and the residue was redissolved in DMSO. Purification by reverse-phase HPLC (Waters XSelect CSH C18, 5 μm, 19 mm × 100 mm column, mobile phase H2O (A) and MeCN (B), and gradient 5-35% B (0.2% NH4OH final v / v% modifier), flow rate 30 mL / min) yielded (R)- or (S)-1-(4-((7-(1-methyl-1H-pyrazole-4-yl)imidazo[1,2-c]pyrimidine-5-yl)oxy)azepan-1-yl)propa-2-en-1-one (11 mg, yield: 27%) as a yellow oil. ESI-MS (M+H) + : 367.2. 1 H NMR (500 MHz, DMSO-d6) δ 8.26 (d, J =12.82Hz,1H),8.04(d,J = 3.05 Hz, 1H), 7.70 (s, 1H), 7.51 (t, J =1.53Hz,1H),7.44(s,1H),6.82(ddd,J = 8.55, 10.38, 16.48 Hz, 1H), 6.17 (dd, J =2.14,16.18Hz,1H),5.69(dt,J = 2.44, 10.38 Hz, 1H), 5.53-5.64 (m, 1H), 3.89 (s, 3H), 3.75-3.83 (m, 1H), 3.50-3.71 (m, 3H), 2.18-2.26 (m, 1H), 2.06-2.17 (m, 2H), 1.91-2.02 (m, 2H), 1.69-1.82 (m, 1H).

[0269] Example 39: (R)-1-(3-((7-(1-methyl-1H-pyrazole-4-yl)imidazo[1,2-c]pyrimidine-5-yl)oxy)pyrrolidine-1-yl)prop-2-in-1-one [ka]

[0270] Synthesis of tert-butyl=(R)-3-((7-(1-methyl-1H-pyrazole-4-yl)imidazo[1,2-c]pyrimidine-5-yl)oxy)pyrrolidine-1-carboxylate [ka] 5-chloro-7-(1-methylpyrazole-4-yl)imidazo[1,2-c]pyrimidine (250 mg, 1.07 mmol), DMF (5.4 mL), sodium hydride (64 mg, 1.61 mmol, 60% suspension in mineral oil), and tert-butyl=(3R)-3-hydroxypyrrolidine-1-carboxylate (200 mg, 1.07 mmol) were added to the vial. The vial was stirred overnight at 80°C. The mixture was then diluted with MeOH and concentrated. The residue was then purified by silica gel column chromatography (10-100% [3:1 SiO:EtOH] / heptane) to obtain tert-butyl=(3R)-3-[7-(1-methylpyrazole-4-yl)imidazo[1,2-c]pyrimidine-5-yl]oxypyrrolidine-1-carboxylate (310 mg, 75% yield) as a mixture with the starting aryl chloride, which was used without further purification. LCMS m / z = 385.1 (M+H)+.

[0271] Synthesis of (R)-7-(1-methyl-1H-pyrazole-4-yl)-5-(pyrrolidine-3-yloxy)imidazo[1,2-c]pyrimidine hydrochloride [ka] A solution of tert-butyl=(3R)-3-[7-(1-methylpyrazole-4-yl)imidazo[1,2-c]pyrimidine-5-yl]oxypyrrolidine-1-carboxylate (310 mg, 806 μmol) in methanol (4 mL) was treated with HCl (4 M in dioxane, 2.0 mL), and the resulting mixture was stirred at room temperature for 1 hour. The mixture was then concentrated under vacuum, and the solid residue was used without further purification. LCMS m / z = 285.0 (M+H)+.

[0272] Synthesis of (R)-1-(3-((7-(1-methyl-1H-pyrazole-4-yl)imidazo[1,2-c]pyrimidine-5-yl)oxy)pyrrolidine-1-yl)propa-2-in-1-one [ka] 7-(1-methylpyrazole-4-yl)-5-[(3R)-pyrrolidine-3-yl]oxyimidazo[1,2-c]pyrimidine hydrochloride (114 mg, 355 μmol), DCM (3.6 mL), N-ethyl-N-isopropyl-propan-2-amine (310 μL, 1.78 mmol), and then propa-2-ic acid (33 μL, 533 μmol) were added to the vial. The vial was stirred at room temperature for 16 hours. The mixture was then concentrated, and the residue was purified by silica gel column chromatography (10-100% [3:1 HCl:EtOH] / heptane). The fractions were combined, concentrated, and then purified by preparative HPLC (Waters SunFire Prep, C18 5μm, OBD 30×50mm, eluted with 10-70% MeCN:H2O [containing 0.1% TFA modifier]) to obtain 1-[(3R)-3-[7-(1-methylpyrazole-4-yl)imidazo[1,2-c]pyrimidine-5-yl]oxypyrrolidine-1-yl]propa-2-in-1-one (27.3 mg, yield 23%) as a solid. LCMS m / z = 337.0 (M+H)+. 1H NMR (500 MHz, MeOD-d4)δ:8.46(d,J = 4.3 Hz, 1H), 8.23 ​​(d, J =2.4Hz,1H),8.12-8.07(m,1H),7.92(d,J = 2.4 Hz, 1H), 7.65 (d, J =4.9Hz,1H),6.21-6.09(m,1H),4.33-4.22(m,1H),4.16-4.07(m,1H),4.01(d,J = 1.2 Hz, 5H), 3.92-3.68 (m, 1H), 2.66-2.47 (m, 2H).

[0273] Examples 40-53. The compounds listed in the following table were prepared from 5-chloro-7-(1-methylpyrazole-4-yl)imidazo[1,2-c]pyrimidine and suitable alcohols and carboxylic acids according to the steps described in Example 39: [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4]

[0274] Example 54: (S)-1-(6-((6-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl)oxy)-1,4-oxazepan-4-yl)propa-2-en-1-one [ka]

[0275] Synthesis of tert-butyl=(6S)-6-[6-(1-methylpyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl]oxy-1,4-oxazepan-4-carboxylate [ka] A flask containing tert-butyl=(6S)-6-hydroxy-1,4-oxazepan-4-carboxylate (247 mg, 1.14 mmol) in anhydrous THF (2 mL) was cooled in an ice bath. Then, sodium tert-butoxide (168 mg, 1.74 mmol) was carefully added to the cooled mixture in several portions. After 10 minutes, 4-chloro-6-(1-methylpyrazole-4-yl)pyrazolo[1,5-a]pyrazine (235 mg, 1.01 mmol) was carefully added to the cooled heterogeneous mixture in several portions. After the addition of 4-chloro-6-(1-methylpyrazole-4-yl)pyrazolo[1,5-a]pyrazine was complete, the mixture was warmed to 23°C and monitored by LC-MS. After 18 hours, the reaction was carefully quenched by slowly adding water, and then the two-phase mixture was extracted three times with ethyl acetate. The organic matter was pooled and then dried over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the residue was loaded onto a silica gel column and purified with (30-100% ethyl acetate / heptane). The desired fraction was pooled and then concentrated under reduced pressure to obtain a white solid as tert-butyl=(6S)-6-[6-(1-methylpyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl]oxy-1,4-oxazepan-4-carboxylate (319 mg, 76% yield), which was used without further purification. LCMS m / z = 415.1(M+H) + . 1 HNMR(500MHz,DMSO-d6)d=8.77(s,1H),8.29-8.17(m,1H),8.11-7.91(m,2H),6.85-6.75(m,1H),5.62-5. 53(m,1H),4.28-3.94(m,3H),3.93-3.74(m,4H),3.47-3.36(m,1H),3.73-3.32(m,3H),1.76-0.98(m,9H).

[0276] Synthesis of (6S)-6-[6-(1-methylpyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl]oxy-1,4-oxazepane [ka] A vial containing tert-butyl=(6S)-6-[6-(1-methylpyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl]oxy-1,4-oxazepane-4-carboxylate (319 mg, 769 μmol) in anhydrous dichloromethane (2 mL) was cooled in an ice bath. Trifluoroacetic acid (1 mL, 13 mmol) was then carefully added dropwise to the cooled mixture. After the addition of TFA was complete, the mixture was warmed to 23°C and monitored by LC-MS. After 1 hour, the reaction was carefully concentrated under reduced pressure to obtain a pale yellow film as (6S)-6-[6-(1-methylpyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl]oxy-1,4-oxazepane (345 mg, TFA salt), which was used without further purification. LC-MS m / z = 315.0(M+H) + .

[0277] Synthesis of 1-[(6S)-6-[6-(1-methylpyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl]oxy-1,4-oxazepan-4-yl]propa-2-en-1-one [ka] To a vial containing (6S)-6-[6-(1-methylpyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl]oxy-1,4-oxazepane (329 mg, 769 μmol, TFA salt) in anhydrous dichloromethane (3 mL), Hünig base (0.7 mL, 4.02 mmol) was carefully added dropwise at -25°C. After 5 minutes, acryloyl chloride (0.2 mL, 2.46 mmol) was carefully added dropwise to the cooled homogeneous solution. After the addition of acryloyl chloride was complete, the reaction mixture was warmed to 23°C and monitored by LC-MS and TLC. After 3 minutes, the reaction mixture was carefully quenched by slowly adding saturated sodium bicarbonate aqueous solution. The two-phase mixture was loaded onto a silica gel column and purified with (15-75% [3:1 ethyl acetate:ethanol] / heptane). The desired fraction was pooled and then concentrated under reduced pressure to obtain a white solid as 1-[(6S)-6-[6-(1-methylpyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl]oxy-1,4-oxazepan-4-yl]propa-2-en-1-one (226 mg, 76% yield). 1 H NMR (500MHz, DMSO-d6)d= 8.82 - 8.74 (m, 1H), 8.27 - 8.19 (m, 1H), 8.13 - 7.96 (m, 2H), 6.92 - 6.73 (m, 2H), 6.19 (dd, J LCMS m / z = 369.1(M+H) + .

[0278] Example 55: (S)-1-(3-((6-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl)oxy)azepan-1-yl)propa-2-en-1-one [ka] Synthesis of tert-butyl=(3S)-3-[6-(1-methylpyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl]oxyazepan-1-carboxylate [ka] A vial containing tert-butyl=(3S)-3-hydroxyazepan-1-carboxylate (464 mg, 2.16 mmol) in anhydrous THF (8 mL) was cooled in an ice bath. Then, sodium tert-butoxide (314 mg, 3.27 mmol) was carefully added to the cooled mixture in several portions. After 15 minutes, 4-chloro-6-(1-methylpyrazole-4-yl)pyrazolo[1,5-a]pyrazine (495 mg, 2.12 mmol) was carefully added to the cooled heterogeneous mixture in several portions. After the addition of 4-chloro-6-(1-methylpyrazole-4-yl)pyrazolo[1,5-a]pyrazine was complete, the mixture was warmed to 23°C and monitored by LC-MS. After 2.5 hours, the reaction was carefully quenched by slowly adding water. The two-phase mixture was extracted three times with ethyl acetate and then dried over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the residue was loaded onto a silica gel column and purified with (0-30% [3:1 ethyl acetate:ethanol] / heptane). The desired fraction was pooled and then concentrated under reduced pressure to obtain a yellow film as tert-butyl=(3S)-3-[6-(1-methylpyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl]oxyazepan-1-carboxylate, which was used without further purification. LCMS m / z = 413.2(M+H) + .

[0279] Synthesis of 4-[(3S)-azepan-3-yl]oxy-6-(1-methylpyrazole-4-yl)pyrazolo[1,5-a]pyrazine [ka] A vial containing tert-butyl=(3S)-3-[6-(1-methylpyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl]oxyazepan-1-carboxylate (787 mg, 1.91 mmol) in anhydrous methanol (2 mL) was cooled in an ice bath. Then, HCl (1.25 M in methanol, 4 mL) was carefully added dropwise to the cooled mixture. After the addition of 1.25 M HCl in methanol was complete, the mixture was warmed to 23°C and monitored by LC-MS. After 6 days, the reaction was carefully concentrated under reduced pressure to obtain a pale yellow film as 4-[(3S)-azepan-3-yl]oxy-6-(1-methylpyrazole-4-yl)pyrazolo[1,5-a]pyrazine hydrochloride (672 mg, crude), which was used without further purification. LC-MS: m / z = 313.2(M+H) + .

[0280] Synthesis of 1-[(3S)-3-[6-(1-methylpyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl]oxyazepan-1-yl]propa-2-en-1-one [ka] To a vial containing 4-[(3S)-azepan-3-yl]oxy-6-(1-methylpyrazole-4-yl)pyrazolo[1,5-a]pyrazine hydrochloride (288 mg, 824 μmol) in anhydrous dichloromethane (2 mL), Hünig base (0.7 mL, 4.02 mmol) was carefully added dropwise at -25°C. After 5 minutes, acryloyl chloride (0.15 mL, 1.85 mmol) was carefully added dropwise to the cooled homogeneous solution. After the addition of acryloyl chloride was complete, the reaction mixture was warmed to 23°C and monitored by LC-MS and TLC. After 3 minutes, the reaction mixture was carefully quenched by slowly adding saturated sodium bicarbonate aqueous solution. The two-phase mixture was loaded onto a silica gel column and purified with (15-75% [3:1 ethyl acetate:ethanol] / heptane). The desired fraction was pooled and then concentrated under reduced pressure to obtain a white solid as 1-[(3S)-3-[6-(1-methylpyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl]oxyazepan-1-yl]propa-2-en-1-one (73 mg, 23% yield). 1 H NMR (500MHz, DMSO-d6)d= 8.76 (d, J =6.1Hz,1H),8.29- 8.18 (m, 1H), 8.06 - 7.99 (m, 1H), 6.88 - 6.68 (m, 2H), 6.16 (dt, J =2.4,16.8Hz,1H),5.74- 5.51 (m, 2H), 4.33 (br dd, J =5.5,13.4Hz,1H),4.01- 3.91 (m, 1H), 3.90 - 3.64 (m, 3H), 3.64 - 3.43 (m, 2H), 2.13 - 2.00 (m, 1H), 2.00 - 1.62 (m, 4H), 1.62 - 1.37 (m, 2H).LCMS m / z = 367.1(M+H) + .

[0281] Example 56: (R)-1-(3-((6-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl)oxy)azepan-1-yl)propa-2-en-1-one [ka]

[0282] Synthesis of tert-butyl=(3R)-3-[6-(1-methylpyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl]oxyazepan-1-carboxylate [ka] A vial containing tert-butyl=(3R)-3-hydroxyazepan-1-carboxylate (550 mg, 2.56 mmol) in anhydrous THF (9 mL) was cooled in an ice bath. Then, sodium tert-butoxide (338 mg, 3.52 mmol) was carefully added to the cooled mixture in several portions. After 15 minutes, 4-chloro-6-(1-methylpyrazole-4-yl)pyrazolo[1,5-a]pyrazine (537 mg, 2.30 mmol) was carefully added to the cooled heterogeneous mixture in several portions. After the addition of 4-chloro-6-(1-methylpyrazole-4-yl)pyrazolo[1,5-a]pyrazine was complete, the mixture was warmed to 23°C and monitored by LC-MS. After 2 hours, the reaction was carefully quenched by slowly adding water. The two-phase mixture was extracted three times with ethyl acetate and then dried over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the residue was loaded onto a silica gel column and purified with (20-65% ethyl acetate / heptane). The desired fraction was pooled and then concentrated under reduced pressure to obtain a yellow film as tert-butyl=(3R)-3-[6-(1-methylpyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl]oxyazepan-1-carboxylate (905.5 mg, 96% yield), which was used without further purification. LCMS: m / z = 413.2(M+H) + . 1H NMR (500MHz, DMSO-d6)d= 8.79 - 8.72 (m, 1H), 8.28 - 8.18 (m, 1H), 8.11 - 7.97 (m, 2H), 6.78 (dd, J = 1.2, 18.3 Hz, 1H), 5.58 - 5.47 (m, 1H), 4.09 - 4.02 (m, 1H), 4.01 - 3.87 (m, 3H), 3.61 - 3.19 (m, 4H), 1.97 - 1.78 (m, 3H), 1.78 - 1.62 (m, 2H), 1.41 (s, 3H), 1.46 - 1.05 (m, 6H).

[0283] Synthesis of 4-[(3R)-azepan-3-yl]oxy-6-(1-methylpyrazole-4-yl)pyrazolo[1,5-a]pyrazine [ka] A vial containing tert-butyl=(3R)-3-[6-(1-methylpyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl]oxyazepan-1-carboxylate (905.5 mg, 2.20 mmol) in anhydrous dichloromethane (2 mL) was cooled in an ice bath. Then, trifluoroacetic acid (2 mL, 26.1 mmol) was carefully added dropwise to the cooled mixture. After the addition of TFA was complete, the mixture was warmed to 23°C and monitored by LC-MS. After 1 hour, the reaction was carefully concentrated under reduced pressure to obtain a pale yellow film as 4-[(3R)-azepan-3-yl]oxy-6-(1-methylpyrazole-4-yl)pyrazolo[1,5-a]pyrazine (941.1 mg, 100% yield, TFA salt), which was used without further purification. LC-MS m / z = 313.1(M+H) + .

[0284] Synthesis of 1-[(3R)-3-[6-(1-methylpyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl]oxyazepan-1-yl]propa-2-en-1-one [ka] To a vial containing 4-[(3R)-azepan-3-yl]oxy-6-(1-methylpyrazole-4-yl)pyrazolo[1,5-a]pyrazine (191 mg, 612 mmol, TFA salt) in anhydrous dichloromethane (2 mL), Hünig base (0.5 mL, 2.87 mmol) was carefully added dropwise at -25°C. After 5 minutes, acryloyl chloride (0.1 mL, 1.23 mmol) was carefully added dropwise to the cooled homogeneous solution. After the addition of acryloyl chloride was complete, the reaction mixture was warmed to 23°C and monitored by LC-MS and TLC. After 3 minutes, the reaction mixture was carefully quenched by slowly adding saturated sodium bicarbonate aqueous solution. The two-phase mixture was loaded onto a silica gel column and purified with (15-75% [3:1 ethyl acetate:ethanol] / heptane). The desired fraction was pooled and then concentrated under reduced pressure to obtain a white solid as 1-[(3R)-3-[6-(1-methylpyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl]oxyazepan-1-yl]propa-2-en-1-one. 1 H NMR (500MHz, DMSO-d6)d= 8.76 (d, J =5.5Hz,1H),8.29- 8.18 (m, 1H), 8.06 - 8.01 (m, 1H), 6.88 - 6.71 (m, 2H), 6.16 (dt, J =2.1,16.9Hz,1H),5.74- 5.51 (m, 2H), 4.33 (br dd, J =5.5,14.0Hz,1H),3.99- 3.91 (m, 1H), 3.90 - 3.68 (m, 3H), 3.59 - 3.43 (m, 2H), 2.06 (ddd, J =4.3,8.9,13.7Hz,1H),1.98- 1.66 (m, 4H), 1.65 - 1.42 (m, 2H).LCMS m / z = 367.1(M+H) + .

[0285] Example 57: 1-(4-((6-(1-methyl-1H-pyrazole-4-yl)-[1,2,4]triazolo[1,5-a]pyrazine-8-yl)oxy)azepan-1-yl)propa-2-en-1-one [ka]

[0286] Synthesis of tert-butyl=4-((6-bromo-[1,2,4]triazolo[1,5-a]pyrazine-8-yl)oxy)azepan-1-carboxylate [ka] A flask containing tert-butyl 4-hydroxyazepan-1-carboxylate (659 mg, 3.06 mmol) in anhydrous THF (10 mL) was cooled in an ice bath. Then, sodium tert-butoxide (454 mg, 4.72 mmol) was carefully added to the cooled mixture in several portions. After 15 minutes, 6,8-dibromo-[1,2,4]triazolo[1,5-a]pyrazine (850 mg, 3.06 mmol) was carefully added to the cooled heterogeneous mixture in several portions. After the addition of 6,8-dibromo-[1,2,4]triazolo[1,5-a]pyrazine was complete, the mixture was warmed to 23°C and monitored by LC-MS. After 2.5 hours, the reaction was carefully quenched by slowly adding water. The two-phase mixture was extracted three times with ethyl acetate and then dried over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the residue was loaded onto a silica gel column and purified with (20-45% ethyl acetate / heptane). The desired fraction was pooled and then concentrated under reduced pressure to obtain a slightly yellow film as tert-butyl=4-((6-bromo-[1,2,4]triazolo[1,5-a]pyrazine-8-yl)oxy)azepan-1-carboxylate (952.3 mg, 76% yield), which was used without further purification. LCMS: m / z = 412.0(M+H) + . 1H NMR (500MHz, DMSO-d6)d= 9.03 (s, 1H), 8.60 (s, 1H), 5.35 - 5.29 (m, 1H), 3.48 - 3.39 (m, 3H), 3.34 - 3.25 (m, 1H), 2.24 - 2.10 (m, 1H), 1.98 - 1.83 (m, 4H), 1.68 (br dd, J= 4.9, 9.2 Hz, 1H), 1.42 (s, 9H).

[0287] Synthesis of tert-butyl=4-((6-(1-methyl-1H-pyrazole-4-yl)-[1,2,4]triazolo[1,5-a]pyrazine-8-yl)oxy)azepan-1-carboxylate [ka] A flask containing tert-butyl=4-((6-bromo-[1,2,4]triazolo[1,5-a]pyrazine-8-yl)oxy)azepan-1-carboxylate (952 mg, 2.31 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (971 mg, 4.67 mmol), Pd(dppf)Cl2 dichloromethane adduct (300 mg, 367 μmol), and potassium carbonate (961 mg, 6.95 mmol) was degassed and then refilled with nitrogen. Dioxane (6 mL) and then water (0.6 mL) were added to the mixture. After the addition of water was complete, the reaction mixture was heated to 90°C and monitored by LC-MS. After 2.5 hours, the reaction mixture was carefully quenched by slowly adding water. The two-phase mixture was extracted three times with ethyl acetate and then dried over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the residue was loaded onto a silica gel column and purified with (25-100% ethyl acetate / heptane). The desired fraction was pooled and then concentrated under reduced pressure to obtain a viscous yellow foam as tert-butyl=4-((6-(1-methyl-1H-pyrazole-4-yl)-[1,2,4]triazolo[1,5-a]pyrazine-8-yl)oxy)azepan-1-carboxylate (707.6 mg, yield 74%), which was used without further purification.1 H NMR (500MHz, DMSO-d6)d= 8.97 (s, 1H), 8.55 (s, 1H), 8.25 (br d, J= 15.3 Hz, 1H), 8.04 (d, J= 9.8 Hz, 1H), 5.52 - 5.45 (m, 1H), 3.59 - 3.42 (m, 3H), 3.41 - 3.35 (m, 1H), 3.35 - 3.25 (m, 4H), 2.26 - 2.19 (m, 1H), 2.05 - 1.85 (m, 4H), 1.73 (br dd, J = 4.6, 8.9 Hz, 2H), 1.43 (d, J = 6.7 Hz, 7H).LCMS m / z = 414.2(M+H) + .

[0288] Synthesis of 8-(azepan-4-yloxy)-6-(1-methyl-1H-pyrazole-4-yl)-[1,2,4]triazolo[1,5-a]pyrazine [ka] A vial containing tert-butyl=4-((6-(1-methyl-1H-pyrazole-4-yl)-[1,2,4]triazolo[1,5-a]pyrazine-8-yl)oxy)azepan-1-carboxylate (708 mg, 1.71 mmol) in anhydrous dichloromethane (1 mL) was cooled in an ice bath. Then, trifluoroacetic acid (1 mL, 13.1 mmol) was carefully added dropwise to the cooled mixture. After the addition of TFA was complete, the mixture was warmed to 23°C and monitored by LC-MS. After 1 hour, the reaction product was carefully concentrated under reduced pressure to obtain a pale yellow film as 8-(azepan-4-yloxy)-6-(1-methyl-1H-pyrazole-4-yl)-[1,2,4]triazolo[1,5-a]pyrazine (301 mg, TFA salt), which was used without further purification. LCMS m / z = 314.1(M+H) + .

[0289] Synthesis of 1-(4-((6-(1-methyl-1H-pyrazole-4-yl)-[1,2,4]triazolo[1,5-a]pyrazine-8-yl)oxy)azepan-1-yl)propa-2-en-1-one [ka] To a vial containing 8-(azepan-4-yloxy)-6-(1-methyl-1H-pyrazole-4-yl)-[1,2,4]triazolo[1,5-a]pyrazine (301 mg, 704.5 μmol, TFA salt) in anhydrous dichloromethane (2 mL), Hünig base (0.5 mL, 2.87 mmol) was carefully added dropwise at -25°C. After 5 minutes, acryloyl chloride (0.1 mL, 1.23 mmol) was carefully added dropwise to the cooled homogeneous solution. After the addition of acryloyl chloride was complete, the reaction mixture was warmed to 23°C and monitored by LC-MS and TLC. After 3 minutes, the reaction mixture was carefully quenched by slowly adding saturated sodium bicarbonate aqueous solution. The two-phase mixture was loaded onto a silica gel column and purified with (20-85% [3:1 ethyl acetate:ethanol] / heptane). The desired fraction was pooled and then concentrated under reduced pressure to obtain a white solid as 1-(4-((6-(1-methyl-1H-pyrazole-4-yl)-[1,2,4]triazolo[1,5-a]pyrazine-8-yl)oxy)azepan-1-yl)propa-2-en-1-one (96 mg, 35% yield). 1H NMR (500MHz, DMSO-d6)d= 8.97 (s, 1H), 8.55 (d, J =1.2Hz,1H),8.28- 8.21 (m, 1H), 8.04 (d, J =7.3Hz,1H),6.82(ddd,J = 10.4, 12.2, 16.5 Hz, 1H), 6.18 (td, J =2.2,16.9Hz,1H),5.70(dd,J = 2.4, 10.4 Hz, 1H), 5.53 -5.44(m,1H),3.90(d,J = 1.8 Hz, 3H), 3.88 -3.61(m,3H),3.59- 3.49 (m, 2H), 2.31 - 2.21 (m, 1H), 2.06 - 1.97 (m, 3H), 1.83 - 1.71 (m, 1H).LCMS m / z = 368.1(M+H) + .

[0290] Example 58: (R)-1-(6-((6-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl)oxy)-1,4-oxazepan-4-yl)propa-2-en-1-one [ka]

[0291] Synthesis of tert-butyl=(6R)-6-[6-(1-methylpyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl]oxy-1,4-oxazepan-4-carboxylate [ka]

[0292] A flask containing tert-butyl=(6R)-6-hydroxy-1,4-oxazepan-4-carboxylate (496 mg, 2.28 mmol) in anhydrous THF (4 mL) was cooled in an ice bath. Then, sodium tert-butoxide (308 mg, 3.20 mmol) was carefully added to the cooled mixture in several portions. After 10 minutes, 4-chloro-6-(1-methylpyrazole-4-yl)pyrazolo[1,5-a]pyrazine (465 mg, 1.99 mmol) was carefully added to the cooled heterogeneous mixture in several portions. After the addition of 4-chloro-6-(1-methylpyrazole-4-yl)pyrazolo[1,5-a]pyrazine was complete, the mixture was warmed to 23°C and monitored by LC-MS. After 2 hours, the reaction was carefully quenched by slowly adding water, and then the two-phase mixture was extracted three times with ethyl acetate. The organic matter was pooled and then dried over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the residue was loaded onto a silica gel column and purified with (30-100% ethyl acetate / heptane). The desired fraction was pooled and then concentrated under reduced pressure to obtain a white solid as tert-butyl=(6R)-6-[6-(1-methylpyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl]oxy-1,4-oxazepan-4-carboxylate (757.9 mg, 92% yield), which was used without further purification. 1 H NMR (500MHz, DMSO-d6)d=8.77(s,1H),8.27-8.19(m,1H),8.08-7.95(m,2H),6.82-6.76(m,1H),5.58(brd,J = 3.7 Hz, 1H), 4.14 -3.92(m,3H),3.88(s,3H),3.85- 3.80 (m, 1H), 3.79 - 3.57 (m, 3H), 3.45 - 3.37 (m, 1H), 1.46 - 1.04 (m, 9H).LCMS m / z = 415.1(M+H) + .

[0293] Synthesis of (6R)-6-[6-(1-methylpyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl]oxy-1,4-oxazepane [ka] A vial containing tert-butyl=(6R)-6-[6-(1-methylpyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl]oxy-1,4-oxazepan-4-carboxylate (758 mg, 1.83 mmol) in anhydrous dichloromethane (2 mL) was cooled in an ice bath, and then trifluoroacetic acid (2 mL, 26.1 mmol) was carefully added dropwise to the cooled mixture. After the addition of TFA was complete, the mixture was warmed to 23°C and monitored by LC-MS. After 18 hours, the reaction product was carefully concentrated under reduced pressure to obtain a pale yellow film as (6R)-6-[6-(1-methylpyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl]oxy-1,4-oxazepan (783.3 mg, crude, TFA salt), which was used without further purification. LCMS m / z = 315.0(M+H) + .

[0294] Synthesis of 1-[(6R)-6-[6-(1-methylpyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl]oxy-1,4-oxazepan-4-yl]propa-2-en-1-one [ka] To a vial containing (6R)-6-[6-(1-methylpyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl]oxy-1,4-oxazepane (253 mg, 591 μmol, TFA salt) in anhydrous dichloromethane (2 mL), Hünig base (0.5 mL, 2.87 mmol) was carefully added dropwise at -25°C. After 5 minutes, acryloyl chloride (0.1 mL, 1.23 mmol) was carefully added dropwise to the cooled homogeneous solution. After the addition of acryloyl chloride was complete, the reaction mixture was warmed to 23°C and monitored by LC-MS and TLC. After 3 minutes, the reaction mixture was carefully quenched by slowly adding saturated sodium bicarbonate aqueous solution. The two-phase mixture was loaded onto a silica gel column and purified with (15-100% [3:1 ethyl acetate:ethanol] / heptane). The desired fraction was pooled and then concentrated under reduced pressure to obtain a white solid as 1-[(6R)-6-[6-(1-methylpyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl]oxy-1,4-oxazepan-4-yl]propa-2-en-1-one. LCMS: m / z = 369.1(M+H) + . 1 H NMR (500MHz, DMSO-d6)d= 8.80 - 8.73 (m, 1H), 8.28 - 8.19 (m, 1H), 8.13 - 7.99 (m, 2H), 6.92 - 6.73 (m, 2H), 6.19 (dd, J =2.1,16.8Hz,1H),5.90- 5.59 (m, 3H), 4.56 - 4.42 (m, 1H), 4.18 - 4.09 (m, 1H), 4.03 - 3.92 (m, 2H), 3.90 - 3.84 (m, 3H), 3.78 - 3.54 (m, 3H).

[0295] Example 59: (R)-4-((1-acryloylazepan-4-yl)oxy)-6-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyrazine-3-carbonitrile [ka]

[0296] Synthesis of 4-chloro-3-iodo-6-(1-methylpyrazole-4-yl)pyrazolo[1,5-a]pyrazine [ka] A vial containing 4-chloro-6-(1-methylpyrazole-4-yl)pyrazolo[1,5-a]pyrazine (477 mg, 2.04 mmol) in anhydrous DMF (5 mL) was cooled in an ice bath. Then, N-iodosuccinimide (1.23 g, 5.48 mmol) was carefully added to the cooled mixture in several portions. After 15 minutes, the turbid yellow mixture was carefully heated to 50°C and monitored by LC-MS. After 2 hours, the reaction mixture was cooled to 23°C and stirred overnight. After 19 hours, the heterogeneous mixture was filtered. The off-white solid was identified as 4-chloro-3-iodo-6-(1-methylpyrazole-4-yl)pyrazolo[1,5-a]pyrazine, which was used without purification. 1 H NMR (500MHz, DMSO-d6)δ= 9.29 (s, 1H), 8.31 (s, 1H), 8.27 (s, 1H), 8.06 - 8.00 (m, 1H), 3.95 - 3.84 (m, 3H).LCMS m / z = 359.9(M+H) + .

[0297] Synthesis of tert-butyl=(4R)-4-[3-iodo-6-(1-methylpyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl]oxyazepan-1-carboxylate [ka] A vial containing tert-butyl=(4R)-4-hydroxyazepan-1-carboxylate (113 mg, 525 μmol) in anhydrous THF (2 mL) was cooled in an ice bath. Then, sodium tert-butoxide (79.5 mg, 827 μmol) was carefully added to the cooled mixture in several portions. After 10 minutes, 4-chloro-3-iodo-6-(1-methylpyrazole-4-yl)pyrazolo[1,5-a]pyrazine (181 mg, 504 μmol) was carefully added to the cooled heterogeneous mixture in several portions. After the addition of 4-chloro-3-iodo-6-(1-methylpyrazole-4-yl)pyrazolo[1,5-a]pyrazine was complete, the mixture was warmed to 23°C and monitored by LC-MS. After 18 hours, the heterogeneous reaction product was carefully concentrated under reduced pressure. The residue was diluted with ethyl acetate and then washed with saturated sodium chloride aqueous solution. The organic layer was dried over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the residue was loaded onto a silica gel column and purified with (20-65% ethyl acetate / heptane). The desired fraction was pooled and then concentrated under reduced pressure to obtain a colorless, viscous film as tert-butyl=(4R)-4-[3-iodo-6-(1-methylpyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl]oxyazepan-1-carboxylate (99.3 mg, 36% yield), which was used without further purification. 1 H NMR (400MHz, DMSO-d6)δ= 8.78 (s, 1H), 8.19 (d, J = 6.0 Hz, 1H), 8.09 (s, 1H), 7.99 (d, J = 2.5 Hz, 1H), 5.59 (br s, 1H), 3.88 (s, 3H), 3.72 - 3.38 (m, 4H), 2.09 - 1.97 (m, 3H), 1.83 - 1.71 (m, 2H), 1.55 - 1.46 (m, 1H), 1.42 (d, J = 5.0 Hz, 9H).LCMS m / z = 539.0(M+H) + .

[0298] Synthesis of tert-butyl=(4R)-4-[3-cyano-6-(1-methylpyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl]oxyazepan-1-carboxylate [ka] Vials containing tert-butyl=(4R)-4-[3-iodo-6-(1-methylpyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl]oxyazepan-1-carboxylate (106 mg, 196 μmol), potassium hexacyanoferrate(II) trihydrate (44 mg, 104 μmol), dicyclohexyl-[2-(2,4,6-triisopropylphenyl)phenyl]phosphane (Xphos) (10 mg, 21 μmol), [2-(2-aminophenyl)phenyl]-methylsulfonyloxypalladium; dicyclohexyl-[2-(2,4,6-triisopropylphenyl)phenyl]phosphane (Xphos G3) (17 mg, 20 μmol), and potassium acetate (40 mg, 408 μmol) in dioxane (1 mL) and water (1 mL) were degassed and refilled with nitrogen. (The mixture was evacuated and refilled with nitrogen three times.) The heterogeneous white reaction mixture was carefully heated to 90°C and monitored by LC-MS. After 18 hours, the heterogeneous reaction mixture was cooled to room temperature and then carefully partitioned into water and ethyl acetate. The aqueous layer was extracted twice more with ethyl acetate. The organic extract was pooled and then washed once with saturated sodium chloride aqueous solution, and the organic layer was dried over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the residue was loaded onto a silica gel column and purified with (25-80% ethyl acetate / heptane). The desired fraction was pooled and then concentrated under reduced pressure to obtain a colorless, sticky film as tert-butyl=(4R)-4-[3-cyano-6-(1-methylpyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl]oxyazepan-1-carboxylate (10.2 mg, yield 12%), which was used without further purification. LC-MS m / z = 460.1(M+Na) + .

[0299] Synthesis of 4-[(4R)-azepan-4-yl]oxy-6-(1-methylpyrazole-4-yl)pyrazolo[1,5-a]pyrazine-3-carbonitrile [ka] A vial containing tert-butyl=(4R)-4-[3-cyano-6-(1-methylpyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl]oxyazepan-1-carboxylate (10 mg, 23 μmol) in anhydrous dichloromethane (0.5 mL) was cooled in an ice bath, and then TFA (0.05 mL, 653 μmol) was carefully added dropwise to the cooled mixture. After the addition of TFA was complete, the mixture was warmed to 23°C and monitored by LC-MS. After 15 minutes, the reaction product was carefully concentrated under reduced pressure to obtain a pale yellow film as 4-[(4R)-azepan-4-yl]oxy-6-(1-methylpyrazole-4-yl)pyrazolo[1,5-a]pyrazine-3-carbonitrile (11 mg, trifluoroacetate), which was used without purification. LCMS m / z = 338.1(M+H) + .

[0300] Synthesis of 6-(1-methylpyrazole-4-yl)-4-[(4R)-1-propa-2-enoylazepan-4-yl]oxypyrazolo[1,5-a]pyrazine-3-carbonitrile [ka] To a vial containing 4-[(4R)-azepan-4-yl]oxy-6-(1-methylpyrazole-4-yl)pyrazolo[1,5-a]pyrazine-3-carbonitrilate (11 mg, 24.4 μmol, trifluoroacetate) in anhydrous THF (0.5 mL), Hünig base (0.1 mL, 574 μmol) was carefully added dropwise at -25°C. After 5 minutes, acryloyl chloride (0.01 mL, 123 μmol) was carefully added dropwise to the cooled homogeneous solution. After the addition of acryloyl chloride was complete, the reaction mixture was warmed to 23°C and monitored by LC-MS and TLC. After 3 minutes, the reaction mixture was carefully quenched by slowly adding saturated sodium bicarbonate aqueous solution. The two-phase mixture was loaded onto a silica gel column and purified with (25-85% [3:1 ethyl acetate:ethanol] / heptane). The desired fraction was pooled and then concentrated under reduced pressure to obtain a colorless film as 6-(1-methylpyrazole-4-yl)-4-[(4R)-1-propa-2-enoylazepan-4-yl]oxy-pyrazolo[1,5-a]pyrazine-3-carbonitrile. 1 H NMR (400MHz, dichloromethane-d2)δ= 8.30 - 8.16 (m, 2H), 7.96 - 7.89 (m, 1H), 7.88 - 7.87 (m, 1H), 6.75 - 6.61 (m, 1H), 6.33 - 6.25 (m, 1H), 5.71 - 5.64 (m, 2H), 4.16 - 3.95 (m, 4H), 3.86 - 3.54 (m, 3H), 3.49 - 3.34 (m, 1H), 2.35 - 2.13 (m, 4H), 1.96 (br d, J = 11.5 Hz, 1H).LCMS m / z = 392.1(M+H) + .

[0301] Example 60: N-methyl-N-((trans)-3-((3-methyl-6-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl)oxy)cyclobutyl)acrylamide [ka]

[0302] Synthesis of tert-butyl=((trans)-3-((3-iodo-6-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl)oxy)cyclobutyl)(methyl)carbamate [ka] A vial containing racemic trans tert-butyl=N-(3-hydroxycyclobutyl)-N-methyl-carbamate (406 mg, 2.0 mmol) in anhydrous THF (6 mL) was cooled in an ice bath. Then, sodium tert-butoxide (333 mg, 3.47 mmol) was carefully added to the cooled mixture in several portions. After 10 minutes, 4-chloro-3-iodo-6-(1-methylpyrazole-4-yl)pyrazolo[1,5-a]pyrazine (593 mg, 1.65 mmol) was carefully added to the cooled mixture. After the addition of 4-chloro-3-iodo-6-(1-methylpyrazole-4-yl)pyrazolo[1,5-a]pyrazine was complete, the mixture was warmed to 23°C. After 1 hour, the reaction was carefully quenched by slowly adding saturated sodium bicarbonate aqueous solution, and then the two-phase mixture was extracted three times with ethyl acetate. The organic matter was pooled and then dried over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the residue was loaded onto a silica gel column and purified with (15-70% ethyl acetate / heptane). The desired fraction was pooled and then concentrated under reduced pressure to obtain a white solid as tert-butyl=((trans)-3-((3-iodo-6-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl)oxy)cyclobutyl)(methyl)carbamate (698.5 mg, crude), which was used without further purification. 1H NMR (500MHz, DMSO-d6)δ= 8.79 (s, 1H), 8.16 (s, 1H), 8.11 (s, 1H), 7.98 (s, 1H), 5.45 (br t, J= 6.7 Hz, 1H), 4.89 (br s, 1H), 3.88 (s, 3H), 2.89 - 2.84 (m, 3H), 2.79 - 2.72 (m, 2H), 2.48 - 2.42 (m, 2H), 1.41 (s, 9H).LCMS: m / z = 525.0(M+H) + .

[0303] Synthesis of tert-butyl=methyl((trans)-3-((3-methyl-6-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl)oxy)cyclobutyl)carbamate [ka]

[0304] A vial containing tert-butyl=((trans)-3-((3-iodo-6-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl)oxy)cyclobutyl)(methyl)carbamate (204 mg, 389 μmol), methylboronic acid (81 mg, 1.35 mmol), tricyclohexylphosphane (29 mg, 105 μmol), Pd2(dba)3 (36 mg, 39 μmol), Pd(dppf)Cl2·CH2Cl2 (68 mg, 84 μmol), and tripotassium phosphate (1.0 M solution, 1.2 mL) in dioxane (4 mL) was degassed and refilled with nitrogen. The evacuation and refilling with nitrogen was repeated three times. The heterogeneous reaction mixture was carefully heated to 90°C. After 18 hours, the heterogeneous reaction mixture was cooled to room temperature and then carefully partitioned into water and ethyl acetate. The aqueous layer was extracted twice more with ethyl acetate. The organic extract was pooled and then washed once with saturated sodium chloride aqueous solution, and the organic layer was dried over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the residue was loaded onto a silica gel column and purified with (30-90% ethyl acetate / heptane). The desired fraction was pooled and then concentrated under reduced pressure to obtain a dark yellow film as tert-butyl=methyl((trans)-3-((3-methyl-6-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl)oxy)cyclobutyl)carbamate (125.7 mg, yield 78%), which was used without further purification. LCMS m / z = 413.2(M+H) + .

[0305] Synthesis of (trans)-N-methyl-3-((3-methyl-6-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl)oxy)cyclobutan-1-amine [ka]

[0306] A vial containing tert-butyl=methyl((trans)-3-((3-methyl-6-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl)oxy)cyclobutyl)carbamate (125.7 mg, 305 μmol) in anhydrous dichloromethane (2 mL) was cooled in an ice bath, and then trifluoroacetic acid (0.23 mL, 3 mmol) was carefully added dropwise to the cooled mixture. After the addition of TFA was complete, the mixture was warmed to 23°C. After 1.5 hours, the reaction product was carefully concentrated under reduced pressure to obtain a pale yellow film as (trans)-N-methyl-3-((3-methyl-6-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl)oxy)cyclobutan-1-amine=trifluoroacetate (133.9 mg, crude), which was used without purification. LCMS m / z = 313.1(M+H) + .

[0307] Synthesis of N-methyl-N-((trans)-3-((3-methyl-6-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl)oxy)cyclobutyl)acrylamide [ka] (trans)-N-methyl-3-((3-methyl-6-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl)oxy)cyclobutan-1-amine=trifluoroacetate (133.9 mg, 314 μmol) was carefully added dropwise to a vial containing (trans)-N-methyl-3-((3-methyl-6-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl)oxy)cyclobutan-1-amine=trifluoroacetate (133.9 mg, 314 μmol) at -25°C. After 5 minutes, acryloyl chloride (0.05 mL, 615 μmol) was carefully added dropwise to the cooled homogeneous solution. After the addition of acryloyl chloride was complete, the reaction mixture was warmed to 23°C and monitored by LC-MS and TLC. After 3 minutes, the reaction mixture was carefully quenched by slowly adding saturated sodium bicarbonate aqueous solution. The mixture was stirred at 23°C for 1 hour, and then the two-phase mixture was extracted three times with ethyl acetate. The organic matter was pooled and washed once with saturated sodium bicarbonate aqueous solution. The organic layer was separated and then dried over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the residue was loaded onto a silica gel column and purified with (15-65% [3:1 ethyl acetate:ethanol] / heptane). The desired fraction was pooled and then concentrated under reduced pressure to obtain a white foamy substance, which was diluted with DMSO and then filtered. The homogeneous mixture was purified by reversed-phase mass spectrometry-connected HPLC. (Liquid chromatography was performed using a Waters XSelect CSH C18, 5 μm, 19 mm × 100 mm column, mobile phases H2O(A) and MeCN(B), and a gradient of 5-60% B (with a final v / v% modifier of 0.2% NH4OH), at a flow rate of 30 mL / min.) The fraction containing the desired product was pooled and then concentrated to obtain a colorless film as N-methyl-N-((trans)-3-((3-methyl-6-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl)oxy)cyclobutyl)acrylamide. 1H NMR (500MHz, DMSO-d6) δ = 8.62 (s, 1H), 8.14 (s, 1H), 7.97 (s, 1H), 7.84 (s, 1H), 6.76 (br dd, J= 11.0, 16.5 Hz, 1H), 6.09 (br s, 1H), 5.68 (br s, 1H), 5.49 (br s, 1H), 5.35 - 4.90 (m, 1H), 3.88 (s, 3H), 3.15 - 2.77 (m, 5H), 2.67 - 2.52 (m, 2H), 2.47 (s, 3H).LCMS m / z = 367.2(M+H) + .

[0308] Example 61: 1-[(4R)-4-[3-fluoro-6-(1-methylpyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl]oxyazepan-1-yl]propa-2-en-1-one [ka]

[0309] Synthesis of tert-butyl=(4R)-4-[3-fluoro-6-(1-methylpyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl]oxyazepan-1-carboxylate [ka] A solution of tert-butyl=(4R)-4-[3-iodo-6-(1-methylpyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl]oxyazepan-1-carboxylate (224 mg, 416 μmol) in THF (3 mL) was cooled to -78 °C, and butyllithium (2.5 M, 200 μL) was added and the mixture was stirred for 20 minutes. Then, N-fluorobenzenesulfonimide (157 mg, 499 μmol) in THF was added, and the reaction mixture was stirred for 1 hour. The reaction mixture was quenched by adding aqueous NH4Cl. The reaction mixture was diluted with ELISA, the layers were separated, and the aqueous layer was extracted with ELISA. The combined organic layers were dried over Na2SO4, and the concentrated residue was purified with (SiO2, 0-70% siRNA / DCM) to obtain tert-butyl=(4R)-4-[3-fluoro-6-(1-methylpyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl]oxyazepan-1-carboxylate (25.3 mg, yield 14%) as an amorphous solid. LCMS: Rt = 0.93 min, m / z 431.2. 1 H NMR (400 MHz, chloroform-d)δ7.99 (d, J= 1.51 Hz, 1H), 7.83 (s, 1H), 7.74-7.83 (m, 1H), 7.70 (d, J= 3.76 Hz, 1H), 5.52-5.61 (m, 1H), 3.97 (s, 3H), 3.51-3.82 (m, 2H), 3.25-3.48 (m, 2H), 2.07-2.17 (m, 3H), 1.98 (br d, J= 12.05 Hz, 2H), 1.78 (br d, J = 5.02 Hz, 1H), 1.49 (s, 9H). 19 F NMR (376 MHz, chloroform-d)δ-174.27 (s, 1F).

[0310] Synthesis of 4-[(4R)-azepan-4-yl]oxy-3-fluoro-6-(1-methylpyrazole-4-yl)pyrazolo[1,5-a]pyrazine [ka] To a solution of tert-butyl=(4R)-4-[3-fluoro-6-(1-methylpyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl]oxyazepan-1-carboxylate (25 mg, 59 μmol) in DCM (1 mL), TFA (1.49 g, 13.1 mmol, 1 mL) was added and the mixture was stirred at room temperature for 1 hour. After concentration, the crude residue 4-[(4R)-azepan-4-yl]oxy-3-fluoro-6-(1-methylpyrazole-4-yl)pyrazolo[1,5-a]pyrazine was used directly in the next step. LCMS: Rt = 0.63 min, m / z 183.2.

[0311] Synthesis of 1-[(4R)-4-[3-fluoro-6-(1-methylpyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl]oxyazepan-1-yl]propa-2-en-1-one [ka] To a solution of 4-[(4R)-azepan-4-yl]oxy-3-fluoro-6-(1-methylpyrazole-4-yl)pyrazolo[1,5-a]pyrazine (48 mg, 146 μmol) in DCM (4 mL), TEA (30 mg, 292 μmol, 41 μL) was added, and the reaction mixture was stirred for 5 minutes. After cooling to 0°C, acryloyl chloride (16 mg, 175 μmol, 14 μL) was added, and the mixture was stirred for 3 minutes. The reaction mixture was quenched with saturated NaHCO3 aqueous solution and extracted with DCM. The organic layer was dried over Na2SO4, and the concentrated residue was chromatographically treated on silica gel (siRNA / MeOH 0-30%) to obtain 1-[(4R)-4-[3-fluoro-6-(1-methylpyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl]oxyazepan-1-yl]propa-2-en-1-one (12.6 mg, yield 21%, purity 95%). LCMS: Rt = 0.70 min, m / z 385.0. 1¹H NMR (400 MHz, chloroform-d)δ 8.01 (d, J = 1.51 Hz, 1H), 7.85 (br s, 1H), 7.76 (s, 1H), 7.71 (d, J = 3.76 Hz, 1H), 6.58-6.68 (m, 1H), 6.35-6.44 (m, 1H), 5.73 (br d, J = 10.54 Hz, 1H), 5.62 (br s, 1H), 3.99 (br d, J = 2.51 Hz, 3H), 3.79 (br dd, J = 6.78, 13.55 Hz, 1H), 3.62-3.73 (m, 1H), 3.52-3.61 (m, 1H), 3.41-3.51 (m, 1H), 2.16-2.29 (m, 4H), 1.74-2.00 (m, 2H). 19 1F NMR (376 MHz, chloroform-d)δ-174.12 (br d, J= 58.58 Hz, 1F).

[0312] Example 62: 1-[(4R)-4-[6-(1-methylpyrazole-4-yl)-3-(trifluoromethyl)pyrazolo[1,5-a]pyrazine-4-yl]oxyazepan-1-yl]propa-2-en-1-one [ka]

[0313] Synthesis of tert-butyl=(4R)-4-[6-(1-methylpyrazole-4-yl)-3-(trifluoromethyl)pyrazolo[1,5-a]pyrazine-4-yl]oxyazepan-1-carboxylate [ka] To a solution of tert-butyl=(4R)-4-[3-iodo-6-(1-methylpyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl]oxyazepan-1-carboxylate (125 mg, 232 μmol) in DMF (1 mL) and hexamethylphosphoramide (42 mg, 232 μmol, 40 μL), fluorosulfonyl difluoroacetate methyl (223 mg, 1.16 mmol, 148 μL) and copper(I) iodide (66 mg, 348 μmol) were added and the mixture was degassed. The mixture was heated overnight at 80°C. The cooled mixture was diluted with SiO2, washed with NH4Cl aqueous solution, filtered through Celite, and dried over Na2SO4. The concentrated residue was chromatographically treated on silica gel (heptane / ethyl acetate 0-70%) to obtain tert-butyl=(4R)-4-[6-(1-methylpyrazole-4-yl)-3-(trifluoromethyl)pyrazolo[1,5-a]pyrazine-4-yl]oxyazepan-1-carboxylate (18 mg, yield 15%, purity 95%). LCMS: Rt = 1.03 min, m / z 481.2.381.2.

[0314] Synthesis of 4-[(4R)-azepan-4-yl]oxy-6-(1-methylpyrazole-4-yl)-3-(trifluoromethyl)pyrazolo[1,5-a]pyrazine [ka] To a solution of tert-butyl=(4R)-4-[6-(1-methylpyrazole-4-yl)-3-(trifluoromethyl)pyrazolo[1,5-a]pyrazine-4-yl]oxyazepan-1-carboxylate (18 mg, 37 μmol) in DCM (1 mL), TFA (1.49 g, 13.1 mmol, 1 mL) was added, and the reaction mixture was stirred at room temperature for 1 hour. The crude product was concentrated to obtain 4-[(4R)-azepan-4-yl]oxy-6-(1-methylpyrazole-4-yl)-3-(trifluoromethyl)pyrazolo[1,5-a]pyrazine (19.0 mg, crude, trifluoroacetic acid) as a residue, which was used directly for the next step. LCMS: Rt = 0.64 min, m / z 381.2.

[0315] Synthesis of 1-[(4R)-4-[6-(1-methylpyrazole-4-yl)-3-(trifluoromethyl)pyrazolo[1,5-a]pyrazine-4-yl]oxyazepan-1-yl]propa-2-en-1-one [ka] To a solution of 4-[(4R)-azepan-4-yl]oxy-6-(1-methylpyrazole-4-yl)-3-(trifluoromethyl)-pyrazolo[1,5-a]pyrazine (19 mg, 38 μmol, trifluoroacetic acid) in DCM (2 mL), TEA (7.8 mg, 77 μmol, 11 μL) was added, and the reaction mixture was stirred for 5 minutes. After cooling to 0°C, acryloyl chloride (4.2 mg, 46 μmol, 3.8 μL) was added, and the reaction mixture was stirred for 3 minutes. The reaction product was quenched with saturated NaHCO3 aqueous solution and extracted with DCM. The organic layer was dried over Na2SO4, and the concentrated residue was chromatographically treated on silica gel (siRNA / MeOH 0-30%) to obtain 1-[(4R)-4-[6-(1-methylpyrazole-4-yl)-3-(trifluoromethyl)pyrazolo[1,5-a]pyrazine-4-yl]oxyazepan-1-yl]propa-2-en-1-one (9 mg, yield 51%, purity 95%). LCMS: Rt = 0.80 min, m / z 457.1 [M+Na] + . 1 ¹H NMR (400 MHz, chloroform-d)δ 8.24 (s, 1H), 8.11 (s, 1H), 7.88 (s, 1H), 7.78-7.87 (m, 1H), 6.58-6.70 (m, 1H), 6.39 (br t, J = 15.18 Hz, 1H), 5.73 (br d, J = 10.54 Hz, 1H), 5.67 (br s, 1H), 4.11-4.22 (m, 1H), 4.00 (s, 3H), 3.73-3.83 (m, 1H), 3.52-3.70 (m, 1H), 3.37 (br dd, J = 5.52, 14.31 Hz, 1H), 2.18-2.38 (m, 4H), 1.86-1.95 (m, 2H). 191F NMR (376 MHz, chloroform-d)d-54.80 (d, J = 5.45 Hz, 3F).

[0316] Example 63: N-((cis)-3-((3-fluoro-6-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl)oxy)cyclobutyl)-N-methylacrylamide [ka]

[0317] Synthesis of tert-butyl=((cis)-3-((3-iodo-6-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl)oxy)cyclobutyl)(methyl)carbamate [ka] A vial containing tert-butyl=((cis)-3-hydroxycyclobutyl)(methyl)carbamate (175 mg, 868 μmol) in anhydrous THF (10 mL) was cooled in an ice bath. Then, sodium tert-butoxide (132 mg, 1.37 mmol) was carefully added to the cooled mixture in several portions. After 10 minutes, 4-chloro-3-iodo-6-(1-methylpyrazole-4-yl)pyrazolo[1,5-a]pyrazine (300 mg, 834 μmol) was carefully added to the cooled heterogeneous mixture in several portions. After the addition of 4-chloro-3-iodo-6-(1-methylpyrazole-4-yl)pyrazolo[1,5-a]pyrazine was complete, the mixture was warmed to 23°C and monitored by LC-MS. After 18 hours, the residue was diluted with ethyl acetate and filtered through Celite. The concentrated residue was loaded onto a silica gel column and purified with (20-65% ethyl acetate / heptane) to obtain tert-butyl=((cis)-3-((3-iodo-6-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl)oxy)cyclobutyl)(methyl)carbamate (252 mg, yield 58%). LCMS: Rt = 1.00 min, m / z 525.2.

[0318] Synthesis of tert-butyl=((cis)-3-((3-fluoro-6-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl)oxy)cyclobutyl)(methyl)carbamate [ka] A solution of tert-butyl=((cis)-3-((3-iodo-6-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl)oxy)cyclobutyl)(methyl)carbamate (292 mg, 557 μmol) in THF (3 mL) was cooled to -78 °C, and butyllithium (2.5 M, 267.30 μL) was added. The reaction mixture was stirred for 20 minutes. Then, N-fluorobenzenesulfonimide (211 mg, 668 μmol) in THF (1 mL) was added, and the reaction mixture was stirred for 1 hour. The reaction mixture was quenched by adding aqueous NH4Cl. The reaction mixture was diluted with butyl, the layers were separated, and the aqueous layer was extracted with butyl. The combined organic layers were dried over Na2SO4, and the concentrated residue was purified with (FCC, SiO2, 0-70% siRNA / DCM) to obtain tert-butyl=((cis)-3-((3-fluoro-6-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl)oxy)cyclobutyl)(methyl)-carbamate (75.5 mg, yield 33%) as an amorphous solid. LCMS, Rt = 0.92 min, m / z 439.2, 317.1. 19 F NMR (376 MHz, chloroform-d)δ-174.02 (br s, 1F).

[0319] Synthesis of (cis)-3-((3-fluoro-6-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl)oxy)-N-methylcyclobutan-1-amine [ka]

[0320] To a solution of tert-butyl=((cis)-3-((3-fluoro-6-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl)oxy)cyclobutyl)(methyl)carbamate (76 mg, 181 μmol) in DCM (1 mL), TFA (1.49 g, 13.1 mmol, 1 mL) was added, and the reaction mixture was stirred at room temperature for 1 hour. The crude product was concentrated to obtain (cis)-3-((3-fluoro-6-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl)oxy)-N-methylcyclobutan-1-amine (166 mg, crude, trifluoroacetic acid) as a residue, which was used directly for the next step. LCMS: Rt = 0.57 min, m / z 317.1.

[0321] Synthesis of N-((cis)-3-((3-fluoro-6-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl)oxy)cyclobutyl)-N-methylacrylamide [ka] To a solution of (cis)-3-((3-fluoro-6-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl)oxy)-N-methylcyclobutan-1-amine (166 mg, 386 μmol, trifluoroacetic acid) in DCM (5 mL), TEA (78 mg, 771 μmol, 108 μL) was added, and the reaction mixture was stirred for 5 minutes. After cooling to 0°C, acryloyl chloride (42 mg, 463 μmol, 38 μL) was added, and stirring was continued for 3 minutes. The reaction mixture was quenched with saturated NaHCO3 aqueous solution and extracted with DCM. The organic layer was dried over Na2SO4, and the concentrated residue was chromatographically treated on silica gel to obtain the residue (HCl / MeOH 0-30%). This was further purified by preparative HPLC (10-90% H2O / ACN) to obtain N-((cis)-3-((3-fluoro-6-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl)oxy)cyclobutyl)-N-methylacrylamide (30.1 mg, yield 15%, purity 95%, trifluoroacetic acid). LCMS: Rt = 0.70 min, m / z 371.2 [M+H] + , 393.2 [M+Na] + . 1 H NMR (400 MHz, chloroform-d)δ8.06 (d, J = 1.76 Hz, 1H), 7.91 (br s, 1H), 7.84 (br s, 1H), 7.75 (br d, J = 3.51 Hz, 1H), 6.58 (br dd, J = 10.92, 16.69 Hz, 1H), 6.35 (br d, J= 19.07 Hz, 1H), 5.79 (br d, J = 10.79 Hz, 1H), 5.17-5.25 (m, 1H), 4.82 (br s, 1H), 4.03 (s, 3H), 3.11 (br s, 3H), 3.00 (br s, 2H), 2.59 (br s, 1H), 2.43 (br s, 1H). 19 1F NMR (376 MHz, chloroform-d)δ -75.97 (s, 3F), -173.35 (br s, 1F).

[0322] Example 64: N-((trans)-3-((3-(difluoromethyl)-6-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,4-a]pyrazine-4-yl)oxy)cyclobutyl-N-methacrylamide [ka]

[0323] Synthesis of tert-butyl=methyl((trans)-3-((6-(1-methyl-1H-pyrazole-4-yl)-3-vinylpyrazolo[1,5-a]pyrazine-4-yl)oxy)cyclobutyl)carbamate [ka]

[0324] tert-butyl=((trans)-3-((3-iodo-6-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl)oxy)cyclobutyl)(methyl)carbamate (135 mg, 257 μmol), 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (79 mg, 515 μmol, 87 μL), di-tert-butyl(cyclopentyl)phosphine; dichloropalladium; iron (34 mg, 51 μmol), and potassium carbonate (100 mg, 721 μmol) were placed in a microwave vial and brought under N2. The vial was capped, and dioxane (1.2 mL) and water (0.3 mL) were added by syringe, and the red mixture was brought under N2 again (2 cycles). After stirring at room temperature for 5 minutes, the mixture was heated to 90°C and stirred at that temperature for 5 hours. After cooling to room temperature, the mixture was diluted with ethyl acetate and filtered. The filtrate was evaporated under vacuum, and the residue was purified with 10 g of Si-SPE: Rf=0.27, heptane / ethyl acetate=5 / 1 to obtain tert-butyl=methyl((trans)-3-((6-(1-methyl-1H-pyrazole-4-yl)-3-vinylpyrazolo[1,5-a]pyrazine-4-yl)oxy)cyclobutyl)carbamate (110 mg, yield 91%, purity 90%) as a yellow, rubbery substance.

[0325] Synthesis of tert-butyl=((trans)-3-((3-formyl-6-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl)oxy)cyclobutyl)(methyl)carbamate [ka] 110 mg, 259 μmol of tert-butyl=methyl((trans)-3-((6-(1-methyl-1H-pyrazole-4-yl)-3-vinylpyrazolo[1,5-a]pyrazine-4-yl)oxy)cyclobutyl)carbamate, water (0.5 mL), and THF (1.5 mL) were added to a vial and cooled in an ice bath. Then, 132 mg, 26 μmol, purity 5%; resin-bound, and 4-methyl-4-oxide-morpholine-4-ium (30 mg, 259 μmol) were added, and the mixture was stirred in an ice bath for 1 hour. Then, sodium (meth)periodate (111 mg, 518 μmol) was added, and the reaction mixture was heated to room temperature overnight while stirring in a water bath was continued. Then, saturated Na2S2O3, followed by DCM, was added. The mixture was filtered to separate the organic phase, dried, and evaporated under vacuum to obtain a dark green, sticky, rubbery substance. This substance was not further purified before proceeding. ESI-MS (M+Na) + : 449.4.

[0326] Synthesis of tert-butyl=((trans)-3-((3-(difluoromethyl)-6-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl)oxy)cyclobutyl)(methyl)carbamate [ka] tert-butyl=((trans)-3-((3-formyl-6-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl)oxy)cyclobutyl)(methyl)carbamate (90 mg, 211 μmol) and DCM (2 mL) were placed in a vial, and the mixture was cooled under N2 conditions in an ice bath. Then, N-ethyl-N-(trifluoro-sulfanyl)ethanamine (68 mg, 422 μmol, 56 μL) was added dropwise while stirring. Stirring was continued overnight, during which time the mixture was gradually warmed to room temperature. The mixture was diluted with DCM and silica gel was added. The volatile substances were evaporated under vacuum, and the residual material was purified with 5 g of Si-SPE:Rf=0.5 and ethyl acetate to obtain tert-butyl=((trans)-3-((3-(difluoromethyl)-6-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl)oxy)cyclobutyl)(methyl)carbamate (45 mg, yield 43%, purity 90%) as a pale yellow, sticky, rubbery substance. ESI-MS (M+H) + : 449.5.

[0327] Synthesis of (trans)-3-((3-(difluoromethyl)-6-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl)oxy)-N-methylcyclobutan-1-amine [ka] To a solution of tert-butyl=((trans)-3-((3-(difluoromethyl)-6-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl)oxy)cyclobutyl)(methyl)carbamate (40 mg, 89 μmol) in DCM (2 mL), TFA (102 mg, 892 μmol, 68 μL) was added at room temperature with stirring. After stirring overnight, the mixture was diluted with MeOH, and the product was purified by elution with 2 M NH3-MeOH on a 2 g SCX column to remove volatile substances, yielding (trans)-3-((3-(difluoromethyl)-6-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl)oxy)-N-methylcyclobutan-1-amine (28 mg, yield 81%, purity 90%) as a yellow, rubbery substance.

[0328] Synthesis of N-((trans)-3-((3-(difluoromethyl)-6-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl)oxy)cyclobutyl)-N-methylacrylamide [ka] (trans)-3-((3-(difluoromethyl)-6-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl)oxy)-N-methylcyclobutan-1-amine (28 mg, 80 μmol) and THF (1 mL) were placed in a vial. Next, acryloyl chloride (7.2 mg, 80 μmol) was added, and a precipitate formed instantly. Then, TEA (12 mg, 121 μmol, 17 μL) was added, and the mixture was stirred at room temperature for 1 hour. The volatile substances were evaporated under vacuum, and the residual material was purified by basic preparative HPLC (Waters XSelect CSH C18, 5 μm, 30 mm × 50 mm column, mobile phase H2O (A) and MeCN (B), and gradient 5-60% B (0.2% NH4OH final v / v% modifier), flow rate 60 mL / min). After lyophilization of the HPLC fraction, N-((trans)-3-((3-(difluoromethyl)-6-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl)oxy)cyclobutyl)-N-methylacrylamide (6.8 mg, yield 19%, purity 90%) was obtained as a white solid. ESI-MS (M+H) + : 403.4. 1 H NMR (chloroform-d, 400MHz): δ = 10.39-10.44 (m, 1H), 8.45-8.47 (m, 1H), 8.30 (s, 1H), 7.9 (m, 1H), 7.82 (m, 1H), 6.50-6.66 (m, 1H), 6.31 (br d, J= 15.8 Hz, 1H), 5.72 (br d, J = 10.3 Hz, 1H), 5.63 (br s, 1H), 5.07 (br s, 1H), 4.01 (s, 3H), 3.12 (s, 3H), 2.80-2.90 (m, 2H), 2.70-2.78 (m, 1H), 2.64-2.84 (m, 2H).

[0329] Example 65: 1-[(4R)-4-[7-(1-methylpyrazole-4-yl)imidazo[1,2-a]pyridine-5-yl]oxyazepan-1-yl]propa-2-en-1-one [ka]

[0330] Synthesis of tert-butyl=(4R)-4-(7-iodoimidazo[1,2-a]pyridine-5-yl)oxyazepan-1-carboxylate [ka] A vial containing 155 mg, 557 μmol of 5-chloro-7-iodoimidazo[1,2-a]pyridine in 2 mL of anhydrous THF was cooled in an ice bath. Then, sodium tert-butoxide (93 mg, 970 μmol) was carefully added to the cooled mixture in several portions. After 15 minutes, tert-butyl=(4R)-4-hydroxyazepane-1-carboxylate (142 mg, 661 μmol) was carefully added to the cooled heterogeneous mixture in several portions. After the addition of 5-chloro-7-iodoimidazo[1,2-a]pyridine was complete, the mixture was warmed to 23°C and monitored by LC-MS. After 19 hours, the reaction was carefully quenched by slowly adding water, and the two-phase mixture was extracted three times with ethyl acetate. The organic matter was pooled and then dried over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the residue was loaded onto a silica gel column and purified with (20-65% ethyl acetate / heptane). The desired fraction was pooled and then concentrated under reduced pressure to obtain a pale yellow oily substance as tert-butyl=(4R)-4-(7-iodoimidazo[1,2-a]pyridine-5-yl)oxyazepan-1-carboxylate (119 mg, 47% yield), which was used without further purification. LCMS m / z = 458.0(M+H) + .

[0331] Synthesis of tert-butyl=(4R)-4-[7-(1-methylpyrazole-4-yl)imidazo[1,2-a]pyridine-5-yl]oxyazepan-1-carboxylate [ka] A vial containing tert-butyl=(4R)-4-(7-iodoimidazo[1,2-a]pyridine-5-yl)oxyazepan-1-carboxylate (119 mg, 260 μmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (111 mg, 534 μmol), tricyclohexylphosphane (19.4 mg, 69 μmol), tris(dibenzylideneacetone)dipalladium (25.4 mg, 28 μmol), and tripotassium phosphate (1 M, 0.8 mL) in dioxane (1 mL) was degassed and then refilled with nitrogen. After exhausting and refilling with nitrogen (×3), the reaction mixture was heated to 90°C and monitored by LC-MS. After 2 hours, the reaction mixture was carefully quenched by slowly adding water. The two-phase mixture was extracted three times with ethyl acetate and then dried over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the residue was loaded onto a silica gel column and purified with (20-100% [3:1 ethyl acetate:ethanol] / heptane). The desired fraction was pooled and then concentrated under reduced pressure to obtain a yellow film as tert-butyl=(4R)-4-[7-(1-methylpyrazole-4-yl)imidazo[1,2-a]pyridine-5-yl]oxyazepan-1-carboxylate (75.9 mg, yield 71%), which was used without further purification. LCMS m / z = 412.1(M+H) + . Synthesis of 5-[(4R)-azepan-4-yl]oxy-7-(1-methylpyrazole-4-yl)imidazo[1,2-a]pyridine [ka] A vial containing tert-butyl=(4R)-4-[7-(1-methylpyrazole-4-yl)imidazo[1,2-a]pyridine-5-yl]oxyazepan-1-carboxylate (76 mg, 184 μmol) in anhydrous dichloromethane (0.5 mL) was cooled in an ice bath. Then, trifluoroacetic acid (149 mg, 1.31 mmol, 0.1 mL) was carefully added dropwise to the cooled mixture. After the addition of TFA was complete, the mixture was warmed to 23°C and monitored by LC-MS. After 19 hours, the reaction product was carefully concentrated under reduced pressure to obtain a pale yellow film as 5-[(4R)-azepan-4-yl]oxy-7-(1-methylpyrazole-4-yl)imidazo[1,2-a]pyridine (crude, trifluoroacetic acid), which was used without purification. LC-MS m / z = 312.0(M+H) + .

[0332] Synthesis of 1-[(4R)-4-[7-(1-methylpyrazole-4-yl)imidazo[1,2-a]pyridine-5-yl]oxyazepan-1-yl]propa-2-en-1-one [ka] To a vial containing 5-[(4R)-azepan-4-yl]oxy-7-(1-methylpyrazole-4-yl)imidazo[1,2-a]pyridine (79 mg, 254 μmol, trifluoroacetic acid) in anhydrous THF (1 mL), Hünig base (445 mg, 3.44 mmol, 0.6 mL) was carefully added at -25°C. After 4 minutes, acryloyl chloride (45 mg, 492 μmol, 0.04 mL) was carefully added dropwise to the cooled homogeneous solution. After the addition of acryloyl chloride was complete, the reaction mixture was warmed to 23°C and monitored by LC-MS and TLC. After 3 minutes, the reaction mixture was carefully quenched by slowly adding saturated sodium bicarbonate aqueous solution. The two-phase mixture was loaded onto a silica gel column and purified by (40-100% [3:1 ethyl acetate:ethanol] / heptane, followed by a flush with 20% methanol / dichloromethane). The desired fraction was pooled and then concentrated under reduced pressure to obtain a 67 mg colorless film, which was further purified by mass spectrometry-connected reverse-phase HPLC (Waters XSelect CSH C18, 5 μm, 19 mm × 100 mm column, mobile phases H2O (A) and MeCN (B) and gradient 5-50% B (0.2% NH4OH final v / v% modifier), flow rate 30 mL / min). The fraction containing the desired product was concentrated to obtain a colorless film as 1-[(4R)-4-[7-(1-methylpyrazole-4-yl)imidazo[1,2-a]pyridine-5-yl]oxyazepan-1-yl]propa-2-en-1-one (1.6 mg, yield 2%). 1 H NMR (500MHz, DMSO-d6) δ = 8.52 - 8.12 (m, 2H), 8.02 - 7.64 (m, 2H), 7.47 (s, 1H), 6.96 - 6.77 (m, 2H), 6.23 - 6.13 (m, 1H), 5.75 - 5.65 (m, 1H), 5.28 - 5.16 (m, 1H), 3.96 - 3.85 (m, 3H), 3.84 - 3.46 (m, 6H), 2.12 - 2.07 (m, 1H), 1.99 - 1.91 (m, 2H), 1.83 - 1.72 (m, 1H).LCMS: m / z = 366.1 (M+H)+.

[0333] Example 66: 1-[(4R)-4-[6-(1-methylpyrazole-4-yl)pyrazolo[1,5-a]pyridine-4-yl]oxyazepan-1-yl]propa-2-en-1-one [ka]

[0334] Synthesis of tert-butyl=(4R)-4-(6-bromopyrazolo[1,5-a]pyridine-4-yl)oxyazepan-1-carboxylate [ka] To a solution of tert-butyl=(4S)-4-hydroxyazepan-1-carboxylate (303 mg, 1.41 mmol), 6-bromopyrazolo[1,5-a]pyridine-4-ol (300 mg, 1.41 mmol), and triphenylphosphine (554 mg, 2.11 mmol) in THF (5 mL), DIAD (342 mg, 1.69 mmol, 333 μL) was added and the mixture was stirred at room temperature for 16 hours. The concentrated crude product was chromatographically treated on silica gel (heptane / ethyl acetate 0-60%) to obtain tert-butyl=(4R)-4-(6-bromopyrazolo[1,5-a]pyridine-4-yl)oxyazepan-1-carboxylate (255 mg, yield 42%, purity 95%) as a colorless oil. LCMS: Rt = 1.00 min, m / z 356.1, 412.1 (M+H) + .

[0335] Synthesis of tert-butyl=(4R)-4-[6-(1-methylpyrazole-4-yl)pyrazolo[1,5-a]pyridine-4-yl]oxyazepan-1-carboxylate [ka] A solution of 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (194 mg, 932 μmol), Pd(dppf)Cl2DCM (51 mg, 62 μmol), and K2CO3 (258 mg, 1.86 mmol) in dioxane (3 mL) and water (0.5 mL) was degassed and heated to 95°C for 16 hours. After cooling to room temperature, the mixture was filtered through Celite and concentrated. The residue was chromatographically treated on silica gel (heptane / siRNA 0-100%) to obtain tert-butyl=(4R)-4-[6-(1-methylpyrazole-4-yl)pyrazolo[1,5-a]pyridine-4-yl]oxyazepan-1-carboxylate (192 mg, yield 71%, purity 95%) as a yellow gel. LCMS: Rt = 0.87 min, m / z 412.3 (M+H) + .

[0336] Synthesis of 4-[(4R)-azepan-4-yl]oxy-6-(1-methylpyrazole-4-yl)pyrazolo[1,5-a]pyridine [ka] To a solution of tert-butyl=(4R)-4-[6-(1-methylpyrazole-4-yl)pyrazolo[1,5-a]pyridine-4-yl]oxyazepan-1-carboxylate (192 mg, 467 μmol) in DCM (1 mL), TFA (1.49 g, 13.1 mmol, 1 mL) was added, and the reaction mixture was stirred at room temperature for 1 hour. The crude product was concentrated to obtain 4-[(4R)-azepan-4-yl]oxy-6-(1-methylpyrazole-4-yl)pyrazolo[1,5-a]pyridine (345 mg, crude, trifluoroacetic acid), which was used directly in the next step. LCMS: Rt = 0.50 min, m / z 312.1 (M+H) + .

[0337] Synthesis of 1-[(4R)-4-[6-(1-methylpyrazole-4-yl)pyrazolo[1,5-a]pyridine-4-yl]oxyazepan-1-yl]propa-2-en-1-one [ka] To a solution of 4-[(4R)-azepan-4-yl]oxy-6-(1-methylpyrazole-4-yl)pyrazolo[1,5-a]pyridine (345 mg, 811 μmol, trifluoroacetic acid) in DCM (10 mL), TEA (164 mg, 1.62 mmol, 226 μL) was added, and the reaction mixture was stirred for 5 minutes. After cooling to 0°C, acryloyl chloride (88 mg, 973 μmol, 79 μL) was added, and the reaction mixture was stirred for 3 minutes. The reaction product was quenched with saturated NaHCO3 aqueous solution and extracted with DCM. The organic layer was dried over Na2SO4, and the concentrated residue was chromatographically treated on silica gel (siRNA / MeOH 0-30%) to obtain 1-[(4R)-4-[6-(1-methylpyrazole-4-yl)pyrazolo[1,5-a]pyridine-4-yl]oxyazepan-1-yl]propa-2-en-1-one (112.1 mg, yield 36%, purity 95%). LCMS: Rt = 0.62 min, m / z 366.2 (M+H) + . 1 H NMR (400 MHz, chloroform-d)δ8.25 (s, 1H), 7.84 (t, J = 1.76 Hz, 1H), 7.70 (d, J= 3.26 Hz, 1H), 7.59 (d, J= 6.02 Hz, 1H), 6.55-6.66 (m,2H), 6.44 (d, J= 8.28 Hz, 1H), 6.31-6.41 (m, 1H), 5.68-5.75 (m, 1H), 4.72 (br s, 1H), 3.95 (s, 3H), 3.63-3.80 (m, 2H), 3.45-3.61 (m, 2H), 2.07-2.25(m, 4H), 1.88-1.99 (m, 1H), 1.69-1.86 (m, 1H).

[0338] Example 67: 1-[(4R)-4-[2-amino-6-(1-methylpyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl]oxyazepan-1-yl]propa-2-en-1-one [ka]

[0339] Synthesis of ethyl-4-chloro-6-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyrazine-2-carboxylate [ka] To a suspension of ethyl=4-hydroxy-6-(1-methylpyrazole-4-yl)pyrazolo[1,5-a]pyrazine-2-carboxylate (130 mg, 454 μmol) in anhydrous acetonitrile (2 mL) under nitrogen, phosphoryl chloride (1.11 g, 7.27 mmol, 677 μL) was added dropwise. The resulting mixture was heated to 80°C for 17 hours. After cooling to room temperature, the reaction mixture was diluted with SiO2 and carefully quenched with saturated sodium bicarbonate aqueous solution. The layers were separated, and the organic layer was sequentially washed with saturated bicarbonate solution (2x) and brine. The organic phase was dried over (MgSO4), filtered, and concentrated under vacuum. Ethyl=4-chloro-6-(1-methylpyrazole-4-yl)pyrazolo[1,5-a]pyrazine-2-carboxylate was obtained as a white solid and used directly. Quantitative yield was assumed. 1 ¹H NMR (500 MHz, chloroform-d) δ ppm 8.50 (d, J = 1.2 Hz, 1 H), 7.94 (s, 1 H), 7.90 (s, 1 H), 7.37 - 7.42 (m, 1 H), 4.50 (q, J = 6.9 Hz, 2 H), 3.97 - 4.01 (m, 3 H), 1.46 (t, J = 7.0 Hz, 3 H). LCMS: m / z = 306.3 [M+H]+.

[0340] Synthesis of (R)-1-(tert-butoxycarbonyl)azepan-4-yl=4-(((R)-1-(tert-butoxycarbonyl)azepan-4-yl)oxy)-6-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyrazine-2-carboxylate [ka] A solution of tert-butyl=(4R)-4-hydroxyazepan-1-carboxylate (232 mg, 1.08 mmol) in anhydrous DMF (2 mL) under nitrogen was mixed with NaHMDS (1 M, 1.08 mL) at 20°C. The mixture was stirred at 20°C for 15 minutes. A solution of ethyl=4-chloro-6-(1-methylpyrazole-4-yl)pyrazolo[1,5-a]pyrazine-2-carboxylate (150 mg, 491 μmol) in anhydrous DMF (2 mL) was added, and the resulting mixture was stirred at room temperature for 2 hours, quenched with H2O (1 mL), and diluted with SiO2. The organic layer was washed with brine (3x), dried over MgSO4, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography (0-100% ethyl acetate / heptane) to obtain [(4R)-1-tert-butoxycarbonylazepan-4-yl]=4-[(4R)-1-tert-butoxycarbonylazepan-4-yl]oxy-6-(1-methylpyrazole-4-yl)pyrazolo[1,5-a]pyrazine-2-carboxylate (136 mg, yield 42%) as a pale yellow foam. 1 H NMR (500 MHz, Chloroform-d) δ ppm 8.23 ​​(s, 1 H), 7.76 - 7.90 (m, 2 H), 5.55 (br s, 1 H), 5.22 - 5.32 (m, 1 H), 3.98 (s, 3 H), 3.58 - 3.72 (m, 2 LCMS: m / z = 654.7 [M+H]+.

[0341] Synthesis of (R)-4-((1-(tert-butoxycarbonyl)azepan-4-yl)oxy)-6-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyrazine-2-carboxylic acid [ka] To a solution of [(4R)-1-tert-butoxycarbonylazepan-4-yl]=4-[(4R)-1-tert-butoxycarbonylazepan-4-yl]oxy-6-(1-methylpyrazole-4-yl)pyrazolo[1,5-a]pyrazine-2-carboxylate (41 mg, 63 μmol) in methanol (400 μL), sodium hydroxide solution (2 M, 94 μL) was added, and the resulting mixture was stirred at room temperature for 30 minutes. The reaction mixture was quenched with HCl solution (1 M, 188 μL) and diluted with HCl and water. The layers were separated, the organic layer was washed with water and brine, dried (MgSO4), filtered, and concentrated under vacuum. 4-[(4R)-1-tert-butoxycarbonylazepan-4-yl]oxy-6-(1-methylpyrazole-4-yl)pyrazolo[1,5-a]pyrazine-2-carboxylic acid was obtained as a white solid and used directly. Quantitative yield assumed. LCMS: m / z = 457.4 [M+H]+.

[0342] Synthesis of tert-butyl=(R)-4-((2-((tert-butoxycarbonyl)amino)-6-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl)oxy)azepan-1-carboxylate [ka] To a solution of 4-[(4R)-1-tert-butoxycarbonylazepan-4-yl]oxy-6-(1-methylpyrazole-4-yl)pyrazolo[1,5-a]pyrazine-2-carboxylic acid (110 mg, 241 μmol) in anhydrous DMF (1 mL) and tert-butanol (0.5 mL), triethylamine (37 mg, 361 μmol, 50 μL) was added dropwise, followed by DPPA (99 mg, 361 μmol, 78 μL) at room temperature. The resulting mixture was stirred at 80°C for 17 hours, cooled to room temperature, diluted with ethyl acetate, and washed with water and brine (3x). The organic layer was dried over (MgSO4), filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography (0-5% MeOH / DCM). tert-butyl=(4R)-4-[2-(tert-butoxycarbonylamino)-6-(1-methylpyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl]oxyazepan-1-carboxylate (38 mg, yield 30%) was obtained as an oily substance. 1 H NMR (500 MHz, Chloroform-d) δ ppm 7.99 (s, 1 H), 7.72 - 7.84 (m, 2 H), 7.33 (br s, 1 H), 6.82 - 7.05 (bs, 1 H), 5.47 - 5.55 (m, 1 H), 3.96 (s, 3 LCMS: m / z = 528.3 [M+H]+.

[0343] Synthesis of (R)-4-(azepan-4-yloxy)-6-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyrazine-2-amine dihydrochloride [ka] To a solution of tert-butyl=(4R)-4-[2-(tert-butoxycarbonylamino)-6-(1-methylpyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl]oxyazepan-1-carboxylate (38 mg, 72 μmol) in methanol (0.6 mL), HCl (4 M in dioxane, 360 μL) was added. The resulting solution was stirred at room temperature for 2 hours and concentrated under vacuum. 4-[(4R)-azepan-4-yl]oxy-6-(1-methylpyrazole-4-yl)pyrazolo[1,5-a]pyrazine-2-amine (2-hydrochloride salt) was obtained as an off-white solid and used directly. Quantitative yield assumed. LC-MS: m / z = 328.1[M+H]+.

[0344] Synthesis of 1-[(4R)-4-[2-amino-6-(1-methylpyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl]oxyazepan-1-yl]propa-2-en-1-one [ka] To a suspension of crude 4-[(4R)-azepan-4-yl]oxy-6-(1-methylpyrazole-4-yl)pyrazolo[1,5-a]pyrazine-2-amine (28 mg, 70 μmol, 2-hydrochloride) in anhydrous THF (1 mL) and anhydrous DMF (0.5 mL) under nitrogen, triethylamine (21 mg, 210 μmol, 29 μL) was added, and the resulting suspension was cooled to 0°C. Acryloyl chloride (6 mg, 70 μmol, 6 μL) was added dropwise, and the resulting mixture was stirred at 0°C for 30 minutes. After quenching with saturated sodium bicarbonate solution and dilution with ethyl acetate, the layers were separated. The organic layer was washed with brine (3x), dried, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography, and the desired product was further purified by preparative TLC (96:4 DCM / MeOH). 1-[(4R)-4-[2-amino-6-(1-methylpyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl]oxyazepan-1-yl]propa-2-en-1-one (4.2 mg, yield 15%, purity 95%) was obtained as an off-white solid. 1H NMR (500 MHz, chloroform-d) δ ppm 7.93 (s, 1 H), 7.79 (s, 1 H), 7.68 - 7.76 (m, 1 H), 6.58 - 6.67 (m, 1 H), 6.36 - 6.43 (m, 1 H), 5.94 (d, J = 4.3 Hz, 1 H), 5.72 (dd, J = 10.4, 2.4 Hz, 1 H), 5.49 - 5.60 (m, 1 H), 4.02 (br s, 2 H), 3.96 (s, 3 H), 3.80 - 3.94 (m, 1 H), 3.55 - 3.77 (m, 3 H), 2.11 - 2.32 (m, 3 H), 1.93 - 2.11 (m, 2 H), 1.77 - 1.90 (m, 1 H).LCMS: m / z = 382.1 [M+H]+.

[0345] Example 68: N-((cis)-3-((2-amino-6-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl)oxy)cyclobutyl)-N-methylacrylamide [ka]

[0346] Synthesis of (cis)-3-((tert-butoxycarbonyl)(methyl)amino)cyclobutyl=4-((cis)-3-((tert-butoxycarbonyl)(methyl)amino)cyclobutoxy)-6-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyrazine-2-carboxylate [ka] To a solution of ethyl-4-chloro-6-(1-methylpyrazole-4-yl)pyrazolo[1,5-a]pyrazine-2-carboxylate (300 mg, 981 μmol) and tert-butyl-((cis)-3-hydroxycyclobutyl)(methyl)-carbamate (494 mg, 2.45 mmol) in anhydrous THF (4 mL) and anhydrous DMSO (1 mL) under nitrogen, potassium tert-butoxide solution (1 M in THF, 2.45 mL) was added at 0°C. The mixture was warmed to room temperature, stirred at room temperature for 2 hours, quenched with H2O (1 mL), and diluted with SiO2. The organic layer was washed with brine (2x), dried over MgSO4, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography (0-100% SiO / heptane) to obtain (cis)-3-((tert-butoxycarbonyl)(methyl)amino)cyclobutyl 4-((cis)-3-((tert-butoxycarbonyl)(methyl)amino)cyclobutoxy)-6-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyrazine-2-carboxylate (250 mg, yield 41%) as a pale yellow foam. 1 H NMR (500 MHz, Chloroform-d) δ ppm 8.23 ​​(s, 1 H), 7.74 - 7.92 (m, 2 H), 5.55 (br s, 1 H), 5.28 (br s, 1 H), 3.98 (s, 3 H), 3.59 - 3.74 (m, 2 H), 3.39 - 3.59 (m, 5 H), 3.29 - 3.39 (m, 1 H), 1.89 - 2.32 (m, 10 H), 1.69 - 1.84 (m, 2 H), 1.48 - 1.53 (m, 18 H).LCMS: m / z = 471.2 [M+H]+.

[0347] Synthesis of 4-((cis)-3-((tert-butoxycarbonyl)(methyl)amino)cyclobutoxy)-6-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyrazine-2-carboxylic acid [ka] To a solution of (cis)-3-((tert-butoxycarbonyl)(methyl)amino)cyclobutyl=4-((cis)-3-((tert-butoxycarbonyl)(methyl)amino)cyclobutoxy)-6-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyrazine-2-carboxylate (332 mg, 531 μmol) in methanol (1 mL), sodium hydroxide solution (2 M, 266 μL) was added, and the resulting mixture was stirred at room temperature for 30 minutes. After quenching with HCl (1 M, 531 μL) and dilution with HCl and water, the layers were separated. The organic layer was washed with water and brine, dried (MgSO4), filtered, and concentrated under vacuum. 4-((cis)-3-((tert-butoxycarbonyl)(methyl)amino)cyclobutoxy)-6-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyrazine-2-carboxylic acid was obtained as a white solid and used directly. Quantitative yield was assumed. 1 H NMR (500 MHz, DMSO-d6) δ ppm 13.26 (br s, 1 H), 8.81 (s, 1 H), 8.27 (s, 1 H), 8.05 (s, 1 H), 7.20 (s, 1 H), 5.05 - 5.16 (m, 1 H), 3.91 (s, 3 H), 2.84 (m, 2 H), 2.80 (s, 3 H), 2.32 - 2.42 (m, 2 H), 1.42 (s, 9 H).LCMS: m / z = 443.1 [M+H]+.

[0348] Synthesis of tert-butyl=((cis)-3-((2-((tert-butoxycarbonyl)amino)-6-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl)oxy)cyclobutyl)(methyl)carbamate [ka] To a solution of 4-((cis)-3-((tert-butoxycarbonyl)(methyl)amino)cyclobutoxy)-6-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyrazine-2-carboxylic acid (115 mg, 260 μmol) in anhydrous DMF (1 mL) and tert-butanol (0.5 mL), triethylamine (39 mg, 390 μmol, 54 μL) was added dropwise, followed by DPPA (107 mg, 390 μmol, 84 μL) at room temperature. The resulting mixture was stirred at 80°C for 17 hours, cooled to room temperature, diluted with ethylethanol, and washed with water and brine (3x). The organic layer was dried over (MgSO4), filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography (heptane / ethylethanol 0-100%). tert-butyl=((cis)-3-((2-((tert-butoxycarbonyl)amino)-6-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl)oxy)cyclobutyl)(methyl)carbamate (26 mg, yield 20%) was obtained as a white foam. 1 H NMR (500 MHz, Chloroform-d) δ ppm 8.30-8.00 (br s, 1H), 8.10 (s, 1H), 7.81 (s, 1 H), 7.76 (s, 1 H), 6.82 - 7.09 (bs, 1 H), 5.10 (q, J= 7.2 Hz, 1 LCMS: m / z = 514.2 [M+H]+.

[0349] tert-butyl=((cis)-3-((2-amino-6-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl)oxy)cyclobutyl)(methyl)carbamate (16 mg, yield 15%) was also isolated as an oily substance. 1H NMR (500 MHz, chloroform-d) δ ppm 7.94 (s, 1 H), 7.79 (s, 1 H), 7.72 (s, 1 H), 5.95 (s, 1 H), 5.01 - 5.10 (quin, J = 7.2 Hz, 1 H), 4.01 - 4.09 (bs, 2 LCMS: m / z = 414.2 [M+H]+.

[0350] Synthesis of 6-(1-methyl-1H-pyrazole-4-yl)-4-((cis)-3-(methylamino)cyclobutoxy)pyrazolo[1,5-a]pyrazine-2-amine [ka] A solution of tert-butyl=((cis)-3-((2-((tert-butoxycarbonyl)amino)-6-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl)oxy)cyclobutyl)(methyl)carbamate (26 mg, 51 μmol) in anhydrous methanol (0.5 mL) was treated with HCl (4 M in dioxane, 506 μL). The resulting mixture was stirred at room temperature for 1 hour. A solid was formed. The mixture was concentrated under vacuum. 6-(1-methyl-1H-pyrazole-4-yl)-4-((cis)-3-(methylamino)cyclobutoxy)pyrazolo[1,5-a]pyrazine-2-amine (dihydrochloride) was obtained as a white solid and used directly. Quantitative yield assumed. LCMS: m / z = 314.5 [M+H]+.

[0351] Synthesis of N-((cis)-3-((2-amino-6-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl)oxy)cyclobutyl)-N-methylacrylamide [ka] Triethylamine (11 mg, 109 μmol, 15 μL) was added to a suspension of crude 6-(1-methyl-1H-pyrazole-4-yl)-4-((cis)-3-(methylamino)cyclobutoxy)pyrazolo[1,5-a]pyrazine-2-amine dihydrochloride (14 mg, 36 μmol) in anhydrous THF (0.5 mL) and anhydrous DMF (0.5 mL) under nitrogen. The resulting suspension was cooled to 0°C. Acryloyl chloride (3.3 mg, 36 μmol, 3 μL) was added dropwise, and the resulting mixture was stirred at 0°C for 30 minutes. The reaction mixture was quenched with saturated sodium bicarbonate solution and diluted with ethyl acetate. The layers were separated, the organic layer was washed with brine (3x), dried, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography (0-10% MeOH / DCM). N-((cis)-3-((2-amino-6-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl)oxy)cyclobutyl)-N-methylacrylamide (4.4 mg, yield 32%, purity 95%) was obtained as a white foam. 1 ¹H NMR (500 MHz, chloroform-d) δ ppm 7.94 (s, 1 H), 7.78 (br s, 1 H), 7.73 (br s, 1 H), 6.58 (dd, J = 16.8, 10.7 Hz, 1 H), 6.24 - 6.40 (m, 1 H), 5.95 (s, 1 H), 5.71 (dd, J= 10.4, 1.8 Hz, 1 H), 5.13 (quin, J= 7.2 Hz, 1 H), 4.83 and 4.30 (2 br s, 1 H), 4.02 (bs, 2 H), 3.96 (s, 3 H), 3.06 (br s, 3 H), 2.90 - 2.98 (m, 2 H), 2.51 and 2.36 (2 br s, 2 H). LCMS: m / z = 368.1 [M+H]+.

[0352] Example 69: (S)-1-(4-((6-(1,3-dimethyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl)oxy)azepan-1-yl)propa-2-en-1-one and (R)-1-(4-((6-(1,3-dimethyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl)oxy)azepan-1-yl)propa-2-en-1-one [ka]

[0353] Synthesis of tert-butyl-4-(6-chloropyrazolo[1,5-a]pyrazine-4-yl)oxyazepan-1-carboxylate [ka] To a solution of tert-butyl-4-hydroxyazepan-1-carboxylate (4.0 g, 18.6 mmol) and 4,6-dichloropyrazolo[1,5-a]pyrazine (3.5 g, 18.6 mmol) in THF (100 mL), a solution of potassium tert-butoxide (1 M in THF, 18.6 mL, 18.6 mmol) was slowly added. The flask was stirred at room temperature for 2 hours. The substance was concentrated to half its volume and taken in ethyl acetate and water. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by 80 g silica gel column using a 0-60% ethyl acetate / heptane gradient. The relevant fractions were combined to obtain tert-butyl-4-(6-chloropyrazolo[1,5-a]pyrazine-4-yl)oxyazepan-1-carboxylate (4.32 g, yield 63%) as a yellow oil. LCMS m / z = 367.1 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.36 - 1.47 (m, 9 H) 1.68 (br dd, J =11.7,5.4Hz,1 H) 1.83 (br s, 1 H) 1.90 - 1.98 (m, 3 H) 2.03 - 2.24 (m, 1 H) 3.34 - 3.53 (m, 4 H) 5.22 - 5.44 (m, 1 H) 6.88 - 6.98 (m, 1 H) 8.01 - 8.14 (m, 1 H) 8.65 - 8.76 (m, 1 H)

[0354] Synthesis of tert-butyl-4-[6-(1,3-dimethylpyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl]oxyazepan-1-carboxylate [ka] In a microwave vial, tert-butyl-4-(6-chloropyrazolo[1,5-a]pyrazine-4-yl)oxyazepan-1-carboxylate (1M, 0.55mL, 0.55 mmol), 1,3-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (145 mg, 0.65 mmol), K3PO4 (1M in water, 1.09 mL), Pd-PEPPSI™-IPr (37 mg, 55 μmol), and dioxane (5 mL) were added. The vial was capped and stirred overnight at 60°C. The reaction mixture was concentrated and purified using a 40-70% ethyl acetate / heptane gradient via a 12 g silica gel column. Combining the relevant fractions, tert-butyl-4-[6-(1,3-dimethylpyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl]oxyazepan-1-carboxylate (136 mg, yield 58%) was obtained as a pale yellow oil. LCMSm / z = 427.2(M+H)+.

[0355] Synthesis of 4-[azepan-4-yl]oxy-6-(1,3-dimethylpyrazole-4-yl)pyrazolo[1,5-a]pyrazine hydrochloride [ka] To a solution of tert-butyl-4-[6-(1,3-dimethylpyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl]oxyazepan-1-carboxylate (136 mg, 0.32 mmol) in dioxane (2 mL), HCl (4 M in dioxane, 0.8 mL) was added. The mixture was stirred overnight at room temperature. The substance was concentrated to obtain 4-[azepan-4-yl]oxy-6-(1,3-dimethylpyrazole-4-yl)pyrazolo[1,5-a]pyrazine hydrochloride (115 mg, crude) as an off-white solid. LCMS m / z = 327.1 (M+H)+.

[0356] Synthesis of (S)-1-(4-((6-(1,3-dimethyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl)oxy)azepan-1-yl)propa-2-en-1-one and (R)-1-(4-((6-(1,3-dimethyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl)oxy)azepan-1-yl)propa-2-en-1-one [ka] 4-[azepan-4-yl]oxy-6-(1,3-dimethylpyrazole-4-yl)pyrazolo[1,5-a]pyrazine hydrochloride (115 mg, 0.32 mmol), triethylamine (193 mg, 1.9 mmol, 266 μL), and propa-2-enoyl chloride (35 mg, 0.38 mmol, 31 μL) were added to a vial in the following order in DCM (4 mL). The vial was stirred overnight at room temperature. The reaction mixture was concentrated, transferred to DMSO, and passed through a plug. The substance was purified by reverse-phase purification (column: Waters XSelect CSH Prep C18 5um OBD 19 × 100 mm; conditions: 5-50% acetonitrile / 0.1% v / v ammonium carbonate / water; flow rate: 30 mL / min) to obtain 60.6 mg (50% yield) of the desired product. LCMS m / z = 381.2 (M+H)+. 1H NMR (500 MHz, DMSO-d6) δ ppm 1.67 - 1.80 (m, 1 H) 1.86 - 2.10 (m, 4 H) 2.16 - 2.26 (m, 1 H) 2.42 (s, 3 H) 3.56 - 3.78 (m, 4 H) 3.81 (d, J=1.22 Hz, 3 H) 5.42 - 5.56 (m, 1 H) 5.65 - 5.74 (m, 1 H) 6.13 - 6.21 (m, 1 H) 6.75 - 6.87 (m, 2 H) 7.98 - 8.04 (m, 1 H) 8.08 - 8.15 (m, 1 H) 8.42 - 8.49 (m, 1 H).

[0357] The substance was chiral purified using the following conditions (column: CHIRALPAK AD-H 30×250 mm, 5 μm; method: 30% MeOH (no modifier) / CO2; flow rate: 100 mL / min; ABPR: 120 bar; MBPR: 40 PSI; column temperature: 40 °C). The first eluting peak E1 was concentrated to obtain 11.3 mg of 1-[-4-[6-(1,3-dimethylpyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl]oxyazepan-1-yl]propa-2-en-1-one, one enantiomer, as a white solid. LCMS m / z = 381.2 (M+H)+. The second eluting peak E2 was concentrated to obtain 5.4 mg of 1-[4-[6-(1,3-dimethylpyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl]oxyazepan-1-yl]propa-2-en-1-one, the second enantiomer, as a white solid. LCMS m / z = 381.2 (M+H)+. The stereochemistry of the two isomers could not be assigned.

[0358] Example 70: 1-[(4R)-4-[[6-(1,3-dimethylpyrazole-4-yl)-[1,2,4]triazolo[1,5-a]pyrazine-8-yl]oxy]azepan-1-yl]propa-2-en-1-one [ka]

[0359] Synthesis of tert-butyl=(4R)4-((6-bromo-[1,2,4]triazolo[1,5-a]pyrazine-8-yl)oxy)azepan-1-carboxylate [ka] A solution of tert-butyl=(4R)-4-hydroxyazepan-1-carboxylate (775 mg, 3.60 mmol) and 6,8-dibromo-[1,2,4]triazolo[1,5-a]pyrazine (1 g, 3.60 mmol) in THF (36 mL) was slowly added to a solution of potassium tert-butoxide (1 M in THF, 3.6 mL, 3.6 mmol). The flask was stirred at room temperature for 1 hour. The substance was concentrated to half its volume and taken in ethyl acetate and water. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by a 40 g silica gel column using a 10-70% ethyl acetate / heptane gradient. Combining the relevant fractions, tert-butyl=(4R)-4-[(6-bromo-[1,2,4]triazolo[1,5-a]pyrazine-8-yl)oxy]azepan-1-carboxylate (1.48 g, 2.79 mmol, yield 77.5%) was obtained as a white foam. LCMS m / z = 414.0 (M+H)+. 1 H NMR (500 MHz, DMSO-d6) δ ppm 1.43 (s, 9 H) 1.69 (br dd, J=8.85, 4.58 Hz, 1 H) 1.81 - 2.04 (m, 4 H) 2.10 - 2.31 (m, 1 H) 3.37 - 3.53 (m, 4 H) 5.27 - 5.39 (m, 1 H) 8.52 - 8.66 (m, 1 H) 8.97 - 9.15 (m, 1 H)

[0360] Synthesis of tert-butyl=(4R)-4-[[6-(1,3-dimethylpyrazole-4-yl)-[1,2,4]triazolo[1,5-a]pyrazine-8-yl]oxy]azepan-1-carboxylate [ka] In a microwave vial, tert-butyl=(4R)-4-[(6-bromo-[1,2,4]triazolo[1,5-a]pyrazine-8-yl)oxy]azepan-1-carboxylate (230 mg, 0.56 mmol), 1,3-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (149 mg, 0.67 mmol), K3PO4 (1 M in water, 1.12 mL), Pd-PEPPSI™-IPr (38 mg, 55.8 μmol), and dioxane (5.00 mL) were added. The vial was capped and stirred overnight at 70°C. The reaction mixture was concentrated and purified using a 30-100% ethyl acetate / heptane gradient via a 12 g silica gel column. Combining the relevant fractions, tert-butyl=(4R)-4-[[6-(1,3-dimethylpyrazole-4-yl)-[1,2,4]triazolo[1,5-a]pyrazine-8-yl]oxy]azepan-1-carboxylate (65 mg, yield 27%) was obtained as a pale yellow oil. LCMS m / z = 428.2 (M+H)+

[0361] Synthesis of 8-[(4R)-azepan-4-yl]oxy-6-(1,3-dimethylpyrazole-4-yl)-[1,2,4]triazolo[1,5-a]pyrazine hydrochloride [ka] To a solution of tert-butyl=(4R)-4-[[6-(1,3-dimethylpyrazole-4-yl)-[1,2,4]triazolo[1,5-a]pyrazine-8-yl]oxy]azepan-1-carboxylate (65 mg, 0.15 mmol) in dioxane (5 mL), HCl (4 M in dioxane, 0.38 mL) was added. The mixture was stirred overnight at room temperature. The substance was concentrated to obtain 8-[(4R)-azepan-4-yl]oxy-6-(1,3-dimethylpyrazole-4-yl)-[1,2,4]triazolo[1,5-a]pyrazine hydrochloride (55.3 mg, 100% yield) as an off-white solid. LCMS m / z = 328.1 (M+H)+.

[0362] Synthesis of 1-[(4R)-4-[[6-(1,3-dimethylpyrazole-4-yl)-[1,2,4]triazolo[1,5-a]pyrazine-8-yl]oxy]azepan-1-yl]propa-2-en-1-one [ka] 8-[(4R)-azepan-4-yl]oxy-6-(1,3-dimethylpyrazole-4-yl)-[1,2,4]triazolo[1,5-a]pyrazine hydrochloride (55.3 mg, 0.15 mmol), triethylamine (93 mg, 0.92 mmol, 128 μL), and propa-2-enoyl chloride (17 mg, 0.18 mmol, 15 μL) were added to a vial in the following order in DCM (4 mL). The vial was stirred overnight at room temperature. The reaction mixture was concentrated, transferred to DMSO, and passed through a plug. The substance was purified by reverse-phase purification (column: Waters XSelect CSH Prep C18 5um OBD 19x100 mm; conditions: 5-40% acetonitrile / 0.1% v / v ammonium carbonate / water; flow rate: 30 mL / min) to obtain 26.4 mg (45% yield) of the desired product. LCMS m / z = 382.3 (M+H)+. 1 H NMR (500 MHz, DMSO-d6) δ ppm 1.69 - 1.81 (m, 1 H) 1.91 - 2.07 (m, 4 H) 2.21 - 2.31 (m, 1 H) 2.44 (d, J=1.22 Hz, 3 H) 3.49 - 3.59 (m, 2 H) 3.66 - 3.76 (m, 2 H) 3.82 (d, J=1.83 Hz, 3 H) 5.41 - 5.54 (m, 1 H) 5.65 - 5.77 (m, 1 H) 6.11 - 6.22 (m, 1 H) 6.75 - 6.88 (m, 1 H) 8.11 - 8.23 (m, 1 H) 8.52 - 8.61 (m, 1 H) 8.69 - 8.78 (m, 1 H).

[0363] Example 71: (S)-5-(4-((1-acryloylazepan-4-yl)oxy)pyrazolo[1,5-a]pyrazine-6-yl)-1-methylpyridine-2(1H)-one and (R)-5-(4-((1-acryloylazepan-4-yl)oxy)pyrazolo[1,5-a]pyrazine-6-yl)-1-methylpyridine-2(1H)-one [ka]

[0364] Synthesis of tert-butyl=4-((6-(1-methyl-6-oxo-1,6-dihydropyridine-3-yl)pyrazolo[1,5-a]pyrazine-4-yl)oxy)azepan-1-carboxylate [ka] To a 20 mL scintillation vial containing tert-butyl=4-((6-chloropyrazolo[1,5-a]pyrazine-4-yl)oxy)azepan-1-carboxylate (200 mg, 0.55 mmol) in dioxane (5.0 mL), 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-2(1H)-one (154 mg, 0.64 mmol) was added. Next, an aqueous solution of K3PO4 (1 M, 1.09 mmol, 1.1 mL) was added to the reaction mixture, followed by the addition of Pd-PEPPSI®-IPr (37 mg, 55 μmol). The vial was purged with N2 and heated overnight at 100°C. After this, the reaction mixture was filtered through a Celite® pad and concentrated under reduced pressure to obtain an amber-colored oily substance. The crude substance was purified by silica gel chromatography (0-25% siRNA / heptane, followed by 100% [3:1 siRNA:EtOH]) to obtain tert-butyl=4-((6-(1-methyl-6-oxo-1,6-dihydropyridine-3-yl)pyrazolo[1,5-a]pyrazine-4-yl)oxy)azepan-1-carboxylate (155 mg, yield 65%) as an off-white solid. LC-MS: m / z = 440.0 (M+H) + .

[0365] Synthesis of 5-(4-(azepan-4-yloxy)pyrazolo[1,5-a]pyrazine-6-yl)-1-methylpyridine-2(1H)-one [ka] To a solution of tert-butyl=4-((6-(1-methyl-6-oxo-1,6-dihydropyridine-3-yl)pyrazolo[1,5-a]pyrazine-4-yl)oxy)azepan-1-carboxylate (155 mg, 0.35 mmol) in dioxane (1.4 mL), HCl (4 M in dioxane, 883 μL, 3.5 mmol) was added. The reaction mixture immediately became heterogeneous upon addition of the HCl solution, and was stirred at room temperature for 1.5 hours. The reaction mixture was directly concentrated under reduced pressure to obtain the title compound as an orange solid, which was then removed without further purification (assumed yield 100%). LC-MS: m / z = 361.9 (M+Na) + .

[0366] Synthesis of (S)-5-(4-((1-acryloylazepan-4-yl)oxy)pyrazolo[1,5-a]pyrazine-6-yl)-1-methylpyridine-2(1H)-one and (R)-5-(4-((1-acryloylazepan-4-yl)oxy)pyrazolo[1,5-a]pyrazine-6-yl)-1-methylpyridine-2(1H)-one [ka] To a solution of 5-(4-(azepan-4-yloxy)pyrazolo[1,5-a]pyrazine-6-yl)-1-methylpyridine-2(1H)-one (120 mg, 0.35 mmol) in DCM (1.4 mL), triethylamine (99 μL, 0.71 mmol) was added, followed by acryloyl chloride (57 μL, 0.71 mmol). Upon addition of acryloyl chloride, the solution became uniformly red and was stirred at room temperature for 20 minutes. The reaction mixture was then concentrated under vacuum and loaded into a silica gel cartridge. The crude substance was purified by silica gel chromatography (0-100% siRNA / heptane, followed by 0-15% MeOH / heptane) to obtain 5-(4-((1-acryloylazepan-4-yl)oxy)pyrazolo[1,5-a]pyrazine-6-yl)-1-methylpyridine-2(1H)-one as a white solid (52.1 mg, 38% in 2 steps). LC-MS: m / z = 393.9 (M+H) + . 1 H NMR (400 MHz, CDCl3) δ ppm 1.72 (br s, 1 H) 1.74 - 1.91 (m, 2 H) 1.95 - 2.49 (m, 6 H) 3.46 - 3.64 (m, 2 H) 3.65 - 3.73 (m, 4 H) 3.77 - 4.12 (m, 2 H) 5.46 - 5.65 (m, 1 H) 5.69 - 5.75 (m, 1 H) 6.35 - 6.43 (m, 1 H) 6.58 - 6.70 (m, 2 H) 6.73 - 6.78 (m, 1 H) 7.74 - 7.79 (m, 1 H) 7.91 (dd, J=4.39, 2.38 Hz, 1 H) 7.95 - 8.11 (m, 1 H) 8.23 ​​(d, J=0.75 Hz, 1 H).

[0367] The racemic material was separated by chiral SFC (Chiralpak AD-H 30×250mm, 5μm column; 25% MeOH / CO2 (no modifier); flow rate = 100 mL / min, ABPR 120 bar, MBPR 40 psi, column temperature 40°C) to obtain the enantiomers E1 (7.0 mg, 100% ee, Rf = 4.36 min), which elutes first, and E2 (R arbitrarily assigned, 7.6 mg, 90% ee, Rf = 4.77 min), which elutes second.

[0368] Example 72: 1-(4-((6-(2-methoxypyridine-4-yl)pyrazolo[1,5-a]pyrazine-4-yl)oxy)azepan-1-yl)propa-2-en-1-one (chiral, but absolute chemistry is unknown) [ka]

[0369] Synthesis of tert-butyl=4-((6-(2-methoxypyridine-4-yl)pyrazolo[1,5-a]pyrazine-4-yl)oxy)azepan-1-carboxylate [ka] To a 20 mL scintillation vial containing tert-butyl=4-((6-chloropyrazolo[1,5-a]pyrazine-4-yl)oxy)azepan-1-carboxylate (200 mg, 0.55 mmol) in dioxane (5.0 mL), 2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (100 mg, 0.65 mmol) was added. Next, an aqueous solution of K3PO4 (1 M, 1.09 mmol, 1.09 mL) was added to the reaction mixture, followed by the addition of Pd-PEPPSI®-IPr (37 mg, 55 μmol). The vial was purged with N2 and heated overnight at 100°C. The reaction mixture was allowed to return to room temperature and then filtered through a Celite® pad. The mixture was concentrated under reduced pressure to obtain the crude product as an amber-colored oil. The crude substance was purified by silica gel chromatography (0-25% siRNA / heptane) to obtain tert-butyl=4-((6-(2-methoxypyridine-4-yl)pyrazolo[1,5-a]pyrazine-4-yl)oxy)azepan-1-carboxylate (184 mg, yield 77%) as an off-white solid. LC-MS: m / z = 440.0 (M+H) + .

[0370] Synthesis of 4-(azepan-4-yloxy)-6-(2-methoxypyridine-4-yl)pyrazolo[1,5-a]pyrazine [ka] To a solution of tert-butyl=4-((6-(2-methoxypyridine-4-yl)pyrazolo[1,5-a]pyrazine-4-yl)oxy)azepan-1-carboxylate (184 mg, 0.42 mmol) in dioxane (1.7 mL), HCl solution (4 M in dioxane, 1.05 mL, 4.2 mmol) was added. The reaction mixture was stirred at room temperature for 3 hours, then concentrated under vacuum to obtain crude 4-(azepan-4-yloxy)-6-(2-methoxypyridine-4-yl)pyrazolo[1,5-a]pyrazine as a bright yellow solid. The crude product was used without further purification (assumed yield 100%). LC-MS: m / z = 340.0 (M+H)+ .

[0371] Synthesis of chiral 1-(4-((6-(2-methoxypyridine-4-yl)pyrazolo[1,5-a]pyrazine-4-yl)oxy)azepan-1-yl)propa-2-en-1-one [ka] To a solution of crude 4-(azepan-4-yloxy)-6-(2-methoxypyridine-4-yl)pyrazolo[1,5-a]pyrazine (142 mg, 0.42 mmol) in DCM (1.7 mL), triethylamine (0.29 mL, 2.09 mmol) was added at room temperature, followed immediately by the addition of acryloyl chloride (68 μL, 0.84 mmol). The reaction mixture became a homogeneous crimson color and was stirred at room temperature for 20 minutes. The reaction mixture was then quenched by the addition of saturated NaHCO3 aqueous solution and diluted with ethyl acetate. The resulting layers were separated, and the aqueous layer was further extracted with ethyl acetate (3x). The combined organic matter was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude substance was purified by silica gel chromatography (0-100% siRNA / heptane) to obtain 1-(4-((6-(2-methoxypyridine-4-yl)pyrazolo[1,5-a]pyrazine-4-yl)oxy)azepan-1-yl)propa-2-en-1-one (64.5 mg, 39% in 2 steps) as a colorless oil. LC-MS: m / z = 393.9 (M+H) + . 1HNMR(400MHz,CDCl3)δppm1.81- 1.92 (m, 1 H) 1.97 - 2.13 (m, 2 H) 2.16 - 2.31 (m, 3 H) 3.62 - 3.85 (m, 4 H) 4.01 - 4.04 (m, 3 H) 5.64 - 5.70 (m, 1 H) 5.72 (dd, J=10.29, 2.01 Hz, 1 H) 6.39 (ddd, J=16.75, 7.72, 2.13 Hz, 1 H) 6.57 - 6.68 (m, 1 H) 6.80 (dd, J=4.02, 2.01 Hz, 1 H) 7.31 - 7.39 (m, 2 H) 7.98 (t, J=2.01 Hz, 1 H) 8.24 (d, J=5.27 Hz, 1 H) 8.56 (s, 1 H).

[0372] The racemic material was separated by chiral SFC (Chiralpak IB 30×250mm, 5μm column; 15% MeOH / CO2 (no modifier); flow rate = 100 mL / min, ABPR 120 bar, MBPR 40 psi, column temperature 40°C) to obtain the first eluted enantiomer E1 (12.2 mg, 100% ee, Rf = 6.91 min) and the second eluted enantiomer E2 (3.6 mg, 96% ee, Rf = 7.45 min). The second enantiomer contained impurities that could not be separated, and no further purification was performed.

[0373] Example 73: (R)-1-(4-((6-phenylpyrazolo[1,5-a]pyrazine-4-yl)oxy)azepan-1-yl)propa-2-en-1-one [ka]

[0374] Synthesis of tert-butyl=(R)-4-((6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5-a]pyrazine-4-yl)oxy)azepan-1-carboxylate [ka] To a 20 mL scintillation vial containing tert-butyl=(R)-4-((6-chloropyrazolo[1,5-a]pyrazine-4-yl)oxy)azepan-1-carboxylate (734 mg, 2.0 mmol) dissolved in dioxane (10 mL), bis(pinacolato)diborone (610 mg, 2.4 mmol) was added. Next, KOAc (589 mg, 6.0 mmol) was added to the reaction mixture, followed by [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (293 mg, 0.40 mmol). The vial was purged with N2 and then stirred overnight at 95°C. After this, the reaction mixture was cooled to room temperature and filtered through a Celite® pad using ethyl acetate. The crude substance was dry-loaded onto silica gel and purified by silica gel chromatography (0-40% ethyl acetate / heptane) to obtain tert-butyl=(R)-4-((6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5-a]pyrazine-4-yl)oxy)azepan-1-carboxylate (744 mg, yield 81%) as a colorless oil. LC-MS: m / z = 399.2 (M-86+Na) + .

[0375] Synthesis of tert-butyl=(R)-4-((6-phenylpyrazolo[1,5-a]pyrazine-4-yl)oxy)azepan-1-carboxylate [ka] To a 20 mL scintillation vial containing tert-butyl=(R)-4-((6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5-a]pyrazine-4-yl)oxy)azepan-1-carboxylate (248 mg, 0.54 mmol) in dioxane (1.8 mL), bromobenzene (38 μL, 0.36 mmol), followed sequentially by aqueous K3PO4 solution (0.5 M, 1.44 mL, 0.72 mmol) and Pd-PEPPSI™-IPr (49 mg, 72 μmol). The reaction mixture was heated overnight at 95 °C, then cooled to room temperature and concentrated directly under reduced pressure. The crude substance was purified by silica gel chromatography (0-100% SiO2 / heptane) to obtain tert-butyl=(R)-4-((6-phenylpyrazolo[1,5-a]pyrazine-4-yl)oxy)azepan-1-carboxylate (47.6 mg, yield 32%) as a yellow oil. LC-MS: m / z = 409.2 (M+H) +.

[0376] Synthesis of (R)-4-(azepan-4-yloxy)-6-phenylpyrazolo[1,5-a]pyrazine [ka] To a solution of tert-butyl=(R)-4-((6-phenylpyrazolo[1,5-a]pyrazine-4-yl)oxy)azepan-1-carboxylate (48 mg, 0.12 mmol) in dioxane (1.2 mL), HCl (4 M, 1.2 mmol, 291 μL in dioxane) was added. Upon addition of the HCl solution, the reaction mixture immediately formed a white slurry, which was stirred at room temperature for 4 hours. The reaction mixture was directly concentrated under reduced pressure to obtain crude (R)-4-(azepan-4-yloxy)-6-phenylpyrazolo[1,5-a]pyrazine, which was then removed without further purification (assumed yield 100%). LC-MS: m / z = 332.2 (M+Na) + .

[0377] Synthesis of (R)-1-(4-((6-phenylpyrazolo[1,5-a]pyrazine-4-yl)oxy)azepan-1-yl)propa-2en-1one [ka] A solution of crude (R)-4-(azepan-4-yloxy)-6-phenylpyrazolo[1,5-a]pyrazine (36 mg, 0.12 mmol) in THF (1.2 mL) was cooled to -78°C in a dry ice / acetone bath. Triethylamine (81 μL, 0.58 mmol) was added by microsyringe with stirring, followed immediately by the addition of acryloyl chloride (19 μL, 0.23 mmol). The reaction mixture was removed from the ice bath and slowly warmed to room temperature, during which time it turned red. After stirring at room temperature for 2 hours, the reaction mixture was diluted with ethyl acetate and quenched by the addition of saturated aqueous NaHCO3 solution. The resulting layers were separated, and the aqueous layer was further extracted with ethyl acetate (2x). The combined organic extracts were dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the crude product as a pale yellow oil. The crude substance was purified by reverse-phase HPLC (column: Waters XSelect CSH Prep C18 5μm OBD 19×100mm; conditions: 5-70% acetonitrile / 0.1% v / v ammonium carbonate / water) to obtain (R)-1-(4-((6-phenylpyrazolo[1,5-a]pyrazine-4-yl)oxy)azepan-1-yl)propa-2-en-1-one (16.7 mg in 2 steps, yield 40%) as a yellow film. LC-MS: m / z = 363.3 (M + H) + . 1 HNMR(500MHz,DMSO-d6) δ ppm1.71-1.80(m,1H)1.87-2.13(m,5 H)2.18-2.30(m,1H)3.52-3.78(m,4H)5.54-5.62(m,1H)5.70(dt,J=10.38, 2.14 Hz, 1H) 6.15 - 6.21 (m, 1 H) 6.77 - 6.88 (m, 2 H) 7.37 - 7.42 (m, 1 H) 7.45 - 7.50 (m, 2 H) 8.07 - 8.11 (m, 3 H) 9.03 (s, 1 H).

[0378] Example 74: (R)-1-(4-((6-(6-methoxypyrimidine-4-yl)pyrazolo[1,5-a]pyrazine-4-yl)oxy)azepan-1-yl)propa-2-en-1-one [ka]

[0379] Synthesis of tert-butyl=(R)-4-((6-(6-methoxypyrimidine-4-yl)pyrazolo[1,5-a]pyrazine-4-yl)oxy)azepan-1-carboxylate [ka] To a two-drum scintillation vial containing tert-butyl=(R)-4-((6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5-a]pyrazine-4-yl)oxy)azepan-1-carboxylate (138 mg, 0.30 mmol) in dioxane (3.0 mL), 4-bromo-6-methoxypyrimidine (38 mg, 0.20 mmol) was added. Next, an aqueous solution of K3PO4 (0.5 M, 0.80 mL, 0.40 mmol) was added, followed by Pd-PEPPSI(trademark)-IPr (41 mg, 40 μmol). The reaction mixture was heated overnight at 95°C, then cooled to room temperature and concentrated directly under reduced pressure. The crude substance was purified by silica gel chromatography (0-50% [3:1 SiO:EtOH] / heptane) to obtain tert-butyl=(R)-4-((6-(6-methoxypyrimidine-4-yl)pyrazolo[1,5-a]pyrazine-4-yl)oxy)azepan-1-carboxylate (98.6 mg, yield 75%). LC-MS: m / z = 441.2 (M+H) + .

[0380] Synthesis of (R)-4-(azepan-4-yloxy)-6-(6-methoxypyrimidine-4-yl)pyrazolo[1,5-a]pyrazine [ka] When HCl (4M, 2.2 mmol, 0.56 mL in dioxane) was added to a solution of tert-butyl=(R)-4-((6-(6-methoxypyrimidine-4-yl)pyrazolo[1,5-a]pyrazine-4-yl)oxy)azepan-1-carboxylate (99 mg, 0.22 mmol) in dioxane (2.2 mL), a milky slurry was formed. After stirring at room temperature for 4 hours, the reaction mixture was directly concentrated under reduced pressure to obtain crude (R)-4-(azepan-4-yloxy)-6-(6-methoxypyrimidine-4-yl)pyrazolo[1,5-a]pyrazine, which was used without further purification (assumed yield 100%). LC-MS: m / z = 363.3 (M+Na) + .

[0381] Synthesis of (R)-1-(4-((6-(6-methoxypyrimidine-4-yl)pyrazolo[1,5-a]pyrazine-4-yl)oxy)azepan-1-yl)propa-2-en-1-one [ka] A solution of crude (R)-4-(azepan-4-yloxy)-6-(6-methoxypyrimidine-4-yl)pyrazolo[1,5-a]pyrazine (76 mg, 0.22 mmol) in THF (2.2 mL) was cooled to -78°C in a dry ice / acetone bath. Triethylamine (156 μL, 1.1 mmol) was added with stirring, followed immediately by acryloyl chloride (36 μL, 0.45 mmol). The reaction mixture was removed from the ice bath and slowly warmed to room temperature, during which time it turned red. After stirring at room temperature for 2 hours, the reaction mixture was diluted with ethyl acetate and quenched by adding saturated aqueous NaHCO3 solution. The resulting layers were separated, and the aqueous layer was further extracted with ethyl acetate (2x). The combined organic extracts were dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the crude product as a yellow oily substance. The crude substance was purified by reverse-phase HPLC (column: Waters XSelect CSH Prep C18 5μm OBD 19×100mm; conditions: 5-65% acetonitrile / 0.1% v / v ammonium carbonate / water) to obtain (R)-1-(4-((6-(6-methoxypyrimidine-4-yl)pyrazolo[1,5-a]pyrazine-4-yl)oxy)azepan-1-yl)propa-2-en-1-one (22.7 mg, 26% yield in 2 steps) as a white solid. LC-MS: m / z = 395.3 (M+H) + . 1HNMR(500MHz,DMSO-d6) δ ppm 1.71 - 1.81 (m, 1 H) 1.87 - 1.95 (m, 1 H) 1.97 (br s, 1 H) 1.98 - 2.11 (m, 2 H) 2.20 - 2.30 (m, 1 H) 3.53 - 3.81 (m, 4 H) 3.99 - 4.02 (m, 1 H) 4.00 (s, 1 H) 5.57 - 5.64 (m, 1 H) 5.68 - 5.72 (m, 1 H) 6.18 (dt, J=16.79, 2.59 Hz, 1 H) 6.82 (dt, J=16.48, 10.07Hz, 1H) 6.95 - 6.98 (m, 1 H) 7.53 (dd, J=10.99, 1.22 Hz, 1 H) 8.17 - 8.22 (m, 1 H) 8.19 - 8.19 (m, 1 H) 8.19 - 8.20 (m, 1 H) 8.82 - 8.87 (m, 1 H) 8.83 - 9.11 (m, 1 H) 9.09 (s, 1 H).

[0382] Example 75: (R)-1-(4-((6-(4-methyloxazol-2-yl)pyrazolo[1,5-a]pyrazine-4-yl)oxy)azepan-1-yl)propa-2-en-1-one [ka]

[0383] Synthesis of tert-butyl=(R)-4-((6-(4-methyloxazol-2-yl)pyrazolo[1,5-a]pyrazine-4-yl)oxy)azepan-1-carboxylate [ka] To a two-drum scintillation vial containing tert-butyl=(R)-4-((6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5-a]pyrazine-4-yl)oxy)azepan-1-carboxylate (138 mg, 0.30 mmol) in dioxane (3.0 mL), 2-bromo-4-methyloxazole (32 mg, 0.20 mmol) was added. Next, an aqueous solution of K3PO4 (0.5 M, 0.80 mL, 0.40 mmol) was added, followed by Pd-PEPPSI(trademark)-IPr (41 mg, 40 μmol). The reaction mixture was heated overnight at 95°C, then cooled to room temperature and concentrated directly under reduced pressure. The crude substance was purified by silica gel chromatography (0-50% [3:1 SiO:EtOH] / heptane) to obtain tert-butyl=(R)-4-((6-(4-methyloxazol-2-yl)pyrazolo[1,5-a]pyrazine-4-yl)oxy)azepan-1-carboxylate (95.4 mg, yield 77%). LC-MS: m / z = 441.2 (M+H) +.

[0384] Synthesis of (R)-2-(4-(azepan-4-yloxy)pyrazolo[1,5-a]pyrazine-6-yl)-4-methyloxazole [ka] When HCl (4M, 2.3 mmol, 0.58 mL in dioxane) was added to a solution of tert-butyl=(R)-4-((6-(4-methyloxazole-2-yl)pyrazolo[1,5-a]pyrazine-4-yl)oxy)azepan-1-carboxylate (95 mg, 0.23 mmol) in dioxane (2.3 mL), a bright yellow slurry was formed. After stirring at room temperature for 4 hours, the reaction mixture was directly concentrated under reduced pressure to obtain crude (R)-2-(4-(azepan-4-yloxy)pyrazolo[1,5-a]pyrazine-6-yl)-4-methyloxazole, which was used without further purification (assumed yield 100%). LC-MS: m / z = 314.1 (M+Na) + .

[0385] Synthesis of (R)-1-(4-((6-(4-methyloxazol-2-yl)pyrazolo[1,5-a]pyrazine-4-yl)oxy)azepan-1-yl)propa-2en-1-one [ka] A solution of crude (R)-2-(4-(azepan-4-yloxy)pyrazolo[1,5-a]pyrazine-6-yl)-4-methyloxazole (72 mg, 0.23 mmol) in THF (2.3 mL) was cooled to -78°C in a dry ice / acetone bath. Triethylamine (161 μL, 1.2 mmol) was added with stirring, followed immediately by acryloyl chloride (38 μL, 0.46 mmol). The reaction mixture was removed from the ice bath and slowly warmed to room temperature, during which time it turned red. After stirring at room temperature for 2 hours, the reaction mixture was diluted with ethyl acetate and quenched by adding saturated aqueous NaHCO3 solution. The resulting layers were separated, and the aqueous layer was further extracted with ethyl acetate (2x). The combined organic extracts were dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the crude product as a yellow solid. The crude substance was purified by reverse-phase HPLC (column: Waters XSelect CSH Prep C18 5μm OBD 19×100mm; conditions: 5-55% acetonitrile / 0.1% v / v ammonium carbonate / water) to obtain (R)-1-(4-((6-(4-methyloxazol-2-yl)pyrazolo[1,5-a]pyrazine-4-yl)oxy)azepan-1-yl)propa-2-en-1-one (28.2 mg, 22% yield in 2 steps) as an off-white solid. LC-MS: m / z = 368.3 (M+H) + . 1HNMR(500MHz,DMSO-d6) δ ppm 1.67 - 1.79 (m, 1 H) 1.83 - 1.96 (m, 2 H) 2.02 - 2.13 (m, 3 H) 2.18 (d, J=1.22 Hz, 4 H) 3.54 - 3.77 (m, 3 H) 5.53 - 5.60 (m, 1 H) 5.69 (ddd, J=10.38, 3.66, 2.44 Hz, 1 H) 6.13 - 6.20 (m, 1 H) 6.80 (ddd, J=16.48, 14.04, 10.38 Hz, 1 H) 6.95 - 6.98 (m, 1 H) 7.97 (s, 1 H) 8.18 (d, J=1.22 Hz, 1 H) 8.90 (s, 1 H).

[0386] Example 76: (R)-1-(4-((6-(2-methylthiazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl)oxy)azepan-1-yl)propa-2-en-1-one [ka]

[0387] Synthesis of tert-butyl=(R)-4-((6-(2-methylthiazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl)oxy)azepan-1-carboxylate [ka] A solution of tert-butyl=(R)-4-((6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5-a]pyrazine-4-yl)oxy)azepan-1-carboxylate (193 mg, 0.42 mmol), 4-bromo-2-methylthiazole (50 mg, 0.28 mmol), dichlorobis(di-tert-butylphosphinite)palladium dihydrogen (2-) (7 mg, 14 μmol), and cesium fluoride (128 mg, 0.84 mmol) in isopropanol (1.4 mL) was stirred at 90°C in a microwave for 3 hours. The reaction mixture was quenched with water and brine. The two-phase mixture was extracted three times with ethyl acetate and then dried over anhydrous MgSO4. After filtration and concentration under reduced pressure, the crude tert-butyl=(R)-4-((6-(2-methylthiazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl)oxy)azepan-1-carboxylate (110 mg, yield 91%) was further purified before proceeding. LCMS: m / z = 430.0(M+H) + .

[0388] Synthesis of (R)-1-(4-((6-(2-methylthiazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl)oxy)azepan-1-yl)propa-2en-1-one [ka] Step 1. Crude tert-butyl=(R)-4-((6-(2-methylthiazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl)oxy)azepan-1-carboxylate (110 mg, 0.26 mmol) was dissolved in HCl solution (1.25 M in MeOH, 1.5 mL). The reaction solution was stirred at 40°C. After 16 hours, the reaction product was carefully quenched by slowly adding saturated aqueous NaHCO3 solution. The two-phase mixture was extracted three times with a mixture of chloroform and isopropanol (5:1), and then dried over anhydrous MgSO4. After filtration and concentration under reduced pressure, crude (R)-4-(4-(azepan-4-yloxy)pyrazolo[1,5-a]pyrazine-6-yl)-2-methylthiazole (84 mg, assumed yield 100%) was concentrated to dryness and the process proceeded without purification. LCMS: m / z = 330.0(M+H) + .

[0389] Step 2. Crude (R)-4-(4-(azepan-4-yloxy)pyrazolo[1,5-a]pyrazine-6-yl)-2-methylthiazole (84 mg, 0.25 mmol) was placed in a 20 mL vial, to which DCM (1.0 mL) was added, followed by TEA (129 mg, 1.27 mmol, 178 μL). The reaction mixture was stirred at room temperature for 5 minutes and then cooled to 0°C. Acryloyl chloride (35 mg, 0.38 mmol, 31 μL) was added dropwise. The solution was stirred at 0°C. After 1 hour, the reaction mixture was carefully quenched by slowly adding saturated aqueous NH4Cl. The two-phase mixture was extracted three times with ethyl acetate and then dried over anhydrous MgSO4. After filtration and concentration under reduced pressure, the residue was loaded onto a silica gel column and purified (25-100% ethyl acetate / heptane). The desired fraction was pooled and then concentrated under reduced pressure to obtain (R)-1-(4-((6-(2-methylthiazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl)oxy)azepan-1-yl)propa-2-en-1-one (31.2 mg, yield 32%). 1H NMR (500 MHz, DMSO-d6) δ ppm 8.67 (s, 1 H) 8.08 (s, 1 H) 7.96 (s, 1 H) 7.92 (rotamer, s, 1 H) 6.77 - 6.89 (m, 2 H) 6.14 - 6.20 (m, 1 H) 5.69 (ddd, J =10.22,7.48,2.44Hz,1 H) 5.52 - 5.62 (m, 1 H) 3.58 - 3.78 (m, 4 H) 2.74 (d, J =1.22Hz,3 H) 2.23 (ddt, J =10.91,7.25,3.43,3.43Hz,1 H) 1.87 - 2.09 (m, 4 H) 1.71 - 1.82 (m, 1 H).LCMS m / z = 384.0(M+H) + .

[0390] Example 77: (R)-1-(4-((6-(2-methylthiazole-5-yl)pyrazolo[1,5-a]pyrazine-4-yl)oxy)azepan-1-yl)propa-2-en-1-one [ka]

[0391] Synthesis of tert-butyl=(R)-4-((6-(2-methylthiazole-5-yl)pyrazolo[1,5-a]pyrazine-4-yl)oxy)azepan-1-carboxylate [ka] A solution of tert-butyl=(R)-4-((6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5-a]pyrazine-4-yl)oxy)azepan-1-carboxylate (200 mg, 0.44 mmol), 5-bromo-2-methylthiazole (156 mg, 0.87 mmol), dichlorobis(di-tert-butylphosphinite)palladium(2-) (22 mg, 44 μmol), and cesium fluoride (199 mg, 1.3 mmol) in isopropanol (1.0 mL) was stirred at 90°C. After 16 hours, the reaction product was quenched with water and brine. The two-phase mixture was extracted three times with ethyl acetate and then dried over anhydrous MgSO4. After filtration and concentration under reduced pressure, the crude tert-butyl=(R)-4-((6-(2-methylthiazole-5-yl)pyrazolo[1,5-a]pyrazine-4-yl)oxy)azepan-1-carboxylate (187 mg, assumed yield 100%) was further purified before proceeding. LCMS: m / z = 430.0(M+H) + .

[0392] Synthesis of (R)-1-(4-((6-(2-methylthiazole-5-yl)pyrazolo[1,5-a]pyrazine-4-yl)oxy)azepan-1-yl)propa-2en-1one [ka] Step 1. Crude tert-butyl=(R)-4-((6-(2-methylthiazole-5-yl)pyrazolo[1,5-a]pyrazine-4-yl)oxy)azepan-1-carboxylate (187 mg, 0.44 mmol) was dissolved in HCl solution (1.25 M in MeOH, 1.7 mL). The reaction solution was stirred at 40°C. After 16 hours, the reaction product was carefully quenched by slowly adding saturated aqueous NaHCO3 solution. The two-phase mixture was extracted three times with a mixture of chloroform and isopropanol (5:1), and then dried over anhydrous MgSO4. After filtration and concentration under reduced pressure, crude (R)-5-(4-(azepan-4-yloxy)pyrazolo[1,5-a]pyrazine-6-yl)-2-methylthiazole (143 mg, assumed yield 100%) was concentrated to dryness and the process proceeded without purification. LCMS: m / z = 330.0(M+H) + .

[0393] Step 2. Crude (R)-5-(4-(azepan-4-yloxy)pyrazolo[1,5-a]pyrazine-6-yl)-2-methylthiazole (143 mg, 0.44 mmol) was placed in a 20 mL vial, to which DCM (2 mL) was added, followed by TEA (439 mg, 4.34 mmol, 605 μL). The reaction mixture was stirred at room temperature for 5 minutes and then cooled to 0°C. Acryloyl chloride (79 mg, 0.87 mmol, 71 μL) was added dropwise. The solution was stirred at 0°C. After 1 hour, the reaction mixture was carefully quenched by slowly adding saturated aqueous NH4Cl solution. The two-phase mixture was extracted three times with ethyl acetate and then dried over anhydrous MgSO4. After filtration and concentration under reduced pressure, the residue was loaded onto a silica gel column and purified (25-100% ethyl acetate / heptane). The desired fraction was pooled and then concentrated under reduced pressure to obtain (R)-1-(4-((6-(2-methylthiazole-5-yl)pyrazolo[1,5-a]pyrazine-4-yl)oxy)azepan-1-yl)propa-2-en-1-one (29.8 mg, yield 18%). 1H NMR (500 MHz, DMSO-d6) δ ppm 9.02 - 9.04 (m, 1 H) 8.25 (d, J =2.44Hz,1 H) 8.09 (dd, J =2.44,1.22Hz,1 H) 6.89 (d, J =3.05Hz,1 H) 6.81 (ddd, J =16.48,12.82,10.38Hz,1 H) 6.17 (ddd, J =16.63,7.48,2.75Hz,1 H) 5.70 (dt, J =10.38,2.44Hz,1 H) 5.38 - 5.44 (m, 1 H) 3.55 - 3.75 (m, 4 H) 2.68 (s, 3H) 2.15 - 2.26 (m, 1 H) 1.87 - 2.10 (m, 4 H) 1.68 - 1.80 (m, 1 H).LCMS m / z = 384.0(M+H) + .

[0394] Example 78: (R)-1-(4-((6-(3-methylisothiazol-5-yl)pyrazolo[1,5-a]pyrazine-4-yl)oxy)azepan-1-yl)propa-2-en-1-one [ka]

[0395] Synthesis of tert-butyl=(R)-4-((6-(3-methylisothiazol-5-yl)pyrazolo[1,5-a]pyrazine-4-yl)oxy)azepan-1-carboxylate [ka] A solution of tert-butyl=(R)-4-((6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazolo[1,5-a]pyrazine-4-yl)oxy)azepan-1-carboxylate (80 mg, 175 μmol), 5-bromo-3-methylisothiazole (47 mg, 262 μmol), dichlorobis(di-tert-butylphosphinite)palladium(2-) (4.4 mg, 8.7 μmol), and cesium fluoride (80 mg, 524 μmol) in isopropanol (1.0 mL) was stirred at 90°C. After 16 hours, the reaction product was quenched with water and brine. The two-phase mixture was extracted three times with ethyl acetate and then dried over anhydrous MgSO4. After filtration and concentration under reduced pressure, the crude tert-butyl=(R)-4-((6-(3-methylisothiazol-5-yl)pyrazolo[1,5-a]pyrazine-4-yl)oxy)azepan-1-carboxylate (75 mg, assumed yield 100%) was further purified before proceeding. LCMS: m / z = 430.0(M+H) + .

[0396] Synthesis of (R)-1-(4-((6-(3-methylisothiazol-5-yl)pyrazolo[1,5-a]pyrazine-4-yl)oxy)azepan-1-yl)propa-2-en-1-one [ka] Step 1. Crude tert-butyl=(R)-4-((6-(3-methylisothiazole-5-yl)pyrazolo[1,5-a]pyrazine-4-yl)oxy)azepan-1-carboxylate (75 mg, 175 μmol) was dissolved in HCl solution (1.25 M in MeOH, 1.4 mL). The reaction solution was stirred at 40°C. After 16 hours, the reaction product was carefully quenched by slowly adding saturated aqueous NaHCO3 solution. The two-phase mixture was extracted three times with a mixture of chloroform and isopropanol (5:1), and then dried over anhydrous MgSO4. After filtration and concentration under reduced pressure, crude (R)-5-(4-(azepan-4-yloxy)pyrazolo[1,5-a]pyrazine-6-yl)-3-methylisothiazole (58 mg, assumed yield 100%) was concentrated to dryness and the process proceeded without purification. LCMS: m / z = 330.0(M+H) + .

[0397] Step 2. Crude (R)-5-(4-(azepan-4-yloxy)pyrazolo[1,5-a]pyrazine-6-yl)-3-methylisothiazole (58 mg, 175 μmol) was placed in a 20 mL vial, to which DCM (1.0 mL) was added, followed by TEA (88 mg, 0.87 mmol, 122 μL). The reaction mixture was stirred at room temperature for 5 minutes and then cooled to 0°C. Acryloyl chloride (24 mg, 262 μmol, 21 μL) was added dropwise. The solution was stirred at 0°C. After 1 hour, the reaction mixture was carefully quenched by slowly adding saturated aqueous NH4Cl solution. The two-phase mixture was extracted three times with ethyl acetate and then dried over anhydrous MgSO4. After filtration and concentration under reduced pressure, the residue was loaded onto a silica gel column and purified (25-100% ethyl acetate / heptane). The desired fraction was pooled and then concentrated under reduced pressure to obtain (R)-1-(4-((6-(3-methylisothiazol-5-yl)pyrazolo[1,5-a]pyrazine-4-yl)oxy)azepan-1-yl)propa-2-en-1-one (21.3 mg, yield 32%). 1H NMR (500 MHz, DMSO-d6) δ ppm 9.21 (d, J =1.22Hz,1 H) 8.15 (dd, J =2.44,1.22Hz,1 H) 7.80 (d, J =2.44Hz,1 H) 6.94 (d, J =3.05Hz,1 H) 6.81 (dt, J =16.63,10.30Hz,1 H) 6.14 - 6.21 (m, 1 H) 5.69 (ddd, J =10.38,5.49,2.44Hz,1 H) 5.34 - 5.43 (m, 1 H) 3.65 - 3.76 (m, 2 H) 3.53 - 3.64 (m, 2 H) 2.45 (s, 3 H) 2.17 - 2.29 (m, 1 H) 1.95 - 2.12 (m, 3 H) 1.86 - 1.93 (m, 1 H) 1.63 - 1.83 (m, 1 H).LCMS m / z = 384.0(M+H) + .

[0398] Example 79: N-methyl-N-((1s,3s)-3-methyl-3-((6-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl)oxy)cyclobutyl)acrylamide [ka]

[0399] Synthesis of tert-butyl=methyl((1s,3s)-3-methyl-3-((6-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl)oxy)cyclobutyl)carbamate [ka] In a 100 mL single-neck round-bottom flask equipped with a condenser and under a nitrogen atmosphere, potassium hexamethyldisilazide (1 M in THF, 2.2 mL) was added at room temperature to a solution of tert-butyl=((1s,3s)-3-hydroxy-3-methylcyclobutyl)carbamate (150 mg, 0.75 mmol) in dioxane (7.5 mL). After 5 minutes, a solution of 4,6-dichloropyrazolo[1,5-a]pyrazine (128 mg, 0.68 mmol) in dioxane (2.5 mL) was added dropwise to a dense white suspension. Iodomethane (240 mg, 1.70 mmol, 105 μL) was added to the resulting orange suspension at room temperature, and stirring was continued for a further 30 minutes. The resulting reaction mixture was degassed by purging with nitrogen for 30 minutes, and then a solution of tripotassium phosphate (531 mg, 2.50 mmol) in degassed water (2.5 mL) was added at room temperature. The clear orange reaction mixture was purged with nitrogen for a further 10 minutes, then a solution of 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (212 mg, 1.02 mmol) in pre-degassed dioxane (2.0 mL) was added, followed by the addition of solid Pd-PEPPSI™-IPr catalyst (93 mg, 0.14 mmol). The reaction mixture was purged with nitrogen for a further 15 minutes, and then heated under reflux for 3 hours. Ethyl acetate (20 mL) and then water (20 mL) were added to the vigorously stirred reaction mixture. After 30 minutes, the organic phase was separated, and volatile substances were removed under reduced pressure. The resulting residue was purified by column chromatography (40 g silica gel, 0-80% [3:1 siRNA:EtOH] + 2% NH4OH modifier / heptane) to obtain the title compound as a pale yellow oil (130 mg, yield 47%). LCMS m / z = 413.1 (M+H)+. 1H NMR (500 MHz, methanol-d4)δppm8.42(s,1H),8.05(s,1H),7.93(s,1H),7.91(d,J=2.44Hz,1H),6.77(d,J=1.22 Hz, 1H), 4.10-4.45 (m, 1H), 3.95 (s, 3H), 2.82 (s, 3H), 2.74-2.81 (m, 2H), 2.67 (br s, 2H), 1.81 (s, 3H), 1.46 (s, 9H).

[0400] Synthesis of (1s,3s)-N,3-dimethyl-3-((6-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl)oxy)cyclobutan-1-amine [ka] To a solution of tert-butyl=methyl((1s,3s)-3-methyl-3-((6-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl)oxy)cyclobutyl)carbamate (4.05 g, 9.82 mmol) in HFIP (45 mL), TFA (2.24 g, 19.6 mmol, 1.5 mL) was added at room temperature. The resulting reaction mixture was stirred overnight. Ethyl acetate (50 mL) was added, followed by saturated NaHCO3 aqueous solution (25 mL) and brine (10 mL). After vigorous stirring for 30 minutes, the organic phase was separated, dried over sodium sulfate, filtered, and concentrated. The resulting residue was purified by column chromatography (24g silica gel, 80-100% [3:1 RINKAN:EtOH] + 2% NH4OH modifier / heptane) to obtain the title compound as a pale yellow, rubbery substance (2.53g, 82% yield). LCMS m / z = 313.1 (M+H)+. 1H NMR (500 MHz, Methanol-d4)δppm8.41(d,J=1.22Hz,1H),8.05(s,1H),7.86-7.97(m,2H),6.72-6.81(m,1H),3.95(s,3H) ,2.96-3.11(m,1H),2.76-2.90(m,2H),2.31(s,3H),2.25-2.31(m,2H),2.25-2.31(m,2H),1.80(s,3H).

[0401] Synthesis of N-methyl-N-((1s,3s)-3-methyl-3-((6-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl)oxy)cyclobutyl)acrylamide [ka] To a solution of N-methyl-N-((1s,3s)-3-methyl-3-((6-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl)oxy)cyclobutyl)acrylamide (4.05 g, 9.82 mmol) and DIPEA (2.81 g, 21.7 mmol, 3.8 mL) in THF (50 mL), acryloyl chloride (819 mg, 9.04 mmol, 740 μL) was added at 0°C. After 30 minutes, the reaction mixture was diluted with ELISA (50 mL) and saturated NaHCO3 aqueous solution (50 mL) was added. The two-phase mixture was vigorously stirred, allowed to reach room temperature, and stirring was continued for another 30 minutes. The organic phase was separated, washed with water (25 mL) and brine (25 mL), dried over Na2SO4, filtered, and concentrated. The obtained residue was purified by column chromatography (80 g silica gel, 0-100% [3:1 HCl:EtOH] + 2% NH4OH modifier / heptane). The colorless solid was recrystallized from HCl / heptane (1 / 3, 45 mL) to obtain the title compound as a readily flowing crystalline solid (1.8 g, yield 68%). Melting point = 137.5 °C. LCMS m / z = 389.1.1 (M+Na)+. 1H NMR (500 MHz, methanol-d4)δppm8.44(s,1H),8.06(s,1H),7.85-7.98(m,2H),6.67-6.85(m,2H),6.12-6.26(m,1H),5.74(brd,J=9.16 Hz, 1H), 4.45-4.77 (m, 1H), 3.95 (s, 3H), 2.94-3.12 (m, 3H), 2.62-2.94 (m, 4H), 1.86 (s, 3H).

[0402] Example 80: N-((1s,3s)-3-((6-(1H-pyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl)oxy)-3-methylcyclobutyl)-N-methylacrylamide [ka]

[0403] Synthesis of tert-butyl=((1s,3s)-3-((6-chloropyrazolo[1,5-a]pyrazine-4-yl)oxy)-3-methylcyclobutyl)(methyl)carbamate [ka] In a 100 mL single-neck round-bottom flask equipped with a condenser and under a nitrogen atmosphere, potassium hexamethyldisilazide (1 M in THF, 6.8 mL) was added at room temperature to a solution of tert-butyl=((1s,3s)-3-hydroxy-3-methylcyclobutyl)carbamate (500 mg, 2.48 mmol) in dioxane (25 mL). After 15 minutes, a solution of 4,6-dichloropyrazolo[1,5-a]pyrazine (425 mg, 2.26 mmol) in dioxane (7.5 mL) was added dropwise to a dense white suspension. After 30 minutes, iodomethane (240 mg, 1.70 mmol, 105 μL) was added dropwise to the resulting orange suspension at room temperature, and stirring was continued for 30 minutes. The reaction mixture was diluted with ethyl acetate (40 mL) and washed with water (30 mL). The organic phase was separated, concentrated under reduced pressure, and purified by column chromatography (40g silica gel, 0-80% [3:1 siRNA:EtOH] + 2% NH4OH modifier / heptane) to obtain the title compound as a beige solid (555mg, 67% yield). LCMS m / z = 367.1 (M+H)+.

[0404] Synthesis of tert-butyl=4-(4-((1s,3s)-3-((tert-butoxycarbonyl)(methyl)amino)-1-methylcyclobutoxy)pyrazolo[1,5-a]pyrazine-6-yl)-1H-pyrazole-1-carboxylate [ka] To a solution of tert-butyl=((1s,3s)-3-((6-chloropyrazolo[1,5-a]pyrazine-4-yl)oxy)-3-methylcyclobutyl)(methyl)carbamate (500 mg, 1.36 mmol) and tert-butyl=4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole-1-carboxylate (802 mg, 2.73 mmol) in dioxane (15 mL), Pd-PEPPSI™-IPr catalyst (186 mg, 0.27 mmol), tripotassium phosphate (579 mg, 2.73 mmol), and water (3 mL) were sequentially added. The resulting mixture was degassed by purging with nitrogen for 30 minutes. After heating under reflux for 1 hour, the reaction mixture was cooled to room temperature, and SiO (20 mL) and water (20 mL) were added. After vigorous stirring for 30 minutes, the organic phase was separated, washed with brine (20 mL), dried over Na₂SO₄, and concentrated under reduced pressure. Purification of the crude residue by column chromatography (40 g silica gel, 0-60% [3:1 siRNA:EtOH] + 2% NH₄OH modifier / heptane) yielded the title compound as an orange, rubbery substance (640 mg, 94% yield). LC-MS m / z = 499.2 (M+H)+.

[0405] Synthesis of (1s,3s)-3-((6-(1H-pyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl)oxy)-N,3-dimethylcyclobutan-1-amine [ka]

[0406] To a solution of tert-butyl=4-(4-((1s,3s)-3-((tert-butoxycarbonyl)(methyl)amino)-1-methylcyclobutoxy)pyrazolo[1,5-a]pyrazine-6-yl)-1H-pyrazole-1-carboxylate (360 mg, 0.72 mmol) in HFIP (5 mL), TFA (374 mg, 3.3 mmol, 250 μL) was added at room temperature. The resulting reaction mixture was stirred for 2 hours. Ethyl acetate (20 mL) was added at room temperature, followed by saturated NaHCO3 aqueous solution (10 mL) and brine (10 mL). After vigorous stirring for 30 minutes, the organic phase was separated, dried over sodium sulfate, filtered, and concentrated. The resulting residue was purified by column chromatography (12 g silica gel, 80-100% [3:1 RINKAN:EtOH] + 2% NH4OH modifier / heptane) to obtain the title compound as a colorless, rubbery substance (162 mg, 75% yield). LCMS m / z = 299.0 (M+H)+.

[0407] Synthesis of N-((1s,3s)-3-((6-(1H-pyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl)oxy)-3-methylcyclobutyl)-N-methylacrylamide [ka] To a solution of (1s,3s)-3-((6-(1H-pyrazole-4-yl)pyrazolo[1,5-a]pyrazine-4-yl)oxy)-N,3-dimethylcyclobutan-1-amine (162 mg, 0.54 mmol) and DIPEA (211 mg, 1.63 mmol, 290 μL) in THF (5 mL), acryloyl chloride (54 mg, 0.60 mmol, 50 μL) was added at 0°C. After 30 minutes, the reaction mixture was diluted with ELISA (20 mL) and saturated aqueous NaHCO3 solution (20 mL) was added. The two-phase mixture was brought to room temperature and vigorous stirring was continued for another 30 minutes. The organic phase was separated, washed sequentially with water (10 mL) and brine (10 mL), dried over Na2SO4, filtered, and concentrated. The resulting residue was purified by column chromatography (12g silica gel, 0-100% [3:1 siRNA:EtOH] + 2% NH4OH modifier / heptane) to obtain the title compound as a colorless solid (65mg, 34% yield). LCMS m / z = 375.1 (M+Na)+. 1 H NMR (500 MHz, methanol-d4) δ ppm 8.39-8.48 (m, 1H), 8.07 (br s, 2H), 7.83-7.95 (m, 1H), 6.62-6.86 (m, 2H), 6.08-6.27 (m, 1H), 5.56-5.83 (m, 1H), 4.03-4.75 (m, 1H), 2.88-3.09 (m, 3H), 2.44-2.88 (m, 4H), 1.83 (m, 3H).

[0408] Example 81. 1-(3-(2-((6-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyridine-4-yl)oxy)ethyl)morpholino)propa-2-en-1-one [ka]

[0409] 1. Synthesis of tert-butyl=3-(2-((methylsulfonyl)oxy)ethyl)morpholine-4-carboxylate [ka] TEA (1.1 equivalents) was added to a solution of 6-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyridine-4-ol (1.0 equivalent) in anhydrous DCM (10 mL), followed by the addition of mesylchloride (1.05 equivalents). The reaction mixture was stirred for 14 hours. The mixture was washed with H2O (10 mL), dried over Na2SO4, filtered, and concentrated under vacuum to obtain the crude product, which was used directly in the next step.

[0410] 2. Synthesis of tert-butyl=3-(2-((6-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyridine-4-yl)oxy)ethyl)morpholine-4-carboxylate [ka] A mixture of 6-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyridine-4-ol (intermediate C, step 2, 1.0 equivalent), Cs2CO3 (1.1 equivalent), and tert-butyl=3-(2-((methylsulfonyl)oxy)ethyl)morpholine-4-carboxylate (1.0 equivalent) in anhydrous DMF (1 mL) was heated at 100°C for 16 hours under Ar (g). The reaction mixture was diluted with H2O (10 mL) and extracted with SiO (3 × 10 mL). The combined organic layer was washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated under vacuum to obtain the crude product, which was used directly in the next step.

[0411] 3. Synthesis of 3-(2-((6-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyridine-4-yl)oxy)ethyl)morpholine hydrochloride [ka] To a solution of tert-butyl=3-(2-((6-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyridine-4-yl)oxy)ethyl)morpholine-4-carboxylate (1 equivalent) in DCM (10 mL), 4 M HCl (10 equivalents) in dioxane was added, and the resulting solution was stirred at 25°C for 14 hours. The reaction mixture was concentrated under reduced pressure. The product was recovered by filtration, washed with IPA (3 × 10 mL), and then dried under vacuum at 40°C to obtain 3-(2-((6-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyridine-4-yl)oxy)ethyl)morpholine hydrochloride.

[0412] 4. Synthesis of 1-(3-(2-((6-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyridine-4-yl)oxy)ethyl)morpholino)propa-2-en-1-one [ka] To a solution of 3-(2-((6-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyridine-4-yl)oxy)ethyl)morpholine hydrochloride (1 equivalent) in DCM (10 mL), DIPEA (1.1 equivalents) was added, the mixture was cooled to -10°C, acryloyl chloride (1.05 equivalents) was added, and the reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was washed with water (10 mL), dried over Na2SO4, filtered, and concentrated under vacuum. The crude product was dissolved in DMSO (0.5 mL) and purified by preparative HPLC (Waters SunFire C18 19*100 5 mkm column) to obtain 10.2 mg of 1-(3-(2-((6-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyridine-4-yl)oxy)ethyl)morpholino)propa-2-en-1-one. LCMS m / z = 382.2 (M+H)+.1H NMR (400 MHz, CDCl3) δ ppm: 8.43 - 8.25 (m, 1H), 7.86 (s, 1H), 7.70 (s, 1H), 7.64 - 7.55 (m, 1H), 6.65 - 6.39 (m, 3H), 6.21 (dd, J=16.7, 1.8 Hz, 1H), 5.68 - 4.43 (m, 2H), 4.30 - 4.03 (m, 2H), 4.01 - 3.83 (m, 5H), 3.72 - 3.01 (m, 3H), 2.55 - 2.45 (m, 1H), 2.32 - 2.25 (m, 2H)

[0413] Example 82. N-(5-((6-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyridine-4-yl)oxy)bicyclo[2.2.1]heptan-2-yl)acrylamide [ka]

[0414] Following the steps described in Example 81, N-(5-((6-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyridine-4-ol (intermediate C, step 2) and tert-butyl=(5-hydroxybicyclo[2.2.1]heptan-2-yl)carbamate were used to obtain N-(5-((6-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyridine-4-yl)oxy)bicyclo[2.2.1]heptan-2-yl)acrylamide. LCMS m / z = 378.2 (M+H)+.1H NMR(400 MHz, CDCl3) δ ppm: 8.27 (s, 1H), 7.89 (d, J=2.4 Hz, 1H), 7.72 (s, 1H), 7.59 (s, 1H), 6.58 (d, J=2.5 Hz, 1H), 6.43 (s, 1H), 6.25 (d, J=16.8 Hz, 1H), 6.07 (dd, J=17.0, 10.2 Hz, 1H), 5.83 (d, J=7.3 Hz, 1H), 5.61 (d, J=10.3 Hz, 1H), 4.91 - 4.83 (m, 1H), 4.47 - 4.38 (m, 1H), 3.98 (s, 3H), 2.78 - 2.72 (m, 1H), 2.72 - 2.65 (m, 1H), 2.07 (t, J=13.3, 13.3 Hz, 2H), 1.73 - 1.59 (m, 4H)

[0415] Example 83. (R)-1-(2,2-dimethyl-6-(((6-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyridine-4-yl)oxy)methyl)morpholino)propa-2-en-1-one [ka]

[0416] (R)-1-(2,2-dimethyl-6-(((6-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyridine-4-yl)oxy)methyl)morpholino)propa-2-en-1-one was obtained from tert-butyl=(R)-6-(hydroxymethyl)-2,2-dimethylmorpholin-4-carboxylate and 6-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyridine-4-yl)oxy)methyl)morpholino)propa-2-en-1-one. LCMS m / z = 396.2 (M+H)+.1H NMR (400 MHz, MeOH-d4) δ ppm: 8.36 (s, 1H), 8.01 (s, 1H), 7.88 (s, 1H), 7.86 (d, J=2.4 Hz, 1H), 6.91 - 6.72 (m, 2H), 6.66 (s, 1H), 6.29 (dd, J=16.9, 8.1 Hz, 1H), 5.81 (dd, J=11.0, 5.6 Hz, 1H), 4.54 (dd, J=142.3, 13.0 Hz, 1H), 4.29 - 4.17 (m, 3.5H), 3.97 - 3.90 (m, 3.5H), 3.28 - 3.08 (m, 1H), 2.86 - 2.69 (m, 1H), 1.32 - 1.23 (m, 6H)

[0417] Examples 84 and 85. 1-((1R,5S,6s)-6-(((3-fluoro-6-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyridine-4-yl)oxy)methyl)-3-azabicyclo[3.1.1]heptan-3-yl)propa-2-en-1-one and 1-((1R,5S,6r)-6-(((3-fluoro-6-(1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyridine-4-yl)oxy)methyl)-3-azabicyclo[3.1.1]heptan-3-yl)propa-2-en-1-one [ka]

[0418] 1. Synthesis of tert-butyl=6-(((methylsulfonyl)oxy)methyl)-3-azabicyclo[3.1.1]heptane-3-carboxylate [ka] To a solution of tert-butyl=6-(hydroxymethyl)-3-azabicyclo[3.1.1]heptane-3-carboxylate (1 g, 4.40 mmol) and TEA (1.34 g, 13.2 mmol) in DCM (20 mL), methanesulfonyl chloride (0.72 g, 6.29 mmol) was added, and the reaction mixture was stirred at 0°C for 1 hour. Water (10 mL) was added, and the mixture was extracted with DCM (20 mL x 3). The combined organic matter was washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated under vacuum to obtain tert-butyl=6-(((methylsulfonyl)oxy)methyl)-3-azabicyclo[3.1.1]heptane-3-carboxylate (1.7 g, crude) as a yellow oil. 1H NMR: (500MHz, DMSO-d6) δ: 4.45 (d, J = 8.0 Hz, 1H), 4.16 (d, J = 7.5 Hz, 1H), 3.57-3.31 (m, 5H), 3.18 (d, J = 14.5 Hz, 3H), 2.50-2.35 (m, 2H), 2.31-2.22 (m, 1H), 2.04-1.95 (m, 1H), 1.41 (s, 9H).

[0419] 2. Synthesis of tert-butyl=6-(((6-bromo-3-fluoropyrazolo[1,5-a]pyridine-4-yl)oxy)methyl)-3-azabicyclo[3.1.1]heptane-3-carboxylate [ka] To a solution of 6-bromo-3-fluoropyrazolo[1,5-a]pyridine-4-ol (80 mg, 346 μmol) in DMF (4 mL), Cs2CO3 (200 mg, 614 μmol) and tert-butyl=6-(((methylsulfonyl)oxy)methyl)-3-azabicyclo[3.1.1]heptan-3-carboxylate (212 mg, 693 μmol) were added, and the reaction mixture was stirred at 100 °C for 1 hour. The reaction mixture was concentrated under vacuum, and the crude product was purified by preparative TLC (PE:HCl=3:1) to obtain tert-butyl...

Claims

1. Compound represented by formula (I'): 【Chemistry 1】 or a pharmaceutically acceptable salt thereof (in the formula, Het is phenyl, 5-6 member heteroaryl, or N-(C) １ -C ３ It is alkyl pyridonyl, 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, methyl, halomethyl, cyclopropyl, CN, or phenyl. R １ is H or C １ -C ３ Alkyl, C １ -C ３ - Alkoxy, C １ -C ３ It is a haloalkyl or a monocyclic oxygen-containing heterocyclic ring with 4 to 7 members. R ３ H or halo, X ３ The bond is CH ２ ,CH ２ CH ２ , O, O-CH ２ *, O-CH ２ CH ２ * NH, N(CH ３ ) - *, CH ２ N(CH ３ ) - * or NH-CH ２ * is R ２ It shows the connection point to, X ３ CH is bonded, ２ or CH ２ CH ２ If R ２ This is a bicyclic core or X via a cyclic nitrogen atom. ３ A 4- to 12-membered monocyclic or bicyclic nitrogen-containing heterocycle that is bonded to ("N-bonded") X ３ ga CH ２ ,CH ２ CH ２ , O, O-CH ２ * NH, N(CH ３ ) - *, CH ２ N(CH ３ ) - * or NH-CH ２ *If R ２ X is formed via the ring carbon atoms. ３ A 4- to 12-membered monocyclic or bicyclic nitrogen-containing heterocycle, a 4- to 7-membered monocyclic or bicyclic oxygen-containing heterocycle, a 3- to 12-membered monocyclic or bicyclic carbocyclyl, or a 5- to 6-membered heteroaryl, which is bonded to ("carbon-bonded") X ３ O-CH ２ -CH ２ *If R ２ X is absent, via the ring carbon atoms. ３ A 4- to 12-membered monocyclic or bicyclic nitrogen-containing heterocycle, or a carbon-bonded ("carbon-bonded") heterocycle, or a carbon-bonded ("carbon-bonded") heterocycle. １ -C ３ It is an alkyl group, however R ２ If X is absent, ３ is R ４ It is directly connected to, where the two-ring core is represented by the following: 【Chemistry 2】 R ２ The N-bonded 4-12 member monocyclic or bicyclic nitrogen-containing heterocycle, the 4-7 member monocyclic or bicyclic oxygen-containing heterocycle, the 3-12 member monocyclic or bicyclic carbon ring, the 5-6 member heteroaryl, and the C １ -C ３ Alkyl alkyl groups are R ４ Substituted with a group represented by, and optionally R １０ It is further substituted with 1 to 3 groups represented by, provided that the N-bonded 4 to 12-membered monocyclic or bicyclic nitrogen-containing heterocycle contains two cyclic nitrogen atoms, R ２ The 4-12 member monocyclic or bicyclic nitrogen-containing heterocycles represented by the above N-bonded structure are optionally R ５ N is substituted with a group represented by, and optionally R １０ Further substituted with one or two groups represented by, The aforementioned 4- to 12-membered monocyclic or bicyclic nitrogen-containing heterocycles with carbon bonds are R ５ N is substituted with a group represented by, and optionally R １０ It is further substituted with 1 to 3 groups represented by, R ４ teeth, 【Transformation 3】 And, R ５ teeth, 【Chemistry 4】 And, Each R ６ is independently H, CN, C １ -C ３ -alkyl, C １ -C ３ -haloalkyl, N(R ａ ) ２ or CH ２ N(R ａ ) ２ where each R ａ is independently H, C １ -C ３ -alkyl or C ３ -C ６ -cycloalkyl, Each R ６ ' is independently H, C １ -C ３ Alkyl, C １ -C ３ Haloalkyl or C ３ -C ６ It is a cycloalkyl, Each R ７ H and C are independent of each other. １ -C ２ Alkyl, C １ -C ２ Fluoroalkyl or C ３ -C ６ It is a cycloalkyl, R ８ is H or C １ -C ３ It is alkyl, Each R １０ Hello, C １ -C ３ Alkyl or C ３ -C ６ It is a cycloalkyl, R １１ is H or N (R １２ ) ２ And, Each R １２ H or C １ -C ３ It is alkyl, R １３ is CN or F, R １４ It is a halo, Each n is independently either 0 or 1. Each p is independently either 1 or 2. q is either 1 or 2).

2. The aforementioned compound is of formula (I): 【Transformation 5】 The compound according to claim 1, represented by the formula, or a pharmaceutically acceptable salt thereof (wherein, R ０ is H, halo, methyl, halomethyl, cyclopropyl or CN, X ３ The bond is CH ２ ,CH ２ CH ２ , O, O-CH ２ * NH or NH-CH ２ * is R ２ It shows the connection point to, X ３ CH is bonded, ２ or CH ２ CH ２ If R ２ The two-ring core or X is connected via the ring nitrogen atom. ３ A 4- to 12-membered monocyclic or bicyclic nitrogen-containing heterocycle that is bonded to ("N-bonded") X ３ ga CH ２ ,CH ２ CH ２ , O, O-CH ２ * NH or NH-CH ２ *If R ２ X is formed via the ring carbon atoms. ３ A 4-12 member monocyclic or bicyclic nitrogen-containing heterocycle, a 4-7 member monocyclic oxygen-containing heterocycle, or a 3-12 member monocyclic or bicyclic carbocyclyl that is bonded to ("carbon-bonded") R ２ The nitrogen-containing 4- to 12-membered monocyclic or bicyclic heterocycles, the 4- to 7-membered oxygen-containing heterocycles, and the 3- to 12-membered monocyclic or bicyclic carbon rings represented by R ４ Substituted with a group represented by, and optionally R １０ Further substituted with one or two groups represented by, The aforementioned 4- to 12-membered monocyclic or bicyclic nitrogen-containing heterocycles with carbon bonds are R ５ N is substituted with a group represented by, and optionally R １０ Further substituted with one or two groups represented by, R ４ teeth, 【Transformation 6】 And, R ５ teeth, 【Transformation 7】 And, Each R ６ H and C are independent of each other. １ -C ３ Alkyl, C １ -C ３ Haloalkyl, N(R) ａ ) ２ or CH ２ N(R) ａ ) ２ And here, each R ａ These are independently H or methyl, Each R ６ ' is independently H, C １ -C ３ Alkyl or C １ -C ３ It is a haloalkyl, Each R ７ H and C are independent of each other. １ -C ２ Alkyl or C １ -C ２ It is a fluoroalkyl, Each R １０ (This is either F or methyl).

3. The aforementioned R １１ is H or NH ２ (R １ ) ｑ -Het- 【Transformation 8】 A compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, selected from the above.

4. The aforementioned compound is one of the following: 【Chemistry 9-1】 【Chemistry 9-2】 A compound according to any one of claims 1 to 3, represented by [the specified method], or a pharmaceutically acceptable salt thereof.

5. (i) X ３ However, it is a bond, R ２ However, R is a 4- to 12-membered monocyclic or bicyclic nitrogen-containing heterocycle bonded to the bicyclic core via a ring nitrogen atom, ２ The 4- to 12-member monocyclic or bicyclic nitrogen-containing heterocycle represented by R ４ Substituted with a group represented by, and optionally R １０ It is further substituted with one or two bases represented by; and optionally, R ２ However, R is a 7-10 member bicyclic nitrogen-containing heterocycle bonded to the bicyclic core via a ring nitrogen atom, ２ The 7-10 membered bicyclic nitrogen-containing heterocycle represented by R ４ Substituted with a group represented by, and optionally R １０ It is further replaced by one or two bases represented by; or (ii) R ２ However, it is a 4- to 7-membered monocyclic nitrogen-containing heterocycle bonded to the bicyclic core via a ring nitrogen atom, R ２ The 4- to 7-membered monocyclic nitrogen-containing heterocycle represented by R ４ Substituted with a group represented by, and optionally R １０ A compound according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof, further substituted with a group represented by .

6. The compound described above is represented by a structural formula selected from the following, according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof: 【Chemistry 10】 。

7. R ６ However, H, CH ３ or CH ２ Cl is , p is 2, R ４ However, CH ２ NHC(O)C≡CH,CH ２ NHC(O)CH=CH ２ , N (CH ３ )C(O)C≡CH, NHC(O)CH=CH ２ , NHC(O)C≡CH or NHC(O)CH=CHCH ２ A compound according to any one of claims 1 to 6, wherein the compound is Cl, or a pharmaceutically acceptable salt thereof.

8. X ３ However, O, O-CH ２ *, O-CH ２ CH ２ *, NH, NH-CH ２ *, N(CH ３ ), or CH ２ N(CH ３ ) - * and R ２ However, X via the ring carbon atoms ３ A 4- to 12-membered monocyclic or bicyclic nitrogen-containing heterocycle bonded to ("C bonded"), wherein the 4- to 12-membered nitrogen-containing heterocycle bonded to ("C bonded") is R ５ N is substituted with a group represented by, and optionally R １０ A compound according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof, further substituted with one to three groups represented by .

9. R ２ The 4-12 member nitrogen-containing heterocycle with carbon bonds represented by is a 4-7 member monocycle, a 6-10 member fused dicycle, an 8-12 member spirocycle, or a 7-10 member bridging dicycle, which optionally contains one ring oxygen or one ring sulfur atom. ２ The 4-12 member nitrogen-containing heterocycle with carbon bonds, represented by R ５ N is substituted with a group represented by, and optionally R １０ It is further substituted with one or two bases represented by; optionally, (i) R ２ The 4-12 member nitrogen-containing heterocycles with carbon bonds represented by are azaspiro[3.3]heptanylene, azaspiro[3.5]nonanylene, azaspiro[4.4]nonanylene, azaspiro[3.4]octanylene, azetidinylene, pyrrolinedinylene, piperidinylene, azapanylene, diazepanylene, morpholinylene, octahydrocyclopenta[c]pyrrolylene, oxazapanylene, azabicyclo[3.2.0]heptanylene, azabicyclo[2.2.1]heptanylene The compounds are rhene, azabicyclo[3.1.1]heptanylene, azabicyclo[3.2.1]octanylene, azabicyclo[4.2.0]octanylene, azatricyclo[4.1.1.03,7]octylene, azabicyclo[3.2.0]heptanylene, azabicyclo[2.1.1]heptanylene, azabicyclo[2.1.1]hexanylene, azabicyclo[3.1.0]hexanylene, 2λ2-azaspiro[3.4]octylene or octahydrocyclopenta[c]pyrolene, R ２ The 4-12 member nitrogen-containing heterocycle with carbon bonds, represented by R ５ N is substituted with a group represented by, and optionally R １０ Further substituted with one or two groups represented by, or (ii)R ２ The 4- to 12-membered monocyclic or bicyclic nitrogen-containing heterocycle represented by the C bond is selected from the following: 【Chemistry 11-1】 【Chemistry 11-2】 (In the formula, "**" represents X) ３ The connection point to is indicated by "***", and R ５ The connection point to R is shown, where R ２ Each group represented by can be optionally selected as R １０ A compound according to any one of claims 1 to 4 and 8, or a pharmaceutically acceptable salt thereof, further substituted with one to three groups represented by .

10. X ３ R is bonded to it. ２ The compound according to any one of claims 1 to 4 and 8 to 9 or a pharmaceutically acceptable salt thereof, wherein the stereochemical configuration of the ring carbon atoms in the 4 to 12-membered nitrogen-containing heterocycle that is C-bonded, represented by, is R or S.

11. R ６ and R ６ ', independently, H, CH ３ or CH ２ Cl is , p is 2, R ５ However, SO ２ CH=CH ２ SO ２ CH = CHCH ３ SO ２ CH = CHCH ２ Cl, SO ２ C≡CH, SO ２ C≡CCH ３ SO ２ C≡CCH ２ Cl, COCH=CH ２ , COCH=CHCH ３ , COCH=CHCH ２ Cl, CO-C≡CH, CO-C≡CCH ３ CO-C≡CCH ２ Cl, COCF=CH ２ , COCF=CHCH ３ , COCF=CHCH ２ Cl, 【Chemistry 12】 A compound according to any one of claims 1 to 4 and 8 to 10 or a pharmaceutically acceptable salt thereof.

12. X ３ However, O, O-CH ２ * NH or NH-CH ２ * and R ２ However, it is a 3-12 member monocyclic or bicyclic carbocyrill, a 4-7 member monocyclic or bicyclic oxygen-containing heterocyclic or a 5-6 member heteroaryl, R ２ The 3-12 member monocyclic or bicyclic carbon rings, the 4-7 member monocyclic or bicyclic oxygen-containing heterocyclic rings, and the 5-6 member heteroaryls represented by R ４ Substituted with a group represented by, and optionally R １０ It is further substituted with 1 to 3 groups represented by, and optionally the 4 to 7-membered monocyclic or bicyclic oxygen-containing heterocycle is oxabicyclo[3.1.1]heptanylene or tetrahydro-2H-pyranylene, each of which is R ４ Substituted with a group represented by, and optionally R １０ The 5-6 member heteroaryl is further substituted with one or two groups represented by R ４ Substituted with a group represented by, and optionally R １０ A pyridinylene further substituted with 1 to 3 groups represented by R ２ However, the following can be selected: 【Chemistry 13】 (Each is R ４ Substituted with a group represented by, and optionally R １０ A compound according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof, further substituted with one or two groups represented by .

13. X ３ However, O, O-CH ２ * NH or NH-CH ２ * and R ２ However, it is a monocyclic or bicyclic carbocyclyl with 3 to 12 members, R ２ The 3-12 member monocyclic or bicyclic carbon rings represented by are R ４ Substituted with a group represented by, and optionally R １０ It is further substituted with one or two bases represented by, and optionally R ２ However, phenylene, C ３ -C ７ Cycloalkylene or C ６ -C ９ It is a bicyclic saturated carbon ring, R ２ The phenylene, C represented by ３ -C ７ Cycloalkylene and C ６ -C ９ A bicyclic saturated carbon ring is R ４ Substituted with a group represented by, and optionally R １０ A compound according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof, further substituted with one or two groups represented by .

14. X ３ O is R ２ However, these are phenylene, cyclobutylene, cyclohexylene, cyclopentylene, cyclopropylene, bicyclo[3.3.1]heptylene, bicyclo[2.2.1]heptanylene, bicyclo[4.1.0]heptanylene, or bicyclo[2.1.1]hexanylene, each of which is R ４ Substituted with a group represented by, and optionally R １０ It is further substituted with one or two bases represented by, and optionally R ２ but, 【Chemistry 14】 And in the formula, "**" is X ３ The connection point to is indicated by "***", and R ４ It shows the connection point to R ２ The base represented by R can be chosen at will. １０ A compound according to any one of claims 1 to 4 and 13, or a pharmaceutically acceptable salt thereof, substituted with one or two groups represented by .

15. R ６ However, H, CN, CH ３ ,CH ２ Cl, CF ３ or CH ２ N(R) ａ ) ２ And R ａ However, -CH ３ and cyclopropyl are independently selected, R ６ 'but, H, CN, CH ３ ,CH ２ Cl, CF ３ or cyclopropyl, R ４ is NHC(O)CH=CH ２ , N (CH ３ )C(O)CH=CH ２ ,NHC(O)CH=CHCH ３ , N (CH ３ )C(O)CH=CHCH ３ , N (CH ３ )C(O)CH=CHCN, NHC(O)C≡CH, N(CH ３ )C(O)C≡CH, N(H)C(O)C≡CCH ３ , N (CH ３ )C(O)C≡CCH ３ , N (CH ２ CH ２ F)C(O)CH=CH ２ , N (CH ２ CH ２ F)C(O)CH=CHCH ３ , N (CH ２ CH ２ F)C(O)C≡CH, N(CH ２ CH ２ F)C(O)C≡CCH ３ ,CH ２ N(CH ３ )C(O)CH=CH ２ , N (CH ２ CHF ２ )C(O)CH=CH ２ , N (CH ３ )C(O)CH=CHCH ２ Cl, NHC(O)CH=CHCF ３ , N (CH ３ )C(O)CH=CHCF ３ NHC(O)C≡C-cyclopropyl, NHC(O)CH=CHCH ２ N(CH ３ )-Cyclobutyl, N(CH ２ CHF ２ )C(O)CH=CHCH ２ N(CH ３ ) ２ N(cyclopropyl)C(O)CH=CH ２ , N (CH ３ ) C(O)CH ２ Cl, N(CH) ３ )CH ２ CN, 【Chemistry 15】 (O)CH=CH ２ , or CH(CH ３ )NHC(O)CH=CH ２ A compound according to any one of claims 1 to 4 and 13 to 14 or a pharmaceutically acceptable salt thereof.

16. X ３ R is bonded to it. ２ The compound according to any one of claims 1 to 4 and 13 to 15 or a pharmaceutically acceptable salt thereof, wherein the stereochemical configuration of the ring carbon atoms in the C-bonded 3 to 12-membered carbocyclic ring represented by is R or S.

17. X ３ and R ４ A compound or pharmaceutically acceptable salt thereof according to any one of claims 13 to 15, wherein the orientation is trans or cis.

18. X ３ However, O-CH ２ CH ２ * and R ２ However, R ４ Substituted with a group represented by, and optionally R １０ C further substituted with one or two groups represented by １ -C ３ It is an alkyl group, or R ２ However, X is absent. ３ However, R ４ It is directly connected, and R can be selected as desired. ２ However, **-CH ２ -***, **-CH ２ CH (CH ３ ) - Selected from ***, where "***" is X ３ It represents the connection point to R, and "***" is R ４ Represents the connection point to R ４ N(CH) ３ )C(O)CH=CH ２ The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 4, which is optionally one or more of the following: (i) R １ However, H or C １ -C ３ Alkyl, C １ -C ３ Fluoroalkyl or 4-7 membered monocyclic oxygen-containing heterocycle, (ii) R ０ But, H, F, CN, CH ３ CF ３ , cyclopropyl or phenyl (iii) R ７ However, H, CH ３ ,CH ２ CH ３ ,CH ２ CHF ２ and selected from cyclopropyl, (iv)R ８ However, H or CH ３ That is, (v) R １０ However, F, Cl, CH ３ or cyclopropyl, (vi)R １４ Cl is Cl.

19. The aforementioned compound is of formula (XV): 【Chemistry 16】 The compound according to claim 1, represented by the formula, or a pharmaceutically acceptable salt thereof (wherein, R ０ is H, halo, or cyclopropyl, X ３ is O or O-CH ２ * and R ２ R is a 4-7 member monocyclic or bicyclic saturated carbocyclyl, ２ The 4-7 member monocyclic or bicyclic saturated carbocyclyl represented by R ４ Substituted with a group represented by, and optionally one or two R １０ It is further replaced by, or R ２ X is formed via the ring carbon atoms. ３ A 7-9 member bicyclic nitrogen-containing heterocycle bonded to ("C bonded"), and the C bonded 7-9 member bicyclic nitrogen-containing heterocycle is R ５ Substituted with a group represented by, and optionally one or two R １０ It is further replaced by, R ４ N(R) ７ )C(O)C≡CCH ３ , N(R ７ )C(O)CH=CH ２ And, R ５ C(O)CH=CH ２ And, R ７ H, C １ -C ２ Alkyl, or C １ -C ２ It is a fluoroalkyl, R １０ C １ -C ３ (It is alkyl.)

20. X ３ O is R ２ However, these are cyclobutylene, cyclohexylene, cyclopentylene, or bicyclo[2.1.1]hexanylene, each of which is R ４ Substituted with a group represented by, and optionally one or two R １０ Further substitution occurs with R ７ However, H, CH ３ or CH ２ CHF ２ The compound according to claim 19 or a pharmaceutically acceptable salt thereof.

21. A pharmaceutical composition comprising a compound according to any one of claims 1 to 20 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

22. A pharmaceutical composition for treating a disorder responsive to Bruton's tyrosine kinase inhibition in a subject, comprising an effective amount of the compound described in any one of claims 1 to 20.

23. The pharmaceutical composition according to claim 22, wherein the disorder is an autoimmune disorder, atopic dermatitis, leukemia, or lymphoma.

24. The pharmaceutical composition according to claim 23, wherein the autoimmune disorder is rheumatoid arthritis or systemic lupus erythematosus.

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