BTK inhibitors

Abstract

Compounds of formula (I): [Formula 1] JPEG2024544529000458.jpg86165, or a pharma- ceutically acceptable salt thereof, wherein the variables of formula (I) are as defined herein, and methods of their use and production are provided.

Description

[Technical Field]

[0001] Related Applications This application claims the benefit under 35 U.S.C. §119(e) of the filing date of U.S. Provisional Application No. 63 / 277,879 (filed November 10, 2021), the entire contents of which are incorporated herein by reference.

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

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

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

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

[0006] One aspect of the present disclosure is a compound of formula (I) [ka] or a pharmaceutically acceptable salt thereof, wherein: X 0 is N and X 1 is C and X 2 is N and X 4 is N and X 5 is CH;X 0 is CR 0 and X 1 is C and X 2 is N and X 4 is N and X 5 is CH;X 0 is CR 0 and X 1 is N and X 2 is C and X 4 is N and X 5 is CH;X 0 is CR 0 and X 1 is N and X 2 is C and X 4 is CH and X 5 is CH;X 0 is CR 0 and X 1 is C and X 2 is N and X 4 is CH and X 5 is CH; or X 0 is CH and X 1 is N and X 2 is C and X 4 is CH and X 5 is N, X 3 H, -OR 5 , -N(R 5 ) 2, 5- to 6-membered heteroaryl, or 4- to 7-membered monocyclic heterocyclyl, and the 5- to 6-membered heteroaryl and the 4- to 7-membered monocyclic heterocyclyl may have one or more (e.g., 1 to 6, 1 to 3, or 1, 2, 3, 4, 5, or 6) R 50 is optionally replaced by R 0 is H, halo, methyl, halomethyl, cyclopropyl, or CN; Ring A is phenyl, 5- or 6-membered heteroaryl, or 5- to 10-membered monocyclic or bicyclic heterocyclyl; R 1 is -N(R 1a )2, -OR 1a , phenyl, 3- to 7-membered monocyclic carbocyclyl, 3- to 7-membered monocyclic heterocyclyl, 5- to 6-membered heteroaryl, 7- to 10-membered bicyclic carbocyclyl, 7- to 10-membered bicyclic heterocyclyl, and 8- to 10-membered bicyclic heteroaryl; R 1 The phenyl, the 3- to 7-membered monocyclic carbocyclyl, the 3- to 7-membered monocyclic heterocyclyl, the 5- to 6-membered heteroaryl, the 7- to 10-membered bicyclic carbocyclyl, and the 7- to 10-membered bicyclic heterocyclyl each optionally have one or more (e.g., 1 to 6, 1 to 3, or 1, 2, 3, 4, 5, or 6) R 10 is replaced by R 1a For each occurrence, independently, H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 alkynyl, phenyl, a 3- to 7-membered carbocyclyl ring, a 3- to 7-membered monocyclic heterocyclyl, and a 5- to 6-membered heteroaryl; R 1a The C represented by 1-6 Alkyl, the C 2-6 Alkenyl, the C 2-6 The alkynyl, the phenyl, the 3- to 7-membered carbocyclyl ring, the 3- to 7-membered monocyclic heterocyclyl, and the 5- to 6-membered heteroaryl each optionally contain one or more (e.g., 1 to 6, 1 to 3, or 1, 2, 3, 4, 5, or 6) R 10 is replaced by R 10 is, for each occurrence, independently, a halogen, -OR 10a , -S(O)2R 10a , -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 alkynyl, 3- to 7-membered monocyclic carbocyclyl, and 4- to 6-membered monocyclic heterocyclyl; R 10The C represented by 1-6 Alkyl, the C 2-6 Alkenyl, the C 2-6 The alkynyl, the 3- to 7-membered monocyclic carbocyclyl, and the 4- to 6-membered monocyclic heterocyclyl each optionally have one or more (e.g., 1 to 6, 1 to 3, or 1, 2, 3, 4, 5, or 6) R 15 is replaced by R 10a is optionally substituted with one or more (e.g., 1 to 6, 1 to 3, or 1, 2, 3, 4, 5, or 6) halogens; 1-6 is alkyl, R 15 are, for each occurrence independently, halogens, C 1-6 Alkyl, C 1-6 Haloalkyl, -CN, and -OR 15a is selected from R 15a is C 1-6 is alkyl, R 2 is H, C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 is alkynyl, Or R 1 and R 2 together with their intervening atoms form a ring D selected from a 3- to 7-membered monocyclic heterocyclyl, a 7- to 10-membered bicyclic heterocyclyl, and an 8- to 10-membered bicyclic heteroaryl, and ring D is selected from one or more (e.g., 1 to 6, 1 to 3, or 1, 2, 3, 4, 5, or 6) R 100 is optionally replaced by R 100 is independently generated for each occurrence of C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 R is selected from alkynyl, 3- to 7-membered monocyclic carbocyclyl, 4- to 6-membered monocyclic heterocyclyl, and halogen; 100 The C represented by 1-6 Alkyl, the C 2-6 Alkenyl, the C 2-6The alkynyl, the 3- to 7-membered monocyclic carbocyclyl, and the 4- to 6-membered monocyclic heterocyclyl each optionally have one or more (e.g., 1 to 6, 1 to 3, or 1, 2, 3, 4, 5, or 6) R 150 is replaced by R 150 is, for each occurrence, independently, a halogen, -OR 150a , a 3- to 7-membered carbocyclyl ring, and a 4- to 7-membered monocyclic heterocyclyl; R 150a is H or C 1-6 is alkyl, R 3 is H, halogen, -C(O)N(R 3a )2, -C(O)OR 3a , -C(O)R 3a , C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 alkynyl, and R 3 The C represented by 1-6 Alkyl, the C 2-6 Alkenyl, and the C 2-6 each alkynyl is optionally substituted with one or more (e.g., 1 to 6, 1 to 3, or 1, 2, 3, 4, 5, or 6) substituents selected from halogen and hydroxyl; R 3a For each occurrence, independently, H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 alkynyl, phenyl, a 3- to 7-membered carbocyclyl ring, a 3- to 7-membered monocyclic heterocyclyl, or a 5- or 6-membered heteroaryl; 1-6 Alkyl, the C 2-6 Alkenyl, the C 2-6 The alkynyl, the phenyl, the 3- to 7-membered carbocyclyl ring, the 3- to 7-membered monocyclic heterocyclyl, and the 5- to 6-membered heteroaryl may have one or more (e.g., 1 to 6, 1 to 3, or 1, 2, 3, 4, 5, or 6) R 30 is optionally replaced by Or two R on the same nitrogen3a Groups, taken together with their intervening atoms, form a ring selected from 3- to 7-membered monocyclic heterocyclyl and 5- to 6-membered heteroaryl, and the ring contains one or more (e.g., 1 to 6, 1 to 3, or 1, 2, 3, 4, 5, or 6) R 30 is optionally replaced by R 30 is, for each occurrence, independently, a halogen, -OR 30a , -N(R 30a )2, -C(O)N(R 30a ), -C(O)R 30a , Oxo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 selected from alkynyl, 3- to 7-membered monocyclic carbocyclyl, and 4- to 6-membered monocyclic heterocyclyl; R 30a is H or C 1-6 is alkyl, R 4 are each occurrence independently: H, halogen, -NO2, -CN, -OR 4a , -SR 4a , -N(R 4a )2, -C(O)R 4a , -C(O)OR 4a , -S(O)R 4a , -S(O)2R 4a , -C(O)N(R 4a )2, -SO2N(R 4a )2, -OC(O)R 4a , -N(R 4a )C(O)R 4a , -N(R 4a )C(O)OR 4a , -N(R 4a )SO2R 4a , -OC(O)N(R 4a )2, C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 alkynyl, 1-6 Alkyl, the C 2-6 Alkenyl, and the C 2-6Each alkynyl optionally contains one or more (e.g., 1 to 6, 1 to 3, or 1, 2, 3, 4, 5, or 6) R 40 is replaced by R 4a is H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 alkynyl, phenyl, 3- to 8-membered carbocyclyl ring, 3- to 7-membered monocyclic heterocyclyl, and 5- to 6-membered heteroaryl; R 4a The C represented by 1-6 Alkyl, the C 2-6 Alkenyl, the C 2-6 The alkynyl, the phenyl, the 3- to 8-membered carbocyclyl ring, the 3- to 7-membered monocyclic heterocyclyl, and the 5- to 6-membered heteroaryl each optionally contain one or more (e.g., 1 to 6, 1 to 3, or 1, 2, 3, 4, 5, or 6) R 40 is replaced by Or two R on the same nitrogen 4a Groups, taken together with their intervening atoms, form a ring selected from 3- to 7-membered monocyclic heterocyclyl and 5- to 6-membered heteroaryl, and the ring contains one or more (e.g., 1 to 6, 1 to 3, or 1, 2, 3, 4, 5, or 6) R 40 is optionally replaced by R 40 is, for each occurrence, independently, a halogen, -OR 40a , -N(R 40a )2, -C(O)N(R 40a )2, -C(O)2R 40a , Oxo, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 alkynyl, 3- to 7-membered monocyclic carbocyclyl, and 4- to 6-membered monocyclic heterocyclyl; R 40 The C represented by 1-6 Alkyl, the C 2-6 Alkenyl, the C 2-6The alkynyl, the 3- to 7-membered monocyclic carbocyclyl, and the 4- to 6-membered monocyclic heterocyclyl each optionally have one or more (e.g., 1 to 6, 1 to 3, or 1, 2, 3, 4, 5, or 6) R 45 is replaced by R 40a is H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 alkynyl, 3- to 7-membered monocyclic carbocyclyl, and 4- to 6-membered monocyclic heterocyclyl, 1-6 Alkyl, the C 2-6 Alkenyl, the C 2-6 The alkynyl, the 3- to 7-membered monocyclic carbocyclyl, and the 4- to 6-membered monocyclic heterocyclyl each optionally have one or more (e.g., 1 to 6, 1 to 3, or 1, 2, 3, 4, 5, or 6) R 45 is replaced by R 45 is independently generated for each occurrence of C 1-6 Alkyl, halogen, and -OR 45a is selected from R 45a is H or C 1-6 is alkyl, Or R 3 and R 4 together with the atoms between them form a ring E, and ring E is selected from 4- to 7-membered monocyclic carbocyclyl and 4- to 7-membered monocyclic heterocyclyl, and ring E is selected from R 300 is optionally replaced by R 300 is independently generated for each occurrence of C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 3- to 7-membered monocyclic carbocyclyl, 4- to 6-membered monocyclic heterocyclyl, halogen, -C(O)R 300a , -OR 300a , and -S(O)R 300a Selected from R 300 The C represented by 1-6 Alkyl, the C 2-6 Alkenyl, the C 2-6The alkynyl, the 3- to 7-membered monocyclic carbocyclyl, and the 4- to 6-membered monocyclic heterocyclyl each optionally have one or more (e.g., 1 to 6, 1 to 3, or 1, 2, 3, 4, 5, or 6) R 350 is replaced by R 300a is H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 alkynyl, 3- to 7-membered monocyclic carbocyclyl, and 4- to 6-membered monocyclic heterocyclyl; R 300a The C represented by 1-6 Alkyl, the C 2-6 Alkenyl, the C 2-6 The alkynyl, the 3- to 7-membered monocyclic carbocyclyl, and the 4- to 6-membered monocyclic heterocyclyl each optionally have one or more (e.g., 1 to 6, 1 to 3, or 1, 2, 3, 4, 5, or 6) R 350 is replaced by R 350 is independently generated for each occurrence of C 1-6 Alkyl, halogen, -CN, -C(O)R 350a , -C(O)N(R 350a )2, -N(R 350a )2, and -OR 350a is selected from R 350a is, at each occurrence, independently, H or C optionally substituted with 1 to 3 halogens 1-6 is alkyl, R 5 Ha, Halo, C 1-6 Alkoxy, and C 1-6 C optionally substituted with one or more (e.g., 1 to 6, 1 to 3, or 1, 2, 3, 4, 5, or 6) substituents independently selected from haloalkoxy 1-6 is alkyl, R 50 is, for each occurrence, independently, a halogen, -OR 50a , -N(R 50a )2, -C(O)N(R 50a ), -C(O)R 50a, Oxo, C 1-6 R is selected from alkyl, 3- to 7-membered monocyclic carbocyclyl, and 4- to 6-membered monocyclic heterocyclyl; 50 The C represented by 1-6 The alkyl, the 3- to 7-membered monocyclic carbocyclyl, and the 4- to 6-membered monocyclic heterocyclyl are each optionally selected from the group consisting of C 1-6 Alkyl, CN, halo, and C 1-6 substituted with one or more substituents independently selected from alkoxy; R 50a is H or C 1-6 is alkyl, n is 0, 1, 2, 3, or 4.

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

[0008] In a third aspect, the present disclosure provides a method for treating a disorder responsive to Btk inhibition in a subject. The method includes administering to the subject an effective amount of at least one compound described herein, or a pharmaceutically acceptable salt thereof. The present disclosure also includes the use of at least one compound described herein, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating a disorder responsive to Btk inhibition. Also provided is a compound described herein, or a pharmaceutically acceptable salt thereof, for use in treating a disorder responsive to Btk inhibition.

[0009] Other features or advantages will be apparent from the following detailed description of several embodiments, and from the appended claims. DETAILED DESCRIPTION OF THE INVENTION

[0010] The compounds described herein, or pharmaceutically acceptable salts thereof, can have activity as Btk modulators. In particular, the compounds described herein, or pharmaceutically acceptable salts thereof, can be Btk inhibitors.

[0011] I. Definition The terms "a" and "an" do not denote a limitation of quantity, but rather denote the presence of at least one of the referenced item. The recitation of ranges of values, unless stated otherwise herein, is merely intended to serve as a shorthand method of referring individually to each separate value falling within that range, and each separate value is incorporated herein as if it were individually recited herein. The endpoints of all ranges are included within the range and independently combinable. All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of examples or exemplary language (e.g., "such as") is intended merely to better describe the invention and does not limit the scope of the invention unless otherwise claimed.

[0012] The suffix "yl" at the end of a chemical name indicates that the specified moiety is attached to the molecule at one point. The suffix "ene" at the end of a chemical name indicates that the specified moiety is attached to the molecule at two points. Examples include azetidinylene, pyrrolidinylene, piperidinylene, azapanylene, or oxazapanylene, which indicates that the azetidine, pyrrolidine, piperidine, azapane, or oxazapane is attached to the rest of the compound at two points.

[0013] As used herein, the term "alkyl" refers to a fully saturated branched or unbranched hydrocarbon moiety. In some embodiments, alkyl contains 1 to 20 carbon atoms, 1 to 10 carbon atoms, 1 to 8 carbon atoms, 1 to 6 carbon atoms, or 1 to 4 carbon atoms. In some embodiments, alkyl contains 6 to 20 carbon atoms. Representative examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, or n-hexyl.

[0014] "Alkenyl" refers to an unsaturated hydrocarbon group having at least one carbon-carbon double bond, which may be straight-chained or branched. In some embodiments, alkenyl groups have 2 to 20 carbon atoms, 2 to 10 carbon atoms, or 2 to 6 carbon atoms. Alkenyl groups can contain one, two, or three carbon-carbon double bonds, or more. Examples of alkenyl groups include ethenyl, n-propenyl, isopropenyl, n-but-2-enyl, n-hex-3-enyl, and the like.

[0015] "Alkynyl" refers to an unsaturated hydrocarbon group having at least one carbon-carbon triple bond, which may be straight-chained or branched. In some embodiments, an alkynyl group has 2 to 20 carbon atoms, with 2 to 10 carbon atoms or 2 to 6 carbon atoms being preferred. An alkynyl group may contain one, two, or three carbon-carbon triple bonds, or more. Examples of alkynyl groups include ethynyl, n-propynyl, n-but-2-ynyl, n-hex-3-ynyl, and the like.

[0016] As used herein, the term "alkoxy" refers to a fully saturated branched or unbranched alkyl moiety attached through an oxygen bridge (i.e., --O--C 1-4 Alkyl groups (where C 1-4 Alkyl is as defined herein. Representative examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy, tert-butoxy, and the like. In some embodiments, alkoxy groups have about 1-4 carbons, more preferably about 1-2 carbons.

[0017] As used herein, the term "aryl" is defined to include all-carbon monocyclic or fused-ring polycyclic (i.e., rings that share adjacent pairs of carbon atoms) groups having a fully connected pi-electron system. Aryl groups can have 6, 8, 9, or 10 carbon atoms in the ring(s). In some embodiments, aryl groups can have 6 or 10 carbon atoms in the ring(s). For example, as used herein, the term "(C6-C 10 ")Aryl" is an aromatic radical containing 6 to 10 carbon atoms, such as phenyl, naphthyl, tetrahydronaphthyl, anthracenyl, indanyl, etc. Aryl groups having 6 carbon atoms in the ring(s) may be optionally substituted with 1 to 5 suitable substituents.

[0018] In some embodiments, the number of carbon atoms in a group is indicated herein by the prefix "C x-xx " or "C x -C xx (x and xx are integers). For example, "C 1-4 "Alkyl" is an alkyl group having 1 to 4 carbon atoms.

[0019] As used herein, the terms "carbocyclyl," "carbocycle," or "carbocyclic ring" refer to saturated or partially unsaturated monocyclic or bicyclic (e.g., fused, bridged, or spiro ring systems) ring systems having 4 to 12 ring members, all of which are carbon. The term "carbocyclyl" encompasses cycloalkyl and cycloalkenyl groups.

[0020] In one embodiment, the carbocyclyl is a 3- to 7-membered monocyclic carbocyclyl. Exemplary 3- to 7-membered monocyclic carbocyclyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopropenyl, cyclobutenyl, cyclopenentyl, cyclohexenyl, cycloheptenyl, cyclobutadienyl, cyclopentadienyl, cyclohexadienyl, cycloheptadienyl, phenyl, and cycloheptatrienyl.

[0021] In one embodiment, the carbocyclyl is a 7-10 membered bicyclic carbocyclyl. Exemplary 7-10 membered bicyclic carbocyclyls include bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.1]heptenyl, 6,6-dimethylbicyclo[3.1.1]heptyl, 2,6,6-trimethylbicyclo[3.1.1]heptyl, spiro[3.3]heptanyl, spiro[2.5]octanyl, spiro[2.2]pentanyl, spiro[3.3]heptanyl, bicyclo[3.3.0]octanyl, bicyclo[2.2.2]octanyl, Examples include, but are not limited to, bicyclo[3.3.1]nonanyl, bicyclo[3.3.2]decanyl, decalinyl, naphthyl, and indanyl.

[0022] Fused bicyclic carbocyclyls have a 4- to 7-membered carbocyclyl fused to a 3- to 7-membered non-aromatic carbocyclyl. Examples include decahydronaphthalene, octahydro-1H-indene, octahydropentalene, decahydroazulene, decahydro-1H-annulene, bicyclo[4.2.0]octane, bicyclo[3.2.0]heptane, and the like.

[0023] Bridged bicyclic carbocyclyls include 5- to 7-membered non-aromatic carbocyclyls that share three ring atoms with a 5- to 7-membered non-aromatic carbocyclyl. Examples of bridged bicyclic carbocycles include bicyclo[2.2.1]heptanyl, bicyclo[3.2.1]octanyl, and bicyclo[3.3.1]nonanyl.

[0024] "Cycloalkyl" refers to a fully saturated monocyclic hydrocarbon group of 3 to 7 carbon atoms, including cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cyclopentyl; "cycloalkynyl" refers to an unsaturated non-aromatic monocyclic hydrocarbon group of 3 to 7 carbon atoms, including cyclopenteneyl, cyclohexenyl, and cyclopentenyl. The term "cycloalkyl" includes fully saturated monocyclic, bicyclic, or spiro-type hydrocarbon groups of 3 to 7 carbon atoms, 3 to 6 carbon atoms, or 5 to 7 carbon atoms. In some embodiments, the cycloalkyl is a 3- to 6-membered monocyclic cycloalkyl.

[0025] "Halogen" or "halo" can be fluoro, chloro, bromo, or iodo.

[0026] The term "haloalkyl" or "halo-substituted alkyl" refers to an alkyl group that has at least one halogen substitution.

[0027] A "haloalkoxy" is a haloalkyl group attached to another moiety via an oxygen atom, for example, but not limited to, -OCHCF2 or -OCF3.

[0028] "Heteroaryl" refers to a 5-6 membered aromatic monocyclic ring system having 1-4 heteroatoms independently selected from O, N, and S, where N can be oxidized (e.g., N(O)) or quaternized, and S can optionally be oxidized to sulfoxide and sulfone. Examples of 5-6 membered monocyclic heteroaryls include, but are not limited to, pyrrolyl, furanyl, thiophenyl (or thienyl), imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, furazanyl, oxadiazolyl, thiadiazolyl, dithiazolyl, triazolyl, tetrazolyl, pyridinyl, pyranyl, thiopyranyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazinyl, thiazinyl, dioxinyl, dithinyl, oxathianyl, triazinyl, tetrazinyl, and the like. In one embodiment, heteroaryl is a 5 membered heteroaryl. Examples of 5-membered heteroaryls include pyrazolyl, oxazolyl, isoxazolyl, 1,2,3-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,4-oxadizolyl, 1,2,3-thiadiazolyl, Examples include, but are not limited to, 1,3,4-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, and tetrazolyl.

[0029] "Heterocyclyl" refers to a saturated or partially unsaturated monocyclic or bicyclic (e.g., fused, bridged, or spiro) ring system having 3 to 12 ring members, at least one of which is a heteroatom, and up to four of which (e.g., 1, 2, 3, or 4) can be heteroatoms, where the heteroatoms are independently selected from O, S, and N; C can be oxidized (e.g., C(O)); N can be oxidized (e.g., N(O)) or quaternized; and S can be optionally oxidized to sulfoxide and sulfone. In some embodiments, the heterocyclyl is a 4- to 6-membered or 3- to 7-membered monocyclic heterocyclyl. In some embodiments, the heterocyclyl is a 7- to 10-membered bicyclic heterocyclyl, which can be a fused, bridged, or spiro bicyclic heterocyclyl. In some embodiments, a bicyclic heterocyclyl can include a non-aromatic heterocycle fused to a heteroaromatic ring.

[0030] Examples of monocyclic heterocyclyls include, but are not limited to, oxetanyl, thietanyl, azetedinyl, pyrrolidinyl, tetrahydrofuranyl, thiolanyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, dioxolanyl, dithiolanyl, oxathiolanyl, piperidinyl, tetrahydropyranyl, thianyl, piperazinyl, morpholinyl, thiomorpholinyl, dioxanyl, dithianyl, trioxanyl, trithianyl, azepanyl, oxepanyl, thiepanyl, dihydrofuranyl, imidazolinyl, and dihydropyranyl.

[0031] A "fused ring system" has 8 to 12 members (ring atoms) and two rings that share two adjacent ring atoms. Fused bicyclic heterocyclyls include 4- to 7-membered heterocyclyls fused to a 4- to 7-membered heterocyclyl or a 3- to 7-membered carbocyclyl. Fused bicyclic heterocyclyls also include 4- to 7-membered heterocyclyls fused to a 5- to 6-membered heteroaryl. Examples include cyclopentapyrrolidinyl, cyclopentapiperidinyl, cyclopentazapanyl, cyclohexapyrrolidinyl, cyclohexapiperidinyl, cyclohexaazapanyl, cycloheptapyrrolidinyl, cycloheptapiperidinyl, cycloheptaazapanyl, pyrrolopyrrolidinyl, pyrrolopiperidinyl, pyrroloazapanyl, furanopyrrolidinyl, furanopiperidinyl, furanoazapanyl, pyranopyrrolidinyl, pyranopiperidinyl, pyranoazapanyl, dihydropyrrolo[3,4-d]thiazoyl, and the like.

[0032] A "bridged bicyclic ring system" (also referred to herein as a "bridged bicyclic" or "bridged ring system") has 7 to 10 members (ring atoms) and two rings that share three adjacent ring atoms. Bridged bicyclic heterocyclyls include 5- to 7-membered heterocyclyls that share three ring atoms with a 5- to 7-membered heterocyclyl or a 5- to 7-membered carbocyclyl. Examples of nitrogen-containing bridged bicyclic rings include azabicyclo[2.2.1]hepanyl, azabicyclo[3.2.1]octanyl, azabicyclo[3.3.1]nonanyl, diazabicyclo[2.2.1]hepanyl, diazabicyclo[3.2.1]octanyl, and diazabicyclo[3.3.1]nonanyl. Examples of oxygen-containing bridged bicycles include oxobicyclo[2.2.1]heptanyl, oxobicyclo[3.2.1]octanyl, oxobicyclo[3.3.1]nonanyl, oxa-azabicyclo[2.2.1]heptanyl, oxa-azabicyclo[3.2.1]octanyl, and oxa-azabicyclo[3.3.1]nonanyl.

[0033] A "spiro ring system" (also referred to herein as "spiro ring") has 8 to 12 members (ring atoms) and two rings that share one ring atom. Spiro bicyclic heterocyclyl includes a 4- to 7-membered heterocyclyl that shares one atom with a 4- to 7-membered heterocyclyl or a 4- to 7-membered non-aromatic carbocyclyl. Examples of 8- to 12-nitrogen-containing spiro ring systems include 3,4-azabicyclooctanyl, 4,4-azabicyclononanyl, 3,5-azabicyclononanyl, 3,6-azabicyclodecanyl, 4,5-azabicyclodecanyl, 3,7-azabicycloundecanyl, 4,6-azabicycloundecanyl, and 5,5-azabicycloundecanyl. Examples of spirocyclic ring systems containing 8 to 12 oxygen atoms include 3,4-oxobicyclooctanyl, 4,4-oxobicyclononanyl, 3,5-oxobicyclononanyl, 3,6-oxobicyclodecanyl, 4,5-oxobicyclodecanyl, 3,7-oxobicycloundecanyl, 4,6-oxobicycloundecanyl, and 5,5-oxobicycloundecanyl.

[0034] The term "oxo" refers to the diradical =O.

[0035] When the compounds provided herein are sufficiently basic or acidic to form stable non-toxic acid or base salts, the preparation and administration of the compounds as pharmaceutically acceptable salts may be appropriate. Examples of pharmaceutically acceptable salts include organic acid addition salts formed with acids that form physiologically acceptable anions, such as tosylate, methanesulfonate, acetate, citrate, malonate, tartrate, succinate, benzoate, ascorbate, α-ketoglutarate, or α-glycerophosphate. Inorganic salts may also be formed, including hydrochloride, sulfate, nitrate, bicarbonate, and carbonate.

[0036] Pharmaceutically acceptable salts may be obtained, for example, by reacting a sufficiently basic compound, such as an amine, with a suitable acid to provide 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 formed.

[0037] Pharmaceutically acceptable base addition salts can be prepared from inorganic and organic bases. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, or magnesium salts. Salts derived from organic bases include primary amines, secondary amines, or tertiary amines, such as 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 cycloalkylamines, trisubstituted cycloalkylamines, cycloalkenylamines, di(cycloalkenyl)amines, tri(cycloalkenyl)amines, substituted cycloalkenylamines, disubstituted cyclo Examples of suitable amines include, but are not limited to, salts of alkenylamines, trisubstituted cycloalkenylamines, arylamines, diarylamines, triarylamines, heteroarylamines, diheteroarylamines, triheteroarylamines, heterocycloalkylamines, diheterocycloalkylamines, triheterocycloalkylamines, or mixed amines of diamines and triamines, where at least two of the substituents on the amine can be different and can be alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, heteroaryl, or heterocycloalkyl, etc. Also included are amines where two or three of the substituents, taken together with the amino nitrogen, form a heterocycloalkyl or heteroaryl group.Non-limiting examples of amines include isopropylamine, trimethylamine, diethylamine, tri(isopropyl)amine, tri(n-propyl)amine, ethanolamine, 2-dimethylaminoethanol, trimethamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, N-alkylglucamine, theobromine, purine, piperazine, piperidine, morpholine, or N-ethylpiperidine. Other carboxylic acid derivatives, such as carboxylic acid amides, including carboxamides, lower alkylcarboxamides, or dialkylcarboxamides, may be useful.

[0038] The compounds described herein, or pharmaceutically acceptable salts thereof, may contain one or more asymmetric centers within the molecule. In accordance with the present disclosure, any structure in which stereochemistry is not specified should be understood to encompass all of the various stereoisomers (e.g., diastereomers and enantiomers) in pure or substantially pure form, and mixtures thereof (such as racemic mixtures or enantiomerically enriched mixtures). Methods for preparing such optically active forms (e.g., resolution of racemates by recrystallization techniques, synthesis from optically active starting materials, chiral synthesis, or chromatographic separation using chiral stationary phases) are well known in the art.

[0039] When a particular stereoisomer of a compound is designated by name or structure, the stereochemical purity of the compound is at least 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 97%, 99%, 99.5% or 99.9%. "Stereochemical purity" means the percent by weight of the desired stereoisomer based on the combined weight of all stereoisomers.

[0040] When a specific enantiomer of a compound is designated by name or structure, the stereochemical purity of the compound is at least 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 97%, 99%, 99.5%, or 99.9%. "Stereochemical purity" refers to the percent by weight of the desired enantiomer based on the combined weight of all stereoisomers.

[0041] When the stereochemistry of a disclosed compound is named or depicted in a structure, and the named or depicted structure encompasses more than one stereoisomer (e.g., as in the case of a diastereomeric pair), it is to be understood that one of the encompassed stereoisomers or any mixture of the encompassed stereoisomers is included. Furthermore, it is to be understood that the stereoisomeric purity of the named or depicted stereoisomer is at least 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 97%, 99%, 99.5%, or 99.9%. Stereoisomeric purity is the percent by weight of the desired stereoisomer encompassed by the name or structure relative to the combined weight of all stereoisomers.

[0042] Where a disclosed compound is named or depicted by structure without indicating stereochemistry, and the compound has one chiral center, it should be understood that the name or structure encompasses one enantiomer of the compound in pure or substantially pure form, and mixtures thereof, such as racemic mixtures of the compounds and mixtures in which one enantiomer is enriched relative to its corresponding optical isomer.

[0043] Where a disclosed compound is named or depicted by structure without indicating stereochemistry, and for example, where the compound has at least two chiral centers, it is to be understood that the name or structure encompasses one stereoisomer in pure or substantially pure form, as well as mixtures thereof, including mixtures of stereoisomers and stereoisomeric mixtures in which one or more stereoisomers are enriched relative to the other stereoisomer(s).

[0044] The disclosed compounds may exist in tautomeric forms, and mixtures and separated individual tautomers are contemplated. Additionally, some compounds may exhibit polymorphism.

[0045] In one embodiment, the present invention provides a deuterated compound disclosed herein, where any or more positions occupied by hydrogen can contain an enrichment with deuterium above the natural abundance of deuterium. For example, one or more hydrogen atoms are replaced with deuterium at an abundance at least 3340 times greater than the natural abundance of deuterium, which is 0.015% (i.e., at least 50.1% deuterium incorporation), at least 3500 times (52.5% deuterium incorporation at each designated deuterium atom), at least 4000 times (60% deuterium incorporation), at least 4500 times (67.5% deuterium incorporation), at least 5000 times (75% deuterium), at least 5500 times (82.5% deuterium incorporation), at least 6000 times (90% deuterium incorporation), at least 6333.3 times (95% deuterium incorporation), at least 6466.7 times (97% deuterium incorporation), at least 6600 times (99% deuterium incorporation), or at least 6633.3 times (99.5% deuterium incorporation) greater than the natural abundance of deuterium, which is 0.015%. In one embodiment, hydrogen is present at its natural abundance at all positions. The compounds described herein, or pharmaceutically acceptable salts thereof, may exist in tautomeric forms, and mixtures and separated individual tautomers are contemplated.

[0046] II. Compounds of the Present Disclosure In a first embodiment, the compounds of the present invention are represented by Formula (I) or a pharmaceutically acceptable salt thereof, wherein the variables are as previously described. [ka]

[0047] In a second embodiment of the present disclosure, for a compound of formula (I), or a pharmaceutically acceptable salt thereof, X 3 -OR 5 , -N(R 5) 2, 5- to 6-membered heteroaryl, or 4- to 7-membered monocyclic heterocyclyl, and the 5- to 6-membered heteroaryl and the 4- to 7-membered monocyclic heterocyclyl may have one or more (e.g., 1 to 6, 1 to 3, or 1, 2, 3, 4, 5, or 6) R 50 and the remaining variables are as described in the first embodiment.

[0048] In a third embodiment of the present disclosure, for a compound of formula (I), or a pharmaceutically acceptable salt thereof, R 0 is H, and the remaining variables are as described in the first or second embodiment.

[0049] In a fourth embodiment of the present disclosure, for a compound of formula (I), or a pharmaceutically acceptable salt thereof, the compound is formula: [ka] or a pharmaceutically acceptable salt thereof, and the remaining variables are as described in the first or second embodiment.

[0050] In a fifth embodiment of the present disclosure, for a compound of formula (I), (II), (III), (IV), (V), or (VI), or a pharmaceutically acceptable salt thereof, X 3 -OR 5 , -N(R 5 ) 2, 5-membered heteroaryl, or 4- to 6-membered monocyclic heterocyclyl, wherein the 5-membered heteroaryl and the 4- to 6-membered monocyclic heterocyclyl optionally contain 1 to 3 R 50 is replaced by R 5 is C 1-6 C optionally substituted with alkoxy 1-6 alkyl, and the remaining variables are as described in the first, second, third, or fourth embodiment.

[0051] In a sixth embodiment of the present disclosure, for a compound of formula (I), (II), (III), (IV), (V), or (VI), or a pharmaceutically acceptable salt thereof, X 3 are each optionally followed by one or two R 50 and the remaining variables are as described in the first, second, third, fourth, or fifth embodiment.

[0052] In a seventh embodiment of the present disclosure, for a compound of formula (I), (II), (III), (IV), (V), or (VI), or a pharmaceutically acceptable salt thereof, X 3 is selected from: [ka] m is 0, 1, or 2, and the remaining variables are as described in the first, second, third, fourth, or fifth embodiment.

[0053] In an eighth embodiment of the present disclosure, for a compound of formula (I), (II), (III), (IV), (V), or (VI), or a pharmaceutically acceptable salt thereof, X 3 is -O-CH2-CH2-OCH3, -N(CH3)2, [ka] is selected from During the ceremony, [ka] represents the bond to Ring B, and the remaining variables are as described in the first, second, third, fourth, or fifth embodiment.

[0054] In a ninth embodiment of the present disclosure, for a compound of formula (I), (II), (III), (IV), (V), or (VI), or a pharmaceutically acceptable salt thereof, R 50 is independently generated for each occurrence of C1-6 alkyl or 4- to 6-membered monocyclic heterocyclyl, and R 50 C, represented by 1-6 The alkyl is optionally substituted with halo or CN, and the remaining variables are as described in the first, second, third, fourth, fifth, sixth, seventh, or eighth embodiment.

[0055] In a tenth embodiment of the present disclosure, for a compound of formula (I), (II), (III), (IV), (V), or (VI), or a pharmaceutically acceptable salt thereof, R 50 is, at each occurrence, independently -CH3, -CH2-CN, and [ka] and the remaining variables are as described in the ninth embodiment.

[0056] In an eleventh embodiment of the present disclosure, for a compound of formula (I), (II), (III), (IV), (V), or (VI), or a pharmaceutically acceptable salt thereof, R 50 is —CH 3 , and the remainder of the variables are as described in the ninth embodiment.

[0057] In a twelfth embodiment of the present disclosure, for compounds of formula (I), (II), (III), (IV), (V), or (VI), or a pharmaceutically acceptable salt thereof, ring A is phenyl, 5- or 6-membered heteroaryl, or 5- to 10-membered monocyclic or bicyclic heterocyclyl, each of which optionally contains 1 to 3 R 4 and the remaining variables are as described in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, or eleventh embodiment.

[0058] In a thirteenth embodiment of the present disclosure, for compounds of formula (I), (II), (III), (IV), (V), or (VI), or a pharmaceutically acceptable salt thereof, ring A is selected from 3-azabicyclo[3.2.1]octane, azepane, phenyl, piperidine, pyridine, and pyrrolidine, each of which optionally contains 1 to 3 R 4 and the remaining variables are as described in the twelfth embodiment.

[0059] In a fourteenth embodiment of the present disclosure, for compounds of formula (I), (II), (III), (IV), (V), or (VI), or a pharmaceutically acceptable salt thereof, A is selected from: [ka] During the ceremony, [ka] represents a bond to ring B, and -* represents [ka] and the remaining variables are as described in the twelfth embodiment.

[0060] In a fifteenth embodiment of the present disclosure, for compounds of Formula (I), (II), (III), (IV), (V), or (VI), or a pharmaceutically acceptable salt thereof, n is 0, 1, 2, and the remaining variables are as described in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, or fourteenth embodiment.

[0061] In a sixteenth embodiment of the present disclosure, for compounds of formula (I), (II), (III), (IV), (V), or (VI), or a pharmaceutically acceptable salt thereof, ring A is selected from: [ka] [ka] During the ceremony, [ka] represents a bond to ring B, and -* represents [ka] and the remaining variables are as described in the twelfth embodiment.

[0062] In a seventeenth embodiment of the present disclosure, for a compound of formula (I), (II), (III), (IV), (V), or (VI), or a pharmaceutically acceptable salt thereof, R 4 is a halogen, C 1-6 Alkyl, and C 1-6 haloalkyl, and the remaining variables are as described in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, or sixteenth embodiment.

[0063] In an eighteenth embodiment of the present disclosure, for a compound of formula (I), (II), (III), (IV), (V), or (VI), or a pharmaceutically acceptable salt thereof, R 4 is selected from Cl, F, —CH 3 , and —CHF 2 , and the remainder of the variables are as described in the seventeenth embodiment.

[0064] In an eighteenth embodiment of the present disclosure, for a compound of formula (I), (II), (III), (IV), (V), or (VI), or a pharmaceutically acceptable salt thereof, R 1 optionally one or two R 10 and the remaining variables are as described in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, or eighteenth embodiment.

[0065] In a twentieth embodiment of the present disclosure, for a compound of formula (I), (II), (III), (IV), (V), or (VI), or a pharmaceutically acceptable salt thereof, R 1 is selected from oxazole, oxadiazole, pyrazole, tetrazole, and triazole, each of which optionally contains one or two R 10 and the remaining variables are as described in the nineteenth embodiment.

[0066] In a twenty-first embodiment of the present disclosure, for a compound of formula (I), (II), (III), (IV), (V), or (VI), or a pharmaceutically acceptable salt thereof, R 1 teeth, [ka] and the remaining variables are as described in the nineteenth embodiment.

[0067] In a twenty-second embodiment of the present disclosure, for a compound of formula (I), (II), (III), (IV), (V), or (VI), or a pharmaceutically acceptable salt thereof, R 10 is independently generated for each occurrence of C 1-6 Alkyl and C 3-6 cycloalkyl, each of which optionally contains 1 to 3 R 15 and the remaining variables are as described in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth, twentieth, or twenty-first embodiment.

[0068] In a twenty-third embodiment of the present disclosure, for a compound of formula (I), (II), (III), (IV), (V), or (VI), or a pharmaceutically acceptable salt thereof, R 10 is independently generated for each occurrence of C 1-4 alkyl and cyclopropyl, each of which optionally contains one or three R 15and the remaining variables are as described in the twenty-second embodiment.

[0069] In a twenty-fourth embodiment of the present disclosure, for a compound of formula (I), (II), (III), (IV), (V), or (VI), or a pharmaceutically acceptable salt thereof, R 15 are, for each occurrence independently, halogens, C 1-4 Alkyl and C 1-4 haloalkyl, and the remaining variables are as described in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth, twentieth, twenty-first, twenty-second, or twenty-third embodiment.

[0070] In a twenty-fifth embodiment of the present disclosure, for a compound of formula (I), (II), (III), (IV), (V), or (VI), or a pharmaceutically acceptable salt thereof, R 15 is independently selected at each occurrence from F, —CH 3 , and —CH 2 F, and the remainder of the variables are as described in the twenty-fourth embodiment.

[0071] In a twenty-sixth embodiment of the present disclosure, for a compound of formula (I), (II), (III), (IV), (V), or (VI), or a pharmaceutically acceptable salt thereof, R 10 are, at each occurrence, independently: -C(CH3)3, -C(CH3)2-CH2F, [ka] and the remaining variables are as described in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth, twentieth, or twenty-first embodiment.

[0072] In a twenty-seventh embodiment of the present disclosure, for a compound of formula (I), (II), (III), (IV), (V), or (VI), or a pharmaceutically acceptable salt thereof, R2 is H, and the remaining variables are as described in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth, twentieth, twenty-first, twenty-second, twenty-third, twenty-fourth, twenty-fifth, or twenty-sixth embodiment.

[0073] In a twenty-eighth embodiment of the present disclosure, for a compound of formula (I), (II), (III), (IV), (V), or (VI), or a pharmaceutically acceptable salt thereof, R 1 and R 2 together with their intervening atoms form a ring D selected from a 5- to 7-membered monocyclic heterocyclyl and a 7- to 10-membered bicyclic heterocyclyl, and ring D optionally contains one or more (e.g., 1 to 6, 1 to 3, or 1, 2, 3, 4, 5, or 6) R 100 and the remaining variables are as described in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, or eighteenth embodiment.

[0074] In a twenty-ninth embodiment of the present disclosure, for compounds of formula (I), (II), (III), (IV), (V), or (VI), or a pharmaceutically acceptable salt thereof, ring D is selected from piperazinone and dihydropyrrolo[3,4-d]thiazolone, and ring D optionally contains one or two R 100 and the remaining variables are as described in the 28th embodiment.

[0075] In a thirtieth embodiment of the present disclosure, for compounds of formula (I), (II), (III), (IV), (V), or (VI), or a pharmaceutically acceptable salt thereof, ring D is [ka] is selected from: [ka] is -C(R 3 )-represents a bond to Ring A, and the remainder of the variables are as described in the 28th embodiment.

[0076] In a thirty-first embodiment of the present disclosure, for a compound of formula (I), (II), (III), (IV), (V), or (VI), or a pharmaceutically acceptable salt thereof, R 100 is independently generated for each occurrence of C 1-6 alkyl and 4- to 6-membered monocyclic heterocyclyl, each of which optionally contains one or two R 150 is replaced by R 150 is independently generated for each occurrence of C 3-6 and cycloalkyl and 4-6 membered monocyclic heterocyclyl, and the remaining variables are as described in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth, twentieth, twenty-first, twenty-second, twenty-third, twenty-fourth, twenty-fifth, twenty-sixth, twenty-seventh, twenty-eighth, twenty-ninth, or thirtieth embodiment.

[0077] In a thirty-second embodiment of the present disclosure, for a compound of formula (I), (II), (III), (IV), (V), or (VI), or a pharmaceutically acceptable salt thereof, R 100 is independently generated for each occurrence of C 1-6 alkyl and oxetanyl; R 100 The C represented by 1-6 The alkyl is optionally R 150 is replaced by R 150 is independently selected at each occurrence from cyclobutyl and oxetanyl, and the remainder of the variables are as described in the thirty-first embodiment.

[0078] In a thirty-third embodiment of the present disclosure, for a compound of formula (I), (II), (III), (IV), (V), or (VI), or a pharmaceutically acceptable salt thereof, R 100is, at each occurrence, independently: -CH3, -CH2-CH2-CH3, -CH(CH3)2, -C(CH3)3, -CH2-CH(CH3)2, -CH2-C(CH3)3, [ka] and the remaining variables are as described in the thirty-first embodiment.

[0079] In a thirty-fourth embodiment of the present disclosure, for a compound of formula (I), (II), (III), (IV), (V), or (VI), or a pharmaceutically acceptable salt thereof, R 3 is H and C 1-6 alkyl, and the remaining variables are as described in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth, twentieth, twenty-first, twenty-second, twenty-third, twenty-fourth, twenty-fifth, twenty-sixth, twenty-seventh, twenty-eighth, twenty-ninth, thirty-first, thirty-second, or thirty-third embodiment.

[0080] In a thirty-fifth embodiment of the present disclosure, for a compound of formula (I), (II), (III), (IV), or (V), or a pharmaceutically acceptable salt thereof, R 3 is H or —CH 3 , and the remainder of the variables are as described in the thirty-fourth embodiment.

[0081] In a thirty-sixth embodiment of the present disclosure, for a compound of formula (I), (II), (III), (IV), or (V), or a pharmaceutically acceptable salt thereof, R 3 and R 4 together with the atoms between them form ring E, ring E being selected from a 4- to 7-membered monocyclic carbocycle and a 4- to 7-membered monocyclic heterocycle, ring E optionally being selected from R 300and the remaining variables are as described in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, seventeenth, eighteenth, nineteenth, twentieth, twenty-first, twenty-second, twenty-third, twenty-fourth, twenty-fifth, twenty-sixth, twenty-seventh, twenty-eighth, twenty-ninth, thirty-first, thirty-second, or thirty-third embodiment.

[0082] In a thirty-seventh embodiment of the present disclosure, for compounds of formula (I), (II), (III), (IV), or (V), or a pharmaceutically acceptable salt thereof, ring E is R 300 and the remainder of the variables are as described in the thirty-sixth embodiment.

[0083] In a thirty-eighth embodiment of the present disclosure, for compounds of formula (I), (II), (III), (IV), or (V), or a pharmaceutically acceptable salt thereof, ring E is represented by the following structural formula: [ka] During the ceremony, [ka] represents the fusion point to ring A, and -* represents -N(R 2 )-C(O)-R 1 and the remaining variables are as described in the 36th embodiment.

[0084] In a thirty-ninth embodiment of the present disclosure, for a compound of formula (I), (II), (III), (IV), or (V), or a pharmaceutically acceptable salt thereof, R 300 is independently generated for each occurrence of C 1-6 alkyl and 4- to 6-membered monocyclic heterocyclyl; R 300 The C represented by 1-6 The alkyl and the 4- to 6-membered monocyclic heterocyclyl each optionally have 1 to 3 R 350 is replaced by R 350is independently at each occurrence halogen, and the remaining variables are as described in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth, twentieth, twenty-first, twenty-second, twenty-third, twenty-fourth, twenty-fifth, twenty-sixth, twenty-seventh, twenty-eighth, twenty-ninth, thirty-first, thirty-second, thirty-third, thirty-fourth, thirty-fifth, thirty-sixth, thirty-seventh, or thirty-eighth embodiment.

[0085] In a fortieth embodiment of the present disclosure, for a compound of formula (I), (II), (III), (IV), or (V), or a pharmaceutically acceptable salt thereof, R 300 is, at each occurrence, independently -CH2-CF3 and [ka] and the remaining variables are as described in the thirty-ninth embodiment.

[0086] In a forty-first embodiment of the present disclosure, the compound has the following formula: [ka] or a pharmaceutically acceptable salt thereof, wherein R 1 is R 10 and R is a 5-membered heteroaryl optionally substituted with 10 is C 1-4 Alkyl, C 1-4 Haloalkyl, or C 1-3 C optionally substituted with alkyl 3-6 is cycloalkyl, and X 3 is a 5-membered heteroaryl or a 6-membered monocyclic saturated heterocyclyl, each of which is optionally R 50 is replaced by R 50 is C 1-3 Alkyl or C 1-3 haloalkyl, ring A is phenyl, 6-membered heteroaryl, or 6-membered monocyclic saturated heterocyclyl, and R 4 are, for each occurrence independently, halogens, C 1-3Alkyl, and C 1-3 haloalkyl, and n is 0, 1, or 2.

[0087] In a forty-second embodiment of the present disclosure, for compounds of formula (IIA) or (IIIA), or pharmaceutically acceptable salts thereof, R 1 is selected from oxadiazole, triazole, and tetrazole, each of which is optionally R 10 is replaced by X 3 is pyrozole or piperazine, each of which is optionally R 50 wherein Ring A is phenyl, pyridine, or piperidine, and the remainder of the variables are as described in the forty-first embodiment.

[0088] In a forty-third embodiment of the present disclosure, for a compound of formula (IIA) or (IIIA), or a pharmaceutically acceptable salt thereof, R 1 teeth, [ka] is selected from X 3 teeth, [ka] is selected from Ring A is [ka] is selected from During the ceremony, [ka] represents a bond to ring B, and -* represents [ka] and the remaining variables are as described in the 41st embodiment.

[0089] In a forty-fourth embodiment of the present disclosure, for compounds of formula (IIA) or (IIIA), or a pharmaceutically acceptable salt thereof, ring A is [ka] is selected from During the ceremony, [ka] represents a bond to ring B, and -* represents [ka] and the remaining variables are as described in the 43rd embodiment.

[0090] In a forty-fifth embodiment of the present disclosure, for compounds of formula (IIA) or (IIIA), or pharmaceutically acceptable salts thereof, R 10 is -C(CH3)3 or [ka] and R 4 is, at each occurrence, independently selected from F, —CH and —CHF; R 50 is —CH 3 , and the remaining variables are as described in the 41st, 42nd, 43rd, or 44th embodiment.

[0091] The present invention also includes both the neutral forms and pharmaceutically acceptable salts of the compounds disclosed in the examples (eg, the compounds of Examples 1 to 174).

[0092] III. Pharmaceutical Compositions and Methods of Use 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.

[0093] The compounds described herein, or pharmaceutically acceptable salts thereof, can be used to decrease the activity of Btk or to otherwise affect the properties and / or behavior of Btk, such as stability, phosphorylation, kinase activity, interactions with other proteins, etc.

[0094] In some embodiments, the present invention provides methods for reducing Btk enzymatic activity. In some embodiments, such methods include contacting Btk with an effective amount of a Btk inhibitor. Accordingly, the present invention further provides methods for inhibiting Btk enzymatic activity by contacting Btk with a Btk inhibitor of the present invention.

[0095] One embodiment of the present invention includes a method of treating a disorder responsive to Btk inhibition in a subject, comprising administering to the subject an effective amount of at least one compound described herein, or a pharmaceutically acceptable salt thereof.

[0096] In one embodiment, the present invention provides a method of treating autoimmune disorders, inflammatory diseases, and cancer in a subject in need thereof, comprising administering to the subject an effective amount of at least one compound described herein, or a pharmaceutically acceptable salt thereof.

[0097] The term "autoimmune disorder" includes diseases or disorders involving an inappropriate immune response to natural antigens, such as acute disseminated encephalomyelitis (ADEM), Addison's disease, alopecia areata, antiphospholipid syndrome (APS), autoimmune hemolytic anemia, autoimmune hepatitis, bullous pemphigoid (BP), celiac disease, dermatomyositis, diabetes mellitus type 1, Goodpasture's 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, Sjogren'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 methods of treating rheumatoid arthritis or lupus. In some embodiments, the present invention provides methods of treating multiple sclerosis.

[0098] 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 tumor, pancreatic cancer, bile duct cancer, ovarian cancer, endometrial cancer, prostate cancer, renal cell carcinoma, lymphoma (e.g., anaplastic large cell lymphoma), leukemia (e.g., acute myeloid leukemia, T-cell leukemia, chronic lymphocytic leukemia), multiple myeloma, malignant mesothelioma, malignant melanoma, and colon cancer (e.g., microsatellite instability-high colon cancer). In some embodiments, the present invention provides methods of treating leukemia or lymphoma.

[0099] As used herein, the terms "subject" and "patient" may be used interchangeably and refer to a mammal in need of treatment, such as companion animals (e.g., dogs, cats, etc.), 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 in need of treatment.

[0100] As used herein, the terms "treating" or "treatment" refer to obtaining a desired pharmacological and / or physiological effect. The effect may be therapeutic, which includes partially or substantially achieving one or more of the following results: partially or completely reducing the severity of a disease, disorder, or syndrome; ameliorating or improving clinical symptoms or indicators associated with a disorder; or delaying, inhibiting, or reducing the likelihood of progression of a disease, disorder, or syndrome.

[0101] An effective dose of a compound provided herein, or a pharmaceutically acceptable salt thereof, to be administered to a subject can be from 10 μg to 500 mg.

[0102] Administering the compound described herein or its pharmaceutically acceptable salt to a mammal comprises any suitable delivery method.Administering the compound described herein or its pharmaceutically acceptable salt to a mammal comprises administering the compound described herein or its pharmaceutically acceptable salt to a mammal topically, enterally, parenterally, transdermally, transmucosally, by inhalation, intracisternally, epidurally, intravaginally, intravenously, intramuscularly, subcutaneously, intradermally, or intravitreally.Administering the compound described herein or its pharmaceutically acceptable salt to a mammal also comprises administering the compound that is metabolized to the compound described herein in or on the body surface of the mammal topically, enterally, parenterally, transdermally, transmucosally, by inhalation, intracisternally, epidurally, intravaginally, intravenously, intramuscularly, subcutaneously, intradermally, or intravitreally to a mammal.

[0103] Thus, the compounds described herein, or pharmaceutically acceptable salts thereof, may be administered systemically, e.g., orally, in combination with a pharmaceutically acceptable vehicle, such as an inert diluent or an assimilable edible carrier. They may be enclosed in hard or soft shell gelatin capsules, compressed into tablets, or incorporated directly with the patient's food. For oral therapeutic administration, the compounds described herein, or pharmaceutically acceptable salts thereof, may be combined with one or more excipients and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers, or the like. Such compositions and preparations should contain at least about 0.1% of the active compound. The percentage of the compositions and preparations may, of course, vary and may conveniently be about 2 to about 60% of the weight of a given unit dosage form. The amount of active compound in such therapeutically useful compositions may be such that an effective dosage level will be obtained.

[0104] Tablets, troches, pills, capsules, etc. may contain: a binder such as tragacanth, acacia, corn starch, or gelatin; an excipient such as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch, alginic acid, and the like; a lubricant such as magnesium stearate; or a sweetening or flavoring agent such as sucrose, fructose, lactose, or aspartame.

[0105] The active compound may also be administered intravenously or intraperitoneally by infusion or injection. Solutions of the active compound or its salts can be prepared in water, optionally mixed with a nontoxic surfactant.

[0106] Exemplary pharmaceutical dosage forms for injection or infusion can include sterile aqueous solutions or dispersions or sterile powders containing the active ingredient suitable for the extemporaneous preparation of sterile injectable or infusible solutions or dispersions. In all cases, the ultimate dosage form should be sterile, fluid, and stable under the conditions of manufacture and storage.

[0107] Sterile injectable solutions can be prepared by incorporating the active compound in the required amount in a suitable solvent, along with various other ingredients as mentioned above, as needed, followed by filtered sterilization. In the case of sterile powders for preparing sterile injectable solutions, the preferred preparation method can be vacuum drying and freeze-drying techniques, which can produce a powder that combines the active ingredient and any desired additional ingredients that are present in a previously sterile-filtered solution.

[0108] Exemplary solid carriers can include finely divided solids such as talc, clay, microcrystalline cellulose, silica, alumina, etc. Useful liquid carriers include water, alcohols or glycols or blends of water and alcohols / glycols, in which the compounds described herein or pharmaceutically acceptable salts thereof can be dissolved or dispersed at effective levels, optionally with the use of nontoxic surfactants.

[0109] Useful dosages 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 the extrapolation of effective dosages in mice, and other animals, to humans are known to the art; see, for example, U.S. Patent No. 4,938,949, incorporated by reference in its entirety.

[0110] The amount of the compound described herein or a pharmaceutically acceptable salt thereof required for therapeutic use will vary not only depending on the particular salt selected, but also on the route of administration, the nature of the condition being treated, and the age and condition of the patient, and will ultimately be left to the discretion of the attending physician or clinician. Generally, however, the dosage may range from about 0.1 to about 10 mg / kg body weight per day.

[0111] The compounds described herein, or pharmaceutically acceptable salts thereof, can be conveniently administered in unit dosage form, for example, containing 0.01 to 10 mg, or 0.05 to 1 mg of active ingredient per unit dosage form. In some embodiments, dosages of 5 mg / kg or less may be suitable.

[0112] The desired dose may conveniently be presented in a single dose or as divided doses administered at appropriate intervals.

[0113] The disclosed methods may include kits containing a compound described herein or a pharmaceutically acceptable salt thereof, and instructional materials that can describe administering a compound described herein or a pharmaceutically acceptable salt thereof, or a composition comprising a compound described herein or a pharmaceutically acceptable salt thereof, to a cell or a subject. This should be construed to include other embodiments of kits known to those of skill in the art, such as kits that include a solvent (e.g., sterile) for dissolving or suspending a compound described herein or a pharmaceutically acceptable salt thereof or a composition prior to administering the compound described herein or a pharmaceutically acceptable salt thereof or a composition to a cell or a subject. In some embodiments, the subject may be a human.

[0114] The present invention is illustrated by the following examples, which are not intended to be limiting.

[0115] IV. Working Examples A. Abbreviations and Acronyms Abbreviations and acronyms used herein include the following: ABPR: Automatic back pressure regulator Ac2O: acetic anhydride ACN: acetonitrile Aq.: Aqueous Ar: Argon Bn: Benzyl Boc: tert-butoxycarbonyl Boc2O: di-tert-butyl dicarbonate BPin: Pinacolatoboron (BPin)2 or B2pin2: Bis(pinacolato)diboron, i.e., 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi-1,3,2-dioxaborolane br:Wide t-BuOH: tert-butanol n-BuLi: n-butyllithium ℃: Celsius CHCl3: Chloroform CDCl3: deuterated chloroform CDI: 1,1'-carbonyldiimidazole CO2: Carbon dioxide Cs2CO3: Cesium carbonate CsF: Cesium fluoride CuI: Copper iodide δ: chemical shift d: doublet dd: double doublet ddd: Double doublet of doublets DCM: dichloromethane DIEA or DIPEA: N-ethyldiisopropylamine or N,N-diisopropylethylamine DEA: Diethylamine deg: degrees DIAD: Diisopropyl azodicarboxylate DABCO: 1,4-diazabicyclo[2.2.2]octane DABAL-Me3: Adduct of trimethylaluminum and DABCO DME: 1,2-dimethoxyethane DMF: N,N-dimethylformamide DMSO: dimethyl sulfoxide DMSO-d6: hexadeuterodimethyl sulfoxide DPPA: Diphenylphosphoryl azide Et: Ethyl Et2O: Ether EtOH: ethanol EtOAc: ethyl acetate Eq.:Equivalent g: grams h: time HATU: O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate HBr: Hydrogen bromide HCl: Hydrochloric acid HCO2H: Formic acid Hept: Heptane HFIP: hexafluoroisopropanol 1 HNMR: proton nuclear magnetic resonance H2O: Water H2SO4: sulfuric acid HMPA: hexamethylphosphoramide HPLC: High-pressure liquid chromatography Hz: Hertz IPA or iPrOH: Isopropanol J: Coupling constant K2CO3: Potassium carbonate kg: kilogram KHMDS: potassium hexamethyldisilazide KOAc: Potassium acetate KOH: Potassium hydroxide KOt-Bu: Potassium tert-butoxide K3PO4: Potassium phosphate tribasic K4Fe(CN)6·3H2O: Potassium hexacyanoferrate(II) trihydrate L: Liter LCMS: Liquid Chromatography Mass Spectrometry LG: Leaving group m: multiplet M: mole MBPR: Manual back pressure regulator Me: Methyl MeB(OH)2: methylboronic acid MeCN: acetonitrile MeOH: Methanol MeOH-d4: deuterated methanol mg: milligram MgSO4: Magnesium sulfate MHz: Megahertz min:minutes mL: milliliter mmol: millimolar MMPNO: Methylmorpholine N-oxide mol: mole MS m / z: mass spectrum peak N2: Nitrogen NaOt-Bu: Sodium tert-butoxide NaH: sodium hydride NaHCO3: Sodium bicarbonate NaHMDS: sodium hexamethyldisilylazide NaIO4: Sodium periodate NaOH: Sodium hydroxide Na2S2O3: Sodium thiosulfate Na2SO4: Sodium sulfate NEt3: Triethylamine NFSI: N-fluorobenzenesulfonimide NH3: Ammonia NH4Cl: Ammonium chloride NH4OH: Ammonium hydroxide NH4OAc: Ammonium acetate NIS: N-iodosuccinimide OsO4: Osmium tetroxide P(cy)3: Tricyclohexylphosphine Pd2(dba)3: Tris(dibenzylideneacetone)dipalladium(0) Pd(dppf)Cl2: [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) Pd(dppf)Cl2.DCM: [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane Pd(dtbpf)Cl2: [1,1'-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II) Pd(t-Bu3P)2: Bis(tri-tert-butylphosphine)palladium(0) PE: Petroleum ether PEPPSI-IPr or Pd-PEPPSI-IPr: [1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene](3-chloropyridyl)palladium(II) dichloride PG: Protecting group Ph: Phenyl POCl3: Phosphoryl chloride Pyr: pyridine q:Quartet Rf: Retardation coefficient rt: retention time RT: room temperature Rh(OAc)2 dimer: rhodium(II) acetate dimer RuPhos: 2-dicyclohexylphosphino-2',6'-diisopropoxybiphenyl s:singlet sat.: saturation SCX: Strong cation exchange SFC: Supercritical Fluid Chromatography SiO2: silicon dioxide Si-SPE: Silica solid phase extraction SPE: solid phase extraction t: triplet td: triple doublet t-BuONa: Sodium tert-butoxide TEA: Triethylamine TFA: Trifluoroacetic acid TfO: Trifluoromethanesulfonic anhydride THF: tetrahydrofuran TLC: Thin Layer Chromatography T3P: Propanephosphonic anhydride μL: microliter μmol: micromol μW: microwave v / v: volume / volume Xphos: 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl Xphos G3: (2-Dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate tBuXPhosPd G3: [(2-di-tert-butylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)-2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate B. General Synthetic Scheme According to the first process, where the A ring is phenyl or a 5- or 6-membered heteroaryl, compounds of formula (I) can be prepared from compounds of formula (II'), (III'), (IV'), and (V'), as shown in Scheme 1.

[0116] Scheme 1 [ka] PG is a suitable N-protecting group, typically a carbamate, preferably tert-butylcarbamate. LG is a leaving group, typically a halide, mesylate, or triflate, preferably Br, Cl, or triflate.

[0117] Compounds of formula (IV') can be prepared from compounds of formula (II') and (III') by process step a) a palladium-catalyzed cross-coupling reaction (e.g., Suzuki reaction). Typical cross-coupling reaction conditions include a palladium catalyst containing a suitable phosphine ligand in the presence of an inorganic base in a suitable aqueous solvent at temperatures between ambient and the reflux temperature of the reaction. Preferred conditions include carrying out the reaction of compounds of formula (II') and (III') using tBuXPhos PdG3, Pd(t-Bu3P)2, Pd(dppf)Cl 2、 Alternatively, the reaction may involve the combination of RuPhos with Pd2(dba)3 and a suitable base (e.g., Na2CO3, K2CO3, Cs2CO3, K3PO4, or KF) in a suitable solvent (e.g., aqueous dioxane) at 40°C to 100°C.

[0118] Compounds of formula (V') can be prepared from compounds of formula (IV') under acidic conditions according to process step b) deprotection of the N-protecting group. Preferred conditions include reacting compounds of formula (IV') with HCl or TFA in a suitable solvent (e.g., MeOH, dioxane, EtOAc, or DCM) at temperatures between room temperature and 50°C.

[0119] Compounds of formula (I) can be prepared by combining an amine of formula (V') and R 1 COH in the presence of a suitable coupling agent and an organic base in a suitable polar aprotic solvent. 1 It involves reacting COH with an amine of formula (V') in the presence of a coupling agent, T3P®, HATU, or CDI, in the presence of an organic base (e.g., TEA or DIPEA), in a solvent (e.g., DMF, EtOAc, dioxane, or MeCN) at between room temperature and the reflux temperature of the reaction.

[0120] Alternatively, compounds of formula (I) can be prepared according to process step d), amide bond formation, by converting an amine of formula (V') to R 1 The esters R can be prepared by reacting CO2 (C1-C4 alkyl) with DABAL-Me3 according to the method described by Novak et al. (Tet. Lett. 2006, 47, 5767). 1 It involves reacting CO2(C1-C4 alkyl) with an amine of formula (V') in the presence of DABAL-Me3 in a suitable solvent (e.g., THF or dioxane) at between room temperature and 45°C.

[0121] According to a second process, where the A ring is phenyl or a 5- or 6-membered heteroaryl, compounds of formula (IV') can be prepared from compounds of formulae (II'), (VI'), and (VII') as shown in Scheme 2.

[0122] Scheme 2 [ka] Hal is a halogen, preferably Cl or Br, and W is a boronic acid or boronic ester.

[0123] Compounds of formula (VII') can be obtained from compounds of formulae (II') and (VI') according to the Suzuki reaction in process step (a), as described above in Scheme 1.

[0124] X 3 is a 5-6 membered heteroaryl, the compound of formula (IV) can be prepared by the Suzuki reaction of process step (a) to give a compound of formula (VII') and X, as previously described in Scheme 1. 3 -W can be obtained.

[0125] X 3 -N(R 5 ) 2, or 4-7 membered N-linked monocyclic heterocyclyl, compounds of formula (IV') can be obtained by process step d) Buchwald-Hartwig cross-coupling reaction. Typical conditions are 3 Preferred conditions include reacting H with a compound of formula (VII') in the presence of a suitable inorganic base, a suitable palladium catalyst in the presence of a suitable phosphine ligand, in a suitable solvent at elevated temperature. 3 H in the presence of a combination of RuPhos and Pd(dba) in the presence of a suitable base (e.g., KCO, KPO, or CsCO) in a suitable solvent (e.g., dioxane or toluene) at temperatures between 70°C and 110°C.

[0126] According to a third process, in which the A ring is linked to the B ring via an N atom, compounds of formula (IV') can be prepared from compounds of formulae (III') and (VIII') as shown in Scheme 3.

[0127] Scheme 3 [ka] Compounds of formula (IV') can be prepared according to process step e) amination reaction. Typical conditions include reacting an amine of formula (VIII') with a compound of formula (III'), optionally in the presence of an organic or inorganic base (e.g., DIPEA or Cs2CO3) in IPA or DMF at room temperature.

[0128] According to the fourth process, compounds of formula (I) can be prepared from compounds of formula (II'), (VI'), (X'), (XI'), and (XII') as shown in Scheme 4.

[0129] Scheme 4 [ka] Compounds of formula (II') can be prepared from compounds of formula (XI') according to process step (f), boronate ester formation, which is achieved by treatment with a suitable boronate (e.g., (BPin)2) in the presence of a suitable inorganic base (e.g., K2CO3 or KOAc) and a suitable catalyst (e.g., Pd(dppf)Cl2) in a suitable non-polar solvent at room temperature to elevated temperatures. Preferred conditions include treating compounds of formula (II') with (BPin)2 in the presence of KOAc in dioxane in the presence of Pd(dppf)Cl2 at room temperature to 90°C.

[0130] Compounds of formula (X') can be prepared from compounds of formula (II') according to process step b) deprotection reaction, as described above in Scheme 1.

[0131] Compounds of formula (XI') can be prepared by reacting compounds of formula (X') and R according to process step c), as previously described in Scheme 1. 1 from CO2H or according to process step d) 1 It can be prepared from CO2(C1-C4) alkyl.

[0132] Compounds of formula (XII') can be prepared from compounds of formulae (XI') and (VI') according to process step a), as previously described in Scheme 1.

[0133] The compound of formula (I) can be prepared by combining the compound of formula (XII') and X 3 It can be prepared from H according to process steps a) or e) described above.

[0134] According to a fifth process, compounds of formula (XI') can be prepared from compounds of formula (XII') as shown in Scheme 5.

[0135] Scheme 5 [ka] Compounds of formula (XI') can be prepared from compounds of formula (XII') according to process step f), as previously described in Scheme 4.

[0136] According to the sixth process, where the A ring is linked to the B ring via an N atom, compounds of formula (XI') can be prepared from compounds of formula (XII') as shown in Scheme 6.

[0137] Scheme 6 [ka] Compounds of formula (XV') can be prepared by reacting compounds of formula (X') and R according to process step c), as previously described in Scheme 1. 1 from CO2H or according to process step d) 1 It can be prepared from CO2(C1-C4) alkyl.

[0138] Compounds of formula (XVI') can be obtained from compounds of formula (XVI') according to process step b), as previously described in Scheme 1.

[0139] Compounds of formula (I) can be obtained from compounds of formula (III') and (XVI') according to process step (e), as previously described in Scheme 3.

[0140] Compounds of formula (I) can be converted to alternative compounds of formula (I) by standard chemical transformations (e.g., alkylation of heteroatoms (e.g., N) via reductive amination or alkylation in the presence of an organic or inorganic base in a suitable solvent (e.g., MeCN)) using methods well known to those skilled in the art.

[0141] Compounds of formula (II'), (III'), (VI'), (VIII'), (XI'), (XIII'), and (XIV') are commercially available or can be prepared by methods known in the literature or by analogy with the methods described in the experimental section below.

[0142] Those skilled in the art will appreciate that it may be necessary to utilize a suitable protecting group strategy for the preparation of compounds of formula (I). Typical protecting groups may include carbamates, preferably Boc for amine protection.

[0143] Additionally, it will be understood that it may be necessary or desirable to carry out the transformations in a different order than that depicted in the Schemes, or to modify one or more of the transformations, in order to provide the desired compounds of the invention.

[0144] C. Experiment Preparative HPLC conditions In the examples below, the following preparative HPLC method was used. [Table 1-1] [Table 1-2]

[0145] C. Preparation of 1[1,5-a]pyrazine Example 1: 1-(tert-butyl)-N-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)benzyl)-1H-pyrazole-3-carboxamide [ka]

[0146] 1. Synthesis of diethyl 1-(2-(1-methyl-1H-pyrazol-4-yl)-2-oxoethyl)-1H-pyrazole-3,5-dicarboxylate. [ka] Diethyl 1H-pyrazole-3,5-dicarboxylate (69.6 g, 328 mmol) and CsCO (126 g, 388 mmol) were added to a solution of 2-bromo-1-(1-methyl-1H-pyrazol-4-yl)ethan-1-one (60.6 g, 298 mmol) in DMF (900 mL), and the reaction was stirred at room temperature overnight. The reaction mixture was diluted with water and extracted with DCM. The organic layer was dried (NaSO) and concentrated in vacuo. The crude product was suspended in 1:1 heptane:EtOAc (50-100 mL) and filtered. The solid was washed with EtOAc and heptane to give the product (68.5 g) as a white solid. The mother liquor was concentrated and purified by column chromatography (heptane: EtOAc gradient 0 to 100%) to give additional product (9.7 g) to give 78.2 g (78% yield) of diethyl 1-(2-(1-methyl-1H-pyrazol-4-yl)-2-oxoethyl)-1H-pyrazole-3,5-dicarboxylate as a white solid. LCMS m / z = 335.2 [M+H] +

[0147] 2. Synthesis of ethyl 4-hydroxy-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine-2-carboxylate. [ka] A mixture of diethyl 1-(2-(1-methyl-1H-pyrazol-4-yl)-2-oxoethyl)-1H-pyrazole-3,5-dicarboxylate (15.0 g, 44.9 mmol) and NHOAc (10.4 g, 135 mmol) in EtOH (150 mL) was heated at 130° C. for 24 h in a Berghoff reactor. The resulting suspension was filtered, and the solid was washed with water and dried to give ethyl 4-hydroxy-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine-2-carboxylate (11.8 g, 92%) as a white solid. The reaction was carried out batchwise on a total of 78.2 g of starting material to give a total of 66.6 g of product (92% yield). LCMS mz = 288.3 [M+H] +

[0148] 3. Synthesis of 4-hydroxy-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine-2-carboxylic acid. [ka] Ethyl 4-hydroxy-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine-2-carboxylate (66.6 g, 232 mmol) was suspended in MeOH (1.2 L), 1 M NaOH (696 mL, 696 mmol) was added, and the reaction was stirred at room temperature overnight. The mixture was acidified to pH 2 with concentrated HCl and filtered. The solid was washed with MeOH, transferred to a round-bottom flask, and azeotroped with MeCN. The solid was divided into two portions, and the hydrolysis was repeated. Methyl 4-hydroxy-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine-2-carboxylate (46.0 g, 116 mmol) was suspended in MeOH (1.2 L), 1 M NaOH (348 mL, 348 mmol) and water (10 mL) were added, and the reaction was stirred at room temperature overnight. The mixture was neutralized with concentrated HCl, filtered, and the solid was washed with MeCN, dioxane, and dried under vacuum to give 4-hydroxy-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine-2-carboxylic acid (71.0 g, crude), containing many salts. The reaction was then repeated in a second portion to give an additional 60 g of crude product. LCMS m / z = 258.0 [M+H] +

[0149] 4. Synthesis of 6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-ol. [ka] A three-neck flask was charged with preheated sulfolane (0.24 kg, 2.0 mol) and heated to 50 °C. 4-Hydroxy-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine-2-carboxylic acid (41.8 g, 68 mmol) and a few drops of concentrated sulfuric acid were added portionwise, and the reaction mixture was heated at 350 °C (external) for 4 h. The reaction was cooled to room temperature, diluted with DCM, and purified by filtration through a short silica plug (eluting with 3 L heptane (fr1), 6 L heptane:EtOAc 1:1 (fr2-3), 6 L EtOAc (fr4-5), 4 L DCM (fr6), and 6 L DCM:MeOH 9:1 (fr7-8)). The product (including by-products) (2.88 g, 20% yield) was isolated from fr7 as a brown solid. LCMS m / z = 214.1 [M+H] + .

[0150] 5. Synthesis of 4-chloro-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine. [ka] 6-(1-Methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-ol (2.88 g, 13.4 mmol) was suspended in POCl3 (19.9 mL, 214 mmol) and the reaction was heated at 80 °C overnight. The mixture was diluted with MeCN and concentrated. The residue was suspended in DCM. The mixture was washed with saturated NaHCO3 and brine, dried over Na2SO4, and concentrated. The crude product was purified by column chromatography (DCM: EtOAc / TEA (5%); gradient 0 to 25%) to afford 4-chloro-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine (1.35 g, 43% yield) as a yellow solid. LCMS m / z = 234.0 [M+H] + .

[0151] 6. Synthesis of tert-butyl (4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)benzyl)carbamate [ka] A mixture of tert-butyl (4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)carbamate (300 mg, 900 μmol), 4-chloro-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine (210 mg, 900 μmol), K2CO3 (373 mg, 2.70 mmol), and Pd(dppf)Cl2·DCM (74 mg, 90 μmol) was dissolved in dioxane (7.2 mL) and water (1.8 mL), and N2 was bubbled through the mixture for 5 min. The reaction was heated to 100 °C under N2 and stirred at 100 °C for 3 h. The cooled reaction was concentrated and loaded directly onto a silica gel column. The crude material was purified by column chromatography (gradient: 0-75% [3:1 EtOAc / EtOH]:heptane) to afford tert-butyl (4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)benzyl)carbamate as a white solid (264 mg, 73% yield). LCMS m / z = 405.0 [M+H] + .

[0152] 7. Synthesis of (4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)phenyl)methanamine dihydrochloride [ka] To a solution of tert-butyl (4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)benzyl)carbamate (264 mg, 653 μmol) in EtOAc (1 mL) was added 1 M HCl in EtOAc (6.53 mL, 6.53 mmol) and the reaction was stirred at ambient temperature for 3 days. The reaction mixture was concentrated to dryness to provide (4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)phenyl)methanamine dihydrochloride, which was used without further purification (246 mg, crude). LCMS m / z = 305.0 [M+H] +

[0153] 8. Synthesis of 1-(tert-butyl)-N-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)benzyl)-1H-pyrazole-3-carboxamide [ka] To a solution of 1-(tert-butyl)-1H-pyrazole-3-carboxylic acid (21 mg, 123 μmol) in THF (2 mL) in an ice-water cooling bath was added TEA (33 mg, 329 μmol) and HATU (63 mg, 164 μmol). The mixture was stirred at 0° C. for 10 minutes, and then (4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)phenyl)methanamine dihydrochloride (25 mg, 82 μmol) was added. The reaction mixture was warmed to 23° C. and stirred for 24 hours. The reaction was quenched with HCl (5 mL) and then extracted with EtOAc (3×5 mL). The organic phases were combined, washed with brine, dried (NaSO), filtered, and concentrated. The crude material was purified by reverse-phase HPLC (Method A, 5-60% gradient) to give 1-(tert-butyl)-N-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)benzyl)-1H-pyrazole-3-carboxamide as a beige solid (14.6 mg, 39% yield). LCMS m / z = 455.1 [M+H] + . 1 H NMR (500 MHz, DMSO-d6) δ: 9.12 (s, 1H), 8.66 (t, J = 6.4 Hz, 1H), 8.33 (s, 1H), 8.18 (d, J = 2.4 Hz, 1H), 8.15 - 8.08 (m, 3H), 7.92 (d, J = 2.4 Hz, 1H), 7.54 (d, J = 8.5 Hz, 2H), 7.22 - 7.13 (m, 1H), 6.66 (d, J = 2.4 Hz, 1H), 4.55 (d, J = 6.7 Hz, 2H), 3.95 - 3.83 (m, 3H), 1.57 (s, 9H).

[0154] Example 2: Synthesis of 1-(tert-butyl)-N-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)benzyl)-1H-pyrazole-4-carboxamide [ka] 1-(tert-butyl)-N-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)benzyl)-1H-pyrazole-4-carboxamide as a beige solid (15.7 mg, 42% yield) was obtained from (4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)phenyl)methanamine dihydrochloride (Step 7 of Example 1) and 1-(tert-butyl)-1H-pyrazole-4-carboxylic acid according to a method similar to that described in Step 8 of Example 1. The crude material was purified by reverse-phase HPLC (Method A, 5-55% gradient). LCMS m / z = 455.1 [M+H] + 1 H NMR (500 MHz, DMSO-d6) δ: 9.13 (s, 1H), 8.67 (t, J = 5.8 Hz, 1H), 8.34 - 8.32 (m, 2H), 8.18 (d, J = 2.4 Hz, 1H), 8.13 - 8.10 (m, 3H), 7.92 (s, 1H), 7.52 (d, J = 8.5 Hz, 2H), 7.15 (d, J = 1.8 Hz, 1H), 4.54 (d, J = 6.1 Hz, 2H), 3.90 (s, 3H), 1.53 (s, 9H).

[0155] Example 3: Synthesis of 2-(tert-butyl)-N-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)benzyl)-2H-tetrazole-5-carboxamide [ka] 2-(tert-butyl)-N-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)benzyl)-2H-tetrazole-5-carboxamide was obtained as a beige solid (17.7 mg, 47% yield) from (4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)phenyl)methanamine dihydrochloride (Step 7 of Example 1) and 2-(tert-butyl)-2H-tetrazole-5-carboxylic acid according to a similar method to Step 8 of Example 1. The crude material was purified by reverse-phase HPLC (Method A, 5-55% gradient). LCMS m / z = 457.1 [M+H] + 1 H NMR (500 MHz, DMSO-d6) δ: 9.67 (t, J = 6.1 Hz, 1H), 9.13 (s, 1H), 8.33 (s, 1H), 8.18 (d, J = 2.5 Hz, 1H), 8.14 - 8.10 (m, 3H), 7.56 (d, J = 7.9 Hz, 2H), 7.16 (d, J = 2.6 Hz, 1H), 4.60 (d, J = 6.1 Hz, 2H), 3.90 (s, 3H), 1.74 (s, 9H).

[0156] Example 4: Synthesis of 1-(tert-butyl)-N-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)benzyl)-1H-1,2,3-triazole-4-carboxamide [ka] 1-(tert-butyl)-N-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)benzyl)-1H-1,2,3-triazole-4-carboxamide was obtained as a beige solid (18.2 mg, 49% yield) from (4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)phenyl)methanamine dihydrochloride (Step 7 of Example 1) and 1-(tert-butyl)-1H-1,2,3-triazole-4-carboxylic acid according to a procedure similar to Step 8 of Example 1. The crude material was purified by reverse-phase HPLC (Method A, 5-55% gradient). LCMS m / z = 456.1 [M+H] + . 1 H NMR (500 MHz, DMSO-d6) δ: 9.18 (t, J = 6.0 Hz, 1H), 9.12 (s, 1H), 8.71 (s, 1H), 8.33 (s, 1H), 8.19 - 8.18 (m, 1H), 8.12 - 8.09 (m, 3H), 7.54 (d, J = 8.5 Hz, 2H), 7.15 (d, J = 2.7 Hz, 1H), 4.57 (d, J = 6.1 Hz, 2H), 3.90 (s, 3H), 1.64 (s, 9H).

[0157] Example 5: Synthesis of N-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)benzyl)-5-(1-methylcyclopropyl)-1,2,4-oxadiazole-3-carboxamide [ka] N-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)benzyl)-5-(1-methylcyclopropyl)-1,2,4-oxadiazole-3-carboxamide was obtained as a yellow solid (13.2 mg, 35% yield) from (4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)phenyl)methanamine dihydrochloride (Step 7 of Example 1) and potassium 5-(1-methylcyclopropyl)-1,2,4-oxadiazole-3-carboxylate according to the procedure in Step 8 of Example 1. The crude material was purified by reverse-phase HPLC (Method A, 5-60% gradient). LCMS m / z = 455.0 [M+H] + . 1 H NMR (500 MHz, DMSO-d6) δ: 9.54 (t, J = 6.1 Hz, 1H), 9.13 (s, 1H), 8.34 (s, 1H), 8.19 (d, J = 2.7 Hz, 1H), 8.13 - 8.11 (m, 3H), 7.54 (d, J = 8.5 Hz, 2H), 7.16 (d, J = 1.8 Hz, 1H), 4.56 (d, J = 6.1 Hz, 2H), 3.90 (s, 3H), 1.54 (s, 3H), 1.41 - 1.37 (m, 2H), 1.18 - 1.16 (m, 2H).

[0158] Example 6. 5-(tert-butyl)-N-(2-fluoro-4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)benzyl)-1,3,4-oxadiazole-2-carboxamide [ka] 1. Preparation of tert-butyl (2-fluoro-4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)benzyl)carbamate [ka] To a mixture of tert-butyl (2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)carbamate (200 mg, 569.4 μmol), 4-chloro-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine (Step 5 of Example 1, 133.06 mg, 569.4 μmol), KCO (236.11 mg, 1.71 mmol), and Pd(dppf)Cl (20.83 mg, 28.5 μmol) in dioxane (4.56 mL) and water (1.14 mL) was bubbled with N for 5 minutes. The reaction was heated to 100 °C under a N atmosphere and stirred at 100 °C overnight. The cooled reaction was concentrated and purified by silica gel column chromatography (gradient elution 0-100% EtOAc:heptane) to afford tert-butyl (2-fluoro-4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)benzyl)carbamate (218 mg, 90.6% yield) as a pale yellow solid. LCMS m / z = 432.2 [M+H] + .

[0159] 2. Preparation of (2-fluoro-4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)phenyl)methanamine dihydrochloride [ka] tert-Butyl (2-fluoro-4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)benzyl)carbamate (218 mg, 516.0 μmol) was dissolved in MeOH (5.16 mL), HCl solution (1.25 M in MeOH, 4.13 mL, 5.17 mmol) was added, and the reaction was stirred at 50° C. overnight. The reaction was concentrated to dryness in vacuo to give (2-fluoro-4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)phenyl)methanamine dihydrochloride (208 mg, crude) as a yellow solid. LCMS m / z = 323.1 [M+H] + .

[0160] Preparation of 3.5-(tert-butyl)-N-(2-fluoro-4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)benzyl)-1,3,4-oxadiazole-2-carboxamide [ka] A stock solution of (2-fluoro-4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)phenyl)methanamine dihydrochloride (320 mg), DCM (8 mL), and DIPEA (1.5 mL) was prepared. This stock solution (1.2 mL) was added to a vial containing potassium 5-tert-butyl-1,3,4-oxadiazole-2-carboxylate (25 mg, 121.4 μmol), which was then cooled to 0° C. HATU (52 mg) was added, and the reaction was stirred at room temperature overnight. The reaction mixture was diluted with DCM (2 mL) and water (2 mL), the vial was shaken, and the layers were separated. The aqueous layer was extracted with DCM (2 mL), and the combined organic extracts were evaporated. The residue was purified by preparative HPLC (Method B1, 5-60% gradient) to give 5-(tert-butyl)-N-(2-fluoro-4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)benzyl)-1,3,4-oxadiazole-2-carboxamide. LCMS m / z = 475.1 [M+H] + . 1 H NMR (DMSO-d6) δ: 9.91 (t, J=6.1 Hz, 1H), 9.18 (d, J=1.2 Hz, 1H), 8.37 (s, 1H), 8.21 (d, J=2.4 Hz, 1H), 8.13 (s, 1H), 7.98 (s, 1H), 7.88-7.97 (m, 1H), 7.62 (s, 1H), 7.21 (d, J=2.4 Hz, 1H), 4.62 (d, J=6.1 Hz, 2H), 3.91 (s, 3H), 1.40 (s, 9H).

[0161] Example 7. 2-(tert-butyl)-N-(2-fluoro-4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)benzyl)-2H-tetrazole-5-carboxamide [ka] 2-(tert-butyl)-N-(2-fluoro-4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)benzyl)-2H-tetrazole-5-carboxamide was obtained from 2-tert-butyltetrazole-5-carboxylic acid and (2-fluoro-4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)phenyl)methanamine dihydrochloride (Step 2 of Example 6) according to a procedure similar to that described in Step 3 of Example 6. The crude product was purified by preparative HPLC (Method B1, 5-60% gradient). LCMS m / z = 475.1 [M+H] + 1 H NMR (DMSO-d6) δ: 9.66 (t, J=6.1 Hz, 1H), 9.18 (d, J=1.2 Hz, 1H), 8.37 (s, 1H), 8.25-8.20 (m, 1H), 8.13 (s, 1H), 7.99 (dd, J=7.9, 1.8 Hz, 1H), 7.94 (dd, J=11.0, 1.8 Hz, 1H), 7.64-7.55 (m, 1H), 7.25-7.19 (m, 1H), 4.65 (d, J=6.1 Hz, 2H), 3.91 (s, 3H), 1.74 (s, 9H).

[0162] Example 8. N-(2-fluoro-4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)benzyl)-5-(1-methylcyclopropyl)-1,2,4-oxadiazole-3-carboxamide [ka] N-(2-fluoro-4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)benzyl)-5-(1-methylcyclopropyl)-1,2,4-oxadiazole-3-carboxamide was prepared from (2-fluoro-4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)phenyl)methanamine dihydrochloride (Step 2 of Example 6) and potassium 5-(1-methylcyclopropyl)-1,2,4-oxadiazole-3-carboxylate using a method similar to that used in Step 3 of Example 6. The crude material was purified by preparative HPLC (Method B1, gradient 5-60%). LCMS m / z = 473.0 [M+H] + . 1 H NMR (DMSO-d6) δ: 9.54 (t, J=5.8 Hz, 1H), 9.18 (s, 1H), 8.37 (s, 1H), 8.21 (d, J=2.4 Hz, 1H), 8.13 (s, 1H), 8.00 (dd, J=7.9, 1.8 Hz, 1H), 7.94 (dd, J=11.0, 1.2 Hz, 1H), 7.57 (t, J=7.9 Hz, 1H), 7.22 (d, J=2.4 Hz, 1H), 4.60 (d, J=6.1 Hz, 2H), 3.91 (s, 3H), 1.55 (s, 3H), 1.44-1.32 (m, 2H), 1.25-1.08 (m, 2H).

[0163] Examples 9 to 13 The compounds in the following table were prepared from (2-fluoro-4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)phenyl)methanamine dihydrochloride (Step 2 of Example 6) and the appropriate carboxylic acid following a procedure similar to that described in Step 3 of Example 6. [Table 2-1] [Table 2-2] [Table 2-3] [Table 2-4] [Table 2-5]

[0164] Example 14. 5-(tert-butyl)-N-(2-methyl-4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)benzyl)-1,3,4-oxadiazole-2-carboxamide [ka]

[0165] 1. Preparation of tert-butyl (2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)carbamate [ka] To a solution of tert-butyl (4-bromo-2-methylbenzyl)carbamate (80 g, 266.50 mmol) and (BPin) (81.21 g, 319.80 mmol) in dioxane (1 L) was added KOAc (78.46 g, 799.5 mmol) and Pd(dppf)Cl (9.75 g, 13.32 mmol), and the mixture was stirred at 90 °C for 16 h under a N atmosphere. The reaction mixture was diluted with HO (600 mL) and extracted with EtOAc (3 × 500 mL). The combined organic layers were dried over NaSO and filtered. The filtrate was concentrated in vacuo, and the residue was purified on silica gel by column chromatography (PE / EtOAc = 20 / 1) to give tert-butyl (2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)carbamate (85 g, 91.9% yield) as a yellow solid. H NMR (400 MHz, CDCl) δ: 7.69-7.58 (m, 2H), 7.30-7.26 (m, 1H), 4.72 (br s, 1H), 4.36 (d, J = 4.8 Hz, 2H), 2.35 (s, 3H), 1.48 (m, 9H), 1.38 (s, 12H).

[0166] 2. Preparation of tert-butyl (2-methyl-4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)benzyl)carbamate [ka] 4-Chloro-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine (Step 5 of Example 1, 500 mg, 2.14 mmol), tert-butyl (2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)carbamate (900 mg, 2.59 mmol), KCO (700 mg, 5.06 mmol), and Pd(dppf)Cl (30 mg, 41.0 μmol) were degassed under N, then dioxane (10 mL) and water (2 mL) were added, and the reaction was stirred in a sealed vessel at 90° C. for 20 minutes. The reaction was removed from the heat, cooled to room temperature, and then diluted with water (10 mL) and EtOAc (10 mL). The phases were separated, the aqueous layer was extracted with EtOAc (2 x 10 mL), and the organic layers were combined and evaporated to dryness. The crude material was purified on silica gel (50% to 100% EtOAc in heptane) to give tert-butyl (2-methyl-4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)benzyl)carbamate as a pale yellow solid (830 mg, 92.7% yield). LCMS m / z = 419.3 [M+H] +

[0167] 3. Preparation of 2-(tert-butyl)-N-(2-methyl-4-(5-(piperazin-1-yl)pyrimidin-4-yl)benzyl)-2H-tetrazole-5-carboxamide dihydrochloride [ka] A solution of tert-butyl (2-methyl-4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)benzyl)carbamate (830 mg, 1.98 mmol) in 1.25 M methanolic HCl (16 mL) was stirred at room temperature for 16 hours. The mixture was heated at vigorous reflux for 1 hour and then concentrated in vacuo to give 2-(tert-butyl)-N-(2-methyl-4-(5-(piperazin-1-yl)pyrimidin-4-yl)benzyl)-2H-tetrazole-5-carboxamide dihydrochloride as a pale yellow solid. LCMS m / z = 319.2 [M+H] +

[0168] 4. Preparation of 5-(tert-butyl)-N-(2-methyl-4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)benzyl)-1,3,4-oxadiazole-2-carboxamide [ka] Substrate stock solution: To an 8 mL vial was added 2-(tert-butyl)-N-(2-methyl-4-(5-(piperazin-1-yl)pyrimidin-4-yl)benzyl)-2H-tetrazole-5-carboxamide dihydrochloride (175 mg) and DIPEA (250 μL) in DMF (2.5 mL), and the mixture was stirred for 10 min.

[0169] To a vial containing potassium 5-tert-butyl-1,3,4-oxadiazole-2-carboxylate (20 mg, 96.03 μmol), 600 μL of the substrate stock solution was added, followed by T3P® (125.0 mg, 196.43 μmol, 50% purity), and the reaction was stirred at room temperature for 2 hours. The reaction was quenched by the addition of saturated NaHCO3 (3 mL) and extracted with EtOAc (3 mL). The resulting aqueous slurry was further extracted with EtOAc (3 × 3 mL), and the combined organic layers were concentrated to dryness. The residue was diluted with DMSO (2 mL) and passed through a 0.2 μm syringe filter. The product was isolated by preparative HPLC (Method B1, 5-60% gradient). LCMS m / z = 471.2 [M+H] + 1 H NMR (500 MHz, DMSO-d6) δ ppm 9.85 (t, J=6.10 Hz, 1 H) 9.13 (s, 1 H) 8.34 (s, 1 H) 8.19 (d, J=2.44 Hz, 1 H) 8.12 (s, 1 H) 7.95 (s, 2 H) 7.50 (s, 1 H) 7.15 (d, J=2.44 Hz, 1 H) 4.56 (d, J=6.10 Hz, 2 H) 3.92 (s, 3 H) 2.49 (s, 3 H) 1.41 (s, 9 H).

[0170] Example 15. 2-(tert-butyl)-N-(2-methyl-4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)benzyl)-2H-tetrazole-5-carboxamide [ka] 2-(tert-butyl)-N-(2-methyl-4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)benzyl)-2H-tetrazole-5-carboxamide was prepared from 2-tert-butyl-2H-1,2,3,4-tetrazole-5-carboxylic acid and 2-(tert-butyl)-N-(2-methyl-4-(5-(piperazin-1-yl)pyrimidin-4-yl)benzyl)-2H-tetrazole-5-carboxamide dihydrochloride (Step 3 of Example 14) according to the method used in Step 4 of Example 14. LCMS m / z = 471.3 [M+H] + . 1 H NMR (500 MHz, DMSO-d6) δ ppm 9.58 (s, 1 H) 9.13 (s, 1 H) 8.34 (s, 1 H) 8.19 (d, J=2.44 Hz, 1 H) 8.12 (s, 1 H) 7.95 (s, 2 H) 7.51-7.43 (m, 1 H) 7.18 - 7.12 (m, 1 H) 4.59 (d, J=6.10 Hz, 2 H) 3.91 (s, 3 H) 2.50-2.48 (s, 3 H) 1.75 (s, 9 H).

[0171] Example 16. 1-(tert-butyl)-N-(2-methyl-4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)benzyl)-1H-1,2,3-triazole-4-carboxamide [ka] 1-(tert-butyl)-N-(2-methyl-4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)benzyl)-1H-1,2,3-triazole-4-carboxamide was prepared from 1-tert-butyltriazole-4-carboxylic acid and 2-(tert-butyl)-N-(2-methyl-4-(5-(piperazin-1-yl)pyrimidin-4-yl)benzyl)-2H-tetrazole-5-carboxamide dihydrochloride (Step 3 of Example 14) according to the method used in Step 4 of Example 14. LCMS m / z = 470.2 [M+H] + . 1 H NMR (500 MHz, DMSO-d6) δ ppm 9.12 (s, 1 H) 9.07 (s, 1 H) 8.73 (s, 1 H) 8.34 (s, 1 H) 8.18 (d, J=2.44 Hz, 1 H) 8.12 (s, 1 H) 7.94 (s, 2 H) 7.50 - 7.40 (m, 1 H) 7.16 (d, J=2.44 Hz, 1 H) 4.55 (d, J=6.10 Hz, 2 H) 3.91 (s, 3 H) 2.49 - 2.47 (m, 3 H) 1.65 (s, 9 H).

[0172] Example 17. 1-(tert-butyl)-N-(2-methyl-4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)benzyl)-1H-pyrazole-4-carboxamide [ka] 1-(tert-butyl)-N-(2-methyl-4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)benzyl)-1H-pyrazole-4-carboxamide was prepared from 1-tert-butylpyrazole-4-carboxylic acid and 2-(tert-butyl)-N-(2-methyl-4-(5-(piperazin-1-yl)pyrimidin-4-yl)benzyl)-2H-tetrazole-5-carboxamide dihydrochloride (Step 3 of Example 14) according to the method used in Step 4 of Example 14. LCMS m / z = 469.3 [M+H] + . 1 H NMR (500 MHz, DMSO-d6) δ ppm 9.13 (d, J=1.22 Hz, 1 H) 8.58 - 8.47 (m, 2 H) 8.35 (d, J=5.49 Hz, 2 H) 8.19 (d, J=2.44 Hz, 1 H) 8.12 (s, 1 H) 7.94 (s, 4 H) 7.45 (d, J=8.55 Hz, 1 H) 7.15 (d, J=2.44 Hz, 1 H) 4.51 (d, J=5.49 Hz, 2 H) 3.92 (s, 3 H) 2.47 (s, 3 H) 1.59-1.48 (m, 9 H).

[0173] Example 18. 1-(tert-butyl)-N-(2-methyl-4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)benzyl)-1H-pyrazole-3-carboxamide [ka] 1-(tert-butyl)-N-(2-methyl-4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)benzyl)-1H-pyrazole-3-carboxamide was prepared from 1-tert-butylpyrazole-3-carboxylic acid and 2-(tert-butyl)-N-(2-methyl-4-(5-(piperazin-1-yl)pyrimidin-4-yl)benzyl)-2H-tetrazole-5-carboxamide dihydrochloride (Step 3 of Example 14) according to the method used in Step 4 of Example 14. LCMS m / z = 469.3 [M+H] + . 1 H NMR (500 MHz, DMSO-d6) δ ppm 9.12 (d, J=1.22 Hz, 1 H) 8.54 (t, J=6.10 Hz, 1 H) 8.34 (s, 1 H) 8.18 (d, J=2.44 Hz, 1 H) 8.12 (s, 1 H) 8.01-7.86 (m, 2 H) 7.49 - 7.40 (m, 1 H) 7.16 (s, 1 H) 6.72 - 6.62 (m, 1 H) 4.53 (d, J=6.10 Hz, 2 H) 3.91 (s, 3 H) 2.48 (s, 3 H) 1.58 (s, 9 H).

[0174] Example 19: Synthesis of 3-(tert-butyl)-N-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)benzyl)-1,2,4-oxadiazole-5-carboxamide [ka] To a solution of (4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)phenyl)methanamine dihydrochloride (Step 7 of Example 1, 30 mg, 99 μmol) and ethyl 3-(tert-butyl)-1,2,4-oxadiazole-5-carboxylate (29 mg, 148 μmol) in THF (1.5 mL) was added DABAL-Me3 (38 mg, 148 μmol), and the reaction was heated to 45 °C and stirred at that temperature for 18 h. The reaction mixture was cooled to ambient temperature and diluted with water (1 mL), 1 M HCl solution (1 mL), and EtOAc (5 mL). The layers were separated, and the aqueous phase was extracted with a further portion of EtOAc. The combined organic phase was washed with brine, dried (Na2SO4), filtered, and concentrated. The crude material was purified by reverse-phase HPLC (Method A, 5-65% gradient) to give 3-(tert-butyl)-N-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)benzyl)-1,2,4-oxadiazole-5-carboxamide as a beige solid (4.7 mg, 10% yield). LCMS m / z = 457.0 [M+H] + . 1 H NMR (500 MHz, DMSO-d6) δ: 9.98 (t, J = 6.2 Hz, 1H), 9.13 (s, 1H), 8.34 (s, 1H), 8.19 (d, J = 2.4 Hz, 1H), 8.14 - 8.11 (m, 3H), 7.57 (d, J = 7.9 Hz, 2H), 7.16 (s, 1H), 4.58 (d, J = 6.1 Hz, 2H), 3.90 (s, 3H), 1.37 (s, 9H).

[0175] Example 20: Synthesis of 5-(1-(fluoromethyl)cyclopropyl)-N-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)benzyl)-1,2,4-oxadiazole-3-carboxamide [ka] 5-(1-(fluoromethyl)cyclopropyl)-N-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)benzyl)-1,2,4-oxadiazole-3-carboxamide (29.6 mg, 47% yield) was obtained from (4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)phenyl)methanamine dihydrochloride (Step 7 of Example 1) and ethyl 5-(1-(fluoromethyl)cyclopropyl)-1,2,4-oxadiazole-3-carboxylate according to a method similar to that described in Example 19. The crude material was purified by reverse-phase HPLC (Method C, 5-55% gradient). LCMS m / z = 473.1 [M+H] + 1 H NMR (500 MHz, DMSO-d6) δ: 9.60 (t, J = 6.4 Hz, 1H), 9.13 (s, 1H), 8.34 (s, 1H), 8.19 (d, J = 2.4 Hz, 1H), 8.16 - 8.08 (m, 3H), 7.54 (d, J = 7.9 Hz, 2H), 7.20 - 7.13 (m, 1H), 4.83 (s, 1H), 4.73 (s, 1H), 4.57 (d, J = 6.1 Hz, 2H), 3.90 (s, 3H), 1.60 - 1.52 (m, 2H), 1.51 - 1.44 (m, 2H).

[0176] Example 21: Synthesis of 2-(tert-butyl)-N-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)benzyl)-2H-1,2,3-triazole-4-carboxamide [ka] 2-(tert-butyl)-N-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)benzyl)-2H-1,2,3-triazole-4-carboxamide (23.8 mg, 39% yield) was obtained from (4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)phenyl)methanamine dihydrochloride (Step 7 of Example 1) and ethyl 2-(tert-butyl)-2H-1,2,3-triazole-4-carboxylate (Journal of Medicinal Chemistry (2018), 61(8), 3370-3388) according to a method similar to that described in Example 19. The crude material was purified by reverse-phase HPLC (Method C, 5-60% gradient). LCMS m / z = 456.2 [M+H] + . 1 H NMR (500 MHz, DMSO-d6) δ: 9.13 (s, 1H), 9.05 (t, J = 6.1 Hz, 1H), 8.33 (s, 1H), 8.18 (d, J = 2.4 Hz, 1H), 8.16 (s, 1H), 8.14 - 8.10 (m, 3H), 7.55 (d, J = 7.9 Hz, 2H), 7.19 - 7.14 (m, 1H), 4.57 (d, J = 6.1 Hz, 2H), 3.90 (s, 3H), 1.69 - 1.62 (m, 9H).

[0177] Example 22: 5-(1-fluoro-2-methylpropan-2-yl)-N-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)benzyl)-1,2,4-oxadiazole-3-carboxamide [ka]

[0178] 1. Synthesis of ethyl (E)-2-amino-2-(hydroxyimino)acetate [ka] To a solution of ethyl carbonocyanidate (10 g, 101 mmol) in EtOH (75 mL) and HO (25 mL) was added NaCO (10.7 g, 101 mmol) and hydroxylamine hydrochloride (7.0 g, 101 mmol), and the reaction mixture was stirred at 25 °C for 12 h. The mixture was poured into EtOAc (100 mL), filtered, and the filtrate was concentrated in vacuo. The residue was redissolved in EtOAc (100 mL), filtered, and the filtrate was concentrated in vacuo to give ethyl (E)-2-amino-2-(hydroxyimino)acetate as a yellow solid (10 g, crude), which was carried forward without further purification. 1 H NMR (400 MHz, CDCl3) δ: 4.37-4.32 (m, 2H), 1.38-1.30 (m, 3H).

[0179] 2. Synthesis of ethyl (E)-2-(3-hydroxy-2,2-dimethylpropanamido)-2-(hydroxyimino)acetate [ka] A mixture of ethyl (E)-2-amino-2-(hydroxyimino)acetate (500 mg, 3.8 mmol), 3-hydroxy-2,2-dimethylpropanoic acid (447 mg, 3.8 mmol), HATU (2.9 g, 7.6 mmol), and DIPEA (977 mg, 7.6 mmol) in DCM (10 mL) was stirred at 25 °C for 1 h. An additional amount of DCM (30 mL) was added, and the organic phase was washed with HO (10 mL × 3). The organic phase was dried (NaSO), filtered, and concentrated in vacuo. The crude product was purified by silica gel column chromatography (PE / EtOAc, 5:1 to 0:1) to give ethyl (E)-2-(3-hydroxy-2,2-dimethylpropanamido)-2-(hydroxyimino)acetate as a white solid (500 mg, 57% yield). LCMS m / z = 233.1 [M+H] + .

[0180] 3. Synthesis of ethyl 5-(1-hydroxy-2-methylpropan-2-yl)-1,2,4-oxadiazole-3-carboxylate [ka] A solution of ethyl (E)-2-(3-hydroxy-2,2-dimethylpropanamido)-2-(hydroxyimino)acetate (500 mg, 2.2 mmol) in pyridine (10 mL) was heated to 80° C. and stirred at that temperature for 12 hours. The reaction mixture was concentrated in vacuo, and the residue was purified by silica gel column chromatography (PE / EtOAc, 10:1 to 1:1) to give ethyl 5-(1-hydroxy-2-methylpropan-2-yl)-1,2,4-oxadiazole-3-carboxylate as a colorless oil (250 mg, 54% yield). LCMS m / z = 215.1 [M+H] + .

[0181] 4. Synthesis of ethyl 5-(2-methyl-1-(((trifluoromethyl)sulfonyl)oxy)propan-2-yl)-1,2,4-oxadiazole-3-carboxylate [ka] To a solution of ethyl 5-(1-hydroxy-2-methylpropan-2-yl)-1,2,4-oxadiazole-3-carboxylate (430 mg, 2.0 mmol) and DIPEA (390 mg, 3.0 mmol) in DCM (10 mL) at 0 °C, TfO (566 mg, 2.0 equiv.) was added, and the reaction mixture was stirred at 25 °C for 2 h. An additional amount of DCM (40 mL) was added, and the organic phase was washed with HO (20 mL × 3). The organic phase was dried (NaSO), filtered, and concentrated in vacuo. The crude product was purified by silica gel column chromatography (PE / EtOAc, 10:1 to 1:1) to give ethyl 5-(2-methyl-1-(((trifluoromethyl)sulfonyl)oxy)propan-2-yl)-1,2,4-oxadiazole-3-carboxylate as a colorless oil (600 mg, 86% yield). LCMS m / z = 347.1 [M+H] + .

[0182] 5. Synthesis of ethyl 5-(1-fluoro-2-methylpropan-2-yl)-1,2,4-oxadiazole-3-carboxylate [ka] A solution of ethyl 5-(2-methyl-1-(((trifluoromethyl)sulfonyl)oxy)propan-2-yl)-1,2,4-oxadiazole-3-carboxylate (600 mg, 1.7 mmol) and tetrabutylammonium bifluoride (536 mg, 1.9 mmol) in THF (30 mL) was heated to 40° C. and stirred at that temperature for 12 hours. The reaction mixture was cooled to ambient temperature and concentrated in vacuo. The crude product was purified by silica gel column chromatography (PE / EtOAc, 10:1 to 3:1) to give ethyl 5-(1-fluoro-2-methylpropan-2-yl)-1,2,4-oxadiazole-3-carboxylate as a colorless oil (330 mg, 88% yield). LCMS m / z = 217.1 [M+H] + .

[0183] 6. Synthesis of 5-(1-fluoro-2-methylpropan-2-yl)-N-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)benzyl)-1,2,4-oxadiazole-3-carboxamide [ka] 5-(1-Fluoro-2-methylpropan-2-yl)-N-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)benzyl)-1,2,4-oxadiazole-3-carboxamide (37.6 mg, 60% yield) was obtained from ethyl 5-(1-fluoro-2-methylpropan-2-yl)-1,2,4-oxadiazole-3-carboxylate and (4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)phenyl)methanamine dihydrochloride (Step 7 of Example 1) according to a method similar to that of Example 19. The crude material was purified by reverse-phase HPLC (Method C, gradient 5-55%). LCMS m / z = 475.2 [M+H] + . 1 H NMR (500 MHz, DMSO-d6) δ = 9.65 (t, J = 6.1 Hz, 1H), 9.13 (d, J = 1.2 Hz, 1H), 8.34 (s, 1H), 8.19 (d, J = 2.4 Hz, 1H), 8.16 - 8.08 (m, 3H), 7.55 (d, J = 8.5 Hz, 2H), 7.19 - 7.13 (m, 1H), 4.68 (s, 1H), 4.63 - 4.53 (m, 4H), 3.90 (s, 3H), 1.45 (d, J = 1.2 Hz, 9H)

[0184] Example 23. 5-(tert-butyl)-N-(4-(6-morpholinopyrazolo[1,5-a]pyrazin-4-yl)benzyl)-1,2,4-oxadiazole-3-carboxamide [ka]

[0185] 1. Preparation of tert-butyl (4-(6-chloropyrazolo[1,5-a]pyrazin-4-yl)benzyl)carbamate [ka] A mixture of tert-butyl (4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)carbamate (350 mg, 1.05 mmol), 4,6-dichloropyrazolo[1,5-a]pyrazine (200 mg, 1.06 mmol), KPO (2.0 M, 824.4 μL), and dioxane (5.0 mL) was stirred at room temperature and degassed by bubbling N for 10 minutes. Pd(t-BuP) (15 mg, 29.35 μmol) was added, the vial was sealed, and the reaction was stirred at 40 °C for 72 hours. The reaction was diluted with water (10 mL) and extracted with EtOAc (3 × 10 mL). The combined organic layers were concentrated to dryness and purified by silica gel column chromatography (heptane to EtOAc) to give tert-butyl (4-(6-chloropyrazolo[1,5-a]pyrazin-4-yl)benzyl)carbamate as a pale yellow solid (290 mg, 76.3% yield). LCMS m / z = 359.1 [M+H] + .

[0186] 2. Preparation of tert-butyl (4-(6-morpholinopyrazolo[1,5-a]pyrazin-4-yl)benzyl)carbamate [ka] To a vial containing tert-butyl (4-(6-chloropyrazolo[1,5-a]pyrazin-4-yl)benzyl)carbamate (160 mg, 445.9 μmol) were added Pd(dba) (20 mg, 21.8 μmol), CsCO (450 mg, 1.38 mmol), and RuPhos (20 mg, 42.9 μmol), and the vial was sealed and degassed under N. Dioxane (5.04 mL) and morpholine (65 mg, 746.1 μmol) were added and stirred at 100 °C for 4 h. The cooled reaction was diluted with water (10 mL) and extracted with EtOAc (3 × 10 mL), and the combined organic layers were concentrated to dryness to give a light orange solid. This was purified by silica gel chromatography (heptane to EtOAc) to give tert-butyl (4-(6-morpholinopyrazolo[1,5-a]pyrazin-4-yl)benzyl)carbamate as a pale yellow solid (150 mg, 82.2% yield). LCMS m / z = 410.2 [M+H] +

[0187] 3. Preparation of (4-(6-morpholinopyrazolo[1,5-a]pyrazin-4-yl)phenyl)methanamine dihydrochloride [ka] A solution of tert-butyl (4-(6-morpholinopyrazolo[1,5-a]pyrazin-4-yl)benzyl)carbamate (150 mg, 366.3 μmol) and 4 M HCl (500 μL) in dioxane (5.00 mL) was stirred at 50° C. for 16 hours. The reaction mixture was concentrated in vacuo and azeotroped with MeOH to give (4-(6-morpholinopyrazolo[1,5-a]pyrazin-4-yl)phenyl)methanamine dihydrochloride as a brown solid (148 mg, crude). LCMS m / z = 310.1 [M+H] +

[0188] 4. Preparation of 5-(tert-butyl)-N-(4-(6-morpholinopyrazolo[1,5-a]pyrazin-4-yl)benzyl)-1,2,4-oxadiazole-3-carboxamide [ka] To a vial was added (4-(6-morpholinopyrazolo[1,5-a]pyrazin-4-yl)phenyl)methanamine hydrochloride (20 mg, 57.8 μmol), DABAL-Me3 (15 mg, 58.5 μmol), and ethyl 5-tert-butyl-1,2,4-oxadiazole-3-carboxylate (20 mg, 100.9 μmol) in dioxane (500 μL), the vial was sealed, and the mixture was stirred at 120 °C for 10 min. Celite® (250 mg) was added to the cooled mixture, followed by water (0.5 mL) and EtOH (2 mL), and the mixture was stirred for 15 min. The slurry was centrifuged, and the mother liquor was decanted. The remaining solid was extracted with EtOH (2 × 5 mL), and the centrifugation and collection of the mother liquor were repeated. The combined mother liquor was concentrated to dryness to give a bright yellow solid. This was purified by preparative HPLC (Method C2, 5-60% gradient) to give 5-(tert-butyl)-N-(4-(6-morpholinopyrazolo[1,5-a]pyrazin-4-yl)benzyl)-1,2,4-oxadiazole-3-carboxamide. LCMS m / z = 462.2 [M+H] + 1 H NMR (500 MHz, DMSO-d6) δ ppm 9.59 (br t, J=6.10 Hz, 1 H) 8.16 (s, 1 H) 8.11-7.98 (m, 2 H) 7.53 (d, J=8.55 Hz, 1 H) 7.12 - 7.02 (m, 1 H) 4.65 - 4.45 (m, 2 H) 3.87-3.70 (m, 3 H) 1.44 (s, 9 H).

[0189] Example 24: 3-(tert-butyl)-N-(4-(6-morpholinopyrazolo[1,5-a]pyrazin-4-yl)benzyl)-1,2,4-oxadiazole-5-carboxamide [ka] 3-(tert-butyl)-N-(4-(6-morpholinopyrazolo[1,5-a]pyrazin-4-yl)benzyl)-1,2,4-oxadiazole-5-carboxamide was prepared from 5-tert-butyl-1,2,4-oxadiazole-2-carboxylate and (4-(6-morpholinopyrazolo[1,5-a]pyrazin-4-yl)phenyl)methanamine hydrochloride (Step 3 of Example 23) according to the method used in Step 4 of Example 23. LCMS m / z = 462.2 [M+H] + . 1 H NMR (DMSO-d6) δ: 10.04-9.92 (m, 1H), 8.16 (s, 1 H), 8.11-8.04 (m, 2 H), 8.03 (d, J=2.4 Hz, 1H), 7.53 (d, J=8.55 Hz, 2 H), 7.12 - 7.02 (m, 1 H), 4.65 - 4.45 (m, 2 H), 3.87-3.70 (m, 4 H), 1.44 (s, 9 H).

[0190] Example 25. 2-(tert-butyl)-N-(4-(6-morpholinopyrazolo[1,5-a]pyrazin-4-yl)benzyl)-2H-tetrazole-5-carboxamide [ka] Substrate stock solution: To a vial containing (4-(6-morpholinopyrazolo[1,5-a]pyrazin-4-yl)phenyl)methanamine dihydrochloride (Step 3 of Example 23, 105 mg, 0.339 mmol) was added DMF (5 mL) followed by DIPEA (130 mg) and the mixture was stirred.

[0191] T3P® (50% purity) was added to a mixture of 2-(tert-butyl)-2H-tetrazole-5-carboxylic acid (80 μmol) and substrate stock solution (1 mL) and stirred at 50° C. for 3 hours. The reaction was cooled to room temperature, diluted with water (6 mL), and left overnight. The vial was centrifuged, and the mother liquor was decanted and discarded. The solid was slurried in water (5 mL), vortexed, centrifuged, and the mother liquor was decanted and discarded. The crude material was dissolved in DMSO (2.2 mL) and purified by preparative HPLC (Method C2, gradient 5-60%) to give 2-(tert-butyl)-N-(4-(6-morpholinopyrazolo[1,5-a]pyrazin-4-yl)benzyl)-2H-tetrazole-5-carboxamide. LCMS m / z = 462.2 [M+H] + . 1 H NMR (500 MHz, DMSO-d6) δ ppm 9.66 (t, J=6.41 Hz, 1 H) 8.15 (d, J=1.22 Hz, 1 H) 8.06 (d, J=7.94 Hz, 1 H) 8.03 (d, J=2.44 Hz, 1 H) 7.54 (d, J=8.55 Hz, 1 H) 7.10 - 7.00 (m, 1 H) 4.59 (d, J=6.10 Hz, 2 H), 3.86- 3.72 (m, 4 H) 1.74 (s, 9 H).

[0192] Examples 26 to 29 The compounds in the following table were prepared from (4-(6-morpholinopyrazolo[1,5-a]pyrazin-4-yl)phenyl)methanamine dihydrochloride (Step 3 of Example 23) and the appropriate carboxylic acid according to the method described in Example 25. [Table 3-1] [Table 3-2] [Table 3-3]

[0193] Example 30. 4-Isobutyl-1-(2-methyl-4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)benzyl)piperazin-2-one [ka]

[0194] 1. Preparation of tert-butyl 4-(4-bromo-2-methylbenzyl)-3-oxopiperazine-1-carboxylate [ka] PBr3 (0.95 mL, 10 mmol) was added dropwise to a solution of (4-bromo-2-methylphenyl)methanol (1.3 g, 6.7 mmol) in DCM (50 mL) at 0 °C, and the reaction was stirred at room temperature for 1 h and then quenched with ice-water (50 mL). The pH was adjusted to 7.0 with 50% aqueous NaOH, and the mixture was extracted with EtOAc (100 mL × 2). The combined organic layers were washed with water (50 mL), dried (Na2SO4), and concentrated to give 4-bromo-1-(bromomethyl)-2-methylbenzene (1.56 g, 89% yield) as a white solid, which was used in the next step without further purification.

[0195] To a solution of tert-butyl 3-oxopiperazine-1-carboxylate (1.2 g, 6.0 mmol) in THF (200 mL) was added NaH (320 mg, 8.1 mmol) in an ice bath, and the mixture was stirred at 0° C. for 1 hour. A solution of 4-bromo-1-(bromomethyl)-2-methylbenzene (1.42 g, 5.4 mmol) in THF (5 mL) was added dropwise over 10 minutes, the ice bath was removed, and the mixture was stirred at room temperature for 2 hours. The mixture was diluted with ice water (50 mL) and extracted with EtOAc (100 mL×2). The combined organic phase was washed with brine (50 mL), dried (NaSO), and concentrated in vacuo. The residue was purified by silica gel column (PE / EtOAc=5:1) to give tert-butyl 4-(4-bromo-2-methylbenzyl)-3-oxopiperazine-1-carboxylate (1.6 g, 77% yield) as a white solid. LCMS m / z = 327.0 [M+H] + .

[0196] 2. Preparation of tert-butyl 4-(2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)-3-oxopiperazine-1-carboxylate [ka] A mixture of tert-butyl 4-(4-bromo-2-methylbenzyl)-3-oxopiperazine-1-carboxylate (500 mg, 1.30 mmol), (BPin) (330.12 mg, 1.30 mmol), Pd(dppf)Cl (95.12 mg, 130 μmol), and KOAc (382.75 mg, 3.90 mmol) in dioxane (8.0 mL) was degassed and heated to 95° C. for 16 h. After cooling to room temperature, the crude material was filtered through Celite®, and the filtrate was concentrated. The residue was chromatographed on silica gel (heptane / EtOAc 0-100%) to give tert-butyl 4-(2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)-3-oxopiperazine-1-carboxylate (598 mg, crude). LCMS m / z = 375.3 [M+H] + .

[0197] 3. Preparation of tert-butyl 4-(2-methyl-4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)benzyl)-3-oxopiperazine-1-carboxylate [ka] A mixture of tert-butyl 4-(2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)-3-oxopiperazine-1-carboxylate (238 mg, 553.05 μmol), 4-chloro-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine (Step 5 of Example 1, 129.23 mg, 553.05 μmol), Pd(dppf)Cl (40.47 mg, 55.30 μmol), and KCO (229.31 mg, 1.66 mmol) in dioxane (3.0 mL) and water (1.0 mL) was degassed and heated to 95° C. for 16 h. The cooled mixture was filtered through Celite® and concentrated in vacuo. The residue was chromatographed on silica gel (heptane / EtOAc 0-100%) to give tert-butyl 4-(2-methyl-4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)benzyl)-3-oxopiperazine-1-carboxylate (136 mg, 49% yield). LCMS m / z = 502.3 [M+H] + .

[0198] 4. Preparation of 1-(2-methyl-4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)benzyl)piperazin-2-one hydrochloride [ka] HCl (4M, 203.36 uL) was added to a solution of tert-butyl 4-(2-methyl-4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)benzyl)-3-oxopiperazine-1-carboxylate (136 mg, 271.14 μmol) in MeOH (2.0 mL), and the reaction was stirred at room temperature for 16 hours. The reaction mixture was evaporated under reduced pressure to give 1-(2-methyl-4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)benzyl)piperazin-2-one hydrochloride (114 mg, crude), which was used without further purification. LCMS m / z = 402.3 [M+H] +

[0199] 5. Preparation of 4-isobutyl-1-(2-methyl-4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)benzyl)piperazin-2-one [ka] NaBH(OAc) (62.09 mg, 292.94 μmol) was added to a solution of 1-(2-methyl-4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)benzyl)piperazin-2-one hydrochloride (58.80 mg, 146.47 μmol), isobutyraldehyde (25.23 mg, 351.53 μmol), and AcOH (8.80 mg, 146.47 μmol) in DCM (2.0 mL), and the reaction was stirred at room temperature for 16 h. The mixture was quenched with MeOH and concentrated in vacuo. The residue was purified by preparative HPLC to give 4-isobutyl-1-(2-methyl-4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)benzyl)piperazin-2-one (53 mg, 75% yield). LCMS m / z = 458.3 [M+H] + . 1H NMR (400 MHz, MeOH-d4) δ: 8.84-8.75 (m, 1H), 8.24-8.17 (m, 1H), 8.13-8.04 (m, 2H), 8.00-7.88 (m, 2H), 7.51 - 7.41 (m, 1H), 7.09 - 7.02 (m, 1H), 4.85 (br s, 2H), 4.13-4.05 (m, 2H), 4.01-3.92 (m, 3H), 3.70-3.57 (m, 4H), 3.18 - 3.08 (m, 2H), 2.54 - 2.45 (m, 3H), 2.29-2.14 (m, 1H), 1.08 (d, J = 6.78 Hz, 6H).

[0200] Example 31. 1-(2-methyl-4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)benzyl)-4-neopentylpiperazin-2-one [ka] 1-(2-Methyl-4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)benzyl)-4-neopentylpiperazin-2-one (25.1 mg, 40% yield) was obtained from 1-(2-methyl-4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)benzyl)piperazin-2-one hydrochloride (Step 4 of Example 30) and pivaldehyde according to the method described in Step 5 of Example 30. LCMS m / z=472.2 [M+H] + . 1H NMR (400 MHz, MeOH-d4) δ: 8.87-8.79 (m, 1H), 8.26-8.19 (m, 1H), 8.12-8.06 (m, 2H), 8.01-7.91 (m, 2H), 7.50-7.41 (m, 1H), 7.10- 7.02 (m, 1H), 4.85 - 4.80 (m, 2H), 4.10-4.03 (m, 2H), 4.00-3.94 (m, 3H), 3.67-3.53 (m, 4H), 3.14 - 3.04 (m, 2H), 2.53-2.46 (m, 3H), 1.14 (s, 9H).

[0201] Example 32. 1-(2-methyl-4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)benzyl)-4-(oxetan-3-ylmethyl)piperazin-2-one [ka] 1-(2-methyl-4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)benzyl)-4-(oxetan-3-ylmethyl)piperazin-2-one (19.2 mg, 52% yield) was obtained from 1-(2-methyl-4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)benzyl)piperazin-2-one hydrochloride (Step 4 of Example 30) and oxetane-3-carbaldehyde according to the method described in Step 5 of Example 30. LCMS m / z=472.1 [M+H] + . 1H NMR (400 MHz, MeOH-d4) δ: 8.84-8.78 (m, 1H), 8.23-8.19 (m, 1H), 8.12-8.05 (m, 2H), 8.00-7.91 (m, 2H), 7.48-7.39 (m, 1H), 7.08 - 7.03 (m, 1H), 4.96-4.91 (m, 1H), 4.83 (br s, 2H), 4.55-4.49 (m, 2H), 4.14-4.09 (m, 1H), 4.00-3.98 (m, 5H), 3.74 (dd, J=4.6, 10.7 Hz, 1H), 3.64 - 3.44 (m, 6H), 2.47 (br s, 3H).

[0202] Example 33. 1-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)benzyl)-4-neopentylpiperazin-2-one [ka]

[0203] 1. Preparation of tert-butyl 4-(4-bromobenzyl)-3-oxopiperazine-1-carboxylate [ka] NaH (57.60 mg, 2.40 mmol) was added to a solution of tert-butyl 3-oxopiperazine-1-carboxylate (400 mg, 2.0 mmol) in THF (4.0 mL) at 0 °C, the mixture was stirred for 1 h, 1-bromo-4-(chloromethyl)benzene (410.96 mg, 2.0 mmol) was added, and the reaction was stirred at room temperature for 2 h. The reaction was quenched with aqueous NaHCO and extracted with EtOAc. The organic layer was dried over NaSO and concentrated in vacuo. The residue was chromatographed on silica gel (heptane / EtOAc 0–100%) to give tert-butyl 4-(4-bromobenzyl)-3-oxopiperazine-1-carboxylate (54.50 mg, 7.4% yield).

[0204] 2. Preparation of tert-butyl 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)-3-oxopiperazine-1-carboxylate [ka] A mixture of tert-butyl 4-((4-bromophenyl)methyl)-3-oxo-piperazine-1-carboxylate (54.30 mg, 147.05 μmol), (BPin) (37.34 mg, 147.05 μmol), KOAc (43.29 mg, 441.15 μmol), and Pd(dppf)Cl.DCM (12.01 mg, 14.71 μmol) in dioxane (2.0 mL) was degassed and heated at 95° C. for 16 h. The cooled mixture was filtered through Celite®, and the filtrate was concentrated. The residue was chromatographed on silica gel (heptane / EtOAc 0-100%) to give tert-butyl 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)-3-oxopiperazine-1-carboxylate (53.30 mg, 87.1% yield).

[0205] 3. Preparation of tert-butyl 4-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)benzyl)-3-oxopiperazine-1-carboxylate [ka] tert-Butyl 4-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)benzyl)-3-oxopiperazine-1-carboxylate (31.3 mg, 50.1% yield) was obtained from tert-butyl 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)-3-oxopiperazine-1-carboxylate and 4-chloro-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine (Step 5 of Example 1) following a method similar to that used in Step 3 of Example 30. LCMS m / z=488.4 [M+H] +

[0206] 4. Preparation of 1-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)benzyl)piperazin-2-one hydrochloride [ka] 1-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)benzyl)piperazin-2-one hydrochloride (crude) was obtained from tert-butyl 4-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)benzyl)-3-oxopiperazine-1-carboxylate according to the method used in Step 4 of Example 30. LCMS m / z = 388.3 [M+H] + .

[0207] 5. Preparation of 1-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)benzyl)-4-neopentylpiperazin-2-one [ka] 1-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)benzyl)-4-neopentyl piperazin-2-one (14 mg, 95% purity) was obtained from 1-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)benzyl)piperazin-2-one hydrochloride and pivaldehyde according to a method similar to that used in Step 5 of Example 30. LCMS m / z = 458.3 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ: 8.58 (s, 1H), 8.11-8.04 (m, 3H), 8.02-7.93 (m, 2H), 7.50 - 7.40 (m, 2H), 7.00-6.92 (m, 1H), 4.83 -4.73 (m, 2H), 4.07-3.99 (m, 3H), 3.94-3.86 (m, 2H), 3.60-3.53 (m, 2H), 3.39 - 3.32 (m, 2H), 2.85-2.78 (m, 2H), 1.12 (s, 9H).

[0208] Example 34. 1-(2-Fluoro-4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)benzyl)-4-isobutylpiperazin-2-one [ka]

[0209] 1. Preparation of tert-butyl 4-(4-bromo-2-fluorobenzyl)-3-oxopiperazine-1-carboxylate [ka] tert-Butyl 4-(4-bromo-2-fluorobenzyl)-3-oxopiperazine-1-carboxylate (420 mg, 20.7% yield) was obtained from 4-bromo-1-(chloromethyl)-2-fluorobenzene and tert-butyl 3-oxopiperazine-1-carboxylate according to a method similar to that used in Step 1 of Example 33. 1H NMR (400 MHz, CDCl3) δ: 7.31-7.27 (m, 2H), 7.26-7.22 (m, 1H), 4.63 (s, 2H), 4.14-4.12 (m, 2H), 3.65-3.60 (m, 2H), 3.36-3.31 (m, 2H), 1.47 (s, 9H).

[0210] 2. Preparation of tert-butyl 4-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)-3-oxopiperazine-1-carboxylate [ka] tert-Butyl 4-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)-3-oxopiperazine-1-carboxylate (235 mg, crude) was obtained from tert-butyl 4-(4-bromo-2-fluorobenzyl)-3-oxopiperazine-1-carboxylate according to a method similar to that used in Step 2 of Example 33.

[0211] 3. Preparation of tert-butyl 4-(2-fluoro-4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)benzyl)-3-oxopiperazine-1-carboxylate [ka] tert-Butyl 4-(2-fluoro-4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)benzyl)-3-oxopiperazine-1-carboxylate (54 mg, 19.7% yield) was obtained from tert-butyl 4-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)-3-oxopiperazine-1-carboxylate and 4-chloro-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine (Step 5 of Example 1) following a method similar to that used in Step 3 of Example 30. LCMS m / z = 506.3 [M+H] + .

[0212] 4. Preparation of 1-(2-fluoro-4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)benzyl)piperazin-2-one hydrochloride [ka] 1-(2-Fluoro-4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)benzyl)piperazin-2-one hydrochloride (crude) was obtained from tert-butyl 4-(2-fluoro-4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)benzyl)-3-oxopiperazine-1-carboxylate according to the method used in Step 4 of Example 30. LCMS m / z = 406.3 [M+H] +

[0213] 5. Preparation of 1-(2-fluoro-4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)benzyl)-4-isobutylpiperazin-2-one [ka] 1-(2-Fluoro-4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)benzyl)-4-isobutylpiperazin-2-one (4 mg, 95% purity) was obtained from 1-(2-fluoro-4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)benzyl)piperazin-2-one hydrochloride and isobutyraldehyde according to a method similar to that used in Step 5 of Example 30. LCMS m / z = 462.3 [M+H] + 1 H NMR (400 MHz, CDCl3, d): 8.61-8.53 (m, 1H), 8.09 - 8.03 (m, 1H), 8.00-7.94 (m, 2H), 7.90-7.86 (m, 1H), 7.85-7.79 (m, 1H), 7.58 - 7.51 (m, 1H), 6.99 - 6.94 (m, 1H), 4.80 - 4.70 (m, 2H), 4.00 (s, 3H), 3.41-3.33 (m, 2H), 3.24-3.18 (m, 2H), 2.70-2.62 (m, 2H), 2.20-2.13 (m, 2H), 1.87-1.73 (m, 1H), 0.92 (d, J = 6.5 Hz, 6H).

[0214] Example 35. 1-(2-Fluoro-4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)benzyl)-4-neopentylpiperazin-2-one [ka] 1-(2-Fluoro-4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)benzyl)-4-neopentylpiperazin-2-one (15 mg) was obtained from 1-(2-fluoro-4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)benzyl)piperazin-2-one hydrochloride (Step 4 of Example 34) and pivaldehyde according to a method similar to that used in Step 5 of Example 30. LCMS m / z = 476.4 [M+H] + . 1 H NMR (400 MHz, CDCl3, d): 8.62-8.57 (m, 1H), 8.11-8.05 (m, 1H), 8.03-7.96 (m, 2H), 7.93-7.79 (m, 2H), 7.63-7.49 (m, 1H), 7.04-6.92 (m, 1H), 4.88-4.75 (m, 2H), 4.03 (s, 3H), 3.93-3.86 (m, 2H), 3.72-3.64 (m, 2H), 3.45-3.36 (m, 2H), 2.88-2.79 (m, 2H), 1.12 (s ,9H).

[0215] Example 36: 4-isobutyl-3-methyl-1-(2-methyl-4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)benzyl)piperazin-2-one [ka]

[0216] 1. Preparation of tert-butyl 4-((4-bromo-2-methyl-phenyl)methyl)-2-methyl-3-oxo-piperazine-1-carboxylate [ka] A mixture of 4-bromo-1-(chloromethyl)-2-methyl-benzene (1.02 g, 4.67 mmol), tert-butyl 2-methyl-3-oxo-piperazine-1-carboxylate (1.00 g, 4.67 mmol), and sodium tert-butoxide (1.35 g, 14.0 mmol) in dioxane (5.0 mL) was heated at 95 °C overnight. The cooled mixture was diluted with EtOAc, washed with water, and dried over Na2SO4. The concentrated residue was chromatographed on silica gel (heptane / EtOAc 0-100%) to give tert-butyl 4-((4-bromo-2-methyl-phenyl)methyl)-2-methyl-3-oxo-piperazine-1-carboxylate (1.37 g, 70% yield). LCMS m / z = 297.0 [M+H] +

[0217] 2. Preparation of tert-butyl 2-methyl-4-(2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)-3-oxopiperazine-1-carboxylate [ka] tert-Butyl 2-methyl-4-(2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)-3-oxopiperazine-1-carboxylate (1.41 g, 92% yield) was obtained from tert-butyl 4-((4-bromo-2-methyl-phenyl)methyl)-2-methyl-3-oxopiperazine-1-carboxylate following a method similar to that used in Step 2 of Example 30.

[0218] 3. Preparation of tert-butyl 2-methyl-4-(2-methyl-4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)benzyl)-3-oxopiperazine-1-carboxylate [ka] tert-Butyl 2-methyl-4-(2-methyl-4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)benzyl)-3-oxopiperazine-1-carboxylate (198.3 mg, 43% yield) was obtained from tert-butyl 4-((4-bromo-2-methyl-phenyl)methyl)-2-methyl-3-oxo-piperazine-1-carboxylate and 4-chloro-6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazine (Step 5 of Example 1) following a similar method as described in Step 3 of Example 30. LCMS m / z=516.3 [M+H] +

[0219] 4. Preparation of 3-methyl-1-(2-methyl-4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)benzyl)piperazin-2-one hydrochloride [ka] 3-Methyl-1-(2-methyl-4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)benzyl)piperazin-2-one hydrochloride (crude) was obtained from tert-butyl 2-methyl-4-(2-methyl-4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)benzyl)-3-oxopiperazine-1-carboxylate according to the procedure described in Step 4 of Example 30. LCMS m / z = 416.2 [M+H] +

[0220] 5. Preparation of 4-isobutyl-3-methyl-1-(2-methyl-4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)benzyl)piperazin-2-one [ka] 4-Isobutyl-3-methyl-1-(2-methyl-4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)benzyl)piperazin-2-one (39.5 mg, 30% yield) was obtained from 3-methyl-1-(2-methyl-4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)benzyl)piperazin-2-one hydrochloride and isobutyraldehyde according to a method similar to that used in Step 5 of Example 30. LCMS m / z=472.3 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ: 8.60 (s, 1H), 8.09 - 8.05 (m, 1H), 8.04 (s, 1H), 8.00 (s, 1H), 7.93-7.86 (m, 2H), 7.32 (d, J=7.8 Hz, 1H), 6.99 - 6.95 (m, 1H), 4.89 (d, J=15.1 Hz, 1H), 4.70 (d, J=15.1 Hz, 1H), 4.08 (br s, 1H), 4.03 (s, 3H), 3.72-3.39 (m, 4H), 3.11 (dd, J =8.4, 12.9 Hz, 1H), 2.94 (dd, J=5.5, 13.1 Hz, 1H), 2.43 (s, 3H), 2.23-2.10 (m, 1H), 1.79 (d, J=7.3 Hz, 3H), 1.12 (d, J=6.5 Hz, 3H), 1.10 -1.07 (m, 3H).

[0221] Example 37: 3-methyl-1-(2-methyl-4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)benzyl)-4-(oxetan-3-yl)piperazin-2-one [ka] 3-Methyl-1-(2-methyl-4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)benzyl)-4-(oxetan-3-yl)piperazin-2-one (67.4 mg, 46% yield) was obtained from 3-methyl-1-(2-methyl-4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)benzyl)piperazin-2-one hydrochloride (Step 5 of Example 36) and oxetan-3-one according to a method similar to that used in Step 5 of Example 30. LCMS m / z=472.2 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ: 8.64 (d, J=1.0 Hz, 1H), 8.10 - 8.08 (m, 1H), 8.08 - 8.07 (m, 1H), 8.03 - 8.01 (m, 1H), 7.92-7.87 (m, 2H), 7.31 (d, J=7.8 Hz, 1H), 7.00 (dd, J=1.0, 2.5 Hz, 1H), 4.93-4.68 (m, 6H), 4.31-4.22 (m, 1H), 4.05 (s, 3H), 3.77 (q, J=7.2 Hz, 1H), 3.50-3.43 (m, 2H), 3.40 - 3.30 (m, 1H), 3.16-3.04 (m, 1H), 2.43 (s, 3H), 1.53 (d, J=7.0 Hz, 3H).

[0222] Example 38: 2-(tert-butyl)-5-(2-methyl-4-(7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidin-5-yl)benzyl)-4,5-dihydro-6H-pyrrolo[3,4-d]thiazol-6-one [ka]

[0223] 1. Preparation of 4-(((4-bromo-2-methylbenzyl)amino)methyl)-2-(tert-butyl)thiazole-5-carboxylic acid [ka] To a solution of 4-bromo-2-methylbenzylamine hydrochloride (1.68 g, 6.82 mmol) in DMF (15 mL) was added DIPEA (3.0 mL, 22.8 mmol) and 4-(bromomethyl)-2-(tert-butyl)thiazole-5-carboxylate (1.39 g, 4.54 mmol) in DMF (10 mL) at 0 °C. The reaction was warmed to room temperature and stirred for 12 h. The mixture was diluted with water (40 mL) and extracted with EtOAc (100 mL × 2). The organic phase was washed with water (60 mL × 2), dried, and concentrated. The residue was purified by silica gel column chromatography (EtOAc / PE = 1 / 4) to give 4-(((4-bromo-2-methylbenzyl)amino)methyl)-2-(tert-butyl)thiazole-5-carboxylic acid as a yellow oil (850 mg, 44%). LCMS m / z = 425.1 [M+H] +

[0224] Preparation of 2.5-((4-bromo-2-methyl-phenyl)methyl)-2-tert-butyl-4H-pyrrolo[3,4-d]thiazol-6-one [ka] To a solution of 4-(((4-bromo-2-methylbenzyl)amino)methyl)-2-(tert-butyl)thiazole-5-carboxylic acid (850 mg, 2.0 mmol) in MeOH (10 mL) and HO (5 mL) was added NaOH (320 mg, 8.0 mmol), and the reaction mixture was stirred at room temperature for 16 h. After removing MeOH, the residue was diluted with water (10 mL), and the pH was adjusted to 5-6 with HCl (1N). The mixture was extracted with EtOAc (50 mL × 3). The organic layer was dried over NaSO and concentrated under reduced pressure to give 5-((4-bromo-2-methyl-phenyl)methyl)-2-tert-butyl-4H-pyrrolo[3,4-d]thiazol-6-one as a yellow solid (760 mg, 96% yield), which was used in the next step without further purification. LCMS m / z = 379.1 [M+H] + .

[0225] 3. Preparation of 2-tert-butyl-5-((2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methyl])-4H-pyrrolo[3,4-d]thiazol-6-one [ka] 2-tert-Butyl-5-((2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methyl])-4H-pyrrolo[3,4-d]thiazol-6-one (24.1 mg, 88% yield) was obtained from 5-((4-bromo-2-methyl-phenyl)methyl)-2-tert-butyl-4H-pyrrolo[3,4-d]thiazol-6-one following a method similar to that used in Step 2 of Example 30. LCMS m / z=427.3 [M+H] +

[0226] 4. Preparation of 2-tert-butyl-5-((2-methyl-4-[7-(1-methylpyrazol-4-yl)imidazo[1,2-c]pyrimidin-5-yl]phenyl)methyl)-4H-pyrrolo[3,4-d]thiazol-6-one [ka] A mixture of 2-tert-butyl-5-((2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methyl])-4H-pyrrolo[3,4-d]thiazol-6-one (24.0 mg, 56.29 μmol), 5-chloro-7-(1-methylpyrazol-4-yl)imidazo[1,2-c]pyrimidine (Step 5 of Example 1, 13.15 mg, 56.29 μmol), Pd(dppf)Cl (4.12 mg, 5.63 μmol), and KCO (23.34 mg, 168.87 μmol) in dioxane (2.0 mL) and water (199.98 μL) was degassed and heated at 95 °C for 16 h. The cooled mixture was diluted with EtOAc, filtered through Celite®, and the filtrate was concentrated in vacuo. The residue was purified by chromatography on silica gel (DCM / MeOH 0-30%) to give 2-tert-butyl-5-((2-methyl-4-[7-(1-methylpyrazol-4-yl)imidazo[1,2-c]pyrimidin-5-yl]phenyl)methyl)-4H-pyrrolo[3,4-d]thiazol-6-one (20.0 mg, 68% yield). LCMS m / z = 498.2 [M+H] + . 1 H NMR (400 MHz, MeOH-d4) δ: 8.24-6.63 (m, 8H), 4.47-4.36 (m, 2H), 4.01-3.75 (m, 5H), 2.45 (s, 3H), 1.54-1.41 (m, 9H).

[0227] Example 39: 1-tert-butyl-N-[(5R)-8-[6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl]-2-(oxetan-3-yl)-1,3,4,5-tetrahydro-2-benzazepin-5-yl]triazole-4-carboxamide [ka]

[0228] 1. Synthesis of tert-butyl (R)-5-(1-(tert-butyl)-1H-1,2,3-triazole-4-carboxamido)-8-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)-1,3,4,5-tetrahydro-2H-benzo[c]azepine-2-carboxylate [ka] tert-Butyl (R)-5-(1-(tert-butyl)-1H-1,2,3-triazole-4-carboxamido)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,4,5-tetrahydro-2H-benzo[c]azepine-2-carboxylate (WO2018 / 191577, Step 2 of Example 23, 500 mg, 9 26.8 μmol), 4-chloro-6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazine (Step 5 of Example 1, 259.9 mg, 1.11 mmol), K2CO3 (384.29 mg, 2.78 mmol), and Pd(dppf)Cl2 (33.91 mg, 46.34 μmol) were dissolved in dioxane (4.94 mL) and water (1.24 mL). N2 was bubbled through the mixture for 5 minutes, and the reaction was heated to 100 °C overnight. The cooled reaction was diluted with EtOAc and water, the layers were separated, and the organic layer was washed with brine and concentrated in vacuo. This material was used crude in the next step, assuming 100% yield. LCMS m / z = 611.0 [M+H] + .

[0229] 2. Synthesis of (R)-1-(tert-butyl)-N-(8-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1H-1,2,3-triazole-4-carboxamide hydrochloride [ka] To a solution of tert-butyl (R)-5-(1-(tert-butyl)-1H-1,2,3-triazole-4-carboxamido)-8-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)-1,3,4,5-tetrahydro-2H-benzo[c]azepine-2-carboxylate (488 mg, 0.80 mmol) in dioxane (7.99 mL) was added HCl (4 M, 1.20 mL) and the reaction was stirred at room temperature overnight. The resulting solid was filtered off, washed with EtOAc, and air-dried to give (R)-1-(tert-butyl)-N-(8-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1H-1,2,3-triazole-4-carboxamide hydrochloride (110 mg, 25.2% yield) as an orange solid. 1 H NMR (500 MHz, DMSO-d6) δ : 9.41 (br d, J=7.94 Hz, 1 H), 9.16 (s, 1 H), 8.82 (s, 1 H), 8.36 (s, 1 H), 8.30-8.18 (m, 2 H), 8.14 (s, 1 H), 7.53 (br d, J=7.94 Hz, 1 H), 7.31 (br d, J=2.44 Hz, 1 H), 5.65 (t, J=1.00 Hz, 1 H), 4.74 - 4.54 (m, 2 H), 4.43-4.18 (m, 2 H), 3.91 (s, 3 H), 2.38-2.14 (m, 2 H), 1.67 (s, 9 H).

[0230] 3. Synthesis of 1-tert-butyl-N-[(5R)-8-[6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl]-2-(oxetan-3-yl)-1,3,4,5-tetrahydro-2-benzazepin-5-yl]triazole-4-carboxamide [ka] To a solution of (R)-1-(tert-butyl)-N-(8-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1H-1,2,3-triazole-4-carboxamide hydrochloride (55 mg, 96.95 μmol) in MeOH (1.94 mL) was added oxetan-3-one (34.9 mg, 485 μmol) and NaCNBH (18.3 mg, 291 μmol), and the reaction mixture was stirred at room temperature overnight. This material was concentrated and purified by reverse phase purification (Method B2, 5-45% gradient) to give (R)-1-(tert-butyl)-N-(8-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)-2-(oxetan-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1H-1,2,3-triazole-4-carboxamide (26.4 mg, 45.7% yield) as a pale yellow solid. LCMS m / z = 567.0 [M+H] + . 1 H NMR (500 MHz, DMSO-d6) δ ppm 9.49 (s, 1 H), 9.19 (s, 1 H), 8.81 (s, 1 H), 8.34 (s, 1 H), 8.30-8.18 (m, 2 H), 8.14 (s, 1 H), 7.56 (d, 1.68 (s, 9H)

[0231] Example 40: (R)-1-(tert-butyl)-N-(8-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)-2-(2,2,2-trifluoroethyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1H-1,2,3-triazole-4-carboxamide [ka]

[0232] 1. Synthesis of (R)-1-(tert-butyl)-N-(8-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)-2-(2,2,2-trifluoroethyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1H-1,2,3-triazole-4-carboxamide [ka] To a solution of (R)-1-(tert-butyl)-N-(8-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1H-1,2,3-triazole-4-carboxamide hydrochloride (Step 2 of Example 39, 55.0 mg, 101 μmol) in MeCN (1.01 mL) were added 2,2,2-trifluoroethyl trifluoromethanesulfonate (46.7 mg, 201 μmol) and KCO (41.7 mg, 302 μmol), and the reaction mixture was stirred at 80° C. overnight under a N atmosphere. This material was filtered through Celite®, concentrated, and purified by reverse-phase HPLC (Method B2, 5-45% gradient) to afford (R)-1-(tert-butyl)-N-(8-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)-2-(2,2,2-trifluoroethyl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1H-1,2,3-triazole-4-carboxamide, 16.9 mg (27.8% yield) as a brown solid. LCMS m / z = 593.0 [M+H] + . 1H NMR (500 MHz, DMSO-d6) δ ppm 9.14 (s, 1 H), 9.09 (br d, J=7.94 Hz, 1 H), 8.77 (s, 1 H), 8.33 (s, 1 H), 8.20 (d, J=2.44 Hz, 1 H), 8.12 (s, 1 H), 8.03 (dd, J=7.94, 1.83 Hz, 1 H), 7.96 (d, J=1.83 Hz, 1 H), 7.46 (br d, J=8.55 Hz, 1 H), 7.17 (dd, J=2.44, 1.22 Hz, 1 H), 5.51 (t, J=1.00 Hz, 1 H), 4.35 (br d, J=15.26 Hz, 2 H), 4.10 (br d, J=15.26 Hz, 2 H), 3.91 (s, 3 H), 3.26 - 3.21 (m, 2 H), 2.20 - 2.12 (m, 2 H), 1.67 (s, 9 H)

[0233] Example 41. 5-(tert-butyl)-N-((4-methyl-1-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)piperidin-4-yl)methyl)-1,2,4-oxadiazole-3-carboxamide [ka]

[0234] 1. Preparation of tert-butyl ((4-methyl-1-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)piperidin-4-yl)methyl)carbamate [ka] tert-Butyl N-((4-methyl-4-piperidyl)methyl)carbamate (296.83 mg, 1.30 mmol) followed by CsCO (521.31 mg, 1.60 mmol) was added to a solution of 4-chloro-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine (Step 5 of Example 1, 233.66 mg, 1.00 mmol) in DMF (3.0 mL), and the reaction was stirred overnight at room temperature. The reaction was diluted with water (10 mL) and extracted with EtOAc (2 × 10 mL). The combined organic phase was dried over NaSO, filtered, and evaporated to dryness. The residue was purified by silica gel column chromatography (1:1 heptane:EtOAc) to afford tert-butyl ((4-methyl-1-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)piperidin-4-yl)methyl)carbamate (430 mg, 90% yield) as a dark brown gum. LCMS m / z = 426.1 [M+H] + .

[0235] 2. Preparation of (4-methyl-1-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)piperidin-4-yl)methanamine [ka] To a solution of tert-butyl ((4-methyl-1-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)piperidin-4-yl)methyl)carbamate (429.79 mg, 1.01 mmol) in DCM (3.0 mL) was added TFA (2.30 g, 20.20 mmol) and the reaction was stirred at room temperature overnight. The mixture was diluted with MeOH and purified on a 5 g SCX column, and the product was eluted with 2 M NH3-MeOH to give (4-methyl-1-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)piperidin-4-yl)methanamine (260 mg, 71.2% yield) as a beige solid. LCMS m / z = 326.1 [M+H] + .

[0236] 3. Preparation of 5-(tert-butyl)-N-((4-methyl-1-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)piperidin-4-yl)methyl)-1,2,4-oxadiazole-3-carboxamide [ka] DIPEA (24 mg, 185 μmol) was added to a mixture of (4-methyl-1-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)piperidin-4-yl)methanamine (40.0 mg, 122.92 μmol) and 5-tert-butyl-1,2,4-oxadiazole-3-carboxylic acid (23 mg, 135.2 μmol) in DMF (1 mL), and the mixture was stirred at room temperature for 5 minutes. T3P® (120 mg, 185 μmol, 50% purity) was added, and the reaction was stirred at room temperature overnight. The mixture was diluted with EtOAc (3 mL) and water (3 mL), and the mixture was stirred vigorously. The aqueous phase was discarded, and the remaining organic phase was dried over NaSO and filtered. The filtrate was evaporated, the residue was redissolved in DMSO, and the product was purified by preparative HPLC (Method A, 5-60% gradient). LCMS mz = 478.1 [M+H] + . 1 H NMR (DMSO-d6) δ: 8.96-8.87 (m, 1H), 8.44 (s, 1H), 8.14 (s, 1H), 7.94 (s, 1H), 7.93 (d, J=2.4 Hz, 1H), 6.97-6.88 (m, 1H), 4.08-3.98 (m, 2H), 3.87 (s, 3H), 3.69-3.59 (m, 2H), 3.31-3.25 (m, 2H), 1.66-1.57 (m, 2H), 1.49-1.35 (m, 11H), 1.02 (s, 3H).

[0237] Example 42. 5-(tert-butyl)-N-((3-methyl-1-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)pyrrolidin-3-yl)methyl)-1,2,4-oxadiazole-3-carboxamide [ka]

[0238] 1. Preparation of tert-butyl ((3-methyl-1-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)pyrrolidin-3-yl)methyl)carbamate [ka] tert-Butyl ((3-methyl-1-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)pyrrolidin-3-yl)methyl)carbamate (300 mg, 65.6% yield) was obtained as a dark brown gum from 4-chloro-6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazine (Step 5 of Example 1) and tert-butyl N-((3-methylpyrrolidin-3-yl)methyl)carbamate following a similar method as described in Step 1 of Example 41. LCMS m / z=412.1 [M+H] + .

[0239] 2. Preparation of (3-methyl-1-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)pyrrolidin-3-yl)methanamine [ka] (3-Methyl-1-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)pyrrolidin-3-yl)methanamine (210 mg, 83.2% yield) was obtained as a pale yellow solid from tert-butyl ((3-methyl-1-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)pyrrolidin-3-yl)methyl)carbamate following a similar method to that described in Step 2 of Example 41. LCMS m / z=312.1 [M+H] + .

[0240] Preparation of 3.5-(tert-butyl)-N-((3-methyl-1-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)pyrrolidin-3-yl)methyl)-1,2,4-oxadiazole-3-carboxamide [ka] 5-(tert-butyl)-N-((3-methyl-1-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)pyrrolidin-3-yl)methyl)-1,2,4-oxadiazole-3-carboxamide was obtained from (3-methyl-1-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)pyrrolidin-3-yl)methanamine and 5-tert-butyl-1,2,4-oxadiazole-3-carboxylic acid according to the method used in Step 3 of Example 41. LCMS m / z = 464.0 [M+H] + . 1 H NMR (DMSO-d6) δ: 9.11 (t, J=6.4 Hz, 1H), 8.29 (s, 1H), 8.10 (s, 1H), 7.92 (s, 1H), 7.89 (d, J=2.4 Hz, 1H), 7.04-6.92 (m, 1H), 3.86 (s, 5H), 3.64-3.39 (m, 2H), 2.09-1.92 (m, 1H), 1.84-1.67 (m, 1H), 1.41 (s, 9H), 1.13 (s, 3H).

[0241] Examples 43 to 51 The compounds in the following table were prepared from (4-methyl-1-(6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)-4-piperidyl)methanamine (Step 2 of Example 41) or (3-methyl-1-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)pyrrolidin-3-yl)methanamine (Step 2 of Example 42) and the appropriate carboxylic acid following a method similar to that used in Step 3 of Example 41. [Table 4-1] [Table 4-2] [Table 4-3] [Table 4-4] [Table 4-5] [Table 4-6] [Table 4-7] [Table 4-8] [Table 4-9]

[0242] Example 52: 5-(tert-butyl)-N-(6-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)-6-azaspiro[3.4]octan-2-yl)-1,2,4-oxadiazole-3-carboxamide [ka]

[0243] 1. Preparation of tert-butyl 2-(5-(tert-butyl)-1,2,4-oxadiazole-3-carboxamido)-6-azaspiro[3.4]octane-6-carboxylate [ka] tert-Butyl 2-amino-6-azaspiro[3.4]octane-6-carboxylate (160.0 mg, 706.96 μmol) followed by T3P® (674.83 mg, 1.06 mmol, 50% purity) was added to a solution of lithium 5-(tert-butyl)-1,2,4-oxadiazole-3-carboxylate (373.49 mg, 2.12 mmol) in DMF (1.0 mL), and the reaction was warmed to 50 °C and stirred overnight. The mixture was diluted with water (3 mL), and the product was extracted with EtOAc (2 × 3 mL). The combined organic phase was washed with brine (2 mL), dried over NaSO, and filtered. The filtrate was evaporated to dryness and the material was purified on a 5 g SPE column (eluting with heptane: EtOAc) to give tert-butyl 2-(5-(tert-butyl)-1,2,4-oxadiazole-3-carboxamido)-6-azaspiro[3.4]octane-6-carboxylate as a white solid. LCMS m / z = 313.1 [M-tBu+H] +

[0244] Preparation of 2,5-(tert-butyl)-N-(6-azaspiro[3.4]octan-2-yl)-1,2,4-oxadiazole-3-carboxamide trifluoroacetate [ka] To a solution of tert-butyl 2-(5-(tert-butyl)-1,2,4-oxadiazole-3-carboxamide)-6-azaspiro[3.4]octane-6-carboxylate (180.0 mg, 475.61 μmol) in DCM (3.0 mL) was added TFA (1.08 g, 9.51 mmol) and the reaction was stirred at room temperature overnight. The mixture was diluted with MeOH (5.0 mL) and purified on a 5 g SCX column. The desired compound was eluted with TEA / MeOH (1 mL / 25 mL) to give 5-(tert-butyl)-N-(6-azaspiro[3.4]octan-2-yl)-1,2,4-oxadiazole-3-carboxamide trifluoroacetate (90.0 mg) as a colorless gum. LCMS m / z = 279.1 [M+H] + .

[0245] Preparation of 3.5-(tert-butyl)-N-(6-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)-6-azaspiro[3.4]octan-2-yl)-1,2,4-oxadiazole-3-carboxamide [ka] N-(6-Azaspiro[3.4]octan-2-yl)-5-tert-butyl-1,2,4-oxadiazole-3-carboxamide (42.89 mg, 154.07 μmol) followed by CsCO (62.75 mg, 192.58 μmol) was added to a solution of 4-chloro-6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazine (Step 5 of Example 1, 30.0 mg, 128.39 μmol) in DMF (2.0 mL), and the reaction was stirred overnight at room temperature. The reaction was diluted with water (10 mL) and extracted with EtOAc (2 × 15 mL). The combined organic phase was dried over NaSO, filtered, and evaporated to dryness. The residue was redissolved in DMSO and the product was purified by preparative HPLC (Method A, 5-60% gradient) to give 5-(tert-butyl)-N-(6-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)-6-azaspiro[3.4]octan-2-yl)-1,2,4-oxadiazole-3-carboxamide. LCMS m / z = 476.1 [M+H] + . 1 H NMR (DMSO-d6) δ: 9.21 (dd, J=19.2, 7.6 Hz, 2H), 8.29 (s, 1H), 8.18-8.06 (m, 1H), 7.98-7.91 (m, 1H), 7.89 (d, J=1.8 Hz, 1H), 7.04 (s, 1H), 6.96 (d, J=2.4 Hz, 1H), 4.63-4.44 (m, 1H), 3.87 (d, J=1.8 Hz, 8H), 2.33 (br s, 6H), 2.11 (s, 2H), 2.06-1.98 (m, 1H), 1.43 (d, J=1.8 Hz, 9H).

[0246] Examples 53 and 54. 5-(tert-butyl)-N-((2r,4s)-6-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)-6-azaspiro[3.4]octan-2-yl)-1,2,4-oxadiazole-3-carboxamide and 5-(tert-butyl)-N-((2s,4r)-6-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)-6-azaspiro[3.4]octan-2-yl)-1,2,4-oxadiazole-3-carboxamide [ka] [Stereochemistry arbitrarily assigned] 5-(tert-Butyl)-N-(6-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)-6-azaspiro[3.4]octan-2-yl)-1,2,4-oxadiazole-3-carboxamide was purified by SFC (flow rate: 100 mL / min, ABPR 120 bar, MBPR 40 psi, column temperature 40 °C) on a LUX Cellulose-4 LC 30 x 250 mm, 3 um column (eluted with 45% MeOH and 0.1% DEA in CO) to give the following compounds: Peak 1: 5-(tert-butyl)-N-((2r,4s)-6-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)-6-azaspiro[3.4]octan-2-yl)-1,2,4-oxadiazole-3-carboxamide. LCMS m / z = 476.1 [M+H] + . 1H NMR (CDCl3) δ: 8.00 (s, 1H), 7.85 (s, 3H), 7.22-7.10 (m, 1H), 6.79-6.72 (m, 1H), 4.72 (br d, J=8.0 Hz, 1H), 4.02-3.96 (m, 5H), 3.93 (t, J=6.9 Hz, 2H), 2.69-2.56 (m, 2H), 2.19 (br d, J=3.5 Hz, 3H), 2.15-2.06 (m, 3H), 1.48 (s, 10H), 1.21-1.09 (m, 1H) and Peak 2: 5-(tert-butyl)-N-((2s,4r)-6-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)-6-azaspiro[3.4]octan-2-yl)-1,2,4-oxadiazole-3-carboxamide. LCMS m / z = 476.1 [M+H] + . 1 H NMR (CDCl3) δ: 7.98 (d, J=0.8 Hz, 1H), 7.86 (d, J=0.8 Hz, 1H), 7.82 (d, J=2.5 Hz, 1H), 7.80 (s, 1H), 7.22-7.10 (m, 1H), 6.75 (dd, J=2.4, 0.9 Hz, 1H), 4.78-4.63 (m, 1H), 3.96 (s, 5H), 3.90-3.83 (m, 2H), 2.61-2.52 (m, 2H), 2.28-2.20 (m, 2H), 2.17 (s, 2H), 1.48 (s, 9H), 1.30-1.18 (m, 1H).

[0247] Example 55. 5-(tert-butyl)-N-(2-methyl-4-(6-(1-(oxetan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)benzyl)-1,2,4-oxadiazole-3-carboxamide

[0248] 1. Synthesis of (2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanamine dihydrochloride [ka] A solution of tert-butyl (2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)carbamate (WO2015089327A1, 35.7 g, 103 mmol) in DCM was treated with TFA (85 mL, 1110 mmol), and the reaction was stirred at room temperature for 2 hours. The mixture was concentrated in vacuo, and the residue was azeotroped with toluene. The residue was suspended in saturated NaHCO3 solution, the mixture was extracted with EtOAc (2 x 100 mL), and the combined organic extracts were washed with brine, dried over Na2SO4, and filtered. 4 M HCl in dioxane (30 mL) was added, the solution was concentrated in vacuo, and the residue was stirred in Et2O (500 mL). The resulting suspension was filtered, and the solid was dried to give the title compound as an off-white solid (23.5 g, 84%). 1 H NMR (300 MHz, DMSO-d6) δ: 8.56 (br s, 3H), 7.49-7.52 (m, 2H), 7.41 (dd, 1H), 4.01-4.04 (m, 2H), 2.34 (s, 3H), 1.27 (s, 12H).

[0249] Synthesis of 2,5-(tert-butyl)-N-(2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)-1,2,4-oxadiazole-3-carboxamide [ka] To a suspension of (2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanamine dihydrochloride (34 g, 0.12 mol) and 5-(tert-butyl)-1,2,4-oxadiazole-3-carboxylic acid (29.2 g, 0.15 mol) in anhydrous DMF (500 mL) was added DIPEA (62 mL, 0.36 mol). The resulting mixture was cooled to 0° C., T3P® (50% in DMF, 90 mL, 0.15 mol) was added, and the reaction was warmed to room temperature and stirred for 2 h. The reaction mixture was partitioned between water (300 mL) and EtOAc (300 mL), and the layers were separated. The aqueous phase was extracted with EtOAc (3×100 mL), and the combined organic extracts were washed with water (3×50 mL), a saturated aqueous solution of NaHCO (50 mL), and brine (50 mL). The organic layer was dried over NaSO, filtered, and concentrated in vacuo to give a beige oil, which was purified by column chromatography on silica gel eluting with heptane / EtOAc (100 / 0 to 70 / 30) to give the title compound as a thick, pale yellow oil (29.0 g, 60%).

[0250] Preparation of 3.5-(tert-butyl)-N-(4-(6-chloropyrazolo[1,5-a]pyrazin-4-yl)-2-methylbenzyl)-1,2,4-oxadiazole-3-carboxamide [ka] A mixture of 5-(tert-butyl)-N-(2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)-1,2,4-oxadiazole-3-carboxamide (350 mg, 876.56 μmol), 4,6-dichloropyrazolo[1,5-a]pyrazine (329.60 mg, 1.75 mmol), Pd(t-BuP) (22.40 mg, 43.83 μmol), and KPO (558.20 mg, 2.63 mmol, 1.32 mL) in dioxane (4.40 mL) and water (1.10 mL) was sparged with N for 5 minutes and stirred at room temperature for 18 hours. The mixture was diluted with EtOAc and water, the layers were separated, and the organic phase was washed with brine. The combined aqueous layers were extracted with EtOAc, and the combined organic layers were dried (MgSO), filtered, and concentrated in vacuo. The residue was purified by column chromatography (0-100% EtOAc in heptane) to give 5-(tert-butyl)-N-(4-(6-chloropyrazolo[1,5-a]pyrazin-4-yl)-2-methylbenzyl)-1,2,4-oxadiazole-3-carboxamide (245 mg, 65.8% yield). LCMS m / z = 425.0 [M+H] + .

[0251] 4. Preparation of 5-(tert-butyl)-N-(2-methyl-4-(6-(1-(oxetan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)benzyl)-1,2,4-oxadiazole-3-carboxamide [ka] To a solution of 5-(tert-butyl)-N-(4-(6-chloropyrazolo[1,5-a]pyrazin-4-yl)-2-methylbenzyl)-1,2,4-oxadiazole-3-carboxamide (50 mg, 117.68 μmol) and 1-(oxetan-3-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (35.32 mg, 141.22 μmol) in dioxane (2.10 mL) was added a solution of KPO (2 M, 470.72 μL) in water, and the resulting mixture was sparged with N for 5 minutes. tBuXPhos Pd G (18.70 mg, 23.54 μmol) was added, and the mixture was heated to 60 °C for 17 hours, cooled to room temperature, diluted with EtOAc, and washed with water and brine. The organic layer was dried (MgSO4), filtered, and concentrated in vacuo. The residue was purified by preparative HPLC (Method C2, 5-60% gradient). The product was further purified by preparative TLC (97:3 DCM:MeOH) to give 5-(tert-butyl)-N-(2-methyl-4-(6-(1-(oxetan-3-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)benzyl)-1,2,4-oxadiazole-3-carboxamide (2 mg, 3.32% yield) as a white solid. LCMS m / z = 513.2 [M+H] + 1H NMR (500 MHz, CDCl3) δ ppm 8.58 (s, 1 H), 8.24 (s, 1 H), 8.08 - 8.04 (m, 2 H), 7.97 - 7.90 (m, 2 H), 7.52 (d, J=7.9 Hz, 1 H), 7.18 (br s, 1 H), 6.97 (dd, J=2.4, 1.2 Hz, 1 H), 5.60 - 5.51 (m, 1 H), 5.17 - 5.10 (m, 4 H), 4.78 (d, J=6.1 Hz, 2 H), 2.53 (s, 3 H), 1.50-1.46 (m, 9 H).

[0252] C.2 Preparation of imidazo[1,2-c]pyrimidines Example 56: 1-(tert-butyl)-N-(4-(7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidin-5-yl)benzyl)-1H-pyrazole-3-carboxamide [ka]

[0253] Synthesis of 1,7-chloro-5-(methylthio)imidazo[1,2-c]pyrimidine [ka] 2-Chloroacetaldehyde (220 g, 0.18 L, 1.28 mol) was added to a solution of 6-chloro-2-(methylthio)pyrimidin-4-amine (150 g, 854 mmol) in dioxane (300 mL), and the reaction was stirred at 100° C. for 5 hours, then cooled to room temperature overnight. The suspension was cooled to 0° C., and the solid was filtered to give 7-chloro-5-(methylthio)imidazo[1,2-c]pyrimidine as a yellow solid (151 g, 75% yield). LCMS m / z = 200.1 [M+H] +

[0254] Synthesis of 2,7-chloroimidazo[1,2-c]pyrimidin-5(6H)-one [ka] 7-Chloro-5-(methylthio)imidazo[1,2-c]pyrimidine (52.2 g, 221 mmol) was suspended in MeOH (200 mL) and a solution of KOH (55.9 g, 996 mmol) in water (520 mL) was slowly added. The reaction was heated to reflux for 3 hours and then 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 and then azeotroped with MeCN to give 7-chloroimidazo[1,2-c]pyrimidin-5(6H)-one as a white solid (28.6 g, 76% yield). LCMS m / z = 170.1 [M+H] +

[0255] 3. Synthesis of 7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidin-5(6H)-one [ka] 7-Chloroimidaz[1,2-c]pyrimidin-5(6H)-one (40 g, 236 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (73.6 g, 354 mmol), and XPhos (11.2 g, 24 mmol) were dissolved in IPA (1.8 L) and a 2 M solution of KPO in water (150 g, 0.35 L, 708 mmol) was added. The mixture was purged with N for 15 min, then Pd(dba) (10.8 g, 12 mmol) was added and the mixture was refluxed overnight. Additional Pd2(dba)3 (5 g) and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (25 g) were added, and the mixture was refluxed for an additional 24 hours. The reaction mixture was filtered to remove palladium residues, the organic solvent was evaporated, and the residue was partitioned between water and a 1:1 mixture of heptane:EtOAc. A white solid precipitated in both the organic and aqueous layers and was filtered off. The solid was washed with water, EtOAc, and MeCN and dried in vacuo to give the product (32.8 g). The layers of the filtrate were separated, and the aqueous layer was cooled in an ice bath. The solution was treated with concentrated HCl with stirring to pH 6, and the resulting fine precipitate was collected, washed with HO and Et2O, and dried in vacuo to give an additional product (9.0 g). A total of 41.8 g of 7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidin-5(6H)-one was obtained as a yellow solid (82% yield). LCMS m / z = 215.0 [M+H] +

[0256] Synthesis of 4.5-chloro-7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidine [ka] POCl3 (89.3 g, 54.1 mL, 583 mmol) was added dropwise over 5 min to an ice-cold solution of 7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidin-5(6H)-one (41.8 g, 194 mmol) and DIPEA (126 g, 971 mmol) in dry DCM (300 mL), and the reaction was allowed to warm to room temperature. The mixture was diluted with DCM (150 mL) and then stirred at room temperature for 24 h. The suspension was diluted with hexane, and the solid was collected by filtration (66.0 g). The collected solid was suspended in DCM:DIPEA (5:1, 500 mL) and stirred for 30 min. A saturated aqueous solution of NaHCO3 was then added, and the mixture was stirred for 1 h. The mixture was filtered through Celite®, the layers were separated, and the aqueous layer was extracted with DCM (3 times). The organic layer was dried over NaSO and concentrated in vacuo to give 5-chloro-7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidine as a yellow solid (22.5 g, 50% yield). LCMS m / z = 234.0 [M+H] + .

[0257] 5. Synthesis of tert-butyl (4-(7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidin-5-yl)benzyl)carbamate [ka] tert-Butyl (4-(7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidin-5-yl)benzyl)carbamate as a white solid (380 mg, 63% yield) was obtained from 5-chloro-7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidine and tert-butyl (4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)carbamate according to a procedure similar to that described in Step 6 of Example 1. LCMS m / z=405.1 [M+H] +

[0258] 6. Synthesis of (4-(7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidin-5-yl)phenyl)methanamine dihydrochloride [ka] (4-(7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidin-5-yl)phenyl)methanamine dihydrochloride (crude, 374 mg) was obtained from tert-butyl (4-(7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidin-5-yl)benzyl)carbamate according to a procedure similar to that described in step 7 of Example 1. LCMS m / z = 305.0 [M+H] +

[0259] 7. Synthesis of 1-(tert-butyl)-N-(4-(7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidin-5-yl)benzyl)-1H-pyrazole-3-carboxamide [ka] 1-(tert-butyl)-N-(4-(7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidin-5-yl)benzyl)-1H-pyrazole-3-carboxamide (26.2 mg, 58% yield) was obtained from (4-(7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidin-5-yl)phenyl)methanamine dihydrochloride and 1-(tert-butyl)-1H-pyrazole-3-carboxylic acid according to a procedure similar to that described in Step 8 of Example 1. The crude material was purified by reverse-phase HPLC (Method A, 5-55% gradient). LCMS m / z = 455.2 [M+H] + . 1H NMR (500 MHz, DMSO-d6) δ: 8.70 (t, J = 6.4 Hz, 1H), 8.33 (s, 1H), 8.10 (s, 1H), 7.97 - 7.92 (m, 4H), 7.83 (s, 1H), 7.63 (s, 1H), 7.57 (d, J = 7.9 Hz, 2H), 6.67 - 6.65 (m, 1H), 4.56 (d, J = 6.1 Hz, 2H), 3.88 (s, 3H), 1.57 (s, 9H).

[0260] Examples 57 to 61 The compounds in the following table were prepared from (4-(7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidin-5-yl)phenyl)methanamine dihydrochloride (Step 6 of Example 56) and the appropriate carboxylic acid following a method similar to that used in Step 8 of Example 1. [Table 5-1] [Table 5-2] [Table 5-3] [Table 5-4] [Table 5-5]

[0261] Example 62: 5-(2,3-cis-dimethylcyclopropyl)-N-(4-(7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidin-5-yl)benzyl)-1,2,4-oxadiazole-3-carboxamide [ka]

[0262] 1. Synthesis of ethyl 2,3-cis-dimethylcyclopropane-1-carboxylate [ka] To a solution of (Z)-but-2-ene (22.5 g, 401 mmol) and Rh(OAc)2 dimer (2.35 g, 5.3 mmol) in DCM (1.5 L) at 0 °C was added ethyl 2-diazoacetate (130 g, 1140 mmol) over 4 h. The mixture was stirred at 20 °C for 16 h. The reaction mixture was filtered through a pad of silica gel and concentrated in vacuo to give ethyl 2,3-cis-dimethylcyclopropane-1-carboxylate as a yellow oil (60 g, crude), which was carried forward without further purification.

[0263] 2. Synthesis of 2,3-cis-dimethylcyclopropane-1-carboxylic acid [ka] A solution of ethyl 2,3-cis-dimethylcyclopropane-1-carboxylate (60 g, 422 mmol) in MeOH (400 mL) was added to KOH (90 g, 1.6 mol) in HO (200 mL) at room temperature. After the reaction was complete, the solvent was removed by distillation in vacuo, and DCM (700 mL) was added. The aqueous layer was separated and acidified with 4 M aqueous HCl to pH = 1. The acidic aqueous phase was extracted with EtOAc (3 × 20 mL). The combined organic extracts were washed with brine (50 mL), dried (NaSO), filtered, and concentrated in vacuo to give 2,3-cis-dimethylcyclopropane-1-carboxylic acid (36.1 g, 75% yield for two steps), which was carried forward without further purification.

[0264] 3. Synthesis of ethyl 5-(2,3-cis-dimethylcyclopropyl)-1,2,4-oxadiazole-3-carboxylate [ka] To a solution of oxalyl chloride (28.2 mL, 328 mmol) in DCM (500 mL) was added 2,3-cis-dimethylcyclopropane-1-carboxylic acid (30 g, 263 mmol), and the reaction mixture was stirred at ambient temperature for 1 hour. Excess oxalyl chloride was removed by distillation to give crude 2,3-cis-dimethylcyclopropane-1-carbonyl chloride. To a solution of (E)-2-amino-2-(hydroxyimino)acetate (34.7 g, 263 mmol) and DIPEA (67.8 g, 526 mmol) in DCM (500 mL) at −15° C., crude 2,3-cis-dimethylcyclopropane-1-carbonyl chloride was added dropwise. The resulting solution was stirred while warming to ambient temperature and continued stirring for 16 hours. Water (800 mL) was added, and the layers were separated. The aqueous phase was extracted with DCM (300 mL × 3), and the combined organic phase was dried (Na2SO4), filtered, and concentrated in vacuo. To the residue was added pyridine (400 mL), and the mixture was heated to 110 °C and stirred for 16 h. The reaction mixture was cooled to ambient temperature and concentrated in vacuo. The crude product was purified by silica gel column chromatography (EtOAc / hexane, 1% to 10%) to give ethyl 5-(2,3-cis-dimethylcyclopropyl)-1,2,4-oxadiazole-3-carboxylate as a yellow oil (9 g, 16% yield).

[0265] 4. Synthesis of potassium 5-(2,3-cis-dimethylcyclopropyl)-1,2,4-oxadiazole-3-carboxylate [ka] A solution of ethyl 5-(2,3-cis-dimethylcyclopropyl)-1,2,4-oxadiazole-3-carboxylate (6 g, 28.5 mmol) in MeOH (40 mL) was added to a solution of KOH (1.75 g, 31.2 mmol) dissolved in HO (20 mL). Upon completion of the reaction, the solvent was removed by distillation in vacuo and DCM (70 mL) was added. The aqueous layer was separated and concentrated in vacuo to give potassium 5-(2,3-cis-dimethylcyclopropyl)-1,2,4-oxadiazole-3-carboxylate as a white solid (5.21 g, 82% yield). LCMS m / z = 183.0 [M+H] +

[0266] 5. Synthesis of 5-(-2,3-cis-dimethylcyclopropyl)-N-(4-(7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidin-5-yl)benzyl)-1,2,4-oxadiazole-3-carboxamide [ka] 5-(-2,3-cis-dimethylcyclopropyl)-N-(4-(7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidin-5-yl)benzyl)-1,2,4-oxadiazole-3-carboxamide (13.1 mg, 28% yield) was obtained from potassium 5-(2,3-cis-dimethylcyclopropyl)-1,2,4-oxadiazole-3-carboxylate and (4-(7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidin-5-yl)phenyl)methanamine dihydrochloride (Step 6 of Example 56) using a method similar to that used in Step 8 of Example 1. LCMS m / z = 469.1 [M+H] + . 1H NMR (500 MHz, DMSO-d6) δ: 9.70 - 9.52 (m, 1H), 8.34 (s, 1H), 8.19 - 8.07 (m, 1H), 8.05 - 7.92 (m, 3H), 7.89 - 7.81 (m, 1H), 7.64 (br d, J = 1.2 Hz, 1H), 7.62 - 7.50 (m, 2H), 4.67 - 4.45 (m, 2H), 3.96 - 3.84 (m, 3H), 1.90 (t, J = 4.6 Hz, 1H), 1.80 - 1.63 (m, 2H), 1.23 - 1.13 (m, 6H).

[0267] Example 63: 3-(1-(fluoromethyl)cyclopropyl)-N-(4-(7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidin-5-yl)benzyl)-1,2,4-oxadiazole-5-carboxamide [ka]

[0268] 1. Synthesis of (E)-1-(fluoromethyl)-N'-hydroxycyclopropane-1-carboximidamide [ka] 1-(Fluoromethyl)cyclopropane-1-carbonitrile (850 mg, 8.5 mmol) in EtOH (15 mL) and H O To a solution in 1 mL of HCl was added NaCO (1.8 g, 17 mmol) and hydroxylamine hydrochloride (1.2 g, 17 mmol), and the reaction was heated to 80 °C and stirred at that temperature for 4 h. The reaction mixture was cooled to ambient temperature, poured into HO (50 mL), and extracted with EtOAc (150 mL). The organic phase was dried (NaSO), filtered, and concentrated in vacuo. The crude product was purified by silica gel column chromatography to give (£)-1-(fluoromethyl)-N'-hydroxycyclopropane-1-carboximidamide as a white solid (1 g, 90% yield), which was carried forward without further purification.

[0269] 2. Synthesis of ethyl 3-(1-(fluoromethyl)cyclopropyl)-1,2,4-oxadiazole-5-carboxylate [ka] A solution of (E)-1-(fluoromethyl)-N'-hydroxycyclopropane-1-carboximidamide (5.2 g, 39 mmol) in pyridine (20 mL) was cooled to 0 °C. Chlorooxoacetate (5.3 mL, 47 mmol) was added dropwise, and after the addition was complete, the reaction mixture was heated to 80 °C and stirred at that temperature for 2 h. The reaction mixture was poured into ice water (100 mL), and the aqueous phase was extracted with DCM (30 mL × 3). The organic phase was washed with HCl solution (30 mL, 1 M) and then with brine (30 mL). The organic phase was dried (Na2SO4), filtered, and concentrated in vacuo to give ethyl 3-(1-(fluoromethyl)cyclopropyl)-1,2,4-oxadiazole-5-carboxylate (6.1 g, 85% yield), which was carried forward without further purification.

[0270] 3. Synthesis of potassium 3-(1-(fluoromethyl)cyclopropyl)-1,2,4-oxadiazole-5-carboxylate [ka] Potassium 3-(1-(fluoromethyl)cyclopropyl)-1,2,4-oxadiazole-5-carboxylate (4 g, 78% yield over 3 steps) was obtained from ethyl 3-(1-(fluoromethyl)cyclopropyl)-1,2,4-oxadiazole-5-carboxylate as described in Step 4 of Example 64. LCMS m / z=187.0 [M+H] +

[0271] 4. Synthesis of 3-(1-(fluoromethyl)cyclopropyl)-N-(4-(7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidin-5-yl)benzyl)-1,2,4-oxadiazole-5-carboxamide [ka] 3-(1-(Fluoromethyl)cyclopropyl)-N-(4-(7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidin-5-yl)benzyl)-1,2,4-oxadiazole-5-carboxamide (7.9 mg, 17% yield) was obtained from potassium 3-(1-(fluoromethyl)cyclopropyl)-1,2,4-oxadiazole-5-carboxylate and (4-(7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidin-5-yl)phenyl)methanamine dihydrochloride (Step 6 of Example 56) following a method similar to that described in Step 8 of Example 1. LCMS m / z = 473.1 [M+H] + . 1 H NMR (500 MHz, DMSO-d6) δ: 9.98 (t, J = 6.1 Hz, 1H), 8.33 (s, 1H), 8.10 (s, 1H), 8.00 - 7.94 (m, 2H), 7.94 - 7.91 (m, 1H), 7.84 (s, 1H), 7.64 (d, J = 1.2 Hz, 1H), 7.59 (d, J = 8.5 Hz, 2H), 4.78 (s, 1H), 4.69 (s, 1H), 4.59 (d, J = 6.7 Hz, 2H), 3.89 (s, 3H), 1.37 - 1.28 (m, 4H).

[0272] Example 64: Synthesis of 3-(tert-butyl)-N-(4-(7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidin-5-yl)benzyl)-1,2,4-oxadiazole-5-carboxamide [ka] To a solution of (4-(7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidin-5-yl)phenyl)methanamine dihydrochloride (Step 6 of Example 56, 37 mg, 98 μmol) and ethyl 3-(tert-butyl)-1,2,4-oxadiazole-5-carboxylate (29 mg, 148 μmol) in THF (1.5 mL) was added DABAL-Me3 (38 mg, 148 μmol), and the reaction was heated to 45 °C and stirred at that temperature for 18 h. The reaction mixture was cooled to ambient temperature and diluted with water (1 mL), 1 M HCl solution (1 mL), and EtOAc (5 mL). The layers were separated, and the aqueous phase was extracted with a further portion of EtOAc. The combined organic phases were washed with brine, dried over Na2SO4, filtered, and concentrated. The crude material was purified by reverse-phase HPLC (Method A, 5-55% gradient) to give 3-(tert-butyl)-N-(4-(7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidin-5-yl)benzyl)-1,2,4-oxadiazole-5-carboxamide (5.6 mg, 12% yield). LCMS m / z = 457.2 [M+H] + . 1 H NMR (500 MHz, DMSO-d6) δ: 10.00 (br t, J = 6.1 Hz, 1H), 8.35 (s, 1H), 8.12 (s, 1H), 8.02 - 7.95 (m, 3H), 7.86 (s, 1H), 7.69 (s, 1H), 7.60 (d, J = 7.9 Hz, 2H), 4.60 (d, J=6.1 Hz, 2H), 3.89 (s, 3H), 1.41 - 1.34 (m, 9H).

[0273] C.3 Preparation of pyrazolo[1,5-a]pyridines Example 65: N-(2-methyl-4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)benzyl)-5-(1-methylcyclopropyl)-1,2,4-oxadiazole-3-carboxamide [ka]

[0274] Synthesis of 1,6-bromopyrazolo[1,5-a]pyridin-4-ol [ka] A solution of 6-bromo-4-methoxypyrazolo[1,5-a]pyridine (300 mg, 1.32 mmol) in aqueous HBr (267 mg, 1.32 mmol, 40% purity, 10 mL) was stirred at 130° C. for 12 hours. The reaction mixture was cooled to ambient temperature, and saturated aqueous Na2CO3 solution was added to adjust the pH to 8. The quenched reaction mixture was concentrated in vacuo to give the crude material, which was purified by silica gel column chromatography (PE / EtOAc = 7:3) to give 6-bromopyrazolo[1,5-a]pyridin-4-ol as a brown solid (150 mg, 51% yield). LCMS m / z = 212.9, 214.9 [M+H] + .

[0275] Synthesis of 2,6-bromopyrazolo[1,5-a]pyridin-4-yl trifluoromethanesulfonate [ka] To a solution of 6-bromopyrazolo[1,5-a]pyridin-4-ol (100 mg, 0.47 mmol) in DCM (10 mL) was added TEA (143 mg, 1.41 mmol), and the reaction mixture was cooled to 0 °C in an ice-water cooling bath. Triflic anhydride (265 mg, 0.94 mmol) was added, and the reaction mixture was stirred at 0 °C for 30 minutes. The reaction mixture was concentrated, and the crude material was purified by preparative TLC (PE / EtOAc = 10:1) to give 6-bromopyrazolo[1,5-a]pyridin-4-yl trifluoromethanesulfonate as a clear oil (150 mg, 84% yield). LCMS m / z = 344.9, 346.9 [M+H] + .

[0276] 3. Synthesis of tert-butyl (4-(6-bromopyrazolo[1,5-a]pyridin-4-yl)-2-methylbenzyl)carbamate [ka] A mixture of tert-butyl (2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)carbamate (208 mg, 0.60 mmol), 6-bromopyrazolo[1,5-a]pyridin-4-yl trifluoromethanesulfonate (207 mg, 0.60 mmol), K2CO3 (249 mg, 1.80 mmol), and Pd(dppf)Cl2·DCM (49 mg, 60 μmol) was dissolved in dioxane (4.8 mL) and water (1.2 mL), and N2 was bubbled through the mixture for 5 minutes. The reaction mixture was heated to 100 °C for 1 hour under a N2 atmosphere. The reaction was cooled to ambient temperature and filtered through Celite®. The filtrate was concentrated and the crude material was purified by silica gel column chromatography (EtOAc / heptane, 2% to 100%) to give tert-butyl (4-(6-bromopyrazolo[1,5-a]pyridin-4-yl)-2-methylbenzyl)carbamate as a clear oil (160 mg, 64% yield). LCMS m / z = 416.0, 418.0. [M+H] + .

[0277] 4. Synthesis of tert-butyl (2-methyl-4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)benzyl)carbamate [ka] A mixture of tert-butyl (4-(6-bromopyrazolo[1,5-a]pyridin-4-yl)-2-methylbenzyl)carbamate (75 mg, 0.18 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (56 mg, 0.27 mmol), K2CO3 (75 mg, 0.54 mmol), and Pd(dppf)Cl2·DCM (15 mg, 18 μmol) was dissolved in dioxane (1.4 mL) and water (0.4 mL), and N2 was bubbled through the mixture for 5 minutes. The reaction mixture was heated to 100 °C under a N2 atmosphere and stirred for 1 hour. The reaction mixture was cooled to ambient temperature and filtered through Celite®. The filtrate was concentrated and the crude material was purified by silica gel column chromatography (EtOAc / heptane, 2% to 100%) to give tert-butyl (2-methyl-4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)benzyl)carbamate as a clear oil (44 mg, 59% yield). LCMS m / z = 418.1 [M+H] +

[0278] 5. Synthesis of (2-methyl-4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)phenyl)methanamine dihydrochloride [ka] To a solution of tert-butyl (2-methyl-4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)benzyl)carbamate (44 mg, 0.11 mmol) in minimal EtOAc was added HCl solution (1 M in EtOAc, 1 mL) and the reaction was stirred at ambient temperature for 3 days. The reaction mixture was concentrated to give (2-methyl-4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)phenyl)methanamine dihydrochloride (40 mg, crude), which was carried forward without further purification. LCMS m / z = 318.0 [M+H] +

[0279] 6. Synthesis of N-(2-methyl-4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)benzyl)-5-(1-methylcyclopropyl)-1,2,4-oxadiazole-3-carboxamide [ka] N-(2-methyl-4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)benzyl)-5-(1-methylcyclopropyl)-1,2,4-oxadiazole-3-carboxamide was obtained as a white solid (11.3 mg, 47% yield) from (2-methyl-4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)phenyl)methanamine dihydrochloride and potassium 5-(1-methylcyclopropyl)-1,2,4-oxadiazole-3-carboxylate according to a method similar to that used in Example 5. The crude product was purified by preparative HPLC (Method C1, 5-65% gradient). LCMS m / z = 468.2 [M+H] + . 1 H NMR (500 MHz, DMSO-d6) δ: 9.42 (t, J = 6.1 Hz, 1H), 8.99 (s, 1H), 8.32 (s, 1H), 8.06 (s, 1H), 8.01 (d, J = 2.4 Hz, 1H), 7.61 - 7.50 (m, 3H), 7.39 (d, J = 7.9 Hz, 1H), 6.67 (dd, J = 2.4 Hz, 1.2 Hz, 1H), 4.51 (d, J = 6.1 Hz, 2H), 3.88 (s, 3H), 2.43 (s, 3H), 1.55 (s, 3H), 1.42 - 1.36 (m, 2H), 1.20 - 1.12 (m, 2H).

[0280] Example 66: Synthesis of 1-(tert-butyl)-N-(2-methyl-4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)benzyl)-1H-1,2,3-triazole-4-carboxamide [ka] 1-(tert-butyl)-N-(2-methyl-4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)benzyl)-1H-1,2,3-triazole-4-carboxamide was obtained as a pink solid (10.7 mg, 45% yield) from (2-methyl-4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)phenyl)methanamine dihydrochloride (Step 6 of Example 65) and 1-(tert-butyl)-1H-1,2,3-triazole-4-carboxylic acid following a similar method to that described in Example 4. The crude material was purified by reverse-phase HPLC (Method A, 5-60% gradient). LCMS m / z = 469.3 [M+H] + . 1 H NMR (500 MHz, DMSO-d6) δ: 9.01 (t, J = 6.1 Hz, 1H), 8.99 - 8.97 (m, 1H), 8.71 (s, 1H), 8.32 (s, 1H), 8.05 (s, 1H), 8.01 (d, J = 2.4 Hz, 1H), 7.60 - 7.54 (m, 2H), 7.51 (d, J = 1.2 Hz, 1H), 7.39 (d, J = 7.9 Hz, 1H), 6.70 - 6.64 (m, 1H), 4.52 (d, J = 6.1 Hz, 2H), 3.88 (s, 3H), 2.44 (s, 3H), 1.64 (s, 9H).

[0281] Example 67: N-(2-fluoro-4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)benzyl)-5-(1-methylcyclopropyl)-1,2,4-oxadiazole-3-carboxamide [ka]

[0282] 1. Synthesis of tert-butyl (4-(6-bromopyrazolo[1,5-a]pyridin-4-yl)-2-fluorobenzyl)carbamate [ka] A mixture of tert-butyl (2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)carbamate (211 mg, 0.60 mmol), 6-bromopyrazolo[1,5-a]pyridin-4-yl trifluoromethanesulfonate (207 mg, 0.60 mmol), K2CO3 (249 mg, 1.80 mmol), and Pd(dppf)Cl2·DCM (49 mg, 60 μmol) was dissolved in dioxane (4.8 mL) and water (1.2 mL), and N2 was bubbled through the mixture for 5 minutes. The reaction mixture was heated to 100 °C under a N2 atmosphere and stirred for 1 hour. The reaction mixture was cooled to ambient temperature and filtered through Celite®. The filtrate was concentrated and the crude material was purified by silica gel column chromatography (EtOAc / heptane, 2% to 100%) to give tert-butyl (4-(6-bromopyrazolo[1,5-a]pyridin-4-yl)-2-fluorobenzyl)carbamate as a white solid (151 mg, 60% yield). LCMS m / z = 419.9, 421.9 [M+H] +

[0283] 2. Synthesis of tert-butyl (2-fluoro-4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)benzyl)carbamate [ka] A mixture of tert-butyl (4-(6-bromopyrazolo[1,5-a]pyridin-4-yl)-2-fluorobenzyl)carbamate (151 mg, 0.36 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (112 mg, 0.54 mmol), K2CO3 (149 mg, 1.1 mmol), and Pd(dppf)Cl2·DCM (29 mg, 36 μmol) was dissolved in dioxane (2.9 mL) and water (0.7 mL), and N2 was bubbled through the mixture for 5 minutes. The reaction was heated to 100 °C under a N2 atmosphere and stirred for 1 hour. The reaction mixture was cooled to ambient temperature and filtered through Celite®. The filtrate was concentrated and the crude material was purified by silica gel column chromatography (EtOAc / heptane, 2% to 100%) to give tert-butyl (2-fluoro-4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)benzyl)carbamate as an off-white solid (115 mg, 76% yield). LCMS m / z = 422.1 [M+H] +

[0284] 3. Synthesis of (2-fluoro-4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)phenyl)methanamine dihydrochloride [ka] To a solution of tert-butyl (2-fluoro-4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)benzyl)carbamate (115 mg, 0.27 mmol) in minimal EtOAc was added HCl solution (1 M in EtOAc, 2.7 mL). The reaction mixture was stirred at ambient temperature for 3 days. The reaction mixture was concentrated to give (2-fluoro-4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)phenyl)methanamine dihydrochloride (115 mg, crude), which was carried forward without further purification. LCMS m / z = 322.0 [M+H] +

[0285] 4. Synthesis of N-(2-fluoro-4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)benzyl)-5-(1-methylcyclopropyl)-1,2,4-oxadiazole-3-carboxamide [ka] N-(2-fluoro-4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)benzyl)-5-(1-methylcyclopropyl)-1,2,4-oxadiazole-3-carboxamide was obtained as a white solid (8.3 mg, 25% yield) from (2-fluoro-4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)phenyl)methanamine dihydrochloride and potassium 5-(1-methylcyclopropyl)-1,2,4-oxadiazole-3-carboxylate according to a method similar to that used in Step 8 of Example 1. The crude material was purified by preparative HPLC (Method A, 5-60% gradient). LCMS m / z = 472.4 [M+H] + . 1 H NMR (500 MHz, DMSO-d6) δ: 9.51 (t, J = 6.1 Hz, 1H), 9.03 (s, 1H), 8.34 (s, 1H), 8.07 (s, 1H), 8.04 (d, J = 2.4 Hz, 1H), 7.67 - 7.58 (m, 3H), 7.52 (t, J = 7.9 Hz, 1H), 6.71 (d, J = 2.4 Hz, 1H), 4.57 (d, J = 6.1 Hz, 2H), 3.88 (s, 3H), 1.54 (s, 3H), 1.46 - 1.35 (m, 2H), 1.22 - 1.12 (m, 2H).

[0286] Example 68: Synthesis of 5-(tert-butyl)-N-(2-fluoro-4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)benzyl)-1,2,4-oxadiazole-3-carboxamide [ka] 5-(tert-butyl)-N-(2-fluoro-4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)benzyl)-1,2,4-oxadiazole-3-carboxamide was obtained as a white solid (7.3 mg, 22% yield) from (2-fluoro-4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)phenyl)methanamine dihydrochloride (Example 67, Step 3) and lithium 5-(tert-butyl)-1,2,4-oxadiazole-3-carboxylate according to a method similar to that used in Example 67, Step 4. The crude material was purified by preparative HPLC, Method A, gradient 5-65%. LCMS m / z = 474.4 [M+H] + 1 H NMR (500 MHz, DMSO-d6) δ: 9.56 (t, J = 6.1 Hz, 1H), 9.03 (s, 1H), 8.34 (s, 1H), 8.07 (s, 1H), 8.04 (d, J = 1.8 Hz, 1H), 7.70 - 7.60 (m, 3H), 7.53 (t, J = 7.9 Hz, 1H), 6.76 - 6.67 (m, 1H), 4.58 (d, J = 6.1 Hz, 2H), 3.88 (s, 3H), 1.43 (s, 9H).

[0287] Example 69: Synthesis of 1-(tert-butyl)-N-(2-fluoro-4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)benzyl)-1H-1,2,3-triazole-4-carboxamide [ka] 1-(tert-butyl)-N-(2-fluoro-4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)benzyl)-1H-1,2,3-triazole-4-carboxamide was obtained as a white solid (3.5 mg, 10% yield) from (2-fluoro-4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)phenyl)methanamine dihydrochloride (Step 3 of Example 67) and 1-(tert-butyl)-1H-1,2,3-triazole-4-carboxylic acid according to a method similar to that used in Step 8 of Example 1. The crude material was purified by preparative HPLC (Method A, 5-60% gradient). LCMS m / z = 473.5 [M+H] + . 1 H NMR (500 MHz, DMSO-d6) δ: 9.12 (t, J = 6.1 Hz, 1H), 9.03 (s, 1H), 8.72 (s, 1H), 8.37 - 8.30 (m, 1H), 8.07 (s, 1H), 8.03 (d, J = 2.4 Hz, 1H), 7.63 - 7.59 (m, 3H), 7.54 - 7.47 (m, 1H), 6.71 (d, J = 2.4 Hz, 1H), 4.58 (d, J = 6.1 Hz, 2H), 3.88 (s, 3H), 1.64 (s, 9H).

[0288] Example 70: Synthesis of 1-(tert-butyl)-N-(2-fluoro-4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)benzyl)-1H-pyrazole-3-carboxamide [ka] 1-(tert-butyl)-N-(2-fluoro-4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)benzyl)-1H-pyrazole-3-carboxamide as a white solid (17.9 mg, 53% yield) was obtained from (2-fluoro-4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)phenyl)methanamine dihydrochloride (Step 3 of Example 67) and 1-(tert-butyl)-1H-pyrazole-3-carboxylic acid according to a method similar to that described in Step 8 of Example 1. LCMS m / z = 472.5 [M+H] + . 1 H NMR (500 MHz, DMSO-d6) δ: 9.07 - 8.98 (m, 1H), 8.61 (t, J = 6.1 Hz, 1H), 8.33 (s, 1H), 8.07 (s, 1H), 8.03 (d, J = 2.4 Hz, 1H), 7.93 (d, J = 2.4 Hz, 1H), 7.68 - 7.57 (m, 3H), 7.56 - 7.47 (m, 1H), 6.75 - 6.70 (m, 1H), 6.66 (d, J = 2.4 Hz, 1H), 4.56 (d, J = 6.1 Hz, 2H), 3.88 (s, 3H), 1.57 (s, 9H).

[0289] Example 71: 3-(1-fluoro-2-methylpropan-2-yl)-N-(2-fluoro-4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)benzyl)-1,2,4-oxadiazole-5-carboxamide [ka]

[0290] Synthesis of 1,3-hydroxy-2,2-dimethylpropanenitrile [ka] To a solution of methyl 2-cyano-2-methylpropanoate (100 g, 786 mmol) in THF (800 mL) and water (2 L), NaBH (89.3 g, 2.36 mol) was added slowly over 1 h at 15 °C (ice-water bath), and the mixture was stirred at 20 °C for 4 h. The reaction was quenched by the slow addition of aqueous HCl (6 M) to pH < 7. The mixture was extracted with EtOAc (3 times), and the organic layer was washed with 2 N NaOH and brine. The organic phase was dried over NaSO, filtered, and concentrated in vacuo to give a colorless oil (48 g). Heptane was added, and the mixture was concentrated again to remove volatiles. Crude 3-hydroxy-2,2-dimethylpropanenitrile was obtained as a colorless oil (47 g, 60% yield), which was carried forward without further purification. 1 H NMR (300 MHz, CDCl3) δ: 3.56 (s, 2H), 2.51 (br s, 1H), 1.31 (s, 6H).

[0291] 2. Synthesis of (E)-N',3-dihydroxy-2,2-dimethylpropanimidamide [ka] To a solution of 3-hydroxy-2,2-dimethylpropanenitrile (51.0 g, 515 mmol) in EtOH (800 mL) was added hydroxylamine (50 wt% in water, 120 mL, 2.06 mol) at 25 °C, and the reaction was stirred at 70 °C overnight. The mixture was cooled, concentrated in vacuo, and water was azeotropically removed with toluene (twice) and THF (once). The white solid was triturated with EtO, filtered, and dried again in vacuo to give (£)-N',3-dihydroxy-2,2-dimethylpropanimidamide as a white solid (62.5 g, 91% yield), which was carried forward without further purification. 1 H NMR (300 MHz, DMSO-d6) δ: 8.85 (s, 1H), 5.20 (s, 2H), 4.54 (br s, 1H), 3.31 (s, 2H), 1.03 (s, 6H).

[0292] 3. Synthesis of ethyl 3-(1-hydroxy-2-methylpropan-2-yl)-1,2,4-oxadiazole-5-carboxylate [ka] Ethyl 2-chloro-2-oxo-acetate (53.0 mL, 473 mmol) was added to a solution of (£)-N',3-dihydroxy-2,2-dimethylpropanimidamide (62.5 g, 473 mmol) in pyridine (1 L) cooled in an ice-water bath. After 1 h, the reaction mixture was heated to 80 °C and stirred at that temperature for 16 h. The mixture was concentrated in vacuo to remove pyridine. The residue was dissolved in EtOAc (400 mL) and water (300 mL) and extracted with EtOAc (3 x 300 mL). The combined organic phase was washed with water (100 mL) and brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (eluted with DCM / EtOAc, 10 / 1 to 1 / 1) to give a mixture of ethyl 3-(1-hydroxy-2-methylpropan-2-yl)-1,2,4-oxadiazole-5-carboxylate and 20 mol% of 3-hydroxy-2,2-dimethylpropanenitrile. Most of the 3-hydroxy-2,2-dimethylpropanenitrile was removed by Kugelrohr distillation at 90°C to give ethyl 3-(1-hydroxy-2-methylpropan-2-yl)-1,2,4-oxadiazole-5-carboxylate as a colorless oil (22.5 g, 22% yield), which was carried forward without further purification.

[0293] 4. Synthesis of ethyl 3-(2-methyl-1-(((trifluoromethyl)sulfonyl)oxy)propan-2-yl)-1,2,4-oxadiazole-5-carboxylate [ka] To a solution of ethyl 3-(1-hydroxy-2-methylpropan-2-yl)-1,2,4-oxadiazole-5-carboxylate (22.2 g, 104 mmol) and DIPEA (35.4 mL, 207.3 mmol) in DCM (600 mL) at 0 °C, triflic anhydride (21 mL, 124 mmol) was added and the mixture was stirred at room temperature overnight. Additional DCM (200 mL) was added, followed by water (100 mL). The phases were separated and the organic phase was washed with water (100 mL). The organic phase was dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (heptane / EtOAc = 5 / 1 to 3 / 1) to give ethyl 3-(2-methyl-1-(((trifluoromethyl)sulfonyl)oxy)propan-2-yl)-1,2,4-oxadiazole-5-carboxylate as an orange oil (27.5 g, yield 76%). 1 H NMR (300 MHz, CDCl3) δ: 4.71 (s, 2H), 4.53 (q, J = 7.3 Hz, 2H), 1.56 (s, 6H), 1.43 (t, J = 7.4 Hz, 3H).

[0294] 5. Synthesis of ethyl 3-(1-fluoro-2-methylpropan-2-yl)-1,2,4-oxadiazole-5-carboxylate [ka] A solution of ethyl 3-(2-methyl-1-(((trifluoromethyl)sulfonyl)oxy)propan-2-yl)-1,2,4-oxadiazole-5-carboxylate (27.5 g, 79.4 mmol) and tetrabutylammonium hydrogen difluoride (50% in MeCN, 89.0 g, 159 mmol) in THF (700 mL) was stirred at 40° C. for 48 hours. The mixture was concentrated in vacuo. The residue was dissolved in EtOAc (700 mL) and washed with water (3×100 mL). The organic phase was dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography (eluted with heptane / EtOAc = 5 / 1 to 3 / 1) to give ethyl 3-(1-fluoro-2-methylpropan-2-yl)-1,2,4-oxadiazole-5-carboxylate as a colorless oil (11.3 g, 65% yield). 1 H NMR (300 MHz, CDCl3) δ: 4.63 (s, 1H), 4.54 (q, J=7.4 Hz, 2H), 4.46 (s, 1H), 1.56 - 1.38 (m, 9H).

[0295] 6. Synthesis of 3-(1-fluoro-2-methylpropan-2-yl)-1,2,4-oxadiazole-5-carboxylic acid [ka] To a cold solution of ethyl 3-(1-fluoro-2-methylpropan-2-yl)-1,2,4-oxadiazole-5-carboxylate (9.70 g, 44.9 mmol) in MeOH (90 mL) was added a solution of LiOH.HO (3.76 g, 89.7 mmol) in water (15 mL), and the resulting mixture was stirred at room temperature for 2 h. The MeOH was removed in vacuo, and the aqueous residue (cooled in an ice bath) was acidified with concentrated HCl to pH = 2-3. The mixture was concentrated in vacuo to give a white solid. The residue was dried by coevaporation with toluene (3 × 10 mL). The resulting white solid was suspended in 5% MeOH in DCM (100 mL), the mixture was filtered, and the filter cake was washed with the same mixture (3 × 10 mL). The filtrates were combined, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to give 3-(1-fluoro-2-methylpropan-2-yl)-1,2,4-oxadiazole-5-carboxylic acid as a white solid (7.0 g, crude), which was carried forward without further purification. LCMS m / z = 189.0 [M+H] +

[0296] 7. Synthesis of 3-(1-fluoro-2-methylpropan-2-yl)-N-(2-fluoro-4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)benzyl)-1,2,4-oxadiazole-5-carboxamide [ka] 3-(1-Fluoro-2-methylpropan-2-yl)-N-(2-fluoro-4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)benzyl)-1,2,4-oxadiazole-5-carboxamide was obtained as a white solid (4.5 mg, 13% yield) from (2-fluoro-4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-4-yl)phenyl)methanamine dihydrochloride (Step 3 of Example 67) and 3-(1-fluoro-2-methylpropan-2-yl)-1,2,4-oxadiazole-5-carboxylic acid according to a method similar to that used in Step 8 of Example 1. The crude material was purified by reverse-phase HPLC (Method A, 5-65% gradient). LCMS m / z = 492.4 [M+H] + 1 H NMR (500 MHz, DMSO-d6) δ: 9.98 (t, J = 5.8 Hz, 1H), 9.04 (s, 1H), 8.34 (s, 1H), 8.07 (s, 1H), 8.04 (d, J = 1.8 Hz, 1H), 7.69 - 7.52 (m, 4H), 6.75 - 6.67 (m, 1H), 4.62 (s, 1H), 4.60 (d, J = 6.1 Hz, 2H), 4.53 (s, 1H), 3.88 (s, 3H), 1.38 (d, J = 1.8 Hz, 6H). C.4 Preparation of [1,2,4]triazolo[1,5-a]pyrazine

[0297] Example 72: 2-(tert-butyl)-N-((1-(6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-8-yl)piperidin-4-yl)methyl)-2H-tetrazole-5-carboxamide [ka]

[0298] 1. Preparation of tert-butyl ((1-(6-bromo-[1,2,4]triazolo[1,5-a]pyrazin-8-yl)piperidin-4-yl)methyl)carbamate [ka] A suspension of tert-butyl N-(4-piperidylmethyl)carbamate (500 mg, 2.33 mmol), 6,8-dibromo-[1,2,4]triazolo[1,5-a]pyrazine (647.52 mg, 2.33 mmol), and DIPEA (602.26 mg, 4.66 mmol) in IPA (10 mL) was stirred at room temperature for 2 hours. After 15 minutes, a large amount of white solid formed, so additional IPA (10 mL) was added to allow stirring. The mixture was filtered, and the solid was washed with IPA and dried to give tert-butyl ((1-(6-bromo-[1,2,4]triazolo[1,5-a]pyrazin-8-yl)piperidin-4-yl)methyl)carbamate (864 mg, 90.2% yield) as a white solid. 1 H NMR (500 MHz, CDCl3) δ ppm: 8.20 (s, 1 H), 7.99 (s, 1 H), 5.66-5.30 (br s, 2 H), 4.64 (br s, 1 H), 3.20-3.01 (m, 4 H), 1.95-1.80 (m, 3 H), 1.46 (s, 9 H), 1.39-1.24 (m, 2 H).

[0299] 2. Synthesis of tert-butyl ((1-(6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-8-yl)piperidin-4-yl)methyl)carbamate [ka] A mixture of tert-butyl ((1-(6-bromo-[1,2,4]triazolo[1,5-a]pyrazin-8-yl)piperidin-4-yl)methyl)carbamate (150 mg, 364.7 μmol), (1-methylpyrazol-4-yl)boronic acid (91.85 mg, 729.4 μmol), and CsCO (356.48 mg, 1.09 mmol) in dry dioxane (3.0 mL) was sparged with N for 5 minutes. RuPhos (34.04 mg, 72.94 μmol) and Pd(dba) (33.40 mg, 36.47 μmol) were added, and the resulting mixture was heated at 100° C. for 17 hours. The cooled mixture was filtered through a pad of Celite®, washing with EtOAc, and the filtrate was concentrated in vacuo. The residue was purified by silica gel chromatography (0-100% heptane in EtOAc) to afford tert-butyl ((1-(6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-8-yl)piperidin-4-yl)methyl)carbamate (116 mg, 77.1% yield) as an orange solid. LCMS m / z = 413.2 [M+H] +

[0300] 3. Synthesis of (1-(6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-8-yl)piperidin-4-yl)methanamine hydrochloride [ka] A suspension of tert-butyl ((1-(6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-8-yl)piperidin-4-yl)methyl)carbamate (115 mg, 278.79 μmol) in MeOH (1.0 mL) was treated with 4 M HCl in dioxane (975.77 uL) and the reaction was stirred at room temperature for 2 hours. The mixture was concentrated to dryness to give (1-(6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-8-yl)piperidin-4-yl)methanamine dihydrochloride as a white solid. LCMS m / z = 313.2 [M+H] +

[0301] 4. Synthesis of 2-(tert-butyl)-N-((1-(6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-8-yl)piperidin-4-yl)methyl)-2H-tetrazole-5-carboxamide [ka] T3P® (218.91 mg, 344.01 μmol, 50% purity) was added to a solution of 2-tert-butyltetrazole-5-carboxylic acid (43.90 mg, 258.01 μmol), (1-(6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-8-yl)piperidin-4-yl)methanamine hydrochloride (60 mg, 172 μmol), and DIPEA (111.15 mg, 860.02 μmol) in dry DMF (2.0 mL), and the reaction was stirred at room temperature for 2 days. Additional DIPEA (111.15 mg, 860.02 μmol) and T3P® (218.91 mg, 344.01 μmol, 232.89 μL, 50% purity) were added, and stirring was continued for 2 hours. The reaction was quenched with saturated NaHCO3 solution and extracted with EtOAc. The organic layer was washed with brine (3 times) and the combined aqueous layers were extracted with EtOAc. The combined organic layers were dried (MgSO4), filtered, and concentrated in vacuo. The crude material was purified by preparative HPLC (Method C2, 5-60% gradient) to afford 2-(tert-butyl)-N-((1-(6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-8-yl)piperidin-4-yl)methyl)-2H-tetrazole-5-carboxamide (68.40 mg, 81.3% yield) as an orange solid. LCMS m / z = 465.2 [M+H] +1H NMR (500 MHz, CDCl3) δ ppm: 8.25 - 8.21 (m, 1 H), 8.11-8.08 (m, 1 H), 7.87 (s, 1 H), 7.84 (s, 1 H), 7.34-7.29 (m, 1 H), 5.51 (br d, J=13.4 Hz, 2 H), 4.00-3.96 (m, 3 H), 3.49 (t, J=6.7 Hz, 2 H), 3.19 - 3.11 (m, 2 H), 2.14-2.03 (m, 1 H), 2.03-1.94 (m, 2 H), 1.83 - 1.81 (m, 9 H), 1.52 - 1.42 (m, 2 H).

[0302] Example 73: 5-(tert-butyl)-N-((1-(6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-8-yl)piperidin-4-yl)methyl)-1,2,4-oxadiazole-3-carboxamide [ka] To a suspension of (1-(6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-8-yl)piperidin-4-yl)methanamine dihydrochloride (Step 3 of Example 72, 95.0 mg, 272.34 μmol) and lithium 5-tert-butyl-1,2,4-oxadiazole-3-carboxylate (96.47 mg, 544.68 μmol) in dry DMF (2.0 mL) was added DIPEA (176 mg, 1.36 mmol), followed by T3P® (259.96 mg, 817.02 μmol), and the reaction was stirred at room temperature for 17 hours. The reaction was diluted with EtOAc and washed with saturated NaHCO3, water, and brine (twice). The combined aqueous layer was re-extracted with EtOAc, and the combined organic extracts were dried (MgSO4), filtered, and concentrated in vacuo. The residue was purified by preparative HPLC (Method C2, 5-60% gradient) to give 5-(tert-butyl)-N-((1-(6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-8-yl)piperidin-4-yl)methyl)-1,2,4-oxadiazole-3-carboxamide (79.9 mg, 60% yield) as an off-white solid. LCMS m / z = 465.3 [M+H] + 1H NMR (500 MHz, CDCl3) δ ppm: 8.24 (s, 1 H), 8.09 (s, 1 H), 7.92 (s, 1 H), 7.84 (s, 1 H), 7.12 (br t, J=6.1 Hz, 1 H), 5.48 (br d, J=13.4 Hz, 2 H), 3.97 - 4.03 (m, 3 H), 3.44 (t, J=6.4 Hz, 2 H), 3.18 - 3.08 (m, 2 H), 2.13 - 2.02 (m, 1 H), 1.96 (br d, J=12.8 Hz, 2 H), 1.48 (s, 9 H), 1.47-1.39 (m, 2 H).

[0303] Example 74: 1-(tert-butyl)-N-((1-(6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-8-yl)piperidin-4-yl)methyl)-1H-1,2,3-triazole-4-carboxamide [ka] 1-(tert-butyl)-N-((1-(6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-8-yl)piperidin-4-yl)methyl)-1H-1,2,3-triazole-4-carboxamide as an off-white solid (55.7 mg, 62.9% yield) was obtained from (1-(6-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-8-yl)piperidin-4-yl)methanamine dihydrochloride (Step 3 of Example 72) and 1-tert-butyltriazole-4-carboxylic acid according to the method described in Step 4 of Example 72. LCMS m / z=464.3 [M+H] + 1H NMR (500 MHz, CDCl3) δ ppm 8.24 (s, 1 H), 8.17-8.13 (m, 1 H), 8.09 (s, 1 H), 7.90-7.85 (m, 1 H), 7.84 (s, 1 H), 7.35 - 7.30 (m, 1 H), 5.61-5.43 (m, 2 H), 3.99 (s, 3 H), 3.44 (t, J=6.4 Hz, 2 H), 3.19 - 3.10 (m, 2 H), 2.09 - 2.02 (m, 1 H), 2.02-1.95 (m, 2 H), 1.74 - 1.70 (m, 1 H), 1.52 - 1.40 (m, 2 H). C.5 Preparation of [1,2,4]triazolo[4,3-a]pyridines

[0304] Example 75: 1-(tert-butyl)-N-(4-(7-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-5-yl)benzyl)-1H-1,2,3-triazole-4-carboxamide [ka]

[0305] Synthesis of 1,5-chloro-7-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridine [ka] A mixture of 7-bromo-5-chloro-[1,2,4]triazolo[4,3-a]pyridine (112 mg, 0.48 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (100 mg, 0.48 mmol), K2CO3 (199 mg, 1.4 mmol), and Pd(dppf)Cl2·DCM (39 mg, 48 μmol) was dissolved in dioxane (3.8 mL) and water (1 mL), and N2 was bubbled through the mixture for 5 minutes. The reaction mixture was heated to 100 °C under a N2 atmosphere and stirred at that temperature for 1 hour. The reaction mixture was cooled to ambient temperature and filtered through Celite®. The filtrate was concentrated, and the crude material was purified by silica gel column chromatography (3:1 EtOAc / EtOH:heptane, 2% to 100%) to afford 5-chloro-7-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridine as an off-white solid (84 mg, 75% yield). 1 H NMR (500MHz, MeOH-d4) δ: 9.27 (s, 1H), 8.25 (s, 1H), 8.06 (s, 1H), 7.87 (s, 1H), 7.54 - 7.50 (m, 1H), 3.96 (s, 3H).

[0306] 2. Synthesis of tert-butyl (4-(7-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-5-yl)benzyl)carbamate [ka] A mixture of tert-butyl (4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)carbamate (120 mg, 0.36 mmol), 5-chloro-7-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridine (84 mg, 0.36 mmol), K2CO3 (149 mg, 1.1 mmol), and Pd(dppf)Cl2·DCM (29 mg, 36 μmol) was dissolved in dioxane (2.9 mL) and water (0.7 mL), and N2 was bubbled through the mixture for 5 minutes. The reaction mixture was heated to 100 °C under a N2 atmosphere and stirred for 2 hours. The reaction mixture was cooled to ambient temperature and filtered through Celite®. The filtrate was concentrated and the crude material was purified by silica gel column chromatography ([3:1 EtOAc / EtOH] / heptane 2% to 100%) to give tert-butyl (4-(7-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-5-yl)benzyl)carbamate as a brown solid (129 mg, 89% yield). LCMS m / z = 405.1 [M+H] +

[0307] 3. Synthesis of (4-(7-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-5-yl)phenyl)methanamine dihydrochloride [ka] To a solution of tert-butyl (4-(7-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-5-yl)benzyl)carbamate (125 mg, 309 μmol) in EtOAc (1 mL) was added HCl solution (1 M in EtOAc, 3.09 mL) and the reaction was stirred at ambient temperature for 3 days. The reaction mixture was concentrated and the crude material was carried forward without further purification (94 mg, crude). LCMS m / z = 305 [M+H] +

[0308] 4. Synthesis of 1-(tert-butyl)-N-(4-(7-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-5-yl)benzyl)-1H-1,2,3-triazole-4-carboxamide [ka] To a solution of 1-(tert-butyl)-1H-1,2,3-triazole-4-carboxylic acid (13 mg, 75 μmol) in THF (2 mL) in an ice-water cooling bath, TEA (20 mg, 201 μmol) and HATU (38 mg, 101 μmol) were added. The reaction mixture was stirred at 0° C. for 10 minutes, and then (4-(7-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-5-yl)phenyl)methanamine dihydrochloride (19 mg, 50 μmol) was added. The reaction mixture was warmed to 23° C. and stirred for 24 hours. Water (5 mL) was added to quench the reaction, followed by EtOAc (5 mL), and the layers were separated. The aqueous phase was extracted with EtOAc (2×5 mL). The organic phases were combined, washed with brine, dried over Na2SO4, filtered, and concentrated. The crude material was purified by reverse-phase HPLC (Method C1, 5-45% gradient) to give 1-(tert-butyl)-N-(4-(7-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-5-yl)benzyl)-1H-1,2,3-triazole-4-carboxamide as a white solid (14.7 mg, 51% yield). LCMS m / z = 456.2 [M+H] + 1H NMR (500MHz, DMSO-d6) δ: 9.29 - 9.16 (m, 2H), 8.71 (s, 1H), 8.52 (s, 1H), 8.22 (s, 1H), 8.02 (s, 1H), 7.85 - 7.76 (m, 2H), 7.57 (d, J = 8.5 Hz, 2H), 7.41 (s, 1H), 4.58 (d, J = 6.7 Hz, 2H), 3.89 (s, 3H), 1.68 - 1.61 (m, 9H).

[0309] Example 76: N-(4-(7-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-5-yl)benzyl)-5-(1-methylcyclopropyl)-1,2,4-oxadiazole-3-carboxamide [ka] N-(4-(7-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-5-yl)benzyl)-5-(1-methylcyclopropyl)-1,2,4-oxadiazole-3-carboxamide (13.8 mg, 48% yield) was obtained as a white solid from potassium 5-(1-methylcyclopropyl)-1,2,4-oxadiazole-3-carboxylate and (4-(7-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-5-yl)phenyl)methanamine dihydrochloride (Step 3 of Example 75) according to the method used in Step 4 of Example 75. LCMS m / z = 455.2 [M+H] + 1H NMR (500MHz, DMSO-d6) δ: 9.57 (t, J = 6.1 Hz, 1H), 9.18 (s, 1H), 8.51 (s, 1H), 8.22 (s, 1H), 8.02 (s, 1H), 7.82 (d, J = 8.5 Hz, 2H), 7.57 (d, J = 8.5 Hz, 2H), 7.39 (s, 1H), 4.56 (d, J = 6.7 Hz, 2H), 3.95 - 3.84 (m, 3H), 1.59 - 1.51 (m, 3H), 1.44 - 1.34 (m, 2H), 1.23 - 1.13 (m, 2H).

[0310] Example 77: 1-(tert-butyl)-N-(4-(7-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-5-yl)benzyl)-1H-pyrazole-4-carboxamide [ka] 1-(tert-butyl)-N-(4-(7-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-5-yl)benzyl)-1H-pyrazole-4-carboxamide as a white solid (19.6 mg, 68% yield) was obtained from 1-(tert-butyl)-1H-pyrazole-4-carboxylic acid and (4-(7-(1-methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-5-yl)phenyl)methanamine dihydrochloride (Step 3 of Example 75) according to the method used in Step 4 of Example 75. LCMS m / z = 455.2 [M+H] + . 1H NMR (500MHz, DMSO-d6) δ: 9.18 (s, 1H), 8.72 (t, J = 6.1 Hz, 1H), 8.52 (s, 1H), 8.32 (s, 1H), 8.23 ​​(s, 1H), 8.02 (s, 1H), 7.92 (s, 1H), 7.81 (d, J = 8.5 Hz, 2H), 7.55 (d, J = 7.9 Hz, 2H), 7.40 (s, 1H), 4.54 (d, J = 6.1 Hz, 2H), 3.89 (s, 3H), 1.59 - 1.49 (m, 9H).

[0311] Example 78: 5-(tert-butyl)-N-(2-methyl-4-(7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidin-5-yl)benzyl)-1,2,4-oxadiazole-3-carboxamide [ka] A mixture of 5-(tert-butyl)-N-(2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)-1,2,4-oxadiazole-3-carboxamide (Step 1, Example 55, 100 mg, 250.4 μmol), 5-chloro-7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidine (Step 4, Example 56, 58.52 mg, 250.4 μmol), KCO (103.84 mg, 751.3 μmol), and Pd(dppf)Cl (9.16 mg, 12.5 μmol) was dissolved in dioxane (2.0 mL) and water (0.5 mL), and N was bubbled through the mixture for 5 minutes. The reaction mixture was heated to 100 °C under N2 and stirred at 100 °C overnight. The cooled reaction was concentrated, dissolved in MeOH, and filtered through a 0.45 μM syringe filter. The filtrate was concentrated and purified by HPLC (Method C3, 5-75%) to give 5-(tert-butyl)-N-(2-methyl-4-(7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidin-5-yl)benzyl)-1,2,4-oxadiazole-3-carboxamide (70 mg, 56.4% yield). LCMS m / z = 471.3 [M+H] + . 1 H NMR (500 MHz, DMSO-d6) δ ppm 9.54 (t, J=6.10 Hz, 1H) 8.33 (s, 1H) 8.10 (s, 1H) 7.93 - 7.90 (m, 1H) 7.83 (s, 1H) 7.82 - 7.78 (m, 2 H), 7.64 - 7.61 (m, 1 H) 7.48 (d, J=8.55 Hz, 1H) 4.56 (d, J=6.10 Hz, 2H) 3.89 (s, 3 H) 2.46 (s, 3 H) 1.44 (s, 9H).

[0312] Example 79: 5-(tert-butyl)-N-(3-fluoro-2-methyl-4-(7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidin-5-yl)benzyl)-1,2,4-oxadiazole-3-carboxamide [ka]

[0313] 1. Preparation of (4-bromo-3-fluoro-2-methylphenyl)methanamine hydrochloride [ka] To a solution of 4-bromo-3-fluoro-2-methylbenzonitrile (62.2 g, 290 mmol) in THF (150 mL) was added BH3.THF (49.9 g, 581 mmol), and the solution was stirred at 70 °C overnight. The reaction was quenched by careful addition of MeOH at 0 °C, the mixture was concentrated, the residue was dissolved in DCM (1 L), and 36% aqueous HCl (20 mL) was slowly added. The mixture was stirred for 30 min, and the resulting solid was filtered off, washed with DCM and TBME, and dried under vacuum to give (4-bromo-3-fluoro-2-methylphenyl)methanamine hydrochloride (58.6 g, 79%) as a gray solid. LCMS m / z = 218.2 [M+H] + .

[0314] 2. Preparation of tert-butyl (4-bromo-3-fluoro-2-methylbenzyl)carbamate [ka] To a suspension of 4-bromo-3-fluoro-2-methylphenyl)methanamine hydrochloride (63.0 g, 247 mmol) in DCM (450 mL) was added TEA (75.1 g, 742 mmol) and (Boc)O (64.8 g, 297 mmol), and the reaction was stirred at room temperature overnight. The mixture was washed with water and brine, dried over NaSO, and concentrated. The crude product was used directly in the next step.

[0315] 3. Preparation of tert-butyl (3-fluoro-2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)carbamate [ka] A solution of tert-butyl (4-bromo-3-fluoro-2-methylbenzyl)carbamate (47.4 g, 149 mmol), bis(pinacolato)diboron (45.4 g, 179 mmol), and KOAc (29.3 g, 298 mmol) in dioxane (600 mL) was stirred at room temperature for 10 min under N2. PdCl2(dppf) ⋅DCM (12.2 g, 14.9 mmol) was added, and the reaction mixture was stirred at 90 °C for 16 h. The mixture was filtered through Celite®, and the filtrate was diluted with EtOAc and then washed with water, aqueous NaHCO3, and brine. The organic layer was dried over Na2SO4 and concentrated in vacuo. The crude product was purified by column chromatography (heptane:EtOAc, gradient 0 to 30% EtOAc) to give impure product. The solid was triturated with hexane and the solid was filtered off and dried to give (tert-butyl(3-fluoro-2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)carbamate, 42.3g, 78%.

[0316] 4. Preparation of (3-fluoro-2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanamine hydrochloride [ka] tert-Butyl (3-fluoro-2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)carbamate (30.0 g, 82.1 mmol) was suspended in 4 M HCl in dioxane (62 mL, 246 mmol), and the mixture was stirred at room temperature for 1 hour. The mixture was concentrated in vacuo and azeotroped with toluene (5 × 50 mL) to give (3-fluoro-2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanamine hydrochloride (25.8 g, crude) as a pale pink solid.

[0317] 5. Preparation of (3-fluoro-2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanamine [ka] DIPEA (45 mL, 257 mmol) was added to a solution of (3-fluoro-2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanamine hydrochloride (25.8 g, 85.6 mmol) and 5-(tert-butyl)-1,2,4-oxadiazole-3-carboxylic acid (21.8 g, 128 mmol) in anhydrous DMF (500 mL), and the mixture was cooled to 0° C. T3P® (64.7 mL, 111 mmol) was added, and the resulting mixture was warmed to room temperature and stirred for 2 hours. The reaction was quenched with water (300 mL), and EtOAc (300 mL) was added. The layers were separated, and the aqueous layer was extracted with EtOAc (3×100 mL). The combined organic layers were washed with water (3 × 50 mL), saturated aqueous NaHCO (50 mL), and brine (50 mL), dried over NaSO, filtered, and concentrated in vacuo to give a beige oil, which was purified twice by silica gel column chromatography (heptane:EtOAc, 0–20% gradient) to give (3-fluoro-2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanamine as a thick, pale yellow oil (11.2 g, 31%), which slowly solidified upon standing.

[0318] 6. Preparation of 5-(tert-butyl)-N-(3-fluoro-2-methyl-4-(7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidin-5-yl)benzyl)-1,2,4-oxadiazole-3-carboxamide [ka] A mixture of 5-(tert-butyl)-N-(3-fluoro-2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)-1,2,4-oxadiazole-3-carboxamide (75.0 mg, 179.74 μmol), 5-chloro-7-(1-methylpyrazol-4-yl)imidazo[1,2-c]pyrimidine (42.00 mg, 179.74 μmol), KCO (74.5 mg, 539.2 μmol), and Pd(dppf)Cl (6.58 mg, 8.99 μmol) was dissolved in dioxane (1.44 mL) and water (0.36 mL), and N was bubbled through the mixture for 5 minutes. The reaction mixture was heated to 100 °C under a N atmosphere and stirred at 100 °C for 3 hours. The reaction was concentrated and purified by column chromatography (gradient elution 0-100% [3:1 EtOAc:EtOH]:heptane) to afford 5-(tert-butyl)-N-(3-fluoro-2-methyl-4-(7-(1-methyl-1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidin-5-yl)benzyl)-1,2,4-oxadiazole-3-carboxamide (88 mg, 99.2% yield) as a pale yellow solid. LCMS m / z = 489.2 [M+H] + .1H NMR (400 MHz, DMSO-d6) δ ppm 9.58 (t, J=5.77 Hz, 1 H) 8.31 (s, 1 H) 8.08 (s, 1 H) 7.91 (s, 1 H) 7.66 - 7.60 (m, 2 H) 7.57 (br s, 1 H) 7.35 (d, J=8.03 Hz, 1 H) 4.59 (d, J=6.02 Hz, 2 H) 3.87 (s, 3 H) 2.35 (d, J=2.01 Hz, 3 H) 1.44 (s, 9 H).

[0319] Example 80: 5-(tert-butyl)-N-(2-methyl-4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)benzyl)-1,2,4-oxadiazole-3-carboxamide [ka] 5-(tert-butyl)-N-(2-methyl-4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)benzyl)-1,2,4-oxadiazole-3-carboxamide was obtained as a white solid (74 mg, 82.1% yield) from 5-(tert-butyl)-N-(2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)-1,2,4-oxadiazole-3-carboxamide (Step 1 of Example 55) and 4-chloro-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine (Step 5 of Example 1) according to the procedure described in Step 6 of Example 79. LCMS m / z=471.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ ppm 9.50 (t, J=5.90 Hz, 1 H) 9.12 (d, J=1.00 Hz, 1 H) 8.34 (s, 1 H) 8.18 (d, J=2.51 Hz, 1 H) 8.11 (d, J=0.75 Hz,1 H) 7.95 (d, J=5.02 Hz, 2 H) 7.45 (d, J=8.53 Hz, 1 H) 7.15 (dd, J=2.51, 1.00 Hz, 1 H) 4.55 (d, J=6.27 Hz, 2 H) 3.91 (s, 3 H) 2.48 (s, 3 H) 1.44 (s, 9H).

[0320] Example 81: 5-(tert-butyl)-N-(3-fluoro-2-methyl-4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)benzyl)-1,2,4-oxadiazole-3-carboxamide [ka] 5-(tert-butyl)-N-(3-fluoro-2-methyl-4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)benzyl)-1,2,4-oxadiazole-3-carboxamide was obtained as a pale yellow solid (81 mg, 90.4% yield) from 5-(tert-butyl)-N-(3-fluoro-2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)-1,2,4-oxadiazole-3-carboxamide (Step 5 of Example 79) and 4-chloro-6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazine (Step 5 of Example 1) according to the procedure described in Step 6 of Example 79. LCMS m / z = 489.2 [M+H] + 1H NMR (400 MHz, DMSO-d6) δ ppm 9.55 (t, J=6.15 Hz, 1 H) 9.19 (d, J=1.00 Hz, 1 H) 8.27 (s, 1 H) 8.14 (d, J=2.26 Hz, 1 H) 8.07 (d, J=0.75 Hz, 1 H) 7.59 (t, J=7.53 Hz, 1 H) 7.30 (d, J=8.03 Hz, 1 H) 6.75 (t, J=2.13 Hz, 1 H) 4.58 (d, J=5.77 Hz, 2 H) 3.88 (s, 3 H) 2.35 (d, J=2.01 Hz, 3 H) 1.44 (s, 9 H).

[0321] Example 82: 5-(tert-butyl)-N-(2-chloro-4-(pyrazolo[1,5-a]pyrazin-4-yl)benzyl)-1,2,4-oxadiazole-3-carboxamide 1. Preparation of tert-butyl (2-chloro-4-(pyrazolo[1,5-a]pyrazin-4-yl)benzyl)carbamate [ka] To a solution of tert-butyl (2-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)carbamate (359.1 mg, 0.977 mmol) in dioxane (30 mL) and HO (5 mL) was added 4-chloropyrazolo[1,5-a]pyrazine (150 mg, 0.977 mmol) and KCO (270 mg, 1.95 mmol) at 20° C. Pd(dppf)Cl (71.5 mg, 97.7 μmol) was added and the reaction was stirred at 90° C. for 3 h under a N atmosphere. The mixture was filtered and concentrated in vacuo to give the crude product, which was purified by a chromatography column on silica gel (PE / EtOAc=3 / 1) to give tert-butyl (2-chloro-4-(pyrazolo[1,5-a]pyrazin-4-yl)benzyl)carbamate (200 mg, 57.1% yield) as a yellow solid.

[0322] 2. Preparation of (2-chloro-4-(pyrazolo[1,5-a]pyrazin-4-yl)phenyl)methanamine dihydrochloride [ka] A solution of tert-butyl (2-chloro-4-(pyrazolo[1,5-a]pyrazin-4-yl)benzyl)carbamate (200 mg, 0.557 mmol) in 4 M HCl / EtOAc (20 mL) was stirred for 1 h at 20° C. The mixture was concentrated in vacuo to give (2-chloro-4-pyrazolo[1,5-a]pyrazin-4-yl-phenyl)methanamine dihydrochloride (150 mg) as a white solid, which was used directly in the next step without further purification.

[0323] Preparation of 3.5-(tert-butyl)-1,2,4-oxadiazole-3-carbonyl chloride [ka] To a solution of 5-tert-butyl-1,2,4-oxadiazole-3-carboxylic acid (200 mg, 1.18 mmol) in DCM (10 mL) and DMF (0.2 mL) was added thionyl chloride (559.3 mg, 4.70 mmol) at 15° C. and the reaction was stirred for 0.5 h at 15° C. The mixture was filtered and concentrated in vacuo to give 5-tert-butyl-1,2,4-oxadiazole-3-carbonyl chloride (200 mg, crude) as a white solid.

[0324] 4. Preparation of 5-(tert-butyl)-N-(2-chloro-4-(pyrazolo[1,5-a]pyrazin-4-yl)benzyl)-1,2,4-oxadiazole-3-carboxamide [ka] To a solution of (2-chloro-4-(pyrazolo[1,5-a]pyrazin-4-yl)phenyl)methanamine dihydrochloride (140 mg, 474.3 μmol) in DCM (30 mL) was added DIPEA (122.6 mg, 948.6 μmol) at 20° C. 5-tert-Butyl-1,2,4-oxadiazole-3-carbonyl chloride (Step 3 of Example 82, 134.2 mg, 711.5 μmol) was added, and the reaction mixture was stirred at 20° C. for 1 hour. The mixture was poured into water (50 mL) and extracted with DCM (50 mL×3). The combined organic layers were washed with brine (100 mL), dried over NaSO, filtered, and concentrated in vacuo. The crude product was purified by preparative HPLC (Method D, 48-68% gradient) to give 5-(tert-butyl)-N-(2-chloro-4-(pyrazolo[1,5-a]pyrazin-4-yl)benzyl)-1,2,4-oxadiazole-3-carboxamide (88.9 mg, 45.6% yield) as a white solid. LCMS m / z = 411.0 [M+H] +1H NMR: (400 MHz, DMSO-d6) δ = 9.63-9.59 (m, 1H), 9.47 (m, 1H), 8.26 (s, 1H), 8.09-8.03 (m, 3H), 7.57-7.54 (m, 1H), 7.21 (s, 1H), 4.62 (d, J = 6.0 Hz, 2H), 1.44 (s, 9H).

[0325] Example 83. 5-(tert-butyl)-N-(3-fluoro-4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)benzyl)-1,2,4-oxadiazole-3-carboxamide [ka]

[0326] 1. Preparation of tert-butyl (3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)carbamate [ka] KOAc (8.13 g, 82.86 mmol) and Pd(dppf)Cl DCM (2.26 g, 2.76 mmol) were added to a solution of tert-butyl (4-bromo-3-fluorobenzyl)carbamate (8.40 g, 27.6 mmol) and (BPin) (14.03 g, 55.2 mmol) in dioxane (150 mL), and the reaction was stirred at 90 °C for 12 h under N. The mixture was concentrated to dryness to give the crude product, which was purified by column chromatography on silica gel (PE / EtOAc = 20 / 1) to give tert-butyl (3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)carbamate (9.00 g, 83.5% yield) as a white solid. LCMS m / z = 296.0 [M-CH4+H] + .

[0327] 2. Preparation of tert-butyl (3-fluoro-4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)benzyl)carbamate [ka] K2CO3 (472.7 mg, 3.42 mmol) and Pd(dppf)Cl2·DCM (93.1 mg, 114 μmol) were added to a solution of tert-butyl (3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)carbamate (400 mg, 1.14 mmol) and 4-chloro-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine (Step 5 of Example 1, 266.1 mg, 1.14 mmol) in dioxane (30 mL) and water (3 mL), and the mixture was stirred at 90 °C for 5 h under N2. The mixture was concentrated to dryness, and the crude product was purified by column chromatography (PE / EtOAc=1:4) to give tert-butyl (3-fluoro-4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)benzyl)carbamate (400 mg, yield 74.8%) as a brown solid.

[0328] 3. Preparation of (3-fluoro-4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)phenyl)methanamine dihydrochloride [ka] A solution of tert-butyl (3-fluoro-4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)benzyl)carbamate (400 mg, 946.9 μmol) in HCl / EtOAc (4 M, 20 mL) was stirred at 20° C. for 1 hour. The mixture was concentrated in vacuo to give (3-fluoro-4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)phenyl)methanamine dihydrochloride (340 mg, 90.1% yield) as a yellow solid, which was used in the next step without purification.

[0329] 4. Preparation of 5-(tert-butyl)-N-(3-fluoro-4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)benzyl)-1,2,4-oxadiazole-3-carboxamide [ka] To a solution of (3-fluoro-4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)phenyl)methanamine dihydrochloride (80 mg, 223 μmol) in DCM (50 mL) was added DIPEA (86.45 mg, 668.9 μmol). 5-tert-Butyl-1,2,4-oxadiazole-3-carbonyl chloride (Step 3 of Example 82, 63.08 mg, 334.5 μmol) was added, and the mixture was stirred at 20 ° C. for 1 hour. The mixture was concentrated in vacuo and the crude material was purified by preparative HPLC (Method D, 43-63% gradient) to give 5-(tert-butyl)-N-(3-fluoro-4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)benzyl)-1,2,4-oxadiazole-3-carboxamide (30 mg, 28.4% yield) as a brown solid. LCMS m / z = 475.1 [M+H] + 1H NMR (500 MHz, DMSO-d6) δ: 9.63 (t, J = 5.0 Hz, 1H), 9.20 (s, 1H), 8.28 (s, 1H), 8.15 (s, 1H), 8.07 (s, 1H), 7.78 (t, J = 5.0 Hz, 1H), 7.37 (t, J = 5.0 Hz, 2H), 6.77 (s, 1H), 4.57 (d, J = 5.0 Hz, 2H), 3.88 (s, 3H), 1.43 (s, 9H).

[0330] Example 84. 5-(tert-butyl)-N-(2,5-difluoro-4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)benzyl)-1,2,4-oxadiazole-3-carboxamide [ka]

[0331] 1. Preparation of tert-butyl (2,5-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)carbamate [ka] tert-Butyl (2,5-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)carbamate (8.0 g, 89.5% yield) was obtained as a white solid from tert-butyl (4-bromo-2,5-difluorobenzyl)carbamate and (BPin) according to the procedure described in Step 1 of Example 83. LCMS m / z = 314.0 [M-CH4+ H] +

[0332] 2. Preparation of tert-butyl (2,5-difluoro-4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)benzyl)carbamate [ka] K2CO3 (47.32 mg, 0.342 mmol) and Pd(dppf)Cl2 (12.53 mg, 17.12 μmol) were added to a solution of tert-butyl (2,5-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)carbamate (82.17 mg, 0.223 mmol) and 4-chloro-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine (Step 5 of Example 1, 40.0 mg, 0.172 mmol) in dioxane (8 mL) and water (1 mL), and the mixture was stirred at 90 °C for 2 h under N2. The mixture was filtered and concentrated to dryness, and the crude product was purified by column chromatography (PE / EtOAc = 1:0 to 1 / 2) to give tert-butyl (2,5-difluoro-4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)benzyl)carbamate (40 mg, 53.1% yield) as a white solid. LCMS m / z = 441.1 [M+H] +

[0333] 3. Preparation of (2,5-difluoro-4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)phenyl)methanamine dihydrochloride [ka] A solution of tert-butyl (2,5-difluoro-4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)benzyl)carbamate (650 mg, 1.48 mmol) in HCl / EtOAc (4 M, 15 mL) and DCM (10 mL) was stirred at 20° C. for 1 h. The mixture was concentrated in vacuo to give (2,5-difluoro-4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)phenyl)methanamine dihydrochloride (555 mg) as a white solid, which was used in the next step without purification. LCMS m / z = 341.0 [M+H] +

[0334] 4. Preparation of 5-(tert-butyl)-N-(2,5-difluoro-4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)benzyl)-1,2,4-oxadiazole-3-carboxamide [ka] To a solution of (2,5-difluoro-4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)phenyl)methanamine dihydrochloride (80 mg, 235.1 μmol) in DCM (50 mL) was added DIPEA (151.9 mg, 1.18 mmol). 5-tert-Butyl-1,2,4-oxadiazole-3-carbonyl chloride (Step 3 of Example 82, 88.67 mg, 470.1 μmol) was added, and the mixture was stirred at 20 ° C. for 1 hour. The mixture was concentrated in vacuo and the crude material was purified by preparative HPLC (Method E, 40-70% gradient) to give 5-(tert-butyl)-N-(2,5-difluoro-4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)benzyl)-1,2,4-oxadiazole-3-carboxamide (29 mg, 25.1% yield) as a white solid. LCMS m / z = 493.0 [M+H] + 1H NMR (400 MHz, DMSO-d6) δ: 9.55 (t, J = 6.0 Hz, 1H), 9.20 (s, 1H), 8.27 (s, 1H), 8.14 (d, J = 2.4 Hz, 1H), 8.05 (s, 1H), 7.67-7.62 (m, 1H), 7.43-7.38 (m, 1H), 6.79 (s, 1H), 4.57 (d, J = 6.0 Hz, 2H), 3.86 (s, 3H), 1.41 (s, 9H)

[0335] Example 85: 5-(tert-butyl)-N-(2-methyl-4-(pyrazolo[1,5-a]pyrazin-4-yl)benzyl)-1,2,4-oxadiazole-3-carboxamide [ka]

[0336] 1. Preparation of tert-butyl (2-methyl-4-(pyrazolo[1,5-a]pyrazin-4-yl)benzyl)carbamate [ka] To a solution of tert-butyl (2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)carbamate (Step 1, Example 14, 226.1 mg, 651.2 μmol) in dioxane (20 mL) and HO (2 mL) was added 4-chloropyrazolo[1,5-a]pyrazine (100 mg, 651.2 μmol) and KCO (180 mg, 1.30 mmol) at 20 °C. Pd(dppf)Cl (47.65 mg, 65.1 μmol) was added and the reaction was stirred at 90 °C for 3 h under a N atmosphere. The cooled mixture was filtered and concentrated in vacuo. The crude product was purified by column chromatography on silica gel (PE / EtOAc=4 / 1) to give tert-butyl (2-methyl-4-(pyrazolo[1,5-a]pyrazin-4-yl)benzyl)carbamate (150 mg, 68.1% yield) as a yellow solid. LCMS m / z = 339.0 [M+H] +

[0337] 2. Preparation of (2-methyl-4-(pyrazolo[1,5-a]pyrazin-4-yl)phenyl)methanamine dihydrochloride [ka] A solution of tert-butyl (2-methyl-4-(pyrazolo[1,5-a]pyrazin-4-yl)benzyl)carbamate (150 mg, 443.3 μmol) in HCl / EtOAc (20 mL) was stirred at 20° C. for 1 h. The mixture was concentrated in vacuo to give (2-methyl-4-(pyrazolo[1,5-a]pyrazin-4-yl)phenyl)methanamine dihydrochloride (110 mg, crude) as a white solid, which was used in the next step without further purification. LCMS m / z = 239.0 [M+H]+

[0338] Preparation of 3.5-(tert-butyl)-N-(2-methyl-4-(pyrazolo[1,5-a]pyrazin-4-yl)benzyl)-1,2,4-oxadiazole-3-carboxamide [ka] To a solution of (2-methyl-4-(pyrazolo[1,5-a]pyrazin-4-yl)phenyl)methanamine dihydrochloride (100 mg, 364 μmol) in DCM (30 mL) was added DIPEA (94.1 mg, 727.9 μmol) and HATU (276.8 mg, 0.728 mmol). 5-(tert-Butyl)-1,2,4-oxadiazole-3-carboxylic acid (103 mg, 546 μmol) was added, and the reaction was stirred at 20° C. for 1 hour. The mixture was poured into water (50 mL) and extracted with DCM (50 mL×3). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated in vacuo to give the crude material, which was purified by preparative HPLC (Method D, 45-65% gradient) to give 5-(tert-butyl)-N-(2-methyl-4-(pyrazolo[1,5-a]pyrazin-4-yl)benzyl)-1,2,4-oxadiazole-3-carboxamide (55.7 mg, 39.2% yield) as a white solid. LCMS m / z = 391.1 [M+H] + . 1 H NMR: (400 MHz, DMSO-d6) δ = 9.53-9.49 (m, 1H), 8.78 (d, J = 4.4 Hz, 1H), 8.24 (d, J = 2.4 Hz, 1H), 8.00 (d, J = 4.4 Hz, 1H), 7.88-7.86 (m, 2H), 7.45-7.42 (m, 1H), 7.19 (d, J = 1.6 Hz, 1H), 4.54 (d, J = 6.0 Hz, 2H), 2.45 (s, 3H), 1.43 (s, 9H).

[0339] Example 86. 5-(tert-butyl)-N-(2-(difluoromethyl)-4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)benzyl)-1,2,4-oxadiazole-3-carboxamide [ka]

[0340] 1. Preparation of tert-butyl (2-(difluoromethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)carbamate [ka] To a solution of tert-butyl (4-bromo-2-(difluoromethyl)benzyl)carbamate (4.20 g, 12.49 mmol) in dioxane (120 mL) was added (BPin) (3.33 g, 13.11 mmol), KOAc (3.68 g, 37.47 mmol), and Pd(dppf)Cl (9.14 g, 12.49 mmol), and the reaction was stirred at 85 °C for 16 h. The mixture was concentrated to dryness to give a residue that was purified by silica gel chromatography (PE:EtOAc, 100:0 to 85:5) to give tert-butyl (2-(difluoromethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)carbamate (4.30 g, 62.9% yield) as a clear semisolid.

[0341] 2. Preparation of tert-butyl (2-(difluoromethyl)-4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)benzyl)carbamate [ka] tert-Butyl (2-(difluoromethyl)-4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)benzyl)carbamate as a yellow solid (800 mg, 74% yield) was obtained from tert-butyl (2-(difluoromethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)carbamate and 4-chloro-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine (Step 5 of Example 1) according to the procedure described in Step 2 of Example 83. LCMS m / z=455.1 [M+H] +

[0342] 3. Preparation of (2-(difluoromethyl)-4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)phenyl)methanamine dihydrochloride [ka] (2-(Difluoromethyl)-4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)phenyl)methanamine dihydrochloride was obtained as a yellow solid (700 mg, crude) from tert-butyl (2-(difluoromethyl)-4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)benzyl)carbamate according to the procedure described in Step 2 of Example 85. LCMS m / z = 355.0 [M+H] +

[0343] 4. Preparation of 5-(tert-butyl)-N-(2-(difluoromethyl)-4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)benzyl)-1,2,4-oxadiazole-3-carboxamide [ka] 5-(tert-butyl)-N-(2-(difluoromethyl)-4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)benzyl)-1,2,4-oxadiazole-3-carboxamide as a yellow solid (50.2 mg, 43% yield) was obtained from (2-(difluoromethyl)-4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)phenyl)methanamine dihydrochloride and 5-(tert-butyl)-1,2,4-oxadiazole-3-carboxylic acid according to a procedure similar to that described in Step 3 of Example 85. LCMS m / z=507.1 [M+H] + 1H NMR (400 MHz, DMSO-d6) δ: 9.64-9.60 (m, 1H), 9.15 (s, 1H), 8.31-8.26 (m, 3H), 8.19 (s, 1H), 8.09 (s, 1H), 7.63 (d, J=8.0 Hz, 1H), 7.14-7.13 (m, 1H), 7.12 (s, 1H), 4.71 (d, J=6.0 Hz, 2H), 3.88 (s, 3H), 1.41 (s, 9H).

[0344] Example 87. 2-(tert-butyl)-N-(2,3-difluoro-4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)benzyl)-2H-tetrazole-5-carboxamide [ka]

[0345] 1. Preparation of tert-butyl (2,3-difluoro-4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)benzyl)carbamate [ka] tert-Butyl (2,3-difluoro-4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)benzyl)carbamate as a yellow solid (100 mg, 27.9% yield) was obtained from tert-butyl (2,3-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)carbamate and 4-chloro-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine (Step 5 of Example 1) according to the procedure described in Step 2 of Example 83. LCMS m / z = 441.1 [M+H] + .

[0346] 2. Preparation of (2,3-difluoro-4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)phenyl)methanamine dihydrochloride [ka] To a solution of tert-butyl (2,3-difluoro-4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)benzyl)carbamate (100 mg, 227 μmol) in DCM (2 mL) was added HCl / EtOAc (15 mL, 4 M) and the reaction was stirred at 25° C. for 1 h. The mixture was concentrated to give (2,3-difluoro-4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)phenyl)methanamine dihydrochloride (80 mg, crude) as a yellow solid. LCMS m / z = 341.0 [M+H] +

[0347] 3. Preparation of 2-(tert-butyl)-N-(2,3-difluoro-4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)benzyl)-2H-tetrazole-5-carboxamide [ka] To a solution of (2,3-difluoro-4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)phenyl)methanamine dihydrochloride (80 mg, 235.1 μmol) in DCM (30 mL) was added DIPEA (60.76 mg, 470.1 μmol), 2-(tert-butyl)-2H-tetrazole-5-carboxylic acid (80 mg, 470.14 μmol), and HATU (179.24 mg, 470.1 μmol), and the reaction was stirred at 25° C. for 1 hour. The mixture was diluted with water (30 mL) and extracted with DCM (15 mL×3). The combined organic layers were concentrated in vacuo and the residue was purified by preparative HPLC (Method D, 42-62% gradient) to afford 2-(tert-butyl)-N-(2,3-difluoro-4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)benzyl)-2H-tetrazole-5-carboxamide (37 mg, 32% yield) as a white solid. 1 H NMR (500MHz, DMSO-d6) δ: 9.71 (t, J = 6.0 Hz, 1H), 9.24 (d, J = 0.5 Hz, 1H), 8.28 (s, 1H), 8.18 (d, J = 2.5 Hz, 1H), 8.08 (s, 1H), 7.62 (t, J = 6.5 Hz, 1H), 7.40 (t, J = 7.0 Hz, 1H), 6.87 (s, 1H), 4.67 (d, J = 6.0 Hz, 2H), 3.88 (s, 3H), 1.74 (s, 9H).

[0348] Example 88. 5-(tert-butyl)-N-(2,3-difluoro-4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)benzyl)-1,2,4-oxadiazole-3-carboxamide [ka] To a solution of (2,3-difluoro-4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)phenyl)methanamine dihydrochloride (Step 2 of Example 87, 80 mg, 212.3 μmol) in DCM (30 mL) was added DIPEA (54.88 mg, 424.6 μmol) at 20° C. 5-(tert-butyl)-1,2,4-oxadiazole-3-carboxylic acid (72.26 mg, 424.64 μmol) and HATU (97.13 mg, 254.78 μmol) were added, and the reaction was stirred at 20° C. for 1 h. The mixture was poured into water (50 mL) and extracted with DCM (50 mL × 3). The combined organic layers were washed with brine (100 mL), dried over NaSO, filtered, and concentrated in vacuo. The crude product was purified by preparative HPLC (Method D, 53-73% gradient) to give 5-(tert-butyl)-N-(2,3-difluoro-4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)benzyl)-1,2,4-oxadiazole-3-carboxamide (43.8 mg, 41.9% yield) as a yellow solid. LCMS m / z = 493.1 [M+H] + 1H NMR (400 MHz, DMSO-d6) δ : 9.66-9.62 (m, 1H), 9.24 (s, 1H), 8.29 (s, 1H), 8.18 (s, 1H), 8.08 (s, 1H), 7.65-7.61 (m, 1H), 7.41-7.31 (m, 1H), 6.87 (s, 1H), 4.64 (d, J = 6.0 Hz, 2H), 3.89 (s, 3H), 1.43 (s, 9H).

[0349] Examples 89 to 107 The compounds in the following table were prepared from the appropriate carboxylic acid and amine listed below following a procedure similar to that described in Example 88. Amine 1: (2,3-difluoro-4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)phenyl)methanamine dihydrochloride (Step 2 of Example 87) Amine 2: (2,5-difluoro-4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)phenyl)methanamine dihydrochloride (Step 3 of Example 84) Amine 3: (2-(difluoromethyl)-4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)phenyl)methanamine dihydrochloride (Step 3 of Example 86) [Table 6-1] [Table 6-2] [Table 6-3] [Table 6-4] [Table 6-5] [Table 6-6] [Table 6-7] [Table 6-8] [Table 6-9] [Table 6-10] [Table 6-11] [Table 6-12] [Table 6-13] [Table 6-14] [Table 6-15] [Table 6-16] [Table 6-17] [Table 6-18] [Table 6-19]

[0350] Example 108. 3-(tert-butyl)-N-(3-fluoro-4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)benzyl)-1,2,4-oxadiazole-5-carboxamide [ka] To a solution of (3-fluoro-4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)phenyl)methanamine dihydrochloride (Step 3 of Example 83, 80 mg, 223 μmol) in DCM (50 mL) were added DIPEA (86.45 mg, 669 μmol), 3-(tert-butyl)-1,2,4-oxadiazole-5-carboxylic acid (56.91 mg, 334.5 μmol), and HATU (85 mg, 223 μmol), and the mixture was stirred at 20° C. for 2 h. The mixture was concentrated in vacuo and the crude material was purified by preparative HPLC (Method D, 55-75% gradient) to give 3-(tert-butyl)-N-(3-fluoro-4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)benzyl)-1,2,4-oxadiazole-5-carboxamide (41.8 mg, 39.5% yield) as a yellow solid. LCMS m / z = 475.1 [M+H] +1H NMR (400 MHz, DMSO-d6) δ: 9.97 (t, J = 4.0 Hz, 1H), 9.21 (s, 1H), 8.28 (s, 1H), 8.15 (s, 1H), 8.07 (s, 1H), 7.78 (t, J = 8.0 Hz, 1H), 7.44-7.38 (m, 2H), 6.77 (s, 1H), 4.58 (d, J = 4.0 Hz, 2H), 3.88 (s, 3H), 1.37 (s, 9H).

[0351] Examples 109 to 114 The compounds in the following table were prepared from (3-fluoro-4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)phenyl)methanamine dihydrochloride (Step 3 of Example 83) and the appropriate heterocyclic carboxylic acid following a procedure similar to that described in Example 108. [Table 7-1] [Table 7-2] [Table 7-3] [Table 7-4] [Table 7-5] [Table 7-6]

[0352] Example 115: 2-(tert-butyl)-N-((5-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)pyridin-2-yl)methyl)-2H-tetrazole-5-carboxamide [ka]

[0353] 1. Preparation of tert-butyl ((5-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)pyridin-2-yl)methyl)carbamate [ka] tert-Butyl ((5-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)pyridin-2-yl)methyl)carbamate (85 mg, 77% yield) was obtained as a pale yellow solid from tert-butyl ((5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)methyl)carbamate and 4-chloro-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine (Step 5 of Example 1) according to the procedure described in Step 6 of Example 79. LCMS m / z = 406.2 [M+H] +

[0354] 2. Preparation of (5-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)pyridin-2-yl)methanamine hydrochloride [ka] tert-Butyl ((5-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)pyridin-2-yl)methyl)carbamate (85 mg, 209.6 μmol) was dissolved in MeOH (2.10 mL) and HCl solution (1.25 M in MeOH, 1.68 mL) was added and stirred at 50° C. overnight. The reaction was concentrated and dried in vacuo to give (5-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)pyridin-2-yl)methanamine hydrochloride (75 mg, crude) as a yellow solid. LCMS m / z = 306.1 [M+H] +

[0355] 3. Preparation of 2-(tert-butyl)-N-((5-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)pyridin-2-yl)methyl)-2H-tetrazole-5-carboxamide [ka] A vial was charged with (5-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)pyridin-2-yl)methanamine hydrochloride (35 mg, 102.4 μmol), 2-(tert-butyl)-2H-tetrazole-5-carboxylic acid (20.91 mg, 122.9 μmol), and DCM (1.02 mL), then DIPEA (132.34 mg, 1.02 mmol) was added and the solution was cooled to 0° C. HATU (46.85 mg, 122.9 μmol) was added in one portion and the reaction was stirred at room temperature overnight. The reaction was concentrated and purified by column chromatography (gradient elution 0-100% [3:1 EtOAc:EtOH]:heptane) to afford 2-(tert-butyl)-N-((5-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)pyridin-2-yl)methyl)-2H-tetrazole-5-carboxamide (40 mg, 84.5% yield) as a yellow solid. LCMS m / z = 458.2 [M+H] + 1 H NMR (500 MHz, DMSO-d6) δ ppm 9.66 (t, J=6.10 Hz, 1 H) 9.27 (d, J=2.44 Hz, 1 H) 9.19 (s, 1 H) 8.52 (dd, J=7.94, 2.44 Hz, 1 H) 8.37 (s, 1 H) 8.22 (d, J=2.44 Hz, 1 H) 8.13 (s, 1 H) 7.58 (d, J=7.94 Hz, 1 H) 7.24 (dd, J=2.44, 1.22 Hz, 1 H) 4.73 (d, J=6.10 Hz, 2 H) 3.90 (s, 3 H) 1.75 (s, 9 H).

[0356] Example 116: 5-(tert-butyl)-N-((5-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)pyridin-2-yl)methyl)-1,2,4-oxadiazole-3-carboxamide [ka] 5-(tert-butyl)-N-((5-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)pyridin-2-yl)methyl)-1,2,4-oxadiazole-3-carboxamide as a yellow solid (45 mg, 74.3% yield) was obtained from (5-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)pyridin-2-yl)methanamine hydrochloride and 5-tert-butyl-1,2,4-oxadiazole-3-carboxylic acid according to the method described in Step 3 of Example 115. LCMS m / z = 458.2 [M+H] + 1 H NMR (500 MHz, DMSO-d6) δ ppm 9.58 (t, J=6.10 Hz, 1 H) 9.27 (d, J=1.83 Hz, 1 H) 9.20 (s, 1 H) 8.52 (dd, J=8.24, 2.14 Hz, 1 H) 8.37 (s, 1 H) 8.22 (d, J=2.44 Hz, 1 H) 8.13 (s, 1 H) 7.57 (d, J=7.94 Hz, 1 H) 7.27 -7.20 (m, 1 H) 4.70 (d, J=6.10 Hz, 2 H) 3.91 (s, 3 H) 1.45 (s, 9 H).

[0357] Example 117: 5-(tert-butyl)-N-(2-fluoro-4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)benzyl)-1,2,4-oxadiazole-3-carboxamide [ka] DABAL-Me3 (47.71 mg, 186.1 μmol) was added to a mixture of (2-fluoro-4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)phenyl)methanamine dihydrochloride (Step 2 of Example 6, 40.0 mg, 124.1 μmol) and ethyl 5-tert-butyl-1,2,4-oxadiazole-3-carboxylate (36.90 mg, 186.14 μmol) in THF (1.24 mL), and the reaction was heated at 45° C. overnight. The mixture was diluted with MeOH (forming a thick gel) and filtered. The filtrate was concentrated and purified by column chromatography (gradient elution 0-75% [EtOAc:EtOH]:heptane) to afford 5-(tert-butyl)-N-(2-fluoro-4-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)benzyl)-1,2,4-oxadiazole-3-carboxamide (36.0 mg, 58.1% yield) as a pale yellow solid. LCMS m / z = 475.2 [M+H] + 1H NMR (500 MHz, DMSO-d6) δ ppm 9.59 (t, J=6.10 Hz, 1 H) 9.18 (d, J=1.22 Hz, 1 H) 8.37 (s, 1 H) 8.21 (d, J=2.44 Hz, 1 H) 8.13 (s, 1 H) 8.00 (dd, J=7.94, 1.83 Hz, 1 H) 7.94 (dd, J=11.29, 1.53 Hz, 1 H) 7.58 (t, J=7.94 Hz, 1 H) 7.22 (d, J=1.83 Hz, 1 H) 4.61 (d, J=6.10 Hz, 2 H) 3.91 (s, 3H) 1.44 (s, 9 H).

[0358] Example 118: 3-(tert-butyl)-N-(2-fluoro-4-(6-(4-methylpiperazin-1-yl)pyrazolo[1,5-a]pyrazin-4-yl)benzyl)-1,2,4-oxadiazole-5-carboxamide [ka]

[0359] 1. Preparation of tert-butyl (4-(6-chloropyrazolo[1,5-a]pyrazin-4-yl)-2-fluorobenzyl)carbamate [ka] A mixture of tert-butyl (2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)carbamate (500 mg, 1.42 mmol), 4,6-dichloropyrazolo[1,5-a]pyrazine (267.65 mg, 1.42 mmol), and KPO (2.0 M, 1.14 mL) was dissolved in dioxane (4.73 mL), and N was bubbled through the mixture for 5 min. Pd(t-BuP) (36.38 mg, 71.18 μmol) was added, and the reaction mixture was stirred at room temperature for 2 h. The reaction was concentrated and purified by column chromatography (gradient elution 0-100% EtOAc:heptane) to afford tert-butyl (4-(6-chloropyrazolo[1,5-a]pyrazin-4-yl)-2-fluorobenzyl)carbamate (460 mg, 86% yield) as a white oily solid. LCMS m / z = 377.1 [M+H] +

[0360] 2. Preparation of tert-butyl (2-fluoro-4-(6-(4-methylpiperazin-1-yl)pyrazolo[1,5-a]pyrazin-4-yl)benzyl)carbamate [ka] tert-Butyl (2-fluoro-4-(6-(4-methylpiperazin-1-yl)pyrazolo[1,5-a]pyrazin-4-yl)benzyl)carbamate was obtained as a yellow solid (139 mg, 79.3% yield) from tert-butyl (4-(6-chloropyrazolo[1,5-a]pyrazin-4-yl)-2-fluorobenzyl)carbamate and 1-methylpiperazine according to a procedure similar to that described in Step 2 of Example 23. The crude product was purified by column chromatography (gradient elution 0-100% [3:1 EtOAc:EtOH]:heptane with 1% TEA modifier). LCMS m / z = 441.2 [M+H] +

[0361] 3. Preparation of (2-fluoro-4-(6-(4-methylpiperazin-1-yl)pyrazolo[1,5-a]pyrazin-4-yl)phenyl)methanamine dihydrochloride [ka] (2-Fluoro-4-(6-(4-methylpiperazin-1-yl)pyrazolo[1,5-a]pyrazin-4-yl)phenyl)methanamine dihydrochloride was obtained as a yellow solid (122 mg, crude) from tert-butyl (2-fluoro-4-(6-(4-methylpiperazin-1-yl)pyrazolo[1,5-a]pyrazin-4-yl)benzyl)carbamate according to the procedure described in Step 3 of Example 23. LCMS m / z = 341.1 [M+H] +

[0362] 4. Preparation of 3-(tert-butyl)-N-(2-fluoro-4-(6-(4-methylpiperazin-1-yl)pyrazolo[1,5-a]pyrazin-4-yl)benzyl)-1,2,4-oxadiazole-5-carboxamide [ka] DABAL-Me3 (33.9 mg, 132.2 μmol) was added to a mixture of (2-fluoro-4-(6-(4-methylpiperazin-1-yl)pyrazolo[1,5-a]pyrazin-4-yl)phenyl)methanamine dihydrochloride (30 mg, 88.1 μmol) and ethyl 3-(tert-butyl)-1,2,4-oxadiazole-5-carboxylate (132.2 μmol) in THF (0.88 mL), and the reaction was heated at 45° C. overnight. The mixture was diluted with NaHCO3 solution and DCM, and the layers were separated. The aqueous layer was extracted with DCM, and the combined organic filtrate was washed with brine, dried over MgSO4, filtered, and concentrated in vacuo. The material was purified by HPLC (C3, 5-55%) to give 3-(tert-butyl)-N-(2-fluoro-4-(6-(4-methylpiperazin-1-yl)pyrazolo[1,5-a]pyrazin-4-yl)benzyl)-1,2,4-oxadiazole-5-carboxamide trifluoroacetate (8.30 mg, 15.5% yield) as a yellow solid. LCMS m / z = 493.2 [M+H] + . 1 H NMR (500 MHz, DMSO-d6) δ ppm 9.97 (br t, J=6.1 Hz, 1 H), 9.65 (s, 1 H), 8.42 (s, 1 H), 8.09 (d, J=2.4 Hz, 1 H), 7.95 (br dd, J=7.9, 1.2 Hz, 1 H), 7.87 (br dd, J=11.0, 1.8 Hz, 1 H), 7.61 (br t, J=7.9 Hz, 1 H), 7.14 (br d, J=2.4 Hz, 1 H), 4.60 (br d, J=6.1 Hz, 2 H), 4.31 (br d, J=12.8 Hz, 2 H), 3.54 (br d, J=11.0 Hz, 2 H), 3.24- 3.06 (m, 2 H), 2.86 (br s, 3 H), 1.37 (s, 9 H).

[0363] Example 119: 5-(tert-butyl)-N-(2-fluoro-4-(6-morpholinopyrazolo[1,5-a]pyrazin-4-yl)benzyl)-1,3,4-oxadiazole-2-carboxamide [ka]

[0364] 1. Preparation of tert-butyl (2-fluoro-4-(6-morpholinopyrazolo[1,5-a]pyrazin-4-yl)benzyl)carbamate [ka] tert-Butyl (2-fluoro-4-(6-morpholinopyrazolo[1,5-a]pyrazin-4-yl)benzyl)carbamate as an orange solid (163 mg, 75.6% yield) was obtained from tert-butyl (4-(6-chloropyrazolo[1,5-a]pyrazin-4-yl)-2-fluorobenzyl)carbamate (Step 1 of Example 118) and morpholine according to the procedure described in Step 2 of Example 23. LCMS m / z=428.2 [M+H] +

[0365] 2. Preparation of (2-fluoro-4-(6-morpholinopyrazolo[1,5-a]pyrazin-4-yl)phenyl)methanamine dihydrochloride [ka] (2-Fluoro-4-(6-morpholinopyrazolo[1,5-a]pyrazin-4-yl)phenyl)methanamine dihydrochloride was obtained as a red solid (177 mg) from tert-butyl (2-fluoro-4-(6-morpholinopyrazolo[1,5-a]pyrazin-4-yl)benzyl)carbamate according to the procedure described in step 3 of example 23. LCMS m / z = 328.1 [M+H] +

[0366] Preparation of 3.5-(tert-butyl)-N-(2-fluoro-4-(6-morpholinopyrazolo[1,5-a]pyrazin-4-yl)benzyl)-1,3,4-oxadiazole-2-carboxamide [ka] DIPEA (74.0 mg, 572.7 μmol) was added to a mixture of (2-fluoro-4-(6-morpholinopyrazolo[1,5-a]pyrazin-4-yl)phenyl)methanamine dihydrochloride (30 mg, 67.5 μmol), potassium 5-tert-butyl-1,3,4-oxadiazole-2-carboxylate (16.94 mg, 80.9 μmol), and DCM (0.7 mL), and the solution was cooled to 0 °C. HATU (30.86 mg, 80.9 μmol) was added, and the reaction was stirred at room temperature overnight. The reaction was diluted with water and passed through a phase separator. The aqueous layer was extracted with DCM, and the combined organic extracts were concentrated. The crude product was purified by HPLC (Method A2, 5-60%) and lyophilized to give 5-(tert-butyl)-N-(2-fluoro-4-(6-morpholinopyrazolo[1,5-a]pyrazin-4-yl)benzyl)-1,3,4-oxadiazole-2-carboxamide (0.3 mg, 0.8% yield) as a yellow solid. LCMS m / z = 479.2 [M+H] + .

[0367] Example 120: 1-(tert-butyl)-N-(2-methyl-4-(6-morpholinopyrazolo[1,5-a]pyrazin-4-yl)benzyl)-1H-1,2,3-triazole-4-carboxamide [ka]

[0368] 1. Preparation of tert-butyl (4-(6-chloropyrazolo[1,5-a]pyrazin-4-yl)-2-methylbenzyl)carbamate [ka] tert-Butyl (4-(6-chloropyrazolo[1,5-a]pyrazin-4-yl)-2-methylbenzyl)carbamate as a pale yellow solid (913 mg, 85% yield) was obtained from tert-butyl (2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)carbamate and 4,6-dichloropyrazolo[1,5-a]pyrazine according to the procedure described in Step 1 of Example 118. LCMS m / z=373.1 [M+H] +

[0369] 2. Preparation of tert-butyl (2-methyl-4-(6-morpholinopyrazolo[1,5-a]pyrazin-4-yl)benzyl)carbamate [ka] tert-Butyl (2-methyl-4-(6-morpholinopyrazolo[1,5-a]pyrazin-4-yl)benzyl)carbamate was obtained as a yellow solid from tert-butyl (4-(6-chloropyrazolo[1,5-a]pyrazin-4-yl)-2-methylbenzyl)carbamate and morpholine according to the procedure described in Step 1 of Example 119. LCMS m / z = 424.3 [M+H] +

[0370] 3. Preparation of (2-methyl-4-(6-morpholinopyrazolo[1,5-a]pyrazin-4-yl)phenyl)methanamine dihydrochloride [ka] (2-Methyl-4-(6-morpholinopyrazolo[1,5-a]pyrazin-4-yl)phenyl)methanamine dihydrochloride was obtained as a yellow solid from tert-butyl (2-methyl-4-(6-morpholinopyrazolo[1,5-a]pyrazin-4-yl)benzyl)carbamate according to the procedure described in Step 2 of Example 119. LCMS m / z = 324.2 [M+H] +

[0371] 4. Preparation of 1-(tert-butyl)-N-(2-methyl-4-(6-morpholinopyrazolo[1,5-a]pyrazin-4-yl)benzyl)-1H-1,2,3-triazole-4-carboxamide trifluoroacetate [ka] A vial was charged with (2-methyl-4-(6-morpholinopyrazolo[1,5-a]pyrazin-4-yl)phenyl)methanamine dihydrochloride (40 mg, 100.9 μmol), 1-tert-butyltriazole-4-carboxylic acid (20.49 mg, 121.1 μmol), and DCM (1.01 mL), followed by DIPEA (110.75 mg, 856.9 μmol), and the solution was cooled to 0 °C. HATU (46.17 mg, 121.1 μmol) was added, and the reaction was stirred at room temperature overnight. The reaction was loaded directly onto a silica cartridge and purified by column chromatography (gradient elution 0-100% EtOAc:heptane) to give the product as a deep orange film. This material was repurified by HPLC (Method C3, 10-95%) to give 1-(tert-butyl)-N-(2-methyl-4-(6-morpholinopyrazolo[1,5-a]pyrazin-4-yl)benzyl)-1H-1,2,3-triazole-4-carboxamide trifluoroacetate (16 mg, 26.4% yield) as a yellow solid. LCMS m / z = 475.2 [M+H] + 1H NMR (500 MHz, DMSO-d6) δ ppm 9.04 (t, J=6.10 Hz, 1 H) 8.71 (s, 1 H) 8.13 (s, 1 H) 8.01 (d, J=3.05 Hz, 1 H) 7.89 - 7.83 (m, 2 H) 7.41 (d, J=8.55 Hz, 1 H) 7.03 (d, J=2.44 Hz, 1 H) 4.52 (d, J=6.10 Hz, 2 H) 3.81 -3.74 (m, 4 H) 3.38 - 3.35 (m, 4 H) 2.45 (s, 3 H) 1.64 (s, 9 H)

[0372] Example 121: 1-(tert-butyl)-N-(2-methyl-4-(6-(4-methylpiperazin-1-yl)pyrazolo[1,5-a]pyrazin-4-yl)benzyl)-1H-1,2,3-triazole-4-carboxamide [ka]

[0373] 1. Preparation of tert-butyl (2-methyl-4-(6-(4-methylpiperazin-1-yl)pyrazolo[1,5-a]pyrazin-4-yl)benzyl)carbamate [ka] tert-Butyl (2-methyl-4-(6-(4-methylpiperazin-1-yl)pyrazolo[1,5-a]pyrazin-4-yl)benzyl)carbamate was obtained as an orange solid (232 mg, 66.1% yield) from tert-butyl (4-(6-chloropyrazolo[1,5-a]pyrazin-4-yl)-2-methylbenzyl)carbamate (Step 1 of Example 120) and 1-methylpiperazine according to the procedure described in Step 1 of Example 119. The crude product was purified by column chromatography (gradient elution 0-100% [3:1 EtOAc:EtOH]:heptane with 1% TEA modifier). LCMS m / z = 437.3 [M+H] +

[0374] 2. Preparation of (2-methyl-4-(6-(4-methylpiperazin-1-yl)pyrazolo[1,5-a]pyrazin-4-yl)phenyl)methanamine hydrochloride [ka] (2-Methyl-4-(6-(4-methylpiperazin-1-yl)pyrazolo[1,5-a]pyrazin-4-yl)phenyl)methanamine hydrochloride as a yellow solid (226 mg, crude) was obtained from tert-butyl (2-methyl-4-(6-(4-methylpiperazin-1-yl)pyrazolo[1,5-a]pyrazin-4-yl)benzyl)carbamate according to the procedure described in Step 2 of Example 119. LCMS / z = 337.2 [M+H] +

[0375] 3. Preparation of 1-(tert-butyl)-N-(2-methyl-4-(6-(4-methylpiperazin-1-yl)pyrazolo[1,5-a]pyrazin-4-yl)benzyl)-1H-1,2,3-triazole-4-carboxamide trifluoroacetate [ka] DIPEA (163.1 mg, 1.26 mmol) was added to a solution of (2-methyl-4-(6-(4-methylpiperazin-1-yl)pyrazolo[1,5-a]pyrazin-4-yl)phenyl)methanamine hydrochloride (50 mg, 148.6 μmol) and 1-tert-butyltriazole-4-carboxylic acid (30.17 mg, 178.3 μmol) in DCM (1.49 mL) and the solution was cooled to 0° C. HATU (68 mg, 178.3 μmol) was added in one portion and the reaction was stirred at room temperature overnight. The reaction was diluted with water and passed through a phase separator. The aqueous layer was extracted with DCM, the combined organic layers were concentrated in vacuo, and the residue was purified by HPLC (Method C3, 5-50%) to give 1-(tert-butyl)-N-(2-methyl-4-(6-(4-methylpiperazin-1-yl)pyrazolo[1,5-a]pyrazin-4-yl)benzyl)-1H-1,2,3-triazole-4-carboxamide trifluoroacetate (52 mg, 54.7% yield). LCMS m / z = 488.3 [M+H] +.1H NMR (500 MHz, DMSO-d6) δ ppm 9.06 (br t, J=6.1 Hz, 1 H), 8.74 - 8.68 (m, 1 H), 8.35 (s, 1 H), 8.05 (br d, J=2.4 Hz, 1 H), 7.91 - 7.81 (m, 2H), 7.42 (br d, J=7.9 Hz, 1 H), 7.12 - 7.02 (m, 1 H), 4.53 (br d, J=6.1 Hz, 2 H), 4.30 (br d, J=13.4 Hz, 2 H), 3.54 (br d, J=11.6 Hz, 2 H), 3.20 (br d, J=11.6 Hz, 1 H), 3.15 - 3.05 (m, 2 H), 2.86 (br d, J=3.7 Hz, 3 H), 2.46 (s, 3 H), 1.68 - 1.26 (m, 9 H).

[0376] Example 122: 1-(tert-butyl)-N-(4-(6-(2-methoxyethoxy)pyrazolo[1,5-a]pyrazin-4-yl)-2-methylbenzyl)-1H-1,2,3-triazole-4-carboxamide [ka]

[0377] 1. Preparation of tert-butyl (4-(6-(2-methoxyethoxy)pyrazolo[1,5-a]pyrazin-4-yl)-2-methylbenzyl)carbamate [ka] Toluene (7.24 mL) was added to a mixture of tert-butyl (4-(6-chloropyrazolo[1,5-a]pyrazin-4-yl)-2-methylbenzyl)carbamate (Step 1 of Example 120, 270 mg, 724.2 μmol), Pd(dba) (66.31 mg, 72.4 μmol), CsCO (589.9 mg, 1.81 mmol), and tBuBrettPhos (70.20 mg, 144.8 μmol), and N was bubbled through the solution for 5 minutes. 2-Methoxyethanol (165.30 mg, 2.17 mmol) was added, and the reaction was stirred at 100 °C overnight. The cooled reaction was concentrated and the residue was purified by silica gel column chromatography (gradient elution 0-100% EtOAc:heptane) to afford tert-butyl (4-(6-(2-methoxyethoxy)pyrazolo[1,5-a]pyrazin-4-yl)-2-methylbenzyl)carbamate (155 mg, 51.9% yield) as a yellow solid. LCMS m / z = 413.2 [M+H] + .

[0378] 2. Preparation of (4-(6-(2-methoxyethoxy)pyrazolo[1,5-a]pyrazin-4-yl)-2-methylphenyl)methanamine dihydrochloride [ka] (4-(6-(2-methoxyethoxy)pyrazolo[1,5-a]pyrazin-4-yl)-2-methylphenyl)methanamine dihydrochloride was obtained as a yellow solid from tert-butyl (4-(6-(2-methoxyethoxy)pyrazolo[1,5-a]pyrazin-4-yl)-2-methylbenzyl)carbamate according to the procedure described in step 3 of example 23. LCMS m / z = 313.1 [M+H] +

[0379] 3. Preparation of 1-(tert-butyl)-N-(4-(6-(2-methoxyethoxy)pyrazolo[1,5-a]pyrazin-4-yl)-2-methylbenzyl)-1H-1,2,3-triazole-4-carboxamide [ka] 1-(tert-butyl)-N-(4-(6-(2-methoxyethoxy)pyrazolo[1,5-a]pyrazin-4-yl)-2-methylbenzyl)-1H-1,2,3-triazole-4-carboxamide as an off-white solid (19 mg, 31.2% yield) was obtained from (4-(6-(2-methoxyethoxy)pyrazolo[1,5-a]pyrazin-4-yl)-2-methylphenyl)methanamine dihydrochloride and 1-tert-butyltriazole-4-carboxylic acid according to a procedure similar to that described in Step 4 of Example 120. LCMS m / z=464.2 [M+H] + 1 H NMR (500 MHz, DMSO-d6) δ ppm 9.06 (t, J=6.10 Hz, 1 H) 8.72 (s, 1 H) 8.42 (d, J=1.22 Hz, 1 H) 8.10 (d, J=2.44 Hz, 1 H) 7.92 - 7.84 (m, 2 H) 7.43 (d, J=8.55 Hz, 1 H), 7.15 (d, J=1.83 Hz, 1 H) 4.53 (d, J=6.10 Hz, 2H) 4.45 - 4.37 (m, 2 H) 3.74-3.67 (m, 2 H) 3.32 (s, 3 H) 2.46 (s, 3 H) 1.64 (s, 9 H).

[0380] Example 123: 2-(tert-butyl)-N-(2-methyl-4-(6-morpholinopyrazolo[1,5-a]pyrazin-4-yl)benzyl)-2H-1,2,3-triazole-4-carboxamide [ka] DABAL-Me3 (47.56 mg, 185.5 μmol) was added to a mixture of (2-methyl-4-(6-morpholinopyrazolo[1,5-a]pyrazin-4-yl)phenyl)methanamine dihydrochloride (Step 3 of Example 120, 49.02 mg, 123.7 μmol) and ethyl 2-(tert-butyl)-2H-1,2,3-triazole-4-carboxylate (Example 37a, US10377719-B2, 36.6 mg, 185.5 μmol) in THF (1.24 mL), and the reaction was heated at 45° C. overnight. The reaction was carefully quenched with saturated NaHCO3 solution and diluted with DCM. The mixture was passed through a phase separator, and the aqueous layer was extracted with DCM. The combined organic layers were concentrated and purified by column chromatography (12 g column, gradient elution 0-100% EtOAc:heptane) to give a deep orange film. This material was repurified by reverse-phase HPLC (Method A2, 10-95%) and then lyophilized to give 2-(tert-butyl)-N-(2-methyl-4-(6-morpholinopyrazolo[1,5-a]pyrazin-4-yl)benzyl)-2H-1,2,3-triazole-4-carboxamide (1.30 mg, 2.2% yield) as a yellow solid. LCMS m / z = 475.2 [M+H] + 1 H NMR (500 MHz, DMSO-d6) δ ppm 8.91 (t, J=5.80 Hz, 1 H) 8.17 (s, 1 H) 8.13 (s, 1 H) 8.01 (d, J=2.44 Hz, 1 H) 7.92 - 7.83 (m, 2 H) 7.42 (d, J=7.94 Hz, 1 H) 7.04 (dd, J=2.44, 1.22 Hz, 1 H) 4.53 (d, J=6.10 Hz, 2 H) 3.82 - 3.74 (m, 4 H) 3.38 - 3.35 (m, 4 H) 2.45 (s, 3 H) 1.65 (s, 9 H).

[0381] Example 124: 2-(tert-butyl)-N-(2-methyl-4-(6-(4-methylpiperazin-1-yl)pyrazolo[1,5-a]pyrazin-4-yl)benzyl)-2H-1,2,3-triazole-4-carboxamide trifluoroacetate [ka] 2-(tert-butyl)-N-(2-methyl-4-(6-(4-methylpiperazin-1-yl)pyrazolo[1,5-a]pyrazin-4-yl)benzyl)-2H-1,2,3-triazole-4-carboxamide trifluoroacetate (49 mg, 60.9% yield) was obtained from (2-methyl-4-(6-(4-methylpiperazin-1-yl)pyrazolo[1,5-a]pyrazin-4-yl)phenyl)methanamine dihydrochloride (Step 2 of Example 121) and ethyl 2-(tert-butyl)-2H-1,2,3-triazole-4-carboxylate (Example 37a, US10377719-B2) according to the procedure described in Step 4 of Example 118. LCMS m / z=488.3 [M+H] + 1 H NMR (500 MHz, DMSO-d6) δ ppm 8.93 (br t, J=6.1 Hz, 1 H), 8.35 (s, 1 H), 8.17 (s, 1 H), 8.06 (br d, J=2.4 Hz, 1 H), 7.91 - 7.82 (m, 2 H), 7.43 (br d, J=7.9 Hz, 1 H), 7.08 (d, J=2.4 Hz, 1 H), 4.53 (br d, J=6.1 Hz, 2 H), 4.30 (br d, J=13.4 Hz, 2 H), 3.54 (br d, J=11.6 Hz, 2 H), 3.36 (br d, J=3.7 Hz, 2 H), 3.25 - 3.05 (m, 3 H), 2.87 (br d, J=3.7 Hz, 2 H), 2.46 (s, 3 H), 1.68-1.35 (m, 9 H)

[0382] Examples 125 to 133 The compounds in the following table were prepared from the appropriate carboxylic acid and amine (listed below) following a procedure similar to that described in Step 3 of Example 119. Amine 4: (2-fluoro-4-(6-morpholinopyrazolo[1,5-a]pyrazin-4-yl)phenyl)methanamine dihydrochloride (Step 2 of Example 119) Amine 5: (2-methyl-4-(6-morpholinopyrazolo[1,5-a]pyrazin-4-yl)phenyl)methanamine dihydrochloride (Step 3 of Example 120) Amine 6: (2-fluoro-4-(6-(4-methylpiperazin-1-yl)pyrazolo[1,5-a]pyrazin-4-yl)phenyl)methanamine dihydrochloride (Step 3 of Example 118) Amine 7: (2-methyl-4-(6-(4-methylpiperazin-1-yl)pyrazolo[1,5-a]pyrazin-4-yl)phenyl)methanamine dihydrochloride (Step 2 of Example 121) Amine 8: (4-(6-(2-methoxyethoxy)pyrazolo[1,5-a]pyrazin-4-yl)-2-methylphenyl)methanamine dihydrochloride (Step 2 of Example 122) [Table 8-1] [Table 8-2] [Table 8-3] [Table 8-4] [Table 8-5] [Table 8-6] [Table 8-7] [Table 8-8] [Table 8-9]

[0383] Example 134: N-(4-(6-(azetidin-1-yl)pyrazolo[1,5-a]pyrazin-4-yl)benzyl)-5-(tert-butyl)-1,2,4-oxadiazole-3-carboxamide [ka]

[0384] 1. Preparation of tert-butyl (4-(6-(azetidin-1-yl)pyrazolo[1,5-a]pyrazin-4-yl)benzyl)carbamate [ka] A mixture of tert-butyl (4-(6-chloropyrazolo[1,5-a]pyrazin-4-yl)benzyl)carbamate (Step 1 of Example 23, 200 mg, 557.4 μmol), RuPhos Pd G3 (69.93 mg, 83.6 μmol), azetidine hydrochloride (208.59 mg, 2.23 mmol), and NaOtBu (267.82 mg, 2.79 mmol) in toluene (4 mL) was stirred at 95° C. for 8 hours under a N atmosphere. The cooled mixture was concentrated in vacuo, and the crude product was purified by column chromatography on silica gel eluted with PE / EtOAc (1 / 0 to 2 / 1) to give tert-butyl (4-(6-(azetidin-1-yl)pyrazolo[1,5-a]pyrazin-4-yl)benzyl)carbamate (160 mg, 75.7% yield) as a yellow solid. LCMS m / z = 380.1 [M+H] +

[0385] 2. Preparation of (4-(6-(azetidin-1-yl)pyrazolo[1,5-a]pyrazin-4-yl)phenyl)methanamine trifluoroacetate [ka] To a solution of tert-butyl (4-(6-(azetidin-1-yl)pyrazolo[1,5-a]pyrazin-4-yl)benzyl)carbamate (140 mg, 368.96 μmol) in DCM (12 mL) was added TFA (4 mL) dropwise and the mixture was stirred at 30° C. for 1 h. The mixture was concentrated in vacuo to give (4-(6-(azetidin-1-yl)pyrazolo[1,5-a]pyrazin-4-yl)phenyl)methanamine trifluoroacetate (100 mg, crude) as a yellow solid, which was used in the next step without further purification. LCMS m / z = 280.0 [M+H] +

[0386] 3. Preparation of N-(4-(6-(azetidin-1-yl)pyrazolo[1,5-a]pyrazin-4-yl)benzyl)-5-(tert-butyl)-1,2,4-oxadiazole-3-carboxamide [ka] To a solution of (4-(6-(azetidin-1-yl)pyrazolo[1,5-a]pyrazin-4-yl)phenyl)methanamine trifluoroacetate (80.0 mg, 286.4 μmol) in DCM (50 mL) was added DIPEA (111.04 mg, 859.2 μmol) followed by 5-tert-butyl-1,2,4-oxadiazole-3-carbonyl chloride (Step 3 of Example 82, 108.03 mg, 572.8 μmol) and the mixture was stirred at 20° C. for 1 h. The mixture was concentrated in vacuo and the crude material was purified by preparative HPLC (Method E, 42-72% gradient) to give N-(4-(6-(azetidin-1-yl)pyrazolo[1,5-a]pyrazin-4-yl)benzyl)-5-(tert-butyl)-1,2,4-oxadiazole-3-carboxamide (27.10 mg, 21.9% yield) as a yellow solid. LCMS m / z = 432.1 [M+H] +1H NMR (400 MHz, DMSO-d6) δ: 9.57-9.56 (m, 1H), 8.01-7.98 (m, 2H), 7.95 (d, J = 2.8 Hz, 1H), 7.85 (s, 1H), 7.50 (d, J = 8.8 Hz, 2H), 6.99-6.98 (m, 1H), 4.53 (d, J = 6.0 Hz, 2H), 3.92 (t, J = 7.2 Hz, 4H), 2.36-2.33 (m, 2H), 1.42 (s, 9H).

[0387] Example 135: 5-(tert-butyl)-N-(4-(6-(dimethylamino)pyrazolo[1,5-a]pyrazin-4-yl)benzyl)-1,2,4-oxadiazole-3-carboxamide [ka]

[0388] 1. Preparation of tert-butyl (4-(6-(dimethylamino)pyrazolo[1,5-a]pyrazin-4-yl)benzyl)carbamate [ka] tert-Butyl (4-(6-(dimethylamino)pyrazolo[1,5-a]pyrazin-4-yl)benzyl)carbamate (60 mg, 25.0%) was obtained from methanamine and tert-butyl (4-(6-chloropyrazolo[1,5-a]pyrazin-4-yl)benzyl)carbamate (Step 1 of Example 23) according to a procedure similar to that described in Step 1 of Example 134. LCMS m / z = 368.1 [M+H] +

[0389] 2. Preparation of 4-(4-(aminomethyl)phenyl)-N,N-dimethylpyrazolo[1,5-a]pyrazin-6-amine dihydrochloride [ka] HCl / EtOAc (10.0 mL) was added to tert-butyl (4-(6-(dimethylamino)pyrazolo[1,5-a]pyrazin-4-yl)benzyl)carbamate (60.0 mg, 163.3 μmol), and the reaction mixture was stirred at 30° C. for 2 h. The mixture was concentrated in vacuo to give 4-(4-(aminomethyl)phenyl)-N,N-dimethylpyrazolo[1,5-a]pyrazin-6-amine dihydrochloride (40 mg, crude) as a gray solid, which was used in the next step without further purification. LCMS m / z = 268.0 [M+H] +

[0390] 3. Preparation of N-(4-(6-(azetidin-1-yl)pyrazolo[1,5-a]pyrazin-4-yl)benzyl)-5-(tert-butyl)-1,2,4-oxadiazole-3-carboxamide [ka] 5-tert-Butyl-1,2,4-oxadiazole-3-carbonyl chloride (Step 3 of Example 82, 37.25 mg, 197.5 μmol) was added to a solution of 4-(4-(aminomethyl)phenyl)-N,N-dimethylpyrazolo[1,5-a]pyrazin-6-amine dihydrochloride (40 mg, 131.7 μmol) and DIPEA (68.07 mg, 526.7 μmol) in DCM (45 mL), and the reaction was stirred at 30° C. for 3 h. The mixture was concentrated in vacuo, and the residue was poured into water (120 mL). The aqueous solution was extracted with DCM (70 mL × 3), and the combined organic layers were dried over NaSO and concentrated in vacuo. The crude product was purified by preparative HPLC (Method D, 55-75% gradient) to give N-(4-(6-(azetidin-1-yl)pyrazolo[1,5-a]pyrazin-4-yl)benzyl)-5-(tert-butyl)-1,2,4-oxadiazole-3-carboxamide (30.0 mg, 47.8% yield) as an off-white solid. LCMS m / z = 420.1 [M+H] + 1H NMR (400 MHz, DMSO-d6) δ: 9.57-9.56 (m, 1H), 8.01-7.98 (m, 2H), 7.95 (d, J = 2.8 Hz, 1H), 7.85 (s, 1H), 7.50 (d, J = 8.8 Hz, 2H), 6.99-6.98 (m, 1H), 4.53 (d, J = 6.0 Hz, 2H), 3.92 (t, J = 7.2 Hz, 4H), 2.36-2.33 (m, 2H), 1.42 (s, 9H).

[0391] Example 136: 5-(tert-butyl)-N-((1-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)piperidin-4-yl)methyl)-1,2,4-oxadiazole-3-carboxamide [ka]

[0392] 1. Preparation of tert-butyl ((1-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)piperidin-4-yl)methyl)carbamate [ka] tert-Butyl N-(4-piperidylmethyl)carbamate (110.06 mg, 513.6 μmol), 4-chloro-6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazine (60.0 mg, 256.8 μmol), and CsCO (167.33 mg, 513.56 μmol) were dissolved in DMSO (0.856 mL) and the reaction was stirred overnight at room temperature. The reaction was concentrated and purified by column chromatography (12 g column, gradient elution 0-75% [3:1 EtOAc:EtOH]:heptane) to afford tert-butyl ((1-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)piperidin-4-yl)methyl)carbamate (100 mg, 94.6% yield) as a light brown solid. LCMS m / z = 412.3 [M+H] +

[0393] 2. Preparation of (1-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)piperidin-4-yl)methanamine dihydrochloride [ka] tert-Butyl ((1-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)piperidin-4-yl)methyl)carbamate (82 mg, 199.3 μmol) was dissolved in MeOH (1.99 mL), HCl solution (1.25 M in MeOH, 1.59 mL) was added, and the reaction was stirred at 50° C. overnight. The reaction was concentrated and dried under vacuum to give (1-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)piperidin-4-yl)methanamine dihydrochloride (93 mg, crude) as a red solid. LCMS m / z = 312.2 [M+H] +

[0394] 3. Preparation of 5-(tert-butyl)-N-((1-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)piperidin-4-yl)methyl)-1,2,4-oxadiazole-3-carboxamide [ka] 5-(tert-butyl)-N-((1-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)piperidin-4-yl)methyl)-1,2,4-oxadiazole-3-carboxamide as a white solid (20 mg, 44.8% yield) was obtained from potassium 5-(tert-butyl)-1,2,4-oxadizole-3-carboxylate and (1-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)piperidin-4-yl)methanamine dihydrochloride according to the procedure described in Step 3 of Example 115. LCMS m / z=464.3 [M+H] + 1H NMR (500 MHz, DMSO-d6) δ ppm 9.00 (t, J=5.80 Hz, 1 H) 8.45 (s, 1 H) 8.14 (s, 1 H) 7.98 - 7.88 (m, 2 H) 6.92 (d, J=2.44 Hz, 1 H) 4.54 (br d, J=13.43 Hz, 2 H) 3.87 (s, 3 H) 3.21 (t, J=6.41 Hz, 2 H) 3.07 (br t, J=11.90 Hz, 2 H) 1.99 - 1.90 (m, 1 H) 1.80 (br d, J=10.99 Hz, 2 H) 1.42 (s, 9H) 1.36 - 1.24 (m, 2 H).

[0395] Example 137 N-((1-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)piperidin-4-yl)methyl)-5-(1-methylcyclopropyl)-1,2,4-oxadiazole-3-carboxamide [ka]

[0396] 1. Preparation of ethyl (E)-2-(hydroxyimino)-2-(1-methylcyclopropane-1-carboxamide) acetate [ka] To a solution of ethyl (E)-2-amino-2-(hydroxyimino)acetate (2.5 g, 18.92 mmol) in DCM / DMF (v / v 20 / 1, 210 mL) was added 1-methylcyclopropanecarboxylic acid (2.08 g, 20.81 mmol), HATU (7.94 g, 20.81 mmol), and DIPEA (7.34 g, 56.76 mmol), and the reaction was stirred for 1 h at 25° C. The mixture was poured into water (300 mL) and extracted with DCM (100 mL × 5), and the combined organic layers were evaporated under reduced pressure to give ethyl (E)-2-(hydroxyimino)-2-(1-methylcyclopropane-1-carboxamide)acetate as a yellow oil, which was used directly in the next step.

[0397] 2. Preparation of ethyl 5-(1-methylcyclopropyl)-1,2,4-oxadiazole-3-carboxylate [ka] A solution of ethyl (E)-2-(hydroxyimino)-2-(1-methylcyclopropane-1-carboxamide)acetate (5.30 g, 17.15 mmol) in pyridine (100 mL) was stirred at 100° C. for 17 hours. The reaction solution was concentrated in vacuo, and the residue was poured into HCl solution (1.0 M, 200 mL) and extracted with DCM (100 mL × 3). The combined organic layer was concentrated to give a crude product, which was purified by column chromatography (PE / EtOAc = 30 / 1 to 10 / 1) to give ethyl 5-(1-methylcyclopropyl)-1,2,4-oxadiazole-3-carboxylate (1.40 g, 39.7% yield) as a colorless oil.

[0398] 3. Preparation of 5-(1-methylcyclopropyl)-1,2,4-oxadiazole-3-carboxylic acid [ka] To a solution of ethyl 5-(1-methylcyclopropyl)-1,2,4-oxadiazole-3-carboxylate (1.00 g, 4.86 mmol) in MeOH / HO (v / v = 10 / 1, 44 mL) was added NaOH (213.84 mg, 5.35 mmol), and the mixture was stirred at 25 °C for 2 h. The mixture was acidified with 2 M HCl to pH = 6-7 and then concentrated in vacuo. The crude product was lyophilized to give 5-(1-methylcyclopropyl)-1,2,4-oxadiazole-3-carboxylic acid (740 mg, crude) as a white solid, which was used directly in the next step.

[0399] 4. Preparation of 5-(1-methylcyclopropyl)-1,2,4-oxadiazole-3-carbonyl chloride [ka] To a solution of 5-(1-methylcyclopropyl)-1,2,4-oxadiazole-3-carboxylic acid (100 mg, 594.7 μmol) in DCM (30 mL) was added DMF (1.0 mL). SOCl (353.8 mg, 2.97 mmol) was added dropwise, and the mixture was stirred at 25° C. for 1 hour. The mixture was concentrated to give 5-(1-methylcyclopropyl)-1,2,4-oxadiazole-3-carbonyl chloride (120 mg, crude), which was used directly in the next step.

[0400] 5. Preparation of N-((1-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)piperidin-4-yl)methyl)-5-(1-methylcyclopropyl)-1,2,4-oxadiazole-3-carboxamide [ka] To a mixture of (1-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)piperidin-4-yl)methanamine dihydrochloride (Step 2 of Example 136, 80 mg, 230 μmol) in DCM (50 mL) was added DIPEA (89.17 mg, 690 μmol) followed by 5-(1-methylcyclopropyl)-1,2,4-oxadiazole-3-carbonyl chloride (85.83 mg, 460 μmol) and the reaction was stirred at 20° C. for 1 h. The reaction was concentrated in vacuo and the crude product was purified by preparative HPLC (Method E, 35-65% gradient) to afford N-((1-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)piperidin-4-yl)methyl)-5-(1-methylcyclopropyl)-1,2,4-oxadiazole-3-carboxamide (48.0 mg, 45.2% yield) as a white solid. LCMS m / z = 462.2 [M+H] + 1 HNMR: (400MHz, DMSO-d6) δ: 8.91 (t, J = 6.0 Hz, 1H), 8.41 (d, J = 0.8 Hz, 1H), 8.10 (s, 1H), 7.94-7.87 (m, 2H), 6.91-6.84 (m, 1H), 4.50 (d, J = 13.2 Hz, 2H), 3.83 (s, 3H), 3.16 (t, J = 6.4 Hz, 2H), 3.03 (t, J = 12.0 Hz, 2H), 1.96-1.82 (m, 1H), 1.76 (d, J = 10.8 Hz, 2H), 1.50 (s, 3H), 1.36-1.31 (m, 2H), 1.30-1.19 (m, 2H), 1.15-1.10 (m, 2H).

[0401] Example 138. 1-(tert-butyl)-N-((1-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)piperidin-4-yl)methyl)-1H-1,2,3-triazole-4-carboxamide [ka] To a mixture of (1-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)piperidin-4-yl)methanamine dihydrochloride (Step 2 of Example 136, 80.0 mg, 230 μmol) in DCM (50 mL) was added DIPEA (89.17 mg, 690 μmol), 1-tert-butyltriazole-4-carboxylic acid (77.82 mg, 460 μmol), and HATU (96.45 mg, 253 μmol) and the reaction was stirred at 20° C. for 1 h. The reaction was concentrated in vacuo and the crude purified by preparative HPLC to afford 1-(tert-butyl)-N-((1-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)piperidin-4-yl)methyl)-1H-1,2,3-triazole-4-carboxamide (47.3 mg, 44.5% yield) as a white solid. LCMS m / z = 463.1 [M+H] + 1H NMR: (400MHz, DMSO-d6) δ: 8.61 (s, 1H), 8.51 (t, J = 6.0 Hz, 1H), 8.41 (s, 1H), 8.10 (s, 1H), 7.93-7.88 (m, 2H), 6.87 (d, J = 1.6 Hz, 1H), 4.50 (d, J=13.2 Hz, 2H), 3.83 (s, 3H), 3.17 (t, J=6.4 Hz, 2H), 3.03 (t, J=11.6 Hz, 2H), 1.93-1.90 (m, 1H), 1.77 (d, J = 12.4 Hz, 2H), 1.59 (s, 9H), 1.34-1.18 (m, 2H).

[0402] Example 139: N-((2-methyl-1-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)piperidin-4-yl)methyl)-5-(1-methylcyclopropyl)-1,2,4-oxadiazole-3-carboxamide [ka]

[0403] 1. Preparation of tert-butyl 2-methyl-4-((tosyloxy)methyl)piperidine-1-carboxylate [ka] To a solution of tert-butyl 4-(hydroxymethyl)-2-methylpiperidine-1-carboxylate (3.50 g, 15.26 mmol) and TEA (7.72 g, 76.3 mmol) in DCM (150 mL), TsCl (5.82 g, 30.52 mmol) was slowly added, followed by DMAP (372.86 mg, 3.05 mmol), and the reaction mixture was stirred at 20 °C for 12 h. The reaction mixture was concentrated in vacuo, and the crude product was purified by column chromatography (PE / EtOAc = 4 / 1) to give tert-butyl 2-methyl-4-((tosyloxy)methyl)piperidine-1-carboxylate (5.0 g, crude) as a clear oil. LCMS m / z = 384.0 [M+H] +

[0404] 2. Preparation of tert-butyl 4-((1,3-dioxoindolin-2-yl)methyl)-2-methylpiperidine-1-carboxylate [ka] To a solution of tert-butyl 2-methyl-4-((tosyloxy)methyl)piperidine-1-carboxylate (5.0 g, 13.04 mmol) and isoindoline-1,3-dione (3.84 g, 26.08 mmol) in DMF (100 mL) was added K2CO3 (3.60 g, 26.08 mmol), and the reaction mixture was stirred at 90 °C for 12 h. The mixture was concentrated in vacuo to remove THF, and the crude was poured into saturated K2CO3 (100 mL) and extracted with EtOAc (100 mL × 2). The combined organic layers were washed with water (100 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The crude was purified by column chromatography on silica gel (PE / EtOAc=4 / 1) to give tert-butyl 4-((1,3-dioxoindolin-2-yl)methyl)-2-methylpiperidine-1-carboxylate (5.0 g, crude) as a white solid. LCMS m / z = 359.1 [M+H] + .

[0405] 3. Preparation of 2-((2-methylpiperidin-4-yl)methyl)isoindoline-1,3-dione trifluoroacetate [ka] To a solution of tert-butyl 4-((1,3-dioxoindolin-2-yl)methyl)-2-methylpiperidine-1-carboxylate (1.00 g, 2.79 mmol) in DCM (20 mL) was added TFA (7.45 g, 65.34 mmol) and the mixture was stirred at 20° C. for 2 hours. The mixture was concentrated in vacuo to give 2-((2-methylpiperidin-4-yl)methyl)isoindoline-1,3-dione trifluoroacetate (700 mg, crude) as a clear oil, which was used without further purification. LCMS m / z = 259.0 [M+H] +

[0406] 4. Preparation of 2-((2-methyl-1-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)piperidin-4-yl)methyl)isoindoline-1,3-dione [ka] To a solution of 2-((2-methylpiperidin-4-yl)methyl)isoindoline-1,3-dione trifluoroacetate (250.0 mg, 967.8 μmol) in NMP (2 mL) was added DIPEA (375.25 mg, 2.90 mmol), followed by 4-chloro-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine (Step 5 of Example 1, 226.14 mg, 967.8 μmol), and the reaction was stirred at 180° C. for 2 hours under microwave irradiation. The mixture was poured into HO (100 mL) and extracted with EtOAc (100 mL×2). The combined organic layers were washed with brine (100 mL), dried over NaSO, filtered, and concentrated in vacuo. The crude product was purified by column chromatography on silica gel (PE / EtOAc=1 / 9) to give 2-((2-methyl-1-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)piperidin-4-yl)methyl)isoindoline-1,3-dione (260 mg, 53.1% yield) as a brown oil.

[0407] 5. Preparation of (2-methyl-1-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)piperidin-4-yl)methanamine dihydrochloride [ka] To a solution of 2-((2-methyl-1-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)piperidin-4-yl)methyl)isoindoline-1,3-dione (260 mg, 570.8 μmol) in EtOH (20 mL) was added NHNH.HO (1.00 g, 19.98 mmol) and the reaction was stirred at 50° C. for 5 h. The mixture was concentrated in vacuo to afford (2-methyl-1-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)piperidin-4-yl)methanamine (180 mg, crude) as a brown solid.

[0408] To a solution of this compound (180 mg, 553.15 μmol) and TEA (167.92 mg, 1.66 mmol) in DCM (30 mL) was added tert-butoxycarbonyl tert-butyl carbonate (241.45 mg, 1.11 mmol), and the reaction mixture was stirred for 3 hours at 20° C. The reaction mixture was concentrated in vacuo, and the crude product was purified by column chromatography (PE / EtOAc=1 / 4) to give tert-butyl ((2-methyl-1-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)piperidin-4-yl)methyl)carbamate (130 mg, 55.2% yield) as a brown solid.

[0409] A solution of this solid (130 mg, 305.5 μmol) in HCl / EtOAc (4 M, 10.0 mL) was stirred at 20° C. for 1 h. The mixture was concentrated in vacuo to give 2-methyl-1-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)piperidin-4-yl)methanamine dihydrochloride (120 mg, crude) as a brown solid. LCMS m / z = 326.1 [M+H] +

[0410] 6. Preparation of N-((2-methyl-1-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)piperidin-4-yl)methyl)-5-(1-methylcyclopropyl)-1,2,4-oxadiazole-3-carboxamide [ka] N-((2-methyl-1-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)piperidin-4-yl)methyl)-5-(1-methylcyclopropyl)-1,2,4-oxadiazole-3-carboxamide was obtained as a yellow solid (46 mg, 65% yield) from (2-methyl-1-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)piperidin-4-yl)methanamine dihydrochloride and 5-(1-methylcyclopropyl)-1,2,4-oxadiazole-3-carboxylic acid (Step 3 of Example 137) according to the procedure described in Example 108. LCMS m / z = 476.1 [M+H] + 1H NMR: (400 MHz, DMSO-d6) δ: 8.95-8.89 (m, 1H), 8.45-8.42 (m, 1H), 8.12 (s, 1H), 7.94 (s, 2H), 6.90-6.84 (m, 1H), 4.99-4.20 (m, 2H), 3.86 (s, 3H), 3.57-3.14 (m, 3H), 2.14-1.66 (m, 3H), 1.52(d, J = 4.0 Hz, 3H), 1.41-1.32 (m, 5H), 1.26-1.13 (m, 4H).

[0411] Examples 140, 141, 142, and 143. 1-(tert-butyl)-N-(((2S,4R)-2-methyl-1-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)piperidin-4-yl)methyl)-1H-1,2,3-triazole-4-carboxamide, 1-(tert-butyl)-N-(((2R,4R)-2-methyl-1-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)piperidin-4-yl)methyl)-1H-1,2,3-triazole- 4-carboxamide, 1-(tert-butyl)-N-(((2S,4S)-2-methyl-1-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)piperidin-4-yl)methyl)-1H-1,2,3-triazole-4-carboxamide, and 1-(tert-butyl)-N-(((2R,4S)-2-methyl-1-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)piperidin-4-yl)methyl)-1H-1,2,3-triazole-4-carboxamide [ka] To a solution of (2-methyl-1-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)piperidin-4-yl)methanamine dihydrochloride (Step 5 of Example 139, 150 mg, 414.5 μmol) in DCM (100 mL) was added DIPEA (160.71 mg, 1.24 mmol), 1-(tert-butyl)-1H-1,2,3-triazole-4-carboxylic acid (105.18 mg, 621.8 μmol), and HATU (158.04 mg, 414.51 μmol) and the reaction was stirred at 20° C. for 2 h. The mixture was concentrated in vacuo to give a brown crude material, which was purified by preparative HPLC (Method D, 38-58% gradient) to give 1-(tert-butyl)-N-((2-methyl-1-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)piperidin-4-yl)methyl)-1H-1,2,3-triazole-4-carboxamide (150 mg, crude) as a yellow solid. LCMS m / z = 477.2 [M+H] +

[0412] This solid was further purified by SFC (column: DAICEL CHIRALPAK AD (250 mm x 30 mm, 10 μm), 0.1% NH 3 .H 2 O EtOH, flow rate (mL / min): 80, column temperature: 35°C) to give the following compounds. 1-(tert-butyl)-N-(((2S,4R)-2-methyl-1-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)piperidin-4-yl)methyl)-1H-1,2,3-triazole-4-carboxamide (stereochemistry arbitrarily assigned) (26 mg, 17.3% yield), white solid. LCMS m / z = 477.1 [M+H] +.1HNMR (400MHz, DMSO-d6) δ = 8.64 (s, 1H), 8.54 (t, J = 6.0 Hz, 1H), 8.41 (s, 1H), 8.12 (s, 1H), 7.92 (d, J = 4.0 Hz, 2H), 6.87 (s, 1H), 4.98 (t, J = 6.0 Hz, 1H), 4.44 (d, J = 14.0 Hz, 1H), 3.86 (s, 3H), 3.21-3.16 (m, 3H), 2.15 (s, 1H), 1.84-1.67 (m, 2H), 1.63 (s, 9H), 1.49-1.41 (m, 1H), 1.27-1.24 (m, 4H). 1-(tert-Butyl)-N-(((2R,4R)-2-methyl-1-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)piperidin-4-yl)methyl)-1H-1,2,3-triazole-4-carboxamide (stereochemistry arbitrarily assigned) (18.50 mg, 12.3% yield), white solid. LCMS m / z = 477.1 [M+H] + 1 HNMR (400MHz, DMSO-d6) δ: 8.62 (s, 1H), 8.52 (t, J = 6.0 Hz, 1H), 8.44 (s, 1H), 8.11 (s, 1H), 7.93-7.92 (m, 2H), 6.83 (s, 1H), 4.24-4.20 (m, 1H), 3.93-3.89 (m, 4H), 3.56-3.49 (m, 1H), 3.29-3.18 (m, 2H), 1.98-1.77 (m, 3H), 1.61 (s, 9H), 1.41-1.31 (m, 5H) 1-(tert-Butyl)-N-(((2S,4S)-2-methyl-1-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)piperidin-4-yl)methyl)-1H-1,2,3-triazole-4-carboxamide (stereochemistry arbitrarily assigned) (21 mg, 14% yield), white solid. LCMS m / z=477.1 [M+H] + 1HNMR (400MHz, DMSO-d6) δ: 8.62 (s, 1H), 8.53 (t, J=6.0 Hz, 1H), 8.45 (s, 1H), 8.11 (s, 1H), 7.94-7.92 (m, 2H), 6.83 (s, 1H), 4.25-4.20 (m, 1H), 3.93-3.89 (m, 1H), 3.86 (s, 3H), 3.56-3.49 (m, 1H), 3.27-3.18 (m, 2H), 1.98-1.89 (m, 2H), 1.83-1.77 (m, 1H), 1.61 (s, 9H), 1.41-1.35 (m, 2H), 1.34-1.31 (m, 3H). 1-(tert-butyl)-N-((2-methyl-1-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)piperidin-4-yl)methyl)-1H-1,2,3-triazole-4-carboxamide (stereochemistry optionally assigned) (17.0 mg, 11.3% yield), white solid. LCMS m / z = 477.1 [M+H] + 1 HNMR (400MHz, DMSO-d6) δ : 8.65 (s, 1H), 8.54 (t, J = 6.0 Hz, 1H), 8.41 (s, 1H), 8.12 (s, 1H), 7.94-7.92 (m, 2H), 6.88 (s, 1H), 4.98 (t, J = 6.0 Hz, 1H), 4.45 (d, J = 14.0 Hz, 1H), 3.86 (s, 3H), 3.21-3.16 (m, 3H), 2.15 (s, 1H), 1.84-1.67 (m, 2H), 1.63 (s, 9H), 1.47-1.41 (m, 1H), 1.27-1.24 (m, 4H).

[0413] Example 144: 5-(tert-butyl)-N-((3-methyl-1-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)piperidin-4-yl)methyl)-1,2,4-oxadiazole-3-carboxamide [ka]

[0414] 1. Preparation of tert-butyl ((3-methyl-1-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)piperidin-4-yl)methyl)carbamate [ka] tert-Butyl ((3-methyl-1-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)piperidin-4-yl)methyl)carbamate was obtained from tert-butyl ((3-methylpiperidin-4-yl)methyl)carbamate and 4-chloro-6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazine (Step 5 of Example 1) according to the procedure described in Step 1 of Example 136. LCMS m / z = 426.2 [M+H] +

[0415] 2. Preparation of (3-methyl-1-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)piperidin-4-yl)methanamine dihydrochloride [ka] (3-Methyl-1-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)piperidin-4-yl)methanamine dihydrochloride was obtained as a white solid from tert-butyl ((3-methyl-1-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)piperidin-4-yl)methyl)carbamate according to the procedure described in Step 2 of Example 115. LCMS m / z = 326.2 [M+H] +

[0416] Preparation of 3.5-(tert-butyl)-N-((3-methyl-1-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)piperidin-4-yl)methyl)-1,2,4-oxadiazole-3-carboxamide [ka] 5-(tert-butyl)-N-((3-methyl-1-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)piperidin-4-yl)methyl)-1,2,4-oxadiazole-3-carboxamide as a white solid (11 mg, 13% yield) was obtained from (3-methyl-1-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)piperidin-4-yl)methanamine dihydrochloride and potassium 5-tert-butyl-1,2,4-oxadiazole-3-carboxylate according to the procedure described in Step 3 of Example 136. LCMS m / z=478.2 [M+H] + . 1H NMR (500 MHz, DMSO-d6) δ ppm 9.01 - 8.95 (m, 1 H) 8.91 (t, J=6.41 Hz, 1 H) 8.44 (s, 1 H) 8.17 - 8.11 (m, 1 H) 7.96 - 7.90 (m, 2 H) 6.91 (d, J=1.83 Hz, 1 H) 4.57 - 4.44 (m, 1 H) 4.23 - 4.26 (m, 1 H) 3.87 (s, 3 H) 3.50 (dt, J=13.73, 4.43 Hz, 1 H) 3.30 - 3.23 (m, 1 H) 3.22 - 3.14 (m, 1 H) 3.13 - 3.01 (m, 1 H) 2.85 - 2.76 (m, 1 H) 2.42 (br s, 1 H) 2.17 - 1.99 (m, 1 H) 1.81 (br d, J=10.38 Hz, 1 H) 1.67 - 1.47 (m, 3 H) 1.44 - 1.40 (m, 10 H) 1.40 - 1.30 (m, 1 H) 1.28 - 1.17 (m, 1 H) 1.05 (d, J=6.10 Hz, 2 H) 0.94 (dd, J=9.16, 6.71 Hz, 2 H).

[0417] Examples 145, 146, 147, and 148: N-(((3S,4R)-3-methyl-1-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)piperidin-4-yl)methyl)-5-(1-methylcyclopropyl)-1,2,4-oxadiazole-3-carboxamide, N-(((3S,4S)-3-methyl-1-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)piperidin-4-yl)methyl)-5-(1-methylcyclopropyl)-1,2,4-oxadiazole- 3-carboxamide, N-(((3R,4R)-3-methyl-1-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)piperidin-4-yl)methyl)-5-(1-methylcyclopropyl)-1,2,4-oxadiazole-3-carboxamide, and N-(((3R,4S)-3-methyl-1-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)piperidin-4-yl)methyl)-5-(1-methylcyclopropyl)-1,2,4-oxadiazole-3-carboxamide [ka] DIPEA (143.08 mg, 1.11 mmol) was dissolved in a solution of (3-methyl-1-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)piperidin-4-yl)methanamine dihydrochloride (Step 2 of Example 144, 126 mg, 221.4 μmol) and potassium 5-(1-methylcyclopropyl)-1,2,4-oxadiazole-3-carboxylate (91.78 mg, 442.8 μmol) in DMF (2.21 mL). T3P® (422.7 mg, 664.3 μmol, 50% purity) was added, and the reaction was stirred at room temperature overnight. An additional equivalent of potassium 5-(1-methylcyclopropyl)-1,2,4-oxadiazole-3-carboxylate, DIPEA, and T3P® were added, and the reaction was stirred at room temperature overnight. The reaction was diluted with water and extracted with EtOAc (2×). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. This material was purified by column chromatography (gradient elution 0–75% [3:1 EtOAc:EtOH]:heptane) to give a clear film. This was further purified by SFC: CHIRALPAK AD-H 30 × 250 mm, 5 μm, Method: 40% (1:1) MeOH:DCM and 0.1% DEA in CO2 (Flow rate: 100 mL / min, ABPR 120 bar, MBPR 40 psi, column temperature 40 °C). The compound was repurified by column chromatography (4 g column, gradient elution 0–100% [3:1 EtOAc:EtOH]:heptane) to give the product as a clear film. Peak 1, N-(((3S,4R)-3-methyl-1-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)piperidin-4-yl)methyl)-5-(1-methylcyclopropyl)-1,2,4-oxadiazole-3-carboxamide (4.0 mg, 3.8% yield, 99% purity). LCMS m / z = 476.3 [M+H] + . 1H NMR (600 MHz, DMSO-d6) δ ppm 8.86 (br t, J=5.9 Hz, 1 H), 8.44 (s, 1 H), 8.13 (s, 1 H), 7.96 - 7.92 (m, 2 H), 6.91 (d, J=2.2 Hz, 1 H), 4.53 (br d, J=13.2 Hz, 2 H), 4.40 (br d, J=11.0 Hz, 2 H), 3.87 (s, 3 H), 3.48 (dt, J=12.8, 5.0 Hz, 2 H), 3.19 - 3.12 (m, 2 H), 3.06 (td, J=12.8, 2.2 Hz, 2 H), 2.79 (br dd, J=13.2, 11.0 Hz, 2 H), 1.80 (br dd, J=13.6, 3.3 Hz, 2 H), 1.63 - 1.55 (m, 2 H), 1.52 (s, 3 H), 1.37 - 1.34 (m, 2 H), 1.16 - 1.12 (m, 2 H), 1.05 (d, J=5.9 Hz, 2 H) Peak 2, N-(((3S,4S)-3-methyl-1-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)piperidin-4-yl)methyl)-5-(1-methylcyclopropyl)-1,2,4-oxadiazole-3-carboxamide (2.0 mg, 1.9% yield, 99% purity) LCMS m / z=476.3 [M+H] + 1H NMR (600 MHz, DMSO-d6) δ ppm 8.93 (br t, J=5.9 Hz, 1 H), 8.44 (s, 1 H), 8.14 (s, 1 H), 7.99 - 7.90 (m, 2 H), 6.91 (br d, J=2.2 Hz, 1 H), 4.47 (br d, J=12.5 Hz, 2 H), 4.31 (br d, J=11.7 Hz, 2 H), 3.87 (s, 2 H), 3.25 - 3.21 (m, 2 H), 3.12 - 3.05 (m, 2 H), 2.10 (br s, 1 H), 2.04-1.96 (m, 1 H), 1.60 - 1.56 (m, 2 H), 1.54 (s, 3 H), 1.41 - 1.35 (m, 2 H), 1.17 (br d, J=2.2 Hz, 1 H), 0.92 (br d, J=6.6 Hz, 3 H) Peak 3, N-(((3R,4R)-3-methyl-1-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)piperidin-4-yl)methyl)-5-(1-methylcyclopropyl)-1,2,4-oxadiazole-3-carboxamide (3.0 mg, 2.8% yield, 99% purity) LCMS m / z=476.3 [M+H] + 1H NMR (600 MHz, DMSO-d6) δ ppm 8.93 (br t, J=5.9 Hz, 1 H), 8.43 (s, 1 H), 8.14 (s, 1 H), 7.97 - 7.92 (m, 2 H), 6.91 (d, J=1.5 Hz, 1 H), 4.47 (br d, J=13.9 Hz, 2 H), 4.31 (br d, J=11.7 Hz, 2 H), 3.87 (s, 3 H), 3.25 - 3.20 (m, 3 H), 3.12 - 3.06 (m, 2 H), 2.14 - 2.07 (m, 2 H), 2.04-1.99 (m, 1 H), 1.58 (br dd, J=9.5, 4.4 Hz, 2 H), 1.54 (s, 3 H), 1.40 - 1.35 (m, 3 H), 1.20 - 1.13 (m, 4 H), 0.92 (d, J=7.3 Hz, 4 H) Peak 4, N-(((3R,4S)-3-methyl-1-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)piperidin-4-yl)methyl)-5-(1-methylcyclopropyl)-1,2,4-oxadiazole-3-carboxamide (6.0 mg, 5.6% yield, 99% purity) LCMS m / z=476.3 [M+H] + 1H NMR (600 MHz, DMSO-d6) δ ppm 8.86 (br t, J=5.9 Hz, 1 H), 8.44 (s, 1 H), 8.13 (s, 1 H), 7.97 - 7.92 (m, 2 H), 6.91 (d, J=2.2 Hz, 1 H), 4.53 (br d, J=13.9 Hz, 2 H), 4.45 - 4.36 (m, 2 H), 3.87 (s, 3 H), 3.48 (dt, J=13.2, 4.8 Hz, 1 H), 3.19 - 3.12 (m, 2 H), 3.10 - 3.01 (m, 2 H), 2.79 (br dd, J=13.2, 10.3 Hz, 2 H), 1.80 (br dd, J=13.2, 2.9 Hz, 2 H), 1.63 - 1.56 (m, 2 H), 1.52 (s, 4 H), 1.38 - 1.34 (m, 2 H), 1.34 - 1.28 (m, 1 H), 1.17 - 1.13 (m, 2 H), 1.05 (d, J=6.6 Hz, 3 H)

[0418] Example 149. N-((3-methyl-1-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)piperidin-4-yl)methyl)-5-(1-methylcyclopropyl)-1,2,4-oxadiazole-3-carboxamide

[0419] 1. Preparation of tert-butyl 3-methyl-4-((5-(1-methylcyclopropyl)-1,2,4-oxadiazole-3-carboxamido)methyl)piperidine-1-carboxylate [ka] To a solution of tert-butyl 4-(aminomethyl)-3-methylpiperidine-1-carboxylate (100 mg, 438 μmol) in DCM (20 mL) was added DIPEA (113.20 mg, 875.9 μmol) and 5-(1-methylcyclopropyl)-1,2,4-oxadiazole-3-carbonyl chloride (Step 4 of Example 137, 163.45 mg, 875.9 μmol), and the reaction was stirred at 20° C. for 1 h. The mixture was poured into water (50 mL) and extracted with DCM (50 mL×3). The combined organic layers were washed with brine (100 mL), dried over NaSO, filtered, and concentrated in vacuo. The crude was purified by column chromatography on silica gel (PE / EtOAc=1 / 1) to give tert-butyl 3-methyl-4-((5-(1-methylcyclopropyl)-1,2,4-oxadiazole-3-carboxamido)methyl)piperidine-1-carboxylate (120 mg, 72.4% yield) as a yellow solid. LCMS m / z = 401.1 [M+Na] +

[0420] Preparation of 2.5-(1-methylcyclopropyl)-N-((3-methylpiperidin-4-yl)methyl)-1,2,4-oxadiazole-3-carboxamide [ka] A solution of tert-butyl 3-methyl-4-((5-(1-methylcyclopropyl)-1,2,4-oxadiazole-3-carboxamido)methyl)piperidine-1-carboxylate (120 mg, 317.1 μmol) in HCl / EtOAc (20 mL) was stirred at 20° C. for 1 h. The mixture was concentrated in vacuo to give 5-(1-methylcyclopropyl)-N-((3-methylpiperidin-4-yl)methyl)-1,2,4-oxadiazole-3-carboxamide hydrochloride (60 mg, crude) as a yellow solid, which was used without further purification. LCMS m / z = 279.0 [M+H] +

[0421] 3. Preparation of N-((3-methyl-1-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)piperidin-4-yl)methyl)-5-(1-methylcyclopropyl)-1,2,4-oxadiazole-3-carboxamide [ka] To a solution of 5-(1-methylcyclopropyl)-N-((3-methylpiperidin-4-yl)methyl)-1,2,4-oxadiazole-3-carboxamide hydrochloride (50 mg, 158.8 μmol) in IPA (10 mL) was added DIPEA (61.58 mg, 476.5 μmol) at 20° C. 4-Chloro-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine (Step 5 of Example 1, 74.22 mg, 317.7 μmol) was added, and the mixture was stirred at 90° C. for 48 hours. The reaction was concentrated in vacuo, and the mixture was poured into water (20 mL) and extracted with DCM (20 mL×3). The combined organic layers were washed with brine (10 mL), dried over NaSO, filtered, and concentrated in vacuo. The crude material was purified by preparative HPLC (Method E, 38-65% gradient) to afford N-((3-methyl-1-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)piperidin-4-yl)methyl)-5-(1-methylcyclopropyl)-1,2,4-oxadiazole-3-carboxamide (9.10 mg, 12.1% yield) as a white solid. LCMS m / z = 476.1 [M+H] + 1 H NMR (400 MHz, DMSO-d6) δ: 8.95-8.90 (m, 1H), 8.43 (s, 1H), 8.14 (s, 1H), 7.95-7.93 (m, 2H), 6.91 (s, 1H), 4.49-4.29 (m, 2H), 3.87 (s, 3H), 3.28-3.21 (m, 4H), 2.11-2.00 (m, 2H), 1.58-1.51 (m, 5H), 1.39-1.36 (m, 2H), 1.18-1.16 (m, 2H), 0.92 (d, J = 6.8 Hz, 3H).

[0422] Examples 150 and 151. 1-(tert-butyl)-N-(((3S,4S)-3-methyl-1-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)piperidin-4-yl)methyl)-1H-1,2,3-triazole-4-carboxamide and 1-(tert-butyl)-N-(((3R,4R)-3-methyl-1-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)piperidin-4-yl)methyl)-1H-1,2,3-triazole-4-carboxamide

[0423] 1. Preparation of cis-2-((3-methylpiperidin-4-yl)methyl)isoindoline-1,3-dione trifluoroacetate [ka] A solution of cis-2-((3-methylpiperidin-4-yl)methyl)isoindoline-1,3-dione (800 mg, 2.23 mmol) in TFA (10 mL) and DCM (40 mL) was stirred at 20° C. for 1 h. The mixture was concentrated in vacuo to give cis-2-((3-methylpiperidin-4-yl)methyl)isoindoline-1,3-dione trifluoroacetate (600 mg, crude) as a yellow solid, which was used without further purification. LCMS m / z = 259.0 [M+H] +

[0424] 2. Preparation of cis-tert-butyl (4-((1,3-dioxoindolin-2-yl)methyl)-3-methylpiperidine-1-carboxylate [ka] To a solution of cis-2-((3-methylpiperidin-4-yl)methyl)isoindoline-1,3-dione trifluoroacetate (600 mg, 1.62 mmol) in i-PrOH (20 mL) was added 4-chloro-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazine (Step 5 of Example 1, 300 mg, 1.28 mmol) and DIPEA (497.8 mg, 3.85 mmol), and the reaction was stirred at 90° C. for 48 h. The mixture was filtered and concentrated in vacuo. The crude product was purified by column chromatography on silica gel (PE / EtOAc = 1 / 1 to 0 / 1) to give cis-tert-butyl (4-((1,3-dioxoindolin-2-yl)methyl)-3-methylpiperidine-1-carboxylate (330 mg, 56.6% yield) as a yellow solid. LCMS m / z = 456.1 [M+H] +

[0425] 3. Preparation of cis-2-((3-methyl-1-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)piperidin-4-yl)methyl)isoindoline-1,3-dione [ka] To a solution of cis-tert-butyl (4-((1,3-dioxoindolin-2-yl)methyl)-3-methylpiperidine-1-carboxylate (330 mg, 724.5 μmol) in MeOH (20 mL) was added NHNH.HO (300 mg, 85% purity) and the reaction was stirred at 20 °C for 2 h. The mixture was concentrated in vacuo to afford cis-2-((3-methyl-1-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)piperidin-4-yl)methyl)isoindoline-1,3-dione (230 mg, crude) as a yellow solid, which was used directly without further purification. LCMS m / z = 326.1 [M+H] +

[0426] 4. Preparation of 1-(tert-butyl)-N-(((3S,4S)-3-methyl-1-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)piperidin-4-yl)methyl)-1H-1,2,3-triazole-4-carboxamide and 1-(tert-butyl)-N-(((3R,4R)-3-methyl-1-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)piperidin-4-yl)methyl)-1H-1,2,3-triazole-4-carboxamide [ka] To a solution of cis-2-((3-methyl-1-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)piperidin-4-yl)methyl)isoindoline-1,3-dione (190 mg, 433.4 μmol) in DCM (50 mL) was added DIPEA (112.02 mg, 866.7 μmol) at 20° C. 2-(tert-Butyl)-2H-1,2,3-triazole-4-carboxylic acid (109.97 mg, 650.0 μmol) and HATU (247.82 mg, 650.0 μmol) were added, and the reaction was stirred at 20° C. for 1 hour. The mixture was poured into water (50 mL) and extracted with DCM (50 mL×3). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by preparative HPLC (Method E, 33-63% gradient) to give cis-(3-methyl-1-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)piperidin-4-yl)methanamine (180 mg, 85.4% yield) as a yellow solid. LCMS m / z = 477.1 [M+H] + This compound (180 mg, 377.7 μmol) was purified by SFC (column: Phenomenex-Cellulose-2 (250 mm × 30 mm, 5 μm), 0.1% NH 3 .H 2 O, EtOH (mobile phase), 55-55%, flow rate (mL / min): 70) to obtain the following compound. Peak 1, 1-(tert-butyl)-N-(((3S,4S)-3-methyl-1-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)piperidin-4-yl)methyl)-1H-1,2,3-triazole-4-carboxamide (stereochemistry arbitrarily assigned) (66.6 mg, 37.0% yield), white solid. LCMS m / z = 477.2 [M+H] + 1 H NMR (400 MHz, DMSO-d6) δ: 8.64 (s, 1H), 8.54-8.50 (m, 1H), 8.42 (s, 1H), 8.14-8.12 (m, 1H), 7.95-7.92 (m, 2H), 6.90 (d, J = 1.6 Hz, 1H), 4.50-4.30 (m, 2H), 3.87 (s, 3H), 3.27-3.24 (m, 3H), 3.24-3.09 (m, 1H), 2.12-2.01 (m, 2H), 1.63 (s, 9H), 1.62-1.60 (m, 2H), 0.93 (d, J = 7.2 Hz, 3H). Peak 2, 1-(tert-butyl)-N-(((3R,4R)-3-methyl-1-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)piperidin-4-yl)methyl)-1H-1,2,3-triazole-4-carboxamide (stereochemistry arbitrarily assigned) (54.0 mg, 30% yield), white solid. LCMS m / z = 477.1 [M+H] + 1 H NMR (400 MHz, DMSO-d6) δ: 8.64 (s, 1H), 8.54-8.50 (m, 1H), 8.42 (s, 1H), 8.14-8.12 (m, 1H), 7.95-7.92 (m, 2H), 6.90 (d, J = 1.6 Hz, 1H), 4.50-4.30 (m, 2H), 3.87 (s, 3H), 3.27-3.24 (m, 3H), 3.09-3.24 (m, 1H), 2.12-2.01 (m, 2H), 1.63 (s, 9H), 1.62-1.60 (m, 2H), 0.93 (d, J = 7.2 Hz, 3H).

[0427] Example 152. 1-(tert-butyl)-N-((3-fluoro-1-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)piperidin-4-yl)methyl)-1H-1,2,3-triazole-4-carboxamide [ka]

[0428] 1. Preparation of benzyl (((3S,4R)-3-fluoro-1-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)piperidin-4-yl)methyl)carbamate [ka] A mixture of benzyl(((3S,4R)-3-fluoropiperidin-4-yl)methyl)carbamate hydrochloride (500 mg, 1.65 mmol), 4-chloro-6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrazine (Step 5 of Example 1, 367.5 mg, 1.57 mmol), and DIPEA (813.06 mg, 6.29 mmol) was dissolved in DMF (3.30 mL) and the reaction was stirred at 90° C. overnight. The reaction was diluted with water and extracted with EtOAc (2×). The combined organic layers were washed with brine, dried over NaSO, filtered, and concentrated. This material was triturated with EtOAc and filtered through a pad of Celite® to collect the solid. The filtrate was concentrated and purified by silica gel column chromatography (0-100% EtOAc:heptane) to afford benzyl (((3S,4R)-3-fluoro-1-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)piperidin-4-yl)methyl)carbamate (662.0 mg, 91% yield) as a brown solid. LCMS m / z = 464.2 [M+H] +

[0429] 2. Preparation of ((3S,4R)-3-fluoro-1-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)piperidin-4-yl)methanamine [ka] A vial was charged with benzyl (((3S,4R)-3-fluoro-1-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)piperidin-4-yl)methyl)carbamate (653.6 mg, 1.41 mmol), palladium (300.1 mg, 141 μmol), and MeOH (7.05 mL), purged and back-filled with H three times, then stirred under an atmosphere of H for 4 h. The reaction was filtered through a pad of Celite®, washed with MeOH, and concentrated to give ((3S,4R)-3-fluoro-1-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)piperidin-4-yl)methanamine (441 mg, 95% yield) as a pale yellow solid. LCMS m / z = 330.2 [M+H] +

[0430] 3. Preparation of 1-(tert-butyl)-N-(((3S,4R)-3-fluoro-1-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)piperidin-4-yl)methyl)-1H-1,2,3-triazole-4-carboxamide [ka] DIPEA (147.14 mg, 1.14 mmol) was added to a solution of ((3S,4R)-3-fluoro-1-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)piperidin-4-yl)methanamine (75 mg, 227.7 μmol) and 1-(tert-butyl)-1H-1,2,3-triazole-4-carboxylic acid (57.79 mg, 341.6 μmol) in DMF (2.28 mL). T3P® (434.71 mg, 683.1 μmol, 50% purity) was added and the reaction was stirred at room temperature overnight. The reaction was diluted with water and DCM and passed through a phase separator. The aqueous layer was extracted with DCM and the combined organic layers were concentrated. The residue was purified by HPLC (Method A2, 5-70%). The product-containing fractions were concentrated and dissolved in MeCN (1 mL) and water (1 mL), and the resulting material was frozen in a dry ice / acetone bath and lyophilized to afford 1-(tert-butyl)-N-(((3S,4R)-3-fluoro-1-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)piperidin-4-yl)methyl)-1H-1,2,3-triazole-4-carboxamide (56 mg, 50.7% yield) as a white solid. LCMS m / z = 481.3 [M+H] + 1H NMR (400 MHz, DMSO-d6) δ ppm 8.67 (s, 1 H), 8.61 (t, J=5.9 Hz, 1 H), 8.46 (d, J=0.8 Hz, 1 H), 8.15 (s, 1 H), 7.97 - 7.92 (m, 2 H), 6.92 (dd, J=2.5, 0.8 Hz, 1 H), 4.96 (br s, 1 H), 4.88 - 4.76 (m, 2 H), 4.67 (br d, J=12.0 Hz, 1 H), 3.44 - 3.35 (m, 1 H), 3.30 - 3.23 (m, 1 H), 3.11 - 2.98 (m, 1H), 2.29 - 2.10 (m, 1 H), 1.76 - 1.67 (m, 2 H), 1.64 (s, 9 H).

[0431] Example 153: 2-(tert-butyl)-N-(((3S,4R)-3-fluoro-1-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)piperidin-4-yl)methyl)oxazole-4-carboxamide [ka] 2-(tert-butyl)-N-(((3S,4R)-3-fluoro-1-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)piperidin-4-yl)methyl)oxazole-4-carboxamide as a white solid (44 mg, 39.8% yield) was obtained from ((3S,4R)-3-fluoro-1-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)piperidin-4-yl)methanamine (Step 2 of Example 152) and 2-tert-butyloxazole-4-carboxylic acid according to the procedure described in Step 3 of Example 152. LCMS m / z=481.3 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ ppm 8.49 (s, 1 H), 8.46 (d, J=0.8 Hz, 1 H), 8.20 (br t, J=6.0 Hz, 1 H), 8.15 (s, 1 H), 7.99 - 7.91 (m, 2 H), 6.92 (d, J=2.5 Hz, 1 H), 4.94 (br s, 1 H), 4.88 - 4.76 (m, 2 H), 4.66 (br d, J=11.8 Hz, 1 H), 3.87 (s, 3 H), 3.44 - 3.33 (m, 2 H), 3.30 - 3.20 (m, 2 H), 3.04 (br s, 1 H), 2.27 - 2.08 (m, 2 H), 1.69 (br s, 2 H), 1.36 (s, 9 H).

[0432] Example 154: N-(((3S,4R)-3-fluoro-1-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)piperidin-4-yl)methyl)-5-(1-methylcyclopropyl)-1,2,4-oxadiazole-3-carboxamide [ka] N-(((3S,4R)-3-fluoro-1-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)piperidin-4-yl)methyl)-5-(1-methylcyclopropyl)-1,2,4-oxadiazole-3-carboxamide was obtained as a white solid (29 mg, 26.3% yield) from ((3S,4R)-3-fluoro-1-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)piperidin-4-yl)methanamine (Step 2 of Example 152) and 5-(1-methylcyclopropyl)-1,2,4-oxadiazole-3-carboxylic acid (Step 3 of Example 137) according to the procedure described in Step 3 of Example 152. LCMS m / z=480.2 [M+H] + 1H NMR (400 MHz, DMSO-d6) δ ppm 8.96 - 9.04 (m, 1 H), 8.47 (s, 1 H), 8.15 (s, 1 H), 7.97 - 7.92 (m, 2 H), 6.92 (d, J=2.5 Hz, 1 H), 4.94 (br s, 1H), 4.87 - 4.76 (m, 2 H), 4.67 (br d, J=15.1 Hz, 1 H), 3.87 (s, 3 H), 3.42 - 3.34 (m, 1 H), 3.26 (s, 1 H), 3.05 (s, 1 H), 2.27 - 2.08 (m, 2 H), 1.70 (br s, 2 H), 1.54 (s, 3 H), 1.42 - 1.34 (m, 2 H), 1.21 - 1.11 (m, 2 H).

[0433] Examples 155 and 156: 5-(tert-butyl)-N-(((3S,4R)-3-fluoro-1-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)piperidin-4-yl)methyl)-1,2,4-oxadiazole-3-carboxamide and 5-(tert-butyl)-N-(((3R,4S)-3-fluoro-1-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrazin-4-yl)piperidin-4-yl)methyl)-1,2,4-oxadiazole-3-carboxamide [ka]

[0434] 1. Preparation of tert-butyl cis-4-((5-(tert-butyl)-1,2,4-oxadiazole-3-carboxamido)methyl)-3-fluoropiperidine-1-carboxylate [ka] DIPEA (833.6 mg, 6.45 mmol) was added to a solution of tert-butyl cis-4-(aminomethyl)-3-fluoro-piperidine-1-carboxylate (499.42 mg, 2.15 mmol) and potassium 5-tert-butyl-1,2,4-oxadiazole-3-carboxylate (539.89 mg, 2.58 mmol) in DCM (21.5 mL) and the solution was cooled to 0° C. HATU (983.60 mg, 2.58 mmol) was added in one portion and the reaction was stirred at room temperature overnight. The reaction was concentrated and purified by column chromatography (40 g column, gradient elution 0-100% EtOAc:heptane) to afford tert-butyl cis-4-((5-(tert-butyl)-1,2,4-oxadiazole-3-carboxamido)methyl)-3-fluoropiperidine-1-carboxylate (405 mg, 49% yield) as a white solid. LCMS m / z = 407.2 [M+H] +

[0435] Preparation of 2,5-(tert-butyl)-N-((cis-3-fluoropiperidin-4-yl)methyl)-1,2,4-oxadiazole-3-carboxamide hydrochloride [ka] 5-(tert-butyl)-N-((cis-3-fluoropip...

Claims

1. Compounds represented by formula (I) 【Chemistry 1】 or a pharmaceutically acceptable salt thereof [In the formula, X ０ is N and X １ is C and X ２ is N and X ４ is N and X ５ is CH; X ０ is CR ０ and X １ is C and X ２ is N and X ４ is N and X ５ is CH; X ０ is CR ０ and X １ is N and X ２ is C and X ４ is N and X ５ is CH; X ０ is CR ０ and X １ is N and X ２ is C and X ４ is CH, and X ５ is CH; X ０ is CR ０ and X １ is C and X ２ is N and X ４ is CH, and X ５ is CH; or X ０ is CH, and X １ is N and X ２ is C and X ４ is CH, and X ５ is N, X ３ is -OR ５ , -N(R ５ ) ２ , 5- to 6-membered heteroaryl, or 4- to 7-membered monocyclic heterocyclyl, wherein the 5- to 6-membered heteroaryl and the 4- to 7-membered monocyclic heterocyclyl are each independently selected from the group consisting of one or more R ５０ is optionally replaced by R ０ is H, halo, methyl, halomethyl, cyclopropyl, or CN; Ring A is phenyl, 5- or 6-membered heteroaryl, or 5- to 10-membered monocyclic or bicyclic heterocyclyl; R １ is -N(R １ａ ) ２ , -OR １ａ , phenyl, 3- to 7-membered monocyclic carbocyclyl, 3- to 7-membered monocyclic heterocyclyl, 5- to 6-membered heteroaryl, 7- to 10-membered bicyclic carbocyclyl, 7- to 10-membered bicyclic heterocyclyl, and 8- to 10-membered bicyclic heteroaryl; R １ The phenyl, the 3- to 7-membered monocyclic carbocyclyl, the 3- to 7-membered monocyclic heterocyclyl, the 5- to 6-membered heteroaryl, the 7- to 10-membered bicyclic carbocyclyl, and the 7- to 10-membered bicyclic heterocyclyl each optionally may be one or more R １０ is replaced by R １ａ are independently expressed as H, C for each occurrence. １－６ Alkyl, C ２－６ Alkenyl, C ２－６ alkynyl, phenyl, a 3- to 7-membered carbocyclyl ring, a 3- to 7-membered monocyclic heterocyclyl, and a 5- to 6-membered heteroaryl; R １ａ The C represented by １－６ alkyl, the C ２－６ alkenyl, the C ２－６ The alkynyl, the phenyl, the 3- to 7-membered carbocyclyl ring, the 3- to 7-membered monocyclic heterocyclyl, and the 5- to 6-membered heteroaryl each optionally include one or more R １０ is replaced by R １０ is, at each occurrence, independently a halogen, -OR １０ａ , -S(O) ２ R １０ａ , -CN,C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ alkynyl, 3- to 7-membered monocyclic carbocyclyl, and 4- to 6-membered monocyclic heterocyclyl; R １０ The C represented by １－６ alkyl, the C ２－６ alkenyl, the C ２－６ The alkynyl, the 3- to 7-membered monocyclic carbocyclyl, and the 4- to 6-membered monocyclic heterocyclyl each optionally include one or more R １５ is replaced by R １０ａ is C optionally substituted with one or more halogens １－６ is alkyl, R １５ represents, at each occurrence, independently, a halogen, C １－６ Alkyl, C １－６ Haloalkyl, —CN, and —OR １５ａ is selected from R １５ａ is C １－６ is alkyl, R ２ is H, C １－６ Alkyl, C ２－６ Alkenyl, and C ２－６ is alkynyl, Or R １ and R ２ together with their intervening atoms form a ring D selected from a 3- to 7-membered monocyclic heterocyclyl, a 7- to 10-membered bicyclic heterocyclyl, and an 8- to 10-membered bicyclic heteroaryl, and ring D is selected from one or more R １００ is optionally replaced by R １００ is independently calculated for each occurrence of C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ alkynyl, 3- to 7-membered monocyclic carbocyclyl, 4- to 6-membered monocyclic heterocyclyl, and halogen; １００ The C represented by １－６ alkyl, the C ２－６ alkenyl, the C ２－６ The alkynyl, the 3- to 7-membered monocyclic carbocyclyl, and the 4- to 6-membered monocyclic heterocyclyl each optionally include one or more R １５０ is replaced by R １５０ is, at each occurrence, independently a halogen, -OR １５０ａ , a 3- to 7-membered carbocyclyl ring, and a 4- to 7-membered monocyclic heterocyclyl; R １５０ａ is H or C １－６ is alkyl, R ３ is H, halogen, —C(O)N(R ３ａ ) ２ , -C(O)OR ３ａ , -C(O)R ３ａ , C １－６ Alkyl, C ２－６ Alkenyl, and C ２－６ alkynyl, and R ３ The C represented by １－６ alkyl, the C ２－６ alkenyl, and the C ２－６ each alkynyl is optionally substituted with one or more substituents selected from halogen and hydroxyl; R ３ａ are independently expressed as H, C for each occurrence. １－６ Alkyl, C ２－６ Alkenyl, C ２－６ alkynyl, phenyl, a 3- to 7-membered carbocyclyl ring, a 3- to 7-membered monocyclic heterocyclyl, or a 5- to 6-membered heteroaryl; １－６ alkyl, the C ２－６ alkenyl, the C ２－６ The alkynyl, the phenyl, the 3- to 7-membered carbocyclyl ring, the 3- to 7-membered monocyclic heterocyclyl, and the 5- to 6-membered heteroaryl may each be one or more R ３０ is optionally replaced by Or two R on the same nitrogen ３ａ The groups, taken together with their intervening atoms, form a ring selected from 3- to 7-membered monocyclic heterocyclyl and 5- to 6-membered heteroaryl, said ring containing one or more R ３０ is optionally replaced by R ３０ is, at each occurrence, independently a halogen, -OR ３０ａ , -N(R ３０ａ ) ２ , -C(O)N(R ３０ａ ), —C(O) ２ R ３０ａ , oxo, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ selected from alkynyl, 3- to 7-membered monocyclic carbocyclyl, and 4- to 6-membered monocyclic heterocyclyl; R ３０ａ is H or C １－６ is alkyl, R ４ is, at each occurrence, independently H, a halogen, —NO ２ , -CN, -OR ４ａ , -SR ４ａ , -N(R ４ａ ) ２ , -C(O)R ４ａ , -C(O)OR ４ａ , -S(O)R ４ａ , -S(O) ２ R ４ａ , -C(O)N(R ４ａ ) ２ , -SO ２ N (R ４ａ ) ２ , -OC(O)R ４ａ , -N(R ４ａ ) C(O)R ４ａ , -N(R ４ａ )C(O)OR ４ａ , -N(R ４ａ ) SO ２ R ４ａ , -OC(O)N(R ４ａ ) ２ , C １－６ Alkyl, C ２－６ Alkenyl, and C ２－６ alkynyl, wherein C １－６ alkyl, the C ２－６ alkenyl, and the C ２－６ Each alkynyl optionally has one or more R ４０ is replaced by R ４ａ is H, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ alkynyl, phenyl, 3- to 8-membered carbocyclyl ring, 3- to 7-membered monocyclic heterocyclyl, and 5- to 6-membered heteroaryl; R ４ａ The C represented by １－６ alkyl, the C ２－６ alkenyl, the C ２－６ The alkynyl, the phenyl, the 3- to 8-membered carbocyclyl ring, the 3- to 7-membered monocyclic heterocyclyl, and the 5- to 6-membered heteroaryl each optionally include one or more R ４０ is replaced by Or two R on the same nitrogen ４ａ The groups, taken together with their intervening atoms, form a ring selected from 3- to 7-membered monocyclic heterocyclyl and 5- to 6-membered heteroaryl, said ring containing one or more R ４０ is optionally replaced by R ４０ is, at each occurrence, independently a halogen, -OR ４０ａ , -N(R ４０ａ ) ２ , -C(O)N(R ４０ａ ) ２ , —C(O) ２ R ４０ａ , oxo, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ alkynyl, 3- to 7-membered monocyclic carbocyclyl, and 4- to 6-membered monocyclic heterocyclyl; R ４０ The C represented by １－６ alkyl, the C ２－６ alkenyl, the C ２－６ The alkynyl, the 3- to 7-membered monocyclic carbocyclyl, and the 4- to 6-membered monocyclic heterocyclyl each optionally include one or more R ４５ is replaced by R ４０ａ is H, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ alkynyl, 3- to 7-membered monocyclic carbocyclyl, and 4- to 6-membered monocyclic heterocyclyl, １－６ alkyl, the C ２－６ alkenyl, the C ２－６ The alkynyl, the 3- to 7-membered monocyclic carbocyclyl, and the 4- to 6-membered monocyclic heterocyclyl each optionally include one or more R ４５ is replaced by R ４５ is independently calculated for each occurrence of C １－６ Alkyl, halogen, and —OR ４５ａ is selected from R ４５ａ is H or C １－６ is alkyl, Or R ３ and R ４ together with the atoms between them form ring E, ring E being selected from a 4- to 7-membered monocyclic carbocycle and a 4- to 7-membered monocyclic heterocycle, and ring E being selected from R ３００ is optionally replaced by R ３００ is independently calculated for each occurrence of C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, 3- to 7-membered monocyclic carbocyclyl, 4- to 6-membered monocyclic heterocyclyl, halogen, —C(O)R ３００ａ , -OR ３００ａ , and -S(O) ２ R ３００ａ and R ３００ The C represented by １－６ alkyl, the C ２－６ alkenyl, the C ２－６ The alkynyl, the 3- to 7-membered monocyclic carbocyclyl, and the 4- to 6-membered monocyclic heterocyclyl each optionally include one or more R ３５０ is replaced by R ３００ａ is H, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ alkynyl, 3- to 7-membered monocyclic carbocyclyl, and 4- to 6-membered monocyclic heterocyclyl; R ３００ａ The C represented by １－６ alkyl, the C ２－６ alkenyl, the C ２－６ The alkynyl, the 3- to 7-membered monocyclic carbocyclyl, and the 4- to 6-membered monocyclic heterocyclyl each optionally include one or more R ３５０ is replaced by R ３５０ is independently calculated for each occurrence of C １－６ Alkyl, halogen, —CN, —C(O)R ３５０ａ , -C(O)N(R ３５０ａ ) ２ , -N(R ３５０ａ ) ２ , and -OR ３５０ａ is selected from R ３５０ａ is, at each occurrence, independently H or C optionally substituted with 1 to 3 halogens １－６ is alkyl, R ５ Ha, Halo, C １－６ Alkoxy, and C １－６ C optionally substituted with one or more substituents independently selected from haloalkoxy １－６ is alkyl, R ５０ is, at each occurrence, independently a halogen, -OR ５０ａ , -N(R ５０ａ ) ２ , -C(O)N(R ５０ａ ), —C(O) ２ R ５０ａ , oxo, C １－６ is selected from alkyl, 3- to 7-membered monocyclic carbocyclyl, and 4- to 6-membered monocyclic heterocyclyl; R ５０ The C represented by １－６ alkyl, said 3- to 7-membered monocyclic carbocyclyl, and said 4- to 6-membered monocyclic heterocyclyl are each optionally selected from the group consisting of C １－６ Alkyl, CN, halo, and C １－６ substituted with one or more substituents independently selected from alkoxy; R ５０ａ is H or C １－６ is alkyl, n is 0, 1, 2, 3, or 4.

2. The compound has the following formula: 【Chemistry 2】 2. The compound of claim 1, wherein the compound is represented by the formula: or a pharmaceutically acceptable salt thereof.

3. X ３ But, -OR ５ , -N(R ５ ) ２ , 5-membered heteroaryl, or 4- to 6-membered monocyclic heterocyclyl, wherein the 5-membered heteroaryl and the 4- to 6-membered monocyclic heterocyclyl are each independently selected from 1 to 3 R ５０ is optionally replaced by R ５ But C １－６ C optionally substituted with alkoxy １－６ is alkyl, 3. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R 50 at each occurrence is independently C 1-6 alkyl or 4 to 6 membered monocyclic heterocyclyl, and said C 1-6 alkyl represented by R 50 is optionally substituted with halo or CN.

4. X ３ but, (i) phenyl, azetidine, morpholine, oxadiazole, piperazine, pyrazole, tetrazole (each optionally containing one or two R ５０ (replaced by); (ii) 【Transformation 3】 wherein m is 0, 1, or 2; or (iii) -O-CH 2 -CH 2 -OCH 3 , -N(CH 3 ) 2 , 【Chemistry 4】 (In the formula, 【Transformation 5】 represents a bond to ring B) is selected from 3. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R 50 is —CH 3 .

5. Ring A is (i) phenyl, 5- or 6-membered heteroaryl, or 5- to 10-membered monocyclic or bicyclic heterocyclyl, each of which optionally contains 1 to 3 R ４ is replaced by; (ii) selected from 3-azabicyclo[3.2.1]octane, azepane, phenyl, piperidine, pyridine, and pyrrolidine, each of which is optionally substituted with one to three R 4 ; or (iii) 【Transformation 6】 is selected from During the ceremony, 【Transformation 7】 represents a bond to ring B, and -* represents 【Transformation 8】 and n is 0, 1, or 2; 3. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R 4 is selected from halogen, C 1-6 alkyl, and C 1-6 haloalkyl.

6. Ring A is 【Chemistry 9-1】 【Chemistry 9-2】 is selected from During the ceremony, 【Chemistry 10】 represents a bond to ring B, and -* represents 【Chemistry 11】 represents a bond to 6. The compound of claim 5, or a pharmaceutically acceptable salt thereof, wherein R 4 is selected from halogen, C 1-6 alkyl, and C 1-6 haloalkyl, preferably R 4 is selected from Cl, F, —CH 3 , and —CHF 2 .

7. R １ but, (i) one or two R １０ or a 5-membered heteroaryl optionally substituted with (ii) selected from oxazole, oxadiazole, pyrazole, tetrazole, and triazole, each of which is optionally substituted with one or two R 10 ; wherein R 10 at each occurrence is independently selected from C 1-6 alkyl and C 3-6 cycloalkyl, each of which alkyl is optionally substituted with 1 to 3 R 15 , and R 15 at each occurrence is independently selected from halogen, C 1-4 alkyl and C 1-4 haloalkyl; or R 1 is (iii) 【Chemistry 12】 is selected from 3. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R 10 is selected from C 1-4 alkyl and cyclopropyl and is optionally substituted with one or three R 15 , and R 15 at each occurrence is independently selected from halogen, C 1-4 alkyl and C 1-4 haloalkyl, preferably R 15 is independently selected from F, —CH 3 and —CH 2 F.

8. R １０ is, for each occurrence, independently, -C(CH ３ ) ３ , -C(CH ３ ) ２ -CH ２ F. 【Chemistry 13】 3. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, selected from:

9. R ２ is H; or R 1 and R 2 together with the intervening atoms form a ring D selected from a 5- to 7-membered monocyclic heterocyclyl and a 7- to 10-membered bicyclic heterocyclyl, wherein ring D is optionally substituted with one or more R 100 ; (i) R 100 at each occurrence is independently selected from C 1-6 alkyl and 4- to 6-membered monocyclic heterocyclyl, each of which is optionally substituted with one or two R 150 ; and (ii) The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R 150 at each occurrence is independently selected from C 3-6 cycloalkyl and 4- to 6-membered monocyclic heterocyclyl.

10. Ring D is (i) a ring selected from piperazinone and dihydropyrrolo[3,4-d]thiazolone, wherein ring D is optionally substituted with one or two R １００ is replaced by; or (ii) 【Chemistry 14】 is selected from During the ceremony, 【Chemistry 15】 represents the bond to —C(R 3 )-Ring A; R 100 at each occurrence is independently selected from C 1-6 alkyl and oxetanyl, said C 1-6 alkyl represented by R 100 is optionally substituted with R 150 ; and 10. The compound of claim 9, or a pharmaceutically acceptable salt thereof, wherein each occurrence of R150 is independently selected from cyclobutyl and oxetanyl.

11. R １００ is, for each occurrence independently, -CH ３ , -CH ２ -CH ２ -CH ３ , -CH(CH ３ ) ２ , -C(CH ３ ) ３ , -CH ２ -CH(CH ３ ) ２ , -CH ２ -C(CH ３ ) ３ , 【Chemistry 16】 10. The compound of claim 9 selected from: or a pharmaceutically acceptable salt thereof.

12. (i) R ３ is H or -CH ３ is; or (ii) R 3 and R 4 together with the intervening atoms form Ring E, Ring E is selected from a 4- to 7-membered monocyclic carbocycle and a 4- to 7-membered monocyclic heterocycle, Ring E is optionally substituted with R 300 ; 3. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R 300 at each occurrence is independently selected from C 1-6 alkyl and 4- to 6-membered monocyclic heterocyclyl, and said C 1-6 alkyl and said 4- to 6-membered monocyclic heterocyclyl represented by R 300 are each optionally substituted with 1 to 3 R 350 , and R 350 at each occurrence is independently halogen.

13. Ring E is represented by the following structural formula: 【Chemistry 17】 During the ceremony, [Chemistry 18] represents the fusion point to ring A, and -* represents -N(R ２ )-C(O)-R １ and R 300 at each occurrence independently represents a bond to —CH 2 —CF 3 and 【Chemistry 19】 13. The compound of claim 12, selected from:

14. The compound has the following formula: 【Chemistry 20】 or a pharmaceutically acceptable salt thereof, wherein: R １ is R １０ is a 5-membered heteroaryl optionally substituted with R １０ is C １－４ Alkyl, C １－４ haloalkyl, or C １－３ C optionally substituted with alkyl ３－６ is cycloalkyl, X ３ is a 5-membered heteroaryl or a 6-membered monocyclic saturated heterocyclyl, each of which is optionally R ５０ is replaced by R ５０ is C １－３ Alkyl or C １－３ is haloalkyl, Ring A is phenyl, a 6-membered heteroaryl, or a 6-membered monocyclic saturated heterocyclyl; R ４ represents, at each occurrence, independently, a halogen, C １～３ Alkyl and C １～３ haloalkyl; n is 0, 1, or 2.

15. R １ but, 【Chemistry 21】 is selected from X ３ but, 【Chemistry 22】 is selected from Ring A is 【Chemistry 23】 is selected from During the ceremony, 【Chemistry 24】 represents a bond to ring B, and -* represents 【Chemistry 25】 15. The compound of claim 14, or a pharmaceutically acceptable salt thereof, which represents a bond to:

16. R １０ But -C(CH ３ ) ３ or 【Chemistry 26】 and R ４ are, for each occurrence, independently, F, -CH ３ , and -CHF ２ is selected from R ５０ Ga-CH ３ 16. The compound of claim 14 or 15, wherein:

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

18. 18. The pharmaceutical composition of claim 17 for use in a method for treating a disorder responsive to inhibition of Bruton's tyrosine kinase in a subject.

19. The pharmaceutical composition of claim 17 for use in a method for treating a disorder, wherein the disorder is an autoimmune disorder, rheumatoid arthritis, systemic lupus erythematosus, atopic dermatitis, leukemia or lymphoma.

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