Fused biheterocycles as inhibitors of Bruton's tyrosine kinase

Abstract

Provided are compounds of formula (I): 1 , R 2 , R 3 , R 4 , R 5 , R 6 , A 1 , B 1 , B 2 , Q 1 , and Q 2 are as defined herein), and methods of their use and manufacture. TIFF2023501236000479.tif9767

Description

[Technical Field]

[0001] Related Applications This application claims the benefit of the filing date under 35 U.S.C. §119(e) of U.S. Provisional Patent Application No. 62 / 928,058, filed October 30, 2019, the entire contents of which are incorporated herein by reference.

[0002] Technical Field 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 numerous human diseases in oncology, neurology, and immunology. 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)). These kinases are primarily expressed in hematopoietic cells, although Bmx and Tec expression has been detected in endothelial cells and hepatocytes. The Tec kinases (Itk, Rlk, and Tec) are all expressed in T cells and activated downstream of T cells, where they are involved in regulating B cell activation, proliferation, and differentiation. More specifically, Btk contains a PH domain that binds phosphatidylinositol (3,4,5)-trisphosphate (PIP3). PIP3 binding induces Btk to phosphorylate phospholipase C (PLCy), which then hydrolyzes PIP2 to generate two second messengers, inositol triphosphate (IP3) and diacylglycerol (DAG), that activate the protein kinase PKC, thereby inducing further B cell signaling. Mutations that abolish Btk enzymatic activity cause XLA syndrome (X-linked agammaglobulinemia), a primary immunodeficiency syndrome. Given the important role Tec kinase plays in both B cell and T cell signaling, Tec kinase is an attractive target for autoimmune disorders.

[0004] Therefore, there is a great need in the art for effective inhibitors of Btk. Summary of the Invention

[0005] A first embodiment of the present invention is a compound of formula (I): [ka] or a pharmaceutically acceptable salt thereof, wherein A 1 is CR 7 and N, B 1 and B 2 are each independently 8 , N, and NR 8 is selected from Q 1 and Q 2 one of which is N and the other is C, R 1 is -N(R 1a )2, 3- to 7-membered monocyclic carbocyclyl, 3- to 7-membered monocyclic heterocyclyl, 7- to 10-membered bicyclic carbocyclyl, and 7- to 10-membered bicyclic heterocyclyl; R 1 Each of the 3- to 7-membered monocyclic carbocyclyl, 3- to 7-membered monocyclic heterocyclyl, 7- to 10-membered bicyclic carbocyclyl, and 7- to 10-membered bicyclic heterocyclyl represented by the formula (I) optionally contains one or more (e.g., 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, and R 1a C, represented by 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 Each alkynyl optionally contains one or more (e.g., 1, 2, 3, 4, 5, or 6, etc.) R 10 is replaced by R 10 represents, 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 10 C, represented by 1-6 Alkyl, C 2-6 Alkenyl, C2-6 Alkynyl, 3- to 7-membered monocyclic carbocyclyl, and 4- to 6-membered monocyclic heterocyclyl each optionally contain one or more (e.g., 1, 2, 3, 4, 5, or 6, etc.) R 15 is replaced by R 10a For each occurrence, independently, H, 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 15 For each occurrence, independently, C 1-6 Alkyl, halogen, -CN, and -OR 15a or two R 15 together with their intervening atoms form a 3- to 7-membered monocyclic carbocyclyl or a 4- to 6-membered monocyclic heterocyclyl; R 15a is H or C 1-6 is alkyl, R 2 is H, C 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 alkynyl, R 3 is H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -C(O)N(R 3a )2, -C(O)OR 3a , and -C(O)R 3a Selected from R 3 C, represented by 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 Each alkynyl optionally contains one or more (e.g., 1, 2, 3, 4, 5, or 6, etc.) R 30 Replace with And, R 3a For each occurrence, independently, H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 alkynyl, and R3a C, represented by 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 Each alkynyl optionally contains one or more (e.g., 1, 2, 3, 4, 5, or 6, etc.) R 30 is replaced by R 30 represents, for each occurrence independently, a halogen, -OR 30a , 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, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 selected from alkynyl, 3- to 6-membered monocyclic carbocyclyl, and 4- to 6-membered monocyclic heterocyclyl; Or alternatively, R 2 and R 3 together with their intervening atoms form a ring A selected from a 3- to 7-membered monocyclic heterocyclyl and a 7- to 10-membered bicyclic heterocyclyl, and ring A optionally contains one or more (e.g., 1, 2, 3, 4, 5, or 6, etc.) R 200 is replaced by R 200 For each occurrence, independently, 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, -CN, -C(O)R 200a , -C(O)2R 200a , -C(O)N(R 200a )2, -N(R 200a )2, -N(R 200a )C(O)R 200a , -N(R 200a )C(O)2R 200a , -N(R 200a )C(O)N(R 200a )2, -N(R 200a )S(O)2R 200a , -OR 200a, -OC(O)R 200a , -OC(O)N(R 200a )2, -SR 200a , -S(O)R 200a , -S(O)2R 200a , -S(O)N(R 200a )2, -S(O)2N(R 200a )2 and R 200 C, represented by 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 3- to 7-membered monocyclic carbocyclyl, and 4- to 6-membered monocyclic heterocyclyl each optionally contain one or more (e.g., 1, 2, 3, 4, 5, or 6, etc.) R 250 or two R 200 together with their intervening atoms form a 4- to 6-membered monocyclic heterocyclyl or a 3- to 7-membered monocyclic carbocyclyl, each of which optionally contains one or more (e.g., 1, 2, 3, 4, 5, or 6, etc.) R 250 is replaced by R 200a For each occurrence, independently, 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 200a C, represented by 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 3- to 7-membered monocyclic carbocyclyl, and 4- to 6-membered monocyclic heterocyclyl each optionally contain one or more (e.g., 1, 2, 3, 4, 5, or 6, etc.) R 250 is replaced by R 250 For each occurrence, independently, C 1-6 Alkyl, halogen, and -OR 250a is selected from R 250a is H or C 1-6 is alkyl, R 4 is H, C 1-6 Alkyl, C 2-6 Alkenyl, C2-6 Alkynyl, 3- to 7-membered monocyclic carbocyclyl, 4- to 6-membered monocyclic heterocyclyl, 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)C(O)R 4a , -N(R)C(O)OR 4a , -N(R)SO2R 4a , and -OC(O)N(R 4a )2 and R 4 C, represented by 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 3- to 7-membered monocyclic carbocyclyl, and 4- to 6-membered monocyclic heterocyclyl each optionally contain one or more (e.g., 1, 2, 3, 4, 5, or 6, etc.) R 40 is replaced by R 4a 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 4a C, represented by 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 3- to 7-membered monocyclic carbocyclyl, and 4- to 6-membered monocyclic heterocyclyl each optionally represent one or more R above (e.g., 1, 2, 3, 4, 5, or 6) 40 is replaced by R 40 represents, for each occurrence independently, a halogen, -OR 40a , C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6alkynyl, 3- to 7-membered monocyclic carbocyclyl, and 4- to 6-membered monocyclic heterocyclyl; R 40 C, represented by 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 3- to 7-membered monocyclic carbocyclyl, and 4- to 6-membered monocyclic heterocyclyl each optionally contain one or more (e.g., 1, 2, 3, 4, 5, or 6, etc.) 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, C 2-6 Alkenyl, C 2-6 Alkynyl, 3- to 7-membered monocyclic carbocyclyl, and 4- to 6-membered monocyclic heterocyclyl each optionally contain one or more (e.g., 1, 2, 3, 4, 5, or 6, etc.) R 45 is replaced by R 45 For each occurrence, independently, C 1-6 Alkyl, halogen, and -OR 45a is selected from R 45a is H or C 1-6 is alkyl, Or alternatively, R 3 and R 4 together with their intervening atoms form ring B selected from 5-7 membered monocyclic carbocyclyl and 5-7 membered monocyclic heterocyclyl having 1-2 heteroatoms independently selected from O, N, and S, and ring B optionally contains one or more (e.g., 1, 2, 3, 4, 5, or 6, etc.) R 300 is replaced by R 300 For each occurrence, independently, 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 , -OR300a , and -S(O)R 300a Selected from R 300 C, represented by 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 3- to 7-membered monocyclic carbocyclyl, and 4- to 6-membered monocyclic heterocyclyl each optionally contain one or more (e.g., 1, 2, 3, 4, 5, or 6, etc.) 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 C, represented by 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 3- to 7-membered monocyclic carbocyclyl, and 4- to 6-membered monocyclic heterocyclyl each optionally contain one or more (e.g., 1, 2, 3, 4, 5, or 6, etc.) R 350 is replaced by R 350 For each occurrence, independently, C 1-6 Alkyl, halogen, -CN, -C(O)R 350a , -C(O)N(R 350a )2, -C(R 350a )2N(R 350a )2, and -OR 350a is selected from R 350a is, for each occurrence, independently H, or optionally substituted with 1 to 3 halogens, or C 1-6 alkyl or two R 350a together with the N atom to which they are attached form a 4- to 6-membered monocyclic heterocyclyl having 1 to 2 heteroatoms selected from N and O, R 5 is H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, and -OR 5a Selected from R 5 C, represented by1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 The alkynyl is optionally substituted with one or more (e.g., 1, 2, 3, 4, 5, or 6, etc.) halogens; R 5a 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 5a C, represented by 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 alkynyl, 3- to 6-membered monocyclic carbocyclyl are each optionally substituted with one or more (e.g., 1, 2, 3, 4, 5, or 6, etc.) halogen atoms; R 6 is H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, halogen, -OR 6a Selected from R 6 C, represented by 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 Each alkynyl optionally contains one or more (e.g., 1, 2, 3, 4 , 5, or 6) halogen, R 6a is H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 alkynyl, 3- to 6-membered monocyclic carbocyclyl, and 4- to 6-membered monocyclic heterocyclyl; R 6a C, represented by 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 alkynyl, 3- to 6-membered monocyclic carbocyclyl, and 4- to 6-membered monocyclic heterocyclyl are each optionally substituted with one or more (e.g., 1, 2, 3, 4, 5, or 6, etc.) halogen atoms; R 7 is H, C 1-6 Alkyl, C 2-6 Alkenyl, C2-6 Alkynyl, -CN, -OR 7a , -C(O)N(R 7a )2, -C(O)OR 7a , and -C(O)R 7a Selected from R 7 C, represented by 1-6 Alkyl, C 2-6 Alkenyl, and C 2-6 Each alkynyl optionally contains one or more (e.g., 1, 2, 3, 4, 5, or 6, etc.) R 70 is replaced by R 7a For each occurrence, independently, 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 7a C, represented by 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 3- to 7-membered monocyclic carbocyclyl, and 4- to 6-membered monocyclic heterocyclyl each optionally contain one or more (e.g., 1, 2, 3, 4, 5, or 6, etc.) R 70 is replaced by R 70 represents, for each occurrence independently, a halogen, -OR 70a , 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 70 C, represented by 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 3- to 7-membered monocyclic carbocyclyl, and 4- to 6-membered monocyclic heterocyclyl optionally contain one or more (e.g., 1, 2, 3, 4, 5, or 6) R 75 is replaced by R 70a is H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6alkynyl, 3- to 7-membered monocyclic carbocyclyl, and 4- to 6-membered monocyclic heterocyclyl; R 70a C, represented by 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 3- to 7-membered monocyclic carbocyclyl, and 4- to 6-membered monocyclic heterocyclyl each optionally contain one or more (e.g., 1, 2, 3, 4, 5, or 6, etc.) R 75 is replaced by R 75 For each occurrence, independently, C 1-6 Alkyl, halogen, and -OR 75a is selected from R 75a is H or C 1-6 is alkyl, R 8 is, for each occurrence independently, H, halogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -CN, -C(O)R 8a , -C(O)2R 8a , -C(O)N(R 8a )2, -N(R 8a )2, -N(R 8a )C(O)R 8a , -N(R 8a )C(O)2R 8a , -N(R 8a )C(O)N(R 8a )2, -N(R 8a )S(O)2R 8a , -OR 8a , -OC(O)R 8a , -OC(O)N(R 8a )2, -SR 8a , -S(O)R 8a , -S(O)2R 8a , -S(O)N(R 8a )2, -S(O)2N(R 8a 2, 3- to 7-membered monocyclic carbocyclyl, 4- to 6-membered monocyclic heterocyclyl, and 7- to 10-membered bicyclic heterocyclyl; R 8 C, represented by 1-6 Alkyl, C 2-6 Alkenyl, C2-6 Alkynyl, 3- to 7-membered monocyclic carbocyclyl, 4- to 6-membered monocyclic heterocyclyl, and 7- to 10-membered bicyclic heterocyclyl each optionally contain one or more (e.g., 1, 2, 3, 4, 5, or 6) R 80 is replaced by R 8a For each occurrence, independently, 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 8a C, represented by 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 3- to 7-membered monocyclic carbocyclyl, and 4- to 6-membered monocyclic heterocyclyl each optionally contain one or more (e.g., 1, 2, 3, 4, 5, or 6, etc.) R 80 or two R 8a together with their intervening atoms, one or more (e.g., 1, 2, 3, 4, 5, or 6) R 80 forming a 4- to 6-membered monocyclic heterocyclyl optionally substituted by R 80 represents, for each occurrence independently, a halogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -CN, -C(O)R 80a , -C(O)2R 80a , -C(O)N(R 80a )2, -N(R 80a )2, -N(R 80a )C(O)R 80a , -N(R 80a )C(O)2R 80a , -N(R 80a )C(O)N(R 80a )2, -N(R 80a )S(O)2R 80a , -OR 80a , -OC(O)R 80a , -OC(O)N(R 80a )2, -SR 80a , -S(O)R 80a, -S(O)2R 80a , -S(O)N(R 80a )2, -S(O)2N(R 80a ) 2, 3- to 7-membered monocyclic carbocyclyl, and 4- to 6-membered monocyclic heterocyclyl; R 80 C, represented by 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 3- to 7-membered monocyclic carbocyclyl, and 4- to 6-membered monocyclic heterocyclyl each optionally contain one or more (e.g., 1, 2, 3, 4, 5, or 6, etc.) R 85 or two R 80 together with the carbon atom to which they are attached form an oxo group (-C=O)-), R 80a For each occurrence, independently, H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 alkynyl, 3- to 6-membered monocyclic carbocyclyl, and 4- to 6-membered monocyclic heterocyclyl; R 80a C, represented by 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 3- to 6-membered monocyclic carbocyclyl, and 4- to 6-membered monocyclic heterocyclyl each optionally contain one or more (e.g., 1, 2, 3, 4, 5, or 6) R 85 is replaced by R 85 For each occurrence, independently, C 1-6 Alkyl, halogen, and -OR 85a and R 85a is H or C 1-6 It is alkyl.

[0006] The present invention also provides pharmaceutical compositions comprising at least one compound described herein, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

[0007] In one embodiment, the invention is a method of treating a disorder responsive to inhibition of Btk in a subject, comprising administering to the subject an effective amount of at least one compound described herein, or a pharmaceutically acceptable salt thereof.

[0008] The invention also includes the use of at least one compound described herein, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of a disorder responsive to the inhibition of Btk. Also provided are compounds described herein, or a pharmaceutically acceptable salt thereof, for use in the treatment of a disorder responsive to the inhibition of Btk.

[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] In a second embodiment, the compound of the present invention is represented by formula (I) or a pharmaceutically acceptable salt thereof, wherein A 1 is N and Q 1 is C and Q 2 is N, and the definitions of the other variables are as defined in the first embodiment.

[0012] In a third embodiment, the compound of the present invention is represented by formula (I) or a pharmaceutically acceptable salt thereof, wherein A 1 is CH and Q 1 is N and Q 2 is C, and the definitions of the other variables are as defined in the first embodiment.

[0013] In a fourth embodiment, the compound of the present invention is represented by formula (I) or a pharmaceutically acceptable salt thereof, wherein A 1 is CH and Q 1 is C and Q 2 is N, and the definitions of the other variables are as defined in the first embodiment.

[0014] In a fifth embodiment, the compound of the present invention has the formula: [ka] or a pharmaceutically acceptable salt thereof, wherein the definitions of the variables are as defined in the first embodiment.

[0015] In a sixth embodiment, the compound of the present invention is represented by formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof, wherein R 1 is a 5-6 membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from O, N, and S; R 1 The 5- to 6-membered monocyclic heteroaryl represented by the formula (I) is a 5- to 6-membered monocyclic heteroaryl represented by the formula (I) 10 and optionally substituted with the definitions of the other variables as defined in the first, second, third, fourth, or fifth embodiment.

[0016] In a seventh embodiment, the compound of the present invention is represented by formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof, wherein R 1 is a 5-membered heteroaryl selected from pyrazolyl, oxazolyl, isoxazolyl, 1,2,3-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,4-oxadizolyl, 1,2,3-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, and tetrazolyl, each of which optionally contains one or two R 10 and the definitions of the other variables are as defined in the first, second, third, fourth, fifth, or sixth embodiment.

[0017] In an eighth embodiment, the compound of the invention is represented by formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof, wherein R 1 is expressed by the following formula: [ka] and the definitions of the other variables are as defined in the first, second, third, fourth, fifth, or seventh embodiment.

[0018] In a ninth embodiment, the compound of the invention is represented by formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof, wherein R 10 represents, for each occurrence independently, a halogen, -OR 10a , -S(O)2R 10a , -CN, C 1-6 Alkyl, C 3-6 cycloalkyl, and phenyl; R 10 C, represented by 1-6 Alkyl, C 3-6 Cycloalkyl and phenyl each optionally have 1 to 3 R 15 is replaced by R 10a is, for each occurrence independently, H and C 1-3 alkyl, R 15 For each occurrence, independently, C 1-6 Alkyl, halogen, -CN, and -OR 15a is selected from R 15a is H or C 1-3 alkyl, and the definitions of the other variables are as defined in the first, second, third, fourth, fifth, sixth, seventh, or eighth embodiment.

[0019] In a tenth embodiment, the compound of the invention is represented by formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof, wherein R 10is, for each occurrence, independently selected from -F, -CN, -CHOH, -CF, -CH, -C(CH), -CH(CH), -C(CH-)CHF, -C(CH)CHF, -C(CH)CN, -CHCH(CH), 1-methylcyclopropyl, 2,2-difluorocyclopropyl, phenyl, and -S(O)CH, and the definitions of the other variables are as defined in the first, second, third, fourth, fifth, sixth, seventh, or eighth embodiment.

[0020] In an eleventh embodiment, the compound of the invention is represented by formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof, wherein R 10 For each occurrence, independently, C 1-6 Alkyl and C 3-6 cycloalkyl, C 1-6 Alkyl and C 3-6 Each cycloalkyl optionally has 1 to 3 R 15 is replaced by R 15 is, for each occurrence, independently a halogen or C 1-3 alkyl, and the definitions of the other variables are as defined in the first, second, third, fourth, fifth, sixth, seventh, or eighth embodiment.

[0021] In a twelfth embodiment, the compound of the invention is represented by formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof, wherein R 2 is H or methyl, and the definitions of the other variables are as defined in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, or eleventh embodiment.

[0022] In a thirteenth embodiment, the compound of the invention is represented by formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof, wherein R 3 is H, and the definitions of the other variables are as defined in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, or twelfth embodiment.

[0023] In a fourteenth embodiment, the compound of the invention is represented by formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof, wherein R 4 is halogen, -CN, -OR 4a , C 1-6 Alkyl, and C 3-6 cycloalkyl, R 4 C, represented by 1-6 Alkyl and C 3-6 Each cycloalkyl is optionally substituted with 1 to 3 halogens, and R 4a is C optionally substituted with 1 to 3 halogens 1-4 alkyl, and the definitions of the other variables are as defined in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, or thirteenth embodiment.

[0024] In a fifteenth embodiment, the compound of the invention is represented by formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof, wherein R 4 is selected from -F, -Cl, -OCH3, -CH3, -CF3, -CHF2, -CH2CHF2, and cyclopropyl, and the definitions of the other variables are as defined in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, or thirteenth embodiment.

[0025] In a sixteenth embodiment, the compound of the invention is represented by formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof, wherein R 3 and R 4 are taken together with their intervening atoms to form Ring B which is a 7-membered monocyclic carbocyclyl or a 7-membered monocyclic heterocyclyl having one heteroatom selected from O and N, and the definitions of the other variables are as defined in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, or twelfth embodiment.

[0026] In a seventeenth embodiment, the compound of the present invention has the formula: [ka] or a pharmaceutically acceptable salt thereof, wherein R 301 is H or R 300 and R 300 is C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 4-6 membered monocyclic heterocyclyl, -C(O)R 300a , -OR 300a , and -S(O)R 300a Selected from R 300 C, represented by 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl and 4- to 6-membered monocyclic heterocyclyl each optionally have 1 to 3 R 350 is replaced by R 300a is H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 cycloalkyl, and 4- to 6-membered monocyclic heterocyclyl; 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl and 4- to 6-membered monocyclic heterocyclyl each optionally contain 1 to 3 R 350 is replaced by R 350 For each occurrence, independently, C 1-6 Alkyl, halogen, -CN, -N(R 350a )2, -C(O)R 350a , -C(O)N(R 350a )2, -C(R 350a )2N(R 350a )2, and -OR 350a Selected from C 1-6 The alkyl is optionally substituted with 1 to 3 halogens; R 350a represents, for each occurrence, independently, H or C optionally substituted with 1 to 3 halogens. 1-6 alkyl or two R 350a together with the N atom to which they are attached form a 4-6 membered monocyclic heterocyclyl having 1-2 heteroatoms selected from N and O, and the definitions of the variables are as defined in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, or fifteenth embodiment. This is true.

[0027] In one specific embodiment, R 300 is expressed by one of the following formulas: [ka]

[0028] In an eighteenth embodiment, the compound of the invention is represented by formula (I), (II), (III), (IIA), (IIB), (IIIA), or (IIIB), or a pharmaceutically acceptable salt thereof, wherein R 5 is H or halogen, and the definitions of the variables are as defined in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, or seventeenth embodiment.

[0029] In a nineteenth embodiment, the compound of the invention is represented by formula (I), (II), (III), (IIA), (IIB), (IIIA), or (IIIB), or a pharmaceutically acceptable salt thereof, wherein R 5 is H or F, and the definitions of the variables are as defined in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, or seventeenth embodiment.

[0030] In a twentieth embodiment, the compound of the invention is represented by formula (I), (II), (III), (IIA), (IIB), (IIIA), or (IIIB), or a pharmaceutically acceptable salt thereof, wherein R 6 is H or halogen, and the definitions of the variables are as defined in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, or nineteenth embodiment.

[0031] In a twenty-first embodiment, the compound of the invention is represented by formula (I), (II), (III), (IIA), (IIB), (IIIA), or (IIIB), or a pharmaceutically acceptable salt thereof, wherein R 6 is H or F, and the definitions of the variables are as defined in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, sixteenth, seventeenth, eighteenth, or nineteenth embodiment.

[0032] In a twenty-second embodiment, the compound of the invention is represented by formula (I), (II), (III), (IIA), (IIB), (IIIA), or (IIIB), or a pharmaceutically acceptable salt thereof, wherein R 8 is, for each occurrence independently, H, halogen, C 2-6 Alkynyl, -C(O)R 8a , -C(O)N(R 8a )2, -N(R 8a )2, -OR 8a , -CN, C 1-6 Alkyl, C 2-6 Alkenyl, phenyl, C 3-6 cycloalkyl, 4-6 membered monocyclic heterocyclyl having 1-2 heteroatoms independently selected from O, N, and S, and 4-6 membered monocyclic heterocyclyl having 1-4 heteroatoms independently selected from O, N, and S. R is selected from 7- to 10-membered bicyclic heterocyclyl having 2 atoms; 8 C, represented by 1-6 Alkyl, C 2-6 Alkenyl, C 2-6Alkynyl, phenyl, C 3-6 Cycloalkyl, 4- to 6-membered monocyclic heterocyclyl, and 7- to 10-membered bicyclic heterocyclyl each optionally contain 1 to 3 R 80 is replaced by R 8a For each occurrence, independently, H, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 cycloalkyl, and 4- to 6-membered monocyclic heterocyclyl; R 8a C, represented by 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl and 4- to 6-membered monocyclic heterocyclyl each optionally contain one or three R 80 or two R 8a together with the intervening atoms, R 1 to 3 80 forming a 4- to 6-membered monocyclic heterocyclyl optionally substituted by R 80 is, for each occurrence, independently, a halogen, -CN, -C(O)R 80a , -OR 80a , C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 cycloalkyl, and 4- to 6-membered monocyclic heterocyclyl; R 80 C, represented by 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl and 4- to 6-membered monocyclic heterocyclyl each optionally contain one or three R 85 or two R 80 together with the carbon atom to which they are attached form an oxo group (-C=O)-), R 80a For each occurrence, independently, H, C 1-6 Alkyl, C 2-6 Alkenyl, C2-6 Alkynyl, C 3-6 cycloalkyl and 4-6 membered monocyclic heterocyclyl having 1-2 heteroatoms independently selected from O, N, and S; R 85 represents, for each occurrence independently, a halogen and -OR 85a is selected from R 85a is H or C 1-6 and alkyl, and the definitions of the other variables are as defined in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, seventeenth, eighteenth, nineteenth, twentieth, or twenty-first embodiment.

[0033] In a twenty-third embodiment, the compound of the invention is represented by formula (I), (II), (III), (IIA), (IIB), (IIIA), or (IIIB), or a pharmaceutically acceptable salt thereof, wherein R 8 is, for each occurrence independently, H, halogen, C 1-6 Alkyl, C 2-6 Alkynyl, -C(O)R 8a , -C(O)N(R 8a )2, -N(R 8a )2, -OR 8a , -CN, phenyl, 4- to 6-membered monocyclic heterocyclyl having 1-2 heteroatoms independently selected from O, N, and S, and 7- to 10-membered bicyclic heterocyclyl having 1-4 heteroatoms independently selected from O, N, and S; 8 C, represented by 1-6 Alkyl, C 2-6 Alkynyl, phenyl, 4- to 6-membered monocyclic heterocyclyl, and 7- to 10-membered bicyclic heterocyclyl each optionally contain 1 to 3 R 80 is replaced by R 8a For each occurrence, independently, C 1-6 alkyl and 4- to 6-membered monocyclic heterocyclyl; R 8a C, represented by 1-6The alkyl and 4- to 6-membered monocyclic heterocyclyl each optionally have 1 to 3 R 80 is replaced by R 80 is, for each occurrence, independently, a halogen, -CN, -C(O)R 80a , -OR 80a , C 1-6 Alkyl, C 3-6 cycloalkyl, and 4- to 6-membered monocyclic heterocyclyl; R 80 C, represented by 1-6 Alkyl, C 3-6 Cycloalkyl and 4- to 6-membered monocyclic heterocyclyl each optionally contain 1 to 3 R 85 or two R 80 together with the carbon atom to which they are attached form an oxo group (-C=O)-), R 80a For each occurrence, independently, H, C 1-6 Alkyl and C 2-6 alkenyl, R 85 represents, for each occurrence independently, a halogen and -OR 85a is selected from R 85a is H or C 1-3 alkyl, and the definitions of the other variables are first, second, As defined in the third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, seventeenth, eighteenth, nineteenth, twentieth, or twenty-first embodiment.

[0034] In a twenty-fourth embodiment, the compound of the invention is represented by formula (I), (II), (III), (IIA), (IIB), (IIIA), or (IIIB), or a pharmaceutically acceptable salt thereof, wherein R 8 is H, -CH3, -CH2OCH3, F, Br, -CN, -OCH3, -OC2H5OCH3, -N(CH3)(CH2CH2OCH3), -C(O)N(CH3)2, [ka] and the definitions of the other variables are as defined in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth, fifteenth, seventeenth, eighteenth, nineteenth, twentieth, twenty-first, or twenty-second embodiment.

[0035] In a twenty-fifth embodiment, the compound of the invention is represented by formula (I), (II), (III), (IIA), (IIB), (IIIA), or (IIIB), or a pharmaceutically acceptable salt thereof; 80 is halogen, -CN, -C(O)R 80a , -OR 80a , C 1-3 Alkyl, C 3-6 cycloalkyl, and 4-6 membered monocyclic heterocyclyl having 1-2 heteroatoms selected from O and N; R 80 C, represented by 1-3 Alkyl, C 3-6 Cycloalkyl and 4- to 6-membered monocyclic heterocyclyl each optionally contain 1 to 3 R 85 or two R 80 together with the carbon atom to which they are attached form an oxo (-C(=O)) group, R 80a For each occurrence, independently, C 1-4 Alkyl and C 2-4 alkenyl, R 85 For each occurrence, F, -OH, or C 1-3 and alkoxy, and the definitions of the other variables are as defined 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, or twenty-fourth embodiment.

[0036] In a twenty-sixth embodiment, the compound of the present invention is represented by formula (I), (II), (III), (IIA), (IIB), (IIIA), or (IIIB), or a pharmaceutically acceptable salt thereof, wherein R80 is, for each occurrence, -F, -CH3, -CHF2, -CH2OH, -CH(CH3)2, -C2H5, -CH2CHF2, -CN, -OCH3, -C(O)(CH2=CH), -C(O)(CH=CCH3), -CH2CH2OCH3, [ka] and the definitions of the other variables are as defined 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, or twenty-fourth embodiment.

[0037] In a 27th embodiment, the compound of the present invention has the formula: [ka] or a pharmaceutically acceptable salt thereof, wherein R 1 is a 5-membered heteroaryl selected from 1,2,3-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,4-oxadizolyl, 1,2,3-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, and tetrazolyl, each of which optionally contains one or two R 10 is replaced by R 10 represents, for each occurrence independently, a halogen, -OR 10a , -S(O)2R 10a , -CN, C 1-6 Alkyl, C 3-6 cycloalkyl, and phenyl; R 10 C, represented by 1-6 Alkyl, C 3-6 cycloalkyl, and phenyl each optionally have 1 to 3 R 15 is replaced by R 10a is, for each occurrence independently, H and C 1-3alkyl, R 15 For each occurrence, independently, C 1-6 Alkyl, halogen, -CN, and -OR 15a is selected from R 15a is H or C 1-3 is alkyl, R 4 is halogen, -CN, -OR 4a , C 1-6 Alkyl, and C 3-6 cycloalkyl, R 4 C, represented by 1-6 Alkyl and C 3-6 each cycloalkyl is optionally substituted with 1 to 3 halogen; R 4a is C optionally substituted with 1 to 3 halogens 1-4 is alkyl, R 5 is H or a halogen, R 6 is H or a halogen, R 8 H, -OR 8a or a 4- to 6-membered monocyclic heterocyclyl having 1 to 2 heteroatoms independently selected from O and N, wherein the 4- to 6-membered monocyclic heterocyclyl optionally has one or two R 80 is replaced by R 8a is R 1 to 3 80 C optionally substituted with 1-6 is alkyl, R 80 represents, for each occurrence independently, a halogen, -OR 80a , and R 1 to 3 85 C optionally substituted with 1-3 alkyl, R 80a For each occurrence, independently, H, C 1-6 Alkyl and C 2-6 alkenyl, R 85 represents, for each occurrence independently, a halogen and -OR85a is selected from R 85a is H or C 1-3 alkyl, and the definitions of the other variables are as defined in the first embodiment.

[0038] In a twenty-eighth embodiment, the compound of the present invention is represented by formula (I), (II), (III), (IIA), (IIB), (IIIA), (IIIB), (IV), (V), (VI), (VII), or a pharmaceutically acceptable salt thereof, wherein R 1 teeth, [ka] and R 10 is a halogen or C 1-3 C optionally substituted with alkyl 1-4 Alkyl or C 3-6 cycloalkyl, and the definitions of the other variables are as defined in the first or twenty-seventh embodiment.

[0039] In a twenty-ninth embodiment, the compound of the invention is represented by formula (I), (II), (III), (IIA), (IIB), (IIIA), (IIIB), (IV), (V), (VI), or (VII), or a pharmaceutically acceptable salt thereof, wherein R 10 is —C(CH 3 ) 3 or 1-methylcyclopropyl, and the definitions of the other variables are as defined in the first, twenty-seventh, or twenty-eighth embodiment.

[0040] In a thirtieth embodiment, the compound of the invention is represented by formula (I), (II), (III), (IIA), (IIB), (IIIA), (IIIB), (IV), (V), (VI), or (VII), or a pharmaceutically acceptable salt thereof, wherein R 4 is F, Cl, -CH3, -CHF2, -CF3, -OCH3, or cyclopropyl; R 5 is H or F, R 6is H or F, and the definitions of the other variables are as defined in the first, twenty-seventh, twenty-eighth, or twenty-ninth embodiment.

[0041] In a thirty-first embodiment, the compound of the present invention is represented by formula (I), (II), (III), (IIA), (IIB), (IIIA), (IIIB), (IV), (V), (VI), or (VII), or a pharmaceutically acceptable salt thereof, wherein R 8 H, -OR 8a , [ka] and the definitions of the other variables are as defined in the first, twenty-seventh, twenty-eighth, twenty-ninth, thirtieth, or thirty-first embodiment.

[0042] In a thirty-second embodiment, the compound of the invention is represented by formula (I), (II), (III), (IIA), (IIB), (IIIA), (IIIB), (IV), (V), (VI), or (VII), or a pharmaceutically acceptable salt thereof, wherein R 8 H, [ka] -OR 8a and the definitions of the other variables are as defined in the first, twenty-seventh, twenty-eighth, twenty-ninth, thirtieth, or thirty-first embodiment.

[0043] In a thirty-third embodiment, the compound of the invention is represented by formula (I), (II), (III), (IIA), (IIB), (IIIA), (IIIB), (IV), (V), (VI), or (VII), or a pharmaceutically acceptable salt thereof, wherein R 80 For each occurrence, F, -CH3, [ka] and -CH2CH2OCH3, -OCH3, and -CH2CHF2, and the definitions of the other variables are as defined in the first, twenty-seventh, twenty-eighth, twenty-ninth, thirtieth, thirty-first, or thirty-second embodiment.

[0044] In a thirty-fourth embodiment of the present invention, the compound of the present invention is selected from: 5-tert-butyl-N-[[2-chloro-5-fluoro-4-(6-morpholinopyrrolo[2,1-f][1,2,4]triazin-4-yl)phenyl]methyl]-1,2,4-oxadiazole-3-carboxamide, 3-(tert-butyl)-N-(3-fluoro-2-methyl-4-(6-morpholinopyrrolo[2,1-f][1,2,4]triazin-4-yl)benzyl)-1,2,4-oxadiazole-5-carboxamide, 5-(1,1-difluoro-2-methylpropan-2-yl)-N-(2-methyl-4-(6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)benzyl)-1,3,4-oxadiazole-2-carboxamide, 5-(tert-butyl)-N-(2-methyl-4-(6-(4-methylpiperazin-1-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)benzyl)-1,2,4-oxadiazole-3-carboxamide, 5-(tert-butyl)-N-(2-methyl-4-(6-morpholinopyrrolo[2,1-f][1,2,4]triazin-4-yl)benzyl)-1,2,4-oxadiazole-3-carboxamide, 3-(tert-butyl)-N-(4-(6-(3,6-dihydro-2H-pyran-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-methylbenzyl)-1,2,4-oxadiazole-5-carboxamide, 5-(tert-butyl)-N-(4-(6-(1-(2-methoxyethyl)-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-methylbenzyl)-1,2,4-oxadiazole-3-carboxamide, 5-(tert-butyl)-N-(4-(6-(3-methoxyazetidin-1-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-methylbenzyl)-1,2,4-oxadiazole-3-carboxamide, 5-(tert-butyl)-N-(2-methyl-4-(6-(1-methyl-1H-pyrazol-3-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)benzyl)-1,2,4-oxadiazole-3-carboxamide, 5-(tert-butyl)-N-(4-(6-(1-(2,2-difluoroethyl)-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-methylbenzyl)-1,2,4-oxadiazole-3-carboxamide, 5-(tert-butyl)-N-(4-(6-(3-fluoropyrrolidin-1-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-methylbenzyl)-1,2,4-oxadiazole-3-carboxamide, 5-(tert-butyl)-N-(4-(6-(3,3-difluoropyrrolidine-1- yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-methylbenzyl)-1,2,4-oxadiazole-3-carboxamide, 3-(tert-butyl)-N-(4-(6-(3-methoxypyrrolidin-1-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-methylbenzyl)-1,2,4-oxadiazole-5-carboxamide, 5-(tert-butyl)-N-(2-chloro-4-(6-morpholinopyrrolo[2,1-f][1,2,4]triazin-4-yl)benzyl)-1,2,4-oxadiazole-3-carboxamide, 5-(tert-butyl)-N-(2-methyl-4-(2-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidin-7-yl)benzyl)-1,2,4-oxadiazole-3-carboxamide, 5-(tert-butyl)-N-(2-methyl-4-(pyrrolo[1,2-b]pyridazin-4-yl)benzyl)-1,2,4-oxadiazole-3-carboxamide, 3-(tert-butyl)-N-(2-methyl-4-(pyrrolo[1,2-b]pyridazin-4-yl)benzyl)-1,2,4-oxadiazole-5-carboxamide, 5-(tert-butyl)-N-(4-(5-fluoropyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-methylbenzyl)-1,2,4-oxadiazole-3-carboxamide, 2-(1,1-difluoroethyl)-N-(2-methyl-4-(pyrrolo[2,1-f][1,2,4]triazin-4-yl)benzyl)oxazole-4-carboxamide, 5-(tert-butyl)-N-(4-(imidazo[1,2-b]pyridazin-8-yl)-2-methylbenzyl)-1,2,4-oxadiazole-3-carboxamide, 5-(tert-butyl)-N-(2-methyl-4-(2-morpholinopyrazolo[1,5-a]pyrimidin-7-yl)benzyl)-1,2,4-oxadiazole-3-carboxamide, (R)-3-(tert-butyl)-N-(4-(6-(3,4-dimethylpiperazin-1-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-3-fluoro-2-methylbenzyl)-1,2,4-oxadiazole-5-carboxamide, (S)-3-(tert-butyl)-N-(4-(6-(3,4-dimethylpiperazin-1-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-3-fluoro-2-methylbenzyl)-1,2,4-oxadiazole-5-carboxamide, (R)-3-(tert-butyl)-N-(4-(6-(3,4-dimethylpiperazin-1-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-methylbenzyl)-1,2,4-oxadiazole-5-carboxamide, (S)-3-(tert-butyl)-N-(4-(6-(3,4-dimethylpiperazin-1-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-methylbenzyl)-1,2,4-oxadiazole-5-carboxamide, (S)-5-(tert-butyl)-N-(2-methyl-4-(6-(2-methylmorpholino)pyrrolo[2,1-f][1,2,4]triazin-4-yl)benzyl)-1,2,4-oxadiazole-3-carboxamide, (R)-5-(tert-butyl)-N-(2-methyl-4-(6-(2-methylmorpholino)pyrrolo[2,1-f][1,2,4]triazin-4-yl)benzyl)-1,2,4-oxadiazole-3-carboxamide, (R)-5-(tert-butyl)-N-(1-(3-fluoro-2-methyl-4-(6-morpholinopyrrolo[2,1-f][1,2,4]triazin-4-yl)phenyl)ethyl)-1,2,4-oxadiazole-3-carboxamide, 5-(tert-butyl)-N-(2-methyl-4-(6-(4-(oxetan-3-yl)piperazin-1-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)benzyl)-1,2,4-oxadiazole-3-carboxamide, N-(3-fluoro-2-methyl-4-(6-(1-methyl-1H-pyrazole-4- yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)benzyl)-5-(1-fluoro-2-methylpropan-2-yl)-1,2,4-oxadiazole-3-carboxamide, 5-(tert-butyl)-N-(4-(6-morpholinopyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-(trifluoromethyl)benzyl)-1,2,4-oxadiazole-3-carboxamide, 5-(tert-butyl)-N-(2-methoxy-4-(6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)benzyl)-1,2,4-oxadiazole-3-carboxamide, 5-(tert-butyl)-N-(2-(difluoromethyl)-3-fluoro-4-(6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)benzyl)-1,2,4-oxadiazole-3-carboxamide hydrochloride, 5-(tert-butyl)-N-(2-cyclopropyl-4-(6-morpholinopyrrolo[2,1-f][1,2,4]triazin-4-yl)benzyl)-1,2,4-oxadiazole-3-carboxamide, 5-(tert-butyl)-N-(2-methyl-4-(6-(pyridin-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)benzyl)-1,2,4-oxadiazole-3-carboxamide, 5-(tert-butyl)-N-(4-(6-((2,6-syn)-2,6-dimethylmorpholino)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-methylbenzyl)-1,2,4-oxadiazole-3-carboxamide, N-(2-methyl-4-(6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)benzyl)-5-(1-methylcyclopropyl)-1,2,4-oxadiazole-3-carboxamide, 5-(1-fluoro-2-methylpropan-2-yl)-N-(2-methyl-4-(6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)benzyl)-1,2,4-oxadiazole-3-carboxamide, N-(3-fluoro-2-methyl-4-(6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)benzyl)-5-(1-methylcyclopropyl)-1,2,4-oxadiazole-3-carboxamide hydrochloride, 5-(1-fluoro-2-methylpropan-2-yl)-N-(2-methyl-4-(6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)benzyl)-1,2,4-oxadiazole-3-carboxamide, N-(3-fluoro-2-methyl-4-(6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)benzyl)-5-(1-methylcyclopropyl)-1,2,4-oxadiazole-3-carboxamide hydrochloride, 5-(tert-butyl)-N-(4-(6-((2R,6R)-2,6-dimethylmorpholino)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-methylbenzyl)-1,2,4-oxadiazole-3-carboxamide, 5-(tert-butyl)-N-(4-(6-((2S,6S)-2,6-dimethylmorpholino)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-methylbenzyl)-1,2,4-oxadiazole-3-carboxamide, 3-(tert-butyl)-N-(3-fluoro-2-methoxy-4-(6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)benzyl)-1,2,4-oxadiazole-5-carboxamide, 5-(tert-butyl)-N-(2-methyl-4-(2-methylpyrazolo[1,5-a]pyrimidin-7-yl)benzyl)-1,2,4-oxadiazole-3-carboxamide, N-(4-([1,2,4]triazolo[4,3-b]pyridazin-8-yl)-2-methylbenzyl)-5-(tert-butyl)-1,2,4-oxadiazole-3-carboxamide, 5-(tert-butyl)-N-(2-methyl-4-(5-methylimidazo[5,1-f][1,2,4]triazin-4-yl)benzyl)-1,2,4-oxadiazole-3-carboxamide, 5-(tert-butyl)-N-(2-methyl-4-(5-methylpyrrolo[2,1-f][1,2,4]triazin-4-yl)benzyl)-1,2,4-oxadiazole-3-carboxamide, 5-(tert-butyl)-N-(2-methyl-4-(pyrazolo[1,5-a]pyrimidin-7-yl)benzyl)-1,2,4-oxadiazole-3-carboxamide, N-(4-(6-bromopyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-methylbenzyl)-5-(tert-butyl)-1,2,4-oxadiazole-3-carboxamide, 5-tert-butyl-N-[(4-imidazo[2,1-f][1,2,4]triazin-4-yl-2-methyl-phenyl)methyl]-1,2,4-oxadiazole-3-carboxamide, 5-tert-butyl-N-[[4-(3-cyanopyrrolo[1,2-b]pyridazin-4-yl)-2-methyl-phenyl]methyl]-1,2,4-oxadiazole-3-carboxamide, 5-tert-butyl-N-[(4-imidazo[5,1-f][1,2,4]triazin-4-yl-2-methyl-phenyl)methyl]-1,2,4-oxadiazole-3-carboxamide, 5-(tert-butyl)-N-(2-methyl-4-(6-methylpyrrolo[2,1-f][1,2,4]triazin-4-yl)benzyl)-1,2,4-oxadiazole-3-carboxamide, (R)-5-(tert-butyl)-N-(1-fluoro-2-(pyrrolo[2,1-f][1,2,4]triazin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)-1,2,4-oxadiazole-3-carboxamide, (R)-3-(tert-butyl)-N-(1-(2-methyl-4-(6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)phenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide, 5-(tert-butyl)-N-(4-(6-(2-methoxyethoxy)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-methylbenzyl)-1,2,4-oxadiazole-3-carboxamide, N-(4-(6-(1-acryloyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-methylbenzyl)-5-(tert-butyl)-1,2,4-oxadiazole-3-carboxamide, 5-(tert-butyl)-N-(2-methyl-4-(6-(1-methylazetidin-3-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)benzyl)-1,2,4-oxadiazole-3-carboxamide, 1-(tert-butyl)-N-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-(trifluoromethyl)benzyl)-1H-pyrazole-4-carboxamide, 5-(tert-butyl)-N-(2-cyclopropyl-3-fluoro-4-(pyrrolo[2,1-f][1,2,4]triazin-4-yl)benzyl)-1,2,4-oxadiazole-3-carboxamide, 5-(tert-butyl)-N-(3,5-difluoro-2-methyl-4-(pyrrolo[2,1-f][1,2,4]triazin-4-yl)benzyl)-1,2,4-oxadiazole-3-carboxamide, 1-(tert-butyl)-N-(2-(difluoromethyl)-4-(6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)benzyl)-1H-1,2,3-triazole-4-carboxamide, 3-(tert-butyl)-N-(2-(2,2-difluoroethyl)-4-(6-morpholinopyrrolo[2,1-f][1,2,4]triazin-4-yl)benzyl)-1,2,4-oxadiazole-5-carboxamide, 3-(tert-butyl)-N-(2-(2,2-difluoroethyl)-3-fluoro-4-(6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)benzyl)-1,2,4-oxadiazole-5-carboxamide hydrochloride, 5-(tert-butyl)-N-(4-(6-(dimethylcarbamoyl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-methylbenzyl)-1,2,4-oxadiazole-3-carboxamide, 5-(tert-butyl)-N-(2-methyl-4-(6-(pyrimidin-2-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)benzyl)-1,2,4-oxadiazole-3-carboxamide, 3-(tert-butyl)-N-(2-methyl-4-(6-(4-methylpiperazin-1-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)benzyl)-1,2,4-oxadiazole-5-carboxamide, (R)-5-(tert-butyl)-N-(4-(6-(2,4-dimethylpiperazin-1-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-methylbenzyl)-1,2,4-oxadiazole-3-carboxamide, 5-(tert-butyl)-N-(2-methyl-4-(6-(oxetan-3-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)benzyl)-1,2,4-oxadiazole-3-carboxamide, 3-(tert-butyl)-N-(2-methyl-4-(6-(tetrahydro-2H-pyran-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)benzyl)-1,2,4-oxadiazole-5-carboxamide, N-(4-(6-(3,3-bis(hydroxymethyl)azetidin-1-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-methylbenzyl)-5-(tert-butyl)-1,2,4-oxadiazole-3-carboxamide, 5-(tert-butyl)-N-(4-(6-cyclopropylpyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-methylbenzyl)-1,2,4-oxadiazole-3-carboxamide, (S)-5-(tert-butyl)-N-(2-methyl-4-(6-(2-methyl-4-(oxetan-3-yl)piperazin-1-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)benzyl)-1,2,4-oxadiazole-3-carboxamide, 5-(tert-butyl)-N-(4-(6-ethynylpyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-methylbenzyl)-1,2,4-oxadiazole-3-carboxamide, 5-(tert-butyl)-N-(4-(6-(methoxymethyl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-methylbenzyl)-1,2,4-oxadiazole-3-carboxamide, 5-(tert-butyl)-N-(4-(6-(2,2-dimethylmorpholino)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-methylbenzyl)-1,2,4-oxadiazole-3-carboxamide, 5-(tert-butyl)-N-(2-methyl-4-(6-((tetrahydro-2H-pyran-4-yl)oxy)pyrrolo[2,1-f][1,2,4]triazin-4-yl)benzyl)-1,2,4-oxadiazole-3-carboxamide, 5-(tert-butyl)-N-(2-methyl-4-(6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)benzyl)-1,2,4-oxadiazole-3-carboxamide, 5-tert-butyl-N-[[3-fluoro-2-methyl-4-(6-morpholinopyrrolo[2,1-f][1,2,4]triazin-4-yl)phenyl]methyl]-1,3,4-oxadiazole-2-carboxamide, 5-tert-butyl-N-[[3-fluoro-2-methyl-4-[2-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrimidin-7-yl]phenyl]methyl]-1,2,4-oxadiazole-3-carboxamide, 3-tert-butyl-N-[[3-fluoro-2-methyl-4-[2-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrimidin-7-yl]phenyl]methyl]-1,2,4-oxadiazole-5-carboxamide, 5-(tert-butyl)-N-(3-fluoro-2-methyl-4-(2-morpholinopyrazolo[1,5-a]pyrimidin-7-yl)benzyl)-1,2,4-oxadiazole-3-carboxamide, 5-tert-butyl-N-[[2-methyl-4-[6-(1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl]phenyl]methyl]-1,2,4-oxadiazole-3-carboxamide, 5-(tert-butyl)-N-(3-fluoro-2-methyl-4-(6-morpholinopyrrolo[2,1-f][1,2,4]triazin-4-yl)benzyl)-1,2,4-oxadiazole-3-carboxamide, 1-(tert-butyl)-N-(3-fluoro-2-methyl-4-(6-morpholinopyrrolo[2,1-f][1,2,4]triazin-4-yl)benzyl)-1H-1,2,3-triazole-4-carboxamide, 1-(tert-butyl)-N-(3-fluoro-2-methyl-4-(6-morpholinopyrrolo[2,1-f][1,2,4]triazin-4-yl)benzyl)-1H-pyrazole-4-carboxamide, 1-(tert-butyl)-N-(3-fluoro-2-methyl-4-(6-morpholinopyrrolo[2,1-f][1,2,4]triazin-4-yl)benzyl)-1H-pyrazole-3-carboxamide, 2-(tert-butyl)-N-(2-methyl-4-(6-(2-methylmorpholino)pyrrolo[2,1-f][1,2,4]triazin-4-yl)benzyl)-2H-tetrazole-5-carboxamide, 2-(tert-butyl)-N-(2-methyl-4-(6-(2-methylmorpholino)pyrrolo[2,1-f][1,2,4]triazin-4-yl)benzyl)oxazole-4-carboxamide, (S)-5-(tert-butyl)-N-(4-(6-(2,4-dimethylpiperazin-1-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-methylbenzyl)-1,2,4-oxadiazole-3-carboxamide, 5-(tert-butyl)-N-(2-methyl-4-(6-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)benzyl)-1,2,4-oxadiazole-3-carboxamide, 5-(tert-butyl)-N-(2-methyl-4-(6-((tetrahydro-2H-pyran-4-yl)methyl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)benzyl)-1,2,4-oxadiazole-3-carboxamide, 5-(tert-butyl)-N-(2-methyl-4-(6-(tetrahydrofuran-3 -yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)benzyl)-1,2,4-oxadiazole-3-carboxamide, 5-(tert-butyl)-N-(4-(6-(3,4-dimethylpiperazin-1-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-methylbenzyl)-1,2,4-oxadiazole-3-carboxamide, 3-(tert-butyl)-N-(4-(6-(4-methoxypiperidin-1-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-methylbenzyl)-1,2,4-oxadiazole-5-carboxamide, 2-(tert-butyl)-N-(4-(6-(3,4-dimethylpiperazin-1-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-methylbenzyl)-2H-tetrazole-5-carboxamide, 3-(tert-butyl)-N-(4-(6-(3,4-dimethoxypyrrolidin-1-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-methylbenzyl)-1,2,4-oxadiazole-5-carboxamide, 3-(tert-butyl)-N-(4-(6-(2-isopropylmorpholino)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-methylbenzyl)-1,2,4-oxadiazole-5-carboxamide, 5-(tert-butyl)-N-(4-(6-(3,6-dihydro-2H-thiopyran-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-methylbenzyl)-1,2,4-oxadiazole-3-carboxamide, 5-(tert-butyl)-N-(4-(6-cyanopyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-methylbenzyl)-1,2,4-oxadiazole-3-carboxamide, 3-(tert-butyl)-N-(4-(6-(3,6-dihydro-2H-pyran-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-methylbenzyl)-1,2,4-oxadiazole-5-carboxamide, 5-(tert-butyl)-N-(2-methyl-4-(6-(1-(oxetan-3-yl)-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)benzyl)-1,2,4-oxadiazole-3-carboxamide, 3-(tert-butyl)-N-(2-methyl-4-(6-morpholinopyrrolo[2,1-f][1,2,4]triazin-4-yl)benzyl)-1,2,4-oxadiazole-5-carboxamide, 5-(tert-butyl)-N-(2-methyl-4-(6-(1-methyl-1H-1,2,3-triazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)benzyl)-1,2,4-oxadiazole-3-carboxamide, 5-(tert-butyl)-N-(4-(6-(1-(difluoromethyl)-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-methylbenzyl)-1,2,4-oxadiazole-3-carboxamide, 5-(tert-butyl)-N-(4-(6-(1,3-dimethyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-methylbenzyl)-1,2,4-oxadiazole-3-carboxamide, 5-(tert-butyl)-N-(4-(6-(1,5-dimethyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-methylbenzyl)-1,2,4-oxadiazole-3-carboxamide, 5-(tert-butyl)-N-(2-methyl-4-(6-(oxazol-5-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)benzyl)-1,2,4-oxadiazole-3-carboxamide, 5-(tert-butyl)-N-(2-methyl-4-(6-(1-methyl-1H-imidazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)benzyl)-1,2,4-oxadiazole-3-carboxamide, 5-(tert-butyl)-N-(3-fluoro-2-methyl-4-(6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)benzyl)-1,2,4-oxadiazole-3-carboxamide, 5-(tert-butyl)-N-(3-fluoro-2-methyl-4-(6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)benzyl)-1,2,4-oxadiazole-3-carboxamide, 2-(tert-butyl)-N-(2-methyl-4-(6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)benzyl)-2H-tetrazole-5-carboxamide, 2-(tert-butyl)-N-(2-methyl-4-(6-morpholinopyrrolo[2,1-f][1,2,4]triazin-4-yl)benzyl)-2H-tetrazole-5-carboxamide, 3-(tert-butyl)-N-(4-(6-(3,4-dimethylpiperazin-1-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-3-fluoro-2-methylbenzyl)-1,2,4-oxadiazole-5-carboxamide, (S)-5-(tert-butyl)-N-(4-(6-(3,4-dimethylpiperazin-1-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-methylbenzyl)-1,2,4-oxadiazole-3-carboxamide, (R)-5-(tert-butyl)-N-(4-(6-(3,4-dimethylpiperazin-1-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-methylbenzyl)-1,2,4-oxadiazole-3-carboxamide, 3-(tert-butyl)-N-(3-fluoro-2-methyl-4-(2-morpholinopyrazolo[1,5-a]pyrimidin-7-yl)benzyl)-1,2,4-oxadiazole-5-carboxamide, (S)-5-(tert-butyl)-N-(4-(6-(7,7-difluorohexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-methylbenzyl)-1,2,4-oxadiazole-3-carboxamide, 5-(tert-butyl)-N-(4-(6-(5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-methylbenzyl)-1,2,4-oxadiazole-3-carboxamide trifluoroacetate, -(tert-butyl)-N-(4-(6-(5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-methylbenzyl)-1,2,4-oxadiazole-5-carboxamide trifluoroacetate, 5-(tert-butyl)-N-(4-(6-((3R,4S)-3,4-difluoropyrrolidin-1-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-methylbenzyl)-1,2,4-oxadiazole-3-carboxamide, (S)-3-(tert-butyl)-N-(4-(6-(7,7-difluorohexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-methylbenzyl)-1,2,4-oxadiazole-5-carboxamide, 2-(tert-butyl)-N-(4-(6-(3,6-dihydro-2H-pyran-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-methylbenzyl)oxazole-4-carboxamide, 2-(tert-butyl)-N-(4-(6-(3,6-dihydro-2H-pyran-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-methylbenzyl)oxazole-5-carboxamide, 1-(tert-butyl)-N-(4-(6-(3,6-dihydro-2H-pyran-4 -yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-methylbenzyl)-1H-pyrazole-4-carboxamide, 1-(tert-butyl)-N-(4-(6-(3,6-dihydro-2H-pyran-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-methylbenzyl)-1H-pyrazole-3-carboxamide, 2-(tert-butyl)-N-(4-(6-(3,6-dihydro-2H-pyran-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-methylbenzyl)-2H-tetrazole-5-carboxamide, 1-(tert-butyl)-N-(4-(6-(1,5-dimethyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-methylbenzyl)-1H-pyrazole-4-carboxamide, 2-(tert-butyl)-N-(4-(6-(1,5-dimethyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-methylbenzyl)-2H-tetrazole-5-carboxamide, 2-(tert-butyl)-N-(4-(6-(1,5-dimethyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-methylbenzyl)oxazole-4-carboxamide, 5-(tert-butyl)-N-(2-chloro-5-fluoro-4-(pyrrolo[2,1-f][1,2,4]triazin-4-yl)benzyl)-1,2,4-oxadiazole-3-carboxamide, 3-(tert-butyl)-N-(2-chloro-5-fluoro-4-(pyrrolo[2,1-f][1,2,4]triazin-4-yl)benzyl)-1,2,4-oxadiazole-5-carboxamide, 2-(tert-butyl)-N-(2-chloro-5-fluoro-4-(pyrrolo[2,1-f][1,2,4]triazin-4-yl)benzyl)oxazole-4-carboxamide, 5-(tert-butyl)-N-(2-chloro-5-fluoro-4-(pyrrolo[2,1-f][1,2,4]triazin-4-yl)benzyl)isoxazole-3-carboxamide, 2-(tert-butyl)-N-(2-chloro-5-fluoro-4-(pyrrolo[2,1-f][1,2,4]triazin-4-yl)benzyl)-2H-tetrazole-5-carboxamide, (R)-3-(tert-butyl)-N-(2-methyl-4-(6-(2-methylmorpholino)pyrrolo[2,1-f][1,2,4]triazin-4-yl)benzyl)-1,2,4-oxadiazole-5-carboxamide, (S)-3-(tert-butyl)-N-(2-methyl-4-(6-(2-methylmorpholino)pyrrolo[2,1-f][1,2,4]triazin-4-yl)benzyl)-1,2,4-oxadiazole-5-carboxamide, (R)-2-(tert-butyl)-N-(2-methyl-4-(6-(2-methylmorpholino)pyrrolo[2,1-f][1,2,4]triazin-4-yl)benzyl)-2H-tetrazole-5-carboxamide, (S)-2-(tert-butyl)-N-(2-methyl-4-(6-(2-methylmorpholino)pyrrolo[2,1-f][1,2,4]triazin-4-yl)benzyl)-2H-tetrazole-5-carboxamide, (S)-5-(tert-butyl)-N-(4-(6-(3-fluoropyrrolidin-1-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-methylbenzyl)-1,2,4-oxadiazole-3-carboxamide, (R)-5-(tert-butyl)-N-(4-(6-(3-fluoropyrrolidin-1-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-methylbenzyl)-1,2,4-oxadiazole-3-carboxamide, (R)-2-(tert-butyl)-N-(2-methyl-4-(6-(2-methylmorpholino)pyrrolo[2,1-f][1,2,4]triazin-4-yl)benzyl)oxazole-4-carboxamide, (S)-2-(tert-butyl)-N-(2-methyl-4-(6-(2-methylmorpholino)pyrrolo[2,1-f][1,2,4]triazin-4-yl)benzyl)oxazole-4-carboxamide, 1-(tert-butyl)-N-(4-(6-(1-(2,2-difluoroethyl)-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-methylbenzyl)-1H-pyrazole-4-carboxamide, 2-(tert-butyl)-N-(4-(6-(1-(2,2-difluoroethyl)-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-methylbenzyl)-2H-tetrazole-5-carboxamide, N-(4-(6-(1-(but-2-enoyl)-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-methylbenzyl)-5-(tert-butyl)-1,2,4-oxadiazole-3-carboxamide, 5-(tert-butyl)-N-(2-methyl-4-(6-(6-methyl-3,6-diazabicyclo[3.1.1]heptan-3-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)benzyl)-1,2,4-oxadiazole-3-carboxamide trifluoroacetate, 5-(tert-butyl)-N-(2-methyl-4-(6-(1-methylpyrrolidin-3-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)benzyl)-1,2,4-oxadiazole-3-carboxamide, N-(4-(2-aminopyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-methylbenzyl)-5-(tert-butyl)-1,2,4-oxadiazole-3-carboxamide, 5-(tert-butyl)-N-(2-methyl-4-(pyrrolo[2,1-f][1,2,4]triazin-4-yl)benzyl)-1,2,4-oxadiazole-3-carboxamide, 3-(tert-butyl)-N-(2-methyl-4-(pyrrolo[2,1-f][1,2,4]triazin-4-yl)benzyl)-1,2,4-oxadiazole-5-carboxamide, 3-(tert-butyl)-N-(2-cyclopropyl-3-fluoro-4-(pyrrolo[2,1-f][1,2,4]triazin-4-yl)benzyl)-1,2,4-oxadiazole-5-carboxamide, 5-(tert-butyl)-N-(2-chloro-3-fluoro-4-(6-morpholinopyrrolo[2,1-f][1,2,4]triazin-4-yl)benzyl)-1,2,4-oxadiazole-3-carboxamide, 1-(tert-butyl)-N-(2-chloro-3-fluoro-4-(6-morpholinopyrrolo[2,1-f][1,2,4]triazin-4-yl)benzyl)-1H-pyrazole-4-carboxamide, 5-(tert-butyl)-N-(2-chloro-3-fluoro-4-(6-morpholinopyrrolo[2,1-f][1,2,4]triazin-4-yl)benzyl)-1,3,4-oxadiazole-2-carboxamide, 1-(tert-butyl)-N-(2-chloro-3-fluoro-4-(6-morpholinopyrrolo[2,1-f][1,2,4]triazin-4-yl)benzyl)-1H-1,2,3-triazole-4-carboxamide, 1-(tert-butyl)-N-(2-chloro-3-fluoro-4-(6-morpholinopyrrolo[2,1-f][1,2,4]triazin-4-yl)benzyl)-1H-pyrazole-3-carboxamide, 3-(tert-butyl)-N-(2-chloro-4-(6-morpholinopyrrolo[2,1 -f][1,2,4]triazin-4-yl)benzyl)-1,2,4-oxadiazole-5-carboxamide, 1-(tert-butyl)-N-(2-chloro-4-(6-morpholinopyrrolo[2,1-f][1,2,4]triazin-4-yl)benzyl)-1H-pyrazole-4-carboxamide, 5-(tert-butyl)-N-(2-chloro-4-(6-morpholinopyrrolo[2,1-f][1,2,4]triazin-4-yl)benzyl)-1,3,4-oxadiazole-2-carboxamide, 1-(tert-butyl)-N-(2-chloro-4-(6-morpholinopyrrolo[2,1-f][1,2,4]triazin-4-yl)benzyl)-1H-1,2,3-triazole-4-carboxamide, 5-(tert-butyl)-N-(2-cyclopropyl-3-fluoro-4-(6-morpholinopyrrolo[2,1-f][1,2,4]triazin-4-yl)benzyl)-1,3,4-oxadiazole-2-carboxamide, 1-(tert-butyl)-N-(2-cyclopropyl-3-fluoro-4-(6-morpholinopyrrolo[2,1-f][1,2,4]triazin-4-yl)benzyl)-1H-1,2,3-triazole-4-carboxamide, 5-(tert-butyl)-N-(2-methyl-4-(6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)benzyl)-1,3,4-oxadiazole-2-carboxamide, 1-(tert-butyl)-N-(2-methyl-4-(6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)benzyl)-1H-1,2,3-triazole-4-carboxamide, 1-(tert-butyl)-N-(2-methyl-4-(6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)benzyl)-1H-pyrazole-4-carboxamide, 1-(tert-butyl)-N-(2-methyl-4-(6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)benzyl)-1H-pyrazole-3-carboxamide, 5-(tert-butyl)-N-(2-methyl-4-(6-(pyridin-3-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)benzyl)-1,2,4-oxadiazole-3-carboxamide, 5-(tert-butyl)-N-(2-methyl-4-(6-(6-methylpyridazin-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)benzyl)-1,2,4-oxadiazole-3-carboxamide, 3-(tert-butyl)-N-(2-methyl-4-(6-(6-methylpyridazin-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)benzyl)-1,2,4-oxadiazole-5-carboxamide, 5-(tert-butyl)-N-(4-(6-(isothiazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-methylbenzyl)-1,2,4-oxadiazole-3-carboxamide, 3-(tert-butyl)-N-(4-(6-(isothiazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-methylbenzyl)-1,2,4-oxadiazole-5-carboxamide, 5-(tert-butyl)-N-(4-(6-((2-methoxyethyl)(methyl)amino)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-methylbenzyl)-1,2,4-oxadiazole-3-carboxamide, 1-(tert-butyl)-N-(2-methyl-4-(6-morpholinopyrrolo[2,1-f][1,2,4]triazin-4-yl)benzyl)-1H-pyrazole-3-carboxamide, 2-(tert-butyl)-N-(2-methyl-4-(6-morpholinopyrrolo[2,1-f][1,2,4]triazin-4-yl)benzyl)oxazole-4-carboxamide, 5-(tert-butyl)-N-(2-methyl-4-(6-(4-methyl-3-oxopiperazin-1-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)benzyl)-1,2,4-oxadiazole-3-carboxamide, 5-(tert-butyl)-N-(2-chloro-4-(pyrrolo[2,1-f][1,2,4]triazin-4-yl)benzyl)-1,2,4-oxadiazole-3-carboxamide, 5-(tert-butyl)-N-(4-(pyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-(trifluoromethyl)benzyl)-1,2,4-oxadiazole-3-carboxamide, 5-(tert-butyl)-N-(3-fluoro-2-methoxy-4-(pyrrolo[2,1-f][1,2,4]triazin-4-yl)benzyl)-1,2,4-oxadiazole-3-carboxamide, 5-(tert-butyl)-N-(2-(difluoromethyl)-4-(pyrrolo[2,1-f][1,2,4]triazin-4-yl)benzyl)-1,2,4-oxadiazole-3-carboxamide, 1-(tert-butyl)-N-(2-methyl-4-(pyrrolo[2,1-f][1,2,4]triazin-4-yl)benzyl)-1H-pyrazole-3-carboxamide, 1-(tert-butyl)-N-(2-methyl-4-(pyrrolo[2,1-f][1,2,4]triazin-4-yl)benzyl)-1H-pyrazole-4-carboxamide, 1-(tert-butyl)-N-(2-methyl-4-(pyrrolo[2,1-f][1,2,4]triazin-4-yl)benzyl)-1H-1,2,3-triazole-4-carboxamide, 5-(tert-butyl)-N-(2-methyl-4-(pyrrolo[2,1-f][1,2,4]triazin-4-yl)benzyl)-1,3,4-oxadiazole-2-carboxamide, 3-(tert-butyl)-N-(4-(6-morpholinopyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-(trifluoromethyl)benzyl)-1,2,4-oxadiazole-5-carboxamide, 1-(tert-butyl)-N-(4-(6-morpholinopyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-(trifluoromethyl)benzyl)-1H-1,2,3-triazole-4-carboxamide, 1-(tert-butyl)-N-(2-methoxy-4-(6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)benzyl)-1H-1,2,3-triazole-4-carboxamide, 3-(tert-butyl)-N-(2-methoxy-4-(6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)benzyl)-1,2,4-oxadiazole-5-carboxamide, 3-(tert-butyl)-N-(2-(difluoromethyl)-4-(6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)benzyl)-1,2,4-oxadiazole-5-carboxamide, 5-(tert-butyl)-N-(2-(difluoromethyl)-4-(6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)benzyl)-1,3,4-oxadiazole-2-carboxamide, 3-(tert-butyl)-N-(2-(difluoromethyl)-4-(6-morpholinopyrrolo[2,1-f][1,2,4]triazin-4-yl)benzyl)-1,2,4-oxadiazole-5-carboxamide, 5-(tert-butyl)-N-(2-(difluoromethyl)-4-(6-morpholino) pyrrolo[2,1-f][1,2,4]triazin-4-yl)benzyl)-1,3,4-oxadiazole-2-carboxamide, 3-(tert-butyl)-N-(2-(difluoromethyl)-3-fluoro-4-(6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)benzyl)-1,2,4-oxadiazole-5-carboxamide, 1-(tert-butyl)-N-(2-(difluoromethyl)-3-fluoro-4-(6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)benzyl)-1H-1,2,3-triazole-4-carboxamide, 5-(tert-butyl)-N-(2-methoxy-4-(6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)benzyl)-1,3,4-oxadiazole-2-carboxamide, 2-(tert-butyl)-N-(2-(difluoromethyl)-4-(6-morpholinopyrrolo[2,1-f][1,2,4]triazin-4-yl)benzyl)oxazole-4-carboxamide, 5-(tert-butyl)-N-(2-(difluoromethyl)-3-fluoro-4-(6-morpholinopyrrolo[2,1-f][1,2,4]triazin-4-yl)benzyl)-1,3,4-oxadiazole-2-carboxamide, 1-(tert-butyl)-N-(3-fluoro-2-methoxy-4-(6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)benzyl)-1H-1,2,3-triazole-4-carboxamide, 5-(tert-butyl)-N-(3-fluoro-2-methoxy-4-(6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)benzyl)-1,3,4-oxadiazole-2-carboxamide, 1-(tert-butyl)-N-(3-fluoro-2-methoxy-4-(6-morpholinopyrrolo[2,1-f][1,2,4]triazin-4-yl)benzyl)-1H-pyrazole-3-carboxamidoformate, 3-(tert-butyl)-N-(3-fluoro-2-methoxy-4-(6-morpholinopyrrolo[2,1-f][1,2,4]triazin-4-yl)benzyl)-1,2,4-oxadiazole-5-carboxamide formate, (R)-5-(tert-butyl)-N-(1-(2-chloro-4-(6-morpholinopyrrolo[2,1-f][1,2,4]triazin-4-yl)phenyl)ethyl)-1,3,4-oxadiazole-2-carboxamide, 1-(tert-butyl)-N-(2-cyclopropyl-4-(6-morpholinopyrrolo[2,1-f][1,2,4]triazin-4-yl)benzyl)-1H-1,2,3-triazole-4-carboxamidoformate, 3-(tert-butyl)-N-(2-cyclopropyl-4-(6-morpholinopyrrolo[2,1-f][1,2,4]triazin-4-yl)benzyl)-1,2,4-oxadiazole-5-carboxamide, 3-(tert-butyl)-N-(2-(2,2-difluoroethyl)-4-(6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)benzyl)-1,2,4-oxadiazole-5-carboxamide, 1-(tert-butyl)-N-(2-(difluoromethyl)-4-(6-(3,6-dihydro-2H-pyran-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)benzyl)-1H-pyrazole-4-carboxamide, 1-(tert-butyl)-N-(4-(6-(1-(2,2-difluoroethyl)-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-(difluoromethyl)benzyl)-1H-pyrazole-4-carboxamide, 2-(tert-butyl)-N-(4-(6-(1-(2,2-difluoroethyl)- 1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-(difluoromethyl)benzyl)oxazole-4-carboxamide, 2-(tert-butyl)-N-(2-(difluoromethyl)-4-(6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)benzyl)oxazole-4-carboxamide, 1-(tert-butyl)-N-(2-(difluoromethyl)-4-(6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)benzyl)-1H-pyrazole-4-carboxamide, 5-(tert-butyl)-N-(2-(difluoromethyl)-4-(6-(3,6-dihydro-2H-pyran-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)benzyl)-1,3,4-oxadiazole-2-carboxamide, 2-(tert-butyl)-N-(2-methyl-4-(pyrrolo[2,1-f][1,2,4]triazin-4-yl)benzyl)-2H-tetrazole-5-carboxamide, 5-(tert-butyl)-N-(2-methyl-4-(6-(morpholine-4-carbonyl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)benzyl)-1,2,4-oxadiazole-3-carboxamide, 5-(tert-butyl)-N-(2-methyl-4-(6-(4-methylpiperazine-1-carbonyl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)benzyl)-1,2,4-oxadiazole-3-carboxamide, 5-(tert-butyl)-N-(4-(6-(3-methoxyazetidine-1-carbonyl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-methylbenzyl)-1,2,4-oxadiazole-3-carboxamide, 5-(tert-butyl)-N-(3-fluoro-2-methyl-4-(pyrrolo[2,1-f][1,2,4]triazin-4-yl)benzyl)-1,2,4-oxadiazole-3-carboxamide, 5-(tert-butyl)-N-(2-(difluoromethyl)-4-(6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)benzyl)-1,2,4-oxadiazole-3-carboxamide, 5-(tert-butyl)-N-(2-(difluoromethyl)-4-(6-morpholinopyrrolo[2,1-f][1,2,4]triazin-4-yl)benzyl)-1,2,4-oxadiazole-3-carboxamide, 5-(tert-butyl)-N-(2-(difluoromethyl)-3-fluoro-4-(6-morpholinopyrrolo[2,1-f][1,2,4]triazin-4-yl)benzyl)-1,2,4-oxadiazole-3-carboxamide, 4-(tert-butyl)-N-(2-(difluoromethyl)-4-(6-morpholinopyrrolo[2,1-f][1,2,4]triazin-4-yl)benzyl)oxazole-2-carboxamide, 5-(tert-butyl)-N-(3-fluoro-2-methoxy-4-(6-morpholinopyrrolo[2,1-f][1,2,4]triazin-4-yl)benzyl)-1,2,4-oxadiazole-3-carboxamide, 5-(tert-butyl)-N-(4-(6-(4-fluorophenyl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-methylbenzyl)-1,2,4-oxadiazole-3-carboxamide, 5-(tert-butyl)-N-(4-(6-(4-cyanophenyl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-methylbenzyl)-1,2,4-oxadiazole-3-carboxamide, 5-(tert-butyl)-N-(2-methyl-4-(6-(pyrimidin-5-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)benzyl)-1,2,4-oxadiazole-3-carboxamide, 5-(tert-butyl)-N-(2-methyl-4-(6-(2-methylpyridine-4 -yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)benzyl)-1,2,4-oxadiazole-3-carboxamide, 5-(tert-butyl)-N-(4-(6-(2-methoxypyridin-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-methylbenzyl)-1,2,4-oxadiazole-3-carboxamide, 5-(tert-butyl)-N-(2-methyl-4-(6-(3-methylmorpholino)pyrrolo[2,1-f][1,2,4]triazin-4-yl)benzyl)-1,2,4-oxadiazole-3-carboxamide, 5-(tert-butyl)-N-(2-methyl-4-(6-(pyridin-2-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)benzyl)-1,2,4-oxadiazole-3-carboxamide, 5-(tert-butyl)-N-(2-(2,2-difluoroethyl)-4-(6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)benzyl)-1,2,4-oxadiazole-3-carboxamide, 5-(tert-butyl)-N-(2-(2,2-difluoroethyl)-4-(6-morpholinopyrrolo[2,1-f][1,2,4]triazin-4-yl)benzyl)-1,2,4-oxadiazole-3-carboxamide, and 5-(tert-butyl)-N-(2-(2,2-difluoroethyl)-3-fluoro-4-(6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)benzyl)-1,2,4-oxadiazole-3-carboxamide hydrochloride, 5-(tert-butyl)-N-(2-(2,2-difluoroethyl)-3-fluoro-4-(6-morpholinopyrrolo[2,1-f][1,2,4]triazin-4-yl)benzyl)-1,2,4-oxadiazole-3-carboxamide hydrochloride, 5-(tert-butyl)-N-(3-fluoro-2-methoxy-4-(6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)benzyl)-1,2,4-oxadiazole-3-carboxamide hydrochloride, 5-(tert-butyl)-N-(4-(6-(1-ethyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-methylbenzyl)-1,2,4-oxadiazole-3-carboxamide hydrochloride, 5-(tert-butyl)-N-(4-(6-(1-cyclopropyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-methylbenzyl)-1,2,4-oxadiazole-3-carboxamide hydrochloride, or a pharmaceutically acceptable salt thereof, such as the trifluoroacetate or hydrochloride salt.

[0045] As used herein, the term "alkyl" refers to a fully saturated branched or unbranched hydrocarbon moiety. Preferably, alkyl contains 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, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, or n-hexyl.

[0046] "Alkenyl" refers to an unsaturated hydrocarbon group, which may be linear or branched, and which has at least one carbon-carbon double bond. Alkenyl groups having 2 to 6 carbon atoms may be preferred. Alkenyl groups may contain 1, 2, or 3 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.

[0047] "Alkynyl" refers to an unsaturated hydrocarbon group, which may be straight-chained or branched. Alkynyl groups often have at least one carbon-carbon triple bond. Alkynyl groups having 2 to 6 carbon atoms may be preferred. Alkynyl groups may contain 1, 2, or 3 carbon-carbon triple bonds, or more. Examples of alkynyl groups include ethynyl, n-propynyl, n-butyl-2-ynyl, n-hex-3-ynyl, and the like.

[0048] The number of carbon atoms in a group is indicated herein by the prefix "C x-xx " where x and xx are integers. For example, "C 1-4 "Alkyl" is an alkyl group having 1 to 4 carbon atoms.

[0049] "Halogen" or "halo" can be fluoro, chloro, bromo, or iodo.

[0050] As used herein, the term "heterocyclyl" refers to a saturated or unsaturated, monocyclic or bicyclic (e.g., fused, bridged, or spiro) ring system having 3 to 10 ring members, or particularly 3 to 8 ring members, 3 to 7 ring members, 3 to 6 ring members, or 5 to 7 ring members, 4 to 7 ring members, or 4 to 6 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, where C can be oxidized (e.g., C(O)), N can be oxidized (e.g., N(O)) or quaternized, and S can optionally be oxidized to sulfoxide and sulfone. Unsaturated heterocycles include heteroaryl rings.

[0051] In one embodiment, the heterocyclyl is a 3-7 membered monocyclic heterocyclyl (saturated or partially unsaturated (ie, non-aromatic)) having 1-2 heteroatoms selected from O, S, and N. Examples of 3- to 7-membered monocyclic heterocyclyl include, but are not limited to, aziridinyl, oxiranyl, trilanyl, oxaziridinyl, azetidinyl, oxetanyl, thietanyl, 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. In one embodiment, the heterocyclyl is a 5- to 7-membered monocyclic heterocyclyl (saturated or partially unsaturated).

[0052] In one embodiment, the heterocyclyl is a 4-6 membered monocyclic heterocyclyl (saturated or partially unsaturated) having 1-2 heteroatoms selected from O, S, and N. Examples of 4-6 membered monocyclic heterocyclyls include azetidinyl, pyrrolidinyl, tetrahydrofuranyl, thiolanyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, dioxolanyl, dithiolanyl, oxathiolanyl, piperidinyl, tetrahydropyranyl, thianyl, piperazinyl, morpholinyl, thiomorpholinyl, dioxanyl, dithianyl, dihydrofuranyl, imidazolinyl, dihydropyranyl, and piperidinyl. These include, but are not limited to, aryl, furanyl, thiophenyl (or thienyl), imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, furazanyl, oxadiazolyl, thiadiazolyl, dithiazolyl, triazolyl, tetrazolyl, pyridinyl, pyranyl, thiopyranyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazinyl, thiazinyl, dioxinyl, dithiinyl, oxathianyl, triazinyl, and tetrazinyl.

[0053] In another embodiment, heterocyclyl is selected from 1 to 2 heteroatoms selected from O, S, and N. Examples of saturated 4-6 membered monocyclic heterocyclyl ring systems include, but are not limited to, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, thiolanyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, dioxolanyl, dithiolanyl, oxathiolanyl, piperidinyl, tetrahydropyranyl, thianyl, piperazinyl, morpholinyl, thiomorpholinyl, dioxanyl, and dithynyl. In one embodiment, the saturated 4-6 membered monocyclic heterocyclyl is azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, thiolanyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, dioxolanyl, dithiolanyl, oxathiolanyl, piperidinyl, tetrahydropyranyl, thianyl, piperazinyl, morpholinyl, thiomorpholinyl, or dioxinyl. In another embodiment, the saturated 4-6 membered monocyclic heterocyclyl is oxetanyl, tetrahydrofuranyl, or tetrahydropyranyl.

[0054] In one embodiment, the 4-6 membered monocyclic heterocyclyl is [ka] is selected from.

[0055] In one embodiment, the heterocyclyl is a 7-membered monocyclic heterocyclyl (saturated or partially unsaturated), for example, a 7-membered monocyclic heterocyclyl having one heteroatom selected from O and N. Examples of 7-membered monocyclic heterocyclyls include, but are not limited to, azepanyl, azepinyl, oxepanyl, oxepinyl, thiepanyl, thiepinyl, diazepanyl, diazepinyl, and thiazepinyl.

[0056] In another embodiment, the heterocyclyl is a 7-10 membered bicyclic heterocyclyl. In yet another embodiment, the heterocyclyl is a 9-10 membered non-aromatic bicyclic heterocyclyl. In another embodiment, the heterocyclyl is a 9-10 membered fused non-aromatic bicyclic heterocyclyl. The heterocyclyl group can be attached to the remainder of the compound of the invention at a heteroatom or a carbon atom. In one embodiment, the 9-10 membered fused non-aromatic bicyclic heterocyclyl is: [ka] In another embodiment, heterocyclyl is selected from: [ka] and 7-8 membered bridged non-aromatic bicyclic heterocyclyls such as:

[0057] The term "heteroaryl," as used herein, refers to an aromatic 5-6 membered 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, the heteroaryl is a 5-membered heteroaryl. Examples of 5-membered heteroaryl include, but are not limited to, pyrazolyl, oxazolyl, isoxazolyl, 1,2,3-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,3-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, and tetrazolyl. [ka] is selected from.

[0058] As used herein, the term "fused ring system" refers to a ring system having two rings, each independently selected from carbocyclyl or heterocyclyl, and the two ring structures share two adjacent ring atoms. In one embodiment, the fused ring system has 9 to 12 ring members.

[0059] As used herein, the term "bridged ring system" refers to a ring system having a carbocyclyl or heterocyclyl ring in which two non-adjacent atoms of the ring are connected (bridged) by one or more (preferably 1 to 3) atoms selected from C, N, O, and S. In one embodiment, the bridged ring system has 6 to 8 ring members.

[0060] As used herein, the term "spiro ring system" refers to a ring system having two rings, each independently selected from carbocyclyl or heterocyclyl, wherein the two ring structures share one ring atom. In one embodiment, the spiro ring system has 5 to 8 ring members.

[0061] As used herein, the term "carbocyclyl" refers to a saturated or unsaturated monocyclic or bicyclic hydrocarbon group of 3 to 7 carbon atoms, 3 to 5, 3 to 6, 4 to 6, or 5 to 7 carbon atoms. The term "carbocyclyl" encompasses cycloalkyl groups and aromatic groups (i.e., aryl). The term "cycloalkyl" refers to a fully saturated monocyclic or bicyclic or spiro hydrocarbon group of 3 to 7 carbon atoms, 3 to 6 carbon atoms, or 5 to 7 carbon atoms. Exemplary bicyclic carbocyclyl groups include bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.1]heptenyl, tricyclo[2.2.1.0]cyclopent ... 2,6 ]heptanyl, 6,6-dimethylbicyclo[3.1.1]heptyl, or 2,6,6-trimethylbicyclo[3.1.1]heptyl, spiro[2.2]pentanyl, and spiro[3.3]heptanyl.

[0062] 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. In one embodiment, the carbocyclyl is a 5- to 7-membered monocyclic carbocyclyl. In another embodiment, the carbocyclyl is a 4- to 6-membered monocyclic carbocyclyl, such as, but not limited to, cycloheptyl. In another embodiment, the carbocyclyl is a 4- to 6-membered monocyclic carbocyclyl. In another embodiment, the carbocyclyl is a 3- to 6-membered carbocyclyl. In another embodiment, the carbocyclyl is a 3-6 membered cycloalkyl. In yet another embodiment, the carbocyclyl is phenyl. In yet another embodiment, the carbocyclyl is cyclopropyl.

[0063] When the compounds provided by the present invention 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, including hydrochloride, sulfate, nitrate, bicarbonate, and carbonate, may also be formed.

[0064] Pharmaceutically acceptable salts can be obtained using standard procedures well known in the art, for example, by reacting a sufficiently basic compound, such as an amine, with a suitable acid to yield a physiologically acceptable anion. Alkali metal (e.g., sodium, potassium, or lithium) or alkaline earth metal (e.g., calcium) salts of carboxylic acids can also be made.

[0065] Pharmaceutically acceptable base addition salts can be prepared from inorganic and organic bases. Salts from inorganic bases can include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, or magnesium salts. Salts derived from organic bases include, but are not limited to, alkylamines, dialkylamines, trialkylamines, substituted alkylamines, di(substituted alkyl)amines, tri(substituted alkyl)amines, alkenylamines, dialkenylamines, trikenylamines, substituted alkenylamines, di(substituted alkenyl)amines, tri(substituted alkenyl)amines, cycloalkylamines, Included are amines, di(cycloalkyl)amines, tri(cycloalkyl)amines, substituted cycloalkylamines, disubstituted cycloalkylamines, trisubstituted cycloalkylamines, cycloalkenylamines, di(cycloalkenyl)amines, tri(cycloalkenyl)amines, substituted cycloalkenylamines, disubstituted cycloalkenylamines, trisubstituted cycloalkenylamines, arylamines, diarylamines, triarylamines, heteroarylamines, diheteroarylamines, triheteroarylamines, heterocycloalkylamines, diheterocycloalkylamines, triheterocycloalkylamines, or mixtures of diamines and triamines in which 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. Also included are amines in which two or three of the substituents, together with the amino nitrogen, form a heterocycloalkyl or heteroaryl group. Non-limiting examples of amines include isopropylamine, trimethylamine, diethylamine, tri(isopropyl)amine, tri(n-propyl)amine, ethanolamine, 2-dimethylaminoethanol, trimethamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, N-alkylglucamines, theobromine, purine, piperazine, piperidine, morpholine, or N-ethylpiperidine, etc. Other carboxylic acid derivatives may be useful, such as carboxylic acid amides, including carboxamides, lower alkyl carboxamides, or dialkyl carboxamides, etc.

[0066] The compounds described herein or their pharmaceutically acceptable salts may contain one or more asymmetric centers in the molecule. According to the present disclosure, any structure that does not specify stereochemistry should be understood to encompass all of the various stereoisomers (e.g., diastereomers and enantiomers) in pure or substantially pure form, as well as mixtures thereof (such as racemic mixtures or enantiomer-enriched mixtures). How to prepare such optically active forms is well known (e.g., resolution of racemic forms by recrystallization techniques, synthesis from optically active starting materials, chiral synthesis, or chromatographic separation using chiral stationary phases).

[0067] 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" refers to the percent by weight of the desired stereoisomer relative to the combined weight of all stereoisomers.

[0068] When a particular enantiomer of a compound is designated by name or structure, the stereochemical purity of the compound is at least 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 97%, 99%, 99.5%, or 99.9%. "Stereochemical purity" refers to the percent by weight of the desired enantiomer relative to the combined weight of all stereoisomers.

[0069] When the stereochemistry of a disclosed compound is named or depicted by a structure, and the named or depicted structure encompasses more than one stereoisomer (e.g., as a diastereomeric pair), it is understood that one of the encompassed stereoisomers or any mixture of the encompassed stereoisomers is included. It is further 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.

[0070] When a disclosed compound is named or depicted by structure without indicating stereochemistry, and the compound has one chiral center, it is understood that the name or structure encompasses one enantiomer of the compound in pure or substantially pure form, as well as mixtures thereof (e.g., racemic mixtures of the compound and mixtures enriched in one enantiomer as compared to its corresponding optical isomer).

[0071] When a disclosed compound is named or depicted by structure without indicating stereochemistry, for example, if the compound has at least two chiral centers, it is understood that the name or structure encompasses one stereoisomer in pure or substantially pure form, as well as mixtures thereof (e.g., mixtures of stereoisomers and mixtures of stereoisomers in which one or more stereoisomers are enriched relative to the other stereoisomer(s).

[0072] The disclosed compounds may exist in tautomeric forms, and mixtures and separate individual tautomers are contemplated. Additionally, some compounds may exhibit polymorphism.

[0073] In one embodiment, the present invention provides a deuterated compound disclosed herein, wherein any or multiple positions occupied by hydrogen can comprise an enrichment with deuterium above the natural abundance of deuterium. For example, one or more hydrogen atoms are substituted with deuterium at an abundance at least 3340 times greater than the natural abundance of deuterium (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 incorporation), 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). In one embodiment, hydrogen is present at all positions at its natural abundance. The compounds described herein, or pharmaceutically acceptable salts thereof, may exist in tautomeric forms, and mixtures and separate individual tautomers are contemplated.

[0074] 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.

[0075] The compounds described herein, or pharmaceutically acceptable salts thereof, may be used to decrease the activity of Btk or otherwise affect the properties and / or behavior of Btk, such as stability, phosphorylation, kinase activity, interactions with other proteins, etc.

[0076] In some embodiments, the present invention provides methods for reducing Btk enzymatic activity. In some embodiments, such methods comprise contacting Btk with an effective amount of a Btk inhibitor. Accordingly, the present invention further provides methods for inhibiting the enzymatic activity of Btk by contacting Btk with a Btk inhibitor of the present invention.

[0077] One embodiment of the present invention includes a method of treating a disorder responsive to inhibition of Btk in a subject, comprising administering to the subject an effective amount of at least one compound described herein, or a pharmaceutically acceptable salt thereof.

[0078] In one embodiment, the present invention provides a method of treating autoimmune disorders, inflammatory disorders, and cancer in a subject in need thereof, comprising administering to the subject an effective amount of any of the at least one compounds described herein. The present invention provides methods comprising administering at least one compound, or a pharmaceutically acceptable salt thereof, to a patient in need thereof.

[0079] 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, type 1 diabetes, 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 disorder" 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. In some embodiments, the present invention provides methods of treating systemic lupus erythematosus or atopic dermatitis.

[0080] The term "cancer" includes diseases or disorders involving abnormal cell growth and / or proliferation, 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, cholangiocarcinoma, ovarian cancer, endometrial cancer, prostate cancer, renal cell carcinoma, lymphoma (e.g., anaplastic large cell lymphoma), leukemia (e.g., acute myeloid leukemia, T-cell leukemia, chronic lymphocytic leukemia), multiple myeloma, malignant mesothelioma, malignant melanoma, and colon cancer (e.g., microsatellite instability-high colorectal cancer). In some embodiments, the present invention provides methods of treating leukemia or lymphoma.

[0081] As used herein, the terms "subject" and "patient" may be used interchangeably and refer to a mammal in need of treatment, such as companion animals (e.g., dogs, cats, etc.), farm animals (e.g., cows, pigs, horses, sheep, goats, etc.), and laboratory animals (e.g., rats, mice, guinea pigs, etc.). Typically, the subject is a human in need of treatment.

[0082] As used herein, the term "treating" or "treatment" refers to obtaining a desired pharmacological and / or physiological effect. The effect may be therapeutic, which includes achieving one or more of the following results: partially or substantially partially or completely reducing the extent of a disease, disorder, or syndrome; improving or ameliorating clinical symptoms or indicators associated with a disorder; or delaying, inhibiting, or reducing the likelihood of progression of a disease, disorder, or syndrome.

[0083] The effective dose of a compound provided herein, or a pharmaceutically acceptable salt thereof, administered to a subject can be from 10 μg to 500 mg.

[0084] Administering a compound described herein, or a pharmaceutically acceptable salt thereof, to a mammal includes any suitable delivery method. Administering a compound described herein, or a pharmaceutically acceptable salt thereof, to a mammal includes administering a compound described herein, or a pharmaceutically acceptable salt thereof, to a mammal topically, enterally, parenterally, transdermally, transmucosally, via inhalation, intracisternally, epidurally, intravaginally, intravenously, intramuscularly, subcutaneously, intradermally, or intravitreally. Administering a compound described herein, or a pharmaceutically acceptable salt thereof, to a mammal includes administering a compound described herein, or a pharmaceutically acceptable salt thereof, to a mammal topically, enterally, parenterally, transdermally, transmucosally, via inhalation, intracisternally, epidurally, intravaginally, intravenously, intramuscularly. This also includes administering a compound that metabolizes to a compound described herein, or a pharmaceutically acceptable salt thereof, in or on the surface of the mammalian body, subcutaneously, intradermally, or intravitreally.

[0085] 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 food of the patient's diet. For oral therapeutic administration, the compounds disclosed 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.

[0086] Tablets, troches, pills, capsules and the like can contain binders such as gum tragacanth, gum arabic, corn starch or gelatin, excipients such as dicalcium phosphate, disintegrating agents such as corn starch, potato starch, alginic acid and the like, lubricants such as magnesium stearate, or sweeteners such as sucrose, fructose, lactose or aspartame, or flavoring agents.

[0087] The active compound may be administered intravenously or intraperitoneally by infusion or injection. Solutions of the active compound or its salts can be prepared in water, optionally mixed with a nontoxic surfactant.

[0088] Exemplary pharmaceutical dosage forms for injection or infusion can include sterile aqueous solutions or dispersions or sterile powders containing the active ingredient adapted for the extemporaneous preparation of sterile injectable or infusible solutions or dispersions. In all cases, the ultimate dosage form must be sterile, fluid and stable under the conditions of manufacture and storage.

[0089] Sterile injectable solution can be prepared by incorporating the active compound in the required amount in a suitable solvent with various other ingredients listed above, as needed, followed by filter sterilization.For the preparation of sterile powder for sterile injectable solution, the preferred preparation method can be vacuum drying and freeze-drying techniques, which can obtain the powder of active ingredient plus any additional desired ingredients present in the previously sterile-filtered solution.

[0090] 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 water-alcohol / glycol blends, in which a compound described herein or a pharmaceutically acceptable salt thereof can be dissolved or dispersed at effective levels, optionally with the use of a nontoxic surfactant.

[0091] 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 in the art; see, for example, U.S. Patent No. 4,938,949, which is incorporated by reference in its entirety.

[0092] The amount of the compounds described herein or pharmaceutically acceptable salts thereof required for therapeutic use will vary depending not only 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 at the discretion of the attending physician or clinician. However, in general, dosages may range from about 0.1 to about 10 mg / kg body weight per day.

[0093] 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.

[0094] The desired dose may conveniently be presented in a single dose or as divided doses administered at appropriate intervals.

[0095] The disclosed methods can include kits containing a compound described herein or a pharmaceutically acceptable salt thereof and instructional materials that can describe administering the compound described herein or a pharmaceutically acceptable salt thereof, or a composition comprising the 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 skilled in the art, such as kits that include a (e.g., sterile) solvent for dissolving or suspending the 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 can be a human. [Example]

[0096] Abbreviations and acronyms used herein include the following: AcCl means acetyl chloride. AcOH means acetic acid. AgNO3 means silver nitrate. Aq. means aqueous. Ar means argon. BBBPY means 4,4'-di-tert-butyl-2,2'-dipyridyl. BH3.Me2S means borane-dimethyl sulfide complex solution. BH 3. THF means borane-tetrahydrofuran complex solution. BINAP means (±)-2,2′-bis(diphenylphosphino)-1,1′-binaphthalene. Bn means benzyl. Boc means tert-butoxycarbonyl. Boc2O means di-tert-butyl decarbonate. BPO means 2-(4-biphenyl)-5-phenyloxazole. (BPin)2 means bis(pinacolato)diboron. br means broad. nBuOH means n-butanol. tBuOH means tert-butanol. n-BuLi means n-butyllithium. °C means degrees Celsius. CCl4 means carbon tetrachloride. CHCl3 means chloroform. CDCl3 means deuterated chloroform. CDI means 1,1'-carbonyldiimidazole. CO means carbon monoxide. CO2 means carbon dioxide. (COCl)2 means oxalyl chloride. Cs2CO3 means cesium carbonate. CuBr means copper bromide. CuCN means copper cyanide. δ means chemical shift. d means double line. dd means double double line. DCM means dichloromethane. DABAL-Me3 means bis(trimethylaluminum)-1,4-diazabicyclo[2.2.2]octane adduct. DAST means (diethylamino)sulfur trichloride. DIBAL-H means diisobutylaluminum hydride. DIPEA means N-ethyldiisopropylamine or N,N-diisopropylethylamine. DEA means diethylamine. DME means 1,2-dimethoxyethane. DMF means N,N-dimethylformamide. DMSO means dimethyl sulfoxide. DMSO-d6 means hexadeuterodimethylsulfoxide. D2O means heavy water. Et means ethyl. Et2O means ether. EtOH means ethanol. EtOAc means ethyl acetate. Eq. means equivalent. g means grams. HBr means hydrogen bromide. HCHO means formaldehyde. HCl means hydrochloric acid. HCO2H means formic acid. Hept means heptane. 1 1 H NMR means proton nuclear magnetic resonance. H2O means water. HOAt means 1-hydroxy-7-azabenzotriazole. HPLC means high pressure liquid chromatography. h means hours. JosiPhos means (R)-1-[(SP)-2-(dicyclohexylphosphino)ferrocenyl]ethyl-di-tert-butylphosphine. K2CO3 means potassium carbonate. KF means potassium fluoride. KHSO4 means potassium hydrogen sulfate. KI means potassium iodide. KOAc means potassium acetate. KOH means potassium hydroxide. K3PO4 means potassium phosphate tribasic. L stands for liter. LCMS means liquid chromatography mass spectrometry. LiALH4 means lithium aluminum hydride. LiBr means lithium bromide. LiOH means lithium hydroxide. m means multiplet. M means mole. Me means methyl. MeCN means acetonitrile. MeOH means methanol. MeOH-d4 means deuterated methanol. MeTHF means 2-methyltetrahydrofuran. mg means milligrams. MgSO4 means magnesium sulfate. MHz stands for megahertz. min means minutes. mL means milliliters. mmol means millimole. MS m / z refers to mass spectrum peak. MsCl means methanesulfonyl chloride. M / V means mass to volume ratio. N2 means nitrogen. NaBH3CN means sodium cyanoborohydride. NaBH4 means sodium borohydride. NatBuO means sodium tert-butoxide. Na2CO3 means sodium carbonate. NaH means sodium hydride. NaHCO3 means sodium bicarbonate. NaI means sodium iodide. NaOH means sodium hydroxide. Na2SO3 means sodium thiosulfate. Na2SO4 means sodium sulfate. NBS means N-bromosuccinimide. NH3 means ammonia. NH4Cl means ammonium chloride. NH4HCO3 means ammonium bicarbonate. NH4OH is ammonium hydroxide, NiCl2glyme means nickel(II) chloride ethylene glycol dimethyl ether complex. OMs means mesylate salt. P(cy)3 means tricyclohexylphosphine. Pd / C means palladium on carbon. Pd(OAc)2 means palladium acetate. Pd2(dba)3 means tris(dibenzylideneacetone)dipalladium(0). Pd(dppf)Cl2 means [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II). Pd(dppf)Cl 2. DCM means [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane. Pd(dtbpf)Cl2 means [1,1'-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II). Pd(PPh3)4 means tetrakis(triphenylphosphine)palladium(0). PE means petroleum ether. iPrOH means isopropanol. q means quartet. RT means room temperature. s means single line. sat. means saturated. SCX stands for strong cation exchange. SFC stands for supercritical fluid chromatography. SiO2 means silicon dioxide. SOCl2 means thionyl chloride. soln. means solution. STAB means sodium triacetoxyborohydride. t means triple line. TBAF means tetrabutylammonium fluoride. TBDMS means tert-butyldimethylsilyl. TBME means tert-butyl methyl ether. t-BuONa means sodium tert-butoxide. TEA means triethylamine. TFA means trifluoroacetic acid. Ti(OEt)4 means titanium ethoxide. Tf2O means trifluoromethanesulfonic anhydride. THF means tetrahydrofuran. TLC means thin layer chromatography. TMS means trimethylsilyl. TMSCHN2 means (trimethylsilyl)diazomethane. μL means microliter. μmol means micromolar. Zn(CN)2 means zinc cyanide. ZnCl2 means zinc chloride.

[0097] Preparative HPLC conditions In the Examples section below, the following preparative HPLC method was used.

[0098] Method A: Column: Phenomenex Synergi C18 150 x 30 mm, 4 μm Mobile phase A: MeCN Mobile phase B: H2O Modifier: 0.05% HCl Gradient (% organic matter): 0-100% optimized for each example

[0099] Method B: Column: Sunfire C18 50 x 30 mm, 5 μm Mobile phase A: MeCN Mobile phase B: H2O Modifier: 0.1% TFA Gradient (% organic matter): 5-95% optimized in each case.

[0100] Method C: Column: XSelect C18 100 x 19 mm, 5 μm Mobile phase A: MeCN Mobile phase B: H2O Modifier: 0.1% NH4OH Gradient (% organic matter): 0-100% optimized in each case.

[0101] Method D: Column: Xtimate C18 150 x 25 mm, 5 μm Mobile phase A: MeCN Mobile phase B: H2O Modifier: 10mM NH4HCO3 Gradient (% organic matter): 0-100% optimized in each case.

[0102] Method E: Column: YMC-Actus C18 100 x 30 mm, 5 μm Mobile phase A: MeCN Mobile phase B: H2O Modifier: 0.225% HCO2H Gradient (% organic matter): 0-100% optimized in each case.

[0103] General Procedure First Process According to a first process, a compound of formula (I'), e.g., a compound of formula (I), (II), (III), or a pharmaceutically acceptable salt thereof, can be prepared using the general procedure illustrated in Scheme 1.

[0104] [ka] Compounds of formula (B) can be converted to boronate esters according to step (i), which is achieved by treatment with a suitable boronate (such as (BPin)) in the presence of a suitable inorganic base (such as KCO or KOAc) and a suitable catalyst (such as Pd(dppf)Cl or Pd(dba)) containing a suitable phosphine ligand, such as P(cy) or XPhos or Pd(PPh) at room temperature to elevated temperature in a suitable non-polar solvent, It can be prepared from a compound of formula (A). Preferred conditions include treating a compound of formula (A) with (BPin) in the presence of Pd(dppf)Cl or Pd(dba) with XPhos or P(cy) in the presence of KOAc at 85-90°C in DMSO, toluene, or dioxane.

[0105] Compounds of formula (D) may be prepared from compounds of formula (B) and heterocycles of formula (C) by an organometallic-catalyzed cross-coupling reaction in step (ii). Typical cross-coupling conditions include a palladium catalyst containing a suitable phosphine ligand in an aqueous solvent between room temperature and the reflux temperature of the reaction in the presence of an inorganic or organic base. Preferred conditions include reacting compounds of formula (B) and (D) in the presence of Pd(dppf)Cl or Pd(dtbpf)Cl and a suitable base (e.g., NaCO, KCO, or KPO) in a suitable solvent (e.g., aqueous dioxane) at 70°C to 100°C.

[0106] Amines of formula (E) can be prepared by deprotection of a compound of formula (D) according to process step (iii). Typically, a compound of formula (D) is treated with a suitable acid (e.g., HCl or TFA) in a suitable aprotic solvent (e.g., DCM, MeOH, EtOAc, or dioxane) at between room temperature and reflux. Preferred conditions include reacting a compound of formula (D) with TFA or HCl in DCM, MeOH, EtOAc, or dioxane at room temperature to 50°C.

[0107] Compounds of formula (I') may be prepared by amide bond formation between compounds of formula (F) and amines of formula (E) in the presence of a suitable coupling agent and an organic base in a suitable polar aprotic solvent.

[0108] Z is OH, O - K + , O - Li + In the case where the compound of formula (F) is a methyl group, preferred conditions include reacting the compound of formula (F) with an amine of formula (E) in the presence of a coupling agent, preferably T3P® or HATU, in the presence of a suitable organic base such as TEA or DIPEA, or in the presence of DABAL-Me3, in a suitable solvent such as DMF, DCM or THF, at room temperature to 45°C.

[0109] Alternatively, compounds of formula (I') may be prepared from esters of formula (F) by reaction of amines of formula (E) in the presence of a suitable coupling agent, typically DABAL-Me3, according to the method described by Novak et al. (Tet. Lett. 2006, 47, 5767).

[0110] Alternatively, compounds of formula (I') may be prepared from acid chlorides of formula (F) by reaction of an amine of formula (E) in the presence of a suitable organic base in a suitable solvent. Preferred conditions include reacting an amine of formula (E) with an acid chloride of formula (F) in the presence of DIPEA in DCM at room temperature.

[0111] Second Process According to a second process, compounds of formula (I'), such as formula (I), (II), (III), or a pharmaceutically acceptable salt thereof, can be prepared using the general procedure illustrated in Scheme 2, wherein PG, LG, and Z are as defined in Scheme 1.

[0112] [ka] Compounds of formula (G) may be prepared from protected amines of formula (B) following the deprotection reaction in step (iii), as described in Scheme 1 above.

[0113] Compounds of formula (H) may be prepared from amines of formula (G) and compounds of formula (F) following the amide bond formation of step (iv), as previously described in Scheme 1. Preferred conditions include reacting an acid of formula (F) with an amine of formula (G) in the presence of a coupling agent, preferably T3P®, HBTU or HATU, in the presence of a suitable organic base, such as DIPEA or pyridine, optionally at room temperature to 50° C., in a suitable solvent, such as DMF.

[0114] Compounds of formula (I') may be prepared following the organometallic catalyzed cross-coupling reaction of step (ii), as described in Scheme 1 above.

[0115] The third process According to the third process, R 8 Compounds of formula (M), in which R is a C-linked unsaturated heterocycle, can be prepared from compounds of formula (J), in which R 8 is Br, and compounds of formula (K) and (C) are shown by the general procedure in Scheme 3, where PG is as defined in Scheme 1.

[0116] [ka] Compounds of formula (K) may be prepared from compounds of formula (J) following boronate ester formation in step (i) as previously described in Scheme 1.

[0117] Compounds of formula (V) may be prepared from compounds of formula (K) and (L) following the organometallic catalyzed cross-coupling reaction of step (ii), as previously described in Scheme 1.

[0118] The fourth process According to a fourth process, compounds of formula (M) can be prepared from compounds of formula (J), wherein R 8 is Br, and compounds of formula (L), (N), and (O) are illustrated by the general procedure in Scheme 4, where PG and LG are defined in Scheme 1.

[0119] [ka]

[0120] R 8 When is a C-linked unsaturated substituent, compounds of formula (M) may be prepared following the organometallic catalyzed cross-coupling of compounds of formula (J) with compounds of formula (N) in process step (ii), as previously described in Scheme 1. Preferred conditions include reacting compounds of formula (J) and (N) in the presence of Pd(dppf)Cl and a suitable base (e.g., NaCO or KCO) in a suitable solvent (such as aqueous dioxane) at 70°C to 100°C.

[0121] Alternatively, R 8 When is an alkynyl group, compounds of formula (M) can be prepared by the Sonogashira reaction described in Journal of Organic Chemistry. 1998;63;23;8551-8553.

[0122] R 8 When is an N-linked substituent, compounds of formula (M) may be prepared according to the Buchwald-Hartwig cross-coupling reaction of process step (v). Typical conditions are The reaction conditions include reacting an amine of formula (O) with a bromide of formula (J) in the presence of a suitable inorganic base and a suitable palladium catalyst in a suitable solvent at elevated temperature. Preferred conditions include reacting compounds of formula (J) and (O) in the presence of DavePhos, RuPhos, XPhos, or JosiPhos, optionally with a combination of Pd2(dba)3 or RuPhos Pd G3, BrettPhos Pd G1 methyl t-butyl adduct, RuPhos Pd G1 methyl t-butyl ether adduct, or tBuXPhos-Pd-G3, in a suitable solvent such as dioxane, t-amyl alcohol, THF, or toluene, at 70°C to 110°C, optionally in the presence of a suitable base such as K3PO4, Cs2CO3Na2CO3, NatBuO, or the phosphazene base P2-Et.

[0123] R 8 When is a C-linked saturated substituent, compounds of formula (M) can be prepared according to process step (vi), a photocatalytic iridium-nickel cross-coupling reaction. Typical conditions include reacting an amine of formula (O) with a bromide of formula (J) in the presence of a suitable base, such as LiOH, and a suitable nickel / iridium catalyst combination, such as NiCl2glyme, BBBPY, and Ir[dF(CF3)ppy]2(dtbbpy)PF6, under blue light at room temperature in a suitable solvent, such as DME.

[0124] Compounds of formula (I'), (B), and (M) may be converted to alternative compounds of formula (I'), (B), and (M) by standard chemical transformations such as, for example, organometallic catalyzed cross-coupling reactions, reduction of carboxylic esters, O-alkylation, fluorination, hydrogenation, reductive amination, ester hydrolysis, etc., see, for example, Step 1 of Example 77, Step 2 of Example 77, Step 2 of Example 19, Step 2 of Example 21, and Step 4 of Example 32, Step 4 of Example 67.

[0125] Compounds of formula (A), (M), (F), (L), (N) and (O) are commercially available, may be prepared by methods known in the literature or by methods analogous to those described in the Examples set out below.

[0126] Furthermore, those skilled in the art will understand that it may be necessary or desirable at any stage in the synthesis of the compounds of the present invention to protect one or more sensitive groups to prevent undesired side reactions. In particular, it may be necessary or desirable to protect amino or carboxylic acid groups. The protecting groups used in the preparation of the compounds of the present invention may be used in a conventional manner. See, for example, 'Greene's Protective Groups in Organic Synthesis' by Theodora W. Greene and Peter G.M.Wuts, Fifth Edition (John Wiley and Sons, 2014), especially those described in Chapter 7 ("Protection of Amino Groups") and Chapter 5 ("Protection of Carboxyl Groups"). Each of these is incorporated herein by reference in its entirety, and methods for removing such groups are also described.

[0127] Example 1. 5-tert-butyl-N-[[2-chloro-5-fluoro-4-(6-morpholinopyrrolo[2,1-f][1,2,4]triazin-4-yl)phenyl]methyl]-1,2,4-oxadiazole-3-carboxamide [ka] 1. Synthesis of tert-butyl (2-chloro-5-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)carbamate [ka] To a solution of tert-butyl (4-bromo-2-chloro-5-fluorophenyl)carbamate (WO2015089327,

[0229] , 1.47 g, 4.3 mmol) and (bispinacolato)diboron (1.42 g, 5.6 mmol) in dioxane (20 mL) at 16 °C, Pd(dppf)Cl·DCM (300 mg, 0.36 mmol) and KOAc (843 mg, 8.6 mmol) were added, and the reaction was heated to 100 °C under N and stirred at that temperature for 16 h. The cooled reaction mixture was concentrated in vacuo, and the crude product was purified by silica gel column chromatography (petroleum ether / EtOAc = 20:1 to 4:1) to give the title compound (1 g, crude) as a pale solid, which was used in the next step without further purification. LCMS m / z = 330.1 [M+H] +

[0128] 2. Synthesis of (4-(6-bromopyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-chloro-5-fluorobenzyl)carbamate [ka] A mixture of tert-butyl (2-chloro-5-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)carbamate (618 mg, 1.6 mmol), 6-bromo-4-chloro-pyrrolo[2,1-f][1,2,4]triazine (410 mg, 1.8 mmol), Pd(dppf)Cl·DCM (131 mg, 0.2 mmol), and KCO (443 mg, 3.2 mmol) in dioxane (13.7 mL) and water (3.2 mL) was purged with N for 5 minutes. The reaction mixture was stirred at 100 °C under N for 1 hour. The cooled reaction was concentrated in vacuo, and the residue was partitioned between water (25 mL) and EtOAc (25 mL), and the layers were separated. The aqueous phase was diluted with EtOAc. (2 x 25 mL), and the combined organic layers were washed with brine (75 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (0-100% EtOAc / Hept) to give the title compound (471 mg, 61%) as a yellow solid. LCMS m / z = 485.1 [M+H] +

[0129] 3. Synthesis of tert-butyl (2-chloro-5-fluoro-4-(6-morpholinopyrrolo[2,1-f][1,2,4]triazin-4-yl)benzyl)carbamate [ka] A mixture of tert-butyl (4-(6-bromopyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-chloro-5-fluorobenzyl)carbamate (100 mg, 0.2 mmol), morpholine (29 mg, 0.3 mmol, 28 μL), Pd(dba) (20 mg, 0.02 mmol), CsCO (214 mg, 0.7 mmol), and XPhos (21 mg, 0.04 mmol) in dioxane (2.2 mL) was purged with N, and the reaction was stirred at 100 °C overnight. The cooled mixture was filtered through Celite®, and the filtrate was concentrated in vacuo. The crude material was purified by silica gel column chromatography (2–100% EtOAc / Hept). The crude material was further purified by SFC using a CHIRALPAK AD-H 30×250 mm, 5 um column eluted with 35% MeOH w / 0.1% DEA in CO (flow rate: 100 mL / min) to give the title compound as a yellow solid (12 mg, 13%). LCMS m / z=462.3 [M+H] +

[0130] 4. Synthesis of (2-chloro-5-fluoro-4-(6-morpholinopyrrolo[2,1-f][1,2,4]triazin-4-yl)phenyl)methanamine hydrochloride [ka] To a solution of tert-butyl (2-chloro-5-fluoro-4-(6-morpholinopyrrolo[2,1-f][1,2,4]triazin-4-yl)benzyl)carbamate (12 mg, 0.03 mmol) in EtOAc (0.25 mL) was added 1 M HCl (26 μL) and the reaction was stirred at room temperature for 18 h. The mixture was evaporated in vacuo to give the title compound, which was carried forward assuming quantitative yield. LCMS m / z=362.2 [M+H] +

[0131] 5.5-tert-butyl-N-[[2-chloro-5-fluoro-4-(6-morpholinopyrrolo[2,1-f][1,2,4]triazin-4-yl)phenyl]methyl]-1, Synthesis of 2,4-oxadiazole-3-carboxamide [ka] To an ice-cold solution of potassium 5-(tert-butyl)-1,2,4-oxadiazole-3-carboxylate (8 mg, 0.04 mmol) in THF (0.1 mL) was added EtN (11 mg, 0.1 mmol) and HATU (20 mg, 0.05 mmol). Additional THF (1 mL) was added, and the mixture was stirred at 0 °C for 10 min, followed by the addition of (2-chloro-5-fluoro-4-(6-morpholinopyrrolo[2,1-f][1,2,4]triazin-4-yl)phenyl)methanamine hydrochloride (10 mg, 0.03 mmol). The reaction mixture was warmed to 23 °C and stirred at that temperature for 60 h. The reaction was quenched with HO (5 mL) and extracted with EtOAc (3 × 5 mL). The combined organics were washed with brine, dried (NaSO), and evaporated in vacuo. The residue was purified by preparative HPLC (Method C, 20-80%) to give the title compound (4 mg, 30%). LCMS m / z=514.5 [M+H] + ; 1H NMR(500MHz,MeOH-d4)δ:8.38(s,1H),7.87(s,1H),7.81(d,1H),7.38(d,1H),6. 34(s,1H),4.74(s,2H),3.86-3.78(m,4H),3.19-3.13(m,4H),1.52-1.48(m,9H).

[0132] Example 2. 3-(tert-butyl)-N-(3-fluoro-2-methyl-4-(6-morpholinopyrrolo[2,1-f][1,2,4]triazin-4-yl)benzyl)-1,2,4-oxadiazole-5-carboxamide [ka] 1. Synthesis of tert-butyl (3-fluoro-2-methyl-4-(6-morpholinopyrrolo[2,1-f][1,2,4]triazin-4-yl)benzyl)carbamate (100014-481) [ka] A mixture of tert-butyl (4-(6-bromopyro[2,1-f][1,2,4]triazin-4-yl)-3-fluoro-2-methylbenzyl)carbamate (500 mg, 1.2 mmol), morpholine (150 mg, 1.7 mmol), Pd(dba) (106 mg, 0.12 mmol), CsCO (1.12 g, 3.5 mmol), and XPhos (110 mg, 0.23 mmol) in dioxane (11.5 mL) was purged with N for 5 minutes, and the reaction was heated to 100 °C and stirred at that temperature overnight. The cooled mixture was filtered through Celite®, and the filtrate was concentrated in vacuo. The crude material was purified by silica gel column chromatography (2–100% EtOAc / Hept) to give the title compound (354 mg, 70%) as a yellow solid. LCMS m / z=442.3[M+H] + ; 1H NMR(500MHz,MeOH-d4)δ:8.35(s,1H),7.84(d,1H),7.51(t,1H),7.27(br d,1H),7.20(br d,1H),6.31(s,1H),4.40-4.28(m,2H),3.89-3.75(m,4H),3.20-3.11(m,4H),2.33(d,3H),1.47(s,9H)

[0133] 2. Synthesis of (3-fluoro-2-methyl-4-(6-morpholinopyrrolo[2,1-f][1,2,4]triazin-4-yl)phenyl)methanamine [ka] 1M HCl (29 mg, 0.8 mmol) was added to a solution of tert-butyl (3-fluoro-2-methyl-4-(6-morpholinopyrrolo[2,1-f][1,2,4]triazin-4-yl)benzyl)carbamate (354 mg, 0.8 mmol) in EtOAc (8 mL), and the reaction was stirred at room temperature for 24 h. The mixture was partitioned between water (10 mL) and EtOAc (10 mL), and the layers were separated. The aqueous phase was basified to pH 10 using saturated aqueous NaHCO3 and extracted with EtOAc (3 x 10 mL). The combined organic extracts were washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo to give the title compound (278 mg, 100%) as a yellow solid. LCMS m / z = 342.3 [M+H] + ; 1 H NMR(500MHz,MeOH-d4)δ:8.40-8.38(m,1H),7.89(d,1H),7.63(t,1H),7.41(d,1) H),6.29(t,1H),4.27(s,2H),3.89-3.78(m,4H),3.20-3.12(m,4H),2.42(d,3H).

[0134] 3. Potassium 3-(tert-butyl)-1,2,4-oxadiazole-5-carboxylate Synthesis of silates [ka] To a stirred solution of ethyl 3-tert-butyl-1,2,4-oxadiazole-5-carboxylate (2.7 g, 13.6 mmol) in EtOH / water (4 / 1 v / v, 35 mL) was added powdered KOH (765 mg, 13.6 mmol) and the reaction was stirred for 4 days at 23° C. The solvent was removed in vacuo without heating, the resulting white solid was triturated with EtO, and the crude material was dried in vacuo to give the title compound (2.6 g, 92%) as a white solid, which was used without further purification.

[0135] 4. Synthesis of 3-(tert-butyl)-N-(3-fluoro-2-methyl-4-(6-morpholinopyrrolo[2,1-f][1,2,4]triazin-4-yl)benzyl)-1,2,4-oxadiazole-5-carboxamide [ka] The crude product was obtained from potassium 3-(tert-butyl)-1,2,4-oxadiazole-5-carboxylate and (3-fluoro-2-methyl-4-(6-morpholinopyrrolo[2,1-f][1,2,4]triazin-4-yl)phenyl)methanamine according to the procedure described in Step 5 of Example 1. The crude product was purified by HPLC Method C to give the title compound (31 mg, 19%) as a yellow solid. LCMS m / z=494.3 [M+H] + ; 1 H NMR(500MHz,MeOH-d4)δ:8.36(s,1H),7.85(d,1H),7.54(t,1H),7.35(d,1H),6.32( t,1H),4.69(s,2H),3.88-3.76(m,4H),3.20-3.11(m,4H),2.40(d,3H),1.42(s,9H).

[0136] Example 3. 5-(1,1-Difluoro-2-methylpropan-2-yl)-N-(2-methyl-4-(6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)benzyl)-1,3,4-oxadiazole-2-carboxamide [ka] Synthesis of 1,3-acetoxy-2,2-dimethylpropanoic acid [ka] 3-Hydroxy-2,2-dimethylpropanoic acid (47.2 g, 400 mmol) was dissolved in pyridine (120 mL) and the reaction mixture was cooled to 0 °C. Acetyl chloride (47.2 g, 600 mmol) was added dropwise, and the reaction mixture was then stirred at room temperature for 16 hours. The reaction was acidified with 1N HCl to pH = 3-4 and extracted with EtOAc (3 x 100 mL). The organic extracts were washed with 1N HCl (5 x 30 mL), dried over MgSO4, and concentrated in vacuo to give the title compound (60.0 g, 94%). LCMS m / z = 161.1 [M+H] + . 1 H NMR(400MHz,CDCl3)δ:4.13(s,2H),2.08(s,3H),1.26(s,6H).

[0137] 2. Synthesis of tert-butyl 2-(3-acetoxy-2,2-dimethylpropanoyl)hydrazine-1-carboxylate [ka] To a solution of 3-acetoxy-2,2-dimethylpropanoic acid (0.8 g, 8.0 mmol) in DCM (40 mL) were added oxalyl chloride (3.0 g, 24.0 mmol) and DMF (1 drop, cat.). The mixture was stirred at room temperature for 3 h. After concentration, the freshly prepared acid chloride was dissolved in DCM (30 mL), and BocNH-NH (1.1 g, 8.0 mmol) and EtN (1.6 g, 16 mmol) were added. The mixture was stirred at room temperature for 8 h. Water (50 mL) was then added, and the mixture was extracted with DCM (3 × 100 mL). The combined organic extracts were washed with brine (2 × 80 mL), dried (NaSO), and concentrated in vacuo. The crude product was purified by silica gel column chromatography (petroleum ether / EtOAc = 8:1) to give the title compound (1.2 g, 86%) as a white solid. LCMS m / z=275.2[M+H] +. 1 H NMR(400MHz, CDCl3)δ:7.68(br,1H),6.56(br,1H),4.12(s,2H),2.10(s,3H),1.47(s,9H),1.27(s,6H).

[0138] Synthesis of 3.3-hydrazinyl-2,2-dimethyl-3-oxopropyl acetate hydrochloride [ka] A solution of tert-butyl 2-(3-acetoxy-2,2-dimethylpropanoyl)hydrazine-1-carboxylate (5.5 g, 9.3 mmol) in HCl solution (4 M in dioxane, 20 mL) was stirred at room temperature for 2 hours. The reaction mixture was concentrated in vacuo to give the title compound (3.8 g, 89%), which was carried forward without further purification. LCMS m / z=175.1 [M+H] + . 1 H NMR(400MHz,CDCl3)δ:10.35(br,2H),4.13(s,2H),2.08(s,3H),1.29(s,6H).

[0139] 4. Synthesis of ethyl 2-(2-(3-acetoxy-2,2-dimethylpropanoyl)hydrazinyl)-2-oxoacetate [ka] To a solution of 3-hydrazinyl-2,2-dimethyl-3-oxopropyl acetate (800 mg, 4.6 mmol) in DCM (20 mL) was added ethyl 2-chloro-2-oxoacetate (628 mg, 4.6 mmol) and EtN (1.42 g, 14.0 mmol). The mixture was stirred at room temperature for 16 hours. After dilution with DCM (150 mL), the mixture was washed with brine (60 mL), dried (NaSO), filtered, and concentrated in vacuo. The crude product was purified by silica gel column chromatography (petroleum ether / EtOAc = 1:1) to give the title compound (905 mg, 72%) as a yellow oil. LCMS m / z = 275.1 [M+H] + ;1 H NMR(400MHz,CDCl3)δ:8.95(s,1H),4.39(q,2H),4.13(s,2H)2.12(s,3H),1.39(t,3H),1.30(s,6H)

[0140] 5. Synthesis of ethyl 5-(1-acetoxy-2-methylpropan-2-yl)-1,3,4-oxadiazole-2-carboxylate [ka] To a solution of ethyl 2-(2-(3-acetoxy-2,2-dimethylpropanoyl)hydrazinyl)-2-oxoacetate (1.5 g, 5.6 mmol) in DCM (20 mL) was added p-TsCl (1.3 g, 6.7 mmol) and EtN (735 mg, 7.3 mmol). The mixture was stirred at room temperature for 8 hours. After dilution with DCM (100 mL), The mixture was washed with brine (60 mL), dried (Na2SO4), filtered, and concentrated in vacuo. The crude product was purified by silica gel column chromatography (petroleum ether / EtOAc = 2:1) to give the title compound (1.0 g, 72%) as a yellow solid. LCMS m / z = 257.1 [M+H] + ; 1 H NMR(400MHz,CDCl3)δ:4.52(q,2H),4.28(s,2H),2.03(s,3H),1.52(s,6H),1.46(t,3H).

[0141] 6. Synthesis of ethyl 5-(1-hydroxy-2-methylpropan-2-yl)-1,3,4-oxadiazole-2-carboxylate [ka] To a solution of ethyl 5-(1-acetoxy-2-methylpropan-2-yl)-1,3,4-oxadiazole-2-carboxylate (4.0 g, 15.6 mmol) in EtOH (40 mL) was added concentrated HCl (4 mL). The mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated in vacuo, and the crude material was purified by silica gel column chromatography (petroleum ether / EtOAc = 2:1) to give the title compound as a yellow oil (1.2 g, 36%). LCMS m / z = 215.1 [M+H] + ; 1 H NMR(400MHz, CDCl3)δ:4.52(q,2H),3.84(s,2H),1.47-1.44(m,9H).

[0142] 7. Synthesis of ethyl 5-(2-methyl-1-oxopropan-2-yl)-1,3,4-oxadiazole-2-carboxylate [ka] To a solution of ethyl 5-(1-hydroxy-2-methylpropan-2-yl)-1,3,4-oxadiazole-2-carboxylate (1.0 g, 4.7 mmol) in DCM (150 mL) was added Dess-Martin periodinane (2.4 g, 5.6 mmol). The mixture was stirred at room temperature for 16 h. After dilution with water (20 mL), the mixture was extracted with DCM (2 × 30 mL). The combined organic layers were washed with H2O (2 × 20 mL), dried (Na2SO4), filtered, and concentrated in vacuo to give the title compound (500 mg, 51%) as a yellow solid. LCMS m / z = 213.1 [M+H] + ; 1 H NMR(400MHz, CDCl3)δ:9.68(s,1H),4.53(q,2H),1.66(s,6H),1.26(t,3H).

[0143] 8. Synthesis of ethyl 5-(1,1-difluoro-2-methylpropan-2-yl)-1,3,4-oxadiazole-2-carboxylate [ka] A solution of ethyl 5-(2-methyl-1-oxopropan-2-yl)-1,3,4-oxadiazole-2-carboxylate (1.4 g, 6.6 mmol) in DAST (10 mL) was stirred at 40° C. for 16 hours. The reaction mixture was concentrated, and ice was added, followed by EtOAc (50 mL). The layers were separated, and the organic phase was dried (Na2SO4), filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (petroleum ether / EtOAc = 3:1) to give the title compound (720 mg, 47%) as a yellow oil. LCMS m / z = 235.1 [M+H] + ; 1 H NMR(400MHz,CDCl3)δ:6.01(t,1H),4.53(q,2H),1.58(s,6H),1.46(t,3H).

[0144] 9. Synthesis of potassium 5-(1,1-difluoro-2-methylpropan-2-yl)-1,3,4-oxadiazole-2-carboxylate [ka] Using a method similar to that described in Step 3 of Example 2, ethyl 5-(1,1-difluoro-2-methylpropan-2-yl)-1,3,4-oxadiazole-2-carboxylate, the title compound was obtained.

[0145] 10. Synthesis of 5-(1,1-difluoro-2-methylpropan-2-yl)-N-(2-methyl-4-(6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)benzyl)-1,3,4-oxadiazole-2-carboxamide [ka] (2-methyl-4-(6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)phenyl)methanamine hydrochloride and potassium 5-(1,1-difluoro- The title compound was prepared using a method similar to that described in Step 5 of Example 1 using 2-methylpropan-2-yl)-1,3,4-oxadiazole-2-carboxylate (57.1 mg, 34%). LCMS m / z=507.2 [M+H] + ; 1 H NMR(400MHz,MeOH-d4)δ:8.91-8.98(m,1H),8.33-8.44(m,1H),8.15-8.25(m,1H),7.96-8.03(m,1H),7.87-7.93(m,2H),7.8 2-7.86(m,1H),7.50-7.58(m,1H),7.18-7.28(m,1H),6.12(s,1H),4.70(s,2H),3.92(s,3H),2.51(s,3H),1.53-1.61(m,6H).

[0146] Example 4. 5-(tert-butyl)-N-(2-methyl-4-(6-(4-methylpiperazin-1-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)benzyl)-1,2,4-oxadiazole-3-carboxamide trifluoroacetate [ka] 1. Synthesis of tert-butyl (4-(6-bromopyrrolo[2,1-f][1,2,4]triazin-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 (10.0 g, 28.8 mmol), 6-bromo-4-chloro-pyrrolo[2,1-f][1,2,4]triazine (13.4 g, 57.6 mmol), KCO (11.9 g, 86.4 mmol), and Pd(dppf)Cl (1.1 g, 1.4 mmol) in dioxane (100 mL) and water (25 mL) was purged with N for 5 minutes. The reaction mixture was heated to 100 °C under N and stirred at that temperature for 18 hours. The cooled reaction was diluted with HO (100 mL) and EtOAc (200 mL), filtered, and the layers were separated. The organic layer was washed with brine (100 mL), dried (NaSO) and concentrated in vacuo. The crude was purified by silica gel column chromatography (Et0Ac / Hept=1:3) to give the title compound (10.1 g, 84%) as a yellow solid. LCMS m / z=417.1 [M +H] +

[0147] 2. Synthesis of tert-butyl (2-methyl-4-(6-(4-methylpiperazin-1-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)benzyl)carbamate [ka] N was bubbled through a mixture of tert-butyl (4-(6-bromopyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-methylbenzyl)carbamate (350 mg, 0.84 mmol) and tBuXPhos-Pd-G3 (67 mg, 0.08 mmol) in t-amyl alcohol (4.2 mL) for 5 min. The phosphazene base P2-Et (569 mg, 1.7 mmol) and 1-methylpiperazine (126 mg, 1.3 mmol) were added, and the reaction was stirred at room temperature for 4 h. The reaction was diluted with saturated NH4Cl solution and extracted with EtOAc (2 x 25 mL). The combined organic layers were washed with brine (50 mL), dried (Na2SO4), filtered, and concentrated in vacuo. The crude material was purified by silica gel column chromatography (0-10% MeOH / DCM, 1% NH4OH modifier) ​​to give the title compound as a light yellow solid (75 mg, 20%). LCMS m / z=437.3 [M+H] +

[0148] 3. Synthesis of (2-methyl-4-(6-(4-methylpiperazin-1-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)phenyl)methanamine hydrochloride [ka] A solution of HCl in EtOAc (4 M, 2 mL) was added to tert-butyl (2-methyl-4-(6-(4-methylpiperazin-1-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)benzyl)carbamate and the mixture was stirred at room temperature for 18 hours. The mixture was concentrated in vacuo to give the title compound (4.3 mg) as a yellow solid, which was used in the next step without further purification. LCMS m / z=337.0 [M+H] +

[0149] Synthesis of 4.5-(tert-butyl)-N-(2-methyl-4-(6-(4-methylpiperazin-1-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)benzyl)-1,2,4-oxadiazole-3-carboxamide trifluoroacetate [ka] A vial was charged with (2-methyl-4-(6-(4-methylpiperazin-1-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)phenyl)methanamine hydrochloride (40 mg, 0.08 mmol), potassium 5-tert-butyl-1,2,4-oxadiazole-3-carboxylate (21 mg, 0.1 mmol), and DCM (1 mL), followed by DIPEA (107 mg, 0.8 mmol). The mixture was cooled to 0 °C, HATU (38 mg, 0.1 mmol) was added in one portion, and the reaction was stirred at room temperature overnight. The reaction was concentrated in vacuo, and the residue was dissolved in MeOH and passed through a fritted filter. The filtrate was evaporated in vacuo, and the residue was purified by reverse-phase HLPC (Method A, 5-45%) to give the title compound (20 mg, 40%) as a red solid. LCMS m / z = 489.2 [M+H] + ; 1 H NMR(500MHz,DMSO-d6)δ:9.52(t,1H),8.51(s,1H),8.06(d,1H),7.89-7.98(m,2H),7.43(d,1H),6.81(d,1H),4.54(d,2H),3.91(br d,2H),3.51(br d,2H),3.14-3.24(m,2H),3.00-3.10(m,2H),2.85(d,3H),2.46(s,3H),1.44(s,9H).

[0150] Example 5. 5-(tert-butyl)-N-(2-methyl-4-(6-morpholinopyrrolo[2,1-f][1,2,4]triazin-4-yl)benzyl)-1,2,4-oxadiazole-3-carboxamide trifluoroacetate [ka] 1. Synthesis of tert-butyl (2-methyl-4-(6-morpholinopyrrolo[2,1-f][1,2,4]triazin-4-yl)benzyl)carbamate [ka] A mixture of tert-butyl (4-(6-bromopyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-methylbenzyl)carbamate (501 mg, 1.2 mmol), morpholine (157 mg, 1.8 mmol), Pd(dba) (55 mg, 0.06 mmol), DavEPhos (47 mg, 0.12 mmol), and CsCO (782 mg, 2.4 mmol) in dioxane (12 mL) was purged with N for 5 min and then stirred at 100 °C for 16 h. Additional morpholine (157 mg, 1.8 mmol), Pd(dba) (55 mg, 0.06 mmol), DavePhos (47 mg, 0.12 mmol), and CsCO (782 mg, 2.4 mmol) were added, and the reaction was stirred at 110 °C for an additional 24 h. The cooled reaction was concentrated in vacuo, and the crude product was purified by silica gel column chromatography (0-100% EtOAc / Hept) to give the title compound as a yellow solid (279 mg, 55%). LCMS m / z = 424.3 [M+H] +

[0151] 2. Synthesis of (2-methyl-4-(6-morpholinopyrrolo[2,1-f][1,2,4]triazin-4-yl)phenyl)methanamine hydrochloride [ka] To a solution of tert-butyl (2-methyl-4-(6-morpholinopyrrolo[2,1-f][1,2,4]triazin-4-yl)benzyl)carbamate (64 mg, 0.18 mmol) in MeOH (1.8 mL) was added HCl solution (1.4 mL, 1.8 mmol, 1.25 M in MeOH) and the reaction was stirred at 50° C. for 18 h. The cooled reaction mixture was concentrated in vacuo to give the title compound as a dark red film (52.0 mg), which was carried forward without further purification. LCMS m / z=264.1 [M+H] +

[0152] Synthesis of 3,5-(tert-butyl)-N-(2-methyl-4-(6-morpholinopyrrolo[2,1-f][1,2,4]triazin-4-yl)benzyl)-1,2,4-oxadiazole-3-carboxamide trifluoroacetate [ka] The crude product was obtained from (2-methyl-4-(6-morpholinopyrrolo[2,1-f][1,2,4]triazin-4-yl)phenyl)methanamine hydrochloride and potassium 5-(tert-butyl)-1,2,4-oxadiazole-3-carboxylate according to the procedure described in Step 4 of Example 4. The crude product was purified by reverse-phase HPLC (Method B, 5-55%) to give the title compound as a red solid (33 mg, 47%). LCMS m / z=476.2 [M+H] + ; 1 H NMR(500MHz,DMSO-d6)δ:9.50(t,1H),8.48(s,1H),8.02(d,1H),7.89-7.96(m,2H),7.43(d,1 H),6.73(d,1H),4.54(d,2H),3.72-3.81(m,4H),3.13-3.22(m,4H),2.45(s,3H),1.44(s,9H).

[0153] Example 6. 5-(tert-butyl)-N-(4-(6-(3,6-dihydro-2H-pyran-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-methylbenzyl)-1,2,4-oxadiazole-3-carboxamide [ka] 1. Synthesis of tert-butyl (4-(6-(3,6-dihydro-2H-pyran-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-methylbenzyl)carbamate [ka] tert-Butyl (4-(6-bromopyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-methylbenzyl) in dioxane (1.2 mL) and water (0.6 mL) A mixture of 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (113 mg, 0.5 mmol), Pd(dppf)Cl₂·DCM (15 mg, 0.02 mmol), and K₂CO₃ (75 mg, 0.5 mmol) was purged with nitrogen for 5 minutes and then heated at 100 °C overnight. The reaction mixture was concentrated in vacuo, and the residue was purified by silica gel column chromatography (0–100% EtOAc:Hept) to give the title compound (91 mg, 120%) as a pale yellow solid. LCMS m / z = 421.1 [M+H] +

[0154] 2. Synthesis of (4-(6-(3,6-dihydro-2H-pyran-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-methylphenyl)methanamine trifluoroacetate [ka] To a solution of tert-butyl (4-(6-(3,6-dihydro-2H-pyran-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-methylbenzyl)carbamate (91 mg, 0.2 mmol) in DCM (2 mL) was added TFA (0.5 mL) and the reaction was stirred at room temperature for 18 h. The mixture was concentrated in vacuo to give the title compound as a yellow film, which was carried forward without further purification. LCMS m / z=321.1 [M+H] +

[0155] Synthesis of 3,5-(tert-butyl)-N-(4-(6-(3,6-dihydro-2H-pyran-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-methylbenzyl)-1,2,4-oxadiazole-5-carboxamide [ka] The compound was obtained from [4-[6-(3,6-dihydro-2H-pyran-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl]-2-methyl-phenyl]methanamine trifluoroacetate and potassium 5-tert-butyl-1,2,4-oxadiazole-3-carboxylate according to the procedure described in Step 4 of Example 4. The crude product was purified by silica gel column chromatography (0-100% [3:1 EtOAc:EtOH]:Hept) to give the title compound (21 mg, 49%) as a pale yellow solid. LCMS m / z=473.2[M+H] + ; 1 H NMR(500MHz,DMSO-d6)δ:9.52(t,1H),8.57(s,1H),8.34(d,1H),7.98(d,1H),7.96(s,1H),7.45(d,1H),7.28(d,1H),6.48(br s,1H),4.55(d,2H),4.24(br d,2H),3.83(t,2H),2.46(s,3H),1.44(s,9H).

[0156] Example 7. 5-(tert-butyl)-N-(4-(6-(1-(2-methoxyethyl)-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-methylbenzyl)-1,2,4-oxadiazole-3-carboxamide [ka] 1. Synthesis of tert-butyl (4-(6-(1-(2-methoxyethyl)-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-methylbenzyl)carbamate [ka] A solution of tert-butyl (4-(6-bromopyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-methylbenzyl)carbamate (75 mg, 0.2 mol), 1-(2-methoxyethyl)-1H-pyrazole-4-boronic acid pinacol ester (135 mg, 0.5 mmol), Pd(dppf)Cl·DCM (15 mg, 0.02 mmol), and KCO (75 mg, 0.5 mmol) in dioxane (1.2 mL) and water (0.6 mL) was purged with nitrogen for 5 minutes and then heated at 100 °C overnight. The reaction mixture was concentrated in vacuo, and the residue was purified by silica gel column chromatography (0–100% EtOAc:Hept) to give the title compound (90 mg, 120%) as a pale yellow solid. LCMS m / z = 463.3 [M+H] +

[0157] 2. Synthesis of (4-(6-(1-(2-methoxyethyl)-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-methylphenyl)methanamine hydrochloride [ka] HCl (4 M, 0.5 mL) was added to tert-butyl (4-(6-(1-(2-methoxyethyl)-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-methylbenzyl)carbamate (90 mg, 0.2 mmol) in MeOH (2 mL) and stirred at room temperature overnight. The mixture was concentrated in vacuo to give the title compound (90 mg, crude), which was used in the next step without further purification. LCMS m / z=363.2 [M+H] +

[0158] Synthesis of 3.5-(tert-butyl)-N-(4-(6-(1-(2-methoxyethyl)-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-methylbenzyl)-1,2,4-oxadiazole-3-carboxamide [ka] The compound was obtained from (4-(6-(1-(2-methoxyethyl)-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-methylphenyl)methanamine hydrochloride and potassium 5-tert-butyl-1,2,4-oxadiazole-3-carboxylate according to the procedure described in Step 4 of Example 4. The crude product was purified by silica gel column chromatography (0-75% EtOAc / EtOH (3:1):Hept) to give the title compound (32 mg, 60%) as a yellow solid. LCMS m / z=515.3 [M+H] + ; 1 H NMR(500MHz,DMSO-d6)δ:9.53(t,1H),8.56(s,1H),8.47(d,1H),8.23(s,1H),8.00(br d,1H),7.97(s,2H),7.46(d,1H),7.41(d,1H),4.56(d,2H),4.27(t,2H),3.71(t,2H),3.24(s,3H),2.48(s,3H),1.44(s,9H).

[0159] Example 8. 5-(tert-butyl)-N-(4-(6-(3-methoxyazetidin-1-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-methylbenzyl)-1,2,4-oxadiazole-3-carboxamide [ka] 1. Synthesis of tert-butyl (4-(6-(3-methoxyazetidin-1-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-methylbenzyl)carbamate (100098-698) [ka] A mixture of tert-butyl (4-(6-bromopyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-methylbenzyl)carbamate (95 mg, 0.2 mmol), Pd(dba) (10 mg, 0.01 mmol), JosiPhos (13 mg, 0.02 mmol), and CsCO (223 mg, 0.7 mmol) was dissolved in dioxane (2.3 mL), and the mixture was purged with N for 5 minutes. 3-Methoxyazetidine (30 mg, 0.3 mmol) was added, and the reaction was stirred at 100 °C overnight. The cooled reaction was concentrated in vacuo, and the crude material was purified by silica gel column chromatography (0-100% EtOAc:Hept) to give the title compound (85 mg, 88%) as a yellow solid. LCMS m / z = 424.3 [M+H] +

[0160] 2. Synthesis of (4-(6-(3-methoxyazetidin-1-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-methylphenyl)methanamine [ka] TFA (229 mg, 2.0 mmol) was added to a solution of tert-butyl (4-(6-(3-methoxyazetidin-1-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-methylbenzyl)carbamate (85 mg, 0.2 mmol) in DCM (2.0 mL) and the reaction was stirred at room temperature for 18 hours. The reaction was concentrated in vacuo. The residue was dissolved in MeOH and flushed with MeOH followed by 2M methanolic NH3 and passed through an SCX ion exchange column. The combined organic phases were concentrated in vacuo to give the title compound (67 mg, crude), which was carried forward without further purification. LCMS m / z=324.2 [M+H] +

[0161] Synthesis of 3.5-(tert-butyl)-N-(4-(6-(3-methoxyazetidin-1-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-methylbenzyl)-1,2,4-oxadiazole-3-carboxamide [ka] The compound was obtained from (4-(6-(3-methoxyazetidin-1-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-methylphenyl)methanamine and potassium 5-tert-butyl-1,2,4-oxadiazole-3-carboxylate according to the procedure described in Step 4 of Example 4. The crude product was purified by silica gel column chromatography (0-100% (EtOAc / EtOH (3:1):Hept)) to give the title compound (28 mg, 28%) as a yellow solid. LCMS m / z = 476.3 [M+H] + ; 1 H NMR(500MHz,DMSO-d6)δ:9.49(t,1H),8.46(s,1H),7.84-7.96(m,2H),7.71(d,1H),7.42(d,1H),6.43(d, 1H),4.54(d,2H),4.30-4.38(m,1H),4.09(dd,2H),3.67(dd,2H),3.31(s,3H),2.45(s,3H),1.44(s,9H).

[0162] Example 9. 5-(tert-butyl)-N-(2-methyl-4-(6-(1-methyl-1H-pyrazol-3-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)benzyl)-1,2,4-oxadiazole-3-carboxamide trifluoroacetate [ka] 1. Synthesis of tert-butyl (2-methyl-4-(6-(1-methyl-1H-pyrazol-3-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)benzyl)carbamate [ka] N was bubbled through a mixture of tert-butyl (4-(6-bromopyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-methylbenzyl)carbamate (500 mg, 1.2 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (499 mg, 2.4 mmol), Pd(dppf)Cl·DCM (98 mg, 0.12 mmol), and KCO (498 mg, 3.6 mmol) in dioxane (8 mL) and HO (4 mL) for 5 min. The reaction mixture was then heated to 100 °C overnight. The reaction was concentrated in vacuo, and the crude material was purified by silica gel column chromatography (0–100% EtOAc:Hept) to afford the title compound (461 mg, 92%) as a yellow solid. LCMS m / z=419.3[M+H] + .

[0163] 2. Synthesis of (2-methyl-4-(6-(1-methyl-1H-pyrazol-3-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)phenyl)methanamine hydrochloride [ka] tert-Butyl (2-methyl-4-(6-(1-methyl-1H-pyrazol-3-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)benzyl)carbamate (460 mg, 1.1 mmol) was dissolved in HCl solution (8.8 mL, 1.25 M in MeOH) and the reaction was stirred at 50° C. overnight. The reaction mixture was concentrated in vacuo to give the title compound (445 mg, crude) as a yellow solid, which was used without further purification. LCMS m / z=319.2 [M+H] +

[0164] Synthesis of 3,5-(tert-butyl)-N-(2-methyl-4-(6-(1-methyl-1H-pyrazol-3-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)benzyl)-1,2,4-oxadiazole-3-carboxamide trifluoroacetate [ka] The compound was obtained from (2-methyl-4-(6-(1-methyl-1H-pyrazol-3-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)phenyl)methanamine hydrochloride and potassium 5-tert-butyl-1,2,4-oxadiazole-3-carboxylate according to the procedure described in Step 4 of Example 4. The crude product was purified by silica gel column chromatography (0-100% EtOAc / Hept) followed by preparative HPLC (Method B, 10-90%) to give the title compound as a yellow solid (30 mg, 32%). LCMS m / z=471.3 [M+H] + ; 1 H NMR(400MHz,DMSO-d6)δ:9.52(t,1H),8.60(s,1H),8.46(d,1H),7.94-8.02(m,2H),7.74(d,1H ),7.48(d,1H),7.42(d,1H),6.77(d,1H),4.56(d,2H),3.89(s,3H),2.48(s,3H),1.44(s,9H).

[0165] Example 10. 5-(tert-butyl)-N-(4-(6-(1-(2,2-difluoroethyl)-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-methylbenzyl)-1,2,4-oxadiazole-3-carboxamide trifluoroacetate [ka] 1. Synthesis of (4-(6-(1-(2,2-difluoroethyl)-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-methylbenzyl)carbamate [ka] N was bubbled through a mixture of tert-butyl (4-(6-bromopyro[2,1-f][1,2,4]triazin-4-yl)-2-methylbenzyl)carbamate (100 mg, 0.2 mmol), 1-(2,2-difluoroethyl)-1H-pyrazole-4-boronic acid pinacol ester (124 mg, 0.5 mmol), Pd(dppf)Cl·DCM (20 mg, 0.02 mmol), and KCO (99 mg, 0.5 mmol) in dioxane (1.6 mL) and HO (0.8 mL) for 5 min. The reaction mixture was heated to 100 °C and stirred at that temperature overnight. The cooled reaction was concentrated in vacuo and purified by silica gel column chromatography (0–100% EtOAc:Hept) to give the title compound (92 mg, 82%) as a yellow solid. LCMS m / z=469.2[M+H] + .

[0166] 2. Synthesis of (4-(6-(1-(2,2-difluoroethyl)-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-methylphenyl)methanamine hydrochloride [ka] tert-Butyl (4-(6-(1-(2,2-difluoroethyl)-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-methylbenzyl)carbamate (93 mg, 0.2 mmol) was dissolved in HCl solution (1.5 mL, 1.25 M in MeOH) and the reaction was stirred at 50° C. overnight. The reaction mixture was concentrated in vacuo to give the title compound (80 mg, 92% yield) as a yellow solid, which was used without further purification. LCMS m / z=369.2 [M+H] +

[0167] Synthesis of 3,5-(tert-butyl)-N-(4-(6-(1-(2,2-difluoroethyl)-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-methylbenzyl)-1,2,4-oxadiazole-3-carboxamide trifluoroacetate [ka] Following the procedure described in Step 4 of Example 4, the compound was obtained from (4-(6-(1-(2,2-difluoroethyl)-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-methylphenyl)methanamine hydrochloride and potassium 5-tert-butyl-1,2,4-oxadiazole-3-carboxylate. The crude product was purified by silica gel column chromatography (0-100% EtOAc / Hept) followed by preparative HPLC (Method B, 10-90%) to give the title compound (23 mg, 32%) as a yellow solid. LCMS m / z=521.2 [M+H] + ; 1 H NMR(400MHz,DMSO-d6)δ:9.53(t,1H),8.57(s,1H),8.51(d,1H),8.30(s,1H),8.08(d,1H),7.94-8.0 3(m,2H),7.39-7.52(m,2H),6.18-6.59(m,1H),4.65(td,2H),4.56(d,2H),2.48(s,3H),1.44(s,9H).

[0168] Example 11. 5-(tert-butyl)-N-(4-(6-(3-fluoropyrrolidin-1-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-methylbenzyl)-1,2,4-oxadiazole-3-carboxamide trifluoroacetate [ka] 1. Synthesis of tert-butyl (4-(6-(3-fluoropyrrolidin-1-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-methylbenzyl)carbamate [ka] Following the procedure described in Step 1 of Example 2, the title compound was obtained as a yellow solid (78 mg, 38% yield) from tert-butyl (4-(6-bromopyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-methylbenzyl)carbamate and 3-fluoropyrrolidine. LCMS m / z=426.2 [M+H] +

[0169] 2. Synthesis of (4-(6-(3-fluoropyrrolidin-1-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-methylphenyl)methanamine hydrochloride [ka] To a solution of tert-butyl (4-(6-(3-fluoropyrrolidin-1-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-methylbenzyl)carbamate (78 mg, 0.2 mmol) in MeOH (1.8 mL) was added HCl solution (1.5 mL, 1.25 M in MeOH). The reaction was heated to 50° C. and stirred at that temperature overnight. The cooled reaction was concentrated in vacuo to give the title compound (66 mg, crude) as a red solid, which was carried forward without further purification. LCMS m / z=326.1 [M+H] +

[0170] Synthesis of 3,5-(tert-butyl)-N-(4-(6-(3-fluoropyrrolidin-1-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-methylbenzyl)-1,2,4-oxadiazole-3-carboxamide trifluoroacetate [ka] The compound was prepared by the procedure described in Step 4 of Example 4 using (4-(6-(3-fluoropyrrolidin-1-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-methylphenyl)methanamine hydrochloride and potassium 5-tert-butyl-1,2, The residue was purified by preparative HPLC (Method B, 5-60%) to give the title compound as a red solid (81 mg, 67%). LCMS m / z=478.2 [M+H] + ; 1 H NMR(500MHz,DMSO-d6)δ:9.45-9.60(m,1H),8.44-8.54(m,1H),7.87-7.98(m,2H),7.44(d,1H),6.51( s,1H),5.38-5.56(m,1H),4.55(d,2H),3.40-3.70(m,4H),2.46(s,2H),2.16-2.33(m,2H),1.44(s,9H)

[0171] Example 12. 5-(tert-butyl)-N-(4-(6-(3,3-difluoropyrrolidin-1-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-methylbenzyl)-1,2,4-oxadiazole-3-carboxamide trifluoroacetate [ka] 1. Synthesis of tert-butyl (4-(6-(3,3-difluoropyrrolidin-1-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-methylbenzyl)carbamate [ka] Following the procedure described in Step 1 of Example 11, the title compound was obtained as a yellow solid (88 mg, 41%) from tert-butyl (4-(6-bromopyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-methylbenzyl)carbamate and 3,3-difluoropyrrolidine. LCMS m / z=444.2 [M+H] +

[0172] 2. Synthesis of (4-(6-(3,3-difluoropyrrolidin-1-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-methylphenyl)methanamine hydrochloride [ka] tert-Butyl (4-(6-(3,3-difluoropyrrolidin-1-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-methylbenzyl)carbamate (93 mg, 0.2 mmol) was dissolved in HCl solution (1.5 mL, 1.25 M in MeOH) and the reaction was heated to 50° C. and stirred at that temperature overnight. The reaction mixture was concentrated in vacuo to give the title compound (85 mg, crude) as a red solid that was used without further purification. LCMS m / z=344.2 [M+H] +

[0173] Synthesis of 3,5-(tert-butyl)-N-(4-(6-(3,3-difluoropyrrolidin-1-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-methylbenzyl)-1,2,4-oxadiazole-3-carboxamide trifluoroacetate [ka] The compound was obtained from (4-(6-(3,3-difluoropyrrolidin-1-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-methylphenyl)methanamine hydrochloride and potassium 5-tert-butyl-1,2,4-oxadiazole-3-carboxylate according to the procedure described in Step 4 of Example 4. The crude product was purified by preparative HPLC (Method B, 5-65%) to give the title compound as a red solid (32.5 mg, 48%). LCMS m / z=496.0 [M+H] + ; 1 H NMR(400MHz,DMSO-d6)δ:9.52(t,1H),8.50(s,1H),7.91-7.96(m,2H),7.44(d,1H),6.60(d,1H), 4.55(d,2H),3.72(t,2H),3.51(t,1H),2.51-2.60(m,2H),2.46(s,3H),2.08(s,1H),1.44(s,9H).

[0174] Example 13. 3-(tert-butyl)-N-(4-(6-(3-methoxypyrrolidin-1-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-methylbenzyl)-1,2,4-oxadiazole-5-carboxamide [ka] 1. Synthesis of tert-butyl (4-(6-(3-methoxypyrrolidin-1-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-methylbenzyl)carbamate [ka] Following the procedure described in Step 1 of Example 2, the title compound was obtained from tert-butyl (4-(6-bromopyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-methylbenzyl)carbamate and 3-methoxypyrrolidine (47 mg, 22%). LCMS m / z=438.3 [M+H] +

[0175] Synthesis of 2.4-(6-(3-methoxypyrrolidin-1-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-methylphenyl)methanamine hydrochloride [ka] HCl (4 M, 0.1 mL) was added to tert-butyl (4-(6-(3-methoxypyrrolidin-1-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-methylbenzyl)carbamate (47 mg, 0.1 mmol) in MeOH (2 mL), and the mixture was stirred at room temperature for 16 hours. The reaction was concentrated in vacuo to give the title compound (43 mg, crude), which was used in the next step without further purification.

[0176] 3. Synthesis of 3-(tert-butyl)-N-(4-(6-(3-methoxypyrrolidin-1-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-methylbenzyl)-1,2,4-oxadiazole-5-carboxamide [ka] The compound was prepared from 4-(6-(3-methoxypyrrolidin-1-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-methylphenyl)methanamine hydrochloride and potassium 5-tert-butyl-1,2,4-oxadiazole-3-carboxylate according to the procedure described in Step 4 of Example 4. The residue was purified by preparative HPLC (Method B, 5-60%) to give the title compound as a red solid (81 mg, 67%). LCMS m / z=478.2 [M+H] + ; 1 H NMR(400MHz,MeOH-d4)δ:8.25-8.34(m,1H),7.80-7.90(m,2H),7.60-7.66(m,1H),7.48-7.54(m,1H),6.32-6.39(m,1H),4.65-4.74(m,2H) ),4.12-4.21(m,1H),3.48(dd,1H),3.37-3.39(m,3H),3.34-3.36(m,1H),3.31(m,2H),2.52(s,3H),2.13-2.22(m,2H),1.48-1.52(m,9H).

[0177] Example 14. 3-(tert-butyl)-N-(2-chloro-3-fluoro-4-(6-morpholinopyrrolo[2,1-f][1,2,4]triazin-4-yl)benzyl)-1,2,4-oxadiazole-5-carboxamide trifluoroacetate [ka] Synthesis of 1,2-chloro-3-fluoro-4-iodobenzonitrile [ka] To a mixture of CuI (100 g, 526 mmol) in MeCN (455 mL) was added tert-butyl nitrite (70 mL, 526 mmol) and the brown suspension was heated to 65-66 °C (internal). A solution of 4-amino-2-chloro-3-fluorobenzonitrile (44.8 g, 263 mmol) in MeCN (385 mL) was added dropwise over 50 min, the addition funnel was washed with MeCN (400 mL), and the reaction was stirred at 65 °C for 18 h. The cooled mixture was filtered through Celite®, washing with MeCN. Filtrate was concentrated in vacuo and the resulting black solid was suspended in DCM and a small amount of MeCN, filtered through silica gel and grading from 0% to 33% EtOAc / Hept to give the title compound as a grey / brown solid (44.6 g, 60%). 1 H NMR(300MHz,CDCl3)δ:7.80(dd,1H),7.23(dd,1H).

[0178] 2. Synthesis of (2-chloro-3-fluoro-4-iodophenyl)methanamine hydrochloride [ka] A solution of BH3·Me2S in THF (119 mL, 238 mmol, 2 M) was added to a solution of 2-chloro-3-fluoro-4-iodobenzonitrile (44.6 g, 159 mmol) in THF (350 mL) over 5 min, and the reaction was stirred at 65 °C for 4 h. The reaction was quenched with MeOH (50 mL), cooled to room temperature, and concentrated in vacuo. The residue was suspended in DCM (250 mL), and the mixture was acidified with concentrated HCl solution (37%, 100 mL). The suspension was filtered off and washed with DCM and TBME. The solid was dried in vacuo, the mother liquor was concentrated in vacuo, and the residue was resuspended in DCM. The solid was filtered off and washed with DCM and TBME to give a second crop of the title compound as a pale yellow solid (total: 39.2 g, 77%). 1 H NMR(300MHz,DMSO-d6)δ:8.63(brs,3H),7.89(dd,1H),7.26(dd,1H),4.10(s,2H).

[0179] 3. Synthesis of tert-butyl (2-chloro-3-fluoro-4-iodobenzyl)carbamate [ka] EtN (78.9 mL, 566 mmol) followed by BocO (32 mL, 136 mmol) were added to a suspension of (2-chloro-3-fluoro-4-iodophenyl)methanamine hydrochloride (36.5 g, 113 mmol) in DCM (350 mL), and the reaction was stirred at room temperature for 72 h. HO (100 mL) was added, and the layers were separated. The organic layer was washed with brine (200 mL) and saturated aqueous NaHCO (200 mL). The organic layer was filtered through a fritted glass funnel (P4) and washed sequentially with water (2 × 100 mL) and brine (2 × 100 mL). The organic phase was dried (NaSO), filtered, and concentrated in vacuo to give a dark brown oil. The oil was suspended in TBME, and the precipitate was filtered off and washed with TBME. The filtrate was concentrated in vacuo to give the product as a dark brown solid (35.1 g, 80%). 1 H NMR(300MHz,CDCl3)δ:7.60(dd,1H),6.96(dd,1H),4.35(s,2H),1.44(s,9H).

[0180] 4. Synthesis of tert-butyl (2-chloro-3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)carbamate [ka] (Bis-pinacolato)diboron (27.7 g, 109 mmol) and KOAc (17.9 g, 182 mmol) were added to tert-butyl (2-chloro-3-fluoro-4-iodobenzyl)carbamate (35.1 g, 91.1 mmol), and the mixture was purged with N for 5 minutes. Pd(dppf)Cl·DCM (7.44 g, 9.11 mmol) was added, and the red suspension was stirred at 80 °C for 44 hours. The mixture was cooled to room temperature, and additional (bis-pinacolato)diboron (13.7 g, 53.8 mmol), KOAc (17.9 g, 182 mmol), and Pd(dppf)Cl·DCM (7.44 g, 9.11 mmol) were added. The mixture was stirred at 80 °C for an additional 18 hours. The cooled mixture was poured into HO (1 L) and the suspension was stirred at room temperature for 30 minutes. The mixture was extracted with DCM (500 mL + 2 × 250 mL), and the combined organic layers were washed with brine (500 mL), then filtered through Celite® and concentrated in vacuo. The solid was azeotroped with toluene (3 ×) and heptane (3 ×), and the residue was suspended in heptane and stirred for 1.5 hours. The solid was filtered off, washed with heptane, and dried to give the title compound (47.6 g, crude) as a yellow solid. 1 H NMR(300MHz,CDCl3)δ:7.58(dd,1H),7.17(d,1H),5.00(br s,1H),4.41(d,2H),1.44(s,9H),1.35(s,12H).

[0181] 5. Synthesis of (4-(6-bromopyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-chloro-3-fluorobenzyl)carbamate [ka] A mixture of tert-butyl (2-chloro-3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)carbamate (2.26 g, 5.9 mmol), K2CO3 (2.43 g, 17.6 mmol), 6-bromo-4-chloro-pyrrolo[2,1-f][1,2,4]triazine (2.72 g, 11.7 mmol), and Pd(dppf)Cl2·DCM (479 mg, 0.59 mmol) in dioxane (24 mL) and water (8 mL) was purged with N2, and the reaction was stirred at 100 °C for 18 h. The cooled mixture was diluted with EtOAc, filtered, and washed with EtOAc. The filtrate was concentrated in vacuo, and the residue was purified by silica gel column chromatography (EtOAc / Hept=5:1). The product was recrystallized from EtOAc / Hept (2:1) to give the title compound as a yellow solid (1.9 g, 64%). LCMS m / z=457.1 [M+H] +

[0182] 6. tert-Butyl (2-chloro-3-fluoro-4-(6-morpholinopyrrolo[2, Synthesis of 1-f][1,2,4]triazin-4-yl)benzyl)carbamate [ka] t-Amyl alcohol (2 mL) followed by morpholine (29 mg, 0.3 mmol) was added to a mixture of tert-butyl (4-(6-bromopyro[2,1-f][1,2,4]triazin-4-yl)-2-chloro-3-fluorobenzyl)carbamate (100 mg, 0.2 mmol), Cs2CO3 (143 mg, 0.4 mmol), Pd2(dba)3 (20 mg, 0.02 mmol), and DavePhos (17 mg, 0.04 mmol), and the reaction was purged with N2. The reaction was stirred at room temperature for 5 minutes and then at 100 °C for 18 hours. The cooled mixture was diluted with EtOAc and filtered. The filtrate was concentrated in vacuo, and the crude material was purified by silica gel column chromatography (EtOAc / Hept=1:2) to give the title compound (43 mg, 34%) as a yellow-orange semisolid. LCMS m / z=462.3[M+H] +

[0183] 7. Synthesis of (2-chloro-3-fluoro-4-(6-morpholinopyrrolo[2,1-f][1,2,4]triazin-4-yl)phenyl)methanamine [ka] To a solution of tert-butyl (2-chloro-3-fluoro-4-(6-morpholinopyrrolo[2,1-f][1,2,4]triazin-4-yl)benzyl)carbamate (43 mg, 0.07 mmol) in DCM (2 mL) was added TFA (114 mg, 0.7 mmol) and the reaction was stirred at room temperature for 18 hours. The reaction was concentrated in vacuo and the residue was dissolved in MeOH and passed through an SCX ion exchange column, flushing with MeOH followed by 2M methanolic NH3. The combined organic phases were concentrated in vacuo to give the title compound (22 mg, 59%) as an orange gum. LCMS m / z=362.0 [M+H] +

[0184] 8. Synthesis of 3-(tert-butyl)-N-(2-chloro-3-fluoro-4-(6-morpholinopyrrolo[2,1-f][1,2,4]triazin-4-yl)benzyl)-1,2,4-oxadiazole-5-carboxamide trifluoroacetate [ka] To a mixture of (2-chloro-3-fluoro-4-(6-morpholinopyrrolo[2,1-f][1,2,4]triazin-4-yl)phenyl)methanamine (65 mg, 0.18 mmol), potassium 3-(tert-butyl)-1,2,4-oxadiazole-5-carboxylate (150 mg, 0.72 mmol) in DMF (1 mL) was added DIPEA (70 mg, 0.54 mmol), cooled in an ice-water bath, and stirred for 5 min. T3P® (343 mg, 0.54 mmol, 50% solution in DMF) was added dropwise, and stirring in an ice-water bath was continued for 30 min. The reaction was allowed to warm to room temperature and stirred overnight. The reaction mixture was diluted with EtOAc and washed (NaHCO3). The aqueous phase was back-extracted with EtOAc, and the combined organics were dried (Na2SO4) and concentrated in vacuo. The residue was purified by preparative HPLC (Method B, 10-95%) to give the title compound as a red solid (7.1 mg, 6%). LCMS m / z=514.3 [M+H] + . 1 H NMR(500MHz,CDCl3)δ:8.56(s,1H),7.78(d,1H),7.68(dd,1H),7.64-7.58(m,1H),7.4 7(d,1H),6.30(t,1H),4.86(d,2H),3.91-3.87(m,4H),3.23-3.20(m,4H),1.42(s,9H).

[0185] Example 15. 5-(tert-butyl)-N-(2-chloro-4-(6-morpholinopyrrolo[2,1-f][1,2,4]triazin-4-yl)benzyl)-1,2,4-oxadiazole-3-carboxamide trifluoroacetate [ka] 1. Synthesis of tert-butyl (4-(6-bromopyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-chlorobenzyl)carbamate [ka] A mixture of tert-butyl (2-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)carbamate (2.0 g, 5.4 mmol), 6-bromo-4-chloro-pyrrolo[2,1-f][1,2,4]triazine (1.9 g, 8.2 mmol), and K2CO3 (2.3 g, 16.3 mmol) was suspended in dioxane (20 mL) and HO (2 mL), and N2 was bubbled through the mixture for 5 min. Pd(dppf)Cl2·DCM (398 mg, 0.54 mmol) was added, and the reaction was stirred at 100 °C for 2 h. The cooled reaction was diluted with EtOAc and washed with HO and brine. The aqueous layer was extracted with EtOAc, and the combined organic extracts were dried (MgSO4), filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (0-40% EtOAc / Hept), and the product was recrystallized from hexane / EtOAc (2:1) to give the title compound as an ochre solid (1.3 g, 55% yield). LCMS m / z = 437.0 [M+H] +

[0186] 2. Synthesis of tert-butyl (2-chloro-4-(6-morpholinopyrrolo[2,1-f][1,2,4]triazin-4-yl)benzyl)carbamate [ka] A mixture of tert-butyl (4-(6-bromopyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-chlorobenzyl)carbamate (1.3 g, 3.0 mmol), morpholine (388 mg, 4.5 mmol), and CsCO (1.9 g, 5.9 mmol) in dry dioxane (15 mL) was purged with N for 5 minutes. DavePhos (175 mg, 0.45 mmol) and Pd(dba) (272 mg, 0.30 mmol) were added, and the reaction was heated to 90 °C for 17 hours. The cooled mixture was diluted with EtOAc and washed with water and brine. The aqueous layer was extracted with EtOAc, and the combined organic layers were dried (MgSO), filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (0-40% EtOAc / Hept) to give the title compound as an orange solid (407 mg, 31% yield). LCMS m / z=444.2 [M+H] +

[0187] 3. Synthesis of (2-chloro-4-(6-morpholinopyrrolo[2,1-f][1,2,4]triazin-4-yl)phenyl)methanamine hydrochloride [ka] To tert-butyl (2-chloro-4-(6-morpholinopyrrolo[2,1-f][1,2,4]triazin-4-yl)benzyl)carbamate (407 mg, 0.092 mmol) in MeOH (2 mL) was added HCl (4 M, 0.5 mL), and the reaction was stirred at room temperature. The mixture was concentrated in vacuo to give the title compound (80 mg, 32%), which was used in the next step without further purification. LCMS m / z=344.2 [M+H] +

[0188] Synthesis of 4.5-(tert-butyl)-N-(2-chloro-4-(6-morpholinopyrrolo[2,1-f][1,2,4]triazin-4-yl)benzyl)-1,2,4-oxadiazole-3-carboxamide trifluoroacetate [ka] The crude product was obtained from (2-chloro-4-(6-morpholinopyrrolo[2,1-f][1,2,4]triazin-4-yl)phenyl)methanamine hydrochloride and lithium 5-(tert-butyl)-1,2,4-oxadiazole-3-carboxylate according to the procedure described in Step 8 of Example 14. The residue was purified by preparative HPLC (Method B, 10-90%) to give the title compound as a yellow solid (15 mg, 15%). LCMS m / z=496.2 [M+H] + ; 1 H NMR(500MHz,CDCl3)δ:8.48-8.42(m,1H),8.09(d,1H),7.96-7.90(m,1H),7.64(d,1H),7.59(d,1H),7 .57-7.47(m,1H),6.45(d,1H),4.84(d,2H),3.93-3.86(m,4H),3.22-3.13(m,4H),1.50-1.46(m,9H).

[0189] Example 16. 5-(tert-butyl)-N-(2-methyl-4-(2-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidin-7-yl)benzyl)-1,2,4-oxadiazole-3-carboxamide trifluoroacetate [ka] 1. Synthesis of tert-butyl tert-butyl (4-(2-bromopyrazolo[1,5-a]pyrimidin-7-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 (Example 1 of WO2015089327, 630 mg, 1.8 mmol), 2-bromo-7-chloro-pyrazolo[1,5-a]pyrimidine (842 mg, 3.6 mmol), and K2CO3 (750 mg, 5.4 mmol) was suspended in dioxane (8 mL) and water (1 mL), and N2 was bubbled through for 5 min. Pd(dppf)Cl2·DCM (132 mg, 0.18 mmol) was added, and the reaction was stirred at 100 °C for 2 h. The cooled mixture was diluted with EtOAc and water, filtered through Celite®, and the layers were separated. The aqueous layer was extracted with EtOAc, and the combined organic extracts were dried (MgSO4), filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (0-100% EtOAc / Hept) to give the title compound as a yellow solid (750 mg, 99%). LCMS m / z=417.1 [M+H] + ; 1 H NMR(500MHz,CDCl3)δ:8.53(d,1H),7.87(dd,1H),7.85-7.80(m,1H),7.51-7.45(m,1H),6.94-6.87(m,1H),6.86-6.79(m,1H),4.84(br s,1H),4.42(br d,2H),2.49-2.42(m,3H),1.53-1.48(s,9H).

[0190] 2. Synthesis of tert-butyl (2-methyl-4-(2-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidin-7-yl)benzyl)carbamate [ka] A suspension of tert-butyl (4-(2-bromopyrazolo[1,5-a]pyrimidin-7-yl)-2-methylbenzyl)carbamate (100 mg, 0.24 mmol) and (1-methylpyrazol-4-yl)boronic acid (60 mg, 0.48 mmol) in dioxane (1 mL) and HO (0.1 mL) was purged with N for 5 minutes. KCO (99 mg, 0.72 mmol) and Pd(dppf)Cl (26 mg, 0.04 mmol) were added, and the reaction was stirred at 110 °C for 2 hours. The cooled mixture was diluted with EtOAc and HO, filtered through a plug of Celite®, and the layers were separated. The aqueous layer was extracted with EtOAc, and the combined organic extracts were dried (MgSO), filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (0-100% EtOAc / Hept) to give the title compound as a yellow solid (89 mg, 89%). LCMS m / z=419.3 [M+H] + ; 1 H NMR(400MHz,CDCl3)δ:8.48(br d,1H),8.00(br d,1H),7.97(s,1H),7.94(s,1H),7.88(s,1H),7.49(d,1H),6.91-6.85(m,2H),4.86(br s,1H),4.50-4.40(m,2H),4.00(s,3H),2.47(s,3H),1.51(s,9H).

[0191] 3. Synthesis of (2-methyl-4-(2-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidin-7-yl)phenyl)methanamine hydrochloride [ka] To a solution of tert-butyl (2-methyl-4-(2-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidin-7-yl)benzyl)carbamate (85 mg, 0.2 mmol) in MeOH (1 mL) was added 4 M HCl in dioxane (0.5 mL) and the reaction was stirred at room temperature for 1 h. The reaction mixture was concentrated in vacuo to give the title compound as a yellow solid, which was carried forward without further purification. LCMS m / z=319.2 [M+H] +

[0192] 4. Synthesis of 5-(tert-butyl)-N-(2-methyl-4-(2-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidin-7-yl)benzyl)-1,2,4-oxadiazole-3-carboxamide trifluoroacetate [ka] The crude product was obtained from (2-methyl-4-(2-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidin-7-yl)phenyl)methanamine hydrochloride and lithium 5-(tert-butyl)-1,2,4-oxadiazole-3-carboxylate according to the procedure described in Step 8 of Example 14. The crude product was purified by preparative HPLC using Method B, 10-90%, to give the title compound (23 mg, 25%) as a yellow solid. LCMS m / z=471.2 [M+H] + ; 1 H NMR(500MHz,MeOH-d4)δ:8.37(d,1H),8.02(s,1H),7.92(br d,1H),7.88(s,2H),7.45(d,1H),6.93(d,1H),6.78(s,1H),4.66(s,2H),3.90(s,3H),2.45(s,3H),1.48(s,9H).

[0193] Example 17. 5-(tert-butyl)-N-(2-methyl-4-(pyrrolo[1,2-b]pyridazin-4-yl)benzyl)-1,2,4-oxadiazole-3-carboxamide [ka] 1. Synthesis of tert-butyl (2-methyl-4-(pyrrolo[1,2-b]pyridazin-4-yl)benzyl)carbamate [ka] To a solution of pyrrolo[1,2-b]pyridazin-4-ol (200 mg, 1.5 mmol) and DIPEA (385 mg, 3.0 mmol) in DCM (10 mL) cooled in an ice bath, TfO (505 mg, 1.8 mmol) was added dropwise via syringe, and the mixture was stirred at room temperature for 18 h. The mixture was diluted with DCM and washed with HO. The organic phase was dried (NaSO) and concentrated in vacuo to give pyrrolo[1,2-b]pyridazin-4-yl trifluoromethanesulfonate (400 mg, 91%) as a viscous dark liquid. Dioxane (6 mL) and HO (2 mL) were added to a mixture of pyrrolo[1,2-b]pyridazin-4-yl trifluoromethanesulfonate (400 mg, 1.5 mmol), tert-butyl (2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)carbamate (Example 1 of WO2015089327, 1.03 g, 3.0 mmol), CsCO (971 mg, 3.0 mmol), and Pd(PPh) (172 mg, 0.15 mmol) under N, and the reaction was stirred for 18 hours at 10 °C. The cooled mixture was diluted with EtOAc, and the solids were removed by filtration and washed with additional EtOAc. The combined filtrate was concentrated in vacuo and the residue was purified by silica gel column chromatography (20% EtOAc / Hept) to give the title compound as a sticky yellow gum (410 mg, 73%). LCMS m / z=338.5 [M+H] +

[0194] 2. Synthesis of (2-methyl-4-(pyrrolo[1,2-b]pyridazin-4-yl)phenyl)methanamine [ka] Following the procedure described in Step 7 of Example 14, tert-butyl (2-methyl-4-(pyrrolo[1,2-b]pyridazin-4-yl)benzyl)carbamate gave the title compound as a reddish-brown gum (220 mg, 68%). LCMS m / z=238.5 [M+H] +

[0195] Synthesis of 3.5-(tert-butyl)-N-(2-methyl-4-(pyrrolo[1,2-b]pyridazin-4-yl)benzyl)-1,2,4-oxadiazole-3-carboxamide [ka] The compound was prepared using a method similar to that described in Step 8 of Example 14 using (2-methyl-4-(pyrrolo[1,2-b]pyridazin-4-yl)phenyl)methanamine and potassium 5-(tert-butyl)-1,2,4-oxadiazole-3-carboxylate. The crude product was purified by preparative HPLC (Method C, 0-100%) to give the title compound as a yellow solid (13 mg, 13%). LCMS m / z=390.5 [M+H] + ; 1 H NMR(400MHz,CDCl3)δ:8.09(d,1H),7.84(s,1H),7.59(br s,2H),7.46(d,1H),7.2(br s,1H),6.93-6.90(m,1H),6.66(d,1H),6.54(d,1H),4.76(d,2H),2.47(s,3H),1.48(s,9H).

[0196] Example 18. 3-(tert-butyl)-N-(2-methyl-4-(pyrrolo[1,2-b]pyridazin-4-yl)benzyl)-1,2,4-oxadiazole-5-carboxamide [ka] Synthesis of 1,3-(tert-butyl)-N-(2-methyl-4-(pyrrolo[1,2-b]pyridazin-4-yl)benzyl)-1,2,4-oxadiazole-5-carboxamide [ka] The compound was prepared using a method similar to that described in Step 8 of Example 14 using (2-methyl-4-(pyrrolo[1,2-b]pyridazin-4-yl)phenyl)methanamine and potassium 3-(tert-butyl)-1,2,4-oxadiazole-5-carboxylate. The crude product was purified by preparative HPLC (Method C, 0-100%) to give the title compound as a yellow solid (3.6 mg, 3.8%). LCMS m / z=390.6 [M+H] +

[0197] Example 19. 5-(tert-butyl)-N-(4-(5-fluoropyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-methylbenzyl)-1,2,4-oxadiazole-3-carboxamide trifluoroacetate [ka] 1. Synthesis of tert-butyl (2-methyl-4-(pyrrolo[2,1-f][1,2,4]triazin-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 (1.0 g, 2.9 mmol) in 1,4-dioxane / water (v / v = 10 / 1, 66 mL) was added 4-chloropyro[2,1-f][triazine] (486 mg, 3.2 mmol), Pd(dppf)Cl (105 mg, 0.14 mmol), and KCO (796 mg, 5.8 mmol), and the mixture was stirred at 90 °C for 15 h. The mixture was concentrated in vacuo, and the residue was purified by silica gel column chromatography (petroleum ether / EtOAc = 10:1 to 8:1) to give the title compound (1.00 g, 89%) as a yellow oil. LCMS m / z = 339.1 [M+H] +

[0198] 2. Synthesis of tert-butyl (4-(5-fluoropyro[2,1-f][1,2,4]triazin-4-yl)-2-methylbenzyl)carbamate [ka] To a solution of tert-butyl (2-methyl-4-(pyrrolo[2,1-f][1,2,4]triazin-4-yl)benzyl)carbamate (600 mg, 1.8 mmol) in MeCN (30 mL) cooled in an ice bath, 1-fluoro-4-methyl-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) (1.7 g, 5.3 mmol) was added, and the reaction was stirred at room temperature for 18 h. The mixture was diluted with DCM, filtered, and washed with additional DCM. The filtrate was concentrated in vacuo, and the residue was purified by preparative HPLC method A (5-95%) to give the title compound as a yellow sticky gum (26 mg, 4% yield). LCMS m / z = 357.5 [M+H] +

[0199] 3. Synthesis of (4-(5-fluoropyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-methylphenyl)methanamine [ka] TFA (404 mg, 3.6 mmol) was added to a solution of tert-butyl (4-(5-fluoropyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-methylbenzyl)carbamate (26 mg, 0.07 mmol) in DCM (2 mL) and the reaction was stirred at room temperature for 18 hours. The reaction was concentrated in vacuo and the residue was dissolved in MeOH and flushed with MeOH followed by 2M methanolic NH3 and passed through an SCX ion exchange column. The combined organic phases were concentrated in vacuo to give the title compound (20 mg, 99%) as a sticky yellow oil. LCMS m / z=257.4 [M+H] +

[0200] 4. Synthesis of 5-(tert-butyl)-N-(4-(5-fluoropyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-methylbenzyl)-1,2,4-oxadiazole-3-carboxamide [ka] The title compound was prepared using a method similar to that described in Step 8 of Example 14 using (4-(5-fluoropyro[2,1-f][1,2,4]triazin-4-yl)-2-methylphenyl)methanamine and potassium 5-(tert-butyl)-1,2,4-oxadiazole-3-carboxylate. The crude product was purified by preparative HPLC (Method B, 5-95%) to give the title compound as a yellow solid (22 mg, 55%). LCMS m / z=409.5 [M+H] + ; 1 H NMR(400MHz,CDCl3)δ:8.51(s,1H),7.91(dd,1H),7.79-7.72(m,2H),7.54(d,1H),7.33(br d,1H),6.82(d,1H),4.79(d,2H),2.49(s,3H),1.48(s,9H).

[0201] Example 20. 2-(1,1-Difluoroethyl)-N-(2-methyl-4-(pyrrolo[2,1-f][1,2,4]triazin-4-yl)benzyl)oxazole-4-carboxamide trifluoroacetate [ka] 1. Synthesis of (2-methyl-4-(pyrrolo[2,1-f][1,2,4]triazin-4-yl)phenyl)methanamine hydrochloride [ka] To a solution of tert-butyl (2-methyl-4-(pyrrolo[2,1-f][1,2,4]triazin-4-yl)benzyl)carbamate (1 g, 2.6 mmol) in DCM (20 mL) was added HCl solution (10 mL, 4 M in EtOAc) and the reaction was stirred at room temperature for 1 h. The mixture was filtered and the solid was dried in vacuo to give the title compound (710 mg, 99%) as a yellow solid. LCMS m / z=239.0 [M+H] +

[0202] 2. Synthesis of lithium 2-(1,1-difluoroethyl)oxazole-4-carboxylate [ka] The title compound was obtained from ethyl 2-(1,1-difluoroethyl)oxazole-4-carboxylate and LiOH following a procedure similar to that described in Step 3 of Example 2. The crude product was carried forward without further purification.

[0203] 3. Synthesis of 2-(1,1-difluoroethyl)-N-(2-methyl-4-(pyrrolo[2,1-f][1,2,4]triazin-4-yl)benzyl)oxazole-4-carboxamide trifluoroacetate [ka] The title compound was prepared using a method similar to that described in Step 8 of Example 14 using (2-methyl-4-(pyrrolo[2,1-f][1,2,4]triazin-4-yl)phenyl)methanamine hydrochloride and lithium 2-(1,1-difluoroethyl)oxazole-4-carboxylate. The compound was purified by preparative HPLC (Method B, 10-95%) to give the title compound as a yellow solid (8.5 mg, 9%). LCMS m / z=398.5 [M+H] + ; 1H NMR(400MHz,CDCl3)δ:8.66(s,1H),8.36(s,1H),8.15(dd,1H),7.89-7.83(m,2H),7 .56(d,1H),7.38-7.30(m,2H),7.22(dd,1H),4.75(d,2H),2.50(s,3H),2.11(t,3H).

[0204] Example 21. 5-(tert-butyl)-N-(4-(imidazo[1,2-b]pyridazin-8-yl)-2-methylbenzyl)-1,2,4-oxadiazole-3-carboxamide trifluoroacetate [ka] 1. Synthesis of tert-butyl (4-(6-chloroimidazo[1,2-b]pyridazin-8-yl)-2-methylbenzyl)carbamate [ka] Dioxane (3 mL) and HO (1 mL) were added to a mixture of 8-bromo-6-chloroimidazo[1,2-b]pyridazine (232 mg, 1.0 mmol), tert-butyl (2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)carbamate (Example 1 of WO2015089327, 347 mg, 1.0 mmol), KCO (553 mg, 4.0 mmol), and Pd(dppf)Cl·DCM (82 mg, 0.10 mmol) under N, and the reaction was stirred at room temperature for 5 min and then at 95 °C for 14 h. The cooled mixture was diluted with EtOAc, filtered, and washed with additional EtOAc. The filtrate was concentrated in vacuo and the residue was purified by silica gel column chromatography (EtOAc / Hept, 1:1) to give the title compound as a yellow gum (360 mg, 87%). LCMS m / z=373.2 [M+H] +

[0205] 2. Synthesis of tert-butyl (4-(imidazo[1,2-b]pyridazin-8-yl)-2-methylbenzyl)carbamate [ka] To a solution of tert-butyl (4-(6-chloroimidazo[1,2-b]pyridazin-8-yl)-2-methylbenzyl)carbamate (100 mg, 0.27 mmol) in MeOH (10 mL) was added 10% Pd / C (57 mg, 0.05 mmol) and stirred under an atmosphere of H for 5 days. The reaction mixture was filtered and washed with MeOH. The filtrate was concentrated in vacuo and the residue was purified by silica gel column chromatography (EtOAc / Hept, 1:1) to give the title compound (55 mg, 30%) as a yellow gum. LCMS m / z=339.2 [M+H] +

[0206] 3. Synthesis of (4-(imidazo[1,2-b]pyridazin-8-yl)-2-methylphenyl)methanamine [ka] TFA (909 mg, 8.0 mmol) was added to a solution of tert-butyl (4-(imidazo[1,2-b]pyridazin-8-yl)-2-methylbenzyl)carbamate (50 mg, 0.4 mmol) in DCM (5 mL) and the reaction was stirred at room temperature for 5 days. The reaction was concentrated in vacuo and the residue was dissolved in MeOH and flushed with MeOH followed by 2M methanolic NH3 and passed through an SCX ion exchange column. The combined organic phases were concentrated in vacuo to give the title compound as a sticky yellow-orange gum (53 mg, 50%). LCMS m / z=239.2 [M+H] +

[0207] Synthesis of 4.5-(tert-butyl)-N-(4-(imidazo[1,2-b]pyridazin-8-yl)-2-methylbenzyl)-1,2,4-oxadiazole-3-carboxamide trifluoroacetate [ka] The title compound was prepared using a method similar to that described in Step 8 of Example 14, using (4-(imidazo[1,2-b]pyridazin-8-yl)-2-methylphenyl)methanamine and potassium 5-(tert-butyl)-1,2,4-oxadiazole-3-carboxylate. The compound was purified by preparative HPLC (Method B, 5-95%) to give the title compound as a yellow solid (21.6 mg, 18%). LCMS m / z=391.3 [M+H] + ; 1 H NMR(400MHz,DMSO-d6)δ:9.49(t,1H),8.65(d,1H),8.43(d,1H),8.11(s,1H),8.08-8.0 4(m,1H),7.94(d,1H),7.55(d,1H),7.43(d,1H),4.53(d,2H),2.44(s,3H),1.43(s,9H).

[0208] Example 22. 5-(tert-butyl)-N-(2-methyl-4-(2-morpholinopyrazolo[1,5-a]pyrimidin-7-yl)benzyl)-1,2,4-oxadiazole-3-carboxamide [ka] 1. Synthesis of tert-butyl tert-butyl (4-(2-bromopyrazolo[1,5-a]pyrimidin-7-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 (Example 1 of WO2015089327, 630 mg, 1.8 mmol), 2-bromo-7-chloro-pyrazolo[1,5-a]pyrimidine (842 mg, 3.6 mmol), and K2CO3 (750 mg, 5.4 mmol) was suspended in dioxane (8 mL) and water (1 mL) and degassed with N2 for 5 minutes. Pd(dppf)Cl2 (132 mg, 0.18 mmol) was added, and the reaction was stirred at 100 °C for 2 hours. The cooled mixture was diluted with EtOAc and water, filtered through Celite®, and the layers were separated. The aqueous layer was extracted with EtOAc, and the combined organic extracts were dried (MgSO4), filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (0-100% EtOAc / Hept) to give the title compound as a yellow solid (750 mg, 99%). 1 H NMR(500MHz,CDCl3)δ:8.53(d,1H),7.87(dd,1H),7.85-7.80(m,1H),7.51-7.45(m,1H),6.94-6.87(m,1H),6.86-6.79(m,1H),4.84(br s,1H),4.42(br d,2H),2.49-2.42(m,3H),1.53-1.48(s,9H).LCMS m / z=417.1[M+H] +

[0209] 2. Synthesis of tert-butyl (2-methyl-4-(2-morpholinopyrazolo[1,5-a]pyrimidin-7-yl)benzyl)carbamate [ka] Following the procedure described in Step 1 of Example 13, the title compound was obtained as an orange solid (79 mg, 55%) from tert-butyl (4-(2-bromopyrazolo[1,5-a]pyrimidin-7-yl)-2-methylbenzyl)carbamate and morpholine. LCMS m / z=424.2 [M+H] + ; 1H NMR(500MHz,CDCl3)δ:8.34(d,1H),7.97(d,1H),7.90(s,1H),7.44(d,1H),6.73(d,1H),6.09(s,1H),4.84(br s,1H),4.42(br d,2H),3.89-3.84(m,4H),3.46-3.38(m,4H),2.47-2.41(s,3H),1.52-1.47(s,9H).

[0210] 3. Synthesis of (2-methyl-4-(2-morpholinopyrazolo[1,5-a]pyrimidin-7-yl)phenyl)methanamine hydrochloride [ka] The title compound was obtained as an orange solid from tert-butyl (2-methyl-4-(2-morpholinopyrazolo[1,5-a]pyrimidin-7-yl)benzyl)carbamate according to the procedure described in Step 3 of Example 16. The crude material was carried forward without further purification. LCMS m / z=324.2 [M+H] +

[0211] 4. Synthesis of 5-(tert-butyl)-N-(2-methyl-4-(2-morpholinopyrazolo[1,5-a]pyrimidin-7-yl)benzyl)-1,2,4-oxadiazole-3-carboxamide [ka] The title compound was prepared using a method similar to that described in Step 8 of Example 14, using (2-methyl-4-(2-morpholinopyrazolo[1,5-a]pyrimidin-7-yl)phenyl)methanamine hydrochloride and lithium 5-(tert-butyl)-1,2,4-oxadiazole-3-carboxylate. The crude material was purified by silica gel column chromatography (0-100% EtOAc / Hept) to afford the title compound as a yellow solid (60 mg, 46% over two steps). LCMS m / z=476.2 [M+H] + ; 1H NMR(500MHz,CDCl3)δ:8.33(d,1H),8.00(dd,1H),7.92(s,1H),7.50(d,1H),7.20(br s,1H),6.74(d,1H),6.12(s,1H),4.76(d,2H),3.87-3.82(m,4H),3.45-3.38(m,4H),2.48(s,3H),1.51-1.45(m,9H).

[0212] Example 23 and Example 24. (S)-3-(tert-butyl)-N-(4-(6-(3-methoxypyrrolidin-1-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-methylbenzyl)-1,2,4-oxadiazole-5-carboxamide and (R)-3-(tert-butyl)-N-(4-(6-(3-methoxypyrrolidin-1-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-methylbenzyl)-1,2,4-oxadiazole-5-carboxamide [ka] 1. Synthesis of (S)-3-(tert-butyl)-N-(4-(6-(3-methoxypyrrolidin-1-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-methylbenzyl)-1,2,4-oxadiazole-5-carboxamide (Example 23) and (R)-3-(tert-butyl)-N-(4-(6-(3-methoxypyrrolidin-1-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-methylbenzyl)-1,2,4-oxadiazole-5-carboxamide (Example 24) [ka] 3-(tert-butyl)-N-(4-(6-(3-methoxypyrrolidin-1-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-methylbenzyl)-1,2,4-oxadiazole-5-carboxamide (Example 13, 65 mg) was purified by chiral SFC (CHIRALPAK AD-H 30 × 250 mm, 5 μm, 30% IPA + 0.1% DEA) in CO to give the title compound. The absolute stereochemical configuration was arbitrarily assigned.

[0213] Example 23, Peak 1: (S)-3-(tert-butyl)-N-(4-(6-(3-methoxypyrrolidin-1-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-methylbenzyl)-1,2,4-oxadiazole-5-carboxamide (4.4 mg). LCMS m / z=490.3 [M+H] + ; 1 H NMR(400MHz,MeOH-d4)δ:8.25-8.34(m,1H),7.80-7.90(m,2H),7.60-7.66(m,1H),7.48-7.54(m,1H),6.32-6.39(m,1H),4.65-4.74(m,2H) ),4.12-4.21(m,1H),3.48(dd,1H),3.37-3.39(m,3H),3.34-3.36(m,1H),3.31(m,2H),2.52(s,3H),2.13-2.22(m,2H),1.48-1.52(m,9H).

[0214] Example 24, Peak 2: (R)-3-(tert-butyl)-N-(4-(6-(3-methoxypyrrolidin-1-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-methylbenzyl)-1,2,4-oxadiazole-5-carboxamide (5.9 mg). LCMS m / z=490.3 [M+H] + ; 1H NMR(400MHz,MeOH-d4)δ:8.26-8.33(m,1H),7.81-7.89(m,2H),7.59-7.64(m,1H),7.46-7.54(m,1H),6.30-6.40(m,1H),4.70(s,2H),4.16(br s,1H),3.44-3.53(m,1H),3.37-3.39(m,3H),3.34-3.36(m,1H),3.27-3.32(m,2H),2.51(s,3H),2.13-2.20(m,2H),1.49-1.52(m,9H).

[0215] Example 25 and Example 26. (R)-3-(tert-butyl)-N-(4-(6-(3,4-dimethylpiperazin-1-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-3-fluoro-2-methylbenzyl)-1,2,4-oxadiazole-5-carboxamide and (S)-3-(tert-butyl)-N-(4-(6-(3,4-dimethylpiperazin-1-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-3-fluoro-2-methylbenzyl)-1,2,4-oxadiazole-5-carboxamide [ka] Synthesis of 1,4-bromo-2-fluoro-3-methylaniline [ka] A solution of NBS (28.4 g, 160 mmol) in DCM was added dropwise to an ice-cold solution of 2-fluoro-3-methylaniline (20.0 g, 160 mmol) in DCM (200 mL), and the reaction was stirred at 20 °C for 5 h. The mixture was diluted with saturated aqueous Na2CO3 (100 mL), the layers were separated, and the aqueous phase was extracted with DCM (2 x 100 mL). The combined organic layers were dried (Na2SO4), filtered, and concentrated in vacuo. The crude product was purified by silica gel column chromatography (petroleum ether / EtOAc = 10:1) to give the title compound (32.0 g, crude) as a brown oil. LCMS m / z = 205.8 [M+H] +

[0216] Synthesis of 2,4-amino-3-fluoro-2-methylbenzonitrile [ka] CuCN (35.6 g, 397 mmol) was added to a solution of 4-bromo-2-fluoro-3-methylaniline (27 g, 132 mmol) in DMF (200 mL) under N and the reaction was stirred at 140 °C for 16 h. NH·HO (300 mL) was added to the cooled reaction, the mixture was filtered to remove solids, and the filtrate was poured into HO (300 mL) and extracted with EtOAc (2 × 300 mL). The aqueous phase was extracted with EtOAc (2 × 300 mL), and the combined organic layers were dried (NaSO), filtered, and concentrated in vacuo. The crude product was purified by silica gel column chromatography (petroleum ether / EtOAc = 70:30) to give the title compound (15 g, 75% yield) as a brown oil. LCMS m / z = 151.0 [M+H] +

[0217] Synthesis of 3,4-bromo-3-fluoro-2-methylbenzonitrile [ka] A solution of 4-amino-3-fluoro-2-methylbenzonitrile (15 g, 100 mmol) in MeCN (250 mL) was stirred with a solution of tert-butyl nitrite (17.8 mL, 150 mmol) and CuBr (21.5 g, 150 mmol) in MeCN under N at 65° C. for 3 h. The cooled mixture was filtered, the filtrate was concentrated in vacuo, and the crude product was purified by silica gel column chromatography (petroleum ether / EtOAc=9:1) to give the title compound (11.5 g, crude) as an orange solid. 1 H NMR(400MHz,CDCl3)δ:7.51(dd,1H),7.28(dd,1H),2.52(s,3H).

[0218] 4. Synthesis of tert-butyl (4-bromo-3-fluoro-2-methylbenzyl)carbamate [ka] To a solution of (4-bromo-3-fluoro-2-methylphenyl)methanamine (14 g, 64 mmol) in DCM (100 mL) was added EtN (13 g, 128 mmol) and BocO (16.8 g, 77 mmol), and the mixture was stirred for 2 h at 25° C. The mixture was concentrated in vacuo, and the residue was purified by silica gel column chromatography (petroleum ether / EtOAc = 50:1) to give the title compound (12.0 g, 59%) as a white solid. 1 H NMR(400MHz,DMSO-d6)δ:7.47(dd,1H),7.37(dd,1H),6.96(d,1H),4.07(d,2H),2.19(d,3H),1.37(s,9H).

[0219] 5. Synthesis of tert-butyl (3-fluoro-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-3-fluoro-2-methylbenzyl)carbamate (10 g, 31 mmol) in dioxane (150 mL) was added (bispinacolato)diboron (9.6 g, 38 mmol) and KOAc (6.2 g, 63 mmol). Pd(dppf)Cl·DCM (2.1 g, 2.5 mmol) was added, and the reaction was stirred at 80° C. under N for 17 h. The reaction mixture was concentrated in vacuo, and the crude material was purified by silica gel column chromatography (petroleum ether / EtOAc = 20:1) to give the title compound as a yellow solid (13.0 g, crude). LCMS m / z = 310.1 [M-tBu+H] +

[0220] 6. Synthesis of (4-(6-bromopyrrolo[2,1-f][1,2,4]triazin-4-yl)-3-fluoro-2-methylbenzyl)carbamate [ka] A mixture of tert-butyl (3-fluoro-2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)carbamate (786 mg, 2.2 mmol), 6-bromo-4-chloro-pyrrolo[2,1-f][1,2,4]triazine (1.0 g, 4.3 mmol), Pd(dppf)Cl (157 mg, 0.2 mmol), and KCO (891 mg, 6.5 mmol) in dioxane (8 mL) and HO (0.8 mL) was degassed and heated to 95 °C for 16 h. The cooled mixture was filtered through Celite®, and the filtrate was concentrated in vacuo. The crude product was purified by silica gel column chromatography (0–100% EtOAc / Hept) to give the title compound (960 mg, 100%) as a red solid. LCMS m / z=437.1[M+H] +

[0221] 7. Synthesis of tert-butyl (4-(6-(3,4-dimethylpiperazin-1-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-3-fluoro-2-methylbenzyl)carbamate [ka] The title compound was obtained from tert-butyl (4-(6-bromopyrrolo[2,1-f][1,2,4]triazin-4-yl)-3-fluoro-2-methylbenzyl)carbamate and 1,2-dimethylpiperazine according to the procedure described in Step 1 of Example 13. The residue was purified by silica gel column chromatography (0-30% MeOH / DCM) to give the title compound (73 mg, 34%). LCMS m / z=469.3 [M+H] +

[0222] 8. Synthesis of (4-(6-(3,4-dimethylpiperazin-1-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-3-fluoro-2-methylphenyl)methanamine trifluoroacetate 100233-331 [ka] A solution of tert-butyl (4-(6-(3,4-dimethylpiperazin-1-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-3-fluoro-2-methylbenzyl)carbamate (73 mg, 0.16 mmol) and TFA (0.5 mL) in DCM (1.50 mL) was stirred at room temperature for 16 h. The mixture was concentrated in vacuo to give the title compound, which was carried forward without further purification. LCMS m / z=369.2 [M+H] +

[0223] 9. Synthesis of 3-(tert-butyl)-N-(4-(6-(3,4-dimethylpiperazin-1-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-3-fluoro-2-methylbenzyl)-1,2,4-oxadiazole-5-carboxamide [ka] A mixture of (4-(6-(3,4-dimethylpiperazin-1-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-3-fluoro-2-methylphenyl)methanamine trifluoroacetate (131 mg, 0.36 mmol), potassium 3-(tert-butyl)-1,2,4-oxadiazole-5-carboxylate (89 mg, 0.43 mmol), HATU (163 mg, 0.43 mmol), and DIPEA (184 mg, 1.4 mmol) in DCM (2 mL) was stirred at room temperature for 16 hours. The crude product was filtered through Celite®, and the filtrate was concentrated in vacuo. The crude product was purified by silica gel column chromatography (0-30% MeOH / DCM) to give the title compound (130 mg, 70%). LCMS m / z=521.3 [M+H] +

[0224] 10. Synthesis of (R)-3-(tert-butyl)-N-(4-(6-(3,4-dimethylpiperazin-1-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-3-fluoro-2-methylbenzyl)-1,2,4-oxadiazole-5-carboxamide and (S)-3-(tert-butyl)-N-(4-(6-(3,4-dimethylpiperazin-1-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-3-fluoro-2-methylbenzyl)-1,2,4-oxadiazole-5-carboxamide [ka] 3-(tert-Butyl)-N-(4-(6-(3,4-dimethylpiperazin-1-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-3-fluoro-2-methylbenzyl)-1,2,4-oxadiazole-5-carboxamide (130 mg) was purified by chiral SFC (CHIRALPAK AD-H 30 × 250 mm, 5 μm, 30% EtOH + 0.1% DEA) in CO to give the title compound.

[0225] Example 25, Peak 1: (R)-3-(tert-butyl)-N-(4-(6-(3,4-dimethylpiperazin-1-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-3-fluoro-2-methylbenzyl)-1,2,4-oxadiazole-5-carboxamide (3.7 mg, 2.7%). LCMS m / z=521.3 [M+H] + ; 1 H NMR(400MHz,MeOH-d4)δ:8.35(s,1H),7.85(d,1H),7.54(t,1H),7.36(d,1H),6.30(t,1H),4.70(s,2H),3.43-3.60(m,2 H),2.86-3.00(m,3H),2.51-2.60(m,1H),2.44-2.49(m,1H),2.42(d,3H),2.35(s,3H),1.38-1.48(m,9H),1.17(d,3H).

[0226] Example 26, Peak 2: (S)-3-(tert-butyl)-N-(4-(6-(3,4-dimethylpiperazin-1-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-3-fluoro-2-methylbenzyl)-1,2,4-oxadiazole-5-carboxamide (4.8 mg, 3.5%). LCMS m / z=521.3 [M+H] + ; 1 H NMR(400MHz,MeOH-d4)δ:8.33-8.38(m,1H),7.82-7.89(m,1H),7.51-7.59(m,1H),7.32-7.41(m,1H),6.25-6.33(m,1H),4.67-4.73(m,2H), 3.46-3.59(m,2H),2.88-2.99(m,2H),2.52-2.59(m,1H),2.44-2.50(m ,1H),2.40-2.43(m,3H),2.36(s,3H),1.43(s,9H),1.15-1.19(m,3H).

[0227] Example 27 and Example 28. (R)-3-(tert-butyl)-N-(4-(6-(3,4-dimethylpiperazin-1-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-methylbenzyl)-1,2,4-oxadiazole-5-carboxamide and (S)-3-(tert-butyl)-N-(4-(6-(3,4-dimethylpiperazin-1-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-methylbenzyl)-1,2,4-oxadiazole-5-carboxamide [ka] 1. Synthesis of tert-butyl (4-(6-(3,4-dimethylpiperazin-1-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-methylbenzyl)carbamate [ka] The crude product was obtained from tert-butyl (4-(6-bromopyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-methylbenzyl)carbamate and 1,2-dimethylpiperazine according to the procedure described in Step 1 of Example 2. The crude product was purified by silica gel column chromatography (0-30% MeOH / DCM) to give the title compound (265 mg, crude), which was used without further purification. LCMS m / z=451.2 [M+H] +

[0228] 2. Synthesis of (4-(6-(3,4-dimethylpiperazin-1-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-methylphenyl)methanamine hydrochloride [ka] The title compound was obtained from tert-butyl (4-(6-(3,4-dimethylpiperazin-1-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-methylbenzyl)carbamate according to the procedure described in Step 3 of Example 16 (230 mg, crude). LCMS m / z=351.1 [M+H] +

[0229] 3. Synthesis of 3-(tert-butyl)-N-(4-(6-(3,4-dimethylpiperazin-1-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-methylbenzyl)-1,2,4-oxadiazole-5-carboxamide [ka] The compound was obtained from (4-(6-(3,4-dimethylpiperazin-1-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-methylphenyl)methanamine hydrochloride and 3-(tert-butyl)-1,2,4-oxadiazole-5-carboxylate according to the procedure described in Step 4 of Example 4. The residue was purified by silica gel column chromatography (0-30% MeOH / DCM) to give the title compound (25 mg, 29%). LCMS m / z=503.2 [M+H] +

[0230] 4. Synthesis of (R)-3-(tert-butyl)-N-(4-(6-(3,4-dimethylpiperazin-1-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-methylbenzyl)-1,2,4-oxadiazole-5-carboxamide and (S)-3-(tert-butyl)-N-(4-(6-(3,4-dimethylpiperazin-1-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-methylbenzyl)-1,2,4-oxadiazole-5-carboxamide [ka] 3-(tert-Butyl)-N-(4-(6-(3,4-dimethylpiperazin-1-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-methylbenzyl)-1,2,4-oxadiazole-5-carboxamide (20 mg) was purified by chiral SFC (CHIRALPAK IA 30 × 250 mm, 5 μm, 40% MeOH + 0.1% DEA) in CO to give the title compound.

[0231] Example 27, Peak 1: (R)-3-(tert-butyl)-N-(4-(6-(3,4-dimethylpiperazin-1-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-methylbenzyl)-1,2,4-oxadiazole-5-carboxamide (7.8 mg, 37%). LCMS m / z=504.3 [M+H] + ; 1H NMR(400MHz,MeOH-d4)δ:8.29-8.40(m,1H),7.75-7.92(m,3H),7.53(d,1H),6.61(d,1H),4.70(s,2H),3. 45-3.63(m,2H),2.73-3.01(m,3H),2.42-2.62(m,5H),2.28-2.39(m,4H),1.38-1.48(m,9H),1.19(d,3H).

[0232] Example 28, Peak 2: (S)-3-(tert-butyl)-N-(4-(6-(3,4-dimethylpiperazin-1-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-methylbenzyl)-1,2,4-oxadiazole-5-carboxamide (7.6 mg, 36%). LCMS m / z=504.3 [M+H] + ; 1 H NMR(400MHz,MeOH-d4)δ:8.30-8.39(m,1H),7.76-7.90(m,3H),7.49-7.56(m,1H),6.62(br s,1H),4.70(s,2H),3.48-3.61(m,2H),2.86-3.01(m,2H),2.80(br s,1H),2.45-2.63(m,5H),2.24-2.39(m,4H),1.40-1.45(m,9H),1.19(br d,3H).

[0233] Example 29 and Example 30. (S)-5-(tert-butyl)-N-(2-methyl-4-(6-(2-methylmorpholino)pyrrolo[2,1-f][1,2,4]triazin-4-yl)benzyl)-1,2,4-oxadiazole-3-carboxamide and (R)-5-(tert-butyl)-N-(2-methyl-4-(6-(2-methylmorpholino)pyrrolo[2,1-f][1,2,4]triazin-4-yl)benzyl)-1,2,4-oxadiazole-3-carboxamide 1. Synthesis of tert-butyl (2-methyl-4-(6-(2-methylmorpholino)pyrrolo[2,1-f][1,2,4]triazin-4-yl)benzyl)carbamate [ka] Using a method similar to that described in Step 1 of Example 5, the title compound was prepared from tert-butyl (4-(6-bromopyro[2,1-f][1,2,4]triazin-4-yl)-2-methylbenzyl)carbamate and 2-methylmorpholine as a yellow solid (184 mg, 35%). LCMS m / z=438.2 [M+H] +

[0234] 2. Synthesis of (2-methyl-4-(6-(2-methylmorpholino)pyrrolo[2,1-f][1,2,4]triazin-4-yl)phenyl)methanamine hydrochloride [ka] The title compound was prepared from tert-butyl (2-methyl-4-(6-(2-methylmorpholino)pyrrolo[2,1-f][1,2,4]triazin-4-yl)benzyl)carbamate using a similar method as described in Step 2 of Example 5, and obtained as a red solid (168 mg, crude). LCMS m / z=338.2 [M+H] +

[0235] Synthesis of 3.5-(tert-butyl)-N-(2-methyl-4-(6-(2-methylmorpholino)pyrrolo[2,1-f][1,2,4]triazin-4-yl)benzyl)-1,2,4-oxadiazole-3-carboxamide. [ka] To a solution of (2-methyl-4-(6-(2-methylmorpholino)pyrrolo[2,1-f][1,2,4]triazin-4-yl)phenyl)methanamine hydrochloride (40 mg, 0.12 mmol) and ethyl 5-tert-butyl-1,2,4-oxadiazole-3-carboxylate (35 mg, 0.18 mmol) in THF (1.2 mL) at room temperature was added DABAL-Me3 (46 mg, 0.18 mmol). The reaction mixture was heated at 45° C. overnight. The reaction mixture was diluted with MeOH, filtered, and concentrated in vacuo. The residue was redissolved in MeOH, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (0-100% EtOAc / Hept) to give the title compound (26 mg, 45%) as a yellow solid. LCMS m / z=490 [M+H] +

[0236] 4. Synthesis of (S)-5-(tert-butyl)-N-(2-methyl-4-(6-(2-methylmorpholino)pyrrolo[2,1-f][1,2,4]triazin-4-yl)benzyl)-1,2,4-oxadiazole-3-carboxamide and (R)-5-(tert-butyl)-N-(2-methyl-4-(6-(2-methylmorpholino)pyrrolo[2,1-f][1,2,4]triazin-4-yl)benzyl)-1,2,4-oxadiazole-3-carboxamide [ka] The title compound was obtained by chiral SFC (Chiralpak AD-H, 30 × 250 mm, 5 μm, 0.1% DEA in 40% IPA+CO) purification of 5-(tert-butyl)-N-(2-methyl-4-(6-(2-methylmorpholino)pyrrolo[2,1-f][1,2,4]triazin-4-yl)benzyl)-1,2,4-oxadiazole-3-carboxamide.

[0237] Example 29, Peak 1: (S)-5-(tert-butyl)-N-(2-methyl-4-(6-(2-methylmorpholino)pyrrolo[2,1-f][1,2,4]triazin-4-yl)benzyl)-1,2,4-oxadiazole-3-carboxamide (12 mg). LCMS m / z=490.2 [M+H] + ; 1 H NMR(500MHz,DMSO-d6)δ:9.59-9.44(m,1H),8.64(br d,1H),8.55(s,1H),8.46(s,1H),7.97(br d,1H),7.87-7.95(m,2H),7.39(br d,1H),6.71(br d,1H),4.50(br d,2H),3.89(br d,1H),3.59-3.71(m,3H),3.51(br d,1H),2.70(br dd,2H),2.44(s,3H),2.34-2.37(m,1H),1.37(s,9H),1.15(br d,3H).

[0238] Example 30, Peak 2: (R)-5-(tert-butyl)-N-(2-methyl-4-(6-(2-methylmorpholino)pyrrolo[2,1-f][1,2,4]triazin-4-yl)benzyl)-1,2,4-oxadiazole-3-carboxamide (12 mg). LCMS m / z=490.2 [M+H] + ; 1 H NMR(500MHz,DMSO-d6)δ:9.51(t,1H),8.47(s,1H),7.98(d,1H),7.88-7.95(m,2H),7.42(d,1H),6.72(d,1H),4.54(d,2H),3.90(br d,1H),3.59-3.72(m,3H),3.52(br d,1H),2.65-2.76(m,1H),2.45(s,3H),2.38-2.43(m,1H),1.44(s,9H),1.15(d,3H)

[0239] Example 31 (R)-5-(tert-butyl)-N-(1-(3-fluoro-2-methyl-4-(6-morpholinopyrrolo[2,1-f][1,2,4]triazin-4-yl)phenyl)ethyl)-1,2,4-oxadiazole-3-carboxamide [ka] 1. Synthesis of (S,E)-N-(1-(4-bromo-3-fluoro-2-methylphenyl)ethylidene)-2-methylpropane-2-sulfinamide [ka] (S)-2-Methylpropane-2-sulfinamide (22.6 g, 186 mmol) and Ti(OEt) (46.8 g, 205 mmol) were added to a solution of 1-(4-bromo-3-fluoro-2-methylphenyl)ethan-1-one (WO2015124877, 21.6 g, 93 mmol) in THF (400 mL), and the reaction was stirred at 75 °C for 24 h. The cooled reaction mixture was concentrated in vacuo to reduce the volume to one-third, and then the mixture was filtered through a short silica pad, eluting with Hept / EtOAc (4:1 to 1:1) to give the title compound (28.0 g, 89%) as a beige oil, which was used without further purification.

[0240] 2. Synthesis of (S)-N-((R)-1-(4-bromo-3-fluoro-2-methylphenyl)ethyl)-2-methylpropane-2-sulfinamide [ka] To a solution of (S,E)—N-(1-(4-bromo-3-fluoro-2-methylphenyl)ethylidene)-2-methylpropane-2-sulfinamide (28.0 g, 84 mmol) in THF (575 mL) cooled to −60° C. under N was added L-selectride (251 mL, 251 mmol) slowly to maintain an internal temperature below −55° C. The reaction mixture was allowed to warm to room temperature over 3.5 h, MeOH (70 mL) was added slowly, and the mixture was stirred for 15 min. The reaction was cooled to −30° C., and hydrogen peroxide (66.0 mL, 754 mmol) and NaOH (30.1 g, 754 mmol) in HO (100 mL) were added slowly. The mixture was then stirred at room temperature for 3 days. The mixture was diluted with EtOAc (1 L), washed with saturated aqueous NaSO (3 x 500 mL), dried (NaSO), filtered, and concentrated in vacuo. The crude product was purified by silica gel column chromatography (30% EtOAc / DCM) to give the title product (22 g, 78%) as a white solid. 1 H NMR(300MHz,DMSO-d6)δ:7.51(dd,1H),7.16(dd,1H),5.40(d,1H),4.59-4.55(m,1H),2.24(d,3H),1.40(d,3H),1.07(s,9H)

[0241] 3. Synthesis of (R)-1-(4-bromo-3-fluoro-2-methylphenyl)ethan-1-amine hydrochloride [ka] To a solution of (S)—N—((R)-1-(4-bromo-3-fluoro-2-methylphenyl)ethyl)-2-methylpropane-2-sulfinamide (20.9 g, 62.2 mmol) in dioxane (125 mL) was added 4 N HCl in dioxane (0.2 L, 622 mmol) and the reaction was stirred at room temperature for 1 hour. The reaction mixture was concentrated in vacuo and azeotroped with toluene. The residue was triturated with EtO, the resulting suspension was filtered, and the solid was dried in vacuo to give the title compound (16.5 g, 99%) as a white solid. 1H NMR(300MHz,DMSO-d6)δ:8.65(brs,3H),7.63(dd,1H),7.39(dd,1H),4.54-4.52(m,1H),2.28(d,3H),1.45(d,3H).

[0242] 4. Synthesis of tert-butyl (R)-1-(4-bromo-3-fluoro-2-methylphenyl)ethyl)carbamate [ka] EtN (12.4 g, 123 mmol) and BocO (16.1 g, 92.2 mmol) were added to an ice-cold solution of (R)-1-(4-bromo-3-fluoro-2-methylphenyl)ethan-1-amine hydrochloride (16.5 g, 61.4 mmol) in DCM (275 mL), and the reaction was stirred at room temperature for 3 days. The reaction mixture was diluted with DCM (500 mL) and washed with water (300 mL). The organic layer was dried (NaSO), filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (20% EtOAc / Hept) to give the title product (18.9 g, 92%) as a white-beige solid. 1 H NMR(300MHz,DMSO-d6)δ:7.49(dd,1H),7.10(dd,1H),4.77-4.72(m,1H),2.24(d,3H),1.32(s,9H).

[0243] 5. Synthesis of tert-butyl (R)-1-(3-fluoro-2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)carbamate [ka] To a solution of tert-butyl (R)-1-(4-bromo-3-fluoro-2-methylphenyl)ethyl)carbamate (18.9 g, 57 mmol) and (bispinacolato)diboron (20.2 g, 80 mmol) in DMSO (220 mL) was added KOAc (16.7 g, 171 mmol) and Pd(dppf)Cl·DCM (2.32 g, 2.8 mmol). The reaction was degassed with N for 10 minutes and then stirred at 90 °C overnight. The cooled reaction was diluted with TBME (1 L) and filtered through Celite®. The filtrate was washed with water (3 × 500 mL), then dried (NaSO), filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (20% EtOAc / Hept) to give the title product (16.4 g, 76%) as a beige oil. 1 H NMR(300MHz,DMSO-d6)δ:7.41(dd,1H),7.16(dd,1H),4.80-4.75(m,1H),2.16(s,3H),1.32-1.20(m,15H).

[0244] 6. Synthesis of tert-butyl (R)-(1-(4-(6-bromopyrrolo[2,1-f][1,2,4]triazin-4-yl)-3-fluoro-2-methylphenyl)ethyl)carbamate [ka] A mixture of tert-butyl (R)-1-(3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)carbamate (569 mg, 1.5 mmol), 6-bromo-4-chloro-pyrrolo[2,1-f][1,2,4]triazine (384 mg, 1.7 mmol), Pd(dppf)Cl·DCM (123 mg, 0.15 mmol), and KCO (415 mg, 3.0 mmol) in dioxane (12.8 mL) and water (3.0 mL) was purged with N for 5 minutes. The reaction mixture was stirred at 100 °C under N for 1 hour. The cooled reaction was concentrated in vacuo, and the residue was partitioned between water (100 mL) and EtOAc (100 mL), and the layers were separated. The aqueous phase was extracted with EtOAc (2 x 50 mL), and the combined organic layers were washed with brine (150 mL), dried (Na2SO4), filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (0-100% EtOAc / Hept) and then again (10% EtOAc / Hept) to give the title compound as a yellow foam (117 mg, 17%). LCMS m / z = 450.9 [M+H] +

[0245] 7. Synthesis of tert-butyl (R)-(1-(3-fluoro-2-methyl-4-(6-morpholinopyrrolo[2,1-f][1,2,4]triazin-4-yl)phenyl)ethyl)carbamate [ka] Following the procedure described in Step 1 of Example 2, the title compound was obtained from tert-butyl (R)-(1-(4-(6-bromopyrrolo[2,1-f][1,2,4]triazin-4-yl)-3-fluoro-2-methylphenyl)ethyl)carbamate and morpholine (44 mg, 37%). LCMS m / z=456.0 [M+H] + ; 1H NMR(500MHz,MeOH-d4)δ:8.35(s,1H),7.85(d,1H),7.53(br t,1H),7.35(d,1H),6.33(br s,1H),5.04-4.95(m,1H),3.87-3.78(m,4H),3.20-3.12(m,4H),2.39(d,3H),1.52-1.35(m,9H)

[0246] 8. Synthesis of (R)-1-(3-fluoro-2-methyl-4-(6-morpholinopyrrolo[2,1-f][1,2,4]triazin-4-yl)phenyl)ethan-1-amine hydrochloride [ka] To a solution of tert-butyl (R)-(1-(3-fluoro-2-methyl-4-(6-morpholinopyrrolo[2,1-f][1,2,4]triazin-4-yl)phenyl)ethyl)carbamate (44 mg, 0.1 mmol) in EtOAc (1 mL) was added HCl solution (0.1 mL, 1 M in EtOAc) and the reaction was stirred at room temperature for 24 h. Additional 1 M HCl in EtOAc (0.1 mL) was added and the reaction was stirred for a further 18 h. The mixture was concentrated in vacuo to give the title compound, which was carried forward without further purification. LCMS m / z=356.1 [M+H] +

[0247] 9. Synthesis of (R)-5-(tert-butyl)-N-(1-(3-fluoro-2-methyl-4-(6-morpholinopyrrolo[2,1-f][1,2,4]triazin-4-yl)phenyl)ethyl)-1,2,4-oxadiazole-3-carboxamide [ka] T3P® (37 mg, 0.14 mmol) was added to a mixture of (R)-1-(3-fluoro-2-methyl-4-(6-morpholinopyrrolo[2,1-f][1,2,4]triazin-4-yl)phenyl)ethan-1-amine hydrochloride (41 mg, 0.1 mmol) and ethyl 5-(tert-butyl)-1,2,4-oxadiazole-3-carboxylate (29 mg, 0.14 mmol) in THF (1.5 mL) at room temperature, and the mixture was heated at 45° C. for 18 hours. The reaction mixture was diluted with MeOH and filtered. The filtrate was concentrated in vacuo, and the residue was purified by preparative HPLC (Method C, 10-90%) to give the title compound (16.8 mg, 34%) as a yellow solid. LCMS m / z=508.0 [M+H] + . 1 H NMR(500MHz,DMSO-d6)δ:9.60(d,1H),8.50-8.47(m,1H),8.04-8.01(m,1H),7.59(t,1H),7.46(d,1H),6.35-6.32( m,1H),5.38(t,1H),3.76-3.69(m,4H),3.17-3.08(m,4H),2.41-2.31(m,3H),1.56-1.46(m,3H),1.46-1.36(m,9H).

[0248] Example 32. 5-(tert-butyl)-N-(2-methyl-4-(6-(4-(oxetan-3-yl)piperazin-1-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)benzyl)-1,2,4-oxadiazole-3-carboxamide trifluoroacetate [ka] 1. Synthesis of benzyl 4-(4-(4-(((tert-butoxycarbonyl)amino)methyl)-3-methylphenyl)pyrrolo[2,1-f][1,2,4]triazin-6-yl)piperazine-1-carboxylate [ka] A mixture of tert-butyl (4-(6-bromopyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-methylbenzyl)carbamate (300 mg, 0.72 mmol), benzylpiperazine-1-carboxylate (157 mg, 0.72 mmol), Pd(dba) (66 mg, 0.07 mmol), DavePhos (57 mg, 0.14 mmol), and CsCO (703 mg, 2.2 mmol) in dioxane (12 mL) was purged with N for 5 min and then stirred at 100 °C for 16 h. Additional benzylpiperazine-1-carboxylate (157 mg, 0.72 mmol), Pd(dba) (55 mg, 0.06 mmol), DavePhos (47 mg, 0.12 mmol), and CsCO (782 mg, 2.4 mmol) were added, and the reaction was stirred at 110 °C for an additional 24 h. The cooled reaction was filtered through Celite® and washed with EtOAc. The combined filtrate was concentrated in vacuo, and the crude product was purified by column chromatography (0-100% EtOAc / Hept) to give the title compound (277 mg, 69%) as a yellow solid. LCMS m / z = 557.2 [M+H] +

[0249] 2. Synthesis of benzyl 4-(4-(4-(((tert-butoxycarbonyl)amino)methyl)-3-methylphenyl)pyrrolo[2,1-f][1,2,4]triazin-6-yl)piperazine-1-carboxylate [ka] To 4-(4-(4-(((tert-butoxycarbonyl)amino)methyl)-3-methylphenyl)pyrrolo[2,1-f][1,2,4]triazin-6-yl)piperazine-1-carboxylate (277 mg, 0.5 mmol) in MeOH (2 mL) was added HCl solution (0.5 mL, 4 M in MeOH) and the reaction was stirred at room temperature overnight. The mixture was concentrated in vacuo to give the title compound (230 mg, 94%), which was used in the next step without further purification. LCMS m / z=457.1 [M+H] +

[0250] 3. Synthesis of benzyl 4-(4-(4-((5-(tert-butyl)-1,2,4-oxadiazole-3-carboxamido)methyl)-3-methylphenyl)pyrrolo[2,1-f][1,2,4]triazin-6-yl)piperazine-1-carboxylate [ka] A vial was charged with benzyl 4-(4-(4-(((tert-butoxycarbonyl)amino)methyl)-3-methylphenyl)pyrrolo[2,1-f][1,2,4]triazin-6-yl)piperazine-1-carboxylate (217 mg, 0.4 mmol), potassium 5-tert-butyl-1,2,4-oxadiazole-3-carboxylate (138 mg, 0.7 mmol), and DCM (4 mL). DIPEA (170 mg, 1.3 mmol) was added and the reaction was cooled to 0 °C before adding HATU (252 mg, 0.7 mmol) in one portion. The reaction was stirred at room temperature overnight. The reaction was concentrated in vacuo, and the residue was purified by silica gel column chromatography (0-100% EtOAc:Hept) to give the title compound (236 mg, 88%) as a pale yellow solid. LCMS m / z = 609.2 [M+H] + ,

[0251] Synthesis of 4.5-(tert-butyl)-N-(2-methyl-4-(6-(4-(oxetan-3-yl)piperazin-1-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)benzyl)-1,2,4-oxadiazole-3-carboxamide trifluoroacetate [ka] To a solution of benzyl 4-(4-(4-((5-(tert-butyl)-1,2,4-oxadiazole-3-carboxamido)methyl)-3-methylphenyl)pyrrolo[2,1-f][1,2,4]triazin-6-yl)piperazine-1-carboxylate (236 mg, 0.4 mmol) in MeOH (4 mL) was added Pd / C (4 mg, 0.04 mmol) and stirred under H for 16 h. The mixture was filtered through Celite® and the filtrate was concentrated in vacuo to give a residue that was used without further purification. The residue was redissolved in MeOH (3 mL), oxetan-3-one (43 mg, 0.6 mmol), ZnCl (0.3 mL, 1.9 M in MeTHF) and NaBHCN (38 mg, 0.6 mmol) were added and the mixture was heated at 50° C. for 4 h. The reaction mixture was concentrated in vacuo and the residue was purified by preparative HPLC (Method B, 10-90%) to give the title compound (57 mg, 34%). LCMS m / z=531.2 [M+H] + ; 1 H NMR(400MHz,CDCl3)δ:8.46-8.32(m,1H),7.88-7.79(m,1H),7.76-7.59(m,2H),7.51-7.26(m,2H),6.61-6.561(m,1H),5.06-4.94(m,2H),4.8 0-4.73(m,2H),4.71-4.60(m,2H),4.25-4.12(m,1H),3.80-3.69(m,4H) ,3.67-3.58(m,2H),3.28-3.19(m,2H),2.40(s,3H),1.46-1.34(s,9H).

[0252] Example 33. N-(3-fluoro-2-methyl-4-(6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)benzyl)-5-(1-fluoro-2-methylpropan-2-yl)-1,2,4-oxadiazole-3-carboxamide [ka] 1. Synthesis of tert-butyl (4-(6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-3-fluoro-2-methylbenzyl)carbamate [ka] The crude compound was obtained from tert-butyl (4-(6-bromopyrrolo[2,1-f][1,2,4]triazin-4-yl)-3-fluoro-2-methylbenzyl)carbamate and 1-methylpyrazole-4-boronic acid pinacol ester according to the procedure described in Step 1 of Example 10. The crude was purified by silica gel column chromatography (0-50% EtOAc / petroleum ether) to give the title compound (290 mg, 72%) as a yellow solid. LCMS m / z=437.2 [M+H] +

[0253] 2. 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 was stirred at 25 °C for 12 h. The reaction 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 the title compound (10 g, crude) as a yellow solid. 1 H NMR(400MHz,CDCl3)δ:4.37-4.32(m,2H),1.38-1.30(m,3H).

[0254] 3. 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 portion of DCM (30 mL) was added, and the organic phase was washed with HO (3 × 10 mL). The organic phase was dried (NaSO), filtered, and concentrated in vacuo. The crude product was purified by silica gel column chromatography (16-100% EtOAc / petroleum ether) to give the title compound (500 mg, 57%) as a white solid. LCMS m / z = 233.1 [M+H] + . 1 H NMR(500MHz,MeOH-d4)δ:4.37(q,2H),3.66(s,2H),1.38(t,3H),1.28(s,6H).

[0255] 4. 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 h. The reaction mixture was concentrated in vacuo, and the residue was purified by silica gel column chromatography (9-50% EtOAc / petroleum ether) to give the title compound (250 mg, 54%) as a colorless oil. LCMS m / z = 215.1 [M+H] + . 1 H NMR(500MHz,CDCl3)δ:4.50(q,2H),3.81(s,2H),1.46(s,6H),1.28-1.14(m,3H).

[0256] 5. Ethyl 5-(2-methyl-1-(((trifluoromethyl)sulfonyl)oxy)propan-2-yl)-1,2,4-oxadiazole-3-carboxylate [ka] To a solution of 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) was added TfO (566 mg, 4.0 mmol) at 0 °C. The reaction mixture was stirred at 25 °C for 2 h. An additional 40 mL of DCM was added, and the organic phase was washed with H2O (3 × 20 mL). The organic phase was dried (Na2SO4), filtered, and concentrated in vacuo. The crude product was purified by silica gel column chromatography (9-50% EtOAc / petroleum ether) to give the title compound (600 mg, 86%) as a colorless oil. LCMS m / z = 347.1 [M+H] +

[0257] 6. Synthesis of 5-(2-methyl-1-(((trifluoromethyl)sulfonyl)oxy)propan-2-yl)-1,2,4-oxadiazole-3-carboxylic acid [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 h. The cooled reaction mixture was concentrated in vacuo and the crude product was purified by silica gel column chromatography (9-25% EtOAc / petroleum ether) to give the title compound (330 mg, 88%) as a colorless oil. LCMS m / z=217.1 [M+H] + . 1H NMR(500MHz,CDCl3)δ:4.63(s,1H),4.53-4.51(m,3H),1.52(s,6H),1.44(t,3H).

[0258] 7. Synthesis of 5-(1-fluoro-2-methylpropan-2-yl)-1,2,4-oxadiazole-3-carboxylic acid [ka] To a solution of ethyl 5-(1-fluoro-2-methylpropan-2-yl)-1,2,4-oxadiazole-3-carboxylate (300 mg, 1.4 mmol) in MeOH (20 mL) was added a solution of NaOH (111 mg, 2.8 mmol) in HO (10 mL) and the reaction was stirred at room temperature for 2 hours. 1 M HCl solution was added to adjust the pH of the reaction to 6. The reaction mixture was concentrated in vacuo to remove MeOH, and the aqueous phase was lyophilized to give the title compound (300 mg, crude) as a white solid, which was used without further purification.

[0259] 8. Synthesis of 5-(1-fluoro-2-methylpropan-2-yl)-1,2,4-oxadiazole-3-carbonyl chloride [ka] The title compound was obtained from 5-(1-fluoro-2-methylpropan-2-yl)-1,2,4-oxadiazole-3-carboxylic acid according to the procedure described in Step 7 of Example 34. The crude material was carried forward without further purification (Example 33, Step 10).

[0260] 9. Synthesis of (3-fluoro-2-methyl-4-(6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)phenyl)methanamine hydrochloride [ka] To (4-(6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-3-fluoro-2-methylbenzyl)carbamate (290 mg, 0.7 mmol) was added HCl solution (10 mL, 4 M in EtOAc). The reaction was stirred at 20° C. for 1 hour. The mixture was concentrated in vacuo to give the title compound (240 mg, crude) as a yellow solid, which was used in the next step without further purification. LCMS m / z=337.1 [M+H] +

[0261] 10. Synthesis of N-(3-fluoro-2-methyl-4-(6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)benzyl)-5-(1-fluoro-2-methylpropan-2-yl)-1,2,4-oxadiazole-3-carboxamide [ka] To a solution of (3-fluoro-2-methyl-4-(6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)phenyl)methanamine hydrochloride (95 mg, 0.3 mmol) and DIPEA (73 mg, 0.6 mmol) in DCM (35 mL) was slowly added 5-(1-fluoro-2-methylpropan-2-yl)-1,2,4-oxadiazole-3-carbonyl chloride (117 mg, 0.6 mmol) and the mixture was stirred at 20 °C for 1 h. The mixture was concentrated in vacuo and the residue was purified by preparative HPLC (Method E, 48-75%) to give the title compound as a yellow solid (33 mg, 23%). LCMS m / z = 507.0 [M+H] + ; 1 H NMR(500MHz,DMSO-d6)δ:9.64(t,1H),8.60(s,1H),8.50(d,1H),8.19(s,1H),7.92(s,1H),7.62( t,1H),7.31(d,1H),7.02(s,1H),4.70-4.59(m,4H),3.86(s,3H),2.38-2.37(m,3H),1.47(d,6H).

[0262] Example 34. 5-(tert-butyl)-N-(4-(6-morpholinopyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-(trifluoromethyl)benzyl)-1,2,4-oxadiazole-3-carboxamide hydrochloride [ka] 1. Synthesis of tert-butyl (4-(6-bromopyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-(trifluoromethyl)benzyl)carbamate [ka] To a solution of tert-butyl (2-(trifluoromethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)carbamate (Example 114 of WO2015089327, 400 mg, 1.0 mmol) and 6-bromo-4-chloropyro[2,1-f][1,2,4]triazine (580 mg, 2.5 mmol) in a mixture of dioxane (4 mL) and water (1 mL) was added Na2CO3 (211 mg, 2.0 mmol) and Pd(dppf)Cl2·DCM (122 mg, 0.15 mmol) at 25 °C. The reaction mixture was stirred at 90 °C under N2 for 5 h. The reaction mixture was concentrated in vacuo, and the residue was purified by silica gel chromatography (petroleum ether / EtOAc = 12:1 to 5:1) to give the title compound as a gray solid (250 mg, 53%). LCMS m / z = 471.1 [M+H] +

[0263] 2. Synthesis of tert-butyl (4-(6-morpholinopyrrolo[2,1-f][1,2,4]triazin-4-yl-2-trifluoromethyl)benzyl)carbamate [ka] To a solution of morpholine (479 mg, 5.5 mmol) and tert-butyl (4-(6-bromopyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-(trifluoromethyl)benzyl)carbamate (520 mg, 1.1 mmol) in dioxane (15 mL) was added KPO (467 mg, 2.2 mmol), CsCO (717 mg, 2.2 mmol), and RuPhos-Pd G1 methyl t-butyl ether adduct (90 mg, 0.11 mmol) at 20 °C. The reaction mixture was stirred at 100 °C under N for 12 h. The reaction mixture was concentrated in vacuo, and the residue was purified by silica gel chromatography (petroleum ether / EtOAc = 10:1 to 2:1) to give the title compound (180 mg, 34%) as a yellow solid. LCMS m / z = 478.2 [M+H] +

[0264] 3. Synthesis of (4-(6-morpholinopyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-(trifluoromethyl)phenyl)methanamine hydrochloride [ka] tert-Butyl (4-(6-morpholinopyrrolo[2,1-f][1,2,4]triazin-4-yl-2-trifluoromethyl)benzyl)carbamate (60 mg, 0.13 mmol) was added to HCl solution (12 mL, 1 M in EtOAc) at 20° C. The reaction mixture was stirred at 20° C. for 1 h and then concentrated in vacuo to give the title compound (40 mg) as a yellow solid, which was used in the next step without further purification (Example 34, Step 8). LCMS m / z=361.1 [M-NH] +

[0265] 4. Synthesis of ethyl (Z)-2-amino-2-((pivaloyloxy)imino)acetate [ka] To an ice-cold suspension of ethyl 2-(hydroxyamino)-2-iminoacetate (30.0 g, 227 mmol) in DCM (500 mL) was added pivaloyl chloride (33.5 mL, 272 mmol) dropwise over 15 minutes, and the reaction was stirred at room temperature for 4 hours. Additional pivaloyl chloride (16.5 mL, 136 mmol) was added, and the reaction was stirred for an additional 18 hours. Additional pivaloyl chloride (16.5 mL, 136 mmol) was added, and the reaction was stirred for an additional 24 hours. The mixture was diluted with DCM (200 mL) and washed with water (200 mL). The aqueous layer was extracted with DCM (3 x 200 mL). The combined organic layers were dried (Na2SO4), filtered, and the filtrate was concentrated in vacuo. The residue was suspended in Et2O (100 mL) and the resulting solid was filtered off, washed with Et2O and dried in air to give the title compound as white crystals (24.5 g, 50%). 1 H NMR(300MHz,CDCl3)δ:5.38(br s,2H),4.36(q,2H),1.36(t,3H),1.28(s,9H).

[0266] 5. Synthesis of 5-(tert-butyl)-1,2,4-oxadiazole-3-carboxylate [ka] Ethyl (Z)-2-amino-2-((pivaloyloxy)imino)acetate (24.5 g, 113 mmol) was suspended in AcOH (50 ml) and the reaction heated to 120° C. (external temperature) for 20 h. The cooled mixture was concentrated in vacuo and then azeotroped with toluene. The residue was dissolved in EtOAc (100 mL) and the solution washed with water (50 mL) and brine (50 mL). The organic solution was dried (NaSO), filtered and concentrated in vacuo to give the title compound (19.8 g, 88%) as a colorless oil. 1 H NMR(300MHz,CDCl3)δ:4.51(q,2H),1.48(s,9H),1.41(t,3H).

[0267] 6. Synthesis of 5-(tert-butyl)-1,2,4-oxadiazole-3-carboxylic acid [ka] To a solution of ethyl 5-(tert-butyl)-1,2,4-oxadiazole-3-carboxylate (34.5 g, 174 mmol) in MeOH (350 mL) was added (in one portion) a solution of LiOH·HO (14.6 g, 348 mmol) in water (35 mL), and the reaction was stirred at room temperature for 2 h. The reaction was concentrated in vacuo, and the aqueous residue was acidified with concentrated HCl to pH = 2-3. The mixture was concentrated in vacuo, and the oily residue was azeotroped with toluene (3 × 50 mL). 5% MeOH in DCM (500 mL) was added, the mixture was filtered, and the solid was washed with 5% MeOH in DCM (3 × 100 mL). Mixing, drying (NaSO), filtering, and concentration in vacuo afforded the title compound (29.2 g, 89%) as a white solid. 1 H NMR(300MHz,DMSO-d6)δ:0.96(s,9H).

[0268] 7. Synthesis of 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, 1.2 mmol) in DCM (10 mL) was added thionyl chloride (140 mg, 1.2 mmol) and DMF (200 μL), and the reaction was stirred at room temperature for 1 h. The reaction mixture was concentrated in vacuo to give the title compound (230 mg, crude), which was used directly without further purification.

[0269] 8. Synthesis of 5-(tert-butyl)-N-(4-(6-morpholinopyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-(trifluoromethyl)benzyl)-1,2,4-oxadiazole-3-carboxamide hydrochloride [ka] To a solution of (4-(6-morpholinopyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-(trifluoromethyl)phenyl)methanamine hydrochloride (40 mg, 0.1 mmol) and DIPEA (50 mg, 0.4 mmol) in DCM (15 mL) was added 5-(tert-butyl)-1,2,4-oxadiazole-3-carbonyl chloride (55 mg, 0.3 mmol) at 20° C. The reaction mixture was stirred at 20° C. for 2 h. The reaction mixture was concentrated in vacuo and the residue was purified by preparative HPLC (Method A, 54-74%) to give the title compound as a red solid (20 mg, 36%). LCMS m / z=530.3 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ:9.68(t,1H),8.53(s,1H),8.42-8.37(m,2H),8.12(s,1H),7.6 8(d,1H),6.80(s,1H),4.72(d,2H),3.74-3.72(m,4H),3.18-3.16(m,4H),1.43(m,9H).

[0270] Example 35. 5-(tert-butyl)-N-(2-methoxy-4-(6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)benzyl)-1,2,4-oxadiazole-3-carboxamide hydrochloride [ka] 1. Synthesis of tert-butyl (4-bromo-2-methoxybenzyl)carbamate [ka] BH3·Me2S (17 mL, 10 M, 170 mmol) was added dropwise to a solution of 4-bromo-2-methoxybenzonitrile (18 g, 85 mmol) in THF (300 mL), and the reaction was stirred at 65 °C for 5 h. The cooled mixture was carefully quenched with MeOH (60 mL), followed by the addition of HCl (2 M, 50 mL), and the mixture was concentrated in vacuo. The residue was diluted with DCM (300 mL) and extracted with HO (3 × 300 mL). The combined aqueous phase was basified to pH = 9–10 with NaOH (aq) and extracted with DCM (3 × 200 mL). The combined organic layers were concentrated to give (4-bromo-2-methoxyphenyl)methanamine (11 g, crude). To a solution of this solid in DCM (200 mL) and EtN (10.3 g, 102 mmol), BocO (12.2 g, 56 mmol) was added dropwise, and the reaction was stirred for 17 h at 20° C. The mixture was concentrated in vacuo, and the residue was purified by silica gel column chromatography (petroleum ether / EtOAc = 99.5:0.5 to 98:2) to give the title compound (15 g, 93%) as a pale yellow solid. 1 H NMR(CDCl3,400MHz)δ:7.14-7.11(m,1H),7.06-7.03(m,1H),6.98-6.97(m,1H),4.97(br s,1H),4.23(d,2H),3.83(s,3H),1.43(s,9H).

[0271] 2. Synthesis of tert-butyl (2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)carbamate [ka] The title compound was prepared from tert-butyl (4-bromo-2-methoxybenzyl)carbamate following a similar procedure as described in Example 1, Step 1, as a white solid (16 g, 93%). LCMS m / z=364.1 [M+H] + ; 1H NMR(CDCl3,400MHz)δ:7.37-7.35(m,1H),7.26-7.24(m,2H),5.00(br s,1H),4.29(d,2H),3.86(s,3H),1.41(s,9H),1.32(s,12H).

[0272] 3. Synthesis of tert-butyl (4-(6-bromopyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-methoxybenzyl)carbamate [ka] Following the procedure described in Step 6 of Example 25, tert-butyl (2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)carbamate and 6-bromo-4-chloro-pyrrolo[2,1-f][1,2,4]triazine gave the title compound as a yellow solid (240 mg, 92%). LCMS m / z=433.2 [M+H] +

[0273] 4. Synthesis of tert-butyl (2-methoxy-4-(6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)benzyl)carbamate [ka] The crude product was obtained from tert-butyl (4-(6-bromopyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-methoxybenzyl)carbamate and 1-methylpyrazole-4-boronic acid pinacol ester according to the procedure described in Step 1 of Example 10. The crude product was purified by silica gel column chromatography (petroleum ether / EtOAc=1:9) to give the title compound (110 mg, 65%) as an orange solid. LCMS m / z=435.2 [M+H] +

[0274] 5. Synthesis of (2-methoxy-4-(6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)phenyl)methanamine hydrochloride [ka] To a solution of tert-butyl (2-methoxy-4-(6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)benzyl)carbamate (110 mg, 0.25 mmol) in DCM (30 mL) at 30° C. was added HCl solution (7 mL, 4 M in EtOAc) and the reaction was stirred for 2 h. The mixture was concentrated in vacuo to give the title compound as an orange solid, which was used in the next step. LCMS m / z=335.1 [M+H] +

[0275] Synthesis of 6.5-(tert-butyl)-N-(2-methoxy-4-(6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)benzyl)-1,2,4-oxadiazole-3-carboxamide hydrochloride [ka] The compound was obtained from (2-methoxy-4-(6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)phenyl)methanamine hydrochloride and 5-(tert-butyl)-1,2,4-oxadiazole-3-carbonyl chloride according to the procedure described in Step 8 of Example 34. The crude product was purified by preparative HPLC (Method A, 44-64%) to give the title compound as an orange solid (15.7 mg, 26%). LCMS m / z=487.1 [M+H] + ; 1H NMR(400MHz,DMSO-d6)δ:9.44(t,1H),8.58(s,1H),8.48(s,1H),8.20(s,1H),7.95(s,1H), 7.77-7.68(m,2H),7.42-7.37(m,2H),4.54(d,2H),3.97(s,3H),3.86(s,3H),1.44(s,9H).

[0276] Example 36. 5-(tert-butyl)-N-(2-(difluoromethyl)-3-fluoro-4-(6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)benzyl)-1,2,4-oxadiazole-3-carboxamide hydrochloride [ka] Synthesis of 1,2-fluoro-3-nitrobenzaldehyde [ka] To a solution of 2-chloro-3-nitrobenzaldehyde (9.5 g, 51 mmol) in DMF (100 mL) was added KF (8.9 g, 154 mmol), and the reaction was stirred at 150° C. for 5 h. The cooled reaction mixture was concentrated in vacuo, and the residue was poured into HO (400 mL) and extracted with DCM (4×100 mL). The combined organic extracts were concentrated in vacuo, and the crude material was purified by silica gel column chromatography (petroleum ether / EtOAc=20:1) to give the title compound as a yellow oil (6.7 g, 77%). 1 H NMR(400MHz,CDCl3)δ:10.44(s,1H),8.36-8.30(m,1H),8.22-8.16(m,1H),7.47(dd,1H).

[0277] Synthesis of 2.1-(difluoromethyl)-2-fluoro-3-nitrobenzene [ka] Following a procedure similar to that described in Step 3 of Example 65, 2-fluoro-3-nitrobenzaldehyde gave the title compound as an orange oil (6.6 g, 87%). 1 H NMR(400MHz,CDCl3)δ:8.20(t,1H),7.92(t,1H),7.44(t,1H),6.97(t,1H).

[0278] 3. Synthesis of 3-(difluoromethyl)-2-fluoroaniline [ka] To a solution of 1-(difluoromethyl)-2-fluoro-3-nitrobenzene (6.6 g, 35 mmol) in MeOH (100 mL) was added Pd / C (1.4 g) and the reaction was stirred under an atmosphere of H (15 psi) at 28 °C for 17 h. The mixture was filtered and the filtrate was concentrated in vacuo to give the title compound (4.7 g, 83%) as a yellow oil. LCMS m / z = 162.0 [M+H] +

[0279] 4. Synthesis of 4-bromo-3-(difluoromethyl)-2-fluoroaniline [ka] To a solution of 3-(difluoromethyl)-2-fluoroaniline (4.7 g, 29 mmol) in DCM (100 mL) was slowly added NBS (5.1 g, 29 mmol), and the reaction was stirred for 17 h at 15° C. The reaction mixture was concentrated in vacuo, and the crude material was purified by silica gel column chromatography (petroleum ether / EtOAc = 98:2 to 91:9) to give the title compound (3.3 g, 47%) as a brown solid. 1 H NMR(400MHz, CDCl3)δ:7.16(dd,1H),6.99(td,1H),6.79-6.73(m,1H),3.87(s,2H).

[0280] 5. Synthesis of methyl 4-amino-2-(difluoromethyl)-3-fluorobenzoate [ka] A solution of 4-bromo-3-(difluoromethyl)-2-fluoroaniline (3.1 g, 13 mmol), Pd(dppf)Cl (945 mg, 1.3 mmol), and EtN (6.5 g, 65 mmol) in MeOH (100 mL) was stirred at 80 °C under an atmosphere of CO (50 psi) for 40 h. The cooled reaction mixture was filtered, and the filtrate was concentrated in vacuo. The crude material was purified by silica gel column chromatography (petroleum ether / EtOAc = 20:1) to give the title compound (2.2 g, 75%) as an orange solid. LCMS m / z = 220.0 [M+H] +

[0281] 6. Synthesis of methyl 4-bromo-2-(difluoromethyl)-3-fluorobenzoate [ka] To a suspension of CuBr (2.55 g, 17.8 mmol) in MeCN (40 mL) was added tert-butyl nitrite (1.83 g, 17.8 mmol) at 15 ° C. A solution of methyl 4-bromo-2-(difluoromethyl)-3-fluorobenzoate (2.00 g, 8.9 mmol) in MeCN (20 mL) was added dropwise at 65 ° C., and the reaction was then stirred at that temperature for 17 hours. The cooled mixture was concentrated in vacuo, and the crude material was purified by silica gel column chromatography (petroleum ether / EtOAc = 20:1) to give the title compound (1.7 g, 68%) as a pale yellow solid. 1 H NMR(400MHz, CDCl3)δ:7.77-7.73(m,1H),7.64-7.61(m,1H),7.62-7.42(m,1H),3.95(s,3H).

[0282] 7. Synthesis of (4-bromo-2-(difluoromethyl)-3-fluorophenyl)methanamine [ka] To a solution of methyl 4-bromo-2-(difluoromethyl)-3-fluorobenzoate (1.2 g, 4.2 mmol) in DCM (60 mL) in an EtOH-dry ice bath, DIBAL-H (1.0 M, 10.6 mL) was slowly added, and the reaction mixture was stirred at 10 °C for 17 h. HO (1 mL) was added, followed by 10% NaOH solution (1 mL), additional HO (1 mL), and NaSO. The reaction mixture was filtered, and the filtrate was concentrated in vacuo to give (4-bromo-2-(difluoromethyl)-3-fluorophenyl)methanol (1.1 g, crude). To a solution of this product (1.1 g, 4.3 mmol) in DCM (50 mL) and DMF (1 mL), SOCl (2.5 g, 22 mmol) was added dropwise, and the reaction was stirred at 20 °C for 2 h. The reaction mixture was poured into HO (100 mL) and extracted with DCM (3 × 50 mL). The combined organic extracts were dried (NaSO), filtered, and concentrated in vacuo to give 1-bromo-4-(chloromethyl)-3-(difluoromethyl)-2-fluorobenzene (1.1 g, crude), which was carried forward without further purification. To a solution of 1-bromo-4-(chloromethyl)-3-(difluoromethyl)-2-fluorobenzene (1.1 g, 4.0 mmol) in i-PrOH (60 mL) was added NHOH (100 mL), and the reaction was stirred at 65 °C for 17 h. The cooled reaction mixture was concentrated in vacuo, and the residue was dissolved in DCM (100 mL). The organic phase was washed with HO (100 mL), dried (NaSO), filtered, and concentrated in vacuo to give the title compound (1.0 g, crude). LCMS m / z=236.9[M-NH2] +

[0283] 8. Synthesis of tert-butyl (4-bromo-2-(difluoromethyl)-3-fluorobenzyl)carbamate [ka] To a solution of (4-bromo-2-(difluoromethyl)-3-fluorophenyl)methanamine (1.0 g, 3.9 mmol) in DCM (30 mL) was added EtN (797 mg, 7.9 mmol), followed by BocO (902 mg, 4.1 mmol), and the reaction was stirred at room temperature for 2 h. The mixture was poured into HO (100 mL), the layers were separated, and the aqueous phase was extracted with DCM (3 × 50 mL). The combined organic extracts were concentrated in vacuo, and the crude material was purified by silica gel column chromatography (petroleum ether / EtOAc = 20:1 to 10:1) to give the title compound (900 mg, 78%) as a yellow oil. LCMS m / z = 297.9 [M+Ht-Bu] +

[0284] 9. Synthesis of tert-butyl (3-fluoro-2-(difluoromethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)carbamate [ka] The title compound was prepared as a white solid from tert-butyl (4-bromo-2-(difluoromethyl)-3-fluorobenzyl)carbamate according to the procedure described in Step 1 of Example 1 (700 mg, 80%). 1 H NMR(500MHz,CDCl3)δ:7.81(dd,1H),7.32(d,1H),7.09(t,1H),4.96(t,1H),4.56(d,2H),1.44(s,9H),1.35(s,12H).

[0285] 10. Synthesis of (4-(6-bromopyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-(difluoromethyl)-3-fluorobenzyl)carbamate [ka] To a solution of tert-butyl (3-fluoro-2-(difluoromethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)carbamate (923 mg, 4.0 mmol) and 6-bromo-4-chloro-pyrrolo[2,1-f][1,2,4]triazine (760 mg, 1.9 mmol) in a mixture of dioxane (9 mL) and HO (1 mL) was added KCO (524 mg, 3.8 mmol) and Pd(dppf)Cl·DCM (155 mg, 0.19 mmol), and the reaction mixture was stirred at 95 °C under N for 4 h. The cooled reaction mixture was concentrated in vacuo, and the crude product was purified by silica gel chromatography (petroleum ether / EtOAc = 15:1 to 4:1) to give the title compound (470 mg, 53% yield) as a yellow solid. LCMS m / z=471.1[M+H] +

[0286] 11. Synthesis of tert-butyl (2-(difluoromethyl)-3-fluoro-4-(6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)benzyl)carbamate [ka] The crude product was obtained from 1-methylpyrazole-4-boronic acid pinacol ester and tert-butyl (4-(6-bromopyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-(difluoromethyl)-3-fluorobenzyl)carbamate according to the procedure described in Step 1 of Example 10. The crude product was purified by silica gel chromatography (petroleum ether / EtOAc = 10:1 to 1:1) to give the title compound (165 mg, 82%) as a pale yellow solid. LCMS m / z = 473.2 [M+H] +

[0287] 12. Synthesis of (2-(difluoromethyl)-3-fluoro-4-(6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)phenyl)methanamine hydrochloride [ka] A solution of tert-butyl (2-(difluoromethyl)-3-fluoro-4-(6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)benzyl)carbamate (165 mg, 0.349 mmol) in HCl solution (20 mL, 1 M in EtOAc) was stirred at room temperature for 2 hours. The mixture was concentrated in vacuo to give the title compound (140 mg, crude) as a grey solid. LCMS m / z=373.1 [M+H] +

[0288] 13. Synthesis of 5-(tert-butyl)-N-(2-(difluoromethyl)-3-fluoro-4-(6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)benzyl)-1,2,4-oxadiazole-3-carboxamide hydrochloride. [ka] The crude product was obtained from (2-(difluoromethyl)-3-fluoro-4-(6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)phenyl)methanamine hydrochloride and 5-(tert-butyl)-1,2,4-oxadiazole-3-carbonyl chloride according to the procedure described in Step 7 of Example 34. The crude product was purified by preparative HPLC method A (44-74%) to give the title compound as a white solid (30.2 mg, 47%). LCMS m / z=525.1 [M+H] + ; 1 H NMR(400MHz,DMSO-d6)δ:9.69-9.65(m,1H),8.60(s,1H),8.53(d,1H),8.16(s,1H),7.97-7.9 4(m,1H),7.89(s,1H),7.65-7.44(m,2H),7.04(s,1H),4.77(d,2H),3.82(s,3H),1.41(s,9H).

[0289] Example 37. 5-(tert-butyl)-N-(2-cyclopropyl-4-(6-morpholinopyrrolo[2,1-f][1,2,4]triazin-4-yl)benzyl)-1,2,4-oxadiazole-3-carboxamide [ka] 1. Synthesis of tert-butyl (4-chloro-2-cyclopropylphenyl)carbamate [ka] To a solution of (4-chloro-2-cyclopropylphenyl)methanamine (1 g, 5.5 mmol) and DIPEA (2.13 g, 16.5 mmol) in DCM (30 mL) was added (Boc)2O (1.56 g, 7.2 mmol) and stirred at 20 °C for 1 h. The mixture was concentrated in vacuo and the crude product was purified by silica gel column chromatography (petroleum ether / EtOAc = 95:5) to give the title compound (1.10 g, 71%) as a clear oil. LCMS m / z = 226.0 [M-tBu+H + ]

[0290] 2. Synthesis of tert-butyl (2-cyclopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)carbamate [ka] To a solution of tert-butyl (4-chloro-2-cyclopropylphenyl)carbamate (1.10 g, 3.9 mmol) and (bispinacolato)diboron (1.98 g, 7.8 mmol) in toluene (40 mL) was added P(Cy) (328 mg, 1.2 mmol) and KPO (2.49 g, 11.7 mmol) at 20 °C. Pd(dba) (358 mg, 0.39 mmol) was added, and the reaction was stirred at 90 °C under N for 12 h. The cooled mixture was concentrated in vacuo and azeotroped with EtOAc. The crude product was purified by silica gel column chromatography (petroleum ether / EtOAc = 9:1) to give the title compound (2.0 g, crude) as an orange oil. LCMS m / z = 318.2 [M-tBu+H] +

[0291] 3. Synthesis of tert-butyl (2-cyclopropyl-4-(6-morpholinopyrrolo[2,1-f][1,2,4]triazin-4-yl)benzyl)carbamate [ka] To a solution of tert-butyl (2-cyclopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)carbamate (1.0 g, 2.7 mmol) in dioxane (30 mL) and HO (3 mL) was added 6-bromo-4-chloro-pyrrolo[2,1-f][1,2,4]triazine (623 mg, 2.7 mmol). NaCO (852 mg, 8.0 mmol) and Pd(dppf)Cl·DCM (219 mg, 0.27 mmol) were added, and the reaction mixture was stirred at 95 °C under N for 6 h. The cooled mixture was concentrated in vacuo, and the crude material was purified by silica gel column chromatography (petroleum ether / EtOAc=5:1) to give tert-butyl (4-(6-bromopyro[2,1-f][1,2,4]triazin-4-yl)-2-cyclopropylbenzyl)carbamate (410 mg, 35%) as an orange solid.

[0292] To a solution of this solid (410 mg, 0.93 mmol) and morpholine (403 mg, 5.3 mmol) in dioxane (20 mL) under N was added KPO (393 mg, 1.9 mmol), CsCO (603 mg, 1.9 mmol), and BrettPhos Pd G1 methyl t-butyl ether adduct (76 mg, 0.09 mmol), and the reaction was stirred at 95 °C for 12 h. The cooled mixture was concentrated in vacuo, and the crude material was purified by silica gel column chromatography (petroleum ether / EtOAc = 7:3) to give the title compound (52 mg, 22%) as a yellow oil. LCMS m / z = 450.3 [M+H] +

[0293] 4. Synthesis of (2-cyclopropyl-4-(6-morpholinopyrrolo[2,1-f][1,2,4]triazin-4-yl)phenyl)methanamine hydrochloride [ka] Following the procedure described in Step 5 of Example 35, tert-butyl(2-cyclopropyl-4-(6-morpholinopyrrolo[2,1-f][1,2,4]triazin-4-yl)benzyl) gave the title compound as an orange solid (54 mg, crude). LCMS m / z=333.1 [M-NH] +

[0294] 5. Synthesis of 5-(tert-butyl)-N-(2-cyclopropyl-4-(6-morpholinopyrrolo[2,1-f][1,2,4]triazin-4-yl)benzyl)-1,2,4-oxadiazole-3-carboxamide. [ka] To a solution of (2-cyclopropyl-4-(6-morpholinopyrrolo[2,1-f][1,2,4]triazin-4-yl)phenyl)methanamine hydrochloride (40 mg, 0.10 mmol) in DCM (20 mL) was added DIPEA (27 mg, 0.21 mmol). 5-(tert-butyl)-1,2,4-oxadiazole-3-carbonyl chloride (39 mg, 0.21 mmol) was then slowly added to the mixture, and the mixture was stirred at 20 °C for 2 h. The mixture was poured into water (50 mL) and extracted with DCM (3 × 50 mL). The combined extracts were washed with brine, dried (Na SO ), and concentrated in vacuo. The residue was purified by preparative HPLC (Method E, 56-75%) to give the title compound (14 mg, 26%) as a red solid. LCMS m / z = 502.2 [M+H] + ; 1 H NMR(400MHz,DMSO-d6)δ:9.51-9.48(m,1H),8.45(s,1H),7.96(s,1H),7.89(d,1H),7.67(s,1H),7.39(d,1H),6.61(s,1H) ,4.72(d,2H),3.73-3.70(m,4H),3.13-3.10(m,4H),2.13-2.08(m,1H),1.41(s,9H),1.02-0.97(m,2H),0.71-0.68(m,2H).

[0295] Example 38. 5-(tert-butyl)-N-(2-methyl-4-(6-(pyridin-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)benzyl)-1,2,4-oxadiazole-3-carboxamide [ka] 1. Synthesis of tert-butyl (2-methyl-4-(6-(pyridin-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)benzyl)carbamate [ka] A mixture of tert-butyl (4-(6-bromopyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-methylbenzyl)carbamate (180 mg, 0.43 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (106 mg, 0.52 mol), KCO (119 mg, 0.86 mmol), and Pd(dppf)Cl (32 mg, 0.04 mmol) in dioxane (30 mL) and water (3 mL) was stirred at 90 °C under N for 2 h. The mixture was concentrated in vacuo, and the crude product was purified by silica gel column chromatography (petroleum ether / EtOAc = 100:0 to 0:100) to give the title compound (150 mg, 84%) as a white solid, which was carried forward without further purification.

[0296] 2. Synthesis of (2-methyl-4-(6-(pyridin-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)phenyl)methanamine hydrochloride [ka] Following the procedure described in Step 12 of Example 36, tert-butyl (2-methyl-4-(6-(pyridin-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)benzyl)carbamate gave the title compound (113 mg, crude), which was used without further purification. LCMS m / z=316.2 [M+H] +

[0297] Synthesis of 3.5-(tert-butyl)-N-(2-methyl-4-(6-(pyridin-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)benzyl)-1,2,4-oxadiazole-3-carboxamide [ka] To a mixture of (2-methyl-4-(6-(pyridin-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)phenyl)methanamine hydrochloride (80 mg, 0.23 mmol) in DCM (40 mL) was added DIPEA (88 mg, 0.68 mmol). 5-(tert-butyl)-1,2,4-oxadiazole-3-carbonyl chloride (86 mg, 0.46 mmol) was added and the reaction was stirred at 20 °C for 1 h. The mixture was concentrated in vacuo to give the crude product, which was purified by preparative HPLC (Method D 45-75%) to give the title compound as a brown solid (46 mg, 43%). LCMS m / z = 468.1 [M+H] + ; 1 H NMR(500MHz,DMSO-d6)δ:9.57(t,1H),8.93(d,1H),8.67(s,1H),8.63-8.61(m,2H),8.08(d,1H), 8.04(s,1H),8.00-7.94(m,2H),7.83(d,1H),7.50(d,1H),4.59(d,2H),2.53(s,3H),1.46(s,9H).

[0298] Example 39. 5-(tert-butyl)-N-(4-(6-((2,6-syn)-2,6-dimethylmorpholino)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-methylbenzyl)-1,2,4-oxadiazole-3-carboxamide [ka] 1. Synthesis of racemic tert-butyl (4-(6-((2,6-syn)-2,6-dimethylmorpholino)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-methylbenzyl)carbamate [ka] A mixture of tert-butyl (4-(6-bromopyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-methylbenzyl)carbamate (160 mg, 0.38 mmol), cis-2,6-dimethylmorpholine (221 mg, 1.9 mmol), t-BuONa (74 mg, 0.77 mmol), RuPhos (36 mg, 0.08 mmol), and Pd(dba) (35 mg, 0.04 mmol) in dioxane (10 mL) and THF (10 mL) was stirred at 100 °C for 4 h under N. The mixture was concentrated in vacuo, and the residue was purified by silica gel column chromatography (EtOAc / petroleum ether = 0:100 to 3:7) to give the title compound (160 mg, 78%) as a yellow oil. LCMS m / z = 452.2 [M+H] +

[0299] 2. Synthesis of racemic (4-(6-((2,6-syn)-2,6-dimethylmorpholino)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-methylphenyl)methanamine hydrochloride [ka] A mixture of racemic tert-butyl (4-(6-((2,6-syn)-2,6-dimethylmorpholino)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-methylbenzyl)carbamate (160 mg, 0.35 mmol) in HCl solution (10 mL, 4 M in EtOAc) was stirred at room temperature for 1 h. The mixture was concentrated in vacuo to give the title compound (120 mg, crude) as a yellow solid. LCMS m / z=352.2 [M+H] +

[0300] Synthesis of 3.5-(tert-butyl)-N-(4-(6-((2,6-syn)-2,6-dimethylmorpholino)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-methylbenzyl)-1,2,4-oxadiazole-3-carboxamide [ka] The compound was obtained from (4-(6-((2,6-syn)-2,6-dimethylmorpholino)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-methylphenyl)methanamine hydrochloride and 5-(tert-butyl)-1,2,4-oxadiazole-3-carbonyl chloride according to the method described in Step 8 of Example 34. The crude product was purified by preparative HPLC (Method A, 46-66%) to give the title compound (65 mg, 43%). LCMS m / z=526.1 [M+Na] + ; 1 H NMR(500MHz,DMSO-d6)δ:9.54(t,1H),8.53(s,1H),8.12(s,1H),7.97-7.90(m,2H),7.45(d,1H),6.78-6.77(m ,1H),4.55(d,2H),3.75-3.71(m,2H),3.65(d,2H),2.47(s,3H),2.39-2.33(m,2H),1.45(s,9H),1.16(d,6H).

[0301] Example 40. N-(2-methyl-4-(6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)benzyl)-5-(1-methylcyclopropyl)-1,2,4-oxadiazole-3-carboxamide [ka] 1. Synthesis of tert-butyl (4-(6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-methylbenzyl)carbamate [ka] To a solution of tert-butyl (4-(6-bromopyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-methylbenzyl)carbamate (336 mg, 0.81 mmol) and HO (2 mL) in dioxane (6 mL) was added 1-methyl-1H-pyrazole-4-boronic acid pinacol ester (168 mg, 0.81 mmol), KCO (223 mg, 1.6 mmol), and Pd(dppf)Cl (66 mg, 0.081 mmol), and the reaction was stirred at 80 °C under N for 1 h. The cooled mixture was concentrated in vacuo, the residue was dissolved in EtOAc, and the mixture was washed with water (20 mL) and extracted with EtOAc (3 × 20 mL). The combined organic layers were dried (NaSO), filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (petroleum ether / EtOAc = 100:0 to 0:100) to give the title compound as a yellow solid (300 mg, 89%). LCMS m / z = 419.2 [M+H] + ; 1 H NMR(400MHz,DMSO-d6)δ:8.55(s,1H),8.46(d,1H),8.21(s,1H),7.99(br d,1H),7.97-7.93(m,2H),7.49(br t,1H),7.43-7.39(m,2H),4.22(br d,2H),3.87(s,3H),2.41(s,3H),1.42(s,9H)

[0302] 2. Synthesis of (2-methyl-4-(6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)phenyl)methanamine hydrochloride [ka] A solution of tert-butyl (4-(6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-methylbenzyl)carbamate (300 mg, 0.72 mmol) in HCl solution (30 mL, 1 M in EtOAc) was stirred at 20° C. for 1 h. The mixture was concentrated in vacuo to give the title compound (200 mg, 88%) as a white solid. 1H NMR(400MHz,DMSO-d6)δ:8.61-8.52(m,3H),8.23(s,1H),8.08-8.02(m,2H),7.97(s,1H),7.67(br d,1H),7.42(s,1H),5.76(s,1H),4.14(br d,2H),3.88(s,3H),1.98(s,3H).

[0303] Synthesis of 3.5-(1-methylcyclopropyl)-1,2,4-oxadiazole-3-carbonyl chloride [ka] The title compound was obtained from 5-(1-methylcyclopropyl)-1,2,4-oxadiazole-3-carboxylic acid according to the procedure described in Step 7 of Example 34. The crude material was carried forward directly.

[0304] 4. Synthesis of N-(2-methyl-4-(6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)benzyl)-5-(1-methylcyclopropyl)-1,2,4-oxadiazole-3-carboxamide [ka] The product was prepared from (2-methyl-4-(6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)phenyl)methanamine hydrochloride and 5-(1-methylcyclopropyl)-1,2,4-oxadiazole-3-carbonyl hydrochloride according to the procedure described in Step 8 of Example 34. The crude product was purified by preparative HPLC using Method E to give the title compound (19 mg, 22%) as a yellow solid. LCMS m / z=469.1 [M+H] + ; 1H NMR(400MHz,DMSO-d6)δ:9.48(t,1H),8.55(s,1H),8.45(s,1H),8.20(s,1H),8 .01-7.92(m,3H),7.45(d,1H),7.39(s,1H),4.54(d,2H),3.87(s,3H),2.47(br s,3H),1.55(s,3H),1.41-1.38(m,2H),1.20-1.16(m,2H).

[0305] Example 41. 5-(1-fluoro-2-methylpropan-2-yl)-N-(2-methyl-4-(6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)benzyl)-1,2,4-oxadiazole-3-carboxamide [ka] Synthesis of 1,5-(1-fluoro-2-methylpropan-2-yl)-N-(2-methyl-4-(6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)benzyl)-1,2,4-oxadiazole-3-carboxamide [ka] The compound was prepared using a method similar to that described in Step 10 of Example 33 using (2-methyl-4-(6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)phenyl)methanamine hydrochloride and 5-(1-fluoro-2-methylpropan-2-yl)-1,2,4-oxadiazole-3-carbonyl chloride. The crude product was purified by preparative HPLC (Method E, 50-72%) as a yellow solid (14 mg, 17%). LCMS m / z=489.2 [M+H] + ; 1H NMR(400MHz,DMSO-d6)δ:9.58-9.54(m,1H),8.60-8.42(m,2H),8.17(s,1H),7.98-7.91(m ,3H),7.43(d,1H),7.37(s,1H),4.68-4.53(m,4H),3.84(s,3H),2.45(s,3H),1.43(d,6H).

[0306] Example 42. N-(3-fluoro-2-methyl-4-(6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)benzyl)-5-(1-methylcyclopropyl)-1,2,4-oxadiazole-3-carboxamide hydrochloride [ka] 1. Synthesis of N-(3-fluoro-2-methyl-4-(6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)benzyl)-5-(1-methylcyclopropyl)-1,2,4-oxadiazole-3-carboxamide hydrochloride. [ka] The title compound was prepared using a method similar to that described in Step 10 of Example 33 using (3-fluoro-2-methyl-4-(6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)phenyl)methanamine hydrochloride and 5-(1-methylcyclopropyl)-1,2,4-oxadiazole-3-carbonyl chloride. The product was purified by preparative HPLC (Method A, 49-69%) as a yellow solid (47 mg, 97%). LCMS m / z=487.1 [M+H] + ; 1H NMR(500MHz,DMSO-d6)δ:9.56-9.53(m,1H),8.60(s,1H),8.51(s,1H),8.19(s,1H),7.92(s,1H),7.62(t,1H),7.30( d,1H),7.03(s,1H),4.58(d,2H),3.86(s,3H),2.37-2.36(m,3H),1.58(s,3H),1.41-1.40(m,2H),1.19-1.18(m,2H).

[0307] Example 43 and Example 44. 5-(tert-butyl)-N-(4-(6-((2R,6R)-2,6-dimethylmorpholino)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-methylbenzyl)-1,2,4-oxadiazole-3-carboxamide and 5-(tert-butyl)-N-(4-(6-((2S,6S)-2,6-dimethylmorpholino)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-methylbenzyl)-1,2,4-oxadiazole-3-carboxamide Hydrochloride [ka] 1. Synthesis of racemic tert-butyl (4-(6-((2,6-trans)-2,6-dimethylmorpholino)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-methylbenzyl)carbamate [ka] Following the procedure described in Step 1 of Example 39, the title compound was obtained as a yellow solid (150 mg, 31%) from tert-butyl (4-(6-bromopyro[2,1-f][1,2,4]triazin-4-yl)-2-methylbenzyl)carbamate and racemic (2,6-trans)-2,6-dimethylmorpholine. LCMS m / z=452.3 [M+H] +

[0308] 2. Synthesis of racemic (4-(6-((2R,6R)-2,6-dimethylmorpholino)pyrrolo[2,1-f][1,2,4]triazin-4-yl)phenyl)methanamine hydrochloride [ka] Following the procedure described in Step 12 of Example 36, racemic tert-butyl (4-(6-((2,6-trans)-2,6-dimethylmorpholino)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-methylbenzyl)carbamate gave the title compound as a yellow solid (100 mg, 95%). LCMS m / z=352.2 [M+H] +

[0309] 3. Synthesis of rac-5-(tert-butyl)-N-(4-(6-((2R,6R)-2,6-dimethylmorpholino)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-methylbenzyl)-1,2,4-oxadiazole-3-carboxamide hydrochloride [ka] Following the procedure described in Step 8 of Example 38, racemic (4-(6-((2,6-trans)-2,6-dimethylmorpholino)pyrrolo[2,1-f][1,2,4]triazin-4-yl)phenyl)methanamine hydrochloride was prepared to give the product as a yellow solid. The crude product was purified by preparative HPLC (Method A, 45-65%). LCMS m / z=504.3 [M+H] +

[0310] 4. Synthesis of 5-(tert-butyl)-N-(4-(6-((2R,6R)-2,6-dimethylmorpholino)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-methylbenzyl)-1,2,4-oxadiazole-3-carboxamide and 5-(tert-butyl)-N-(4-(6-((2S,6S)-2,6-dimethylmorpholino)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-methylbenzyl)-1,2,4-oxadiazole-3-carboxamide hydrochloride [ka] The title compound was prepared by SFC separation (Diacel Chiralcel OJ-H, 250 × 30 mm, 5 mm, 0.1% NHOH / EtOH) of rac-5-(tert-butyl)-N-(4-(6-((2,6-trans)-2,6-dimethylmorpholino)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-methylbenzyl)-1,2,4-oxadiazole-3-carboxamide hydrochloride.

[0311] Example 43. Peak 1: 5-(tert-butyl)-N-(4-(6-((2R,6R)-2,6-dimethylmorpholino)pyrrolo[2,1-f][1,2,4]triazine-4 (-yl)-2-methylbenzyl)-1,2,4-oxadiazole-3-carboxamide (arbitrarily assigned absolute stereochemistry). Yellow solid, 21 mg. LCMS m / z=504.2 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ:9.51(br t,1H),8.46(s,1H),8.05-7.87(m,3H),7.42(d,1H),6.71(d,1H),4.54(d,2H),4.07(br dd,2H),3.23(dd,2H),2.88(dd,2H),2.45(s,3H),1.44(s,9H),1.21(d,6H).

[0312] Example 44. Peak 2 was further purified by preparative HPLC (Method A, 52-72%) to give 5-(tert-butyl)-N-(4-(6-((2S,6S)-2,6-dimethylmorpholino)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-methylbenzyl)-1,2,4-oxadiazole-3-carboxamide hydrochloride (arbitrarily assigned absolute stereochemistry). Red solid, 15 mg. LCMS m / z=504.2 [M+H] + . 1H NMR(400MHz,DMSO-d6)δ:9.51(br t,1H),8.46(s,1H),8.05-7.87(m,3H),7.42(d,1H),6.71(d,1H),4.54(d,2H),4.07(br dd,2H),3.23(dd,2H),2.88(dd,2H),2.45(s,3H),1.44(s,9H),1.21(d,6H).

[0313] Example 45. 3-(tert-butyl)-N-(3-fluoro-2-methoxy-4-(6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)benzyl)-1,2,4-oxadiazole-5-carboxamide [ka] Synthesis of 1,4-bromo-3-fluoro-2-methoxybenzonitrile [ka] To a solution of 4-bromo-2,3-difluorobenzonitrile (9.50 g, 43.6 mmol) in DMF (30 mL) was added KCO (18.1 g, 131 mmol) and MeOH (7.1 mL, 174 mmol), and the reaction was stirred at 55 °C for 16 h. The reaction mixture was diluted with HO (300 mL), and the resulting solid was filtered off and washed with HO (200 mL). The solid was dried in vacuo to give the title compound (12.0 g, crude) as a white solid. 1 H NMR(400MHz,CDCl3)δ:7.30-7.20(m,2H),4.16(s,3H).

[0314] 2. tert-Butyl (4-bromo-3-fluoro-2-methoxybenzyl)carbamate Synthesis of To [ka] Following a procedure similar to that described in Step 1 of Example 35, 4-bromo-3-fluoro-2-methoxybenzonitrile gave the title compound as an oil (5.7 g, 50%). LCMS m / z=277.9 [M-tBu+H] +

[0315] 3. Synthesis of tert-butyl (3-fluoro-2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)carbamate [ka] The title compound was prepared from tert-butyl (4-bromo-3-fluoro-2-methoxybenzyl)carbamate following a procedure similar to that described in Step 5 of Example 25. LCMS m / z=326.1 [M-tBu+H] +

[0316] 4. Synthesis of (4-(6-bromopyrrolo[2,1-f][1,2,4]triazin-4-yl)-3-fluoro-2-methoxybenzyl)carbamate [ka] To a solution of 6-bromo-4-chloro-pyrrolo[2,1-f][1,2,4]triazine (350 mg, 0.92 mmol) in dioxane (30 mL) and water (3 mL) was added tert-butyl (3-fluoro-2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)carbamate (470 mg, 2.0 mmol) and K2CO3 (381 mg, 2.8 mmol). Pd(dppf)Cl2 (34 mg, 0.05 mmol) was added and stirred at 85 °C under N2 for 16 h. The solvent was concentrated in vacuo and purified by silica gel chromatography (petroleum ether / EtOAc = 100:0 to 75:25) to give the title compound (450 mg, crude) as a yellow oil. LCMS m / z = 453.1 [M+H] +

[0317] 5. Synthesis of tert-butyl (3-fluoro-2-methoxy-4-(6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)benzyl)carbamate [ka] Following the procedure described in Step 1 of Example 38, tert-butyl (4-(6-bromopyro[2,1-f][1,2,4]triazin-4-yl)-3-fluoro-2-methoxybenzyl)carbamate and 1-methylpyrazole-4-boronic acid pinacol ester gave the title compound as a yellow oil (170 mg, 81% over 3 steps). LCMS m / z=453.2 [M+H] +

[0318] 6. Synthesis of (3-fluoro-2-methoxy-4-(6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)phenyl)methanamine hydrochloride [ka] Following the procedure described in Step 5 of Example 35, tert-butyl (3-fluoro-2-methoxy-4-(6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)benzyl)carbamate gave the title compound as a white solid. LCMS m / z=353.1 [M+H] +

[0319] 7. Synthesis of 3-(tert-butyl)-N-(3-fluoro-2-methoxy-4-(6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)benzyl)-1,2,4-oxadiazole-5-carboxamide. [ka] To a solution of (3-fluoro-2-methoxy-4-(6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)phenyl)methanamine hydrochloride (40 mg, 0.11 mmol) in DCM (30 mL) and DMF (3 mL) was added 3-(tert-butyl)-1,2,4-oxadiazole-5-carboxylic acid (39 mg, 0.23 mmol), HATU (43 mg, 0.11 mmol), and DIPEA (44 mg, 0.34 mmol) and stirred at 20 °C for 4 h. The reaction was concentrated in vacuo, and the residue was purified by preparative HPLC (Method E, 50-73%) to give the title compound as a yellow solid (15 mg, 26% over two steps). LCMS m / z = 505.1 [M+H] + ; 1 H NMR(400MHz,DMSO-d6)δ:9.92(t,1H),8.59(s,1H),8.51(s,1H),8.18(s,1H),7.92(s,1H), 7.50(t,1H),7.33(d,1H),7.05(s,1H),4.61(d,2H),4.00(s,3H),3.85(s,3H),1.37(s,9H).

[0320] Examples 46 to 55 The title compounds were prepared in parallel using the following general protocol. [ka]

[0321] 1. Synthesis of (2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanamine hydrochloride [ka] tert-Butyl N-[[2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl]carbamate (WO A solution of 2015089327A1 (35.7 g, 103 mmol) 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 aqueous NaHCO3 and extracted with EtOAc (2 x 100 mL). The combined organic extracts were washed with brine, dried (Na2SO4), and filtered. 4 M HCl in dioxane (30 mL) was added and the solution was concentrated in vacuo. Diethyl ether (500 mL) was added and the suspension was stirred and filtered. The solid was dried in vacuo to give the title compound (23.5 g, 84%) as an off-white solid. 1 H NMR(300MHz,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).

[0322] 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 hydrochloride (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 allowed to warm to room temperature and stirred for 2 hours. 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 x 100 mL), and the combined organic extracts were washed with water (3 x 50 mL), saturated aqueous NaHCO (50 mL), and brine (50 mL). The organic layer was dried (NaSO), filtered, and concentrated in vacuo to give a beige oil. The crude oil was purified by silica gel column chromatography (0-30% EtOAc / Hept) to give the title compound as a thick, pale yellow oil that slowly solidified upon standing (29.0 g, 60%). LCMS m / z = 400.2 [M+H] + ; 1 H NMR(500MHz,CDCl3)δ:7.70-7.62(m,2H),7.31(d,1H),7.09(br s,1H),4.68(d,2H),2.39(s,3H),1.45(s,9H),1.36(s,12H).

[0323] 3. Synthesis of Examples 46-55 using parallel chemistry protocols. [ka] A 2-dram vial was charged with 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, the appropriate chloride (HetCl), Pd(dppf)Cl₂·DCM, and K₂CO₃. Dioxane (1 mL) and HO (1 mL) were added, and each reaction mixture was purged with a stream of N₂ for approximately 1 min. The reactions were heated at 90–100 °C for 16 h. The cooled reaction mixtures were concentrated in vacuo to give a black solid / oil, and the residue was taken up in MeCN, filtered through a silica plug, and purified by preparative HPLC (Method B or Method C, gradient optimized for each compound). [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4]

[0324] Example 56 (R)-5-(tert-butyl)-N-(1-fluoro-2-(pyrrolo[2,1-f][1,2,4]triazin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)-1,2,4-oxadiazole-3-carboxamide [ka] Synthesis of 1,5-(2-fluoro-3-methoxyphenyl)pent-4-enoic acid [ka] NaH (13.0 g, 324 mmol, 60% in mineral oil) was added to a solution of (3-carboxypropyl)triphenylphosphonium bromide (55.6 g, 129 mmol) in DMSO (500 mL) at 0° C., and the mixture was stirred for 30 min. 2-Fluoro-3-methoxybenzaldehyde (20.0 g, 129 mmol) in DMSO (50 mL) was added, and the mixture was stirred at room temperature for 14 h. The reaction mixture was quenched with water (500 mL) and extracted with EtOAc (500 mL). The aqueous layer was acidified to pH 3 with aqueous HCl (1 N). The residue was purified by silica gel column chromatography (petroleum ether / EtOAc = 5:1 to 1:1) to give the title compound (22 g, 76%) as a yellow oil as a mixture of cis / trans isomers. 1 H NMR(400MHz,CDCl3)δ:11.27(brs,1H),7.00-7.10(m,1.5H),6.80-6.90(m,1.5H),6.60-6.70(m,0.5H) ,6.40-6.50(m,0.5H),6.30-6.40(m,0.5H),5.70-5.80(m,0.5H),3.85-3.90(m,3H),2.40-2.60(m,4H).

[0325] Synthesis of 2,5-(2-fluoro-3-methoxyphenyl)pentanoic acid [ka] To a mixture of 5-(2-fluoro-3-methoxyphenyl)pent-4-enoic acid (22 g, 98 mmol) in EtOH (50 mL) was added Pd / C (4.00 g, 10% w / w, wet) and the mixture was stirred under H (15 psi) at 20° C. for 1 h. The reaction mixture was filtered through Celite® and the filtrate was concentrated in vacuo to give the title compound as an off-white solid (22 g, 99%). 1H NMR:(400MHz,DMSO-d6)δ:12.04(br s,1H),6.90-7.10(m,2H),6.70-6.80(m,1H),3.80(s,3H),2.58(t,2H),2.22(t,2H),0.90-1.10(m,4H).

[0326] 3. Synthesis of 1-fluoro-2-methoxy-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-one [ka] A solution of 5-(2-fluoro-3-methoxyphenyl)pentanoic acid (22.0 g, 97.2 mmol) in PPA (100 mL) was stirred at 100° C. for 30 min. The mixture was cooled to 15° C., diluted with aqueous NaOH (1 N, 300 mL), and extracted with EtOAc (2×300 mL). The combined organics were washed with brine (500 mL), dried (NaSO), and concentrated in vacuo. The residue was purified by silica gel column chromatography (petroleum ether / EtOAc=3:1) to give the title compound (15 g, 74%) as a yellow oil. 1 H NMR:(400MHz,CDCl3)δ:7.58(dd,1H),6.89(t,1H),3.94(s,3H),3.01(t,2H),2.73(t,2H),1.60-1.90(m,4H).

[0327] 4. Synthesis of 1-fluoro-2-hydroxy-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-one [ka] To a solution of 1-fluoro-2-methoxy-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-one (5.0 g, 24 mmol) in toluene (50 mL) under N was added AlBr (28.8 mL, 29 mmol, 1 M in CHBr). The mixture was stirred at 95 °C under N for 2 h. The reaction mixture was poured into aqueous HCl (100 mL, 1 M) and extracted with EtOAc (2 × 100 mL). The combined organics were washed with brine (100 mL), dried (NaSO), and concentrated in vacuo. The residue was purified by silica gel column chromatography (petroleum ether / EtOAc = 5:1) to give the title compound (5.4 g, 96%) as a brown solid. 1 H NMR(400MHz,CDCl3)δ:7.53(dd,1H),6.92(t,1H),5.88-5.87(m,1H),2.99(t,2H),2.73(t,2H),1.92-1.79(m,4H).

[0328] 5. Synthesis of (R,Z)-N-(1-fluoro-2-hydroxy-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-ylidene)-2-methylpropane-2-sulfinamide. [ka] To a solution of 1-fluoro-2-hydroxy-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-one (5.0 g, 25.8 mmol) in THF (300 mL) was added (S)-2-methylpropane-2-sulfinamide (25 g, 206 mmol) and titanium ethoxide (47 g, 206 mmol), and the mixture was stirred at 80 °C for 17 h. The reaction mixture was poured into HO (1 L) and extracted with EtOAc (3 × 500 mL). The combined organics were dried (NaSO) and concentrated in vacuo. The residue was purified by silica gel column chromatography (petroleum ether / EtOAc = 5:1) to give the title compound (6.0 g, 78%) as a yellow solid. 1H NMR:(400MHz,DMSO-d6)δ:10.30(s,1H),7.23(d,1H),6.84(t,1H),3.13-2.77(m,4H),1.74-1.69(m,4H),1.18(s,9H).

[0329] 6. (S)-N-((R)-1-Fluoro-2-hydroxy-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)-2-methylpropane-2-sulfine Synthesis of amides. [ka] L-Selectride (26.9 mL, 26.9 mmol) was slowly added to a solution of (R,Z)-N-(1-fluoro-2-hydroxy-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-ylidene)-2-methylpropane-2-sulfinamide (2.0 g, 6.7 mmol) in THF (40 mL) at 20 °C and stirred for 2 h. The reaction was quenched with saturated aqueous NH4Cl (30 mL), poured into HO (100 mL), and extracted with EtOAc (2 x 100 mL). The combined organics were washed with brine (100 mL), dried (Na2SO4), and concentrated in vacuo. The residue was purified by preparative HPLC (Waters Xbridge Prep OBD C18 150 x 30 mm, 5 μm, water (0.05% NH4OH)-MeCN, 26-56%) to give the title compound as a white solid (500 mg, 25%). 1 H NMR:(400MHz,DMSO-d6)δ:9.56(s,1H),6.86(d,1H),6.65(t,1H),5.14(d,J= 3.6Hz, 1H), 4.34(s, 1H), 2.87-2.65(m, 2H), 1.92-1.48(m, 6H), 1.11(s, 9H).

[0330] 7. Synthesis of (R)-5-amino-1-fluoro-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-ol [ka] To a solution of (S)-N-((R)-1-fluoro-2-hydroxy-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)-2-methylpropane-2-sulfinamide (550 mg, 1.8 mmol) in EtOAc (1 mL) was added HCl solution (5 mL, 4 M in EtOAc) and the mixture was stirred at 10° C. for 1 h. The reaction mixture was concentrated in vacuo and the residue was used directly in the next step without further purification. LCMS m / z=179.0 [M-OH] +

[0331] 8. Synthesis of tert-butyl (R)-(1-fluoro-2-hydroxy-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)carbamate [ka] To a solution of (R)-5-amino-1-fluoro-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-ol (360 mg, 1.8 mmol) and EtN (373 mg, 3.7 mmol) in DCM (5 mL) was added BocO (402 mg, 1.84 mmol), and the mixture was stirred at 20° C. for 2 hours. The reaction mixture was concentrated in vacuo, and the residue was purified by silica gel column chromatography (petroleum ether / EtOAc=20:1) to give the title compound (250 mg, 46%) as a white solid. 1 H NMR:(400MHz,DMSO-d6)δ:9.46(s,1H),7.37(d,1H),6.75(d,1H),6.66(t,1H),4.59(t,1H),3.07-3. 03(m,1H),2.45-2.42(m,1H),1.77-1.64(m,4H),1.47-1.45(m,1H),1.37(s,9H),1.28-1.16(m,1H).

[0332] 9. Synthesis of (R)-5-((tert-butoxycarbonyl)amino)-1-fluoro-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl trifluoromethanesulfonate [ka] To a solution of tert-butyl (R)-(1-fluoro-2-hydroxy-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)carbamate (250 mg, 0.85 mmol) in DCM (5 mL) was added TfO (263 mg, 0.93 mmol) and pyridine (134 mg, 1.7 mmol) at 10 °C, and the resulting mixture was stirred at 10 °C for 1 h. The reaction mixture was poured into water (20 mL) and extracted with DCM (2 × 2 mL). The combined organics were washed with brine (60 mL), dried (NaSO), and concentrated in vacuo. The residue was purified by silica gel column chromatography (petroleum ether / EtOAc = 10:1) to give the title compound (380 mg, quantitative) as a yellow solid. 1 H NMR:(400MHz,DMSO-d6)δ:7.64(d,1H),7.47(t,1H),7.12(d,1H),4.73(t,1H),3.16-3.11(m, 1H),2.65-2.58(m,1H),1.81-1.74(m,4H),1.54-1.45(m,1H),1.38(s,9H),1.22-1.20(m,1H).

[0333] 10. Synthesis of tert-butyl (R)-(1-fluoro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)carbamate [ka] To a solution of (R)-5-((tert-butoxycarbonyl)amino)-1-fluoro-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl trifluoromethanesulfonate (380 mg, 0.9 mmol) in dioxane (5 mL) was added bis(pinacolato)diboron (339 mg, 1.3 mmol), Pd(dppf)Cl.sub.2·DCM (73 mg, 0.09 mmol), and KOAc (175 mg, 1.8 mmol). The mixture was stirred at 85°C under N for 17 hours. The mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / EtOAc = 10:1) to give the title compound (350 mg, crude) as a yellow solid. LCMS m / z = 268.0 [M-(CH 10 )-tBu+H] +

[0334] 11. Synthesis of tert-butyl (R)-(1-fluoro-2-(pyrrolo[2,1-f][1,2,4]triazin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)carbamate [ka] To a solution of tert-butyl (R)-(1-fluoro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)carbamate (250 mg, 0.62 mmol) in dioxane (30 mL) and water (5 mL) was added 4-chloropyro[2,1-f][1,2,4]triazine (104 mg, 0.68 mmol) and K2CO3 (171 mg, 1.2 mmol) at 20 °C. Pd(dppf)2Cl2 (45 mg, 0.06 mmol) was added under N2 atmosphere at 20 °C, and the mixture was stirred at 85 °C under N2 for 4 h. The cooled reaction mixture was filtered and concentrated in vacuo, and the residue was purified by silica gel column chromatography (petroleum ether / EtOAc=5:1) to give the title compound as a yellow solid (180 mg, 74%). LCMS m / z=397.1 [M+H] +

[0335] 12. Synthesis of (R)-1-fluoro-2-(pyrrolo[2,1-f][1,2,4]triazin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-amine hydrochloride [ka] A solution of tert-butyl (R)-(1-fluoro-2-(pyrrolo[2,1-f][1,2,4]triazin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)carbamate (180 mg, 0.45 mmol) in HCl solution (30 mL, 4 M in EtOAc) was stirred at 20° C. for 1 h. The mixture was concentrated in vacuo to give the title compound (150 mg, crude) as a yellow solid, which was used in the next step without further purification. LCMS m / z=297.1 [M+H] +

[0336] 13. Synthesis of (R)-5-(tert-butyl)-N-(1-fluoro-2-(pyrrolo[2,1-f][1,2,4]triazin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-yl)-1,2,4-oxadiazole-3-carboxamide hydrochloride [ka] To a solution of (R)-1-fluoro-2-(pyrrolo[2,1-f][1,2,4]triazin-4-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-amine hydrochloride (100 mg, 0.3 mmol) in DCM (30 mL) was added DIPEA (78 mg, 0.6 mmol) at 20 °C. 5-(tert-butyl)-1,2,4-oxadiazole-3-carboxylic acid (77 mg, 0.5 mmol) and HATU (172 mg, 0.5 mmol) were added slowly at 20 °C, and the mixture was stirred at 20 °C for 1 h. The reaction mixture was poured into HO (50 mL) and extracted with DCM (3 × 50 mL). The combined organics were washed with brine (100 mL), dried (NaSO), and concentrated in vacuo. The residue was purified by preparative HPLC (Method A, 50-70%) to give the title compound as a white solid (90 mg, 67%). LCMS m / z=449.1 [M+H] + . 1 H NMR:(400MHz,DMSO-d6)δ:9.67(d,1H),8.62(s,1H),8.18(s,1H),7.61-7.56(m,1H),7.22(d,1H),7.08-7.0 5(m,1H),6.86(s,1H),5.32(t,1H),3.28(d,1H),2.66(d,1H),1.93-1.81(m,5H),1.44(s,9H),1.29(d,1H).

[0337] Example 57 (R)-3-(tert-butyl)-N-(1-(2-methyl-4-(6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)phenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide Samid [ka] 1. Synthesis of 1-(4-bromo-2-methylphenyl)ethan-1-one [ka] Methylmagnesium iodide (3 M, 10.2 mL) was added dropwise to a solution of 4-bromo-2-methyl-benzonitrile (4.0 g, 20 mmol) in THF (20 mL) at room temperature. The reaction mixture was heated under reflux for 2 hours, cooled to room temperature, and stirred for an additional 72 hours. The reaction mixture was cooled to 0° C., quenched with saturated aqueous NH4Cl (100 mL), and extracted into EtOAc (2×100 mL). The combined organics were concentrated in vacuo, and the residue was treated with aqueous HCl (4 N, 20 mL) at 0° C., and the mixture was then stirred at room temperature for 18 hours. The reaction mixture was extracted with EtOAc (50 mL), washed with H2O (50 mL), dried (Na2SO4), and concentrated in vacuo to give the title compound (3.0 g, 70%) as a pale orange oil. LCMS m / z=213.0 [M+H] +

[0338] 2. Synthesis of (R,E)-N-(1-(4-bromo-2-methylphenyl)ethylidene)-2-methylpropane-2-sulfinamide [ka] To a solution of 1-(4-bromo-2-methylphenyl)ethan-1-one (3.0 g, 14 mmol) in THF (48 mL) was added (R)-(+)-2-methyl-2-propanesulfinamide (1.7 g, 14 mmol) and Ti(OEt) (6.5 g, 28 mmol), and the mixture was heated at 70 °C for 20 h. The cooled reaction mixture was quenched with brine (100 mL) and diluted with EtOAc (100 mL) to give a biphasic mixture with a thick white precipitate. The solids were removed by filtration, the layers were separated, and the combined organics were dried. (Na2SO4) and concentrated in vacuo. The residue was purified by silica gel column chromatography (0-50% EtOAc / Hept) to give the title compound as a yellow oil (2.96 g, 66%). LCMS m / z=318.0 [M+H] +

[0339] 3. Synthesis of (R)-N-((R)-1-(4-bromo-2-methylphenyl)ethyl)-2-methylpropane-2-sulfinamide [ka] NaBH4 (1.06 g, 28 mmol) was added slowly in small portions to a solution of (R,E)—N-(1-(4-bromo-2-methylphenyl)ethylidene)-2-methylpropane-2-sulfinamide (2.96 g, 9.4 mmol) in THF / HO (98 / 2, 62.4 mL) at −50° C. The mixture was stirred at −50° C. for 7 h and then warmed to room temperature over 18 h. The reaction was quenched with HO (20 mL) and extracted with EtOAc (100 mL). The combined organics were dried (Na2SO4) and concentrated in vacuo. The residue was purified by silica gel column chromatography (20-100% EtOAc / Hept) to give the title compound (1.6 g, 55% yield) as a colorless oil. LCMS m / z=320.1 [M+H] +

[0340] 4. Synthesis of (R)-1-(4-bromo-2-methylphenyl)ethan-1-amine hydrochloride [ka] To a solution of (R)-N-((R)-1-(4-bromo-2-methylphenyl)ethyl)-2-methylpropane-2-sulfinamide (4.5 g, 14 mmol) in EtOAc (5 mL) was added HCl solution (30 mL, 4 M in EtOAc) at 15° C., and the reaction mixture was stirred for 2 h. The mixture was filtered, and the filter cake was dried in vacuo to give the title compound (3.3 g, 93%) as a white solid, which was used in the next step without further purification. LCMS m / z=198.9 [M-NH] +

[0341] 5. Synthesis of tert-butyl (R)-(1-(4-bromo-2-methylphenyl)ethyl)carbamate [ka] To a solution of (R)-1-(4-bromo-2-methylphenyl)ethan-1-amine hydrochloride (3.3 g, 13.2 mmol) in DCM (40 mL) was added EtN (2.67 g, 26.3 mmol) and BocO (3.7 g, 17.1 mmol) at 15 °C, and the mixture was stirred at 15 °C for 17 h. The reaction mixture was concentrated in vacuo, and the residue was purified by silica gel column chromatography (petroleum ether / EtOAc = 20:1) to give the title compound (3.8 g, 92%) as a white solid. LCMS m / z = 198.8 [M-Boc-NH] +

[0342] 6. Synthesis of tert-butyl (R)-(1-fluoro-2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)carbamate [ka] To a solution of tert-butyl (R)-(1-(4-bromo-2-methylphenyl)ethyl)carbamate (3.8 g, 12.1 mmol) in 1,4-dioxane (30 mL) under N was added bis(pinacolato)diboron (3.7 g, 14.5 mmol), Pd(dppf)Cl·DCM (987 mg, 1.2 mmol), and KOAc (2.4 g, 24.2 mmol). The reaction mixture was heated at 85 °C under N for 17 h. The reaction mixture was concentrated in vacuo, and the residue was purified by silica gel column chromatography (petroleum ether / EtOAc = 20:1) to give the title compound (4.0 g, 87%) as a yellow oil. 1 H NMR:(400MHz,MeOH-d4)δ:7.53(d,1H),7.50(s,1H),7.30(d,1H),3.65(s,1H),2.37(s,3H),1.41(s,9H),1.33(s,12H),1.25-1.22(m,3H).

[0343] 7. Synthesis of tert-butyl (R)-(1-(4-(6-bromopyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-methylphenyl)ethyl)carbamate [ka] tert-Butyl (R)-(1-(2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)carbamate (405 mg, 1.1 mmol), 6-bromo-4-chloropyro[2,1-f][1,2,4]triazine (520 mg, 2.2 mmol) in dioxane (10 mL) and water (0.1 mL). A mixture of Pd(dppf)Cl₂·DCM (82 mg, 0.11 mmol) and K₂CO₃ (310 mg, 2.2 mmol) was stirred under N₂ at 100°C for 12 h. The mixture was concentrated in vacuo, and the residue was purified by silica gel column chromatography (0-33% EtOAc / petroleum ether) to give the title compound (380 mg, 79%) as a red solid. LCMS m / z = 433.1 [M+H] +

[0344] 8. Synthesis of tert-butyl (R)-(1-(2-methyl-4-(6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)phenyl)ethyl)carbamate [ka] A mixture of tert-butyl (R)-(1-(4-(6-bromopyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-methylphenyl)ethyl)carbamate (380 mg, 0.88 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (183 mg, 0.88 mmol), Pd(dppf)Cl (64 mg, 0.09 mmol), and KCO (244 mg, 1.76 mmol) in a mixture of dioxane (10 mL) and water (1 mL) was stirred at 90 °C under N for 12 h. The mixture was concentrated in vacuo, and the residue was purified by silica gel column chromatography (0–50% EtOAc / petroleum ether) to give the title compound (260 mg, 68%) as a yellow oil. LCMS m / z=433.1[M+H] +

[0345] 9. Synthesis of (R)-1-(2-methyl-4-(6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)phenyl)ethan-1-amine hydrochloride [ka] HCl solution (10 mL, 4 M in EtOAc) was added to tert-butyl (R)-(1-(2-methyl-4-(6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)phenyl)ethyl)carbamate (260 mg, 0.6 mmol) and the mixture was stirred at 20° C. for 1 h. The mixture was concentrated in vacuo to give the title compound (220 mg, crude) as a yellow solid, which could be further purified. Used in the next step without further purification. LCMS m / z=333.3[M+H] +

[0346] 10. Synthesis of (R)-3-(tert-butyl)-N-(1-(2-methyl-4-(6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)phenyl)ethyl)-1,2,4-oxadiazole-5-carboxamide [ka] To a solution of (R)-1-(2-methyl-4-(6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)phenyl)ethan-1-amine hydrochloride (80 mg, 0.22 mmol) and 3-(tert-butyl)-1,2,4-oxadiazole-5-carboxylic acid (74 mg, 0.44 mmol) in DCM (45 mL) was added DIPEA (84 mg, 0.65 mmol), followed by the slow addition of HATU (99 mg, 0.26 mmol). The reaction mixture was stirred at 20° C. for 1 h and concentrated in vacuo. The residue was purified by preparative HPLC (Method A, 51-71%) to give the title compound as a yellow solid (55.6 mg, 52%). LCMS m / z=485.2 [M+H] + ; 1 H NMR:(500MHz,DMSO-d6)δ:10.01(d,1H),8.59(s,1H),8.50(d,1H),8.22(s,1H),8.03-8.01(m,1H),7.98-7. 96(m,2H),7.70(d,1H),7.45(d,1H),5.42-5.35(m,1H),3.88(s,3H),2.55(s,3H),1.56(d,3H),1.38(s,9H).

[0347] Example 58. 5-(tert-butyl)-N-(4-(6-(2-methoxyethoxy)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-methylbenzyl)-1,2,4-oxadiazole-3-carboxamide [ka] 1. Synthesis of tert-butyl (2-methyl-4-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)benzyl)carbamate [ka] (Bispinacolate)diboron (183 mg, 0.72 mmol), KOAc (71 mg, 0.72 mmol), and Pd(dppf)Cl (29 mg, 0.036 mmol) were added to a solution of tert-butyl (4-(6-bromopyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-methylbenzyl)carbamate (150 mg, 0.36 mmol) in dioxane (15 mL) and stirred at 80 °C under N for 16 h. The cooled mixture was concentrated in vacuo to give the title compound, which was carried forward without further purification. LCMS m / z = 465.3 [M+H] +

[0348] 2. Synthesis of tert-butyl (4-(6-hydroxypyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-methylbenzyl)carbamate [ka] To a solution of tert-butyl (2-methyl-4-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)benzyl)carbamate (680 mg, 1.5 mmol) in THF (20 mL) was added HO (498 mg, 4.4 mmol, 30% purity) and AcOH (264 mg, 4.4 mmol), and the mixture was stirred at 50 °C for 2 h. The reaction was poured into HO (20 mL) and extracted with DCM (3 × 10 mL). The combined organics were treated with NaSO, and the mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography (0–100% petroleum ether / EtOAc) to give the title compound (350 mg, 68%) as a yellow oil. LCMS m / z = 355.1 [M+H] +

[0349] 3. Synthesis of tert-butyl (4-(6-(2-methoxyethoxy)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-methylbenzyl)carbamate [ka] To a solution of tert-butyl (4-(6-hydroxypyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-methylbenzyl)carbamate (130 mg, 0.37 mmol) in DMF (3 mL) was added 1-bromo-2-methoxyethane (153 mg, 1.1 mmol) and K2CO3 (152 mg, 1.1 mmol), and the mixture was stirred at 100 °C for 5 h. The reaction was diluted with brine (20 mL) and extracted with EtOAc (3 × 10 mL). The combined organics were dried (Na2SO4) and concentrated in vacuo. The residue was purified by preparative TLC (50% petroleum ether / EtOAc) to afford the title compound (120 mg, 79%) as a yellow oil. 1 H NMR(400MHz,CDCl3)δ:8.46(s,1H),7.82(s,2H),7.62(d,1H),7.41-7.37(m,1H),6.58(d,1H),4.84 (s,1H),4.38(d,2H),4.20-4.17(m,2H),3.77-3.74(m,2H),3.44(s,3H),2.40(s,3H),1.46(s,9H).

[0350] 4. Synthesis of (4-(6-(2-methoxyethoxy)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-methylphenyl)methanamine hydrochloride [ka] tert-Butyl (4-(6-(2-methoxyethoxy)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-methylbenzyl)carbamate (110 mg, 0.27 mmol) was dissolved in HCl solution (25 mL, 4 M in EtOAc) and the mixture was stirred at 20° C. for 1 h. The resulting solid was collected by filtration to give the title compound (100 mg, crude) as a yellow solid, which was used in the next step without further purification. LCMS m / z=312.7 [M+H] +

[0351] 5. Synthesis of 5-(tert-butyl)-N-(4-(6-(2-methoxyethoxy)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-methylbenzyl)-1,2,4-oxadiazole-3-carboxamide [ka] To a solution of (4-(6-(2-methoxyethoxy)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-methylphenyl)methanamine hydrochloride (100 mg, 0.29 mmol) in DCM (30 mL) was added DIPEA (74 mg, 0.57 mmol) and 5-(tert-butyl)-1,2,4-oxadiazole-3-carbonyl chloride (54 mg, 0.29 mmol), and the mixture was stirred at 20 °C for 10 min. The mixture was diluted with water (30 mL) and extracted with DCM (3 × 15 mL). The combined organics were concentrated in vacuo, and the residue was purified by preparative HPLC (Method D, 43-73%) to give the title compound as a yellow solid (70.5 mg, 53%). LCMS m / z = 465.1 [M+H] + . 1 H NMR:(400MHz,DMSO-d6)δ:9.52(t,1H),8.57(s,1H),8.05(d,1H),7.95-7.92(m,2H),7.43(d,1H),6. 84(d,1H),4.54(d,2H),4.24-4.21(m,2H),3.69-3.66(m,2H),3.31(s,3H),2.45(s,3H),1.44(s,9H).

[0352] Example 59. N-(4-(6-(1-acryloyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-methylbenzyl)-5-(tert-butyl)-1,2,4-oxadiazole-3-carboxamide [ka] 1. Synthesis of tert-butyl (4-(6-(1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-methylbenzyl)carbamate [ka] A mixture of tert-butyl (4-(6-bromopyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-methylbenzyl)carbamate (500 mg, 1.2 mmol), 1H-pyrazol-4-ylboronic acid (168 mg, 1.5 mmol), Pd(dppf)Cl·DCM (98 mg, 0.12 mmol), and KCO (332 mg, 2.4 mmol) in dioxane (10.3 mL) and water (2.4 mL) was purged with N for 5 minutes. The reaction mixture was stirred at 100 °C under N for 24 hours. The cooled reaction was concentrated in vacuo, and the residue was partitioned between water (100 mL) and EtOAc (100 mL). The layers were separated, the aqueous phase was extracted with EtOAc (2 × 50 mL), and the combined organic layers were washed with brine (150 mL). The organic phase was dried (Na2SO4), filtered, and concentrated, and the residue was purified by silica gel column chromatography (0-100% EtOAc / Hept) to give the title compound as a yellow solid (96 mg, 20%). LCMS m / z=405.0 [M+H] +1 H NMR(500MHz,MeOH-d4)δ:8.41(s,1H),8.28(d,1H),8.12(br s,1H),8.02-7.88(m,3H),7.49(d,1H),7.32(d,1H),7.17(br d,1H),4.39-4.31(m,2H),2.47(s,3H),1.49(s,9H)

[0353] 2. Synthesis of (4-(6-(1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-methylphenyl)methanamine hydrochloride [ka] To a solution of tert-butyl (4-(6-(1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-methylbenzyl)carbamate (96 mg, 0.24 mmol) in EtOAc (2.3 mL) was added HCl solution (0.2 mL, 1 M in EtOAc) and the reaction was stirred at room temperature for 5 days. The mixture was concentrated in vacuo to give the title compound (72 mg, crude), which was carried forward without further purification. LCMS m / z=305.0 [M+H] +

[0354] 3. Synthesis of N-(4-(6-(1-acryloyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-methylbenzyl)-5-(tert-butyl)-1,2,4-oxadiazole-3-carboxamide [ka] Part A: EtN (0.13 mL, 0.95 mmol) and HATU (140 mg, 0.36 mmol) were added to a solution of potassium 5-(tert-butyl)-1,2,4-oxadiazole-3-carboxylate potassium (54 mg, 0.26 mmol) in THF (3.9 mL) in an ice-water cooling bath, and the reaction mixture was stirred at 0 °C for 10 min before adding (4-(6-(1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-methylphenyl)methanamine hydrochloride (72 mg, 0.24 mmol). The reaction was allowed to warm to room temperature and stirred for 24 h. The reaction was quenched with HO (5 mL) and extracted with EtOAc (3 × 5 mL). The combined organics were washed with brine, dried (NaSO), and concentrated in vacuo. The crude product was purified by silica gel column chromatography (2-100% EtOAc / Hept) to give N-(4-(6-(1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-methylbenzyl)-5-(tert-butyl)-1,2,4-oxadiazole-3-carboxamide as a yellow solid (72 mg, crude). LCMS m / z=457.0 [M+H] +

[0355] Part B: To a solution of N-(4-(6-(1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-methylbenzyl)-5-(tert-butyl)-1,2,4-oxadiazole-3-carboxamide (Part A, 33 mg, 0.07 mmol) in DCM (1.7 mL) at 0 °C, EtN (22 mg, 0.22 mmol) and acryloyl chloride (8 mg, 0.09 mmol) were added. The reaction mixture was warmed to room temperature and stirred for 0.5 h, after which an additional portion of acryloyl chloride (8 mg, 0.09 mmol) was added. The reaction was concentrated in vacuo, and the residue was purified by silica gel column chromatography (0–100% EtOAc / Hept) to afford the title compound (12 mg, 31%) as a pale yellow solid. LCMS m / z=511.0[M+H] + ; 1 H NMR(500MHz,DMSO-d6)δ:9.55(t,1H),9.13(s,1H),8.71(d,1H),8.61(s,1H),8.56(s,1H),8.07-7.9 8(m,2H),7.73(d,1H),7.57-7.46(m,2H),6.68(dd,1H),6.28-6.20(m,1H),4.57(d,2H),1.44(s,9H).

[0356] Example 60. 5-(tert-butyl)-N-(2-methyl-4-(6-(1-methylazetidin-3-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)benzyl)-1,2,4-oxadiazole-3-carboxamide trifluoroacetate [ka] 1. Synthesis of (4-(6-bromopyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-methylphenyl)methanamine hydrochloride [ka] To a solution of tert-butyl (4-(6-bromopyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-methylbenzyl)carbamate (186 mg, 0.45 mmol) in MeOH (2 mL) was added HCl solution (0.2 mL, 4 M in dioxane) and the reaction was stirred at room temperature for 18 hours. The reaction mixture was concentrated in vacuo to give the title compound (185 mg, crude). LCMS m / z=319.0 [M+H] +

[0357] 2. Synthesis of (4-(6-bromopyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-methylbenzyl)carbamate [ka] To a solution of (4-(6-bromopyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-methylphenyl)methanamine hydrochloride (185 mg, 0.52 mmol) in DCM (4 mL) was added EtN (0.2 mL, 1.6 mmol) and benzyl chloroformate (89 μL, 0.63 mmol), and the reaction was stirred at room temperature for 18 h. The mixture was concentrated in vacuo, and the crude product was purified by silica gel column chromatography (0-100% EtOAc / Hept) to give the title compound (163 mg, 69%). LCMS m / z=451.1 [M+H] +

[0358] 3. Synthesis of tert-butyl 3-(4-(4-(((benzyloxy)carbonyl)amino)methyl)-3-methylphenyl)pyrrolo[2,1-f][1,2,4]triazin-6-yl)azetidine-1-carboxylate [ka] A mixture of benzyl (4-(6-bromopyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-methylbenzyl)carbamate (163 mg, 0.36 mmol), tert-butyl 3-bromoazetidine-1-carboxylate (128 mg, 0.54 mmol), tris(trimethylsilyl)silane (0.22 mL, 0.72 mmol), and LiOH (35 mg, 1.4 mmol) in DME (4 mL) was degassed (Mixture 1). A mixture of NiCl·glyme (8 mg, 0.04 mmol), BBBPY (10 mg, 0.04 mmol), and Ir[dF(CF)ppy](dtbbpy)PF (4 mg, 3.6 μmol) in DME (4 mL) was degassed and transferred to Mixture 1. The combined reaction mixture was degassed and then irradiated with a 30 W CREE 450 nm EvoluChem lamp (blue light) at room temperature for 18 hours, and the mixture was filtered. The filtrate was concentrated in vacuo, and the residue was purified by silica gel column chromatography (0-100% EtOAc / Hept) to give the title compound (46 mg, 24%). LCMS m / z=528.2 [M+H] +

[0359] 4. Synthesis of tert-butyl 3-(4-(4-(aminomethyl)-3-methylphenyl)pyrrolo[2,1-f][1,2,4]triazin-6-yl)azetidine-1-carboxylate [ka] A mixture of tert-butyl 3-(4-(4-((((benzyloxy)carbonyl)amino)methyl)-3-methylphenyl)pyrrolo[2,1-f][1,2,4]triazin-6-yl)azetidine-1-carboxylate (46 mg, 0.09 mmol) and Pd / C (5 mg, 0.04 mmol) in MeOH (2 mL) was stirred under H for 6 h. The mixture was filtered through Celite® and the filtrate was concentrated in vacuo to give the title compound, which was carried forward without further purification. LCMS m / z=394.4 [M+H] +

[0360] Synthesis of potassium 5,5-tert-butyl-1,2,4-oxadiazole-3-carboxylate [ka] The title compound was obtained from ethyl 5-tert-butyl-1,2,4-oxadiazole-3-carboxylate following a procedure similar to that described in Step 3 of Example 2. The crude material was carried forward without further purification.

[0361] 6. Synthesis of tert-butyl 3-(4-(4-((5-(tert-butyl)-1,2,4-oxadiazole-3-carboxamido)methyl)-3-methylphenyl)pyrrolo[2,1-f][1,2,4]triazin-6-yl)azetidine-1-carboxylate [ka] A mixture of tert-butyl 3-(4-(4-(aminomethyl)-3-methylphenyl)pyrrolo[2,1-f][1,2,4]triazin-6-yl)azetidine-1-carboxylate (40 mg, 0.1 mmol), potassium 5-tert-butyl-1,2,4-oxadiazole-3-carboxylate (42 mg, 0.2 mmol), HATU (78 mg, 0.2 mmol), and DIPEA (53 μL, 0.3 mmol) in DCM (2 mL) was stirred at room temperature for 18 h. The reaction mixture was concentrated in vacuo, and the crude product was purified by silica gel column chromatography (0-100% EtOAc / Hept) to give the title compound (10 mg, 18%). LCMS m / z = 546.3 [M+H] +

[0362] 7. Synthesis of 5-(tert-butyl)-N-(2-methyl-4-(6-(1-methylazetidin-3-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)benzyl)-1,2,4-oxadiazole-3-carboxamide trifluoroacetate [ka] Part A: A solution of tert-butyl 3-(4-(4-((5-(tert-butyl)-1,2,4-oxadiazole-3-carboxamido)methyl)-3-methylphenyl)pyrrolo[2,1-f][1,2,4]triazin-6-yl)azetidine-1-carboxylate (10 mg, 0.02 mmol) in DCM (2 mL) and TFA (0.5 mL) was stirred at room temperature for 16 hours. The mixture was concentrated in vacuo, and the residue was used in Part B (9 mg, crude). LCMS m / z=446.3 [M+H] +

[0363] Part B: AcOH (1 mg, 0.02 mmol) and formaldehyde (8 mg, 0.1 mmol, 37% purity) were added to a solution of N-(4-(6-(azetidin-3-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-methylbenzyl)-5-(tert-butyl)-1,2,4-oxadiazole-3-carboxamide trifluoroacetate (Part A, 9 mg, 0.02 mmol) in MeOH (2 mL). NaBHCN (4 mg, 0.06 mmol) was added, and the reaction mixture was stirred at room temperature for 1 h. The mixture was concentrated in vacuo, and the residue was purified by preparative HPLC (Method B, 10-90%) to give the title compound (5 mg, 41%). LCMS m / z = 460.3 [M+H] + ; 1 H NMR(400MHz,MeOH-d4)δ:9.19-9.28(m,1H),7.92-7.98(m,1H),7.28-7.34(m,1H),7.13-7.21(m,3H),6.78-6.82(m,1H),5.68-5.74(m,2) H),4.55-4.61(m,2H),4.41-4.48(m,1H),4.15-4.27(m,2H),3.95-4.05(m,1H),2.88-2.98(m,3H),2.37-2.42(m,3H),1.47-1.50(m,9H).

[0364] Example 61. 1-(tert-butyl)-N-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-(trifluoromethyl)benzyl)-1H-pyrazole-4-carboxamide [ka] 1. Synthesis of (4-(6-bromopyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-(trifluoromethyl)phenyl)methanamine hydrochloride [ka] Following the procedure described in Step 1 of Example 60, the title compound was obtained as an orange solid from tert-butyl (4-(6-bromopyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-(trifluoromethyl)benzyl)carbamate. LCMS m / z=371.0 [M+H] +

[0365] 2. Synthesis of N-(4-(6-bromopyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-(trifluoromethyl)benzyl)-1-(tert-butyl)-1H-pyrazole-4-carboxamide [ka] To a solution of (4-(6-bromopyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-(trifluoromethyl)phenyl)methanamine hydrochloride (430 mg, 1.1 mmol), 1-tert-butylpyrazole-4-carboxylic acid (353 mg, 2.1 mmol), and DIPEA (0.92 mL, 5.3 mmol) in anhydrous DMF (5 mL) was added T3P® (2.1 mL, 3.2 mmol, 50% purity), and the reaction was stirred at room temperature for 17 h. The reaction was quenched with saturated aqueous NaHCO3, diluted with EtOAc, the layers were separated, and the aqueous phase was extracted with EtOAc. The combined organic layers were dried (MgSO4), filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (0–100% EtOAc / Hept) to give the title compound (226 mg, 41%) as a yellow solid. LCMS m / z=521.1[M+H] +

[0366] 3. Synthesis of 1-(tert-butyl)-N-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-(trifluoromethyl)benzyl)-1H-pyrazole-4-carboxamide [ka] A mixture of N-(4-(6-bromopyrrolo[2,1-f][1,2,4]triazin-4-yl)-2-(trifluoromethyl)benzyl)-1-(tert-butyl)-1H-pyrazole-4-carboxamide (100 mg, 0.19 mmol), (1-methylpyrazol-4-yl)boronic acid (27 mg, 0.21 mmol), and KCO (80 mg, 0.58 mmol) in dioxane (2 mL) and HO (0.5 mL) was degassed with N for 5 min. Pd(dppf)Cl·DCM (151 mg, 0.19 mmol) was added, and the resulting mixture was heated to 100 °C overnight. The cooled reaction mixture was filtered through Celite® with EtOAc and HO. The layers were separated, and the aqueous phase was extracted with EtOAc. The combined extracts were dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by preparative HPLC (Method B, 10-90%) to give a yellow solid. The title compound was obtained (5.9 mg, 5.3%). LCMS m / z=523.2 [M+H] + , 1 H NMR(500MHz,CDCl3)δ:8.49-8.58(m,1H),8.41(s,1H),8.26(br d,1H),8.06(br d,2H),7.87(br d,1H),7.85-7.77(m,2H),7.74-7.63(m,1H),7.06(s,1H),6.37-6.20(m,1H),4.90(br d,2H), 3.99(s,3H), 1.62(s,9H).

[0367] Example 62. 5-(tert-butyl)-N-(2-cyclopropyl-3-fluoro-4-(pyrrolo[2,1-f][1,2,4]triazin-4-yl)benzyl)-1,2,4-oxadiazole-3-carboxamide trifluoroacetate [ka] 1. Synthesis of (E)-N-(2-bromo-4-chloro-3-fluorobenzylidene)-2-methylpropane-2-sulfinamide [ka] To a solution of 2-bromo-4-chloro-3-fluorobenzaldehyde (131 g, 0.55 mol) in THF (1 L) was added tert-butylsulfinamide (73 g, 0.60 mol) and Ti(OEt) (232 mL, 1.1 mol), and the reaction was stirred at room temperature for 12 h. HO was added, the resulting solid was filtered off, washed with EtOAc (2×), and the layers were separated. The filtrate was extracted with EtOAc (2×), and the combined organic layers were washed sequentially with 2 M HCl solution, water, and brine, dried (NaSO), filtered, and concentrated in vacuo to give the title compound (144 g, 77%) as a beige solid. 1 H NMR(300MHz,CDCl3)δ:8.89(s,1H),7.81(dd,1H),7.45(dd,1H),1.35(s,9H).

[0368] 2. Synthesis of (2-bromo-4-chloro-3-fluorobenzyl)methanamine hydrochloride [ka] (E)-N-(2-bromo-4-chloro-3-fluorobenzoate) in MeOH (1.5 L) To a solution of (2-methylpropane-2-sulfinamide)-2-(2-methyl-2-pyridin-2-yl)propane-2-sulfinamide (144 g, 0.42 mol) was added NaBH (19.2 g, 0.51 mol) and the reaction was stirred at room temperature for 1 hour. The reaction mixture was concentrated to approximately 150 mL, the mixture was diluted with water, and the solution was extracted with EtOAc (3 times). The organic layer was dried (NaSO), filtered, and concentrated in vacuo. The residue was dissolved in 2 M HCl in EtO and stirred at room temperature for 10 minutes. The resulting solid was filtered off, washed with heptane, and dried in vacuo to give the title compound (92 g, 80%) as a white solid. 1 H NMR(300MHz,DMSO-d6)δ:8.75(brs,3H),7.80(dd,1H),7.57(dd,1H).

[0369] 3. Synthesis of tert-butyl (2-bromo-4-chloro-3-fluorobenzyl)carbamate [ka] To a solution of (2-bromo-4-chloro-3-fluorobenzyl)methanamine hydrochloride (92 g, 0.33 mol) and EtN (233 mL, 1.7 mol) in DCM (1.5 L) was added BocO (80 g, 0.37 mol) and the reaction was stirred at room temperature for 16 h. The mixture was diluted with water and extracted with DCM (2×). The combined organic layers were washed with water, 1 M aqueous HCl, and brine, dried (NaSO), filtered, and concentrated in vacuo to give the title compound (95 g, 84%) as a white solid. 1 H NMR(300MHz,CDCl3)δ:7.33(dd,1H),7.15(dd,1H),4.36(br s,1H),5.14(s,2H),1.49(s,9H).

[0370] 4. Synthesis of tert-butyl (4-chloro-2-cyclopropyl-3-fluorobenzyl)carbamate [ka] A solution of tert-butyl (2-bromo-4-chloro-3-fluorobenzyl)carbamate (72 g, 0.21 mol), cyclopropylboronic acid (23 g, 0.27 mol), K2CO3 (58 g, 0.42 mol), Pd(dppf)Cl2·DCM (26 g, 32 mmol), and HO (200 mL) in dioxane (1 L) was stirred at 90 °C under N2 for 16 h. The cooled mixture was concentrated in vacuo, diluted with EtOAc, and filtered through Celite®. The filtrate was washed with HO, 1 M aqueous HCl, and brine, then dried (Na2SO4), filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (0–5% EtOAc / Hept) to give the title compound (48 g, 76%) as a white solid. LCMS m / z = 244.0 [M-tBu+H] +

[0371] 5. Synthesis of tert-butyl (2-cyclopropyl-3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)carbamate [ka] KOAc (16 g, 170 mmol), tert-butyl (4-chloro-2-cyclopropyl-3-fluorobenzyl)carbamate (25 g, 83 mmol), and (bispinacolato)diboron (32 g, 125 mmol) were added to a mixture of Pd2(dba)3 (2.4 g, 4.2 mmol) and XPhos (4 g, 8.3 mmol) in dioxane (500 mL), and the reaction was stirred at 100 °C for 12 h. The cooled reaction mixture was filtered through Celite® and concentrated. The residue was diluted with EtOAc and washed with water and brine. The organic layer was dried (Na2SO4), filtered, and concentrated. The crude product was purified by silica gel column chromatography (0–10% EtOAc / Hept) to give a brown oil. This was dissolved in EtOAc, activated charcoal was added, and the mixture was stirred for 30 min. The mixture was filtered, the filtrate concentrated in vacuo, and the residue purified by silica gel column chromatography (0-10% EtOAc / Hept) to give the title compound as a yellow oil that solidified to a white solid upon standing (35.6 g, 68%). LCMS m / z=336.2 [M+H] +

[0372] 6. Synthesis of tert-butyl (2-cyclopropyl-3-fluoro-4-(pyrrolo[2,1-f][1,2,4]triazin-4-yl)benzyl)carbamate [ka] A mixture of 4-chloropyro[2,1-f][1,2,4]triazine (110 mg, 0.72 mmol), tert-butyl (2-cyclopropyl-3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)carbamate (561 mg, 1.4 mmol), K2CO3 (297 mg, 2.2 mmol), and Pd(dppf)Cl2·DCM (58 mg, 0.07 mmol) in dioxane (3 mL) and water (1 mL) was purged with N2. The mixture was stirred at room temperature for 5 minutes and then at 95 °C for 18 hours. The cooled mixture was diluted with EtOAc, filtered, and washed with additional EtOAc. The filtrate was concentrated in vacuo, and the crude material was purified by silica gel column chromatography (Hept / EtOAc = 5:1) to give the title compound (300 mg, 98%) as a yellow foam. LCMS m / z=383.5[M+H] +

[0373] 7. Synthesis of (2-cyclopropyl-3-fluoro-4-(pyrrolo[2,1-f][1,2,4]triazin-4-yl)phenyl)methanamine [ka] Following the procedure described in Step 7 of Example 14, tert-butyl (2-cyclopropyl-3-fluoro-4-(pyrrolo[2,1-f][1,2,4]triazin-4-yl)benzyl)carbamate, the title compound was obtained as a pale yellow solid (200 mg, 37%), which was used without further purification.

[0374] 8. Synthesis of 5-(tert-butyl)-N-(2-cyclopropyl-3-fluoro-4-(pyrrolo[2,1-f][1,2,4]triazin-4-yl)benzyl)-1,2,4-oxadiazole-3-carboxamide trifluoroacetate [ka] The crude compound was obtained from (2-cyclopropyl-3-fluoro-4-(pyrrolo[2,1-f][1,2,4]triazin-4-yl)phenyl)methanamine and potassium 5-(tert-butyl)-1,2,4-oxadiazole-3-carboxylate according to the procedure described in Step 8 of Example 14. The crude product was purified by preparative HPLC using Method B (20-80%) to give the title compound as a yellow solid (26 mg, 18%). LCMS m / z=435.6 [M+H] + . 1 H NMR(400MHz,CDCl3)δ:8.67(s,1H),8.15(dd,1H),7.63-7.57(m,1H),7.56-7.49(m,1H),7.36(d,1H),7.24-7.2 0(m,1H),7.17-7.13(m,1H),5.00(d,2H),1.84-1.75(m,1H),1.49(s,9H),1.19-1.12(m,2H),0.91-0.86(m,2H).

[0375] Example 63. 5-(tert-butyl)-N-(3,5-difluoro-2-methyl-4-(pyrrolo[2,1-f][1,2,4]triazin-4-yl)benzyl)-1,2,4-oxadiazole-3-carboxamide hydrochloride [ka] 1. Synthesis of 3,5-difluoro-4-hydroxy-2-methylbenzonitrile [ka] To a solution of 4-bromo-2,6-difluoro-3-methyl-phenol (5.5 g, 24.7 mmol) in DMF (100 mL) was added CuCN (4.4 g, 49.3 mmol), and the reaction was stirred at 125° C. for 12 h. The cooled mixture was concentrated in vacuo, and the residue was purified by silica gel column chromatography (petroleum ether / EtOAc = 16:1 to 2:1) to give the title compound (2.3 g, 55%) as a gray solid. 1H NMR(400MHz,CDCl3)δ:7.22-7.19(m,1H),6.02(br s,1H),2.44(d,3H).

[0376] Synthesis of 2,4-(aminomethyl)-2,6-difluoro-3-methylphenol [ka] To a solution of 3,5-difluoro-4-hydroxy-2-methylbenzonitrile (1.5 g, 8.9 mmol) in THF (35 mL) was added BH3·THF (28 mmol, 1 M, 28 mL) and stirred at 60 °C under N2 for 12 h. The cooled reaction was quenched with MeOH (5 mL) and the mixture was concentrated in vacuo to give the title compound (1.3 g, crude) as a white solid. LCMS m / z = 174.1 [M+H] +

[0377] 3. Synthesis of tert-butyl (3,5-difluoro-4-hydroxy-2-methylbenzyl)carbamate [ka] To a solution of 4-(aminomethyl)-2,6-difluoro-3-methylphenol (750 mg, crude) and DIPEA (1.68 g, 13 mmol) in DCM (65 mL) was added (Boc)2O (1.04 g, 4.8 mmol), and the reaction mixture was stirred at 25 °C for 2 h. The reaction mixture was concentrated in vacuo, and the crude product was purified by silica gel chromatography (petroleum ether / EtOAc = 10:1 to 3:1) to give the title compound (550 mg, 46%) as a light gray solid. LCMS m / z = 218.0 [M+H] +

[0378] 4. Synthesis of 4-(((tert-butoxycarbonyl)amino)methyl)-2,6-difluoro-3-methylphenyl trifluoromethanesulfonate [ka] TfO (851 mg, 3.0 mmol) was added to a solution of tert-butyl (3,5-difluoro-4-hydroxy-2-methylbenzyl)carbamate (550 mg, 2.0 mmol) and 2,4,6-trimethylpyridine (731 mg, 6.0 mmol) in DCM (45 mL), and the reaction was stirred at 25 °C for 2 h. The reaction mixture was quenched with MeOH (5 mL) and then concentrated in vacuo. The crude product was purified by silica gel column chromatography (3-6% EtOAc / petroleum ether) to give the title compound (490 mg, 60%) as a white solid. LCMS m / z = 447.2 [M+H] +

[0379] 5. Synthesis of tert-butyl (3,5-difluoro-2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaboralan-2-yl)benzyl)carbamate [ka] Pd2(dba)3 (166 mg, 0.18 mmol), P(Cy)3 (85 mg, 0.30 mmol), and KOAc (238 mg, 2.4 mmol) were added to a solution of 4-(((tert-butoxycarbonyl)amino)methyl)-2,6-difluoro-3-methylphenyl trifluoromethanesulfonate (490 mg, 1.2 mmol) and (bispinacolato)diboron (615 mg, 2.4 mmol) in dioxane (25 mL). The reaction was stirred at 85° C. under N for 12 h. The reaction mixture was concentrated in vacuo and the crude product was purified by si...

Claims

1. Formula (II) or Formula (III): 【Chemical 1】 or a pharmaceutically acceptable salt thereof, wherein R １ is a 5-6 membered monocyclic heteroaryl having 1-4 heteroatoms independently selected from O, N, and S; R １ The 5- to 6-membered monocyclic heteroaryl represented by the formula (I) may optionally be one or two R １０ is replaced by R １０ is, for each occurrence, independently a halogen, -OR １０ａ , S(O) ２ R １０ａ , -CN,C １－６ Alkyl, C ３－６ cycloalkyl, and phenyl; R １０ The C represented by １－６ Alkyl, C ３－６ cycloalkyl, and phenyl each optionally have 1 to 3 R １５ is replaced by R １０ａ for each occurrence independently, H and C １－３ alkyl, R １５ For each occurrence, independently, C １－６ Alkyl, halogen, —CN, and —OR １５ａ is selected from R １５ａ is H or C １－３ is alkyl, R ２ is H or methyl, R ３ is H, R ４ is halogen, -CN, -OR ４ａ , C １－６ Alkyl, and C ３－６ cycloalkyl; R ４ The C represented by １－６ Alkyl and C ３－６ each cycloalkyl is optionally substituted with 1 to 3 halogens; R ４ａ C optionally substituted with 1 to 3 halogens １－４ Is it alkyl? Or alternatively, R ３ and R ４ together with their intervening atoms form ring B which is a 7-membered monocyclic carbocyclyl or a 7-membered monocyclic heterocyclyl having one heteroatom selected from O and N; R ５ is H or a halogen, R ６ is H or a halogen, R ８ is, for each occurrence independently, H, halogen, C ２－６ Alkynyl, —C(O)R ８ａ , -C(O)N(R ８ａ ) ２ , -N(R ８ａ ) ２ , -OR ８ａ , -CN,C １－６ Alkyl, C ２－６ Alkenyl, phenyl, C ３－６ cycloalkyl, 4-6 membered monocyclic heterocyclyl having 1-2 heteroatoms independently selected from O, N, and S, and 7-10 membered bicyclic heterocyclyl having 1-4 heteroatoms independently selected from O, N, and S; ８ The C represented by １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, phenyl, C ３－６ Cycloalkyl, 4- to 6-membered monocyclic heterocyclyl, and 7- to 10-membered bicyclic heterocyclyl each optionally contain 1 to 3 R ８０ is replaced by R ８ａ For each occurrence, independently, H, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－６ cycloalkyl, and 4- to 6-membered monocyclic heterocyclyl; R ８ａ The C represented by １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－６ Cycloalkyl and 4- to 6-membered monocyclic heterocyclyl each optionally contain one or three R ８０ or two R ８ａ together with the intervening atoms, 1 to 3 R ８０ forming a 4-6 membered monocyclic heterocyclyl optionally substituted with R ８０ is, for each occurrence, independently a halogen, —CN, —C(O)R ８０ａ , -OR ８０ａ , C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－６ cycloalkyl, and 4- to 6-membered monocyclic heterocyclyl; R ８０ The C represented by １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－６ Cycloalkyl and 4- to 6-membered monocyclic heterocyclyl each optionally contain one or three R ８５ or two R ８０ together with the carbon atom to which they are attached form an oxo group (—C═O)—), R ８０ａ For each occurrence, independently, H, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－６ cycloalkyl and 4-6 membered monocyclic heterocyclyl having 1-2 heteroatoms independently selected from O, N, and S; R ８５ is, for each occurrence, independently selected from halogen and -OR ８５ａ is selected from R ８５ａ is H or C １－６ alkyl, or a pharmaceutically acceptable salt thereof.

2. R １ is a 5-membered heteroaryl selected from pyrazolyl, oxazolyl, isoxazolyl, 1,2,3-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,4-oxadizolyl, 1,2,3-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, and tetrazolyl, each of which optionally is selected from one or two R １０ 10. The compound of claim 1, or a pharmaceutically acceptable salt thereof, substituted with:

3. R １ is expressed by the following formula: 【Chemistry 2】 2. The compound of claim 1, wherein:

4. The compound has the following formula: 【Chemistry 3】 10. The compound of claim 1, represented by one of the formulas: R ３０１ is H or R ３００ and R ３００ But C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, 4- to 6-membered monocyclic heterocyclyl, —C(O)R ３００ａ , -OR ３００ａ , and -S(O) ２ R ３００ａ and R ３００ The C represented by １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl and 4- to 6-membered monocyclic heterocyclyl are each optionally selected from 1 to 3 R ３５０ is replaced by R ３００ａ But H, C １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－６ cycloalkyl, and 4- to 6-membered monocyclic heterocyclyl; １－６ Alkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－６ cycloalkyl, and 4- to 6-membered monocyclic heterocyclyl, each optionally having 1 to 3 R ３５０ is replaced by R ３５０ For each occurrence, independently, C １－６ Alkyl, halogen, —CN, —N(R ３５０ａ ) ２ , -C(O)R ３５０ａ , -C(O)N(R ３５０ａ ) ２ , -C(R ３５０ａ ) ２ N (R ３５０ａ ) ２ , and -OR ３５０ａ and C is selected from １－６ the alkyl is optionally substituted with 1 to 3 halogens; R ３５０ａ is, for each occurrence, independently H or C optionally substituted with 1 to 3 halogens １－６ alkyl or two R ３５０ａ together with the N atom to which they are attached form a 4- to 6-membered monocyclic heterocyclyl having 1 to 2 heteroatoms selected from N and O, or a pharmaceutically acceptable salt thereof.

5. R ８ が、H、-CH ３ 、-CH ２ OCH ３ ,F,B,-CN,-OCH ３ 、-OC ２ H ５ OCH ３ 、-N(CH ３ )(CH ２ CH ２ OCH ３ ),-C(O)N(CH ３ ) ２ 、 【Chemistry 4】 2. The compound of claim 1, selected from:

6. R ８０ is halogen, -CN, -C(O)R ８０ａ , -OR ８０ａ , C １－３ Alkyl, C ３－６ cycloalkyl and 4-6 membered monocyclic heterocyclyl having 1-2 heteroatoms selected from O and N; R ８０ The C represented by １－３ Alkyl, C ３－６ cycloalkyl, and 4- to 6-membered monocyclic heterocyclyl, each optionally having 1 to 3 R ８５ or two R ８０ together with the carbon atom to which they are attached form an oxo (—C(═O)) group, R ８０ａ For each occurrence, independently, C １－４ Alkyl and C ２－４ alkenyl, R ８５ is, for each occurrence, independently F, —OH, or C １－３ 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, selected from alkoxy.

7. The compound has the following formula: 【Chemistry 5】 2. The compound of claim 1, wherein the compound is represented by the formula: R １ is a 5-membered heteroaryl selected from 1,2,3-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,4-oxadizolyl, 1,2,3-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, and tetrazolyl, each of which optionally is selected from one or two R １０ is replaced by R １０ is, for each occurrence, independently a halogen, -OR １０ａ , -S(O) ２ R １０ａ , -CN,C １－６ Alkyl, C ３－６ cycloalkyl, and phenyl; R １０ The C represented by １－６ Alkyl, C ３－６ cycloalkyl, and phenyl each optionally have 1 to 3 R １５ is replaced by R １０ａ for each occurrence independently, H and C １－３ alkyl, R １５ For each occurrence, independently, C １－６ Alkyl, halogen, —CN, and —OR １５ａ is selected from R １５ａ is H or C １－３ is alkyl, R ４ is halogen, -CN, -OR ４ａ , C １－６ Alkyl, and C ３－６ cycloalkyl; R ４ The C represented by １－６ Alkyl and C ３－６ each cycloalkyl is optionally substituted with 1 to 3 halogens; R ４ａ C optionally substituted with 1 to 3 halogens １－４ is alkyl, R ５ is H or a halogen, R ６ is H or a halogen; R ８ But H, -OR ８ａ or a 4- to 6-membered monocyclic heterocyclyl having 1 to 2 heteroatoms independently selected from O and N, wherein the 4- to 6-membered monocyclic heterocyclyl optionally has one or two R ８０ is replaced by R ８ａ However, R1 to R3 ８０ C optionally substituted with １－６ is alkyl, R ８０ is, for each occurrence, independently a halogen, -OR ８０ａ , and R 1 to 3 ８５ C optionally substituted with １－３ alkyl, R ８０ａ For each occurrence, independently, H, C １－６ Alkyl and C ２－６ alkenyl, R ８５ is, for each occurrence, independently selected from halogen and -OR ８５ａ is selected from R ８５ａ is H or C １－３ alkyl, or a pharmaceutically acceptable salt thereof.

8. R １ but, 【Chemistry 6】 and R １０ is halogen or C １－３ C optionally substituted with alkyl １－４ Alkyl or C ３－６ 8. The compound of claim 7, or a pharmaceutically acceptable salt thereof, which is cycloalkyl.

9. R ８ が、H、-OR ８ａ 、 【Chemistry 7】 9. The compound of claim 7 or 8, or a pharmaceutically acceptable salt thereof, selected from:

10. R ８ But, H, 【Chemistry 8】 or -OR ８ａ and R ８０ is, for each occurrence independently, F, -CH ３ , 【Chemistry 9】 -CH ２ CH ２ OCH ３ , -OCH ３ , and -CH ２ CHF ２ 10. The compound of claim 9 selected from: or a pharmaceutically acceptable salt thereof.

11. A pharmaceutical composition comprising the compound of any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

12. A pharmaceutical composition comprising an effective amount of a compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 11, for use in treating a disorder responsive to inhibition of Bruton's tyrosine kinase in a subject.

13. 13. The pharmaceutical composition of claim 12, wherein the disorder is an autoimmune disorder.

14. 13. The pharmaceutical composition of claim 12, wherein the disorder is multiple sclerosis.

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