WO2022072634A1

WO2022072634A1 - Bicyclic compounds for use in the treatment cancer

Info

Publication number: WO2022072634A1
Application number: PCT/US2021/052878
Authority: WO
Inventors: Benjamin C. MILGRAM; JR. David St. Jean; Ryan D. WHITE; Angel Guzman-Perez
Original assignee: Scorpion Therapeutics, Inc.
Priority date: 2020-09-30
Filing date: 2021-09-30
Publication date: 2022-04-07
Also published as: TW202229282A

Abstract

This disclosure provides chemical entities (e.g., a compound or a pharmaceutically acceptable salt, and/or hydrate, and/or cocrystal, and/or drug combination of the compound) that inhibit epidermal growth factor receptor (EGFR, ERBB1) and/or Human epidermal growth factor receptor 2 (HER2, ERBB2). These chemical entities are useful, e.g., for treating a condition, disease or disorder in which increased (e.g., excessive) EGFR and/or HER2 activation contributes to the pathology and/or symptoms and/or progression of the condition, disease or disorder (e.g., cancer) in a subject (e.g., a human). This disclosure also provides compositions containing the same as well as methods of using and making the same.

Description

BICYCLIC COMPOUNDS FOR USE IN THE TREATMENT CANCER CROSS REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Application Serial No. 63/085,686, filed on September 30, 2020; and U.S. Provisional Application Serial No. 63/143,442, filed on January 29, 2021; each of which is incorporated herein by reference in its entirety. TECHNICAL FIELD This disclosure provides chemical entities (e.g., a compound or a pharmaceutically acceptable salt, and/or hydrate, and/or cocrystal, and/or drug combination of the compound) that inhibit epidermal growth factor receptor (EGFR, ERBB1) and/or Human epidermal growth factor receptor 2 (HER2, ERBB2). These chemical entities are useful, e.g., for treating a condition, disease or disorder in which increased (e.g., excessive) EGFR and/or HER2 activation contributes to the pathology and/or symptoms and/or progression of the condition, disease or disorder (e.g., cancer) in a subject (e.g., a human). This disclosure also provides compositions containing the same as well as methods of using and making the same. BACKGROUND Epidermal growth factor receptor (EGFR, ERBB1) and Human epidermal growth factor receptor 2 (HER2, ERBB2) are members of a family of proteins which regulate cellular processes implicated in tumor growth, including proliferation and differentiation. Several investigators have demonstrated the role of EGFR and HER2 in development and cancer (Reviewed in Salomon, et al., Crit. Rev. Oncol. Hematol. (1995) 19:183-232, Klapper, et al., Adv. Cancer Res. (2000) 77, 25-79 and Hynes and Stern, Biochim. Biophys. Acta (1994) 1198:165-184). EGFR overexpresmion is present in at least 70% of human cancers, such as non-small cell lung carcinoma (NSCLC), breast cancer, glioma, and prostate cancer. HER2 overexpression occurs in approximately 30% of all breast cancer. It has also been implicated in other human cancers including colon, ovary, bladder, stomach, esophagus, lung, uterus and prostate. HER2 overexpression has also been correlated with poor prognosis in human cancer, including metastasis, and early relapse. EGFR and HER2 are, therefore, widely recognized as targets for the design and development of therapies that can specifically bind and inhibit tyrosine kinase activity and its signal transduction pathway in cancer cells, and thus can serve as diagnostic or therapeutic agents. For example, EGFR tyrosine kinase inhibitors (TKIs) are effective clinical therapies for EGFR mutant advanced non-small cell lung cancer (NSCLC) patients. However, the vast majority of patients develop disease progression following successful treatment with an EGFR TKI. Common mechanisms of resistance include acquired, secondary mutation T790M, C797S, and EGFR exon 20 insertion mutations. For example, NSCLC tumors can have EGFR exon 20 insertion mutations that are intrinsically resistant to current EGFR TKIs. Overexpression of another protein, BUB1 (Budding uninhibited by benzimidazole, BUB1) kinase, is often associated with proliferating cells, including cancer cells, and tissues (Bolanos-Garcia VM and Blundell TL, Trends Biochem. Sci.36, 141 , 2010). This protein is an essential part of the complex network of proteins that form the mitotic checkpoint. The major function of an unsatisfied mitotic checkpoint is to keep the anaphase-promoting complex/cyclosome (APC/C) in an inactive state. As soon as the checkpoint gets satisfied the APC/C ubiquitin-ligase targets cyclin B and securin for proteolytic degradation leading to separation of the paired chromosomes and exit from mitosis. Incomplete mitotic checkpoint function has been linked with aneuploidy and tumourigenesis (see Weaver BA and Cleveland DW, Cancer Res.67, 10103, 2007; King RW, Biochim Biophys Acta 1786, 4, 2008). In contrast, complete inhibition of the mitotic checkpoint has been recognized to result in severe chromosome missegregation and induction of apoptosis in tumour cells (see Kops GJ et al., Nature Rev. Cancer 5, 773, 2005; Schmidt M and Medema RH, Cell Cycle 5, 159, 2006; Schmidt M and Bastians H, Drug Res. Updates 10, 162, 2007). Thus, mitotic checkpoint inhibition through inhibition of BUB1 kinase represents an approach for the treatment of proliferative disorders, including solid tumors such as carcinomas, sarcomas, leukemias and lymphoid malignancies or other disorders, associated with uncontrolled cellular proliferation. SUMMARY This disclosure provides chemical entities (e.g., a compound or a pharmaceutically acceptable salt, and/or hydrate, and/or cocrystal, and/or drug combination of the compound) that inhibit epidermal growth factor receptor (EGFR, ERBB1) and/or Human epidermal growth factor receptor 2 (HER2, ERBB2). These chemical entities are useful, e.g., for treating a condition, disease or disorder in which increased (e.g., excessive) EGFR and/or HER2 activation contributes to the pathology and/or symptoms and/or progression of the condition, disease or disorder (e.g., cancer) in a subject (e.g., a human). This disclosure also provides compositions containing the same as well as methods of using and making the same. In one aspect, this disclosure features compounds of Formula (I):

Formula (I) or a pharmaceutically acceptable salt thereof, in which R^1c, R^2a, R^2b, R^3a, R^3b, Ring A, and Ring C can be as defined anywhere herein. In one aspect, this disclosure features compounds of Formula (I):

Formula (I) or a pharmaceutically acceptable salt thereof, wherein: Ring C is selected from the group consisting of: • C_3-10 cycloalkyl or C_3-10 cycloalkenyl, each of which is optionally substituted with X¹ and further optionally substituted with from 1-4 substituents independently selected from the group consisting of oxo and R^c; • heterocyclyl or heterocycloalkenyl including from 3-10 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R^d), O, and S(O)_0-2, and wherein the heterocyclyl or heterocycloalkenyl is optionally substituted with X¹ and further optionally substituted with from 1-4 substituents independently selected from the group consisting of oxo and R^c; • heteroaryl including from 5-10 ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R^d), O, and S(O)_0-2, and wherein the heteroaryl is optionally substituted with X¹ and further optionally substituted with from 1-4 R^c; and • C_6-10 aryl optionally substituted with X¹ and further optionally substituted with from 1-4 R^c; X¹ is –(X²)_m-L¹-R⁵, wherein: m is 0 or 1; X² is selected from the group consisting of: • -O-, -N(R^N)-, or –S(O)_0-2; •

• -C(=O)O-*, -C(=O)N(R^N)-*, or –S(O)_1-2N(R^N)-*; • -OC(=O)-*, -N(R^N)C(=O)-*, or –N(R^N)S(O)_1-2-*; and • -OC(=O)N(R^N)-*, -N(R^N)C(=O)O-*, -N(R^N)C(=O)N(R^N)-*, or – N(R^N)S(O)_1-2N(R^N)-*, wherein the asterisk represents point of attachment to L¹; L¹ is selected from the group consisting of: a bond and C_1-10 alkylene optionally substituted with from 1-6 R^a; R⁵ is selected from the group consisting of: • H; • halo; • -OH; • -NR^eR^f; • -C_1-6 alkoxy or -S(O)_0-2(C_1-6 alkyl), each optionally substituted with from 1-6 R^a; • -R^g; • -L⁵-R^g; • -R^g2-R^W or -R^g2-R^Y; and • -L⁵-R^g2-R^W or –L⁵-R^g2-R^Y; provided that: when L¹ is a bond, then R⁵ is selected from the group consisting of: H, -R^g, -R^g2- R^W, and -R^g2-R^Y; and X¹ is other than H, -OH, or NH₂; L⁵ is selected from the group consisting of: –O-, -S(O)_0-2, -NH, and -N(R^d)-; R^W is –L^W-W, wherein L^W is C(=O), S(O)_1-2, OC(=O)*, NHC(=O)*, NR^dC(=O)*, NHS(O)_1-2*, or NR^dS(O)_1-2*, wherein the asterisk represents point of attachment to W, and W is C_2-6 alkenyl; C_2-6 alkynyl; or C_3-10 allenyl, each of which is optionally substituted with from 1-3 R^a and further optionally substituted with R^g, wherein W is attached to L^W via an sp² or sp hybridized carbon atom, thereby providing an α, β- unsaturated system; and R^Y is selected from the group consisting of: -R^g and -(L^g)_g-R^g; each of R^1c, R^2a, R^2b, R^3a, and R^3b is independently selected from the group consisting of: H; halo; -OH; -C(O)OH or –C(O)NH₂; -CN; -R^b; -L^b-R^b; -C_1-6 alkoxy or - C_1-6 thioalkoxy, each optionally substituted with from 1-6 R^a; -NR^eR^f; -R^g; and -(L^g)g-R^g; provided that R^1c is other than halo, –CN, or –C(O)OH; or or two of variables R^1c, R^2a, R^2b, R^3a, and R^3b, together with the Ring B ring atoms to which each is attached, form a fused saturated or unsaturated ring of 3-12 ring atoms; • wherein from 0-2 of the ring atoms are each an independently selected heteroatom (in addition to –N(R^1c)- when –N(R^1c)- forms part of the fused saturated or unsaturated ring), wherein each of the independently selected heteroatoms is selected from the group consisting of N, NH, N(R^d), O, and S(O)_0-2; and • wherein the fused saturated or unsaturated ring of 3-12 ring atoms is optionally substituted with from 1-4 substituents independently selected from the group consisting of oxo and R^c; Ring A is R^g; each occurrence of R^a is independently selected from the group consisting of: – OH; -halo; –NR^eR^f; C_1-4 alkoxy; C_1-4 haloalkoxy; -C(=O)O(C_1-4 alkyl); -C(=O)(C_1-4 alkyl); -C(=O)OH; -CONR’R’’; -S(O)_1-2NR’R’’; -S(O)_1-2(C_1-4 alkyl); and cyano; each occurrence of R^b is independently C_1-6 alkyl, C_2-6 alkenyl, or C_2-6 alkynyl, each of which is optionally substituted with from 1-6 R^a; each occurrence of L^b is independently C(=O); C(=O)O; S(O)_1-2; C(=O)NH*; C(=O)NR^d*; S(O)_1-2NH*; or S(O)_1-2N(R^d)*, wherein the asterisk represents point of attachment to R^b; each occurrence of R^c is independently selected from the group consisting of: halo; cyano; C_1-10 alkyl which is optionally substituted with from 1-6 independently selected R^a; C_2-6 alkenyl; C_2-6 alkynyl; C_1-4 alkoxy optionally substituted with C_1-4 alkoxy or C_1-4 haloalkoxy; C_1-4 haloalkoxy; -S(O)_1-2(C_1-4 alkyl); -S(O)(=NH)(C_1-4 alkyl); -NR^eR^f; –OH; -S(O)_1-2NR’R’’; -C_1-4 thioalkoxy; -NO2; -C(=O)(C_1-10 alkyl); -C(=O)O(C_1-4 alkyl); - C(=O)OH; -C(=O)NR’R’’; and –SF₅; each occurrence of R^d is independently selected from the group consisting of: C_1-6 alkyl optionally substituted with from 1-3 independently selected R^a; -C(O)(C_1-4 alkyl); - C(O)O(C_1-4 alkyl); -CONR’R’’; -S(O)_1-2NR’R’’; - S(O)_1-2(C_1-4 alkyl); -OH; and C_1-4 alkoxy; each occurrence of R^e and R^f is independently selected from the group consisting of: H; C_1-6 alkyl optionally substituted with from 1-3 substituents each independently selected from the group consisting of NR’R’’, -OH, C_1-6 alkoxy, C_1-6 haloalkoxy, and halo; -C(O)(C_1-4 alkyl); -C(O)O(C_1-4 alkyl); -CONR’R’’; -S(O)_1-2NR’R’’; - S(O)_1-2(C_1-4 alkyl); -OH; and C_1-4 alkoxy; each occurrence of R^g is independently selected from the group consisting of: • C_3-10 cycloalkyl or C_3-10 cycloalkenyl, each of which is optionally substituted with from 1-4 substituents independently selected from the group consisting of oxo and R^c; • heterocyclyl or heterocycloalkenyl including from 3-10 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R^d), O, and S(O)_0-2, and wherein the heterocyclyl or heterocycloalkenyl is optionally substituted with from 1-4 substituents independently selected from the group consisting of oxo and R^c; • heteroaryl including from 5-10 ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R^d), O, and S(O)_0-2, and wherein the heteroaryl is optionally substituted with from 1-4 R^c; and • C_6-10 aryl optionally substituted with from 1-4 R^c; each occurrence of L^g is independently selected from the group consisting of: -O-, -NH-, -NR^d , -S(O)_0-2, C(O), and C_1-3 alkylene optionally substituted with from 1-3 R^a; each g is independently 1, 2, or 3; each R^g2 is a divalent R^g group; each occurrence of R’ and R’’ is independently selected from the group consisting of: H; -OH; and C_1-4 alkyl; and each occurrence of R^N is independently H, C_1-3 alkyl, or C_3-6 cycloalkyl. In one aspect, this disclosure features compounds of Formula (I):

; • -C(=O)O-*, -C(=O)N(R^N)-*, or –S(O)_1-2N(R^N)-*; • -OC(=O)-*, -N(R^N)C(=O)-*, or –N(R^N)S(O)_1-2-*; and • -OC(=O)N(R^N)-*, -N(R^N)C(=O)O-*, -N(R^N)C(=O)N(R^N)-*, or – N(R^N)S(O)_1-2N(R^N)-*, wherein the asterisk represents point of attachment to L¹; L¹ is selected from the group consisting of: a bond and C_1-10 alkylene optionally substituted with from 1-6 R^a; R⁵ is selected from the group consisting of: • H; • halo; • -OH; • -NR^eR^f; • -C_1-6 alkoxy or -S(O)_0-2(C_1-6 alkyl), each optionally substituted with from 1-6 R^a; • -R^g; • -L⁵-R^g; • -R^g2-R^W or -R^g2-R^Y; • -L⁵-R^g2-R^W or –L⁵-R^g2-R^Y; and • -R^W provided that: when L¹ is a bond, then R⁵ is selected from the group consisting of: H, -R^g, -R^g2- R^W, and -R^g2-R^Y; and X¹ is other than H, -OH, or NH₂; L⁵ is selected from the group consisting of: –O-, -S(O)_0-2, -NH, and -N(R^d)-; R^W is –L^W-W, wherein L^W is C(=O), S(O)_1-2, OC(=O)*, NHC(=O)*, NR^dC(=O)*, NHS(O)_1-2*, or NR^dS(O)_1-2*, wherein the asterisk represents point of attachment to W, and W is selected from the group consisting of: • C_2-6 alkenyl; C_2-6 alkynyl; or C_3-10 allenyl, each of which is optionally substituted with from 1-3 R^a and further optionally substituted with R^g, wherein W is attached to L^W via an sp² or sp hybridized carbon atom, thereby providing an α, β- unsaturated system; and • bicyclo[x.y.0]cycloalkyl which is optionally substituted with from 1-2 R^c, wherein x is 1 or 2; and y is an integer from 1 to 6; R^Y is selected from the group consisting of: -R^g and -(L^g)_g-R^g; each of R^1c, R^2a, R^2b, R^3a, and R^3b is independently selected from the group consisting of: H; halo; -OH; -C(O)OH or –C(O)NH₂; -CN; -R^b; -L^b-R^b; -C_1-6 alkoxy or - C_1-6 thioalkoxy, each optionally substituted with from 1-6 R^a; -NR^eR^f; -R^g; and -(L^g)g-R^g; provided that R^1c is other than halo, –CN, or –C(O)OH; or two of variables R^1c, R^2a, R^2b, R^3a, and R^3b, together with the Ring B ring atoms to which each is attached, form a fused saturated or unsaturated ring of 3-12 ring atoms; • wherein from 0-2 of the ring atoms are each an independently selected heteroatom (in addition to –N(R^1c)- when –N(R^1c)- forms part of the fused saturated or unsaturated ring), wherein each of the independently selected heteroatoms is selected from the group consisting of N, NH, N(R^d), O, and S(O)_0-2; and • wherein the fused saturated or unsaturated ring of 3-12 ring atoms is optionally substituted with from 1-4 substituents independently selected from the group consisting of oxo, R^c, and R^W; or one of R^2a and R^2b and one of R^3a and R^3b combine to form a double bond between the Ring B atoms to which each is attached; Ring A is R^g; each occurrence of R^a is independently selected from the group consisting of: – OH; -halo; –NR^eR^f; C_1-4 alkoxy; C_1-4 haloalkoxy; -C(=O)O(C_1-4 alkyl); -C(=O)(C_1-4 alkyl); -C(=O)OH; -CONR’R’’; -S(O)_1-2NR’R’’; -S(O)_1-2(C_1-4 alkyl); and cyano; each occurrence of R^b is independently C_1-6 alkyl, C_2-6 alkenyl, or C_2-6 alkynyl, each of which is optionally substituted with from 1-6 R^a; each occurrence of L^b is independently C(=O); C(=O)O; S(O)_1-2; C(=O)NH*; C(=O)NR^d*; S(O)_1-2NH*; or S(O)_1-2N(R^d)*, wherein the asterisk represents point of attachment to R^b; each occurrence of R^c is independently selected from the group consisting of: halo; cyano; C_1-10 alkyl which is optionally substituted with from 1-6 independently selected R^a; C_2-6 alkenyl; C_2-6 alkynyl; C_1-4 alkoxy optionally substituted with C_1-4 alkoxy or C_1-4 haloalkoxy; C_1-4 haloalkoxy; -S(O)_1-2(C_1-4 alkyl); -S(O)(=NH)(C_1-4 alkyl); -NR^eR^f; –OH; -S(O)_1-2NR’R’’; -C_1-4 thioalkoxy; -NO2; -C(=O)(C_1-10 alkyl); -C(=O)O(C_1-4 alkyl); - C(=O)OH; -C(=O)NR’R’’; and –SF₅; each occurrence of R^d is independently selected from the group consisting of: C_1-6 alkyl optionally substituted with from 1-3 independently selected R^a; -C(O)(C_1-4 alkyl); - C(O)O(C_1-4 alkyl); -CONR’R’’; -S(O)_1-2NR’R’’; -S(O)_1-2(C_1-4 alkyl); -OH; and C_1-4 alkoxy; each occurrence of R^e and R^f is independently selected from the group consisting of: H; C_1-6 alkyl optionally substituted with from 1-3 substituents each independently selected from the group consisting of NR’R’’, -OH, C_1-6 alkoxy, C_1-6 haloalkoxy, and halo; -C(O)(C_1-4 alkyl); -C(O)O(C_1-4 alkyl); -CONR’R’’; -S(O)_1-2NR’R’’; -S(O)_1-2(C_1-4 alkyl); -OH; and C_1-4 alkoxy; each occurrence of R^g is independently selected from the group consisting of: • C_3-10 cycloalkyl or C_3-10 cycloalkenyl, each of which is optionally substituted with from 1-4 substituents independently selected from the group consisting of oxo and R^c; • heterocyclyl or heterocycloalkenyl including from 3-10 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R^d), O, and S(O)_0-2, and wherein the heterocyclyl or heterocycloalkenyl is optionally substituted with from 1-4 substituents independently selected from the group consisting of oxo and R^c; • heteroaryl including from 5-10 ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R^d), O, and S(O)_0-2, and wherein the heteroaryl is optionally substituted with from 1-4 R^c; and • C_6-10 aryl optionally substituted with from 1-4 R^c; each occurrence of L^g is independently selected from the group consisting of: -O-, -NH-, -NR^d _, -S(O)_0-2, C(O), and C_1-3 alkylene optionally substituted with from 1-3 R^a; each g is independently 1, 2, or 3; each R^g2 is a divalent R^g group; each occurrence of R’ and R’’ is independently selected from the group consisting of: H; -OH; and C_1-4 alkyl; and each occurrence of R^N is independently H, C_1-3 alkyl, or C_3-6 cycloalkyl. Also provided herein is a pharmaceutical composition comprising a compound of Formula (I) (e.g., Formula (I-a), (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b), (I-c), (I-d), (I- e), (I-f), (I-g), (I-g1), (I-g1-1), (I-g1-2),or (I-h)), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. Provided herein is a method for treating cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of Formula (I) (e.g., Formula (I-a), (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-g1), (I-g1-1), (I-g1-2),or (I-h)), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as provided herein. Also provided herein is a method for treating cancer in a subject in need thereof, the method comprising (a) determining that the cancer is associated with a dysregulation of an EGFR gene, an EGFR kinase, or expression or activity or level of any of the same; and (b) administering to the subject a therapeutically effective amount of a compound of Formula (I) (e.g., Formula (I-a), (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b), (I-c), (I-d), (I- e), (I-f), (I-g), (I-g1), (I-g1-1), (I-g1-2),or (I-h)), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as provided herein. Provided herein is a method of treating an EGFR-associated disease or disorder in a subject, the method comprising administering to a subject identified or diagnosed as having an EGFR-associated disease or disorder a therapeutically effective amount of a compound of Formula (I) (e.g., Formula (I-a), (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-g1), (I-g1-1), (I-g1-2),or (I-h)), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as provided herein. This disclosure also provides a method of treating an EGFR-associated disease or disorder in a subject, the method comprising: determining that the cancer in the subject is an EGFR-associated disease or disorder; and administering to the subject a therapeutically effective amount of a compound of Formula (I) (e.g., Formula (I-a), (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-g1), (I-g1-1), (I-g1-2),or (I-h)), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as provided herein. Further provided herein is a method of treating an EGFR-associated cancer in a subject, the method comprising administering to a subject identified or diagnosed as having an EGFR-associated cancer a therapeutically effective amount of a compound of Formula (I) (e.g., Formula (I-a), (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-g1), (I-g1-1), (I-g1-2),or (I-h)), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as provided herein. This disclosure also provides a method of treating an EGFR-associated cancer in a subject, the method comprising: determining that the cancer in the subject is an EGFR- associated cancer; and administering to the subject a therapeutically effective amount of a compound of Formula (I) (e.g., Formula (I-a), (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-g1), (I-g1-1), (I-g1-2),or (I-h)), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as provided herein. Provided herein is a method of treating a subject, the method comprising administering a therapeutically effective amount of a compound of Formula (I) (e.g., Formula (I-a), (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I- g1), (I-g1-1), (I-g1-2),or (I-h)), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as provided herein, to a subject having a clinical record that indicates that the subject has a dysregulation of an EGFR gene, an EGFR kinase, or expression or activity or level of any of the same. Also provided herein is a method of treating a subject having a cancer, wherein the method comprises: (a) administering one or more doses of a first EGFR inhibitor to the subject for a period of time; (b) after (a), determining whether a cancer cell in a sample obtained from the subject has at least one EGFR inhibitor resistance mutation that confers increased resistance to a cancer cell or tumor to treatment with the first EGFR inhibitor of step (a); and (c) administering a therapeutically effective amount of a compound of Formula (I) (e.g., Formula (I-a), (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b), (I-c), (I-d), (I-e), (I-f), (I- g), (I-g1), (I-g1-1), (I-g1-2),or (I-h)), or a pharmaceutically acceptable salt thereof, as a monotherapy or in conjunction with another anticancer agent to the subject if the subject has been determined to have a cancer cell that has at least one EGFR inhibitor resistance mutation that confers increased resistance to a cancer cell or tumor to treatment with the first EGFR inhibitor of step (a); or (d) administering additional doses of the first EGFR inhibitor of step (a) to the subject if the subject has not been determined to have a cancer cell that has at least one EGFR inhibitor resistance mutation that confers increased resistance to a cancer cell or tumor to treatment with the first EGFR inhibitor of step (a). Further provided herein is a method of treating a subject having a cancer, wherein the method comprises: (a) determining whether a cancer cell in a sample obtained from a subject having a cancer and previously administered one or more doses of a first EGFR inhibitor has one or more EGFR inhibitor resistance mutations that confer increased resistance to a cancer cell or tumor to treatment with the first EGFR inhibitor that was previously administered to the subject; and (b) administering a therapeutically effective amount of a compound of Formula (I) (e.g., Formula (I-a), (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b), (I-c), (I-d), (I-e), (I-f), (I- g), (I-g1), (I-g1-1), (I-g1-2),or (I-h)), or a pharmaceutically acceptable salt thereof, as a monotherapy or in conjunction with another anticancer agent to the subject if the subject has been determined to have a cancer cell that has at least one EGFR inhibitor resistance mutation that confers increased resistance to a cancer cell or tumor to treatment with the first EGFR inhibitor that was previously administered to the subject; or (c) administering additional doses of the first EGFR inhibitor to the subject if the subject has not been determined to have a cancer cell that has at least one EGFR inhibitor resistance mutation that confers increased resistance to a cancer cell or tumor to treatment with the first EGFR inhibitor previously administered to the subject. Also provided herein is a method of treating a subject having a cancer, wherein the method comprises: (a) determining that a cancer cell in a sample obtained from a subject having a cancer and previously administered one or more doses of a first EGFR inhibitor has one or more EGFR inhibitor resistance mutations that confer increased resistance to a cancer cell or tumor to treatment with the first EGFR inhibitor that was previously administered to the subject; and (b) administering a therapeutically effective amount of a compound of Formula (I) (e.g., Formula (I-a), (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b), (I-c), (I-d), (I-e), (I-f), (I- g), (I-g1), (I-g1-1), (I-g1-2),or (I-h)), or a pharmaceutically acceptable salt thereof, as a monotherapy or in conjunction with another anticancer agent to the subject. Further provided herein is a method of treating a subject having a cancer, wherein the method comprises: (a) determining that a cancer cell in a sample obtained from a subject having a cancer and previously administered one or more doses of a first EGFR inhibitor does not have one or more EGFR inhibitor resistance mutations that confer increased resistance to a cancer cell or tumor to treatment with the first EGFR inhibitor that was previously administered to the subject; and (b) administering additional doses of the first EGFR inhibitor to the subject. This disclosure also provides a method for inhibiting EGFR in a mammalian cell, the method comprising contacting the mammalian cell with an effective amount of a compound of Formula (I) (e.g., Formula (I-a), (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-g1), (I-g1-1), (I-g1-2),or (I-h)), or a pharmaceutically acceptable salt thereof. Also provided herein is a method for treating cancer in a subject in need thereof, the method comprising (a) determining that the cancer is associated with a dysregulation of a HER2 gene, a HER2 kinase, or expression or activity or level of any of the same; and (b) administering to the subject a therapeutically effective amount of a compound of Formula (I) (e.g., Formula (I-a), (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b), (I-c), (I-d), (I- e), (I-f), (I-g), (I-g1), (I-g1-1), (I-g1-2),or (I-h)), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as provided herein. Further provided herein is a method of treating a HER2-associated cancer in a subject, the method comprising administering to a subject identified or diagnosed as having a HER2-associated cancer a therapeutically effective amount of a compound of Formula (I) (e.g., Formula (I-a), (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-g1), (I-g1-1), (I-g1-2),or (I-h)), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as provided herein. This disclosure also provides a method of treating a HER2-associated cancer in a subject, the method comprising: determining that the cancer in the subject is a HER2- associated cancer; and administering to the subject a therapeutically effective amount of a compound of Formula (I) (e.g., Formula (I-a), (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-g1), (I-g1-1), (I-g1-2),or (I-h)), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as provided herein. Provided herein is a method of treating a subject having a cancer, the method comprising administering a therapeutically effective amount of a compound of Formula (I) (e.g., Formula (I-a), (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b), (I-c), (I-d), (I-e), (I-f), (I- g), (I-g1), (I-g1-1), (I-g1-2),or (I-h)), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as provided herein, to a subject having a clinical record that indicates that the subject has a dysregulation of a HER2 gene, a HER2 kinase, or expression or activity or level of any of the same. Also provided herein is a method of treating a subject having a cancer, wherein the method comprises: (a) administering one or more doses of a first HER2 inhibitor to the subject for a period of time; (b) after (a), determining whether a cancer cell in a sample obtained from the subject has at least one HER2 inhibitor resistance mutation that confers increased resistance to a cancer cell or tumor to treatment with the first HER2 inhibitor of step (a); and (c) administering a therapeutically effective amount of a compound of Formula (I) (e.g., Formula (I-a), (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b), (I-c), (I-d), (I-e), (I-f), (I- g), (I-g1), (I-g1-1), (I-g1-2),or (I-h)), or a pharmaceutically acceptable salt thereof, as a monotherapy or in conjunction with another anticancer agent to the subject if the subject has been determined to have a cancer cell that has at least one HER2 inhibitor resistance mutation that confers increased resistance to a cancer cell or tumor to treatment with the first HER2 inhibitor of step (a); or (d) administering additional doses of the first HER2 inhibitor of step (a) to the subject if the subject has not been determined to have a cancer cell that has at least one HER2 inhibitor resistance mutation that confers increased resistance to a cancer cell or tumor to treatment with the first HER2 inhibitor of step (a). Further provided herein is a method of treating a subject having a cancer, wherein the method comprises: (a) determining whether a cancer cell in a sample obtained from a subject having a cancer and previously administered one or more doses of a first HER2 inhibitor has one or more HER2 inhibitor resistance mutations that confer increased resistance to a cancer cell or tumor to treatment with the first HER2 inhibitor that was previously administered to the subject; and (b) administering a therapeutically effective amount of a compound of Formula (I) (e.g., Formula (I-a), (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b), (I-c), (I-d), (I-e), (I-f), (I- g), (I-g1), (I-g1-1), (I-g1-2),or (I-h)), or a pharmaceutically acceptable salt thereof, as a monotherapy or in conjunction with another anticancer agent to the subject if the subject has been determined to have a cancer cell that has at least one HER2 inhibitor resistance mutation that confers increased resistance to a cancer cell or tumor to treatment with the first HER2 inhibitor that was previously administered to the subject; or (c) administering additional doses of the first HER2 inhibitor to the subject if the subject has not been determined to have a cancer cell that has at least one HER2 inhibitor resistance mutation that confers increased resistance to a cancer cell or tumor to treatment with the first HER2 inhibitor previously administered to the subject. Also provided herein is a method of treating a subject having a cancer, wherein the method comprises: (a) determining that a cancer cell in a sample obtained from a subject having a cancer and previously administered one or more doses of a first HER2 inhibitor has one or more HER2 inhibitor resistance mutations that confer increased resistance to a cancer cell or tumor to treatment with the first HER2 inhibitor that was previously administered to the subject; and (b) administering a therapeutically effective amount of a compound of Formula (I) (e.g., Formula (I-a), (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b), (I-c), (I-d), (I-e), (I-f), (I- g), (I-g1), (I-g1-1), (I-g1-2),or (I-h)), or a pharmaceutically acceptable salt thereof, as a monotherapy or in conjunction with another anticancer agent to the subject. Further provided herein is a method of treating a subject having a cancer, wherein the method comprises: (a) determining that a cancer cell in a sample obtained from a subject having a cancer and previously administered one or more doses of a first HER2 inhibitor does not have one or more HER2 inhibitor resistance mutations that confer increased resistance to a cancer cell or tumor to treatment with the first HER2 inhibitor that was previously administered to the subject; and (b) administering additional doses of the first HER2 inhibitor to the subject. This disclosure also provides a method for inhibiting HER2 in a mammalian cell, the method comprising contacting the mammalian cell with an effective amount of a compound of Formula (I) (e.g., Formula (I-a), (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-g1), (I-g1-1), (I-g1-2),or (I-h)), or a pharmaceutically acceptable salt thereof. Also provided herein is a method for treating cancer in a subject in need thereof, the method comprising (a) determining that the cancer is associated with a dysregulation of an EGFR gene, an EGFR kinase, or expression or activity or level of any of the same and that the cancer is associated with a dysregulation of a HER2 gene, a HER2 kinase, or expression or activity or level of any of the same; and (b) administering to the subject a therapeutically effective amount of a compound of Formula (I) (e.g., Formula (I-a), (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-g1), (I-g1-1), (I-g1-2),or (I-h)), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as provided herein. Further provided herein is a method of treating an EGFR-associated and HER2- associated cancer in a subject, the method comprising administering to a subject identified or diagnosed as having an EGFR-associated and a HER2-associated cancer a therapeutically effective amount of a compound of Formula (I) (e.g., Formula (I-a), (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-g1), (I-g1-1), (I-g1-2),or (I-h)), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as provided herein. This disclosure also provides a method of treating a an EGFR-associated and HER2-associated cancer in a subject, the method comprising: determining that the cancer in the subject is an EGFR-associated and a HER2-associated cancer; and administering to the subject a therapeutically effective amount of a compound of Formula (I) (e.g., Formula (I-a), (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-g1), (I-g1- 1), (I-g1-2),or (I-h)), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as provided herein. Provided herein is a method of treating a subject, the method comprising administering a therapeutically effective amount of a compound of Formula (I) (e.g., Formula (I-a), (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I- g1), (I-g1-1), (I-g1-2),or (I-h)), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as provided herein, to a subject having a clinical record that indicates that the subject has a dysregulation of an EGFR gene, an EGFR kinase, or expression or activity or level of any of the same and a dysregulation of a HER2 gene, a HER2 kinase, or expression or activity or level of any of the same. This disclosure also provides a method for inhibiting EGFR and HER2 in a mammalian cell, the method comprising contacting the mammalian cell with an effective amount of a compound of Formula (I) (e.g., Formula (I-a), (I-a1), (I-a2), (I-a3), (I-a4), (I- a5), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-g1), (I-g1-1), (I-g1-2),or (I-h)), or a pharmaceutically acceptable salt thereof. In addition to the above, provided herein is a method for inhibiting a BUB (budding uninhibited by benzimidazole, BUB1-3) kinase. In some embodiments, the methods provided herein include methods for inhibiting BUB11. For example, a method for inhibiting BUB1 in a mammalian cell, the method comprising contacting the mammalian cell with an effective amount of a compound of Formula (I) (e.g., Formula (I-a), (I-a1), (I- a2), (I-a3), (I-a4), (I-a5), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-g1), (I-g1-1), (I-g1-2),or (I-h)), or a pharmaceutically acceptable salt thereof. Other embodiments include those described in the Detailed Description and/or in the claims. Additional Definitions To facilitate understanding of the disclosure set forth herein, a number of additional terms are defined below. Generally, the nomenclature used herein and the laboratory procedures in organic chemistry, medicinal chemistry, and pharmacology described herein are those well-known and commonly employed in the art. Unless defined otherwise, all technical and scientific terms used herein generally have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. Each of the patents, applications, published applications, and other publications that are mentioned throughout the specification and the attached appendices are incorporated herein by reference in their entireties. The term “acceptable” with respect to a formulation, composition or ingredient, as used herein, means having no persistent detrimental effect on the general health of the subject being treated. “API” refers to an active pharmaceutical ingredient. The terms “effective amount” or “therapeutically effective amount,” as used herein, refer to a sufficient amount of a chemical entity being administered which will relieve to some extent one or more of the symptoms of the disease or condition being treated. The result includes reduction and/or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system. For example, an “effective amount” for therapeutic uses is the amount of the composition comprising a compound as disclosed herein required to provide a clinically significant decrease in disease symptoms. An appropriate “effective” amount in any individual case is determined using any suitable technique, such as a dose escalation study. The term “excipient” or “pharmaceutically acceptable excipient” means a pharmaceutically-acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, carrier, solvent, or encapsulating material. In one embodiment, each component is “pharmaceutically acceptable” in the sense of being compatible with the other ingredients of a pharmaceutical formulation, and suitable for use in contact with the tissue or organ of humans and animals without excessive toxicity, irritation, allergic response, immunogenicity, or other problems or complications, commensurate with a reasonable benefit/risk ratio. See, e.g., Remington: The Science and Practice of Pharmacy, 21st ed.; Lippincott Williams & Wilkins: Philadelphia, PA, 2005; Handbook of Pharmaceutical Excipients, 6th ed.; Rowe et al., Eds.; The Pharmaceutical Press and the American Pharmaceutical Association: 2009; Handbook of Pharmaceutical Additives, 3rd ed.; Ash and Ash Eds.; Gower Publishing Company: 2007; Pharmaceutical Preformulation and Formulation, 2nd ed.; Gibson Ed.; CRC Press LLC: Boca Raton, FL, 2009. The term “pharmaceutically acceptable salt” refers to a formulation of a compound that does not cause significant irritation to an organism to which it is administered and does not abrogate the biological activity and properties of the compound. In certain instances, pharmaceutically acceptable salts are obtained by reacting a compound described herein, with acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid and the like. In some instances, pharmaceutically acceptable salts are obtained by reacting a compound having acidic group described herein with a base to form a salt such as an ammonium salt, an alkali metal salt, such as a sodium or a potassium salt, an alkaline earth metal salt, such as a calcium or a magnesium salt, a salt of organic bases such as dicyclohexylamine, N-methyl-D-glucamine, tris(hydroxymethyl)methylamine, and salts with amino acids such as arginine, lysine, and the like, or by other methods previously determined. The pharmacologically acceptable salt s not specifically limited as far as it can be used in medicaments. Examples of a salt that the compounds described hereinform with a base include the following: salts thereof with inorganic bases such as sodium, potassium, magnesium, calcium, and aluminum; salts thereof with organic bases such as methylamine, ethylamine and ethanolamine; salts thereof with basic amino acids such as lysine and ornithine; and ammonium salt. The salts may be acid addition salts, which are specifically exemplified by acid addition salts with the following: mineral acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, and phosphoric acid:organic acids such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, methanesulfonic acid, and ethanesulfonic acid; acidic amino acids such as aspartic acid and glutamic acid. The term “pharmaceutical composition” refers to a mixture of a compound described herein with other chemical components (referred to collectively herein as “excipients”), such as carriers, stabilizers, diluents, dispersing agents, suspending agents, and/or thickening agents. The pharmaceutical composition facilitates administration of the compound to an organism. Multiple techniques of administering a compound exist in the art including, but not limited to: rectal, oral, intravenous, aerosol, parenteral, ophthalmic, pulmonary, and topical administration. The term “subject” refers to an animal, including, but not limited to, a primate (e.g., human), monkey, cow, pig, sheep, goat, horse, dog, cat, rabbit, rat, or mouse. The terms “subject” and “patient” are used interchangeably herein in reference, for example, to a mammalian subject, such as a human. The term "halo" refers to fluoro (F), chloro (Cl), bromo (Br), or iodo (I). The term “oxo” refers to a divalent doubly bonded oxygen atom (i.e., “=O”). As used herein, oxo groups are attached to carbon atoms to form carbonyls. The term "alkyl" refers to a saturated acyclic hydrocarbon radical that may be a straight chain or branched chain, containing the indicated number of carbon atoms. For example, C_1-10 indicates that the group may have from 1 to 10 (inclusive) carbon atoms in it. Alkyl groups can either be unsubstituted or substituted with one or more substituents. Non-limiting examples include methyl, ethyl, iso-propyl, tert-butyl, n-hexyl. The term “saturated” as used in this context means only single bonds present between constituent carbon atoms and other available valences occupied by hydrogen and/or other substituents as defined herein. The term "haloalkyl" refers to an alkyl, in which one or more hydrogen atoms is/are replaced with an independently selected halo. The term "alkoxy" refers to an -O-alkyl radical (e.g., -OCH₃). The term "alkylene" refers to a divalent alkyl (e.g., -CH₂-). Similarly, terms such as “cycloalkylene” and “heterocyclylene” refer to divalent cycloalkyl and heterocyclyl respectively. For avoidance of doubt, in “cycloalkylene” and “heterocyclylene”, the two radicals can be on the same ring carbon atom (e.g., a geminal diradical such as or

) or on different ring atoms (e.g., ring carbon and/or nitrogen atoms (e.g., vicinal ring carbon and/or nitrogen atoms)) (e.g.,

). The term "alkenyl" refers to an acyclic hydrocarbon chain that may be a straight chain or branched chain having one or more carbon-carbon double bonds. The alkenyl moiety contains the indicated number of carbon atoms. For example, C_2-6 indicates that the group may have from 2 to 6 (inclusive) carbon atoms in it. Alkenyl groups can either be unsubstituted or substituted with one or more substituents. The term "alkynyl" refers to an acyclic hydrocarbon chain that may be a straight chain or branched chain having one or more carbon-carbon triple bonds. The alkynyl moiety contains the indicated number of carbon atoms. For example, C_2-6 indicates that the group may have from 2 to 6 (inclusive) carbon atoms in it. Alkynyl groups can either be unsubstituted or substituted with one or more substituents. The term "aryl" refers to a 6-20 carbon mono-, bi-, tri- or polycyclic group wherein at least one ring in the system is aromatic (e.g., 6-carbon monocyclic, 10-carbon bicyclic, or 14-carbon tricyclic aromatic ring system); and wherein 0, 1, 2, 3, or 4 atoms of each ring may be substituted by a substituent. Examples of aryl groups include phenyl, naphthyl, tetrahydronaphthyl, and the like. The term "cycloalkyl" as used herein refers to cyclic saturated hydrocarbon groups having, e.g., 3 to 20 ring carbons, preferably 3 to 16 ring carbons, and more preferably 3 to 12 ring carbons or 3-10 ring carbons or 3-6 ring carbons, wherein the cycloalkyl group may be optionally substituted. Examples of cycloalkyl groups include, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Cycloalkyl may include multiple fused and/or bridged rings. Non-limiting examples of fused/bridged cycloalkyl includes: bicyclo[1.1.0]butane, bicyclo[2.1.0]pentane, bicyclo[1.1.1]pentane, bicyclo[3.1.0]hexane, bicyclo[2.1.1]hexane, bicyclo[3.2.0]heptane, bicyclo[4.1.0]heptane, bicyclo[2.2.1]heptane, bicyclo[3.1.1]heptane, bicyclo[4.2.0]octane, bicyclo[3.2.1]octane, bicyclo[2.2.2]octane, and the like. Cycloalkyl also includes spirocyclic rings (e.g., spirocyclic bicycle wherein two rings are connected through just one atom). Non-limiting examples of spirocyclic cycloalkyls include spiro[2.2]pentane, spiro[2.5]octane, spiro[3.5]nonane, spiro[3.5]nonane, spiro[3.5]nonane, spiro[4.4]nonane, spiro[2.6]nonane, spiro[4.5]decane, spiro[3.6]decane, spiro[5.5]undecane, and the like. The term “saturated” as used in this context means only single bonds present between constituent carbon atoms. The term "cycloalkenyl" as used herein means partially unsaturated cyclic hydrocarbon groups having 3 to 20 ring carbons, preferably 3 to 16 ring carbons, and more preferably 3 to 12 ring carbons or 3-10 ring carbons or 3-6 ring carbons, wherein the cycloalkenyl group may be optionally substituted. Examples of cycloalkenyl groups include, without limitation, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. As partially unsaturated cyclic hydrocarbon groups, cycloalkenyl groups may have any degree of unsaturation provided that one or more double bonds is present in the ring, none of the rings in the ring system are aromatic, and the cycloalkenyl group is not fully saturated overall. Cycloalkenyl may include multiple fused and/or bridged and/or spirocyclic rings. The term “heteroaryl”, as used herein, means a mono-, bi-, tri- or polycyclic group having 5 to 20 ring atoms, alternatively 5, 6, 9, 10, or 14 ring atoms; wherein at least one ring in the system contains one or more heteroatoms independently selected from the group consisting of N, O, and S and at least one ring in the system is aromatic (but does not have to be a ring which contains a heteroatom, e.g. tetrahydroisoquinolinyl, e.g., tetrahydroquinolinyl). Heteroaryl groups can either be unsubstituted or substituted with one or more substituents. Examples of heteroaryl include thienyl, pyridinyl, furyl, oxazolyl, oxadiazolyl, pyrrolyl, imidazolyl, triazolyl, thiodiazolyl, pyrazolyl, isoxazolyl, thiadiazolyl, pyranyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, thiazolyl benzothienyl, benzoxadiazolyl, benzofuranyl, benzimidazolyl, benzotriazolyl, cinnolinyl, indazolyl, indolyl, isoquinolinyl, isothiazolyl, naphthyridinyl, purinyl, thienopyridinyl, pyrido[2,3- d]pyrimidinyl, pyrrolo[2,3-b]pyridinyl, quinazolinyl, quinolinyl, thieno[2,3-c]pyridinyl, pyrazolo[3,4-b]pyridinyl, pyrazolo[3,4-c]pyridinyl, pyrazolo[4,3-c]pyridine, pyrazolo[4,3-b]pyridinyl, tetrazolyl, chromane, 2,3-dihydrobenzo[b][1,4]dioxine, benzo[d][1,3]dioxole, 2,3-dihydrobenzofuran, tetrahydroquinoline, 2,3- dihydrobenzo[b][1,4]oxathiine, isoindoline, and others. In some embodiments, the heteroaryl is selected from thienyl, pyridinyl, furyl, pyrazolyl, imidazolyl, isoindolinyl, pyranyl, pyrazinyl, and pyrimidinyl. For purposes of clarification, heteroaryl also includes aromatic lactams, aromatic cyclic ureas, or vinylogous analogs thereof, in which each ring nitrogen adjacent to a carbonyl is tertiary (i.e., all three valences are occupied by non- hydrogen substituents), such as one or more of pyridone (e.g.,

, ,

(e.g.,

), wherein each ring nitrogen adjacent to a carbonyl is tertiary (i.e., the oxo group (i.e.,

) herein is a constituent part of the heteroaryl ring). The term "heterocyclyl" refers to a mono-, bi-, tri-, or polycyclic saturated ring system with 3-16 ring atoms (e.g., 5-8 membered monocyclic, 8-12 membered bicyclic, or 11-14 membered tricyclic ring system) having 1-3 heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9 heteroatoms if tricyclic or polycyclic, said heteroatoms selected from O, N, or S (e.g., carbon atoms and 1-3, 1-6, or 1-9 heteroatoms of N, O, or S if monocyclic, bicyclic, or tricyclic, respectively), wherein 0, 1, 2 or 3 atoms of each ring may be substituted by a substituent. Examples of heterocyclyl groups include piperazinyl, pyrrolidinyl, dioxanyl, morpholinyl, tetrahydrofuranyl, and the like. Heterocyclyl may include multiple fused and bridged rings. Non-limiting examples of fused/bridged heteorocyclyl includes: 2-azabicyclo[1.1.0]butane, 2-azabicyclo[2.1.0]pentane, 2- azabicyclo[1.1.1]pentane, 3-azabicyclo[3.1.0]hexane, 5-azabicyclo[2.1.1]hexane, 3- azabicyclo[3.2.0]heptane, octahydrocyclopenta[c]pyrrole, 3-azabicyclo[4.1.0]heptane, 7- azabicyclo[2.2.1]heptane, 6-azabicyclo[3.1.1]heptane, 7-azabicyclo[4.2.0]octane, 2- azabicyclo[2.2.2]octane, 3-azabicyclo[3.2.1]octane, 2-oxabicyclo[1.1.0]butane, 2- oxabicyclo[2.1.0]pentane, 2-oxabicyclo[1.1.1]pentane, 3-oxabicyclo[3.1.0]hexane, 5- oxabicyclo[2.1.1]hexane, 3-oxabicyclo[3.2.0]heptane, 3-oxabicyclo[4.1.0]heptane, 7- oxabicyclo[2.2.1]heptane, 6-oxabicyclo[3.1.1]heptane, 7-oxabicyclo[4.2.0]octane, 2- oxabicyclo[2.2.2]octane, 3-oxabicyclo[3.2.1]octane, and the like. Heterocyclyl also includes spirocyclic rings (e.g., spirocyclic bicycle wherein two rings are connected through just one atom). Non-limiting examples of spirocyclic heterocyclyls include 2- azaspiro[2.2]pentane, 4-azaspiro[2.5]octane, 1-azaspiro[3.5]nonane, 2- azaspiro[3.5]nonane, 7-azaspiro[3.5]nonane, 2-azaspiro[4.4]nonane, 6- azaspiro[2.6]nonane, 1,7-diazaspiro[4.5]decane, 7-azaspiro[4.5]decane 2,5- diazaspiro[3.6]decane, 3-azaspiro[5.5]undecane, 2-oxaspiro[2.2]pentane, 4- oxaspiro[2.5]octane, 1-oxaspiro[3.5]nonane, 2-oxaspiro[3.5]nonane, 7- oxaspiro[3.5]nonane, 2-oxaspiro[4.4]nonane, 6-oxaspiro[2.6]nonane, 1,7- dioxaspiro[4.5]decane, 2,5-dioxaspiro[3.6]decane, 1-oxaspiro[5.5]undecane, 3- oxaspiro[5.5]undecane, 3-oxa-9-azaspiro[5.5]undecane and the like. The term “saturated” as used in this context means only single bonds present between constituent ring atoms and other available valences occupied by hydrogen and/or other substituents as defined herein. The term "heterocycloalkenyl" as used herein means partially unsaturated cyclic ring system with 3-16 ring atoms (e.g., 5-8 membered monocyclic, 8-12 membered bicyclic, or 11-14 membered tricyclic ring system) having 1-3 heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9 heteroatoms if tricyclic or polycyclic, said heteroatoms selected from O, N, or S (e.g., carbon atoms and 1-3, 1-6, or 1-9 heteroatoms of N, O, or S if monocyclic, bicyclic, or tricyclic, respectively), wherein 0, 1, 2 or 3 atoms of each ring may be substituted by a substituent. Examples of heterocycloalkenyl groups include, without limitation, tetrahydropyridyl, dihydropyrazinyl, dihydropyridyl, dihydropyrrolyl, dihydrofuranyl, dihydrothiophenyl. As partially unsaturated cyclic groups, heterocycloalkenyl groups may have any degree of unsaturation provided that one or more double bonds is present in the ring, none of the rings in the ring system are aromatic, and the heterocycloalkenyl group is not fully saturated overall. Heterocycloalkenyl may include multiple fused and/or bridged and/or spirocyclic rings. As used herein, examples of aromatic rings include: benzene, pyridine, pyrimidine, pyrazine, pyridazine, pyridone, pyrrole, pyrazole, oxazole, thioazole, isoxazole, isothiazole, and the like. As used herein, when a ring is described as being “partially unsaturated”, it means said ring has one or more additional degrees of unsaturation (in addition to the degree of unsaturation attributed to the ring itself; e.g., one or more double or tirple bonds between constituent ring atoms), provided that the ring is not aromatic. Examples of such rings include: cyclopentene, cyclohexene, cycloheptene, dihydropyridine, tetrahydropyridine, dihydropyrrole, dihydrofuran, dihydrothiophene, and the like. For the avoidance of doubt, and unless otherwise specified, for rings and cyclic groups (e.g., aryl, heteroaryl, heterocyclyl, heterocycloalkenyl, cycloalkenyl, cycloalkyl, and the like described herein) containing a sufficient number of ring atoms to form bicyclic or higher order ring systems (e.g., tricyclic, polycyclic ring systems), it is understood that such rings and cyclic groups encompass those having fused rings, including those in which the points of fusion are located (i) on adjacent ring atoms (e.g., [x.x.0] ring systems, in which 0 represents a zero atom bridge (e.g.,

)); (ii) a single ring atom (spiro- fused ring systems) (e.g., or ), or (iii) a contiguous

array of ring atoms (bridged ring systems having all bridge lengths > 0) (e.g.,

,

or ). In addition, atoms making up the compounds of the present embodiments are intended to include all isotopic forms of such atoms. Isotopes, as used herein, include those atoms having the same atomic number but different mass numbers. By way of general example and without limitation, isotopes of hydrogen include tritium and deuterium, and isotopes of carbon include ¹³C and ¹⁴C. In addition, the compounds generically or specifically disclosed herein are intended to include all tautomeric forms. Thus, by way of example, a compound containing the moiety:

encompasses the tautomeric form containing the moiety:

. Similarly, a pyridinyl or pyrimidinyl moiety that is described to be optionally substituted with hydroxyl encompasses pyridone or pyrimidone tautomeric forms. The compounds provided herein may encompass various stereochemical forms. The compounds also encompass diastereomers as well as optical isomers, e.g., mixtures of enantiomers including racemic mixtures, as well as individual enantiomers and diastereomers, which arise as a consequence of structural asymmetry in certain compounds. Unless otherwise indicated, when a disclosed compound is named or depicted by a structure without specifying the stereochemistry and has one or more chiral centers, it is understood to represent all possible stereoisomers of the compound. The details of one or more embodiments of the invention are set forth in the accompanying drawings and the description below. Other features and advantages of the invention will be apparent from the description and drawings, and from the claims. DETAILED DESCRIPTION This disclosure provides chemical entities (e.g., a compound or a pharmaceutically acceptable salt, and/or hydrate, and/or cocrystal, and/or drug combination of the compound) that inhibit epidermal growth factor receptor (EGFR, ERBB1) and/or Human epidermal growth factor receptor 2 (HER2, ERBB2). These chemical entities are useful, e.g., for treating a condition, disease or disorder in which increased (e.g., excessive) EGFR and/or HER2 activation contributes to the pathology and/or symptoms and/or progression of the condition, disease or disorder (e.g., cancer) in a subject (e.g., a human). In some embodiments, the chemical entities provided herein can inhibit an EGFR kinase and/or a HER2 kinase that has an exon 20 mutation (e.g., any of the exon 20 mutations described herein). Exon 20 mutations can confer intrinsic resistance to EGFR and/or HER2 inhibitors, and there are currently only limited targeted therapies that have been approved for subjects with these mutations. This disclosure also provides compositions containing the chemical entities provided herein as well as methods of using and making the same. Formula (I) Compounds In one aspect, this disclosure features compounds of Formula (I):

• -C(=O)O-*, -C(=O)N(R^N)-*, or –S(O)_1-2N(R^N)-*; • -OC(=O)-*, -N(R^N)C(=O)-*, or –N(R^N)S(O)_1-2-*; and • -OC(=O)N(R^N)-*, -N(R^N)C(=O)O-*, -N(R^N)C(=O)N(R^N)-*, or – N(R^N)S(O)_1-2N(R^N)-*, wherein the asterisk represents point of attachment to L¹; L¹ is selected from the group consisting of: a bond and C_1-10 alkylene optionally substituted with from 1-6 R^a; R⁵ is selected from the group consisting of: • H; • halo; • -OH; • -NR^eR^f; • -C_1-6 alkoxy or -S(O)_0-2(C_1-6 alkyl), each optionally substituted with from 1-6 R^a; • -R^g; • -L⁵-R^g; • -R^g2-R^W or -R^g2-R^Y; and • -L⁵-R^g2-R^W or –L⁵-R^g2-R^Y; provided that: when L¹ is a bond, then R⁵ is selected from the group consisting of: H, -R^g, -R^g2- R^W, and -R^g2-R^Y; and X¹ is other than H, -OH, or NH₂; L⁵ is selected from the group consisting of: –O-, -S(O)_0-2, -NH, and -N(R^d)-; R^W is –L^W-W, wherein L^W is C(=O), S(O)_1-2, OC(=O)*, NHC(=O)*, NR^dC(=O)*, NHS(O)_1-2*, or NR^dS(O)_1-2*, wherein the asterisk represents point of attachment to W, and W is selected from the group consisting of: • C_2-6 alkenyl; C_2-6 alkynyl; or C_3-10 allenyl, each of which is optionally substituted with from 1-3 R^a and further optionally substituted with R^g, wherein W is attached to L^W via an sp² or sp hybridized carbon atom, thereby providing an α, β- unsaturated system; and • bicyclo[x.y.0]cycloalkyl which is optionally substituted with from 1-2 R^c, wherein x is 1 or 2; and y is an integer from 1 to 6; R^Y is selected from the group consisting of: -R^g and -(L^g)_g-R^g; each of R^1c, R^2a, R^2b, R^3a, and R^3b is independently selected from the group consisting of: H; halo; -OH; -C(O)OH or –C(O)NH₂; -CN; -R^b; -L^b-R^b; -C_1-6 alkoxy or - C_1-6 thioalkoxy, each optionally substituted with from 1-6 R^a; -NR^eR^f; -R^g; and -(L^g)_g-R^g; provided that R^1c is other than halo, –CN, or –C(O)OH; or two of variables R^1c, R^2a, R^2b, R^3a, and R^3b, together with the Ring B ring atoms to which each is attached, form a fused saturated or unsaturated ring of 3-12 ring atoms; • wherein from 0-2 of the ring atoms are each an independently selected heteroatom (in addition to –N(R^1c)- when –N(R^1c)- forms part of the fused saturated or unsaturated ring), wherein each of the independently selected heteroatoms is selected from the group consisting of N, NH, N(R^d), O, and S(O)_0-2; and • wherein the fused saturated or unsaturated ring of 3-12 ring atoms is optionally substituted with from 1-4 substituents independently selected from the group consisting of oxo, R^c, and R^W; or one of R^2a and R^2b and one of R^3a and R^3b combine to form a double bond between the Ring B atoms to which each is attached; Ring A is R^g; each occurrence of R^a is independently selected from the group consisting of: – OH; -halo; –NR^eR^f; C_1-4 alkoxy; C_1-4 haloalkoxy; -C(=O)O(C_1-4 alkyl); -C(=O)(C_1-4 alkyl); -C(=O)OH; -CONR’R’’; -S(O)_1-2NR’R’’; -S(O)_1-2(C_1-4 alkyl); and cyano; each occurrence of R^b is independently C_1-6 alkyl, C_2-6 alkenyl, or C_2-6 alkynyl, each of which is optionally substituted with from 1-6 R^a; each occurrence of L^b is independently C(=O); C(=O)O; S(O)_1-2; C(=O)NH*; C(=O)NR^d*; S(O)_1-2NH*; or S(O)_1-2N(R^d)*, wherein the asterisk represents point of attachment to R^b; each occurrence of R^c is independently selected from the group consisting of: halo; cyano; C_1-10 alkyl which is optionally substituted with from 1-6 independently selected R^a; C_2-6 alkenyl; C_2-6 alkynyl; C_1-4 alkoxy optionally substituted with C_1-4 alkoxy or C_1-4 haloalkoxy; C_1-4 haloalkoxy; -S(O)_1-2(C_1-4 alkyl); -S(O)(=NH)(C_1-4 alkyl); -NR^eR^f; –OH; -S(O)_1-2NR’R’’; -C_1-4 thioalkoxy; -NO₂; -C(=O)(C_1-10 alkyl); -C(=O)O(C_1-4 alkyl); - C(=O)OH; -C(=O)NR’R’’; and –SF₅; each occurrence of R^d is independently selected from the group consisting of: C_1-6 alkyl optionally substituted with from 1-3 independently selected R^a; -C(O)(C_1-4 alkyl); - C(O)O(C_1-4 alkyl); -CONR’R’’; -S(O)_1-2NR’R’’; - S(O)_1-2(C_1-4 alkyl); -OH; and C_1-4 alkoxy; each occurrence of R^e and R^f is independently selected from the group consisting of: H; C_1-6 alkyl optionally substituted with from 1-3 substituents each independently selected from the group consisting of NR’R’’, -OH, C_1-6 alkoxy, C_1-6 haloalkoxy, and halo; -C(O)(C_1-4 alkyl); -C(O)O(C_1-4 alkyl); -CONR’R’’; -S(O)_1-2NR’R’’; - S(O)_1-2(C_1-4 alkyl); -OH; and C_1-4 alkoxy; each occurrence of R^g is independently selected from the group consisting of: • C_3-10 cycloalkyl or C_3-10 cycloalkenyl, each of which is optionally substituted with from 1-4 substituents independently selected from the group consisting of oxo and R^c; • heterocyclyl or heterocycloalkenyl including from 3-10 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R^d), O, and S(O)_0-2, and wherein the heterocyclyl or heterocycloalkenyl is optionally substituted with from 1-4 substituents independently selected from the group consisting of oxo and R^c; • heteroaryl including from 5-10 ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R^d), O, and S(O)_0-2, and wherein the heteroaryl is optionally substituted with from 1-4 R^c; and • C_6-10 aryl optionally substituted with from 1-4 R^c; each occurrence of L^g is independently selected from the group consisting of: -O-, -NH-, -NR^d , -S(O)_0-2, C(O), and C_1-3 alkylene optionally substituted with from 1-3 R^a; each g is independently 1, 2, or 3; each R^g2 is a divalent R^g group; each occurrence of R’ and R’’ is independently selected from the group consisting of: H; -OH; and C_1-4 alkyl; and each occurrence of R^N is independently H, C_1-3 alkyl, or C_3-6 cycloalkyl. In one aspect, this disclosure features compounds of Formula (I):

• -C(=O)O-*, -C(=O)N(R^N)-*, or –S(O)_1-2N(R^N)-*; • -OC(=O)-*, -N(R^N)C(=O)-*, or –N(R^N)S(O)_1-2-*; and • -OC(=O)N(R^N)-*, -N(R^N)C(=O)O-*, -N(R^N)C(=O)N(R^N)-*, or – N(R^N)S(O)_1-2N(R^N)-*, wherein the asterisk represents point of attachment to L¹; L¹ is selected from the group consisting of: a bond and C_1-10 alkylene optionally substituted with from 1-6 R^a; R⁵ is selected from the group consisting of: • H; • halo; • -OH; • -NR^eR^f; • -C_1-6 alkoxy or -S(O)_0-2(C_1-6 alkyl), each optionally substituted with from 1-6 R^a; • -R^g; • -L⁵-R^g; • -R^g2-R^W or -R^g2-R^Y; and • -L⁵-R^g2-R^W or –L⁵-R^g2-R^Y; provided that: when L¹ is a bond, then R⁵ is selected from the group consisting of: H, -R^g, -R^g2- R^W, and -R^g2-R^Y; and X¹ is other than H, -OH, or NH₂; L⁵ is selected from the group consisting of: –O-, -S(O)_0-2, -NH, and -N(R^d)-; R^W is –L^W-W, wherein L^W is C(=O), S(O)_1-2, OC(=O)*, NHC(=O)*, NR^dC(=O)*, NHS(O)_1-2*, or NR^dS(O)_1-2*, wherein the asterisk represents point of attachment to W, and W is selected from the group consisting of: • C_2-6 alkenyl; C_2-6 alkynyl; or C_3-10 allenyl, each of which is optionally substituted with from 1-3 R^a and further optionally substituted with R^g, wherein W is attached to L^W via an sp² or sp hybridized carbon atom, thereby providing an α, β- unsaturated system; and • bicyclo[x.y.0]cycloalkyl which is optionally substituted with from 1-2 R^c, wherein x is 1 or 2; and y is an integer from 1 to 6; R^Y is selected from the group consisting of: -R^g and -(L^g)_g-R^g; each of R^1c, R^2a, R^2b, R^3a, and R^3b is independently selected from the group consisting of: H; halo; -OH; -C(O)OH or –C(O)NH₂; -CN; -R^b; -L^b-R^b; -C_1-6 alkoxy or - C_1-6 thioalkoxy, each optionally substituted with from 1-6 R^a; -NR^eR^f; -R^g; and -(L^g)_g-R^g; provided that R^1c is other than halo, –CN, or –C(O)OH; or or two of variables R^1c, R^2a, R^2b, R^3a, and R^3b, together with the Ring B ring atoms to which each is attached, form a fused saturated or unsaturated ring of 3-12 ring atoms; • wherein from 0-2 of the ring atoms are each an independently selected heteroatom (in addition to –N(R^1c)- when –N(R^1c)- forms part of the fused saturated or unsaturated ring), wherein each of the independently selected heteroatoms is selected from the group consisting of N, NH, N(R^d), O, and S(O)_0-2; and • wherein the fused saturated or unsaturated ring of 3-12 ring atoms is optionally substituted with from 1-4 substituents independently selected from the group consisting of oxo and R^c; Ring A is R^g; each occurrence of R^a is independently selected from the group consisting of: – OH; -halo; –NR^eR^f; C_1-4 alkoxy; C_1-4 haloalkoxy; -C(=O)O(C_1-4 alkyl); -C(=O)(C_1-4 alkyl); -C(=O)OH; -CONR’R’’; -S(O)_1-2NR’R’’; -S(O)_1-2(C_1-4 alkyl); and cyano; each occurrence of R^b is independently C_1-6 alkyl, C_2-6 alkenyl, or C_2-6 alkynyl, each of which is optionally substituted with from 1-6 R^a; each occurrence of L^b is independently C(=O); C(=O)O; S(O)_1-2; C(=O)NH*; C(=O)NR^d*; S(O)_1-2NH*; or S(O)_1-2N(R^d)*, wherein the asterisk represents point of attachment to R^b; each occurrence of R^c is independently selected from the group consisting of: halo; cyano; C_1-10 alkyl which is optionally substituted with from 1-6 independently selected R^a; C_2-6 alkenyl; C_2-6 alkynyl; C_1-4 alkoxy optionally substituted with C_1-4 alkoxy or C_1-4 haloalkoxy; C_1-4 haloalkoxy; -S(O)_1-2(C_1-4 alkyl); -S(O)(=NH)(C_1-4 alkyl); -NR^eR^f; –OH; -S(O)_1-2NR’R’’; -C_1-4 thioalkoxy; -NO2; -C(=O)(C_1-10 alkyl); -C(=O)O(C_1-4 alkyl); - C(=O)OH; -C(=O)NR’R’’; and –SF₅; each occurrence of R^d is independently selected from the group consisting of: C_1-6 alkyl optionally substituted with from 1-3 independently selected R^a; -C(O)(C_1-4 alkyl); - C(O)O(C_1-4 alkyl); -CONR’R’’; -S(O)_1-2NR’R’’; - S(O)_1-2(C_1-4 alkyl); -OH; and C_1-4 alkoxy; each occurrence of R^e and R^f is independently selected from the group consisting of: H; C_1-6 alkyl optionally substituted with from 1-3 substituents each independently selected from the group consisting of NR’R’’, -OH, C_1-6 alkoxy, C_1-6 haloalkoxy, and halo; -C(O)(C_1-4 alkyl); -C(O)O(C_1-4 alkyl); -CONR’R’’; -S(O)_1-2NR’R’’; - S(O)_1-2(C_1-4 alkyl); -OH; and C_1-4 alkoxy; each occurrence of R^g is independently selected from the group consisting of: • C_3-10 cycloalkyl or C_3-10 cycloalkenyl, each of which is optionally substituted with from 1-4 substituents independently selected from the group consisting of oxo and R^c; • heterocyclyl or heterocycloalkenyl including from 3-10 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R^d), O, and S(O)_0-2, and wherein the heterocyclyl or heterocycloalkenyl is optionally substituted with from 1-4 substituents independently selected from the group consisting of oxo and R^c; • heteroaryl including from 5-10 ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R^d), O, and S(O)_0-2, and wherein the heteroaryl is optionally substituted with from 1-4 R^c; and • C_6-10 aryl optionally substituted with from 1-4 R^c; each occurrence of L^g is independently selected from the group consisting of: -O-, -NH-, -NR^d , -S(O)_0-2, C(O), and C_1-3 alkylene optionally substituted with from 1-3 R^a; each g is independently 1, 2, or 3; each R^g2 is a divalent R^g group; each occurrence of R’ and R’’ is independently selected from the group consisting of: H; -OH; and C_1-4 alkyl; and each occurrence of R^N is independently H, C_1-3 alkyl, or C_3-6 cycloalkyl. In one aspect, this disclosure features compounds of Formula (I):

• -C(=O)O-*, -C(=O)N(R^N)-*, or –S(O)_1-2N(R^N)-*; • -OC(=O)-*, -N(R^N)C(=O)-*, or –N(R^N)S(O)_1-2-*; and • -OC(=O)N(R^N)-*, -N(R^N)C(=O)O-*, -N(R^N)C(=O)N(R^N)-*, or – N(R^N)S(O)_1-2N(R^N)-*, wherein the asterisk represents point of attachment to L¹; L¹ is selected from the group consisting of: a bond and C_1-10 alkylene optionally substituted with from 1-6 R^a; R⁵ is selected from the group consisting of: • H; • halo; • -OH; • -NR^eR^f; • -C_1-6 alkoxy or -S(O)_0-2(C_1-6 alkyl), each optionally substituted with from 1-6 R^a; • -R^g; • -L⁵-R^g; • -R^g2-R^W or -R^g2-R^Y; and • -L⁵-R^g2-R^W or –L⁵-R^g2-R^Y; provided that: when L¹ is a bond, then R⁵ is selected from the group consisting of: H, -R^g, -R^g2- R^W, and -R^g2-R^Y; and X¹ is other than H, -OH, or NH₂; L⁵ is selected from the group consisting of: –O-, -S(O)_0-2, -NH, and -N(R^d)-; R^W is –L^W-W, wherein L^W is C(=O), S(O)_1-2, OC(=O)*, NHC(=O)*, NR^dC(=O)*, NHS(O)_1-2*, or NR^dS(O)_1-2*, wherein the asterisk represents point of attachment to W, and W is C_2-6 alkenyl; C_2-6 alkynyl; or C_3-10 allenyl, each of which is optionally substituted with from 1-3 R^a and further optionally substituted with R^g, wherein W is attached to L^W via an sp² or sp hybridized carbon atom, thereby providing an α, β- unsaturated system; and R^Y is selected from the group consisting of: -R^g and -(L^g)g-R^g; each of R^1c, R^2a, R^2b, R^3a, and R^3b is independently selected from the group consisting of: H; halo; -OH; -C(O)OH or –C(O)NH₂; -CN; -R^b; -L^b-R^b; -C_1-6 alkoxy or - C_1-6 thioalkoxy, each optionally substituted with from 1-6 R^a; -NR^eR^f; -R^g; and -(L^g)g-R^g; provided that R^1c is other than halo, –CN, or –C(O)OH; or or two of variables R^1c, R^2a, R^2b, R^3a, and R^3b, together with the Ring B ring atoms to which each is attached, form a fused saturated or unsaturated ring of 3-12 ring atoms; • wherein from 0-2 of the ring atoms are each an independently selected heteroatom (in addition to –N(R^1c)- when –N(R^1c)- forms part of the fused saturated or unsaturated ring), wherein each of the independently selected heteroatoms is selected from the group consisting of N, NH, N(R^d), O, and S(O)_0-2; and • wherein the fused saturated or unsaturated ring of 3-12 ring atoms is optionally substituted with from 1-4 substituents independently selected from the group consisting of oxo and R^c; Ring A is R^g; each occurrence of R^a is independently selected from the group consisting of: – OH; -halo; –NR^eR^f; C_1-4 alkoxy; C_1-4 haloalkoxy; -C(=O)O(C_1-4 alkyl); -C(=O)(C_1-4 alkyl); -C(=O)OH; -CONR’R’’; -S(O)_1-2NR’R’’; -S(O)_1-2(C_1-4 alkyl); and cyano; each occurrence of R^b is independently C_1-6 alkyl, C_2-6 alkenyl, or C_2-6 alkynyl, each of which is optionally substituted with from 1-6 R^a; each occurrence of L^b is independently C(=O); C(=O)O; S(O)_1-2; C(=O)NH*; C(=O)NR^d*; S(O)_1-2NH*; or S(O)_1-2N(R^d)*, wherein the asterisk represents point of attachment to R^b; each occurrence of R^c is independently selected from the group consisting of: halo; cyano; C_1-10 alkyl which is optionally substituted with from 1-6 independently selected R^a; C_2-6 alkenyl; C_2-6 alkynyl; C_1-4 alkoxy optionally substituted with C_1-4 alkoxy or C_1-4 haloalkoxy; C_1-4 haloalkoxy; -S(O)_1-2(C_1-4 alkyl); -S(O)(=NH)(C_1-4 alkyl); -NR^eR^f; –OH; -S(O)_1-2NR’R’’; -C_1-4 thioalkoxy; -NO2; -C(=O)(C_1-10 alkyl); -C(=O)O(C_1-4 alkyl); - C(=O)OH; -C(=O)NR’R’’; and –SF₅; each occurrence of R^d is independently selected from the group consisting of: C_1-6 alkyl optionally substituted with from 1-3 independently selected R^a; -C(O)(C_1-4 alkyl); - C(O)O(C_1-4 alkyl); -CONR’R’’; -S(O)_1-2NR’R’’; - S(O)_1-2(C_1-4 alkyl); -OH; and C_1-4 alkoxy; each occurrence of R^e and R^f is independently selected from the group consisting of: H; C_1-6 alkyl optionally substituted with from 1-3 substituents each independently selected from the group consisting of NR’R’’, -OH, C_1-6 alkoxy, C_1-6 haloalkoxy, and halo; -C(O)(C_1-4 alkyl); -C(O)O(C_1-4 alkyl); -CONR’R’’; -S(O)_1-2NR’R’’; - S(O)_1-2(C_1-4 alkyl); -OH; and C_1-4 alkoxy; each occurrence of R^g is independently selected from the group consisting of: • C_3-10 cycloalkyl or C_3-10 cycloalkenyl, each of which is optionally substituted with from 1-4 substituents independently selected from the group consisting of oxo and R^c; • heterocyclyl or heterocycloalkenyl including from 3-10 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R^d), O, and S(O)_0-2, and wherein the heterocyclyl or heterocycloalkenyl is optionally substituted with from 1-4 substituents independently selected from the group consisting of oxo and R^c; • heteroaryl including from 5-10 ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R^d), O, and S(O)_0-2, and wherein the heteroaryl is optionally substituted with from 1-4 R^c; and • C_6-10 aryl optionally substituted with from 1-4 R^c; each occurrence of L^g is independently selected from the group consisting of: -O-, -NH-, -NR^d , -S(O)_0-2, C(O), and C_1-3 alkylene optionally substituted with from 1-3 R^a; each g is independently 1, 2, or 3; each R^g2 is a divalent R^g group; each occurrence of R’ and R’’ is independently selected from the group consisting of: H; -OH; and C_1-4 alkyl; and each occurrence of R^N is independently H, C_1-3 alkyl, or C_3-6 cycloalkyl. In one aspect, this disclosure features compounds of Formula (I):

• -C(=O)O-*, -C(=O)N(R^N)-*, or –S(O)_1-2N(R^N)-*; • -OC(=O)-*, -N(R^N)C(=O)-*, or –N(R^N)S(O)_1-2-*; and • -OC(=O)N(R^N)-*, -N(R^N)C(=O)O-*, -N(R^N)C(=O)N(R^N)-*, or – N(R^N)S(O)_1-2N(R^N)-*, wherein the asterisk represents point of attachment to L¹; L¹ is selected from the group consisting of: a bond and C_1-10 alkylene optionally substituted with from 1-6 R^a; R⁵ is selected from the group consisting of: • H; • halo; • -OH; • -NR^eR^f; • -C_1-6 alkoxy or -S(O)_0-2(C_1-6 alkyl), each optionally substituted with from 1-6 R^a; • -R^g; • -L⁵-R^g; • -R^g2-R^W or -R^g2-R^Y; • -L⁵-R^g2-R^W or –L⁵-R^g2-R^Y; and • -R^W provided that: when L¹ is a bond, then R⁵ is selected from the group consisting of: H, -R^g, -R^g2- R^W, and -R^g2-R^Y; and X¹ is other than H, -OH, or NH₂; L⁵ is selected from the group consisting of: –O-, -S(O)_0-2, -NH, and -N(R^d)-; R^W is –L^W-W, wherein L^W is C(=O), S(O)_1-2, OC(=O)*, NHC(=O)*, NR^dC(=O)*, NHS(O)_1-2*, or NR^dS(O)_1-2*, wherein the asterisk represents point of attachment to W, and W is selected from the group consisting of: • C_2-6 alkenyl; C_2-6 alkynyl; or C_3-10 allenyl, each of which is optionally substituted with from 1-3 R^a and further optionally substituted with R^g, wherein W is attached to L^W via an sp² or sp hybridized carbon atom, thereby providing an α, β- unsaturated system; and • bicyclo[x.y.0]cycloalkyl which is optionally substituted with from 1-2 R^c, wherein x is 1 or 2; and y is an integer from 1 to 6; R^Y is selected from the group consisting of: -R^g and -(L^g)g-R^g; each of R^1c, R^2a, R^2b, R^3a, and R^3b is independently selected from the group consisting of: H; halo; -OH; -C(O)OH or –C(O)NH₂; -CN; -R^b; -L^b-R^b; -C_1-6 alkoxy or - C_1-6 thioalkoxy, each optionally substituted with from 1-6 R^a; -NR^eR^f; -R^g; and -(L^g)g-R^g; provided that R^1c is other than halo, –CN, or –C(O)OH; or two of variables R^1c, R^2a, R^2b, R^3a, and R^3b, together with the Ring B ring atoms to which each is attached, form a fused saturated or unsaturated ring of 3-12 ring atoms; • wherein from 0-2 of the ring atoms are each an independently selected heteroatom (in addition to –N(R^1c)- when –N(R^1c)- forms part of the fused saturated or unsaturated ring), wherein each of the independently selected heteroatoms is selected from the group consisting of N, NH, N(R^d), O, and S(O)_0-2; and • wherein the fused saturated or unsaturated ring of 3-12 ring atoms is optionally substituted with from 1-4 substituents independently selected from the group consisting of oxo, R^c, and R^W; or one of R^2a and R^2b and one of R^3a and R^3b combine to form a double bond between the Ring B atoms to which each is attached; Ring A is R^g; each occurrence of R^a is independently selected from the group consisting of: – OH; -halo; –NR^eR^f; C_1-4 alkoxy; C_1-4 haloalkoxy; -C(=O)O(C_1-4 alkyl); -C(=O)(C_1-4 alkyl); -C(=O)OH; -CONR’R’’; -S(O)_1-2NR’R’’; -S(O)_1-2(C_1-4 alkyl); and cyano; each occurrence of R^b is independently C_1-6 alkyl, C_2-6 alkenyl, or C_2-6 alkynyl, each of which is optionally substituted with from 1-6 R^a; each occurrence of L^b is independently C(=O); C(=O)O; S(O)_1-2; C(=O)NH*; C(=O)NR^d*; S(O)_1-2NH*; or S(O)_1-2N(R^d)*, wherein the asterisk represents point of attachment to R^b; each occurrence of R^c is independently selected from the group consisting of: halo; cyano; C_1-10 alkyl which is optionally substituted with from 1-6 independently selected R^a; C_2-6 alkenyl; C_2-6 alkynyl; C_1-4 alkoxy optionally substituted with C_1-4 alkoxy or C_1-4 haloalkoxy; C_1-4 haloalkoxy; -S(O)_1-2(C_1-4 alkyl); -S(O)(=NH)(C_1-4 alkyl); -NR^eR^f; –OH; -S(O)_1-2NR’R’’; -C_1-4 thioalkoxy; -NO₂; -C(=O)(C_1-10 alkyl); -C(=O)O(C_1-4 alkyl); - C(=O)OH; -C(=O)NR’R’’; and –SF₅; each occurrence of R^d is independently selected from the group consisting of: C_1-6 alkyl optionally substituted with from 1-3 independently selected R^a; -C(O)(C_1-4 alkyl); - C(O)O(C_1-4 alkyl); -CONR’R’’; -S(O)_1-2NR’R’’; -S(O)_1-2(C_1-4 alkyl); -OH; and C_1-4 alkoxy; each occurrence of R^e and R^f is independently selected from the group consisting of: H; C_1-6 alkyl optionally substituted with from 1-3 substituents each independently selected from the group consisting of NR’R’’, -OH, C_1-6 alkoxy, C_1-6 haloalkoxy, and halo; -C(O)(C_1-4 alkyl); -C(O)O(C_1-4 alkyl); -CONR’R’’; -S(O)_1-2NR’R’’; -S(O)_1-2(C_1-4 alkyl); -OH; and C_1-4 alkoxy; each occurrence of R^g is independently selected from the group consisting of: • C_3-10 cycloalkyl or C_3-10 cycloalkenyl, each of which is optionally substituted with from 1-4 substituents independently selected from the group consisting of oxo and R^c; • heterocyclyl or heterocycloalkenyl including from 3-10 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R^d), O, and S(O)_0-2, and wherein the heterocyclyl or heterocycloalkenyl is optionally substituted with from 1-4 substituents independently selected from the group consisting of oxo and R^c; • heteroaryl including from 5-10 ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R^d), O, and S(O)_0-2, and wherein the heteroaryl is optionally substituted with from 1-4 R^c; and • C_6-10 aryl optionally substituted with from 1-4 R^c; each occurrence of L^g is independently selected from the group consisting of: -O-, -NH-, -NR^d , -S(O)_0-2, C(O), and C_1-3 alkylene optionally substituted with from 1-3 R^a; each g is independently 1, 2, or 3; each R^g2 is a divalent R^g group; each occurrence of R’ and R’’ is independently selected from the group consisting of: H; -OH; and C_1-4 alkyl; and each occurrence of R^N is independently H, C_1-3 alkyl, or C_3-6 cycloalkyl. In some embodiments, when Ring C or R^g is heteroaryl, the heteroaryl is other than aromatic lactams, aromatic cyclic ureas, or vinylogous analogs thereof, in which each ring nitrogen adjacent to a carbonyl is tertiary (i.e., all three valences are occupied by non- hydrogen substituents), such as one or more of pyridone (e.g.,

, or

), pyrimidone (e.g.,

), pyridazinone (e.g.,

or

), pyrazinone (e.g.,

and imidazolone (e.g.,

), wherein each ring nitrogen adjacent to a carbonyl is tertiary (i.e., the oxo group (i.e., “=O”) herein is a constituent part of the heteroaryl ring). In some embodiments, when Ring C or R^g is heteroaryl, said heteroaryl is not substituted with –OH. In some embodiments, when Ring C or R^g is heteroaryl, the heteroaryl is selected from the group consisting of: aromatic lactams, aromatic cyclic ureas, and vinylogous analogs thereof, in which each ring nitrogen adjacent to a carbonyl is tertiary (i.e., all three valences are occupied by non-hydrogen substituents), such as one or more of pyridone (e.g.,

, , , or

), pyrimidone (e.g.,

or

), pyridazinone (e.g.,

or ), pyrazinone (e.g.,

or

), and imidazolone (e.g.,

), wherein each ring nitrogen adjacent to a carbonyl is tertiary (i.e., the oxo group (i.e., herein is a constituent part of the heteroaryl ring). In some embodiments, when Ring C or R^g is heteroaryl, said heteroaryl is substituted with –OH. Variable Ring C In some embodiments, Ring C is selected from the group consisting of: • heteroaryl including from 5-10 ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R^d), O, and S(O)_0-2, and wherein the heteroaryl is optionally substituted with X¹ and further optionally substituted with from 1-4 R^c; and • C_6-10 aryl optionally substituted with X¹ and further optionally substituted with from 1-4 R^c. In certain embodiments, Ring C is heteroaryl including from 5-10 ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R^d), O, and S(O)_0-2, and wherein the heteroaryl is substituted with X¹ and further optionally substituted with from 1-4 R^c. In certain of these embodiments, Ring C is monocyclic heteroaryl including from 5-6 ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R^d), O, and S(O)_0-2, and wherein the heteroaryl is substituted with X¹ and further optionally substituted with from 1-3 R^c. In certain of the foregoing embodiments, Ring C is monocyclic heteroaryl including from 6 ring atoms, wherein from 1-4 ring atoms are heteroatoms each independently selected from the group consisting of N, N(H), and N(R^d), and wherein the heteroaryl is substituted with X¹ and further optionally substituted with from 1-3 R^c. As non-limiting examples of the foregoing embodiments, Ring C can be pyridyl or pyrimidyl, each of which is substituted with X¹ and further optionally substituted with from 1-3 R^c. In certain embodiments (when Ring C is monocyclic heteroaryl including from 6 ring atoms, wherein from 1-4 ring atoms are heteroatoms each independently selected from the group consisting of N, N(H), and N(R^d), and wherein the heteroaryl is substituted with X¹ and further optionally substituted with from 1-3 R^c), Ring C is

, wherein n is 0, 1, or 2. For example, n can be 0. In certain embodiments, Ring C is

, wherein n is 0, 1, or 2. For example, n can be 0. In certain embodiments, Ring C is bicyclic heteroaryl including from 8-10 ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R^d), O, and S(O)_0-2, and wherein the heteroaryl is substituted with X¹ and further optionally substituted with from 1-3 R^c. In certain of the foregoing embodiments Ring C is bicyclic heteroaryl including from 9-10 (e.g., 10) ring atoms, wherein from 1-4 (e.g., 2-4) ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R^d), O, and S(O)_0-2, and wherein the heteroaryl is substituted with X¹ and further optionally substituted with from 1-3 R^c. In certain of the foregoing embodiments, Ring C is bicyclic heteroaryl including 10 ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R^d), O, and S(O)_0-2, and wherein the heteroaryl is substituted with X¹ and further optionally substituted with from 1-3 R^c. As non-limiting examples of the foregoing embodiments, Ring C can be selected from the group consisting of: quinolinyl; naphthyridinyl (e.g., 1,5-naphthyridin-4-yl); and pyridopyrimidinyl (e.g., pyrido[3,2-d]pyrimidin-4-yl), each of which is substituted with X¹ and further optionally substituted with from 1-3 R^c. In certain embodiments, Ring C is selected from the group consisting of:

and

, each of which is optionally substituted with from 1-2 R^c. For example, Ring C can be

. As another non-limiting example, Ring C can be

. As further non-limiting examples, Ring C can be selected from the group consisting of:

and

each of which is optionally substituted with from 1-2 R^c. For example, Ring C can be

. For example, Ring C can be

For example, Ring C can be

. As another non- limiting example, Ring C can be

In certain embodiments, Ring C is bicyclic heteroaryl including 9 ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R^d), O, and S(O)_0-2, and wherein the heteroaryl is substituted with X¹ and further optionally substituted with from 1-3 R^c. In certain of these embodiments, Ring C is thieno[3,2-b]pyridyl, which is substituted with X¹ and further optionally substituted with from 1-3 R^c. In certain of these embodiments, Ring C is thieno[3,2-b]pyridyl, which is substituted with X¹ and further optionally substituted with from 1-3 R^c. For example, Ring C is

.

As non-limiting examples of the foregoing embodiments, Ring C can be

which is optionally substituted with from 1-2 R^c. For example, Ring C can be

. In certain embodiments, Ring C is selected from the group consisting of: • heteroaryl including from 5-10 ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R^d), O, and S(O)_0-2, and wherein the heteroaryl is optionally substituted with 1-4 R^c; and • C_6-10 aryl optionally substituted with from 1-4 R^c. In certain of these embodiments, Ring C is monocyclic heteroaryl including from 5-6 ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R^d), O, and S(O)_0-2, and wherein the heteroaryl is optionally substituted with 1-4 R^c. In certain of the foregoing embodiments, Ring C is monocyclic heteroaryl including 5 ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R^d), O, and S(O)_0-2, and wherein the heteroaryl is optionally substituted with 1-3 R^c. In certain embodiments, Ring C is selected from the group consisting of: pyrazolyl, imidazolyl, oxazolyl, thiazolyl, isooxazolyl, isothiazolyl, triazolyl, oxadiazolyl, and thiadiazolyl, each optionally substituted with from 1-2 R^c, and wherein a ring nitrogen atom is optionally substituted with R^d. As non-limiting examples, Ring C can be selected from the group consisting of:

. For example, Ring C can be

As non-limiting examples, Ring C can be selected from the group consisting of:

. In certain embodiments, Ring C is monocyclic heteroaryl including 6 ring atoms, wherein from 1-4 ring atoms are heteroatoms each independently selected from the group consisting of N, N(H), and N(R^d), and wherein the heteroaryl is optionally substituted with from 1-4 R^c. As non-limiting examples of the foregoing embodiments, Ring C can be selected from the group consisting of:

, , , , , and

As non-limiting examples, Ring C can be selected from the group consisting of:

, , , , and

In certain embodiments, Ring C pyridyl or pyrimidyl, each of which is optionally substituted with from 1-2 R^c. For example, Ring C can be selected from the group consisting of: , and

In certain embodiments, Ring C is selected from the group consisting of: w ^c

herein the R present in Ring C is C_1-3 alkyl optionally substituted with from 1-3 R^a, such as C_1-3 alkyl optionally substituted with from 1-3 independently selected halo. In certain embodiments, Ring C is selected from the group consisting of:

wherein the R^c present in Ring C is selected from the group consisting of: halo and C_1-3 alkyl optionally substituted with from 1-3 R^a, optionally wherein the R^c is –F, -Cl, or C_1-3 alkyl optionally substituted with from 1-3 independently selected halo. In certain embodiments, Ring C is bicyclic heteroaryl including from 8-10 ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R^d), O, and S(O)_0-2, and wherein the heteroaryl is optionally substituted with 1-4 R^c. In certain embodiments, Ring C is bicyclic heteroaryl including 9 ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R^d), O, and S(O)_0-2, and wherein the heteroaryl is optionally substituted with 1-4 R^c. In certain of these embodiments, Ring C is attached to

via a 5- membered ring. As non-limiting examples of the foregoing embodiments, Ring C can be selected from the group consisting of:

, , , ,

, , , , , ,

In certain embodiments (when Ring C is bicyclic heteroaryl including 9 ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R^d), O, and S(O)_0-2, and wherein the heteroaryl is optionally substituted with 1-4 R^c), Ring C is attached to

via a 6-membered ring. In certain of these embodiments, Ring C is:

, wherein Z⁰ is N or CH; and Ring D is an aromatic or partially unsaturated ring including 5 ring atoms, wherein from 1-3 ring atoms are heteroatoms each independently selected from the group consisting of: N, NH, N(R^d), O, and S(O)_0-2, wherein Ring D is optionally substituted with from 1-2 R^c. As non-limiting examples, Ring C can be selected from the group consisting of:

For example, Ring C can be

As another non-limiting example, Ring C can be ^c

(e.g., the R present in Ring C is halo or C_1-3 alkyl which is optionally substituted with from 1-3 R^a). As another non-limiting example, Ring C can be

As further non-limiting examples of the foregoing embodiments, Ring C can be selected from the group consisting of:

, , ,

, , , , , , , and , each further optionally substituted w ^c

ith from 1-2 R . In certain embodiments, Ring C is bicyclic heteroaryl including 10 ring atoms, wherein from 1-4 ring atoms are heteroatoms each independently selected from the group consisting of N, N(H), and N(R^d), and wherein the heteroaryl is optionally substituted with from 1-4 R^c. As non-limiting examples of the foregoing embodiments, Ring C can be selected from the group consisting of:

As further non-limiting examples, Ring C can be

and

(e.g., each R^c present in Ring C is independently selected from the group consisting of C_1-4 alkoxy and C_1-4 haloalkoxy). In certain embodiments, Ring C is heterocyclyl or heterocycloalkenyl including from 3-10 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R^d), O, and S(O)_0-2, and wherein the heterocyclyl or heterocycloalkenyl is optionally substituted with X¹ and further optionally substituted with from 1-4 substituents independently selected from the group consisting of oxo and R^c. In certain of these embodiments, Ring C is heterocyclyl including from 4-8 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R^d), O, and S(O)_0-2, and wherein the heterocyclyl is optionally substituted with from 1-4 substituents independently selected from the group consisting of oxo and R^c. As a non-limiting example of the foregoing embodiments, Ring C can be tetrahydropyranyl (e.g.,

In certain embodiments, each occurrence of R^c present on one or more ring atoms of Ring C is independently selected from the group consisting of: C_1-3 alkyl; C_1-3 alkyl substituted with from 1-3 R^a; halo; cyano; NR^eR^f, such as NH₂, NH(C_1-3 alkyl), N(C_1-3 alkyl)₂, or NHC(=O)C_1-3 alkyl; -OH; C_1-4 alkoxy; and C_1-4 haloalkoxy. In certain embodiments, each R^c present on one or more ring atoms of Ring C is independently selected from the group consisting of: halo, cyano, C_1-4 alkoxy, C_1-4 haloalkoxy, C_1-6 alkyl, and C_1-6 alkyl optionally substituted with from 1-3 independently selected halo. For example, each of the R^c can be independently selected C_1-6 alkyl (e.g., methyl)). As another non-limiting example, each of the R^c can be independently selected from the group consisting of C_1-4 alkoxy and C_1-4 haloalkoxy (e.g., -OMe). Variables m, X², L¹, and R⁵ In certain embodiments, m is 1. In other embodiments, m is 0. In certain embodiments, X² is -O-, -N(R^N)-, or –S(O)_0-2. In certain of these embodiments, X² is –O-. In certain embodiments, X² is –N(R^N)-. As a non-limiting example of the foregoing embodiments, X² can be –N(H)-. In certain embodiments, X² is

In certain embodiments, X² is selected from the group consisting of: -OC(=O)-*, - N(R^N)C(=O)-*, and –N(R^N)S(O)_1-2-*. In certain of these embodiments, X² is - N(R^N)C(=O)-*. As a non-limiting example of the foregoing embodiments, X² can be – N(H)C(=O)-*. In certain embodiments, X² is –N(R^N)S(O)_1-2-*. For example, X² can be – N(H)S(O)₂-*. In certain embodiments, X² is selected from the group consisting of: - OC(=O)N(R^N)-*, -N(R^N)C(=O)O-*, -N(R^N)C(=O)N(R^N)-*, and –N(R^N)S(O)_1-2N(R^N)-. In certain of these embodiments, X² is -N(R^N)C(=O)O-*, such as –N(H)C(=O)O-*. In certain of the foregoing embodiments, X² is –N(H)C(=O)N(R^N)-*. For example, X² can be – N(H)C(=O)N(C_1-3 alkyl)-* (e.g., -N(H)C(=O)N(Me)). In certain embodiments, L¹ is C_1-10 alkylene optionally substituted with from 1-6 R^a. In certain of these embodiments, L¹ is C_1-3 alkylene optionally substituted with from 1-6 R^a. In certain of the foregoing embodiments, L¹ is C_1-3 alkylene. For example, L¹ can be –CH₂-. As another non-limiting example, L¹ can be –CH(Me)- (e.g.,

or

As another non-limiting example, L¹ can be –CH₂CH₂-. In certain embodiments, L¹ is C_3-8 alkylene optionally substituted with from 1-6 R^a. In certain of these embodiments, L¹ is branched C_3-6 alkylene optionally substituted with from 1-6 R^a. In certain of the foregoing embodiments, L¹ is branched C_3-6 alkylene. As non-limiting examples of the foregoing embodiments, L¹ can be selected from the group consisting of:

wherein aa is the point of attachment to R⁵. In certain embodiments, L¹ is a bond. In certain embodiments, R⁵ is selected from the group consisting of: -OH; -NR^eR^f; and C_1-6 alkoxy or -S(O)_0-2(C_1-6 alkyl) each optionally substituted with from 1-6 R^a. In certain of the foregoing embodiments, R⁵ is C_1-6 alkoxy optionally substituted with from 1-6 R^a. In certain of these embodiments, R⁵ is C_1-3 alkoxy (e.g., methoxy). In certain embodiments, R⁵ is -S(O)_0-2(C_1-6 alkyl) which is optionally substituted with from 1-6 R^a. In certain of these embodiments, R⁵ is –S(O)₂(C_1-6 alkyl) which is optionally substituted with from 1-6 R^a. As a non-limiting example of the foregoing embodiments, R⁵ can be –S(O)₂(C_1-3 alkyl) (e.g., -S(O)₂Me). In certain embodiments, R⁵ is –R^g. In certain of the foregoing embodiments, R⁵ is heterocyclyl or heterocycloalkenyl including from 3-10 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R^d), O, and S(O)_0-2, and wherein the heterocyclyl or heterocycloalkenyl is optionally substituted with from 1-4 substituents independently selected from the group consisting of oxo and R^c. In certain of these embodiments, R⁵ is heterocyclyl including from 3-10 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R^d), O, and S(O)_0-2, and wherein the heterocyclyl is optionally substituted with from 1-4 substituents independently selected from the group consisting of oxo and R^c. In certain of these embodiments, R⁵ is heterocyclyl including from 4-8 (e.g., 4, 5, 6, 7, or 8) ring atoms, wherein from 1-2 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R^d), O, and S(O)_0-2, and wherein the heterocyclyl is optionally substituted with from 1-3 (e.g., 1, 2, or 3) substituents independently selected from the group consisting of oxo and R^c. In certain embodiments, R⁵ is

which is optionally substituted with from 1-2 R^c, wherein X^a is O, N(H), or N(R^d); x1 is 0, 1, or 2; and x0 is 0, 1, 2, or 3, provided that x0+x1≥1. In certain of the foregoing embodiments, R⁵ is

which is optionally substituted with from 1-2 R^c, wherein X^a is O, N(H), or N(R^d); and x1 and x2 are each independently 0, 1, or 2. In certain embodiments (when R⁵ is

x1 is 0. In certain embodiments (when R⁵ is

X^a is –O-. As a non- limiting example of the foregoing embodiments, R⁵ can be

). As further non-limiting examples, R⁵ can be

In certain embodiments (when R⁵ is X^a is N( ^d

H) or N(R ). In certain of these embodiments, X^a is N(H). In certain embodiments, X^a is N(R^d). In certain embodiments, X^a is N(R^d), wherein the R^d present in X^a is C_1-4 alkyl. In certain embodiments, X^a is N(R^d), wherein the R^d present in X^a is C(=O)(C_1-4 alkyl) or S(O)₂(C1- 4 alkyl). As non-limitng examples, R⁵ can be selected from the group consisting of:

optionally wherein R^d

is C_1-4 alkyl or wherein R^d is C(=O)(C_1-4 alkyl) or S(O)₂(C_1-4 alkyl). For exampleR⁵ can be selected from the group consisting of:

such as

, optionally wherein R^d is C alk ^d

_1-4 yl or wherein R is C(=O)(C_1-4 alkyl) or S(O)₂(C_1-4 alkyl). In certain embodiments (when R⁵ is

), x1 is 1 or 2. For example x1 can be 1. As another non-limiting example, x1 can be 2. In certain embodiments (when R⁵ is and x1 is 1 or 2), X^a

is –O-. As non-limiting examples of the foregoing embodiments, R⁵ can be selected from the group consisting of:

In certain embodiments (when R⁵ is ^a

; and x1 is 1 or 2), X is N(H) or N(R^d). For example, X^a can be N(R^d). In certain of these embodiment, X^a is N(R^d); and R^d is C_1-4 alkyl. In certain embodiments, X^a is N(R^d); and R^d is C(=O)(C_1-4 alkyl) or S(O)₂(C_1-4 alkyl). As a non-limiting example, R⁵ can be ^d

wherein R is C_1- ₄ alkyl; or wherein R^d is C(=O)(C_1-4 alkyl) or S(O)₂(C_1-4 alkyl). In certain embodiments, R⁵ is

which is optionally substituted with from 1-2 R^c, wherein X^b and X^c are each independently selected from the group consisting of: O, N(H), N(R^d), and S(O)_0-2. In certain of these embodiments, X^b and X^c are independently selected from the group consisting of O and N(R^d) (e.g., O and N(C_1-3 alkyl)). As non-limiting examples of the foregoing embodiments, R⁵ can be selected from the group consisting of:

optionally wherein R^d is C_1-4 alkyl, such as methyl. In certain embodiments, R⁵ is bicyclic heterocyclyl including from 6-10 (e.g., 6-8 or 8-10 (e.g., 6-8)) ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R^d), O, and S(O)_0-2, and wherein the heterocyclyl is optionally substituted with from 1-4 substituents independently selected from the group consisting of oxo and R^c. As a non-limiting example, R⁵ can be

In certain embodiments, R⁵ is bicyclic heterocyclyl including from 7-10 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R^d), O, and S(O)_0-2, and wherein the heterocyclyl is optionally substituted with from 1-4 substituents independently selected from the group consisting of oxo and R^c.For example, R⁵ is

In certain embodiments (when R⁵ is –R^g), R⁵ is heteroaryl including from 5-10 ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R^d), O, and S(O)_0-2, and wherein the heteroaryl is optionally substituted with from 1-4 R^c. In certain of these embodiments, R⁵ is monocyclic heteroaryl including from 5-6 ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R^d), O, and S(O)_0-2, and wherein the heteroaryl is optionally substituted with from 1-4 R^c. In certain of the foregoing embodiments, R⁵ is monocyclic heteroaryl including 5 ring atoms, wherein from 1-4, such as 2-3, ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R^d), O, and S(O)_0-2, and wherein the heteroaryl is optionally substituted with from 1-3 R^c. In certain of these embodiments, R⁵ is selected from the group consisting of pyrazolyl, imidazolyl, oxazolyl, thiazolyl, isooxazolyl, isothiazolyl, triazolyl, oxadiazolyl, and thiadiazolyl, each optionally substituted with from 1-2 R^c, and wherein a ring nitrogen atom is optionally substituted with R^d. As non-limiting examples, R⁵ can be selected from the group consisting of:

For example, R⁵ can be selected from the group consisting of:

In certain embodiments, R⁵ is monocyclic heteroaryl including 6 ring atoms, wherein from 1-4, such as 1-2, ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), and N(R^d), and wherein the heteroaryl is optionally substituted with from 1-4 R^c. As non-limiting examples of the foregoing embodiments, R⁵ can be selected from the group consisting of:

For example, R⁵ can be selected from the group consisting of:

In certain embodiments (when R⁵ is –R^g), R⁵ is bicyclic heteroaryl including from 8-10 ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R^d), O, and S(O)_0-2, and wherein the heteroaryl is optionally substituted with from 1-4 R^c. In certain of these embodiments, R⁵ is bicyclic heteroaryl including 8 ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R^d), O, and S(O)_0-2, and wherein the heteroaryl is optionally substituted with from 1-4 R^c. As non-limiting examples of the foregoing embodiments, R⁵ can be selected from the group consisting of:

each optionally substituted with from 1-2 R^c. In certain embodiments, R⁵ is bicyclic heteroaryl including from 9-10, such as 9, ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R^d), O, and S(O)_0-2, and wherein the heteroaryl is optionally substituted with from 1-4 R^c, such as wherein R⁵ is .

In certain embodiments, R⁵ is phenyl optionally substituted with from 1-2 R^c, such as unsubstituted phenyl. In certain embodiments, R⁵ is C_3-10 cycloalkyl or C_3-10 cycloalkenyl, each of which is optionally substituted with from 1-4 substituents independently selected from the group consisting of oxo and R^c. In certain of these embodiments, R⁵ is C_3-10 cycloalkyl which is optionally substituted with from 1-4 substituents independently selected from the group consisting of oxo and R^c. In certain of the foregoing embodiments, R⁵ is C_3-6 cycloalkyl. For example, R⁵ can be cyclopropyl. As another non-limiting example, R⁵ can be cyclopentyl. In certain embodiments, R⁵ is C_3-6 cycloalkyl substituted with a substituent selected from the group consisting of: C_1-4 alkyl; C_1-4 alkyl substituted with R^a, such as C_1-4 alkyl substituted with C_1-4 alkoxy; C_1-4 alkoxy; and C_1-4 haloalkoxy, and wherein the cycloalkyl is further optionally substituted with from 1-2 R^c. As non-limiting examples of the foregoing embodiments, R⁵ can be selected from the group consisting of:

As a non-limiting example of the foregoing embodiments, R⁵ can be

In certain embodiments, R⁵ is H or halo. In certain of these embodiments, R⁵ is H. In some embodiments, R⁵ is R^W. In certain embodiments, R⁵ is -R^g2-R^W or -R^g2-R^Y. In certain embodiments, R⁵ is –R^g2-R^W. In certain embodiments (when R⁵ is -R^g2-R^W or -R^g2-R^Y (e.g., –R^g2-R^W)), the –R^g2 group present in R⁵ is

which is optionally substituted with from 1-2 R^c, wherein bb is the point of attachment to R^W or R^Y; and x1 and x2 are each independently 0, 1, or 2. In certain of these embodiments, x1 is 0. In certain embodiments, x2 is 1 or 2. In certain embodiments, x2 is 0. As non-limiting examples of the foregoing embodiments, the –R^g2 group present in R⁵ can be selected from the group consisting of:

wherein bb is the point of attachment to R^W or R^Y. In certain embodiments (when R⁵ is -R^g2-R^W or -R^g2-R^Y (e.g., –R^g2-R^W)), the –R^g2 group present in R⁵ is

which is optionally substituted with from 1-2 R^c; X^b is selected from the group consisting of: O, N(H), N(R^d), and S(O)_0-2; and bb is the point of attachment to R^W or R^Y. As non-limiting examples of the foregoing embodiments, the –R^g2 group present in R⁵ can be selected from the group consisting of:

wherein bb is the point of attachment to R^W or R^Y; and optionally wherein R^d is C_1-4 alkyl, such as methyl. In certain embodiments (when R⁵ is -R^g2-R^W or -R^g2-R^Y (e.g., –R^g2-R^W)), the R^g2 group present in R⁵ is bicyclic heterocyclylene including from 6-10 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R^d), O, and S(O)_0-2, and wherein the heterocyclylene is optionally substituted with from 1-4 substituents independently selected from the group consisting of oxo and R^c (e.g., R^g2 is

wherein bb is the point of ^{W Y}

attachment to R or R . In certain embodiments (when R⁵ is -R^g2-R^W), the R^W present in R⁵ is –C(=O)-W or –S(O)₂-W, such as wherein R^W is –C(=O)-W. In certain embodiments (when R⁵ is -R^g2-R^W or -R^W), the R^W present in R⁵ is – C(=O)-W, –S(O)₂-W, or –NH-C(=O)-W, such as wherein R^W is –C(=O)-W or –NH- C(=O)-W. In certain embodiments (when R⁵ is -R^g2-R^W), W is C_2-6 alkenyl (e.g., C2-4 alkenyl (e.g., C2-3 alkenyl)) optionally substituted with from 1-3 R^a. In certain embodiments (when R⁵ is -R^g2-R^W or -R^W), W is C_2-6 alkenyl or C_2-6 alkynyl optionally substituted with from 1-3 R^a. As non-limiting examples of the foregoing embodiments, R^W can be

or

As further non-limiting examples of the foregoing embodiments, R^W can be

Non-Limiting Combinations of m, X², L¹, and R⁵ [AA] In certain embodiments, m is 0 or 1; X² is –O-, -N(R^N)-, ^N

–N(R )C(=O)- *, or -N(R^N)S(O)₂-*; L¹ is C_1-3 alkylene optionally substituted with from 1-3 R^a; and R⁵ is selected from the group consisting of: C_1-6 alkoxy or S(O)₂(C_1-6 alkyl) each optionally substituted with from 1-6 R^a; -OH; and –NR^eR^f. In certain embodiments of [AA], R⁵ is C_1-6 alkoxy optionally substituted with from 1-6 R^a. In certain of these embodiments, R⁵ is C_1-3 alkoxy, such as methoxy. In certain embodiments of [AA], R⁵ is S(O)₂(C_1-6 alkyl) which is optionally substituted with from 1-6 R^a. In certain of these embodiments, R⁵ is S(O)₂(C_1-3 alkyl). For example, R⁵ can be S(O)₂Me. In certain embodiments of [AA], L¹ is CH₂. In certain embodiments of [AA], L¹ is –CH(Me)-. In certain embodiments of [AA], L¹ is –CH₂CH₂-. In certain embodiments of [AA], m is 1. In certain embodiments of [AA], X² is –O-. In certain embodiments of [AA], X² is -N(R^N)- (e.g., –N(H)-). In certain embodiments of [AA], X² is

In certain embodiments of [AA], X² is –N(R^N)C(=O)* or -N(R^N)S(O)₂-*. For example, X² can be –N(H)C(=O)* or –N(H)S(O)₂-* (e.g., –N(H)C(=O)*). In certain embodiments of [AA], m is 0. [BB] In certain embodiments, m is 0 or 1; X² is –O-, -N(R^N)-,

, – N(R^N)C(=O)*, or -N(R^N)S(O)₂-*; L¹ is a bond or C_1-3 alkylene optionally substituted with from 1-3 R^a; and R⁵ is heterocyclyl including from 3-10 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R^d), O, and S(O)_0-2, and wherein the heterocyclyl is optionally substituted with from 1-4 substituents independently selected from the group consisting of oxo and R^c. In certain embodiments of [BB], R⁵ is

which is optionally substituted with from 1-2 R^c, wherein X^a is O, N(H), or N(R^d); x1 is 0, 1, or 2; and x0 is 0, 1, 2, or 3, provided that x0+x1≥1.In certain of these embodiments, x1 is 0. In certain embodiments, X^a is –O-. In certain embodiments of [BB], R⁵ is

which is optionally substituted with from 1-2 R^c, wherein X^a is O, N(H), or N(R^d); and x1 and x2 are each independently 0, 1, or 2. In certain of these embodiments, x1 is 0. In certain embodiments, X^a is –O-. As a non-limiting example of the foregoing embodiments, R⁵ can be

As further non-limiting examples, R⁵ can be

(e.g.,

or

). In certain embodiments of [BB] (when R⁵ is X^a is N(R^d),

optionally wherein R^d is C_1-4 alkyl or wherein R^d is C(=O)(C_1-4 alkyl) or S(O)₂(C_1-4 alkyl). As non-limiting examples of the foregoing embodiments, R⁵ can be selected from the group consisting of:

, ; ( g,

, optionally wherein R^d is C ^d

_1-4 alkyl or wherein R is C(=O)(C_1-4 alkyl) or S(O)₂(C_1- ₄ alkyl). As non-limiting examples of the foregoing embodiments, R⁵ can be selected from the group consisting of:

, op ^d

tionally wherein R is C_1-4 alkyl or wherein R^d is C(=O)(C_1-4 alkyl) or S(O)₂(C_1-4 alkyl). In certain embodiments of [BB] (when R⁵ is

x1 is 1 or 2. As non-limiting examples of the foregoing embodiments, R⁵ can be selected from the group consisting of:

In certain embodiments of [BB], R⁵ is

which is optionally substituted with from 1-2 R^c, wherein X^b and X^c are each independently selected from the group consisting of: O, N(H), N(R^d), and S(O)_0-2. As non-limiting examples of the foregoing embodiments, R⁵ is selected from the group consisting of:

, ; ,

optionally wherein R^d is C_1-4 alkyl, such as methyl. In certain embodiments of [BB], R⁵ is bicyclic heterocyclyl including from 6-10 (e.g., 6-8) ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R^d), O, and S(O)_0-2, and wherein the heterocyclyl is optionally substituted with from 1-4 substituents independently selected from the group consisting of oxo and R^c. For example, R⁵ can be

In certain embodiments of [BB], R⁵ is bicyclic heterocyclyl including from 7-10 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R^d), O, and S(O)_0-2, and wherein the heterocyclyl is optionally substituted with from 1-4 substituents independently selected from the group consisting of oxo and R^c, such as wherein R⁵ is

In certain embodiments of [BB], L¹ is CH₂. In certain embodiments of [BB], L¹ is –CH(Me)-. In certain embodiments of [BB], L¹ is –CH₂CH₂-. In certain embodiments of [BB], L¹ is a bond. In certain embodiments of [BB], m is 1. In certain embodiments of [BB], X² is –O-. In certain embodiments of [BB], X² is -N(R^N)- (e.g., –N(H)-). In certain embodiments of [BB], X² is

In certain embodiments of [BB], X² is –N(R^N)C(=O)* or -N(R^N)S(O)₂-*. For example, X² can be –N(H)C(=O)* or –N(H)S(O)₂-* (e.g., –N(H)C(=O)*). In certain embodiments of [BB], m is 0. [CC] In certain embodiments, m is 0 or 1; X² is –O-, -N(R^N)-,

, – N(R^N)C(=O)*, or -N(R^N)S(O)₂-*; L¹ is a bond or C_1-3 alkylene optionally substituted with from 1-3 R^a; and R⁵ is selected from the group consisting of: • heteroaryl including from 5-10 ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R^d), O, and S(O)_0-2, and wherein the heteroaryl is optionally substituted with from 1-4 R^c; and • C_6-10 aryl optionally substituted with from 1-4 R^c In certain embodiments of [CC], R⁵ is monocyclic heteroaryl including 5 ring atoms, wherein from 1-4, such as 2-3, ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R^d), O, and S(O)_0-2, and wherein the heteroaryl is optionally substituted with from 1-3 R^c. In certain of these embodiments, R⁵ is selected from the group consisting of pyrazolyl, imidazolyl, oxazolyl, thiazolyl, isooxazolyl, isothiazolyl, triazolyl, oxadiazolyl, and thiadiazolyl, each optionally substituted with from 1-2 R^c, and wherein a ring nitrogen atom is optionally substituted with R^d. As non-limiting examples of the foregoing embodiments, R⁵ can be

,

For example, R⁵ can be

In certain embodiments of [CC], R⁵ is monocyclic heteroaryl including 6 ring atoms, wherein from 1-4, such as 1-2, ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), and N(R^d), and wherein the heteroaryl is optionally substituted with from 1-4 R^c. As non-limiting examples of the foregoing embodiments, R⁵ can be

For example, R⁵ can be

In certain embodiments of [CC], R⁵ is bicyclic heteroaryl including from 8-10 ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R^d), O, and S(O)_0-2, and wherein the heteroaryl is optionally substituted with from 1-4 R^c. In certain of these embodiments, R⁵ is bicyclic heteroaryl including 8 ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R^d), O, and S(O)_0-2, and wherein the heteroaryl is optionally substituted with from 1-4 R^c. For example, R⁵ can be selected from the group consisting of: each optionally substituted with fr ^c

om 1-2 R . In certain embodiments of [CC], R⁵ is bicyclic heteroaryl including from 9-10, such as 9, ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R^d), O, and S(O)_0-2, and wherein the heteroaryl is optionally substituted with from 1-4 R^c, such as wherein R⁵ is .

In certain embodiments of [CC], R⁵ is phenyl optionally substituted with from 1-2 R^c, such as unsubstituted phenyl. In certain embodiments of [CC], L¹ is CH₂. In certain embodiments of [CC], L¹ is –CH(Me)-. In certain embodiments of [CC], L¹ is –CH₂CH₂-. In certain embodiments of [CC], L¹ is a bond. In certain embodiments of [CC], m is 1. In certain embodiments of [CC], X² is –O-. In certain embodiments of [CC], X² is -N(R^N)- (e.g., –N(H)-). In certain embodiments of [CC], X² is

In certain embodiments of [CC], X² is –N(R^N)C(=O)* or -N(R^N)S(O)₂-*. For example, X² can be –N(H)C(=O)* or –N(H)S(O)₂-* (e.g., –N(H)C(=O)*). In certain embodiments of [CC], m is 0. [DD] In certain embodiments, m is 0 or 1; X² is –O-, -N(R^N)-,

– N(R^N)C(=O)*, or -N(R^N)S(O)₂-*; L¹ is a bond or C_1-3 alkylene optionally substituted with from 1-3 R^a; and R⁵ is C_3-10 cycloalkyl which is optionally substituted with from 1-4 substituents independently selected from the group consisting of oxo and R^c. In certain embodiments of [DD], R⁵ is C_3-6 cycloalkyl. For example, R⁵ can be cyclopropyl. As another non-limiting example, R⁵ can be cyclopentyl. In certain embodiments of [DD], R⁵ is C_3-6 cycloalkyl substituted with a substituent selected from the group consisting of: C_1-4 alkyl; C_1-4 alkyl substituted with R^a, such as C_1- 4 alkyl substituted with C_1-4 alkoxy; C_1-4 alkoxy; and C_1-4 haloalkoxy, and wherein the cycloalkyl is further optionally substituted with from 1-2 R^c. As non-limiting examples of the foregoing embodiments, R⁵ can be selected from the group consisting of:

In certain embodiments of [DD], L¹ is CH₂. In certain embodiments of [DD], L¹ is –CH(Me)-. In certain embodiments of [DD], L¹ is –CH₂CH₂-. In certain embodiments of [DD], L¹ is a bond. In certain embodiments of [DD], m is 1. In certain embodiments of [DD], X² is –O-. In certain embodiments of [DD], X² is -N(R^N)- (e.g., –N(H)-). In certain embodiments of [DD], X² is

In certain embodiments of [DD], X² is –N(R^N)C(=O)* or -N(R^N)S(O)₂-*. For example, X² can be –N(H)C(=O)* or –N(H)S(O)₂-* (e.g., –N(H)C(=O)*). In certain embodiments of [DD], m is 0. [EE] In certain embodiments, m is 1; X² is –N(R^N)C(=O)-*, -N(R^N)C(=O)O-* or - N(R^N)C(=O)N(R^N)-*; L¹ is C_1-3 alkylene optionally substituted with from 1-3 R^a; and R⁵ is H. In certain embodiments of [EE], L¹ is CH₂. In certain embodiments of [EE], L¹ is –CH(Me)-. In certain embodiments of [EE], L¹ is –CH₂CH₂-. In certain embodiments of [EE], X² is -N(R^N)C(=O)-* (e.g., –N(H)C(=O)-*). In certain embodiments of [EE], X² is selected from the group consisting of - N(R^N)C(=O)N(R^N)-* (e.g., –N(H)C(=O)N(R^N)-* (e.g., -N(H)C(=O)N(C_1-3 alkyl)); and - N(R^N)C(=O)O-* (e.g., –N(H)C(=O)O-*). [FF] In certain embodiments, m is 1; X² is –O-, -N(R^N)-,

–N(R^N)C(=O)*, or -N(R^N)S(O)₂-*; L¹ is branched C_3-6 alkylene optionally substituted with from 1-6 R^a; and R⁵ is selected from the group consisting of: C_1-6 alkoxy or S(O)₂(C_1-6 alkyl) each optionally substituted with from 1-6 R^a; -OH; and –NR^eR^f. In certain embodiments of [FF], R⁵ is C_1-6 alkoxy optionally substituted with from 1-6 R^a. In certain of these embodiments, R⁵ is C_1-3 alkoxy. In certain embodiments of [FF], R⁵ is S(O)₂(C_1-6 alkyl) optionally substituted with from 1-6 R^a. In certain embodiments of [FF], X² is –O-. In certain embodiments of [FF], X² is -N(R^N)- (e.g., –N(H)-). In certain embodiments of [FF], X² is

. In certain embodiments of [FF], X² is –N(R^N)C(=O)* or -N(R^N)S(O)₂-* (e.g., – N(H)C(=O)-* or –N(H)S(O)₂-*). For example, X² can be –N(H)C(=O)-*. In certain embodiments of [FF], L¹ is branched C_3-6 alkylene. In certain of these embodiments, L¹ is selected from the group consisting of:

wherein aa is the point of attachment to R⁵. [GG] In certain embodiments, m is 0 or 1; X² is –O-, -N(R^N)-,

– N(R^N)C(=O)*, or -N(R^N)S(O)₂-*; L¹ is a bond or C_1-3 alkylene optionally substituted with from 1-3 R^a; and R⁵ is –R^g2-R^W, wherein: the -R^g2 of R⁵ is heterocyclylene including from 4-8 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R^d), O, and S(O)_0-2, and wherein the heterocyclylene is optionally substituted with from 1-4 substituents independently selected from the group consisting of oxo and R^c; and -R^W is –C(=O)-W or –S(O)₂-W. In certain embodiments of [GG], R^g2 is

which is optionally substituted with from 1-2 R^c, wherein bb is the point of attachment to R^W; and x1 and x2 are each independently 0, 1, or 2, optionally wherein x1 is 0. As non-limiting examples of the foregoing embodiments, R^g2 is selected from the group consisting of:

wherein bb is the p ^W

oint of attachment to R . In certain embodiments of [GG], R^g2 is

which is optionally substituted with from 1-2 R^c; X^b is selected from the group consisting of: O, N(H), N(R^d), and S(O)_0-2; and bb is the point of attachment to R^W. As non-limiting examples of the foregoing embodiments, R^g2 is selected from the group consisting of:

such as , wherein bb is the point ^W

of attachment to R ; and optionally wherein R^d is C_1-4 alkyl, such as methyl. In certain embodiments of [GG], R^g2 is is bicyclic heterocyclylene including from 6-8 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R^d), O, and S(O)_0-2, and wherein the heterocyclylene is optionally substituted with from 1-4 substituents independently selected from the group consisting of oxo and R^c, wherein bb is the point of attachment to R^W. For example, R^g2 can be

wherein bb is the p ^W

oint of attachment to R . In certain embodiments of [GG], R^W is –C(=O)-W. In certain embodiments of [GG], W is C_2-6 alkenyl optionally substituted with from 1-3 R^a. As non-limiting examples of the foregoing embodiments, R^W can be

or

In certain embodiments of [GG], L¹ is CH₂. In certain embodiments of [GG], L¹ is –CH(Me)-. In certain embodiments of [GG], L¹ is –CH₂CH₂-. In certain embodiments of [GG], L¹ is a bond. In certain embodiments of [GG], m is 1. In certain embodiments of [GG], X² is –O-. In certain embodiments of [GG], X² is -N(R^N)- (e.g., –N(H)-). In certain embodiments of [GG], X² is

In certain embodiments of [GG], X² is –N(R^N)C(=O)* or -N(R^N)S(O)₂-*. For example, X² can be –N(H)C(=O)* or –N(H)S(O)₂-* (e.g., –N(H)C(=O)*). In certain embodiments of [GG], m is 0. Variables R^1c, R^2a, R^2b, R^3a, and R^3b In some embodiments, R^1c is H. In some embodiments, R^2a and R^2b are H. In some embodiments, 1-2, such as 1, of R^2a and R^2b is a substituent other than H. For example, R^2a can be a substituent other than H. In certain of these embodiments, one of R^2a and R^2b (e.g., R^2a) is C_1-3 alkyl optionally substituted with from 1-3 R^a, such as C_1-3 alkyl; and the other of R^2a and R^2b is H. In certain embodiments, one of R^2a and R^2b (e.g., R^2a) is R^g; and the other of R^2a and R^2b is H. In certain of these embodiments, one of R^2a and R^2b (e.g., R^2a) is heterocyclyl including from 4-6 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R^d), O, and S(O)_0-2, and wherein the heterocyclyl is optionally substituted with from 1-4 substituents independently selected from the group consisting of oxo and R^c; and the other of R^2a and R^2b is H. In some embodiments, R^2a and R^2b, together with the Ring B ring atom to which each is attached, form a fused saturated or unsaturated ring of 3-12 ring atoms; • wherein from 0-2 of the ring atoms are each an independently selected heteroatom, wherein each of the independently selected heteroatoms is selected from the group consisting of N, NH, N(R^d), O, and S(O)_0-2; and • wherein the fused saturated or unsaturated ring of 3-12 ring atoms is optionally substituted with from 1-4 substituents independently selected from the group consisting of oxo and R^c. In certain embodiments, R^2a and R^2b, together with the Ring B ring atom to which each is attached, form a fused saturated ring of 3-6 ring atoms; • wherein from 0-2 of the ring atoms are each an independently selected heteroatom, wherein each of the independently selected heteroatoms is selected from the group consisting of N, NH, N(R^d), O, and S(O)_0-2; and • wherein the fused saturated ring of 3-6 ring atoms is optionally substituted with from 1-4 substituents independently selected from the group consisting of oxo and R^c. In certain embodiments, R^2a and R^2b together with the Ring B ring atom to which each is attached form a cycloalkyl ring of 3-6 ring atoms, such as 3 ring atoms, wherein the fused cycloalkyl ring is optionally substituted with from 1-2 R^c. In some embodiments, R^3a and R^3b are H. In some embodiments, from 1-2, such as 1, of R^3a and R^3b is a substituent other than H. For example, R^3a can be a substituent other than H. In certain embodiments, one of R^3a and R^3b (e.g., R^3a) is R^b; and the other of R^3a and R^3b is H. In certain embodiments, one of R^3a and R^3b (e.g., R^3a) is C_1-3 alkyl optionally substituted with from 1-3 R^a, such as C_1-3 alkyl optionally substituted with from 1-3 independently selected halo; and the other of R^3a and R^3b is H. In certain embodiments, one of R^3a and R^3b (e.g., R^3a) is C_1-3 alkyl optionally substituted with from 1-3 R^a; and the other of R^3a and R^3b is H. In certain of the foregoing embodiments, one of R^3a and R^3b (e.g., R^3a) is C_1-3 alkyl optionally substituted with from 1-3 independently selected halo (e.g., –CH₃, –CH₂F, - CH₂CH₂F, or –CHF₂); and the other of R^3a and R^3b is H. In certain embodiments, one of R^3a and R^3b (e.g., R^3a) is C_1-3 alkyl; and the other of R^3a and R^3b is H. For example, one of R^3a and R^3b (e.g., R^3a) can be methyl, ethyl, or isopropyl; and the other of R^3a and R^3b can be H. In certain embodiments, one of R^3a and R^3b (e.g., R^3a) is C_1-3 alkyl substituted with from 1-3 independently selected halo; and the other of R^3a and R^3b is H. For example, one of R^3a and R^3b (e.g., R^3a) can be CH₂F, -CHF₂, -CF₃, -CH₂CHF₂, or -CH₂CH₂F; and the other of R^3a and R^3b can be H. In certain embodiments, one of R^3a and R^3b (e.g., R^3a) is C_1-3 alkyl substituted with C_1-4 alkoxy, C_1-4 haloalkoxy, or NR^eR^f; and the other of R^3a and R^3b is H. For example, one of R^3a and R^3b (e.g., R^3a) can be –CH₂OMe, -CH₂CH₂OMe, -CH(Me)CH₂OMe, - CH₂CH(Me)OMe, -CH₂OEt, -CH₂CH₂OCHF₂, -CH₂NR^eR^f (e.g., -CH₂N(CF₃)Me), or – CH₂CH₂NR^eR^f (e.g., -CH₂CH₂NMe₂); and the other of R^3a and R^3b can be H. In certain embodiments, one of R^3a and R^3b (e.g., R^3a) is C_1-3 alkyl substituted with C_1-4 alkoxy; and the other of R^3a and R^3b is H. For example, one of R^3a and R^3b (e.g., R^3a) can be –CH₂OMe, -CH₂CH₂OMe, -CH(Me)CH₂OMe, -CH₂CH(Me)OMe, or -CH₂OEt. For example, one of R^3a and R^3b (e.g., R^3a) can be –CH₂OMe. In certain embodiments, one of R^3a and R^3b (e.g., R^3a) is C_1-3 alkyl substituted with C_1-4 alkoxy or C_1-4 haloalkoxy; and the other of R^3a and R^3b is H. For example, one of R^3a and R^3b (e.g., R^3a) can be –CH₂OMe, -CH₂CH₂OMe, -CH(Me)CH₂OMe, - CH₂CH(Me)OMe, or -CH₂OEt; and the other of R^3a and R^3b can be H. In certain embodiments, one of R^3a and R^3b (e.g., R^3a) is R^g or –(L^g)_g-R^g; and the other of R^3a and R^3b is H. In certain embodiments, one of R^3a and R^3b (e.g., R^3a) is R^g; and the other of R^3a and R^3b is H. In certain embodiments, one of R^3a and R^3b (e.g., R^3a) is C_3-6 cycloalkyl optionally substituted with from 1-4 R^c; and the other of R^3a and R^3b is H. In certain embodiments, one of R^3a and R^3b (e.g., R^3a) is heterocyclyl including from 4-6 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R^d), O, and S(O)_0-2, and wherein the heterocyclyl is optionally substituted with from 1-4 substituents independently selected from the group consisting of oxo and R^c; and the other of R^3a and R^3b is H. In certain embodiments, one of R^3a and R^3b (e.g., R^3a) is selected from the group consisting of: cyclopropyl, cyclobutyl, oxetanyl, and azetidinyl, each of which is optionally substituted with from 1-2 substituents independently selected from the group consisting of: C_1-3 alkyl and halo, wherein the ring nitrogen of the azetidinyl is optionally substituted with R^d; and the other of R^3a and R^3b is H. In certain embodiments, one of R^3a and R^3b (e.g., R^3a) is –(C_1-3 alkylene)-R^g or - (C_1-3 alkylene)-O-R^g, optionally wherein the R^g group of R^3a or R^3b is: C_3-6 cycloalkyl optionally substituted with from 1-4 R^c, or heterocyclyl including from 4-6 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R^d), O, and S(O)_0-2, and wherein the heterocyclyl is optionally substituted with from 1-4 substituents independently selected from the group consisting of oxo and R^c; and the other of R^3a and R^3b is H. In certain embodiments, one of R^3a and R^3b (e.g., R^3a) is –(C_1-3 alkylene)-R^g, optionally wherein the R^g group of R^3a or R^3b is: C_3-6 cycloalkyl optionally substituted with from 1-4 R^c, or heterocyclyl including from 4-6 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R^d), O, and S(O)_0-2, and wherein the heterocyclyl is optionally substituted with from 1-4 substituents independently selected from the group consisting of oxo and R^c; and the other of R^3a and R^3b is H. In certain embodiments, one of R^3a and R^3b (e.g., R^3a) is –CH₂-R^g, –CH₂CH₂R^g, or –CH₂-O-R^g, wherein the R^g group of R^3a or R^3b is: C_3-6 cycloalkyl optionally substituted with from 1-4 R^c, or heterocyclyl including from 4-6 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R^d), O, and S(O)_0-2, and wherein the heterocyclyl is optionally substituted with from 1-4 substituents independently selected from the group consisting of oxo and R^c; and the other of R^3a and R^3b is H. In certain of these embodiments, one of R^3a and R^3b (e.g., R^3a) is –CH₂-R^g, – CH₂CH₂R^g, or –CH₂-O-R^g, wherein the R^g group of R^3a or R^3b is selected from the group consisting of: cyclopropyl, cyclobutyl, oxetanyl, and azetidinyl, each of which is optionally substituted with from 1-2 substituents independently selected from the group consisting of: C_1-3 alkyl and halo, wherein the ring nitrogen of the azetidinyl is optionally substituted with R^d; and the other of R^3a and R^3b is H. As non-limiting examples of the foregoing embodiments, one of R^3a and R^3b can be selected from the group consisting of:

; ; a ^{3a 3b}

nd the other of R and R can be H. In certain embodiments, R^3a and R^3b are each independently selected R^b. In certain of these embodiments, R^3a and R^3b are each independently selected C_1-3 alkyl which is optionally substituted with from 1-3 R^a. For example, R^3a and R^3b can each be independently C_1-3 alkyl (e.g., methyl). In certain embodiments, R^3a and R^3b, together with the Ring B ring atom to which each is attached, form a fused saturated or unsaturated ring of 3-12 ring atoms; • wherein from 0-2 of the ring atoms are each an independently selected heteroatom, wherein each of the independently selected heteroatoms is selected from the group consisting of N, NH, N(R^d), O, and S(O)_0-2; and • wherein the fused saturated or unsaturated ring of 3-12 ring atoms is optionally substituted with from 1-4 substituents independently selected from the group consisting of oxo, R^c, and R^W. In certain embodiments, R^3a and R^3b, together with the Ring B ring atom to which each is attached, form a fused saturated or unsaturated ring of 3-12 ring atoms; • wherein from 0-2 of the ring atoms are each an independently selected heteroatom, wherein each of the independently selected heteroatoms is selected from the group consisting of N, NH, N(R^d), O, and S(O)_0-2; and • wherein the fused saturated or unsaturated ring of 3-12 ring atoms is optionally substituted with from 1-4 substituents independently selected from the group consisting of oxo and R^c. In certain embodiments, R^3a and R^3b, together with the Ring B ring atom to which each is attached, form a fused saturated ring of 3-6 ring atoms; • wherein from 0-2 of the ring atoms are each an independently selected heteroatom, wherein each of the independently selected heteroatoms is selected from the group consisting of N, NH, N(R^d), O, and S(O)_0-2; and • wherein the fused saturated ring of 3-6 ring atoms is optionally substituted with from 1-4 substituents independently selected from the group consisting of oxo and R^c. In certain embodiments, R^3a and R^3b together with the Ring B ring atom to which each is attached form a cycloalkyl ring of 3-6 ring atoms, such as 3 ring atoms, wherein the fused cycloalkyl ring is optionally substituted with from 1-2 R^c. For example, R^3a and R^3b together with the Ring B ring atom to which each is attached can form a fused cyclopropyl or cyclobutyl. In certain embodiments, R^3a and R^3b together with the Ring B ring atom to which each is attached, form a fused saturated ring of 4-6 ring atoms; • wherein from 1-2 of the ring atoms are each an independently selected heteroatom, wherein each of the independently selected heteroatoms is selected from the group consisting of N, NH, N(R^d), O, and S(O)_0-2; and • wherein the fused saturated ring of 4-6 ring atoms is optionally substituted with from 1-2 substituents independently selected from the group consisting of oxo and R^c. For example, R^3a and R^3b, together with the Ring B ring atom to which each is attached, can form

, , As further non-limiting examples, R^3a and R^3b, together with the Ring B ring atom to which each is attached, can form

For example, R^3a and R^3b, together with the Ring B ring atom to which each is attached, can form

wherein R^d is C_1-3 alkyl optionally substituted with from 1-3 independently selected halo (e.g., R^d is C_1-3 alkyl substituted with from 1-3 independently selected halo (e.g., -CH₂CF₃)). In certain embodiments, R^3a and R^3b together with the Ring B ring atom to which each is attached, form a fused saturated ring of 4-6 ring atoms; • wherein from 1-2 of the ring atoms are each an independently selected heteroatom, wherein each of the independently selected heteroatoms is selected from the group consisting of N, NH, N(R^d), O, and S(O)_0-2; and • wherein the fused saturated ring of 4-6 ring atoms is substituted with R^W and further optionally substituted with from 1-2 substituents independently selected from the group consisting of oxo and R^c. In certain embodiments, one of R^2a and R^2b (e.g., R^2a) and one of R^3a and R^3b (e.g., R^3a) taken together with the Ring B ring atoms to which each is attached, form a fused saturated or unsaturated ring of 3-12 ring atoms; • wherein from 0-2 of the ring atoms are each an independently selected heteroatom, wherein each of the independently selected heteroatoms is selected from the group consisting of N, NH, N(R^d), O, and S(O)_0-2; and • wherein the fused saturated or unsaturated ring of 3-12 ring atoms is optionally substituted with from 1-4 substituents independently selected from the group consisting of oxo and R^c. In certain embodiments, one of R^2a and R^2b (e.g., R^2a) and one of R^3a and R^3b (e.g., R^3a) taken together with the Ring B ring atoms to which each is attached, form a fused saturated ring of 3-8 ring atoms; • wherein from 0-2 of the ring atoms are each an independently selected heteroatom, wherein each of the independently selected heteroatoms is selected from the group consisting of N, NH, N(R^d), O, and S(O)_0-2; and • wherein the fused saturated ring of 3-8 ring atoms is optionally substituted with from 1-4 substituents independently selected from the group consisting of oxo and R^c. In certain of these embodiments, R^3a and R^3b together with the Ring B ring atom to which each is attached, form:

In certain embodiments, R^3a and R^3b together with the Ring B ring atom to which each is attached, form: , , , wherei ^{W W W}

n R is –L -W, wherein L is C(=O) or S(O)₂; and R^W is C_2-6 alkenyl which is optionally substituted with from 1-3 R^a and further optionally substituted with R^g, wherein W is attached to L^W via an sp² hybridized carbon atom. In certain embodiments, R^3a and R^3b together with the Ring B ring atom to which each is attached, form:

, , , R^W is

or

For example, R^3a and R^3b together with the Ring B ring atom to which each is attached, can form

, wherein R^W is

. In certain embodiments (when R^3a and R^3b together with the Ring B ring atom to which each is attached form a fused ring as described anywhere supra), R^1c, R^2a, and R^2b are each H. In certain of the foregoing embodiments, one of R^2a and R^2b (e.g., R^2a) and one of R^3a and R^3b (e.g., R^3a) taken together with the Ring B ring atoms to which each is attached, form a fused C_3-6 cycloalkyl which is optionally substituted with from 1-2 R^c. In certain of these embodiments, the other of R^2a and R^2b and the other of R^3a and R^3b are each H. For example, one of R^2a and R^2b (e.g., R^2a) and one of R^3a and R^3b (e.g., R^3a) taken together with the Ring B ring atoms to which each is attached, form a fused cyclopropyl or cyclobutyl. For example, the compound can have formula

or

. In certain embodiments, wherein one of R^2a and R^2b (e.g., R^2a) and one of R^3a and R^3b (e.g., R^3a) combine to form a double bond between the Ring B ring atoms to which each is attached. In certain of these embodiments, the other of R^2a and R^2b and the other of R^3a and R^3b are each H. In certain embodiments (when one of R^2a and R^2b (e.g., R^2a) and one of R^3a and R^3b (e.g., R^3a) combine to form a double bond between the Ring B ring atoms to which each is attached), the other of R^2a and R^2b is H; and the other of R^3a and R^3b is selected from the group consisting of: R^b, R^g, and –(L^g)_g-R^g. In certain of these embodiments, the other of R^2a and R^2b is H; and the other of R^3a and R^3b is selected from the group consisting of: (i) C_1-3 alkyl; (ii) C_1-3 alkyl substituted with from 1-3 independently selected halo; (iii) C_1-3 alkyl substituted with C_1-4 alkoxy, C_1-4 haloalkoxy, or NR^eR^f; (iv) C_1-3 alkyl substituted with C_1-4 alkoxy or C_1-4 haloalkoxy; or (v) –R^g, –CH₂-R^g, –CH₂CH₂R^g, or –CH₂-O-R^g, wherein the R^g group of R^3a or R^3b is: C_3-6 cycloalkyl optionally substituted with from 1-4 R^c, or heterocyclyl including from 4-6 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R^d), O, and S(O)_0-2, and wherein the heterocyclyl is optionally substituted with from 1-4 substituents independently selected from the group consisting of oxo and R^c. In certain embodiments (when one of R^2a and R^2b (e.g., R^2a) and one of R^3a and R^3b (e.g., R^3a) combine to form a double bond between the Ring B ring atoms to which each is attached), the other of R^2a and R^2b is H; and the other of R^3a and R^3b is: (i) C_1-3 alkyl substituted with C_1-4 alkoxy, C_1-4 haloalkoxy, or NR^eR^f; or (ii) –CH₂OMe, -CH₂CH₂OMe, -CH(Me)CH₂OMe, -CH₂CH(Me)OMe, -CH₂OEt, - CH₂CH₂OCHF₂, -CH₂NR^eR^f (e.g., -CH₂N(CF₃)Me), or –CH₂CH₂NR^eR^f (e.g., - CH₂CH₂NMe₂) In certain of these embodiments, the other of R^2a and R^2b is H; and the other of R^3a and R^3b is: (i) C_1-3 alkyl substituted with C_1-4 alkoxy or C_1-4 haloalkoxy; or (ii) –CH₂OMe, -CH₂CH₂OMe, -CH(Me)CH₂OMe, -CH₂CH(Me)OMe, -CH₂OEt, or -CH₂CH₂OCHF₂; or (iii) –CH₂OMe or –CH₂CH₂OMe. In certain embodiments (when one of R^2a and R^2b (e.g., R^2a) and one of R^3a and R^3b (e.g., R^3a) combine to form a double bond between the Ring B ring atoms to which each is attached), R^2a, R^2b, R^3a, and R^3b taken together with the Ring B ring atoms to which each is attached form:

, wherein: R^3c is C_1-4 alkoxy, C_1-4 haloalkoxy, NR^eR^f, or R^g; and bb is the point of attachment to N(R^1c). For example, the compound can have the following formula:

(e.g., R^3c can be C_1-4 alkoxy). In certain embodiments (when one of R^2a and R^2b (e.g., R^2a) and one of R^3a and R^3b (e.g., R^3a) taken together with the Ring B ring atoms to which each is attached, form a fused ring as described anywhere supra; or when one of R^2a and R^2b (e.g., R^2a) and one of R^3a and R^3b (e.g., R^3a) combine to form a double bond between the Ring B ring atoms to which each is attached), R^1c is H. In certain embodiments, R^1c, R^2a, and R^2b are each H; one of R^3a and R^3b (e.g., R^3a) is C_1-3 alkyl optionally substituted with from 1-3 R^a; optionally the other of R^3a and R^3b is H; and optionally each R^a substituent present in R^3a or R^3b is independently selected from the group consisting of: halo, C_1-4 alkoxy, and C_1-4 haloalkoxy. In certain embodiments, R^1c, R^2a, and R^2b are each H; one of R^3a and R^3b (e.g., R^3a) is C_1-3 alkyl (e.g., methyl, ethyl, or isopropyl); and the other of R^3a and R^3b is H. In certain embodiments, R^1c, R^2a, and R^2b are each H; one of R^3a and R^3b (e.g., R^3a) is C_1-3 alkyl substituted with from 1-3 independently selected halo (e.g., -CH₂F, -CHF₂, CF₃, or –CH₂CH₂F); and the other of R^3a and R^3b is H. In certain embodiments, R^1c, R^2a, and R^2b are each H; one of R^3a and R^3b is C_1-3 alkyl substituted with C_1-4 alkoxy or C_1-4 haloalkoxy (e.g., –CH₂OMe, -CH₂CH₂OMe, - CH(Me)CH₂OMe, -CH₂CH(Me)OMe, or -CH₂OEt); and the other of R^3a and R^3b (e.g., R^3a) is H. In certain embodiments, R^1c, R^2a, and R^2b are each H; one of R^3a and R^3b (e.g., R^3a) is –R^g, –(C_1-3 alkylene)-R^g, or –(C_1-3 alkylene)-O-R^g, optionally wherein the R^g group of R^3a or R^3b is: C_3-6 cycloalkyl optionally substituted with from 1-4 R^c, or heterocyclyl including from 4-6 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R^d), O, and S(O)_0-2, and wherein the heterocyclyl is optionally substituted with from 1-4 substituents independently selected from the group consisting of oxo and R^c; and the other of R^3a and R^3b is H. In certain embodiments, R^1c, R^2a, and R^2b are each H; one of R^3a and R^3b (e.g., R^3a) is –R^g or –(C_1-3 alkylene)-R^g, optionally wherein the R^g group of R^3a or R^3b is: C_3-6 cycloalkyl optionally substituted with from 1-4 R^c, or heterocyclyl including from 4-6 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R^d), O, and S(O)_0-2, and wherein the heterocyclyl is optionally substituted with from 1-4 substituents independently selected from the group consisting of oxo and R^c; and optionally the other of R^3a and R^3b is H. In certain embodiments, R^1c, R^2a, and R^2b are each H; and R^3a and R^3b taken together with the Ring B ring carbon atom to which each is attached form a fused cycloalkyl ring of 3-6 (e.g., 3 or 4) ring atoms, such as 3 ring atoms, wherein the fused cycloalkyl ring is optionally substituted with from 1-2 R^c. In certain embodiments, R^1c, R^2a, and R^2b are each H; and R^3a and R^3b taken together with the Ring B ring atom to which each is attached, form a fused saturated ring of 4-6 ring atoms; • wherein from 1-2 of the ring atoms are each an independently selected heteroatom, wherein each of the independently selected heteroatoms is selected from the group consisting of N, NH, N(R^d), O, and S(O)_0-2; and • wherein the fused saturated ring of 4-6 ring atoms is optionally substituted with from 1-2 substituents independently selected from the group consisting of oxo and R^c. For example, R^3a and R^3b, together with the Ring B ring atom to which each is attached, can form

Variable Ring A In some embodiments, Ring A is w ^cB

herein each R is an independently selected R^c; and m is 0, 1, 2, 3, or 4. In certain of these embodiments, m is 1, 2, or 3. In certain of the foregoing embodiments, m is 1 or 2 (e.g., 2). In certain embodiments, Ring A is

), wherein each R^cB is an independently selected R^c. In certain embodiments, each R^cB is independently selected from the group consisting of: -halo, such as -Cl and -F; -CN; C_1-4 alkoxy; C_1-4 haloalkoxy; C_1-3 alkyl; and C_1-3 alkyl substituted with from 1-6 independently selected halo. In certain embodiments, Ring A is wher ^{cB1 c cB2}

ein R is R ; and R is H or R^c, optionally wherein R^cB1 and R^cB2 are each independently selected from the group consisting of: -halo, such as -Cl and -F; -CN; C_1-4 alkoxy; C_1-4 haloalkoxy; C_1-3 alkyl; and C_1-3 alkyl substituted with from 1-6 independently selected halo. In certain of these embodiments, R^cB1 is halo (e.g., –F or –Cl (e.g., –F)). In certain embodiments, R^cB1 is C_1-3 alkyl or C_1-3 alkyl substituted with from 1-6 independently selected halo, such as wherein R^cB1 is methyl, –CHF₂, or –CF₃. In certain embodiments, R^cB2 is selected from the group consisting of: halo; -CN; C_1-4 alkoxy; C_1-4 haloalkoxy; C_1-3 alkyl; and C_1-3 alkyl substituted with from 1-6 independently selected halo. In certain embodiments, R^cB2 is C_1-4 alkoxy or C_1-4 haloalkoxy. In certain embodiments, R^cB2 is selected from the group consisting of cyano; C_1-3 alkyl; and C_1-3 alkyl substituted with from 1-6 independently selected halo, such as wherein R^cB2 is cyano, methyl, ethyl, -CHF₂, -CF₃, or -CH₂CHF₂. In certain embodiments, Ring A is selected from the group consisting of:

In some embodiments, Ring A is heteroaryl including from 5-10 ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R^d), O, and S(O)_0-2, and wherein the heteroaryl is optionally substituted with from 1-4 substituents independently selected from the group consisting of R^c and oxo. In certain of these embodiments, Ring A is bicyclic heteroaryl including from 9-10 ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R^d), O, and S(O)_0-2, and wherein the heteroaryl is optionally substituted with from 1-4 substituents independently selected from the group consisting of R^c and oxo. As non-limiting examples of the foregoing embodiments, Ring A can be selected from the group consisting of:

each of which is furthe ^c

r optionally substituted with R . Non-Limiting Combinations In certain embodiments, the compound of Formula (I) is a compound of Formula (I-a):

Formula (I-a) or a pharmaceutically acceptable salt thereof, wherein n is 0, 1, or 2. In certain of these embodiments, n is 0. In certain embodiments, the compound of Formula (I) is a compound of Formula (I-b):

Formula (I-b) or a pharmaceutically acceptable salt thereof, wherein n is 0, 1, or 2. In certain of these embodiments, n is 0. In certain embodiments, the compound of Formula (I) is a compound of Formula (I-c):

Formula (I-c) or a pharmaceutically acceptable salt thereof, wherein n is 0, 1, or 2. In certain of these embodiments, n is 0. In certain embodiments, the compound of Formula (I) is a compound of Formula (I-d):

Formula (I-d) or a pharmaceutically acceptable salt thereof, wherein n is 0, 1, or 2. In certain of these embodiments, n is 0. In certain embodiments, the compound of Formula (I) is a compound of Formula (I-e):

Formula (I-e) or a pharmaceutically acceptable salt thereof. In certain of these embodiments, n is 0. In Formula (I-a), (I-b), (I-c), (I-d), or (I-e), m, X², L¹, and R⁵ can be as defined for Formula (I) anywhere herein. In certain embodiments of Formula (I-a), (I-b), (I-c), (I-d), or (I-e), m, X², L¹, and R⁵ are as defined in [AA1]: [AA1]: m is 0 or 1; X² is –O-, -N(R^N)-,

, –N(R^N)C(=O)-*, or - N(R^N)S(O)₂-*; L¹ is C_1-3 alkylene optionally substituted with from 1-3 R^a; and R⁵ is selected from the group consisting of: C_1-6 alkoxy or S(O)₂(C_1-6 alkyl) each optionally substituted with from 1-6 R^a; -OH; and –NR^eR^f. In certain embodiments of [AA1], R⁵ is C_1-6 alkoxy optionally substituted with from 1-6 R^a. In certain of these embodiments, R⁵ is C_1-3 alkoxy, such as methoxy. In certain embodiments of [AA1], R⁵ is S(O)₂(C_1-6 alkyl) which is optionally substituted with from 1-6 R^a. In certain of these embodiments, R⁵ is S(O)₂(C_1-3 alkyl). For example, R⁵ can be S(O)₂Me. In certain embodiments of [AA1], L¹ is CH₂. In certain embodiments of [AA1], L¹ is –CH(Me)-. In certain embodiments of [AA1], L¹ is –CH₂CH₂-. In certain embodiments of [AA1], m is 1. In certain embodiments of [AA1], X² is –O-. In certain embodiments of [AA1], X² is -N(R^N)- (e.g., –N(H)-). In certain embodiments of [AA1], X² is

In certain embodiments of [AA1], X² is –N(R^N)C(=O)* or -N(R^N)S(O)₂-*. For example, X² can be –N(H)C(=O)* or –N(H)S(O)₂-* (e.g., –N(H)C(=O)*). In certain embodiments of [AA1], m is 0. In certain embodiments of Formula (I-a), (I-b), (I-c), (I-d), or (I-e), m, X², L¹, and R⁵ are as defined in [BB1]: [BB1]: m is 0 or 1; X² is –O-, -N(R^N)-, ^N

–N(R )C(=O)*, or - N(R^N)S(O)₂-*; L¹ is a bond or C_1-3 alkylene optionally substituted with from 1-3 R^a; and R⁵ is heterocyclyl including from 3-10 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R^d), O, and S(O)_0-2, and wherein the heterocyclyl is optionally substituted with from 1-4 substituents independently selected from the group consisting of oxo and R^c. In certain embodiments of [BB1], R⁵ is

which is optionally substituted with from 1-2 R^c, wherein X^a is O, N(H), or N(R^d); x1 is 0, 1, or 2; and x0 is 0, 1, 2, or 3, provided that x0+x1≥1. In certain embodiments of [BB1], R⁵ is

which is optionally substituted with from 1-2 R^c, wherein X^a is O, N(H), or N(R^d); and x1 and x2 are each independently 0, 1, or 2. In certain embodiments of [BB1] (when R⁵ is

x1 is 0. In certain embodiments of [BB1] (when R⁵ is ^a

), X is –O-. As a non-limiting example of the foregoing embodiments, R⁵ can be

(e.g., As a further non- ⁵

limiting example, R can be

(e.g.,

or

In certain embodiments, X^a is N(R^d), optionally wherein R^d is C_1-4 alkyl or wherein R^d is C(=O)(C_1-4 alkyl) or S(O)₂(C_1-4 alkyl). As non-limiting examples, R⁵ can be selected from the group consisting of:

optionally wherein R^d

is C_1-4 alkyl or wherein R^d is C(=O)(C_1-4 alkyl) or S(O)₂(C_1-4 alkyl). As non-limiting examples of the foregoing embodiments, R⁵ can be selected from the group consisting of:

optionally w ^d

herein R is C_1-4 alkyl or wherein R^d is C(=O)(C_1-4 alkyl) or S(O)₂(C_1-4 alkyl). In certain embodiments of [BB1] (when R⁵ is

In certain embodiments of [BB1], R⁵ is

which is optionally substituted with from 1-2 R^c, wherein X^b and X^c are each independently selected from the group consisting of: O, N(H), N(R^d), and S(O)_0-2. As non-limiting examples of the foregoing embodiments, R⁵ can be selected from the group consisting of:

optionally wherein R^d is C_1-4 alkyl, such as methyl. In certain embodiments of [BB1], R⁵ is bicyclic heterocyclyl including from 6-10 (e.g., 6-8) ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R^d), O, and S(O)_0-2, and wherein the heterocyclyl is optionally substituted with from 1-4 substituents independently selected from the group consisting of oxo and R^c. For example, R⁵ can be

(e.g.,

In certain embodiments of [BB1], R⁵ is bicyclic heterocyclyl including from 7-10 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R^d), O, and S(O)_0-2, and wherein the heterocyclyl is optionally substituted with from 1-4 substituents independently selected from the group consisting of oxo and R^c, such as wherein R⁵ is

In certain embodiments of [BB1], L¹ is CH₂. In certain embodiments of [BB1], L¹ is –CH(Me)-. In certain embodiments of [BB1], L¹ is –CH₂CH₂-. In certain embodiments of [BB1], L¹ is a bond. In certain embodiments of [BB1], m is 1. In certain embodiments of [BB1], X² is –O-. In certain embodiments of [BB1], X² is -N(R^N)- (e.g., –N(H)-). In certain embodiments of [BB1], X² is

In certain embodiments of [BB1], X² is –N(R^N)C(=O)* or -N(R^N)S(O)₂-*. For example, X² can be – N(H)C(=O)* or –N(H)S(O)₂-* (e.g., –N(H)C(=O)*). In certain embodiments of [BB1], m is 0. In certain embodiments of Formula (I-a), (I-b), (I-c), (I-d), or (I-e), m, X², L¹, and R⁵ are as defined in [CC1]: [CC1]: m is 0 or 1; X² is –O-, -N(R^N)-, ^N

–N(R )C(=O)*, or - N(R^N)S(O)₂-*; L¹ is a bond or C_1-3 alkylene optionally substituted with from 1-3 R^a; and R⁵ is selected from the group consisting of: • heteroaryl including from 5-10 ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R^d), O, and S(O)_0-2, and wherein the heteroaryl is optionally substituted with from 1-4 R^c; and • C_6-10 aryl optionally substituted with from 1-4 R^c In certain embodiments of [CC1], R⁵ is monocyclic heteroaryl including 5 ring atoms, wherein from 1-4, such as 2-3, ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R^d), O, and S(O)_0-2, and wherein the heteroaryl is optionally substituted with from 1-3 R^c. In certain of these embodiments, R⁵ is selected from the group consisting of pyrazolyl, imidazolyl, oxazolyl, thiazolyl, isooxazolyl, isothiazolyl, triazolyl, oxadiazolyl, and thiadiazolyl, each optionally substituted with from 1-2 R^c, and wherein a ring nitrogen atom is optionally substituted with R^d. As non-limiting examples, R⁵ can be

,

example, R⁵ can be

In certain embodiments of [CC1], R⁵ is monocyclic heteroaryl including 6 ring atoms, wherein from 1-4, such as 1-2, ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), and N(R^d), and wherein the heteroaryl is optionally substituted with from 1-4 R^c. As non-limiting examples, R⁵ can be

, , , , For example, R⁵ can be

In certain embodiments of [CC1], R⁵ is bicyclic heteroaryl including from 8-10 ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R^d), O, and S(O)_0-2, and wherein the heteroaryl is optionally substituted with from 1-4 R^c. In certain of these embodiments, R⁵ is bicyclic heteroaryl including 8 ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R^d), O, and S(O)_0-2, and wherein the heteroaryl is optionally substituted with from 1-4 R^c. For example, R⁵ can be selected from the group consisting

each optionall ^c

y substituted with from 1-2 R . In certain embodiments of [CC1], R⁵ is bicyclic heteroaryl including from 9-10, such as 9, ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R^d), O, and S(O)_0-2, and wherein the heteroaryl is optionally substituted with from 1-4 R^c, such as wherein R⁵ is

or

In certain embodiments of [CC1], R⁵ is phenyl optionally substituted with from 1- 2 R^c, such as unsubstituted phenyl. In certain embodiments of [CC1], L¹ is CH₂. In certain embodiments of [CC1], L¹ is –CH(Me)-. In certain embodiments of [CC1], L¹ is –CH₂CH₂-. In certain embodiments of [CC1], L¹ is a bond. In certain embodiments of [CC1], m is 1. In certain embodiments of [CC1], X² is –O-. In certain embodiments of [CC1], X² is -N(R^N)- (e.g., –N(H)-). In certain embodiments of [CC1], X² is

In certain embodiments of [CC1], X² is –N(R^N)C(=O)* or -N(R^N)S(O)₂-*. For example, X² can be –N(H)C(=O)* or –N(H)S(O)₂-* (e.g., –N(H)C(=O)*). In certain embodiments of [CC1], m is 0. In certain embodiments of Formula (I-a), (I-b), (I-c), (I-d), or (I-e), m, X², L¹, and R⁵ are as defined in [DD1]: [DD1]: m is 0 or 1; X² is –O-, -N(R^N)-,

, –N(R^N)C(=O)*, or - N(R^N)S(O)₂-*; L¹ is a bond or C_1-3 alkylene optionally substituted with from 1-3 R^a; and R⁵ is C_3-10 cycloalkyl which is optionally substituted with from 1-4 substituents independently selected from the group consisting of oxo and R^c. In certain embodiments of [DD1], R⁵ is C_3-6 cycloalkyl. For example, R⁵ can be cyclopropyl. In certain embodiments of [DD1], R⁵ is C_3-6 cycloalkyl substituted with a substituent selected from the group consisting of: C_1-4 alkyl; C_1-4 alkyl substituted with R^a, such as C_1-4 alkyl substituted with C_1-4 alkoxy; C_1-4 alkoxy; and C_1-4 haloalkoxy, and wherein the cycloalkyl is further optionally substituted with from 1-2 R^c. As non-limiting examples, R⁵ can be selected from the group consisting of:

such as

In certain embodiments of [DD1], L¹ is CH₂. In certain embodiments of [DD1], L¹ is –CH(Me)-. In certain embodiments of [DD1], L¹ is –CH₂CH₂-. In certain embodiments of [DD1], L¹ is a bond. In certain embodiments of [DD1], m is 1. In certain embodiments of [DD1], X² is –O-. In certain embodiments of [DD1], X² is -N(R^N)- (e.g., –N(H)-). In certain embodiments of [DD1], X² is

In certain embodiments of [DD1], X² is –N(R^N)C(=O)* or -N(R^N)S(O)₂-*. For example, X² can be –N(H)C(=O)* or –N(H)S(O)₂-* (e.g., –N(H)C(=O)*). In certain embodiments of [DD1], m is 0. In certain embodiments of Formula (I-a), (I-b), (I-c), (I-d), or (I-e), m, X², L¹, and R⁵ are as defined in [EE1]: [EE1]: m is 1; X² is –N(R^N)C(=O)-*, -N(R^N)C(=O)O-* or -N(R^N)C(=O)N(R^N)-*; L¹ is C_1-3 alkylene optionally substituted with from 1-3 R^a; and R⁵ is H. In certain embodiments of [EE1], L¹ is CH₂. In certain embodiments of [EE1], L¹ is –CH(Me)-. In certain embodiments of [EE1], L¹ is –CH₂CH₂-. In certain embodiments of [EE1], X² is -N(R^N)C(=O)-* (e.g., –N(H)C(=O)-*). In certain embodiments of [EE1], X² is selected from the group consisting of - N(R^N)C(=O)N(R^N)-* (e.g., –N(H)C(=O)N(R^N)-* (e.g., -N(H)C(=O)N(C_1-3 alkyl)); and - N(R^N)C(=O)O-* (e.g., –N(H)C(=O)O-*). In certain embodiments of Formula (I-a), (I-b), (I-c), (I-d), or (I-e), m, X², L¹, and R⁵ are as defined in [FF1]: [FF1]: m is 1; X² is –O-, -N(R^N)-, –N( ^{N N}

R )C(=O)*, or -N(R )S(O)₂-*; L¹ is branched C_3-6 alkylene optionally substituted with from 1-6 R^a; and R⁵ is selected from the group consisting of: H; C_1-6 alkoxy or S(O)₂(C_1-6 alkyl) each optionally substituted with from 1-6 R^a; -OH; and –NR^eR^f; or [FF1]: m is 1; X² is –O-, -N(R^N)-, ^{N N}

, –N(R )C(=O)*, or -N(R )S(O)₂-*; L¹ is branched C_3-6 alkylene optionally substituted with from 1-6 R^a; and R⁵ is selected from the group consisting of: C_1-6 alkoxy or S(O)₂(C_1-6 alkyl) each optionally substituted with from 1-6 R^a; -OH; and –NR^eR^f. In certain embodiments of [FF1], R⁵ is C_1-6 alkoxy optionally substituted with from 1-6 R^a. In certain of these embodiments, R⁵ is C_1-3 alkoxy. In certain embodiments of [FF1], R⁵ is S(O)₂(C_1-6 alkyl) optionally substituted with from 1-6 R^a. In certain embodiments of [FF1], X² is –O-. In certain embodiments of [FF1], X² is -N(R^N)- (e.g., –N(H)-). In certain embodiments of [FF1], X² is

. In certain embodiments of [FF1], X² is –N(R^N)C(=O)* or -N(R^N)S(O)₂-* (e.g., –N(H)C(=O)-* or – N(H)S(O)₂-*). For example, X² can be –N(H)C(=O)-*. In certain embodiments of [FF1], L¹ is branched C_3-6 alkylene. In certain of these embodiments, L¹ is selected from the group consisting of:

w ⁵

herein aa is the point of attachment to R . In certain embodiments of Formula (I-a), (I-b), (I-c), (I-d), or (I-e), m, X², L¹, and R⁵ are as defined in [GG1]: [GG1]: m is 0 or 1; X² is –O-, -N(R^N)-, ^N

, –N(R )C(=O)*, or - N(R^N)S(O)₂-*; L¹ is a bond or C_1-3 alkylene optionally substituted with from 1-3 R^a; and R⁵ is –R^g2-R^W, wherein: the -R^g2 of R⁵ is heterocyclylene including from 4-8 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R^d), O, and S(O)_0-2, and wherein the heterocyclylene is optionally substituted with from 1-4 substituents independently selected from the group consisting of oxo and R^c; and -R^W is –C(=O)-W or –S(O)₂-W. In certain embodiments of [GG1], R^g2 is

wherein bb is the point of ^W

attachment to R . In certain embodiments of [GG1], R^g2 is

such as wherein bb is the point of attac ^W

hment to R ; and optionally wherein R^d is C_1-4 alkyl, such as methyl. In certain embodiments of [GG1], R^g2 is is bicyclic heterocyclylene including from 6-8 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R^d), O, and S(O)_0-2, and wherein the heterocyclylene is optionally substituted with from 1-4 substituents independently selected from the group consisting of oxo and R^c, wherein bb is the point of attachment to R^W. For example, R^g2 can be

wherein bb is the point of attachmen ^W

t to R . In certain embodiments of [GG1], R^W is –C(=O)-W. In certain embodiments of [GG1], W is C_2-6 alkenyl optionally substituted with from 1-3 R^a. As non-limiting examples of the foregoing embodiments, R^W can be

or

In certain embodiments of [GG1], L¹ is CH₂. In certain embodiments of [GG1], L¹ is –CH(Me)-. In certain embodiments of [GG1], L¹ is –CH₂CH₂-. In certain embodiments of [GG1], L¹ is a bond. In certain embodiments of [GG1], m is 1. In certain embodiments of [GG1], X² is –O-. In certain embodiments of [GG1], X² is -N(R^N)- (e.g., –N(H)-). In certain embodiments of [GG1], X² is

In certain embodiments of [GG1], X² is –N(R^N)C(=O)* or -N(R^N)S(O)₂-*. For example, X² can be –N(H)C(=O)* or –N(H)S(O)₂-* (e.g., –N(H)C(=O)*). In certain embodiments of [GG1], m is 0. In certain embodiments, the compound of Formula (I) is a compound of Formula (I-a1):

Formula (I-a1) or a pharmaceutically acceptable salt thereof, wherein: n is 0, 1, or 2; and R⁵ is heterocyclyl including from 4-10 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R^d), O, and S(O)_0-2, and wherein the heterocyclyl is optionally substituted with from 1-4 substituents independently selected from the group consisting of oxo and R^c. In certain embodiments of Formula (I-a1), R⁵ is

which is optionally substituted with from 1-2 R^c, wherein X^a is O, N(H), or N(R^d); x1 is 0, 1, or 2; and x0 is 0, 1, 2, or 3, provided that x0+x1≥1. In certain of these embodiments, x1 is 0. In certain embodiments, x0 is 1, 2, or 3. In certain embodiments, X^a is –O-. In certain embodiments of Formula (I-a1), R⁵ is

In certain embodiments of Formula (I-a1), R⁵ is

In certain embodiments of Formula (I-a1) (when R⁵ is ^{a d}

X is N(R ), optionally wherein R^d is C_1-4 alkyl or wherein R^d is C(=O)(C_1-4 alkyl) or S(O)₂(C_1-4 alkyl). In ccertain of these embodiments, x1 is 0. In certain embodiments of Formula (I-a1), R⁵ is selected from the group consisting of:

; , , optionally wherein R^d

is C_1-4 alkyl or wherein R^d is C(=O)(C_1-4 alkyl) or S(O)₂(C_1-4 alkyl). In certain embodiments of Formula (I-a1) (when R⁵ is

), x1 is 1 or 2. In certain of these embodiments, R⁵ is selected from the group consisting of:

. In certain embodiments of Formula (I-a1), R⁵ is

which is optionally substituted with from 1-2 R^c, wherein X^b and X^c are each independently selected from the group consisting of: O, N(H), N(R^d), and S(O)_0-2. In certain of these embodiments, R⁵ is selected from the group consisting of:

, ,

optionally wherein R^d is C_1-4 alkyl, such as methyl. In certain embodiments of Formula (I-a1), R⁵ is bicyclic heterocyclyl including from 6-10 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R^d), O, and S(O)_0-2, and wherein the heterocyclyl is optionally substituted with from 1-4 substituents independently selected from the group consisting of oxo and R^c, such as wherein R⁵ is

such as

In certain embodiments of Formula (I-a1), n is 0. In certain embodiments, the compound of Formula (I) is a compound of Formula (I-a2):

Formula (I-a2) or a pharmaceutically acceptable salt thereof, wherein: n is 0, 1, or 2; and R⁵ is selected from the group consisting of: • heteroaryl including from 5-6 ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R^d), O, and S, and wherein the heteroaryl is optionally substituted with from 1-3 R^c; and • C6 aryl optionally substituted with from 1-4 R^c. In certain embodiments of Formula (I-a2), R⁵ is monocyclic heteroaryl including 5 ring atoms, wherein from 1-4, such as 2-3, ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R^d), O, and S, and wherein the heteroaryl is optionally substituted with from 1-3 R^c. In certain of these embodiments, R⁵ is

In certain embodiments of Formula (I-a2), R⁵ is monocyclic heteroaryl including 6 ring atoms, wherein from 1-4, such as 1-2, ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), and N(R^d), and wherein the heteroaryl is optionally substituted with from 1-4 R^c. In certain of these embodiments, R⁵ is

. In certain embodiments of Formula (I-a2), n is 0. In certain embodiments, the compound of Formula (I) is a compound of Formula (I-a3):

Formula (I-a3) or a pharmaceutically acceptable salt thereof, wherein: n is 0, 1, or 2; and R⁵ is C_3-10 cycloalkyl which is optionally substituted with from 1-4 substituents independently selected from the group consisting of oxo and R^c. In certain embodiments of Formula (I-a3), R⁵ is monocyclic heteroaryl including 5 ring atoms, wherein from 1-4, such as 2-3, ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R^d), O, and S, and wherein the heteroaryl is optionally substituted with from 1-3 R^c. In certain of these embodiments, R⁵ is

In certain embodiments of Formula (I-a3), R⁵ is monocyclic heteroaryl including 6 ring atoms, wherein from 1-4, such as 1-2, ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), and N(R^d), and wherein the heteroaryl is optionally substituted with from 1-4 R^c. In certain of these embodiments, R⁵ is

In certain embodiments of Formula (I-a3), n is 0. In certain embodiments, the compound of Formula (I) is a compound of Formula (I-a4):

Formula (I-a4) or a pharmaceutically acceptable salt thereof, wherein: n is 0, 1, or 2; and R⁵ is –R^g2-R^W, wherein: the -R^g2 of R⁵ is heterocyclylene including from 4-8 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R^d), O, and S(O)_0-2, and wherein the heterocyclylene is optionally substituted with from 1-4 substituents independently selected from the group consisting of oxo and R^c; and -R^W is –C(=O)-W or –S(O)₂-W. In certain embodiments of Formula (I-a4), R^g2 is

which is optionally substituted with from 1-2 R^c, wherein bb is the point of attachment to R^W; and x1 and x2 are each independently 0, 1, or 2. In certain of these embodiments, x1 is 0. In certain embodiments of Formula (I-a4), R^g2 is selected from the group consisting

wherein ^W

bb is the point of attachment to R . In certain embodiments of Formula (I-a4), R^g2 is

which is optionally substituted with from 1-2 R^c; X^b is selected from the group consisting of: O, N(H), N(R^d), and S(O)_0-2; and bb is the point of attachment to R^W. In certain of these embodiments, R^g2 is selected from the group consisting of:

or wherein bb is the point of attachment to R^W; and option ^d

ally wherein R is C_1-4 alkyl, such as methyl. In certain embodiments of Formula (I-a4), R^g2 is is bicyclic heterocyclylene including from 6-8 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R^d), O, and S(O)_0-2, and wherein the heterocyclylene is optionally substituted with from 1-4 substituents independently selected from the group consisting of oxo and R^c (e.g., R^g2 is

such as

wherein bb is the point of attachment to R^W. In certain embodiments of Formula (I-a4), R^W is –C(=O)-W. In certain embodiments of Formula (I-a4), W is C_2-6 alkenyl (e.g., C_2-4 alkenyl) optionally substituted with from 1-3 R^a. In certain embodiments of Formula (I-a4), R^W is

or

such as

. In certain embodiments of Formula (I-a4), n is 0. In certain embodiments, the compound is a compound of Formula (I-a5):

Formula (I-a5) or a pharmaceutically acceptable salt thereof, wherein: n is 0, 1, or 2; L¹ is C_1-6 alkylene optionally substituted with from 1-6 R^a; and R⁵ is selected from the group consisting of: H; C_1-6 alkoxy or S(O)₂(C_1-6 alkyl) each optionally substituted with from 1-6 R^a; -OH; and –NR^eR^f. In certain embodiments of Formula (I-a5), L¹ is branched C_3-6 alkylene. In certain embodiments of Formula (I-a5), L¹ is selected from the group consisting of:

, , , and

wherein aa is the point of attachment to R⁵. In certain embodiments of Formula (I-a5), R⁵ is H. In certain embodiments of Formula (I-a5), R⁵ is C_1-6 alkoxy optionally substituted with from 1-6 R^a. In certain embodiments of Formula (I-a5), R⁵ is –OH. In certain embodiments of Formula (I-a5), R⁵ is –NR^eR^f. In certain embodiments of Formula (I-a5), n is 0. In certain embodiments, the compound is a compound of Formula (I-f):

Formula (I-f) or a pharmaceutically acceptable salt thereof, wherein: Ring C1 monocyclic heteroaryl including from 5-6 ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R^d), O, and S(O)_0-2, and wherein the heteroaryl is optionally substituted with 1-4 R^c. In certain embodiments of Formula (I-f), Ring C1 is monocyclic heteroaryl including 5 ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R^d), O, and S(O)_0-2, and wherein the heteroaryl is optionally substituted with 1-3 R^c. In certain embodiments of Formula (I-f), Ring C1 is selected from the group consisting of: pyrazolyl, imidazolyl, oxazolyl, thiazolyl, isooxazolyl, isothiazolyl, triazolyl, oxadiazolyl, and thiadiazolyl, each optionally substituted with from 1-2 R^c, and wherein a ring nitrogen atom is optionally substituted with R^d. As non-limiting examples of the foregoing embodiments, Ring C1 can be selected from the group consisting of:

. For example, Ring C1 can be

As non-limiting examples, Ring C1 can be selected from the group consisting of:

. In certain embodiments of Formula (I-f), Ring C1 is monocyclic heteroaryl including 6 ring atoms, wherein from 1-4 ring atoms are heteroatoms each independently selected from the group consisting of N, N(H), and N(R^d), and wherein the heteroaryl is optionally substituted with from 1-4 R^c. As non-limiting examples of the foregoing embodiments, Ring C1 can be selected from the group consisting of:

, , , , , and

As non-limiting examples, Ring C1 can be selected from the group consisting of:

. In certain embodiments, Ring C1 pyridyl or pyrimidyl, each of which is optionally substituted with from 1-2 R^c. For example, Ring C can be selected from the group consisting of:

. In certain embodiments, Ring C1 is selected from the group consisting of:

wherein the R^c present in Ring C is C_1-3 alkyl optionally substituted with from 1-3 R^a, such as C_1-3 alkyl optionally substituted with from 1-3 independently selected halo. In certain embodiments, Ring C1 is selected from the group consisting of:

wherein the R^c present in Ring C1 is selected from the group consisting of: halo and C_1-3 alkyl optionally substituted with from 1-3 R^a, optionally wherein the R^c is –F, -Cl, or C_1-3 alkyl optionally substituted with from 1-3 independently selected halo. In certain embodiments, the compound is a compound of Formula (I-g):

Formula (I-g) or a pharmaceutically acceptable salt thereof, wherein: Ring C2 is bicyclic heteroaryl including from 8-10 ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R^d), O, and S(O)_0-2, and wherein the heteroaryl is optionally substituted with 1-4 R^c. In certain embodiments of Formula (I-g), Ring C2 is bicyclic heteroaryl including 9 ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R^d), O, and S(O)_0-2, and wherein the heteroaryl is optionally substituted with 1-4 R^c. As non-limiting examples of the foregoing embodiments, Ring C2 can be selected from the group consisting of:

, , , each further optionally substituted with from 1- 2 R^c. For example, Ring C2 can be selected from the group consisting of:

As further non-limiting examples, Ring C2 can be selected from the group consisting of:

each further optionally substituted with from 1-2 R^c. For example, Ring C2 can be selected from the group consisting of:

In certain embodiments of Formula (I-g), Ring C2 is bicyclic heteroaryl including 10 ring atoms, wherein from 1-4 ring atoms are heteroatoms each independently selected from the group consisting of N, N(H), and N(R^d), and wherein the heteroaryl is optionally substituted with from 1-4 R^c. As non-limiting examples of the foregoing embodiments, Ring C2 can be selected from the group consisting of:

In certain embodiments, the compound is a compound of Formula (I-g1):

Formula (I-g1) or a pharmaceutically acceptable salt thereof, wherein: n is 0 or 1; Y¹, Y², and Y³ are each independently selected from the group consisting of: N, NH, NR^d, CH, CR^c, CX¹, O, and S; and each

is independently a single bond or a double bond, provided that the 5-membered ring including Y¹, Y², and Y³ is heteroaryl; and from 0-1 of Y¹, Y², and Y³ is selected from the group consisting of: O, S, and CR^X1. In certain embodiments of Formula (I-g1), Y¹ is S. In certain embodiments of Formula (I-g1), Y² is selected from the group consisting of: N, CH, CR^c, and CX¹. In certain of these embodiments, Y² is CH or CR^c. In certain embodiments, Y² is N. In certain embodiments of Formula (I-g1), Y³ is selected from the group consisting of CH and CR^c. In certain of these embodiments, Y³ is CH. In certain embodiments of Formula (I-g1), Y¹ is S; and Y² and Y² are each CH. In certain embodiments of Formula (I-g1), Y¹ is S; Y² is N; and Y³ is CH. In certain embodiments of Formula (I-g1), Y¹ is S; Y² is CR^c; and Y³ is CH. In certain embodiments of Formula (I-g1) (when Y² is CR^c), the R^c group present in Y² is selected from the group consisting of: (i) C_1-6 alkyl; (ii) halo; and (iii) C_1-6 alkyl substituted with from 1-6 independently selected R^a. In certain embodiments of Formula (I-g1) (when Y² is CR^c), the R^c group present in Y² is selected from the group consisting of: (i) C_1-3 alkyl; (ii) halo; and (iii) C_1-3 alkyl substituted with from 1-3 independently selected halo. In certain embodiments of Formula (I-g1) (when Y² is CR^c), the R^c group present in Y² is selected from the group consisting of: (i) methyl; (ii) -F; and (iii) –CHF₂. In certain embodiments of Formula (I-g1) (when Y² is CR^c), the R^c group present in Y² is selected from the group consisting of: (i) C_1-3 alkyl (e.g., methyl); (ii) halo (e.g., -F); and (iii) C_1-3 alkyl substituted with from 1-3 independently selected halo (e.g., R^c is – CHF₂ ⁾ . In certain embodiments, the compound is a compound of Formula (I-g1-1):

Formula (I-g1-1) or a pharmaceutically acceptable salt thereof, wherein: n is 0 or 1, such as 0; In certain embodiments, the compound is a compound of Formula (I-g1-2):

Formula (I-g1-2) or a pharmaceutically acceptable salt thereof. In certain embodiments of Formula (I-g1), (I-g1-1) and (I-g1-2), one of Y¹, Y², Y³ (e.g., Y²) is CX¹; and X¹ can be defined anywhere herein. For example, X¹ can be defined according to [AA1], [BB1], [CC1], [DD1], [EE1], [FF1], or [GG1]. In certain embodiments of Formula (I-g1) or (I-g1-1), n is 0. In certain embodiments, the compound is a compound of Formula (I-h):

Formula (I-h) or a pharmaceutically acceptable salt thereof, wherein: Ring C3 is heterocyclyl or heterocycloalkenyl including from 3-10 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R^d), O, and S(O)_0-2, and wherein the heterocyclyl or heterocycloalkenyl is optionally substituted with X¹ and further optionally substituted with from 1-4 substituents independently selected from the group consisting of oxo and R^c. In certain embodiments of Formula (I-h), Ring C3 is heterocyclyl including from 4-8 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R^d), O, and S(O)_0-2, and wherein the heterocyclyl is optionally substituted with from 1-4 substituents independently selected from the group consisting of oxo and R^c, such as wherein Ring C is tetrahydropyranyl, such as

. In certain embodiments of Formula (I-f), (I-g), or (I-h), each occurrence of R^c present on one or more ring atoms of Ring C1, Ring C2, or Ring C3 is independently selected from the group consisting of: C_1-3 alkyl; C_1-3 alkyl substituted with from 1-3 R^a; halo; cyano; NR^eR^f, such as NH₂, NH(C_1-3 alkyl), or N(C_1-3 alkyl)₂; -OH; C_1-4 alkoxy; and C_1-4 haloalkoxy. For example, each occurrence of R^c present on one or more ring atoms of Ring C1, Ring C2, or Ring C3 can be independently selected from the group consisting of: halo; C_1-6 alkyl; C_1-6 alkyl substituted with from 1-6 independently selected halo; C_1-4 alkoxy; and C_1-4 haloalkoxy. In certain embodiments of Formula (I-a), (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I- b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-g1), (I-g1-1), (I-g1-2), or (I-h), R^1c is H. In certain embodiments of Formula (I-a), (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I- b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-g1), (I-g1-1), (I-g1-2), or (I-h), R^2a and R^2b are H. In certain embodiments of Formula (I-a), (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I- b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-g1), (I-g1-1), (I-g1-2), or (I-h), from 1-2, such as 1, of R^2a and R^2b a substituent other than H. In certain embodiments of Formula (I-a), (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I- b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-g1), (I-g1-1), (I-g1-2), or (I-h), one of R^2a and R^2b (e.g., R^2a) is C_1-3 alkyl optionally substituted with from 1-3 R^a, such as C_1-3 alkyl; and the other of R^2a and R^2b is H. In certain embodiments of Formula (I-a), (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I- b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-g1), (I-g1-1), (I-g1-2), or (I-h), one of R^2a and R^2b (e.g., R^2a) is C_1-3 alkyl optionally substituted with from 1-3 R^a, such as C_1-3 alkyl (e.g., methyl); and the other of R^2a and R^2b is H. In certain embodiments of Formula (I-a), (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I- b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-g1), (I-g1-1), (I-g1-2), or (I-h), one of R^2a and R^2b (e.g., R^2a) is heterocyclyl including from 4-6 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R^d), O, and S(O)_0-2, and wherein the heterocyclyl is optionally substituted with from 1-4 substituents independently selected from the group consisting of oxo and R^c; and the other of R^2a and R^2b is H. In certain embodiments of Formula (I-a), (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I- b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-g1), (I-g1-1), (I-g1-2),or (I-h), R^2a and R^2b together with the Ring B ring atom to which each is attached form a cycloalkyl ring of 3-6 ring atoms, such as 3 ring atoms, wherein the fused cycloalkyl ring is optionally substituted with from 1-2 R^c. In certain embodiments of Formula (I-a), (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I- b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-g1), (I-g1-1), (I-g1-2),or (I-h), R^3a and R^3b are H. In certain embodiments of Formula (I-a), (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I- b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-g1), (I-g1-1), (I-g1-2),or (I-h), from 1-2, such as 1, of R^3a and R^3b is a substituent other than H. In certain embodiments of Formula (I-a), (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I- b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-g1), (I-g1-1), (I-g1-2),or (I-h), one of R^3a and R^3b (e.g., R^3a) is C_1-3 alkyl optionally substituted with from 1-3 R^a, such as C_1-3 alkyl optionally substituted with from 1-3 independently selected halo; and the other of R^3a and R^3b is H. In certain embodiments of Formula (I-a), (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I- b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-g1), (I-g1-1), (I-g1-2),or (I-h), one of R^3a and R^3b (e.g., R^3a) is C_1-3 alkyl optionally substituted with from 1-3 independently selected halo, such as –CH₃, –CH₂F, -CH₂CH₂F, or –CHF₂; and the other of R^3a and R^3b is H. In certain embodiments of Formula (I-a), (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I- b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-g1), (I-g1-1), (I-g1-2),or (I-h), one of R^3a and R^3b (e.g., R^3a) is C_1-3 alkyl substituted with C_1-4 alkoxy, C_1-4 haloalkoxy or NR^eR^f (e.g., –CH₂OMe, -CH₂CH₂OMe, -CH(Me)CH₂OMe, -CH₂CH(Me)OMe, -CH₂OEt, -CH₂NR^eR^f (e.g., - CH₂N(CF₃)Me), or –CH₂CH₂NR^eR^f (e.g., -CH₂CH₂NMe₂)); and the other of R^3a and R^3b is H. In certain embodiments of Formula (I-a), (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I- b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-g1), (I-g1-1), (I-g1-2),or (I-h), one of R^3a and R^3b (e.g., R^3a) is C_1-3 alkyl substituted with C_1-4 alkoxy or C_1-4 haloalkoxy; and the other of R^3a and R^3b is H. In certain embodiments of Formula (I-a), (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I- b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-g1), (I-g1-1), (I-g1-2),or (I-h), one of R^3a and R^3b (e.g., R^3a) is heterocyclyl including from 4-6 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R^d), O, and S(O)_0-2, and wherein the heterocyclyl is optionally substituted with from 1-4 substituents independently selected from the group consisting of oxo and R^c; and the other of R^3a and R^3b is H. In certain embodiments of Formula (I-a), (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I- b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-g1), (I-g1-1), (I-g1-2),or (I-h), one of R^3a and R^3b (e.g., R^3a) is C_3-6 cycloalkyl optionally substituted with from 1-4 R^c; and the other of R^3a and R^3b is H. In certain embodiments of Formula (I-a), (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I- b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-g1), (I-g1-1), (I-g1-2),or (I-h), one of R^3a and R^3b (e.g., R^3a) is –(C_1-3 alkylene)-R^g (e.g., -CH₂-R^g or –CH₂CH₂-R^g) or –(C_1-3 alkylene)-O-R^g (e.g., -CH₂O-R^g), wherein the R^g group of R^3a or R^3b is: C_3-6 cycloalkyl optionally substituted with from 1-4 R^c, or heterocyclyl including from 4-6 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R^d), O, and S(O)_0-2, and wherein the heterocyclyl is optionally substituted with from 1-4 substituents independently selected from the group consisting of oxo and R^c; and the other of R^3a and R^3b is H. In certain embodiments of Formula (I-a), (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I- b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-g1), (I-g1-1), (I-g1-2),or (I-h), one of R^3a and R^3b (e.g., R^3a) is –(C_1-3 alkylene)-R^g, optionally wherein the R^g group of R^3a or R^3b is: C_3-6 cycloalkyl optionally substituted with from 1-4 R^c, or heterocyclyl including from 4-6 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R^d), O, and S(O)_0-2, and wherein the heterocyclyl is optionally substituted with from 1-4 substituents independently selected from the group consisting of oxo and R^c; and the other of R^3a and R^3b is H. In certain embodiments of Formula (I-a), (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I- b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-g1), (I-g1-1), (I-g1-2),or (I-h), R^3a and R^3b together with the Ring B ring atom to which each is attached form a cycloalkyl ring of 3-6 ring atoms, such as 3 ring atoms, wherein the fused cycloalkyl ring is optionally substituted with from 1-2 R^c. In certain embodiments of Formula (I-a), (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I- b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-g1), (I-g1-1), (I-g1-2),or (I-h), R^3a and R^3b together with the Ring B ring atom to which each is attached, form a fused saturated ring of 4-6 ring atoms; • wherein from 1-2 of the ring atoms are each an independently selected heteroatom, wherein each of the independently selected heteroatoms is selected from the group consisting of N, NH, N(R^d), O, and S(O)_0-2; and • wherein the fused saturated ring of 4-6 ring atoms is optionally substituted with from 1-2 substituents independently selected from the group consisting of oxo and R^c. In certain embodiments of Formula (I-a), (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I- b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-g1), (I-g1-1), (I-g1-2),or (I-h), R^3a and R^3b together with the Ring B ring atom to which each is attached, form a fused saturated ring of 4-6 ring atoms; • wherein from 1-2 of the ring atoms are each an independently selected heteroatom, wherein each of the independently selected heteroatoms is selected from the group consisting of N, NH, N(R^d), O, and S(O)_0-2; and • wherein the fused saturated ring of 4-6 ring atoms is substituted with R^W and further optionally substituted with from 1-2 substituents independently selected from the group consisting of oxo and R^c. In certain of these embodiments, R^3a and R^3b together with the Ring B ring atom to which each is attached, form:

In certain of these embodiments, R^W is –L^W-W, wherein L^W is C(=O) or S(O)₂; and R^W is C_2-6 alkenyl which is optionally substituted with from 1-3 R^a and further optionally substituted with R^g, wherein W is attached to L^W via an sp² hybridized carbon atom. In certain of the foregoing embodiments, R^W is

or

. For example, R^3a and R^3b together with the Ring B ring atom to which each is attached, can form wherein R^W is

.

In certain embodiments of Formula (I-a), (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I- b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-g1), (I-g1-1), (I-g1-2),or (I-h), one of R^2a and R^2b (e.g., R^2a) and one of R^3a and R^3b (e.g., R^3a) taken together with the Ring B ring atoms to which each is attached, form a fused C_3-6 (e.g., C₃ or C₄) cycloalkyl which is optionally substituted with from 1-2 R^c. In certain of these embodiments, the other of R^2a and R^2b and the other of R^3a and R^3b are each H. In certain embodiments of Formula (I-a), (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I- b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-g1), (I-g1-1), (I-g1-2),or (I-h) (when one of R^2a and R^2b (e.g., R^2a) and one of R^3a and R^3b (e.g., R^3a) taken together with the Ring B ring atoms to which each is attached, form a fused C_3-6 (e.g., C₃ or C₄) cycloalkyl which is optionally substituted with from 1-2 R^c), the other of R^2a and R^2b is H; and the other of R^3a and R^3b is selected from the group consisting of: R^b, R^g, and –(L^g)_g-R^g. In certain of these embodiments, the other of R^2a and R^2b is H; and the other of R^3a and R^3b is selected from the group consisting of: (i) C_1-3 alkyl; (ii) C_1-3 alkyl substituted with from 1-3 independently selected halo; (iii) C_1-3 alkyl substituted with C_1-4 alkoxy, C_1-4 haloalkoxy, or NR^eR^f; (iv) C_1-3 alkyl substituted with C_1-4 alkoxy or C_1-4 haloalkoxy; or (v) –R^g, –CH₂-R^g, –CH₂CH₂R^g, or –CH₂-O-R^g, wherein the R^g group of R^3a or R^3b is: C_3-6 cycloalkyl optionally substituted with from 1-4 R^c, or heterocyclyl including from 4-6 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R^d), O, and S(O)_0-2, and wherein the heterocyclyl is optionally substituted with from 1-4 substituents independently selected from the group consisting of oxo and R^c. In certain of the foregoing embodiments, the other of R^2a and R^2b is H; and the other of R^3a and R^3b is C_1-3 alkyl substituted with C_1-4 alkoxy, C_1-4 haloalkoxy, or NR^eR^f. In certain embodiments of Formula (I-a), (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I- b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-g1), (I-g1-1), (I-g1-2),or (I-h), one of R^2a and R^2b (e.g., R^2a) and one of R^3a and R^3b (e.g., R^3a) combine to form a double bond between the Ring B ring atoms to which each is attached. In certain of these embodiments, the other of R^2a and R^2b and the other of R^3a and R^3b are each H. In certain embodiments of Formula (I-a), (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I- b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-g1), (I-g1-1), (I-g1-2),or (I-h) (when one of R^2a and R^2b (e.g., R^2a) and one of R^3a and R^3b (e.g., R^3a) combine to form a double bond between the Ring B ring atoms to which each is attached), the other of R^2a and R^2b is H; and the other of R^3a and R^3b is selected from the group consisting of: R^b, R^g, and –(L^g)_g-R^g. In certain of these embodiments, the other of R^2a and R^2b is H; and the other of R^3a and R^3b is selected from the group consisting of: (i) C_1-3 alkyl; (ii) C_1-3 alkyl substituted with from 1-3 independently selected halo; (iii) C_1-3 alkyl substituted with C_1-4 alkoxy, C_1-4 haloalkoxy, or NR^eR^f; (iv) C_1-3 alkyl substituted with C_1-4 alkoxy or C_1-4 haloalkoxy; or (v) –R^g, –CH₂-R^g, –CH₂CH₂R^g, or –CH₂-O-R^g, wherein the R^g group of R^3a or R^3b is: C_3-6 cycloalkyl optionally substituted with from 1-4 R^c, or heterocyclyl including from 4-6 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R^d), O, and S(O)_0-2, and wherein the heterocyclyl is optionally substituted with from 1-4 substituents independently selected from the group consisting of oxo and R^c. In certain of the foregoing embodiments, the other of R^2a and R^2b is H; and the other of R^3a and R^3b is C_1-3 alkyl substituted with C_1-4 alkoxy, C_1-4 haloalkoxy, or NR^eR^f. In certain embodiments of Formula (I-a), (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I- b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-g1), (I-g1-1), (I-g1-2),or (I-h), R^1c, R^2a, and R^2b are each H; one of R^3a and R^3b (e.g., R^3a) is C_1-3 alkyl optionally substituted with from 1-3 R^a; and the other of R^3a and R^3b is H, optionally each R^a substituent present in R^3a or R^3b is independently selected from the group consisting of: halo, C_1-4 alkoxy, and C_1-4 haloalkoxy. In certain of these embodiments, R^1c, R^2a, and R^2b are each H; one of R^3a and R^3b is C_1-3 alkyl substituted with C_1-4 alkoxy or C_1-4 haloalkoxy; and the other of R^3a and R^3b is H. In certain embodiments of Formula (I-a), (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I- b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-g1), (I-g1-1), (I-g1-2),or (I-h), R^1c, R^2a, and R^2b are each H; and R^3a and R^3b are independently selected C_1-3 alkyl. In certain embodiments of Formula (I-a), (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I- b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-g1), (I-g1-1), (I-g1-2),or (I-h), R^1c, R^2a, and R^2b are each H; one of R^3a and R^3b (e.g., R^3a) is –R^g, –(C_1-3 alkylene)-R^g (e.g., -CH₂-R^g or –CH- ₂CH₂-R^g), or –(C_1-3 alkylene)-O-R^g (e.g., -CH₂-O-R^g), optionally wherein the R^g group of R^3a or R^3b is: C_3-6 cycloalkyl optionally substituted with from 1-4 R^c, or heterocyclyl including from 4-6 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R^d), O, and S(O)_0-2, and wherein the heterocyclyl is optionally substituted with from 1-4 substituents independently selected from the group consisting of oxo and R^c; and the other of R^3a and R^3b is H. In certain embodiments of Formula (I-a), (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I- b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-g1), (I-g1-1), (I-g1-2),or (I-h), R^1c, R^2a, and R^2b are each H; one of R^3a and R^3b (e.g., R^3a) is –R^g or –(C_1-3 alkylene)-R^g, optionally wherein the R^g group of R^3a or R^3b is: C_3-6 cycloalkyl optionally substituted with from 1-4 R^c, or heterocyclyl including from 4-6 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R^d), O, and S(O)_0-2, and wherein the heterocyclyl is optionally substituted with from 1-4 substituents independently selected from the group consisting of oxo and R^c; and the other of R^3a and R^3b is H. In certain embodiments of Formula (I-a), (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I- b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-g1), (I-g1-1), (I-g1-2),or (I-h), R^1c, R^2a, and R^2b are each H; and R^3a and R^3b taken together with the Ring B ring carbon atom to which each is attached form a fused cycloalkyl ring of 3-6 (e.g., 3 or 4) ring atoms, such as 3 ring atoms, wherein the fused cycloalkyl ring is optionally substituted with from 1-2 R^c. In certain embodiments of Formula (I-a), (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I- b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-g1), (I-g1-1), (I-g1-2),or (I-h), R^1c, R^2a, and R^2b are each H; and R^3a and R^3b together with the Ring B ring atom to which each is attached, form a fused saturated ring of 4-6 ring atoms; • wherein from 1-2 of the ring atoms are each an independently selected heteroatom, wherein each of the independently selected heteroatoms is selected from the group consisting of N, NH, N(R^d), O, and S(O)_0-2; and • wherein the fused saturated ring of 4-6 ring atoms is optionally substituted with from 1-2 substituents independently selected from the group consisting of oxo and R^c. In certain embodiments of Formula (I-a), (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I- b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-g1), (I-g1-1), (I-g1-2),or (I-h), R^1c, R^2a, and R^2b are each H; and R^3a and R^3b together with the Ring B ring atom to which each is attached, form:

(ii) any group of (i), wherein R^W is –L^W-W, wherein L^W is C(=O) or S(O)₂; and R^W is C_2-6 alkenyl which is optionally substituted with from 1-3 R^a and further optionally substituted with R^g, wherein W is attached to L^W via an sp² hybridized carbon atom; or (iii) any group of (i), wherein R^W is

In certain embodiments of Formula (I-a), (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I- b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-g1), (I-g1-1), (I-g1-2),or (I-h), R^1c is H; one of R^2a and R^2b (e.g., R^2a) and one of R^3a and R^3b (e.g., R^3a) taken together with the Ring B ring atoms to which each is attached, form a fused C_3-6 (e.g., C₃ or C₄) cycloalkyl which is optionally substituted with from 1-2 R^c; and the other of R^2a and R^2b and the other of R^3a and R^3b are each H. In certain embodiments of Formula (I-a), (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I- b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-g1), (I-g1-1), (I-g1-2),or (I-h), R^1c is H; one of R^2a and R^2b (e.g., R^2a) and one of R^3a and R^3b (e.g., R^3a) combine to form a double bond between the Ring B ring atoms to which each is attached; and the other of R^2a and R^2b and the other of R^3a and R^3b are each H. In certain embodiments of Formula (I-a), (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I- b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-g1), (I-g1-1), (I-g1-2),or (I-h), R^1c is H; one of R^2a and R^2b and one of R^3a and R^3b combine to form a double bond between the Ring B ring atoms to which each is attached; the other of R^2a and R^2b is H; and the other of R^3a and R^3b is selected from the group consisting of: (i) C_1-3 alkyl; (ii) C_1-3 alkyl substituted with from 1-3 independently selected halo; (iii) C_1-3 alkyl substituted with C_1-4 alkoxy, C_1-4 haloalkoxy, or NR^eR^f; (iv) C_1-3 alkyl substituted with C_1-4 alkoxy or C_1-4 haloalkoxy; or (v) –R^g, –CH₂-R^g, –CH₂CH₂R^g, or –CH₂-O-R^g, wherein the R^g group of R^3a or R^3b is: C_3-6 cycloalkyl optionally substituted with from 1-4 R^c, or heterocyclyl including from 4-6 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R^d), O, and S(O)_0-2, and wherein the heterocyclyl is optionally substituted with from 1-4 substituents independently selected from the group consisting of oxo and R^c. In certain embodiments of Formula (I-a), (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I- b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-g1), (I-g1-1), (I-g1-2),or (I-h), R^1c is H; one of R^2a and R^2b and one of R^3a and R^3b combine to form a double bond between the Ring B ring atoms to which each is attached; the other of R^2a and R^2b is H; and the other of R^3a and R^3b is C_1- 3 alkyl substituted with C_1-4 alkoxy or C_1-4 haloalkoxy. In certain embodiments of Formula (I-a), (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I- b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-g1), (I-g1-1), (I-g1-2),or (I-h), Ring A is

wherein each R^cB is an independently selected R^c; and m is 0, 1, 2, 3, or 4. In certain of these embodiments, m is 1 or 2, such as 2. In certain of the foregoing embodiments, each R^cB is independently selected from the group consisting of: -halo, such as -Cl and -F; -CN; C_1-4 alkoxy; C_1-4 haloalkoxy; C_1-3 alkyl; and C_1-3 alkyl substituted with from 1-6 independently selected halo. In certain embodiments of Formula (I-a), (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I- b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-g1), (I-g1-1), (I-g1-2),or (I-h), Ring A is

wherein each R^cB is an independently selected R^c. In

certain of these embodiments, each R^cB is independently selected from the group consisting of: -halo, such as -Cl and -F; -CN; C_1-4 alkoxy; C_1-4 haloalkoxy; C_1-3 alkyl; and C_1-3 alkyl substituted with from 1-6 independently selected halo. In certain embodiments of Formula (I-a), (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I- b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-g1), (I-g1-1), (I-g1-2),or (I-h), Ring A is selected from the group consisting of:

.

In certain embodiments of Formula (I-a), (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I- b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-g1), (I-g1-1), (I-g1-2),or (I-h), Ring A is heteroaryl including from 5-10 ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R^d), O, and S(O)_0-2, and wherein the heteroaryl is optionally substituted with from 1-4 substituents independently selected from the group consisting of R^c and oxo. In certain embodiments of Formula (I-a), (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I- b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-g1), (I-g1-1), (I-g1-2),or (I-h), Ring A is bicyclic heteroaryl including from 9-10 ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R^d), O, and S(O)_0-2, and wherein the heteroaryl is optionally substituted with from 1-4 substituents independently selected from the group consisting of R^c and oxo. As non-limiting examples of the foregoing embodiments, Ring A can be selected from the group consisting of:

, each of which is further optio ^c

nally substituted with R . In certain embodiments of Formula (I), (I-a), (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-g1), (I-g1-1), (I-g1-2),or (I-h), the

moiety is

In certain embodiments of Formula (I), (I-a), (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-g1), (I-g1-1), (I-g1-2),or (I-h), the

moiety is

. In certain embodiments of Formula (I), (I-a), (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-g1), (I-g1-1), (I-g1-2),or (I-h), the

moiety is

moiety is

. Non-Limiting Exemplary Compounds In some embodiments, the compound is selected from the group consisting of the compounds delineated in Table C1, or a pharmaceutically acceptable salt thereof. Table C1 For certain compounds, the symbol * at a chiral center denotes that this chiral center has been resolved (i.e., is a single epimer) and the absolute stereochemistry at that center has not been determined.”

143

175

Pharmaceutical Compositions and Administration General In some embodiments, a chemical entity (e.g., a compound that inhibits EGFR and/or HER2, or a pharmaceutically acceptable salt, and/or hydrate, and/or cocrystal, and/or drug combination thereof) is administered as a pharmaceutical composition that includes the chemical entity and one or more pharmaceutically acceptable excipients, and optionally one or more additional therapeutic agents as described herein. In some embodiments, the chemical entities can be administered in combination with one or more conventional pharmaceutical excipients. Pharmaceutically acceptable excipients include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, self-emulsifying drug delivery systems (SEDDS) such as d-α-tocopherol polyethylene glycol 1000 succinate, surfactants used in pharmaceutical dosage forms such as Tweens, poloxamers or other similar polymeric delivery matrices, serum proteins, such as human serum albumin, buffer substances such as phosphates, tris, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium-chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, and wool fat. Cyclodextrins such as α-, E, and γ-cyclodextrin, or chemically modified derivatives such as hydroxyalkylcyclodextrins, including 2- and 3- hydroxypropyl-β-cyclodextrins, or other solubilized derivatives can also be used to enhance delivery of compounds described herein. Dosage forms or compositions containing a chemical entity as described herein in the range of 0.005% to 100% with the balance made up from non-toxic excipient may be prepared. The contemplated compositions may contain 0.001%-100% of a chemical entity provided herein, in one embodiment 0.1-95%, in another embodiment 75-85%, in a further embodiment 20-80%. Actual methods of preparing such dosage forms are known, or will be apparent, to those skilled in this art; for example, see Remington: The Science and Practice of Pharmacy, 22^nd Edition (Pharmaceutical Press, London, UK.2012). Routes of Administration and Composition Components In some embodiments, the chemical entities described herein or a pharmaceutical composition thereof can be administered to subject in need thereof by any accepted route of administration. Acceptable routes of administration include, but are not limited to, buccal, cutaneous, endocervical, endosinusial, endotracheal, enteral, epidural, interstitial, intra-abdominal, intra-arterial, intrabronchial, intrabursal, intracerebral, intracisternal, intracoronary, intradermal, intraductal, intraduodenal, intradural, intraepidermal, intraesophageal, intragastric, intragingival, intraileal, intralymphatic, intramedullary, intrameningeal, intramuscular, intraovarian, intraperitoneal, intraprostatic, intrapulmonary, intrasinal, intraspinal, intrasynovial, intratesticular, intrathecal, intratubular, intratumoral, intrauterine, intravascular, intravenous, nasal, nasogastric, oral, parenteral, percutaneous, peridural, rectal, respiratory (inhalation), subcutaneous, sublingual, submucosal, topical, transdermal, transmucosal, transtracheal, ureteral, urethral and vaginal. In certain embodiments, a preferred route of administration is parenteral (e.g., intratumoral). Compositions can be formulated for parenteral administration, e.g., formulated for injection via the intravenous, intramuscular, sub-cutaneous, or even intraperitoneal routes. Typically, such compositions can be prepared as injectables, either as liquid solutions or suspensions; solid forms suitable for use to prepare solutions or suspensions upon the addition of a liquid prior to injection can also be prepared; and the preparations can also be emulsified. The preparation of such formulations will be known to those of skill in the art in light of the present disclosure. The pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions; formulations including sesame oil, peanut oil, or aqueous propylene glycol; and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases the form must be sterile and must be fluid to the extent that it may be easily injected. It also should be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms, such as bacteria and fungi. The carrier also can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), suitable mixtures thereof, and vegetable oils. The proper fluidity can be maintained, for example, by the use of a coating, such as lecithin, by the maintenance of the required particle size in the case of dispersion, and by the use of surfactants. The prevention of the action of microorganisms can be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like. In many cases, it will be preferable to include isotonic agents, for example, sugars or sodium chloride. Prolonged absorption of the injectable compositions can be brought about by the use in the compositions of agents delaying absorption, for example, aluminum monostearate and gelatin. Sterile injectable solutions are prepared by incorporating the active compounds in the required amount in the appropriate solvent with various of the other ingredients enumerated above, as required, followed by filtered sterilization. Generally, dispersions are prepared by incorporating the various sterilized active ingredients into a sterile vehicle which contains the basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum-drying and freeze-drying techniques, which yield a powder of the active ingredient, plus any additional desired ingredient from a previously sterile-filtered solution thereof. Intratumoral injections are discussed, e.g., in Lammers, et al., “Effect of Intratumoral Injection on the Biodistribution and the Therapeutic Potential of HPMA Copolymer-Based Drug Delivery Systems” Neoplasia.2006, 10, 788–795. Pharmacologically acceptable excipients usable in the rectal composition as a gel, cream, enema, or rectal suppository, include, without limitation, any one or more of cocoa butter glycerides, synthetic polymers such as polyvinylpyrrolidone, PEG (like PEG ointments), glycerine, glycerinated gelatin, hydrogenated vegetable oils, poloxamers, mixtures of polyethylene glycols of various molecular weights and fatty acid esters of polyethylene glycol Vaseline, anhydrous lanolin, shark liver oil, sodium saccharinate, menthol, sweet almond oil, sorbitol, sodium benzoate, anoxid SBN, vanilla essential oil, aerosol, parabens in phenoxyethanol, sodium methyl p-oxybenzoate, sodium propyl p- oxybenzoate, diethylamine, carbomers, carbopol, methyloxybenzoate, macrogol cetostearyl ether, cocoyl caprylocaprate, isopropyl alcohol, propylene glycol, liquid paraffin, xanthan gum, carboxy-metabisulfite, sodium edetate, sodium benzoate, potassium metabisulfite, grapefruit seed extract, methyl sulfonyl methane (MSM) , lactic acid, glycine, vitamins, such as vitamin A and E and potassium acetate. In certain embodiments, suppositories can be prepared by mixing the chemical entities described herein with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum and release the active compound. In other embodiments, compositions for rectal administration are in the form of an enema. In other embodiments, the compounds described herein or a pharmaceutical composition thereof are suitable for local delivery to the digestive or GI tract by way of oral administration (e.g., solid or liquid dosage forms.). Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the chemical entity is mixed with one or more pharmaceutically acceptable excipients, such as sodium citrate or dicalcium phosphate and/or: a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like. In one embodiment, the compositions will take the form of a unit dosage form such as a pill or tablet and thus the composition may contain, along with a chemical entity provided herein, a diluent such as lactose, sucrose, dicalcium phosphate, or the like; a lubricant such as magnesium stearate or the like; and a binder such as starch, gum acacia, polyvinylpyrrolidine, gelatin, cellulose, cellulose derivatives or the like. In another solid dosage form, a powder, marume, solution or suspension (e.g., in propylene carbonate, vegetable oils, PEG’s, poloxamer 124 or triglycerides) is encapsulated in a capsule (gelatin or cellulose base capsule). Unit dosage forms in which one or more chemical entities provided herein or additional active agents are physically separated are also contemplated; e.g., capsules with granules (or tablets in a capsule) of each drug; two-layer tablets; two- compartment gel caps, etc. Enteric coated or delayed release oral dosage forms are also contemplated. Other physiologically acceptable compounds include wetting agents, emulsifying agents, dispersing agents or preservatives that are particularly useful for preventing the growth or action of microorganisms. Various preservatives are well known and include, for example, phenol and ascorbic acid. In certain embodiments the excipients are sterile and generally free of undesirable matter. These compositions can be sterilized by conventional, well-known sterilization techniques. For various oral dosage form excipients such as tablets and capsules sterility is not required. The USP/NF standard is usually sufficient. In certain embodiments, solid oral dosage forms can further include one or more components that chemically and/or structurally predispose the composition for delivery of the chemical entity to the stomach or the lower GI; e.g., the ascending colon and/or transverse colon and/or distal colon and/or small bowel. Exemplary formulation techniques are described in, e.g., Filipski, K.J., et al., Current Topics in Medicinal Chemistry, 2013, 13, 776-802, which is incorporated herein by reference in its entirety. Examples include upper-GI targeting techniques, e.g., Accordion Pill (Intec Pharma), floating capsules, and materials capable of adhering to mucosal walls. Other examples include lower-GI targeting techniques. For targeting various regions in the intestinal tract, several enteric/pH-responsive coatings and excipients are available. These materials are typically polymers that are designed to dissolve or erode at specific pH ranges, selected based upon the GI region of desired drug release. These materials also function to protect acid labile drugs from gastric fluid or limit exposure in cases where the active ingredient may be irritating to the upper GI (e.g., hydroxypropyl methylcellulose phthalate series, Coateric (polyvinyl acetate phthalate), cellulose acetate phthalate, hydroxypropyl methylcellulose acetate succinate, Eudragit series (methacrylic acid–methyl methacrylate copolymers), and Marcoat). Other techniques include dosage forms that respond to local flora in the GI tract, Pressure-controlled colon delivery capsule, and Pulsincap. Ocular compositions can include, without limitation, one or more of any of the following: viscogens (e.g., Carboxymethylcellulose, Glycerin, Polyvinylpyrrolidone, Polyethylene glycol); Stabilizers (e.g., Pluronic (triblock copolymers), Cyclodextrins); Preservatives (e.g., Benzalkonium chloride, ETDA, SofZia (boric acid, propylene glycol, sorbitol, and zinc chloride; Alcon Laboratories, Inc.), Purite (stabilized oxychloro complex; Allergan, Inc.)). Topical compositions can include ointments and creams. Ointments are semisolid preparations that are typically based on petrolatum or other petroleum derivatives. Creams containing the selected active agent are typically viscous liquid or semisolid emulsions, often either oil-in-water or water-in-oil. Cream bases are typically water-washable, and contain an oil phase, an emulsifier and an aqueous phase. The oil phase, also sometimes called the “internal” phase, is generally comprised of petrolatum and a fatty alcohol such as cetyl or stearyl alcohol; the aqueous phase usually, although not necessarily, exceeds the oil phase in volume, and generally contains a humectant. The emulsifier in a cream formulation is generally a nonionic, anionic, cationic or amphoteric surfactant. As with other carriers or vehicles, an ointment base should be inert, stable, nonirritating and non- sensitizing. In any of the foregoing embodiments, pharmaceutical compositions described herein can include one or more one or more of the following: lipids, interbilayer crosslinked multilamellar vesicles, biodegradeable poly(D,L-lactic-co-glycolic acid) [PLGA]-based or poly anhydride-based nanoparticles or microparticles, and nanoporous particle-supported lipid bilayers. Dosages The dosages may be varied depending on the requirement of the patient, the severity of the condition being treating and the particular compound being employed. Determination of the proper dosage for a particular situation can be determined by one skilled in the medical arts. The total daily dosage may be divided and administered in portions throughout the day or by means providing continuous delivery. In some embodiments, the compounds described herein are administered at a dosage of from about 0.001 mg/Kg to about 500 mg/Kg (e.g., from about 0.001 mg/Kg to about 200 mg/Kg; from about 0.01 mg/Kg to about 200 mg/Kg; from about 0.01 mg/Kg to about 150 mg/Kg; from about 0.01 mg/Kg to about 100 mg/Kg; from about 0.01 mg/Kg to about 50 mg/Kg; from about 0.01 mg/Kg to about 10 mg/Kg; from about 0.01 mg/Kg to about 5 mg/Kg; from about 0.01 mg/Kg to about 1 mg/Kg; from about 0.01 mg/Kg to about 0.5 mg/Kg; from about 0.01 mg/Kg to about 0.1 mg/Kg; from about 0.1 mg/Kg to about 200 mg/Kg; from about 0.1 mg/Kg to about 150 mg/Kg; from about 0.1 mg/Kg to about 100 mg/Kg; from about 0.1 mg/Kg to about 50 mg/Kg; from about 0.1 mg/Kg to about 10 mg/Kg; from about 0.1 mg/Kg to about 5 mg/Kg; from about 0.1 mg/Kg to about 1 mg/Kg; from about 0.1 mg/Kg to about 0.5 mg/Kg). Regimens The foregoing dosages can be administered on a daily basis (e.g., as a single dose or as two or more divided doses) or non-daily basis (e.g., every other day, every two days, every three days, once weekly, twice weeks, once every two weeks, once a month). In some embodiments, the period of administration of a compound described herein is for 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, or more. In a further embodiment, a period of during which administration is stopped is for 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, or more. In an embodiment, a therapeutic compound is administered to an individual for a period of time followed by a separate period of time. In another embodiment, a therapeutic compound is administered for a first period and a second period following the first period, with administration stopped during the second period, followed by a third period where administration of the therapeutic compound is started and then a fourth period following the third period where administration is stopped. In an aspect of this embodiment, the period of administration of a therapeutic compound followed by a period where administration is stopped is repeated for a determined or undetermined period of time. In a further embodiment, a period of administration is for 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, or more. In a further embodiment, a period of during which administration is stopped is for 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, or more. Methods of Treatment Indications Provided herein are methods for inhibiting epidermal growth factor receptor tyrosine kinase (EGFR) and/or human epidermal growth factor receptor 2 (HER2). For example, provided herein are inhibitors of EGFR useful for treating or preventing diseases or disorders associated with dysregulation of an EGFR gene, an EGFR kinase, or the expression or activity or level of any of the same (i.e., an EGFR-associated disease or disorder), such as a central nervous system diseases, a pulmonary disorder, cardiovascular disease, ischemia, liver disease, a gastrointestinal disorder, a viral or bacterial infection, an inflammatory and/or autoimmune disease, or cancer (e.g., EGFR-associated cancer). In some embodiments, provided herein are inhibitors of HER2 useful for treating or preventing diseases or disorders associated with dysregulation of a HER2 gene, a HER2 kinase, or expression or activity or level of any of the same, such as cancer (e.g., HER2- associated cancer). In some embodiments, provided herein are inhibitors of EGFR and HER2. An “EGFR inhibitor” as used herein includes any compound exhibiting EGFR inactivation activity (e.g., inhibiting or decreasing). In some embodiments, an EGFR inhibitor can be selective for an EGFR kinase having one or more mutations. For example, an EGFR inhibitor can bind to the adenosine triphosphate (ATP)-binding site in the tyrosine kinase domain. In some embodiments, an EGFR inhibitor is an allosteric inhibitor. The compounds provided herein can inhibit EGFR. In some embodiments, the compounds can bind to the EGFR adenosine triphosphate (ATP)-binding site in the tyrosine kinase domain. The ability of test compounds to act as inhibitors of EGFR may be demonstrated by assays known in the art. The activity of the compounds and compositions provided herein as EGFR inhibitors can be assayed in vitro, in vivo, or in a cell line. In vitro assays include assays that determine inhibition of the kinase and/or ATPase activity. Alternate in vitro assays quantitate the ability of the inhibitor to bind to the protein kinase and can be measured either by radio labelling the compound prior to binding, isolating the compound/kinase complex and determining the amount of radio label bound, or by running a competition experiment where new compounds are incubated with the kinase bound to known radioligands. In some cases, an EGFR inhibitor can be evaluated by its effect on the initial velocity of EGFR tyrosine kinase catalyzed peptide phosphorylation (e.g., Yun et al. Cancer Cell.2007;11(3):217–227). In some embodiments, the binding constant of an EGFR inhibitor can be determined using fluorescence kinetics (e.g., Yun et al. Cancer Cell. 2007;11(3):217–227). Examples of surface plasmon resonance (SPR) binding assays include those disclosed in Li, Shiqing, et al. Cancer cell 7.4 (2005): 301-311. Additional EGFR inhibitor assays can be found, for example, in WO 2019/246541 and WO 2019/165358 both of which are incorporated by reference in their entireties). Assays can include, for example, proliferation inhibition assays such as those that measure cell growth inhibition, such as an MTS assay or by Cell Titer Glo Luminescent Cell viability assay (Promega®). To perform such an assay, cells are seeded and grown in cell culture plates before being exposed to a test compound for varying durations. Assessment of the viability of the cells following this exposure is then performed. Data are normalized with respect to untreated cells and can be displayed graphically. Growth curves can be fitted using a nonlinear regression model with sigmoidal dose response. As another example, a Western Blot analysis can be used. In such assays cells are seeded and grown in culture plates and then treated with a test compound the following day for varying durations. Cells are washed with PBS and lysed. SDS-PAGE gels are used to separate the lysates which are transferred to nitrocellulose membranes, and probed with appropriate antibodies (e.g., phospho-EGFR(Tyrl 068)(3777), total EGFR (2232), p-Akt(Ser473) (4060), total Akt (9272), p-ERK(Thr202/Tyr204)(4370), total ERK (9102), and HSP90 (SC-7947)). Additional assays can include, for example, assays based on ALPHALISA TECHNOLOGY® (e.g., see the ALPHALISA® EGF/EGFR binding kit from Promega). Such assays use a luminescent oxygen-channeling chemistry to detect molecules of interest in, for example, buffer, cell culture media, serum, and plasma. For example, a biotinylated EGF is bound to streptavidin-coated Alpha donor beads, and EGFR-Fc is captured by anti- human IgG Fc-specific AlphaLISA acceptor beads. When EGF is bound to EGFR, donor beads and acceptor beads come into close proximity, and the excitation of the donor beads provokes the release of singlet oxygen molecules that triggers a cascade of energy transfers in the acceptor beads. This results in a sharp peak of light emission at 615 nm. Such assays can be used, for example, in competitive binding experiments. Further examples of assays can include assays based on Sox technology (e.g., see the PHOSPHOSENS® Sox-based Homogeneous, Kinetic or Endpoint/Red Fluorescence- based Assays from ASSAYQUANT®). Such assays utilize chelation-enhanced fluorescence (CHEF) using a sulfonamido-oxine (Sox) chromophore in peptide or protein substrates to create real-time sensors of phosphorylation. See, e.g., U.S. Patent Nos. 8,586,570 and 6,906,194. Potency of an EGFR inhibitor as provided herein can be determined by EC50 value. A compound with a lower EC50 value, as determined under substantially similar conditions, is a more potent inhibitor relative to a compound with a higher EC₅₀ value. In some embodiments, the substantially similar conditions comprise determining an EGFR- dependent phosphorylation level, in vitro or in vivo (e.g., in tumor cells, A431 cells, Ba/F3 cells, or 3T3 cells cells expressing a wild type EGFR, a mutant EGFR, or a fragment of any thereof). Potency of an EGFR inhibitor as provided herein can also be determined by IC₅₀ value. A compound with a lower IC₅₀ value, as determined under substantially similar conditions, is a more potent inhibitor relative to a compound with a higher IC₅₀ value. In some embodiments, the substantially similar conditions comprise determining an EGFR- dependent phosphorylation level, in vitro or in vivo (e.g., in tumor cells, A431 cells, Ba/F3 cells, or 3T3 cells expressing a wild type EGFR, a mutant EGFR, or a fragment of any thereof). The selectivity between wild type EGFR and EGFR containing one or more mutations as described herein can also be measured using cellular proliferation assays where cell proliferation is dependent on kinase activity. For example, murine Ba/F3 cells transfected with a suitable version of wild type EGFR (such as VIII; containing a wild type EGFR kinase domain), or Ba/F3 cells transfected with L858R/T790M, Del/T790M/L718Q, L858R/T790M/L718Q, L858R/T790M/C797S, Del/T790M/C797S, L858R/T790M/I941R, exon 19 deletion/T790M, or an exon 20 insertion such as V769_D770insX, D770_N771insX, N771_P772insX, P772_H773insX, or H773_V774insX (e.g., A767_V769dupASV, V769_D770insASV, D770_N771insNPG, D770_N771insNPY, D770_N771insSVD, D770_N771insGL, N771_H773dupNPH, N771_P772insN, N771_P772insH, N771_P772insV, P772_H773insDNP, P772_H773insPNP, H773_V774insNPH, H773_V774insH, H773_V774insPH, H773_V774insAH, or P772_H773insPNP) can be used. Proliferation assays are performed at a range of inhibitor concentrations (e.g., 10 μM, 3 μM, 1.1 μM, 330 nM, 110 nM, 33 nM, 11 nM, 3 nM, 1 nM) and an EC50 is calculated. An alternative method to measure effects on EGFR activity is to assay EGFR phosphorylation. Wildtype or mutant (L858R/T790M, Del/T790M, Del/T790M/L718Q, L858R/T790M/C797S, Del/T790M/C797S, L858R/T790M/I941R, or L858R/T790M/L718Q) EGFR can be transfected into cells which do not normally express endogenous EGFR and the ability of the inhibitor (e.g., using concentrations as above) to inhibit EGFR phosphorylation can be assayed. Cells are exposed to increasing concentrations of inhibitor and stimulated with EGF. The effects on EGFR phosphorylation are assayed by Western Blotting using phospho-specific EGFR antibodies. In some embodiments, the compounds provided herein can exhibit potent and selective inhibition of EGFR. For example, the compounds provided herein can bind to the EGFR adenosine triphosphate (ATP)-binding site in the tyrosine kinase domain. In some embodiments, the compounds provided herein can exhibit nanomolar potency against an EGFR kinase including an activating mutation or an EGFR inhibitor resistance mutation, including, for example, the resistance mutations in Table 2a and 2b (e.g., L747S, D761Y, T790M, and T854A), with minimal activity against related kinases (e.g., wild type EGFR). Inhibition of wild type EGFR can cause undesireable side effects (e.g., diarrhea and skin rashes) that can impact quality of life and compliance. In some cases, the inhibititon of wild type EGFR can lead to dose limiting toxicities. See, e.g., Morphy. J. Med. Chem. 2010, 53, 4, 1413–1437 and Peters. J. Med. Chem.2013, 56, 22, 8955–8971. In some embodiments, the compounds of Formula (I) (e.g., Formula (I-a), (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-g1), (I-g1-1), (I-g1-2),or (I-h)), or a pharmaceutically acceptable salt thereof, can selectively target an EGFR kinase. For example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can selectively target an EGFR kinase over another kinase or non-kinase target. In some embodiments, a compound of Formula (I) (e.g., Formula (I-a), (I-a1), (I- a2), (I-a3), (I-a4), (I-a5), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-g1), (I-g1-1), (I-g1-2),or (I-h)), or a pharmaceutically acceptable salt thereof, can exhibit greater inhibition of EGFR containing one or more mutations as described herein (e.g., one or more mutations as described in Table 1a and 1b) relative to inhibition of wild type EGFR. In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof can exhibit at least 2-fold, 3-fold, 5-fold, 10-fold, 25-fold, 50-fold or 100-fold greater inhibition of EGFR containing one or more mutations as described herein relative to inhibition of wild type EGFR. In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can exhibit up to 1000-fold greater inhibition of EGFR containing one or more mutations as described herein relative to inhibition of wild type EGFR. In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can exhibit up to 10000-fold greater inhibition of EGFR having a combination of mutations described herein relative to inhibition of wild type EGFR. In some embodiments, a compound of Formula (I) (e.g., Formula (I-a), (I-a1), (I- a2), (I-a3), (I-a4), (I-a5), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-g1), (I-g1-1), (I-g1-2),or (I-h)), or a pharmaceutically acceptable salt thereof, can exhibit from about 2-fold to about 10-fold greater inhibition of EGFR containing one or more mutations as described herein relative to inhibition of wild type EGFR. In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can exhibit from about 10-fold to about 100-fold greater inhibition of EGFR containing one or more mutations as described herein relative to inhibition of wild type EGFR. In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can exhibit from about 100-fold to about 1000-fold greater inhibition of EGFR containing one or more mutations as described herein relative to inhibition of wild type EGFR. In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can exhibit from about 1000-fold to about 10000-fold greater inhibition of EGFR containing one or more mutations as described herein relative to inhibition of wild type EGFR. In other embodiments, a compound of Formula (I) (e.g., Formula (I-a), (I-a1), (I- a2), (I-a3), (I-a4), (I-a5), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-g1), (I-g1-1), (I-g1-2),or (I-h)), or a pharmaceutically acceptable salt thereof, in combination with a second EGFR inhibitor can exhibit greater inhibition of EGFR containing one or more mutations as described herein (e.g., one or more mutations as described in Table 1a and 1b) relative to inhibition of wild type EGFR. In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, in combination with a second EGFR inhibitor can exhibit at least 2-fold, 3-fold, 5-fold, 10-fold, 25-fold, 50-fold or 100-fold greater inhibition of EGFR containing one or more mutations as described herein relative to inhibition of wild type EGFR. In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, in combination with a second EGFR inhibitor can exhibit up to 1000-fold greater inhibition of EGFR containing one or more mutations as described herein relative to inhibition of wild type EGFR. In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, in combination with a second EGFR inhibitor can exhibit up to 10000-fold greater inhibition of EGFR having a combination of mutations described herein relative to inhibition of wild type EGFR. In other embodiments, a compound of Formula (I) (e.g., Formula (I-a), (I-a1), (I- a2), (I-a3), (I-a4), (I-a5), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-g1), (I-g1-1), (I-g1-2),or (I-h)), or a pharmaceutically acceptable salt thereof, in combination with a second EGFR inhibitor can exhibit from about 2-fold to about 10-fold greater inhibition of EGFR containing one or more mutations as described herein relative to inhibition of wild type EGFR. In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, in combination with a second EGFR inhibitor can exhibit from about 10-fold to about 100-fold greater inhibition of EGFR containing one or more mutations as described herein relative to inhibition of wild type EGFR. In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, in combination with a second EGFR inhibitor can exhibit from about 100-fold to about 1000-fold greater inhibition of EGFR containing one or more mutations as described herein relative to inhibition of wild type EGFR. In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, in combination with a second EGFR inhibitor can exhibit from about 1000-fold to about 10000-fold greater inhibition of EGFR containing one or more mutations as described herein relative to inhibition of wild type EGFR. Compounds of Formula (I) (e.g., Formula (I-a), (I-a1), (I-a2), (I-a3), (I-a4), (I- a5), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-g1), (I-g1-1), (I-g1-2),or (I-h)), or pharmaceutically acceptable salts or solvates thereof, are useful for treating diseases and disorders which can be treated with an EGFR inhibitor, such as EGFR-associated diseases and disorders, e.g., central nervous system diseases (e.g., neurodegenerative diseases), pulmonary disorders, cardiovascular disease, ischemia, liver disease, gastrointestinal disorders, viral or bacterial infections, inflammatory and/or autoimmune diseases (e.g., psoriasis and atopic dermatitis), and proliferative disorders such as cancers, including hematological cancers and solid tumors (e.g., advanced solid tumors). A “HER2 inhibitor” as used herein includes any compound exhibiting HER2 inactivation activity (e.g., inhibiting or decreasing). In some embodiments, a HER2 inhibitor can be selective for a HER2 kinase having one or more mutations. In some embodiments, a HER2 inhibitor can bind to the HER2 adenosine triphosphate (ATP)- binding site in the tyrosine kinase domain. The compounds provided herein can inhibit HER2. For example, the compounds can bind to the HER2 adenosine triphosphate (ATP)-binding site in the tyrosine kinase domain. In some embodiments, the compounds provided herein can inhibit wild type HER2. In some embodiments, the compounds provided herein can inhibit HER2 having one or more mutations as described herein. The ability of test compounds to act as inhibitors of HER2 may be demonstrated by assays known in the art. The activity of the compounds or compositions provided herein as HER2 inhibitors can be assayed in vitro, in vivo, or in a cell line. In vitro assays include assays that determine inhibition of the kinase and/or ATPase activity. Alternate in vitro assays quantitate the ability of the inhibitor to bind to the protein kinase and can be measured either by radio labelling the compound prior to binding, isolating the compound/kinase complex and determining the amount of radio label bound, or by running a competition experiment where new compounds are incubated with the kinase bound to known radioligands. In some cases, a HER2 inhibitor can be evaluated by its effect on the initial velocity of HER2 tyrosine kinase catalyzed peptide phosphorylation (e.g., Yun et al. Cancer Cell. 2007;11(3):217–227). For example, an assay that indirectly measures ADP formed from the HER2 kinase reaction can be used (see, e.g., ATP/NADH coupled assay systems and luminescent kinase assays such as ADP-GLO^TM Kinase Assay from Promega). See, e.g., Hanker et al. Cancer Discov.2017 Jun;7(6):575-585; Robichaux et al. Nat Med. 2018 May; 24(5): 638–646; and Yun et al. Proc Natl Acad Sci U S A. 2008 Feb 12;105(6):2070-5. In some embodiments, an assay that detects substrate phosphorylation using a labeled anti-phospho-tyrosine antibody can be used (see, e.g., Rabindran et al. Cancer Res.2004 Jun 1;64(11):3958-65). In some embodiments, the binding constant of a HER2 inhibitor can be determined using fluorescence kinetics (e.g., Yun et al. Cancer Cell. 2007;11(3):217–227). Examples of SPR binding assays include those disclosed in Li, Shiqing, et al. Cancer cell 7.4 (2005): 301-311. In some embodiments, covalent binding of a HER2 inhibitor to HER2 can be detected using mass spectrometry, see, e.g., Irie et al. Mol Cancer Ther. 2019 Apr;18(4):733-742. Additional HER2 inhibitor assays can be found, for example, in U.S. Patent No.9,920,060, WO 2019/241715, and U.S. Publication No.2017/0166598, each of which are incorporated by reference in their entireties. Potency of a HER2 inhibitor as provided herein can be determined by EC50 value. A compound with a lower EC50 value, as determined under substantially similar conditions, is a more potent inhibitor relative to a compound with a higher EC₅₀ value. In some embodiments, the substantially similar conditions comprise determining an HER2- dependent phosphorylation level, in vitro or in vivo (e.g., in tumor cells or Ba/F3 cells expressing a wild type HER2, a mutant HER2, or a fragment of any thereof). Potency of an HER2 inhibitor as provided herein can also be determined by IC₅₀ value. A compound with a lower IC₅₀ value, as determined under substantially similar conditions, is a more potent inhibitor relative to a compound with a higher IC₅₀ value. In some embodiments, the substantially similar conditions comprise determining an HER2- dependent phosphorylation level, in vitro or in vivo (e.g., in tumor cells or Ba/F3 cells expressing a wild type HER2, a mutant HER2, or a fragment of any thereof). Assays can include, for example, proliferation inhibition assays such as those that measure cell growth inhibition, such as an MTS assay or by Cell Titer Glo Luminescent Cell viability assay (Promega®). To perform such an assay, cells are seeded and grown in cell culture plates before being exposed to a test compound for varying durations. Assessment of the viability of the cells following this exposure is then performed. Data are normalized with respect to untreated cells and can be displayed graphically. Growth curves can be fitted using a nonlinear regression model with sigmoidal dose response. As another example, a Western Blot analysis can be used. In such assays cells are seeded and grown in culture plates and then treated with a test compound the following day for varying durations. Cells are washed with PBS and lysed. SDS-PAGE gels are used to separate the lysates which are transferred to nitrocellulose membranes, and probed with appropriate antibodies (e.g., phospho-HER2(Tyr1248)(2247), phospho-EGFR-Tyr1173 phospho- HER2-Tyr877, phospho-HER2-Tyr1221, total HER2, phospho-AKT-Thr308, phospho- AKT-Ser374, total AKT, phospho-p44/42 MAPK-Thr202/Tyr204, and p44/42 MAPK). The selectivity between wild type HER2 and HER2 containing one or more mutations as described herein can also be measured using cellular proliferation assays where cell proliferation is dependent on kinase activity. For example, murine Ba/F3 cells transfected with a suitable version of wild type HER2, or Ba/F3 cells transfected with HER2 having one or more mutations such as S310F, S310Y, R678Q, R678W, R678P, I767M, V773M, V777L, V842I, M774AYVM, M774del insWLV, A775_G776insYVMA, A775_G776insAVMA, A775_G776insSVMA, A775_G776insVAG, A775insV G776C, A775_G776insI, G776del insVC2, G776del insVV, G776del insLC, G776C V777insC, G776C V777insV, V777_G778insCG, G778_S779insCPG, or P780_Y781insGSP can be used. Proliferation assays are performed at a range of inhibitor concentrations (e.g., 10 μM, 3 μM, 1.1 μM, 330 nM, 110 nM, 33 nM, 11 nM, 3 nM, 1 nM) and an EC50 is calculated. An alternative method to measure effects on HER2 activity is to assay HER2 phosphorylation. Wildtype or mutant (S310F, S310Y, R678Q, R678W, R678P, I767M, V773M, V777L, V842I, M774AYVM, M774del insWLV, A775_G776insYVMA, A775_G776insAVMA, A775_G776insSVMA, A775_G776insVAG, A775insV G776C, A775_G776insI, G776del insVC2, G776del insVV, G776del insLC, G776C V777insC, G776C V777insV, V777_G778insCG, G778_S779insCPG, or P780_Y781insGSP) HER2 can be transfected into cells which do not normally express endogenous HER2 and the ability of the inhibitor (e.g., using concentrations as above) to inhibit HER2 phosphorylation can be assayed. Cells are exposed to increasing concentrations of inhibitor and stimulated with EGF. The effects on HER2 phosphorylation are assayed by Western Blotting using phospho-specific HER2 antibodies. In some embodiments, the compounds provided herein can exhibit potent and selective inhibition of HER2. For example, the compounds provided herein can bind to the HER2 adenosine triphosphate (ATP)-binding site in the tyrosine kinase domain. In some embodiments, the compounds provided herein can exhibit nanomolar potency against a HER2 kinase including an activating mutation or a HER2 inhibitor resistance mutation, including, for example, exon 20 insertions and/or the resistance mutations in Table 5 (e.g., L755S, L755P, T798I, and T798M), with minimal activity against related kinases (e.g., wild type EGFR). In some embodiments, the compounds of Formula (I) (e.g., Formula (I-a), (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-g1), (I-g1-1), (I-g1-2),or (I-h)), or a pharmaceutically acceptable salt thereof, can selectively target a HER2 kinase. For example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can selectively target a HER2 kinase over another kinase (e.g., wild type EGFR) or non- kinase target. It can be desireable to selectively target a HER2 kinase over a wild type EGFR kinase due to undesireable side effects (e.g., diarrhea and skin rashes) that can impact quality of life and compliance. See, e.g., Morphy. J. Med. Chem.2010, 53, 4, 1413– 1437 and Peters. J. Med. Chem.2013, 56, 22, 8955–8971. In some embodiments, a compound of Formula (I) (e.g., Formula (I-a), (I-a1), (I- a2), (I-a3), (I-a4), (I-a5), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-g1), (I-g1-1), (I-g1-2),or (I-h)), or a pharmaceutically acceptable salt thereof, can exhibit greater inhibition of wild type HER2 or HER2 containing one or more mutations as described herein (e.g., one or more mutations as described in Table 3) relative to inhibition of another kinase (e.g., wild type EGFR) or non-kinase target. In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof can exhibit at least 2-fold, 3-fold, 5-fold, 10-fold, 25-fold, 50-fold or 100-fold greater inhibition of wild type HER2 or HER2 containing one or more mutations as described herein relative to inhibition of another kinase (e.g., wild type EGFR) or non-kinase target. In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can exhibit up to 1000-fold greater inhibition of wild type HER2 or HER2 containing one or more mutations as described herein relative to inhibition of another kinase (e.g., wild type EGFR) or non-kinase target. In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can exhibit up to 10000-fold greater inhibition of wild type HER2 or HER2 having a combination of mutations described herein relative to inhibition of another kinase (e.g., wild type EGFR) or non-kinase target. In some embodiments, a compound of Formula (I) (e.g., Formula (I-a), (I-a1), (I- a2), (I-a3), (I-a4), (I-a5), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-g1), (I-g1-1), (I-g1-2),or (I-h)), or a pharmaceutically acceptable salt thereof, can exhibit from about 2-fold to about 10-fold greater inhibition of wild type HER2 or HER2 containing one or more mutations as described herein relative to inhibition of another kinase (e.g., wild type EGFR) or non- kinase target. In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can exhibit from about 10-fold to about 100-fold greater inhibition of wild type HER2 or containing one or more mutations as described herein relative to inhibition of another kinase (e.g., wild type EGFR) or non-kinase target. In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can exhibit from about 100-fold to about 1000-fold greater inhibition of wild type HER2 or HER2 containing one or more mutations as described herein relative to inhibition of another kinase (e.g., wild type EGFR) or non-kinase target. In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can exhibit from about 1000-fold to about 10000-fold greater inhibition of wild type HER2 or HER2 containing one or more mutations as described herein relative to inhibition of another kinase (e.g., wild type EGFR) or non-kinase target. In other embodiments, a compound of Formula (I) (e.g., Formula (I-a), (I-a1), (I- a2), (I-a3), (I-a4), (I-a5), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-g1), (I-g1-1), (I-g1-2),or (I-h)), or a pharmaceutically acceptable salt thereof, in combination with a second EGFR inhibitor can exhibit greater inhibition of wild type HER2 or HER2 containing one or more mutations as described herein (e.g., one or more mutations as described in Table 3) relative to inhibition of another kinase (e.g., wild type EGFR) or non-kinase target. In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, in combination with a second HER2 inhibitor can exhibit at least 2-fold, 3-fold, 5-fold, 10- fold, 25-fold, 50-fold or 100-fold greater inhibition of wild type HER2 or HER2 containing one or more mutations as described herein relative to inhibition of another kinase (e.g., wild type EGFR) or non-kinase target. In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, in combination with a second HER2 inhibitor can exhibit up to 1000-fold greater inhibition of wild type HER2 or HER2 containing one or more mutations as described herein relative to inhibition of another kinase (e.g., wild type EGFR) or non-kinase target. In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, in combination with a second HER2 inhibitor can exhibit up to 10000-fold greater inhibition of wild type HER2 or HER2 having a combination of mutations described herein relative to inhibition of another kinase (e.g., wild type EGFR) or non-kinase target. In other embodiments, a compound of Formula (I) (e.g., Formula (I-a), (I-a1), (I- a2), (I-a3), (I-a4), (I-a5), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-g1), (I-g1-1), (I-g1-2),or (I-h)), or a pharmaceutically acceptable salt thereof, in combination with a second HER2 inhibitor can exhibit from about 2-fold to about 10-fold greater inhibition of wild type HER2 or HER2 containing one or more mutations as described herein relative to inhibition of another kinase (e.g., wild type EGFR) or non-kinase target. In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, in combination with a second HER2 inhibitor can exhibit from about 10-fold to about 100-fold greater inhibition of wild type HER2 or HER2 containing one or more mutations as described herein relative to inhibition of another kinase (e.g., wild type EGFR) or non-kinase target. In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, in combination with a second HER2 inhibitor can exhibit from about 100-fold to about 1000-fold greater inhibition of wild type HER2 or HER2 containing one or more mutations as described herein relative to inhibition of another kinase (e.g., wild type EGFR) or non-kinase target. In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, in combination with a second HER2 inhibitor can exhibit from about 1000-fold to about 10000-fold greater inhibition of wild type HER2 or HER2 containing one or more mutations as described herein relative to inhibition of another kinase (e.g., wild type EGFR) or non-kinase target. Compounds of Formula (I) (e.g., Formula (I-a), (I-a1), (I-a2), (I-a3), (I-a4), (I- a5), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-g1), (I-g1-1), (I-g1-2),or (I-h)), or pharmaceutically acceptable salts or solvates thereof, are useful for treating diseases and disorders which can be treated with a HER2 inhibitor, such as HER2-associated diseases and disorders, e.g., proliferative disorders such as cancers (e.g., a HER2-associated cancer), including hematological cancers and solid tumors (e.g., advanced solid tumors). In some embodiments, the compounds provided herein can also inhibit EGFR and HER2 as described herein. In some embodiments, the compounds provided herein can exhibit potent and selective inhibition of EGFR and HER2. In some embodiments, the compounds provided herein can exhibit nanomolar potency against an EGFR kinase having one or more mutations, including, for example, one or more of the mutations in Tables 1a, 1b and 2a, 2b , and a HER2 kinase having one or more mutations, including, for example, the mutations in Table 3, with minimal activity against related kinases (e.g., wild type EGFR). In some embodiments, the compounds of Formula (I) (e.g., Formula (I-a), (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-g1), (I-g1-1), (I-g1-2),or (I-h)), or a pharmaceutically acceptable salt thereof, can selectively target an EGFR and a HER2 kinase. For example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can selectively target an EGFR kinase and a HER2 kinase over another kinase or non-kinase target. In some embodiments, a compound of Formula (I) (e.g., Formula (I-a), (I-a1), (I- a2), (I-a3), (I-a4), (I-a5), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-g1), (I-g1-1), (I-g1-2),or (I-h)), or a pharmaceutically acceptable salt thereof, can exhibit greater inhibition of EGFR containing one or more mutations as described herein and wild type HER2 or HER2 containing one or more mutations as described herein (e.g., one or more mutations as described in Tables 3-5) relative to inhibition of another kinase (e.g., wild type EGFR) or non-kinase target. In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof can exhibit at least 2-fold, 3-fold, 5-fold, 10-fold, 25-fold, 50-fold or 100-fold greater inhibition of EGFR containing one or more mutations as described herein and wild type HER2 or HER2 containing one or more mutations as described herein relative to inhibition of another kinase (e.g., wild type EGFR) or non- kinase target. In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can exhibit up to 1000-fold greater inhibition of EGFR containing one or more mutations as described herein and wild type HER2 or HER2 containing one or more mutations as described herein relative to inhibition of another kinase (e.g., wild type EGFR) or non-kinase target. In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can exhibit up to 10000-fold greater inhibition of EGFR containing one or more mutations as described herein and wild type HER2 or HER2 having one or more mutations described herein relative to inhibition of another kinase (e.g., wild type EGFR) or non-kinase target. In some embodiments, a compound of Formula (I) (e.g., Formula (I-a), (I-a1), (I- a2), (I-a3), (I-a4), (I-a5), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-g1), (I-g1-1), (I-g1-2),or (I-h)), or a pharmaceutically acceptable salt thereof, can exhibit from about 2-fold to about 10-fold greater inhibition of EGFR containing one or more mutations as described herein and wild type HER2 or HER2 containing one or more mutations as described herein relative to inhibition of another kinase (e.g., wild type EGFR) or non-kinase target. In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can exhibit from about 10-fold to about 100-fold greater inhibition of EGFR containing one or more mutations as described herein and wild type HER2 or HER2 containing one or more mutations as described herein relative to inhibition of another kinase (e.g., wild type EGFR) or non-kinase target. In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can exhibit from about 100-fold to about 1000- fold greater inhibition of EGFR containing one or more mutations as described herein and wild type HER2 or HER2 containing one or more mutations as described herein relative to inhibition of another kinase (e.g., wild type EGFR) or non-kinase target. In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can exhibit from about 1000-fold to about 10000-fold greater inhibition of EGFR containing one or more mutations as described herein and wild type HER2 or HER2 containing one or more mutations as described herein relative to inhibition of another kinase (e.g., wild type EGFR) or non-kinase target. In other embodiments, a compound of Formula (I) (e.g., Formula (I-a), (I-a1), (I- a2), (I-a3), (I-a4), (I-a5), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-g1), (I-g1-1), (I-g1-2),or (I-h)), or a pharmaceutically acceptable salt thereof, in combination with a second EGFR and/or second HER2 inhibitor can exhibit greater inhibition of EGFR containing one or more mutations as described herein and wild type HER2 or HER2 containing one or more mutations as described herein (e.g., one or more mutations as described in Table 3) relative to inhibition of another kinase (e.g., wild type EGFR) or non-kinase target. In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, in combination with a second EGFR and/or second HER2 inhibitor can exhibit at least 2- fold, 3-fold, 5-fold, 10-fold, 25-fold, 50-fold or 100-fold greater inhibition of EGFR containing one or more mutations as described herein and wild type HER2 or HER2 containing one or more mutations as described herein relative to inhibition of another kinase (e.g., wild type EGFR) or non-kinase target. In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, in combination with a second EGFR and/or second HER2 inhibitor can exhibit up to 1000-fold greater inhibition of EGFR containing one or more mutations as described herein and wild type HER2 or HER2 containing one or more mutations as described herein relative to inhibition of another kinase (e.g., wild type EGFR) or non-kinase target. In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, in combination with a second EGFR and/or HER2 inhibitor can exhibit up to 10000-fold greater inhibition of EGFR containing one or more mutations as described herein and wild type HER2 or HER2 having a combination of mutations described herein relative to inhibition of another kinase (e.g., wild type EGFR) or non-kinase target. In other embodiments, a compound of Formula (I) (e.g., Formula (I-a), (I-a1), (I- a2), (I-a3), (I-a4), (I-a5), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-g1), (I-g1-1), (I-g1-2),or (I-h)), or a pharmaceutically acceptable salt thereof, in combination with a second EGFR and/or second HER2 inhibitor can exhibit from about 2-fold to about 10-fold greater inhibition of EGFR containing one or more mutations as described herein and HER2 containing one or more mutations as described herein relative to inhibition of another kinase (e.g., wild type EGFR) or non-kinase target. In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, in combination with a second EGFR and/or second HER2 inhibitor can exhibit from about 10-fold to about 100-fold greater inhibition of EGFR containing one or more mutations as described herein and HER2 containing one or more mutations as described herein relative to inhibition of another kinase (e.g., wild type EGFR) or non-kinase target. In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, in combination with a second EGFR and/or second HER2 inhibitor can exhibit from about 100-fold to about 1000-fold greater inhibition of EGFR containing one or more mutations as described herein and second HER2 containing one or more mutations as described herein relative to inhibition of another kinase (e.g., wild type EGFR) or non-kinase target. In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, in combination with a second EGFR and/or second HER2 inhibitor can exhibit from about 1000-fold to about 10000-fold greater inhibition of EGFR containing one or more mutations as described herein and HER2 containing one or more mutations as described herein relative to inhibition of another kinase (e.g., wild type EGFR) or non-kinase target. Also provided herein are methods for inhibiting a BUB (budding uninhibited by benzimidazole, BUB1-3) kinase. For example, provided herein are inhibitors of BUB1 kinase useful for treating or preventing diseases or disorders associated with enhanced uncontrolled proliferative cellular processes such as, for example, cancer, inflammation, arthritis, viral diseases, cardiovascular diseases, or fungal diseases. See, for example, WO 2013/050438, WO 2013/092512, WO 2013/167698, WO 2014/147203, WO 2014/147204, WO 2014/202590, WO 2014/202588, WO 2014/202584, WO 2014/202583, WO 2015/063003, WO2015/193339, WO 2016/202755, and WO 2017/021348. In some embodiments, the disease or disorder is cancer. A “BUB1 inhibitor” as used herein includes any compound exhibiting BUB1 inactivation activity (e.g., inhibiting or decreasing). In some embodiments, a BUB1 inhibitor can be selective for BUB1 over other kinases (e.g., wildtype EGFR). The compounds provided herein can inhibit a Bub kinase. In some embodiments, the compounds provided herein can inhibit BUB1 kinase. The ability of test compounds to act as inhibitors of BUB1 may be demonstrated by assays known in the art. The activity of the compounds and compositions provided herein as BUB1 inhibitors can be assayed in vitro, in vivo, or in a cell line. In vitro assays include assays that determine inhibition of the kinase. For example, BUB1 inhibition of a compound provided herein can be determined using a time-resolved fluorescence energy transfer (TR-FRET) assay which measures phosphorylation of a synthetic peptide (e.g., Biotin-AHX-VLLPKKSFAEPG (C-terminus in amide form) by the (recombinant) catalytic domain of human BUB1 (amino acids 704-1085), expressed in Hi5 insect cells with an N-terminal His6-tag and purified by affinity- (Ni-NTA) and size exclusion chromatography. See, for example, WO 2017/021348. In addition, BUB1 activity can be determined at a high ATP concentration using a BUB1 TR-FRET high ATP kinase assay using similar methods as those described above. See, e.g. WO 2019/081486. In some embodiments, the compounds provided herein exhibit central nervous system (CNS) penetrance. For example, such compounds can be capable of crossing the blood brain barrier (BBB) and inhibiting an EGFR and/or HER2 kinase in the brain and/or other CNS structures. In some embodiments, the compounds provided herein are capable of crossing the blood brain barrier in a therapeutically effective amount. For example, treatment of a patient with cancer (e.g., an EGFR-associated cancer or a HER2-associated cancer such as an EGFR- or HER2-associated brain or CNS cancer or an EGFR-associated or a HER2-associated cancer that has metastasized to the brain or CNS) can include administration (e.g., oral administration) of the compound to the patient. The ability of the compounds described herein, to cross the BBB can be demonstrated by assays known in the art. Such assays include BBB models such as the transwell system, the hollow fiber (dynamic in vitro BBB) model, other microfluidic BBB systems, the BBB spheroid platform, and other cell aggregate-based BBB models. See, e.g., Cho et al. Nat Commun.2017; 8: 15623; Bagchi et al. Drug Des Devel Ther.2019; 13: 3591–3605; Gastfriend et al. Curr Opin Biomed Eng.2018 Mar; 5: 6–12; and Wang et al. Biotechnol Bioeng.2017 Jan; 114(1): 184–194. In some embodiments, the compounds described herein, are fluorescently labeled, and the fluorescent label can be detected using microscopy (e.g., confocal microscopy). In some such embodiments, the ability of the compound to penetrate the surface barrier of the model can be represented by the fluorescence intensity at a given depth below the surface. In some assays, such as a calcein- AM-based assay, the fluorescent label is non-fluorescent until it permeates live cells and is hydrolyzed by intracellular esterases to produce a fluorescent compound that is retained in the cell and can be quantified with a spectrophotometer. Non-limiting examples of fluorescent labels that can be used in the assays described herein include Cy5, rhodamine, infrared IRDye® CW-800 (LICOR #929-71012), far-red IRDye® 650 (LICOR #929- 70020), sodium fluorescein (Na-F), lucifer yellow (LY), 5’carboxyfluorescein, and calcein-acetoxymethylester (calcein-AM). In some embodiments, the BBB model (e.g., the tissue or cell aggregate) can be sectioned, and a compound described herein can be detected in one or more sections using mass spectrometry (e.g., MALDI-MSI analyses). In some embodiments, the ability of a compound described herein to cross the BBB through a transcellular transport system, such as receptor-mediated transport (RMT), carrier- mediated transport (CMT), or active efflux transport (AET), can be demonstrated by assays known in the art. See, e.g., Wang et al. Drug Deliv. 2019; 26(1): 551–565. In some embodiments, assays to determine if compounds can be effluxed by the P-glycoprotein (Pgp) include monolayer efflux assays in which movement of compounds through Pgp is quantified by measuring movement of digoxin, a model Pgp substrate (see, e.g., Doan et al.2002. J Pharmacol Exp Ther.303(3):1029-1037). Alternative in vivo assays to identify compounds that pass through the blood-brain barriers include phage-based systems (see, e.g., Peng et al. 2019. ChemRxiv. Preprint doi.org/10.26434/chemrxiv.8242871.v1). In some embodiments, binding of the compounds described herein to brain tissue is quantified. For example, a brain tissue binding assay can be performed using equilibrium dialysis, and the fraction of a compound described herein unbound to brain tissue can be detected using LC-MS/MS (Cyprotex: Brain Tissue Binding Assay www.cyprotex.com/admepk/protein_binding/brain-tissue-binding/). Compounds of Formula (I) (e.g., Formula (I-a), (I-a1), (I-a2), (I-a3), (I-a4), (I- a5), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-g1), (I-g1-1), (I-g1-2),or (I-h)), or pharmaceutically acceptable salts or solvates thereof, are useful for treating diseases and disorders which can be treated with an EGFR inhibitor, a HER2 inhibitor, a dual EGFR and HER2 inhibitor, and/or a BUB1 inhibitor, such as those described herein, e.g., cancer. Accordingly, provided herein is a method for treating a disease or disorder as provided herein in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the disease or disorder is cancer. As used herein, terms "treat" or "treatment" refer to therapeutic or palliative measures. Beneficial or desired clinical results include, but are not limited to, alleviation, in whole or in part, of symptoms associated with a disease or disorder or condition, diminishment of the extent of disease, stabilized (i.e., not worsening) state of disease, delay or slowing of disease progression, amelioration or palliation of the disease state (e.g., one or more symptoms of the disease), and remission (whether partial or total), whether detectable or undetectable. "Treatment" can also mean prolonging survival as compared to expected survival if not receiving treatment. As used herein, the terms "subject," "individual," or "patient," are used interchangeably, refers to any animal, including mammals such as mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses, primates, and humans. In some embodiments, the subject is a human. In some embodiments, the subject has experienced and/or exhibited at least one symptom of the disease or disorder to be treated and/or prevented. In some embodiments, the subject has been identified or diagnosed as having a cancer with a dysregulation of an EGFR gene, an EGFR protein, or expression or activity, or level of any of the same (an EGFR-associated cancer) (e.g., as determined using a regulatory agency-approved, e.g., FDA-approved, assay or kit). In some embodiments, the subject has a tumor that is positive for a dysregulation of an EGFR gene, an EGFR protein, or expression or activity, or level of any of the same (e.g., as determined using a regulatory agency-approved assay or kit). For example, the subject has a tumor that is positive for a mutation as described in Table 1a and 1b. The subject can be a subject with a tumor(s) that is positive for a dysregulation of an EGFR gene, an EGFR protein, or expression or activity, or level of any of the same (e.g., identified as positive using a regulatory agency-approved, e.g., FDA-approved, assay or kit). The subject can be a subject whose tumors have a dysregulation of an EGFR gene, an EGFR protein, or expression or activity, or a level of the same (e.g., where the tumor is identified as such using a regulatory agency-approved, e.g., FDA-approved, kit or assay). In some embodiments, the subject is suspected of having an EGFR-associated cancer. In some embodiments, the subject has a clinical record indicating that the subject has a tumor that has a dysregulation of an EGFR gene, an EGFR protein, or expression or activity, or level of any of the same (and optionally the clinical record indicates that the subject should be treated with any of the compositions provided herein). In some embodiments, the subject has been identified or diagnosed as having a cancer with a dysregulation of a HER2 gene, a HER2 protein, or expression or activity, or level of any of the same (a HER2-associated cancer) (e.g., as determined using a regulatory agency-approved, e.g., FDA-approved, assay or kit). In some embodiments, the subject has a tumor that is positive for a dysregulation of a HER2 gene, a HER2 protein, or expression or activity, or level of any of the same (e.g., as determined using a regulatory agency- approved assay or kit). For example, the subject has a tumor that is positive for a mutation as described in Table 3. The subject can be a subject with a tumor(s) that is positive for a dysregulation of a HER2 gene, a HER2 protein, or expression or activity, or level of any of the same (e.g., identified as positive using a regulatory agency-approved, e.g., FDA- approved, assay or kit). The subject can be a subject whose tumors have a dysregulation of a HER2 gene, a HER2 protein, or expression or activity, or a level of the same (e.g., where the tumor is identified as such using a regulatory agency-approved, e.g., FDA-approved, kit or assay). In some embodiments, the subject is suspected of having a HER2-associated cancer. In some embodiments, the subject has a clinical record indicating that the subject has a tumor that has a dysregulation of a HER2 gene, a HER2 protein, or expression or activity, or level of any of the same (and optionally the clinical record indicates that the subject should be treated with any of the compositions provided herein). In some embodiments, the subject is a pediatric subject. The term “pediatric subject” as used herein refers to a subject under the age of 21 years at the time of diagnosis or treatment. The term “pediatric” can be further be divided into various subpopulations including: neonates (from birth through the first month of life); infants (1 month up to two years of age); children (two years of age up to 12 years of age); and adolescents (12 years of age through 21 years of age (up to, but not including, the twenty-second birthday)). Berhman RE, Kliegman R, Arvin AM, Nelson WE. Nelson Textbook of Pediatrics, 15th Ed. Philadelphia: W.B. Saunders Company, 1996; Rudolph AM, et al. Rudolph’s Pediatrics, 21st Ed. New York: McGraw-Hill, 2002; and Avery MD, First LR. Pediatric Medicine, 2nd Ed. Baltimore: Williams & Wilkins; 1994. In some embodiments, a pediatric subject is from birth through the first 28 days of life, from 29 days of age to less than two years of age, from two years of age to less than 12 years of age, or 12 years of age through 21 years of age (up to, but not including, the twenty-second birthday). In some embodiments, a pediatric subject is from birth through the first 28 days of life, from 29 days of age to less than 1 year of age, from one month of age to less than four months of age, from three months of age to less than seven months of age, from six months of age to less than 1 year of age, from 1 year of age to less than 2 years of age, from 2 years of age to less than 3 years of age, from 2 years of age to less than seven years of age, from 3 years of age to less than 5 years of age, from 5 years of age to less than 10 years of age, from 6 years of age to less than 13 years of age, from 10 years of age to less than 15 years of age, or from 15 years of age to less than 22 years of age. In certain embodiments, compounds of Formula (I) (e.g., Formula (I-a), (I-a1), (I- a2), (I-a3), (I-a4), (I-a5), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-g1), (I-g1-1), (I-g1-2),or (I-h)), or pharmaceutically acceptable salts or solvates thereof, are useful for preventing diseases and disorders as defined herein (for example, autoimmune diseases, inflammatory diseases, pulmonary disorders, cardiovascular disease, ischemia, liver disease, gastrointestinal disorders, viral or bacterial infections, central nervous system diseases (e.g., neurodegenerative diseases), and cancer). The term "preventing” as used herein means to delay the onset, recurrence or spread, in whole or in part, of the disease or condition as described herein, or a symptom thereof. The term "EGFR-associated disease or disorder" as used herein refers to diseases or disorders associated with or having a dysregulation of an EGFR gene, an EGFR kinase (also called herein an EGFR kinase protein), or the expression or activity or level of any (e.g., one or more) of the same (e.g., any of the types of dysregulation of an EGFR gene, an EGFR kinase, an EGFR kinase domain, or the expression or activity or level of any of the same described herein). Non-limiting examples of an EGFR-associated disease or disorder include, for example, cancer, a central nervous system disease, a pulmonary disorder, cardiovascular disease, ischemia, liver disease, a gastrointestinal disorder, a viral or bacterial infection, and an inflammatory and/or autoimmune disease (e.g., psoriasis, eczema, atopic dermatitis, and atherosclerosis). In some embodiments of any of the methods or uses described herein, the inflammatory and/or autoimmune disease is selected from arthritis, systemic lupus erythematosus, atherosclerosis, and skin related disorders such as psoriasis, eczema, and atopic dermatitis. See, e.g., Wang et al. Am J Transl Res.2019; 11(2): 520–528; Starosyla et al. World J Pharmacol. Dec 9, 2014; 3(4): 162-173; Choi et al. Biomed Res Int.2018 May 15;2018:9439182; and Wang et al. Sci Rep.2017; 7: 45917. In some embodiments of any of the methods or uses described herein, the central nervous system disease is a neurodegenerative disease. In some embodiments, the central nervous system disease is selected from Alzheimer's disease, Parkinson's disease, Huntington’s disease, amyotrophic lateral sclerosis, spinal cord injury, peripheral neuropathy, brain ischemia, and a psychiatric disorder such as schizophrenia. See, e.g., Iwakura and Nawa. Front Cell Neurosci..2013 Feb 13;7:4; and Chen et al. Sci Rep.2019 Feb 21;9(1):2516. The term “EGFR-associated cancer” as used herein refers to cancers associated with or having a dysregulation of an EGFR gene, an EGFR kinase (also called herein an EGFR kinase protein), or expression or activity, or level of any of the same. Non-limiting examples of an EGFR-associated cancer are described herein. The phrase “dysregulation of an EGFR gene, an EGFR kinase, or the expression or activity or level of any of the same” refers to a genetic mutation (e.g., a mutation in an EGFR gene that results in the expression of an EGFR protein that includes a deletion of at least one amino acid as compared to a wild type EGFR protein, a mutation in an EGFR gene that results in the expression of an EGFR protein with one or more point mutations as compared to a wild type EGFR protein, a mutation in an EGFR gene that results in the expression of an EGFR protein with at least one inserted amino acid as compared to a wild type EGFR protein, a gene duplication that results in an increased level of EGFR protein in a cell, or a mutation in a regulatory sequence (e.g., a promoter and/or enhancer) that results in an increased level of EGFR protein in a cell), an alternative spliced version of an EGFR mRNA that results in an EGFR protein having a deletion of at least one amino acid in the EGFR protein as compared to the wild type EGFR protein), or increased expression (e.g., increased levels) of a wild type EGFR kinase in a mammalian cell due to aberrant cell signaling and/or dysregulated autocrine/paracrine signaling (e.g., as compared to a control non-cancerous cell). As another example, a dysregulation of an EGFR gene, an EGFR protein, or expression or activity, or level of any of the same, can be a mutation in an EGFR gene that encodes an EGFR protein that is constitutively active or has increased activity as compared to a protein encoded by an EGFR gene that does not include the mutation. Non-limiting examples of EGFR kinase protein point mutations/insertions/deletions are described in Table 1a and 1b. Additional examples of EGFR kinase protein mutations (e.g., point mutations) are EGFR inhibitor resistance mutations (e.g., EGFR inhibitor mutations). Non-limiting examples of EGFR inhibitor resistance mutations are described in Table 2a and 2b. For example, the one or more EGFR inhibitor resistance mutations can include a substitution at amino acid position 718, 747, 761, 790, 797, or 854 (e.g., L718Q, L747S, D761Y, T790M, C797S, or T854A). Such mutation and overexpression is associated with the development of a variety of cancers (Shan et al., Cell 2012, 149(4) 860-870). In some embodiments, dysregulation of an EGFR gene, an EGFR kinase, or the expression or activity or level of any of the same can be caused by an activating mutation in an EGFR gene. In some embodiments, dysregulation of an EGFR gene, an EGFR kinase, or the expression or activity or level of any of the same can be caused by a genetic mutation that results in the expression of an EGFR kinase that has increased resistance to an EGFR inhibitor, a tyrosine kinase inhibitor (TKI), and/or a multi-kinase inhibitor (MKI), e.g., as compared to a wild type EGFR kinase (see, e.g., the amino acid substitutions in Table 2a and 2b). In some embodiments, dysregulation of an EGFR gene, an EGFR kinase, or the expression or activity or level of any of the same can be caused by a mutation in a nucleic acid encoding an altered EGFR protein (e.g., an EGFR protein having a mutation (e.g., a primary mutation)) that results in the expression of an altered EGFR protein that has increased resistance to inhibition by an EGFR inhibitor, a tyrosine kinase inhibitor (TKI), and/or a multi-kinase inhibitor (MKI), e.g., as compared to a wild type EGFR kinase (see, e.g., the amino acid substitutions in Table 2a and 2b). The exemplary EGFR kinase point mutations, insertions, and deletions shown in Tables 1a, 1b and 2a, 2b can be caused by an activating mutation and/or can result in the expression of an EGFR kinase that has increased resistance to an EGFR inhibitor), tyrosine kinase inhibitor (TKI), and/or a multi- kinase inhibitor (MKI). In some embodiments, the individual has two or more EGFR inhibitor resistance mutations that increase resistance of the cancer to a first EGFR inhibitor. For example, the individual can have two EGFR inhibitor resistance mutations. In some embodiments, the two mutations occur in the same EGFR protein. In some embodiments, the two mutations occur in separate EGFR proteins. In some embodiments, the individual can have three EGFR inhibitor resistance mutations. In some embodiments, the three mutations occur in the same EGFR protein. In some embodiments, the three mutations occur in separate EGFR proteins. For example, the individual has two or more EGFR inhibitor resistance mutations selected from Del 19/L718Q, Del 19/T790M, Del 19/L844V, Del 19/T790M/L718Q, Del/T790M/C797S, Del 19/T790M/L844V, L858R/L718Q, L858R/L844V, L858R/T790M, L858R/T790M/L718Q, L858R/T790M/C797S, and L858R/T790M/I941R, or any combination thereof; e.g., any two of the aforementioned EGFR inhibitor resistance mutations. The term “activating mutation” in reference to EGFR describes a mutation in an EGFR gene that results in the expression of an EGFR kinase that has an increased kinase activity, e.g., as compared to a wild type EGFR kinase, e.g., when assayed under identical conditions. For example, an activating mutation can be a mutation in an EGFR gene that results in the expression of an EGFR kinase that has one or more (e.g., two, three, four, five, six, seven, eight, nine, or ten) amino acid substitutions (e.g., any combination of any of the amino acid substitutions described herein) that has increased kinase activity, e.g., as compared to a wild type EGFR kinase, e.g., when assayed under identical conditions. In another example, an activating mutation can be a mutation in an EGFR gene that results in the expression of an EGFR kinase that has one or more (e.g., two, three, four, five, six, seven, eight, nine, or ten) amino acids deleted, e.g., as compared to a wild type EGFR kinase, e.g., when assayed under identical conditions. In another example, an activating mutation can be a mutation in an EGFR gene that results in the expression of an EGFR kinase that has at least one (e.g., at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 12, at least 14, at least 16, at least 18, or at least 20) amino acid inserted as compared to a wild type EGFR kinase, e.g., the exemplary wild type EGFR kinase described herein, e.g., when assayed under identical conditions. Additional examples of activating mutations are known in the art. The term "wild type" or "wild-type" describes a nucleic acid (e.g., an EGFR gene or an EGFR mRNA) or protein (e.g., an EGFR protein) sequence that is typically found in a subject that does not have a disease or disorder related to the reference nucleic acid or protein. The term "wild type EGFR" or "wild-type EGFR" describes an EGFR nucleic acid (e.g., an EGFR gene or an EGFR mRNA) or protein (e.g., an EGFR protein) that is found in a subject that does not have an EGFR-associated disease, e.g., an EGFR-associated cancer (and optionally also does not have an increased risk of developing an EGFR- associated disease and/or is not suspected of having an EGFR-associated disease), or is found in a cell or tissue from a subject that does not have an EGFR-associated disease, e.g., an EGFR-associated cancer (and optionally also does not have an increased risk of developing an EGFR-associated disease and/or is not suspected of having an EGFR- associated disease). Provided herein is a method of treating cancer (e.g., an EGFR-associated cancer) in a subject in need of such treatment, the method comprising administering to the subject a therapeutically effective amount of a compound of Formula (I) (e.g., Formula (I-a), (I- a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-g1), (I-g1-1), (I- g1-2),or (I-h)), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. For example, provided herein are methods for treating an EGFR- associated cancer in a subject in need of such treatment, the method comprising a) detecting a dysregulation of an EGFR gene, an EGFR kinase, or the expression or activity or level of any of the same in a sample from the subject; and b) administering a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof. In some embodiments, the dysregulation of an EGFR gene, an EGFR kinase, or the expression or activity or level of any of the same includes one or more EGFR kinase protein point mutations/insertions. Non-limiting examples of EGFR kinase protein point mutations/insertions/deletions are described in Table 1a and 1b. In some embodiments, the EGFR kinase protein point mutations/insertions/deletions are selected from the group consisting of G719S, G719C, G719A, L747S, D761Y, T790M, T854A, L858R, L861Q, a deletion in exon 19 (e.g., L747_A750del), and an insertion in exon 20 (e.g., V769_D770insX, D770_N771insX, N771_P772insX, P772_H773insX, or H773_V774insX). In some embodiments, the EGFR kinase protein point mutations/insertions/deletions are selected from the group consisting of L858R, deletions in exon 19 (e.g., L747_A750del), L747S, D761Y, T790M, and T854A. In some embodiments, the EGFR kinase protein insertion is an exon 20 insertion. In some embodiments, the EGFR kinase protein insertion is an exon 20 insertion selected from the group consisting of: V769_D770insX, D770_N771insX, N771_P772insX, P772_H773insX, and H773_V774insX. For example, the EGFR kinase protein insertion is an exon 20 insertion selected from the group consisting of: A767_V769dupASV, V769_D770insASV, D770_N771insNPG, D770_N771insNPY, D770_N771insSVD, D770_N771insGL, N771_H773dupNPH, N771_P772insN, N771_P772insH, N771_P772insV, P772_H773insDNP, P772_H773insPNP, H773_V774insNPH, H773_V774insH, H773_V774insPH, H773_V774insAH, and P772_H773insPNP; or any combination thereof; e.g., any two or more independently selected exon 20 insertions; e.g., any two independently selected exon 20 insertions (e.g., V769_D770insASV and D770_N771insSVD). In some embodiments of any of the methods or uses described herein, the cancer (e.g., EGFR-associated cancer) is selected from a hematological cancer (e.g., acute lymphocytic cancer, Hodgkin lymphoma, non-Hodgkin lymphoma, and leukemia such as acute-myelogenous leukemia (AML), chronic-myelogenous leukemia (CML), acute- promyelocytic leukemia, and acute lymphocytic leukemia (ALL)), central or peripheral nervous system tissue cancer, an endocrine or neuroendocrine cancer including multiple neuroendocrine type I and type II tumors, Li-Fraumeni tumors, alveolar rhabdomyosarcoma, bone cancer, brain cancer, breast cancer, cancer of the anus, anal canal, or anorectum, cancer of the eye, cancer of the intrahepatic bile duct, cancer of the joints, cancer of the neck, gallbladder, or pleura, cancer of the nose, nasal cavity, or middle ear, oral cancer, oropharyngeal cancer, nasopharyngeal cancer, respiratory cancer, urogenital cancer, cancer of the vulva, colon cancer, esophageal cancer, tracheal cancer, cervical cancer, gastrointestinal carcinoid tumor, hypopharynx cancer, kidney cancer, larynx cancer, liver cancer, lung cancer, malignant mesothelioma, melanoma, multiple myeloma, nasopharynx cancer, ovarian cancer, pancreatic cancer including pancreatic islet cell cancer, peritoneum, omentum, and mesentery cancer, pharynx cancer, prostate cancer, rectal cancer, renal cancer (e.g., renal cell carcinoma (RCC)), small intestine cancer, soft tissue cancer, stomach cancer, testicular cancer, thyroid cancer, parathyroid cancer, pituitary tumors, adrenal gland tumors, ureter cancer, biliary cancer, and urinary bladder cancer. In some embodiments, the cancer is selected from the group consisting of: head and neck, ovarian, cervical, bladder and oesophageal cancers, pancreatic, gastrointestinal cancer, gastric, breast, endometrial and colorectal cancers, hepatocellular carcinoma, glioblastoma, bladder, lung cancer, e.g., non-small cell lung cancer (NSCLC), bronchioloalveolar carcinoma. In some embodiments, the cancer is pancreatic cancer, head and neck cancer, melanoma, colon cancer, renal cancer, leukemia, lung cancer, or breast cancer. In some cases, the cancer is melanoma, colon cancer, renal cancer, leukemia, or breast cancer. In some such embodiments, the compounds provided herein are useful for treating a primary brain tumor or metastatic brain tumor. For example, the compounds can be used in the treatment of one or more of gliomas such as glioblastoma (also known as glioblastoma multiforme), astrocytomas, oligodendrogliomas, ependymomas, and mixed gliomas, meningiomas, medulloblastomas, gangliogliomas, schwannomas (neurilemmomas), and craniopharyngiomas (see, for example, Liu et al. J Exp Clin Cancer Res.2019 May 23;38(1):219); and Ding et al. Cancer Res.2003 Mar 1;63(5):1106-13). In some embodiments, the brain tumor is a primary brain tumor. In some embodiments, the brain tumor is a metastatic brain tumor, e.g., a metastatic brain tumor from lung cancer, melanoma, breast cancer, ovarian cancer, colorectal cancer, kidney cancer, bladder cancer, or undifferentiated carcinoma. In some embodiments, the brain tumor is a metastatic brain tumor from lung cancer (e.g., non-small cell lung cancer). In some embodiments, the compounds provided herein exhibit brain and/or central nervous system (CNS) penetrance. In some embodiments, the patient has previously been treated with another anticancer agent, e.g., another EGFR and/or HER2 inhibitor (e.g., a compound that is not a compound of Formula I) or a multi-kinase inhibitor. In some embodiments, the cancer is a cancer of B cell origin. In some embodiments, the cancer is a lineage dependent cancer. In some embodiments, the cancer is a lineage dependent cancer where EGFR or the dysregulation of an EGFR gene, an EGFR kinase, or expression or activity or level of any of the same, plays a role in the initiation and/or development of the cancer. In some embodiments, the cancer is an EGFR-associated cancer. Accordingly, also provided herein is a method for treating a subject diagnosed with or identified as having an EGFR-associated cancer, e.g., any of the exemplary EGFR-associated cancers disclosed herein, comprising administering to the subject a therapeutically effective amount of a compound of Formula (I) (e.g., Formula (I-a), (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-g1), (I-g1-1), (I-g1-2),or (I-h)), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, as defined herein. In some embodiments, the dysregulation of an EGFR gene, an EGFR kinase, or expression or activity or level of any of the same, includes one or more deletions (e.g., deletion of an amino acid at position 4), insertions, or point mutation(s) in an EGFR kinase. In some embodiments, dysregulation of an EGFR gene, an EGFR kinase, or expression or activity or level of any of the same, includes at least one deletion, insertion, or point mutation in an EGFR gene that results in the production of an EGFR kinase that has one or more of the amino acid substitutions, insertions, or deletions in Table 1a and 1b. In some embodiments, the dysregulation of an EGFR gene, an EGFR kinase, or expression or activity or level of any of the same, includes a deletion of one or more residues from the EGFR kinase, resulting in constitutive activity of the EGFR kinase domain. In some embodiments, the dysregulation of an EGFR gene, an EGFR kinase, or expression or activity or level of any of the same, includes at least one point mutation in an EGFR gene that results in the production of an EGFR kinase that has one or more amino acid substitutions, insertions, or deletions as compared to the wild type EGFR kinase (see, for example, the point mutations listed in Table 1a and 1b).In some embodiments, dysregulation of an EGFR gene, an EGFR kinase, or expression or activity or level of any of the same, includes at least one point mutation in an EGFR gene that results in the production of an EGFR kinase that has one or more of the amino acid substitutions, insertions, or deletions in Table 1a and 1b. In some embodiments, the dysregulation of an EGFR gene, an EGFR kinase, or expression or activity or level of any of the same, includes an insertion of one or more residues in exon 20 of the EGFR gene (e.g., any of the exon 20 insertions described in Table 1a and 1b). Exon 20 of EGFR has two major regions, the c -helix (residues 762- 766) and the loop following the c-helix (residues 767-774). Studies suggest that for some exon 20 insertions (e.g., insertions after residue 764), a stabilized and ridged active conformation induces resistance to first generation EGFR inhibitors. In some embodiments, the dysregulation of an EGFR gene, an EGFR kinase, or expression or activity or level of any of the same, includes an insertion of one or more residues in exon 20 selected from the group consisting of: V769_D770insX, D770_N771insX, N771_P772insX, P772_H773insX, and H773_V774insX. For example, the EGFR kinase protein insertion is an exon 20 insertion selected from the group consisting of: A767_V769dupASV, V769_D770insASV, D770_N771insNPG, D770_N771insNPY, D770_N771insSVD, D770_N771insGL, N771_H773dupNPH, N771_P772insN, N771_P772insH, N771_P772insV, P772_H773insDNP, P772_H773insPNP, H773_V774insNPH, H773_V774insH, H773_V774insPH, H773_V774insAH, and P772_H773insPNP; or any combination thereof; e.g., any two 10 or more independently selected exon 20 insertions; e.g., any two independently selected exon 20 insertions (e.g., V769_D770insASV and D770_N771insSVD)..

Table 1a. EGFR Protein Amino Acid Substitutions/Insertions/Deletions^A

^A The EGFR mutations shown may be activating mutations and/or confer increased resistance of EGFR to an EGFR inhibitor and/or a multi-kinase inhibitor (MKI), e.g., as compared to a wild type EGFR ^B Potentially oncogenic variant. See, e.g., Kohsaka, Shinji, et al. Science translational medicine 9.416 (2017): eaan6566. ¹ PCT Patent Application Publication No. WO2019/246541. ² Grosse A, Grosse C, Rechsteiner M, Soltermann A. Diagn Pathol. 2019;14(1):18. Published 2019 Feb 11. doi:10.1186/s13000-019-0789-1. ³ Stewart EL, Tan SZ, Liu G, Tsao MS. Transl Lung Cancer Res. 2015;4(1):67–81. doi:10.3978/j.issn.2218-6751.2014.11.06. ⁴ Pines, Gur, Wolfgang J. Köstler, and Yosef Yarden. FEBS letters 584.12 (2010): 2699- 2706. ⁵ Yasuda, Hiroyuki, Susumu Kobayashi, and Daniel B. Costa. The Lancet Oncology 13.1 (2012): e23-e31. ⁶ Kim EY, Cho EN, Park HS, et al. Cancer Biol Ther. 2016;17(3):237–245. doi:10.1080/15384047.2016.1139235. ⁷Shah, Riyaz, and Jason F. Lester. Clinical Lung Cancer (2019). ⁸ Aran, Veronica, and Jasminka Omerovic. International journal of molecular sciences 20.22 (2019): 5701. doi: 10.3390/ijms20225701. ⁹ Beau-Faller, Michele, et al. (2012): 10507-10507. doi: 10.1016/j.semcancer.2019.09.015. ¹⁰ Masood, Ashiq, Rama Krishna Kancha, and Janakiraman Subramanian. Seminars in oncology. WB Saunders, 2019. doi: 10.1053/j.seminoncol.2019.08.004. ¹¹ Kohsaka, Shinji, et al. Science translational medicine 9.416 (2017): eaan6566. ¹² Vyse and Huang et al. Signal Transduct Target Ther. 2019 Mar 8;4:5. doi: 10.1038/s41392-019-0038-9. ¹³ PCT Patent Application Publication No. WO2019/046775. ¹⁴ PCT Patent Application Publication No. WO 2018/094225. Table 1b. EGFR Protein Amino Acid Substitutions/Insertions/Deletions^A

^A The EGFR mutations shown may be activating mutations and/or confer increased resistance of EGFR to an EGFR inhibitor and/or a multi-kinase inhibitor (MKI), e.g., as compared to a wild type EGFR ^B Potentially oncogenic variant. See, e.g., Kohsaka, Shinji, et al. Science translational medicine 9.416 (2017): eaan6566. ¹ PCT Patent Application Publication No. WO2019/246541. ² Grosse A, Grosse C, Rechsteiner M, Soltermann A. Diagn Pathol. 2019;14(1):18. Published 2019 Feb 11. doi:10.1186/s13000-019-0789-1. ³ Stewart EL, Tan SZ, Liu G, Tsao MS. Transl Lung Cancer Res. 2015;4(1):67–81. doi:10.3978/j.issn.2218-6751.2014.11.06. ⁴ Pines, Gur, Wolfgang J. Köstler, and Yosef Yarden. FEBS letters 584.12 (2010): 2699- 2706. ⁵ Yasuda, Hiroyuki, Susumu Kobayashi, and Daniel B. Costa. The Lancet Oncology 13.1 (2012): e23-e31. ⁶ Kim EY, Cho EN, Park HS, et al. Cancer Biol Ther. 2016;17(3):237–245. doi:10.1080/15384047.2016.1139235. ⁷Shah, Riyaz, and Jason F. Lester. Clinical Lung Cancer (2019). ⁸ Aran, Veronica, and Jasminka Omerovic. International journal of molecular sciences 20.22 (2019): 5701. doi: 10.3390/ijms20225701. ⁹ Beau-Faller, Michele, et al. (2012): 10507-10507. doi: 10.1016/j.semcancer.2019.09.015. ¹⁰ Masood, Ashiq, Rama Krishna Kancha, and Janakiraman Subramanian. Seminars in oncology. WB Saunders, 2019. doi: 10.1053/j.seminoncol.2019.08.004. ¹¹ Kohsaka, Shinji, et al. Science translational medicine 9.416 (2017): eaan6566. ¹² Vyse and Huang et al. Signal Transduct Target Ther. 2019 Mar 8;4:5. doi: 10.1038/s41392-019-0038-9. ¹³ PCT Patent Application Publication No. WO2019/046775. ¹⁴ PCT Patent Application Publication No. WO 2018/094225. ¹⁵Mondal, Gourish, et al. Acta Neuropathol.2020; 139(6): 1071-1088 ¹⁶Udager, Aaron M., et al. Cancer Res, 2015; 75(13): 2600-2606 In some embodiments, the dysregulation of an EGFR gene, an EGFR kinase, or expression or activity or level of any of the same, includes a splice variation in an EGFR mRNA which results in an expressed protein that is an alternatively spliced variant of EGFR having at least one residue deleted (as compared to the wild type EGFR kinase) resulting in a constitutive activity of an EGFR kinase domain. In some embodiments, the dysregulation of an EGFR gene, an EGFR kinase, or expression or activity or level of any of the same, includes at least one point mutation in an EGFR gene that results in the production of an EGFR kinase that has one or more amino acid substitutions or insertions or deletions in an EGFR gene that results in the production of an EGFR kinase that has one or more amino acids inserted or removed, as compared to the wild type EGFR kinase. In some cases, the resulting EGFR kinase is more resistant to inhibition (e.g., inhibition of its signaling activity) by one or more first EGFR inhibitors, as compared to a wild type EGFR kinase or an EGFR kinase not including the same mutation. Such mutations, optionally, do not decrease the sensitivity of the cancer cell or tumor having the EGFR kinase to treatment with a compound of Formula (I) (e.g., Formula (I-a), (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-g1), (I-g1- 1), (I-g1-2),or (I-h)), or a pharmaceutically acceptable salt thereof, (e.g., as compared to a cancer cell or a tumor that does not include the particular EGFR inhibitor resistance mutation). In other embodiments, the dysregulation of an EGFR gene, an EGFR kinase, or expression or activity or level of any of the same, includes at least one point mutation in an EGFR gene that results in the production of an EGFR kinase that has one or more amino acid substitutions as compared to the wild type EGFR kinase, and which has increased resistance to a compound of Formula (I) (e.g., Formula (I-a), (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-g1), (I-g1-1), (I-g1-2),or (I-h)), or a pharmaceutically acceptable salt thereof, as compared to a wild type EGFR kinase or an EGFR kinase not including the same mutation. In such embodiments, an EGFR inhibitor resistance mutation can result in an EGFR kinase that has one or more of an increased Vmax, a decreased Km, and a decreased KD in the presence of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, as compared to a wild type EGFR kinase or an EGFR kinase not having the same mutation in the presence of the same compound of Formula (I), or a pharmaceutically acceptable salt thereof. Exemplary Sequence of Mature Human EGFR Protein (UniProtKB entry P00533) (SEQ ID NO: 1)

In some embodiments, dysregulation of an EGFR gene, an EGFR kinase, or expression or activity or level of any of the same, includes at least one EGFR inhibitor resistance mutation in an EGFR gene that results in the production of an EGFR kinase that has one or more of the amino acid substitutions, insertions, or deletions as described in Table 2a and 2b. In some embodiments, compounds of Formula (I) (e.g., Formula (I-a), (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-g1), (I-g1-1), (I- g1-2),or (I-h)) and pharmaceutically acceptable salts and solvates thereof, are useful in treating subjects that develop cancers with EGFR inhibitor resistance mutations (e.g., that result in an increased resistance to a first EGFR inhibitor, e.g., a substitution at amino acid position 718, 747, 761, 790, 797, or 854 (e.g., L718Q, L747S, D761Y, T790M, C797S, T854A), and/or one or more EGFR inhibitor resistance mutations listed in Table 2a and 2b) by either dosing in combination or as a subsequent or additional (e.g., follow-up) therapy to existing drug treatments (e.g., other inhibitors of EGFR; e.g., first and/or second EGFR inhibitors).

Table 2a. EGFR Protein Amino Acid Resistance Mutations

¹ PCT Patent Application Publication No. WO2019/246541 ² Stewart EL, Tan SZ, Liu G, Tsao MS. Transl Lung Cancer Res. 2015;4(1):67–81. doi:10.3978/j.issn.2218-6751.2014.11.06 ³ Yasuda, Hiroyuki, Susumu Kobayashi, and Daniel B. Costa. The Lancet Oncology 13.1 (2012): e23-e31. ⁴ Kim EY, Cho EN, Park HS, et al. Cancer Biol Ther. 2016;17(3):237–245. doi:10.1080/15384047.2016.1139235 ⁵Shah, Riyaz, and Jason F. Lester. Clinical Lung Cancer (2019). ⁶ Aran, Veronica, and Jasminka Omerovic. International journal of molecular sciences 20.22 (2019): 5701. doi: 10.3390/ijms20225701. ⁷ Beau-Faller, Michele, et al. (2012): 10507-10507. doi: 10.1016/j.semcancer.2019.09.015 ⁸ Masood, Ashiq, Rama Krishna Kancha, and Janakiraman Subramanian. Seminars in oncology. WB Saunders, 2019. doi: 10.1053/j.seminoncol.2019.08.004 Table 2b. EGFR Protein Amino Acid Resistance Mutations

¹ PCT Patent Application Publication No. WO2019/246541 ² Stewart EL, Tan SZ, Liu G, Tsao MS. Transl Lung Cancer Res. 2015;4(1):67–81. doi:10.3978/j.issn.2218-6751.2014.11.06 ³ Yasuda, Hiroyuki, Susumu Kobayashi, and Daniel B. Costa. The Lancet Oncology 13.1 (2012): e23-e31. ⁴ Kim EY, Cho EN, Park HS, et al. Cancer Biol Ther. 2016;17(3):237–245. doi:10.1080/15384047.2016.1139235 ⁵Shah, Riyaz, and Jason F. Lester. Clinical Lung Cancer (2019). ⁶ Aran, Veronica, and Jasminka Omerovic. International journal of molecular sciences 20.22 (2019): 5701. doi: 10.3390/ijms20225701. ⁷ Beau-Faller, Michele, et al. (2012): 10507-10507. doi: 10.1016/j.semcancer.2019.09.015 ⁸ Masood, Ashiq, Rama Krishna Kancha, and Janakiraman Subramanian. Seminars in oncology. WB Saunders, 2019. doi: 10.1053/j.seminoncol.2019.08.004 ⁹Papadimitrakopoulou, V.A., et al. Annals of Oncology 2018; 29 Supplement 8 VIII741 In some embodiments, the EGFR Protein Amino Acid Substitutions/Insertions/Deletions include any one or more, or any two or more (e.g., any two), of the EGFR Protein Amino Acid Substitutions/Insertions/Deletions delineated in Table 1a, 1b and/or Table 2a, 2b; e.g., any one or more, or any two or more (e.g., any two), of the following and independently selected EGFR Protein Amino Acid Substitutions/Insertions/Deletions: V769L; V769M; M766delinsMASVx2; A767_V769dupASV; A767delinsASVDx3; A767delinsASVG; S768_V769insX; V769_D770insX; V769_D770insASV; D770delinsDN; D770delinsDNPH; D770_N771insSV; N771delinsNPH; N771_H773dup; L858R/C797S (or C797G); or Del_19 and C797S (or C797G), or any combination thereof. As used herein, a “first inhibitor of EGFR” or “first EGFR inhibitor” is an EGFR inhibitor as defined herein, but which does not include a compound of Formula (I) (e.g., Formula (I-a), (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I- g1), (I-g1-1), (I-g1-2),or (I-h)), or a pharmaceutically acceptable salt thereof, as defined herein. As used herein, a “second inhibitor of EGFR” or a “second EGFR inhibitor” is an EGFR inhibitor as defined herein, but which does not include a compound of Formula (I), or a pharmaceutically acceptable salt thereof, as defined herein. When both a first and a second inhibitor of EGFR are present in a method provided herein, the first and second inhibitors of EGFR are different. In some embodiments, the first and/or second inhibitor of EGFR bind in a different location than a compound of Formula (I). For example, in some embodiments, a first and/or second inhibitor of EGFR can inhibit dimerization of EGFR, while a compound of Formula (I) can inhibit the active site. In some embodiments, a first and/or second EGFR inhibitor can be an allosteric inhibitor of EGFR, while a compound of Formula (I) can inhibit the EGFR active site. Exemplary first and second inhibitors of EGFR are described herein. In some embodiments, a first or second inhibitor of EGFR can be selected from the group consisting of osimertinib, gefitinib, erlotinib, afatinib, lapatinib, neratinib, AZD-9291, CL-387785, CO-1686, or WZ4002. In some embodiments, compounds of Formula (I) (e.g., Formula (I-a), (I-a1), (I- a2), (I-a3), (I-a4), (I-a5), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-g1), (I-g1-1), (I-g1-2),or (I-h)), or pharmaceutically acceptable salts and solvates thereof, are useful for treating a cancer that has been identified as having one or more EGFR inhibitor resistance mutations (that result in an increased resistance to a first or second inhibitor of EGFR, e.g., a substitution described in Table 2a and 2b including substitutions at amino acid position 747, 761, 790, 797, or 854 (e.g., L718Q, L747S, D761Y, T790M, C797S, T854A)). In some embodiments, the one or more EGFR inhibitor resistance mutations occurs in a nucleic acid sequence encoding a mutant EGFR protein (e.g., a mutant EGFR protein having any of the mutations described in Table 2a and 2b) resulting in a mutant EGFR protein that exhibits EGFR inhibitor resistance. The epidermal growth factor receptor (EGFR) belongs to the ErbB family of receptor tyrosine kinases (RTKs) and provides critical functions in epithelial cell physiology (Schlessinger J (2014) Cold Spring Harb Perspect Biol 6, a008912). It is frequently mutated and/or overexpressed in different types of human cancers and is the target of multiple cancer therapies currently adopted in the clinical practice (Yarden Y and Pines G (2012) Nat Rev Cancer 12, 553–563). Accordingly, provided herein are methods for treating a subject diagnosed with (or identified as having) a cancer that include administering to the subject a therapeutically effective amount of a compound of Formula (I) (e.g., Formula (I-a), (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-g1), (I-g1-1), (I-g1-2),or (I-h)), or a pharmaceutically acceptable salt thereof. Also provided herein are methods for treating a subject identified or diagnosed as having an EGFR-associated cancer that include administering to the subject a therapeutically effective amount of a compound of Formula (I) (e.g., Formula (I-a), (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-g1), (I-g1-1), (I-g1-2),or (I-h)), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. In some embodiments, the subject that has been identified or diagnosed as having an EGFR-associated cancer through the use of a regulatory agency-approved, e.g., FDA- approved test or assay for identifying dysregulation of an EGFR gene, an EGFR kinase, or expression or activity or level of any of the same, in a subject or a biopsy sample from the subject or by performing any of the non-limiting examples of assays described herein. In some embodiments, the test or assay is provided as a kit. In some embodiments, the cancer is an EGFR-associated cancer. For example, the EGFR-associated cancer can be a cancer that includes one or more EGFR inhibitor resistance mutations. The term "regulatory agency" refers to a country's agency for the approval of the medical use of pharmaceutical agents with the country. For example, a non-limiting example of a regulatory agency is the U.S. Food and Drug Administration (FDA). Also provided are methods for treating cancer in a subject in need thereof, the method comprising: (a) detecting an EGFR-associated cancer in the subject; and (b) administering to the subject a therapeutically effective amount of a compound of Formula (I) (e.g., Formula (I-a), (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-g1), (I-g1-1), (I-g1-2),or (I-h)), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. Some embodiments of these methods further include administering to the subject another anticancer agent (e.g., a second EGFR inhibitor, a second compound of Formula (I), or a pharmaceutically acceptable salt thereof, or an immunotherapy). In some embodiments, the subject was previously treated with a first EGFR inhibitor or previously treated with another anticancer treatment, e.g., at least partial resection of the tumor or radiation therapy. In some embodiments, the subject is determined to have an EGFR-associated cancer through the use of a regulatory agency-approved, e.g., FDA-approved test or assay for identifying dysregulation of an EGFR gene, an EGFR kinase, or expression or activity or level of any of the same, in a subject or a biopsy sample from the subject or by performing any of the non-limiting examples of assays described herein. In some embodiments, the test or assay is provided as a kit. In some embodiments, the cancer is an EGFR-associated cancer. For example, the EGFR-associated cancer can be a cancer that includes one or more EGFR inhibitor resistance mutations. Also provided are methods of treating a subject that include performing an assay on a sample obtained from the subject to determine whether the subject has a dysregulation of an EGFR gene, an EGFR kinase, or expression or activity or level of any of the same, and administering (e.g., specifically or selectively administering) a therapeutically effective amount of a compound of Formula (I) (e.g., Formula (I-a), (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-g1), (I-g1-1), (I-g1-2),or (I-h)), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, to the subject determined to have a dysregulation of an EGFR gene, an EGFR kinase, or expression or activity or level of any of the same. Some embodiments of these methods further include administering to the subject another anticancer agent (e.g., a second EGFR inhibitor, a second compound of Formula (I), or a pharmaceutically acceptable salt thereof, or immunotherapy). In some embodiments of these methods, the subject was previously treated with a first EGFR inhibitor or previously treated with another anticancer treatment, e.g., at least partial resection of a tumor or radiation therapy. In some embodiments, the subject is a subject suspected of having an EGFR-associated cancer, a subject presenting with one or more symptoms of an EGFR-associated cancer, or a subject having an elevated risk of developing an EGFR-associated cancer. In some embodiments, the assay utilizes next generation sequencing, pyrosequencing, immunohistochemistry, or break apart FISH analysis. In some embodiments, the assay is a regulatory agency-approved assay, e.g., FDA-approved kit. In some embodiments, the assay is a liquid biopsy. Additional, non- limiting assays that may be used in these methods are described herein. Additional assays are also known in the art. In some embodiments, the dysregulation of an EGFR gene, an EGFR kinase, or expression or activity or level of any of the same includes one or more EGFR inhibitor resistance mutations. Also provided is a compound of Formula (I) (e.g., Formula (I-a), (I-a1), (I-a2), (I- a3), (I-a4), (I-a5), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-g1), (I-g1-1), (I-g1-2),or (I-h)), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for use in treating an EGFR-associated cancer in a subject identified or diagnosed as having an EGFR-associated cancer through a step of performing an assay (e.g., an in vitro assay) on a sample obtained from the subject to determine whether the subject has a dysregulation of an EGFR gene, an EGFR kinase, or expression or activity or level of any of the same, where the presence of a dysregulation of an EGFR gene, an EGFR kinase, or expression or activity or level of any of the same, identifies that the subject has an EGFR-associated cancer. Also provided is the use of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating an EGFR- associated cancer in a subject identified or diagnosed as having an EGFR-associated cancer through a step of performing an assay on a sample obtained from the subject to determine whether the subject has a dysregulation of an EGFR gene, an EGFR kinase, or expression or activity or level of any of the same where the presence of dysregulation of an EGFR gene, an EGFR kinase, or expression or activity or level of any of the same, identifies that the subject has an EGFR-associated cancer. Some embodiments of any of the methods or uses described herein further include recording in the subject’s clinical record (e.g., a computer readable medium) that the subject is determined to have a dysregulation of an EGFR gene, an EGFR kinase, or expression or activity or level of any of the same, through the performance of the assay, should be administered a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. In some embodiments, the assay utilizes next generation sequencing, pyrosequencing, immunohistochemistry, or break apart FISH analysis. In some embodiments, the assay is a regulatory agency-approved assay, e.g., FDA-approved kit. In some embodiments, the assay is a liquid biopsy. In some embodiments, the dysregulation of an EGFR gene, an EGFR kinase, or expression or activity or level of any of the same includes one or more EGFR inhibitor resistance mutations. Also provided is a compound of Formula (I) (e.g., Formula (I-a), (I-a1), (I-a2), (I- a3), (I-a4), (I-a5), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-g1), (I-g1-1), (I-g1-2),or (I-h)), or a pharmaceutically acceptable salt thereof, for use in the treatment of a cancer in a subject in need thereof, or a subject identified or diagnosed as having an EGFR-associated cancer. Also provided is the use of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating a cancer in a subject identified or diagnosed as having an EGFR-associated cancer. In some embodiments, the cancer is an EGFR-associated cancer, for example, an EGFR-associated cancer having one or more EGFR inhibitor resistance mutations. In some embodiments, a subject is identified or diagnosed as having an EGFR-associated cancer through the use of a regulatory agency-approved, e.g., FDA-approved, kit for identifying dysregulation of an EGFR gene, an EGFR kinase, or expression or activity or level of any of the same, in a subject or a biopsy sample from the subject. As provided herein, an EGFR-associated cancer includes those described herein and known in the art. In some embodiments of any of the methods or uses described herein, the subject has been identified or diagnosed as having a cancer with a dysregulation of an EGFR gene, an EGFR kinase, or expression or activity or level of any of the same. In some embodiments of any of the methods or uses described herein, the subject has a tumor that is positive for a dysregulation of an EGFR gene, an EGFR kinase, or expression or activity or level of any of the same. In some embodiments of any of the methods or uses described herein, the subject can be a subject with a tumor(s) that is positive for a dysregulation of an EGFR gene, an EGFR kinase, or expression or activity or level of any of the same. In some embodiments of any of the methods or uses described herein, the subject can be a subject whose tumors have a dysregulation of an EGFR gene, an EGFR kinase, or expression or activity or level of any of the same. In some embodiments of any of the methods or uses described herein, the subject is suspected of having an EGFR-associated cancer (e.g., a cancer having one or more EGFR inhibitor resistance mutations). In some embodiments, provided herein are methods for treating an EGFR-associated cancer in a subject in need of such treatment, the method comprising a) detecting a dysregulation of an EGFR gene, an EGFR kinase, or the expression or activity or level of any of the same in a sample from the subject; and b) administering a therapeutically effective amount of a compound of Formula (I) (e.g., Formula (I-a), (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b), (I-c), (I-d), (I- e), (I-f), (I-g), (I-g1), (I-g1-1), (I-g1-2),or (I-h)), or a pharmaceutically acceptable salt thereof. In some embodiments, the dysregulation of an EGFR gene, an EGFR kinase, or the expression or activity or level of any of the same includes one or more EGFR kinase protein point mutations/insertions/deletions. Non-limiting examples of EGFR kinase protein point mutations/insertions/deletions are described in Table 1a and 1b. In some embodiments, the EGFR kinase protein point mutations/insertions/deletions are selected from the group consisting of G719S, G719C, G719A, L747S, D761Y, T790M, T854A, L858R, L861Q, a deletion in exon 19 (e.g., L747_A750del), and an insertion in exon 20. In some embodiments, the EGFR kinase protein point mutations/insertions/deletions are selected from the group consisting of L858R, deletions in exon 19 (e.g., L747_A750del), L747S, D761Y, T790M, and T854A. In some embodiments, the dysregulation of an EGFR gene, an EGFR kinase, or the expression or activity or level of any of the same includes one or more EGFR inhibitor resistance mutations. Non-limiting examples of EGFR inhibitor resistance mutations are described in Table 2a and 2b. In some embodiments, the EGFR inhibitor resistance mutation is a substitution at amino acid position 718, 747, 761, 790, 797, or 854 (e.g., L718Q, L747S, D761Y, T790M, C797S, and T854A). In some embodiments, the dysregulation of an EGFR gene, an EGFR kinase, or the expression or activity or level of any of the same includes one or more point mutations/insertions/deletions in exon 20. Non-limiting examples of EGFR exon 20 mutations are described in Tables 1a, 1b and 2a, 2b . In some embodiments, the EGFR exon 20 mutation is an exon 20 insertion such as V769_D770insX, D770_N771insX, N771_P772insX, P772_H773insX, and H773_V774insX. For example, the EGFR kinase protein insertion is an exon 20 insertion selected from the group consisting of: A767_V769dupASV, V769_D770insASV, D770_N771insNPG, D770_N771insNPY, D770_N771insSVD, D770_N771insGL, N771_H773dupNPH, N771_P772insN, N771_P772insH, N771_P772insV, P772_H773insDNP, P772_H773insPNP, H773_V774insNPH, H773_V774insH, H773_V774insPH, H773_V774insAH, and P772_H773insPNP. In some embodiments, the cancer with a dysregulation of an EGFR gene, an EGFR kinase, or expression or activity or level of any of the same is determined using a regulatory agency-approved, e.g., FDA-approved, assay or kit. In some embodiments, the tumor that is positive for a dysregulation of an EGFR gene, an EGFR kinase, or expression or activity or level of any of the same is a tumor positive for one or more EGFR inhibitor resistance mutations. In some embodiments, the tumor with a dysregulation of an EGFR gene, an EGFR kinase, or expression or activity or level of any of the same is determined using a regulatory agency-approved, e.g., FDA-approved, assay or kit. In some embodiments of any of the methods or uses described herein, the subject has a clinical record indicating that the subject has a tumor that has a dysregulation of an EGFR gene, an EGFR kinase, or expression or activity or level of any of the same (e.g., a tumor having one or more EGFR inhibitor resistance mutations). Also provided are methods of treating a subject that include administering a therapeutically effective amount of a compound of Formula (I) (e.g., Formula (I-a), (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I- b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-g1), (I-g1-1), (I-g1-2),or (I-h)), or a pharmaceutically acceptable salt thereof, to a subject having a clinical record that indicates that the subject has a dysregulation of an EGFR gene, an EGFR kinase, or expression or activity or level of any of the same. In some embodiments, the methods provided herein include performing an assay on a sample obtained from the subject to determine whether the subject has a dysregulation of an EGFR gene, an EGFR protein, or expression or level of any of the same. In some such embodiments, the method also includes administering to a subject determined to have a dysregulation of an EGFR gene, an EGFR protein, or expression or activity, or level of any of the same a therapeutically effective amount of a compound of Formula (I) (e.g., Formula (I-a), (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I- g1), (I-g1-1), (I-g1-2),or (I-h)), or a pharmaceutically acceptable salt thereof. In some embodiments, the method includes determining that a subject has a dysregulation of an EGFR gene, an EGFR protein, or expression or level of any of the same via an assay performed on a sample obtained from the subject. In such embodiments, the method also includes administering to a subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof. In some embodiments, the dysregulation in an EGFR gene, an EGFR kinase protein, or expression or activity or level of any of the same is one or more point mutation in the EGFR gene (e.g., any of the one or more of the EGFR point mutations described herein). The one or more point mutations in an EGFR gene can result, e.g., in the translation of an EGFR protein having one or more of the following amino acid substitutions, deletions, and insertions: G719S, G719C, G719A, L747S, D761Y, T790M, T854A, L858R, L861Q, a deletion in exon 19 (e.g., L747_A750del), and an insertion in exon 20 (e.g., V769_D770insX, D770_N771insX, N771_P772insX, P772_H773insX, and H773_V774insX). The one or more mutations in an EGFR gene can result, e.g., in the translation of an EGFR protein having one or more of the following amino acid substitutions or deletions: L858R, deletions in exon 19 (e.g., L747_A750del), L747S, D761Y, T790M, and T854A. In some embodiments, the dysregulation in an EGFR gene, an EGFR kinase protein, or expression or activity or level of any of the same is one or more EGFR inhibitor resistance mutations (e.g., any combination of the one or more EGFR inhibitor resistance mutations described herein). In some embodiments, the dysregulation in an EGFR gene, an EGFR kinase protein, or expression or activity or level of any of the same is one or more EGFR exon 20 insertions (e.g., any of the exon 20 insertions described herein). In some embodiments, the EGFR kinase protein insertion is an exon 20 insertion selected from the group consisting of: V769_D770insX, D770_N771insX, N771_P772insX, P772_H773insX, and H773_V774insX. In some embodiments, the EGFR kinase protein insertion is an exon 20 insertion selected from the group consisting of: V769_D770insX, D770_N771insX, N771_P772insX, P772_H773insX, and H773_V774insX. In some embodiments, the EGFR kinase protein insertion is an exon 20 insertion selected from the group consisting of: A767_V769dupASV, V769_D770insASV, D770_N771insNPG, D770_N771insNPY, D770_N771insSVD, D770_N771insGL, N771_H773dupNPH, N771_P772insN, N771_P772insH, N771_P772insV, P772_H773insDNP, P772_H773insPNP, H773_V774insNPH, H773_V774insH, H773_V774insPH, H773_V774insAH, and P772_H773insPNP. Some embodiments of these methods further include administering to the subject another anticancer agent (e.g., a second EGFR inhibitor, a second compound of Formula (I) (e.g., Formula (I-a), (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b), (I-c), (I-d), (I- e), (I-f), (I-g), (I-g1), (I-g1-1), (I-g1-2),or (I-h)), or a pharmaceutically acceptable salt thereof, or immunotherapy). In some embodiments of any of the methods or uses described herein, an assay used to determine whether the subject has a dysregulation of an EGFR gene, or an EGFR kinase, or expression or activity or level of any of the same, using a sample from a subject can include, for example, next generation sequencing, immunohistochemistry, fluorescence microscopy, break apart FISH analysis, Southern blotting, Western blotting, FACS analysis, Northern blotting, and PCR-based amplification (e.g., RT-PCR and quantitative real-time RT-PCR). As is well-known in the art, the assays are typically performed, e.g., with at least one labelled nucleic acid probe or at least one labelled antibody or antigen- binding fragment thereof. Assays can utilize other detection methods known in the art for detecting dysregulation of an EGFR gene, an EGFR kinase, or expression or activity or levels of any of the same (see, e.g., the references cited herein). In some embodiments, the dysregulation of the EGFR gene, the EGFR kinase, or expression or activity or level of any of the same includes one or more EGFR inhibitor resistance mutations. In some embodiments, the sample is a biological sample or a biopsy sample (e.g., a paraffin- embedded biopsy sample) from the subject. In some embodiments, the subject is a subject suspected of having an EGFR-associated cancer, a subject having one or more symptoms of an EGFR-associated cancer, and/or a subject that has an increased risk of developing an EGFR-associated cancer). In some embodiments, dysregulation of an EGFR gene, an EGFR kinase, or the expression or activity or level of any of the same can be identified using a liquid biopsy (variously referred to as a fluid biopsy or fluid phase biopsy). See, e.g., Karachialiou et al., “Real-time liquid biopsies become a reality in cancer treatment”, Ann. Transl. Med., 3(3):36, 2016. Liquid biopsy methods can be used to detect total tumor burden and/or the dysregulation of an EGFR gene, an EGFR kinase, or the expression or activity or level of any of the same. Liquid biopsies can be performed on biological samples obtained relatively easily from a subject (e.g., via a simple blood draw) and are generally less invasive than traditional methods used to detect tumor burden and/or dysregulation of an EGFR gene, an EGFR kinase, or the expression or activity or level of any of the same. In some embodiments, liquid biopsies can be used to detect the presence of dysregulation of an EGFR gene, an EGFR kinase, or the expression or activity or level of any of the same at an earlier stage than traditional methods. In some embodiments, the biological sample to be used in a liquid biopsy can include, blood, plasma, urine, cerebrospinal fluid, saliva, sputum, broncho-alveolar lavage, bile, lymphatic fluid, cyst fluid, stool, ascites, and combinations thereof. In some embodiments, a liquid biopsy can be used to detect circulating tumor cells (CTCs). In some embodiments, a liquid biopsy can be used to detect cell-free DNA. In some embodiments, cell-free DNA detected using a liquid biopsy is circulating tumor DNA (ctDNA) that is derived from tumor cells. Analysis of ctDNA (e.g., using sensitive detection techniques such as, without limitation, next-generation sequencing (NGS), traditional PCR, digital PCR, or microarray analysis) can be used to identify dysregulation of an EGFR gene, an EGFR kinase, or the expression or activity or level of any of the same. The term "HER2-associated disease or disorder" as used herein refers to diseases or disorders associated with or having a dysregulation of a HER2 gene, a HER2 kinase, or the expression or activity or level of any (e.g., one or more) of the same (e.g., any of the types of dysregulation of a HER2 gene, a HER2 kinase, a HER2 kinase domain, or the expression or activity or level of any of the same described herein). Non-limiting examples of a HER2-associated disease or disorder include, for example, cancer. The term “HER2-associated cancer” as used herein refers to cancers associated with or having a dysregulation of a HER2 gene, a HER2 kinase (also called herein a HER2 protein), or expression or activity, or level of any of the same. Non-limiting examples of a HER2-associated cancer are described herein. In some embodiments, the EGFR-associated cancer is also a HER2-associated cancer. For example, an EGFR-associated cancer can also have a dysregulation of a HER2 gene, a HER2 kinase, or the expression or activity or level of any of the same. The phrase “dysregulation of a HER2 gene, a HER2 kinase, or the expression or activity or level of any of the same” refers to a genetic mutation (e.g., a mutation in a HER2 gene that results in the expression of a HER2 protein that includes a deletion of at least one amino acid as compared to a wild type HER2 protein, a mutation in a HER2 gene that results in the expression of a HER2 protein with one or more point mutations as compared to a wild type HER2 protein, a mutation in a HER2 gene that results in the expression of a HER2 protein with at least one inserted amino acid as compared to a wild type HER2 protein, a gene duplication that results in an increased level of HER2 protein in a cell, or a mutation in a regulatory sequence (e.g., a promoter and/or enhancer) that results in an increased level of HER2 protein in a cell), an alternative spliced version of a HER2 mRNA that results in a HER2 protein having a deletion of at least one amino acid in the HER2 protein as compared to the wild-type HER2 protein), or increased expression (e.g., increased levels) of a wild type HER2 kinase in a mammalian cell due to aberrant cell signaling and/or dysregulated autocrine/paracrine signaling (e.g., as compared to a control non-cancerous cell). As another example, a dysregulation of a HER2 gene, a HER2 protein, or expression or activity, or level of any of the same, can be a mutation in a HER2 gene that encodes a HER2 protein that is constitutively active or has increased activity as compared to a protein encoded by a HER2 gene that does not include the mutation. Non- limiting examples of HER2 kinase protein fusions and point mutations/insertions/deletions are described in Tables 3-5. Such mutation and overexpression is associated with the development of a variety of cancers (Moasser. Oncogene.2007 Oct 4; 26(45): 6469–6487). Compounds of Formula (I) (e.g., Formula (I-a), (I-a1), (I-a2), (I-a3), (I-a4), (I- a5), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-g1), (I-g1-1), (I-g1-2),or (I-h)), or pharmaceutically acceptable salts or solvates thereof, are useful for treating diseases and disorders such as HER2-associated diseases and disorders, e.g., proliferative disorders such as cancers, including hematological cancers and solid tumors (e.g., advanced solid tumors). In some embodiments, dysregulation of a HER2 gene, a HER2 kinase, or the expression or activity or level of any of the same can be caused by an activating mutation in a HER2 gene. The exemplary HER2 kinase fusions or point mutations, insertions, and deletions shown in Tables 3-5 can be caused by an activating mutation. The term “activating mutation” in reference to HER2 describes a mutation in a HER2 gene that results in the expression of a HER2 kinase that has an increased kinase activity, e.g., as compared to a wild type HER2 kinase, e.g., when assayed under identical conditions. For example, an activating mutation can be a mutation in a HER2 gene (that results in the expression of a HER2 kinase that has one or more (e.g., two, three, four, five, six, seven, eight, nine, or ten) amino acid substitutions (e.g., any combination of any of the amino acid substitutions described herein) that has increased kinase activity, e.g., as compared to a wild type HER2 kinase, e.g., when assayed under identical conditions. In another example, an activating mutation can be a mutation in a HER2 gene that results in the expression of a HER2 kinase that has one or more (e.g., two, three, four, five, six, seven, eight, nine, or ten) amino acids deleted, e.g., as compared to a wild type HER2 kinase, e.g., when assayed under identical conditions. In another example, an activating mutation can be a mutation in a HER2 gene that results in the expression of a HER2 kinase that has at least one (e.g., at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 12, at least 14, at least 16, at least 18, or at least 20) amino acid inserted as compared to a wild type HER2 kinase, e.g., the exemplary wild type HER2 kinase described herein, e.g., when assayed under identical conditions. Additional examples of activating mutations are known in the art. The term "wild type HER2" or "wild-type HER2 kinase" describes a HER2nucleic acid (e.g., a HER2 gene or a HER2 mRNA) or protein (e.g., a HER2 protein) that is found in a subject that does not have a HER2-associated disease, e.g., a HER2-associated cancer (and optionally also does not have an increased risk of developing a HER2-associated disease and/or is not suspected of having a HER2-associated disease), or is found in a cell or tissue from a subject that does not have a HER2-associated disease, e.g., a HER2- associated cancer (and optionally also does not have an increased risk of developing a HER2-associated disease and/or is not suspected of having a HER2-associated disease). Provided herein is a method of treating a HER2-associated cancer (in a subject in need of such treatment, the method comprising administering to the subject a therapeutically effective amount of a compound of Formula (I) (e.g., Formula (I-a), (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-g1), (I-g1-1), (I-g1-2),or (I-h)), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. For example, provided herein are methods for treating a HER2-associated cancer in a subject in need of such treatment, the method comprising a) detecting a dysregulation of a HER2 gene, a HER2 kinase, or the expression or activity or level of any of the same in a sample from the subject; and b) administering a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof. In some embodiments, the dysregulation of a HER2 gene, a HER2 kinase, or the expression or activity or level of any of the same includes one or more HER2 kinase protein point mutations/insertions. Non-limiting examples of HER2 kinase protein fusions and point mutations/insertions/deletions are described in Tables 3-5. In some embodiments, the HER2 kinase protein point mutations/insertions/deletions are selected from the group consisting of S310F, S310Y, R678Q, R678W, R678P, I767M, V773M, V777L, V842I, Y772_A775dup, A775_G776insYVMA, G776delinsVC, G776delinsVV, V777_G778insGSP, and P780_Y781insGSP. In some embodiments, the HER2 kinase protein point mutations/insertions/deletions are exon 20 point mutations/insertions/deletions selected from the group consisting of V773M, G776C, G776V, G776S, V777L, V777M, S779T, P780L, S783P, M774AYVM, M774del insWLV, A775_G776insYVMA, A775_G776insAVMA, A775_G776insSVMA, A775_G776insVAG, A775insV G776C, A775_G776insI, G776del insVC2, G776del insVV, G776del insLC, G776C V777insC, G776C V777insV, V777_G778insCG, G778_S779insCPG, and P780_Y781insGSP. In some embodiments, the HER2 kinase protein point mutations/insertions/deletions are exon 20 point mutations/insertions/deletions selected from the group consisting of Y772_A775dup, A775_G776insYVMA, G776delinsVC, G776delinsVV, V777_G778insGSP, and P780_Y781insGSP. In some embodiments of any of the methods or uses described herein, the cancer (e.g., HER2-associated cancer) is selected from a hematological cancer (e.g., Hodgkin lymphoma, non-Hodgkin lymphoma, and leukemia such as acute-myelogenous leukemia (AML), chronic-myelogenous leukemia (CML), acute-promyelocytic leukemia, and acute lymphocytic leukemia (ALL)), alveolar rhabdomyosarcoma, central or peripheral nervous system tissue cancer, an endocrine or neuroendocrine cancer including multiple neuroendocrine type I and type II tumors, Li-Fraumeni tumors, alveolar rhabdomyosarcoma, bone cancer, brain cancer, breast cancer, cancer of the anus, anal canal, or anorectum, cancer of the eye, cancer of the intrahepatic bile duct, cancer of the joints, cancer of the neck, gallbladder, or pleura, cancer of the nose, nasal cavity, or middle ear, tracheal cancer, oral cancer, oropharyngeal cancer, nasopharyngeal cancer, respiratory cancer, urogenital cancer, cancer of the vulva, colon cancer, esophageal cancer, cervical cancer, gastrointestinal carcinoid tumor, hypopharynx cancer, kidney cancer, larynx cancer, liver cancer, lung cancer, malignant mesothelioma, melanoma, multiple myeloma, nasopharynx cancer, non-Hodgkin lymphoma, ovarian cancer, pancreatic cancer including pancreatic islet cell cancer, peritoneum, omentum, and mesentery cancer, pharynx cancer, prostate cancer, rectal cancer, renal cancer (e.g., renal cell carcinoma (RCC)), small intestine cancer, soft tissue cancer, stomach cancer, testicular cancer, thyroid cancer, parathyroid cancer, pituitary tumors, adrenal gland tumors, ureter cancer, biliary cancer, and urinary bladder cancer. In some embodiments, the cancer is selected from the group consisting of: head and neck, ovarian, cervical, bladder and oesophageal cancers, pancreatic, gastrointestinal cancer, gastric, breast, endometrial and colorectal cancers, hepatocellular carcinoma, glioblastoma, bladder, lung cancer, e.g., non-small cell lung cancer (NSCLC), bronchioloalveolar carcinoma. In some embodiments, the cancer is pancreatic cancer, head and neck cancer, melanoma, colon cancer, renal cancer, leukemia, lung cancer, or breast cancer. In some cases, the cancer is melanoma, colon cancer, renal cancer, leukemia, or breast cancer. In some such embodiments, the compounds provided herein are useful for treating a primary brain tumor or metastatic brain tumor. For example, the compounds can be used in the treatment of one or more of gliomas such as glioblastoma (also known as glioblastoma multiforme), astrocytomas, oligodendrogliomas, ependymomas, and mixed gliomas, meningiomas, medulloblastomas, gangliogliomas, schwannomas (neurilemmomas), and craniopharyngiomas (see, for example, Liu et al. J Exp Clin Cancer Res.2019 May 23;38(1):219); and Ding et al. Cancer Res.2003 Mar 1;63(5):1106-13). In some embodiments, the brain tumor is a primary brain tumor. In some embodiments, the brain tumor is a metastatic brain tumor, e.g., a metastatic brain tumor from lung cancer, melanoma, breast cancer, ovarian cancer, colorectal cancer, kidney cancer, bladder cancer, or undifferentiated carcinoma. In some embodiments, the brain tumor is a metastatic brain tumor from lung cancer (e.g., non-small cell lung cancer). In some embodiments, the compounds provided herein exhibit brain and/or central nervous system (CNS) penetrance. In some embodiments, the patient has previously been treated with another anticancer agent, e.g., another EGFR and/or HER2 inhibitor (e.g., a compound that is not a compound of Formula I) or a multi-kinase inhibitor. In some embodiments, the cancer is a cancer of B cell origin. In some embodiments, the cancer is a lineage dependent cancer. In some embodiments, the cancer is a lineage dependent cancer where HER2 or the dysregulation of an HER2 gene, an HER2 kinase, or expression or activity or level of any of the same, plays a role in the initiation and/or development of the cancer. Also provided herein is a method for treating a subject diagnosed with or identified as having a HER2-associated cancer, e.g., any of the exemplary HER2-associated cancers disclosed herein, comprising administering to the subject a therapeutically effective amount of a compound of Formula (I) (e.g., Formula (I-a), (I-a1), (I-a2), (I-a3), (I-a4), (I- a5), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-g1), (I-g1-1), (I-g1-2),or (I-h)), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, as defined herein. In some embodiments, the dysregulation of a HER2 gene, a HER2 kinase, or expression or activity or level of any of the same, includes one or more deletions (e.g., deletion of an amino acid at position 12), insertions, or point mutation(s) in a HER2 kinase. In some embodiments, the dysregulation of a HER2 gene, a HER2 kinase, or expression or activity or level of any of the same, includes a deletion of one or more residues from the HER2 kinase, resulting in increased signaling activity of HER2. In some embodiments, the dysregulation of a HER2 gene, a HER2 kinase, or expression or activity or level of any of the same, includes at least one point mutation in a HER2 gene that results in the production of a HER2 kinase that has one or more amino acid substitutions, insertions, or deletions as compared to the wild-type HER2 kinase (see, for example, the point mutations listed in Table 3). In some embodiments, dysregulation of a HER2 gene, a HER2 kinase, or expression or activity or level of any of the same, includes at least one point mutation in a HER2 gene that results in the production of a HER2 kinase that has one or more of the amino acid substitutions, insertions, or deletions in Table 3. In some embodiments, the dysregulation of an HER2 gene, an HER2 kinase, or expression or activity or level of any of the same, includes an insertion of one or more residues in exon 20 of the HER2 gene (e.g., any of the exon 20 insertions described in Table 1a and 1b). Exon 20 of HER2 has two major regions, the c-helix (residues 770-774) and the loop following the c-helix (residues 775-783). In some embodiments, the dysregulation of an HER2 gene, an HER2 kinase, or expression or activity or level of any of the same, includes an insertion of one or more residues in exon 20 selected from the group consisting of: Y772_A775dup, A775_G776insYVMA, G776delinsVC, G776delinsVV, V777_G778insGSP, and P780_Y781insGSP. Table 3. HER2 Protein Amino Acid Substitutions/Insertions/Deletions^A

A The HER2 mutations shown may be activating mutations and/or confer increased resistance of HER2 to a HER2 inhibitor and/or a multi-kinase inhibitor (MKI), e.g., as compared to a wildtype HER2. 1 Li et al. J Thorac Oncol.2016 Mar;11(3):414-9. 2 Arcila et al. Clin Cancer Res. 2012 Sep 15; 18(18): 10.1158/1078-0432.CCR-12- 0912. 3 Bose et al. Cancer Discov.2013 Feb;3(2):224-37. 4 Hanker et al. Cancer Discov.2017 Jun;7(6):575-585. ⁵ Christgen et al. Virchows Arch.2018 Nov;473(5):577-582. 6 Si et al. Cancer Biomark.2018;23(2):165-171. 7 Kavuri et al. Cancer Discov.2015 Aug; 5(8): 832–841. 8 Robichaux et al. Nat Med.2018 May; 24(5): 638–646. 9 Kosaka et al. Cancer Res.2017 May 15; 77(10): 2712–2721. 1⁰ Pahuja et al. Cancer Cell.2018 Nov 12; 34(5): 792–806.e5. 1¹ Ross et al. Cancer.2018 Apr 1;124(7):1358-1373. 1² Gharib et al. J Cell Physiol.2019 Aug;234(8):13137-13144. 1³ Krawczyk et al. Oncol Lett.2013 Oct; 6(4): 1063–1067. 1⁴ Lai et al. Eur J Cancer.2019 Mar; 109: 28–35. 1⁵ Sun et al. J Cell Mol Med.2015 Dec; 19(12): 2691–2701. 1⁶ Xu et al. Thorac Cancer.2020 Mar;11(3):679-685. In some embodiments, the dysregulation of a HER2 gene, a HER2 kinase, or expression or activity or level of any of the same, includes a splice variation in a HER2 mRNA which results in an expressed protein that is an alternatively spliced variant of HER2 having at least one residue deleted (as compared to the wild-type HER2 kinase) resulting in a constitutive activity of a HER2 kinase domain. In some embodiments, the splice variant of HER2 is Δ16HER-3 or p95HER‐2. See, e.g., Sun et al. J Cell Mol Med. 2015 Dec; 19(12): 2691–2701. In some embodiments, dysregulation of an HER2 gene, an HER2 kinase, or the expression or activity or level of any of the same can be caused by a splice variation in a HER2 mRNA that results in the expression of an altered HER2 protein that has increased resistance to inhibition by an HER2 inhibitor, a tyrosine kinase inhibitor (TKI), and/or a multi-kinase inhibitor (MKI), e.g., as compared to a wild type HER2 kinase (e.g., the HER2 variants described herein). See, e.g., Rexer and Arteaga. Crit Rev Oncog.2012; 17(1): 1– 16. In some embodiments, the dysregulation of a HER2 gene, a HER2 kinase, or expression or activity or level of any of the same, includes one or more chromosome translocations or inversions resulting in HER2 gene fusions, respectively. In some embodiments, the dysregulation of a HER2 gene, a HER2 kinase, or expression or activity or level of any of the same, is a result of genetic translocations in which the expressed protein is a fusion protein containing residues from a non-HER2 partner protein and HER2, and include a minimum of a functional HER2 kinase domain, respectively. Table 4. Exemplary HER2 Fusion Proteins and Cancers

1 Yu et al. J Transl Med.2015; 13: 116. In some embodiments, the dysregulation of a HER2 gene, a HER2 kinase, or expression or activity or level of any of the same, includes at least one point mutation in a HER2 gene that results in the production of a HER2 kinase that has one or more amino acid substitutions or insertions or deletions in a HER2 gene that results in the production of a HER2 kinase that has one or more amino acids inserted or removed, as compared to the wild-type HER2 kinase. In other embodiments, the dysregulation of a HER2 gene, a HER2 kinase, or expression or activity or level of any of the same, includes at least one point mutation in a HER2 gene that results in the production of a HER2 kinase that has one or more amino acid substitutions as compared to the wild-type HER2 kinase, and which has increased resistance to a compound of Formula (I) (e.g., Formula (I-a), (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-g1), (I-g1-1), (I-g1-2),or (I-h)), or a pharmaceutically acceptable salt thereof, as compared to a wild type HER2 kinase or a HER2 kinase not including the same mutation. Exemplary Sequence of Mature Human HER2 Protein (UniProtKB entry P04626) (SEQ ID NO: 2)

In some embodiments, dysregulation of an HER2 gene, an HER2 kinase, or expression or activity or level of any of the same, includes at least one HER2 inhibitor resistance mutation in an HER2 gene that results in the production of an HER2 kinase that has one or more of the amino acid substitutions, insertions, or deletions as described in Table 5. In some embodiments, compounds of Formula (I) (e.g., Formula (I-a), (I-a1), (I- a2), (I-a3), (I-a4), (I-a5), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-g1), (I-g1-1), (I-g1-2),or (I-h)) and pharmaceutically acceptable salts and solvates thereof, are useful in treating subjects that develop cancers with HER2 inhibitor resistance mutations (e.g., that result in an increased resistance to a first HER2 inhibitor, e.g., a substitution at amino acid position 755 or 798 (e.g., L755S, L755P, T798I, and T798M), and/or one or more HER2 inhibitor resistance mutations listed in Table 5) by either dosing in combination or as a subsequent or additional (e.g., follow-up) therapy to existing drug treatments (e.g., other inhibitors of HER2; e.g., first and/or second HER2 inhibitors). Table 5. HER2 Protein Amino Acid Resistance Mutations

1 Hanker et al. Cancer Discov.2017 Jun;7(6):575-585. 2 Sun et al. J Cell Mol Med.2015 Dec; 19(12): 2691–2701. As used herein, a “first inhibitor of HER2” or “first HER2 inhibitor” is a HER2 inhibitor as defined herein, but which does not include a compound of Formula (I) (e.g., Formula (I-a), (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I- g1), (I-g1-1), (I-g1-2),or (I-h)), or a pharmaceutically acceptable salt thereof, as defined herein. As used herein, a “second inhibitor of HER2” or a “second HER2 inhibitor” is a HER2 inhibitor as defined herein, but which does not include a compound of Formula (I), or a pharmaceutically acceptable salt thereof, as defined herein. When both a first and a second inhibitor of HER2 are present in a method provided herein, the first and second inhibitors of HER2 are different. In some embodiments, the first and/or second inhibitor of HER2 bind in a different location than a compound of Formula (I). For example, in some embodiments, a first and/or second inhibitor of HER2 can inhibit dimerization of HER2, while a compound of Formula (I) can inhibit the active site. In some embodiments, a first and/or second inhibitor of HER2 can be an allosteric inhibitor of HER2, while a compound of Formula (I) can inhibit the HER2 active site. Exemplary first and second inhibitors of HER2 are described herein. In some embodiments, a first or second inhibitor of HER2 can be selected from the group consisting of: trastuzumab (e.g., TRAZIMERA™, HERCEPTIN®), pertuzumab (e.g., PERJETA®), trastuzumab emtansine (T-DM1 or ado-trastuzumab emtansine, e.g., KADCYLA®), lapatinib, KU004, neratinib (e.g., NERLYNX®), dacomitinib (e.g., VIZIMPRO®), afatinib (GILOTRIF®), tucatinib (e.g., TUKYSA™), erlotinib (e.g., TARCEVA®), pyrotinib, poziotinib, CP-724714, CUDC-101, sapitinib (AZD8931), tanespimycin (17- AAG), IPI-504, PF299, pelitinib, S- 222611, and AEE-788. In some embodiments, compounds of Formula (I) (e.g., Formula (I-a), (I-a1), (I- a2), (I-a3), (I-a4), (I-a5), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-g1), (I-g1-1), (I-g1-2),or (I-h)), or pharmaceutically acceptable salts and solvates thereof, are useful for treating a cancer that has been identified as having one or more HER2 inhibitor resistance mutations (that result in an increased resistance to a first or second inhibitor of HER2, e.g., a substitution described in Table 5 including substitutions at amino acid position 755 or 798 (e.g., L755S, L755P, T798I, and T798M)). In some embodiments, the one or more HER2 inhibitor resistance mutations occurs in a nucleic acid sequence encoding a mutant HER2 protein (e.g., a mutant HER2 protein having any of the mutations described in Table 3) resulting in a mutant HER2 protein that exhibits HER2 inhibitor resistance. Like EGFR, the epidermal growth factor receptor 2 (HER2) belongs to the ErbB family of receptor tyrosine kinases (RTKs) and provides critical functions in epithelial cell physiology (Schlessinger J (2014) Cold Spring Harb Perspect Biol 6, a008912; and Moasser. Oncogene. 2007 Oct 4; 26(45): 6469–6487). It is frequently mutated and/or overexpressed in different types of human cancers and is the target of multiple cancer therapies currently adopted in the clinical practice (Moasser. Oncogene. 2007 Oct 4; 26(45): 6469–6487). Accordingly, provided herein are methods for treating a subject identified or diagnosed as having a HER2-associated cancer that include administering to the subject a therapeutically effective amount of a compound of Formula (I) (e.g., Formula (I-a), (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-g1), (I-g1-1), (I-g1-2),or (I-h)), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. In some embodiments, the subject that has been identified or diagnosed as having a HER2-associated cancer through the use of a regulatory agency-approved, e.g., FDA- approved test or assay for identifying dysregulation of a HER2 gene, a HER2 kinase, or expression or activity or level of any of the same, in a subject or a biopsy sample from the subject or by performing any of the non-limiting examples of assays described herein. In some embodiments, the test or assay is provided as a kit. In some embodiments, the cancer is a HER2-associated cancer. Also provided are methods for treating cancer in a subject in need thereof, the method comprising: (a) detecting a HER2-associated cancer in the subject; and (b) administering to the subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. Some embodiments of these methods further include administering to the subject another anticancer agent (e.g., a second HER2 inhibitor, a second compound of Formula (I), or a pharmaceutically acceptable salt thereof, or an immunotherapy). In some embodiments, the subject was previously treated with a first HER2 inhibitor or previously treated with another anticancer treatment, e.g., at least partial resection of the tumor or radiation therapy. In some embodiments, the subject is determined to have a HER2-associated cancer through the use of a regulatory agency-approved, e.g., FDA-approved test or assay for identifying dysregulation of a HER2 gene, a HER2 kinase, or expression or activity or level of any of the same, in a subject or a biopsy sample from the subject or by performing any of the non-limiting examples of assays described herein. In some embodiments, the test or assay is provided as a kit. In some embodiments, the cancer is a HER2-associated cancer. Also provided are methods of treating a subject that include performing an assay on a sample obtained from the subject to determine whether the subject has a dysregulation of a HER2 gene, a HER2 kinase, or expression or activity or level of any of the same, and administering (e.g., specifically or selectively administering) a therapeutically effective amount of a compound of Formula (I) (e.g., Formula (I-a), (I-a1), (I-a2), (I-a3), (I-a4), (I- a5), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-g1), (I-g1-1), (I-g1-2),or (I-h)), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, to the subject determined to have a dysregulation of a HER2 gene, a HER2 kinase, or expression or activity or level of any of the same. Some embodiments of these methods further include administering to the subject another anticancer agent (e.g., a second HER2 inhibitor, a second compound of Formula (I), or a pharmaceutically acceptable salt thereof, or immunotherapy). In some embodiments of these methods, the subject was previously treated with a first HER2 inhibitor or previously treated with another anticancer treatment, e.g., at least partial resection of a tumor or radiation therapy. In some embodiments, the subject is a subject suspected of having a HER2-associated cancer, a subject presenting with one or more symptoms of a HER2-associated cancer, or a subject having an elevated risk of developing a HER2-associated cancer. In some embodiments, the assay utilizes next generation sequencing, pyrosequencing, immunohistochemistry, or break apart FISH analysis. In some embodiments, the assay is a regulatory agency-approved assay, e.g., FDA-approved kit. In some embodiments, the assay is a liquid biopsy. Additional, non- limiting assays that may be used in these methods are described herein. Additional assays are also known in the art. As used herein, a “first inhibitor of HER2” or “first HER2 inhibitor” is a HER2 inhibitor as defined herein, which does not include a compound of Formula (I) (e.g., Formula (I-a), (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I- g1), (I-g1-1), (I-g1-2),or (I-h)), or a pharmaceutically acceptable salt thereof, as defined herein. As used herein, a “second inhibitor of HER2” or a “second HER2 inhibitor” is an inhibitor of HER2 as defined herein, which does not include a compound of Formula (I), or a pharmaceutically acceptable salt thereof, as defined herein. When both a first and a second HER2 inhibitor are present in a method provided herein, the first and second HER2 inhibitors are different. Also provided is a compound of Formula (I) (e.g., Formula (I-a), (I-a1), (I-a2), (I- a3), (I-a4), (I-a5), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-g1), (I-g1-1), (I-g1-2),or (I-h)), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for use in treating a HER2-associated cancer in a subject identified or diagnosed as having a HER2-associated cancer through a step of performing an assay (e.g., an in vitro assay) on a sample obtained from the subject to determine whether the subject has a dysregulation of a HER2 gene, a HER2 kinase, or expression or activity or level of any of the same, where the presence of a dysregulation of a HER2 gene, a HER2 kinase, or expression or activity or level of any of the same, identifies that the subject has a HER2-associated cancer. Also provided is the use of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating a HER2-associated cancer in a subject identified or diagnosed as having a HER2-associated cancer through a step of performing an assay on a sample obtained from the subject to determine whether the subject has a dysregulation of a HER2 gene, a HER2 kinase, or expression or activity or level of any of the same where the presence of dysregulation of a HER2 gene, a HER2 kinase, or expression or activity or level of any of the same, identifies that the subject has a HER2-associated cancer. Some embodiments of any of the methods or uses described herein further include recording in the subject’s clinical record (e.g., a computer readable medium) that the subject is determined to have a dysregulation of a HER2 gene, a HER2 kinase, or expression or activity or level of any of the same, through the performance of the assay, should be administered a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. In some embodiments, the assay utilizes next generation sequencing, pyrosequencing, immunohistochemistry, or break apart FISH analysis. In some embodiments, the assay is a regulatory agency- approved assay, e.g., FDA-approved kit. In some embodiments, the assay is a liquid biopsy. Also provided is a compound of Formula (I) (e.g., Formula (I-a), (I-a1), (I-a2), (I- a3), (I-a4), (I-a5), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-g1), (I-g1-1), (I-g1-2),or (I-h)), or a pharmaceutically acceptable salt thereof, for use in the treatment of a cancer in a subject in need thereof, or a subject identified or diagnosed as having a HER2-associated cancer. Also provided is the use of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating a cancer in a subject identified or diagnosed as having a HER2-associated cancer (. In some embodiments, a subject is identified or diagnosed as having a HER2-associated cancer through the use of a regulatory agency-approved, e.g., FDA-approved, kit for identifying dysregulation of a HER2 gene, a HER2 kinase, or expression or activity or level of any of the same, in a subject or a biopsy sample from the subject. As provided herein, a HER2- associated cancer includes those described herein and known in the art. In some embodiments of any of the methods or uses described herein, the subject has been identified or diagnosed as having a cancer with a dysregulation of a HER2 gene, a HER2 kinase, or expression or activity or level of any of the same. In some embodiments of any of the methods or uses described herein, the subject has a tumor that is positive for a dysregulation of a HER2 gene, a HER2 kinase, or expression or activity or level of any of the same. In some embodiments of any of the methods or uses described herein, the subject can be a subject with a tumor(s) that is positive for a dysregulation of a HER2 gene, a HER2 kinase, or expression or activity or level of any of the same. In some embodiments of any of the methods or uses described herein, the subject can be a subject whose tumors have a dysregulation of a HER2 gene, a HER2 kinase, or expression or activity or level of any of the same. In some embodiments of any of the methods or uses described herein, the subject is suspected of having a HER2-associated cancer. In some embodiments, provided herein are methods for treating a HER2-associated cancer in a subject in need of such treatment, the method comprising a) detecting a dysregulation of a HER2 gene, a HER2 kinase, or the expression or activity or level of any of the same in a sample from the subject; and b) administering a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof. In some embodiments, the dysregulation of a HER2 gene, a HER2 kinase, or the expression or activity or level of any of the same includes one or more HER2 kinase protein point mutations/insertions/deletions. Non- limiting examples of HER2 kinase protein fusions and point mutations/insertions/deletions are described in Tables 3-5. In some embodiments, the HER2 kinase protein point mutations/insertions/deletions are selected from the group consisting of a point mutation at amino acid position 310, 678, 755, 767, 773, 777, or 842 (e.g., S310F, S310Y, R678Q, R678W, R678P, I767M, V773M, V777L, and V842I) and/or an insertion or deletion at amino acid positions 772, 775, 776, 777, and 780 (e.g., Y772_A775dup, A775_G776insYVMA, G776delinsVC, G776delinsVV, V777_G778insGSP, and P780_Y781insGSP). In some embodiments, the HER2 kinase protein point mutation/insertion/deletion is an exon 20 point mutation/insertion/deletion. In some embodiments, the HER2 exon 20 point mutation/insertion/deletion is a point mutation at amino acid position 773, 776, 777, 779, 780, and 783 (e.g., V773M, G776C, G776V, G776S, V777L, V777M, S779T, P780L, and S783P) and/or an exon 20 insertion/deletion such as an insertion/deletion at amino acid positions 774, 775, 776, 777, 778, and 780. In some embodiments, the HER2 kinase protein insertion is an exon 20 insertion selected from the group consisting of: A775_G776insYVMA, A775_G776insAVMA, A775_G776insSVMA, A775_G776insVAG, A775insV G776C, A775_G776insI, G776del insVC2, G776del insVV, G776del insLC, G776C V777insC, G776C V777insV, V777_G778insCG, G778_S779insCPG, and P780_Y781insGSP. In some embodiments, the HER2 kinase protein mutation/insertion/deletion is an exon 20 insertion/deletion selected from the group consisting of: is Y772_A775dup, A775_G776insYVMA, G776delinsVC, G776delinsVV, V777_G778insGSP, or P780_Y781insGSP. In some embodiments, the cancer with a dysregulation of a HER2 gene, a HER2 kinase, or expression or activity or level of any of the same is determined using a regulatory agency- approved, e.g., FDA-approved, assay or kit. In some embodiments, the tumor that is positive for a dysregulation of a HER2 gene, a HER2 kinase, or expression or activity or level of any of the same is a tumor positive for one or more HER2 inhibitor resistance mutations. In some embodiments, the tumor with a dysregulation of a HER2 gene, a HER2 kinase, or expression or activity or level of any of the same is determined using a regulatory agency-approved, e.g., FDA-approved, assay or kit. In some embodiments of any of the methods or uses described herein, the subject has a clinical record indicating that the subject has a tumor that has a dysregulation of a HER2 gene, a HER2 kinase, or expression or activity or level of any of the same. Also provided are methods of treating a subject that include administering a therapeutically effective amount of a compound of Formula (I) (e.g., Formula (I-a), (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-g1), (I-g1-1), (I-g1-2),or (I-h)), or a pharmaceutically acceptable salt thereof, to a subject having a clinical record that indicates that the subject has a dysregulation of a HER2 gene, a HER2 kinase, or expression or activity or level of any of the same. In some embodiments, the methods provided herein include performing an assay on a sample obtained from the subject to determine whether the subject has a dysregulation of a HER2 gene, a HER2 kinase, or expression or level of any of the same. In some such embodiments, the method also includes administering to a subject determined to have a dysregulation of a HER2 gene, a HER2 kinase, or expression or activity, or level of any of the same a therapeutically effective amount of a compound of Formula (I) (e.g., Formula (I-a), (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-g1), (I-g1- 1), (I-g1-2),or (I-h)), or a pharmaceutically acceptable salt thereof. In some embodiments, the method includes determining that a subject has a dysregulation of a HER2 gene, a HER2 kinase, or expression or level of any of the same via an assay performed on a sample obtained from the subject. In such embodiments, the method also includes administering to a subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof. In some embodiments, the dysregulation in a HER2 gene, a HER2 kinase, or expression or activity or level of any of the same is one or more point mutation in the HER2 gene (e.g., any of the one or more of the HER2 point mutations described herein). The one or more point mutations in a HER2 gene can result, e.g., in the translation of a HER2 protein having one or more of the following amino acid substitutions: S310F, S310Y, R678Q, R678W, R678P, I767M, V773M, V777L, and V842I. The one or more point mutations in a HER2 gene can result, e.g., in the translation of a HER2 protein having one or more of the following exon 20 amino acid substitutions: V773M, G776C, G776V, G776S, V777L, V777M, S779T, P780L, and S783P. In some embodiments, the dysregulation in a HER2 gene, a HER2 kinase, or expression or activity or level of any of the same is one or more insertions in the HER2 gene (e.g., any of the one or more of the HER2 insertions described herein). The one or more insertions in a HER2 gene can result, e.g., in the translation of a HER2 protein having one or more of the following exon 20 insertions: M774AYVM, M774del insWLV, A775_G776insYVMA, A775_G776insAVMA, A775_G776insSVMA, A775_G776insVAG, A775insV G776C, A775_G776insI, G776del insVC2, G776del insVV, G776del insLC, G776C V777insC, G776C V777insV, V777_G778insCG, G778_S779insCPG, and P780_Y781insGSP. In some embodiments, the one or more insertions in a HER2 gene can result, e.g., in the translation of a HER2 protein having one or more of the following exon 20 insertions: Y772_A775dup, A775_G776insYVMA, G776delinsVC, G776delinsVV, V777_G778insGSP, and P780_Y781insGSP. Some embodiments of these methods further include administering to the subject another anticancer agent (e.g., a second HER2 inhibitor, a second compound of Formula (I), or a pharmaceutically acceptable salt thereof, or immunotherapy). In some embodiments of any of the methods or uses described herein, an assay used to determine whether the subject has a dysregulation of a HER2 gene, a HER2 kinase, or expression or activity or level of any of the same, using a sample from a subject can include, for example, next generation sequencing, immunohistochemistry, fluorescence microscopy, break apart FISH analysis, Southern blotting, Western blotting, FACS analysis, Northern blotting, and PCR-based amplification (e.g., RT-PCR and quantitative real-time RT-PCR). As is well-known in the art, the assays are typically performed, e.g., with at least one labelled nucleic acid probe or at least one labelled antibody or antigen- binding fragment thereof. Assays can utilize other detection methods known in the art for detecting dysregulation of a HER2 gene, a HER2 kinase, or expression or activity or levels of any of the same (see, e.g., the references cited herein). In some embodiments, the sample is a biological sample or a biopsy sample (e.g., a paraffin-embedded biopsy sample) from the subject. In some embodiments, the subject is a subject suspected of having a HER2- associated cancer, a subject having one or more symptoms of a HER2-associated cancer, and/or a subject that has an increased risk of developing a HER2-associated cancer. In some embodiments, dysregulation of a HER2 gene, a HER2 kinase, or the expression or activity or level of any of the same can be identified using a liquid biopsy (variously referred to as a fluid biopsy or fluid phase biopsy). See, e.g., Karachialiou et al., “Real-time liquid biopsies become a reality in cancer treatment”, Ann. Transl. Med., 3(3):36, 2016. Liquid biopsy methods can be used to detect total tumor burden and/or the dysregulation of a HER2 gene, a HER2 kinasev, or the expression or activity or level of any of the same. Liquid biopsies can be performed on biological samples obtained relatively easily from a subject (e.g., via a simple blood draw) and are generally less invasive than traditional methods used to detect tumor burden and/or dysregulation of a HER2 gene, a HER2 kinase, or the expression or activity or level of any of the same. In some embodiments, liquid biopsies can be used to detect the presence of dysregulation of a HER2 gene, a HER2 kinase, or the expression or activity or level of any of the same at an earlier stage than traditional methods. In some embodiments, the biological sample to be used in a liquid biopsy can include, blood, plasma, urine, cerebrospinal fluid, saliva, sputum, broncho-alveolar lavage, bile, lymphatic fluid, cyst fluid, stool, ascites, and combinations thereof. In some embodiments, a liquid biopsy can be used to detect circulating tumor cells (CTCs). In some embodiments, a liquid biopsy can be used to detect cell-free DNA. In some embodiments, cell-free DNA detected using a liquid biopsy is circulating tumor DNA (ctDNA) that is derived from tumor cells. Analysis of ctDNA (e.g., using sensitive detection techniques such as, without limitation, next-generation sequencing (NGS), traditional PCR, digital PCR, or microarray analysis) can be used to identify dysregulation of a HER2 gene, a HER2 kinase, or the expression or activity or level of any of the same. Also provided is a method for inhibiting EGFR activity in a cell, comprising contacting the cell with a compound of Formula (I) (e.g., Formula (I-a), (I-a1), (I-a2), (I- a3), (I-a4), (I-a5), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-g1), (I-g1-1), (I-g1-2),or (I-h)), or a pharmaceutically acceptable salt thereof. Also provided is a method for inhibiting HER2 activity in a cell, comprising contacting the cell with a compound of Formula (I), or a pharmaceutically acceptable salt thereof. Further provided herein is a method for inhibiting EGFR and HER2 activity in a cell, comprising contacting the cell with a compound of Formula (I), or a pharmaceutically acceptable salt thereof. In some embodiments, the contacting is in vitro. In some embodiments, the contacting is in vivo. In some embodiments, the contacting is in vivo, wherein the method comprises administering an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, to a subject having a cell having aberrant EGFR activity and/or HER2 activity. In some embodiments, the cell is a cancer cell. In some embodiments, the cancer cell is any cancer as described herein. In some embodiments, the cancer cell is an EGFR-associated cancer cell. In some embodiments, the cancer cell is a HER2-associated cancer cell. As used herein, the term "contacting" refers to the bringing together of indicated moieties in an in vitro system or an in vivo system. For example, "contacting" an EGFR kinase with a compound provided herein includes the administration of a compound provided herein to an individual or subject, such as a human, having an EGFR kinase, as well as, for example, introducing a compound provided herein into a sample containing a cellular or purified preparation containing the EGFR kinase. Also provided herein is a method of inhibiting cell proliferation, in vitro or in vivo, the method comprising contacting a cell with an effective amount of a compound of Formula (I) (e.g., Formula (I-a), (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b), (I-c), (I-d), (I- e), (I-f), (I-g), (I-g1), (I-g1-1), (I-g1-2),or (I-h)), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof as defined herein. Further provided herein is a method of increase cell death, in vitro or in vivo, the method comprising contacting a cell with an effective amount of a compound of Formula (I) (e.g., Formula (I-a), (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-g1), (I-g1-1), (I-g1-2),or (I-h)), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof as defined herein. Also provided herein is a method of increasing tumor cell death in a subject. The method comprises administering to the subject an effective compound of Formula (I), or a pharmaceutically acceptable salt thereof, in an amount effective to increase tumor cell death. The phrase "therapeutically effective amount" means an amount of compound that, when administered to a subject in need of such treatment, is sufficient to (i) treat an EGFR kinase-associated disease or disorder or a HER2 kinase-associated disease or disorder, (ii) attenuate, ameliorate, or eliminate one or more symptoms of the particular disease, condition, or disorder, or (iii) delay the onset of one or more symptoms of the particular disease, condition, or disorder described herein. The amount of a compound of Formula (I) (e.g., Formula (I-a), (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b), (I-c), (I-d), (I-e), (I-f), (I- g), (I-g1), (I-g1-1), (I-g1-2),or (I-h)), or a pharmaceutically acceptable salt thereof, that will correspond to such an amount will vary depending upon factors such as the particular compound, disease condition and its severity, the identity (e.g., weight) of the subject in need of treatment, but can nevertheless be routinely determined by one skilled in the art. When employed as pharmaceuticals, the compounds of Formula (I) (e.g., Formula (I-a), (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-g1), (I-g1- 1), (I-g1-2),or (I-h)), including pharmaceutically acceptable salts or solvates thereof, can be administered in the form of pharmaceutical compositions as described herein. Also provided herein is a method of treating a subject having a cancer, wherein the method comprises: (a) determining that a cancer cell in a sample obtained from a subject having a cancer and previously administered one or more doses of a first EGFR inhibitor has one or more EGFR inhibitor resistance mutations that confer increased resistance to a cancer cell or tumor to treatment with the first EGFR inhibitor that was previously administered to the subject; and (b) administering a therapeutically effective amount of a compound of Formula (I) (e.g., Formula (I-a), (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b), (I-c), (I-d), (I-e), (I-f), (I- g), (I-g1), (I-g1-1), (I-g1-2),or (I-h)), or a pharmaceutically acceptable salt thereof, as a monotherapy or in conjunction with another anticancer agent to the subject. Further provided herein is a method of treating a subject having a cancer, wherein the method comprises: (a) determining that a cancer cell in a sample obtained from a subject having a cancer and previously administered one or more doses of a first EGFR inhibitor does not have one or more EGFR inhibitor resistance mutations that confer increased resistance to a cancer cell or tumor to treatment with the first EGFR inhibitor that was previously administered to the subject; and (b) administering additional doses of the first EGFR inhibitor to the subject. Combinations In the field of medical oncology it is normal practice to use a combination of different forms of treatment to treat each subject with cancer. In medical oncology the other component(s) of such conjoint treatment or therapy in addition to compositions provided herein may be, for example, surgery, radiotherapy, and chemotherapeutic agents, such as other kinase inhibitors, signal transduction inhibitors and/or monoclonal antibodies. For example, a surgery may be open surgery or minimally invasive surgery. Compounds of Formula (I) (e.g., Formula (I-a), (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b), (I-c), (I-d), (I- e), (I-f), (I-g), (I-g1), (I-g1-1), (I-g1-2),or (I-h)), or pharmaceutically acceptable salts or solvates thereof, therefore may also be useful as adjuvants to cancer treatment, that is, they can be used in combination with one or more additional therapies or therapeutic agents, for example, a chemotherapeutic agent that works by the same or by a different mechanism of action. In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can be used prior to administration of an additional therapeutic agent or additional therapy. For example, a subject in need thereof can be administered one or more doses of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, for a period of time and then undergo at least partial resection of the tumor. In some embodiments, the treatment with one or more doses of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, reduces the size of the tumor (e.g., the tumor burden) prior to the at least partial resection of the tumor. In some embodiments, a subject in need thereof can be administered one or more doses of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, for a period of time and under one or more rounds of radiation therapy. In some embodiments, the treatment with one or more doses of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, reduces the size of the tumor (e.g., the tumor burden) prior to the one or more rounds of radiation therapy. In some embodiments, a subject has a cancer (e.g., a locally advanced or metastatic tumor) that is refractory or intolerant to standard therapy (e.g., administration of a chemotherapeutic agent, such as a first EGFR inhibitor, a first HER2 inhibitor, or a multi- kinase inhibitor, immunotherapy, or radiation (e.g., radioactive iodine)). In some embodiments, a subject has a cancer (e.g., a locally advanced or metastatic tumor) that is refractory or intolerant to prior therapy (e.g., administration of a chemotherapeutic agent, such as a first EGFR inhibitor, a first HER2 inhibitor, or a multi-kinase inhibitor, immunotherapy, or radiation (e.g., radioactive iodine)). In some embodiments, a subject has a cancer (e.g., a locally advanced or metastatic tumor) that has no standard therapy. In some embodiments, a subject is EGFR inhibitor naïve. For example, the subject is naïve to treatment with a selective EGFR inhibitor. In some embodiments, a subject is not EGFR inhibitor naïve. In some embodiments, a subject is HER2 inhibitor naïve. For example, the subject is naïve to treatment with a selective HER2 inhibitor. In some embodiments, a subject is not HER2 inhibitor naïve. In some embodiments, a subject has undergone prior therapy. For example, treatment with a multi-kinase inhibitor (MKI), an EGFR tyrosine kinase inhibitor (TKI), osimertinib, gefitinib, erlotinib, afatinib, lapatinib, neratinib, AZD- 9291, CL-387785, CO-1686, or WZ4002. In some embodiments of any the methods described herein, the compound of Formula (I) (e.g., Formula (I-a), (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b), (I-c), (I-d), (I- e), (I-f), (I-g), (I-g1), (I-g1-1), (I-g1-2),or (I-h)) (or a pharmaceutically acceptable salt thereof) is administered in combination with a therapeutically effective amount of at least one additional therapeutic agent selected from one or more additional therapies or therapeutic (e.g., chemotherapeutic) agents. Non-limiting examples of additional therapeutic agents include: other EGFR- targeted therapeutic agents (i.e., a first or second EGFR inhibitor), other HER2-targeted therapeutic agents (i.e., a first or second HER2 inhibitor), RAS pathway targeted therapeutic agents, PARP inhibitors, other kinase inhibitors (e.g., receptor tyrosine kinase- targeted therapeutic agents (e.g., Trk inhibitors or multi-kinase inhibitors)), farnesyl transferase inhibitors, signal transduction pathway inhibitors, checkpoint inhibitors, modulators of the apoptosis pathway (e.g., obataclax); cytotoxic chemotherapeutics, angiogenesis-targeted therapies, immune-targeted agents, including immunotherapy, and radiotherapy. In some embodiments, the other EGFR-targeted therapeutic is a multi-kinase inhibitor exhibiting EGFR inhibition activity. In some embodiments, the other EGFR- targeted therapeutic inhibitor is selective for an EGFR kinase. Non-limiting examples of EGFR-targeted therapeutic agents (e.g., a first EGFR inhibitor or a second EGFR inhibitor) include an EGFR-selective inhibitor, a panHER inhibitor, and an anti-EGFR antibody. In some embodiments, the EGFR inhibitor is a covalent inhibitor. In some embodiments, the EGFR-targeted therapeutic agent is osimertinib (AZD9291, merelectinib, TAGRISSOTM), erlotinib (TARCEVA®), gefitinib (IRESSA®), cetuximab (ERBITUX®), necitumumab (PORTRAZZATM, IMC-11F8), neratinib (HKI-272, NERLYNX®), lapatinib (TYKERB®), panitumumab (ABX-EGF, VECTIBIX®), vandetanib (CAPRELSA®), rociletinib (CO-1686), olmutinib (OLITATM, HM61713, BI-1482694), naquotinib (ASP8273), nazartinib (EGF816, NVS- 816), PF-06747775, icotinib (BPI-2009H), afatinib (BIBW 2992, GILOTRIF®), dacomitinib (PF-00299804, PF-804, PF-299, PF-299804), avitinib (AC0010), AC0010MA EAI045, matuzumab (EMD-7200), nimotuzumab (h-R3, BIOMAb EGFR®), zalutumab, MDX447, depatuxizumab (humanized mAb 806, ABT-806), depatuxizumab mafodotin (ABT-414), ABT-806, mAb 806, canertinib (CI-1033), shikonin, shikonin derivatives (e.g., deoxyshikonin, isobutyrylshikonin, acetylshikonin, β,β-dimethylacrylshikonin and acetylalkannin), poziotinib (NOV120101, HM781-36B), AV-412, ibrutinib, WZ4002, brigatinib (AP26113, ALUNBRIG®), pelitinib (EKB-569), tarloxotinib (TH-4000, PR610), BPI-15086, Hemay022, ZN-e4, tesevatinib (KD019, XL647), YH25448, epitinib (HMPL-813), CK-101, MM-151, AZD3759, ZD6474, PF-06459988, varlintinib (ASLAN001, ARRY-334543), AP32788, HLX07, D-0316, AEE788, HS-10296, avitinib, GW572016, pyrotinib (SHR1258), SCT200, CPGJ602, Sym004, MAb-425, Modotuximab (TAB-H49), futuximab (992 DS), zalutumumab, KL-140, RO5083945, IMGN289, JNJ- 61186372, LY3164530, Sym013, AMG 595, BDTX-189, avatinib, Disruptin, CL-387785, EGFRBi-Armed Autologous T Cells, and EGFR CAR-T Therapy. In some embodiments, the EGFR-targeted therapeutic agent is selected from osimertinib, gefitinib, erlotinib, afatinib, lapatinib, neratinib, AZD-9291, CL-387785, CO-1686, or WZ4002. Additional EGFR-targeted therapeutic agents (e.g., a first EGFR inhibitor or a second EGFR inhibitor) include those disclosed in WO 2019/246541; WO 2019/165385; WO 2014/176475; and US 9,029,502, each of which is incorporated by reference in its entirety. In some embodiments, the other HER2-targeted therapeutic is a multi-kinase inhibitor exhibiting HER2 inhibition activity. In some embodiments, the other HER2- targeted therapeutic inhibitor is selective for a HER2 kinase. Non-limiting examples of HER2-targeted therapeutic agents (e.g., a first HER2 inhibitor or a second HER2 inhibitor) include a HER2-selective inhibitor, a panHER inhibitor, and an anti-HER2 antibody. Exemplary HER2-targeted therapeutic agents include trastuzumab (e.g., TRAZIMERA™, HERCEPTIN®), pertuzumab (e.g., PERJETA®), trastuzumab emtansine (T-DM1 or ado-trastuzumab emtansine, e.g., KADCYLA®), lapatinib, KU004, neratinib (e.g., NERLYNX®), dacomitinib (e.g., VIZIMPRO®), afatinib (GILOTRIF®), tucatinib (e.g., TUKYSA™), erlotinib (e.g., TARCEVA®), pyrotinib, poziotinib, CP-724714, CUDC-101, sapitinib (AZD8931), tanespimycin (17-AAG), IPI-504, PF299, pelitinib, S- 222611, and AEE-788. Additional HER2-targeted therapeutic agents (e.g., a first HER2 inhibitor or a second HER2 inhibitor) include those disclosed in WO 2019/246541; WO 2019/165385; WO 2014/176475; and US 9,029,502, each of which is incorporated by reference in its entirety. A “RAS pathway targeted therapeutic agent” as used herein includes any compound exhibiting inactivation activity of any protein in a RAS pathway (e.g., kinase inhibition, allosteric inhibition, inhibition of dimerization, and induction of degradation). Non- limiting examples of a protein in a RAS pathway include any one of the proteins in the RAS-RAF-MAPK pathway or PI3K/AKT pathway such as RAS (e.g., KRAS, HRAS, and NRAS), RAF, BRAF, MEK, ERK, PI3K, AKT, and mTOR. In some embodiments, a RAS pathway modulator can be selective for a protein in a RAS pathway, e.g., the RAS pathway modulator can be selective for RAS (also referred to as a RAS modulator). In some embodiments, a RAS modulator is a covalent inhibitor. In some embodiments, a RAS pathway targeted therapeutic agent is a “KRAS pathway modulator.” A KRAS pathway modulator includes any compound exhibiting inactivation activity of any protein in a KRAS pathway (e.g., kinase inhibition, allosteric inhibition, inhibition of dimerization, and induction of degradation). Non-limiting examples of a protein in a KRAS pathway include any one of the proteins in the KRAS-RAF-MAPK pathway or PI3K/AKT pathway such as KRAS, RAF, BRAF, MEK, ERK, PI3K, AKT, and mTOR. In some embodiments, a KRAS pathway modulator can be selective for a protein in a RAS pathway, e.g., the KRAS pathway modulator can be selective for KRAS (also referred to as a KRAS modulator). In some embodiments, a KRAS modulator is a covalent inhibitor. Non-limiting examples of a KRAS-targeted therapeutic agents (e.g., KRAS inhibitors) include BI 1701963, AMG 510, ARS-3248, ARS1620, AZD4785, SML-8-73-1, SML-10-70-1, VSA9, AA12, and MRTX-849. Further non-limiting examples of RAS-targeted therapeutic agents include BRAF inhibitors, MEK inhibitors, ERK inhibitors, PI3K inhibitors, AKT inhibitors, and mTOR inhibitors. In some embodiments, the BRAF inhibitor is vemurafenib (ZELBORAF®), dabrafenib (TAFINLAR®), and encorafenib (BRAFTOVITM), BMS-908662 (XL281), sorafenib, LGX818, PLX3603, RAF265, RO5185426, GSK2118436, ARQ 736, GDC- 0879, PLX-4720, AZ304, PLX-8394, HM95573, RO5126766, LXH254, or a combination thereof. In some embodiments, the MEK inhibitor is trametinib (MEKINIST®, GSK1120212), cobimetinib (COTELLIC®), binimetinib (MEKTOVI®, MEK162), selumetinib (AZD6244), PD0325901, MSC1936369B, SHR7390, TAK-733, RO5126766, CS3006, WX-554, PD98059, CI1040 (PD184352), hypothemycin, or a combination thereof. In some embodiments, the ERK inhibitor is FRI-20 (ON-01060), VTX-11e, 25- OH-D3-3-BE (B3CD, bromoacetoxycalcidiol), FR-180204, AEZ-131 (AEZS-131), AEZS-136, AZ-13767370, BL-EI-001, LY-3214996, LTT-462, KO-947, KO-947, MK- 8353 (SCH900353), SCH772984, ulixertinib (BVD-523), CC-90003, GDC-0994 (RG- 7482), ASN007, FR148083, 5-7-Oxozeaenol, 5-iodotubercidin, GDC0994, ONC201, or a combination thereof. In some embodiments, PI3K inhibitor is selected from buparlisib (BKM120), alpelisib (BYL719), WX-037, copanlisib (ALIQOPATM, BAY80-6946), dactolisib (NVP-BEZ235, BEZ-235), taselisib (GDC-0032, RG7604), sonolisib (PX-866), CUDC- 907, PQR309, ZSTK474, SF1126, AZD8835, GDC-0077, ASN003, pictilisib (GDC- 0941), pilaralisib (XL147, SAR245408), gedatolisib (PF-05212384, PKI-587), serabelisib (TAK-117, MLN1117, INK 1117), BGT-226 (NVP-BGT226), PF-04691502, apitolisib (GDC-0980), omipalisib (GSK2126458, GSK458), voxtalisib (XL756, SAR245409), AMG 511, CH5132799, GSK1059615, GDC-0084 (RG7666), VS-5584 (SB2343), PKI- 402, wortmannin, LY294002, PI-103, rigosertib, XL-765, LY2023414, SAR260301, KIN- 193 (AZD-6428), GS-9820, AMG319, GSK2636771, or a combination thereof. In some embodiments, the AKT inhibitor is selected from miltefosine (IMPADIVO®), wortmannin, NL-71-101, H-89, GSK690693, CCT128930, AZD5363, ipatasertib (GDC-0068, RG7440), A-674563, A-443654, AT7867, AT13148, uprosertib, afuresertib, DC120, 2-[4-(2-aminoprop-2-yl)phenyl]-3-phenylquinoxaline, MK-2206, edelfosine, miltefosine, perifosine, erucylphophocholine, erufosine, SR13668, OSU-A9, PH-316, PHT-427, PIT-1, DM-PIT-1, triciribine (Triciribine Phosphate Monohydrate), API-1, N-(4-(5-(3-acetamidophenyl)-2-(2-aminopyridin-3-yl)-3H-imidazo[4,5-b] pyridin- 3-yl)benzyl)-3-fluorobenzamide, ARQ092, BAY 1125976, 3-oxo-tirucallic acid, lactoquinomycin, boc-Phe-vinyl ketone, Perifosine (D-21266), TCN, TCN-P, GSK2141795, ONC201, or a combination thereof. In some embodiments, the mTOR inhibitor is selected from MLN0128, AZD-2014, CC-223, AZD2014, CC-115, everolimus (RAD001), temsirolimus (CCI-779), ridaforolimus (AP-23573), sirolimus (rapamycin), or a combination thereof. Non-limiting examples of farnesyl transferase inhibitors include lonafarnib, tipifarnib, BMS-214662, L778123, L744832, and FTI-277. In some embodiments, a chemotherapeutic agent includes an anthracycline, cyclophosphamide, a taxane, a platinum-based agent, mitomycin, gemcitabine, eribulin (HALAVEN^TM), or combinations thereof. Non-limiting examples of a taxane include paclitaxel, docetaxel, abraxane, and taxotere. In some embodiments, the anthracycline is selected from daunorubicin, doxorubicin, epirubicin, idarubicin, and combinations thereof. In some embodiments, the platinum-based agent is selected from carboplatin, cisplatin, oxaliplatin, nedplatin, triplatin tetranitrate, phenanthriplatin, picoplatin, satraplatin and combinations thereof Non-limiting examples of PARP inhibitors include olaparib (LYNPARZA®), talazoparib, rucaparib, niraparib, veliparib, BGB-290 (pamiparib), CEP 9722, E7016, iniparib, IMP4297, NOV1401, 2X-121, ABT-767, RBN-2397, BMN 673, KU-0059436 (AZD2281), BSI-201, PF-01367338, INO-1001, and JPI-289. Non-limiting examples of immunotherapy include immune checkpoint therapies, atezolizumab (TECENTRIQ®), albumin-bound paclitaxel. Non-limiting examples of immune checkpoint therapies include inhibitors that target CTLA-4, PD-1, PD-L1, BTLA, LAG-3, A2AR, TIM-3, B7-H3, VISTA, IDO, and combinations thereof. In some embodimetnts the CTLA-4 inhibitor is ipilimumab (YERVOY®). In some embodiments, the PD-1 inhibitor is selected from pembrolizumab (KEYTRUDA®), nivolumab (OPDIVO®), cemiplimab (LIBTAYO®), or combinations thereof. In some embodiments, the PD-L1 inhibitor is selected from atezolizumab (TECENTRIQ®), avelumab (BAVENCIO®), durvalumab (IMFINZI®), or combinations thereof. In some embodiments, the LAG-3 inhibitor is IMP701 (LAG525). In some embodiments, the A2AR inhibitor is CPI-444. In some embodiments, the TIM-3 inhibitor is MBG453. In some embodiments, the B7-H3 inhibitor is enoblituzumab. In some embodiments, the VISTA inhibitor is JNJ-61610588. In some embodiments, the IDO inhibitor is indoximod. See, for example, Marin-Acevedo, et al., J Hematol Oncol.11: 39 (2018). In some embodiments, the additional therapy or therapeutic agent is a combination of atezolizumab and nab-paclitaxel. Accordingly, also provided herein is a method of treating cancer, comprising administering to a subject in need thereof a pharmaceutical combination for treating cancer which comprises (a) a compound of Formula (I) (e.g., Formula (I-a), (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-g1), (I-g1-1), (I-g1-2),or (I-h)), or a pharmaceutically acceptable salt thereof, (b) an additional therapeutic agent, and (c) optionally at least one pharmaceutically acceptable carrier for simultaneous, separate or sequential use for the treatment of cancer, wherein the amounts of the compound of Formula (I), or a pharmaceutically acceptable salt thereof, and the additional therapeutic agent are together effective in treating the cancer. In some embodiments, the additional therapeutic agent(s) includes any one of the above listed therapies or therapeutic agents which are standards of care in cancers wherein the cancer has a dysregulation of an EGFR gene, an EGFR protein, or expression or activity, or level of any of the same. In some embodiments, the additional therapeutic agent(s) includes any one of the above listed therapies or therapeutic agents which are standards of care in cancers wherein the cancer has a dysregulation of a HER2 gene, a HER2 kinase, or expression or activity, or level of any of the same. These additional therapeutic agents may be administered with one or more doses of the compound of Formula (I) (e.g., Formula (I-a), (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I- b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-g1), (I-g1-1), (I-g1-2),or (I-h)), or a pharmaceutically acceptable salt thereof, or pharmaceutical composition thereof, as part of the same or separate dosage forms, via the same or different routes of administration, and/or on the same or different administration schedules according to standard pharmaceutical practice known to one skilled in the art. Also provided herein is (i) a pharmaceutical combination for treating a cancer in a subject in need thereof, which comprises (a) a compound of Formula (I) (e.g., Formula (I- a), (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-g1), (I-g1-1), (I-g1-2),or (I-h)), or a pharmaceutically acceptable salt thereof, (b) at least one additional therapeutic agent (e.g., any of the exemplary additional therapeutic agents described herein or known in the art), and (c) optionally at least one pharmaceutically acceptable carrier for simultaneous, separate or sequential use for the treatment of cancer, wherein the amounts of the compound of Formula (I), or pharmaceutically acceptable salt thereof, and of the additional therapeutic agent are together effective in treating the cancer; (ii) a pharmaceutical composition comprising such a combination; (iii) the use of such a combination for the preparation of a medicament for the treatment of cancer; and (iv) a commercial package or product comprising such a combination as a combined preparation for simultaneous, separate or sequential use; and to a method of treatment of cancer in a subject in need thereof. In some embodiments, the cancer is an EGFR-associated cancer. For example, an EGFR-associated cancer having one or more EGFR inhibitor resistance mutations. In some embodiments, the cancer is a HER2-associated cancer. For example, a HER2-associated cancer having one or more HER2 inhibitor resistance mutations. The term "pharmaceutical combination", as used herein, refers to a pharmaceutical therapy resulting from the mixing or combining of more than one active ingredient and includes both fixed and non-fixed combinations of the active ingredients. The term "fixed combination" means that a compound of Formula (I) (e.g., Formula (I-a), (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-g1), (I-g1-1), (I-g1-2),or (I- h)), or a pharmaceutically acceptable salt thereof, and at least one additional therapeutic agent (e.g., a chemotherapeutic agent), are both administered to a subject simultaneously in the form of a single composition or dosage. The term "non-fixed combination" means that a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and at least one additional therapeutic agent (e.g., chemotherapeutic agent) are formulated as separate compositions or dosages such that they may be administered to a subject in need thereof simultaneously, concurrently or sequentially with variable intervening time limits, wherein such administration provides effective levels of the two or more compounds in the body of the subject. These also apply to cocktail therapies, e.g., the administration of three or more active ingredients Accordingly, also provided herein is a method of treating a cancer, comprising administering to a subject in need thereof a pharmaceutical combination for treating cancer which comprises (a) a compound of Formula (I) (e.g., Formula (I-a), (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-g1), (I-g1-1), (I-g1-2),or (I-h)), or pharmaceutically acceptable salt thereof, and (b) an additional therapeutic agent, wherein the compound of Formula (I) and the additional therapeutic agent are administered simultaneously, separately or sequentially, wherein the amounts of the compound of Formula (I), or pharmaceutically acceptable salt thereof, and the additional therapeutic agent are together effective in treating the cancer. In some embodiments, the compound of Formula (I), or pharmaceutically acceptable salt thereof, and the additional therapeutic agent are administered simultaneously as separate dosages. In some embodiments, the compound of Formula (I), or pharmaceutically acceptable salt thereof, and the additional therapeutic agent are administered as separate dosages sequentially in any order, in jointly therapeutically effective amounts, e.g., in daily or intermittently dosages. In some embodiments, the compound of Formula (I), or pharmaceutically acceptable salt thereof, and the additional therapeutic agent are administered simultaneously as a combined dosage. In some embodiments, the cancer is an EGFR-associated cancer. For example, an EGFR-associated cancer having one or more EGFR inhibitor resistance mutations. In some embodiments, the cancer is a HER2-associated cancer. For example, a HER2-associated cancer having one or more HER2 inhibitor resistance mutations. In some embodiments, the presence of one or more EGFR inhibitor resistance mutations in a tumor causes the tumor to be more resistant to treatment with a first EGFR inhibitor. Methods useful when an EGFR inhibitor resistance mutation causes the tumor to be more resistant to treatment with a first EGFR inhibitor are described below. For example, provided herein are methods of treating a subject having a cancer that include: identifying a subject having a cancer cell that has one or more EGFR inhibitor resistance mutations; and administering to the identified subject a compound of Formula (I) (e.g., Formula (I-a), (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I- g1), (I-g1-1), (I-g1-2),or (I-h)), or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered in combination with the first EGFR inhibitor. Also provided are methods of treating a subject identified as having a cancer cell that has one or more EGFR inhibitor resistance mutations that include administering to the subject a compound of Formula (I), or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered in combination with the first EGFR inhibitor. In some embodiments, the one or more EGFR inhibitor resistance mutations confer increased resistance to a cancer cell or tumor to treatment with the first EGFR inhibitor. In some embodiments, the one or more EGFR inhibitor resistance mutations include one or more EGFR inhibitor resistance mutations listed in Table 2a and 2b. For example, the one or more EGFR inhibitor resistance mutations can include a substitution at amino acid position 718, 747, 761, 790, 797, or 854 (e.g., L718Q, L747S, D761Y, T790M, C797S, and T854A). For example, provided herein are methods for treating an EGFR-associated cancer in a subject in need of such treatment, the method comprising (a) detecting a dysregulation of an EGFR gene, an EGFR kinase, or the expression or activity or level of any of the same in a sample from the subject; and (b) administering to the subject a therapeutically effective amount of a first EGFR inhibitor, wherein the first EGFR inhibitor is selected from the group consisting of osimertinib, gefitinib, erlotinib, afatinib, lapatinib, neratinib, AZD- 9291, CL-387785, CO-1686, or WZ4002. In some embodiments, the methods further comprise (after (b)) (c) determining whether a cancer cell in a sample obtained from the subject has at least one EGFR inhibitor resistance mutation; and (d) administering a compound of Formula (I) (e.g., Formula (I-a), (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-g1), (I-g1-1), (I-g1-2),or (I-h)), or a pharmaceutically acceptable salt thereof, as a monotherapy or in conjunction with another anticancer agent to the subject if the subject has been determined to have a cancer cell that has at least one EGFR inhibitor resistance mutation; or (e) administering additional doses of the first EGFR inhibitor of step (b) to the subject if the subject has not been determined to have a cancer cell that has at least one EGFR inhibitor resistance mutation. Methods useful when a HER2 activating mutation is present in a tumor are described herein. For example, provided herein are methods of treating a subject having a cancer that include: identifying a subject having a cancer cell that has one or more HER2 activating mutations; and administering to the identified subject a compound of Formula (I) (e.g., Formula (I-a), (I-a1), (I-a2), (I-a3), (I-a4), (I-a5), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-g1), (I-g1-1), (I-g1-2),or (I-h)), or a pharmaceutically acceptable salt thereof. Also provided are methods of treating a subject identified as having a cancer that has one or more HER2 activating mutations that include administering to the subject a compound of Formula (I), or a pharmaceutically acceptable salt thereof. In some embodiments, the one or more HER2 activating mutations include one or more HER2 activating mutations listed in Tables 3-5. Methods useful when an activating mutation (e.g., HER2 activating mutation) is present in a tumor in a subject are described herein. For example, provided herein are methods of treating a subject having a cancer that include: identifying a subject having a cancer cell that has one or more HER2 activating mutations; and administering to the identified subject a compound of Formula (I) (e.g., Formula (I-a), (I-a1), (I-a2), (I-a3), (I- a4), (I-a5), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-g1), (I-g1-1), (I-g1-2),or (I-h)), or a pharmaceutically acceptable salt thereof. Compound Preparation The compounds disclosed herein can be prepared in a variety of ways using commercially available starting materials, compounds known in the literature, or from readily prepared intermediates, by employing standard synthetic methods and procedures either known to those skilled in the art, or in light of the teachings herein. The synthesis of the compounds disclosed herein can be achieved by generally following the schemes provided herein, with modification for specific desired substituents. Standard synthetic methods and procedures for the preparation of organic molecules and functional group transformations and manipulations can be obtained from the relevant scientific literature or from standard textbooks in the field. Although not limited to any one or several sources, classic texts such as R. Larock, Comprehensive Organic Transformations, VCH Publishers (1989); L. Fieser and M. Fieser, Fieser and Fieser's Reagents for Organic Synthesis, John Wiley and Sons (1994); Smith, M. B., March, J., March' s Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 5th edition, John Wiley & Sons: New York, 2001 ; and Greene, T.W., Wuts, P.G. M., Protective Groups in Organic Synthesis, 3rd edition, John Wiley & Sons: New York, 1999, are useful and recognized reference textbooks of organic synthesis known to those in the art. The following descriptions of synthetic methods are designed to illustrate, but not to limit, general procedures for the preparation of compounds of the present disclosure. The synthetic processes disclosed herein can tolerate a wide variety of functional groups; therefore, various substituted starting materials can be used. The processes generally provide the desired final compound at or near the end of the overall process, although it may be desirable in certain instances to further convert the compound to a pharmaceutically acceptable salt thereof. Example 1: N-(4-(3-((3-fluoro-2-methoxyphenyl)amino)-4-oxo-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazin-2-yl)pyridin-3-yl)pivalamide (Compound 101)

Int1A is reacted with tert-butyl 1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide under basic conditions (e.g., with NaH in DMF) to provide Int1B. Removal of the Boc protecting group from Int1B under acidic conditions (e.g., HCl in dioxane and DCM) followed by lactamization of the resulting amine under basic conditions (e.g., MeONa in MeOH) provides Int1D. Sequential Miyaura borylation of Int1D and Suzuki-Miyaura coupling of the resulting boronic acid (Int 1E) with 4-chloropyridin-3-amine provides Int1F. Int1F is reacted with pivaloyl chloride under basic conditions (e.g., Et3N in DCM) followed by treatment with NaOH and H₂O in THF to provide Int1G. Bromination of Int1G e.g., with 1,3-dibromo-5,5-dimethylimidazolidine-2,4-dione in AcOH at 100 °C provides Int1H. Finally, Buchwald-Hartwig amination of Int1H with 3-fluoro-2- methoxyaniline affords Compound 101. Example 2: N-(4-(3-((3-fluoro-2-methoxyphenyl)amino)-4-oxo-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrazin-2-yl)pyridin-3-yl)-2-methoxy-2-methylpropanamide (Compound 102)

Part 1: Synthesis of 2-methoxy-2-methylpropanoyl chloride 2-Methoxy-2-methylpropanoic acid is reacted with 2-chloroacryloyl chloride (e.g., in the presence of DCM and DMF) at 0 °C. The reaction mixture is then warmed to about 40 °C to provide 2-methoxy-2-methylpropanoyl chloride.

Part 2: Synthesis of Compound 102 Int2A is prepared using the method as described in Example 1. Int2A is reacted with 2-methoxy-2-methylpropanoyl chloride under basic conditions (e.g., Et3N in DCM) to provide Int2B. Int2B is brominated e.g., with 1,3-dibromo-5,5-dimethylimidazolidine- 2,4-dione in AcOH at 100 °C to provide Int2C. Finally, Buchwald-Hartwig amination of Int2C (e.g., in the presence of Ephos Pd G4, Ephos, Cs₂CO₃ in dioxane) with 3-fluoro-2- methoxyaniline affords Compound 102. Example 3: 3-((3-fluoro-2-methoxyphenyl)amino)-2-(3-((2- methoxyethyl)amino)pyridin-4-yl)-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one (Compound 103)

Int3D is prepared using the method as described for Example 1. Int3A is reacted with 1-iodo-2-methoxyethane under basic conditions (e.g., NaH in DMF) to provide Int3B. Removal of the Boc protecting group from Int3B followed by Suzuki-Miyaura coupling with Int3D provides Int3E. Int3E is brominated with e.g., 1,3-dibromo-5,5- dimethylimidazolidine-2,4-dione in AcOH at 100 °C to provide Int3F. Buchwald-Hartwig amination of Int3F (e.g., in the presence of Ephos Pd G4, Ephos, Cs₂CO₃ in dioxane) with 3-fluoro-2-methoxyaniline affords Int3G. Acidic treatment of Int3G (e.g., with TFA) affords Compound 103. Example 4. 3-[(3-chloro-2-methoxyphenyl)amino]-2-(1,6-naphthyridin-4-yl)-5H,6H,7H- pyrazolo[1,5-a]pyrazin-4-one (compound 347)

3-chloro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5H,6H,7H-pyrazolo[1,5- a]pyrazin-4-one (200 mg) was dissolved in 1,4-dioxane(5 mL) and H₂O (1 mL), 4-chloro- 7-methoxy-1,6-naphthyridine (156.98 mg), Cs₂CO₃(438 mg),PCy3(37.7 mg) and Pd₂(dba)₃ (123.1 mg) was added, the reaction was stirred for 12 hours, the reaction was stirred for 12 hours under N₂ atmosphere. The resulting mixture was concentrated under reduced pressure. The crude product (260 mg) was purified by Prep-HPLC with the following conditions (Column: Xselect CSH OBD Column 30*150mm 5um; Mobile Phase A: Water (0.1%FA), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 30% B to 45% B in 8 min, 45% B; Wave Length: 254/220 nm; RT1(min): 7.10) to afford 3- chloro-2-(1,6-naphthyridin-4-yl)-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (116.1 mg, 48.50%) as a light yellow solid. LC-MS: M+H found: 300.

3-chloro-2-(1,6-naphthyridin-4-yl)-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one(100 mg) was dissolved in DMF(5 mL), 3-chloro-2-methoxyaniline (105 mg), Cs₂CO₃(326 mg), EPhos Pd G4(306 mg) and EPhos (89 mg) was added, the reaction was stirred for 4 hours under N₂ atmosphere.The resulting mixture was concentrated under reduced pressure.The crude p roduct (100 mg) was purified by Prep-HPLC with the following conditions (Column: XBridge Shield RP18 OBD Column, 30*150 mm, 5μm; Mobile Phase A: Water(10 mmol/L NH₄HCO₃+0.1%NH3.H2O), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 17% B to 50% B in 7 min, 50% B; Wave Length: 254/220 nm; RT1(min): 6.18) to afford 3-[(3-chloro-2-methoxyphenyl)amino]-2-(1,6-naphthyridin-4-yl)- 5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (24.7 mg, 17.50%) as a light yellow solid. LC-MS: M+H found: 421. ¹H NMR (300 MHz, DMSO-d6) δ 9.82 (s, 1H), 9.08 (d, J = 4.6 Hz, 1H), 8.73 (d, J = 5.8 Hz, 1H), 8.37 (s, 1H), 7.91 (d, J = 6.0 Hz, 1H), 7.73 (d, J = 4.6 Hz, 1H), 7.46 (s, 1H), 6.57 (dt, J = 15.8, 7.7 Hz, 2H), 6.17 (d, J = 7.8 Hz, 1H), 4.52 (s, 2H), 3.75 (s, 2H), 3.68 (s, 3H). Example 5. 3-[(3-chloro-2-methoxyphenyl)amino]-2-(pyridin-4-yl)-5H,6H,7H- pyrazolo[1,5-a]pyrazin-4-one (compound 344)

A mixture of 2-bromo-3-chloro-5H,6H,7H-pyrazolo[1,5-a] pyrazin-4-one (500.00 mg, 1.996 mmol, 1.00 equiv), pyridin-4-ylboronic acid (368.05 mg, 2.994 mmol, 1.50 equiv), Pd(dppf)Cl₂ (146.06 mg, 0.200 mmol, 0.10 equiv) and K₂CO₃ (827.64 mg, 5.988 mmol, 3.00 equiv) in 1,4-dioxane (10.00 mL) and water (1.00 mL) was stirred for overnight at 70 degrees C under nitrogen atmosphere. The resulting mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with DCM / MeOH (40:1) to afford 3-chloro-2-(pyridin-4-yl)-5H,6H,7H-pyrazolo[1,5-a] pyrazin-4-one (200 mg, 40.29%) as a yellow solid. LC-MS: M+H found: 249.

A mixture of 3-chloro-2-(pyridin-4-yl)-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (100.00 mg, 0.402 mmol, 1.00 equiv), 3-chloro-2-methoxyaniline (95.07 mg, 0.603 mmol, 1.50 equiv), EPhos Pd G4 (36.94 mg, 0.040 mmol, 0.10 equiv), EPhos (21.51 mg, 0.040 mmol, 0.10 equiv) and K₂CO₃ (166.73 mg, 1.206 mmol, 3.00 equiv) in 1,4-dioxane (1.00 mL) and Toluene (1.00 mL) was stirred for overnight at 60 degrees C under nitrogen atmosphere. The resulting mixture was diluted with water. The resulting mixture was extracted with EtOAc. The combined organic layers were washed with brine , dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The crude product (120 mg) was purified by Prep-HPLC with the following conditions (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water (10 mmol/L NH₄HCO₃+0.1% NH₃*H₂O), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 26% B to 56% B in 8 min, 56% B; Wave Length: 254; 220 nm; RT1(min): 6.58) to afford 3-[(3-chloro-2-methoxyphenyl)amino]-2-(pyridin-4-yl)-5H,6H,7H- pyrazolo[1,5-a]pyrazin-4-one (35.6 mg, 23.87%) as a white solid. LC-MS: (M+H)⁺ found: 370. 1H NMR (300 MHz, Chloroform-d) δ 8.57 (s, 2H), 7.69 (d, J = 5.1 Hz, 2H), 7.08 (s, 1H), 6.80 (dd, J = 8.1, 1.5 Hz, 1H), 6.73 – 6.50 (m, 2H), 6.19 (dd, J = 8.1, 1.5 Hz, 1H), 4.46 (dd, J = 7.1, 5.0 Hz, 2H), 4.05 (s, 3H), 3.94 – 3.75 (m, 2H). Example 6. 3-[(3-chloro-2-methoxyphenyl)amino]-2-(7-methoxy-1,6-naphthyridin-4-yl)- 5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (compound 348)

3-chloro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5H,6H,7H-pyrazolo[1,5- a]pyrazin-4-one (200 mg) was dissolved in 1,4-dioxane(5 mL) and H₂O (1 mL), 4-chloro- 7-methoxy-1,6-naphthyridine (156.98 mg), Cs₂CO₃(438 mg), PCy3(37.7 mg) and Pd₂(dba)₃ (123.1 mg) was added, the reaction was stirred for 12 hours, the reaction was stirred for 12 hours under N₂ atmosphere. The resulting mixture was concentrated under reduced pressure.The crude product (260 mg) was purified by Prep-HPLC with the following conditions (Column: Xselect CSH OBD Column 30*150mm 5um, n; Mobile Phase A: Water(0.1% FA), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 30% B to 45% B in 8 min, 45% B; Wave Length: 254/220 nm; RT1(min): 7.10) to afford 3-chloro-2-(7-methoxy-1,6-naphthyridin-4-yl)- 5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (102.1 mg, 45.50%) as a light yellow solid. LC-MS: M+H found: 330.

3-chloro-2-(7-methoxy-1,6-naphthyridin-4-yl)-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4- one(100 mg) was dissolved in DMF (10 mL), 3-chloro-2-methoxyaniline(96 mg), Cs₂CO₃(296 mg), EPhos Pd G4(139 mg) and EPhos (81 mg) was added, the reaction was stirred for 12 hours under N₂ atmosphere. The resulting mixture was concentrated under reduced pressure.The crude product (100 mg) was purified by Prep-HPLC with the following conditions (Column: Xselect CSH OBD Column 30*150mm 5um, n; Mobile Phase A: Water(0.1% FA), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 30% B to 45% B in 8 min, 45% B; Wave Length: 254/220 nm; RT1(min): 7.10) to afford 3-[(3-chloro-2-methoxyphenyl)amino]-2-(7- methoxy-1,6-naphthyridin-4-yl)-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (46.1 mg, 17.50%) as a light yellow solid. LC-MS: M+H found: 451. ¹H NMR (300 MHz, DMSO-d6) δ 9.60 (s, 1H), 8.95 (d, J = 4.5 Hz, 1H), 8.37 (s, 1H), 7.54 – 7.42 (m, 2H), 7.22 (s, 1H), 6.67 – 6.50 (m, 2H), 6.16 (dd, J = 7.9, 1.7 Hz, 1H), 4.50 (t, J = 5.9 Hz, 2H), 3.99 (s, 3H), 3.78 (s, 3H), 3.99 (s, 2H). Example 7. 3-[(3-chloro-2-methoxyphenyl) amino]-2-{1H-pyrrolo[3,2-b] pyridin-7-yl}- 5H,6H,7H-pyrazolo[1,5-a] pyrazin-4-one (compound 346)

A mixture of 7-bromo-1H-pyrrolo[3,2-b] pyridine (500 mg, 2.538 mmol, 1.00 equiv), Boc2O (664.59 mg, 3.046 mmol, 1.2 equiv) and DMAP (31.00 mg, 0.254 mmol, 0.1 equiv) in THF (10 mL, 123.430 mmol) was stirred for overnight at room temperature under nitrogen atmosphere. The resulting mixture was diluted with water. The resulting mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. This resulted in tert-butyl 7-bromopyrrolo[3,2-b] pyridine-1-carboxylate (700 mg, 92.83%) as a brown oil. LC-MS: M+H found: 297.

A mixture of tert-butyl 7-bromopyrrolo[3,2-b]pyridine-1-carboxylate (700 mg, 2.356 mmol, 1.00 equiv), 3-chloro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5H,6H,7H- pyrazolo[1,5-a]pyrazin-4-one (841.13 mg, 2.827 mmol, 1.2 equiv), Pd(DtBPF)Cl₂ (153.53 mg, 0.236 mmol, 0.1 equiv) and K₂CO₃ (976.71 mg, 7.068 mmol, 3 equiv) in 1,4- dioxane (15 mL, 170.251 mmol) was stirred for 4 h at 70 °C under nitrogen atmosphere. The resulting mixture was extracted with DCM. The combined organic layers were dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by reverse flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in water, 10% to 50% gradient in 20 min; detector, UV 254 nm. This resulted in tert-butyl 7-{3-chloro-4-oxo-5H,6H,7H-pyrazolo[1,5-a]pyrazin- 2-yl}pyrrolo[3,2-b]pyridine-1-carboxylate (500 mg, 54.73%) as a white solid. LC-MS: (M+H)⁺ found: 388.

A mixture of tert-butyl 7-{3-chloro-4-oxo-5H,6H,7H-pyrazolo[1,5-a] pyrazin-2- yl}pyrrolo [3,2-b]pyridine-1-carboxylate (200 mg, 0.516 mmol, 1.00 equiv) , EPhos Pd G4 (47.37 mg, 0.052 mmol, 0.1 equiv)and Cs2CO3 (504.08 mg, 1.548 mmol, 3 equiv) in 1,4-dioxane (4 mL) was stirred for overnight at 70 °C under nitrogen atmosphere. The resulting mixture was extracted with DCM. The combined organic layers were dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with DCM / MeOH (50:1) to afford tert-butyl 7-{3-[(3-chloro-2-methoxyphenyl) amino]-4-oxo-5H,6H,7H-pyrazolo[1,5-a] pyrazin-2-yl} pyrrolo [3,2-b] pyridine-1-carboxylate (35 mg, 13.33%) as a white solid. LC-MS: (M+H)⁺ found: 509.

A mixture of tert-butyl 7-{3-[(3-chloro-2-methoxyphenyl) amino]-4-oxo-5H,6H,7H- pyrazolo[1,5-a] pyrazin-2-yl} pyrrolo [3,2-b] pyridine-1-carboxylate (50 mg, 0.098 mmol, 1.00 equiv) and TFA (56.01 mg, 0.490 mmol, 5 equiv) in DCM (1 mL, 15.730 mmol) was stirred for overnight at room temperature under nitrogen atmosphere. The resulting mixture was diluted with water. The resulting mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄. The residue was purified by reverse flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeOH in water, 10% to 50% gradient in 10 min; detector, UV 254 nm. This resulted in 3-[(3-chloro-2-methoxyphenyl) amino]- 2-{1H-pyrrolo[3,2-b] pyridin-7-yl}-5H,6H,7H-pyrazolo[1,5-a] pyrazin-4-one (37 mg, 92.12%) as a yellow solid. LC-MS: (M+H)⁺ found: 409. ¹H NMR (300 MHz, DMSO-d₆) δ 11.23 (s, 1H), 8.36 (d, J = 3.1 Hz, 1H), 8.26 (d, J = 5.1 Hz, 1H), 7.70 (t, J = 3.1 Hz, 1H), 7.42 – 7.33 (m, 2H), 6.77 – 6.65 (m, 2H), 6.65 – 6.58 (m, 1H), 6.16 (dd, J = 6.8, 2.9 Hz, 1H), 4.51 (t, J = 5.7 Hz, 2H), 3.91 (s, 3H), 3.72 (s, 2H). Example 8.2-(2-aminopyridin-4-yl)-3-[(3-chloro-2-methoxyphenyl)amino]-5H,6H,7H- pyrazolo[1,5-a]pyrazin-4-one (compound 335)

To a solution of 2-bromo-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (1.00 g, 4.629 mmol, 1.00 equiv) and tert-butyl N-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2- yl]carbamate (1.78 g, 5.555 mmol, 1.20 equiv) in dioxane (10.00 mL) and H₂O (2.00 mL)were added K₂CO₃ (1.28 g, 9.258 mmol, 2.00 equiv) and Pd(dppf)Cl₂*CH₂Cl₂ (0.75 g, 0.926 mmol, 0.20 equiv). After stirring for 2 h at 80 degrees C under a nitrogen atmosphere. The resulting mixture was filtered, the filter cake was washed with EA (20 mL). The filter cake was concentrated under reduced pressure to afford tert-butyl N-(4- [4-oxo-5H,6H,7H-pyrazolo[1,5-a]pyrazin-2-yl]pyridin-2-yl)carbamate (1.05 g, 68.87%) as a white solid. LC-MS: M+H found: 330.

To a stirred solution of tert-butyl N-(4-[4-oxo-5H,6H,7H-pyrazolo[1,5-a]pyrazin-2- yl]pyridin-2-yl)carbamate (1.00 g, 3.036 mmol, 1.00 equiv) in DMF (20.00 mL) was added NBS (0.54 g, 3.036 mmol, 1.00 equiv) in portions at 0 degrees C . The resulting mixture was stirred for 2 h at 80 degrees C. The resulting mixture was filtered, and the filter cake was washed with H₂O and EA. The filter cake was concentrated under reduced pressure to afford tert-butyl N-(4-[3-bromo-4-oxo-5H,6H,7H-pyrazolo[1,5-a]pyrazin-2- yl]pyridin-2-yl)carbamate (700 mg, 56.47%) as a white solid. LC-MS: M+H found: 408.

To a solution tert-butyl N-(4-[3-bromo-4-oxo-5H,6H,7H-pyrazolo[1,5-a]pyrazin-2- yl]pyridin-2-yl)carbamate (200.00 mg, 0.490 mmol, 1.00 equiv) of and 3-chloro-2- methoxyaniline (154.41 mg, 0.980 mmol, 2.00 equiv) in THF (4.00 mL)were added t- BuONa (70.62 mg, 0.735 mmol, 1.50 equiv) and Pd PEPPSI IPentCl (42.16 mg, 0.049 mmol, 0.10 equiv). After stirring for 4 h at 80 degrees C under a nitrogen atmosphere, the resulting mixture was diluted with H₂O (20 mL). The resulting mixture was extracted with EA (3 x 20mL). The combined organic layers were washed with brine (1x10mL), dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (DCM:MeOH=15:1) to afford tert-butyl N-(4-[3-[(3-chloro-2-methoxyphenyl)amino]-4-oxo-5H,6H,7H-pyrazolo[1,5-a]pyrazin- 2-yl]pyridin-2-yl)carbamate (30 mg, 12.63%) as a pink solid. LC-MS: M+H found: 485.

To a stirred solution of tert-butyl N-(4-[3-[(3-chloro-2-methoxyphenyl)amino]-4-oxo- 5H,6H,7H-pyrazolo[1,5-a]pyrazin-2-yl]pyridin-2-yl)carbamate (30.00 mg) in DCM (6.00 mL) was added TFA (2.00 mL) dropwise at rt . The resulting mixture was stirred for 2 h at rt. The resulting mixture was concentrated under reduced pressure. The crude product was purified by Prep-HPLC with the following conditions (Column: XBridge Prep OBD C18 Column, 30x150mm 5um; Mobile Phase A: Water (10 mmol/L NH₄HCO₃+0.1%NH₃*H₂O), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 20% B to 50% B in 8 min, 50% B; Wave Length: 254; 220 nm; RT1(min): 6.97) to afford 2- (2-aminopyridin-4-yl)-3-[(3-chloro-2-methoxyphenyl)amino]-5H,6H,7H-pyrazolo[1,5- a]pyrazin-4-one (6.0 mg, 25.0%) as a light yellow solid. LC-MS: M+H found: 385. ¹H NMR (400 MHz, DMSO-d6): δ 8.27 (s, 1H), 7.89 (s, 1H), 7.65 (s, 1H), 7.02 (s, 2H), 6.79 (t, J = 8.1 Hz, 1H), 6.65 (dd, J = 8.0, 1.5 Hz, 1H), 6.31 (dd, J = 8.2, 1.5 Hz, 1H), 5.94 (s, 2H), 4.35 (dd, J = 7.1, 5.1 Hz, 2H), 3.84 (s, 3H), 3.61 (ddd, J = 7.7, 4.7, 2.6 Hz, 2H). Example 9. 3-[(3-chloro-2-methoxyphenyl)amino]-2-[1H-pyrazolo[3,4-b]pyridin-4-yl]- 5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (compound 351)

To a solution of 2-bromo-3-chloro-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (100.00 mg, 0.399 mmol, 1.00 equiv) and 1H-pyrazolo[3,4-b]pyridin-4-ylboronic acid (78.06 mg, 0.000 mmol, 1.20 equiv) in dioxane (2.00 mL) and H₂O (0.40 mL) were added K₂CO₃ (110.35 mg, 0.798 mmol, 2.00 equiv) and Pd(dppf)Cl₂*CH₂Cl₂ (32.52 mg, 0.040 mmol, 0.10 equiv). After stirring for 2 h at 80 degrees C under a nitrogen atmosphere, the resulting mixture was concentrated under reduced pressure. The residue was purified by Prep-TLC/silica gel column chromatography, eluted with DCM:MeOH (20:1) to afford 3-chloro-2-[1H-pyrazolo[3,4-b]pyridin-4-yl]-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (400 mg, 69.41%) as a yellow solid. LC-MS: M+H found: 289.

To a solution of 3-chloro-2-[1H-pyrazolo[3,4-b]pyridin-4-yl]-5H,6H,7H-pyrazolo[1,5- a]pyrazin-4-one (400.00 mg, 1.386 mmol, 1.00 equiv) in DMF (8.00 mL)was added NaH (66.50 mg, 1.663 mmol, 1.20 equiv, 60%) at 0 degrees C. The mixture was stirred for 15 min. [2-(chloromethoxy)ethyl]trimethylsilane (277.19 mg, 1.663 mmol, 1.20 equiv) was added, and the mixture was allowed to warm to RT and stirred for 2 h. The reaction was quenched with H₂O (50 ml) at 0 degrees C. The resulting mixture was filtered, the filter cake was washed with H₂O (30 mL). The filterate was concentrated under reduced pressure to afford 3-chloro-5-[[2-(trimethylsilyl)ethoxy]methyl]-2-(1-[[2- (trimethylsilyl)ethoxy]methyl]pyrazolo [3,4-b]pyridin-4-yl)-6H,7H-pyrazolo[1,5- a]pyrazin-4-one (500 mg, 40.61%) as a yellow solid. LC-MS: M+H found: 549.

To a solution of 3-chloro-5-{[2-(trimethylsilyl)ethoxy]methyl}-2-(1-{[2- (trimethylsilyl)ethoxy]methyl}pyrazolo[3,4-b]pyridin-4-yl)-6H,7H-pyrazolo[1,5- a]pyrazin-4-one (500 mg, 0.910 mmol, 1 equiv) and 3-chloro-2-methoxyaniline (286.95 mg, 1.820 mmol, 2 equiv) in DMF (12.50 mL, 161.452 mmol, 177.42 equiv) were added Cs₂CO₃ (593.24 mg, 1.820 mmol, 2 equiv) and EPhos Pd G4 (418.12 mg, 0.455 mmol, 0.5 equiv), EPhos (486.87 mg, 0.910 mmol, 1 equiv). After stirring for 2 h at 50 degrees C under a nitrogen atmosphere, the resulting mixture was diluted with H₂O (50 mL). The resulting mixture was extracted with EA (3 x 30 mL). The combined organic layers were washed with brine (1x20 mL), dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (DCM:MeOH=15:1) to afford 3-[(3-chloro-2-methoxyphenyl)amino]-5-{[2- (trimethylsilyl)ethoxy]methyl}-2-(1-{[2-(trimethylsilyl)ethoxy] methyl}pyrazolo[3,4- b]pyridin-4-yl)-6H,7H-pyrazolo[1,5-a]pyrazin-4-one (200 mg, 14.98%) as a brown solid. LC-MS: M+H found: 670.

3-[(3-chloro-2-methoxyphenyl)amino]-5-[[2-(trimethylsilyl)ethoxy]methyl]-2-(1-[[2- (trimethylsilyl)ethoxy]methyl]pyrazolo[3,4-b]pyridin-4-yl)-6H,7H-pyrazolo[1,5- a]pyrazin-4-one (200.00 mg) was dissolved in 1,4-dioxane (5.00 mL) containing HCl(g). The resulting mixture was stirred for 2 h at rt. The reaction mixture was concentrated under vacuum. The residue was dissolved in DCM (5 mL), EDA (1 mL) was added at 0 degrees C, then the mixture was stirred for 2 h at rt. The resulting mixture was diluted with H₂O (50 mL). The resulting mixture was extracted with EA (3 x 30mL). The combined organic layers were washed with brine (1x20mL), dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (DCM:MeOH=15:1) to afford crude product. The crude product (25 mg) was purified by Prep-HPLC with the following conditions (Column: XBridge Shield RP18 OBD Column, 30*150 mm, 5μm; Mobile Phase A: Water (10 mmol/L NH₄HCO₃+0.1%NH₃*H₂O), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 15% B to 51% B in 7 min, 51% B; Wave Length: 254/220 nm; RT1(min): 6.37) to afford 3-[(3-chloro-2-methoxyphenyl)amino]-2-[1H-pyrazolo[3,4-b]pyridin-4-yl]- 5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (2.4 mgˈ11.4%) as a white solid. LC-MS: M+H found: 410. ¹H NMR (400 MHz, DMSO-d6): δ 8.90 (d, J = 2.1 Hz, 1H), 8.48 (d, J = 2.0 Hz, 1H), 8.27 (s, 1H), 8.15 (s, 1H), 7.33 (s, 1H), 6.72 – 6.64 (m, 2H), 6.21 – 6.12 (m, 1H), 4.41 (t, J = 5.9 Hz, 2H), 3.89 (s, 3H), 3.67 (t, J = 5.8 Hz, 2H). Example 10.3-[(3-chloro-2-methoxyphenyl)amino]-2-[thieno[2,3-b]pyridin-4-yl]- 5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (compound 352)

To a stirred solution of 3-chloro-4-oxo-5H,6H,7H-pyrazolo[1,5-a]pyrazin-2-ylboronic acid (380.95 mg, 1.768 mmol, 2.00 equiv) and 4-chlorothieno[2,3-b]pyridine (150.00 mg, 0.884 mmol, 1.00 equiv) in dioxane (5.00 mL, 59.020 mmol, 66.74 equiv) and H2O (1.00 mL, 0.056 mmol, 0.06 equiv) were added Pd(dppf)Cl₂ (64.70 mg, 0.088 mmol, 0.10 equiv) and K₂CO₃ (244.42 mg, 1.768 mmol, 2.00 equiv) at rt under N₂ atmosphere. Then, the solution was stirred at 80 degrees C for 2 h. The mixture was diluted with 300 ml water and filtrate the solid to afford 3-chloro-2-[thieno[2,3-b]pyridin-4-yl]- 5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (109 mg, 40.45%) as a black solid. LC-MS: M+1 found: 304.95.

To a stirred solution of 3-chloro-2-[thieno[2,3-b]pyridin-4-yl]-5H,6H,7H-pyrazolo[1,5- a]pyrazin-4-one (130.00 mg, 0.427 mmol, 1.00 equiv) and 3-chloro-2-methoxyaniline (134.46 mg, 0.853 mmol, 2 equiv) in DMF (7.00 mL, 0.008 mmol, 0.25 equiv) were added Cs₂CO₃ (277.98 mg, 0.853 mmol, 2.00 equiv), EPhos (228.13 mg, 0.427 mmol, 1.00 equiv) and EPhos Pd G4 (195.92 mg, 0.213 mmol, 0.50 equiv) at rt under N₂ atmosphere. Then, the solution was stirred at 50 degrees C for 2h. The resulting mixture was diluted with water (50 mL) and washed with 3×40 mL of EA. The filtrate was concentrated under reduced pressure.The residue was purified by reverse flash chromatography with the following conditions: Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water (10 mmol/L NH₄HCO3+0.1%NH₃*H₂O), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 36% B to 56% B in 8 min, 56% B; Wave Length: 254; 220 nm; RT1(min): 6.62) to afford 3-[(3-chloro-2-methoxyphenyl)amino]-2-[thieno[2,3- b]pyridin-4-yl]-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (5.9 mg, 3.25%) as a yellow solid. LC-MS: M+1 found: 425.9. ¹H NMR (400 MHz, DMSO-d6) δ 8.50 (d, J = 4.9 Hz, 1H), 8.33 (s, 1H), 8.01 (d, J = 6.1 Hz, 1H), 7.91 (d, J = 6.1 Hz, 1H), 7.61 (d, J = 5.0 Hz, 1H), 7.44 (s, 1H), 6.67 (dd, J = 8.1, 1.8 Hz, 1H), 6.63 (t, J = 7.9 Hz, 1H), 6.12 (dd, J = 7.8, 1.8 Hz, 1H), 4.48 (dd, J = 7.1, 5.0 Hz, 2H), 3.85 (s, 3H), 3.70 (s, 2H). Example 11.3-[(3-chloro-2-methoxyphenyl)amino]-2-{1H-pyrazolo[4,3-b]pyridin-7- yl}-5H,6H,7H-pyrazolo [1,5-a]pyrazin-4-one (compound 353)

A solution of 2-bromo-3-chloro-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (500 mg, 2.00 mmol, 1.00 equiv) and bis(pinacolato)diboron (1013.81 mg, 3.99 mmol, 2.00 equiv), KOAc (489.77 mg, 4.99 mmol, 2.50 equiv) and Pd(dppf)Cl₂ (146.06 mg, 0.200 mmol, 0.1 equiv) in DME (30.00 mL, 309.92 mmol,) was stirred 2h at 100°C under N₂ atmosphere. The mixture was allowed to cool down to RT. The resulting mixture was filtered; the filter cake was washed with DCM (2x210 mL). The filtrate was concentrated under reduced pressure. The residue was dissolved in EA (5ml). The resulting mixture was filtered; the filter cake was washed with EA (2x210ml). The filtrate was concentrated under reduced pressure to afford crude product 3-chloro-4-oxo-5H,6H,7H-pyrazolo[1,5- a]pyrazin-2-ylboronic acid (800 mg) as a black oil. LC-MS: (M+H)⁺ found: 216.3.

To a solution of 7-bromo-1H-pyrazolo[4,3-b]pyridine (500 mg, 2.52 mmol, 1.00 equiv) in DMF (5 mL, 64.61 mmol, 25.59 equiv) was added sodium hydride (60% in oil, 90.98 mg) at 0 degrees C. The mixture was stirred for 15 min, then [2- (chloromethoxy)ethyl]trimethylsilane (547.25 mg, 3.28 mmol, 1.30 equiv) was added, and the mixture was allowed to warm to RT where it was stirred for 3 h. The reaction mixture was quenched with water and extracted with DCM (3*25 mL). The residue was purified by prep-TLC (DCM:MeOH =15:1) to afford 7-bromo-1-{[2- (trimethylsilyl)ethoxy]methyl}pyrazolo[4,3-b]pyridine(400 mg, 48.26%) as a brown solid. LC-MS: (M+H)⁺ found: 328.1.

To a solution of 7-bromo-1-{[2-(trimethylsilyl)ethoxy]methyl}pyrazolo[4,3-b]pyridine (400 mg, 1.22 mmol, 1.00 equiv) and 3-chloro-4-oxo-5H,6H,7H-pyrazolo[1,5-a]pyrazin- 2-ylboronic acid (787.36 mg, 3.65 mmol, 3 equiv) in dioxane (20.00 mL) and H₂O (4.00 mL) were added K₂CO₃ (420.99 mg, 3.045 mmol, 2.5 equiv) and Pd(dppf)Cl₂ (89.15 mg, 0.122 mmol, 0.10 equiv) . After stirring for 5h at 80°C under a nitrogen atmosphere, the resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with DCM:MeOH (20:1) to afford 3-chloro-2- (1-{[2-(trimethylsilyl) ethoxy] methyl}pyrazolo[4,3-b]pyridin-7-yl)-5H,6H,7H- pyrazolo[1,5-a]pyrazin-4-one (250 mg, 48.97%) as a brown solid. LC-MS: (M+H)⁺ found: 419.3.

To a solution of 3-chloro-2-(1-{[2-(trimethylsilyl)ethoxy]methyl}pyrazolo[4,3- b]pyridin-7-yl)-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (200 mg, 0.477 mmol, 1.00 equiv) and 3-chloro-2-methoxyaniline (112.85 mg, 0.716 mmol, 1.5 equiv) in DMF (10.00 mL) and EPhos (127.65 mg, 0.238 mmol, 0.5 equiv) were added Cs₂CO₃ (388.84 mg, 1.192 mmol, 2.50 equiv) and EPhos Pd G4 (219.25 mg, 0.239 mmol, 0.50 equiv). After stirring for 3 h at 50°C under a nitrogen atmosphere, the resulting mixture was extracted with EA (3x50 mL). The combined organic layers were washed with brine(3x20ml), dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified three times by prep-TLC (DCM:MeOH 20:1) to afford 3-[(3-chloro-2-methoxyphenyl)amino]-2-[(2Z)-3-[(E)-(2- iminoethylidene) amino]prop-2-en-1-yl]-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (20 mg, purity:50%) as off-white solid. LC-MS: (M+H)⁺ found: 540.4.

3-[(3-chloro-2-methoxyphenyl) amino]-2-(1-{[2-(trimethylsilyl) ethoxy] methyl} pyrazolo[4,3-b]pyridin-7-yl)-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (500 mg) was dissolved in dioxane (250 mL) containing HCl (g). The solution was stirred at RT under N₂ atmosphere for 2 h. The resulting mixture was extracted with EA (3 x 20ml). The combined organic layers were washed with brine (3x15ml), dried over anhydrous Na₂SO₄. After extraction, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-HPLC with the following conditions (Column: YMC-Actus Triart C18, 30*150 mm, 5μm; Mobile Phase A: Water (10 mmol/L NH₄HCO₃+0.1%NH₃*H₂O), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 25% B to 45% B in 10 min, 45% B; Wave Length: 254/220 nm; RT1(min): 9.42) to afford 3-[(3-chloro-2- methoxyphenyl)amino]-2-{1H-pyrazolo[4,3-b]pyridin-7-yl}-5H,6H,7H-pyrazolo [1,5- a]pyrazin-4-one (7.1 mg, 1.9 %) as a white solid. LC-MS: (M+H)⁺ found: 410.2. ¹H NMR (300 MHz, DMSO-d6) δ 13.28 (s, 1H), 8.46 (d, J = 4.7 Hz, 1H), 8.37 (d, J = 3.6 Hz, 2H), 7.47 (d, J = 4.7 Hz, 1H), 6.80 – 6.67 (m, 2H), 6.18 (dd, J = 6.6, 3.1 Hz, 1H), 4.54 (dd, J = 7.0, 5.1 Hz, 2H), 3.92 (s, 3H), 3.73 (s, 2H). Example 12. (7S)-3-[(3-fluoro-2-methoxyphenyl)amino]-7-methyl-2-{1H-pyrazolo[4,3- b]pyridin-7-yl}-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (compound 302)

Into a 40 mL vial were added (7S)-3-amino-2-bromo-7-methyl-5H,6H,7H-pyrazolo[1,5- a]pyrazin-4-one (200 mg, 0.816 mmol, 1 equiv) and 3-fluoro-2-methoxyphenylboronic acid (208.03 mg, 1.224 mmol, 1.5 equiv) and Cu(OAc)₂ (29.64 mg, 0.163 mmol, 0.2 equiv) and Pyridine (32.28 mg, 0.408 mmol, 0.5 equiv) in MeOH (15mL) at room temperature. The resulting mixture was stirred for overnight at room temperature under air atmosphere. The reaction was monitored by LCMS. Desired product could be detected by LCMS. The resulting mixture was filtered, and the filter cake was washed with MeOH (3x10 mL). The filtrate was concentrated under reduced pressure. The resulting mixture was extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine (3x5 mL), dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (DCM/MeOH 15:1) to afford (7S)-2- bromo-3-[(3-fluoro-2-methoxyphenyl)amino]-7-methyl-5H,6H,7H-pyrazolo[1,5- a]pyrazin-4-one (170 mg) as a pink solid. LC-MS: M+H found: 370.80.

Into a 8-mL vial, was placed (7S)-2-bromo-3-[(3-fluoro-2-methoxyphenyl)amino]-7- methyl-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (100 mg, 0.271 mmol, 1 equiv), 7- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazolo[4,3-b]pyridine (212.43 mg, 0.867 mmol, 3.2 equiv), K₂CO₃ (93.59 mg, 0.677 mmol, 2.5 equiv), Pd(dppf)Cl₂*CH₂Cl₂ (22.06 mg, 0.027 mmol, 0.1 equiv) in 1,4-Dioxane (10 mL) and H₂O (0.4 mL). The resulting solution was stirred for 3 h at 80 degrees C under a nitrogen atmosphere. The reaction was monitored by LCMS. Desired product could be detected by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by Prep-TLC/silica gel column chromatography, eluted with DCM/MeOH (12:1) to afford (7S)-3-[(3-fluoro-2-methoxyphenyl)amino]-7-methyl-2-{1H-pyrazolo[4,3-b]pyridin-7- yl}-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one as a yellow crude solid. The crude product was purified by Prep-HPLC with the following conditions (Column: YMC-Actus Triart C18, 30*150 mm, 5μm; Mobile Phase A: Water (10 mmol/L NH₄HCO₃+0.1%NH₃*H₂O), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 35% B to 50% B in 8 min, 50% B; Wave Length: 254;220 nm; RT1(min): 7.7 to afford (7S)-3-[(3-fluoro-2- methoxyphenyl)amino]-7-methyl-2-{1H-pyrazolo[4,3-b]pyridin-7-yl}-5H,6H,7H- pyrazolo[1,5-a]pyrazin-4-one (40.6 mg, 18.40%) as a off-white solid. LC-MS: (M+H)⁺ found: 408.05. ¹H NMR (400 MHz, DMSO-d6) δ 13.17 – 13.12 (m, 1H), 8.44 (d, J = 4.7 Hz, 1H), 8.35 (d, J = 1.5 Hz, 1H), 8.34 (s, 1H), 7.48 (d, J = 4.7 Hz, 1H), 7.39 (s, 1H), 6.72 – 6.62 (m, 1H), 6.59 – 6.50 (m, 1H), 6.00 (d, J = 8.2 Hz, 1H), 4.76 – 4.67 (m, 1H), 3.96 – 3.91 (m, 3H), 3.83 – 3.75 (m, 1H), 3.49 – 3.41 (m, 1H), 1.65 (d, J = 6.5 Hz, 3H). Example 13. (7S)-3-[(3-chloro-2-methoxyphenyl)amino]-7-methyl-2-{1H-pyrazolo[4,3- b]pyridin-7-yl}-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (compound 301)

Into a 40 mL vial were added (7S)-3-amino-2-bromo-7-methyl-5H,6H,7H-pyrazolo[1,5- a]pyrazin-4-one (200 mg, 0.816 mmol, 1 equiv) and 3-chloro-2-methoxyphenylboronic acid (228.17 mg, 1.224 mmol, 1.5 equiv) and Cu(OAc)₂ (29.64 mg, 0.163 mmol, 0.2 equiv) and Pyridine (32.28 mg, 0.408 mmol, 0.5 equiv) in MeOH (15mL) at room temperature. The resulting mixture was stirred for overnight at room temperature under air atmosphere. The reaction was monitored by LCMS. Desired product could be detected by LCMS. The resulting mixture was filtered, the filter cake was washed with MeOH (3x10 mL). The filtrate was concentrated under reduced pressure. The resulting mixture was extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine (3x5 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (CHCl3/MeOH 15:1) to afford (7S)-2-bromo-3-[(3-chloro-2-methoxyphenyl)amino]-7-methyl-5H,6H,7H-pyrazolo[1,5- a]pyrazin-4-one (150 mg, 47.66%) as a pink solid. LC-MS: M+H found: 385.00.

Into a vial was placed (7S)-2-bromo-3-[(3-chloro-2-methoxyphenyl)amino]-7-methyl- 5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (100 mg, 0.259 mmol, 1 equiv), 7-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazolo[4,3-b]pyridine (203.37 mg, 0.829 mmol, 3.2 equiv), K₂CO₃ (89.59 mg, 0.647 mmol, 2.5 equiv), Pd(dppf)Cl₂*CH₂Cl₂ (21.12 mg, 0.026 mmol, 0.1 equiv), 1,4-Dioxane (20 mL), and H₂O (1 mL). The resulting solution was stirred for 3 h at 80 degrees C under a nitrogen atmosphere. Desired product could be detected by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by Prep-TLC/silica gel column chromatography, eluted with DCM/MeOH (12:1) to afford (7S)-3-[(3-chloro-2-methoxyphenyl)amino]-7- methyl-2-{1H-pyrazolo[4,3-b]pyridin-7-yl}-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (33.5 mg, 30.48%) as a yellow crude solid. The crude product was purified by Prep-HPLC with the following conditions (Column: YMC-Actus Triart C18, 30*150 mm, 5μm; Mobile Phase A: Water(10 mmol/L NH₄HCO₃+0.1%NH₃*H₂O), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 35% B to 50% B in 8 min, 50% B; Wave Length: 254;220 nm; RT1(min): 7.7) to afford (7S)-3-[(3-chloro-2-methoxyphenyl)amino]-7- methyl-2-{1H-pyrazolo[4,3-b]pyridin-7-yl}-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (33.5 mg, 30.48%) as a off-white solid. LC-MS: (M+H)⁺ found: 424.00. ¹H NMR (400 MHz, DMSO-d6) δ 13.15 (s, 1H), 8.45 (d, J = 4.7 Hz, 1H), 8.38 – 8.32 (m, 2H), 7.51 – 7.42 (m, 2H), 6.77 – 6.67 (m, 2H), 6.15 (dd, J = 7.3, 2.4 Hz, 1H), 4.76 – 4.67 (m, 1H), 3.91 (s, 3H), 3.83 – 3.75 (m, 1H), 3.44 (ddd, J = 13.0, 6.8, 2.9 Hz, 1H), 1.66 (d, J = 6.5 Hz, 3H). Example 14. 2-[2-(2-aminoethoxy)thieno[3,2-b]pyridin-7-yl]-3-[(3-chloro-2- methoxyphenyl)amino]-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (compound 314)

To a stirred solution of 7-chlorothieno[3,2-b]pyridine (5 g, 29.476 mmol, 1.00 equiv) in THF (12 mL) was added LDA (3.79 g, 35.371 mmol, 1.20 equiv) dropwise at -78 °C under argon atmosphere. The resulting mixture was stirred for 1 h at -78 °C under argon atmosphere. To the above mixture was added a solution of Iodine (9.35 g, 36.845 mmol, 1.25 equiv) in THF (5.2 mL) dropwise, and the solution was stirred for 2 h at -78 °C. The reaction was monitored by LCMS. The reaction was quenched by the addition of sat. NH₄Cl (aq.) (10 mL) at 0 °C. The resulting mixture was extracted with EtOAc (3 x 20 mL). The combined organic layers were dried over anhydrous Na₂SO₄. The residue was purified by silica gel column chromatography, eluted with PE / EA (2:1) to afford 7- chloro-2-iodothieno[3,2-b]pyridine (5.6 g, 64.29%) as a yellow solid. LC-MS: M+H found: 296.

To a stirred solution of 7-chloro-2-iodothieno[3,2-b]pyridine (1 g, 3.384 mmol, 1 equiv) and tert-butyl N-(2-hydroxyethyl)carbamate (545.48 mg, 3.384 mmol, 1 equiv) in Toluene, were added RockPhos Pd G3 (170.23 mg, 0.203 mmol, 0.06 equiv) and Cs₂CO₃ (2205.06 mg, 6.768 mmol, 2 equiv). The reaction mixture was stirred at room temperature under nitrogen atmosphere then heated for 2 h at 90 degrees C. The resulting mixture was concentrated under reduced pressure. The residue was purified by Prep-TLC (PE/EA 1:1) to afford tert-butyl N-[2-({7-chlorothieno[3,2-b]pyridin-2-yl}oxy)ethyl]carbamate (450 mg, 40.44%) as a red solid. LC-MS: M+H found: 329.

A mixture of bis(pinacolato)diboron (154.46 mg, 0.608 mmol, 2 equiv), tert-butyl N-[2- ({7-chlorothieno[3,2-b]pyridin-2-yl}oxy)ethyl]carbamate (100 mg, 0.304 mmol, 1.00 equiv) and Pd(dppf)Cl₂*CH₂Cl₂ (24.77 mg, 0.030 mmol, 0.1 equiv) in dioxane was stirred for 16 h at 120°C under N₂ atmosphere. LCMS indicated the reaction was complete. The resulting mixture was concentrated under vacuum. The resulting mixture was diluted with DCM (10 mL). The resulting mixture was filtered, then the filter cake was washed with DCM (3x3mL). The filtrate was concentrated under reduced pressure. The resulting mixture was diluted with EA (10 mL). The resulting mixture was filtered, the filter cake was washed with EA (3X3mL). The filtrate was concentrated under reduced pressure. The crude product got 2-{2-[(tert-butoxycarbonyl)amino]ethoxy}thieno[3,2-b]pyridin-7- ylboronic acid (300 mg, 291.68%). LC-MS: M+H found: 421.

A solution of 2-{2-[(tert-butoxycarbonyl)amino]ethoxy}thieno[3,2-b]pyridin-7- ylboronic acid (136.51 mg, 0.404 mmol, 1.5 equiv), 2-bromo-3-[(3-chloro-2- methoxyphenyl)amino]-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (100 mg, 0.269 mmol, 1.00 equiv), Pd(dppf)Cl₂*CH₂Cl₂ (21.92 mg, 0.027 mmol, 0.1 equiv) and K₂CO₃ (74.38 mg, 0.538 mmol, 2 equiv) in dioxone/H₂O (0.5mL, 5:1) was stirred for 16 h at 100°C under N₂ atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with DCM/MEOH (10:1) to afford tert-butyl N-{2-[(7-{3-[(3-chloro-2-methoxyphenyl)amino]-4-oxo- 5H,6H,7H-pyrazolo[1,5-a]pyrazin-2-yl}thieno[3,2-b]pyridin-2-yl)oxy]ethyl}carbamate (80 mg, 50.81%) as an off-white solid LC-MS: M+H found: 585.

To a stirred solution/mixture of tert-butyl N-{2-[(7-{3-[(3-chloro-2- methoxyphenyl)amino]-4-oxo-5H,6H,7H-pyrazolo[1,5-a]pyrazin-2-yl}thieno[3,2- b]pyridin-2-yl)oxy]ethyl}carbamate (100 mg, 0.171 mmol, 1 equiv) in DCM (1 mL) was added 1,4-dioxane) containing HCl (g) (1 mL). The resulting mixture was stirred for 2 h at room temperature, then concentrated under vacuum. The crude product was purified by Prep-HPLC with the following conditions (Column: XBridge Shield RP18 OBD Column, 30*150 mm, 5m; Mobile Phase A: Water (10 mmol/L NH₄HCO₃+0.1%NH₃*H₂O), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 10% B to 57% B in 10 min, 57% B; Wave Length: 254/220 nm; RT1(min): 7.37) to afford 2-[2-(2- aminoethoxy)thieno[3,2-b]pyridin-7-yl]-3-[(3-chloro-2-methoxyphenyl)amino]- 5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (27.5 mg, 33.04%) as a white solid. LC-MS: M+H found: 485. ¹H NMR (300 MHz, DMSO-d6) δ 8.43 – 8.32 (m, 2H), 7.50 – 7.39 (m, 2H), 6.79 – 6.67 (m, 3H), 6.13 (dd, J = 6.3, 3.3 Hz, 1H), 4.47 (dd, J = 7.1, 5.0 Hz, 2H), 4.21 (t, J = 5.6 Hz, 2H), 3.91 (s, 3H), 3.69 (s, 2H), 2.95 (t, J = 5.6 Hz, 2H). Example 15. 3-[(3-chloro-2-methoxyphenyl)amino]-2-{2-[2- (dimethylamino)ethoxy]thieno[3,2-b]pyridin-7-yl}-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4- one (compound 312)

To a stirred solution of 2-[2-(2-aminoethoxy)thieno[3,2-b]pyridin-7-yl]-3-[(3-chloro-2- methoxyphenyl)amino]-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (80 mg, 0.165 mmol, 1 equiv) in MeOH were added HCHO (9.91 mg, 0.330 mmol, 2 equiv) and a drop of AcOH. The resulting mixture was stirred for 20 min at room temperature. NaBH3CN (103.67 mg, 1.650 mmol, 10 equiv) was added, anf the resulting mixture was stirred for 2 h at room temperature. The resulting mixture was concentrated under vacuum. The crude product was purified by Prep-HPLC with the following conditions (Column: YMC-Actus Triart C18, 30*150 mm, 5m; Mobile Phase A: Water(10 mmol/L NH₄HCO₃+0.1%NH₃*H₂O), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 47% B to 57% B in 8 min, 57% B; Wave Length: 254 ˗ 220 nm; RT1(min): 7.32) to afford 3-[(3-chloro-2- methoxyphenyl)amino]-2-{2-[2-(dimethylamino)ethoxy]thieno[3,2-b]pyridin-7-yl}- 5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (33.1 mg, 38.96%) as a white solid. LC-MS: M+H found: 513. ¹H NMR (300 MHz, DMSO-d6) δ 8.43 – 8.29 (m, 2H), 7.50 – 7.39 (m, 2H), 6.73 (t, J = 3.2 Hz, 3H), 6.13 (dd, J = 6.4, 3.2 Hz, 1H), 4.47 (t, J = 6.1 Hz, 2H), 4.34 (t, J = 5.5 Hz, 2H), 3.91 (s, 3H), 3.69 (s, 2H), 2.71 (t, J = 5.4 Hz, 2H), 2.24 (s, 6H). Example 16.3-[(3-chloro-2-methoxyphenyl)amino]-2-{2-[2- (methylamino)ethoxy]thieno[3,2-b]pyridin-7-yl}-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4- one (compound 313)

A solution of tert-butyl N-[2-({7-chlorothieno[3,2-b]pyridin-2-yl}oxy)ethyl]carbamate (250 mg, 0.760 mmol, 1 equiv) in MeOH was treated with HCHO (45.66 mg, 1.520 mmol, 2 equiv) and a drop of acetic acid for 30 min at RT under nitrogen atmosphere followed by the addition of NaBH3CN (477.80 mg, 7.600 mmol, 10 equiv) added in portions at rt. The reaction was quenched with H₂O, and extracted extracted with EA (3x35 mL). The combined organic phase was concentrated to afford tert-butyl N-[2-({7-chlorothieno[3,2- b]pyridin-2-yl}oxy)ethyl]-N-methylcarbamate (230 mg, 88.24%) as a brown solid. LC-MS: M+H found: 343.

A solution of bis(pinacolato)diboron (148.14 mg, 0.584 mmol, 2 equiv), tert-butyl N-[2- ({7-chlorothieno[3,2-b]pyridin-2-yl}oxy)ethyl]-N-methylcarbamate (100 mg, 0.292 mmol, 1.00 equiv), AcOK (57.25 mg, 0.584 mmol, 2 equiv), and Pd(dppf)Cl₂ (21.34 mg, 0.029 mmol, 0.1 equiv) in dioxane was stirred for 16 h at 120°C under N₂ atmosphere. The resulting mixture was concentrated under vacuum then redissolved in DCM (10 mL). The resulting mixture was filtered, the filter cake was washed with DCM (3x3mL). The filtrate was concentrated under reduced pressure. The resulting mixture was diluted with EA (10mL). The resulting mixture was filtered, then the filter cake was washed with EA (3X3 mL). The filtrate was concentrated under reduced pressure to afford 2-{2-[(tert- butoxycarbonyl)(methyl)amino]ethoxy}thieno[3,2-b]pyridin-7-ylboronic acid (300 mg, 292.02%) LC-MS: M+H found: 353.

A solution of 2-bromo-3-[(3-chloro-2-methoxyphenyl)amino]-5H,6H,7H-pyrazolo[1,5- a]pyrazin-4-one (100 mg, 0.269 mmol, 1 equiv), 2-{2-[(tert- butoxycarbonyl)(methyl)amino]ethoxy}thieno[3,2-b]pyridin-7-ylboronic acid (189.55 mg, 0.538 mmol, 2 equiv) , Pd(dppf)Cl₂ (19.69 mg, 0.027 mmol, 0.1 equiv), and K₂CO₃ (74.38 mg, 0.538 mmol, 2 equiv) in dioxane/H₂O (0.5 mL, 5:1) was stirred for 16 h at 100°C under N₂ atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with DCM/MEOH (10:1) to afford tert-butyl N-{2-[(7-{3-[(3-chloro-2- methoxyphenyl)amino]-4-oxo-5H,6H,7H-pyrazolo[1,5-a]pyrazin-2-yl}thieno[3,2- b]pyridin-2-yl)oxy]ethyl}-N-methylcarbamate (40 mg, 24.81%) as an off-white solid LC-MS: M+H found: 599.

To a stirred solution/mixture of tert-butyl N-{2-[(7-{3-[(3-chloro-2- methoxyphenyl)amino]-4-oxo-5H,6H,7H-pyrazolo[1,5-a]pyrazin-2-yl}thieno[3,2- b]pyridin-2-yl)oxy]ethyl}-N-methylcarbamate (200 mg, 0.334 mmol, 1 equiv) in DCM (2.00 mL) was added 2 mL HCl/dioxane . The resulting mixture was stirred for 2 h at room temperature under nitrogen atmosphere. The resulting mixture was concentrated under vacuum. The crude product was purified by Prep-HPLC with the following conditions (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water(10 mmol/L NH₄HCO₃+0.1%NH₃*H₂O), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 27% B to 47% B in 8 min, 47% B; Wave Length: 254; 220 nm; RT1(min): 7.02) to afford 3-[(3-chloro-2-methoxyphenyl)amino]-2-{2-[2- (methylamino)ethoxy]thieno[3,2-b]pyridin-7-yl}-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4- one (84.1 mg, 50.49%) as a white solid. LC-MS: M+H found: 499. ¹H NMR (400 MHz, DMSO-d₆) δ 8.37 (dd, J = 16.4, 4.3 Hz, 2H), 7.49 – 7.40 (m, 2H), 6.78 – 6.68 (m, 3H), 6.13 (dd, J = 6.8, 2.8 Hz, 1H), 4.39 (dt, J = 56.5, 5.8 Hz, 4H), 3.91 (s, 3H), 3.69 (s, 2H), 2.95 (t, J = 5.4 Hz, 2H), 2.38 (s, 3H). Example 17. 3-[(3-chloro-2-methoxyphenyl)amino]-2-[2-oxo-1H,3H-imidazo[4,5- b]pyridin-7-yl]-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (compound 336)

To a stirred solution of methyl 4-nitro-2H-pyrazole-3-carboxylate (5.00 g, 29.221 mmol, 1.00 equiv) and tert-butyl N-(2-bromoethyl)carbamate (9.82 g, 43.831 mmol, 1.5 equiv) in DMF (50.00 mL) were added K₂CO₃ (8.08 g, 58.441 mmol, 2 equiv) and NaI (2.19 g, 14.610 mmol, 0.5 equiv) at rt. The solution was stirred at rt about 16 h. The resulting mixture was diluted with water (50 mL) and extracted with EA (4x50mL). The combined organic phase was concentrated under reduced pressure to afford methyl 2-[2-[(tert- butoxycarbonyl)amino]ethyl]-4-nitropyrazole-3-carboxylate (11.8 g) as a white solid. LC-MS: M+Na found: 337.10.

A solution of methyl 2-[2-[(tert-butoxycarbonyl)amino]ethyl]-4-nitropyrazole-3- carboxylate (6.00 g) 1,4-dioxane/HCl (20.00 mL) and DCM (40.00 mL) was stirred at rt about 2 h. The resulting mixture was extracted with DCM, the combined organic layers were washed with saturation NaHCO₃, dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to afford the methyl 2-(2- aminoethyl)-4-nitropyrazole-3-carboxylate about 4.2 g as a yellow solid. LC-MS: M+H found: 215.20.

A solution of methyl 2-(2-aminoethyl)-4-nitropyrazole-3-carboxylate (4.20 g, 19.610 mmol, 1.00 equiv) and K₂CO₃ (9.49 g, 68.635 mmol, 3.50 equiv) in EtOH (40.00 mL, 688.541 mmol, 35.11 equiv) was stirred at 50 degrees C for about 16 h. The resulting mixture was diluted with water (50 mL) and extracted with EA (4x50mL). The combined organic layers were washed with saturated salt solution (3x30 mL), dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure and get the 3-nitro-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one about 650 mg as a white solid. LC-MS: M+H found: 183.10.

Into a 100 mL Stand-up flask were added 3-nitro-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4- one (0.6 g) , Pd/C (0.26 g) and EtOH (35.00 mL) at rt. The flask was sealed, purged/evacuated, and then attached to the hydrogen packet. The solution was stirred at rt for 16 h.The resulting mixture was filtered, the filter cake was washed with MeOH.The filtrate was concentrated under reduced pressure to afford 3-amino-5H,6H,7H- pyrazolo[1,5-a]pyrazin-4-one about 520mg as a white solid. LC-MS: M+H found: 153.10.

To a stirred solution of 3-amino-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (500.00 mg, 3.286 mmol, 1.00 equiv) in MeCN (5.00 mL) were added NBS (643.36 mg, 3.615 mmol, 1.10 equiv) dropwise at 0 degrees C. The solution was stirred at rt about 30 min. The resulting mixture was diluted with water (50 mL) and extracted with EA(4x50mL). The combined organic layers was concentrated under reduced pressure to afford 3-amino-2- bromo-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one about 370 mg (yield = 49%) as a yellow solid. LC-MS: M+H found: 231.

A mixture of 3-amino-2-bromo-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (10.00 mg, 0.043 mmol, 1.00 equiv) and 3-chloro-2-methoxyphenylboronic acid (9.68 mg, 0.052 mmol, 1.20 equiv), Cu(OAc)₂ (8.65 mg, 0.048 mmol, 1.1 equiv), Et3N (13.14 mg, 0.130 mmol, 3 equiv) in DCE (0.50 mL) was stirred for 12 h at 25 °C under oxygen atmosphere. The residue was dissolved in water (10 mL).The resulting mixture was extracted with DCM (10 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (DCM/MeOH=15/1) to afford 2-bromo-3-[(3- chloro-2-methoxyphenyl)amino]-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (5 mg, 29.53%) as a white solid. LC-MS: M+H found: 371.05.

To a stirred solution of 7-bromo-1H,3H-imidazo[4,5-b]pyridin-2-one (325.00 mg, 1.519 mmol, 1.00 equiv) and bis(pinacolato)diboron (771.23 mg, 3.037 mmol, 2.00 equiv) in DMF (4.00 mL, 51.687 mmol, 44.25 equiv) were added KOAc (298.07 mg, 3.037 mmol, 2.00 equiv) and Pd(dppf)Cl₂ (222.22 mg, 0.304 mmol, 0.20 equiv) at RT under N₂ atmosphere. The solution was stirred at 150 degrees C in a microwave reactor. The resulting mixture was diluted with 5 mL of DMF and filtrated. The residue was purified by reverse flash chromatography with the following conditions: (column, C18 silica gel; mobile phase, ACN in water, 1% to 100% gradient in 10 min; detector, UV 254 nm) to afford 2-oxo-1H,3H-imidazo[4,5-b]pyridin-7-ylboronic acid (138 mg, 66.02%) as a brown solid. LC-MS: M+H found: 180.05.

To a stirred mixture of 2-bromo-3-[(3-chloro-2-methoxyphenyl)amino]-5H,6H,7H- pyrazolo[1,5-a]pyrazin-4-one (40.00 mg, 0.108 mmol, 1.00 equiv) and 2-oxo-1H,3H- imidazo[4,5-b]pyridin-7-ylboronic acid (38.52 mg, 0.215 mmol, 2 equiv) in THF (0.40 mL) and H₂O (0.10 mL) were added K₂CO₃ (29.75 mg, 0.216 mmol, 2.00 equiv) and XPhos Pd G3 (18.22 mg, 0.022 mmol, 0.2 equiv) in portions at RT under N₂ atmosphere. The resulting mixture was stirred for 16 hours at 80 degrees C under N₂ atmosphere. The resulting mixture was filtered, the filter cake was washed with EA (1x110 mL). The filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (EA and MeOH 50:1) to afford 3-[(3-chloro-2-methoxyphenyl)amino]-2-[2-oxo-1H,3H- imidazo[4,5-b]pyridin-7-yl]-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (3.8 mg, 8.17%) as a off-white solid. LC-MS: M+H found: 426.2. ¹H NMR (400 MHz, DMSO-d6) δ 11.40 (s, 1H), 10.46 (s, 1H), 8.30 (s, 1H), 7.81 (d, J = 5.5 Hz, 1H), 7.27 (s, 1H), 7.14 (d, J = 5.6 Hz, 1H), 6.74 – 6.68 (m, 2H), 6.13 (p, J = 4.1 Hz, 1H), 4.46 (t, J = 6.0 Hz, 2H), 3.89 (s, 3H), 3.68 (q, J = 6.6, 4.8 Hz, 2H). Example 18. 3-[(3-chloro-2-methoxyphenyl)amino]-2-(6-methoxy-1,7-naphthyridin-4- yl)-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (compound 350)

To a stirred mixture of 6-methoxy-1H-1,7-naphthyridin-4-one (300 mg, 1.703 mmol, 1.00 equiv) and phosphorus oxychloride (3 mL, 19.567 mmol, 11.49 equiv) for 2 hours at 100 degrees C under N₂ atmosphere. The reaction was quenched with H₂O at 0 degrees C. The aqueous layer was extracted with EA and H₂O 3x1150 mL). The residue was purified by Prep-TLC (DCM and MeOH 18:1) to afford 4-chloro-6-methoxy-1,7-naphthyridine (120 mg, 36.21%) as a light yellow oil. LC-MS: M+H found: 194.95.

To a stirred mixture of 4-chloro-6-methoxy-1,7-naphthyridine (360 mg, 1.850 mmol, 1.00 equiv) and 3-chloro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5H,6H,7H- pyrazolo[1,5-a]pyrazin-4-one (1100.79 mg, 3.700 mmol, 2 equiv) in dioxane (4 mL, 47.216 mmol, 25.53 equiv) and H₂O (1 mL, 55.508 mmol, 30.01 equiv) were added Pd(dppf)Cl₂*CH₂Cl₂ (150.69 mg, 0.185 mmol, 0.1 equiv) and K₂CO₃ (511.29 mg, 3.700 mmol, 2 equiv) in portions at RT. The resulting mixture was stirred for 2 hours at 80 degrees C under N₂ atmosphere. The resulting mixture was filtered; the filter cake was washed with EA (10 mL). The filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (DCM: MeOH= 10:1) to afford 3-chloro-2-(6- methoxy-1,7-naphthyridin-4-yl)-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (320 mg, 52.46%) as a light yellow solid. LC-MS: M+H found: 330.2.

To a stirred mixture of 3-chloro-2-(6-methoxy-1,7-naphthyridin-4-yl)-5H,6H,7H- pyrazolo[1,5-a]pyrazin-4-one (200.00 mg, 0.607 mmol, 1.00 equiv) and 3-chloro-2- methoxyaniline (114.71 mg, 0.728 mmol, 1.2 equiv) in dioxane (5.00 mL) were added Cs₂CO₃ (592.87 mg, 1.821 mmol, 3.00 equiv) and EPhos (32.44 mg, 0.061 mmol, 0.10 equiv) and EPhos Pd G4 (55.71 mg, 0.061 mmol, 0.10 equiv) in portions at RT under N₂ atmosphere. The resulting mixture was stirred for 16 hours at 50 degrees C under N₂ atmosphere. The resulting mixture was filtered; the filter cake was washed with EA (1x1 10 mL). The filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (DCM and MeOH 18:1) to afford 3-[(3-chloro-2-methoxyphenyl)amino]- 2-(6-methoxy-1,7-naphthyridin-4-yl)-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (37.0 mg, 13.57%) as a light yellow solid. LC-MS: M+H found: 451.0. ¹H NMR (400 MHz, DMSO-d6) δ 9.15 (d, J = 0.9 Hz, 1H), 8.80 (d, J = 4.4 Hz, 1H), 8.35 (d, J = 3.1 Hz, 1H), 7.76 – 7.69 (m, 2H), 7.44 (s, 1H), 6.61 (dd, J = 8.1, 1.5 Hz, 1H), 6.54 (t, J = 8.1 Hz, 1H), 6.12 (dd, J = 8.1, 1.6 Hz, 1H), 4.49 (dd, J = 7.1, 5.0 Hz, 2H), 3.96 (s, 3H), 3.79 (s, 3H), 3.77 – 3.69 (m, 2H). Example 19. (7R)-3-[(3-chloro-2-methoxyphenyl) amino]-2-(6-methoxyquinolin-4-yl)- 7-methyl-5H,6H,7H-pyrazolo[1,5-a] pyrazin-4-one (compound 359)

To a solution of (7R)-3-chloro-7-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)-5H,6H,7H-pyrazolo[1,5-a]pyrazine-4-one (651.62 mg, 2.092 mmol, 2.5 equiv) and 4-bromo-6-methoxy-1,7-naphthyridine (200 mg, 0.837 mmol, 1.00 equiv) in DMF (10 mL) were added K₂CO₃ (289.05 mg, 2.092 mmol, 2.5 equiv) and Pd(dppf)Cl₂ (61.21 mg, 0.084 mmol, 0.1 equiv). After stirring for 2 h at 80°C under a nitrogen atmosphere, the resulting mixture was concentrated under reduced pressure. The residue was purified by Prep-TLC, eluted with DCM:MeOH (15:1) to afford the (7R)-3-chloro-2-(6-methoxy- 1,7-naphthyridin-4-yl)-7-methyl-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (150 mg 73.2%) as a brown solid. LC-MS: M+H found: 344.0.

To a stirred solution of (7R)-3-chloro-2-(6,7-dimethoxyquinolin-4-yl)-7-methyl- 5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (100.00 mg, 0.268 mmol, 1.00 equiv), Cs₂CO₃ (262.19 mg, 0.804 mmol, 3.00 equiv) and 3-chloro-2-methoxyaniline (50.73 mg, 0.322 mmol, 1.20 equiv) in DMF (5.00 mL) was added EPhos (71.72 mg, 0.134 mmol, 0.50 equiv) and EPhos Pd G4 (123.19 mg, 0.134 mmol, 0.50 equiv) in portions at 80°C under N₂ atmosphere. The mixture was allowed to cool down to RT. The resulting mixture was extracted with EA (3 x 50ml). The combined organic layers were washed with brine (2x1 20ml), dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (DCM: MeOH=15:1) to afford the crude product (50mg, 78%). The crude product (mg) was purified by Prep-HPLC with the following conditions (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water (10 mmol/L NH₄HCO₃+0.1%NH₃*H₂O), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 29% B to 59% B in 8 min, 59% B; Wave Length: 254; 220 nm; RT1(min): 6.77) to afford (7R)-3-[(3-chloro-2-methoxyphenyl) amino]-2-(6- methoxyquinolin-4-yl)-7-methyl-5H,6H,7H-pyrazolo[1,5-a] pyrazin-4-one(8.1mg 99.4%) as a white solid. LC-MS: M+H found: 464.95. ¹H NMR (400 MHz, DMSO-d6) δ 9.15 (s, 1H), 8.80 (d, J = 4.4 Hz, 1H), 8.35 (s, 1H), 7.77 – 7.70 (m, 2H), 7.48 (s, 1H), 6.65 – 6.58 (m, 1H), 6.54 (t, J = 8.1 Hz, 1H), 6.10 (d, J = 8.1 Hz, 1H), 4.73 – 4.64 (m, 1H), 3.96 (s, 3H), 3.77 (t, J = 3.8 Hz, 1H), 3.53 ̢ 3.43 (m, 1H), 1.60 (d, J = 6.4 Hz, 3H). Example 20. (7S)-3-[(3-chloro-2-methoxyphenyl)amino]-2-(6-methoxyquinolin-4-yl)-7- methyl-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (compound 357)

To a solution of 4-chloro-6-methoxyquinoline (150.00 mg, 0.775 mmol, 1.00 equiv) and (7S)-3-chloro-7-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5H,6H,7H- pyrazolo[1,5-a]pyrazin-4-one (965.46 mg, 3.10 mmol, 4.00 equiv) in dioxane (5.00 mL) and H₂O (1.00 mL) were added K₂CO₃ (214.13 mg, 1.550 mmol, 2.00 equiv) and Pd(dppf)Cl₂*CH₂Cl₂ (63.11 mg, 0.078 mmol, 0.10 equiv). After stirring for 2 h at 80 degrees C under a nitrogen atmosphere, the resulting mixture was diluted with H₂O (100 mL). The resulting mixture was extracted with EA (3 x 50mL). The combined organic layers were washed with brine (1x30mL), dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep- TLC/silica gel column chromatography, eluted with DCM:MeOH (15:1) to afford (7S)- 3-chloro-2-(6-methoxyquinolin-4-yl)-7-methyl-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (150 mg, 43.55%) as a brown solid. LC-MS: M+H found: 343.

To a solution of (7S)-3-chloro-2-(6-methoxyquinolin-4-yl)-7-methyl-5H,6H,7H- pyrazolo[1,5-a]pyrazin-4-one (150.00 mg, 0.438 mmol, 1.00 equiv) and 3-chloro-2- methoxyaniline (137.93 mg, 0.876 mmol, 2.00 equiv) in DMF (5.00 mL) was added Cs₂CO₃ (285.16 mg, 0.876 mmol, 2.00 equiv), E Phos Pd G4 (200.98 mg, 0.219 mmol, 0.50 equiv) and EPhos (234.03 mg, 0.438 mmol, 1.00 equiv). After stirring for 2 h at 50 degrees C under a nitrogen atmosphere, the resulting mixture was diluted with H₂O (100 mL). The resulting mixture was extracted with EA (3 x 50 mL). The combined organic layers were washed with brine (1x30 mL), dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep- TLC/silica gel column chromatography, developed with DCM:MeOH (15:1) followed by Prep-HPLC (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water (10 mmol/L NH₄HCO₃+0.1% NH₃*H₂O), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 35% B to 55% B in 8 min, 55% B; Wave Length: 254; 220 nm; RT1(min): 6.85) to afford (7S)-3-[(3-chloro-2-methoxyphenyl)amino]-2-(6- methoxyquinolin-4-yl)-7-methyl-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (44.4 mg, 21.70%)as a light yellow solid. LC-MS: M+H found: 464. ¹H NMR (400 MHz, DMSO-d6):δ 8.70 (d, J = 4.5 Hz, 1H), 8.34 (t, J = 2.7 Hz, 1H), 7.95 (d, J = 9.2 Hz, 1H), 7.86 (d, J = 2.8 Hz, 1H), 7.58 (d, J = 4.5 Hz, 1H), 7.46 (s, 1H), 7.42 (dd, J = 9.2, 2.8 Hz, 1H), 6.60 (dd, J = 8.0, 1.5 Hz, 1H), 6.52 (t, J = 8.1 Hz, 1H), 6.13 (dd, J = 8.1, 1.6 Hz, 1H), 4.71 – 4.60 (m, 1H), 3.83 (s, 3H), 3.80 (dd, J = 8.0, 3.9 Hz, 1H), 3.76 (s, 3H), 3.49 (ddd, J = 13.1, 8.5, 2.2 Hz, 1H), 1.62 (d, J = 6.4 Hz, 3H). Example 21. (7R)-3-[(3-chloro-2-methoxyphenyl) amino]-2-(6-methoxyquinolin-4-yl)-7- methyl-5H,6H,7H-pyrazolo[1,5-a] pyrazin-4-one (compound 358)

To a solution of 4-bromo-6-methoxyquinoline (200 mg, 0.840 mmol, 1.00 equiv) and (7R)-3-chloro-7-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5H,6H,7H- pyrazolo[1,5-a]pyrazin-4-one (654.33 mg, 2.100 mmol, 2.5 equiv) in DMF (2 mL) were added K₂CO₃ (290.25 mg, 2.100 mmol, 2.5 equiv) and Pd(dppf)Cl₂ (61.47 mg, 0.084 mmol, 0.10 equiv) . After stirring for 2 h at 80°C under a nitrogen atmosphere, the resulting mixture was concentrated under reduced pressure. The residue was purified by Prep-TLC, eluted with DCM: MeOH (15:1) to afford (7R)-3-chloro-2-(6- methoxyquinolin-4-yl)-7-methyl-5H,6H,7H-pyrazolo [1,5-a]pyrazine-4-one(150mg 66.9%) a brown solid. LC-MS: M+H found: 343.0.

To a stirred solution of (7R)-3-chloro-2-(6,7-dimethoxyquinolin-4-yl)-7-methyl- 5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (100.00 mg, 0.268 mmol, 1.00 equiv), Cs₂CO₃ (262.19 mg, 0.804 mmol, 3.00 equiv) and 3-chloro-2-methoxyaniline (50.73 mg, 0.322 mmol, 1.20 equiv) in DMF (5.00 mL) was added EPhos (71.72 mg, 0.134 mmol, 0.50 equiv) and EPhos Pd G4 (123.19 mg, 0.134 mmol, 0.50 equiv) in portions at 80°C under N₂ atmosphere. The mixture was allowed to cool down to RT. The resulting mixture was extracted with EA (3 x 50 mL). The combined organic layers were washed with brine (2 x 20 mL), dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (DCM: MeOH 15:1) to afford the crude product. The crude product (mg) was purified by Prep-HPLC with the following conditions (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water (10 mmol/L NH₄HCO₃+0.1%NH₃*H₂O), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 35% B to 55% B in 8 min, 55% B; Wave Length: 254; 220 nm; RT1(min): 6.82) to afford (7R)-3-[(3-chloro-2-methoxyphenyl) amino]-2-(6- methoxyquinolin-4-yl)-7-methyl-5H,6H,7H-pyrazolo[1,5-a] pyrazin-4-one(15mg 98.2%) as a as a white solid. LC-MS: M+H found: 464.0. ¹H NMR (400 MHz, DMSO-d6) δ 8.69 (d, J = 4.5 Hz, 1H), 8.34 (t, J = 2.7 Hz, 1H), 7.94 (d, J = 9.1 Hz, 1H), 7.85 (d, J = 2.9 Hz, 1H), 7.56 (d, J = 4.5 Hz, 1H), 7.46 (s, 1H), 7.42 (dd, J = 9.2, 2.8 Hz, 1H), 6.60 (dd, J = 8.1, 1.6 Hz, 1H), 6.52 (t, J = 8.1 Hz, 1H), 6.12 (dd, J = 8.1, 1.6 Hz, 1H), 4.71 – 4.62 (m, 1H), 3.82 (s, 3H), 3.79 (dd, J = 8.1, 4.1 Hz, 1H), 3.76 (s, 3H), 3.49 (ddd, J = 13.2, 8.4, 2.2 Hz, 1H), 1.62 (d, J = 6.4 Hz, 3H). Example 22. (7S)-3-[(3-chloro-2-methoxyphenyl)amino]-2-(6,7-dimethoxyquinolin-4- yl)-7-methyl-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (compound 361)

To a solution of 4-bromo-6,7-dimethoxyquinoline (150.00 mg, 0.559 mmol, 1.00 equiv) and (7S)-3-chloro-7-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5H,6H,7H- pyrazolo[1,5-a]pyrazin-4-one (697.26 mg, 2.236 mmol, 4.00 equiv) in dioxane (5.00 mL) and H₂O (1.00 mL) were added K₂CO₃ (154.64 mg, 1.118 mmol, 2.00 equiv) and Pd(dppf)Cl₂ CH₂Cl₂ (45.58 mg, 0.056 mmol, 0.10 equiv). After stirring for 2 h at 80 degrees C under a nitrogen atmosphere, The resulting mixture was diluted with H₂O (100 mL). The resulting mixture was extracted with EA (3 x 50 mL). The combined organic layers were washed with brine (1 x 20 mL), dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep- TLC/silica gel column chromatography, eluted with DCM:MeOH (15:1) to afford (7S)- 3-chloro-2-(6,7-dimethoxyquinolin-4-yl)-7-methyl-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4- one (150 mg, 68.61%) as a brown solid. LC-MS: M+H found: 373.

To a solution of (7S)-3-chloro-2-(6,7-dimethoxyquinolin-4-yl)-7-methyl-5H,6H,7H- pyrazolo[1,5-a]pyrazin-4-one (150.00 mg, 0.402 mmol, 1.00 equiv)and 3-chloro-2- methoxyaniline (137.93 mg, 0.876 mmol, 2.00 equiv) in DMF (5.00 mL) was added Cs₂CO₃ (285.16 mg, 0.876 mmol, 2.00 equiv), EPhos Pd G4 (200.98 mg, 0.219 mmol, 0.50 equiv) and EPhos (234.03 mg, 0.438 mmol, 1.00 equiv). After stirring for 2 h at 50 degrees C under a nitrogen atmosphere, The resulting mixture was diluted with H₂O (100 mL). The resulting mixture was extracted with EA (3 x 50 mL). The combined organic layers were washed with brine (1 x 30 mL), dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep- TLC/silica gel column chromatography, eluted with DCM:MeOH (15:1) and Prep-HPLC (Column: YMC-Actus Triart C18, 30*150 mm, 5μm; Mobile Phase A: Water (10 mmol/L NH₄HCO₃+0.1%NH₃*H₂O), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 43% B to 53% B in 8 min, 53% B; Wave Length: 254/220 nm; RT1(min): 6.60) to afford (7S)- 3-[(3-chloro-2-methoxyphenyl)amino]-2-(6,7-dimethoxyquinolin-4-yl)-7-methyl- 5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (42.8 mg, 21.43%)as a light yellow solid. LC-MS: M+H found: 494. ¹H NMR (400 MHz, DMSO-d6): δ 8.63 (d, J = 4.7 Hz, 1H), 8.37 – 8.32 (m, 1H), 7.86 (s, 1H), 7.47 (d, J = 4.9 Hz, 2H), 7.39 (s, 1H), 6.61 (dd, J = 8.0, 1.5 Hz, 1H), 6.53 (t, J = 8.1 Hz, 1H), 6.11 (dd, J = 8.1, 1.6 Hz, 1H), 4.66 (ddd, J = 8.6, 6.4, 4.4 Hz, 1H), 3.94 (s, 3H), 3.83 (s, 3H), 3.78-3.72 (m, 4H), 3.48 (ddd, J = 13.0, 8.6, 2.2 Hz, 1H), 1.62 (d, J = 6.4 Hz, 3H). Example 23. (7R)-3-[(3-chloro-2-methoxyphenyl)amino]-2-(6,7-dimethoxyquinolin-4- yl)-7-methyl-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (compound 360)

To a solution of 4-bromo-6,7-dimethoxyquinoline (300 mg, 1.119 mmol, 1 equiv) and (7R)-2-boranyl-3-chloro-7-methyl-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (552.28 mg, 2.797 mmol, 2.5 equiv) in DMF (6 mL)were added K2CO3 (386.61 mg, 2.797 mmol, 2.50 equiv) and Pd(dppf)Cl₂ (122.81 mg, 0.168 mmol, 0.15 equiv) . After stirring for 2 h at 80°C under a nitrogen atmosphere, the resulting mixture was concentrated under reduced pressure. The residue was purified by Prep-TLC, eluted with DCM:MeOH (20:1) to afford (7R)-3-chloro-2-(6,7-dimethoxyquinolin-4-yl)-7-methyl-5H,6H,7H- pyrazolo[1,5-a]pyrazin-4-one (300 mg, 90.8%) as a brown solid. LC-MS: M+H found: 373.00.

To a stirred solution of (7R)-3-chloro-2-(6,7-dimethoxyquinolin-4-yl)-7-methyl- 5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (300 mg, 0.805 mmol, 1 equiv),Cs2CO3 (655.47 mg, 2.013 mmol, 2.5 equiv) and 3-chloro-2-methoxyaniline (380.46 mg, 2.414 mmol, 3.00 equiv) in DMF (5 mL) was added EPhos Pd G4 (369.58 mg, 0.403 mmol, 0.5 equiv) and EPhos (215.17 mg, 0.403 mmol, 0.5 equiv) at 50°C under N₂ atmosphere. The resulting mixture was extracted with EA (3 x 30 mL). The combined organic layers were washed with brine (3 x 20 mL), dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by Prep-HPLC with the following conditions (Column: XBridge Shield RP18 OBD Column, 30*150 mm, 5μm; Mobile Phase A: Water (10 mmol/L NH₄HCO₃+0.1%NH₃*H₂O), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 23% B to 59% B in 7 min, 59% B; Wave Length: 254/220 nm; RT1(min): 6.42) to afford(7R)-3-[(3-chloro-2-methoxyphenyl)amino]-2-(6,7-dimethoxyquinolin-4-yl)-7- methyl-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (10.3 mg, 98.4%) as a white solid. LC-MS: M+H found: 494.00. ¹H NMR (400 MHz, DMSO-d6) δ 8.61 (d, J = 4.7 Hz, 1H), 8.34 (s, 1H), 7.84 (s, 1H), 7.49 – 7.41 (m, 2H), 7.37 (s, 1H), 6.60 (d, J = 7.9 Hz, 1H), 6.52 (t, J = 8.1 Hz, 1H), 6.10 (d, J = 8.2 Hz, 1H), 4.65 (s, 1H), 3.93 (s, 3H), 3.83 (s, 3H), 3.77 (m, 4H), 3.50 (d, J = 10.5 Hz, 1H), 1.62 (d, J = 6.4 Hz, 3H). Example 24. (7S)-3-[(3-fluoro-2-methoxyphenyl)amino]-7-methyl-2-{[1,2]thiazolo[4,5- b]pyridin-7-yl}-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (compound 368)

Into a 20 mL sealed tube was placed (7S)-3-chloro-7-methyl-2-{[1,2]thiazolo[4,5- b]pyridin-7-yl}-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (150 mg, 0.469 mmol, 1.00 equiv) in DMF (2 mL), 3-fluoro-2-methoxyaniline (198.63 mg, 1.407 mmol, 3 equiv) , EPhos Pd G4 (129.26 mg, 0.141 mmol, 0.3 equiv) and Cs2CO3 (458.51 mg, 1.407 mmol, 3 equiv). The resulting solution was stirred at 50°C for 2 h. The resulting solution was concentrated under vacuum, and the residue was purified by Prep-TLC with DCM/MeOH (25:1). The semi-pure product was purified further by Prep-HPLC with following conditions (Column: YMC-Actus Triart C18, 30*150 mm, 5μm; Mobile Phase A: Water (10 mmol/L NH₄HCO₃+0.1%NH₃*H₂O), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 46% B to 56% B in 8 min, 56% B; Wave Length: 254/220 nm; RT1(min): 6.60).This resulted in 67mg of (7S)-3-[(3-fluoro-2-methoxyphenyl)amino]-7-methyl-2- {[1,2]thiazolo[4,5-b]pyridin-7-yl}-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (67.8 mg, 33.10%) as a white solid LC-MS: M+H found: 425. ¹H NMR (300 MHz, DMSO-d6) δ 9.31 (d, J = 1.4 Hz, 1H), 8.79 (d, J = 4.8 Hz, 1H), 8.42 (d, J = 3.2 Hz, 1H), 7.67 (d, J = 4.8 Hz, 1H), 7.48 (s, 1H), 6.78 – 6.68 (m, 1H), 6.66 – 6.57 (m, 1H), 6.05 (d, J = 8.1 Hz, 1H), 4.97 – 4.51 (m, 1H), 3.98 (s, 3H), 3.81 – 3.67 (m, 1H), 3.56 – 3.40 (m, 1H), 1.71 (d, J = 6.4 Hz, 3H). Example 25. 2-(6-amino-1,7-naphthyridin-4-yl)-3-[(3-chloro-2-methoxyphenyl)amino]- 5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (compound 369)

Into a 20 mL sealed tube was placed (7R)-3-chloro-7-methyl-2-{[1,2]thiazolo[4,5- b]pyridin-7-yl}-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (150 mg, 0.469 mmol, 1.00 equiv) in DMF (2 mL), 3-fluoro-2-methoxyaniline (198.63 mg, 1.407 mmol, 3 equiv), EPhos Pd G4 (129.26 mg, 0.141 mmol, 0.3 equiv), EPhos (75.26 mg, 0.141 mmol, 0.3 equiv) and Cs₂CO₃ (458.51 mg, 1.407 mmol, 3 equiv). The resulting solution was stirred at 50°C for 2 h. The resulting solution was concentrated under vacuum, and the residue was purified by Prep-TLC with DCM/MeOH (30:1). The semi-pure product was further purified by Prep- -HPLC with following conditions (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water(10 mmol/L NH₄HCO₃+0.1%NH₃*H₂O), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 36% B to 56% B in 8 min, 56% B; Wave Length: 254; 220 nm; RT1(min): 6.95). This resulted in (7R)-3-[(3-fluoro-2-methoxyphenyl)amino]-7-methyl-2-{[1,2]thiazolo[4,5-b]pyridin- 7-yl}-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (53.6 mg, 26.81%) as a white solid. LC-MS: M+H found: 425. ¹H NMR (400 MHz, DMSO-d6) δ 9.32 (s, 1H), 8.80 (d, J = 4.9 Hz, 1H), 8.42 (s, 1H), 7.68 (d, J = 4.9 Hz, 1H), 7.49 (s, 1H), 6.74 (q, J = 7.8 Hz, 1H), 6.62 (t, J = 9.8 Hz, 1H), 6.05 (d, J = 8.3 Hz, 1H), 4.69 (d, J = 10.2 Hz, 1H), 3.98 (s, 3H), 3.75 (d, J = 13.2 Hz, 1H), 3.54 – 3.43 (m, 1H), 1.71 (d, J = 6.4 Hz, 3H). Example 26. 2-(6-amino-1,7-naphthyridin-4-yl)-3-[(3-chloro-2-methoxyphenyl)amino]- 5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (compound 298)

To a stirred mixture of 6-chloro-1H-1,7-naphthyridin-4-one (300 mg, 1.661 mmol, 1.00 equiv) and benzyl bromide (340.95mg, 1.993 mmol, 1.2 equiv) in DMF (10 mL) were added K₂CO₃ (459.18 mg, 3.322 mmol,2 equiv) in portions at rt under N₂ atmosphere. The resulting mixture was stirred for 2 h at rt under N₂ atmosphere. The resulting mixture was extracted with EA (3 x 150 mL). The combined organic layers were washed with brine (3 x 100 mL), dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with DCM/MeOH (30:1) to afford 4- (benzyloxy)-6-chloro-1,7-naphthyridine (372.8 mg, 82.89%) as a yellow solid. LC-MS: (M+H) found: 271.

To a stirred mixture of 4-(benzyloxy)-6-chloro-1,7-naphthyridine (440 mg, 1.625 mmol, 1 equiv) and tert-butyl carbamate (761.60 mg, 6.500 mmol, 4 equiv) in THF (20 mL) were added X-Phos (232.44 mg, 0.487 mmol, 0.3 equiv) and Cs₂CO₃ (1482.75 mg, 4.550 mmol, 2.8 equiv) and Pd₂(dba)3*CHCl3 (504.70 mg, 0.487 mmol, 0.3 equiv) in portions at 100°C under N₂ atmosphere. The resulting mixture was stirred for 16 h at 100°C under N₂ atmosphere. The resulting mixture was extracted with EA (3 x 400 mL). The combined organic layers were washed with brine (3 x 200 mL), dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with DCM/MeOH (25:1) to afford tert-butyl N-[4-(benzyloxy)-1,7-naphthyridin-6- yl]carbamate(745.8mg, 97.86%) as a brown yellow solid. LC-MS: (M+H) found: 352.

To a stirred solution of bis(tert-butyl N-[4-(benzyloxy)-1,7-naphthyridin-6-yl]carbamate) (989 mg, 1.407 mmol, 1equiv) in MeOH (200 mL) was added Pd/C (200 mg, 60%) in portions rt under H₂ atmosphere. The resulting mixture was stirred for 16h at rt under N₂ atmosphere. The resulting mixture was filtered, the filter cake was washed with MeOH (3x300 mL). The filtrate was concentrated under reduced pressure. The crude product was used in the next step directly without further purification to afford bis(tert- butyl N-(4-hydroxy-1,7-naphthyridin-6-yl)carbamate)( 765.7 mg, 83.72%) as a orange yellow solid. LC-MS: (M+H) found: 262.

To a stirred solution of tert-butyl N-(4-hydroxy-1,7-naphthyridin-6-yl)carbamate (230 mg, 0.880 mmol, 1 equiv) and NTf₂Ph (2199.82 mg, 6.160 mmol, 7 equiv) in DCM (10 mL) was added TEA (712.60 mg, 7.040 mmol, 8 equiv) dropwise at rt under N₂ atmosphere. The resulting mixture was stirred for 16 h at rt under N₂ atmosphere. The resulting mixture was extracted with EA (3 x 300 mL). The combined organic layers were washed with brine (3 x 200 mL), dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with DCM/MeOH (25:1) to afford tert-butyl N-[4-(trifluoromethanesulfonyloxy)-1,7-naphthyridin-6-yl]carbamate(322 mg, 71.14%) as a light yellow solid. LC-MS: (M+H) found: 394.

To a stirred mixture of tert-butyl N-[4-(trifluoromethanesulfonyloxy)-1,7-naphthyridin- 6-yl]carbamate (260 mg, 0.661 mmol, 1.00 equiv) and 3-chloro-4-oxo-5H,6H,7H- pyrazolo[1,5-a]pyrazin-2-ylboronic acid (170.86 mg, 0.793 mmol, 1.2 equiv) in 1,4- dioxane (7.5 mL) and H₂O (1.5 mL) were added Pd₂(dba)₃*CHCl3 (68.42 mg, 0.066 mmol, 0.1 equiv) and PCy3 (18.54 mg, 0.066 mmol, 0.1 equiv) and Cs₂CO₃ (646.11 mg, 1.983 mmol, 3 equiv) in portions at 60°C under N₂ atmosphere. The resulting mixture was stirred for 2 h at 60°C under N₂ atmosphere. The resulting mixture was filtered, the filter cake was washed with DCM (3 x 200 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with DCM / MeOH (25:1) to afford tert-butyl N-(4-{3-chloro-4-oxo-5H,6H,7H- pyrazolo[1,5-a]pyrazin-2-yl}-1,7-naphthyridin-6-yl)carbamate(130mg, 42.81%) as a light yellow solid. LC-MS: (M+H) found: 415.

To a stirred solution tert-butyl N-(4-{3-chloro-4-oxo-5H,6H,7H-pyrazolo[1,5-a]pyrazin- 2-yl}-1,7-naphthyridin-6-yl)carbamate (62 mg, 0.149 mmol, 1 equiv) and 3-chloro-2- methoxyaniline (42.40 mg, 0.268mmol, 1.8 equiv) in DMF (3 mL) were added EPhos Pd G4 (96.10 mg, 0.104 mmol, 0.7 equiv) and EPhos (55.95 mg, 0.104 mmol, 0.7 equiv) and Cs₂CO₃(194.78 mg, 0.596 mmol, 4 equiv) in portions at 60°C under N₂ atmosphere. The resulting mixture was stirred for 8 h at 60°C under N₂ atmosphere. The resulting mixture was filtered, the filter cake was washed with DCM (3 x 20 mL). The filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (DCM: MeOH=25:1 ) to afford tert-butyl N-(4-{3-[(3-chloro-2-methoxyphenyl)amino]- 4-oxo-5H,6H,7H-pyrazolo[1,5-a]pyrazin-2-yl}-1,7-naphthyridin-6-yl)carbamate(62.4 mg, 36.85%) as a brown yellow solid. LC-MS: (M+H) found: 536.

A mixture of tert-butyl N-(4-{3-[(3-chloro-2-methoxyphenyl)amino]-4-oxo-5H,6H,7H- pyrazolo[1,5-a]pyrazin-2-yl}-1,7-naphthyridin-6-yl)carbamate (60 mg, 0.112 mmol, 1 equiv) and TFA (1 mL) in DCM (3 mL) was stirred for 20 min at rt under N₂ atmosphere. The resulting mixture was concentrated under reduced pressure. The crude product was purified by Prep-HPLC with the following conditions (Column: Xselect CSH F-Phenyl OBD column, 19*250 mm, 5μm; Mobile Phase A: Water(0.1% FA), Mobile Phase B: ACN; Flow rate: 25 mL/min; Gradient: 28% B to 38% B in 8 min, 38% B; Wave Length: 254;220 nm; RT1(min): 6.9) to afford 2-(6-amino-1,7-naphthyridin-4-yl)-3-[(3- chloro-2-methoxyphenyl)amino]-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one(4.1 mg, 8.27%) as a yellow green solid. LC-MS: (M+H)+ found: 436.1. ¹H NMR (300 MHz, DMSO-d6) δ 8.85 (d, J = 0.9 Hz, 1H), 8.49 (d, J = 4.3 Hz, 1H), 8.45 – 8.31 (m, 1H), 7.51 (d, J = 4.3 Hz, 1H), 7.31 (s, 1H), 7.08 (d, J = 0.9 Hz, 1H), 6.68 – 6.48 (m, 2H), 6.15 (s, 2H), 6.08 (dd, J = 7.8, 1.8 Hz, 1H), 4.45 (dd, J = 7.1, 4.9 Hz, 2H), 3.76 (s, 5H). Example 27.2-(6-amino-1,7-naphthyridin-4-yl)-3-[(3-fluoro-2-methoxyphenyl)amino]- 5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (compound 317)

To a stirred mixture of 6-chloro-1H-1,7-naphthyridin-4-one (300 mg, 1.661 mmol, 1.00equiv) and benzyl bromide (340.95 mg, 1.993 mmol, 1.2 equiv) in DMF (10 mL) were added K₂CO₃ (459.18 mg, 3.322 mmol, 2 equiv) in portions at rt under N₂ atmosphere. The resulting mixture was stirred for 2 h at rt under N₂ atmosphere. The resulting mixture was extracted with EA (3 x 150 mL). The combined organic layers were washed with brine (3 x 100 mL), dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with DCM/MeOH (30:1) to afford 4- (benzyloxy)-6-chloro-1,7-naphthyridine (372.8 mg, 82.89%) as a yellow solid. LC-MS: M+H found: 271.

To a stirred mixture of 4-(benzyloxy)-6-chloro-1,7-naphthyridine (440 mg, 1.625 mmol, 1 equiv) and tert-butyl carbamate (761.60 mg, 6.500 mmol, 4 equiv) in THF (20 mL) were added X-Phos (232.44 mg, 0.487 mmol, 0.3 equiv) and Cs₂CO₃ (1482.75 mg, 4.550 mmol, 2.8 equiv) and Pd₂(dba)₃CHCl₃ (504.70 mg, 0.487 mmol, 0.3 equiv) in portions at 100°C under N₂ atmosphere. The resulting mixture was stirred for 16 h at 100 °C under N₂ atmosphere. The resulting mixture was extracted with EA (3 x 400 ml). The combined organic layers were washed with brine(3x200mL), dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with DCM / MeOH (25:1) to afford tert-butyl N-[4-(benzyloxy)-1,7-naphthyridin-6- yl]carbamate(745.8mg, 97.86%) as a brown yellow solid. LC-MS: (M+H)⁺ found: 352.

To a stirred solution of bis(tert-butyl N-[4-(benzyloxy)-1,7-naphthyridin-6-yl]carbamate) (989 mg, 1.407 mmol, 1equiv) in MeOH(200 mL) was added Pd/C (200 mg, 60%) in portions rt under H₂ atmosphere. The resulting mixture was stirred for 16 h at rt under N₂ atmosphere. The resulting mixture was filtered, the filter cake was washed with MeOH (3 x 300 mL), and the filtrate was concentrated under reduced pressure to afford bis(tert- butyl N-(4-hydroxy-1,7-naphthyridin-6-yl)carbamate)( 765.7 mg, 83.72%) as a orange yellow solid. The crude product was used in the next step directly without further purification. LC-MS: (M+H)+ found: 262.

To a stirred solution of tert-butyl N-(4-hydroxy-1,7-naphthyridin-6-yl)carbamate (230 mg, 0.880 mmol, 1 equiv) and NTf2Ph (2199.82 mg, 6.160 mmol, 7 equiv) in DCM (10 mL) was added TEA (712.60 mg, 7.040 mmol, 8 equiv) dropwise at rt under N₂ atmosphere. The resulting mixture was stirred for 16 h at rt under N₂ atmosphere. The resulting mixture was extracted with EA (3 x 300 mL). The combined organic layers were washed with brine (3 x 200 mL), dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with DCM/MeOH (25:1) to afford tert-butyl N-[4-(trifluoromethanesulfonyloxy)-1,7-naphthyridin-6-yl]carbamate(322mg, 71.14%) as a light yellow solid. LC-MS: (M+H)⁺ found: 394.

To a stirred mixture of tert-butyl N-[4-(trifluoromethanesulfonyloxy)-1,7-naphthyridin- 6-yl]carbamate (260 mg, 0.661 mmol, 1.00 equiv) and 3-chloro-4-oxo-5H,6H,7H- pyrazolo[1,5-a]pyrazin-2-ylboronic acid (170.86 mg, 0.793 mmol, 1.2 equiv) in 1,4- dioxane (7.5 mL) and H₂O (1.5 mL) were added Pd₂(dba)₃CHCl₃ (68.42 mg, 0.066 mmol, 0.1 equiv) and PCy3 (18.54 mg, 0.066 mmol, 0.1 equiv) and Cs₂CO₃ (646.11 mg, 1.983 mmol, 3 equiv) in portions at 60°C under N₂ atmosphere. The resulting mixture was stirred for 2 h at 60°C under N₂ atmosphere. The resulting mixture was filtered, the filter cake was washed with DCM (3x200ml). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with DCM / MeOH (25:1) to afford tert-butyl N-(4-{3-chloro-4-oxo-5H,6H,7H- pyrazolo[1,5-a]pyrazin-2-yl}-1,7-naphthyridin-6-yl)carbamate (130mg, 42.81%) as a light yellow solid. LC-MS: (M+H)⁺ found: 415.

To a stirred solution of tert-butyl 2-{6-[(tert-butoxycarbonyl)amino]-1,7-naphthyridin-4- yl}-3-chloro-4-oxo-6H,7H-pyrazolo[1,5-a]pyrazine-5-carboxylate (125 mg, 0.243 mmol, 1 equiv) and 3-fluoro-2-methoxyaniline (102.78 mg, 0.729 mmol, 3 equiv) in DMF (5 mL) were added EPhos Pd G4 (44.59 mg, 0.049 mmol, 0.2 equiv) and EPhos (25.96 mg, 0.049 mmol, 0.2 equiv) and Cs₂CO₃ (158.17 mg, 0.486 mmol, 2 equiv) in portions at 60°C under N₂ atmosphere. The resulting mixture was stirred for 3 h at 60°C under N₂ atmosphere. The resulting mixture was concentrated under reduced pressure. The precipitated solids were collected by filtration and washed with DCM (3x100ml). The residue was purified by Prep-TLC (DCM:MeOH 25:1) to afford tert-butyl 2-{6-[(tert- butoxycarbonyl)amino]-1,7-naphthyridin-4-yl}-3-[(3-fluoro-2-methoxyphenyl)amino]- 4-oxo-6H,7H-pyrazolo[1,5-a]pyrazine-5-carboxylate (44 mg, 26.33%) as a light yellow solid. LC-MS: (M+H)⁺ found: 520.

A mixture of tert-butyl N-(4-{3-[(3-fluoro-2-methoxyphenyl)amino]-4-oxo-5H,6H,7H- pyrazolo[1,5-a]pyrazin-2-yl}-1,7-naphthyridin-6-yl)carbamate (50 mg, 0.096 mmol, 1 equiv) and TFA (2 mL) in DCM (6 mL) was stirred for 20min at rt under N₂ atmosphere. The resulting mixture was concentrated under reduced pressure. The crude product was purified by Prep-HPLC with the following conditions (Column: YMC-Actus Triart C_18, 30*150 mm, 5μm; Mobile Phase A: Water (10 mmol/L NH₄HCO₃+0.1%NH₃*H₂O), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 25% B to 35% B in 8 min, 35% B; Wave Length: 254;220 nm; RT₁(min): 7.7) to afford 2-(6-amino-1,7-naphthyridin-4- yl)-3-[(3-fluoro-2-methoxyphenyl)amino]-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (4.5 mg, 11.14%) as a yellow green solid. ¹H NMR (300 MHz, DMSO-d6) δ 8.85 (d, J = 0.9 Hz, 1H), 8.48 (d, J = 4.3 Hz, 1H), 8.37 (d, J = 2.8 Hz, 1H), 7.50 (d, J = 4.3 Hz, 1H), 7.27 (s, 1H), 7.09 (d, J = 1.0 Hz, 1H), 6.53 – 6.35 (m, 2H), 6.16 (s, 2H), 5.93 (dt, J = 8.1, 1.4 Hz, 1H), 4.44 (dd, J = 7.1, 4.9 Hz, 2H), 3.84 – 3.77 (m, 3H), 3.73 (d, J = 7.1 Hz, 2H). Example 28. N-(4-{3-[(3-fluoro-2-methoxyphenyl)amino]-4-oxo-5H,6H,7H- pyrazolo[1,5-a]pyrazin-2-yl}-1,7-naphthyridin-6-yl)prop-2-enamide (compound 322)

To a stirred mixture of 6-chloro-1H-1,7-naphthyridin-4-one (300 mg, 1.661 mmol, 1.00equiv) and benzyl bromide (340.95 mg, 1.993 mmol, 1.2 equiv) in DMF (10 mL) were added K₂CO₃ (459.18 mg, 3.322 mmol,2 equiv) in portions at rt under N₂ atmosphere. The resulting mixture was stirred for 2h at rt under N₂ atmosphere. The resulting mixture was extracted with EA (3 x 150 mL). The combined organic layers were washed with brine (3 x 100 mL), dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with DCM/MeOH (30:1) to afford 4- (benzyloxy)-6-chloro-1,7-naphthyridine (372.8 mg, 82.89%) as a yellow solid. LC-MS: M+H found: 271.

To a stirred mixture of 4-(benzyloxy)-6-chloro-1,7-naphthyridine (440 mg, 1.625 mmol, 1 equiv) and tert-butyl carbamate (761.60 mg, 6.500 mmol, 4 equiv) in THF (20 mL) were added X-Phos (232.44 mg, 0.487 mmol, 0.3 equiv) and Cs₂CO₃ (1482.75 mg, 4.550 mmol, 2.8 equiv) and Pd₂(dba)₃CHCl₃ (504.70 mg, 0.487 mmol, 0.3 equiv) in portions at 100°C under N₂ atmosphere. The resulting mixture was stirred for 16h at 100 °C under N₂ atmosphere. The resulting mixture was extracted with EA (3 x 400 mL). The combined organic layers were washed with brine (3 x 200 mL), dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with DCM / MeOH (25:1) to afford tert-butyl N-[4-(benzyloxy)-1,7-naphthyridin-6- yl]carbamate(745.8mg, 97.86%) as a brown yellow solid. LC-MS: (M+H)⁺ found: 352.

To a stirred solution of bis(tert-butyl N-[4-(benzyloxy)-1,7-naphthyridin-6-yl]carbamate) (989 mg, 1.407 mmol, 1equiv) in MeOH (200 mL) was added Pd/C (200 mg, 60%)2 in portions rt under H₂ atmosphere. The resulting mixture was stirred for 16h at rt under N₂ atmosphere .The resulting mixture was filtered, the filter cake was washed with MeOH (3x300 mL). The filtrate was concentrated under reduced pressure. The crude product was used in the next step directly without further purification to afford bis(tert- butyl N-(4-hydroxy-1,7-naphthyridin-6-yl)carbamate) (765.7 mg, 83.72%) as a orange yellow solid. LC-MS: (M+H) found: 262.

To a stirred solution of tert-butyl N-(4-hydroxy-1,7-naphthyridin-6-yl)carbamate (230 mg, 0.880 mmol, 1 equiv) and NTf₂Ph (2199.82 mg, 6.160 mmol, 7 equiv) in DCM (10 mL) was added TEA (712.60 mg, 7.040 mmol, 8 equiv) dropwise at rt under N₂ atmosphere. The resulting mixture was stirred for 16h at rt under N₂ atmosphere. The resulting mixture was extracted with EA (3 x 300 mL). The combined organic layers were washed with brine (3 x 200 mL), dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with DCM/MeOH (25:1) to afford tert-butyl N-[4-(trifluoromethanesulfonyloxy)-1,7-naphthyridin-6-yl]carbamate(322mg, 71.14%) as a light yellow solid. LC-MS: (M+H)⁺ found: 394.

To a stirred mixture of tert-butyl N-[4-(trifluoromethanesulfonyloxy)-1,7-naphthyridin- 6-yl]carbamate (260 mg, 0.661 mmol, 1.00 equiv) and 3-chloro-4-oxo-5H,6H,7H- pyrazolo[1,5-a]pyrazin-2-ylboronic acid (170.86 mg, 0.793 mmol, 1.2 equiv) in 1,4- dioxane (7.5 mL) and H₂O (1.5 mL) were added Pd₂(dba)₃CHCl₃ (68.42 mg, 0.066 mmol, 0.1 equiv) and PCy₃ (18.54 mg, 0.066 mmol, 0.1 equiv) and Cs₂CO₃ (646.11 mg, 1.983 mmol, 3 equiv) in portions at 60°C under N₂ atmosphere. The resulting mixture was stirred for 2 h at 60°C under N₂ atmosphere. The resulting mixture was filtered, the filter cake was washed with DCM (3x200 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with DCM / MeOH (25:1) to afford tert-butyl N-(4-{3-chloro-4-oxo-5H,6H,7H- pyrazolo[1,5-a]pyrazin-2-yl}-1,7-naphthyridin-6-yl)carbamate(130 mg, 42.81%) as a light yellow solid. LC-MS: (M+H)⁺ found: 415.

To a stirred solution of tert-butyl 2-{6-[(tert-butoxycarbonyl)amino]-1,7-naphthyridin-4- yl}-3-chloro-4-oxo-6H,7H-pyrazolo[1,5-a]pyrazine-5-carboxylate (125 mg, 0.243 mmol, 1 equiv) and 3-fluoro-2-methoxyaniline (102.78 mg, 0.729 mmol, 3 equiv) in DMF (5 mL) were added EPhos Pd G4 (44.59 mg, 0.049 mmol, 0.2 equiv) and EPhos (25.96 mg, 0.049 mmol, 0.2 equiv) and Cs₂CO₃ (158.17 mg, 0.486 mmol, 2 equiv) in portions at 60°C under N₂ atmosphere. The resulting mixture was stirred for 3 h at 60°C under N₂ atmosphere. The resulting mixture was concentrated under reduced pressure. The precipitated solids were collected by filtration and washed with DCM (3 x 100 mL). The residue was purified by Prep-TLC (DCM:MeOH 25:1) to afford tert-butyl 2-{6-[(tert- butoxycarbonyl)amino]-1,7-naphthyridin-4-yl}-3-[(3-fluoro-2-methoxyphenyl)amino]- 4-oxo-6H,7H-pyrazolo[1,5-a]pyrazine-5-carboxylate (44 mg, 26.33%) as a light yellow solid. LC-MS: (M+H)⁺ found: 520.

A mixture of tert-butyl N-(4-{3-[(3-fluoro-2-methoxyphenyl)amino]-4-oxo-5H,6H,7H- pyrazolo[1,5-a]pyrazin-2-yl}-1,7-naphthyridin-6-yl)carbamate (44 mg, 0.085 mmol, 1 equiv) and TFA (2 mL) in DCM (6 mL) was stirred for 30 min at rt under N₂ atmosphere. The resulting mixture was concentrated under reduced pressure. The crude product was used in the next step directly without further purification to afford 2-(6- amino-1,7-naphthyridin-4-yl)-3-[(3-fluoro-2-methoxyphenyl)amino]-5H,6H,7H- pyrazolo[1,5-a]pyrazin-4-one (56 mg, 152.92%) as a light yellow solid. LC-MS: (M+H)⁺ found: 420.

To a stirred solution of 2-(6-amino-1,7-naphthyridin-4-yl)-3-[(3-fluoro-2- methoxyphenyl)amino]-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (46 mg, 0.110 mmol, 1 equiv) and acryloyl chloride (5.96 mg, 0.066 mmol, 0.6 equiv) in THF (2 mL) were added NaHCO₃ (2 mL, 23.808 mmol) in portions at rt under N₂ atmosphere. The resulting mixture was stirred for 2 h at 60°C under N₂ atmosphere. The resulting mixture was extracted with EA (3 x 20 mL). The combined organic layers were washed with brine (3 x 30 mL), dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by Prep-HPLC with the following conditions (Column: XBridge Shield RP18 OBD Column, 30*150 mm, 5μm; Mobile Phase A: Water (10 mmol/L NH₄HCO₃+0.1%NH₃*H₂O), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 3% B to 51% B in 10 min, 51% B; Wave Length: 254/220 nm; RT1(min): 6.5/9.07) to afford N-(4-{3-[(3-fluoro-2-methoxyphenyl)amino]- 4-oxo-5H,6H,7H-pyrazolo[1,5-a]pyrazin-2-yl}-1,7-naphthyridin-6-yl)prop-2-enamide (9.9 mg, 19.01%) as a light yellow solid. ¹H NMR (400 MHz, DMSO-d6) δ 10.95 (s, 1H), 9.20 (s, 1H), 9.11 (s, 1H), 8.88 (d, J = 4.4 Hz, 1H), 8.40 (d, J = 2.9 Hz, 1H), 7.78 (d, J = 4.4 Hz, 1H), 7.28 (s, 1H), 6.66 (dd, J = 17.0, 10.2 Hz, 1H), 6.45 – 6.34 (m, 3H), 5.91 (d, J = 8.0 Hz, 1H), 5.81 (dd, J = 10.1, 2.0 Hz, 1H), 4.48 (dd, J = 7.1, 5.0 Hz, 2H), 3.74 (d, J = 6.2 Hz, 5H). Example 29. N-(4-{3-[(3-chloro-2-methoxyphenyl)amino]-4-oxo-5H,6H,7H- pyrazolo[1,5-a]pyrazin-2-yl}-1,7-naphthyridin-6-yl)prop-2-enamide (compound 321)

To a stirred mixture of 6-chloro-1H-1,7-naphthyridin-4-one (300 mg, 1.661 mmol, 1.00 equiv) and benzyl bromide (340.95 mg, 1.993 mmol, 1.2 equiv) in DMF (10 mL) were added K₂CO₃ (459.18 mg, 3.322 mmol,2 equiv) in portions at rt under N₂ atmosphere. The resulting mixture was stirred for 2 h at rt under N₂ atmosphere. The resulting mixture was extracted with EA (3 x 150 mL). The combined organic layers were washed with brine (3 x 100 mL), dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with DCM/MeOH (30:1) to afford 4- (benzyloxy)-6-chloro-1,7-naphthyridine (372.8 mg, 82.89%) as a yellow solid. LC-MS: M+H found: 271.

To a stirred mixture of 4-(benzyloxy)-6-chloro-1,7-naphthyridine (440 mg, 1.625 mmol, 1 equiv) and tert-butyl carbamate (261.60 mg, 6.500 mmol, 4 equiv) in THF (20 mL) were added X-Phos (232.44 mg, 0.487 mmol, 0.3 equiv) and Cs₂CO₃ (1482.75 mg, 4.550 mmol, 2.8 equiv) and Pd₂(dba)₃CHCl3 (504.70 mg, 0.487 mmol, 0.3 equiv) in portions at 100°C under N₂ atmosphere. The resulting mixture was stirred for 16 h at 100 °C under N₂ atmosphere. The resulting mixture was extracted with EA (3 x 400 mL). The combined organic layers were washed with brine (3 x 200 mL), dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with DCM/MeOH (25:1) to afford tert-butyl N-[4-(benzyloxy)-1,7-naphthyridin-6- yl]carbamate(745.8mg, 97.86%) as a brown yellow solid. LC-MS: (M+H) found: 352.

To a stirred solution of bis(tert-butyl N-[4-(benzyloxy)-1,7-naphthyridin-6-yl]carbamate) (989 mg, 1.407 mmol, 1equiv) in MeOH (200 mL) was added Pd/C (200 mg, 60%) in portions rt under H₂ atmosphere. The resulting mixture was stirred for 16h at rt under N₂ atmosphere .The resulting mixture was filtered, the filter cake was washed with MeOH (3x300ml). The filtrate was concentrated under reduced pressure. The crude product was used in the next step directly without further purification to afford bis(tert- butyl N-(4-hydroxy-1,7-naphthyridin-6-yl)carbamate)( 765.7 mg, 83.72%) as a orange yellow solid. LC-MS: (M+H)⁺ found: 262.

To a stirred solution of tert-butyl N-(4-hydroxy-1,7-naphthyridin-6-yl)carbamate (230 mg, 0.880 mmol, 1 equiv) and NTf₂Ph (2199.82 mg, 6.160 mmol, 7 equiv) in DCM (10 mL) was added TEA (712.60 mg, 7.040mmol, 8 equiv) dropwise at rt under N₂ atmosphere. The resulting mixture was stirred for 16h at rt under N₂ atmosphere. The resulting mixture was extracted with EA (3 x 300ml). The combined organic layers were washed with brine (3 x 200 mL), dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with DCM/MeOH (25:1) to afford tert-butyl N-[4-(trifluoromethanesulfonyloxy)-1,7-naphthyridin-6-yl]carbamate(322 mg, 71.14%) as a light yellow solid. LC-MS: (M+H)⁺ found: 394.

To a stirred mixture of tert-butyl N-[4-(trifluoromethanesulfonyloxy)-1,7-naphthyridin- 6-yl]carbamate (260 mg, 0.661 mmol, 1.00 equiv) and 3-chloro-4-oxo-5H,6H,7H- pyrazolo[1,5-a]pyrazin-2-ylboronic acid (170.86 mg, 0.793 mmol, 1.2 equiv) in 1,4- dioxane (7.5 mL) and H₂O (1.5 mL) were added Pd₂(dba)₃CHCl3 (68.42 mg, 0.066 mmol, 0.1 equiv) and PCy₃ (18.54 mg, 0.066 mmol, 0.1 equiv) and Cs₂CO₃ (646.11 mg, 1.983 mmol, 3 equiv) in portions at 60°C under N₂ atmosphere. The resulting mixture was stirred for 2 h at 60°C under N₂ atmosphere. The resulting mixture was 7iltered, the filter cake was washed with DCM (3 x 200mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with DCM/MeOH (25:1) to afford tert-butyl N-(4-{3-chloro-4-oxo-5H,6H,7H- pyrazolo[1,5-a]pyrazin-2-yl}-1,7-naphthyridin-6-yl)carbamate(130mg, 42.81%) as a light yellow solid. LC-MS: (M+H)⁺ found: 415.

To a stirred solution tert-butyl N-(4-{3-chloro-4-oxo-5H,6H,7H-pyrazolo[1,5-a]pyrazin- 2-yl}-1,7-naphthyridin-6-yl)carbamate (62 mg, 0.149 mmol, 1 equiv) and 3-chloro-2- methoxyaniline (42.40 mg, 0.268mmol, 1.8 equiv) in DMF (3 mL) were added EPhos Pd G4 (96.10 mg, 0.104 mmol, 0.7 equiv) and EPhos (55.95 mg, 0.104 mmol, 0.7equiv) and Cs₂CO₃ (194.78 mg, 0.596 mmol, 4 equiv) in portions at 60°C under N₂ atmosphere. The resulting mixture was stirred for 8 h at 60°C under N₂ atmosphere. The resulting mixture was filtered, the filter cake was washed with DCM (3x20). The filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (DCM: MeOH=25:1 ) to afford tert-butyl N-(4-{3-[(3-chloro-2-methoxyphenyl)amino]-4-oxo- 5H,6H,7H-pyrazolo[1,5-a]pyrazin-2-yl}-1,7-naphthyridin-6-yl)carbamate(62.4 mg, 36.85%) as a brown yellow solid. LC-MS: (M+H)⁺ found: 536.

To a stirred mixture of tert-butyl N-(4-{3-[(3-chloro-2-methoxyphenyl)amino]-4-oxo- 5H,6H,7H-pyrazolo[1,5-a]pyrazin-2-yl}-1,7-naphthyridin-6-yl)carbamate (57 mg, 0.106 mmol, 1 equiv) in DCM (3 mL) were added TFA (1 mL) in portions at rt under N₂ atmosphere. The resulting mixture was stirred for 20min at rt under N₂ atmosphere. The resulting mixture was concentrated under reduced pressure. The crude product was used in the next step directly without further purification to afford 2-(6-amino-1,7- naphthyridin-4-yl)-3-[(3-chloro-2-methoxyphenyl)amino]-5H,6H,7H-pyrazolo[1,5- a]pyrazin-4-one (14 mg, 21.93%) as a yellow green solid.. LC-MS: (M+H) found: 436.

To a stirred solution of 2-(6-amino-1,7-naphthyridin-4-yl)-3-[(3-chloro-2- methoxyphenyl)amino]-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (65 mg, 0.149mmol, 1equiv) and acryloyl chloride (9.45 mg, 0.104 mmol, 0.7 equiv) in THF (2 mL) were added NaHCO₃ (2 mL, 23.808 mmol) in portions at rt under N₂ atmosphere. The resulting mixture was stirred for 2 h at rt under N₂ atmosphere. The resulting mixture was extracted with EA (3 x 50 mL). The combined organic layers were washed with brine (3 x 90 mL), dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by Prep-HPLC with the following conditions (Column: XBridge Shield RP18 OBD Column, 30*150 mm, 5μm; Mobile Phase A: Water(10 mmol/L NH₄HCO₃+0.1%NH₃*H₂O), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 10% B to 54% B in 10 min, 54% B; Wave Length: 254/220 nm; RT1(min): 8.65) to afford N-(4-{3-[(3-chloro-2-methoxyphenyl)amino]-4-oxo- 5H,6H,7H-pyrazolo[1,5-a]pyrazin-2-yl}-1,7-naphthyridin-6-yl)prop-2-enamide (3 mg, 4.08%) as a light yellow solid. ¹H NMR (300 MHz, DMSO-d6) δ 10.96 (s, 1H), 9.21 (d, J = 0.9 Hz, 1H), 9.12 (d, J = 0.9 Hz, 1H), 8.89 (d, J = 4.4 Hz, 1H), 8.40 (s, 1H), 7.79 (d, J = 4.4 Hz, 1H), 7.33 (s, 1H), 6.70 – 6.56 (m, 2H), 6.50 (t, J = 8.1 Hz, 1H), 6.34 (dd, J = 17.0, 2.0 Hz, 1H), 6.08 (dd, J = 8.1, 1.6 Hz, 1H), 5.81 (dd, J = 10.1, 2.0 Hz, 1H), 4.49 (t, J = 6.1 Hz, 2H), 3.78 (d, J = 18.9 Hz, 2H), 3.70 (s, 3H). Example 30. (7S)-3-[(3-chloro-2-methoxyphenyl)amino]-7-[(dimethylamino)methyl]-2- (pyridin-4-yl)-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (compound 279)

To a stirred solution of methyl 5-bromo-2H-pyrazole-3-carboxylate (6 g, 29.267 mmol, 1.00 equiv) and DIEA (11.35 g, 87.801 mmol, 3 equiv) in DCM (60.00 mL, 943.861 mmol, 32.25 equiv) was added SEM-Cl (6.83 g, 40.974 mmol, 1.4 equiv) dropwise at 0 degrees C under nitrogen atmosphere. The resulting mixture was stirred for 1 h at room temperature under nitrogen atmosphere. The aqueous layer was extracted with EtOAc (3x50 mL). The residue was purified by silica gel column chromatography, eluted with PE / EtOAc (50:1) to afford methyl 5-bromo-2-{[2- (trimethylsilyl)ethoxy]methyl}pyrazole-3-carboxylate (5.68 g, 57.89%) as a white oil. LCMS: [M+H]⁺ found: 335.

To a mixture of methyl 5-bromo-2-{[2-(trimethylsilyl)ethoxy]methyl}pyrazole-3- carboxylate (2.73 g, 8.143 mmol, 1.00 equiv) and pyridin-4-ylboronic acid (3.00 g, 24.429 mmol, 3 equiv) in dioxane (83 mL, 979.739 mmol, 120.32 equiv) and H₂O (8.3 mL, 460.719 mmol, 56.58 equiv) were added K₃PO₄ (3.46 g, 16.286 mmol, 2 equiv) and Pd(dppf)Cl₂*CH₂Cl₂ (1.33 g, 1.629 mmol, 0.20 equiv) in portions at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 1 h at 80 degrees C under nitrogen atmosphere. The aqueous layer was extracted with EtOAc (3x50 mL).The residue was purified by silica gel column chromatography, eluted with PE/EtOAc (2:1) to afford methyl 5-(pyridin-4-yl)-2-{[2-(trimethylsilyl)ethoxy]methyl}pyrazole-3-carboxylate (2.23 g, 82.13%) as a brown solid. LCMS: [M+H]⁺ found: 334.

To a stirred mixture of methyl 5-(pyridin-4-yl)-2-{[2- (trimethylsilyl)ethoxy]methyl}pyrazole-3-carboxylate (2.2 g, 6.597 mmol, 1.00 equiv)methyl 5-(pyridin-4-yl)-2-{[2-(trimethylsilyl)ethoxy]methyl}pyrazole-3- carboxylate (2.2 g, 6.597 mmol, 1.00 equiv) were added TFA (20 mL, 269.261 mmol, 40.81 equiv) dropwise at 0 degrees C under nitrogen atmosphere. The resulting mixture was stirred for 30 min at 0 degrees C under nitrogen atmosphere. The aqueous layer was extracted with EtOAc (3x50 mL). This resulted in methyl 5-(pyridin-4-yl)-2H-pyrazole-3- carboxylate (1.83 g, 136.51%) as a light yellow solid. The crude product/ resulting mixture was used in the next step directly without further purification. LCMS: [M+H]⁺ found: 204.

To a stirred mixture of methyl 5-(pyridin-4-yl)-2H-pyrazole-3-carboxylate (1.38 g, 6.791 mmol, 1.00 equiv) in CH₂Cl₂ (15.50 mL, 243.865 mmol, 35.91 equiv) were added NBS (1.21 g, 6.791 mmol, 1.0 equiv) in portions at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 1 h at room temperature under nitrogen atmosphere. The aqueous layer was extracted with EtOAc (3 x 50 mL). This resulted in methyl 4-bromo- 5-(pyridin-4-yl)-2H-pyrazole-3-carboxylate (1.4 g, 73.08%) as a white solid.The crude product/ resulting mixture was used in the next step directly without further purification. LC-MS: [M+H]⁺ found: 282.

To a stirred mixture of methyl 4-bromo-5-(pyridin-4-yl)-2H-pyrazole-3-carboxylate (1.4 g, 4.963 mmol, 1.00 equiv) and 2-bromoacetonitrile (0.71 g, 5.956 mmol, 1.2 equiv) in MeCN (30 mL) were added K₂CO₃ (1.37 g, 9.926 mmol, 2.0 equiv) in portions at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 1 h at 80 degrees C under nitrogen atmosphere. The aqueous layer was extracted with EtOAc (3x50 mL).The residue was purified by silica gel column chromatography, eluted with PE / EA (1:1) to afford methyl 4-bromo-2-(cyanomethyl)-5-(pyridin-4-yl)pyrazole-3-carboxylate as a white solid. LCMS: [M+H]+ found: 321.

A mixture of (HCHO)n (2.10 g, 46.70 mmol, 6 equiv) in dimethylamine (23.35 mL, 2M in THF, 6 equiv) was stirred for 2 h and added to a mixture of methyl 4-bromo-2- (cyanomethyl)-5-(pyridin-4-yl)pyrazole-3-carboxylate (2.5 g, 7.785 mmol, 1.00 equiv) in DMF (25 mL) dropwise at room temperature. The resulting mixture was stirred for 30 min at 100 degrees C under nitrogen atmosphere. The aqueous layer was extracted with EtOAc (3 x 50 mL).The residue was purified by silica gel column chromatography, eluted with EtOAc to afford methyl 4-bromo-2-[1-cyano-2-(dimethylamino)ethyl]-5-(pyridin-4- yl)pyrazole-3-carboxylate (460 mg, 15.62%) as a yellow solid. LCMS: [M+H]⁺ found: 378.

To a mixture of Methyl 4-bromo-2-[1-cyano-2-(dimethylamino)ethyl]-5-(pyridin-4- yl)pyrazole-3-carboxylate (200 mg, 0.529 mmol, 1.00 equiv) and CoCl₂ (205.97 mg, 1.587 mmol, 3 equiv) in MeOH (10.00 mL, 247.091 mmol, 467.09 equiv) was added NaBH₄ (60.02 mg, 1.587 mmol, 3 equiv) in portions at 0 degrees C under nitrogen atmosphere. The resulting mixture was stirred for 1 h at room temperature under nitrogen atmosphere. The residue was purified by reverse phase flash with the following conditions to afford 3- bromo-7-[(dimethylamino)methyl]-2-(pyridin-4-yl)-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4- one (90 mg, 48.60%) as a yellow solid. LCMS: [M+H]⁺ found: 350.

To a mixture of 3-bromo-7-[(dimethylamino)methyl]-2-(pyridin-4-yl)-5H,6H,7H- pyrazolo[1,5-a]pyrazin-4-one (90 mg, 0.257 mmol, 1.00 equiv) and 3-chloro-2- methoxyaniline (40.50 mg, 0.257 mmol, 1 equiv) in DMF (2 mL) were added Cs2CO3 (251.19 mg, 0.771 mmol, 3 equiv) and Ephos (13.74 mg, 0.026 mmol, 0.1 equiv) and Ephos Pd G4 (23.61 mg, 0.026 mmol, 0.1 equiv) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 1 h at 80 degrees C under nitrogen atmosphere. The crude product was purified by Pre-Chiral-HPLC with the following conditions (Column: CHIRAL ART Amylose-SA, 2*25 cm, 5 μm; Mobile Phase A: Hex(0.5% 2M NH₃- MeOH)--HPLC, Mobile Phase B: EtOH--HPLC; Flow rate: 20 mL/min; Gradient: 20% B to 20% B in 12.5 min; Wave Length: 220/254 nm; RT1(min): 4.54; RT2(min): 5.66) to afford (7S)-3-[(3-chloro-2-methoxyphenyl)amino]-7-[(dimethylamino)methyl]-2- (pyridin-4-yl)-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (7.0 mg, 6.10%) as a white solid. LCMS: [M+H]⁺ found: 427. ¹H NMR (300 MHz, Chloroform-d) δ 8.57 (s, 2H), 7.68 (d, J = 5.2 Hz, 2H), 7.14 (s, 1H), 6.80 (dd, J = 8.1, 1.5 Hz, 1H), 6.64 (t, J = 8.1 Hz, 1H), 6.17 (dd, J = 8.1, 1.4 Hz, 1H), 5.86 (s, 1H), 4.64 (s, 1H), 4.05 (s, 3H), 3.98 (s, 2H), 2.94 (dd, J = 35.1, 22.1 Hz, 2H), 2.49 (s, 6H). Example 31. (7R)-3-[(3-chloro-2-methoxyphenyl)amino]-7-[(dimethylamino)methyl]-2- (pyridin-4-yl)-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (compound 280)

To a stirred mixture of 3-bromo-7-[(dimethylamino)methyl]-2-(pyridin-4-yl)-5H,6H,7H- pyrazolo[1,5-a]pyrazin-4-one (90 mg, 0.257 mmol, 1.00 equiv) and 3-chloro-2- methoxyaniline (40.50 mg, 0.257 mmol, 1 equiv) in DMF (2 mL) were added Cs₂CO₃ (251.19 mg, 0.771 mmol, 3 equiv) and Ephos (13.74 mg, 0.026 mmol, 0.1 equiv) and Ephos Pd G4 (23.61 mg, 0.026 mmol, 0.1 equiv) in portions at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 1 h at 80 degrees C under nitrogen atmosphere. The residue/crude product was purified by reverse phase flash with the following conditions (Column: CHIRAL ART Amylose-SA, 2*25 cm, 5 μm; Mobile Phase A: Hex(0.5% 2M NH₃-MeOH)-HPLC, Mobile Phase B: EtOH-HPLC; Flow rate: 20 mL/min; Gradient: 20% B to 20% B in 12.5 min; Wave Length: 220/254 nm; RT1(min): 4.54; RT2(min): 5.66) to afford (7R)-3-[(3-chloro-2-methoxyphenyl)amino]-7- [(dimethylamino)methyl]-2-(pyridin-4-yl)-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (8.6 mg) as a white solid. LCMS: [M+H]⁺ found: 427. ¹H NMR (300 MHz, Chloroform-d) δ 8.65 – 8.48 (m, 2H), 7.66 (d, J = 5.8 Hz, 2H), 7.15 (s, 1H), 6.79 (dd, J = 8.1, 1.4 Hz, 1H), 6.61 (t, J = 8.1 Hz, 1H), 6.12 (dd, J = 8.1, 1.4 Hz, 1H), 6.06 (s, 1H), 4.76 – 4.53 (m, 1H), 4.02 (s, 5H), 3.31 (s, 2H), 2.82 (s, 6H). Example 32. (7S)-3-[(3-chloro-2-methoxyphenyl)amino]-7-(2-hydroxy-2- methylpropyl)-2-(pyridin-4-yl)-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (compound 283)

A mixture of methyl 2-(cyanomethyl)-5-(pyridin-4-yl)pyrazole-3-carboxylate (2 g, 8.256 mmol, 1 equiv) and tert-butyl 2-bromoacetate (2.42 g, 12.384 mmol, 1.5 equiv) in THF (50 mL) was stirred 0.5 h at 0°C under nitrogen atmosphere, NaH (0.20 g, 8.256 mmol, 1 equiv) was added, The mixture was stirred 2 h at room temperature under nitrogen atmosphere. After the reaction, the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with Petroleum ether /EtOAc (2:1) to afford methyl 2-[3-(tert-butoxy)-1-cyano-3-oxopropyl]-5-(pyridin-4-yl)pyrazole-3- carboxylate (1.1 g, 37.38%) as a yellow solid. LC-MS: M+H found: 357.1.

To a mixture of methyl 2-[3-(tert-butoxy)-1-cyano-3-oxopropyl]-5-(pyridin-4-yl)pyrazole- 3-carboxylate (1.1 g, 3.087 mmol, 1 equiv) in MeOH (20 mL) was added CoCl₂ (1.20 g, 9.261 mmol, 3 equiv) at 0°C . The mixture was stirred 0.5 h at 0°C under nitrogen atmosphere, and NaBH₄ (1.17 g, 30.870 mmol, 10 equiv) was added. The reaction mixture was stirred 3 h at room temperature under nitrogen atmosphere. After the reaction, the resulting mixture was diluted with NH₄Cl (50 mL). The aqueous layer was extracted with EtOAc 50 mL three times. The combined organic phase was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with petroleum ether /EtOAc (1:1) to afford tert-butyl 2-[4-oxo-2-(pyridin-4-yl)-5H,6H,7H- pyrazolo[1,5-a]pyrazin-7-yl]acetate (400 mg, 39.47%) as a yellow solid. LC-MS: (M+H)⁺ found: 329.0.

To a mixture of tert-butyl 2-[4-oxo-2-(pyridin-4-yl)-5H,6H,7H-pyrazolo[1,5-a]pyrazin-7- yl]acetate (500 mg, 1.523 mmol, 1 equiv) and KOAc (224.16 mg, 2.284 mmol, 1.5 equiv) in HOAc (10 mL) was added Br₂ (267.67 mg, 1.675 mmol, 1.1 equiv) at room temperature. The mixture was stirred 3 h at room temperature under nitrogen atmosphere. The resulting mixture was diluted with H₂O (40 mL), and extracted with EtOAc 50 mL three times. The combined organic phase was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with petroleum ether /EtOAc (2:1) to afford tert-butyl 2-[3-bromo-4-oxo-2-(pyridin-4-yl)-5H,6H,7H-pyrazolo[1,5-a]pyrazin- 7-yl]acetate (420 mg, 67.73%) as a yellow solid. LC-MS: (M+H)⁺ found: 406.9.

A mixture of tert-butyl 2-[3-bromo-4-oxo-2-(pyridin-4-yl)-5H,6H,7H-pyrazolo[1,5- a]pyrazin-7-yl]acetate (420 mg, 1.031 mmol, 1 equiv), 3-chloro-2-methoxyaniline (243.79 mg, 1.546 mmol, 1.5 equiv), EPhos Pd G4 (94.73 mg, 0.103 mmol, 0.1 equiv), EPhos (55.15 mg, 0.103 mmol, 0.1 equiv) and Cs₂CO₃ (672.01 mg, 2.062 mmol, 2 equiv) in 1,4-dioxane (10 mL) at room temperature, The mixture was stirred 3 h at 80°C under nitrogen atmosphere. The reaction mixture was diluted with H₂O (40 mL) and extracted with EtOAc 50 mL three times. The combined organic phase was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with petroleum ether /EtOAc (1:1) to afford tert-butyl 2-{3-[(3-chloro-2- methoxyphenyl)amino]-4-oxo-2-(pyridin-4-yl)-5H,6H,7H-pyrazolo[1,5-a]pyrazin-7- yl}acetate (200 mg, 40.07%) as a yellow solid. LC-MS: (M+H)⁺ found: 484.0.

To a mixture of tert-butyl 2-{3-[(3-chloro-2-methoxyphenyl)amino]-4-oxo-2-(pyridin-4- yl)-5H,6H,7H-pyrazolo[1,5-a]pyrazin-7-yl}acetate (200 mg, 0.413 mmol, 1 equiv) in THF (10 mL) was added CH₃MgBr(in 3M Et2O) (1.239 mL, 1.239 mmol, 3 equiv) at 0°C, The mixture was stirred 3 h at room temperature under nitrogen atmosphere. Desired product could be detected by LCMS. After the reaction was complete, the resulting mixture was concentrated to afford 3-[(3-chloro-2-methoxyphenyl)amino]-7-(2-oxopropyl)-2-(pyridin- 4-yl)-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (120 mg, 68.18%) as a yellow solid. LC-MS: (M+H)⁺ found: 426.0.

To a mixture of d3-[(3-chloro-2-methoxyphenyl)amino]-7-(2-oxopropyl)-2-(pyridin-4-yl)- 5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (120 mg, 0.282 mmol, 1 equiv) in THF (10 mL) was added CH₃Li (0.846 mL, 0.846 mmol, 3 equiv) at 0°C. The mixture was stirred 3 h at room temperature under nitrogen atmosphere. Desired product could be detected by LCMS. After the reaction, the resulting mixture was diluted with NH₄Cl (30 mL).The aqueous layer was extracted with EtOAc 40 mL for three times, and the combined organic phase was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with petroleum ether/EtOAc (1:2) to afford 3-[(3-chloro-2- methoxyphenyl)amino]-7-(2-hydroxy-2-methylpropyl)-2-(pyridin-4-yl)-5H,6H,7H- pyrazolo[1,5-a]pyrazin-4-one (40 mg, 32.12%) as a yellow solid. LC-MS: (M+H)⁺ found: 442.3.

3-[(3-chloro-2-methoxyphenyl)amino]-7-(2-hydroxy-2-methylpropyl)-2-(pyridin-4-yl)- 5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (30 mg, 0.068 mmol, 1.00 equiv) was used for chiral separation(Column: CHIRALPAK IG, 2*25 cm, 5 μm; Mobile Phase A: Hex: DCM=3: 1(0.5% 2M NH₃-MeOH)-HPLC, Mobile Phase B: IPA-HPLC; Flow rate: 20 mL/min; Gradient: 20% B to 20% B in 19 min; Wave Length: 220/254 nm; RT1(min): 7.92; RT2(min): 9.81) resulted in (7S)-3-[(3-chloro-2-methoxyphenyl)amino]-7-(2- hydroxy-2-methylpropyl)-2-(pyridin-4-yl)-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (4.5 mg, 14.93%) as a white solid. LC-MS: (M+H)⁺ found: 442.3. ¹H NMR (400 MHz, Chloroform-d) δ 8.58 (s, 2H), 7.82 (s, 2H), 7.24 (s, 1H), 6.83 (s, 1H), 6.66 (s, 1H), 6.15 (s, 1H), 5.95 (s, 1H), 4.76 (s, 1H), 4.37 – 3.39 (m, 5H), 2.95 (s, 1H), 2.46 (d, J = 15.0 Hz, 1H), 2.03 (s, 1H), 1.42 (s, 6H). Example 33. (7R)-3-[(3-chloro-2-methoxyphenyl)amino]-7-(2-hydroxy-2- methylpropyl)-2-(pyridin-4-yl)-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (compound 284)

3-[(3-chloro-2-methoxyphenyl)amino]-7-(2-hydroxy-2-methylpropyl)-2-(pyridin-4-yl)- 5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (30 mg, 0.068 mmol, 1.00 equiv) was used for chiral separation(Column: CHIRALPAK IG, 2*25 cm, 5 μm; Mobile Phase A: Hex: DCM=3: 1(0.5% 2M NH₃-MeOH)-HPLC, Mobile Phase B: IPA-HPLC; Flow rate: 20 mL/min; Gradient: 20% B to 20% B in 19 min; Wave Length: 220/254 nm; RT1(min): 7.92; RT2(min): 9.81) resulted in (7R)-3-[(3-chloro-2-methoxyphenyl)amino]-7-(2- hydroxy-2-methylpropyl)-2-(pyridin-4-yl)-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (peak 2, 4.7 mg, 14.99%) as a white solid. LC-MS: (M+H)⁺ found: 442.3. ¹H NMR (400 MHz, Chloroform-d) δ 8.57 (s, 2H), 7.79 (s, 2H), 7.24 (s, 1H), 6.83 (dd, J = 8.1, 1.4 Hz, 1H), 6.66 (t, J = 8.1 Hz, 1H), 6.15 (dd, J = 8.1, 1.4 Hz, 1H), 5.96 (s, 1H), 4.75 (p, J = 6.0 Hz, 1H), 4.06 (s, 3H), 4.02 – 3.89 (m, 1H), 3.79 (ddd, J = 13.0, 7.7, 2.6 Hz, 1H), 3.00 (s, 1H), 2.51 – 2.42 (m, 1H), 2.03 (dd, J = 14.9, 6.3 Hz, 1H), 1.42 (d, J = 1.4 Hz, 6H). Example 34. 3-[(3-chloro-2-methoxyphenyl)amino]-2-{2-[(2-methoxypyrimidin-4- yl)amino]pyridin-4-yl}-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (compound 311)

To a stirred solution of methyl 4-nitro-1H-pyrazole-3-carboxylate (1 g, 5.844 mmol, 1.00 equiv) and PPh₃ (2299.24 mg, 8.766 mmol, 1.5 equiv) in THF (20 mL) was added DIAD (1418.07 mg, 7.013 mmol, 1.2 equiv) dropwise at 0 degrees C under nitrogen atmosphere.The resulting mixture was stirred for 1h at room temperature under nitrogen atmosphere. After the reaction, The resulting mixture was concentrated under vacuum, and methyl 2-{2-[(tert-butoxycarbonyl)amino]ethyl}-4-nitropyrazole-3-carboxylate (2 g, crude) as a yellow solid was obtained. LC-MS: (M+H)⁺ found: 315.

A mixture of methyl 2-{2-[(tert-butoxycarbonyl)amino]ethyl}-4-nitropyrazole-3- carboxylate (1 g, 3.182 mmol, 1 equiv) and HCl(gas)in 1,4-dioxane (5 mL, 164.564 mmol, 51.72 equiv) in DCM (10 mL) stirred 1 h at room temperature under nitrogen atmosphere. After the reaction, the mixture was concentrated under reduced pressure. After the reaction, the resulting mixture was concentrated under vacuum, and methyl 2-(2-aminoethyl)-4- nitropyrazole-3-carboxylate (700 mg, 102.72%) as a yellow solid was obtained. LC-MS: (M+H)⁺ found: 215.

A mixture of methyl 2-(2-aminoethyl)-4-nitropyrazole-3-carboxylate (1 g, 4.669 mmol, 1.00 equiv) and Et₃N (708.68 mg, 7.003 mmol, 1.50 equiv) in Toluene (10 mL) was stirred for 1h at 100 degrees C under nitrogen atmosphere. The resulting mixture was diluted with water (10 mL). The precipitated solids were collected by filtration and washed with water (2 x 10 mL). The solid was concentrated under reduced pressure to afford 3-nitro- 5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (240 mg, 28.22%) as a brown solid. LC-MS: (M+H)⁺ found: 183.

To a solution of 3-nitro-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (1 g, 5.490 mmol, 1.00 equiv) in EtOH (20 mL) was added Pd/C (116.86 mg, 1.098 mmol, 0.2 equiv) under nitrogen atmosphere. The mixture was hydrogenated at room temperature for 3h, filtered through a Celite pad and concentrated under reduced pressure. The resulting mixture was filtered, the filter cake was washed with EtOH (2 x 20 mL). The filtrate was concentrated under reduced pressure to afford 3-amino-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (650 mg, 77.81%) as a off-white solid. LC-MS: (M+H)⁺ found: 153.

To a stirred solution of 3-amino-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (500 mg, 3.286 mmol, 1.00 equiv) in DMF (10 mL) was added NBS (701.84 mg, 3.943 mmol, 1.20 equiv) in portions at -35°C under nitrogen atmosphere. The reaction solution was stirred at room temperature for 1 h. The resulting mixture was extracted with EtOAc (4 x 40 mL). The combined organic layers were washed with brine (1 x 20 mL), dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (PE/EtOAc 1:1) to afford 3-amino-2-bromo-5H,6H,7H- pyrazolo[1,5-a]pyrazin-4-one (320 mg, 42.15%) as a white solid. LC-MS: (M+H)⁺ found: 231.

To a stirred mixture of 3-amino-2-bromo-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (10 g, 43.280 mmol, 1 equiv.) and 1-chloro-3-iodo-2-methoxybenzene (17.43 g, 64.920 mmol, 1.5 equiv.) in toluene (100 mL) were added Xantphos (5.01 g, 8.656 mmol, 0.2 equiv.) and tert-butoxysodium (4.16 g, 43.280 mmol, 1 equiv.) at room temperature under nitrogen atmosphere. The resulting mixture was stirred overnight at 80 °C. Desired product could be detected by LCMS. The resulting mixture was extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (2 x 300 mL), dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EtOAc (3:1) to afford 2-bromo-3-[(3-chloro-2-methoxyphenyl)amino]-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (10 g, 62.17%) as a grey solid. LC-MS: M+H found: 373.0.

To a stirred mixture of 2-bromo-3-[(3-chloro-2-methoxyphenyl)amino]-5H,6H,7H- pyrazolo[1,5-a]pyrazin-4-one (3.6 g, 9.687 mmol, 1 equiv.) and hexamethyldistannane (12.70 g, 38.748 mmol, 4 equiv.) in toluene (50 mL) was added Pd(PPh3)4 (2.24 g, 1.937 mmol, 0.2 equiv.) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for overnight at 140°C. Desired product could be detected by LCMS. The resulting mixture was filtered, the filter cake was washed with MeCN (3 x 10 mL). The filtrate was concentrated under reduced pressure. The residue was purified by reverse flash chromatography with the following conditions: column, silica gel; mobile phase, MeCN in water, 40% to 60% gradient in 10 min; detector, UV 254 nm. This resulted in 3-[(3-chloro- 2-methoxyphenyl)amino]-2-(trimethylstannyl)-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (1.5 g, 33.99%) as a white solid. LC-MS: M+H found: 457.25.

To a stirred mixture of 3-[(3-chloro-2-methoxyphenyl)amino]-2-(trimethylstannyl)- 5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (200 mg, 0.439 mmol, 1 equiv) and N-(4- bromopyridin-2-yl)-2-methoxypyrimidin-4-amine (135.76 mg, 0.483 mmol, 1.1 equiv) in DMF (5 mL) were added XPhos Pd G3 (37.16 mg, 0.044 mmol, 0.1 equiv), XPhos (20.93 mg, 0.044 mmol, 0.1 equiv) and ZnCl₂ (119.70 mg, 0.878 mmol, 2 equiv) in portions at room temperature under nitrogen atmosphere. The resulting mixture was stirred for overnight at 90 °C under nitrogen atmosphere. The reaction was monitored by LCMS. The crude product was purified by Prep-HPLC with the following conditions (Column: XBridge Prep C18 OBD Column, 30*100 mm, 5μm; Mobile Phase A: Water (10 mmol/L NH₄HCO₃), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 30% B to 50% B in 9 min, 50% B; Wave Length: 254/220 nm; RT1(min): 7.17) to afford 3-[(3-chloro-2- methoxyphenyl)amino]-2-{2-[(2-methoxypyrimidin-4-yl)amino]pyridin-4-yl}- 5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (3.8 mg, 1.74%) as a white solid. LC-MS: (M+H)⁺ found: 493. ¹H NMR (400 MHz, Chloroform-d) δ 8.24 – 8.18 (m, 2H), 8.08 (s, 1H), 7.35 (dd, J = 5.4, 1.5 Hz, 1H), 7.13 (s, 1H), 7.03 (d, J = 5.5 Hz, 1H), 6.78 (dd, J = 8.1, 1.4 Hz, 1H), 6.66 (t, J = 8.1 Hz, 1H), 6.22 (dd, J = 8.1, 1.5 Hz, 1H), 6.00 (s, 1H), 4.46 (t, J = 6.0 Hz, 2H), 4.02 (d, J = 2.5 Hz, 6H), 3.89 – 3.81 (m, 2H). Example 35. 3-[(3-chloro-2-methoxyphenyl)amino]-2-{2-[(6-methoxypyrimidin-4- yl)amino]pyridin-4-yl}-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (compound 310)

To a stirred mixture of 3-[(3-chloro-2-methoxyphenyl)amino]-2-(trimethylstannyl)- 5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (200 mg, 0.439 mmol, 1 equiv) and N-(4- bromopyridin-2-yl)-6-methoxypyrimidin-4-amine (135.76 mg, 0.483 mmol, 1.1 equiv) in DMF (5 mL) were added XPhos Pd G3 (37.16 mg, 0.044 mmol, 0.1 equiv), XPhos (20.93 mg, 0.044 mmol, 0.1 equiv) and ZnCl₂ (119.70 mg, 0.878 mmol, 2 equiv) in portions at room temperature under nitrogen atmosphere. The resulting mixture was stirred for overnight at 90 °C under nitrogen atmosphere. The reaction was monitored by LCMS. The crude product was purified by Prep-HPLC with the following conditions (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water(10 mmol/L NH₄HCO₃), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 42% B to 72% B in 7 min; Wave Length: 254 nm; RT1(min): 6.5) to afford 3-[(3-chloro-2- methoxyphenyl)amino]-2-{2-[(6-methoxypyrimidin-4-yl)amino]pyridin-4-yl}- 5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (39.1 mg, 17.92%) as a white solid. LC-MS: (M+H)⁺ found: 493. ¹H NMR (400 MHz, DMSO-d6) δ 10.12 (s, 1H), 8.29 (dd, J = 4.0, 1.8 Hz, 2H), 8.23 (dd, J = 5.4, 0.7 Hz, 1H), 8.03 (t, J = 1.1 Hz, 1H), 7.33 – 7.26 (m, 2H), 7.21 (d, J = 1.0 Hz, 1H), 6.79 – 6.68 (m, 2H), 6.17 (dd, J = 7.3, 2.3 Hz, 1H), 4.41 (dd, J = 7.1, 5.0 Hz, 2H), 3.87 (d, J = 9.6 Hz, 6H), 3.66 (dq, J = 7.8, 4.6, 3.6 Hz, 2H). Example 36. 3-[(3-chloro-2-methoxyphenyl)amino]-2-{2-[(4-methoxypyrimidin-2- yl)amino]pyridin-4-yl}-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (compound 309)

To a stirred mixture of 3-[(3-chloro-2-methoxyphenyl)amino]-2-(trimethylstannyl)- 5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (200 mg, 0.439 mmol, 1 equiv) and N-(4- bromopyridin-2-yl)-4-methoxypyrimidin-2-amine (135.76 mg, 0.483 mmol, 1.1 equiv) in DMF (5 mL, 68.404 mmol) were added XPhos Pd G3 (37.16 mg, 0.044 mmol, 0.1 equiv), XPhos (20.93 mg, 0.044 mmol, 0.1 equiv) and ZnCl₂ (119.70 mg, 0.878 mmol, 2 equiv) in portions at room temperature under nitrogen atmosphere. The resulting mixture was stirred for overnight at 90 °C under nitrogen atmosphere. The reaction was monitored by LCMS. The crude product was purified by filtration to afford 3-[(3-chloro-2- methoxyphenyl)amino]-2-{2-[(4-methoxypyrimidin-2-yl)amino]pyridin-4-yl}- 5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (58.6 mg, 24.56%) as a white solid. LC-MS: (M+H)⁺ found: 493. ¹H NMR (400 MHz, DMSO-d6) δ 9.69 (s, 1H), 8.91 – 8.85 (m, 1H), 8.29 (t, J = 2.8 Hz, 1H), 8.22 (dd, J = 5.2, 0.8 Hz, 1H), 8.20 – 8.10 (m, 1H), 7.33 – 7.25 (m, 2H), 6.79 – 6.66 (m, 2H), 6.37 (d, J = 5.7 Hz, 1H), 6.17 (dd, J = 7.6, 2.0 Hz, 1H), 4.39 (dd, J = 7.1, 5.0 Hz, 2H), 3.98 (s, 3H), 3.85 (s, 3H), 3.66 (dq, J = 7.7, 4.3, 3.5 Hz, 2H). Example 37. (R)-3-((3-fluoro-2-methoxyphenyl)amino)-2-(isothiazolo[4,5-b]pyridin-7- yl)-7-(trifluoromethyl)-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one (compound 288)

To a stirred mixture of methyl 5-bromo-2H-pyrazole-3-carboxylate (10 g, 48.778 mmol, 1.00 equiv) in MeCN (100 mL) was added NCS (6.51 g, 48.778 mmol, 1 equiv) at room temperature. The resulting mixture was stirred for 2 h at 80 degrees C. Desired product could be detected by LCMS. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with Petroleum ether / EtOAc (1:1) to afford methyl 5-bromo-4-chloro-2H-pyrazole-3-carboxylate as a white solid. LC-MS: (M+H)⁺ found: 239.00.

To a stirred mixture of methyl 5-bromo-4-chloro-2H-pyrazole-3-carboxylate (11.4 g, 47.609 mmol, 1.00 equiv) in MeOH (100 mL) was added NaOH (20 mL, 500.036 mmol, 10.50 equiv) at room temperature. The resulting mixture was stirred for overnight at 60 degrees C. The resulting mixture was concentrated under vacuum. The residue was purified by reverse flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeOH in water, 10% to 50% gradient in 10 min; detector, UV 254 nm. This resulted in 5-bromo-4-chloro-2H-pyrazole-3-carboxylic acid as an off-white solid. LC-MS: M+H found: 225.00.

To a stirred mixture of 5-bromo-4-chloro-2H-pyrazole-3-carboxylic acid (10 g, 44.360 mmol, 1.00 equiv) and oxalyl chloride (11.26 g, 88.720 mmol, 2 equiv) in DCM (100 mL) was added DMF (2 mL, 25.844 mmol, 0.58 equiv) dropwise at room temperature. The resulting mixture was stirred for 0.6 h at room temperature. Desired product could be detected by LCMS.The resulting mixture was concentrated under vacuum. To the above mixture was added Et3N (13.47 g, 133.080 mmol, 3 equiv) and 1,1,1-trifluoro-3-{[(4- methoxyphenyl)methyl]amino}propan-2-ol (11.06 g, 44.360 mmol, 1 equiv) in DCM (100 mL) at room temperature. The resulting mixture was stirred for additional 2 h at room temperature. Desired product could be detected by LCMS. The resulting mixture was extracted with DCM (3 x 150 mL). The combined organic layers were dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with Petroleum ether / EtOAc (1:1) to afford 5-bromo-4-chloro-N-[(4-methoxyphenyl)methyl]-N-(3,3,3-trifluoro-2- hydroxypropyl)-2H-pyrazole-3-carboxamide as a yellow solid. LC-MS: M+H found: 456.00.

To a stirred mixture of 5-bromo-4-chloro-N-[(4-methoxyphenyl)methyl]-N-(3,3,3- trifluoro-2-hydroxypropyl)-2H-pyrazole-3-carboxamide (6 g, 13.139 mmol, 1.00 equiv) and Et3N (3.99 g, 39.417 mmol, 3 equiv) in DCM (100 mL) was added TsCl (5.01 g, 26.278 mmol, 2 equiv) in DCM (20 mL) dropwise at 0 degree C .The resulting mixture was stirred for 0.5 h at room temperature. Desired product could be detected by LCMS. The reaction was quenched by the addition of Water (300 mL) at room temperature. The aqueous layer was dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was dissolved in DMF (100 mL). To the above mixture was added K₂CO₃ (5.45 g, 39.417 mmol, 3 equiv) in portions at room temperature. The resulting mixture was stirred for additional 2 h at 100 degree C. Desired product could be detected by LCMS. The resulting mixture was diluted with water (100 mL). The resulting mixture was extracted with CH₂Cl₂ (3x100 mL). The combined organic layers were dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with Petroleum ether / EtOAc (1:1) to afford 2-bromo-3-chloro- 5-[(4-methoxyphenyl)methyl]-7-(trifluoromethyl)-6H,7H-pyrazolo[1,5-a]pyrazin-4-one as a yellow solid. LC-MS: M+H found: 438.00.

The 2-bromo-3-chloro-5-[(4-methoxyphenyl)methyl]-7-(trifluoromethyl)-6H,7H- pyrazolo[1,5-a]pyrazin-4-one (3.5 g) was dissolved in trifluoroacetaldehyde (20 mL).The resulting mixture was stirred for 3 h at 60°C. Desired product could be detected by LCMS. The resulting mixture was concentrated under reduced pressure. The mixture/residue was acidified/basified/neutralized to pH 7 with saturated NaHCO₃ (aq.). The resulting mixture was extracted with CH₂Cl₂ (3 x 50 mL). The combined organic layers were washed with brine (2x50 mL), dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with petroleum ether/EtOAc to afford 2-bromo-3-chloro-7- (trifluoromethyl)-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one) as a yellow solid. LC-MS: M+H found: 318.00.

To a stirred mixture of 2-bromo-3-chloro-7-(trifluoromethyl)-5H,6H,7H-pyrazolo[1,5- a]pyrazin-4-one (1.7 g, 5.338 mmol, 1.00 equiv) and 7-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)isothiazolo[4,5-b]pyridine (1.44 g, 10.676 mmol, 2 equiv) in dioxane (10 mL) and H₂O (2 mL) were added Na₂CO₃ (1.13 g, 10.676 mmol, 2 equiv) and XPhos Pd G3 (0.90 g, 1.068 mmol, 0.2 equiv) in portions at room temperature under nitrogen atmosphere. The resulting mixture was stirred for overnight at 120°C under nitrogen atmosphere.The resulting mixture was extracted with CH₂Cl₂ (3 x30 mL). The combined organic layers were washed with brine (2x20 mL), dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure.The residue was purified by silica gel column chromatography, eluted with Petroleum ether / EtOAc (1:3) to afford 3-chloro-2-{[1,2]thiazolo[4,5-b]pyridin-7-yl}-7-(trifluoromethyl)-5H,6H,7H- pyrazolo[1,5-a]pyrazin-4-one as a yellow solid. LC-MS: M+H found: 374.00.

To a stirred mixture of 3-chloro-2-{[1,2]thiazolo[4,5-b]pyridin-7-yl}-7-(trifluoromethyl)- 5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (490 mg, 1.311 mmol, 1.00 equiv) and 3-fluoro- 2-methoxyaniline (222.06 mg, 1.573 mmol, 1.2 equiv) in dioxane (10 mL) were added Cs₂CO₃ (854.35 mg, 2.622 mmol, 2 equiv) and EPhos Pd G4 (120.43 mg, 0.131 mmol, 0.1 equiv) and EPhos (70.12 mg, 0.131 mmol, 0.1 equiv) in portions at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 2 h at 60 degree C under nitrogen atmosphere. Desired product could be detected by LCMS. The resulting mixture was extracted with CH₂Cl₂ (3 x 20 mL). The combined organic layers were washed with brine (2x20 mL), dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The crude product (180 mg) was purified by Prep- HPLC with the following conditions(Column: Xselect CSH C18 OBD Column 30*150mm 5μm, n; Mobile Phase A: Water (0.1%FA), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 38% B to 63% B in 8 min, 63% B; Wave Length: 254/220 nm; RT1(min): 8) to afford 3-[(3-fluoro-2-methoxyphenyl)amino]-2-{[1,2]thiazolo[4,5- b]pyridin-7-yl}-7-(trifluoromethyl)-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one as a yellow solid. LC-MS: M+H found: 479.00.

The product was separated by Chiral-Sep (Column: CHIRALPAK IH, 2*25 cm, 5 μm; Mobile Phase A: Hex(0.5% 2M NH₃-MeOH)--HPLC, Mobile Phase B: EtOH-HPLC; Flow rate: 20 mL/min; Gradient: 50% B to 50% B in 22 min; Wave Length: 220/254 nm; RT1(min): 6.08; RT2(min): 16.38) to give 8.0 mg of (R)-3-((3-fluoro-2- methoxyphenyl)amino)-2-(isothiazolo[4,5-b]pyridin-7-yl)-7-(trifluoromethyl)-6,7- dihydropyrazolo[1,5-a]pyrazin-4(5H)-one (peak 1) as a white solid. LC-MS: M+H found: 479.00. ¹H NMR (400 MHz, Chloroform-d) δ 9.39 (s, 1H), 8.69 (d, J = 5.0 Hz, 1H), 7.65 (d, J = 5.1 Hz, 1H), 7.28 (s, 1H), 6.69 – 6.60 (m, 2H), 6.01 (t, J = 4.6 Hz, 1H), 5.89 (d, J = 4.6 Hz, 1H), 5.24 – 5.16 (m, 1H), 4.32 – 4.23 (m, 1H), 4.13 (m, J = 1.7 Hz, 4H). Example 38. (S)-3-((3-fluoro-2-methoxyphenyl)amino)-2-(isothiazolo[4,5-b]pyridin-7- yl)-7-(trifluoromethyl)-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one (compound 289)

The product was separated by Chiral-Sep (Column: CHIRALPAK IH, 2*25 cm, 5 μm; Mobile Phase A: Hex(0.5% 2M NH₃-MeOH)--HPLC, Mobile Phase B: EtOH-HPLC; Flow rate: 20 mL/min; Gradient: 50% B to 50% B in 22 min; Wave Length: 220/254 nm; RT1(min): 6.08; RT2(min): 16.38) to afford 10.6 mg of (S)-3-((3-fluoro-2- methoxyphenyl)amino)-2-(isothiazolo[4,5-b]pyridin-7-yl)-7-(trifluoromethyl)-6,7- dihydropyrazolo[1,5-a]pyrazin-4(5H)-one(peak 2) as a white solid. LC-MS: M+H found: 479.00. ¹H NMR (400 MHz, Chloroform-d) δ 9.25 (s, 1H), 8.70 (d, J = 4.9 Hz, 1H), 7.60 (d, J = 4.8 Hz, 1H), 7.23 (s, 1H), 6.66 – 6.57 (m, 2H), 6.09 – 5.98 (m, 2H), 5.18 (m, J = 6.0 Hz, 1H), 4.25 (m, J = 14.2, 5.1 Hz, 1H), 4.17 – 4.03 (m, 4H). Example 39. 3-[(3-chloro-2-methoxyphenyl)amino]-2-{2-[(1-methyl-1,2,3-triazol-4- yl)amino]pyridin-4-yl}-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (compound 292)

To a stirred mixture of 3-[(3-chloro-2-methoxyphenyl)amino]-2-(trimethylstannyl)- 5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (90 mg, 0.198 mmol, 1.00 equiv.) and 4-bromo- N-(1-methyl-1,2,3-triazol-4-yl)pyridin-2-amine (55.22 mg, 0.218 mmol, 1.1 equiv.) in dimethylformamide (2 mL) were added XPhos Pd G3 (16.72 mg, 0.020 mmol, 0.1 equiv.), XPhos (9.42 mg, 0.020 mmol, 0.1 equiv.) and ZnCl₂ (53.86 mg, 0.396 mmol, 2 equiv.) in portions at room temperature under nitrogen atmosphere. The resulting mixture was stirred for overnight at 90 °C under nitrogen atmosphere. The reaction was monitored by LCMS. The crude product (100 mg) was purified by Prep-HPLC with the following conditions (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water(10 mmol/L NH₄HCO₃+0.1%NH₃*H₂O), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 17% B to 47% B in 7 min, 47% B; Wave Length: 254 nm; RT1(min): 6.98) to afford 3-[(3-chloro-2-methoxyphenyl)amino]-2-{2-[(1-methyl-1,2,3-triazol-4- yl)amino]pyridin-4-yl}-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (33.4 mg, 36.18%) as a white solid. LC-MS: (M+H)⁺ found: 465.90. ¹H NMR (300 MHz, DMSO-d6) δ 9.78 (s, 1H), 8.28 (s, 1H), 8.08 (d, J = 4.5 Hz, 2H), 7.30 (d, J = 14.3 Hz, 2H), 7.06 (d, J = 5.9 Hz, 1H), 6.73 (q, J = 5.3, 4.8 Hz, 2H), 6.15 (dd, J = 6.7, 2.9 Hz, 1H), 4.39 (t, J = 5.9 Hz, 2H), 4.00 (s, 3H), 3.90 (s, 3H), 3.66 (d, J = 6.8 Hz, 2H). Example 40.3-[(3-chloro-2-methoxyphenyl)amino]-2-{2-[(3-methyl-1,2-thiazol-5- yl)amino]pyridin-4-yl}-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (compound 307)

To a stirred mixture of 3-[(3-chloro-2-methoxyphenyl)amino]-2-(trimethylstannyl)- 5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (90 mg, 0.198 mmol, 1 equiv.) and 4-bromo-N- (3-methyl-1,2-thiazol-5-yl)pyridin-2-amine (58.71 mg, 0.218 mmol, 1.1 equiv.) in dimethylformamide (2 mL) were added XPhos Pd G3 (16.72 mg, 0.020 mmol, 0.1 equiv.) XPhos (9.42 mg, 0.020 mmol, 0.1 equiv.) and ZnCl₂ (53.86 mg, 0.396 mmol, 2 equiv.) in portions at room temperature under nitrogen atmosphere. The resulting mixture was stirred for overnight at 90 °C under nitrogen atmosphere. The reaction was monitored by LCMS. The crude product (100 mg) was purified by Prep-HPLC with the following conditions (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water(10 mmol/L NH₄HCO₃), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 29% B to 47% B in 10 min, 47% B; Wave Length: 254 nm; RT1(min): 9.72) to afford 3- [(3-chloro-2-methoxyphenyl)amino]-2-{2-[(3-methyl-1,2-thiazol-5-yl)amino]pyridin-4- yl}-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (25.1 mg, 26.31%) as a yellow solid. LC-MS: (M+H)⁺ found: 481.90. ¹H NMR (300 MHz, DMSO-d6) δ 10.98 (s, 1H), 8.35 – 8.16 (m, 2H), 7.34 (d, J = 9.5 Hz, 2H), 7.23 (d, J = 5.6 Hz, 1H), 6.74 (q, J = 5.2, 4.6 Hz, 2H), 6.54 (s, 1H), 6.17 (dd, J = 6.6, 3.0 Hz, 1H), 4.41 (t, J = 6.0 Hz, 2H), 3.92 (s, 3H), 3.67 (d, J = 7.1 Hz, 2H), 2.26 (s, 3H). Example 41.3-[(3-chloro-2-methoxyphenyl)amino]-2-{2-[(1-methylimidazol-4- yl)amino]pyridin-4-yl}-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (compound 293)

To a stirred mixture of 3-[(3-chloro-2-methoxyphenyl)amino]-2-(trimethylstannyl)- 5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (90 mg, 0.198 mmol, 1.00 equiv.) and 4-bromo- N-(1-methylimidazol-4-yl)pyridin-2-amine (55.01 mg, 0.218 mmol, 1.1 equiv.) in DMF (2 mL) were added Xphos Pd G3 (16.72 mg, 0.020 mmol, 0.1 equiv.) and ZnCl₂ (53.86 mg, 0.396 mmol, 2 equiv.) in portions at room temperature under nitrogen atmosphere. The resulting mixture was stirred for overnight at 90 °C under nitrogen atmosphere. The reaction was monitored by LCMS. The crude product (100 mg) was purified by Prep- HPLC with the following conditions (Column: Xcelect CSH F-pheny OBD Column, 19*250 mm, 5μm; Mobile Phase A: Water(0.05%FA), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 5% B to 30% B in 7 min; Wave Length: 254 nm; RT1(min): 6.5) to afford 3-[(3-chloro-2-methoxyphenyl)amino]-2-{2-[(1-methylimidazol-4- yl)amino]pyridin-4-yl}-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (3.5 mg, 3.80%) as a yellow solid. LC-MS: (M+H)⁺ found: 465.25 ¹H NMR (300 MHz, Chloroform-d) δ 8.91 (s, 1H), 7.98 (d, J = 5.7 Hz, 1H), 7.36 (s, 1H), 7.22 (s, 1H), 7.16 (d, J = 5.8 Hz, 1H), 7.05 (s, 1H), 6.85 (s, 1H), 6.77 (dd, J = 8.1, 1.5 Hz, 1H), 6.67 (t, J = 8.1 Hz, 1H), 6.20 (dd, J = 8.1, 1.5 Hz, 1H), 5.98 (s, 1H), 4.44 (t, J = 6.0 Hz, 2H), 4.03 (s, 3H), 3.82 (s, 2H), 3.65 (s, 3H). Example 42.3-[(3-chloro-2-methoxyphenyl)amino]-2-{2-[(3-methyl-1,2-oxazol-5- yl)amino]pyridin-4-yl}-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (compound 306)

To a mixture of 3-[(3-chloro-2-methoxyphenyl)amino]-2-(trimethylstannyl)-5H,6H,7H- pyrazolo[1,5-a]pyrazin-4-one (100 mg, 0.220 mmol, 1 equiv.) and 4-bromo-N-(3-methyl- 1,2-oxazol-5-yl)pyridin-2-amine (61.36 mg, 0.242 mmol, 1.1 equiv.) in dimethylformamide (2 mL) were added XPhos Pd G3 (18.58 mg, 0.022 mmol, 0.1 equiv.) and ZnCl₂ (59.85 mg, 0.440 mmol, 2 equiv.) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for overnight at 90°C under nitrogen atmosphere. The reaction was monitored by LCMS. Desired product could be detected by LCMS. The crude product (100 mg) was purified by Prep-HPLC with the following conditions (Column: XBridge Shield RP18 OBD Column, 30*150 mm, 5μm; Mobile Phase A: Water(10 mmol/L NH₄HCO₃), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 35% B to 65% B in 10 min, 65% B; Wave Length: 220/254 nm; RT1(min): 10.13) to afford 3-[(3-chloro-2-methoxyphenyl)amino]-2-{2-[(3-methyl-1,2-oxazol-5- yl)amino]pyridin-4-yl}-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (9.9 mg, 9.41%) as a yellow solid. LC-MS: (M+H)⁺ found: 466.25. ¹H NMR (300 MHz, Chloroform-d) δ 8.32 (d, J = 5.7 Hz, 1H), 8.07 (s, 1H), 7.87 (s, 1H), 7.75 (s, 1H), 7.20 – 7.13 (m, 2H), 7.02 (t, J = 8.1 Hz, 1H), 6.94 – 6.86 (m, 2H), 5.98 (s, 1H), 4.51 (dd, J = 7.0, 4.6 Hz, 2H), 4.26 (dd, J = 7.0, 4.6 Hz, 2H), 3.92 (s, 3H), 2.28 (s, 3H). Example 43. 3-[(3-chloro-2-methoxyphenyl)amino]-2-{2-[(1-methylpyrazol-3- yl)amino]pyridin-4-yl}-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (compound 305)

To a stirred mixture of 3-[(3-chloro-2-methoxyphenyl)amino]-2-(trimethylstannyl)- 5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (100 mg, 0.220 mmol, 1 equiv.) and 4-bromo- N-(1-methylpyrazol-3-yl)pyridin-2-amine (61.12 mg, 0.242 mmol, 1.1 equiv.) in dimethylformamide (2 mL) were added XPhos Pd G3 (18.58 mg, 0.022 mmol, 0.1 equiv.) and ZnCl₂ (59.85 mg, 0.440 mmol, 2 equiv.) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for overnight at 90°C under nitrogen atmosphere. The reaction was monitored by LCMS. Desired product could be detected by LCMS. The crude product (100 mg) was purified by Prep-HPLC with the following conditions (Column: XSelect CSH Prep C18 OBD Column, 19*250 mm, 5μm; Mobile Phase A: Water(0.05%TEA), Mobile Phase B: MeOH--HPLC; Flow rate: 25 mL/min; Gradient: 36% B to 56% B in 7 min, 56% B; Wave Length: 254/220 nm; RT1(min): 10.5) to afford 3-[(3-chloro-2-methoxyphenyl)amino]-2-{2-[(1-methylpyrazol-3- yl)amino]pyridin-4-yl}-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (24.3 mg, 23.69%) as a white solid. LC-MS: (M+H)⁺ found: 465.25. ¹H NMR (400 MHz, Chloroform-d) δ 8.05 (s, 1H), 7.50 (s, 1H), 7.27 (s, 1H), 7.25 (d, J = 1.4 Hz, 1H), 7.15 (d, J = 2.3 Hz, 1H), 7.05 (s, 1H), 6.78 (dd, J = 8.1, 1.5 Hz, 1H), 6.68 (d, J = 8.1 Hz, 1H), 6.22 (dd, J = 8.1, 1.5 Hz, 1H), 5.91 (s, 1H), 5.74 (s, 1H), 4.48 – 4.40 (m, 2H), 3.99 (s, 3H), 3.85 – 3.79 (m, 2H), 3.77 (s, 3H). Example 44.3-[(3-chloro-2-methoxyphenyl)amino]-2-{2-[(2-methyl-1,2,3-triazol-4- yl)amino]pyridin-4-yl}-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (compound 294)

To a stirred mixture of 3-[(3-chloro-2-methoxyphenyl)amino]-2-(trimethylstannyl)- 5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (150 mg, 0.329 mmol, 1 equiv.) and 4-bromo- N-(2-methyl-1,2,3-triazol-4-yl)pyridin-2-amine (100.40 mg, 0.395 mmol, 1.2 equiv.) in dimethylformamide (3 mL) were added XPhos Pd G3 (27.87 mg, 0.033 mmol, 0.1 equiv.), XPhos (15.70 mg, 0.033 mmol, 0.1 equiv.) and ZnCl₂ (89.77 mg, 0.658 mmol, 2 equiv.) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for overnight at 90 °C. The reaction was monitored by LCMS. Desired product could be detected by LCMS. The crude product (100 mg) was purified by Prep-HPLC with the following conditions (Column: Xselect CSH C18 OBD Column 30*150mm 5μm, n; Mobile Phase A: Water(0.1%FA), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 14% B to 38% B in 8 min, 38% B; Wave Length: 254/220 nm; RT1(min): 8) to afford 3-[(3-chloro-2-methoxyphenyl)amino]-2-{2-[(2-methyl-1,2,3-triazol-4- yl)amino]pyridin-4-yl}-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (16.1 mg, 10.46%) as a light yellow solid. LC-MS: (M+H)⁺ found: 465.95. ¹H NMR (400 MHz, Chloroform-d) δ 8.14 (s, 1H), 7.96 – 7.87 (m, 2H), 7.42 (dd, J = 6.1, 1.5 Hz, 1H), 7.31 (s, 1H), 7.17 (s, 1H), 6.78 (dd, J = 8.1, 1.5 Hz, 1H), 6.68 (t, J = 8.1 Hz, 1H), 6.16 (s, 1H), 6.15 (dd, J = 8.1, 1.5 Hz, 1H), 4.52 – 4.44 (m, 2H), 4.05 (d, J = 14.0 Hz, 6H), 3.86 (dd, J = 12.0, 2.8 Hz, 2H). Example 45.3-[(3-chloro-2-methoxyphenyl)amino]-2-{2-[(4-methoxy-1-methylpyrazol- 3-yl)amino]pyridin-4-yl}-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (compound 300)

To a stirred mixture of 3-[(3-chloro-2-methoxyphenyl)amino]-2-(trimethylstannyl)- 5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (200 mg, 0.439 mmol, 1 equiv.) and 4-bromo-N- (4-methoxy-1-methylpyrazol-3-yl)pyridin-2-amine (149.17 mg, 0.527 mmol, 1.2 equiv.) in dimethylformamide (3 mL) were added XPhos Pd G3 (37.16 mg, 0.044 mmol, 0.1 equiv.) and ZnCl₂ (119.70 mg, 0.878 mmol, 2 equiv.) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for overnight at 90 °C. The reaction was monitored by LCMS. Desired product could be detected by LCMS. The crude product (200 mg) was purified by Prep-HPLC with the following conditions (Column: YMC-Actus Triart C18 ExRS, 30*250 mm, 5μm; Mobile Phase A: Water(10 mmol/L NH₄HCO₃), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 33% B to 49% B in 10 min, 49% B; Wave Length: 254/220 nm; RT1(min): 9.25) to afford 3-[(3-chloro-2- methoxyphenyl)amino]-2-{2-[(4-methoxy-1-methylpyrazol-3-yl)amino]pyridin-4-yl}- 5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (44 mg, 19.72%) as a off-white solid. LC-MS: (M+H)⁺ found: 494.95. ¹H NMR (400 MHz, Chloroform-d) δ 8.17 (d, J = 5.7 Hz, 1H), 8.04 (s, 1H), 7.72 (s, 1H), 7.33 (s, 1H), 7.14 (dd, J = 8.1, 1.5 Hz, 1H), 7.00 (t, J = 8.1 Hz, 1H), 6.91 – 6.82 (m, 2H), 6.60 (s, 1H), 6.37 (d, J = 1.9 Hz, 1H), 4.48 – 4.40 (m, 2H), 4.17 – 4.09 (m, 2H), 3.90 (s, 3H), 3.76 (d, J = 15.9 Hz, 6H). Example 46.3-[(3-chloro-2-methoxyphenyl)amino]-2-{2-[(6-methylpyridin-2- yl)amino]pyridin-4-yl}-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (compound 308)

To a stirred mixture of 3-[(3-chloro-2-methoxyphenyl)amino]-2-(trimethylstannyl)- 5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (150 mg, 0.329 mmol, 1 equiv.) and 4-bromo-N- (6-methylpyridin-2-yl)pyridin-2-amine (104.37 mg, 0.395 mmol, 1.2 equiv.) in dimethylformamide (3 mL) were added XPhos Pd G3 (27.87 mg, 0.033 mmol, 0.1 equiv.) and ZnCl₂ (89.77 mg, 0.658 mmol, 2 equiv.) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for overnight at 90 °C. The reaction was monitored by LCMS. Desired product could be detected by LCMS. The crude product (150 mg) was purified by Prep-HPLC with the following conditions (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water(10 mmol/L NH₄HCO₃), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 37% B to 67% B in 7 min; Wave Length: 254 nm; RT1(min): 6.5) to afford 3-[(3-chloro-2-methoxyphenyl)amino]-2-{2-[(6- methylpyridin-2-yl)amino]pyridin-4-yl}-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (27.0 mg, 16.92%) as a white solid. LC-MS: (M+H)⁺ found: 468.90. ¹H NMR (400 MHz, DMSO-d6) δ 12.22 (s, 1H), 8.45 (d, J = 5.8 Hz, 1H), 8.31 (s, 1H), 8.22 (s, 1H), 7.99 (s, 1H), 7.36 – 7.29 (m, 2H), 7.18 (dd, J = 5.9, 1.9 Hz, 1H), 7.10 (t, J = 8.2 Hz, 1H), 6.92 (dd, J = 8.1, 1.3 Hz, 1H), 4.52 (dd, J = 7.1, 4.5 Hz, 2H), 4.33 (dd, J = 7.0, 4.7 Hz, 2H), 3.82 (s, 3H). Example 47. 3-[(3-chloro-2-methoxyphenyl)amino]-2-{2-[(6-methylpyridin-2- yl)amino]pyridin-4-yl}-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (compound 304)

To a stirred mixture of 3-[(3-chloro-2-methoxyphenyl)amino]-2-(trimethylstannyl)- 5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (150 mg, 0.329 mmol, 1 equiv.) and 4-bromo-N- (6-methylpyridin-2-yl)pyridin-2-amine (104.37 mg, 0.395 mmol, 1.2 equiv.) in dimethylformamide (3 mL) were added XPhos Pd G3 (27.87 mg, 0.033 mmol, 0.1 equiv.) and ZnCl₂ (89.77 mg, 0.658 mmol, 2 equiv.) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for overnight at 90 °C. The reaction was monitored by LCMS. Desired product could be detected by LCMS. The crude product (150 mg) was purified by Prep-HPLC with the following conditions (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water(10 mmol/L NH₄HCO₃), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 37% B to 67% B in 7 min; Wave Length: 254 nm; RT1(min): 6.5) to afford 3-[(3-chloro-2-methoxyphenyl)amino]-2-{2-[(6- methylpyridin-2-yl)amino]pyridin-4-yl}-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (27.0 mg, 16.92%) as a white solid. LC-MS: (M+H)⁺ found: 476.00 ¹H NMR (300 MHz, DMSO-d6) δ 9.63 (s, 1H), 8.28 (s, 1H), 8.14 (d, J = 5.3 Hz, 1H), 8.02 (s, 1H), 7.62 (d, J = 8.3 Hz, 1H), 7.50 (t, J = 7.8 Hz, 1H), 7.28 (s, 1H), 7.15 (d, J = 5.3 Hz, 1H), 6.73 (q, J = 7.8 Hz, 3H), 6.17 (dd, J = 7.3, 2.4 Hz, 1H), 4.40 (t, J = 5.9 Hz, 2H), 3.86 (s, 3H), 3.66 (s, 2H), 2.34 (s, 3H). Example 48. (6S)-3-[(3-chloro-2-methoxyphenyl)amino]-6-methyl-2-{[1,2]thiazolo[4,5- b]pyridin-7-yl}-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (compound 278)

To a stirred solution of (6S)-3-amino-2-bromo-6-methyl-5H,6H,7H-pyrazolo[1,5- a]pyrazin-4-one (800 mg, 3.264 mmol, 1 equiv) 1-chloro-3-iodo-2-methoxybenzene (1.31 g, 4.896 mmol, 1.5 equiv) and t-BuONa (627.41 mg, 6.528 mmol, 2 equiv) in Toluene (30 mL) were added XantPhos (377.75 mg, 0.653 mmol, 0.2 equiv) and Pd₂(dba)₃ (597.83 mg, 0.653 mmol, 0.2 equiv) in portions at room temperature under nitrogen atmosphere. The resulting mixture was stirred for overnight at 80°C under nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine (3x10 mL), dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse flash chromatography with the following conditions: column, silica gel; mobile phase, MeCN in water, 40% to 50% gradient in 10 min; detector, UV 254 nm. This resulted in (6S)-2-bromo-3-[(3-chloro-2-methoxyphenyl)amino]-6- methyl-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (1.2 g, 95.32%) as a light yellow solid. LC-MS: (M+H)⁺ found: 384.90.

To a stirred solution of (6S)-2-bromo-3-[(3-chloro-2-methoxyphenyl)amino]-6-methyl- 5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (300 mg, 0.778 mmol, 1 equiv) and 7-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,2]thiazolo[4,5-b]pyridine (305.87 mg, 1.167 mmol, 1.5 equiv) in dioxane (10 mL) and H₂O (2 mL) were added Cs₂CO₃ (506.92 mg, 1.556 mmol, 2 equiv) and 2nd Generation XPhos Precatalyst (61.21 mg, 0.078 mmol, 0.1 equiv) in portions at room temperature under nitrogen atmosphere. The resulting mixture was stirred for overnight at 80 °C under nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine (2 x 20 mL), dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The crude product (132 mg) was purified by Prep-HPLC with the following conditions (Column: Xselect CSH C18 OBD Column 30*150mm 5μm, n; Mobile Phase A: Water(0.05%TFA ), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 39% B to 57% B in 8 min, 57% B; Wave Length: 254/220 nm; RT1(min): 8) to afford (6S)-3-[(3-chloro-2-methoxyphenyl)amino]-6- methyl-2-{[1,2]thiazolo[4,5-b]pyridin-7-yl}-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (68.3 mg, 19.91%) as a yellow solid. LC-MS: (M+H)⁺ found: 440.90. ¹H NMR (400 MHz, DMSO-d6) δ 9.31 (s, 1H), 8.81 (d, J = 4.8 Hz, 1H), 8.45 (d, J = 1.6 Hz, 1H), 7.73 (d, J = 4.8 Hz, 1H), 7.54 (s, 1H), 6.84 – 6.71 (m, 2H), 6.20 (dd, J = 7.4, 2.2 Hz, 1H), 4.65 (dd, J = 12.8, 4.3 Hz, 1H), 4.28 – 4.20 (m, 1H), 4.14 – 4.06 (m, 1H), 3.94 (s, 3H), 1.29 (d, J = 6.4 Hz, 3H). Example 49. (6R)-3-[(3-chloro-2-methoxyphenyl)amino]-6-methyl-2-{[1,2]thiazolo[4,5- b]pyridin-7-yl}-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (compound 277)

To a stirred solution of (6R)-3-amino-2-bromo-6-methyl-5H,6H,7H-pyrazolo[1,5- a]pyrazin-4-one (480 mg, 1.959 mmol, 1.00 equiv) 1-chloro-3-iodo-2-methoxybenzene (788.74 mg, 2.939 mmol, 1.5 equiv) and t-BuONa (376.45 mg, 3.918 mmol, 2 equiv) in Toluene (15 mL) were added XantPhos (226.65 mg, 0.392 mmol, 0.2 equiv) and Pd2(dba)₃ (358.70 mg, 0.392 mmol, 0.2 equiv) in portions at room temperature under nitrogen atmosphere. The resulting mixture was stirred for overnight at 80°C under nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine (3x10 mL), dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse flash chromatography with the following conditions: column, silica gel; mobile phase, MeCN in water, 40% to 50% gradient in 10 min; detector, UV 254 nm. This resulted in (6R)-2-bromo-3-[(3-chloro-2- methoxyphenyl)amino]-6-methyl-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (720 mg, 95.32%) as a light yellow solid. LC-MS: (M+H)⁺ found: 384.90.

To a stirred solution of (6R)-2-bromo-3-[(3-chloro-2-methoxyphenyl)amino]-6-methyl- 5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (300 mg, 0.778 mmol, 1 equiv) and 7-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-[1,2]thiazolo[4,5-b]pyridine (305.87 mg, 1.167 mmol, 1.5 equiv) in dioxane (10 mL) and H₂O (2 mL) were added Cs₂CO₃ (506.92 mg, 1.556 mmol, 2 equiv) and 2nd Generation XPhos Precatalyst/ (122.41 mg, 0.156 mmol, 0.2 equiv) in portions at room temperature under nitrogen atmosphere. The resulting mixture was stirred for overnight at 80 °C under nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine (2 x 20 mL), dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The crude product (225mg) was purified by Prep-HPLC with the following conditions (Column: Xselect CSH F-Phenyl OBD column, 30*250 mm, 5μm; Mobile Phase A: Water(0.05%TFA ), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 41% B to 71% B in 7 min; Wave Length: 254 nm; RT1(min): 6.5) to afford (6R)-3-[(3-chloro-2- methoxyphenyl)amino]-6-methyl-2-{[1,2]thiazolo[4,5-b]pyridin-7-yl}-5H,6H,7H- pyrazolo[1,5-a]pyrazin-4-one (91.9 mg, 26.79%) as a yellow solid. LC-MS: (M+H)⁺ found: 440.95. ¹H NMR (400 MHz, DMSO-d6) δ 9.31 (s, 1H), 8.81 (d, J = 4.8 Hz, 1H), 8.45 (s, 1H), 7.74 (d, J = 4.8 Hz, 1H), 7.54 (s, 1H), 6.80 – 6.74 (m, 2H), 6.20 (dd, J = 7.4, 2.2 Hz, 1H), 4.65 (dd, J = 12.8, 4.3 Hz, 1H), 4.24 (dd, J = 12.9, 9.4 Hz, 1H), 4.11 (d, J = 9.4 Hz, 1H), 3.94 (s, 3H), 1.29 (d, J = 6.5 Hz, 3H). Example 50.3-((3-chloro-2-methoxyphenyl)amino)-2-(2-((1-methyl-1H-pyrazol-4- yl)amino)pyridin-4-yl)-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one (compound 291)

A mixture of (3-chloro-4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)boronic acid (1.80 g, 8.37 mmol, 1.00 equiv), 4-bromo-2-fluoropyridine (1.46 g, 8.37 mmol, 1.00 equiv), K₃PO₄ (5.37 g, 25.1 mmol, 3.00 equiv), Pd(dppf)Cl₂ (0.67 g, 0.83 mmol, 0.1 equiv) and water (1 mL) in 1,4-dioxane (10 mL) was stirred for 12 h at 100 degrees C. The reaction was quenched with Water at room temperature. The resulting mixture was extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine (3x30 mL), dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with petroleum ether/EtOAc (4:1) to afford 3-chloro-2-(2-fluoropyridin-4-yl)-6,7- dihydropyrazolo[1,5-a]pyrazin-4(5H)-one (0.9 g, 36%) as yellow oil. LC-MS: M+H found: 267.0.

To a stirred solution of 3-chloro-2-(2-fluoropyridin-4-yl)-6,7-dihydropyrazolo[1,5- a]pyrazin-4(5H)-one (900.00 mg, 3.36 mmol, 1.00 equiv), 3-chloro-2-methoxyaniline (689 mg, 4.36 mmol, 1.3 equiv), and Cs₂CO₃ (2.18 g, 6.72 mmol, 2.00 equiv) in 1,4- dioxane(10.00 mL) were added EPhos (387 mg, 0.67 mmol, 0.20 equiv) and EPhos Pd G4 (300 mg, 0.33 mmol, 0.10 equiv) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 2 h at 50 °C under nitrogen atmosphere. The reaction was quenched with Water at room temperature. The resulting mixture was extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine (2 x 50 mL), dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (EtOAc /Petroleum ether 1:3) to afford 3-((3-chloro-2-methoxyphenyl)amino)-2-(2-fluoropyridin-4-yl)-6,7- dihydropyrazolo[1,5-a]pyrazin-4(5H)-one (400 mg, 31%) as a yellow solid. LC-MS: (M+H)⁺ found: 388.

To a stirred solution of 3-((3-chloro-2-methoxyphenyl)amino)-2-(2-fluoropyridin-4-yl)- 6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one (100.00 mg, 0.26 mmol, 1.00 equiv), 1- methyl-1H-pyrazol-4-amine (38 mg, 0.39 mmol, 1.5 equiv) in 1,4-dioxane(1.00 mL) was added 3N HCl (0.1 mL) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 2 h at 110 °C under nitrogen atmosphere. The reaction was quenched with water at room temperature. The resulting mixture was extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine (2 x 50 mL), dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-HPLC (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water(10 mmol/L NH₄HCO₃), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 20% B to 50% B in 7 min, 50% B; Wave Length: 254/220 nm; RT1(min): 6.32) to afford 3-((3-chloro-2- methoxyphenyl)amino)-2-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyridin-4-yl)-6,7- dihydropyrazolo[1,5-a]pyrazin-4(5H)-one (20.7 mg, 17%) as a white solid. LC-MS: (M+H)⁺ found: 465. ¹H NMR (400 MHz, DMSO-d6) δ 8.79 – 8.66 (m, 1H), 8.34 – 8.21 (m, 1H), 8.11 – 7.98 (m, 1H), 7.82 – 7.73 (m, 1H), 7.33 – 7.24 (m, 2H), 7.11 – 7.04 (m, 1H), 7.01 – 6.97 (m, 1H), 6.83 – 6.71 (m, 2H), 6.22 – 6.11 (m, 1H), 4.45 – 4.34 (m, 2H), 3.93 – 3.85 (m, 3H), 3.81 – 3.73 (m, 3H), 3.71 – 3.62 (m, 2H). Example 51. N-(4-[3-[(3-fluoro-2-methoxyphenyl) amino]-4-oxo-5H,6H,7H- yrazolo[1,5-]pyrazin-2-yl]pyridin-3-yl)acetamide (compound 337)

To a stirring solution of 2-(3-aminopyridin-4-yl)-3-[(3-fluoro-2-methoxyphenyl) amino]- 5H,6H,7H-pyrazolo[1,5-a] pyrazine-4-on (60 mg, 0.16 mmol, 1.00 equiv) in pyridine were added Ac₂O (33 mg, 0.33 mmol, 2.00 equiv) in 0.5 ml DCM dropwise at 0°C under nitrogen atmosphere. The resulting mixture was stirred for 30 min at room temperature under nitrogen. The crude product (70 mg) was purified by Prep- HPLC with the following conditions (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water (10 mmol/L NH₄HCO₃), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 13% B to 43% B in 7 min, 43% B; Wave Length: 254 nm; RT1(min): 6.5) to afford N-(4-[3-[(3-fluoro-2-methoxyphenyl) amino]-4-oxo-5H,6H,7H- yrazolo[1,5-]pyrazin-2-yl]pyridin-3-yl)acetamide (13.2 mg, 18.38%) as white solid. LC-MS: (M+H)⁺ found: 411.05. ¹H NMR (300 MHz, DMSO-d6) δ 9.90 (s, 1H), 9.14 (s, 1H), 8.36 (t, 1H), 8.24 (d, 1H), 7.55 (d, 1H), 7.33 (s, 1H), 6.64-6.47 (m, 2H), 6.07 (d, 1H), 4.44 (t, 2H), 3.89 (s, 3H), 3.69 (t, 2H), 2.34 (s, 3H). Example 52.3-((3-chloro-2-methoxyphenyl)amino)-2-(isothiazolo[4,5-b]pyridin-7-yl)- 6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one-6,6,7,7-d4 (compound 276)

To a stirred solution of glycine-2,2-d2 (2.0 g, 25.95 mmol, 1.00 equiv) in MeOH (100.00 mL) was added acetyl chloride (3.46 g, 44.11 mmol, 1.70 equiv) dropwise at 0 °C. The mixture was stirred for 1 h at 68°C under nitrogen atmosphere. The reaction was monitored by LCMS. Desired product could be detected by LCMS. The resulting mixture was concentrated under reduced pressure. The crude product was used in the next step directly without further purification. LC-MS: (M+H)⁺ found: 91.95.

To a stirred solution of methyl glycinate-2,2-d2 (2.30 g, 25.24 mmol, 1.00 equiv) in THF (80.00 mL) was added LiAlD₄ (2.12 g, 50.49 mmol, 2.00 equiv) dropwise at 0°C. The mixture was stirred for overnight from 0°C to room temperature under argon atmosphere. The reaction was monitored by LCMS and TLC. The reaction was quenched with water (20 mL) at 0°C and stirred for 10 min at room temperature. The crude product was used in the next step directly without further purification. LC-MS: (M+H)⁺ found: 66.25.

To a stirred solution of 2-aminoethan-1,1,2,2-d4-1-ol (1.9 g, 29.18 mmol, 1.00 equiv) in THF (100 mL) was added di-tert-butyl dicarbonate (6.37 g, 29.18 mmol, 1.00 equiv) at room temperature and stirred for 10min. Na₂CO₃ (sat.) was added to adjust PH to 10. The mixture was stirred for 1 h at room temperature under argon atmosphere. The reaction was monitored by LCMS and TLC. The aqueous layer was extracted with CH₂Cl₂ (3x20 mL). The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (0:100) to afford tert-butyl (2- hydroxyethyl-1,1,2,2-d4)carbamate (2.7 g, 56.00%) as a colorless oil. LC-MS: (M+H+Na)⁺ found: 188.05. ¹H NMR (400 MHz, CDCl₃): δ 5.05 (s, 1H), 2.72 (s, 1H), 1.46 (d, 1H).

To a stirred solution of methyl 5-bromo-2H-pyrazole-3-carboxylate (1.0 g, 4.88 mmol, 1.00 equiv) in THF (50.00 mL) was added PPh₃ (1.92 g, 7.32 mmol, 1.50 equiv) and tert- butyl (2-hydroxyethyl-1,1,2,2-d4)carbamate (0.81 g, 4.88 mmol, 1.00 equiv) at room temperature. The mixture was stirred for 30min at 0°C under argon atmosphere. DIAD (1.48 g, 7.32 mmol, 1.50 equiv) was added in portions at 0°C. The mixture was stirred for overnight from 0°C to room temperature under argon atmosphere. The reaction was monitored by LCMS. The reaction was quenched with water (2 mL) at room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (4:1) to afford methyl 5-bromo- 2-{2-[(tert-butoxycarbonyl)amino](1,1,2,2-d4)ethyl}pyrazole-3-carboxylate (1.9 g, 95.11%) as a colorless oil. LC-MS: (M+H-56)⁺ found: 298.1.

To a stirred solution of methyl 5-bromo-2-{2-[(tert-butoxycarbonyl)amino](1,1,2,2- 2H4)ethyl}pyrazole-3-carboxylate (1.8 g, 5.11 mmol, 1.00 equiv) in DCM (5.00 mL) was added HCl(gas) (4M in 1,4-dioxane, 15.00 mL) in portions at 0°C. The mixture was stirred for 1 h at room temperature under nitrogen atmosphere. Desired product could be detected by LCMS. The resulting mixture was concentrated under reduced pressure. The crude product was used in the next step directly without further purification. LC-MS: (M+H)⁺ found: 252.1.

To a stirred solution of MeONa (1.37 g, 25.38 mmol, 5.00 equiv) in MeOH (20.00 mL) was added methyl 2-[2-amino(1,1,2,2-2H4)ethyl]-5-bromopyrazole-3-carboxylate (1.28 g, 5.08mmol, 1.00 equiv) dropwise at 0°C. The mixture was stirred for 2 h at room temperature under nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH₂Cl₂/MeOH (98:2) to afford 2- bromo(6,6,7,7-2H4)-5H-pyrazolo[1,5-a]pyrazin-4-one (1.0 g, 89.50%) as a white solid. LC-MS: (M+H)⁺ found: 220.1.

To a stirred solution of 2-bromo(6,6,7,7-2H4)-5H-pyrazolo[1,5-a]pyrazin-4-one (1.0 g, 4.54 mmol, 1.00 equiv) in DMF (20.00 mL) was added NCS (607 mg, 4.54 mmol, 1.00 equiv) at room temperature. The mixture was stirred for 0.5 h at 50°C under nitrogen atmosphere. The reaction was monitored by LCMS. Desired product could be detected by LCMS. The reaction was quenched with Na₂SO₃ (aq.) (2 mL) at room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH₂Cl₂/MeOH (97:3) to afford 2-bromo-3- chloro(6,6,7,7-2H4)-5H-pyrazolo[1,5-a]pyrazin-4-one (1.0 g, 86.47%) as a white solid. LC-MS: (M+H)⁺ found: 254.1.

To a stirred solution of 2-bromo-3-chloro(6,6,7,7-2H4)-5H-pyrazolo[1,5-a]pyrazin-4-one (1.0 g, 3.93 mmol, 1.00 equiv) in 1,4-dioxane (15.00 mL) was added Pd(dppf)Cl₂CH₂Cl₂ (320 mg, 0.39 mmol, 0.10 equiv), KOAc (1.16 g, 11.79 mmol, 3.00 equiv) and 4,4,5,5- tetramethyl-2-(4,4,5,5-tetramethyl-1,3-dioxolan-2-yl)-1,3,2-dioxaborolane (2.01 g, 7.86 mmol, 2.00 equiv) at room temperature. The mixture was stirred for overnight at 100 °C under argon atmosphere. The reaction was monitored by LCMS. Desired product could be detected by LCMS. The resulting mixture was filtered, and the filter cake was washed with DCM (3x5 mL). The filtrate was concentrated under reduced pressure. The residue was triturated with ethyl acetate (5 mL) then purified by silica gel column chromatography, eluting with PE/EA (0:100) to afford 3-chloro-4-oxo(6,6,7,7-2H4)-5H-pyrazolo[1,5- a]pyrazin-2-ylboronic acid (700 mg, 81.19%) as a white solid. LC-MS: (M+H)⁺ found: 220.2.

To a stirred solution of 7-chloro-[1,2]thiazolo[4,5-b]pyridine (460 mg, 2.70 mmol, 1 equiv) in 1,4-dioxane (10 mL) was added Na₂CO₃ (857 mg, 8.09 mmol, 3.00 equiv) in H₂O (2.00 mL), Xphos Pd G2 (212 mg, 0.27 mmol, 0.10 equiv) and 3-chloro-4-oxo(6,6,7,7-2H4)-5H- pyrazolo[1,5-a]pyrazin-2-ylboronic acid (710 mg, 3.23 mmol, 1.20 equiv) at room temperature. The mixture was stirred for 2 h at 50 °C under argon atmosphere. The reaction was monitored by LCMS. Desired product could be detected by LCMS. The resulting mixture was concentrated under reduced pressure. The precipitated solids were collected by filtration and washed with MeCN (3 x 3 mL) and H₂O (3 x 3 mL). Then the filter cake was washed with MeCN (2 x 2 mL). The filtrate was concentrated under reduced pressure. This resulted in 3-chloro-2-{[1,2]thiazolo[4,5-b]pyridin-7-yl}(6,6,7,7-2H4)-5H- pyrazolo[1,5-a]pyrazin-4-one (700 mg, 83.81%) as a yellow solid. LC-MS: (M+H)⁺ found: 309.90.

To a stirred solution of 3-chloro-2-{[1,2]thiazolo[4,5-b]pyridin-7-yl}(6,6,7,7-2H4)-5H- pyrazolo[1,5-a]pyrazin-4-one (460 mg, 1.49 mmol, 1.00 equiv) in DMF (7.00 mL) was added Cs₂CO₃ (968 mg, 2.97 mmol, 2.00 equiv), 3-chloro-2-methoxyaniline (234 mg, 1.49 mmol, 1.00 equiv) and EPhos Pd G4 (245 mg, 0.28 mmol, 0.20 equiv), the mixture was stirred for 2 h at 50 °C under argon atmosphere. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH₂Cl₂/MeOH (94:6) to afford crude product, The crude product (400 mg) was purified by Prep-HPLC with the following conditions (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water (0.05% TEA), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 32% B to 62% B in 7 min, 62% B; Wave Length: 254 nm; RT1(min): 6.5) to afford 3-((3-chloro- 2-methoxyphenyl)amino)-2-(isothiazolo[4,5-b]pyridin-7-yl)-6,7-dihydropyrazolo[1,5- a]pyrazin-4(5H)-one-6,6,7,7-d4 (191.8 mg, 29.40%) as a light yellow solid. LC-MS: (M+H)⁺ found: 431.20. ¹H NMR (400 MHz, DMSO-d6): δ 9.31 (s, 1H), 8.81 (d, 1H), 8.38 (s, 1H), 7.73 (d, 1H), 7.53 (s, 1H), 6.81 – 6.74 (m, 2H), 6.21 – 6.18 (m, 1H), 3.95 (s, 3H). Example 53.3-{[2-(difluoromethoxy)-3-fluorophenyl]amino}-2-{thieno[3,2-b]pyridin-7- yl}-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (compound 282)

To a stirred mixture of 3-chloro-4-oxo-5H,6H,7H-pyrazolo[1,5-a]pyrazin-2-ylboronic acid (150 mg, 0.70 mmol, 1.00 equiv) and 7-chlorothieno[3,2-b]pyridine (236 mg, 1.40 mmol, 2.00 equiv) in 1,4-dioxane (4.00 mL) and H₂O (0.80 mL) were added 2nd Generation XPhos Precatalyst (54 mg, 0.07 mmol, 0.10 equiv) and Na₂CO₃ (221 mg, 2.10 mmol, 3.00 equiv) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 2 h at 50 °C under argon atmosphere. The reaction was monitored by LCMS. LCMS showed the reaction was completed. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH₂Cl₂ / MeOH (10:1) to afford 3-chloro-2-{thieno[3,2-b]pyridin-7-yl}-5H,6H,7H- pyrazolo[1,5-a]pyrazin-4-one (70 mg, 32.98%) as an off-white solid. LC-MS: (M+H)⁺ found: 304.85.

To a stirred solution of 3-chloro-2-{thieno[3,2-b]pyridin-7-yl}-5H,6H,7H-pyrazolo[1,5- a]pyrazin-4-one (60 mg, 0.20 mmol, 1.00 equiv) in DMF (2.00 mL) was added EPhos Pd G4 (36 mg, 0.04 mmol, 0.20 equiv) and Cs₂CO₃ (128 mg, 0.40 mmol, 2.00 equiv) in portions at room temperature under nitrogen atmosphere. To the above mixture was added 2-(difluoromethoxy)-3-fluoroaniline (105 mg, 0.60 mmol, 3.00 equiv) dropwise at room temperature. The resulting mixture was stirred for additional 2h at 50 °C under nitrogen atmosphere. The reaction was monitored by LCMS. LCMS showed the reaction was completed. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH₂Cl₂/MeOH (10:1) to afford 3-{[2-(difluoromethoxy)-3-fluorophenyl]amino}-2-{thieno[3,2-b]pyridin-7-yl}- 5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (14.8 mg, 16.07%) as an off-white solid. LC-MS: (M+H)⁺ found: 445.90. ¹H NMR (400 MHz, DMSO-d₆) δ 8.58 (d, 1H), 8.38 (s, 1H), 8.19 (d, 1H), 7.69 (d, 1H), 7.64 - 7.57 (m, 2H), 7.20 (t, 1H), 6.90 - 6.85(m, 1H), 6.66 - 6.61(m, 1H), 6.13 (d, 1H), 4.51 (t, 2H), 3.72 (s, 2H). Example 54.3-{[2-(difluoromethoxy)-3-fluorophenyl]amino}-2-{[1,2]thiazolo[4,5- b]pyridin-7-yl}-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (compound 281)

To a stirred mixture of 3-chloro-2-{[1,2]thiazolo[4,5-b]pyridin-7-yl}-5H,6H,7H- pyrazolo[1,5-a]pyrazin-4-one (80 mg, 0.26 mmol, 1.00 equiv) and 2-(difluoromethoxy)-3- fluoroaniline (139 mg, 0.78 mmol, 3.00 equiv) in DMF (2.00 mL) were added Cs₂CO₃ (171 mg, 0.52 mmol, 2.00 equiv) and Ephos Pd G4 (48 mg, 0.05 mmol, 0.20 equiv) dropwise at room temperature. The resulting mixture was stirred for 2 h at 50 degrees C under argon atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH₂Cl₂/MeOH (20:1) to afford 50 mg crude product. The crude product was dissolved in MeCN (2 mL). The precipitated solids were collected by filtration and washed with MeCN (1 mL) to obtain 3- {[2-(difluoromethoxy)-3-fluorophenyl]amino}-2-{[1,2]thiazolo[4,5-b]pyridin-7-yl}- 5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (29.8 mg, 25.23%) as a white solid. LC-MS: (M+H)⁺ found: 447.20. ¹H NMR (300 MHz, DMSO-d6) δ 9.32 (s, 1H), 8.79 (d, 1H), 8.42 (d, 1H), 7.83 (d, 1H), 7.71 (s, 1H), 7.23 (t, 1H), 7.02 - 6.87 (m, 1H), 6.72 - 6.68 (m, 1H), 6.20 (d, 1H), 4.56 (t, 2H), 3.73 (s, 2H). Example 55.3-[(3-chloro-2-methoxyphenyl)amino]-2-[3-(difluoromethyl)pyridin-4-yl]- 5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (compound 285)

To a stirred solution of 4-chloropyridine-3-carbaldehyde (300 mg, 2.12 mmol, 1.00 equiv) in DCM (20.00 mL) was added DAST (1.71 g, 10.60 mmol, 5.00 equiv) dropwise at -78 degrees C under argon atmosphere. The mixture was stirred for overnight from -78 degrees C to room temperature. The reaction was monitored by TLC. The resulting mixture was extracted with CH₂Cl₂ (3x20 mL). The combined organic layers were dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure at 0 °C. The crude product was used in the next step directly without further purification.

To a stirred solution of 3-chloro-4-oxo-5H,6H,7H-pyrazolo[1,5-a] pyrazin-2-ylboronic acid (200 mg, 0.93 mmol, 1.00 equiv) in 1,4-dioxane (5.00 mL) was added Na₂CO₃ (295 mg, 2.79 mmol, 3.00 equiv) in H₂O (1.00 mL), Xphos Pd G2 (73 mg, 0.09 mmol, 0.10 equiv) and 4-chloro-3-(difluoromethyl)pyridine (304 mg, 1.86 mmol, 2.00 equiv) at room temperature. The mixture was stirred for overnight at 50 degrees C under argon atmosphere. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH₂Cl₂/MeOH (97:3) to afford 3-chloro-2-[3-(difluoromethyl)pyridin-4-yl]- 5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (220 mg, 65.84%) as a yellow solid. LC-MS: (M+H)⁺ found: 298.85.

To a stirred solution of 3-chloro-2-[3-(difluoromethyl)pyridin-4-yl]-5H,6H,7H- pyrazolo[1,5-a]pyrazin-4-one (100 mg, 0.28 mmol, 1.00 equiv) in DMF (3.00 mL) was added Cs₂CO₃ (181 mg, 0.56 mmol, 2.00 equiv) , EPhos Pd G4 (26 mg, 0.02 mmol, 0.10 equiv) and 3-chloro-2-methoxyaniline (44 mg, 0.28 mmol, 1.00 equiv) at room temperature. The mixture was stirred for overnight at 50 degrees C under argon atmosphere. The reaction was monitored by LCMS. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with CH₂Cl₂/MeOH (98:2) to afford crude product. The crude product (70 mg) was purified by Prep-HPLC with the following conditions (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water (10 mmol/L NH₄HCO₃), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 32% B to 47% B in 8 min, 47% B; Wave Length: 254/220 nm; RT1(min): 8) to afford 3-[(3-chloro-2-methoxyphenyl)amino]-2-[3- (difluoromethyl)pyridin-4-yl]-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (15.6 mg, 13.35%) as a white solid. LC-MS: (M+H)⁺ found 420.20. ¹H NMR (400 MHz, DMSO-d6) δ 8.91 (s, 1H), 8.67 (d, 1H), 8.33 (s, 1H), 7.63 - 7.34 (m, 3H), 6.68 - 6.63 (m, 2H), 6.18 - 6.15 (m, 1H), 4.43 (t, 2H), 3.80 (s, 3H), 3.69 (t, 2H). Example 56.3-[(3-chloro-2-methoxyphenyl)amino]-2-[2-(difluoromethyl)pyridin-4-yl]- 5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (compound 287)

To a stirred solution of 4-bromopyridine-2-carbaldehyde (200 mg, 1.07 mmol, 1.00 equiv) in DCM (11.00 mL) was added DAST (347 mg, 2.15 mmol, 2.00 equiv) in portions at - 78 °C under argon atmosphere. The mixture was stirred for overnight from -78 °C to room temperature. The reaction was monitored by TLC. The reaction was quenched with sat. sodium sulfite at 0 degrees C. The resulting mixture was extracted with 2-methoxy-2- methylpropane (3x10 mL). The combined organic layers were dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure at 0 °C. The crude product was used in the next step directly without further purification.

To a stirred solution of 3-chloro-4-oxo-5H,6H,7H-pyrazolo[1,5-a]pyrazin-2-ylboronic acid (100 mg, 0.46 mmol, 1.00 equiv) in 1,4-dioxane (5.00 mL) was added Na₂CO₃ (148 mg, 1.39 mmol, 3.00 equiv) in H₂O (1.00 mL) , XPhos Pd G2 (37 mg, 0.05 mmol, 0.10 equiv) and 4-bromo-2-(difluoromethyl)pyridine (193 mg, 0.93 mmol, 2.00 equiv) at room temperature. The mixture was stirred for 2 h at 50 °C under argon atmosphere. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH₂Cl₂/MeOH (97:3) to afford 3-chloro-2-[2-(difluoromethyl)pyridin-4-yl]-5H,6H,7H-pyrazolo[1,5- a]pyrazin-4-one (75 mg, 54.09%) as a yellow solid. LC-MS: (M+H)⁺ found: 299.20.

To a stirred solution of 3-chloro-2-[2-(difluoromethyl)pyridin-4-yl]-5H,6H,7H- pyrazolo[1,5-a]pyrazin-4-one (90 mg, 0.30 mmol, 1.00 equiv) in DMF (3.00 mL) was added Cs₂CO₃ (197 mg, 0.60 mmol, 2.00 equiv), Ephos Pd G4 (17 mg, 0.03 mmol, 0.10 equiv) and 3-chloro-2-methoxyaniline (47 mg, 0.30 mmol, 1.00 equiv) at room temperature. The mixture was stirred for 2 h at 50 °C under argon atmosphere. The reaction was monitored by LCMS. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with CH₂Cl₂/MeOH (98:2) to afford crude product. The crude product (70 mg) was purified by Prep-HPLC with the following conditions (Column: YMC-Actus Triart C18 ExRS, 30*150 mm, 5μm; Mobile Phase A: Water (10 mmol/L NH₄HCO₃), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 35% B to 53% B in 10 min, 53% B; Wave Length: 220/254 nm; RT1(min): 8.00) to afford 3-[(3-chloro-2-methoxyphenyl)amino]-2-[2-(difluoromethyl)pyridin-4-yl]- 5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (10.8 mg, 8.51%) as a white solid. LC-MS: (M+H)⁺ found: 420.20. ¹H NMR (400 MHz, DMSO-d6) δ 8.66 (d, 1H), 8.33 (s, 1H), 8.01 (s, 1H), 7.83 (d, 1H), 7.40 (s, 1H), 6.92 (t, 1H), 6.78 - 6.71 (m, 2H), 6.17 - 6.13 (m, 1H), 4.45 (t, 2H), 3.88 (s, 3H), 3.70 - 3.65 (m, 2H). Example 57.3-[(3-chloro-2-methoxyphenyl)amino]-2-(2-fluoropyridin-4-yl)-5H,6H,7H- pyrazolo[1,5-a]pyrazin-4-one (compound 286)

To a stirred mixture of 3-chloro-4-oxo-5H,6H,7H-pyrazolo[1,5-a]pyrazin-2-ylboronic acid (100 mg, 0.46 mmol, 1.00 equiv) and 4-bromo-2-fluoropyridine (98 mg, 0.55 mmol, 1.20 equiv) in 1,4-dioxane (5.00 mL) and H₂O (1.00 mL) were added 2nd Generation XPhos Precatalyst (39 mg, 0.05 mmol, 0.10 equiv) and Na₂CO₃ (147 mg, 1.38 mmol, 3.00 equiv) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 2h at 50 °C under argon atmosphere. The reaction was monitored by LCMS. LCMS showed the reaction was completed. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH₂Cl₂/MeOH (10:1) to afford 3-chloro-2-(2-fluoropyridin-4-yl)-5H,6H,7H- pyrazolo[1,5-a]pyrazin-4-one (65 mg, 52.51%) as an off-white solid. LC-MS: (M+H)⁺ found: 266.90.

To a stirred solution of 3-chloro-2-(2-fluoropyridin-4-yl)-5H,6H,7H-pyrazolo[1,5- a]pyrazin-4-one (60 mg, 0.23 mmol, 1.00 equiv) in DMF (2.00 mL) was added EPhos Pd G4 (41 mg, 0.04 mmol, 0.20 equiv) and Cs₂CO₃ (146 mg, 0.46 mmol, 2.00 equiv) at room temperature under nitrogen atmosphere. To the above mixture was added 3-chloro-2- methoxyaniline (35 mg, 0.23 mmol, 1.00 equiv) at room temperature. The resulting mixture was stirred for additional 5h at 50 °C. LCMS showed the reaction was completed. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH₂Cl₂/MeOH (10:1) to afford the crude product. The crude product (45 mg) was purified by Prep-HPLC with the following conditions (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water(10 mmol/L NH₄HCO₃), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 32% B to 56% B in 8 min, 56% B; Wave Length: 254/220 nm; RT1(min): 7.5) to afford 3- [(3-chloro-2-methoxyphenyl)amino]-2-(2-fluoropyridin-4-yl)-5H,6H,7H-pyrazolo[1,5- a]pyrazin-4-one (12.2 mg, 13.95%) as a white solid. LC-MS: (M+H)⁺ found: 388.20. ¹H NMR (300 MHz, DMSO-d₆) δ 8.34 (s, 1H), 8.24 (d, 1H), 7.67 (d, 1H), 7.39 (d, 2H), 6.84 - 6.71 (m, 2H), 6.19 - 6.15 (m, 1H), 4.43 (t, 2H), 3.89 (s, 3H), 3.67 (s, 2H). Example 58.2-[6-(tert-butylamino)-7-methoxyquinolin-4-yl]-3-[(3-chloro-2- methoxyphenyl)amino]-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (compound 296)

To a mixture of 2-methoxy-4-nitroaniline (3.00 g, 17.84 mmol, 1.00 equiv) and Boc₂O (20.00 mL) was added bis(trifluoromethanesulfonyloxy) scandio trifluoromethanesulfonate (439 mg, 0.89 mmol, 0.05 equiv) at room temperature. The resulting mixture was stirred for overnight at 50 °C. Desired product could be detected by LCMS. The resulting mixture was purified by silica gel column chromatography, eluted with PE/EA (10:1) to afford N-tert-butyl-2-methoxy-4-nitroaniline (720 mg, 18.00%) as a yellow solid. LC-MS: (M+H)⁺ found: 168.90.

To a stirred solution of N-tert-butyl-2-methoxy-4-nitroaniline (1.53 g, 6.82 mmol, 1.00 equiv) in MeOH (20.00 mL) was added 10 % Pd/C (300 mg, 20 w/w%) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 1h at room temperature under hydrogen atmosphere. LCMS showed the reaction was completed. The resulting mixture was filtered to afford N1-tert-butyl-2-methoxybenzene-1,4-diamine (1.08 g, 83.07%) as a yellow oil. LC-MS: (M+H)+ found: 195.00.

To a stirred solution of N1-tert-butyl-2-methoxybenzene-1,4-diamine (1.08 g, 5.54 mmol, 1.00 equiv) in DMF (10.00 mL) was added 5-(methoxymethylidene)-2,2-dimethyl-1,3- dioxane-4,6-dione (1.03 g, 5.54 mmol, 1.00 equiv) at room temperature. The mixture was stirred at 80 °C under nitrogen atmosphere for 1h. The reaction was monitored by LCMS. LCMS showed the reaction was completed. The residue was diluted with MeOH (10 mL). The resulting mixture was filtered, the filter cake was washed with MeOH (3x10.00 mL). The filtrate was concentrated under reduced pressure to afford 5-[(1E)-{[4-( tert- butylamino)-3- methoxyphenyl] imino} methyl]-2,2-dimethyl-1,3-dioxane-4,6-dione) (1.90 g, 98.29%) as a yellow solid. LC-MS: (M+H)⁺ found: 349.10.

Into hot (230 °C) diphenyl ether (100.00 mL) was added 5-[(1E)-{[4-(tert-butylamino)-3- methoxyphenyl]imino}methyl]-2,2-dimethyl-1,3-dioxane-4,6-dione (2.00 g, 5.74 mmol, 1.00 equiv). The resulting mixture was stirred for 5 min at 230 °C. The reaction was monitored by LCMS. The mixture was allowed to cool down to 30 °C. The resulting mixture was diluted with n-hexane (200 mL). The precipitated solids were collected by filtration and washed with hexane (50.00 mL) to give 6-(tert-butylamino)-7- methoxyquinolin-4-ol (1.50 g, 95.48%) as a brown oil. LC-MS: (M+H)⁺ found: 247.00.

To a stirred solution of 6-(tert-butylamino)-7-methoxyquinolin-4-ol (1.40 g, 5.68 mmol, 1.00 equiv) in DMF (40.00 mL) was added PBr3 (1.69 g, 6.25 mmol, 1.10 equiv) dropwise at 0 degrees C under N₂ atmosphere. The resulting mixture was stirred for 1 h at room temperature under nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was extracted with EA (3 x 100 mL). The combined organic layers were washed with saturated salt solution (3x10 mL), dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with EA/PE (20%) to give to give 4-bromo- N-tert-butyl-7-methoxyquinolin-6-amine (200 mg, 10.81%) as a white solid. LC-MS: (M+H)⁺ found: 310.85.

To a stirred mixture of 4-bromo-N-tert-butyl-7-methoxyquinolin-6-amine (130 mg, 0.42 mmol, 1.00 equiv) and 3-chloro-4-oxo-5H,6H,7H-pyrazolo[1,5-a]pyrazin-2-ylboronic acid (108 mg, 0.50 mmol, 1.20 equiv) in 1,4-dioxane (3.50 mL) and H₂O (0.70 mL) was added 2nd Generation XPhos Precatalyst (33 mg, 0.04 mmol, 0.10 equiv) and Na₂CO₃ (133 mg, 1.26 mmol, 3.00 equiv) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 1h at 50 °C under argon atmosphere. The reaction was monitored by LCMS. LCMS showed the reaction was completed. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH₂Cl₂/MeOH (10:1) to afford 2-[6-(tert-butylamino)-7- methoxyquinolin-4-yl]-3-chloro-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (130 mg, 77.32%) as an off-white solid. LC-MS: (M+H)⁺ found: 400.00.

To a stirred solution of 2-[6-(tert-butylamino)-7-methoxyquinolin-4-yl]-3-chloro- 5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (100 mg, 0.25 mmol, 1.00 equiv) and 3-chloro- 2-methoxyaniline (39 mg, 0.25 mmol, 1.00 equiv) in DMF (2.00 mL) were added Cs₂CO₃ (163 mg, 0.50 mmol, 2.00 equiv) and EPhos Pd G4 (23 mg, 0.02 mmol, 0.10 equiv) dropwise at room temperature under argon atmosphere. The resulting mixture was stirred for 12 h at 50°C under argon atmosphere. The reaction was monitored by LCMS. The crude product was purified by Prep-HPLC with the following conditions (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water (10 mmol/L NH₄HCO₃), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 37% B to 67% B in 7 min; Wave Length: 254 nm; RT1(min): 6.5) to afford 2-[6-(tert-butylamino)-7-methoxyquinolin-4- yl]-3-[(3-chloro-2-methoxyphenyl)amino]-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (18.9 mg, 14.46%) as a solid. LC-MS: (M+H)⁺ found: 521.00. ¹H NMR (400 MHz, DMSO-d6) δ 8.38 (d, 1H), 8.32 (s, 1H), 7.72 (s, 1H), 7.32 (d, 2H), 7.24 (s, 1H),6.73 - 6.51 (m, 2H), 6.60 (d, 1H), 4.83 (s, 1H),4.42 (d, 2H), 3.96 (s, 3H), 3.78 (s, 3H), 3.71 (s, 2H), 1.56 (s, 9H). Example 59.3-[(3-fluoro-2-methoxyphenyl)amino]-2-{1H-pyrazolo[4,3-b]pyridin-7-yl}- 5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (compound 274)

To a stirred solution of 7-bromo-1H-pyrazolo[4,3-b]pyridine (2.00 g, 10.10 mmol, 1.00 equiv) and Cs₂CO₃ (6.58 g, 20.20 mmol, 2.00 equiv) in dimethylformamide (20.00 mL) was added PMBCl (2.37 g, 15.15 mmol, 1.50 equiv) dropwise at 0 degrees C under N₂ atmosphere. The resulting mixture was stirred for 1 h at room temperature under nitrogen atmosphere. The reaction was monitored by LCMS. Desired product could be detected by LCMS. The resulting mixture was extracted with EA (3x 50 mL). The combined organic layers were washed with saturated salt solution (3x 50 mL), dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with EA/PE (20%) to give 7-bromo- 1-[(4-methoxyphenyl)methyl]pyrazolo[4,3-b]pyridine (1.20 g, 33.61%) as a white solid. LC-MS: (M+H)⁺ found: 319.80.

To a solution of 7-bromo-1-[(4-methoxyphenyl)methyl]pyrazolo[4,3-b]pyridine (1.00 g, 3.14 mmol, 1.00 equiv) and 3-chloro-4-oxo-5H,6H,7H-pyrazolo[1,5-a]pyrazin-2- ylboronic acid (0.81 g, 3.77 mmol, 1.20 equiv) in 1,4-dioxane (20.00 mL) and XPhos Pd G3 (0.27 g, 0.31 mmol, 0.10 equiv) were added Na₂CO₃ (1.00 g, 9.42 mmol, 3.00 equiv) in H₂O (4.00 mL). After stirring for 20 min at 50 degrees C under a nitrogen atmosphere, the resulting mixture was concentrated under reduced pressure. Desired product could be detected by LCMS. The mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with EA/PE (20%) to afford 3- chloro-2-{1-[(4-methoxyphenyl)methyl]pyrazolo[4,3-b]pyridin-7-yl}-5H,6H,7H- pyrazolo[1,5-a]pyrazin-4-one (600 mg, 44.36%) as a white solid. LC-MS: (M+H)⁺ found: 408.95.

To a stirred solution of 3-chloro-2-{1-[(4-methoxyphenyl)methyl]pyrazolo[4,3-b]pyridin- 7-yl}-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (100 mg, 0.24 mmol, 1.00 equiv) and 3- fluoro-2-methoxyaniline (103 mg, 0.72 mmol, 3.00 equiv) in DMF (2.00 mL) were added Ephos Pd G4 (22 mg, 0.02 mmol, 0.10 equiv) and Cs₂CO₃ (159 mg, 0.48 mmol, 2.00 equiv) dropwise at room temperature under argon atmosphere. The resulting mixture was stirred for 1h at room temperature under argon atmosphere. The reaction was monitored by LCMS. Desired product could be detected by LCMS. The mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with MeOH/DCM (3%) to afford 3-[(3-fluoro-2-methoxyphenyl)amino]-2-{1-[(4- methoxyphenyl)methyl]pyrazolo[4,3-b]pyridin-7-yl}-5H,6H,7H-pyrazolo[1,5-a]pyrazin- 4-one (90 mg, 64.49%) as a yellow green oil. LC-MS: (M+H)⁺ found: 514.10.

Into TFA (2.00 mL) was added 3-[(3-fluoro-2-methoxyphenyl)amino]-2-{1-[(4- methoxyphenyl)methyl]pyrazolo[4,3-b]pyridin-7-yl}-5H,6H,7H-pyrazolo[1,5-a]pyrazin- 4-one (100 mg, 0.19 mmol, 1.00 equiv) at room temperature. The resulting mixture was stirred for 3 h at 70 °C. The reaction was monitored by LCMS. The resulting mixture was concentrated under vacuum. The crude product was purified by Prep-HPLC with the following conditions (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water(10 mmol/L NH₄HCO₃), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 18% B to 48% B in 7 min; Wave Length: 254 nm; RT1(min): 6.5) to afford 3-[(3-fluoro-2-methoxyphenyl)amino]-2-{1H-pyrazolo[4,3-b]pyridin-7-yl}- 5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (16.7 mg, 21.74%) as a white solid. LC-MS: (M+H)⁺ found: 394.25. ¹H NMR (300 MHz, DMSO-d₆) δ 13.25 (s, 1H), 8.44 (d, 1H), 8.35 (d, 1H), 7.46 (d, 1H), 7.37 (s, 1H), 6.72 - 6.52 (m, 2H), 6.03 (d, 1H), 4.53 (d, 1H), 3.94 (s, 3H), 3.72 (s, 2H). Example 60.3-[(3-chloro-2-methoxyphenyl)amino]-2-{2-methoxypyrido[3,2- d]pyrimidin-8-yl}-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (compound 319)

To a stirred mixture of 8-bromo-2-methoxypyrido[3,2-d]pyrimidine (260 mg, 1.08 mmol, 1.00 equiv) and 4,4,5,5-tetramethyl-2-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2- dioxaborolane (412 mg, 1.62 mmol, 1.50 equiv) in 1,4-dioxane (2.00 mL) was added Pd(dppf)Cl₂CH₂Cl₂ (88 mg, 0.11 mmol, 0.10 equiv) and KOAc (319 mg, 3.25 mmol, 3.00 equiv) in portions at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 1h at 100 degrees C under argon atmosphere. The reaction was monitored by LCMS. LCMS showed the reaction was completed. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in water, 0% to 70% gradient in 30 min; detector, UV 254 nm. to afford 2- methoxypyrido[3,2-d]pyrimidin-8-ylboronic acid (170 mg, 72.75%) as a white solid. LC-MS: (M+H)⁺ found: 206.20.

To a solution of 2-methoxypyrido[3,2-d]pyrimidin-8-ylboronic acid (79 mg, 0.39 mmol, 1.80 equiv) in 1,4-dioxane (3.00 mL) and H₂O (0.50 mL) were added 2-bromo-3-[(3- chloro-2-methoxyphenyl)amino]-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (80 mg, 0.22 mmol, 1.00 equiv), Na₂CO₃ (46 mg, 0.43 mmol, 2.00 equiv), XPhos Pd G2 (18 mg, 0.02 mmol, 0.10 equiv). The reaction was stirred for 2 h at 50 °C under a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with MeOH/DCM (3%) to afford crude product (80 mg). The crude product was purified by Prep-HPLC with the following conditions (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water(10 mmol/L NH₄HCO₃), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 21% B to 51% B in 7 min, 51% B; Wave Length: 254 nm; RT1(min): 6.1) to afford 3-[(3- chloro-2-methoxyphenyl)amino]-2-{2-methoxypyrido[3,2-d]pyrimidin-8-yl}-5H,6H,7H- pyrazolo[1,5-a]pyrazin-4-one (37.8 mg, 38.63%) as a yellow solid. LC-MS: (M+H)⁺ found: 452.20. ¹H NMR (300 MHz, DMSO-d6) δ 9.59 (s, 1H), 8.97 (d, 1H), 8.27 (s, 1H), 8.05 (d, 1H), 7.74 (s, 1H), 6.68 – 6.58 (m, 2H), 6.37-6.34 (m, 1H), 4.48 (t, 2H), 4.11 (s, 3H), 3.74 (s, 2H), 3.49 (s, 3H). Example 61.2-(6-amino-7-methoxyquinolin-4-yl)-3-[(3-fluoro-2- methoxyphenyl)amino]-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one; formic acid (compound 316)

A mixture of 3-methoxy-4-nitroaniline (5.00 g, 29.74 mmol, 1.00 equiv) and 5- (methoxymethylidene)-2,2-dimethyl-1,3-dioxane-4,6-dione (6.64 g, 35.67 mmol, 1.20 equiv) in DMF (50.00 mL) was stirred for 1h at 80℃ under nitrogen atmosphere. The mixture was allowed to cool down to RT. The product was precipitated by the addition of MeOH (50 mL). The precipitated solids were collected by filtration and washed with MeOH (20 mL). This resulted in 5-[(1E)-[(3-methoxy-4-nitrophenyl)imino]methyl]-2,2- dimethyl-1,3-dioxane-4,6-dione (8.92 g, 93.08%) as a yellow solid. LC-MS: (M+H)⁺ found: 323.95.

To a stirred solution of diphenyl-ether (80.00 mL) was added 5-[(1E)-[(3-methoxy-4- nitrophenyl)imino]methyl]-2,2-dimethyl-1,3-dioxane-4,6-dione (1.60 g, 4.97 mmol, 1.00 equiv) dropwise at 230°C for 10 min. The product was precipitated by the addition of hexane (200 mL). The precipitated solids were collected by filtration and washed with hexane (100 mL) to afford 7-methoxy-6-nitroquinolin-4-ol (0.90 g, 82.33%) as a brown solid. LC-MS: (M+H)⁺ found: 220.90.

To a stirred solution of 7-methoxy-6-nitroquinolin-4-ol (0.95 g, 4.31 mmol, 1.00 equiv) in DMF (28.00 mL) were added PBr₃ (1.28 g, 4.75 mmol, 1.10 equiv) dropwise at 0°C under nitrogen atmosphere. The resulting mixture was stirred for 30 min at room temperature under nitrogen atmosphere. The reaction was quenched by the addition of saturated aqueous Na₂CO₃. The resulting mixture was extracted with EA (50ml x 3). The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with DCM/MeOH=30:1 to afford 4-bromo-7-methoxy-6- nitroquinoline (0.90 g, 73.69%) as a yellow solid. LC-MS: (M+H)⁺ found: 282.97

To a stirred mixture of 4-bromo-7-methoxy-6-nitroquinoline (300 mg, 1.06 mmol, 1.00 equiv) and 3-chloro-4-oxo-5H,6H,7H-pyrazolo[1,5-a]pyrazin-2-ylboronic acid (273 mg, 1.27 mmol, 1.20 equiv) in 1,4-dioxane (10.00 mL) and H₂O (2.00 mL) were added 2nd Generation XPhos Precatalyst (83 mg, 0.11 mmol, 0.10 equiv) and Na₂CO₃ (337 mg, 3.18 mmol, 3.00 equiv) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 1h at 50 degrees C under argon atmosphere. The reaction was monitored by LCMS. LCMS showed the reaction was completed. The resulting mixture was concentrated under reduced pressure. The resulting mixture was washed with 2 x 5 mL of water. The precipitated solids were collected by filtration and washed with acetonitrile (3 x 3 mL). The resulting mixture was concentrated under reduced pressure to obtain 3- chloro-2-(7-methoxy-6-nitroquinolin-4-yl)-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (310 mg, 78.27%) as a yellow solid. LC-MS: (M+H)⁺ found: 374.10.

To a stirred solution of 3-chloro-2-(7-methoxy-6-nitroquinolin-4-yl)-5H,6H,7H- pyrazolo[1,5-a]pyrazin-4-one (280 mg, 0.75 mmol, 1.00 equiv) in DMF (5.00 mL) was added Cs₂CO₃ (488 mg, 1.49 mmol, 2.00 equiv) and EPhos Pd G4 (137 mg, 0.15 mmol, 0.20 equiv) at room temperature under nitrogen atmosphere. To the above mixture was added 3-fluoro-2-methoxyaniline (317 mg, 2.25 mmol, 3.00 equiv) at room temperature. The resulting mixture was stirred for additional 3h at 50 °C under nitrogen atmosphere. LCMS showed the reaction was completed. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH₂Cl₂ / MeOH (10:1) to afford 3-[(3-fluoro-2-methoxyphenyl)amino]-2-(7- methoxy-6-nitroquinolin-4-yl)-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (330 mg, 92.07%) as a yellow solid. LC-MS: (M+H)⁺ found: 479.15.

To a stirred solution of 3-[(3-fluoro-2-methoxyphenyl)amino]-2-(7-methoxy-6- nitroquinolin-4-yl)-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (100 mg, 0.21 mmol, 1.00 equiv) in EtOH (2.50 mL) and H₂O (0.50 mL) was added Fe (70 mg, 1.26 mmol, 6.00 equiv) and NH₄Cl (67 mg, 1.26 mmol, 6.00 equiv) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 1h at 80 degrees C under nitrogen atmosphere. LCMS showed the reaction was completed. The resulting mixture was filtered, the filter cake was washed with MeOH (3x30 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH₂Cl₂ / MeOH (10:1) to afford crude product. The crude product (70 mg) was purified by Prep-HPLC with the following conditions (Column: Xselect CSH C18 OBD Column 30*150mm 5μm, n; Mobile Phase A: Water (0.1%FA), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 8% B to 27% B in 8 min, 27% B; Wave Length: 254/220 nm; RT1(min): 7.5) to afford 2-(6-amino-7-methoxyquinolin-4-yl)-3-[(3-fluoro-2- methoxyphenyl)amino]-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one; formic acid (37.7 mg, 36.00%) as a yellow solid. LC-MS: (M+H)⁺ found: 449.25. ¹H NMR (400 MHz, DMSO-d6) δ 8.40 (d, 1H), 8.33 (s, 1H), 8.15 (s, 1H), 7.32 - 7.25 (m, 2H), 7.20 (d, 2H), 6.45 - 6.31 (m, 2H), 5.92 (d, 1H), 5.37 (s, 2H), 4.43 (t, 2H), 3.93 (s, 3H), 3.75(s, 3H), 3.74 - 3.69 (m, 2H). Example 62. N-(4-{3-[(3-chloro-2-methoxyphenyl)amino]-4-oxo-5H,6H,7H- pyrazolo[1,5-a]pyrazin-2-yl}-7-methoxyquinolin-6-yl)prop-2-enamide (compound 320)

To a stirred solution of 3-chloro-2-(7-methoxy-6-nitroquinolin-4-yl)-5H,6H,7H- pyrazolo[1,5-a] pyrazin-4-one (300 mg, 0.80 mmol, 1.00 equiv) in DMF (6 mL) were added Cs₂CO₃ (523 mg, 1.60 mmol, 2.00 equiv) and EPhos Pd G4 (147 mg, 0.16 mmol, 0.20 equiv) at room temperature under nitrogen atmosphere. To the above mixture was added 3-chloro-2-methoxyaniline (126 mg, 0.80 mmol, 1.00 equiv) at room temperature. The resulting mixture was stirred for additional 3h at 50 °C under nitrogen atmosphere. LCMS showed the reaction was completed. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH₂Cl₂/MeOH (10:1) to afford 3-[(3-chloro-2-methoxyphenyl)amino]-2-(7- methoxy-6-nitroquinolin-4-yl)-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (160 mg, 40.28%) as a yellow solid. LC-MS: (M+H)⁺ found: 495.1.

To a stirred mixture of 3-[(3-chloro-2-methoxyphenyl)amino]-2-(7-methoxy-6- nitroquinolin-4-yl)-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (150 mg, 0.30 mmol, 1.00 equiv) and Fe (101 mg, 1.82 mmol, 6.00 equiv) in EtOH (3.00 mL) and H₂O (0.60 mL) were added NH₄Cl (97 mg, 1.82 mmol, 6.00 equiv) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 1h at 80 °C under nitrogen atmosphere. LCMS showed the reaction was completed. The resulting mixture was filtered, the filter cake was washed with MeOH (3x 20 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH₂Cl₂/MeOH (10:1) to afford 2-(6-amino-7-methoxyquinolin-4-yl)-3-[(3-chloro-2- methoxyphenyl)amino]-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (140 mg, 99.35%) as an off-white solid. LC-MS: (M+H)⁺ found: 465.00.

To a stirred solution of 2-(6-amino-7-methoxyquinolin-4-yl)-3-[(3-chloro-2- methoxyphenyl)amino]-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (70 mg, 0.15 mmol, 1.00 equiv) in 4-methylmorpholine (0.50 mL) and THF (2.00 mL) was added acryloyl chloride (16 mg, 0.17 mmol, 1.15 equiv) dropwise at 0 °C under nitrogen atmosphere. The resulting mixture was stirred for 3 h at 0°C under nitrogen atmosphere. LCMS showed the reaction was completed. The reaction was quenched with water at 0°C. The resulting mixture was concentrated under reduced pressure. The crude product (50 mg) was purified by Prep- HPLC with the following conditions (Column: XBridge Shield RP18 OBD Column, 30*150 mm, 5μm; Mobile Phase A: Water(10 mmol/L NH₄HCO₃), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 21% B to 44% B in 10 min, 44% B; Wave Length: 220/254 nm; RT1(min): 10.17) to afford N-(4-{3-[(3-chloro-2-methoxyphenyl)amino]-4- oxo-5H,6H,7H-pyrazolo[1,5-a]pyrazin-2-yl}-7-methoxyquinolin-6-yl)prop-2-enamide (10.8 mg, 13.74%) as an off-white solid. LC-MS: (M+H)⁺ found: 518.95. ¹H NMR (400 MHz, DMSO-d6) δ 9.63 (s, 1H), 9.03 (s, 1H), 8.72 (d, 1H), 8.38 (d, 1H), 7.45 (d, 2H), 7.23 (s, 1H), 6.81-6.73 (m,1H), 6.55-6.53 (m,1H), 6.46 (t, 1H), 6.31-6.26 (m,1H), 6.08-6.05 (m,1H), 5.78-5.75 (m,1H), 4.55 (t, 2H), 4.02 (s, 3H), 3.75-3.73 (m, 2H), 3.64 (s, 3H). Example 63. N-(4-{3-[(3-fluoro-2-methoxyphenyl)amino]-4-oxo-5H,6H,7H- pyrazolo[1,5-a]pyrazin-2-yl}-7-methoxyquinolin-6-yl)prop-2-enamide (compound 290)

To a stirred solution of 2-(6-amino-7-methoxyquinolin-4-yl)-3-[(3-fluoro-2- methoxyphenyl)amino]-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (100 mg, 0.22 mmol, 1.00 equiv) in DMF (2.50 mL) and 4-methylmorpholine (0.50 mL) was added acryloyl chloride (23 mg, 0.25 mmol, 1.15 equiv) dropwise at 0°C under nitrogen atmosphere. The resulting mixture was stirred for overnight at room temperature under nitrogen atmosphere. The reaction was monitored by LCMS. LCMS showed the reaction was completed. The reaction was quenched with water at 0°C. The resulting mixture was concentrated under reduced pressure. The crude product (80 mg) was purified by Prep-HPLC with the following conditions (Column: XBridge Shield RP18 OBD Column, 30*150 mm, 5μm; Mobile Phase A: Water(10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 14% B to 44% B in 10 min, 44% B; Wave Length: 220/254 nm; RT1(min): 11.32) to afford N-(4-{3-[(3-fluoro-2-methoxyphenyl)amino]-4-oxo- 5H,6H,7H-pyrazolo[1,5-a]pyrazin-2-yl}-7-methoxyquinolin-6-yl)prop-2-enamide (17.4 mg, 15.48%) as an off-white solid. LC-MS: (M+H)⁺ found: 502.95. ¹H NMR (400 MHz, DMSO-d₆) δ 9.63 (s, 1H), 9.05 (s, 1H), 8.71 (d, 1H), 8.37 (d, 1H), 7.45 (d, 2H), 7.19 (s, 1H), 6.82-6.73 (m,1H), 6.45 – 6.26 (m, 3H), 5.90 (d, 1H), 5.77 (d, 1H), 4.45 (t, 2H), 4.02 (s, 3H), 3.73 (s, 2H), 3.67 (s, 3H). Example 64.3-[(3-chloro-2-methoxyphenyl)amino]-2-[7-methoxy-6- (methylamino)quinolin-4-yl]-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (compound 295)

To a solution of 2-methoxy-4-nitroaniline (2.00 g, 11.89 mmol, 1.00 equiv) in THF (50.00 mL) was added NaH (1.19 g, 29.74 mmol, 2.50 equiv, 60%) at 0 degrees C under nitrogen atmosphere. The resulting mixture was stirred for 15 min at room temperature. Then was added MeI (2.03 g, 14.27 mmol, 1.20 equiv) and stirred for overnight at room temperature. Desired product could be detected by LCMS. The reaction was quenched with water at 0 degrees C. The mixture was extracted with EtOAc and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse flash chromatography to afford 2-methoxy-N-methyl-4-nitroaniline (1.00 g, 46.15%) as a yellow solid. LC-MS: M+H found: 182.90

To a solution of 2-methoxy-N-methyl-4-nitroaniline (1.00 g, 5.49 mmol, 1.00 equiv) in EA (50 mL) was added 10% Pd/C (115 mg, 10w/w%) at room temperature under hydrogen atmosphere. The resulting mixture was stirred for 2 h at room temperature under hydrogen atmosphere. The resulting mixture was filtered, the filter cake was washed with EtOAc. The filtrate was concentrated under reduced pressure to afford crude product 2-methoxy-N1-methylbenzene-1,4-diamine (800 mg) as a yellow solid. LC-MS: M+H found: 153.10

A mixture of 2-methoxy-N1-methylbenzene-1,4-diamine (700 mg, 4.60 mmol, 1.00 equiv) and 5-(methoxymethylidene)-2,2-dimethyl-1,3-dioxane-4,6-dione (942 mg, 5.06 mmol, 1.10 equiv) in DMF (7.00 mL). The resulting mixture was stirred for 1 h at 80 degrees C. Desired product could be detected by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (5:1) to afford 5-[(1E)-{[3-methoxy-4- (methylamino)phenyl]imino}methyl]-2,2-dimethyl-1,3-dioxane-4,6-dione (750 mg, 53.23%) as a yellow solid. LC-MS: M+H found: 306.95.

A mixture of 5-[(1E)-{[3-methoxy-4-(methylamino)phenyl]imino}methyl]-2,2-dimethyl- 1,3-dioxane-4,6-dione (650 mg, 2.12 mmol, 1.00 equiv) in diphenyl-ether (40 mL). The resulting mixture was stirred for 30 min at 230 degrees C under air atmosphere. Desired product could be detected by LCMS. The resulting mixture was down to room temperature and diluted with hexane (80 mL). The precipitated solids were collected by filtration and washed with hexane to afford crude product 7-methoxy-6-(methylamino)quinolin-4-ol (550 mg) as a brown solid. LC-MS: M+H found: 205.05.

To a mixture of 7-methoxy-6-(methylamino)quinolin-4-ol (200 mg, 0.98 mmol, 1.00 equiv) in POCl₃ (5.00 mL). The resulting mixture was stirred for 1 h at 100 degrees C. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH₂Cl₂/MeOH (10:1) to afford 4-chloro-7- methoxy-N-methylquinolin-6-amine (70 mg, 32.10%) as a yellow oil. LC-MS: M+H found: 222.90.

To a solution of 4-chloro-7-methoxy-N-methylquinolin-6-amine (130 mg, 0.58 mmol, 1.00 equiv) and 3-chloro-4-oxo-5H,6H,7H-pyrazolo[1,5-a]pyrazin-2-ylboronic acid (151 mg, 0.70 mmol, 1.20 equiv) in dioxane (1.00 mL) and H₂O (0.1 mL) were added AcOK (172 mg, 1.75 mmol, 3.00 equiv) and PCy3*HBF4 (43 mg, 0.12 mmol, 0.20 equiv), and Pd₂(dba)₃ (54 mg, 0.06 mmol, 0.10 equiv) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 1 h at 100 degrees C under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH₂Cl₂/MeOH (10:1) to afford 3-chloro-2-[7-methoxy-6-(methylamino)quinolin-4- yl]-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (60 mg, 28.72%) as a yellow solid. LC-MS: M+H found: 357.90.

To a solution of 3-chloro-2-[7-methoxy-6-(methylamino)quinolin-4-yl]-5H,6H,7H- pyrazolo[1,5-a]pyrazin-4-one (60 mg, 0.17 mmol, 1.00 equiv) and 3-chloro-2- methoxyaniline (26 mg, 0.17 mmol, 1.00 equiv) in DMF (2.00 mL) were added EPhos Pd G4 (31 mg, 0.03 mmol, 0.20 equiv) and Cs₂CO₃ (109 mg, 0.34 mmol, 2.00 equiv) at room temperature under argon atmosphere. The resulting mixture was stirred for 2 h at 50 degrees C under argon atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH₂Cl₂ / MeOH (10:1) to afford crude product. The crude product (30 mg) was purified by Prep-HPLC with the following conditions (Column: YMC-Actus Triart C18 ExRS, 30*150 mm, 5μm; Mobile Phase A: Water (10 mmol/L NH₄HCO₃), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 21% B to 49% B in 8 min, 49% B; Wave Length: 254/220 nm; RT1(min): 7.53) to afford 3-[(3-chloro-2-methoxyphenyl)amino]-2-[7- methoxy-6-(methylamino)quinolin-4-yl]-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (5.3 mg, 6.49%) as a yellow solid. LC-MS: M+H found: 479.25. ¹H NMR (300 MHz, DMSO-d6) δ 8.41 (d, 1H), 8.30 (s, 1H), 7.39-7.27 (m, 2H), 7.20 (s, 1H), 7.00 (s, 1H), 6.63-6.43 (m, 2H), 6.20-6.07 (m, 1H), 5.81-5.66 (m, 1H), 4.44 (t, 2H), 3.94 (s, 3H), 3.79-3.63 (m, 5H), 2.79-2.64 (m, 3H). Example 65.3-[(3-fluoro-2-methoxyphenyl)amino]-2-[7-methoxy-6- (methylamino)quinolin-4-yl]-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (compound 315)

To a solution of 2-methoxy-4-nitroaniline (2.00 g, 11.9 mmol, 1.00 equiv) in THF (50 mL) was added NaH (1.19 g, 29.7 mmol, 2.5 equiv, 60%) at 0 degrees C under nitrogen atmosphere. The resulting mixture was stirred for 15 min at room temperature. Then was added MeI (2.03 g, 14.3 mmol, 1.2 equiv) and stirred for overnight at room temperature. The reaction was quenched with water at 0 degrees C. The mixture was extracted with EtOAc and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse flash chromatography with the following conditions: (column, silica gel; mobile phase, MeCN in water, 10% to 50% gradient in 20 min; detector, UV 254 nm) to afford 2- methoxy-N-methyl-4-nitroaniline (1.00 g, 46.15%) as a yellow solid. LC-MS: M+H found: 182.90

To a solution of 2-methoxy-N-methyl-4-nitroaniline (1.00 g, 5.49 mmol, 1.00 equiv) in EA (50 mL) was added 10% Pd/C (115 mg, 10 w/w%) at room temperature under hydrogen atmosphere. The resulting mixture was stirred for 2 h at room temperature under hydrogen atmosphere. The resulting mixture was filtered, the filter cake was washed with EtOAc. The filtrate was concentrated under reduced pressure to afford crude product 2-methoxy-N1-methylbenzene-1,4-diamine (800 mg) as a yellow solid. LC-MS: M+H found: 153.10

A mixture of 2-methoxy-N1-methylbenzene-1,4-diamine (700 mg, 4.60 mmol, 1.00 equiv) and 5-(methoxymethylidene)-2,2-dimethyl-1,3-dioxane-4,6-dione (942 mg, 5.06 mmol, 1.1 equiv) in DMF (7 mL). The resulting mixture was stirred for 1 h at 80 degrees C. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EA (5:1) to afford 5-[(1E)- {[3-methoxy-4-(methylamino)phenyl]imino}methyl]-2,2-dimethyl-1,3-dioxane-4,6-dione (750 mg, 53.23%) as a yellow solid. LC-MS: M+H found: 306.95.

A mixture of 5-[(1E)-{[3-methoxy-4-(methylamino)phenyl]imino}methyl]-2,2-dimethyl- 1,3-dioxane-4,6-dione (650 mg, 2.12 mmol, 1.00 equiv) in diphenyl-ether (40 mL). The resulting mixture was stirred for 30 min at 230 degrees C. The resulting mixture was down to room temperature and diluted with hexane (80 mL). The precipitated solids were collected by filtration and washed with hexane to afford crude product 7-methoxy-6- (methylamino)quinolin-4-ol (550 mg) as a brown solid. LC-MS: M+H found: 205.05

To a mixture of 7-methoxy-6-(methylamino)quinolin-4-ol (200 mg, 0.979 mmol, 1.00 equiv) in POCl3 (5 mL). The resulting mixture was stirred for 1 h at 100 degrees C. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH₂Cl₂ / MeOH (10:1) to afford 4-chloro- 7-methoxy-N-methylquinolin-6-amine (70 mg, 32.10%) as a yellow oil. LC-MS: M+H found: 222.90

To a solution of 4-chloro-7-methoxy-N-methylquinolin-6-amine (500 mg, 2.24 mmol, 1 equiv) and 3-chloro-4-oxo-5H,6H,7H-pyrazolo[1,5-a]pyrazin-2-ylboronic acid (580 mg, 2.69 mmol, 1.2 equiv) in dioxane (6 mL) and H₂O (0.6 mL) were added AcOK (661 mg, 6.74 mmol, 3 equiv), PCy3HBF4 (165 mg, 0.449 mmol, 0.2 equiv) and Pd₂(dba)₃ (206 mg, 0.225 mmol, 0.1 equiv) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 1 h at 100 degrees C under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH₂Cl₂/MeOH (10:1) to afford 3-chloro-2-[7- methoxy-6-(methylamino)quinolin-4-yl]-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (150 mg, 18.67%) as a yellow solid. LC-MS: M+H found: 357.90.

To a mixture of 3-chloro-2-[7-methoxy-6-(methylamino)quinolin-4-yl]-5H,6H,7H- pyrazolo[1,5-a]pyrazin-4-one (70 mg, 0.196 mmol, 1 equiv), 3-fluoro-2-methoxyaniline (55.2 mg, 0.392 mmol, 2 equiv), Ephos Pd G4 (35.94 mg, 0.039 mmol, 0.2 equiv) and Cs₂CO₃ (127.49 mg, 0.392 mmol, 2 equiv) in DMF (1 mL) at room temperature under Ar atmosphere. The resulting mixture was stirred for 2 h at 50°C under Ar atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with DCM/MeOH (10:1) to afford crude product. The crude product was purified by Prep-HPLC with the following conditions (Column: Sunfire Prep C18 OBD Column, 19*250 mm, 10μm; Mobile Phase A: Water(0.1%FA), Mobile Phase B: ACN; Flow rate: 25 mL/min; Gradient: 10% B to 40% B in 7 min, 40% B; Wave Length: 254/220 nm; RT1(min): 5.98) to afford 3-[(3-fluoro-2- methoxyphenyl)amino]-2-[7-methoxy-6-(methylamino)quinolin-4-yl]-5H,6H,7H- pyrazolo[1,5-a]pyrazin-4-one (17.2 mg, 19.01%) as a yellow solid. LC-MS: M+H found: 463.30 ¹H NMR (400 MHz, DMSO-d6) δ 8.42 (d, 1H), 8.31 (s, 1H), 7.33-7.31 (m, 2H), 7.19 (s, 1H), 6.98 (s, 1H), 6.48-6.32 (m, 2H), 5.97 (d, 1H), 5.79-5.70 (m, 1H), 4.44 (t, 2H), 3.94 (s, 3H), 3.75 (s, 3H), 3.71 (s, 2H), 2.71 (d, 3H). Example 66.3-[(3-fluoro-2-methoxyphenyl)amino]-2-{2-methoxythieno[3,2-b]pyridin- 7-yl}-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (compound 275)

To a solution of anise alcohol (860 mg, 6.19 mmol, 1.05 equiv) in DMF (10 mL) was added sodium hydride (260 mg, 6.50 mmol, 1.10 equiv, 60% in oil) at 0 degrees C. The mixture was stirred for 15 min.7-chlorothieno[3,2-b]pyridine (1.00 g, 5.90 mmol, 1.00 equiv) was added and the mixture was allowed to warm to RT and stirred for 1h. The reaction mixture was quenched by water and extracted with DCM (3*25 mL). The residue was purified by silica gel column chromatography, eluted with PE / EA (1:1) to afford 7- [(4-methoxyphenyl)methoxy]thieno[3,2-b]pyridine (1.4 g, 87.53%) as a white solid. LC-MS: M+H⁺ found: 272.1.

A solution of 7-[(4-methoxyphenyl)methoxy]thieno[3,2-b]pyridine (1.30 g, 4.79 mmol, 1.00 equiv) in tetrahydrofuran (40 mL) was treated with n-BuLi (4.2 mL, 10.54 mmol, 2.20 equiv) for 1h at -78 degrees C under nitrogen atmosphere followed by the addition of carbon tetrabromide (1.59 g, 4.79 mmol, 1.00 equiv) dropwise at -78 degrees C. The resulting mixture was stirred for 1h at -78 degrees C under argon atmosphere. The reaction was quenched by the addition of sat. NH₄Cl (aq.) (40 mL) at 0 degrees C. The resulting mixture was extracted with EtOAc (3 x 40mL). The combined organic layers were washed with brine (1x20 mL), dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (1:1) to afford 2-bromo-7-[(4- methoxyphenyl)methoxy]thieno[3,2-b]pyridine (1.2 g, 71.51%) as a white solid. LC-MS: (M+H)⁺ found: 350.0.

A mixture of 2-bromo-7-[(4-methoxyphenyl)methoxy]thieno[3,2-b]pyridine (1.10 g, 3.15 mmol, 1.00 equiv) in TFA (15 mL) and DCM (15 mL) was stirred for 1h at room temperature under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The crude product is recrystallized with ether and pentanes to afford 2- bromothieno[3,2-b]pyridin-7-ol; trifluoroacetic acid (1.2 g, 99.93%) as a white solid. LC-MS: (M+H)⁺ found: 230.0.

To a stirred mixture of 2-bromothieno[3,2-b]pyridin-7-ol; trifluoroacetic acid (1.10 g, 3.20 mmol, 1.00equiv) and NaOMe in MeOH (4.30 g, 15.99 mmol, 5.00 equiv, 30w/w%) in MeOH (30 mL) was added CuBr (70 mg, 0.48 mmol, 0.10 equiv) at 120 degrees C under argon atmosphere. The resulting mixture was stirred for 2 days at 120 degrees C under argon atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH₂Cl₂/MeOH (10:1) to afford 2-methoxythieno[3,2-b]pyridin-7-ol (530 mg, 61.18%) as a light brown solid. LC-MS: (M+H)⁺ found: 182.00.

A mixture of 2-methoxythieno[3,2-b]pyridin-7-ol (530 mg, 2.93 mmol, 1.00 equiv) in phosphorus oxychloride (6 mL) was stirred for 2h at 90 degrees C under nitrogen atmosphere. The reaction was quenched by the addition of water/ice (30 mL) at 0 degrees C, treated with aqueous 50 % sodium hydroxide solution. The resulting mixture was extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine (1x10 mL), dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure.The residue was purified by silica gel column chromatography, eluted with PE/EA (3:1) to afford 7-chloro-2-methoxythieno[3,2-b]pyridine (250 mg, 42.81%) as a white solid. LC-MS: (M+H)⁺ found: 199.90.

Into a 8 mL vial were added 7-chloro-2-methoxythieno[3,2-b]pyridine (40 mg, 0.20 mmol, 1.00 equiv) and bis(pinacolato)diboron (102 mg, 0.40 mmol, 2.00 equiv) and Pd(dppf)Cl₂ (14 mg, 0.02 mmol, 0.10 equiv) and KOAc (39 mg, 0.40 mmol, 2.00 equiv) and dioxane (2 mL). The resulting mixture was stirred for 1 days at 120 degrees C under nitrogen atmosphere. The reaction was monitored by LCMS. The crude product was used in the next step directly without further purification. LC-MS: (M+H)⁺ found: 210.2.

To a stirred mixture of 2-bromo-3-[(3-fluoro-2-methoxyphenyl)amino]-5H,6H,7H- pyrazolo[1,5-a]pyrazin-4-one (50 mg, 0.14 mmol, 1.00 equiv) and 2-methoxy-7-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)thieno[3,2-b]pyridine (49 mg, 0.17 mmol, 1.20 equiv) in dioxane (1.0 mL) and H₂O (0.2 mL) were added XPhos palladium(II) biphenyl-2-amine chloride (11 mg, 0.01 mmol, 0.10 equiv) and Na₂CO₃ (30 mg, 0.28 mmol, 2.00 equiv) in portions at room temperature under argon atmosphere.The resulting mixture was stirred for overnight at 50 degrees C under argon atmosphere. The resulting mixture was filtered, the filter cake was washed with CH₂Cl₂ (3x10 mL). The filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (PE/EA 1:1) to afford 3-[(3- fluoro-2-methoxyphenyl)amino]-2-{2-methoxythieno[3,2-b]pyridin-7-yl}-5H,6H,7H- pyrazolo[1,5-a]pyrazin-4-one (11.7 mg, 18.87%) as a white solid. LC-MS: (M+H)⁺ found: 439.95. ¹H NMR (400 MHz, DMSO-d6) δ 8.31 – 8.42 (m, 2H), 7.47 (d, 1H), 7.36 (s, 1H), 6.63 – 6.73 (m, 2H), 6.58 – 6.55 (m, 1H), 5.98 – 5.96 (m, 1H), 4.47 – 4.45 (m, 2H), 4.04 (s, 3H), 3.93 (s, 3H), 3.69 (t, 2H) Example 67.3-[(3-chloro-2-methoxyphenyl)amino]-2-{2-methoxythieno[3,2-b]pyridin- 7-yl}-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (compound (365)

Into a 8 mL vial were added 2-methoxythieno[3,2-b]pyridin-7-ylboronic acid (40 mg, 0.19 mmol, 1.00 equiv) and 2-bromo-3-[(3-chloro-2-methoxyphenyl)amino]-5H,6H,7H- pyrazolo[1,5-a]pyrazin-4-one (71 mg, 0.19 mmol, 1.00 equiv) and 2nd Generation XPhos Precatalyst (15 mg, 0.02 mmol, 0.10 equiv) and Na₂CO₃ (61 mg, 0.57 mmol, 3.00 equiv) and dioxane (2.0 mL) and H₂O (0.4 mL) at room temperature. The resulting mixture was stirred for overnight at 50 degrees C under nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH₂Cl₂ / MeOH (50:1) to afford crude product (100 mg).The crude product (100 mg) was purified by Prep-HPLC with the following conditions (Column: YMC-Actus Triart C18 ExRS, 30*150 mm, 5μm; Mobile Phase A: Water (10 mmol/L NH₄HCO₃), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 47% B to 69% B in 10 min, 69% B; Wave Length: 254/220 nm; RT1(min): 5.63) to afford 3-[(3-chloro-2-methoxyphenyl)amino]-2-{2- methoxythieno[3,2-b]pyridin-7-yl}-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (17.2 mg, 19.62%) as a white solid. LC-MS: M+H⁺ found: 455.90. ¹H NMR (400 MHz, DMSO-d6) δ 8.40 (d, 1H), 8.35 (t, 1H), 7.47 (d, 1H), 7.42 (s, 1H), 6.80 – 6.67 (m, 3H), 6.16 - 6.10 (m, 1H), 4.50 - 4.44 (m, 2H), 4.05 (s, 3H), 3.91 (s, 3H), 3.70 - 3.64 (m, 2H). Example 68.8-{3-[(3-chloro-2-methoxyphenyl)amino]-4-oxo-5H,6H,7H-pyrazolo[1,5- a]pyrazin-2-yl}-1H-1,5-naphthyridin-2-one (compound 345)

To a stirred solution of methyl 4-nitro-1H-pyrazole-3-carboxylate (50.00 g, 292.21 mmol, 1.00 equiv) and PPh₃ (91.97 g, 350.65 mmol, 1.20 equiv) in dry THF (500 mL) was added tert-butyl N-(2-hydroxyethyl)carbamate (56.52 g, 350.65 mmol, 1.20 equiv) dropwise at 0 degrees C under argon atmosphere. The resulting mixture was stirred for 20 min at 0 degrees C under argon atmosphere. Then, the above mixture was added DIAD (70.90 g, 350.65 mmol, 1.20 equiv) dropwise at 0 degrees C under argon atmosphere. The resulting mixture was stirred for 1 h at 0 degrees C under argon atmosphere. Desired product could be detected by LCMS. The resulting mixture was concentrated under reduced pressure. The resulting mixture was diluted with water (100 mL). The resulting mixture was extracted with EtOAc (3 x 500 mL). The combined organic layers dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure to afford methyl 2-{2-[(tert-butoxycarbonyl)amino]ethyl}-4-nitropyrazole-3-carboxylate (150 g, crude) as a yellow solid. The crude product was used in the next step directly without further purification. LC-MS: (M+H)⁺ found: 315.

To a stirred solution of methyl 2-{2-[(tert-butoxycarbonyl)amino]ethyl}-4-nitropyrazole- 3-carboxylate (150 g, 477.25 mmol, 1.00 equiv) in DCM (200 mL) was added 4 M HCl in dioxane (600 mL) dropwise at 0 degrees C. The resulting mixture was stirred for 1 h at room temperature. The precipitated solids were collected by filtration and washed with CH₂Cl₂ (3x100 mL) to afford methyl 2-(2-aminoethyl)-4-nitropyrazole-3-carboxylate (108 g, crude) as an off-white solid. The crude product was used in the next step directly without further purification. LC-MS: (M+H)⁺ found: 215.

To a stirred solution of methyl 2-(2-aminoethyl)-4-nitropyrazole-3-carboxylate (108.00 g, 504.25 mmol, 1.00 equiv) in toluene (1000 mL) was added TEA (102.05 g, 1.00 mol, 2.00 equiv) dropwise at room temperature under air atmosphere. The resulting mixture was stirred for 3 h at 100 degrees C under air atmosphere. The precipitated solids were collected by filtration and washed with DCM (3x50 mL) to afford 3-nitro-5H,6H,7H- pyrazolo[1,5-a]pyrazin-4-one (68 g, 74.04%) as an off-white solid. LC-MS: (M+H)⁺ found: 183.

To a stirred solution of 3-nitro-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (15.00 g, 82.36 mmol, 1.00 equiv) in methanol (150 mL) was added 10% wet Pd/C (5.00 g, 33w/w%) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for overnight at room temperature under hydrogen atmosphere. Desired product could be detected by LCMS. The resulting mixture was filtered, the filter cake was washed with MeOH (4x100 mL). The filtrate was concentrated under reduced pressure. This resulted in 3-amino-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (12 g, 95.76%) as an off-white solid. LC-MS: (M+H)⁺ found:153.

To a stirred solution of 3-amino-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one (2.00 g, 13.14 mmol, 1.00 equiv) in ACN (200 mL) in ACN (200 mL) was added NBS (2.34 g, 13.14 mmol, 1.00 equiv) at -30°C. The resulting mixture was stirred for 1h. Desired product could be detected by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse flash chromatography (mobile phase, MeCN in water, 0% to 100% in 30 min) to afford 3-amino-2-bromo-6,7- dihydropyrazolo[1,5-a]pyrazin-4(5H)-one (2.00 g, 65.85%) as yellow solid. LC-MS: (M+H)⁺ found: 231.

To a solution of 3-amino-2-bromo-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (800 mg, 3.46 mmol, 1.00 equiv) and Cs₂CO₃ (2256 mg, 6.92 mmol, 2.00 equiv) in DMF (15.00 mL) were added Ephos Pd G4 (477 mg, 0.52 mmol, 0.15 equiv) and 1-chloro-3-iodo-2- methoxybenzene (1115 mg, 4.15 mmol, 1.20 equiv) at room temperature under argon atmosphere. The resulting mixture was stirred for 4 h at 50 °C under argon atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH₂Cl₂/MeOH (30:1) to afford 2-bromo-3-[(3-chloro-2-methoxyphenyl)amino]-5H,6H,7H-pyrazolo[1,5- a]pyrazin-4-one (500 mg, 38.86%) as a yellow solid. LC-MS: (M+H)⁺ found: 371.

To a solution of 8-bromo-2-fluoro-1,5-naphthyridine (500 mg, 2.20 mmol, 1.00 equiv) and 4,4,5,5-tetramethyl-2-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (671 mg, 2.64 mmol, 1.20 equiv) in THF (10 mL) were added KOAc (540 mg, 5.51 mmol, 2.50 equiv) and Pd(dppf)Cl₂*CH₂Cl₂ (179 mg, 0.22 mmol, 0.10 equiv). After stirring for 2 h at 80 degrees C under a nitrogen atmosphere. Desired product could be detected by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with DCM:CH₃OH (10:1) to afford 6-fluoro-1,5-naphthyridin-4-ylboronic acid (200 mg, 47.31%) as a yellow solid. LC-MS: (M+H)⁺ found: 193.

To a solution of 6-fluoro-1,5-naphthyridin-4-ylboronic acid (62 mg, 0.32 mmol, 1.50 equiv) and 2-bromo-3-[(3-chloro-2-methoxyphenyl)amino]-5H,6H,7H-pyrazolo[1,5- a]pyrazin-4-one (80 mg, 0.21 mmol, 1.00 equiv) in dioxane (1.0 mL) and H₂O (0.1 mL) were added Na₂CO₃ (69 mg, 0.65 mmol, 3.00 equiv) and 2nd Generation XPhos precatalyst (17 mg, 0.02 mmol, 0.10 equiv). After stirring for 2h at 80 degrees C under a nitrogen atmosphere. Desired product could be detected by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with DCM:CH₃OH (10:1) to afford 3-[(3-chloro-2- methoxyphenyl)amino]-2-(6-fluoro-1,5-naphthyridin-4-yl)-5H,6H,7H-pyrazolo[1,5- a]pyrazin-4-one (60 mg, 63.51%) as a yellow solid. LC-MS: (M+H)⁺ found: 439.

To a stirred solution of 3-[(3-chloro-2-methoxyphenyl)amino]-2-(6-fluoro-1,5- naphthyridin-4-yl)-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (50 mg, 0.11 mmol, 1.00 equiv) in DMF (2.00 mL) and THF (5.00 mL), DMSO (0.2 mL) and H₂O (1.5 mL) were added NaOH (9 mg, 0.23 mmol, 2.00 equiv). The resulting mixture was stirred for 5 h at 50 degrees C. The reaction was monitored by LCMS. The resulting mixture was concentrated under vacuum. The crude product was purified by Prep-HPLC with the following conditions (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water (10 mmol/L NH₄HCO₃), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 21% B to 51% B in 7 min; Wave Length: 254 nm; RT1(min): 6.5) to afford 8-{3-[(3-chloro-2-methoxyphenyl)amino]-4-oxo-5H,6H,7H-pyrazolo[1,5- a]pyrazin-2-yl}-1H-1,5-naphthyridin-2-one (15.2 mg, 29.01%) as a yellow solid. LC-MS: (M+H)⁺ found: 436.90. ¹H NMR (300 MHz, DMSO-d6) δ 11.53 (s, 1H), 8.50 – 8.36 (m, 2H), 8.00 (d, 1H), 7.80 (d, 1H), 7.45 (s, 1H), 6.85 (d, 1H), 6.77 – 6.62 (m, 2H), 6.25 – 6.17 (m, 1H), 4.53 (t, 2H), 3.89 (s, 3H), 3.70 (d, 2H). Example 69.3-[(3-chloro-2-methoxyphenyl)amino]-2-{2-methoxy-1H-pyrrolo[3,2- b]pyridin-7-yl}-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (compound 299)

A solution of Trimethyloxonium tetrafluoroborate (78 mg, 0.53 mmol, 1.13 equiv) in chloroform (5 mL) was treated with 7-bromo-1H,3H-pyrrolo[3,2-b]pyridin-2-one (100 mg, 0.47 mmol, 1.00 equiv) for 10 min at 10 degrees C under nitrogen .The resulting mixture was stirred for 2 day at room temperature under nitrogen atmosphere. The resulting mixture was washed with 1x5 mL of EtOAc. The resulting mixture was extracted with EtOEt (3 x 10mL). The combined organic layers were washed with brine (1x10 mL), dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (CH₂Cl₂/MeOH 10:1) to afford 7-bromo-2-methoxy-1H-pyrrolo[3,2-b]pyridine (80 mg, 75.06%) as a light yellow solid. LC-MS: M+H⁺ found: 226.95.

Into a 8 mL vial were added 7-bromo-2-methoxy-1H-pyrrolo[3,2-b]pyridine (45 mg, 0.20 mmol, 1.00 equiv) and bis(pinacolato)diboron (100 mg, 0.40 mmol, 2.00 equiv) and Pd(dppf)Cl₂*CH₂Cl₂ (16 mg, 0.02 mmol, 0.10 equiv) and KOAc (39 mg, 0.40 mmol, 2.00 equiv) and dioxane (2 mL) at room temperature. The resulting mixture was stirred for 2 h at 120 degrees C under nitrogen atmosphere. The reaction was monitored by LCMS. After filtration, the filtrate was concentrated under reduced pressure. The crude product (50 mg) was used in the next step directly without further purification LC-MS : M+H found: 275.2.

Into a 20 mL vial were added 2-methoxy-1H-pyrrolo[3,2-b]pyridin-7-ylboronic acid (35 mg, 0.18 mmol, 1.00 equiv) and 2-bromo-3-[(3-chloro-2-methoxyphenyl)amino]- 5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (68 mg, 0.18 mmol, 1.00 equiv) and Na₂CO₃ (58 mg, 0.55 mmol, 3.00 equiv)and 2nd Generation XPhos Precatalyst (14 mg, 0.02 mmol, 0.10 equiv) and dioxane (3.5 mL) and H₂O (0.7 mL) at room temperature. The resulting mixture was stirred for 2 h at 60 degrees C under nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH₂Cl₂/MeOH (10:1) to afford crude product (60 mg).The crude product (60 mg) was purified by Prep-HPLC with the following conditions (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water(10 mmol/L NH₄HCO₃), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 17% B to 47% B in 7 min; Wave Length: 254 nm; RT1(min): 6.5) to afford 3-[(3-chloro-2-methoxyphenyl)amino]-2-{2-methoxy- 1H-pyrrolo[3,2-b]pyridin-7-yl}-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (11.9 mg, 14.75%) as a yellow solid. LC-MS: M+H⁺ found: 439.25. ¹H NMR (400 MHz, DMSO-d6) δ 9.52 (s, 1H), 8.29 (s, 1H), 7.34 – 7.21 (m, 2H), 6.80 – 6.69 (m, 2H), 6.67 (d, 1H), 6.19 – 6.13 (m, 1H), 4.92 (d, 1H), 4.46 (t, 2H), 3.88 (s, 3H), 3.68 (d, 3H), 3.61 (s, 2H). Example 70.3-[(3-chloro-2-methoxyphenyl)amino]-2-(3-{2-[1- (difluoromethyl)cyclopropyl]ethynyl}pyridin-4-yl)-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4- one (compound 364)

To a stirred solution of 4-bromo-3-iodopyridine (500 mg, 1.77 mmol, 1.00 equiv), palladium chloride; bis(triphenylphosphine) (124 mg, 0.18 mmol, 0.10 equiv), TEA (535 mg, 5.31 mmol, 3.0 equiv) in MeCN (6 mL) was added CuI (34 mg, 0.18 mmol, 0.10 equiv) and 1-(difluoromethyl)-1-ethynylcyclopropane (250 mg, 2.12 mmol, 1.20 equiv) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 2 h at room temperature under nitrogen atmosphere. The resulting mixture was filtered, the filter cake was washed with MeCN (2x10 mL). The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EtOAc (20:1) to afford 4-bromo-3-{2-[1- (difluoromethyl)cyclopropyl]ethynyl}pyridine (465 mg, 97.03%) as a yellow oil. LC-MS: M+H found: 272.0.

To a stirred solution of 4-bromo-3-{2-[1-(difluoromethyl)cyclopropyl]ethynyl}pyridine (300 mg, 1.10 mmol, 1.00 equiv), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2- dioxaborolane) (420 mg, 1.16 mmol, 1.50 equiv), Pd2(dba)3.CHCl3 (100 mg, 0.11 mmol, 0.10 equiv) in dioxane (10 mL) was added PPh3 (28 mg, 0.11 mmol, 0.10 equiv) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 2 h at 80 degrees under nitrogen atmosphere. The resulting mixture was filtered, the filter cake was washed with MeOH (10 mL). The resulting mixture was concentrated under reduced pressure to afford 3-{2-[1-(difluoromethyl)cyclopropyl]ethynyl}-4-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)pyridine (400 mg) as a yellow solid. The crude product mixture was used in the next step directly without further purification. LC-MS: (M+H)⁺ found: 320.1.

Into a 40-mL vial were placed 2-bromo-3-[(3-chloro-2-methoxyphenyl)amino]- 5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (100 mg, 0.27 mmol, 1.00 equiv), 3-{2-[1- (difluoromethyl)cyclopropyl]ethynyl}pyridin-4-ylboronic acid (77 mg, 0.32 mmol, 1.20 equiv), Na₂CO₃ (86 mg, 0.81 mmol, 2.00 equiv), Pd(PPh3)4 (31.2 mg, 0.03 mmol, 0.10 equiv) in dioxane (5 mL) and H₂O (1 mL). The resulting solution was stirred for overnight at 100 degrees C. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The resulting mixture was diluted with DCM (6 mL). The resulting mixture was filtered, the filter cake was washed with MeOH (2x1 mL). The filtrate was concentrated under reduced pressure. The crude product was purified by Prep-HPLC with the following conditions (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water(10 mmol/L NH₄HCO₃), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 37% B to 53% B in 8 min, 53% B; Wave Length: 254/220 nm; RT1(min): 7.18) to afford 3-[(3-chloro-2-methoxyphenyl)amino]-2-(3-{2- [1-(difluoromethyl)cyclopropyl]ethynyl}pyridin-4-yl)-5H,6H,7H-pyrazolo[1,5- a]pyrazin-4-one (46.9 mg, 36.0%) as a white solid. LC-MS: (M+H)+ found: 484.25. ¹H NMR (400 MHz, DMSO-d6): δ 8.62 (s, 1H), 8.49 (d,1H), 8.30 (s, 1H), 7.48 (d, 1H), 7.13 (s, 1H), 6.67 (d, 2H), 6.15 (t, 1H), 5.76 (t, 1H), 4.39 (t, 2H), 3.80 (s, 3H), 3.67 (d, 2H), 1.35 – 1.10 (m, 4H). Example 71. N-(4-[3-[(3-fluoro-2-methoxyphenyl)amino]-4-oxo-5H,6H,7H- pyrazolo[1,5-a]pyrazin-2-yl]pyridin-3-yl)-2-methoxyaceta-mide (compound 333)

To a stirred solution of 3-[(3-fluoro-2-methoxyphenyl)amino]-2-(3-fluoropyridin-4-yl)- 5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (100 mg, 0.26 mmol, 1.00 equiv) and 1-(2,4- dimethoxyphenyl)methanamine (54 mg, 0.32 mmol, 1.2 equiv) in DMSO (3 mL) was added DIEA (522 mg, 4.03 mmol, 15 equiv) at room temperature under argon atmosphere. The resulting mixture was stirred for overnight at 120 degrees C under argon atmosphere. The reaction was monitored by LCMS. The mixture was allowed to cool down to room temperature. The resulting mixture was diluted with water (15 mL). The precipitated solids were collected by filtration and washed with water (3 x 5 mL). The residue was purified by Prep-TLC (CH₂Cl₂ / MeOH = 10:1) to afford 2-(3-{[(2,4- dimethoxyphenyl)methyl]amino}pyridin-4-yl)-3-[(3-fluoro-2-methoxyphenyl)amino]- 5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (70 mg, 50.35%) as a light yellow solid. LC-MS: (M+H)⁺ found: 519.05.

To a stirred solution of 3-[(3-fluoro-2-methoxyphenyl)amino]-2-(3-fluoropyridin-4-yl)- 5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (70 mg, 0.19 mmol, 1.00 equiv) was added trifluoroacetaldehyde (2.00 mL) dropwise at 0 degrees C under air atmosphere. The resulting mixture was stirred for 2 h at 50 degrees C under air atmosphere. Desired product could be detected by LCMS. The resulting mixture was concentrated under reduced pressure. The resulting mixture was diluted with DCM (10 mL). The mixture was basified to pH 8 with aqueous ammonia. The resulting mixture was concentrated under vacuum. The crude product mixture was used in the next step directly without further purification. LC-MS: (M+H)⁺ found: 368.95.

To a stirred mixture of 2-(3-aminopyridin-4-yl)-3-[(3-fluoro-2-methoxyphenyl)amino]- 5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (55 mg, 0.14 mmol, 1.00 equiv) in pyridine (1 mL) was added methoxyacetyl chloride (32 mg, 0.29 mmol, 2 equiv) in DCM (0.5 mL) dropwise at 0 degrees C under argon atmosphere. The resulting mixture was stirred for 1 h at room temperature under argon atmosphere. The reaction was monitored by LCMS. The reaction was quenched by the addition of MeOH (1 mL) at 0 degrees C. The resulting mixture was concentrated under reduced pressure. The crude product (70 mg) was purified by Prep-HPLC with the following conditions (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water(10 MMOL/L NH₄HCO₃), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 33% B to 63% B in 7 min; Wave Length: 254 nm; RT1(min): 6.5) to afford N-(4-[3-[(3-fluoro-2-methoxyphenyl)amino]-4-oxo-5H,6H,7H- pyrazolo[1,5-a]pyrazin-2-yl]pyridin-3-yl)-2-methoxyaceta-mide (8.8 mg, 13.18%) as an off-white solid. LC-MS: (M+H)⁺ found: 441.05. ¹H NMR (400 MHz, DMSO-d6) δ 11.20 (s, 1H), 9.61 (s, 1H), 8.48 - 8.10 (m, 2H), 7.64 (d, 1H), 7.37 (s, 1H), 6.73 - 6.65 (m, 1H), 6.63 - 6.45 (m, 1H), 6.00 (d, 1H), 4.46 - 4.43 (m, 2H), 4.08 (s, 2H), 3.90 (s, 3H), 3.72 (d, 2H), 3.49 (s, 3H). Example 72.3-[(3-fluoro-2-methoxyphenyl)amino]-2-[3-[(2-hydroxy-2- methylpropyl)amino]pyridin-4-yl]-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (compound 334)

To a stirred solution of 3-[(3-fluoro-2-methoxyphenyl)amino]-2-(3-fluoropyridin-4-yl)- 5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (70 mg, 0.18 mmol, 1.00 equiv) and 1-amino-2- methylpropan-2-ol (1.00 mL) in DMSO (1.00 mL) was added DIEA (365 mg, 2.83 mmol, 15.00 equiv) in portions at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 2 days at 120 degrees C under nitrogen atmosphere. Desired product could be detected by LCMS. The crude product was purified by Prep-HPLC with the following conditions (Column: Xselect CSH OBD Column 30*150mm 5um; Mobile Phase A: Water(0.1%FA), Mobile Phase B: ACN; Flow rate: 50 mL/min; Gradient: 10% B to 30% B in 7 min, 30% B; Wave Length: 220 nm; RT1(min): 5.9) to afford 3-[(3-fluoro-2- methoxyphenyl)amino]-2-[3-[(2-hydroxy-2-methylpropyl)amino]pyridin-4-yl]- 5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (5.7 mg, 6.86%) as a white solid. LC-MS: (M+H)⁺ found: 441.10. ¹H NMR (300 MHz, DMSO-d6) δ 8.33 (t, J = 2.8 Hz, 1H), 8.11 (s, 1H), 7.67 (d, J = 5.0 Hz, 1H), 7.49 - 6.98 (m, 3H), 6.80 - 6.38 (m, 2H), 5.97 (dt, J = 8.2, 1.4 Hz, 1H), 4.62 (s, 1H), 4.37 (dd, J = 7.1, 5.0 Hz, 2H), 3.90 (s, 3H), 3.75 - 3.62 (m, 2H), 3.17 (d, J = 5.2 Hz, 2H), 1.23 (s, 6H). Example 73.2-[3-[(2,2-dimethylpropyl)amino]pyridin-4-yl]-3-[(3-fluoro-2- methoxyphenyl)amino]-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (compound 343)

A solution of 3-[(3-fluoro-2-methoxyphenyl)amino]-2-(3-fluoropyridin-4-yl)-5H,6H,7H- pyrazolo[1,5-a]pyrazin-4-one (150 mg, 0.40 mmol, 1.00 equiv) and DIEA (783 mg, 6.06 mmol, 15.00 equiv) in 2,2-dimethyl-1-propylamin (3 mL) and DMSO (2 mL) at room temperature under air atmosphere. The resulting mixture was stirred for 36 h at 120 degrees C under air atmosphere. Desired product could be detected by LCMS. The resulting mixture was concentrated under vacuum. The crude product (100 mg) was purified by Prep-HPLC with the following conditions (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water(10MMOL/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 35% B to 65% B in 7 min; Wave Length: 254 nm; RT1(min): 6.5;) to afford 2-[3-[(2,2-dimethylpropyl)amino]pyridin-4-yl]-3-[(3-fluoro-2- methoxyphenyl)amino]-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (20.60 mg, 11.51%) as a light yellow solid. LC-MS: M+H found: 439.10. ¹H NMR (400 MHz, DMSO-d6) δ 8.32 (s, 1H), 8.14 (s, 1H), 7.67 (d, J = 5.0 Hz, 1H), 7.47 (d, J = 5.0 Hz, 1H), 7.31 (s, 1H), 7.11 (t, J = 5.3 Hz, 1H), 6.68 (m, J = 8.3, 6.0 Hz, 1H), 6.54 (m, J = 11.0, 8.3, 1.4 Hz, 1H), 5.97 (m, J = 8.3, 1.3 Hz, 1H), 4.39 (dd, J = 6.9, 5.3 Hz, 2H), 3.91 (d, J = 0.8 Hz, 3H), 3.69 (d, J = 7.5 Hz, 2H), 3.08 (d, J = 5.3 Hz, 2H), 1.04 (s, 9H) Example 74. N-(4-[3-[(3-fluoro-2-methoxyphenyl)amino]-4-oxo-5H,6H,7H- pyrazolo[1,5-a]pyrazin-2-yl]pyridin-3-yl)cyclopropanecarboxamide (compound 338)

Into a Volume were added 3-[(3-fluoro-2-methoxyphenyl) amino]-2-(3-fluoropyridin-4- yl)-5H,6H,7H-pyrazolo[1,5-a] pyrazin-4-one (100 mg, 0.27 mmol, 1.00 equiv), DIEA (522 mg, 4.04 mmol, 15.00 equiv), 1-(2,4-dimethoxyphenyl) methanamine (1.50 mL) and DMSO (1.50 mL) at room temperature under air atmosphere. The resulting mixture was stirred for 50 h at 120 degrees C under air atmosphere. Desired product could be detected by LCMS. The residue was purified by reverse flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeOH in water, 10% to 50% gradient in 10 min; detector, UV 254 nm. This resulted in 2-(3-[[(2,4-dimethoxyphenyl) methyl] amino] pyridin-4-yl)-3-[(3-fluoro-2-methoxyphenyl)amino]-5H,6H,7H-pyrazolo[1,5- a]pyrazin-4-one(47 mg, 33.66%) as a light yellow solid. LC-MS: M+H found: 519.05.

To a stirred solution of 2-(3-[[(2,4-dimethoxyphenyl) methyl] amino]pyridin-4-yl)-3-[(3- fluoro-2-methoxyphenyl)amino]-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (47 mg, 0.09 mmol, 1.00 equiv) was added trifluoroacetaldehyde (2.00 mL) dropwise at 0 degrees C under air atmosphere. The resulting mixture was stirred for 2 h at 0 degrees C under air atmosphere. Desired product could be detected by LCMS. The resulting mixture was concentrated under reduced pressure. The resulting mixture was diluted with DCM (10 mL). The mixture was basified to pH 8 with aqueous ammonia. The resulting mixture was concentrated under vacuum. This resulted in 2-(3-aminopyridin-4-yl)-3-[(3-fluoro-2- methoxyphenyl) amino]-5H,6H,7H-pyrazolo[1,5-a] pyrazin-4-one (30 mg, 89.85%) as a light yellow solid. The crude product mixture was used in the next step directly without further purification. LC-MS: (M+H)⁺ found: 369.10.

To a stirred solution of 2-(3-aminopyridin-4-yl)-3-[(3-fluoro-2-methoxyphenyl) amino]- 5H,6H,7H-pyrazolo[1,5-a] pyrazin-4-one (46 mg, 0.13 mmol, 1.00 equiv) in pyridine (1.50 mL) was added cyclopropanecarbonyl chloride (14 mg, 0.14 mmol, 1.10 equiv) in DCM (0.10 mL) dropwise at -30 degrees C under argon atmosphere. The resulting mixture was stirred for 1 h at -30 degrees C under argon atmosphere. Desired product could be detected by LCMS. The resulting mixture was concentrated under vacuum. The crude product (40 mg) was purified by Prep-HPLC with the following conditions (Column: Xselect CSH C18 OBD Column 30*150mm 5μm; Mobile Phase A: Water(0.1%FA), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 10% B to 34% B in 8 min; Wave Length: 220 nm; RT1(min): 8) to afford N-(4-[3-[(3-fluoro-2- methoxyphenyl)amino]-4-oxo-5H,6H,7H-pyrazolo[1,5-a]pyrazin-2-yl]pyridin-3- yl)cyclopropanecarboxamide (5.80 mg, 10.64%) as a light yellow solid. LC-MS: (M+H)⁺ found: 437.05. ¹H NMR (300 MHz, DMSO-d6) δ 10.28 (s, 1H), 9.25 (s, 1H), 8.38 (d, J = 2.8 Hz, 1H), 8.22 (d, J = 5.1 Hz, 1H), 7.56 (d, J = 5.0 Hz, 1H), 7.37 (s, 1H), 6.74 – 6.44 (m, 2H), 6.08 (d, J = 8.1 Hz, 1H), 4.46 (t, J = 5.8 Hz, 2H), 3.89 (s, 3H), 3.71 (d, J = 6.8 Hz, 2H), 1.89 (p, J = 6.3 Hz, 1H), 0.83 (d, J = 6.1 Hz, 4H). Example 75. N-(4-[3-[(3-fluoro-2-methoxyphenyl)amino]-4-oxo-5H,6H,7H- pyrazolo[1,5-a]pyrazin-2-yl]pyridin-3-yl)-2-methylpropanamide (compound 339)

To a stirred mixture of 2-(3-aminopyridin-4-yl)-3-[(3-fluoro-2-methoxyphenyl)amino]- 5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (50 mg, 0.13 mmol, 1.00 equiv) and propanoyl chloride, 2-methyl-(28.9 mg, 0.271 mmol, 2.00 equiv) in pyridine (2.0 mL) in portions at 0 degrees C under nitrogen atmosphere. The resulting mixture was stirred for 30 min at 0 degrees C under nitrogen atmosphere. Desired product could be detected by LCMS. The crude product (60 mg) was purified by Prep-HPLC with the following conditions (Column: Xselect CSH OBD Column 30*150mm 5um, n; Mobile Phase A: Water (0.1%FA), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 15% B to 36% B in 8 min, 36% B; Wave Length: 254/220 nm; RT1(min): 7.75) to afford N-(4-[3-[(3-fluoro-2- methoxyphenyl)amino]-4-oxo-5H,6H,7H-pyrazolo[1,5-a]pyrazin-2-yl]pyridin-3-yl)-2- methylpropanamide (4.2 mg,12.93%) as a white solid. LC-MS: (M+H)⁺ found: 438. ¹H NMR (400 MHz, DMSO-d6) δ 10.10 (s, 1H), 9.25 (s, 1H), 8.36 (d, J = 2.8 Hz, 1H), 8.21 (d, J = 5.1 Hz, 1H), 7.56 (d, J = 5.1 Hz, 1H), 7.33 (s, 1H), 6.64 (td, J = 8.2, 5.9 Hz, 1H), 6.52 (ddd, J = 10.0, 8.4, 1.5 Hz, 1H), 6.12 (dd, J = 8.2, 1.5 Hz, 1H), 4.42 (dd, J = 7.1, 5.0 Hz, 2H), 3.93 (s, 3H), 3.69 (ddd, J = 7.8, 4.8, 2.6 Hz, 2H), 2.75 – 2.57 (m, 1H), 1.16 (d, J = 6.8 Hz, 6H). Example 76.2,2,2-trifluoro-N-(4-[3-[(3-fluoro-2-methoxyphenyl)amino]-4-oxo- 5H,6H,7H-pyrazolo[1,5-a]pyrazin-2-yl]pyridin-3-yl)acetamide; formic acid (compound 340)

A mixture of 2-(3-aminopyridin-4-yl)-3-[(3-fluoro-2-methoxyphenyl)amino]-5H,6H,7H- pyrazolo[1,5-a]pyrazin-4-one (50 mg, 0.13 mmol, 1.00 equiv) in trifluoroacetic anhydride (2.00 mL) at RT under nitrogen atmosphere. The resulting mixture was stirred for 1h at room temperatur e under nitrogen atmosphere. The resulting mixture was concentrated under reduced press ure. The crude product (40 mg) was purified by Prep-HPLC with the following conditions (Column: Xselect CSH OBD Column 30*150mm 5um, n; Mobile Phase A: Water (0.1%FA), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 30% B to 50% B in 8 min, 50% B; Wave Length: 254/220 nm; RT1(min): 7) to afford 2,2,2-trifluoro-N- (4-[3-[(3-fluoro-2-methoxyphenyl)amino]-4-oxo-5H,6H,7H-pyrazolo[1,5-a]pyrazin-2- yl]pyridin-3-yl)acetamide; formic acid (10.4 mg, 15%) as a light yellow solid. LC-MS: (M+H)⁺ found: 465.25. ¹H NMR (300 MHz, DMSO-d6) δ 11.59 (s, 1H), 8.91 (s, 1H), 8.51 – 8.05 (m, 2H), 7.71 (d, J = 5.2 Hz, 1H), 7.35 (s, 1H), 6.77 – 6.35 (m, 3H), 6.19 (dt, J = 7.9, 1.4 Hz, 1H), 4.35 (dd, J = 7.1, 5.0 Hz, 2H), 3.92 (s, 3H), 3.67 (ddd, J = 7.8, 4.9, 2.8 Hz, 2H). Example 77. N-(4-[3-[(3-fluoro-2-methoxyphenyl)amino]-4-oxo-5H,6H,7H- pyrazolo[1,5-a]pyrazin-2-yl]pyridin-3-yl)cyclobutanecarboxamide (compound 341)

A mixture of 2-(3-aminopyridin-4-yl)-3-[(3-fluoro-2-methoxyphenyl) amino]-5H,6H,7H- pyrazolo[1,5-a]pyrazin-4-one (50 mg, 0.13 mmol, 1.00 equiv) in pyridine (2.00 mL) at 0 degrees C under argon atmosphere. To the above mixture was added cyclobutanecarbonyl chloride (32 mg, 0.27 mmol, 2.00 equiv) dropwise at 0 degrees C. The resulting mixture was stirred for additional 30 min at room temperature. The resulting mixture was concentrated under reduced pressure. The crude product (50mg) was purified by Prep- HPLC with the following conditions (Column: Xselect CSH OBD Column 30*150mm 5um, n; Mobile Phase A: Water (0.1%FA), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 19% B to 35% B in 8 min, 35% B; Wave Length: 254/220 nm; RT1(min): 7.7) to afford N-(4-[3-[(3-fluoro-2-methoxyphenyl)amino]-4-oxo-5H,6H,7H-pyrazolo[1,5- a]pyrazin-2-yl]pyridin-3-yl)cyclobutanecarboxamide (6.8 mg, 11.00%) as an off- white solid. LC-MS: (M+H)⁺ found: 451.05. ¹H NMR (300 MHz, DMSO-d6) δ 10.09 (s, 1H), 9.31 (s, 1H), 8.37 (s, 1H), 8.21 (d, J = 5.1 Hz, 1H), 7.58 (d, J = 5.0 Hz, 1H), 7.34 (s, 1H), 6.87 - 6.26 (m, 2H), 6.08 (d, J = 8.1 Hz, 1H), 4.43 (t, J = 5.9 Hz, 2H), 3.90 (s, 3H), 3.70 (d, J = 6.6 Hz, 2H), 3.22 (d, J = 27.9 Hz, 1H), 2.21 (dq, J = 19.4, 9.6 Hz, 4H), 2.09 - 1.49 (m, 2H). Example 78. (1r,3r)-3-(dimethylamino)-N-(4-[3-[(3-fluoro-2-methoxyphenyl)amino]-4- oxo-5H,6H,7H-pyrazolo[1,5-a]pyrazin-2-yl]pyridin-3-yl)cyclobutane-1-carboxamide; formic acid (compound 342)

To a stirred solution of (1r,3r)-3-(dimethylamino)cyclobutane-1-carboxylic acid (60 mg, 0.41 mmol, 1.00 equiv) in THF (4 mL) was added oxalyl chloride (79 mg, 0.62 mmol, 1.5 equiv) and DMF (0.1 mL) dropwise at 0 degrees C under argon atmosphere. The resulting mixture was stirred for 30 min at 0 degrees C under argon atmosphere. The reaction was monitored by TLC (DCM/MeOH = 5/1). The resulting mixture was used in the next step directly without further purification.

To a stirred solution of 2-(3-aminopyridin-4-yl)-3-[(3-fluoro-2-methoxyphenyl)amino]- 5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (50 mg, 0.13 mmol, 1.00 equiv) in pyridine (0.3 mL) was added (1r,3r)-3-(dimethylamino)cyclobutane-1-carbonyl chloride (65 mg, 0.40 mmol, 3 equiv) in DCM (0.5 mL) dropwise at 0 degrees C under argon atmosphere. The resulting mixture was stirred for 1 h at room temperature under argon atmosphere. The reaction was monitored by LCMS. The reaction was quenched by the addition of MeOH (1mL) at 0 degrees C. The resulting mixture was concentrated under reduced pressure. The crude product (70 mg) was purified by Prep-HPLC with the following conditions (Column: Xselect CSH OBD Column 30*150mm 5um, n; Mobile Phase A: Water (0.1%FA), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 7% B to 20% B in 8 min, 20% B; Wave Length: 254/220 nm; RT1(min): 7.5) to afford (1r,3r)-3-(dimethylamino)-N-(4-[3-[(3- fluoro-2-methoxyphenyl)amino]-4-oxo-5H,6H,7H-pyrazolo[1,5-a]pyrazin-2-yl]pyridin- 3-yl)cyclobutane-1-carboxamide; formic acid (14.4 mg, 18.84%) as an off-white solid. LC-MS: (M+H)⁺ found: 494.10. ¹H NMR (400 MHz, DMSO-d6) δ 10.03 (s, 1H), 9.23 (s, 1H), 8.36 (d, 1H), 8.26 - 8.14 (m, 2H), 7.55 (d, 1H), 7.32 (s, 1H), 6.70 - 6.57 (m, 1H), 6.56 - 6.50 (m, 1H), 6.11 (d, 1H), 4.45 - 4.37 (m, 2H), 3.72 - 3.64 (m, 2H), 3.12 (m, 1H), 2.89 - 2.83 (m, 1H), 2.32 - 2.27 (m, 2H), 2.15 - 2.06 (m, 8H). Example 79.3-[(3-fluoro-2-methoxyphenyl)amino]-2-(3-hydroxypyridin-4-yl)- 5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (compound 349)

To a stirred mixture of 3-[(3-fluoro-2-methoxyphenyl)amino]-2-(3-fluoropyridin-4-yl)- 5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one(150 mg, 0.40 mmol, 1.00 equiv) and benzyl alcohol (7.77 mL) was added K₂CO₃ (334 mg, 2.42 mmol, 6 equiv) in portions at 120 degrees C under argon atmosphere. The resulting mixture was stirred for 4 days at 120 degrees C under argon atmosphere. Desired product could be detected by LCMS. The residue product was purified by reverse phase flash to afford 2-[3-(benzyloxy)pyridin-4- yl]-3-[(3-fluoro-2-methoxyphenyl)amino]-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (48 mg, 25.86%) as a light yellow solid. LC-MS: (M+H)⁺ found: 460.05.

To a stirred mixture of 2-[3-(benzyloxy)pyridin-4-yl]-3-[(3-fluoro-2- methoxyphenyl)amino]-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (40 mg, 0.087 mmol, 1.00 equiv) in HAc (5.00 mL) was added Pd/C (55 mg, 0.52 mmol, 6.00 equiv) in portions at room temperature under argon atmosphere. The resulting mixture was stirred for 4 h at room temperature under argon atmosphere. The resulting mixture was concentrated under reduced pressure. The crude product was purified by Prep-HPLC with the following conditions (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water (10 mmol/L NH₄HCO₃), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 12% B to 42% B in 7 min; Wave Length: 254 nm; RT1(min): 6.5) to afford 3-[(3-fluoro- 2-methoxyphenyl)amino]-2-(3-hydroxypyridin-4-yl)-5H,6H,7H-pyrazolo[1,5-a]pyrazin- 4-one (12.8 mg, 39.81%) as a white solid. LC-MS: (M+H)⁺ found: 370.25. ¹H NMR (300 MHz, DMSO-d6) δ 9.97 (s, 1H), 8.47 -7.94 (m, 3H), 7.50 (dd, J = 2.8, 1.8 Hz, 1H), 7.21 (s, 1H), 6.70 (td, J = 8.3, 6.0 Hz, 1H), 6.53 (ddd, J = 10.9, 8.3, 1.5 Hz, 1H), 6.00 (dt, J = 8.1, 1.3 Hz, 1H), 4.38 (dd, J = 7.1, 5.0 Hz, 2H), 3.90 (d, J = 0.8 Hz, 3H), 3.65 (dt, J = 7.7, 3.1 Hz, 2H). Example 80.3-[(3-chloro-2-methoxyphenyl)amino]-2-(3-fluoropyridin-4-yl)-5H,6H,7H- pyrazolo[1,5-a]pyrazin-4-one (compound 354)

To a stirred mixture of 2-(3-fluoropyridin-4-yl)-3-iodo-5H,6H,7H-pyrazolo[1,5-a]pyrazin- 4-one (50 mg, 0.69 mmol, 1.00 equiv) and 3-chloro-2-methoxyaniline (132 mg, 0.83 mmol, 1.2 equiv) in dioxane (2.50 mL) were added Cs₂CO₃ (454 mg, 1.39 mmol, 2 equiv) and Ephos Pd G4 (128 mg, 0.14 mmol, 0.20 equiv) in portions at 50 degrees C under argon atmosphere. Desired product could be detected by LCMS. The crude product (30 mg) was purified by Prep-HPLC with the following conditions (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water 10 mmol/L NH₄HCO₃), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 29% B to 59% B in 7 min; Wave Length: 254 nm; RT1(min): 6.5) to afford 3-[(3-chloro-2-methoxyphenyl)amino]-2-(3-fluoropyridin-4- yl)-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (5.7 mg, 10.53%) as a white solid. LC-MS: (M+H)⁺ found: 388.00. ¹H NMR (300 MHz, DMSO-d6) δ 8.79 (t, J = 1.7 Hz, 1H), 8.52 (d, J = 2.8 Hz, 1H), 8.30 (d, J = 2.9 Hz, 1H), 7.93 (ddd, J = 10.3, 2.9, 1.7 Hz, 1H), 7.37 (s, 1H), 6.83 - 6.62 (m, 2H), 6.16 (dd, J = 6.4, 3.2 Hz, 1H), 4.42 (dd, J = 7.1, 5.0 Hz, 2H), 3.87 (s, 3H), 3.72 - 3.55 (m, 2H). Example 81.3-[(3-chloro-2-methoxyphenyl)amino]-2-[3-(2-methoxyethoxy)pyridin-4- yl]-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (compound 355)

To a stirred mixture of 3-[(3-chloro-2-methoxyphenyl)amino]-2-(3-fluoropyridin-4-yl)- 5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (50 mg, 0.12 mmol, 1.00 equiv) in 2- methoxyethanol (5.00 mL) was added potassium methaneperoxoate potassium (125 mg, 0.90 mmol, 7.00 equiv) in portions at room temperature under argon atmosphere. The resulting mixture was stirred for 1.5 days at 150 degrees C under argon atmosphere. Desired product could be detected by LCMS. The crude product was purified by Prep- HPLC with the following conditions (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water (10 mmol/L NH₄HCO₃), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 24% B to 54% B in 7 min; Wave Length: 254 nm; RT1(min): 6.5) to afford 3-[(3-chloro-2-methoxyphenyl)amino]-2-[3-(2-methoxyethoxy)pyridin-4- yl]-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (8.1 mg, 14.15%) as a white solid. LC-MS: (M+H)⁺ found: 444.00. ¹H NMR (300 MHz, DMSO-d6) δ 8.53 (d, J = 1.7 Hz, 1H), 8.25 (dd, J = 25.5, 2.7 Hz, 2H), 7.62 (dd, J = 2.8, 1.7 Hz, 1H), 7.33 (s, 1H), 6.89 - 6.56 (m, 2H), 6.15 (dd, J = 6.4, 3.3 Hz, 1H), 4.40 (dd, J = 7.1, 5.0 Hz, 2H), 4.17 - 3.98 (m, 2H), 3.86 (s, 3H), 3.75 - 3.44 (m, 4H), 3.30 (d, J = 19.3 Hz, 3H). Example 82.3-[(3-chloro-2-methoxyphenyl)amino]-2-(3-cyclopropylpyridin-4-yl)- 5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (compound 356)

To a stirred mixture of 3-bromo-4-chloropyridine (500 mg, 2.59 mmol, 1.00 equiv) and cyclopropylboronic acid (245 mg, 2.85 mmol, 1.10 equiv) and Cs₂CO₃ (1693 mg, 5.19 mmol, 2.00 equiv) and Pd(dppf)Cl₂ CH₂Cl₂ (105 mg, 0.13 mmol, 0.05 equiv) in dioxane (10.0 mL) and H₂O (2.0 mL) in portions at room temperature under argon atmosphere. The resulting mixture was stirred for 4 h at 100 degrees C under argon atmosphere. Desired product could be detected by LCMS. The residue was purified by Prep-TLC (CH₂Cl₂/MeOH 20/1) to afford 4-chloro-3-cyclopropylpyridine (290 mg, 72.66%) as a yellow oil. LC-MS: (M+H)⁺ found: 154.

To a stirred mixture of 4-chloro-3-cyclopropylpyridine (200 mg, 1.30 mmol, 1.00 equiv) and 4-oxo-5H,6H,7H-pyrazolo[1,5-a]pyrazin-2-ylboronic acid (235 mg, 1.30 mmol, 1.00 equiv) and Na₂CO₃ (413 mg, 3.90 mmol, 3 equiv) and XPhos palladium(II) biphenyl-2- amine chloride(102 mg, 0.13 mmol, 0.1 equiv) in dioxane (13.0 mL) and H₂O (1.3 mL) in portions at room temperature under argon atmosphere. The resulting mixture was stirred for 1 h at 60 degrees C under argon atmosphere. Desired product could be detected by LCMS. The residue was purified by prep-TLC (CH₂Cl₂/MeOH 20:1) to afford 2-(3- cyclopropylpyridin-4-yl)-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (230 mg, 69.47%) as a yellow oil. LC-MS: (M+H)⁺ found: 255.

To a stirred mixture of 2-(3-cyclopropylpyridin-4-yl)-5H,6H,7H-pyrazolo[1,5-a]pyrazin- 4-one (200 mg, 0.786 mmol, 1.00 equiv) and dbdmh (337 mg, 1.18 mmol, 1.50 equiv) in AcOH (7.8 mL) in portions at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 1 h at 100 degrees C under nitrogen atmosphere. Desired product could be detected by LCMS. The residue was purified by prep-TLC (CH₂Cl₂/MeOH 15:1) to afford 3-bromo-2-(3-cyclopropylpyridin-4-yl)-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (130 mg, 49.61%) as a white solid. LC-MS: (M+H)⁺ found: 333.

To a stirred mixture of 3-bromo-2-(3-cyclopropylpyridin-4-yl)-5H,6H,7H-pyrazolo[1,5- a]pyrazin-4-one (100 mg, 0.30 mmol, 1.00 equiv) and 3-chloro-2-methoxyaniline (47 mg, 0.30 mmol, 1.00 equiv) and Ephos Pd G4 (27 mg, 0.03 mmol, 0.10 equiv) and EPhos (32 mg, 0.06 mmol, 0.20 equiv) and Cs₂CO₃ (195 mg, 0.60 mmol, 2.00 equiv) in DMF (0.50 mL) in portions at room temperature under argon atmosphere. The resulting mixture was stirred for 4 h at 50 degrees C under argon atmosphere. Desired product could be detected by LCMS. The crude product (100 mg) was purified by Prep-HPLC with the following conditions (Column: Xselect CSH OBD Column 30*150mm 5um; Mobile Phase A: Water(0.1%FA), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 10% B to 36% B in 8 min, 36% B; Wave Length: 254/220 nm; RT1(min): 7.62) to afford 3-[(3-chloro-2- methoxyphenyl)amino]-2-(3-cyclopropylpyridin-4-yl)-5H,6H,7H-pyrazolo[1,5- a]pyrazin-4-one (12.6 mg, 10.18%) as a red solid. LC-MS: (M+H)⁺ found: 410. ¹H NMR (400 MHz, DMSO-d6) δ 8.43 - 8.23 (m, 2H), 8.13 (s, 1H), 7.39 - 7.20 (m, 2H), 6.76 - 6.48 (m, 2H), 6.18 (dd, J = 6.6, 3.1 Hz, 1H), 4.40 (dd, J = 7.1, 4.9 Hz, 2H), 3.77 (s, 3H), 3.68 (ddd, J = 7.6, 4.9, 2.7 Hz, 2H), 2.21 (tt, J = 8.5, 5.3 Hz, 1H), 1.00 - 0.81 (m, 2H), 0.79 - 0.62 (m, 2H). Example 83.3-[(3-fluoro-2-methoxyphenyl) amino]-2-[2-methylthieno[3,2-b]pyridin-7- yl]-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (compound 363)

A mixture of 2-bromo-3-chloro-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (500 mg, 1.99 mmol, 1.00 equiv), bis(pinacolato)diboron (1 g, 3.99 mmol, 2.00 equiv) and KOAc (392 mg, 3.99 mmol, 2.00 equiv) in DME (20.00 mL) were added Pd(dppf)Cl₂ CH₂Cl₂ (243 mg, 0.29 mmol, 0.15 equiv) at room temperature under argon atmosphere. The resulting mixture was stirred for overnight at 100 degrees C under argon atmosphere. The mixture was allowed to cool down to room temperature. The resulting mixture was washed with DCM (3 x 100 mL). The resulting mixture was concentrated under reduced pressure. The resulting mixture was diluted with ethyl acetate (100 mL). The precipitated solids were collected by filtration and washed with ethyl acetate (3 x 5 mL). This resulted in 3-chloro- 4-oxo-5H,6H,7H-pyrazolo[1,5-a]pyrazin-2-ylboronic acid (400 mg, 83.73%) as a brown yellow solid. LC-MS: (M+H)⁺ found: 216.0.

A mixture of 3-chloro-4-oxo-5H,6H,7H-pyrazolo[1,5-a]pyrazin-2-ylboronic acid (530 mg, 2.46 mmol, 1.00 equiv), 7-chloro-2-methylthieno[3,2-b]pyridine (542 mg, 2.95 mmol, 1.20 equiv), PCy3 (138 mg, 0.49 mmol, 0.20 equiv) and Cs₂CO₃ (2.4 g, 7.38 mmol, 3.00 equiv) in dioxane (20.00 mL) and H₂O (4.00 mL) at room temperature under nitrogen atmosphere. To the above mixture was added Pd₂(dba)₃ (225 mg, 0.24 mmol, 0.10 equiv) under nitrogen atmosphere. The resulting mixture was stirred for additional overnight at 60 degrees C. The resulting mixture was filtered and the filter cake was washed with MeOH (3 x 10 mL). The filtrate was concentrated under reduced pressure. The residue was purified by reverse flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeOH in water, 10% to 50% gradient in 10 min; detector, UV 254 nm. This resulted in 3- chloro-2-[2-methylthieno[3,2-b]pyridin-7-yl]-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (210 mg, 25.70%) as a brown solid. LC-MS: (M+H)⁺ found: 319.0.

A mixture of 3-chloro-2-[2-methylthieno[3,2-b]pyridin-7-yl]-5H,6H,7H-pyrazolo[1,5- a]pyrazin-4-one (100 mg, 0.31 mmol, 1.00 equiv) in DMF (3.00 mL) under argon atmosphere. To the above mixture was added 3-fluoro-2-methoxyaniline (88 mg, 0.62 mmol, 2.00 equiv), EPhos (83 mg, 0.15 mmol, 0.50equiv), EPhos Pd G4 (144 mg, 0.15 mmol, 0.50 equiv) and Cs₂CO₃ (306 mg, 0.94 mmol, 3.00 equiv) under argon atmosphere. The resulting mixture was stirred for additional overnight at 50 degrees C. The residue was purified by silica gel column chromatography, eluted with CH₂Cl₂/MeOH (10:1) to afford crude product. The product was precipitated by the addition of Column: XBridge Prep C18 OBD Column, 30*100 mm, 5μm; Mobile Phase A: Water (10 mmol/L NH₄HCO₃), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 25% B to 48% B in 10 min, 48% B; Wave Length: 254/220 nm; RT1(min): 9.28). This resulted in 3-[(3-fluoro-2-methoxyphenyl) amino]-2-[2-methylthieno[3,2-b]pyridin-7-yl]-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (17.5 mg, 13.09%) as an off-white solid. LC-MS: (M+H)⁺ found: 423.95. ¹H NMR (300 MHz, DMSO-d6) δ 8.49 (d, J = 5.0 Hz, 1H), 8.36 (d, J = 2.8 Hz, 1H), 7.54 (d, J = 5.0 Hz, 1H), 7.39 (s, 1H), 7.28 (d, J = 1.4 Hz, 1H), 6.76 - 6.49 (m, 2H), 5.98 (dt, J = 8.1, 1.3 Hz, 1H), 4.48 (dd, J = 7.1, 5.0 Hz, 2H), 3.95 (s, 3H), 3.72 (dd, J = 6.9, 3.4 Hz, 2H), 2.65 (d, J = 1.2 Hz, 3H). Example 84.3-[(3-chloro-2-methoxyphenyl)amino]-2-[2-methylthieno[3,2-b]pyridin-7- yl]-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (compound 362)

A mixture of 3-chloro-2-[2-methylthieno[3,2-b]pyridin-7-yl]-5H,6H,7H-pyrazolo[1,5- a]pyrazin-4-one (80 mg, 0.25 mmol, 1.00 equiv) in DMF (3.00 mL) under argon atmosphere. To the above mixture was added 3-chloro-2-methoxyaniline (79 mg, 0.50 mmol, 2.00 equiv), EPhos (67 mg, 0.12 mmol, 0.50 equiv), EPhos Pd G4 (115 mg, 0.12 mmol, 0.50 equiv) and Cs₂CO₃ (245 mg, 0.75 mmol, 3.00 equiv) under argon atmosphere. The resulting mixture was stirred for additional overnight at 50 degrees C. The residue was purified by silica gel column chromatography, eluted with CH₂Cl₂/MeOH (10:1) to afford crude product. The product was precipitated by Column: Xselect CSH OBD Column 30*150mm 5um, n; Mobile Phase A: Water (10 mmol/L NH₄HCO₃), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 34% B to 50% B in 10 min, 50% B; Wave Length: 220/254 nm; RT1(min): 9.0). This resulted in 3-[(3-chloro-2-methoxyphenyl)amino]-2-[2- methylthieno[3,2-b]pyridin-7-yl]-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (9 mg, 8.01%) as an off-white solid. LC-MS: (M+H)⁺ found: 440.20. ¹H NMR (300 MHz, DMSO-d6) δ 8.49 (d, J = 5.0 Hz, 1H), 8.36 (t, J = 2.8 Hz, 1H), 7.54 (d, J = 5.0 Hz, 1H), 7.45 (s, 1H), 7.29 (d, J = 1.3 Hz, 1H), 6.78 - 6.67 (m, 2H), 6.13 (dd, J = 7.1, 2.5 Hz, 1H), 4.49 (dd, J = 7.1, 4.9 Hz, 2H), 3.92 (s, 3H), 3.71 (ddd, J = 7.9, 4.7, 2.6 Hz, 2H), 2.65 (d, J = 1.2 Hz, 3H). Example 85.3-[(3-fluoro-2-methoxy-4-{thieno[3,2-b]pyridin-7-yl}phenyl)amino]-7,7- dimethyl-5H,6H-pyrazolo[1,5-a]pyrazin-4-one (compound 367)

To a stirred mixture of methyl 4-bromo-2H-pyrazole-3-carboxylate (1 g, 4.87 mmol, 1 equiv) and tert-butyl N-(2-hydroxy-2-methylpropyl)carbamate (1.85 g, 9.75 mmol, 2 equiv) in THF (20 mL) were added DIAD (1.78 g, 8.78 mmol, 1.8 equiv) and PPh₃ (2.30 g, 8.78 mmol, 1.8 equiv) in portions at room temperature under nitrogen atmosphere. The resulting mixture was stirred for overnight at room temperature under nitrogen atmosphere. Desired product could be detected by LCMS. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with PE/EA (8:1) to afford methyl 4-bromo-2-{1-[(tert-butoxycarbonyl)amino]-2-methylpropan-2- yl}pyrazole-3-carboxylate (1.5 g, 81.73%) as a white solid. LC-MS: [M+H]⁺ found: 375.90.

A mixture of methyl 4-bromo-2-{1-[(tert-butoxycarbonyl)amino]-2-methylpropan-2- yl}pyrazole-3-carboxylate (2 g, 5.316 mmol, 1 equiv) in HCl (gas) in 1,4-dioxane (10 mL) and DCM (10 mL) was stirred for 1 h at 0 °C under nitrogen atmosphere. Desired product could be detected by LCMS. The resulting mixture was concentrated under reduced pressure. This resulted in methyl 2-(1-amino-2-methylpropan-2-yl)-4-bromopyrazole-3- carboxylate (1.3 g, 88.57%) as a light yellow oil. LC-MS: [M+H]⁺ found: 275.90.

A mixture of methyl 2-(1-amino-2-methylpropan-2-yl)-4-bromopyrazole-3-carboxylate (1.3 g, 4.70 mmol, 1 equiv) and sodium methoxide (1.27 g, 23.54 mmol, 5 equiv) in methanol (13 mL) was stirred for 1 h at room temperature under air atmosphere. Desired product could be detected by LCMS. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with PE/EA (1:1) to afford 3-bromo-7,7-dimethyl-5H,6H-pyrazolo[1,5-a]pyrazin-4-one (650 mg, 56.56%) as a white solid. LC-MS: [M+H]⁺ found: 244.00.

To a stirred mixture of 3-bromo-7,7-dimethyl-5H,6H-pyrazolo[1,5-a]pyrazin-4-one (300 mg, 1.22 mmol, 1 equiv) and 3-fluoro-2-methoxyaniline (520 mg, 3.68 mmol, 3 equiv) in DMF (10 mL) were added Ephos Pd G4 (338 mg, 0.36 mmol, 0.3 equiv) and Cs₂CO₃ (800 mg, 2.45 mmol, 2 equiv) in portions at room temperature under argon atmosphere. The resulting mixture was stirred for 2 h at 50 °C under argon atmosphere. Desired product could be detected by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH₂Cl₂/MeOH (20:1) to afford 3-[(3-fluoro-2-methoxyphenyl)amino]-7,7-dimethyl- 5H,6H-pyrazolo[1,5-a]pyrazin-4-one (300 mg, 80.21%) as a yellow solid. LC-MS: [M-H]- found: 302.90.

A mixture of 3-[(3-fluoro-2-methoxyphenyl)amino]-7,7-dimethyl-5H,6H-pyrazolo[1,5- a]pyrazin-4-one (150 mg, 0.49 mmol, 1 equiv) and NBS (87 mg, 0.49 mmol, 1 equiv) in DMF (2 mL) was stirred for overnight at room temperature under nitrogen atmosphere. Desired product could be detected by LCMS. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with CH₂Cl₂/MeOH (20:1) to afford 3-[(4-bromo-3-fluoro-2-methoxyphenyl)amino]-7,7- dimethyl-5H,6H-pyrazolo[1,5-a]pyrazin-4-one (180 mg, 95.29%) as a yellow solid. LC-MS: [M+H]⁺ found: 383.00.

To a stirred mixture of 3-[(4-bromo-3-fluoro-2-methoxyphenyl)amino]-7,7-dimethyl- 5H,6H-pyrazolo[1,5-a]pyrazin-4-one (190 mg, 0.49 mmol, 1 equiv) and 7-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)thieno[3,2-b]pyridine (258 mg, 0.99 mmol, 2 equiv) in 1,4-dioxane (2 mL) and water (0.4 mL) were added XPhos palladium(II) biphenyl-2- amine chloride (39 mg, 0.05 mmol, 0.1 equiv) and Na₂CO₃ (157 mg, 1.48 mmol, 3 equiv) in portions at room temperature under argon atmosphere. The resulting mixture was stirred for 2 h at 50 °C under argon atmosphere. The resulting mixture was concentrated under reduced pressure. The crude product was purified by Prep-HPLC with the following conditions (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water (10 mmol/L NH₄HCO₃), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 38% B to 54% B in 8 min, 54% B; Wave Length: 254/220 nm; RT1(min): 7) to afford 3- [(3-fluoro-2-methoxy-4-{thieno[3,2-b]pyridin-7-yl}phenyl)amino]-7,7-dimethyl-5H,6H- pyrazolo[1,5-a]pyrazin-4-one (49.6 mg, 22.87%) as a light yellow solid. LC-MS: [M+H]⁺ found: 438.00. ¹H NMR (300 MHz, DMSO-d6) δ 8.74 (d, J = 4.8 Hz, 1H), 8.43 (s, 1H), 8.29 (s, 1H), 8.19 (d, J = 5.5 Hz, 1H), 7.98 (s, 1H), 7.65 (d, J = 5.6 Hz, 1H), 7.42 - 7.37 (m, 2H), 7.28 (d, J = 8.6 Hz, 1H), 3.95 (s, 3H), 3.49 (d, J = 2.8 Hz, 2H), 1.48 (s, 6H). Example 86.3-[(3-chloro-2-methoxy-4-{thieno[3,2-b]pyridin-7-yl}phenyl)amino]-7,7- dimethyl-5H,6H-pyrazolo[1,5-a]pyrazin-4-one (compound 366)

To a stirred mixture of 3-bromo-7,7-dimethyl-5H,6H-pyrazolo[1,5-a]pyrazin-4-one (300 mg, 1.22 mmol, 1 equiv) and 3-chloro-2-methoxyaniline (290 mg, 1.84 mmol, 1.5 equiv) in DMF (10 mL) were added Ephos Pd G4 (112 mg, 0.12 mmol, 0.1 equiv) and Cs₂CO₃ (800 mg, 2.45 mmol, 2 equiv) in portions at room temperature under argon atmosphere. The resulting mixture was stirred for 2 h at 50 °C under argon atmosphere. Desired product could be detected by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with DCM/MeOH (20:1) to afford 3-[(3-chloro-2-methoxyphenyl)amino]-7,7-dimethyl- 5H,6H-pyrazolo[1,5-a]pyrazin-4-one (200 mg, 50.73%) as a yellow solid. LC-MS: [M-H]- found: 320.95.

A mixture of 3-[(3-chloro-2-methoxyphenyl)amino]-7,7-dimethyl-5H,6H-pyrazolo[1,5- a]pyrazin-4-one (190 mg, 0.59 mmol, 1 equiv) and NBS (105 mg, 0.59 mmol, 1 equiv) in DMF (2 mL) was stirred for overnight at room temperature under nitrogen atmosphere. Desired product could be detected by LCMS. The reaction was quenched with sat. sodium sulfite (aq.) at room temperature. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with DCM/MeOH (15:1) to afford 3-[(4-bromo-3-chloro-2-methoxyphenyl)amino]-7,7-dimethyl-5H,6H- pyrazolo[1,5-a]pyrazin-4-one (200 mg, 84.49%) as a yellow solid. LC-MS: [M+H]⁺ found: 399.00.

To a stirred mixture of 7-bromothieno[3,2-b]pyridine (300 mg, 1.40 mmol, 1 equiv), bis(pinacolato)diboron (391 mg, 1.54 mmol, 1.1 equiv) and KOAc (206 mg, 2.10 mmol, 1.5 equiv) in 1,4-dioxane (6 mL) were added PCy₃*HBF₄ (36 mg, 0.098 mmol, 0.07 equiv) and Pd₂(dba)₃ (38 mg, 0.04 mmol, 0.03 equiv) in portions at room temperature under argon atmosphere. The resulting mixture was stirred for overnight at 120 °C under argon atmosphere. Desired product could be detected by LCMS. The resulting mixture was filtered and the filter cake was washed with 1,4-dioxane (1 x 4 mL). The filtrate directly used for the next step response. LC-MS: [M+H]⁺ found: 262.00.

To a stirred mixture of 3-[(4-bromo-3-chloro-2-methoxyphenyl)amino]-7,7-dimethyl- 5H,6H-pyrazolo[1,5-a]pyrazin-4-one (190 mg, 0.47 mmol, 1 equiv) and 7-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)thieno[3,2-b]pyridine (248 mg, 0.95 mmol, 2 equiv) in 1,4-dioxane (2 mL) and water (0.5 mL) were added XPhos palladium(II) biphenyl-2- amine chloride (37 mg, 0.048 mmol, 0.1 equiv) and Na₂CO₃ (100 mg, 0.95 mmol, 2 equiv) in portions at room temperature under argon atmosphere. The resulting mixture was stirred for 2 h at 50 °C under argon atmosphere. The resulting mixture was concentrated under reduced pressure. The crude product was purified by prep-HPLC with the following conditions (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water (10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 38% B to 54% B in 8 min, 54% B; Wave Length: 254/220 nm; RT1(min): 7) to afford 3- [(3-chloro-2-methoxy-4-{thieno[3,2-b]pyridin-7-yl}phenyl)amino]-7,7-dimethyl-5H,6H- pyrazolo[1,5-a]pyrazin-4-one (26.4 mg, 12.01%) as a white solid. LC-MS: [M+H]⁺ found: 454.00. ¹H NMR (300 MHz, DMSO-d6) δ 8.74 (d, J = 4.8 Hz, 1H), 8.42 (s, 1H), 8.29 (s, 1H), 8.16 (d, J = 5.5 Hz, 1H), 7.97 (s, 1H), 7.64 (d, J = 5.6 Hz, 1H), 7.41 – 7.27 (m, 3H), 3.88 (s, 3H), 3.49 (d, J = 2.8 Hz, 2H), 1.48 (s, 6H). Example 87. 3-[(3-chloro-2-methoxyphenyl)amino]-6,6-dimethyl-2-{[1,2]thiazolo[4,5- b]pyridin-7-yl}-5H,7H-pyrazolo[1,5-a]pyrazin-4-one (compound 297)

A solution of imidazole (431 mg, 6.34 mmol, 6.00 equiv) in DCM (10 mL) was treated with SO2Cl₂ (256 mg, 1.90 mmol, 1.8 equiv) for 30 min at -5 degrees C under nitrogen atmosphere followed by the addition of tert-butyl N-(1-hydroxy-2-methylpropan-2- yl)carbamate (200 mg, 1.05 mmol, 1.00 equiv) in portions at 0 degrees C. Desired product could be detected by TLC. The aqueous layer was extracted with CH₂Cl₂ (2x100 mL). The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EA (10:1) to afford tert-butyl 4,4- dimethyl-2-oxo-1,2lambda4,3-oxathiazolidine-3-carboxylate (220 mg, 88.47%) as a colorless oil.

A mixture of tert-butyl 4,4-dimethyl-2-oxo-1,2lambda4,3-oxathiazolidine-3-carboxylate (240 mg, 1.02 mmol, 1.00 equiv), NaIO₄ (218 mg, 1.00 mmol, 1.00 equiv) and RuCl₃.H₂O (0.11 mg, 0.001 mmol, 0.0005 equiv) in MeCN (10 mL) and H₂O (7 mL) was stirred for 0.5 h at room temperature under air atmosphere. Desired product could be detected by TLC. The aqueous layer was extracted with CH₂Cl₂ (2 x 100 mL). The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EA (10:1) to afford tert-butyl 4,4-dimethyl-2,2-dioxo- 1,2lambda6,3-oxathiazolidine-3-carboxylate (170 mg, 66.32%) as a white solid.

A mixture of methyl 5-bromo-2H-pyrazole-3-carboxylate (500 mg, 2.43 mmol, 1 equiv) and Cs₂CO₃ (371 mg, 4.87 mmol, 2 equiv) in DMF (20.00 mL) was stirred for 2 h at 80 °C under nitrogen atmosphere. Desired product could be detected by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (7:1) to afford methyl 5-bromo-2-{2-[(tert- butoxycarbonyl)amino]-2-methylpropyl}pyrazole-3-carboxylate (450 mg, 49.04%) as an off-white solid. LC-MS: (M-H)- found: 375.95.

A solution of methyl 5-bromo-2-{2-[(tert-butoxycarbonyl)amino]-2- methylpropyl}pyrazole-3-carboxylate (450 mg, 1.19 mmol, 1 equiv) in DCM (4 mL) and HCl (gas) in 1,4-dioxane (4 mL) was stirred for 1 h at room temperature under nitrogen atmosphere. Desired product could be detected by LCMS. The resulting mixture was concentrated under reduced pressure. The resulting mixture was used in the next step directly without further purification. LC-MS: (M+H)⁺ found: 275.80.

A mixture of methyl 2-(2-amino-2-methylpropyl)-5-bromopyrazole-3-carboxylate (430 mg, 1.55 mmol, 1 equiv) and sodium methoxide (420 mg, 7.78 mmol, 5 equiv) in methanol (10 mL) was stirred for 1 h at room temperature under nitrogen atmosphere. Desired product could be detected by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EA (5:1) to afford 2-bromo-6,6-dimethyl-5H,7H-pyrazolo[1,5-a]pyrazin-4-one (310 mg, 81.56%) as an off-white solid. LC-MS: (M+H)⁺ found: 243.85.

A mixture of 2-bromo-6,6-dimethyl-5H,7H-pyrazolo[1,5-a]pyrazin-4-one (300 mg, 1.22 mmol, 1 equiv) and NCS (196 mg, 1.47 mmol, 1.2 equiv) in DMF (10 mL) was stirred for overnight at 100 °C under air atmosphere. Desired product could be detected by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with DCM/MeOH (20:1) to afford 2-bromo- 3-chloro-6,6-dimethyl-5H,7H-pyrazolo[1,5-a]pyrazin-4-one (330 mg, 96.40%) as a light yellow solid. LC-MS: [M+H]⁺ found: 277.80.

A mixture of 2-bromo-3-chloro-6,6-dimethyl-5H,7H-pyrazolo[1,5-a]pyrazin-4-one (50 mg, 0.18 mmol, 1 equiv), bis(pinacolato)diboron (68 mg, 0.27 mmol, 1.5 equiv), potassium acetate (52 mg, 0.54 mmol, 3 equiv) and Pd(dppf)Cl₂ (13 mg, 0.018 mmol, 0.1 equiv) in dioxane (2 mL) was stirred for overnight at 100 °C under nitrogen atmosphere. Desired product could be detected by LCMS. The resulting mixture was used in the next step directly without further purification. LC-MS: (M+H)⁺ found 326.00.

A mixture of 7-chloro-[1,2]thiazolo[4,5-b]pyridine (200 mg, 1.17 mmol, 1 equiv), 3- chloro-6,6-dimethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5H,7H- pyrazolo[1,5-a]pyrazin-4-one (458 mg, 1.40 mmol, 1.2 equiv), XPhos palladium(II) biphenyl-2-amine chloride (92 mg, 0.11 mmol, 0.1 equiv) and Na₂CO₃ (372 mg, 3.51 mmol, 3 equiv) in dioxane (5 mL) and water (1 mL) was stirred for 2 h at 50 °C under argon atmosphere. Desired product could be detected by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH₂Cl₂/MeOH (20:1) to afford 3-chloro-6,6-dimethyl-2- {[1,2]thiazolo[4,5-b]pyridin-7-yl}-5H,7H-pyrazolo[1,5-a]pyrazin-4-one (185 mg, 47.28%) as a yellow solid. LC-MS: (M+H)⁺ found: 333.90.

A solution of 3-chloro-6,6-dimethyl-2-{[1,2]thiazolo[4,5-b]pyridin-7-yl}-5H,7H- pyrazolo[1,5-a]pyrazin-4-one (100 mg, 0.30 mmol, 1.00 equiv) ,EPhos Pd G4 (27 mg, 0.03 mmol, 0.1 equiv) and Cs₂CO₃ (195 mg, 0.60 mmol, 2 equiv) in DMF (2 mL) was stirred for 2 h at 50 degrees C under argon atmosphere. Desired product could be detected by LCMS. The crude product was purified by Prep-HPLC with the following conditions (Column: XBridge Prep C18 OBD Column, 30*100 mm, 5μm; Mobile Phase A: Water (10 mmol/L NH₄HCO₃), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 36% B to 64% B in 8 min, 64% B; Wave Length: 254/220 nm; RT1(min): 6.32) to afford 3-[(3- chloro-2-methoxyphenyl)amino]-6,6-dimethyl-2-{[1,2]thiazolo[4,5-b]pyridin-7-yl}- 5H,7H-pyrazolo[1,5-a]pyrazin-4-one (7.2 mg, 5.24%) as a white solid. LC-MS: (M+H)⁺ found: 454.93. ¹H NMR (300 MHz, DMSO-d6) δ 9.31 (s, 1H), 8.81 (d, J = 4.8 Hz, 1H), 8.50 (s, 1H), 7.76 (d, J = 4.8 Hz, 1H), 7.56 (s, 1H), 6.80 - 6.73 (m, 2H), 6.22 - 6.15 (m, 1H), 4.45 (s, 2H), 3.94 (s, 3H), 1.34 (s, 6H). Example 88.3-[(3-chloro-2-methoxyphenyl)amino]-2-{3-[(3- methoxypropyl)amino]pyridin-4-yl}-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (compound 303)

To a stirred mixture of 3-[(3-chloro-2-methoxyphenyl)amino]-2-(3-fluoropyridin-4-yl)- 5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (80 mg, 0.20 mmol, 1.00 equiv) and 3- methoxypropylamine (0.5 mL) in DMSO (1 mL) was added DIEA (399 mg, 3.09 mmol, 15 equiv) in portions at room temperature under argon atmosphere. The resulting mixture was stirred for overnight at 120 degrees C under argon atmosphere. Desired product could be detected by LCMS. The resulting mixture was concentrated under reduced pressure. The crude product (80 mg) was purified by Prep-HPLC with the following conditions (Column: YMC-Actus Triart C18 ExRS, 30*150 mm, 5μm; Mobile Phase A: Water (10 mmol/L NH₄HCO₃), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 20% B to 40% B in 10 min, 40% B; Wave Length: 254/220 nm; RT1(min): 10.38) to afford 3-[(3- chloro-2-methoxyphenyl)amino]-2-{3-[(3-methoxypropyl)amino]pyridin-4-yl}- 5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (7.5 mg, 7.90%) as a white solid. LC-MS: (M+H)⁺ found: 457. ¹H NMR (300 MHz, DMSO-d6) δ 1.84 (m, J = 6.5 Hz, 2H), 3.30 (d, J = 6.1 Hz, 5H), 3.45 (t, J = 6.1 Hz, 2H), 3.68 (q, J = 6.7, 4.9 Hz, 2H), 3.85 (s, 3H), 4.41 (dd, J = 7.1, 5.0 Hz, 2H), 6.11 (t, J = 4.8 Hz, 1H), 6.69 (dd, J = 8.3, 5.0 Hz, 3H), 7.2–7.4 (m, 2H), 7.72 (d, J = 5.0 Hz, 1H), 8.08 (s, 1H), 8.33 (t, J = 2.7 Hz, 1H) Example 89.3-[(3-chloro-2-methoxyphenyl)amino]-2-[3-(2-cyclopropylethynyl)pyridin- 4-yl]-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (compound 185)

A mixture of 3-amino-2-bromo-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (220 mg, 0.95 mmol, 1.00 equiv) in DCE (10.00 mL) was added 3-chloro-2-methoxyphenylboronic acid(425 mg, 2.29 mmol, 2.40 equiv), Cu(OAc)₂ (190 mg, 1.05 mmol, 1.10 equiv), TEA (289 mg, 2.85 mmol, 3.00 equiv) in DCE (10.00 mL) was stirred overnight at room temperature under oxygen atmosphere. Desired product could be detected by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EA (5:1) to afford 2-bromo-3-[(3- chloro-2-methoxyphenyl)amino]-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (120 mg, 33.91%) as an off-white solid. LC-MS: [M+H]⁺ found: 372.90.

A mixture of 2-bromo-3-[(3-chloro-2-methoxyphenyl)amino]-5H,6H,7H-pyrazolo[1,5- a]pyrazin-4-one (100 mg, 0.26 mmol, 1.00 equiv), 3-(2-cyclopropylethynyl)pyridin-4- ylboronic acid (50 mg, 0.26 mmol, 1.00 equiv), Na₂CO₃ (57 mg, 0.52 mmol, 2.00 equiv) and XPhos Pd G2 (21 mg, 0.03 mmol, 0.10 equiv) in 1,4-dioxane (2.00 mL) and water (0.50 mL) was stirred for 2 h at 50 degrees C under argon atmosphere. Desired product could be detected by LCMS. The resulting mixture was concentrated under reduced pressure. The crude product was purified by Prep-HPLC with the following conditions (Column: XBridge Prep OBD C18 Column, 19*250 mm, 5μm; Mobile Phase A: Water (10 mmol/L NH₄HCO₃), Mobile Phase B: ACN; Flow rate: 25 mL/min; Gradient: 40% B to 46% B in 10 min, 46% B; Wave Length: 254 nm; RT1(min): 8.88) to afford 3-[(3-chloro- 2-methoxyphenyl)amino]-2-[3-(2-cyclopropylethynyl)pyridin-4-yl]-5H,6H,7H- pyrazolo[1,5-a]pyrazin-4-one (11.3 mg, 9.62%) as a light yellow solid. LC-MS: (M+H)⁺ found: 434.00. ¹H NMR (300 MHz, MeOD-d₄) δ 8.40 (s, 1H), 8.28 (d, 1H), 7.41 - 7.39 (m, 1H), 6.59 - 6.46 (m, 2H), 6.13 -6.10 (m, 1H), 4.37 - 4.33 (m, 2H), 3.80 (s, 3H), 3.77 - 3.70 (m, 2H), 1.38 - 1.31 (m, 1H), 0.83 - 0.79 (m, 2H), 0.70 - 0.60(m, 2H). Example 90.3-[(3-chloro-2-methoxyphenyl)amino]-2-(6,7-dimethoxyquinolin-4-yl)- 5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (compound 252)

A mixture of 4-bromo-6,7-dimethoxyquinoline (200 mg, 0.74 mmol, 1.00 equiv) in 1,4- dioxane (3.00 mL) was added bis(pinacolato)diboron (284 mg, 1.11 mmol, 1.50 equiv), KOAc (146 mg, 1.48 mmol, 2.00 equiv), Pd(dppf)Cl₂ (54 mg, 0.07 mmol, 0.10 equiv). The reaction was stirred for overnight at 50 degrees C under argon atmosphere. Desired product could be detected by LCMS. The precipitated solids were collected by filtration. The resulting mixture was concentrated under reduced pressure. The crude product was used in the next step directly without further purification. LC-MS: (M+H) ⁺ found: 316.15.

A mixture of 6,7-dimethoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline (100 mg, 0.32 mmol, 1.00 equiv), 2-bromo-3-[(3-chloro-2-methoxyphenyl)amino]- 5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (141 mg, 0.38 mmol, 1.20 equiv), Na₂CO₃ (67 mg, 0.64 mmol, 2.00 equiv) and XPhos Pd G2 (24 mg, 0.03 mmol, 0.10 equiv) in 1,4- dioxane (5.00 mL) and water (1.00 mL) was stirred overnight at 80 degrees C under argon atmosphere. Desired product could be detected by LCMS. The resulting mixture was concentrated under reduced pressure. The crude product was purified by Prep-HPLC with the following conditions (Column: XBridge Prep C18 OBD Column, 30*100 mm, 5μm; Mobile Phase A: Water(10 mmol/L NH₄HCO₃), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 22% B to 42% B in 10 min, 42% B; Wave Length: 254/220 nm; RT1(min): 10.38) to afford 3-[(3-chloro-2-methoxyphenyl)amino]-2-(6,7- dimethoxyquinolin-4-yl)-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (25.3 mg, 16.48%) as a white solid. LC-MS: (M+H)⁺ found: 480.00. ¹H NMR (300 MHz, DMSO-d6) δ 8.63 (d, 1H), 8.32 (s, 1H), 7.62 (s, 1H), 7.45 (d, 1H), 7.41 (s, 1H), 7.36 (s, 1H), 6.60 - 6.57 (m, 2H), 6.15 - 6.12 (m, 1H), 4.47 (t, 2H), 3.91 (s, 3H), 3.72 (s, 2H), 3.63 (s, 6H). Example 91.3-[(3-chloro-2-methoxyphenyl)amino]-2-{[1,2]thiazolo[4,5-b]pyridin-7- yl}-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (compound 221)

In a 250-mL round bottom flask, to a solution of 2,2,6,6-tetramethylpiperidine (4.73 g, 33.45 mmol, 1.10 equiv) in THF (30.00 mL) was added dropwise n-BuLi (2.05 g, 31.93 mmol, 1.05 equiv) solution (1.6 M in hexane, 20 mL) at -78 degrees C under N₂ atmosphere. The reaction mixture was stirred at -78 degrees C for 10 mins. The resulting mixture was stirred for 1h at room temperature under nitrogen atmosphere. Then a solution of 4-chloro- 3-fluoropyridine (4.00 g, 30.41 mmol, 1.00 equiv) in 20 mL THF was added dropwise and the mixture was stirred for another 20 mins. The resulting mixture was stirred for 30min at -78 degrees C under nitrogen atmosphere. To the above mixture was added morpholine-4- carbaldehyde (3.68 g, 31.93 mmol, 1.05 equiv) dropwise over 10 min at -78 degrees C. The resulting mixture was stirred for additional 20 min at -78 degrees C. The reaction was quenched with ice water (1 mL). The resulting mixture was dried Na₂SO₄. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with PE / EA (20:1) to afford 4-chloro-3-fluoropyridine-2- carbaldehyde (1.50 g, 30.92%) as a yellow solid. LC-MS: (M+H)⁺ found: 158.9.

To a stirred solution of (4-methoxyphenyl)methanethiol (4.06 g, 26.33 mmol, 0.70 equiv) in THF (80.00 mL) was added t-BuOK (2.95 g, 26.33 mmol, 0.70 equiv) dropwise at 0 degrees C under nitrogen atmosphere. The resulting mixture was stirred for 1h at 0 degrees C under nitrogen atmosphere. To the above mixture was added 4-chloro-3-fluoropyridine- 2-carbaldehyde (6.00 g, 37.61 mmol, 1.00 equiv) dropwise over 20 min at -78 degrees C. The resulting mixture was stirred for additional 30min at 0 degrees C. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with PE/EA (30:1) to afford 4-chloro-3-{[(4- methoxyphenyl)methyl] sulfanyl}pyridine-2-carbaldehyde (4.80 g, 43.45%) as a yellow oil. LC-MS: (M+H)⁺ found: 293.80.

To a stirred solution of 4-chloro-3-{[(4-methoxyphenyl)methyl]sulfanyl}pyridine-2- carbaldehyde (18.00 g, 61.27 mmol, 1.00 equiv) in DCE (400 mL) was added SO₂Cl₂ (16.54 g, 1.23 mol, 2.00 equiv) dropwise at 0 degrees C under nitrogen atmosphere. The resulting mixture was stirred for 1h at 0 degrees C under nitrogen atmosphere. To the above mixture was added Ammonia (7.0 M Solution in MeOH, 44.00 mL, 308.00 mmol, 5.00 equiv) dropwise over 20 min at 0 degrees C. The resulting mixture was stirred for additional 1h at 0 degrees C. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with EA / PE (1:4) to afford 7-chloro- [1,2]thiazolo[4,5-b]pyridine (2.50 g, 23.8%) as an off-white solid. LC-MS: (M+H)⁺ found: 171.0.

To a stirred mixture of 7-chloro-[1,2]thiazolo[4,5-b]pyridine (3.60 g, 21.10 mmol, 1.00 equiv) and 3-chloro-4-oxo-5H,6H,7H-pyrazolo[1,5-a]pyrazin-2-ylboronic acid (5.45 g, 25.32 mmol, 1.20 equiv) in 1,4-dioxane (100.00 mL) and H₂O (20.00 mL) were added 2nd Generation XPhos Precatalyst (1.66 g, 2.11 mmol, 0.10 equiv) and Na₂CO₃ (6.71 g, 63.30 mmol, 3.00 equiv) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 2h at 50 °C under argon atmosphere. The reaction was monitored by LCMS. LCMS showed the reaction was completed. The resulting mixture was concentrated under reduced pressure. The resulting mixture was washed with 2 x 20 mL of water. The precipitated solids were collected by filtration and washed with acetonitrile (3 x 20 mL). The resulting mixture was concentrated under reduced pressure to obtain 3-chloro-2- {[1,2]thiazolo[4,5-b]pyridin-7-yl}-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one(2.64 g, 40.9%) as a light yellow solid. LC-MS: (M+H)⁺ found: 305.90.

To a stirred solution of 3-chloro-2-{[1,2]thiazolo[4,5-b]pyridin-7-yl}-5H,6H,7H- pyrazolo[1,5-a]pyrazin-4-one (8.00 g, 26.17 mmol, 1.00 equiv) in DMF (80.00 mL) was added Cs₂CO₃ (17.05 g, 52.33 mmol, 2.00 equiv) and EPhos Pd G4 (4.81 g, 5.23 mmol, 0.20 equiv) at room temperature under nitrogen atmosphere. To the above mixture was added 3-chloro-2-methoxyaniline (4.12 g, 26.17 mmol, 1.00 equiv) at room temperature. The resulting mixture was stirred for additional 3h at 50 °C. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH₂Cl₂/MeOH (10:1) to afford the crude product. The crude product was purified by Prep-HPLC with the following conditions (Column: Xselect CSH C18 OBD Column 30*150mm 5μm, n; Mobile Phase A: Water(0.1%FA), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 32% B to 62% B in 7 min, 62% B; Wave Length: 254/220 nm; RT1(min): 6.52) to afford 3-[(3-chloro-2-methoxyphenyl)amino]-2- {[1,2]thiazolo[4,5-b]pyridin-7-yl}-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (2.4125 g, 21.34%) as an off-white solid. LC-MS: (M+H)⁺ found: 427.10. ¹H NMR (400 MHz, DMSO-d₆) δ 9.30 (s, 1H), 8.80 (d, 1H), 8.40 (d, 1H), 7.72 (d, 1H), 7.51 (s, 1H), 6.80 - 6.73 (m, 2H), 6.20 (d, 1H), 4.54 (t, 2H), 3.95 (s, 3H), 3.72 (s, 2H). Example 92.3-{[2-(difluoromethoxy)-3-fluorophenyl]amino}-2-{thieno[3,2-b]pyridin-7- yl}-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (compound 282)

To a stirred mixture of 3-chloro-4-oxo-5H,6H,7H-pyrazolo[1,5-a]pyrazin-2-ylboronic acid (150 mg, 0.70 mmol, 1.00 equiv) and 7-chlorothieno[3,2-b]pyridine (236 mg, 1.40 mmol, 2.00 equiv) in 1,4-dioxane (4.00 mL) and H₂O (0.80 mL) were added 2nd Generation XPhos Precatalyst (54 mg, 0.07 mmol, 0.10 equiv) and Na₂CO₃ (221 mg, 2.10 mmol, 3.00 equiv) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 2h at 50 degrees C under argon atmosphere. The reaction was monitored by LCMS. LCMS showed the reaction was completed. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH₂Cl₂/MeOH (10:1) to afford 3-chloro-2-{thieno[3,2-b]pyridin-7-yl}-5H,6H,7H- pyrazolo[1,5-a]pyrazin-4-one (70 mg, 32.98%) as an off-white solid. LC-MS: (M+H)⁺ found: 304.85.

To a stirred solution of 3-chloro-2-{thieno[3,2-b]pyridin-7-yl}-5H,6H,7H-pyrazolo[1,5- a]pyrazin-4-one (60 mg, 0.20 mmol, 1.00 equiv) in DMF (2.00 mL) was added EPhos Pd G4 (36 mg, 0.04 mmol, 0.20 equiv) and Cs₂CO₃ (128 mg, 0.40 mmol, 2.00 equiv) in portions at room temperature under nitrogen atmosphere. To the above mixture was added 2-(difluoromethoxy)-3-fluoroaniline (105 mg, 0.60 mmol, 3.00 equiv) dropwise at room temperature. The resulting mixture was stirred for additional 2h at 50 degrees C under nitrogen atmosphere. LCMS showed the reaction was completed. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH₂Cl₂/MeOH (10:1) to afford 3-{[2-(difluoromethoxy)-3- fluorophenyl]amino}-2-{thieno[3,2-b]pyridin-7-yl}-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4- one (14.8 mg, 16.07%) as an off-white solid. LC-MS: (M+H)⁺ found: 445.90. ¹H NMR (400 MHz, DMSO-d₆) δ 8.58 (d, 1H), 8.38 (s, 1H), 8.19 (d, 1H), 7.69 (d, 1H), 7.64 - 7.57 (m, 2H), 7.20 (t, 1H), 6.90 - 6.85(m, 1H), 6.66 - 6.61(m, 1H), 6.13 (d, 1H), 4.51 (t, 2H), 3.72 (s, 2H). Example 93.3-{[2-(difluoromethoxy)-3-fluorophenyl]amino}-2-{[1,2]thiazolo[4,5- b]pyridin-7-yl}-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (compound 281)

To a stirred mixture of 3-chloro-2-{[1,2]thiazolo[4,5-b]pyridin-7-yl}-5H,6H,7H- pyrazolo[1,5-a]pyrazin-4-one (80 mg, 0.26 mmol, 1.00 equiv) and 2-(difluoromethoxy)-3- fluoroaniline (139 mg, 0.78 mmol, 3.00 equiv) in DMF (2.00 mL) were added Cs₂CO₃ (171 mg, 0.52 mmol, 2.00 equiv) and Ephos Pd G4 (48 mg, 0.05 mmol, 0.20 equiv) dropwise at room temperature. The resulting mixture was stirred for 2 h at 50 degrees C under argon atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH₂Cl₂ / MeOH (20:1) to afford 50 mg crude product. The crude product was dissolved in MeCN (2 mL). The precipitated solids were collected by filtration and washed with MeCN (1 mL) to obtain 3- {[2-(difluoromethoxy)-3-fluorophenyl]amino}-2-{[1,2]thiazolo[4,5-b]pyridin-7-yl}- 5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (29.8 mg, 25.23%) as a white solid. LC-MS: (M+H)⁺ found: 447.20. ¹H NMR (300 MHz, DMSO-d6) δ 9.32 (s, 1H), 8.79 (d, 1H), 8.42 (d, 1H), 7.83 (d, 1H), 7.71 (s, 1H), 7.23 (t, 1H), 7.02 - 6.87 (m, 1H), 6.72 - 6.68 (m, 1H), 6.20 (d, 1H), 4.56 (t, 2H), 3.73 (s, 2H). Example 94.3-[(3-chloro-2-methoxyphenyl)amino]-2-[3-(difluoromethyl)pyridin-4-yl]- 5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (compound 285)

To a stirred solution of 3-chloro-4-oxo-5H,6H,7H-pyrazolo[1,5-a] pyrazin-2-ylboronic acid (200 mg, 0.93 mmol, 1.00 equiv) in 1,4-dioxane (5.00 mL) was added Na₂CO₃ (295 mg, 2.79 mmol, 3.00 equiv) in H₂O (1.00 mL), Xphos Pd G2 (73 mg, 0.09 mmol, 0.10 equiv) and 4-chloro-3-(difluoromethyl)pyridine (304 mg, 1.86 mmol, 2.00 equiv) at room temperature. The mixture was stirred for overnight at 50 degrees C under argon atmosphere. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH₂Cl₂ / MeOH (97:3) to afford 3-chloro-2-[3-(difluoromethyl)pyridin-4-yl]- 5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (220 mg, 65.84%) as a yellow solid. LC-MS: (M+H)⁺ found: 298.85.

To a stirred solution of 3-chloro-2-[3-(difluoromethyl)pyridin-4-yl]-5H,6H,7H- pyrazolo[1,5-a]pyrazin-4-one (100 mg, 0.28 mmol, 1.00 equiv) in DMF (3.00 mL) was added Cs₂CO₃ (181 mg, 0.56 mmol, 2.00 equiv) , EPhos Pd G4 (26 mg, 0.02 mmol, 0.10 equiv) and 3-chloro-2-methoxyaniline (44 mg, 0.28 mmol, 1.00 equiv) at room temperature. The mixture was stirred for overnight at 50 degrees C under argon atmosphere. The reaction was monitored by LCMS. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with CH₂Cl₂ / MeOH (98:2) to afford crude product. The crude product (70 mg) was purified by Prep- HPLC with the following conditions (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water (10 mmol/L NH₄HCO₃), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 32% B to 47% B in 8 min, 47% B; Wave Length: 254/220 nm; RT1(min): 8) to afford 3-[(3-chloro-2-methoxyphenyl)amino]-2-[3- (difluoromethyl)pyridin-4-yl]-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (15.6 mg, 13.35%) as a white solid. LC-MS: (M+H)⁺ found: 420.20. ¹H NMR (400 MHz, DMSO-d6) δ 8.91 (s, 1H), 8.67 (d, 1H), 8.33 (s, 1H), 7.63 - 7.34 (m, 3H), 6.68 - 6.63 (m, 2H), 6.18 - 6.15 (m, 1H), 4.43 (t, 2H), 3.80 (s, 3H), 3.69 (t, 2H). Example 95.3-[(3-chloro-2-methoxyphenyl)amino]-2-[2-(difluoromethyl)pyridin-4-yl]- 5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (compound 287)

To a stirred solution of 4-bromopyridine-2-carbaldehyde (200 mg, 1.07 mmol, 1.00 equiv) in DCM (11.00 mL) was added DAST (347 mg, 2.15 mmol, 2.00 equiv) in portions at -78 degrees C under argon atmosphere. The mixture was stirred for overnight from -78 degrees C to room temperature. The reaction was monitored by TLC. The reaction was quenched with sat. sodium sulfite at 0 degrees C. The resulting mixture was extracted with 2- methoxy-2-methylpropane (3x10 mL). The combined organic layers were dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure at 0 °C. The crude product was used in the next step directly without further purification.

To a stirred solution of 3-chloro-4-oxo-5H,6H,7H-pyrazolo[1,5-a]pyrazin-2-ylboronic acid (100 mg, 0.46 mmol, 1.00 equiv) in 1,4-dioxane (5.00 mL) was added Na₂CO₃ (148 mg, 1.39 mmol, 3.00 equiv) in H₂O (1.00 mL), XPhos Pd G2 (37 mg, 0.05 mmol, 0.10 equiv), and 4-bromo-2-(difluoromethyl)pyridine (193 mg, 0.93 mmol, 2.00 equiv) at room temperature. The mixture was stirred for 2 h at 50 degrees C under argon atmosphere. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH₂Cl₂/MeOH (97:3) to afford 3-chloro-2-[2-(difluoromethyl)pyridin-4-yl]-5H,6H,7H- pyrazolo[1,5-a]pyrazin-4-one (75 mg, 54.09%) as a yellow solid. LC-MS: (M+H)⁺ found: 299.20.

To a stirred solution of 3-chloro-2-[2-(difluoromethyl)pyridin-4-yl]-5H,6H,7H- pyrazolo[1,5-a]pyrazin-4-one (90 mg, 0.30 mmol, 1.00 equiv) in DMF (3.00 mL) was added Cs₂CO₃ (197 mg, 0.60 mmol, 2.00 equiv) , Ephos Pd G4 (17 mg, 0.03 mmol, 0.10 equiv) and 3-chloro-2-methoxyaniline (47 mg, 0.30 mmol, 1.00 equiv) at room temperature. The mixture was stirred for 2 h at 50 degrees C under argon atmosphere. The reaction was monitored by LCMS. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with CH₂Cl₂/MeOH (98:2) to afford crude product. The crude product (70 mg) was purified by Prep-HPLC with the following conditions (Column: YMC-Actus Triart C18 ExRS, 30*150 mm, 5μm; Mobile Phase A: Water (10 mmol/L NH₄HCO₃), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 35% B to 53% B in 10 min, 53% B; Wave Length: 220/254 nm; RT1(min): 8.00) to afford 3-[(3-chloro-2-methoxyphenyl)amino]-2-[2-(difluoromethyl)pyridin-4-yl]- 5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (10.8 mg, 8.51%) as a white solid. LC-MS: (M+H)⁺ found: 420.20. ¹H NMR (400 MHz, DMSO-d6) δ 8.66 (d, 1H), 8.33 (s, 1H), 8.01 (s, 1H), 7.83 (d, 1H), 7.40 (s, 1H), 6.92 (t, 1H), 6.78 - 6.71 (m, 2H), 6.17 - 6.13 (m, 1H), 4.45 (t, 2H), 3.88 (s, 3H), 3.70 - 3.65 (m, 2H). Example 96.3-[(3-chloro-2-methoxyphenyl)amino]-2-(2-fluoropyridin-4-yl)-5H,6H,7H- pyrazolo[1,5-a]pyrazin-4-one (compound 286)

To a stirred mixture of 3-chloro-4-oxo-5H,6H,7H-pyrazolo[1,5-a]pyrazin-2-ylboronic acid (100 mg, 0.46 mmol, 1.00 equiv) and 4-bromo-2-fluoropyridine (98 mg, 0.55 mmol, 1.20 equiv) in 1,4-dioxane (5.00 mL) and H₂O (1.00 mL) were added 2nd Generation XPhos Precatalyst (39 mg, 0.05 mmol, 0.10 equiv) and Na₂CO₃ (147 mg, 1.38 mmol, 3.00 equiv) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 2h at 50 degrees C under argon atmosphere. LCMS showed the reaction was completed. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH₂Cl₂ / MeOH (10:1) to afford 3-chloro- 2-(2-fluoropyridin-4-yl)-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (65 mg, 52.51%) as an off-white solid. LC-MS: (M+H)⁺ found: 266.90.

To a stirred solution of 3-chloro-2-(2-fluoropyridin-4-yl)-5H,6H,7H-pyrazolo[1,5- a]pyrazin-4-one (60 mg, 0.23 mmol, 1.00 equiv) in DMF (2.00 mL) was added EPhos Pd G4 (41 mg, 0.04 mmol, 0.20 equiv) and Cs₂CO₃ (146 mg, 0.46 mmol, 2.00 equiv) at room temperature under nitrogen atmosphere. To the above mixture was added 3-chloro-2- methoxyaniline (35 mg, 0.23 mmol, 1.00 equiv) at room temperature. The resulting mixture was stirred for additional 5h at 50 degrees C. LCMS showed the reaction was completed. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH₂Cl₂/MeOH (10:1) to afford the crude product. The crude product (45 mg) was purified by Prep-HPLC with the following conditions (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water (10 mmol/L NH₄HCO₃), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 32% B to 56% B in 8 min, 56% B; Wave Length: 254/220 nm; RT1(min): 7.5) to afford 3- [(3-chloro-2-methoxyphenyl)amino]-2-(2-fluoropyridin-4-yl)-5H,6H,7H-pyrazolo[1,5- a]pyrazin-4-one (12.2 mg, 13.95%) as a white solid. LC-MS: (M+H)⁺ found: 388.20. ¹H NMR (300 MHz, DMSO-d6) δ 8.34 (s, 1H), 8.24 (d, 1H), 7.67 (d, 1H), 7.39 (d, 2H), 6.84 - 6.71 (m, 2H), 6.19 - 6.15 (m, 1H), 4.43 (t, 2H), 3.89 (s, 3H), 3.67 (s, 2H). Example 97.2-[6-(tert-butylamino)-7-methoxyquinolin-4-yl]-3-[(3-chloro-2- methoxyphenyl)amino]-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (compound 296)

To a mixture of 2-methoxy-4-nitroaniline (3.00 g, 17.84 mmol, 1.00 equiv) and Boc2O (20.00 mL) was added bis(trifluoromethanesulfonyloxy) scandio trifluoromethanesulfonate (439 mg, 0.89 mmol, 0.05 equiv) at room temperature. The resulting mixture was stirred for overnight at 50 degrees C. Desired product could be detected by LCMS. The resulting mixture was purified by silica gel column chromatography, eluted with PE / EA (10:1) to afford N-tert-butyl-2-methoxy-4- nitroaniline (720 mg, 18.00%) as a yellow solid. LC-MS: (M+H)⁺ found: 168.90.

To a stirred solution of N-tert-butyl-2-methoxy-4-nitroaniline (1.53 g, 6.82 mmol, 1.00 equiv) in MeOH (20.00 mL) was added 10 % Pd/C (300 mg, 20 w/w%) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 1h at room temperature under hydrogen atmosphere. The reaction was monitored by LCMS. LCMS showed the reaction was completed. The resulting mixture was filtered to afford N1-tert- butyl-2-methoxybenzene-1,4-diamine) (1.08 g, 83.07%) as a yellow oil. LC-MS: (M+H)+ found: 195.00.

To a stirred solution of N1-tert-butyl-2-methoxybenzene-1,4-diamine (1.08 g, 5.54 mmol, 1.00 equiv) in DMF (10.00 mL) was added 5-(methoxymethylidene)-2,2-dimethyl-1,3- dioxane-4,6-dione (1.03 g, 5.54 mmol, 1.00 equiv) at room temperature. The mixture was stirred at 80 degrees C under nitrogen atmosphere for 1h. The reaction was monitored by LCMS. LCMS showed the reaction was completed. The residue was diluted with MeOH (10 mL). The resulting mixture was filtered, the filter cake was washed with MeOH (3x10.00 mL). The filtrate was concentrated under reduced pressure to afford 5-[(1E)- {[4- ( tert-butylamino)-3- methoxyphenyl] imino} methyl]-2,2-dimethyl-1,3-dioxane-4,6-dione) (1.90 g, 98.29%) as a yellow solid. LC-MS: (M+H)⁺ found: 349.10.

Into a Diphenyl ether (100.00 mL) (230 degrees C) were added 5-[(1E)-{[4-(tert- butylamino)-3-methoxyphenyl]imino}methyl]-2,2-dimethyl-1,3-dioxane-4,6-dione (2.00 g, 5.74 mmol, 1.00 equiv) at 230 degrees C. The resulting mixture was stirred for 5 min at 230 degrees C. The reaction was monitored by LCMS. The mixture was allowed to cool down to 30 degrees C. The resulting mixture was diluted with hexane (200 mL). The precipitated solids were collected by filtration and washed with hexane (50.00 mL) to give 6-(tert-butylamino)-7-methoxyquinolin-4-ol (1.50 g, 95.48%) as a brown oil. LC-MS: (M+H)⁺ found: 247.00.

To a stirred solution of 6-(tert-butylamino)-7-methoxyquinolin-4-ol (1.40 g, 5.68 mmol, 1.00 equiv) in DMF (40.00 mL) was added PBr3 (1.69 g, 6.25 mmol, 1.10 equiv) dropwise at 0 degrees C under N₂ atmosphere. The resulting mixture was stirred for 1 h at room temperature under N₂ atmosphere. The reaction was monitored by LCMS. The resulting mixture was extracted with EA (3x 100 mL). The combined organic layers were washed with saturated salt solution (3x10 mL), dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with EA/PE (20%) to give to give 4-bromo-N-tert-butyl- 7-methoxyquinolin-6-amine (200 mg, 10.81%) as a white solid. LC-MS: (M+H)⁺ found: 310.85.

To a stirred mixture of 4-bromo-N-tert-butyl-7-methoxyquinolin-6-amine (130 mg, 0.42 mmol, 1.00 equiv) and 3-chloro-4-oxo-5H,6H,7H-pyrazolo[1,5-a]pyrazin-2-ylboronic acid (108 mg, 0.50 mmol, 1.20 equiv) in 1,4-dioxane (3.50 mL) and H₂O (0.70 mL) was added 2nd Generation XPhos Precatalyst (33 mg, 0.04 mmol, 0.10 equiv) and Na₂CO₃ (133 mg, 1.26 mmol, 3.00 equiv) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 1h at 50 degrees C under argon atmosphere. LCMS showed the reaction was completed. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH₂Cl₂ / MeOH (10:1) to afford 2-[6-(tert-butylamino)-7-methoxyquinolin-4-yl]-3-chloro- 5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (130 mg, 77.32%) as an off-white solid. LC-MS: (M+H)⁺ found: 400.00.

To a stirred solution of 2-[6-(tert-butylamino)-7-methoxyquinolin-4-yl]-3-chloro- 5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (100 mg, 0.25 mmol, 1.00 equiv) and 3-chloro- 2-methoxyaniline (39 mg, 0.25 mmol, 1.00 equiv) in DMF (2.00 mL) were added Cs₂CO₃ (163 mg, 0.50 mmol, 2.00 equiv) and EPhos Pd G4 (23 mg, 0.02 mmol, 0.10 equiv) dropwise at RT under Ar atmosphere. The resulting mixture was stirred for 12 h at 50degrees C under Ar atmosphere. The reaction was monitored by LCMS. The crude product was purified by Prep-HPLC with the following conditions (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water (10 mmol/L NH₄HCO₃), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 37% B to 67% B in 7 min; Wave Length: 254 nm; RT1(min): 6.5) to afford 2-[6-(tert-butylamino)-7-methoxyquinolin-4- yl]-3-[(3-chloro-2-methoxyphenyl)amino]-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (18.9 mg, 14.46%) as a solid. LC-MS: (M+H)⁺ found: 521.00. ¹H NMR (400 MHz, DMSO-d6) δ 8.38 (d, 1H), 8.32 (s, 1H), 7.72 (s, 1H), 7.32 (d, 2H), 7.24 (s, 1H),6.73 - 6.51 (m, 2H), 6.60 (d, 1H), 4.83 (s, 1H),4.42 (d, 2H), 3.96 (s, 3H), 3.78 (s, 3H), 3.71 (s, 2H), 1.56 (s, 9H). Example 98.3-[(3-chloro-2-methoxyphenyl)amino]-6,6-dimethyl-2-{[1,2]thiazolo[4,5- b]pyridin-7-yl}-5H,7H-pyrazolo[1,5-a]pyrazin-4-one (compound 297)

A solution of Imidazole (431 mg, 6.36 mmol, 6.00 equiv) in DCM (10.00 mL) was treated with SO₂Cl₂ (257 mg, 1.91 mmol, 1.80 equiv) for 30 min at -5 degrees C under nitrogen atmosphere followed by the addition of tert-butyl N-(1-hydroxy-2-methylpropan-2- yl)carbamate (200 mg, 1.06 mmol, 1.00 equiv) in portions at 0 degrees C. Desired product could be detected by TLC. The aqueous layer was extracted with CH₂Cl₂ (2x100 mL). The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EA (10:1) to afford tert-butyl 4,4- dimethyl-2-oxo-1,2lambda4,3-oxathiazolidine-3-carboxylate (220 mg, 88.47%) as a colorless oil.

A mixture of tert-butyl 4,4-dimethyl-2-oxo-1,2lambda4,3-oxathiazolidine-3-carboxylate (240 mg, 1.02 mmol, 1.00 equiv), NaIO₄ (218 mg, 1.02 mmol, 1.00 equiv) and RuCl₃.H₂O (1 mg, 0.01 mmol, 0.005 equiv) in MeCN (10.00 mL) and H₂O (7.00 mL) was stirred for 0.5 h at room temperature under air atmosphere. Desired product could be detected by TLC. The aqueous layer was extracted with CH₂Cl₂ (2x100 mL). The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EA (10:1) to afford tert-butyl 4,4-dimethyl-2,2-dioxo- 1,2lambda6,3-oxathiazolidine-3-carboxylate (170 mg, 66.32%) as a white solid.

A mixture of methyl 5-bromo-2H-pyrazole-3-carboxylate (500 mg, 2.43 mmol, 1.00 equiv) in DMF (10.00 mL) was added Cs₂CO₃ (371 mg, 4.86 mmol, 2.00 equiv), tert-butyl 4,4- dimethyl-2,2-dioxo-1,2lambda6,3-oxathiazolidine-3-carboxylate(612 mg, 2.43 mmol, 1.00 equiv). The reaction was stirred for 2 h at 80 °C under nitrogen atmosphere. Desired product could be detected by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (7:1) to afford methyl 5-bromo-2-{2-[(tert-butoxycarbonyl)amino]-2- methylpropyl}pyrazole-3-carboxylate (450 mg, 49.04%) as an off-white solid. LC-MS: [M+H]⁺ found: 375.95.

A solution of methyl 5-bromo-2-{2-[(tert-butoxycarbonyl)amino]-2- methylpropyl}pyrazole-3-carboxylate (450 mg, 1.20 mmol, 1.00 equiv) in DCM (4.00 mL) and 4M HCl in 1,4-dioxane (4.00 mL) was stirred for 1 h at room temperature under nitrogen atmosphere. Desired product could be detected by LCMS. The resulting mixture was concentrated under reduced pressure. The resulting mixture was used in the next step directly without further purification. LC-MS: [M+H]⁺ found: 277.80.

A mixture of methyl 2-(2-amino-2-methylpropyl)-5-bromopyrazole-3-carboxylate (430 mg, 1.56 mmol, 1.00 equiv) in methanol (10.00 mL) was added sodium methoxide (421 mg, 7.80 mmol, 5.00 equiv) slowly at 0 °C. The reaction was stirred for 1 h at room temperature under nitrogen atmosphere. Desired product could be detected by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EA (5:1) to afford 2-bromo-6,6- dimethyl-5H,7H-pyrazolo[1,5-a]pyrazin-4-one (310 mg, 81.56%) as an off-white solid. LC-MS: [M+H]⁺ found: 243.85.

A mixture of 2-bromo-6,6-dimethyl-5H,7H-pyrazolo[1,5-a]pyrazin-4-one (300 mg, 1.23 mmol, 1.00 equiv) and NCS (196 mg, 1.47 mmol, 1.20 equiv) in DMF (10.00 mL) was stirred for overnight at 100 °C under nitrogen atmosphere. Desired product could be detected by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH₂Cl₂/MeOH (20:1) to afford 2-bromo-3-chloro-6,6-dimethyl-5H,7H-pyrazolo[1,5-a]pyrazin-4-one (330 mg, 96.40%) as a light yellow solid. LC-MS: [M+H]⁺ found: 279.80.

A mixture of 2-bromo-3-chloro-6,6-dimethyl-5H,7H-pyrazolo[1,5-a]pyrazin-4-one (50 mg, 0.18 mmol, 1.00 equiv) bis(pinacolato)diboron (68 mg, 0.27 mmol, 1.50 equiv), potassium acetate (52 mg, 0.54 mmol, 3.00 equiv) and Pd(dppf)Cl₂ (13 mg, 0.02 mmol, 0.10 equiv) in 1,4-dioxane (2.00 mL) was stirred for overnight at 100 °C under nitrogen atmosphere. Desired product could be detected by LCMS. The resulting mixture was used in the next step directly without further purification. LC-MS: [M+H]⁺ found: 326.00.

A mixture of 7-chloro-[1,2]thiazolo[4,5-b]pyridine (200 mg, 1.17 mmol, 1.00 equiv) 3- chloro-6,6-dimethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5H,7H- pyrazolo[1,5-a]pyrazin-4-one (458 mg, 1.40 mmol, 1.20 equiv), XPhos palladium(II) biphenyl-2-amine chloride (92 mg, 0.12 mmol, 0.10 equiv) and Na₂CO₃ (372 mg, 3.52 mmol, 3.00 equiv) in dioxane (5.00 mL) and water (1.00 mL) was stirred for 2 h at 50 °C under argon atmosphere. Desired product could be detected by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH₂Cl₂/MeOH (20:1) to afford 3-chloro-6,6- dimethyl-2-{[1,2]thiazolo[4,5-b]pyridin-7-yl}-5H,7H-pyrazolo[1,5-a]pyrazin-4-one (185 mg, 47.28%) as a yellow solid. LC-MS: [M+H]⁺ found: 333.90.

A solution of 3-chloro-6,6-dimethyl-2-{[1,2]thiazolo[4,5-b]pyridin-7-yl}-5H,7H- pyrazolo[1,5-a]pyrazin-4-one (100 mg, 0.30 mmol, 1.00 equiv), 3-chloro-2- methoxyaniline(47 mg, 0.30 mmol, 1.00 equiv) , EPhos Pd G4 (27 mg, 0.03 mmol, 0.10 equiv) and Cs₂CO₃ (195 mg, 0.60 mmol, 2.00 equiv) in DMF (2.00 mL) was stirred for 2 h at 50 degrees C under argon atmosphere. Desired product could be detected by LCMS. The crude product was purified by Prep-HPLC with the following conditions (Column: XBridge Prep C18 OBD Column, 30*100 mm, 5μm; Mobile Phase A: Water (10 mmol/L NH₄HCO₃), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 36% B to 64% B in 8 min, 64% B; Wave Length: 254/220 nm; RT1(min): 6.32) to afford 3-[(3-chloro-2- methoxyphenyl)amino]-6,6-dimethyl-2-{[1,2]thiazolo[4,5-b]pyridin-7-yl}-5H,7H- pyrazolo[1,5-a]pyrazin-4-one (7.2 mg, 5.24%) as a white solid. LC-MS: (M+H)⁺ found: 454.93. ¹H NMR (300 MHz, DMSO-d6) δ 9.31 (s, 1H), 8.81 (d, 1H), 8.50 (s, 1H), 7.76 (d, 1H), 7.56 (s, 1H), 6.80 - 6.73 (m, 2H), 6.22 - 6.15 (m, 1H), 4.45 (s, 2H), 3.94 (s, 3H), 1.34 (s, 6H). Example 99.3-[(3-fluoro-2-methoxyphenyl)amino]-2-{1H-pyrazolo[4,3-b]pyridin-7-yl}- 5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (compound 274)

To a stirred solution of 7-bromo-1H-pyrazolo[4,3-b]pyridine (2.00 g, 10.10 mmol, 1.00 equiv) and Cs₂CO₃ (6.58 g, 20.20 mmol, 2.00 equiv) in dimethylformamide (20.00 mL) was added PMBCl (2.37 g, 15.15 mmol, 1.50 equiv) dropwise at 0 degrees C under N₂ atmosphere. The resulting mixture was stirred for 1 h at room temperature under N₂ atmosphere. The reaction was monitored by LCMS. Desired product could be detected by LCMS. The resulting mixture was extracted with EA (3x 50 mL). The combined organic layers were washed with saturated salt solution (3x50 mL), dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with EA/PE (20%) to give 7-bromo- 1-[(4-methoxyphenyl)methyl]pyrazolo[4,3-b]pyridine (1.20 g, 33.61%) as a white solid. LC-MS: (M+H)⁺ found: 319.80.

To a stirred solution of 3-chloro-2-{1-[(4-methoxyphenyl)methyl]pyrazolo[4,3-b]pyridin- 7-yl}-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (100 mg, 0.24 mmol, 1.00 equiv) and 3- fluoro-2-methoxyaniline (103 mg, 0.72 mmol, 3.00 equiv) in DMF (2.00 mL) were added Ephos Pd G4 (22 mg, 0.02 mmol, 0.10 equiv) and Cs₂CO₃ (159 mg, 0.48 mmol, 2.00 equiv) dropwise at RT under argon atmosphere. The resulting mixture was stirred for 1h at room temperature under argon atmosphere. The reaction was monitored by LCMS. Desired product could be detected by LCMS. The mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with MeOH/DCM (3%) to afford 3-[(3-fluoro-2-methoxyphenyl)amino]-2-{1-[(4- methoxyphenyl)methyl]pyrazolo[4,3-b]pyridin-7-yl}-5H,6H,7H-pyrazolo[1,5-a]pyrazin- 4-one (90 mg, 64.49%) as a yellow green oil. LC-MS: (M+H)⁺ found: 514.10.

Into a TFA (2.00 mL) was added 3-[(3-fluoro-2-methoxyphenyl)amino]-2-{1-[(4- methoxyphenyl)methyl]pyrazolo[4,3-b]pyridin-7-yl}-5H,6H,7H-pyrazolo[1,5-a]pyrazin- 4-one (100 mg, 0.19 mmol, 1.00 equiv) at room temperature. The resulting mixture was stirred for 3 h at 70 °C. The reaction was monitored by LCMS. The resulting mixture was concentrated under vacuum. The crude product was purified by Prep-HPLC with the following conditions (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water (10 mmol/L NH₄HCO₃), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 18% B to 48% B in 7 min; Wave Length: 254 nm; RT1(min): 6.5) to afford 3-[(3-fluoro-2-methoxyphenyl)amino]-2-{1H-pyrazolo[4,3-b]pyridin-7-yl}- 5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (16.7 mg, 21.74%) as a white solid. LC-MS: (M+H)⁺ found: 394.25. ¹H NMR (300 MHz, DMSO-d₆) δ 13.25 (s, 1H), 8.44 (d, 1H), 8.35 (d, 1H), 7.46 (d, 1H), 7.37 (s, 1H), 6.72 - 6.52 (m, 2H), 6.03 (d, 1H), 4.53 (d, 1H), 3.94 (s, 3H), 3.72 (s, 2H). Example 100.2-(6-amino-7-methoxyquinolin-4-yl)-3-[(3-fluoro-2- methoxyphenyl)amino]-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one; formic acid (compound 316)

A mixture of 3-methoxy-4-nitroaniline (5.00 g, 29.74 mmol, 1.00 equiv) and 5- (methoxymethylidene)-2,2-dimethyl-1,3-dioxane-4,6-dione (6.64 g, 35.67 mmol, 1.20 equiv) in DMF (50.00 mL) was stirred for 1h at 80°C under N₂ atmosphere. The mixture was allowed to cool down to RT. The product was precipitated by the addition of MeOH (50 mL). The precipitated solids were collected by filtration and washed with MeOH (20 mL). This resulted in 5-[(1E)-[(3-methoxy-4-nitrophenyl)imino]methyl]-2,2-dimethyl-1,3- dioxane-4,6-dione (8.92 g, 93.08%) as a yellow solid. LC-MS: (M+H)⁺ found: 323.95.

To a stirred solution of 7-methoxy-6-nitroquinolin-4-ol (0.95 g, 4.31 mmol, 1.00 equiv) in DMF (28.00 mL) were added PBr3 (1.28 g, 4.75 mmol, 1.10 equiv) dropwise at 0°C under N₂ atmosphere. The resulting mixture was stirred for 30 min at room temperature under N₂ atmosphere. The reaction was quenched by the addition of Na₂CO₃ Saturated aqueous. The resulting mixture was extracted with EA (50ml x 3). The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with DCM/MeOH=30:1 to afford 4-bromo-7-methoxy-6- nitroquinoline (0.90 g, 73.69%) as a yellow solid. LC-MS: (M+H)⁺ found: 282.97

To a stirred solution of 3-chloro-2-(7-methoxy-6-nitroquinolin-4-yl)-5H,6H,7H- pyrazolo[1,5-a]pyrazin-4-one (280 mg, 0.75 mmol, 1.00 equiv) in DMF (5.00 mL) was added Cs₂CO₃ (488 mg, 1.49 mmol, 2.00 equiv) and EPhos Pd G4 (137 mg, 0.15 mmol, 0.20 equiv) at room temperature under nitrogen atmosphere. To the above mixture was added 3-fluoro-2-methoxyaniline (317 mg, 2.25 mmol, 3.00 equiv) at room temperature. The resulting mixture was stirred for additional 3h at 50 °C under nitrogen atmosphere. The reaction was monitored by LCMS. LCMS showed the reaction was completed. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH₂Cl₂/MeOH (10:1) to afford 3-[(3- fluoro-2-methoxyphenyl)amino]-2-(7-methoxy-6-nitroquinolin-4-yl)-5H,6H,7H- pyrazolo[1,5-a]pyrazin-4-one (330 mg, 92.07%) as a yellow solid. LC-MS: (M+H)⁺ found: 479.15.

To a stirred solution of 3-[(3-fluoro-2-methoxyphenyl)amino]-2-(7-methoxy-6- nitroquinolin-4-yl)-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (100 mg, 0.21 mmol, 1.00 equiv) in EtOH (2.50 mL) and H₂O (0.50 mL) was added Fe (70 mg, 1.26 mmol, 6.00 equiv) and NH₄Cl (67 mg, 1.26 mmol, 6.00 equiv) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 1h at 80 degrees C under nitrogen atmosphere. LCMS showed the reaction was completed. The resulting mixture was filtered, the filter cake was washed with MeOH (3x30 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH₂Cl₂/MeOH (10:1) to afford crude product. The crude product (70 mg) was purified by Prep-HPLC with the following conditions (Column: Xselect CSH C18 OBD Column 30*150mm 5μm, n; Mobile Phase A: Water(0.1%FA), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 8% B to 27% B in 8 min, 27% B; Wave Length: 254/220 nm; RT1(min): 7.5) to afford 2-(6-amino-7-methoxyquinolin-4-yl)-3-[(3-fluoro-2- methoxyphenyl)amino]-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one; formic acid (37.7 mg, 36.00%) as a yellow solid. LC-MS: (M+H)⁺ found: 449.25. ¹H NMR (400 MHz, DMSO-d6) δ 8.40 (d, 1H), 8.33 (s, 1H), 8.15 (s, 1H), 7.32 - 7.25 (m, 2H), 7.20 (d, 2H), 6.45 - 6.31 (m, 2H), 5.92 (d, 1H), 5.37 (s, 2H), 4.43 (t, 2H), 3.93 (s, 3H), 3.75(s, 3H), 3.74 - 3.69 (m, 2H). Example 101.3-[(3-fluoro-2-methoxyphenyl)amino]-2-[3-[(2-hydroxy-2- methylpropyl)amino]pyridin-4-yl]-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (compound 334)

To a stirred solution of 2-bromo-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one(2.00 g, 9.26 mmol, 1.00 equiv) in 1,4-dioxane(24.00 mL) and water(6.00 mL) were added 3- fluoropyridin-4-ylboronic acid(1.57 g, 11.10 mmol, 1.20 equiv) and Pd(dppf)Cl₂*CH₂Cl₂(0.75 g, 9.26 mmol, 0.10 equiv) and K₃PO₄(5.89 g, 27.78 mmol, 3.00 equiv) in portions at room temperature under nitrogen atmosphere. The resulting mixture was stirred for additional 3h at 60 degrees C. The reaction was monitored by LCMS. LCMS showed the reaction was completed. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH₂Cl₂/MeOH (10:1) to afford 2-(3-fluoropyridin-4-yl)- 5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one(1.6 g, 74.4%) as a light-yellow solid. LC-MS: (M+H)⁺ found: 233.08.

To a stirred solution of 2-(3-fluoropyridin-4-yl)-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4- one(1.00 g, 4.30 mmol, 1.00 equiv) in HOAc(21.00 mL) was added 1,3-Dibromo-5,5- dimethylhydantoin (1.85 g, 6.459 mmol, 1.50 equiv) in portions at room temperature under nitrogen atmosphere. The resulting mixture was stirred overnight at 60 degrees C under nitrogen atmosphere. The reaction was monitored by LCMS. LCMS showed the reaction was completed. The reaction was quenched with sat. Na₂SO₃ (aq.) (10 mL) at room temperature. The resulting mixture was concentrated under reduced pressure. The mixture was basified to pH 7 with saturated Na₂CO₃ (aq.). The precipitated solids were collected by filtration and washed with EtOAc (3x50 mL) to obtain 3-bromo-2-(3- fluoropyridin-4-yl)-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one(1.3 g, 96.9%) as a light– yellow solid. LC-MS: (M+H)⁺ found: 310.99.

To a stirred solution of 3-bromo-2-(3-fluoropyridin-4-yl)-5H,6H,7H-pyrazolo[1,5- a]pyrazin-4-one(600 mg, 1.93 mmol, 1.00 equiv) in 1,4-dioxane(10.00 mL) were added EPhos Pd G4(354 mg, 0.38 mmol, 0.20 equiv) and Cs₂CO₃(1.25 g, 3.86 mmol, 2.00 equiv) in portions at room temperature under nitrogen atmosphere. To the above mixture was added 3-fluoro-2-methoxyaniline(816 mg, 5.78 mmol, 3.00 equiv) at room temperature. The resulting mixture was stirred overnight at 50 degrees C. LCMS showed the reaction was completed. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH₂Cl₂/MeOH (10:1) to afford to afford 3-[(3-fluoro-2-methoxyphenyl)amino]-2-(3- fluoropyridin-4-yl)-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one(500 mg, 74.7%) as an off- white solid. LC-MS: (M+H)⁺ found: 372.13.

To a stirred solution of 3-[(3-fluoro-2-methoxyphenyl)amino]-2-(3-fluoropyridin-4-yl)- 5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (70 mg, 0.19 mmol, 1.00 equiv) and 1-amino-2- methylpropan-2-ol (1.00 mL) in DMSO (1.00 mL) was added DIEA (365 mg, 2.84 mmol, 15.00 equiv) in portions at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 2 days at 120 degrees C under nitrogen atmosphere. Desired product could be detected by LCMS. The crude product was purified by Prep-HPLC with the following conditions (Column: Xselect CSH OBD Column 30*150mm 5um, n; Mobile Phase A: Water(0.1%FA), Mobile Phase B: ACN; Flow rate: 50 mL/min; Gradient: 10% B to 30% B in 7 min, 30% B; Wave Length: 220 nm; RT1(min): 5.9) to afford 3-[(3-fluoro- 2-methoxyphenyl)amino]-2-[3-[(2-hydroxy-2-methylpropyl)amino]pyridin-4-yl]- 5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (5.7 mg, 6.86%) as a white solid. LC-MS: (M+H)⁺ found: 441.10. ¹H NMR (300 MHz, DMSO-d₆) δ 8.32 (s, 1H), 8.10 (s, 1H), 7.66 (d, 1H), 7.41 (d, 1H), 7.29 (s, 1H), 7.03(t, 1H), 6.70 – 6.45 (m, 2H), 5.96 (d, 1H), 4.61 (s, 1H), 4.36 (t, 2H), 3.89 (s, 3H), 3.67 (s, 2H), 3.16 (d, 2H), 1.21 (s, 6H). Example 102.3-[(3-fluoro-2-methoxyphenyl)amino]-2-(3-hydroxypyridin-4-yl)- 5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (compound 349)

To a stirred mixture of 3-[(3-fluoro-2-methoxyphenyl)amino]-2-(3-fluoropyridin-4-yl)- 5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one(150 mg, 0.40 mmol, 1.00 equiv) and benzyl alcohol(7.00 mL) was added K₂CO₃(334 mg, 2.42 mmol, 6.00 equiv) in portions at 120 degrees C under argon atmosphere. The resulting mixture was stirred for 4 days at 120 degrees C under argon atmosphere. The resulting mixture was concentrated under reduced pressure. The residue product was purified by Prep-MPLC to afford 2-[3- (benzyloxy)pyridin-4-yl]-3-[(3-fluoro-2-methoxyphenyl)amino]-5H,6H,7H-pyrazolo[1,5- a]pyrazin-4-one (48 mg, 25.86%) as a light yellow solid. LC-MS: M+H found: 460.05.

To a stirred mixture of 2-[3-(benzyloxy)pyridin-4-yl]-3-[(3-fluoro-2- methoxyphenyl)amino]-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (40 mg, 0.087 mmol, 1.00 equiv) in HOAc (5.00 mL) was added 10% Pd/C (55 mg) at room temperature under argon atmosphere. The flask was evacuated and flushed three times with nitrogen, followed by flushing with hydrogen. The resulting mixture was stirred for 4 h at room temperature under hydrogen atmosphere. The mixture was filtered through a Celite pad. The solid was filtered out. The filtrate was concentrated under vacuum. The crude product was purified by Prep-HPLC with the following conditions (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water (10 mmol/L NH₄HCO₃), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 12% B to 42% B in 7 min; Wave Length: 254 nm; RT1(min): 6.5) to afford 3-[(3-fluoro-2-methoxyphenyl)amino]-2-(3-hydroxypyridin-4- yl)-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (12.8 mg, 39.81%) as a white solid. LC-MS: (M+H)⁺ found: 370.25. ¹H NMR (300 MHz, DMSO-d₆) δ 9.96 (s, 1H), 8.39 (d, 1H), 8.25(s, 1H), 8.02(d, 1H) 7.50- 7.48 (m, 1H), 7.20 (s, 1H), 6.76-6.62 (m, 1H), 6.58-6.48 (m, 1H), 5.99 (d, 1H), 4.37 (t, 2H), 3.89 (s, 3H), 3.64 (s, 2H). Example 103.3-[(3-chloro-2-methoxyphenyl)amino]-2-(3-fluoropyridin-4-yl)- 5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (compound 354)

To a stirred mixture of 2-(3-fluoropyridin-4-yl)-3-iodo-5H,6H,7H-pyrazolo[1,5-a]pyrazin- 4-one (50 mg, 0.69 mmol, 1.00 equiv) and 3-chloro-2-methoxyaniline (132 mg, 0.84 mmol, 1.2 equiv) in 1,4-dioxane (2.50 mL) were added Cs₂CO₃ (455 mg, 1.39 mmol, 2.00 equiv) and Ephos Pd G4 (128 mg, 0.14 mmol, 0.20 equiv) at room temperature under argon atmosphere. The mixture was stirred for 2 h at 50 degrees C under argon atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH₂Cl₂/MeOH (10:1) to afford the crude product. The crude product (30 mg) was purified by Prep-HPLC with the following conditions (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water (10 mmol/L NH₄HCO₃), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 29% B to 59% B in 7 min; Wave Length: 254 nm; RT1(min): 6.5) to afford 3-[(3-chloro- 2-methoxyphenyl)amino]-2-(3-fluoropyridin-4-yl)-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4- one(5.7 mg,10.53%) as a white solid. LC-MS: M+H found: 388.00. ¹H NMR (300 MHz, DMSO-d6) δ 8.78 (t, 1H), 8.51 (d, 1H), 8.30 (s, 1H), 7.98-7.88 (m, 1H), 7.36 (s, 1H), 6.78 -6.69 (m, 2H), 6.19-6.11 (m, 1H), 4.41 (t, 2H), 3.86 (s, 3H), 3.66(s, 2H). Example 104.3-[(3-chloro-2-methoxyphenyl)amino]-2-[3-(2-methoxyethoxy)pyridin-4- yl]-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (compound 355)

To a stirred mixture of 3-[(3-chloro-2-methoxyphenyl)amino]-2-(3-fluoropyridin-4-yl)- 5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (50 mg, 0.13 mmol, 1.00 equiv) in 2- methoxyethanol (5.00 mL) was added Potassium carbonate (126 mg, 0.90 mmol, 7.00 equiv) at room temperature under argon atmosphere. The resulting mixture was stirred for 1.5 days at 150 degrees C under argon atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH₂Cl₂/MeOH (10:1) to afford the crude product. The crude product was purified by Prep-HPLC with the following conditions (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water (10 mmol/L NH₄HCO₃), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 24% B to 54% B in 7 min; Wave Length: 254 nm; RT1(min): 6.5) to afford 3-[(3-chloro-2-methoxyphenyl)amino]-2-[3-(2- methoxyethoxy)pyridin-4-yl]-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (8.1 mg, 14.15%) as a white solid. LC-MS: M+H found: 444.00. ¹H NMR (300 MHz, DMSO-d₆) δ 8.52 (d, 1H), 8.28 (s, 1H), 8.20(d, 1H), 764-7.59 (m, 1H), 7.32 (s, 1H), 6.78 - 6.69 (m, 2H), 6.8-6.12 (m, 1H), 4.39 (t, 2H), 4.10-4.02 (m, 2H), 3.85 (s, 3H), 3.65 (s, 1H), 3.60-3.52(m, 3H), 3.26(s, 3H). Example 105.3-[(3-fluoro-2-methoxyphenyl)amino]-2-(3-[[(2R)-oxolan-2- ylmethyl]amino]pyridin-4-yl)-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (compound 105a)

Into a 8-mL sealed tube, was placed 3-[(3-fluoro-2-methoxyphenyl)amino]-2-(3- fluoropyridin-4-yl)-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (120 mg, 0.32 mmol, 1.00 equiv), DMSO (3.00 mL), DIEA (626 mg, 4.85 mmol, 15.00 equiv), 1-[(2R)-oxolan-2- yl]methanamine (1.50 mL). The resulting solution was stirred for 2 days at 120 degrees C. The resulting mixture was concentrated under reduced pressure. The crude product (150 mg) was purified by Prep-HPLC with the following conditions (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water (10 mmol/L NH₄HCO₃), Mobile Phase B: ACN; Flow rate: 50 mL/min; Gradient: 25% B to 50% B in 8 min, 50% B; Wave Length: 254 nm; RT1(min): 5.7) to afford 3-[(3-fluoro-2-methoxyphenyl)amino]- 2-(3-[[(2R)-oxolan-2-ylmethyl]amino]pyridin-4-yl)-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4- one (19.6 mg, 13.31%) as an off-white solid. LC-MS: (M+H)⁺ found: 453.10. ¹H NMR (300 MHz, DMSO-d6) δ 8.32 (s, 1H), 8.13 (s, 1H), 7.71-7.70 (m, 1H), 7.43-7.41 (m, 1H), 7.29 (s, 1H), 6.95-6.91 (m, 1H), 6.80-6.61 (m, 1H), 6.55-6.45 (m, 1H), 6.01-5.82 (m, 1H), 4.40-4.36 (m, 2H), 4.11-4.08 (m, 1H), 3.89-3.83 (m, 4H), 3.73-3.61 (m, 3H), 3.40- 3.24 (m, 2H), 2.03-1.86 (m, 3H), 1.69-1.62 (m, 1H). Example 106.3-[(3-fluoro-2-methoxyphenyl)amino]-2-(3-[[(2s)-oxolan-2- ylmethyl]amino]pyridin-4-yl)-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (compound 105b)

Into a 8-mL sealed tube, was placed 3-[(3-fluoro-2-methoxyphenyl)amino]-2-(3- fluoropyridin-4-yl)-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (120 mg, 0.32 mmol, 1.00 equiv), DMSO (3.00 mL), DIEA (626 mg, 4.85 mmol, 15.00 equiv), 1-[(2s)-oxolan-2- yl]methanamine (1.50 mL). The resulting solution was stirred for 2 days at 120 degrees C. The resulting mixture was concentrated under reduced pressure. The crude product (150 mg) was purified by Prep-HPLC with the following conditions (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water (10MMOL/L NH₄HCO₃), Mobile Phase B: ACN; Flow rate: 50 mL/min; Gradient: 25% B to 40% B in 8 min, 40% B; Wave Length: 254 nm; RT1(min): 7.03) to afford 3-[(3-fluoro-2- methoxyphenyl)amino]-2-(3-[[(2s)-oxolan-2-ylmethyl]amino]pyridin-4-yl)-5H,6H,7H- pyrazolo[1,5-a]pyrazin-4-one (20.9 mg, 14.26%) as a white solid. LC-MS: (M+H)⁺ found: 453.10. ¹H NMR (300 MHz, DMSO-d6) δ 8.32 (s, 1H), 8.13 (s, 1H), 7.71-7.70 (m, 1H), 7.43-7.41 (m, 1H), 7.29 (s, 1H), 6.95-6.91 (m, 1H), 6.69-6.61 (m, 1H), 6.56-6.45 (m, 1H), 6.05-5.89 (m, 1H), 4.38 (t, 2H), 4.11-4.08 (m, 1H), 3.89-3.83 (m, 4H), 3.75-3.61 (m, 3H), 3.40-3.24 (m, 2H), 2.03-1.86 (m, 3H), 1.69-1.62 (m, 1H). Example 107.3-[(3-chloro-2-methoxyphenyl)amino]-2-[7-methoxy-6- (methylamino)quinolin-4-yl]-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (compound 295)

To a solution of 2-methoxy-4-nitroaniline (2.00 g, 11.89 mmol, 1.00 equiv) in THF (50.00 mL) was added NaH (1.19 g, 29.74 mmol, 2.50 equiv, 60%) at 0 degrees C under nitrogen atmosphere. The resulting mixture was stirred for 15 min at room temperature. Then was added MeI (2.03 g, 14.27 mmol, 1.20 equiv) and stirred for overnight at room temperature. Desired product could be detected by LCMS. The reaction was quenched with water at 0 degrees C. The mixture was extracted with EtOAc and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse flash chromatography to afford 2-methoxy-N-methyl-4-nitroaniline (1.00 g, 46.15%) as a yellow solid. LC-MS: M+H found: 182.90.

To a solution of 2-methoxy-N-methyl-4-nitroaniline (1.00 g, 5.49 mmol, 1.00 equiv) in EA (50 mL) was added 10% Pd/C (115 mg, 10 w/w%) at room temperature under hydrogen atmosphere. The resulting mixture was stirred for 2 h at room temperature under hydrogen atmosphere. The resulting mixture was filtered, the filter cake was washed with EtOAc. The filtrate was concentrated under reduced pressure to afford crude product 2-methoxy-N1-methylbenzene-1,4-diamine (800 mg) as a yellow solid. LC-MS: M+H found: 153.10.

A mixture of 2-methoxy-N1-methylbenzene-1,4-diamine (700 mg, 4.60 mmol, 1.00 equiv) and 5-(methoxymethylidene)-2,2-dimethyl-1,3-dioxane-4,6-dione (942 mg, 5.06 mmol, 1.10 equiv) in DMF (7.00 mL) was stirred for 1 h at 80 degrees C. Desired product could be detected by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EA (5:1) to afford 5-[(1E)-{[3-methoxy-4-(methylamino)phenyl] imino}methyl]- 2,2-dimethyl-1,3-dioxane-4,6-dione (750 mg, 53.23%) as a yellow solid. LC-MS: M+H found: 306.95.

A mixture of 5-[(1E)-{[3-methoxy-4-(methylamino)phenyl]imino}methyl]-2,2-dimethyl- 1,3-dioxane-4,6-dione (650 mg, 2.12 mmol, 1.00 equiv) in diphenyl-ether (40 mL) was stirred for 30 min at 230 degrees C under air atmosphere. Desired product could be detected by LCMS. The resulting mixture was diluted with hexane (80 mL). The precipitated solids were collected by filtration and washed with hexane to afford crude product 7-methoxy-6-(methylamino)quinolin-4-ol (550 mg) as a brown solid. LC-MS: M+H found: 205.05.

To a mixture of 7-methoxy-6-(methylamino)quinolin-4-ol (200 mg, 0.98 mmol, 1.00 equiv) in POCl3 (5.00 mL) was stirred for 1 h at 100 degrees C. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH₂Cl₂/MeOH (10:1) to afford 4-chloro-7-methoxy-N- methylquinolin-6-amine (70 mg, 32.10%) as a yellow oil. LC-MS: M+H found: 222.90.

To a solution of 4-chloro-7-methoxy-N-methylquinolin-6-amine (130 mg, 0.58 mmol, 1.00 equiv) and 3-chloro-4-oxo-5H,6H,7H-pyrazolo[1,5-a]pyrazin-2-ylboronic acid (151 mg, 0.70 mmol, 1.20 equiv) in dioxane (1.00 mL) and H₂O (0.1 mL) were added AcOK (172 mg, 1.75 mmol, 3.00 equiv) and PCy₃.HBF₄ (43 mg, 0.12 mmol, 0.20 equiv) and Pd₂(dba)₃ (54 mg, 0.06 mmol, 0.10 equiv) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 1 h at 100 degrees C under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH₂Cl₂ / MeOH (10:1) to afford 3-chloro- 2-[7-methoxy-6-(methylamino)quinolin-4-yl]-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (60 mg, 28.72%) as a yellow solid. LC-MS: M+H found: 357.90.

To a solution of 3-chloro-2-[7-methoxy-6-(methylamino)quinolin-4-yl]-5H,6H,7H- pyrazolo[1,5-a]pyrazin-4-one (60 mg, 0.17 mmol, 1.00 equiv) and 3-chloro-2- methoxyaniline (26 mg, 0.17 mmol, 1.00 equiv) in DMF (2.00 mL) were added EPhos Pd G4 (31 mg, 0.03 mmol, 0.20 equiv) and Cs₂CO₃ (109 mg, 0.34 mmol, 2.00 equiv) at 50 degrees C under argon atmosphere. The resulting mixture was stirred for 2 h at 50 degrees C under argon atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH₂Cl₂/MeOH (10:1) to afford crude product. The crude product (30 mg) was purified by Prep-HPLC with the following conditions (Column: YMC-Actus Triart C18 ExRS, 30*150 mm, 5μm; Mobile Phase A: Water (10 mmol/L NH₄HCO₃), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 21% B to 49% B in 8 min, 49% B; Wave Length: 254/220 nm; RT1(min): 7.53) to afford 3-[(3-chloro-2-methoxyphenyl)amino]-2-[7- methoxy-6-(methylamino)quinolin-4-yl]-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (5.3 mg, 6.49%) as a yellow solid. LC-MS: M+H found: 479.25. ¹H NMR (300 MHz, DMSO-d₆) δ 8.41 (d, 1H), 8.30 (s, 1H), 7.39-7.27 (m, 2H), 7.20 (s, 1H), 7.00 (s, 1H), 6.63-6.43 (m, 2H), 6.20-6.07 (m, 1H), 5.81-5.66 (m, 1H), 4.44 (t, 2H), 3.94 (s, 3H), 3.79-3.63 (m, 5H), 2.79-2.64 (m, 3H). Example 108.2,2,2-trifluoro-N-(4-[3-[(3-fluoro-2-methoxyphenyl) amino]-4-oxo- 5H,6H,7H-pyrazolo[1,5-a] pyrazin-2-yl]pyridin-3-yl)acetamide; formic acid (compound 340)

A mixture of 2-(3-aminopyridin-4-yl)-3-[(3-fluoro-2-methoxyphenyl) amino]-5H,6H,7H- pyrazolo[1,5-a]pyrazin-4-one(50 mg, 0.13 mmol, 1.00 equiv) in trifluoroacetic anhydride(2.00 mL) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 1 h at room temperature under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The crude product (40 mg) was purified by Prep- HPLC with the following conditions (Column: Xselect CSH OBD Column 30*150mm 5um; Mobile Phase A: Water (0.1%FA), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 30% B to 50% B in 8 min, 50% B; Wave Length: 254/220 nm; RT1(min): 7) to afford 2,2,2-trifluoro-N-(4-[3-[(3-fluoro-2-methoxyphenyl) amino]-4-oxo-5H,6H,7H- pyrazolo[1,5-a] pyrazin-2-yl]pyridin-3-yl)acetamide; formic acid (10.4 mg, 15%) as a light yellow solid. LC-MS: (M+H)⁺ found: 465.25. ¹H NMR (300 MHz, DMSO-d6) δ 11.59 (s, 1H), 8.91 (s, 1H), 8.51 – 8.38 (m, 2H), 7.71 (d, 1H), 7.35 (s, 1H), 6.77 – 6.35 (m, 3H), 6.19 – 6.11 (m, 1H), 4.47 – 4.32 (m, 2H), 3.92 (s, 3H), 3.68 – 3.66 (m, 2H). Example 109. N-(4-[3-[(3-fluoro-2-methoxyphenyl)amino]-4-oxo-5H,6H,7H- pyrazolo[1,5-a]pyrazin-2-yl]pyridin-3-yl)cyclobutanecarboxamide (compound 341)

A mixture of 2-(3-aminopyridin-4-yl)-3-[(3-fluoro-2-methoxyphenyl) amino]-5H,6H,7H- pyrazolo[1,5-a]pyrazin-4-one(50 mg, 0.13 mmol, 1.00 equiv) in Pyridine(2.00 mL) at 0 degrees C under argon atmosphere. To the above mixture was added cyclobutanecarbonyl chloride (32 mg, 0.27 mmol, 2.00 equiv) dropwise at 0 degrees C. The resulting mixture was stirred for additional 30 min at room temperature. The resulting mixture was concentrated under reduced pressure. The crude product (50mg) was purified by Prep- HPLC with the following conditions (Column: Xselect CSH OBD Column 30*150mm 5um; Mobile Phase A: Water (0.1%FA), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 19% B to 35% B in 8 min, 35% B; Wave Length: 254/220 nm; RT1(min): 7.7) to afford N-(4-[3-[(3-fluoro-2-methoxyphenyl)amino]-4-oxo-5H,6H,7H-pyrazolo[1,5- a]pyrazin-2-yl]pyridin-3-yl)cyclobutanecarboxamide (6.8 mg, 11.00%) as a off-white solid. LC-MS: (M+H)⁺ found: 451.05. ¹H NMR (300 MHz, DMSO-d6) δ 10.09 (s, 1H), 9.31 (s, 1H), 8.37 (s, 1H), 8.21 (d, 1H), 7.58 (d, 1H), 7.34 (s, 1H), 6.87 – 6.26 (m, 2H), 6.08 (d, 1H), 4.43 (t, 2H), 3.90 (s, 3H), 3.70 (t, 2H), 3.56 – 3.29 (m, 1H), 2.31 – 2.16 (m, 4H), 2.09 – 1.82 (m, 2H). Example 110.3-[(3-fluoro-2-methoxyphenyl) amino]-2-[2-methylthieno[3,2-b]pyridin- 7-yl]-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (compound 363)

A mixture of 2-bromo-3-chloro-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (500 mg, 1.99 mmol, 1.00 equiv), bis(pinacolato)diboron (1.04 g, 3.99 mmol, 2.00 equiv) and KOAc (392 mg, 3.99 mmol, 2.00 equiv) in DME (20.00 mL) were added Pd(dppf)Cl₂*CH₂Cl₂ (243 mg, 0.29 mmol, 0.15 equiv) at room temperature under argon atmosphere. The resulting mixture was stirred for overnight at 100 degrees C under argon atmosphere. The mixture was allowed to cool down to room temperature. The resulting mixture was washed with 3x100 mL of DCM. The resulting mixture was concentrated under reduced pressure. The resulting mixture was diluted with ethyl acetate (100mL). The precipitated solids were collected by filtration and washed with ethyl acetate (3x5 mL). This resulted in 3-chloro- 4-oxo-5H,6H,7H-pyrazolo[1,5-a]pyrazin-2-ylboronic acid (400 mg, 83.73%) as a brown- yellow solid. LC-MS: (M+H)⁺ found: 216.0.

A mixture of 3-chloro-4-oxo-5H,6H,7H-pyrazolo[1,5-a]pyrazin-2-ylboronic acid (530 mg, 2.46 mmol, 1.00 equiv) ,7-chloro-2-methylthieno[3,2-b]pyridine (542 mg, 2.95 mmol, 1.20 equiv), PCy₃(138 mg, 0.49 mmol, 0.20 equiv) and Cs₂CO₃ (2.4 g, 7.38 mmol, 3.00 equiv) in dioxane (20.00 mL) and H₂O (4.00 mL) at room temperature under nitrogen atmosphere. To the above mixture was added Pd₂(dba)₃ (225 mg, 0.24 mmol, 0.10 equiv) under nitrogen atmosphere. The resulting mixture was stirred for additional overnight at 60 degrees C. The resulting mixture was filtered, the filter cake was washed with MeOH (3x10 mL). The filtrate was concentrated under reduced pressure. The residue was purified by reverse flash chromatography with the following conditions: column, C18 spherical column; mobile phase, MeOH in water, 10% to 50% gradient in 30 min; detector, UV 254 nm. This resulted in 3-chloro-2-[2-methylthieno[3,2-b]pyridin-7-yl]-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4- one (210mg,25.70%) as a brown solid. LC-MS: (M+H)⁺ found: 319.0.

A mixture of 3-chloro-2-[2-methylthieno[3,2-b]pyridin-7-yl]-5H,6H,7H-pyrazolo[1,5- a]pyrazin-4-one (100 mg, 0.31 mmol, 1.00 equiv) in DMF (3.00 mL) under argon atmosphere. To the above mixture was added 3-fluoro-2-methoxyaniline (88 mg, 0.62 mmol, 2.00 equiv), EPhos (83 mg, 0.15 mmol, 0.50 equiv), EPhos Pd G4 (144 mg, 0.15 mmol, 0.50 equiv) and Cs₂CO₃ (306 mg, 0.94 mmol, 3.00 equiv) under argon atmosphere. The resulting mixture was stirred for additional overnight at 50 degrees C. The residue was purified by silica gel column chromatography, eluted with CH₂Cl₂/MeOH (10:1) to afford crude product. The product was purified by prep-HPLC using the following conditions: Column: XBridge Prep C18 OBD Column, 30*100 mm, 5μm; Mobile Phase A: Water (10 mmol/L NH₄HCO₃), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 25% B to 48% B in 10 min, 48% B; Wave Length: 254/220 nm; RT1(min): 9.28. This resulted in 3- [(3-fluoro-2-methoxyphenyl) amino]-2-[2-methylthieno[3,2-b]pyridin-7-yl]-5H,6H,7H- pyrazolo[1,5-a]pyrazin-4-one (17.5 mg, 13.09%) as a off-white solid. LC-MS: (M+H)⁺ found: 423.95. ¹H NMR (300 MHz, DMSO-d6) δ 8.49 (d, 1H), 8.36 (t, 1H), 7.54 (d, 1H), 7.39 (s, 1H), 7.28 (d, 1H), 6.76 – 6.49 (m, 2H), 5.98 – 5.96 (m, 1H), 4.49 – 4.55 (m, 2H), 3.95 (s, 3H), 3.73 – 3.68 (m, 2H), 2.65 (d, 3H). Example 111.3-[(3-chloro-2-methoxyphenyl)amino]-2-[2-methylthieno[3,2-b]pyridin-7- yl]-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (compound 362)

A mixture of 3-chloro-2-[2-methylthieno[3,2-b]pyridin-7-yl]-5H,6H,7H-pyrazolo[1,5- a]pyrazin-4-one (80 mg, 0.25 mmol, 1.00 equiv) in DMF (3.00 mL) under argon atmosphere. To the above mixture was added 3-chloro-2-methoxyaniline (79 mg, 0.50 mmol, 2.00 equiv), EPhos (67 mg, 0.12 mmol, 0.50 equiv), EPhos Pd G4 (115 mg, 0.12 mmol, 0.50 equiv) and Cs₂CO₃ (245 mg, 0.75 mmol, 3.00 equiv) under argon atmosphere. The resulting mixture was stirred for additional overnight at 50 degrees C. The residue was purified by silica gel column chromatography, eluted with CH₂Cl₂/MeOH (10:1) to afford crude product. The product was precipitated by Column: Xselect CSH OBD Column 30*150mm 5um, n; Mobile Phase A: Water(10 mmol/L NH₄HCO₃), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 34% B to 50% B in 10 min, 50% B; Wave Length: 220/254 nm; RT1(min): 9.0. This resulted in 3-[(3-chloro-2-methoxyphenyl)amino]-2-[2- methylthieno[3,2-b]pyridin-7-yl]-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (9 mg, 8.01%) as a off-white solid. LC-MS: (M+H)⁺ found: 440.20. ¹H NMR (300 MHz, DMSO-d6) δ 8.49 (d, 1H), 8.36 (t, 1H), 7.54 (d, 1H), 7.45 (s, 1H), 7.29 (d, 1H), 6.78 – 6.67 (m, 2H), 6.13 – 6.10 (m, 1H), 4.50 – 4.46 (m, 2H), 3.92 (s, 3H), 3.74 – 3.68 (m, 2H), 2.65 (d, 3H). Example 112.3-[(3-chloro-2-methoxyphenyl)amino]-2-(3-{2-[1- (difluoromethyl)cyclopropyl] ethynyl}pyridin-4-yl)-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4- one (compound 364)

To a stirred solution of 4-bromo-3-iodopyridine (500 mg, 1.77 mmol, 1.00 equiv), palladium chloride; bis(triphenylphosphine) (124 mg, 0.18 mmol, 0.10 equiv), TEA (535 mg, 5.31 mmol, 3.00 equiv) in MeCN (6 mL) was added CuI (34 mg, 0.18 mmol, 0.10 equiv) and 1-(difluoromethyl)-1-ethynylcyclopropane (1.17 g, 2.12 mmol, 1.20 equiv) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 2 h at room temperature under nitrogen atmosphere. The resulting mixture was filtered, the filter cake was washed with MeCN (2x10 mL). The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EtOAc (20:1) to afford 4-bromo-3-{2-[1- (difluoromethyl)cyclopropyl]ethynyl}pyridine (490 mg, 99%) as a yellow oil. LC-MS: M+H⁺ found: 272.

To a stirred solution of 4-bromo-3-{2-[1-(difluoromethyl)cyclopropyl]ethynyl}pyridine (300 mg, 1.10 mmol, 1.00 equiv), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (420 mg, 1.16 mmol, 1.50 equiv), Pd₂(dba)₃.CHCl₃ (100 mg, 0.11 mmol, 0.10 equiv) in dioxane (10 mL) was added PPh3 (28 mg, 0.11 mmol, 0.10 equiv) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 2 h at 80 degrees under nitrogen atmosphere. The resulting mixture was filtered, the filter cake was washed with MeOH (10 mL). The resulting mixture was concentrated under reduced pressure to afford 3-{2-[1-(difluoromethyl)cyclopropyl]ethynyl}-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan- 2-yl)pyridine (400 mg) as a yellow solid. The crude product mixture was used in the next step directly without further purification. LC-MS: (M+H)⁺ found: 320.1.

Into a 40-mL vial were placed 2-bromo-3-[(3-chloro-2-methoxyphenyl)amino]- 5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (100 mg, 0.27 mmol, 1.00 equiv), 3-{2-[1- (difluoromethyl)cyclopropyl]ethynyl}pyridin-4-ylboronic acid (77 mg, 0.32 mmol, 1.20 equiv), Na₂CO₃ (86 mg, 0.81 mmol, 2.00 equiv), Pd(PPh₃)₄ (31 mg, 0.03 mmol, 0.10 equiv) in dioxane (5 mL) and H₂O (1 mL). The resulting solution was stirred for overnight at 100 degrees C. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The resulting mixture was diluted with DCM (6 mL). The resulting mixture was filtered, the filter cake was washed with MeOH (2x1 mL). The filtrate was concentrated under reduced pressure. The crude product was purified by Prep-HPLC with the following conditions (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water (10 mmol/L NH₄HCO₃), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 37% B to 53% B in 8 min, 53% B; Wave Length: 254/220 nm; RT1(min): 7.18) to afford 3-[(3-chloro-2-methoxyphenyl)amino]-2-(3-{2-[1- (difluoromethyl)cyclopropyl] ethynyl}pyridin-4-yl)-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4- one (46.9 mg, 36.0%) as a white solid. LC-MS: (M+H)⁺ found: 484.25. ¹H NMR (400 MHz, DMSO-d6) δ 8.62 (s, 1H), 8.49 (d, 1H), 8.30 (s, 1H), 7.48 (d, 1H), 7.13 (s, 1H), 6.67 (d, J = 4.8 Hz, 2H), 6.15 (t, 1H), 5.76 (t, 1H), 4.41 – 4.37 (m, 2H), 3.80 (s, 3H), 3.69 – 3.66 (m, 2H), 1.26 – 1.13 (m, 4H). Example 113.3-[(3-fluoro-2-methoxyphenyl)amino]-2-{[1,2]thiazolo[4,5-b]pyridin-7- yl}-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (compound 228)

A mixture of 3-chloro-2-{[1,2] thiazolo[4,5-b]pyridin-7-yl}-5H,6H,7H-pyrazolo[1,5- a]pyrazin-4-one (120 mg, 0.39 mmol, 1.00 equiv) in DMF (4.00 mL) were added 3-fluoro- 2-methoxyaniline (110 mg, 0.78 mmol, 2.00 equiv), EPhos (104 mg, 0.19 mmol, 0.50 equiv), EPhos Pd G4 (180 mg, 0.19 mmol, 0.50 equiv)and Cs₂CO₃ (383 mg, 1.17 mmol, 3.00 equiv) at room temperature under argon atmosphere. The resulting mixture was stirred for 2 h at 50 degrees C under argon atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH₂Cl₂ / MeOH (40:1) to afford crude product. The crude product (35 mg) was purified by Prep-HPLC with the following conditions (Column: XBridge Shield RP18 OBD Column, 30*150 mm, 5μm; Mobile Phase A: Water(10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 31% B to 50% B in 8 min; Wave Length: 254/220 nm; RT1(min): 8;) to afford 3-[(3-fluoro-2-methoxyphenyl)amino]-2- {[1,2]thiazolo[4,5-b]pyridin-7-yl}-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (8.2 mg, 5.04%) as a off-white solid. LC-MS: (M+H)⁺ found: 411.25. ¹H NMR (300 MHz, DMSO-d6) δ 9.32 (s, 1H), 8.81 (d, 1H), 8.41 (s, 1H), 7.72 (d, 1H), 7.48 (s, 1H), 6.89 – 6.53 (m, 2H), 6.08 – 6.03 (m, 1H), 4.56 – 4.52 (m, 2H), 3.98 (s, 3H), 3.74 – 3.70 (m, 2H). Example 114.3-[(3-fluoro-2-methoxyphenyl)amino]-2-{2-methoxythieno[3,2-b]pyridin- 7-yl}-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (compound 275)

To a solution of anise alcohol (860 mg, 6.19 mmol, 1.05 equiv) in DMF (10 mL) was added sodium hydride (260 mg, 6.50 mmol, 1.10 equiv, 60% in oil) at 0 degrees C. The mixture was stirred for 15 min.7-chlorothieno[3,2-b]pyridine (1.00 g, 5.90 mmol, 1.00 equiv) was added and the mixture was allowed to warm to RT and stirred for 1h. The reaction mixture was quenched by water and extracted with DCM (3*25 mL). The residue was purified by silica gel column chromatography, eluted with PE/EA (1:1) to afford 7-[(4- methoxyphenyl)methoxy]thieno[3,2-b]pyridine (1.4 g, 87.53%) as a white solid. LC-MS: M+H⁺ found: 272.1.

A solution of 7-[(4-methoxyphenyl)methoxy]thieno[3,2-b]pyridine (1.30 g, 4.79 mmol, 1.00 equiv) in tetrahydrofuran (40 mL) was treated with n-BuLi (4.2 mL, 10.54 mmol, 2.20 equiv) for 1h at -78 degrees C under nitrogen atmosphere followed by the addition of carbon tetrabromide (1.59 g, 4.79 mmol, 1.00 equiv) dropwise at -78 degrees C. The resulting mixture was stirred for 1h at -78 degrees C under argon atmosphere. The reaction was quenched by the addition of sat. NH₄Cl (aq.) (40 mL) at 0 degrees C. The resulting mixture was extracted with EtOAc (3 x 40mL). The combined organic layers were washed with brine (1x20 mL), dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EA (1:1) to afford 2-bromo-7-[(4- methoxyphenyl)methoxy]thieno[3,2-b]pyridine (1.2 g, 71.51%) as a white solid. LC-MS: (M+H)⁺ found: 350.0.

To a stirred mixture of 2-bromothieno[3,2-b]pyridin-7-ol; trifluoroacetic acid (1.10 g, 3.20 mmol, 1.00equiv) and NaOMe in MeOH (4.30 g, 15.99 mmol, 5.00 equiv, 30w/w%) in MeOH (30 mL) was added CuBr (70 mg, 0.48 mmol, 0.10 equiv) at 120 degrees C under argon atmosphere. The resulting mixture was stirred for 2 days at 120 degrees C under argon atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH₂Cl₂/MeOH (10:1) to afford 2-methoxythieno[3,2-b]pyridin-7-ol (530 mg, 61.18%) as a light brown solid. LC-MS: (M+H)⁺ found:182.00.

A mixture of 2-methoxythieno[3,2-b]pyridin-7-ol (530 mg, 2.93 mmol, 1.00 equiv) in phosphorus oxychloride (6 mL) was stirred for 2h at 90 degrees C under nitrogen atmosphere. The reaction was quenched by the addition of Water/Ice (30 mL) at 0degrees C, treated with aqueous 50 % sodium hydroxide solution. The resulting mixture was extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine (1x10 mL), dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure.The residue was purified by silica gel column chromatography, eluted with PE/EA (3:1) to afford 7-chloro-2-methoxythieno[3,2-b]pyridine (250 mg, 42.81%) as a white solid. LC-MS: (M+H)⁺ found:199.90.

To a stirred mixture of 2-bromo-3-[(3-fluoro-2-methoxyphenyl)amino]-5H,6H,7H- pyrazolo[1,5-a]pyrazin-4-one (50 mg, 0.14 mmol, 1.00 equiv) and 2-methoxy-7-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)thieno[3,2-b]pyridine (49 mg, 0.17 mmol, 1.20 equiv) in dioxane (1.0 mL) and H₂O (0.2 mL) were added XPhos palladium(II) biphenyl-2-amine chloride (11 mg, 0.01 mmol, 0.10 equiv) and Na₂CO₃ (30 mg, 0.28 mmol, 2.00 equiv) in portions at room temperature under argon atmosphere.The resulting mixture was stirred for overnight at 50 degrees C under argon atmosphere. The resulting mixture was filtered, the filter cake was washed with CH₂Cl₂ (3x10 mL). The filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (PE / EA 1:1) to afford 3-[(3- fluoro-2-methoxyphenyl)amino]-2-{2-methoxythieno[3,2-b]pyridin-7-yl}-5H,6H,7H- pyrazolo[1,5-a]pyrazin-4-one (11.7 mg, 18.87%) as a white solid. LC-MS: (M+H)⁺ found: 439.95. ¹H NMR (400 MHz, DMSO-d6) δ 8.31 – 8.42 (m, 2H), 7.47 (d, 1H), 7.36 (s, 1H), 6.63 – 6.73 (m, 2H), 6.58 – 6.55 (m, 1H), 5.98 – 5.96 (m, 1H), 4.47 – 4.45 (m, 2H), 4.04 (s, 3H), 3.93 (s, 3H), 3.69 (t, 2H) Example 115.3-[(3-chloro-2-methoxyphenyl)amino]-2-{2-methoxythieno[3,2-b]pyridin- 7-yl}-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (compound 365)

Into a 8 mL vial were added 2-methoxythieno[3,2-b]pyridin-7-ylboronic acid (40 mg, 0.19 mmol, 1.00 equiv) and 2-bromo-3-[(3-chloro-2-methoxyphenyl)amino]-5H,6H,7H- pyrazolo[1,5-a]pyrazin-4-one (71 mg, 0.19 mmol, 1.00 equiv) and 2nd Generation XPhos Precatalyst (15 mg, 0.02 mmol, 0.10 equiv) and Na₂CO₃ (61 mg, 0.57 mmol, 3.00 equiv) and dioxane (2.0 mL) and H₂O (0.4 mL) at room temperature. The resulting mixture was stirred for overnight at 50 degrees C under nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH₂Cl₂/MeOH (50:1) to afford crude product (100 mg).The crude product (100 mg) was purified by Prep- HPLC with the following conditions (Column: YMC-Actus Triart C18 ExRS, 30*150 mm, 5μm; Mobile Phase A: Water(10 mmol/L NH₄HCO₃), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 47% B to 69% B in 10 min, 69% B; Wave Length: 254/220 nm; RT1(min): 5.63) to afford 3-[(3-chloro-2-methoxyphenyl)amino]-2-{2- methoxythieno[3,2-b]pyridin-7-yl}-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (17.2 mg, 19.62%) as a white solid. LC-MS: M+H⁺ found: 455.90. ¹H NMR (400 MHz, DMSO-d6) δ 8.40 (d, 1H), 8.35 (t, 1H), 7.47 (d, 1H), 7.42 (s, 1H), 6.80 – 6.67 (m, 3H), 6.16 - 6.10 (m, 1H), 4.50 - 4.44 (m, 2H), 4.05 (s, 3H), 3.91 (s, 3H), 3.70 - 3.64 (m, 2H). Example 116.8-{3-[(3-chloro-2-methoxyphenyl)amino]-4-oxo-5H,6H,7H-pyrazolo[1,5- a]pyrazin-2-yl}-1H-1,5-naphthyridin-2-one (compound 345)

To a stirred solution of methyl 4-nitro-1H-pyrazole-3-carboxylate (50.00 g, 292.21 mmol, 1.00 equiv) and PPh3 (91.97 g, 350.65 mmol, 1.20 equiv) in dry THF (500 mL) was added tert-butyl N-(2-hydroxyethyl)carbamate (56.52 g, 350.65 mmol, 1.20 equiv) dropwise at 0 degrees C under argon atmosphere. The resulting mixture was stirred for 20 min at 0 degrees C under argon atmosphere. Then, the above mixture was added DIAD (70.90 g, 350.65 mmol, 1.20 equiv) dropwise at 0 degrees C under argon atmosphere. The resulting mixture was stirred for 1 h at 0 degrees C under argon atmosphere. Desired product could be detected by LCMS. The resulting mixture was concentrated under reduced pressure. The resulting mixture was diluted with water (100 mL). The resulting mixture was extracted with EtOAc (3 x 500 mL). The combined organic layers dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure to afford methyl 2-{2-[(tert-butoxycarbonyl)amino]ethyl}-4-nitropyrazole-3-carboxylate (150 g, crude) as a yellow solid. The crude product was used in the next step directly without further purification. LC-MS: (M+H)⁺ found: 315.

To a stirred solution of methyl 2-(2-aminoethyl)-4-nitropyrazole-3-carboxylate (108.00 g, 504.25 mmol, 1.00 equiv) in toluene (1000 mL) was added TEA (102.05 g, 1.00 mol, 2.00 equiv) dropwise at room temperature under air atmosphere. The resulting mixture was stirred for 3 h at 100 degrees C under air atmosphere. The precipitated solids were collected by filtration and washed with DCM (3x50 mL) to afford 3-nitro-5H,6H,7H-pyrazolo[1,5- a]pyrazin-4-one (68 g, 74.04%) as an off-white solid. LC-MS: (M+H)⁺ found: 183.

To a stirred solution of 3-amino-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one (2.00 g, 13.14 mmol, 1.00 equiv) in ACN (200 mL) in ACN (200 mL) was added NBS (2.34 g, 13.14 mmol, 1.00 equiv) at -30°C. The resulting mixture was stirred for 1h. Desired product could be detected by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse flash chromatography (mobile phase, MeCN in water, 0% to 100% in 30 min) to afford 3-amino-2-bromo-6,7-dihydropyrazolo[1,5- a]pyrazin-4(5H)-one (2.00 g, 65.85%) as yellow solid. LC-MS: (M+H)⁺ found: 231.

To a solution of 8-bromo-2-fluoro-1,5-naphthyridine (500 mg, 2.20 mmol, 1.00 equiv) and 4,4,5,5-tetramethyl-2-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (671 mg, 2.64 mmol, 1.20 equiv) in THF (10 mL) were added KOAc (540 mg, 5.51 mmol, 2.50 equiv) and Pd(dppf)Cl₂*CH₂Cl₂ (179 mg, 0.22 mmol, 0.10 equiv). After stirring for 2hrs at 80 degrees C under a nitrogen atmosphere. Desired product could be detected by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with DCM:CH₃OH (10:1) to afford 6-fluoro- 1,5-naphthyridin-4-ylboronic acid (200 mg, 47.31%) as a yellow solid. LC-MS: (M+H)⁺ found: 193.

To a solution of 6-fluoro-1,5-naphthyridin-4-ylboronic acid (62 mg, 0.32 mmol, 1.50 equiv) and 2-bromo-3-[(3-chloro-2-methoxyphenyl)amino]-5H,6H,7H-pyrazolo[1,5-a]pyrazin- 4-one (80 mg, 0.21 mmol, 1.00 equiv) in dioxane (1.0 mL) and H₂O (0.1 mL) were added Na₂CO₃ (69 mg, 0.65 mmol, 3.00 equiv) and 2nd Generation XPhos precatalyst (17 mg, 0.02 mmol, 0.10 equiv) . After stirring for 2h at 80 degrees C under a nitrogen atmosphere. Desired product could be detected by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with DCM:CH₃OH (10:1) to afford 3-[(3-chloro-2-methoxyphenyl)amino]-2-(6-fluoro- 1,5-naphthyridin-4-yl)-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (60 mg, 63.51%) as a yellow solid. LC-MS: (M+H)⁺ found: 439.

To a To a stirred solution of 3-[(3-chloro-2-methoxyphenyl)amino]-2-(6-fluoro-1,5- naphthyridin-4-yl)-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (50 mg, 0.11 mmol, 1.00 equiv) in DMF (2.00 mL) and THF (5.00 mL), DMSO (0.2 mL) and H₂O (1.5 mL) were added NaOH (9 mg, 0.23 mmol, 2.00 equiv). The resulting mixture was stirred for 5h at 50 degrees C. The reaction was monitored by LCMS. The resulting mixture was concentrated under vacuum. The crude product was purified by Prep-HPLC with the following conditions (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water (10 mmol/L NH₄HCO₃), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 21% B to 51% B in 7 min; Wave Length: 254 nm; RT1(min): 6.5) to afford 8-{3-[(3- chloro-2-methoxyphenyl)amino]-4-oxo-5H,6H,7H-pyrazolo[1,5-a]pyrazin-2-yl}-1H-1,5- naphthyridin-2-one (15.2 mg, 29.01%) as a yellow solid. LC-MS: (M+H)⁺ found: 436.90. ¹H NMR (300 MHz, DMSO-d6) δ 11.53 (s, 1H), 8.50 – 8.36 (m, 2H), 8.00 (d, 1H), 7.80 (d, 1H), 7.45 (s, 1H), 6.85 (d, 1H), 6.77 – 6.62 (m, 2H), 6.25 – 6.17 (m, 1H), 4.53 (t, 2H), 3.89 (s, 3H), 3.70 (d, 2H). Example 117.3-[(3-chloro-2-methoxyphenyl)amino]-2-{2-methoxy-1H-pyrrolo[3,2- b]pyridin-7-yl}-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (compound 299)

A solution of Trimethyloxonium tetrafluoroborate (78 mg, 0.53 mmol, 1.13 equiv) in chloroform (5 mL) was treated with 7-bromo-1H,3H-pyrrolo[3,2-b]pyridin-2-one (100 mg, 0.47 mmol, 1.00 equiv) for 10 min at 10 degrees C under nitrogen .The resulting mixture was stirred for 2 days at room temperature under nitrogen atmosphere. The resulting mixture was washed with 1x5 mL of EtOAc. The resulting mixture was extracted with EtOEt (3 x 10mL). The combined organic layers were washed with brine (1x10 mL), dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (CH₂Cl₂/MeOH 10:1) to afford 7-bromo- 2-methoxy-1H-pyrrolo[3,2-b]pyridine (80 mg, 75.06%) as a light yellow solid. LC-MS: M+H⁺ found 226.95.

Into a 8 mL vial were added 7-bromo-2-methoxy-1H-pyrrolo[3,2-b]pyridine (45 mg, 0.20 mmol, 1.00 equiv) and bis(pinacolato)diboron (100 mg, 0.40 mmol, 2.00 equiv) and Pd(dppf)Cl₂.CH₂Cl₂ (16 mg, 0.02 mmol, 0.10 equiv) and KOAc (39 mg, 0.40 mmol, 2.00 equiv) and dioxane (2 mL) at room temperature. The resulting mixture was stirred for 2 h at 120 degrees C under nitrogen atmosphere. The reaction was monitored by LCMS. After filtration, the filtrate was concentrated under reduced pressure The crude product (50 mg) was used in the next step directly without further purification LC-MS : M+H found: 275.2.

Into a 20 mL vial were added 2-methoxy-1H-pyrrolo[3,2-b]pyridin-7-ylboronic acid (35 mg, 0.18 mmol, 1.00 equiv) and 2-bromo-3-[(3-chloro-2-methoxyphenyl)amino]- 5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (68 mg, 0.18 mmol, 1.00 equiv) and Na₂CO₃ (58 mg, 0.55 mmol, 3.00 equiv)and 2nd Generation XPhos Precatalyst (14 mg, 0.02 mmol, 0.10 equiv) and dioxane (3.5 mL) and H₂O (0.7 mL) at room temperature. The resulting mixture was stirred for 2 h at 60 degrees C under nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH₂Cl₂/MeOH (10:1) to afford crude product (60 mg).The crude product (60 mg) was purified by Prep- HPLC with the following conditions (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water(10 mmol/L NH₄HCO₃), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 17% B to 47% B in 7 min; Wave Length: 254 nm; RT1(min): 6.5) to afford 3-[(3-chloro-2-methoxyphenyl)amino]-2-{2-methoxy-1H-pyrrolo[3,2- b]pyridin-7-yl}-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (11.9 mg, 14.75%) as a yellow solid. LC-MS: M+H⁺ found: 439.25. ¹H NMR (400 MHz, DMSO-d6) δ 9.52 (s, 1H), 8.29 (s, 1H), 7.34 – 7.21 (m, 2H), 6.80 – 6.69 (m, 2H), 6.67 (d, 1H), 6.19 – 6.13 (m, 1H), 4.92 (d, 1H), 4.46 (t, 2H), 3.88 (s, 3H), 3.68 (d, 3H), 3.61 (s, 2H). Example 118.3-[(3-chloro-2-methoxyphenyl)amino]-2-{3-[(3- methoxypropyl)amino]pyridin-4-yl}-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (compound 303)

To a stirred mixture of 3-[(3-chloro-2-methoxyphenyl )amino]-2-(3-fluoropyridin-4-yl)- 5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (80 mg, 0.21 mmol, 1.00 equiv) and 3- methoxypropylamine (0.50 mL) in DMSO (1.00 mL) was added DIEA (400 mg, 3.15 mmol, 15.00 equiv) dropwise at room temperature under argon atmosphere. The resulting mixture was stirred for overnight at 120 degrees C under argon atmosphere. Desired product could be detected by LCMS. The resulting mixture was concentrated under reduced pressure. The crude product (80 mg) was purified by Prep-HPLC with the following conditions (Column: YMC-Actus Triart C18 ExRS, 30*150 mm, 5μm; Mobile Phase A: Water (10 mmol/L NH₄HCO₃), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 20% B to 40% B in 10 min, 40% B; Wave Length: 254/220 nm; RT1(min): 10.38) to afford 3-[(3-chloro-2-methoxyphenyl)amino]-2-{3-[(3-methoxypropyl)amino]pyridin- 4-yl}-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (7.5 mg, 7.90%) as a white solid. LC-MS: (M+H)⁺ found: 457.00. ¹H NMR (300 MHz, DMSO-d6) δ 8.33 (s, 1H), 8.08 (s, 1H), 7.72 (d, 1H), 7.42-7.30 (m, 2H), 6.81-6.49 (m, 3H), 6.19-6.02 (m, 1H), 4.41 (m, 2H), 3.85 (s, 3H), 3.70-3.55 (m, 2H), 3.51-3.39 (m, 2H), 3.29-3.17 (m, 5H), 1.98-1.70(m, 2H). Example 119. N-(4-[3-[(3-fluoro-2-methoxyphenyl)amino]-4-oxo-5H,6H,7H- pyrazolo[1,5-a]pyrazin-2-yl]pyridin-3-yl)-2-methoxyacetamide (compound 333)

To a stirred solution of 3-[(3-fluoro-2-methoxyphenyl)amino]-2-(3-fluoropyridin-4-yl)- 5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (100 mg, 0.27 mmol, 1.00 equiv) and 1-(2,4- dimethoxyphenyl)methanamine (54 mg, 0.32 mmol, 1.20 equiv) in DMSO (3.00 mL) was added DIEA (522 mg, 4.04 mmol, 15.00 equiv) at room temperature under argon atmosphere. The resulting mixture was stirred for overnight at 120 degrees C under argon atmosphere. Desired product could be detected by LCMS. The mixture was allowed to cool down to room temperature. The resulting mixture was diluted with water (15 mL). The precipitated solids were collected by filtration and washed with water (3x5 mL). The residue was purified by Prep-TLC (CH₂Cl₂/MeOH 10:1) to afford 2-(3-{[(2,4- dimethoxyphenyl)methyl]amino}pyridin-4-yl)-3-[(3-fluoro-2-methoxyphenyl)amino]- 5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one as a light yellow solid(70.0 mg, 50.35%). LC-MS: (M+H)⁺ found: 519.05.

To a stirred solution of 3-[(3-fluoro-2-methoxyphenyl)amino]-2-(3-fluoropyridin-4-yl)- 5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (70 mg, 0.19 mmol, 1.00 equiv) was added TFA (2.00 mL) dropwise at 0 degrees C. The resulting mixture was stirred for 2h at 50 degrees C. Desired product could be detected by LCMS. The resulting mixture was concentrated under reduced pressure. The resulting mixture was diluted with DCM (10 mL). The mixture was basified to pH 8 with aqueous ammonia. The resulting mixture was concentrated under vacuum. The crude product mixture was used in the next step directly without further purification. LC-MS: (M+H)⁺ found: 368.95.

To a stirred mixture of 2-(3-aminopyridin-4-yl)-3-[(3-fluoro-2-methoxyphenyl)amino]- 5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (55 mg, 0.15 mmol, 1.00 equiv) in Pyridine (1.00 mL) was added methoxyacetyl chloride (32 mg, 0.30 mmol, 2.00 equiv) in DCM (0.50 mL) dropwise at 0 degrees C under argon atmosphere. The resulting mixture was stirred for 1 h at room temperature under argon atmosphere. Desired product could be detected by LCMS. The reaction was quenched by the addition of MeOH (1mL) at 0 degrees C. The resulting mixture was concentrated under reduced pressure. The crude product (70 mg) was purified by Prep-HPLC with the following conditions (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water (10 mmol/L NH₄HCO₃), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 33% B to 63% B in 7 min; Wave Length: 254 nm; RT1(min): 6.5) to afford N-(4-[3-[(3-fluoro-2-methoxyphenyl)amino]-4-oxo- 5H,6H,7H-pyrazolo[1,5-a]pyrazin-2-yl]pyridin-3-yl)-2-methoxyaceta-mide (8.8 mg, 13.18%) as an off-white solid. LC-MS: (M+H)⁺ found: 441.05. ¹H NMR (400 MHz, DMSO-d6) δ 11.20 (s, 1H), 9.61 (s, 1H), 8.48-8.10 (m, 2H), 7.64 (d, 1H), 7.37 (s, 1H), 6.75-6.60 (m, 1H), 6.59-6.47 (m, 1H), 6.00 (d, 1H), 4.65-4.37 (m, 2H), 4.08 (s, 2H), 3.90 (s, 3H), 3.72 (s, 2H), 3.49 (s, 3H). Example 120.3-[(3-chloro-2-methoxyphenyl)amino]-2-{3-[(2- methoxyethyl)amino]pyridin-4-yl}-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (compound 332)

To a stirred mixture of 3-[(3-chloro-2-methoxyphenyl)amino]-2-(3-fluoropyridin-4-yl)- 5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (80 mg, 0.21 mmol, 1.00 equiv) and DIEA (400 mg, 3.15 mmol, 15.00 equiv) in ethanamine, 2-methoxy- (0.50 mL) and DMSO (1.00 mL) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for overnight at 120 degrees C under nitrogen atmosphere. Desired product could be detected by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse flash chromatography with the following conditions: column, silica gel; mobile phase, MeCN in water, 10% to 50% gradient in 10 min; detector, UV 254 nm. This resulted in 3-[(3-chloro-2-methoxyphenyl)amino]-2-{3-[(2- methoxyethyl)amino]pyridin-4-yl}-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (5.9 mg, 5.84%) as a white solid. LC-MS: (M+H)⁺ found: 443.30. ¹H NMR (400 MHz, DMSO-d6) δ 8.46-8.29 (m, 1H), 8.12 (s, 1H), 7.72 (d, 1H), 7.41 (d, 1H), 7.33 (s, 1H), 6.97-6.92 (m, 1H), 6.73-6.61 (m, 2H), 6.12-6.04 (m, 1H), 4.46-4.28 (m, 2H), 3.90 (s, 3H), 3.62-3.73 (m, 2H), 3.61-3.55 (m, 2H), 3.42-3.36 (m, 2H), 3.33 (s, 3H). Example 121. N-(4-[3-[(3-fluoro-2-methoxyphenyl)amino]-4-oxo-5H,6H,7H- pyrazolo[1,5-a]pyrazin-2-yl]pyridin-3-yl)-2-methylpropanamide (compound 339)

To a stirred mixture of 2-(3-aminopyridin-4-yl)-3-[(3-fluoro-2-methoxyphenyl)amino]- 5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one(50 mg, 0.14 mmol, 1.00 equiv) and propanoyl chloride, 2-methyl-(30 mg, 0.27 mmol, 2.00 equiv) in Pyridine (2.00 mL) in portions at 0 degrees C under nitrogen atmosphere. The resulting mixture was stirred for 30 min at 0 degrees C under nitrogen atmosphere. Desired product could be detected by LCMS. The crude product (60 mg) was purified by Prep-HPLC with the following conditions (Column: Xselect CSH OBD Column 30*150mm 5um, n; Mobile Phase A: Water(0.1%FA), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 15% B to 36% B in 8 min, 36% B; Wave Length: 254/220 nm; RT1(min): 7.75) to afford N-(4-[3-[(3-fluoro-2- methoxyphenyl)amino]-4-oxo-5H,6H,7H-pyrazolo[1,5-a]pyrazin-2-yl]pyridin-3-yl)-2- methylpropanamide(4.2 mg,12.93%) as a white solid. LC-MS: (M+H)⁺ found: 439.05. ¹H NMR (400 MHz, DMSO-d6) δ 10.10 (s, 1H), 9.25 (s, 1H), 8.36 (d, 1H), 8.21 (d, 1H), 7.56 (d, J = 5.1 Hz, 1H), 7.33 (s, 1H), 6.68-6.60 (m, 1H), 6.59-6.45 (m, 1H), 6.14-6.10 (m, 1H), 4.61-4.30 (m, 2H), 3.93 (s, 3H),3.72-3.60 (m, 2H), 2.75-2.57 (m, 1H), 1.16 (s, 6H). Example 122. N-(4-[3-[(3-fluoro-2-methoxyphenyl) amino]-4-oxo-5H,6H,7H- yrazolo[1,5-]pyrazin-2-yl]pyridin-3-yl)acetamide (compound 337)

To a stirring solution of 2-(3-aminopyridin-4-yl)-3-[(3-fluoro-2-methoxyphenyl) amino]- 5H,6H,7H-pyrazolo[1,5-a] pyrazine-4-on (60 mg, 0.16 mmol, 1.00 equiv) in pyridine were added Ac₂O (33 mg, 0.33 mmol, 2.00 equiv) in 0.5 ml DCM dropwise at degree C under nitrogen atmosphere. The resulting mixture was stirred for 30 min at room temperature under nitrogen. The crude product (70 mg) was purified by Prep- HPLC with the following conditions (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water (10 mmol/L NH₄HCO₃), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 13% B to 43% B in 7 min, 43% B; Wave Length: 254 nm; RT1(min): 6.5) to afford N-(4-[3-[(3-fluoro-2-methoxyphenyl) amino]-4-oxo-5H,6H,7H- yrazolo[1,5-]pyrazin-2-yl]pyridin-3-yl)acetamide (13.2 mg, 18.38%) as white solid. LC-MS: (M+H)⁺ found: 411.05. ¹H NMR (300 MHz, DMSO-d₆) δ 9.90 (s, 1H), 9.14 (s, 1H), 8.36 (t, 1H), 8.24 (d, 1H), 7.55 (d, 1H), 7.33 (s, 1H), 6.64-6.47 (m, 2H), 6.07 (d, 1H), 4.44 (t, 2H), 3.89 (s, 3H), 3.69 (t, 2H), 2.34 (s, 3H). Example 123. (1r,3r)-3-(dimethylamino)-N-(4-[3-[(3-fluoro-2-methoxyphenyl)amino]-4- oxo-5H,6H,7H-pyrazolo[1,5-a]pyrazin-2-yl]pyridin-3-yl)cyclobutane-1-carboxamide; formic acid (compound 342)

To a stirred solution of (1r,3r)-3-(dimethylamino)cyclobutane-1-carboxylic acid (60 mg, 0.42 mmol, 1.00 equiv) in THF (4.00 mL) was added oxalyl chloride (80 mg, 0.63 mmol, 1.50 equiv) and DMF (0.10 mL) dropwise at 0 degrees C under argon atmosphere. The resulting mixture was stirred for 30 min at 0 degrees C under argon atmosphere. The reaction was monitored by TLC (DCM/MeOH = 5/1). The resulting mixture was used in the next step directly without further purification.

To a stirred solution of 2-(3-aminopyridin-4-yl)-3-[(3-fluoro-2-methoxyphenyl)amino]- 5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (50 mg, 0.14 mmol, 1.00 equiv) in Pyridine (0.30 mL) was added (1r,3r)-3-(dimethylamino)cyclobutane-1-carbonyl chloride (66 mg, 0.41 mmol, 3.00 equiv) in DCM (0.50 mL) dropwise at 0 degrees C under argon atmosphere. The resulting mixture was stirred for 1 h at room temperature under argon atmosphere. The reaction was monitored by LCMS. The reaction was quenched by the addition of MeOH (1 mL) at 0 degrees C. The resulting mixture was concentrated under reduced pressure. The crude product (70 mg) was purified by Prep-HPLC with the following conditions (Column: Xselect CSH OBD Column 30*150mm 5um, n; Mobile Phase A: water (0.1%FA), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 7% B to 20% B in 8 min, 20% B; Wave Length: 254/220 nm; RT1(min): 7.5) to afford (1r,3r)-3- (dimethylamino)-N-(4-[3-[(3-fluoro-2-methoxyphenyl)amino]-4-oxo-5H,6H,7H- pyrazolo[1,5-a]pyrazin-2-yl]pyridin-3-yl)cyclobutane-1-carboxamide; formic acid (14.4 mg, 18.84%) as a off-white solid. LC-MS: (M+H)⁺ found: 494.10 ¹H NMR (400 MHz, DMSO-d6) δ 10.03 (s, 1H), 9.23 (s, 1H), 8.36 (d, 1H), 8.26-8.14 (m, 2H), 7.55 (d, 1H), 7.32 (s, 1H), 6.69-6.60 (m, 1H), 6.55-6.49 (m, 1H), 6.11 (d, 1H), 4.69- 4.31 (m, 2H), 3.90 (s, 3H), 3.72-3.64 (m, 2H), 3.15-3.10 (m, 1H), 2.90-2.81 (m, 1H), 2.35- 2.27 (m, 2H), 2.12-2.01 (m, 8H). Example 124. N-(4-[3-[(3-fluoro-2-methoxyphenyl)amino]-4-oxo-5H,6H,7H- pyrazolo[1,5-a]pyrazin-2-yl]pyridin-3-yl)cyclopropanecarboxamide (compound 338)

Into a Volume were added 3-[(3-fluoro-2-methoxyphenyl) amino]-2-(3-fluoropyridin-4- yl)-5H,6H,7H-pyrazolo[1,5-a] pyrazin-4-one (100 mg, 0.27 mmol, 1.00 equiv), DIEA (522 mg, 4.04 mmol, 15.00 equiv), 1-(2,4-dimethoxyphenyl) methanamine (1.50 mL) and DMSO (1.50 mL) at room temperature under air atmosphere. The resulting mixture was stirred for 50 h at 120 degrees C under air atmosphere. Desired product could be detected by LCMS. The residue was purified by reverse flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeOH in water, 10% to 50% gradient in 10 min; detector, UV 254 nm. This resulted in 2-(3-[[(2,4-dimethoxyphenyl) methyl] amino] pyridin-4-yl)-3-[(3-fluoro-2-methoxyphenyl)amino]-5H,6H,7H-pyrazolo[1,5- a]pyrazin-4-one(47 mg,33.66%) as a light yellow solid. LC-MS: (M+H)⁺ found: 519.05.

To a stirred solution of 2-(3-[[(2,4-dimethoxyphenyl) methyl] amino]pyridin-4-yl)-3-[(3- fluoro-2-methoxyphenyl)amino]-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (47 mg, 0.09 mmol, 1.00 equiv) was added TFA (2.00 mL) dropwise at 0 degrees C under air atmosphere. The resulting mixture was stirred for 2 h at 50 degrees C under air atmosphere. Desired product could be detected by LCMS. The resulting mixture was concentrated under reduced pressure. The resulting mixture was diluted with DCM (10 mL). The mixture was basified to pH 8 with aqueous ammonia. The resulting mixture was concentrated under vacuum. The crude product mixture was used in the next step directly without further purification. LC-MS: (M+H)⁺ found: 369.10.

To a stirred solution of 2-(3-aminopyridin-4-yl)-3-[(3-fluoro-2-methoxyphenyl) amino]- 5H,6H,7H-pyrazolo[1,5-a] pyrazin-4-one (46 mg, 0.13 mmol, 1.00 equiv) in pyridine (1.50 mL) was added cyclopropanecarbonyl chloride (14 mg, 0.14 mmol, 1.10 equiv) in DCM (0.10 mL) dropwise at -30 degrees C under argon atmosphere. The resulting mixture was stirred for 1 h at -30 degrees C under argon atmosphere. Desired product could be detected by LCMS. The resulting mixture was concentrated under vacuum. The crude product (40 mg) was purified by Prep-HPLC with the following conditions (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water(10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 20% B to 50% B in 7 min; Wave Length: 254/220 nm; RT1(min): 6.32;) to afford N-(4-[3-[(3-fluoro-2- methoxyphenyl)amino]-4-oxo-5H,6H,7H-pyrazolo[1,5-a]pyrazin-2-yl]pyridin-3- yl)cyclopropanecarboxamide (5.80 mg, 10.64%) as a light yellow solid. LC-MS: (M+H)⁺ found: 437.05. ¹H NMR (300 MHz, DMSO-d6) δ 10.28 (s, 1H), 9.25 (s, 1H), 8.38-8.22 (m, 2H), 7.56 (d, 1H), 7.37 (s, 1H), 6.74-6.44 (m, 2H), 6.11-5.98 (m, 1H), 4.46 (t, 2H), 3.89 (s, 3H), 3.71 (d, 2H), 1.90-1.76 (m, 1H), 0.89-0.76 (m, 4H). Example 125.2-[3-[(2,2-dimethylpropyl)amino]pyridin-4-yl]-3-[(3-fluoro-2- methoxyphenyl)amino]-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (compound 343)

A solution of 3-[(3-fluoro-2-methoxyphenyl)amino]-2-(3-fluoropyridin-4-yl)-5H,6H,7H- pyrazolo[1,5-a]pyrazin-4-one (150 mg, 0.40 mmol, 1.00 equiv) and DIEA (783 mg, 6.06 mmol, 15.00 equiv) in 2,2-dimethyl-1-propylamin (3 mL) and DMSO (2 mL) at room temperature under air atmosphere. The resulting mixture was stirred for 36 h at 120 degrees C under air atmosphere. Desired product could be detected by LCMS. The resulting mixture was concentrated under vacuum. The crude product (100 mg) was purified by Prep-HPLC with the following conditions (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water(10MMOL/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 35% B to 65% B in 7 min; Wave Length: 254 nm; RT1(min): 6.5;) to afford 2-[3-[(2,2-dimethylpropyl)amino]pyridin-4-yl]-3-[(3-fluoro-2- methoxyphenyl)amino]-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (20.60 mg, 11.51%) as a light yellow solid. LC-MS: (M+H)⁺ found: 439.10 ¹H NMR (400 MHz, DMSO-d6) δ 8.32 (s, 1H), 8.14 (s, 1H), 7.67 (d, 1H), 7.47 (d, 1H), 7.31 (s, 1H), 7.11 (t, 1H), 6.70-6.61 (m, 1H), 6.60-6.49 (m, 1H), 5.99-5.91 (m, 1H), 4.49- 4.30 (m, 2H), 3.91 (s, 3H), 3.69 (d, 2H), 3.08 (d, 2H), 1.04 (s, 9H). Example 126.3-[(3-chloro-2-methoxyphenyl)amino]-2-(3-cyclopropylpyridin-4-yl)- 5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (compound 356)

To a stirred mixture of 3-bromo-4-chloropyridine(500 mg, 2.60 mmol, 1.00 equiv) and cyclopropylboronic acid (246 mg, 2.86 mmol, 1.10 equiv) and Cs₂CO₃(1.69 g, 5.20 mmol, 2.00 equiv) and Pd(dppf)Cl₂ CH₂Cl₂(106 mg, 0.13 mmol, 0.05 equiv) in dioxane(10.0 mL) and H₂O(2.0 mL) at room temperature under argon atmosphere. The resulting mixture was stirred for 4 h at 100 degrees C under argon atmosphere. Desired product could be detected by LCMS. The residue was purified by Prep-TLC (CH₂Cl₂/MeOH 20:1) to afford 4- chloro-3-cyclopropylpyridine (290 mg, 72.66%) as a yellow oil. LC-MS: (M+H)⁺ found: 154.1.

To a stirred mixture of 4-chloro-3-cyclopropylpyridine(200 mg, 1.30 mmol, 1.00 equiv) and 4-oxo-5H,6H,7H-pyrazolo[1,5-a]pyrazin-2-ylboronic acid(236 mg, 1.30 mmol, 1.00 equiv) and Na₂CO₃(414 mg, 3.90 mmol, 3.00 equiv) and XPhos palladium(II) biphenyl-2- amine chloride(102 mg, 0.13 mmol, 0.10 equiv) in dioxane(13.0 mL) and H₂O(1.3 mL) at room temperature under argon atmosphere. The resulting mixture was stirred for 1 h at 60 degrees C under argon atmosphere. Desired product could be detected by LCMS. The residue was purified by Prep-TLC (CH₂Cl₂/MeOH 20:1) to afford 2-(3- cyclopropylpyridin-4-yl)-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (230 mg, 69.47%) as a yellow oil. LC-MS: (M+H)⁺ found: 254.9.

To a stirred mixture of 2-(3-cyclopropylpyridin-4-yl)-5H,6H,7H-pyrazolo[1,5-a]pyrazin- 4-one(200 mg, 0.77 mmol, 1.00 equiv) and 1,3-Dibromo-5,5-dimethylhydantoin (337 mg, 1.18 mmol, 1.50 equiv) in AcOH(7.8 mL) in portions at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 1 h at 100 degrees C under nitrogen atmosphere. Desired product could be detected by LCMS. The residue was purified by Prep-TLC (CH₂Cl₂ / MeOH 15:1) to afford 3-bromo-2-(3-cyclopropylpyridin-4-yl)- 5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (130.00 mg, 49.61%) as a white solid. LC-MS: (M+H)⁺ found: 334.8.

To a stirred mixture of 3-bromo-2-(3-cyclopropylpyridin-4-yl)-5H,6H,7H-pyrazolo[1,5- a]pyrazin-4-one (100 mg, 0.30 mmol, 1.00 equiv) and 3-chloro-2-methoxyaniline (47 mg, 0.30 mmol, 1.00 equiv) and Ephos Pd G4 (28 mg, 0.03 mmol, 0.10 equiv) and EPhos(32 mg, 0.06 mmol, 0.20 equiv) and Cs₂CO₃ (196 mg, 0.60 mmol, 2.00 equiv) in DMF (0.50 mL) in portions at room temperature under argon atmosphere. The resulting mixture was stirred for 4 h at 50 degrees C under argon atmosphere. Desired product could be detected by LCMS. The crude product (100 mg) was purified by Prep-HPLC with the following conditions (Column: Xselect CSH OBD Column 30*150mm 5um; Mobile Phase A: Water(0.1%FA), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 10% B to 36% B in 8 min, 36% B; Wave Length: 254/220 nm; RT1(min): 7.62) to afford 3-[(3-chloro-2- methoxyphenyl)amino]-2-(3-cyclopropylpyridin-4-yl)-5H,6H,7H-pyrazolo[1,5- a]pyrazin-4-one (12.6 mg, 10.18%) as a red solid. LC-MS: (M+H)⁺ found: 410.25. ¹H NMR (400 MHz, DMSO-d6) δ 8.43-8.23 (m, 2H), 8.13 (s, 1H), 7.39-7.20 (m, 2H), 6.76-6.48 (m, 2H), 6.09-6.21 (m, 1H), 4.30-4.43 (m, 2H), 3.77 (s, 3H), 3.70-3.61(m, 2H), 2.21-2.10 (m, 1H), 1.00-0.81 (m, 2H), 0.79-0.62 (m, 2H). Example 127.2-(2-aminopyridin-4-yl)-3-[(3-chloro-2-methoxyphenyl)amino]- 5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (compound 335)

To a solution of 2-bromo-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (1.00 g, 4.629 mmol, 1.00 equiv) and tert-butyl N-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2- yl]carbamate (1.78 g, 5.555 mmol, 1.20 equiv) in dioxane (10.00 mL) and H₂O (2.00 mL) were added K₂CO₃ (1.28 g, 9.258 mmol, 2.00 equiv) and Pd(dppf)Cl₂ CH₂Cl₂ (0.75 g, 0.926 mmol, 0.20 equiv).After stirring for 2 h at 80 degrees C under a nitrogen atmosphere.The resulting mixture was filtered, the filter cake was washed with EA (20 mL). The filter cake was concentrated under reduced pressure to afford tert-butyl N-(4- [4-oxo-5H,6H,7H-pyrazolo[1,5-a]pyrazin-2-yl]pyridin-2-yl)carbamate (1.05 g, 68.87%) as a white solid. LC-MS: M+H found: 330.

To a stirred solution of tert-butyl N-(4-[4-oxo-5H,6H,7H-pyrazolo[1,5-a]pyrazin-2- yl]pyridin-2-yl)carbamate (1.00 g, 3.036 mmol, 1.00 equiv)in DMF (20.00 mL)was added NBS (0.54 g, 3.036 mmol, 1.00 equiv) in portions at 0 degrees C. The resulting mixture was stirred for 2h at 80degrees C.The resulting mixture was filtered, the filter cake was washed with H₂O and EA.The filter cake was concentrated under reduced pressure to afford tert-butyl N-(4-[3-bromo-4-oxo-5H,6H,7H-pyrazolo[1,5-a]pyrazin-2-yl]pyridin- 2-yl)carbamate (700 mg, 56.47%) as a white solid. LC-MS: M+H found: 408.

To a solution tert-butyl N-(4-[3-bromo-4-oxo-5H,6H,7H-pyrazolo[1,5-a]pyrazin-2- yl]pyridin-2-yl)carbamate (200.00 mg, 0.490 mmol, 1.00 equiv)of and 3-chloro-2- methoxyaniline (154.41 mg, 0.980 mmol, 2.00 equiv) in THF (4.00 mL)were added t- BuONa (70.62 mg, 0.735 mmol, 1.50 equiv)and Pd PEPPSI IPentCl (42.16 mg, 0.049 mmol, 0.10 equiv). After stirring for 4h at 80degrees C under a nitrogen atmosphere. The resulting mixture was diluted with H₂O (20mL). The resulting mixture was extracted with EA (3 x 20 mL). The combined organic layers were washed with brine (1 x 10 mL), dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (DCM:MeOH=15:1) to afford tert-butyl N-(4-[3-[(3-chloro-2-methoxyphenyl)amino]-4-oxo-5H,6H,7H-pyrazolo[1,5-a]pyrazin- 2-yl]pyridin-2-yl)carbamate (30 mg, 12.63%) as a pink solid. LC-MS: M+H found: 485.

To a stirred solution of tert-butyl N-(4-[3-[(3-chloro-2-methoxyphenyl)amino]-4-oxo- 5H,6H,7H-pyrazolo[1,5-a]pyrazin-2-yl]pyridin-2-yl)carbamate (30.00 mg) in DCM (6.00 mL)was added TFA (2.00 mL)dropwise at rt . The resulting mixture was stirred for 2h at rt. The resulting mixture was concentrated under reduced pressure. The crude product was purified by Prep-HPLC with the following conditions (Column: XBridge Prep OBD C18 Column, 30x150mm 5um; Mobile Phase A: Water (10 mmol/L NH₄HCO₃+0.1%NH₃* H₂O), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 20% B to 50% B in 8 min, 50% B; Wave Length: 254; 220 nm; RT1(min): 6.97) to afford 2- (2-aminopyridin-4-yl)-3-[(3-chloro-2-methoxyphenyl)amino]-5H,6H,7H-pyrazolo[1,5- a]pyrazin-4-one (6.0 mg, 25.0%) as a light yellow solid. LC-MS: M+H found: 385. ¹H NMR (400 MHz, DMSO-d6): δ 8.27 (s, 1H), 7.89 (s, 1H), 7.65 (s, 1H), 7.02 (s, 2H), 6.79 (t, J = 8.1 Hz, 1H), 6.65 (dd, J = 8.0, 1.5 Hz, 1H), 6.31 (dd, J = 8.2, 1.5 Hz, 1H), 5.94 (s, 2H), 4.35 (dd, J = 7.1, 5.1 Hz, 2H), 3.84 (s, 3H), 3.61 (ddd, J = 7.7, 4.7, 2.6 Hz, 2H). Example 129.3-[(3-chloro-2-methoxyphenyl)amino]-2-[2-oxo-1H,3H-imidazo[4,5- b]pyridin-7-yl]-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (compound 336)

To a stirred solution of methyl 4-nitro-2H-pyrazole-3-carboxylate (5.00 g, 29.221 mmol, 1.00 equiv) and tert-butyl N-(2-bromoethyl)carbamate (9.82 g, 43.831 mmol, 1.5 equiv) in DMF (50.00 mL) were added K2CO3 (8.08 g, 58.441 mmol, 2 equiv) and NaI (2.19 g, 14.610 mmol, 0.5 equiv) at rt . Then the solution was stirred at rt about 16 h.The resulting mixture was diluted with water (50mL) and was washed with EA (4x50mL). The filtrate was concentrated under reduced pressure and get the methyl 2-[2-[(tert- butoxycarbonyl)amino]ethyl]-4-nitropyrazole-3-carboxylate about 11.8 g as a white solid. LC-MS: M+Na found: 337.10.

To a stirred solution of methyl 2-[2-[(tert-butoxycarbonyl)amino]ethyl]-4-nitropyrazole- 3-carboxylate (6.00 g) and HCl(gas)in 1,4-dioxane (20.00 mL) in DCM (40.00 mL) ,and then the solution was stirred at rt about 2h. The resulting mixture was extracted with DCM, the combined organic layers were washed with saturation NaHCO₃, dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure and get the methyl 2-(2-aminoethyl)-4-nitropyrazole-3-carboxylate about 4.2 g as a yellow solid. LC-MS: M+H found: 215.20.

To a stirred solution of methyl 2-(2-aminoethyl)-4-nitropyrazole-3-carboxylate (4.20 g, 19.610 mmol, 1.00 equiv) and K₂CO₃ (9.49 g, 68.635 mmol, 3.50 equiv) in EtOH (40.00 mL, 688.541 mmol, 35.11 equiv). The solution was stirred at 50 degrees C about 16h. The resulting mixture was diluted with water (50 mL) and was washed with EA (4 x 50 mL). The combined organic layers were washed with saturated salt solution (3 x 30 mL), dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure and get the 3-nitro-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one about 650 mg as a white solid. LC-MS: M+H found: 183.10.

Into a 100 mL Stand-up flask were added 3-nitro-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4- one (0.6 g) , Pd/C (0.26 g) and EtOH (35.00 mL) at rt. Then replace the hydrogen and attach the stand-up flask to the hydrogen packet. The solution was stirred at rt for 16h.The resulting mixture was filtered, the filter cake was washed with MeOH. The filtrate was concentrated under reduced pressure to obtain crude product 3-amino-5H,6H,7H- pyrazolo[1,5-a]pyrazin-4-one (520 mg) as a white solid. LC-MS: M+H found: 153.10.

To a stirred solution of 3-amino-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (500.00 mg, 3.286 mmol, 1.00 equiv) in MeCN (5.00 mL) were added NBS (643.36 mg, 3.615 mmol, 1.10 equiv) dropwise at 0 degrees C. Then the solution was stirred at rt about 30 min. The resulting mixture was diluted with water (50 mL) and was washed with EA (4 x 50 mL). The combined organic layers was concentrated under reduced pressure and get the 3- amino-2-bromo-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one about 370 mg(yield = 49%) as a yellow solid. LC-MS: M+H found: 231.

A mixture of 3-amino-2-bromo-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (10.00 mg, 0.043 mmol, 1.00 equiv) and 3-chloro-2-methoxyphenylboronic acid (9.68 mg, 0.052 mmol, 1.20 equiv), Cu(OAc)₂ (8.65 mg, 0.048 mmol, 1.1 equiv), Et₃N (13.14 mg, 0.130 mmol, 3 equiv) in DCE (0.50 mL) was stirred for 12h at 25 °C under oxygen atmosphere. The residue was dissolved in water (10 mL).The resulting mixture was extracted with DCM (10 mL). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (DCM/MeOH=15/1) to afford 2-bromo-3-[(3- chloro-2-methoxyphenyl)amino]-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (5 mg, 29.53%) as a white solid. LC-MS: M+H found: 371.05.

To a stirred solution of 7-bromo-1H,3H-imidazo[4,5-b]pyridin-2-one (325.00 mg, 1.519 mmol, 1.00 equiv) and bis(pinacolato)diboron (771.23 mg, 3.037 mmol, 2.00 equiv) in DMF (4.00 mL, 51.687 mmol, 44.25 equiv) were added KOAc (298.07 mg, 3.037 mmol, 2.00 equiv) and Pd(dppf)Cl₂ (222.22 mg, 0.304 mmol, 0.20 equiv)at RT under N₂ atmosphere. Then, the solution was stirred at 150 degrees C in microwave. The resulting mixture was diluted with 5ml of DMF and filtrated. Then, The residue was purified by reverse flash chromatography with the following conditions: column, C18 silica gel; mobile phase, ACN in water, 1% to 100% gradient in 10 min; detector, UV 254 nm to afford 2-oxo-1H,3H-imidazo[4,5-b]pyridin-7-ylboronic acid (138 mg, 66.02%) as a brown solid. LC-MS: M+H found: 180.05.

To a stirred mixture of 2-bromo-3-[(3-chloro-2-methoxyphenyl)amino]-5H,6H,7H- pyrazolo[1,5-a]pyrazin-4-one (40.00 mg, 0.108 mmol, 1.00 equiv) and 2-oxo-1H,3H- imidazo[4,5-b]pyridin-7-ylboronic acid (38.52 mg, 0.215 mmol, 2 equiv) in THF (0.40 mL) and H₂O (0.10 mL) were added K₂CO₃ (29.75 mg, 0.216 mmol, 2.00 equiv) and XPhos Pd G3 (18.22 mg, 0.022 mmol, 0.2 equiv) in portions at RT under N2 atmosphere. The resulting mixture was stirred for 16 hours at 80 degrees C under N2 atmosphere. The resulting mixture was filtered, the filter cake was washed with EA (1x110 mL). The filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (EA and MeOH 50:1) to afford 3-[(3-chloro-2-methoxyphenyl)amino]-2-[2-oxo-1H,3H- imidazo[4,5-b]pyridin-7-yl]-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (3.8 mg, 8.17%) as a off-white solid. LC-MS: M+H found: 426.2 ¹H NMR (400 MHz, DMSO-d6) δ 11.40 (s, 1H), 10.46 (s, 1H), 8.30 (s, 1H), 7.81 (d, J = 5.5 Hz, 1H), 7.27 (s, 1H), 7.14 (d, J = 5.6 Hz, 1H), 6.74 – 6.68 (m, 2H), 6.13 (p, J = 4.1 Hz, 1H), 4.46 (t, J = 6.0 Hz, 2H), 3.89 (s, 3H), 3.68 (q, J = 6.6, 4.8 Hz, 2H). Example 130.3-[(3-chloro-2-methoxyphenyl)amino]-2-(6-methoxy-1,7-naphthyridin-4- yl)-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (compound 350)

To a stirred mixture of 4-chloro-6-methoxy-1,7-naphthyridine (360 mg, 1.850 mmol, 1.00 equiv) and 3-chloro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5H,6H,7H- pyrazolo[1,5-a]pyrazin-4-one (1100.79 mg, 3.700 mmol, 2 equiv) in dioxane (4 mL, 47.216 mmol, 25.53 equiv) and H₂O (1 mL, 55.508 mmol, 30.01 equiv) were added Pd(dppf)Cl₂CH₂Cl₂ (150.69 mg, 0.185 mmol, 0.1 equiv) and K₂CO₃ (511.29 mg, 3.700 mmol, 2 equiv) in portions at RT. The resulting mixture was stirred for 2 hours at 80 degrees C under N₂ atmosphere. The resulting mixture was filtered; the filter cake was washed with EA (10 mL). The filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (DCM: MeOH= 10:1) to afford 3-chloro-2-(6- methoxy-1,7-naphthyridin-4-yl)-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (320 mg, 52.46%) as a light yellow solid. LC-MS: M+H found: 330.2.

To a stirred mixture of 3-chloro-2-(6-methoxy-1,7-naphthyridin-4-yl)-5H,6H,7H- pyrazolo[1,5-a]pyrazin-4-one (200.00 mg, 0.607 mmol, 1.00 equiv) and 3-chloro-2- methoxyaniline (114.71 mg, 0.728 mmol, 1.2 equiv) in dioxane (5.00 mL) were added Cs₂CO₃ (592.87 mg, 1.821 mmol, 3.00 equiv) and EPhos (32.44 mg, 0.061 mmol, 0.10 equiv) and EPhos Pd G4 (55.71 mg, 0.061 mmol, 0.10 equiv) in portions at RT under N2 atmosphere. The resulting mixture was stirred for 16 hours at 50 degrees C under N₂ atmosphere. The resulting mixture was filtered; the filter cake was washed with EA (1x1 10 mL). The filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (DCM and MeOH 18:1) to afford 3-[(3-chloro-2-methoxyphenyl)amino]-2-(6- methoxy-1,7-naphthyridin-4-yl)-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (37.0 mg, 13.57%) as a light yellow solid. LC-MS: M+H found: 451.0. ¹H NMR (400 MHz, DMSO-d6) δ 9.15 (d, J = 0.9 Hz, 1H), 8.80 (d, J = 4.4 Hz, 1H), 8.35 (d, J = 3.1 Hz, 1H), 7.76 – 7.69 (m, 2H), 7.44 (s, 1H), 6.61 (dd, J = 8.1, 1.5 Hz, 1H), 6.54 (t, J = 8.1 Hz, 1H), 6.12 (dd, J = 8.1, 1.6 Hz, 1H), 4.49 (dd, J = 7.1, 5.0 Hz, 2H), 3.96 (s, 3H), 3.79 (s, 3H), 3.77 – 3.69 (m, 2H). Example 131. 3-[(3-chloro-2-methoxyphenyl)amino]-2-[1H-pyrazolo[3,4-b]pyridin-4- yl]-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (compound 351)

To a solution of 2-bromo-3-chloro-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (100.00 mg, 0.399 mmol, 1.00 equiv) and 1H-pyrazolo[3,4-b]pyridin-4-ylboronic acid (78.06 mg, 0.000 mmol, 1.20 equiv) in dioxane (2.00 mL) and H₂O (0.40 mL) were added K₂CO₃ (110.35 mg, 0.798 mmol, 2.00 equiv) and Pd(dppf)Cl₂*CH₂Cl2 (32.52 mg, 0.040 mmol, 0.10 equiv). After stirring for 2 h at 80 degrees C under a nitrogen atmosphere, the resulting mixture was concentrated under reduced pressure. The residue was purified by Prep-TLC/silica gel column chromatography, eluted with DCM:MeOH (20:1) to afford 3-chloro-2-[1H-pyrazolo[3,4-b]pyridin-4-yl]-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (400 mg, 69.41%) as a yellow solid. LC-MS: M+H found: 289

To a solution of 3-chloro-2-[1H-pyrazolo[3,4-b]pyridin-4-yl]-5H,6H,7H-pyrazolo[1,5- a]pyrazin-4-one (400.00 mg, 1.386 mmol, 1.00 equiv) in DMF (8.00 mL)was added NaH (66.50 mg, 1.663 mmol, 1.20 equiv, 60%) at 0 degrees C. The mixture was stirred for 15 min. [2-(chloromethoxy)ethyl]trimethylsilane (277.19 mg, 1.663 mmol, 1.20 equiv)was added and the mixture was allowed to warm to RT and stirred for 2 h.The reaction was quenched with H₂O (50 ml) at 0 degrees C. The resulting mixture was filtered, the filter cake was washed with H₂O (30 mL). The filter cake was concentrated under reduced pressure to afford 3-chloro-5-[[2-(trimethylsilyl)ethoxy]methyl]-2-(1-[[2- (trimethylsilyl)ethoxy]methyl] pyrazolo[3,4-b]pyridin-4-yl)-6H,7H-pyrazolo[1,5- a]pyrazin-4-one (500 mg, 40.61%) as a yellow solid. LC-MS: M+H found: 549.

To a solution of 3-chloro-5-{[2-(trimethylsilyl)ethoxy]methyl}-2-(1-{[2- (trimethylsilyl)ethoxy]methyl}pyrazolo[3,4-b]pyridin-4-yl)-6H,7H-pyrazolo[1,5- a]pyrazin-4-one (500 mg, 0.910 mmol, 1 equiv) and 3-chloro-2-methoxyaniline (286.95 mg, 1.820 mmol, 2 equiv) in DMF (12.50 mL, 161.452 mmol, 177.42 equiv) were added Cs₂CO₃ (593.24 mg, 1.820 mmol, 2 equiv) and EPhos Pd G4 (418.12 mg, 0.455 mmol, 0.5 equiv), EPhos (486.87 mg, 0.910 mmol, 1 equiv). After stirring for 2 h at 50 degrees C under a nitrogen atmosphere. The resulting mixture was diluted with H₂O (50 mL). The resulting mixture was extracted with EA (3 x 30 mL). The combined organic layers were washed with brine (1 x 20 mL), dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (DCM:MeOH=15:1) to afford 3-[(3-chloro-2-methoxyphenyl)amino]-5-{[2- (trimethylsilyl)etho xy]methyl}-2-(1-{[2-(trimethylsilyl)ethoxy]methyl}pyrazolo[3,4-b]pyridin-4-yl)-6H,7H- pyrazolo[1,5-a]pyrazin-4-one (200 mg, 14.98%) as a brown solid. LC-MS: M+H found: 670.

To a stirred solution of 3-[(3-chloro-2-methoxyphenyl)amino]-5-[[2- (trimethylsilyl)ethoxy]methyl]-2-(1-[[2-(trimethylsilyl)ethoxy]methyl]pyrazolo[3,4- b]pyridin-4-yl)-6H,7H-pyrazolo[1,5-a]pyrazin-4-one (200.00 mg) in HCl (gas )in 1,4- dioxane (5.00 mL) at rt. The resulting mixture was stirred for 2 h at rt. The reaction mixture was concentrated under vacuum. The residue was dissolved in DCM (5 mL). EDA(1 ml) was added at 0 degrees C. The resulting mixture was stirred for 2 h at rt.The resulting mixture was diluted with H₂O (50 mL). The resulting mixture was extracted with EA (3 x 30mL). The combined organic layers were washed with brine (1 x 20mL), dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (DCM:MeOH=15:1) to afford crude product. The crude product (25 mg) was purified by Prep-HPLC with the following conditions (Column: XBridge Shield RP18 OBD Column, 30*150 mm, 5μm; Mobile Phase A: Water(10 mmol/L NH₄HCO₃+0.1%NH₃.H₂O), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 15% B to 51% B in 7 min, 51% B; Wave Length: 254/220 nm; RT1(min): 6.37) to afford 3-[(3-chloro-2-methoxyphenyl)amino]-2-[1H- pyrazolo[3,4-b]pyridin-4-yl]-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (2.4 mgˈ11.4%) as a white solid. LC-MS: M+H found: 410. ¹H NMR (400 MHz, DMSO-d6): δ 8.90 (d, J = 2.1 Hz, 1H), 8.48 (d, J = 2.0 Hz, 1H), 8.27 (s, 1H), 8.15 (s, 1H), 7.33 (s, 1H), 6.72 – 6.64 (m, 2H), 6.21 – 6.12 (m, 1H), 4.41 (t, J = 5.9 Hz, 2H), 3.89 (s, 3H), 3.67 (t, J = 5.8 Hz, 2H). Example 132. 3-[(3-chloro-2-methoxyphenyl)amino]-2-[thieno[2,3-b]pyridin-4-yl]- 5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (compound 352)

To a stirred solution of 3-chloro-4-oxo-5H,6H,7H-pyrazolo[1,5-a]pyrazin-2-ylboronic acid (380.95 mg, 1.768 mmol, 2.00 equiv) and 4-chlorothieno[2,3-b]pyridine (150.00 mg, 0.884 mmol, 1.00 equiv) in dioxane (5.00 mL, 59.020 mmol, 66.74 equiv) and H₂O (1.00 mL, 0.056 mmol, 0.06 equiv) were added Pd(dppf)Cl₂ (64.70 mg, 0.088 mmol, 0.10 equiv) and K₂CO₃ (244.42 mg, 1.768 mmol, 2.00 equiv) at rt under N₂ atmosphere. Then, the solution was stirred at 80 degrees C for 2 h. The mixture was diluted with 300 ml water and filtrate the solid to afford 3-chloro-2-[thieno[2,3-b]pyridin-4-yl]-5H,6H,7H- pyrazolo[1,5-a]pyrazin-4-one (109 mg, 40.45%) as a black solid. LC-MS: M+1 found: 304.95.

To a stirred solution of 3-chloro-2-[thieno[2,3-b]pyridin-4-yl]-5H,6H,7H-pyrazolo[1,5- a]pyrazin-4-one (130.00 mg, 0.427 mmol, 1.00 equiv) and 3-chloro-2-methoxyaniline (134.46 mg, 0.853 mmol, 2 equiv) in DMF (7.00 mL, 0.008 mmol, 0.25 equiv) were added Cs₂CO₃ (277.98 mg, 0.853 mmol, 2.00 equiv), EPhos (228.13 mg, 0.427 mmol, 1.00 equiv) and EPhos Pd G4 (195.92 mg, 0.213 mmol, 0.50 equiv) at rt under N₂ atmosphere. Then, the solution was stirred at 50 degrees C for 2 h. The resulting mixture was diluted with water (50 mL) and washed with 3×40 ml of EA. The filtrate was concentrated under reduced pressure.The residue was purified by reverse flash chromatography with the following conditions: (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water(10 mmol/L NH₄HCO₃+0.1%NH₃.H₂O), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 36% B to 56% B in 8 min, 56% B; Wave Length: 254; 220 nm; RT1(min): 6.62) to afford 3-[(3-chloro-2-methoxyphenyl)amino]-2-[thieno[2,3- b]pyridin-4-yl]-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (5.9 mg, 3.25%) as a yellow solid. LC-MS: M+1 found: 425.9. ¹H NMR (400 MHz, DMSO-d6) δ 8.50 (d, J = 4.9 Hz, 1H), 8.33 (s, 1H), 8.01 (d, J = 6.1 Hz, 1H), 7.91 (d, J = 6.1 Hz, 1H), 7.61 (d, J = 5.0 Hz, 1H), 7.44 (s, 1H), 6.67 (dd, J = 8.1, 1.8 Hz, 1H), 6.63 (t, J = 7.9 Hz, 1H), 6.12 (dd, J = 7.8, 1.8 Hz, 1H), 4.48 (dd, J = 7.1, 5.0 Hz, 2H), 3.85 (s, 3H), 3.70 (s, 2H). Example 133. 3-[(3-chloro-2-methoxyphenyl)amino]-2-{1H-pyrazolo[4,3-b]pyridin-7- yl}-5H,6H,7H-pyrazolo [1,5-a]pyrazin-4-one (compound 353)

A solution of 2-bromo-3-chloro-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (500 mg, 2.00 mmol, 1.00 equiv) and bis(pinacolato)diboron (1013.81 mg, 3.99 mmol, 2.00 equiv), KOAc (489.77 mg, 4.99 mmol, 2.50 equiv) and Pd(dppf)Cl2 (146.06 mg, 0.200 mmol, 0.1 equiv) in DME (30.00 mL, 309.92 mmol,) was stirred 2h at 100°C under N2 atmosphere. The mixture was allowed to cool down to RT. The resulting mixture was filtered; the filter cake was washed with DCM (2x210ml). The filtrate was concentrated under reduced pressure. The residue was dissolved in EA (5ml). The resulting mixture was filtered; the filter cake was washed with EA (2x210ml). The filtrate was concentrated under reduced pressure to afford crude product 3-chloro-4-oxo-5H,6H,7H-pyrazolo[1,5- a]pyrazin-2-ylboronic acid (800 mg) as a black oil. LC-MS: (M+H) + found: 216.3.

To a solution of 7-bromo-1H-pyrazolo[4,3-b]pyridine (500 mg, 2.52 mmol, 1.00 equiv) in DMF (5 mL, 64.61 mmol, 25.59 equiv) was added sodium hydride (60% in oil, 90.98 mg) at 0 degrees C. The mixture was stirred for 15 min. [2- (chloromethoxy)ethyl]trimethylsilane (547.25 mg, 3.28 mmol, 1.30 equiv) was added and the mixture was allowed to warm to RT and stirred for 3h. The reaction mixture was quenched with water and extracted with DCM (3*25 mL). The residue was purified by prep-TLC (DCM:MeOH =15:1) to afford 7-bromo-1-{[2- (trimethylsilyl)ethoxy]methyl}pyrazolo[4,3-b]pyridine(400 mg, 48.26%) as a brown solid. LC-MS: (M+H)+ found: 328.1.

To a solution of 7-bromo-1-{[2-(trimethylsilyl)ethoxy]methyl}pyrazolo[4,3-b]pyridine (400 mg, 1.22 mmol, 1.00 equiv) and 3-chloro-4-oxo-5H,6H,7H-pyrazolo[1,5-a]pyrazin- 2-ylboronic acid (787.36 mg, 3.65 mmol, 3 equiv) in dioxane (20.00 mL) and H2O (4.00 mL) were added K2CO3 (420.99 mg, 3.045 mmol, 2.5 equiv) and Pd(dppf)Cl2 (89.15 mg, 0.122 mmol, 0.10 equiv) . After stirring for 5h at 80°C under a nitrogen atmosphere, the resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with DCM:MeOH (20:1) to afford 3-chloro- 2-(1-{[2-(trimethylsilyl) ethoxy] methyl}pyrazolo[4,3-b]pyridin-7-yl)-5H,6H,7H- pyrazolo[1,5-a]pyrazin-4-one (250 mg, 48.97%) as a brown solid. LC-MS: (M+H)+ found: 419.3.

To a solution of 3-chloro-2-(1-{[2-(trimethylsilyl)ethoxy]methyl}pyrazolo[4,3- b]pyridin-7-yl)-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (200 mg, 0.477 mmol, 1.00 equiv) and 3-chloro-2-methoxyaniline (112.85 mg, 0.716 mmol, 1.5 equiv) in DMF (10.00 mL) and EPhos (127.65 mg, 0.238 mmol, 0.5 equiv) were added Cs2CO3 (388.84 mg, 1.192 mmol, 2.50 equiv) and EPhos Pd G4 (219.25 mg, 0.239 mmol, 0.50 equiv) . After stirring for 3h at 50°C under a nitrogen atmosphere, the resulting mixture was extracted with EA (3x50ml). The combined organic layers were washed with brine (3x20ml), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. the resulting mixture was concentrated under reduced pressure. The residue was purified three times by prep-TLC (DCM:MeOH 20:1) to afford 3-[(3- chloro-2-methoxyphenyl)amino]-2-[(2Z)-3-[(E)-(2-iminoethylidene) amino]prop-2-en- 1-yl]-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (20 mg, purity:50%) as off-white solid. LC-MS: (M+H)⁺ found: 540.4.

To a stirred solution of 3-[(3-chloro-2-methoxyphenyl) amino]-2-(1-{[2-(trimethylsilyl) ethoxy] methyl} pyrazolo[4,3-b]pyridin-7-yl)-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (500 mg) in HCl of dioxane (2.5 mL) at RT under N₂ atmosphere for 2h. The resulting mixture was extracted with EA (3 x 20ml). The combined organic layers were washed with brine (3x15ml), dried over anhydrous Na₂SO₄. After extraction, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-HPLC with the following conditions (Column: YMC-Actus Triart C18, 30*150 mm, 5μm; Mobile Phase A: Water (10 mmol/L NH₄HCO₃+0.1%NH₃*H₂O), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 25% B to 45% B in 10 min, 45% B; Wave Length: 254/220 nm; RT1(min): 9.42) to afford 3-[(3-chloro-2-methoxyphenyl)amino]-2-{1H-pyrazolo[4,3- b]pyridin-7-yl}-5H,6H,7H-pyrazolo [1,5-a]pyrazin-4-one (7.1 mg, 1.9 %) as a white solid. LC-MS: (M+H)⁺ found: 410.2. ¹H NMR (300 MHz, DMSO-d6) δ 13.28 (s, 1H), 8.46 (d, J = 4.7 Hz, 1H), 8.37 (d, J = 3.6 Hz, 2H), 7.47 (d, J = 4.7 Hz, 1H), 6.80 – 6.67 (m, 2H), 6.18 (dd, J = 6.6, 3.1 Hz, 1H), 4.54 (dd, J = 7.0, 5.1 Hz, 2H), 3.92 (s, 3H), 3.73 (s, 2H). Example 134. (7S)-3-[(3-chloro-2-methoxyphenyl)amino]-2-(6-methoxyquinolin-4-yl)- 7-methyl-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (compound 357)

To a solution of 4-chloro-6-methoxyquinoline (150.00 mg, 0.775 mmol, 1.00 equiv) and (7S)-3-chloro-7-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5H,6H,7H- pyrazolo[1,5-a]pyrazin-4-one (965.46 mg, 3.1 mmol, 4.00 equiv) in dioxane (5.00 mL) and H₂O (1.00 mL) were added K₂CO₃ (214.13 mg, 1.550 mmol, 2.00 equiv) and Pd(dppf)Cl₂ CH₂Cl₂ (63.11 mg, 0.078 mmol, 0.10 equiv). After stirring for 2h at 80 degrees C under a nitrogen atmosphere, the resulting mixture was diluted with H₂O (100mL). The resulting mixture was extracted with EA (3 x 50mL). The combined organic layers were washed with brine (1x30mL), dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC/silica gel column chromatography, eluted with DCM:MeOH (15:1) to afford (7S)-3-chloro-2-(6-methoxyquinolin-4-yl)-7-methyl-5H,6H,7H-pyrazolo[1,5- a]pyrazin-4-one (150 mg, 43.55%) as a brown solid. LC-MS: M+H found: 343.

To a solution of (7S)-3-chloro-2-(6-methoxyquinolin-4-yl)-7-methyl-5H,6H,7H- pyrazolo[1,5-a]pyrazin-4-one (150.00 mg, 0.438 mmol, 1.00 equiv) and 3-chloro-2- methoxyaniline (137.93 mg, 0.876 mmol, 2.00 equiv) in DMF (5.00 mL) was added Cs₂CO₃ (285.16 mg, 0.876 mmol, 2.00 equiv), EPhos Pd G4 (200.98 mg, 0.219 mmol, 0.50 equiv) and EPhos (234.03 mg, 0.438 mmol, 1.00 equiv). After stirring for 2 h at 50 degrees C under a nitrogen atmosphere, The resulting mixture was diluted with H₂O (100 mL). The resulting mixture was extracted with EA (3 x 50mL). The combined organic layers were washed with brine (1x30mL), dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep- TLC/silica gel column chromatography, eluted with DCM:MeOH (15:1) and Prep-HPLC (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water(10 mmol/L NH₄HCO₃+0.1%NH₃*H₂O), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 35% B to 55% B in 8 min, 55% B; Wave Length: 254; 220 nm; RT1(min): 6.85) to afford (7S)-3-[(3-chloro-2-methoxyphenyl)amino]-2-(6- methoxyquinolin-4-yl)-7-methyl-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (44.4 mg, 21.70%)as a light yellow solid. LC-MS: M+H found: 464. ¹H NMR (400 MHz, DMSO-d6):δ 8.70 (d, J = 4.5 Hz, 1H), 8.34 (t, J = 2.7 Hz, 1H), 7.95 (d, J = 9.2 Hz, 1H), 7.86 (d, J = 2.8 Hz, 1H), 7.58 (d, J = 4.5 Hz, 1H), 7.46 (s, 1H), 7.42 (dd, J = 9.2, 2.8 Hz, 1H), 6.60 (dd, J = 8.0, 1.5 Hz, 1H), 6.52 (t, J = 8.1 Hz, 1H), 6.13 (dd, J = 8.1, 1.6 Hz, 1H), 4.71 – 4.60 (m, 1H), 3.83 (s, 3H), 3.80 (dd, J = 8.0, 3.9 Hz, 1H), 3.76 (s, 3H), 3.49 (ddd, J = 13.1, 8.5, 2.2 Hz, 1H), 1.62 (d, J = 6.4 Hz, 3H). Example 135. (7R)-3-[(3-chloro-2-methoxyphenyl) amino]-2-(6-methoxyquinolin-4-yl)- 7-methyl-5H,6H,7H-pyrazolo[1,5-a] pyrazin-4-one (compound 358)

To a solution of 4-bromo-6-methoxyquinoline (200 mg, 0.840 mmol, 1.00 equiv) and (7R)-3-chloro-7-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5H,6H,7H- pyrazolo[1,5-a]pyrazin-4-one (654.33 mg, 2.100 mmol, 2.5 equiv) in DMF (2mL) were added K₂CO₃ (290.25 mg, 2.100 mmol, 2.5 equiv) and Pd(dppf)Cl₂ (61.47 mg, 0.084 mmol, 0.10 equiv). After stirring for 2h at 80°C under a nitrogen atmosphere, the resulting mixture was concentrated under reduced pressure. The residue was purified by Prep-TLC, eluted with DCM:MeOH (15:1) to afford (7R)-3-chloro-2-(6-methoxyquinolin-4-yl)-7- methyl-5H,6H,7H-pyrazolo [1,5-a]pyrazine-4-one(150 mg 66.9%) a brown solid. LC-MS: M+H found: 343.0.

To a stirred solution of (7R)-3-chloro-2-(6,7-dimethoxyquinolin-4-yl)-7-methyl- 5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (100.00 mg, 0.268 mmol, 1.00 equiv), Cs₂CO₃ (262.19 mg, 0.804 mmol, 3.00 equiv) and 3-chloro-2-methoxyaniline (50.73 mg, 0.322 mmol, 1.20 equiv) in DMF (5.00 mL) was added EPhos (71.72 mg, 0.134 mmol, 0.50 equiv) and EPhos Pd G4 (123.19 mg, 0.134 mmol, 0.50 equiv) in portions at 80°C under N₂ atmosphere. The mixture was allowed to cool down to RT. The resulting mixture was extracted with EA (3 x 50 mL). The combined organic layers were washed with brine (2x120ml), dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (DCM: MeOH 15:1) to afford the crude product. The crude product (mg) was purified by Prep-HPLC with the following conditions (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water(10 mmol/L NH₄HCO₃+0.1%NH₃.H₂O), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 35% B to 55% B in 8 min, 55% B; Wave Length: 254; 220 nm; RT1(min): 6.82) to afford (7R)-3-[(3-chloro-2-methoxyphenyl) amino]-2-(6- methoxyquinolin-4-yl)-7-methyl-5H,6H,7H-pyrazolo[1,5-a] pyrazin-4-one(15mg 98.2%) as a as a white solid. LC-MS: M+H found: 464.0. ¹H NMR (400 MHz, DMSO-d6) δ 8.69 (d, J = 4.5 Hz, 1H), 8.34 (t, J = 2.7 Hz, 1H), 7.94 (d, J = 9.1 Hz, 1H), 7.85 (d, J = 2.9 Hz, 1H), 7.56 (d, J = 4.5 Hz, 1H), 7.46 (s, 1H), 7.42 (dd, J = 9.2, 2.8 Hz, 1H), 6.60 (dd, J = 8.1, 1.6 Hz, 1H), 6.52 (t, J = 8.1 Hz, 1H), 6.12 (dd, J = 8.1, 1.6 Hz, 1H), 4.71 – 4.62 (m, 1H), 3.82 (s, 3H), 3.79 (dd, J = 8.1, 4.1 Hz, 1H), 3.76 (s, 3H), 3.49 (ddd, J = 13.2, 8.4, 2.2 Hz, 1H), 1.62 (d, J = 6.4 Hz, 3H). Example 136. (7R)-3-[(3-chloro-2-methoxyphenyl) amino]-2-(6-methoxyquinolin-4-yl)- 7-methyl-5H,6H,7H-pyrazolo[1,5-a] pyrazin-4-one (compound 359)

To a solution of (7R)-3-chloro-7-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)-5H,6H,7H-pyrazolo[1,5-a]pyrazine-4-one (651.62 mg, 2.092 mmol, 2.5 equiv) and 4-bromo-6-methoxy-1,7-naphthyridine (200 mg, 0.837 mmol, 1.00 equiv) in DMF (10 mL) were added K₂CO₃ (289.05 mg, 2.092 mmol, 2.5 equiv) and Pd(dppf)Cl₂ (61.21 mg, 0.084 mmol, 0.1 equiv) . After stirring for 2h at 80°C under a nitrogen atmosphere, the resulting mixture was concentrated under reduced pressure. The residue was purified by Prep-TLC, eluted with DCM:MeOH (15:1) to afford the (7R)-3-chloro-2-(6-methoxy- 1,7-naphthyridin-4-yl)-7-methyl-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (150 mg 73.2%) as a brown solid. LC-MS: M+H found: 344.0.

To a stirred solution of (7R)-3-chloro-2-(6,7-dimethoxyquinolin-4-yl)-7-methyl- 5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (100.00 mg, 0.268 mmol, 1.00 equiv), Cs₂CO₃ (262.19 mg, 0.804 mmol, 3.00 equiv) and 3-chloro-2-methoxyaniline (50.73 mg, 0.322 mmol, 1.20 equiv) in DMF (5.00 mL) was added EPhos (71.72 mg, 0.134 mmol, 0.50 equiv) and EPhos Pd G4 (123.19 mg, 0.134 mmol, 0.50 equiv) in portions at 80°C under N₂ atmosphere. The mixture was allowed to cool down to RT. The resulting mixture was extracted with EA (3 x 50ml). The combined organic layers were washed with brine (2x1 20ml), dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (DCM: MeOH=15:1) to afford the crude product (50mg, 78%). The crude product (mg) was purified by Prep-HPLC with the following conditions (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water (10 mmol/L NH₄HCO₃+0.1%NH₃.H₂O), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 29% B to 59% B in 8 min, 59% B; Wave Length: 254; 220 nm; RT1(min): 6.77) to afford (7R)-3-[(3-chloro-2-methoxyphenyl) amino]-2-(6- methoxyquinolin-4-yl)-7-methyl-5H,6H,7H-pyrazolo[1,5-a] pyrazin-4-one(8.1mg 99.4%) as a white solid. LC-MS: M+H found: 464.95. ¹H NMR (400 MHz, DMSO-d6) δ 9.15 (s, 1H), 8.80 (d, J = 4.4 Hz, 1H), 8.35 (s, 1H), 7.77 – 7.70 (m, 2H), 7.48 (s, 1H), 6.65 – 6.58 (m, 1H), 6.54 (t, J = 8.1 Hz, 1H), 6.10 (d, J = 8.1 Hz, 1H), 4.73 – 4.64 (m, 1H), 3.96 (s, 3H), 3.77 (t, J = 3.8 Hz, 1H), 3.53 ̢ 3.43 (m, 1H), 1.60 (d, J = 6.4 Hz, 3H). Example 137. (7S)-3-[(3-chloro-2-methoxyphenyl)amino]-2-(6-methoxy-1,7- naphthyridin-4-yl)-7-methyl-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (compound 253)

To a solution of 4-chloro-6-methoxy-1,7-naphthyridine (150.00 mg, 0.771 mmol, 1.00 equiv)and (7S)-3-chloro-7-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)- 5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (960.55 mg, 3.083 mmol, 4.00 equiv) in dioxane (5.00 mL) and H₂O (1.00 mL) were added K2CO3 (213.04 mg, 1.541 mmol, 2.00 equiv) and Pd(dppf)Cl₂ CH₂Cl₂ (62.79 mg, 0.077 mmol, 0.10 equiv). After stirring for 2h at 80degrees C under a nitrogen atmosphere. The resulting mixture was diluted with H₂O (100mL). The resulting mixture was extracted with EA (3 x 50 mL). The combined organic layers were washed with brine (1x20 mL), dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC/silica gel column chromatography, eluted with DCM:MeOH (15:1) to afford (7S)-3-chloro-2-(6-methoxy-1,7-naphthyridin-4-yl)-7-methyl-5H,6H,7H- pyrazolo[1,5-a]pyrazin-4-one (150 mg, 46.82%) as a brown solid. LC-MS: M+H found: 344.

To a solution of (7S)-3-chloro-2-(6-methoxy-1,7-naphthyridin-4-yl)-7-methyl- 5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (200.00 mg, 0.582 mmol, 1.00 equiv)and 3- chloro-2-methoxyaniline (183.38 mg, 1.164 mmol, 2 equiv) in DMF (5.00 mL) were added EPhos Pd G4 (267.20 mg, 0.291 mmol, 0.5 equiv)EPhos (311.14 mg, 0.582 mmol, 1 equiv) and Cs₂CO₃ (379.11 mg, 1.164 mmol, 2.00 equiv) . After stirring for 2h at 50 degrees C under a nitrogen atmosphere, The resulting mixture was diluted with H₂O (100 mL). The resulting mixture was extracted with EA (3 x 50mL). The combined organic layers were washed with brine (2x20 mL), dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. the resulting mixture was concentrated under reduced pressure. The residue was purified by Prep- TLC(DCM:MeOH=15:1) and Prep-HPLC(Column: XBridge Shield RP18 OBD Column, 30*150 mm, 5μm; Mobile Phase A: Water(10 mmol/L NH₄HCO₃+0.1%NH₃.H₂O), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 24% B to 60% B in 7 min, 60% B; Wave Length: 254/220 nm; RT1(min): 6.57) to afford (7S)-3-[(3-chloro-2- methoxyphenyl)amino]-2-(6-methoxy-1,7-naphthyridin-4-yl)-7-methyl-5H,6H,7H- pyrazolo[1,5-a]pyrazin-4-one (75.3 mg, 27.51%) as a light yellow solid. LC-MS: M+H found: 465. ¹H NMR (400 MHz, DMSO-d6): δ 9.15 (s, 1H), 8.80 (d, J = 4.3 Hz, 1H), 8.35 (t, J = 2.9 Hz, 1H), 7.77 – 7.70 (m, 2H), 7.48 (s, 1H), 6.62 (dd, J = 8.1, 1.6 Hz, 1H), 6.54 (t, J = 8.1 Hz, 1H), 6.10 (dd, J = 8.1, 1.6 Hz, 1H), 4.73 – 4.64 (m, 1H), 3.96 (s, 3H), 3.79 (s, 3H), 3.77 (d, J = 7.9 Hz, 1H), 3.48 (ddd, J = 13.3, 8.2, 2.3 Hz, 1H), 1.60 (d, J = 6.5 Hz, 3H). Example 138. (7S)-3-[(3-chloro-2-methoxyphenyl)amino]-2-(6,7-dimethoxyquinolin-4- yl)-7-methyl-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (compound 361)

To a solution of 4-bromo-6,7-dimethoxyquinoline (150.00 mg, 0.559 mmol, 1.00 equiv) and (7S)-3-chloro-7-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5H,6H,7H- pyrazolo[1,5-a]pyrazin-4-one (697.26 mg, 2.236 mmol, 4.00 equiv)in dioxane (5.00 mL) and H2O (1.00 mL) were added K₂CO₃ (154.64 mg, 1.118 mmol, 2.00 equiv) and Pd(dppf)Cl₂ CH₂Cl₂ (45.58 mg, 0.056 mmol, 0.10 equiv). After stirring for 2h at 80degrees C under a nitrogen atmosphere, The resulting mixture was diluted with H₂O (100mL). The resulting mixture was extracted with EA (3 x 50mL). The combined organic layers were washed with brine (1x20mL), dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC/silica gel column chromatography, eluted with DCM:MeOH (15:1) to afford (7S)-3-chloro-2-(6,7-dimethoxyquinolin-4-yl)-7-methyl-5H,6H,7H-pyrazolo[1,5- a]pyrazin-4-one (150 mg, 68.61%) as a brown solid. LC-MS: M+H found: 373

To a solution of (7S)-3-chloro-2-(6,7-dimethoxyquinolin-4-yl)-7-methyl-5H,6H,7H- pyrazolo[1,5-a]pyrazin-4-one (150.00 mg, 0.402 mmol, 1.00 equiv)and 3-chloro-2- methoxyaniline (137.93 mg, 0.876 mmol, 2.00 equiv) in DMF (5.00 mL) was added Cs₂CO₃ (285.16 mg, 0.876 mmol, 2.00 equiv), EPhos Pd G4 (200.98 mg, 0.219 mmol, 0.50 equiv) and EPhos (234.03 mg, 0.438 mmol, 1.00 equiv). After stirring for 2 h at 50 degrees C under a nitrogen atmosphere, The resulting mixture was diluted with H₂O (100 mL). The resulting mixture was extracted with EA (3 x 50mL). The combined organic layers were washed with brine (1x30 mL), dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep- TLC/silica gel column chromatography, eluted with DCM:MeOH (15:1) and Prep-HPLC (Column: YMC-Actus Triart C18, 30*150 mm, 5μm; Mobile Phase A: Water(10 mmol/L NH₄HCO₃+0.1%NH₃.H₂O), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 43% B to 53% B in 8 min, 53% B; Wave Length: 254/220 nm; RT1(min): 6.60) to afford (7S)-3-[(3-chloro-2-methoxyphenyl)amino]-2-(6,7-dimethoxyquinolin-4-yl)-7-methyl- 5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (42.8 mg, 21.43%) as a light yellow solid. LC-MS: M+H found: 494. ¹H NMR (400 MHz, DMSO-d6): δ 8.63 (d, J = 4.7 Hz, 1H), 8.37 – 8.32 (m, 1H), 7.86 (s, 1H), 7.47 (d, J = 4.9 Hz, 2H), 7.39 (s, 1H), 6.61 (dd, J = 8.0, 1.5 Hz, 1H), 6.53 (t, J = 8.1 Hz, 1H), 6.11 (dd, J = 8.1, 1.6 Hz, 1H), 4.66 (ddd, J = 8.6, 6.4, 4.4 Hz, 1H), 3.94 (s, 3H), 3.83 (s, 3H), 3.78-3.72 (m, 4H), 3.48 (ddd, J = 13.0, 8.6, 2.2 Hz, 1H), 1.62 (d, J = 6.4 Hz, 3H). Example 139. (7R)-3-[(3-chloro-2-methoxyphenyl)amino]-2-(6,7-dimethoxyquinolin-4- yl)-7-methyl-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (compound 360)

To a solution of 4-bromo-6,7-dimethoxyquinoline (300 mg, 1.119 mmol, 1 equiv) and (7R)-2-boranyl-3-chloro-7-methyl-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (552.28 mg, 2.797 mmol, 2.5 equiv) in DMF (6 mL)were added K₂CO₃ (386.61 mg, 2.797 mmol, 2.50 equiv) and Pd(dppf)Cl₂ (122.81 mg, 0.168 mmol, 0.15 equiv) . After stirring for 2h at 80°C under a nitrogen atmosphere, the resulting mixture was concentrated under reduced pressure. The residue was purified by Prep-TLC, eluted with DCM:MeOH (20:1) to afford (7R)-3-chloro-2-(6,7-dimethoxyquinolin-4-yl)-7-methyl-5H,6H,7H-pyrazolo[1,5- a]pyrazin-4-one (300 mg, 90.8%) as a brown solid. LC-MS: M+H found: 373.00.

To a stirred solution of (7R)-3-chloro-2-(6,7-dimethoxyquinolin-4-yl)-7-methyl- 5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (300 mg, 0.805 mmol, 1 equiv), Cs₂CO₃ (655.47 mg, 2.013 mmol, 2.5 equiv) and 3-chloro-2-methoxyaniline (380.46 mg, 2.414 mmol, 3.00 equiv) in DMF (5 mL) was added EPhos Pd G4 (369.58 mg, 0.403 mmol, 0.5 equiv) and EPhos (215.17 mg, 0.403 mmol, 0.5 equiv) dropwise at 50°C under N₂ atmosphere. The resulting mixture was extracted with EA (3 x 30ml). The combined organic layers were washed with brine (3x220ml), dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by Prep- HPLC with the following conditions (Column: XBridge Shield RP18 OBD Column, 30*150 mm, 5μm; Mobile Phase A: Water(10 mmol/L NH₄HCO₃+0.1%NH₃*H₂O), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 23% B to 59% B in 7 min, 59% B; Wave Length: 254/220 nm; RT1(min): 6.42) to afford(7R)-3-[(3-chloro-2- methoxyphenyl)amino]-2-(6,7-dimethoxyquinolin-4-yl)-7-methyl-5H,6H,7H- pyrazolo[1,5-a]pyrazin-4-one (10.3 mg, 98.4%) as a white solid. LC-MS: M+H found: 494.00. ¹H NMR (400 MHz, DMSO-d6) δ 8.61 (d, J = 4.7 Hz, 1H), 8.34 (s, 1H), 7.84 (s, 1H), 7.49 – 7.41 (m, 2H), 7.37 (s, 1H), 6.60 (d, J = 7.9 Hz, 1H), 6.52 (t, J = 8.1 Hz, 1H), 6.10 (d, J = 8.2 Hz, 1H), 4.65 (s, 1H), 3.93 (s, 3H), 3.83 (s, 3H), 3.77 (m, 4H), 3.50 (d, J = 10.5 Hz, 1H), 1.62 (d, J = 6.4 Hz, 3H). Example 140. (7R)-3-[(3-chloro-2-methoxyphenyl)amino]-7-methyl-2-[thien [3,2- b]pyridin-7-yl]-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (compound 239b)

To a solution of 7-chlorothieno[3,2-b]pyridine (300 mg, 1.769 mmol, 1.00 equiv) and (7R)-2-boranyl-3-chloro-7-methyl-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (872.91 mg, 4.422 mmol, 2.5 equiv) in DMF (5 mL, 1.769 mmol, 1.00 equiv) were added K₂CO₃ (611.06 mg, 4.422 mmol, 2.5 equiv) and Pd(dppf)Cl₂ (194.11 mg, 0.265 mmol, 0.15 equiv) . After stirring for 2h at 80°C under a nitrogen atmosphere, the resulting mixture was concentrated under reduced pressure. The residue was purified by Prep-TLC, eluted with DCM:MeOH (25:1) to afford (7R)-3-chloro-7-methyl-2-{thieno[3,2-b]pyridin-7- yl}-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (350 mg, 35.2%) as a black solid. LC-MS: M+H found: 318.90.

To a stirred solution of (7R)-3-chloro-7-methyl-2-[thieno[3,2-b]pyridin-7-yl]-5H,6H,7H- pyrazolo[1,5-a]pyrazin-4-one (200.00 mg, 0.627 mmol, 1.00 equiv) and 3-chloro-2- methoxyaniline (197.75 mg, 1.254 mmol, 2.00 equiv) in DMF (5.00 mL) was added Cs₂CO₃ (613.25 mg, 1.882 mmol, 3 equiv) in portions at 50°C under N₂ atmosphere. The resulting mixture was extracted with EA (2 x 50ml). The combined organic layers were washed with NaCl (2x250ml), dried over anhydrous Na₂SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by The crude product (mg) was purified by Prep-HPLC with the following conditions (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water (10 mmol/L NH₄HCO₃+0.1%NH₃.H₂O), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 29% B to 59% B in 8 min, 59% B; Wave Length: 254; 220 nm; RT1(min): 6.77) to afford (7R)-3-[(3-chloro-2-methoxyphenyl)amino]-7-methyl-2-[thien [3,2-b]pyridin-7-yl]- 5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (25.3 mg, 98.2%) as a white solid. LC-MS: M+H found: 439.95. ¹H NMR (400 MHz, DMSO-d6) δ 8.60 (d, J = 5.0 Hz, 1H), 8.38 (s, 1H), 8.22 – 8.14 (m, 2H), 7.60 (dd, J = 8.6, 5.3 Hz, 2H), 7.50 (s, 1H), 6.78 – 6.68 (m, 2H), 6.14 (dd, J = 7.6, 2.0 Hz, 1H), 4.67 (ddd, J = 9.1, 6.5, 4.5 Hz, 1H), 3.93 (s, 3H), 3.75 (dt, J = 12.9, 4.2 Hz, 1H), 3.52 – 3.43 (m, 1H), 1.67 (d, J = 6.4 Hz, 3H). Example 141. (7S)-3-[(3-chloro-2-methoxyphenyl)amino]-7-methyl-2-[thieno[3,2- b]pyridin-7-yl]-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (compound 239a)

To a solution of 7-chlorothieno[3,2-b]pyridine (100.00 mg, 0.590 mmol, 1.00 equiv) and (7S)-3-chloro-7-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5H,6H,7H- pyrazolo[1,5-a]pyrazin-4-one (367.35 mg, 1.179 mmol, 2.00 equiv) in dioxane (5.00 mL) and H₂O (1.00 mL) were added K₂CO₃ (162.95 mg, 1.179 mmol, 2.00 equiv) and Pd(dppf)Cl₂ CH₂Cl₂ (48.02 mg, 0.059 mmol, 0.10 equiv). After stirring for 2 h at 80 degrees C under a nitrogen atmosphere, the resulting mixture was diluted with H₂O (50mL) and EA (50 mL).The resulting mixture was filtered, the filter cake was washed with H₂O (10mL). The filterate was concentrated under reduced pressure to afford (7S)- 3-chloro-7-methyl-2-[thieno[3,2-b]pyridin-7-yl]-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4- one (140 mg, 74.50%) as a dark grey solid. LC-MS: M+H found: 319.

To a solution of (7S)-3-chloro-7-methyl-2-[thieno[3,2-b]pyridin-7-yl]-5H,6H,7H- pyrazolo[1,5-a]pyrazin-4-one (120.00 mg, 0.376 mmol, 1.00 equiv) and 3-chloro-2- methoxyaniline (118.65 mg, 0.752 mmol, 2.00 equiv) in DMF (5.00 mL) were added EPhos Pd G4 (172.89 mg, 0.188 mmol, 0.50 equiv),EPhos (201.32 mg, 0.376 mmol, 1.00 equiv)and Cs₂CO₃ (245.30 mg, 0.753 mmol, 2.00 equiv).After stirring for 2 h at 50 degrees C under a nitrogen atmosphere,The resulting mixture was diluted with H₂O (100mL). The resulting mixture was extracted with EA (3 x 50mL). The combined organic layers were washed with brine (1x30mL), dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (DCM:MeOH=15:1) to afford crude product.The crude product was purified by Prep-HPLC with the following conditions (Column: YMC-Actus Triart C18, 30*150 mm, 5μm; Mobile Phase A: Water (10 mmol/L NH₄HCO₃+0.1%NH₃.H₂O), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 41% B to 71% B in 8 min, 71% B; Wave Length: 254/220 nm; RT1(min): 6.93) to afford (7S)-3-[(3-chloro-2- methoxyphenyl)amino]-7-methyl-2-[thieno[3,2-b]pyridin-7-yl]-5H,6H,7H-pyrazolo[1,5- a]pyrazin-4-one (46.0 mg, 27.11%) as a white solid. LC-MS: M+H found: 440. ¹H NMR (400 MHz, DMSO-d6): δ 8.60 (d, J = 4.9 Hz, 1H), 8.39 (dd, J = 4.1, 1.9 Hz, 1H), 8.19 (d, J = 5.6 Hz, 1H), 7.60 (dd, J = 8.9, 5.3 Hz, 2H), 7.50 (s, 1H), 6.80 – 6.68 (m, 2H), 6.14 (dd, J = 7.6, 2.0 Hz, 1H), 4.74 – 4.61 (m, 1H), 3.93 (s, 3H), 3.75 (dt, J = 13.0, 4.2 Hz, 1H), 3.47 (ddd, J = 13.2, 9.2, 1.9 Hz, 1H), 1.68 (d, J = 6.5 Hz, 3H). Example 142. (7S)-3-[(3-chloro-2-methoxyphenyl)amino]-7-methyl-2- {[1,2]thiazolo[4,5-b]pyridin-7-yl}-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (compound 247b)

To a stirred solution of 2,2,6,6-tetramethylpiperidine (11.81 g, 83.631 mmol, 1.1 equiv) in THF (40 mL) was added n-BuLi (5.11 g, 79.829 mmol, 1.05 equiv) dropwise at 0 degrees C under argon atmosphere. The resulting mixture was stirred for 1 h at -5 degrees C under argon atmosphere. Then, the mixture was cooled to -78 degrees C. To the above mixture was added a solution of 4-chloro-3-fluoropyridine (5 g, 38.014 mmol, 1.00 equiv) in THF (40mL) dropwise and stirred for 2 h at -78 degrees C. Then, a solution of DMF (5.84 g, 79.829 mmol, 1.05 equiv) in THF (40 mL) was added into the above mixture. The resulting mixture was stirred for additional 1 h at -78 degrees C. The reaction was monitored by LCMS. The reaction was quenched by the addition of sat. NH4Cl (aq.) (20 mL) at 0 degrees C.The resulting mixture was extracted with EtOAc (3 x 20 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE/EA (2:1) to afford 4-chloro-3-fluoropyridine-2- carbaldehyde (9.5g) as a yellow liquid. LC-MS: M+H found: 159.

To a stirred solution of 4-chloro-3-fluoropyridine-2-carbaldehyde (5 g, 28.833 mmol, 1.00 equiv) and (4-methoxyphenyl)methanethiol (4.45 g, 28.853 mmol, 1.00 equiv) in THF (125.00 mL, 1542.854 mmol, 53.51 equiv) was added t-BuOK (3.24 g, 28.833 mmol, 1 equiv) in portions at 0 degrees C under argon atmosphere. The reaction was monitored by LCMS. The resulting mixture was filtered; the filter cake was washed with ethyl acetate (3x10 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH₂Cl₂/MeOH (50:1) to afford 4-chloro-3-{[(4-methoxyphenyl)methyl]sulfanyl}pyridine-2- carbaldehyde (4.5 g, 53.13%) as a yellow solid. LC-MS: M+H found: 294.

To a stirred solution of 4-chloro-3-{[(4-methoxyphenyl)methyl]sulfanyl}pyridine-2- carbaldehyde (4.5 g, 15.318 mmol, 1.00 equiv) in DCE (102.28 mL, 1291.920 mmol, 84.34 equiv) was added SO2Cl2 (2.48 mL, 30.636 mmol, 2 equiv) dropwise at 0 degrees C under argon atmosphere. The resulting mixture was stirred for 1 h at room temperature under argon atmosphere. To the above mixture was added NH3(g) in MeOH (10.94 mL, 76.590 mmol, 5 equiv) dropwise over 5 min at room temperature. The resulting mixture was stirred for additional 1 h at room temperature. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH₂Cl₂ / MeOH (10:1) to afford 7- chloro-[1,2]thiazolo[4,5-b]pyridine (800 mg, 27.86%) as a yellow solid. LC-MS: M+H found: 171.

Into a 8-mL sealed tube was placed 7-chloro-[1,2]thiazolo[4,5-b]pyridine (350 mg, 2.051 mmol, 1.00 equiv) in diaxone/H2O(3mL; 5:1), (7S)-3-chloro-7-methyl-2-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (2556.70 mg, 8.204 mmol, 4 equiv) , Pd₂(dba)₃ (187.86 mg, 0.205 mmol, 0.1 equiv) , PCy3 (57.53 mg, 0.205 mmol, 0.1 equiv) and Cs₂CO₃ (2005.22 mg, 6.153 mmol, 3 equiv) . The resulting solution was stirred at 60oC for 2h. The mixture was allowed to cool down to room temperature. The precipitated solids were collected by filtration and washed with MeOH (3x5 mL) to afford (7S)-3-chloro-7-methyl-2-{[1,2]thiazolo[4,5-b]pyridin-7-yl}- 5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (300 mg, 45.73%) as a grey solid LC-MS: M+H found: 320.

Into a 20-mL sealed tube was placed 3-chloro-2-methoxyaniline (221.78 mg, 1.407 mmol, 3 equiv) in DMF (2 mL), (7S)-3-chloro-7-methyl-2-{[1,2]thiazolo[4,5-b]pyridin-7-yl}- 5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (150 mg, 0.469 mmol, 1.00 equiv) , Cs₂CO₃ (458.51 mg, 1.407 mmol, 3 equiv), EPhos Pd G4 (129.26 mg, 0.141 mmol, 0.3 equiv) and EPhos (75.26 mg, 0.141 mmol, 0.3 equiv) The resulting solution was stirred at 50°C for 2 h. The resulting solution was concentrated under vacuum. The residue was purified by Prep-TLC with DCM/MeOH (25:1). The semi-pure product was further purified by Prep-Flash-HPLC with the following conditions: (Column: YMC-Actus Triart C18, 30*150 mm, 5μm; Mobile Phase A: Water (10 mmol/L NH₄HCO₃+0.1%NH₃.H₂O), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 42% B to 72% B in 8 min, 72% B; Wave Length: 254/220 nm; RT1(min): 6.85). This resulted in (7S)-3-[(3-chloro-2- methoxyphenyl)amino]-7-methyl-2-{[1,2]thiazolo[4,5-b]pyridin-7-yl}-5H,6H,7H- pyrazolo[1,5-a]pyrazin-4-one (87 mg) as an off-white solid. LC-MS: M+H found: 441. ¹H NMR (300 MHz, DMSO-d6) δ 9.33 (s, 1H), 8.81 (d, J = 4.7 Hz, 1H), 8.44 (d, J = 3.4 Hz, 1H), 7.69 (d, J = 4.8 Hz, 1H), 7.56 (s, 1H), 6.86 – 6.72 (m, 2H), 6.20 (dd, J = 7.3, 2.3 Hz, 1H), 4.72 (ddd, J = 10.7, 6.5, 4.4 Hz, 1H), 3.96 (s, 3H), 3.75 (dt, J = 13.3, 4.3 Hz, 1H), 3.49 (dd, J = 13.0, 9.6 Hz, 1H), 1.72 (d, J = 6.4 Hz, 3H). Example 143. (7S)-3-[(3-fluoro-2-methoxyphenyl)amino]-7-methyl-2- {[1,2]thiazolo[4,5-b]pyridin-7-yl}-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (compound 368)

Into a 20-mL sealed tube was placed (7S)-3-chloro-7-methyl-2-{[1,2]thiazolo[4,5- b]pyridin-7-yl}-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (150 mg, 0.469 mmol, 1.00 equiv) in DMF (2 mL), 3-fluoro-2-methoxyaniline (198.63 mg, 1.407 mmol, 3 equiv), EPhos Pd G4 (129.26 mg, 0.141 mmol, 0.3 equiv) and Cs₂CO₃ (458.51 mg, 1.407 mmol, 3 equiv). The resulting solution was stirred at 50°C for 2 h. The resulting solution was concentrated under vacuum. The residue was purified by Prep-TLC with DCM/MeOH (25:1). The semi-pure product was purified by Prep-Flash-HPLC with the following conditions: (Column: YMC-Actus Triart C18, 30*150 mm, 5μm; Mobile Phase A: Water(10 mmol/L NH₄HCO₃+0.1%NH₃.H₂O), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 46% B to 56% B in 8 min, 56% B; Wave Length: 254/220 nm; RT1(min): 6.60). This resulted in 67 mg of (7S)-3-[(3-fluoro-2-methoxyphenyl)amino]- 7-methyl-2-{[1,2]thiazolo[4,5-b]pyridin-7-yl}-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (67.8 mg, 33.10%) as a white solid LC-MS: M+H found: 425. ¹H NMR (300 MHz, DMSO-d6) δ 9.31 (d, J = 1.4 Hz, 1H), 8.79 (d, J = 4.8 Hz, 1H), 8.42 (d, J = 3.2 Hz, 1H), 7.67 (d, J = 4.8 Hz, 1H), 7.48 (s, 1H), 6.78 – 6.68 (m, 1H), 6.66 – 6.57 (m, 1H), 6.05 (d, J = 8.1 Hz, 1H), 4.97 – 4.51 (m, 1H), 3.98 (s, 3H), 3.81 – 3.67 (m, 1H), 3.56 – 3.40 (m, 1H), 1.71 (d, J = 6.4 Hz, 3H). Example 144. (7R)-3-[(3-chloro-2-methoxyphenyl)amino]-7-methyl-2- {[1,2]thiazolo[4,5-b]pyridin-7-yl}-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (compound 247a)

To a stirred solution of (7R)-2-bromo-7-methyl-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (2 g, 8.693 mmol, 1 equiv) in DMF (20 mL) was added NCS (1.28 g, 9.586 mmol, 1.10 equiv) . The resulting mixture was stirred for 2 h at 50oC. The reaction was monitored by LCMS. The resulting mixture was diluted with H₂O (200 mL). The resulting mixture was filtered and the filter cake was washed with H₂O (20mL). The filter cake was concentrated under reduced pressure to afford (7R)-2-bromo-3-chloro-7-methyl-5H,6H,7H- pyrazolo[1,5-a]pyrazin-4-one (2 g, 86.98%) as a white solid. LC-MS: M+H found: 266.

To a solution of bis(pinacolato)diboron (480.02 mg, 1.890 mmol, 1.00 equiv) and (7R)- 2-bromo-3-chloro-7-methyl-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (500 mg, 1.890 mmol, 1.00 equiv) in DME (5.00 mL) were added KOAc (371.03 mg, 3.780 mmol, 2 equiv) and Pd(dppf)Cl₂ (414.94 mg, 0.567 mmol, 0.3 equiv). After stirring for 16 h at 100°C under a nitrogen atmosphere.The resulting mixture was filtered, the filter cake was washed with DCM .The filtrate was concentrated under reduced pressure and diluted with EA .The resulting mixture was filtered, the filter cake was washed with EA .The filtrate was concentrated under reduced pressure to afford (7R)-3-chloro-7-methyl-4-oxo- 5H,6H,7H-pyrazolo[1,5-a]pyrazin-2-ylboronic acid (1.5 g, crude) as a black solid. LC-MS: M+H found: 230.

Into a 8-mL sealed tube was placed (7R)-3-chloro-7-methyl-4-oxo-5H,6H,7H- pyrazolo[1,5-a]pyrazin-2-ylboronic acid (403.43 mg, 1.758 mmol, 1 equiv) in diaxone/H2O(3mL; 5:1), 7-chloro-[1,2]thiazolo[4,5-b]pyridine (300 mg, 1.758 mmol, 1.00 equiv) , Pd2(dba)3 (161.02 mg, 0.176 mmol, 0.1 equiv) , PCy3 (49.31 mg, 0.176 mmol, 0.1 equiv) and Cs₂CO₃ (1718.76 mg, 5.274 mmol, 3 equiv). The resulting solution was stirred at 60oC for 2h. The mixture was allowed to cool down to room temperature. The precipitated solids were collected by filtration and washed with MeOH (3x5 mL) to afford (7R)-3-chloro-7-methyl-2-{[1,2]thiazolo[4,5-b]pyridin-7-yl}-5H,6H,7H- pyrazolo[1,5-a]pyrazin-4-one (300 mg, 53.35%) as a grey solid. LC-MS: M+H found: 171.

To a solution of (7R)-3-chloro-7-methyl-2-{[1,2]thiazolo[4,5-b]pyridin-7-yl}- 5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (150 mg, 0.469 mmol, 1.00 equiv)Cs₂CO₃ (458.51 mg, 1.407 mmol, 3 equiv) and 3-chloro-2-methoxyaniline (221.78 mg, 1.407 mmol, 3 equiv) in DMF (1.5 mL) were added EPhos Pd G4 (129.26 mg, 0.141 mmol, 0.3 equiv), EPhos (75.26 mg, 0.141 mmol, 0.3 equiv) and Cs₂CO₃ (458.51 mg, 1.407 mmol, 3 equiv). After stirring for 2 h at 50 degrees C under a nitrogen atmosphere, the resulting solution was concentrated under vacuum. The residue was purified by Prep-TLC with DCM/MeOH (25:1). The crude product was purified by Prep-Flash-HPLC with following conditions (Column: XBridge Shield RP18 OBD Column, 30*150 mm, 5μm; Mobile Phase A: Water(10 mmol/L NH₄HCO₃+0.1%NH₃.H₂O), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 24% B to 67% B in 10 min, 67% B; Wave Length: 254/220 nm; RT1(min): 8.77). This resulted in (7R)-3-[(3-chloro-2-methoxyphenyl)amino]-7- methyl-2-{[1,2]thiazolo[4,5-b]pyridin-7-yl}-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (39.6 mg, 19.11%) as a white solid. LC-MS: M+H found: 441. ¹H NMR (400 MHz, DMSO-d6) δ 9.32 (s, 1H), 8.81 (d, J = 4.8 Hz, 1H), 8.42 (s, 1H), 7.69 (d, J = 4.8 Hz, 1H), 7.55 (s, 1H), 6.84 – 6.73 (m, 2H), 6.20 (d, J = 7.6 Hz, 1H), 4.71 (s, 1H), 3.95 (s, 3H), 3.75 (d, J = 12.7 Hz, 1H), 3.54 – 3.44 (m, 1H), 1.71 (d, J = 6.4 Hz, 3H). Example 145. (7R)-3-[(3-fluoro-2-methoxyphenyl)amino]-7-methyl-2- {[1,2]thiazolo[4,5-b]pyridin-7-yl}-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (compound 369)

Into a 20-mL sealed tube was placed (7R)-3-chloro-7-methyl-2-{[1,2]thiazolo[4,5- b]pyridin-7-yl}-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (150 mg, 0.469 mmol, 1.00 equiv) in DMF (2 mL), 3-fluoro-2-methoxyaniline (198.63 mg, 1.407 mmol, 3 equiv), EPhos Pd G4 (129.26 mg, 0.141 mmol, 0.3 equiv), EPhos (75.26 mg, 0.141 mmol, 0.3 equiv) and Cs₂CO₃ (458.51 mg, 1.407 mmol, 3 equiv). The resulting solution was stirred at 50°C for 2 h. The resulting solution was concentrated under vacuum. The residue was purified by Prep-TLC with DCM/MeOH (30:1). The semi-pure product was purified by Prep-Flash-HPLC with following conditions: (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water(10 mmol/L NH₄HCO₃+0.1%NH₃.H₂O), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 36% B to 56% B in 8 min, 56% B; Wave Length: 254; 220 nm; RT1(min): 6.95). This resulted in (7R)-3-[(3-fluoro-2- methoxyphenyl)amino]-7-methyl-2-{[1,2]thiazolo[4,5-b]pyridin-7-yl}-5H,6H,7H- pyrazolo[1,5-a]pyrazin-4-one (53.6 mg, 26.81%) as a white solid LC-MS: M+H found: 425. ¹H NMR (400 MHz, DMSO-d6) δ 9.32 (s, 1H), 8.80 (d, J = 4.9 Hz, 1H), 8.42 (s, 1H), 7.68 (d, J = 4.9 Hz, 1H), 7.49 (s, 1H), 6.74 (q, J = 7.8 Hz, 1H), 6.62 (t, J = 9.8 Hz, 1H), 6.05 (d, J = 8.3 Hz, 1H), 4.69 (d, J = 10.2 Hz, 1H), 3.98 (s, 3H), 3.75 (d, J = 13.2 Hz, 1H), 3.54 – 3.43 (m, 1H), 1.71 (d, J = 6.4 Hz, 3H). Example 146. (7R)-3-[(3-chloro-2-methoxyphenyl)amino]-7-(2-methoxyethyl)-2- (pyridin-4-yl)-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (compound 257b)

To a stirred solution of methyl 5-bromo-2H-pyrazole-3-carboxylate (500 mg, 2.439 mmol, 1.00 equiv) and 2-bromoacetonitrile (351.05 mg, 2.927 mmol, 1.2 equiv) in ACN (5 mL, 95.123 mmol, 39.00 equiv) was added Cs₂CO₃ (1589.28 mg, 4.878 mmol, 2 equiv) in portions at room temperature. The resulting mixture was stirred for 5 hours at room temperature under N₂ atmosphere. The resulting mixture was diluted with H₂O (40 mL), The aqueous layer was extracted with EtOAc (50 mL) for three times, the organic solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with Petroleum ether /EtOAc (4:1) to afford methyl 5-bromo-2- (cyanomethyl)pyrazole-3-carboxylate (500 mg, 84.00%) as a light yellow solid. LC-MS: (M+H)⁺ found: 244.1.

A mixture of methyl 5-bromo-2-(cyanomethyl)pyrazole-3-carboxylate (500 mg, 2.049 mmol, 1.00 equiv), pyridin-4-ylboronic acid (377.75 mg, 3.074 mmol, 1.5 equiv), K₃PO₄ (869.77 mg, 4.098 mmol, 2 equiv) and Pd(dppf)Cl₂ (299.82 mg, 0.410 mmol, 0.2 equiv) in 1,4-dioxane (6 mL, 70.825 mmol, 34.57 equiv) and H₂O (1.5 mL, 83.263 mmol, 40.64 equiv) was stirred for 2h at 80°C under nitrogen atmosphere. After the reaction, The resulting mixture was diluted with H₂O (50 mL), The aqueous layer was extracted with EtOAc 50 mL for three times, the organic solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with Petroleum ether /EtOAc (3:1) to afford methyl 2-(cyanomethyl)-5-(pyridin-4-yl)pyrazole- 3-carboxylate (250 mg, 50.37%) as a light yellow solid. LC-MS: (M+H)⁺ found: 243.0.

Into a 50 mL round-bottom flask were added methyl 2-(cyanomethyl)-5-(pyridin-4- yl)pyrazole-3-carboxylate (450 mg, 1.858 mmol, 1 equiv), 2-bromoethyl methyl ether (309.84 mg, 2.230 mmol, 1.2 equiv) and DMF (20 mL) at 0°C. The mixture was stirred 0.5 h at 0°C under nitrogen atmosphere and NaH (44.58 mg, 1.858 mmol, 1 equiv) was added, The mixture was stirred 2 h at room temperature under nitrogen atmosphere. After the reaction, the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with Petroleum ether /EtOAc (3:2) to afford methyl 2-(1-cyano-3-methoxypropyl)-5-(pyridin-4-yl)pyrazole-3-carboxylate (100 mg, 17.92%) as a yellow solid. LC-MS: (M+H)⁺ found: 301.0.

To a mixture of methyl 2-(1-cyano-3-methoxypropyl)-5-(pyridin-4-yl)pyrazole-3- carboxylate (400 mg, 1.332 mmol, 1 equiv) in MeOH (20 mL) was added CoCl₂ (518.81 mg, 3.996 mmol, 3 equiv)at 0°C. The mixture was stirred 0.5 h at 0°C under nitrogen atmosphere and NaBH₄ (503.91 mg, 13.320 mmol, 10 equiv) was added. The mixture was stirred 3 h at room temperature under nitrogen atmosphere. After the reaction, The resulting mixture was diluted with NH₄Cl (50 mL), The aqueous layer was extracted with EtOAc 50mL for three times, the organic solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with Petroleum ether /EtOAc (1:1) to afford 7-(2-methoxyethyl)-2-(pyridin-4-yl)-5H,6H,7H-pyrazolo[1,5- a]pyrazin-4-one (170 mg, 46.87%) as a yellow solid. LC-MS: (M+H)⁺ found: 273.0.

Into a 25 mL round-bottom flask were added 7-(2-methoxyethyl)-2-(pyridin-4-yl)- 5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (140 mg, 0.514 mmol, 1 equiv), Br2 (90.38 mg, 0.565 mmol, 1.1 equiv), KOAc (75.69 mg, 0.771 mmol, 1.5 equiv) and HOAc (5 mL) at room temperature, The mixture was stirred 3 h at room temperature under nitrogen atmosphere. After the reaction, The resulting mixture was diluted with H₂O (30 mL), The aqueous layer was extracted with EtOAc 30 mL for three times, the organic solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with Petroleum ether /EtOAc (2:1) to afford 3-bromo-7-(2- methoxyethyl)-2-(pyridin-4-yl)-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (100 mg, 55.38%) as a yellow solid. LC-MS: (M+H)⁺ found: 350.9.

A mixture of 3-bromo-7-(2-methoxyethyl)-2-(pyridin-4-yl)-5H,6H,7H-pyrazolo[1,5- a]pyrazin-4-one (90 mg, 0.256 mmol, 1 equiv), 3-chloro-2-methoxyaniline (60.58 mg, 0.384 mmol, 1.5 equiv), EPhos Pd G4 (23.54 mg, 0.026 mmol, 0.1 equiv), EPhos (13.70 mg, 0.026 mmol, 0.1 equiv) and Cs₂CO₃ (166.99 mg, 0.512 mmol, 2 equiv) in 1,4-dioxane (5 mL) was stirred for 3 h at 80°C under nitrogen atmosphere. After the reaction. The resulting mixture was diluted with H₂O (30 mL), The aqueous layer was extracted with EtOAc 30 mL for three times, the organic solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with Petroleum ether /EtOAc (2:1) to afford 3-[(3-chloro-2-methoxyphenyl)amino]-7-(2- methoxyethyl)-2-(pyridin-4-yl)-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (50 mg, 45.60%) as a yellow solid. LC-MS: (M+H)⁺ found: 428.0.

3-[(3-chloro-2-methoxyphenyl)amino]-7-(2-methoxyethyl)-2-(pyridin-4-yl)-5H,6H,7H- pyrazolo[1,5-a]pyrazin-4-one (50 mg, 0.117 mmol, 1.00 equiv) was used for chiral separation(Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water(10 mmol/L NH₄HCO₃), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 41% B to 67% B in 8 min, 67% B; Wave Length: 254/220 nm; RT1(min): 8), and 2 peak was splitted from the material, the first peak is the product (7R)-3-[(3-chloro-2- methoxyphenyl)amino]-7-(2-methoxyethyl)-2-(pyridin-4-yl)-5H,6H,7H-pyrazolo[1,5- a]pyrazin-4-one (13.2 mg, 26.22%), This resulted in (7R)-3-[(3-chloro-2- methoxyphenyl)amino]-7-(2-methoxyethyl)-2-(pyridin-4-yl)-5H,6H,7H-pyrazolo[1,5- a]pyrazin-4-one (13.2 mg, 26.22%) as a yellow solid. LC-MS: (M+H)⁺ found: 428.2. ¹H NMR (300 MHz, Chloroform-d) δ 8.56 (d, J = 5.2 Hz, 2H), 7.72 (d, J = 5.2 Hz, 2H), 7.16 (s, 1H), 6.80 (d, J = 8.0 Hz, 1H), 6.65 (t, J = 8.1 Hz, 1H), 6.18 (d, J = 8.1 Hz, 1H), 5.87 (s, 1H), 4.65 (s, 1H), 4.06 (s, 3H), 3.98 (d, J = 13.0 Hz, 1H), 3.71 (s, 1H), 3.63 (t, J = 5.8 Hz, 2H), 3.41 (s, 3H), 2.55 – 2.43 (m, 1H), 2.15 (dd, J = 14.3, 7.1 Hz, 1H). Example 147. (7S)-3-[(3-chloro-2-methoxyphenyl)amino]-7-(2-methoxyethyl)-2- (pyridin-4-yl)-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (compound 257a)

3-[(3-chloro-2-methoxyphenyl)amino]-7-(2-methoxyethyl)-2-(pyridin-4-yl)-5H,6H,7H- pyrazolo[1,5-a]pyrazin-4-one (50 mg, 0.117 mmol, 1.00 equiv) was used for chiral separation(Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water (10 mmol/L NH₄HCO₃), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 41% B to 67% B in 8 min, 67% B; Wave Length: 254/220 nm; RT1(min): 8), and 2 peak was splitted from the material, the first peak is the product (7S)-3-[(3-chloro-2- methoxyphenyl)amino]-7-(2-methoxyethyl)-2-(pyridin-4-yl)-5H,6H,7H-pyrazolo[1,5- a]pyrazin-4-one (12.9 mg, 25.59%), This resulted in (7S)-3-[(3-chloro-2- methoxyphenyl)amino]-7-(2-methoxyethyl)-2-(pyridin-4-yl)-5H,6H,7H-pyrazolo[1,5- a]pyrazin-4-one (12.9 mg, 25.59%) as a yellow solid. LC-MS: (M+H)⁺ found: 428.3 ¹H NMR (300 MHz, Chloroform-d) δ 8.57 (s, 2H), 7.72 (s, 2H), 7.16 (s, 1H), 6.80 (d, J = 7.9 Hz, 1H), 6.65 (s, 1H), 6.18 (d, J = 8.2 Hz, 1H), 5.94 (s, 1H), 4.65 (s, 1H), 4.06 (s, 3H), 3.98 (d, J = 12.6 Hz, 1H), 3.71 (s, 1H), 3.63 (t, J = 5.8 Hz, 2H), 3.41 (s, 3H), 2.49 (s, 1H), 2.15 (s, 1H). Example 148. (7S)-3-[(3-chloro-2-methoxyphenyl)amino]-7-(2-hydroxy-2- methylpropyl)-2-(pyridin-4-yl)-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (compound 283)

Into a 100 mL round-bottom flask were added methyl 2-(cyanomethyl)-5-(pyridin-4- yl)pyrazole-3-carboxylate (2 g, 8.256 mmol, 1 equiv), tert-butyl 2-bromoacetate (2.42 g, 12.384 mmol, 1.5 equiv) and THF (50 mL) at 0°C. The mixture was stirred 0.5 h at 0°C under nitrogen atmosphere and NaH (0.20 g, 8.256 mmol, 1 equiv) was added. The mixture was stirred 2 h at room temperature under nitrogen atmosphere. After the reaction, the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with Petroleum ether/EtOAc (2:1) to afford methyl 2-[3- (tert-butoxy)-1-cyano-3-oxopropyl]-5-(pyridin-4-yl)pyrazole-3-carboxylate (1.1 g, 37.38%) as a yellow solid. LC-MS: M+H found: 357.1.

To a mixture of methyl 2-[3-(tert-butoxy)-1-cyano-3-oxopropyl]-5-(pyridin-4-yl)pyrazole- 3-carboxylate (1.1 g, 3.087 mmol, 1 equiv) in MeOH (20 mL) was added CoCl₂ (1.20 g, 9.261 mmol, 3 equiv) at 0°C . The mixture was stirred 0.5 h at 0°C under nitrogen atmosphere and NaBH₄ (1.17 g, 30.870 mmol, 10 equiv) was added, The mixture was stirred 3 h at room temperature under nitrogen atmosphere. After the reaction, The resulting mixture was diluted with NH₄CL (50 mL),The aqueous layer was extracted with EtOAc 50 mL for three times, the organic solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with Petroleum ether /EtOAc (1:1) to afford tert-butyl 2-[4-oxo-2-(pyridin-4-yl)-5H,6H,7H-pyrazolo[1,5- a]pyrazin-7-yl]acetate (400 mg, 39.47%) as a yellow solid. LC-MS: (M+H)⁺ found: 329.0.

To a mixture of tert-butyl 2-[4-oxo-2-(pyridin-4-yl)-5H,6H,7H-pyrazolo[1,5-a]pyrazin-7- yl]acetate (500 mg, 1.523 mmol, 1 equiv) and KOAc (224.16 mg, 2.284 mmol, 1.5 equiv) in HOAc (10 mL) was added Br₂ (267.67 mg, 1.675 mmol, 1.1 equiv) at room temperature. The mixture was stirred 3 h at room temperature under nitrogen atmosphere. After the reaction, The resulting mixture was diluted with H₂O (40 mL), The aqueous layer was extracted with EtOAc 50 mL for three times, the organic solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with Petroleum ether/EtOAc (2:1) to afford tert-butyl 2-[3-bromo-4-oxo-2-(pyridin-4-yl)- 5H,6H,7H-pyrazolo[1,5-a]pyrazin-7-yl]acetate (420 mg, 67.73%) as a yellow solid. LC-MS: (M+H)⁺ found: 406.9.

A mixture of tert-butyl 2-[3-bromo-4-oxo-2-(pyridin-4-yl)-5H,6H,7H-pyrazolo[1,5- a]pyrazin-7-yl]acetate (420 mg, 1.031 mmol, 1 equiv), 3-chloro-2-methoxyaniline (243.79 mg, 1.546 mmol, 1.5 equiv), EPhos Pd G4 (94.73 mg, 0.103 mmol, 0.1 equiv), EPhos (55.15 mg, 0.103 mmol, 0.1 equiv) and Cs₂CO₃ (672.01 mg, 2.062 mmol, 2 equiv) in 1,4- dioxane (10 mL) at room temperature, The mixture was stirred 3 h at 80°C under nitrogen atmosphere. After the reaction, The resulting mixture was diluted with H₂O (40 mL),The aqueous layer was extracted with EtOAc 50 mL for three times, the organic solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with Petroleum ether /EtOAc (1:1) to afford tert-butyl 2-{3-[(3- chloro-2-methoxyphenyl)amino]-4-oxo-2-(pyridin-4-yl)-5H,6H,7H-pyrazolo[1,5- a]pyrazin-7-yl}acetate (200 mg, 40.07%) as a yellow solid. LC-MS: (M+H)⁺ found: 484.0.

To a mixture of tert-butyl 2-{3-[(3-chloro-2-methoxyphenyl)amino]-4-oxo-2-(pyridin-4- yl)-5H,6H,7H-pyrazolo[1,5-a]pyrazin-7-yl}acetate (200 mg, 0.413 mmol, 1 equiv) in THF (10 mL) was added CH₃MgBr(in 3M Et₂O) (1.239 mL, 1.239 mmol, 3 equiv) at 0°C, The mixture was stirred 3 h at room temperature under nitrogen atmosphere. The reaction was monitored by LCMS. Desired product could be detected by LCMS. After the reaction, The resulting mixture was concentrated to afford 3-[(3-chloro-2-methoxyphenyl)amino]-7-(2- oxopropyl)-2-(pyridin-4-yl)-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (120 mg, 68.18%) as a yellow solid. LC-MS: (M+H)⁺ found: 426.0.

To a mixture of d3-[(3-chloro-2-methoxyphenyl)amino]-7-(2-oxopropyl)-2-(pyridin-4-yl)- 5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (120 mg, 0.282 mmol, 1 equiv) in THF (10 mL) was added CH₃Li (0.846 mL, 0.846 mmol, 3 equiv) at 0°C, The mixture was stirred 3 h at room temperature under nitrogen atmosphere. Desired product could be detected by LCMS. After the reaction, the resulting mixture was diluted with NH₄Cl (30 mL),The aqueous layer was extracted with EtOAc 40 mL for three times, the organic solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with Petroleum ether /EtOAc (1:2) to afford 3-[(3-chloro-2- methoxyphenyl)amino]-7-(2-hydroxy-2-methylpropyl)-2-(pyridin-4-yl)-5H,6H,7H- pyrazolo[1,5-a]pyrazin-4-one (40 mg, 32.12%) as a yellow solid. LC-MS: (M+H)⁺ found: 442.3.

3-[(3-chloro-2-methoxyphenyl)amino]-7-(2-hydroxy-2-methylpropyl)-2-(pyridin-4-yl)- 5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (30 mg, 0.068 mmol, 1.00 equiv) was used for chiral separation(Column: CHIRALPAK IG, 2*25 cm, 5 μm; Mobile Phase A: Hex: DCM=3: 1(0.5% 2M NH₃-MeOH)- HPLC, Mobile Phase B: IPA-HPLC; Flow rate: 20 mL/min; Gradient: 20% B to 20% B in 19 min; Wave Length: 220/254 nm; RT1(min): 7.92; RT2(min): 9.81), and 2 peak was splitted from the material, the prepeak is the product (7S)-3-[(3-chloro-2-methoxyphenyl)amino]-7-(2-hydroxy-2-methylpropyl)-2-(pyridin-4- yl)-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (4.5 mg, 14.93%). This resulted in (7S)-3-[(3- chloro-2-methoxyphenyl)amino]-7-(2-hydroxy-2-methylpropyl)-2-(pyridin-4-yl)- 5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (4.5 mg, 14.93%) as a white solid. LC-MS: (M+H)⁺ found: 442.3. ¹H NMR (400 MHz, Chloroform-d) δ 8.58 (s, 2H), 7.82 (s, 2H), 7.24 (s, 1H), 6.83 (s, 1H), 6.66 (s, 1H), 6.15 (s, 1H), 5.95 (s, 1H), 4.76 (s, 1H), 4.37 – 3.39 (m, 5H), 2.95 (s, 1H), 2.46 (d, J = 15.0 Hz, 1H), 2.03 (s, 1H), 1.42 (s, 6H). Example 149. (7R)-3-[(3-chloro-2-methoxyphenyl)amino]-7-(2-hydroxy-2- methylpropyl)-2-(pyridin-4-yl)-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (compound 284)

3-[(3-chloro-2-methoxyphenyl)amino]-7-(2-hydroxy-2-methylpropyl)-2-(pyridin-4-yl)- 5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (30 mg, 0.068 mmol, 1.00 equiv) was used for chiral separation(Column: CHIRALPAK IG, 2*25 cm, 5 μm; Mobile Phase A: Hex: DCM=3: 1(0.5% 2M NH3-MeOH)--HPLC, Mobile Phase B: IPA--HPLC; Flow rate: 20 mL/min; Gradient: 20% B to 20% B in 19 min; Wave Length: 220/254 nm; RT1(min): 7.92; RT2(min): 9.81), and 2 peak was splitted from the material, the postpeak is the product (7R)-3-[(3-chloro-2-methoxyphenyl)amino]-7-(2-hydroxy-2-methylpropyl)-2- (pyridin-4-yl)-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (4.7 mg, 14.99%). This resulted in (7R)-3-[(3-chloro-2-methoxyphenyl)amino]-7-(2-hydroxy-2-methylpropyl)-2-(pyridin-4- yl)-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (4.7 mg, 14.99%)as a white solid. LC-MS: (M+H)⁺ found: 442.3. ¹H NMR (400 MHz, Chloroform-d) δ 8.57 (s, 2H), 7.79 (s, 2H), 7.24 (s, 1H), 6.83 (dd, J = 8.1, 1.4 Hz, 1H), 6.66 (t, J = 8.1 Hz, 1H), 6.15 (dd, J = 8.1, 1.4 Hz, 1H), 5.96 (s, 1H), 4.75 (p, J = 6.0 Hz, 1H), 4.06 (s, 3H), 4.02 – 3.89 (m, 1H), 3.79 (ddd, J = 13.0, 7.7, 2.6 Hz, 1H), 3.00 (s, 1H), 2.51 – 2.42 (m, 1H), 2.03 (dd, J = 14.9, 6.3 Hz, 1H), 1.42 (d, J = 1.4 Hz, 6H). Example 150. (7S)-3-[(3-chloro-2-methoxyphenyl)amino]-7-[(dimethylamino)methyl]-2- (pyridin-4-yl)-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (compound 279)

To a stirred solution of methyl 5-bromo-2H-pyrazole-3-carboxylate (6 g, 29.267 mmol, 1.00 equiv) and DIEA (11.35 g, 87.801 mmol, 3 equiv) in DCM (60.00 mL, 943.861 mmol, 32.25 equiv) were added SEM-Cl (6.83 g, 40.974 mmol, 1.4 equiv) dropwise at 0 degrees C under nitrogen atmosphere. The resulting mixture was stirred for 1 h at room temperature under nitrogen atmosphere. The aqueous layer was extracted with EtOAc (3x50 mL). The residue was purified by silica gel column chromatography, eluted with PE / EA (50:1) to afford methyl 5-bromo-2-{[2-(trimethylsilyl)ethoxy]methyl}pyrazole-3-carboxylate (5.68 g, 57.89%) as a white oil. LCMS: [M-H]⁺ found: 335.

To a mixture of methyl 5-bromo-2-{[2-(trimethylsilyl)ethoxy]methyl}pyrazole-3- carboxylate (2.73 g, 8.143 mmol, 1.00 equiv) and pyridin-4-ylboronic acid (3.00 g, 24.429 mmol, 3 equiv) in dioxane (83 mL, 979.739 mmol, 120.32 equiv) and H₂O (8.3 mL, 460.719 mmol, 56.58 equiv) were added K₃PO₄ (3.46 g, 16.286 mmol, 2 equiv) and Pd(dppf)Cl₂*CH₂Cl₂ (1.33 g, 1.629 mmol, 0.20 equiv) in portions at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 1 h at 80 degrees C under nitrogen atmosphere. The aqueous layer was extracted with EtOAc (3x50 mL).The residue was purified by silica gel column chromatography, eluted with PE/EA (2:1) to afford methyl 5-(pyridin-4-yl)-2-{[2-(trimethylsilyl)ethoxy]methyl}pyrazole-3-carboxylate (2.23 g, 82.13%) as a brown solid. LCMS: [M-H]⁺ found: 334.

To a stirred mixture of methyl 5-(pyridin-4-yl)-2-{[2- (trimethylsilyl)ethoxy]methyl}pyrazole-3-carboxylate (2.2 g, 6.597 mmol, 1.00 equiv)methyl 5-(pyridin-4-yl)-2-{[2-(trimethylsilyl)ethoxy]methyl}pyrazole-3- carboxylate (2.2 g, 6.597 mmol, 1.00 equiv) were added TFA (20 mL, 269.261 mmol, 40.81 equiv) dropwise at 0 degrees C under nitrogen atmosphere. The resulting mixture was stirred for 30 min at 0 degrees C under nitrogen atmosphere. The aqueous layer was extracted with EtOAc (3x50 mL).This resulted in methyl 5-(pyridin-4-yl)-2H-pyrazole- 3-carboxylate (1.83 g, 136.51%) as a light yellow solid.The crude product/ resulting mixture was used in the next step directly without further purification. LCMS: [M-H]⁺ found: 204.

To a stirred mixture of methyl 5-(pyridin-4-yl)-2H-pyrazole-3-carboxylate (1.38 g, 6.791 mmol, 1.00 equiv) in CH₂Cl₂ (15.50 mL, 243.865 mmol, 35.91 equiv) were added NBS (1.21 g, 6.791 mmol, 1.0 equiv) in portions at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 1 h at room temperature under nitrogen atmosphere. The aqueous layer was extracted with EtOAc (3x50 mL). This resulted in methyl 4-bromo- 5-(pyridin-4-yl)-2H-pyrazole-3-carboxylate (1.4 g, 73.08%) as a white solid.The crude product/ resulting mixture was used in the next step directly without further purification. LCMS: [M-H]⁺ found: 282.

To a stirred mixture of methyl 4-bromo-5-(pyridin-4-yl)-2H-pyrazole-3-carboxylate (1.4 g, 4.963 mmol, 1.00 equiv) and 2-bromoacetonitrile (0.71 g, 5.956 mmol, 1.2 equiv) in MeCN (30 mL) were added K₂CO₃ (1.37 g, 9.926 mmol, 2.0 equiv) in portions at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 1 h at 80 degrees C under nitrogen atmosphere. The aqueous layer was extracted with EtOAc (3x50 mL).The residue was purified by silica gel column chromatography, eluted with PE / EA (1:1) to afford methyl 4-bromo-2-(cyanomethyl)-5-(pyridin-4-yl)pyrazole-3- carboxylate as a white solid. LCMS: [M-H]⁺ found: 321.

A mixture of (HCHO)n (2.10 g, 46.70 mmol, 6 equiv) in dimethylamine (23.35mL, 2M in THF, 6 equiv) was stirred for 2h and added to a mixture of methyl 4-bromo-2- (cyanomethyl)-5-(pyridin-4-yl)pyrazole-3-carboxylate (2.5 g, 7.785 mmol, 1.00 equiv) in DMF (25 mL) dropwise at room temperature. The resulting mixture was stirred for 30 min at 100 degrees C under nitrogen atmosphere. The aqueous layer was extracted with EtOAc (3x50 mL).The residue was purified by silica gel column chromatography, eluted with PE / EA (0:1) to afford methyl 4-bromo-2-[1-cyano-2-(dimethylamino)ethyl]-5-(pyridin-4- yl)pyrazole-3-carboxylate (460 mg, 15.62%) as a yellow solid. LCMS: [M-H]⁺ found: 378.

Methyl 4-bromo-2-[1-cyano-2-(dimethylamino)ethyl]-5-(pyridin-4-yl)pyrazole-3- carboxylate (200 mg, 0.529 mmol, 1.00 equiv) and CoCl₂ (205.97 mg, 1.587 mmol, 3 equiv) in MeOH (10.00 mL, 247.091 mmol, 467.09 equiv) were added NaBH₄ (60.02 mg, 1.587 mmol, 3 equiv) in portions at 0 degrees C under nitrogen atmosphere. The resulting mixture was stirred for 1 h at room temperature under nitrogen atmosphere. The residue/crude product was purified by reverse phase flash with the following conditions () to afford 3-bromo-7-[(dimethylamino)methyl]-2-(pyridin-4-yl)-5H,6H,7H-pyrazolo[1,5- a]pyrazin-4-one (90 mg, 48.60%) as a yellow solid. LCMS: [M-H]⁺ found: 350.

To a mixture of 3-bromo-7-[(dimethylamino)methyl]-2-(pyridin-4-yl)-5H,6H,7H- pyrazolo[1,5-a]pyrazin-4-one (90 mg, 0.257 mmol, 1.00 equiv) and 3-chloro-2- methoxyaniline (40.50 mg, 0.257 mmol, 1 equiv) in DMF (2 mL) were added Cs₂CO₃ (251.19 mg, 0.771 mmol, 3 equiv) and Ephos (13.74 mg, 0.026 mmol, 0.1 equiv) and Ephos Pd G4 (23.61 mg, 0.026 mmol, 0.1 equiv) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 1 h at 80 degrees C under nitrogen atmosphere. The crude product was purified by Pre-Chiral-HPLC with the following conditions: (Column: CHIRAL ART Amylose-SA, 2*25 cm, 5 μm; Mobile Phase A: Hex (0.5% 2M NH₃- MeOH)-HPLC, Mobile Phase B: EtOH-HPLC; Flow rate: 20 mL/min; Gradient: 20% B to 20% B in 12.5 min; Wave Length: 220/254 nm; RT1(min): 4.54; RT2(min): 5.66) to afford (7S)-3-[(3-chloro-2-methoxyphenyl)amino]-7-[(dimethylamino)methyl]-2-(pyridin-4-yl)- 5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (7.0 mg, 6.10%) as a white solid. LCMS: [M-H]⁺ found: 427. ¹H NMR (300 MHz, Chloroform-d) δ 8.57 (s, 2H), 7.68 (d, J = 5.2 Hz, 2H), 7.14 (s, 1H), 6.80 (dd, J = 8.1, 1.5 Hz, 1H), 6.64 (t, J = 8.1 Hz, 1H), 6.17 (dd, J = 8.1, 1.4 Hz, 1H), 5.86 (s, 1H), 4.64 (s, 1H), 4.05 (s, 3H), 3.98 (s, 2H), 2.94 (dd, J = 35.1, 22.1 Hz, 2H), 2.49 (s, 6H). Example 151. (7R)-3-[(3-chloro-2-methoxyphenyl)amino]-7-[(dimethylamino)methyl]- 2-(pyridin-4-yl)-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (compound 280)

To a stirred mixture of 3-bromo-7-[(dimethylamino)methyl]-2-(pyridin-4-yl)-5H,6H,7H- pyrazolo[1,5-a]pyrazin-4-one (90 mg, 0.257 mmol, 1.00 equiv) and 3-chloro-2- methoxyaniline (40.50 mg, 0.257 mmol, 1 equiv) in DMF (2 mL) were added Cs2CO₃ (251.19 mg, 0.771 mmol, 3 equiv) and Ephos (13.74 mg, 0.026 mmol, 0.1 equiv) and Ephos Pd G4 (23.61 mg, 0.026 mmol, 0.1 equiv) in portions at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 1 h at 80 degrees C under nitrogen atmosphere. The residue/crude product was purified by reverse phase flash with the following conditions (Column: CHIRAL ART Amylose-SA, 2*25 cm, 5 μm; Mobile Phase A: Hex (0.5% 2M NH₃-MeOH)--HPLC, Mobile Phase B: EtOH--HPLC; Flow rate: 20 mL/min; Gradient: 20% B to 20% B in 12.5 min; Wave Length: 220/254 nm; RT1(min): 4.54; RT2(min): 5.66) to afford (7R)-3-[(3-chloro-2-methoxyphenyl)amino]-7- [(dimethylamino)methyl]-2-(pyridin-4-yl)-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (8.6 mg) as a white solid. LCMS: [M-H]⁺ found: 427. ¹H NMR (300 MHz, Chloroform-d) δ 8.65 – 8.48 (m, 2H), 7.66 (d, J = 5.8 Hz, 2H), 7.15 (s, 1H), 6.79 (dd, J = 8.1, 1.4 Hz, 1H), 6.61 (t, J = 8.1 Hz, 1H), 6.12 (dd, J = 8.1, 1.4 Hz, 1H), 6.06 (s, 1H), 4.76 – 4.53 (m, 1H), 4.02 (s, 5H), 3.31 (s, 2H), 2.82 (s, 6H). Example 152. (R)-3-((3-fluoro-2-methoxyphenyl)amino)-2-(isothiazolo[4,5-b]pyridin-7- yl)-7-(trifluoromethyl)-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one (compound 288)

To a stirred mixture of methyl 5-bromo-2H-pyrazole-3-carboxylate (10 g, 48.778 mmol, 1.00 equiv) in MeCN (100 mL) were added NCS (6.51 g, 48.778 mmol, 1 equiv). The resulting mixture was stirred for 2h at 80 degree C. Desired product could be detected by LCMS. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with Petroleum ether / EtOAc (1:1) to afford methyl 5-bromo-4-chloro-2H-pyrazole-3-carboxylate as a white solid. LC-MS: M+H found: 239.0

To a stirred mixture of methyl 5-bromo-4-chloro-2H-pyrazole-3-carboxylate (11.4 g, 47.609 mmol, 1.00 equiv) in MeOH (100 mL) was added NaOH (20 mL, 500.036 mmol, 10.50 equiv) at room temperature. The resulting mixture was stirred for overnight at 60 degrees C. The resulting mixture was concentrated under vacuum. The residue was purified by reverse flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeOH in water, 10% to 50% gradient in 10 min; detector, UV 254 nm. This resulted in 5-bromo-4-chloro-2H-pyrazole-3-carboxylic acid as an off-white solid.

To a stirred mixture of 5-bromo-4-chloro-2H-pyrazole-3-carboxylic acid (10 g, 44.360 mmol, 1.00 equiv) and oxalyl chloride (11.26 g, 88.720 mmol, 2 equiv) in DCM (100 mL) was added DMF (2 mL, 25.844 mmol, 0.58 equiv) dropwise at room temperature. The resulting mixture was stirred for 0.6 h at room temperature. Desired product could be detected by LCMS.The resulting mixture was concentrated under vacuum. To the above mixture was added Et3N (13.47 g, 133.080 mmol, 3 equiv) and 1,1,1-trifluoro-3-{[(4- methoxyphenyl)methyl]amino}propan-2-ol (11.06 g, 44.360 mmol, 1 equiv) in DCM (100 mL) at room temperature. The resulting mixture was stirred for additional 2 h at room temperature. Desired product could be detected by LCMS. The resulting mixture was extracted with CH₂Cl₂ (3 x 150 mL). The combined organic layers were washed with brine (3x100 mL), dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with Petroleum ether / EtOAc (1:1) to afford 5-bromo-4-chloro- N-[(4-methoxyphenyl)methyl]-N-(3,3,3-trifluoro-2-hydroxypropyl)-2H-pyrazole-3- carboxamide as a yellow solid. LC-MS: M+H found: 456.00.

To a stirred mixture of 5-bromo-4-chloro-N-[(4-methoxyphenyl)methyl]-N-(3,3,3- trifluoro-2-hydroxypropyl)-2H-pyrazole-3-carboxamide (6 g, 13.139 mmol, 1.00 equiv) and Et3N (3.99 g, 39.417 mmol, 3 equiv) in DCM (100 mL) was added TsCl (5.01 g, 26.278 mmol, 2 equiv) in DCM(20 ml) dropwise at 0 degree C .The resulting mixture was stirred for 0.5 h at room temperature. Desired product could be detected by LCMS. The reaction was quenched by the addition of Water (300 mL) at room temperature. The aqueous layer was dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was dissolved in DMF (100 mL).To the above mixture was added K₂CO₃ (5.45 g, 39.417 mmol, 3 equiv) in portions at room temperature. The resulting mixture was stirred for additional 2 h at 100 degree C. Desired product could be detected by LCMS. The resulting mixture was diluted with water (100 mL). The resulting mixture was extracted with CH₂Cl₂ (3x100 mL). The combined organic layers were washed with brine (3x100 mL), dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with Petroleum ether / EtOAc (1:1) to afford 2-bromo-3-chloro-5-[(4-methoxyphenyl)methyl]-7-(trifluoromethyl)-6H,7H- pyrazolo[1,5-a]pyrazin-4-one as a yellow solid. LC-MS: M+H found: 438.00.

The 2-bromo-3-chloro-5-[(4-methoxyphenyl)methyl]-7-(trifluoromethyl)-6H,7H- pyrazolo[1,5-a]pyrazin-4-one (3.5 g) was dissolved in trifluoroacetaldehyde (20 mL).The resulting mixture was stirred for 3 h at 60°C. Desired product could be detected by LCMS. The resulting mixture was concentrated under reduced pressure. The mixture/residue was acidified/basified/neutralized to pH 7 with saturated NaHCO₃ (aq.). The resulting mixture was extracted with CH₂Cl₂ (3 x 50 mL). The combined organic layers were washed with brine (2 x 50 mL), dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with Petroleum ether/EtOAc to afford 2-bromo-3-chloro-7- (trifluoromethyl)-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one) as a yellow solid. LC-MS: M+H found: 318.00.

To a stirred mixture of 3-chloro-2-{[1,2]thiazolo[4,5-b]pyridin-7-yl}-7-(trifluoromethyl)- 5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (490 mg, 1.311 mmol, 1.00 equiv) and 3-fluoro- 2-methoxyaniline (222.06 mg, 1.573 mmol, 1.2 equiv) in dioxane (10 mL) were added Cs₂CO₃ (854.35 mg, 2.622 mmol, 2 equiv) and EPhos Pd G4 (120.43 mg, 0.131 mmol, 0.1 equiv) and EPhos (70.12 mg, 0.131 mmol, 0.1 equiv) in portions at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 2h at 60 degree C under nitrogen atmosphere. Desired product could be detected by LCMS. The resulting mixture was extracted with CH₂Cl₂ (3 x 20 mL). The combined organic layers were washed with brine (2x20 mL), dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The crude product (180 mg) was purified by Prep- HPLC with the following conditions(Column: Xselect CSH C18 OBD Column 30*150mm 5μm, n; Mobile Phase A: Water(0.1%FA), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 38% B to 63% B in 8 min, 63% B; Wave Length: 254/220 nm; RT1(min): 8) to afford 3-[(3-fluoro-2-methoxyphenyl)amino]-2-{[1,2]thiazolo[4,5- b]pyridin-7-yl}-7-(trifluoromethyl)-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one as a yellow solid. LC-MS: M+H found: 479.00.

The product was separated by Chiral-Sep (Column: CHIRALPAK IH, 2*25 cm, 5 μm; Mobile Phase A: Hex(0.5% 2M NH₃-MeOH)-HPLC, Mobile Phase B: EtOH-HPLC; Flow rate: 20 mL/min; Gradient: 50% B to 50% B in 22 min; Wave Length: 220/254 nm; RT1(min): 6.08; RT2(min): 16.38). Obtained (R)-3-((3-fluoro-2-methoxyphenyl)amino)- 2-(isothiazolo[4,5-b]pyridin-7-yl)-7-(trifluoromethyl)-6,7-dihydropyrazolo[1,5- a]pyrazin-4(5H)-one. LC-MS: M+H found: 479.00. ¹H NMR (400 MHz, Chloroform-d) δ 9.39 (s, 1H), 8.69 (d, J = 5.0 Hz, 1H), 7.65 (d, J = 5.1 Hz, 1H), 7.28 (s, 1H), 6.69 – 6.60 (m, 2H), 6.01 (t, J = 4.6 Hz, 1H), 5.89 (d, J = 4.6 Hz, 1H), 5.24 – 5.16 (m, 1H), 4.32 – 4.23 (m, 1H), 4.13 (m, J = 1.7 Hz, 4H). Example 153. (S)-3-((3-fluoro-2-methoxyphenyl)amino)-2-(isothiazolo[4,5-b]pyridin-7- yl)-7-(trifluoromethyl)-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one (compound 289)

To a stirred mixture of methyl 5-bromo-2H-pyrazole-3-carboxylate (10 g, 48.778 mmol, 1.00 equiv) in MeCN (100 mL) were added NCS (6.51 g, 48.778 mmol, 1 equiv). The resulting mixture was stirred for 2h at 80 degree C. Desired product could be detected by LCMS. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with Petroleum ether / EtOAc (1:1) to afford methyl 5-bromo-4-chloro-2H-pyrazole-3-carboxylate as a white solid. LC-MS: M+H found: 239.00

The 2-bromo-3-chloro-5-[(4-methoxyphenyl)methyl]-7-(trifluoromethyl)-6H,7H- pyrazolo[1,5-a]pyrazin-4-one (3.5 g) was dissolved in trifluoroacetaldehyde (20 mL).The resulting mixture was stirred for 3 h at 60°C .Desired product could be detected by LCMS. The resulting mixture was concentrated under reduced pressure. The mixture/residue was acidified/basified/neutralized to pH 7 with saturated NaHCO₃ (aq.). The resulting mixture was extracted with CH₂Cl₂ (3 x 50 mL). The combined organic layers were washed with brine (2x50 mL), dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with Petroleum ether / EtOAc to afford 2-bromo-3-chloro-7- (trifluoromethyl)-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one) as a yellow solid. LC-MS: M+H found: 318.00.

To a stirred mixture of 2-bromo-3-chloro-7-(trifluoromethyl)-5H,6H,7H-pyrazolo[1,5- a]pyrazin-4-one (1.7 g, 5.338 mmol, 1.00 equiv) and 7-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)isothiazolo[4,5-b]pyridine (1.44 g, 10.676 mmol, 2 equiv) in dioxane (10 mL) and H₂O (2 mL) were added Na₂CO₃ (1.13 g, 10.676 mmol, 2 equiv) and XPhos Pd G3 (0.90 g, 1.068 mmol, 0.2 equiv) in portions at room temperature under nitrogen atmosphere. The resulting mixture was stirred for overnight at 120°C under nitrogen atmosphere.The resulting mixture was extracted with CH₂Cl₂ (3 x30 mL). The combined organic layers were washed with brine (2x20 mL), dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure.The residue was purified by silica gel column chromatography, eluted with Petroleum ether/EtOAc (1:3) to afford 3-chloro-2-{[1,2]thiazolo[4,5-b]pyridin-7-yl}-7-(trifluoromethyl)-5H,6H,7H- pyrazolo[1,5-a]pyrazin-4-one as a yellow solid. LC-MS: M+H found: 374.00.

The product was separated by Chiral-Sep (Column: CHIRALPAK IH, 2*25 cm, 5 μm; Mobile Phase A: Hex(0.5% 2M NH3-MeOH)--HPLC, Mobile Phase B: EtOH-HPLC; Flow rate: 20 mL/min; Gradient: 50% B to 50% B in 22 min; Wave Length: 220/254 nm; RT1(min): 6.08; RT2(min): 16.38). Obtained (S)-3-((3-fluoro-2-methoxyphenyl)amino)- 2-(isothiazolo[4,5-b]pyridin-7-yl)-7-(trifluoromethyl)-6,7-dihydropyrazolo[1,5- a]pyrazin-4(5H)-one. LC-MS: M+H found: 479.00. ¹H NMR (400 MHz, Chloroform-d) δ 9.25 (s, 1H), 8.70 (d, J = 4.9 Hz, 1H), 7.60 (d, J = 4.8 Hz, 1H), 7.23 (s, 1H), 6.66 – 6.57 (m, 2H), 6.09 – 5.98 (m, 2H), 5.18 (m, J = 6.0 Hz, 1H), 4.25 (m, J = 14.2, 5.1 Hz, 1H), 4.17 – 4.03 (m, 4H). Example 154.3-((3-chloro-2-methoxyphenyl)amino)-2-(2-((1-methyl-1H-pyrazol-4- yl)amino)pyridin-4-yl)-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one (compound 291)

To a stirred solution of 3-chloro-2-(2-fluoropyridin-4-yl)-6,7-dihydropyrazolo[1,5- a]pyrazin-4(5H)-one (900.00 mg, 3.36 mmol, 1.00 equiv), 3-chloro-2-methoxyaniline (689 mg, 4.36 mmol, 1.3 equiv), and Cs₂CO₃ (2.18 g, 6.72 mmol, 2.00 equiv) in 1,4-dioxane (10.00 mL) were added EPhos (387 mg, 0.67 mmol, 0.20 equiv) and EPhos Pd G4 (300 mg, 0.33 mmol, 0.10 equiv) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 2 h at 50 °C under nitrogen atmosphere. The reaction was quenched with Water at room temperature. The resulting mixture was extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine (2 x 50 mL), dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (EtOAc /Petroleum ether 1:3) to afford 3-((3-chloro-2-methoxyphenyl)amino)-2-(2-fluoropyridin-4-yl)-6,7- dihydropyrazolo[1,5-a]pyrazin-4(5H)-one (400 mg, 31%) as a yellow solid. LC-MS: (M+H)⁺ found: 388.

To a stirred solution of 3-((3-chloro-2-methoxyphenyl)amino)-2-(2-fluoropyridin-4-yl)- 6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one (100.00 mg, 0.26 mmol, 1.00 equiv), 1- methyl-1H-pyrazol-4-amine (38 mg, 0.39 mmol, 1.5 equiv) in 1,4-dioxane(1.00 mL) was added 3N HCl (0.1 mL) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 2 h at 110 °C under nitrogen atmosphere. The reaction was quenched with Water at room temperature. The resulting mixture was extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine (2 x 50 mL), dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-HPLC (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water (10 mmol/L NH₄HCO₃), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 20% B to 50% B in 7 min, 50% B; Wave Length: 254/220 nm; RT1(min): 6.32) to afford 3-((3-chloro-2- methoxyphenyl)amino)-2-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyridin-4-yl)-6,7- dihydropyrazolo[1,5-a]pyrazin-4(5H)-one (20.7 mg, 17%) as a white solid. LC-MS: (M+H)⁺ found: 465. 1H NMR (400 MHz, DMSO-d6) δ 8.71 (s, 1H), 8.27 (s, 1H), 8.04 (d, J = 5.6 Hz, 1H), 7.78 (s, 1H), 7.29 (d, J = 8.8 Hz, 2H), 7.06 (s, 1H), 6.99 (d, J = 5.2 Hz, 1H), 6.78-6.74 (m, 2H), 6.17-6.15 (m, 1H), 4.38 (t, J = 6 Hz, 2H), 3.88 (s 3H), 3.76 (s, 3H), 3.65 (s, 2H). Example 155. rac-(6R)-3-[(3-chloro-2-methoxyphenyl)amino]-6-methyl-2- {[1,2]thiazolo[4,5-b]pyridin-7-yl}-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (compound 278)

To a stirred solution of methyl 5-bromo-2H-pyrazole-3-carboxylate (10 g, 48.778 mmol, 1.00 equiv), tert-butyl N-(1-hydroxypropan-2-yl)carbamate (10.26 g, 58.534 mmol, 1.2 equiv) and PPh3 (19.19 g, 73.167 mmol, 1.5 equiv) in THF (200 mL) was added DIAD (14.79 g, 73.167 mmol, 1.5 equiv) dropwise at 0 °C under nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (3 x 100 mL), dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with Petroleum ether/EtOAc (7:1) to afford methyl 5-bromo-2-{2-[(tert- butoxycarbonyl)amino]propyl}pyrazole-3-carboxylate (16 g, 90.56%) as a white solid. LC-MS: M+H found: 362.15.

To a stirred solution of methyl 5-bromo-2-{2-[(tert- butoxycarbonyl)amino]propyl}pyrazole-3-carboxylate (16 g, 44.172 mmol, 1.00 equiv) in DCM (120 mL) was added HCl (gas) in 1,4-dioxane (30 mL, 822.797 mmol, 18.63 equiv) dropwise at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 3 h at room temperature under nitrogen atmosphere. The reaction was monitored by LCMS. The precipitated solids were collected by filtration and washed with CH₂Cl₂ (3 x 20 mL). This resulted in methyl 2-(2-aminopropyl)-5-bromopyrazole-3-carboxylate (10.5 g, 90.69%) as a white solid. The crude product was used in the next step directly without further purification. LC-MS: (M+H)⁺ found: 262.2.

To a stirred solution of methyl 2-(2-aminopropyl)-5-bromopyrazole-3-carboxylate (10 g, 38.152 mmol, 1.00 equiv) in EtOH (20 mL) was added Et3N (11.58 g, 114.456 mmol, 3 equiv) dropwise at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 2 h at 80 °C under nitrogen atmosphere. The reaction was monitored by LCMS. The precipitated solids were collected by filtration and washed with EtOH (3 x 20 mL). This resulted in 2-bromo-6-methyl-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (8 g, 91.14%) as a white solid. The crude product was used in the next step directly without further purification. LC-MS: (M+H)⁺ found: 230.

A solution of 2-bromo-6-methyl-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (6 g, 26.080 mmol, 1.00 equiv) and NCS (3.48 g, 26.080 mmol, 1 equiv) in DMF (200 mL) was stirred for 3 h at 60 °C under nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was extracted with EtOAc (3 x 200 mL). The combined organic layers were washed with brine (3 x 200 mL), dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with Petroleum ether/EtOAc (5:1) to afford 2-bromo-3- chloro-6-methyl-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (6.5 g, 94.23%) as a white solid. LC-MS: (M+H)⁺ found: 264.0.

To a stirred solution of 2-bromo-3-chloro-6-methyl-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4- one (400 mg, 1.512 mmol, 1 equiv) and 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)- [1,2]thiazolo[4,5-b]pyridine (594.60 mg, 2.268 mmol, 1.5 equiv) in were added Na₂CO₃ (320.56 mg, 3.024 mmol, 2 equiv) and 2nd Generation XPhos Precatalyst (237.96 mg, 0.302 mmol, 0.2 equiv) in portions at room temperature under nitrogen atmosphere. The resulting mixture was stirred for overnight at 80 °C under nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was extracted with EtOAc (3 x20 mL). The combined organic layers were washed with brine (2x20 mL), dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse flash chromatography with the following conditions: column, silica gel; mobile phase, MeCN in water, 10% to 50% gradient in 10 min; detector, UV 254 nm. This resulted in 3-chloro-6-methyl-2-{[1,2]thiazolo[4,5-b]pyridin-7-yl}- 5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (280 mg, 57.90%) as a light yellow solid. LC-MS: (M+H)⁺ found: 264.0.

To a stirred solution of 3-chloro-6-methyl-2-{[1,2]thiazolo[4,5-b]pyridin-7-yl}- 5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (130 mg, 0.407 mmol, 1.00 equiv), 3-chloro-2- methoxyaniline (76.89 mg, 0.488 mmol, 1.2 equiv) and Cs₂CO₃ (264.92 mg, 0.814 mmol, 2 equiv) in dioxane (5 mL) were added EPhos Pd G4 (37.34 mg, 0.041 mmol, 0.1 equiv) and EPhos (43.48 mg, 0.081 mmol, 0.2 equiv) in portions at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 3 h at 100 °C under nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine (2x20 mL), dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The crude product (20mg) was purified by Prep-HPLC with the following conditions (Column: XBridge Prep C18 OBD Column, 30*100 mm, 5μm; Mobile Phase A: Water (10 mmol/L NH₄HCO₃+0.1%NH₃*H₂O), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 33% B to 55% B in 9 min, 55% B; Wave Length: 254/220 nm; RT1(min): 8.85) and Prep-Chiral-HPLC with the following conditions(Column: (R, R)- WHELK-O1-Kromasil, 2.11*25 cm, 5 μm; Mobile Phase A: Hex(0.5% 2M NH₃-MeOH)- HPLC, Mobile Phase B: EtOH--HPLC; Flow rate: 20 mL/min; Gradient: 50% B to 50% B in 38 min; Wave Length: 220/254 nm; RT1(min): 27.906; RT2(min): 32.398) to afford rac- (6R)-3-[(3-chloro-2-methoxyphenyl)amino]-6-methyl-2-{[1,2]thiazolo[4,5-b]pyridin-7- yl}-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (0.8 mg, 0.45%) as a white solid. LC-MS: (M+H)⁺ found: 441.20. ¹H NMR (300 MHz, Chloroform-d) δ 9.19 (s, 1H), 8.67 (d, J = 4.8 Hz, 1H), 7.52 (d, J = 4.8 Hz, 1H), 7.15 (s, 1H), 6.85 (d, J = 8.1 Hz, 1H), 6.66 (t, J = 8.1 Hz, 1H), 6.16 (d, J = 8.1 Hz, 1H), 5.83 (s, 1H), 4.63 (d, J = 9.1 Hz, 1H), 4.21 (d, J = 9.7 Hz, 2H), 4.09 (s, 3H), 1.50 (d, J = 5.5 Hz, 3H). Example 156. rac-(6R)-3-[(3-chloro-2-methoxyphenyl)amino]-6-methyl-2- {[1,2]thiazolo[4,5-b]pyridin-7-yl}-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (compound 277)

To a stirred solution of methyl 5-bromo-2H-pyrazole-3-carboxylate (10 g, 48.778 mmol, 1.00 equiv), tert-butyl N-(1-hydroxypropan-2-yl)carbamate (10.26 g, 58.534 mmol, 1.2 equiv) and PPh3 (19.19 g, 73.167 mmol, 1.5 equiv) in THF (200 mL) was added DIAD (14.79 g, 73.167 mmol, 1.5 equiv) dropwise at 0 °C under nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (3 x 100 mL), dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with Petroleum ether / EtOAc (7:1) to afford methyl 5-bromo-2-{2-[(tert- butoxycarbonyl)amino]propyl}pyrazole-3-carboxylate (16 g, 90.56%) as a white solid. LC-MS: M+H found: 362.15.

To a stirred solution of 2-bromo-3-chloro-6-methyl-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4- one (400 mg, 1.512 mmol, 1 equiv) and 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)- [1,2]thiazolo[4,5-b]pyridine (594.60 mg, 2.268 mmol, 1.5 equiv) in 1,4-dioxane(5 mL) were added Na₂CO₃ (320.56 mg, 3.024 mmol, 2 equiv) and 2nd Generation XPhos Precatalyst (237.96 mg, 0.302 mmol, 0.2 equiv) in portions at room temperature under nitrogen atmosphere. The resulting mixture was stirred for overnight at 80 °C under nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was extracted with EtOAc (3 x20 mL). The combined organic layers were washed with brine (2x20 mL), dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse flash chromatography with the following conditions: column, silica gel; mobile phase, MeCN in water, 10% to 50% gradient in 10 min; detector, UV 254 nm. This resulted in 3-chloro-6-methyl-2- {[1,2]thiazolo[4,5-b]pyridin-7-yl}-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (280 mg, 57.90%) as a light yellow solid. LC-MS: (M+H)⁺ found: 320.

To a stirred solution of 3-chloro-6-methyl-2-{[1,2]thiazolo[4,5-b]pyridin-7-yl}- 5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (130 mg, 0.407 mmol, 1.00 equiv), 3-chloro-2- methoxyaniline (76.89 mg, 0.488 mmol, 1.2 equiv) and Cs₂CO₃ (264.92 mg, 0.814 mmol, 2 equiv) in dioxane (5 mL) were added EPhos Pd G4 (37.34 mg, 0.041 mmol, 0.1 equiv) and EPhos (43.48 mg, 0.081 mmol, 0.2 equiv) in portions at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 3 h at 100 °C under nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was extracted with EtOAc (3 x 20mL). The combined organic layers were washed with brine (2x20 mL), dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The crude product (20 mg) was purified by Prep-HPLC with the following conditions (Column: XBridge Prep C18 OBD Column, 30*100 mm, 5μm; Mobile Phase A: Water(10 mmol/L NH₄HCO₃+0.1%NH₃.H₂O), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 33% B to 55% B in 9 min, 55% B; Wave Length: 254/220 nm; RT1(min): 8.85) and Prep-Chiral-HPLC with the following conditions(Column: (R, R)- WHELK-O1-Kromasil, 2.11*25 cm, 5 μm; Mobile Phase A: Hex(0.5% 2M NH3-MeOH)- -HPLC, Mobile Phase B: EtOH--HPLC; Flow rate: 20 mL/min; Gradient: 50% B to 50% B in 38 min; Wave Length: 220/254 nm; RT1(min): 27.906; RT2(min): 32.398) to afford rac-(6R)-3-[(3-chloro-2-methoxyphenyl)amino]-6-methyl-2-{[1,2]thiazolo[4,5-b]pyridin- 7-yl}-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (6.4 mg, 3.57%) as a white solid. LC-MS: (M+H)⁺ found: 441.20. ¹H NMR (300 MHz, Chloroform-d) δ 9.19 (s, 1H), 8.67 (d, J = 4.8 Hz, 1H), 7.52 (d, J = 4.8 Hz, 1H), 7.15 (s, 1H), 6.89 – 6.80 (m, 1H), 6.66 (t, J = 8.1 Hz, 1H), 6.21 – 6.12 (m, 1H), 5.88 (s, 1H), 4.63 (d, J = 9.1 Hz, 1H), 4.26 – 4.17 (m, 2H), 4.09 (s, 3H), 1.49 (d, J = 5.7 Hz, 3H). Example 157.3-[(3-chloro-2-methoxyphenyl)amino]-2-(pyridin-4-yl)-5H,6H,7H- pyrazolo[1,5-a]pyrazin-4-one (compound 344)

A mixture of 2-bromo-3-chloro-5H,6H,7H-pyrazolo[1,5-a] pyrazin-4-one (500.00 mg, 1.996 mmol, 1.00 equiv), pyridin-4-ylboronic acid (368.05 mg, 2.994 mmol, 1.50 equiv), Pd(dppf)Cl₂ (146.06 mg, 0.200 mmol, 0.10 equiv) and K₂CO₃ (827.64 mg, 5.988 mmol, 3.00 equiv) in 1,4-dioxane (10.00 mL) and water (1.00 mL) was stirred for overnight at 70 degrees C under nitrogen atmosphere. The resulting mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH₂Cl₂ / MeOH (40:1) to afford 3-chloro-2-(pyridin-4-yl)-5H,6H,7H-pyrazolo[1,5-a] pyrazin-4-one (200 mg, 40.29%) as a yellow solid. LC-MS: M+H found: 249.

A mixture of 3-chloro-2-(pyridin-4-yl)-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (100.00 mg, 0.402 mmol, 1.00 equiv), 3-chloro-2-methoxyaniline (95.07 mg, 0.603 mmol, 1.50 equiv), EPhos Pd G4 (36.94 mg, 0.040 mmol, 0.10 equiv), EPhos (21.51 mg, 0.040 mmol, 0.10 equiv) and K₂CO₃ (166.73 mg, 1.206 mmol, 3.00 equiv) in 1,4-dioxane (1.00 mL) and Toluene (1.00 mL) was stirred for overnight at 60 degrees C under nitrogen atmosphere. The resulting mixture was diluted with water. The resulting mixture was extracted with EtOAc. The combined organic layers were washed with brine , dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The crude product (120 mg) was purified by Prep-HPLC with the following conditions (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5μm; Mobile Phase A: Water (10 mmol/L NH₄HCO₃+0.1%NH_3.H₂O), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 26% B to 56% B in 8 min, 56% B; Wave Length: 254; 220 nm; RT1(min): 6.58) to afford 3-[(3-chloro-2-methoxyphenyl)amino]-2-(pyridin-4-yl)-5H,6H,7H- pyrazolo[1,5-a]pyrazin-4-one(35.6mg,23.87%) as a white solid. LC-MS: (M+H)⁺ found: 370. ¹H NMR (300 MHz, Chloroform-d) δ 8.57 (s, 2H), 7.69 (d, J = 5.1 Hz, 2H), 7.08 (s, 1H), 6.80 (dd, J = 8.1, 1.5 Hz, 1H), 6.73 – 6.50 (m, 2H), 6.19 (dd, J = 8.1, 1.5 Hz, 1H), 4.46 (dd, J = 7.1, 5.0 Hz, 2H), 4.05 (s, 3H), 3.94 – 3.75 (m, 2H). Example 158.3-[(3-chloro-2-methoxyphenyl) amino]-2-{1H-pyrrolo[3,2-b] pyridin-7- yl}-5H,6H,7H-pyrazolo[1,5-a] pyrazin-4-one (compound 346)

A mixture of tert-butyl 7-bromopyrrolo[3,2-b]pyridine-1-carboxylate (700 mg, 2.356 mmol, 1.00 equiv), 3-chloro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5H,6H,7H- pyrazolo[1,5-a]pyrazin-4-one (841.13 mg, 2.827 mmol, 1.2 equiv), Pd(DtBPF)Cl₂ (153.53 mg, 0.236 mmol, 0.1 equiv) and K₂CO₃ (976.71 mg, 7.068 mmol, 3 equiv) in 1,4- dioxane (15 mL, 170.251 mmol) was stirred for 4 h at 70 °C under nitrogen atmosphere. The resulting mixture was extracted with CH₂Cl₂. The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in water, 10% to 50% gradient in 20 min; detector, UV 254 nm. This resulted in tert-butyl 7-{3-chloro-4-oxo-5H,6H,7H-pyrazolo[1,5-a]pyrazin-2-yl}pyrrolo[3,2- b]pyridine-1-carboxylate (500 mg, 54.73%) as a white solid. LC-MS: (M+H)⁺ found: 388.

A mixture of tert-butyl 7-{3-chloro-4-oxo-5H,6H,7H-pyrazolo[1,5-a] pyrazin-2- yl}pyrrolo [3,2-b]pyridine-1-carboxylate (200 mg, 0.516 mmol, 1.00 equiv) , EPhos Pd G4 (47.37 mg, 0.052 mmol, 0.1 equiv)and Cs₂CO₃ (504.08 mg, 1.548 mmol, 3 equiv) in 1,4-dioxane (4 mL) was stirred for overnight at 70 °C under nitrogen atmosphere. The resulting mixture was extracted with CH₂Cl₂. The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH₂Cl₂ / MeOH (50:1) to afford tert-butyl 7-{3-[(3-chloro-2-methoxyphenyl) amino]-4-oxo-5H,6H,7H-pyrazolo[1,5-a] pyrazin-2-yl} pyrrolo [3,2-b] pyridine-1- carboxylate (35 mg, 13.33%) as a white solid. LC-MS: (M+H)⁺ found: 509.

A mixture of tert-butyl 7-{3-[(3-chloro-2-methoxyphenyl) amino]-4-oxo-5H,6H,7H- pyrazolo[1,5-a] pyrazin-2-yl} pyrrolo [3,2-b] pyridine-1-carboxylate (50 mg, 0.098 mmol, 1.00 equiv) and TFA (56.01 mg, 0.490 mmol, 5 equiv) in DCM (1 mL, 15.730 mmol) was stirred for overnight at room temperature under nitrogen atmosphere. The resulting mixture was diluted with water. The resulting mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄. The residue was purified by reverse flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeOH in water, 10% to 50% gradient in 10 min; detector, UV 254 nm. This resulted in 3-[(3-chloro-2-methoxyphenyl) amino]- 2-{1H-pyrrolo[3,2-b] pyridin-7-yl}-5H,6H,7H-pyrazolo[1,5-a] pyrazin-4-one (37 mg, 92.12%) as a yellow solid. LC-MS: (M+H)⁺ found: 409. ¹H NMR (300 MHz, DMSO-d6) δ 11.23 (s, 1H), 8.36 (d, J = 3.1 Hz, 1H), 8.26 (d, J = 5.1 Hz, 1H), 7.70 (t, J = 3.1 Hz, 1H), 7.42 – 7.33 (m, 2H), 6.77 – 6.65 (m, 2H), 6.65 – 6.58 (m, 1H), 6.16 (dd, J = 6.8, 2.9 Hz, 1H), 4.51 (t, J = 5.7 Hz, 2H), 3.91 (s, 3H), 3.72 (s, 2H). Example 159.3-[(3-chloro-2-methoxyphenyl)amino]-2-(1,6-naphthyridin-4-yl)- 5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (compound 347)

3-chloro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5H,6H,7H-pyrazolo[1,5- a]pyrazin-4-one (200 mg) was dissolved in 1,4-dioxane(5 mL) and H2O (1 mL), 4-chloro- 7-methoxy-1,6-naphthyridine (156.98 mg), Cs₂CO₃(438 mg), PCy3(37.7 mg) and Pd₂(dba)₃ (123.1 mg) was added, the reaction was stirred for 12 hours, the reaction was stirred for 12 hours under N₂ atmosphere.The resulting mixture was concentrated under reduced pressure.The crude product (260 mg) was purified by Prep-HPLC with the following conditions (Column: Xselect CSH OBD Column 30*150mm 5um; Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 30% B to 45% B in 8 min, 45% B; Wave Length: 254/220 nm; RT1(min): 7.10) to afford 3- chloro-2-(1,6-naphthyridin-4-yl)-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (116.1 mg, 48.50%) as a light yellow solid. LC-MS: M+H found: 300.

3-chloro-2-(1,6-naphthyridin-4-yl)-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one(100 mg) was dissolved in DMF(5 mL), 3-chloro-2-methoxyaniline(105 mg), Cs₂CO₃(326 mg), EPhos Pd G4(306 mg) and EPhos (89 mg) was added, the reaction was stirred for 4 hours under N₂ atmosphere.The resulting mixture was concentrated under reduced pressure.The crude product (100 mg) was purified by Prep-HPLC with the following conditions (Column: XBridge Shield RP18 OBD Column, 30*150 mm, 5μm; Mobile Phase A: Water (10 mmol/L NH₄HCO₃+0.1%NH₃*H₂O), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 17% B to 50% B in 7 min, 50% B; Wave Length: 254/220 nm; RT1(min): 6.18) to afford 3-[(3-chloro-2-methoxyphenyl)amino]-2-(1,6-naphthyridin-4-yl)-5H,6H,7H- pyrazolo[1,5-a]pyrazin-4-one (24.7 mg, 17.50%) as a light yellow solid. LC-MS: M+H found: 421. ¹H NMR (300 MHz, DMSO-d6) δ 9.82 (s, 1H), 9.08 (d, J = 4.6 Hz, 1H), 8.73 (d, J = 5.8 Hz, 1H), 8.37 (s, 1H), 7.91 (d, J = 6.0 Hz, 1H), 7.73 (d, J = 4.6 Hz, 1H), 7.46 (s, 1H), 6.57 (dt, J = 15.8, 7.7 Hz, 2H), 6.17 (d, J = 7.8 Hz, 1H), 4.52 (s, 2H), 3.75 (s, 2H), 3.68 (s, 3H). Example 160.3-[(3-chloro-2-methoxyphenyl)amino]-2-(7-methoxy-1,6-naphthyridin-4- yl)-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (compound 348)

3-Chloro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5H,6H,7H-pyrazolo[1,5- a]pyrazin-4-one (200 mg) was dissolved in 1,4-dioxane (5 mL) and H₂O (1 mL), 4-chloro- 7-methoxy-1,6-naphthyridine (156.98 mg), Cs₂CO₃(438 mg), PCy₃(37.7 mg) and Pd₂(dba)₃ (123.1 mg) was added. The reaction was stirred for 12 hours under N₂ atmosphere. The resulting mixture was concentrated under reduced pressure. The crude product (260 mg) was purified by Prep-HPLC with the following conditions (Column: Xselect CSH OBD Column 30*150mm 5um, n; Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 30% B to 45% B in 8 min, 45% B; Wave Length: 254/220 nm; RT1(min): 7.10) to afford 3-chloro-2-(7-methoxy-1,6- naphthyridin-4-yl)-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (102.1 mg, 45.50%) as a light yellow solid. LC-MS: M+H found: 330.

3-Chloro-2-(7-methoxy-1,6-naphthyridin-4-yl)-5H,6H,7H-pyrazolo[1,5-a]pyrazin-4- one(100 mg) was dissolved in DMF (10 mL), and 3-chloro-2-methoxyaniline (96 mg), Cs₂CO₃ (296 mg), EPhos Pd G4(139 mg) and EPhos (81 mg) was added. The reaction mixture was stirred for 12 hours under N₂ atmosphere. The resulting mixture was concentrated under reduced pressure. The crude product (100 mg) was purified by Prep- HPLC with the following conditions (Column: Xselect CSH OBD Column 30*150mm 5um; Mobile Phase A: Water (0.1% FA), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 30% B to 45% B in 8 min, 45% B; Wave Length: 254/220 nm; RT1(min): 7.10) to afford 3-[(3-chloro-2-methoxyphenyl)amino]-2-(7-methoxy-1,6-naphthyridin-4-yl)- 5H,6H,7H-pyrazolo[1,5-a]pyrazin-4-one (46.1 mg, 17.50%) as a light yellow solid. LC-MS: M+H found: 451. ¹H NMR (300 MHz, DMSO-d6) δ 9.60 (s, 1H), 8.95 (d, J = 4.5 Hz, 1H), 8.37 (s, 1H), 7.54 – 7.42 (m, 2H), 7.22 (s, 1H), 6.67 – 6.50 (m, 2H), 6.16 (dd, J = 7.9, 1.7 Hz, 1H), 4.50 (t, J = 5.9 Hz, 2H), 3.99 (s, 3H), 3.78 (s, 3H), 3.99 (s, 2H). Bioactivity EXAMPLE A. Inhibitor activity on EGFR-dependent cell growth Cell lines are generated by transducing Ba/F3 cells with retroviruses containing vectors with EGFR WT, EGFR L858R, EGFR exon 19del, EGFR L858R/C797S, EGFR exon 20 NPG Ins D770_N771, EGFR exon 20 ASV Ins V769_D770, EGFR exon 20 SVD Ins D770_N771, or EGFR exon 20 FQEA Ins A763_V764 genes and a puromycin selection marker. Transduced cells are selected with puromycin for 7 days and are then be transferred into culture media without Interleukin 3 (IL3). EGFR WT cells are maintained with supplemental EGF. Surviving cells are confirmed to express EGFR by Western blot and maintained as a pool. Study Design 1 Cell seeding 1.1 Cells are harvested from flask into cell culture medium and the cell number counted. 1.2 Cells are diluted with culture medium to the desired density and 40 μL of cell suspension is added into each well of 384-well cell culture plate and the seeding density is 800 (FQEA, exon 19del), 600 (WT, NPG, L858R/C797S), or 400 (ASV, SVD, L858R) cells/well. 2 Compound preparation and treatment 2.1 Test compounds are dissolved to 10 mM in a DMSO stock solution.45 μL of stock solution is transferred to a 384 polypropylene plate (pp-plate). Perform 3-fold, 10-point dilution via transferring 15 μL compound into 30 μL DMSO using a TECAN (EVO200) liquid handler. 2.2 Spin plates at room temperature at 1,000 RPM for 1 minute. 2.3 Transfer 120 nL of diluted compound from compound source plate into the cell plate. 2.4 After compound treatment for 72 hours, perform CTG detection for compound treatment plates as described in "Detection" section. 3 Detection 3.1 Plates are removed from incubators and equilibrated at room temperature for 15 minutes. 3.2 Thaw the CellTiter Glo reagents and allow to equilibrate to room temperature before the experiment. 3.3 Add 40 μL of CellTiter-Glo reagent into each well (at 1:1 to culture medium). Then place the plates at room temperature for 30 min followed by reading on EnVision. 4 Data analysis 4.1 Inhibition activity is calculated following the formula below: %Inhibition = 100 x (LumHC – LumSample) / (LumHC –LumLC) where HC is obtained from cells treated with 0.1% DMSO only; and LC is obtained from culture medium only. 4.22. Calculate the IC₅₀ by fitting the Curve using Xlfit (v5.3.1.3), equation 201: Y = Bottom + (Top - Bottom)/(1 + 10^((LogIC₅₀ - X)*HillSlope)) The IC50 date are included in Table 6 and Table 7. EXAMPLE B. Inhibitor Activity on EGFR phosphorylation (pEGFR) EGFR mutant Ba/F3 cells were generated by transduction with retrovirus containing vectors expressing EGFR L858R, EGFR exon 19del, EGFR L858R/C797S, EGFR exon 20 NPG Ins D770_N771, EGFR exon 20 ASV Ins V769_D770, or EGFR exon 20 SVD Ins D770_N771 genes along with a puromycin selection marker. Transduced cells are selected with puromycin for 7 days and are then be transferred into culture media without Interleukin 3 (IL3). Surviving cells are confirmed to express EGFR by Western blot and maintained as a pool. CUTO14 cells were obtained from Dr. Robert C. Doebele at the University of Colorado. The IC50 date are included in Table 6 and Table 7. Study Design 1 Cell seeding 1.1 Cells are harvested from flask into cell culture medium and the cell number counted. 1.2 Cells are diluted with culture medium to the desired density and 40 μL of cell suspension is added into each well of 384-well cell culture plate and the seeding density is 50K cells/well (Ba/F3) or 12.5K cells/well (CUTO14). 2 Compound preparation and treatment 2.1 Test compounds are dissolved to 10 mM in a DMSO stock solution.45 μL of stock solution is transferred to a 384 polypropylene plate (pp-plate). Perform 3-fold, 10-point dilution via transferring 15 μL compound into 30 μL DMSO using a TECAN (EVO200) liquid handler. 2.2 Spin plates at room temperature at 1,000 RPM for 1 minute. 2.3 Transfer 5 nL of diluted compound from compound source plate into the cell plate. 2.4 After compound treatment for 2 hours, perform pEGFR detection by AlphaLISA for compound treatment plates as described in "Detection" section. 3 Detection by pEGFR AlphaLISA (Perkin-Elmer) 3.1 Plates are removed from incubators and equilibrated at room temperature for 10 minutes, and media was removed 3.210 μL of lysis buffer is added and plates shaken at 600 rpm for 1 hr. 3.3 Prepare acceptor mix just before use and dispense 5 μL of acceptor mix to all the wells. Shake 350 rpm for 1hr in the dark 3.4 Prepare donor mix under low light conditions prior to use. Dispense 5 μL of donor mix to all the wells. Mix well on the shaker, seal and wrap in aluminum foil and incubate 1.5 hrs at room temperature in the dark 3.5 Transfer 18.5 μL mixture to OptiPlate 384, and read using an Envision. The IC50 date are included in Table 6 and Table 7. Table 6. IC50 Data for EGFR Activity and Inhibitor Activity on EGFR phosphorylation (pEGFR)¹

1 “+++” indicates that IC50 < 100 nM; “++” indicates that 100 nM <= IC50 < 1000 nM; “+” indicates that IC50 >= 1000 nM. “NA” indicates that the IC50 data is not available for this compound; Table 7. IC50 Data for EGFR Activity and Inhibitor Activity on EGFR phosphorylation (pEGFR) - continued¹

1 “+++” indicates that IC50 < 100 nM; “++” indicates that 100 nM <= IC50 < 1000 nM; “+” indicates that IC50 >= 1000 nM. “NA” indicates that the IC50 data is not available for this compound;

Claims

WHAT IS CLAIMED IS: 1. A compound of Formula (I):

• -C(=O)O-*, -C(=O)N(R^N)-*, or –S(O)_1-2N(R^N)-*; • -OC(=O)-*, -N(R^N)C(=O)-*, or –N(R^N)S(O)_1-2-*; and • -OC(=O)N(R^N)-*, -N(R^N)C(=O)O-*, -N(R^N)C(=O)N(R^N)-*, or – N(R^N)S(O)_1-2N(R^N)-*, wherein the asterisk represents point of attachment to L¹; L¹ is selected from the group consisting of: a bond and C_1-10 alkylene optionally substituted with from 1-6 R^a; R⁵ is selected from the group consisting of: • H; • halo; • -OH; • -NR^eR^f; • -C_1-6 alkoxy or -S(O)_0-2(C_1-6 alkyl), each optionally substituted with from 1-6 R^a; • -R^g; • -L⁵-R^g; • -R^g2-R^W or -R^g2-R^Y; • -L⁵-R^g2-R^W or –L⁵-R^g2-R^Y; and • -R^W provided that: when L¹ is a bond, then R⁵ is selected from the group consisting of: H, -R^g, -R^g2- R^W, and -R^g2-R^Y; and X¹ is other than H, -OH, or NH₂; L⁵ is selected from the group consisting of: –O-, -S(O)_0-2, -NH, and -N(R^d)-; R^W is –L^W-W, wherein L^W is C(=O), S(O)_1-2, OC(=O)*, NHC(=O)*, NR^dC(=O)*, NHS(O)_1-2*, or NR^dS(O)_1-2*, wherein the asterisk represents point of attachment to W, and W is selected from the group consisting of: • C_2-6 alkenyl; C_2-6 alkynyl; or C_3-10 allenyl, each of which is optionally substituted with from 1-3 R^a and further optionally substituted with R^g, wherein W is attached to L^W via an sp² or sp hybridized carbon atom, thereby providing an α, β- unsaturated system; and • bicyclo[x.y.0]cycloalkyl which is optionally substituted with from 1-2 R^c, wherein x is 1 or 2; and y is an integer from 1 to 6; R^Y is selected from the group consisting of: -R^g and -(L^g)_g-R^g; each of R^1c, R^2a, R^2b, R^3a, and R^3b is independently selected from the group consisting of: H; halo; -OH; -C(O)OH or –C(O)NH₂; -CN; -R^b; -L^b-R^b; -C_1-6 alkoxy or - C_1-6 thioalkoxy, each optionally substituted with from 1-6 R^a; -NR^eR^f; -R^g; and -(L^g)g-R^g; provided that R^1c is other than halo, –CN, or –C(O)OH; or two of variables R^1c, R^2a, R^2b, R^3a, and R^3b, together with the Ring B ring atoms to which each is attached, form a fused saturated or unsaturated ring of 3-12 ring atoms; • wherein from 0-2 of the ring atoms are each an independently selected heteroatom (in addition to –N(R^1c)- when –N(R^1c)- forms part of the fused saturated or unsaturated ring), wherein each of the independently selected heteroatoms is selected from the group consisting of N, NH, N(R^d), O, and S(O)_0-2; and • wherein the fused saturated or unsaturated ring of 3-12 ring atoms is optionally substituted with from 1-4 substituents independently selected from the group consisting of oxo, R^c, and R^W; or one of R^2a and R^2b and one of R^3a and R^3b combine to form a double bond between the Ring B atoms to which each is attached; Ring A is R^g; each occurrence of R^a is independently selected from the group consisting of: – OH; -halo; –NR^eR^f; C_1-4 alkoxy; C_1-4 haloalkoxy; -C(=O)O(C_1-4 alkyl); -C(=O)(C_1-4 alkyl); -C(=O)OH; -CONR’R’’; -S(O)_1-2NR’R’’; -S(O)_1-2(C_1-4 alkyl); and cyano; each occurrence of R^b is independently C_1-6 alkyl, C_2-6 alkenyl, or C_2-6 alkynyl, each of which is optionally substituted with from 1-6 R^a; each occurrence of L^b is independently C(=O); C(=O)O; S(O)_1-2; C(=O)NH*; C(=O)NR^d*; S(O)_1-2NH*; or S(O)_1-2N(R^d)*, wherein the asterisk represents point of attachment to R^b; each occurrence of R^c is independently selected from the group consisting of: halo; cyano; C_1-10 alkyl which is optionally substituted with from 1-6 independently selected R^a; C_2-6 alkenyl; C_2-6 alkynyl; C_1-4 alkoxy optionally substituted with C_1-4 alkoxy or C_1-4 haloalkoxy; C_1-4 haloalkoxy; -S(O)_1-2(C_1-4 alkyl); -S(O)(=NH)(C_1-4 alkyl); -NR^eR^f; –OH; -S(O)_1-2NR’R’’; -C_1-4 thioalkoxy; -NO2; -C(=O)(C_1-10 alkyl); -C(=O)O(C_1-4 alkyl); - C(=O)OH; -C(=O)NR’R’’; and –SF₅; each occurrence of R^d is independently selected from the group consisting of: C_1-6 alkyl optionally substituted with from 1-3 independently selected R^a; -C(O)(C_1-4 alkyl); - C(O)O(C_1-4 alkyl); -CONR’R’’; -S(O)_1-2NR’R’’; -S(O)_1-2(C_1-4 alkyl); -OH; and C_1-4 alkoxy; each occurrence of R^e and R^f is independently selected from the group consisting of: H; C_1-6 alkyl optionally substituted with from 1-3 substituents each independently selected from the group consisting of NR’R’’, -OH, C_1-6 alkoxy, C_1-6 haloalkoxy, and halo; -C(O)(C_1-4 alkyl); -C(O)O(C_1-4 alkyl); -CONR’R’’; -S(O)_1-2NR’R’’; -S(O)_1-2(C_1-4 alkyl); -OH; and C_1-4 alkoxy; each occurrence of R^g is independently selected from the group consisting of: • C_3-10 cycloalkyl or C_3-10 cycloalkenyl, each of which is optionally substituted with from 1-4 substituents independently selected from the group consisting of oxo and R^c; • heterocyclyl or heterocycloalkenyl including from 3-10 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R^d), O, and S(O)_0-2, and wherein the heterocyclyl or heterocycloalkenyl is optionally substituted with from 1-4 substituents independently selected from the group consisting of oxo and R^c; • heteroaryl including from 5-10 ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R^d), O, and S(O)_0-2, and wherein the heteroaryl is optionally substituted with from 1-4 R^c; and • C_6-10 aryl optionally substituted with from 1-4 R^c; each occurrence of L^g is independently selected from the group consisting of: -O-, -NH-, -NR^d , -S(O)_0-2, C(O), and C_1-3 alkylene optionally substituted with from 1-3 R^a; each g is independently 1, 2, or 3; each R^g2 is a divalent R^g group; each occurrence of R’ and R’’ is independently selected from the group consisting of: H; -OH; and C_1-4 alkyl; and each occurrence of R^N is independently H, C_1-3 alkyl, or C_3-6 cycloalkyl.

2. The compound of claim 1, wherein Ring C is selected from the group consisting of: • heteroaryl including from 5-10 ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R^d), O, and S(O)_0-2, and wherein the heteroaryl is optionally substituted with X¹ and further optionally substituted with from 1-4 R^c; and • C_6-10 aryl optionally substituted with X¹ and further optionally substituted with from 1-4 R^c.

3. The compound of claims 1 or 2, wherein Ring C is heteroaryl including from 5-10 ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R^d), O, and S(O)_0-2, and wherein the heteroaryl is substituted with X¹ and further optionally substituted with from 1-4 R^c.

4. The compound of any one of claims 1-3, wherein Ring C is monocyclic heteroaryl including from 5-6 ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R^d), O, and S(O)_0-2, and wherein the heteroaryl is substituted with X¹ and further optionally substituted with from 1-3 R^c.

5. The compound of any one of claims 1-4, wherein Ring C is monocyclic heteroaryl including from 6 ring atoms, wherein from 1-4 ring atoms are heteroatoms each independently selected from the group consisting of N, N(H), and N(R^d), and wherein the heteroaryl is substituted with X¹ and further optionally substituted with from 1-3 R^c.

6. The compound of any one of claims 1-5, wherein Ring C is pyridyl or pyrimidyl, each of which is substituted with X¹ and further optionally substituted with from 1-3 R^c.

7. The compound of any one of claims 1-6, wherein Ring C is

wherein n is 0, 1, or 2.

8. The compound of any one of claims 1-6, wherein Ring C is

, wherein n is 0, 1, or 2.

9. The compound of any one of claims 1-6, wherein Ring C is

wherein n is 0, 1, or 2.

10. The compound of any one of claims 1-3, wherein Ring C is bicyclic heteroaryl including from 8-10 ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R^d), O, and S(O)_0-2, and wherein the heteroaryl is substituted with X¹ and further optionally substituted with from 1-3 R^c.

11. The compound of any one of claims 1-3 or 10, wherein Ring C is bicyclic heteroaryl including from 9-10 ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R^d), O, and S(O)_0-2, and wherein the heteroaryl is substituted with X¹ and further optionally substituted with from 1-3 R^c.

12. The compound of any one of claims 1-3 or 10-11, wherein: (i) Ring C is bicyclic heteroaryl including 10 ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R^d), O, and S(O)_0-2, and wherein the heteroaryl is substituted with X¹ and further optionally substituted with from 1-3 R^c; (ii) Ring C is selected from the group consisting of: quinolinyl; naphthyridinyl such as 1,5-naphthyridin-4-yl; and pyridopyrimidinyl, such as pyrido[3,2-d]pyrimidin-4-yl, each of which is substituted with X¹ and further optionally substituted with from 1-3 R^c; or (iii) Ring C is selected from the group consisting of:

and each of which is optionally substituted with ^c

from 1-2 R .

13. The compound of any one of claims 1-3 or 10-11, wherein: (i) Ring C is bicyclic heteroaryl including 9 ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R^d), O, and S(O)_0-2, and wherein the heteroaryl is substituted with X¹ and further optionally substituted with from 1-3 R^c; for example, Ring C is

. (ii) Ring C is thieno[3,2-b]pyridyl, which is substituted with X¹ and further optionally substituted with from 1-3 R^c; or (iii) Ring C is which is optionally substituted with fro ^c

m 1-2 R.

14. The compound of any one of claims 1-13, wherein m is 1.

15. The compound of any one of claims 1-13, wherein m is 0.

16. The compound of any one of claims 1-14, wherein X² is -O-, -N(R^N)-, or – S(O)_0-2.

17. The compound of any one of claims 1-14 or 16, wherein X² is –O-.

18. The compound of any one of claims 1-14 or 16, wherein X² is –N(R^N)-.

19. The compound of any one of claims 1-14, 16, or 18, wherein X² is –N(H)-.

20. The compound of any one of claims 1-14, wherein X² is

21. The compound of any one of claims 1-14, wherein X² is selected from the group consisting of: -OC(=O)-*, -N(R^N)C(=O)-*, and –N(R^N)S(O)_1-2-*.

22. The compound of any one of claims 1-14 or 21, wherein X² is - N(R^N)C(=O)-*, such as –N(H)C(=O)-*.

23. The compound of any one of claims 1-14 or 21, wherein X² is –N(R^N)S(O)_1- _2-*, such as –N(H)S(O)₂-*.

24. The compound of any one of claims 1-14, wherein X² is selected from the group consisting of: -OC(=O)N(R^N)-*, -N(R^N)C(=O)O-*, -N(R^N)C(=O)N(R^N)-*, and – N(R^N)S(O)_1-2N(R^N)-.

25. The compound of any one of claims 1-14 or 24, wherein X² is - N(R^N)C(=O)O-*, such as –N(H)C(=O)O-*.

26. The compound of any one of claims 1-14 or 24, wherein X² is – N(H)C(=O)N(R^N)-*, such as –N(H)C(=O)N(C_1-3 alkyl)-*.

27. The compound of any one of claims 1-26, wherein L¹ is C_1-10 alkylene optionally substituted with from 1-6 R^a.

28. The compound of any one of claims 1-27, wherein L¹ is C_1-3 alkylene optionally substituted with from 1-6 R^a.

29. The compound of any one of claims 1-28, wherein L¹ is C_1-3 alkylene.

30. The compound of any one of claims 1-29, wherein L¹ is –CH₂-.

31. The compound of any one of claims 1-29, wherein L¹ is –CH(Me)-, such as

or

32. The compound of any one of claims 1-29, wherein L¹ is –CH₂CH₂-.

33. The compound of any one of claims 1-27, wherein L¹ is C_3-8 alkylene optionally substituted with from 1-6 R^a.

34. The compound of any one of claims 1-27 or 33, wherein L¹ is branched C_3- ₆ alkylene optionally substituted with from 1-6 R^a.

35. The compound of any one of claims 1-27 or 33-34, wherein L¹ is branched C_3-6 alkylene.

36. The compound of any one of claims 1-27 or 33-35, wherein L¹ is selected from the group consisting of:

and

wherein aa is the point of attachment to R⁵.

37. The compound of any one of claims 1-26, wherein L¹ is a bond.

38. The compound of any one of claims 1-36, wherein R⁵ is selected from the group consisting of: -OH; -NR^eR^f; and C_1-6 alkoxy or -S(O)_0-2(C_1-6 alkyl) each optionally substituted with from 1-6 R^a.

39. The compound of any one of claims 1-36 or 38, wherein R⁵ is C_1-6 alkoxy optionally substituted with from 1-6 R^a.

40. The compound of any one of claims 1-36 or 38-39, wherein R⁵ is C_1-3 alkoxy, such as methoxy.

41. The compound of any one of claims 1-36 or 38, wherein R⁵ is -S(O)_0-2(C_1-6 alkyl) which is optionally substituted with from 1-6 R^a.

42. The compound of any one of claims 1-36, 38, or 41, wherein R⁵ is – S(O)₂(C_1-6 alkyl) which is optionally substituted with from 1-6 R^a.

43. The compound of any one of claims 1-36, 38, or 41-42, wherein R⁵ is – S(O)₂(C_1-3 alkyl).

44. The compound of any one of claims 1-37, wherein R⁵ is –R^g.

45. The compound of any one of claims 1-37 or 44, wherein R⁵ is heterocyclyl or heterocycloalkenyl including from 3-10 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R^d), O, and S(O)_0-2, and wherein the heterocyclyl or heterocycloalkenyl is optionally substituted with from 1-4 substituents independently selected from the group consisting of oxo and R^c.

46. The compound of any one of claims 1-37 or 44-45, wherein R⁵ is heterocyclyl including from 3-10 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R^d), O, and S(O)_0-2, and wherein the heterocyclyl is optionally substituted with from 1-4 substituents independently selected from the group consisting of oxo and R^c.

47. The compound of any one of claims 1-37 or 44-46, wherein R⁵ is heterocyclyl including from 4-8 ring atoms, wherein from 1-2 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R^d), O, and S(O)_0-2, and wherein the heterocyclyl is optionally substituted with from 1-3 substituents independently selected from the group consisting of oxo and R^c.

48. The compound of any one of claims 1-37 or 44-47, wherein R⁵ is

which is optionally substituted with from 1-2 R^c, wherein X^a is O, N(H), or N(R^d); x1 is 0, 1, or 2; and x0 is 0, 1, 2, or 3, provided that x0+x1≥1.

49. The compound of any one of claims 1-37 or 44-48, wherein R⁵ is

which is optionally substituted with from 1-2 R^c, wherein X^a is O, N(H), or N(R^d); and x1 and x2 are each independently 0, 1, or 2.

50. The compound of claims 48 or 49, wherein x1 is 0.

51. The compound of any one of claims 48-50, wherein X^a is –O-.

52. The compound of any one of claims 1-37 or 44-51, wherein R⁵ is

such as

or

53. The compound of any one of claims 1-37 or 44-51, wherein R⁵ is

such as

or

54. The compound of any one of claims 48-50, wherein X^a is N(H) or N(R^d), such as N(R^d), optionally wherein R^d is C_1-4 alkyl or wherein R^d is C(=O)(C_1-4 alkyl) or S(O)₂(C_1-4 alkyl).

55. The compound of any one of claims 1-37, 44-50, or 54, wherein R⁵ is selected from the group consisting of:

, such as

or

;

(e.g.,

), such as

(e.g.,

) or

(e.g.,

) ;

, such as

or

; and , such as

or

, optionally wherein R^d is ^d

C_1-4 alkyl or wherein R is C(=O)(C_1-4 alkyl) or S(O)₂(C_1-4 alkyl).

56. The compound of claims 48 or 49, wherein x1 is 1 or 2.

57. The compound of any one of claims 48-49 or 56, wherein X^a is –O-.

58. The compound of any one of claims 1-37, 44-49, or 56-57, wherein R⁵ is selected from the group consisting of:

such as

or

;

; and

59. The compound of any one of claims 48-49 or 56, wherein X^a is N(H) or N(R^d), such as N(R^d), optionally wherein R^d is C_1-4 alkyl or wherein R^d is C(=O)(C_1-4 alkyl) or S(O)₂(C_1-4 alkyl).

60. The compound of any one of claims 1-37, 44-49, 56, or 59, wherein R⁵ is

61. The compound of any one of claims 1-37 or 44-47, wherein R⁵ is

which is optionally substituted with from 1-2 R^c, wherein X^b and X^c are each independently selected from the group consisting of: O, N(H), N(R^d), and S(O)_0-2.

62. The compound of any one of claims 1-37, 44-47, or 61, wherein R⁵ is selected from the group consisting of:

optionally wherein R^d is C_1-4

alkyl, such as methyl.

63. The compound of any one of claims 1-37 or 44-46, wherein R⁵ is bicyclic heterocyclyl including from 6-10 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R^d), O, and S(O)_0-2, and wherein the heterocyclyl is optionally substituted with from 1-4 substituents independently selected from the group consisting of oxo and R^c.

64. The compound of any one of claims 1-37, 44-46, or 63, wherein R⁵ is

65. The compound of any one of claims 1-37 or 44, wherein R⁵ is heteroaryl including from 5-10 ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R^d), O, and S(O)_0-2, and wherein the heteroaryl is optionally substituted with from 1-4 R^c.

66. The compound of any one of claims 1-37, 44, or 65, wherein R⁵ is monocyclic heteroaryl including from 5-6 ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R^d), O, and S(O)_0-2, and wherein the heteroaryl is optionally substituted with from 1-4 R^c.

67. The compound of any one of claims 1-37, 44, or 65-66, wherein R⁵ is monocyclic heteroaryl including 5 ring atoms, wherein from 1-4, such as 2-3, ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R^d), O, and S(O)_0-2, and wherein the heteroaryl is optionally substituted with from 1-3 R^c.

68. The compound of any one of claims 1-37, 44, or 65-67, wherein R⁵ is selected from the group consisting of pyrazolyl, imidazolyl, oxazolyl, thiazolyl, isooxazolyl, isothiazolyl, triazolyl, oxadiazolyl, and thiadiazolyl, each optionally substituted with from 1-2 R^c, and wherein a ring nitrogen atom is optionally substituted with R^d.

69. The compound of any one of claims 1-37, 44, or 65-68, wherein R⁵ is selected from the group consisting of:

70. The compound of any one of claims 1-37, 44, or 65-66, wherein R⁵ is monocyclic heteroaryl including 6 ring atoms, wherein from 1-4, such as 1-2, ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), and N(R^d), and wherein the heteroaryl is optionally substituted with from 1-4 R^c.

71. The compound of any one of claims 1-37, 44, 65-66, or 70, wherein R⁵ is selected from the group consisting of:

72. The compound of any one of claims 1-37, 44, or 65, wherein R⁵ is bicyclic heteroaryl including from 8-10 ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R^d), O, and S(O)_0-2, and wherein the heteroaryl is optionally substituted with from 1-4 R^c.

73. The compound of any one of claims 1-37, 44, 65, or 72, wherein R⁵ is bicyclic heteroaryl including 8 ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R^d), O, and S(O)_0-2, and wherein the heteroaryl is optionally substituted with from 1-4 R^c.

74. The compound of any one of claims 1-37, 44, 65, or 72-73, wherein R⁵ is selected from the group consisting of: each optionally substituted

with from 1-2 R^c.

75. The compound of any one of claims 1-37, 44, 65, or 72, wherein R⁵ is bicyclic heteroaryl including from 9-10, such as 9, ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R^d), O, and S(O)_0-2, and wherein the heteroaryl is optionally substituted with from 1-4 R^c, such as wherein R⁵ is

o .

76. The compound of any one of claims 1-37 or 44, wherein R⁵ is phenyl optionally substituted with from 1-2 R^c, such as unsubstituted phenyl.

77. The compound of any one of claims 1-37 or 44, wherein R⁵ is C_3-10 cycloalkyl or C_3-10 cycloalkenyl, each of which is optionally substituted with from 1-4 substituents independently selected from the group consisting of oxo and R^c.

78. The compound of any one of claims 1-37, 44, or 77, wherein R⁵ is C_3-10 cycloalkyl which is optionally substituted with from 1-4 substituents independently selected from the group consisting of oxo and R^c.

79. The compound of any one of claims 1-37, 44, or 77-78, wherein R⁵ is C_3-6 cycloalkyl, such as cyclopropyl or cyclopentyl.

80. The compound of any one of claims 1-37, 44, or 77-78, wherein R⁵ is C_3-6 cycloalkyl substituted with a substituent selected from the group consisting of: C_1-4 alkyl; C_1-4 alkyl substituted with R^a, such as C_1-4 alkyl substituted with C_1-4 alkoxy; C_1-4 alkoxy; and C_1-4 haloalkoxy, and wherein the cycloalkyl is further optionally substituted with from 1-2 R^c.

81. The compound of any one of claims 1-37, 44, 77-78, or 80, wherein R⁵ is selected from the group consisting of:

82. The compound of any one of claims 1-37, wherein R⁵ is H or halo, such as H.

83. The compound of claims 1-37, wherein R⁵ is R^W.

84. The compound of any one of claims 1-37, wherein R⁵ is -R^g2-R^W or -R^g2- R^Y., optionally wherein R⁵ is –R^g2-R^W.

85. The compound of any one of claims 1-37 or 83-84, wherein the –R^g2 group present in R⁵ is heterocyclylene including from 4-8 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R^d), O, and S(O)_0-2, and wherein the heterocyclylene is optionally substituted with from 1-4 substituents independently selected from the group consisting of oxo and R^c.

86. The compound of any one of claims 1-37 or 83-85, wherein the –R^g2 group present in R⁵ is

which is optionally substituted with from 1-2 R^c, wherein bb is the point of attachment to R^W or R^Y; and x1 and x2 are each independently 0, 1, or 2.

87. The compound of claim 86, wherein x1 is 0.

88. The compound of any one of claims 1-37 or 83-86, wherein the –R^g2 group present in R⁵ is selected from the group consisting of:

wherein bb is the point of attachment to R^W or R^Y.

89. The compound of any one of claims 1-37 or 83-85, wherein the –R^g2 group present in R⁵ is

such as

which is optionally substituted with from 1-2 R^c; X^b is selected from the group consisting of: O, N(H), N(R^d), and S(O)_0-2; and bb is the point of attachment to R^W or R^Y.

90. The compound of any one of claims 1-37, 83-85, or 89, wherein the –R^g2 group present in R⁵ is selected from the group consisting of:

such as

wherein bb is the point of attachment to R^W or R^Y; and optionally wherein R^d is C_1-4 alkyl, such as methyl.

91. The compound of any one of claims 1-37 or 83-85, wherein the R^g2 group present in R⁵ is bicyclic heterocyclylene including from 6-10 ring atoms, wherein from 1- 3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R^d), O, and S(O)_0-2, and wherein the heterocyclylene is optionally substituted with from 1-4 substituents independently selected from the group consisting of oxo and R^c, such as wherein R^g2 is

, wherein bb is the point of attachment to R^W or R^Y.

92. The compound of any one of claims 1-37 or 83-91, wherein the R^W present in R⁵ is –C(=O)-W, –S(O)₂-W, or –NH-C(=O)-W, such as wherein R^W is –C(=O)-W or – NH-C(=O)-W.

93. The compound of claim 92, wherein W is C_2-6 alkenyl or C_2-6 alkynyl optionally substituted with from 1-3 R^a.

94. The compound of claims 92 or 93, wherein R^W is

; ; , ;

95. The compound of any one of claims 1-13, wherein m is 0 or 1; X² is –O-, -N(R^N)-, ^{N N}

, –N(R )C(=O)-*, or -N(R )S(O)₂-*; L¹ is C_1-3 alkylene optionally substituted with from 1-3 R^a; and R⁵ is selected from the group consisting of: C_1-6 alkoxy or S(O)₂(C_1-6 alkyl) each optionally substituted with from 1-6 R^a; -OH; and –NR^eR^f.

96. The compound of claim 95, wherein R⁵ is C_1-6 alkoxy optionally substituted with from 1-6 R^a.

97. The compound of claims 95 or 96, wherein R⁵ is C_1-3 alkoxy.

98. The compound of claim 95, wherein R⁵ is S(O)₂(C_1-6 alkyl) which is optionally substituted with from 1-6 R^a.

99. The compound of claims 95 or 98, wherein R⁵ is S(O)₂(C_1-3 alkyl).

100. The compound of any one of claims 1-13, wherein: m is 0 or 1; X² is –O-, -N(R^N)-, ^{N N}

, –N(R )C(=O)*, or -N(R )S(O)₂-*; L¹ is a bond or C_1-3 alkylene optionally substituted with from 1-3 R^a; and R⁵ is heterocyclyl including from 3-10 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R^d), O, and S(O)_0-2, and wherein the heterocyclyl is optionally substituted with from 1-4 substituents independently selected from the group consisting of oxo and R^c.

101. The compound of claim 100, wherein R⁵ is

102. The compound of claim 100, wherein R⁵ is

103. The compound of claims 101 or 102, wherein x1 is 0.

104. The compound of any one of claims 101-103, wherein X^a is –O-.

105. The compound of any one of claims 100-104, wherein R⁵ is

such as ; or whe ⁵

rein R is

106. The compound of any one of claims 101-103, wherein X^a is N(R^d), optionally wherein R^d is C_1-4 alkyl or wherein R^d is C(=O)(C_1-4 alkyl) or S(O)₂(C_1-4 alkyl).

107. The compound of any one of claims 100-103 or 106, wherein R⁵ is selected from the group consisting of:

, ;

, optionally wherein R^d is ^d

C_1-4 alkyl or wherein R is C(=O)(C_1-4 alkyl) or S(O)₂(C1- 4 alkyl).

108. The compound of claims 101 or 102, wherein x1 is 1 or 2.

109. The compound of any one of claims 100-102 or 108, wherein R⁵ is selected from the group consisting of:

110. The compound of claim 100, wherein R⁵ is

111. The compound of claims 100 or 110, wherein R⁵ is selected from the group consisting of:

optionally wherein R^d is C_1-4 alkyl, such as methyl.

112. The compound of claim 100, wherein R⁵ is bicyclic heterocyclyl including from 6-10 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R^d), O, and S(O)_0-2, and wherein the heterocyclyl is optionally substituted with from 1-4 substituents independently selected from the group consisting of oxo and R^c, such as wherein R⁵ is

such as

113. The compound of any one of claims 1-13, wherein: m is 0 or 1; X² is –O-, -N(R^N)-,

, –N(R^N)C(=O)*, or -N(R^N)S(O)₂-*; L¹ is a bond or C_1-3 alkylene optionally substituted with from 1-3 R^a; and R⁵ is selected from the group consisting of: • heteroaryl including from 5-10 ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R^d), O, and S(O)_0-2, and wherein the heteroaryl is optionally substituted with from 1-4 R^c; and • C_6-10 aryl optionally substituted with from 1-4 R^c.

114. The compound of claim 113, wherein R⁵ is monocyclic heteroaryl including 5 ring atoms, wherein from 1-4, such as 2-3, ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R^d), O, and S(O)_0-2, and wherein the heteroaryl is optionally substituted with from 1-3 R^c.

115. The compound of claims 113 or 114, wherein R⁵ is selected from the group consisting of pyrazolyl, imidazolyl, oxazolyl, thiazolyl, isooxazolyl, isothiazolyl, triazolyl, oxadiazolyl, and thiadiazolyl, each optionally substituted with from 1-2 R^c, and wherein a ring nitrogen atom is optionally substituted with R^d, such as

116. The compound of claim 113, wherein R⁵ is monocyclic heteroaryl including 6 ring atoms, wherein from 1-4, such as 1-2, ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), and N(R^d), and wherein the heteroaryl is optionally substituted with from 1-4 R^c, such as

117. The compound of claim 113, wherein R⁵ is bicyclic heteroaryl including from 8-10 ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R^d), O, and S(O)_0-2, and wherein the heteroaryl is optionally substituted with from 1-4 R^c.

118. The compound of claims 113 or 117, wherein R⁵ is bicyclic heteroaryl including 8 ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R^d), O, and S(O)_0-2, and wherein the heteroaryl is optionally substituted with from 1-4 R^c, such as wherein R⁵ is selected from the group consisting of:

each optionally substituted with from 1-2 R^c.

119. The compound of claim 113, wherein R⁵ is bicyclic heteroaryl including from 9-10, such as 9, ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R^d), O, and S(O)_0-2, and wherein the heteroaryl is optionally substituted with from 1-4 R^c, such as wherein R⁵ is

120. The compound of claim 113, wherein R⁵ is phenyl optionally substituted with from 1-2 R^c, such as unsubstituted phenyl.

121. The compound of any one of claims 1-13, wherein: m is 0 or 1; X² is –O-, -N(R^N)-, , –N(R^N)C(=O)*, or ^N

-N(R )S(O)₂-*; L¹ is a bond or C_1-3 alkylene optionally substituted with from 1-3 R^a; and R⁵ is C_3-10 cycloalkyl which is optionally substituted with from 1-4 substituents independently selected from the group consisting of oxo and R^c.

122. The compound of claim 121, wherein R⁵ is C_3-6 cycloalkyl, such as cyclopropyl or cyclopentyl.

123. The compound of claim 121, wherein R⁵ is C_3-6 cycloalkyl substituted with a substituent selected from the group consisting of: C_1-4 alkyl; C_1-4 alkyl substituted with R^a, such as C_1-4 alkyl substituted with C_1-4 alkoxy; C_1-4 alkoxy; and C_1-4 haloalkoxy, and wherein the cycloalkyl is further optionally substituted with from 1-2 R^c, such as: wherein R⁵ is selected from the group consisting of:

124. The compound of any one of claims 1-13, wherein: m is 0 or 1; X² is –O-, -N(R^N)-,

, –N(R^N)C(=O)*, or -N(R^N)S(O)₂-*; L¹ is a bond or C_1-3 alkylene optionally substituted with from 1-3 R^a; and R⁵ is –R^g2-R^W, wherein: the -R^g2 of R⁵ is heterocyclylene including from 4-8 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R^d), O, and S(O)_0-2, and wherein the heterocyclylene is optionally substituted with from 1-4 substituents independently selected from the group consisting of oxo and R^c; and -R^W is –C(=O)-W or –S(O)₂-W.

125. The compound of claim 124, wherein R^g2 is

which is optionally substituted with from 1-2 R^c, wherein bb is the point of attachment to R^W; and x1 and x2 are each independently 0, 1, or 2, optionally wherein x1 is 0.

126. The compound of claims 124 or 125, wherein R^g2 is selected from the group consisting of:

, such as

or

such as

or

; (e.g.,

), such as

(e.g.,

wherein bb is the point of attachment to ^W

R .

127. The compound of claim 124, wherein R^g2 is

which is optionally substituted with from 1-2 R^c; X^b is selected from the group consisting of: O, N(H), N(R^d), and S(O)_0-2; and bb is the point of attachment to R^W.

128. The compound of claims 124 or 127, wherein R^g2 is selected from the group consisting of: such as

or , wherein bb is the point of at ^W

tachment to R ; and optionally wherein R^d is C_1-4 alkyl, such as methyl.

129. The compound of claim 124, wherein R^g2 is is bicyclic heterocyclylene including from 6-8 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R^d), O, and S(O)_0-2, and wherein the heterocyclylene is optionally substituted with from 1-4 substituents independently selected from the group consisting of oxo and R^c, such as wherein R^g2 is

, such as or wherein bb is

the point of attachment to R^W.

130. The compound of any one of claims 124-129, wherein R^W is –C(=O)-W.

131. The compound of any one of claims 124-130, wherein W is C_2-6 alkenyl optionally substituted with from 1-3 R^a.

132. The compound of any one of claims 124-131, wherein R^W is

or

, such as

.

133. The compound of any one of claims 95-132, wherein m is 1.

134. The compound of any one of claims 95-133, wherein X² is –O-.

135. The compound of any one of claims 95-133, wherein X² is -N(R^N)-, such as –N(H)-.

136. The compound of any one of claims 95-133, wherein X² is

.

137. The compound of any one of claims 95-133, wherein X² is –N(R^N)C(=O)* or -N(R^N)S(O)₂-*, such as –N(H)C(=O)* or –N(H)S(O)₂-*.

138. The compound of any one of claims 95-132, wherein m is 0.

139. The compound of any one of claims 1-13, wherein: m is 1; X² is –N(R^N)C(=O)-*, -N(R^N)C(=O)O-* or -N(R^N)C(=O)N(R^N)-*; L¹ is C_1-3 alkylene optionally substituted with from 1-3 R^a; and R⁵ is H.

140. The compound of claim 139, wherein X² is -N(R^N)C(=O)-*, such as – N(H)C(=O)-*.

141. The compound of claim 139, wherein X² is selected from the group consisting of -N(R^N)C(=O)N(R^N)-*, such as –N(H)C(=O)N(R^N)-*; and -N(R^N)C(=O)O- *, such as –N(H)C(=O)O-*.

142. The compound of any one of claims 95-141, wherein L¹ is CH₂.

143. The compound of any one of claims 95-141, wherein L¹ is –CH(Me)-.

144. The compound of any one of claims 95-141, wherein L¹ is –CH₂CH₂-.

145. The compound of any one of claims 100-138, wherein L¹ is a bond.

146. The compound of any one of claims 1-13, wherein: m is 1; X² is –O-, -N(R^N)-, ^{N N}

, –N(R )C(=O)*, or -N(R )S(O)₂-*; L¹ is branched C_3-6 alkylene optionally substituted with from 1-6 R^a; and R⁵ is selected from the group consisting of: C_1-6 alkoxy or S(O)₂(C_1-6 alkyl) each optionally substituted with from 1-6 R^a; -OH; –NR^eR^f; and H.

147. The compound of claim 146, wherein R⁵ is C_1-6 alkoxy optionally substituted with from 1-6 R^a.

148. The compound of claims 146 or 147, wherein R⁵ is C_1-3 alkoxy.

149. The compound of claim 146, wherein R⁵ is S(O)₂(C_1-6 alkyl) optionally substituted with from 1-6 R^a.

150. The compound of any one of claims 146-149, wherein X² is –O-.

151. The compound of any one of claims 146-149, wherein X² is -N(R^N)-, such as –N(H)-.

152. The compound of any one of claims 146-149, wherein X² is

.

153. The compound of any one of claims 146-149, wherein X² is –N(R^N)C(=O)* or -N(R^N)S(O)₂-*, such as –N(H)C(=O)-* or –N(H)S(O)₂-*.

154. The compound of any one of claims 146-153, wherein L¹ is branched C_3-6 alkylene.

155. The compound of any one of claims 146-154, wherein L¹ is selected from the group consisting of: and

wherein aa is the point of attachment to R⁵.

156. The compound of claims 1 or 2, wherein Ring C is selected from the group consisting of: • heteroaryl including from 5-10 ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R^d), O, and S(O)_0-2, and wherein the heteroaryl is optionally substituted with 1-4 R^c; and • C_6-10 aryl optionally substituted with from 1-4 R^c.

157. The compound of any one of claims 1-2 or 156, wherein Ring C is monocyclic heteroaryl including from 5-6 ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R^d), O, and S(O)_0-2, and wherein the heteroaryl is optionally substituted with 1-4 R^c.

158. The compound of any one of claims 1-2 or 156-157, wherein Ring C is monocyclic heteroaryl including 5 ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R^d), O, and S(O)_0-2, and wherein the heteroaryl is optionally substituted with 1-3 R^c.

159. The compound of any one of claims 1-2 or 156-158, wherein Ring C is selected from the group consisting of: pyrazolyl, imidazolyl, oxazolyl, thiazolyl, isooxazolyl, isothiazolyl, triazolyl, oxadiazolyl, and thiadiazolyl, each optionally substituted with from 1-2 R^c, and wherein a ring nitrogen atom is optionally substituted with R^d.

160. The compound of any one of claims 1-2 or 156-159, wherein Ring C is selected from the group consisting of:

, such as

161. The compound of any one of claims 1-2 or 156-157, wherein Ring C is monocyclic heteroaryl including 6 ring atoms, wherein from 1-4 ring atoms are heteroatoms each independently selected from the group consisting of N, N(H), and N(R^d), and wherein the heteroaryl is optionally substituted with from 1-4 R^c.

162. The compound of any one of claims 1-2, 156-157, or 161, wherein Ring C is: (i) selected from the group consisting of:

(ii) selected from the group consisting of:

and

(iii) selected from the group consisting of:

and

, wherein the R^c present in Ring C is C_1-3 alkyl optionally substituted with from 1-3 R^a, such as C_1-3 alkyl optionally substituted with from 1-3 independently selected halo; or (iv) selected from the group consisting of: and

wherein the

R^c present in Ring C is selected from the group consisting of: halo and C_1-3 alkyl optionally substituted with from 1-3 R^a, optionally wherein the R^c is –F, -Cl, or C_1-3 alkyl optionally substituted with from 1-3 independently selected halo.

163. The compound of any one of claims 1-2 or 156, wherein Ring C is bicyclic heteroaryl including from 8-10 ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R^d), O, and S(O)_0-2, and wherein the heteroaryl is optionally substituted with 1-4 R^c.

164. The compound of any one of claims 1-2, 156, or 163, wherein Ring C is bicyclic heteroaryl including 9 ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R^d), O, and S(O)_0-2, and wherein the heteroaryl is optionally substituted with 1-4 R^c.

165. The compound of claim 164, wherein Ring C is attached to

via a 5-membered ring.

166. The compound of any one of claims 1-2, 156, or 163-165, wherein Ring C is selected from the group consisting of:

, and

.

167. The compound of claim 164, wherein Ring C is attached to

via a 6-membered ring.

168. The compound of any one of claims 1-2, 156, 164, or 167, wherein Ring C is:

, wherein Z⁰ is N or CH (e.g., CH); and Ring D is an aromatic or partially unsaturated (e.g., aromatic) ring including 5 ring atoms, wherein from 1-3 (e.g., 1 or 2) ring atoms are heteroatoms each independently selected from the group consisting of: N, NH, N(R^d), O, and S(O)_0-2, wherein Ring D is optionally substituted with from 1-2 R^c.

169. The compound of any one of claims 1-2, 156, 163-164, or 167-168, wherein Ring C is selected from the group consisting of:

, , ,

, , , , , ,

, and

, each further optionally substituted with from 1-2 R^c.

170. The compound of any one of claims 1-2, 156, 163-164, or 167-168, wherein Ring C is selected from the group consisting of:

and .

171. The compound of any one of claims 1-2, 156, or 163, wherein Ring C is: (i) bicyclic heteroaryl including 10 ring atoms, wherein from 1-4 ring atoms are heteroatoms each independently selected from the group consisting of N, N(H), and N(R^d), and wherein the heteroaryl is optionally substituted with from 1-4 R^c; (ii) selected from the group consisting of:

, , , , , and

or (iii) selected from the group consisting of:

and

172. The compound of claims 1 or 2, wherein Ring C is heterocyclyl or heterocycloalkenyl including from 3-10 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R^d), O, and S(O)_0-2, and wherein the heterocyclyl or heterocycloalkenyl is optionally substituted with X¹ and further optionally substituted with from 1-4 substituents independently selected from the group consisting of oxo and R^c, such as: wherein Ring C is heterocyclyl including from 4-8 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R^d), O, and S(O)_0-2, and wherein the heterocyclyl is optionally substituted with from 1-4 substituents independently selected from the group consisting of oxo and R^c, such as wherein Ring C is tetrahydropyranyl, such as

.

173. The compound of any one of claims 1-172, wherein each occurrence of R^c present on one or more ring atoms of Ring C is independently selected from the group consisting of: C_1-3 alkyl; C_1-3 alkyl substituted with from 1-3 R^a; halo; cyano; NR^eR^f, such as NH₂, NH(C_1-3 alkyl), N(C_1-3 alkyl)₂, or NHC(=O)C_1-3 alkyl; -OH; C_1-4 alkoxy; and C_1-4 haloalkoxy.

174. The compound of any one of claims 1-173, wherein R^1c is H.

175. The compound of any one of claims 1-174, wherein R^2a and R^2b are H.

176. The compound of any one of claims 1-174, wherein from 1-2, such as 1, of R^2a and R^2b is a substituent other than H.

177. The compound of any one of claims 1-174 or 176, wherein one of R^2a and R^2b is C_1-3 alkyl optionally substituted with from 1-3 R^a, such as C_1-3 alkyl; and the other of R^2a and R^2b is H.

178. The compound of any one of claims 1-174 or 176, wherein one of R^2a and R^2b is R^g; and the other of R^2a and R^2b is H.

179. The compound of any one of claims 1-174, 176, or 178, wherein one of R^2a and R^2b is heterocyclyl including from 4-6 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R^d), O, and S(O)_0-2, and wherein the heterocyclyl is optionally substituted with from 1-4 substituents independently selected from the group consisting of oxo and R^c; and the other of R^2a and R^2b is H.

180. The compound of any one of claims 1-174, wherein R^2a and R^2b, together with the Ring B ring atom to which each is attached, form a fused saturated or unsaturated ring of 3-12 ring atoms; x wherein from 0-2 of the ring atoms are each an independently selected heteroatom, wherein each of the independently selected heteroatoms is selected from the group consisting of N, NH, N(R^d), O, and S(O)_0-2; and x wherein the fused saturated or unsaturated ring of 3-12 ring atoms is optionally substituted with from 1-4 substituents independently selected from the group consisting of oxo and R^c.

181. The compound of any one of claims 1-174 or 180, wherein R^2a and R^2b together with the Ring B ring atom to which each is attached form a cycloalkyl ring of 3- 6 ring atoms, such as 3 ring atoms, wherein the fused cycloalkyl ring is optionally substituted with from 1-2 R^c.

182. The compound of any one of claims 1-181, wherein R^3a and R^3b are H.

183. The compound of any one of claims 1-181, wherein from 1-2, such as 1, of R^3a and R^3b is a substituent other than H.

184. The compound of any one of claims 1-181 or 183, wherein one of R^3a and R^3b is R^b; and the other of R^3a and R^3b is H.

185. The compound of any one of claims 1-181 or 183-184, wherein one of R^3a and R^3b is C_1-3 alkyl optionally substituted with from 1-3 R^a; and the other of R^3a and R^3b is H.

186. The compound of any one of claims 1-181 or 183-185, wherein one of R^3a and R^3b is C_1-3 alkyl; and the other of R^3a and R^3b is H.

187. The compound of any one of claims 1-181 or 183-186, wherein one of R^3a and R^3b is methyl, ethyl, or isopropyl; and the other of R^3a and R^3b is H.

188. The compound of any one of claims 1-181 or 183-185, wherein one of R^3a and R^3b is C_1-3 alkyl substituted with from 1-3 independently selected halo; and the other of R^3a and R^3b is H.

189. The compound of any one of claims 1-181, 183-185, or 188, wherein one of R^3a and R^3b is –CH₂F, -CHF₂, -CF₃, -CH₂CHF₂, or -CH₂CH₂F; and the other of R^3a and R^3b is H.

190. The compound of any one of claims 1-181 or 183-185, wherein one of R^3a and R^3b is C_1-3 alkyl substituted with C_1-4 alkoxy, C_1-4 haloalkoxy, or NR^eR^f; and the other of R^3a and R^3b is H.

191. The compound of any one of claims 1-181, 183-185, or 190, wherein one of R^3a and R^3b is –CH₂OMe, -CH₂CH₂OMe, -CH(Me)CH₂OMe, -CH₂CH(Me)OMe, - CH₂OEt, -CH₂CH₂OCHF₂, -CH₂NR^eR^f (e.g., -CH₂N(CF₃)Me), or –CH₂CH₂NR^eR^f (e.g., - CH₂CH₂NMe2); and the other of R^3a and R^3b is H.

192. The compound of any one of claims 1-181 or 183, wherein one of R^3a and R^3b is R^g or –(L^g)_g-R^g; and the other of R^3a and R^3b is H.

193. The compound of any one of claims 1-181, 183, or 192, wherein one of R^3a and R^3b is selected from the group consisting of: heterocyclyl including from 4-6 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R^d), O, and S(O)_0-2, and wherein the heterocyclyl is optionally substituted with from 1-4 substituents independently selected from the group consisting of oxo and R^c; and C_3-6 cycloalkyl optionally substituted with from 1-4 R^c; and the other of R^3a and R^3b is H.

194. The compound of any one of claims 1-181, 183, or 192-193, wherein one of R^3a and R^3b is selected from the group consisting of: cyclopropyl, cyclobutyl, oxetanyl, and azetidinyl, each of which is optionally substituted with from 1-2 substituents independently selected from the group consisting of: C_1-3 alkyl and halo, wherein the ring nitrogen of the azetidinyl is optionally substituted with R^d; and the other of R^3a and R^3b is H.

195. The compound of any one of claims 1-181, 183, or 192, wherein one of R^3a and R^3b is –(C_1-3 alkylene)-R^g or -(C_1-3 alkylene)-O-R^g, optionally wherein the R^g group of R^3a or R^3b is: C_3-6 cycloalkyl optionally substituted with from 1-4 R^c, or heterocyclyl including from 4-6 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R^d), O, and S(O)_0-2, and wherein the heterocyclyl is optionally substituted with from 1-4 substituents independently selected from the group consisting of oxo and R^c; and the other of R^3a and R^3b is H.

196. The compound of any one of claims 1-181, 183, 192, or 195, wherein one of R^3a and R^3b is –CH₂-R^g, –CH₂CH₂R^g, or –CH₂-O-R^g, wherein the R^g group of R^3a or R^3b is: C_3-6 cycloalkyl optionally substituted with from 1-4 R^c, or heterocyclyl including from 4-6 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R^d), O, and S(O)_0-2, and wherein the heterocyclyl is optionally substituted with from 1-4 substituents independently selected from the group consisting of oxo and R^c; and the other of R^3a and R^3b is H.

197. The compound of any one of claims 1-181, 183, 192, or 195-196, wherein one of R^3a and R^3b is –CH₂-R^g, –CH₂CH₂R^g, or –CH₂-O-R^g, wherein the R^g group of R^3a or R^3b is selected from the group consisting of: cyclopropyl, cyclobutyl, oxetanyl, and azetidinyl, each of which is optionally substituted with from 1-2 substituents independently selected from the group consisting of: C_1-3 alkyl and halo, wherein the ring nitrogen of the azetidinyl is optionally substituted with R^d; and the other of R^3a and R^3b is H; optionally, wherein one of R^3a and R^3b is selected from the group consisting of: such as or ; , such

as or

; , such as

or

; and

198. The compound of any one of claims 1-181 or 183, wherein R^3a and R^3b are each independently selected R^b.

199. The compound of any one of claims 1-181, 183, or 198, wherein R^3a and R^3b are each independently selected C_1-3 alkyl which is optionally substituted with from 1- 3 R^a.

200. The compound of any one of claims 1-181, 183, or 198-199, wherein R^3a and R^3b are each independently C_1-3 alkyl, such as methyl.

201. The compound of any one of claims 1-181, wherein R^3a and R^3b, together with the Ring B ring atom to which each is attached, form a fused saturated or unsaturated ring of 3-12 ring atoms; • wherein from 0-2 of the ring atoms are each an independently selected heteroatom, wherein each of the independently selected heteroatoms is selected from the group consisting of N, NH, N(R^d), O, and S(O)_0-2; and • wherein the fused saturated or unsaturated ring of 3-12 ring atoms is optionally substituted with from 1-4 substituents independently selected from the group consisting of oxo and R^c.

202. The compound of any one of claims 1-181 or 201, wherein R^3a and R^3b together with the Ring B ring atom to which each is attached form a cycloalkyl ring of 3- 6 ring atoms, such as 3 ring atoms, wherein the fused cycloalkyl ring is optionally substituted with from 1-2 R^c.

203. The compound of any one of claims 1-181 or 201-202, wherein R^3a and R^3b together with the Ring B ring atom to which each is attached form a fused cyclopropyl or cyclobutyl.

204. The compound of any one of claims 1-181 or 201, wherein R^3a and R^3b together with the Ring B ring atom to which each is attached, form a fused saturated ring of 4-6 ring atoms; • wherein from 1-2 of the ring atoms are each an independently selected heteroatom, wherein each of the independently selected heteroatoms is selected from the group consisting of N, NH, N(R^d), O, and S(O)_0-2; and • wherein the fused saturated ring of 4-6 ring atoms is optionally substituted with from 1-2 substituents independently selected from the group consisting of oxo and R^c.

205. The compound of any one of claims 1-181, 201, or 204, wherein R^3a and R^3b, together with the Ring B ring atom to which each is attached, form: (i)

, or

; (ii)

or

; (iii) any group in (ii), wherein R^d is C_1-3 alkyl optionally substituted with from 1-3 independently selected halo; (iv) any group in (ii), wherein R^d is C_1-3 alkyl substituted with from 1-3 independently selected halo; or (v) any group in (ii), wherein R^d is –CH₂CF₃.

206. The compound of any one of claims 1-181, wherein R^3a and R^3b together with the Ring B ring atom to which each is attached, form a fused saturated ring of 4-6 ring atoms; • wherein from 1-2 of the ring atoms are each an independently selected heteroatom, wherein each of the independently selected heteroatoms is selected from the group consisting of N, NH, N(R^d), O, and S(O)_0-2; and • wherein the fused saturated ring of 4-6 ring atoms is substituted with R^W and further optionally substituted with from 1-2 substituents independently selected from the group consisting of oxo and R^c.

207. The compound of any one of claims 1-181 or 206, wherein R^3a and R^3b together with the Ring B ring atom to which each is attached, form: (i)

, , or

; (ii) any group of (i), wherein R^W is –L^W-W, wherein L^W is C(=O) or S(O)₂; and R^W is C_2-6 alkenyl which is optionally substituted with from 1-3 R^a and further optionally substituted with R^g, wherein W is attached to L^W via an sp² hybridized carbon atom; (iii) any group of (i), wherein R^W is

or

or (iv) , whe ^W

rein R is

208. The compound of any one of claims 201-207, wherein R^1c, R^2a, and R^2b are each H.

209. The compound of any one of claims 1-174, wherein one of R^2a and R^2b and one of R^3a and R^3b taken together with the Ring B ring atoms to which each is attached, form a fused saturated or unsaturated ring of 3-12 ring atoms; x wherein from 0-2 of the ring atoms are each an independently selected heteroatom, wherein each of the independently selected heteroatoms is selected from the group consisting of N, NH, N(R^d), O, and S(O)_0-2; and x wherein the fused saturated or unsaturated ring of 3-12 ring atoms is optionally substituted with from 1-4 substituents independently selected from the group consisting of oxo and R^c.

210. The compound of any one of claims 1-174 or 209, wherein one of R^2a and R^2b and one of R^3a and R^3b taken together with the Ring B ring atoms to which each is attached, form a fused saturated ring of 3-8 ring atoms; x wherein from 0-2 of the ring atoms are each an independently selected heteroatom, wherein each of the independently selected heteroatoms is selected from the group consisting of N, NH, N(R^d), O, and S(O)_0-2; and x wherein the fused saturated ring of 3-8 ring atoms is optionally substituted with from 1-4 substituents independently selected from the group consisting of oxo and R^c.

211. The compound of any one of claims 1-174 or 209-210, wherein one of R^2a and R^2b and one of R^3a and R^3b taken together with the Ring B ring atoms to which each is attached, form a fused C_3-6 cycloalkyl which is optionally substituted with from 1-2 R^c, such as: wherein one of R^2a and R^2b and one of R^3a and R^3b taken together with the Ring B ring atoms to which each is attached, form a fused cyclopropyl or cyclobutyl.

212. The compound of any one of claims 1-174, wherein one of R^2a and R^2b and one of R^3a and R^3b combine to form a double bond between the Ring B ring atoms to which each is attached.

213. The compound of any one of claims 209-212, wherein the other of R^2a and R^2b and the other of R^3a and R^3b are each H.

214. The compound of any one of claims 209-212, wherein the other of R^2a and R^2b is H; and the other of R^3a and R^3b is selected from the group consisting of: R^b, R^g, and –(L^g)_g-R^g.

215. The compound of any one of claims 209-212 or 214, wherein the other of R^2a and R^2b is H; and the other of R^3a and R^3b is selected from the group consisting of: (i) C_1-3 alkyl; (ii) C_1-3 alkyl substituted with from 1-3 independently selected halo; (iii) C_1-3 alkyl substituted with C_1-4 alkoxy, C_1-4 haloalkoxy, or NR^eR^f; (iv) C_1-3 alkyl substituted with C_1-4 alkoxy or C_1-4 haloalkoxy; or (v) –R^g, –CH₂-R^g, –CH₂CH₂R^g, or –CH₂-O-R^g, wherein the R^g group of R^3a or R^3b is: C_3-6 cycloalkyl optionally substituted with from 1-4 R^c, or heterocyclyl including from 4-6 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R^d), O, and S(O)_0-2, and wherein the heterocyclyl is optionally substituted with from 1-4 substituents independently selected from the group consisting of oxo and R^c.

216. The compound of any one of claims 209-212 or 214-215, wherein the other of R^2a and R^2b is H; and the other of R^3a and R^3b is: (i) C_1-3 alkyl substituted with C_1-4 alkoxy, C_1-4 haloalkoxy, or NR^eR^f; or (ii) –CH₂OMe, -CH₂CH₂OMe, -CH(Me)CH₂OMe, -CH₂CH(Me)OMe, -CH₂OEt, - CH₂CH₂OCHF₂, -CH₂NR^eR^f (e.g., -CH₂N(CF₃)Me), or –CH₂CH₂NR^eR^f (e.g., - CH₂CH₂NMe₂).

217. The compound of any one of claims 209-212 or 214-215, wherein the other of R^2a and R^2b is H; and the other of R^3a and R^3b is: (i) C_1-3 alkyl substituted with C_1-4 alkoxy or C_1-4 haloalkoxy; (ii) –CH₂OMe, -CH₂CH₂OMe, -CH(Me)CH₂OMe, -CH₂CH(Me)OMe, -CH₂OEt, or -CH₂CH₂OCHF2; or (iii) –CH₂OMe or –CH₂CH₂OMe.

218. The compound of any one of claims 209-217, wherein R^1c is –H.

219. The compound of any one of claims 1-173, wherein R^1c, R^2a, and R^2b are each H; one of R^3a and R^3b is C_1-3 alkyl optionally substituted with from 1-3 R^a; and the other of R^3a and R^3b is H; and optionally each R^a substituent present in R^3a or R^3b is independently selected from the group consisting of: halo, C_1-4 alkoxy, and C_1-4 haloalkoxy.

220. The compound of any one of claims 1-173 or 219, wherein R^1c, R^2a, and R^2b are each H; one of R^3a and R^3b is C_1-3 alkyl; and the other of R^3a and R^3b is H.

221. The compound of any one of claims 1-173 or 219, wherein R^1c, R^2a, and R^2b are each H; one of R^3a and R^3b is C_1-3 alkyl substituted with from 1-3 independently selected halo; and the other of R^3a and R^3b is H.

222. The compound of any one of claims 1-173 or 219, wherein R^1c, R^2a, and R^2b are each H; one of R^3a and R^3b is C_1-3 alkyl substituted with C_1-4 alkoxy or C_1-4 haloalkoxy; and the other of R^3a and R^3b is H.

223. The compound of any one of claims 1-173, wherein R^1c, R^2a, and R^2b are each H; one of R^3a and R^3b is –R^g, –(C_1-3 alkylene)-R^g, or –(C_1-3 alkylene)-O-R^g, optionally wherein the R^g group of R^3a or R^3b is: C_3-6 cycloalkyl optionally substituted with from 1-4 R^c, or heterocyclyl including from 4-6 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R^d), O, and S(O)_0-2, and wherein the heterocyclyl is optionally substituted with from 1-4 substituents independently selected from the group consisting of oxo and R^c; and the other of R^3a and R^3b is H.

224. The compound of any one of claims 1-173, wherein R^1c, R^2a, and R^2b are each H; and R^3a and R^3b taken together with the Ring B ring carbon atom to which each is attached form a fused cycloalkyl ring of 3-6 ring atoms, such as 3 ring atoms, wherein the fused cycloalkyl ring is optionally substituted with from 1-2 R^c.

225. The compound of any one of claims 1-173, wherein R^1c, R^2a, and R^2b are each H; and R^3a and R^3b taken together with the Ring B ring atom to which each is attached, form a fused saturated ring of 4-6 ring atoms; • wherein from 1-2 of the ring atoms are each an independently selected heteroatom, wherein each of the independently selected heteroatoms is selected from the group consisting of N, NH, N(R^d), O, and S(O)_0-2; and • wherein the fused saturated ring of 4-6 ring atoms is optionally substituted with from 1-2 substituents independently selected from the group consisting of oxo and R^c.

226. The compound of any one of claims 1-225, wherein Ring A is

wherein each R^cB is an independently selected R^c; and m is 0, 1, 2, 3, or 4.

227. The compound of claim 226, wherein m is 1, 2, or 3.

228. The compound of claims 226 or 227, wherein m is 1 or 2, such as 2.

229. The compound of any one of claims 1-228, wherein Ring A is

or (e.g., ^{cB c}

), wherein each R is an independently selected R .

230. The compound of any one of claims 226-229, wherein each R^cB is independently selected from the group consisting of: -halo, such as -Cl and -F; -CN; C_1-4 alkoxy; C_1-4 haloalkoxy; C_1-3 alkyl; and C_1-3 alkyl substituted with from 1-6 independently selected halo.

231. The compound of any one of claims 1-228, wherein Ring A is

, wherein R^cB1 is R^c; and R^cB2 is H or R^c, optionally wherein R^cB1 and R^cB2 are each independently selected from the group consisting of: -halo, such as -Cl and -F; -CN; C_1-4 alkoxy; C_1-4 haloalkoxy; C_1-3 alkyl; and C_1-3 alkyl substituted with from 1-6 independently selected halo.

232. The compound of claim 231, wherein R^cB1 is halo, such as –F or –Cl, such as –F.

233. The compound of claim 231, wherein R^cB1 is C_1-3 alkyl or C_1-3 alkyl substituted with from 1-6 independently selected halo, such as wherein R^cB1 is methyl, – CHF₂, or –CF₃.

234. The compound of any one of claims 231-233, wherein R^cB2 is selected from the group consisting of: halo; -CN; C_1-4 alkoxy; C_1-4 haloalkoxy; C_1-3 alkyl; and C_1-3 alkyl substituted with from 1-6 independently selected halo.

235. The compound of any one of claims 231-234, wherein R^cB2 is C_1-4 alkoxy or C_1-4 haloalkoxy.

236. The compound of any one of claims 231-234, wherein R^cB2 is selected from the group consisting of cyano; C_1-3 alkyl; and C_1-3 alkyl substituted with from 1-6 independently selected halo, such as wherein R^cB2 is cyano, methyl, ethyl, -CHF₂, -CF₃, or -CH₂CHF₂.

237. The compound of any one of claims 1-225, wherein Ring A is heteroaryl including from 5-10 ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R^d), O, and S(O)_0-2, and wherein the heteroaryl is optionally substituted with from 1-4 substituents independently selected from the group consisting of R^c and oxo.

238. The compound of any one of claims 1-225 or 237, wherein Ring A is bicyclic heteroaryl including from 9-10 ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R^d), O, and S(O)_0-2, and wherein the heteroaryl is optionally substituted with from 1-4 substituents independently selected from the group consisting of R^c and oxo.

239. The compound of any one of claims 1-225 or 237-238, wherein Ring A is selected from the group consisting of:

, , ,

and each of which is further optionally substituted

with R^c.

240. The compound of claim 1, wherein the compound of Formula (I) is a compound of Formula (I-a):

Formula (I-a) or a pharmaceutically acceptable salt thereof, wherein n is 0, 1, or 2.

241. The compound of claim 1, wherein the compound of Formula (I) is a compound of Formula (I-b):

Formula (I-b) or a pharmaceutically acceptable salt thereof, wherein n is 0, 1, or 2.

242. The compound of claim 1, wherein the compound of Formula (I) is a compound of Formula (I-c):

Formula (I-c) or a pharmaceutically acceptable salt thereof, wherein n is 0, 1, or 2.

243. The compound of claim 1, wherein the compound of Formula (I) is a compound of Formula (I-d):

Formula (I-d) or a pharmaceutically acceptable salt thereof, wherein n is 0, 1, or 2.

244. The compound of claim 1, wherein the compound of Formula (I) is a compound of Formula (I-e):

Formula (I-e) or a pharmaceutically acceptable salt thereof.

245. The compound of any one of claims 240-244, wherein m is 0 or 1; X² is –O-, -N(R^N)-, –N(R^N)C(=O)-*, or -N(R^N

)S(O)₂-*; L¹ is C_1-3 alkylene optionally substituted with from 1-3 R^a; and R⁵ is selected from the group consisting of: C_1-6 alkoxy or S(O)₂(C_1-6 alkyl) each optionally substituted with from 1-6 R^a; -OH; and –NR^eR^f.

246. The compound of claim 245, wherein R⁵ is C_1-6 alkoxy optionally substituted with from 1-6 R^a, such as wherein R⁵ is C_1-3 alkoxy.

247. The compound of claim 245, wherein R⁵ is S(O)₂(C_1-6 alkyl) which is optionally substituted with from 1-6 R^a, such as wherein R⁵ is S(O)₂(C_1-3 alkyl).

248. The compound of any one of claims 240-244, wherein: m is 0 or 1; X² is –O-, -N(R^N)-,

–N(R^N)C(=O)*, or -N(R^N)S(O)₂-*; L¹ is a bond or C_1-3 alkylene optionally substituted with from 1-3 R^a; and R⁵ is heterocyclyl including from 3-10 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R^d), O, and S(O)_0-2, and wherein the heterocyclyl is optionally substituted with from 1-4 substituents independently selected from the group consisting of oxo and R^c.

249. The compound of claim 248, wherein R⁵ is

250. The compound of claim 248, wherein R⁵ is

251. The compound of claims 249 or 250, wherein x1 is 0.

252. The compound of any one of claims 249-251, wherein X^a is –O-.

253. The compound of any one of claims 248-252, wherein R⁵ is

, such as or whe ⁵

rein R is

254. The compound of any one of claims 249-251, wherein X^a is N(R^d), optionally wherein R^d is C_1-4 alkyl or wherein R^d is C(=O)(C_1-4 alkyl) or S(O)₂(C_1-4 alkyl).

255. The compound of any one of claims 248-251 or 254, wherein R⁵ is selected from the group consisting of:

, optionally wherein R^d is C ^d

_1-4 alkyl or wherein R is C(=O)(C_1-4 alkyl) or S(O)₂(C1- 4 alkyl).

256. The compound of claims 249 or 250, wherein x1 is 1 or 2.

257. The compound of any one of claims 248-250 or 256, wherein R⁵ is selected from the group consisting of:

258. The compound of claim 248, wherein R⁵ is

259. The compound of claims 248 or 258, wherein R⁵ is selected from the group consisting of:

, ; ,

optionally wherein R^d is C_1-4 alkyl, such as methyl.

260. The compound of claim 248, wherein R⁵ is bicyclic heterocyclyl including from 6-10 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R^d), O, and S(O)_0-2, and wherein the heterocyclyl is optionally substituted with from 1-4 substituents independently selected from the group consisting of oxo and R^c, such as wherein R⁵ is

or

such as

261. The compound of any one of claims 240-244, wherein: m is 0 or 1; X² is –O-, -N(R^N)-,

–N(R^N)C(=O)*, or -N(R^N)S(O)₂-*; L¹ is a bond or C_1-3 alkylene optionally substituted with from 1-3 R^a; and R⁵ is selected from the group consisting of: • heteroaryl including from 5-10 ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R^d), O, and S(O)_0-2, and wherein the heteroaryl is optionally substituted with from 1-4 R^c; and • C_6-10 aryl optionally substituted with from 1-4 R^c.

262. The compound of claim 261, wherein R⁵ is monocyclic heteroaryl including 5 ring atoms, wherein from 1-4, such as 2-3, ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R^d), O, and S(O)_0-2, and wherein the heteroaryl is optionally substituted with from 1-3 R^c.

263. The compound of claims 261 or 262, wherein R⁵ is selected from the group consisting of pyrazolyl, imidazolyl, oxazolyl, thiazolyl, isooxazolyl, isothiazolyl, triazolyl, oxadiazolyl, and thiadiazolyl, each optionally substituted with from 1-2 R^c, and wherein a ring nitrogen atom is optionally substituted with R^d, such as

264. The compound of claim 261, wherein R⁵ is monocyclic heteroaryl including 6 ring atoms, wherein from 1-4, such as 1-2, ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), and N(R^d), and wherein the heteroaryl is optionally substituted with from 1-4 R^c, such as

265. The compound of claim 261, wherein R⁵ is bicyclic heteroaryl including 8 ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R^d), O, and S(O)_0-2, and wherein the heteroaryl is optionally substituted with from 1-4 R^c, such as wherein R⁵ is selected from the group consisting of: , each optio ^c

nally substituted with from 1-2 R .

266. The compound of claim 261, wherein R⁵ is bicyclic heteroaryl including from 9-10, such as 9, ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R^d), O, and S(O)_0-2, and wherein the heteroaryl is optionally substituted with from 1-4 R^c, such as wherein R⁵ is

267. The compound of claim 261, wherein R⁵ is phenyl optionally substituted with from 1-2 R^c, such as unsubstituted phenyl.

268. The compound of any one of claims 240-244, wherein: m is 0 or 1; X² is –O-, -N(R^N)-, –N(R^N)C(=O)*, or ^N

269. The compound of claim 268, wherein R⁵ is C_3-6 cycloalkyl, such as cyclopropyl or cyclopentyl.

270. The compound of claim 268, wherein R⁵ is C_3-6 cycloalkyl substituted with a substituent selected from the group consisting of: C_1-4 alkyl; C_1-4 alkyl substituted with R^a, such as C_1-4 alkyl substituted with C_1-4 alkoxy; C_1-4 alkoxy; and C_1-4 haloalkoxy, and wherein the cycloalkyl is further optionally substituted with from 1-2 R^c, such as: wherein R⁵ is selected from the group consisting of:

g such as

g g

271. The compound of any one of claims 240-244, wherein: m is 0 or 1; X² is –O-, -N(R^N)-,

272. The compound of claim 271, wherein R^g2 is

273. The compound of claims 271 or 272, wherein R^g2 is selected from the group consisting of:

, wherein bb is the point of attachment t ^W

o R .

274. The compound of claim 271, wherein R^g2 is

275. The compound of claims 271 or 274, wherein R^g2 is selected from the group consisting of:

; , wherein bb is the point of attac ^W

hment to R ; and optionally wherein R^d is C_1-4 alkyl, such as methyl.

276. The compound of claim 271, wherein R^g2 is is bicyclic heterocyclylene including from 6-8 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R^d), O, and S(O)_0-2, and wherein the heterocyclylene is optionally substituted with from 1-4 substituents independently selected from the group consisting of oxo and R^c, such as wherein R^g2 is

, such as

, wherein bb is the point of attachment to R^W.

277. The compound of any one of claims 271-276, wherein R^W is –C(=O)-W.

278. The compound of any one of claims 271-277, wherein W is C_2-6 alkenyl optionally substituted with from 1-3 R^a.

279. The compound of any one of claims 271-278, wherein R^W is

or

, such as

280. The compound of any one of claims 240-279, wherein m is 1.

281. The compound of any one of claims 240-280, wherein X² is –O-.

282. The compound of any one of claims 240-280, wherein X² is -N(R^N)-, such as –N(H)-.

283. The compound of any one of claims 240-280, wherein X² is

284. The compound of any one of claims 240-280, wherein X² is –N(R^N)C(=O)* or -N(R^N)S(O)₂-*, such as –N(H)C(=O)* or –N(H)S(O)₂-*.

285. The compound of any one of claims 240-279, wherein m is 0.

286. The compound of any one of claims 240-244, wherein: m is 1; X² is –N(R^N)C(=O)-*, -N(R^N)C(=O)O-* or -N(R^N)C(=O)N(R^N)-*; L¹ is C_1-3 alkylene optionally substituted with from 1-3 R^a; and R⁵ is H.

287. The compound of claim 286, wherein X² is -N(R^N)C(=O)-*, such as – N(H)C(=O)-*.

288. The compound of claim 286, wherein X² is selected from the group consisting of -N(R^N)C(=O)N(R^N)-*, such as –N(H)C(=O)N(R^N)-*; and -N(R^N)C(=O)O- *, such as –N(H)C(=O)O-*.

289. The compound of any one of claims 240-288, wherein L¹ is CH₂.

290. The compound of any one of claims 240-288, wherein L¹ is –CH(Me)-.

291. The compound of any one of claims 240-288, wherein L¹ is –CH₂CH₂-.

292. The compound of any one of claims 240-244 or 248-285, wherein L¹ is a bond.

293. The compound of any one of claims 240-244, wherein: m is 1; X² is –O-, -N(R^N)-, ^{N N}

, –N(R )C(=O)*, or -N(R )S(O)₂-*; L¹ is branched C_3-6 alkylene optionally substituted with from 1-6 R^a; and R⁵ is selected from the group consisting of: H; C_1-6 alkoxy or S(O)₂(C_1-6 alkyl) each optionally substituted with from 1-6 R^a; -OH; and –NR^eR^f.

294. The compound of claim 293, wherein R⁵ is C_1-6 alkoxy optionally substituted with from 1-6 R^a, such as wherein R⁵ is C_1-3 alkoxy.

295. The compound of claim 293, wherein R⁵ is S(O)₂(C_1-6 alkyl) which is optionally substituted with from 1-6 R^a.

296. The compound of any one of claims 293-295, wherein X² is –O-.

297. The compound of any one of claims 293-295, wherein X² is -N(R^N)-, such as –N(H)-.

298. The compound of any one of claims 293-295, wherein X² is

.

299. The compound of any one of claims 293-295, wherein X² is –N(R^N)C(=O)* or -N(R^N)S(O)₂-*, such as –N(H)C(=O)-* or –N(H)S(O)₂-*.

300. The compound of any one of claims 240-244 or 293-299, wherein L¹ is branched C_3-6 alkylene.

301. The compound of any one of claims 240-244 or 293-299, wherein L¹ is selected from the group consisting of:

, and , wherein aa is the point of attachme ⁵

nt to R _.

302. The compound of claim 1, wherein the compound is a compound of Formula (I-f):

Formula (I-f) or a pharmaceutically acceptable salt thereof, wherein: Ring C1 monocyclic heteroaryl including from 5-6 ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R^d), O, and S(O)_0-2, and wherein the heteroaryl is optionally substituted with 1-4 R^c.

303. The compound of claim 302, wherein Ring C1 is monocyclic heteroaryl including 5 ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R^d), O, and S(O)_0-2, and wherein the heteroaryl is optionally substituted with 1-3 R^c.

304. The compound of claims 302 or 303, wherein Ring C1 is selected from the group consisting of: pyrazolyl, imidazolyl, oxazolyl, thiazolyl, isooxazolyl, isothiazolyl, triazolyl, oxadiazolyl, and thiadiazolyl, each optionally substituted with from 1-2 R^c, and wherein a ring nitrogen atom is optionally substituted with R^d.

305. The compound of claim 302, wherein Ring C1 is selected from the group consisting of:

, such as wherein Ring C1 is:

306. The compound of claim 302, wherein Ring C1 is monocyclic heteroaryl including 6 ring atoms, wherein from 1-4 ring atoms are heteroatoms each independently selected from the group consisting of N, N(H), and N(R^d), and wherein the heteroaryl is optionally substituted with from 1-4 R^c.

307. The compound of claims 302 or 306, wherein Ring C1 is selected from the group consisting of:

, and

308. The compound of any one of claims 302 or 306-307, wherein Ring C1 is: (i) selected from the group consisting of:

and

, wherein the R^c present in Ring C is C_1-3 alkyl optionally substituted with from 1-3 R^a, such as C_1-3 alkyl optionally substituted with from 1-3 independently selected halo; or (ii) selected from the group consisting of:

and

wherein the R^c present in Ring C is selected from the group consisting of: halo and C_1-3 alkyl optionally substituted with from 1-3 R^a, optionally wherein the R^c is –F, -Cl, or C_1-3 alkyl optionally substituted with from 1-3 independently selected halo.

309. The compound of claim 1, wherein the compound is a compound of Formula (I-g):

Formula (I-g) or a pharmaceutically acceptable salt thereof, wherein: Ring C2 is bicyclic heteroaryl including from 8-10 ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R^d), O, and S(O)_0-2, and wherein the heteroaryl is optionally substituted with 1-4 R^c.

310. The compound of claim 309, wherein Ring C2 is bicyclic heteroaryl including 9 ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R^d), O, and S(O)_0-2, and wherein the heteroaryl is optionally substituted with 1-4 R^c.

311. The compound of claims 309 or 310, wherein Ring C2 is selected from the group consisting of:

, each further optionally substituted with from 1-2 R^c; or (iii)

312. The compound of claim 309, wherein: (i) Ring C2 is bicyclic heteroaryl including 10 ring atoms, wherein from 1-4 ring atoms are heteroatoms each independently selected from the group consisting of N, N(H), and N(R^d), and wherein the heteroaryl is optionally substituted with from 1-4 R^c; (ii) Ring C2 is selected from the group consisting of:

,

(iii) Ring C2 is selected from the group consisting of:

;

;

313. The compound of claim 1, wherein the compound is a compound of Formula (I-h):

Formula (I-h) or a pharmaceutically acceptable salt thereof, wherein: Ring C3 is heterocyclyl or heterocycloalkenyl including from 3-10 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R^d), O, and S(O)_0-2, and wherein the heterocyclyl or heterocycloalkenyl is optionally substituted with X¹ and further optionally substituted with from 1-4 substituents independently selected from the group consisting of oxo and R^c.

314. The compound of claim 313, wherein Ring C3 is heterocyclyl including from 4-8 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R^d), O, and S(O)_0-2, and wherein the heterocyclyl is optionally substituted with from 1-4 substituents independently selected from the group consisting of oxo and R^c, such as wherein Ring C is tetrahydropyranyl, such as

315. The compound of any one of claims 302-314, wherein each occurrence of R^c present on one or more ring atoms of Ring C1, Ring C2, or Ring C3 is independently selected from the group consisting of: C_1-3 alkyl; C_1-3 alkyl substituted with from 1-3 R^a; halo; cyano; NR^eR^f, such as NH₂, NH(C_1-3 alkyl), or N(C_1-3 alkyl)₂; -OH; C_1-4 alkoxy; and C_1-4 haloalkoxy.

316. The compound of claim 1, wherein the compound of Formula (I) is a compound of Formula (I-a1):

Formula (I-a1) or a pharmaceutically acceptable salt thereof, wherein: n is 0, 1, or 2; and R⁵ is heterocyclyl including from 4-10 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R^d), O, and S(O)_0-2, and wherein the heterocyclyl is optionally substituted with from 1-4 substituents independently selected from the group consisting of oxo and R^c.

317. The compound of claim 316, wherein R⁵ is

318. The compound of claim 317, wherein x1 is 0.

319. The compound of claims 317 or 318, wherein X^a is –O-.

320. The compound of any one of claims 316-319, wherein R⁵ is

, such as ; or w ⁵

herein R is

321. The compound of claims 317 or 318, wherein X^a is N(R^d), optionally wherein R^d is C_1-4 alkyl or wherein R^d is C(=O)(C_1-4 alkyl) or S(O)₂(C_1-4 alkyl).

322. The compound of any one of claims 316-318 or 321, wherein R⁵ is selected from the group consisting of:

) ; , ; , , optionally wherein ^{d d}

R is C_1-4 alkyl or wherein R is C(=O)(C_1-4 alkyl) or S(O)₂(C1- 4 alkyl).

323. The compound of claim 317, wherein x1 is 1 or 2.

324. The compound of any one of claims 316-317 or 323, wherein R⁵ is selected from the group consisting of:

325. The compound of claim 316, wherein R⁵ is

326. The compound of claims 316 or 325, wherein R⁵ is selected from the group

g , ; ,

optionally wherein R^d is C_1-4 alkyl, such as methyl.

327. The compound of claim 316, wherein R⁵ is bicyclic heterocyclyl including from 6-10 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R^d), O, and S(O)_0-2, and wherein the heterocyclyl is optionally substituted with from 1-4 substituents independently selected from the group consisting of oxo and R^c, such as wherein R⁵ is

328. The compound of claim 1, wherein the compound of Formula (I) is a compound of Formula (I-a2):

Formula (I-a2) or a pharmaceutically acceptable salt thereof, wherein: n is 0, 1, or 2; and R⁵ is selected from the group consisting of: • heteroaryl including from 5-6 ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R^d), O, and S, and wherein the heteroaryl is optionally substituted with from 1-3 R^c; and • C6 aryl optionally substituted with from 1-4 R^c.

329. The compound of claim 328, wherein R⁵ is monocyclic heteroaryl including 5 ring atoms, wherein from 1-4, such as 2-3, ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R^d), O, and S, and wherein the heteroaryl is optionally substituted with from 1-3 R^c, such as: wherein R⁵ is

330. The compound of claim 328, wherein R⁵ is monocyclic heteroaryl including 6 ring atoms, wherein from 1-4, such as 1-2, ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), and N(R^d), and wherein the heteroaryl is optionally substituted with from 1-4 R^c, such as

, , ,

331. The compound of claim 1, wherein the compound of Formula (I) is a compound of Formula (I-a3):

Formula (I-a3) or a pharmaceutically acceptable salt thereof, wherein: n is 0, 1, or 2; and R⁵ is C_3-10 cycloalkyl which is optionally substituted with from 1-4 substituents independently selected from the group consisting of oxo and R^c.

332. The compound of claim 331, wherein R⁵ is C_3-6 cycloalkyl, such as cyclopropyl or cyclopentyl.

333. The compound of claim 331, wherein R⁵ is C_3-6 cycloalkyl substituted with a substituent selected from the group consisting of: C_1-4 alkyl; C_1-4 alkyl substituted with R^a, such as C_1-4 alkyl substituted with C_1-4 alkoxy; C_1-4 alkoxy; and C_1-4 haloalkoxy, and wherein the cycloalkyl is further optionally substituted with from 1-2 R^c, such as: wherein R⁵ is selected from the group consisting of:

334. The compound of claim 1, wherein the compound of Formula (I) is a compound of Formula (I-a4):

Formula (I-a4) or a pharmaceutically acceptable salt thereof, wherein: n is 0, 1, or 2; and R⁵ is –R^g2-R^W, wherein: the -R^g2 of R⁵ is heterocyclylene including from 4-8 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R^d), O, and S(O)_0-2, and wherein the heterocyclylene is optionally substituted with from 1-4 substituents independently selected from the group consisting of oxo and R^c; and -R^W is –C(=O)-W or –S(O)₂-W.

335. The compound of claim 334, wherein R^g2 is

which is optionally substituted with from 1-2 R^c, wherein bb is the point of attachment to R^W; and x1 and x2 are each independently 0, 1, or 2.

336. The compound of claim 335, wherein x1 is 0.

337. The compound of any one of claims 334-336, wherein R^g2 is selected from the group consisting of:

, ; ,

, wherein bb is the point of att ^W

achment to R .

338. The compound of claim 334, wherein R^g2 is

339. The compound of claims 334 or 338, wherein R^g2 is selected from the group consisting of:

such as or ; and , such as

or , wher ^W

ein bb is the point of attachment to R ; and optionally wherein R^d is C_1-4 alkyl, such as methyl.

340. The compound of claim 334, wherein R^g2 is is bicyclic heterocyclylene including from 6-8 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R^d), O, and S(O)_0-2, and wherein the heterocyclylene is optionally substituted with from 1-4 substituents independently selected from the group consisting of oxo and R^c, such as wherein R^g2 is

, such as , or

, wherein bb is

the point of attachment to R^W.

341. The compound of any one of claims 334-340, wherein R^W is –C(=O)-W.

342. The compound of any one of claims 334-341, wherein W is C_2-6 alkenyl optionally substituted with from 1-3 R^a.

343. The compound of any one of claims 334-342, wherein R^W is

or

, such as

344. The compound of claim 1, wherein the compound is a compound of Formula (I-a5):

Formula (I-a5) or a pharmaceutically acceptable salt thereof, wherein: n is 0, 1, or 2; L¹ is C_1-6 alkylene optionally substituted with from 1-6 R^a; and R⁵ is selected from the group consisting of: H; C_1-6 alkoxy or S(O)₂(C_1-6 alkyl) each optionally substituted with from 1-6 R^a; -OH; and –NR^eR^f.

345. The compound of claim 344, wherein L¹ is branched C_3-6 alkylene.

346. The compound of claims 344 or 345, wherein L¹ is selected from the group consisting of:

and

, wherein aa is the point of attachment to R⁵.

347. The compound of any one of claims 344-346, wherein R⁵ is H.

348. The compound of claim 1, wherein the compound is a compound of Formula (I-g1):

Formula (I-g1) or a pharmaceutically acceptable salt thereof, wherein: n is 0 or 1; Y¹, Y², and Y³ are each independently selected from the group consisting of: N, NH, NR^d, CH, CR^c, CX¹, O, and S; and each is independently a single bond or a double bond, provided that the 5-membered ring including Y¹, Y², and Y³ is heteroaryl; and from 0-1 of Y¹, Y², and Y³ is selected from the group consisting of: O, S, and CR^X1.

349. The compound of claim 348, wherein Y¹ is S.

350. The compound of claims 348 or 349, wherein Y² is selected from the group consisting of: N, CH, CR^c, and CX¹.

351. The compound of any one of claims 348-350, wherein Y² is CH or CR^c.

352. The compound of any one of claims 348-350, wherein Y² is N.

353. The compound of any one of claims 348-352, wherein Y³ is selected from the group consisting of CH and CR^c.

354. The compound of any one of claims 348-353, wherein Y³ is CH.

355. The compound of claim 348, wherein Y¹ is S; and Y² and Y² are each CH.

356. The compound of claim 348, wherein Y¹ is S; Y² is N; and Y³ is CH.

357. The compound of claim 348, wherein Y¹ is S; Y² is CR^c; and Y³ is CH.

358. The compound of any one of claims 348-351, 353-354, or 357, wherein the R^c group present in Y² is selected from the group consisting of: (i) C_1-6 alkyl; (ii) halo; and (iii) C_1-6 alkyl substituted with from 1-6 independently selected R^a.

359. The compound of claim 358, wherein the R^c group present in Y² is selected from the group consisting of: (i) C_1-3 alkyl (e.g., methyl); (ii) halo (e.g., -F); and (iii) C_1-3 alkyl substituted with from 1-3 independently selected halo (e.g., R^c is – CHF₂ ⁾ .

360. The compound of claim 1 or 348, wherein the compound is a compound of Formula (I-g1-1):

Formula (I-g1-1) or a pharmaceutically acceptable salt thereof, wherein: n is 0 or 1, such as 0.

361. The compound of any one of claims 240-360, wherein R^1c is H.

362. The compound of any one of claims 240-361, wherein R^2a and R^2b are H.

363. The compound of any one of claims 240-361, wherein from 1-2, such as 1, of R^2a and R^2b is a substituent other than H.

364. The compound of any one of claims 240-361 or 363, wherein one of R^2a and R^2b is C_1-3 alkyl optionally substituted with from 1-3 R^a, such as C_1-3 alkyl (e.g., methyl) ; and the other of R^2a and R^2b is H.

365. The compound of any one of claims 240-361 or 363, wherein one of R^2a and R^2b is heterocyclyl including from 4-6 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R^d), O, and S(O)_0-2, and wherein the heterocyclyl is optionally substituted with from 1-4 substituents independently selected from the group consisting of oxo and R^c; and the other of R^2a and R^2b is H.

366. The compound of any one of claims 240-361, wherein R^2a and R^2b together with the Ring B ring atom to which each is attached form a cycloalkyl ring of 3-6 ring atoms, such as 3 ring atoms, wherein the fused cycloalkyl ring is optionally substituted with from 1-2 R^c.

367. The compound of any one of claims 240-366, wherein R^3a and R^3b are H.

368. The compound of any one of claims 240-366, wherein from 1-2, such as 1, of R^3a and R^3b is a substituent other than H.

369. The compound of any one of claims 240-366 or 368, wherein one of R^3a and R^3b is C_1-3 alkyl optionally substituted with from 1-3 R^a; and the other of R^3a and R^3b is H.

370. The compound of any one of claims 240-366 or 368-369, wherein one of R^3a and R^3b is C_1-3 alkyl optionally substituted with from 1-3 independently selected halo, such as –CH₃, –CH₂F, -CH₂CH₂F, or –CHF₂; and the other of R^3a and R^3b is H.

371. The compound of any one of claims 240-366 or 368-369, wherein one of R^3a and R^3b is C_1-3 alkyl substituted with C_1-4 alkoxy, C_1-4 haloalkoxy, or NR^eR^f, such as wherein one of R^3a and R^3b is –CH₂OMe, -CH₂CH₂OMe, -CH(Me)CH₂OMe, - CH₂CH(Me)OMe, -CH₂OEt, -CH₂NR^eR^f (e.g., -CH₂N(CF₃)Me), or –CH₂CH₂NR^eR^f (e.g., -CH₂CH₂NMe₂); and the other of R^3a and R^3b is H.

372. The compound of any one of claims 240-366 or 368, wherein one of R^3a and R^3b is selected from the group consisting of: heterocyclyl including from 4-6 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R^d), O, and S(O)_0-2, and wherein the heterocyclyl is optionally substituted with from 1-4 substituents independently selected from the group consisting of oxo and R^c; and C_3-6 cycloalkyl optionally substituted with from 1-4 R^c; and the other of R^3a and R^3b is H.

373. The compound of any one of claims 240-366 or 368, one of R^3a and R^3b is –(C_1-3 alkylene)-R^g or –(C_1-3 alkylene)-O-R^g, wherein the R^g group of R^3a or R^3b is: C_3-6 cycloalkyl optionally substituted with from 1-4 R^c, or heterocyclyl including from 4-6 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R^d), O, and S(O)_0-2, and wherein the heterocyclyl is optionally substituted with from 1-4 substituents independently selected from the group consisting of oxo and R^c; and the other of R^3a and R^3b is H.

374. The compound of any one of claims 240-366, wherein R^3a and R^3b together with the Ring B ring atom to which each is attached form a cycloalkyl ring of 3-6 ring atoms, such as 3 or 4 ring atoms, wherein the fused cycloalkyl ring is optionally substituted with from 1-2 R^c.

375. The compound of any one of claims 240-366, wherein R^3a and R^3b together with the Ring B ring atom to which each is attached, form a fused saturated ring of 4-6 ring atoms; • wherein from 1-2 of the ring atoms are each an independently selected heteroatom, wherein each of the independently selected heteroatoms is selected from the group consisting of N, NH, N(R^d), O, and S(O)_0-2; and • wherein the fused saturated ring of 4-6 ring atoms is optionally substituted with from 1-2 substituents independently selected from the group consisting of oxo and R^c.

376. The compound of any one of claims 240-366, wherein R^3a and R^3b together with the Ring B ring atom to which each is attached, form a fused saturated ring of 4-6 ring atoms; • wherein from 1-2 of the ring atoms are each an independently selected heteroatom, wherein each of the independently selected heteroatoms is selected from the group consisting of N, NH, N(R^d), O, and S(O)_0-2; and • wherein the fused saturated ring of 4-6 ring atoms is substituted with R^W and further optionally substituted with from 1-2 substituents independently selected from the group consisting of oxo and R^c.

377. The compound of any one of claims 240-366 or 376, wherein R^3a and R^3b together with the Ring B ring atom to which each is attached, form: (i)

, , ; (ii) any group of (i), wherein R^W is –L^W-W, wherein L^W is C(=O) or S(O)₂; and R^W is C_2-6 alkenyl which is optionally substituted with from 1-3 R^a and further optionally substituted with R^g, wherein W is attached to L^W via an sp² hybridized carbon atom; or (iii) any group of (i), wherein R^W is or

; or

(iv) , wherein R^W is

378. The compound of any one of claims 240-361, wherein one of R^2a and R^2b and one of R^3a and R^3b taken together with the Ring B ring atoms to which each is attached, form a fused C_3-6 (e.g., C₃ or C₄) cycloalkyl which is optionally substituted with from 1-2 R^c.

379. The compound of any one of claims 240-361, wherein one of R^2a and R^2b and one of R^3a and R^3b combine to form a double bond between the Ring B ring atoms to which each is attached.

380. The compound of claims 378 or 379, wherein the other of R^2a and R^2b and the other of R^3a and R^3b are each H.

381. The compound of claims 378 or 379, wherein the other of R^2a and R^2b is H; and the other of R^3a and R^3b is selected from the group consisting of: R^b, R^g, and –(L^g)_g- R^g.

382. The compound of any one of claims 378-379 or 381, wherein the other of R^2a and R^2b is H; and the other of R^3a and R^3b is selected from the group consisting of: (i) C_1-3 alkyl; (ii) C_1-3 alkyl substituted with from 1-3 independently selected halo; (iii) C_1-3 alkyl substituted with C_1-4 alkoxy, C_1-4 haloalkoxy, or NR^eR^f; (iv) C_1-3 alkyl substituted with C_1-4 alkoxy or C_1-4 haloalkoxy; or (v) –R^g, –CH₂-R^g, –CH₂CH₂R^g, or –CH₂-O-R^g, wherein the R^g group of R^3a or R^3b is: C_3-6 cycloalkyl optionally substituted with from 1-4 R^c, or heterocyclyl including from 4-6 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R^d), O, and S(O)_0-2, and wherein the heterocyclyl is optionally substituted with from 1-4 substituents independently selected from the group consisting of oxo and R^c.

383. The compound of any one of claims 378-379 or 381-382, wherein the other of R^2a and R^2b is H; and the other of R^3a and R^3b is C_1-3 alkyl substituted with C_1-4 alkoxy, C_1-4 haloalkoxy, or NR^eR^f.

384. The compound of any one of claims 240-360, wherein R^1c, R^2a, and R^2b are each H; one of R^3a and R^3b is C_1-3 alkyl optionally substituted with from 1-3 R^a; and the other of R^3a and R^3b is H, optionally each R^a substituent present in R^3a or R^3b is independently selected from the group consisting of: halo, C_1-4 alkoxy, and C_1-4 haloalkoxy.

385. The compound of any one of claims 240-360 or 384, wherein R^1c, R^2a, and R^2b are each H; one of R^3a and R^3b is C_1-3 alkyl substituted with C_1-4 alkoxy or C_1-4 haloalkoxy; and the other of R^3a and R^3b is H.

386. The compound of any one of claims 240-360, wherein R^1c, R^2a, and R^2b are each H; and R^3a and R^3b are independently selected C_1-3 alkyl.

387. The compound of any one of claims 240-360, wherein R^1c, R^2a, and R^2b are each H; one of R^3a and R^3b is –R^g, –(C_1-3 alkylene)-R^g, or –(C_1-3 alkylene)-O-R^g, optionally wherein the R^g group of R^3a or R^3b is: C_3-6 cycloalkyl optionally substituted with from 1-4 R^c, or heterocyclyl including from 4-6 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R^d), O, and S(O)_0-2, and wherein the heterocyclyl is optionally substituted with from 1-4 substituents independently selected from the group consisting of oxo and R^c; and the other of R^3a and R^3b is H.

388. The compound of any one of claims 240-360, wherein R^1c, R^2a, and R^2b are each H; and R^3a and R^3b taken together with the Ring B ring carbon atom to which each is attached form a fused cycloalkyl ring of 3-6 ring atoms, such as 3 ring atoms, wherein the fused cycloalkyl ring is optionally substituted with from 1-2 R^c.

389. The compound of any one of claims 240-360, wherein R^1c, R^2a, and R^2b are each H; and R^3a and R^3b together with the Ring B ring atom to which each is attached, form a fused saturated ring of 4-6 ring atoms; • wherein from 1-2 of the ring atoms are each an independently selected heteroatom, wherein each of the independently selected heteroatoms is selected from the group consisting of N, NH, N(R^d), O, and S(O)_0-2; and • wherein the fused saturated ring of 4-6 ring atoms is optionally substituted with from 1-2 substituents independently selected from the group consisting of oxo and R^c.

390. The compound of any one of claims 240-360, wherein R^1c, R^2a, and R^2b are each H; and R^3a and R^3b together with the Ring B ring atom to which each is attached, form: (i)

.

391. The compound of any one of claims 240-360, wherein R^1c is H; one of R^2a and R^2b and one of R^3a and R^3b taken together with the Ring B ring atoms to which each is attached, form a fused C_3-6 (e.g., C₃ or C₄) cycloalkyl which is optionally substituted with from 1-2 R^c; and the other of R^2a and R^2b and the other of R^3a and R^3b are each H.

392. The compound of any one of claims 240-360, wherein R^1c is H; one of R^2a and R^2b and one of R^3a and R^3b combine to form a double bond between the Ring B ring atoms to which each is attached; and the other of R^2a and R^2b and the other of R^3a and R^3b are each H.

393. The compound of any one of claims 240-360, wherein R^1c is H; one of R^2a and R^2b and one of R^3a and R^3b combine to form a double bond between the Ring B ring atoms to which each is attached; the other of R^2a and R^2b is H; and the other of R^3a and R^3b is selected from the group consisting of: (i) C_1-3 alkyl; (ii) C_1-3 alkyl substituted with from 1-3 independently selected halo; (iii) C_1-3 alkyl substituted with C_1-4 alkoxy, C_1-4 haloalkoxy, or NR^eR^f; (iv) C_1-3 alkyl substituted with C_1-4 alkoxy or C_1-4 haloalkoxy; or (v) –R^g, –CH₂-R^g, –CH₂CH₂R^g, or –CH₂-O-R^g, wherein the R^g group of R^3a or R^3b is: C_3-6 cycloalkyl optionally substituted with from 1-4 R^c, or heterocyclyl including from 4-6 ring atoms, wherein from 1-3 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R^d), O, and S(O)_0-2, and wherein the heterocyclyl is optionally substituted with from 1-4 substituents independently selected from the group consisting of oxo and R^c.

394. The compound of any one of claims 240-360, wherein R^1c is H; one of R^2a and R^2b and one of R^3a and R^3b combine to form a double bond between the Ring B ring atoms to which each is attached; the other of R^2a and R^2b is H; and the other of R^3a and R^3b is C_1-3 alkyl substituted with C_1-4 alkoxy or C_1-4 haloalkoxy.

395. The compound of any one of claims 240-394, wherein Ring A is , wherein each R^cB is an independently ^c

selected R ; and m is 0, 1, 2, 3, or 4.

396. The compound of claim 395, wherein m is 1 or 2, such as 2.

397. The compound of any one of claims 240-396, wherein Ring A is

or

(e.g., ), wherein each R^cB is an independently

selected R^c.

398. The compound of any one of claims 395-397, wherein each R^cB is independently selected from the group consisting of: -halo, such as -Cl and -F; -CN; C_1-4 alkoxy; C_1-4 haloalkoxy; C_1-3 alkyl; and C_1-3 alkyl substituted with from 1-6 independently selected halo.

399. The compound of any one of claims 240-398, wherein Ring A is selected from the group consisting of:

, and

.

400. The compound of any one of claims 240-394, wherein Ring A is heteroaryl including from 5-10 ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R^d), O, and S(O)_0-2, and wherein the heteroaryl is optionally substituted with from 1-4 substituents independently selected from the group consisting of R^c and oxo.

401. The compound of any one of claims 240-394 or 400, wherein Ring A is bicyclic heteroaryl including from 9-10 ring atoms, wherein from 1-4 ring atoms are heteroatoms, each independently selected from the group consisting of N, N(H), N(R^d), O, and S(O)_0-2, and wherein the heteroaryl is optionally substituted with from 1-4 substituents independently selected from the group consisting of R^c and oxo, such as: wherein Ring A is selected from the group consisting of:

, and

, each of which is further optionally substituted with R^c.

402. The compound of any one of claims 7-9, 240-244, or 316-401, wherein n is 0.

403. The compound of claim 1, wherein the compound is selected from the group consisting of the compounds delineated in Table C1, or a pharmaceutically acceptable salt thereof.

404. A pharmaceutical composition comprising a compound of any one of claims 1-403, or a pharmaceutically acceptable salt thereof, and pharmaceutically acceptable diluent or carrier.

405. A method for treating cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of any one of claims 1-403, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 404.

406. A method for treating cancer in a subject in need thereof, the method comprising (a) determining that the cancer is associated with a dysregulation of an EGFR gene, an EGFR kinase, or expression or activity or level of any of the same; and (b) administering to the subject a therapeutically effective amount of a compound of any one of claims 1-403, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 404.

407. A method of treating an EGFR-associated cancer in a subject, the method comprising administering to a subject identified or diagnosed as having an EGFR- associated cancer a therapeutically effective amount of a compound of any one of claims 1-403 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 404.

408. A method of treating an EGFR-associated cancer in a subject, the method comprising: (a) determining that the cancer in the subject is an EGFR-associated cancer; and (b) administering to the subject a therapeutically effective amount of a compound of any one of claims 1-403 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 404.

409. A method of treating a subject, the method comprising administering a therapeutically effective amount of a compound of any one of claims 1-403 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 404, to a subject having a clinical record that indicates that the subject has a dysregulation of an EGFR gene, an EGFR kinase, or expression or activity or level of any of the same.

410. The method of claims 406 or 408, wherein the step of determining that the cancer in the subject is an EGFR-associated cancer includes performing an assay to detect dysregulation in an EGFR gene, an EGFR kinase protein, or expression or activity or level of any of the same in a sample from the subject.

411. The method of claim 410, further comprising obtaining a sample from the subject.

412. The method of claim 411, wherein the sample is a biopsy sample.

413. The method of any one of claims 410-412, wherein the assay is selected from the group consisting of sequencing, immunohistochemistry, enzyme-linked immunosorbent assay, and fluorescence in situ hybridization (FISH).

414. The method of claim 413, wherein the FISH is break apart FISH analysis.

415. The method of claim 413, wherein the sequencing is pyrosequencing or next generation sequencing.

416. The method of any one of claims 406, 409, or 410, wherein the dysregulation in an EGFR gene, an EGFR kinase protein, or expression or activity or level of any of the same is one or more point mutations in the EGFR gene.

417. The method of claim 416, wherein the one or more point mutations in an EGFR gene results in the translation of an EGFR protein having one or more amino acid substitutions at one or more of the following amino acid positions exemplified in Table 1a and 1b.

418. The method of claim 417, wherein the one or more point mutations is selected from the mutations in Table 1a and 1b (e.g., L858R, G719S, G719C, G719A, L861Q, a deletion in exon 19 and/or an insertion in exon 20).

419. The method of claim 417, wherein the one or more point mutations is an EGFR inhibitor resistance mutation (e.g., L718Q, L747S, D761Y, T790M, C797S, T854A).

420. The method of claim 417, wherein the one or more point mutations in an EGFR gene include a deletion in exon 19 of a human EGFR gene.

421. The method of claim 417, wherein the one or more mutations is an EGFR insertion in exon 20 of a human EGFR gene.

422. The method of claim 421, wherein the insertion in exon 20 of a human EGFR gene is selected from: V769_D770insX, D770_N771insX, N771_P772insX, P772_H773insX, and H773_V774insX.

423. The method of claims 421 or 422, wherein the insertion in exon 20 of a human EGFR gene is selected from: Y772_A775dup, A775_G776insYVMA, G776delinsVC, G776delinsVV, V777_G778insGSP, and P780_Y781insGSP.

424. The method of any one of claims 406-408 and 410-423, wherein the EGFR- associated cancer is selected from the group consisting of: oral cancer, oropharyngeal cancer, nasopharyngeal cancer, respiratory cancer, urogenital cancer, gastrointestinal cancer, central or peripheral nervous system tissue cancer, an endocrine or neuroendocrine cancer, a hematopoietic cancer, glioma, sarcoma, carcinoma, lymphoma, melanoma, fibroma, meningioma, brain cancer, oropharyngeal cancer, nasopharyngeal cancer, renal cancer, biliary cancer, pheochromocytomaLi-Fraumeni tumor, thyroid cancer, parathyroid cancer, pituitary tumors, adrenal gland tumors, osteogenic sarcoma tumors, breast cancer, lung cancer, head and neck cancer, prostate cancer, esophageal cancer, tracheal cancer, liver cancer, bladder cancer, stomach cancer, pancreatic cancer, ovarian cancer, uterine cancer, cervical cancer, testicular cancer, colon cancer, rectal cancer and skin cancer.

425. The method of any one of claims 407, 408, and 410-424, wherein the EGFR-associated cancer is selected from the group consisting of: lung cancer, pancreatic cancer, head and neck cancer, melanoma, colon cancer, renal cancer, leukemia, glioblastoma, or breast cancer.

426. The method of claim 424 or 425, wherein the lung cancer is non-small cell lung cancer.

427. The method of any one of claims 405-426, wherein the cancer is a HER2- associated cancer.

428. The method of claim 427, wherein the HER2-associated cancer is associated with a dysregulation of a HER2 gene, a HER2 kinase, or expression or activity or level of any of the same.

429. The method of any one of claims 427 and 428, wherein determining that the cancer in the subject is a HER2-associated cancer includes performing an assay to detect dysregulation in a HER2 gene, a HER2 kinase protein, or expression or activity or level of any of the same in a sample from the subject.

430. The method of claim 429, further comprising obtaining a sample from the subject.

431. The method of claim 430, wherein the sample is a biopsy sample.

432. The method of any one of claims 429-431, wherein the assay is selected from the group consisting of sequencing, immunohistochemistry, enzyme-linked immunosorbent assay, and fluorescence in situ hybridization (FISH).

433. The method of claim 432, wherein the sequencing is pyrosequencing or next generation sequencing.

434. The method of any one of claims 428-433, wherein the dysregulation in a HER2 gene, a HER2 kinase protein, or expression or activity or level of any of the same is one or more point mutations in the HER2 gene.

435. The method of claim 434, wherein the one or more point mutations in a HER2 gene results in the translation of a HER2 protein having one or more amino acid substitutions at one or more of the following amino acid positions exemplified in Table 3.

436. The method of claim 435, wherein the one or more point mutations is selected from the mutations in Table 3 (e.g., S310F, S310Y, R678Q, R678W, R678P, I767M, V773M, V777L, and V842I).

437. The method of any one of claims 405-436, wherein the cancer is selected from the group consisting of: non-small cell lung cancer, pancreatic cancer, and colorectal cancer.

438. The method of any one of claims 405-437, further comprising administering an additional therapy or therapeutic agent to the subject.

439. The method of claim 438, wherein the additional therapy or therapeutic agent is selected from radiotherapy, cytotoxic chemotherapeutics, kinase targeted- therapeutics, apoptosis modulators, signal transduction inhibitors, immune-targeted therapies, and angiogenesis-targeted therapies.

440. The method of claim 439, wherein said additional therapeutic agent is selected from one or more kinase targeted therapeutics.

441. The method of claim 440, wherein said additional therapeutic agent is a tyrosine kinase inhibitor.

442. The method of claim 441, wherein said additional therapeutic agent is a second EGFR inhibitor.

443. The method of any one of claims 438-442, wherein said additional therapeutic agent is selected from osimertinib, gefitinib, erlotinib, afatinib, lapatinib, neratinib, AZD-9291, CL-387785, CO-1686, WZ4002, and combinations thereof.

444. The method of claim 438, wherein said additional therapeutic agent is a second compound of any one of claims 1-403 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 404.

445. The method of claim 438, wherein said additional therapeutic agent is a HER2 inhibitor.

446. The method of claim 445, wherein the HER2 inhibitor is selected from trastuzumab, pertuzumab, trastuzumab emtansine, lapatinib, KU004, neratinib, dacomitinib, afatinib, tucatinib, erlotinib, pyrotinib, poziotinib, CP-724714, CUDC-101, sapitinib (AZD8931), tanespimycin (17-AAG), IPI-504, PF299, pelitinib, S- 222611, and AEE-788.

447. The method of any one of claims 438-446, wherein the compound of any one of claims 1-403 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 404, and the additional therapeutic agent are administered simultaneously as separate dosages.

448. The method of any one of claims 438-446, wherein the compound of any one of claims 1-403 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 404, and the additional therapeutic agent are administered as separate dosages sequentially in any order.

449. A method of treating a subject having a cancer, wherein the method comprises: (a) administering one or more doses of a first EGFR inhibitor to the subject for a period of time; (b) after (a), determining whether a cancer cell in a sample obtained from the subject has at least one EGFR inhibitor resistance mutation that confers increased resistance to a cancer cell or tumor to treatment with the first EGFR inhibitor of step (a); and (c) administering a compound of any one of claims 1-403 or a pharmaceutically acceptable salt thereof, as a monotherapy or in conjunction with another anticancer agent to the subject if the subject has been determined to have a cancer cell that has at least one EGFR inhibitor resistance mutation that confers increased resistance to a cancer cell or tumor to treatment with the first EGFR inhibitor of step (a); or (d) administering additional doses of the first EGFR inhibitor of step (a) to the subject if the subject has not been determined to have a cancer cell that has at least one EGFR inhibitor resistance mutation that confers increased resistance to a cancer cell or tumor to treatment with the first EGFR inhibitor of step (a).

450. The method of claim 449, wherein the anticancer agent in step (c) is a second EGFR inhibitor, an immunotherapy, a HER2 inhibitor, or a combination thereof.

451. The method of claim 449, wherein the anticancer agent in step (c) is the first EGFR inhibitor administered in step (a).

452. The method of claim 449, wherein the subject is administered additional doses of the first inhibitor of EGFR of step (a), and the method further comprises (e) administering another anticancer agent to the subject.

453. The method of claim 452, wherein the anticancer agent of step (e) is a second EGFR inhibitor, an immunotherapy, or a combination thereof.

454. The method of claim 452, wherein the anticancer agent of step (e) is a compound of any one of claims 1-403 or a pharmaceutically acceptable salt thereof.

455. The method of any one of claims 449-454, wherein the EGFR inhibitor resistance mutation is a substitution at amino acid position 718, 747, 761, 790, 797, or 854 (e.g., L718Q, L747S, D761Y, T790M, C797S, T854A).

456. A method of treating an EGFR-associated cancer in a subject, the method comprising administering to a subject identified or diagnosed as having an EGFR- associated cancer that has one or more EGFR inhibitor resistance mutations a therapeutically effective amount of a compound of any one of claims 1-403 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 404.

457. A method of treating an EGFR-associated cancer in a subject, the method comprising: (a) determining that the cancer in the subject has one or more EGFR inhibitor resistance mutations; and (b) administering to the subject a therapeutically effective amount of a compound of any one of claims 1-403 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 404.

458. A method of treating a subject having a cancer, wherein the method comprises: (a) determining whether a cancer cell in a sample obtained from a subject having a cancer and previously administered one or more doses of a first EGFR inhibitor has one or more EGFR inhibitor resistance mutations that confer increased resistance to a cancer cell or tumor to treatment with the first EGFR inhibitor that was previously administered to the subject; and (b) administering a compound of any one of claims 1-403 or a pharmaceutically acceptable salt thereof, as a monotherapy or in conjunction with another anticancer agent to the subject if the subject has been determined to have a cancer cell that has at least one EGFR inhibitor resistance mutation that confers increased resistance to a cancer cell or tumor to treatment with the first modulator of EGFR that was previously administered to the subject; or (c) administering additional doses of the first modulator of EGFR to the subject if the subject has not been determined to have a cancer cell that has at least one EGFR modulator resistance mutation that confers increased resistance to a cancer cell or tumor to treatment with the first modulator of EGFR previously administered to the subject.

459. The method of claim 458, wherein the anticancer agent of step (b) is a second EGFR innhibitor, an immunotherapy, a HER2 inhibitor, or a combination thereof.

460. The method of claim 458, wherein the anticancer agent of step (b) is the first EGFR inhibitor previously administered to the subject.

461. The method of claim 458, wherein the subject is administered additional doses of the first EGFR inhibitor previously administered to the subject, and the method further comprises (d) administering another anticancer agent to the subject.

462. The method of claim 461, wherein the anticancer agent of step (d) is a second EGFR inhibitor, an immunotherapy, or a combination thereof.

463. The method of claim 461, wherein the anticancer agent of step (d) is a compound of any one of claims 1-403 or a pharmaceutically acceptable salt thereof.

464. The method of claim 462, wherein the second EGFR inhibitor is selected from osimertinib, gefitinib, erlotinib, afatinib, lapatinib, neratinib, AZD-9291, CL-387785, CO-1686, WZ4002, and combinations thereof.

465. The method of any one of claims 456-464, wherein the cancer is selected from the group consisting of: non-small cell lung cancer, pancreatic cancer, and colorectal cancer.

466. The method of any one of claims 456-465, wherein the cancer is associated with a dysregulation of a HER2 gene, a HER2 kinase, or expression or activity or level of any of the same.

467. The method of claim 466, wherein the dysregulation in a HER2 gene, a HER2 kinase protein, or expression or activity or level of any of the same is one or more point mutations in the HER2 gene.

468. The method of claim 467, wherein the one or more point mutations in a HER2 gene results in the translation of a HER2 protein having one or more amino acid substitutions at one or more of the following amino acid positions exemplified in Table 3.

469. The method of claim 468, wherein the one or more point mutations is selected from the mutations in Table 3 (e.g., S310F, S310Y, R678Q, R678W, R678P, I767M, V773M, V777L, and V842I).

470. A method for modulating EGFR in a mammalian cell, the method comprising contacting the mammalian cell with an effective amount of a compound of any one of claims 1-403, or a pharmaceutically acceptable salt thereof.

471. The method of claim 470, wherein the contacting occurs in vivo.

472. The method of claim 470, wherein the contacting occurs in vitro.

473. The method of any one of claims 470-472, wherein the mammalian cell is a mammalian cancer cell.

474. The method of claim 473, wherein the mammalian cancer cell is a mammalian EGFR-associated cancer cell.

475. The method of any one of claims 470-473, wherein the cell has a dysregulation of an EGFR gene, an EGFR kinase protein, or expression or activity or level of any of the same.

476. The method of claim 475, wherein the dysregulation in an EGFR gene, an EGFR kinase protein, or expression or activity or level of any of the same is one or more point mutations in the EGFR gene.

477. The method of claim 476, wherein the one or more point mutations in an EGFR gene results in the translation of an EGFR protein having one or more amino acid substitutions at one or more of the following amino acid positions exemplified in Table 1a and 1b.

478. The method of claim 476, wherein the one or more point mutations is selected from the mutations in Table 1a and 1b (e.g., L858R, G719S, G719C, G719A, L861Q, a deletion in exon 19 and/or an insertion in exon 20).

479. The method of claim 476, wherein the one or more point mutations is an EGFR inhibitor resistance mutation (e.g., L718Q, L747S, D761Y, T790M, C797S, T854A).

480. The method of claim 476, wherein the one or more point mutations in an EGFR gene include a deletion in exon 19 of a human EGFR gene.

481. The method of claim 476, wherein the one or more point mutations is an EGFR insertion in exon 20 of a human EGFR gene.

482. The method of claims 476 or 481, wherein the insertion in exon 20 of a human EGFR gene is selected from: A767_V769insX, V769_D770insX, D770_N771insX, N771_P772insX, P772_H773insX, and H773_V774insX.

483. The method of claim 482, wherein the insertion in exon 20 of a human EGFR gene is selected from: A767_V769dupASV, V769_D770insASV, D770_N771insNPG, D770_N771insNPY, D770_N771insSVD, D770_N771insGL, N771_H773dupNPH, N771_P772insN, N771_P772insH, N771_P772insV, P772_H773insDNP, P772_H773insPNP, H773_V774insNPH, H773_V774insH, H773_V774insPH, H773_V774insAH, and P772_H773insPNP.

484. A method for treating cancer in a subject in need thereof, the method comprising (a) determining that the cancer is associated with a dysregulation of a HER2 gene, a HER2 kinase, or expression or activity or level of any of the same; and (b) administering to the subject a therapeutically effective amount of a compound of any one of claims 1-403, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 404.

485. A method of treating a HER2-associated cancer in a subject, the method comprising administering to a subject identified or diagnosed as having a HER2-associated cancer a therapeutically effective amount of a compound of any one of claims 1-403 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 404.

486. A method of treating a HER2-associated cancer in a subject, the method comprising: (a) determining that the cancer in the subject is a HER2-associated cancer; and (b) administering to the subject a therapeutically effective amount of a compound of any one of claims 1-403 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 404.

487. A method of treating a subject, the method comprising administering a therapeutically effective amount of a compound of any one of claims 1-403 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 404, to a subject having a clinical record that indicates that the subject has a dysregulation of a HER2 gene, a HER2 kinase, or expression or activity or level of any of the same.

488. The method of any one of claims 484 and 486, wherein the step of determining that the cancer in the subject is a HER2-associated cancer includes performing an assay to detect dysregulation in a HER2 gene, a HER2 kinase protein, or expression or activity or level of any of the same in a sample from the subject.

489. The method of claim 488, further comprising obtaining a sample from the subject.

490. The method of claim 489, wherein the sample is a biopsy sample.

491. The method of any one of claims 484-490, wherein the assay is selected from the group consisting of sequencing, immunohistochemistry, enzyme-linked immunosorbent assay, and fluorescence in situ hybridization (FISH).

492. The method of claim 491, wherein the FISH is break apart FISH analysis.

493. The method of claim 491, wherein the sequencing is pyrosequencing or next generation sequencing.

494. The method of any one of claims 484-488, wherein the dysregulation in a HER2 gene, a HER2 kinase protein, or expression or activity or level of any of the same is one or more point mutations in the HER2 gene.

495. The method of claim 494, wherein the one or more point mutations in a HER2 gene results in the translation of a HER2 protein having one or more amino acid substitutions at one or more of the following amino acid positions exemplified in Table 3.

496. The method of claim 494, wherein the one or more point mutations is selected from the mutations in Table 3 (e.g., S310F, S310Y, R678Q, R678W, R678P, I767M, V773M, V777L, and V842I).

497. The method of any one of claims 484-488, wherein the dysregulation in a HER2 gene, a HER2 kinase protein, or expression or activity or level of any of the same is an insertion in exon 20 of the human HER2 gene.

498. The method of claim 497, wherein the insertion in exon 20 of the human HER2 gene is deletions at an amino acid position selected from: 774, 775, 776, 777, 778, and 780.

499. The method of claim 498, wherein the insertion in exon 20 of a human HER2 gene is selected from: M774AYVM, M774del insWLV, A775_G776insYVMA, A775_G776insAVMA, A775_G776insSVMA, A775_G776insVAG, A775insV G776C, A775_G776insI, G776del insVC2, G776del insVV, G776del insLC, G776C V777insC, G776C V777insV, V777_G778insCG, G778_S779insCPG, and P780_Y781insGSP.

500. The method of any one of claims 485, 486, and 488, wherein the HER2- associated cancer is selected from the group consisting of: colon cancer, lung cancer, or breast cancer.

501. The method of claim 500, wherein the lung cancer is non-small cell lung cancer.

502. The method of any one of claims 487-501, further comprising administering an additional therapy or therapeutic agent to the subject.

503. The method of claim 502, wherein the additional therapy or therapeutic agent is selected from radiotherapy, cytotoxic chemotherapeutics, kinase targeted- therapeutics, apoptosis modulators, signal transduction inhibitors, immune-targeted therapies and angiogenesis-targeted therapies.

504. The method of claim 502, wherein said additional therapeutic agent is a second compound of any one of claims 1-403 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 404.

505. The method of claim 502, wherein said additional therapeutic agent is selected from one or more kinase targeted therapeutics.

506. The method of claim 502, wherein said additional therapeutic agent is a tyrosine kinase inhibitor.

507. The method of claim 502, wherein said additional therapeutic agent is an EGFR inhibitor.

508. The method of claim 502, wherein said additional therapeutic agent is selected from osimertinib, gefitinib, erlotinib, afatinib, lapatinib, neratinib, AZD-9291, CL-387785, CO-1686, WZ4002, and combinations thereof.

509. The method of claim 502, wherein said additional therapeutic agent is a HER2 inhibitor.

510. The method of claim 509, wherein the HER2 inhibitor is selected from trastuzumab, pertuzumab, trastuzumab emtansine, lapatinib, KU004, neratinib, dacomitinib, afatinib, tucatinib, erlotinib, pyrotinib, poziotinib, CP-724714, CUDC-101, sapitinib (AZD8931), tanespimycin (17-AAG), IPI-504, PF299, pelitinib, S- 222611, and AEE-788.

511. The method of any one of claims 505-510, wherein the compound of any one of claims 1-403 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 404, and the additional therapeutic agent are administered simultaneously as separate dosages.

512. The method of any one of claims 505-510, wherein the compound of any one of claims 1-403 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 404, and the additional therapeutic agent are administered as separate dosages sequentially in any order.