FGFR2 and FGFR3 inhibitors and uses thereof

Abstract

Inhibitors of FGFR2 and FGFR3 of formula (I) and pharmaceutical compositions comprising said inhibitors are provided. The compounds and compositions are useful for the treatment of diseases or disorders associated with FGFR2 and / or FGFR3. # imgabs0 #

Description

[0001] Cross-references

[0002] This patent application claims the benefit of International Application No. PCT / CN2022 / 102136, filed on June 29, 2022, International Application No. PCT / CN2023 / 082796, filed on March 21, 2023, and International Application No. PCT / CN2023 / 097992, filed on June 2, 2023; the entire contents of which are incorporated herein by reference.

[0003] background

[0004] Fibroblast growth factor receptors (FGFR1, FGFR2, FGFR3 and FGFR4) are a subfamily of receptor tyrosine kinases (RTKs) consisting of an extracellular ligand binding domain and an intracellular kinase domain. Binding of FGF ligands triggers receptor dimerization and subsequent phosphorylation of substrates such as FGFR substrate 2 (FRS2) and phospholipase Cγ (PLC-γ), which further activate downstream signaling cascades, leading to the regulation of key cellular functions, including cell survival, proliferation, differentiation, migration and angiogenesis (Clin. Cancer Res. 21 (12) June 15, 2015). Abnormal activation of FGFR signaling pathways by FGFR fusion, mutation and / or amplification can lead to tumorigenesis, progression and resistance to traditional cancer treatments. Pan-FGFR inhibitors have achieved significant clinical responses in a variety of FGFR-altered cancers; however, on-target toxicities have also been observed, including FGFR1-mediated dose-limiting toxicities such as hyperphosphatemia and tissue mineralization, and FGFR4-mediated dose-limiting toxicities such as diarrhea. Therefore, the development of next-generation dual FGFR2 / 3 inhibitors with greater selectivity, particularly against FGFR1, is desirable for the treatment of cancer and other disorders.

[0005] Overview

[0006] Disclosed herein are compounds of formula (I) or pharmaceutically acceptable salts or stereoisomers thereof:

[0007]

[0008] in:

[0009] Z 1 Does not exist, is C(R 5 )、C(R 5 )(R 5a ), N or N(R 9 );

[0010] Z 2 C(R 6 )、C(R 6 )(R6a ), O, S, N or N(R 9 );

[0011] Z 3 C(R 7 )、C(R 7 )(R 7a ), O, S, N or N(R 9 );

[0012] Z 4 C(R 8 )、C(R 8 )(R 8a ), O, S, N or N(R 9 );

[0013] Among them, when Z 1 C(R 5 )、C(R 5 )(R 5a ), N or N(R 9 ) when Z 1 , Z 2 , Z 3 and Z 4 No more than two of them are N or N(R 9 ); and when Z 1 When Z does not exist, 2 , Z 3 and Z 4 No more than one of them is O, S, N or N(R 9 );

[0014] R 1 and R 2 are independently selected from hydrogen, C 1-6 Alkyl and C 1-6 alkyl halide;

[0015] R 3 Selected from C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl and C 1-9 Heteroaryl, wherein C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl and C 1-9 Heteroaryl is optionally substituted with 1, 2 or 3 groups selected from R 15a ;

[0016] R 4 Selected from C 3-6 Cycloalkylene, C 2-9 Heterocycloalkylene, C 6-10 Arylene and C1-9 Heteroarylene, wherein C 3-6 Cycloalkylene, C 2-9 Heterocycloalkylene, C 6-10 Arylene and C 1-9 Heteroarylene is optionally substituted with 1, 2 or 3 groups selected from R 15b ;

[0017] L 1 For valence bond, -N(R 9a )-、-N(R 9a )C(O)-、-C(O)N(R 9a )-、-N(R 9a )S(O)2-、-S(O)2N(R 9a )-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -C(S)-, -S-, -S(O)-, -S(O)2-, -OS(O)-, -OS(O)2-, C 1-6 Alkylene, C 2-6 Alkenylene, C 2-6 Alkynylidene, C 3-6 Cycloalkylene, C 2-9 Heterocycloalkylene or C 1-9 Heteroarylene, wherein C 1-6 Alkylene, C 2-6 Alkenylene, C 2-6 Alkynylidene, C 3-6 Cycloalkylene, C 2-9 Heterocycloalkylene and C 1-9 Heteroarylene is optionally substituted with 1, 2 or 3 groups selected from R 15c ;

[0018] L 2 For valence bond, C 1-6 Alkylene, C 2-6 Alkenylene or C 2-6 Alkynylidene, where C 1-6 Alkylene, C 2-6 Alkenylene or C 2-6 Alkynylidene is optionally substituted with 1, 2 or 3 groups selected from R 15c ;

[0019] R 4a Selected from halogen, -CN,

[0020] R 4b 、R 4c and R 4d are each independently selected from hydrogen, halogen, -CN, -C(O)R 13 、-C(O)OR10 、-C(O)N(R 10 )(R 11 )、-N(R 10 )(R 11 ),-C 1-6 Alkyl-N(R 10 )(R 11 )、-C(O)N(R 10 )OR 10 、C 1-6 alkyl, phenyl, 3 to 7-membered heterocycloalkyl or 5 or 6-membered heteroaryl, wherein the C 1-6 Alkyl, phenyl, 3 to 7-membered heterocycloalkyl or 5 or 6-membered heteroaryl are optionally substituted by 1, 2 or 3 groups selected from R 15d ;or

[0021] R 4b and R 4c Together with the atoms to which they are attached, they form a 3 to 14-membered cycloalkyl group or a 3 to 14-membered heterocycloalkyl group; wherein the 3 to 14-membered cycloalkyl group and the 3 to 14-membered heterocycloalkyl group are optionally substituted by 1, 2, 3 or 4 R 15d Substitute; or R 4d and R 4c Together with the atoms to which they are attached, they form a 3 to 14-membered cycloalkyl group or a 3 to 14-membered heterocycloalkyl group; wherein the 3 to 14-membered cycloalkyl group and the 3 to 14-membered heterocycloalkyl group are optionally substituted by 1, 2, 3 or 4 R 15d replace;

[0022] R 4e Halogen or -OS(O)2R 13 ;

[0023] R 5 、R 5a 、R 6 、R 6a 、R 7 、R 7a 、R 8 and R 8a independently selected from hydrogen, halogen, -CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, C 1-9 Heteroaryl, -OR 10 、-SR 10 、-SF5、-N(R 10 )(R 11 )、-C(O)OR 10、-OC(O)N(R 10 )(R 11 )、-N(R 12 )C(O)N(R 10 )(R 11 )、-N(R 12 )C(O)OR 13 、-N(R 12 )S(O)2R 13 、-C(O)R 13 、-S(O)R 13 、-OC(O)R 13 、-C(O)N(R 10 )(R 11 )、-C(O)C(O)N(R 10 )(R 11 )、-N(R 12 )C(O)R 13 、-S(O)2R 13 、-S(O)2N(R 10 )(R 11 )-、-N=S(=O)(R 13 )2、-S(=O)(=NH)N(R 10 )(R 11 )、-S(=O)(=NH)(R 13 ),-S(=O)(=NR 13 )R 13 、-CH2C(O)N(R 10 )(R 11 )、-CH2N(R 12 )C(O)R 13 、-CH2S(O)2R 13 、-CH2S(O)2N(R 10 )(R 11 )、-Si(C 1-6 alkyl)3 and -P(O)(R 10 )2, where C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl and C 1-9 Heteroaryl is optionally substituted with 1, 2 or 3 groups selected from R 15e ;

[0024] R 9 Selected from hydrogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, C 1-9 Heteroaryl, -C(O)OR 10 、-C(O)R 13 、-S(O)R 13 、-C(O)N(R 10 )(R 11 ) and -S(O)2R 13 , where C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl and C 1-9 Heteroaryl is optionally substituted with 1, 2 or 3 groups selected from R 15f ;

[0025] R 9a Selected from hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl and C 1-9 Heteroaryl, wherein C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl and C 1-9 Heteroaryl is optionally substituted with 1, 2 or 3 groups selected from R 15g ;

[0026] R 10 are each independently selected from hydrogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, -CH2-C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, -CH2-C 2-9 Heterocycloalkyl, -CH2-C 6-10 Aryl, C 6-10 Aryl, C 1-9 Heteroaryl and -CH2-C 1-9 Heteroaryl, wherein C 1-6 Alkyl, C2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, -CH2-C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, -CH2-C 2-9 Heterocycloalkyl, -CH2-C 6-10 Aryl, C 6-10 Aryl, C 1-9 Heteroaryl and -CH2-C 1-9 Heteroaryl is optionally substituted with 1, 2 or 3 groups selected from halogen, -CN, hydroxy, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl and C 1-9 heteroaryl;

[0027] R 11 are each independently selected from hydrogen, C 1-6 Alkyl and C 1-6 haloalkyl; or R 10 and R 11 Together with the attached nitrogen, it forms C 2-9 heterocycloalkyl;

[0028] R 12 are each independently selected from hydrogen, C 1-6 Alkyl and C 1-6 alkyl halide;

[0029] R 13 Each independently selected from C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl and C 1-9 Heteroaryl, wherein C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl and C 1-9 Heteroaryl is optionally substituted with 1, 2 or 3 groups selected from halogen, -CN, hydroxy, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C6-10 Aryl and C 1-9 heteroaryl;

[0030] Each R 15a 、R 15b 、R 15c 、R 15d 、R 15e 、R 15f and R 15g Each independently selected from halogen, oxo, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, -CH2-C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, -CH2-C 2-9 Heterocycloalkyl, C 6-10 Aryl, -CH2-C 6-10 Aryl, C 1-9 Heteroaryl, -CH2-C 1-9 Heteroaryl, -OR 10 、-SR 10 、-SF5、-N(R 10 )(R 11 )、-C(O)OR 10 、-OC(O)N(R 10 )(R 11 )、-N(R 12 )C(O)N(R 10 )(R 11 )、-N(R 12 )C(O)OR 13 、-N(R 12 )S(O)2R 13 、-C(O)R 13 、-S(O)R 13 、-OC(O)R 13 、-C(O)N(R 10 )(R 11 )、-C(O)C(O)N(R 10 )(R 11 )、-N(R 12 )C(O)R 13 、-S(O)2R 13 、-S(O)2N(R 10 )(R 11 )-、-N=S(=O)(R 13 )2、-S(=O)(=NH)N(R 10 )(R 11 )、-S(=O)(=NH)(R 13),-S(=O)(=NR 13 )R 13 、-CH2C(O)N(R 10 )(R 11 )、-CH2N(R 12 )C(O)R 13 、-CH2S(O)2R 13 、-CH2S(O)2N(R 10 )(R 11 )、-Si(C 1-6 alkyl)3 and -P(O)(R 10 )2, where C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, -CH2-C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, -CH2-C 2-9 Heterocycloalkyl, C 6-10 Aryl, -CH2-C 6-10 Aryl, -CH2-C 1-9 Heteroaryl and C 1-9 Heteroaryl is optionally substituted with 1, 2 or 3 groups independently selected from halogen, oxo, -CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -OR 10 、-SR 10 、-SF5、-N(R 10 )(R 11 )、-C(O)OR 10 、-OC(O)N(R 10 )(R 11 )、-N(R 12 )C(O)N(R 10 )(R 11 )、-N(R 12 )C(O)OR 13 、-N(R 12 )S(O)2R 13 、-C(O)R 13 、-S(O)R 13 、-OC(O)R 13 、-C(O)N(R 10 )(R 11 )、-C(O)C(O)N(R 10 )(R 11 )、-N(R 12 )C(O)R13 、-S(O)2R 13 、-S(O)2N(R 10 )(R 11 )-、-N=S(=O)(R 13 )2、-S(=O)(=NH)N(R 10 )(R 11 )、-S(=O)(=NH)(R 13 ),-S(=O)(=NR 13 )R 13 、-CH2C(O)N(R 10 )(R 11 )、-CH2N(R 12 )C(O)R 13 、-CH2S(O)2R 13 、-CH2S(O)2N(R 10 )(R 11 ) and -P(O)(R 10 )2, and

[0031] Represent single or double bonds so that all valences are satisfied.

[0032] In some embodiments, disclosed herein are compounds having the structure of Formula (Ia) or pharmaceutically acceptable salts or stereoisomers thereof:

[0033]

[0034] where R 1 、R 2 、R 3 、R 4 、R 4a 、R 5 、R 7 、R 8 , L 1 and L 2 has the meaning as defined herein.

[0035] In some embodiments, disclosed herein are compounds having the structure of Formula (Ib) or pharmaceutically acceptable salts or stereoisomers thereof:

[0036]

[0037] where R 1 、R 2 、R 3 、R 4 、R 4a 、R 5 、R 6 、R 8 , L1 and L 2 has the meaning as defined herein.

[0038] In some embodiments, disclosed herein are compounds having the structure of Formula (Ic) or pharmaceutically acceptable salts or stereoisomers thereof:

[0039]

[0040] where R 1 、R 2 、R 3 、R 4 、R 4a 、R 5 、R 6 、R 7 , L 1 and L 2 has the meaning as defined herein.

[0041] In some embodiments, disclosed herein are compounds having the structure of Formula (Id) or pharmaceutically acceptable salts or stereoisomers thereof:

[0042]

[0043] where R 1 、R 2 、R 3 、R 4 、R 4a 、R 6 、R 7 、R 8 , L 1 and L 2 has the meaning as defined herein.

[0044] In some embodiments, disclosed herein are compounds having the structure of Formula (Ie) or pharmaceutically acceptable salts or stereoisomers thereof:

[0045]

[0046] where R 1 、R 2 、R 3 、R 4 、R 4a 、R 5 、R 7 、R 8 、R 9 , L 1 and L 2 has the meaning as defined herein.

[0047] In some embodiments, disclosed herein are compounds having the structure of Formula (Ia') or Formula (Ia"), or pharmaceutically acceptable salts or stereoisomers thereof:

[0048]

[0049]

[0050] where R 1 、R 2 、R 4 、R 4a 、R 5 、R 7 、R 8 、R 10 、R 15aa and L 1 has the meaning as defined herein.

[0051] In some embodiments, disclosed herein are compounds having the structure of Formula (Ib') or Formula (Ib"), or pharmaceutically acceptable salts or stereoisomers thereof:

[0052]

[0053] where R 1 、R 2 、R 4 、R 4a 、R 5 、R 6 、R 8 、R 10 、R 15aa and L 1 has the meaning as defined herein.

[0054] In some embodiments, disclosed herein are compounds having the structure of Formula (Ic') or Formula (Ic"), or pharmaceutically acceptable salts or stereoisomers thereof:

[0055]

[0056] where R 1 、R 2 、R 4 、R 4a 、R 5 、R 6 、R 7 、R 10 、R 15aa and L 1 has the meaning as defined herein.

[0057] Some embodiments are pharmaceutical compositions comprising a compound of Formula (I), (Ia), (Ia'), (Ia"), (Ib), (Ib'), (Ib"), (Ic), (Ic'), (Ic"), (Id), or (Ie), or a pharmaceutically acceptable salt or stereoisomer thereof, and at least one pharmaceutically acceptable excipient.

[0058] Some embodiments are methods of treating cancer in a mammal in need thereof, comprising administering to the mammal a compound of Formula (I), (Ia), (Ia'), (Ia"), (Ib), (Ib'), (Ib"), (Ic), (Ic'), (Ic"), (Id), or (Ie), or a pharmaceutically acceptable salt or stereoisomer thereof. Some embodiments are methods of treating cancer in a mammal in need thereof, comprising administering to the mammal a compound of Formula (I), (Ia), (Ia'), (Ia"), (Ib), (Ib'), (Ib"), (Ic), (Ic'), (Ic"), (Id), or (Ie), or a pharmaceutically acceptable salt or stereoisomer thereof, wherein the cancer is a solid tumor. Some embodiments are methods of treating cancer in a mammal in need thereof, comprising administering to the mammal a compound of Formula (I), (Ia), (Ia'), (Ia"), (Ib), (Ib'), (Ib"), (Ic), (Ic'), (Ic"), (Id), or (Ie), or a pharmaceutically acceptable salt or stereoisomer thereof, wherein the cancer is intrahepatic bile duct cancer, urothelial cancer, gastric cancer, bladder cancer, breast cancer, endometrial cancer, kidney cancer, liver cancer, lung cancer, melanoma, pancreatic cancer, prostate cancer, or thyroid cancer.

[0059] Citations

[0060] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference.

[0061] Detailed description

[0062] definition

[0063] In the following description, certain specific details are set forth in order to provide a thorough understanding of the various embodiments. However, it will be understood by those skilled in the art that the disclosed technology can be implemented without these details. In other cases, well-known structures are not shown or described in detail to avoid unnecessarily obscuring the description of the embodiments. Unless the context otherwise requires, in the following description and claims, the word "comprise" and its variations, such as "comprises" and "comprising" should be interpreted in an open, inclusive sense, that is, "including but not limited to". In addition, the titles provided herein are for convenience only and do not interpret the scope or meaning of the claimed invention.

[0064] References in this specification to "some embodiments" or "one embodiment" mean that the particular features, structures or characteristics described using the embodiment are included in at least one embodiment. Therefore, the phrases "in one embodiment" or "in an embodiment" appearing in different places in this specification do not necessarily all refer to the same embodiment. Furthermore, in one or more embodiments, the particular features, structures or characteristics may be combined in any suitable manner. Furthermore, as used in this specification and the appended claims, the singular forms "a", "an" and "the" include plural referents, unless the context clearly states otherwise. It should also be noted that the term "or" generally includes "and / or" in its usage meaning, unless the context clearly states otherwise.

[0065] As used herein, the following terms have the following meanings, unless otherwise indicated:

[0066] "Oxo" refers to =0.

[0067] "Carboxyl" refers to -COOH.

[0068] "Cyano" refers to -CN.

[0069] "Alkyl" refers to a straight or branched chain saturated hydrocarbon monoradical having 1 to about 10 carbon atoms, more preferably 1 to 6 carbon atoms. Examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1-butyl, 3-methyl-1-butyl, 2-methyl-3-butyl, 2,2-dimethyl-1-propyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl and hexyl, and longer alkyl groups such as heptyl, octyl, etc. Wherever it appears herein, a numerical range, such as "C1-C6 alkyl" or "C1-6 The term "alkyl" means that the alkyl group can be composed of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, however, this definition also covers the occurrence of the term "alkyl" without specifying a numerical range. In some embodiments, the alkyl group is C 1-10 In some embodiments, the alkyl group is C 1-6 In some embodiments, the alkyl group is C 1-5 In some embodiments, the alkyl group is C 1-4 In some embodiments, the alkyl group is C 1-3 Alkyl. Unless otherwise specifically described in this specification, alkyl can be optionally substituted by, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, alkyl is optionally substituted by oxo, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH or -NO. In some embodiments, alkyl is optionally substituted by halogen, -CN, -OH or -OMe. In some embodiments, alkyl is optionally substituted by halogen.

[0070] "Alkenyl" refers to a straight or branched hydrocarbon monoradical having one or more carbon-carbon double bonds and having 2 to about 10 carbon atoms, more preferably 2 to about 6 carbon atoms. The group can be in the cis or trans configuration of the double bond and is understood to include both isomers. Examples include, but are not limited to, ethenyl (-CH=CH2), 1-propenyl (-CH2CH=CH2), isopropenyl [-C(CH3)=CH2], butenyl, 1,3-butadienyl, and the like. Wherever it appears herein, numerical ranges, such as "C2-C6 alkenyl" or "C 2-6 "Alkenyl" means that the alkenyl group can be composed of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, however, this definition also covers the occurrence of the term "alkenyl" without specifying a numerical range. Unless otherwise specifically described in this specification, the alkenyl group can be optionally substituted by, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, the alkenyl group is optionally substituted by oxo, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH2 or -NO2. In some embodiments, the alkenyl group is optionally substituted by halogen, -CN, -OH or -OMe. In some embodiments, the alkenyl group is optionally substituted by halogen.

[0071] "Alkynyl" refers to a straight or branched hydrocarbon monogroup having one or more carbon-carbon triple bonds and having 2 to about 10 carbon atoms, more preferably 2 to about 6 carbon atoms. Examples include, but are not limited to, ethynyl, 2-propynyl, 2-butynyl, 1,3-butadiynyl, and the like. Wherever it appears herein, numerical ranges, such as "C2-C6 alkynyl" or "C 2-6 "Alkynyl" means that the alkynyl group can be composed of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, however, the present definition also covers the occurrence of the term "alkynyl" without specifying a numerical range. Unless otherwise specifically described in the present specification, the alkynyl group can be optionally substituted by, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, the alkynyl group is optionally substituted by oxo, halogen, -CN, -COOH, COOMe, -OH, -OMe, -NH2 or -NO2. In some embodiments, the alkynyl group is optionally substituted by halogen, -CN, -OH or -OMe. In some embodiments, the alkynyl group is optionally substituted by halogen.

[0072] "Alkylene" refers to a straight or branched divalent hydrocarbon chain. Unless otherwise specifically described in this specification, alkylene can be optionally substituted by, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, alkylene is optionally substituted by oxo, halogen, -CN, -COOH, COOMe, -OH, -OMe, -NH or -NO. In some embodiments, alkylene is optionally substituted by halogen, -CN, -OH or -OMe. In some embodiments, alkylene is optionally substituted by halogen.

[0073] "Alkoxy" refers to a group of the formula -OR a A group in which R a For alkyl as defined. Unless otherwise specifically described in this specification, alkoxy can be optionally substituted by, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl etc. In some embodiments, alkoxy is optionally substituted by halogen, -CN, -COOH, COOMe, -OH, -OMe, -NH or -NO. In some embodiments, alkoxy is optionally substituted by halogen, -CN, -OH or -OMe. In some embodiments, alkoxy is optionally substituted by halogen.

[0074] "Aryl" refers to a group derived from a hydrocarbon ring system containing 6 to 30 carbon atoms and at least one aromatic ring. Aryl can be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which can include a fused (when fused to a cycloalkyl or heterocycloalkyl ring, the aryl is bonded through an aromatic ring atom) or bridged ring system. In some embodiments, aryl is a 6- to 10-membered aryl. In some embodiments, aryl is a 6-membered aryl (phenyl). Aryl includes, but is not limited to, anthrylene, naphthylene, phenanthrylene, anthracene, azulene, benzene, Fluoranthene, fluorene, asymmetric indacene, symmetric indacene, indane, indene, naphthalene, phenanthren, phenanthren, pyrene and triphenylene (triphenylene) hydrocarbon ring system aryl.Unless otherwise specifically described in this specification, aryl can be optionally substituted by, for example, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl etc. In some embodiments, aryl is optionally substituted by halogen, methyl, ethyl, -CN, -COOH, COOMe, -CF3, -OH, -OMe, -NH2 or -NO2. In some embodiments, aryl is optionally substituted by halogen, methyl, ethyl, -CN, -CF3, -OH or -OMe. In some embodiments, aryl is optionally substituted by halogen. As used herein, " arylene " refers to a divalent aryl as described herein. Arylene can be bonded by aryl at any suitable position. In some embodiments, when the arylene group comprises an aryl group fused to a cycloalkyl or heterocycloalkyl ring, the arylene group is bonded to the aryl group and the cycloalkyl group or the aryl group and the heterocycloalkyl group. In some embodiments, when the arylene group comprises an aryl group fused to a cycloalkyl or heterocycloalkyl ring, the arylene group is bonded only to the aryl group.

[0075] "Cycloalkyl" refers to a partially or fully saturated monocyclic or polycyclic carbocyclic ring, which may include fused (when fused to an aryl or heteroaryl ring, the cycloalkyl is bonded through a non-aromatic ring atom), spiro, or bridged ring systems. In some embodiments, the cycloalkyl is fully saturated. Representative cycloalkyls include, but are not limited to, cycloalkyls having 3 to 15 carbon atoms (e.g., C3-C 15 Fully saturated cycloalkyl or C3-C 15 cycloalkenyl), 3 to 10 carbon atoms (e.g. C3-C 10 Fully saturated cycloalkyl or C3-C 10In some embodiments, the cycloalkyl group is a 3- to 10-membered fully saturated cycloalkyl group or a 3- to 10-membered cycloalkenyl group. In some embodiments, the cycloalkyl group is a 3- to 6-membered fully saturated cycloalkyl group or a 3- to 6-membered cycloalkenyl group. In some embodiments, the cycloalkyl group is a 5- to 6-membered fully saturated cycloalkyl group or a 5- to 6-membered cycloalkenyl group. Monocyclic cycloalkyl groups include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic cycloalkyl includes, for example, adamantyl, norbornyl, decahydronaphthalene, bicyclo[3.3.0]octane, bicyclo[4.3.0]nonane, cis-decalin, trans-decalin, bicyclo[2.1.1]hexane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, cyclo[3.2.2]nonane and bicyclo[3.3.2]decane and 7,7-dimethyl-bicyclo[2.2.1]heptyl. Partially saturated cycloalkyl includes, for example, cyclopentenyl, cyclohexenyl, cycloheptenyl and cyclooctenyl. Unless otherwise specifically described in this specification, cycloalkyl is optionally substituted by, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, cycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -COOH, COOMe, -CF3, -OH, -OMe, -NH2 or -NO2. In some embodiments, cycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH or -OMe. In some embodiments, cycloalkyl is optionally substituted with halogen. As used herein, "cycloalkylene" refers to a divalent cycloalkyl as described herein. In some embodiments, when the cycloalkylene comprises a cycloalkyl fused to an aryl or heteroaryl ring, the cycloalkylene is bonded to the cycloalkyl and aryl or the cycloalkyl and heteroaryl. In some embodiments, when the cycloalkylene comprises a cycloalkyl fused to an aryl or heteroaryl ring, the cycloalkylene is only bonded to the cycloalkyl.

[0076] "Halo" or "halogen" refers to bromo, chloro, fluoro, or iodo. In some embodiments, halogen is fluoro or chloro. In some embodiments, halogen is fluoro.

[0077] "Haloalkyl" refers to an alkyl group as defined above substituted with one or more halo groups as defined above, for example, trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, and the like.

[0078] "Hydroxyalkyl" refers to an alkyl group as defined above that is substituted with one or more hydroxy groups. In some embodiments, the alkyl group is substituted with one hydroxy group. In some embodiments, the alkyl group is substituted with 1, 2, or 3 hydroxy groups. Hydroxyalkyl groups include, for example, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, or hydroxypentyl. In some embodiments, the hydroxyalkyl group is hydroxymethyl.

[0079] "Aminoalkyl" refers to an alkyl group as defined above that is substituted with one or more amines. In some embodiments, the alkyl group is substituted with one amine. In some embodiments, the alkyl group is substituted with 1, 2, or 3 amines. Aminoalkyl groups include, for example, aminomethyl, aminoethyl, aminopropyl, aminobutyl, or aminopentyl. In some embodiments, the aminoalkyl group is aminomethyl.

[0080] " assorted alkyl " refers to an alkyl group, wherein one or more alkyl backbone atoms are selected from the atom of non-carbon, such as oxygen, nitrogen (such as-NH-,-N (alkyl)-), sulphur, phosphorus or its combination.Assorted alkyl is connected to the remainder of molecule on the carbon atom of this assorted alkyl group. In one aspect, assorted alkyl is C1-C6 assorted alkyl, wherein assorted alkyl is made up of 1 to 6 carbon atoms and one or more non-carbon atoms, such as oxygen, nitrogen (such as-NH-,-N (alkyl)-), sulphur, phosphorus or its combination, wherein assorted alkyl is connected to the remainder of molecule on the carbon atom of this assorted alkyl group. The example of this type of assorted alkyl is such as-CH2OCH3,-CH2CH2OCH3,-CH2CH2OCH2CH2OCH3,-CH(CH3)OCH3,-CH2NHCH3,-CH2N(CH3)2,-CH2CH2NHCH3 or-CH2CH2N(CH3)2. Unless otherwise specifically described in this specification, heteroalkyl is optionally substituted by, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, heteroalkyl is optionally substituted by oxo, halogen, methyl, ethyl, -CN, -CF , -OH, -OMe, -NH or -NO . In some embodiments, heteroalkyl is optionally substituted by oxo, halogen, methyl, ethyl, -CN, -CF , -OH or -OMe. In some embodiments, heteroalkyl is optionally substituted by halogen.

[0081] "Heterocycloalkyl" refers to a 3- to 24-membered partially or fully saturated ring group containing 2 to 23 carbon atoms and 1 to 8 heteroatoms selected from nitrogen, oxygen, phosphorus, silicon, and sulfur. In some embodiments, the heterocycloalkyl is fully saturated. In some embodiments, the heterocycloalkyl contains 1 to 3 heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the heterocycloalkyl contains 1 to 3 heteroatoms selected from nitrogen and oxygen. In some embodiments, the heterocycloalkyl contains 1 to 3 nitrogen groups. In some embodiments, the heterocycloalkyl contains 1 or 2 nitrogen groups. In some embodiments, the heterocycloalkyl contains 1 nitrogen group. In some embodiments, the heterocycloalkyl contains 1 nitrogen group and 1 oxygen group. Unless otherwise specifically described in this specification, heterocycloalkyl groups may be monocyclic, bicyclic, tricyclic or tetracyclic ring systems, which may include fused (when fused to an aryl or heteroaryl ring, the heterocycloalkyl group is bonded through a non-aromatic ring atom), spiro or bridged ring systems; and the nitrogen, carbon or sulfur atoms on the heterocycloalkyl group may be optionally oxidized; the nitrogen atom may be optionally quaternized. Representative heterocycloalkyl groups include, but are not limited to, groups having 2 to 15 carbon atoms (e.g., C2-C 15 Fully saturated heterocycloalkyl or C2-C 15 Heterocycloalkenyl), 2 to 10 carbon atoms (e.g. C2-C 10 Fully saturated heterocycloalkyl or C2-C 10The present invention also includes heterocycloalkyl groups of 2 to 8 carbon atoms (e.g., C2-C8 fully saturated heterocycloalkyl or C2-C8 heterocycloalkenyl), heterocycloalkyl groups of 2 to 7 carbon atoms (e.g., C2-C7 fully saturated heterocycloalkyl or C2-C7 heterocycloalkenyl), heterocycloalkyl groups of 2 to 6 carbon atoms (e.g., C2-C6 fully saturated heterocycloalkyl or C2-C6 heterocycloalkenyl), heterocycloalkyl groups of 2 to 5 carbon atoms (e.g., C2-C5 fully saturated heterocycloalkyl or C2-C5 heterocycloalkenyl), or heterocycloalkyl groups of 2 to 4 carbon atoms (e.g., C2-C4 fully saturated heterocycloalkyl or C2-C4 heterocycloalkenyl). Examples of such heterocycloalkyl groups include, but are not limited to, aziridinyl, azetidinyl, oxetanyl, dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolinyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinolin ... Cyclic group, thiazolidinyl, tetrahydrofuranyl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, 1,1-dioxo-thiomorpholinyl, 1,3-dihydroisobenzofuran-1-yl, 3-oxo-1,3-dihydroisobenzofuran-1-yl, methyl-2-oxo-1,3-dioxol-4-yl and 2-oxo-1,3-dioxol-4-yl. The term heterocycloalkyl also includes all ring forms of carbohydrates, including but not limited to monosaccharides, disaccharides and oligosaccharides. In some embodiments, heterocycloalkyl has 2 to 10 carbon atoms on the ring. It should be understood that when referring to the number of carbon atoms on heterocycloalkyl, the number of carbon atoms on heterocycloalkyl is different from the total number of atoms (including heteroatoms) constituting heterocycloalkyl (i.e., the backbone atoms of the heterocycloalkyl ring). In some embodiments, heterocycloalkyl is a 3- to 8-membered heterocycloalkyl. In some embodiments, heterocycloalkyl is a 3- to 7-membered heterocycloalkyl. In some embodiments, heterocycloalkyl is a 3- to 6-membered heterocycloalkyl. In some embodiments, heterocycloalkyl is a 4- to 6-membered heterocycloalkyl. In some embodiments, heterocycloalkyl is a 5- to 6-membered heterocycloalkyl. In some embodiments, heterocycloalkyl is a 3- to 8-membered heterocycloalkenyl. In some embodiments, heterocycloalkyl is a 3- to 7-membered heterocycloalkenyl. In some embodiments, heterocycloalkyl is a 3- to 6-membered heterocycloalkenyl. In some embodiments, heterocycloalkyl is a 4- to 6-membered heterocycloalkenyl. In some embodiments, heterocycloalkyl is a 5- to 6-membered heterocycloalkenyl. Unless otherwise specifically described in the specification, heterocycloalkyl groups may be optionally substituted by, for example, oxo, halogen, amino, nitrile, nitro, hydroxy, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc., as described below.In some embodiments, heterocycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -COOH, COOMe, -CF , -OH, -OMe, -NH or -NO . In some embodiments, heterocycloalkyl is optionally substituted with halogen, methyl, ethyl, -CN, -CF , -OH or -OMe. In some embodiments, heterocycloalkyl is optionally substituted with halogen.

[0082] As used herein, "heterocycloalkylene" refers to a divalent heterocycloalkyl group as described herein. In some embodiments, when the heterocycloalkylene group comprises a heterocycloalkyl group fused to an aryl or heteroaryl ring, the heterocycloalkylene group is bonded to the heterocycloalkyl group and the aryl group or to the heterocycloalkyl group and the heteroaryl group. In some embodiments, when the heterocycloalkylene group comprises a heterocycloalkyl group fused to an aryl or heteroaryl ring, the heterocycloalkylene group is bonded only to the heterocycloalkyl group.

[0083] "Heteroaryl" refers to a 5- to 14-membered ring system radical containing 1 to 13 carbon atoms, 1 to 6 heteroatoms selected from nitrogen, oxygen, phosphorus, and sulfur, and at least one aromatic ring. In some embodiments, the heteroaryl group contains 1 to 3 heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the heteroaryl group contains 1 to 3 heteroatoms selected from nitrogen and oxygen. In some embodiments, the heteroaryl group contains 1 to 3 nitrogen atoms. In some embodiments, the heteroaryl group contains 1 or 2 nitrogen atoms. In some embodiments, the heteroaryl group contains 1 nitrogen. The heteroaryl group can be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which can include a fused (when fused to a cycloalkyl or heterocycloalkyl ring, the heteroaryl group is bonded through an aromatic ring atom) or a bridged ring system; and the nitrogen, carbon, or sulfur atoms on the heteroaryl group can be optionally oxidized; the nitrogen atom can be optionally quaternized. In some embodiments, the heteroaryl group is a 5- to 10-membered heteroaryl group. In some embodiments, the heteroaryl group is a 5- to 6-membered heteroaryl group. In some embodiments, heteroaryl is a 6-membered heteroaryl. In some embodiments, heteroaryl is a 5-membered heteroaryl. Examples include, but are not limited to, aza benzo[b][1,4]dioxepin benzothiophenyl, benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furanonyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, dihydroindole, isoindolyl, isoquinolinyl, indolizinyl, isoxazolyl, naphthyridinyl, oxadiazolyl, 2-oxoazepine The heteroaryl group may be optionally substituted with, for example, halogen, amino, nitrile, nitro, hydroxy, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc., unless otherwise specifically described in the specification. In some embodiments, heteroaryl is optionally substituted with halogen, methyl, ethyl, -CN, -COOH, COOMe, -CF3, -OH, -OMe, -NH2 or -NO2. In some embodiments, heteroaryl is optionally substituted with halogen, methyl, ethyl, -CN, -CF3, -OH or -OMe. In some embodiments, heteroaryl is optionally substituted with halogen. As used herein, "heteroarylene" refers to a divalent heteroaryl as described herein. In some embodiments, when the heteroarylene comprises a heteroaryl fused to a cycloalkyl or heterocycloalkyl ring, the heteroarylene is bonded to the heteroaryl and cycloalkyl or the heteroaryl and heterocycloalkyl. In some embodiments, when the heteroarylene comprises a heteroaryl fused to a cycloalkyl or heterocycloalkyl ring, the heteroarylene is only bonded to the heteroaryl.

[0084] The term "optional" or "optionally" refers to an event or situation that may or may not occur as described subsequently, and the description includes situations in which the event or situation occurs and situations in which it does not occur. For example, "optionally substituted alkyl" refers to "alkyl" or "substituted alkyl" as defined above. In addition, the optionally substituted group can be unsubstituted (e.g., -CH2CH3), completely substituted (e.g., -CF2CF3), monosubstituted (e.g., -CH2CH2F) or substituted (e.g., -CH2CHF2, -CH2CF3, -CF2CH3, -CFHCHF2, etc.) at any level between completely substituted and monosubstituted. It will be understood by those skilled in the art that for any group comprising one or more substituents, such groups are not intended to introduce any spatially impractical and / or synthetically unfeasible substitution or substitution pattern. Therefore, any substituent described is generally understood to have a maximum molecular weight of about 1000 daltons, and more generally, at most about 500 daltons.

[0085] "Effective amount" or "therapeutically effective amount" refers to that amount of a compound administered to a mammalian subject, whether in a single dose or as part of a series of doses, effective to produce the desired therapeutic effect.

[0086] "Treatment" of an individual (e.g., a mammal, such as a human) or cell is any type of intervention used in an attempt to alter the natural course of the individual or cell. In some embodiments, treatment comprises administering a pharmaceutical composition after a pathological event or exposure to a pathogen, and includes stabilizing the condition (e.g., the condition does not worsen) or ameliorating the condition.

[0087] Compound

[0088] Described herein are compounds of Formula (I), (Ia), (Ia'), (Ia"), (Ib), (Ib'), (Ib"), (Ic), (Ic'), (Ic"), (Id), or (Ie), or pharmaceutically acceptable salts or stereoisomers thereof, which are useful for treating diseases or disorders associated with FGFR2 and FGFR3 inhibition. In some embodiments, compounds of Formula (I), (Ia), (Ia'), (Ia"), (Ib), (Ib'), (Ib"), (Ic), (Ic'), (Ic"), (Id), or (Ie), or pharmaceutically acceptable salts or stereoisomers thereof, are useful for treating cancer. In some embodiments, the cancer is selected from intrahepatic bile duct cancer, urothelial cancer, gastric cancer, bladder cancer, breast cancer, endometrial cancer, kidney cancer, liver cancer, lung cancer, melanoma, pancreatic cancer, prostate cancer, or thyroid cancer.

[0089] In some embodiments, disclosed herein is a compound of formula (I) or a pharmaceutically acceptable salt or stereoisomer thereof:

[0090]

[0091] in:

[0092] Z 1 Does not exist, is C(R 5 )、C(R 5 )(R 5a ), N or N(R 9 );

[0093] Z 2 C(R 6 )、C(R 6 )(R 6a ), O, S, N or N(R 9 );

[0094] Z 3 C(R 7 )、C(R 7 )(R 7a ), O, S, N or N(R 9 );

[0095] Z 4 C(R 8 )、C(R 8 )(R 8a ), O, S, N or N(R 9 );

[0096] Among them, when Z 1 C(R 5 )、C(R 5 )(R 5a ), N or N(R 9 ) when Z 1 , Z 2 , Z 3 and Z 4 No more than two of them are N or N(R 9 ); and when Z 1 When Z does not exist, 2 , Z 3 and Z 4 No more than one of them is O, S, N or N(R 9 );

[0097] R 1 and R 2 are independently selected from hydrogen, C 1-6 Alkyl and C 1-6 alkyl halide;

[0098] R 3 Selected from C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10Aryl and C 1-9 Heteroaryl, wherein C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl and C 1-9 Heteroaryl is optionally substituted with 1, 2 or 3 groups selected from R 15a ;

[0099] R 4 Selected from C 3-6 Cycloalkylene, C 2-9 Heterocycloalkylene, C 6-10 Arylene and C 1-9 Heteroarylene, wherein C 3-6 Cycloalkylene, C 2-9 Heterocycloalkylene, C 6-10 Arylene and C 1-9 Heteroarylene is optionally substituted with 1, 2 or 3 groups selected from R 15b ;

[0100] L 1 For valence bond, -N(R 9a )-、-N(R 9a )C(O)-、-C(O)N(R 9a )-、-N(R 9a )S(O)2-、-S(O)2N(R 9a )-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -C(S)-, -S-, -S(O)-, -S(O)2-, -OS(O)-, -OS(O)2-, C 1-6 Alkylene, C 2-6 Alkenylene, C 2-6 Alkynylidene, C 3-6 Cycloalkylene, C 2-9 Heterocycloalkylene or C 1-9 Heteroarylene, wherein C 1-6 Alkylene, C 2-6 Alkenylene, C 2-6 Alkynylidene, C 3-6 Cycloalkylene, C 2-9 Heterocycloalkylene and C 1-9 Heteroarylene is optionally substituted with 1, 2 or 3 groups selected from R 15c ;

[0101] L 2 For valence bond, C 1-6 Alkylene, C 2-6 Alkenylene or C 2-6 Alkynylidene, where C 1-6 Alkylene, C 2-6 Alkenylene or C 2-6Alkynylidene is optionally substituted with 1, 2 or 3 groups selected from R 15c ;

[0102] R 4a Selected from halogen, -CN,

[0103]

[0104] R 4b 、R 4c and R 4d are each independently selected from hydrogen, halogen, -CN, -C(O)R 13 、-C(O)OR 10 、-C(O)N(R 10 )(R 11 )、-N(R 10 )(R 11 ),-C 1-6 Alkyl-N(R 10 )(R 11 )、-C(O)N(R 10 )OR 10 、C 1-6 alkyl, phenyl, 3- to 7-membered heterocycloalkyl, or 5- or 6-membered heteroaryl; or

[0105] R 4b and R 4c Together with the atoms to which they are attached, they form a 3 to 14-membered cycloalkyl group or a 3 to 14-membered heterocycloalkyl group; wherein the 3 to 14-membered cycloalkyl group and the 3 to 14-membered heterocycloalkyl group are optionally substituted by 1, 2, 3 or 4 R 15d Substitute; or R 4d and R 4c Together with the atoms to which they are attached, they form a 3 to 14-membered cycloalkyl group or a 3 to 14-membered heterocycloalkyl group; wherein the 3 to 14-membered cycloalkyl group and the 3 to 14-membered heterocycloalkyl group are optionally substituted by 1, 2, 3 or 4 R 15d replace;

[0106] R 4e Halogen or -OS(O)2R 13 ;

[0107] R 5 、R 5a 、R 6 、R 6a 、R 7 、R 7a 、R 8 and R 8a independently selected from hydrogen, halogen, -CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, C 1-9 Heteroaryl, -OR 10 、-SR 10 、-SF5、-N(R 10 )(R 11 )、-C(O)OR 10 、-OC(O)N(R 10 )(R 11 )、-N(R 12 )C(O)N(R 10 )(R 11 )、-N(R 12 )C(O)OR 13 、-N(R 12 )S(O)2R 13 、-C(O)R 13 、-S(O)R 13 、-OC(O)R 13 、-C(O)N(R 10 )(R 11 )、-C(O)C(O)N(R 10 )(R 11 )、-N(R 12 )C(O)R 13 、-S(O)2R 13 、-S(O)2N(R 10 )(R 11 )-、-N=S(=O)(R 13 )2、-S(=O)(=NH)N(R 10 )(R 11 )、-S(=O)(=NH)(R 13 ),-S(=O)(=NR 13 )R 13 、-CH2C(O)N(R 10 )(R 11 )、-CH2N(R 12 )C(O)R 13 、-CH2S(O)2R 13 、-CH2S(O)2N(R 10 )(R 11 )、-Si(C 1-6 alkyl)3 and -P(O)(R 10 )2, where C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl and C 1-9 Heteroaryl is optionally substituted with 1, 2 or 3 groups selected from R 15e ;

[0108] R 9 Selected from hydrogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, C 1-9 Heteroaryl, -C(O)OR 10 、-C(O)R 13 、-S(O)R 13 、-C(O)N(R 10 )(R 11 ) and -S(O)2R 13 , where C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl and C 1-9 Heteroaryl is optionally substituted with 1, 2 or 3 groups selected from R 15f ;

[0109] R 9a Selected from hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl and C 1-9 Heteroaryl, wherein C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl and C 1-9 Heteroaryl is optionally substituted with 1, 2 or 3 groups selected from R 15g ;

[0110] R 10 are each independently selected from hydrogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C2-6 Alkynyl, C 3-6 Cycloalkyl, -CH2-C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, -CH2-C 2-9 Heterocycloalkyl, -CH2-C 6-10 Aryl, C 6-10 Aryl, C 1-9 Heteroaryl and -CH2-C 1-9 Heteroaryl, wherein C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, -CH2-C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, -CH2-C 2-9 Heterocycloalkyl, -CH2-C 6-10 Aryl, C 6-10 Aryl, C 1-9 Heteroaryl and -CH2-C 1-9 Heteroaryl is optionally substituted with 1, 2 or 3 groups selected from halogen, -CN, hydroxy, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl and C 1-9 heteroaryl;

[0111] R 11 are each independently selected from hydrogen, C 1-6 Alkyl and C 1-6 haloalkyl; or R 10 and R 11 Together with the attached nitrogen, it forms C 2-9 heterocycloalkyl;

[0112] R 12 are each independently selected from hydrogen, C 1-6 Alkyl and C 1-6 alkyl halide;

[0113] R 13 Each independently selected from C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl and C 1-9 Heteroaryl, wherein C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl and C 1-9 Heteroaryl is optionally substituted with 1, 2 or 3 groups selected from halogen, -CN, hydroxy, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl and C 1-9 heteroaryl;

[0114] Each R 15a 、R 15b 、R 15c 、R 15d 、R 15e 、R 15f and R 15g Each independently selected from halogen, oxo, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, -CH2-C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, -CH2-C 2-9 Heterocycloalkyl, C 6-10 Aryl, -CH2-C 6-10 Aryl, C 1-9 Heteroaryl, -CH2-C 1-9 Heteroaryl, -OR 10 、-SR 10 、-SF5、-N(R 10 )(R 11 )、-C(O)OR 10 、-OC(O)N(R 10 )(R 11 )、-N(R 12 )C(O)N(R 10 )(R 11 )、-N(R 12 )C(O)OR 13 、-N(R 12 )S(O)2R 13 、-C(O)R 13 、-S(O)R 13 、-OC(O)R 13 、-C(O)N(R 10 )(R 11 )、-C(O)C(O)N(R 10 )(R 11)、-N(R 12 )C(O)R 13 、-S(O)2R 13 、-S(O)2N(R 10 )(R 11 )-、-N=S(=O)(R 13 )2、-S(=O)(=NH)N(R 10 )(R 11 )、-S(=O)(=NH)(R 13 ),-S(=O)(=NR 13 )R 13 、-CH2C(O)N(R 10 )(R 11 )、-CH2N(R 12 )C(O)R 13 、-CH2S(O)2R 13 、-CH2S(O)2N(R 10 )(R 11 )、-Si(C 1-6 alkyl)3 and -P(O)(R 10 )2, where C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, -CH2-C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, -CH2-C 2-9 Heterocycloalkyl, C 6-10 Aryl, -CH2-C 6-10 Aryl, -CH2-C 1-9 Heteroaryl and C 1-9 Heteroaryl is optionally substituted with 1, 2 or 3 groups independently selected from halogen, oxo, -CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -OR 10 、-SR 10 、-SF5、-N(R 10 )(R 11 )、-C(O)OR 10 、-OC(O)N(R 10 )(R 11 )、-N(R 12 )C(O)N(R 10 )(R 11 )、-N(R 12 )C(O)OR 13 、-N(R 12)S(O)2R 13 、-C(O)R 13 、-S(O)R 13 、-OC(O)R 13 、-C(O)N(R 10 )(R 11 )、-C(O)C(O)N(R 10 )(R 11 )、-N(R 12 )C(O)R 13 、-S(O)2R 13 、-S(O)2N(R 10 )(R 11 )-、-N=S(=O)(R 13 )2、-S(=O)(=NH)N(R 10 )(R 11 )、-S(=O)(=NH)(R 13 ),-S(=O)(=NR 13 )R 13 、-CH2C(O)N(R 10 )(R 11 )、-CH2N(R 12 )C(O)R 13 、-CH2S(O)2R 13 、-CH2S(O)2N(R 10 )(R 11 ) and -P(O)(R 10 )2, and

[0115] Represent single or double bonds so that all valences are satisfied.

[0116] In some embodiments of the compound of Formula (I) or a pharmaceutically acceptable salt or stereoisomer thereof, Z 1 C(R 5 ), Z 2 N, Z 3 C(R 7 ), and Z 4 C(R 8 In some embodiments of the compound of formula (I) or a pharmaceutically acceptable salt or stereoisomer thereof, Z 1 C(R 5 ), Z 2 C(R 6 ), Z 3 is N, and Z 4 C(R 8 In some embodiments of the compound of formula (I) or a pharmaceutically acceptable salt or stereoisomer thereof, Z1 N, Z 2 C(R 6 ), Z 3 C(R 7 ) and Z 4 C(R 8 In some embodiments of the compound of formula (I) or a pharmaceutically acceptable salt or stereoisomer thereof, Z 1 C(R 5 ), Z 2 C(R 6 ), Z 3 C(R 7 ), and Z 4 is N. In some embodiments of the compound of Formula (I) or a pharmaceutically acceptable salt or stereoisomer thereof, Z 1 C(R 5 )(R 5a ), Z 2 N(R 9 ), Z 3 C(R 7 )(R 7a ), and Z 4 C(R 8 )(R 8a In some embodiments of the compound of formula (I) or a pharmaceutically acceptable salt or stereoisomer thereof, Z 1 Doesn't exist, Z 2 S, Z 3 C(R 7 ), and Z 4 C(R 8 In some embodiments of the compound of formula (I) or a pharmaceutically acceptable salt or stereoisomer thereof, Z 1 Does not exist, is Z 2 O, Z 3 C(R 7 ) and Z 4 C(R 8 In some embodiments of the compound of formula (I) or a pharmaceutically acceptable salt or stereoisomer thereof, Z 1 Doesn't exist, Z 2 N(R 9 ), Z 3 C(R 7 ), and Z 4 C(R 8 ).

[0117] In some embodiments, disclosed herein is a compound of formula (Ia) or a pharmaceutically acceptable salt or stereoisomer thereof:

[0118]

[0119] in:

[0120] R 1 and R 2 are independently selected from hydrogen, C 1-6 Alkyl and C 1-6 alkyl halide;

[0121] R 3 Selected from C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl and C 1-9 Heteroaryl, wherein C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl and C 1-9 Heteroaryl is optionally substituted with 1, 2 or 3 groups selected from R 15a ;

[0122] R 4 Selected from C 3-6 Cycloalkylene, C 2-9 Heterocycloalkylene, C 6-10 Arylene and C 1-9 Heteroarylene, wherein C 3-6 Cycloalkylene, C 2-9 Heterocycloalkylene, C 6-10 Arylene and C 1-9 Heteroarylene is optionally substituted with 1, 2 or 3 groups selected from R 15b ;

[0123] L 1 For valence bond, -N(R 9a )-、-N(R 9a )C(O)-、-C(O)N(R 9a )-、-N(R 9a )S(O)2-、-S(O)2N(R 9a )-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -C(S)-, -S-, -S(O)-, -S(O)2-, -OS(O)-, -OS(O)2-, C 1-6 Alkylene, C 2-6 Alkenylene, C 2-6 Alkynylidene, C 3-6 Cycloalkylene, C 2-9 Heterocycloalkylene or C 1-9 Heteroarylene, wherein C 1-6 Alkylene, C 2-6 Alkenylene, C 2-6 Alkynylidene, C3-6 Cycloalkylene, C 2-9 Heterocycloalkylene and C 1-9 Heteroarylene is optionally substituted with 1, 2 or 3 groups selected from R 15c ;

[0124] L 2 For valence bond, C 1-6 Alkylene, C 2-6 Alkenylene or C 2-6 Alkynylidene, where C 1-6 Alkylene, C 2-6 Alkenylene or C 2-6 Alkynylidene is optionally substituted with 1, 2 or 3 groups selected from R 15c ;

[0125] R 4a Selected from halogen, -CN,

[0126] R 4b 、R 4c and R 4d are each independently selected from hydrogen, halogen, -CN, -C(O)R 13 、-C(O)OR 10 、-C(O)N(R 10 )(R 11 )、-N(R 10 )(R 11 ),-C 1-6 Alkyl-N(R 10 )(R 11 )、-C(O)N(R 10 )OR 10 、C 1-6 alkyl, phenyl, 3 to 7-membered heterocycloalkyl or 5 or 6-membered heteroaryl, wherein the C 1-6 Alkyl, phenyl, 3 to 7-membered heterocycloalkyl or 5 or 6-membered heteroaryl are optionally substituted by 1, 2 or 3 groups selected from R 15d ;or

[0127] R 4b and R 4c Together with the atoms to which they are attached, they form a 3 to 14-membered cycloalkyl group or a 3 to 14-membered heterocycloalkyl group; wherein the 3 to 14-membered cycloalkyl group and the 3 to 14-membered heterocycloalkyl group are optionally substituted by 1, 2, 3 or 4 R 15d Substitute; or R 4d and R 4c Together with the atoms to which they are attached, they form a 3 to 14-membered cycloalkyl group or a 3 to 14-membered heterocycloalkyl group; wherein the 3 to 14-membered cycloalkyl group and the 3 to 14-membered heterocycloalkyl group are optionally substituted by 1, 2, 3 or 4 R15d replace;

[0128] R 4e Halogen or -OS(O)2R 13 ;

[0129] R 5 、R 7 and R 8 independently selected from hydrogen, halogen, -CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, C 1-9 Heteroaryl, -OR 10 、-SR 10 、-SF5、-N(R 10 )(R 11 )、-C(O)OR 10 、-OC(O)N(R 10 )(R 11 )、-N(R 12 )C(O)N(R 10 )(R 11 )、-N(R 12 )C(O)OR 13 、-N(R 12 )S(O)2R 13 、-C(O)R 13 、-S(O)R 13 、-OC(O)R 13 、-C(O)N(R 10 )(R 11 )、-C(O)C(O)N(R 10 )(R 11 )、-N(R 12 )C(O)R 13 、-S(O)2R 13 、-S(O)2N(R 10 )(R 11 )-、-N=S(=O)(R 13 )2、-S(=O)(=NH)N(R 10 )(R 11 )、-S(=O)(=NH)(R 13 ),-S(=O)(=NR 13 )R 13 、-CH2C(O)N(R 10 )(R 11)、-CH2N(R 12 )C(O)R 13 、-CH2S(O)2R 13 、-CH2S(O)2N(R 10 )(R 11 )、-Si(C 1-6 alkyl)3 and -P(O)(R 10 )2, where C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl and C 1-9 Heteroaryl is optionally substituted with 1, 2 or 3 groups selected from R 15e ;

[0130] R 9a Selected from hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl and C 1-9 Heteroaryl, wherein C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl and C 1-9 Heteroaryl is optionally substituted with 1, 2 or 3 groups selected from R 15g ;

[0131] R 10 are each independently selected from hydrogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, -CH2-C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, -CH2-C 2-9 Heterocycloalkyl, -CH2-C 6-10 Aryl, C 6-10 Aryl, C 1-9 Heteroaryl and -CH2-C 1-9 Heteroaryl, wherein C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, -CH2-C3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, -CH2-C 2-9 Heterocycloalkyl, -CH2-C 6-10 Aryl, C 6-10 Aryl, C 1-9 Heteroaryl and -CH2-C 1-9 Heteroaryl is optionally substituted with 1, 2 or 3 groups selected from halogen, -CN, hydroxy, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl and C 1-9 heteroaryl;

[0132] R 11 are each independently selected from hydrogen, C 1-6 Alkyl and C 1-6 haloalkyl; or R 10 and R 11 Together with the attached nitrogen, it forms C 2-9 heterocycloalkyl;

[0133] R 12 are each independently selected from hydrogen, C 1-6 Alkyl and C 1-6 alkyl halide;

[0134] R 13 Each independently selected from C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl and C 1-9 Heteroaryl, wherein C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl and C 1-9 Heteroaryl is optionally substituted with 1, 2 or 3 groups selected from halogen, -CN, hydroxy, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl and C 1-9 heteroaryl; and

[0135] Each R 15a 、R 15b 、R 15c 、R 15d 、R 15e and R 15g Each independently selected from halogen, oxo, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, -CH2-C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, -CH2-C 2-9 Heterocycloalkyl, C 6-10 Aryl, -CH2-C 6-10 Aryl, C 1-9 Heteroaryl, -CH2-C 1-9 Heteroaryl, -OR 10 、-SR 10 、-SF5、-N(R 10 )(R 11 )、-C(O)OR 10 、-OC(O)N(R 10 )(R 11 )、-N(R 12 )C(O)N(R 10 )(R 11 )、-N(R 12 )C(O)OR 13 、-N(R 12 )S(O)2R 13 、-C(O)R 13 、-S(O)R 13 、-OC(O)R 13 、-C(O)N(R 10 )(R 11 )、-C(O)C(O)N(R 10 )(R 11 )、-N(R 12 )C(O)R 13 、-S(O)2R 13 、-S(O)2N(R 10 )(R 11 )-、-N=S(=O)(R 13 )2、-S(=O)(=NH)N(R 10 )(R 11 )、-S(=O)(=NH)(R 13 ),-S(=O)(=NR 13 )R 13 、-CH2C(O)N(R 10 )(R11 )、-CH2N(R 12 )C(O)R 13 、-CH2S(O)2R 13 、-CH2S(O)2N(R 10 )(R 11 )、-Si(C 1-6 alkyl)3 and -P(O)(R 10 )2, where C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, -CH2-C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, -CH2-C 2-9 Heterocycloalkyl, C 6-10 Aryl, -CH2-C 6-10 Aryl, -CH2-C 1-9 Heteroaryl and C 1-9 Heteroaryl is optionally substituted with 1, 2 or 3 groups independently selected from halogen, oxo, -CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -OR 10 、-SR 10 、-SF5、-N(R 10 )(R 11 )、-C(O)OR 10 、-OC(O)N(R 10 )(R 11 )、-N(R 12 )C(O)N(R 10 )(R 11 )、-N(R 12 )C(O)OR 13 、-N(R 12 )S(O)2R 13 、-C(O)R 13 、-S(O)R 13 、-OC(O)R 13 、-C(O)N(R 10 )(R 11 )、-C(O)C(O)N(R 10 )(R 11 )、-N(R 12 )C(O)R 13 、-S(O)2R 13 、-S(O)2N(R 10 )(R 11)-、-N=S(=O)(R 13 )2、-S(=O)(=NH)N(R 10 )(R 11 )、-S(=O)(=NH)(R 13 ),-S(=O)(=NR 13 )R 13 、-CH2C(O)N(R 10 )(R 11 )、-CH2N(R 12 )C(O)R 13 、-CH2S(O)2R 13 、-CH2S(O)2N(R 10 )(R 11 ) and -P(O)(R 10 )2.

[0136] In some embodiments, disclosed herein is a compound of Formula (Ia) having the structure of Formula (Ia') or a pharmaceutically acceptable salt or stereoisomer thereof:

[0137]

[0138] in

[0139] R 1 、R 2 、R 4 、R 4a 、R 5 、R 7 、R 8 and L 1 have the same meanings as those in formula (Ia), and

[0140] R 10 C 1-9 Heteroaryl, which is optionally substituted by 1, 2 or 3 groups selected from halogen, -CN, hydroxy, C 1-6 Alkyl, C 1-6 Haloalkyl and C 1-6 Alkoxy.

[0141] In some embodiments, disclosed herein is a compound of Formula (Ia) having the structure of Formula (Ia") or a pharmaceutically acceptable salt or stereoisomer thereof:

[0142]

[0143] in

[0144] R 1 、R 2 、R 4 、R 4a 、R5 、R 7 、R 8 and L 1 have the same meanings as those in formula (Ia), and

[0145] R 15aa Having the same R as in formula (Ia) 15a Same meaning.

[0146] In some embodiments, disclosed herein is a compound of formula (Ib) or a pharmaceutically acceptable salt or stereoisomer thereof:

[0147]

[0148] in:

[0149] R 1 and R 2 are independently selected from hydrogen, C 1-6 Alkyl and C 1-6 alkyl halide;

[0150] R 3 Selected from C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl and C 1-9 Heteroaryl, wherein C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl and C 1-9 Heteroaryl is optionally substituted with 1, 2 or 3 groups selected from R 15a ;

[0151] R 4 Selected from C 3-6 Cycloalkylene, C 2-9 Heterocycloalkylene, C 6-10 Arylene and C 1-9 Heteroarylene, wherein C 3-6 Cycloalkylene, C 2-9 Heterocycloalkylene, C 6-10 Arylene and C 1-9 Heteroarylene is optionally substituted with 1, 2 or 3 groups selected from R 15b ;

[0152] L 1 For valence bond, -N(R 9a )-、-N(R 9a )C(O)-、-C(O)N(R 9a )-、-N(R 9a )S(O)2-、-S(O)2N(R 9a)-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -C(S)-, -S-, -S(O)-, -S(O)2-, -OS(O)-, -OS(O)2-, C 1-6 Alkylene, C 2-6 Alkenylene, C 2-6 Alkynylidene, C 3-6 Cycloalkylene, C 2-9 Heterocycloalkylene or C 1-9 Heteroarylene, wherein C 1-6 Alkylene, C 2-6 Alkenylene, C 2-6 Alkynylidene, C 3-6 Cycloalkylene, C 2-9 Heterocycloalkylene and C 1-9 Heteroarylene is optionally substituted with 1, 2 or 3 groups selected from R 15c ;

[0153] L 2 For valence bond, C 1-6 Alkylene, C 2-6 Alkenylene or C 2-6 Alkynylidene, where C 1-6 Alkylene, C 2-6 Alkenylene or C 2-6 Alkynylidene is optionally substituted with 1, 2 or 3 groups selected from R 15c ;

[0154] R 4a Selected from halogen, -CN,

[0155] R 4b 、R 4c and R 4d are each independently selected from hydrogen, halogen, -CN, -C(O)R 13 、-C(O)OR 10 、-C(O)N(R 10 )(R 11 )、-N(R 10 )(R 11 ),-C 1-6 Alkyl-N(R 10 )(R 11 )、-C(O)N(R 10 )OR 10 、C 1-6 alkyl, phenyl, 3 to 7-membered heterocycloalkyl or 5 or 6-membered heteroaryl, wherein C 1-6 Alkyl, phenyl, 3 to 7-membered heterocycloalkyl or 5 or 6-membered heteroaryl are optionally substituted by 1, 2 or 3 groups selected from R 15d;or

[0156] R 4b and R 4c Together with the atoms to which they are attached, they form a 3 to 14-membered cycloalkyl group or a 3 to 14-membered heterocycloalkyl group; wherein the 3 to 14-membered cycloalkyl group and the 3 to 14-membered heterocycloalkyl group are optionally substituted by 1, 2, 3 or 4 R 15d Substitute; or R 4d and R 4c Together with the atoms to which they are attached, they form a 3 to 14-membered cycloalkyl group or a 3 to 14-membered heterocycloalkyl group; wherein the 3 to 14-membered cycloalkyl group and the 3 to 14-membered heterocycloalkyl group are optionally substituted by 1, 2, 3 or 4 R 15d replace;

[0157] R 4e Halogen or -OS(O)2R 13 ;

[0158] R 5 、R 6 and R 8 independently selected from hydrogen, halogen, -CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, C 1-9 Heteroaryl, -OR 10 、-SR 10 、-SF5、-N(R 10 )(R 11 )、-C(O)OR 10 、-OC(O)N(R 10 )(R 11 )、-N(R 12 )C(O)N(R 10 )(R 11 )、-N(R 12 )C(O)OR 13 、-N(R 12 )S(O)2R 13 、-C(O)R 13 、-S(O)R 13 、-OC(O)R 13 、-C(O)N(R 10 )(R 11 )、-C(O)C(O)N(R 10 )(R 11 )、-N(R 12 )C(O)R 13 、-S(O)2R13 、-S(O)2N(R 10 )(R 11 )-、-N=S(=O)(R 13 )2、-S(=O)(=NH)N(R 10 )(R 11 )、-S(=O)(=NH)(R 13 ),-S(=O)(=NR 13 )R 13 、-CH2C(O)N(R 10 )(R 11 )、-CH2N(R 12 )C(O)R 13 、-CH2S(O)2R 13 、-CH2S(O)2N(R 10 )(R 11 )、-Si(C 1-6 alkyl)3 and -P(O)(R 10 )2, where C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl and C 1-9 Heteroaryl is optionally substituted with 1, 2 or 3 groups selected from R 15e ;

[0159] R 9a Selected from hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl and C 1-9 Heteroaryl, wherein C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl and C 1-9 Heteroaryl is optionally substituted with 1, 2 or 3 groups selected from R 15g ;

[0160] R 10 are each independently selected from hydrogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C3-6 Cycloalkyl, -CH2-C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, -CH2-C 2-9 Heterocycloalkyl, -CH2-C 6-10 Aryl, C 6-10 Aryl, C 1-9 Heteroaryl and -CH2-C 1-9 Heteroaryl, wherein C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, -CH2-C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, -CH2-C 2-9 Heterocycloalkyl, -CH2-C 6-10 Aryl, C 6-10 Aryl, C 1-9 Heteroaryl and -CH2-C 1-9 Heteroaryl is optionally substituted with 1, 2 or 3 groups selected from halogen, -CN, hydroxy, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl and C 1-9 heteroaryl;

[0161] R 11 are each independently selected from hydrogen, C 1-6 Alkyl and C 1-6 haloalkyl; or R 10 and R 11 Together with the attached nitrogen, it forms C 2-9 heterocycloalkyl;

[0162] R 12 are each independently selected from hydrogen, C 1-6 Alkyl and C 1-6 alkyl halide;

[0163] R 13 Each independently selected from C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl and C 1-9 Heteroaryl, wherein C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl and C 1-9 Heteroaryl is optionally substituted with 1, 2 or 3 groups selected from halogen, -CN, hydroxy, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl and C 1-9 heteroaryl; and

[0164] R 15a 、R 15b 、R 15c 、R 15d 、R 15e and R 15g Each is independently selected from halogen, oxo, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, -CH2-C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, -CH2-C 2-9 Heterocycloalkyl, C 6-10 Aryl, -CH2-C 6-10 Aryl, C 1-9 Heteroaryl, -CH2-C 1-9 Heteroaryl, -OR 10 、-SR 10 、-SF5、-N(R 10 )(R 11 )、-C(O)OR 10 、-OC(O)N(R 10 )(R 11 )、-N(R 12 )C(O)N(R 10 )(R 11 )、-N(R 12 )C(O)OR 13 、-N(R 12 )S(O)2R 13 、-C(O)R 13 、-S(O)R 13 、-OC(O)R 13 、-C(O)N(R 10 )(R 11 )、-C(O)C(O)N(R 10 )(R 11 )、-N(R 12 )C(O)R13 、-S(O)2R 13 、-S(O)2N(R 10 )(R 11 )-、-N=S(=O)(R 13 )2、-S(=O)(=NH)N(R 10 )(R 11 )、-S(=O)(=NH)(R 13 ),-S(=O)(=NR 13 )R 13 、-CH2C(O)N(R 10 )(R 11 )、-CH2N(R 12 )C(O)R 13 、-CH2S(O)2R 13 、-CH2S(O)2N(R 10 )(R 11 )、-Si(C 1-6 alkyl)3 and -P(O)(R 10 )2, where C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, -CH2-C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, -CH2-C 2-9 Heterocycloalkyl, C 6-10 Aryl, -CH2-C 6-10 Aryl, -CH2-C 1-9 Heteroaryl and C 1-9 Heteroaryl is optionally substituted with 1, 2 or 3 groups independently selected from halogen, oxo, -CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -OR 10 、-SR 10 、-SF5、-N(R 10 )(R 11 )、-C(O)OR 10 、-OC(O)N(R 10 )(R 11 )、-N(R 12 )C(O)N(R 10 )(R 11 )、-N(R 12 )C(O)OR 13 、-N(R 12 )S(O)2R 13、-C(O)R 13 、-S(O)R 13 、-OC(O)R 13 、-C(O)N(R 10 )(R 11 )、-C(O)C(O)N(R 10 )(R 11 )、-N(R 12 )C(O)R 13 、-S(O)2R 13 、-S(O)2N(R 10 )(R 11 )-、-N=S(=O)(R 13 )2、-S(=O)(=NH)N(R 10 )(R 11 )、-S(=O)(=NH)(R 13 ),-S(=O)(=NR 13 )R 13 、-CH2C(O)N(R 10 )(R 11 )、-CH2N(R 12 )C(O)R 13 、-CH2S(O)2R 13 、-CH2S(O)2N(R 10 )(R 11 ) and -P(O)(R 10 )2.

[0165] In some embodiments, disclosed herein is a compound of Formula (Ib) having the structure of Formula (Ib') or a pharmaceutically acceptable salt or stereoisomer thereof:

[0166]

[0167] in

[0168] R 1 、R 2 、R 4 、R 4a 、R 5 、R 6 、R 8 and L 1 have the same meanings as those in formula (Ib), and

[0169] R 10 C 1-9 Heteroaryl, which is optionally substituted by 1, 2 or 3 groups selected from halogen, -CN, hydroxy, C 1-6 Alkyl, C 1-6 Haloalkyl and C 1-6Alkoxy.

[0170] In some embodiments, disclosed herein is a compound of Formula (Ib) having the structure of Formula (Ib") or a pharmaceutically acceptable salt or stereoisomer thereof:

[0171]

[0172] in

[0173] R 1 、R 2 、R 4 、R 4a 、R 5 、R 6 、R 8 、R 10 and L 1 have the same meanings as those in formula (Ib), and

[0174] R 15aa Having the same R as in formula (Ib) 15a Same meaning.

[0175] In some embodiments, disclosed herein is a compound of formula (Ic) or a pharmaceutically acceptable salt or stereoisomer thereof:

[0176]

[0177] in:

[0178] R 1 and R 2 are independently selected from hydrogen, C 1-6 Alkyl and C 1-6 alkyl halide;

[0179] R 3 Selected from C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl and C 1-9 Heteroaryl, wherein C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl and C 1-9 Heteroaryl is optionally substituted with 1, 2 or 3 groups selected from R 15a ;

[0180] R 4 Selected from C 3-6 Cycloalkylene, C 2-9 Heterocycloalkylene, C 6-10 Arylene and C 1-9 Heteroarylene, wherein C 3-6 Cycloalkylene, C 2-9Heterocycloalkylene, C 6-10 Arylene and C 1-9 Heteroarylene is optionally substituted with 1, 2 or 3 groups selected from R 15b ;

[0181] L 1 For valence bond, -N(R 9a )-、-N(R 9a )C(O)-、-C(O)N(R 9a )-、-N(R 9a )S(O)2-、-S(O)2N(R 9a )-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -C(S)-, -S-, -S(O)-, -S(O)2-, -OS(O)-, -OS(O)2-, C 1-6 Alkylene, C 2-6 Alkenylene, C 2-6 Alkynylidene, C 3-6 Cycloalkylene, C 2-9 Heterocycloalkylene or C 1-9 Heteroarylene, wherein C 1-6 Alkylene, C 2-6 Alkenylene, C 2-6 Alkynylidene, C 3-6 Cycloalkylene, C 2-9 Heterocycloalkylene and C 1-9 Heteroarylene is optionally substituted with 1, 2 or 3 groups selected from R 15c ;

[0182] L 2 For valence bond, C 1-6 Alkylene, C 2-6 Alkenylene or C 2-6 Alkynylidene, where C 1-6 Alkylene, C 2-6 Alkenylene or C 2-6 Alkynylidene is optionally substituted with 1, 2 or 3 groups selected from R 15c ;

[0183] R 4a Selected from halogen, -CN,

[0184] R 4b 、R 4c and R 4d are each independently selected from hydrogen, halogen, -CN, -C(O)R 13 、-C(O)OR 10 、-C(O)N(R 10 )(R 11)、-N(R 10 )(R 11 ),-C 1-6 Alkyl-N(R 10 )(R 11 )、-C(O)N(R 10 )OR 10 、C 1-6 alkyl, phenyl, 3 to 7-membered heterocycloalkyl or 5 or 6-membered heteroaryl, wherein the C 1-6 Alkyl, phenyl, 3 to 7-membered heterocycloalkyl or 5 or 6-membered heteroaryl are optionally substituted by 1, 2 or 3 groups selected from R 15d ;or

[0185] R 4b and R 4c Together with the atoms to which they are attached, they form a 3 to 14-membered cycloalkyl group or a 3 to 14-membered heterocycloalkyl group; wherein the 3 to 14-membered cycloalkyl group and the 3 to 14-membered heterocycloalkyl group are optionally substituted by 1, 2, 3 or 4 R 15d Substitute; or R 4d and R 4c Together with the atoms to which they are attached, they form a 3 to 14-membered cycloalkyl group or a 3 to 14-membered heterocycloalkyl group; wherein the 3 to 14-membered cycloalkyl group and the 3 to 14-membered heterocycloalkyl group are optionally substituted by 1, 2, 3 or 4 R 15d replace;

[0186] R 4e Halogen or -OS(O)2R 13 ;

[0187] R 5 、R 6 and R 7 independently selected from hydrogen, halogen, -CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, C 1-9 Heteroaryl, -OR 10 、-SR 10 、-SF5、-N(R 10 )(R 11 )、-C(O)OR 10 、-OC(O)N(R 10 )(R 11 )、-N(R 12 )C(O)N(R 10 )(R 11 )、-N(R 12 )C(O)OR13 、-N(R 12 )S(O)2R 13 、-C(O)R 13 、-S(O)R 13 、-OC(O)R 13 、-C(O)N(R 10 )(R 11 )、-C(O)C(O)N(R 10 )(R 11 )、-N(R 12 )C(O)R 13 、-S(O)2R 13 、-S(O)2N(R 10 )(R 11 )-、-N=S(=O)(R 13 )2、-S(=O)(=NH)N(R 10 )(R 11 )、-S(=O)(=NH)(R 13 ),-S(=O)(=NR 13 )R 13 、-CH2C(O)N(R 10 )(R 11 )、-CH2N(R 12 )C(O)R 13 、-CH2S(O)2R 13 、-CH2S(O)2N(R 10 )(R 11 )、-Si(C 1-6 alkyl)3 and -P(O)(R 10 )2, where C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl and C 1-9 Heteroaryl is optionally substituted with 1, 2 or 3 groups selected from R 15e ;

[0188] R 9a Selected from hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl and C 1-9 Heteroaryl, wherein C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl and C 1-9 Heteroaryl is optionally substituted with 1, 2 or 3 groups selected from R 15g ;

[0189] R 10 are each independently selected from hydrogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, -CH2-C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, -CH2-C 2-9 Heterocycloalkyl, -CH2-C 6-10 Aryl, C 6-10 Aryl, C 1-9 Heteroaryl and -CH2-C 1-9 Heteroaryl, wherein C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, -CH2-C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, -CH2-C 2-9 Heterocycloalkyl, -CH2-C 6-10 Aryl, C 6-10 Aryl, C 1-9 Heteroaryl and -CH2-C 1-9 Heteroaryl is optionally substituted with 1, 2 or 3 groups selected from halogen, -CN, hydroxy, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl and C 1-9 heteroaryl;

[0190] R 11 are each independently selected from hydrogen, C 1-6 Alkyl and C 1-6 haloalkyl; or R 10 and R 11 Together with the attached nitrogen, it forms C 2-9 heterocycloalkyl;

[0191] R 12 are each independently selected from hydrogen, C 1-6 Alkyl and C 1-6 alkyl halide;

[0192] R 13 Each independently selected from C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl and C 1-9 Heteroaryl, wherein C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl and C 1-9 Heteroaryl is optionally substituted with 1, 2 or 3 groups selected from halogen, -CN, hydroxy, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl and C 1-9 heteroaryl; and

[0193] Each R 15a 、R 15b 、R 15c 、R 15d 、R 15e and R 15g Each independently selected from halogen, oxo, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, -CH2-C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, -CH2-C 2-9 Heterocycloalkyl, C 6-10 Aryl, -CH2-C 6-10 Aryl, C 1-9 Heteroaryl, -CH2-C 1-9 Heteroaryl, -OR 10 、-SR 10 、-SF5、-N(R 10 )(R 11 )、-C(O)OR 10 、-OC(O)N(R 10 )(R 11 )、-N(R 12 )C(O)N(R 10 )(R 11 )、-N(R12 )C(O)OR 13 、-N(R 12 )S(O)2R 13 、-C(O)R 13 、-S(O)R 13 、-OC(O)R 13 、-C(O)N(R 10 )(R 11 )、-C(O)C(O)N(R 10 )(R 11 )、-N(R 12 )C(O)R 13 、-S(O)2R 13 、-S(O)2N(R 10 )(R 11 )-、-N=S(=O)(R 13 )2、-S(=O)(=NH)N(R 10 )(R 11 )、-S(=O)(=NH)(R 13 ),-S(=O)(=NR 13 )R 13 、-CH2C(O)N(R 10 )(R 11 )、-CH2N(R 12 )C(O)R 13 、-CH2S(O)2R 13 、-CH2S(O)2N(R 10 )(R 11 )、-Si(C 1-6 alkyl)3 and -P(O)(R 10 )2, where C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, -CH2-C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, -CH2-C 2-9 Heterocycloalkyl, C 6-10 Aryl, -CH2-C 6-10 Aryl, -CH2-C 1-9 Heteroaryl and C 1-9 Heteroaryl is optionally substituted with 1, 2 or 3 groups independently selected from halogen, oxo, -CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -OR 10 、-SR 10、-SF5、-N(R 10 )(R 11 )、-C(O)OR 10 、-OC(O)N(R 10 )(R 11 )、-N(R 12 )C(O)N(R 10 )(R 11 )、-N(R 12 )C(O)OR 13 、-N(R 12 )S(O)2R 13 、-C(O)R 13 、-S(O)R 13 、-OC(O)R 13 、-C(O)N(R 10 )(R 11 )、-C(O)C(O)N(R 10 )(R 11 )、-N(R 12 )C(O)R 13 、-S(O)2R 13 、-S(O)2N(R 10 )(R 11 )-、-N=S(=O)(R 13 )2、-S(=O)(=NH)N(R 10 )(R 11 )、-S(=O)(=NH)(R 13 ),-S(=O)(=NR 13 )R 13 、-CH2C(O)N(R 10 )(R 11 )、-CH2N(R 12 )C(O)R 13 、-CH2S(O)2R 13 、-CH2S(O)2N(R 10 )(R 11 ) and -P(O)(R 10 )2.

[0194] In some embodiments, disclosed herein is a compound of Formula (Ic) having the structure of Formula (Ic') or a pharmaceutically acceptable salt or stereoisomer thereof:

[0195]

[0196] in

[0197] R 1 、R 2 、R 4 、R4a 、R 5 、R 6 、R 7 and L 1 have the same meanings as those in formula (Ic), and

[0198] R 10 C 1-9 Heteroaryl, which is optionally substituted by 1, 2 or 3 groups selected from halogen, -CN, hydroxy, C 1-6 Alkyl, C 1-6 Haloalkyl and C 1-6 Alkoxy.

[0199] In some embodiments, disclosed herein is a compound of Formula (Ic) having the structure of Formula (Ic") or a pharmaceutically acceptable salt or stereoisomer thereof:

[0200]

[0201] in

[0202] R 1 、R 2 、R 4 、R 4a 、R 5 、R 7 、R 8 and L 1 have the same meanings as those in formula (Ic), and

[0203] R 15aa Having the same R as in formula (Ic) 15a Same meaning.

[0204] In some embodiments of the compound of Formula (Ia"), (Ib"), or (Ic"), or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 15aa Selected from halogen, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, -CH2-C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, -CH2-C 2-9 Heterocycloalkyl, C 6-10 Aryl, -CH2-C 6-10 Aryl, C 1-9 Heteroaryl, -CH2-C 1-9 Heteroaryl, -OR 10 、-SR 10 、-SF5、-N(R 10 )(R 11)、-C(O)OR 10 、-OC(O)N(R 10 )(R 11 )、-N(R 12 )C(O)N(R 10 )(R 11 )、-N(R 12 )C(O)OR 13 、-N(R 12 )S(O)2R 13 、-C(O)R 13 、-S(O)R 13 、-OC(O)R 13 、-C(O)N(R 10 )(R 11 )、-C(O)C(O)N(R 10 )(R 11 )、-N(R 12 )C(O)R 13 、-S(O)2R 13 、-S(O)2N(R 10 )(R 11 )-、-N=S(=O)(R 13 )2、-S(=O)(=NH)N(R 10 )(R 11 )、-S(=O)(=NH)(R 13 ),-S(=O)(=NR 13 )R 13 、-CH2C(O)N(R 10 )(R 11 )、-CH2N(R 12 )C(O)R 13 、-CH2S(O)2R 13 、-CH2S(O)2N(R 10 )(R 11 )、-Si(C 1-6 alkyl)3 and -P(O)(R 10 )2, where C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, -CH2-C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, -CH2-C 2-9 Heterocycloalkyl, C 6-10 Aryl, -CH2-C 6-10 Aryl, -CH2-C 1-9 Heteroaryl and C 1-9Heteroaryl is optionally substituted with 1, 2 or 3 groups independently selected from halogen, oxo, -CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -OR 10 、-SR 10 、-SF5、-N(R 10 )(R 11 )、-C(O)OR 10 、-OC(O)N(R 10 )(R 11 )、-N(R 12 )C(O)N(R 10 )(R 11 )、-N(R 12 )C(O)OR 13 、-N(R 12 )S(O)2R 13 、-C(O)R 13 、-S(O)R 13 、-OC(O)R 13 、-C(O)N(R 10 )(R 11 )、-C(O)C(O)N(R 10 )(R 11 )、-N(R 12 )C(O)R 13 、-S(O)2R 13 、-S(O)2N(R 10 )(R 11 )-、-N=S(=O)(R 13 )2、-S(=O)(=NH)N(R 10 )(R 11 )、-S(=O)(=NH)(R 13 ),-S(=O)(=NR 13 )R 13 、-CH2C(O)N(R 10 )(R 11 )、-CH2N(R 12 )C(O)R 13 、-CH2S(O)2R 13 、-CH2S(O)2N(R 10 )(R 11 ) and -P(O)(R 10 )2. In some embodiments of the compound of Formula (Ia"), (Ib") or (Ic"), or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 15aaSelected from halogen, -CN, C 1-6 Alkyl, -OR 10 、-N(R 10 )(R 11 )、-C(O)OR 10 、-N(R 12 )S(O)2R 13 、-C(O)R 13 、-S(O)R 13 、-C(O)N(R 10 )(R 11 )、-C(O)C(O)N(R 10 )(R 11 )、-N(R 12 )C(O)R 13 、-S(O)2R 13 and -S(O)2N(R 10 )(R 11 )-, where C 1-6 The alkyl group is optionally substituted with 1, 2 or 3 groups independently selected from halogen, -CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -OR 10 and -N(R 10 )(R 11 In some embodiments, disclosed herein are compounds of Formula (Ia"), (Ib"), or (Ic"), or pharmaceutically acceptable salts or stereoisomers thereof, wherein R 15aa Selected from halogen, C 1-6 In some embodiments, disclosed herein are compounds of Formula (Ia"), (Ib"), or (Ic"), or pharmaceutically acceptable salts or stereoisomers thereof, wherein R 15aa In some embodiments, disclosed herein are compounds of Formula (Ia"), (Ib"), or (Ic"), or pharmaceutically acceptable salts or stereoisomers thereof, wherein R 15aa In some embodiments, disclosed herein are compounds of Formula (Ia"), (Ib"), or (Ic"), or pharmaceutically acceptable salts or stereoisomers thereof, wherein R 15aa For fluorine.

[0205] In some embodiments, disclosed herein are compounds of Formula (Ia'), (Ia"), (Ib'), (Ib"), (Ic'), or (Ic"), or pharmaceutically acceptable salts or stereoisomers thereof, wherein R 10 C 1-9Heteroaryl, which is optionally substituted by 1, 2 or 3 groups selected from halogen, -CN, hydroxy, C 1-6 Alkyl, C 1-6 Haloalkyl and C 1-6 In some embodiments, disclosed herein are compounds of Formula (Ia'), (Ia"), (Ib'), (Ib"), (Ic'), or (Ic"), or pharmaceutically acceptable salts or stereoisomers thereof, wherein R 10 is a 5- to 6-membered heteroaryl group, which is optionally substituted by 1, 2 or 3 groups selected from halogen, -CN, hydroxy, C 1-6 Alkyl, C 1-6 Haloalkyl and C 1-6 In some embodiments, disclosed herein are compounds of Formula (Ia'), (Ia"), (Ib'), (Ib"), (Ic'), or (Ic"), or pharmaceutically acceptable salts or stereoisomers thereof, wherein R 10 is a 5- to 6-membered heteroaryl group, which is optionally substituted by 1 group selected from C 1-6 In some embodiments, disclosed herein are compounds of Formula (Ia'), (Ia"), (Ib'), (Ib"), (Ic'), or (Ic"), or pharmaceutically acceptable salts or stereoisomers thereof, wherein R 10 is pyridinyl or pyrimidinyl, wherein the pyridinyl or pyrimidinyl is optionally substituted by 1, 2 or 3 groups selected from halogen, -CN, hydroxyl, C 1-6 Alkyl, C 1-6 Haloalkyl and C 1-6 In some embodiments, disclosed herein are compounds of Formula (Ia'), (Ia"), (Ib'), (Ib"), (Ic'), or (Ic"), or pharmaceutically acceptable salts or stereoisomers thereof, wherein R 10 is pyridyl or pyrimidinyl, wherein the pyridyl or pyrimidinyl is substituted by 1, 2 or 3 groups selected from C 1-6 In some embodiments, disclosed herein are compounds of Formula (Ia'), (Ia"), (Ib'), (Ib"), (Ic'), or (Ic"), or pharmaceutically acceptable salts or stereoisomers thereof, wherein R 10Optionally substituted with one or more substituents selected from halogen, -CN, -OH, -SF5, -SH, -S(=O)C1-C3 alkyl, -S(=O)2C1-C3 alkyl, -S(=O)2NH2, -S(=O)2NHC1-C3 alkyl, -S(=O)2N(C1-C3 alkyl)2, -S(=O)(=NC1-C3 alkyl)(C1-C3 alkyl), -NH2, -NHC1-C3 alkyl, -N(C1-C3 alkyl)2, -N=S(=O)(C1-C3 alkyl)2, -O-C1-C4 alkylene- -OH, -O-C1-C4 alkylene-NH2, -C(=O)C1-C3 alkyl, -C(=O)OH, -C(=O)OC1-C3 alkyl, -C(=O)NH2, -C(=O)NHC1-C3 alkyl, -C(=O)N(C1-C3 alkyl)2, -P(=O)(C1-C3 alkyl)2, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, C1-C3 hydroxyalkyl, C1-C3 aminoalkyl, C1-C3 heteroalkyl, C3-C6 cycloalkyl and 3- to 6-membered heterocycloalkyl. In some embodiments, disclosed herein are compounds of formula (Ia'), (Ia"), (Ib'), (Ib"), (Ic') or (Ic"), or pharmaceutically acceptable salts or stereoisomers thereof, wherein R 10 Optionally substituted with one or more substituents selected from halogen, -CN, -OH, -SF5, -SH, -S(=O)2NH2, -S(=O)2NHC1-C3 alkyl, -S(=O)2N(C1-C3 alkyl)2, -S(=O)(=NC1-C3 alkyl)(C1-C3 alkyl), -NH2, -NHC1-C3 alkyl, -N(C1-C3 alkyl)2, -O-C1-C4 alkylene-OH, -O-C 1-C4 alkylene-NH2, -C(=O)C1-C3 alkyl, -C(=O)OH, -C(=O)OC1-C3 alkyl, -C(=O)NH2, -C(=O)NHC1-C3 alkyl, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, C1-C3 hydroxyalkyl, C1-C3 aminoalkyl, C1-C3 heteroalkyl, C3-C6 cycloalkyl and 3- to 6-membered heterocycloalkyl. In some embodiments, disclosed herein are compounds of formula (Ia'), (Ia"), (Ib'), (Ib"), (Ic') or (Ic"), or pharmaceutically acceptable salts or stereoisomers thereof, wherein R 10 for In some embodiments, disclosed herein are compounds of Formula (Ia'), (Ia"), (Ib'), (Ib"), (Ic'), or (Ic"), or pharmaceutically acceptable salts or stereoisomers thereof, wherein R10 for In some embodiments, disclosed herein are compounds of Formula (Ia'), (Ia"), (Ib'), (Ib"), (Ic'), or (Ic"), or pharmaceutically acceptable salts or stereoisomers thereof, wherein R 10 for

[0206] In some embodiments, disclosed herein is a compound of formula (Id) or a pharmaceutically acceptable salt or stereoisomer thereof:

[0207]

[0208] in:

[0209] R 1 and R 2 are independently selected from hydrogen, C 1-6 Alkyl and C 1-6 alkyl halide;

[0210] R 3 Selected from C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl and C 1-9 Heteroaryl, wherein C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl and C 1-9 Heteroaryl is optionally substituted with 1, 2 or 3 groups selected from R 15a ;

[0211] R 4 Selected from C 3-6 Cycloalkylene, C 2-9 Heterocycloalkylene, C 6-10 Arylene and C 1-9 Heteroarylene, wherein C 3-6 Cycloalkylene, C 2-9 Heterocycloalkylene, C 6-10 Arylene and C 1-9 Heteroarylene is optionally substituted with 1, 2 or 3 groups selected from R 15b ;

[0212] L 1 For valence bond, -N(R 9a )-、-N(R 9a )C(O)-、-C(O)N(R 9a )-、-N(R 9a )S(O)2-、-S(O)2N(R 9a)-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -C(S)-, -S-, -S(O)-, -S(O)2-, -OS(O)-, -OS(O)2-, C 1-6 Alkylene, C 2-6 Alkenylene, C 2-6 Alkynylidene, C 3-6 Cycloalkylene, C 2-9 Heterocycloalkylene or C 1-9 Heteroarylene, wherein C 1-6 Alkylene, C 2-6 Alkenylene, C 2-6 Alkynylidene, C 3-6 Cycloalkylene, C 2-9 Heterocycloalkylene and C 1-9 Heteroarylene is optionally substituted with 1, 2 or 3 groups selected from R 15c ;

[0213] L 2 For valence bond, C 1-6 Alkylene, C 2-6 Alkenylene or C 2-6 Alkynylidene, where C 1-6 Alkylene, C 2-6 Alkenylene or C 2-6 Alkynylidene is optionally substituted with 1, 2 or 3 groups selected from R 15c ;

[0214] R 4a Selected from halogen, -CN,

[0215] R 4b 、R 4c and R 4d are each independently selected from hydrogen, halogen, -CN, -C(O)R 13 、-C(O)OR 10 、-C(O)N(R 10 )(R 11 )、-N(R 10 )(R 11 ),-C 1-6 Alkyl-N(R 10 )(R 11 )、-C(O)N(R 10 )OR 10 、C 1-6 alkyl, phenyl, 3 to 7-membered heterocycloalkyl or 5 or 6-membered heteroaryl, wherein C 1-6 Alkyl, phenyl, 3 to 7-membered heterocycloalkyl or 5 or 6-membered heteroaryl are optionally substituted by 1, 2 or 3 groups selected from R 15d;or

[0216] R 4b and R 4c Together with the atoms to which they are attached, they form a 3 to 14-membered cycloalkyl group or a 3 to 14-membered heterocycloalkyl group; wherein the 3 to 14-membered cycloalkyl group and the 3 to 14-membered heterocycloalkyl group are optionally substituted by 1, 2, 3 or 4 R 15d Substitute; or R 4d and R 4c Together with the atoms to which they are attached, they form a 3 to 14-membered cycloalkyl group or a 3 to 14-membered heterocycloalkyl group; wherein the 3 to 14-membered cycloalkyl group and the 3 to 14-membered heterocycloalkyl group are optionally substituted by 1, 2, 3 or 4 R 15d replace;

[0217] R 4e Halogen or -OS(O)2R 13 ;

[0218] R 6 、R 7 and R 8 independently selected from hydrogen, halogen, -CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, C 1-9 Heteroaryl, -OR 10 、-SR 10 、-SF5、-N(R 10 )(R 11 )、-C(O)OR 10 、-OC(O)N(R 10 )(R 11 )、-N(R 12 )C(O)N(R 10 )(R 11 )、-N(R 12 )C(O)OR 13 、-N(R 12 )S(O)2R 13 、-C(O)R 13 、-S(O)R 13 、-OC(O)R 13 、-C(O)N(R 10 )(R 11 )、-C(O)C(O)N(R 10 )(R 11 )、-N(R 12 )C(O)R 13 、-S(O)2R13 、-S(O)2N(R 10 )(R 11 )-、-N=S(=O)(R 13 )2、-S(=O)(=NH)N(R 10 )(R 11 )、-S(=O)(=NH)(R 13 ),-S(=O)(=NR 13 )R 13 、-CH2C(O)N(R 10 )(R 11 )、-CH2N(R 12 )C(O)R 13 、-CH2S(O)2R 13 、-CH2S(O)2N(R 10 )(R 11 )、-Si(C 1-6 alkyl)3 and -P(O)(R 10 )2, where C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl and C 1-9 Heteroaryl is optionally substituted with 1, 2 or 3 groups selected from R 15e ;

[0219] R 9a Selected from hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl and C 1-9 Heteroaryl, wherein C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl and C 1-9 Heteroaryl is optionally substituted with 1, 2 or 3 groups selected from R 15g ;

[0220] R 10 are each independently selected from hydrogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C3-6 Cycloalkyl, -CH2-C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, -CH2-C 2-9 Heterocycloalkyl, -CH2-C 6-10 Aryl, C 6-10 Aryl, C 1-9 Heteroaryl and -CH2-C 1-9 Heteroaryl, wherein C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, -CH2-C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, -CH2-C 2-9 Heterocycloalkyl, -CH2-C 6-10 Aryl, C 6-10 Aryl, C 1-9 Heteroaryl and -CH2-C 1-9 Heteroaryl is optionally substituted with 1, 2 or 3 groups selected from halogen, -CN, hydroxy, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl and C 1-9 heteroaryl;

[0221] R 11 are each independently selected from hydrogen, C 1-6 Alkyl and C 1-6 haloalkyl; or R 10 and R 11 Together with the attached nitrogen, it forms C 2-9 heterocycloalkyl;

[0222] R 12 are each independently selected from hydrogen, C 1-6 Alkyl and C 1-6 alkyl halide;

[0223] R 13 Each independently selected from C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl and C 1-9 Heteroaryl, wherein C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl and C 1-9 Heteroaryl is optionally substituted with 1, 2 or 3 groups selected from halogen, -CN, hydroxy, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl and C 1-9 heteroaryl; and

[0224] Each R 15a 、R 15b 、R 15c 、R 15d 、R 15e and R 15g Each independently selected from halogen, oxo, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, -CH2-C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, -CH2-C 2-9 Heterocycloalkyl, C 6-10 Aryl, -CH2-C 6-10 Aryl, C 1-9 Heteroaryl, -CH2-C 1-9 Heteroaryl, -OR 10 、-SR 10 、-SF5、-N(R 10 )(R 11 )、-C(O)OR 10 、-OC(O)N(R 10 )(R 11 )、-N(R 12 )C(O)N(R 10 )(R 11 )、-N(R 12 )C(O)OR 13 、-N(R 12 )S(O)2R 13 、-C(O)R 13 、-S(O)R 13 、-OC(O)R 13 、-C(O)N(R 10 )(R 11 )、-C(O)C(O)N(R 10 )(R 11 )、-N(R 12 )C(O)R13 、-S(O)2R 13 、-S(O)2N(R 10 )(R 11 )-、-N=S(=O)(R 13 )2、-S(=O)(=NH)N(R 10 )(R 11 )、-S(=O)(=NH)(R 13 ),-S(=O)(=NR 13 )R 13 、-CH2C(O)N(R 10 )(R 11 )、-CH2N(R 12 )C(O)R 13 、-CH2S(O)2R 13 、-CH2S(O)2N(R 10 )(R 11 )、-Si(C 1-6 alkyl)3 and -P(O)(R 10 )2, where C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, -CH2-C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, -CH2-C 2-9 Heterocycloalkyl, C 6-10 Aryl, -CH2-C 6-10 Aryl, -CH2-C 1-9 Heteroaryl and C 1-9 Heteroaryl is optionally substituted with 1, 2 or 3 groups independently selected from halogen, oxo, -CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -OR 10 、-SR 10 、-SF5、-N(R 10 )(R 11 )、-C(O)OR 10 、-OC(O)N(R 10 )(R 11 )、-N(R 12 )C(O)N(R 10 )(R 11 )、-N(R 12 )C(O)OR 13 、-N(R 12 )S(O)2R 13、-C(O)R 13 、-S(O)R 13 、-OC(O)R 13 、-C(O)N(R 10 )(R 11 )、-C(O)C(O)N(R 10 )(R 11 )、-N(R 12 )C(O)R 13 、-S(O)2R 13 、-S(O)2N(R 10 )(R 11 )-、-N=S(=O)(R 13 )2、-S(=O)(=NH)N(R 10 )(R 11 )、-S(=O)(=NH)(R 13 ),-S(=O)(=NR 13 )R 13 、-CH2C(O)N(R 10 )(R 11 )、-CH2N(R 12 )C(O)R 13 、-CH2S(O)2R 13 、-CH2S(O)2N(R 10 )(R 11 ) and -P(O)(R 10 )2.

[0225] In some embodiments, disclosed herein is a compound of formula (Ie) or a pharmaceutically acceptable salt or stereoisomer thereof:

[0226]

[0227] in:

[0228] R 1 and R 2 are independently selected from hydrogen, C 1-6 Alkyl and C 1-6 alkyl halide;

[0229] R 3 Selected from C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl and C 1-9 Heteroaryl, wherein C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl and C 1-9 Heteroaryl is optionally substituted with 1, 2 or 3 groups selected from R15a ;

[0230] R 4 Selected from C 3-6 Cycloalkylene, C 2-9 Heterocycloalkylene, C 6-10 Arylene and C 1-9 Heteroarylene, wherein C 3-6 Cycloalkylene, C 2-9 Heterocycloalkylene, C 6-10 Arylene and C 1-9 Heteroarylene is optionally substituted with 1, 2 or 3 groups selected from R 15b ;

[0231] L 1 For valence bond, -N(R 9a )-、-N(R 9a )C(O)-、-C(O)N(R 9a )-、-N(R 9a )S(O)2-、-S(O)2N(R 9a )-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -C(S)-, -S-, -S(O)-, -S(O)2-, -OS(O)-, -OS(O)2-, C 1-6 Alkylene, C 2-6 Alkenylene, C 2-6 Alkynylidene, C 3-6 Cycloalkylene, C 2-9 Heterocycloalkylene or C 1-9 Heteroarylene, wherein C 1-6 Alkylene, C 2-6 Alkenylene, C 2-6 Alkynylidene, C 3-6 Cycloalkylene, C 2-9 Heterocycloalkylene and C 1-9 Heteroarylene is optionally substituted with 1, 2 or 3 groups selected from R 15c ;

[0232] L 2 For valence bond, C 1-6 Alkylene, C 2-6 Alkenylene or C 2-6 Alkynylidene, where C 1-6 Alkylene, C 2-6 Alkenylene or C 2-6 Alkynylidene is optionally substituted with 1, 2 or 3 groups selected from R 15c ;

[0233] R 4a Selected from halogen, -CN,

[0234] R 4b 、R 4c and R 4d are each independently selected from hydrogen, halogen, -CN, -C(O)R 13 、-C(O)OR 10 、-C(O)N(R 10 )(R 11 )、-N(R 10 )(R 11 ),-C 1-6 Alkyl-N(R 10 )(R 11 )、-C(O)N(R 10 )OR 10 、C 1-6 alkyl, phenyl, 3 to 7-membered heterocycloalkyl or 5 or 6-membered heteroaryl, wherein the C 1-6 Alkyl, phenyl, 3 to 7-membered heterocycloalkyl or 5 or 6-membered heteroaryl are optionally substituted by 1, 2 or 3 groups selected from R 15d ;or

[0235] R 4b and R 4c Together with the atoms to which they are attached, they form a 3 to 14-membered cycloalkyl group or a 3 to 14-membered heterocycloalkyl group; wherein the 3 to 14-membered cycloalkyl group and the 3 to 14-membered heterocycloalkyl group are optionally substituted by 1, 2, 3 or 4 R 15d Substitute; or R 4d and R 4c Together with the atoms to which they are attached, they form a 3 to 14-membered cycloalkyl group or a 3 to 14-membered heterocycloalkyl group; wherein the 3 to 14-membered cycloalkyl group and the 3 to 14-membered heterocycloalkyl group are optionally substituted by 1, 2, 3 or 4 R 15d replace;

[0236] R 4e Halogen or -OS(O)2R 13 ;

[0237] R 5 、R 7 and R 8 independently selected from hydrogen, halogen, -CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, C 1-9 Heteroaryl, -OR 10 、-SR 10 、-SF5、-N(R 10)(R 11 )、-C(O)OR 10 、-OC(O)N(R 10 )(R 11 )、-N(R 12 )C(O)N(R 10 )(R 11 )、-N(R 12 )C(O)OR 13 、-N(R 12 )S(O)2R 13 、-C(O)R 13 、-S(O)R 13 、-OC(O)R 13 、-C(O)N(R 10 )(R 11 )、-C(O)C(O)N(R 10 )(R 11 )、-N(R 12 )C(O)R 13 、-S(O)2R 13 、-S(O)2N(R 10 )(R 11 )-、-N=S(=O)(R 13 )2、-S(=O)(=NH)N(R 10 )(R 11 )、-S(=O)(=NH)(R 13 ),-S(=O)(=NR 13 )R 13 、-CH2C(O)N(R 10 )(R 11 )、-CH2N(R 12 )C(O)R 13 、-CH2S(O)2R 13 、-CH2S(O)2N(R 10 )(R 11 )、-Si(C 1-6 alkyl)3 and -P(O)(R 10 )2, where C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl and C 1-9 Heteroaryl is optionally substituted with 1, 2 or 3 groups selected from R 15e ;

[0238] R 9 Selected from hydrogen, C 1-6Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, C 1-9 Heteroaryl, -C(O)OR 10 、-C(O)R 13 、-S(O)R 13 、-C(O)N(R 10 )(R 11 ) and -S(O)2R 13 , where C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl and C 1-9 Heteroaryl is optionally substituted with 1, 2 or 3 groups selected from R 15f ;

[0239] R 9a Selected from hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl and C 1-9 Heteroaryl, wherein C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl and C 1-9 Heteroaryl is optionally substituted with 1, 2 or 3 groups selected from R 15g ;

[0240] R 10 are each independently selected from hydrogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, -CH2-C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, -CH2-C 2-9 Heterocycloalkyl, -CH2-C 6-10 Aryl, C 6-10 Aryl, C 1-9 Heteroaryl and -CH2-C1-9 Heteroaryl, wherein C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, -CH2-C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, -CH2-C 2-9 Heterocycloalkyl, -CH2-C 6-10 Aryl, C 6-10 Aryl, C 1-9 Heteroaryl and -CH2-C 1-9 Heteroaryl is optionally substituted with 1, 2 or 3 groups selected from halogen, -CN, hydroxy, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl and C 1-9 heteroaryl;

[0241] R 11 are each independently selected from hydrogen, C 1-6 Alkyl and C 1-6 haloalkyl; or R 10 and R 11 Together with the attached nitrogen, it forms C 2-9 heterocycloalkyl;

[0242] R 12 are each independently selected from hydrogen, C 1-6 Alkyl and C 1-6 alkyl halide;

[0243] R 13 Each independently selected from C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl and C 1-9 Heteroaryl, wherein C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl and C 1-9 Heteroaryl is optionally substituted with 1, 2 or 3 groups selected from halogen, -CN, hydroxy, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl and C 1-9 heteroaryl; and

[0244] Each R 15a 、R 15b 、R 15c 、R 15d 、R 15e 、R 15f and R 15g Each independently selected from halogen, oxo, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, -CH2-C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, -CH2-C 2-9 Heterocycloalkyl, C 6-10 Aryl, -CH2-C 6-10 Aryl, C 1-9 Heteroaryl, -CH2-C 1-9 Heteroaryl, -OR 10 、-SR 10 、-SF5、-N(R 10 )(R 11 )、-C(O)OR 10 、-OC(O)N(R 10 )(R 11 )、-N(R 12 )C(O)N(R 10 )(R 11 )、-N(R 12 )C(O)OR 13 、-N(R 12 )S(O)2R 13 、-C(O)R 13 、-S(O)R 13 、-OC(O)R 13 、-C(O)N(R 10 )(R 11 )、-C(O)C(O)N(R 10 )(R 11 )、-N(R 12 )C(O)R 13 、-S(O)2R 13 、-S(O)2N(R 10 )(R 11 )-、-N=S(=O)(R 13 )2、-S(=O)(=NH)N(R 10 )(R11 )、-S(=O)(=NH)(R 13 ),-S(=O)(=NR 13 )R 13 、-CH2C(O)N(R 10 )(R 11 )、-CH2N(R 12 )C(O)R 13 、-CH2S(O)2R 13 、-CH2S(O)2N(R 10 )(R 11 )、-Si(C 1-6 alkyl)3 and -P(O)(R 10 )2, where C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, -CH2-C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, -CH2-C 2-9 Heterocycloalkyl, C 6-10 Aryl, -CH2-C 6-10 Aryl, -CH2-C 1-9 Heteroaryl and C 1-9 Heteroaryl is optionally substituted with 1, 2 or 3 groups independently selected from halogen, oxo, -CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -OR 10 、-SR 10 、-SF5、-N(R 10 )(R 11 )、-C(O)OR 10 、-OC(O)N(R 10 )(R 11 )、-N(R 12 )C(O)N(R 10 )(R 11 )、-N(R 12 )C(O)OR 13 、-N(R 12 )S(O)2R 13 、-C(O)R 13 、-S(O)R 13 、-OC(O)R 13 、-C(O)N(R 10 )(R 11 )、-C(O)C(O)N(R 10 )(R11 )、-N(R 12 )C(O)R 13 、-S(O)2R 13 、-S(O)2N(R 10 )(R 11 )-、-N=S(=O)(R 13 )2、-S(=O)(=NH)N(R 10 )(R 11 )、-S(=O)(=NH)(R 13 ),-S(=O)(=NR 13 )R 13 、-CH2C(O)N(R 10 )(R 11 )、-CH2N(R 12 )C(O)R 13 、-CH2S(O)2R 13 、-CH2S(O)2N(R 10 )(R 11 ) and -P(O)(R 10 )2.

[0245] In some embodiments of the compound of Formula (Ie) or a pharmaceutically acceptable salt or stereoisomer thereof, R 9 Selected from hydrogen and C 1-6 Alkyl, which is optionally substituted by 1, 2 or 3 groups selected from R 15f In some embodiments of the compound of formula (Ie) or a pharmaceutically acceptable salt or stereoisomer thereof, R 9 selected from hydrogen and unsubstituted C 1-6 In some embodiments of the compound of Formula (Ie) or a pharmaceutically acceptable salt or stereoisomer thereof, R 9 In some embodiments of the compound of Formula (Ie) or a pharmaceutically acceptable salt or stereoisomer thereof, R 9 C 1-6 Alkyl, which is optionally substituted by 1, 2 or 3 groups selected from R 15f In some embodiments of the compound of formula (Ie) or a pharmaceutically acceptable salt or stereoisomer thereof, R 9 For unsubstituted C 1-6 alkyl.

[0246] In some embodiments of a compound of Formula (I), (Ia), (Ia'), (Ia"), (Ib), (Ib'), (Ib"), (Ic), (Ic'), (Ic"), or (Ie), or a pharmaceutically acceptable salt or stereoisomer thereof, R 5 Selected from hydrogen, halogen, -OR 10and C 1-6 Alkyl, where C 1-6 The alkyl group is optionally substituted with 1, 2 or 3 groups selected from R 15e In some embodiments of the compound of Formula (I), (Ia), (Ia'), (Ia"), (Ib), (Ib'), (Ib"), (Ic), (Ic'), (Ic"), or (Ie), or a pharmaceutically acceptable salt or stereoisomer thereof, R 5 Selected from hydrogen and C 1-6 Alkyl, which is optionally substituted by 1, 2 or 3 groups selected from R 15e In some embodiments of the compound of Formula (I), (Ia), (Ia'), (Ia"), (Ib), (Ib'), (Ib"), (Ic), (Ic'), (Ic"), or (Ie), or a pharmaceutically acceptable salt or stereoisomer thereof, R 5 selected from hydrogen and unsubstituted C 1-6 In some embodiments of the compound of Formula (I), (Ia), (Ia'), (Ia"), (Ib), (Ib'), (Ib"), (Ic), (Ic'), (Ic"), or (Ie), or a pharmaceutically acceptable salt or stereoisomer thereof, R 5 is hydrogen. In some embodiments of the compound of Formula (I), (Ia), (Ia'), (Ia"), (Ib), (Ib'), (Ib"), (Ic), (Ic'), (Ic"), or (Ie), or a pharmaceutically acceptable salt or stereoisomer thereof, R 5 C 1-6 Alkyl, which is optionally substituted by 1, 2 or 3 groups selected from R 15e In some embodiments of the compound of Formula (I), (Ia), (Ia'), (Ia"), (Ib), (Ib'), (Ib"), (Ic), (Ic'), (Ic"), or (Ie), or a pharmaceutically acceptable salt or stereoisomer thereof, R 5 For unsubstituted C 1-6 In some embodiments of the compound of Formula (I), (Ia), (Ia'), (Ia"), (Ib), (Ib'), (Ib"), (Ic), (Ic'), (Ic"), or (Ie), or a pharmaceutically acceptable salt or stereoisomer thereof, R 5 In some embodiments of the compound of Formula (I), (Ia), (Ia'), (Ia"), (Ib), (Ib'), (Ib"), (Ic), (Ic'), (Ic"), or (Ie), or a pharmaceutically acceptable salt or stereoisomer thereof, R 5 For-OR 10In some embodiments of the compound of Formula (I), (Ia), (Ia'), (Ia"), (Ib), (Ib'), (Ib"), (Ic), (Ic'), (Ic"), or (Ie), or a pharmaceutically acceptable salt or stereoisomer thereof, R 5 For-OR 10 , and R 10 Selected from hydrogen and C 1-6 alkyl.

[0247] In some embodiments of the compound of Formula (I), (Ib), (Ib'), (Ib"), (Ic), (Ic'), (Ic"), or (Id), or a pharmaceutically acceptable salt or stereoisomer thereof, R 6 Selected from hydrogen, halogen, -OR 10 and C 1-6 Alkyl, where C 1-6 The alkyl group is optionally substituted with 1, 2 or 3 groups selected from R 15e In some embodiments of the compound of Formula (I), (Ib), (Ib'), (Ib"), (Ic), (Ic'), (Ic"), or (Id), or a pharmaceutically acceptable salt or stereoisomer thereof, R 6 Selected from hydrogen and C 1-6 Alkyl, which is optionally substituted by 1, 2 or 3 groups selected from R 15e In some embodiments of the compound of Formula (I), (Ib), (Ib'), (Ib"), (Ic), (Ic'), (Ic"), or (Id), or a pharmaceutically acceptable salt or stereoisomer thereof, R 6 selected from hydrogen and unsubstituted C 1-6 In some embodiments of the compound of Formula (I), (Ib), (Ib'), (Ib"), (Ic), (Ic'), (Ic"), or (Id), or a pharmaceutically acceptable salt or stereoisomer thereof, R 6 In some embodiments of the compound of Formula (I), (Ib), (Ib'), (Ib"), (Ic), (Ic'), (Ic"), or (Id), or a pharmaceutically acceptable salt or stereoisomer thereof, R 6 C 1-6 Alkyl, which is optionally substituted by 1, 2 or 3 groups selected from R 15e In some embodiments of the compound of Formula (I), (Ib), (Ib'), (Ib"), (Ic), (Ic'), (Ic"), or (Id), or a pharmaceutically acceptable salt or stereoisomer thereof, R 6 For unsubstituted C 1-6In some embodiments of the compound of Formula (I), (Ib), (Ib'), (Ib"), (Ic), (Ic'), (Ic"), or (Id), or a pharmaceutically acceptable salt or stereoisomer thereof, R 6 For unsubstituted C 1-3 In some embodiments of the compound of Formula (I), (Ib), (Ib'), (Ib"), (Ic), (Ic'), (Ic"), or (Id), or a pharmaceutically acceptable salt or stereoisomer thereof, R 6 In some embodiments of the compound of formula (I) or a pharmaceutically acceptable salt or stereoisomer thereof, R 6 In some embodiments of the compound of Formula (I), (Ib), (Ib'), (Ib"), (Ic), (Ic'), (Ic"), or (Id), or a pharmaceutically acceptable salt or stereoisomer thereof, R 6 For-OR 10 In some embodiments of the compound of Formula (I), (Ib), (Ib'), (Ib"), (Ic), (Ic'), (Ic"), or (Id), or a pharmaceutically acceptable salt or stereoisomer thereof, R 6 For-OR 10 , and R 10 Selected from hydrogen and C 1-6 alkyl.

[0248] In some embodiments of a compound of Formula (I), (Ia), (Ia'), (Ia"), (Ic), (Ic'), (Ic"), (Id), or (Ie), or a pharmaceutically acceptable salt or stereoisomer thereof, R 7 Selected from hydrogen, halogen, -OR 10 and C 1-6 Alkyl, where C 1-6 The alkyl group is optionally substituted with 1, 2 or 3 groups selected from R 15e In some embodiments of the compound of Formula (I), (Ia), (Ia'), (Ia"), (Ic), (Ic'), (Ic"), (Id), or (Ie), or a pharmaceutically acceptable salt or stereoisomer thereof, R 7 Selected from hydrogen and C 1-6 Alkyl, which is optionally substituted by 1, 2 or 3 groups selected from R 15e In some embodiments of the compound of Formula (I), (Ia), (Ia'), (Ia"), (Ic), (Ic'), (Ic"), (Id), or (Ie), or a pharmaceutically acceptable salt or stereoisomer thereof, R 7 selected from hydrogen and unsubstituted C 1-6In some embodiments of the compound of Formula (I), (Ia), (Ia'), (Ia"), (Ic), (Ic'), (Ic"), (Id), or (Ie), or a pharmaceutically acceptable salt or stereoisomer thereof, R 7 is hydrogen. In some embodiments of the compound of Formula (I), (Ia), (Ia'), (Ia"), (Ic), (Ic'), (Ic"), (Id), or (Ie), or a pharmaceutically acceptable salt or stereoisomer thereof, R 7 C 1-6 Alkyl, which is optionally substituted by 1, 2 or 3 groups selected from R 15e In some embodiments of the compound of Formula (I), (Ia), (Ia'), (Ia"), (Ic), (Ic'), (Ic"), (Id), or (Ie), or a pharmaceutically acceptable salt or stereoisomer thereof, R 7 For unsubstituted C 1-6 In some embodiments of the compound of Formula (I), (Ia), (Ia'), (Ia"), (Ic), (Ic'), (Ic"), (Id), or (Ie), or a pharmaceutically acceptable salt or stereoisomer thereof, R 7 In some embodiments of the compound of Formula (I), (Ia), (Ia'), (Ia"), (Ic), (Ic'), (Ic"), (Id) or (Ie), or a pharmaceutically acceptable salt or stereoisomer thereof, R 7 For-OR 10 In some embodiments of the compound of Formula (I), (Ia), (Ia'), (Ia"), (Ic), (Ic'), (Ic"), (Id), or (Ie), or a pharmaceutically acceptable salt or stereoisomer thereof, R 7 For-OR 10 , and R 10 Selected from hydrogen and C 1-6 alkyl.

[0249] In some embodiments of the compound of Formula (I), (Ia), (Ia'), (Ia"), (Ib), (Ib'), (Ib"), (Id), or (Ie), or a pharmaceutically acceptable salt or stereoisomer thereof, R 8 Selected from hydrogen, halogen, -OR 10 and C 1-6 Alkyl, where C 1-6 The alkyl group is optionally substituted with 1, 2 or 3 groups selected from R 15e In some embodiments of the compound of Formula (I), (Ia), (Ia'), (Ia"), (Ib), (Ib'), (Ib"), (Id) or (Ie), or a pharmaceutically acceptable salt or stereoisomer thereof, R8 Selected from hydrogen and C 1-6 Alkyl, which is optionally substituted by 1, 2 or 3 groups selected from R 15e In some embodiments of the compound of Formula (I), (Ia), (Ia'), (Ia"), (Ib), (Ib'), (Ib"), (Id), or (Ie), or a pharmaceutically acceptable salt or stereoisomer thereof, R 8 selected from hydrogen and unsubstituted C 1-6 In some embodiments of the compound of Formula (I), (Ia), (Ia'), (Ia"), (Ib), (Ib'), (Ib"), (Id), or (Ie), or a pharmaceutically acceptable salt or stereoisomer thereof, R 8 is hydrogen. In some embodiments of the compound of Formula (I), (Ia), (Ia'), (Ia"), (Ib), (Ib'), (Ib"), (Id), or (Ie), or a pharmaceutically acceptable salt or stereoisomer thereof, R 8 C 1-6 Alkyl, which is optionally substituted by 1, 2 or 3 groups selected from R 15e In some embodiments of the compound of Formula (I), (Ia), (Ia'), (Ia"), (Ib), (Ib'), (Ib"), (Id), or (Ie), or a pharmaceutically acceptable salt or stereoisomer thereof, R 8 For unsubstituted C 1-6 In some embodiments of the compound of Formula (I), (Ia), (Ia'), (Ia"), (Ib), (Ib'), (Ib"), (Id), or (Ie), or a pharmaceutically acceptable salt or stereoisomer thereof, R 8 In some embodiments of the compound of Formula (I), (Ia), (Ia'), (Ia"), (Ib), (Ib'), (Ib"), (Id) or (Ie), or a pharmaceutically acceptable salt or stereoisomer thereof, R 8 For-OR 10 In some embodiments of the compound of Formula (I), (Ia), (Ia'), (Ia"), (Ib), (Ib'), (Ib"), (Id), or (Ie), or a pharmaceutically acceptable salt or stereoisomer thereof, R 8 For-OR 10 , and R 10 Selected from hydrogen and C 1-6 alkyl.

[0250] In some embodiments of the compound of Formula (I), (Ia), (Ib), (Ic), (Id), or (Ie), or a pharmaceutically acceptable salt or stereoisomer thereof, L 2 For valence bond or C 1-6Alkylene, which is optionally substituted by 1, 2 or 3 groups selected from R 15c In some embodiments of the compound of Formula (I), (Ia), (Ib), (Ic), (Id), or (Ie), or a pharmaceutically acceptable salt or stereoisomer thereof, L 2 In some embodiments of the compound of Formula (I), (Ia), (Ib), (Ic), (Id), or (Ie), or a pharmaceutically acceptable salt or stereoisomer thereof, L 2 C 1-6 Alkylene, which is optionally substituted by 1, 2 or 3 groups selected from R 15c In some embodiments of the compound of Formula (I), (Ia), (Ib), (Ic), (Id), or (Ie), or a pharmaceutically acceptable salt or stereoisomer thereof, L 2 For unsubstituted C 1-6 Alkylene.

[0251] In some embodiments of the compound of Formula (I), (Ia), (Ib), (Ic), (Id), or (Ie), or a pharmaceutically acceptable salt or stereoisomer thereof, R 3 Selected from C 6-10 Aryl and C 1-9 Heteroaryl, wherein C 6-10 Aryl and C 1-9 Heteroaryl is optionally substituted with 1, 2 or 3 groups selected from R 15a In some embodiments of the compound of Formula (I), (Ia), (Ib), (Ic), (Id), or (Ie), or a pharmaceutically acceptable salt or stereoisomer thereof, R 3 C 6-10 Aryl, which is optionally substituted by 1, 2 or 3 groups selected from R 15a In some embodiments of the compound of Formula (I), (Ia), (Ib), (Ic), (Id), or (Ie), or a pharmaceutically acceptable salt or stereoisomer thereof, R 3 is phenyl, which is optionally substituted by 1, 2 or 3 groups selected from R 15a In some embodiments of the compound of Formula (I), (Ia), (Ib), (Ic), (Id), or (Ie), or a pharmaceutically acceptable salt or stereoisomer thereof, R 3 is phenyl, which is substituted by 1, 2 or 3 groups selected from R 15a In some embodiments of the compound of Formula (I), (Ia), (Ib), (Ic), (Id), or (Ie), or a pharmaceutically acceptable salt or stereoisomer thereof, R 3 C 1-9Heteroaryl, which is optionally substituted by 1, 2 or 3 groups selected from R 15a In some embodiments of the compound of Formula (I), (Ia), (Ib), (Ic), (Id), or (Ie), or a pharmaceutically acceptable salt or stereoisomer thereof, R 3 C 1-9 Heteroaryl, which is substituted by 1, 2 or 3 groups selected from R 15a .

[0252] In some embodiments of the compound of Formula (I), (Ia), (Ib), (Ic), (Id), or (Ie), or a pharmaceutically acceptable salt or stereoisomer thereof, R 3 R 15a Replace, and R 15a Selected from -OCH3,

[0253] In some embodiments of the compound of Formula (I), (Ia), (Ib), (Ic), (Id), or (Ie), or a pharmaceutically acceptable salt or stereoisomer thereof, R 3 R 15a Replace, and R 15a for In some embodiments of the compound of Formula (I), (Ia), (Ib), (Ic), (Id), or (Ie), or a pharmaceutically acceptable salt or stereoisomer thereof, R 3 R 15a Replace, and R 15a for In some embodiments of the compound of Formula (I), (Ia), (Ib), (Ic), (Id), or (Ie), or a pharmaceutically acceptable salt or stereoisomer thereof, R 3 R 15a Replace, and R 15a for In some embodiments of the compound of Formula (I), (Ia), (Ib), (Ic), (Id), or (Ie), or a pharmaceutically acceptable salt or stereoisomer thereof, R 3 R 15a Replace, and R 15a for In some embodiments of the compound of Formula (I), (Ia), (Ib), (Ic), (Id), or (Ie), or a pharmaceutically acceptable salt or stereoisomer thereof, R 3 R 15a Replace, and R 15a for In some embodiments of the compound of Formula (I), (Ia), (Ib), (Ic), (Id), or (Ie), or a pharmaceutically acceptable salt or stereoisomer thereof, R 3 R 15a Replace, and R 15a for In some embodiments of the compound of Formula (I), (Ia), (Ib), (Ic), (Id), or (Ie), or a pharmaceutically acceptable salt or stereoisomer thereof, R 3 R 15a Replace, and R 15a for In some embodiments of the compound of Formula (I), (Ia), (Ib), (Ic), (Id), or (Ie), or a pharmaceutically acceptable salt or stereoisomer thereof, R 3 R 15a Replace, and R 15a for In some embodiments of the compound of Formula (I), (Ia), (Ib), (Ic), (Id), or (Ie), or a pharmaceutically acceptable salt or stereoisomer thereof, R 3 R 15a Replace, and R 15a for In some embodiments of the compound of Formula (I), (Ia), (Ib), (Ic), (Id), or (Ie), or a pharmaceutically acceptable salt or stereoisomer thereof, R 3 R 15a Replace, and R 15a for In some embodiments of the compound of Formula (I), (Ia), (Ib), (Ic), (Id), or (Ie), or a pharmaceutically acceptable salt or stereoisomer thereof, R 3 R 15a Replace, and R 15a for In some embodiments of the compound of Formula (I), (Ia), (Ib), (Ic), (Id), or (Ie), or a pharmaceutically acceptable salt or stereoisomer thereof, R 3 R 15a Replace, and R 15a In some embodiments of the compound of Formula (I), (Ia), (Ib), (Ic), (Id), or (Ie), or a pharmaceutically acceptable salt or stereoisomer thereof, R 3 By the second R 15a Replace, where the second R 15aIn some embodiments of the compound of Formula (I), (Ia), (Ib), (Ic), (Id), or (Ie), or a pharmaceutically acceptable salt or stereoisomer thereof, R 3 By the second R 15a Replace, where the second R 15a In some embodiments of the compound of Formula (I), (Ia), (Ib), (Ic), (Id), or (Ie), or a pharmaceutically acceptable salt or stereoisomer thereof, R 3 By the second R 15a Replace, where the second R 15a C 1-6 In some embodiments of the compound of Formula (I), (Ia), (Ib), (Ic), (Id), or (Ie), or a pharmaceutically acceptable salt or stereoisomer thereof, R 3 By the second R 15a Replace, where the second R 15a In some embodiments of the compound of Formula (I), (Ia), (Ib), (Ic), (Id), or (Ie), or a pharmaceutically acceptable salt or stereoisomer thereof, R 3 By the second R 15a Replace, where the second R 15a C 1-6 In some embodiments of the compound of Formula (I), (Ia), (Ib), (Ic), (Id), or (Ie), or a pharmaceutically acceptable salt or stereoisomer thereof, R 3 By the second R 15a Replace, where the second R 15a is -CH3.

[0254] In some embodiments of the compound of Formula (I), (Ia), (Ib), (Ic), (Id), or (Ie), or a pharmaceutically acceptable salt or stereoisomer thereof, R 3 for

[0255] In some embodiments of a compound of Formula (I), (Ia), (Ia'), (Ia"), (Ib), (Ib'), (Ib"), (Ic), (Ic'), (Ic"), (Id), or (Ie), or a pharmaceutically acceptable salt or stereoisomer thereof, R 4 Selected from C 6-10 Arylene and C 1-9 Heteroarylene, wherein C 6-10 Arylene and C 1-9 Heteroarylene is optionally substituted with 1, 2 or 3 groups selected from R 15bIn some embodiments of the compound of Formula (I), (Ia), (Ia'), (Ia"), (Ib), (Ib'), (Ib"), (Ic), (Ic'), (Ic"), (Id), or (Ie), or a pharmaceutically acceptable salt or stereoisomer thereof, R 4 Selected from C 2-9 Heterocycloalkylene, C 6-10 Arylene and C 1-9 Heteroarylene, wherein the C 2-9 Heterocycloalkylene, C 6-10 Arylene and C 1-9 Heteroarylene is optionally substituted with 1, 2 or 3 groups selected from R 15b In some embodiments of the compound of Formula (I), (Ia), (Ia'), (Ia"), (Ib), (Ib'), (Ib"), (Ic), (Ic'), (Ic"), (Id), or (Ie), or a pharmaceutically acceptable salt or stereoisomer thereof, R 4 C 6-10 Arylene, which is optionally substituted by 1, 2 or 3 groups selected from R 15b In some embodiments of the compound of Formula (I), (Ia), (Ia'), (Ia"), (Ib), (Ib'), (Ib"), (Ic), (Ic'), (Ic"), (Id), or (Ie), or a pharmaceutically acceptable salt or stereoisomer thereof, R 4 is phenylene, which is optionally substituted by 1, 2 or 3 groups selected from R 15b In some embodiments of the compound of Formula (I), (Ia), (Ia'), (Ia"), (Ib), (Ib'), (Ib"), (Ic), (Ic'), (Ic"), (Id), or (Ie), or a pharmaceutically acceptable salt or stereoisomer thereof, R 4 is phenylene, which is substituted by 1, 2 or 3 groups selected from R 15b In some embodiments of the compound of Formula (I), (Ia), (Ia'), (Ia"), (Ib), (Ib'), (Ib"), (Ic), (Ic'), (Ic"), (Id), or (Ie), or a pharmaceutically acceptable salt or stereoisomer thereof, R 4 is unsubstituted phenylene. In some embodiments of the compound of Formula (I), (Ia), (Ia'), (Ia"), (Ib), (Ib'), (Ib"), (Ic), (Ic'), (Ic"), (Id) or (Ie), or a pharmaceutically acceptable salt or stereoisomer thereof, R 4 for In some embodiments of a compound of Formula (I), (Ia), (Ia'), (Ia"), (Ib), (Ib'), (Ib"), (Ic), (Ic'), (Ic"), (Id), or (Ie), or a pharmaceutically acceptable salt or stereoisomer thereof, R 4 C 6-10 Arylene, comprising C 2-9 Heterocycloalkyl-fused phenyl, wherein C 6-10 Arylene is optionally substituted with 1, 2 or 3 groups selected from R 15b In some embodiments of the compound of Formula (I), (Ia), (Ia'), (Ia"), (Ib), (Ib'), (Ib"), (Ic), (Ic'), (Ic"), (Id), or (Ie), or a pharmaceutically acceptable salt or stereoisomer thereof, R 4 C 6-10 Arylene comprising a phenyl group fused to a 5-6 membered heterocycloalkyl group, wherein C 6-10 Arylene is optionally substituted with 1, 2 or 3 groups selected from R 15b In some embodiments, the fused C 2-9 The heterocycloalkyl group contains 1, 2 or 3 heteroatoms selected from O, S, N or any combination thereof. 2-9 The heterocycloalkylene group contains 1, 2, or 3 nitrogen atoms. 2-9 In some embodiments of the compound of Formula (I), (Ia), (Ia'), (Ia"), (Ib), (Ib'), (Ib"), (Ic), (Ic'), (Ic"), (Id), or (Ie), or a pharmaceutically acceptable salt or stereoisomer thereof, R 4 for In some embodiments of a compound of Formula (I), (Ia), (Ia'), (Ia"), (Ib), (Ib'), (Ib"), (Ic), (Ic'), (Ic"), (Id), or (Ie), or a pharmaceutically acceptable salt or stereoisomer thereof, R 4 C 1-9 Heteroarylene, which is optionally substituted by 1, 2 or 3 groups selected from R 15b In some embodiments of the compound of Formula (I), (Ia), (Ia'), (Ia"), (Ib), (Ib'), (Ib"), (Ic), (Ic'), (Ic"), (Id), or (Ie), or a pharmaceutically acceptable salt or stereoisomer thereof, R 4 C 1-9 Heteroarylene, which is substituted by 1, 2 or 3 groups selected from R 15bIn some embodiments of the compound of Formula (I), (Ia), (Ia'), (Ia"), (Ib), (Ib'), (Ib"), (Ic), (Ic'), (Ic"), (Id), or (Ie), or a pharmaceutically acceptable salt or stereoisomer thereof, R 4 is pyridyl, which is optionally substituted by 1, 2 or 3 groups selected from R 15b In some embodiments of the compound of Formula (I), (Ia), (Ia'), (Ia"), (Ib), (Ib'), (Ib"), (Ic), (Ic'), (Ic"), (Id), or (Ie), or a pharmaceutically acceptable salt or stereoisomer thereof, R 4 is pyridyl, which is substituted by 1, 2 or 3 groups selected from R 15b In some embodiments of the compound of Formula (I), (Ia), (Ia'), (Ia"), (Ib), (Ib'), (Ib"), (Ic), (Ic'), (Ic"), (Id), or (Ie), or a pharmaceutically acceptable salt or stereoisomer thereof, R 4 C 2-9 Heterocycloalkylene, which is optionally substituted by 1, 2 or 3 groups selected from R 15b In some embodiments of the compound of Formula (I), (Ia), (Ia'), (Ia"), (Ib), (Ib'), (Ib"), (Ic), (Ic'), (Ic"), (Id), or (Ie), or a pharmaceutically acceptable salt or stereoisomer thereof, R 4 C 2-9 Heterocycloalkylene, which is substituted by 1, 2 or 3 groups selected from R 15b In some embodiments, C 2-9 The heterocycloalkylene group contains 1, 2, 3, 4, 5, or 6 heteroatoms selected from O, S, N, or any combination thereof. 2-9 The heterocycloalkylene group contains 1, 2, or 3 heteroatoms selected from O, S, N, or any combination thereof. 2-9 The heterocycloalkylene group contains 1, 2, or 3 nitrogen atoms. 2-9 In some embodiments, the heterocycloalkylene group contains 1 nitrogen. 2-9 In some embodiments, C 2-9 Heterocycloalkylene is bicyclic. In some embodiments, C 2-9 Heterocycloalkylene is a spiro ring system. In some embodiments, C 2-9 Heterocycloalkylene is In some embodiments of a compound of Formula (I), (Ia), (Ia'), (Ia"), (Ib), (Ib'), (Ib"), (Ic), (Ic'), (Ic"), (Id), or (Ie), or a pharmaceutically acceptable salt or stereoisomer thereof, R 4 C 3-6 Cycloalkylene, which is optionally substituted by 1, 2 or 3 groups selected from R 15b In some embodiments of the compound of Formula (I), (Ia), (Ia'), (Ia"), (Ib), (Ib'), (Ib"), (Ic), (Ic'), (Ic"), (Id), or (Ie), or a pharmaceutically acceptable salt or stereoisomer thereof, R 4 C 3-6 Cycloalkylene, which is optionally substituted by 1, 2 or 3 groups selected from R 15b In some embodiments, C 3-6 In some embodiments, the cycloalkylene group is saturated. 3-6 In some embodiments, the cycloalkylene group is unsaturated. 3-6 In some embodiments, the cycloalkylene group is partially saturated. 3-6 In some embodiments, the cycloalkylene group contains a double bond. 3-6 Cycloalkylene contains two double bonds. In some embodiments, C 3-6 Cycloalkylene is In some embodiments of a compound of Formula (I), (Ia), (Ia'), (Ia"), (Ib), (Ib'), (Ib"), (Ic), (Ic'), (Ic"), (Id), or (Ie), or a pharmaceutically acceptable salt or stereoisomer thereof, R 4 for

[0256] In some embodiments of a compound of Formula (I), (Ia), (Ia'), (Ia"), (Ib), (Ib'), (Ib"), (Ic), (Ic'), (Ic"), (Id), or (Ie), or a pharmaceutically acceptable salt or stereoisomer thereof, R 4 C 3-6 Cycloalkylene, which is optionally substituted by 1, 2 or 3 groups selected from R 15b .

[0257] In some embodiments of a compound of Formula (I), (Ia), (Ia'), (Ia"), (Ib), (Ib'), (Ib"), (Ic), (Ic'), (Ic"), (Id), or (Ie), or a pharmaceutically acceptable salt or stereoisomer thereof, R 4 C 3-10Cycloalkylene, which is optionally substituted by 1, 2 or 3 groups selected from R 15b In some embodiments, C 3-10 In some embodiments, C 3-10 Cycloalkylene comprises a cycloalkyl group fused to an aryl or heteroaryl group. 3-10 Cycloalkylene comprises a cycloalkyl group fused to an aryl or heteroaryl group, wherein the cycloalkyl group is attached to the carbon marked with an *. and an aryl or heteroaryl group is attached to L 1 .

[0258] In some embodiments of a compound of Formula (I), (Ia), (Ia'), (Ia"), (Ib), (Ib'), (Ib"), (Ic), (Ic'), (Ic"), (Id), or (Ie), or a pharmaceutically acceptable salt or stereoisomer thereof, R 4 C 2-9 Heterocycloalkylene, which is optionally substituted by 1, 2 or 3 groups selected from R 15b In some embodiments, C 2-9 In some embodiments, R 4 for In some embodiments, C 2-9 In some embodiments, R 4 for In some embodiments, C 2-9 Heterocycloalkylene comprises a heterocycloalkyl fused to an aryl or heteroaryl group. 2-9 Heterocycloalkylene comprises a heterocycloalkyl fused to an aryl or heteroaryl group, wherein the heterocycloalkyl group is attached to the carbon marked with * and an aryl or heteroaryl group is attached to L 1 .

[0259] In some embodiments of a compound of Formula (I), (Ia), (Ia'), (Ia"), (Ib), (Ib'), (Ib"), (Ic), (Ic'), (Ic"), (Id), or (Ie), or a pharmaceutically acceptable salt or stereoisomer thereof, R 4 C 6-10 Arylene, which is optionally substituted by 1, 2 or 3 groups selected from R 15b In some embodiments, C 6-10 In some embodiments, R 4 In some embodiments, R 4 for In some embodiments, R 4 for In some embodiments, R 4 for In some embodiments, R 4 for In some embodiments, R 4 for In some embodiments, C 6-10 In some embodiments, C 6-10 Arylene comprises a phenyl group fused to a cycloalkyl or heterocycloalkyl group. 6-10 Arylene comprises a phenyl group fused to a 5-6 membered cycloalkyl or 5-6 membered heterocycloalkyl group. 6-10 Arylene comprises a phenyl group fused to a cycloalkyl or heterocycloalkyl group, wherein the phenyl group is attached to the carbon marked with * and a cycloalkyl group or a heterocycloalkyl group is connected to L 1 In some embodiments, R 4 for

[0260] In some embodiments of a compound of Formula (I), (Ia), (Ia'), (Ia"), (Ib), (Ib'), (Ib"), (Ic), (Ic'), (Ic"), (Id), or (Ie), or a pharmaceutically acceptable salt or stereoisomer thereof, R 4 C 1-9 Heteroarylene, which is optionally substituted by 1, 2 or 3 groups selected from R 15b In some embodiments, C 1-9 In some embodiments, R 4 for In some embodiments, R 4 for In some embodiments, R 4 for In some embodiments, C 1-9 In some embodiments, C 1-9 Heteroarylene groups include heteroaryl groups fused to cycloalkyl or heterocycloalkyl groups. 1-9 Heteroarylene comprises a heteroaryl group fused to a 5-6 membered cycloalkyl or a 5-6 membered heterocycloalkyl. 1-9 Heteroarylene groups include heteroaryl groups fused to cycloalkyl or heterocycloalkyl groups, wherein the heteroaryl group is attached to the carbon atom marked with an *. and a cycloalkyl group or a heterocycloalkyl group is connected to L 1 In some embodiments, R 4 for In some embodiments of a compound of Formula (I), (Ia), (Ia'), (Ia"), (Ib), (Ib'), (Ib"), (Ic), (Ic'), (Ic"), (Id), or (Ie), or a pharmaceutically acceptable salt or stereoisomer thereof, L 1 For valence bond, -N(R 9a )-、-N(R 9a )C(O)-、-C(O)N(R 9a )-、-N(R 9a )S(O)2-、-S(O)2N(R 9a )-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)-, -S(O)2- or C 1-6 Alkylene, which is optionally substituted by 1, 2 or 3 groups selected from R 15c In some embodiments of a compound of Formula (I), (Ia), (Ia'), (Ia"), (Ib), (Ib'), (Ib"), (Ic), (Ic'), (Ic"), (Id), or (Ie), or a pharmaceutically acceptable salt or stereoisomer thereof, L 1 For valence bond, -N(R 9a )-、-N(R 9a )C(O)-、-C(O)N(R 9a In some embodiments of the compound of Formula (I), (Ia), (Ia'), (Ia"), (Ib), (Ib'), (Ib"), (Ic), (Ic'), (Ic"), (Id), or (Ie), or a pharmaceutically acceptable salt or stereoisomer thereof, L 1 -N(R 9a In some embodiments of a compound of Formula (I), (Ia), (Ia'), (Ia"), (Ib), (Ib'), (Ib"), (Ic), (Ic'), (Ic"), (Id), or (Ie), or a pharmaceutically acceptable salt or stereoisomer thereof, L 1 In some embodiments of the compound of Formula (I), (Ia), (Ia'), (Ia"), (Ib), (Ib'), (Ib"), (Ic), (Ic'), (Ic"), (Id), or (Ie), or a pharmaceutically acceptable salt or stereoisomer thereof, L 1 -N(R 9a )C(O)-. In some embodiments of a compound of Formula (I), (Ia), (Ia'), (Ia"), (Ib), (Ib'), (Ib"), (Ic), (Ic'), (Ic"), (Id), or (Ie), or a pharmaceutically acceptable salt or stereoisomer thereof, L1 In some embodiments of the compound of Formula (I), (Ia), (Ia'), (Ia"), (Ib), (Ib'), (Ib"), (Ic), (Ic'), (Ic"), (Id), or (Ie), or a pharmaceutically acceptable salt or stereoisomer thereof, L 1 -C(O)N(R 9a In some embodiments of a compound of Formula (I), (Ia), (Ia'), (Ia"), (Ib), (Ib'), (Ib"), (Ic), (Ic'), (Ic"), (Id), or (Ie), or a pharmaceutically acceptable salt or stereoisomer thereof, L 1 In some embodiments of the compound of Formula (I), (Ia), (Ia'), (Ia"), (Ib), (Ib'), (Ib"), (Ic), (Ic'), (Ic"), (Id), or (Ie), or a pharmaceutically acceptable salt or stereoisomer thereof, L 1 In some embodiments of the compound of Formula (I), (Ia), (Ia'), (Ia"), (Ib), (Ib'), (Ib"), (Ic), (Ic'), (Ic"), (Id), or (Ie), or a pharmaceutically acceptable salt or stereoisomer thereof, L 1 is a valence bond. In some embodiments of the compound of Formula (I), (Ia), (Ia'), (Ia"), (Ib), (Ib'), (Ib"), (Ic), (Ic'), (Ic"), (Id), or (Ie), or a pharmaceutically acceptable salt or stereoisomer thereof, L 1 C 2-9 Heterocycloalkylene, which is optionally substituted by 1, 2 or 3 groups selected from R 15c In some embodiments of a compound of Formula (I), (Ia), (Ia'), (Ia"), (Ib), (Ib'), (Ib"), (Ic), (Ic'), (Ic"), (Id), or (Ie), or a pharmaceutically acceptable salt or stereoisomer thereof, L 1 is a 4-6 membered heterocycloalkylene group, which is optionally substituted by 1, 2 or 3 groups selected from R 15c In some embodiments of a compound of Formula (I), (Ia), (Ia'), (Ia"), (Ib), (Ib'), (Ib"), (Ic), (Ic'), (Ic"), (Id), or (Ie), or a pharmaceutically acceptable salt or stereoisomer thereof, L 1 for

[0261] In some embodiments of a compound of Formula (I), (Ia), (Ia'), (Ia"), (Ib), (Ib'), (Ib"), (Ic), (Ic'), (Ic"), (Id), or (Ie), or a pharmaceutically acceptable salt or stereoisomer thereof, R 4a Selected from In some embodiments of the compound of Formula (I), (Ia), (Ia'), (Ia"), (Ib), (Ib'), (Ib"), (Ic), (Ic'), (Ic"), (Id), or (Ie), or a pharmaceutically acceptable salt or stereoisomer thereof, R 4a for In some embodiments, disclosed herein are compounds of Formula (I), (Ia), (Ia'), (Ia"), (Ib), (Ib'), (Ib"), (Ic), (Ic'), (Ic"), (Id), or (Ie), or pharmaceutically acceptable salts or stereoisomers thereof, wherein R 4a for In some embodiments, disclosed herein are compounds of Formula (I), (Ia), (Ia'), (Ia"), (Ib), (Ib'), (Ib"), (Ic), (Ic'), (Ic"), (Id), or (Ie), or pharmaceutically acceptable salts or stereoisomers thereof, wherein R 4a for In some embodiments, disclosed herein are compounds of Formula (I), (Ia), (Ia'), (Ia"), (Ib), (Ib'), (Ib"), (Ic), (Ic'), (Ic"), (Id), or (Ie), or pharmaceutically acceptable salts or stereoisomers thereof, wherein R 4a for In some embodiments, disclosed herein are compounds of Formula (I), (Ia), (Ia'), (Ia"), (Ib), (Ib'), (Ib"), (Ic), (Ic'), (Ic"), (Id), or (Ie), or pharmaceutically acceptable salts or stereoisomers thereof, wherein R 4a for In some embodiments, disclosed herein are compounds of Formula (I), (Ia), (Ia'), (Ia"), (Ib), (Ib'), (Ib"), (Ic), (Ic'), (Ic"), (Id), or (Ie), or pharmaceutically acceptable salts or stereoisomers thereof, wherein R 4a for In some embodiments, disclosed herein are compounds of Formula (I), (Ia), (Ia'), (Ia"), (Ib), (Ib'), (Ib"), (Ic), (Ic'), (Ic"), (Id), or (Ie), or pharmaceutically acceptable salts or stereoisomers thereof, wherein R 4a for In some embodiments, disclosed herein are compounds of Formula (I), (Ia), (Ia'), (Ia"), (Ib), (Ib'), (Ib"), (Ic), (Ic'), (Ic"), (Id), or (Ie), or pharmaceutically acceptable salts or stereoisomers thereof, wherein R 4a for In some embodiments, disclosed herein are compounds of Formula (I), (Ia), (Ia'), (Ia"), (Ib), (Ib'), (Ib"), (Ic), (Ic'), (Ic"), (Id), or (Ie), or pharmaceutically acceptable salts or stereoisomers thereof, wherein R 4a for In some embodiments of a compound of Formula (I), (Ia), (Ia'), (Ia"), (Ib), (Ib'), (Ib"), (Ic), (Ic'), (Ic"), (Id), or (Ie), or a pharmaceutically acceptable salt or stereoisomer thereof, R 4a for In some embodiments, disclosed herein are compounds of Formula (I), (Ia), (Ia'), (Ia"), (Ib), (Ib'), (Ib"), (Ic), (Ic'), (Ic"), (Id), or (Ie), or pharmaceutically acceptable salts or stereoisomers thereof, wherein R 4a for In some embodiments of a compound of Formula (I), (Ia), (Ia'), (Ia"), (Ib), (Ib'), (Ib"), (Ic), (Ic'), (Ic"), (Id), or (Ie), or a pharmaceutically acceptable salt or stereoisomer thereof, R 4a for In some embodiments of a compound of Formula (I), (Ia), (Ia'), (Ia"), (Ib), (Ib'), (Ib"), (Ic), (Ic'), (Ic"), (Id), or (Ie), or a pharmaceutically acceptable salt or stereoisomer thereof, R 4a for In some embodiments, disclosed herein are compounds of Formula (I), (Ia), (Ia'), (Ia"), (Ib), (Ib'), (Ib"), (Ic), (Ic'), (Ic"), (Id), or (Ie), or pharmaceutically acceptable salts or stereoisomers thereof, wherein R 4a for In some embodiments, disclosed herein are compounds of Formula (I), (Ia), (Ia'), (Ia"), (Ib), (Ib'), (Ib"), (Ic), (Ic'), (Ic"), (Id), or (Ie), or pharmaceutically acceptable salts or stereoisomers thereof, wherein R 4a for In some embodiments, disclosed herein are compounds of Formula (I), (Ia), (Ia'), (Ia"), (Ib), (Ib'), (Ib"), (Ic), (Ic'), (Ic"), (Id), or (Ie), or pharmaceutically acceptable salts or stereoisomers thereof, wherein R 4a for

[0262] In some embodiments of a compound of Formula (I), (Ia), (Ia'), (Ia"), (Ib), (Ib'), (Ib"), (Ic), (Ic'), (Ic"), (Id), or (Ie), or a pharmaceutically acceptable salt or stereoisomer thereof, R 4b 、R 4c and R 4d are each independently selected from hydrogen, halogen, -CN, -C(O)R 13 、-C(O)OR 10 、-C(O)N(R 10 )(R 11 )、-N(R 10 )(R 11 ),-C 1-6 Alkyl-N(R 10 )(R 11 )、-C(O)N(R 10 )OR 10 、C 1-6 In some embodiments of the compound of Formula (I), (Ia), (Ia'), (Ia"), (Ib), (Ib'), (Ib"), (Ic), (Ic'), (Ic"), (Id), or (Ie), or a pharmaceutically acceptable salt or stereoisomer thereof, R 4b 、R 4c and R 4d are each independently selected from hydrogen, C 1-6 Alkyl or -C 1-6 Alkyl-N(R 10 )(R 11In some embodiments of a compound of Formula (I), (Ia), (Ia'), (Ia"), (Ib), (Ib'), (Ib"), (Ic), (Ic'), (Ic"), (Id), or (Ie), or a pharmaceutically acceptable salt or stereoisomer thereof, R 4b 、R 4c and R 4d are each independently selected from hydrogen, halogen, C 1-6 Alkyl or -C 1-6 Alkyl-N(R 10 )(R 11 ), wherein the alkyl group is optionally substituted with 1, 2 or 3 R 15d In some embodiments of the compounds of Formula (I), (Ia), (Ia'), (Ia"), (Ib), (Ib'), (Ib"), (Ic), (Ic'), (Ic"), (Id), or (Ie), or pharmaceutically acceptable salts or stereoisomers thereof, R 4b is hydrogen. In some embodiments of the compound of Formula (I), (Ia), (Ia'), (Ia"), (Ib), (Ib'), (Ib"), (Ic), (Ic'), (Ic"), (Id), or (Ie), or a pharmaceutically acceptable salt or stereoisomer thereof, R 4b is hydrogen, halogen or C 1-6 Alkyl, wherein the alkyl group is optionally substituted by 1, 2 or 3 R 15d In some embodiments of the compounds of Formula (I), (Ia), (Ia'), (Ia"), (Ib), (Ib'), (Ib"), (Ic), (Ic'), (Ic"), (Id), or (Ie), or pharmaceutically acceptable salts or stereoisomers thereof, R 4b is hydrogen. In some embodiments of the compound of Formula (I), (Ia), (Ia'), (Ia"), (Ib), (Ib'), (Ib"), (Ic), (Ic'), (Ic"), (Id), or (Ie), or a pharmaceutically acceptable salt or stereoisomer thereof, R 4b In some embodiments of the compound of Formula (I), (Ia), (Ia'), (Ia"), (Ib), (Ib'), (Ib"), (Ic), (Ic'), (Ic"), (Id), or (Ie), or a pharmaceutically acceptable salt or stereoisomer thereof, R 4b is F. In some embodiments of a compound of Formula (I), (Ia), (Ia'), (Ia"), (Ib), (Ib'), (Ib"), (Ic), (Ic'), (Ic"), (Id), or (Ie), or a pharmaceutically acceptable salt or stereoisomer thereof, R 4b C 1-6In some embodiments of the compound of Formula (I), (Ia), (Ia'), (Ia"), (Ib), (Ib'), (Ib"), (Ic), (Ic'), (Ic"), (Id), or (Ie), or a pharmaceutically acceptable salt or stereoisomer thereof, R 4b C 1-6 Alkyl, which is optionally substituted by 1, 2 or 3 R 15d In some embodiments of the compounds of Formula (I), (Ia), (Ia'), (Ia"), (Ib), (Ib'), (Ib"), (Ic), (Ic'), (Ic"), (Id), or (Ie), or pharmaceutically acceptable salts or stereoisomers thereof, R 4b C 1-3 In some embodiments of the compound of Formula (I), (Ia), (Ia'), (Ia"), (Ib), (Ib'), (Ib"), (Ic), (Ic'), (Ic"), (Id), or (Ie), or a pharmaceutically acceptable salt or stereoisomer thereof, R 4b In some embodiments of the compound of Formula (I), (Ia), (Ia'), (Ia"), (Ib), (Ib'), (Ib"), (Ic), (Ic'), (Ic"), (Id), or (Ie), or a pharmaceutically acceptable salt or stereoisomer thereof, R 4b C 1-6 Alkyl, which is replaced by 1, 2 or 3 R 15d In some embodiments of the compounds of Formula (I), (Ia), (Ia'), (Ia"), (Ib), (Ib'), (Ib"), (Ic), (Ic'), (Ic"), (Id), or (Ie), or pharmaceutically acceptable salts or stereoisomers thereof, R 4b C 1-6 Alkyl-OR 10 In some embodiments of the compound of Formula (I), (Ia), (Ia'), (Ia"), (Ib), (Ib'), (Ib"), (Ic), (Ic'), (Ic"), (Id), or (Ie), or a pharmaceutically acceptable salt or stereoisomer thereof, R 4b C 1-3 Alkyl-OR 10 In some embodiments of the compound of Formula (I), (Ia), (Ia'), (Ia"), (Ib), (Ib'), (Ib"), (Ic), (Ic'), (Ic"), (Id), or (Ie), or a pharmaceutically acceptable salt or stereoisomer thereof, R 4bis -CH2OH or CHOCH3. In some embodiments of the compound of Formula (I), (Ia), (Ia'), (Ia"), (Ib), (Ib'), (Ib"), (Ic), (Ic'), (Ic"), (Id) or (Ie), or a pharmaceutically acceptable salt or stereoisomer thereof, R 4c is hydrogen. In some embodiments of the compound of Formula (I), (Ia), (Ia'), (Ia"), (Ib), (Ib'), (Ib"), (Ic), (Ic'), (Ic"), (Id), or (Ie), or a pharmaceutically acceptable salt or stereoisomer thereof, R 4c C 1-6 In some embodiments of the compound of Formula (I), (Ia), (Ia'), (Ia"), (Ib), (Ib'), (Ib"), (Ic), (Ic'), (Ic"), (Id), or (Ie), or a pharmaceutically acceptable salt or stereoisomer thereof, R 4c -C 1-6 Alkyl-N(R 10 )(R 11 In some embodiments of a compound of Formula (I), (Ia), (Ia'), (Ia"), (Ib), (Ib'), (Ib"), (Ic), (Ic'), (Ic"), (Id), or (Ie), or a pharmaceutically acceptable salt or stereoisomer thereof, R 4c is -CH2-N(CH3)2. In some embodiments of the compound of Formula (I), (Ia), (Ia'), (Ia"), (Ib), (Ib'), (Ib"), (Ic), (Ic'), (Ic"), (Id) or (Ie), or a pharmaceutically acceptable salt or stereoisomer thereof, R 4d is hydrogen. In some embodiments of the compound of Formula (I), (Ia), (Ia'), (Ia"), (Ib), (Ib'), (Ib"), (Ic), (Ic'), (Ic"), (Id), or (Ie), or a pharmaceutically acceptable salt or stereoisomer thereof, R 4d C 1-6 In some embodiments of the compound of Formula (I), (Ia), (Ia'), (Ia"), (Ib), (Ib'), (Ib"), (Ic), (Ic'), (Ic"), (Id), or (Ie), or a pharmaceutically acceptable salt or stereoisomer thereof, R 4d -C 1-6 Alkyl-N(R 10 )(R 11In some embodiments of a compound of Formula (I), (Ia), (Ia'), (Ia"), (Ib), (Ib'), (Ib"), (Ic), (Ic'), (Ic"), (Id), or (Ie), or a pharmaceutically acceptable salt or stereoisomer thereof, R 4d is -CH2-N(CH3)2. In some embodiments of the compound of Formula (I), (Ia), (Ia'), (Ia"), (Ib), (Ib'), (Ib"), (Ic), (Ic'), (Ic"), (Id) or (Ie), or a pharmaceutically acceptable salt or stereoisomer thereof, R 4c and R 4d are each independently selected from hydrogen or -C 1-6 Alkyl-N(R 10 )(R 11 In some embodiments of a compound of Formula (I), (Ia), (Ia'), (Ia"), (Ib), (Ib'), (Ib"), (Ic), (Ic'), (Ic"), (Id), or (Ie), or a pharmaceutically acceptable salt or stereoisomer thereof, R 4c and R 4d are each independently selected from hydrogen or -CH2-N(CH3)2. In some embodiments of the compound of Formula (I), (Ia), (Ia'), (Ia"), (Ib), (Ib'), (Ib"), (Ic), (Ic'), (Ic"), (Id) or (Ie), or a pharmaceutically acceptable salt or stereoisomer thereof, R 4c and R 4d are each independently hydrogen. In some embodiments of a compound of Formula (I), (Ia), (Ia'), (Ia"), (Ib), (Ib'), (Ib"), (Ic), (Ic'), (Ic"), (Id), or (Ie), or a pharmaceutically acceptable salt or stereoisomer thereof, R 4c is -CH2-N(CH3)2 and R 4d In some embodiments, R 4b 、R 4c and / or R 4d is hydrogen containing a percentage of deuterium above its natural abundance. In some embodiments, R 4b 、R 4c and / or R 4d is hydrogen in which one or more protiums are replaced by one or more deuteriums.

[0263] In some embodiments of a compound of Formula (I), (Ia), (Ia'), (Ia"), (Ib), (Ib'), (Ib"), (Ic), (Ic'), (Ic"), (Id), or (Ie), or a pharmaceutically acceptable salt or stereoisomer thereof, for In some embodiments of a compound of Formula (I), (Ia), (Ia'), (Ia"), (Ib), (Ib'), (Ib"), (Ic), (Ic'), (Ic"), (Id), or (Ie), or a pharmaceutically acceptable salt or stereoisomer thereof, for In some embodiments of a compound of Formula (I), (Ia), (Ia'), (Ia"), (Ib), (Ib'), (Ib"), (Ic), (Ic'), (Ic"), (Id), or (Ie), or a pharmaceutically acceptable salt or stereoisomer thereof, for In some embodiments of a compound of Formula (I), (Ia), (Ia'), (Ia"), (Ib), (Ib'), (Ib"), (Ic), (Ic'), (Ic"), (Id), or (Ie), or a pharmaceutically acceptable salt or stereoisomer thereof, for

[0264] In some embodiments of a compound of Formula (I), (Ia), (Ia'), (Ia"), (Ib), (Ib'), (Ib"), (Ic), (Ic'), (Ic"), (Id), or (Ie), or a pharmaceutically acceptable salt or stereoisomer thereof, R 1 and R 2 independently selected from hydrogen and C 1-6 In some embodiments of the compound of Formula (I), (Ia), (Ia'), (Ia"), (Ib), (Ib'), (Ib"), (Ic), (Ic'), (Ic"), (Id), or (Ie), or a pharmaceutically acceptable salt or stereoisomer thereof, R 1 and R 2 In some embodiments of the compound of formula (I) or a pharmaceutically acceptable salt or stereoisomer thereof, R 1 is hydrogen, R 2 C 1-6 alkyl.

[0265] In some embodiments, disclosed herein are compounds of Formula (I), (Ia), (Ia'), (Ia"), (Ib), (Ib'), (Ib"), (Ic), (Ic'), (Ic"), (Id), or (Ie), or pharmaceutically acceptable salts or stereoisomers thereof, wherein R 10Optionally substituted with one or more substituents selected from halogen, -CN, -OH, -SF5, -SH, -S(=O)C1-C3 alkyl, -S(=O)2C1-C3 alkyl, -S(=O)2NH2, -S(=O)2NHC1-C3 alkyl, -S(=O)2N(C1-C3 alkyl)2, -S(=O)(=NC1-C3 alkyl)(C1-C3 alkyl), -NH2, -NHC1-C3 alkyl, -N(C1-C3 alkyl)2, -N=S(=O)(C1-C3 alkyl)2, -O-C1-C4 alkylene- -OH, -O-C1-C4 alkylene-NH2, -C(=O)C1-C3 alkyl, -C(=O)OH, -C(=O)OC1-C3 alkyl, -C(=O)NH2, -C(=O)NHC1-C3 alkyl, -C(=O)N(C1-C3 alkyl)2, -P(=O)(C1-C3 alkyl)2, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, C1-C3 hydroxyalkyl, C1-C3 aminoalkyl, C1-C3 heteroalkyl, C3-C6 cycloalkyl and 3- to 6-membered heterocycloalkyl. In some embodiments, disclosed herein are compounds of Formula (I), (Ia), (Ia'), (Ia"), (Ib), (Ib'), (Ib"), (Ic), (Ic'), (Ic"), (Id), or (Ie), or pharmaceutically acceptable salts or stereoisomers thereof, wherein R 10 Optionally substituted with one or more substituents selected from halogen, -CN, -OH, -SF5, -SH, -S(=O)2NH2, -S(=O)2NHC1-C3 alkyl, -S(=O)2N(C1-C3 alkyl)2, -S(=O)(=NC1-C3 alkyl)(C1-C3 alkyl), -NH2, -NHC1-C3 alkyl, -N(C1-C3 alkyl)2, -O-C1-C4 alkylene-OH, -O-C 1-C4 alkylene-NH2, -C(=O)C1-C3 alkyl, -C(=O)OH, -C(=O)OC1-C3 alkyl, -C(=O)NH2, -C(=O)NHC1-C3 alkyl, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, C1-C3 hydroxyalkyl, C1-C3 aminoalkyl, C1-C3 heteroalkyl, C3-C6 cycloalkyl and 3- to 6-membered heterocycloalkyl.

[0266] In some embodiments of a compound of Formula (I), (Ia), (Ia'), (Ia"), (Ib), (Ib'), (Ib"), (Ic), (Ic'), (Ic"), (Id), or (Ie), or a pharmaceutically acceptable salt or stereoisomer thereof, R 11 are each independently selected from hydrogen, C1-6 Alkyl and C 1-6 Halogenated alkyl.

[0267] In some embodiments of a compound of Formula (I), (Ia), (Ia'), (Ia"), (Ib), (Ib'), (Ib"), (Ic), (Ic'), (Ic"), (Id), or (Ie), or a pharmaceutically acceptable salt or stereoisomer thereof, R 10 and R 11 Together with the attached nitrogen, it forms C 2-9 In some embodiments of the compound of Formula (I), (Ia), (Ia'), (Ia"), (Ib), (Ib'), (Ib"), (Ic), (Ic'), (Ic"), (Id), or (Ie), or a pharmaceutically acceptable salt or stereoisomer thereof, R 10 and R 11 Together with the attached nitrogen,

[0268] In some embodiments of a compound of Formula (I), (Ia), (Ia'), (Ia"), (Ib), (Ib'), (Ib"), (Ic), (Ic'), (Ic"), (Id), or (Ie), or a pharmaceutically acceptable salt or stereoisomer thereof, R 13 Each independently selected from C 1-6 Alkyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, wherein C 1-6 Alkyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl is optionally substituted by 1, 2 or 3 groups selected from halogen, C 1-6 Alkyl, C 1-6 In some embodiments of the compound of Formula (I), (Ia), (Ia'), (Ia"), (Ib), (Ib'), (Ib"), (Ic), (Ic'), (Ic"), (Id), or (Ie), or a pharmaceutically acceptable salt or stereoisomer thereof, R 13 Each for

[0269] In some embodiments of compound formula (I), (Ia), (Ia'), (Ia"), (Ib), (Ib'), (Ib"), (Ic), (Ic'), (Ic"), (Id), or (Ie), or a pharmaceutically acceptable salt or stereoisomer thereof, R 15b Each independently selected from halogen, oxo, -CN, C 1-6 Alkyl, C 3-10 Cycloalkyl, -CH2-C 3-6 Cycloalkyl, C2-9 Heterocycloalkyl, -CH2-C 2-9 Heterocycloalkyl, -OR 10 、-SR 10 、-SF5、-N(R 10 )(R 11 )、-C(O)OR 10 , where C 1-6 Alkyl, C 3-10 Cycloalkyl, -CH2-C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl and -CH2-C 2-9 Heterocycloalkyl is optionally substituted with 1, 2 or 3 groups independently selected from halogen, oxo, -CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 In some embodiments of the compound of Formula (I), (Ia), (Ia'), (Ia"), (Ib), (Ib'), (Ib"), (Ic), (Ic'), (Ic"), (Id), or (Ie), or a pharmaceutically acceptable salt or stereoisomer thereof, R 15b are each independently selected from halogen, C 1-6 Alkyl, -OR 10 , where C 1-6 The alkyl group is optionally substituted with 1, 2 or 3 groups independently selected from halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 In some embodiments of the compound of Formula (I), (Ia), (Ia'), (Ia"), (Ib), (Ib'), (Ib"), (Ic), (Ic'), (Ic"), (Id), or (Ie), or a pharmaceutically acceptable salt or stereoisomer thereof, R 15b In some embodiments of the compound of Formula (I), (Ia), (Ia'), (Ia"), (Ib), (Ib'), (Ib"), (Ic), (Ic'), (Ic"), (Id), or (Ie), or a pharmaceutically acceptable salt or stereoisomer thereof, R 15b Each is C 1-6 Alkyl, where C 1-6 The alkyl group is optionally substituted with 1, 2 or 3 groups independently selected from halogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6In some embodiments of the compound of Formula (I), (Ia), (Ia'), (Ia"), (Ib), (Ib'), (Ib"), (Ic), (Ic'), (Ic"), (Id), or (Ie), or a pharmaceutically acceptable salt or stereoisomer thereof, R 15b In some embodiments of the compound of Formula (I), (Ia), (Ia'), (Ia"), (Ib), (Ib'), (Ib"), (Ic), (Ic'), (Ic"), (Id), or (Ie), or a pharmaceutically acceptable salt or stereoisomer thereof, R 15b Each is C 1-6 Alkyl, where C 1-6 The alkyl group is optionally substituted with 1, 2, or 3 groups independently selected from -OH. In some embodiments of the compound of Formula (I), (Ia), (Ia'), (Ia"), (Ib), (Ib'), (Ib"), (Ic), (Ic'), (Ic"), (Id), or (Ie), or a pharmaceutically acceptable salt or stereoisomer thereof, R 15b Each is -OR 10 .

[0270] In some embodiments of a compound of Formula (I), (Ia), (Ia'), (Ia"), (Ib), (Ib'), (Ib"), (Ic), (Ic'), (Ic"), (Id), or (Ie), or a pharmaceutically acceptable salt or stereoisomer thereof, R 15c Each independently selected from halogen, oxo, -CN, C 1-6 Alkyl, C 3-10 Cycloalkyl, -CH2-C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, -CH2-C 2-9 Heterocycloalkyl, -OR 10 、-SR 10 、-SF5、-N(R 10 )(R 11 )、-C(O)OR 10 , where C 1-6 Alkyl, C 3-10 Cycloalkyl, -CH2-C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl and -CH2-C 2-9 Heterocycloalkyl is optionally substituted with 1, 2 or 3 groups independently selected from halogen, oxo, -CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6In some embodiments of the compound of Formula (I), (Ia), (Ia'), (Ia"), (Ib), (Ib'), (Ib"), (Ic), (Ic'), (Ic"), (Id), or (Ie), or a pharmaceutically acceptable salt or stereoisomer thereof, R 15c Each independently selected from halogen, oxo, -OH, -CN, C 1-6 Alkyl, C 1-6 Alkoxy and amino groups, where C 1-6 The alkyl group is optionally substituted with 1, 2, or 3 groups independently selected from halogen, oxo, -CN, -OH, -SH, and amino. In some embodiments of the compound of Formula (I), (Ia), (Ia'), (Ia"), (Ib), (Ib'), (Ib"), (Ic), (Ic'), (Ic"), (Id), or (Ie), or a pharmaceutically acceptable salt or stereoisomer thereof, R 15c Each independently selected from halogen, -OH, C 1-6 Alkoxy and C 1-6 Alkyl, where C 1-6 The alkyl group is optionally substituted with 1, 2 or 3 halogens.

[0271] In some embodiments of a compound of Formula (I), (Ia), (Ia'), (Ia"), (Ib), (Ib'), (Ib"), (Ic), (Ic'), (Ic"), (Id), or (Ie), or a pharmaceutically acceptable salt or stereoisomer thereof, R 15d Each independently selected from halogen, oxo, -CN, C 1-6 Alkyl, C 3-10 Cycloalkyl, -CH2-C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, -CH2-C 2-9 Heterocycloalkyl, -OR 10 、-SR 10 、-SF5、-N(R 10 )(R 11 )、-C(O)OR 10 , where C 1-6 Alkyl, C 3-10 Cycloalkyl, -CH2-C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl and -CH2-C 2-9 Heterocycloalkyl is optionally substituted with 1, 2 or 3 groups independently selected from halogen, oxo, -CN, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6In some embodiments of the compound of Formula ((I), (Ia), (Ia'), (Ia"), (Ib), (Ib'), (Ib"), (Ic), (Ic'), (Ic"), (Id) or (Ie), or a pharmaceutically acceptable salt or stereoisomer thereof, R 15d Each independently selected from halogen, oxo, -OH, -CN, C 1-6 Alkyl, C 1-6 Alkoxy and amino groups, where C 1-6 The alkyl group is optionally substituted with 1, 2, or 3 groups independently selected from halogen, oxo, -CN, -OH, -SH, and amino. In some embodiments of the compound of Formula (I), (Ia), (Ia'), (Ia"), (Ib), (Ib'), (Ib"), (Ic), (Ic'), (Ic"), (Id), or (Ie), or a pharmaceutically acceptable salt or stereoisomer thereof, R 15d are each independently selected from halogen, -OH and C 1-6 Alkyl, where C 1-6 The alkyl group is optionally substituted with 1, 2 or 3 halogens.

[0272] In some embodiments of the compound of Formula (I) or a pharmaceutically acceptable salt or stereoisomer thereof, R 15e are each independently selected from hydrogen, C 1-6 Alkyl and C 1-6 Halogenated alkyl.

[0273] In some embodiments of the compound of Formula (I) or a pharmaceutically acceptable salt or stereoisomer thereof, R 15f are each independently selected from hydrogen, C 1-6 Alkyl and C 1-6 Halogenated alkyl.

[0274] In some embodiments of a compound of Formula (I), (Ia), (Ia'), (Ia"), (Ib), (Ib'), (Ib"), (Ic), (Ic'), (Ic"), (Id), or (Ie), or a pharmaceutically acceptable salt or stereoisomer thereof, R 15g are each independently selected from hydrogen, C 1-6 Alkyl and C 1-6 Halogenated alkyl.

[0275] Any combination of the above groups for the various variables is contemplated herein. Throughout the specification, groups and substituents thereof are selected by one skilled in the art to provide stable moieties and compounds.

[0276] In some embodiments, disclosed herein is a compound or a pharmaceutically acceptable salt or stereoisomer thereof selected from:

[0277]

[0278]

[0279]

[0280]

[0281]

[0282] In some embodiments, disclosed herein is a compound or a pharmaceutically acceptable salt or stereoisomer thereof selected from:

[0283]

[0284]

[0285] Other forms of the compounds disclosed herein

[0286] Isomers / stereoisomers

[0287] In some embodiments, the compounds described herein exist as geometric isomers. In some embodiments, the compounds described herein have one or more double bonds. The compounds provided herein include all cis (cis), trans (trans), cis (syn), trans (anti), trans (entgegen) (E) and cis (zusammen) (Z) isomers and their corresponding mixtures. In some cases, the compounds described herein have one or more chiral centers and each center exists in the R configuration or S configuration. The compounds described herein include all diastereoisomers, enantiomers and epimers and their corresponding mixtures. In other embodiments of the compounds and methods provided herein, the enantiomers and / or diastereoisomer mixtures obtained by a single preparation step, combination or interconversion can be used for the applications described herein. In some embodiments, the compounds described herein are prepared into their single stereoisomers by reacting the racemic mixture of the compound with an optically active resolving agent to form their diastereoisomer compound pairs, separating the diastereoisomers and recovering optically pure enantiomers. In some embodiments, separable complexes are preferred. In some embodiments, diastereomers have different physical properties (e.g., melting points, boiling points, solubility, reactivity, etc.) and these differences are exploited for separation. In some embodiments, diastereomers are separated by chiral chromatography or, preferably, by separation / resolution techniques based on differences in solubility. In some embodiments, the optically pure enantiomers are then recovered along with the resolving agent by any practical method that does not result in racemization.

[0288] Labeled compounds

[0289] In some embodiments, the compounds described herein exist in their isotopically labeled form. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such isotopically labeled compounds. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such isotopically labeled compounds as pharmaceutical compositions. Thus, in some embodiments, the compounds disclosed herein include isotopically labeled compounds that are identical to those described herein, but in which one or more atoms are replaced by atoms having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into the compounds disclosed herein include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, respectively, such as 2 H(D), 3 H. 13 C. 14 C. l5 N. 18 O. 17 O. 31 P. 32 P. 35 S. 18 F and 36 Cl. Compounds described herein and pharmaceutically acceptable salts or stereoisomers thereof that contain the aforementioned isotopes and / or other isotopes of other atoms are within the scope of the present disclosure. Certain isotopically labeled compounds, for example, by incorporation of radioactive isotopes such as 3 H and 14 C can be used in drug and / or substrate tissue distribution assays. 3 H and carbon-14 14 C isotopes are particularly preferred for their ease of preparation and detectability.

[0290] In some embodiments, the abundance of deuterium in each of the substituents disclosed herein is independently at least 1%, at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or 100% molar. In some embodiments, one or more of the substituents disclosed herein comprises deuterium at a percentage greater than the natural abundance of deuterium. In some embodiments, in one or more of the substituents disclosed herein, one or more 1 H is replaced by one or more deuteriums.

[0291] In some embodiments, the compounds described herein are labeled by other means, including but not limited to the use of chromophores or fluorescent moieties, bioluminescent labels, or chemiluminescent labels.

[0292] Pharmaceutically acceptable salts

[0293] In some embodiments, the compounds described herein exist as pharmaceutically acceptable salts thereof. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such pharmaceutically acceptable salts as pharmaceutical compositions.

[0294] In some embodiments, the compounds described herein possess acidic or basic groups and, therefore, can react with any of a variety of inorganic or organic bases, and inorganic and organic acids, to form pharmaceutically acceptable salts. In some embodiments, these salts are prepared in situ during the final isolation and purification of the compounds disclosed herein or their stereoisomers, or by reacting the purified compound in free form with a suitable acid or base separately and isolating the salt thus formed.

[0295] Examples of pharmaceutically acceptable salts include those prepared by reacting the compounds described herein with an inorganic acid, an organic acid, or an inorganic base, such salts including acetate, acrylate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, bisulfite, bromide, butyrate, butyne-1,4-dioate, camphorate, camphorsulfonate, hexanoate, octanoate, chlorobenzoate, chloride, citrate, cyclopentanepropionate, decanoate, digluconate, dihydrogen phosphate, dinitrobenzoate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, glycolate, hemisulfate, heptanoate, hexanoate, hexyne-1,6-dioate, hydroxybenzoate, gamma-hydroxybutyrate salt, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, iodide, isobutyrate, lactate, maleate, malonate, methanesulfonate, mandelate, metaphosphate, methanesulfonate, methoxybenzoate, methylbenzoate, monohydrogen phosphate, 1-naphthalenesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, palmitate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, pyrosulfate, pyrophosphate, propiolate, phthalate, phenylacetate, phenylbutyrate, propanesulfonate, salicylate, succinate, sulfate, sulfite, succinate, suberate, sebacate, sulfonate, tartrate, thiocyanate, toluenesulfonate, undecanoate, and xylenesulfonate.

[0296] In addition, the compounds described herein can be prepared as pharmaceutically acceptable salts by reacting the free base form of the compound with a pharmaceutically acceptable inorganic or organic acid, including but not limited to inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, metaphosphoric acid, and the like; and organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, p-toluenesulfonic acid, tartaric acid, trifluoroacetic acid, citric acid, benzoic acid, 3-[4-(2-methyl-1-oxo-1-yl)-1-piperidinyl)-1-piperidinyl] ... -(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, arylsulfonic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 2-naphthalenesulfonic acid, 4-methoxybicyclo[2.2.2]oct-2-ene-1-carboxylic acid, glucoheptonic acid, 4,4'-methylenebis-(3-hydroxy-2-ene-1-carboxylic acid), 3-phenylpropionic acid, trimethylacetic acid, tert-butylacetic acid, dodecylsulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid and muconic acid. In some embodiments, other acids, such as oxalic acid, while not pharmaceutically acceptable themselves, may be used to prepare salts that serve as intermediates in obtaining the compounds disclosed herein or their stereoisomers and pharmaceutically acceptable acid addition salts thereof.

[0297] In some embodiments, compounds described herein that contain free acid groups are reacted with a suitable base such as a hydroxide, carbonate, bicarbonate, sulfate of a pharmaceutically acceptable metal cation, with ammonia or a pharmaceutically acceptable organic primary, secondary, tertiary or quaternary amine. Representative salts include alkali metal salts or alkaline earth metal salts such as lithium, sodium, potassium, calcium, magnesium and aluminum salts. Illustrative examples of bases include sodium hydroxide, potassium hydroxide, choline hydroxide, sodium carbonate, N + (C 1-4 Alkyl)4, etc.

[0298] Representative organic amines useful for forming base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, and the like. It should be understood that the compounds described herein also include quaternization of any basic nitrogen-containing groups they contain. In some embodiments, water-soluble or oil-soluble or dispersible products are obtained by such quaternization.

[0299] Tautomers

[0300] In some cases, compounds exist as tautomers. The compounds described herein include all possible tautomers within the formulae described herein. Tautomers are compounds that can be interconverted by the migration of a hydrogen atom, with the switching of single bonds and adjacent double bonds. In bonding arrangements where tautomerism is possible, tautomers will exist in chemical equilibrium. All tautomeric forms of the compounds disclosed herein are contemplated. The exact ratio of tautomers depends on several factors, including temperature, solvent, and pH.

[0301] Treatment

[0302] Disclosed herein are methods of treating a disease in which inhibition of FGFR2 and / or FGFR3 is beneficial, comprising administering a compound of Formula (I), (Ia), (Ia'), (Ia"), (Ib), (Ib'), (Ib"), (Ic), (Ic'), (Ic"), (Id), or (Ie) disclosed herein, or a pharmaceutically acceptable salt or stereoisomer thereof. Disclosed herein are some embodiments of a method of treating a disease in which inhibition of FGFR2 is beneficial, comprising administering a compound of Formula (I), (Ia), (Ia'), (Ia"), (Ib), (Ib'), (Ib"), (Ic), (Ic'), (Ic"), (Id), or (Ie) disclosed herein, or a pharmaceutically acceptable salt or stereoisomer thereof. Some embodiments disclosed herein are methods of treating a disease in which inhibition of FGFR3 is beneficial, comprising administering a compound of Formula (I), (Ia), (Ia'), (Ia"), (Ib), (Ib'), (Ib"), (Ic), (Ic'), (Ic"), (Id), or (Ie) disclosed herein, or a pharmaceutically acceptable salt or stereoisomer thereof. Some embodiments disclosed herein are methods of treating a disease in which inhibition of FGFR2 and FGFR3 is beneficial, comprising administering a compound of Formula (I), (Ia), (Ia'), (Ia"), (Ib), (Ib'), (Ib"), (Ic), (Ic'), (Ic"), (Id), or (Ie) disclosed herein, or a pharmaceutically acceptable salt or stereoisomer thereof.

[0303] Disclosed herein are methods of treating a disease or disorder associated with FGFR2 and / or FGFR3, comprising administering to a subject a compound of Formula (I), (Ia), (Ia'), (Ia"), (Ib), (Ib'), (Ib"), (Ic), (Ic'), (Ic"), (Id), or (Ie) disclosed herein, or a pharmaceutically acceptable salt or stereoisomer thereof. Disclosed herein are some embodiments of a method of treating a disease or disorder associated with FGFR2, comprising administering to a subject a compound of Formula (I), (Ia), (Ia'), (Ia"), (Ib), (Ib'), (Ib"), (Ic), (Ic'), (Ic"), (Id), or (Ie) disclosed herein, or a pharmaceutically acceptable salt or stereoisomer thereof. Some embodiments disclosed herein are methods of treating a disease or disorder associated with FGFR3, comprising administering to a subject a compound of Formula (I), (Ia), (Ia'), (Ia"), (Ib), (Ib'), (Ib"), (Ic), (Ic'), (Ic"), (Id), or (Ie) disclosed herein, or a pharmaceutically acceptable salt or stereoisomer thereof. Some embodiments disclosed herein are methods of treating a disease or disorder associated with FGFR2 and FGFR3, comprising administering to a subject a compound of Formula (I), (Ia), (Ia'), (Ia"), (Ib), (Ib'), (Ib"), (Ic), (Ic'), (Ic"), (Id), or (Ie) disclosed herein, or a pharmaceutically acceptable salt thereof.

[0304] Disclosed herein are methods of treating cancer in an individual, comprising administering to the individual a compound of Formula (I), (Ia), (Ia'), (Ia"), (Ib), (Ib'), (Ib"), (Ic), (Ic'), (Ic"), (Id), or (Ie) disclosed herein, or a pharmaceutically acceptable salt or stereoisomer thereof. Some embodiments are methods of treating cancer in an individual, comprising administering to the individual a compound of Formula (I), (Ia), (Ia'), (Ia"), (Ib), (Ib'), (Ib"), (Ic), (Ic'), (Ic"), (Id), or (Ie) disclosed herein, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein the cancer is selected from intrahepatic bile duct cancer, urothelial cancer, gastric cancer, bladder cancer, breast cancer, endometrial cancer, kidney cancer, liver cancer, lung cancer, melanoma, pancreatic cancer, prostate cancer, or thyroid cancer. Some embodiments are methods of treating intrahepatic bile duct cancer in a subject, comprising administering to the subject a compound of Formula (I), (Ia), (Ia'), (Ia"), (Ib), (Ib'), (Ib"), (Ic), (Ic'), (Ic"), (Id), or (Ie) disclosed herein, or a pharmaceutically acceptable salt or stereoisomer thereof. Some embodiments are methods of treating urothelial cancer in a subject, comprising administering to the subject a compound of Formula (I), (Ia), (Ia'), (Ia"), (Ib), (Ib'), (Ib"), (Ic), (Ic'), (Ic"), (Id), or (Ie) disclosed herein, or a pharmaceutically acceptable salt or stereoisomer thereof. Some embodiments are methods of treating gastric cancer in an individual, comprising administering to the individual a compound of Formula (I), (Ia), (Ia'), (Ia"), (Ib), (Ib'), (Ib"), (Ic), (Ic'), (Ic"), (Id), or (Ie) disclosed herein, or a pharmaceutically acceptable salt or stereoisomer thereof. Some embodiments are methods of treating bladder cancer in an individual, comprising administering to the individual a compound of Formula (I), (Ia), (Ia'), (Ia"), (Ib), (Ib'), (Ib"), (Ic), (Ic'), (Ic"), (Id), or (Ie) disclosed herein, or a pharmaceutically acceptable salt or stereoisomer thereof. Some embodiments are methods of treating breast cancer in an individual, comprising administering to the individual a compound of Formula (I), (Ia), (Ia'), (Ia"), (Ib), (Ib'), (Ib"), (Ic), (Ic'), (Ic"), (Id), or (Ie) disclosed herein, or a pharmaceutically acceptable salt or stereoisomer thereof.Some embodiments are methods of treating endometrial cancer in an individual, comprising administering to the individual a compound of Formula (I), (Ia), (Ia'), (Ia"), (Ib), (Ib'), (Ib"), (Ic), (Ic'), (Ic"), (Id), or (Ie) disclosed herein, or a pharmaceutically acceptable salt or stereoisomer thereof. Some embodiments are methods of treating renal cancer in an individual, comprising administering to the individual a compound of Formula (I), (Ia), (Ia'), (Ia"), (Ib), (Ib'), (Ib"), (Ic), (Ic'), (Ic"), (Id), or (Ie) disclosed herein, or a pharmaceutically acceptable salt or stereoisomer thereof. Some embodiments are methods of treating liver cancer in a subject, comprising administering to the subject a compound of Formula (I), (Ia), (Ia'), (Ia"), (Ib), (Ib'), (Ib"), (Ic), (Ic'), (Ic"), (Id), or (Ie) disclosed herein, or a pharmaceutically acceptable salt or stereoisomer thereof. Some embodiments are methods of treating lung cancer in a subject, comprising administering to the subject a compound of Formula (I), (Ia), (Ia'), (Ia"), (Ib), (Ib'), (Ib"), (Ic), (Ic'), (Ic"), (Id), or (Ie) disclosed herein, or a pharmaceutically acceptable salt or stereoisomer thereof. Some embodiments are methods of treating melanoma in an individual, comprising administering to the individual a compound of Formula (I), (Ia), (Ia'), (Ia"), (Ib), (Ib'), (Ib"), (Ic), (Ic'), (Ic"), (Id), or (Ie) disclosed herein, or a pharmaceutically acceptable salt or stereoisomer thereof. Some embodiments are methods of treating pancreatic cancer in an individual, comprising administering to the individual a compound of Formula (I), (Ia), (Ia'), (Ia"), (Ib), (Ib'), (Ib"), (Ic), (Ic'), (Ic"), (Id), or (Ie) disclosed herein, or a pharmaceutically acceptable salt or stereoisomer thereof. Some embodiments are methods of treating prostate cancer in an individual, comprising administering to the individual a compound of Formula (I), (Ia), (Ia'), (Ia"), (Ib), (Ib'), (Ib"), (Ic), (Ic'), (Ic"), (Id), or (Ie) disclosed herein, or a pharmaceutically acceptable salt or stereoisomer thereof. Some embodiments are methods of treating thyroid cancer in an individual, comprising administering to the individual a compound of Formula (I), (Ia), (Ia'), (Ia"), (Ib), (Ib'), (Ib"), (Ic), (Ic'), (Ic"), (Id), or (Ie) disclosed herein, or a pharmaceutically acceptable salt or stereoisomer thereof.

[0305] Drug administration

[0306] In certain embodiments, the compositions comprising the compounds described herein are administered for preventive and / or therapeutic treatment. In certain therapeutic applications, the compositions are administered to patients already suffering from a disease or condition in an amount sufficient to cure or at least partially alleviate at least one symptom of the disease or condition. The effective amount for this use depends on the severity and course of the disease or condition, prior therapy, the patient's health, weight, and response to the drug, and the judgment of the attending physician. The therapeutically effective amount is optionally determined by methods including, but not limited to, dose escalation and / or dose ranging clinical trials.

[0307] In preventive applications, compositions comprising the compounds described herein are administered to patients susceptible to or at risk for a particular disease, disorder, or condition. Such an amount is defined as a "prophylactically effective amount or dose." In this use, the precise amount also depends on the patient's health, weight, etc. When used in a patient, the effective amount for this use depends on the severity and course of the disease, disorder, or condition, previous therapy, the patient's health and response to drugs, and the judgment of the attending physician. In one aspect, preventive treatment comprises administering a pharmaceutical composition comprising a compound described herein, or a pharmaceutically acceptable salt thereof, to a mammal that has previously experienced at least one symptom or risk factor for the disease being treated and is currently in remission to prevent the recurrence of symptoms of the disease or condition.

[0308] In certain embodiments, where the patient's condition does not improve, the clinician, at their discretion, administers the compound chronically, i.e., for an extended period of time, including throughout the patient's lifetime, to ameliorate or control or limit the symptoms of the patient's disease or condition.

[0309] The amount of a given active agent equivalent to this amount will vary depending on factors such as the specific compound, the disease state and its severity, the identity of the individual or host in need of treatment (e.g., weight, sex), but will be determined based on the specific circumstances of the case, including, for example, the specific active agent being administered, the route of administration, the condition being treated, and the individual or host being treated.

[0310] However, in general, dosages for adult treatment are generally in the range of 0.01 mg / day to 5000 mg / day. In one aspect, dosages for adult treatment are from about 1 mg / day to about 1000 mg / day. In one embodiment, the desired dose is conveniently presented in a single dose or divided doses administered simultaneously or at appropriate intervals, for example, two, three, four or more sub-doses per day.

[0311] In one embodiment, the daily dose of a compound described herein, or a pharmaceutically acceptable salt thereof, is about 0.01 to about 50 mg / kg body weight. In some embodiments, the daily dose or amount of the active ingredient in the dosage form is lower or higher than the ranges shown herein based on a number of variables related to the individual treatment regimen. In various embodiments, the daily dose and unit dose vary depending on a number of variables, including but not limited to the activity of the compound used, the disease or condition to be treated, the mode of administration, the requirements of the individual, the severity of the disease or condition to be treated, and the judgment of the physician.

[0312] Toxicity and therapeutic efficacy of such treatment regimens are determined by standard pharmaceutical procedures in cell culture or experimental animals, including but not limited to LD 10 and ED 90 The dose ratio between toxic and therapeutic effects is the therapeutic index and is expressed as LD 50 With ED 50 In certain embodiments, data obtained from cell culture assays and animal studies are used to formulate therapeutically effective daily dose ranges and / or therapeutically effective unit doses for mammals, including humans. In some embodiments, the daily dose of the compounds described herein is within a circulating concentration range that includes the ED with minimal toxicity. 50 In certain embodiments, the daily dosage range and / or the unit dosage within this range varies depending upon the dosage form employed and the route of administration utilized.

[0313] Any of the above aspects is a further embodiment, wherein an effective amount of a compound as described herein, or a pharmaceutically acceptable salt thereof, is: (a) administered systemically to a mammal; and / or (b) administered orally to a mammal; and / or (c) administered intravenously to a mammal; and / or (d) administered by injection to a mammal; and / or (e) administered topically to a mammal; and / or (f) administered non-systemically or topically to a mammal.

[0314] In any of the above aspects, further embodiments include a single administration of an effective amount of the compound, including further embodiments wherein (i) the compound is administered once daily; or (ii) the compound is administered to the mammal multiple times throughout the day.

[0315] In any of the above aspects, further embodiments include multiple administrations of an effective amount of the compound, including further embodiments wherein (i) the compound is administered continuously or intermittently: as a single dose or multiple doses; (ii) the time between multiple administrations is every 6-12 hours; (iii) the compound is administered to the mammal every 1 to 2 days; or (iv) the compound is administered to the individual weekly or monthly.

[0316] Route of administration

[0317] Suitable routes of administration include, but are not limited to, oral, intravenous, rectal, aerosol, parenteral, ocular, pulmonary, transmucosal, transdermal, vaginal, otic, nasal, and topical administration. In addition, parenteral delivery includes, by way of example only, intramuscular, subcutaneous, intravenous, intramedullary injection, as well as intrathecal, direct intracerebroventricular, intraperitoneal, intralymphatic, and intranasal injection.

[0318] In certain embodiments, the compounds described herein are administered in a local rather than systemic manner, for example, by injecting the compound directly into an organ, typically in the form of a reservoir formulation or a sustained-release formulation. In a particular embodiment, the long-acting formulation is administered by implantation (e.g., subcutaneously or intramuscularly) or intramuscular injection. Additionally, in other embodiments, the drug is delivered in a targeted drug delivery system, for example, in a liposome-coated organ-specific antibody. In such embodiments, the liposome is targeted to the organ and selectively absorbed by it. In additional embodiments, the compounds described herein are provided in the form of a quick-release formulation, a delayed-release formulation, or an intermediate-release formulation. In other embodiments, the compounds described herein are administered topically.

[0319] Pharmaceutical compositions / preparations

[0320] The compounds described herein are administered to individuals in need thereof, either alone or in combination with a pharmaceutically acceptable carrier, excipient, or diluent according to standard pharmaceutical practice in a pharmaceutical composition. In some embodiments, the compounds of the present disclosure can be administered to animals. The compounds can be administered orally or parenterally, including intravenous, intramuscular, intraperitoneal, subcutaneous, rectal, and topical routes of administration.

[0321] In another aspect, provided herein are pharmaceutical compositions comprising a compound of Formula (I), (Ia), (Ia'), (Ia"), (Ib), (Ib'), (Ib"), (Ic), (Ic'), (Ic"), (Id), or (Ie) as described herein, or a pharmaceutically acceptable salt or stereoisomer thereof, and at least one pharmaceutically acceptable excipient. Some embodiments are pharmaceutical compositions comprising a compound of Formula (I) as described herein, or a pharmaceutically acceptable salt or stereoisomer thereof, and at least one pharmaceutically acceptable excipient. Some embodiments are pharmaceutical compositions comprising a compound of Formula (Ia) as described herein, or a pharmaceutically acceptable salt or stereoisomer thereof, and at least one pharmaceutically acceptable excipient. Some embodiments are pharmaceutical compositions comprising a compound of formula (Ib) as described herein, or a pharmaceutically acceptable salt or stereoisomer thereof, and at least one pharmaceutically acceptable excipient. Some embodiments are pharmaceutical compositions comprising a compound of formula (Ic) as described herein, or a pharmaceutically acceptable salt or stereoisomer thereof, and at least one pharmaceutically acceptable excipient. Some embodiments are pharmaceutical compositions comprising a compound of formula (Id) as described herein, or a pharmaceutically acceptable salt or stereoisomer thereof, and at least one pharmaceutically acceptable excipient. Some embodiments are pharmaceutical compositions comprising a compound of formula (Ie) as described herein, or a pharmaceutically acceptable salt or stereoisomer thereof, and at least one pharmaceutically acceptable excipient.

[0322] In a conventional manner, pharmaceutical compositions are formulated using one or more pharmaceutically acceptable excipients that assist in processing the active compound into a pharmaceutically acceptable formulation. Suitable formulations depend on the selected route of administration. An overview of the pharmaceutical compositions described herein can be found in, for example, Remington: The Science and Practice of Pharmacy, 19th edition (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, HA and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, NY, 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, 17th edition (Lippincott Williams & Wilkins 1999), which are incorporated herein by reference.

[0323] In some embodiments, the pharmaceutically acceptable excipient is selected from the group consisting of carriers, binders, fillers, suspending agents, flavoring agents, sweeteners, disintegrants, dispersants, surfactants, lubricants, colorants, diluents, solubilizers, wetting agents, plasticizers, stabilizers, penetration enhancers, wetting agents, defoaming agents, antioxidants, preservatives, and any combination thereof.

[0324] The pharmaceutical compositions described herein are administered to an individual by a suitable route of administration, including but not limited to oral, parenteral (e.g., intravenous, subcutaneous, intramuscular), intranasal, oral, topical, rectal, or transdermal routes of administration. Pharmaceutical formulations described herein include but are not limited to aqueous liquid dispersions, liquids, gels, syrups, elixirs, slurries, suspensions, self-emulsifying dispersions, solid solutions, liposomal dispersions, aerosols, solid oral dosage forms, powders, immediate release formulations, controlled release formulations, fast melt formulations, tablets, capsules, pills, powders, lozenges, effervescent formulations, lyophilized formulations, delayed release formulations, sustained release formulations, pulsatile release formulations, multiparticulate formulations, and mixed immediate and controlled release formulations.

[0325] Pharmaceutical compositions containing a compound described herein, or a pharmaceutically acceptable salt or stereoisomer thereof, are prepared in a conventional manner, such as by way of example only, by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or compression processes.

[0326] Pharmaceutical compositions for oral use are prepared by mixing one or more solid excipients with one or more of the compounds described herein, optionally grinding the resulting mixture, and processing the granular mixture after adding suitable adjuvants (if desired) to obtain tablets or dragees. Suitable excipients include, for example, fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations such as corn starch, wheat starch, rice starch, potato starch, gelatin, tragacanth, methylcellulose, microcrystalline cellulose, hydroxypropyl methylcellulose, and sodium carboxymethylcellulose; or other such as polyvinylpyrrolidone (PVP or povidone) or calcium phosphate. If desired, disintegrants such as cross-linked sodium carboxymethylcellulose, polyvinylpyrrolidone, agar, or alginic acid or a salt thereof, such as sodium alginate, may be added. In some embodiments, dyes or pigments may be added to the tablet or dragee coating for identification or characterization of different combinations of active compound doses.

[0327] Pharmaceutical compositions for oral administration include push-fit capsules made of gelatin and soft sealed capsules made of gelatin and a plasticizer (e.g., glycerol or sorbitol). Push-fit capsules contain the active ingredient mixed with a filler such as lactose, a binder such as starch, and / or a lubricant such as talc or magnesium stearate, and optionally a stabilizer. In soft capsules, the active compound is dissolved or suspended in a suitable liquid, such as a fatty oil, liquid paraffin, or liquid polyethylene glycol. In some embodiments, a stabilizer is added.

[0328] The pharmaceutical composition for parenteral application is formulated into an infusion or injection. In some embodiments, the pharmaceutical composition suitable for injection or infusion includes a sterile aqueous solution or dispersant or sterile powder containing a compound as described herein or a pharmaceutically acceptable salt or stereoisomer thereof. In some embodiments, the pharmaceutical composition includes a liquid carrier. In some embodiments, the liquid carrier is a solvent or a liquid dispersion medium containing, for example, water, saline, ethanol, a polyol (such as glycerol, propylene glycol, liquid polyethylene glycol, etc.), a vegetable oil, a non-toxic glyceride and any combination thereof. In some embodiments, the pharmaceutical composition further includes a preservative to prevent microbial growth. Example

[0329] The following examples are offered for illustrative purposes only and are not intended to limit the scope of the claims presented herein.

[0330] As used above and throughout the specification of the present disclosure, unless otherwise indicated, the following abbreviations shall be understood to have the following meanings:

[0331] ACN or MeCN Acetonitrile

[0332] AcOH acetic acid

[0333] Ac acetyl

[0334] Bn benzyl

[0335] BOC or Boc tert-butyl carbamate

[0336] i-Bu isobutyl

[0337] t-Bu tert-butyl

[0338] CDI 1,1-Carbonyldiimidazole

[0339] DBU 1,8-diazabicyclo[5.4.0]undec-7-ene

[0340] DCE Dichloroethane (ClCH2CH2Cl)

[0341] DCM dichloromethane (CH2Cl2)

[0342] DIBAL-H Diisobutylaluminum hydride

[0343] DIPEA or DIEA diisopropylethylamine

[0344] DMAP 4-(N,N-dimethylamino)pyridine

[0345] DME 1,2-dimethoxyethane

[0346] DMF N,N-dimethylformamide

[0347] DMA N,N-dimethylacetamide

[0348] DMPU N,N'-dimethylpropylene urea

[0349] DMSO dimethyl sulfoxide

[0350] DPPA diphenylphosphoryl azide

[0351] Dppf or dppf 1,1'-bis(diphenylphosphino)ferrocene

[0352] EDC or EDCI N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride

[0353] eq equivalent

[0354] Et ethyl

[0355] Et2O ether

[0356] EtOH

[0357] EA or EtOAc Ethyl acetate

[0358] HATU 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate

[0359] HOBt 1-Hydroxybenzotriazole

[0360] HPLC high-performance liquid chromatography

[0361] KOAc potassium acetate

[0362] KOtBu Potassium tert-butoxide

[0363] KHMDS Potassium bis(trimethylsilyl)amide

[0364] NaHMDS Sodium bis(trimethylsilyl)amide

[0365] LiHMDS Lithium bis(trimethylsilyl)amide

[0366] LAH / LiAlH4 lithium aluminum anhydride

[0367] LCMS liquid chromatography mass spectrometry

[0368] Me methyl

[0369] MeOH methanol

[0370] MS

[0371] MTBE methyl tert-butyl ether

[0372] NBS N-bromosuccinimide

[0373] NMP N-Methyl-2-pyrrolidinone

[0374] NMR Nuclear Magnetic Resonance

[0375] PE petroleum ether

[0376] Ph Phenyl

[0377] iPr / i-Pr isopropyl

[0378] PyAOP (7-azabenzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate)

[0379] RP-HPLC reversed-phase high-pressure liquid chromatography

[0380] rt room temperature

[0381] SEM 2-(trimethylsilyl)ethoxymethyl

[0382] TBS tert-Butyldimethylsilyl

[0383] TEA triethylamine

[0384] TFA trifluoroacetic acid

[0385] THF Tetrahydrofuran

[0386] TLC thin layer chromatography

[0387] TMS trimethylsilyl

[0388] Example 1: 6-(4-acrylamidophenyl)-7-(4-((6-methylpyridin-2-yl)oxy)phenyl)pyrrolo[1,2-a]pyrazine-8-carboxamide

[0389]

[0390] Step 1: tert-Butyl 2-cyano-2-(pyrazin-2-yl)acetate

[0391] To a solution of 2-chloropyrazine (8.0 g, 69.85 mmol) in THF (250 mL) were added tert-butyl cyanoacetate (19.72 g, 139.70 mmol) and t-BuOK (19.59 g, 174.62 mmol). The reaction mixture was stirred at 80°C for 48 hours. After cooling to room temperature, the mixture was poured into water (300 mL) and extracted with EtOAc (3×300 mL) to remove impurities. The aqueous layer was adjusted to pH ˜3 with 1N HCl solution and extracted with DCM (3×300 mL). The combined organic layers were washed with brine, dried over Na 2 SO 4 , filtered, and concentrated under reduced pressure to give the title compound (9.5 g, 62%). LC-MS (ESI+): m / z 164.0 [M+H-56] + .

[0392] Step 2: 2-(Pyrazin-2-yl)acetonitrile

[0393] To a solution of tert-butyl 2-cyano-2-(pyrazine-2-yl)acetate (4.5 g, 20.53 mmol) in DCM (20 mL) was added TFA (20 mL). The reaction mixture was stirred at room temperature for 5 hours. The mixture was then slowly poured into a saturated NaHCO solution (300 mL) and extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with salt water, dried over Na SO, filtered, and concentrated under reduced pressure to give a residue which was purified by flash column chromatography on silica gel (eluted with PE: EtOAc = 1: 1) to give the title compound (1.1 g, 45%) as a yellow oil. 1H NMR (400MHz, DMSO-d6) δ8.78-8.53 (m, 3H), 4.33 (s, 2H).

[0394] Step 3: 6-amino-7-(4-((6-methylpyridin-2-yl)oxy)phenyl)pyrrolo[1,2-a]pyrazine-8-carbonitrile

[0395] To a solution of 2-(pyrazin-2-yl)acetonitrile (500 mg, 4.20 mmol) in MeOH (15 mL) was added 4-((6-methylpyridin-2-yl)oxy)benzaldehyde (895 mg, 4.20 mmol), DBU (1.9 g, 12.60 mmol) and acetyl cyanide (290 mg, 4.20 mmol). The reaction mixture was stirred at 120 ° C under microwave irradiation for 20 minutes. After cooling to room temperature, the mixture was quenched with water (100 mL) and extracted with DCM (3×100 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue, which was purified by flash column chromatography on silica gel (eluted with MeOH:DCM=10:1) to give the title compound (0.9 g, 63%). LC-MS (ESI+): m / z 342.2 [M+H] + .

[0396] Step 4: 6-Bromo-7-(4-((6-methylpyridin-2-yl)oxy)phenyl)pyrrolo[1,2-a]pyrazine-8-carbonitrile

[0397] To a solution of 6-amino-7-(4-((6-methylpyridin-2-yl)oxy)phenyl)pyrrolo[1,2-a]pyrazine-8-carbonitrile (1.3 g, 3.81 mmol) in MeCN (40 mL) was added tert-butyl nitrite (1.18 g, 11.42 mmol) and CuBr2 (1.28 g, 5.71 mmol). The reaction mixture was stirred at room temperature for 0.5 h. The mixture was then concentrated under reduced pressure to give a residue, which was purified by preparative-HPLC (eluting with 5%-70% MeCN in H2O containing 0.1% NH4OH) to give the title compound (170 mg, 11%). LC-MS (ESI+): m / z 405.0 [M+H] + .

[0398] Step 5: 6-(4-aminophenyl)-7-(4-((6-methylpyridin-2-yl)oxy)phenyl)pyrrolo[1,2-a]pyrazine-8-carbonitrile

[0399] To a solution of 6-bromo-7-(4-((6-methylpyridin-2-yl)oxy)phenyl)pyrrolo[1,2-a]pyrazine-8-carbonitrile (170 mg, 0.42 mmol) in 1,4-dioxane (3 mL) and water (0.3 mL) was added 4-aminophenylboronic acid pinacol ester (137.86 mg, 0.63 mmol), K2CO3 (116 mg, 0.84 mmol) and Pd(dppf)Cl2 (31 mg, 0.04 mmol). The mixture was stirred at 100 ° C under microwave irradiation and N2 for 1 hour. After cooling to room temperature, the mixture was quenched with water (30 mL) and extracted with EtOAc (3×30 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue, which was purified by flash column chromatography on silica gel (eluted with MeOH:DCM=20:1) to give the title compound (140 mg, 81%). LC-MS (ESI+): m / z 418.2 [M+H] + .

[0400] Step 6: 6-(4-aminophenyl)-7-(4-((6-methylpyridin-2-yl)oxy)phenyl)pyrrolo[1,2-a]pyrazine-8-carboxamide

[0401] A mixture of 6-(4-aminophenyl)-7-(4-((6-methylpyridin-2-yl)oxy)phenyl)pyrrolo[1,2-a]pyrazine-8-carbonitrile (130 mg, 0.31 mmol) and concentrated H2SO4 (6 mL) was stirred at 30°C for 8 hours. The mixture was slowly poured into water (100 mL), adjusted to pH ~8 with 6N NaOH solution, and extracted with DCM (3 x 100 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give the crude product (130 mg, 97%). LC-MS (ESI+): m / z 436.2 [M+H] + .

[0402] Step 7: 6-(4-Acrylamidophenyl)-7-(4-((6-methylpyridin-2-yl)oxy)phenyl)pyrrolo[1,2-a]pyrazine-8-carboxamide

[0403] To a solution of 6-(4-aminophenyl)-7-(4-((6-methylpyridin-2-yl)oxy)phenyl)pyrrolo[1,2-a]pyrazine-8-carboxamide (130 mg, 0.30 mmol) in acetone (5 mL) was added KCO solution (1.65 mL, 0.5 mol / L in water) and acryloyl chloride (0.55 mL, 0.5 mol / L in acetone) at 0 ° C. The mixture was stirred at 0 ° C for 1 hour. The mixture was quenched with water (50 mL) and extracted with DCM (3 × 50 mL). The combined organic layers were washed with brine, dried over NaSO, filtered, and concentrated under reduced pressure to give a residue, which was purified by preparative HPLC (eluted with 26%-36% MeCN in H O containing 0.1% FA) to give the title compound (16 mg, 12%). LC-MS (ESI+): m / z 490.2 [M+H] + . 1 HNMR(400MHz,DMSO-d6)δ10.31(s,1H),9.33(s,1H),8.05(m,1H),7.84-7.71(m,3H),7.67(m,1H),7.41(bs,1H),7.36- 7.25(m,4H),7.07(m,2H),7.02(m,1H),6.76(m,1H),6.65(bs,1H),6.45(m,1H),6.28(m,1H),5.78(m,1H),2.34(s,3H).

[0404] Example 2: 6-(4-acrylamidophenyl)-7-(4-((4-methylpyrimidin-2-yl)oxy)phenyl)pyrrolo[1,2-a]pyrazine-8-carboxamide

[0405]

[0406] Step 1: 4-((4-methylpyrimidin-2-yl)oxy)benzaldehyde

[0407] To a solution of 4-hydroxybenzaldehyde (500 mg, 4.09 mmol) and 2-chloro-4-methylpyrimidine (632 mg, 4.91 mmol) in DMF (10 mL) was added CsF (1.87 g, 12.28 mmol). The reaction mixture was stirred at 120°C for 12 hours. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure to give a residue, which was purified by flash column chromatography on silica gel (eluting with 0-50% ethyl acetate in petroleum ether) to give the title compound (380 mg, 43%). LC-MS (ESI+): m / z 215.4 [M+H] + .

[0408] Step 2: 6-amino-7-(4-((4-methylpyrimidin-2-yl)oxy)phenyl)pyrrolo[1,2-a]pyrazine-8-carbonitrile

[0409] To a mixture of 4-((4-methylpyrimidin-2-yl)oxy)benzaldehyde (576 mg, 2.69 mmol) and 2-(pyrazin-2-yl)acetonitrile (320 mg, 2.69 mmol) in MeOH (10 mL) was added DBU (1.23 g, 8.06 mmol) and acetyl cyanide (186 mg, 2.69 mmol). The reaction mixture was stirred at 100 ° C under microwave irradiation in N2 for 20 minutes. After cooling to room temperature, the reaction mixture was quenched with 20 mL of water and extracted with ethyl acetate (30 mL×3). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue, which was purified by flash column chromatography on silica gel (eluted with 0-10% methanol in dichloromethane) to give the title compound (450 mg, 49%). LC-MS (ESI+): m / z 343.0 [M+H] + .

[0410] Step 3: 6-Bromo-7-(4-((4-methylpyrimidin-2-yl)oxy)phenyl)pyrrolo[1,2-a]pyrazine-8-carbonitrile

[0411] To a solution of 6-amino-7-(4-((4-methylpyrimidin-2-yl)oxy)phenyl)pyrrolo[1,2-a]pyrazine-8-carbonitrile (450 mg, 1.31 mmol) in HBr (10 mL, 33% in AcOH) was added CuBr2 (382 mg, 1.71 mmol) at 0°C. A solution of NaNO2 (454 mg, 6.57 mmol) in H2O (4 mL) was then added to the mixture. The reaction mixture was stirred at 0°C for 0.5 hours. The pH of the solution was then adjusted to 7-8 with Na2CO3 (aqueous solution). The mixture was extracted with DCM (20 ml x 3). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue that was purified by flash column chromatography on silica gel (eluted with 0-10% methanol in dichloromethane) to give the title compound (280 mg, 53%). LC-MS (ESI+): m / z 405.8 [M+H] + .

[0412] Step 4: 6-(4-aminophenyl)-7-(4-((4-methylpyrimidin-2-yl)oxy)phenyl)pyrrolo[1,2-a]pyrazine-8-carbonitrile

[0413] A mixture of 6-bromo-7-(4-((4-methylpyrimidin-2-yl)oxy)phenyl)pyrrolo[1,2-a]pyrazine-8-carbonitrile (280 mg, 689 μmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (302 mg, 1.38 mmol), NaCO (219 mg, 2.07 mmol), and Pd-118 (45 mg, 68.9 μmol) in dioxane (10 mL) and H O (1 mL) was degassed and purged with N three times. The mixture was stirred at 90° C. under an N atmosphere for 2 hours. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure to give a residue, which was purified by flash column chromatography on silica gel (eluting with 0-30% ethyl acetate in petroleum ether) to give the title compound (180 mg, 62%). LC-MS (ESI+): m / z 419.1 [M+H] + .

[0414] Step 5: 6-(4-aminophenyl)-7-(4-((4-methylpyrimidin-2-yl)oxy)phenyl)pyrrolo[1,2-a]pyrazine-8-carboxamide

[0415] A mixture of 6-(4-aminophenyl)-7-(4-((4-methylpyrimidin-2-yl)oxy)phenyl)pyrrolo[1,2-a]pyrazine-8-carbonitrile (180 mg, 430 μmol) in concentrated H2SO4 (3 mL) was stirred at 30°C for 8 hours. The mixture was then slowly poured into water (20 mL), adjusted to pH ~7 with Na2CO3, and extracted with EtOAc (3×20 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give the title compound (160 mg, 85%). LC-MS (ESI+): m / z 437.2 [M+H] + .

[0416] Step 6: 6-(4-acrylamidophenyl)-7-(4-((4-methylpyrimidin-2-yl)oxy)phenyl)pyrrolo[1,2-a]pyrazine-8-carboxamide

[0417] To a solution of 6-(4-aminophenyl)-7-(4-((4-methylpyrimidin-2-yl)oxy)phenyl)pyrrolo[1,2-a]pyrazine-8-carboxamide (160 mg, 367 μmol) in acetone (2 mL) and H2O (0.4 mL) was added K2CO3 (102 mg, 734.8 μmol). To the solution was then added prop-2-enoyl chloride (40 mg, 440.9 μmol) at 0°C. The reaction mixture was stirred at 25°C for 1 hour. 10 mL of water was then added to the mixture. After extraction with ethyl acetate (10 mL x 3), the combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue, which was purified by flash column chromatography on silica gel (eluted with 0-10% MeOH in DCM) to give the title compound (26 mg, 15%). LC-MS (ESI+): m / z 491.2 [M+H] + . 1 HNMR(400MHz,DMSO-d6)δ10.33(s,1H),9.28(d,J=1.5Hz,1H),8.47(d,J=5.0Hz,1H) ,7.99(dd,J=1.4,4.9Hz,1H),7.77(d,J=8.8Hz,2H),7.66(d,J=4.8Hz,1H),7.44(br s,1H),7.32(m,4H),7.20-7.11(m,3H),6.75(br s,1H),6.51-6.39(m,1H),6.33-6.20(m,1H),5.83-5.75(m,1H),2.41(s,3H).

[0418] Example 3: 6-(6-acrylamidopyridin-3-yl)-7-(4-((6-methylpyridin-2-yl)oxy)phenyl)pyrrolo[1,2-a]pyrazine-8-carboxamide

[0419]

[0420] Step 1: N-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)acrylamide

[0421] To a solution of 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine (200 mg, 908.8 μmol) and TEA (138 mg, 1.36 mmol, 189.7 μL) in DCM (3 mL) was added propenyl chloride (82 mg, 908.8 μmol, 74.1 μL) at 0°C. The reaction mixture was stirred at 0°C for 0.5 hours. The mixture was then concentrated under reduced pressure to give a residue, which was purified by flash column chromatography on silica gel (eluted with 0-30% ethyl acetate in petroleum ether) to give the title compound (100 mg, 40%) as a colorless oil. 1 H NMR (400MHz, DMSO-d6) δ10.92(s,1H),8.55(d,J=0.8Hz,1H),8.22(d,J=8.3Hz,1H),8.01(dd,J=1 .8,8.3Hz,1H),6.68-6.54(m,1H),6.33(dd,J=1.8,17.1Hz,1H),5.84-5.72(m,1H),1.31(s,12H).

[0422] Step 2: 6-Bromo-7-(4-((6-methylpyridin-2-yl)oxy)phenyl)pyrrolo[1,2-a]pyrazine-8-carboxamide

[0423] A mixture of 6-bromo-7-(4-((6-methylpyridin-2-yl)oxy)phenyl)pyrrolo[1,2-a]pyrazine-8-carbonitrile (100 mg, 246.8 μmol) in H2SO4 (2 mL) was stirred at 30°C for 12 hours. The mixture was then slowly poured into water (20 mL), adjusted to pH ~7 with Na2CO3, and extracted with EtOAc (3×20 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give the title compound (100 mg). LC-MS (ESI+): m / z 423.0 [M+H] + .

[0424] Step 3: 6-(6-Acrylamidopyridin-3-yl)-7-(4-((6-methylpyridin-2-yl)oxy)phenyl)pyrrolo[1,2-a]pyrazine-8-carboxamide

[0425] A mixture of 6-bromo-7-(4-((6-methylpyridin-2-yl)oxy)phenyl)pyrrolo[1,2-a]pyrazine-8-carboxamide (100 mg, 236.3 μmol), N-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)acrylamide (65 mg, 236.3 μmol), KCO (82 mg, 590.7 μmol), and Pd-118 (15 mg, 23.6 μmol) in dioxane (4 mL) and H O (1 mL) was degassed and purged with N three times. The mixture was stirred at 80° C. for 2 hours. After cooling to room temperature, the mixture was diluted with 10 mL of water and extracted with ethyl acetate (10 mL×3). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue which was purified by preparative-HPLC (column: Boston Prime C 18 150×30mm×5um; mobile phase: [water (NH3H2O+NH4HCO3)-ACN]; B%: 30%-50%, 9 minutes) to obtain the title compound (18 mg, 15%). LC-MS (ESI+): m / z 491.1 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ10.89(s,1H),9.35(d,J=1.3Hz,1H),8.28(d,J=8.5Hz,1H),8.2 4(d,J=1.8Hz,1H),8.11(m,1H),7.87(dd,J=2.3,8.5Hz,1H),7.79-7.67(m,2H),7.43(br s,1H),7.36-7.28(m,2H),7.09(d,J=8.8Hz,2H),7.03(d,J=7.5Hz,1H),6.78(d ,J=8.3Hz,1H),6.69-6.56(m,2H),6.34(m,1H),5.86-5.77(m,1H),2.34(s,3H).

[0426] Example 4: 6-(6-acrylamido-4-methylpyridin-3-yl)-7-(4-((6-methylpyridin-2-yl)oxy)phenyl)pyrrolo[1,2-a]pyrazine-8-carboxamide

[0427]

[0428] Step 1: 6-(6-amino-4-methylpyridin-3-yl)-7-(4-((6-methylpyridin-2-yl)oxy)phenyl)pyrrolo[1,2-a]pyrazine-8-carbonitrile

[0429] To a solution of 6-bromo-7-(4-((6-methylpyridin-2-yl)oxy)phenyl)pyrrolo[1,2-a]pyrazine-8-carbonitrile (100 mg, 0.24 mmol) in 1,4-dioxane (10 mL) and water (0.1 mL) was added 4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine (300 mg, 1.28 mmol), K2CO3 (102 mg, 0.74 mmol) and XPhosPdG2 (19 mg, 0.03 mmol). The mixture was stirred at 100 ° C under microwave irradiation and N2 for 1 hour. After cooling to room temperature, the mixture was quenched with water (30 mL) and extracted with EtOAc (3×30 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue, which was purified by flash column chromatography on silica gel (eluted with DCM:MeOH=20:1) to give the title compound (65 mg, 63%). LC-MS (ESI+): m / z 433.2 [M+H] + .

[0430] Step 2: 6-(6-amino-4-methylpyridin-3-yl)-7-(4-((6-methylpyridin-2-yl)oxy)phenyl)pyrrolo[1,2-a]pyrazine-8-carboxamide

[0431] A mixture of 6-(6-amino-4-methylpyridin-3-yl)-7-(4-((6-methylpyridin-2-yl)oxy)phenyl)pyrrolo[1,2-a]pyrazine-8-carbonitrile (65 mg, 0.15 mmol) and concentrated H2SO4 (3 mL) was stirred at 30°C for 8 hours. The mixture was then slowly poured into water (20 mL), adjusted to pH ~8 with 6N NaOH solution, and extracted with DCM (3 x 30 mL). The combined organic layers were dried over Na2SO4, filtered, and evaporated to give the title compound (30 mg, 45%). LC-MS (ESI+): m / z 451.2 [M+H] + .

[0432] Step 3: 6-(6-Acrylamido-4-methylpyridin-3-yl)-7-(4-((6-methylpyridin-2-yl)oxy)phenyl)pyrrolo[1,2-a]pyrazine-8-carboxamide

[0433] To a solution of 6-(6-amino-4-methylpyridin-3-yl)-7-(4-((6-methylpyridin-2-yl)oxy)phenyl)pyrrolo[1,2-a]pyrazine-8-carboxamide (20 mg, 0.044 mmol) in DCM (2 mL) was added TEA (0.1 mL, 0.67 mmol), acrylic acid (3.1 mL, 0.1 M in DCM, 0.31 mmol) and T3P (200 mg, 50% in EtOAc, 0.31 mmol) at 0°C. The mixture was stirred at 25°C for 1 hour. The mixture was then quenched with water (15 mL) and extracted with DCM (3 x 10 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue which was purified by preparative HPLC (eluting with 30%-46% MeCN in H2O containing 0.1% FA) to give the title compound (0.59 mg, 2%). LC-MS (ESI+): m / z 505.3 [M+H] + . 1 H NMR (400MHz, CDCl3) δ10.02(s,1H),8.85(s,1H),8.39(s,1H),8.05(s,1H),7.81( s,1H),7.63(t,J=8.0Hz,1H),7.52(s,1H),7.25(m,2H),7.14(d,J=8.0Hz,2H),6.9 5(d,J=8.0Hz,1H),6.73(d,J=8.0Hz,1H),6.53(d,J=16.0Hz,1H),6.33(dd,J=16. 0,8.0Hz,1H),5.90(d,J=8.0Hz,1H),5.78-5.63(m,1H),2.45(s,3H),2.06(s,3H).

[0434] Example 5: 6-(4-acrylamidophenyl)-4-methyl-7-(4-((6-methylpyridin-2-yl)oxy)phenyl)pyrrolo[1,2-a]pyrazine-8-carboxamide

[0435]

[0436] Preparation of tert-butyl 2-cyano-2-(6-methylpyrazin-2-yl)acetate (Intermediate 5.1)

[0437]

[0438] Intermediate 5.1 was synthesized in a manner analogous to the procedure for Intermediate 1.1 by substituting 2-chloro-6-methylpyrazine for 2-chloropyrazine.

[0439] Preparation of 2-(6-methylpyrazin-2-yl)acetonitrile (Intermediate 5.2)

[0440] To a solution of tert-butyl 2-cyano-2-(6-methylpyrazin-2-yl)acetate (7.0 g, 30.01 mmol) in DMSO (70 mL) and H2O (70 mL) was added LiBr (3.92 g, 45.01 mmol). The mixture was stirred at 130°C for 1 hour. After cooling to room temperature, the mixture was slowly poured into saturated NaHCO3 solution (300 mL) and extracted with EtOAc (3×100 mL). The combined organic layers were washed with brine (200 mL), dried over Na2SO4, filtered, and evaporated to give the title compound (3.5 g, 88%) as a yellow oil. LC-MS (ESI+): m / z 134.2 [M+H] + .

[0441] Preparation of 6-(4-acrylamidophenyl)-4-methyl-7-(4-((6-methylpyridin-2-yl)oxy)phenyl)pyrrolo[1,2-a]pyrazine-8-carboxamide (Example 5)

[0442] Example 5 was synthesized in a manner analogous to the procedure of Example 1 by substituting 2-(6-methylpyrazin-2-yl)acetonitrile (Intermediate 5.2) for 2-(pyrazin-2-yl)acetonitrile. The residue was purified by preparative HPLC (eluting with 55%-60% MeCN in H2O containing 0.1% FA) to afford the title compound (17 mg, 19%). LC-MS (ESI+): m / z 504.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ10.30 (s, 1H), 9.29 (s, 1H), 7.71 (t, J = 8.0Hz, 1H), 7.63 (d, J=8.0Hz,2H),7.44(s,1H),7.35(d,J=8.0Hz,3H),7.24(d,J=8.0Hz,2H),7.00(d,J= 8.0Hz,3H),6.71(d,J=8.0Hz,1H),6.44(dd,J1=16.8,J2=10.0Hz,2H),6.27(dd,J1 =16.0, J2=2.0Hz, 1H), 5.77 (dd, J1=10.0, J2=2.0Hz, 1H), 2.31 (s, 3H), 1.98 (s, 3H).

[0443] Example 6: 6-(4-acrylamidophenyl)-4-methyl-7-(4-((4-methylpyrimidin-2-yl)oxy)phenyl)pyrrolo[1,2-a]pyrazine-8-carboxamide

[0444]

[0445] Example 6

[0446] Preparation of intermediate 6.2

[0447]

[0448] Step 1: 2-(6-methylpyrazin-2-yl)-3-(4-((4-methylpyrimidin-2-yl)oxy)phenyl)acrylonitrile

[0449] To a solution of 2-(6-methylpyrazin-2-yl)acetonitrile (2 g, 15.02 mmol) in MeOH (200 mL) was added 4-((4-methylpyrimidin-2-yl)oxy)benzaldehyde (Intermediate 2.1) (3.86 g, 18.02 mmol) and NHOAc (8.34 g, 108.15 mmol). The mixture was stirred at 70°C for 3 hours. After cooling to room temperature, the precipitate was filtered. The solid was washed with water (20 mL) and dried under vacuum to give the title compound (3.5 g, 71%). LC-MS (ESI+): m / z 330.3 [M+H] + .

[0450] Step 2: 6-amino-4-methyl-7-(4-((4-methylpyrimidin-2-yl)oxy)phenyl)pyrrolo[1,2-a]pyrazine-8-carbonitrile

[0451] To a solution of 2-(6-methylpyrazin-2-yl)-3-(4-((4-methylpyrimidin-2-yl)oxy)phenyl)acrylonitrile (1.0 g, 3.04 mmol) in MeOH (20 mL) was added DBU (1.39 g, 9.11 mmol) and acetyl cyanide (0.21 g, 3.04 mmol). The mixture was stirred at 120 ° C. under microwave irradiation and N2 for 20 minutes. After cooling to room temperature, the mixture was quenched with water (100 mL) and extracted with DCM (3×100 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue, which was purified by flash column chromatography on silica gel (eluted with MeOH:DCM=20:1) to give the title compound (1 g, 92%). LC-MS (ESI+): m / z 357.2 [M+H] + .

[0452] Example 6 was synthesized in a manner similar to the method of Example 2 by replacing 6-amino-7-(4-((4-methylpyrimidin-2-yl)oxy)phenyl)pyrrolo[1,2-a]pyrazine-8-carbonitrile with 6-amino-4-methyl-7-(4-((4-methylpyrimidin-2-yl)oxy)phenyl)pyrrolo[1,2-a]pyrazine-8-carbonitrile. The residue was purified by preparative HPLC (eluting with 55%-60% MeCN in H2O containing 0.1% FA) to give the title compound (6 mg, 8% yield over two steps). LC-MS (ESI+): m / z 505.1 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ10.29(s,1H),9.25(s,1H),8.44(d,J=8.0Hz,1H),8.37(s,1H),7.64(d,J=8.0Hz,2H),7.43(s,1H), 7.37(d,J=8.0Hz,2H),7.27(d,J=8.0Hz,2H),7.13(d,J=8.0Hz,1H),7.09(d,J=8.0Hz,2H),6.53(s,1H),6.44(dd,J1=16.0,J 2＝ 12.0Hz,1H),6.30-6.22(m,1H),5.79-5.74(m,1H),2.38(s,3H),1.97(s,3H).

[0453] Example 7: 6-(4-acrylamidophenyl)-3-methyl-7-(4-((6-methylpyridin-2-yl)oxy)phenyl)pyrrolo[1,2-a]pyrazine-8-carboxamide

[0454]

[0455] Example 7

[0456] Preparation of intermediate 7.1

[0457] Step 1: 2-(5-methylpyrazin-2-yl)acetonitrile

[0458]

[0459] A mixture of 2-(chloromethyl)-5-methylpyrazine hydrochloride (4.00 g, 22.3 mmol), KI (1.11 g, 6.70 mmol) and KCN (2.18 g, 33.51 mmol) in EtOH (200 mL) and H O (40 mL) was degassed and purged three times with N. The mixture was stirred at 80°C under an N atmosphere for 5 hours. After cooling to room temperature, 200 mL of NaCO (aqueous solution) was added to the solution. The solution was diluted with 200 mL of water and extracted with ethyl acetate (250 mL x 2). The combined organic layers were washed with brine, dried over NaSO, filtered, and concentrated under reduced pressure to give a residue which was purified by flash column chromatography on silica gel (eluting with 0-30% ethyl acetate in petroleum ether) to give the title compound (2.10 g, 71%). 1 H NMR: (400MHz, CDCl3) δ8.59 (s, 1H), 8.51-8.40 (m, 1H), 3.94 (s, 2H), 2.67-2.57 (m, 3H).

[0460] Example 7 was synthesized in a manner similar to the method of Example 2 by substituting 2-(5-methylpyrazin-2-yl)acetonitrile for 2-(pyrazin-2-yl)acetonitrile and 4-((6-methylpyridin-2-yl)oxy)benzaldehyde for 4-((4-methylpyrimidin-2-yl)oxy)benzaldehyde. The residue was purified by preparative HPLC (FA conditions; column: Boston Prime C 18 150×30mm×5um; mobile phase: [water (FA)-ACN]; B%: 20%-40%, 2 minutes) to obtain the title compound (26 mg, 13%). LC-MS (ESI+): m / z 504.2 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ10.31(s,1H),9.27(s,1H),7.85(s,1H),7.79-7.70(m,3H),7.42-7.24(m,5H),7.12-6.98(m,3H), 6.76(d,J=8.0Hz,1H),6.45(dd,J=10.0,17.1Hz,2H),6.33-6.23(m,1H),5.79(d,J=10.5Hz,1H),2.35(s,3H),2.34(s,3H).

[0461] Example 8: 6-(4-acrylamidophenyl)-3-methyl-7-(4-((4-methylpyrimidin-2-yl)oxy)phenyl)pyrrolo[1,2-a]pyrazine-8-carboxamide

[0462]

[0463] Example 8

[0464] Example 8 was synthesized in a manner similar to the method of Example 2 by replacing 2-(5-methylpyrazin-2-yl)acetonitrile with 2-(pyrazin-2-yl)acetonitrile. The residue was purified by preparative HPLC (eluting with 20%-36% MeCN in H2O containing 0.1% FA) to give the title compound (40 mg, 38%). LC-MS (ESI+): m / z 505.2 [M+H] + . 1 HNMR(400MHz,DMSO-d6)δ10.31(s,1H),9.24(s,1H),8.46(d,J=8.0Hz,1H),7.81(s,1H) ,7.76(d,J=8.0Hz,2H),7.37-7.28(m,5H),7.16(s,2H),7.15(d,J=8.0Hz,1H),6.57(br s,1H),6.48-6.39(m,1H),6.28(dd,J1=16.0,J2=2.0Hz,1H),5.81-5.75(m,1H),2.41(s,3H),2.34(s,3H).

[0465] Example 9: (E)-6-(4-(4-(dimethylamino)but-2-enoylamino)phenyl)-3-methyl-7-(4-((6-methylpyridin-2-yl)oxy)phenyl)pyrrolo[1,2-a]pyrazine-8-carboxamide

[0466]

[0467] Step 1: (E)-4-(Dimethylamino)but-2-enoyl chloride hydrochloride

[0468] To a solution of (E)-4-(dimethylamino)but-2-enoic acid hydrochloride (200 mg, 1.212 mmol) in THF (2 mL) was added oxalyl chloride (0.1 mL, 1.212 mmol) and DMF (0.001 mL, 0.012 mmol) at 0° C. The mixture was stirred at 30° C. for 1.5 hours. The mixture was used directly in the next step.

[0469] Step 2: (E)-6-(4-(4-(dimethylamino)but-2-enoylamino)phenyl)-3-methyl-7-(4-((6-methylpyridin-2-yl)oxy)phenyl)pyrrolo[1,2-a]pyrazine-8-carboxamide

[0470] Intermediate 9.2 was synthesized in a manner analogous to the procedure for Intermediate 2.5 by substituting 2-(5-methylpyrazin-2-yl)acetonitrile for 2-(pyrazin-2-yl)acetonitrile and 4-((6-methylpyridin-2-yl)oxy)benzaldehyde for 4-((4-methylpyrimidin-2-yl)oxy)benzaldehyde.

[0471] To a solution of 6-(4-aminophenyl)-3-methyl-7-(4-((6-methylpyridin-2-yl)oxy)phenyl)pyrrolo[1,2-a]pyrazine-8-carboxamide (80 mg, 0.18 mmol) in DCM (3 mL) was added TEA (0.074 mL, 0.534 mmol) and (E)-4-(dimethylamino)but-2-enoyl chloride hydrochloride (0.44 mL, from step 1, 0.26 mmol) at 0 ° C. The mixture was stirred at 0 ° C for 3 hours. The mixture was then quenched with water (50 mL) and extracted with DCM (3×30 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue that was purified by preparative-HPLC (eluted with 25%-37% MeCN in H2O containing 0.1% FA) to give the title compound (6.5 mg, 7%). LC-MS (ESI+): m / z 561.4 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ10.20(s,1H),9.27(s,1H),7.83(s,1H),7.77-7.69(m,3H),7.3 3-7.22(m,4H),7.06(d,J=8.0Hz,2H),7.01(d,J=8.0Hz,1H),6.80-6.70(m,2H),6.46(br s, 1H), 6.28 (d, J = 16.0Hz, 1H), 3.06 (d, J = 8.0Hz, 2H), 2.34 (s, 6H), 2.18 (s, 6H).

[0472] Example 10: (E)-6-(6-(4-(dimethylamino)but-2-enoylamino)pyridin-3-yl)-3-methyl-7-(4-((6-methylpyridin-2-yl)oxy)phenyl)pyrrolo[1,2-a]pyrazine-8-carboxamide

[0473]

[0474] Step 1: (E)-6-(6-(4-bromobut-2-enoylamino)pyridin-3-yl)-3-methyl-7-(4-((6-methylpyridin-2-yl)oxy)phenyl)pyrrolo[1,2-a]pyrazine-8-carboxamide

[0475] Intermediate 10.1 was synthesized by following the procedure for Intermediate 2.5 by substituting 2-(5-methylpyrazin-2-yl)acetonitrile for 2-(pyrazin-2-yl)acetonitrile, 4-((6-methylpyridin-2-yl)oxy)benzaldehyde for 4-((4-methylpyrimidin-2-yl)oxy)benzaldehyde, and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine for 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline.

[0476] To a solution of 6-(6-aminopyridin-3-yl)-3-methyl-7-(4-((6-methylpyridin-2-yl)oxy)phenyl)pyrrolo[1,2-a]pyrazine-8-carboxamide (80 mg, 0.18 mmol) in DCM (2 mL) was added TEA (54 mg, 0.36 mmol) and (E)-4-bromobut-2-enoyl chloride (65 mg, 0.36 mmol) at 0 ° C. The mixture was stirred at room temperature for 18 hours. The mixture was quenched with water (10 mL) and extracted with DCM (3×10 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue, which was purified by preparative-TLC (DCM:MeOH=20:1) to give the title compound (12 mg, 0.02 mmol, 11%) as a yellow oil. LC-MS (ESI+): m / z 597.1 [M+H] + .

[0477] Step 2: (E)-6-(6-(4-(dimethylamino)but-2-enoylamino)pyridin-3-yl)-3-methyl-7-(4-((6-methylpyridin-2-yl)oxy)phenyl)pyrrolo[1,2-a]pyrazine-8-carboxamide

[0478] To a solution of (E)-6-(6-(4-bromobut-2-enoylamino)pyridin-3-yl)-3-methyl-7-(4-((6-methylpyridin-2-yl)oxy)phenyl)pyrrolo[1,2-a]pyrazine-8-carboxamide (12 mg, 0.02 mmol) in MeCN (2 mL) was added KCO (3 mg, 0.02 mmol) and dimethylamine hydrochloride (0.1 mL, 0.2 M in MeCN). The mixture was stirred at 60 ° C for 2 hours. After cooling to room temperature, the mixture was quenched with water (10 mL) and extracted with DCM (3×10 mL). The combined organic layers were washed with brine, dried over NaSO, filtered, and concentrated under reduced pressure to give a residue that was purified by preparative-HPLC (eluting with 22%-35% MeCN in H O containing 0.1% FA) to give the title compound (0.6 mg, 5%). LC-MS (ESI+): m / z 562.2 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ10.74(s,1H),9.30(s,1H),8.43-8.22(m,3H),8.19(s,1 H),7.94(s,1H),7.82(dd,J=8.0,2.0Hz,1H),7.74(t,J=8.0Hz,1H),7.30(d,J=8 .0Hz,2H),7.08(d,J=8.0Hz,2H),7.02(d,J=8.0Hz,1H),6.90-6.65(m,2H),6.45 (d, J=16.0Hz, 1H), 3.05 (d, J=8.0Hz, 2H), 2.36 (s, 3H), 2.33 (s, 3H), 2.17 (s, 6H).

[0479] Example 11: 6-(4-acrylamidophenyl)-3-(hydroxymethyl)-7-(4-((6-methylpyridin-2-yl)oxy)phenyl)pyrrolo[1,2-a]pyrazine-8-carboxamide

[0480]

[0481] Preparation of methyl 5-(cyanomethyl)pyrazine-2-carboxylate (Intermediate 11.2)

[0482]

[0483] Intermediate 11.1 was synthesized in a manner analogous to the procedure for Intermediate 1.1 by substituting methyl 5-chloropyrazine-2-carboxylate for 2-chloropyrazine.

[0484] To a mixture of methyl 5-(2-(tert-butoxy)-1-cyano-2-oxoethyl)pyrazine-2-carboxylate (9.2 g, 33.18 mmol) in toluene (200 mL) was added p-TsOH (5.71 g, 33.18 mmol). The reaction mixture was stirred at 120° C. for 18 hours. After cooling to room temperature, the mixture was slowly poured into water (300 mL) and extracted with EtOAc (3×100 mL). The combined organic layers were washed with brine, dried over Na 2 SO 4 , filtered, and concentrated under reduced pressure to give a residue, which was purified by flash column chromatography on silica gel (eluted with PE:EtOAc=1:1) to give Intermediate 11.2 (900 mg, 15%). LC-MS (ESI+): m / z 178.1 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ9.20 (d, J = 1.3Hz, 1H), 8.81 (s, 1H), 4.48 (s, 2H), 3.94 (s, 3H).

[0485] Step 1: 6-(4-aminophenyl)-3-(hydroxymethyl)-7-(4-((6-methylpyridin-2-yl)oxy)phenyl)pyrrolo[1,2-a]pyrazine-8-carboxamide

[0486] Intermediate 11.3 was synthesized in a manner analogous to the procedure for Intermediate 2.5 by substituting methyl 5-(cyanomethyl)pyrazine-2-carboxylate for 2-(pyrazin-2-yl)acetonitrile and 4-((6-methylpyridin-2-yl)oxy)benzaldehyde for 4-((4-methylpyrimidin-2-yl)oxy)benzaldehyde.

[0487] To a solution of methyl 6-(4-aminophenyl)-8-carbamoyl-7-(4-((6-methylpyridin-2-yl)oxy)phenyl)pyrrolo[1,2-a]pyrazine-3-carboxylate (150 mg, 0.30 mmol) in DCM (5 mL) and MeOH (5 mL) was added NaBH4 (57.49 mg, 1.52 mmol) and CaCl2 (3.37 mg, 0.03 mmol) at 0 ° C. The mixture was stirred at 25 ° C for 5 hours. The mixture was then quenched with water (20 mL) and extracted with DCM (3 × 20 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue, which was purified by flash column chromatography on silica gel (eluting with MeOH:DCM=20:1) to give the title compound (15 mg, 10%) as a yellow oil. LC-MS (ESI+): m / z 466.2 [M+H] + .

[0488] Step 2: 6-(4-acrylamidophenyl)-3-(hydroxymethyl)-7-(4-((6-methylpyridin-2-yl)oxy)phenyl)pyrrolo[1,2-a]pyrazine-8-carboxamide

[0489] To a solution of 6-(4-aminophenyl)-3-(hydroxymethyl)-7-(4-((6-methylpyridin-2-yl)oxy)phenyl)pyrrolo[1,2-a]pyrazine-8-carboxamide (15 mg, 0.03 mmol) in acetone (5 mL) was added KCO (13 mg, 0.10 mmol, 0.5 M in water) and acryloyl chloride (0.1 mL, 0.3 M in acetone) at 0 ° C. The mixture was stirred at 0 ° C for 30 minutes. The mixture was then quenched with water (10 mL) and extracted with DCM (3×10 mL). The combined organic layers were washed with brine, dried over NaSO, filtered, and concentrated under reduced pressure to give a residue, which was purified by preparative HPLC (eluted with 35%-40% MeCN in H O containing 0.1% FA) to give the title compound (1.3 mg, 7%). LC-MS (ESI+): m / z 520.3 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ10.33(s,1H),9.27(s,1H),7.89(s,1H),7.79-7.71(m,3H),7.40- 7.25(m,5H),7.07(d,J=8.4Hz,2H),7.01(d,J=7.2Hz,1H),6.76(d,J=8.0Hz,1H),6.55(br s,1H),6.45(dd,J1=16.0,J 2＝ 12.0Hz,1H),6.28(dd,J1=16.0,J 2＝ 2.0Hz,1H),5.78(dd,J1=10.0,J 2＝ 2.0Hz,1H),5.40(br s,1H),4.53(s,2H),2.34(s,3H).

[0490] Example 12: 6-(4-acrylamidophenyl)-1-(methylamino)-7-(4-((6-methylpyridin-2-yl)oxy)phenyl)pyrrolo[1,2-a]pyrazine-8-carboxamide

[0491]

[0492] Step 1: tert-Butyl 2-(3-chloropyrazin-2-yl)-2-cyanoacetate

[0493] To a solution of 2,3-dichloropyrazine (10.0 g, 67.1 mmol) in DMF (100 mL) was added Cs2CO3 (43.7 g, 134.3 mmol). 2-tert-Butyl cyanoacetate (12.3 g, 87.3 mmol, 12.5 mL) was then added. The reaction mixture was stirred at 80°C for 4 hours. After cooling to room temperature, 300 mL of water was added to the mixture, and the pH of the mixture was adjusted to 3-5 with 1N HCl (aqueous solution). The mixture was extracted with EtOAc (200 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue, which was purified by flash column chromatography on silica gel (eluted with 0-50% ethyl acetate in petroleum ether) to give the title compound (15.0 g, 88%) as a yellow oil.

[0494] Step 2: 2-(3-chloropyrazin-2-yl)acetonitrile

[0495] To a solution of tert-butyl 2-(3-chloropyrazin-2-yl)-2-cyanoacetate (15.0 g, 59.1 mmol) in toluene (170 mL) was added p-TsOH (815 mg, 4.73 mmol). The reaction mixture was stirred at 120° C. for 12 hours. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was purified by flash column chromatography on silica gel (eluting with 0-50% ethyl acetate in petroleum ether) to afford the title compound (6.0 g, 66%) as a yellow oil. 1 H NMR (400MHz, DMSO-d6) δ 8.70 (d, J = 2.5 Hz, 1H), 8.54 (d, J = 2.5 Hz, 1H), 4.47 (s, 2H).

[0496] Step 3: 6-amino-1-chloro-7-(4-((6-methylpyridin-2-yl)oxy)phenyl)pyrrolo[1,2-a]pyrazine-8-carbonitrile

[0497] To a mixture of 4-((6-methylpyridin-2-yl)oxy)benzaldehyde (694 mg, 3.26 mmol) and 2-(3-chloropyrazin-2-yl)acetonitrile (500 mg, 3.26 mmol) in MeOH (10 mL) was added DBU (1.49 g, 9.77 mmol, 1.47 mL) and acetyl cyanide (225 mg, 3.26 mmol) at 25 ° C. The reaction mixture was purged with N2 three times, stirred, and heated at 100 ° C under microwave irradiation for 20 minutes. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure to give a residue, which was purified by flash column chromatography on silica gel (eluted with 0-80% ethyl acetate in petroleum ether) to give the title compound (600 mg, 49%). LC-MS (ESI+): m / z 376.0 [M+H] + .

[0498] Step 4: 6-Bromo-1-chloro-7-(4-((6-methylpyridin-2-yl)oxy)phenyl)pyrrolo[1,2-a]pyrazine-8-carbonitrile

[0499] To a solution of 6-amino-1-chloro-7-(4-((6-methylpyridin-2-yl)oxy)phenyl)pyrrolo[1,2-a]pyrazine-8-carbonitrile (300 mg, 798.3 μmol) in HBr / AcOH (10 mL) was added CuBr2 (232 mg, 1.04 mmol, 48.6 μL) at 0°C. The mixture was stirred for 20 minutes. A solution of NaNO2 (275 mg, 3.99 mmol) in H2O (4 mL) was then added. The reaction mixture was stirred at 0°C for 0.5 hours. The pH of the solution was then adjusted to 7 with Na2CO3 (aq.). After extraction with ethyl acetate (20 mL x 3), the combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue, which was purified by flash column chromatography on silica gel (eluting with 0-2% MeOH in DCM) to give the title compound (300 mg, 86%). LC-MS (ESI+): m / z 438.8 [M+H] + .

[0500] Step 5: 6-Bromo-1-(methylamino)-7-(4-((6-methylpyridin-2-yl)oxy)phenyl)pyrrolo[1,2-a]pyrazine-8-carbonitrile

[0501] To a mixture of 6-bromo-1-chloro-7-(4-((6-methylpyridin-2-yl)oxy)phenyl)pyrrolo[1,2-a]pyrazine-8-carbonitrile (300 mg, 682.3 μmol) and methylamine hydrochloride (138 mg, 2.05 mmol) in THF (3 mL) was added DBU (519 mg, 3.41 mmol) at 25 °C. The reaction mixture was purged with N2 three times, stirred, and heated at 120 °C under microwave irradiation for 3 hours. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure to give a residue, which was purified by flash column chromatography on silica gel (eluted with 0-30% ethyl acetate in petroleum ether) to give the title compound (210 mg, 71%). LC-MS (ESI+): m / z 433.8 [M+H] + .

[0502] Step 6: 6-Bromo-1-(methylamino)-7-(4-((6-methylpyridin-2-yl)oxy)phenyl)pyrrolo[1,2-a]pyrazine-8-carboxamide

[0503] A mixture of 6-bromo-1-(methylamino)-7-(4-((6-methylpyridin-2-yl)oxy)phenyl)pyrrolo[1,2-a]pyrazine-8-carbonitrile (250 mg, 575.7 μmol) in H2SO4 (5.52 g, 56.3 mmol, 3 mL) was stirred at 30°C for 16 hours. The mixture was then slowly poured into water (100 mL), adjusted to pH ~7 with Na2CO3, and extracted with EtOAc (3×100 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give the title compound (260 mg). LC-MS (ESI+): m / z 451.9 [M+H] + .

[0504] Step 7: 6-(4-acrylamidophenyl)-1-(methylamino)-7-(4-((6-methylpyridin-2-yl)oxy)phenyl)pyrrolo[1,2-a]pyrazine-8-carboxamide

[0505] To a solution of 6-bromo-1-(methylamino)-7-(4-((6-methylpyridin-2-yl)oxy)phenyl)pyrrolo[1,2-a]pyrazine-8-carboxamide (140 mg, 309.5 μmol) and N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acrylamide (169 mg, 619.1 μmol) in dioxane (3 mL) and H O (1 mL) was added K CO (128 mg, 928.6 μmol) and Pd-118 (20 mg, 31.0 μmol). The mixture was degassed, purged with N 3 times, and stirred at 90° C. under N atmosphere for 2 hours. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure to give a residue, which was purified by reverse phase HPLC (column: Boston Prime C18 150×30 mm×5 μm; mobile phase: [water (FA)-ACN]; B%: 20%-40%, 9 minutes) to give the title compound (23 mg, 15%). LC-MS (ESI+): m / z 519.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ10.35-10.18(m,1H),9.13-8.82(m,1H),7.78-7.68(m,3H),7.62(br s,1H),7.28-7.15(m,6H),7.11-6.95(m,3H),6.74(d,J=8.1Hz,1H),6.50-6.22(m,3H),5.82-5.73(m,1H),2.98(d,J=4.6Hz,3H),2.34(s,3H).

[0506] Example 13: 6-(4-acrylamidophenyl)-2-methyl-7-(4-((6-methylpyridin-2-yl)oxy)phenyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-8-carboxamide

[0507]

[0508] Step 1: 1-(tert-Butyl)-3-methyl 4-(4-nitrobenzoyl)piperazine 1-,3-dicarboxylate

[0509] To a solution of 1-(tert-butyl) 3-methyl piperazine-1,3-dicarboxylate (17.4 g, 71.23 mmol) in DCM (600 mL) was added TEA (21.8 mL, 156.69 mmol). The mixture was stirred at 0 ° C for 30 minutes. 4-Nitrobenzoyl chloride (14.54 g, in 85 mL DCM, 78.35 mmol) was added and the mixture was stirred at room temperature for 3 hours. The mixture was quenched with water (500 mL) and extracted with DCM (3×100 mL). The combined organic layers were dried over Na2SO4, filtered, and evaporated to give the title compound (27 g), which was used directly in the next step. LC-MS (ESI+): m / z 338.2 (M+H-56) + .

[0510] Step 2: Sodium 4-(tert-butoxycarbonyl)-1-(4-nitrobenzoyl)piperazine-2-carboxylate

[0511] To a solution of 1-(tert-butyl)-3-methyl-4-(4-nitrobenzoyl)piperazine-1-,3-dicarboxylate (27 g) in MeOH (300 mL) was slowly added NaOH solution (2N, 41 mL, 82.00 mmol) at 0°C. The mixture was stirred at room temperature for 18 hours. The mixture was then evaporated and dried in vacuo to give the title compound (30 g), which was used directly in the next step. LC-MS (ESI+): m / z 378.1 (M-Na) - .

[0512] Step 3: tert-Butyl 8-cyano-6-(4-nitrophenyl)-3,4-dihydropyrrolo[1,2-a]pyrazine-2(1H)-carboxylate

[0513] To a mixture of sodium 4-(tert-butoxycarbonyl)-1-(4-nitrobenzoyl)piperazine-2-carboxylate (15 g) in DCM (300 mL) was added 4-toluenesulfonyl chloride (7.84 g, 41.11 mmol) at 0°C. After stirring at room temperature for 1 hour, 2-chloroacrylonitrile (3.0 mL, 37.37 mmol) and TEA (11.94 mL, 85.96 mmol) were added sequentially. The mixture was stirred at room temperature for 18 hours. The mixture was then quenched with water (400 mL) and extracted with DCM (3×100 mL). The combined organic layers were washed with brine, dried over Na 2 SO 4 , filtered, and concentrated under reduced pressure to give a residue, which was purified by flash column chromatography on silica gel (eluted with PE:EtOAc=1:1) to give the title compound (3.7 g, 28% total yield over 3 steps). LC-MS (ESI+): m / z 369.1 [M+H] + .

[0514] Step 4: tert-Butyl 7-bromo-8-cyano-6-(4-nitrophenyl)-3,4-dihydropyrrolo[1,2-a]pyrazine-2(1H)-carboxylate

[0515] To a solution of tert-butyl 8-cyano-6-(4-nitrophenyl)-3,4-dihydropyrrolo[1,2-a]pyrazine-2(1H)-carboxylate (3.0 g, 8.14 mmol) in DCM (30 mL) was added NBS (1.59 g, 8.958 mmol) at room temperature. The mixture was stirred at room temperature for 2 hours. The mixture was then diluted with DCM (100 mL) and washed with saturated NaHCO3 solution (2×100 mL). The organic layer was dried over Na2SO4, filtered, and evaporated to give the title compound (3.6 g, 82%). LC-MS (ESI+): m / z 469.0 (M+Na) + .

[0516] Step 5: tert-Butyl 8-cyano-7-(4-((6-methylpyridin-2-yl)oxy)phenyl)-6-(4-nitrophenyl)-3,4-dihydropyrrolo[1,2-a]pyrazine-2(1H)-carboxylate

[0517] To a solution of tert-butyl 7-bromo-8-cyano-6-(4-nitrophenyl)-3,4-dihydropyrrolo[1,2-a]pyrazine-2(1H)-carboxylate (4.27 g, 9.54 mmol) and 2-methyl-6-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)pyridine (3.24 g, 10.42 mmol) in 1,4-dioxane (85 mL) and water (17 mL) was added KCO (3.60 g, 26.06 mmol) and XPhos Pd G (0.38 g, 0.47 mmol). The mixture was stirred at 100 ° C. under N for 1 hour. After cooling to room temperature, the mixture was slowly poured into water (100 mL) and extracted with EtOAc (3×100 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue, which was purified by flash column chromatography on silica gel (eluted with DCM:MeOH = 20:1) to give the title compound (1.4 g, 27%). LC-MS (ESI+): m / z 552.1 [M+H] + .

[0518] Step 6: 7-(4-((6-methylpyridin-2-yl)oxy)phenyl)-6-(4-nitrophenyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-8-carbonitrile

[0519] To a solution of tert-butyl 8-cyano-7-(4-((6-methylpyridin-2-yl)oxy)phenyl)-6-(4-nitrophenyl)-3,4-dihydropyrrolo[1,2-a]pyrazine-2(1H)-carboxylate (0.7 g, 1.27 mmol) in DCM (7 mL) was added TFA (3.5 mL) at 0°C. The mixture was stirred at room temperature for 2 hours. The mixture was then slowly poured into saturated NaHCO3 solution (200 mL) and extracted with EtOAc (3×100 mL). The combined organic layers were dried over Na2SO4, filtered, and evaporated to give the title compound (570 mg, 99%). LC-MS (ESI+): m / z 452.2 [M+H] + .

[0520] Step 7: 2-Methyl-7-(4-((6-methylpyridin-2-yl)oxy)phenyl)-6-(4-nitrophenyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-8-carbonitrile

[0521] To a solution of 7-(4-((6-methylpyridin-2-yl)oxy)phenyl)-6-(4-nitrophenyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-8-carbonitrile (525 mg, 1.16 mmol) in DMF (12 mL) was added KCO (193 mg, 1.39 mmol) and MeI (2.3 mL, 1.16 mmol). The mixture was stirred at 30 ° C for 1.5 hours. The mixture was then poured into water (20 mL) and extracted with EtOAc (3×20 mL). The combined organic layers were washed with saturated NH4Cl solution (3×50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue, which was purified by flash column chromatography on silica gel (eluted with DCM:MeOH=50:1) to give the title compound (300 mg, 55%). LC-MS (ESI+): m / z 466.2 [M+H] + .

[0522] Step 8: 6-(4-aminophenyl)-2-methyl-7-(4-((6-methylpyridin-2-yl)oxy)phenyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-8-carbonitrile

[0523] To a solution of 2-methyl-7-(4-((6-methylpyridin-2-yl)oxy)phenyl)-6-(4-nitrophenyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-8-carbonitrile (200 mg, 0.43 mmol) in EtOH (18 mL) and water (4.5 mL) was added NH4Cl (115 mg, 2.15 mmol) and iron (120 mg, 2.15 mmol). The mixture was stirred at 70°C for 5 hours. The mixture was then filtered at 70°C. The filtrate was diluted with water (50 mL) and extracted with DCM (3×50 mL). The combined organic layers were dried over Na2SO4, filtered, and evaporated to give the title compound (120 mg, 63%). LC-MS (ESI+): m / z 436.1 [M+H] + .

[0524] Step 9: 6-(4-aminophenyl)-2-methyl-7-(4-((6-methylpyridin-2-yl)oxy)phenyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-8-carboxamide

[0525] A mixture of 6-(4-aminophenyl)-2-methyl-7-(4-((6-methylpyridin-2-yl)oxy)phenyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-8-carbonitrile (120 mg, 0.27 mmol) and concentrated H2SO4 (10 mL) was stirred at 30°C for 18 hours. The mixture was then slowly poured into water (100 mL), adjusted to pH~8 with 6N NaOH solution, and extracted with DCM (3×100 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue that was purified by preparative-TLC (DCM:MeOH=20:1) to give the title compound (70 mg, 56%). LC-MS (ESI+): m / z 454.2 [M+H] + .

[0526] Step 10: 6-(4-Acrylamidophenyl)-2-methyl-7-(4-((6-methylpyridin-2-yl)oxy)phenyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-8-carboxamide

[0527] To a solution of 6-(4-aminophenyl)-2-methyl-7-(4-((6-methylpyridin-2-yl)oxy)phenyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-8-carboxamide (70 mg, 0.154 mmol) in acetone (5 mL) was added KCO (0.92 mL, 0.46 mmol, 0.5 mol / L in water) and acryloyl chloride (0.37 mL, 0.18 mmol, 0.5 mol / L in acetone) at 0 ° C. The mixture was stirred at room temperature for 2 hours. The mixture was quenched with water (50 mL) and extracted with EtOAc (3×20 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue which was purified by preparative HPLC (eluting with 20%-25% MeCN in H2O containing 0.1% FA) to give the title compound (22 mg, 28%). LC-MS (ESI+): m / z 508.2 [M+H] + . 1 H NMR (400MHz, CDCl3) δ7.57(t,J=8.0Hz,1H),7.55-7.37(m,3H),7.19(d,J=8.0Hz,2H),7.09(d,J=8.0Hz,2H),7.01(d,J=8.0Hz,2H) ,6.89(d,J=8.0Hz,1H),6.61(d,J=8.0Hz,1H),6.42(d,J=16.0Hz,1H),6.25(dd,J=16.0,8.0Hz,1H),5.77(d,J=8.0Hz,1H),5.26(br s,2H),4.20(br s,2H),3.94(br s,2H),2.89(br s,2H),2.60(s,3H),2.44(s,3H).

[0528] Example 14: 6-(1-acryloyldihydroindolin-5-yl)-7-(4-((6-methylpyridin-2-yl)oxy)phenyl)pyrrolo[1,2-a]pyrazine-8-carboxamide

[0529]

[0530] Step 1: 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indoline

[0531] To a solution of 5-bromoindoline (2.0 g, 10.1 mmol) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolan (3.85 g, 15.1 mmol) in dioxane (20 mL) were added KOAc (2.97 g, 30.3 mmol) and Pd(dppf)Cl (0.74 g, 1.01 mmol) sequentially. The reaction mixture was stirred at 80°C under an N atmosphere for 16 hours. After cooling to room temperature, the mixture was diluted with H2O (20 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic layers were concentrated under reduced pressure to give a residue, which was purified by flash column chromatography on silica gel (eluting with 0-30% ethyl acetate in petroleum ether) to give the title compound (2.0 g, 81%). LC-MS (ESI+): m / z 245.8 [M+H] + .

[0532] Step 2: 1-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indolin-1-yl)prop-2-en-1-one

[0533] To a solution of 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indoline (1.9 g, 7.75 mmol) in THF (20 mL) was added TEA (2.16 mL, 15.5 mmol). A solution of prop-2-enoyl chloride (0.84 g, 9.30 mmol) in THF (5 mL) was added dropwise to the mixture. The solution was then stirred at 0°C for 0.5 hours. The mixture was diluted with H2O (20 mL) and extracted with ethyl acetate (20 mL×3). The combined organic layers were concentrated under reduced pressure to give a residue, which was purified by flash column chromatography on silica gel (eluted with 0-30% ethyl acetate in petroleum ether) to give the title compound (1.0 g, 43%). LC-MS (ESI+): m / z 300.2 [M+H] + .

[0534] Step 3: 6-(1-acryloyldihydroindolin-5-yl)-7-(4-((6-methylpyridin-2-yl)oxy)phenyl)pyrrolo[1,2-a]pyrazine-8-carboxamide

[0535] To a solution of 6-bromo-7-[4-[(6-methyl-2-pyridyl)oxy]phenyl]pyrrolo[1,2-a]pyrazine-8-carboxamide (150 mg, 354.4 μmol) and 1-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indolin-1-yl]prop-2-en-1-one (159.0 mg, 531.6 μmol) in dioxane (6 mL) and H2O (2 mL) were added K2CO3 (123 mg, 886.0 μmol) and Pd-118 (23 mg, 35.4 μmol) in sequence. The reaction mixture was stirred at 90 ° C. under N2 atmosphere for 2 hours. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure to give a residue, which was purified by preparative HPLC (column: YMC-Triart Prep C 18 150×40mm×7um; mobile phase: [water (FA)-ACN]; B%: 13%-53%, 9 minutes) to obtain the title compound (44 mg, 24%). LC-MS (ESI+): m / z 516.1 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ9.31(s,1H),8.18(d,J=8.3Hz,1H),8.06-7.99(m,1H),7.80-7.70(m,1H),7.67(d,J=4.9Hz,1H),7.40(br s,1H),7.31(d,J=8.6Hz,2H),7.26(s,1H),7.13(dd,J=1.5,8.4Hz,1H),7.08(d,J=8.6Hz,2H),7.02(d,J=7.4Hz,1H),6.85-6.70(m,2H),6.61(br s,1H),6.32(dd,J=1.6,16.7Hz,1H),5.89-5.79(m,1H),4.25(t,J=8.3Hz,2H),3.17(t,J=8.4Hz,2H),2.34(s,3H).

[0536] Example 15: 7-(4-acrylamidophenyl)-6-(4-((6-methylpyridin-2-yl)oxy)phenyl)pyrrolo[1,2-c]pyrimidine-5-carboxamide

[0537]

[0538] Step 1: N,N-dimethyl-2-(pyrimidin-4-yl)ethen-1-amine

[0539] To a solution of 4-methylpyrimidine (8.0 g, 85.0 mmol) in DMF (39.2 mL) was added DMF-DMA (30.4 g, 255.0 mmol, 33.9 mL). The reaction mixture was stirred at 140° C. for 12 hours. The mixture was then concentrated in vacuo to afford the title compound (15.0 g) as a brown liquid.

[0540] Step 2: 2-(pyrimidin-4-yl)acetonitrile

[0541] To a solution of N,N-dimethyl-2-(pyrimidin-4-yl)ethene-1-amine (8.0 g, 53.6 mmol) in H2O (80 mL) was added hydroxylamine-O-sulfonic acid (15.2 g, 134.1 mmol). The reaction mixture was stirred at 50°C for 0.5 hours. After cooling to room temperature, the pH of the reaction solution was adjusted to 7 with aqueous sodium carbonate. After extraction with ethyl acetate (200 mL x 3), the combined organic layers were washed with brine (200 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue, which was purified by flash column chromatography on silica gel (eluted with 0-30% ethyl acetate in petroleum ether) to give the title compound (2.0 g, 31%). 1 HNMR (400MHz, DMSO-d6) δ9.19 (d, J = 0.8Hz, 1H), 8.83 (d, J = 5.0Hz, 1H), 7.61-7.49 (m, 1H), 4.40-4.28 (m, 2H).

[0542] Step 3: 7-amino-6-(4-((6-methylpyridin-2-yl)oxy)phenyl)pyrrolo[1,2-c]pyrimidine-5-carbonitrile

[0543] To a mixture of 2-(pyrimidin-4-yl)acetonitrile (400 mg, 3.36 mmol) and 4-((6-methylpyridin-2-yl)oxy)benzaldehyde (716.0 mg, 3.36 mmol) in MeOH (12 mL) was added DBU (1.53 g, 10.1 mmol) and acetyl cyanide (231.9 mg, 3.36 mmol) at 25 ° C. The reaction mixture was purged with N2 three times, stirred, and heated at 100 ° C under microwave irradiation for 20 minutes. After cooling to room temperature, water (50 mL) was added to the reaction mixture. After extraction with ethyl acetate (50 mL×3), the combined organic layers were washed with brine (60 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue, which was purified by flash column chromatography on silica gel (eluted with 0-3% MeOH in DCM) to give the title compound (410 mg, 36%). LC-MS (ESI+): m / z 342.1 [M+H] + .

[0544] Step 4: 7-iodo-6-(4-((6-methylpyridin-2-yl)oxy)phenyl)pyrrolo[1,2-c]pyrimidine-5-carbonitrile

[0545] To a solution of 7-amino-6-(4-((6-methylpyridin-2-yl)oxy)phenyl)pyrrolo[1,2-c]pyrimidine-5-carbonitrile (280 mg, 820.2 μmol) and CHCl (3.36 g, 12.6 mmol, 1.01 mL) in CHCl (5 mL) stirred at 70°C was added isoamyl nitrite (384 mg, 3.28 mmol) portionwise over 30 minutes while maintaining the internal temperature at 70°C. The reaction mixture was stirred at 70°C for 4 hours. After cooling to room temperature, the mixture was concentrated under reduced pressure to give a residue that was purified by flash column chromatography on silica gel (eluting with 0-20% ethyl acetate in petroleum ether) to give the title compound (200 mg, 54%). LC-MS (ESI+): m / z 453.0 [M+H] + .

[0546] Step 5: N-(4-(5-cyano-6-(4-((6-methylpyridin-2-yl)oxy)phenyl)pyrrolo[1,2-c]pyrimidin-7-yl)phenyl)acrylamide

[0547] To a mixture of N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acrylamide (181 mg, 663.4 μmol) and 7-iodo-6-(4-((6-methylpyridin-2-yl)oxy)phenyl)pyrrolo[1,2-c]pyrimidine-5-carbonitrile (200 mg, 442.2 μmol) in dioxane (3 mL) and H2O (1 mL) was added K2CO3 (183 mg, 1.33 mmol) and Pd-118 (29 mg, 44.2 μmol) in N2. The reaction mixture was stirred at 90°C under N2 for 2 hours. After cooling to room temperature, the mixture was concentrated under reduced pressure to give a residue, which was purified by flash column chromatography on silica gel (eluting with 0-20% ethyl acetate in petroleum ether) to give the title compound (90 mg, 43%). LC-MS (ESI+): m / z 472.1 [M+H] + .

[0548] Step 6: 7-(4-Acrylamidophenyl)-6-(4-((6-methylpyridin-2-yl)oxy)phenyl)pyrrolo[1,2-c]pyrimidine-5-carboxamide

[0549] A mixture of N-(4-(5-cyano-6-(4-((6-methylpyridin-2-yl)oxy)phenyl)pyrrolo[1,2-c]pyrimidin-7-yl)phenyl)acrylamide (90 mg, 190.9 μmol) in concentrated H2SO4 (3 mL) was stirred at 30°C for 16 hours. The pH of the reaction mixture was then adjusted to 7 with aqueous sodium carbonate. After extraction with ethyl acetate (20 mL x 3), the combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue, which was purified by preparative HPLC (column: Boston Green ODS 150 x 30 mm x 5 μm; mobile phase: [water (NH3H2O ​​+ NH4HCO3)-ACN]; B%: 25%-55%, 10 minutes) to give the title compound (21 mg, 22%). LC-MS (ESI+): m / z 490.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ10.29(s,1H),8.87(d,J=1.3Hz,1H),7.94(d,J=6.4Hz,1H),7.78-7.65(m,4H),7.38-7.16(m, 5H),7.11-6.99(m,3H),6.77(d,J=8.1Hz,1H),6.50-6.40(m,1H),6.32-6.12(m,2H),5.82-5.71(m,1H),2.34(s,3H).

[0550] Example 16: 6-(4-acrylamidophenyl)-7-(4-(((1-fluorocyclobutyl)methyl)carbamoyl)phenyl)pyrrolo[1,2-a]pyrazine-8-carboxamide

[0551]

[0552] Step 1: 4-(6-Bromo-8-cyanopyrrolo[1,2-a]pyrazin-7-yl)benzoic acid

[0553] Intermediate 16.1 was synthesized in analogy to the procedure for Intermediate 2.2 by substituting methyl 4-formylbenzoate for 4-((4-methylpyrimidin-2-yl)oxy)benzaldehyde.

[0554] To a solution of methyl 4-(6-bromo-8-cyanopyrrolo[1,2-a]pyrazin-7-yl)benzoate (Intermediate 16.1) (480 mg, 1.35 mmol) in THF (10.0 mL) was added LiOH·H2O (2M in water, 3.37 mL) at 25°C. The reaction mixture was stirred at 25°C for 12 hours. The mixture was then extracted with DCM (20.0 mL). The pH of the aqueous phase was adjusted to 7 with 1N HCl. After extraction with DCM (20.0 mL×3), the combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to give the title compound (300 mg, 43%). LC-MS (ESI+): m / z 341.8 [M+H] + .

[0555] Step 2: 4-(6-Bromo-8-cyanopyrrolo[1,2-a]pyrazin-7-yl)-N-((1-fluorocyclobutyl)methyl)benzamide

[0556] To a solution of 4-(6-bromo-8-cyanopyrrolo[1,2-a]pyrazin-7-yl)benzoic acid (370 mg, 1.08 mmol) in DCM (10 mL) was added DIPEA (698 mg, 5.41 mmol), (1-fluorocyclobutyl)methylamine hydrochloride (166 mg, 1.19 mmol) and HATU (616 mg, 1.62 mmol) at 25°C. The reaction mixture was stirred at 25°C for 12 hours. The mixture was then diluted with H2O (50 mL) and extracted with DCM (10 mL×3). The combined organic layers were washed with brine (60 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue, which was purified by flash column chromatography on silica gel (eluted with 1-50% EtOAc in petroleum ether) to give the title compound (500 mg). LC-MS (ESI+): m / z 426.8 [M+H] + .

[0557] Step 3: 6-Bromo-7-(4-(((1-fluorocyclobutyl)methyl)carbamoyl)phenyl)pyrrolo[1,2-a]pyrazine-8-carboxamide

[0558] To a solution of 4-(6-bromo-8-cyanopyrrolo[1,2-a]pyrazin-7-yl)-N-((1-fluorocyclobutyl)methyl)benzamide (100 mg, 234.0 μmol) in DMSO (25.0 mL) was added K2CO3 (113 mg, 819.0 μmol). H2O2 (1.09 mL, 11.3 mmol, 30% purity) was added dropwise at 0°C. The reaction mixture was stirred at 25°C for 5 hours. The mixture was then quenched by the addition of aqueous Na2SO3 (40.0 mL). After extraction with DCM (30.0 mL×3), the combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to give the title compound (100 mg) as a yellow oil. LC-MS (ESI+): m / z 444.9 [M+H] + .

[0559] Step 4: 6-(4-Acrylamidophenyl)-7-(4-(((1-fluorocyclobutyl)methyl)carbamoyl)phenyl)pyrrolo[1,2-a]pyrazine-8-carboxamide

[0560] To a mixture of 6-bromo-7-(4-(((1-fluorocyclobutyl)methyl)carbamoyl)phenyl)pyrrolo[1,2-a]pyrazine-8-carboxamide (100 mg, 224.0 μmol) in dioxane (4.0 mL) and H2O (1.0 mL) was added N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acrylamide (122 mg, 449 μmol), Na2CO3 (71 mg, 673.0 μmol) and Pd(PPh3)4 (26 mg, 22.4 μmol) at 25°C under N2. The reaction mixture was stirred at 70°C under N2 for 12 hours. After cooling to room temperature, the reaction mixture was filtered and concentrated under reduced pressure to give a residue, which was purified by preparative HPLC (column: Phenomenex luna C18 150×25 mm×10 um; mobile phase: [water (HCl)-MeOH]; B%: 16%-46%, 10 minutes) to give the title compound (20 mg, 17%). LC-MS (ESI+): m / z 512.3 [M+H] + . 1H NMR (400MHz, DMSO-d6) δ10.30 (s, 1H), 9.26 (d, J = 1.3Hz, 1H), 8.71 (m, 1H), 8.04-7.97 (m, 1H), 7.85-7.62 (m, 5H), 7.41-7.25 (m, 5H), 6.82-6.71 (m,1H),6.48-6.39(m,1H),6.31-6.23(m,1H),5.81-5.73(m,1H),3.68 -3.56(m,2H),2.23-2.10(m,4H),1.81-1.70(m,1H),1.58-1.42(m,1H).

[0561] Preparation of 6-iodo-3-methoxy-7-(4-((6-methylpyridin-2-yl)oxy)phenyl)pyrrolo[1,2-a]pyrazine-8-carbonitrile (Intermediate 17.6)

[0562]

[0563] Step 1: (5-methoxypyrazin-2-yl)methanol

[0564] To a solution of (5-chloropyrazin-2-yl)methanol (4.0 g, 27.67 mmol) in methanol (120 mL) was added sodium methoxide (14.95 g, 276.70 mmol) portionwise at 25°C over 10 minutes. The reaction mixture was stirred at 25°C for 18 hours. Water (50 mL) was then added to the reaction mixture. After extraction with ethyl acetate (50 mL x 3), the combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue which was purified by flash column chromatography on silica gel (eluting with 0%-25% ethyl acetate in petroleum ether) to give the title compound (2.6 g, 67%). LC-MS (ESI+): m / z 141.0 [M+H] + .

[0565] Step 2: 2-(Chloromethyl)-5-methoxypyrazine

[0566] To a solution of (5-methoxypyrazin-2-yl)methanol (2.6 g, 18.55 mmol) in dichloromethane (52 mL) was slowly added sulfenyl chloride (6.73 mL, 92.76 mmol) at 25°C. The reaction mixture was stirred at 25°C for 18 hours. The mixture was then concentrated under reduced pressure to afford the title compound (2.7 g, 92%) as a yellow oil, which was used directly in the next step. LC-MS (ESI+): m / z 159.0 [M+H] + .

[0567] Step 3: 2-(5-methoxypyrazin-2-yl)acetonitrile

[0568] To a solution of 2-(chloromethyl)-5-methoxypyrazine (2.7 g, 17.02 mmol) in ethanol (150 mL) and H₂O (50 mL) were added potassium iodide (0.85 g, 5.11 mmol), K₂CO₃ (2.35 g, 17.03 mmol), and KCN (1.22 g, 18.73 mmol). The reaction mixture was stirred at 80°C for 18 hours. After cooling to room temperature, saturated Na₂CO₃ solution (100 mL) was added to the mixture. After extraction with ethyl acetate (100 mL x 3), the combined organic layers were dried over Na₂SO₄, filtered, and concentrated under reduced pressure to give a residue which was purified by silica gel column chromatography (eluting with 0%-25% ethyl acetate in petroleum ether) to give the title compound (1.7 g, 67%). LC-MS (ESI+): m / z 150.0 [M+H] + .

[0569] Step 4: 2-(5-methoxypyrazin-2-yl)-3-(4-((6-methylpyridin-2-yl)oxy)phenyl)acrylonitrile

[0570] To a solution of 2-(5-methoxypyrazin-2-yl)acetonitrile (1.80 g, 12.07 mmol) in methanol (20 mL) were added 4-((4-methylpyrimidin-2-yl)oxy)benzaldehyde (3.09 g, 14.48 mmol) and DBU (5.51 g, 36.20 mmol). The reaction mixture was stirred at 80° C. for 3 hours. After cooling to room temperature, the precipitate was filtered. The solid was washed with water (20 mL) and concentrated under reduced pressure to give the title compound (3 g, 72%). LC-MS (ESI+): m / z 345.0 [M+H] + .

[0571] Step 5: 6-amino-3-methoxy-7-(4-((6-methylpyridin-2-yl)oxy)phenyl)pyrrolo[1,2-a]pyrazine-8-carbonitrile

[0572] To a mixture of 2-(5-methoxypyrazin-2-yl)-3-(4-((6-methylpyridin-2-yl)oxy)phenyl)acrylonitrile (3 g, 8.71 mmol) in methanol (90 mL) was added DBU (4 g, 26.14 mmol) and acetyl cyanide (0.72 g, 10.45 mmol). The reaction mixture was stirred at 120° C. under microwave irradiation for 20 minutes. After cooling to room temperature, water (200 mL) was added to the reaction. After extraction with ethyl acetate (200 mL×3), the combined organic layers were dried over Na 2 SO 4 , filtered, and concentrated under reduced pressure to give a residue, which was purified by silica gel column chromatography (eluted with 0%-5% methanol in dichloromethane) to give the title compound (740 mg, 23%). LC-MS (ESI+): m / z 372.3 [M+H] + .

[0573] Step 6: 6-iodo-3-methoxy-7-(4-((6-methylpyridin-2-yl)oxy)phenyl)pyrrolo[1,2-a]pyrazine-8-carbonitrile

[0574] To a solution of 6-amino-3-methoxy-7-(4-((6-methylpyridin-2-yl)oxy)phenyl)pyrrolo[1,2-a]pyrazine-8-carbonitrile (560 mg, 1.51 mmol) in chloroform (50 mL) was added 3-methyl-1-(nitrosooxy)butane (530 mg, 4.5 mmol) and diiodomethane (606 mg, 2.26 mmol). The reaction mixture was stirred at 70 ° C for 1 hour. After cooling to room temperature, water (50 mL) was added to the reaction. After extraction with DCM (50 mL×3), the combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue, which was purified by silica gel column chromatography (eluted with 0%-50% ethyl acetate in petroleum ether) to give the title compound (50 mg, 7%). LC-MS (ESI+): m / z 482.8 [M+H] + .

[0575] Example 17: 6-(4-acrylamidophenyl)-3-methoxy-7-(4-((6-methylpyridin-2-yl)oxy)phenyl)pyrrolo[1,2-a]pyrazine-8-carboxamide

[0576]

[0577] Example 17

[0578] Example 17 was synthesized in a manner similar to the procedure of Example 1 by replacing 6-bromo-7-(4-((6-methylpyridin-2-yl)oxy)phenyl)pyrrolo[1,2-a]pyrazine-8-carbonitrile with 6-iodo-3-methoxy-7-(4-((6-methylpyridin-2-yl)oxy)phenyl)pyrrolo[1,2-a]pyrazine-8-carbonitrile. The crude product was purified by preparative HPLC (eluting with 45%-55% MeCN in H2O containing 0.1% FA) to give the title compound (6 mg, 20%). LC-MS (ESI+): m / z 520.3 [M+H] + . 1 HNMR(400MHz,DMSO-d6)δ10.33(s,1H),9.14(d,J=1.0Hz,1H),7.77-7.70( m,3H),7.45(s,1H),7.31-7.27(m,5H),7.07(d,J=8.0Hz,2H),7.015(d,J= 4.0Hz,1H),6.76(d,J=8.0Hz,1H),6.50-6.38(m,2H),6.27(dd,J1=16.0,J 2=2.0Hz,1H),5.78(dd,J1=12.0,J2=2.0Hz,1H),3.82(s,3H),2.34(s,3H).

[0579] Preparation of intermediate 18.5

[0580]

[0581] Step 1: 2-(Benzylthio)-5-chloropyrazine

[0582] To a solution of 2,5-dichloropyrazine (7.85 g, 52.70 mmol) in 1,4-dioxane (160 mL) was added phenylmethyl mercaptan (6.54 g, 52.70 mmol), Xantphos (6.10 g, 10.54 mmol), Pd2(dba)3 (4.83 g, 5.27 mmol) and DIPEA (26.13 mL, 158.08 mmol). The reaction mixture was stirred at 100 ° C under N2 for 2 hours. After cooling to room temperature, the mixture was diluted with brine (100 mL) and extracted with DCM (100 mL×3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue, which was purified by silica gel column chromatography eluting with petroleum ether to give the title compound (3.77 g, 30%) as a yellow oil. LC-MS (ESI+): m / z 237.2 [M+H] + .

[0583] Step 2: 5-Chloropyrazine-2-sulfonyl chloride

[0584] To a solution of 2-(benzylthio)-5-chloropyrazine (3.1 g, 13.09 mmol) in DCM (60 mL) and H O (6 mL) was added sulfonyl chloride (11.84 g, 87.74 mmol) at 0-10° C. The reaction mixture was stirred at 0° C. under N for 2 hours. Water (100 mL) was added to the reaction mixture. After extraction with DCM (100 mL×3), the combined organic layers were dried over Na SO , filtered, and concentrated under reduced pressure to give a residue which was purified by silica gel column chromatography eluting with ethyl acetate (0%-10%) in petroleum ether to give the title compound (1.99 g, 71%). 1 H NMR (400MHz, CDCl3) δ9.095 (d, J = 4.0 Hz, 1H), 8.775 (d, J = 4.0 Hz, 1H).

[0585] Step 3: 5-Chloro-N-methylpyrazine-2-sulfonamide

[0586] To a suspension of methylamine hydrochloride (0.60 g, 8.92 mmol) in DCM (10 mL) was added triethylamine (1.24 mL, 8.92 mmol) and 5-chloropyrazine-2-sulfonyl chloride (1.9 g, 8.92 mmol) at 0°C. The reaction mixture was stirred at 25°C for 2 hours. Salt water (100 mL) was added to the reaction mixture. After extraction with DCM (100 mL × 3), the combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue which was purified by silica gel column chromatography eluting with ethyl acetate (0%-50%) in petroleum ether to give the title compound (1.46 g, 79%) as an oil. 1 H NMR (400MHz, CDCl3) δ 8.985 (d, J = 4.0 Hz, 1H), 8.66 (d, J = 1.3 Hz, 1H), 4.82 (br s, 1H), 2.835 (d, J = 4.0 Hz, 3H).

[0587] Step 4: tert-Butyl 2-cyano-2-(5-(N-methylsulfamoyl)pyrazin-2-yl)acetate

[0588] To a solution of 5-chloro-N-methylpyrazine-2-sulfonamide (650 mg, 3.13 mmol) in THF (20 mL) were added tert-butyl 2-cyanoacetate (884 mg, 6.26 mmol) and Cs2CO3 (2.55 g, 7.82 mmol). The reaction mixture was stirred at 80°C for 1 hour. After cooling to room temperature, water (100 mL) was added to the mixture. After extraction with ethyl acetate (50 mL×3), the pH of the aqueous layer was adjusted to 3 with dilute HCl solution (1 N). After extraction with DCM (100 mL×3), the combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue, which was purified by silica gel column chromatography eluting with DCM to give the title compound (850 mg, 87%). LC-MS (ESI+): m / z 313.2 [M+H] + .

[0589] Step 5: 5-(Cyanomethyl)-N-methylpyrazine-2-sulfonamide

[0590] To a solution of tert-butyl 2-cyano-2-(5-(N-methylsulfamoyl)pyrazin-2-yl)acetate (840 mg, 2.69 mmol) in toluene (25 mL) was added 4-methylbenzenesulfonic acid (463 mg, 2.69 mmol). The reaction mixture was stirred at 120° C. under N for 1 hour. After cooling to room temperature, water (100 mL) was added to the mixture. After extraction with DCM (100 mL×3), the combined organic layers were dried over NaSO, filtered, and concentrated under reduced pressure to give a residue which was purified by silica gel column chromatography eluting with dichloromethane to give the title compound (260 mg, 46%) as a yellow oil. 1 H NMR (400MHz, DMSO-d6) δ9.10 (s, 1H), 8.83 (s, 1H), 8.02 (d, J = 8.0Hz, 1H), 4.49 (s, 2H), 2.585 (d, J = 4.0Hz, 3H).

[0591] Example 18: 6-(4-acrylamidophenyl)-7-(4-((6-methylpyridin-2-yl)oxy)phenyl)-3-(N-methylsulfamoyl)pyrrolo[1,2-a]pyrazine-8-carboxamide

[0592]

[0593] Example 18

[0594] Example 18 was synthesized in a manner analogous to the procedure of Example 1 by substituting 5-(cyanomethyl)-N-methylpyrazine-2-sulfonamide (Intermediate 18.5) for 2-(pyrazin-2-yl)acetonitrile. The crude product was purified by preparative HPLC (eluting with 40%-50% MeCN in H2O containing 0.1% FA) to afford the title compound (8 mg, 16%). LC-MS (ESI+): m / z 583.2 [M+H] + . 1 H NMR (400MHz, CDCl3) δ9.84(d,J=1.2Hz,1H),8.59(d,J=1.2Hz,1H),7.69-7.62(m,3H),7. 37(s,1H),7.29(d,J=8.0Hz,2H),7.23(d,J=8.0Hz,2H),7.13(d,J=8.0Hz,2H),6.95(d,J =8.0Hz,1H),6.71(d,J=8.0Hz,1H),6.46(d,J=20.0Hz,1H),6.35-6.20(m,1H),5.82(d,J =12.0Hz,1H),5.67-5.35(m,2H),5.02-4.92(m,1H),2.71(d,J=4.0Hz,3H),2.47(s,3H).

[0595] Example 19: 6-(4-acrylamidophenyl)-7-(4-((4-methylthiazol-2-yl)oxy)phenyl)pyrrolo[1,2-a]pyrazine-8-carboxamide

[0596]

[0597] Example 19

[0598] Preparation of intermediate 19.1

[0599]

[0600] To a solution of 4-hydroxybenzaldehyde (10.0 g, 81.9 mmol) in DMF (100 mL) was added 2-bromo-4-methylthiazole (16.0 g, 90.0 mmol) and CsF (37.3 g, 245.0 mmol) at 25 ° C. The reaction mixture was stirred at 120 ° C for 12 hours. The mixture was then diluted with H2O (100 mL) and extracted with ethyl acetate (50.0 mL×3). The combined organic layers were washed with brine (50.0 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue which was purified by silica gel column chromatography eluting with EtOAc (1%-50%) in petroleum ether to give the title compound (2.50 g, 12%) as a yellow oil. 1 H NMR (400MHz, DMSO-d6) δ9.99(s,1H),8.05-7.96(m,2H),7.57-7.47(m,2H),6.90(s,1H),2.22(s,3H).

[0601] Example 19 was synthesized in a manner similar to the method of Example 15 by substituting 4-((4-methylthiazol-2-yl)oxy)benzaldehyde for 4-((6-methylpyridin-2-yl)oxy)benzaldehyde and 2-(pyrazin-2-yl)acetonitrile for 2-(pyrimidin-4-yl)acetonitrile. The crude product was purified by preparative HPLC (column: Waters Xbridge 150×25 mm×5 μm; mobile phase: [water(NH4HCO3)-ACN]; B%: 25%-55%, 8 minutes) to give the title compound (25 mg, 12%). LC-MS (ESI+): m / z 496.3 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ10.31(s,1H),9.26(d,J=1.3Hz,1H),8.00(dd,J=1.4,4.9Hz,1H),7.75(d,J=8.6Hz,2H),7.65(d,J=4.9 Hz,1H),7.40-7.27(m,7H),6.84-6.68(m,2H),6.49-6.39(m,1H),6.32-6.24(m,1H),5.82-5.74(m,1H),2.21(d,J=1.0Hz,3H).

[0602] Example 20: 7-(4-acrylamidophenyl)-6-(4-((6-methylpyridin-2-yl)oxy)phenyl)pyrrolo[1,2-b]pyridazine-5-carboxamide

[0603]

[0604] Step 1: 1-(4-Nitrobenzyl)pyridazin-1-ium bromide

[0605] To a mixture of pyridazine (5.87 g, 73.2 mmol) in EtOAc (30.0 mL) was added 1-(bromomethyl)-4-nitro-benzene (19.0 g, 87.9 mmol) in one portion at 25 ° C. under N2. The mixture was stirred at 80 ° C. for 12 hours. The mixture was then cooled to room temperature and filtered. The filter cake was dried under reduced pressure to give the title compound (15.0 g). LC-MS (ESI+): m / z 216.0 (M + ).

[0606] Step 2: 7-(4-nitrophenyl)pyrrolo[1,2-b]pyridazine-5-carbonitrile

[0607] To a solution of 1-(4-nitrobenzyl)pyridazin-1-ium bromide (10.0 g, 33.9 mmol) in DME (100 mL) was added propanenitrile (9.31 g, 175 mmol). MnO2 (15.2 g, 175 mmol) and TEA (10.7 g, 106 mmol, 14.8 mL) were then added to the solution at room temperature. The reaction mixture was then stirred at 80°C for 7 hours. After cooling to room temperature, the mixture was filtered and the filtrate was concentrated under reduced pressure to give a residue which was purified by silica gel column chromatography eluting with EtOAc (1%-10%) in petroleum ether to give the title compound (6.40 g, 72%). 1 H NMR (400MHz, DMSO-d6) δ8.72-8.68(m,1H),8.45-8.39(m,3H),8.39-8.34(m,2H),8.15(s,1H),7.34-7.29(m,1H).

[0608] Step 3: 6-Bromo-7-(4-nitrophenyl)pyrrolo[1,2-b]pyridazine-5-carboxamide

[0609] To a solution of 7-(4-nitrophenyl)pyrrolo[1,2-b]pyridazine-5-carbonitrile (2.00 g, 7.57 mmol) in H2SO4 (15.0 mL) was added NBS (2.69 g, 15.1 mmol). The reaction mixture was stirred at 25 ° C for 4 hours. The mixture was poured into ice and the pH was adjusted to 7 by dropwise addition of saturated Na2CO3 aqueous solution. After extraction with ethyl acetate (50 mL × 3), the combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to give the title compound (800 mg, 29%).

[0610] Step 4: 6-(4-((6-methylpyridin-2-yl)oxy)phenyl)-7-(4-nitrophenyl)pyrrolo[1,2-b]pyridazine-5-carboxamide

[0611] To a solution of 6-bromo-7-(4-nitrophenyl)pyrrolo[1,2-b]pyridazine-5-carboxamide (526 mg, 1.46 mmol) in DMF (16 mL) and H2O (1 mL) was added 2-methyl-6-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)pyridine (498 mg, 1.60 mmol), Pd(DtBPF)Cl2 (95 mg, 145 μmol) and K3PO4 (927 mg, 4.37 mmol). The reaction mixture was stirred at 95 ° C for 4 hours. After cooling to room temperature, the mixture was diluted with water (20 mL) and extracted with DCM (20 mL × 3). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue, which was purified by preparative HPLC (column: Phenomenex C18 250×50 mm×10 μm; mobile phase: [water(NH4HCO3)-ACN]; B%: 37%-67%, 8 minutes) to give the title compound (50 mg, 7%). LC-MS (ESI+): m / z 466.1 [M+H] + .

[0612] Step 5: 7-(4-aminophenyl)-6-(4-((6-methylpyridin-2-yl)oxy)phenyl)pyrrolo[1,2-b]pyridazine-5-carboxamide

[0613] To a solution of 6-(4-((6-methylpyridin-2-yl)oxy)phenyl)-7-(4-nitrophenyl)pyrrolo[1,2-b]pyridazine-5-carboxamide (35 mg, 75.1 μmol) in EtOH (2 mL) and H2O (2 mL) was added Fe (27 mg, 488 μmol) and CaCl2 (25 mg, 225 μmol) at room temperature. The reaction mixture was stirred at 80 ° C for 12 hours. After cooling to room temperature, the mixture was filtered and the filtrate was concentrated under reduced pressure to give the title compound (30 mg). LC-MS (ESI+): m / z 436.3 [M+H] + .

[0614] Step 6: 7-(4-Acrylamidophenyl)-6-(4-((6-methylpyridin-2-yl)oxy)phenyl)pyrrolo[1,2-b]pyridazine-5-carboxamide

[0615] To a solution of 7-(4-aminophenyl)-6-(4-((6-methylpyridin-2-yl)oxy)phenyl)pyrrolo[1,2-b]pyridazine-5-carboxamide (30 mg, 68.8 μmol) in acetone (2 mL) and H2O (0.4 mL) was added K2CO3 (19.0 mg, 137.0 μmol) at 0°C. Propyl-2-enoyl chloride (7.48 mg, 82.6 μmol) was then added to the solution at 0°C. The reaction mixture was stirred at 0°C for 1 hour. The mixture was then diluted with water (10 mL) and extracted with ethyl acetate (10 mL×3). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to give a residue which was purified by preparative-TLC (SiO2, petroleum ether:ethyl acetate=0:1) to give the title compound (10 mg, 29%). LC-MS (ESI+): m / z 490.1 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ10.25(d,J=8.1Hz,1H),8.50-8.44(m,1H),8.35-8.29( m,1H),7.74(t,J=7.8Hz,1H),7.64(d,J=7.6Hz,2H),7.36-7.28(m,4H),7.25(br s,1H),7.13(d,J=8.6Hz,2H),7.06-6.94(m,2H),6.77(d,J=8.1Hz,1H),6.53-6.40(m,1H),6.35-6.15(m,2H),5.81-5.70(m,1H),2.36(s,3H).

[0616] Example 21: 6-(4-acrylamidophenyl)-3-(1-methylazetidin-3-yl)-7-(4-((6-methylpyridin-2-yl)oxy)phenyl)pyrrolo[1,2-a]pyrazine-8-carboxamide

[0617]

[0618] Step 1: tert-Butyl 3-(6-amino-8-cyano-7-(4-((6-methylpyridin-2-yl)oxy)phenyl)pyrrolo[1,2-a]pyrazin-3-yl)azetidine-1-carboxylate

[0619] Intermediate 21.1 was synthesized in a manner analogous to the procedure for Intermediate 12.3 by substituting 2,5-dibromopyrazine for 2,3-dichloropyrazine.

[0620] To a mixture of Zn (498 mg, 7.61 mmol) in THF (10 mL) were added 1,2-dibromoethane (27 mg, 142.77 μmol) and TMSCl (31 mg, 285.54 μmol). The reaction mixture was warmed to 65°C. A solution of tert-butyl 3-iodoazetidine-1-carboxylate (808 mg, 2.86 mmol) in THF (2 mL) was added. The mixture was then stirred at 65°C under N2 for 1 hour. 6-amino-3-bromo-7-[4-[(6-methyl-2-pyridyl)oxy]phenyl]pyrrolo[1,2-a]pyrazine-8-carbonitrile (400 mg, 951.8 μmol), CuI (22.7 mg, 119.0 μmol), and Pd(dppf)Cl2·CH2Cl2 (47 mg, 57.1 μmol) were then added. The reaction mixture was stirred at 80°C for 1 hour. After cooling to room temperature, the reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue which was purified by flash column chromatography on silica gel (eluted with 0-10% MeOH in DCM) to give the title compound (400 mg, 85%). LC-MS (ESI+): m / z 441.1 (M+H-56) + .

[0621] Step 2: tert-Butyl 3-(8-cyano-6-iodo-7-(4-((6-methylpyridin-2-yl)oxy)phenyl)pyrrolo[1,2-a]pyrazin-3-yl)azetidine-1-carboxylate

[0622] To a mixture of tert-butyl 3-(6-amino-8-cyano-7-(4-((6-methylpyridin-2-yl)oxy)phenyl)pyrrolo[1,2-a]pyrazin-3-yl)azetidine-1-carboxylate (500 mg, 1.01 mmol) in CHCl₃ (5 mL) were added CH₂I₂ (4.13 g, 15.4 mmol) and isoamyl nitrite (472 mg, 4.03 mmol) sequentially. The reaction mixture was stirred at 70°C for 1 hour. After cooling to room temperature, the mixture was concentrated under reduced pressure to give a residue, which was purified by flash column chromatography on silica gel (eluted with 0-35% ethyl acetate in petroleum ether) to give the title compound (230 mg, 38%). LC-MS (ESI+): m / z 607.8 [M+H] + .

[0623] Step 3: 3-(azetidin-3-yl)-6-iodo-7-(4-((6-methylpyridin-2-yl)oxy)phenyl)pyrrolo[1,2-a]pyrazine-8-carboxamide

[0624] A mixture of tert-butyl 3-(8-cyano-6-iodo-7-(4-((6-methylpyridin-2-yl)oxy)phenyl)pyrrolo[1,2-a]pyrazin-3-yl)azetidine-1-carboxylate (220 mg, 362.2 μmol) in H2SO4 (4.40 mL, 82.5 mmol) was stirred at 30 ° C for 12 hours. After cooling to room temperature, the mixture was poured into ice water (30 mL) and the pH was adjusted to 7 with aqueous sodium carbonate solution. After extraction with ethyl acetate (20 mL×3), the combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give the title compound (150 mg). LC-MS (ESI+): m / z 526.1 [M+H] + .

[0625] Step 4: 6-iodo-3-(1-methylazetidin-3-yl)-7-(4-((6-methylpyridin-2-yl)oxy)phenyl)pyrrolo[1,2-a]pyrazine-8-carboxamide

[0626] To a solution of 3-(azetidin-3-yl)-6-iodo-7-(4-((6-methylpyridin-2-yl)oxy)phenyl)pyrrolo[1,2-a]pyrazine-8-carboxamide (150 mg, 285.5 μmol) and HCHO (43 mg, 571.1 μmol, 40% purity) in MeOH (5 mL) was added NaBH3CN (63 mg, 999.4 μmol). The reaction mixture was stirred at 25 ° C for 2 hours. The mixture was then diluted with water (10 mL) and extracted with ethyl acetate (10 mL×3). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give the title compound (120 mg). LC-MS (ESI+): m / z 540.0 [M+H] + .

[0627] Step 5: 6-(4-acrylamidophenyl)-3-(1-methylazetidin-3-yl)-7-(4-((6-methylpyridin-2-yl)oxy)phenyl)pyrrolo[1,2-a]pyrazine-8-carboxamide

[0628] To a solution of 6-iodo-3-(1-methylazetidin-3-yl)-7-(4-((6-methylpyridin-2-yl)oxy)phenyl)pyrrolo[1,2-a]pyrazine-8-carboxamide (100 mg, 185.4 μmol) and N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acrylamide (61 mg, 222.5 μmol) in dioxane (3 mL) and H2O (1 mL) was added K2CO3 (64 mg, 463.5 μmol) and Pd-118 (12 mg, 18.5 μmol) in sequence. The reaction mixture was stirred at 90 ° C. under N2 atmosphere for 2 hours. After cooling to room temperature, the mixture was diluted with water (20 mL) and extracted with ethyl acetate (10 mL×3). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue which was purified by preparative-HPLC (column: Boston Prime C 18 150×30mm×5um; mobile phase: [water (ammonium hydroxide v / v)-ACN]; B%: 25%-47%, 22 minutes) to obtain the title compound (1.6 mg, 2%). LC-MS (ESI+): m / z 559.4 [M+H] + . 1 H NMR(400MHz, CDCl3)δ9.88(s,1H),7.77(s,1H),7.70-7.60(m,3H),7.52(s,1H),7.30-7.25 (m,2H),7.22(d,J=8.3Hz,2H),7.12(d,J=8.7Hz,2H),6.95(d,J=7.3Hz,1H),6.70(d,J=7.7H z,1H),6.52-6.44(m,1H),6.30(dd,J=10.2,16.7Hz,1H),5.83(d,J=10.0Hz,1H),5.60-5.26 (m,2H),3.97-3.89(m,2H),3.82-3.73(m,1H),3.63-3.55(m,2H),2.57(s,3H),2.47(s,3H).

[0629] Example 22: Preparation of 6-(4-acrylamidophenyl)-7-(4-methoxyphenyl)pyrrolo[1,2-a]pyrazine-8-carboxamide

[0630]

[0631] Step 1: Preparation of Example 22

[0632] Example 22 was synthesized from compound 22.1 in a manner similar to that of Example 15. Spectral data of Example 22: LCMS: 413.1 [M+H] + ; 1 H NMR:(400MHz,DMSO-d6)δ10.30(br s,1H),9.35(s,1H),8.00(d,J=4.8Hz,1H),7.73(d,J=8.3Hz,2H),7.66(d,J=4.8Hz,1H),7.35-7.25(m,3H),7.21(d,J =8.8Hz,2H),6.92(d,J=8.5Hz,2H),6.49-6.38(m,1H),6.35-6.23(m,2H),5.78(dd,J=10.2,1.6Hz,1H),3.75(s,3H).

[0633] Example 23: Preparation of 5-(4-acrylamidophenyl)-6-(4-((6-methylpyridin-2-yl)oxy)phenyl)pyrrolo[2,1-b]thiazole-7-carboxamide

[0634]

[0635] Step 1: Preparation of Example 23

[0636] A solution of Example 24 (45.0 mg, 0.094 mmol) in H2SO4 (1 mL) was stirred at 30°C for 16 hours. The reaction solution was poured into ice, and the reaction solvent was adjusted to 7 with aqueous sodium carbonate. After extraction with EA (10 mL x 3), the combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered, concentrated, and purified by preparative-HPLC to give Example 23. LCMS: m / z 495.1 [M+H] + ; 1 H NMR: (400MHz, DMSO-d6) δ10.22(s,1H),7.85(d,J=4.2Hz,1H),7.75(t,J=7.8H z,1H),7.65(d,J=8.6Hz,2H),7.37(d,J=8.6Hz,2H),7.32(d,J=4.2Hz,1H),7.2 3(d,J=8.6Hz,2H),7.15(d,J=8.4Hz,2H),7.03(d,J=7.3Hz,1H),6.80(d,J=8.1 Hz,1H),6.47-6.37(m,1H),6.30-6.21(m,1H),5.81-5.72(m,1H),2.35(s,3H).

[0637] Example 24: Preparation of N-(4-(7-cyano-6-(4-((6-methylpyridin-2-yl)oxy)phenyl)pyrrolo[2,1-b]thiazol-5-yl)phenyl)acrylamide

[0638]

[0639] Step 1: Preparation of compound 24.3

[0640] To a solution of compound 24.1 (10.0 g, 61.0 mmol) in DMF (100 mL) was added Cs2CO3 (39.7 g, 121.9 mmol). Compound 24.2 (11.2 g, 79.3 mmol) was then added, and the reaction mixture was stirred at 80°C for 16 hours. After cooling to room temperature, the reaction mixture was filtered, and the filtrate was concentrated and purified by silica gel flash column chromatography to give compound 24.3 (8.00 g, 58.51%) as a yellow solid. LCMS: 168.8 [M+H-56] + .

[0641] Step 2: Preparation of compound 24.4

[0642] To a solution of compound 24.3 (6.00 g, 26.8 mmol) in toluene (90 mL) was added 4-methylbenzenesulfonic acid (0.37 g, 2.14 mmol), and the solution was stirred at 140° C. for 16 hours. After cooling to room temperature, the reaction mixture was concentrated and purified by silica gel flash column chromatography to give compound 24.4 (1.50 g, 45.16%) as a yellow solid. LCMS: 124.8 [M+H] + .

[0643] Step 3: Preparation of compound 24.6

[0644] To a solution of compound 24.4 (1.50 g, 12.1 mmol) in MeOH (60 mL) was added compound 24.5 (2.58 g, 12.1 mmol) and DBU (5.52 g, 36.2 mmol). Acetyl cyanide (0.83 g, 12.1 mmol) was then added dropwise to the solution under N2, and the reaction mixture was stirred at 100°C in a microwave for 20 minutes. After cooling to room temperature, the reaction mixture was concentrated and purified by silica gel flash column chromatography to give compound 24.6. LCMS: 347.2 [M+H] +

[0645] Step 4: Preparation of compound 24.7

[0646] To a solution of compound 24.6 (500.0 mg, 1.44 mmol) in chloroform (8 mL) was added diiodomethane (5.80 g, 21.7 mmol). 3-Methyl-1-(nitrosooxy)butane (676.4 mg, 5.77 mmol) in chloroform (2 mL) was then added to the solution at 70° C., and the reaction solution was stirred at 70° C. for 1 hour. After cooling to room temperature, the reaction mixture was concentrated and purified by silica gel flash column chromatography to give compound 24.7. LCMS: m / z 457.9 [M+H] +

[0647] Step 5: Preparation of Example 24

[0648] To a solution of compound 24.7 (100.0 mg, 0.219 mmol) and compound 24.8 (71.7 mg, 0.262 mmol) in dioxane (2 mL) and H2O (0.4 mL) was added K2CO3 (60.4 mg, 0.437 mmol). Pd(PPh3)4 (25.3 mg, 0.022 mmol) was then added to the solution under N2, and the reaction solution was stirred at 80°C for 1 hour. After cooling to room temperature, the reaction solution was diluted with water (2 mL) and extracted with EA (2 mL×3). The combined organic layers were washed with brine (2 mL), dried over Na2SO4, filtered, concentrated, and purified by preparative-HPLC to give Example 24. LCMS: 477.2 [M+H] + ; 1 H NMR: (400MHz, CD3OD) δ7.78(d,J=4.3Hz,1H),7.76-7.69(m,3H),7.38(dd,J=15.6,8.5Hz,4H),7.27(d,J=4.1Hz,1H),7.08( d,J=8.5Hz,2H),7.03(d,J=7.4Hz,1H),6.71(d,J=8.3Hz,1H),6.49-6.37(m,2H),5.81(dd,J=9.4,2.1Hz,1H),2.45(s,3H).

[0649] Example 25: Preparation of 6-(4-acrylamidophenyl)-7-(3-methoxy-4-((6-methylpyridin-2-yl)oxy)phenyl)pyrrolo[1,2-a]pyrazine-8-carboxamide

[0650]

[0651] Step 1: Preparation of compound 25.3

[0652] To a solution of compound 25.1 (11.70 mL, 113.38 mmol) in DMF (110 mL) was added compound 25.2 (34.50 g, 226.75 mmol) and CsCO (110.82 g, 340.13 mmol). The mixture was stirred at 130° C. for 18 hours. NaOH (40 mL, 2.00 mmol) was added to the reaction mixture and stirred at 25° C. for 0.5 hours and extracted with EA (3×100 mL). The organic layer was washed with brine (3×100 mL), dried over NaSO, filtered, and evaporated to give the crude product, which was purified by flash chromatography to give compound 25.3 (1.68 g). 1 H NMR: (400MHz, DMSO-d6) δ9.97 (s, 1H), 7.72 (t, J = 8.0Hz, 1H), 7.64-7.56 (m, 2H), 7.32 (d ,J=8.0Hz,1H),6.97(d,J=8.0Hz,1H),6.81(d,J=8.0Hz,1H),3.78(s,3H),2.27(s,3H).

[0653] Step 2: Preparation of compound 25.4

[0654] To a solution of compound 1.2 (587.67 mg, 4.93 mmol) in methanol (16 mL) was added compound 25.3 (1.2 g, 4.93 mmol), acetyl cyanide (0.350 mL, 4.93 mmol) and DBU (2.21 mL, 14.80 mmol), and the reaction was stirred at 100° C. under microwave irradiation for 20 minutes. After cooling to room temperature, the reaction mixture was diluted with water (50 mL) and extracted with EA (3×70 mL). The organic layer was washed with brine (3×50 mL), dried over Na 2 SO 4 , filtered, and evaporated to give compound 25.4 (1.83 g, 99.0% yield). LCMS: 371.9 [M+H] + .

[0655] Step 3: Preparation of Example 25

[0656] Example 25 was synthesized from compound 25.4 in a manner similar to that of Example 15. Spectral data of Example 25: LCMS: 520.3 [M+H] + ; 1H NMR: (400MHz, DMSO-d6) δ10.31(s,1H),9.34(d,J=1.32Hz,1H),8.03(dd,J=4.8,1.4Hz,1H), 7.77(d,J=8.6Hz,2H),7.66(dd,J=6.2,5.0Hz,2H),7.41(s,1H),7.33(d,J=8.6Hz,2H),7.05 (dd,J=12.2,8.1Hz,2H),6.95-6.87(m,2H),6.61(d,J=8.2Hz,2H),6.45(dd,J=16.9,10.0Hz ,1H),6.28(dd,J=17.0,2.0Hz,1H),5.78(dd,J=10.0,1.9Hz,1H),3.52(s,3H),2.29(s,3H).

[0657] Example 26: Preparation of 6-(4-acrylamidophenyl)-7-(4-(pyridin-2-yloxy)phenyl)pyrrolo[1,2-a]pyrazine-8-carboxamide

[0658]

[0659] Step 1: Preparation of compound 26.3

[0660] To a solution of compound 26.1 (4.17 mL, 44.04 mmol) in DMF (50 mL) were added compound 26.2 (8.07 g, 66.06 mmol), potassium carbonate (18.26 g, 132.11 mmol), and cuprous oxide (1.28 g, 8.81 mmol). The mixture was stirred at 150° C. for 18 hours. After cooling to room temperature, the reaction mixture was poured into water (80 mL) and extracted with EA (3×50 mL). The combined organic layers were washed with brine (3×25 mL), dried over Na 2 SO 4 , filtered, and concentrated under reduced pressure to give a residue that was purified by silica gel column chromatography to give compound 26.3 (4.79 g, 54.61% yield). LCMS: 241.0 [M+42] + .

[0661] Step 2: Preparation of compound 26.4

[0662] To a solution of compound 26.3 (836.08 mg, 4.20 mmol) in MeOH (15 mL) were added compound 1.2 (500 mg, 4.20 mmol), DBU (1.88 mL, 12.59 mmol), and acetyl cyanide (0.30 mL, 4.20 mmol). The mixture was stirred at 120° C. for 20 minutes. After cooling to room temperature, the reaction mixture was poured into water (80 mL) and extracted with EA (3×50 mL). The combined organic layers were dried over Na 2 SO 4 , filtered, and concentrated under reduced pressure to give a residue, which was purified by silica gel column chromatography to give compound 26.4 (695 mg, 50.48% yield). LCMS: 328.2 [M+H] + .

[0663] Step 3: Preparation of Example 26

[0664] Example 26 was synthesized from compound 26.4 in a manner similar to that of Example 15. Spectral data of Example 26: LCMS: 476.3 [M+H] + . 1 H NMR: (400MHz, DMSO-d6) δ10.33(s,1H),9.30(s,1H),8.19(dd,J ＝ 5.0,1.6Hz,1H),7.99(dd,J=4.8,0.8Hz,1H),7.91-7.83(m,1H),7.76(d,J=8.8Hz,2 H),7.65(d,J=4.8Hz,1H),7.38(s,1H),7.31(d,J=8.4Hz,4H),7.15(dd,J=4.8,0.8Hz ,1H),7.12-7.07(dt,J=8.8Hz,2.4Hz,2H),7.03(d,J=8.0Hz,1H),6.63(s,1H),6.45( dd,J=16.8,10.0Hz,1H), 6.28(dd,J=17.2,2.0Hz,1H), 5.78(dd,J=10.0,2.0Hz,1H).

[0665] Example 27: Preparation of 6-(4-acrylamidophenyl)-7-(4-(cyclopropylsulfonyl)phenyl)pyrrolo[1,2-a]pyrazine-8-carboxamide

[0666]

[0667] Step 1: Preparation of Example 27

[0668] Example 27 was synthesized from compound 27.1 in a manner similar to that of Example 12. Spectral data of Example 27: LCMS: 487.3 [M+H] + ; 1 H NMR: (400MHz, DMSO-d6) δ10.34(s,1H),9.18(s,1H),8.01-7.97(m,1H),7.81(d,J=8. 3Hz,2H),7.76(d,J=8.5Hz,2H),7.65(d,J=4.8Hz,1H),7.47(d,J=8.3Hz,2H),7.42(br s,1H),7.28(d,J=8.5Hz,3H),6.49-6.39(m,1H),6.32-6.24(m,1H),5.8 2-5.75(m,1H),2.93-2.83(m,1H),1.15-1.10(m,2H),1.08-1.01(m,2H).

[0669] Example 28: Preparation of 6-(4-acrylamidophenyl)-7-(4-(cyclopentyloxy)phenyl)pyrrolo[1,2-a]pyrazine-8-carboxamide

[0670]

[0671] Step 1: Preparation of compound 28.1

[0672] To a solution of compound 26.2 (5 g, 40.94 mmol) in DMF (60 mL) was added potassium carbonate (11.32 g, 81.88 mmol). The mixture was heated to 65°C and bromocyclopentane (12.20 g, 81.88 mmol) was added. The reaction mixture was stirred at 100°C under N2 for 5 hours. After cooling to room temperature, the reaction was diluted with H2O (300 mL) and extracted with EA (3×300 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to give compound 28.1 (6.94 g, 89.10% yield). LCMS: 191.2 [M+H] +

[0673] Step 2: Preparation of compound 28.2

[0674] To a solution of compound 1.2 (500 mg, 4.19 mmol) in MeOH (15 mL) was added compound 28.1 (798.46 mg, 4.19 mmol), DBU (1916.90 mg, 12.59 mmol) and 2-hydroxy-2-methylpropionitrile (357.21 mg, 4.19 mmol). The mixture was stirred at 120° C. in a microwave under N 2 for 20 minutes. After cooling to room temperature, the mixture was quenched with water (100 mL) and extracted with dichloromethane (3×100 mL). The combined organic layers were dried over Na 2 SO 4 , filtered, and concentrated under reduced pressure to give a residue that was purified by silica gel column chromatography to give compound 28.2 (800 mg, 59.87% yield). LCMS: 319.2 [M+H] + .

[0675] Step 3: Preparation of Example 28

[0676] Example 28 was synthesized from compound 28.2 in a manner similar to that of Example 1. Spectral data of Example 28: LCMS: 467.2 [M+H] + ; 1 H NMR: (400MHz, DMSO-d6) δ10.30(s,1H),9.34(s,1H),7.99(d,J=4.8Hz,1H),7.72(d,J =8.4Hz,2H),7.65(d,J=4.8Hz,1H),7.27(d,J=8.8Hz,3H),7.18(d,J=8.8Hz,2H),6.87 (d,J=8.4Hz,2H),6.44(dd,J=16.8,10.0Hz,1H),6.27(d,J=16.8Hz,2H),5.78(d,J=1 2Hz,1H),4.80-4.78(m,1H),1.92-1.88(3,2H),1.73-1.67(m,4H),1.65-1.52(m,2H).

[0677] Example 29: Preparation of 6-(4-acrylamidophenyl)-3-((dimethylamino)methyl)-7-(4-((6-methylpyridin-2-yl)oxy)phenyl)pyrrolo[1,2-a]pyrazine-8-carboxamide

[0678]

[0679] Step 1: Preparation of Example 29

[0680] Compound 29.1 was synthesized in a manner similar to the method of Example 15.

[0681] A solution of compound 29.1 (130 mg, 248 μmol), compound 29.2 (81.9 mg, 496 μmol), Cs2CO3 (162.0 mg, 496.0 μmol) and Xphos Pd G3 (21.0 mg, 24.8 μmol) in dioxane (2.5 mL) and H2O (0.5 mL) was stirred at 100°C under N2 for 12 hours. The reaction solution was filtered and the filtrate was concentrated in vacuo. The residue was purified by preparative HPLC to give Example 29. LCMS: 547.4 [M+H] + . 1 H NMR: (400MHz, DMSO-d6) δ10.33(s,1H),9.27(s,1H),7.89(s,1H),7.82-7.69(m,3H),7.38(br s,1H),7.29(dd,J=8.0,5.5Hz,4H),7.06(d,J=8.3Hz,2H),7.01(d,J=7.3Hz,1H),6.76(d,J=8.3Hz,1H),6.58(br s,1H),6.49-6.41(m,1H),6.32-6.23(m,1H),5.79(d,J=11.0Hz,1H),3.54(s,2H),2.33(s,3H),2.23(s,6H).

[0682] Example 30: Preparation of 7-(4-(2-azaspiro[3.3]heptane-2-carbonyl)phenyl)-6-(4-acrylamidophenyl)pyrrolo[1,2-a]pyrazine-8-carboxamide

[0683]

[0684] Step 1: Preparation of Example 30

[0685] Example 30 was synthesized from compound 30.1 in a manner similar to that of Example 12. Spectral data of Example 30: LCMS: 506.3 [M+H] + ; 1H NMR: (400MHz, DMSO-d6) δ10.32(s,1H),9.24(s,1H),7.99(d,J=5.0Hz,1H),7.74(d,J=8.3Hz,2H),7.65(d,J=5.0Hz,1H),7.56(d,J=8.0Hz,2H),7.37(br s,1H),7.31(d,J=8.0Hz,2H),7.26(d,J=8.3Hz,2H),6.84(br s,1H),6.50-6.38(m,1H),6.35-6.19(m,1H),5.78(d,J=10.3Hz,1H),4.26(s,2H),3.99(s,2H),2.13(t,J=7.7Hz,4H),1.84-1.64(m,2H).

[0686] Example 32: Preparation of 6-(4-acrylamidophenyl)-7-(3-fluoro-4-((6-methylpyridin-2-yl)oxy)phenyl)pyrrolo[1,2-a]pyrazine-8-carboxamide

[0687]

[0688] Step 1: Preparation of compound 32.2

[0689] To a suspension of compound 25.1 (6 g, 54.00 mmol) in NMP (200 mL) were added compound 32.1 (10.31 g, 53.60 mmol) and Cs2CO3 (52.78 g, 161.99 mmol). The reaction mixture was stirred at 150°C for 18 hours. After cooling to room temperature, the reaction mixture was diluted with water (200 mL) and extracted with EA (3×200 mL). The combined organic layers were washed with saturated brine (200 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue which was purified by silica gel column chromatography to give compound 32.2 (7.7 g, 48.16% yield). LCMS: 281.8 [M+H] + .

[0690] Step 2: Preparation of compound 32.3

[0691] To a solution of compound 32.2 (3 g, 10.63 mmol) in THF (150 mL) was added a solution of BuLi (7.31 mL, 11.70 mmol) in THF at -78°C. The reaction mixture was stirred at -78°C for 30 minutes, then DMF (0.98 mL, 12.76 mmol) was added to the mixture, and the reaction mixture was stirred at -78°C for 30 minutes. After warming to room temperature, the reaction mixture was diluted with water (200 mL) and extracted with EA (3×200 mL). The combined organic layers were washed with saturated brine (200 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue, which was purified by silica gel column chromatography to give compound 32.3 (460 mg, 18.71% yield). LCMS: 232.0 [M+H] + .

[0692] Step 3: Preparation of compound 32.4

[0693] To a solution of compound 1.2 (400 mg, 3.36 mmol) and compound 32.3 (776 mg, 3.36 mmol) in MeOH (15 mL) was added DBU (1533 mg, 10.07 mmol) and 2-oxopropionitrile (255 mg, 3.69 mmol). The reaction mixture was stirred at 100 ° C in a microwave under N2 for 20 minutes. After cooling to room temperature, the reaction mixture was diluted with water (50 mL) and extracted with EA (3×50 mL). The combined organic layers were washed with saturated brine (50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue, which was purified by silica gel column chromatography to give compound 32.4 (900 mg, 74.59% yield). LCMS: 360.0 [M+H] + .

[0694] Step 4: Preparation of Example 32

[0695] Example 32 was synthesized from compound 32.4 in a manner similar to that of Example 15. Spectral data of Example 32: LCMS: 508.3 [M+H] + . 1H NMR: (400MHz, DMSO-d6) δ10.36 (s, 1H), 9.26 (d, J = 1.2Hz, 1H), 8.41 (s, 1H), 7.83-7.76 (m, 2H), 7.73(d,J=8.0Hz,1H),7.66(d,J=4.8Hz,1H),7.44(s,1H),7.32(d,J=8.4Hz,2H),7.28-7.17(m, 2H),7.09(d,J=9.2Hz,1H),7.00(d,J=7.2Hz,1H),6.93(s,1H),6.84(d,J=8.0Hz,1H),6.46(dd ,J=16.0,10.1Hz,1H),6.28(dd,J=16.0,1.9Hz,1H),5.78(dd,J=10.0,1.9Hz,1H),2.29(s,3H).

[0696] Example 33: Preparation of 6-(4-acrylamidophenyl)-7-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)pyrrolo[1,2-a]pyrazine-8-carboxamide

[0697]

[0698] Step 1: Preparation of compound 33.3

[0699] To a solution of compound 33.1 (15.0 g, 107.1 mmol) and compound 33.2 (16.5 g, 128.5 mmol) in DMF (250 mL) was added CsF (32.5 g, 214.1 mmol). The reaction mixture was stirred at 120° C. for 12 hours. After cooling to room temperature, the reaction mixture was filtered, and the filtrate was concentrated and purified by silica gel flash column chromatography to give compound 33.3 (6.00 g, 24.14%) as a yellow solid. LCMS: 232.9 [M+H] + .

[0700] Step 2: Preparation of compound 33.4

[0701] To a mixture of compound 33.3 (974.7 mg, 4.20 mmol) and compound 1.2 (500.0 mg, 4.20 mmol) in n-BuOH (10 mL) was added DBU (1.28 g, 8.39 mmol, 1.27 mL). Acetyl cyanide (322.1 mg, 4.20 mmol, 90% purity) was then added to the solution at 25°C and purged with N2 three times. After addition, the reaction mixture was heated to 100°C in a microwave for 20 minutes. The reaction solution was cooled to room temperature and diluted with water (100 mL). After extraction with EA (50 mL×3), the combined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered, concentrated, and purified by silica gel flash column chromatography to give compound 33.4 (400.0 mg, 26.45% yield) as a yellow solid. LCMS: 361.0 [M+H] + .

[0702] Step 3: Preparation of Example 33

[0703] Example 33 was synthesized from compound 33.4 in a manner similar to that of Example 15. Spectral data of Example 33: LCMS: 509.1 [M+H] + ; 1 H NMR: (400MHz, DMSO-d6) δ10.36(s,1H),9.23(s,1H),8.48(d,J=4.8Hz,1H),7.99(d,J=4.3Hz,1H),7.79(d,J=8.3Hz,2H),7.66(d,J=4.8Hz,1H),7.48(br s,1H),7.38-7.29(m,3H),7.26(d,J=11.8Hz,1H),7.19(d,J=5.0Hz,1H),7.11(d,J =8.5Hz,2H),6.52-6.38(m,1H),6.35-6.21(m,1H),5.85-5.73(m,1H),2.42(s,3H).

[0704] Example 34: Preparation of 7-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-6-(4-methylacrylamidophenyl)pyrrolo[1,2-a]pyrazine-8-carboxamide

[0705]

[0706] Step 1: Preparation of compound 34.3

[0707] To a solution of compound 34.1 (2.00 g, 9.13 mmol) in DCM (20 mL) was added TEA (2.77 g, 27.4 mmol). Compound 34.2 (1.05 g, 10.0 mmol) dissolved in DCM (10 mL) was then added to the solution at 0°C. The reaction was stirred at 0°C for 1 hour. The reaction solution was diluted with water (50 mL) and extracted with DCM (30 mL x 3). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered, concentrated, and purified by silica gel flash column chromatography to give compound 34.3 (1.20 g, 45.78% yield) as a white solid. LCMS: 288.2 [M+H] +

[0708] Step 2: Preparation of Example 34

[0709] Compound 34.4 was synthesized from compound 33.4 in a manner analogous to the procedure of Example 15.

[0710] To a solution of compound 34.4 (240.0 mg, 490.6 μmol) and compound 34.3 (211.3 mg, 735.8 μmol) in dioxane (6 mL) and H2O (3 mL) was added Na2CO3 (104.0 mg, 981.1 μmol). Pd(PPh3)4 (56.7 mg, 49.1 μmol) was then added to the mixture, and the reaction was stirred at 80°C under N2 for 2 hours. After cooling to room temperature, the reaction solution was diluted with water (20 mL) and extracted with EA (20 mL×3). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered, concentrated, and purified by preparative-HPLC to give Example 34. LCMS: 523.4 [M+H] + ; 1 H NMR: (400MHz, DMSO-d6) δ9.98 (s, 1H), 9.23 (s, 1H), 8.48 (d, J = 5.0Hz, 1H), 7.9 8(dd,J=4.9,1.2Hz,1H),7.82(d,J=8.6Hz,2H),7.66(d,J=4.9Hz,1H),7.59-7 .37(m,1H),7.36-7.29(m,3H),7.26(dd,J=11.6,1.8Hz,1H),7.19(d,J=5.0Hz ,1H),7.15-7.01(m,2H),5.82(s,1H),5.55(s,1H),2.43(s,3H),1.96(s,3H).

[0711] Example 35: Preparation of 6-(4-acrylamidophenyl)-7-(3-fluoro-4-((4-methylpyrimidin-2-yl)oxy)phenyl)-3-methylpyrrolo[1,2-a]pyrazine-8-carboxamide

[0712]

[0713] Step 1: Preparation of compound 35.1

[0714] To a solution of compound 33.3 (872.0 mg, 3.76 mmol) and compound 7.1 (500.0 mg, 3.76 mmol) in n-BuOH (10 mL) was added DBU (1.14 g, 7.51 mmol, 1.13 mL). Acetyl cyanide (288.2 mg, 3.76 mmol, 90% purity) was then added to the solution at 25°C and purged with N2 three times. After the addition, the reaction mixture was heated to 100°C in a microwave for 20 minutes. The solution was cooled to room temperature and diluted with water (100 mL). After extraction with EA (50 mL×3), the combined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered, concentrated, and purified by silica gel flash column chromatography to give compound 35.1 (300.0 mg, 21.34% yield) as a yellow solid. LCMS: 374.8 [M+H] + .

[0715] Step 2: Preparation of compound 35.2

[0716] To a mixture of compound 35.1 (280.0 mg, 747.9 μmol) in CH 3 CN (5 mL) was added CH 2 I 2 (3.06 g, 11.44 mmol). Isoamyl nitrite (350.5 mg, 2.99 mmol) was then added to the mixture and the reaction was stirred at 40° C. for 1 hour. After cooling to room temperature, the reaction solution was concentrated and purified by silica gel flash column chromatography to give compound 35.2. LCMS: 485.9 [M+H] + .

[0717] Step 3: Preparation of compound 35.3

[0718] A solution of compound 35.2 (140.0 mg, 288.5 μmol) in H2SO4 (9.20 g, 93.8 mmol, 5 mL) was stirred at 30°C for 16 hours. After cooling to room temperature, the reaction solution was diluted with ice water (30 mL) and the pH of the reaction solution was adjusted to 7 with NaHCO3 (saturated solution). After extraction with EA (20 mL×3), the combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated to give compound 35.3. LCMS: 504.0 [M+H] + .

[0719] Step 4: Preparation of Example 35

[0720] To a solution of compound 35.3 (90.0 mg, 178.8 μmol) and compound 24.8 (63.5 mg, 232.5 μmol) in dioxane (3 mL) and H2O (1 mL) was added Na2CO3 (37.9 mg, 357.7 μmol). Pd(PPh3)4 (20.7 mg, 17.9 μmol) was then added to the mixture under N2, and the mixture was stirred at 80°C for 2 hours. After cooling to room temperature, the reaction solution was diluted with water (20 mL) and extracted with EA (20 mL×3). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered, concentrated, and purified by preparative-HPLC to give Example 35. LCMS: 523.1 [M+H] + . 1 HNMR: (400MHz, DMSO-d6) δ10.35(s,1H),9.18(s,1H),8.47(d,J=5.0Hz,1H) ,7.84-7.76(m,3H),7.50-7.38(m,1H),7.34-7.28(m,3H),7.27-7.21(m,1H ),7.19(d,J=5.0Hz,1H),7.10(d,J=8.4Hz,1H),7.03-6.90(m,1H),6.50-6. 41(m,1H),6.33-6.25(m,1H),5.83-5.77(m,1H),2.42(s,3H),2.35(s,3H).

[0721] Examples 36-55 were prepared using procedures similar to those described in Example 35.

[0722]

[0723]

[0724]

[0725]

[0726]

[0727]

[0728]

[0729]

[0730] Example 50: Preparation of 6-(5-(2-fluoroacrylamido)pyridin-2-yl)-3-methyl-7-(4-((4-methylpyrimidin-2-yl)oxy)phenyl)pyrrolo[1,2-a]pyrazine-8-carboxamide

[0731]

[0732] Step 1: Preparation of compound 50.3

[0733] Compound 50.1 was synthesized in a manner similar to the methods of Example 15 and Example 35.

[0734] A solution of compound 50.1 (150.0 mg, 0.342 mmol), compound 50.2 (88.8 mg, 0.513 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolan (156 mg, 0.616 mmol), KCO (94.6 mg, 0.684 mmol), and Pd(dppf)Cl (37.6 mg, 0.051 mmol) in dioxane (3 mL) was stirred at 100° C. under N for 16 hours. After cooling to room temperature, the reaction mixture was diluted with EA (50 mL), washed with brine (15 mL), dried over NaSO, filtered, and purified by silica gel flash column chromatography to give compound 50.3. LCMS: 451.0 [M+H] + .

[0735] Step 2: Preparation of Example 50

[0736] To a solution of compound 50.3 (100 mg, 0.221 mmol) and 2-fluoroprop-2-enoic acid (39.9 mg, 0.443 mmol) in pyridine (3 mL) was added EDCI (127 mg, 0.664 mmol). The mixture was stirred at 50° C. for 2 hours. The mixture was diluted with DCM (20 mL), washed with water (10 mL×2) and brine (20 mL), dried over Na 2 SO 4 , filtered, concentrated, and purified by preparative-HPLC to give Example 50. LCMS: 524.2 [M+H] + . 1 H NMR: (400MHz, DMSO-d6) δ10.67(s,1H),9.31(s,1H),9.11(d,J=2.3Hz,1H),8. 63(s,1H),8.49(d,J=4.8Hz,1H),8.03(dd,J=8.9,2.4Hz,1H),7.40-7.29(m,3 H),7.23(d,J=8.5Hz,2H),7.18(d,J=5.0Hz,1H),6.95(d,J=8.8Hz,1H),6.66- 6.48(m,1H),5.85-5.69(m,1H),5.54-5.46(m,1H),2.43(s,3H),2.41(s,3H).

[0737] Example 57: Preparation of (E)-6-(4-(4-(dimethylamino)but-2-enoylamino)phenyl)-3-methyl-7-(4-((4-methylpyrimidin-2-yl)oxy)phenyl)pyrrolo[1,2-a]pyrazine-8-carboxamide

[0738]

[0739] Step 1: Preparation of compound 57.2

[0740] To a solution of compound 34.1 (600.0 mg, 2.74 mmol) and compound 57.1 (540.0 mg, 3.29 mmol) in DCM (10 mL) was added DIEA (1.06 g, 8.22 mmol). HATU (1.09 g, 2.88 mmol) was then added to the solution, and the solution was stirred at 25° C. for 3 hours. The reaction solution was diluted with water (30 mL) and extracted with DCM (20 mL×3). The combined organic layers were washed with brine (30 mL), dried over Na 2 SO 4 , filtered, concentrated, and purified by silica gel flash column chromatography to give compound 57.2 (300.0 mg, 33.17%) as a white solid. LCMS: 331.3 [M+H] + .

[0741] Step 2: Preparation of Example 57

[0742] Compound 57.3 was synthesized in a manner similar to the procedure for compound 35.3.

[0743] To a solution of compound 57.3 (120.0 mg, 0.247 mmol) and compound 57.2 (163.3 mg, 0.495 mmol) in dioxane (3 mL) and H2O (1.5 mL) was added K2CO3 (102.5 mg, 0.742 mmol). Pd(PPh3)4 (28.5 mg, 0.025 mmol) was then added to the mixture, and the mixture was stirred at 90°C under N2 for 2 hours. After cooling to room temperature, the reaction mixture was diluted with H2O (20 mL) and extracted with EA (30 mL×3). The combined organic layers were concentrated and purified by preparative HPLC to give Example 57. LCMS: 562.3 [M+H] + . 1 H NMR: (400MHz, DMSO-d6) δ10.22(s,1H),9.24(s,1H),8.46(d,J=4.8Hz,1H),7.84-7.70(m,3H),7.33-7.26(m,5H),7. 18-7.12(m,3H),6.78-6.71(m,1H),6.32-6.29(m,1H),3.07(d,J=4.5Hz,2H),2.41(s,3H),2.35(s,3H),2.19(s,6H).

[0744] Example 58: Preparation of 6-(4-(2-(hydroxymethyl)acrylamido)phenyl)-3-methyl-7-(4-((4-methylpyrimidin-2-yl)oxy)phenyl)pyrrolo[1,2-a]pyrazine-8-carboxamide

[0745]

[0746] Step 1: Preparation of compound 58.1

[0747] To a solution of compound 50.1 (250.0 mg, 0.497 mmol) and compound 24.8 (187.0 mg, 0.684 mmol) in dioxane (5 mL) and H2O (1 mL) was added K2CO3 (189.2 mg, 1.37 mmol). Pd-118 (30.0 mg, 0.046 mmol) was then added to the mixture, and the mixture was stirred at 90°C under N2 for 2 hours. After cooling to room temperature, the reaction solution was diluted with water (10 mL) and extracted with EA (15 mL×3). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue, which was purified by silica gel flash column chromatography to give compound 58.1. LCMS: 505.1 [M+H] + .

[0748] Step 2: Preparation of Example 58

[0749] To a solution of compound 58.1 (70.0 mg, 0.139 mmol) and formaldehyde (56.3 mg, 0.694 mmol, 37%) in dioxane (1 mL) and H2O (0.3 mL) was added DABCO (46.7 mg, 0.416 mmol). The mixture was stirred at 80°C for 8 hours. After cooling to room temperature, the reaction mixture was diluted with H2O (5 mL) and extracted with EA (10 mL x 3). The combined organic layers were concentrated and purified by preparative HPLC to give Example 58. LCMS: 535.1 [M+H] + ; 1 H NMR: (400MHz, DMSO-d6) δ10.33(s,1H),9.19(s,1H),8.46(d,J=5.0Hz,1H),8.11(t,J=6.3Hz,1H),7.84-7.74(m,3H),7.33-7.26(m,4H),7.1 7-7.10(m,3H),6.50-6.41(m,1H),6.32-6.25(m,1H),5.82-5.77(m,1H ),5.73-5.64(m,1H),4.65(t,J=6.2Hz,2H),2.41(s,3H),2.35(s,3H).

[0750] Example 59: Preparation of 6-(4-(2-((dimethylamino)methyl)acrylamido)phenyl)-3-methyl-7-(4-((4-methylpyrimidin-2-yl)oxy)phenyl)pyrrolo[1,2-a]pyrazine-8-carboxamide

[0751]

[0752] Step 1: Preparation of Example 59

[0753] Compound 59.1 was synthesized in a manner similar to the methods of Example 1 and Example 35.

[0754] Example 59 was synthesized from compound 59.1 in a manner similar to that of Example 50. LCMS: 562.3 [M+H] + . 1 H NMR: (400MHz, DMSO-d6) δ11.27(s,1H),9.25(s,1H),8.47(d,J=5.0Hz,1H),7.8 1(s,1H),7.71(d,J=8.5Hz,2H),7.33-7.29(m,5H),7.20-7.13(m,3H),6.58(br s,1H),6.02(s,1H),5.59(s,1H),3.23(s,2H),2.41(s,3H),2.35(s,3H),2.25(s,6H).

[0755] Example 60: Preparation of 6-(4-(2-(methoxymethyl)acrylamido)phenyl)-3-methyl-7-(4-((4-methylpyrimidin-2-yl)oxy)phenyl)pyrrolo[1,2-a]pyrazine-8-carboxamide

[0756]

[0757] Step 1: Preparation of Example 60

[0758] Example 60 was synthesized from compound 50.1 in a manner similar to that of Example 35. LCMS: 549.3 [M+H] + . 1 H NMR: (400MHz, DMSO-d6) δ10.09(s,1H),9.25(s,1H),8.47(d,J=5.1Hz,1H),7.84-7.74(m,3H),7.41-7.25(m,5H),7.18-7.13(m,3H),6.56(br s,1H),5.95(s,1H),5.71(s,1H),4.18-4.14(m,2H),3.30(s,3H),2.41(s,3H),2.35(s,3H).

[0759] Example 61: Preparation of (E)-3-methyl-7-(4-((4-methylpyrimidin-2-yl)oxy)phenyl)-6-(4-(3-(1-methylpyrrolidin-2-yl)acrylamido)phenyl)pyrrolo[1,2-a]pyrazine-8-carboxamide

[0760]

[0761] Step 1: Preparation of compound 61.2

[0762] To a solution of compound 61.1 (500.0 mg, 2.07 mmol) in DCM (5 mL) was added compound 34.1 (454.00 mg, 2.07 mmol), DIEA (1.03 mL, 6.22 mmol) and HATU (866.7 mg, 2.28 mmol). The reaction mixture was stirred at 25° C. for 12 hours. The reaction mixture was poured into H2O (10 mL) and extracted with EA (20 mL×3). The combined organic layers were washed with brine (50 mL), concentrated, and purified by silica gel flash column chromatography to give compound 61.2 (690.0 mg, 75.3%) as a white solid. LCMS: 443.2 [M+H] + .

[0763] Step 2: Preparation of compound 61.3

[0764] To a solution of compound 50.1 (200.0 mg, 0.456 mmol) in dioxane (5 mL) and H2O (1 mL) was added compound 61.2 (242.2 mg, 0.548 mmol). Pd-118 (29.7 mg, 0.046 mmol) and K2CO3 (189.2 mg, 1.37 mmol) were then added to the solution under N2. The solution was stirred at 90°C for 2 hours. After cooling to room temperature, the reaction mixture was concentrated and purified by silica gel flash column chromatography to give compound 61.3. LCMS: 674.3 [M+H] + .

[0765] Step 3: Preparation of compound 61.4

[0766] To a solution of compound 61.3 (160.0 mg, 0.24 mmol) in DCM (2 mL) was added TFA (0.5 mL, 0.007 mmol), and the solution was stirred at 25° C. for 1 hour. After the reaction was complete, the solution was concentrated under reduced pressure to give compound 61.4. LCMS: 574.4 [M+H] + .

[0767] Step 4: Preparation of Example 61

[0768] To a solution of compound 61.4 (160.0 mg, 0.279 mmol) and HCHO (45.3 mg, 0.558 mmol) in MeOH (2 mL) was added NaBH3CN (61.3 mg, 0.976 mmol) and DIEA (0.138 mL, 0.837 mmol). The mixture was stirred at 25 ° C for 2 hours. After the reaction was completed, the mixture was diluted with water (10 mL) and extracted with EA (8 mL×3). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered, concentrated, and purified by preparative-HPLC to give Example 61. LCMS: 588.3 [M+H] + ; 1 H NMR: (400MHz, DMSO-d6) δ10.21(s,1H),9.24(s,1H),8.46(d,J=5.1Hz,1H),7.81(s,1H),7.73(d,J=8.6Hz,2H),7.36(br s,1H),7.31-7.25(m,4H),7.17-7.11(m,3H),6.65(dd,J=15.2,7.5Hz,1H),6.58(br s,1H),6.26(d,J=15.2Hz,1H),3.06-2.99(m,1H),2.77-2.73(m,1H),2.40(s,3H),2.3 4(s,3H),2.26-2.13(m,4H),2.06-1.95(m,1H),1.79-1.68(m,2H),1.61-1.49(m,1H).

[0769] Example 62: Preparation of 6-(4-(but-2-ynylamino)phenyl)-3-methyl-7-(4-((4-methylpyrimidin-2-yl)oxy)phenyl)pyrrolo[1,2-a]pyrazine-8-carboxamide

[0770]

[0771] Step 1: Preparation of compound 62.2

[0772] To a solution of compound 34.1 (700.0 mg, 3.65 mmol) and compound 62.1 (340.0 mg, 4.02 mmol) in DCM (10 mL) was added DIEA (1.42 g, 10.9 mmol). HATU (1.46 g, 3.83 mmol) was then added to the solution, and the solution was stirred at 25° C. for 3 hours. The reaction solution was diluted with water (30 mL) and extracted with DCM (20 mL×3). The combined organic layers were washed with brine (30 mL), dried over Na 2 SO 4 , filtered, concentrated, and purified by silica gel flash column chromatography to give compound 62.2 (650.0 mg, 62.43%) as a white solid. LCMS: 286.2 [M+H] + .

[0773] Step 2: Preparation of Example 62

[0774] To a solution of compound 57.3 (120.0 mg, 0.247 mmol) and compound 62.2 (105.8 mg, 0.371 mmol) in dioxane (3 mL) and H2O (1.5 mL) was added K2CO3 (102.5 mg, 0.742 mmol). Pd(PPh3)4 (28.5 mg, 0.025 mmol) was then added to the mixture, and the mixture was stirred at 90°C under N2 for 2 hours. After cooling to room temperature, the reaction mixture was diluted with H2O (20 mL) and extracted with EA (10 mL×3). The combined organic layers were concentrated and purified by preparative HPLC to give Example 62. LCMS: 517.1 [M+H] + . 1 H NMR: (400MHz, DMSO-d6) δ10.78(s,1H),9.25(d,J=1.0Hz,1H),8.46(d,J=5.0Hz,1H),7.81(s,1H),7.67(d,J=8.4Hz,2H ),7.40-7.33(m,1H),7.31-7.26(m,4H),7.18-7.12(m,3H),6.69-6.40(m,1H),2.41(s,3H),2.34(s,3H),2.06(s,3H).

[0775] Example 63: Preparation of 6-(4-(2-fluoroacrylamido)phenyl)-7-(4-(((3-fluorooxetan-3-yl)methyl)carbamoyl)phenyl)-3-methylpyrrolo[1,2-a]pyrazine-8-carboxamide

[0776]

[0777] Step 1: Preparation of compound 63.2

[0778] To a solution of compound 1.2 (500.0 mg, 3.75 mmol) in MeOH (8 mL) were added compound 63.1 (616.4 mg, 3.75 mmol), DBU (114.3 mg, 0.75 mmol) and acetyl cyanide (259.4 mg, 3.75 mmol), and the solution was stirred at 100° C. for 30 minutes. After cooling to room temperature, the reaction mixture was concentrated and purified by silica gel flash column chromatography to give compound 63.2 (690.0 mg, 60.0%) as a yellow solid. LCMS: 307.1 [M+H] + .

[0779] Step 2: Preparation of compound 63.3

[0780] To a solution of compound 63.2 (690.0 mg, 2.25 mmol) in HBr / AcOH (5 mL) was added CuBr2 (654.1 mg, 2.93 mmol) at 0°C, and sodium nitrite (777.2 mg, 11.3 mmol) in H2O (5 mL) was added. The mixture was stirred at 0°C for 1 hour. After cooling to room temperature, the reaction solution was dissolved in 20 mL of water. The pH of the solution was adjusted to 8 with Na2CO3 (aqueous solution). The reaction solution was extracted with EA (30 mL×3). The combined organic phases were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, concentrated in vacuo, and purified by flash column chromatography on silica gel to give compound 63.3 (160.0 mg, 19.2%) as a yellow solid. LCMS: 370.0 [M+H] + .

[0781] Step 3: Preparation of compound 63.4

[0782] A solution of compound 63.3 (160.0 mg, 0.432 mmol) in H2SO4 (1.5 mL) was stirred at 25°C for 12 hours. After cooling to room temperature, the reaction solution was dissolved in water (20 mL). The pH of the solution was adjusted to 8 with Na2CO3 (aqueous solution). The reaction solution was extracted with EA (20 mL×3). The combined organic phases were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to give compound 63.4 (100 mg, crude product) as a brown solid. LCMS: 390.0 [M+H] + .

[0783] Step 4: Preparation of compound 63.5

[0784] To a solution of compound 63.4 (95.0 mg, 0.245 mmol) in THF (2 mL) was added potassium trimethylsilanol (31.4 mg, 0.245 mmol), and the solution was stirred at 25° C. for 2 hours. After the solution operation was completed, the reaction mixture was concentrated to give compound 63.5. LCMS: 373.9 [M+H] + .

[0785] Step 5: Preparation of compound 63.7

[0786] To a solution of compound 63.5 (91.0 mg, 0.243 mmol) in DCM (1 mL) was added compound 63.6 (25.6 mg, 0.243 mmol), DIEA (0.12 mL, 0.73 mmol) and HATU (97.1 mg, 0.255 mmol). The solution was stirred at 25 ° C for 12 hours. After the reaction was complete, the solution was concentrated and purified by silica gel flash column chromatography to give compound 63.7. LCMS: 461.0 [M+H] + .

[0787] Step 6: Preparation of Example 63

[0788] To a solution of compound 63.7 (50.0 mg, 0.108 mmol) and compound 63.8 (47.3 mg, 0.163 mmol) in dioxane (1 mL) was added Pd(PPh 3 ) 4 (12.5 mg, 0.011 mmol) and K 2 CO 3 (44.9 mg, 0.325 mmol) under N 2 . The solution was stirred at 90 ° C for 3 hours. The reaction solution was diluted with water (10 mL) and extracted with EA (10 mL×3). The combined organic phase was washed with brine (15 mL), dried over anhydrous Na 2 SO 4 , filtered, concentrated, and purified by preparative-HPLC to give Example 63. LCMS: 546.2 [M+H] + ; 1 H NMR: (400MHz, DMSO-d6) δ10.43(s,1H),9.22(s,1H),8.80(t,J=6.1Hz,1H),7.85-7.76(m,5H),7.35-7.26(m,5H),6.66(br s,1H),5.81-5.65(m,1H),5.46(dd,J=15.6,3.7Hz,1H),4.72-4.56(m,4H),3.83-3.75(m,2H),2.34(s,3H).

[0789] Example 64: Preparation of 6-(4-acrylamidophenyl)-7-(4-(((3-fluorooxetane-3-yl)methyl)carbamoyl)phenyl)-3-methylpyrrolo[1,2-a]pyrazine-8-carboxamide

[0790]

[0791] Step 1: Preparation of Example 64

[0792] Example 64 was synthesized from compound 63.7 in a manner similar to that of Example 63. LCMS: 528.1 [M+H] + . 1 H NMR: (400MHz, DMSO-d6) δ10.33(s,1H),9.22(s,1H),8.84-8.76(m,1H),7.84(s,1H),7.80 (d,J=8.1Hz,2H),7.74(d,J=8.6Hz,2H),7.34(d,J=8.4Hz,2H),7.28-7.25(m,2H),6.67(br s,1H),6.49-6.39(m,1H),6.33-6.24(m,1H),5.83-5.73(m,1H),4.75-4.54(m,5H),3.80(dd,J=19.6,5.9Hz,2H),2.35(s,3H).

[0793] Example 65: Preparation of 6-(4-(but-2-ynylamino)phenyl)-7-(4-(((3-fluorooxetane-3-yl)methyl)carbamoyl)phenyl)-3-methylpyrrolo[1,2-a]pyrazine-8-carboxamide

[0794]

[0795] Step 1: Preparation of Example 65

[0796] Example 65 was synthesized from compound 63.7 in a manner similar to that of Example 63. Spectral data of Example 65: LCMS: 540.2 [M+H] + . 1H NMR: (400MHz, DMSO-d6) δ10.77(s,1H),9.23(s,1H),8.80(t,J=5.6Hz,1H),7.96-7.80(m,3H),7.66-7.64(m,2H),7.34-7.3 2(m,3H),7.26-7.24(m,2H),6.70-6.61(m,1H),4.71-4.58(m,4H),3.80(dd,J=20.0,6.0Hz,2H),2.35(s,3H),2.06(s,3H).

[0797] Example 66: Preparation of 6-(2-ethynyl-1-methyl-1H-benzo[d]imidazol-6-yl)-3-methyl-7-(4-((4-methylpyrimidin-2-yl)oxy)phenyl)pyrrolo[1,2-a]pyrazine-8-carboxamide

[0798]

[0799] Step 1: Preparation of compound 66.2

[0800] To a solution of compound 66.1 (1.00 g, 4.18 mmol) and (Bpin)2 (3.10 g, 8.37 mmol) in dioxane (15 mL) was added AcOK (0.80 g, 8.37 mmol). Pd(dppf)Cl2 (0.30 g, 0.42 mmol) was then added to the mixture, and the mixture was stirred at 90°C under N2 for 16 hours. After cooling to room temperature, the reaction solution was diluted with water (20 mL) and extracted with EA (30 mL×3). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered, concentrated, and purified by silica gel flash co...

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt or stereoisomer thereof: in: Z 1 does not exist, is C(R 5 )、C(R 5 )(R 5a ), N or N(R 9 ); Z 2 C(R 6 )、C(R 6 )(R 6a ), O, S, N or N(R 9 ); Z 3 C(R 7 )、C(R 7 )(R 7a ), O, S, N or N(R 9 ); Z 4 C(R 8 )、C(R 8 )(R 8a ), O, S, N or N(R 9 ); Among them, when Z 1 C(R 5 )、C(R 5 )(R 5a ), N or N(R 9 ),Z 1 , Z 2 , Z 3 and Z 4 No more than 2 of them are N or N(R 9 ); and when Z 1 When Z does not exist, 2 , Z 3 and Z 4 No more than one of them is O, S, N or N(R 9 ); R 1 and R 2 are independently selected from hydrogen, C 1-6 Alkyl and C 1-6 Haloalkyl; R 3 Selected from C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl and C 1-9 Heteroaryl, wherein C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl and C 1-9 Heteroaryl is optionally substituted by 1, 2 or 3 groups selected from R 15a ; R 4 Selected from C 3-6 Cycloalkylene, C 2-9 Heterocycloalkylene, C 6-10 Arylene and C 1-9 Heteroarylene, wherein C 3-6 Cycloalkylene, C 2-9 Heterocycloalkylene, C 6-10 Arylene and C 1-9 Heteroarylene is optionally substituted by 1, 2 or 3 groups selected from R 15b ; L 1 is a valence bond, -N(R 9a )-、-N(R 9a )C(O)-、-C(O)N(R 9a )-、-N(R 9a )S(O)2-、-S(O)2N(R 9a )-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -C(S)-, -S-, -S(O)-, -S(O)2-, -OS(O)-, -OS(O)2-, C 1-6 Alkylene, C 2-6 Alkenylene, C 2-6 Alkynylidene, C 3-6 Cycloalkylene, C 2-9 Heterocycloalkylene or C 1-9 Heteroarylene, wherein C 1-6 Alkylene, C 2-6 Alkenylene, C 2-6 Alkynylidene, C 3-6 Cycloalkylene, C 2-9 Heterocycloalkylene and C 1-9 Heteroarylene is optionally substituted by 1, 2 or 3 groups selected from R 15c ; L 2 For valence bond, C 1-6 Alkylene, C 2-6 Alkenylene or C 2-6 Alkyne, where C 1-6 Alkylene, C 2-6 Alkenylene or C 2-6 Alkyne is optionally substituted by 1, 2 or 3 groups selected from R 15c ; R 4a Selected from halogen, -CN, R 4b , R 4c and R 4d are each independently selected from hydrogen, halogen, -CN, -C(O)R 13 、-C(O)OR 10 、-C(O)N(R 10 )(R 11 )、-N(R 10 )(R 11 ),-C 1-6 Alkyl-N(R 10 )(R 11 )、-C(O)N(R 10 )OR 10 , C 1-6 alkyl, phenyl, 3 to 7-membered heterocycloalkyl or 5 or 6-membered heteroaryl, wherein the C 1-6 Alkyl, phenyl, 3 to 7-membered heterocycloalkyl or 5 or 6-membered heteroaryl are optionally substituted by 1, 2 or 3 groups selected from R 15d ;or R 4b and R 4c Together with the atoms to which they are attached, they form a 3 to 14-membered cycloalkyl group or a 3 to 14-membered heterocycloalkyl group; wherein the 3 to 14-membered cycloalkyl group and the 3 to 14-membered heterocycloalkyl group are optionally substituted by 1, 2, 3 or 4 R 15d Replacement; or R 4d and R 4c Together with the atoms to which they are attached, they form a 3 to 14-membered cycloalkyl group or a 3 to 14-membered heterocycloalkyl group; wherein the 3 to 14-membered cycloalkyl group and the 3 to 14-membered heterocycloalkyl group are optionally substituted by 1, 2, 3 or 4 R 15d replace; R 4e Halogen or -OS(O)2R 13 ; R 5 , R 5a , R 6 , R 6a , R 7 , R 7a , R 8 and R 8a are independently selected from hydrogen, halogen, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, C 1-9 Heteroaryl, -OR 10 、-SR 10 、-SF5、-N(R 10 )(R 11 )、-C(O)OR 10 、-OC(O)N(R 10 )(R 11 )、-N(R 12 )C(O)N(R 10 )(R 11 )、-N(R 12 )C(O)OR 13 、-N(R 12 )S(O)2R 13 、-C(O)R 13 、-S(O)R 13 、-OC(O)R 13 、-C(O)N(R 10 )(R 11 )、-C(O)C(O)N(R 10 )(R 11 )、-N(R 12 )C(O)R 13 、-S(O)2R 13 、-S(O)2N(R 10 )(R 11 )-、-N=S(=O)(R 13 )2, -S(=O)(=NH)N(R 10 )(R 11 )、-S(=O)(=NH)(R 13 )、-S(=O)(=NR 13 )R 13 、-CH2C(O)N(R 10 )(R 11 )、-CH2N(R 12 )C(O)R 13 、-CH2S(O)2R 13 、-CH2S(O)2N(R 10 )(R 11 )、-Si(C 1-6 alkyl)3 and -P(O)(R 10 )2, where C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl and C 1-9 Heteroaryl is optionally substituted by 1, 2 or 3 groups selected from R 15e ; R 9 Selected from hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl, C 1-9 Heteroaryl, -C(O)OR 10 、-C(O)R 13 、-S(O)R 13 、-C(O)N(R 10 )(R 11 ) and -S(O)2R 13 , where C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl and C 1-9 Heteroaryl is optionally substituted by 1, 2 or 3 groups selected from R 15f ; R 9a Selected from hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl and C 1-9 Heteroaryl, wherein C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl and C 1-9 Heteroaryl is optionally substituted by 1, 2 or 3 groups selected from R 15g ; R 10 are each independently selected from hydrogen, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, -CH2-C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, -CH2-C 2-9 Heterocycloalkyl, -CH2-C 6-10 Aryl, C 6-10 Aryl, C 1-9 Heteroaryl and -CH2-C 1-9 Heteroaryl, wherein C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, -CH2-C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, -CH2-C 2-9 Heterocycloalkyl, -CH2-C 6-10 Aryl, C 6-10 Aryl, C 1-9 Heteroaryl and -CH2-C 1-9 The heteroaryl group is optionally substituted by 1, 2 or 3 groups selected from halogen, -CN, hydroxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl and C 1-9 heteroaryl; R 11 are each independently selected from hydrogen, C 1-6 Alkyl and C 1-6 haloalkyl; or R 10 and R 11 Together with the attached nitrogen, it forms C 2-9 Heterocycloalkyl; R 12 are each independently selected from hydrogen, C 1-6 Alkyl and C 1-6 Haloalkyl; R 13 Each independently selected from C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl and C 1-9 Heteroaryl, wherein C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl and C 1-9 The heteroaryl group is optionally substituted by 1, 2 or 3 groups selected from halogen, -CN, hydroxyl, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, C 6-10 Aryl and C 1-9 heteroaryl; Each R 15a , R 15b , R 15c , R 15d , R 15e , R 15f and R 15g are independently selected from halogen, oxo, -CN, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, -CH2-C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, -CH2-C 2-9 Heterocycloalkyl, C 6-10 Aryl, -CH2-C 6-10 Aryl, C 1-9 Heteroaryl, -CH2-C 1-9 Heteroaryl, -OR 10 、-SR 10 、-SF5、-N(R 10 )(R 11 )、-C(O)OR 10 、-OC(O)N(R 10 )(R 11 )、-N(R 12 )C(O)N(R 10 )(R 11 )、-N(R 12 )C(O)OR 13 、-N(R 12 )S(O)2R 13 、-C(O)R 13 、-S(O)R 13 、-OC(O)R 13 、-C(O)N(R 10 )(R 11 )、-C(O)C(O)N(R 10 )(R 11 )、-N(R 12 )C(O)R 13 、-S(O)2R 13 、-S(O)2N(R 10 )(R 11 )-、-N=S(=O)(R 13 )2, -S(=O)(=NH)N(R 10 )(R 11 )、-S(=O)(=NH)(R 13 )、-S(=O)(=NR 13 )R 13 、-CH2C(O)N(R 10 )(R 11 )、-CH2N(R 12 )C(O)R 13 、-CH2S(O)2R 13 、-CH2S(O)2N(R 10 )(R 11 )、-Si(C 1-6 alkyl)3 and -P(O)(R 10 )2, where C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-10 Cycloalkyl, -CH2-C 3-6 Cycloalkyl, C 2-9 Heterocycloalkyl, -CH2-C 2-9 Heterocycloalkyl, C 6-10 Aryl, -CH2-C 6-10 Aryl, -CH2-C 1-9 Heteroaryl and C 1-9 Heteroaryl is optionally substituted with 1, 2 or 3 groups independently selected from halogen, oxo, -CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, -OR 10 、-SR 10 、-SF5、-N(R 10 )(R 11 )、-C(O)OR 10 、-OC(O)N(R 10 )(R 11 )、-N(R 12 )C(O)N(R 10 )(R 11 )、-N(R 12 )C(O)OR 13 、-N(R 12 )S(O)2R 13 、-C(O)R 13 、-S(O)R 13 、-OC(O)R 13 、-C(O)N(R 10 )(R 11 )、-C(O)C(O)N(R 10 )(R 11 )、-N(R 12 )C(O)R 13 、-S(O)2R 13 、-S(O)2N(R 10 )(R 11 )-、-N=S(=O)(R 13 )2, -S(=O)(=NH)N(R 10 )(R 11 )、-S(=O)(=NH)(R 13 )、-S(=O)(=NR 13 )R 13 、-CH2C(O)N(R 10 )(R 11 )、-CH2N(R 12 )C(O)R 13 、-CH2S(O)2R 13 、-CH2S(O)2N(R 10 )(R 11 ) and -P(O)(R 10 )2, and Denote single or double bonds so that all valences are satisfied.

2. The compound of claim 1 or a pharmaceutically acceptable salt or stereoisomer thereof, which has the structure of formula (Ia):

3. The compound of claim 1 or a pharmaceutically acceptable salt or stereoisomer thereof, which has the structure of formula (Ib):

4. The compound of claim 1 or a pharmaceutically acceptable salt or stereoisomer thereof, which has the structure of formula (Ic):

5. The compound of claim 1 or a pharmaceutically acceptable salt or stereoisomer thereof, which has the structure of formula (Id):

6. The compound of claim 1 or a pharmaceutically acceptable salt or stereoisomer thereof, which has the structure of formula (Ie):

7. The compound of claim 6 or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 9 Selected from hydrogen, C 1-6 Alkyl and C 1-6 Halogenated alkyl.

8. The compound of claim 7 or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 9 C 1-6 alkyl.

9. The compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 5 , R 6 , R 7 and R 8 are independently selected from hydrogen, halogen, -OR 10 and C 1-6 Alkyl, where C 1-6 The alkyl group is optionally substituted by 1, 2 or 3 groups selected from R 15e .

10. The compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 5 , R 6 , R 7 and R 8 are independently selected from hydrogen and unsubstituted C 1-6 alkyl.

11. The compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 5 , R 6 , R 7 and R 8 Each is hydrogen.

12. The compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 3 Selected from C 6-10 Aryl and C 1-9 Heteroaryl, wherein C 6-10 Aryl and C 1-9 Heteroaryl is optionally substituted by 1, 2 or 3 groups selected from R 15a .

13. The compound according to any one of claims 1 to 12, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 3 is phenyl, which is optionally substituted by 1, 2 or 3 groups selected from R 15a .

14. The compound according to any one of claims 1 to 13, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 3 is phenyl, which is substituted by 1, 2 or 3 groups selected from R 15a .

15. The compound of claim 13 or a pharmaceutically acceptable salt or stereoisomer thereof, which has a structure of Formula (Ia') or Formula (Ia"): in R 10 C 1-9 Heteroaryl, which is optionally substituted by 1, 2 or 3 groups selected from halogen, -CN, hydroxyl, C 1-6 Alkyl, C 1-6 Haloalkyl and C 1-6 alkoxy; and R 15aa Having the same R as in claim 1 15a Same meaning.

16. The compound of claim 13 or a pharmaceutically acceptable salt or stereoisomer thereof, which has a structure of Formula (Ib') or Formula (Ib"): in R 10 C 1-9 Heteroaryl, which is optionally substituted by 1, 2 or 3 groups selected from halogen, -CN, hydroxyl, C 1-6 Alkyl, C 1-6 Haloalkyl and C 1-6 alkoxy; and R 15aa Having the same R as in claim 1 15a Same meaning.

17. The compound of claim 13 or a pharmaceutically acceptable salt or stereoisomer thereof, which has a structure of Formula (Ic') or Formula (Ic"): in R 10 C 1-9 Heteroaryl, which is optionally substituted by 1, 2 or 3 groups selected from halogen, -CN, hydroxyl, C 1-6 Alkyl, C 1-6 Haloalkyl and C 1-6 alkoxy; and R 15aa Having the same R as in claim 1 15a Same meaning.

18. The compound according to any one of claims 15 to 17, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 15aa Selected from halogen, C 1-6 Alkyl and -OCH3.

19. The compound according to any one of claims 15 to 18, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 15aa It is a halogen.

20. The compound according to any one of claims 15 to 19, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 10 C 1-9 Heteroaryl, which is optionally substituted by 1, 2 or 3 groups selected from halogen, -CN, hydroxyl, C 1-6 Alkyl, C 1-6 Haloalkyl and C 1-6 Alkoxy.

21. The compound of any one of claims 15 to 20, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 10 is pyridyl or pyrimidinyl, wherein the pyridyl or pyrimidinyl is optionally substituted by 1, 2 or 3 groups selected from halogen, -CN, hydroxyl, C 1-6 Alkyl, C 1-6 Haloalkyl and C 1-6 Alkoxy.

22. The compound of any one of claims 15 to 21, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 10 is pyridyl or pyrimidinyl, wherein the pyridyl or pyrimidinyl is substituted by 1, 2 or 3 groups selected from C 1-6 alkyl.

23. The compound of any one of claims 15 to 22, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 10 for 24. The compound of any one of claims 1 to 23, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 4 Selected from C 2-9 Heterocycloalkylene, C 6-10 Aryl and C 1-9 Heteroaryl, wherein C 2-9 Heterocycloalkylene, C 6-10 Aryl and C 1-9 Heteroaryl is optionally substituted by 1, 2 or 3 groups selected from R 15b .

25. The compound of any one of claims 1 to 24, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 4 is phenyl, which is optionally substituted by 1, 2 or 3 groups selected from R 15b .

26. The compound of any one of claims 1 to 25, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 4 is phenyl, which is optionally substituted by 1, 2 or 3 groups selected from R 15b .

27. The compound of any one of claims 1 to 26, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein L 1 is a valence bond, -N(R 9a )-、-N(R 9a )C(O)-、-C(O)N(R 9a )-、-N(R 9a )S(O)2-、-S(O)2N(R 9a )-, -O-, -C(O)-, -OC(O)-, -C(O)O-, -S-, -S(O)-, -S(O)2- or C 1-6 Alkylene, which is optionally substituted by 1, 2 or 3 groups selected from R 15c .

28. The compound of any one of claims 1 to 27, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein L 1 is a valence bond, -N(R 9a )-、-N(R 9a )C(O)-、-C(O)N(R 9a )- or -C(O)-.

29. The compound of any one of claims 1 to 28, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein L 1 -N(R 9a )-.

30. The compound of any one of claims 1 to 29, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 9a Selected from hydrogen and C 1-6 Alkyl, which is optionally substituted by 1, 2 or 3 groups selected from R 15g .

31. The compound of any one of claims 1 to 30, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 9a For hydrogen.

32. The compound of any one of claims 1 to 31, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 4a Selected from 33. The compound of any one of claims 1 to 32, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 4a for 34. The compound of any one of claims 1 to 33, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 4b , R 4c and R 4d are independently hydrogen, halogen, C 1-6 Alkyl or -C 1-6 Alkyl-N(R 10 )(R 11 ), wherein the alkyl group is optionally substituted with 1, 2 or 3 R 15d replace.

35. The compound of any one of claims 1 to 34, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 4c and R 4d are each independently hydrogen or -C 1-6 Alkyl-N(R 10 )(R 11 ).

36. The compound of any one of claims 1 to 35, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 4c and R 4d Each is independently hydrogen or -CH2-N(CH3)2.

37. The compound of any one of claims 1 to 36, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 4b is hydrogen, halogen or C 1-6 Alkyl, wherein the alkyl group is optionally substituted by 1, 2 or 3 R 15d replace.

38. The compound of any one of claims 1-14 or 8-37, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein L 2 For the price key.

39. The compound of any one of claims 1 to 38, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 1 and R 2 are independently selected from hydrogen and C 1-6 alkyl.

40. The compound of any one of claims 1 to 39, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 1 and R 2 For hydrogen.

41. A compound or a pharmaceutically acceptable salt or stereoisomer thereof selected from:

42. A pharmaceutical composition comprising a compound according to any one of claims 1 to 41 or a pharmaceutically acceptable salt or stereoisomer thereof and at least one pharmaceutically acceptable excipient.

43. A method of treating cancer in a mammal in need thereof, the method comprising administering to the mammal a compound of any one of claims 1-41 or a pharmaceutically acceptable salt or stereoisomer thereof.

44. The method of claim 43, wherein the cancer is a solid tumor.

45. The method of claim 44, wherein the cancer is intrahepatic bile duct cancer, urothelial carcinoma, gastric cancer, bladder cancer, breast cancer, endometrial cancer, kidney cancer, liver cancer, lung cancer, melanoma, pancreatic cancer, prostate cancer, or thyroid cancer.

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