Pyrrotriazine compounds as TAM inhibitors

Abstract

To provide compounds which are inhibitors of TAM kinases which are useful for treatment of disorders such as cancer.SOLUTION: This application relates to compounds of Formula I in the figure or pharmaceutically acceptable salts thereof.SELECTED DRAWING: None

Description

[Technical Field]

[0001] Cross-reference of related applications This application claims priority to U.S. Provisional Patent Application No. 62 / 314,066 filed on 28 March 2016, U.S. Provisional Patent Application No. 62 / 362,934 filed on 15 July 2016, and U.S. Provisional Patent Application No. 62 / 438,750 filed on 23 December 2016. These provisional applications are incorporated herein by reference in their entirety.

[0002] This application relates to pyrrotriazine inhibitors of TAM kinase, and in one embodiment, to inhibitors of AXL and MER kinase. These are useful for the treatment of diseases such as cancer and for related pharmaceutical compositions. [Background technology]

[0003] Receptor tyrosine kinases (RTKs) are cell surface proteins that transmit signals from the extracellular environment to the cytoplasm and nucleus, regulating cellular events such as survival, growth, proliferation, differentiation, adhesion, and migration.

[0004] The TAM subfamily consists of three RTKs: Tyro3, ​​AXL, and Mer (Graham et al., 2014, Nature Reviews Cancer 14, 769-785; Linger et al., 2008, Advances in Cancer Research 100, 35-83). TAM kinases are characterized by an extracellular ligand-binding domain consisting of two immunoglobulin-like domains and two fibronectin type III domains. Two ligands, namely growth arrest-specific 6 (GAS6) and protein S (PROS1), have been identified for TAM kinases. GAS6 can bind to and activate all three TAM kinases, while PROS1 is a ligand for Mer and Tyro3 (Graham et al., 2014, Nature Reviews Cancer 14, 769-785).

[0005] AXL (also known as UFO, ARK, JTK11, and TYRO7) was originally identified as a transformant gene derived from the DNA of patients with chronic myeloid leukemia (O'Bryan et al., 1991, Mol Cell Biol 11, 5016-5031; Graham et al., 2014, Nature Reviews Cancer 14, 769-785; Linger et al., 2008, Advances in Cancer Research 100, 35-83). GAS6 binds to AXL, subsequently inducing autophosphorylation and activation of AXL tyrosine kinase. AXL activates several downstream signaling pathways, including PI3K-Akt, Raf-MAPK, and PLC-PKC (Feneyrolles et al., 2014, Molecular Cancer Therapeutics 13, 2141-2148; Linger et al., 2008, Advances in Cancer Research 100, 35-83).

[0006] MER (also known as MERTK, EYK, RYK, RP38, NYK, and TYRO12) was originally identified as a phosphoprotein from a lymphoblast-like expression library (Graham et al., 1995, Oncogene 10, 2349-2359; Graham et al., 2014, Nature Reviews Cancer 14, 769-785; Linger et al., 2008, Advances in Cancer Research 100, 35-83). Both GAS6 and PROS1 can bind to Mer and induce phosphorylation and activation of Mer kinase (Lew et al., 2014). Similar to AXL, MER activation also transmits downstream signaling pathways including PI3K-Akt and Raf-MAPK (Linger et al., 2008, Advances in Cancer Research 100, 35-83).

[0007] TYRO3 (also known as DTK, SKY, RSE, BRT, TIF, and ETK2) was originally identified through PCR-based cloning studies (Lai et al., Neuron 6, 691-70, 1991; Graham et al., 2014, Nature Reviews Cancer 14, 769-785; Linger et al., 2008, Advances in Cancer Research 100, 35-83). Both ligands, GAS6 and PROS1, can bind to and activate TYRO3. The downstream signaling pathways of TYRO3 activation are the least studied among TAM RTKs, but both the PI3K-Akt and Raf-MAPK pathways are thought to be involved (Linger et al., 2008, Advances in Cancer Research 100, 35-83). AXL, MER, and TYRO3 have been found to be overexpressed in cancer cells.

[0008] Therefore, compounds for regulating TAM kinases in cancer treatment and methods for their use are needed. [Overview of the project]

[0009] In one embodiment, this application relates to Formula I: [ka] With respect to compounds having or pharmaceutically acceptable salts thereof, in the formula, the variable element R 1 , R 2 , R 3 Cy C , and Cy B This is as described herein.

[0010] This application further provides compositions comprising a compound described herein, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.

[0011] This application also provides methods for inhibiting TAM kinases, and in one embodiment, methods for inhibiting AXL and MER kinases, which involve contacting one or more TAM kinases with a compound described herein or a pharmaceutically acceptable salt thereof.

[0012] This application also provides a compound described herein or a pharmaceutically acceptable salt thereof for use in any of the methods described herein.

[0013] This application further provides the use of a compound described herein or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for use in any of the methods described herein.

Embodiments for Carrying out the Invention

[0014] Detailed Description This application particularly relates to a compound of formula I:

Chemical Formula

[0015] In some embodiments, the herein provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein: R 1 is, A 1 -A 2 -A 3 -R A And, R 2 H, Haro, CN, C 1-4Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Haloalkoxy, cyano-C 1-3 Alkyl, or C 1-6 It is an alkoxyalkyl, R 3 H, Haro, CN, C 1-6 Alkyl, C 1-6 Haloalkyl, OR a , SR a , C(O)NR c R d , NR c R d , NR c C(O)R b , NR c S(O)2R b , or S(O)2R b and C 1-6 Alkyl and C 1-6 Haloalkyl can optionally be Halo, CN, OR a , SR a , C(O)NR c R d , NR c R d , NR c C(O)R b , NR c S(O)2R b S(O)2R b , NR c C(O)OR a , NR c C(O)NR c R d , NR c S(O)2NR c R d , and Cy R3 Substituted with one, two, or three substituents independently selected from, A 1 is a combination, Cy A1 -Y-, -C 1-3 Alkylene-,-C 1-3 Alkilen-Y-, -YC 1-3 Alkylene-, and -C 1-2 Alkilen-YC 1-2Selected from alkylene groups, each of which can be optionally halo, CN, OH, or C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl, C 1-3 Haloalkoxy, amino, C 1-3 Alkylamino and di(C) 1-3 Substituted with one, two, or three substituents independently selected from alkyl)amino, A 2 is a combination, Cy A2 -Y-, -C 1-3 Alkylene-,-C 1-3 Alkilen-Y-, -YC 1-3 Alkylene-, and -C 1-2 Alkilen-YC 1-2 Selected from alkylene groups, each of which can be optionally halo, CN, OH, or C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl, C 1-3 Haloalkoxy, amino, C 1-3 Alkylamino and di(C) 1-3 Substituted with one, two, or three substituents independently selected from alkyl)amino, A 3 is a combination, Cy A3 -Y-, -C 1-3 Alkylene-,-C 1-3 Alkilen-Y-, -YC 1-3 Alkylene-, and -C 1-2 Alkilen-YC 1-2 Selected from alkylene groups, each of which can be optionally halo, CN, OH, or C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl, C 1-3 Haloalkoxy, amino, C 1-3 Alkylamino and di(C) 1-3 Substituted with one, two, or three substituents independently selected from alkyl)amino, R A H, C 1-6 Alkyl, C 1-6Haloalkyl, Halo, CN, NO2, OR a1 , SR a1 , C(O)R b1 , C(O)NR c1 R d1 , C(O)OR a1 ,OC(O)R b1 , OC(O)NR c1 R d1 , NR c1 R d1 , NR c1 Ure d1 , NR c1 C(O)R b1 , NR c1 C(O)OR a1 , NR c1 C(O)NR c1 R d1 , C(=NR e1 )R b1 , C(=NR e1 )NR c1 R d1 , NR c1 C(=NR e1 )NR c1 R d1 , NR c1 S(O)R b1 , NR c1 S(O)2R b1 , NR c1 S(O)2NR c1 R d1 S(O)R b1 , S(O)NR c1 R d1 S(O)2R b1 , or S(O)2NR c1 R d1 and C 1-6 Alkyl or C 1-6 Haloalkyls are optional, R 11 Substituted with 1, 2, 3, or 4 substituents independently selected from, Y is O, S, S(O), S(O)2, C(O), C(O)NR f , NR f C(O), NR f C(O)NR f , NR f S(O)2NR f , S(O)2NR f , NRf S(O)2, or NR f And, Each R f H and C 1-3 Selected independently of alkyl, Cy A1 C 3-7 The compounds are cycloalkyl, phenyl, 5-6 membered heteroaryl, or 4-7 membered heterocycloalkyl, each having at least one ring-forming carbon atom and 1, 2, 3, or 4 ring-forming heteroatoms independently selected from N, O, and S, wherein the N and S are optionally oxidized, and C 3-7 The ring-forming carbon atoms of cycloalkyl and 4- to 7-membered heterocycloalkyl groups are optionally substituted with oxo atoms to form a carbonyl group, and the C 3-7 Cycloalkyls, phenyls, 5-6 member heteroaryls, and 4-7 member heterocycloalkyls are each optionally R A1 Substituted with 1, 2, 3, or 4 substituents independently selected from, Each R A1 These are independently OH, NO2, CN, Halo, and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, cyano-C 1-3 Alkyl, HO-C 1-3 Alkyl, H2N-C 1-3 Alkyl, amino, C 1-6 Alkylamino, di(C 1-6 Alkyl)amino, thio, C 1-6 Alkylthio, C 1-6 Alkyl sulfinyl, C 1-6 Alkyl sulfonyl, carbamyl, C 1-6 Alkylcarbamyl, di(C 1-6 Alkyl)carbamyl, carboxy, C 1-6 Alkylcarbonyl, C 1-6 Alkoxycarbonyl, C 1-6 Alkylcarbonylamino, C 1-6 Alkylsulfonylamino, aminosulfonyl, C 1-6Alkylaminosulfonyl, di(C 1-6 Alkyl)aminosulfonyl, aminosulfonylamino, C 1-6 Alkylaminosulfonylamino, di(C 1-6 Alkyl)aminosulfonylamino, aminocarbonylamino, C 1-6 Alkylaminocarbonylamino, and di(C 1-6 Selected from alkyl)aminocarbonylamino, Cy A2 C 3-7 The compounds are cycloalkyl, phenyl, 5-6 membered heteroaryl, or 4-7 membered heterocycloalkyl, each having at least one ring-forming carbon atom and 1, 2, 3, or 4 ring-forming heteroatoms independently selected from N, O, and S, wherein the N and S are optionally oxidized, and C 3-7 The ring-forming carbon atoms of cycloalkyl and 4- to 7-membered heterocycloalkyl groups are optionally substituted with oxo atoms to form a carbonyl group, and the C 3-7 Cycloalkyls, phenyls, 5-6 member heteroaryls, and 4-7 member heterocycloalkyls are each optionally R A2 Substituted with 1, 2, 3, or 4 substituents independently selected from, Each R A2 These are independently OH, NO2, CN, Halo, and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, cyano-C 1-3 Alkyl, HO-C 1-3 Alkyl, H2N-C 1-3 Alkyl, amino, C 1-6 Alkylamino, di(C 1-6 Alkyl)amino, thio, C 1-6 Alkylthio, C 1-6 Alkyl sulfinyl, C 1-6 Alkyl sulfonyl, carbamyl, C 1-6 Alkylcarbamyl, di(C 1-6 Alkyl)carbamyl, carboxy, C 1-6 Alkylcarbonyl, C1-6 Alkoxycarbonyl, C 1-6 Alkylcarbonylamino, C 1-6 Alkylsulfonylamino, aminosulfonyl, C 1-6 Alkylaminosulfonyl, di(C 1-6 Alkyl)aminosulfonyl, aminosulfonylamino, C 1-6 Alkylaminosulfonylamino, di(C 1-6 Alkyl)aminosulfonylamino, aminocarbonylamino, C 1-6 Alkylaminocarbonylamino, and di(C 1-6 Selected from alkyl)aminocarbonylamino, Cy A3 C 3-7 The compounds are cycloalkyl, phenyl, 5-6 membered heteroaryl, or 4-7 membered heterocycloalkyl, each having at least one ring-forming carbon atom and 1, 2, 3, or 4 ring-forming heteroatoms independently selected from N, O, and S, wherein the N and S are optionally oxidized, and C 3-7 The ring-forming carbon atoms of cycloalkyl and 4- to 7-membered heterocycloalkyl groups are optionally substituted with oxo atoms to form a carbonyl group, and the C 3-7 Cycloalkyls, phenyls, 5-6 member heteroaryls, and 4-7 member heterocycloalkyls are each optionally R A3 Substituted with 1, 2, 3, or 4 substituents independently selected from, Each R A3 These are independently OH, NO2, CN, Halo, and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, cyano-C 1-3 Alkyl, HO-C 1-3 Alkyl, H2N-C 1-3 Alkyl, amino, C 1-6 Alkylamino, di(C 1-6 Alkyl)amino, thio, C 1-6 Alkylthio, C 1-6 Alkyl sulfinyl, C 1-6Alkyl sulfonyl, carbamyl, C 1-6 Alkylcarbamyl, di(C 1-6 Alkyl)carbamyl, carboxy, C 1-6 Alkylcarbonyl, C 1-6 Alkoxycarbonyl, C 1-6 Alkylcarbonylamino, C 1-6 Alkylsulfonylamino, aminosulfonyl, C 1-6 Alkylaminosulfonyl, di(C 1-6 Alkyl)aminosulfonyl, aminosulfonylamino, C 1-6 Alkylaminosulfonylamino, di(C 1-6 Alkyl)aminosulfonylamino, aminocarbonylamino, C 1-6 Alkylaminocarbonylamino, and di(C 1-6 Selected from alkyl)aminocarbonylamino, Cy R3 C 3-7 The compounds are cycloalkyl, phenyl, 5-6 membered heteroaryl, or 4-7 membered heterocycloalkyl, each having at least one ring-forming carbon atom and 1, 2, 3, or 4 ring-forming heteroatoms independently selected from N, O, and S, wherein the N and S are optionally oxidized, and C 3-7 The ring-forming carbon atoms of cycloalkyl and 4- to 7-membered heterocycloalkyl groups are optionally substituted with oxo atoms to form a carbonyl group, and the C 3-7 Cycloalkyls, phenyls, 5-6 member heteroaryls, and 4-7 member heterocycloalkyls are each optionally R g Substituted with 1, 2, 3, or 4 substituents independently selected from, Cy C is phenylene or a 5-6 membered heteroarylene, the 5-6 membered heteroarylene having at least one ring-forming carbon atom and one or two ring-forming heteroatoms independently selected from N, O, and S, and the phenylene and the 5-6 membered heteroarylene are each optionally R C Substituted with 1, 2, 3, or 4 substituents independently selected from, Each RC These are independently OH, CN, Haro, and C. 1-4 Alkyl, C 1-3 Haloalkyl, C 1-4 Alkoxy, C 1-3 Haloalkoxy, cyano-C 1-3 Alkyl, HO-C 1-3 Alkyl, amino, C 1-4 Alkylamino, di(C 1-4 Alkyl)amino, C 1-4 Alkyl sulfinyl, C 1-4 Alkyl sulfonyl, carbamyl, C 1-4 Alkylcarbamyl, di(C 1-4 Alkyl)carbamyl, carboxy, C 1-4 Alkylcarbonyl, C 1-4 Alkoxycarbonyl, C 1-4 Alkylcarbonylamino, C 1-4 Alkylsulfonylamino, aminosulfonyl, C 1-4 Alkylaminosulfonyl and di(C 1-4 Selected from alkyl)aminosulfonyl, Cy B C 3-10 It is a cycloalkyl or a 4-10 member heterocycloalkyl, C 3-10 At least one ring-forming carbon atom of a cycloalkyl or 4-10 membered heterocycloalkyl is substituted with an oxo to form a carbonyl group, and the 4-10 membered heterocycloalkyl has at least one ring-forming carbon atom and 1, 2, 3, or 4 ring-forming heteroatoms independently selected from N, O, and S, wherein the N and S are optionally oxidized, and the C 3-10 Cycloalkyls and 4-10 member heterocycloalkyls are each optionally R B It is substituted with 1, 2, 3, or 4 substituents independently selected from, or Cy BThe aryl group is a 6-10 membered aryl group or a 5-10 membered heteroaryl group, the 5-10 membered heteroaryl group having at least one ring-forming carbon atom and 1, 2, 3, or 4 ring-forming heteroatoms independently selected from N, O, and S, wherein the N and S are optionally oxidized, where: (a) at least one ring-forming carbon atom of the 5-10 membered heteroaryl group is substituted with an oxo atom to form a carbonyl group, or (b) the 6-10 membered aryl group or 5-10 membered heteroaryl group is oxidized with a halo, CN, NO2, OR a2 , SR a2 , C(O)R b2 , C(O)NR c2 R d2 , C(O)OR a2 ,OC(O)R b2 , OC(O)NR c2 R d2 , NR c2 R d2 , NR c2 Ure d2 , NR c2 C(O)R b2 , NR c2 C(O)OR a2 , NR c2 C(O)NR c2 R d2 , NR c2 S(O)R b2 , NR c2 S(O)2R b2 , NR c2 S(O)2NR c2 R d2 S(O)R b2 , S(O)NR c2 R d2 S(O)2R b2 , and S(O)2NR c2 R d2 The 6-10 member aryl or 5-10 member heteroaryl is further optionally R B Substituted with 1, 2, 3, or 4 substituents independently selected from, Each R B It is independently, Halo, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6Cycloalkyl, phenyl, 5-6 member heteroaryl, 4-7 member heterocycloalkyl, CN, NO2, OR a2 , SR a2 , C(O)R b2 , C(O)NR c2 R d2 , C(O)OR a2 , OC(O)R b2 , OC(O)NR c2 R d2 , NR c2 R d2 , NR c2 , OR d2 , NR c2 , C(O)R b2 , NR c2 , C(O)OR a2 , NR c2 , C(O)NR c2 [[ID=三十八]]R d2 , NR c2 , S(O)R b2 , NR c2 , S(O)2R b2 [[ID=4十八]], NR c2 , S(O)2NR c2 R d2 , S(O)R b2 , S(O)NR c2 R d2 , S(O)2R b2 , and S(O)2NR c2 R d2 selected from, the C 1-6 alkyl, C 3-6 cycloalkyl, phenyl, 5-6 member heteroaryl, and 4-7 member heterocycloalkyl are each optionally substituted with 1, 2, 3, or 4 substituents independently selected from R 12 , each R 11 is independently CN, NO2, OR a3 , SR a3 , C(O)R b3 , C(O)NR c3 R d3 , C(O)OR a3 , OC(O)R b3 , OC(O)NR c3 R d3 , NR c3 R d3 , NR c3OR d3 、 NR c3 C(O)R b3 、 NR c3 C(O)OR a3 、 NR c3 C(O)NR c3 R d3 、 NR c3 S(O)R b3 、 NR c3 S(O)2R b3 、 NR c3 S(O)2NR c3 R d3 、 S(O)R b3 、 S(O)NR c3 R<0**********>、 S(O)2R b3 、 及び S(O)2NR c3 R d3 から選択され、 各 R 12 は、独立して、 ハロ、 CN、 NO2、 C 1-6 アルキル、 C 1-6 ハロアルキル、 C 3-6 シクロアルキル、 フェニル、 5~6員のヘテロアリール、 4~7員のヘテロシクロアルキル、 OR a4 、 SR a4 、 C(O)R b4 、 C(O)NR c4 R d4 、 C(O)OR[[ID=**]] a4 、 OC(O)R b4 、 OC(O)NR c4 R d4 、 NR c4 R d4 、 NR c4 OR d4 、 NR c4 C(O)R b4 、 NR c4 C(O)OR a4 、 NR c4 C(O)NR c4 R d4 、 NR c4 S(O)R b4 、 NR c4 S(O)2R b4 、 NR c4 S(O)2NR c4 R d4 、 S(O)R b4 、 S(O)NRc4 R d4 S(O)2R b4 , and S(O)2NR c4 R d4 Selected from, the C 1-6 Alkyl, C 3-6 Cycloalkyls, phenyls, 5-6 member heteroaryls, and 4-7 member heterocycloalkyls are each optionally R g Substituted with 1, 2, 3, or 4 substituents independently selected from, R a H, C 1-6 Alkyl and C 1-6 Selected from haloalkyl groups, R b C 1-6 Alkyl and C 1-6 Selected from haloalkyl groups, R c and R d These are H and C, which are independent of each other. 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, phenyl, 5-6 member heteroaryl, 4-6 member heterocycloalkyl, C 3-6 Cycloalkyl-C 1-3 Alkylene, Phenyl-C 1-3 Alkylene, 5-6 member heteroaryl-C 1-3 Alkylenes and 4-6 member heterocycloalkyl-C 1-3 Selected from alkylene, the C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, phenyl, 5-6 member heteroaryl, 4-6 member heterocycloalkyl, C 3-6 Cycloalkyl-C 1-3 Alkylene, Phenyl-C 1-3 Alkylene, 5-6 member heteroaryl-C 1-3 Alkylenes and 4-6 member heterocycloalkyl-C 1-3 Alkylenes are each arbitrarily R g Substituted with one, two, or three substituents independently selected from, R a1 , R c1 , and Rd1 These are H and C, which are independent of each other. 1-6 Alkyl and C 1-6 Selected from haloalkyl, the C 1-6 Alkyl is optional, R g It is substituted with 1, 2, 3, or 4 substituents independently selected from, or Alternatively, R bonded to the same N atom c1 and R d1 Along with the N atom to which they are bonded, R g Forming a 4, 5, 6, or 7-membered heterocycloalkyl group which is optionally substituted with 1, 2, or 3 substituents independently selected from the above, R b1 C 1-6 Alkyl and C 1-6 Selected from haloalkyls, each of which optionally includes R g Substituted with 1, 2, 3, or 4 substituents independently selected from, R e1 H, CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkylthio, C 1-6 Alkyl sulfonyl, C 1-6 Alkylcarbonyl, C 1-6 Alkylaminosulfonyl, Carbamyl, C 1-6 Alkylcarbamyl, di(C 1-6 Alkyl)carbamyl, aminosulfonyl, C 1-6 Alkylaminosulfonyl and di(C 1-6 Selected from alkyl)aminosulfonyl, Each R a2 , R c2 , and R d2 H and C are independent of each other. 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Selected from cycloalkyl, phenyl, 5-6 membered heteroaryl, and 4-7 membered heterocycloalkyl, the C 1-6 Alkyl, C 3-6 Cycloalkyls, phenyls, 5-6 member heteroaryls, and 4-7 member heterocycloalkyls are each optionally R12 It is substituted with 1, 2, 3, or 4 substituents independently selected from, or Alternatively, any R bonded to the same N atom c2 and R d2 Along with the N atom to which they are bonded, R 12 Forming a 4, 5, 6, or 7-membered heterocycloalkyl group which is optionally substituted with 1, 2, or 3 substituents independently selected from the above, Each R b2 Independently, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Selected from cycloalkyls, phenyls, 5-6 membered heteroaryls, and 4-7 membered heterocycloalkyls, each of which optionally includes R 12 Substituted with 1, 2, 3, or 4 substituents independently selected from, Each R a3 , R c3 , and R d3 H and C are independent of each other. 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, phenyl, 5-6 member heteroaryl, 4-7 member heterocycloalkyl, C 3-6 Cycloalkyl-C 1-4 Alkylene, Phenyl-C 1-4 Alkylene, 5-6 member heteroaryl-C 1-4 Alkylenes and 4-7 member heterocycloalkyl-C 1-4 Selected from alkylene, the C 1-6 Alkyl, C 3-6 Cycloalkyl, phenyl, 5-6 member heteroaryl, 4-7 member heterocycloalkyl, C 3-6 Cycloalkyl-C 1-4 Alkylene, Phenyl-C 1-4 Alkylene, 5-6 member heteroaryl-C 1-4 Alkylenes and 4-7 member heterocycloalkyl-C 1-4 Alkylenes are each arbitrarily R g It is substituted with 1, 2, 3, or 4 substituents independently selected from, or Alternatively, any R bonded to the same N atom c3 and R d3 Along with the N atom to which they are bonded, R g Forming a 4, 5, 6, or 7-membered heterocycloalkyl group which is optionally substituted with 1, 2, or 3 substituents independently selected from the above, Each R b3 Independently, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, phenyl, 5-6 member heteroaryl, 4-7 member heterocycloalkyl, C 3-6 Cycloalkyl-C 1-4 Alkylene, Phenyl-C 1-4 Alkylene, 5-6 member heteroaryl-C 1-4 Alkylenes and 4-7 member heterocycloalkyl-C 1-4 Selected from alkylenes, each of which is optionally R g Substituted with 1, 2, 3, or 4 substituents independently selected from, Each R a4 , R c4 , and R d4 H and C are independent of each other. 1-6 Alkyl and C 1-6 Selected from haloalkyl, the C 1-6 Alkyl is optional, R g It is substituted with 1, 2, 3, or 4 substituents independently selected from, or Alternatively, any R bonded to the same N atom c4 and R d4 Along with the N atom to which they are bonded, R g Forming a 4, 5, 6, or 7-membered heterocycloalkyl group which is optionally substituted with 1, 2, or 3 substituents independently selected from the above, Each R b4 Independently, C 1-6 Alkyl and C 1-6 Selected from haloalkyls, each of which optionally includes R g Substituted with 1, 2, 3, or 4 substituents independently selected from, Each R gThese are independently OH, NO2, CN, Halo, and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, cyano-C 1-3 Alkyl, HO-C 1-3 Alkyl, H2N-C 1-3 Alkyl, amino, C 1-6 Alkylamino, di(C 1-6 Alkyl)amino, thio, C 1-6 Alkylthio, C 1-6 Alkyl sulfinyl, C 1-6 Alkyl sulfonyl, carbamyl, C 1-6 Alkylcarbamyl, di(C 1-6 Alkyl)carbamyl, carboxy, C 1-6 Alkylcarbonyl, C 1-6 Alkoxycarbonyl, C 1-6 Alkylcarbonylamino, C 1-6 Alkylsulfonylamino, aminosulfonyl, C 1-6 Alkylaminosulfonyl, di(C 1-6 Alkyl)aminosulfonyl, aminosulfonylamino, C 1-6 Alkylaminosulfonylamino, di(C 1-6 Alkyl)aminosulfonylamino, aminocarbonylamino, C 1-6 Alkylaminocarbonylamino, and di(C 1-6 Selected from alkyl)aminocarbonylamino. However: 1) A 1 -A 2 -A 3 is, A 1 , A 2 , or A 3 If one of them is a combination, it is neither YY nor YYY, and 2) A 3 is -Y- or -C 1-3 In the case of alkylene-Y-, R A H, C 1-6 Alkyl, or C 1-6 It is a haloalkyl, and the C 1-6 Alkyl or C 1-6Haloalkyls are optional, R 11 The condition is that it is substituted with 1, 2, 3, or 4 substituents selected independently of it.

[0016] In some embodiments, A 1 It is a combination.

[0017] In some embodiments, A 2 It is a combination.

[0018] In some embodiments, A 3 It is a combination.

[0019] In some embodiments, R A H, Halo, C 1-6 Alkyl, or C 1-6 It is a haloalkyl group.

[0020] In some embodiments, R A is C 1-6 It is alkyl.

[0021] In some embodiments, R A It is either methyl or ethyl.

[0022] In some embodiments, A 1 This is a combination. For example, R 1 is, A 2 -A 3 -R A That is the case.

[0023] In some embodiments, A 1 is a combination, A 2 is a combination, A 3 is Cy A3 For example, R 1 Cy A3 -R A That is the case.

[0024] In some embodiments, A 1 , A 2 , and A 3One of them is not a combination.

[0025] In some embodiments, A 1 , A 2 , and A 3 One of them is -C 1-3 Alkylene-, -Y-, -C 1-3 Alkylene-Y- or -YC 1-3 It is alkylene-. In some embodiments, A 1 , A 2 , and A 3 One of them is -C 1-6 It is alkylene- or -Y-. In some embodiments, A 1 , A 2 , and A 3 One of them is -C 1-6 It is alkylene-. In some embodiments, A 1 , A 2 , and A 3 One of them is methylene.

[0026] In some embodiments, R 1 H, Halo, C 1-6 Alkyl, or C 1-6 It is a haloalkyl group.

[0027] In some embodiments, R 1 C 1-6 It is alkyl. In some embodiments, R 1 It is either methyl or ethyl.

[0028] In some embodiments, R 1 is, A 2 -A 3 -R A That is the case.

[0029] In some embodiments, R 1 Cy A3 -R A That is the case.

[0030] In some embodiments, Cy A3 C3-7 A cycloalkyl group, a 5-6 member heteroaryl group, or a 4-7 member heterocycloalkyl group, each optionally consisting of R A3 It is substituted with one, two, three, or four substituents independently selected from the given molecule.

[0031] In some embodiments, Cy A3 C 3-6 A cycloalkyl or 4-6 member heterocycloalkyl, each optionally R A3 It is substituted with one or two substituents independently selected from the original molecule.

[0032] In some embodiments, Cy A3 is piperidinyl, cyclohexyl, or tetrahydropyranil, each optionally R A3 It is substituted with one or two substituents independently selected from the original molecule.

[0033] In some embodiments, Cy A3 R is selected from 1, 2, 3, or 4 independently. A3 C is arbitrarily substituted by the base. 3-6 It is a cycloalkyl. In some embodiments, Cy A3 R is selected from 1, 2, 3, or 4 independently. A3 These are cyclohexyl and cyclopropyl compounds that are optionally substituted with a group.

[0034] In some embodiments, Cy A3 R is selected from 1, 2, 3, or 4 independently. A3 It is a 4- to 6-membered heterocycloalkyl group that is optionally substituted with a group. In some embodiments, Cy A3 R is selected from 1, 2, 3, or 4 independently. A3 It is a piperidinyl or morpholinyl compound that is optionally substituted with a group.

[0035] In some embodiments, Cy A3 R is selected from 1, 2, 3, or 4 independently. A3It is a 5-10 member heteroaryl that is optionally substituted with a group. In some embodiments, Cy A3 R is selected from 1, 2, 3, or 4 independently. A3 It is a pyridyl that can be optionally substituted at the base.

[0036] In some embodiments, Cy A3 These are piperidinyl, cyclohexyl, tetrahydropyranil, pyrazolyl, pyridinyl, azetidinyl, cyclopropyl, or morpholinyl, each of which may be R A3 It is substituted with one or two substituents independently selected from the original molecule.

[0037] In some embodiments, Cy A3 The compounds are piperidinyl, pyridyl, morpholinyl, cyclohexyl, or tetrahydropyranil, each of which may be 1, 2, 3, or 4 independently selected R A3 It is replaced by the base.

[0038] In some embodiments, Cy A3 R is selected from 1, 2, 3, or 4 independently. A3 It is a piperidinyl compound that can be optionally substituted with a group.

[0039] In some embodiments, Cy A3 R is selected from 1, 2, 3, or 4 independently. A3 It is a cyclohexyl compound that can be optionally substituted with a group.

[0040] In some embodiments, Cy A3 R is selected from 1, 2, 3, or 4 independently. A3 It is a morpholinyl that can be arbitrarily substituted with the group.

[0041] In some embodiments, Cy A3 teeth, [ka] And here, Cy A3 -1, Cy A3-2, and Cy A3 -3 is arbitrarily R A3 It is substituted with one, two, or three substituents independently selected from the given molecule.

[0042] In some embodiments, A 1 is a combination, A 2 is a combination, A 3 It is a bond, R A is methyl or ethyl, or A 1 is a combination, A 2 is a combination, A 3 teeth, [ka] Selected from Cy A3 -R A That is the case.

[0043] In some embodiments, R A C 1-6 Alkyl, CN, OR a1 , NR c1 R d1 , C(O)R b1 , C(O)NR c1 R d1 , C(O)OR a1 S(O)R b1 , S(O)NR c1 R d1 S(O)2R b1 , or S(O)2NR c1 R d1 and C 1-6 Alkyl is optional, R 11 It is substituted with one or two substituents independently selected from R. A When R is bonded to a nitrogen atom, A is CN, OR a1 But, NR c1 R d1 But no.

[0044] In some embodiments, R A C 1-6 Alkyl, CN, OR a1 , C(O)Rb1 , C(O)NR c1 R d1 , C(O)OR a1 , and S(O)2R b1 and C 1-6 Alkyl is optional, R 11 It is replaced with one substituent selected from R. A When R is bonded to a nitrogen atom, A is CN or OR a1 Not either. In some embodiments, R b1 It is isopropyl.

[0045] Several embodiments, each R A Independently, C 1-3 Selected from alkyl, CN, OH, methylcarbonyl, methoxycarbonyl, N,N-dimethylaminocarbonyl, and methylsulfonyl, the C 1-3 Alkyl groups may optionally be substituted with OH or OCH3 groups. However, R A When R is bonded to a nitrogen atom, A It is neither CN nor OH.

[0046] Several embodiments, each R A These are independently selected from CH3, CH2CH3, CN, OH, CH2CH2OH, CH2CH2OCH3, C(O)CH3, C(O)CH2OH, C(O)CH(OH)CH3, S(O)2CH3, C(O)OCH3, C(O)N(CH3)2, C(O)NHCH3, C(O)N(CH2CH3)2, and C(O)N(CH3)(CH2CH3).

[0047] Several embodiments, each R AThese are independently selected from CH3, CH2CH3, CH(CH3)2, CN, OH, CH2CH2OH, CH2CH2OCH3, C(O)CH3, C(O)CH2CH3, C(O)CH(CH3)2, C(O)CH2OH, C(O)CH(OH)CH3, S(O)2CH3, C(O)OCH3, C(O)N(CH3)2, C(O)N(CH2CH3)2, C(O)N(CH3)(CH2CH3), C(O)NHCH3, C(O)NH(CH2CH3), and C(O)[morpholine-4-yl].

[0048] Several embodiments, each R 11 OR a3 That is the case.

[0049] Several embodiments, each R 11 These are independently OH or OCH3.

[0050] In some embodiments, Cy A3 These are piperidinyl, cyclohexyl, tetrahydropyranyl, pyrazolyl, pyridinyl, azetidinyl, cyclopropyl, or morpholinyl, each optionally being CH3, CN, OH, CH2CH2OH, CH2CH2OCH3, C(O)CH3, C(O)CH2CH3, C(O)CH(CH3)2, C(O)CH2OH, C(O)CH(CH3)OH, S(O)2CH3, R independently selected from C(O)OCH3, C(O)N(CH3)2, C(O)NH(CH3), C(O)N(CH2CH3)2, C(O)NH(CH2CH3), C(O)N(CH3)(CH2CH3), CH2C(O)N(CH3)2, 1-methyl-2-oxopyrrolidine-3-yl, C(O)(cyclopropyl), N(CH3)2, and C(O)(morpholine-4-yl) A It will be replaced by this.

[0051] In some embodiments, Cy A3R is piperidinyl, cyclohexyl, or tetrahydropyranyl, each of which is optionally independently selected from CH3, CN, OH, CH2CH2OH, CH2CH2OCH3, C(O)CH3, C(O)CH2OH, C(O)CH(CH3)OH, S(O)2CH3, C(O)OCH3, C(O)N(CH3)2, C(O)NH(CH3), C(O)N(CH2CH3)2, C(O)NH(CH2CH3), and C(O)N(CH3)(CH2CH3). A It will be replaced by this.

[0052] In some embodiments, Cy A3 R is piperidinyl, cyclohexyl, or tetrahydropyranyl, each of which is optionally independently selected from CH3, CH2CH3, CH(CH3)2, CN, OH, CH2CH2OH, CH2CH2OCH3, C(O)CH3, C(O)CH2CH3, C(O)CH(CH3)2, C(O)CH2OH, C(O)CH(OH)CH3, S(O)2CH3, C(O)OCH3, C(O)N(CH3)2, C(O)N(CH2CH3)2, C(O)N(CH3)(CH2CH3), C(O)NHCH3, C(O)NH(CH2CH3), and C(O)(morpholine-4-yl). A It will be replaced by this.

[0053] In some embodiments, Cy A3 is piperidinyl, pyridyl, morpholinyl, cyclohexyl, or tetrahydropyranyl, each optionally substituted with 1, 2, 3, or 4 groups independently selected from CH3, CH2CH3, CN, OH, CH2CH2OH, CH2CH2OCH3, C(O)CH3, C(O)CH2OH, C(O)CH(OH)CH3, S(O)2CH3, C(O)OCH3, C(O)N(CH3)2, C(O)NHCH3, C(O)N(CH2CH3)2, and C(O)N(CH3)(CH2CH3).

[0054] In some embodiments, A 1 is a combination, A 2 is Cy A2 A 3 is -Y- and RA is C 3-6 It is a cycloalkyl (e.g., cyclopropyl), where -Y- is C(O), and Cy A2 It is a 4-7 member heterocycloalkyl group (e.g., piperidinyl).

[0055] In some embodiments, R 1 teeth [ka] In some embodiments, R 1 teeth [ka] In some embodiments, R 1 teeth [ka] In some embodiments, R 1 teeth [ka] In some embodiments, R 1 teeth [ka] That is the case.

[0056] In some embodiments, R 2 H, Halo, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, or C 1-4 It is a haloalkoxy. In some embodiments, R 2 is H or C 1-4 It is alkyl. In some embodiments, R 2 H is H.

[0057] In some embodiments, R 3 H is H.

[0058] In a preferred embodiment, Cy B It forms a hydrogen bond with the NH of the amide group. For example, Cy B If the group has an oxo group, the Cy B Cy can form hydrogen bonds via the NH of the amide group and the carbonyl group. B This can be substituted with an electron-donating substituent that can form a hydrogen bond with the NH of the amide group. The following is an example to illustrate this, where W is an electron-donating group, e.g., halo, CN, NO2, OR a2 , SR a2 , C(O)R b2 , C(O)NR c2 R d2 , C(O)OR a2 ,OC(O)R b2 , OC(O)NR c2 R d2 , NR c2 R d2 , NR c2 Ure d2 , NR c2 C(O)R b2 , NR c2 C(O)OR a2 , NR c2 C(O)NR c2 R d2 , NR c2 S(O)R b2 , NR c2 S(O)2R b2 , NR c2 S(O)2NR c2 R d2 S(O)R b2 , S(O)NR c2 R d2 S(O)2R b2 , and S(O)2NR c2 R d2 is: [ka]

[0059] In some embodiments, Cy B C 3-10It is a cycloalkyl or a 4-10 member heterocycloalkyl, C 3-10 At least one ring-forming carbon atom of a cycloalkyl or 4-10 membered heterocycloalkyl is substituted with an oxo to form a carbonyl group, and the 4-10 membered heterocycloalkyl has at least one ring-forming carbon atom and 1, 2, 3, or 4 ring-forming heteroatoms independently selected from N, O, and S, wherein the N and S are optionally oxidized, and the C 3-10 Cycloalkyls and 4-10 member heterocycloalkyls are each optionally R B It is substituted with 1, 2, 3, or 4 substituents independently selected from, or Cy B A is a 5-10 member heteroaryl, which has at least one ring-forming carbon atom and 1, 2, 3, or 4 ring-forming heteroatoms independently selected from N, O, and S, wherein the N and S are optionally oxidized, where: (a) at least one ring-forming carbon atom of the 5-10 member heteroaryl is substituted with an oxo to form a carbonyl group, or (b) the 5-10 member heteroaryl is oxidized with a halo, CN, NO2, OR a2 , SR a2 , C(O)R b2 , C(O)NR c2 R d2 , C(O)OR a2 ,OC(O)R b2 , OC(O)NR c2 R d2 , NR c2 R d2 , NR c2 Ure d2 , NR c2 C(O)R b2 , NR c2 C(O)OR a2 , NR c2 C(O)NR c2 R d2 , NR c2 S(O)R b2 , NR c2 S(O)2R b2 , NR c2 S(O)2NR c2 R d2 S(O)R b2, S(O)NR c2 R d2 S(O)2R b2 , and S(O)2NR c2 R d2 The 5-10 member heteroaryl is substituted with, and optionally, R B It is substituted with one, two, three, or four substituents independently selected from the given molecule.

[0060] In some embodiments, Cy B C 3-10 It is a cycloalkyl or a 4-10 member heterocycloalkyl, C 3-10 At least one ring-forming carbon atom of a cycloalkyl or 4-10 membered heterocycloalkyl is substituted with an oxo to form a carbonyl group, and the 4-10 membered heterocycloalkyl has at least one ring-forming carbon atom and 1, 2, 3, or 4 ring-forming heteroatoms independently selected from N, O, and S, wherein the N and S are optionally oxidized, and the C 3-10 Cycloalkyls and 4-10 member heterocycloalkyls are each optionally R B It is substituted with one, two, three, or four substituents independently selected from the given molecule.

[0061] In some embodiments, Cy B A is a 5-10 member heteroaryl, which has at least one ring-forming carbon atom and 1, 2, 3, or 4 ring-forming heteroatoms independently selected from N, O, and S, wherein the N and S are optionally oxidized, where: (a) at least one ring-forming carbon atom of the 5-10 member heteroaryl is substituted with an oxo to form a carbonyl group, or (b) the 5-10 member heteroaryl is oxidized with a halo, CN, NO2, OR a2 , SR a2 , C(O)R b2 , C(O)NR c2 R d2 , C(O)OR a2 ,OC(O)R b2 , OC(O)NR c2 R d2 , NR c2 Rd2 , NR c2 Ure d2 , NR c2 C(O)R b2 , NR c2 C(O)OR a2 , NR c2 C(O)NR c2 R d2 , NR c2 S(O)R b2 , NR c2 S(O)2R b2 , NR c2 S(O)2NR c2 R d2 S(O)R b2 , S(O)NR c2 R d2 S(O)2R b2 , and S(O)2NR c2 R d2 The 5-10 member heteroaryl is substituted with, and optionally, R B It is substituted with one, two, three, or four substituents independently selected from the given molecule.

[0062] In some embodiments, Cy B The 4-10 member heterocycloalkyl group is a 4-10 member heterocycloalkyl group in which at least one ring-forming carbon atom is substituted with an oxo atom to form a carbonyl group, and the 4-10 member heterocycloalkyl group has at least one ring-forming carbon atom and 1, 2, 3, or 4 ring-forming heteroatoms independently selected from N, O, and S, and the 4-10 member heterocycloalkyl group optionally has R B It is substituted with one, two, or three substituents independently selected from it, or Cy B This is a 5-6 member heteroaryl, which has at least one ring-forming carbon atom substituted with an oxo to form a carbonyl group, and one or two ring-forming heteroatoms independently selected from N, O, and S, wherein the N and S are optionally oxidized, and the 5-6 member heteroaryl can further optionally be R B It is substituted with one, two, or three substituents independently selected from the given molecule.

[0063] In some embodiments, Cy B The 4-10 member heterocycloalkyl group is a 4-10 member heterocycloalkyl group in which at least one ring-forming carbon atom is substituted with an oxo atom to form a carbonyl group, and the 4-10 member heterocycloalkyl group has at least one ring-forming carbon atom and 1, 2, 3, or 4 ring-forming heteroatoms independently selected from N, O, and S, and the 4-10 member heterocycloalkyl group optionally has R B It is substituted with one, two, or three substituents independently selected from the given molecule.

[0064] In some embodiments, Cy B This is a 5-10 member heteroaryl, which has at least one ring-forming carbon atom substituted with an oxo to form a carbonyl group, and one or two ring-forming heteroatoms independently selected from N, O, and S, wherein the N and S are optionally oxidized, and the 5-6 member heteroaryl can further optionally be R B It is substituted with one, two, or three substituents independently selected from the given molecule.

[0065] In some embodiments, Cy B This is a 4-10 membered heterocycloalkyl or 5-10 membered heteroaryl, where one ring-forming carbon atom at the ortho position is substituted with an oxo to form a carbonyl group. The ortho position is the Cy B The base is -C(=O)NH-Cy C - Refers to a ring-forming carbon atom directly adjacent to a ring-forming atom bonded to a linker.

[0066] In some embodiments, Cy B teeth, [ka] And here, Cy B -1, Cy B -2, Cy B -3, Cy B -4, Cy B -5, Cy B -6, and CyB -7 is each of 1, 2, or 3 independently selected R B It is replaced by the base.

[0067] In some embodiments, Cy B teeth, [ka] And here, Cy B -8, Cy B -9, Cy B -10, Cy B -4, and Cy B -11 is each of 1, 2, or 3 independently selected R B It is replaced by the base.

[0068] In some embodiments, Cy B teeth, [ka] And here, Cy B -1, Cy B -2, Cy B -3, Cy B -8, Cy B -9, Cy B -10, Cy B -4, and Cy B -11 is each of 1, 2, or 3 independently selected R B It is replaced by the base.

[0069] In some embodiments, Cy B R is selected from 1, 2, or 3 independently. B Cy which is arbitrarily substituted by the base B In some embodiments, Cy B R is selected from 1, 2, or 3 independently. B Cy which is arbitrarily substituted by the base B In some embodiments, Cy B R is selected from 1, 2, or 3 independently. B Cy which is arbitrarily substituted by the base BIn some embodiments, Cy B R is selected from 1, 2, or 3 independently. B Cy which is arbitrarily substituted by the base B In some embodiments, Cy B R is selected from 1, 2, or 3 independently. B Cy which is arbitrarily substituted by the base B In some embodiments, Cy B R is selected from 1, 2, or 3 independently. B Cy which is arbitrarily substituted by the base B In some embodiments, Cy B R is selected from 1, 2, or 3 independently. B Cy which is arbitrarily substituted by the base B It is -7.

[0070] In some embodiments, Cy B teeth, [ka] That is the case.

[0071] In some embodiments, Cy B is Cy B In some embodiments, Cy B is Cy B In some embodiments, Cy B is Cy B -3a is the case in some embodiments. B is Cy B In some embodiments, Cy B is Cy B In some embodiments, Cy B is Cy B In some embodiments, Cy B is Cy B It is -7a.

[0072] In some embodiments, Cy B R is selected from 1, 2, or 3 independently.B C is arbitrarily substituted by the base. 3-10 It is a cycloalkyl. In some embodiments, Cy B It is cyclopropyl.

[0073] In some embodiments, Cy B , cyclopropyl, [ka] The cyclopropyl, Cy B -1, and Cy B -2 is a set of 1, 2, or 3 independently selected R values, each arbitrarily chosen. B It is replaced by the base.

[0074] In some embodiments, Cy B teeth, [ka] And here, Cy B -1, Cy B -2, Cy B -3, and Cy B -10 is arbitrarily R B It is substituted with one, two, or three substituents independently selected from the given molecule.

[0075] In some embodiments, Cy B teeth, [ka] And here, Cy B -1 and Cy B -2 is a set of 1, 2, or 3 independently selected R values, each arbitrarily chosen. B It is replaced by the base.

[0076] In some embodiments, Cy B teeth, [ka] And here, Cy B -1, CyB -2, Cy B -3, Cy B -4, and Cy B -5 is a set of 1, 2, or 3 independently selected R values. B It is replaced by the base.

[0077] In some embodiments, Cy B teeth, [ka] And here, Cy B -1 and Cy B -2 is arbitrarily R B It is substituted with one, two, or three substituents independently selected from the given molecule.

[0078] In some embodiments, Cy B teeth, [ka] And here, Cy B -1, Cy B -2, and Cy B -3 is a set of 1, 2, or 3 independently selected R values, each arbitrarily chosen. B It is replaced by the base.

[0079] In some embodiments, Cy B teeth, [ka] And here, Cy B -1 is an optional number of R values, where 1, 2, or 3 independently selected values ​​are used. B It is replaced by the base.

[0080] In some embodiments, Cy B teeth, [ka] And here, Cy B -2 is an optional R of 1, 2, or 3 independently selected values.B It is replaced by the base.

[0081] In some embodiments, Cy B teeth, [ka] And here, Cy B -3 is an optional R of 1, 2, or 3 independently selected values. B It is replaced by the base.

[0082] In some embodiments, Cy B teeth, [ka] And here, Cy B -1 and Cy B -2 is arbitrarily R B Substituted with one, two, or three substituents independently selected from, Each R B These are independently methyl, ethyl, isopropyl, sec-butyl, or phenyl, each of which is optionally R 12 Substituted with one or two substituents independently selected from, Each R 12 These are independently halo, phenyl, and OR a4 Selected from, the phenyl is optionally R g Substituted with one or two substituents independently selected from the base, Each R a4 is H or C 1-3 It is alkyl, Each R g It is selected independently from Haro.

[0083] In some embodiments, Cy B teeth, [ka] And here, Cy B -1, Cy B -2, Cy B-3, and Cy B -10 is arbitrarily R B Substituted with one, two, or three substituents independently selected from, Each R B These are independently methyl, ethyl, isopropyl, sec-butyl, 2-pyridinyl, or phenyl, each of which is optionally R 12 Substituted with one or two substituents independently selected from, Each R 12 Independently, C 1-6 Alkyl, halo, phenyl, and OR a4 Selected from, the C 1-6 Alkyl and phenyl are each optionally R g Substituted with one or two substituents independently selected from the base, Each R a4 is H or C 1-3 It is alkyl, Each R g It is selected independently from Haro.

[0084] In some embodiments, Cy B teeth, [ka] And here, Cy B -1, Cy B -2, and Cy B -3 is arbitrarily R B Substituted with one, two, or three substituents independently selected from, Each R B These are independently methyl, ethyl, isopropyl, sec-butyl, or phenyl, each of which is optionally R 12 Substituted with one or two substituents independently selected from, Each R 12 These are independently halo, phenyl, and OR a4 Selected from, the phenyl is optionally R g Substituted with one or two substituents independently selected from the base, Each R a4 is H or C1-3 It is alkyl, Each R g It is selected independently from Haro.

[0085] In some embodiments, Cy B teeth, [ka] And here, Cy B -1 and Cy B -2 is optionally substituted with one, two, or three groups independently selected from unsubstituted phenyl, 4-fluorophenyl, CH2(phenyl), CH(CH2OH)phenyl, CH3, CH2CH3, CH(CH2OH)CH2CH3, CH(CH2OH)CH3, CH2CH2OH, OCH2CH3, and OCH3.

[0086] In some embodiments, Cy B teeth, [ka] And here, Cy B -1, Cy B -2, and Cy B -3 is optionally substituted with one, two, or three groups independently selected from unsubstituted phenyl, 4-fluorophenyl, 3-fluorophenyl, 2-fluorophenyl, 2-pyridinyl, CH2(phenyl), CH(CH2OH)phenyl, CH3, CH2CH3, CH(CH3)2, CH(CH2OH)CH2CH3, CH(CH2OH)CH3, CH2CH2OH, OCH2CH3, and OCH3.

[0087] In some embodiments, Cy B teeth, [ka] And here, Cy B -1, Cy B -2, and Cy B-3 is optionally substituted with one, two, or three substituents independently selected from unsubstituted phenyl, 4-fluorophenyl, 3-fluorophenyl, 2-fluorophenyl, CH2(phenyl), CH(CH2OH)phenyl, CH3, CH2CH3, CH(CH3)2, CH(CH2OH)CH2CH3, CH(CH2OH)CH3, CH2CH2OH, OCH2CH3, and OCH3.

[0088] In some embodiments, Cy B teeth, [ka] And here, Cy B -2 and Cy B -3 is optionally substituted with one, two, or three groups independently selected from unsubstituted phenyl, CH(CH3)2, and 2-pyridinyl.

[0089] In some embodiments, Cy B teeth, [ka] And here, Cy B -2 is optionally substituted with one, two, or three groups independently selected from unsubstituted phenyl, CH(CH3)2, and 2-pyridinyl.

[0090] In some embodiments, Cy B teeth, [ka] And here, Cy B -3 is optionally substituted with one, two, or three groups independently selected from unsubstituted phenyl, CH(CH3)2, and 2-pyridinyl.

[0091] In some embodiments, Cy B teeth, [ka] And here, Cy B -3 is substituted with unsubstituted phenyl and CH(CH3)2.

[0092] In some embodiments, Cy B teeth, [ka] And here, Cy B -3 is substituted with pyridinyl (e.g., 2-pyridinyl, 3-pyridinyl, and 4-pyridinyl) and CH(CH3)2.

[0093] Several embodiments, each R B It is independently, Halo, C 1-6 Alkyl, C 2-6 Alkinyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, phenyl, 5-6 member heteroaryl, 4-7 member heterocycloalkyl, CN, OR a2 , C(O)R b2 , C(O)NR c2 R d2 , C(O)OR a2 , NR c2 R d2 , NR c2 C(O)R b2 , and NR c2 C(O)OR a2 Selected from, the C 1-6 Alkyl, C 2-6 Alkinyl, C 3-6 Cycloalkyls, phenyls, 5-6 member heteroaryls, and 4-7 member heterocycloalkyls are each optionally R 12 It is substituted with one, two, three, or four substituents independently selected from the given molecule.

[0094] Several embodiments, each R BThese are independently unsubstituted phenyl, 4-fluorophenyl, 3-fluorophenyl, 2-fluorophenyl, CH2(phenyl), CH(CH2OH)phenyl, Br, Cl, CN, CH3, CHF2, CH2CH3, CH2OCH3, CH2OCH2CH3, CH(CH3)2, CH(CH2OH)CH2CH3, CH(CH2OH)CH3, CH2CH2OH, CH2CH(OH)(CH3), OCH3, OCH2CH3, C(O)NH2, C(O)CH3, 2,5-difluorophenyl, 3-pyridinyl, 2-pyridinyl, 1-methyl-1H-pyrazole-4-yl, 1-methyl-1H-pyrazole-3-yl, 1-methyl-1H-pyrazole These are ru-5-yl, 1,4-dimethyl-1H-pyrazole-3-yl, 1,5-dimethyl-1H-pyrazole-3-yl, 2-methylthiazole-5-yl, cyclohexyl, 3-cyanophenyl, 5-methylisoxazole-3-yl, 5-fluoropyridine-3-yl, 5-fluoropyridine-2-yl, 3-cyanophenyl, CH2CN, thiazole-4-yl, 6-methylpyridine-3-yl, 2-methylpyridine-3-yl, 6-methylpyridine-2-yl, pyrimidine-2-yl, morpholine-4-yl, cyclopropyl, oxazole-2-yl, CCCH(OH)(CH3), or C(O)NH(4-fluorophenyl).

[0095] Several embodiments, each R BThese are independently unsubstituted phenyl, 4-fluorophenyl, 3-fluorophenyl, 2-fluorophenyl, CH2(phenyl), CH(CH2OH)phenyl, Br, CN, CH3, CH2CH3, CH(CH3)2, CH(CH2OH)CH2CH3, CH(CH2OH)CH3, CH2CH2OH, CH2CH(OH)(CH3), OCH3, OCH2CH3, C(O)NH2, C(O)CH3, 2,5-difluorophenyl, 3-pyridinyl, 2-pyridinyl, 1-methyl-1H-pyrazole-4-yl, These are 1-methyl-1H-pyrazole-3-yl, 1-methyl-1H-pyrazole-5-yl, 2-methylthiazole-5-yl, cyclohexyl, 3-cyanophenyl, 5-methylisoxazole-3-yl, 5-fluoropyridine-3-yl, 3-cyanophenyl, CH2CN, thiazole-4-yl, 6-methylpyridine-3-yl, pyrimidine-2-yl, morpholine-4-yl, cyclopropyl, oxazole-2-yl, CCCH(OH)(CH3), or C(O)NH(4-fluorophenyl).

[0096] Several embodiments, each R B These are independently unsubstituted phenyl, 4-fluorophenyl, 3-fluorophenyl, 2-fluorophenyl, 2-pyridinyl, CH2(phenyl), CH(CH2OH)phenyl, CH3, CH2CH3, CH(CH3)2, CH(CH2OH)CH2CH3, CH(CH2OH)CH3, CH2CH2OH, OCH3, OCH2CH3, or C(O)NH(4-fluorophenyl).

[0097] Several embodiments, each R B These are independently unsubstituted phenyl, 4-fluorophenyl, CH2(phenyl), CH(CH2OH)phenyl, CH3, CH2CH3, CH(CH2OH)CH2CH3, CH(CH2OH)CH3, CH2CH2OH, OCH3, OCH2CH3, or C(O)NH(4-fluorophenyl).

[0098] Several embodiments, each R BThese are independently unsubstituted phenyl, 4-fluorophenyl, 3-fluorophenyl, 2-fluorophenyl, CH2(phenyl), CH(CH2OH)phenyl, CH3, CH2CH3, CH(CH3)2, CH(CH2OH)CH2CH3, CH(CH2OH)CH3, CH2CH2OH, OCH3, OCH2CH3, or C(O)NH(4-fluorophenyl).

[0099] Several embodiments, each R B R is independently unsubstituted phenyl, or 4-fluorophenyl, 3-fluorophenyl, 2-fluorophenyl, 2-pyridinyl, CH3, CH2CH3, or CH(CH3)2. In some embodiments, each R B R is independently unsubstituted phenyl, or 4-fluorophenyl, 3-fluorophenyl, 2-fluorophenyl, CH3, CH2CH3, or CH(CH3)2. In some embodiments, each R B is unsubstituted phenyl, CH(CH3)2, or 2-pyridinyl. In some embodiments, each R B R is independently unsubstituted phenyl or 4-fluorophenyl. In some embodiments, each R B is an unsubstituted phenyl. In some embodiments, each R B is 4-fluorophenyl. In some embodiments, each R B is pyridinyl (e.g., 2-pyridinyl). In some embodiments, each R B R is independently unsubstituted phenyl or CH(CH3)2. In some embodiments, each R B R is independently unsubstituted phenyl or CH2CH3. In some embodiments, each R B R is independently 4-fluorophenyl or CH(CH3)2. In some embodiments, each R B R is independently 4-fluorophenyl or CH2CH3. In some embodiments, each R B R is independently 3-fluorophenyl or CH(CH3)2. In some embodiments, each RB R is independently 3-fluorophenyl or CH2CH3. In some embodiments, each R B R is independently 2-fluorophenyl or CH(CH3)2. In some embodiments, each R B These are independently 2-fluorophenyl or CH2CH3.

[0100] In some embodiments, Cy C R C Phenylene is optionally substituted with one, two, three, or four substituents independently selected from the given molecule.

[0101] In some embodiments, Cy C teeth, [ka] And here, the R of the phenylene ring C The base is ortho relative to the pyrolo[2,1-f][1,2,4]triazine ring of formula I.

[0102] Several embodiments, each R C These are independently OH, Halo, and C. 1-4 Alkyl and C 1-3 Selected from haloalkyls. In some embodiments, each R C These are independently, halo or C 1-4 It is alkyl. In some embodiments, each R C R is independently F, Cl, or methyl. In some embodiments, each R C It is F.

[0103] In some embodiments, Cy C teeth, [ka] And here, R C The phenyl ring is F, Cl, or methyl, and the pyrrolo[2,1-f][1,2,4]triazine ring is bonded to the left-side bond site.

[0104] In some embodiments, Cy C teeth, [ka] And here, R C is F, and the phenyl ring is bonded to the pyrrolo[2,1-f][1,2,4]triazine ring at the left-side bonding site.

[0105] In some embodiments, R 1 teeth, [ka] And, R A These are CH3, CH2CH3, CN, OH, CH2CH2OH, CH2CH2OCH3, C(O)CH3, C(O)CH(CH3)2, C(O)(cyclopropyl), C(O)CH2CH3, C(O)CH2OH, C(O)CH(OH)CH3, SO2CH3, C(O)OCH3, C(O)N(CH3)2, C(O)NHCH3, C(O)N(CH2CH3)2, C(O)N(CH3)(CH2CH3), or C(O)(morpholine-4-yl). Cy B teeth, [ka] And here, Cy B -1, Cy B -2, and Cy B -3 is arbitrarily R B Substituted with one or two substituents independently selected from, Each R B These are independently unsubstituted phenyl, 4-F-phenyl, 3-F-phenyl, 2-F-phenyl, 2-pyridinyl, CH2(phenyl), CH(phenyl)CH2OH, methyl, ethyl, isopropyl, CH(CH2OH)CH2CH3, CH(CH2OH)CH3, CH2CH2OH, or OCH2CH3. Cy C is one R CIt is a phenylene that can be arbitrarily substituted with the base, R C It is F, Cl, or Br.

[0106] In some embodiments, R 1 teeth, [ka] And, R A is CH3, CH2CH3, CN, OH, CH2CH2OH, CH2CH2OCH3, C(O)CH3, C(O)CH2OH, C(O)CH(OH)CH3, SO2 CH3, C(O)OCH3, C(O)N(CH3)2, C(O)NHCH3, C(O)N(CH2CH3)2, or C(O)N(CH3)(CH2CH3), Cy B teeth, [ka] And here, Cy B -1 and Cy B -2 is arbitrarily R B Substituted with one or two substituents independently selected from, Each R B These are independently unsubstituted phenyl, 4-F-phenyl, CH2(phenyl), CH(phenyl)CH2OH, methyl, ethyl, CH(CH2OH)CH2CH3, CH(CH2OH)CH3, CH2CH2OH, or OCH2CH3. Cy C is one R C It is a phenylene that can be arbitrarily substituted with the base, R C It is F, Cl, or Br.

[0107] In some embodiments, R 1 teeth, [ka] And, R Aare CH3, CH2CH3, CN, OH, CH2CH2OH, CH2CH2OCH3, C(O)CH3, C(O)CH(CH3)2, C(O)CH2CH3, C(O)CH2OH, C(O)CH(OH)CH3, SO2CH3, C(O)OCH3, C(O)N(CH3)2, C(O)NHCH3, C(O)N(CH2CH3)2, C(O)N(CH3)(CH2CH3), or C(O)(morpholin-4-yl), Cy B teeth, [ka] And here, Cy B -1, Cy B -2, and Cy B -3 is arbitrarily R B Substituted with one or two substituents independently selected from, Each R B These are independently unsubstituted phenyl, 4-F-phenyl, 3-F-phenyl, 2-F-phenyl, CH2(phenyl), CH(phenyl)CH2OH, methyl, ethyl, isopropyl, CH(CH2OH)CH2CH3, CH(CH2OH)CH3, CH2CH2OH, or OCH2CH3. Cy C is one R C It is a phenylene that can be arbitrarily substituted with the base, R C It is F, Cl, or Br.

[0108] In some embodiments, for example, Cy A , and Cy B The heteroaryl group can be optionally substituted with an oxo to form a carbonyl group. For example, Cy B The 5-10 membered heteroaryl group can be substituted with an oxo to form a carbonyl group, which can be 2-pyridone, for example, [ka] These include groups such as heteroaryl groups, as well as substituted pyridones (e.g., substituted 2-pyridones), for example, [ka] It can include...

[0109] In some embodiments: (1) A 1 , A 2 , and A 3 Each is a combination, R A is C 1-6 (2)A 1 and A 2 Each is a combination, A 3 is Cy A3 And each R A Independently, C 1-6 Alkyl, CN, OR a1 , C(O)R b1 , C(O)NR c1 R d1 , C(O)OR a1 , and S(O)2R b1 Selected from, the C 1-6 Alkyl is optional, R 11 It is substituted with the base. However, R A When R is bonded to a nitrogen atom, A is CN or OR a1 Not either, Each R a1 , R c1 , and R d1 H or C 1-4 It is alkyl, Each R b1 Independently, C 1-4 It is alkyl, Each R 11 Independently, OR a3 And, R 2 H is H, R 3 H is H, Cy B This is a 7,8-dihydroquinoline-2,5(1H,6H)-dione or 2-pyridone ring, which is optionally one or two independently selected R B Substituted with the base, Each R BR is independently methyl, ethyl, isopropyl, sec-butyl, or phenyl, each of which is optionally one or two independently selected R 12 Substituted with the base, Each R 12 These are independently halo, phenyl, and OR a4 Selected from, the phenyl is optionally one or two independently selected R g Substituted with the base, Each R g It is independently a halo, Each R a4 H or C 1-4 It is alkyl, Cy C is one R C It is a phenylene that can be arbitrarily substituted with the base, Each R C These are independently, halo or C 1-4 It is alkyl.

[0110] In some embodiments: (1) A 1 , A 2 , and A 3 Each is a combination, R A (2)A 1 and A 2 Each is a combination, A 3 -R A teeth, [ka] Selected from, Each R A Independently, C 1-3 Selected from alkyl, CN, OH, methylcarbonyl, methoxycarbonyl, N,N-dimethylaminocarbonyl, and methylsulfonyl, the C 1-3 Alkyl groups may optionally be substituted with OH or OCH3 groups. However, R A When R is bonded to a nitrogen atom, A It is neither CN nor OH, R 2 H is H, R 3H is H, Cy B This is a 7,8-dihydroquinoline-2,5(1H,6H)-dione or 2-pyridone ring, which is optionally R B Substituted with the base, Each R B R is independently methyl, ethyl, isopropyl, sec-butyl, or phenyl, each of which is optionally one or two independently selected R 12 Substituted with the base, Each R 12 R is independently selected from halo, phenyl, and OH, and the phenyl is optionally one or two independently selected R g Substituted with the base, Each R g is F, Cy C teeth, [ka] And here, R C is F, and the phenyl ring is bonded to the pyrrolo[2,1-f][1,2,4]triazine ring at the left-side bonding site.

[0111] In some embodiments, A 1 and A 2 Each is a combination, A 3 -R A teeth, [ka] And, Each R A Independently, C 1-3 Selected from alkyl, methylcarbonyl, ethylcarbonyl, isopropylcarbonyl, N,N-dimethylaminocarbonyl, N,N-diethylaminocarbonyl, N,N-(methyl)(ethyl)aminocarbonyl, and C(O)[morpholine-4-yl], R 2 H is H, R 3 H is H, Cy BR is a 7,8-dihydroquinoline-2,5(1H,6H)-dione or 2,4-dioxo-1,2,3,4-tetrahydropyrimidine ring, which is optionally one or two independently selected R B Substituted with the base, Each R B R is independently methyl, ethyl, isopropyl, sec-butyl, or phenyl, each of which is optionally one or two independently selected R 12 Substituted with the base, Each R 12 They are independently selected from Halo, Cy C This is unsubstituted phenylene.

[0112] In some embodiments, this disclosure relates to formula (IIa): [ka] The invention provides a compound having or a pharmaceutically acceptable salt thereof, wherein the variable element of formula (IIa) is as defined in formula (I) or as defined in any embodiment of the compound of formula (I) described herein.

[0113] In some embodiments, this disclosure relates to formula (IIa1) or formula (IIa2): [ka] The present invention provides a compound having or a pharmaceutically acceptable salt thereof, wherein the variable elements of formula (IIa1) and formula (IIa2) are as defined in formula (I) or as defined in any embodiment of the compound of formula (I) described herein.

[0114] In some embodiments, this disclosure relates to formula (IIb1) or formula (IIb2): [ka] The present invention provides a compound having or a pharmaceutically acceptable salt thereof, wherein the variable elements of formula (IIb1) and formula (IIb2) are as defined in formula (I) or as defined in any embodiment of the compound of formula (I) described herein.

[0115] In some embodiments, this disclosure relates to formula (IIc1) or formula (IIc2): [ka] The present invention provides a compound having or a pharmaceutically acceptable salt thereof, wherein the variable elements of formula (IIc1) and formula (IIc2) are as defined in formula (I) or as defined in any embodiment of the compound of formula (I) described herein.

[0116] In some embodiments, this disclosure refers to formula (IId1) or formula (IId2): [ka] The present invention provides a compound having or a pharmaceutically acceptable salt thereof, wherein the variable elements of formula (IId1) and formula (IId2) are as defined in formula (I) or as defined in any embodiment of the compound of formula (I) described herein.

[0117] In some embodiments, this disclosure relates to formula (IIe1): [ka] The invention provides a compound having or a pharmaceutically acceptable salt thereof, wherein the variable element of formula (IIe1) is as defined in formula (I) or as defined in any embodiment of the compound of formula (I) described herein.

[0118] In some embodiments, this disclosure refers to formula (IIf1) or formula (IIf2): [ka] The invention provides a compound having or a pharmaceutically acceptable salt thereof, wherein the variable elements of formula (IIf1) are as defined in formula (I) or as defined in any embodiment of the compound of formula (I) described herein.

[0119] In some embodiments, this disclosure relates to formula (IIg1) or formula (IIg2): [ka] The present invention provides a compound having or a pharmaceutically acceptable salt thereof, wherein the variable elements of formula (IIg1) and formula (IIg2) are as defined in formula (I) or as defined in any embodiment of the compound of formula (I) described herein.

[0120] In some embodiments, this disclosure relates to formulas (IIg3), (IIg4), and (IIg5): [ka] The invention provides a compound having or a pharmaceutically acceptable salt thereof, wherein the variable elements of formula (IIg3), formula (IIg4), and formula (IIg5) are as defined in formula (I) or as defined in any embodiment of the compound of formula (I) described herein, and t is 0, 1, 2, 3, or 4.

[0121] In some embodiments, this disclosure uses formula (IIh1): [ka] The present invention provides a compound having or a pharmaceutically acceptable salt thereof, wherein the variable element of formula (IIh1) is as defined in formula (I) or as defined in any embodiment of the compound of formula (I) described herein.

[0122] In some embodiments, this disclosure relates to formula (IIi1): [ka] The invention provides a compound having or a pharmaceutically acceptable salt thereof, wherein the variable element of formula (IIi1) is as defined in formula (I) or as defined in any embodiment of the compound of formula (I) described herein.

[0123] In some embodiments, this disclosure refers to formulas (IIIa), (IVa), (Va), (VIa), (VIIa), or (VIIIa): [ka] The invention provides compounds having or pharmaceutically acceptable salts thereof, wherein the variable elements of formula (IIIa), formula (IVa), formula (Va), formula (VIa), formula (VIIa), and formula (VIIIa) are as defined in formula (I) or as defined in any embodiment of the compounds of formula (I) described herein.

[0124] In some embodiments, this disclosure applies to formulas (IIIb), (IVb), (Vb), (VIb), (VIIb), or (VIIIb): [ka] The invention provides compounds having or pharmaceutically acceptable salts thereof, wherein the variable elements of formula (IIIb), formula (IVb), formula (Vb), formula (VIb), formula (VIIb), and formula (VIIIb) are as defined in formula (I) or as defined in any embodiment of the compounds of formula (I) described herein.

[0125] In some embodiments: R 1 is, A 1 -A 2 -A 3 -R A And, R 2 H, Haro, CN, C1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy, C 1-4 Haloalkoxy, cyano-C 1-3 Alkyl, or C 1-6 It is an alkoxyalkyl, R 3 H, Haro, CN, C 1-6 Alkyl, C 1-6 Haloalkyl, OR a , SR a , C(O)NR c R d , NR c R d , NR c C(O)R b , NR c S(O)2R b , or S(O)2R b and C 1-6 Alkyl and C 1-6 Haloalkyl can optionally be Halo, CN, OR a , SR a , C(O)NR c R d , NR c R d , NR c C(O)R b , NR c S(O)2R b S(O)2R b , NR c C(O)OR a , NR c C(O)NR c R d , NR c S(O)2NR c R d , and Cy R3 Substituted with one, two, or three substituents independently selected from, A 1 is a combination, Cy A1 -Y-, -C 1-3 Alkylene-,-C 1-3 Alkilen-Y-, -YC 1-3 Alkylene-, and -C 1-2 Alkilen-YC 1-2Selected from alkylene groups, each of which can be optionally halo, CN, OH, or C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl, C 1-3 Haloalkoxy, amino, C 1-3 Alkylamino and di(C) 1-3 Substituted with one, two, or three substituents independently selected from alkyl)amino, A 2 is a combination, Cy A2 -Y-, -C 1-3 Alkylene-,-C 1-3 Alkilen-Y-, -YC 1-3 Alkylene-, and -C 1-2 Alkilen-YC 1-2 Selected from alkylene groups, each of which can be optionally halo, CN, OH, or C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl, C 1-3 Haloalkoxy, amino, C 1-3 Alkylamino and di(C) 1-3 Substituted with one, two, or three substituents independently selected from alkyl)amino, A 3 is a combination, Cy A3 -Y-, -C 1-3 Alkylene-,-C 1-3 Alkilen-Y-, -YC 1-3 Alkylene-, and -C 1-2 Alkilen-YC 1-2 Selected from alkylene groups, each of which can be optionally halo, CN, OH, or C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl, C 1-3 Haloalkoxy, amino, C 1-3 Alkylamino and di(C) 1-3 Substituted with one, two, or three substituents independently selected from alkyl)amino, R A H, C 1-6 Alkyl, C 1-6Haloalkyl, Halo, CN, NO2, OR a1 , SR a1 , C(O)R b1 , C(O)NR c1 R d1 , C(O)OR a1 ,OC(O)R b1 , OC(O)NR c1 R d1 , NR c1 R d1 , NR c1 Ure d1 , NR c1 C(O)R b1 , NR c1 C(O)OR a1 , NR c1 C(O)NR c1 R d1 , C(=NR e1 )R b1 , C(=NR e1 )NR c1 R d1 , NR c1 C(=NR e1 )NR c1 R d1 , NR c1 S(O)R b1 , NR c1 S(O)2R b1 , NR c1 S(O)2NR c1 R d1 S(O)R b1 , S(O)NR c1 R d1 S(O)2R b1 , or S(O)2NR c1 R d1 and C 1-6 Alkyl or C 1-6 Haloalkyls are optional, R 11 Substituted with 1, 2, 3, or 4 substituents independently selected from, Y is O, S, S(O), S(O)2, C(O), C(O)NR f , NR f C(O), NR f C(O)NR f , NR f S(O)2NR f , S(O)2NR f , NRf S(O)2, or NR f And, Each R f H and C 1-3 Selected independently of alkyl, Cy A1 C 3-7 The compounds are cycloalkyl, phenyl, 5-6 membered heteroaryl, or 4-7 membered heterocycloalkyl, each having at least one ring-forming carbon atom and 1, 2, 3, or 4 ring-forming heteroatoms independently selected from N, O, and S, wherein the N and S are optionally oxidized, and C 3-7 The ring-forming carbon atoms of cycloalkyl and 4- to 7-membered heterocycloalkyl groups are optionally substituted with oxo atoms to form a carbonyl group, and the C 3-7 Cycloalkyls, phenyls, 5-6 member heteroaryls, and 4-7 member heterocycloalkyls are each optionally R A1 Substituted with 1, 2, 3, or 4 substituents independently selected from, Each R A1 These are independently OH, NO2, CN, Halo, and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, cyano-C 1-3 Alkyl, HO-C 1-3 Alkyl, H2N-C 1-3 Alkyl, amino, C 1-6 Alkylamino, di(C 1-6 Alkyl)amino, thio, C 1-6 Alkylthio, C 1-6 Alkyl sulfinyl, C 1-6 Alkyl sulfonyl, carbamyl, C 1-6 Alkylcarbamyl, di(C 1-6 Alkyl)carbamyl, carboxy, C 1-6 Alkylcarbonyl, C 1-6 Alkoxycarbonyl, C 1-6 Alkylcarbonylamino, C 1-6 Alkylsulfonylamino, aminosulfonyl, C 1-6Alkylaminosulfonyl, di(C 1-6 Alkyl)aminosulfonyl, aminosulfonylamino, C 1-6 Alkylaminosulfonylamino, di(C 1-6 Alkyl)aminosulfonylamino, aminocarbonylamino, C 1-6 Alkylaminocarbonylamino, and di(C 1-6 Selected from alkyl)aminocarbonylamino, Cy A2 C 3-7 The compounds are cycloalkyl, phenyl, 5-6 membered heteroaryl, or 4-7 membered heterocycloalkyl, each having at least one ring-forming carbon atom and 1, 2, 3, or 4 ring-forming heteroatoms independently selected from N, O, and S, wherein the N and S are optionally oxidized, and C 3-7 The ring-forming carbon atoms of cycloalkyl and 4- to 7-membered heterocycloalkyl groups are optionally substituted with oxo atoms to form a carbonyl group, and the C 3-7 Cycloalkyls, phenyls, 5-6 member heteroaryls, and 4-7 member heterocycloalkyls are each optionally R A2 Substituted with 1, 2, 3, or 4 substituents independently selected from, Each R A2 These are independently OH, NO2, CN, Halo, and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, cyano-C 1-3 Alkyl, HO-C 1-3 Alkyl, H2N-C 1-3 Alkyl, amino, C 1-6 Alkylamino, di(C 1-6 Alkyl)amino, thio, C 1-6 Alkylthio, C 1-6 Alkyl sulfinyl, C 1-6 Alkyl sulfonyl, carbamyl, C 1-6 Alkylcarbamyl, di(C 1-6 Alkyl)carbamyl, carboxy, C 1-6 Alkylcarbonyl, C1-6 Alkoxycarbonyl, C 1-6 Alkylcarbonylamino, C 1-6 Alkylsulfonylamino, aminosulfonyl, C 1-6 Alkylaminosulfonyl, di(C 1-6 Alkyl)aminosulfonyl, aminosulfonylamino, C 1-6 Alkylaminosulfonylamino, di(C 1-6 Alkyl)aminosulfonylamino, aminocarbonylamino, C 1-6 Alkylaminocarbonylamino, and di(C 1-6 Selected from alkyl)aminocarbonylamino, Cy A3 C 3-7 The compounds are cycloalkyl, phenyl, 5-6 membered heteroaryl, or 4-7 membered heterocycloalkyl, each having at least one ring-forming carbon atom and 1, 2, 3, or 4 ring-forming heteroatoms independently selected from N, O, and S, wherein the N and S are optionally oxidized, and C 3-7 The ring-forming carbon atoms of cycloalkyl and 4- to 7-membered heterocycloalkyl groups are optionally substituted with oxo atoms to form a carbonyl group, and the C 3-7 Cycloalkyls, phenyls, 5-6 member heteroaryls, and 4-7 member heterocycloalkyls are each optionally R A3 Substituted with 1, 2, 3, or 4 substituents independently selected from, Each R A3 These are independently OH, NO2, CN, Halo, and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, cyano-C 1-3 Alkyl, HO-C 1-3 Alkyl, H2N-C 1-3 Alkyl, amino, C 1-6 Alkylamino, di(C 1-6 Alkyl)amino, thio, C 1-6 Alkylthio, C 1-6 Alkyl sulfinyl, C 1-6Alkyl sulfonyl, carbamyl, C 1-6 Alkylcarbamyl, di(C 1-6 Alkyl)carbamyl, carboxy, C 1-6 Alkylcarbonyl, C 1-6 Alkoxycarbonyl, C 1-6 Alkylcarbonylamino, C 1-6 Alkylsulfonylamino, aminosulfonyl, C 1-6 Alkylaminosulfonyl, di(C 1-6 Alkyl)aminosulfonyl, aminosulfonylamino, C 1-6 Alkylaminosulfonylamino, di(C 1-6 Alkyl)aminosulfonylamino, aminocarbonylamino, C 1-6 Alkylaminocarbonylamino, and di(C 1-6 Selected from alkyl)aminocarbonylamino, Cy R3 C 3-7 The compounds are cycloalkyl, phenyl, 5-6 membered heteroaryl, or 4-7 membered heterocycloalkyl, each having at least one ring-forming carbon atom and 1, 2, 3, or 4 ring-forming heteroatoms independently selected from N, O, and S, wherein the N and S are optionally oxidized, and C 3-7 The ring-forming carbon atoms of cycloalkyl and 4- to 7-membered heterocycloalkyl groups are optionally substituted with oxo atoms to form a carbonyl group, and the C 3-7 Cycloalkyls, phenyls, 5-6 member heteroaryls, and 4-7 member heterocycloalkyls are each optionally R g Substituted with 1, 2, 3, or 4 substituents independently selected from, Cy C is phenylene or a 5-6 membered heteroarylene, the 5-6 membered heteroarylene having at least one ring-forming carbon atom and one or two ring-forming heteroatoms independently selected from N, O, and S, and the phenylene and the 5-6 membered heteroarylene are each optionally R C Substituted with 1, 2, 3, or 4 substituents independently selected from, Each RC These are independently OH, CN, Haro, and C. 1-4 Alkyl, C 1-3 Haloalkyl, C 1-4 Alkoxy, C 1-3 Haloalkoxy, cyano-C 1-3 Alkyl, HO-C 1-3 Alkyl, amino, C 1-4 Alkylamino, di(C 1-4 Alkyl)amino, C 1-4 Alkyl sulfinyl, C 1-4 Alkyl sulfonyl, carbamyl, C 1-4 Alkylcarbamyl, di(C 1-4 Alkyl)carbamyl, carboxy, C 1-4 Alkylcarbonyl, C 1-4 Alkoxycarbonyl, C 1-4 Alkylcarbonylamino, C 1-4 Alkylsulfonylamino, aminosulfonyl, C 1-4 Alkylaminosulfonyl and di(C 1-4 Selected from alkyl)aminosulfonyl, Cy B C 3-10 It is a cycloalkyl or a 4-10 member heterocycloalkyl, C 3-10 At least one ring-forming carbon atom of a cycloalkyl or 4-10 membered heterocycloalkyl is substituted with an oxo to form a carbonyl group, and the 4-10 membered heterocycloalkyl has at least one ring-forming carbon atom and 1, 2, 3, or 4 ring-forming heteroatoms independently selected from N, O, and S, wherein the N and S are optionally oxidized, and the C 3-10 Cycloalkyls and 4-10 member heterocycloalkyls are each optionally R B It is substituted with 1, 2, 3, or 4 substituents independently selected from, or Cy BA is a 5-10 member heteroaryl, which has at least one ring-forming carbon atom and 1, 2, 3, or 4 ring-forming heteroatoms independently selected from N, O, and S, wherein the N and S are optionally oxidized, where: (a) at least one ring-forming carbon atom of the 5-10 member heteroaryl is substituted with an oxo to form a carbonyl group, or (b) the 5-10 member heteroaryl is oxidized with a halo, CN, NO2, OR a2 , SR a2 , C(O)R b2 , C(O)NR c2 R d2 , C(O)OR a2 ,OC(O)R b2 , OC(O)NR c2 R d2 , NR c2 R d2 , NR c2 Ure d2 , NR c2 C(O)R b2 , NR c2 C(O)OR a2 , NR c2 C(O)NR c2 R d2 , NR c2 S(O)R b2 , NR c2 S(O)2R b2 , NR c2 S(O)2NR c2 R d2 S(O)R b2 , S(O)NR c2 R d2 S(O)2R b2 , and S(O)2NR c2 R d2 The 5-10 member heteroaryl is substituted with, and optionally, R B Substituted with 1, 2, 3, or 4 substituents independently selected from, Each R B It is independently, Halo, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, phenyl, 5-6 member heteroaryl, 4-7 member heterocycloalkyl, CN, NO2, OR a2, SR a2 , C(O)R b2 , C(O)NR c2 R d2 , C(O)OR a2 ,OC(O)R b2 , OC(O)NR c2 R d2 , NR c2 R d2 , NR c2 Ure d2 , NR c2 C(O)R b2 , NR c2 C(O)OR a2 , NR c2 C(O)NR c2 R d2 , NR c2 S(O)R b2 , NR c2 S(O)2R b2 , NR c2 S(O)2NR c2 R d2 S(O)R b2 , S(O)NR c2 R d2 S(O)2R b2 , and S(O)2NR c2 R d2 Selected from, the C 1-6 Alkyl, C 3-6 Cycloalkyls, phenyls, 5-6 member heteroaryls, and 4-7 member heterocycloalkyls are each optionally R 12 Substituted with 1, 2, 3, or 4 substituents independently selected from, Each R 11 These are independently CN, NO2, OR a3 , SR a3 , C(O)R b3 , C(O)NR c3 R d3 , C(O)OR a3 ,OC(O)R b3 , OC(O)NR c3 R d3 , NR c3 R d3 , NR c3 Ure d3 , NR c3 C(O)R b3 , NR c3C(O)OR a3 , NR c3 C(O)NR c3 R d3 , NR c3 S(O)R b3 , NR c3 S(O)2R b3 , NR c3 S(O)2NR c3 R d3 S(O)R b3 , S(O)NR c3 R d3 S(O)2R b3 , and S(O)2NR c3 R d3 Selected from, Each R 12 These are independently: Haro, CN, NO2, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, phenyl, 5-6 member heteroaryl, 4-7 member heterocycloalkyl, OR a4 , SR a4 , C(O)R b4 , C(O)NR c4 R d4 , C(O)OR a4 ,OC(O)R b4 , OC(O)NR c4 R d4 , NR c4 R d4 , NR c4 Ure d4 , NR c4 C(O)R b4 , NR c4 C(O)OR a4 , NR c4 C(O)NR c4 R d4 , NR c4 S(O)R b4 , NR c4 S(O)2R b4 , NR c4 S(O)2NR c4 R d4 S(O)R b4 , S(O)NR c4 R d4 S(O)2R b4 , and S(O)2NR c4 Rd4 Selected from, the C 1-6 Alkyl, C 3-6 Cycloalkyls, phenyls, 5-6 member heteroaryls, and 4-7 member heterocycloalkyls are each optionally R g Substituted with 1, 2, 3, or 4 substituents independently selected from, R a H, C 1-6 Alkyl and C 1-6 Selected from haloalkyl groups, R b C 1-6 Alkyl and C 1-6 Selected from haloalkyl groups, R c and R d These are H and C, which are independent of each other. 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, phenyl, 5-6 member heteroaryl, 4-6 member heterocycloalkyl, C 3-6 Cycloalkyl-C 1-3 Alkylene, Phenyl-C 1-3 Alkylene, 5-6 member heteroaryl-C 1-3 Alkylenes and 4-6 member heterocycloalkyl-C 1-3 Selected from alkylene, the C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, phenyl, 5-6 member heteroaryl, 4-6 member heterocycloalkyl, C 3-6 Cycloalkyl-C 1-3 Alkylene, Phenyl-C 1-3 Alkylene, 5-6 member heteroaryl-C 1-3 Alkylenes and 4-6 member heterocycloalkyl-C 1-3 Alkylenes are each arbitrarily R g Substituted with one, two, or three substituents independently selected from, R a1 , R c1 , and R d1 These are H and C, which are independent of each other. 1-6 Alkyl and C 1-6Selected from haloalkyl, the C 1-6 Alkyl is optional, R g It is substituted with 1, 2, 3, or 4 substituents independently selected from, or Alternatively, R bonded to the same N atom c1 and R d1 Along with the N atom to which they are bonded, R g Forming a 4, 5, 6, or 7-membered heterocycloalkyl group which is optionally substituted with 1, 2, or 3 substituents independently selected from the above, R b1 C 1-6 Alkyl and C 1-6 Selected from haloalkyls, each of which optionally includes R g Substituted with 1, 2, 3, or 4 substituents independently selected from, R e1 H, CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkylthio, C 1-6 Alkyl sulfonyl, C 1-6 Alkylcarbonyl, C 1-6 Alkylaminosulfonyl, Carbamyl, C 1-6 Alkylcarbamyl, di(C 1-6 Alkyl)carbamyl, aminosulfonyl, C 1-6 Alkylaminosulfonyl and di(C 1-6 Selected from alkyl)aminosulfonyl, Each R a2 , R c2 , and R d2 H and C are independent of each other. 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Selected from cycloalkyl, phenyl, 5-6 membered heteroaryl, and 4-7 membered heterocycloalkyl, the C 1-6 Alkyl, C 3-6 Cycloalkyls, phenyls, 5-6 member heteroaryls, and 4-7 member heterocycloalkyls are each optionally R 12 It is substituted with 1, 2, 3, or 4 substituents independently selected from, or Alternatively, any R bonded to the same N atom c2 and R d2 Along with the N atom to which they are bonded, R 12 Forming a 4, 5, 6, or 7-membered heterocycloalkyl group which is optionally substituted with 1, 2, or 3 substituents independently selected from the above, Each R b2 Independently, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Selected from cycloalkyls, phenyls, 5-6 membered heteroaryls, and 4-7 membered heterocycloalkyls, each of which optionally includes R 12 Substituted with 1, 2, 3, or 4 substituents independently selected from, Each R a3 , R c3 , and R d3 H and C are independent of each other. 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, phenyl, 5-6 member heteroaryl, 4-7 member heterocycloalkyl, C 3-6 Cycloalkyl-C 1-4 Alkylene, Phenyl-C 1-4 Alkylene, 5-6 member heteroaryl-C 1-4 Alkylenes and 4-7 member heterocycloalkyl-C 1-4 Selected from alkylene, the C 1-6 Alkyl, C 3-6 Cycloalkyl, phenyl, 5-6 member heteroaryl, 4-7 member heterocycloalkyl, C 3-6 Cycloalkyl-C 1-4 Alkylene, Phenyl-C 1-4 Alkylene, 5-6 member heteroaryl-C 1-4 Alkylenes and 4-7 member heterocycloalkyl-C 1-4 Alkylenes are each arbitrarily R g It is substituted with 1, 2, 3, or 4 substituents independently selected from, or Alternatively, any R bonded to the same N atom c3 and R d3 Along with the N atom to which they are bonded, Rg Forming a 4, 5, 6, or 7-membered heterocycloalkyl group which is optionally substituted with 1, 2, or 3 substituents independently selected from the above, Each R b3 Independently, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, phenyl, 5-6 member heteroaryl, 4-7 member heterocycloalkyl, C 3-6 Cycloalkyl-C 1-4 Alkylene, Phenyl-C 1-4 Alkylene, 5-6 member heteroaryl-C 1-4 Alkylenes and 4-7 member heterocycloalkyl-C 1-4 Selected from alkylenes, each of which is optionally R g Substituted with 1, 2, 3, or 4 substituents independently selected from, Each R a4 , R c4 , and R d4 H and C are independent of each other. 1-6 Alkyl and C 1-6 Selected from haloalkyl, the C 1-6 Alkyl is optional, R g It is substituted with 1, 2, 3, or 4 substituents independently selected from, or Alternatively, any R bonded to the same N atom c4 and R d4 Along with the N atom to which they are bonded, R g Forming a 4, 5, 6, or 7-membered heterocycloalkyl group which is optionally substituted with 1, 2, or 3 substituents independently selected from the above, Each R b4 Independently, C 1-6 Alkyl and C 1-6 Selected from haloalkyls, each of which optionally includes R g Substituted with 1, 2, 3, or 4 substituents independently selected from, Each R g These are independently OH, NO2, CN, Halo, and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C1-6 Haloalkoxy, cyano-C 1-3 Alkyl, HO-C 1-3 Alkyl, H2N-C 1-3 Alkyl, amino, C 1-6 Alkylamino, di(C 1-6 Alkyl)amino, thio, C 1-6 Alkylthio, C 1-6 Alkyl sulfinyl, C 1-6 Alkyl sulfonyl, carbamyl, C 1-6 Alkylcarbamyl, di(C 1-6 Alkyl)carbamyl, carboxy, C 1-6 Alkylcarbonyl, C 1-6 Alkoxycarbonyl, C 1-6 Alkylcarbonylamino, C 1-6 Alkylsulfonylamino, aminosulfonyl, C 1-6 Alkylaminosulfonyl, di(C 1-6 Alkyl)aminosulfonyl, aminosulfonylamino, C 1-6 Alkylaminosulfonylamino, di(C 1-6 Alkyl)aminosulfonylamino, aminocarbonylamino, C 1-6 Alkylaminocarbonylamino, and di(C 1-6 Selected from alkyl)aminocarbonylamino. however: 1) A 1 -A 2 -A 3 is, A 1 , A 2 , or A 3 If one of them is a combination, it is neither YY nor YYY, and 2) A 3 is -Y- or -C 1-3 In the case of alkylene-Y-, R A H, C 1-6 Alkyl, or C 1-6 It is a haloalkyl, and the C 1-6 Alkyl or C 1-6 Haloalkyls are optional, R 11 The condition is that it is substituted with 1, 2, 3, or 4 substituents selected independently of it.

[0126] In some embodiments: R 1 is, A 1 -A 2 -A 3 -R A And, R 2 H, Haro, CN, C 1-4 Alkyl, or C 1-4 It is a haloalkyl, R 3 H, Haro, CN, C 1-6 Alkyl, or C 1-6 It is a haloalkyl, A 1 is a combination, Cy A1 -Y-, -C 1-3 Alkylene-,-C 1-3 Alkylene-Y- and -YC 1-3 Selected from alkylene, A 2 is a combination, Cy A2 -Y-, -C 1-3 Alkylene-,-C 1-3 Alkylene-Y- and -YC 1-3 Selected from alkylene, A 3 is a combination, Cy A3 -Y-, -C 1-3 Alkylene-,-C 1-3 Alkylene-Y- and -YC 1-3 Selected from alkylene, R A H, C 1-6 Alkyl, C 1-6 Haloalkyl, Halo, CN, NO2, OR a1 , SR a1 , C(O)R b1 , C(O)NR c1 R d1 , C(O)OR a1 ,OC(O)R b1 , OC(O)NR c1 R d1 , NR c1 R d1 , NR c1 C(O)R b1, NR c1 C(O)OR a1 S(O)R b1 , S(O)NR c1 R d1 S(O)2R b1 , or S(O)2NR c1 R d1 and C 1-6 Alkyl or C 1-6 Haloalkyls are optional, R 11 Substituted with 1, 2, 3, or 4 substituents independently selected from, Y is O, S, S(O), S(O)2, or C(O), Cy A1 C 3-7 The compounds are cycloalkyl, phenyl, 5-6 membered heteroaryl, or 4-7 membered heterocycloalkyl, each having at least one ring-forming carbon atom and 1, 2, 3, or 4 ring-forming heteroatoms independently selected from N, O, and S, wherein the N and S are optionally oxidized, and C 3-7 The ring-forming carbon atoms of cycloalkyl and 4- to 7-membered heterocycloalkyl groups are optionally substituted with oxo atoms to form a carbonyl group, and the C 3-7 Cycloalkyls, phenyls, 5-6 member heteroaryls, and 4-7 member heterocycloalkyls are each optionally R A1 Substituted with 1, 2, 3, or 4 substituents independently selected from, Each R A1 These are independently OH, NO2, CN, Halo, and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, cyano-C 1-3 Alkyl, HO-C 1-3 Alkyl, H2N-C 1-3 Alkyl, amino, C 1-6 Alkylamino, di(C 1-6 Alkyl)amino, thio, C 1-6 Alkylthio, C 1-6 Alkyl sulfinyl, C 1-6 Alkyl sulfonyl, carbamyl, C1-6 Alkylcarbamyl, di(C 1-6 Alkyl)carbamyl, carboxy, C 1-6 Alkylcarbonyl, C 1-6 Alkoxycarbonyl, C 1-6 Alkylcarbonylamino, C 1-6 Alkylsulfonylamino, aminosulfonyl, C 1-6 Alkylaminosulfonyl, di(C 1-6 Alkyl)aminosulfonyl, aminosulfonylamino, C 1-6 Alkylaminosulfonylamino, di(C 1-6 Alkyl)aminosulfonylamino, aminocarbonylamino, C 1-6 Alkylaminocarbonylamino, and di(C 1-6 Selected from alkyl)aminocarbonylamino, Cy A2 C 3-7 The compounds are cycloalkyl, phenyl, 5-6 membered heteroaryl, or 4-7 membered heterocycloalkyl, each having at least one ring-forming carbon atom and 1, 2, 3, or 4 ring-forming heteroatoms independently selected from N, O, and S, wherein the N and S are optionally oxidized, and C 3-7 The ring-forming carbon atoms of cycloalkyl and 4- to 7-membered heterocycloalkyl groups are optionally substituted with oxo atoms to form a carbonyl group, and the C 3-7 Cycloalkyls, phenyls, 5-6 member heteroaryls, and 4-7 member heterocycloalkyls are each optionally R A2 Substituted with 1, 2, 3, or 4 substituents independently selected from, Each R A2 These are independently OH, NO2, CN, Halo, and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, cyano-C 1-3 Alkyl, HO-C 1-3 Alkyl, H2N-C 1-3 Alkyl, amino, C 1-6 Alkylamino, di(C1-6 Alkyl)amino, thio, C 1-6 Alkylthio, C 1-6 Alkyl sulfinyl, C 1-6 Alkyl sulfonyl, carbamyl, C 1-6 Alkylcarbamyl, di(C 1-6 Alkyl)carbamyl, carboxy, C 1-6 Alkylcarbonyl, C 1-6 Alkoxycarbonyl, C 1-6 Alkylcarbonylamino, C 1-6 Alkylsulfonylamino, aminosulfonyl, C 1-6 Alkylaminosulfonyl, di(C 1-6 Alkyl)aminosulfonyl, aminosulfonylamino, C 1-6 Alkylaminosulfonylamino, di(C 1-6 Alkyl)aminosulfonylamino, aminocarbonylamino, C 1-6 Alkylaminocarbonylamino, and di(C 1-6 Selected from alkyl)aminocarbonylamino, Cy A3 C 3-7 The compounds are cycloalkyl, phenyl, 5-6 membered heteroaryl, or 4-7 membered heterocycloalkyl, each having at least one ring-forming carbon atom and 1, 2, 3, or 4 ring-forming heteroatoms independently selected from N, O, and S, wherein the N and S are optionally oxidized, and C 3-7 The ring-forming carbon atoms of cycloalkyl and 4- to 7-membered heterocycloalkyl groups are optionally substituted with oxo atoms to form a carbonyl group, and the C 3-7 Cycloalkyls, phenyls, 5-6 member heteroaryls, and 4-7 member heterocycloalkyls are each optionally R A3 Substituted with 1, 2, 3, or 4 substituents independently selected from, Each R A3 These are independently OH, NO2, CN, Halo, and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, cyano-C1-3 Alkyl, HO-C 1-3 Alkyl, H2N-C 1-3 Alkyl, amino, C 1-6 Alkylamino, di(C 1-6 Alkyl)amino, thio, C 1-6 Alkylthio, C 1-6 Alkyl sulfinyl, C 1-6 Alkyl sulfonyl, carbamyl, C 1-6 Alkylcarbamyl, di(C 1-6 Alkyl)carbamyl, carboxy, C 1-6 Alkylcarbonyl, C 1-6 Alkoxycarbonyl, C 1-6 Alkylcarbonylamino, C 1-6 Alkylsulfonylamino, aminosulfonyl, C 1-6 Alkylaminosulfonyl, di(C 1-6 Alkyl)aminosulfonyl, aminosulfonylamino, C 1-6 Alkylaminosulfonylamino, di(C 1-6 Alkyl)aminosulfonylamino, aminocarbonylamino, C 1-6 Alkylaminocarbonylamino, and di(C 1-6 Selected from alkyl)aminocarbonylamino, Cy C is phenylene or a 5-6 membered heteroarylene, the 5-6 membered heteroarylene having at least one ring-forming carbon atom and one or two ring-forming heteroatoms independently selected from N, O, and S, and the phenylene and the 5-6 membered heteroarylene are each optionally R C Substituted with 1, 2, 3, or 4 substituents independently selected from, Each R C These are independently OH, CN, Haro, and C. 1-4 Alkyl, C 1-3 Haloalkyl, C 1-4 Alkoxy, C 1-3 Haloalkoxy, cyano-C 1-3 Alkyl, HO-C 1-3 Alkyl, amino, C 1-4 Alkylamino, di(C 1-4 Alkyl)amino, C1-4 Alkyl sulfinyl, C 1-4 Alkyl sulfonyl, carbamyl, C 1-4 Alkylcarbamyl, di(C 1-4 Alkyl)carbamyl, carboxy, C 1-4 Alkylcarbonyl, C 1-4 Alkoxycarbonyl, C 1-4 Alkylcarbonylamino, C 1-4 Alkylsulfonylamino, aminosulfonyl, C 1-4 Alkylaminosulfonyl and di(C 1-4 Selected from alkyl)aminosulfonyl, Cy B C 3-10 It is a cycloalkyl or a 4-10 member heterocycloalkyl, C 3-10 At least one ring-forming carbon atom of a cycloalkyl or 4-10 membered heterocycloalkyl is substituted with an oxo to form a carbonyl group, and the 4-10 membered heterocycloalkyl has at least one ring-forming carbon atom and 1, 2, 3, or 4 ring-forming heteroatoms independently selected from N, O, and S, wherein the N and S are optionally oxidized, and the C 3-10 Cycloalkyls and 4-10 member heterocycloalkyls are each optionally R B It is substituted with 1, 2, 3, or 4 substituents independently selected from, or Cy B The aryl group is a 6-10 membered aryl group or a 5-10 membered heteroaryl group, the 5-10 membered heteroaryl group having at least one ring-forming carbon atom and 1, 2, 3, or 4 ring-forming heteroatoms independently selected from N, O, and S, wherein the N and S are optionally oxidized, where: (a) at least one ring-forming carbon atom of the 5-10 membered heteroaryl group is substituted with an oxo atom to form a carbonyl group, or (b) the 6-10 membered aryl group or 5-10 membered heteroaryl group is oxidized with a halo, CN, NO2, OR a2 , SR a2 , C(O)R b2 , C(O)NR c2 R d2 , C(O)OR a2,OC(O)R b2 , OC(O)NR c2 R d2 , NR c2 R d2 , NR c2 Ure d2 , NR c2 C(O)R b2 , NR c2 C(O)OR a2 , NR c2 C(O)NR c2 R d2 , NR c2 S(O)R b2 , NR c2 S(O)2R b2 , NR c2 S(O)2NR c2 R d2 S(O)R b2 , S(O)NR c2 R d2 S(O)2R b2 , and S(O)2NR c2 R d2 The 6-10 member aryl or 5-10 member heteroaryl is further optionally R B Substituted with 1, 2, 3, or 4 substituents independently selected from, Each R B It is independently, Halo, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, phenyl, 5-6 member heteroaryl, 4-7 member heterocycloalkyl, CN, NO2, OR a2 , SR a2 , C(O)R b2 , C(O)NR c2 R d2 , C(O)OR a2 ,OC(O)R b2 , OC(O)NR c2 R d2 , NR c2 R d2 , NR c2 Ure d2 , NR c2 C(O)R b2 , NR c2 C(O)OR a2 , NR c2C(O)NR c2 R d2 , NR c2 S(O)R b2 , NR c2 S(O)2R b2 , NR c2 S(O)2NR c2 R d2 S(O)R b2 , S(O)NR c2 R d2 S(O)2R b2 , and S(O)2NR c2 R d2 Selected from, the C 1-6 Alkyl, C 3-6 Cycloalkyls, phenyls, 5-6 member heteroaryls, and 4-7 member heterocycloalkyls are each optionally R 12 Substituted with 1, 2, 3, or 4 substituents independently selected from, Each R 11 These are independently CN, NO2, OR a3 , SR a3 , C(O)R b3 , C(O)NR c3 R d3 , C(O)OR a3 ,OC(O)R b3 , OC(O)NR c3 R d3 , NR c3 R d3 , NR c3 Ure d3 , NR c3 C(O)R b3 , NR c3 C(O)OR a3 , NR c3 C(O)NR c3 R d3 , NR c3 S(O)R b3 , NR c3 S(O)2R b3 , NR c3 S(O)2NR c3 R d3 S(O)R b3 , S(O)NR c3 R d3 S(O)2R b3 , and S(O)2NR c3 Rd3 Selected from, Each R 12 These are independently: Haro, CN, NO2, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, phenyl, 5-6 member heteroaryl, 4-7 member heterocycloalkyl, OR a4 , SR a4 , C(O)R b4 , C(O)NR c4 R d4 , C(O)OR a4 ,OC(O)R b4 , OC(O)NR c4 R d4 , NR c4 R d4 , NR c4 Ure d4 , NR c4 C(O)R b4 , NR c4 C(O)OR a4 , NR c4 C(O)NR c4 R d4 , NR c4 S(O)R b4 , NR c4 S(O)2R b4 , NR c4 S(O)2NR c4 R d4 S(O)R b4 , S(O)NR c4 R d4 S(O)2R b4 , and S(O)2NR c4 R d4 Selected from, the C 1-6 Alkyl, C 3-6 Cycloalkyls, phenyls, 5-6 member heteroaryls, and 4-7 member heterocycloalkyls are each optionally R g Substituted with 1, 2, 3, or 4 substituents independently selected from, R a1 , R c1 , and R d1 These are H and C, which are independent of each other. 1-6 Alkyl and C 1-6 Selected from haloalkyl, the C 1-6Alkyl is optional, R g It is substituted with 1, 2, 3, or 4 substituents independently selected from, or Alternatively, R bonded to the same N atom c1 and R d1 Along with the N atom to which they are bonded, R g Forming a 4, 5, 6, or 7-membered heterocycloalkyl group which is optionally substituted with 1, 2, or 3 substituents independently selected from the above, R b1 C 1-6 Alkyl and C 1-6 Selected from haloalkyls, each of which optionally includes R g Substituted with 1, 2, 3, or 4 substituents independently selected from, Each R a2 , R c2 , and R d2 H and C are independent of each other. 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Selected from cycloalkyl, phenyl, 5-6 membered heteroaryl, and 4-7 membered heterocycloalkyl, the C 1-6 Alkyl, C 3-6 Cycloalkyls, phenyls, 5-6 member heteroaryls, and 4-7 member heterocycloalkyls are each optionally R 12 It is substituted with 1, 2, 3, or 4 substituents independently selected from, or Alternatively, any R bonded to the same N atom c2 and R d2 Along with the N atom to which they are bonded, R 12 Forming a 4, 5, 6, or 7-membered heterocycloalkyl group which is optionally substituted with 1, 2, or 3 substituents independently selected from the above, Each R b2 Independently, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Selected from cycloalkyls, phenyls, 5-6 membered heteroaryls, and 4-7 membered heterocycloalkyls, each of which optionally includes R 12Substituted with 1, 2, 3, or 4 substituents independently selected from, Each R a3 , R c3 , and R d3 H and C are independent of each other. 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, phenyl, 5-6 member heteroaryl, 4-7 member heterocycloalkyl, C 3-6 Cycloalkyl-C 1-4 Alkylene, Phenyl-C 1-4 Alkylene, 5-6 member heteroaryl-C 1-4 Alkylenes and 4-7 member heterocycloalkyl-C 1-4 Selected from alkylene, the C 1-6 Alkyl, C 3-6 Cycloalkyl, phenyl, 5-6 member heteroaryl, 4-7 member heterocycloalkyl, C 3-6 Cycloalkyl-C 1-4 Alkylene, Phenyl-C 1-4 Alkylene, 5-6 member heteroaryl-C 1-4 Alkylenes and 4-7 member heterocycloalkyl-C 1-4 Alkylenes are each arbitrarily R g It is substituted with 1, 2, 3, or 4 substituents independently selected from, or Alternatively, any R bonded to the same N atom c3 and R d3 Along with the N atom to which they are bonded, R g Forming a 4, 5, 6, or 7-membered heterocycloalkyl group which is optionally substituted with 1, 2, or 3 substituents independently selected from the above, Each R b3 Independently, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, phenyl, 5-6 member heteroaryl, 4-7 member heterocycloalkyl, C 3-6 Cycloalkyl-C 1-4 Alkylene, Phenyl-C 1-4 Alkylene, 5-6 member heteroaryl-C 1-4Alkylenes and 4-7 member heterocycloalkyl-C 1-4 Selected from alkylenes, each of which is optionally R g Substituted with 1, 2, 3, or 4 substituents independently selected from, Each R a4 , R c4 , and R d4 H and C are independent of each other. 1-6 Alkyl and C 1-6 Selected from haloalkyl, the C 1-6 Alkyl is optional, R g It is substituted with 1, 2, 3, or 4 substituents independently selected from, or Alternatively, any R bonded to the same N atom c4 and R d4 Along with the N atom to which they are bonded, R g Forming a 4, 5, 6, or 7-membered heterocycloalkyl group which is optionally substituted with 1, 2, or 3 substituents independently selected from the above, Each R b4 Independently, C 1-6 Alkyl and C 1-6 Selected from haloalkyls, each of which optionally includes R g Substituted with 1, 2, 3, or 4 substituents independently selected from, Each R g These are independently OH, NO2, CN, Halo, and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, cyano-C 1-3 Alkyl, HO-C 1-3 Alkyl, H2N-C 1-3 Alkyl, amino, C 1-6 Alkylamino, di(C 1-6 Alkyl)amino, thio, C 1-6 Alkylthio, C 1-6 Alkyl sulfinyl, C 1-6 Alkyl sulfonyl, carbamyl, C 1-6 Alkylcarbamyl, di(C 1-6 Alkyl)carbamyl, carboxy, C 1-6Alkylcarbonyl, C 1-6 Alkoxycarbonyl, C 1-6 Alkylcarbonylamino, C 1-6 Alkylsulfonylamino, aminosulfonyl, C 1-6 Alkylaminosulfonyl, di(C 1-6 Alkyl)aminosulfonyl, aminosulfonylamino, C 1-6 Alkylaminosulfonylamino, di(C 1-6 Alkyl)aminosulfonylamino, aminocarbonylamino, C 1-6 Alkylaminocarbonylamino, and di(C 1-6 Selected from alkyl)aminocarbonylamino. However: 1) A 1 -A 2 -A 3 is, A 1 , A 2 , or A 3 If one of them is a combination, it is neither YY nor YYY, and 2) A 3 is -Y- or -C 1-3 In the case of alkylene-Y-, R A H, C 1-6 Alkyl, or C 1-6 It is a haloalkyl, and the C 1-6 Alkyl or C 1-6 Haloalkyls are optional, R 11 The condition is that it is substituted with 1, 2, 3, or 4 substituents selected independently of it.

[0127] In some embodiments: R 1 is, A 1 -A 2 -A 3 -R A And, R 2 is H, halo, or C 1-4 It is alkyl, R 3 is H, halo, or C 1-6 It is alkyl, A 1 These are the combination, -Y-, and -C1-3 Selected from alkylene, A 2 These are the combination, -Y-, and -C 1-3 Selected from alkylene, A 3 is a combination, Cy A3 , -Y-, and -C 1-3 Selected from alkylene, R A H, C 1-6 Alkyl, C 1-6 Haloalkyl, Halo, CN, OR a1 , SR a1 , C(O)R b1 , C(O)NR c1 R d1 , C(O)OR a1 , NR c1 R d1 , NR c1 C(O)R b1 S(O)R b1 , S(O)NR c1 R d1 S(O)2R b1 , or S(O)2NR c1 R d1 and C 1-6 Alkyl or C 1-6 Haloalkyls are optional, R 11 Substituted with 1, 2, 3, or 4 substituents independently selected from, Y is O, S, S(O), S(O)2, or C(O), Cy A3 C 3-7 The compounds are cycloalkyl, phenyl, 5-6 membered heteroaryl, or 4-7 membered heterocycloalkyl, each having at least one ring-forming carbon atom and 1, 2, 3, or 4 ring-forming heteroatoms independently selected from N, O, and S, wherein the N and S are optionally oxidized, and C 3-7 The ring-forming carbon atoms of cycloalkyl and 4- to 7-membered heterocycloalkyl groups are optionally substituted with oxo atoms to form a carbonyl group, and the C 3-7Cycloalkyls, phenyls, 5-6 member heteroaryls, and 4-7 member heterocycloalkyls are each optionally R A3 Substituted with 1, 2, 3, or 4 substituents independently selected from, Each R A3 These are independently OH, CN, Haro, and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, cyano-C 1-3 Alkyl, HO-C 1-3 Alkyl, H2N-C 1-3 Alkyl, amino, C 1-6 Alkylamino, di(C 1-6 Alkyl)amino, thio, C 1-6 Alkylthio, C 1-6 Alkyl sulfinyl, C 1-6 Alkyl sulfonyl, carbamyl, C 1-6 Alkylcarbamyl, di(C 1-6 Alkyl)carbamyl, carboxy, C 1-6 Alkylcarbonyl, and C 1-6 Selected from alkoxycarbonyls, Cy C is phenylene, and the phenylene may optionally be R C Substituted with 1, 2, 3, or 4 substituents independently selected from, Each R C These are independently OH, CN, Haro, and C. 1-4 Alkyl, C 1-3 Haloalkyl, C 1-4 Alkoxy, C 1-3 Haloalkoxy, cyano-C 1-3 Alkyl, HO-C 1-3 Alkyl, amino, C 1-4 Alkylamino and di(C) 1-4 Selected from alkyl)amino, Cy B C 3-10 It is a cycloalkyl or a 4-10 member heterocycloalkyl, C 3-10At least one ring-forming carbon atom of a cycloalkyl or 4-10 membered heterocycloalkyl is substituted with an oxo to form a carbonyl group, and the 4-10 membered heterocycloalkyl has at least one ring-forming carbon atom and 1, 2, 3, or 4 ring-forming heteroatoms independently selected from N, O, and S, wherein the N and S are optionally oxidized, and the C 3-10 Cycloalkyls and 4-10 member heterocycloalkyls are each optionally R B It is substituted with 1, 2, 3, or 4 substituents independently selected from, or Cy B The aryl group is a 6-10 membered aryl group or a 5-10 membered heteroaryl group, the 5-10 membered heteroaryl group having at least one ring-forming carbon atom and 1, 2, 3, or 4 ring-forming heteroatoms independently selected from N, O, and S, wherein the N and S are optionally oxidized, and at least one ring-forming carbon atom of the 5-10 membered heteroaryl group is substituted with an oxo atom to form a carbonyl group, and the aryl group is further optionally R B Substituted with 1, 2, 3, or 4 substituents independently selected from, Each R B It is independently, Halo, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, phenyl, 5-6 member heteroaryl, 4-7 member heterocycloalkyl, CN, NO2, OR a2 , SR a2 , C(O)R b2 , C(O)NR c2 R d2 , C(O)OR a2 , NR c2 R d2 , NR c2 C(O)R b2 , NR c2 S(O)R b2 , NR c2 S(O)2R b2 , NR c2 S(O)2NR c2 R d2 S(O)R b2, S(O)NR c2 R d2 S(O)2R b2 , and S(O)2NR c2 R d2 Selected from, the C 1-6 Alkyl, C 3-6 Cycloalkyls, phenyls, 5-6 member heteroaryls, and 4-7 member heterocycloalkyls are each optionally R 12 Substituted with 1, 2, 3, or 4 substituents independently selected from, Each R 11 CN, OR a3 , SR a3 , C(O)R b3 , C(O)NR c3 R d3 , C(O)OR a3 , NR c3 R d3 , NR c3 C(O)R b3 , NR c3 C(O)OR a3 , NR c3 S(O)R b3 , NR c3 S(O)2R b3 , NR c3 S(O)2NR c3 R d3 S(O)R b3 , S(O)NR c3 R d3 S(O)2R b3 , and S(O)2NR c3 R d3 Selected from, Each R 12 They are independent: Hello, CN, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, phenyl, 5-6 member heteroaryl, 4-7 member heterocycloalkyl, OR a4 , SR a4 , C(O)R b4 , C(O)NR c4 R d4 , C(O)OR a4 , NR c4 R d4 , NR c4 C(O)Rb4 , NR c4 C(O)OR a4 , NR c4 S(O)R b4 , NR c4 S(O)2R b4 , NR c4 S(O)2NR c4 R d4 S(O)R b4 , S(O)NR c4 R d4 S(O)2R b4 , and S(O)2NR c4 R d4 Selected from, the C 1-6 Alkyl, C 3-6 Cycloalkyls, phenyls, 5-6 member heteroaryls, and 4-7 member heterocycloalkyls are each optionally R g Substituted with 1, 2, 3, or 4 substituents independently selected from, R a1 , R c1 , and R d1 These are H and C, which are independent of each other. 1-6 Alkyl and C 1-6 Selected from haloalkyl, the C 1-6 Alkyl is optional, R g Substituted with 1, 2, 3, or 4 substituents independently selected from, R b1 C 1-6 Alkyl and C 1-6 Selected from haloalkyls, each of which optionally includes R g Substituted with 1, 2, 3, or 4 substituents independently selected from, Each R a2 , R c2 , and R d2 H and C are independent of each other. 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Selected from cycloalkyl, phenyl, 5-6 membered heteroaryl, and 4-7 membered heterocycloalkyl, the C 1-6 Alkyl, C 3-6 Cycloalkyls, phenyls, 5-6 member heteroaryls, and 4-7 member heterocycloalkyls are each optionally R12 Substituted with 1, 2, 3, or 4 substituents independently selected from, Each R b2 Independently, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Selected from cycloalkyls, phenyls, 5-6 membered heteroaryls, and 4-7 membered heterocycloalkyls, each of which optionally includes R 12 Substituted with 1, 2, 3, or 4 substituents independently selected from, Each R a3 , R c3 , and R d3 H and C are independent of each other. 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, phenyl, 5-6 member heteroaryl, 4-7 member heterocycloalkyl, C 3-6 Cycloalkyl-C 1-4 Alkylene, Phenyl-C 1-4 Alkylene, 5-6 member heteroaryl-C 1-4 Alkylenes and 4-7 member heterocycloalkyl-C 1-4 Selected from alkylene, the C 1-6 Alkyl, C 3-6 Cycloalkyl, phenyl, 5-6 member heteroaryl, 4-7 member heterocycloalkyl, C 3-6 Cycloalkyl-C 1-4 Alkylene, Phenyl-C 1-4 Alkylene, 5-6 member heteroaryl-C 1-4 Alkylenes and 4-7 member heterocycloalkyl-C 1-4 Alkylenes are each arbitrarily R g Substituted with 1, 2, 3, or 4 substituents independently selected from, Each R b3 Independently, C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, phenyl, 5-6 member heteroaryl, 4-7 member heterocycloalkyl, C 3-6 Cycloalkyl-C 1-4 Alkylene, Phenyl-C1-4 Alkylene, 5-6 member heteroaryl-C 1-4 Alkylenes and 4-7 member heterocycloalkyl-C 1-4 Selected from alkylenes, each of which is optionally R g Substituted with 1, 2, 3, or 4 substituents independently selected from, Each R a4 , R c4 , and R d4 H and C are independent of each other. 1-6 Alkyl and C 1-6 Selected from haloalkyl, the C 1-6 Alkyl is optional, R g Substituted with 1, 2, 3, or 4 substituents independently selected from, Each R b4 Independently, C 1-6 Alkyl and C 1-6 Selected from haloalkyls, each of which optionally includes R g Substituted with 1, 2, 3, or 4 substituents independently selected from, Each R g These are independently OH, NO2, CN, Halo, and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, cyano-C 1-3 Alkyl, HO-C 1-3 Alkyl, H2N-C 1-3 Alkyl, amino, C 1-6 Alkylamino, di(C 1-6 Alkyl)amino, thio, C 1-6 Alkylthio, C 1-6 Alkyl sulfinyl, C 1-6 Alkyl sulfonyl, carbamyl, C 1-6 Alkylcarbamyl, di(C 1-6 Alkyl)carbamyl, carboxy, C 1-6 Alkylcarbonyl, C 1-6 Alkoxycarbonyl, C 1-6 Alkylcarbonylamino, C 1-6 Alkylsulfonylamino, aminosulfonyl, C 1-6Alkylaminosulfonyl, di(C 1-6 Alkyl)aminosulfonyl, aminosulfonylamino, C 1-6 Alkylaminosulfonylamino, di(C 1-6 Alkyl)aminosulfonylamino, aminocarbonylamino, C 1-6 Alkylaminocarbonylamino, and di(C 1-6 Selected from alkyl)aminocarbonylamino. However: 1) A 1 -A 2 -A 3 is, A 1 , A 2 , or A 3 If one of them is a combination, it is neither YY nor YYY, and 2) A 3 is -Y- or -C 1-3 In the case of alkylene-Y-, R A H, C 1-6 Alkyl, or C 1-6 It is a haloalkyl, and the C 1-6 Alkyl or C 1-6 Haloalkyls are optional, R 11 The condition is that it is substituted with 1, 2, 3, or 4 substituents selected independently of it.

[0128] In some embodiments: R 1 is, A 1 -A 2 -A 3 -R A And, R 2 is H or C 1-4 It is alkyl, R 3 is H or C 1-6 It is alkyl, A 1 This involves bonding and -C 1-3 Selected from alkylene, A 2 This involves bonding and -C 1-3 Selected from alkylene, A 3 is a combination, Cy A3, and -C 1-3 Selected from alkylene, R A H, C 1-6 Alkyl, CN, OR a1 , C(O)R b1 , C(O)NR c1 R d1 , C(O)OR a1 , NR c1 R d1 , NR c1 C(O)R b1 S(O)R b1 , S(O)NR c1 R d1 S(O)2R b1 , or S(O)2NR c1 R d1 and C 1-6 Alkyl is optional, R 11 Substituted with 1, 2, 3, or 4 substituents independently selected from, Cy A3 C 3-7 The compounds are cycloalkyl, phenyl, 5-6 membered heteroaryl, or 4-7 membered heterocycloalkyl, each having at least one ring-forming carbon atom and 1, 2, 3, or 4 ring-forming heteroatoms independently selected from N, O, and S, wherein the N and S are optionally oxidized, and C 3-7 The ring-forming carbon atoms of cycloalkyl and 4- to 7-membered heterocycloalkyl groups are optionally substituted with oxo atoms to form a carbonyl group, and the C 3-7 Cycloalkyls, phenyls, 5-6 member heteroaryls, and 4-7 member heterocycloalkyls are each optionally R A3 Substituted with 1, 2, 3, or 4 substituents independently selected from, Each R A3 These are independently OH, CN, Haro, and C. 1-6 Alkyl, C 1-6 Haloalkyl and C 1-6 Selected from alkoxy, Cy C is phenylene, and the phenylene may optionally be R CSubstituted with 1, 2, 3, or 4 substituents independently selected from, Each R C These are independently OH, CN, Haro, and C. 1-4 Alkyl, C 1-3 Haloalkyl, C 1-4 Alkoxy, and C 1-3 Selected from haloalkoxys, Cy B C 3-10 It is a cycloalkyl or a 4-10 member heterocycloalkyl, C 3-10 At least one ring-forming carbon atom of a cycloalkyl or 4-10 membered heterocycloalkyl is substituted with an oxo to form a carbonyl group, and the 4-10 membered heterocycloalkyl has at least one ring-forming carbon atom and 1, 2, 3, or 4 ring-forming heteroatoms independently selected from N, O, and S, wherein the N and S are optionally oxidized, and the C 3-10 Cycloalkyls and 4-10 member heterocycloalkyls are each optionally R B It is substituted with 1, 2, 3, or 4 substituents independently selected from, or Cy B This is a 5-10 member heteroaryl, which has at least one ring-forming carbon atom and 1, 2, 3, or 4 ring-forming heteroatoms independently selected from N, O, and S, wherein the N and S are optionally oxidized, and at least one ring-forming carbon atom of the 5-10 member heteroaryl is substituted with an oxo to form a carbonyl group, and the 5-10 member heteroaryl may further optionally have R B Substituted with 1, 2, 3, or 4 substituents independently selected from, Each R B It is independently, Halo, C 1-6 Alkyl, C 1-6 Haloalkyl, phenyl, OR a2 , SR a2 , C(O)R b2 , C(O)NR c2 R d2 , and C(O)OR a2 Selected from, the C 1-6Alkyl and phenyl are each optionally R 12 Substituted with 1, 2, 3, or 4 substituents independently selected from, Each R 11 These are independently CN or OR a3 Selected from, Each R 12 They are independent: Hello, CN, C 1-6 Alkyl, C 1-6 Haloalkyl, phenyl, OR a4 , C(O)R b4 , C(O)NR c4 R d4 , and C(O)OR a4 Selected from, the C 1-6 Alkyl, C 3-6 Cycloalkyls, phenyls, 5-6 member heteroaryls, and 4-7 member heterocycloalkyls are each optionally R g Substituted with 1, 2, 3, or 4 substituents independently selected from, R a1 , R c1 , and R d1 These are H and C, which are independent of each other. 1-6 Alkyl and C 1-6 Selected from haloalkyl, the C 1-6 Alkyl is optional, R g Substituted with 1, 2, 3, or 4 substituents independently selected from, R b1 C 1-6 Alkyl and C 1-6 Selected from haloalkyls, each of which optionally includes R g Substituted with 1, 2, 3, or 4 substituents independently selected from, Each R a2 , R c2 , and R d2 H and C are independent of each other. 1-6 Alkyl, C 1-6 Selected from haloalkyl and phenyl, the C 1-6 Alkyl and phenyl are each optionally R 12 Substituted with 1, 2, 3, or 4 substituents independently selected from, Each R b2 Independently, C1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 Selected from cycloalkyl and phenyl, each of which optionally includes R 12 Substituted with 1, 2, 3, or 4 substituents independently selected from, Each R a3 H and C are independent of each other. 1-6 Alkyl, C 1-6 Haloalkyl, phenyl, phenyl-C 1-4 Selected from alkylene, the C 1-6 Alkyl, phenyl, and phenyl-C 1-4 Alkylenes are each arbitrarily R g Substituted with 1, 2, 3, or 4 substituents independently selected from, Each R a4 , R c4 , and R d4 H and C are independent of each other. 1-6 Alkyl and C 1-6 Selected from haloalkyl, the C 1-6 Alkyl is optional, R g Substituted with 1, 2, 3, or 4 substituents independently selected from, Each R b4 Independently, C 1-6 Alkyl and C 1-6 Selected from haloalkyls, each of which optionally includes R g Substituted with 1, 2, 3, or 4 substituents independently selected from, Each R g These are independently OH, NO2, CN, Halo, and C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, cyano-C 1-3 Alkyl, HO-C 1-3 Alkyl, H2N-C 1-3 Alkyl, amino, C 1-6 Alkylamino and di(C) 1-6 Selected from alkyl)amino.

[0129] In some embodiments: R1 is, A 1 -A 2 -A 3 -R A (1) The A 1 , A 2 , and A 3 Each is a combination, R A is C 1-6 Alkyl or C(O)NR c1 R d1 (2) the A 1 is a combination, A 2 is a combination or -C 1-3 It is alkylene- and A 3 is Cy A3 And R A C 1-6 Alkyl, CN, OR a1 , NR c1 R d1 , C(O)R b1 , C(O)NR c1 R d1 , C(O)OR a1 , or S(O)2R b1 And here, R A of C 1-6 Alkyl is optional, R 11 Substituted with 1, 2, 3, or 4 substituents independently selected from (3)A 1 is Cy A1 A 2 is a bond or C(O), A 3 is Cy A3 And R A H is H, R 2 H is H, R 3 H is H, Cy A1 C 3-7 A cycloalkyl or a 4- to 7-membered heterocycloalkyl, the 4- to 7-membered heterocycloalkyl having at least one ring-forming carbon atom and 1, 2, 3, or 4 ring-forming heteroatoms independently selected from N, O, and S, wherein the N and S are optionally oxidized, C 3-7The ring-forming carbon atoms of cycloalkyl and 4- to 7-membered heterocycloalkyl groups are optionally substituted with oxo atoms to form carbonyl groups. Cy A3 C 3-7 A cycloalkyl, a 6-membered heteroaryl, or a 4- to 7-membered heterocycloalkyl, each of which has at least one ring-forming carbon atom and 1, 2, 3, or 4 ring-forming heteroatoms independently selected from N, O, and S, wherein the N and S are optionally oxidized, C 3-7 The ring-forming carbon atoms of cycloalkyl and 4- to 7-membered heterocycloalkyl groups are optionally substituted with oxo atoms to form a carbonyl group, and the C 3-7 Cycloalkyls, 6-membered heteroaryls, and 4- to 7-membered heterocycloalkyls each optionally contain 1, 2, 3, or 4 carbon atoms. 1-6 Substituted with alkyl, Cy B C 3-10 It is a cycloalkyl or a 4-10 member heterocycloalkyl, C 3-10 At least one ring-forming carbon atom of a cycloalkyl and a 4-10 membered heterocycloalkyl is substituted with an oxo to form a carbonyl group, and the 4-10 membered heterocycloalkyl has at least one ring-forming carbon atom and 1, 2, 3, or 4 ring-forming heteroatoms independently selected from N, O, and S, and the C 3-10 Cycloalkyls and 4-10 member heterocycloalkyls are each optionally R B It is substituted with one or two substituents independently selected from, or Cy B This is a 5-10 member heteroaryl, which has one ring-forming carbon atom substituted with an oxo to form a carbonyl group, and one, two, three, or four ring-forming heteroatoms independently selected from N, O, and S, wherein the N and S are optionally oxidized, and the 5-10 member heteroaryl can further optionally be R B Substituted with 1, 2, 3, or 4 substituents independently selected from, Each R B Independently, C 1-6Alkyl, C 2-6 Alkynyl, CN, halo, phenyl, 5-6 member heteroaryl, C 3-7 Cycloalkyl, 4-7 member heterocycloalkyl, OR a2 , C(O)R b2 , and C(O)NR c2 R d2 Selected from, the C 1-6 Alkyl, C 2-6 Alkynyl, phenyl, 5-6 member heteroaryl, C 3-7 Cycloalkyls and 4- to 7-membered heterocycloalkyls are each optionally R 12 Substituted with 1, 2, 3, or 4 substituents independently selected from, Cy C R C Phenylene which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from, Each R C These are independently Halo and C 1-4 Selected from alkyl groups, Each R 11 Independently, OR a3 or C(O)NR c3 R d3 And, Each R 12 It is independently, Halo, C 1-6 Alkyl, CN, phenyl, and OR a4 Selected from, Each R a1 , R c1 , and R d1 H and C are independent of each other. 1-6 Selected from alkyl groups, Each R b1 Independently, C 1-6 Selected from alkyl groups, Each R a3 , R c3 , R d3 , and R a4 H and C are independent of each other. 1-6 Selected from alkyl groups, Each R a2 , R b2 , R c2 , and R d2 H and C are independent of each other.1-6 Selected from alkyl and phenyl, the C 1-6 Alkyl and phenyl are each optionally R 12 It is substituted with one, two, three, or four substituents independently selected from the given molecule.

[0130] In some embodiments: R 1 is, A 1 -A 2 -A 3 -R A (1) The A 1 , A 2 , and A 3 Each is a combination, R A is C 1-6 (2) The A 1 is a combination, A 2 is a combination or -C 1-3 It is alkylene- and A 3 is Cy A3 And R A C 1-6 Alkyl, CN, OR a1 , NR c1 R d1 , C(O)R b1 , C(O)NR c1 R d1 , C(O)OR a1 , or S(O)2R b1 And here, R A of C 1-6 Alkyl is optional, R 11 Substituted with 1, 2, 3, or 4 substituents independently selected from, R 2 H is H, R 3 H is H, Cy A3 C 3-7 A cycloalkyl, a 6-membered heteroaryl, or a 4- to 7-membered heterocycloalkyl, each of which has at least one ring-forming carbon atom and 1, 2, 3, or 4 ring-forming heteroatoms independently selected from N, O, and S, wherein the N and S are optionally oxidized, C 3-7The ring-forming carbon atoms of cycloalkyl and 4- to 7-membered heterocycloalkyl groups are optionally substituted with oxo atoms to form carbonyl groups. Cy B C 3-10 It is a cycloalkyl or a 4-10 member heterocycloalkyl, C 3-10 At least one ring-forming carbon atom of a cycloalkyl and a 4-10 membered heterocycloalkyl is substituted with an oxo to form a carbonyl group, and the 4-10 membered heterocycloalkyl has at least one ring-forming carbon atom and 1, 2, 3, or 4 ring-forming heteroatoms independently selected from N, O, and S, and the C 3-10 Cycloalkyls and 4-10 member heterocycloalkyls are each optionally R B It is substituted with one or two substituents independently selected from, or Cy B This is a 5-10 member heteroaryl, which has one ring-forming carbon atom substituted with an oxo to form a carbonyl group, and one, two, three, or four ring-forming heteroatoms independently selected from N, O, and S, wherein the N and S are optionally oxidized, and the 5-10 member heteroaryl can further optionally be R B Substituted with 1, 2, 3, or 4 substituents independently selected from, Each R B Independently, C 1-6 Alkyl, phenyl, OR a2 , and C(O)NR c2 R d2 Selected from, the C 1-6 Alkyl and phenyl are R 12 Optionally substituted with 1, 2, 3, or 4 substituents independently selected from, Cy C R C Phenylene which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from, Each R C These are independently Halo and C 1-4 Selected from alkyl groups, Each R 11 Independently, OR a3 And, Each R 12 These are independently halo, phenyl, and OR a4 Selected from, Each R a1 , R c1 , and R d1 H and C are independent of each other. 1-6 Selected from alkyl groups, Each R b1 Independently, C 1-6 Selected from alkyl groups, Each R a3 and R a4 H and C are independent of each other. 1-6 Selected from alkyl groups, Each R a2 , R c2 , and R d2 H and C are independent of each other. 1-6 Selected from alkyl and phenyl, the C 1-6 Alkyl and phenyl are each optionally R 12 It is substituted with one, two, three, or four substituents independently selected from the given molecule.

[0131] In some embodiments: R 1 is, A 1 -A 2 -A 3 -R A (1) The A 1 , A 2 , and A 3 Each is a combination, R A is C 1-6 (2) The A 1 and A 2 Each is a combination, A 3 is Cy A3 And R A C 1-6 Alkyl, CN, OR a1 , C(O)R b1 , C(O)NR c1 R d1 , C(O)OR a1 , or S(O)2R b1 And here, the C 1-6 Alkyl is R 11Optionally substituted with 1, 2, 3, or 4 substituents independently selected from, R 2 H is H, R 3 H is H, Cy A3 C 3-7 A cycloalkyl or a 4- to 7-membered heterocycloalkyl, wherein the 4- to 7-membered heterocycloalkyl has at least one ring-forming carbon atom and 1, 2, 3, or 4 ring-forming heteroatoms independently selected from N, O, and S, and C 3-7 The ring-forming carbon atoms of cycloalkyl and 4- to 7-membered heterocycloalkyl groups are optionally substituted with oxo atoms to form carbonyl groups. Cy B The 5-10 member heterocycloalkyl group is a heterocycloalkyl group having at least one ring-forming carbon atom and 1, 2, 3, or 4 ring-forming heteroatoms independently selected from N, O, and S, the at least one ring-forming carbon atom of the 5-10 member heterocycloalkyl group being substituted with an oxo atom to form a carbonyl group, and the 5-10 member heterocycloalkyl group is R B It may be optionally substituted with one or two substituents independently selected from it, or Cy B This is a 5-10 member heteroaryl, which has one ring-forming carbon atom substituted with an oxo to form a carbonyl group, and one, two, three, or four ring-forming heteroatoms independently selected from N, O, and S, wherein the N and S are optionally oxidized, and the 5-10 member heteroaryl is further R B Optionally substituted with 1, 2, 3, or 4 substituents independently selected from, Each R B Independently, C 1-6 Selected from alkyl and phenyl, the C 1-6 Alkyl and phenyl are R 12 Optionally substituted with 1, 2, 3, or 4 substituents independently selected from, Cy C R CPhenylene which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from, Each R C It is independently a halo, Each R 11 Independently, OR a3 And, Each R 12 These are independently halo, phenyl, and OR a4 Selected from, Each R a1 , R c1 , and R d1 H and C are independent of each other. 1-6 Selected from alkyl groups, Each R b1 Independently, C 1-6 Selected from alkyl groups, Each R a3 and R a4 H and C are independent of each other. 1-6 Selected from alkyl groups.

[0132] In some embodiments: R 1 is, A 1 -A 2 -A 3 -R A (1) The A 1 , A 2 , and A 3 Each is a combination, R A is C 1-6 (2) The A 1 and A 2 Each is a combination, A 3 is Cy A3 And R A C 1-6 Alkyl, CN, OR a1 , C(O)R b1 , C(O)NR c1 R d1 , C(O)OR a1 , or S(O)2R b1 And here, the C 1-6 Alkyl is R 11 Optionally substituted with 1, 2, 3, or 4 substituents independently selected from, R 2H is H, R 3 H is H, Cy A3 C 3-7 A cycloalkyl or a 4- to 7-membered heterocycloalkyl, wherein the 4- to 7-membered heterocycloalkyl has at least one ring-forming carbon atom and 1, 2, 3, or 4 ring-forming heteroatoms independently selected from N, O, and S, and C 3-7 The ring-forming carbon atoms of cycloalkyl and 4- to 7-membered heterocycloalkyl groups are optionally substituted with oxo atoms to form carbonyl groups. Cy B This is a 5-6 member heteroaryl, which has one ring-forming carbon atom substituted with an oxo to form a carbonyl group, and one or two ring-forming heteroatoms independently selected from N, O, and S, wherein the N and S are optionally oxidized, and the 5-6 member heteroaryl is further R B Optionally substituted with one or two substituents independently selected from, Each R B Independently, C 1-6 Selected from alkyl and phenyl, the C 1-6 Alkyl and phenyl are R 12 Optionally substituted with 1, 2, 3, or 4 substituents independently selected from, Cy C R C Phenylene which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from, Each R C It is independently a halo, Each R 11 Independently, OR a3 And, Each R 12 These are independently halo, phenyl, and OR a4 Selected from, Each R a1 , R c1 , and R d1 H and C are independent of each other. 1-6 Selected from alkyl groups, Each R b1 Independently, C 1-6Selected from alkyl groups, Each R a3 and R a4 H and C are independent of each other. 1-6 Selected from alkyl groups.

[0133] In some embodiments: R 1 is, A 1 -A 2 -A 3 -R A (1) The A 1 , A 2 , and A 3 Each is a combination, R A is C 1-6 (2) The A 1 and A 2 Each is a combination, A 3 is Cy A3 And R A C 1-6 Alkyl, CN, OR a1 , C(O)R b1 , C(O)NR c1 R d1 , C(O)OR a1 , or S(O)2R b1 And here, the C 1-6 Alkyl is optional, R 11 Substituted with 1, 2, 3, or 4 substituents independently selected from, R 2 H is H, R 3 H is H, Cy A3 C 3-7 A cycloalkyl or a 4- to 7-membered heterocycloalkyl, wherein the 4- to 7-membered heterocycloalkyl has at least one ring-forming carbon atom and 1, 2, 3, or 4 ring-forming heteroatoms independently selected from N, O, and S, and C 3-7 The ring-forming carbon atoms of cycloalkyl and 4- to 7-membered heterocycloalkyl groups are optionally substituted with oxo atoms to form carbonyl groups. Cy BThe 5-10 member heterocycloalkyl group is a heterocycloalkyl group having at least one ring-forming carbon atom and 1, 2, 3, or 4 ring-forming heteroatoms independently selected from N, O, and S, the at least one ring-forming carbon atom of the 5-10 member heterocycloalkyl group being substituted with an oxo atom to form a carbonyl group, and the 5-10 member heterocycloalkyl group is R B Optionally substituted with one or two substituents independently selected from each R B Independently, C 1-6 Selected from alkyl and phenyl, the C 1-6 Alkyl and phenyl are R 12 Optionally substituted with 1, 2, 3, or 4 substituents independently selected from, Cy C R C Phenylene which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from, Each R C It is independently a halo, Each R 11 Independently, OR a3 And, Each R 12 These are independently halo, phenyl, and OR a4 Selected from, Each R a1 , R c1 , and R d1 H and C are independent of each other. 1-6 Selected from alkyl groups, Each R b1 Independently, C 1-6 Selected from alkyl groups, Each R a3 and R a4 H and C are independent of each other. 1-6 Selected from alkyl groups.

[0134] In some embodiments: R 1 is, A 1 -A 2 -A 3 -R A (1) The A 1 , A 2 , and A3 Each is a combination, R A is C 1-6 (2) The A 1 and A 2 Each is a combination, A 3 is Cy A3 And R A C 1-6 Alkyl, CN, OR a1 , C(O)R b1 , C(O)NR c1 R d1 , C(O)OR a1 , or S(O)2R b1 And here, the C 1-6 Alkyl is R 11 Optionally substituted with 1, 2, 3, or 4 substituents independently selected from, R 2 H is H, R 3 H is H, Cy A3 C 3-7 A cycloalkyl or a 4- to 7-membered heterocycloalkyl, wherein the 4- to 7-membered heterocycloalkyl has at least one ring-forming carbon atom and 1, 2, 3, or 4 ring-forming heteroatoms independently selected from N, O, and S, and C 3-7 The ring-forming carbon atoms of cycloalkyl and 4- to 7-membered heterocycloalkyl groups are optionally substituted with oxo atoms to form carbonyl groups. Cy B The 5-10 member heterocycloalkyl group is a 5-10 member heterocycloalkyl group having at least one ring-forming carbon atom and 1, 2, 3, or 4 ring-forming heteroatoms independently selected from N, O, and S, where at least one ring-forming carbon atom of the 5-10 member heterocycloalkyl group is substituted with an oxo atom to form a carbonyl group, and the 5-10 member heterocycloalkyl group is R B It may be optionally substituted with one or two substituents independently selected from it, or Cy BThis is a 5-10 member heteroaryl, which has one ring-forming carbon atom substituted with an oxo to form a carbonyl group, and one, two, three, or four ring-forming heteroatoms independently selected from N, O, and S, wherein the N and S are optionally oxidized, and the 5-10 member heteroaryl is further R B Optionally substituted with 1, 2, 3, or 4 substituents independently selected from, Each R B Independently, C 1-6 Selected from alkyl and phenyl, the C 1-6 Alkyl and phenyl are R 12 Optionally substituted with 1, 2, 3, or 4 substituents independently selected from, Cy C R C Phenylene which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from, Each R C It is independently a halo, Each R 11 Independently, OR a3 And, Each R 12 These are independently halo, phenyl, and OR a4 Selected from, Each R a1 , R c1 , and R d1 H and C are independent of each other. 1-6 Selected from alkyl groups, Alternatively, R bonded to the same N atom c1 and R d1 Together with the N atom to which they are bonded, they form a 6-membered heterocycloalkyl group. Each R b1 Independently, C 1-6 Selected from alkyl groups, Each R a3 and R a4 H and C are independent of each other. 1-6 Selected from alkyl groups.

[0135] In some embodiments: R 1 is, A 1 -A 2-A 3 -R A (1) The A 1 , A 2 , and A 3 Each is a combination, R A is C 1-6 (2) The A 1 and A 2 Each is a combination, A 3 is Cy A3 And R A C 1-6 Alkyl, CN, OR a1 , C(O)R b1 , C(O)NR c1 R d1 , C(O)OR a1 , or S(O)2R b1 And here, the C 1-6 Alkyl is optional, R 11 Substituted with 1, 2, 3, or 4 substituents independently selected from, R 2 H is H, R 3 H is H, Cy A3 C 3-7 A cycloalkyl or a 4- to 7-membered heterocycloalkyl, wherein the 4- to 7-membered heterocycloalkyl has at least one ring-forming carbon atom and 1, 2, 3, or 4 ring-forming heteroatoms independently selected from N, O, and S, and C 3-7 The ring-forming carbon atoms of cycloalkyl and 4- to 7-membered heterocycloalkyl groups are optionally substituted with oxo atoms to form carbonyl groups. Cy B This is a 5-6 member heteroaryl, which has one ring-forming carbon atom substituted with an oxo to form a carbonyl group, and one or two ring-forming heteroatoms independently selected from N, O, and S, wherein the N and S are optionally oxidized, and the 5-6 member heteroaryl can further optionally be R B Substituted with one or two substituents independently selected from, Each R B Independently, C 1-6 Selected from alkyl and phenyl, the C1-6 Alkyl and phenyl are R 12 Optionally substituted with 1, 2, 3, or 4 substituents independently selected from, Cy C R C Phenylene which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from, Each R C It is independently a halo, Each R 11 Independently, OR a3 And, Each R 12 These are independently halo, phenyl, and OR a4 Selected from, Each R a1 , R c1 , and R d1 H and C are independent of each other. 1-6 Selected from alkyl groups, Alternatively, R bonded to the same N atom c1 and R d1 Together with the N atom to which they are bonded, they form a 6-membered heterocycloalkyl group. Each R b1 Independently, C 1-6 Selected from alkyl groups, Each R a3 and R a4 H and C are independent of each other. 1-6 Selected from alkyl groups.

[0136] In some embodiments: R 1 is, A 1 -A 2 -A 3 -R A (1) The A 1 , A 2 , and A 3 Each is a combination, R A is C 1-6 (2) The A 1 and A 2 Each is a combination, A 3 is Cy A3 And R A C 1-6 Alkyl, CN, ORa1 , C(O)R b1 , C(O)NR c1 R d1 , C(O)OR a1 , or S(O)2R b1 And here, the C 1-6 Alkyl is R 11 Optionally substituted with 1, 2, 3, or 4 substituents independently selected from, R 2 H is H, R 3 H is H, Cy A3 C 3-7 A cycloalkyl or a 4- to 7-membered heterocycloalkyl, wherein the 4- to 7-membered heterocycloalkyl has at least one ring-forming carbon atom and 1, 2, 3, or 4 ring-forming heteroatoms independently selected from N, O, and S, and C 3-7 The ring-forming carbon atoms of cycloalkyl and 4- to 7-membered heterocycloalkyl groups are optionally substituted with oxo atoms to form carbonyl groups. Cy B The 5-10 member heterocycloalkyl group is a 5-10 member heterocycloalkyl group having at least one ring-forming carbon atom and 1, 2, 3, or 4 ring-forming heteroatoms independently selected from N, O, and S, where at least one ring-forming carbon atom of the 5-10 member heterocycloalkyl group is substituted with an oxo atom to form a carbonyl group, and the 5-10 member heterocycloalkyl group is R B Optionally substituted with one or two substituents independently selected from each R B Independently, C 1-6 Selected from alkyl and phenyl, the C 1-6 Alkyl and phenyl are R 12 Optionally substituted with 1, 2, 3, or 4 substituents independently selected from, Cy C R C Phenylene which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from, Each R C It is independently a halo, Each R11 Independently, OR a3 And, Each R 12 These are independently halo, phenyl, and OR a4 Selected from, Each R a1 , R c1 , and R d1 H and C are independent of each other. 1-6 Selected from alkyl groups, Alternatively, R bonded to the same N atom c1 and R d1 Together with the N atom to which they are bonded, they form a 6-membered heterocycloalkyl group. Each R b1 Independently, C 1-6 Selected from alkyl groups, Each R a3 and R a4 H and C are independent of each other. 1-6 Selected from alkyl groups.

[0137] In some embodiments: R 1 is, A 1 -A 2 -A 3 -R A (1) The A 1 , A 2 , and A 3 Each is a combination, R A is C(O)NR c1 R d1 Or C 1-6 (2) The A 1 is a combination, A 2 is a combination or -C 1-3 It is alkylene- and A 3 is Cy A3 And R A H, C 1-6 Alkyl, CN, OR a1 , C(O)R b1 , C(O)NR c1 R d1 , NR c1 R d1 , C(O)OR a1 , or S(O)2R b1 And here, the C1-6 Alkyl is R 11 (3)A 1 is Cy A1 A 2 is Y, Y is C(O), and A 3 is Cy A3 And R A (4)A 1 is a combination, A 2 is Cy A2 A 3 is Cy A3 And R A is C 1-6 It is alkyl, R 2 H is H, R 3 H is H, Cy A3 C is a 5-6 member heteroaryl compound. 3-7 A cycloalkyl or a 4- to 7-membered heterocycloalkyl, wherein the 4- to 7-membered heterocycloalkyl has at least one ring-forming carbon atom and 1, 2, 3, or 4 ring-forming heteroatoms independently selected from N, O, and S, and C 3-7 The ring-forming carbon atoms of cycloalkyl and 4- to 7-membered heterocycloalkyl groups are optionally substituted with oxo atoms to form carbonyl groups. Cy B The 5-10 member heterocycloalkyl group is a heterocycloalkyl group having at least one ring-forming carbon atom and 1, 2, 3, or 4 ring-forming heteroatoms independently selected from N, O, and S, the at least one ring-forming carbon atom of the 5-10 member heterocycloalkyl group being substituted with an oxo atom to form a carbonyl group, and the 5-10 member heterocycloalkyl group is R B Optionally substituted with one or two substituents independently selected from, Each R B They are independent: Hello, CN, C 1-6 Alkyl, C 2-6 Alkinyl, C 3-6Cycloalkyl, 5-6 member heteroaryl, 4-7 member heterocycloalkyl, phenyl, OR a2 , C(O)R b2 , C(O)NR c2 R d2 Selected from, the C 1-6 Alkyl, C 2-6 Alkinyl, C 3-6 Cycloalkyl groups, 5-6 membered heteroaryl groups, 4-7 membered heterocycloalkyl groups, and phenyl groups are R 12 Optionally substituted with 1, 2, 3, or 4 substituents independently selected from, Cy C R C Phenylene which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from, Each R C It is independently a halo, Each R 11 Independently, OR a3 or C(O)NR c3 R d3 And, Each R 12 They are independent: Hello, CN, C 1-6 Alkyl and OR a4 Selected from, Each R a1 , R c1 , and R d1 H and C are independent of each other. 1-6 Selected from alkyl groups, Alternatively, R bonded to the same N atom c1 and R d1 Together with the N atom to which they are bonded, they form a 6-membered heterocycloalkyl group. Each R b1 Independently, C 1-6 Selected from alkyl groups, Each R a3 and R a4 H and C are independent of each other. 1-6 Selected from alkyl groups.

[0138] In some embodiments, Cy B teeth, [ka] And, Here, Cy B -1, Cy B -2, Cy B -3, Cy B -8, Cy B -9, Cy B -10, Cy B -4, and Cy B -11 is each of 1, 2, or 3 independently selected R B Substituted with the base, R 1 is, A 1 -A 2 -A 3 -R A (1) The A 1 , A 2 , and A 3 Each is a combination, R A is C(O)NR c1 R d1 Or C 1-6 (2) The A 1 is a combination, A 2 is a combination or -C 1-3 It is alkylene- and A 3 is Cy A3 And R A H, C 1-6 Alkyl, CN, OR a1 , C(O)R b1 , C(O)NR c1 R d1 , NR c1 R d1 , C(O)OR a1 , or S(O)2R b1 And here, the C 1-6 Alkyl is R 11 (3)A 1 is Cy A1 A 2 is Y, Y is C(O), and A 3 is Cy A3 And R A (4)A 1 is a combination, A2 is Cy A2 A 3 is Cy A3 And R A is C 1-6 It is alkyl, R 2 H is H, R 3 H is H, Cy A3 C is a 5-6 member heteroaryl compound. 3-7 A cycloalkyl or a 4- to 7-membered heterocycloalkyl, wherein the 4- to 7-membered heterocycloalkyl has at least one ring-forming carbon atom and 1, 2, 3, or 4 ring-forming heteroatoms independently selected from N, O, and S, and C 3-7 The ring-forming carbon atoms of cycloalkyl and 4- to 7-membered heterocycloalkyl groups are optionally substituted with oxo atoms to form carbonyl groups. Each R B They are independent: Hello, CN, C 1-6 Alkyl, C 2-6 Alkinyl, C 3-6 Cycloalkyl, 5-6 member heteroaryl, 4-7 member heterocycloalkyl, phenyl, OR a2 , C(O)R b2 , C(O)NR c2 R d2 Selected from, the C 1-6 Alkyl, C 2-6 Alkinyl, C 3-6 Cycloalkyl groups, 5-6 membered heteroaryl groups, 4-7 membered heterocycloalkyl groups, and phenyl groups are R 12 Optionally substituted with 1, 2, 3, or 4 substituents independently selected from, Cy C R C Phenylene which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from, Each R C It is independently a halo, Each R 11 Independently, OR a3 or C(O)NR c3 R d3 And, Each R12 They are independent: Hello, CN, C 1-6 Alkyl and OR a4 Selected from, Each R a1 , R c1 , and R d1 H and C are independent of each other. 1-6 Selected from alkyl groups, Alternatively, R bonded to the same N atom c1 and R d1 Together with the N atom to which they are bonded, they form a 6-membered heterocycloalkyl group. Each R b1 Independently, C 1-6 Selected from alkyl groups, Each R a3 and R a4 H and C are independent of each other. 1-6 Selected from alkyl groups.

[0139] Furthermore, for clarity, it is understood that certain features of the present invention described in separate embodiments can also be combined and provided in a single embodiment. Conversely, various features of the present invention described in a single embodiment for brevity can also be provided separately or in any suitable small combination.

[0140] Throughout this specification, substituents of the compounds provided herein are disclosed in groups or ranges. The present invention is particularly intended to include all individual subbonds of members of such groups and ranges. For example, "C 1-6 The term "alkyl" is intended to disclose, in particular, methyl, ethyl, C3 alkyl, C4 alkyl, C5 alkyl, and C6 alkyl groups individually.

[0141] In certain places, definitions or embodiments refer to specific rings (e.g., azetidine rings, pyridine rings, etc.). Unless otherwise indicated, these rings can be bonded at any ring member, provided that the valence of the atoms in question is not exceeded. For example, an azetidine ring can be bonded at any position on the ring, while an azetidine-3-yl ring is bonded at position 3.

[0142] The term "n-membered" when n is an integer usually refers to the number of ring-forming atoms in a given part, in this case n. For example, piperidinyl is an example of a 6-membered heterocycloalkyl ring, pyrazolyl is an example of a 5-membered heteroaryl ring, pyridyl is an example of a 6-membered heteroaryl ring, and 1,2,3,4-tetrahydronaphthalene is an example of a 10-membered cycloalkyl group.

[0143] For compounds in which the variable elements provided herein appear two or more times, each variable element may be a different part independently selected from the group defining the variable element. For example, if a structure is described having two R groups present in the same compound at the same time, these two R groups can represent different parts independently selected from the group defining R. In another example, optionally multiple substituents may be in the structure: [ka] When specified as such, the substituent R can appear p times in the ring, and it should be understood that each appearance of R can be a different part. Each R group is (CH2) n It should be understood that any hydrogen atom bonded to the ring atom may be substituted, including one or both of the hydrogen atoms in the ring. Furthermore, in the above example, the variable element Q is defined to contain hydrogen, and for example, if Q is said to be CH2, NH, etc., any floating substituent such as R in the above example may substitute for the hydrogen in the variable element Q and for the hydrogen in any other non-variable component of the ring.

[0144] As used herein, the expression "optionally substituted" means either unsubstituted or substituted. Substituents are selected independently, and substitution may occur at any chemically possible position. As used herein, the expression "substituted" means that a hydrogen atom is removed and replaced by a substituent. A single divalent substituent, e.g., oxo, can replace two hydrogen atoms. It should be understood that substitution at a given atom is limited by its valence.

[0145] Through this definition, "C n-m The term "range" indicates a range including the endpoints, where n and m are integers representing the number of carbon atoms. For example, C 1-4 , C 1-6 These are some examples.

[0146] As used herein, "C n-m The term "alkyl" is used alone or in combination with other terms to refer to a saturated hydrocarbon group having n to m carbon atoms, which may be linear or branched. Examples of alkyl moieties include, but are not limited to, chemical groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, and sec-butyl, and higher homologs such as 2-methyl-1-butyl, n-pentyl, 3-pentyl, n-hexyl, and 1,2,2-trimethylpropyl. In some embodiments, the alkyl group contains 1 to 6 carbon atoms, 1 to 4 carbon atoms, 1 to 3 carbon atoms, or 1 to 2 carbon atoms.

[0147] As used herein, "C n-m The term "alkenyl" refers to an alkyl group having one or more double carbon-carbon bonds and n to m carbon atoms. Examples of alkenyl groups include, but are not limited to, ethenyl, n-propenyl, isopropenyl, n-butenyl, and sec-butenyl. In some embodiments, the alkenyl moiety contains 2 to 6, 2 to 4, or 2 to 3 carbon atoms.

[0148] As used herein, "C n-m "Alkynyl" refers to an alkyl group having one or more triple carbon-carbon bonds and n to m carbon atoms. Examples of alkynyl groups include, but are not limited to, ethynyl, propyne-1-yl, and propyne-2-yl. In some embodiments, the alkynyl moiety contains 2 to 6, 2 to 4, or 2 to 3 carbon atoms.

[0149] As used herein, "C n-mThe term "alkylene," used alone or in combination with other terms, refers to a divalent alkyl linking group having n to m carbon atoms. Examples of alkylene groups include, but are not limited to, ethane-1,1-diyl, ethane-1,2-diyl, propane-1,1-diyl, propane-1,3-diyl, propane-1,2-diyl, butane-1,4-diyl, butane-1,3-diyl, butane-1,2-diyl, 2-methylpropane-1,3-diyl, etc. In some embodiments, the alkylene moiety contains 2 to 6, 2 to 4, 2 to 3, 1 to 6, 1 to 4, or 1 to 2 carbon atoms.

[0150] As used herein, "C n-m The term "alkoxy" is used alone or in combination with other terms and refers to a group of the formula -O-alkyl, wherein the alkyl group has n to m carbon atoms. Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy (e.g., n-propoxy and isopropoxy), and butoxy (e.g., n-butoxy and tert-butoxy). In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

[0151] As used herein, "C n-m The term "alkylamino" refers to a group of the formula -NH(alkyl), where the alkyl group has n to m carbon atoms. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms. Examples of alkylamino groups include, but are not limited to, N-methylamino, N-ethylamino, N-propylamino (e.g., N-(n-propyl)amino and N-isopropylamino), and N-butylamino (e.g., N-(n-butyl)amino and N-(tert-butyl)amino).

[0152] As used herein, "C n-mThe term "alkoxycarbonyl" refers to a group of the formula -C(O)O-(alkyl), where the alkyl group has n to m carbon atoms. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms. Examples of alkoxycarbonyl groups include, but are not limited to, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl (e.g., n-propoxycarbonyl and isopropoxycarbonyl), and butoxycarbonyl (e.g., n-butoxycarbonyl and tert-butoxycarbonyl).

[0153] As used herein, "C n-m The term "alkylcarbonyl" refers to a group of the formula -C(O)-(alkyl), where the alkyl group has n to m carbon atoms. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms. Examples of alkylcarbonyl groups include, but are not limited to, methylcarbonyl, ethylcarbonyl, propylcarbonyl (e.g., n-propylcarbonyl and isopropylcarbonyl), and butylcarbonyl (e.g., n-butylcarbonyl and tert-butylcarbonyl).

[0154] As used herein, "C n-m The term "alkylcarbonylamino" refers to a group of the formula -NHC(O)-alkyl, where the alkyl group has n to m carbon atoms. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

[0155] As used herein, "C n-m The term "alkylsulfonylamino" refers to a group of the formula -NHS(O)2-alkyl, where the alkyl group has n to m carbon atoms. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

[0156] As used herein, the term "aminosulfonyl" refers to the group of the formula -S(O)2NH2.

[0157] As used herein, "C n-m The term "alkylaminosulfonyl" refers to a group of the formula -S(O)2NH(alkyl), where the alkyl group has n to m carbon atoms. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

[0158] The term "(C)" used herein refers to the term "(C) n-m The term "alkyl)aminosulfonyl" refers to a group of the formula -S(O)2NH(alkyl)2, where each alkyl group independently has n to m carbon atoms. In some embodiments, each alkyl group independently has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

[0159] As used herein, the term "aminosulfonylamino" refers to the group of the formula -NHS(O)2NH2.

[0160] As used herein, "C n-m The term "alkylaminosulfonylamino" refers to a group of the formula -NHS(O)2NH(alkyl), where the alkyl group has n to m carbon atoms. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

[0161] The term "(C)" used herein refers to the term "(C) n-m The term "alkyl)aminosulfonylamino" refers to a group of the formula -NHS(O)2NH(alkyl)2, where each alkyl group independently has n to m carbon atoms. In some embodiments, each alkyl group independently has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

[0162] As used herein, the term "aminocarbonylamino," used alone or in combination with other terms, refers to the group of the formula -NHC(O)NH2.

[0163] As used herein, "C n-mThe term "alkylaminocarbonylamino" refers to a group of the formula -NHC(O)NH(alkyl), where the alkyl group has n to m carbon atoms. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

[0164] The term "(C)" used herein refers to the term "(C) n-m The term "alkyl)aminocarbonylamino" refers to a group of the formula -NHC(O)NH(alkyl)2, where each alkyl group independently has n to m carbon atoms. In some embodiments, each alkyl group independently has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

[0165] As used herein, "C n-m The term "alkylcarbamyl" refers to a group of the formula -C(O)-NH(alkyl), where the alkyl group has n to m carbon atoms. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

[0166] As used herein, the term "thio" refers to the group of formula -SH.

[0167] As used herein, "C n-m The term "alkylthio" refers to a group of the formula -S-alkyl, where the alkyl group has n to m carbon atoms. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

[0168] As used herein, "C n-m The term "alkylsulfinyl" refers to a group of the formula -S(O)-alkyl, where the alkyl group has n to m carbon atoms. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

[0169] As used herein, "C n-mThe term "alkylsulfonyl" refers to a group of the formula -S(O)2-alkyl, where the alkyl group has n to m carbon atoms. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

[0170] As used herein, the term "amino" refers to the group of formula -NH2.

[0171] As used herein, the term "carbamyl" refers to the group of the formula -C(O)NH2.

[0172] As used herein, the term "carbonyl" is used alone or in combination with other terms to refer to a -C(=O)- group, which may also be written as C(O).

[0173] As used herein, the term "carboxy" refers to the -C(O)OH group.

[0174] The term "cyano-C" is used herein. 1-3 The term "alkyl" is derived from the formula -(C 1-3 This refers to the alkylene-CN group.

[0175] The term "HO-C" is used herein. 1-3 The term "alkyl" is derived from the formula -(C 1-3 This refers to the alkylene-OH group.

[0176] As used herein, the term "HO-C1-3 alkyl" refers to a group of the formula -(C1-3 alkylene)-OH.

[0177] The term "(C)" used herein refers to the term "(C) n-m The term "alkyl)amino" refers to a group of the formula -N(alkyl)2, where each of the two alkyl groups independently has n to m carbon atoms. In some embodiments, each alkyl group independently has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

[0178] The term "(C)" used herein refers to the term "(C)n-m The term "alkyl)carbamyl" refers to a group of the formula -C(O)N(alkyl)2, where each of the two alkyl groups independently has n to m carbon atoms. In some embodiments, each alkyl group independently has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

[0179] As used herein, "halo" refers to F, Cl, Br, or I. In some embodiments, the halo is F, Cl, or Br. In some embodiments, the halo is F or Cl.

[0180] As used herein, "C n-m A "haloalkoxy" refers to a -O-haloalkyl group having n to m carbon atoms. An example of a haloalkoxy group is OCF3. In some embodiments, the haloalkoxy group is simply fluorinated. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

[0181] As used herein, "C n-m The term "haloalkyl" is used alone or in combination with other terms to refer to an alkyl group having 2s+1 halogen atoms, which may be the same or different, from one halogen atom, where "s" is the number of carbon atoms in the alkyl group, and the alkyl group has n to m carbon atoms. In some embodiments, the haloalkyl group is fluorinated only. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

[0182] As used herein, “cycloalkyl” refers to non-aromatic cyclic hydrocarbons, which include cyclized alkyl and / or alkenyl groups. Cycloalkyl groups may include monocyclic or polycyclic (e.g., having two, three, or four fused rings) groups and spiro rings. The ring-forming carbon atoms of a cycloalkyl group may optionally be substituted with oxo or sulfide (e.g., C(O) or C(S)). Also included in the definition of a cycloalkyl group are moieties having one or more aromatic rings fused to (i.e., sharing a bond with) the cycloalkyl ring, such as benzo or thienyl derivatives of cyclopentane, cyclohexane, etc. Cycloalkyl groups containing fused aromatic rings may be bonded via any ring-forming atoms, including the ring-forming atoms of the fused aromatic ring. Cycloalkyl groups may have three, four, five, six, seven, eight, nine, or ten ring-forming carbon atoms (C 3-10 ). In some embodiments, the cycloalkyl is C 3-10 It is a monocyclic or bicyclic cycloalkyl. In some embodiments, the cycloalkyl is C 3-7 It is a monocyclic cycloalkyl. In some embodiments, the cycloalkyl is C 3-10 A monocyclic or bicyclic non-aromatic carbocyclic ring, which optionally has ring members having oxo (=O) or sulfide (=S) substitutions, and optionally has a phenyl or 5-6 member aromatic heterocycle condensed to the non-aromatic portion of the ring structure, in which case the heterocycle has 1-3 ring members independently selected from N, S, or O. In some embodiments, the cycloalkyl is C 3-7 A monocyclic non-aromatic carbon ring, which optionally has ring members having oxo (=O) or sulfide (=S) substitutions, and optionally has a phenyl or 5-6 member aromatic heteroring condensed to the non-aromatic portion of the ring structure, in which case the heteroring has 1-3 ring members independently selected from N, S, or O. In some embodiments, the cycloalkyl is C 3-7It is a monocyclic cycloalkyl group. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl, norbornyl, norpinyl, norcarnyl, etc. In some embodiments, the cycloalkyl group is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

[0183] As used herein, the term “aryl” is used alone or in combination with other terms and refers to an aromatic hydrocarbon group, which may be monocyclic or polycyclic (e.g., having two, three, or four fused rings). Examples of aryl rings include, but are not limited to, phenyl, 1-naphthyl, and 2-naphthyl. In some embodiments, the aryl group has 6 to 10 carbon atoms or 6 carbon atoms. In some embodiments, the aryl group is monocyclic or polycyclic. In some embodiments, the aryl group is phenyl or naphthyl. In some embodiments, the aryl group is phenyl.

[0184] As used herein, the term "phenylene" refers to a divalent phenyl linking group. In some embodiments, the phenylene may be optionally substituted as described herein.

[0185] As used herein, “heteroaryl” refers to a monocyclic or polycyclic aromatic heterocycle having at least one heteroatom ring member selected from sulfur, oxygen, and nitrogen. In some embodiments, the heteroaryl ring has 1, 2, 3, or 4 heteroatom ring members independently selected from nitrogen, sulfur, and oxygen. In some embodiments, any ring-forming N of the heteroaryl moiety may be an N-oxide. In one embodiment, the heteroaryl group is a 5- to 10-membered heteroaryl group. In another embodiment, the heteroaryl group is a 5- to 6-membered heteroaryl group. In a particular embodiment, the heteroaryl group is a monocyclic or bicyclic aromatic ring system having 5- to 10 ring-forming atoms, in which case 1- to 4 ring-forming atoms are heteroatoms independently selected from N, O, and S, and the N and S as ring members may each be optionally oxidized, and the carbon ring member may optionally be replaced by a carbonyl. In another preferred embodiment, the heteroaryl group is a monocyclic aromatic ring system having 5 to 6 ring-forming atoms, in which case 1 to 4 ring-forming atoms are heteroatoms independently selected from N, O, and S, and the N and S as ring members are optionally oxidized, and the carbon ring members may optionally be replaced by carbonyls.

[0186] In some embodiments, the heteroaryl is a five-membered or six-membered heteroaryl ring. A five-membered heteroaryl ring is a ring heteroaryl having five ring atoms, in which case one or more (e.g., 1, 2, or 3) ring atoms are independently selected from N, O, and S. Exemplary five-membered ring heteroaryls are thienyl, furyl, pyrrolyl, imidazolyl, thiazolyl, oxazolyl, pyrazolyl, isothiazolyl, isoxazolyl, 1,2,3-triazolyl, tetrazolyl, 1,2,3-thiadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-triazolyl, 1,2,4-thiadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-triazolyl, 1,3,4-thiadiazolyl, and 1,3,4-oxadiazolyl. A six-membered heteroaryl ring is a heteroaryl ring having six ring atoms, in which case one or more (e.g., 1, 2, or 3) ring atoms are independently selected from N, O, and S. Exemplary six-membered heteroaryl rings are pyridyl, pyrazinyl, pyrimidinyl, triazinyl, pyridone, uracil, and pyridazinyl. In some embodiments, pyridone is substituted with, for example, 1-methylpyridine-2(1H)-one and 1-phenylpyridine-2(1H)-one. In some embodiments, uracil is substituted with, for example, phenyl, isopropyl, and pyridinyl. In some embodiments, uracil is substituted with phenyl and isopropyl, for example, 1-isopropyl-2,4-dioxo-3-phenyl-1,2,3,4-tetrahydropyrimidine. In some embodiments, uracil is substituted with pyridinyl and isopropyl, for example, 1-isopropyl-2,4-dioxo-3-(pyridine-2-yl)-1,2,3,4-tetrahydropyrimidine.

[0187] As used herein, the term “heteroarylene” refers to a divalent heteroaryl linking group. In some embodiments, the heteroarylene is optionally substituted as described herein.

[0188] As used herein, “heterocycloalkyl” refers to a non-aromatic monocyclic or polycyclic heterocycle having one or more ring-forming heteroatoms selected from O, N, or S. Heterocycloalkyls include monocyclic 4, 5, 6, 7, 8, 9, or 10-membered heterocycloalkyl groups. Heterocycloalkyl groups may also include spiro rings. Examples of heterocycloalkyl groups include pyrrolidine-2-one, 1,3-isoxazolidine-2-one, pyranyl, tetrahydropuran, oxetanyl, azetidinyl, morpholino, thiomorpholino, piperazinyl, tetrahydrofuranyl, tetrahydrothienyl, piperidinyl, pyrrolidinyl, isoxazolidinyl, isothiazolidinyl, pyrazolidinyl, oxazolidinyl, thiazolidinyl, imidazolidinyl, azepanyl, and benzazapene. The ring-forming carbon atoms and heteroatoms of a heterocycloalkyl group can optionally be substituted with oxo or sulfide (e.g., C(O), S(O), C(S), or S(O)2). The heterocycloalkyl group can be bonded via ring-forming carbon atoms or ring-forming heteroatoms. In some embodiments, the heterocycloalkyl group contains 0 to 3 double bonds. In some embodiments, the heterocycloalkyl group contains 0 to 2 double bonds. Also included in the definition of a heterocycloalkyl group is a moiety having one or more aromatic rings condensed (i.e., sharing a bond) to the cycloalkyl ring, such as benzo or thienyl derivatives of piperidine, morpholine, azepine, etc. A heterocycloalkyl group containing a condensed aromatic ring can be bonded via any ring-forming atoms, including the ring-forming atoms of the condensed aromatic ring. In some embodiments, the heterocycloalkyl group is a morpholine ring, a pyrrolidine ring, a piperazine ring, a piperidine ring, a dihydropyran ring, a tetrahydroplan ring, a tetrahydropyridine ring, an azetidine ring, or a tetrahydrofuran ring.In certain embodiments, the heterocycloalkyl group is a monocyclic or bicyclic non-aromatic ring or ring system having 4 to 10 ring-forming atoms, in which case 1 to 4 ring-forming atoms are heteroatoms independently selected from N, O, and S, the N and S as ring members may each be optionally oxidized, and the carbon ring members may optionally be replaced by carbonyls, and the heterocycloalkyl group can optionally be condensed into a 5 to 6-membered heteroaryl or phenyl ring, in which case the 5 to 6-membered heteroaryl ring may have 1 to 3 heteroatom ring members independently selected from N, S, and O. In another embodiment, the heterocycloalkyl group is a monocyclic non-aromatic ring or ring system having 4 to 6 ring-forming atoms, in which case 1 to 2 ring-forming atoms are heteroatoms independently selected from N, O, and S, and the N and S as ring members are optionally oxidized, and the carbon ring member may optionally be replaced by a carbonyl, and the heterocycloalkyl group can optionally be condensed into a 5 to 6-membered heteroaryl or phenyl ring, in which case the 5 to 6-membered heteroaryl ring may have 1 to 3 heteroatom ring members independently selected from N, S, and O. In some embodiments, the 10-membered heterocycloalkyl group is 7,8-dihydroquinoline-2,5(1H,6H)-dione. In some embodiments, the 6-membered heterocycloalkyl group is piperidinyl, piperazinyl, or tetrahydropyranyl.

[0189] In some embodiments, the aryl group (e.g., phenyl), heteroaryl group, heterocycloalkyl group, or cycloalkyl group (e.g., variable element Cy) used herein A1 Cy A2 Cy A3 Cy CThese groups may be terminal groups or internal groups (e.g., divalent linkers). In some embodiments, the terms aryl, heteroaryl, heterocycloalkyl, and cycloalkyl, and the corresponding terms arylene, heteroarylene, heterocycloalkylene, and cycloalkylene are used interchangeably. To those skilled in the art, whether such groups are terminal substituents or linkers is readily identifiable based on the structure, the substituents described herein, and the context in which such terms appear. For example, this disclosure is Cy A2 Even if phenyl is described in the definition of variable elements such as, depending on the substitution pattern, this disclosure also covers the phenylene group.

[0190] As used herein, "C n-m Cycloalkyl-C o-p "Alkylene" refers to a group of the formula -alkylene-cycloalkyl, in which the cycloalkyl group has n to m ring members and the alkylene group has 0 to p carbon atoms.

[0191] As used herein, "C n-m Heterocycloalkyl-C o-p "Alkylene" refers to a group of the formula -alkylene-heterocycloalkyl, in which the heterocycloalkyl group has n to m ring members and the alkylene group has 0 to p carbon atoms.

[0192] The term "phenyl-C" is used herein. o-p "Alkylene" refers to the group of the formula -alkylene-phenyl, in which case the alkylene group has 0 to p carbon atoms.

[0193] As used herein, "C n-m Aryl-C o-p "Alkylene" refers to a group of the formula -alkylene-aryl, in which the aryl group has n to m ring members and the alkylene group has 0 to p carbon atoms.

[0194] As used herein, "C n-m Heteroaryl-Co-p "Alkylene" refers to the group of the formula -alkylene-heteroaryl, in which the heteroaryl group has n to m ring members and the alkylene group has 0 to p carbon atoms.

[0195] As used herein, the term "oxo" refers to an oxygen atom as a divalent substituent, which, when bonded to carbon, forms a carbonyl group (e.g., C=O), or when bonded to a heteroatom, forms a sulfoxide or sulfone group.

[0196] In certain places, definitions or embodiments refer to specific rings (e.g., azetidine rings, pyridine rings, etc.). Unless otherwise indicated, these rings can be bonded at any ring member, provided that the valence of the atoms in question is not exceeded. For example, an azetidine ring can be bonded at any position on the ring, while a pyridine-3-yl ring is bonded at position 3.

[0197] The compounds described herein may be asymmetric (e.g., having one or more stereocenters). All stereoisomers, e.g., enantiomers and diastereomers, are covered unless otherwise indicated. Compounds of this disclosure containing asymmetrically substituted carbon atoms may be isolated as optically active or racemic compounds. Methods for preparing optically active compounds from optically inert starting materials are known in the art, including by resolution of racemic mixtures and stereoselective synthesis. Numerous geometric isomers, such as olefins and C=N double bonds, may also exist in the compounds described herein, and all such stable isomers are intended in this disclosure. The cis and trans geometric isomers of the compounds of this disclosure are characterized as isomeric mixtures or separate isomers, and may be isolated as isomeric mixtures or as separate isomers. In some embodiments, the compounds have an (R) configuration. In some embodiments, the compounds have an (S) configuration.

[0198] The separation of racemic mixtures of compounds can be carried out by any of the numerous methods known in the art. An example of such a method is fractional recrystallization using chiral splitting acids, which are optically active salt-forming organic acids. Suitable resolving agents for fractional recrystallization include, for example, optically active acids such as D and L-type tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid, or various optically active camphorsulfonic acids, such as □-camphorsulfonic acid. Other suitable resolving agents for fractional crystallization include stereoisomerically pure forms of α-methylbenzylamine (e.g., S and R types, or diastereomerically pure forms), 2-phenylglycinol, norephedrine, ephedrine, N-methylephedrine, cyclohexylethylamine, and 1,2-diaminocyclohexane.

[0199] The separation of racemic mixtures can also be carried out by elution using a column packed with an optically active resolving agent (e.g., dinitrobenzoylphenylglycine). A suitable elution solvent composition can be determined by those skilled in the art.

[0200] The compounds provided herein also include tautomers. Interchangeable isomers arise from the exchange of a single bond and an adjacent double bond, simultaneously with a proton transfer. Tautomers include proton-transfer tautomers, which are the protonated states of isomers having the same empirical formula and total charge. Examples of proton-transfer tautomers include ketone-enol pairs, amide-imoid acid pairs, lactam-lactime pairs, enamine-imine pairs, and ring structures in which protons can occupy two or more positions in a heterocyclic system, such as 1H- and 3H-imidazoles, 1H-, 2H-, and 4H-1,2,4-triazoles, 1H- and 2H-isoindoles, and 1H- and 2H-pyrazoles. Tautomers can exist in equilibrium or be sterically fixed into a single structure by appropriate substitution.

[0201] All compounds and their pharmaceutically acceptable salts may be found together with other substances such as water and solvents (e.g., hydrates and solvates), or they may be isolated.

[0202] In some embodiments, the preparation of the compound may involve the addition of an acid or base to influence the catalytic activity of the desired reaction or formation in the form of a salt, such as an acid addition salt.

[0203] Examples of acids may be inorganic or organic acids, and may include, but are not limited to, strong and weak acids. Some examples of acids include hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, p-toluenesulfonic acid, 4-nitrobenzoic acid, methanesulfonic acid, benzenesulfonic acid, trifluoroacetic acid, and nitric acid. Some examples of weak acids include, but are not limited to, acetic acid, propionic acid, butanoic acid, benzoic acid, tartaric acid, pentanoic acid, hexanoic acid, heptanoic acid, octanoic acid, nonanoic acid, and decanoic acid.

[0204] Examples of bases include lithium hydroxide, sodium hydroxide, potassium hydroxide, lithium carbonate, sodium carbonate, potassium carbonate, and sodium bicarbonate. Some examples of strong bases include hydroxides, alkoxides, metal amides, metal hydrides, metal dialkylamides, and arylamines. Alkoxides include lithium, sodium, and potassium salts of methyl, ethyl, and t-butyl oxides; metal amides include sodium amides, potassium amides, and lithium amides; metal hydrides include sodium hydride, potassium hydride, and lithium hydride; and metal dialkylamides include, but are not limited to, lithium, sodium, and potassium salts of methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, trimethylsilyl, and cyclohexyl-substituted amides.

[0205] In some embodiments, the compounds provided herein, or salts thereof, are substantially isolated. "Substantially isolated" means that the compound is separated, at least partially or substantially, from the environment in which it was formed or detected. Partial isolation can be, for example, a composition in which the compounds provided herein are concentrated. Substantial isolation can be, for example, a composition containing at least about 50% by weight, at least about 60% by weight, at least about 70% by weight, at least about 80% by weight, at least about 90% by weight, at least about 95% by weight, at least about 97% by weight, or at least about 99% by weight of the compounds provided herein or salts thereof. Methods for isolating compounds and salts thereof are common in the art.

[0206] The compounds of the present invention may contain all isotopes of an atom that occurs in an intermediate or final compound. Isotopes include atoms with the same atomic number but different mass numbers. For example, isotopes of hydrogen include tritium and deuterium. One or more constituent atoms of the compounds of the present invention may be replaced or substituted with isotopes of that atom in natural or unnatural abundance. In some embodiments, the compound contains at least one deuterium atom. For example, one or more hydrogen atoms in the compounds of this disclosure may be replaced or substituted with deuterium. In some embodiments, the compound contains two or more deuterium atoms. In some embodiments, the compound contains 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 deuterium atoms. Methods for synthesizing organic compounds to include isotopes are known in the art.

[0207] Substitution with heavy isotopes such as deuterium may offer certain therapeutic advantages due to their high metabolic stability, such as an extended in vivo half-life or reduced required dose, and is therefore preferable in certain situations (A. Kerekes et al. J. Med. Chem. 2011, 54, 201-210; R. Xu et al. J. Label Compd. Radiopharm. 2015, 58, 308-312).

[0208] As used herein, the term “compound” includes all stereoisomers, geometric isomers, tautomers, and isotopes of the structure shown. Unless otherwise specified, any compound identified by name or structure as a particular tautomer is intended to include other tautomers.

[0209] The term "medically acceptable" is used herein to mean, within the bounds of sound medical judgment, a compound, material, composition, and / or drug form that is suitable for use in contact with human and animal tissues, free from excessive toxicity, irritation, allergic reactions, or other problems or complications, and that has a reasonable benefit-to-risk ratio.

[0210] This application also includes pharmaceutically acceptable salts of the compounds described herein. As used herein, “pharmaceutically acceptable salt” refers to a derivative of a compound of the disclosed compound modified by converting an existing acidic or base moiety of the parent compound to its salt form. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines, and alkali or organic salts of acidic residues such as carboxylic acids. pharmaceutically acceptable salts of the disclosed compound include conventional non-toxic salts of the parent compound, which are formed, for example, from non-toxic inorganic or organic acids. pharmaceutically acceptable salts of the disclosed compound can be synthesized from parent compounds containing basic or acidic moieties by conventional chemical methods. Generally, such salts can be prepared by reacting these compounds in their free acidic or basic forms with a stoichiometric amount of a suitable base or acid in water or an organic solvent, or a mixture thereof. Typically, non-aqueous solvents such as ether, ethyl acetate, alcohols (e.g., methanol, ethanol, isopropanol, or butanol), or acetonitrile (ACN) are preferred. A list of suitable salts can be found in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418 and Journal of Pharmaceutical Science, 66, 2 (1977). Each of these is incorporated herein by reference in its entirety.

[0211] The following abbreviations may be used herein: AcOH (acetic acid), Ac2O (acetic anhydride), aq. (aqueous solution), atm. (atmospheric pressure), Boc (t-butoxycarbonyl), br (broad), Cbz (carboxybenzyl), calc. (calculated value), d (doublet), dd (doublet of doublet), DCM (dichloromethane), DEAD (diethyl azodicarboxylate), DIAD (N,N'-diisopropyl azidodicarboxylate), DIPEA (N,N-diisopropylethylamine), DMF (N,N-dimethic acid (Formamide), Et (ethyl), SiO (ethyl acetate), g (gram), h (hour), HATU (N,N,N',N'-tetramethyl-O-(7-azabenzotriazole-1-yl)uronium hexafluorophosphate), HCl (hydrochloric acid), HPLC (high-performance liquid chromatography), Hz (Hertz), J (coupling constant), LCMS (liquid chromatography-mass spectrometry), m (multinote), M (Molar), mCPBA (3-chloroperoxybenzoic acid), MgSO4 (magnesium sulfate), MS (Mass Spectrometry), Me (Methyl), MeCN (Acetonitrile), MeOH (Methanol), mg (Milligram), min. (Minute), mL (Milliliter), mmol (Millimoles), N (Normal), NaHCO3 (Sodium Bicarbonate), NaOH (Sodium Hydroxide), Na2SO4 (Sodium Sulfate), NH4Cl (Ammonium Chloride), NH4OH (Ammonium Hydroxide), nM (Nanomolar), NMR (Nuclear Magnetic Resonance Spectroscopy), OTf (Trifluoromethanesulfonate), Pd (Palladium), Ph (Ph phenyl), pM (picomolar), PMB (para-methoxybenzyl), POCl3 (phosphoryl chloride), RP-HPLC (reverse-phase high-performance liquid chromatography), s (singlet), t (triplet or tert), TBS (tert-butyldimethylsilyl), tert (tert), tt (triplet of triplets), t-Bu (tert-butyl), TFA (trifluoroacetic acid), THF (tetrahydrofuran), μg (microgram), μL (microliter), μM (micromolar), wt% (weight percent).

[0212] As used herein, the term “cell” means in vitro, ex vivo, or in vivo cells. In some embodiments, ex vivo cells may be part of a tissue sample extracted from an organism such as a mammal. In some embodiments, in vitro cells may be cells in a cell culture. In some embodiments, in vivo cells are cells living in an organism such as a mammal.

[0213] As used herein, the term “contact” refers to bringing together the indicated parts in vitro or in vivo. For example, “contact” a TAM kinase with a compound of the Disclosure includes administering the compound of the Disclosure to an individual or patient having TAM, e.g., a human, and introducing the compound of the Disclosure into a sample containing a cell preparation or purified modifier containing a TAM kinase, e.g.

[0214] As used herein, the interchangeable terms “individual” or “patient” refer to any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, pigs, cattle, sheep, horses, or primates, and most preferably humans.

[0215] As used herein, the term "therapeutic dose" refers to the amount of an active compound or drug that elicits a biological or medical response in a tissue, system, animal, individual, or human being as desired by a researcher, veterinarian, physician, or other clinician.

[0216] As used herein, the terms “treating” or “treatment” mean 1) inhibiting a disease, e.g., inhibiting a disease, condition, or disorder in an individual who is experiencing or exhibiting the symptoms or condition of the disease, condition, or disorder (i.e., cessation of further progression of the symptoms or condition), or 2) improving a disease, e.g., improving a disease, condition, or disorder in an individual who is experiencing or exhibiting the symptoms or condition of the disease, condition, or disorder (i.e., reversal of the symptoms or condition).

[0217] As used herein, the terms “preventing” or “prevention” refer to the prevention of disease, for example, the prevention of disease, condition, or disorder in an individual who is susceptible to a disease, condition, or disorder but has not yet experienced or shown any symptoms of such disease.

[0218] synthesis The compounds provided herein, including their salts, can be prepared using known organic synthesis techniques and according to various possible synthetic routes.

[0219] The reactions for preparing the compounds provided herein can be carried out in suitable solvents that can be readily selected by those skilled in the art of organic synthesis. Suitable solvents may be substantially inactive with respect to the starting materials (reactants), intermediates, or products at temperatures ranging from the freezing point to the boiling point of the solvent. A given reaction can be carried out in one solvent or a mixture of solvents. Depending on the specific reaction step, a solvent suitable for that step can be selected by those skilled in the art.

[0220] The preparation of the compounds provided herein may include the protection and deprotection of various chemical groups. The need for protection and deprotection, as well as the selection of appropriate protecting groups, can be readily determined by those skilled in the art. The chemistry of protecting groups can be found, for example, in TW Greene and PGMWuts, Protective Groups in Organic Synthesis, 3rd Ed., Wiley & Sons, Inc., New York (1999), which is incorporated herein by reference in its entirety.

[0221] The reaction can be observed according to any suitable method known in the art. For example, the formation of the product can be observed by spectroscopic means, e.g., nuclear magnetic resonance spectroscopy (e.g., 1 H or 13 C) It can be observed by infrared spectroscopy, spectrophotometric methods (e.g., UV-Vis), mass spectrometry, or chromatography, such as high-performance liquid chromatography (HPLC) or thin-layer chromatography.

[0222] As used herein, the terms “ambient temperature,” “room temperature,” and “rt” are understood in the art and typically refer to temperature, for example, reaction temperature, which is usually the temperature of the room in which the reaction takes place, for example, a temperature between approximately 20°C and approximately 30°C.

[0223] The compounds disclosed herein can be prepared by those skilled in the art according to preparation routes known in the literature and various possible synthetic routes. An example of a synthetic method for preparing the compounds of this application is shown in Scheme 1 below.

[0224] The reactions for preparing the compounds provided herein can be carried out in suitable solvents that can be readily selected by those skilled in the art of organic synthesis. Suitable solvents may be substantially inactive with respect to the starting materials (reactants), intermediates, or products at temperatures ranging from the freezing point to the boiling point of the solvent. A given reaction can be carried out in one solvent or a mixture of solvents. Depending on the specific reaction step, a solvent suitable for that step can be selected by those skilled in the art.

[0225] The preparation of the compounds provided herein may include the protection and deprotection of various chemical groups. The need for protection and deprotection, as well as the selection of appropriate protecting groups, can be readily determined by those skilled in the art. The chemistry of protecting groups can be found, for example, in TW Greene and PGMWuts, Protective Groups in Organic Synthesis, 3rd Ed., Wiley & Sons, Inc., New York (1999), which is incorporated herein by reference in its entirety.

[0226] The reaction can be observed according to any suitable method known in the art. For example, the formation of the product can be observed by spectroscopic methods, e.g., nuclear magnetic resonance spectroscopy (e.g., 1 H or 13 C) It can be observed by infrared spectroscopy, spectrophotometric methods (e.g., UV-Vis), mass spectrometry, or chromatography, such as high-performance liquid chromatography (HPLC) or thin-layer chromatography.

[0227] As used herein, the terms “ambient temperature,” “room temperature,” and “rt” are understood in the art and typically refer to temperature, for example, reaction temperature, which is approximately the temperature of the room in which the reaction takes place, for example, a temperature between about 20°C and about 30°C.

[0228] The compounds disclosed herein can be prepared by those skilled in the art according to preparation routes known in the literature. Compounds of formula I can be prepared according to scheme 1. Compound (i) can be prepared by a standard Suzuki coupling of bromide (ia) and boronic acid ester or boronic acid (ib). In this case, R 1 It contains an alkenylene functional group. R using Pd carbon or another suitable catalyst. 1 By catalytic hydrogenation of the functional group, compound (ii) can be obtained, in this case, R 1 The compound contains an alkylene functional group. For example, bromide (iii) can be obtained by selective bromination of compound (ii) using NBS, which is then reacted directly with a boronic acid ester or boronic acid (iv) under standard Suzuki coupling conditions to obtain the compound of formula I. Alternatively, the compound of formula I can be prepared by Suzuki coupling of bromide (iii) with a boronic acid ester or boronic acid (v), followed by the reaction of the resulting amine (vi) with a carboxylic acid (vii) and a suitable coupling reagent, such as HATU or BOP. [ka]

[0229] The present invention will be described in more detail through specific examples. The following examples are provided for illustrative purposes and are not intended to limit the present invention in any way. Those skilled in the art will readily recognize various non-deterministic parameters that can be changed or modified to obtain essentially the same results. The compounds of the examples were found to be inhibitors of TAM kinase, as described below.

[0230] Some of the prepared compounds were purified by preparative LC-MS using a Waters mass spectrometry fractionation system. The basic equipment setup, protocols, and control software for operating these systems are described in detail in the literature. See, for example, “Two-Pump At Column Dilution Configuration for Preparative LC-MS”, K. Blom, J. Combi. Chem., 4, 295 (2002); “Optimizing Preparative LC-MS Configurations and Methods for Parallel Synthesis Purification”, K. Blom, R. Sparks, J. Doughty, G. Everlof, T. Haque, A. Combs, J. Combi. Chem., 5, 670 (2003); and “Preparative LC-MS Purification: Improved Compound Specific Method Optimization”, K. Blom, B. Glass, R. Sparks, A. Combs, J. Combi. Chem., 6, 874-883 (2004). The separated compounds were typically subjected to analytical liquid chromatography-mass spectrometry (LC / MS) to confirm their purity under the following conditions: Instrument: Agilent 1100 series, LC / MSD; Column: Waters Sunfire® C 18 Particle size 5 μm, 2.1 × 5.0 mm, buffer: mobile phase A: 0.025% TFA aqueous solution and mobile phase B: acetonitrile, gradient of B from 2% to 80% over 3 minutes, flow rate 2.0 mL / min.

[0231] Some of the prepared compounds were also separated on a preparative scale by reversed-phase high-performance liquid chromatography (RP-HPLC) with an MS detector or by flash chromatography (silica gel), as shown in the examples. Typical preparative reversed-phase high-performance liquid chromatography (RP-HPLC) column conditions are as follows:

[0232] Purification at pH=2: Waters Sunfire (trademark) C 18A 5 μm particle size, 19 × 100 mm column was used. Elution was performed with mobile phase A: 0.1% TFA (trifluoroacetic acid) aqueous solution and mobile phase B: acetonitrile. The flow rate was 30 mL / min. The separation gradient was optimized for each compound using the Compound Specific Method Optimization protocol as described in the literature [see "Preparative LCMS Purification: Improved Compound Specific Method Optimization", K. Blom, B. Glass, R. Sparks, A. Combs, J. Comb. Chem., 6, 874-883 (2004)]. Typically, a flow rate of 60 mL / min was used with a 30 × 100 mm column.

[0233] Purification at pH=10: Waters XBridge C 18 A 5 μm particle size, 19 × 100 mm column was used, with elution using mobile phase A: 0.15% NH4OH aqueous solution and mobile phase B: acetonitrile. The flow rate was 30 mL / min, and the separation gradient was optimized for each compound using the Compound Specific Method Optimization protocol as described in the literature [see "Preparative LCMS Purification: Improved Compound Specific Method Optimization", K. Blom, B. Glass, R. Sparks, A. Combs, J. Comb. Chem., 6, 874-883 (2004)]. Typically, a flow rate of 60 mL / min was used with a 30 × 100 mm column.

[0234] TAM kinase Receptor tyrosine kinases (RTKs) are cell surface proteins that transmit signals from the extracellular environment to the cytoplasm and nucleus, regulating cellular events such as survival, growth, proliferation, differentiation, adhesion, and migration. All RTKs contain an extracellular ligand-binding domain and a cytoplasmic protein tyrosine kinase domain. Ligand binding leads to dimerization of the RTK, which induces activation of the cytoplasmic kinase and initiates downstream signaling pathways. RTKs can be classified into different subfamilies based on their sequence similarity. The TAM subfamily consists of three RTKs: TYRO3, AXL, and MER (Graham et al., 2014, Nature reviews Cancer 14, 769-785, and Linger et al., 2008, Oncogene 32, 3420-3431). TAM kinases are characterized by an extracellular ligand-binding domain consisting of two immunoglobulin-like domains and two fibronectin type III domains. Two ligands, namely growth arrest-specific 6 (GAS6) and protein S (ProS), have been identified for TAM kinases. GAS6 can bind to and activate all three TAM kinases, while ProS is a ligand for MER and TYRO3 (Graham et al., 2014, Nature Reviews Cancer 14, 769-785).

[0235] TAM kinases are overexpressed in many cancers and play a crucial role in tumor development and maintenance. Therefore, inhibiting TAMs presents an attractive way to target another class of oncogenetic RTKs (Graham et al., 2014, Nature Reviews Cancer 14, 769-785, and Linger et al., 2008, Oncogene 32, 3420-3431).

[0236] Axl was originally identified as a transformant gene derived from the DNA of patients with chronic myeloid leukemia (O'Bryan et al., 1991, Molecular and Cellular Biology 11, 5016-5031). GAS6 binds to Axl, subsequently inducing autophosphorylation and activation of Axl tyrosine kinase. Axl activates several downstream signaling pathways, including PI3K-Akt, Raf-MAPK, and PLC-PKC (Feneyrolles et al., 2014, Molecular Cancer Therapeutics 13, 2141-2148; Linger et al., 2008, Oncogene 32, 3420-3431). AXL is overexpressed or enhanced in various malignancies, including lung cancer, prostate cancer, colon cancer, breast cancer, melanoma, and renal cell carcinoma (Linger et al., 2008, Oncogene 32, 3420-3431). AXL overexpression is associated with poor prognosis (Linger et al., 2008, Oncogene 32, 3420-3431). As a result, AXL activation promotes cancer cell survival, proliferation, angiogenesis, metastasis, and resistance to chemotherapy and targeted therapy. AXL knockdown or AXL antibodies can inhibit the migration of breast cancer and NSCLC cancer in vitro and suppress tumor growth in xenograft tumor models (Li et al., 2009, Oncogene 28, 3442-3455). In pancreatic cancer cells, inhibition of AXL reduced cell proliferation and survival (Koorstra et al., 2009, Cancer biology & therapy 8, 618-626). In prostate cancer, inhibition of AXL reduced cell migration, invasion, and proliferation (Tai et al., 2008, Oncogene 27, 4044-4055). Furthermore, overexpression or enhancement of AXL is a major mechanism of EGFR inhibitor resistance in lung cancer cells, and inhibition of AXL can reverse this resistance (Zhang et al., 2012, Nature genetics 44, 852-860).

[0237] Mer was originally identified as a phosphoprotein from a lymphoblast-like expression library (Graham et al., 1995, Oncogene 10, 2349-2359). Both GAS6 and ProS can bind to Mer and induce phosphorylation and activation of Mer kinase (Lew et al., 2014, eLife, 3:e03385). Similar to Axl, Mer activation also transmits downstream signaling pathways including PI3K-Akt and Raf-MAPK (Linger et al., 2008, Oncogene 32, 3420-3431). MER is overexpressed in many cancers, including multiple myeloma, gastric cancer, prostate cancer, breast cancer, melanoma, and rhabdomyosarcoma (Linger et al., 2008, Oncogene 32, 3420-3431). Knockdown of MER inhibited the growth of multiple myeloma cells in in vitro and xenograft models (Waizenegger et al., 2014, Leukemia, 1-9). In acute myeloid leukemia, knockdown of MER induced apoptosis, reduced colony formation, and extended survival in mouse models (Lee-Sherick et al., 2013, Oncogene 32, 5359-5368). Inhibition of MER increased apoptosis, reduced colony formation, increased chemotherapy sensitivity, and reduced tumor growth in NSCLC (Linger et al., 2013, Oncogene 32, 3420-3431). Similar effects have been observed with MER knockdown in melanoma (Schlegel et al., 2013) and glioblastoma (Wang et al., 2013, Oncogene 32, 872-882).

[0238] Tyro3 was originally identified through PCR-based cloning studies (Lai and Lemke, 1991, Neuron 6, 691-704). Both ligands, GAS6 and ProS, can bind to and activate Tyro3. TYRO3 is also involved in cancer growth and proliferation. TYRO3 is overexpressed in melanoma cells, and knockdown of TYRO3 induces apoptosis in these cells (Demarest et al., 2013, Biochemistry 52, 3102-3118).

[0239] In addition to its role as a transforming oncogene, TAM kinase is emerging as a potential immuno-oncological target. The persistent clinical response to immune checkpoint blockade observed in cancer patients clearly demonstrates the crucial role the immune system plays in tumor development and maintenance. Genetic mutations originating from cancer cells can provide a diverse array of antigens that immune cells can use to distinguish tumor cells from normal cells. However, cancer cells have evolved multiple mechanisms to evade host immune surveillance. Indeed, one characteristic of human cancer is its ability to evade immune destruction. Cancer cells can induce an immunosuppressive microenvironment by promoting the formation of M2 tumor-associated macrophages, myeloid-derived suppressor cells (MDSCs), and regulatory T cells. Cancer cells can also produce high levels of immune checkpoint proteins such as PD-L1, inducing T cell anergy or depletion. It is now clear that tumors incorporate certain immune checkpoint pathways as a primary mechanism of immune resistance (Pardoll, 2012, Cancer 12, 252-264). Antibodies antagonizing these negative regulators of T-cell function have shown remarkable efficacy in clinical trials for multiple malignancies, including advanced melanoma, non-small cell lung cancer, and bladder cancer. While these treatments have shown promising results, not all patients experience an enhanced antitumor response, suggesting that other immunosuppressive pathways may also be important.

[0240] TAM kinases have been shown to function as checkpoints for immune activation in the tumor environment. All TAM kinases are expressed in NK cells, and TAM kinases inhibit the antitumor activity of NK cells. The small molecule TAM inhibitor LDC1267 activates NK cells and suppresses metastasis in tumor models with different tissue structures (Paolino et al., 2014, Nature 507, 508-512). Furthermore, MER kinases promote the activity of tumor-associated macrophages by increasing the secretion of immunosuppressive cytokines such as IL10 and IL4 and decreasing the production of immunoactivating cytokines such as IL12 (Cook et al., 2013, The Journal of Clinical Investigation 123, 3231-3242). Inhibition of MER has been shown to reverse this effect. As a result, MER knockout mice are resistant to PyVmT tumorigenesis (Cook et al., 2013, The Journal of Clinical Investigation 123, 3231-3242). The role of TAM kinase in immune responses is also supported by knockout mouse studies. TAM triple knockout mice (TKO) are viable. However, these mice exhibited signs of autoimmune diseases, including splenomegaly and lymphadenopathy, autoantibody production, swelling of the soles and joints, skin damage, and systemic lupus erythematosus (Lu and Lemke, 2001, Science 293, 306-311). This is consistent with knockout phenotypes of approved immuno-oncology targets such as CTLA4 and PD-1. Both CTLA4 knockout mice and PD-1 knockout mice exhibit signs of autoimmune diseases, and these mice die within the first few weeks of life (Chambers et al., 1997, Immunity 7, 885-895, and Nishimura et al., 2001, Science 291, 319-322).

[0241] Inhibition of TAMs not only has direct activity against newly generated cells but also activates the anti-cancer immune response. Therefore, TAM inhibitors present an attractive approach to cancer treatment as monotherapy. Furthermore, TAM inhibitors can be combined with other targeted therapies, chemotherapy, radiation, or immunotherapies to achieve maximum clinical efficacy.

[0242] How to use The compounds of this disclosure can modulate or inhibit the activity of TAM kinase. For example, the compounds of this disclosure can be used to inhibit the activity of TAM kinase in cells, or in individuals or patients who require inhibition of the kinase by administering an inhibitory dose of the compounds of this disclosure to the cells, individuals, or patients.

[0243] In some embodiments, the compounds of the Disclosure are more selective to TAM kinase than one or more other kinases. In some embodiments, this selectivity is 2-fold or more, 3-fold or more, 5-fold or more, 10-fold or more, 25-fold or more, 50-fold or more, or 100-fold or more.

[0244] The compounds of the present invention can inhibit one or more of AXL, MER, and TYRO3. In some embodiments, the compound is more selective for one TAM kinase than another. "Selective" means that the compound binds to or inhibits the TAM kinase with greater affinity or efficacy compared to a reference enzyme such as another TAM kinase. For example, the compound may be selective for AXL over MER and TYRO3, or may be selective for MER over AXL and TYRO3, or may be selective for AXL and MER over TYRO3. In some embodiments, the compound inhibits all of the TAM family members (e.g., AXL, MER, and TYRO3). In some embodiments, the compound may be selective for AXL and MER over TYRO3 and other kinases. In some embodiments, methods of inhibiting AXL and MER kinases are provided herein, which include contacting the AXL and MER kinases with a compound provided herein or a pharmaceutically acceptable salt thereof.

[0245] As a TAM kinase inhibitor, the compounds of the present disclosure are useful for the treatment of various diseases associated with abnormal expression or activity of TAM kinases. Compounds that inhibit TAM kinases are useful in providing a means to prevent tumor growth or induce apoptosis in tumors, particularly by inhibiting angiogenesis. Therefore, it is expected that the compounds will prove useful for the treatment or prevention of proliferative diseases such as cancer. In particular, tumors with activating mutants of receptor tyrosine kinases or tumors that upregulate receptor tyrosine kinases may be particularly sensitive to the inhibitor.

[0246] In certain embodiments, the present disclosure provides a method of treating a disease or disorder mediated by a TAM kinase in a patient who needs it, the method comprising administering to the patient a compound provided herein or a pharmaceutically acceptable composition thereof.

[0247] For example, the compounds of this disclosure are useful in the treatment of cancer. Examples of cancers include bladder cancer, breast cancer, cervical cancer, colorectal cancer, small intestine cancer, colon cancer, rectal cancer, anal cancer, endometrial cancer, gastric cancer, head and neck cancers (e.g., laryngeal cancer, hypopharyngeal cancer, nasopharyngeal cancer, oropharyngeal cancer, lip cancer, and oral cancer), kidney cancer, liver cancers (e.g., hepatocellular carcinoma, cholangiocarcinoma), lung cancers (e.g., adenocarcinoma, small cell lung cancer and non-small cell lung cancer, small cell and non-small cell lung cancer, bronchial cancer, bronchial adenoma, pleuroblastoma), ovarian cancer, prostate cancer, testicular cancer, uterine cancer, esophageal cancer, gallbladder cancer, pancreatic cancer (e.g., exocrine pancreatic carcinoma), and stomach cancer. Examples include cancers such as thyroid cancer, parathyroid cancer, skin cancers (e.g., squamous cell carcinoma, Kaposi's sarcoma, Merkel cell carcinoma), and brain cancers (e.g., astrocytoma, medulloblastoma, ependymoma, neuroectodermal tumor, pineal tumor).

[0248] Other cancers treatable with the compounds disclosed herein include bone cancer, intraocular cancer, gynecological cancer, endocrine cancer, adrenal cancer, soft tissue sarcoma, urethral cancer, penile cancer, pituitary cancer, trine negative breast cancer (TNBC), and environmentally induced cancers, including those induced by asbestos.

[0249] Further examples of cancer include hematopoietic malignancies, such as leukemia or lymphoma, multiple myeloma, chronic lymphocytic lymphoma, adult T-cell leukemia, B-cell lymphoma, cutaneous T-cell lymphoma, acute myeloid leukemia, Hodgkin lymphoma or non-Hodgkin lymphoma, myeloproliferative disorders (e.g., polycythemia vera, essential thrombocythemia, and primary myelofibrosis), Waldenström macroglobulinemia, hairy cell lymphoma, chronic myeloid lymphoma, acute lymphoblastic lymphoma, AIDS-related lymphoma, and Burkitt lymphoma.

[0250] Other cancers treatable with the compounds of this disclosure include ocular tumors, glioblastoma, melanoma, rhabdomyosarcoma, lymphosarcoma, and osteosarcoma.

[0251] The compounds disclosed herein may also be useful in suppressing tumor metastasis.

[0252] In some embodiments, diseases and conditions treatable with the compounds of this disclosure include, but are not limited to, blood cancers, sarcomas, lung cancers, gastrointestinal cancers, genitourinary cancers, liver cancers, bone cancers, nervous system cancers, gynecological cancers, and skin cancers.

[0253] Examples of hematological cancers include lymphomas and leukemias, such as acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), acute promyelocytic leukemia (APL), chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), chronic myeloid leukemia (CML), diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), marginal zone lymphoma (MZL), non-Hodgkin lymphoma (including relapsed or refractory NHL), and follicular lymphoma. These include (FL), Hodgkin lymphoma, lymphoblastic lymphoma, myeloproliferative disorders (e.g., primary myelofibrosis (PMF), polycythemia vera (PV), essential thrombocythemia (ET)), myelodysplastic syndromes (MDS), acute T-cell lymphoblastic lymphoma (T-ALL), multiple myeloma, cutaneous T-cell lymphoma, peripheral T-cell lymphoma, Waldenström macroglobulinemia, hairy cell lymphoma, chronic myeloid lymphoma, and Burkitt lymphoma.

[0254] Examples of sarcomas include chondrosarcoma, Ewing's sarcoma, osteosarcoma, rhabdomyosarcoma, angiosarcoma, fibrosarcoma, liposarcoma, myxoma, rhabdomyomas, rhabdomyomas, fibromas, lipomas, hamartomas, and teratomas.

[0255] Examples of lung cancer include non-small cell lung cancer (NSCLC), small cell lung cancer, bronchial cancer (squamous cell, anaplastic small cell, anaplastic large cell, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, chondrolytic hamartoma, and mesothelioma.

[0256] Examples of gastrointestinal cancers include esophageal cancer (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), gastric cancer (carcinoma, lymphoma, leiomyosarcoma), pancreatic cancer (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumor, vipoma), small intestine cancer (adenocarcinoma, lymphoma, carcinoid tumor, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), colorectal cancer (adenocarcinoma, tubular adenoma, chorioadenoma, hamartoma, leiomyoma), colorectal cancer, and bile duct cancer.

[0257] Examples of urogenital cancers include kidney cancer (adenocarcinoma, Wilms' tumor [nephroblastoma], renal cell carcinoma), bladder and urethral cancer (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma, urothelial carcinoma), prostate cancer (adenocarcinoma, sarcoma), and testicular cancer (seminoma, teratoma, embryonic carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, stromal cell carcinoma, fibroma, fibroadenoma, adenomatous tumor, lipoma).

[0258] Examples of liver cancer include hepatocellular carcinoma, cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, and hemangioma.

[0259] Examples of bone cancers include osteogenic sarcoma, fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticuloma), multiple myeloma, malignant giant cell tumor chordoma, osteochondrodysplasia, benign chondroma, chondroblastoma, chondromyxofibroma, osteoidoma, and giant cell tumor.

[0260] Examples of cancers of the nervous system include cancers of the skull (osteoma, hemangioma, granuloma, xanthomas, osteoosteitis), meningeal cancers (meningioma, meningiosarcoma, gliomas), brain cancers (astrocytoma, medulloblastoma, glioma, ependymoma, germ cell tumor (pineal glandoma), glioblastoma, glioblastoma multiforme, oligodendroglioma, schwannoma, retinoblastoma, congenital tumors), and spinal cord cancers (neurofibroma, meningioma, glioma, sarcoma), as well as neuroblastoma, Lhermitt-Dukuro disease, neoplasms of the central nervous system (CNS), primary CNS lymphoma, and tumors of the spinal axis.

[0261] Examples of gynecological cancers include uterine cancer (endometrial cancer), cervical cancer (cervical cancer, pre-tumor cervical dysplasia), ovarian cancer (ovarian cancer (serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified epithelial malignant tumors), granulosa-vagus cell tumor, Sertoli-Leydig cell tumor, undifferentiated germ cell tumor, malignant teratoma), vulvar cancer (squamous cell carcinoma, carcinoma in situ, adenocarcinoma, fibrosarcoma, melanoma), vaginal cancer (clear cell carcinoma, squamous cell carcinoma, staphylosarcoma (embryonic rhabdomyosarcoma)), and fallopian tube cancer (epithelial malignant tumor).

[0262] Examples of skin cancers include melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, Merkel cell carcinoma, dysplastic nevi of moles, lipoma, hemangioma, dermatofibroma, and keloid.

[0263] Examples of head and neck cancers include glioblastoma, melanoma, rhabdomyosarcoma, lymphosarcoma, osteosarcoma, squamous cell carcinoma, adenocarcinoma, oral cancer, laryngeal cancer, nasopharyngeal cancer, nasal cavity and paranasal sinus cancer, thyroid cancer, and parathyroid cancer.

[0264] In some embodiments, the present disclosure provides a method for treating hepatocellular carcinoma in a patient in need thereof, the method comprising administering to the patient a compound of formula (I) or a compound disclosed herein, or a pharmaceutically acceptable salt thereof, or a composition comprising a compound of formula (I) or a compound disclosed herein.

[0265] In some embodiments, the present disclosure provides a method for treating rhabdomyosarcoma, esophageal cancer, breast cancer, or head and neck cancer in a patient in need thereof, the method comprising administering to the patient a compound of formula (I) or a compound disclosed herein, or a pharmaceutically acceptable salt thereof, or a composition comprising a compound of formula (I) or a compound disclosed herein.

[0266] In some embodiments, the present disclosure provides a method for treating cancer, in which case the cancer is selected from hepatocellular carcinoma, breast cancer, bladder cancer, colorectal cancer, melanoma, mesothelioma, lung cancer, prostate cancer, pancreatic cancer, testicular cancer, thyroid cancer, squamous cell carcinoma, glioblastoma, neuroblastoma, uterine cancer, and rhabdomyosarcoma.

[0267] Targeting TAM receptor tyrosine kinases may lead to therapeutic methods for viral diseases (T Shibata, et al. The Journal of Immunology, 2014, 192, 3569-3581). This disclosure provides a method for treating infectious diseases such as viral infections. The method comprises administering to a patient in need a therapeutically effective amount of a compound of formula (I) or any of the formulas described herein, any of the compounds listed in any of the claims, or a salt thereof. Examples of viruses that cause infectious diseases treatable by the method of this disclosure include, but are not limited to, human immunodeficiency virus, human papillomavirus, influenza, hepatitis A, B, C, or D virus, adenovirus, poxvirus, herpes simplex virus, human cytomegalovirus, severe acute respiratory syndrome virus, Ebola virus, Marburg virus, and measles virus. In some embodiments, viruses that cause infections treatable by the methods of the present disclosure include, but are not limited to, hepatitis (types A, B, or C), herpesviruses (e.g., VZV, HSV-1, HAV-6, HSV-II, and CMV, Epstein-Barr virus), adenoviruses, influenza viruses, flaviviruses (e.g., West Nile, dengue fever, tick-borne encephalitis, yellow fever, Zika), echoviruses, rhinoviruses, coxsackieviruses, cornoviruses, respiratory syncytial viruses, mumps viruses, rotaviruses, measles viruses, rubella viruses, parvoviruses, vaccinia viruses, HTLV viruses, dengue viruses, papillomaviruses, molluscum contagiosum viruses, polioviruses, rabies viruses, JC viruses, and arboviral encephalitis viruses.

[0268] In some embodiments, this disclosure provides methods for treating thrombosis (JMEMCosemans et al. J. of Thrombosis and Haemostasis 2010, 8, 1797-1808 and A. Angelillo-Scherrer et al. J. Clin. Invest. 2008, 118, 583-596).

[0269] Combination therapy One or more additional pharmaceuticals or therapeutic methods, such as antiviral agents, chemotherapeutic agents, or other anticancer agents, immunoenhancing agents, immunosuppressants, radiation, antitumor and antiviral vaccines, cytokine therapies (e.g., IL-2, GM-CSF, etc.), and / or tyrosine kinase inhibitors, may be used in combination with the compound of formula (I) or the compounds described herein for the treatment of TAM-related diseases, disorders, or conditions. These agents may be combined with the compound in a single dosage form, or they may be administered simultaneously or sequentially in separate dosage forms.

[0270] Suitable antiviral agents intended for use in combination with the compounds of this disclosure may include nucleoside and nucleotide reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), protease inhibitors, and other antiviral agents.

[0271] Examples of appropriate non-reactive antibiotics (NRTIs) include zidovudine (AZT), didanosine (ddl), zalcitabine (ddC), stabudine (d4T), lamivudine (3TC), abacavir (1592U89), adefovir dipivoxil [bis(POM)-PMEA], lobucavir (BMS-180194), BCH-10652, emitricitabine [(-)-FTC], beta-L-FD4 (also known as beta-L-D4C, named beta-L-2',3'-dideoxy-5-fluorocytidine), DAPD, ((-)-beta-D-2,6-diaminopurine dioxolane), and rhodenosine (FddA). Representative appropriate NNRTIs include nevirapine (BI-RG-587), delavirazine (BHAP, U-90152), efavirenz (DMP-266), PNU-142721, AG-1549, MKC-442 (1-(ethoxymethyl)-5-(1-methylethyl)-6-(phenylmethyl)-(2,4(1H,3H)-pyrimidinedione), and (+)-caranolide A Examples include (NSC-675451) and B. Representative appropriate protease inhibitors include saquinavir (Ro31-8959), ritonavir (ABT-538), indinavir (MK-639), nelfinavir (AG-1343), amprenavir (141W94), lasinavir (BMS-234475), DMP-450, BMS-2322623, ABT-378, and AG-1 549. Other antiviral agents include hydroxyurea, ribavirin, IL-2, IL-12, pentafusid, and Yissum Project No. 11607.

[0272] Suitable agents for use in combination with the compounds of this application for the treatment of cancer include chemotherapeutic agents, targeted cancer therapies, immunotherapies, or radiotherapy. The compounds of this application may be effective in combination with antihormone agents for the treatment of breast cancer and other tumors. Suitable examples include, but are not limited to, anti-estrogen agents such as tamoxifen and toremifene, aromatase inhibitors such as letrozole, anastrozole, and exemestane, corticosteroids (e.g., prednisone), progestins (e.g., megestrol acetate), and estrogen receptor antagonists (e.g., fulvestrant). Suitable antihormone agents for use in the treatment of prostate cancer and other cancers can also be combined with the compounds of this disclosure. These include, but are not limited to, flutamide, bicalutamide, and nilutamide; luteinizing hormone-releasing hormone (LHRH) analogues including leuprolide, oserelin, triptorelin, and histrelin; LHRH antagonists (e.g., degarelix); androgen receptor blockers (e.g., enzalutamide); and agents that inhibit androgen production (e.g., abiraterone).

[0273] The compounds of this disclosure may be used in combination with or in sequence with other agents against membrane receptor kinases, particularly for patients who have developed primary or acquired resistance to targeted therapy. These therapeutic agents include inhibitors or antibodies against EGFR, Her2, VEGFR, c-Met, Ret, IGFR1, PDGFR, FGFR1, FGFR2, FGFR3, FGFR4, TrkA, TrkB, TrkC, ROS, c-Kit, or Flt-3, as well as inhibitors or antibodies against cancer-related fusion protein kinases such as Bcr-Abl and EML4-Alk. Examples of inhibitors against EGFR include gefitinib and erlotinib, and examples of inhibitors against EGFR / Her2 include, but are not limited to, dacomitinib, afatinib, rapitinib, and neratinib. Examples of antibodies against EGFR include, but are not limited to, cetuximab, panitumumab, and nesitumumab. c-Met inhibitors can be used in combination with TAM inhibitors. These include onaltumuzumab, tivantinib, and INC-280. Drugs for FGFR include, but are not limited to, AZD4547, BAY1187982, ARQ087, BGJ398, BIBF1120, TKI258, lucitanib, dovitinib, TAS-120, JNJ-42756493, and Debio1347. Drugs for Trk include, but are not limited to, LOXO-101 and RXDX-101. Drugs for Ab1 (or Bcr-Ab1) include imatinib, dasatinib, nilotinib, and ponatinib, and a drug for Alk (or EML4-ALK) is crizotinib.

[0274] Angiogenesis inhibitors may be effective in combination with TAM inhibitors in some tumors. These include antibodies against VEGF or VEGFR, or VEGFR kinase inhibitors. Examples of antibodies against VEGF or other therapeutic proteins include bevacizumab and aflibercept. Examples of VEGFR kinase inhibitors and other anti-angiogenic inhibitors include, but are not limited to, sunitinib, sorafenib, axitinib, sediranib, pazopanib, regorafenib, brivanib, and vandetanib.

[0275] Activation of intracellular signaling pathways frequently occurs in cancer, and drugs targeting components of these pathways are combined with receptor targeters to enhance efficacy and reduce resistance. Examples of drugs that may be combined with the compounds of this disclosure include inhibitors of the PI3K-AKT-mTOR pathway, Raf-MAPK pathway, JAK-STAT pathway, Pim kinase, and inhibitors of protein chaperones and cell cycle progression.

[0276] Examples of PI3 kinase inhibitors include, but are not limited to, piralalisib, idelalisib, buparlisib, and IPI-549. In some embodiments, the PI3K inhibitor is selective for PI3K alpha, PI3K beta, PI3K gamma, or PI3K delta. Inhibitors of mTOR, such as rapamycin, sirolimus, temsirolimus, and everolimus, may be combined with TAM kinase inhibitors. Other suitable examples include, but are not limited to, vemurafenib and dabrafenib (Raf inhibitors), as well as trametinib, selumetinib, and GDC-0973 (MEK inhibitors). Inhibitors of one or more JAKs (e.g., ruxolitinib, baricitinib, tofacitinib), Hsp90 (e.g., tanespimycin), cyclin-dependent kinases (e.g., palbociclib), PARP (e.g., olaparib), and proteasomes (e.g., bortezomib, carfilzomib) can also be combined with the compounds of this disclosure. In some embodiments, the JAK inhibitors are selective for JAK1 rather than for JAK2 and JAK3. Examples of agents targeting Pim kinase include, but are not limited to, LGH447, INCB053914, and SGI-1776.

[0277] Other agents suitable for use in combination with the compounds disclosed herein include combinations of chemotherapy, such as platinum-based doublets (cisplatin or carboplatin plus gemcitabine, cisplatin or carboplatin plus docetaxel, cisplatin or carboplatin plus paclitaxel, cisplatin or carboplatin plus pemetrexed) or gemcitabine plus paclitaxel-bound particles (Abraxane®) used for lung cancer and other solid tumors.

[0278] Suitable chemotherapeutic agents or other anticancer agents include, for example, alkylating agents (without limitation, including nitrogen mustard, ethyleneimine derivatives, alkyl sulfonates, nitrosoureas, and triazenes), such as uracil mustard, chlormethine, cyclophosphamide (Cytoxan®), ifosphamide, melphalan, chlorambucil, pipobromane, triethylenemelamine, triethylenethiophosphoramine, busulfan, carmustine, lomustine, streptozocin, dacarbazine, and temozolomide.

[0279] Other agents suitable for use in combination with the compounds disclosed herein include: dacarbazine (DTIC) optionally used in combination with other chemotherapeutic agents such as carmustine (BCNU) and cisplatin; the "Dartmouth regimen" consisting of DTIC, BCNU, cisplatin, and tamoxifen; a combination of cisplatin, vinblastine, and DTIC; or temozolomide. The compounds provided herein can also be used in combination with immunotherapeutic agents including cytokines such as interferon alpha, interleukin-2, and tumor necrosis factor (TNF) inhibitors.

[0280] Suitable chemotherapeutic agents or other anticancer agents include, for example, antimetabolites (without limitation, including folate antagonists, pyrimidine analogs, purine analogs, and adenosine deaminase inhibitors), such as methotrexate, 5-fluorouracil, phloxuridine, cytarabine, 6-mercaptopurine, 6-thioguanine, fludarabine phosphate, pentostatin, and gemcitabine.

[0281] Appropriate chemotherapeutic agents or other anticancer agents include, for example, certain natural products and their derivatives (e.g., vinca alkaloids, antitumor antibiotics, enzymes, lymphokines, and epipodophyllotoxins), such as vinblastine, vincristine, vindesine, bleomycin, dactinomycin, daunorubicin, doxorubicin, epirubicin, idarubicin, ara-C, paclitaxel (TAXOL®), mitramycin, deoxycoformycin, mitomycin-C, L-asparaginase, interferon (especially IFN-α), etoposide, and teniposide.

[0282] Other cytotoxic substances include navelbine, CPT-11, anastrozole, letrozole, capecitabine, reloxafine, cyclophosphamide, ifosphamide, and droloxafine.

[0283] Similarly appropriate are cytotoxic drugs, such as epipodophyllotoxin, antitumor enzymes, topoisomerase inhibitors, procarbazine, mitoxantrone, platinum-coordinate compounds, such as cisplatin and carboplatin, bioreaction modifiers, growth inhibitors, antihormone agents, leucovorin, tegafur, and hematopoietic growth factors.

[0284] Other anticancer drugs (multiple options are possible) include antibody therapies, such as antibodies against costimulatory molecules like trastuzumab (Herceptin), CTLA-4, 4-1BB, and PD-1, or antibodies against cytokines (IL-10, TGF-β, etc.).

[0285] Other anticancer drugs include CSF1R inhibitors (such as PLX3397 and LY3022855) and CSF1R antibodies (such as IMC-CS4 and RG7155).

[0286] Other anticancer drugs include BET inhibitors (INCB054329, OTX015, CPI-0610, etc.), LSD1 inhibitors (GSK2979552, INCB059872, etc.), HDAC inhibitors (panobinostat, vorinostat, etc.), DNA methyltransferase inhibitors (azacitidine and decitabine), and other epigenetic modulators.

[0287] Other anticancer drugs include the Bcl2 inhibitor ABT-199 and other Bcl-2 family protein inhibitors.

[0288] Other anticancer drugs include TGF beta receptor kinase inhibitors such as LY2157299.

[0289] Other anticancer drugs include BTK inhibitors such as ibrutinib.

[0290] Other anticancer drugs include beta-catenin pathway inhibitors, Notch pathway inhibitors, and Hedgehog pathway inhibitors.

[0291] Other anticancer agents include inhibitors of kinases associated with proliferative disorders. These kinases include, but are not limited to, Aurora kinase A, CDK1, CDK2, CDK3, CDK5, CDK7, CDK8, CDK9, ephrin receptor kinase, CHK1, CHK2, SRC, Yes, Fyn, Lck, Fer, Fes, Syk, Itk, Bmx, GSK3, JNK, PAK1, PAK2, PAK3, PAK4, PDK1, PKA, PKC, Rsk, and SGK.

[0292] Other anticancer agents include those that suppress the migration of immune cells, such as chemokine receptor antagonists, including CCR2 and CCR4.

[0293] Other anticancer agents include those that enhance the immune system, such as adjuvants and adoptive T-cell transplantation.

[0294] Examples of anti-cancer vaccines include dendritic cell-based vaccines, synthetic peptide vaccines, DNA vaccines, and recombinant viruses.

[0295] One or more additional immune checkpoint inhibitors may be used in combination with the compounds described herein for the treatment of TAM-related diseases, disorders, or conditions. Exemplary immune checkpoint inhibitors include inhibitors of immune checkpoint molecules such as CD27, CD28, CD40, CD122, CD96, CD73, CD47, OX40, GITR, CSF1R, JAK, PI3K delta, PI3K gamma, TAM, arginase, CD137 (also known as 4-1BB), ICOS, A2AR, B7-H3, B7-H4, BTLA, CTLA-4, LAG3, TIM3, VISTA, CD96, TIGIT, PD-1, PD-L1, and PD-L2. In some embodiments, the immune checkpoint molecule is a stimulant checkpoint molecule selected from CD27, CD28, CD40, ICOS, OX40, GITR, and CD137. In some embodiments, the immune checkpoint molecule is an inhibitory checkpoint molecule selected from A2AR, B7-H3, B7-H4, BTLA, CTLA-4, IDO, KIR, LAG3, PD-1, TIM3, CD96, TIGIT, and VISTA. In some embodiments, the compounds provided herein can be used in combination with one or more agents selected from KIR inhibitors, TIGIT inhibitors, LAIR1 inhibitors, CD160 inhibitors, 2B4 inhibitors, and TGFR beta inhibitors.

[0296] In some embodiments, the inhibitor of the immune checkpoint molecule is an anti-PD1 antibody, an anti-PD-L1 antibody, or an anti-CTLA-4 antibody.

[0297] In some embodiments, the inhibitor of the immune checkpoint molecule is a PD-1 inhibitor, such as an anti-PD-1 monoclonal antibody. In some embodiments, the anti-PD-1 monoclonal antibody is nivolumab, pembrolizumab (also known as MK-3475), pidilizumab, SHR-1210, PDR001, or AMP-224. In some embodiments, the anti-PD-1 monoclonal antibody is nivolumab, pembrolizumab, or PDR001. In some embodiments, the anti-PD1 antibody is pembrolizumab.

[0298] In some embodiments, the inhibitor of the immune checkpoint molecule is a PD-L1 inhibitor, such as an anti-PD-L1 monoclonal antibody. In some embodiments, the anti-PD-L1 monoclonal antibody is BMS-935559, MEDI4736, MPDL3280A (also known as RG7446), or MSB0010718C. In some embodiments, the anti-PD-L1 monoclonal antibody is MPDL3280A (atezolizumab) or MEDI4736 (durvalumab).

[0299] In some embodiments, the inhibitor of the immune checkpoint molecule is an inhibitor of CTLA-4, for example, an anti-CTLA-4 antibody. In some embodiments, the anti-CTLA-4 antibody is ipilimumab or tremelimumab.

[0300] In some embodiments, the inhibitor of the immune checkpoint molecule is an inhibitor of LAG3, for example, an anti-LAG3 antibody. In some embodiments, the anti-LAG3 antibody is BMS-986016 or LAG525.

[0301] In some embodiments, the inhibitor of the immune checkpoint molecule is an inhibitor of GITR, such as an anti-GITR antibody. In some embodiments, the anti-GITR antibody is TRX518, MK-4166, INCAGN01876, or MK-1248.

[0302] In some embodiments, the inhibitor of the immune checkpoint molecule is an inhibitor of OX40, such as an anti-OX40 antibody or an OX40L fusion protein. In some embodiments, the anti-OX40 antibody is MEDI0562, INCAGN01949, GSK2831781, GSK-3174998, MOXR-0916, PF-04518600, or LAG525. In some embodiments, the OX40L fusion protein is MEDI6383.

[0303] In some embodiments, the inhibitor of the immune checkpoint molecule is a CD20 inhibitor, such as an anti-CD20 antibody. In some embodiments, the anti-CD20 antibody is obinutuzumab or rituximab.

[0304] The compounds of this disclosure can be used in combination with bispecific antibodies. In some embodiments, one of the domains of the bispecific antibody targets PD-1, PD-L1, CTLA-4, GITR, OX40, TIM3, LAG3, CD137, ICOS, CD3, or the TGFβ receptor.

[0305] The compounds of this disclosure can be used in combination with one or more agents for the treatment of diseases such as cancer. In some embodiments, the agent is an alkylating agent, a proteasome inhibitor, a corticosteroid, or an immunomodulator. Examples of alkylating agents include cyclophosphamide (CY), melphalan (MEL), and bendamustine. In some embodiments, the proteasome inhibitor is carfilzomib. In some embodiments, the corticosteroid is dexamethasone (DEX). In some embodiments, the immunomodulator is lenalidomide (LEN) or pomalidomide (POM).

[0306] The compounds of this disclosure can be combined with other immunosuppressants, such as cancer cells, purified tumor antigens (including recombinant proteins, peptides, and carbohydrate molecules), cells, and cells transfected with genes encoding immunostimulatory cytokines. Non-limiting examples of tumor vaccines that may be used include melanoma antigen peptides, such as gp100, MAGE antigen, Trp-2, MARTI, and / or tyrosinase peptides, or tumor cells transfected to express the cytokine GM-CSF.

[0307] The compounds of this disclosure can be used in combination with vaccination protocols for the treatment of cancer. In some embodiments, tumor cells are transduced to express GM-CSF. In some embodiments, tumor vaccines include proteins derived from viruses involved in human cancer, such as human papillomavirus (HPV), hepatitis viruses (HBV and HCV), and Kaposi's sarcoma-associated herpesvirus (KHSV). In some embodiments, the compounds of this disclosure can be used in combination with tumor-specific antigens, such as heat shock proteins isolated from tumor tissue itself. In some embodiments, the compounds of this disclosure can be combined with dendritic cell immunization to activate a potent antitumor response.

[0308] The compounds of this disclosure can be used in combination with bispecific macrocyclic peptides that target Fc-alpha or Fc-gamma receptor-expressing effector cells to tumor cells. The compounds of this disclosure can also be combined with macrocyclic peptides that activate the host immune response.

[0309] The compounds of this disclosure can be used in combination with arginase inhibitors, such as CB-1158.

[0310] The compounds of this disclosure can be used in combination with bone marrow transplantation for the treatment of various tumors of hematopoietic origin.

[0311] The compounds of this disclosure can be used as anticoagulants, either alone or in combination with other anticoagulants, including but not limited to apixaban, dabigatran, edoxaban, fondaparinex, heparin, rivaroxaban, and warfarin.

[0312] Methods for the safe and effective administration of most of these chemotherapeutic agents are known to those skilled in the art. Furthermore, their administrations are described in standard literature. For example, many administrations of these chemotherapeutic agents are described in the “Physicians’ Desk Reference” (PDR, e.g., 1996 edition, Medical Economics Company, Montvale, NJ), and its disclosure is incorporated herein by reference as if it were described in its entirety.

[0313] Pharmaceutical preparations and drug administration methods When used as pharmaceuticals, the compounds provided herein may be administered in the form of pharmaceutical compositions, which refer to a combination of the compounds provided herein, or pharmaceutically acceptable salts thereof, and at least one pharmaceutically acceptable carrier. These compositions can be prepared in methods well known in the field of compounding and may be administered by various routes, depending on whether topical or systemic treatment is required and on the site of treatment. Administration may be topical (ophthalmic, as well as to mucous membranes, including nasal, transvaginal, and rectal delivery, etc.), pulmonary (e.g., by nebulizer, inhalation or insufflation of powder or aerosol; intratracheal, nasal, epidermal, and transdermal), intraocular, oral, or parenteral. Methods for intraocular delivery include topical administration (eye drops), intravitreal injection or induction via balloon catheter or ocular implant surgically placed subconjunctival, periorbital, or in the conjunctival sac. Parenteral administration may include intravenous, intra-arterial, subcutaneous, intraperitoneal, or intramuscular injection or infusion, or intracranial administration, such as intrathecal or intraventricular. Parenteral administration may be in the form of a single bolus or, for example, by a continuous infusion pump. Pharmaceutical compositions and formulations for topical administration may include transdermal patches, ointments, lotions, creams, gels, drops, suppositories, sprays, liquids, and powders. Conventional pharmaceutical carriers, aqueous, powder, or oily bases, thickeners, etc., may be necessary or desirable.

[0314] This application also includes pharmaceutical compositions comprising one or more of the compounds provided herein as active ingredients in combination with one or more pharmaceutically acceptable carriers. In the preparation of the compositions of this disclosure, the active ingredient is typically mixed with an excipient, diluted with an excipient, or encapsulated in a carrier such as a capsule, pouch, paper, or other container. If the excipient acts as a diluent, it may be a solid, semi-solid, or liquid material and function as a medium, carrier, or solvent for the active ingredient. Accordingly, the composition may be in the form of tablets, pills, powders, medicinal candies, pouches, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as solid or in a liquid medium), for example, ointments, soft and hard gelatin capsules, suppositories, sterile injection solutions, and sterile packaged powders containing up to 10% by weight of the active compound.

[0315] In the preparation of the formulation, the active compound may be ground to an appropriate particle size before being mixed with other components. If the active compound is substantially insoluble, it may be ground to a particle size of less than 200 mesh. If the active compound is substantially water-soluble, the particle size may be adjusted to, for example, about 40 mesh by grinding to give a substantially uniform distribution in the formulation.

[0316] Some examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starch, acacia gum, calcium phosphate, alginate, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, and methylcellulose. The formulation may further include lubricants, such as talc, magnesium stearate, and mineral oil, humectants, emulsifiers and suspending agents, preservatives, such as methyl and propyl hydroxybenzoates, sweeteners, and flavorings. The compositions of this disclosure may be formulated to result in immediate, sustained, or delayed release of the active ingredient after administration to a patient using procedures known in the art.

[0317] The composition can be formulated into unit dosage forms, each formulation containing approximately 5 to approximately 100 mg, more generally, approximately 10 to approximately 30 mg, of the active ingredient. The term "unit dosage form" refers to physically separate units suitable as single formulations for human subjects and other mammals, each unit containing a predetermined amount of the active ingredient calculated to obtain the desired therapeutic effect in combination with appropriate pharmaceutical excipients.

[0318] The active compound may be effective across a broad dose range, but is usually administered in a pharmaceutically effective dose. However, it should be understood that the actual amount of the compound administered will usually be determined by a physician, depending on relevant circumstances including the condition to be treated, the chosen route of administration, the compound actually administered, the individual patient's age, weight, and response, and the severity of the patient's symptoms.

[0319] For the preparation of solid compositions such as tablets, the main active ingredient is mixed with a pharmaceutical excipient to form a solid pre-formulation composition containing a homogeneous mixture of the compound of the Disclosure. When these pre-formulation compositions are referred to as homogeneous, the active ingredient is usually uniformly dispersed throughout the composition so that the composition can be easily divided into equally effective unit dosage forms, such as tablets, pills, and capsules. This solid pre-formulation is then divided into the above-described unit dosage forms, for example, containing 0.1 to about 500 mg of the active ingredient of the Disclosure.

[0320] The tablets or pills of this disclosure may be coated or otherwise formulated to provide a dosage form that offers the advantage of sustained action. For example, the tablets or pills may contain an inner and an outer component, the latter forming the outer coating of the former. The two components may be separated by an enteric coating that withstands disintegration in the stomach and serves to allow the inner component to enter the duodenum intact, or to delay the release of the inner component. Various substances can be used for such enteric coatings or coatings, including several polymer acids and mixtures of polymer acids with substances such as shellac, cetyl alcohol, and cellulose acetate.

[0321] Liquid forms in which the compounds and compositions of this disclosure may be incorporated for oral or injectable administration include aqueous solutions, appropriately flavored syrups, aqueous or oily suspensions, and flavored emulsions containing edible oils, such as cottonseed oil, sesame oil, coconut oil, or peanut oil, as well as elixirs and similar pharmaceutical solvents.

[0322] Compositions for inhalation or inhalation include pharmaceutically acceptable aqueous or organic solvents, or mixtures thereof, solutions and suspensions, and powders. The liquid or solid composition may contain suitable pharmaceutically acceptable excipients as described above. In some embodiments, the composition is administered orally or nasally for topical or systemic effects. The composition may be sprayed using an inert gas. The sprayed solution may be inhaled directly from a spraying device, or the spraying device may be attached to a face mask tent or an intermittent positive pressure respirator. The solution, suspension, or powder composition may be administered orally or nasally from a device that delivers the formulation in an appropriate manner.

[0323] The amount of compound or composition administered to a patient will vary depending on what is being administered, the purpose of administration (e.g., prevention or treatment), the patient's condition, and the method of administration. For therapeutic purposes, a composition may be administered to a patient already suffering from a disease in an amount sufficient to cure or at least partially halt the symptoms of the disease and its complications. The effective dose will be determined by the attending clinician based on the condition being treated, the severity of the disease, the patient's age, weight, and overall health, and other relevant factors.

[0324] The composition administered to the patient may be in the form of the pharmaceutical composition described above. These compositions can be sterilized by conventional sterilization techniques or by filtration sterilization. The aqueous solution may be packaged for use as is or lyophilized, but the lyophilized formulation is mixed with a sterile aqueous carrier before administration. The pH of the compound formulation is usually between 3 and 11, more preferably between 5 and 9, and most preferably between 7 and 8. It will be understood that the use of certain excipients, carriers, or stabilizers described above will result in the formation of a drug salt.

[0325] The therapeutic doses of the compounds disclosed herein may vary depending, for example, the specific use in which the treatment is performed, the method of administration of the compound, the patient's health and condition, and the judgment of the prescribing physician. The ratio or concentration of the compounds provided herein in pharmaceutical compositions may vary depending on several factors, including the dose, chemical properties (e.g., hydrophobicity), and route of administration. For example, for parenteral administration, the compounds provided herein may be provided in aqueous physiological buffer containing about 0.1 to about 10% w / v of the compound. Some typical dose ranges are about 1 μg / kg to about 1 g / kg of body weight per day. In some embodiments, the dose range is about 0.01 mg / kg to about 100 mg / kg of body weight per day. The dose is likely to depend on variable factors such as the type and progression of the disease or disorder, the overall health status of the individual patient, the relative biological efficiency of the selected compound, the formulation of excipients, and its route of administration. The effective dose may be estimated from dose-response curves obtained from in vitro or animal model testing systems.

[0326] The compounds provided herein can also be formulated in combination with one or more additional active ingredients, such as any pharmaceutical product, for example, an antiviral agent, a vaccine, an antibody, an immunostimulant, an immunosuppressant, an anti-inflammatory agent, and the like.

[0327] Labeled compounds and assay methods Another aspect of this disclosure relates to compounds provided herein that are labeled with fluorescent dyes, spin-labeled, heavy metal-labeled, or radioactively labeled, which are useful for locating and quantifying TAM kinases in tissue samples, including human samples, as well as in imaging and assays both in vitro and in vivo, and for identifying ligands for TAM kinases by inhibitory binding of the labeled compounds. Accordingly, this disclosure includes TAM kinase assays comprising such labeled compounds.

[0328] This disclosure further includes isotope-labeled compounds of the present invention. An “isotope” or “radio-labeled” compound is a compound provided herein in which one or more atoms are replaced or substituted with atoms having atomic masses or mass numbers different from those commonly found in nature (i.e., naturally occurring atomic masses or mass numbers). Suitable radionuclides that may be incorporated into the compounds of this disclosure include: 2 H (also written as D for Deuterium), 3 H (also written as T for tritium), 11 C, 13 C, 14 C, 13 N, 15 N, 15 O, 17 O, 18 O, 18 F, 35 S, 36 Cl, 82 Br, 75 Br, 76 Br, 77 Br, 123 I, 124 I, 125 I, and 131 I is one example, but is not limited to these. The radionuclide incorporated into the radiolabeled compound depends on the specific application of the radiolabeled compound. For example, for in vitro TAM kinase labeling and competitive assays, 3 H, 14 C, 82 Br, 125 I, 131 I, or 35 Compounds incorporating sulfur (S) are generally the most useful. For imaging applications using radioactive materials,11 C, 18 F, 125 I, 123 I, 124 I, 131 I, 75 Br, 76 Br, or 77 Br will generally be the most useful.

[0329] "Radioactive label" or "labeled compound" is understood to be a compound into which at least one radionuclide has been introduced. In some embodiments, the radionuclide is 3 H, 14 C, 125 I, 35 S, and 82 Selected from the group consisting of Br.

[0330] Synthetic methods for incorporating radioactive isotopes into organic compounds are applicable to the compounds provided herein and are well known in the art.

[0331] The radiolabeled compounds provided herein can be used in screening tests for the identification / evaluation of compounds. Generally, newly synthesized or identified compounds (i.e., test compounds) can be evaluated for their ability to reduce the binding of the radiolabeled compounds of this application to TAM kinase. Thus, the ability of the test compound to compete with the radiolabeled compound for binding to TAM kinase is directly correlated with its binding affinity.

[0332] The compounds of the present invention may also contain all isotopes of an atom that occurs in an intermediate or final compound. Isotopes include atoms with the same atomic number but different mass numbers. For example, isotopes of hydrogen include tritium and deuterium. One or more constituent atoms of the compounds of the present invention may be replaced or substituted with isotopes of that atom in natural or unnatural abundance. In some embodiments, the compound contains at least one deuterium atom. For example, one or more hydrogen atoms in the compounds of the present disclosure may be replaced or substituted with deuterium. In some embodiments, the compound contains two or more deuterium atoms. In some embodiments, the compound contains one, two, three, four, five, six, seven, or eight deuterium atoms. Synthetic methods for incorporating isotopes into organic compounds are known in the art.

[0333] kit This disclosure also includes, for example, a pharmaceutical kit useful for the treatment or prevention of TAM-related diseases or disorders, obesity, diabetes, and other diseases referred to herein, which comprises one or more containers containing a pharmaceutical composition comprising a therapeutically effective amount of the compounds provided herein. Such a kit may further, optionally, include one or more components of various conventional pharmaceutical kits, for example, a container with one or more pharmaceutically acceptable carriers, additional containers, etc., as will be readily apparent to those skilled in the art. Instructions for use indicating the amount of the component to be administered, guidelines for administration, and / or guidelines for mixing the components may also be included in the kit, either as an insert or as a label.

[0334] The present invention will be described in more detail through specific examples. The following examples are provided for illustrative purposes only and are not intended to limit the invention in any way. Those skilled in the art will readily recognize various non-deterministic parameters that can be changed or modified to obtain essentially the same results. The compounds of the examples were found to be inhibitors of TAM kinase, as described below.

[0335] Some of the prepared compounds were purified by preparative LC-MS using a Waters mass spectrometry fractionation system. The basic equipment setup, protocols, and control software for operating these systems are described in detail in the literature. See, for example, “Two-Pump At Column Dilution Configuration for Preparative LC-MS”, K. Blom, J. Combi. Chem., 4, 295 (2002); “Optimizing Preparative LC-MS Configurations and Methods for Parallel Synthesis Purification”, K. Blom, R. Sparks, J. Doughty, G. Everlof, T. Haque, A. Combs, J. Combi. Chem., 5, 670 (2003); and “Preparative LC-MS Purification: Improved Compound Specific Method Optimization”, K. Blom, B. Glass, R. Sparks, A. Combs, J. Combi. Chem., 6, 874-883 (2004). The separated compounds were typically subjected to analytical liquid chromatography-mass spectrometry (LC / MS) to confirm their purity under the following conditions: Instrument: Agilent 1100 series, LC / MSD; Column: Waters Sunfire® C 18 Particle size 5 μm, 2.1 × 5.0 mm, buffer: mobile phase A: 0.025% TFA aqueous solution and mobile phase B: acetonitrile, gradient of B from 2% to 80% over 3 minutes, flow rate 2.0 mL / min.

[0336] Some of the prepared compounds were also separated on a preparative scale by reversed-phase high-performance liquid chromatography (RP-HPLC) with an MS detector or by flash chromatography (silica gel), as shown in the examples. Typical preparative reversed-phase high-performance liquid chromatography (RP-HPLC) column conditions are as follows:

[0337] Purification at pH=2: Waters Sunfire (trademark) C 18A 5 μm particle size, 19 × 100 mm column was used. Elution was performed with mobile phase A: 0.1% TFA (trifluoroacetic acid) aqueous solution and mobile phase B: acetonitrile. The flow rate was 30 mL / min. The separation gradient was optimized for each compound using the Compound Specific Method Optimization protocol as described in the literature [see "Preparative LCMS Purification: Improved Compound Specific Method Optimization", K. Blom, B. Glass, R. Sparks, A. Combs, J. Comb. Chem., 6, 874-883 (2004)]. Typically, a flow rate of 60 mL / min was used with a 30 × 100 mm column.

[0338] Purification at pH=10: Waters XBridge C 18 A 5 μm particle size, 19 × 100 mm column was used, with elution using mobile phase A: 0.15% NH4OH aqueous solution and mobile phase B: acetonitrile. The flow rate was 30 mL / min, and the separation gradient was optimized for each compound using the Compound Specific Method Optimization protocol as described in the literature [see "Preparative LCMS Purification: Improved Compound Specific Method Optimization", K. Blom, B. Glass, R. Sparks, A. Combs, J. Comb. Chem., 6, 874-883 (2004)]. Typically, a flow rate of 60 mL / min was used with a 30 × 100 mm column. [Examples]

[0339] Example 1. N-[4-(4-amino-7-ethylpyrrolo[2,1-f][1,2,4]triazine-5-yl)phenyl]-1-(4-fluorophenyl)-2,5-dioxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide [ka] Step 1: N-[(2,6-dioxocyclohexylidene)methyl]urea [ka] A mixture of 1,3-cyclohexanedione (Aldrich, 500 mg, 4.46 mmol) and urea (268 mg, 4.46 mmol) dissolved in N,N-dimethylformamide (1.73 mL, 50°C) was mixed with ethyl orthoformate (1.11 mL, 6.69 mmol) and acetic acid (8.9 mL). This reaction mixture was heated in a sealed tube at 90°C for 3 hours. The reaction mixture was cooled, concentrated under vacuum, and allowed to crystallize at room temperature. The resulting precipitate was filtered under vacuum, and the cake was washed with cold sec-BuOH to obtain the desired product as an off-white powder (536 mg, 66%). LCMS C8H 11 N2O3(M+H) + Calculated value for m / z: 183.1. Measured value: 183.1.

[0340] Step 2: Methyl 2,5-dioxo-5,6,7,8-tetrahydro-2H-chromene-3-carboxylate [ka] N-[(2,6-dioxocyclohexylidene)methyl]urea (50 mg, 0.27 mmol) was dissolved in dry N,N-dimethylformamide (0.54 mL), and then cyanomethyl acetate (35.4 mg, 0.36 mmol) and potassium tert-butoxide (61.6 mg, 0.55 mmol) were added while stirring. This reaction mixture was heated at 100°C for 1 hour. After filtration and solvent removal, an oily residue (70 mg) was obtained as the desired product. This crude product was used directly in the next step without further purification. LCMS C 11 H 11 O5(M+H) + Calculated value for m / z: 223.1. Measured value: 223.1.

[0341] Step 3: Methyl 1-(4-fluorophenyl)-2,5-dioxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxylate [ka] To a solution of methyl 2,5-dioxo-5,6,7,8-tetrahydro-2H-chromene-3-carboxylate (30 mg, 0.14 mmol) at room temperature in tetrahydrofuran (0.4 mL) and N,N-dimethylformamide (0.1 mL), p-fluoroaniline (15 mg, 0.14 mmol) was added. This reaction mixture was stirred at room temperature for 3 hours, and then N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (34 mg, 0.18 mmol) and 4-dimethylaminopyridine (4.1 mg, 0.034 mmol) were added at room temperature. This reaction mixture was stirred at room temperature for a further 20 hours. After filtration, the crude substance was purified by preparative LC-MS (pH=2 method, Waters SunFire PrepC18 5μm OBD™ column, 30×100mm, 60mL / min, elution with MeCN and 0.1% TFA aqueous solution gradient) to obtain the desired product (12 mg, 28%). LCMS C 17 H 15 FNO4(M+H) + Calculated value for m / z: 316.1. Measured value: 316.1.

[0342] Step 4: 1-(4-fluorophenyl)-2,5-dioxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxylic acid [ka] To a solution of methyl 1-(4-fluorophenyl)-2,5-dioxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxylate (5.0 mg, 0.016 mmol) in methanol (0.10 mL), 1.0 M aqueous sodium hydroxide solution (0.15 mL) was added. The reaction mixture was stirred at room temperature for 30 minutes, and the crude product was neutralized with HCl (1 N) and diluted with HCl. The HCl layer was separated, and the aqueous layer was washed twice with HCl. The combined organic layers were dried and concentrated under vacuum to obtain the desired acid product as an off-white powder. LCMS C 16 H 13 FNO4(M+H) + Calculated value for m / z: 302.1. Measured value: 302.2.

[0343] Step 5: 7-Vinylpyrrolo[2,1-f][1,2,4]triazine-4-amine [ka] In a sealed flask, a mixture of 1,4-dioxane (20 mL) and water (0.97 mL) containing 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (1.52 g, 9.86 mmol from Aldrich), 7-bromopyrrolo[2,1-f][1,2,4]triazine-4-amine (1.50 g, 7.04 mmol from J&W Pharm Lab), and N,N-diisopropylethylamine (3.7 mL, 21 mmol) was stirred and flushed with N2 for 5 minutes, after which bis(tri-t-butylphosphine)palladium (540 mg, 1.0 mmol) was added. The reaction mixture was sealed and heated in an oil bath at 110°C for 60 minutes, filtered through a Celite pad, and concentrated. This crude substance was purified by Biotage silica gel column chromatography (40g column, 0-100% ethyl hexane) to obtain the desired product as a white powder (541mg, 48%). LCMS C8H9N4(M+H) + Calculated value for m / z: 161.1. Measured value: 161.1.

[0344] Step 6: 7-Ethylpyrrolo[2,1-f][1,2,4]triazine-4-amine [ka] A palladium (1.33 g) (5% Pd carbon) mixture was added to a methanol (30 mL) solution of 7-vinylpyrrolo[2,1-f][1,2,4]triazine-4-amine (1.00 g, 6.24 mmol). This reaction mixture was placed in a hydrogen Parr shaker at 25 psi for 2 hours. After filtration through a Celite pad, the filtrate was concentrated under vacuum to obtain the desired product as an off-white powder. LCMS C8H 11 N4(M+H) + Calculated value for m / z: 163.1. Measured value: 163.1.

[0345] Step 7: 5-bromo-7-ethylpyrrolo[2,1-f][1,2,4]triazine-4-amine [ka] To a solution of 7-ethylpyrrolo[2,1-f][1,2,4]triazine-4-amine (600 mg, 3.7 mmol) in N,N-dimethylformamide (16 mL), N-bromosuccinimide (395 mg, 2.22 mmol) was added. The resulting mixture was stirred at room temperature for 30 minutes, diluted with ethylammonium ammonium phosphate, and filtered. The filtrate was washed with saturated NaHCO3 and water, dried over Na2SO4, filtered, and concentrated under vacuum to obtain the desired product as a yellowish-brown solid. LCMS C8H 10 BrN4(M+H) + Calculated values ​​for m / z: 241.0, 243.0. Measured values: 241.0, 243.0.

[0346] Step 8: 5-(4-aminophenyl)-7-ethylpyrrolo[2,1-f][1,2,4]triazine-4-amine [ka] In a sealed tube, a mixture of 1,4-dioxane (3.24 mL) and water (0.30 mL) consisting of 5-bromo-7-ethylpyrrolo[2,1-f][1,2,4]triazine-4-amine (200 mg, 0.83 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (from Aldrich, 236 mg, 1.08 mmol), and N,N-diisopropylethylamine (0.43 mL, 2.5 mmol) was stirred and flushed with N2 for 5 minutes, after which bis(tri-t-butylphosphine)palladium (130 mg, 0.25 mmol) was added. The reaction mixture was sealed and heated in an oil bath at 110°C for 1 hour. After filtration, the crude substance was diluted with MeOH and purified by preparative LC-MS (pH=10 method, XBridge® PrepC18 5μm OBD® column, 30×100mm, 60mL / min, eluted with a gradient of MeCN and 0.15% NH4OH aqueous solution) to obtain the desired product as a light brown powder (88 mg, 42%). LCMS C 14 H 16 N5(M+H) + Calculated value for m / z: 254.1. Measured value: 254.1.

[0347] Step 9: N-[4-(4-amino-7-ethylpyrrolo[2,1-f][1,2,4]triazine-5-yl)phenyl]-1-(4-fluorophenyl)-2,5-dioxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxamide 5-(4-aminophenyl)-7-ethylpyrrolo[2,1-f][1,2,4]triazine-4-amine (3.2 mg, 0.013 mmol), 1-(4-fluorophenyl)-2,5-dioxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxylic acid (4.6 mg, 0.015 mmol) (prepared in Example 1, Step 4), and N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (12 mg, 0.032 mmol) were mixed in N,N-dimethylformamide (0.10 mL) and N,N-diisopropylethylamine (5.0 mg, 0.04 mmol), and stirred at room temperature for 20 minutes. This mixture was filtered, concentrated, and purified by preparative LC-MS (pH=10 method, XBridge® PrepC18 5μm OBD® column, 30×100mm, 60mL / min, eluted with a gradient of MeCN and 0.15% NH4OH aqueous solution) to obtain the desired product as a white powder (1.6 mg, 20%). LCMS C 30 H 26 FN6O3(M+H) + Calculated value for m / z: 537.2. Measured value: 537.2.

[0348] Example 2. N-[4-(4-amino-7-ethylpyrrolo[2,1-f][1,2,4]triazine-5-yl)phenyl]-1-[(1R)-2-hydroxy-1-phenylethyl]-2-oxo-1,2-dihydropyridine-3-carboxamide [ka] Step 1: 1-[(1R)-2-hydroxy-1-phenylethyl]-2-oxo-1,2-dihydropyridine-3-carboxylic acid [ka] Dimethyl[(2E)-3-methoxypropa-2-ene-1-ylidene]malonate (Acros Organics, 0.20 g, 1.00 mmol) was added to methanol (1.8 mL) and mixed with (2R)-2-amino-2-phenylethanol (0.14 g, 1.00 mmol) and N,N-diisopropylethylamine (0.55 mL, 3.2 mmol). The reaction mixture was sealed and stirred at 130°C for 2 hours. Then, this reaction mixture was mixed with a methanol solution of 2.0 M sodium hydroxide (5.0 mL) and a 2.0 M aqueous sodium hydroxide solution (5.0 mL), and stirred continuously at room temperature for 2 hours. The crude mixture was neutralized with HCl (3N) and extracted three times with ethyl acetate. The combined organic layers were dried, filtered, and concentrated under vacuum to obtain the desired product as a light brown viscous substance. LCMS C 14 H 14 NO4(M+H) + Calculated value for m / z: 260.1. Measured value: 260.1.

[0349] Step 2: N-[4-(4-amino-7-ethylpyrrolo[2,1-f][1,2,4]triazine-5-yl)phenyl]-1-[(1R)-2-hydroxy-1-phenylethyl]-2-oxo-1,2-dihydropyridine-3-carboxamide 5-(4-aminophenyl)-7-ethylpyrrolo[2,1-f][1,2,4]triazine-4-amine (3.0 mg, 0.012 mmol) (Prepared in Example HF1, Step 8), 1-[(1R)-2-hydroxy-1-phenylethyl]-2-oxo-1,2-dihydropyridine-3-carboxylic acid (3.6 mg, 0.014 mmol), and N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (11.2 mg, 0.03 mmol) were mixed in N,N-dimethylformamide (0.10 mL) and N,N-diisopropylethylamine (4.6 mg, 0.035 mmol), and stirred at room temperature for 60 minutes. The reaction mixture was filtered, concentrated, and purified by preparative LC-MS (pH=10 method, XBridge® PrepC18 5μm OBD® column, 30×100mm, 60mL / min, eluted with a gradient of MeCN and 0.15% NH4OH aqueous solution) to obtain the desired product as a white powder (2.0 mg, 34%). LCMS C 28 H 27 N6O3(M+H) + Calculated value for m / z: 495.2. Measured value: 495.2.

[0350] Example 3. N-[4-(4-amino-7-ethylpyrrolo[2,1-f][1,2,4]triazine-5-yl)phenyl]-1-[(1R)-2-hydroxy-1-methylethyl]-2-oxo-1,2-dihydropyridine-3-carboxamide [ka] Step 1: 1-[(1R)-2-hydroxy-1-methylethyl]-2-oxo-1,2-dihydropyridine-3-carboxylic acid [ka] Dimethyl[(2E)-3-methoxypropa-2-ene-1-ylidene]malonate (Acros Organics, 200 mg, 1.00 mmol) was added to methanol (1.82 mL) and mixed with (R)-(-)-2-amino-1-propanol (Aldrich, 75.0 mg, 1.00 mmol) and N,N-diisopropylethylamine (0.55 mL, 3.2 mmol). The reaction mixture was sealed and stirred at 130°C for 2 hours. Then, the reaction mixture was mixed with a methanol solution of 2.0 M sodium hydroxide (5.0 mL) and a 2.0 M aqueous sodium hydroxide solution (5.0 mL), and stirred continuously at room temperature for 2 hours. The reaction mixture was acidified with 5.0 mL of HCl (3N), concentrated under vacuum to remove the solvent. The residue was washed with THF and ethyl acetate, dried, filtered, and concentrated under vacuum to obtain the desired product as an off-white powder. LCMS C9H 12 NO4(M+H) + Calculated value for m / z: 198.1. Measured value: 198.1.

[0351] Step 2: N-[4-(4-amino-7-ethylpyrrolo[2,1-f][1,2,4]triazine-5-yl)phenyl]-1-[(1R)-2-hydroxy-1-methylethyl]-2-oxo-1,2-dihydropyridine-3-carboxamide 5-(4-aminophenyl)-7-ethylpyrrolo[2,1-f][1,2,4]triazine-4-amine (5.0 mg, 0.020 mmol) (Prepared in Example HF1, Step 8), 1-[(1R)-2-hydroxy-1-methylethyl]-2-oxo-1,2-dihydropyridine-3-carboxylic acid (4.7 mg, 0.024 mmol), and N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (18.8 mg, 0.05 mmol) were mixed in N,N-dimethylformamide (0.1 mL) and N,N-diisopropylethylamine (7.7 mg, 0.06 mmol), and stirred at room temperature for 30 minutes. This mixture was filtered, concentrated, and purified by preparative LC-MS (pH=10 method, XBridge® PrepC18 5μm OBD® column, 30×100mm, 60mL / min, eluted with a gradient of MeCN and 0.15% NH4OH aqueous solution) to obtain the desired product as a white powder (2.0 mg, 23%). LCMS C 23 H 25 N6O3(M+H) + Calculated value for m / z: 433.2. Measured value: 433.2.

[0352] Example 4. N-[4-(4-amino-7-ethylpyrrolo[2,1-f][1,2,4]triazine-5-yl)phenyl]-1-[(1R)-1-(hydroxymethyl)propyl]-2-oxo-1,2-dihydropyridine-3-carboxamide [ka] Step 1: 1-[(1R)-1-(hydroxymethyl)propyl]-2-oxo-1,2-dihydropyridine-3-carboxylic acid [ka] Dimethyl[(2E)-3-methoxypropa-2-ene-1-ylidene]malonate (Acros Organics, 200 mg, 1.00 mmol) was added to methanol (1.82 mL) and mixed with (2R)-2-aminobutan-1-ol (89.0 mg, 1.00 mmol) and N,N-diisopropylethylamine (0.55 mL, 3.2 mmol). The reaction mixture was sealed and stirred at 130°C for 2 hours. Then, the reaction mixture was mixed with a methanol solution of 2.0 M sodium hydroxide (5.0 mL) and a 2.0 M aqueous sodium hydroxide solution (5.0 mL), and stirred continuously at room temperature for 1 hour. The reaction mixture was acidified with 5.0 mL of HCl (3N), concentrated under vacuum to remove the solvent. The residue was washed with THF and Â, dried, filtered, and concentrated under vacuum to obtain the desired product as an off-white powder. LCMS C 10 H 14 NO4(M+H) + Calculated value for m / z: 212.1. Measured value: 212.1.

[0353] Step 2: N-[4-(4-amino-7-ethylpyrrolo[2,1-f][1,2,4]triazine-5-yl)phenyl]-1-[(1R)-1-(hydroxymethyl)propyl]-2-oxo-1,2-dihydropyridine-3-carboxamide 5-(4-aminophenyl)-7-ethylpyrrolo[2,1-f][1,2,4]triazine-4-amine (5.0 mg, 0.020 mmol) (Prepared in Example HF1, Step 8), 1-[(1R)-1-(hydroxymethyl)propyl]-2-oxo-1,2-dihydropyridine-3-carboxylic acid (5.0 mg, 0.024 mmol), and N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (18.8 mg, 0.049 mmol) were mixed in N,N-dimethylformamide (0.1 mL) and N,N-diisopropylethylamine (7.7 mg, 0.06 mmol), and stirred at room temperature for 30 minutes. The reaction mixture was filtered, concentrated, and purified by preparative LC-MS (pH=10 method, XBridge® PrepC18 5μm OBD® column, 30×100mm, 60mL / min, eluted with a gradient of MeCN and 0.15% NH4OH aqueous solution) to obtain the desired product as a white powder (1.7 mg, 19%). LCMS C 24 H 27 N6O3(M+H) + Calculated value for m / z: 447.2. Measured value: 447.2.

[0354] Example 5. N-[4-(4-amino-7-ethylpyrrolo[2,1-f][1,2,4]triazine-5-yl)phenyl]-1-benzyl-2-oxo-1,2-dihydropyridine-3-carboxamide [ka] 5-(4-aminophenyl)-7-ethylpyrrolo[2,1-f][1,2,4]triazine-4-amine (4.6 mg, 0.02 mmol) (prepared in Example 1, Step 8), 1-benzyl-2-oxo-1,2-dihydropyridine-3-carboxylic acid (from Aurum Pharmatech, 5 mg, 0.02 mmol), and N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (17.3 mg, 0.05 mmol) were mixed in N,N-dimethylformamide (0.1 mL) and N,N-diisopropylethylamine (7 mg, 0.05 mmol) and stirred at room temperature for 30 minutes. The reaction mixture was filtered, concentrated, and purified by preparative LC-MS (pH=10 method, XBridge® PrepC18 5μm OBD® column, 30×100mm, 60mL / min, eluted with a gradient of MeCN and 0.15% NH4OH aqueous solution) to obtain the desired product as a white powder (2.4 mg, 28%). LCMS C 27 H 25 N6O2(M+H) + Calculated value for m / z: 465.2. Measured value: 465.2.

[0355] Example 6. N-[4-(4-amino-7-ethylpyrrolo[2,1-f][1,2,4]triazine-5-yl)phenyl]-1-methyl-2-oxo-1,2-dihydropyridine-3-carboxamide [ka] 5-(4-aminophenyl)-7-ethylpyrrolo[2,1-f][1,2,4]triazine-4-amine (4 mg, 0.02 mmol) (prepared in Example 1, Step 8), 1-methyl-2-oxo-1,2-dihydropyridine-3-carboxylic acid (from Synthonix, 2.9 mg, 0.02 mmol), and N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (12 mg, 0.03 mmol) were mixed in N,N-dimethylformamide (0.1 mL) and triethylamine (4.8 mg, 0.05 mmol), and stirred at room temperature for 30 minutes. The reaction mixture was filtered, concentrated, and purified by preparative LC-MS (pH=10 method, XBridge® PrepC18 5μm OBD® column, 30×100mm, 60mL / min, eluted with a gradient of MeCN and 0.15% NH4OH aqueous solution) to obtain the desired product as a white powder (1.6 mg, 26%). LCMS C 21 H 21 N6O2(M+H) + Calculated value for m / z: 389.2. Measured value: 389.2.

[0356] Example 7a. N-{4-[4-amino-7-(cis-4-hydroxycyclohexyl)pyrrolo[2,1-f][1,2,4]triazine-5-yl]phenyl}-2-oxo-1-phenyl-1,2-dihydropyridine-3-carboxamide Example 7b. N-{4-[4-amino-7-(trans-4-hydroxycyclohexyl)pyrrolo[2,1-f][1,2,4]triazine-5-yl]phenyl}-2-oxo-1-phenyl-1,2-dihydropyridine-3-carboxamide [ka] Step 1: Methyl 2-oxo-1-phenyl-1,2-dihydropyridine-3-carboxylate [ka] A mixture of methyl 2-oxo-1,2-dihydropyridine-3-carboxylate (Aldrich, 1.50 g, 9.80 mmol), phenylboronic acid (3.6 g, 29 mmol), activated 4 Å molecular sieve (2.8 g, 12 mmol), and cupric acetate (3.6 g, 20.0 mmol) in methylene chloride (60 mL) was reacted with pyridine (2.4 mL, 29 mmol). The reaction mixture was stirred at room temperature for 60 hours and filtered through a Celite pad. The filtrate was concentrated under vacuum. The crude product was purified by Biotage silica gel chromatography (0 to 100% ethyl acetate in hexane) to obtain the desired product as a white powder (1.26 g, 56%). LCMS C 13 H 12 NO3 (M+H) + Calculated value for m / z: 230.1. Measured value: 230.1.

[0357] Step 2: 2-oxo-1-phenyl-1,2-dihydropyridine-3-carboxylic acid [ka] Methyl 2-oxo-1-phenyl-1,2-dihydropyridine-3-carboxylate (800 mg, 3.49 mmol) was dissolved in tetrahydrofuran (7.4 mL) and methanol (3.7 mL). This mixture was then reacted with 1.0 M aqueous sodium hydroxide solution (14.0 mL) and stirred at room temperature for 30 minutes. The reaction mixture was neutralized with HCl (12 M) to a pH of 6-7. The solvent was removed under vacuum, and the product precipitated. This solid was collected by vacuum filtration, the cake was washed with water, and dried overnight to obtain the desired acid product as a white powder (636 mg, 85%). LCMS C 12 H 10 NO3 (M+H) + Calculated value for m / z: 216.1. Measured value: 216.1.

[0358] Step 3: 2-Oxo-1-phenyl-N-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1,2-dihydropyridine-3-carboxamide [ka] To a mixture of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (Aldrich, 214 mg, 0.98 mmol) and 2-oxo-1-phenyl-1,2-dihydropyridine-3-carboxylic acid (200 mg, 0.93 mmol) in N,N-dimethylformamide (4.5 mL), triethylamine (194 μL, 1.4 mmol) was added, followed by N,N,N',N'-tetramethyl-O-(7-azabenzotriazole-1-yl)uronium hexafluorophosphate (424 mg, 1.12 mmol). The resulting reaction mixture rapidly became a solid mixture, which was stirred at room temperature for 1 hour. This solid was filtered and washed with water. By drying under vacuum suction, the desired product was obtained as a white solid (306 mg, 79%). LCMS C 24 H 26 BN2O4(M+H) + Calculated value for m / z: 417.2. Measured value: 417.2.

[0359] Step 4: 7-(4-{[tert-butyl(dimethyl)silyl]oxy}cyclohexa-1-en-1-yl)pyrrolo[2,1-f][1,2,4]triazine-4-amine [ka] A mixture of tert-butyl(dimethyl){[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl))cyclohexa-3-en-1-yl]oxysilane (450 mg, 1.33 mmol), 7-bromopyrrolo[2,1-f][1,2,4]triazine-4-amine (283 mg, 1.33 mmol), sodium carbonate (470 mg, 4.4 mmol), and [1,1'-bis(dicyclohexylphosphino)ferrocene]dichloropalladium(II) (101 mg, 0.133 mmol) in tert-butyl alcohol (4.0 mL) and water (1.5 mL) was degassed with nitrogen, then heated with stirring at 110°C for 2 hours, followed by heating at 95°C overnight. The mixture was diluted with ethyl acetate, washed with saturated NaHCO3 and water, dried over Na2SO4, filtered, and concentrated. This product was purified by Biotage silica gel chromatography (0 to 50% Â in hexane) to obtain the desired product as an off-white powder (242.3 mg, 53%). LCMS C 18 H 29 N4OSi (M+H) + Calculated value for m / z: 345.2. Measured value: 345.2.

[0360] Step 5: 7-(4-{[tert-butyl(dimethyl)silyl]oxy}cyclohexyl)pyrrolo[2,1-f][1,2,4]triazine-4-amine [ka] 7-(4-{[tert-butyl(dimethyl)silyl]oxy}cyclohexa-1-en-1-yl)pyrrolo[2,1-f][1,2,4]triazine-4-amine (230 mg, 0.67 mmol) was dissolved in methanol (2.8 mL) and tetrahydrofuran (1.4 mL), to which a palladium mixture (4.6 mg) (10% Pd carbon) was added. The reaction mixture was reduced in pressure and placed under a hydrogen balloon for 1 hour. After filtration through a Celite pad, the filtrate was concentrated under vacuum to obtain the desired product (161.9 mg, 70%). LCMS C 18 H 31 N4OSi (M+H) +Calculated value for m / z: 347.2. Measured value: 347.2.

[0361] Step 6: 5-Bromo-7-(4-{[tert-butyl(dimethyl)silyl]oxy}cyclohexyl)pyrrolo[2,1-f][1,2,4]triazine-4-amine [ka] 7-(4-{[tert-butyl(dimethyl)silyl]oxy}cyclohexyl)pyrrolo[2,1-f][1,2,4]triazine-4-amine (80.0 mg, 0.23 mmol) was dissolved in N,N-dimethylformamide (1.0 mL), to which N-bromosuccinimide (39.0 mg, 0.22 mmol) was added. The resulting mixture was stirred at room temperature for 10 minutes. This reaction mixture was diluted with ethyl acetate and filtered. The filtrate was washed with saturated NaHCO3 and water, dried, filtered again, and concentrated under vacuum to obtain the desired product as a yellowish-brown solid. LCMS C 18 H 30 BrN4OSi (M+H) + Calculated values ​​for m / z: 425.1, 427.1. Measured values: 425.1, 427.1.

[0362] Step 7: N-{4-[4-amino-7-(4-{[tert-butyl(dimethyl)silyl]oxy}cyclohexyl)pyrrolo[2,1-f][1,2,4]triazine-5-yl]phenyl}-2-oxo-1-phenyl-1,2-dihydropyridine-3-carboxamide [ka] 2-Oxo-1-phenyl-N-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1,2-dihydropyridine-3-carboxamide (48.9 mg, 0.12 mmol) (Example 7, prepared in Step 3), 5-bromo-7-(4-{[tert-butyl(dimethyl)silyl]oxy}cyclohexyl)pyrrolo[2,1-f][1,2,4] A mixture of lyazin-4-amine (50 mg, 0.12 mmol), sodium carbonate (42 mg, 0.39 mmol), and [1,1'-bis(dicyclohexylphosphino)ferrocene]dichloropalladium(II) (13.4 mg, 0.018 mmol) in tert-butyl alcohol (0.35 mL) and water (0.13 mL) was degassed with nitrogen, and then stirred and heated at 110°C for 1 hour. This mixture was diluted with ethyl acetate, washed with saturated NaHCO3 and water, dried over Na2SO4, filtered, and concentrated. The crude product was purified by Biotage silica gel chromatography (0 to 100% ethyl acetate in hexane) to obtain the desired product as a white powder (34 mg, 46%). LCMS C 36 H 43 N6O3Si (M+H) + Calculated value for m / z: 635.3. Measured value: 635.3.

[0363] Step 8: N-{4-[4-amino-7-(4-hydroxycyclohexyl)pyrrolo[2,1-f][1,2,4]triazine-5-yl]phenyl}-2-oxo-1-phenyl-1,2-dihydropyridine-3-carboxamide A solution of N-{4-[4-amino-7-(4-{[tert-butyl(dimethyl)silyl]oxy}cyclohexyl)pyrrolo[2,1-f][1,2,4]triazine-5-yl]phenyl}-2-oxo-1-phenyl-1,2-dihydropyridine-3-carboxamide (34 mg, 0.05 mmol) in tetrahydrofuran (0.2 mL) was reacted with a solution of 4.0 M hydrogen chloride in dioxane (0.9 mL, 3.6 mmol). The reaction mixture was stirred at room temperature for 30 minutes. This crude substance (trans and cis isomers in a 1:4 ratio) was concentrated under vacuum and purified by preparative LC-MS (pH=10 method, XBridge® PrepC18 5μm OBD® column, 30×100mm, 60mL / min, eluted with a gradient of MeCN and 0.15% NH4OH aqueous solution) to obtain the desired cis isomer (9.2 mg, 33%). A small amount of trans isomer (3.5 mg, 12%) was also isolated. Retention time (RT) for the small amount of trans isomer = RT=1.189 min, first peak from the column. Retention time (RT) for the cis isomer of the main component = RT=1.216 min, second peak from the column. LCMS C 30 H 29 N6O3(M+H) + Calculated value for m / z: 521.2. Measured value: 521.2. 1 H NMR (500 MHz, dmso) δ 12.06 (s, 1H), 8.62 (dd, J = 7.3, 2.2 Hz, 1H), 8.14 (dd, J = 6.6, 2.2 Hz, 1H), 7.90 (s, 1H), 7.82 (d, J = 8.6 Hz, 2H), 7.66 - 7.52 (m, 6H), 7.47 (d, J = 8.5 Hz, 2H), 6.78 - 6.72 (m, 2H), 6.55 (s, 1H), 4.38 (d, J = 2.9 Hz, 1H), 3.92 (s, 1H), 3.62 (d, J = 6.5 Hz, 1H), 3.16 (t, J = 11.4 Hz, 1H), 1.99 - 1.84 (m, 2H), 1.84 - 1.70 (m, 4H), 1.62 (t, J = 12.2 Hz, 1H).

[0364] Example 8. N-[4-(4-amino-7-methylpyrrolo[2,1-f][1,2,4]triazine-5-yl)phenyl]-2-oxo-1-phenyl-1,2-dihydropyridine-3-carboxamide [ka] Step 1: 7-Methylpyrrolo[2,1-f][1,2,4]triazine-4-amine [ka] Under N2 conditions, 150 mg, 0.70 mmol of 7-bromopyrrolo[2,1-f][1,2,4]triazine-4-amine (from J&W Pharm Lab, 2.86 mL) was dissolved in tetrahydrofuran (2.86 mL) at room temperature. Tetrakis(triphenylphosphine)palladium (0) (163 mg, 0.14 mmol) was added to this mixture. The mixture was reduced in a sealed flask under reduced pressure, and N2 was added several times. Then, a 2.0 M solution of zinc dimethyltoluene (5.3 mL, 10 mmol) was added at room temperature. The reaction mixture was heated at 90 °C for 4 hours. The reaction mixture was quenched in ice water and extracted with ethyl acetate. The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum to obtain the crude product. This was purified by preparative LC-MS (pH=10 method, XBridge® PrepC18 5μm OBD® column, 30×100mm, 60mL / min, eluted with a gradient of MeCN and 0.15% NH4OH aqueous solution) to obtain the desired product as a white powder (29.2 mg, 28%). LCMS C7H9N4(M+H) + Calculated value for m / z: 149.1. Measured value: 149.1.

[0365] Step 2: 5-bromo-7-methylpyrrolo[2,1-f][1,2,4]triazine-4-amine [ka] To a solution of 7-methylpyrrolo[2,1-f][1,2,4]triazine-4-amine (29.2 mg, 0.20 mmol) in N,N-dimethylformamide (0.85 mL), N-bromosuccinimide (33.3 mg, 0.19 mmol) was added. The resulting mixture was stirred at room temperature for 15 minutes, the reaction mixture was diluted with ELISA, filtered, washed with saturated NaHCO3 and water, filtered again, and concentrated under vacuum to obtain the desired product as an off-white powder. LCMS C7H8BrN4(M+H) + Calculated values ​​for m / z: 227.0, 229.0. Measured values: 227.0, 229.0.

[0366] Step 3: N-[4-(4-amino-7-methylpyrrolo[2,1-f][1,2,4]triazine-5-yl)phenyl]-2-oxo-1-phenyl-1,2-dihydropyridine-3-carboxamide In a sealed tube, a mixture of 5-bromo-7-methylpyrrolo[2,1-f][1,2,4]triazine-4-amine (5.6 mg, 0.02 mmol), 2-oxo-1-phenyl-N-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1,2-dihydropyridine-3-carboxamide (8.0 mg, 0.02 mmol) (prepared in Example 7, Step 3), and N,N-diisopropylethylamine (0.01 mL, 0.06 mmol) in 1,4-dioxane (0.14 mL) and water (20 μL) was stirred and flushed with N2 bubbles for 5 minutes, after which bis(tri-t-butylphosphine)palladium (4.7 mg, 0.01 mmol) was added. The reaction mixture was sealed and then heated at 110°C for 1 hour. After separation and extraction of the aqueous layer with RINKAN, the organic layer was dried, filtered, and concentrated under vacuum. This crude material was purified by preparative LC-MS (pH=10 method, XBridge® PrepC18 5μm OBD® column, 30×100mm, 60mL / min, eluted with a gradient of MeCN and 0.15% NH4OH aqueous solution) to obtain the desired product (2.8 mg, 36%). LCMS C 25 H 21 N6O2(M+H) +Calculated value for m / z: 437.2. Measured value: 437.2.

[0367] Example 9. N-[4-(4-amino-7-methylpyrrolo[2,1-f][1,2,4]triazine-5-yl)phenyl]-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide [ka] Step 1: Methyl 1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxylate [ka] A mixture of methyl 2-oxo-1,2-dihydropyridine-3-carboxylate (Aldrich, 1.50 g, 9.8 mmol), 4-fluorophenylboronic acid (Aldrich, 4.1 g, 29 mmol), activated 4 Å molecular sieve (2.8 g, 12 mmol), and cupric acetate (3.6 g, 20 mmol) in methylene chloride (60 mL) was reacted with pyridine (2.4 mL) and then stirred at room temperature for 18 hours. The mixture was filtered through Celite, and the filtrate was concentrated under vacuum. The crude substance was purified by Biotage silica gel column chromatography (0 to 100% ethyl acetate in hexane) to obtain the desired product as an off-white viscous substance (1.33 g, 55%). LCMS C 13 H 11 FNO3(M+H) + Calculated value for m / z: 248.1. Measured value: 248.1.

[0368] Step 2: 1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid [ka] Methyl 1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxelate (800 mg, 3.24 mmol) was dissolved in tetrahydrofuran (6.82 mL) and methanol (3.41 mL). This mixture was then reacted with 1.0 M aqueous sodium hydroxide solution (12.9 mL), and the reaction mixture was stirred at room temperature for 30 minutes. The reaction mixture was neutralized with HCl (12 M) to a pH of 6-7. After removing the solvent under vacuum, the product precipitated. This solid was collected by vacuum filtration, the cake was washed with water, and dried overnight to obtain the desired acid product as a white powder (540 mg, 72%). LCMS C 12 H9FNO3(M+H) + Calculated value for m / z: 234.1. Measured value: 234.1.

[0369] Step 3: 1-(4-fluorophenyl)-2-oxo-N-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1,2-dihydropyridine-3-carboxamide [ka] To a mixture of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (Aldrich, 197.3 mg, 0.90 mmol) and 1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid (Aldrich, 200 mg, 0.86 mmol) in N,N-dimethylformamide (4.0 mL), triethylamine (180 μL, 1.3 mmol) was added, followed by N,N,N',N'-tetramethyl-O-(7-azabenzotriazole-1-yl)uronium hexafluorophosphate (391 mg, 1.03 mmol). The resulting mixture rapidly became a solid mixture, which was stirred at room temperature for 1 hour. This solid was filtered and washed with water. By drying under vacuum suction, the desired product was obtained as a white solid (343 mg, 92%). LCMS C 24 H 25 BFN2O4(M+H) +Calculated value for m / z: 435.2. Measured value: 435.2.

[0370] Step 4: N-[3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-2-oxo-1-phenyl-1,2-dihydropyridine-3-carboxamide [ka] To a mixture of 3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (from Aldrich, 289.2 mg, 1.22 mmol) and 2-oxo-1-phenyl-1,2-dihydropyridine-3-carboxylic acid (250 mg, 1.16 mmol) (prepared in Example 7, Step 2) in N,N-dimethylformamide (5.0 mL), triethylamine (243 μL, 1.74 mmol) was added, followed by N,N,N',N'-tetramethyl-O-(7-azabenzotriazole-1-yl)uronium hexafluorophosphate (530 mg, 1.39 mmol). The resulting mixture rapidly became a solid mixture, which was stirred at room temperature for 1 hour. This solid was filtered and washed with water. By drying under vacuum suction, the desired product was obtained as a white solid (335 mg, 66%). LCMS C 24 H 25 BFN2O4(M+H) + Calculated value for m / z: 435.2. Measured value: 435.2.

[0371] Step 5: 1-(4-fluorophenyl)-N-[3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-2-oxo-1,2-dihydropyridine-3-carboxamide [ka] To a mixture of 3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (Aldrich, 213.5 mg, 0.90 mmol) and 1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid (200 mg, 0.86 mmol) (prepared in Example 9, Step 2) in N,N-dimethylformamide (4.7 mL), triethylamine (179 μL, 1.29 mmol) was added, followed by N,N,N',N'-tetramethyl-O-(7-azabenzotriazole-1-yl)uronium hexafluorophosphate (391 mg, 1.03 mmol). The resulting mixture quickly became a solid mixture, which was stirred at room temperature for 1 hour. This solid was filtered and washed with water. The desired product was obtained as a white solid by drying under vacuum suction (305 mg, 79%). LCMS C 24 H 24 BF2N2O4(M+H) + Calculated value for m / z: 453.2. Measured value: 453.2.

[0372] Step 6: N-[4-(4-amino-7-methylpyrrolo[2,1-f][1,2,4]triazine-5-yl)phenyl]-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide In a sealed tube, a mixture of 5-bromo-7-methylpyrrolo[2,1-f][1,2,4]triazine-4-amine (5 mg, 0.02 mmol) (Prepared in Example 8, Step 2), 1-(4-fluorophenyl)-2-oxo-N-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1,2-dihydropyridine-3-carboxamide (8 mg, 0.02 mmol) (Prepared in Example 9, Step 3), and N,N-diisopropylethylamine (0.01 mL, 0.05 mmol) in 1,4-dioxane (0.13 mL) and water (20 μL) was stirred, flushed with N2 for 5 minutes, and then bis(tri-t-butylphosphine)palladium (4.2 mg, 0.01 mmol) was added. The reaction mixture was sealed and then heated at 110°C for 1 hour. After separation and extraction of the aqueous layer with RINKAN, the organic layer was dried, filtered, and concentrated under vacuum. This crude material was purified by preparative LC-MS (pH=10 method, XBridge® PrepC18 5μm OBD® column, 30×100mm, 60mL / min, eluted with a gradient of MeCN and 0.15% NH4OH aqueous solution) to obtain the desired product (2.4 mg, 32%). LCMS C 25 H 20 FN6O2(M+H) + Calculated value for m / z: 455.2. Measured value: 455.2.

[0373] Example 10. N-[4-(4-amino-7-methylpyrrolo[2,1-f][1,2,4]triazine-5-yl)-3-fluorophenyl]-2-oxo-1-phenyl-1,2-dihydropyridine-3-carboxamide [ka] In a sealed tube, a mixture of 5-bromo-7-methylpyrrolo[2,1-f][1,2,4]triazine-4-amine (5 mg, 0.016 mmol) (Prepared in Example 8, Step 2), N-[3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-2-oxo-1-phenyl-1,2-dihydropyridine-3-carboxamide (7.5 mg, 0.017 mmol) (Prepared in Example 9, Step 4), and N,N-diisopropylethylamine (0.01 mL, 0.049 mmol) in 1,4-dioxane (0.128 mL) and water (20 μL) was stirred, flushed with N2 for 5 minutes, and then bis(tri-t-butylphosphine)palladium (4.2 mg, 0.01 mmol) was added. The reaction mixture was sealed and then heated at 110°C for 1 hour. After separation and extraction of the aqueous layer with RINKAN, the organic layer was dried, filtered, and concentrated under vacuum. The crude material was purified by preparative LC-MS (pH=10 method, XBridge® PrepC18 5μm OBD® column, 30×100mm, 60mL / min, eluted with a gradient of MeCN and 0.15% NH4OH aqueous solution) to obtain the desired product (1.7 mg, 23%). LCMS C 25 H 20 FN6O2(M+H) + Calculated value for m / z: 455.2. Measured value: 455.2.

[0374] Example 11. N-[4-(4-amino-7-methylpyrrolo[2,1-f][1,2,4]triazine-5-yl)-3-fluorophenyl]-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide [ka] In a sealed tube, a mixture of 5-bromo-7-methylpyrrolo[2,1-f][1,2,4]triazine-4-amine (3.2 mg, 0.01 mmol) (Prepared in Example 8, Step 2), 1-(4-fluorophenyl)-N-[3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-2-oxo-1,2-dihydropyridine-3-carboxamide (5 mg, 0.01 mmol) (Prepared in Example 9, Step 5), and N,N-diisopropylethylamine (0.01 mL, 0.04 mmol) in 1,4-dioxane (0.15 mL) and water (20 μL) was stirred, flushed with N2 for 5 minutes, and then bis(tri-t-butylphosphine)palladium (2.7 mg, 0.005 mmol) was added. The reaction mixture was sealed and then heated at 110°C for 1 hour. After separation and extraction of the aqueous layer with RINKAN, the organic layer was dried, filtered, and concentrated under vacuum. The crude material was purified by preparative LC-MS (pH=10 method, XBridge® PrepC18 5μm OBD® column, 30×100mm, 60mL / min, eluted with a gradient of MeCN and 0.15% NH4OH aqueous solution) to obtain the desired product (2.0 mg, 40%). LCMS C 25 H 19 F2N6O2(M+H) + Calculated value for m / z: 473.2. Measured value: 473.2.

[0375] Example 12. N-[4-(4-amino-7-ethylpyrrolo[2,1-f][1,2,4]triazine-5-yl)-3-fluorophenyl]-2-oxo-1-phenyl-1,2-dihydropyridine-3-carboxamide [ka] In a sealed tube, a mixture of 5-bromo-7-ethylpyrrolo[2,1-f][1,2,4]triazine-4-amine (6 mg, 0.018 mmol) (Prepared in Example 1, Step 7), N-[3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-2-oxo-1-phenyl-1,2-dihydropyridine-3-carboxamide (8.3 mg, 0.02 mmol) (Prepared in Example 9, Step 4), and N,N-diisopropylethylamine (0.02 mL, 0.11 mmol) in 1,4-dioxane (0.14 mL) and water (20 μL) was stirred, flushed with N2 for 5 minutes, and then bis(tri-t-butylphosphine)palladium (4.6 mg, 0.01 mmol) was added. The reaction mixture was sealed and then heated at 110°C for 1 hour. After separation and extraction of the aqueous layer with RINKAN, the organic layer was dried, filtered, and concentrated under vacuum. The crude material was purified by preparative LC-MS (pH=10 method, XBridge® PrepC18 5μm OBD® column, 30×100mm, 60mL / min, eluted with a gradient of MeCN and 0.15% NH4OH aqueous solution) to obtain the desired product (2.4 mg, 28%). LCMS C 26 H 22 FN6O2(M+H) + Calculated value for m / z: 469.2. Measured value: 469.2.

[0376] Example 13. N-{4-[4-amino-7-(tetrahydro-2H-pyran-4-yl)pyrrolo[2,1-f][1,2,4]triazine-5-yl]phenyl}-2-oxo-1-phenyl-1,2-dihydropyridine-3-carboxamide [ka] Step 1: 7-(3,6-dihydro-2H-pyran-4-yl)pyrrolo[2,1-f][1,2,4]triazine-4-amine [ka] In a sealed flask, a mixture of 1,4-dioxane (6 mL) and water (0.32 mL) containing 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyran (from Aldrich, 0.64 g, 3.01 mmol), 7-bromopyrrolo[2,1-f][1,2,4]triazine-4-amine (from J&W Pharm Lab, 0.500 g, 2.35 mmol), and N,N-diisopropylethylamine (1.2 mL, 7.0 mmol) was stirred and flushed with N2 for 5 minutes, after which bis(tri-t-butylphosphine)palladium (100 mg, 0.24 mmol) was added. The reaction mixture was then sealed and heated at 120°C for 4 hours, filtered through a Celite pad, and concentrated. This crude substance was purified by Biotage silica gel column chromatography (40g column, 0 to 100% Â in hexane) to obtain the desired product as a white powder (168.5 mg, 33%). LCMS C 11 H 13 N4O (M+H) + Calculated value for m / z: 217.1. Measured value: 217.1.

[0377] Step 2: 7-(tetrahydro-2H-pyran-4-yl)pyrrolo[2,1-f][1,2,4]triazine-4-amine [ka] To a solution of 7-(3,6-dihydro-2H-pyran-4-yl)pyrrolo[2,1-f][1,2,4]triazine-4-amine (120 mg, 0.55 mmol) in methanol (2.67 mL) and THF (1.3 mL), a palladium mixture (120 mg) (10% Pd carbon) was added. This reaction mixture was placed under a hydrogen balloon for 2 hours. After filtering through a Celite pad, the filtrate was concentrated under vacuum to obtain the desired product as a white powder (90.2 mg, 75%). LCMS C 11 H 15 N4O (M+H) + Calculated value for m / z: 219.1. Measured value: 219.1.

[0378] Step 3: 5-Bromo-7-(tetrahydro-2H-pyran-4-yl)pyrrolo[2,1-f][1,2,4]triazine-4-amine [ka] To a solution of 7-(tetrahydro-2H-pyran-4-yl)pyrrolo[2,1-f][1,2,4]triazine-4-amine (50 mg, 0.23 mmol) in N,N-dimethylformamide (0.99 mL), N-bromosuccinimide (41 mg, 0.23 mmol) was added. The resulting mixture was stirred at room temperature for 15 minutes. This reaction mixture was diluted with ethyl acetate and filtered. The filtrate was washed with saturated NaHCO3 and water, dried, filtered again, and concentrated under vacuum to obtain the desired product as a yellowish-brown solid. LCMS C 11 H 14 BrN4O (M+H) + Calculated values ​​for m / z: 297.0, 299.0. Measured values: 297.0, 299.0.

[0379] Step 4: N-{4-[4-amino-7-(tetrahydro-2H-pyran-4-yl)pyrrolo[2,1-f][1,2,4]triazine-5-yl]phenyl}-2-oxo-1-phenyl-1,2-dihydropyridine-3-carboxamide In a sealed tube, a mixture of 5-bromo-7-(tetrahydro-2H-pyran-4-yl)pyrrolo[2,1-f][1,2,4]triazine-4-amine (6 mg, 0.02 mmol), 2-oxo-1-phenyl-N-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1,2-dihydropyridine-3-carboxamide (8.8 mg, 0.02 mmol) (prepared in Example 7, Step 3), and N,N-diisopropylethylamine (0.01 mL, 0.06 mmol) in 1,4-dioxane (0.15 mL) and water (20 μL) was stirred, flushed with N2 for 5 minutes, and then bis(tri-t-butylphosphine)palladium (5.2 mg, 0.01 mmol) was added. The reaction mixture was sealed and then heated at 110°C for 1 hour. After separation and extraction of the aqueous layer with RINKAN, the organic layer was dried, filtered, and concentrated under vacuum. The crude material was purified by preparative LC-MS (pH=10 method, XBridge® PrepC18 5μm OBD® column, 30×100mm, 60mL / min, eluted with a gradient of MeCN and 0.15% NH4OH aqueous solution) to obtain the desired product (3.2 mg, 31%). LCMS C 29 H 27 N6O3(M+H) + Calculated value for m / z: 507.2. Measured value: 507.2.

[0380] Example 14. N-{4-[4-amino-7-(tetrahydro-2H-pyran-4-yl)pyrrolo[2,1-f][1,2,4]triazine-5-yl]phenyl}-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide [ka] In a sealed tube, a mixture of 5-bromo-7-(tetrahydro-2H-pyran-4-yl)pyrrolo[2,1-f][1,2,4]triazine-4-amine (6 mg, 0.02 mmol) (Prepared in Example 13, Step 3), 1-(4-fluorophenyl)-2-oxo-N-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1,2-dihydropyridine-3-carboxamide (9.2 mg, 0.02 mmol) (Prepared in Example 9, Step 3), and N,N-diisopropylethylamine (0.01 mL, 0.06 mmol) in 1,4-dioxane (0.15 mL) and water (20 μL) was stirred, flushed with N2 for 5 minutes, and then bis(tri-t-butylphosphine)palladium (5.2 mg, 0.01 mmol) was added. The reaction mixture was sealed and then heated at 110°C for 1 hour. After separation and extraction of the aqueous layer with RINKAN, the organic layer was dried, filtered, and concentrated under vacuum. The crude material was purified by preparative LC-MS (pH=10 method, XBridge® PrepC18 5μm OBD® column, 30×100mm, 60mL / min, eluted with a gradient of MeCN and 0.15% NH4OH aqueous solution) to obtain the desired product (4.8 mg, 45%). LCMS C 29 H 26 FN6O3(M+H) + Calculated value for m / z: 525.2. Measured value: 525.2.

[0381] Example 15. N-{4-[4-amino-7-(tetrahydro-2H-pyran-4-yl)pyrrolo[2,1-f][1,2,4]triazine-5-yl]-3-fluorophenyl}-2-oxo-1-phenyl-1,2-dihydropyridine-3-carboxamide [ka] In a sealed tube, a mixture of 5-bromo-7-(tetrahydro-2H-pyran-4-yl)pyrrolo[2,1-f][1,2,4]triazine-4-amine (5 mg, 0.02 mmol) (Prepared in Example 13, Step 3), N-[3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-2-oxo-1-phenyl-1,2-dihydropyridine-3-carboxamide (7.3 mg, 0.017 mmol) (Prepared in Example 9, Step 4), and N,N-diisopropylethylamine (0.01 mL, 0.06 mmol) in 1,4-dioxane (0.15 mL) and water (20 μL) was stirred, flushed with N2 for 5 minutes, and then bis(tri-t-butylphosphine)palladium (4.3 mg, 0.01 mmol) was added. The reaction mixture was sealed and then heated at 110°C for 2 hours. After separation and extraction of the aqueous layer with SiO2, the organic layer was dried, filtered, and concentrated under vacuum. The crude material was purified by preparative LC-MS (pH=2 method, Waters SunFire PrepC18 5μm OBD® column, 30×100mm, 60mL / min, eluted with a gradient of MeCN and 0.1% TFA aqueous solution) to obtain the desired product as a white powder (6.4 mg, 72%). LCMS C 29 H 26 FN6O3(M+H) + Calculated value for m / z: 525.2. Measured value: 525.2.

[0382] Example 16. N-{4-[4-amino-7-(tetrahydro-2H-pyran-4-yl)pyrrolo[2,1-f][1,2,4]triazine-5-yl]-3-fluorophenyl}-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide [ka] In a sealed tube, 5-bromo-7-(tetrahydro-2H-pyran-4-yl)pyrrolo[2,1-f][1,2,4]triazine-4-amine (6 mg, 0.02 mmol) (Example 13, prepared in Step 3), 1-(4-fluorophenyl)-N-[3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-2-oxo-1,2-dihydr A mixture of lopyridine-3-carboxamide (9.6 mg, 0.02 mmol) (prepared in Example 9, Step 5) and N,N-diisopropylethylamine (0.01 mL, 0.06 mmol) in 1,4-dioxane (0.15 mL) and water (20 μL) was stirred, flushed with N2 for 5 minutes, and then bis(tri-t-butylphosphine)palladium (5.2 mg, 0.01 mmol) was added. The reaction mixture was sealed and then heated at 110°C for 1 hour. After separation and extraction of the aqueous layer with ethyl acetate, the organic layer was dried, filtered, and concentrated under vacuum. This crude substance was purified by preparative LC-MS (pH=10 method, XBridge® PrepC18 5μm OBD® column, 30×100mm, 60mL / min, elution with MeCN and 0.15% NH4OH aqueous solution gradient) to obtain the desired product (4.4 mg, 40%). LCMS C 29 H 25 F2N6O3(M+H) + Calculated value for m / z: 543.2. Measured value: 543.2.

[0383] Example 17a. N-{4-[4-amino-7-(cis-4-hydroxycyclohexyl)pyrrolo[2,1-f][1,2,4]triazine-5-yl]phenyl}-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide Example 17b. N-{4-[4-amino-7-(trans-4-hydroxycyclohexyl)pyrrolo[2,1-f][1,2,4]triazine-5-yl]phenyl}-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide [ka] Step 1: N-{4-[4-amino-7-(4-{[tert-butyl(dimethyl)silyl]oxy}cyclohexyl)pyrrolo[2,1-f][1,2,4]triazine-5-yl]phenyl}-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide [ka] In a sealed tube, 5-bromo-7-(4-{[tert-butyl(dimethyl)silyl]oxy}cyclohexyl)pyrrolo[2,1-f][1,2,4]triazine-4-amine (5 mg, 0.012 mmol) (Example 7, prepared in Step 6), 1-(4-fluorophenyl)-2-oxo-N-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1,2 -Dihydropyridine-3-carboxamide (5.4 mg, 0.012 mmol) (prepared in Example 9, Step 3) and N,N-diisopropylethylamine (0.012 mL, 0.07 mmol) were mixed with 1,4-dioxane (0.15 mL) and water (20 μL) and stirred. After flushing with N2 for 5 minutes, bis(tri-t-butylphosphine)palladium (3 mg, 0.006 mmol) was added. The reaction mixture was sealed and then heated at 110°C for 1 hour. After separation and extraction of the aqueous layer with ethyl acetate, the organic layer was dried, filtered, and concentrated under vacuum. This crude material was used directly in the next step. LCMS C 36 H 42 FN6O3Si (M+H) + Calculated value for m / z: 653.3. Measured value: 653.3.

[0384] Step 2: N-{4-[4-amino-7-(4-hydroxycyclohexyl)pyrrolo[2,1-f][1,2,4]triazine-5-yl]phenyl}-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide A solution of N-{4-[4-amino-7-(4-{[tert-butyl(dimethyl)silyl]oxy}cyclohexyl)pyrrolo[2,1-f][1,2,4]triazine-5-yl]phenyl}-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide (7.7 mg, 0.012 mmol) in methanol (0.05 mL) was reacted with a solution of 4.0 M dioxane hydrogen chloride (0.20 mL). The reaction mixture was stirred at room temperature for 20 minutes. This crude substance was concentrated under vacuum and purified by preparative LC-MS (pH=10 method, XBridge® PrepC18 5μm OBD® column, 30×100mm, 60mL / min, eluted with a gradient of MeCN and 0.15% NH4OH aqueous solution) to obtain the desired product (cis isomer) as a white powder (2.8 mg, 44%). The cis isomer of the main component was the second peak from the column at RT=2.047 min. The trans isomer was a small amount of product and is the first peak from the column. This trans isomer was not isolated. LCMSC 30 H 28 FN6O3(M...

Claims

1. 5-bromo-7-(piperidine-4-yl)pyrrolo[2,1-f][1,2,4]triazine-4-amine; 1-(4-(4-amino-5-bromopyrrolo[1,2-f][1,2,4]triazine-7-yl)piperidine-1-yl)-2-methylpropan-1-one; 1-(4-(4-amino-5-(4-aminophenyl)pyrrolo[1,2-f][1,2,4]triazine-7-yl)piperidine-1-yl)-2-methylpropan-1-one; Diethyl 2-((3-pyridine-2-ylureido)methylene)malonate; Ethyl 2,4-dioxo-3-(pyridine-2-yl)-1,2,3,4-tetrahydropyrimidine-5-carboxylate; Ethyl 1-isopropyl-2,4-dioxo-3-(pyridine-2-yl)-1,2,3,4-tetrahydropyrimidine-5-carboxylate; and 1-Isopropyl-2,4-dioxo-3-(pyridine-2-yl)-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid A compound selected from, or a salt thereof.

2. The compound or salt thereof according to claim 1, wherein the compound is 5-bromo-7-(piperidine-4-yl)pyrrolo[2,1-f][1,2,4]triazine-4-amine or a salt thereof.

3. The compound according to claim 1, wherein the compound is 5-bromo-7-(piperidine-4-yl)pyrrolo[2,1-f][1,2,4]triazine-4-amine.

4. The compound or a salt thereof according to claim 1, wherein the compound is 1-(4-(4-amino-5-bromopyrrolo[1,2-f][1,2,4]triazine-7-yl)piperidine-1-yl)-2-methylpropan-1-one or a salt thereof.

5. The compound according to claim 1, wherein the compound is 1-(4-(4-amino-5-bromopyrrolo[1,2-f][1,2,4]triazine-7-yl)piperidine-1-yl)-2-methylpropan-1-one.

6. The compound or a salt thereof according to claim 1, wherein the compound is 1-(4-(4-amino-5-(4-aminophenyl)pyrrolo[1,2-f][1,2,4]triazine-7-yl)piperidine-1-yl)-2-methylpropan-1-one or a salt thereof.

7. The compound according to claim 1, wherein the compound is 1-(4-(4-amino-5-(4-aminophenyl)pyrrolo[1,2-f][1,2,4]triazine-7-yl)piperidine-1-yl)-2-methylpropan-1-one.

8. The compound or salt thereof according to claim 1, wherein the compound is diethyl 2-((3-pyridine-2-ylureido)methylene)malonate or a salt thereof.

9. The compound according to claim 1, wherein the compound is diethyl 2-((3-pyridine-2-ylureido)methylene)malonate.

10. The compound according to claim 1, wherein the compound is ethyl 2,4-dioxo-3-(pyridine-2-yl)-1,2,3,4-tetrahydropyrimidine-5-carboxylate or a salt thereof, or a salt thereof.

11. The compound according to claim 1, wherein the compound is ethyl 2,4-dioxo-3-(pyridine-2-yl)-1,2,3,4-tetrahydropyrimidine-5-carboxylate.

12. The compound or salt thereof according to claim 1, wherein the compound is ethyl 1-isopropyl-2,4-dioxo-3-(pyridine-2-yl)-1,2,3,4-tetrahydropyrimidine-5-carboxylate or a salt thereof.

13. The compound according to claim 1, wherein the compound is ethyl 1-isopropyl-2,4-dioxo-3-(pyridine-2-yl)-1,2,3,4-tetrahydropyrimidine-5-carboxylate.

14. The compound or a salt thereof according to claim 1, wherein the compound is 1-isopropyl-2,4-dioxo-3-(pyridine-2-yl)-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid or a salt thereof.

15. The compound according to claim 1, wherein the compound is 1-isopropyl-2,4-dioxo-3-(pyridine-2-yl)-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid.

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