Urea, Amide, and Substituted Heteroaryl Compounds for the Inhibition of Cbl-b

Abstract

Formulas (I) and (II) for use in inhibiting the E3 enzyme Cbl-b in the ubiquitin proteasome pathway [Formula 1] JPEG2022542323000295.jpg79104 Disclosed are compounds, compositions, and methods that can be used to modulate the immune system, treat diseases that are amenable to modulation of the immune system, and treat cells in vivo, in vitro, or ex vivo.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. Provisional Patent Application No. 62 / 880,310, filed July 30, 2019, the contents of which are incorporated herein by reference in their entirety.

[0002] Provided herein are compounds and compositions for the inhibition of the Cbl-b enzyme, and methods of their use in modulating the immune system, treating disease, and treating cells in vivo, in vitro, or ex vivo. [Background technology]

[0003]

[0003] The ubiquitin proteasome pathway is a complex system involved in the control of protein function and catabolism. Proteins in eukaryotic cells are conjugated with ubiquitin, a 76 amino acid, 8.5 kilodalton protein. This conjugation, known as ubiquitination, results in the alteration of the function or degradation of the target protein. Ubiquitination of a target protein occurs through a series of linked reactions involving ubiquitin and a set of enzymes known as E1, E2, and E3 enzymes. Ubiquitin is activated by a ubiquitin-activating enzyme, or E1 enzyme. Ubiquitin is then transferred to a ubiquitin-conjugating enzyme, or E2 enzyme. Finally, a ubiquitin ligase, or E3 enzyme, facilitates the transfer of ubiquitin from the E2 enzyme to the target protein. Polyubiquitination of a target protein serves as a signal that leads to the degradation of the ubiquitin-conjugated protein primarily by the proteasome, where it undergoes proteolysis. Ubiquitination by E3 ligases can result in changes in protein activity, interaction, or localization, and it controls diverse biological responses, including cell division, DNA repair, and cell signaling.

[0004]

[0004] Protein synthesis and degradation in cells are important for cell cycle control, cell proliferation, apoptosis, and many other cellular processes. Therefore, the ability to regulate the ubiquitin proteasome pathway provides ample opportunities to intervene in disease processes. Intervention mechanisms may include enhancing the degradation of oncogene products, reducing the degradation of tumor suppressor proteins, and modulating immune cell responses.

[0005]

[0005] Approximately 35 E2 enzymes and over 500 E3 enzymes are encoded in the human genome. Casitas B-lineage lymphoma proto-oncogene-b (Cbl-b) is an E3 ubiquitin ligase that negatively regulates T cell activation (Wallner et al., Clin Dev Immunol, 2012: 692639). Thus, the discovery of agents that modulate E2 or E3 enzymes offers the potential for therapeutics directed at disease processes involving specific E2 or E3 enzymes. The present disclosure is directed to agents that inhibit one such E3 enzyme, Casitas B-lineage lymphoma proto-oncogene-b (Cbl-b). Summary of the Invention [Problem to be solved by the invention]

[0006]

[0006] Disclosed herein are compounds and compositions for the inhibition of Cbl-b enzyme, and methods of their use in regulating the immune system, treating disease, and in vivo, in vitro, or ex vivo treatment of cells. Also disclosed herein are methods of using Cbl-b inhibitors in treating cancer. In brief, Cbl-b inhibitors can be administered to individuals with cancer alone or as part of a combination therapy with one or more of immune checkpoint inhibitors, anti-neoplastic agents, and radiation therapy. In addition, cells treated in vivo and / or in vitro with the compounds or compositions disclosed herein can be used in adoptive cell therapy to treat cancer. [Means for solving the problem]

[0007] Disclosed herein is a compound of formula (I):

[0008] [ka] or a tautomer thereof, or a pharma- ceutically acceptable salt thereof; During the ceremony, R 1 and R 2 are independently H, C 1 ~C 6 Alkyl, halo, or C 1 ~C 6 haloalkyl, but when X is S, R 1 and R 2 provided that neither of R and Y are H, and if Y is S or a bond, then R 1 and R 2 is not a halo; or R 1 and R 2 together with the carbon atoms to which they are attached;

[0009] [ka] It is formed, X is CR 3 R 4 Or S; R 3 and R 4 are independently H, C 1 ~C 6 Alkyl, halo, or C 1 ~C 6 haloalkyl; or R 1 and R 3 together with the carbon atom to which they are attached, form a moiety;

[0010] [ka] It is formed, R 5 is C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, or C 3 ~C 6 is cycloalkyl; Z is CH or N; n is 0 or 1; R 6 , H, C 1 ~C 6 Alkyl, or C 1 ~C 6 is haloalkyl; R 7 is C 1 ~C 6 Alkyl-OH, -(CR 8 R 9 ) m -(5-10 membered monocyclic or fused bicyclic heteroaryl), -(CR 8 R 9 ) m -(4-10 membered monocyclic or fused bicyclic heterocyclyl), -(CR 8 R 9 ) m -(C 6 ~C 10aryl), or -(CR 8 R 9 ) m -(C 3 ~C 6 cycloalkyl), Each heteroaryl, heterocyclyl, aryl, or cycloalkyl group optionally contains 1 to 5 R 10 or R 6 and R 7 together with the nitrogen atom to which they are attached form a 5-10 membered monocyclic or fused bicyclic heteroaryl, or a 4-10 membered monocyclic or fused bicyclic heterocyclyl, each heteroaryl or heterocyclyl optionally containing 1-2 additional heteroatoms selected from the group consisting of N, S, and O, and each heteroaryl or heterocyclyl optionally containing 1-5 R 10 is substituted by a group; m is 0 or 1; R 8 and R 9 are independently H, C 1 ~C 6 Alkyl, or C 1 ~C 6 is haloalkyl; Each R 10 is independently 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, C 1 ~C 6 Alkyl-OH, -CN, C 1 ~C 6 Alkyl-CN, -O(C 1 ~C 6 alkyl), -O(C 1 ~C 6 haloalkyl), halo, hydroxy, oxo, -CO 2 H, -C(O)NH(C 1 ~C 6 alkyl), -C(O)N(C 1 ~C 6 Alkyl) 2 , -C(O)NH(C1 ~C 6 haloalkyl), -C(O)O(C 1 ~C 6 Alkyl), -SO 2 -(C 1 ~C 6 Alkyl), -SO 2 -NH(C 1 ~C 6 Alkyl), -SO 2 -N(C 1 ~C 6 Alkyl) 2 , -C(O)(C 1 ~C 6 alkyl), -(C 1 ~C 6 alkylene)-C(O)N(C 1 ~C 6 Alkyl) 2 , -(C 1 ~C 6 alkylene)-C(O)NH(C 1 ~C 6 Alkyl), C 3 ~C 6 Cycloalkyl, 5- to 6-membered heterocyclyl, 5- to 6-membered heteroaryl, -(C 1 ~C 6 alkylene)-(5-6 membered heterocyclyl), -(C 1 ~C 6 alkylene)-(5- to 6-membered heteroaryl), -C(O)-(5- to 6-membered heterocyclyl), -C(O)-(5- to 6-membered heteroaryl), or C 6 ~C 10 is aryl, Each cycloalkyl, heterocyclyl, heteroaryl, or aryl group optionally has 1 to 5 R 11 or Two R's attached to the same carbon atom 10 The groups, together with the carbon atoms to which they are attached, form spiro C 3 ~C 6 cycloalkyl or spiro 4-6 membered heterocyclyl, each of which is optionally represented by 1 to 5 R 11 is substituted by a group; Each R11 is independently 1 ~C 6 Alkyl, hydroxy, oxo, or -C(O)(C 1 ~C 6 alkyl); R 12 , H, C 1 ~C 6 Alkyl, or C 1 ~C 6 haloalkyl, or R 6 and R 7 together with the nitrogen atom to which they are attached form a 4-10 membered monocyclic or fused bicyclic heterocyclyl, optionally containing 1-2 additional heteroatoms selected from the group consisting of N, S, and O; R 12 is linked to a 4-10 membered monocyclic or fused bicyclic heterocyclyl to form a 7-14 membered fused bicyclic or tricyclic heterocyclyl 1 ~C 6 alkylene, and each heterocyclyl optionally has 1 to 5 R 10 is substituted by a group; Each R 13 are independently H, C 1 ~C 3 Alkyl, C 1 ~C 3 Alkyl-OH, or C 1 ~C 3 It is haloalkyl.

[0011] In some embodiments, R 1 and R 2 are independently H, C 1 ~C 3 Alkyl, halo, or C 1 ~C 3 In some embodiments, R 1 and R 2 are independently H, -CH 3 , F, or -CF 3 In some embodiments, R 1 and R 2together with the carbon atom to which they are attached form the group

[0012] [ka] It is formed.

[0013] In some embodiments, X is S. In some embodiments, X is CR 3 R 4 It is.

[0014] In some embodiments, R 3 and R 4 are independently H, halo, and C 1 ~C 3 Alkyl, or C 1 ~C 3 In some embodiments, R 3 and R 4 are independently H, F, -CH 3 , or -CF 3 It is.

[0015] In some embodiments, R 1 and R 3 Together with the carbon atoms to which they are attached,

[0016] [ka] In some embodiments, R 2 , H, C 1 ~C 3 Alkyl, halo, or C 1 ~C 3 haloalkyl; R 4 , H, C 1 ~C 3 Alkyl, halo, or C 1 ~C 3 haloalkyl; each R 13 are independently H, C 1 ~C2 Alkyl, C 1 ~C 2 Alkyl-OH, or C 1 ~C 2 In some embodiments, R 2 -H, -CH 3 , F, or -CF 3 ;R 4 -H, -CH 3 , F, or -CF 3 and each R 13 are independently H, -CH 3 , -CH 2 OH, or -CF 3 In some embodiments, R 2 and R 4 Each is H; each R 13 is H.

[0017] In some embodiments, R 5 is C 1 ~C 3 Alkyl, C 1 ~C 3 Haloalkyl, or C 3 ~C 4 In some embodiments, R 5 -CH 3 , -CHF 2 or cyclopropyl.

[0018] In some embodiments, Z is CH. In some embodiments, Z is N.

[0019] In some embodiments, n is 0. In some embodiments, n is 1.

[0020] In some embodiments, R 6 , H, C 1 ~C 3 Alkyl, or C 1 ~C 3 In some embodiments, R 6is H or -CH 3 It is.

[0021] In some embodiments, R 7 is C 1 ~C 3 Alkyl-OH, -(CR 8 R 9 ) m -(5-6 membered monocyclic heteroaryl), -(CR 8 R 9 ) m -(8-10 membered fused bicyclic heteroaryl), -(CR 8 R 9 ) m -(4-6 membered monocyclic heterocyclyl), -(CR 8 R 9 ) m -(8-10 membered fused bicyclic heterocyclyl), -(CR 8 R 9 ) m -(C 6 ~C 10 aryl), or -(CR 8 R 9 ) m -(C 3 ~C 6 cycloalkyl), each heteroaryl, heterocyclyl, aryl, or cycloalkyl group optionally being selected from 1 to 5 R 10 In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, R 8 and R 9 are independently H, C 1 ~C 3 Alkyl, or C 1 ~C 3 In some embodiments, R 8 and R 9 are independently H, -CH 3 , or -CF 3 In some embodiments, R 7 teeth,

[0022] [ka] is selected from the group consisting of:

[0023] In some embodiments, R 6 and R 7 together with the nitrogen atom to which they are attached form a 5-10 membered monocyclic or fused bicyclic heteroaryl, or a 4-10 membered monocyclic or fused bicyclic heterocyclyl, each heteroaryl or heterocyclyl optionally containing 1-2 additional heteroatoms selected from the group consisting of N, S, and O, and each heteroaryl or heterocyclyl optionally containing 1-5 R 10 In some embodiments, R 6 and R 7 together with the nitrogen atom to which they are attached form a 5-6 membered monocyclic heteroaryl, an 8-10 membered fused bicyclic heteroaryl, a 4-6 membered monocyclic heterocyclyl, or an 8-10 membered fused bicyclic heterocyclyl, each heteroaryl or heterocyclyl optionally containing 1-2 additional heteroatoms selected from the group consisting of N, S, and O, and each heteroaryl or heterocyclyl optionally contains 1-5 R 10 In some embodiments, R 6 and R 7 together with the nitrogen atom to which they are attached,

[0024] [ka] It is formed.

[0025] In some embodiments, each R 10 If present, independently, C 1 ~C 3 Alkyl, C 1 ~C 3 Haloalkyl, C 1 ~C 3Alkyl-OH, -CN, C 1 ~C 3 Alkyl-CN, -O(C 1 ~C 3 alkyl), -O(C 1 ~C 3 haloalkyl), halo, hydroxy, oxo, -CO 2 H, -C(O)NH(C 1 ~C 3 alkyl), -C(O)NH(C 1 ~C 3 haloalkyl), -C(O)O(C 1 ~C 3 Alkyl), -SO 2 -(C 1 ~C 3 Alkyl), -SO 2 -NH(C 1 ~C 3 Alkyl), -SO 2 -N(C 1 ~C 3 Alkyl) 2 , -C(O)(C 1 ~C 3 alkyl), -(C 1 ~C 3 alkylene)-C(O)N(C 1 ~C 3 Alkyl) 2 , -(C 1 ~C 3 alkylene)-C(O)NH(C 1 ~C 3 Alkyl), C 3 ~C 6 Cycloalkyl, 5- to 6-membered heterocyclyl, 5- to 6-membered heteroaryl, -(C 1 ~C 3 alkylene)-(5-6 membered heterocyclyl), -(C 1 ~C 3 alkylene)-(5- to 6-membered heteroaryl), -C(O)-(5- to 6-membered heterocyclyl), -C(O)-(5- to 6-membered heteroaryl), or C 6 ~C 10 aryl, each cycloalkyl, heterocyclyl, heteroaryl, or aryl group optionally containing 1 to 5 R 11or two R 10 The groups, together with the carbon atoms to which they are attached, form spiro C 3 ~C 6 cycloalkyl or spiro 4-6 membered heterocyclyl, each of which is optionally represented by 1 to 5 R 11 In some embodiments, each R 10 are independently -CH 3 , -CH 2 CH 3 , -CH(CH 3 ) 2 , -CF 3 , -CHF 2 , -CH 2 CF 3 , -CH 2 OH, -CN, -CH 2 CN, -OCH 3 , -OCF 3 , Br, F, hydroxy, oxo, -CO 2 H, -C(O)NH(CH 3 ), -C(O)N(CH 3 ) 2 , -C(O)NH(CF 3 ), -C(O)OCH 3 , -SO 2 CH 3 , -SO 2 NH(CH 3 ), -SO 2 N(CH 3 ) 2 , -C(O)CH 3 , -(CH 2 )-C(O)N(CH 3 ) 2 , -(CH 2 )-C(O)NH(CH 3 ),

[0026] [ka] In some embodiments, two R 10 Groups, together with the carbon atoms to which they are attached,

[0027] [ka] The nitrogen atom of the heterocyclyl group is R 11 If it is not substituted by then it is bonded to H.

[0028] In some embodiments, each R 11 If present, independently, C 1 ~C 3 Alkyl, hydroxy, oxo, or -C(O)(C 1 ~C 3 In some embodiments, each R 11 are independently -CH 3 , hydroxy, oxo, or -C(O)CH 3 It is.

[0029] In some embodiments, R 12 , H, C 1 ~C 3 Alkyl, or C 1 ~C 3 In some embodiments, R 12 -H, -CH 3 , or -CF 3 In some embodiments, R 12 is H.

[0030] In some embodiments, R 6 and R 7 together with the nitrogen atom to which they are attached form a 4-10 membered monocyclic or fused bicyclic heterocyclyl, optionally containing 1-2 additional heteroatoms selected from the group consisting of N, S, and O; R 12 is linked to a 4-10 membered monocyclic or fused bicyclic heterocyclyl to form a 7-18 membered fused bicyclic or tricyclic heterocyclyl 1 ~C 6alkylene, and each heterocyclyl optionally has 1 to 5 R 10 In some embodiments, R 6 and R 7 together with the nitrogen atom to which they are attached form a 4-6 membered monocyclic heterocyclyl optionally containing 1-2 additional heteroatoms selected from the group consisting of N, S, and O; R 12 is linked to a 4-6 membered monocyclic heterocyclyl to form a 7-11 membered fused bicyclic heterocyclyl 1 ~C 3 alkylene, and each heterocyclyl optionally has 1 to 5 R 10 or R 6 and R 7 together with the nitrogen atom to which they are attached form an 8-10 membered fused bicyclic heterocyclyl optionally containing 1-2 additional heteroatoms selected from the group consisting of N, S, and O; R 12 is linked to an 8-10 membered fused bicyclic heterocyclyl to form an 11-15 membered fused tricyclic heterocyclyl 1 ~C 3 alkylene, and each heterocyclyl optionally has 1 to 5 R 10 In some embodiments, R 6 and R 7 together with the nitrogen atom to which they are attached form a 5- to 6-membered monocyclic heterocyclyl; R 12 is attached to a 5-6 membered monocyclic heterocyclyl:

[0031] [ka] -CH 2 -It is.

[0032] Also disclosed herein is a compound of formula (II):

[0033] [ka] or a tautomer thereof, or a pharma- ceutically acceptable salt thereof, wherein: R 21 and R 22 are independently H, C 1 ~C 6 Alkyl, halo, C 1 ~C 6 Haloalkyl or C 3 ~C 6 cycloalkyl, but when Y is S or a bond, R 21 and R 22 is not a halo; or R 21 and R 22 together with the carbon atoms to which they are attached;

[0034] [ka] It is formed, Y is CR 23 R 24 , S, or a bond; R 23 and R 24 are independently H, halo, and C 1 ~C 6 Alkyl or C 1 ~C 6 haloalkyl; or R 21 and R 23 together with the carbon atom to which they are attached, form a moiety;

[0035] [ka] It is formed, R 25 is C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, or C3 ~C 6 is cycloalkyl; W is CH or N;

[0036] [ka] teeth,

[0037] [ka] is selected from the group consisting of where nitrogen atoms are represented by R if necessary to satisfy valences. 26 is bonded to H when not substituted by Each R 26 is independently 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, C 1 ~C 6 Alkyl-OH, C 1 ~C 6 Alkyl-CN, -(CR 28 R 29 ) p -(4-6 membered heterocyclyl), -(CR 28 R 29 ) p -(5-6 membered heteroaryl), -(CR 28 R 29 ) p -(C 6 ~C 10 aryl), or -(CR 28 R 29 ) p -(C 3 ~C 6 cycloalkyl), each cycloalkyl, heterocyclyl, heteroaryl, or aryl group optionally containing 1 to 5 R 27 is substituted by a group; Each R 27 is independently 1 ~C 6 Alkyl, C 1 ~C6 Alkyl-OH, C 1 ~C 6 Haloalkyl, C 1 ~C 6 Alkyl-CN, -CN, halo, hydroxy, -O-(C 1 ~C 6 alkyl), -O(C 1 ~C 6 haloalkyl), oxo, -C(O)NH 2 , -C(O)NH(C 1 ~C 6 alkyl), -C(O)N(C 1 ~C 6 Alkyl) 2 , -C(O)NH(C 1 ~C 6 haloalkyl), -CO 2 H, -C(O)O(C 1 ~C 6 Alkyl), -SO 2 -(C 1 ~C 6 Alkyl), -SO 2 -NH(C 1 ~C 6 Alkyl), -SO 2 -N(C 1 ~C 6 Alkyl) 2 , -C(O)(C 1 ~C 6 alkyl), -(C 1 ~C 6 alkylene)-C(O)N(C 1 ~C 6 Alkyl) 2 , or -(C 1 ~C 6 alkylene)-C(O)NH(C 1 ~C 6 alkyl); p is 0 or 1; R 28 and R 29 are independently H, C 1 ~C 6 Alkyl, or C 1 ~C 6 is haloalkyl; Each R 30 are independently H, C1 ~C 3 Alkyl, C 1 ~C 3 Haloalkyl, or C 1 ~C 3 It is alkyl-OH.

[0038] In some embodiments, R 21 and R 22 are independently H, C 1 ~C 3 Alkyl, halo, C 1 ~C 3 Haloalkyl, or C 3 ~C 5 In some embodiments, R 21 and R 22 are independently H, -CH 3 , F, -CF 3 or cyclobutyl. In some embodiments, R 21 and R 22 together with the carbon atom to which they are attached,

[0039] [ka] It is formed.

[0040] In some embodiments, Y is S. In some embodiments, Y is CR 23 R 24 In some embodiments, Y is a bond.

[0041] In some embodiments, R 23 and R 24 are independently H, halo, and C 1 ~C 3 Alkyl, or C 1 ~C 3 In some embodiments, R 23 and R 24 are independently H, F, -CH 3 , or -CF3 It is.

[0042] In some embodiments, R 21 and R 23 Together with the carbon atoms to which they are attached,

[0043] [ka] In some embodiments, R 22 , H, C 1 ~C 3 Alkyl, halo, or C 1 ~C 3 haloalkyl; R 24 , H, C 1 ~C 3 Alkyl, halo, or C 1 ~C 3 haloalkyl; each R 30 are independently H, C 1 ~C 2 Alkyl, C 1 ~C 2 Haloalkyl, or C 1 ~C 2 In some embodiments, R 22 -H, -CH 3 , F, or -CF 3 ;R 24 -H, -CH 3 , F, or -CF 3 and each R 30 are independently H, -CH 3 , -CF 3 , or -CH 2 In some embodiments, R 22 and R 24 Each is H; each R 30 is H.

[0044] In some embodiments, R 25 is C 1 ~C 3 Alkyl, C 1 ~C3 Haloalkyl, or C 3 ~C 4 In some embodiments, R 25 is -CH 3 , -CF 3 or cyclopropyl.

[0045] In some embodiments, W is CH. In some embodiments, W is N.

[0046] In some embodiments, each R 26 If present, independently, C 1 ~C 3 Alkyl, C 1 ~C 3 Haloalkyl, C 1 ~C 3 Alkyl-OH, C 1 ~C 3 Alkyl-CN, -(CR 28 R 29 ) p -(4-6 membered heterocyclyl), -(CR 28 R 29 ) p -(5-6 membered heteroaryl), -(CR 28 R 29 ) p -(C 6 ~C 10 aryl), or -(CR 28 R 29 ) p -(C 3 ~C 6 cycloalkyl), each heterocyclyl, heteroaryl, aryl, or cycloalkyl group optionally having 1 to 5 R 27 In some embodiments, p is 0. In some embodiments, p is 1. In some embodiments, R 28 and R 29 are independently H, C 1 ~C 3 Alkyl, or C 1 ~C 3 In some embodiments, R28 and R 29 are independently H, -CH 3 , or -CF 3 In some embodiments, each R 26 are independently -CH 3 , -CF 3 , -CH 2 OH, -CH 2 C.N.,

[0047] [ka] It is.

[0048] In some embodiments, each R 27 If present, independently, C 1 ~C 3 Alkyl, C 1 ~C 3 Alkyl-OH, C 1 ~C 3 Haloalkyl, C 1 ~C 3 Alkyl-CN, -CN, halo, hydroxy, -O-(C 1 ~C 3 alkyl), -O(C 1 ~C 3 haloalkyl), oxo, -C(O)NH 2 , -C(O)NH(C 1 ~C 3 alkyl), -C(O)NH(C 1 ~C 3 haloalkyl), -C(O)N(C 1 ~C 3 Alkyl) 2 , -CO 2 H, -C(O)O(C 1 ~C 3 Alkyl), -SO 2 -(C 1 ~C 3 Alkyl), -SO 2 -NH(C 1 ~C 3 Alkyl), -SO 2 -N(C 1 ~C 3Alkyl) 2 , -C(O)(C 1 ~C 3 alkyl), -(C 1 ~C 3 alkylene)-C(O)N(C 1 ~C 3 Alkyl) 2 , or -(C 1 ~C 3 alkylene)-C(O)NH(C 1 ~C 3 In some embodiments, each R 27 are independently -CH 3 , -CH 2 OH, -CF 3 , -CH 2 CN, -CN, F, Cl, hydroxy, -OCH 3 , -OCF 3 , oxo, -C(O)NH 2 , -C(O)NH(CH 3 ), -C(O)NH(CF 3 ), -C(O)N(CH 3 ) 2 , -CO 2 H, -C(O)OCH 3 , -SO 2 -(CH 3 ), -SO 2 -NH(CH 3 ), -SO 2 -N(CH 3 ) 2 , -C(O)(CH 3 ), -(CH 2 )-C(O)N(CH 3 ) 2 , or -(CH 2 )-C(O)NH(CH 3 ).

[0049]

[0031] Also disclosed herein is a compound selected from the compounds in Table 1, or a tautomer thereof, or a pharma- ceutically acceptable salt thereof. Also disclosed herein is a compound selected from the compounds in Table 2, or a tautomer thereof, or a pharma- ceutically acceptable salt thereof. Also disclosed herein is a compound selected from any compound disclosed above or herein, or a tautomer thereof, or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable excipient.

[0050]

[0032] Also disclosed herein is a method for modulating the activity of an immune cell, comprising contacting an immune cell with an effective amount of any compound previously or disclosed herein, or a tautomer thereof, or a pharma- ceutically acceptable salt thereof.

[0051]

[0033] Also disclosed in the present specification is a method for treating a cancer that responds to inhibition of Cbl-b activity in an individual in need of such treatment, the method comprising administering to the individual an effective amount of any compound disclosed above or in the present specification, or a tautomer thereof, or a pharma- ceutically acceptable salt thereof.

[0052]

[0034] Also disclosed in the present specification is a method for inhibiting Cbl-b activity in an individual in need of inhibition of Cbl-b activity, comprising administering to the individual an effective amount of any compound disclosed above or in the present specification, or a tautomer thereof, or a pharma- ceutically acceptable salt thereof.

[0053]

[0035] Also disclosed in the present specification is a method for treating or preventing a disease or condition associated with Cbl-b activity in an individual in need of such treatment or prevention, the method comprising administering to the individual any compound disclosed above or in the present specification, or a tautomer thereof, or a pharma- ceutically acceptable salt thereof.

[0054]

[0036] Also disclosed herein is a method for producing modified immune cells, the method comprising culturing a cell population containing immune cells in the presence of an effective amount of any compound disclosed above or herein, or a tautomer thereof, or a pharma- ceutically acceptable salt thereof.

[0055]

[0037] Also disclosed in the present specification are modified immune cells comprising a Cbl-b inhibitor, wherein the Cbl-b inhibitor is any compound disclosed above or in the present specification, or a tautomer thereof, or a pharma-ceutically acceptable salt thereof.

[0056]

[0038] Also disclosed in the present specification are isolated modified immune cells, which have been or are in contact with any compound disclosed in the present specification, or a tautomer thereof, or a pharma- ceutically acceptable salt thereof.

[0057]

[0039] Also disclosed herein is a composition comprising a cell population containing isolated modified immune cells, where the immune cells have been or have been in contact with any compound disclosed herein, or a tautomer thereof, or a pharma- ceutically acceptable salt thereof.

[0058]

[0040] Also disclosed herein is a method of inhibiting abnormal cell proliferation comprising administering to an individual in need of inhibition of abnormal cell proliferation an effective amount of isolated modified immune cells that have previously been or have been in contact with any compound disclosed herein, or a tautomer thereof, or a pharma-ceutically acceptable salt thereof.

[0059]

[0041] Also disclosed herein is a method of inhibiting abnormal cell proliferation comprising administering to an individual in need a composition comprising a cell population containing isolated modified immune cells that has previously or has been in contact with or is in contact with any compound disclosed herein, or a tautomer thereof, or a pharma-ceutically acceptable salt thereof.

[0060]

[0042] Also disclosed herein is a method for inhibiting abnormal cell proliferation, comprising administering an effective amount of any compound disclosed above or herein, or a tautomer thereof, or a pharma- ceutically acceptable salt thereof.

[0061]

[0043] Also disclosed in the present specification is a cell culture composition comprising a cell population containing immune cells and a Cbl-b inhibitor, wherein the Cbl-b inhibitor is any compound disclosed above or in the present specification, or a tautomer thereof, or a pharma-ceutically acceptable salt thereof.

[0062]

[0044] Also disclosed in the present specification is a pharmaceutical composition comprising a Cbl-b inhibitor and one or both of an adjuvant and an antigen, wherein the Cbl-b inhibitor is any compound disclosed above or in the present specification, or a tautomer thereof, or a pharma-ceutically acceptable salt thereof.

[0063]

[0045] Also disclosed herein is an article of manufacture comprising any modified immune cell disclosed herein, any composition comprising a cell population disclosed herein, any cell culture composition disclosed herein, or any pharmaceutical composition disclosed herein.

[0064]

[0046] Also disclosed herein is a kit comprising any of the modified immune cells disclosed herein, or any composition comprising a cell population disclosed herein.

[0065]

[0047] Also disclosed in the present specification is the use of a Cbl-b inhibitor in the manufacture of a medicament for treating or preventing a disease or condition associated with Cbl-b activity, wherein the Cbl-b inhibitor is any compound disclosed above or in the present specification, or a tautomer thereof, or a pharma-ceutically acceptable salt thereof.

[0066] In any of the embodiments disclosed herein, the Cbl-b protein may be mammalian Cbl-b or human Cbl-b. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0067] Provided herein are compounds and pharmaceutical compositions that inhibit the Cbl-b enzyme, and methods of treatment using such compounds and pharmaceutical compositions.The compounds and compositions can be used in methods of regulating the immune system, treating disease, and treating cells in vivo, in vitro, or ex vivo.

[0068]

[0050] T cell activation and T cell tolerance are tightly regulated processes that control immune responses to tumors while preventing autoimmunity. Tolerance prevents the immune system from attacking cells that express "self" antigens. During peripheral tolerance, T cells that recognize "self" antigens (i.e., autoreactive T cells) become functionally unresponsive or are deleted after encountering "self" antigens outside the thymus. Thus, peripheral tolerance processes are important to prevent autoimmune diseases. Normally, cancer cells are eliminated by activated T cells that recognize tumor antigens expressed on the surface of cancer cells. However, in cancer, the tumor microenvironment supports T cell tolerance to cancer cells, which allows them to avoid recognition and elimination by the immune system. The ability of cancer cells to evade tumor immune surveillance can contribute to unregulated tumor growth. Thus, T cell tolerance can be a form of T cell dysfunction. The general principles of T cell dysfunction are well known in the art (see Schietinger et al., Trends Immunol., vol. 35: 51-60, 2014). Additional types of T cell dysfunction that may contribute to unregulated tumor growth include T cell exhaustion, T cell senescence, and / or T cell anergy. Thus, treating T cell dysfunction, for example, by increasing T cell activation, increasing T cell proliferation, decreasing T cell tolerance, and / or decreasing T cell exhaustion, is beneficial for preventing or treating cancer. Additional cells of the immune system are important for the recognition and elimination of cancer cells during immune surveillance. For example, natural killer (NK) cells are lymphocytes of the innate immune system that can identify and kill cancer cells (see Martinez-Losato et al., Clin Cancer Res., vol. 21: 5048-5056, 2015). Recent studies have also demonstrated that phenotypically and functionally distinct B cell subsets exhibit diverse roles in antitumor responses (Saravaria et al., Cell Mol Immunol. 14:662-674, 2017). Due to their role in tumor surveillance, NK cells and B cells may be applicable as therapeutic targets for the prevention or treatment of cancer.

[0069] Cbl-b is a RING-type E3 ligase that plays an important role in the immune system due to its function as a negative regulator of immune activation. Cbl-b has an essential role in enhancing T cell tolerance by reducing T cell activation. Studies have found that Cbl-b-deficient T cells exhibit a lower threshold for activation by antigen recognition receptors and costimulatory molecules (e.g., CD28). For example, loss of Cbl-b in T cells uncouples the requirement for CD28 costimulation during T cell activation and proliferation (see Bachmaier et al., Nature, vol. 403: pp. 211-216, 2000). Such cbl-b- / - T cells are largely resistant to T cell anergy, a tolerance mechanism in which T cells are functionally inactive and T cell proliferation is severely impaired (see Jeon et al., Immunity, 21:167-177, 2004; and Schwartz et al., Annu Rev Immunol., 21:305-34, 2003). In support of this, loss of Cbl-b in cbl-b knockout mice resulted in impaired induction of T cell tolerance and exacerbated autoimmunity (see Jeon et al., Immunity, 21:167-177, 2004). Importantly, loss of Cbl-b in mice also resulted in robust antitumor responses that were primarily dependent on cytotoxic T cells. One study showed that cbl-b- / - CD8+ T cells were resistant to T regulatory cell-mediated suppression and exhibited enhanced activation and tumor infiltration. Therapeutic transfer of naive cbl-b- / - CD8+ T cells was sufficient to mediate rejection of established tumors (see Loeser et al., J Exp Med. 204:879-891, 2007). Recent studies also show that Cbl-b plays a role in NK cell activation. Genetic deletion of Cbl-b or targeted inactivation of its E3 ligase activity enables NK cells to spontaneously reject metastatic tumors in mouse models (see Paolino et al., Nature 507:508-512, 2014).

[0070] Provided herein are compounds and compositions that are potent inhibitors of Cbl-b and can be used to treat disease, such as cancer, in a new approach.In some embodiments, provided herein are compounds and compositions that can be used in the method of regulating immune system, for example, increasing the activation of T cells, NK cells, and B cells, and in vivo, in vitro, or ex vivo treatment of such cells.

[0071] I. Definition

[0053] An "effective amount" of an agent disclosed herein is an amount sufficient to carry out a specifically defined purpose. An "effective amount" may be determined empirically and in a routine manner in relation to the defined purpose. An "effective amount" or a "sufficient amount" of an agent is that amount appropriate to produce a desired biological effect, such as a beneficial outcome, including a beneficial clinical outcome. In some embodiments, the term "effective amount" refers to an amount of an agent effective to "treat" a disease or disorder in an individual (e.g., a mammal such as a human).

[0072]

[0054] The term "Cbl-b" as used herein refers to Cbl-b protein. The term also includes naturally occurring variants of Cbl-b, including splice variants or allelic variants. The term also includes non-naturally occurring variants of Cbl-b, such as recombinant Cbl-b proteins or truncated variants thereof, that generally preserve the binding ability (e.g., ability to bind E2 enzyme) of native Cbl-b or naturally occurring variants of Cbl-b.

[0073]

[0055] The terms "pharmaceutical formulation" and "pharmaceutical composition" refer to a preparation that is in a form that allows the biological activity of the active ingredient to be effective and does not contain additional ingredients that are unacceptably toxic to the individual to whom the formulation or composition is administered. Such a formulation or composition may be sterile.

[0074]

[0056] As used herein, "excipient" includes a pharma- ceutically acceptable excipient, carrier, vehicle, or stabilizer that is non-toxic to cells or mammals exposed thereto at the doses and concentrations used. Often, the physiologically acceptable excipient is an aqueous pH buffered solution.

[0075]

[0057] References to a compound described in a pharmaceutical composition, or to a compound described in a claim to a pharmaceutical composition, refer to the compound described by the formula shown in the pharmaceutical composition, without other elements of the pharmaceutical composition, i.e., carriers, excipients, etc.

[0076] The term "treating" a disease or "treatment" refers to carrying out a protocol that may include administering one or more therapeutic agents to an individual (such as a human) to obtain a beneficial or desired result in the individual, including a clinical result. Beneficial or desired clinical results include, but are not limited to, reduction or remission of one or more symptoms of the disease, reduction in the extent of the disease, a stabilized (i.e., non-progressing) state of the disease, preventing the spread of the disease, delay or slowing of disease progression, remission or alleviation of the disease state, and remission (whether partial or complete). "Treatment" can also mean extending survival compared to the expected survival of an individual not receiving treatment. Furthermore, "treating" and "treatment" may occur by a single administration of one or more therapeutic agents, or may occur during a series of multiple administrations of one or more therapeutic agents. "Treating" or "treatment" does not require complete reduction of signs or symptoms, and does not require a cure. "Treatment" can also refer to clinical intervention, such as administering to an individual one or more therapeutic agents designed to modify the natural processes of the individual or cells being treated (i.e., to modify the processes of the individual or cells that would occur in the absence of clinical intervention). The term "therapeutic agent" can refer to a Cbl-b inhibitor, modified immune cells or compositions thereof.

[0077]

[0059] As used herein, an "individual" or "subject" is a mammal. For purposes of treatment, "mammals" include humans, non-human primates, domestic and farm animals, zoo animals, sports animals or pet animals, such as dogs, horses, rabbits, cows, pigs, hamsters, gerbils, mice, ferrets, rats, cats, etc. In some embodiments, the individual or subject is a human.

[0078]

[0060] As used herein, the term "T cell dysfunction" refers to a situation in which immune responsiveness to antigen stimulation is reduced. The term "T cell dysfunction" includes the general elements of both T cell exhaustion and / or T cell anergy, in which antigen recognition can occur but the subsequent immune response is ineffective in controlling tumor growth. The term "T cell dysfunction" also includes refractory or non-responsive to antigen recognition, such as impaired ability to translate antigen recognition into downstream T cell effector functions, such as proliferation, cytokine production and / or target cell killing.

[0079] The term "T cell anergy" refers to a state of unresponsiveness to antigenic stimulation resulting from defective or insufficient signals delivered through the T cell receptor. "T cell anergy" can also occur upon stimulation by antigen in the absence of costimulation, thereby rendering the cells refractory to subsequent activation by antigen even in the context of costimulation.

[0080] The term "T cell exhaustion" refers to a state of T cell dysfunction resulting from sustained TCR signaling that can occur during cancer. It is distinct from anergy in that it results from sustained signaling rather than through defective or deficient signaling. It is defined by poor effector function, sustained expression of inhibitory receptors, and a transcriptional landscape distinct from functional effector or memory T cells.

[0081]

[0063] "T cell dysfunction disorder" is a disorder or condition characterized by a decreased responsiveness of T cells to antigenic stimulation. The decreased responsiveness may result in ineffective tumor control. In some embodiments, the term "T cell dysfunction disorder" encompasses cancer, such as hematological or non-hematological cancer. In some embodiments, "T cell dysfunction disorder" is one in which T cells are anergic or have a decreased ability to secrete cytokines, proliferate, or carry out cytolytic activity.

[0082] "Enhancing T cell function" means inducing, causing or stimulating the persistence or amplification of biological function of T cells, or regenerating or reactivating exhausted or inactive T cells. Examples of enhancing T cell function include increased T cell activation (e.g., increased cytokine production, increased expression of T cell activation markers, etc.), increased T cell proliferation, decreased T cell exhaustion, and / or decreased T cell tolerance, compared to the status of T cells before treatment with a Cbl-b inhibitor. Methods for measuring enhanced T cell function are known in the art.

[0083] "Proliferation" is used herein to refer to the proliferation of cells. An increase in proliferation encompasses the production of more cells compared to a baseline value. A decrease in proliferation encompasses the production of fewer cells compared to a baseline value. In some embodiments, the cells are immune cells, such as T cells, and an increase in proliferation is desired. In some embodiments, the cells are cancer cells, and a decrease in proliferation is desired.

[0084] As used herein, "alkyl" refers to a saturated linear (i.e., unbranched) or branched monovalent hydrocarbon chain or combinations thereof. Particular alkyl groups are those having a given number of carbon atoms, for example, alkyl groups having 1 to 20 carbon atoms ("C 1 ~C 20 alkyl) and alkyl groups having 1 to 10 carbon atoms ("C 1 ~C 10" alkyl), alkyl groups having 1 to 8 carbon atoms ("C 1 ~C 8 alkyl) and alkyl groups having 1 to 6 carbon atoms ("C 1 ~C 6 alkyl) and alkyl groups having 2 to 6 carbon atoms ("C 2 ~C 6 alkyl) or an alkyl group having 1 to 4 carbon atoms ("C 1 ~C 4 Examples of alkyl groups include, but are not limited to, groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, and homologs and isomers of, for example, n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like.

[0085] As used herein, "alkenyl" refers to an unsaturated linear (i.e., unbranched) or branched monovalent hydrocarbon chain, or combinations thereof, having at least one site of olefinic unsaturation (i.e., having at least one moiety of the formula C=C). Particular alkenyl groups are those having a given number of carbon atoms, for example, alkenyl groups having 2 to 20 carbon atoms ("C 2 ~C 20 alkenyl) having 2 to 10 carbon atoms ("C 2 ~C 10 " alkenyl), alkenyl groups having 2 to 8 carbon atoms ("C 2 ~C 8 alkenyl) and alkenyl groups having 2 to 6 carbon atoms ("C 2 ~C 6 alkenyl) or an alkenyl group having 2 to 4 carbon atoms ("C 2 ~C 4Alkenyl groups may be in the "cis" or "trans" configuration, or alternatively, in the "E" or "Z" configuration. Examples of alkenyl groups include, but are not limited to, groups such as ethenyl (or vinyl), prop-1-enyl, prop-2-enyl (or allyl), 2-methylprop-1-enyl, but-1-enyl, but-2-enyl, but-3-enyl, buta-1,3-dienyl, 2-methylbuta-1,3-dienyl, homologs and isomers thereof.

[0086] As used herein, "alkynyl" refers to an unsaturated linear (i.e., unbranched) or branched monovalent hydrocarbon chain, or combinations thereof, having at least one site of acetylenic unsaturation (i.e., having at least one moiety of the formula C≡C). Particular alkynyl groups are those having a given number of carbon atoms, for example, alkynyl groups having 2 to 20 carbon atoms ("C 2 ~C 20 alkynyl groups having 2 to 10 carbon atoms ("C 2 ~C 10 alkynyl groups having 2 to 8 carbon atoms ("C 2 ~C 8 alkynyl groups having 2 to 6 carbon atoms ("C 2 ~C 6 alkynyl) or an alkynyl group having 2 to 4 carbon atoms ("C 2 ~C 4 Examples of alkynyl groups include, but are not limited to, groups such as ethynyl (or acetylenyl), prop-1-ynyl, prop-2-ynyl (or propargyl), but-1-ynyl, but-2-ynyl, but-3-ynyl, homologs and isomers thereof.

[0087]

[0069] As used herein, "alkylene" refers to a residue the same as alkyl, but having two valencies. Particular alkylene groups are those having 1 to 6 carbon atoms ("C 1~C 6 alkylene) having 1 to 5 carbon atoms ("C 1 ~C 5 alkylene), those having 1 to 4 carbon atoms ("C 1 ~C 4 alkylene"), or those having 1 to 3 carbon atoms ("C 1 ~C 3 An example of an alkylene group is methylene (-CH 2 -), ethylene (-CH 2 CH 2 -), propylene (-CH 2 CH 2 CH 2 -), butylene (-CH 2 CH 2 CH 2 CH 2 -), but are not limited to these.

[0088] As used herein, "cycloalkyl" refers to a non-aromatic saturated cyclic monovalent hydrocarbon structure or a non-aromatic unsaturated cyclic monovalent hydrocarbon structure. Particular cycloalkyl groups are those having a certain number of cyclic (i.e., ring) carbon atoms, such as cycloalkyl groups having 3 to 12 cyclic carbon atoms ("C 3 ~C 12 A particular cycloalkyl is a cyclic hydrocarbon having 3 to 8 ring carbon atoms ("C 3 ~C 8 cycloalkyl"), or a cyclic hydrocarbon having 3 to 6 ring carbon atoms ("C 3 ~C 6 Cycloalkyl groups include cycloalkyl groups, such as cyclohexyl, cyclohexane, cyclopropyl, cyclohexane-1, cyclohexane-2, cyclohexane-3, cyclohexane-4, cyclohexane-5, cyclohexane-6, cyclohexane-7, cyclohexane-8, cyclohexane-9, cyclohexane-10, cyclohexane-11, cyclohexane-12, cyclohexane-13, cyclohexane-14, cyclohexane-15, cyclohexane-16, cyclohexane-17, cyclohexane-18, cyclohexane-19, cyclohexane-20, cyclohexane-21, cyclohexane-22, cyclohexane-23, cyclohexane-24, cyclohexane-25, cyclohexane-36, cyclohexane-37, cyclohexane-40, cyclohexane-58, cyclohexane-60, cyclohexane-71, cyclohexane-82, cyclohexane-91, cyclohexane-112,

[0089] [ka]

[0090] Cyclobutyl

[0091] [ka]

[0092] Cyclopentyl

[0093] [ka]

[0094] Cyclohexyl

[0095] [ka]

[0096] 1-Cyclohexenyl, 3-Cyclohexenyl, cycloheptyl

[0097] [ka]

[0098] Norbornyl, but are not limited to these.

[0099]

[0071] As used herein, "cycloalkylene" refers to a residue the same as cycloalkyl, but having two valencies. Particular cycloalkylene groups are those having 3 to 12 ring carbon atoms ("C 3 ~C 12 Cycloalkylene"), those with 3 to 8 cyclic carbon atoms ("C 3 ~C 8 cycloalkylene"), or those having 3 to 6 cyclic carbon atoms ("C 3 ~C 6Examples of cycloalkylene groups include cyclopropylene.

[0100] [ka]

[0101] Cyclobutylene

[0102] [ka]

[0103] Cyclopentylene

[0104] [ka]

[0105] Cyclohexylene

[0106] [ka]

[0107] 1,2-cyclohexenylene, 1,3-cyclohexenylene, 1,4-cyclohexenylene, cycloheptylene

[0108] [ka]

[0109] Norbornylene, but is not limited thereto.

[0110] As used herein, "aryl" refers to an aromatic carbocyclic group having a single ring (e.g., phenyl) or an aromatic carbocyclic group having multiple fused rings where one or more of the fused rings may not be aromatic (e.g., naphthyl or anthryl). Particular aryl groups are those having 6 to 14 annular (i.e., ring) carbon atoms ("C 6 ~C 14 Aryl groups having two or more rings, where at least one ring is non-aromatic, may be linked to the parent structure at an aromatic ring position or a non-aromatic ring position. In one variation, aryl groups having two or more rings, where at least one ring is non-aromatic, are linked to the parent structure at an aromatic ring position. Examples of aryl include phenyl, naphthyl, 1-naphthyl, 2-naphthyl, 1,2,3,4-tetrahydronaphthalene-6- ...

[0111] [ka]

[0112] Groups such as, but not limited to, are included.

[0113]

[0073] "Carbocyclyl" or "carbocyclic" refers to an aromatic or non-aromatic monovalent cyclic radical in which all of the ring members are carbon atoms, eg, cyclohexyl, phenyl, 1,2-dihydronaphthyl, and the like.

[0114]

[0074] As used herein, "arylene" refers to a residue the same as aryl, but having two valencies. Particular arylene groups are those having 6 to 14 ring carbon atoms ("C 6 ~C 14Examples of arylene include, but are not limited to, groups such as phenylene, o-phenylene (i.e., 1,2-phenylene), m-phenylene (i.e., 1,3-phenylene), p-phenylene (i.e., 1,4-phenylene), naphthylene, 1,2-naphthylene, 1,3-naphthylene, 1,4-naphthylene, 2,7-naphthylene, and 2,6-naphthylene.

[0115]

[0075] As used herein, "heteroaryl" refers to an unsaturated aromatic ring group having 1 to 14 ring carbon atoms and at least one ring heteroatom, including, but not limited to, heteroatoms such as nitrogen (N), oxygen (O) and sulfur (S). Heteroaryl groups may have a single ring (e.g., pyridyl or imidazolyl) or multiple fused rings where at least one of the fused rings is aromatic (e.g., indolizinyl, indolyl or quinolinyl). Particular heteroaryl groups are 5-14 membered rings having 1-12 annular carbon atoms and 1-6 annular heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur ("5-14 membered heteroaryl"), 5-10 membered rings having 1-8 annular carbon atoms and 1-4 annular heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur ("5-10 membered heteroaryl"), or 5-, 6-, or 7-membered rings having 1-5 annular carbon atoms and 1-4 annular heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur ("5-7 membered heteroaryl"). In one variation, heteroaryl includes a monocyclic aromatic 5-, 6-, or 7-membered ring having 1-6 annular carbon atoms and 1-4 annular heteroatoms independently selected from the group consisting of nitrogen (N), oxygen (O), and sulfur (S). In another variation, heteroaryl includes polycyclic aromatic rings having 1-12 ring carbon atoms and 1-6 ring heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur. Heteroaryl groups having two or more rings, where at least one ring is non-aromatic, may be linked to the parent structure at an aromatic or non-aromatic ring position. Examples of heteroaryl include, but are not limited to, groups such as pyridyl, benzimidazolyl, benzotriazolyl, benzo[b]thienyl, quinolinyl, indolyl, and benzothiazolyl. "Heteroaryl" refers to

[0116] [ka]

[0117] (2,4-dihydro-3H-1,2,4-triazol-3-one-2-yl), wherein the (2,4-dihydro-3H-1,2,4-triazol-3-one-2-yl) is an aromatic tautomeric structure.

[0118] [ka]

[0119] (1H-1,2,4-triazol-5-ol-1-yl) is also included.

[0120]

[0076] As used herein, "heterocyclyl" and "heterocyclic group" refer to a non-aromatic saturated or partially unsaturated cyclic group having a specified number of atoms and heteroatoms, or, if the number of atoms or heteroatoms is not specified, a non-aromatic saturated or partially unsaturated cyclic group having at least three ring atoms, 1-14 ring carbon atoms, and at least one ring heteroatom, including but not limited to heteroatoms such as nitrogen, oxygen, and sulfur. Heterocyclic groups may have a single ring (e.g., tetrahydrothiophenyl, oxazolidinyl) or multiple condensed rings (e.g., decahydroquinolinyl, octahydrobenzo[d]oxazolyl). Multiple condensed rings include, but are not limited to, bicyclic, tricyclic, and quadracylic rings, as well as bridged or spirocyclic ring systems. Examples of heterocyclic groups include, but are not limited to, aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, oxiranyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, oxazolidinyl, piperazinyl, morpholinyl, dioxanyl, 3,6-dihydro-2H-pyranyl, 2,3-dihydro-1H-imidazolyl, and the like.

[0121]

[0077] As used herein, "heteroarylene" refers to a residue the same as heteroaryl, but with a divalent ring. Particular heteroarylene groups are 5-14 membered rings having 1-12 ring carbon atoms and 1-6 ring heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur ("5-14 membered heteroarylenes"), 5-10 membered rings having 1-8 ring carbon atoms and 1-4 ring heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur ("5-10 membered heteroarylenes"), or 5-, 6-, or 7-membered rings having 1-5 ring carbon atoms and 1-4 ring heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur ("5-7 membered heteroarylenes"). Examples of heteroarylene include, but are not limited to, groups such as pyridylene, benzimidazolylene, benzotriazolylene, benzo[b]thienylene, quinolinylene, indolylene, and benzothiazolylene.

[0122]

[0078] "Halo" or "halogen" refers to elements of the Group 17 series having atomic numbers 9 through 85. Halo groups include fluoro (F), chloro (Cl), bromo (Br) and iodo (I).

[0123]

[0079] "Haloalkyl", "haloalkylene", "haloaryl", "haloarylene", "haloheteroaryl" and similar terms refer to a moiety substituted with at least one halo group. When a haloalkyl moiety or other halo-substituted moiety is substituted with more than one halogen, it may be designated using a prefix corresponding to the number of halogen moieties added. For example, dihaloaryl, dihaloalkyl, trihaloaryl, trihaloalkyl, etc. refer to aryl and alkyl substituted with two ("di") or three ("tri") halo groups, which may be, but not necessarily, the same halo, thus, for example, the haloaryl group 4-chloro-3-fluorophenyl is within the scope of dihaloaryl. The subset of haloalkyl groups in which each hydrogen (H) of the alkyl group is replaced with a halo group is referred to as "perhaloalkyl". Certain perhaloalkyl groups include trifluoroalkyl (-CF 3 Similarly, "perhaloalkoxy" refers to an alkoxy group in which a halogen replaces each hydrogen (H) in the hydrocarbon that makes up the alkyl portion of the alkoxy group. An example of a perhaloalkoxy group is trifluoromethoxy (-OCF 3 "Haloalkyl" includes monohaloalkyl, dihaloalkyl, trihaloalkyl, perhaloalkyl, and any other number of halo substituents possible on an alkyl group, as well as other groups such as haloalkylene, haloaryl, haloarylene, haloheteroaryl, and the like.

[0124] "Amino" refers to the group -NH 2 Refers to...

[0125]

[0081] "Oxo" refers to the group =O, ie, an oxygen atom double bonded to carbon or other chemical element.

[0126]

[0082] Unless otherwise indicated, "optionally substituted" means that a group is unsubstituted or substituted with one or more (e.g., 1, 2, 3, 4, or 5) of the substituents listed for that group, where the substituents may be the same or different. In one embodiment, an optionally substituted group is unsubstituted. In one embodiment, an optionally substituted group has one substituent. In another embodiment, an optionally substituted group has two substituents. In another embodiment, an optionally substituted group has three substituents. In another embodiment, an optionally substituted group has four substituents. In some embodiments, an optionally substituted group has 1-2, 1-3, 1-4, or 1-5 substituents. When multiple substituents are present, each substituent is independently selected unless otherwise indicated. For example, the group -N(C 1 ~C 4 Alkyl)(C 1 ~C 4 Each (C alkyl) 1 ~C 4 Alkyl) substituents include groups such as -N(CH 3 )(CH 2 CH 3 ), etc.

[0127]

[0083] In addition to the disclosures herein, the term "substituted" when used to modify a particular group or radical can also mean that one or more hydrogen atoms (H) of the particular group or radical are each independently replaced with the same or different substituents as defined herein. In some embodiments, a substituted group has one, two, three or four substituents, one, two or three substituents, one or two substituents, or one substituent.

[0128]

[0084] Substituents may be attached at any chemically possible position on a particular group or radical, unless otherwise specified. Thus, in one embodiment, -C 1 ~C 8 Examples of alkyl-OH include -CH 2 CH 2 OH, -CH(OH)-CH 3 , -CH 2 C(OH)(CH 3 ) 2 As a further example, in one embodiment, 1 ~C 6 Examples of alkyl-OH include -CH 2 CH 2 OH, -CH(OH)CH 3 , -CH 2 C(OH)(CH 3 ) 2 As a further example, in one embodiment, 1 ~C 6 Examples of alkyl-CN include -CH 2 CH 2 CN, -CH(CN)CH 3 , -CH 2 C(CN)(CH 3 ) 2 etc.

[0129]

[0085] Unless a specific isotope of an element is indicated in a formula, the present disclosure is directed to, for example, 2 H, i.e., deuterium (D), and all isotopologues of the compounds disclosed herein. Deuterated compounds may provide favorable changes in pharmacokinetic (ADME) properties. Isotopologues may have isotopic substitutions at some or all positions in the structure, or may have atoms present at natural abundance at some or all positions in the structure.

[0130] As used herein, "small molecule" refers to a compound having a molecular weight below 1,000 daltons.

[0131]

[0087] Hydrogen atoms can be substituted with close bioisosteres, such as fluorine, provided that such substitution results in a stable compound.

[0132]

[0088] The present disclosure includes any or all of the stereochemical forms, including any enantiomeric or diastereomeric forms, of the compounds described herein, as well as cis / trans or E / Z isomers. Unless stereochemistry is explicitly indicated in a chemical structure or chemical name, the structure or name is intended to encompass all possible stereoisomers of the compound shown. Furthermore, when a specific stereochemical form is shown, it is understood that all other stereochemical forms, as well as general non-stereospecific forms and non-stereospecific mixtures of the disclosed compounds in any ratio, such as mixtures of two or more stereochemical forms of the disclosed compounds in any ratio, are also described and encompassed in the present disclosure, thereby encompassing racemic, non-racemic, enantioenriched and scalemic mixtures of the compounds. Compositions including the disclosed compounds, such as compositions of substantially pure compounds containing their specific stereochemical forms, are also contemplated. Compositions comprising mixtures of the disclosed compounds in any ratio are also encompassed by the disclosure, such as compositions comprising mixtures of two or more stereochemical forms of the disclosed compounds in any ratio, such that racemic, non-racemic, enantioenriched and scalemic mixtures of the compounds are encompassed by the disclosure. When stereochemistry is explicitly shown for a portion or portions of a molecule but not for another portion or portions of the molecule, the structure is intended to encompass all possible stereoisomers for the portion or portions where stereochemistry is not explicitly shown.

[0133]

[0089] The present disclosure also encompasses some and all tautomeric forms of the compounds described herein.

[0134]

[0090] The present disclosure is intended to encompass all salts of the compounds described herein and methods of using such salts of the compounds. In one embodiment, the salts of the compounds include pharma- ceutically acceptable salts. Pharmaceutically acceptable salts are those salts that can be administered as drugs or medicines to humans and / or animals and that retain at least a portion of the biological activity of the free compounds (i.e., neutral or non-salt compounds) upon administration. The desired salts of basic compounds may be prepared by methods known to those skilled in the art by treating the compound with an acid. Examples of inorganic acids include, but are not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid. Examples of organic acids include, but are not limited to, formic acid, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, sulfonic acid, and salicylic acid. Salts of basic compounds with amino acids can be prepared, such as aspartic acid salts and glutamic acid salts. Desired salts of acidic compounds can be prepared by methods known to those skilled in the art by treating the compound with a base. Examples of inorganic salts of acidic compounds include, but are not limited to, alkali metal salts and alkaline earth salts, such as sodium salts, potassium salts, magnesium salts and calcium salts; ammonium salts; and aluminum salts. Examples of organic salts of acidic compounds include, but are not limited to, procaine salts, dibenzylamine salts, N-ethylpiperidine salts, N,N'-dibenzylethylenediamine salts and triethylamine salts. Salts of acidic compounds with amino acids can also be prepared, such as lysine salts. For a list of pharmaceutically acceptable salts, see, for example, P.H. Stahl and C.G. Wermuth (eds.), "Handbook of Pharmaceutical Salts, Properties, Selection and Use," Wiley-VCH, 2011 (ISBN: 978-3-90639-051-2). Some pharma- ceutically acceptable salts are also disclosed in Berge, J. Pharm. Sci. 66:1 (1977).

[0135] As described in Biological Example 1A, IC for Cbl-b inhibition 50 The Cbl-b activity assay (Cbl-b inhibition assay) used to measure the IC value uses a mixture containing the candidate compound, Cbl-b (truncated, Avitag-bearing, biotinylated), fluorescently labeled E2 enzyme UbcH5B labeled with ubiquitin conjugated to BODIPY-fluorescein (UbcH5B-Ub), streptavidin-terbium, and assay buffer. In one embodiment, the IC value for inhibition of Cbl-b is 50 The Cbl-b activity assay (Cbl-b inhibition assay) used to measure Cbl-b activity uses the conditions described in Biological Example 1A with 12 nM Cbl-b. Inhibition of fluorescence energy transfer indicates Cbl-b activity. In another embodiment, the IC for inhibition of Cbl-b is 50 The Cbl-b activity assay (Cbl-b inhibition assay) used to measure Cbl-b activity uses the conditions described in Biological Example 1B with candidate compounds, 0.125 nM Cbl-b (truncated, avitag-bearing, biotinylated), fluorescently labeled inhibitor probe and assay buffer. Displacement of the inhibitor probe indicates Cbl-b activity.

[0136] It is recognized that certain features disclosed herein that are described in the context of separate embodiments for clarity may be provided in combination in a single embodiment. Conversely, various features disclosed herein that are described in the context of a single embodiment for brevity may be provided separately or in any suitable subcombination. All combinations of the embodiments relating to the chemical groups represented by the variants are specifically included in the present disclosure and are disclosed herein simply as if any combination were individually and explicitly disclosed to the extent that such combinations include compounds that are stable compounds (i.e., compounds that can be isolated, characterized, and tested for biological activity). Furthermore, all subcombinations of the chemical groups shown in the embodiments describing such variants are also specifically included in the present disclosure and are disclosed herein simply as if any such subcombination of the chemical groups were individually and explicitly disclosed herein.

[0137]

[0093] Aspects and embodiments described in this specification as "comprising" are understood to include the embodiments "consisting of" and "consisting essentially of."

[0138]

[0094] As used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless specifically stated otherwise or clear from the context. For example, "an" excipient includes one or more excipients.

[0139]

[0095] References to a value preceded by "about" include 90% to 110% of that value. For example, "about 50,000,000,000 cells" refers to 45,000,000,000 to 55,000,000,000 cells, including 50,000,000,000 cells. For example, a temperature of "about 100 degrees" refers to a temperature of about 90 degrees to about 110 degrees.

[0140]

[0096] When numerical ranges of compounds are given, all compounds within those numerical limits specified by "a" and "b" are included unless specifically and explicitly excluded. For example, reference to compounds 20-25 refers to compounds 20, 21, 22, 23, 24, and 25.

[0141] II. Compounds In one embodiment, provided is a compound of formula (I):

[0142] [ka] or a tautomer thereof, or a pharma- ceutically acceptable salt thereof; During the ceremony, R 1 and R 2 are independently H, C 1 ~C 6 Alkyl, halo, or C 1 ~C 6 haloalkyl, but when X is S, R 1 and R 2 provided that neither of R and Y are H, and if Y is S or a bond, then R 1 and R 2 is not a halo; or R 1 and R 2 together with the carbon atoms to which they are attached;

[0143] [ka] It is formed, X is CR 3 R 4 Or S; R 3 and R 4 are independently H, C 1 ~C 6 Alkyl, halo, or C 1 ~C6 haloalkyl; or R 1 and R 3 together with the carbon atom to which they are attached, form a moiety;

[0144] [ka] It is formed, R 5 is C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, or C 3 ~C 6 is cycloalkyl; Z is CH or N; n is 0 or 1; R 6 , H, C 1 ~C 6 Alkyl, or C 1 ~C 6 is haloalkyl; R 7 is C 1 ~C 6 Alkyl-OH, -(CR 8 R 9 ) m -(5-10 membered monocyclic or fused bicyclic heteroaryl), -(CR 8 R 9 ) m -(4-10 membered monocyclic or fused bicyclic heterocyclyl), -(CR 8 R 9 ) m -(C 6 ~C 10 aryl), or -(CR 8 R 9 ) m -(C 3 ~C 6 cycloalkyl), each heteroaryl, heterocyclyl, aryl, or cycloalkyl group optionally being selected from 1 to 5 R 10 or R 6and R 7 together with the nitrogen atom to which they are attached form a 5-10 membered monocyclic or fused bicyclic heteroaryl, or a 4-10 membered monocyclic or fused bicyclic heterocyclyl, each heteroaryl or heterocyclyl optionally containing 1-2 additional heteroatoms selected from the group consisting of N, S, and O, and each heteroaryl or heterocyclyl optionally containing 1-5 R 10 is substituted by a group; m is 0 or 1; R 8 and R 9 are independently H, C 1 ~C 6 Alkyl, or C 1 ~C 6 is haloalkyl; Each R 10 is independently 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, C 1 ~C 6 Alkyl-OH, -CN, C 1 ~C 6 Alkyl-CN, -O(C 1 ~C 6 alkyl), -O(C 1 ~C 6 haloalkyl), halo, hydroxy, oxo, -CO 2 H, -C(O)NH(C 1 ~C 6 alkyl), -C(O)N(C 1 ~C 6 Alkyl) 2 , -C(O)NH(C 1 ~C 6 haloalkyl), -C(O)O(C 1 ~C 6 Alkyl), -SO 2 -(C 1 ~C 6 Alkyl), -SO 2 -NH(C 1 ~C 6 Alkyl), -SO 2 -N(C 1~C 6 Alkyl) 2 , -C(O)(C 1 ~C 6 alkyl), -(C 1 ~C 6 alkylene)-C(O)N(C 1 ~C 6 Alkyl) 2 , -(C 1 ~C 6 alkylene)-C(O)NH(C 1 ~C 6 Alkyl), C 3 ~C 6 Cycloalkyl, 5- to 6-membered heterocyclyl, 5- to 6-membered heteroaryl, -(C 1 ~C 6 alkylene)-(5-6 membered heterocyclyl), -(C 1 ~C 6 alkylene)-(5- to 6-membered heteroaryl), -C(O)-(5- to 6-membered heterocyclyl), -C(O)-(5- to 6-membered heteroaryl), or C 6 ~C 10 aryl, each cycloalkyl, heterocyclyl, heteroaryl, or aryl group optionally containing 1 to 5 R 11 or Two R's attached to the same carbon atom 10 The groups, together with the carbon atoms to which they are attached, form spiro C 3 ~C 6 cycloalkyl or spiro 4-6 membered heterocyclyl, each of which is optionally represented by 1 to 5 R 11 is substituted by a group; Each R 11 is independently 1 ~C 6 Alkyl, hydroxy, oxo, or -C(O)(C 1 ~C 6 alkyl); R 12 , H, C 1 ~C 6 Alkyl, or C 1 ~C 6 haloalkyl, or R6 and R 7 together with the nitrogen atom to which they are attached form a 4-10 membered monocyclic or fused bicyclic heterocyclyl, optionally containing 1-2 additional heteroatoms selected from the group consisting of N, S, and O; R 12 is linked to a 4-10 membered monocyclic or fused bicyclic heterocyclyl to form a 7-14 membered fused bicyclic or tricyclic heterocyclyl 1 ~C 6 alkylene, and each heterocyclyl optionally has 1 to 5 R 10 groups; each R 13 are independently H, C 1 ~C 3 Alkyl, C 1 ~C 3 Alkyl-OH, or C 1 ~C 3 It is haloalkyl.

[0145]

[0098] In some embodiments, Z is CH or N. In some embodiments, Z is CH. In other embodiments, Z is N.

[0146] In some embodiments, R 1 and R 2 are independently H, C 1 ~C 6 Alkyl, halo, or C 1 ~C 6 haloalkyl, but when X is S, R 1 and R 2 provided that neither of R is H, and Y is S or a bond, then R 1 and R 2 is not a halo (i.e., if Y is S or a bond, then R 1 Also 2 and R is not halo. 1 and R 2 are independently H, C 1 ~C 3 Alkyl, halo, or C 1~C 3 haloalkyl, but when X is S, R 1 and R 2 provided that neither of R is H, and Y is S or a bond, then R 1 and R 2 is not halo. 1 and R 2 are independently H, -CH 3 , F, or -CF 3 But if X is S, then R 1 and R 2 provided that neither of R is H, and Y is S or a bond, then R 1 and R 2 is only applicable if it is not a halo.

[0147] In some embodiments, R 1 is H.

[0148] In some embodiments, R 1 is C 1 ~C 6 In some embodiments, R 1 is C 1 ~C 3 In some embodiments, R 1 is methyl, ethyl, n-propyl, or isopropyl. 1 Ha-CH 3 It is.

[0149] In some embodiments, R 1 is halo. In some embodiments, R 1 is chloro, fluoro, or bromo. 1 is chloro or fluoro. In some embodiments, R 1 is fluoro.

[0150] In some embodiments, R 1 is C1 ~C 6 In some embodiments, R 1 C containing 1 to 7 halogen atoms 1 ~C 6 In some embodiments, R 1 is C 1 ~C 3 In some embodiments, R 1 C containing 1 to 7 halogen atoms 1 ~C 3 In some embodiments, R 1 C containing 1 to 5 halogen atoms 1 ~C 3 In some embodiments, the halogen atoms are independently selected from the group consisting of chloro, bromo, and fluoro atoms. In some embodiments, the halogen atoms are independently selected from the group consisting of chloro and fluoro atoms. In some embodiments, all of the halogen atoms are fluoro atoms. In some embodiments, the halogen atoms are a combination of chloro and fluoro atoms. In some embodiments, R 1 -CF 3 , -CCl 3 , -CF 2 Cl, -CFCl 2 , -CHF 2 , -CH 2 F, -CHCl 2 or -CHFCl. In some embodiments, R 1 -CF 3 It is.

[0151] In some embodiments, R 2 is H.

[0152] In some embodiments, R 2 is C 1 ~C 6 In some embodiments, R 2 is C 1 ~C 3In some embodiments, R 2 is methyl, ethyl, n-propyl, or isopropyl. 2 Ha-CH 3 It is.

[0153] In some embodiments, R 2 is halo. In some embodiments, R 2 is chloro, fluoro, or bromo. 2 is chloro or fluoro. In some embodiments, R 2 is fluoro.

[0154] In some embodiments, R 2 is C 1 ~C 6 In some embodiments, R 2 C containing 1 to 7 halogen atoms 1 ~C 6 In some embodiments, R 2 is C 1 ~C 3 In some embodiments, R 2 C containing 1 to 7 halogen atoms 1 ~C 3 In some embodiments, R 2 C containing 1 to 5 halogen atoms 1 ~C 3 In some embodiments, the halogen atoms are independently selected from the group consisting of chloro, bromo, and fluoro atoms. In some embodiments, the halogen atoms are independently selected from the group consisting of chloro and fluoro atoms. In some embodiments, all of the halogen atoms are fluoro atoms. In some embodiments, the halogen atoms are a combination of chloro and fluoro atoms. In some embodiments, R 2 -CF 3 , -CCl 3 , -CF2 Cl, -CFCl 2 , -CHF 2 , -CH 2 F, -CHCl 2 or -CHFCl. In some embodiments, R 2 -CF 3 It is.

[0155] In some embodiments, R 1 is H and R 2 is C 1 ~C 6 In some embodiments, R 1 is H and R 2 is C 1 ~C 3 In some embodiments, R 1 is H and R 2 is methyl, ethyl, n-propyl, or isopropyl. 1 is H and R 2 is methyl. In some embodiments, R 1 and R 2 are respectively, X is CR 3 R 4 is H. In some embodiments, R 2 is H and R 1 is C 1 ~C 6 In some embodiments, R 2 is H and R 1 is C 1 ~C 3 In some embodiments, R 2 is H and R 1 is methyl, ethyl, n-propyl, or isopropyl. 2 is H and R 1 is methyl.

[0156] In some embodiments, R 1 is the halo, R 2 is C 1 ~C6 In some embodiments, R 1 is halo (e.g., chloro, fluoro, or bromo), and R 2 is C 1 ~C 3 In some embodiments, R is an alkyl group (e.g., methyl, ethyl, n-propyl, or isopropyl). 1 is fluoro and R 2 is methyl.

[0157] In some embodiments, R 2 is the halo, R 1 is C 1 ~C 6 In some embodiments, R 2 is halo (e.g., chloro, fluoro, or bromo), and R 1 is C 1 ~C 3 In some embodiments, R is an alkyl group (e.g., methyl, ethyl, n-propyl, or isopropyl). 2 is fluoro and R 1 is methyl.

[0158] In some embodiments, R 1 and R 2 together with the carbon atom to which they are attached,

[0159] [ka] In some embodiments, R 1 and R 2 together with the carbon atom to which they are attached,

[0160] [ka] In some embodiments, R 1 and R 2together with the carbon atom to which they are attached,

[0161] [ka] In some embodiments, R 1 and R 2 together with the carbon atom to which they are attached,

[0162] [ka] It is formed.

[0163] In some embodiments, X is CR 3 R 4 or S. In some embodiments, X is S. In other embodiments, X is CR 3 R 4 It is.

[0164] In some embodiments, R 3 and R 4 are independently H, C 1 ~C 6 Alkyl, halo, or C 1 ~C 6 In some embodiments, R 3 and R 4 are independently H, halo, and C 1 ~C 3 Alkyl, or C 1 ~C 3 In some embodiments, R 3 and R 4 are independently H, F, -CH 3 , or -CF 3 It is.

[0165] In some embodiments, R 3 is H.

[0166] In some embodiments, R 3 is C 1 ~C 6 In some embodiments, R 3 is C 1 ~C 3 In some embodiments, R 3 is methyl, ethyl, n-propyl, or isopropyl. 3 Ha-CH 3 It is.

[0167] In some embodiments, R 3 is halo. In some embodiments, R 3 is chloro, fluoro, or bromo. 3 is chloro or fluoro. In some embodiments, R 3 is fluoro.

[0168] In some embodiments, R 3 is C 1 ~C 6 In some embodiments, R 3 C containing 1 to 7 halogen atoms 1 ~C 6 In some embodiments, R 3 is C 1 ~C 3 In some embodiments, R 3 C containing 1 to 7 halogen atoms 1 ~C 3 In some embodiments, R 3 C containing 1 to 5 halogen atoms 1 ~C 3In some embodiments, the halogen atoms are independently selected from the group consisting of chloro, bromo, and fluoro atoms. In some embodiments, the halogen atoms are independently selected from the group consisting of chloro and fluoro atoms. In some embodiments, all of the halogen atoms are fluoro atoms. In some embodiments, the halogen atoms are a combination of chloro and fluoro atoms. In some embodiments, R 3 -CF 3 , -CCl 3 , -CF 2 Cl, -CFCl 2 , -CHF 2 , -CH 2 F, -CHCl 2 or -CHFCl. In some embodiments, R 3 -CF 3 It is.

[0169] In some embodiments, R 4 is H.

[0170] In some embodiments, R 4 is C 1 ~C 6 In some embodiments, R 4 is C 1 ~C 3 In some embodiments, R 4 is methyl, ethyl, n-propyl, or isopropyl. 4 Ha-CH 3 It is.

[0171] In some embodiments, R 4 is halo. In some embodiments, R 4 is chloro, fluoro, or bromo. 4 is chloro or fluoro. In some embodiments, R 4 is fluoro.

[0172] In some embodiments, R 4 is C 1 ~C 6 In some embodiments, R 4 C containing 1 to 7 halogen atoms 1 ~C 6 In some embodiments, R 4 is C 1 ~C 3 In some embodiments, R 4 C containing 1 to 7 halogen atoms 1 ~C 3 In some embodiments, R 4 C containing 1 to 5 halogen atoms 1 ~C 3 In some embodiments, the halogen atoms are independently selected from the group consisting of chloro, bromo, and fluoro atoms. In some embodiments, the halogen atoms are independently selected from the group consisting of chloro and fluoro atoms. In some embodiments, all of the halogen atoms are fluoro atoms. In some embodiments, the halogen atoms are a combination of chloro and fluoro atoms. In some embodiments, R 4 -CF 3 , -CCl 3 , -CF 2 Cl, -CFCl 2 , -CHF 2 , -CH 2 F, -CHCl 2 or -CHFCl. In some embodiments, R 4 -CF 3 It is.

[0173] In some embodiments, R 3 and R 4 Each is H. In some embodiments, R 3 is H and R 4 is C 1 ~C 6 In some embodiments, R3 is H and R 4 is C 1 ~C 3 In some embodiments, R 3 is H and R 4 is methyl. In some embodiments, R 4 is H and R 3 is C 1 ~C 6 In some embodiments, R 4 is H and R 3 is C 1 ~C 3 In some embodiments, R 4 is H and R 3 is methyl.

[0174] In some embodiments, R 3 and R 4 Each is independently halo. 3 is fluoro and R 4 is fluoro, chloro, or bromo. 4 is fluoro and R 3 is fluoro, chloro, or bromo. 3 and R 4 are each fluoro.

[0175] In some embodiments, R 1 and R 3 Together with the carbon atoms to which they are attached,

[0176] [ka] In some embodiments, R 2 , H, C 1 ~C 6 Alkyl, halo, or C 1 ~C 6 haloalkyl; R 4, H, C 1 ~C 6 Alkyl, halo, or C 1 ~C 6 haloalkyl; each R 13 are independently H, C 1 ~C 3 Alkyl, C 1 ~C 3 Alkyl-OH, or C 1 ~C 3 In some embodiments, R 2 , H, C 1 ~C 3 Alkyl, halo, or C 1 ~C 3 haloalkyl; R 4 , H, C 1 ~C 3 Alkyl, halo, or C 1 ~C 3 haloalkyl; each R 13 are independently H, C 1 ~C 2 Alkyl, C 1 ~C 2 Alkyl-OH, or C 1 ~C 2 In some embodiments, R 2 -H, -CH 3 , F, or -CF 3 ;R 4 -H, -CH 3 , F, or -CF 3 and each R 13 are independently H, -CH 3 , -CH 2 OH, or -CF 3 In some embodiments, R 2 and R 4 Each is H; each R 13 is H.

[0177] In some embodiments, R 5 is C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, or C3 ~C 6 In some embodiments, R 5 is C 1 ~C 3 Alkyl, C 1 ~C 3 Haloalkyl, or C 3 ~C 4 In some embodiments, R 5 is -CH 3 , -CHF 2 or cyclopropyl.

[0178] In some embodiments, R 5 is C 1 ~C 6 In some embodiments, R 5 is C 1 ~C 3 In some embodiments, R 5 is methyl, ethyl, n-propyl, or isopropyl. 5 Ha-CH 3 It is.

[0179] In some embodiments, R 5 is C 1 ~C 6 In some embodiments, R 5 C containing 1 to 7 halogen atoms 1 ~C 6 In some embodiments, R 5 is C 1 ~C 3 In some embodiments, R 5 C containing 1 to 7 halogen atoms 1 ~C 3 In some embodiments, R 5 C containing 1 to 5 halogen atoms 1 ~C 3In some embodiments, the halogen atoms are independently selected from the group consisting of chloro, bromo, and fluoro atoms. In some embodiments, the halogen atoms are independently selected from the group consisting of chloro and fluoro atoms. In some embodiments, all of the halogen atoms are fluoro atoms. In some embodiments, the halogen atoms are a combination of chloro and fluoro atoms. In some embodiments, R 5 -CF 3 , -CCl 3 , -CF 2 Cl, -CFCl 2 , -CHF 2 , -CH 2 F, -CHCl 2 or -CHFCl. In some embodiments, R 5 -CHF 2 It is.

[0180] In some embodiments, R 5 is C 3 ~C 6 In some embodiments, R 5 is C 3 ~C 5 In some embodiments, R 5 is C 3 ~C 4 In some embodiments, R 5 is cyclopropyl, cyclobutyl, or cyclopentyl. 5 is cyclopropyl.

[0181] In some embodiments, n is 0. In other embodiments, n is 1.

[0182] In some embodiments, R 6 , H, C 1 ~C 6 Alkyl, or C 1 ~C 6In some embodiments, R 6 , H, C 1 ~C 3 Alkyl, or C 1 ~C 3 In some embodiments, R 6 is H or -CH 3 It is.

[0183] In some embodiments, R 6 is H.

[0184] In some embodiments, R 6 is C 1 ~C 6 In some embodiments, R 6 is C 1 ~C 3 In some embodiments, R 6 is methyl, ethyl, n-propyl, or isopropyl. 6 Ha-CH 3 It is.

[0185] In some embodiments, R 6 is C 1 ~C 6 In some embodiments, R 6 C containing 1 to 7 halogen atoms 1 ~C 6 In some embodiments, R 6 is C 1 ~C 3 In some embodiments, R 6 C containing 1 to 7 halogen atoms 1 ~C 3 In some embodiments, R 6 C containing 1 to 5 halogen atoms 1 ~C 3In some embodiments, the halogen atoms are independently selected from the group consisting of chloro, bromo, and fluoro atoms. In some embodiments, the halogen atoms are independently selected from the group consisting of chloro and fluoro atoms. In some embodiments, all of the halogen atoms are fluoro atoms. In some embodiments, the halogen atoms are a combination of chloro and fluoro atoms. In some embodiments, R 6 -CF 3 , -CCl 3 , -CF 2 Cl, -CFCl 2 , -CHF 2 , -CH 2 F, -CHCl 2 , -CHFCl, -CH 2 CF 3 , -CH 2 CCl 3 , -CH 2 CH 2 F, or -CH 2 CH 2 It is Cl.

[0186] In some embodiments, R 7 is C 1 ~C 6 Alkyl-OH, -(CR 8 R 9 ) m -(5-10 membered monocyclic or fused bicyclic heteroaryl), -(CR 8 R 9 ) m -(4-10 membered monocyclic or fused bicyclic heterocyclyl), -(CR 8 R 9 ) m -(C 6 ~C 10 aryl), or -(CR 8 R 9 ) m -(C 3 ~C 6 cycloalkyl), each heteroaryl, heterocyclyl, aryl, or cycloalkyl group optionally being selected from 1 to 5 R 10In some embodiments, R 7 is C 1 ~C 3 Alkyl-OH, -(CR 8 R 9 ) m -(5-6 membered monocyclic heteroaryl), -(CR 8 R 9 ) m -(8-10 membered fused bicyclic heteroaryl), -(CR 8 R 9 ) m -(4-6 membered monocyclic heterocyclyl), -(CR 8 R 9 ) m -(8-10 membered fused bicyclic heterocyclyl), -(CR 8 R 9 ) m -(C 6 ~C 10 aryl), or -(CR 8 R 9 ) m -(C 3 ~C 6 cycloalkyl), each heteroaryl, heterocyclyl, aryl, or cycloalkyl group optionally being selected from 1 to 5 R 10 is substituted by a group.

[0187] In some embodiments, R 7 is C 1 ~C 6 In some embodiments, R 7 is linear C 1 ~C 6 In some embodiments, R 7 is branched C 1 ~C 6 In some embodiments, R 7 is C 1 ~C 4 In some embodiments, R 7 is C 1 ~C 3 In some embodiments, R 7-CH 2 OH 2 , -CH 2 CH 2 OH, -CH 2 CH 2 CH 2 OH, or -C(CH 3 )OH. In some embodiments, R 7 is -CH(CH 3 )CH 2 OH, -C(CH 3 ) 2 CH 2 OH, -CH 2 CH(CH 3 )OH, or -CH 2 C(CH 3 ) 2 In some embodiments, R 7 -CH(CH 3 )CH 2 It is OH.

[0188] In some embodiments, R 7 CR 8 R 9 ) m -(5-10 membered monocyclic or fused bicyclic heteroaryl), wherein the heteroaryl is optionally selected from 1-5 R 10 In some embodiments, m is 0 and R 7 is a 5-10 membered monocyclic or fused bicyclic heteroaryl, the heteroaryl optionally containing 1-5 R 10 In some embodiments, m is 1 and R 7 HA-CR 8 R 9 -(5-10 membered monocyclic or fused bicyclic heteroaryl), wherein the heteroaryl is optionally selected from 1-5 R 10 In some embodiments, R 7 CR 8 R 9 ) m -(5-6 membered monocyclic heteroaryl), the heteroaryl optionally having 1-5 R10 In some embodiments, m is 0 and R 7 is a 5-6 membered monocyclic heteroaryl, the heteroaryl optionally containing 1-5 R 10 In some embodiments, m is 1 and R 7 HA-CR 8 R 9 -(5-6 membered monocyclic heteroaryl), the heteroaryl optionally having 1-5 R 10 In some embodiments, R 7 CR 8 R 9 ) m -(8-10 membered fused bicyclic heteroaryl), wherein the heteroaryl is optionally selected from 1 to 5 R 10 In some embodiments, m is 0 and R 7 is an 8-10 membered fused bicyclic heteroaryl, the heteroaryl optionally containing 1-5 R 10 In some embodiments, m is 1 and R 7 HA-CR 8 R 9 -(8-10 membered fused bicyclic heteroaryl), wherein the heteroaryl is optionally selected from 1 to 5 R 10In some embodiments, the fused bicyclic heteroaryl contains an unsaturated or partially saturated ring fused to an aromatic ring. In some embodiments, the fused bicyclic heteroaryl contains an aromatic ring fused to a second aromatic ring. In some embodiments, the heteroaryl contains 1-3 nitrogen atoms. In some embodiments, the heteroaryl contains 1 nitrogen atom. In some embodiments, the heteroaryl contains 2 nitrogen atoms. In some embodiments, the heteroaryl contains 1-2 nitrogen atoms and 1-2 sulfur atoms. In some embodiments, the heteroaryl contains 2 nitrogen atoms and 1 sulfur atom. In some embodiments, the heteroaryl contains 1-2 nitrogen atoms and 1-2 oxygen atoms. In some embodiments, the heteroaryl contains 1 nitrogen atom and 1 oxygen atom. In some embodiments, the heteroaryl contains 1-5 R 10 In some embodiments, the heteroaryl is substituted with one R 10 In some embodiments, the heteroaryl is substituted with two R 10 In some embodiments, the heteroaryl is substituted with three R 10 In some embodiments, the heteroaryl is substituted with four R groups. 10 In some embodiments, the heteroaryl is substituted with five R groups. 10 In some embodiments, the heteroaryl is unsubstituted. In some embodiments, the heteroaryl is pyridyl, imidazolyl, triazolyl, pyrrolyl, quinolinyl, isoquinolinyl, pyridazinyl, pyrazolyl, pyrimidinyl, pyrazinyl, or thiazolyl. In some embodiments, R 7 teeth,

[0189] [ka] In the formula, -(R 10 )0~5 represents optional substitution of any of the two rings constituting a fused bicyclic ring system or any atom of a monocyclic ring system, and a nitrogen atom may be optionally substituted with R if necessary to satisfy the valence of the nitrogen atom. 10 When not substituted by, it is bonded to H. In some embodiments, both rings of the fused bicyclic ring system are substituted. In some embodiments, one of the two rings of the fused bicyclic ring system is substituted and the other ring is unsubstituted. In some embodiments, both rings of the fused bicyclic ring system are unsubstituted.

[0190] In some embodiments, R 7 CR 8 R 9 ) m -(4-10 membered monocyclic or fused bicyclic heterocyclyl), the heterocyclyl optionally being selected from 1 to 5 R 10 In some embodiments, m is 0 and R 7 is a 4-10 membered monocyclic or fused bicyclic heterocyclyl, the heterocyclyl optionally being selected from 1-5 R 10 In some embodiments, m is 1 and R 7 HA-CR 8 R 9 -(4-10 membered monocyclic or fused bicyclic heterocyclyl), the heterocyclyl optionally being selected from 1 to 5 R 10 In some embodiments, R 7 CR 8 R 9 ) m -(4-6 membered monocyclic heterocyclyl), the heterocyclyl optionally being selected from 1 to 5 R 10 In some embodiments, m is 0 and R 7 is a 4-6 membered monocyclic heterocyclyl, the heterocyclyl optionally being selected from 1 to 5 R 10 In some embodiments, m is 1 and R 7 HA-CR 8 R9 -(4-6 membered monocyclic heterocyclyl), the heterocyclyl optionally being selected from 1 to 5 R 10 In some embodiments, R 7 CR 8 R 9 ) m -(8-10 membered fused bicyclic heterocyclyl), the heterocyclyl optionally being selected from 1 to 5 R 10 In some embodiments, m is 0 and R 7 is an 8-10 membered fused bicyclic heterocyclyl, the heterocyclyl optionally containing 1-5 R 10 In some embodiments, m is 1 and R 7 HA-CR 8 R 9 -(8-10 membered fused bicyclic heterocyclyl), the heterocyclyl optionally being selected from 1 to 5 R 10 In some embodiments, the heterocyclyl is substituted by a group. In some embodiments, the heterocyclyl contains 1 to 3 nitrogen atoms. In some embodiments, the heterocyclyl contains 1 nitrogen atom. In some embodiments, the heterocyclyl contains 2 nitrogen atoms. In some embodiments, the heterocyclyl contains 1 to 2 nitrogen atoms and 1 to 2 sulfur atoms. In some embodiments, the heterocyclyl contains 2 nitrogen atoms and 1 sulfur atom. In some embodiments, the heterocyclyl contains 1 to 2 nitrogen atoms and 1 to 2 oxygen atoms. In some embodiments, the heterocyclyl contains 1 nitrogen atom and 1 oxygen atom. In some embodiments, the heterocyclyl contains 1 oxygen atom. In some embodiments, the heterocyclyl contains 1 sulfur atom. In some embodiments, the heterocyclyl contains 1 to 5 R 10 In some embodiments, the heterocyclyl is substituted by one R 10 In some embodiments, the heterocyclyl is substituted by two R 10In some embodiments, the heterocyclyl is substituted by three R 10 In some embodiments, the heterocyclyl is substituted by four R 10 In some embodiments, the heterocyclyl is substituted by five R 10 In some embodiments, the heterocyclyl is unsubstituted. In some embodiments, the heterocyclyl is pyrrolidinyl, piperidinyl, or tetrahydrofuranyl. In some embodiments, R 7 teeth

[0191] [ka] and the nitrogen atom is R 10 If it is not substituted by then it is bonded to H.

[0192] In some embodiments, R 7 CR 8 R 9 ) m -(C 6 ~C 10 aryl), wherein aryl is optionally selected from 1 to 5 R 10 In some embodiments, m is 0 and R 7 is C 6 ~C 10 aryl, optionally containing 1 to 5 R 10 In some embodiments, m is 1 and R 7 HA-CR 8 R 9 -(C 6 ~C 10 aryl), wherein aryl is optionally selected from 1 to 5 R 10 In some embodiments, R 7 CR 8 R 9 ) m -(C 6aryl), wherein aryl is optionally selected from 1 to 5 R 10 In some embodiments, m is 0 and R 7 is C 6 ~C 10 aryl, optionally containing 1 to 5 R 10 In some embodiments, the aryl is substituted by a group. In some embodiments, the aryl is a monocyclic aromatic ring. In some embodiments, the aryl is a fused bicyclic ring. In some embodiments, the aryl contains an aromatic ring fused to a second aromatic ring. In some embodiments, the aryl contains an aromatic ring fused to a saturated or partially unsaturated ring. In some embodiments, the aryl is substituted by 1 to 5 R 10 In some embodiments, the aryl is substituted with one R 10 In some embodiments, the aryl is substituted with two R 10 In some embodiments, the aryl is substituted with three R 10 In some embodiments, the aryl is substituted with four R 10 In some embodiments, the aryl is substituted with five R groups. 10 In some embodiments, the aryl is substituted by a phenyl group. In some embodiments, the aryl is unsubstituted. In some embodiments, the aryl is phenyl. In some embodiments, R 7 teeth,

[0193] [ka] It is.

[0194] In some embodiments, R 7 CR 8 R 9 ) m -(C 3 ~C 6 cycloalkyl), wherein cycloalkyl optionally contains 1 to 5 R 10In some embodiments, m is 0 and R 7 is C 3 ~C 6 cycloalkyl, optionally having 1 to 5 R 10 In some embodiments, m is 1 and R 7 HA-CR 8 R 9 -(C 3 ~C 6 cycloalkyl), wherein cycloalkyl optionally contains 1 to 5 R 10 In some embodiments, the cycloalkyl is substituted with 1 to 5 R 10 In some embodiments, the cycloalkyl is substituted with one R 10 In some embodiments, the cycloalkyl is substituted with two R 10 In some embodiments, the cycloalkyl is substituted with three R 10 In some embodiments, the cycloalkyl is substituted with four R groups. 10 In some embodiments, the cycloalkyl is substituted with five R groups. 10 In some embodiments, the cycloalkyl is substituted by a cycloalkyl group. In some embodiments, the cycloalkyl is unsubstituted. In some embodiments, the cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In some embodiments, the cycloalkyl is cyclobutyl or cyclohexyl. In some embodiments, R 7 teeth,

[0195] [ka] It is.

[0196] In some embodiments, R 7 teeth,

[0197] [ka] -(R 10 ) 0~5 represents optional substitution of any of the two rings constituting a fused bicyclic ring system or any atom of a monocyclic ring system, and a nitrogen atom may be optionally substituted with R if necessary to satisfy the valence of the nitrogen atom. 10 When not substituted by, it is bonded to H. In some embodiments, both rings of the fused bicyclic ring system are substituted. In some embodiments, one of the two rings of the fused bicyclic ring system is substituted and the other ring is unsubstituted. In some embodiments, both rings of the fused bicyclic ring system are unsubstituted.

[0198] In some embodiments, R 6 and R 7 together with the nitrogen atom to which they are attached form a 5-10 membered monocyclic or fused bicyclic heteroaryl, or a 4-10 membered monocyclic or fused bicyclic heterocyclyl, each heteroaryl or heterocyclyl optionally containing 1-2 additional heteroatoms selected from the group consisting of N, S, and O, and each heteroaryl or heterocyclyl optionally containing 1-5 R 10 In some embodiments, R 6 and R 7 together with the nitrogen atom to which they are attached form a 5-6 membered monocyclic heteroaryl, an 8-10 membered fused bicyclic heteroaryl, a 4-6 membered monocyclic heterocyclyl, or an 8-10 membered fused bicyclic heterocyclyl, each heteroaryl or heterocyclyl optionally containing 1-2 additional heteroatoms selected from the group consisting of N, S, and O, and each heteroaryl or heterocyclyl optionally contains 1-5 R 10 is substituted by a group.

[0199] In some embodiments, R 6 and R 7together with the nitrogen atom to which they are attached form a 5-10 membered monocyclic or fused bicyclic heteroaryl, the heteroaryl optionally containing 1-2 additional heteroatoms selected from the group consisting of N, S, and O, the heteroaryl optionally containing 1-5 R 10 In some embodiments, R 6 and R 7 together with the nitrogen atom to which they are attached form a 5-6 membered monocyclic heteroaryl, which optionally contains 1-2 additional heteroatoms selected from the group consisting of N, S, and O, and which optionally contains 1-5 R 10 In some embodiments, R 6 and R 7 together with the nitrogen atom to which they are attached form an 8-10 membered fused bicyclic heteroaryl, the heteroaryl optionally containing 1-2 additional heteroatoms selected from the group consisting of N, S, and O, the heteroaryl optionally containing 1-5 R 10 In some embodiments, the fused bicyclic heteroaryl contains a saturated or partially unsaturated ring fused to an aromatic ring. In some embodiments, the fused bicyclic heteroaryl contains an aromatic ring fused to a second aromatic ring. In some embodiments, the heteroaryl contains 1-2 additional heteroatoms selected from the group consisting of N, S, and O. In some embodiments, the heteroaryl contains 1 additional nitrogen atom. In some embodiments, the heteroaryl contains 2 additional nitrogen atoms. In some embodiments, the heteroaryl contains 1 additional nitrogen atom and 1 oxygen atom. In some embodiments, the heteroaryl contains 1 additional nitrogen atom and 1 sulfur atom. In some embodiments, the heteroaryl contains 1-5 R 10 In some embodiments, the heteroaryl is substituted with one R 10In some embodiments, the heteroaryl is substituted with two R 10 In some embodiments, the heteroaryl is substituted with three R 10 In some embodiments, the heteroaryl is substituted with four R groups. 10 In some embodiments, the heteroaryl is substituted with five R groups. 10 In some embodiments, the heteroaryl is unsubstituted. In some embodiments, both rings of the fused bicyclic heteroaryl are substituted. In some embodiments, one of the rings of the fused bicyclic heteroaryl is substituted and the second ring is unsubstituted. In some embodiments, R 6 and R 7 together with the nitrogen atom to which they are attached,

[0200] [ka] It forms -(R 10 ) 0~5 represents optional substitution of either of the two rings that make up the fused bicyclic ring system, and the nitrogen atom may be replaced by R 10 When not substituted by, it is bonded to H. In some embodiments, both rings of the fused bicyclic ring system are substituted. In some embodiments, one of the two rings of the fused bicyclic ring system is substituted and the other ring is unsubstituted. In some embodiments, both rings of the fused bicyclic ring system are unsubstituted.

[0201] In some embodiments, R 6 and R 7 together with the nitrogen atom to which they are attached form a 4-10 membered monocyclic or fused bicyclic heterocyclyl, the heterocyclyl optionally containing 1-2 additional heteroatoms selected from the group consisting of N, S, and O, and the heterocyclyl optionally containing 1-5 R10 In some embodiments, R 6 and R 7 together with the nitrogen atom to which they are attached form a 4-6 membered monocyclic heterocyclyl, which optionally contains 1-2 additional heteroatoms selected from the group consisting of N, S, and O, and which optionally contains 1-5 R 10 In some embodiments, R 6 and R 7 together with the nitrogen atom to which they are attached form an 8-10 membered fused bicyclic heterocyclyl, the heterocyclyl optionally containing 1-2 additional heteroatoms selected from the group consisting of N, S, and O, and the heterocyclyl optionally containing 1-5 R 10 In some embodiments, the heterocyclyl is substituted by a group. In some embodiments, the heterocyclyl contains 1 to 2 additional heteroatoms selected from the group consisting of N, S, and O. In some embodiments, the heterocyclyl contains 1 additional nitrogen atom. In some embodiments, the heterocyclyl contains 2 additional nitrogen atoms. In some embodiments, the heterocyclyl contains 1 additional nitrogen atom and 1 oxygen atom. In some embodiments, the heterocyclyl contains 1 additional nitrogen atom and 1 sulfur atom. In some embodiments, the heterocyclyl contains 1 to 5 R 10 In some embodiments, the heterocyclyl is substituted by one R 10 In some embodiments, the heterocyclyl is substituted by two R 10 In some embodiments, the heterocyclyl is substituted by three R 10 In some embodiments, the heterocyclyl is substituted by four R 10 In some embodiments, the heterocyclyl is substituted by five R 10In some embodiments, the heterocyclyl is unsubstituted. In some embodiments, both rings of the fused bicyclic heterocyclyl are substituted. In some embodiments, one of the rings of the fused bicyclic heterocyclyl is substituted and the second ring is unsubstituted. In some embodiments, R 6 and R 7 together with the nitrogen atom to which they are attached,

[0202] [ka] It forms -(R 10 ) 0~5 represents optional substitution of any of the two rings constituting a fused bicyclic ring system or any atom of a monocyclic ring system, and a nitrogen atom may be optionally substituted with R if necessary to satisfy the valence of the nitrogen atom. 10 When not substituted by, it is bonded to H. In some embodiments, both rings of the fused bicyclic ring system are substituted. In some embodiments, one of the two rings of the fused bicyclic ring system is substituted and the other ring is unsubstituted. In some embodiments, both rings of the fused bicyclic ring system are unsubstituted.

[0203] In some embodiments, R 6 and R 7 together with the nitrogen atom to which they are attached,

[0204] [ka] In the formula -(R 10 ) 0~5 represents optional substitution of any of the two rings constituting a fused bicyclic ring system or any atom of a monocyclic ring system, and a nitrogen atom may be optionally substituted with R if necessary to satisfy the valence of the nitrogen atom. 10When not substituted by, it is bonded to H. In some embodiments, both rings of the fused bicyclic ring system are substituted. In some embodiments, one of the two rings of the fused bicyclic ring system is substituted and the other ring is unsubstituted. In some embodiments, both rings of the fused bicyclic ring system are unsubstituted.

[0205] In some embodiments, m is 0. In other embodiments, m is 1.

[0206] In some embodiments, R 8 and R 9 are independently H, C 1 ~C 6 Alkyl, or C 1 ~C 6 In some embodiments, R 8 and R 9 are independently H, C 1 ~C 3 Alkyl, or C 1 ~C 3 In some embodiments, R 8 and R 9 are independently H, -CH 3 , or -CF 3 It is.

[0207] In some embodiments, R 8 is H. In some embodiments, R 9 is H. In some embodiments, R 8 and R 9 are both H. In some embodiments, R 8 and R 9 One of them is H and the other is C 1 ~C 6 Alkyl or C 1 ~C 6 In some embodiments, R 8 and R 9 One of them is H and the other is C 1 ~C 3Alkyl or C 1 ~C 3 In some embodiments, R 8 and R 9 One of the groups is H and the other is -CH 3 Or -CF 3 It is.

[0208] In some embodiments, R 8 and R 9 is independently 1 ~C 6 In some embodiments, R 8 and R 9 is independently 1 ~C 3 In some embodiments, R 8 and R 9 is independently methyl, ethyl, n-propyl, or isopropyl. 8 and R 9 are independently -CH 3 In some embodiments, R 8 and R 9 Both are -CH 3 It is.

[0209] In some embodiments, R 8 and R 9 is independently 1 ~C 6 In some embodiments, R 8 and R 9 each independently represents a C group containing 1 to 7 halogen atoms; 1 ~C 6 In some embodiments, R 8 and R 9 is independently 1 ~C 3 In some embodiments, R 8 and R 9 each independently represents a C group containing 1 to 7 halogen atoms; 1 ~C 3In some embodiments, R 8 and R 9 each independently represents a C group containing 1 to 5 halogen atoms; 1 ~C 3 In some embodiments, the halogen atoms are independently selected from the group consisting of chloro, bromo, and fluoro atoms. In some embodiments, the halogen atoms are independently selected from the group consisting of chloro and fluoro atoms. In some embodiments, all of the halogen atoms are fluoro atoms. In some embodiments, the halogen atoms are a combination of chloro and fluoro atoms. In some embodiments, R 8 and R 9 are independently -CF 3 , -CCl 3 , -CF 2 Cl, -CFCl 2 , -CHF 2 , -CH 2 F, -CHCl 2 or -CHFCl. In some embodiments, R 8 and R 9 are independently -CF 3 In some embodiments, R 8 and R 9 Both are -CF 3 It is.

[0210] In some embodiments, each R 10 is independently 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, C 1 ~C 6 Alkyl-OH, -CN, C 1 ~C 6 Alkyl-CN, -O(C 1 ~C 6 alkyl), -O(C 1 ~C 6 haloalkyl), halo, hydroxy, oxo, -CO 2 H, -C(O)NH(C 1 ~C 6alkyl), -C(O)N(C 1 ~C 6 Alkyl) 2 , -C(O)NH(C 1 ~C 6 haloalkyl), -C(O)O(C 1 ~C 6 Alkyl), -SO 2 -(C 1 ~C 6 Alkyl), -SO 2 -NH(C 1 ~C 6 Alkyl), -SO 2 -N(C 1 ~C 6 Alkyl) 2 , -C(O)(C 1 ~C 6 alkyl), -(C 1 ~C 6 alkylene)-C(O)N(C 1 ~C 6 Alkyl) 2 , -(C 1 ~C 6 alkylene)-C(O)NH(C 1 ~C 6 Alkyl), C 3 ~C 6 Cycloalkyl, 5- to 6-membered heterocyclyl, 5- to 6-membered heteroaryl, -(C 1 ~C 6 alkylene)-(5-6 membered heterocyclyl), -(C 1 ~C 6 alkylene)-(5- to 6-membered heteroaryl), -C(O)-(5- to 6-membered heterocyclyl), -C(O)-(5- to 6-membered heteroaryl), or C 6 ~C 10 aryl, each cycloalkyl, heterocyclyl, heteroaryl, or aryl group optionally containing 1 to 5 R 11 In some embodiments, each R 10 If present, independently, C 1 ~C 3 Alkyl, C 1 ~C 3 Haloalkyl, C 1 ~C 3Alkyl-OH, -CN,C 1 ~C 3 Alkyl-CN, -O(C 1 ~C 3 alkyl), -O(C 1 ~C 3 haloalkyl), halo, hydroxy, oxo, -CO 2 H, -C(O)NH(C 1 ~C 3 alkyl), -C(O)NH(C 1 ~C 3 haloalkyl), -C(O)O(C 1 ~C 3 Alkyl), -SO 2 -(C 1 ~C 3 Alkyl), -SO 2 -NH(C 1 ~C 3 Alkyl), -SO 2 -N(C 1 ~C 3 Alkyl) 2 , -C(O)(C 1 ~C 3 alkyl), -(C 1 ~C 3 alkylene)-C(O)N(C 1 ~C 3 Alkyl) 2 , -(C 1 ~C 3 alkylene)-C(O)NH(C 1 ~C 3 Alkyl), C 3 ~C 6 Cycloalkyl, 5- to 6-membered heterocyclyl, 5- to 6-membered heteroaryl, -(C 1 ~C 3 alkylene)-(5-6 membered heterocyclyl), -(C 1 ~C 3 alkylene)-(5- to 6-membered heteroaryl), -C(O)-(5- to 6-membered heterocyclyl), -C(O)-(5- to 6-membered heteroaryl), or C 6 ~C 10 aryl, each cycloalkyl, heterocyclyl, heteroaryl, or aryl group optionally containing 1 to 5 R 11 is substituted by a group.

[0211] In some embodiments, R 10 is C 1 ~C 6 In some embodiments, R 10 is C 1 ~C 3 In some embodiments, R 10 is methyl, ethyl, n-propyl, or isopropyl. 10 is methyl, ethyl, or isopropyl. 10 Ha-CH 3 In some embodiments, R 10 Ha-CH 2 CH 3 In some embodiments, R 10 -CH(CH 3 ) 2 It is.

[0212] In some embodiments, R 10 is C 1 ~C 6 In some embodiments, R 10 C containing 1 to 7 halogen atoms 1 ~C 6 In some embodiments, R 10 is C 1 ~C 3 In some embodiments, R 10 C containing 1 to 7 halogen atoms 1 ~C 3 In some embodiments, R 10 C containing 1 to 5 halogen atoms 1 ~C 3In some embodiments, the halogen atoms are independently selected from the group consisting of chloro, bromo, and fluoro atoms. In some embodiments, the halogen atoms are independently selected from the group consisting of chloro and fluoro atoms. In some embodiments, all of the halogen atoms are fluoro atoms. In some embodiments, the halogen atoms are a combination of chloro and fluoro atoms. In some embodiments, R 10 -CF 3 , -CCl 3 , -CF 2 Cl, -CFCl 2 , -CHF 2 , -CH 2 F, -CHCl 2 , -CHFCl, -CH 2 CF 3 , -CH 2 CCl 3 , -CH 2 CH 2 F, or -CH 2 CH 2 In some embodiments, R 10 -CF 3 , -CHF 2 , or -CH 2 CF 3 In some embodiments, R 10 -CF 3 In some embodiments, R 10 -CHF 2 In some embodiments, R 10 Ha-CH 2 CF 3 It is.

[0213] In some embodiments, R 10 is C 1 ~C 6 In some embodiments, R 10 is C 1 ~C 3 In some embodiments, R 10 is -CH 2 OH, -CH 2 CH2 OH, -CH 2 CH 2 CH 2 OH, or -C(CH 3 ) 2 In some embodiments, R 10 Ha-CH 2 It is OH.

[0214] In some embodiments, R 10 is -CN.

[0215] In some embodiments, R 10 is C 1 ~C 6 In some embodiments, R 10 is C 1 ~C 3 In some embodiments, R 10 -CH 2 CN, -CH 2 CH 2 CN, -CH 2 CH 2 CH 2 CN, or -C(CH 3 ) 2 CN. In some embodiments, R 10 Ha-CH 2 It is CN.

[0216] In some embodiments, R 10 is -O(C 1 ~C 6 In some embodiments, R 10 is -O(C 1 ~C 3 In some embodiments, R 10 -OCH 3 , -OCH 2 CH 3 , -OCH 2 CH 2 CH 3 , or -OCH 2 (CH 3 In some embodiments, R10 HA-OCH 3 It is.

[0217] In some embodiments, R 10 is -O(C 1 ~C 6 haloalkyl). In some embodiments, R 10 contains 1 to 7 halogen atoms -O(C 1 ~C 6 haloalkyl). In some embodiments, R 10 is -O(C 1 ~C 3 haloalkyl). In some embodiments, R 10 contains 1 to 7 halogen atoms -O(C 1 ~C 3 haloalkyl). In some embodiments, R 10 contains 1 to 5 halogen atoms -O(C 1 ~C 3 In some embodiments, the halogen atoms are independently selected from the group consisting of chloro, bromo, and fluoro atoms. In some embodiments, the halogen atoms are independently selected from the group consisting of chloro and fluoro atoms. In some embodiments, all of the halogen atoms are fluoro atoms. In some embodiments, the halogen atoms are a combination of chloro and fluoro atoms. In some embodiments, R 10 -OCF 3 , -OCCl 3 , -OCF 2 Cl, -OCFCl 2 , -OCHF 2 , -OCH 2 F, -OCHCl 2 , -OCHFCl, -OCH 2 CF 3 , -OCH 2 CCl 3 , -OCH 2 CH 2 F, or -OCH 2 CH 2 In some embodiments, R10 -OCF 3 It is.

[0218] In some embodiments, R 10 is halo. In some embodiments, R 10 is chloro, fluoro, or bromo. 10 is chloro or fluoro. In some embodiments, R 10 is bromo or fluoro. 10 is fluoro. In some embodiments, R 10 is bromo.

[0219] In some embodiments, R 10 is hydroxy.

[0220] In some embodiments, R 10 is oxo.

[0221] In some embodiments, R 10 HA-CO 2 It's H.

[0222] In some embodiments, R 10 is -C(O)NH(C 1 ~C 6 In some embodiments, R 10 is -C(O)NH(C 1 ~C 3 In some embodiments, R 10 is -C(O)NH(CH 3 ), -C(O)NH(CH 2 CH 3 ), -C(O)NH(CH 2 CH 2 CH 3 ), or -C(O)NH(CH(CH 3 ) 2 In some embodiments, R 10 is -C(O)NH(CH3 ).

[0223] In some embodiments, R 10 -C(O)N(C 1 ~C 6 Alkyl) 2 In some embodiments, two C 1 ~C 6 The alkyl groups are the same. In another embodiment, two C 1 ~C 6 The alkyl groups are different. In some embodiments, R 10 is -C(O)N(C 1 ~C 3 Alkyl) 2 In some embodiments, R 10 is -C(O)N(CH 3 ) 2 , -C(O)N(CH 2 CH 3 ) 2 , -C(O)N(CH 2 CH 2 CH 3 ) 2 , or -C(O)N(CH(CH 3 ) 2 ) 2 In some embodiments, R 10 is -C(O)N(CH 3 )(CH 2 CH 3 ), -C(O)N(CH 3 )(CH 2 CH 2 CH 3 ), -C(O)N(CH 3 )(CH(CH 3 ) 2 ), -C(O)N(CH 2 CH 3 )(CH 2 CH 2 CH 3 ), or -C(O)N(CH 2 CH 3 )(CH(CH 3 ) 2 In some embodiments, R 10is -C(O)N(CH 3 ) 2 It is.

[0224] In some embodiments, R 10 is -C(O)NH(C 1 ~C 6 haloalkyl). In some embodiments, R 10 -C(O)NH(C 1 ~C 6 haloalkyl). In some embodiments, R 10 is -C(O)NH(C 1 ~C 3 haloalkyl). In some embodiments, R 10 -C(O)NH(C 1 ~C 3 haloalkyl). In some embodiments, R 10 -C(O)NH(C 1 ~C 3 In some embodiments, the halogen atoms are independently selected from the group consisting of chloro, bromo, and fluoro atoms. In some embodiments, the halogen atoms are independently selected from the group consisting of chloro and fluoro atoms. In some embodiments, all of the halogen atoms are fluoro atoms. In some embodiments, the halogen atoms are a combination of chloro and fluoro atoms. In some embodiments, R 10 is -C(O)NH(CF 3 ), -C(O)NH(CHF 2 ), -C(O)NH(CCl 3 ), -C(O)NH(CF 2 Cl), -C(O)NH(CFCl 2 ), -C(O)NH(CH 2 F), -C(O)NH(CHCl 2 ), or —C(O)NH(CHFCl). In some embodiments, R 10 is -C(O)NH(CF 3 ).

[0225] In some embodiments, R 10 is -C(O)O(C 1 ~C 6 In some embodiments, R 10 is -C(O)O(C 1 ~C 3 In some embodiments, R 10 is -C(O)O(CH 3 ), -C(O)O(CH 2 CH 3 ), -C(O)O(CH 2 CH 2 CH 3 ), or -C(O)O(CH(CH 3 ) 2 In some embodiments, R 10 is -C(O)O(CH 3 ).

[0226] In some embodiments, R 10 -SO 2 -(C 1 ~C 6 In some embodiments, R 10 -SO 2 -(C 1 ~C 3 In some embodiments, R 10 -SO 2 -(CH 3 ), -SO 2 -(CH 2 CH 3 ), -SO 2 -(CH 2 CH 2 CH 3 ), or -SO 2 -(CH(CH 3 ) 2 In some embodiments, R 10 -SO 2 -(CH 3 ).

[0227] In some embodiments, R10 -SO 2 -NH(C 1 ~C 6 In some embodiments, R 10 -SO 2 -NH(C 1 ~C 3 In some embodiments, R 10 -SO 2 -NH(CH 3 ), -SO 2 -NH(CH 2 CH 3 ), -SO 2 -NH(CH 2 CH 2 CH 3 ), or -SO 2 -NH(CH(CH 3 ) 2 In some embodiments, R 10 -SO 2 -NH(CH 3 In some embodiments, R 10 -SO 2 -N(C 1 ~C 6 Alkyl) 2 In some embodiments, two C 1 ~C 6 The alkyl groups are the same. In another embodiment, two C 1 ~C 6 The alkyl groups are different. In some embodiments, R 10 -SO 2 -N(C 1 ~C 3 Alkyl) 2 In some embodiments, R 10 -SO 2 -N(CH 3 ) 2 , -SO 2 -N(CH 2 CH 3 ) 2 , -SO 2 -N(CH 2 CH 2 CH 3 ) 2 , or -SO2 -N(CH(CH 3 ) 2 ) 2 In some embodiments, R 10 -SO 2 -N(CH 3 )(CH 2 CH 3 ), -SO 2 -N(CH 3 )(CH 2 CH 2 CH 3 ), -SO 2 -N(CH 3 )(CH(CH 3 ) 2 ), -SO 2 -N(CH 2 CH 3 )(CH 2 CH 2 CH 3 ), or -SO 2 -N(CH 2 CH 3 )(CH(CH 3 ) 2 In some embodiments, R 10 -SO 2 -N(CH 3 ) 2 It is.

[0228] In some embodiments, R 10 -C(O)(C 1 ~C 6 In some embodiments, R 10 -C(O)(C 1 ~C 3 In some embodiments, R 10 is -C(O)(CH 3 ), -C(O)(CH 2 CH 3 ), -C(O)(CH 2 CH 2 CH 3 ), or -C(O)(CH(CH 3 ) 2 In some embodiments, R 10 is -C(O)(CH3 ).

[0229] In some embodiments, R 10 Ha-(C 1 ~C 6 alkylene)-C(O)N(C 1 ~C 6 Alkyl) 2 In some embodiments, two C 1 ~C 6 The alkyl groups are the same. In another embodiment, two C 1 ~C 6 The alkyl groups are different. In some embodiments, R 10 Ha-(C 1 ~C 3 alkylene)-C(O)N(C 1 ~C 3 Alkyl) 2 In some embodiments, R 10 is -(CH 2 )-C(O)N(C 1 ~C 3 Alkyl) 2 , -(CH 2 CH 2 )-C(O)N(C 1 ~C 3 Alkyl) 2 , or -(CH 2 CH 2 CH 2 )-C(O)N(C 1 ~C 3 Alkyl) 2 In some embodiments, R 10 is -(CH 2 )-C(O)N(CH 3 ) 2 , -(CH 2 )-C(O)N(CH 2 CH 3 ) 2 , -(CH 2 )-C(O)N(CH 2 CH 2 CH 3 ) 2 , -(CH 2 )-C(O)N(CH(CH 3 )2 ) 2 、 -(CH 2 )-C(O)N(CH 3 )(CH 2 CH 3 )、 -(CH 2 )-C(O)N(CH 3 )(CH 2 CH 2 CH 3 ) 2 、 -(CH 2 )-C(O)N(CH 3 )(CH(CH 3 ) 2 )、 -(CH 2 CH 2 )-C(O)N(CH 3 ) 2 、 -(CH 2 CH 2 )-C(O)N(CH 2 CH 3 ) 2 、 -(CH 2 CH 2 )-C(O)N(CH 2 CH 2 CH 3 ) 2 、 -(CH 2 CH 2 )-C(O)N(CH(CH 3 ) 2 ) 2 、 -(CH 2 CH 2 )-C(O)N(CH 3 )(CH 2 CH 3 )、 -(CH 2 CH 2 )-C(O)N(CH 3 )(CH 2 CH 2 CH 3 ) 2 、 or -(CH 2 CH 2 )-C(O)N(CH 3 )(CH(CH 3 ) 2 )). In some embodiments, R 10 is -(CH 2 )-C(O)N(CH 3 )2 It is.

[0230] In some embodiments, R 10 Ha-(C 1 ~C 6 alkylene)-C(O)NH(C 1 ~C 6 In some embodiments, R 10 Ha-(C 1 ~C 3 alkylene)-C(O)NH(C 1 ~C 3 In some embodiments, R 10 is -(CH 2 )-C(O)NH(C 1 ~C 3 alkyl), -(CH 2 CH 2 )-C(O)NH(C 1 ~C 3 alkyl), or -(CH 2 CH 2 CH 2 )-C(O)NH(C 1 ~C 3 In some embodiments, R 10 is -(CH 2 )-C(O)NH(CH 3 ), -(CH 2 )-C(O)NH(CH 2 CH 3 ), -(CH 2 )-C(O)NH(CH 2 CH 2 CH 3 ), -(CH 2 )-C(O)NH(CH(CH 3 ) 2 ), -(CH 2 CH 2 )-C(O)NH(CH 3 ), -(CH 2 CH 2 )-C(O)NH(CH 2 CH 3 ), -(CH 2 CH 2 )-C(O)NH(CH 2 CH2 CH 3 ), or -(CH 2 CH 2 )-C(O)NH(CH(CH 3 ) 2 In some embodiments, R 10 Ha-(CH 2 )-C(O)NH(CH 3 ).

[0231] In some embodiments, R 10 Optionally, select 1 to 5 R 11 substituted with a C 3 ~C 6 In some embodiments, R 10 Optionally, select 1 to 5 R 11 substituted with a C 3 ~C 5 In some embodiments, R 10 is cyclopropyl, cyclobutyl, or cyclopentyl, each of which is optionally selected from 1 to 5 R 11 In some embodiments, R 10 is cyclopropyl or cyclobutyl, each of which optionally contains 1 to 5 R 11 In some embodiments, R 10 Optionally, select 1 to 5 R 11 In some embodiments, R is cyclopropyl, substituted with a cyclopropyl group. 10 Optionally, select 1 to 5 R 11 In some embodiments, the cycloalkyl group is substituted with 1 to 5 R 11 In some embodiments, the cycloalkyl is substituted with one R 11 In some embodiments, the cycloalkyl is substituted with two R 11 In some embodiments, the cycloalkyl is substituted with three R 11In some embodiments, the cycloalkyl is substituted with four R groups. 11 In some embodiments, the cycloalkyl is substituted with five R groups. 11 In some embodiments, the cycloalkyl is unsubstituted.

[0232] In some embodiments, R 10 Optionally, select 1 to 5 R 11 In some embodiments, R is a 5- to 6-membered heterocyclyl substituted by a group. 10 Optionally, select 1 to 5 R 11 In some embodiments, R is a 5-membered heterocyclyl substituted by a 5-membered heterocyclyl group. 10 Optionally, select 1 to 5 R 11 In some embodiments, the heterocyclyl is a 6-membered heterocyclyl substituted by a group. In some embodiments, the heterocyclyl contains 1-3 heteroatoms selected from the group consisting of N, O, and S. In some embodiments, the heterocyclyl contains 1-3 heteroatoms selected from the group consisting of N and O. In some embodiments, the heterocyclyl contains one nitrogen atom. In some embodiments, the heterocyclyl contains two nitrogen atoms. In some embodiments, the heterocyclyl contains one oxygen atom. In some embodiments, the heterocyclyl contains two oxygen atoms. In some embodiments, the heterocyclyl contains one oxygen atom and one nitrogen atom. In some embodiments, the heterocyclyl is a 6-membered heterocyclyl substituted by a group. In some embodiments, the heterocyclyl contains 1-3 heteroatoms selected from the group consisting of N, O, and S. In some embodiments, the heterocyclyl contains 1-3 heteroatoms selected from the group consisting of N and O. In some embodiments, the heterocyclyl contains one nitrogen atom. In some embodiments, the heterocyclyl contains two nitrogen atoms. In some embodiments, the heterocyclyl contains one oxygen atom and one nitrogen atom. In some embodiments, the heterocyclyl contains 1-5 R 11 In some embodiments, the heterocyclyl is substituted by one R 11 In some embodiments, the heterocyclyl is substituted by two R 11 In some embodiments, the heterocyclyl is substituted by three R 11 In some embodiments, the heterocyclyl is substituted by four R 11In some embodiments, the heterocyclyl is substituted by five R 11 In some embodiments, the heterocyclyl is unsubstituted. In some embodiments, the heterocyclyl is piperazinyl, piperidinyl, pyrrolidinyl, morpholinyl, dioxanyl, tetrahydropyranyl, or tetrahydrofuranyl, each of which is optionally selected from 1 to 5 R 11 In some embodiments, R 10 teeth,

[0233] [ka] It is.

[0234] In some embodiments, R 10 Optionally, select 1 to 5 R 11 In some embodiments, R is a 5-6 membered heteroaryl substituted with a aryl group. 10 Optionally, select 1 to 5 R 11 In some embodiments, R is a 5-membered heteroaryl substituted with a aryl group. 10 Optionally, select 1 to 5 R 11In some embodiments, the heteroaryl is a 6-membered heteroaryl substituted by a cyclic group. In some embodiments, the heteroaryl contains 1-3 heteroatoms selected from the group consisting of N, O, and S. In some embodiments, the heteroaryl contains 1-3 heteroatoms selected from the group consisting of N and O. In some embodiments, the heteroaryl contains 1 nitrogen atom. In some embodiments, the heteroaryl contains 2 nitrogen atoms. In some embodiments, the heteroaryl contains 1 oxygen atom. In some embodiments, the heteroaryl contains 2 oxygen atoms. In some embodiments, the heteroaryl contains 1 oxygen atom and 1 nitrogen atom. In some embodiments, the heteroaryl contains 1 oxygen atom and 2 nitrogen atoms. In some embodiments, the heteroaryl contains 1-5 R 11 In some embodiments, the heteroaryl is substituted with one R 11 In some embodiments, the heteroaryl is substituted with two R 11 In some embodiments, the heteroaryl is substituted with three R 11 In some embodiments, the heteroaryl is substituted with four R groups. 11 In some embodiments, the heteroaryl is substituted with five R groups. 11 In some embodiments, the heteroaryl is unsubstituted. In some embodiments, the heteroaryl is pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, or triazolyl, each of which is optionally selected from 1 to 5 R 11 In some embodiments, R 10 teeth,

[0235] [ka] where the nitrogen atom is optionally substituted with R 11 If it is not substituted by then it is bonded to H.

[0236] In some embodiments, R 10 Ha-(C 1 ~C 6 alkylene)-(5- to 6-membered heterocyclyl), the heterocyclyl optionally being selected from 1 to 5 R 11 In some embodiments, R 10 Ha-(C 1 ~C 3 alkylene)-(5- to 6-membered heterocyclyl), the heterocyclyl optionally being selected from 1 to 5 R 11 In some embodiments, R 10 Ha-(C 1 ~C 3 alkylene)-(5-membered heterocyclyl), the heterocyclyl optionally being selected from 1 to 5 R 11 In some embodiments, R 10 Ha-(C 1 ~C 3 alkylene)-(6-membered heterocyclyl), the heterocyclyl optionally being selected from 1 to 5 R 11 In some embodiments, R 10 Ha-(CH 2 )-(5- to 6-membered heterocyclyl), the heterocyclyl optionally containing 1 to 5 R 11 In some embodiments, R 10 Ha-(CH 2 CH 2 )-(5- to 6-membered heterocyclyl), the heterocyclyl optionally containing 1 to 5 R 11In some embodiments, the heterocyclyl contains 1 to 3 heteroatoms selected from the group consisting of N, O, and S. In some embodiments, the heterocyclyl contains 1 to 3 heteroatoms selected from the group consisting of N and O. In some embodiments, the heterocyclyl contains 1 nitrogen atom. In some embodiments, the heterocyclyl contains 2 nitrogen atoms. In some embodiments, the heterocyclyl contains 1 oxygen atom. In some embodiments, the heterocyclyl contains 2 oxygen atoms. In some embodiments, the heterocyclyl contains 1 oxygen atom and 1 nitrogen atom. In some embodiments, the heterocyclyl contains 1 to 5 R 11 In some embodiments, the heterocyclyl is substituted by one R 11 In some embodiments, the heterocyclyl is substituted by two R 11 In some embodiments, the heterocyclyl is substituted by three R 11 In some embodiments, the heterocyclyl is substituted by four R 11 In some embodiments, the heterocyclyl is substituted by five R 11 In some embodiments, the heterocyclyl is unsubstituted. In some embodiments, the heterocyclyl is piperazinyl, piperidinyl, pyrrolidinyl, morpholinyl, dioxanyl, tetrahydropyranyl, or tetrahydrofuranyl, each of which is optionally selected from 1 to 5 R 11 is substituted by a group.

[0237] In some embodiments, R 10 Optionally, select 1 to 5 R 11 substituted by a -(C 1 ~C 6 In some embodiments, R 10 Ha-(C 1 ~C 3alkylene)-(5-6 membered heteroaryl), wherein the heteroaryl is optionally selected from 1 to 5 R 11 In some embodiments, R 10 Ha-(C 1 ~C 3 alkylene)-(5-membered heteroaryl), wherein the heteroaryl is optionally selected from 1 to 5 R 11 In some embodiments, R 10 Ha-(C 1 ~C 3 alkylene)-(6-membered heteroaryl), wherein the heteroaryl is optionally selected from 1 to 5 R 11 In some embodiments, R 10 Ha-(CH 2 )-(5- to 6-membered heteroaryl), the heterocyclyl optionally containing 1 to 5 R 11 In some embodiments, R 10 Ha-(CH 2 CH 2 )-(5-6 membered heteroaryl), the heteroaryl optionally containing 1 to 5 R 11 In some embodiments, the heteroaryl contains 1-3 heteroatoms selected from the group consisting of N, O, and S. In some embodiments, the heteroaryl contains 1-3 heteroatoms selected from the group consisting of N and O. In some embodiments, the heteroaryl contains 1 nitrogen atom. In some embodiments, the heteroaryl contains 2 nitrogen atoms. In some embodiments, the heteroaryl contains 1 oxygen atom. In some embodiments, the heteroaryl contains 2 oxygen atoms. In some embodiments, the heteroaryl contains 1 oxygen atom and 1 nitrogen atom. In some embodiments, the heteroaryl contains 1 oxygen atom and 2 nitrogen atoms. In some embodiments, the heteroaryl contains 1-5 R 11 In some embodiments, the heteroaryl is substituted with one R 11In some embodiments, the heteroaryl is substituted with two R 11 In some embodiments, the heteroaryl is substituted with three R 11 In some embodiments, the heteroaryl is substituted with four R groups. 11 In some embodiments, the heteroaryl is substituted with five R groups. 11 In some embodiments, the heteroaryl is unsubstituted. In some embodiments, the heteroaryl is pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, or triazolyl, each of which is optionally selected from 1 to 5 R 11 is substituted by a group.

[0238] In some embodiments, R 10 is -C(O)-(5- to 6-membered heterocyclyl), the heterocyclyl optionally being selected from 1 to 5 R 11 In some embodiments, R 10 is -C(O)-(5-membered heterocyclyl), the heterocyclyl optionally being selected from 1 to 5 R 11 In some embodiments, R 10 is -C(O)-(6-membered heterocyclyl), the heterocyclyl optionally containing 1 to 5 R 11In some embodiments, the heterocyclyl contains 1 to 3 heteroatoms selected from the group consisting of N, O, and S. In some embodiments, the heterocyclyl contains 1 to 3 heteroatoms selected from the group consisting of N and O. In some embodiments, the heterocyclyl contains 1 nitrogen atom. In some embodiments, the heterocyclyl contains 2 nitrogen atoms. In some embodiments, the heterocyclyl contains 1 oxygen atom. In some embodiments, the heterocyclyl contains 2 oxygen atoms. In some embodiments, the heterocyclyl contains 1 oxygen atom and 1 nitrogen atom. In some embodiments, the heterocyclyl contains 1 to 5 R 11 In some embodiments, the heterocyclyl is substituted by one R 11 In some embodiments, the heterocyclyl is substituted by two R 11 In some embodiments, the heterocyclyl is substituted by three R 11 In some embodiments, the heterocyclyl is substituted by four R 11 In some embodiments, the heterocyclyl is substituted by five R 11 In some embodiments, the heterocyclyl is unsubstituted. In some embodiments, the heterocyclyl is piperazinyl, piperidinyl, pyrrolidinyl, morpholinyl, dioxanyl, tetrahydropyranyl, or tetrahydrofuranyl, each of which is optionally selected from 1 to 5 R 11 In some embodiments, R 10 teeth,

[0239] [ka] It is.

[0240] In some embodiments, R 10is -C(O)-(5-6 membered heteroaryl), the heteroaryl optionally being selected from 1 to 5 R 11 In some embodiments, R 10 is —C(O)—(5-membered heteroaryl), the heteroaryl optionally containing 1 to 5 R 11 In some embodiments, R 10 is —C(O)—(6-membered heteroaryl), the heteroaryl optionally containing 1 to 5 R 11 In some embodiments, the heteroaryl contains 1-3 heteroatoms selected from the group consisting of N, O, and S. In some embodiments, the heteroaryl contains 1-3 heteroatoms selected from the group consisting of N and O. In some embodiments, the heteroaryl contains 1 nitrogen atom. In some embodiments, the heteroaryl contains 2 nitrogen atoms. In some embodiments, the heteroaryl contains 1 oxygen atom. In some embodiments, the heteroaryl contains 2 oxygen atoms. In some embodiments, the heteroaryl contains 1 oxygen atom and 1 nitrogen atom. In some embodiments, the heteroaryl contains 1-5 R 11 In some embodiments, the heteroaryl is substituted with one R 11 In some embodiments, the heteroaryl is substituted with two R 11 In some embodiments, the heteroaryl is substituted with three R 11 In some embodiments, the heteroaryl is substituted with four R groups. 11 In some embodiments, the heteroaryl is substituted with five R groups. 11In some embodiments, the heteroaryl is unsubstituted. In some embodiments, the heteroaryl is pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, or triazolyl, each of which is optionally selected from 1 to 5 R 11 is substituted by a group.

[0241] In some embodiments, R 10 Optionally, select 1 to 5 R 11 substituted by a C group; 6 ~C 10 In some embodiments, R 10 Optionally, select 1 to 5 R 11 substituted by a C group; 6 In some embodiments, aryl is selected from 1 to 5 R 11 In some embodiments, the aryl is substituted with one R 11 In some embodiments, the aryl is substituted with two R 11 In some embodiments, the aryl is substituted with three R 11 In some embodiments, the aryl is substituted with four R 11 In some embodiments, the aryl is substituted with five R groups. 11 In some embodiments, the aryl is unsubstituted. In some embodiments, R 10 Optionally, select 1 to 5 R 11 The phenyl is substituted by a group.

[0242] In some embodiments, each R 10 are independently -CH 3 , -CH 2 CH 3 , -CH(CH 3 ) 2 , -CF 3, -CHF 2 , -CH 2 CF 3 , -CH 2 OH, -CN, -CH 2 CN, -OCH 3 , -OCF 3 , Br, F, hydroxy, oxo, -CO 2 H, -C(O)NH(CH 3 ), C(O)N(CH 3 ) 2 , -C(O)NH(CF 3 ), -C(O)OCH 3 , -SO 2 CH 3 , -SO 2 NH(CH 3 ), -SO 2 N(CH 3 ) 2 , -C(O)CH 3 , -(CH 2 )-C(O)N(CH 3 ) 2 , -(CH 2 )-C(O)NH(CH 3 ),

[0243] [ka] It is.

[0244]

[0180] In some embodiments, two R 10 The groups, together with the carbon atoms to which they are attached, form spiro C 3 ~C 6 cycloalkyl or spiro 4-6 membered heterocyclyl, each of which is optionally represented by 1 to 5 R 11 is substituted by a group.

[0245]

[0181] In some embodiments, two R 10 Groups, together with the carbon atom to which they are attached, optionally contain 1 to 5 R 11 substituted by a spiro C group3 ~C 6 In some embodiments, two R 1 and R 2 are bonded to the same carbon atom to form a cycloalkyl. 10 Groups, together with the carbon atom to which they are attached, optionally contain 1 to 5 R 11 substituted by a spiro C group 3 ~C 5 In some embodiments, the cycloalkyl is cyclopropyl, cyclobutyl, or cyclopentyl, each of which is optionally selected from 1 to 5 R 11 In some embodiments, two R 10 The groups, together with the carbon atom to which they are attached, form a spirocyclopropyl or cyclobutyl, each of which optionally contains 1 to 5 R 11 In some embodiments, two R 10 Groups, together with the carbon atom to which they are attached, optionally contain 1 to 5 R 11 In some embodiments, two R 1 , R 2 and R 3 are bonded to the same carbon atom, forming a spirocyclopropyl group. 10 Groups, together with the carbon atom to which they are attached, optionally contain 1 to 5 R 11 In some embodiments, the cycloalkyl group is substituted with 1 to 5 R 11 In some embodiments, the cycloalkyl is substituted with one R 11 In some embodiments, the cycloalkyl is substituted with two R 11 In some embodiments, the cycloalkyl is substituted with three R 11 In some embodiments, the cycloalkyl is substituted with four R groups. 11 In some embodiments, the cycloalkyl is substituted with five R groups. 11In some embodiments, the cycloalkyl is unsubstituted.

[0246]

[0182] In some embodiments, two R 10 Groups, together with the carbon atom to which they are attached, optionally contain 1 to 5 R 11 In some embodiments, two R 1 -R 2 -R 3 -R 4 -R 5 -R 6 -R 7 -R 8 -R 9 -R 10 -R 11 -R 12 -R 13 -R 14 -R 15 -R 16 -R 17 -R 18 -R 19 -R 20 -R 21 -R 22 -R 23 -R 24 -R 25 -R 26 -R 10 Groups, together with the carbon atom to which they are attached, optionally contain 1 to 5 R 11 In some embodiments, two R 1 -R 2 -R 3 -R 4 -R 5 -R 6 -R 7 -R 8 -R 9 -R 10 -R 11 -R 12 -R 13 -R 14 -R 15 -R 16 -R 17 -R 18 -R 19 -R 20 -R 21 -R 22 -R 23 -R 24 -R 25 -R 26 -R 10 Groups, together with the carbon atom to which they are attached, optionally contain 1 to 5 R 11 In some embodiments, two R 1 -R 2 -R 3 -R 4 -R 5 -R 6 -R 7 -R 8 -R 9 -R 10 -R 11 -R 12 -R 13 -R 14 -R 15 -R 16 -R 17 -R 18 -R 19 -R 20 -R 21 -R 22 -R 23 -R 24 -R 25 -R 26 -R 10 Groups, together with the carbon atom to which they are attached, optionally contain 1 to 5 R 11 In some embodiments, the heterocyclyl contains 1-3 heteroatoms selected from the group consisting of N, O, and S. In some embodiments, the heterocyclyl contains 1-3 heteroatoms selected from the group consisting of N and O. In some embodiments, the heterocyclyl contains 1 nitrogen atom. In some embodiments, the heterocyclyl contains 2 nitrogen atoms. In some embodiments, the heterocyclyl contains 1 oxygen atom. In some embodiments, the heterocyclyl contains 2 oxygen atoms. In some embodiments, the heterocyclyl contains 1 oxygen atom and 1 nitrogen atom. In some embodiments, the heterocyclyl contains 1-5 R 11 In some embodiments, the heterocyclyl is substituted by one R 11In some embodiments, the heterocyclyl is substituted by two R 11 In some embodiments, the heterocyclyl is substituted by three R 11 In some embodiments, the heterocyclyl is substituted by four R 11 In some embodiments, the heterocyclyl is substituted by five R 11 In some embodiments, the heterocyclyl is unsubstituted. In some embodiments, the heterocyclyl is azetidinyl, piperazinyl, piperidinyl, pyrrolidinyl, morpholinyl, dioxanyl, tetrahydropyranyl, or tetrahydrofuranyl, each of which is optionally selected from 1 to 5 R 11 In some embodiments, the heterocyclyl is substituted with at least one R 11 is substituted by a group, R 11 The group is oxo. In some embodiments, two R 10 Groups, together with the carbon atoms to which they are attached,

[0247] [ka] The nitrogen atom of the heterocyclyl group is R 11 If it is not substituted by then it is bonded to H.

[0248]

[0183] In some embodiments, two R 10 Groups, together with the carbon atoms to which they are attached,

[0249] [ka] The nitrogen atom of the heterocyclyl group is R 11 If it is not substituted by then it is bonded to H.

[0250] In some embodiments, each R 11 is independently 1 ~C 6 Alkyl, hydroxy, oxo, or -C(O)(C 1 ~C 6 In some embodiments, each R 11 is independently 1 ~C 3 Alkyl, hydroxy, oxo, or -C(O)(C 1 ~C 3 In some embodiments, each R 11 are independently -CH 3 , hydroxy, oxo, or -C(O)CH 3 It is.

[0251] In some embodiments, R 11 is C 1 ~C 6 In some embodiments, R 11 is C 1 ~C 3 In some embodiments, R 11 is methyl, ethyl, n-propyl, or isopropyl. 11 is methyl, ethyl, or isopropyl. 11 Ha-CH 3 It is.

[0252] In some embodiments, R 11 is hydroxyl.

[0253] In some embodiments, R 11 is oxo.

[0254] In some embodiments, R 11 -C(O)(C 1 ~C 6 In some embodiments, R 11 -C(O)(C1 ~C 3 In some embodiments, R 11 is -C(O)CH 3 , -C(O)CH 2 CH 3 , -C(O)CH 2 CH 2 CH 3 , or -C(O)CH(CH 3 ) 2 In some embodiments, R 11 -C(O)CH 3 It is.

[0255] In some embodiments, R 12 , H, C 1 ~C 6 Alkyl, or C 1 ~C 6 In some embodiments, R 12 , H, C 1 ~C 3 Alkyl, or C 1 ~C 3 In some embodiments, R 12 -H, -CH 3 , or -CF 3 It is.

[0256] In some embodiments, R 12 is H.

[0257] In some embodiments, R 12 is C 1 ~C 6 In some embodiments, R 12 is C 1 ~C 3 In some embodiments, R 12 is methyl, ethyl, n-propyl, or isopropyl. 12 is methyl, ethyl, or isopropyl. 12 Ha-CH 3 It is.

[0258] In some embodiments, R 12 is C 1 ~C 6 In some embodiments, R 12 C containing 1 to 7 halogen atoms 1 ~C 6 In some embodiments, R 12 is C 1 ~C 3 In some embodiments, R 12 C containing 1 to 7 halogen atoms 1 ~C 3 In some embodiments, R 12 C containing 1 to 5 halogen atoms 1 ~C 3 In some embodiments, the halogen atoms are independently selected from the group consisting of chloro, bromo, and fluoro atoms. In some embodiments, the halogen atoms are independently selected from the group consisting of chloro and fluoro atoms. In some embodiments, all of the halogen atoms are fluoro atoms. In some embodiments, the halogen atoms are a combination of chloro and fluoro atoms. In some embodiments, R 12 -CF 3 , -CCl 3 , -CF 2 Cl, -CFCl 2 , -CHF 2 , -CH 2 F, -CHCl 2 or -CHFCl. In some embodiments, R 12 -CF 3 It is.

[0259] In some embodiments, R 6 and R 7are taken together with the nitrogen atom to which they are attached to form a 4-10 membered monocyclic or fused bicyclic heterocyclyl, optionally containing 1-2 additional heteroatoms selected from the group consisting of N, S, and O, then R 12 is linked to a 4-10 membered monocyclic or fused bicyclic heterocyclyl to form a 7-14 membered fused bicyclic or tricyclic heterocyclyl 1 ~C 6 alkylene, and each heterocyclyl optionally has 1 to 5 R 10 In some embodiments, R 6 and R 7 together with the nitrogen atom to which they are attached form a 5- to 6-membered monocyclic heterocyclyl; R 12 is attached to a 5-6 membered monocyclic heterocyclyl,

[0260] [ka] -CH 2 -It is.

[0261] In some embodiments, R 6 and R 7 are taken together with the nitrogen atom to which they are attached to form a 4-10 membered monocyclic or fused bicyclic heterocyclyl, optionally containing 1-2 additional heteroatoms selected from the group consisting of N, S, and O, then R 12 is linked to a 4-10 membered monocyclic or fused bicyclic heterocyclyl to form a 7-14 membered fused bicyclic or tricyclic heterocyclyl 1 ~C 3 alkylene, and each heterocyclyl optionally has 1 to 5 R 10 In some embodiments, R 6 and R 7are taken together with the nitrogen atom to which they are attached to form a 4-10 membered monocyclic or fused bicyclic heterocyclyl, optionally containing 1-2 additional heteroatoms selected from the group consisting of N, S, and O, then R 12 is linked to a 4-10 membered monocyclic or fused bicyclic heterocyclyl to form a 7-14 membered fused bicyclic or tricyclic heterocyclyl 1 ~C 2 alkylene, and each heterocyclyl optionally has 1 to 5 R 10 In some embodiments, R 6 and R 7 are taken together with the nitrogen atom to which they are attached to form a 4-10 membered monocyclic or fused bicyclic heterocyclyl, optionally containing 1-2 additional heteroatoms selected from the group consisting of N, S, and O, then R 12 is a methylene bonded to a 4-10 membered monocyclic or fused bicyclic heterocyclyl to form a 7-14 membered fused bicyclic or tricyclic heterocyclyl, each heterocyclyl optionally being joined by 1-5 R 10 is substituted by a group.

[0262] In some embodiments, R 6 and R 7 are taken together with the nitrogen atom to which they are attached to form a 4-10 membered monocyclic heterocyclyl, optionally containing 1-2 additional heteroatoms selected from the group consisting of N, S, and O, then R 12 is attached to a 4-10 membered monocyclic heterocyclyl, and optionally has 1-5 R 10 In some embodiments, R is a methylene forming a 7-13 membered fused bicyclic heterocyclyl substituted with a cyclic heterocyclic ring. 6 and R 7 When these, together with the nitrogen atom to which they are attached, form a 5- to 6-membered monocyclic heterocyclyl, R 12 is attached to a 5-6 membered monocyclic heterocyclyl and optionally has 1 to 5 R10 forming an 8-9 membered fused bicyclic heterocyclyl substituted by a -CH group; 2 In some embodiments, R 6 and R 7 together with the nitrogen atom to which they are attached form a 5-membered monocyclic heterocyclyl; R 12 is attached to a 5-membered monocyclic heterocyclyl;

[0263] [ka] -CH 2 In some embodiments, R 6 and R 7 together with the nitrogen atom to which they are attached form a 6-membered monocyclic heterocyclyl; R 12 is attached to a 6-membered monocyclic heterocyclyl;

[0264] [ka] -CH 2 -It is.

[0265] In some embodiments, R 6 and R 7 are taken together with the nitrogen atom to which they are attached to form a 4-10 membered fused bicyclic heterocyclyl, optionally containing 1-2 additional heteroatoms selected from the group consisting of N, S, and O, then R 12 is attached to a 4-10 membered fused bicyclic heterocyclyl and optionally has 1-5 R 10 C forming a 7-14 membered fused tricyclic heterocyclyl substituted by a group 1 ~C 3 In some embodiments, R 6 and R 7are taken together with the nitrogen atom to which they are attached to form a 4-10 membered fused bicyclic heterocyclyl, optionally containing 1-2 additional heteroatoms selected from the group consisting of N, S, and O, then R 12 is attached to a 4-10 membered fused bicyclic heterocyclyl and optionally has 1-5 R 10 and methylene forming a 7-13 membered fused tricyclic heterocyclyl substituted by a group.

[0266] In some embodiments, each R 13 are independently H, C 1 ~C 3 Alkyl, C 1 ~C 3 Alkyl-OH, or C 1 ~C 3 In some embodiments, each R 13 are independently H, C 1 ~C 2 Alkyl, C 1 ~C 2 Alkyl-OH, or C 1 ~C 2 In some embodiments, each R 13 are independently H, -CH 3 , -CH 2 OH, or -CF 3 It is.

[0267] In some embodiments, each R 13 is independently H. In some embodiments, one R 13 is H, and the other R 13 is C 1 ~C 3 In some embodiments, one R 13 is H, and the other R 13 is C 1 ~C 2 In some embodiments, one R 13 is H, and the other R 13 is methyl. In some embodiments, one R13 is H, and the other R 13 is ethyl. In some embodiments, one R 13 is H, and the other R 13 is C 1 ~C 3 In some embodiments, one R 13 is H, and the other R 13 is C 1 ~C 2 In some embodiments, one R 13 is H, and the other R 13 is C 1 In some embodiments, one R 13 is H, and the other R 13 -CF 3 In some embodiments, each R 13 is H.

[0268] In some embodiments, R 13 is C 1 ~C 3 In some embodiments, R 13 is C 1 ~C 2 In some embodiments, R 13 is methyl, ethyl, n-propyl, or isopropyl. 13 is methyl or ethyl. In some embodiments, R 13 Ha-CH 3 It is.

[0269] In some embodiments, R 13 is C 1 ~C 3 In some embodiments, R 13 is C 1 ~C 2 In some embodiments, R 13 -CH 2 OH, -CH 2 CH 2 OH, or -CH2 CH 2 CH 2 In some embodiments, R 13 Ha-CH 2 It is OH.

[0270] In some embodiments, R 13 is C 1 ~C 3 In some embodiments, R 13 C containing 1 to 5 halogen atoms 1 ~C 3 In some embodiments, R 13 is C 1 ~C 2 In some embodiments, R 13 C containing 1 to 3 halogen atoms 1 ~C 2 In some embodiments, the halogen atoms are independently selected from the group consisting of chloro, bromo, and fluoro atoms. In some embodiments, the halogen atoms are independently selected from the group consisting of chloro and fluoro atoms. In some embodiments, all of the halogen atoms are fluoro atoms. In some embodiments, the halogen atoms are a combination of chloro and fluoro atoms. In some embodiments, R 13 -CF 3 , -CCl 3 , -CF 2 Cl, -CFCl 2 , -CHF 2 , -CH 2 F, -CHCl 2 or -CHFCl. In some embodiments, R 13 -CF 3 It is.

[0271] [Table 1-1]

[0272] [Table 1-2]

[0273] [Table 1-3]

[0274] [Table 1-4]

[0275] [Table 1-5]

[0276]

[0202] In some embodiments, provided is a compound selected from compound numbers 1-54 and 121-166 in Table 1, or a tautomer thereof, or a pharma- ceutically acceptable salt thereof.

[0277]

[0203] In another aspect, provided is a compound of formula (II):

[0278] [ka] or a tautomer thereof, or a pharma- ceutically acceptable salt thereof; During the ceremony: R 21 and R 22 are independently H, C 1 ~C 6 Alkyl, halo, C 1 ~C 6 Haloalkyl or C 3 ~C 6 cycloalkyl, but when Y is S or a bond, R 21 and R 22 is not a halo; or R 21 and R 22 together with the carbon atom to which they are attached,

[0279] [ka] It forms; Y is CR 23 R 24 , S, or a bond; R 23 and R 24 are independently H, halo, and C 1 ~C 6 Alkyl or C 1 ~C 6 haloalkyl; or R 21 and R 22 Together with the carbon atoms to which they are attached,

[0280] [ka] It forms; R 25 is C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, or C 3 ~C 6 is cycloalkyl; W is CH or N;

[0281] [ka] teeth,

[0282] [ka] is selected from the group consisting of where nitrogen atoms are represented by R if necessary to satisfy valences. 26 is bonded to H when not substituted by Each R 26 is independently 1~C 6 Alkyl, C 1 ~C 6 Haloalkyl, C 1 ~C 6 Alkyl-OH, C 1 ~C 6 Alkyl-CN, -(CR 28 R 29 ) p -(4-6 membered heterocyclyl), -(CR 28 R 29 ) p -(5-6 membered heteroaryl), -(CR 28 R 29 ) p -(C 6 ~C 10 aryl), or -(CR 28 R 29 ) p -(C 3 ~C 6 cycloalkyl), each cycloalkyl, heterocyclyl, heteroaryl, or aryl group optionally containing 1 to 5 R 27 is substituted by a group; Each R 27 is independently 1 ~C 6 Alkyl, C 1 ~C 6 Alkyl-OH, C 1 ~C 6 Haloalkyl, C 1 ~C 6 Alkyl-CN, -CN, halo, hydroxy, -O-(C 1 ~C 6 alkyl), -O(C 1 ~C 6 haloalkyl), oxo, -C(O)NH 2 , -C(O)NH(C 1 ~C 6 alkyl), -C(O)N(C 1 ~C 6 Alkyl) 2 , -C(O)NH(C 1 ~C 6 haloalkyl), -CO 2 H, -C(O)O(C 1 ~C 6 Alkyl), -SO2 -(C 1 ~C 6 Alkyl), -SO 2 -NH(C 1 ~C 6 Alkyl), -SO 2 -N(C 1 ~C 6 Alkyl) 2 , -C(O)(C 1 ~C 6 alkyl), -(C 1 ~C 6 alkylene)-C(O)N(C 1 ~C 6 Alkyl) 2 , or -(C 1 ~C 6 alkylene)-C(O)NH(C 1 ~C 6 alkyl); p is 0 or 1; R 28 and R 29 are independently H, C 1 ~C 6 Alkyl, or C 1 ~C 6 is haloalkyl; Each R 30 are independently H, C 1 ~C 3 Alkyl, C 1 ~C 3 Haloalkyl, or C 1 ~C 3 It is alkyl-OH.

[0283]

[0204] In some embodiments,

[0284] [ka] (i.e., ring B portion) is

[0285] [ka] wherein nitrogen atoms, if necessary to satisfy valences, are selected from the group consisting of R 26 When not substituted by, it is bonded to H. In some embodiments, the Ring B moiety is

[0286] [ka] where nitrogen atoms are optionally selected from R 26 When not substituted by, it is bonded to H. In some embodiments, the Ring B moiety is

[0287] [ka] In some embodiments, the Ring B moiety is

[0288] [ka] In some embodiments, the Ring B moiety is

[0289] [ka] In some embodiments, the Ring B moiety is

[0290] [ka] where nitrogen atoms are optionally selected from R 26 When not substituted by, it is bonded to H. In some embodiments, the Ring B moiety is

[0291] [ka] where nitrogen atoms are optionally selected from R26 When not substituted by R, the ring B moiety is bonded to H. 26 In some embodiments, the Ring B moiety is substituted with one R 26 In some embodiments, the Ring B moiety is substituted with two R 26 In some embodiments, the Ring B moiety is substituted with three R 26 In some embodiments, the Ring B moiety is substituted with four R 26 In some embodiments, the Ring B moiety is substituted with five R 26 In some embodiments, the Ring B moiety is unsubstituted.

[0292] In some embodiments, R 21 and R 22 are independently H, C 1 ~C 6 Alkyl, halo, C 1 ~C 6 Haloalkyl, or C 3 ~C 6 In some embodiments, R 21 and R 22 are independently H, C 1 ~C 3 Alkyl, halo, C 1 ~C 3 Haloalkyl, or C 3 ~C 5 In some embodiments, R 21 and R 22 are independently H, -CH 3 , F, -CF 3 or cyclobutyl.

[0293] In some embodiments, R 21 is H.

[0294] In some embodiments, R 21 is C 1~C 6 In some embodiments, R 21 is C 1 ~C 3 In some embodiments, R 21 is methyl, ethyl, n-propyl, or isopropyl. 21 Ha-CH 3 It is.

[0295] In some embodiments, R 21 is halo. In some embodiments, R 21 is chloro, fluoro, or bromo. 21 is chloro or fluoro. In some embodiments, R 21 is fluoro.

[0296] In some embodiments, R 21 is C 1 ~C 6 In some embodiments, R 21 C containing 1 to 7 halogen atoms 1 ~C 6 In some embodiments, R 21 is C 1 ~C 3 In some embodiments, R 21 C containing 1 to 7 halogen atoms 1 ~C 3 In some embodiments, R 21 C containing 1 to 5 halogen atoms 1 ~C 3In some embodiments, the halogen atoms are independently selected from the group consisting of chloro, bromo, and fluoro atoms. In some embodiments, the halogen atoms are independently selected from the group consisting of chloro and fluoro atoms. In some embodiments, all of the halogen atoms are fluoro atoms. In some embodiments, the halogen atoms are a combination of chloro and fluoro atoms. In some embodiments, R 21 -CF 3 , -CCl 3 , -CF 2 Cl, -CFCl 2 , -CHF 2 , -CH 2 F, -CHCl 2 or -CHFCl. In some embodiments, R 21 -CF 3 It is.

[0297] In some embodiments, R 21 is C 3 ~C 6 In some embodiments, R 21 is C 3 ~C 5 In some embodiments, R 21 is C 3 ~C 4 In some embodiments, R 21 is cyclopropyl, cyclobutyl, or cyclopentyl. 21 is cyclopropyl. In some embodiments, R 21 is cyclobutyl.

[0298] In some embodiments, R 22 is H.

[0299] In some embodiments, R 22 is C 1 ~C 6 In some embodiments, R22 is C 1 ~C 3 In some embodiments, R 22 is methyl, ethyl, n-propyl, or isopropyl. 22 Ha-CH 3 It is.

[0300] In some embodiments, R 22 is halo. In some embodiments, R 22 is chloro, fluoro, or bromo. 22 is chloro or fluoro. In some embodiments, R 22 is fluoro.

[0301] In some embodiments, Y is CR 23 R 24 If so, then R 21 and R 22 In some embodiments, Y is CR 23 R 24 If so, then R 21 In some embodiments, Y is CR 23 R 24 If so, then R 22 In some embodiments, Y is CR 23 R 24 If so, then R 21 and R 22 are halos.

[0302] In some embodiments, R 22 is C 1 ~C 6 In some embodiments, R 22 C containing 1 to 7 halogen atoms 1 ~C 6 In some embodiments, R 22 is C 1 ~C 3In some embodiments, R 22 C containing 1 to 7 halogen atoms 1 ~C 3 In some embodiments, R 22 C containing 1 to 5 halogen atoms 1 ~C 3 In some embodiments, the halogen atoms are independently selected from the group consisting of chloro, bromo, and fluoro atoms. In some embodiments, the halogen atoms are independently selected from the group consisting of chloro and fluoro atoms. In some embodiments, all of the halogen atoms are fluoro atoms. In some embodiments, the halogen atoms are a combination of chloro and fluoro atoms. In some embodiments, R 22 -CF 3 , -CCl 3 , -CF 2 Cl, -CFCl 2 , -CHF 2 , -CH 2 F, -CHCl 2 or -CHFCl. In some embodiments, R 22 -CF 3 It is.

[0303] In some embodiments, R 22 is C 3 ~C 6 In some embodiments, R 22 is C 3 ~C 5 In some embodiments, R 22 is C 3 ~C 4 In some embodiments, R 22 is cyclopropyl, cyclobutyl, or cyclopentyl. 22 is cyclopropyl. In some embodiments, R 22 is cyclobutyl.

[0304] In some embodiments, R 21 is H and R 22 is C 1 ~C 6 In some embodiments, R 21 is H and R 22 is C 1 ~C 3 In some embodiments, R 21 is H and R 22 is methyl, ethyl, n-propyl, or isopropyl. 21 is H and R 22 is methyl. In some embodiments, R 21 and R 22 Each is H. In some embodiments, R 21 is H and R 22 is C 3 ~C 6 In some embodiments, R 21 is H and R 22 is C 3 ~C 5 In some embodiments, R 21 is H and R 22 is cyclopropyl, cyclobutyl, or cyclopentyl. 21 is H and R 22 is cyclobutyl. In some embodiments, R 22 is H and R 21 is C 1 ~C 6 In some embodiments, R 22 is H and R 21 is C 1 ~C 3 In some embodiments, R 22 is H and R 21 is methyl, ethyl, n-propyl, or isopropyl. 22 is H and R 21 is methyl. In some embodiments, R 22 is H and R21 is C 3 ~C 6 In some embodiments, R 22 is H and R 21 is C 3 ~C 5 In some embodiments, R 22 is H and R 21 is cyclopropyl, cyclobutyl, or cyclopentyl. 22 is H and R 21 is cyclobutyl.

[0305] In some embodiments, R 21 is the halo, R 22 is C 1 ~C 6 In some embodiments, R 21 is halo (e.g., chloro, fluoro, or bromo), and R 22 is C 1 ~C 3 In some embodiments, R is an alkyl group (e.g., methyl, ethyl, n-propyl, or isopropyl). 21 is fluoro and R 22 is methyl.

[0306] In some embodiments, R 22 is the halo, R 21 is C 1 ~C 6 In some embodiments, R 22 is halo (e.g., chloro, fluoro, or bromo), and R 21 is C 1 ~C 3 In some embodiments, R is an alkyl group (e.g., methyl, ethyl, n-propyl, or isopropyl). 22 is fluoro and R 21 is methyl.

[0307] In some embodiments, R 21 and R22 together with the carbon atom to which they are attached,

[0308] [ka] In some embodiments, R 21 and R 22 together with the carbon atom to which they are attached,

[0309] [ka] In some embodiments, R 21 and R 22 together with the carbon atom to which they are attached,

[0310] [ka] In some embodiments, R 21 and R 22 together with the carbon atom to which they are attached,

[0311] [ka] It is formed.

[0312] In some embodiments, Y is CR 23 R 24 In some embodiments, Y is S. In some embodiments, Y is a bond. When Y is S or a bond, R 21 Also 22 Also not halo.

[0313] In some embodiments, R 23 and R 24 are independently H, C 1 ~C6 Alkyl, halo, or C 1 ~C 6 In some embodiments, R 23 and R 24 are independently H, halo, and C 1 ~C 3 Alkyl, or C 1 ~C 3 In some embodiments, R 23 and R 24 are independently H, F, -CH 3 , or -CF 3 It is.

[0314] In some embodiments, R 23 is H.

[0315] In some embodiments, R 23 is C 1 ~C 6 In some embodiments, R 23 is C 1 ~C 3 In some embodiments, R 23 is methyl, ethyl, n-propyl, or isopropyl. 23 Ha-CH 3 It is.

[0316] In some embodiments, R 23 is halo. In some embodiments, R 23 is chloro, fluoro, or bromo. 23 is chloro or fluoro. In some embodiments, R 23 is fluoro.

[0317] In some embodiments, R 23 is C 1 ~C 6 In some embodiments, R 23 C containing 1 to 7 halogen atoms1 ~C 6 In some embodiments, R 23 is C 1 ~C 3 In some embodiments, R 23 C containing 1 to 7 halogen atoms 1 ~C 3 In some embodiments, R 23 C containing 1 to 5 halogen atoms 1 ~C 3 In some embodiments, the halogen atoms are independently selected from the group consisting of chloro, bromo, and fluoro atoms. In some embodiments, the halogen atoms are independently selected from the group consisting of chloro and fluoro atoms. In some embodiments, all of the halogen atoms are fluoro atoms. In some embodiments, the halogen atoms are a combination of chloro and fluoro atoms. In some embodiments, R 23 -CF 3 , -CCl 3 , -CF 2 Cl, -CFCl 2 , -CHF 2 , -CH 2 F, -CHCl 2 or -CHFCl. In some embodiments, R 23 -CF 3 It is.

[0318] In some embodiments, R 24 is H.

[0319] In some embodiments, R 24 is C 1 ~C 6 In some embodiments, R 24 is C 1 ~C 3 In some embodiments, R 24 is methyl, ethyl, n-propyl, or isopropyl. 24Ha-CH 3 It is.

[0320] In some embodiments, R 24 is halo. In some embodiments, R 24 is chloro, fluoro, or bromo. 24 is chloro or fluoro. In some embodiments, R 24 is fluoro.

[0321] In some embodiments, R 24 is C 1 ~C 6 In some embodiments, R 24 C containing 1 to 7 halogen atoms 1 ~C 6 In some embodiments, R 24 is C 1 ~C 3 In some embodiments, R 24 C containing 1 to 7 halogen atoms 1 ~C 3 In some embodiments, R 24 C containing 1 to 5 halogen atoms 1 ~C 3 In some embodiments, the halogen atoms are independently selected from the group consisting of chloro, bromo, and fluoro atoms. In some embodiments, the halogen atoms are independently selected from the group consisting of chloro and fluoro atoms. In some embodiments, all of the halogen atoms are fluoro atoms. In some embodiments, the halogen atoms are a combination of chloro and fluoro atoms. In some embodiments, R 24 -CF 3 , -CCl 3 , -CF 2 Cl, -CFCl 2 , -CHF 2 , -CH 2 F, -CHCl 2or -CHFCl. In some embodiments, R 24 -CF 3 It is.

[0322] In some embodiments, R 23 and R 24 Each is H. In some embodiments, R 23 is H and R 24 is C 1 ~C 6 In some embodiments, R 23 is H and R 24 is C 1 ~C 3 In some embodiments, R 23 is H and R 24 is methyl. In some embodiments, R 24 is H and R 23 is C 1 ~C 6 In some embodiments, R 24 is H and R 23 is C 1 ~C 3 In some embodiments, R 24 is H and R 23 is methyl.

[0323] In some embodiments, R 23 and R 24 Each is independently halo. 23 is fluoro and R 24 is fluoro, chloro, or bromo. 24 is fluoro and R 23 is fluoro, chloro, or bromo. 23 and R 24 are each fluoro.

[0324] In some embodiments, R 21 and R 23Together with the carbon atoms to which they are attached,

[0325] [ka] In some embodiments, R 22 , H, C 1 ~C 6 Alkyl, halo, or C 1 ~C 6 haloalkyl; R 24 , H, C 1 ~C 6 Alkyl, halo, or C 1 ~C 6 haloalkyl; each R 30 are independently H, C 1 ~C 3 Alkyl, C 1 ~C 3 Haloalkyl, or C 1 ~C 3 In some embodiments, R 22 , H, C 1 ~C 3 Alkyl, halo, or C 1 ~C 3 haloalkyl; R 24 , H, C 1 ~C 3 Alkyl, halo, or C 1 ~C 3 haloalkyl; each R 30 are independently H, C 1 ~C 2 Alkyl, C 1 ~C 2 Haloalkyl, or C 1 ~C 2 In some embodiments, R 22 -H, -CH 3 , F, or -CF 3 ;R 24 -H, -CH 3 , F, or -CF 3 and each R 30 are independently H, -CH 3, -CF 3 , or -CH 2 In some embodiments, R 22 and R 24 Each is H; each R 30 is H.

[0326] In some embodiments, W is CH. In some embodiments, W is N.

[0327] In some embodiments, R 25 is C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, or C 3 ~C 6 In some embodiments, R 25 is C 1 ~C 3 Alkyl, C 1 ~C 3 Haloalkyl, or C 3 ~C 4 In some embodiments, R 25 -CH 3 , -CHF 2 or cyclopropyl.

[0328] In some embodiments, R 25 is C 1 ~C 6 In some embodiments, R 25 is C 1 ~C 3 In some embodiments, R 25 is methyl, ethyl, n-propyl, or isopropyl. 25 Ha-CH 3 It is.

[0329] In some embodiments, R 25 is C 1 ~C 6In some embodiments, R 25 C containing 1 to 7 halogen atoms 1 ~C 6 In some embodiments, R 25 is C 1 ~C 3 In some embodiments, R 25 C containing 1 to 7 halogen atoms 1 ~C 3 In some embodiments, R 25 C containing 1 to 5 halogen atoms 1 ~C 3 In some embodiments, the halogen atoms are independently selected from the group consisting of chloro, bromo, and fluoro atoms. In some embodiments, the halogen atoms are independently selected from the group consisting of chloro and fluoro atoms. In some embodiments, all of the halogen atoms are fluoro atoms. In some embodiments, the halogen atoms are a combination of chloro and fluoro atoms. In some embodiments, R 25 -CF 3 , -CCl 3 , -CF 2 Cl, -CFCl 2 , -CHF 2 , -CH 2 F, -CHCl 2 or -CHFCl. In some embodiments, R 25 -CHF 2 It is.

[0330] In some embodiments, R 25 is C 3 ~C 6 In some embodiments, R 25 is C 3 ~C 5 In some embodiments, R 25 is C 3 ~C 4 In some embodiments, R 25is cyclopropyl, cyclobutyl, or cyclopentyl. 25 is cyclopropyl.

[0331] In some embodiments, each R 26 is independently 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, C 1 ~C 6 Alkyl-OH, C 1 ~C 6 Alkyl-CN, -(CR 28 R 29 ) p -(4-6 membered heterocyclyl), -(CR 28 R 29 ) p -(5-6 membered heteroaryl), -(CR 28 R 29 ) p -(C 6 ~C 10 aryl), or -(CR 28 R 29 ) p -(C 3 ~C 6 cycloalkyl), each cycloalkyl, heterocyclyl, heteroaryl, or aryl group optionally containing 1 to 5 R 27 In some embodiments, each R 26 is independently 1 ~C 3 Alkyl, C 1 ~C 3 Haloalkyl, C 1 ~C 3 Alkyl-OH, C 1 ~C 3 Alkyl-CN, -(CR 28 R 29 ) p -(4-6 membered heterocyclyl), -(CR 28 R 29 ) p -(5-6 membered heteroaryl), -(CR 28 R 29 )p -(C 6 ~C 10 aryl), or -(CR 28 R 29 ) p -(C 3 ~C 6 cycloalkyl), each heterocyclyl, heteroaryl, aryl, or cycloalkyl group optionally having 1 to 5 R 27 is substituted by a group.

[0332] In some embodiments, R 26 is C 1 ~C 6 In some embodiments, R 26 is C 1 ~C 3 In some embodiments, R 26 is methyl, ethyl, n-propyl, or isopropyl. 26 Ha-CH 3 It is.

[0333] In some embodiments, R 26 is C 1 ~C 6 In some embodiments, R 26 C containing 1 to 7 halogen atoms 1 ~C 6 In some embodiments, R 26 is C 1 ~C 3 In some embodiments, R 26 C containing 1 to 7 halogen atoms 1 ~C 3 In some embodiments, R 26 C containing 1 to 5 halogen atoms 1 ~C 3In some embodiments, the halogen atoms are independently selected from the group consisting of chloro, bromo, and fluoro atoms. In some embodiments, the halogen atoms are independently selected from the group consisting of chloro and fluoro atoms. In some embodiments, all of the halogen atoms are fluoro atoms. In some embodiments, the halogen atoms are a combination of chloro and fluoro atoms. In some embodiments, R 26 -CF 3 , -CCl 3 , -CF 2 Cl, -CFCl 2 , -CHF 2 , -CH 2 F, -CHCl 2 or -CHFCl. In some embodiments, R 26 -CF 3 It is.

[0334] In some embodiments, R 26 is C 1 ~C 6 In some embodiments, R 26 is C 1 ~C 3 In some embodiments, R 26 is -CH 2 OH, -CH 2 CH 2 OH, -CH 2 CH 2 CH 2 OH, or -C(CH 3 ) 2 In some embodiments, R 26 Ha-CH 2 It is OH.

[0335] In some embodiments, R 26 is C 1 ~C 6 In some embodiments, R 26 is C 1 ~C 3In some embodiments, R 26 -CH 2 CN, -CH 2 CH 2 CN, -CH 2 CH 2 CH 2 CN, or -C(CH 3 ) 2 CN. In some embodiments, R 26 Ha-CH 2 It is CN.

[0336] In some embodiments, R 26 CR 28 R 29 ) p -(4- to 6-membered heterocyclyl), the heterocyclyl optionally having 1 to 5 R 27 In some embodiments, p is 0 and R 26 Optionally, select 1 to 5 R 27 In some embodiments, p is 1 and R 26 HA-CR 28 R 29 -(4- to 6-membered heterocyclyl), the heterocyclyl optionally having 1 to 5 R 27In some embodiments, the heterocyclyl is substituted by a group. In some embodiments, the heterocyclyl contains 1 to 3 nitrogen atoms. In some embodiments, the heterocyclyl contains 1 nitrogen atom. In some embodiments, the heterocyclyl contains 2 nitrogen atoms. In some embodiments, the heterocyclyl contains 1 to 2 nitrogen atoms and 1 sulfur atom. In some embodiments, the heterocyclyl contains 2 nitrogen atoms and 1 sulfur atom. In some embodiments, the heterocyclyl contains 1 to 2 nitrogen atoms and 1 oxygen atom. In some embodiments, the heterocyclyl contains 1 nitrogen atom and 1 oxygen atom. In some embodiments, the heterocyclyl contains 1 oxygen atom. In some embodiments, the heterocyclyl contains 1 sulfur atom. In some embodiments, the heterocyclyl contains 1 to 5 R 27 In some embodiments, the heterocyclyl is substituted by one R 27 In some embodiments, the heterocyclyl is substituted by two R 27 In some embodiments, the heterocyclyl is substituted by three R 27 In some embodiments, the heterocyclyl is substituted by four R 27 In some embodiments, the heterocyclyl is substituted by five R 27 In some embodiments, the heterocyclyl is unsubstituted. In some embodiments, the heterocyclyl is azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, oxetanyl, tetrahydrofuranyl, or morpholinyl. In some embodiments, R 26 teeth,

[0337] [ka] It is.

[0338] In some embodiments, R 26 CR28 R 29 ) p -(5-6 membered heteroaryl), the heteroaryl optionally having 1 to 5 R 27 In some embodiments, p is 0 and R 26 Optionally, select 1 to 5 R 27 In some embodiments, p is 1 and R 26 HA-CR 28 R 29 -(5-6 membered heteroaryl), the heteroaryl optionally having 1 to 5 R 27 In some embodiments, the heteroaryl contains 1-3 nitrogen atoms. In some embodiments, the heteroaryl contains 1 nitrogen atom. In some embodiments, the heteroaryl contains 2 nitrogen atoms. In some embodiments, the heteroaryl contains 1-2 nitrogen atoms and 1 sulfur atom. In some embodiments, the heteroaryl contains 2 nitrogen atoms and 1 sulfur atom. In some embodiments, the heteroaryl contains 1-2 nitrogen atoms and 1 oxygen atom. In some embodiments, the heteroaryl contains 1 nitrogen atom and 1 oxygen atom. In some embodiments, the heteroaryl contains 1 oxygen atom. In some embodiments, the heteroaryl contains 1 sulfur atom. In some embodiments, the heteroaryl contains 1-5 R 27 In some embodiments, the heteroaryl is substituted with one R 27 In some embodiments, the heteroaryl is substituted with two R 27 In some embodiments, the heteroaryl is substituted with three R 27 In some embodiments, the heteroaryl is substituted with four R groups. 27 In some embodiments, the heteroaryl is substituted with five R groups. 27In some embodiments, the heteroaryl is unsubstituted. In some embodiments, the heteroaryl is pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, or thiazolyl. In some embodiments, R 26 teeth,

[0339] [ka] It is.

[0340] In some embodiments, R 26 CR 28 R 29 ) p -(C 6 ~C 10 aryl), wherein aryl is optionally selected from 1 to 5 R 27 In some embodiments, p is 0 and R 26 is C 6 ~C 10 aryl, optionally containing 1 to 5 R 27 In some embodiments, p is 1 and R 26 HA-CR 28 R 29 -(C 6 ~C 10 aryl), wherein aryl is optionally selected from 1 to 5 R 27 In some embodiments, R 26 CR 28 R 29 ) p -(C 6 aryl), wherein aryl is optionally selected from 1 to 5 R 27 In some embodiments, p is 0 and R 26 is C 6 aryl, optionally containing 1 to 5 R 27In some embodiments, the aryl is substituted by a group. In some embodiments, the aryl is a monocyclic aromatic ring. In some embodiments, the aryl is a fused bicyclic ring. In some embodiments, the aryl contains an aromatic ring fused to a second aromatic ring. In some embodiments, the aryl contains an aromatic ring fused to a saturated or partially unsaturated ring. In some embodiments, the aryl is substituted by 1 to 5 R 27 In some embodiments, the aryl is substituted with one R 27 In some embodiments, the aryl is substituted with two R 27 In some embodiments, the aryl is substituted with three R 27 In some embodiments, the aryl is substituted with four R 27 In some embodiments, the aryl is substituted with five R groups. 27 In some embodiments, the aryl is substituted by a phenyl group. In some embodiments, the aryl is unsubstituted. In some embodiments, the aryl is phenyl. In some embodiments, R 26 teeth

[0341] [ka] It is.

[0342] In some embodiments, R 26 CR 28 R 29 ) p -(C 3 ~C 6 cycloalkyl), wherein cycloalkyl optionally contains 1 to 5 R 27 In some embodiments, p is 0 and R 26 Optionally, select 1 to 5 R 27 substituted by a C group; 3 ~C 6 In some embodiments, p is 1 and R 26 HA-CR28 R 29 -(C 3 ~C 6 cycloalkyl), wherein cycloalkyl optionally contains 1 to 5 R 27 In some embodiments, the cycloalkyl is substituted with 1 to 5 R 27 In some embodiments, the cycloalkyl is substituted with one R 27 In some embodiments, the cycloalkyl is substituted with two R 27 In some embodiments, the cycloalkyl is substituted with three R 27 In some embodiments, the cycloalkyl is substituted with four R groups. 27 In some embodiments, the cycloalkyl is substituted with five R groups. 27 In some embodiments, the cycloalkyl is substituted by a cycloalkyl group. In some embodiments, the cycloalkyl is unsubstituted. In some embodiments, the cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In some embodiments, the cycloalkyl is cyclobutyl or cyclopentyl. In some embodiments, R 26 teeth

[0343] [ka] It is.

[0344] In some embodiments, each R 26 are independently -CH 3 , -CF 3 , -CH 2 OH, -CH 2 C.N.,

[0345] [ka] It is.

[0346] In some embodiments, p is 0. In some embodiments, p is 1.

[0347] In some embodiments, R 28 and R 29 are independently H, C 1 ~C 6 Alkyl, or C 1 ~C 6 In some embodiments, R 28 and R 29 are independently H, C 1 ~C 3 Alkyl, or C 1 ~C 3 In some embodiments, R 28 and R 29 are independently H, -CH 3 , or -CF 3 It is.

[0348] In some embodiments, R 28 is H. In some embodiments, R 29 is H. In some embodiments, R 28 and R 29 are both H. In some embodiments, R 28 and R 29 One of them is H and the other is C 1 ~C 6 Alkyl or C 1 ~C 6 In some embodiments, R 28 and R 29 One of them is H and the other is C 1 ~C 3 Alkyl or C 1 ~C 3 In some embodiments, R 28 and R 29 One of the groups is H and the other is -CH 3 Or -CF 3 It is.

[0349] In some embodiments, R 28 and R 29 is independently 1 ~C 6 In some embodiments, R 28 and R 29 is independently 1 ~C 3 In some embodiments, R 28 and R 29 is independently methyl, ethyl, n-propyl, or isopropyl. 28 and R 29 are independently -CH 3 In some embodiments, R 28 and R 29 Both are -CH 3 It is.

[0350] In some embodiments, R 28 and R 29 is independently 1 ~C 6 In some embodiments, R 28 and R 29 each independently represents a C group containing 1 to 7 halogen atoms; 1 ~C 6 In some embodiments, R 28 and R 29 is independently 1 ~C 3 In some embodiments, R 28 and R 29 each independently represents a C group containing 1 to 7 halogen atoms; 1 ~C 3 In some embodiments, R 28 and R 29 each independently represents a C group containing 1 to 5 halogen atoms; 1 ~C 3In some embodiments, the halogen atoms are independently selected from the group consisting of chloro, bromo, and fluoro atoms. In some embodiments, the halogen atoms are independently selected from the group consisting of chloro and fluoro atoms. In some embodiments, all of the halogen atoms are fluoro atoms. In some embodiments, the halogen atoms are a combination of chloro and fluoro atoms. In some embodiments, R 28 and R 29 are independently -CF 3 , -CCl 3 , -CF 2 Cl, -CFCl 2 , -CHF 2 , -CH 2 F, -CHCl 2 or -CHFCl. In some embodiments, R 28 and R 29 are independently -CF 3 In some embodiments, R 28 and R 29 Both are -CF 3 It is.

[0351] In some embodiments, each R 27 is independently 1 ~C 6 Alkyl, C 1 ~C 6 Alkyl-OH, C 1 ~C 6 Haloalkyl, C 1 ~C 6 Alkyl-CN, -CN, halo, hydroxy, -O-(C 1 ~C 6 alkyl), -O(C 1 ~C 6 haloalkyl), oxo, -C(O)NH 2 , -C(O)NH(C 1 ~C 6 alkyl), -C(O)N(C 1 ~C 6 Alkyl) 2 , -C(O)NH(C 1 ~C 6haloalkyl), -CO 2 H, -C(O)O(C 1 ~C 6 Alkyl), -SO 2 -(C 1 ~C 6 Alkyl), -SO 2 -NH(C 1 ~C 6 Alkyl), -SO 2 -N(C 1 ~C 6 Alkyl) 2 , -C(O)(C 1 ~C 6 alkyl), -(C 1 ~C 6 alkylene)-C(O)N(C 1 ~C 6 Alkyl) 2 , or -(C 1 ~C 6 alkylene)-C(O)NH(C 1 ~C 6 In some embodiments, each R 27 is independently 1 ~C 3 Alkyl, C 1 ~C 3 Alkyl-OH, C 1 ~C 3 Haloalkyl, C 1 ~C 3 Alkyl-CN, -CN, halo, hydroxy, -O-(C 1 ~C 3 alkyl), -O(C 1 ~C 3 haloalkyl), oxo, -C(O)NH 2 , -C(O)NH(C 1 ~C 3 alkyl), -C(O)NH(C 1 ~C 3 haloalkyl), -C(O)N(C 1 ~C 3 Alkyl) 2 , -CO 2 H, -C(O)O(C 1 ~C 3 Alkyl), -SO 2 -(C 1 ~C3 Alkyl), -SO 2 -NH(C 1 ~C 3 Alkyl), -SO 2 -N(C 1 ~C 3 Alkyl) 2 , -C(O)(C 1 ~C 3 alkyl), -(C 1 ~C 3 alkylene)-C(O)N(C 1 ~C 3 Alkyl) 2 , or -(C 1 ~C 3 alkylene)-C(O)NH(C 1 ~C 3 In some embodiments, each R 27 are independently -CH 3 , -CH 2 OH, -CF 3 , -CH 2 CN, -CN, F, Cl, hydroxy, -OCH 3 , -OCF 3 , oxo, -C(O)NH 2 , -C(O)NH(CH 3 ), -C(O)NH(CF 3 ), -C(O)N(CH 3 ) 2 , -CO 2 H, -C(O)OCH 3 , -SO 2 -(CH 3 ), -SO 2 -NH(CH 3 ), -SO 2 -N(CH 3 ) 2 , -C(O)(CH 3 ), -(CH 2 )-C(O)N(CH 3 ) 2 , or -(CH 2 )-C(O)NH(CH 3 ).

[0352] In some embodiments, R 27 is C 1~C 6 In some embodiments, R 27 is C 1 ~C 3 In some embodiments, R 27 is methyl, ethyl, n-propyl, or isopropyl. 27 Ha-CH 3 It is.

[0353] In some embodiments, R 27 is C 1 ~C 6 In some embodiments, R 27 is C 1 ~C 3 In some embodiments, R 27 -CH 2 OH, -CH 2 CH 2 OH, -CH 2 CH 2 CH 2 OH, or -C(CH 3 ) 2 In some embodiments, R 27 Ha-CH 2 It is OH.

[0354] In some embodiments, R 27 is -CN.

[0355] In some embodiments, R 27 is C 1 ~C 6 In some embodiments, R 27 is C 1 ~C 3 In some embodiments, R 27 -CH 2 CN, -CH 2 CH 2 CN, -CH 2 CH 2 CH 2 CN, or -C(CH 3) 2 CN. In some embodiments, R 27 Ha-CH 2 It is CN.

[0356] In some embodiments, R 27 is halo. In some embodiments, R 27 is chloro, fluoro, or bromo. 27 is chloro or fluoro. In some embodiments, R 27 is fluoro. In some embodiments, R 27 is chloro.

[0357] In some embodiments, R 27 is C 1 ~C 6 In some embodiments, R 27 C containing 1 to 7 halogen atoms 1 ~C 6 In some embodiments, R 27 is C 1 ~C 3 In some embodiments, R 27 C containing 1 to 7 halogen atoms 1 ~C 3 In some embodiments, R 27 C containing 1 to 5 halogen atoms 1 ~C 3 In some embodiments, the halogen atoms are independently selected from the group consisting of chloro, bromo, and fluoro atoms. In some embodiments, the halogen atoms are independently selected from the group consisting of chloro and fluoro atoms. In some embodiments, all of the halogen atoms are fluoro atoms. In some embodiments, the halogen atoms are a combination of chloro and fluoro atoms. In some embodiments, R 27 -CF 3 , -CCl 3 , -CF 2Cl, -CFCl 2 , -CHF 2 , -CH 2 F, -CHCl 2 , -CHFCl, -CH 2 CF 3 , -CH 2 CCl 3 , -CH 2 CH 2 F, or -CH 2 CH 2 In some embodiments, R 27 -CF 3 or -CHF 2 In some embodiments, R 27 -CF 3 It is.

[0358] In some embodiments, R 27 is hydroxy.

[0359] In some embodiments, R 27 is -O(C 1 ~C 6 In some embodiments, R 27 is -O(C 1 ~C 3 In some embodiments, R 27 -OCH 3 , -OCH 2 CH 3 , -OCH 2 CH 2 CH 3 , or -OCH(CH 3 ) 2 In some embodiments, R 27 HA-OCH 3 It is.

[0360] In some embodiments, R 27 is -O(C 1 ~C 6 haloalkyl). In some embodiments, R 27 contains 1 to 7 halogen atoms -O(C 1 ~C6 haloalkyl). In some embodiments, R 27 is -O(C 1 ~C 3 haloalkyl). In some embodiments, R 27 contains 1 to 7 halogen atoms -O(C 1 ~C 3 haloalkyl). In some embodiments, R 27 contains 1 to 5 halogen atoms -O(C 1 ~C 3 In some embodiments, the halogen atoms are independently selected from the group consisting of chloro, bromo, and fluoro atoms. In some embodiments, the halogen atoms are independently selected from the group consisting of chloro and fluoro atoms. In some embodiments, all of the halogen atoms are fluoro atoms. In some embodiments, the halogen atoms are a combination of chloro and fluoro atoms. In some embodiments, R 27 -OCF 3 , -OCCl 3 , -OCF 2 Cl, -OCFCl 2 , -OCHF 2 , -OCH 2 F, -OCHCl 2 , -OCHFCl, -OCH 2 CF 3 , -OCH 2 CCl 3 , -OCH 2 CH 2 F, or -OCH 2 CH 2 In some embodiments, R 27 -OCF 3 It is.

[0361] In some embodiments, R 27 is oxo.

[0362] In some embodiments, R 27 -C(O)NH 2 It is.

[0363] In some embodiments, R 27 is -C(O)NH(C 1 ~C 6 In some embodiments, R 27 is -C(O)NH(C 1 ~C 3 In some embodiments, R 27 is -C(O)NH(CH 3 ), -C(O)NH(CH 2 CH 3 ), -C(O)NH(CH 2 CH 2 CH 3 ), or -C(O)NH(CH(CH 3 ) 2 In some embodiments, R 27 is -C(O)NH(CH 3 ).

[0364] In some embodiments, R 27 -C(O)N(C 1 ~C 6 Alkyl) 2 In some embodiments, two C 1 ~C 6 The alkyl groups are the same. In another embodiment, two C 1 ~C 6 The alkyl groups are different. In some embodiments, R 27 -C(O)N(C 1 ~C 3 Alkyl) 2 In some embodiments, R 27 is -C(O)N(CH 3 ) 2 , -C(O)N(CH 2 CH 3 ) 2 , -C(O)N(CH 2 CH 2 CH 3 ) 2 , or -C(O)N(CH(CH 3 ) 2 ) 2In some embodiments, R 27 is -C(O)N(CH 3 )(CH 2 CH 3 ), -C(O)N(CH 3 )(CH 2 CH 2 CH 3 ), -C(O)N(CH 3 )(CH(CH 3 ) 2 ), -C(O)N(CH 2 CH 3 )(CH 2 CH 2 CH 3 ), or -C(O)N(CH 2 CH 3 )(CH(CH 3 ) 2 In some embodiments, R 27 is -C(O)N(CH 3 ) 2 It is.

[0365] In some embodiments, R 27 HA-CO 2 It's H.

[0366] In some embodiments, R 27 is -C(O)NH(C 1 ~C 6 haloalkyl). In some embodiments, R 27 -C(O)NH(C 1 ~C 6 haloalkyl). In some embodiments, R 27 is -C(O)NH(C 1 ~C 3 haloalkyl). In some embodiments, R 27 -C(O)NH(C 1 ~C 3 haloalkyl). In some embodiments, R 27 -C(O)NH(C 1 ~C3 In some embodiments, the halogen atoms are independently selected from the group consisting of chloro, bromo, and fluoro atoms. In some embodiments, the halogen atoms are independently selected from the group consisting of chloro and fluoro atoms. In some embodiments, all of the halogen atoms are fluoro atoms. In some embodiments, the halogen atoms are a combination of chloro and fluoro atoms. In some embodiments, R 27 is -C(O)NH(CF 3 ), -C(O)NH(CHF 2 ), -C(O)NH(CCl 3 ), -C(O)NH(CF 2 Cl), -C(O)NH(CFCl 2 ), -C(O)NH(CH 2 F), -C(O)NH(CHCl 2 ), or —C(O)NH(CHFCl). In some embodiments, R 27 is -C(O)NH(CF 3 ).

[0367] In some embodiments, R 27 is -C(O)O(C 1 ~C 6 In some embodiments, R 27 is -C(O)O(C 1 ~C 3 In some embodiments, R 27 is -C(O)O(CH 3 ), -C(O)O(CH 2 CH 3 ), -C(O)O(CH 2 CH 2 CH 3 ), or -C(O)O(CH(CH 3 ) 2 In some embodiments, R 27 is -C(O)O(CH 3 ).

[0368] In some embodiments, R 27-SO 2 -(C 1 ~C 6 In some embodiments, R 27 -SO 2 -(C 1 ~C 3 In some embodiments, R 27 -SO 2 -(CH 3 ), -SO 2 -(CH 2 CH 3 ), -SO 2 -(CH 2 CH 2 CH 3 ), or -SO 2 -(CH(CH 3 ) 2 In some embodiments, R 27 -SO 2 -(CH 3 ).

[0369] In some embodiments, R 27 -SO 2 -NH(C 1 ~C 6 In some embodiments, R 27 -SO 2 -NH(C 1 ~C 3 In some embodiments, R 27 -SO 2 -NH(CH 3 ), -SO 2 -NH(CH 2 CH 3 ), -SO 2 -NH(CH 2 CH 2 CH 3 ), or -SO 2 -NH(CH(CH 3 ) 2 In some embodiments, R 27 -SO 2 -NH(CH 3 ).

[0370] In some embodiments, R 27 -SO 2 -N(C 1 ~C 6 Alkyl) 2 In some embodiments, two C 1 ~C 6 The alkyl groups are the same. In another embodiment, two C 1 ~C 6 The alkyl groups are different. In some embodiments, R 27 -SO 2 -N(C 1 ~C 3 Alkyl) 2 In some embodiments, R 27 -SO 2 -N(CH 3 ) 2 , -SO 2 -N(CH 2 CH 3 ) 2 , -SO 2 -N(CH 2 CH 2 CH 3 ) 2 , or -SO 2 -N(CH(CH 3 ) 2 ) 2 In some embodiments, R 27 -SO 2 -N(CH 3 )(CH 2 CH 3 ), -SO 2 -N(CH 3 )(CH 2 CH 2 CH 3 ), -SO 2 -N(CH 3 )(CH(CH 3 ) 2 ), -SO 2 -N(CH 2 CH 3 )(CH 2 CH 2 CH 3 ), or -SO 2 -N(CH 2CH 3 )(CH(CH 3 ) 2 In some embodiments, R 27 -SO 2 -N(CH 3 ) 2 It is.

[0371] In some embodiments, R 27 -C(O)(C 1 ~C 6 In some embodiments, R 27 -C(O)(C 1 ~C 3 In some embodiments, R 27 is -C(O)(CH 3 ), -C(O)(CH 2 CH 3 ), -C(O)(CH 2 CH 2 CH 3 ), or -C(O)(CH(CH 3 ) 2 In some embodiments, R 27 is -C(O)(CH 3 ).

[0372] In some embodiments, R 27 Ha-(C 1 ~C 6 alkylene)-C(O)N(C 1 ~C 6 Alkyl) 2 In some embodiments, two C 1 ~C 6 The alkyl groups are the same. In another embodiment, two C 1 ~C 6 The alkyl groups are different. In some embodiments, R 27 Ha-(C 1 ~C 3 alkylene)-C(O)N(C 1 ~C 3 Alkyl) 2 In some embodiments, R 27 Ha-(CH2 )-C(O)N(C 1 ~C 3 Alkyl) 2 , -(CH 2 CH 2 )-C(O)N(C 1 ~C 3 Alkyl) 2 , or -(CH 2 CH 2 CH 2 )-C(O)N(C 1 ~C 3 Alkyl) 2 In some embodiments, R 27 is -(CH 2 )-C(O)N(CH 3 ) 2 , -(CH 2 )-C(O)N(CH 2 CH 3 ) 2 , -(CH 2 )-C(O)N(CH 2 CH 2 CH 3 ) 2 , -(CH 2 )-C(O)N(CH(CH 3 ) 2 ) 2 , -(CH 2 )-C(O)N(CH 3 )(CH 2 CH 3 ), -(CH 2 )-C(O)N(CH 3 )(CH 2 CH 2 CH 3 ) 2 , -(CH 2 )-C(O)N(CH 3 )(CH(CH 3 ) 2 ), -(CH 2 CH 2 )-C(O)N(CH 3 ) 2 , -(CH 2 CH 2 )-C(O)N(CH 2 CH 3 ) 2 , -(CH 2 CH2 )-C(O)N(CH 2 CH 2 CH 3 ) 2 , -(CH 2 CH 2 )-C(O)N(CH(CH 3 ) 2 ) 2 , -(CH 2 CH 2 )-C(O)N(CH 3 )(CH 2 CH 3 ), -(CH 2 CH 2 )-C(O)N(CH 3 )(CH 2 CH 2 CH 3 ) 2 , or -(CH 2 CH 2 )-C(O)N(CH 3 )(CH(CH 3 ) 2 In some embodiments, R 27 is -(CH 2 )-C(O)N(CH 3 ) 2 It is.

[0373] In some embodiments, R 27 is -(C 1 ~C 6 alkylene)-C(O)NH(C 1 ~C 6 In some embodiments, R 27 is -(C 1 ~C 3 alkylene)-C(O)NH(C 1 ~C 3 In some embodiments, R 27 is -(CH 2 )-C(O)NH(C 1 ~C 3 alkyl), -(CH 2 CH 2 )-C(O)NH(C 1 ~C 3 alkyl), or -(CH2 CH 2 CH 2 )-C(O)NH(C 1 ~C 3 In some embodiments, R 27 is -(CH 2 )-C(O)NH(CH 3 ), -(CH 2 )-C(O)NH(CH 2 CH 3 ), -(CH 2 )-C(O)NH(CH 2 CH 2 CH 3 ), -(CH 2 )-C(O)NH(CH(CH 3 ) 2 ), -(CH 2 CH 2 )-C(O)NH(CH 3 ), -(CH 2 CH 2 )-C(O)NH(CH 2 CH 3 ), -(CH 2 CH 2 )-C(O)NH(CH 2 CH 2 CH 3 ), or -(CH 2 CH 2 )-C(O)NH(CH(CH 3 ) 2 In some embodiments, R 27 is -(CH 2 )-C(O)NH(CH 3 ).

[0374] In some embodiments, each R 30 are independently H, C 1 ~C 3 Alkyl, C 1 ~C 3 Alkyl-OH, or C 1 ~C 3 In some embodiments, each R 30 are independently H, C 1 ~C 2 Alkyl, C 1~C 2 Alkyl-OH, or C 1 ~C 2 In some embodiments, each R 30 are independently H, -CH 3 , -CH 2 OH, or -CF 3 It is.

[0375] In some embodiments, each R 30 is independently H. In some embodiments, one R 30 is H, and the other R 30 is C 1 ~C 3 In some embodiments, one R 30 is H, and the other R 30 is C 1 ~C 2 In some embodiments, one R 30 is H, and the other R 30 is methyl. In some embodiments, one R 30 is H, and the other R 30 is ethyl. In some embodiments, one R 30 is H, and the other R 30 is C 1 ~C 3 In some embodiments, one R 30 is H, and the other R 30 is C 1 ~C 2 In some embodiments, one R 30 is H, and the other R 30 is C 1 In some embodiments, one R 30 is H, and the other R 30 -CF 3 In some embodiments, each R 30 is H.

[0376] In some embodiments, R 30 is C 1 ~C3 In some embodiments, R 30 is C 1 ~C 2 In some embodiments, R 30 is methyl, ethyl, n-propyl, or isopropyl. 30 is methyl or ethyl. In some embodiments, R 30 Ha-CH 3 It is.

[0377] In some embodiments, R 30 is C 1 ~C 3 In some embodiments, R 30 is C 1 ~C 2 In some embodiments, R 30 -CH 2 OH, -CH 2 CH 2 OH, or -CH 2 CH 2 CH 2 In some embodiments, R 30 Ha-CH 2 It is OH.

[0378] In some embodiments, R 30 is C 1 ~C 3 In some embodiments, R 30 C containing 1 to 5 halogen atoms 1 ~C 3 In some embodiments, R 30 is C 1 ~C 2 In some embodiments, R 30 C containing 1 to 3 halogen atoms 1 ~C 2In some embodiments, the halogen atoms are independently selected from the group consisting of chloro, bromo, and fluoro atoms. In some embodiments, the halogen atoms are independently selected from the group consisting of chloro and fluoro atoms. In some embodiments, all of the halogen atoms are fluoro atoms. In some embodiments, the halogen atoms are a combination of chloro and fluoro atoms. In some embodiments, R 30 -CF 3 , -CCl 3 , -CF 2 Cl, -CFCl 2 , -CHF 2 , -CH 2 F, -CHCl 2 or -CHFCl. In some embodiments, R 30 -CF 3 It is.

[0379]

[0282] In some embodiments, the compound of formula (II) is a compound of formula (II-A):

[0380] [ka] or a tautomer thereof, or a pharma- ceutically acceptable salt thereof, wherein R 21 , R 22 , and R 25 is as defined for compounds of formula (II).

[0381] [Table 2-1]

[0382] [Table 2-2]

[0383] [Table 2-3]

[0384]

[0283] In some embodiments, provided is a compound selected from compound numbers 55-120 and 167 in Table 2, or a tautomer thereof, or a pharma- ceutically acceptable salt thereof.

[0385] In one aspect, provided herein is a method for preparing a compound of formula (I) as described herein. In another aspect, provided herein is an intermediate compound for preparing a compound of formula (I). In one aspect, provided herein is a method for preparing a compound of formula (II) as described herein. In another aspect, provided herein is an intermediate compound for preparing a compound of formula (II). Also provided herein is a compound that is an assay probe, optionally tagged, for example, by a fluorescent label. In a further aspect, provided herein is a method for assaying the inhibition of Cbl-b. In one variation, provided herein is a method for assaying the inhibition of Cbl-b, comprising pre-incubating Cbl-b with an assay probe, for example an assay probe tagged by a fluorescent label, followed by exposing the Cbl-b / assay probe mixture to a candidate compound, and then using, for example, FRET signal detection, to determine whether and to what extent the assay probe has been displaced by the candidate compound.

[0386]

[0285] The following schemes describe methods for synthesizing the compounds disclosed herein. Mixtures of stereoisomers produced during synthesis, such as racemic mixtures of the final compounds, can be separated into their respective enantiomers using common chromatographic techniques, such as supercritical fluid chromatography (SFC) in combination with chiral stationary phases, chiral column chromatography, or other methods known in the art.

[0387] [ka]

[0388] Here, R 6 and R 7 is as defined for compounds of formula (I), and X' is a methyl ester or NH 2 It is.

[0389] Compounds of formula (I) where X is S can be synthesized as outlined in Scheme I. Benzophenone I-1 is enantioselectively reduced with a suitable catalyst such as CBS reagent to give the enantioenriched alcohol I-2. A Mitunobu reaction introduces a triazole to give intermediate I-4. When X' is an ester, hydrolysis to the acid gives acid I-5 which is then coupled with an amine with a dehydrating reagent such as HATU or T3P to give amide I-6. When X' is an amine, p-NO 2 Coupling with a bis-electrophile such as PhOC(O)Cl forms the urea I-7.

[0390] [ka]

[0391] Here, R 1 , R 2 , R 6 , and R 7 is as defined for compounds of formula (I), and X' is Br or NH 2 and R a and R b is a suitable protecting group.

[0392] Compounds of formula (I) where X is carbon can be synthesized as outlined in Scheme II. Rhodium catalyzed coupling of boronic ester II-1 with alkene II-2 gives (oxetane) ester II-3. Triazole assembly by hydrazide formation, cyclization, and desulfurization gives triazole II-6. When X' is bromine, palladium catalyzed carbonylation and hydrolysis gives acid II-7, which is coupled with an amine to give amide II-8. When X' is an amine, p-NO 2 Coupling with a bis-electrophile such as PhOC(O)Cl forms the urea II-9.

[0393] [ka]

[0394] Here, R 6 and R 7 is as defined for compounds of formula (I), and X' is Br or NH 2 It is.

[0395]

[0225] R 1 is methyl and X is CH 2 Compounds of formula (I) can be assembled as illustrated in Scheme III. Substituted cinnamic acid III-1 is coupled with an Evans chiral auxiliary to form imide III-2. LiMe 2 Conjugate addition of Cu affords the enantioenriched intermediate III-3. Displacement of the chiral auxiliary with hydrazine affords the hydrazide III-4, which is then converted to the triazole III-5 as in Scheme I. Formation of the amide III-7 and urea III-8 can be achieved as in Scheme II.

[0396] [ka]

[0397] Here, R 6 and R 7 is as defined for compounds of formula (I).

[0398]

[0226] Fluorinated compounds of formula IV-7 can be synthesized as illustrated in Scheme IV. Addition of ethyl 2-bromo-2,2-difluoroacetate to acetophenone IV-1 under the action of Zn metal gives hydroxyester IV-2. This ester is converted to triazole IV-3 as in Scheme II. Fluorination of the hydroxy group with a reagent such as DAST gives trifluoro IV-4. After acidic Boc deprotection, separation of the enantiomers by chiral HPLC gives enantiopure IV-6, which is converted to urea IV-7 as in Scheme I.

[0399] [ka]

[0400] Here, R 6 and R 7 is as defined for compounds of formula (I).

[0401] Compounds of formula V-5 can be synthesized as illustrated in Scheme V. Cyclopropyl ester V-1 is converted to hydrazide V-2 and then to triazole V-3. Reduction of the nitro to an amine followed by chiral chromatographic resolution gives intermediate V-4, which is converted to V-5 as in Scheme I.

[0402] [ka]

[0403] Here, R 1 , R 2 , X, and n are as defined for compounds of formula (I).

[0404] Compounds of formula VI-8 can be synthesized as illustrated in Scheme VI. Hydroxyester VI-1 is condensed with nitro-fluoropyridine VI-2 by a strong base such as NaH. Reduction of the nitro with Fe(0) proceeds with concomitant lactam formation to give intermediate VI-4. BH 3 Reduction of the lactam with THF affords the amine VI-5. Coupling to the aniline intermediate VI-6 as in Scheme I completes the urea example VI-8.

[0405] [ka]

[0406] Here, R 5 , R 6 , and R 7 is as defined for compounds of formula (I) and X' is NHBoc or OMe.

[0407] Compounds of formula VII-8 can be synthesized as illustrated in Scheme VII. Ester VII-1 is converted to methyl ketone VII-2 by Weinreb amide formation and methyl Grignard addition. When X is NHBoc, the ketone is converted to NaBH 4 and the resulting alcohol VII-3 is resolved by enzymatic acylation to give the enantiopure alcohol VII-4. Urea example VIII-8 is completed as described in Scheme I.

[0408] [ka]

[0409] Here, R 5 and R 7 is as defined for compounds of formula (I).

[0410] Compounds of formula VIII-8 can be synthesized as illustrated in Scheme VIII. Ketone VIII-2 is homologated to ester VIII-1 with the HWE reagent. 2 Reduction with Pd C and subsequent triazole formation affords intermediate VIII-3. Hydrolysis and POCl 3 Chlorination with ##STR00011## converts the methoxy group to a chlorine. After resolution by chiral chromatography, the chlorine is converted to an acid by palladium-catalyzed carbonylation and hydrolysis of the ester to give acid VIII-7. The example compounds are completed similarly to Scheme I.

[0411] [ka]

[0412] Here, R 1 , R 2 , R 5 , R 10 , X, and Z are as defined for compounds of formula (I), and X' is chlorine or bromine.

[0413] Compounds IX-5 can be synthesized as illustrated in Scheme IX. Substituted IX-1 is converted to the hydantoin IX-2 with potassium cyanate and subsequently reduced to the urea IX-3. Palladium-catalyzed coupling with the halogen IX-4 completes example compound IX-5.

[0414] [ka]

[0415] Here, R 21 , R 22 , R 25 , R 26 , R 27 , W, and Y are as defined for compounds of formula (II).

[0416]

[0232] Oxazole compounds X-5 can be synthesized as depicted in Scheme X. Alkyne X-1 is treated with a nitrile oxide generated in situ by oxidation of oxime X-2 to give oxazole X-3, which is then converted to a ketone similar to Scheme I to give compounds of formula X-5. Alternatively, the converted intermediate X-4 can be treated with a nitrile oxide generated in situ by oxidation of oxime X-2 to give oxazole X-5.

[0417] [ka]

[0418] Here, R 21 , R 22 , R 25 , R 26 , R 27 , W, and Y are as defined for compounds of formula (II), and X' is chlorine or bromine.

[0419] Compounds XI-4 and XI-5 can be synthesized as illustrated in Scheme XI. Terminal acetylene compound XI-1 can be prepared by the synthesis of TMS-N 3 This is converted to the 1,2,3-triazole by reaction with XI-3. Subsequent palladium catalyzed coupling with halo intermediate XI-3 provides compounds of formula XI-4 and XI-5.

[0420] [ka]

[0421] Here, R 21 , R 22 , R 25 , R 26 , R 27 , W, and Y are as defined for compounds of formula (II), and Y' is Cl or NMe(OMe).

[0422]

[0234] Examples of pyrazoles can be synthesized as illustrated in Scheme XII. In some embodiments, acid chloride XII-1 (Y' is Cl) is coupled with terminal alkyne XII-2 under palladium catalysis to give yne-one XII-3. Treatment with hydrazine gives pyrazole XII-4. The remaining ketone is then converted to example XII-5 as illustrated in Formula I. In other embodiments, the converted alkyne, such as XII-7, is deprotonated with a strong base, such as n-BuLi, and treatment with Weinreb amide XII-1 (Y' is NMe(OMe)) gives yne-one XII-7, which is converted to pyrazole XII-8 with hydrazine.

[0423] [ka]

[0424] Here, R 21 , R 22 , R 25 , R 26 , W, and Y are as defined for compounds of formula (II); Z 2 is CH or N, and Y a is Br or I, and R a and R b is a suitable protecting group.

[0425] Benzopyrazole analogs can be assembled as illustrated in Scheme XIII. In some embodiments, protected benzopyrazole compound XIII-1 is coupled with boronic acid or ester XIII-2 under palladium catalysis. The protecting group is removed during the coupling step or in a separate step. The ketone is converted to triazole XIII-4 as illustrated in Scheme I. In other embodiments, protected benzopyrazole compound XIII-1 is coupled with converted core XIII-5 under palladium catalysis. The protecting group is removed during the coupling step or in a separate step to give compounds of formula XIII-6.

[0426] [ka]

[0427] Here, R 6 , R 7 , and R 12 is as defined for compounds of formula (I), and R a is defined for compounds of formula (I) 5 or R as defined for compounds of formula (II) 25 and Y' is COOR b or NH 2 and R b and P is a suitable protecting group and the Ring B moiety is as defined for compounds of formula (II).

[0428] Scheme XIV outlines the synthesis of compounds of general formula XIV-8 and XIV-9. The alcohol of XIV-1 is converted to the sulfide (XIV-3) by displacement with a thiol source such as trityl SH (Croft, Rosemary A. et al., Chemistry - A European Journal, 24(4), 818-821; 2018). n Ar substitution introduces the triazole to give XIV-4. The bromine is then converted to an ester or amine XIV-5. The protecting group is then removed under Ni catalysis (Correa, Arkaitz et al., Journal of the American Chemical Society, 136(3), 1062-1069; 2014) to give intermediate XIV-6, which is converted to compound XIV-7 as in Scheme III. In some embodiments, intermediate XIV-4 is converted to heterocycle XIV-9 via intermediate XIV-8 as in Scheme XIII, and then the OP group is reduced as described above to give compounds of formula XIV-10.

[0429] Compounds 10, 19, 26-30, 113, and 122 had IC values ​​of less than 0.1 μM in the Cbl-b inhibition assay of Biological Example 1A. 50 Compounds 2, 3, 9, 13, 14, 16, 20-25, 31, 45, 74, 88, 95, 99, 102, 105-107, 109-112, and 116 have IC values ​​of 0.1 μM to less than 1 μM in the Cbl-b inhibition assay of Biological Example 1A. 50 Compounds 11, 15, 17, 32, 36, 39, 40, 46, 50, 55-62, 64, 65, 67, 69, 72, 73, 75-79, 82, 84, 86, 87, 89, 90, 93, 96, 97, 104, 108, 117-120, and 167 have IC values ​​of less than 1 μM to 5 μM in the Cbl-b inhibition assay of Biological Example 1A. 50 Compounds 1, 4-8, 12, 18, 33-35, 37, 38, 41-44, 47-49, 51-54, 63, 66, 68, 70, 71, 80, 81, 83, 85, 91, 92, 94, 98, 100, 101, 103, and 122-166 have IC values ​​of 5 μM or greater in the Cbl-b inhibition assay of Biological Example 1A. 50 The values ​​shown are used in one embodiment for the pharmaceutical compositions and methods disclosed herein.

[0430] In various embodiments, and as further described herein, the compounds provided herein (as well as compositions comprising the compounds described herein, and methods of using the compounds or compositions) have an IC50 of less than 0.1 μM, between 0.1 μM and less than 1 μM, between 1 μM and less than 5 μM, or 5 μM or greater, as determined by the Cbl-b inhibition assay of Biological Example 1A. 50In further embodiments, and as further described herein, the compounds provided herein (as well as compositions comprising the compounds described herein, and methods of using the compounds or compositions) have an IC value of less than 0.1 μM, as determined by the Cbl-b inhibition assay of Biological Example 1A. 50 In further embodiments, and as further described herein, the compounds provided herein (as well as compositions comprising the compounds described herein, and methods of using the compounds or compositions) have an IC value of less than 0.1 μM to 1 μM, as determined by the Cbl-b inhibition assay of Biological Example 1A. 50 In further embodiments, and as further described herein, the compounds provided herein (as well as compositions comprising the compounds described herein, and methods of using the compounds or compositions) have an IC value of less than 1 μM to 5 μM, as determined by the Cbl-b inhibition assay of Biological Example 1A. 50 In further embodiments, and as further described herein, the compounds provided herein (as well as compositions comprising the compounds described herein, and methods of using the compounds or compositions) have an IC value of 5 μM or greater, as determined by the Cbl-b inhibition assay of Biological Example 1A. 50 It has a value.

[0431] Compounds 114 and 115 had IC of less than 0.1 μM in the Cbl-b inhibition assay of Biological Example 1B. 50 The values ​​shown are used in one embodiment for the pharmaceutical compositions and methods disclosed herein.

[0432] In various embodiments, and as further described herein, the compounds provided herein (as well as compositions comprising the compounds described herein, and methods of using the compounds or compositions) have an IC50 of less than 0.1 μM, between 0.1 μM and less than 1 μM, between 1 μM and less than 5 μM, or 5 μM or greater, as determined by the Cbl-b inhibition assay of Biological Example 1B. 50 In further embodiments, and as further described herein, the compounds provided herein (as well as compositions comprising the compounds described herein, and methods of using the compounds or compositions) have an IC value of less than 0.1 μM, as determined by the Cbl-b inhibition assay of Biological Example 1B. 50 In further embodiments, and as further described herein, the compounds provided herein (as well as compositions comprising the compounds described herein, and methods of using the compounds or compositions) have an IC value of less than 0.1 μM to 1 μM, as determined by the Cbl-b inhibition assay of Biological Example 1B. 50 In further embodiments, and as further described herein, the compounds provided herein (as well as compositions comprising the compounds described herein, and methods of using the compounds or compositions) have an IC value of less than 1 μM to 5 μM, as determined by the Cbl-b inhibition assay of Biological Example 1B. 50 In further embodiments, and as further described herein, the compounds provided herein (as well as compositions comprising the compounds described herein, and methods of using the compounds or compositions) have an IC value of 5 μM or greater, as determined by the Cbl-b inhibition assay of Biological Example 1B. 50 It has a value.

[0433] III. Uses and Methods

[0241] Provided herein is a method of modulating the activity of an immune cell (e.g., a T cell, a B cell, or an NK cell), for example, by contacting the immune cell with an effective amount of a Cbl-b inhibitor or a composition thereof as described herein. Also provided is an in vitro method of generating said immune cell having modulated activity, referred to herein as a "modified immune cell," in which said modified immune cell can be administered to an individual in need thereof (e.g., an individual having cancer) by ex vivo methods. Further provided is an in vivo method of modulating a response in an individual in need thereof (e.g., an individual having cancer), comprising administering an effective amount of a Cbl-b inhibitor or a composition thereof as described herein. Moreover, the present disclosure provides an in vitro method of generating an expanded population of lymphocytes following in vivo lymphocyte pretreatment in an individual with cancer, wherein said lymphocyte pretreatment results from administration to the individual of an effective amount of a Cbl-b inhibitor or a composition thereof as described herein. The expanded population of lymphocytes can then be administered to the individual with cancer. In some embodiments, the modified immune cells, or expanded populations of lymphocytes, are generated from a biological sample comprising immune cells obtained from an individual, such as a blood sample comprising peripheral blood mononuclear cells or a tumor biopsy comprising tumor infiltrating lymphocytes (TILs).

[0434]

[0242] Further, a Cbl-b inhibitor is provided for use as a therapeutic active substance. A Cbl-b inhibitor is provided for use in treating or preventing a disease or condition associated with Cbl-b activity. Also provided is a Cbl-b inhibitor for use in treating cancer. Further provided is the use of a Cbl-b inhibitor in the manufacture of a medicament for treating or preventing a disease or condition associated with Cbl-b activity. Also provided is the use of a Cbl-b inhibitor in the manufacture of a medicament for treating cancer.

[0435]

[0243] Furthermore, the present disclosure provides therapeutic methods, medicines and uses comprising a Cbl-b inhibitor as part of a combination therapy for treating cancer including one or more of an immune checkpoint inhibitor, an anti-neoplastic agent and radiation therapy.

[0436] In some embodiments of the disclosed methods of treatment, medicaments and uses, the cancer is a blood cancer, such as lymphoma, leukemia or myeloma. In other embodiments of the disclosed methods of treatment, medicaments and uses, the cancer is a non-blood cancer, such as sarcoma, carcinoma or melanoma.

[0437]

[0245] Hematological cancers include one or more leukemias such as B-cell acute lymphoblastic leukemia ("BALL"), T-cell acute lymphoblastic leukemia ("TALL"), acute lymphoblastic leukemia (ALL); one or more chronic leukemias including, but not limited to, chronic myeloid leukemia (CML) and chronic lymphocytic leukemia (CLL); B-cell prolymphocytic leukemia, blastic plasmacytoid dendritic cell neoplasm, Burkitt's lymphoma, diffuse large B-cell lymphoma, follicular lymphoma, hairy cell leukemia, small cell follicular lymphoma, or large cell follicular lymphoma, Additional blood cancers or hematological conditions include, but are not limited to, malignant lymphoproliferative conditions, MALT lymphoma, mantle cell lymphoma, marginal zone lymphoma, multiple myeloma, myelodysplastic and myelodysplastic syndromes, non-Hodgkin's lymphoma, plasmablastic lymphoma, plasmacytoid dendritic cell neoplasm, Waldenstrom's macroglobulinemia, and "preleukemias," which are a diverse collection of hematological conditions linked to the ineffective production (or dysplasia) of myeloid blood cells.

[0438]

[0246] Non-hematological cancers include, but are not limited to, neuroblastoma, renal cell carcinoma, colon cancer, colorectal cancer, breast cancer, epithelial squamous cell carcinoma, melanoma, gastric cancer, brain cancer, lung cancer (e.g., NSCLC), pancreatic cancer, cervical cancer, ovarian cancer, liver cancer, bladder cancer, prostate cancer, testicular cancer, thyroid cancer, uterine cancer, adrenal cancer, and head and neck cancer.

[0439] In some embodiments, the efficacy of administering a Cbl-b inhibitor in treating a disease or disorder, such as cancer, is measured by evaluating clinical outcomes, such as reduction in tumor size or number of tumors, and / or survival time.In certain embodiments, "treating cancer" includes evaluating the patient's response to a treatment regimen according to the new guidelines for evaluating the efficacy of treatment in solid cancers (RECIST version 1.1) described (see, for example, Eisenhauer et al., Eur J Cancer, 45:228-247, 2009; and Nishino et al., Am J Roentgenol, 195:281-289, 2010).The response criteria for determining objective anti-tumor response in RECIST1.1 include complete response (CR), partial response (PR), progressive disease (PD) and stable disease (SD).

[0440] A. Cell isolation and processing Methods are provided for the preparation and processing of immune cells generated (e.g., modified immune cells) and used in the methods herein. As used herein, the term "modified immune cells" refers to immune cells or cell populations comprising immune cells cultured, incubated, and / or contacted with an effective amount of a Cbl-b inhibitor to modulate the activity of said immune cells. In some embodiments, the modified immune cells can be used for immunotherapy, such as those associated with adoptive immunotherapy methods.

[0441] 1. Sample In some embodiments, the modified immune cells or cell populations comprising the modified immune cells are isolated from a sample, such as a biological sample, e.g., obtained or derived from an individual (e.g., a human). In some embodiments, the individual from which the immune cells are isolated has a particular disease or condition (e.g., cancer) or is in need of cell therapy or is to be administered cell therapy. The individual is, in some embodiments, a human in need of a particular therapeutic intervention, such as adoptive cell therapy, from which the immune cells are isolated, treated, and / or modified. Thus, the cells isolated from the individual are, in some embodiments, primary cells (e.g., primary human cells). As used herein, the term "primary cells" refers to cells isolated directly from mammalian biological fluids or biological tissues (e.g., human biological fluids or human biological tissues).

[0442] In some embodiments, the modified immune cells are hematopoietic cells, pluripotent stem cells, myeloid progenitor cells, lymphoid progenitor cells, T cells, B cells, and / or NK cells. As used herein, the term "hematopoietic cells" includes hematopoietic stem cells and hematopoietic progenitor cells. In some embodiments, the modified immune cells are present in a heterogeneous cell population or in a composition comprising a heterogeneous cell population. For example, the modified immune cells may be hematopoietic cells present in a heterogeneous cell population including cells such as differentiated cells derived from a tissue or organ. In some embodiments, the modified immune cells are present in a homogeneous cell population or in a composition comprising a homogeneous cell population. For example, the modified immune cells may be hematopoietic cells present in a homogeneous cell population including only hematopoietic cells. In some embodiments, the modified immune cells, or the cell population comprising the modified immune cells, include one or more subsets of immune cells. For example, one or more subsets of immune cells may be CD4+ cells, CD8+ cells and subpopulations thereof, defined, for example, by function, activation status, maturity, differentiation potential, expansion, localization, survival potential, surface marker profile, cytokine secretion profile and / or degree of differentiation.

[0443] In some embodiments, biological samples as described herein include tissue, fluid and other samples obtained directly from an individual, as well as samples resulting from one or more processing steps, such as separation, centrifugation, genetic manipulation (e.g., transduction with a viral vector encoding a recombinant chimeric receptor), washing and / or incubation. Biological samples can be samples obtained directly from a biological source or processed samples. Biological samples include, but are not limited to, bodily fluids, such as blood, plasma, serum, cerebrospinal fluid, synovial fluid, urine, sweat, and tissue and organ samples, including processed samples derived therefrom (e.g., samples from tissues or organs, including tumors). In some embodiments, the biological sample is a biological fluid sample or a biological tissue sample. In some embodiments, the biological sample is a biological tissue sample. In some aspects, the biological sample from which immune cells are derived or isolated is a blood or blood-derived sample, or is derived from an apheresis or leukapheresis product.

[0444] Exemplary biological samples include whole blood, peripheral blood mononuclear cells (PBMC), white blood cells, bone marrow, thymus, tissue biopsy, tumor, leukemia, lymphoma, lymph node, gut-associated lymphoid tissue, mucosa-associated lymphoid tissue, spleen, other lymphoid tissue, liver, lung, stomach, intestine, colon, kidney, pancreas, breast, bone, prostate, cervix, testis, ovary, tonsil or other organ, and / or cells derived therefrom. Biological samples include samples from autologous sources (i.e., obtained from or derived from an individual in need of cell therapy) and allogeneic sources (i.e., obtained from or derived from an individual in need of cell therapy or a source other than the individual in need of cell therapy or the individual in need of cell therapy) in the context of cell therapy (e.g., adoptive cell therapy).

[0445] In some embodiments, the modified immune cells, or cell populations comprising modified immune cells, are derived from a cell line (e.g., a T cell line, a B cell line, a NK cell line, etc.). In some embodiments, the modified immune cells, or cell populations comprising modified immune cells, are obtained from a heterologous source, e.g., from a mouse, a rat, a non-human primate, or a pig.

[0446] 2. Cell processing and isolation In some embodiments, the isolation of the modified immune cells includes one or more preparation and / or cell separation steps. The one or more cell separation steps can be non-affinity-based or affinity-based separation. By way of example, the non-affinity-based separation can be centrifugation of the composition comprising the modified immune cells. In some embodiments, the non-affinity-based separation method can include density-based cell separation methods, such as preparation of white blood cells from peripheral blood by lysing red blood cells or centrifugation through a Percoll or Ficoll gradient. The affinity-based separation method can include contacting the composition comprising the modified immune cells with antibody-coated beads. Antibody-coated beads contemplated herein include, but are not limited to, magnetic beads (e.g., Dynabeads® sold by Life Technologies, Carlsbad, Calif., USA, MACS® microbeads sold by Miltenyi Biotec Inc., Auburn, Calif., USA, or EasySep™ Direct RapidSpheres™ sold by Stemcell Technologies, Vancouver, British Columbia, Canada) coated with an antibody that binds to a marker expressed on the surface of the modified immune cells. In some embodiments, specific subpopulations of T cells, such as cells positive for or otherwise expressing high levels of one or more surface markers, e.g., CD4+, CD8+, etc., are isolated by positive or negative selection techniques. Positive selection can be based on an approach where target cells (e.g., modified immune cells) bind to a reagent and are retained for further use. For example, T cells that are CD3+ can be positively selected using magnetic beads conjugated with anti-CD3 antibodies (e.g., MACS® CD3 human microbeads). Negative selection can be based on a procedure that retains target cells (e.g., modified immune cells) that did not bind to the reagent.For example, total human primary T cells can be isolated from peripheral blood mononuclear cells (PMBCs) by incubating a cocktail of antibodies against surface markers CD14, CD15, CD16, CD19, CD34, CD36, CD56, CD123, and CD235a in a sample containing PBMCs, then passing the sample through magnetic beads for removal of cells expressing the surface markers, and using negative selection to retain the remaining cells in the sample for further processing. In some embodiments, immune cells, or cell populations including modified immune cells, are washed, centrifuged, and / or incubated in the presence of one or more reagents, for example, to remove undesirable components, enrich for desired components, and / or lyse or remove cells sensitive to a particular reagent. In some examples, immune cells are separated based on one or more characteristics, such as density, adherence, size, sensitivity, and / or resistance to a particular component. The cell separation step does not require 100% enrichment or removal of a particular cell. In some embodiments, positive selection or enrichment for a particular type of immune cell (e.g., CD4+ T cells) refers to increasing the number or proportion of such cells. In some embodiments, removal or depletion of a particular type of cell that is not of interest, such as by negative selection, refers to decreasing the number or proportion of such cells.

[0447] In some embodiments, immune cells, or cell populations comprising immune cells, are obtained from the circulating blood of an individual, for example by apheresis or leukapheresis. In some aspects, the sample comprising the modified immune cells comprises lymphocytes, including T cells, B cells and NK cells, as well as monocytes, granulocytes, red blood cells and / or platelets, and in some aspects, cells other than red blood cells and platelets.

[0448] In some embodiments, blood cells collected from an individual are washed, for example to remove plasma fractions and to place the cell population comprising modified immune cells in a suitable buffer or medium for subsequent processing steps. In some embodiments, the cell population comprising modified immune cells is washed with phosphate buffered saline. In some embodiments, the wash solution does not contain calcium and / or magnesium. In some aspects, the washing step is accomplished by a semi-automated "flow-through" centrifuge. In some aspects, the washing step is accomplished by tangential flow filtration. In some embodiments, the modified immune cells or cell population comprising modified immune cells are resuspended in various suitable buffers after washing, for example, phosphate buffered saline without calcium and / or magnesium. In some embodiments, components of the blood cell sample are removed and the modified immune cells or cell population comprising modified immune cells are directly resuspended in a suitable cell culture medium.

[0449] Representative methods for processing and / or isolating immune cells, such as hematopoietic cells, from a sample containing a cell population containing said hematopoietic cells (e.g., a sample containing PBMCs) are described in Biological Example 2 and Biological Example 3 herein. Methods and techniques for processing and / or isolating immune cells, such as hematopoietic cells, pluripotent stem cells, myeloid progenitor cells, lymphoid progenitor cells, T cells, B cells, and / or NK cells, are well known in the art. See, for example, US Patent Application No. 2017 / 0037369, US Patent Application No. 2012 / 0148553, US Patent No. 6,461,645, US Patent No. 6,352,694, and US Patent No. 7,776,562.

[0450] 3. Incubation and treatment Provided herein are methods for modulating the activity of immune cells, such as the treated and / or isolated immune cells described above, by contacting the immune cells with an effective amount of a Cbl-b inhibitor as described herein. Provided herein are modified immune cells produced by any of the methods described herein, such as, for example, by culturing a cell population comprising immune cells (e.g., the treated and / or isolated immune cells described above) in the presence of an effective amount of a Cbl-b inhibitor to modulate the activity of the immune cells, thereby producing the modified immune cells.

[0451] In some embodiments, the modified immune cells (e.g., treated and / or separated immune cells as described above) are incubated and / or cultured in a suitable culture medium prior to contacting the immune cells with a Cbl-b inhibitor provided herein. In some embodiments, the modified immune cells are incubated and / or cultured in a suitable culture medium simultaneously with contacting the immune cells with a Cbl-b inhibitor provided herein.

[0452] The treated and / or separated modified immune cells or cell populations comprising the damaged modified immune cells can be differentiated and / or expanded in vitro. In some embodiments, the modified immune cells are hematopoietic cells, pluripotent stem cells, myeloid progenitor cells, lymphoid progenitor cells, T cells, B cells and / or NK cells. In some embodiments, the modified immune cells are incubated in a suitable cell culture medium comprising a Cbl-b inhibitor as described herein prior to differentiation and / or expansion of the immune cells. In some embodiments, the modified immune cells are incubated in a suitable cell culture medium comprising a Cbl-b inhibitor as described herein following differentiation and / or expansion of the immune cells. The immune cells are modified (i.e., modified immune cells) upon contact with an effective amount of a Cbl-b inhibitor provided herein to modulate the activity of the immune cells. In some embodiments, the modified immune cells are not differentiated and / or expanded in vitro, and thus the modified immune cells are of the same cell type as the modified immune cells contacted with the Cbl-b inhibitor. For example, T cells can be incubated in a suitable medium containing a Cbl-b inhibitor without differentiation of T cells. In other embodiments, modified immune cells are differentiated and / or expanded in vitro, and thus the modified immune cells are of a different cell type than the modified immune cells contacted with the Cbl-b inhibitor. For example, hematopoietic cells can be incubated in a suitable medium containing a Cbl-b inhibitor and other agents that cause differentiation of hematopoietic cells into mature hematopoietic cells. Thus, in some aspects of the embodiments herein, the modified immune cells are hematopoietic cells, pluripotent stem cells, myeloid progenitor cells, lymphoid progenitor cells, T cells, B cells and / or NK cells. Methods for expansion and / or differentiation of immune cells are well known in the art. See, for example, International Patent Application No. WO2017 / 037083.

[0453]

[0261] An effective amount of a Cbl-b inhibitor is an amount or concentration of the Cbl-b inhibitor sufficient to modulate the activity of immune cells compared to a reference sample. The reference sample may be immune cells that have not been contacted with a Cbl-b inhibitor. In some embodiments, the concentration of the Cbl-b inhibitor added to a composition (e.g., cell culture medium) containing modified immune cells is about 1 pM to about 100 μM, about 5 pM to about 100 μM, about 10 pM to about 100 μM, about 20 pM to about 100 μM, about 40 pM to about 100 μM, about 60 pM to about 100 μM, about 80 pM to about 100 μM, about 1 nM to about 100 μM, about 3 nM to about 100 μM, about 10 nM to about 100 μM, about 15 nM to about 100 μM, about 20 nM to about 10 0 μM, about 40 nM to about 100 μM, about 60 nM to about 100 μM, about 80 nM to about 100 μM, about 0.1 μM to about 100 μM, about 0.1 μM to about 90 μM, about 0.1 μM to about 80 μM, about 0.1 μM to about 70 μM, about 0.1 μM to about 60 μM, about 0.1 μM to about 50 μM, about 0.1 μM to about 40 μM, about 0.1 μM to about 30 μM, about 0.1 μM to about 20 μM, about 0.1 μM to about 10 μM, about 0.2 μM to about 10 μM, or about 0.3 μM to about 8 μM. In some embodiments, the concentration of the Cbl-b inhibitor added to the composition (e.g., cell culture medium) comprising the modified immune cells is about 1 pM, about 2 pM, about 3 pM, about 4 pM, about 5 pM, about 10 pM, about 20 pM, about 30 pM, about 40 pM, about 50 pM, about 60 pM, about 70 pM, about 80 pM, about 90 pM, about 1 nM, about 3 nM, about 5 nM, about 1 The concentration of the Cbl-b inhibitor added to the composition (e.g., cell culture medium) comprising the modified immune cells is about 0.3 μM, about 1 μM, about 40 nM, about 50 nM, about 80 nM, about 0.1 μM, about 0.2 μM, about 0.3 μM, about 0.4 μM, about 0.5 μM, about 1 μM, about 5 μM, about 10 μM, about 15 μM, about 20 μM, about 25 μM, about 30 μM, about 40 μM, about 50 μM, about 60 μM, about 70 μM, about 80 μM, about 90 μM, or about 100 μM. In some embodiments, the concentration of the Cbl-b inhibitor added to the composition (e.g., cell culture medium) comprising the modified immune cells is about 0.3 μM, about 1 μM, or about 4 μM. In some embodiments, the concentration of the Cbl-b inhibitor added to the composition (e.g., cell culture medium) comprising the modified immune cells is about 1 μM, or about 8 μM.

[0454] The effective amount of the Cbl-b inhibitor is contacted with the immune cells for a sufficient time to regulate the activity of the immune cells compared to a reference sample.The reference sample may be immune cells that are not contacted with the Cbl-b inhibitor but are incubated with the immune cells and a composition (e.g., cell culture medium) that includes the Cbl-b inhibitor for the same time. In some embodiments, the Cbl-b inhibitor is contacted and / or incubated with the immune cells for about 1 minute to about 1 hour, about 5 minutes to about 1 hour, about 10 minutes to about 1 hour, about 15 minutes to about 1 hour, about 20 minutes to about 1 hour, about 30 minutes to about 1 hour, about 45 minutes to about 1 hour, about 1 hour to about 2 hours, about 1 hour to about 4 hours, about 1 hour to about 6 hours, about 1 hour to about 8 hours, about 1 hour to about 12 hours, about 1 hour to about 24 hours, about 2 hours to about 24 hours, about 6 hours to about 7 hours, about 6 hours to about 24 hours, about 8 hours to about 24 hours, about 10 hours to about 24 hours, about 15 hours to about 24 hours, about 20 hours to about 24 hours, about 12 hours to about 48 hours, about 24 hours to about 48 hours, or about 36 hours to about 48 hours. In some embodiments, the Cbl-b inhibitor is contacted and / or incubated with the immune cells for about 1 minute, about 5 minutes, about 10 minutes, about 15 minutes, about 20 minutes, about 30 minutes, about 40 minutes, about 50 minutes, about 1 hour, about 2 hours, about 3 hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about 8 hours, about 9 hours, about 10 hours, about 12 hours, about 14 hours, about 16 hours, about 18 hours, about 20 hours, about 22 hours, or about 24 hours. In some embodiments, the Cbl-b inhibitor is contacted and / or incubated with the immune cells for about 1 day to about 7 days, about 2 days to about 7 days, about 3 days to about 7 days, about 4 days to about 7 days, about 5 days to about 7 days, or about 6 days to about 7 days. In some embodiments, the Cbl-b inhibitor is contacted with and / or incubated with the immune cells for about 7 days to about 14 days, about 14 days to about 21 days, or about 21 days to about 28 days. In some embodiments, the Cbl-b inhibitor is contacted with and / or incubated with the immune cells for about 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, about 7 days, about 8 days, about 9 days, about 10 days, about 11 days, about 12 days, about 13 days, or about 14 days.

[0455] In some embodiments, immune cells, or cell populations comprising immune cells, are incubated under appropriate conditions to induce proliferation, expansion, activation and / or survival of immune cells. Suitable conditions during incubation include, but are not limited to, the use of one or more cell culture media, temperature, incubation time, the presence of stimulants (e.g., anti-CD3 and / or anti-CD28 antibodies), and the presence of any other beneficial agents, such as growth factors, cytokines, chemokines and / or recombinant soluble receptors.

[0456] In some embodiments, the appropriate conditions for inducing the proliferation, expansion, activation and / or survival of immune cells include providing stimulatory conditions including an agent capable of activating immune cells (e.g., NK cells). For example, the appropriate conditions for inducing the proliferation, expansion, activation and / or survival of T cells include providing stimulatory conditions and / or agents capable of activating intracellular signaling in T cells. Full activation of T cells generally requires recognition of an antigen by the T cell receptor, referred to herein as "TCR" (signal 1), and recognition of a costimulatory factor, such as CD28 (signal 2). In some embodiments, one or more agents switch on or initiate a TCR complex-mediated intracellular signaling cascade in T cells. For example, a first agent is capable of binding to a component of the TCR complex to activate the T cells, and a second agent is capable of stimulating the activated T cells by binding to a costimulatory molecule on the surface of the T cells. In some embodiments, the first agent stimulated a TCR / CD3 complex-associated signal in the T cell by specifically binding to CD3 (e.g., an anti-CD3 antibody). In further embodiments, the costimulatory molecule on the surface of the T cell may be CD28, and the second agent specifically binds to CD28 (e.g., an anti-CD28 antibody). Such agents include, but are not limited to, antibodies, bivalent antibody fragments, and binding molecules, such as those specific for a TCR complex component (e.g., an anti-CD3 antibody) and / or those specific for a costimulatory receptor (e.g., an anti-CD28 antibody). In some embodiments, the agent that specifically binds to CD3 is an anti-CD3 antibody, a bivalent antibody fragment of an anti-CD3 antibody (e.g., a (Fab)2' fragment or a bivalent scFv fragment), a monovalent antibody fragment of an anti-CD3 antibody (e.g., a Fab fragment, an Fv fragment, or an scFv fragment), or a CD3 binding molecule (e.g., an aptamer).In some embodiments, the agent that specifically binds to CD28 is an anti-CD28 antibody, a bivalent antibody fragment of an anti-CD28 antibody (e.g., a (Fab)2' fragment or a bivalent scFv fragment), a monovalent antibody fragment of an anti-CD28 antibody (e.g., a Fab fragment, an Fv fragment or an scFv fragment), and a CD28 binding molecule (e.g., an aptamer). One or more agents provided herein (e.g., an anti-CD3 antibody and an anti-CD28 antibody) can be bound to a solid support, such as, for example, a bead, or crosslinked to an anti-Fc antibody. In some embodiments, the steps of the expansion method can further include adding an anti-CD3 antibody and / or an anti-CD28 antibody to the culture medium. In some embodiments, the stimulatory agent added to the cell culture medium includes one or more cytokines, such as, but not limited to, one or more of IL-2, IL-7, IL-15, and IL-21. For example, IL-2 can be added to cell culture medium containing immune cells and agents, such as anti-CD3 and / or anti-CD28 antibodies, at a concentration of at least about 10 units / mL.

[0457] In some embodiments, the appropriate conditions for inducing T cell proliferation, expansion, activation and / or survival include providing stimulatory conditions or agents capable of activating intracellular signaling by the T cell receptor (TCR) complex and a Cbl-b inhibitor as described herein. In some embodiments, immune cells, or a cell population comprising immune cells, are incubated with a first agent that stimulates a TCR / CD3 complex-associated signal in T cells by specifically binding to CD3 (e.g., an anti-CD3 antibody). In further embodiments, immune cells, or a cell population comprising immune cells, are incubated with a first agent that stimulates a TCR / CD3 complex-associated signal in T cells by specifically binding to CD3 (e.g., an anti-CD3 antibody), a second agent that binds to the costimulatory molecule CD28 (e.g., an anti-CD28 antibody), and a Cbl-b inhibitor at a concentration of about 1 pM to about 100 μM (e.g., about 0.3 μM, about 1 μM, or about 4 μM). In some embodiments, the appropriate conditions for inducing T cell proliferation, expansion, activation and / or survival do not require stimulation with a costimulatory molecule (e.g., CD28) when in the presence of a Cbl-b inhibitor. By contacting T cells with a Cbl-b inhibitor or a composition thereof, the need for costimulation required for T cells to enter an activation state can be avoided. In some embodiments, immune cells, or a cell population comprising immune cells, are incubated with a first agent that stimulates a TCR / CD3 complex-associated signal in T cells by specifically binding to CD3 (e.g., an anti-CD3 antibody) and a Cbl-b inhibitor at a concentration of about 0.001 μM to about 1,000 μM, about 0.01 μM to about 100 μM, about 0.1 μM to about 10 μM, or about 0.1 μM to about 50 μM (e.g., about 1 μM or about 8 μM).

[0458] In some embodiments of the method of modulating the activity of an immune cell, the immune cell is a T cell, and modulating the activity of the T cell includes increasing T cell activation and / or increasing T cell proliferation. The T cell contemplated in the embodiments herein can be in a tolerant state even in the presence of an activator that binds to a component of the TCR complex, such as an anti-CD3 antibody, and even in the presence of a stimulator that binds to a costimulatory molecule, such as an anti-CD28 antibody. In some embodiments, the method of modulating the activity of a T cell includes contacting the T cell with an effective amount of a Cbl-b inhibitor or a composition thereof in the presence of an anti-CD3 antibody in combination with an anti-CD28 antibody. In some embodiments, the method of modulating the activity of a T cell includes contacting the T cell with an effective amount of a Cbl-b inhibitor or a composition thereof, the T cell having previously been contacted with an anti-CD3 antibody in combination with an anti-CD28 antibody. In some embodiments, stimulation via a costimulatory CD28 molecule is not required to modulate the activity of a T cell (e.g., increasing T cell activation and / or increasing T cell proliferation). In some embodiments, the method of modulating T cell activity comprises contacting a T cell with an effective amount of a Cbl-b inhibitor or composition thereof in the presence of an anti-CD3 antibody alone. In some embodiments, the method of modulating T cell activity comprises contacting a T cell with an effective amount of a Cbl-b inhibitor or composition thereof, wherein the T cell has previously been contacted with one or more agents that activate the T cell (e.g., an anti-CD3 antibody), and the agents do not include an agent that stimulates a CD28 costimulatory molecule (e.g., an anti-CD28 antibody).

[0459] In some embodiments, the immune cell is a T cell, and modulating the activity of the T cell includes enhancing T cell activation and / or enhancing T cell proliferation. For example, the T cells contemplated in the embodiments herein can be in an activated state, for example, in the presence of an agent that activates the T cell (e.g., an anti-CD3 antibody), and in some further embodiments, in the presence of an agent that stimulates the T cell (e.g., an anti-CD28 antibody). Contacting the T cell with a Cbl-b inhibitor or composition thereof can lower the threshold required for activation, thereby enhancing the activation and / or proliferation of the T cell in the presence of an activator (e.g., an anti-CD3 antibody), and in some further embodiments, a stimulator (e.g., an anti-CD28 antibody). In some embodiments, the method of modulating the activity of a T cell includes contacting the T cell with an effective amount of a Cbl-b inhibitor or composition thereof in the presence of an anti-CD3 antibody in combination with an anti-CD28 antibody. In some embodiments, the method of modulating the activity of a T cell includes contacting the T cell with an effective amount of a Cbl-b inhibitor or composition thereof, and the T cell has previously been contacted with an anti-CD3 antibody in combination with an anti-CD28 antibody. In some embodiments, stimulation via a costimulatory CD28 molecule is not required to modulate T cell activity (e.g., enhancing T cell activation and / or enhancing T cell proliferation). In some embodiments, a method of modulating T cell activity comprises contacting a T cell with an effective amount of a Cbl-b inhibitor or composition thereof in the presence of an anti-CD3 antibody alone. In some embodiments, a method of modulating T cell activity comprises contacting a T cell with an effective amount of a Cbl-b inhibitor or composition thereof, where the T cell has previously been contacted with one or more agents that activate T cells (e.g., an anti-CD3 antibody).

[0460] In some embodiments, the immune cells are T cells, and modulating the activity of the T cells includes reducing T cell dysfunction, including reducing T cell exhaustion, reducing T cell tolerance, and / or reducing T cell anergy. The general principles of T cell dysfunction are well known in the art (see, for example, Schietinger et al., Trends Immunol., vol. 35: 51-60, 2014). Immune tolerance is a process that is part of the normal functioning of the immune system. Antigen-specific immune tolerance is characterized by a reduced responsiveness to an antigen, which is induced by previous exposure to that antigen. When a particular lymphocyte (e.g., T cell) encounters an antigen, the lymphocyte can be activated to provide an antigen-specific immune response, or the lymphocyte (e.g., T cell) can be inactivated or eliminated to provide antigen-specific immune tolerance instead. In some embodiments, tolerance can be caused by clonal anergy, peripheral clonal deletion, suppression of T cells, and / or other forms of antigen-specific tolerance. In some embodiments, tolerance can result from or be characterized by the induction of anergy. In some aspects, anergy can result from exposure of T cells to antigen in the absence of costimulation. Prolonged antigen recognition by TCR alone in the absence of costimulatory signals can result in anergy (i.e., functional unresponsiveness). Anergic T cells can be refractory to subsequent antigen challenge and may be able to suppress other immune responses. Usually, in a natural setting, tolerance involves non-responsiveness or non-productive responsiveness to self-antigens. However, in some cases, tolerance to "non-self" antigens can be induced. Thus, in some embodiments, the same mechanism that causes mature T cells that recognize self-antigens in peripheral tissues to subsequently fail to respond to antigens can also control unresponsiveness to foreign or "non-self" antigens, such as those expressed by cancer cells. Thus, the T cells contemplated in the embodiments herein can be in a tolerant state even in the presence of stimulatory agents, such as agents that bind to costimulatory molecules, such as CD28.Contacting T cells with a Cbl-b inhibitor or a composition thereof provided herein can circumvent aspects of T cell dysfunction, such as T cell tolerance, T cell anergy, and / or T cell exhaustion. In some embodiments, the method of modulating the activity of T cells (e.g., reducing T cell tolerance, reducing T cell anergy, and / or reducing T cell exhaustion) comprises contacting T cells with an effective amount of a Cbl-b inhibitor or a composition thereof. In some embodiments of the methods herein, modulating the activity of T cells (e.g., reducing T cell tolerance, reducing T cell anergy, and / or reducing T cell exhaustion) comprises contacting T cells with an effective amount of a Cbl-b inhibitor or a composition thereof in the presence of an anti-CD3 antibody in combination with an anti-CD28 antibody. In some embodiments of the methods herein, the method of modulating the activity of T cells (e.g., reducing T cell tolerance, reducing T cell anergy, and / or reducing T cell exhaustion) comprises contacting T cells with an effective amount of a Cbl-b inhibitor or a composition thereof, wherein the T cells have previously been contacted with an anti-CD3 antibody in combination with an anti-CD28 antibody. In some embodiments, stimulation via a costimulatory CD28 molecule is not required to modulate the activity of T cells (e.g., reducing T cell tolerance, reducing T cell anergy, and / or reducing T cell exhaustion). In some embodiments of the methods herein, the method of modulating the activity of T cells (e.g., reducing T cell tolerance, reducing T cell anergy, and / or reducing T cell exhaustion) comprises contacting T cells with an effective amount of a Cbl-b inhibitor or a composition thereof in the presence of an anti-CD3 antibody alone. In some embodiments, a method of modulating T cell activity (e.g., reducing T cell tolerance, reducing T cell anergy, and / or reducing T cell exhaustion) comprises contacting a T cell with an effective amount of a Cbl-b inhibitor or a composition thereof, where the T cell has previously been contacted with one or more agents that activate the T cell, e.g., an anti-CD3 antibody alone.

[0461]

[0269] T cell activation and T cell tolerance are tightly regulated processes that control immune responses. Thus, provided herein are methods of modulating the activity of T cells, where modulating the activity of T cells includes increasing T cell activation, increasing T cell proliferation, decreasing T cell exhaustion, and / or decreasing T cell tolerance. In some embodiments, modulating the activity of T cells (e.g., increasing T cell activation, increasing T cell proliferation, decreasing T cell exhaustion, and / or decreasing T cell tolerance) includes contacting T cells with an effective amount of a Cbl-b inhibitor or a composition thereof. In some embodiments of the methods herein, modulating the activity of T cells (e.g., increasing T cell activation, increasing T cell proliferation, decreasing T cell exhaustion, and / or decreasing T cell tolerance) includes contacting T cells with an effective amount of a Cbl-b inhibitor or a composition thereof in the presence of an anti-CD3 antibody in combination with an anti-CD28 antibody. In some embodiments of the methods herein, the method of modulating the activity of a T cell (e.g., increasing T cell activation, increasing T cell proliferation, decreasing T cell exhaustion, and / or decreasing T cell tolerance) comprises contacting a T cell with an effective amount of a Cbl-b inhibitor or a composition thereof, wherein the T cell has previously been contacted with an anti-CD3 antibody in combination with an anti-CD28 antibody. In some embodiments, stimulation via a costimulatory CD28 molecule is not required to modulate the activity of a T cell (e.g., increasing T cell activation, increasing T cell proliferation, decreasing T cell exhaustion, and / or decreasing T cell tolerance). In some embodiments of the methods herein, the method of modulating the activity of a T cell (e.g., increasing T cell activation, increasing T cell proliferation, decreasing T cell exhaustion, and / or decreasing T cell tolerance) comprises contacting a T cell with an effective amount of a Cbl-b inhibitor or a composition thereof provided herein in the presence of an anti-CD3 antibody alone.In some embodiments, a method of modulating the activity of a T cell (e.g., increasing T cell activation, increasing T cell proliferation, decreasing T cell exhaustion, and / or decreasing T cell tolerance) comprises contacting a T cell with an effective amount of a Cbl-b inhibitor or a composition thereof, wherein the T cell has previously been contacted with one or more agents that activate the T cell (e.g., an anti-CD3 antibody).

[0462] In some embodiments of the methods herein, the increased T cell activation includes increased production of one or more cytokines from T cells or surrounding immune cells (e.g., bone marrow cells) in the activated T cell microenvironment. In some embodiments, the one or more cytokines include, but are not limited to, IFN-γ, IL-1β, IL-2, IL-4, IL-5, IL-6, IL-13, IL-18, TNFα, and GM-CSF. In some embodiments, the cytokine is one or more of IL-2, IFN-γ, TNFα, and GM-CSF. In some embodiments, the cytokine is a chemokine. In some embodiments, the one or more chemokines include, but are not limited to, IP-10, eotaxin, GRO alpha, RANTES, MIP-1α, MIP-1β, MIP-2, MCP-1, and MCP-3. The increased expression of cytokines can be measured by ELISA.

[0463] In some embodiments of the methods herein, the increase in T cell activation comprises the increase in cell surface expression of one or more T cell activation markers. In some embodiments, the one or more T cell activation markers include, but are not limited to, CD25, CD44, CD62L, CD69, CD152 (CTLA4), CD154, CD137, and CD279. In some embodiments, the T cell activation marker is one or more of CD25, CD69, and CTLA4. The increase in the expression of cell surface markers can be measured by FACS.

[0464]

[0272] Methods for experimentally determining increased T cell activation, increased T cell proliferation, decreased T cell exhaustion, and / or decreased T cell tolerance are well known in the art. In some embodiments, representative methods for determining T cell activation can be found in Biological Example 2 provided herein. In some embodiments, representative in vitro and in vivo methods for determining increased T cell activation, increased T cell proliferation, decreased T cell exhaustion, and / or decreased T cell tolerance can be found in Biological Example 3 provided herein.

[0465] In some embodiments of the method of modulating the activity of an immune cell, the immune cell is a B cell, and modulating the activity of a B cell comprises increasing B cell activation. In some embodiments, increasing B cell activation comprises increasing cell surface expression of one or more B cell activation markers. In some embodiments, the one or more B cell activation markers include, but are not limited to, CD69, CD86, and MHC class II (e.g., HLA-DR). In some embodiments, the B cell activation marker is CD69. The increased expression of the cell surface marker can be measured by FACS. In some embodiments, increasing B cell activation comprises increasing activation of proteins in signal transduction pathways, such as those mediated by ERK, JNK, and Syk. The increased activation of the protein can be detected by measuring the level of phosphorylation at the protein using reagents, such as anti-phospho antibodies available in the art.

[0466] In some embodiments of the method of modulating the activity of an immune cell, the immune cell is a NK cell, and modulating the activity of the NK cell comprises increasing NK cell activation. In some embodiments, increasing NK cell activation comprises secretion of one or more cytokines. In some embodiments, the one or more cytokines include, but are not limited to, IFN-γ, TNFα, and MIP-1β. The increased expression of the cytokines can be measured by ELISA. In some embodiments, increasing NK cell activation comprises increasing cell surface expression of one or more NK cell activation markers. In some embodiments, the one or more NK cell activation markers include, but are not limited to, CD69 and CD107a. The increased expression of the cell surface markers can be measured by FACS. In some embodiments, increasing NK cell activation comprises increasing killing of target cells, e.g., tumor cells, including primary tumor cells, and cell lines derived from tumor cells, e.g., K562 cell line.

[0467] Methods for experimentally determining the increase in B cell activation and NK cell activation are well known in the art (see, for example, Fauriat et al., Blood, 115:2167-76, 2010; Beano et al., J. Transl. Med. 6:25, 2008; Claus et al., J. Immunol. Methods, 341:154-64, 2009; and Fujisaki et al., Cancer Res. 69:4010-4017, 2009). In some embodiments, a representative method for determining B cell activation can be found in Biological Example 3 provided herein. In some embodiments, a representative method for determining NK cell activation can be found in Biological Example 3 provided herein.

[0468] The modulation of immune cell, e.g., T cell, B cell, or NK cell activity can be measured by determining a baseline value for a parameter of interest (e.g., cytokine secretion). For example, T cell activation, e.g., from an in vitro experiment of cells contacted with a Cbl-b inhibitor in a sample, can be measured before contacting or administering the Cbl-b inhibitor to determine a baseline value. A reference value is then obtained for T cell activation after contacting or administering the Cbl-b inhibitor. The reference value is compared to the baseline value to determine the amount of T cell activation resulting from contacting or administering the Cbl-b inhibitor or composition thereof. For example, in some embodiments, immune cell (e.g., T cell) activation is increased by at least 0.1-fold in the sample compared to the baseline value, where the immune cell (e.g., T cell) is contacted with the Cbl-b inhibitor or composition thereof since the baseline value was obtained. In some embodiments, immune cell (e.g., T cell) activation is increased by at least about 0.1-fold, about 0.2-fold, about 0.3-fold, about 0.4-fold, about 0.5-fold, about 0.6-fold, about 0.7-fold, about 0.8-fold, about 0.9-fold, about 1-fold, about 2-fold, about 4-fold, about 6-fold, about 8-fold, about 10-fold, about 20-fold, about 30-fold, about 40-fold, about 50-fold, about 75-fold, or about 100-fold (e.g., about 0.1-fold to about 100-fold, or about 1-fold to about 100-fold) relative to a baseline value. Immune cell activation can be assessed by measuring biological markers of activation, such as increased cytokine secretion, increased cell surface expression of activation markers (e.g., cell surface markers), or increased phosphorylation of proteins in downstream signaling pathways. A fold increase relative to a baseline value indicative of immune cell activation can be determined for the parameter being tested and the conditions under which the immune cells are treated. For example, to measure T cell activation, a baseline value can be obtained from T cells stimulated with anti-CD3 antibody in combination with anti-CD28 antibody, where the cells are not incubated with a Cbl-b inhibitor. A reference value is then obtained from T cells stimulated with anti-CD3 antibody in combination with anti-CD28 antibody, where the T cells have been or are in contact with a Cbl-b inhibitor.Then, the positive response of immune cell activation can be judged by the obtained reference value.Similar reference value measurements can be obtained and compared with baseline values ​​to evaluate T cell activation, T cell proliferation, T cell depletion, T cell tolerance, B cell activation, and / or NK cell activation.The measurements of these parameters can be obtained using techniques well known in the art and those provided in Biological Examples 2 and 3.

[0469]

[0277] The term "baseline" or "baseline value" as used herein may refer to a measurement or characterization prior to or at the start of administration of a therapeutic agent disclosed herein (e.g., a composition comprising a Cbl-b inhibitor as described herein). The baseline value may be compared to a reference value to determine an increase or decrease in immune cell function (e.g., increased T cell activation, increased T cell proliferation, decreased T cell exhaustion, and / or decreased T cell tolerance). The term "reference" or "reference value" as used herein may refer to a measurement or characterization following administration of a therapeutic agent disclosed herein (e.g., a composition comprising a Cbl-b inhibitor as described herein). The reference value may be measured one or more times during an experimental time course, dosing regimen, or treatment cycle, or at the completion of an experimental time course, dosing regimen, or treatment cycle. A "reference value" may be an absolute value, a relative value, a value with upper and / or lower limits, a range of values, an average value, a median value, a mean value, or a value compared to a baseline value. Similarly, a "baseline value" can be an absolute value, a relative value, a value with upper and / or lower limits, a range of values, an average value, a median value, a mean value, or a value compared to a reference value. Reference and / or baseline values ​​can be obtained from one sample (e.g., one sample from an individual), from two different samples (e.g., samples from two different individuals), or from a group of samples (e.g., samples from a group of 2, 3, 4, 5, or more individuals).

[0470] In some embodiments, a positive response for T cell activation measured by cytokine secretion (e.g., IL-2 secretion) by T cells stimulated with anti-CD3 antibody in combination with anti-CD28 antibody in the presence of a Cbl-b inhibitor is at least 2.5-fold relative to a baseline value for cytokine secretion (e.g., IL-2 secretion) obtained from T cells stimulated with anti-CD3 antibody in combination with anti-CD28 antibody in the absence of a Cbl-b inhibitor. In some embodiments, a positive response for T cell activation measured by surface marker expression (e.g., CD25 surface marker staining) by T cells stimulated with anti-CD3 antibody in combination with anti-CD28 antibody in the presence of a Cbl-b inhibitor is at least 1.3-fold relative to a baseline value for surface marker expression (e.g., CD25 surface marker staining) obtained from T cells stimulated with anti-CD3 antibody in combination with anti-CD28 antibody in the absence of a Cbl-b inhibitor. In some embodiments, the baseline value can be obtained from T cells stimulated with anti-CD3 antibody alone, where the cells are not incubated with a Cbl-b inhibitor. In some embodiments, a positive response for T cell activation as measured by cytokine secretion (e.g., IL-2 secretion) by T cells stimulated with anti-CD3 antibody alone in the presence of a Cbl-b inhibitor is at least 0.1-fold higher than the baseline value for cytokine secretion (e.g., IL-2 secretion) obtained from T cells stimulated with anti-CD3 antibody alone in the absence of a Cbl-b inhibitor. In some embodiments, a positive response for T cell activation as measured by surface marker expression (e.g., CD25 surface marker staining) by T cells stimulated with anti-CD3 antibody alone in the presence of a Cbl-b inhibitor is at least 0.6-fold higher than the baseline value for surface expression marker (e.g., CD25 surface marker staining) obtained from T cells stimulated with anti-CD3 antibody alone in the absence of a Cbl-b inhibitor.

[0471] In some aspects, provided herein is a method of generating a modified immune cell, comprising culturing a cell population containing an immune cell in the presence of a Cbl-b inhibitor or composition thereof provided herein in an amount effective to modulate the activity of the immune cell, thereby generating the modified immune cell. In some embodiments, the immune cell is a T cell, a B cell, or a natural killer (NK) cell.

[0472] In some embodiments of the method of generating modified immune cells, the immune cells to be modified are cells selected from the group consisting of hematopoietic cells, pluripotent stem cells, myeloid progenitor cells, lymphoid progenitor cells, T cells, B cells, and NK cells. In some embodiments, the method further comprises culturing the immune cells with a stimulant, such as a cytokine or an antibody that binds to an activating protein expressed by the immune cells (e.g., an anti-CD3 antibody and / or an anti-CD28 antibody). In some embodiments, the immune cells to be modified are in a cell population containing immune cells, and the cell population is obtained as a sample from an individual. In some embodiments, the immune cells to be modified are in a cell population containing immune cells, and the cell population is obtained by culturing a biological sample (e.g., a blood sample, a bone marrow sample, etc.) from an individual. In some embodiments, the immune cells are modified by contacting the cell population containing immune cells with a Cbl-b inhibitor or a composition thereof, thereby generating the modified immune cells. In some embodiments, the modified immune cells are cells selected from the group consisting of hematopoietic cells, pluripotent stem cells, myeloid progenitor cells, lymphoid progenitor cells, T cells, B cells, and NK cells. In some embodiments, the immune cells are of the same cell type as the modified immune cells. For example, the immune cells can be inactive T cells and the modified immune cells can be activated T cells. In some embodiments, the immune cells are of a different cell type than the modified immune cells. For example, the immune cells can be hematopoietic stem cells and the modified immune cells can be NK cells differentiated from hematopoietic stem cells. In some embodiments of the method of generating modified immune cells, the method further comprises recovering the modified immune cells. In some embodiments, the cell population containing the immune cells, the immune cells, or the modified immune cells are from an individual (e.g., a human). In some embodiments, the immune cells or the modified immune cells are human immune cells or human modified immune cells, respectively.

[0473]

[0281] Further provided herein are modified immune cells generated by any of the methods described herein, for example, by culturing a cell population containing an immune cell in the presence of an amount of a Cbl-b inhibitor effective to modulate the activity of the immune cell, thereby generating the modified immune cell.

[0474] In some embodiments, the Cbl-b inhibitor provided herein is cell membrane permeable.Thus, in some embodiments, the modified immune cell provided herein can comprise the Cbl-b inhibitor described herein, for example, in the cytoplasm of the modified immune cell.

[0475] In some aspects, provided herein is an isolated modified immune cell, the modified immune cell has been or is in contact with a Cbl-b inhibitor or a composition thereof described herein. In some embodiments, the modified immune cell is a T cell, a B cell, or a natural killer (NK) cell. In some embodiments, the modified immune cell is a hematopoietic cell, a pluripotent stem cell, a myeloid progenitor cell, a lymphoid progenitor cell, a T cell, a B cell, or a NK cell.

[0476] In some embodiments of the isolated modified immune cells, the modified immune cells are T cells, and the T cells exhibit increased T cell activation, increased T cell proliferation, decreased T cell exhaustion, and / or decreased T cell tolerance. In some embodiments, the increased T cell activation comprises increased production of one or more cytokines from the T cells or surrounding immune cells (e.g., bone marrow cells) within the activated T cell microenvironment. In some embodiments, the one or more cytokines include, but are not limited to, IFN-γ, IL-1β, IL-2, IL-4, IL-5, IL-6, IL-13, IL-18, TNFα, and GM-CSF. In some embodiments, the one or more cytokines are one or more selected from the group consisting of IL-2, IFN-γ, TNFα, and GM-CSF. In some embodiments, the cytokine is a chemokine. In some embodiments, the one or more chemokines include, but are not limited to, IP-10, eotaxin, GRO alpha, RANTES, MIP-1α, MIP-1β, MIP-2, MCP-1, and MCP-3. In some embodiments, the increased T cell activation comprises increased cell surface expression of one or more T cell activation markers. In some embodiments, the one or more T cell activation markers include, but are not limited to, CD25, CD44, CD62L, CD69, CD152 (CTLA4), CD154, CD137, and CD279. In some embodiments, the one or more T cell activation markers include, but are not limited to, CD25, CD69, and CTLA4. In some embodiments, the T cell activation marker is CD25 and / or CD69. In some embodiments, the T cells have been or are contacted with an anti-CD3 antibody. In some embodiments, the T cells have been or are contacted with an anti-CD3 antibody in combination with an anti-CD28 antibody.

[0477] In some embodiments of the isolated modified immune cells, the modified immune cells are NK cells, and the NK cells exhibit increased NK cell activation. In some embodiments, the increased NK cell activation comprises increased secretion of one or more cytokines (e.g., IFN-γ, TNFα, and / or MIP-1β). In some embodiments, the increased NK cell activation comprises increased cell surface expression of one or more NK cell activation markers (e.g., CD69 and / or CD107a).

[0478] In some embodiments of the isolated modified immune cells, the modified immune cells are B cells and the B cells exhibit increased B cell activation. In some embodiments, increased B cell activation comprises increased cell surface expression of one or more B cell activation markers (e.g., CD69, CD86, and / or HLA-DR).

[0479] In some embodiments of any of the methods or modified immune cells provided herein, the immune cell or modified immune cell is a mammalian cell (e.g., a human cell). In some embodiments, the immune cell or modified immune cell is a human cell.

[0480]

[0288] In some embodiments, incubation is carried out according to techniques such as those described in U.S. Pat. No. 6,040,177; Klebanoff et al., J Immunother., 35:651-660, 2012; Terakura et al., Blood, 119:72-82, 2012; and Wang et al., J Immunother., 35:689-701, 2012.

[0481] The immune cells or modified immune cells provided herein to be modified can be engineered to express a recombinant chimeric receptor, e.g., a chimeric antigen receptor (CAR). In some embodiments, a CAR comprises, from its N-terminus to its C-terminus, an extracellular ligand binding domain, a transmembrane domain, an intracellular costimulatory domain, and an activating cytoplasmic signaling domain. In some embodiments, a CAR comprises, from its N-terminus to its C-terminus, an extracellular ligand binding domain, a transmembrane domain, and an activating cytoplasmic signaling domain. The immune cells can be engineered to express a recombinant chimeric receptor (e.g., a CAR) before, during, or after contact with a Cbl-b inhibitor provided herein. In some embodiments, the immune cells to be modified can be T cells (e.g., CD4 + T cells or CD8 + In further embodiments, the T cell comprises a recombinant chimeric receptor, e.g., a CAR. In some embodiments, the modified immune cell is a modified T cell (e.g., a CD4 + T cells or CD8 + In a further embodiment, the modified T cell comprises a recombinant chimeric receptor, e.g., a CAR. Methods for generating immune cells expressing recombinant chimeric receptors are well known in the art, for example, by introducing a nucleic acid encoding a recombinant chimeric receptor (e.g., a CAR) into an immune cell (e.g., a T cell) via a vector (e.g., a viral vector). See, e.g., WO 2017 / 096329 and U.S. Patent Publication No. 2017 / 0204372.

[0482] In particular, the present disclosure provides a method of generating an expanded population of lymphocytes, comprising: (a) obtaining a biological sample comprising lymphocytes from an individual having cancer, the individual having received or receiving an effective amount of a Cbl-b inhibitor as a monotherapy or as part of a combination therapy; and (b) culturing the lymphocytes in a cell culture medium comprising at least one T cell growth factor to generate an expanded population of lymphocytes. In certain embodiments, the lymphocytes are tumor infiltrating lymphocytes (TILs). In certain embodiments, the lymphocytes are peripheral blood mononuclear cells (PBMCs). In certain embodiments, the at least one T cell growth factor comprises one or more of the group consisting of IL-2, IL-7, IL-15, and IL-21, and optionally, the at least one T cell growth factor comprises IL-2. In some embodiments, the cell culture medium further comprises an anti-CD3 antibody, or both an anti-CD3 antibody and an anti-CD28 antibody. In some embodiments, the cell culture medium further comprises a Cbl-b inhibitor. In some embodiments, the cell culture medium further comprises irradiated feeder cells. In some embodiments, the individual is a human patient. Also provided by the present disclosure is a composition comprising an expanded expanded population of TILs produced by the above-mentioned method and a physiologically acceptable buffer.

[0483] In some embodiments, the method of isolation and processing of immune cells to be modified or modified immune cells (i.e., modified immune cells) includes freezing (e.g., cryopreserving) the cells before or after isolation, incubation (e.g., incubation with a Cbl-b inhibitor), and / or manipulation (e.g., introduction of a nucleic acid encoding a recombinant chimeric receptor into the immune cells). A variety of freezing solutions and parameters known in the art can be used.

[0484] B. Adoptive cell therapy

[0292] The modified immune cells, e.g., expanded populations of lymphocytes generated by the methods described herein, or compositions thereof, can be used as therapeutic agents in methods of treatment of individuals in need of treatment, e.g., individuals with cancer. Such methods of treatment include adoptive cell therapy. In some embodiments, the methods of treatment include isolating cells from an individual, preparing, processing, culturing, and / or manipulating the cells as described herein, and reintroducing the cells into the same individual, before or after cryopreservation. In some embodiments, the methods of treatment include isolating cells from an individual, preparing, processing, culturing, and / or manipulating the cells as described herein, and reintroducing the cells into a different individual, before or after cryopreservation.

[0485]

[0293] Thus, in some aspects, provided herein is a method of modulating an immune response in an individual, comprising administering an effective amount of a modified immune cell or composition thereof described herein to an individual in need of modulating an immune response (e.g., an individual having a T cell dysfunction disorder). In some embodiments, the individual has cancer. In some embodiments, provided herein is a method of treating a cancer that responds to inhibition of Cbl-b activity, comprising administering an effective amount of a modified immune cell or composition thereof described herein to an individual having a cancer that responds to inhibition of Cbl-b activity. In some embodiments, provided herein is a method of inhibiting abnormal cell proliferation, comprising administering an effective amount of a modified immune cell or composition thereof described herein to an individual in need of inhibition of abnormal cell proliferation. As used herein, the term "abnormal cell proliferation" includes hyperplasia or cancer cell proliferation. The cancer cells may be derived from a hematological or non-hematological cancer. In some embodiments, the cancer is a hematological cancer, e.g., lymphoma, leukemia, or myeloma. In other embodiments, the cancer cells are from a non-hematological cancer, such as a sarcoma, carcinoma, or melanoma.

[0486] In certain embodiments, an individual in need of treatment, e.g., an individual having cancer or a T cell dysfunction disorder, can be administered a composition comprising modified immune cells provided herein in a range of about 1 million to about 100 billion cells, e.g., 1 million to about 50 billion cells (e.g., about 5 million cells, about 25 million cells, about 500 million cells, about 1 billion cells, about 5 billion cells, about 20 billion cells, about 30 billion cells, about 40 billion cells, or a range defined by any two of the aforesaid values), e.g., about 10 million to about 100 billion cells (e.g., about 20 million cells, about 30 million cells, about 40 million cells, or a range defined by any two of the aforesaid values). cells, about 60 million cells, about 70 million cells, about 80 million cells, about 90 million cells, about 10 billion cells, about 25 billion cells, about 50 billion cells, about 75 billion cells, about 90 billion cells, or a range defined by any two of the foregoing values), in some cases about 100 million cells to about 50 billion cells (e.g., about 120 million cells, about 250 million cells, about 350 million cells, about 450 million cells, about 650 million cells, about 800 million cells, about 900 million cells, about 3 billion cells, about 30 billion cells, about 45 billion cells), or any value within these ranges.

[0487] The modified immune cells and compositions thereof are administered using standard administration techniques, formulations, and / or devices. Provided are formulations and devices, such as syringes and vials, for storage and administration of the compositions. The formulations or pharmaceutical compositions comprising the modified immune cells include those for intravenous, intraperitoneal, subcutaneous, or intramuscular administration. In some embodiments, the modified immune cells are administered parenterally. The term "parenteral" as used herein includes, but is not limited to, intravenous, intramuscular, subcutaneous, and intraperitoneal administration. In some embodiments, the cell population is administered to a subject using peripheral systemic delivery by intravenous, intraperitoneal, or subcutaneous injection. The modified immune cell compositions can be provided as sterile liquid preparations, such as isotonic aqueous solutions, suspensions, emulsions, dispersions, or viscous compositions, which in some embodiments may be buffered to a selected pH. Viscous compositions can be formulated within an appropriate viscosity range to provide a longer period of contact with a particular tissue. Liquid or viscous compositions may contain a carrier, which may be a solvent or dispersion medium containing, for example, water, saline, phosphate buffered saline, polyol (e.g., glycerol, propylene glycol, and liquid polyethylene glycol), and suitable mixtures thereof. Injectable sterile solutions can be prepared by incorporating the modified immune cells in a solvent, for example, a mixture with a suitable carrier, diluent, or excipient, such as sterile water, physiological saline, glucose, or dextrose.

[0488] In some embodiments, the modified immune cells are co-administered with one or more additional therapeutic agents or with another therapeutic intervention, simultaneously or sequentially in any order. For example, in some therapeutic regimens of the present disclosure, both the modified immune cells and the Cbl-b inhibitor are administered to a mammalian subject in need thereof, and the Cbl-b inhibitor is a compound of formula (I), (II), (II-A), or any variation thereof. In some embodiments, the Cbl-b inhibitor is a compound of Table 1 or a compound of Table 2. Thus, in some embodiments, the therapeutic regimen includes both adoptive cell therapy and chemotherapy.

[0489] After the modified immune cells are administered to an individual (e.g., a human), the biological activity of the modified immune cell population can be measured by methods known in the art. Parameters to be evaluated include specific binding of the modified immune cells or other immune cells to antigens in vivo (e.g., by imaging) or ex vivo (e.g., by ELISA or flow cytometry). In some embodiments, the ability of the modified immune cells to destroy target cells can be measured using cytotoxicity assays (see, e.g., Kochenderfer et al., J. Immunotherapy, 32:689-702, 2009; and Herman et al., J. Immunological Methods, 285:25-40, 2004). In some embodiments, the biological activity of the modified immune cells can also be measured by assaying the expression and / or secretion of certain cytokines, e.g., IL-2 and IFNγ.

[0490] C. Administration of Cbl-b inhibitors In some embodiments, a Cbl-b inhibitor or a composition thereof can be administered directly to an individual to modulate an immune response, treat a disease or condition (e.g., cancer and / or abnormal cell proliferation), and / or inhibit Cbl-b activity in the individual. The Cbl-b inhibitor can be a compound of Table 1, a compound of Table 2, a tautomer thereof, or a pharma-ceutically acceptable salt thereof.

[0491] In some embodiments, provided herein is a method of modulating an immune response, comprising administering to an individual an amount of a Cbl-b inhibitor provided herein or a composition thereof effective to modulate the immune response in the individual. In some embodiments, the individual has cancer, such as a hematological or non-hematological cancer described herein.

[0492] In some embodiments, provided herein is a method of treating a cancer that responds to inhibition of Cbl-b activity, comprising administering to an individual an amount of a Cbl-b inhibitor provided herein or a composition thereof effective to treat the cancer that responds to inhibition of Cbl-b activity. In some embodiments, the cancer is a hematological or non-hematological cancer, such as those described herein.

[0493]

[0301] In some embodiments, provided herein is a method for inhibiting abnormal cell proliferation (e.g., hyperplasia), comprising administering to an individual a Cbl-b inhibitor provided herein, or a composition thereof, in an amount effective to inhibit abnormal cell proliferation in the individual.

[0494]

[0302] In some embodiments, provided herein is a method for inhibiting Cbl-b activity comprising administering to an individual a Cbl-b inhibitor provided herein or a composition thereof in an amount effective to inhibit Cbl-b activity in the individual.

[0495]

[0303] In some embodiments, for example, in modulating an immune response in an individual in need thereof (e.g., an individual having a T cell dysfunction disorder), treating a disease or condition in an individual (e.g., cancer and / or abnormal cell proliferation in an individual), and / or inhibiting Cbl-b activity in an individual, the appropriate dosage of the active agent will depend on the type of condition, disease, or disorder to be treated, the severity and course of the condition, disease, or disorder as defined above, whether the agent is administered for prophylactic or therapeutic purposes, previous therapy, the medical history of the subject, the response to the Cbl-b inhibitor, and the discretion of the attending physician.

[0496]

[0304] The Cbl-b inhibitor or composition thereof is suitably administered to an individual once or over a series of treatments. In some embodiments, the treatment includes multiple administrations of the Cbl-b inhibitor or composition, and the interval between administrations may vary. For example, the interval between the first administration and the second administration is about one month, and the interval between subsequent administrations is about three months. In some embodiments, the Cbl-b inhibitors described herein are administered in a flat dose. In some embodiments, the Cbl-b inhibitors described herein are administered to an individual in a fixed dose based on the individual's body weight (e.g., mg / kg).

[0497] In some embodiments of the present disclosure, the cancer is a blood cancer. For example, the blood cancer may be lymphoma, leukemia, or myeloma. In other embodiments of the present disclosure, the cancer is a non-blood cancer. In particular, the non-blood cancer may be a carcinoma, sarcoma, or melanoma.

[0498] In some embodiments, Cbl-b inhibitor is co-administered with one or more additional therapeutic agents or with another therapeutic intervention, simultaneously or sequentially in any order.For example, in some therapeutic regimens of the present disclosure, Cbl-b inhibitor and modified immune cells are both administered to a mammalian subject in need thereof, and Cbl-b inhibitor is a compound of formula (I), (II), (II-A), or any variation thereof.Thus, in some embodiments, therapeutic regimens include both adoptive cell therapy and chemotherapy.

[0499] In some embodiments, the effectiveness of administration of a Cbl-b inhibitor in a method herein (e.g., a method of modulating an immune response in an individual) can be assessed by measuring the biological activity of immune cells present in a sample (e.g., a blood sample) isolated from a treated individual. For example, the ability of immune cells isolated from an individual after treatment with a Cbl-b inhibitor to destroy target cells in a cytotoxicity assay can be measured to assess therapeutic efficacy. In some embodiments, the biological activity of immune cells present in a sample (e.g., a blood sample) can be measured by assaying the expression and / or secretion of certain cytokines, such as IL-2 and IFNγ.

[0500]

[0308] The present disclosure provides a method of treating cancer, comprising administering to an individual having cancer an effective amount of a Cbl-b inhibitor and administering to the individual an effective amount of an additional therapeutic agent. Also provided is a method of treating an individual having cancer, comprising administering to the individual an effective amount of a Cbl-b inhibitor; and administering to the individual an effective amount of an additional therapeutic agent. Additionally, the present disclosure provides a method of increasing an anti-cancer immune response, comprising administering to an individual having cancer an effective amount of a Cbl-b inhibitor and administering to the individual an effective amount of an additional therapeutic agent. Also provided is a method of treating cancer, comprising administering to an individual having cancer an effective amount of a Cbl-b inhibitor, wherein the individual has received or is receiving an effective amount of the additional therapeutic agent.

[0501] In some embodiments of the method of the preceding paragraph, the Cbl-b inhibitor and the additional therapeutic agent are administered consecutively in any order. As used herein, the terms "consecutively," "serially," and "sequentially" refer to administration of the Cbl-b inhibitor after the additional therapeutic agent, or administration of the additional therapeutic agent after the Cbl-b inhibitor. For example, the sequential administration may include a post-induction treatment phase that includes administration of the Cbl-b inhibitor in the absence of the additional therapeutic agent during the induction phase (initial therapy), followed by administration of the additional therapeutic agent. The method may further include a maintenance phase that includes administration of the Cbl-b inhibitor or the additional therapeutic agent. Alternatively, the sequential administration may include a post-induction treatment phase that includes administration of the Cbl-b inhibitor in the absence of the Cbl-b inhibitor during the induction phase (initial therapy), followed by administration of the additional therapeutic agent. The method may further include a maintenance phase that includes administration of the Cbl-b inhibitor or the additional therapeutic agent.

[0502] In some embodiments of combination therapy, the Cbl-b inhibitor and the additional therapeutic agent are administered simultaneously. As used herein, the terms "concurrently," "concurrently," and "in parallel" refer to the administration of the Cbl-b inhibitor and the additional therapeutic agent during the same physician visit or during the same phase of treatment. For example, both the Cbl-b inhibitor and the additional therapeutic agent may be administered during one or more of the induction phase, treatment phase, and maintenance phase. However, simultaneous administration does not require that the Cbl-b inhibitor and the additional therapeutic agent be present together in a single formulation or pharmaceutical composition, nor that the Cbl-b inhibitor and the additional therapeutic agent be administered at exactly the same time.

[0503] 1. Combination therapy including Cbl-b inhibitor and immune checkpoint inhibitor In some embodiments of the combination therapy of the present disclosure, the additional therapeutic agent comprises an immune checkpoint inhibitor. The term "immune checkpoint" refers to a signaling pathway that prevents the activation of immune cells, while the term "immune checkpoint inhibitor" refers to a compound that inhibits an immune checkpoint to remove the brakes on the activation of immune cells. In some embodiments, the immune checkpoint inhibitor is an antagonist of at least one inhibitory checkpoint molecule. In certain embodiments, the inhibitory checkpoint molecule is selected from the group consisting of PD-1 (CD279), PD-L1 (CD274), CTLA-4 (CD125), LAG3 (CD223), PVR (CD155), PVRL2 (CD112), PVRL3 (CD113), TIGIT, TIM3 (CD366), and VISTA. In certain embodiments, the immune checkpoint inhibitor is an antagonist of at least one inhibitory checkpoint molecule selected from the group consisting of PD-1 (CD279), PD-L1 (CD274), and CTLA-4 (CD152).

[0504] PD-1 refers to programmed cell death protein 1 (PD-1). PD-1 antagonists suitable for the therapeutic methods, medicaments, and uses of the present disclosure include any compound or biomolecule that blocks the binding of PD-L1 expressed on cancer cells or antigen-presenting cells to PD-1 expressed on lymphocytes (T cells, B cells, and / or NK cells). Alternative names or synonyms for PD-1 and its ligands include CD279, PDCD1, PD1, and SLEB2 for PD-1; and CD274, PDCD1L1, PDL1, B7H1, B7-4, and B7-H for programmed cell death 1 ligand 1 (PD-L1). In some embodiments where a human subject is to be treated, the PD-1 antagonist blocks the binding of human PD-L1 to human PD-1. The amino acid sequence of the mature form of human PD-1 is represented in NCBI locus number NP_005009 as residues 21-288. The amino acid sequence of the mature form of human PD-L1 is represented in NCBI locus number NP_054862 as residues 19-290.

[0505] CTLA-4 refers to cytotoxic T-lymphocyte associated protein 4. CTLA-4 antagonists suitable for the therapeutic methods, medicaments, and uses of the present disclosure include any compound or biomolecule that blocks the binding of CTLA-4 expressed on lymphocytes (T cells, B cells, and / or NK cells) to ligands (CD80 and / or CD86) expressed on antigen presenting cells. Alternative names or synonyms for CTLA-4 include CD152, CTLA4, ALPS5, CELIAC3, GRD4, GSE, and IDDM12. In some embodiments where a human subject is to be treated, the CTLA-4 antagonist blocks the binding of human CTLA-4 to a human ligand. The amino acid sequence of the mature form of human CTLA-4 is shown as residues 36-223 within NCBI locus number NP_005205.

[0506] LAG3 refers to lymphocyte activation gene 3 protein. LAG3 antagonists suitable for the therapeutic methods, medicaments, and uses of the present disclosure include any compound or biomolecule that blocks the binding of LAG3 expressed on lymphocytes (T cells, B cells, and / or NK cells) to a ligand (MHC class II) expressed on antigen presenting cells. LAG3 is also known as CD223. In some embodiments in which a human subject is to be treated, the LAG3 antagonist blocks the binding of human LAG3 to a human ligand. The amino acid sequence of the mature form of human LAG3 is shown as residues 23-525 in NCBI locus number NP_002277.

[0507] PVR refers to poliovirus receptor. PVR antagonists suitable for the therapeutic methods, medicaments, and uses of the present disclosure include any compound or biomolecule that blocks the binding of PVR expressed on cancer cells or antigen-presenting cells to TIGIT expressed on lymphocytes (T cells, B cells, and / or NK cells). Alternative names or synonyms for PVR include CD155, PVS, HVED, NECL5, nectin-like protein 5, and TAGE4. In some embodiments in which a human subject is to be treated, the PVR antagonist blocks the binding of human PVR to human TIGIT. There are multiple isoforms of human PVR. The amino acid sequence of the alpha isoform of human PVR is shown in NCBI locus number NP_006496. The amino acid sequence of the beta isoform of human PVR is shown in NCBI locus number NP_001129240. The amino acid sequence of the gamma isoform of human PVR is represented in NCBI locus number NP_001129241. The amino acid sequence of the delta isoform of human PVR is represented in NCBI locus number NP_001129242.

[0508] PVRL2 refers to poliovirus receptor related 2. PVRL2 antagonists suitable for the therapeutic methods, medicaments, and uses of the present disclosure include any compound or biomolecule that blocks the binding of PVRL2 expressed on cancer cells or antigen presenting cells to TIGIT expressed on lymphocytes (T cells, B cells, and / or NK cells). Alternative names or synonyms for PVRL2 include CD112, NECTIN2, HVEB, herpes virus entry mediator B, PRR2, and PVRR2. In some embodiments in which a human subject is to be treated, the PVRL2 antagonist blocks the binding of human PVRL2 to human TIGIT. The amino acid sequence of the alpha isoform of human PVRL2 is set forth in NCBI locus number NP_002847. The amino acid sequence of the delta isoform of human PVRL2 is set forth in NCBI locus number NP_001036189.

[0509] PVRL3 refers to poliovirus receptor related 3. PVRL3 antagonists suitable for the therapeutic methods, medicaments, and uses of the present disclosure include any compound or biomolecule that blocks the binding of PVRL3 expressed on cancer cells or antigen presenting cells to TIGIT expressed on lymphocytes (T cells, B cells, and / or NK cells). Alternative names or synonyms for PVRL3 include CD113, NECTIN3, PRR3, and PVRR3. In some embodiments in which a human subject is to be treated, the PVRL3 antagonist blocks the binding of human PVRL3 to human TIGIT. The amino acid sequence of isoform 1 of human PVRL3 is shown in NCBI locus number NP_056295. The amino acid sequence of isoform 2 of human PVRL3 is shown in NCBI locus number NP_001230215. The amino acid sequence of human PVRL3 isoform 3 is shown within NCBI locus number NP_001230217.

[0510]

[0318] TIGIT refers to T-cell immunoreceptor with Ig and ITIM domains protein. TIGIT antagonists suitable for the therapeutic methods, medicaments, and uses of the present disclosure include any compound or biomolecule that blocks the binding of TIGIT expressed on lymphocytes (T cells, B cells, or NK cells) to ligands (CD112, CD113, and / or CD155) expressed on cancer cells or antigen-presenting cells. Alternative names or synonyms for TIGIT include VSIG9, V-set and immunoglobulin domain containing 9, VSTM3, V-set and transmembrane domain containing 3, and Washington University cell adhesion molecule (WUCAM). In some embodiments where a human subject is to be treated, the TIGIT antagonist blocks the binding of human TIGIT to human ligands. The amino acid sequence of the mature form of human TIGIT is shown as residues 22 to 244 within NCBI locus number NP_776160.

[0511] TIM3 refers to T cell immunoglobulin and mucin domain-containing 3 protein. TIM3 antagonists suitable for the therapeutic methods, medicaments, and uses of the present disclosure include any compound or biomolecule that blocks the binding of TIM3 expressed on lymphocytes (T cells, B cells, or NK cells) to a ligand (galectin-9 phosphatidylserine) expressed on antigen-presenting cells. Alternative names or synonyms for TIM3 include CD366, HAVCR2, Hepatitis A virus cell receptor 2, KIM3, and SPTCL. In some embodiments where a human subject is to be treated, the TIM3 antagonist blocks the binding of human TIM3 to a human ligand. The amino acid sequence of the mature form of human TIM3 is shown as residues 22-301 in NCBI locus number NP_116171.

[0512] VISTA refers to V-domain Ig suppressor of T-cell activation. VISTA antagonists suitable for the therapeutic methods, medicaments, and uses of the present disclosure include any compound or biomolecule that blocks the binding of VISTA expressed on lymphocytes (T cells, B cells, and / or NK cells) to ligands expressed on cancer cells or antigen-presenting cells. Alternative names or synonyms for VISTA include VSIR, V-set immunoregulatory receptor, PD-1H, B7H5, GI24, PP2135, SISP1, and Dies1. In some embodiments where a human subject is to be treated, the VISTA antagonist blocks the binding of human VISTA to a human ligand. The amino acid sequence of the mature form of human VISTA is shown as residues 33-311 in NCBI locus number NP_071436.

[0513] The immune checkpoint inhibitor may be a biomolecule. For example, the immune checkpoint inhibitor may comprise an antibody or an antigen-binding fragment thereof. The antibody or fragment may be a monoclonal antibody (mAb), a human antibody, a humanized antibody, or a chimeric antibody, and may comprise a human constant region. In some embodiments, the human constant region is selected from the group consisting of IgG1, IgG2, IgG3, and IgG4 constant regions, and in certain embodiments, the human constant region is an IgG1 or IgG4 constant region. In some embodiments, the antibody or fragment is a bispecific antibody. In some embodiments, the antigen-binding fragment comprises one of the group consisting of Fab, Fab'-SH, F(ab')2, scFv, and Fv fragments.

[0514] In some embodiments, the at least one inhibitory checkpoint molecule comprises PD-1. In certain embodiments, the immune checkpoint inhibitor is selected from the group consisting of pembrolizumab, nivolumab, cemiplimab, and biosimilars thereof. In one embodiment, the anti-PD-1 antibody is pembrolizumab (MK-3475, marketed as KEYTRUDA® by Merck & Co.). In one embodiment, the anti-PD-1 antibody is nivolumab (BMS-936558 or MDX-1106, marketed as OPDIVO® by Bristol-Myers Squibb). In one embodiment, the anti-PD-1 antibody is cemiplimab (REGN2810, Regeneron). In some embodiments, the immune checkpoint inhibitor is a variant of pembrolizumab, nivolumab, or cemiplimab.

[0515] In some embodiments, the at least one inhibitory checkpoint molecule comprises PD-L1. In certain embodiments, the immune checkpoint inhibitor is selected from the group consisting of atezolizumab, avelumab, durvalumab, and biosimilars thereof. In one embodiment, the anti-PD-L1 antibody is atezolizumab (marketed as TECENTRIQ® by Genentech, Inc.). In one embodiment, the anti-PD-L1 antibody is avelumab (marketed as BAVENCIO® by EMD Serono, Inc. and Pfizer, Inc.). In one embodiment, the anti-PD-L1 antibody is durvalumab (MEDI4736, marketed as IMFINZI® by AstraZeneca). In some embodiments, the immune checkpoint inhibitor is a variant of atezolizumab, avelumab, or durvalumab.

[0516] In some embodiments, the at least one inhibitory checkpoint molecule comprises CTLA-4. In certain embodiments, the immune checkpoint inhibitor is selected from the group consisting of ipilimumab, tremelimumab, and biosimilars thereof. In one embodiment, the anti-CTLA4 antibody is ipilimumab (MDX-010 or BMS-734016, marketed as YERVOY® by Bristol-Myers Squibb). In one embodiment, the anti-CTLA4 antibody is tremelimumab (ticilimumab, CP-675,206 developed by AstraZeneca). In some embodiments, the immune checkpoint inhibitor is a variant of ipilimumab or tremelimumab.

[0517] In some embodiments, the monoclonal antibody is a "mutated" antibody that includes heavy and light chain sequences that are identical to those in the "reference" antibody, except that they have three, two, or one conservative amino acid substitutions at positions located outside the light chain CDRs, and / or six, five, four, three, two, or one conservative amino acid substitutions located outside the heavy chain CDRs (e.g., the mutated positions are located in framework or constant regions). In other words, the reference antibody and the mutated antibody include identical CDR sequences, but differ from each other by having conservative amino acid substitutions at no more than three or no more than six other positions in the full-length light and heavy chain sequences, respectively. The mutated antibody is substantially the same as the reference antibody in terms of the following properties: binding affinity to an inhibitory checkpoint molecule, and ability to block binding of an inhibitory checkpoint molecule to its ligand.

[0518]

[0326] In other embodiments, the immune checkpoint inhibitor may comprise an immunoadhesin that comprises one inhibitory checkpoint molecule binding domain of a ligand fused to a constant region, such as the Fc region, of an immunoglobulin molecule.

[0519]

[0327] As used herein, the term "biosimilar" refers to a biological product that is similar to a Federal Drug Administration (FDA) approved reference product, but does not have clinically meaningful differences in safety and efficacy. For example, there may be differences between the biosimilar product and the reference product in clinically inactive components (e.g., differences in formulation excipients, minor differences in glycosylation, etc.). Clinically meaningful characteristics can be evaluated through pharmacokinetic and pharmacodynamic studies. In some embodiments, the biosimilar product is an interchangeable product as determined by the FDA.

[0520] 2. Combination therapy including a Cbl-b inhibitor and an anti-neoplastic agent In some embodiments of the combination therapy of the present disclosure, the additional therapeutic agent comprises an anti-neoplastic agent. As used herein, the terms "antineoplastic agent" and "antineoplastic agent" refer to therapeutic agents classified according to the Anatomical Therapeutic Chemical Classification System (ATC) code L01 developed by the World Health Organization. In certain embodiments, the anti-neoplastic agent is classified as one of the groups consisting of cytotoxic antibiotics (ATC code L01D), plant alkaloids (ATC code L01C), antimetabolites (ATC code L01B), alkylating agents (ATC code L01A), and other anti-neoplastic agents (ATC code L01X). In some embodiments, the anti-neoplastic agent is a small molecule drug (e.g., a cancer chemotherapeutic agent) as opposed to a biomolecule.

[0521]

[0329] Cytotoxic antibiotics are suitable antineoplastic agents for the therapeutic methods, medicaments, and uses of the present disclosure. In some embodiments, the cytotoxic antibiotic is selected from the group consisting of ixabepilone, mitomycin, plicamycin, bleomycin, pixantrone, amrubicin, valrubicin, pirarubicin, mitoxantrone, idarubicin, zorubicin, aclarubicin, epirubicin, daunorubicin, doxorubicin, and dactinomycin.

[0522]

[0330] Plant alkaloids are suitable anti-neoplastic agents for the treatment methods, medicaments, and uses of the present disclosure. In some embodiments, the plant alkaloids are selected from the group consisting of trabectedin, cabazitaxel, paclitaxel poliglumex, docetaxel, paclitaxel, demecolcine, teniposide, etoposide, vintafolide, vinflunine, vinorelbine, vindesine, vincristine, and vinblastine.

[0523]

[0331] Antimetabolites are suitable anti-neoplastic agents for the treatment methods, medicaments and uses of the present disclosure.In some embodiments, antimetabolites are pyrimidine analogs, purine analogs, or folic acid analogs.In some embodiments, antimetabolites are selected from the group consisting of floxuridine, trifluridine, tegafur, fluorouracil, decitabine, azacitidine, capecitabine, gemcitabine, carmofur, tegafur, fluorouracil, cytarabine, nelarabine, clofarabine, fludarabine, cladribine, thioguanine, mercaptopurine, pralatrexate, pemetrexed, raltitrexed, and methotrexate.

[0524]

[0332] The alkylating agent is an anti-neoplastic agent suitable for the treatment methods, medicaments, and uses of the present disclosure. In some embodiments, the alkylating agent is selected from the group consisting of dacarbazine, temozolomide, pipobroman, mitobronitol, etoglucide, uracil mustard, ranimustine, nimustine, fotemustine, streptozocin, semustine, lomustine, carmustine, carboquone, triaziquone, thiotepa, mannosulfan, treosulfan, busulfan, bendamustine, prednimustine, trofosfamide, ifosfamide, mechlorethamine, melphalan, chlorambucil, and cyclophosphamide.

[0525]

[0333] In other embodiments, the antineoplastic agent comprises another antineoplastic agent selected from the group consisting of platinum compounds (ATC Code L01XA), methylhydrazine (ATC Code L01XB), sensitizers (ATC Code L01XD), protein kinase inhibitors (ATC Code L01XE), and other agents (ATC Code L01XA).

[0526]

[0334] Platinum compounds are suitable anti-neoplastic agents for the therapeutic methods, medicaments, and uses of the present disclosure. In some embodiments, the platinum compound is selected from the group consisting of cisplatin, carboplatin, oxaliplatin, satraplatin, and polyplatylene.

[0527] 3. Combination therapy including Cbl-b inhibitors and radiation therapy

[0335] The present disclosure provides a method of treating cancer, comprising administering to an individual having cancer an effective amount of a Cbl-b inhibitor and administering to the individual an effective amount of radiation therapy. Also provided is a method of treating an individual having cancer, comprising administering to the individual an effective amount of Cbl-b and administering to the individual an effective amount of radiation therapy. In addition, the present disclosure provides a method of increasing an anti-cancer immune response, comprising administering to an individual having cancer an effective amount of a Cbl-b inhibitor and administering to the individual an effective amount of radiation therapy. Also provided is a method of treating cancer, comprising administering to an individual having cancer an effective amount of a Cbl-b inhibitor, wherein the individual has received or is receiving an effective amount of radiation therapy.

[0528]

[0336] In some embodiments, the radiation therapy is external beam radiation therapy. In other embodiments, the radiation therapy is internal radiation therapy. In some embodiments, the radiation therapy is ablative radiation therapy.

[0529]

[0337] In some embodiments, the combination therapy regimen of the present disclosure includes administration of a Cbl-b inhibitor, radiation therapy, and one or both of an immune checkpoint inhibitor and an anti-neoplastic agent.

[0530] IV. Compositions, Formulations, and Routes of Administration Pharmaceutical compositions of any of the compounds disclosed herein, or salts or solvates thereof, are included by the present disclosure. Thus, the present disclosure includes pharmaceutical compositions comprising a Cbl-B inhibitor, which is a compound of formula (I), (II), or (II-A), or any variation thereof disclosed herein, or a pharma- ceutically acceptable salt or solvate thereof, or a tautomer thereof, or a stereoisomer or mixture of stereoisomers thereof, and a pharma- ceutically acceptable excipient, such as a pharma- ceutical acceptable vehicle or a pharma- ceutical acceptable carrier. In some embodiments, the compound is a compound selected from compound numbers 1-54 and 121-166 in Table 1, or a pharma- ceutical acceptable salt or solvate thereof, or a tautomer thereof, or a stereoisomer or mixture of stereoisomers thereof. In some embodiments, the compound is a compound selected from compound numbers 55-120 and 167 in Table 2, or a pharma- ceutical acceptable salt or solvate thereof, or a tautomer thereof, or a stereoisomer or mixture of stereoisomers thereof. In one aspect, the pharma- ceutically acceptable salt is an acid addition salt, for example, a salt formed with an inorganic or organic acid. In some embodiments, the Cbl-b inhibitor is a compound of Table 1 or Table 2, a tautomer thereof, or a salt thereof.

[0531] The compounds and compositions disclosed herein may be administered in any suitable form and by any suitable route that provides sufficient levels of the compound for the treatment of a disease or disorder. In some embodiments, the Cbl-b inhibitor and / or additional therapeutic agent are administered by enteral administration. In certain embodiments, the enteral administration is oral administration. In other embodiments, the Cbl-b inhibitor and / or additional therapeutic agent are administered by parenteral administration. In certain embodiments, the parenteral administration is intratumoral injection. In certain embodiments, the parenteral administration is by a route selected from the group consisting of intravenous, intraperitoneal, and subcutaneous.

[0532] Suitable routes of administration include oral, enteral, and parenteral administration, including subcutaneous, intravenous, intraarterial, intramuscular, intrasternal, intraperitoneal, intralesional, intraarticular, intratumoral, or infusion techniques. Compounds and compositions can also be administered sublingually, by mucosal administration, by buccal administration, subcutaneously, by spinal administration, by epidural administration, by ventricular administration, by inhalation (e.g., as a mist or spray), nasal administration, vaginal administration, rectal administration, topical administration, or transdermal administration, or by sustained or extended release mechanisms. Compounds and compositions can be administered in unit dosage formulations containing conventional pharmacologic carriers, excipients, adjuvants, and vehicles, if desired. Compounds and compositions can be administered directly to a specific or affected organ or tissue. The compound can be mixed with pharma- ceutically acceptable carriers, excipients, adjuvants, and vehicles to form a composition suitable for the desired route of administration. In some embodiments, the compound can be mixed with either or both of an antigen and an adjuvant. In some embodiments, the antigen is a cancer antigen.

[0533]

[0341] In certain embodiments disclosed herein, particularly those in which the formulation is used for injection or other parenteral administration, including the routes described herein, but also any other route of administration (e.g., oral, enteral, gastric, etc.) described herein, the formulations and preparations used in the methods are sterile. Sterile pharmaceutical formulations are synthesized or manufactured according to pharmaceutical grade sterilization standards known to those skilled in the art (United States Pharmacopeia Chapters 797, 1072, and 1211; California Business & Professions Code 4127.7; California Code 16 of Regulations 1751, Code 21 of Federal Regulations 211). A "sterile" formulation is aseptic or free or essentially free of all living microorganisms and their spores. Examples of sterilization methods for pharmaceutical formulations include, but are not limited to, sterile filtration through sterile filtration membranes, exposure to radiation, e.g., gamma radiation, and heat sterilization.

[0534] Oral administration is advantageous due to its ease of implementation and patient compliance.If a patient has difficulty swallowing, enteral administration can be achieved by using the introduction of medicine via feeding tube, feeding syringe, or gastrostomy.Active compound and, if present, other co-administered agents can be enterally administered by any other pharmacologic acceptable excipient suitable for the formulation for administration via feeding tube, feeding syringe, or gastrostomy.

[0535]

[0343] Intravenous administration can also be advantageously used to deliver the compound or composition to the bloodstream as rapidly as possible and avoid the need for absorption from the digestive tract.

[0536] The compounds and compositions described for use herein may be administered in solid, liquid, aerosol form, or in the form of tablets, pills, caplets, capsules (e.g., hard gelatin capsules or soft elastic gelatin capsules), powder mixtures, granules, injections, solutions, suppositories, enemas, colonic washes, emulsions, dispersions, food premixes, cachets, troches, lozenges, gums, ointments, poultices, pastes, powders, dressings, creams, patches, aerosols (e.g., nasal sprays or inhalers), gels, suspensions (e.g., aqueous or non-aqueous liquid suspensions, oil-in-water or water-in-oil liquid emulsions), elixirs, or other forms appropriate for the route of administration. The compounds and compositions may also be administered in liposomal formulations. The compounds may also be administered as prodrugs, where the prodrug is converted to a therapeutically effective form in the treated subject.

[0537]

[0345] In addition, pharmaceutical preparations may contain preservatives, solubilizers, stabilizers, rewetting agents, emulsifiers, sweeteners, dyes, regulators, and salts for adjusting osmotic pressure, buffers, coating agents or antioxidants. Preparations containing compounds may contain other substances that have valuable therapeutic properties. Pharmaceutical preparations may be prepared by known pharmaceutical methods. Further formulation and administration methods are known in the art. Suitable formulations may be found, for example, in Remington: The Science and Practice of Pharmacy, Lippincott Williams & Wilkins, 21st Edition (2005), which is incorporated herein by reference.

[0538]

[0346] Injectable preparations, for example, sterile injectable aqueous suspensions or sterile injectable oleaginous suspensions, may be formulated according to methods known in the art using suitable dispersing or wetting agents and suspending agents. Sterile injectable preparations may also be sterile injectable solutions or suspensions in parenterally acceptable diluents or solvents, for example, as a solution in propylene glycol. Acceptable vehicles and solvents that may be used include water, saline, Ringer's solution and isotonic sodium chloride solution. In addition, sterile fixed oils are also conventionally used as solvents or suspension media. For this purpose, mild fixed oils may be used, including synthetic monoglycerides or synthetic diglycerides. In addition, fatty acids such as oleic acid may be used in the preparation of injectables.

[0539]

[0347] The solid dosage form for oral administration can include capsules, tablets, pills, powders and granules. In such solid dosage forms, the active compound may be mixed with at least one inert diluent such as sucrose, lactose, talc or starch. Such dosage forms may also contain additional excipient substances other than the inert diluent, for example, lubricants such as magnesium stearate. In the case of capsules, tablets and pills, the dosage form may also contain buffering agents. Tablets and pills can further be prepared with enteric coating agents. Acceptable excipients for gel capsules with soft shells are, for example, vegetable oils, waxes, fats, semi-solid polyols and liquid polyols.

[0540]

[0348] The liquid dosage form for oral administration may comprise pharma- ceutically acceptable emulsions, solutions, suspensions, syrups and elixirs, including inert diluents generally used in the art, such as water.Such compositions may also comprise additional agents, such as wetting agents, emulsifying and suspending agents, cyclodextrins, and sweeteners, flavoring agents and perfumes.In other cases, the compound may be administered in pure form if appropriate.

[0541]

[0349] The compounds and compositions can also be administered in the form of liposomes. As known in the art, liposomes are usually derived from phospholipids or other lipid substances. Liposomes are formed by mono- or multi-lamellar hydrated liquid crystals dispersed in an aqueous medium. Any physiologically acceptable and metabolizable lipid capable of forming liposomes can be used. The composition of the present disclosure in the form of liposomes may contain, in addition to the compounds disclosed herein, stabilizers, preservatives, excipients, and the like. Useful lipids include phospholipids and phosphatidylcholines (lecithins), both natural and synthetic. Methods for forming liposomes are known in the art. See, for example, Gregoriadis, G., ed., Liposome Technology 3rd Edition: Liposome Technology: Liposome Preparation and Related Techniques, CRC Press, Boca Raton, Florida (2006); and Prescott, ed., Methods in Cell Biology, Vol. XIV, Academic Press, New York, NW, p. 33 et seq. (1976).

[0542] The amount of active ingredient that can be combined with carrier material to produce a single dosage form can vary depending on the patient to whom the active ingredient is administered and the specific mode of administration.However, of course, the specific dosage level for any specific patient will depend on various factors, including the specific compound used; the patient's age, weight, body surface area, body mass index (BMI), health condition, sex, and diet; the time of administration and the route of administration used; excretion rate; and the drug combination, if any, used.The compound can be administered by a unit dosage formulation.The pharmaceutical unit dosage selected to provide sufficient concentration of drug in the patient, subject, or individual is manufactured and administered.

[0543] The compounds for use described herein can be administered as the only active pharmaceutical agent, but can also be used in combination with one or more other active agents.When an additional active agent is used in combination with the compounds for use described herein, the additional active agent can be typically used in a therapeutic amount as indicated in the Physicians' Desk Reference (PDR) 71st Edition (2017), which is incorporated herein by reference, or in a therapeutically useful amount as known to those skilled in the art, or as determined empirically for each patient.

[0544] Also, combinations of two or more of the compounds and compositions disclosed herein can be used. Two or more compounds or compositions can be administered together, simply mixed before administration. Two or more compounds or compositions can be administered simultaneously, either by the same or different routes of administration. Two or more compounds or compositions can be administered sequentially, either by the same or different routes of administration. In one embodiment, the kit form may contain two or more compounds or compositions, together with printed or electronic instructions for administration, as individual compounds or compositions, as mixtures of compounds or compositions, as separate compounds or compositions administered simultaneously, or as separate compounds or compositions administered sequentially. When three or more compounds or compositions are administered, they can be administered as mixtures of compounds or compositions, as separate compounds or compositions administered simultaneously, as separate compounds or compositions administered sequentially, as separate compounds or compositions where two or more are administered simultaneously and the rest may be administered sequentially before or after the simultaneous administration, or in any other conceivable combination of mixed, simultaneous, and sequential administration.

[0545]

[0353] The compounds disclosed herein may be in a purified form in one aspect, and compositions comprising the compounds in a purified form are disclosed herein. Compositions comprising the compounds disclosed herein or salts thereof, such as compositions of substantially pure compounds, are provided. In some embodiments, compositions containing the compounds disclosed herein or salts thereof are in substantially pure form. In one variation, "substantially pure" refers to a composition containing 35% or less impurities, where impurities represent compounds other than the compound (or compounds, if a combination of compounds is used) or salts or solvates of the compound (or compounds, if a combination is used) to be administered in the composition. The weight of any vehicle, carrier, or excipient added is excluded from such calculation, and the vehicle, carrier, or excipient added is not considered an impurity. For example, a composition of a substantially pure compound selected from the compounds of Table 1 or Table 2 refers to a composition containing 35% or less impurities, where impurities represent compounds other than the compound or salts or solvates thereof. In one variation, a composition of a substantially pure compound or a salt or solvate thereof is provided, the composition containing 25% or less of impurities. In another variation, a composition of a substantially pure compound or a salt or solvate thereof is provided, the composition containing 20% ​​or less of impurities. In yet another variation, a composition of a substantially pure compound or a salt or solvate thereof is provided, the composition containing 10% or less of impurities. In a further variation, a composition of a substantially pure compound or a salt or solvate thereof is provided, the composition containing 5% or less of impurities. In another variation, a composition of a substantially pure compound or a salt or solvate thereof is provided, the composition containing 3% or less of impurities. In yet another variation, a composition of a substantially pure compound or a salt or solvate thereof is provided, the composition containing 1% or less of impurities. In a further variation, a composition of a substantially pure compound or a salt or solvate thereof is provided, the composition containing 0.5% or less of impurities.In yet another variation, a composition of a substantially pure compound means that the composition contains 15% or less, 10% or less, 5% or less, 3% or less, or 1% or less of an impurity. An impurity can be a compound of a ...

Claims

1. Compounds of formula (I) 【Chemistry 1】 or a tautomer thereof, or a pharma- ceutically acceptable salt thereof, During the ceremony, R １ and R ２ are independently hydrogen, C １ ~C ６ Alkyl, halo, or C １ ~C ６ Although haloalkyl, When X is sulfur, R １ and R ２ provided that neither of R and X are hydrogen, and when X is sulfur or a bond, R １ and R ２ is not a halo; Or R １ and R ２ together with the carbon atoms to which they are attached; 【Chemistry 2】 It is formed, X is CR ３ R ４ or sulfur; R ３ and R ４ are independently hydrogen, C １ ~C ６ Alkyl, halo, or C １ ~C ６ haloalkyl; Or R １ and R ３ Together with the carbon atoms to which they are attached, 【Chemistry 3】 forming R ５ is C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, or C ３ ~C ６ is cycloalkyl; Z is CH or nitrogen; n is 0 or 1; R ６ is hydrogen, C １ ~C ６ Alkyl, or C １ ~C ６ haloalkyl; R ７ is C １ ~C ６ Alkyl-OH, -(CR ８ R ９ ) ｍ -(5-10 membered monocyclic or fused bicyclic heteroaryl), -(CR ８ R ９ ) ｍ -(4- to 10-membered monocyclic or fused bicyclic heterocyclyl), -(CR ８ R ９ ) ｍ - (C ６ ~C １０ aryl), or -(CR ８ R ９ ) ｍ - (C ３ ~C ６ cycloalkyl), Each heteroaryl, heterocyclyl, aryl, or cycloalkyl group is optionally Therefore, 1 to 5 R １０ is substituted by a group; Or R ６ and R ７ together with the nitrogen atom to which they are attached form a 5-10 membered monocyclic or fused bicyclic heteroaryl, or a 4-10 membered monocyclic or fused bicyclic heterocyclyl, each heteroaryl or heterocyclyl optionally containing 1-2 additional heteroatoms selected from the group consisting of nitrogen, sulfur, and oxygen, and each heteroaryl or heterocyclyl optionally containing 1-5 R １０ is substituted by a group; m is 0 or 1; R ８ and R ９ are independently hydrogen, C １ ~C ６ Alkyl, or C １ ~C ６ haloalkyl; Each R １０ is independently １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, C １ ~C ６ Alkyl-OH, -CN, C １ ~C ６ Alkyl-CN, -O(C １ ~C ６ alkyl), -O(C １ ~C ６ haloalkyl), halo, hydroxy, oxo, -CO ２ H, -C(O)NH(C １ ~C ６ alkyl), -C(O)N(C １ ~C ６ Alkyl) ２ , -C(O)NH(C １ ~C ６ haloalkyl), -C(O)O(C １ ~C ６ Alkyl), -SO ２ - (C １ ~C ６ Alkyl), -SO ２ -NH(C １ ~C ６ Alkyl), -SO ２ -N(C １ ~C ６ Alkyl) ２ , -C(O)(C １ ~C ６ alkyl), -(C １ ~C ６ alkylene)-C(O)N(C １ ~C ６ Alkyl) ２ , -(C １ ~C ６ alkylene)-C(O)NH(C １ ~C ６ Alkyl), C ３ ~C ６ Cycloalkyl, 5- to 6-membered heterocyclyl, 5- to 6-membered heteroaryl, -(C １ ~C ６ alkylene)-(5-6 membered heterocyclyl), -(C １ ~C ６ alkylene)-(5- to 6-membered heteroaryl), -C(O)-(5- to 6-membered heterocyclyl), -C(O)-(5- to 6-membered heteroaryl), or C ６ ~C １０ is aryl, Each cycloalkyl, heterocyclyl, heteroaryl, or aryl group optionally has 1 to 5 R １１ is substituted by a group; Or two R's bonded to the same carbon atom １０ The groups, together with the carbon atom to which they are attached, are spiro C ３ ~C ６ cycloalkyl or spiro 4-6 membered heterocyclyl, each of which is optionally represented by 1 to 5 R １１ is substituted by a group; Each R １１ is independently １ ~C ６ Alkyl, hydroxy, oxo, or -C(O)(C １ ~C ６ alkyl); R １２ is hydrogen, C １ ~C ６ Alkyl, or C １ ~C ６ is haloalkyl, Or R ６ and R ７ together with the nitrogen atom to which they are attached form a 4-10 membered monocyclic or fused bicyclic heterocyclyl optionally containing 1-2 additional heteroatoms selected from the group consisting of nitrogen, sulfur, and oxygen; R １２ is linked to a 4-10 membered monocyclic or fused bicyclic heterocyclyl to form a 7-14 membered fused bicyclic or tricyclic heterocyclyl; １ ~C ６ alkylene, and each heterocyclyl optionally has 1 to 5 R １０ is substituted by a group; Each R １３ are independently hydrogen, C １ ~C ３ Alkyl, C １ ~C ３ Alkyl-OH, or C １ ~C ３ haloalkyl, A compound, or a tautomer thereof, or a pharma- ceutically acceptable salt thereof.

2. R １ and R ２ are independently hydrogen, C １ ~C ３ Alkyl, halo, or C １ ~C ３ Is it a haloalkyl? R １ and R ２ are independently hydrogen, -CH ３ , fluoro, or -CF ３ or R １ and R ２ together with the carbon atom to which they are attached form the group 【Chemistry 4】 2. The compound of claim 1, wherein the compound is formed as follows:

3. X is sulfur or X is CR ３ R ４ 3. The compound of claim 1 or 2, wherein:

4. R ３ and R ４ are independently hydrogen, halo, C １ ~C ３ Alkyl, or C １ ~C ３ Is it a haloalkyl? R ３ and R ４ are independently hydrogen, fluoro, -CH ３ , or -CF ３ 3. The compound of claim 1 or 2, wherein:

5. R １ and R ３ Together with the carbon atoms to which they are attached, 【Chemistry 5】 3. The compound of claim 1 or 2, wherein the compound is formed as follows:

6. R ２ is hydrogen, C １ ~C ３ Alkyl, halo, or C １ ~C ３ haloalkyl; R ４ is hydrogen, C １ ~C ３ Alkyl, halo, or C １ ~C ３ haloalkyl; Each R １３ are independently hydrogen, C １ ~C ２ Alkyl, C １ ~C ２ Alkyl-OH, or C １ ~C ２ Is it a haloalkyl? Or R ２ is hydrogen, -CH ３ , fluoro, or -CF ３ and R ４ is hydrogen, -CH ３ , fluoro, or -CF ３ and Each R １３ are independently hydrogen, -CH ３ , -CH ２ OH, or -CF ３ or Or R ２ and R ４ are each hydrogen; Each R １３ is hydrogen, or a tautomer thereof, or a pharma- ceutically acceptable salt thereof.

7. R ５ But, C １ ~C ３ Alkyl, C １ ~C ３ Haloalkyl, or C ３ ~C ４ cycloalkyl, or R ５ But -CH ３ , -CHF ２ or cyclopropyl, or a tautomer thereof, or a pharma- ceutically acceptable salt thereof.

8. 8. The compound according to any one of claims 1 to 7, wherein Z is CH or Z is nitrogen, or a tautomer thereof, or a pharma- ceutically acceptable salt thereof.

9. 9. The compound according to any one of claims 1 to 8, wherein n is 0, or a tautomer thereof, or a pharma- ceutically acceptable salt thereof.

10. 9. The compound according to any one of claims 1 to 8, wherein n is 1, or a tautomer thereof, or a pharma- ceutically acceptable salt thereof.

11. R ６ is hydrogen, C １ ~C ３ Alkyl, or C １ ~C ３ haloalkyl or R ６ is hydrogen or -CH ３ 11. The compound according to any one of claims 1 to 10, wherein:

12. R ７ But, C １ ~C ３ Alkyl-OH, -(CR ８ R ９ ) ｍ -(5-6 membered monocyclic heteroaryl), -(CR ８ R ９ ) ｍ -(8-10 membered fused bicyclic heteroaryl), -(CR ８ R ９ ) ｍ -(4- to 6-membered monocyclic heterocyclyl), -(CR ８ R ９ ) ｍ -(8- to 10-membered fused bicyclic heterocyclyl), -(CR ８ R ９ ) ｍ - (C ６ ~C １０ aryl), or -(CR ８ R ９ ) ｍ - (C ３ ~C ６ cycloalkyl), Each heteroaryl, heterocyclyl, aryl, or cycloalkyl group optionally comprises 1 to 5 R １０ is substituted with a group, Or R ７ but, 【Chemistry 6】 12. The compound according to any one of claims 1 to 11, selected from the group consisting of: or a tautomer thereof, or a pharma- ceutically acceptable salt thereof.

13. 13. The compound of claim 12, or a tautomer thereof, or a pharma- ceutically acceptable salt thereof, wherein m is 0 or 1.

14. R ８ and R ９ are independently hydrogen, C １ ~C ３ Alkyl, or C １ ~C ３ Is it a haloalkyl? R ８ and R ９ are independently hydrogen, -CH ３ , or -CF ３ 13. The compound of claim 12, wherein:

15. R ６ and R ７ together with the nitrogen atom to which they are attached form a 5-10 membered monocyclic or fused bicyclic heteroaryl, or a 4-10 membered monocyclic or fused bicyclic heterocyclyl, each heteroaryl or heterocyclyl optionally containing 1-2 additional heteroatoms selected from the group consisting of nitrogen, sulfur, and oxygen, and each heteroaryl or heterocyclyl optionally containing 1-5 R １０ is substituted by a group, Or R ６ and R ７ together with the nitrogen atom to which they are attached form a 5-6 membered monocyclic heteroaryl, an 8-10 membered fused bicyclic heteroaryl, a 4-6 membered monocyclic heterocyclyl, or an 8-10 membered fused bicyclic heterocyclyl, each heteroaryl or heterocyclyl optionally containing 1-2 additional heteroatoms selected from the group consisting of nitrogen, sulfur, and oxygen, and each heteroaryl or heterocyclyl optionally containing 1-5 R １０ is substituted by a group, Or R ６ and R ７ together with the nitrogen atom to which they are attached, 【Chemistry 7】 Are you forming a Or R ６ and R ７ together with the nitrogen atom to which they are attached form a 4-10 membered monocyclic or fused bicyclic heterocyclyl optionally containing 1-2 additional heteroatoms selected from the group consisting of nitrogen, sulfur, and oxygen; R １２ is attached to a 4-10 membered monocyclic or fused bicyclic heterocyclyl to form a 7-18 membered fused bicyclic or tricyclic heterocyclyl １ ~C ６ alkylene, and each heterocyclyl is optionally selected from 1 to 5 R １０ is substituted with a group, Or R ６ and R ７ together with the nitrogen atom to which they are attached form a 4-6 membered monocyclic heterocyclyl optionally containing 1-2 additional heteroatoms selected from the group consisting of nitrogen, sulfur, and oxygen; R １２ is linked to a 4- to 6-membered monocyclic heterocyclyl to form a 7- to 11-membered fused bicyclic heterocyclyl １ ~C ３ alkylene, and each heterocyclyl is optionally selected from 1 to 5 R １０ is substituted with a group, Or R ６ and R ７ together with the nitrogen atom to which they are attached form an 8-10 membered fused bicyclic heterocyclyl optionally containing 1-2 additional heteroatoms selected from the group consisting of nitrogen, sulfur, and oxygen; R １２ is attached to an 8-10 membered fused bicyclic heterocyclyl to form an 11-15 membered fused tricyclic heterocyclyl １ ~C ３ alkylene, and each heterocyclyl is optionally selected from 1 to 5 R １０ is substituted with a group, Or R ６ and R ７ together with the nitrogen atom to which they are attached form a 5- to 6-membered monocyclic heterocyclyl; R １２ is attached to a 5-6 membered monocyclic heterocyclyl: 【Chemistry 8】 Forming -CH ２ 11. The compound according to any one of claims 1 to 10, wherein R is -, or a tautomer thereof, or a pharma- ceutically acceptable salt thereof.

16. Each R １０ is, if present, independently １ ~C ３ Alkyl, C １ ~C ３ Haloalkyl, C １ ~C ３ Alkyl-OH, -CN, C １ ~C ３ Alkyl-CN, -O(C １ ~C ３ alkyl), -O(C １ ~C ３ haloalkyl), halo, hydroxy, oxo, -CO ２ H, -C(O)NH(C １ ~C ３ alkyl), -C(O)NH(C １ ~C ３ haloalkyl), -C(O)O(C １ ~C ３ Alkyl), -SO ２ - (C １ ~C ３ Alkyl), -SO ２ -NH(C １ ~C ３ Alkyl), -SO ２ -N(C １ ~C ３ Alkyl) ２ , -C(O)(C １ ~C ３ alkyl), -(C １ ~C ３ alkylene)-C(O)N(C １ ~C ３ Alkyl) ２ , -(C １ ~C ３ alkylene)-C(O)NH(C １ ~C ３ Alkyl), C ３ ~C ６ Cycloalkyl, 5- to 6-membered heterocyclyl, 5- to 6-membered heteroaryl, -(C １ ~C ３ alkylene)-(5-6 membered heterocyclyl), -(C １ ~C ３ alkylene)-(5- to 6-membered heteroaryl), -C(O)-(5- to 6-membered heterocyclyl), -C(O)-(5- to 6-membered heteroaryl), or C ６ ~C １０ is aryl, Each cycloalkyl, heterocyclyl, heteroaryl, or aryl group optionally has 1 to 5 R １１ is substituted with a group; Or two R's bonded to the same carbon atom １０ The groups, together with the carbon atoms to which they are attached, form a spiro C ３ ~C ６ cycloalkyl or spiro 4-6 membered heterocyclyl, each of which is optionally represented by 1 to 5 R １１ is substituted by a group, Or each R １０ are independently -CH ３ , -CH ２ CH ３ , -CH(CH ３ ) ２ , -CF ３ , -CHF ２ , -CH ２ CF ３ , -CH ２ OH, -CN, -CH ２ CN, -OCH ３ , -OCF ３ , bromo, fluoro, hydroxy, oxo, -CO ２ H, -C(O)NH(CH ３ ), -C(O)N(CH ３ ) ２ , -C(O)NH(CF ３ ), -C(O)OCH ３ , -SO ２ CH ３ , -SO ２ NH (CH ３ ), -SO ２ N (CH ３ ) ２ , -C(O)CH ３ , -(CH ２ )-C(O)N(CH ３ ) ２ , -(CH ２ )-C(O)NH(CH ３ ), 【Chemistry 9】 or Or two R's bonded to the same carbon atom １０ The groups, together with the carbon atoms to which they are attached, 【Chemistry 10】 It is formed, The nitrogen atom of the heterocyclyl group is R １１ 16. The compound of any one of claims 12 to 15, wherein when not substituted by: is bonded to hydrogen, or a tautomer thereof, or a pharma- ceutically acceptable salt thereof.

17. Each R １１ is, if present, independently １ ~C ３ Alkyl, hydroxy, oxo, or -C(O)(C １ ~C ３ alkyl) or Each R １１ are independently -CH ３ , hydroxy, oxo, or -C(O)CH ３ 17. The compound of claim 16, wherein:

18. R １２ is hydrogen, C １ ~C ３ Alkyl, or C １ ~C ３ Is it a haloalkyl? R １２ is hydrogen, -CH ３ , or -CF ３ or R １２ The compound according to any one of claims 1 to 17, or a pharma- ceutically acceptable salt thereof, wherein is hydrogen. 【Request 19】 【Table 1-1】 【Table 1-2】 【Table 1-3】 【Table 1-4】 【Table 1-5】 【Table 1-6】 or a tautomer thereof, or a pharma- ceutically acceptable salt thereof.

20. Compound of formula (II) 【Chemistry 11】 or a tautomer thereof, or a pharma- ceutically acceptable salt thereof, During the ceremony, R ２１ and R ２２ are independently hydrogen, C １ ~C ６ Alkyl, halo, C １ ~C ６ Haloalkyl or C ３ ~C ６ Although it is a cycloalkyl, When Y is sulfur or a bond, R ２１ and R ２２ is not a halo; Or R ２１ and R ２２ together with the carbon atoms to which they are attached; 【Chemistry 12】 It is formed, Y is CR ２３ R ２４ , sulfur, or a bond; R ２３ and R ２４ are independently hydrogen, halo, C １ ~C ６ Alkyl or C １ ~C ６ haloalkyl; Or R ２１ and R ２３ Together with the carbon atoms to which they are attached, 【Chemistry 13】 forming R ２５ is C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, or C ３ ~C ６ is cycloalkyl; W is CH or nitrogen; 【Chemistry 14】 teeth, 【Chemistry 15】 is selected from the group consisting of where nitrogen atoms are, if necessary to satisfy valences, R ２６ is bonded to hydrogen when not substituted by Each R ２６ is independently １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, C １ ~C ６ Alkyl-OH, C １ ~C ６ Alkyl-CN, -(CR ２８ R ２９ ) ｐ -(4- to 6-membered heterocyclyl), -(CR ２８ R ２９ ) ｐ -(5- to 6-membered heteroaryl), -(CR ２８ R ２９ ) ｐ - (C ６ ~C １０ aryl), or -(CR ２８ R ２９ ) ｐ - (C ３ ~C ６ cycloalkyl), Each cycloalkyl, heterocyclyl, heteroaryl, or aryl group optionally has 1 to 5 R ２７ is substituted with a group; Each R ２７ is independently １ ~C ６ Alkyl, C １ ~C ６ Alkyl-OH, C １ ~C ６ Haloalkyl, C １ ~C ６ Alkyl-CN, -CN, halo, hydroxy, -O-(C １ ~C ６ alkyl), -O(C １ ~C ６ haloalkyl), oxo, -C(O)NH ２ , -C(O)NH(C １ ~C ６ alkyl), -C(O)N(C １ ~C ６ Alkyl) ２ , -C(O)NH(C １ ~C ６ haloalkyl), -CO ２ H, -C(O)O(C １ ~C ６ Alkyl), -SO ２ - (C １ ~C ６ Alkyl), -SO ２ -NH(C １ ~C ６ Alkyl), -SO ２ -N(C １ ~C ６ Alkyl) ２ , -C(O)(C １ ~C ６ alkyl), -(C １ ~C ６ alkylene)-C(O)N(C １ ~C ６ Alkyl) ２ , or -(C １ ~C ６ alkylene)-C(O)NH(C １ ~C ６ alkyl); p is 0 or 1; R ２８ and R ２９ are independently hydrogen, C １ ~C ６ Alkyl, or C １ ~C ６ haloalkyl; Each R ３０ are independently hydrogen, C １ ~C ３ Alkyl, C １ ~C ３ Haloalkyl, or C １ ~C ３ alkyl-OH; A compound, or a tautomer thereof, or a pharma- ceutically acceptable salt thereof.

21. R ２１ and R ２２ are independently hydrogen, C １ ~C ３ Alkyl, halo, C １ ~C ３ Haloalkyl, or C ３ ~C ５ cycloalkyl, or R ２１ and R ２２ are independently hydrogen, -CH ３ , fluoro, -CF ３ or cyclobutyl; R ２１ and R ２２ together with the carbon atom to which they are attached, 【Chemistry 16】 21. The compound of claim 20, wherein the compound is formed as follows: or a tautomer thereof, or a pharma- ceutically acceptable salt thereof.

22. Y is sulfur or Y is CR ２３ R ２４ or Y is a bond, or a tautomer thereof, or a pharma- ceutically acceptable salt thereof.

23. R ２３ and R ２４ are independently hydrogen, halo, C １ ~C ３ Alkyl, or C １ ~C ３ Is it a haloalkyl? R ２３ and R ２４ are independently hydrogen, fluoro, -CH ３ , or -CF ３ 22. The compound of claim 20 or 21, wherein:

24. R ２１ and R ２３ Together with the carbon atoms to which they are attached, 【Chemistry 17】 22. The compound of claim 20 or 21, wherein the compound is formed as follows: or a tautomer thereof, or a pharma- ceutically acceptable salt thereof.

25. R ２２ is hydrogen, C １ ~C ３ Alkyl, halo, or C １ ~C ３ haloalkyl; R ２４ is hydrogen, C １ ~C ３ Alkyl, halo, or C １ ~C ３ haloalkyl; Each R ３０ are independently hydrogen, C １ ~C ２ Alkyl, C １ ~C ２ Haloalkyl, or C １ ~C ２ alkyl-OH; Or R ２２ is hydrogen, -CH ３ , F, or -CF ３ and R ２４ is hydrogen, -CH ３ , F, or -CF ３ and Each R ３０ are independently hydrogen, -CH ３ , -CF ３ , or -CH ２ Is it OH? Or R ２２ and R ２４ are each hydrogen; Each R ３０ 25. The compound of claim 24, or a tautomer thereof, or a pharma- ceutically acceptable salt thereof, wherein is hydrogen.

26. R ２５ But, C １ ~C ３ Alkyl, C １ ~C ３ Haloalkyl, or C ３ ~C ４ cycloalkyl, or R ２５ But -CH ３ , -CF ３ or cyclopropyl, or a tautomer thereof, or a pharma- ceutically acceptable salt thereof.

27. 27. The compound according to any one of claims 20 to 26, wherein W is CH, or a tautomer thereof, or a pharma- ceutically acceptable salt thereof.

28. 27. The compound according to any one of claims 20 to 26, or a tautomer thereof, or a pharma- ceutically acceptable salt thereof, wherein W is nitrogen.

29. Each R ２６ is, if present, independently １ ~C ３ Alkyl, C １ ~C ３ Haloalkyl, C １ ~C ３ Alkyl-OH, C １ ~C ３ Alkyl-CN, -(CR ２８ R ２９ ) ｐ -(4- to 6-membered heterocyclyl), -(CR ２８ R ２９ ) ｐ -(5- to 6-membered heteroaryl), -(CR ２８ R ２９ ) ｐ - (C ６ ~C １０ aryl), or -(CR ２８ R ２９ ) ｐ - (C ３ ~C ６ cycloalkyl), Each heterocyclyl, heteroaryl, aryl, or cycloalkyl group optionally has 1 to 5 R ２７ is substituted with a group, Or each R ２６ are independently -CH ３ , -CF ３ , -CH ２ OH, -CH ２ C.N., 【Chemistry 18】 29. The compound according to any one of claims 20 to 28, wherein:

30. 30. The compound of claim 29, or a tautomer thereof, or a pharma- ceutically acceptable salt thereof, wherein p is 0 or 1.

31. R ２８ and R ２９ are independently hydrogen, C １ ~C ３ Alkyl, or C １ ~C ３ Is it a haloalkyl? R ２８ and R ２９ are independently hydrogen, -CH ３ , or -CF ３ 31. The compound of claim 30, wherein:

32. Each R ２７ is, if present, independently １ ~C ３ Alkyl, C １ ~C ３ Alkyl-OH, C １ ~C ３ Haloalkyl, C １ ~C ３ Alkyl-CN, -CN, halo, hydroxy, -O-(C １ ~C ３ alkyl), -O(C １ ~C ３ haloalkyl), oxo, -C(O)NH ２ , -C(O)NH(C １ ~C ３ alkyl), -C(O)NH(C １ ~C ３ haloalkyl), -C(O)N(C １ ~C ３ Alkyl) ２ , -CO ２ H, -C(O)O(C １ ~C ３ Alkyl), -SO ２ - (C １ ~C ３ Alkyl), -SO ２ -NH(C １ ~C ３ Alkyl), -SO ２ -N(C １ ~C ３ Alkyl) ２ , -C(O)(C １ ~C ３ alkyl), -(C １ ~C ３ alkylene)-C(O)N(C １ ~C ３ Alkyl) ２ , or -(C １ ~C ３ alkylene)-C(O)NH(C １ ~C ３ alkyl) or Each R ２７ are independently -CH ３ , -CH ２ OH, -CF ３ , -CH ２ CN, -CN, F, Cl, hydroxy, -OCH ３ , -OCF ３ , oxo, -C(O)NH ２ , -C(O)NH(CH ３ ), -C(O)NH(CF ３ ), -C(O)N(CH ３ ) ２ , -CO ２ H, -C(O)OCH ３ , -SO ２ - (CH ３ ), -SO ２ -NH(CH ３ ), -SO ２ -N(CH ３ ) ２ , -C(O)(CH ３ ), -(CH ２ )-C(O)N(CH ３ ) ２ , or -(CH ２ )-C(O)NH(CH ３ 32. The compound according to any one of claims 29 to 31, wherein:

33. Formula (II-A) 【Chemistry 19】 having R ２１ , R ２２ , and R ２５ is as defined in the compound of formula (II), or a tautomer thereof, or a pharma- ceutically acceptable salt thereof. 【Request 34】 【Table 2-1】 【Table 2-2】 【Table 2-3】 【Table 2-4】 or a tautomer thereof, or a pharma- ceutically acceptable salt thereof.

35. A pharmaceutical composition comprising a compound according to any one of claims 1 to 34, or a tautomer thereof, or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable excipient.

36. A method of modulating immune cell activity in vitro or ex vivo, comprising contacting said immune cell with a Cbl-b inhibitor in an amount effective to modulate the activity of said immune cell, said Cbl-b inhibitor being a compound according to any one of claims 1 to 34; the immune cells include T cells, B cells, or natural killer (NK) cells; the immune cells have been or will be isolated from a blood sample from a mammalian subject; the immune cell is a tumor infiltrating lymphocyte (TIL) isolated or to be isolated from a tumor from a mammalian subject having cancer; wherein the immune cells comprise T cells and modulating the activity of the T cells comprises one or more of increasing T cell activation, increasing T cell proliferation, decreasing T cell exhaustion, and decreasing T cell tolerance; and / or wherein the increased T cell activation comprises increased production of cytokines, and / or said cytokines comprise one or more selected from the group consisting of IL-2, IFN-γ, TNFα, and GM-CSF; and / or and / or wherein the increased T cell activation comprises increased cell surface expression of one or more T cell activation markers, and / or said T cell activation markers comprise one or more selected from the group consisting of CD25, CD69, and CTLA4, and / or the T cells have been or have been contacted with an anti-CD3 antibody, either alone or in combination with an anti-CD28 antibody; and / or and / or further comprising culturing said immune cells with IL-2, either alone or in combination with an anti-CD3 antibody and / or an anti-CD28 antibody; the immune cells comprise NK cells, and modulating the activity of NK cells comprises increasing NK cell activation; and / or and / or, wherein the increased NK cell activation comprises increased cytokine production; the cytokines comprise one or more selected from the group consisting of IFN-γ, TNFα, and MIP1β; the immune cells comprise B cells, and modulating the activity of B cells comprises increasing B cell activation, optionally increasing B cell activation comprises increasing expression of CD69; and / or the immune cells are human immune cells, and / or the immune cell comprises a recombinant chimeric receptor, the recombinant chimeric receptor optionally being a chimeric antigen receptor; method.

37. A method for generating modified immune cells in vitro or ex vivo, comprising culturing a cell population containing immune cells in the presence of a Cbl-b inhibitor in an amount effective to modulate activity of the immune cells, thereby generating the modified immune cells, wherein the Cbl-b inhibitor is a compound described in any one of claims 1 to 34.

38. further comprising culturing the immune cells with an anti-CD3 antibody, either alone or in combination with an anti-CD28 antibody; further comprising culturing the immune cells with IL-2, either alone or in combination with an anti-CD3 antibody and / or an anti-CD28 antibody; 38. The method of claim 37, further comprising recovering the modified immune cells.

39. the immune cells are isolated or are isolated from a blood sample from a mammalian subject, or the immune cells are tumor infiltrating lymphocytes (TILs) isolated or are isolated from a tumor from a mammalian subject with cancer; the immune cell is a cell selected from the group consisting of a hematopoietic cell, a pluripotent stem cell, a myeloid progenitor cell, a lymphoid progenitor cell, a T cell, a B cell, and a NK cell; the modified immune cell is a cell selected from the group consisting of a hematopoietic cell, a pluripotent stem cell, a myeloid progenitor cell, a lymphoid progenitor cell, a T cell, a B cell, and a NK cell; the immune cells are tumor infiltrating lymphocytes (TILs); the immune cells are human immune cells, the immune cell or the modified immune cell comprises a recombinant chimeric receptor, The recombinant chimeric receptor is a chimeric antigen receptor.

39. The method of claim 37 or 38.

40. 35. Use of a Cbl-b inhibitor in the manufacture of a medicament for treating or preventing a disease or condition associated with Cbl-b activity, wherein said Cbl-b inhibitor is a compound according to any one of claims 1 to 34.

41. 35. Use of a Cbl-b inhibitor in the manufacture of a medicament for treating cancer, wherein the Cbl-b inhibitor is a compound according to any one of claims 1 to 34.

42. A Cbl-b inhibitor for use in treating or preventing a disease or condition associated with Cbl-b activity, said Cbl-b inhibitor being a compound according to any one of claims 1 to 34.

43. 35. A Cbl-b inhibitor for use in treating cancer, wherein said Cbl-b inhibitor is a compound according to any one of claims 1 to 34.

44. 35. A composition comprising a compound according to any one of claims 1 to 34 in combination with an effective amount of an additional therapeutic agent for use in the treatment of cancer.

45. The composition and the additional therapeutic agent are administered sequentially, in either order; 45. The composition of claim 44, wherein the composition and the additional therapeutic agent are administered simultaneously.

46. the additional therapeutic agent comprises an immune checkpoint inhibitor; 46. ​​The composition of claim 44 or 45, wherein the additional therapeutic agent comprises an anti-neoplastic agent.

47. the immune checkpoint inhibitor is an antagonist of at least one inhibitory checkpoint molecule selected from the group consisting of PD-1 (CD279), PD-L1 (CD274), CTLA-4 (CD125), LAG3 (CD223), PVR (CD155), PVRL2 (CD112), PVRL3 (CD113), TIGIT, TIM3 (CD366), and VISTA; the immune checkpoint inhibitor is an antagonist of at least one inhibitory checkpoint molecule selected from the group consisting of PD-1 (CD279), PD-L1 (CD274), and CTLA-4 (CD152); the at least one inhibitory checkpoint molecule comprises PD-1, and optionally the immune checkpoint inhibitor is selected from the group consisting of pembrolizumab, nivolumab, cemiplimab, and biosimilars thereof; the at least one inhibitory checkpoint molecule comprises PD-L1, and optionally the immune checkpoint inhibitor is selected from the group consisting of atezolizumab, avelumab, durvalumab, and biosimilars thereof; the at least one inhibitory checkpoint molecule comprises CTLA-4, and optionally the immune checkpoint inhibitor is selected from the group consisting of ipilimumab, tremelimumab, and biosimilars thereof; the immune checkpoint inhibitor comprises an antibody or antigen-binding fragment thereof, optionally wherein the antibody or fragment is a human or humanized antibody or fragment; the antineoplastic agent is classified in the group consisting of cytotoxic antibiotics, plant alkaloids, antimetabolites, alkylating agents, and other antineoplastic agents; the antineoplastic agent comprises a cytotoxic antibiotic, optionally wherein the cytotoxic antibiotic is selected from the group consisting of ixabepilone, mitomycin, plicamycin, bleomycin, pixantrone, amrubicin, valrubicin, pirarubicin, mitoxantrone, idarubicin, zorubicin, aclarubicin, epirubicin, daunorubicin, doxorubicin, and dactinomycin; the antineoplastic agent comprises a plant alkaloid, optionally wherein the plant alkaloid is selected from the group consisting of trabectedin, cabazitaxel, paclitaxel poliglumex, docetaxel, paclitaxel, demecolcine, teniposide, etoposide, vintafolide, vinflunine, vinorelbine, vindesine, vincristine, and vinblastine; the antineoplastic agent comprises an antimetabolite, optionally the antimetabolite is a pyrimidine analog, a purine analog, or a folate analog, optionally the antimetabolite is selected from the group consisting of floxuridine, trifluridine, tegafur, fluorouracil, decitabine, azacitidine, capecitabine, gemcitabine, carmofur, tegafur, fluorouracil, cytarabine, nelarabine, clofarabine, fludarabine, cladribine, thioguanine, mercaptopurine, pralatrexate, pemetrexed, raltitrexed, and methotrexate; the antineoplastic agent comprises an alkylating agent, optionally wherein the alkylating agent is selected from the group consisting of dacarbazine, temozolomide, pipobroman, mitobronitol, etoglucide, uracil mustard, ranimustine, nimustine, fotemustine, streptozocin, semustine, lomustine, carmustine, carboquone, triaziquone, thiotepa, mannosulfan, treosulfan, busulfan, bendamustine, prednimustine, trofosfamide, ifosfamide, mechlorethamine, melphalan, chlorambucil, and cyclophosphamide; the anti-neoplastic agent comprises another anti-neoplastic agent selected from the group consisting of platinum compounds, protein kinase inhibitors, and other agents; the anti-neoplastic agent comprises a platinum compound, optionally wherein the platinum compound is selected from the group consisting of cisplatin, carboplatin, oxaliplatin, satraplatin, and polyplatinone; the anti-neoplastic agent comprises a protein kinase inhibitor; 47. The composition of claim 46, wherein the anti-neoplastic agent comprises another agent.

48. A composition comprising a compound according to any one of claims 1 to 34 for use in the treatment of cancer in combination with an effective amount of radiation therapy.

49. the radiation therapy being external beam radiation therapy; 49. The composition of claim 48, wherein the radiation therapy is internal radiation therapy.

50. A composition for administration by enteral administration, optionally wherein said enteral administration is oral administration or the composition is formulated for administration by parenteral administration, optionally wherein the parenteral administration is intratumoral injection, or wherein the parenteral administration is through a route selected from the group consisting of intravenous, intraperitoneal, and subcutaneous; 50. The composition according to any one of claims 44 to 49.

51. the cancer is a blood cancer; the hematological cancer is lymphoma, leukemia, or myeloma; the cancer is a non-hematological cancer; The non-hematological cancer is a carcinoma, a sarcoma, or a melanoma. The composition according to any one of claims 44 to 50.

52. 1. A method for generating an expanded population of tumor infiltrating lymphocytes (TILs), comprising: (a) obtaining a biological sample comprising TILs from an individual treated with a composition according to any one of claims 44 to 51; (b) culturing the TILs in a cell culture medium containing at least one T cell growth factor to generate an expanded population of TILs; The method includes:

53. 53. The method of claim 52, wherein the at least one T cell growth factor comprises IL-2.

54. the cell culture medium further comprises an anti-CD3 antibody, or both an anti-CD3 antibody and an anti-CD28 antibody; the cell culture medium further comprises the Cbl-b inhibitor; The cell culture medium further comprises irradiated feeder cells.

54. The method of claim 52 or 53.

55. A composition comprising an expanded population of TILs produced by the method of any one of claims 52-54, and a physiologically acceptable buffer.

56. 1. A method for generating an expanded population of tumor infiltrating lymphocytes (TILs), comprising: (a) obtaining a biological sample containing TILs from an individual with cancer who has received or is receiving an effective amount of a Cbl-b inhibitor, the compound being any one of claims 1 to 34; (b) culturing the TILs in a cell culture medium containing at least one T cell growth factor to generate an expanded population of TILs; The method includes:

57. wherein the cancer in the mammalian subject is a non-hematological cancer, and optionally the non-hematological cancer is a sarcoma, carcinoma, or melanoma; the mammalian subject having cancer is a human; 37. The method of claim 36.

58. 36. The pharmaceutical composition of claim 35 for use in generating a population of tumor infiltrating lymphocytes (TIL).

59. 37. Use of cells modulated by the method of claim 36 in the manufacture of a medicament for treating or preventing a disease or condition associated with Cbl-b activity.

60. 37. Use of cells modulated by the method of claim 36 in the manufacture of a medicament for treating cancer.

61. A composition comprising cells modulated by the method of claim 36 for use in the treatment or prevention of a disease or condition associated with Cbl-b activity.

62. 37. A composition comprising cells modulated by the method of claim 36 for use in the treatment of cancer.

63. 40. Use of cells produced by the method of claim 37 in the manufacture of a medicament for treating or preventing a disease or condition associated with Cbl-b activity.

64. 40. Use of cells produced by the method of claim 37 in the manufacture of a medicament for treating cancer.

65. 38. A composition comprising cells produced by the method of claim 37 for use in the treatment or prevention of a disease or condition associated with Cbl-b activity.

66. 40. A composition comprising cells produced by the method of claim 37 for use in the treatment of cancer.

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