Heteroaromatic indole sulfoneamide

Abstract

The present invention relates to compounds that may be useful as modulators of the splicing factor RBM39. Also disclosed herein are pharmaceutical compositions containing compounds of formula (I), their use and preparation.

Claims

[Claim 1] A compound of formula (I) or a pharmaceutically acceptable salt thereof, 【Chemistry 1】 [In the formula, A 1 teeth, 【Chemistry 2】 Selected from, * represents a bond point that forms a fused bicyclic ring, Y is either O or NH. Z 1 , Z 2 and Z 3 Each of them is independent of C(R 1a ) or N, Each R 1a is independently selected from the group consisting of H, halogen, -(C 1 ~C 6 )alkyl and -(C 1 ~C 6 )haloalkyl, R 2 H, -(C 1 ~C 6 ) alkyl or -C(O)R 6 And, R 3 is, -(C 1 ~C 6 ) Alkyl, furan, thiophene, 5-membered monocyclic nitrogen-containing heteroaryl, or 6-12 membered nitrogen-containing bicyclic heterocycline, -(C 1 ~C 6 Alkyl, furan, thiophene, 5-membered monocyclic nitrogen-containing heteroaryl and 6-12 membered nitrogen-containing bicyclic heterocyclils are R 4 It may be optionally substituted with one, two, or three substituents selected from the following: Each R 4 -R is independent of the above. x1 ,-R x2 ,-(C 1 ~C 6 )alkyl, -(C 1 ~C 6 ) Haloalkyl, -(C 1 ~C 6 ) Alkoxy, -CN, halogen, -NH 2 , -N((C 1 ~C 6 )alkyl) 2 ,-NHC(O)(C 1 ~C 6 )alkyl, -NHBoc, -(CH 2 ) n S(O) 2 (C 1 ~C 6 )alkyl and -C(O)R z1 Selected from, R 5a -H, -CN, halogen, -(C 1 ~C 6 )alkyl, -(C 1 ~C 6 ) Haloalkyl, -(C 2 ~C 6 ) Alkenyl and -(C 2 ~C 6 ) Selected from the group consisting of alkinyls, R 5b ha-(C 1 ~C 6 ) Alkyl or R 5a R 5b R 5a and R 5b Together with the bonded atom, it forms an optionally substituted 3- to 7-membered monocyclic cycloalkyl group. R 6 is H or -(C 1 ~C 6 ) is alkyl, R 7a and R 7b These are H, halogen, -CN, and -(C) respectively, independently. 1 ~C 6 )alkyl, -(C 1 ~C 6 )alkoxy, 3-7 membered monocyclic cycloalkyl and -(C 1 ~C 6 ) Selected from the group consisting of haloalkyls, or R 7a R 7b R 7a and R 7b Together with the atom to which it is bonded, it becomes -C (=O), R x1 R is selected from the group consisting of cycloalkyl, heterocyclyl, and heterocyclyl(alkyl), and cycloalkyl, heterocyclyl, and heterocyclyl(alkyl) are R y1 Each is arbitrarily replaced, R x2 is, -(C 1 ~C 6 )alkyl, -(C 1 ~C 6 ) Selected from the group consisting of alkoxy, alkylamino, and amino, -(C 1 ~C 6 )alkyl, -(C 1 ~C 6 ) Alkoxy, alkylamino, and amino are one or two R y2 It is arbitrarily replaced with, R y1 is selected from the group consisting of H, -CN, -OH, -C(O)O(C 1 to C 6 )alkyl, -(C 1 to C 6 )alkyl, -(C 1 to C 6 )haloalkyl, -(C 1 to C 6 )alkoxy, heterocyclyl, BOC, -C(O)(C 1 to C 6 )alkyl, -S(O) 2 (C 1 to C 6 )alkyl, -CH 2 S(O) 2 (C 1 to C 6 )alkyl and -CH 2 CN, Each R y2 These are independently -CN, -OH, and -(C 1 ~C 6 )alkyl, -(C 1 ~C 6 ) Haloalkyl, -(C 1 ~C 6 )alkoxy, -N((C 1 ~C 6 )alkyl) 2 ,-CH 2 CN, -C(O)CH 2 CH 2 N((C 1 ~C 6 )alkyl) 2 , -C(O)(heterocyclyl) and -(CH 2 ) n S(O) 2 (C 1 ~C 6 ) Selected from the group consisting of alkyl groups, n is 0, 1, 2, 3, or 4. R z1 teeth, 【Transformation 3】 However, 【Chemistry 4-1】 【Chemistry 4-2】 【Chemistry 4-3】 【Chemistry 4-4】 [Chemistry 4-5] [Chemistry 4-6] 【Chemistry 4-7】 【Chemistry 4-8】 【Chemistry 4-9】 【Chemistry 4-10】 【Chemistry 4-11】 【Chemistry 4-12】 【Chemistry 4-13】 【Chemistry 4-14】 【Chemistry 4-15】 【Chemistry 4-16】 【Chemistry 4-17】 【Chemistry 4-18】 【Chemistry 4-19】 【Chemistry 4-20】 A compound or its pharmaceutically acceptable salt that is not a compound. [Claim 2] Z 3 The compound according to claim 1, wherein is N. [Claim 3] Z 1 The compound according to claim 1 or claim 2, wherein is N. [Claim 4] R 1a ga-(C 1 ~C 6 The compound according to any one of claims 1 to 3, wherein it is alkyl. [Claim 5] R 1a ga-CH 3 The compound according to claim 4. [Claim 6] R 1a A compound according to any one of claims 1 to 3, wherein is a halogen. [Claim 7] R 1a ga-(C 1 ~C 6 The compound according to any one of claims 1 to 3, wherein it is a haloalkyl compound. [Claim 8] R 2 A compound according to any one of claims 1 to 7, wherein is -H. [Claim 9] R 2 ga-(C 1 ~C 6 The compound according to any one of claims 1 to 7, wherein it is alkyl. [Claim 10] R 2 -C(O)R 6 The compound according to any one of claims 1 to 7. [Claim 11] R 2 -C(O)(C 1 ~C 6 The compound according to claim 10, wherein it is alkyl. [Claim 12] R 3 However, R 4 The compound according to any one of claims 1 to 11, which is a five-membered monocyclic nitrogen-containing heteroaryl that is optionally substituted with one, two, or three substituents selected from the following. [Claim 13] R 5a The compound according to any one of claims 1 to 12, wherein is -CN. [Claim 14] R 5a A compound according to any one of claims 1 to 12, wherein is a halogen. [Claim 15] R 5a ga-(C 1 ~C 6 The compound according to any one of claims 1 to 12, wherein it is a haloalkyl compound. [Claim 16] R 5a ga-(C 1 ~C 6 The compound according to any one of claims 1 to 12, wherein it is alkyl. [Claim 17] R 7a The compound according to any one of claims 1 to 16, wherein is -CN. [Claim 18] R 7a The compound according to any one of claims 1 to 16, wherein is a halogen. [Claim 19] R 7a ga-(C 1 ~C 6 The compound according to any one of claims 1 to 16, wherein it is a haloalkyl compound. [Claim 20] R 7a ga-(C 1 ~C 6 ) an alkyl compound according to any one of claims 1 to 16, wherein the formula is: [Claim 21] A 1 but, 【Transformation 5】 The compound according to any one of claims 1 to 16. [Claim 22] A 1 but, 【Transformation 6】 The compound according to any one of claims 1 to 12 or 17 to 20. [Claim 23] A 1 but, 【Transformation 7】 The compound according to any one of claims 1 to 20. [Claim 24] structure: 【Transformation 8】 [In the formula, X 1 is S, O, or N(R 4 ) and X 2 , X 3 and X 4 Each of them is independent of C(R 4 ) or N, however X 1 N(R 4 ) or X 2 , X 3 and X 4 The compound according to claim 23, which is a compound of formula (II) or a pharmaceutically acceptable salt thereof, having [at least one of which is N]. [Claim 25] X 1 The compound according to claim 24, wherein is S. [Claim 26] X 2 and X 3 The compound according to claim 24 or 25, wherein at least one of the elements is N. [Claim 27] structure: 【Chemistry 9】 [In the formula, X 1 is O or S, X 2 is C(R 4 The compound according to claim 24, which is a compound of formula (III) or a pharmaceutically acceptable salt thereof, having [ ] or N. [Claim 28] X 3 is C(R 4 The compound according to claim 27, which is the compound described in claim 27. [Claim 29] X 3 The compound according to claim 27, wherein is N. [Claim 30] structure: 【Chemistry 10】 [In the formula, X 1 The compound according to claim 24, which is a compound of formula (IV) or a pharmaceutically acceptable salt thereof, having [where is O or S]. [Claim 31] X 1 The compound according to claim 30, wherein is S. [Claim 32] X 1 The compound according to claim 30, wherein is O. [Claim 33] structure: 【Chemistry 11】 [In the formula, X 1 is S or O, X 2 is C(R 4 The compound according to claim 24, which is a compound of formula (V) or a pharmaceutically acceptable salt thereof, having [ ] or N. [Claim 34] X 1 The compound according to claim 33, wherein is S. [Claim 35] X 1 The compound according to claim 33, wherein is O. [Claim 36] X 2 is C(R 4 The compound according to any one of claims 33 to 35, which is the compound described in the previous claim. [Claim 37] X 2 The compound according to any one of claims 33 to 35, wherein is N. [Claim 38] structure: 【Chemistry 12】 [In the formula, X 1 and X 2 Each of them is independent of C(R 4 ) or N, X 3 is S, O, or N(R 4 ) However, X 3 N(R 4 ) or X 1 and X 2 The compound according to claim 1, which is a compound of formula (VI) or a pharmaceutically acceptable salt thereof, having [at least one of which is N]. [Claim 39] X 3 The compound according to claim 38, wherein is S. [Claim 40] X 3 The compound according to claim 38, wherein is O. [Claim 41] X 3 N(R 4 The compound according to claim 38, which is the compound described in claim 38. [Claim 42] X 2 The compound according to any one of claims 38 to 41, wherein is N. [Claim 43] X 2 is C(R 4 The compound according to any one of claims 38 to 41, which is the compound described in the previous claim. [Claim 44] X 1 The compound according to any one of claims 38 to 43, wherein is N. [Claim 45] X 1 is C(R 4 The compound according to any one of claims 38 to 43, which is the compound described above. [Claim 46] A 1 but, 【Chemistry 13】 The compound according to any one of claims 1 to 20. [Claim 47] R 5b ga-(C 1 ~C 6 The compound according to claim 1 or 46, wherein it is alkyl. [Claim 48] R 5a However, R 5b R 5a and R 5b The compound according to claim 1 or 46, wherein together with the bonded atom, it forms an optionally substituted 3- to 7-membered monocyclic cycloalkyl group. [Claim 49] R 5a However, R 5b R 5a and R 5b The compound according to claim 48, wherein together with the bonded atom, it forms an optionally substituted cyclopropyl. [Claim 50] R 3 However, R 4 Optionally substituted with one, two, or three substituents selected from -(C 1 ~C 6 The compound according to any one of claims 1 to 11, wherein it is alkyl. [Claim 51] Each R 4 However, independently, -H, halogen, -CN, -(C 1 ~C 6 )alkyl, -(C 1 ~C 6 ) Haloalkyl, -(C 1 ~C 6 )alkoxy, -(CH 2 ) n S(O) 2 (C 1 ~C 6 ) alkyl or -C(O)R z1 The compound according to any one of claims 1 to 50. [Claim 52] R 4 CH 3 The compound according to any one of claims 1 to 51. [Claim 53] R 4 is CD 3 The compound according to any one of claims 1 to 51. [Claim 54] R 4 NH 2 The compound according to any one of claims 1 to 51. [Claim 55] R 4 A compound according to any one of claims 1 to 51, wherein is NHBoc. [Claim 56] R 4 is NHC(O)(C 1 ~C 6 The compound according to any one of claims 1 to 51, wherein it is alkyl. [Claim 57] R 4 ga-R x1 The compound according to any one of claims 1 to 50. [Claim 58] -R x1 but, 【Chemistry 14】 A compound according to claim 57, selected from the group consisting of the following. [Claim 59] R y1 The compound according to claim 57 or 58, wherein is -H. [Claim 60] R y1 ga-(C 1 ~C 6 The compound according to claim 57 or 58, wherein it is alkyl. [Claim 61] R y1 is -CN or -CH 2 The compound according to claim 57 or 58, wherein CN. [Claim 62] R y1 The compound according to claim 57 or 58, wherein is BOC. [Claim 63] R y1 -C(O)(C 1 ~C 6 The compound according to claim 57 or 58, wherein it is alkyl. [Claim 64] R y1 ga-(CH 2 ) n S(O) 2 (C 1 ~C 6 The compound according to claim 57 or 58, wherein it is alkyl. [Claim 65] R y1 The compound according to claim 57 or 58, wherein is a heterocyclyl. [Claim 66] R y1 but, 【Chemistry 15】 The compound according to claim 65. [Claim 67] R 4 ga-R x2 The compound according to any one of claims 1 to 50. [Claim 68] -R x2 but, 【Chemistry 16】 A compound according to claim 67, selected from the group consisting of the following. [Claim 69] -R x2 but, 【Chemistry 17】 And each R y2 However, they are independent of -H, -OH, -CN, and -(C 1 ~C 6 )alkoxy, -N((C 1 ~C 6 )alkyl) 2 , or -(CH 2 ) n S(O) 2 (C 1 ~C 6 The compound according to claim 68, wherein it is alkyl. [Claim 70] R x2 but, [Chemistry 18] And each R y2 ga-(C 1 ~C 6 The compound according to claim 68, wherein it is alkyl. [Claim 71] R y2 The compound according to any one of claims 68 to 70, wherein is -OH. [Claim 72] R x2 but, 【Chemistry 19】 The compound according to claim 68. [Claim 73] -R x2 but, 【Chemistry 20】 The compound according to claim 68. [Claim 74] R y2 is -CN or -CH 2 The compound according to any one of claims 68 to 73, wherein the compound is CN. [Claim 75] R y2 ga-(CH 2 ) n S(O) 2 (C 1 ~C 6 The compound according to claim 73, wherein it is alkyl. [Claim 76] R x2 but, 【Chemistry 21】 And each R y2 However, independently, -(C 1 ~C 6 ) alkyl, -CH 2 CN, -C(O)CH 2 CH 2 N((C 1 ~C 6 )alkyl) 2 , or -(CH 2 ) n S(O) 2 (C 1 ~C 6 The compound according to claim 68, wherein it is alkyl. [Claim 77] R 3 ga-CH 3 The compound according to claim 50. [Claim 78] R 3 The compound according to claim 50, wherein isopropyl. [Claim 79] R 3 R 4 It is replaced with R 4 ga-R x1 The compound according to claim 50. [Claim 80] -R x1 but, 【Chemistry 22】 The compound according to claim 79. [Claim 81] R 3 However, R 4 The compound according to any one of claims 1 to 11, which is a 6- to 12-membered nitrogen-containing bicyclic heterocycline optionally substituted with one, two, or three substituents selected from the above. [Claim 82] 6-12 member nitrogen-containing bicyclic heterocyclines 【Chemistry 23】 A compound according to claim 81, selected from the group consisting of the following. [Claim 83] R 4 The compound according to claim 82, wherein is -CN. 【Request Item 84】 【Chemistry 24-1】 【Chemistry 24-2】 【Chemistry 24-3】 【Chemistry 24-4】 【Chemistry 24-5】 【Chemistry 24-6】 【Chemistry 24-7】 【Chemistry 24-8】 【Chemistry 24-9】 【Chemistry 24-10】 A compound according to claim 1, selected from the group consisting of the above, or a pharmaceutically acceptable salt of any of the above. [Claim 85] A pharmaceutical composition comprising an effective amount of a compound according to any one of claims 1 to 84 or a pharmaceutically acceptable salt thereof, and an excipient. [Claim 86] A method for treating cancer in a subject, comprising the step of administering an effective amount of a compound or a pharmaceutically acceptable salt thereof described in any one of claims 1 to 84 to a subject in need thereof. [Claim 87] The method according to claim 86, further comprising the step of administering surgery, radiotherapy, chemotherapy, targeted therapy, immunotherapy, immune checkpoint therapy, hormone therapy, or antiviral therapy. [Claim 88] A compound according to any one of claims 1 to 84 or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer. [Claim 89] The compound according to claim 88, further comprising administering surgery, radiotherapy, chemotherapy, targeted therapy, immunotherapy, immune checkpoint therapy, hormone therapy, or antiviral therapy. [Claim 90] Use of a compound according to any one of claims 1 to 84 or a pharmaceutically acceptable salt thereof in the preparation of a pharmaceutical for use in the treatment of cancer. [Claim 91] The use according to claim 90, further comprising administering surgery, radiotherapy, chemotherapy, targeted therapy, immunotherapy, immune checkpoint therapy, hormone therapy, or antiviral therapy. [Claim 92] A method for treating cancer in a subject, comprising an effective amount of the compound of formula (I) or a pharmaceutically acceptable salt thereof. 【Chemistry 25】 [In the formula, A 1 teeth, 【Chemistry 26】 Selected from, * represents a bond point that forms a fused bicyclic ring, Y is either O or NH. Z 1 , Z 2 and Z 3 Each of them is independent of C(R 1a ) or N, Each R 1a These are independently H, halogen, -(C 1 ~C 6 ) Alkyl and -(C 1 ~C 6 ) Selected from the group consisting of haloalkyls, R 2 H, -(C 1 ~C 6 ) alkyl or -C(O)R 6 And, R 3 is, -(C 1 ~C 6 ) Alkyl, furan, thiophene, 5-membered monocyclic nitrogen-containing heteroaryl, or 6-12 membered nitrogen-containing bicyclic heterocycline, -(C 1 ~C 6 Alkyl, furan, thiophene, 5-membered monocyclic nitrogen-containing heteroaryl and 6-12 membered nitrogen-containing bicyclic heterocyclils are R 4 It may be optionally substituted with one, two, or three substituents selected from the following: Each R 4 -R is independent of the above. x1 ,-R x2 ,-(C 1 ~C 6 )alkyl, -(C 1 ~C 6 ) Haloalkyl, -(C 1 ~C 6 ) Alkoxy, -CN, halogen, -NH 2 , -N((C 1 ~C 6 )alkyl) 2 ,-NHC(O)(C 1 ~C 6 )alkyl, -NHBoc, -(CH 2 ) n S(O) 2 (C 1 ~C 6 )alkyl and -C(O)R z1 Selected from, R 5a -H, -CN, halogen, -(C 1 ~C 6 )alkyl, -(C 1 ~C 6 ) Haloalkyl, -(C 2 ~C 6 ) Alkenyl and -(C 2 ~C 6 ) Selected from the group consisting of alkinyls, R 5b ha-(C 1 ~C 6 ) Alkyl or R 5a R 5b R 5a and R 5b Together with the bonded atom, it forms an optionally substituted 3- to 7-membered monocyclic cycloalkyl group. R 6 is H or -(C 1 ~C 6 ) is alkyl, R 7a and R 7b These are H, halogen, -CN, and -(C) respectively, independently. 1 ~C 6 )alkyl, -(C 1 ~C 6 )alkoxy, 3-7 membered monocyclic cycloalkyl and -(C 1 ~C 6 ) Selected from the group consisting of haloalkyls, or R 7a R 7b R 7a and R 7b Together with the atom to which it is bonded, it becomes -C (=O), R x1 R is selected from the group consisting of cycloalkyl, heterocyclyl, and heterocyclyl(alkyl), and cycloalkyl, heterocyclyl, and heterocyclyl(alkyl) are R y1 Each is arbitrarily replaced, R x2 is, -(C 1 ~C 6 )alkyl, -(C 1 ~C 6 ) Selected from the group consisting of alkoxy, alkylamino, and amino, -(C 1 ~C 6 )alkyl, -(C 1 ~C 6 ) Alkoxy, alkylamino, and amino are one or two R y2 It is arbitrarily replaced with, R y1 is H, -CN, -OH, -C(O)O(C 1 ~C 6 )alkyl, -(C 1 ~C 6 )alkyl, -(C 1 ~C 6 ) Haloalkyl, -(C 1 ~C 6 )alkoxy, heterocyclyl, BOC, -C(O)(C 1 ~C 6 ) alkyl, -S(O) 2 (C 1 ~C 6 ) alkyl, -CH 2 S(O) 2 (C 1 ~C 6 ) Alkyl and -CH 2 Selected from the group consisting of CN, Each R y2 These are independently -CN, -OH, and -(C 1 ~C 6 )alkyl, -(C 1 ~C 6 ) Haloalkyl, -(C 1 ~C 6 )alkoxy, -N((C 1 ~C 6 )alkyl) 2 ,-CH 2 CN, -C(O)CH 2 CH 2 N((C 1 ~C 6 )alkyl) 2 , -C(O)(heterocyclyl) and -(CH 2 ) n S(O) 2 (C 1 ~C 6 ) Selected from the group consisting of alkyl groups, n is 0, 1, 2, 3, or 4. R z1 teeth, 【Chemistry 27】 However, 【Chemistry 28】 A method comprising the step of administering a compound or a pharmaceutically acceptable salt thereof to a subject in need thereof, wherein the cancer is selected from the group consisting of pleural mesothelioma (PM), cutaneous squamous cell carcinoma (CSCC); tumor mutational burden high (TMB-H), Calmette-Guérin bacillus bladder cancer, endometrial cancer (EC), esophageal squamous cell carcinoma (ESCC), Merkel cell carcinoma (MCC), primary mediastinal large B-cell lymphoma (PMBCL), urothelial carcinoma, classical Hodgkin lymphoma, head and neck squamous cell carcinoma, sarcoma, non-small cell lung cancer (NSCLC), small cell lung cancer, triple-negative breast cancer, and luminal B breast cancer. [Claim 93] The method according to claim 92, further comprising the step of administering surgery, radiotherapy, chemotherapy, targeted therapy, immunotherapy, immune checkpoint therapy, hormone therapy, or antiviral therapy.

Images