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KR-20260068066-A - PI3K inhibitor

KR20260068066AKR 20260068066 AKR20260068066 AKR 20260068066AKR-20260068066-A

Abstract

A compound having the structure of the following chemical formula I, [Chemical Formula I] Or stereoisomers of the compound, tautomers of the compound, or pharmaceutically acceptable salts thereof, wherein in Formula I, R1 , R2 , R3 , R4 , R5 , R8 , A, X, Z, and Y are as defined herein. Pharmaceutical compositions comprising the compound and the use thereof in methods for treating diseases are also described.

Inventors

  • 차터지, 파얄
  • 로드리게즈, 마사 이.
  • 살리투로, 리아 제이.
  • 스미스, 애런 씨.
  • 스턴카드, 리 엠.
  • 저우, 예윤
  • 칼슨, 폴 알.
  • 니만, 스콧 더블유.
  • 서터, 패트릭 제이.
  • 트루히요, 존 아이.
  • 바인, 로건 이.
  • 치카렐리, 마크 제이.
  • 벤타이허, 브루클린
  • 코너, 마이클 엘.
  • 피셔, 존
  • 풀턴, 제니퍼
  • 잘루리, 라비 쿠마르
  • 녹스, 헤일리 제이.
  • 쿠마르, 비제이
  • 뉴하우스, 브래들리 제이.

Assignees

  • 코젠트 바이오사이언시스, 인크.

Dates

Publication Date
20260513
Application Date
20240726
Priority Date
20230728

Claims (20)

  1. A compound having the structure of the following chemical formula I, or as a stereoisomer of the above compound, a tautomer of the above compound, or a salt thereof, in the above formula I, X is CR 7 or N, and Z is CHR 6 , NR 6 , or O, and n is an integer from 0 to 1, and R1 , R2 , and R7 are each independently hydrogen, halo, C1 - C3 alkyl, C1 - C3 heteroalkyl, C3 - C7 cycloalkyl, and R3 is hydrogen, C1 - C3 alkyl, C1 - C3 heteroalkyl, C3 - C7 cycloalkyl, quaternary to hexacyclic heterocyclyl, aryl, or heteroaryl, and R5 and R6 are each independently hydrogen, C1 - C3 alkyl, or C1 - C3 heteroalkyl, and R4 is -C≡CR9 , -NR9R10 , -OR9 , C1 - C6 heteroalkyl, 3- to 12 -membered carbocyclile, 3- to 12-membered heterocyclile, or 5- to 10-membered heteroaryl, wherein the C1- C6 heteroalkyl, 3- to 12-membered carbocyclile, 3- to 12-membered heterocyclile, or 5- to 10-membered heteroaryl is optionally substituted, and R9 and R10 are each independently hydrogen, C1 - C6 alkyl, C3 - C7 cycloalkyl, 3- to 7- membered heterocyclyl, or 5- to 10-membered heteroaryl, wherein the C1 - C6 alkyl, C3 - C7 cycloalkyl, 3- to 7-membered heterocyclyl, or 5- to 10-membered heteroaryl are optionally substituted, and A is phenylene, 5- to 10-membered heteroarylene, or 3- to 12-membered heterocyclylene, each of which is optionally substituted, and Y is -SO₂NHC (=O)-, -C(=O) NHSO₂- , -SO₂- , or O, and If Y is -SO₂NHC (=O)-, -C(=O) NHSO₂- , or -SO₂- , is a single bond, or if Y is O, it is a double bond, and R8 is hydrogen, halo, -OR 11a , -NR 11a R 11b , C3 - C7 cycloalkyl, ternary to hexacyclic, C1 - C4 alkyl, C1 - C4 haloalkyl, aryl, heteroaryl, or absent, R 11a and R 11b are each independently hydrogen, C 1 -C 3 alkyl, C 3 -C 7 cycloalkyl, C 3 -C 7 heterocyclyl, aryl, or heteroaryl, If Y is -SO₂ and R₅ is NR₁¹¹a R₁¹¹b , and R₁¹¹a and R₁¹¹b are each independently hydrogen or C₁ - C₃alkyl , then A is not phenylene, and When Y is O, the above compound has the following structure A compound having, wherein A' is an unsaturated pentagonal to hexavalent heterocyclilene, or a stereoisomer of said compound, a tautomer of said compound, or a salt thereof.
  2. In claim 1, the compound is a compound having one of the structures of the following chemical formulas IA to IB, Or a stereoisomer, tautomer, or salt of the above compound.
  3. A compound according to claim 1 or 2, wherein A is optionally substituted with 1 to 3 R A , each R A being independently hydrogen, halo, cyano, C1 - C3 alkyl, C1 - C3 heteroalkyl, C3 - C7 cycloalkyl, -OR 11a , or -NR 11a R 11b .
  4. A compound according to any one of claims 1 to 3, wherein A is phenylene optionally substituted with 1 to 2 R A.
  5. In paragraph 4, A is the following structure arbitrarily substituted with 1 to 2 R A A compound having, where * indicates the attachment point to Y.
  6. A compound according to any one of claims 1 to 3, wherein the 5- to 10-membered heteroarylene of A is pyrrolylene, imidazolylene, pyrazolilene, triazolilene, pyridinyllene, diazinyllene, triazinyllene, thiazolilene, isothiazolylene, oxazolilene, or isoxazolilene, each of which is optionally substituted with 1 to 2 R A.
  7. In claim 6, the above 5- to 10-membered heteroarylene of A has the following structure , or A compound having one of the following, each arbitrarily substituted with 1 to 2 R A , where * indicates the attachment site for Y.
  8. A compound according to any one of claims 1 to 3, wherein the 3 to 12-membered heterocyclilene of A is an unsaturated 5 to 6-membered heterocyclilene, wherein the unsaturated 5 to 6-membered heterocyclilene is 1,2-dihydropyridineylene, 1,4-dihydropyridineylene, 2,3-dihydropyridineylene, 2,5-dihydropyridineylene, 1,2-dihydropyridazineylene, or 1,4-dihydropyridazineylene, and each thereof is optionally substituted with 1 to 2 R A.
  9. In claim 8, the above unsaturated 5- to 6-membered heterocyclylene of A has the following structure , or A compound having one of the following, each arbitrarily substituted with 1 to 2 R A , where * indicates the attachment site for Y.
  10. A compound according to any one of claims 1 to 3, wherein the 3 to 12-membered heterocyclilene of A comprises a 5-membered heterocyclilene conjugated to a phenyl group, or a 5-membered heterocyclilene conjugated to a 6-membered heteroarylene group.
  11. A compound according to any one of claims 1 to 3, wherein the 5- to 10-membered heteroarylene of A comprises a phenyl conjugated to a 5-membered heteroarylene, or a 5-membered heteroarylene conjugated to a 6-membered heteroarylene.
  12. A compound according to any one of claims 1 to 3, wherein the 5- to 10-membered heteroarylene of A is benzimidazolilene, indazolilene, imidazopyridineylene, or pyrazolopyridineylene, each of which is optionally substituted with 1 to 2 R A.
  13. In Clause 12, the above 5- to 10-membered heteroarylene of A has the following structure , or A compound having one of the following, each arbitrarily substituted with 1 to 2 R A , where * indicates the attachment site for Y.
  14. In any one of claims 1 to 13, the compound is a compound having one of the structures of the following chemical formulas IA-a to IA-l and IB-a to IB-b, Or a stereoisomer, tautomer, or salt of the above compound.
  15. A compound according to any one of claims 1 to 14, wherein R A is each independently hydrogen , -CN, -Br, -Cl, -F, -CH3 , -CH2CH3 , cyclopropyl, -OCH3 , -NHCH3 , -NHCH2CH3 , -CF3 , -CH2CF3 , or -CF2H .
  16. In any one of paragraphs 1 through 15, Y is , or A compound, wherein * indicates the attachment point to R 8 .
  17. A compound according to any one of claims 1 to 15, wherein Y is O and R 8 is absent.
  18. In any one of claims 1 to 17, the compound is a compound having one of the following chemical formulas IA-1 to IA-3, IB-1 to IB-3 and IC structures, Or a stereoisomer, tautomer, or salt of the above compound.
  19. A compound according to any one of claims 1 to 18, wherein R1 , R2 , and R7 are each independently hydrogen, halo, C1 alkyl, C1 heteroalkyl, or ternary to pentary cycloalkyl.
  20. A compound according to any one of claims 1 to 19, wherein R1 , R2 , and R7 are each independently -H, -F, -CH3 , or cyclopropyl.

Description

PI3K inhibitor Related applications This application claims the benefit and priority of U.S. Provisional Patent Application No. 63/516,375 filed July 28, 2023, the entire contents of said application are incorporated herein by reference in their entirety for all purposes. Technology field The present disclosure relates to a compound acting as a phosphatidylinositol 3-kinase (PI3-kinase or PI3K) inhibitor. The present disclosure also provides a compound of Formula I and a pharmaceutically acceptable salt thereof, and a use of the compound for the treatment of abnormal cell growth of a target, e.g., cancer. The PI3K signaling pathway plays a role in physiological processes that induce tumor progression, including metabolism, cell growth, and proliferation. However, the development of therapeutic PI3K pathway inhibitors has faced challenges, including poor drug tolerance and resistance. There remains a need to discover potent PI3K inhibitors for the treatment of patients suffering from cancer or other proliferative diseases or conditions caused by PI3K mutations, including mutations in the phosphatidylinositol 3-kinase catalytic alpha subunit (PI3-kinase CA or PIK3CA). Briefly, the present disclosure provides a compound comprising stereoisomers, tautomers, or pharmaceutically acceptable salts of the compound, which may be used alone or in combination with other therapeutic agents. In one embodiment, a compound having the structure of the following chemical formula I, Or stereoisomers of the compound, tautomers of the compound, or pharmaceutically acceptable salts thereof are provided, wherein in Formula I, R1 , R2 , R3 , R4 , R5 , R8 , A, X, Z, and Y are as defined herein. A pharmaceutical composition comprising one or more of the compounds of Table 1, or the aforementioned chemical formulas I, IA~IC, IA-1~IA-3, IB-1~IB-3, IA-a~IA-l, IB-a~IB-b, or II, and additional therapeutic agents is also provided. In another embodiment, a treatment method is provided for administering a pharmaceutical composition comprising the aforementioned compounds of Formula I, IA~IC, IA-1~IA-3, IB-1~IB-3, IA-a~IA-l, IB-a~IB-b, or II or Table 1, or the compounds of Formula I, IA~IC, IA-1~IA-3, IB-1~IB-3, IA-a~IA-l, IB-a~IB-b, or II or Table 1 to a subject requiring treatment to treat a disease. Now, various aspects and embodiments will be described in more detail herein. These aspects and embodiments may take many different forms, and the examples disclosed herein should not be interpreted as limiting; rather, these embodiments are provided to ensure that the scope of this disclosure is thorough and complete and fully conveyed to a person skilled in the art. I. Definition For convenience, specific terms used in the specification, embodiments, and claims are gathered herein. Unless otherwise defined, all technical and scientific terms used in this disclosure have the same meaning as generally understood by a person skilled in the art to which this disclosure pertains. Where a range of values is provided, each value interposed between the upper and lower limits of such range and any other mentioned or interposed values within the mentioned range are to be included in the present disclosure. For example, if a range of 1 μM to 8 μM is mentioned, 2 μM, 3 μM, 4 μM, 5 μM, 6 μM, and 7 μM, as well as a range of non-integer values greater than 1 μM and a range of non-integer values less than or equal to 8 μM, are to be to be explicitly disclosed. The singular form includes plural objects unless the context clearly indicates otherwise. Thus, for example, the designation 'polymer' includes not only a single polymer but also two or more identical or different polymers, and the designation 'excipient' includes not only a single excipient but also two or more identical or different excipients, etc. In particular, regarding the given amount, the term 'approximately' means including a deviation of ±5 percent. The composition of the present disclosure may include, essentially constitute, or be composed of the disclosed components. All percentages, parts, and ratios are based on the total weight of the composition, and unless otherwise specified, all measurements are performed at approximately 25°C. As used in this specification and the appended claims, unless otherwise specified, the following terms have the indicated meanings. 'Amino' refers to the -NH₂ , -NHR, or -NR₂ radical, and 'Cyanone' refers to the -CN radical, and 'Hydroxyl' refers to the -OH radical, and 'Imino' refers to =NH or =NR substituents, and 'Nitro' refers to the -NO2 radical, and 'Oxo' refers to the =O substituent, and 'Thio' refers to the =S substituent, and 'Trifluoromethyl' refers to the -CF3 radical, and Hydrazino or hydrazino refers to an N-N substituent, Each R of 'amino' or 'imino' is a compatible substituent described in this disclosure, the R group is chiral, and isomers are considered and included herein. 'Alkyl' refers to a linear, saturated, non-cyclic, monovalent hydro