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KR-20260065819-A - 3H-imidazo[4,5-b]pyridine compound as a non-covalent modifying agent of AKT1 and uses thereof

KR20260065819AKR 20260065819 AKR20260065819 AKR 20260065819AKR-20260065819-A

Abstract

The present invention provides non-covalent modifiers of AKT1 of formulas (I), (II), (II-A), (III), (III-A), (III-B), (IV), (IV-A), (IV-B), (V), (V-A), (V-B), (VI), (VI-A), or (VI-B), and pharmaceutical compositions thereof. In some embodiments, the present disclosure provides a method for controlling wild-type AKT1 using a compound or salt of formulas (I), (II), (II-A), (III), (III-A), (III-B), (IV), (IV-A), (IV-B), (V), (V-A), (V-B), (VI), (VI-A), or (VI-B) and pharmaceutical compositions thereof.

Inventors

  • 추 항
  • 양 킨 에스
  • 라이스버그 솔로몬 에이치
  • 자이드릭 아담
  • 카렐리 조던 디
  • 베스트베이터 브라이언 피
  • 한센 티모시 알
  • 톰슨 피터 에이

Assignees

  • 테레모토 바이오사이언스, 인코포레이티드

Dates

Publication Date
20260511
Application Date
20240802
Priority Date
20230804

Claims (20)

  1. A compound represented by the structure of chemical formula (I), or a pharmaceutically acceptable salt thereof: In the above formula, Ring B is Selected from; R1 is selected from hydrogen, halogen, -OR10 , -SR10 , -N( R10 ) 2 , -NO2 , -CN, optionally substituted C3-8 carbon rings, optionally substituted quaternary to octary heterocyclic rings, and optionally substituted C1-6 alkyls, each of which is optionally substituted with one or more substituents independently selected from halogen, -OR10 , -SR10 , -N( R10 ) 2 , -NO2, and -CN; A 1 and A 2 are (i), (ii) and (iii), respectively: (i) hydrogen, halogen, C 1-4 haloalkyl, -OR 11 , -SR 11 , -N(R 11 ) 2 , -C(O)N(R 11 ) 2 , -N(R 11 )C(O)R 11 , -C(O)OR 11 , -OC(O)R 11 , -N(R 11 )C(O)OR 11 , -OC(O)N(R 11 ) 2 , -N(R 11 )C(O)N(R 11 ) 2 , -S(O)R 11 , -S(O) 2R 11 , -N(R 11 )S(O) 2R 11 , -S(O) 2N (R 11 ) 2 , -NO 2 and -CN ; (ii) C 1-6 alkyl, C 2-6 alkenyl and C 2-6 alkynyl, any of which is Halogen, -OR 11 , -SR 11 , -N(R 11 ) 2 , -C(O)N(R 11 ) 2 , -N(R 11 )C(O)R 11 , -C(O)OR 11 , -OC(O)R 11 , -N(R 11 )C(O)OR 11 , -OC(O)N(R 11 ) 2 , -N(R 11 )C(O)N(R 11 ) 2 , -S(O)R 11 , -S(O) 2 R 11 , -N(R 11 )S(O) 2 R 11 , -S(O) 2 N(R 11 ) 2 , -NO 2 , =O, =S, =N(R 11 ) and -CN; and C 3-10 carbon rings and 4 to 10 heterocyclic rings, any of which is Halogen, -OR 11A , -N(R 11A ) 2 , -C(O)R 11A , -C(O)N(R 11A ) 2 , -N(R 11A )C(O)R 11A , -C(O)OR 11A , -OC(O)R 11A , -NO 2 , =O, =S, =N(R 11A ), -CN; and C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, wherein any one of these is optionally substituted with one or more substituents independently selected from -OR 11A , -SR 11A , -N(R 11A ) 2 , -C(O)R 11A , -C(O)N(R 11A ) 2 , -N(R 11A )C(O)R 11A , -N (R 11A )S(O) 2R 11A, -C(O)OR 11A , -OC(O)R 11A , -NO 2 , =O, =S, = N(R 11A ) and -CN . A C3-10 carbon ring and a 4- to 10-membered heterocyclic ring that is optionally substituted with one or more substituents independently selected from C1-6 alkyl, C2-6 alkenyl, and C2-6 alkenyl that are optionally substituted with one or more substituents independently selected from; and (iii) 5- to 10-membered heterocyclic rings and C3-10 carbon rings, any of which are Halogen, -OR 11 , -SR 11 , -N(R 11 ) 2 , -C(O)R 11 , -C(O)N(R 11 ) 2 , -N(R 11 )C(O)R 11 , -N (R 11 )S(O) 2 R 11 , -NS(O) 2 N(R 11 ) 2 , -C(O)OR 11 , -OC(O)R 11 , -N(R 11 )C(O)OR 11 , -OC(O)N(R 11 ) 2 , -N(R 11 )C(O)N(R 11 ) 2 , -S(O)R 11 , -S(O) 2 R 11 , -S(O) 2 N(R 11 ) 2 , -NO 2 , =O, =S, =N(R 11 ) and -CN; and C1-6 alkyl, C2-6 alkenyl, and C3-6 alkynyl, any one of which is a halogen, -OR 11 , -SR 11 , -N(R 11 ) 2 , -C(O)R 11 , -C(O)N(R 11 ) 2 , -N(R 11 )C(O)R 11 , -C(O)OR 11 , -OC(O)R 11 , -N(R 11 )C(O)OR 11 , -OC(O)N(R 11 ) 2 , -N(R 11 )C(O)N(R 11 ) 2 , -S(O)R 11 , -S(O) 2R 11 , -N(R 11 )S(O) 2R 11 , -S(O) 2 C1-6 alkyl, C2-6 alkenyl, and C3-6 alkenyl optionally substituted with one or more substituents independently selected from N( R11 ) 2 , -NO2 , =O, =S, =N( R11 ) and -CN; and C 3-10 carbon rings and 4 to 10 heterocyclic rings, any of which is Halogen, -OR 11 , -N(R 11 ) 2 , -C(O)R 11 , -C(O)N(R 11 ) 2 , -N(R 11 )C(O)R 11 , -C(O)OR 11 , -OC(O)R 11 , -NO 2 , =O, =S, =N(R 11 ), -CN; and A C1-6 alkyl, C2-6 alkenyl, C3-6 alkynyl, C3-8 carbon ring, or quaternary to 8-membered heterocyclic ring, wherein any one of these is optionally substituted with one or more substituents independently selected from halogen, -OR 11 , -SR 11 , -N(R 11 ) 2 , -C(O)R 11 , -C (O)N(R 11 ) 2 , -N(R 11 )C(O)R 11 , -N(R 11 )S(O) 2R 11 , -C(O)OR 11, -OC(O)R 11 , -NO 2 , =O, = S, =N(R 11 ) , and -CN . or 8-won heterozygous pill A C 3-10 carbon ring and a 4- to 10-membered heterocyclic ring that is arbitrarily substituted with one or more substituents independently selected from 5- to 10-membered heterocyclic rings and C3-10 carbon rings that are arbitrarily substituted with one or more substituents independently selected from Selected independently from; q is selected from 1, 2, and 3; m and n are independently selected from 0, 1, 2 and 3, respectively; R2 is independently selected from halogen, C1-4 alkyl, C1-4 haloalkyl, -OR12 , -SR12 , -N( R12 ) 2 , -NO2 , and -CN in each case; R 3 is for each case Halogen, -OR 13 , -SR 13 , -N(R 13 ) 2 , -C(O)R 13 , -C(O)N(R 13 ) 2 , -N(R 13 )C(O)R 13 , -C(O)OR 13 , -OC(O)R 13 , -NO 2 and -CN; and C 1-6 alkyls optionally substituted with one or more substituents independently selected from halogens, -OR 13 , -SR 13 , -N(R 13 ) 2 , -C(O)R 13 , -C(O)N(R 13 ) 2 , -N(R 13 )C(O)R 13 , -C(O)OR 13 , -OC(O)R 13, -NO 2 , =O, =S, =N(R 13 ) , and -CN Selected independently from; p is selected from 0, 1, 2, 3, 4, and 5; R 4 is for each case Halogen, -OR 14 , -SR 14 , -N(R 14 ) 2 , -C(O)R 14 , -C(O)N(R 14 ) 2 , -N(R 14 )C(O)R 14 , -C(O)OR 14 , -OC(O)R 14 , -NO 2 and -CN; and C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, wherein any one of these is optionally substituted with one or more substituents independently selected from halogen, -OR 14 , -SR 14 , -N(R 14 ) 2 , -C(O)R 14 , -C(O)N(R 14 ) 2 , -N(R 14 )C(O)R 14 , -C(O)OR 14 , -OC(O)R 14 , -NO 2 , =O, = S, =N(R 14 ), and -CN . Selected independently from; Two R₄ groups attached to the same atom together form a group selected from =O, =S, and =N ( R₁₄ ); Two R4 groups attached to the same or adjacent atoms form a group selected from quaternary to octary heterocyclic rings and C3-8 carbon rings together with the carbon to which they are attached, and any of the quaternary to octary heterocyclic rings and C3-8 carbon rings are optionally substituted with one or more substituents independently selected from halogen, C1-4 alkyl, C1-4 haloalkyl, -OR14 , -SR14 , -N( R14 ) 2 , -NO2 , and -CN; L is represented as -L 1 -L 2 -L 3 -L 4 -, and L 1 , L 2 , L 3 and L 4 are (a) and (b), respectively: (a) -O-, -N(R 15 )-, -S-, -S(O)-, -S(O) 2 -, -S(O)(NR 15 )-, -N(R 15 )C(O)-, -N(R 15 )C(O)O-, -N(R 15 )S(O) 2 -, -N(R 15 )S(O) 2 N(R 15 )-, -S(O)(NR 15 )N(R 15 )-, -N(R 15 )N(R 15 )-, -(R 15 )NC(O)N(R 15 )- and -(R 15 )NC(O)N(R 15 )N(R 15 )-; and (b) C 1-6 alkylene, C 2-6 alkenylene, C 2-6 alkynylene, C 3-8 carbocyclene and 4- to 8-membered heterocyclene, wherein any of these is optionally substituted with one or more substituents independently selected from halogen, -OR 15 , -SR 15 , =O, =S and -CN . Selected independently from; L1 , L2 , L3 , and L4 are each arbitrarily absent; Two or fewer of L1 , L2 , L3 , and L4 are selected from (a), and the selected two are not adjacent; R5 is selected from tetra- to decagonal heterocyclic rings and C3-10 carbon rings, any of which is Halogen, C 1-4 haloalkyl, -OR 16 , -SR 16 , -N(R 16 ) 2 , -C(O)N(R 16 ) 2 , -C(O)OR 16 , -OC(O)R 16 , -N(R 16 )C(O)R 16 , - N(R 16 )S(O) 2 R 16 , -S(O) 2 N(R 16 ) 2 , -N(R 16 )C(O)N(R 16 ) 2 , -N(R 16 )C(O)OR 16 , -OC(O)N(R 16 ) 2 , -S(O)R 16 , -S(O) 2 R 16 , -NO 2 , =O, =S, =N(R 16 ) and -CN; C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, wherein each of these is optionally substituted with one or more substituents independently selected from halogen , -OR16 , -SR16 , -N( R16 ) 2 , -NO2 , and -CN ; and 4- to 6-membered heterocyclic rings and C3-8 carbon rings, wherein each of these is optionally substituted with one or more substituents independently selected from halogen, C1-4 alkyl, C1-4 haloalkyl, -OR16 , -SR16 , -N( R16 ) 2 , -NO2 , and -CN, 4- to 6-membered heterocyclic rings and C3-8 carbon rings Randomly substituted with one or more substituents independently selected from; R 10 , R 11 , R 11A , R 12 , R 13 , R 14 , and R 15 are each independently selected from hydrogen, C 1-4 alkyl, C 3-8 carbon ring, quaternary to octary heterocyclic ring, and C 1-4 haloalkyl in each case; R 16 is for cases (iv), (v) and (vi), respectively: (iv) hydrogen; (v) As a C 1-4 alkyl, Halogen, -OR 20 , -SR 20 , -N(R 20 ) 2 , -C(O)R 20 , -C(O)OR 20 , -OC(O)R 20 , -C(O)N(R 20 ) 2 , -N(R 20 )C(O)R 20 , -N(R 20 )C(O)N(R 20 ) 2 , -N(R 20 )C(O)OR 20 , -OC(O)N(R 20 ) 2 , -S(O)R 20 , -S(O) 2 R 20 , -N (R 20 )S(O) 2 R 20 , -S (O) 2 N(R 20 ) 2 , -NO 2 and -CN ; and (vi) C 3-8 carbon rings and 4- to 8-membered heterocyclic rings, wherein any one of these is a halogen, C 1-4 alkyl, C 1-4 haloalkyl, -OR 20 , -SR 20 , -N(R 20 ) 2 , -C(O)R 20 , -C(O)OR 20 , -OC(O)R 20 , -C(O)N(R 20 ) 2 , -N(R 20 )C(O)R 20 , -N(R 20 )C(O)N(R 20 ) 2 , -N(R 20 )C(O)OR 20 , -OC(O)N(R 20 ) 2 , -S(O)R 20 , -S(O) 2R 20 , -N (R 20 )S(O) 2R C3-8 carbon rings and 4- to 8-membered heterocyclic rings optionally substituted with one or more substituents independently selected from 20 , -S (O) 2N ( R20 ) 2 , -NO2 , and -CN C 1-4 alkyl optionally substituted with one or more substituents independently selected from; and (vi) C 3-8 carbon rings and 4- to 8-membered heterocyclic rings, wherein any one of these is a halogen, C 1-4 alkyl, C 1-4 haloalkyl, -OR 20 , -SR 20 , -N(R 20 ) 2 , -C(O)R 20 , -C(O)N(R 20 ) 2 , -C(O)OR 20 , -OC(O)R 20 , -N(R 20 )C(O)R 20 , -N (R 20 )S(O) 2R 20 , -N(R 20 )C(O)N(R 20 ) 2 , -N(R 20 )C(O)OR 20 , -OC(O)N(R 20 ) 2 , -S(O)R 20 , -S(O) 2R 20 , -NO2 , -CN, and one or more substituents independently selected from C3-8 carbon rings or 4- to 8-membered heterocyclic rings are optionally substituted, wherein the substituent C3-8 carbon rings or 4- to 8-membered heterocyclic rings are halogens, C1-4 alkyl, C1-4 haloalkyl, -OR20 , -SR20 , -N( R20 ) 2 , -C(O) R20 , -C(O)N( R20 ) 2 , -C(O) OR20 , -OC(O) R20 , -N( R20 )C(O) R20 , -N ( R20 )S( O)2R20 , -N( R20 )C(O)N( R20 ) 2 , -N( R20 )C(O)OR C3-8 carbon rings and 4- to 8-membered heterocyclic rings optionally additionally substituted with one or more substituents independently selected from 20 , -OC(O)N(R 20 ) 2 , -S(O)R 20 , -S(O) 2 R 20 , -NO 2 , and -CN Selected independently from; R 20 is independently selected from hydrogen, C 1-4 alkyl, C 1-4 haloalkyl, C 3-8 carbon ring, and 4 to 8 heterocyclic rings in each case.
  2. In claim 1, A2 is selected from C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, each of which is Halogen, -OR 11 , -N(R 11 ) 2 , -C(O)N(R 11 ) 2 , -N(R 11 )C(O)R 11 , -N(R 11 )S(O) 2 R 11 , -S(O) 2 N(R 11 ) 2 , =O, -NO 2 and -CN; and C 3-10 carbon rings and 4 to 10 heterocyclic rings, any of which is Halogen, -OR 11A , -N(R 11A ) 2 , -C(O)R 11A , -C(O)N(R 11A ) 2 , -N(R 11A )C(O)R 11A , -NO 2 , =O and -CN; and C1-6 alkyl, C2-6 alkenyl, and C3-6 alkynyl, wherein any one of these is optionally substituted with one or more substituents independently selected from halogen, -OR 11A , -N(R 11A ) 2 , -C(O)R 11A , -C(O)N(R 11A ) 2 , -N ( R 11A )C(O)R 11A , -N (R 11A )S(O) 2R 11A , -NO 2 , =O, and -CN . A C3-10 carbon ring and a 4- to 10-membered heterocyclic ring that is optionally substituted with one or more substituents independently selected from A compound or salt that is optionally substituted with one or more substituents independently selected from.
  3. In paragraph 1 or 2, A 2 is Halogen, -OR 11 , -N(R 11 ) 2 , -C(O)N(R 11 ) 2 , -N(R 11 )C(O)R 11 , -N(R 11 )S(O) 2 R 11 , -S(O) 2 N(R 11 ) 2 , -NO 2 and -CN; and C 3-10 carbon rings and 4 to 10 heterocyclic rings, any of which is Halogen, -OR 11A , -N(R 11A ) 2 , -C(O)R 11A , -C(O)N(R 11A ) 2 , -N(R 11A )C(O)R 11A , -NO 2 , =O and -CN; and C1-6 alkyl, C2-6 alkenyl, and C3-6 alkynyl, wherein any one of these is optionally substituted with one or more substituents independently selected from halogen, -OR 11A , -N(R 11A ) 2 , -C(O)R 11A , -C(O)N(R 11A ) 2 , -N ( R 11A )C(O)R 11A , -N (R 11A )S(O) 2R 11A , -NO 2 , =O, and -CN . A C3-10 carbon ring and a 4- to 10-membered heterocyclic ring that is optionally substituted with one or more substituents independently selected from A compound or salt selected from C 2-6 alkynes that is optionally substituted with one or more substituents independently selected from.
  4. A compound or salt according to any one of claims 1 to 3, wherein A2 is a C2-6 alkynyl optionally substituted with one or more substituents independently selected from a halogen, -OR11 , -N( R11 ) 2 , -NO2 , -CN; a C3-10 carbon ring and a 4- to 10-membered heterocyclic ring, and the C3-10 carbon ring and the 3- to 10-membered heterocyclic ring are each a halogen, -OR11A , -N( R11A ) 2 , -NO2 , =O, and -CN; and optionally substituted with one or more substituents independently selected from a C1-6 alkyl that is optionally substituted with one or more substituents independently selected from a halogen, -OR11A , -N( R11A ) 2 , -NO2 , =O, and -CN.
  5. In paragraph 4, A2 is a C2-6 alkynyl optionally substituted with one or more substituents independently selected from a C3-6 carbon ring and a 4- to 6-membered heterocyclic ring, wherein each of the C3-6 carbon ring and the 4- to 6-membered heterocyclic ring is a halogen, -OR 11A , -N(R 11A ) 2 , -C(O)R 11A , -C(O)N(R 11A ) 2 , -N(R 11A )C(O)R 11A , -NO 2 , =O and -CN; A compound or salt that is optionally substituted with one or more substituents independently selected from C1-6 alkyls, optionally substituted with one or more substituents independently selected from -OR 11A , -N(R 11A ) 2 , -C(O)R 11A , -C(O)N(R 11A ) 2, -N(R 11A )C(O)R 11A , -NO 2 , =O and -CN.
  6. A compound or salt according to claim 4, wherein A2 is a C2-6 alkynyl optionally substituted with one or more substituents independently selected from a C3-6 carbon ring and a 4- to 6-membered heterocyclic ring, and any of the C3-6 carbon ring and the 4- to 6-membered heterocyclic ring is a halogen, -OR 11A , -N(R 11A ) 2 , -C(O)R 11A , -C(O)N(R 11A ) 2 , -N(R 11A )C(O)R 11A , -NO 2 , =O and -CN; and optionally substituted with one or more substituents independently selected from a C1-6 alkyl that is optionally substituted with one or more substituents independently selected from a halogen, -OR 11A and -N(R 11A ) 2 .
  7. A compound or salt according to claim 6, wherein A2 is a C2-6 alkynyl optionally substituted with cyclopropyl, cyclopentyl, oxetanyl, azetidinyl, and oxazolyl, and each of these substituents is optionally substituted with a halogen, -OR11A , -N( R11A ) 2 , -C(O) R11A , -C(O)N( R11A ) 2 , -N( R11A )C(O) R11A , -NO2 , =O, -CN; and optionally substituted with one or more substituents independently selected from a C1-6 alkyl that is optionally substituted with one or more substituents independently selected from a halogen, -OR11A , and -N(R11A) 2 .
  8. In Paragraph 7, A 2 is A compound or salt selected from.
  9. A compound or salt in which L1 , L2 , L3 , and L4 are all absent in any one of claims 1 to 8.
  10. In any one of paragraphs 1 through 9, A 2 is And, where ring B1 is a C3-8 carbon ring or a 4- to 8-membered heterocyclic ring, any one of which is a halogen, C1-4 alkyl, C1-4 haloalkyl, -OR 20 , -SR 20 , -N(R 20 ) 2 , -C(O)R 20 , -C(O)N(R 20 ) 2 , -C(O)OR 20 , -OC(O)R 20 , -N(R 20 )C(O)R 20 , -N (R 20 )S(O) 2R 20 , -N(R 20 )C(O)N(R 20 ) 2 , -N(R 20 )C(O)OR 20 , -OC(O)N(R 20 ) 2 , -S(O)R 20 , A compound or salt that is optionally substituted with one or more substituents independently selected from -S(O) ₂R₂O , -NO₂ , and -CN.
  11. In any one of claims 1 to 10, R5 is selected from tetravalent to decary heterocyclic rings and C3-10 carbon rings, and any of these is Halogen, -OR 16 , -SR 16 , -N(R 16 ) 2 , -C(O)N(R 16 ) 2 , -C(O)OR 16 , -OC(O)R 16 , -N(R 16 )C(O)R 16 , -N (R 16 )S(O) 2 R 16 , -S(O) 2 N(R 16 ) 2 , -N(R 16 )C(O)N(R 16 ) 2 , -N(R 16 )C(O)OR 16 , -OC(O)N(R 16 ) 2 , -S(O)R 16 , -S(O) 2 R 16 , -NO 2 , =O, =S, =N(R 16 ) and -CN; C1-4 alkyl optionally substituted with one or more substituents independently selected from halogen, C1-4 alkyl, C1-4 haloalkyl, -OR 16 , -SR 16 , -N(R 16 ) 2 , -NO 2 and -CN; and 4- to 6-membered heterocyclic rings and C3-8 carbon rings, wherein each of these is optionally substituted with one or more substituents independently selected from halogen, C1-4 alkyl, C1-4 haloalkyl, -OR16 , -SR16 , -N( R16 ) 2 , -NO2 , and -CN, 4- to 6-membered heterocyclic rings and C3-8 carbon rings A compound or salt that is optionally substituted with one or more substituents independently selected from.
  12. In Paragraph 11, R 5 is Halogen, -OR 16 , -SR 16 , -N(R 16 ) 2 , -C(O)N(R 16 ) 2 , -C(O)OR 16 , -OC(O)R 16 , -N(R 16 )C(O)R 16 , -N (R 16 )S(O) 2 R 16 , -S(O) 2 N(R 16 ) 2 , -N(R 16 )C(O)N(R 16 ) 2 , -N(R 16 )C(O)OR 16 , -OC(O)N(R 16 ) 2 , -S(O)R 16 , -S(O) 2 R 16 , -NO 2 , =O, =S, =N(R 16 ) and -CN; C1-4 alkyl optionally substituted with one or more substituents independently selected from halogen, C1-4 alkyl, C1-4 haloalkyl, -OR 16 , -SR 16 , -N(R 16 ) 2 , -NO 2 and -CN; and 4- to 6-membered heterocyclic rings and C3-8 carbon rings, wherein each of these is optionally substituted with one or more substituents independently selected from halogen, C1-4 alkyl, C1-4 haloalkyl, -OR16 , -SR16 , -N( R16 ) 2 , -NO2 , and -CN, 4- to 6-membered heterocyclic rings and C3-8 carbon rings A compound or salt that is a quaternary to 10-membered heterocyclic compound or salt optionally substituted with one or more substituents independently selected from.
  13. In Paragraph 12, R 5 is Halogen, -OR 16 , -SR 16 , -N(R 16 ) 2 , -C(O)N(R 16 ) 2 , -C(O)OR 16 , -OC(O)R 16 , -N(R 16 )C(O)R 16 , -N (R 16 )S(O) 2 R 16 , -S(O) 2 N(R 16 ) 2 , -N(R 16 )C(O)N(R 16 ) 2 , -N(R 16 )C(O)OR 16 , -OC(O)N(R 16 ) 2 , -S(O)R 16 , -S(O) 2 R 16 , -NO 2 , =O, =S, =N(R 16 ) and -CN; C1-4 alkyl optionally substituted with one or more substituents independently selected from halogens, C1-4 alkyls, C1-4 haloalkyls, -OR16 , -SR16 , -N( R16 ) 2 , -NO2 , and -CN. A compound or salt that is a quaternary to 10-membered heterocyclic compound or salt optionally substituted with one or more substituents independently selected from.
  14. In paragraph 13, R 5 is selected from azetidinyl, cyclopentyl, cyclohexyl, imidazolyl, pyrazolyl, 1H-1,2,3-triazolyl, 4H-1,2,4-triazolyl, 1,4-dihydropyridinyl, 3,4-dihydropyrido[3,4-d]pyrimidinyl, and 1H-benzo[d][1,2,3]triazolyl, each of which is Halogen, -OR 16 , -SR 16 , -N(R 16 ) 2 , -C(O)N(R 16 ) 2 , -C(O)OR 16 , -OC(O)R 16 , -N(R 16 )C(O)R 16 , -N (R 16 )S(O) 2 R 16 , -S(O) 2 N(R 16 ) 2 , -N(R 16 )C(O)N(R 16 ) 2 , -N(R 16 )C(O)OR 16 , -OC(O)N(R 16 ) 2 , -S(O)R 16 , -S(O) 2 R 16 , -NO 2 , =O, =S, =N(R 16 ) and -CN; C1-4 alkyl optionally substituted with one or more substituents independently selected from halogens, C1-4 alkyls, C1-4 haloalkyls, -OR16 , -SR16 , -N( R16 ) 2 , -NO2 , and -CN. A compound or salt that is optionally substituted with one or more substituents independently selected from.
  15. In Paragraph 14, R 5 is A compound or salt selected from.
  16. In any one of paragraphs 1 through 15, ring B is Phosphorus compound or salt.
  17. In Paragraph 16, ring B is A compound or salt selected from.
  18. In any one of paragraphs 1 through 15, ring B is Phosphorus compound or salt.
  19. In claim 1, the structure of formula (I) is represented by the structure of the compound of formula (II) or a pharmaceutically acceptable salt thereof, such that the compound or salt: In the above formula, R1 is selected from hydrogen, halogen, -OR10 , -SR10 , -N( R10 ) 2 , -NO2 , and -CN; and C1-6 alkyls optionally substituted with one or more substituents independently selected from halogen, -OR10 , -SR10 , -N( R10 ) 2 , -NO2, and -CN; A 1 and A 2 are (i), (ii) and (iii), respectively: (i) hydrogen, halogen, C 1-4 haloalkyl, -OR 11 , -SR 11 , -N(R 11 ) 2 , -C(O)N(R 11 ) 2 , -N(R 11 )C(O)R 11 , -C(O)OR 11 , -OC(O)R 11 , -N(R 11 )C(O)OR 11 , -OC(O)N(R 11 ) 2 , -N(R 11 )C(O)N(R 11 ) 2 , -S(O)R 11 , -S(O) 2R 11 , -N(R 11 )S(O) 2R 11 , -S(O) 2N (R 11 ) 2 , -NO 2 and -CN ; (ii) C 1-6 alkyl, C 2-6 alkenyl and C 2-6 alkynyl, any of which is a halogen, -OR 11 , -SR 11 , -N(R 11 ) 2 , -C(O)N(R 11 ) 2 , -N(R 11 )C(O)R 11 , -C(O)OR 11 , -OC(O)R 11 , -N(R 11 )C(O)OR 11 , -OC(O)N(R 11 ) 2 , -N(R 11 )C(O)N(R 11 ) 2 , -S(O)R 11 , -S(O) 2R 11 , -N(R 11 )S(O) 2R 11 , -S(O) 2N (R 11 ) 2 C1-6 alkyl, C2-6 alkenyl and C2-6 alkynyl that are optionally substituted with one or more substituents independently selected from , -NO2 , =O, =S, =N( R11 ), and -CN; and (iii) 5- to 10-membered heterocyclic rings and C3-10 carbon rings, any of which are Halogen, -OR 11 , -SR 11 , -N(R 11 ) 2 , -C(O)R 11 , -C(O)N(R 11 ) 2 , -N(R 11 )C(O)R 11 , -N (R 11 )S(O) 2 R 11 , -C(O)OR 11 , -OC(O)R 11 , -N(R 11 )C(O)OR 11 , -OC(O)N(R 11 ) 2 , -N(R 11 )C(O)N(R 11 ) 2 , -S(O)R 11 , -S(O) 2 R 11 , -S(O) 2 N(R 11 ) 2 , -NO 2 , =O, =S, =N(R 11 ) and -CN; and C1-6 alkyl, C2-6 alkenyl, and C3-6 alkynyl, any one of which is a halogen, -OR 11 , -SR 11 , -N(R 11 ) 2 , -C(O)R 11 , -C(O)N(R 11 ) 2 , -N(R 11 )C(O)R 11 , -C(O)OR 11 , -OC(O)R 11 , -N(R 11 )C(O)OR 11 , -OC(O)N(R 11 ) 2 , -N(R 11 )C(O)N(R 11 ) 2 , -S(O)R 11 , -S(O) 2R 11 , -N(R 11 )S(O) 2R 11 , -S(O) 2 C1-6 alkyl, C2-6 alkenyl, and C3-6 alkenyl optionally substituted with one or more substituents independently selected from N( R11 ) 2 , -NO2 , =O, =S, =N( R11 ) and -CN; and C 3-10 carbon rings and 4 to 10 heterocyclic rings, any of which is Halogen, -OR 11 , -N(R 11 ) 2 , -C(O)R 11 , -C(O)N(R 11 ) 2 , -N(R 11 )C(O)R 11 , -C(O)OR 11 , -OC(O)R 11 , -NO 2 , =O, =S, =N(R 11 ), -CN; and C1-6 alkyl, C2-6 alkenyl, and C3-6 alkynyl, wherein any one of these is optionally substituted with one or more substituents independently selected from halogen, -OR 11 , -SR 11 , -N(R 11 ) 2 , -C(O)R 11 , -C(O)N(R 11 ) 2 , -N(R 11 )C(O)R 11 , -N(R 11 )S(O ) 2R 11, -C(O)OR 11 , -OC( O )R 11 , -NO 2 , =O, =S, = N (R 11 ) , and -CN . A C3-10 carbon ring and a 4- to 10-membered heterocyclic ring that is optionally substituted with one or more substituents independently selected from A 5- to 10-membered heterocyclic ring and a C3-10 carbon ring that are optionally substituted with one or more substituents independently selected from Selected independently from; q is selected from 1, 2, and 3; m and n are independently selected from 0, 1, 2 and 3, respectively; R2 is independently selected from halogen, C1-4 alkyl, C1-4 haloalkyl, -OR12 , -SR12 , -N( R12 ) 2 , -NO2 , and -CN in each case; R 3 is for each case Halogen, -OR 13 , -SR 13 , -N(R 13 ) 2 , -C(O)R 13 , -C(O)N(R 13 ) 2 , -N(R 13 )C(O)R 13 , -C(O)OR 13 , -OC(O)R 13 , -NO 2 and -CN; and C 1-6 alkyls optionally substituted with one or more substituents independently selected from halogens, -OR 13 , -SR 13 , -N(R 13 ) 2 , -C(O)R 13 , -C(O)N(R 13 ) 2 , -N(R 13 )C(O)R 13 , -C(O)OR 13 , -OC(O)R 13, -NO 2 , =O, =S, =N(R 13 ) , and -CN Selected independently from; p is selected from 0, 1, 2, 3, 4, and 5; R 4 is for each case Halogen, -OR 14 , -SR 14 , -N(R 14 ) 2 , -C(O)R 14 , -C(O)N(R 14 ) 2 , -N(R 14 )C(O)R 14 , -C(O)OR 14 , -OC(O)R 14 , -NO 2 and -CN; and C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, wherein any one of these is optionally substituted with one or more substituents independently selected from halogen, -OR 14 , -SR 14 , -N(R 14 ) 2 , -C(O)R 14 , -C(O)N(R 14 ) 2 , -N(R 14 )C(O)R 14 , -C(O)OR 14 , -OC(O)R 14 , -NO 2 , =O, = S, =N(R 14 ), and -CN . Selected independently from; Two R₄ groups attached to the same atom together form a group selected from =O, =S, and =N ( R₁₄ ); Two R4 groups attached to the same or adjacent atoms form a group selected from quaternary to octary heterocyclic rings and C3-8 carbon rings together with the carbon to which they are attached, and any of the quaternary to octary heterocyclic rings and C3-8 carbon rings are optionally substituted with one or more substituents independently selected from halogen, C1-4 alkyl, C1-4 haloalkyl, -OR14 , -SR14 , -N( R14 ) 2 , -NO2 , and -CN; L is represented as -L 1 -L 2 -L 3 -L 4 -, and L 1 , L 2 , L 3 and L 4 are (a) and (b), respectively: (a) -O-, -N(R 15 )-, -S-, -S(O)-, -S(O) 2 -, -S(O)(NR 15 )-, -N(R 15 )C(O)-, -N(R 15 )C(O)O-, -N(R 15 )S(O) 2 -, -N(R 15 )S(O) 2 N(R 15 )-, -S(O)(NR 15 )N(R 15 )-, -N(R 15 )N(R 15 )-, -(R 15 )NC(O)N(R 15 )- and -(R 15 )NC(O)N(R 15 )N(R 15 )-; and (b) C 1-6 alkylene, C 2-6 alkenylene, C 2-6 alkynylene, C 3-8 carbocyclene and 4- to 8-membered heterocyclene, wherein any of these is optionally substituted with one or more substituents independently selected from halogen, -OR 15 , -SR 15 , =O, =S and -CN . Selected independently from; L2 , L3 , and L4 are each arbitrarily absent; Two or fewer of L1 , L2 , L3 , and L4 are selected from (a), and the selected two are not adjacent; R5 is selected from tetra- to decagonal heterocyclic rings and C3-10 carbon rings, any of which is Halogen, C 1-4 haloalkyl, -OR 16 , -SR 16 , -N(R 16 ) 2 , -C(O)N(R 16 ) 2 , -C(O)OR 16 , -OC(O)R 16 , -N(R 16 )C(O)R 16 , - N(R 16 )S(O) 2 R 16 , -S(O) 2 N(R 16 ) 2 , -N(R 16 )C(O)N(R 16 ) 2 , -N(R 16 )C(O)OR 16 , -OC(O)N(R 16 ) 2 , -S(O)R 16 , -S(O) 2 R 16 , -NO 2 , =O, =S, =N(R 16 ) and -CN; C1-4 alkyl, C2-6 alkenyl, and C2-6 alkynyl, wherein each of these is optionally substituted with one or more substituents independently selected from halogen, C1-4 alkyl, C1-4 haloalkyl, -OR 16 , -SR 16 , -N(R 16 ) 2 , -NO 2 , and -CN; and 4- to 6-membered heterocyclic rings and C3-8 carbon rings, wherein each of these is optionally substituted with one or more substituents independently selected from halogen, C1-4 alkyl, C1-4 haloalkyl, -OR16 , -SR16 , -N( R16 ) 2 , -NO2 , and -CN, 4- to 6-membered heterocyclic rings and C3-8 carbon rings Randomly substituted with one or more substituents independently selected from; R 10 , R 11 , R 12 , R 13 , R 14 , and R 15 are each independently selected from hydrogen, C 1-4 alkyl, C 3-8 carbon ring, quaternary to octary heterocyclic ring, and C 1-4 haloalkyl in each case; R 16 is for cases (iv), (v) and (vi), respectively: (iv) hydrogen; (v) As a C 1-4 alkyl, Halogen, -OR 20 , -SR 20 , -N(R 20 ) 2 , -C(O)R 20 , -C(O)OR 20 , -OC(O)R 20 , -C(O)N(R 20 ) 2 , -N(R 20 )C(O)R 20 , -N(R 20 )C(O)N(R 20 ) 2 , -N(R 20 )C(O)OR 20 , -OC(O)N(R 20 ) 2 , -S(O)R 20 , -S(O) 2 R 20 , -N (R 20 )S(O) 2 R 20 , -S (O) 2 N(R 20 ) 2 , -NO 2 and -CN ; and (vi) C 3-8 carbon rings and 4- to 8-membered heterocyclic rings, wherein any one of these is a halogen, C 1-4 alkyl, C 1-4 haloalkyl, -OR 20 , -SR 20 , -N(R 20 ) 2 , -C(O)R 20 , -C(O)OR 20 , -OC(O)R 20 , -C(O)N(R 20 ) 2 , -N(R 20 )C(O)R 20 , -N(R 20 )C(O)N(R 20 ) 2 , -N(R 20 )C(O)OR 20 , -OC(O)N(R 20 ) 2 , -S(O)R 20 , -S(O) 2R 20 , -N (R 20 )S(O) 2R C3-8 carbon rings and 4- to 8-membered heterocyclic rings optionally substituted with one or more substituents independently selected from 20 , -S (O) 2N ( R20 ) 2 , -NO2 , and -CN C 1-4 alkyl optionally substituted with one or more substituents independently selected from; and (vi) C 3-8 carbon rings and 4- to 8-membered heterocyclic rings, wherein any one of these is a halogen, C 1-4 alkyl, C 1-4 haloalkyl, -OR 20 , -SR 20 , -N(R 20 ) 2 , -C(O)R 20 , -C(O)N(R 20 ) 2 , -C(O)OR 20 , -OC(O)R 20 , -N(R 20 )C(O)R 20 , -N (R 20 )S(O) 2R 20 , -N(R 20 )C(O)N(R 20 ) 2 , -N(R 20 )C(O)OR 20 , -OC(O)N(R 20 ) 2 , -S(O)R 20 , -S(O) 2R C3-8 carbon rings and 4- to 8-membered heterocyclic rings optionally substituted with one or more substituents independently selected from 20 , -NO2 , and -CN Selected independently from; R 20 is independently selected from hydrogen, C 1-4 alkyl, C 1-4 haloalkyl, C 3-8 carbon ring, and 4 to 8 heterocyclic rings in each case.
  20. In paragraph 19, q is a compound or salt of 1.

Description

3H-imidazo[4,5-b]pyridine compound as a non-covalent modifying agent of AKT1 and uses thereof Cross-reference The present invention claims the benefit of U.S. Provisional Application No. 63/517,760 filed on August 4, 2023 and U.S. Provisional Application No. 63/650,658 filed on May 22, 2024, the full text of each of these applications incorporated herein by reference. Serine/threonine protein kinases of the AKT or protein kinase B (PKB) family consist of three highly homologous members: AKT1, AKT2, and AKT3. The AKT protein family is involved in induction pathways that regulate cellular processes including apoptosis, proliferation, differentiation, and metabolism. The AKT1 pathway is the most frequently overregulated signaling pathway in human cancers. Enhanced activation of all isoforms may be associated with tumorigenesis and progression, as demonstrated in breast, ovarian, pancreatic, and prostate cancers (Song et al., 2019). In cancer cells, AKT1 is involved in proliferation and growth, promoting tumor initiation and inhibiting apoptosis, whereas AKT2 regulates cytoskeletal dynamics, facilitating local tissue invasion and metastasis. The role of AKT3 hyperactivation in cancer is presumed to be related to possible cell proliferation stimulation (Hinz et al., Cell Commun Signal 2019, 17(1), 154; Pascual et al., Ann. Oncol. 2019, 30(7), 1051-1060). The expression of these AKT family members is altered in many human malignant carcinomas, including gastric, breast, prostate, ovarian, and pancreatic carcinomas. Although AKT family members are rarely mutated, the most common mutation is AKT1 E17K, which has been reported in 6% to 8% of breast cancers, 2% to 6% of colorectal cancers, and 6% of meningiomas in humans (Yu et al., PLoS One 2015, 10 (10), No. e014047). Therefore, there is a need to develop new therapies to regulate AKT1 and its mutants. Summary of the Invention In one embodiment, the present disclosure provides a compound represented by the structure of formula (I) or a pharmaceutically acceptable salt thereof: In the above formula, Ring B is Selected from; R1 is hydrogen, halogen, -OR10 , -SR10 , -N( R10 ) 2 , -NO2 , and -CN; A C 1-6 alkyl, C 3-8 carbon ring optionally substituted with one or more substituents independently selected from halogen, and halogen, C 1-4 alkyl, C 1-4 haloalkyl, -OR 20 , -SR 20 , -N(R 20 ) 2 , -C(O)R 20 , -C(O)OR 20 , -OC(O)R 20 , -C(O)N(R 20 ) 2 , -N(R 20 )C(O)R 20 , -N(R 20 )C(O)N(R 20 ) 2 , -N(R 20 )C(O)OR 20 , -OC(O)N(R 20 ) 2 , -S(O)R 20 , -S(O) 2R 20 , -N (R 20 )S(O) A C3-8 carbon ring optionally substituted with one or more substituents independently selected from 2 R 20 , - S(O) 2 N(R 20 ) 2 , - NO 2 and - CN, and a quaternary to octary heteroring comprising a halogen, a C 1-4 alkyl, a C 1-4 haloalkyl, - OR 20 , - SR 20 , - N(R 20 ) 2 , - C(O)R 20 , - C(O)OR 20 , - OC(O)R 20 , - C(O)N(R 20 ) 2 , - N(R 20 )C(O)R 20 , - N(R 20 )C(O)N(R 20 ) 2 , - N(R 20 )C(O)OR 20 , - OC(O)N(R 20 ) 2 , Independently selected from quaternary to octary heterocyclic rings that are optionally substituted with one or more substituents independently selected from -S(O ) R 20 , -S (O) 2 R 20 , -N (R 20 )S(O) 2 R 20 , -S(O) 2 N(R 20) 2 , -NO 2 , and -CN; A 1 and A 2 are (i), (ii) and (iii), respectively: (i) hydrogen, halogen, C 1-4 haloalkyl, -OR 11 , -SR 11 , -N(R 11 ) 2 , -C(O)N(R 11 ) 2 , -N(R 11 )C(O)R 11 , -C(O)OR 11 , -OC(O)R 11 , -N(R 11 )C(O)OR 11 , -OC(O)N(R 11 ) 2 , -N(R 11 )C(O)N(R 11 ) 2 , -S(O)R 11 , -S(O) 2R 11 , -N(R 11 )S(O) 2R 11 , -S(O) 2N (R 11 ) 2 , -NO 2 and -CN ; (ii) C 1-6 alkyl, C 2-6 alkenyl and C 2-6 alkynyl, any of which is Halogen, -OR 11 , -SR 11 , -N(R 11 ) 2 , -C(O)N(R 11 ) 2 , -N(R 11 )C(O)R 11 , -C(O)OR 11 , -OC(O)R 11 , -N(R 11 )C(O)OR 11 , -OC(O)N(R 11 ) 2 , -N(R 11 )C(O)N(R 11 ) 2 , -S(O)R 11 , -S(O) 2 R 11 , -N(R 11 )S(O) 2 R 11 , -S(O) 2 N(R 11 ) 2 , -NO 2 , =O, =S, =N(R 11 ) and -CN; and C 3-10 carbon rings and 4 to 10 heterocyclic rings, any of which is Halogen, -OR 11A , -N(R 11A ) 2 , -C(O)R 11A , -C(O)N(R 11A ) 2 , -N(R 11A )C(O)R 11A , -C(O)OR 11A , -OC(O)R 11A , -NO 2 , =O, =S, =N(R 11A ), -CN; and C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, wherein any one of these is optionally substituted with one or more substituents independently selected from -OR 11A , -SR 11A , -N(R 11A ) 2 , -C(O)R 11A , -C(O)N(R 11A ) 2 , -N(R 11A )C(O)R 11A , -N (R 11A )S(O) 2R 11A, -C(O)OR 11A , -OC(O)R 11A , -NO 2 , =O, =S, = N(R 11A ) and -CN . A C3-10 carbon ring and a 4- to 10-membered heterocyclic ring that is optionally substituted with one or more substituents independently selected from C1-6 alkyl, C2-6 alkenyl, and C2-6 alkenyl that are optionally substituted with one or more substituents independently selected from; and (iii) 5- to 10-membered heterocyclic rings and C3-10 carbon rings, any of which are Halogen, -OR 11 , -SR 11 , -N(R 11 ) 2 , -C(O)R 11 , -C(O)N(R 11 ) 2 , -N(R 11 )C(O)R 11 , -N (R 11 )S(O) 2 R 11 , -NS(O) 2 N(R 11 ) 2 , -C(O)OR 11 , -OC(O)R