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CN-121986101-A - 3H-imidazo [4,5-b ] pyridine compounds as non-covalent modifiers of AKT1 and uses thereof

CN121986101ACN 121986101 ACN121986101 ACN 121986101ACN-121986101-A

Abstract

Provided herein are non-covalent modifiers of AKT1 of formulA (I), (II-A), (III-A), (III-B), (IV-A), (IV-B), (V-A), (V-B), (VI-A) or (VI-B), and pharmaceutical compositions thereof. In some embodiments, the present disclosure provides methods of modulating wild-type AKT1 using compounds or salts of formulas (I), (II-A), (III-A), (III-B), (IV-A), (IV-B), (V-A), (V-B), (VI-A) or (VI-B) and pharmaceutical compositions thereof.

Inventors

  • CHU HANG
  • YANG JIANCHENG
  • Solomon H. Reisberg
  • Adam Ridelik
  • Jordan D. Jiaruili
  • Brian P. Bestwitt
  • TIMOTHY R. HANSEN
  • PETER A. THOMPSON

Assignees

  • 特瑞莫托生物科学股份有限公司

Dates

Publication Date
20260505
Application Date
20240802
Priority Date
20230804

Claims (20)

  1. 1. A compound represented by the structure of formula (I): (I), or a pharmaceutically acceptable salt thereof, wherein: Ring B is selected from: And ; R 1 is selected from the group consisting of hydrogen, halogen, -OR 10 、-SR 10 、-N(R 10 ) 2 、-NO 2 , -CN, an optionally substituted C 3-8 carbocycle, an optionally substituted 4-to 8-membered heterocycle, and an optionally substituted C 1-6 alkyl, each of which is optionally substituted with one OR more substituents independently selected from the group consisting of halogen, -OR 10 、-SR 10 、-N(R 10 ) 2 、-NO 2 , and-CN; Each of a 1 and a 2 is independently selected from (i), (ii) and (iii): (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) 2 R 11 、-N(R 11 )S(O) 2 R 11 、-S(O) 2 N(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 optionally substituted with one or more substituents independently selected from the group consisting of: 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 A C 3-10 carbocycle and a 4-to 10-membered heterocycle, any of which is optionally substituted with one or more substituents independently selected from the group consisting of: 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; C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl, any of which is optionally substituted with one or more substituents independently selected from halogen 、-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) 2 R 11A 、-C(O)OR 11A 、-OC(O)R 11A 、-NO 2 、=O、=S、=N(R 11A ) and-CN, and (Iii) A 5-to 10-membered heterocycle and a C 3-10 -carbocycle, any of which is optionally substituted with one or more substituents independently selected from the group consisting of: 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 C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl, any of which 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 、-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 A C 3-10 carbocycle and a 4-to 10-membered heterocycle, any of which is optionally substituted with one or more substituents independently selected from the group consisting of: 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; C 1-6 alkyl, C 2-6 alkenyl, C 3-6 alkynyl, C 3-8 carbocycle, or 4-to 8-membered heterocycle, any of which 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) 2 R 11 、-C(O)OR 11 、-OC(O)R 11 、-NO 2 、=O、=S、=N(R 11 ) and-CN; q is selected from 1, 2 and 3; m and n are each independently selected from 0,1, 2 and 3; R 2 is independently selected in each occurrence from halogen, C 1-4 alkyl, C 1-4 haloalkyl, -OR 12 、-SR 12 、-N(R 12 ) 2 、-NO 2 , and-CN; R 3 is independently selected in each occurrence from: 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 alkyl optionally substituted with one or more substituents independently selected from 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 、=O、=S、=N(R 13 ) and-CN; p is selected from 0,1, 2,3, 4 and 5; R 4 is independently selected in each occurrence 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 and-CN, and C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, any of which 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, or Two R 4 attached to the same atom together form a group selected from =o, =s and =n (R 14 ), or Two R 4 attached to the same atom OR adjacent atoms together with the carbon to which they are attached form a group selected from the group consisting of a 4-to 8-membered heterocyclic ring and a C 3-8 carbocyclic ring, any of which is optionally substituted with one OR more substituents independently selected from the group consisting of halogen, C 1-4 alkyl, C 1-4 haloalkyl, -OR 14 、-SR 14 、-N(R 14 ) 2 、-NO 2 and-CN; L is represented by-L 1 -L 2 -L 3 -L 4 -, wherein L 1 、L 2 、L 3 and L 4 are each independently selected from (a) and (b): (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 carbocyclylene, and 4-to 8-membered heterocyclylene, any of which is optionally substituted with one OR more substituents independently selected from halogen, -OR 15 、-SR 15 , =o, =s, and-CN; wherein L 1 、L 2 、L 3 and L 4 are each optionally absent; Wherein no more than two of L 1 、L 2 、L 3 and L 4 are selected from (a) and the two selected are not adjacent; R 5 is selected from a 4-to 10-membered heterocycle and a C 3-10 carbocycle, any of which is optionally substituted with one or more substituents independently selected from: 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; C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl, each of which is optionally substituted with one OR more substituents independently selected from halogen, -OR 16 、-SR 16 、-N(R 16 ) 2 、-NO 2 , and-CN, and 4-To 6-membered heterocycles and C 3-8 carbocycles, each of which is optionally substituted with one OR more substituents independently selected from halogen, C 1-4 alkyl, C 1-4 haloalkyl, -OR 16 、-SR 16 、-N(R 16 ) 2 、-NO 2 and-CN; R 10 、R 11 、R 11A 、R 12 、R 13 、R 14 and R 15 are each independently at each occurrence selected from the group consisting of hydrogen, C 1-4 alkyl, C 3-8 carbocycle, 4-to 8-membered heterocycle, and C 1-4 haloalkyl; R 16 is independently selected at each occurrence from (iv), (v) and (vi): (iv) Hydrogen; (v) A C 1-4 alkyl group, wherein the C 1-4 alkyl group is optionally substituted with one or more substituents independently selected from the group consisting of: 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 A C 3-8 carbocycle and a 4-to 8-membered heterocycle, any of which is optionally substituted with one or more substituents independently selected from 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) 2 R 20 、-N(R 20 )S(O) 2 R 20 、-S(O) 2 N(R 20 ) 2 、-NO 2 and-CN, and (Vi) A C 3-8 carbocycle and a 4-to 8-membered heterocycle, any of which is optionally substituted with one or more substituents independently selected from 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) 2 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 、-NO 2 、-CN, and C 3-8 carbocycle or a 4-to 8-membered heterocycle, any of which C 3-8 carbocycle or a 4-to 8-membered heterocycle is optionally further substituted with one or more substituents independently selected from 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) 2 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 、-NO 2 , and-CN, and R 20 is independently at each occurrence selected from hydrogen, C 1-4 alkyl, C 1-4 haloalkyl, C 3-8 carbocycle, and 4-to 8-membered heterocycle.
  2. 2. The compound or salt of claim 1, wherein a 2 is selected from C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl, each of which is optionally substituted with one or more substituents independently selected from: 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 and-NO 2 , -CN, and A C 3-10 carbocycle and a 4-to 10-membered heterocycle, any of which is optionally substituted with one or more substituents independently selected from the group consisting of: 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 C 1-6 alkyl, C 2-6 alkenyl, and C 3-6 alkynyl, any of which 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) 2 R 11A 、-NO 2 、=O and-CN.
  3. 3. A compound or salt according to claim 1 or claim 2, wherein a 2 is selected from C 2-6 alkynyl optionally substituted with one or more substituents independently selected from: 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 A C 3-10 carbocycle and a 4-to 10-membered heterocycle, any of which is optionally substituted with one or more substituents independently selected from the group consisting of: 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 C 1-6 alkyl, C 2-6 alkenyl, and C 3-6 alkynyl, any of which 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) 2 R 11A 、-NO 2 、=O and-CN.
  4. 4. The compound OR salt of any one of claims 1-3, wherein a 2 is C 2-6 alkynyl optionally substituted with one OR more substituents independently selected from halogen, -OR 11 、-N(R 11 ) 2 、-NO 2 、-CN;C 3-10 carbocycle and 4-to 10-membered heterocycle, each of which is optionally substituted with one OR more substituents independently selected from halogen, -OR 11A 、-N(R 11A ) 2 、-NO 2 , =o and-CN, and C 1-6 alkyl optionally substituted with one OR more substituents independently selected from halogen, -OR 11A 、-N(R 11A ) 2 、-NO 2 , =o and-CN.
  5. 5. The compound or salt of claim 4 wherein A 2 is C 2-6 alkynyl optionally substituted with one or more substituents independently selected from C 3-6 carbocycle and 4-to 6-membered heterocycle, each of which 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 、-NO 2 、=O and-CN, and C 1-6 alkyl 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. 6. The compound OR salt of claim 4 wherein A 2 is C 2-6 alkynyl optionally substituted with one OR more substituents independently selected from C 3-6 carbocycle and 4-to 6-membered heterocycle, any of which 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 、-NO 2 、=O and-CN, and C 1-6 alkyl optionally substituted with one OR more substituents independently selected from halogen, -OR 11A and-N (R 11A ) 2 .
  7. 7. The compound OR salt of claim 6, wherein a 2 is C 2-6 alkynyl optionally substituted with cyclopropyl, cyclopentyl, oxetanyl, azetidinyl, and oxazolyl, any of which 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 、-NO 2 、=O、-CN; and C 1-6 alkyl, which is optionally substituted with one OR more substituents independently selected from halogen, -OR 11A , and-N (R 11A ) 2 .
  8. 8. The compound or salt of claim 7, wherein a 2 is selected from 、 、 、 、 、 And 。
  9. 9. The compound or salt of any one of claims 1-8, wherein neither L 1 、L 2 、L 3 nor L 4 is present.
  10. 10. The compound or salt of any one of claims 1-9, wherein a 2 is Wherein ring B 1 is a C 3-8 carbocycle or a 4-to 8-membered heterocycle, any of which is optionally substituted with one or more substituents independently selected from 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) 2 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 、-NO 2 and-CN.
  11. 11. The compound or salt of any one of claims 1-10, wherein R 5 is selected from a 4-to 10-membered heterocycle and a C 3-10 carbocycle, any of which is optionally substituted with one or more substituents independently selected from: 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; C 1-4 alkyl optionally substituted with one OR more substituents independently selected from halogen, C 1-4 alkyl, C 1-4 haloalkyl, -OR 16 、-SR 16 、-N(R 16 ) 2 、-NO 2 , and-CN, and 4-To 6-membered heterocycles and C 3-8 carbocycles, each of which is optionally substituted with one OR more substituents independently selected from halogen, C 1-4 alkyl, C 1-4 haloalkyl, -OR 16 、-SR 16 、-N(R 16 ) 2 、-NO 2 and-CN.
  12. 12. The compound or salt of claim 11, wherein R 5 is a 4-to 10-membered heterocycle optionally substituted with one or more substituents independently selected from: 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; C 1-4 alkyl optionally substituted with one OR more substituents independently selected from halogen, C 1-4 alkyl, C 1-4 haloalkyl, -OR 16 、-SR 16 、-N(R 16 ) 2 、-NO 2 , and-CN, and 4-To 6-membered heterocycles and C 3-8 carbocycles, each of which is optionally substituted with one OR more substituents independently selected from halogen, C 1-4 alkyl, C 1-4 haloalkyl, -OR 16 、-SR 16 、-N(R 16 ) 2 、-NO 2 and-CN.
  13. 13. The compound or salt of claim 12, wherein R 5 is a 4-to 10-membered heterocycle optionally substituted with one or more substituents independently selected from: 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; C 1-4 alkyl optionally substituted with one OR more substituents independently selected from halogen, C 1-4 alkyl, C 1-4 haloalkyl, -OR 16 、-SR 16 、-N(R 16 ) 2 、-NO 2 , and-CN.
  14. 14. A compound or salt according to claim 13, wherein 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, 1H-benzo [ d ] [1,2,3] triazolyl, each of which is optionally substituted with one or more substituents independently selected from: 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; C 1-4 alkyl optionally substituted with one OR more substituents independently selected from halogen, C 1-4 alkyl, C 1-4 haloalkyl, -OR 16 、-SR 16 、-N(R 16 ) 2 、-NO 2 , and-CN.
  15. 15. The compound or salt of claim 14, wherein R 5 is selected from 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 And 。
  16. 16. The compound or salt of any one of claims 1-15, wherein ring B is 。
  17. 17. The compound or salt of claim 16, wherein ring B is selected from And 。
  18. 18. The compound or salt of any one of claims 1-15, wherein ring B is 。
  19. 19. The compound or salt of claim 1, wherein the structure of formula (I) is represented by the structure of formula (II): (II), or a pharmaceutically acceptable salt thereof, wherein: R 1 is selected from the group consisting of hydrogen, halogen, -OR 10 、-SR 10 、-N(R 10 ) 2 、-NO 2 , and-CN, and C 1-6 alkyl optionally substituted with one OR more substituents independently selected from the group consisting of halogen, -OR 10 、-SR 10 、-N(R 10 ) 2 、-NO 2 , and-CN; Each of a 1 and a 2 is independently selected from (i), (ii) and (iii): (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) 2 R 11 、-N(R 11 )S(O) 2 R 11 、-S(O) 2 N(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 optionally substituted with one or more substituents independently selected from 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 (Iii) A 5-to 10-membered heterocycle and a C 3-10 -carbocycle, any of which is optionally substituted with one or more substituents independently selected from the group consisting of: 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 C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl, any of which 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 、-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 A C 3-10 carbocycle and a 4-to 10-membered heterocycle, any of which is optionally substituted with one or more substituents independently selected from the group consisting of: 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; C 1-6 alkyl, C 2-6 alkenyl, and C 3-6 alkynyl, any of which 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) 2 R 11 、-C(O)OR 11 、-OC(O)R 11 、-NO 2 、=O、=S、=N(R 11 ) and-CN; q is selected from 1, 2 and 3; m and n are each independently selected from 0,1, 2 and 3; R 2 is independently selected in each occurrence from halogen, C 1-4 alkyl, C 1-4 haloalkyl, -OR 12 、-SR 12 、-N(R 12 ) 2 、-NO 2 , and-CN; R 3 is independently selected in each occurrence from: 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 alkyl optionally substituted with one or more substituents independently selected from 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 、=O、=S、=N(R 13 ) and-CN; p is selected from 0,1, 2,3, 4 and 5; R 4 is independently selected in each occurrence 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 and-CN, and C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, any of which 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, or Two R 4 attached to the same atom together form a group selected from =o, =s and =n (R 14 ), or Two R 4 attached to the same atom OR adjacent atoms together with the carbon to which they are attached form a group selected from the group consisting of a 4-to 8-membered heterocyclic ring and a C 3-8 carbocyclic ring, any of which is optionally substituted with one OR more substituents independently selected from the group consisting of halogen, C 1-4 alkyl, C 1-4 haloalkyl, -OR 14 、-SR 14 、-N(R 14 ) 2 、-NO 2 and-CN; L is represented by-L 1 -L 2 -L 3 -L 4 -, wherein L 1 、L 2 、L 3 and L 4 are each independently selected from (a) and (b): (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 carbocyclylene, and 4-to 8-membered heterocyclylene, any of which is optionally substituted with one OR more substituents independently selected from halogen, -OR 15 、-SR 15 , =o, =s, and-CN; Wherein L 2 、L 3 and L 4 are each optionally absent; Wherein no more than two of L 1 、L 2 、L 3 and L 4 are selected from (a) and the two selected are not adjacent; R 5 is selected from a 4-to 10-membered heterocycle and a C 3-10 carbocycle, any of which is optionally substituted with one or more substituents independently selected from: 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; c 1-4 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl, each of which is optionally substituted with one OR more substituents independently selected from halogen, C 1-4 alkyl, C 1-4 haloalkyl, -OR 16 、-SR 16 、-N(R 16 ) 2 、-NO 2 , and-CN, and 4-To 6-membered heterocycles and C 3-8 carbocycles, each of which is optionally substituted with one OR more substituents independently selected from halogen, C 1-4 alkyl, C 1-4 haloalkyl, -OR 16 、-SR 16 、-N(R 16 ) 2 、-NO 2 and-CN; R 10 、R 11 、R 12 、R 13 、R 14 and R 15 are each independently at each occurrence selected from the group consisting of hydrogen, C 1-4 alkyl, C 3-8 carbocycle, 4-to 8-membered heterocycle, and C 1-4 haloalkyl; R 16 is independently selected at each occurrence from (iv), (v) and (vi): (iv) Hydrogen; (v) A C 1-4 alkyl group, wherein the C 1-4 alkyl group is optionally substituted with one or more substituents independently selected from the group consisting of: 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 A C 3-8 carbocycle and a 4-to 8-membered heterocycle, any of which is optionally substituted with one or more substituents independently selected from 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) 2 R 20 、-N(R 20 )S(O) 2 R 20 、-S(O) 2 N(R 20 ) 2 、-NO 2 and-CN, and (Vi) A C 3-8 carbocycle and a 4-to 8-membered heterocycle, any of which is optionally substituted with one or more substituents independently selected from 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) 2 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 、-NO 2 and-CN, and R 20 is independently at each occurrence selected from hydrogen, C 1-4 alkyl, C 1-4 haloalkyl, C 3-8 carbocycle, and 4-to 8-membered heterocycle.
  20. 20. The compound or salt of claim 19, wherein q is 1.

Description

3H-imidazo [4,5-b ] pyridine compounds as non-covalent modifiers of AKT1 and uses thereof Cross reference The application claims the benefit of U.S. provisional application Ser. Nos. 63/517,760 and 63/650,658, each filed on 8-4-2023 and 22-5-2024, each of which is hereby incorporated by reference in its entirety. Background The AKT or Protein Kinase B (PKB) family of serine/threonine protein kinases consists of 3 highly homologous members AKT1, AKT2 and AKT 3. The AKT protein family is involved in signal transduction pathways that regulate cellular processes, including apoptosis, proliferation, differentiation, and metabolism. The AKT1 pathway is the most deregulated signaling pathway in human cancers. The enhanced activation of all isoforms may be associated with tumor development and progression and has been demonstrated in breast, ovarian, pancreatic and prostate cancers, as well as other cancers (Song et al 2019). In cancer cells, AKT1 is involved in proliferation and growth, promoting tumor initiation and inhibiting apoptosis, while AKT2 regulates cytoskeletal dynamics, favoring local tissue invasion and metastasis. It is hypothesized that the role of AKT3 over-activation in cancer is associated with the potential to stimulate cell proliferation (Hinz et al Cell Commun Signal 2019, 17 (1), 154; pasceual et al ann. Oncol. 2019, 30 (7), 1051-1060). The expression of these AKT family members is altered in many human malignancies, including gastric, breast, prostate, ovarian and pancreatic cancers. However, few AKT family members mutate, most commonly AKT 1E 17K, which has been reported in 6% -8% of breast cancers, 2% -6% of colorectal cancers and 6% of meningiomas in humans (Yu et al, PLoS One 2015, 10 (10), stage E0140479). Thus, there is a need to develop novel therapies for modulating AKT1 and mutants thereof. Disclosure of Invention In one aspect, the present disclosure provides compounds represented by the structure of formula (I): (I), or a pharmaceutically acceptable salt thereof, wherein: Ring B is selected from: And ; R 1 is selected from the group consisting of hydrogen, halogen, -OR 10、-SR10、-N(R10)2、-NO2, and-CN, and C 1-6 alkyl optionally substituted with one OR more substituents independently selected from the group consisting of halogen, C 3-8 carbocycle (optionally substituted with one OR more substituents independently selected from the group consisting of halogen, C 1-4 alkyl, C 1-4 haloalkyl 、-OR20、-SR20、-N(R20)2、-C(O)R20、-C(O)OR20、-OC(O)R20、-C(O)N(R20)2、-N(R20)C(O)R20、-N(R20)C(O)N(R20)2、-N(R20)C(O)OR20、-OC(O)N(R20)2、-S(O)R20、-S(O)2R20、-N(R20)S(O)2R20、-S(O)2N(R20)2、-NO2, and-CN), 4-to 8-membered heterocycle (optionally substituted with one OR more substituents independently selected from the group consisting of halogen, C 1-4 alkyl, C 1-4 haloalkyl 、-OR20、-SR20、-N(R20)2、-C(O)R20、-C(O)OR20、-OC(O)R20、-C(O)N(R20)2、-N(R20)C(O)R20、-N(R20)C(O)N(R20)2、-N(R20)C(O)OR20、-OC(O)N(R20)2、-S(O)R20、-S(O)2R20、-N(R20)S(O)2R20、-S(O)2N(R20)2、-NO2, and-CN); Each of a 1 and a 2 is independently selected from (i), (ii) and (iii): (i) Hydrogen, halogen, C 1-4 haloalkyl 、-OR11、-SR11、-N(R11)2、-C(O)N(R11)2、-N(R11)C(O)R11、-C(O)OR11、-OC(O)R11、-N(R11)C(O)OR11、-OC(O)N(R11)2、-N(R11)C(O)N(R11)2、-S(O)R11、-S(O)2R11、-N(R11)S(O)2R11、-S(O)2N(R11)2、-NO2 and-CN; (ii) C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl, any of which is optionally substituted with one or more substituents independently selected from the group consisting of: halogen 、-OR11、-SR11、-N(R11)2、-C(O)N(R11)2、-N(R11)C(O)R11、-C(O)OR11、-OC(O)R11、-N(R11)C(O)OR11、-OC(O)N(R11)2、-N(R11)C(O)N(R11)2、-S(O)R11、-S(O)2R11、-N(R11)S(O)2R11、-S(O)2N(R11)2、-NO2、=O、=S、=N(R11) and-CN, and A C 3-10 carbocycle and a 4-to 10-membered heterocycle, any of which is optionally substituted with one or more substituents independently selected from the group consisting of: Halogen 、-OR11A、-N(R11A)2、-C(O)R11A、-C(O)N(R11A)2、-N(R11A)C(O)R11A、-C(O)OR11A、-OC(O)R11A、-NO2、=O、=S、=N(R11A)、-CN; C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl, any of which is optionally substituted with one or more substituents independently selected from halogen 、-OR11A、-SR11A、-N(R11A)2、-C(O)R11A、-C(O)N(R11A)2、-N(R11A)C(O)R11A、-N(R11A)S(O)2R11A、-C(O)OR11A、-OC(O)R11A、-NO2、=O、=S、=N(R11A) and-CN, and (Iii) A 5-to 10-membered heterocycle and a C 3-10 -carbocycle, any of which is optionally substituted with one or more substituents independently selected from the group consisting of: halogen 、-OR11、-SR11、-N(R11)2、-C(O)R11、-C(O)N(R11)2、-N(R11)C(O)R11、-N(R11)S(O)2R11、-NS(O)2N(R11)2、-C(O)OR11、-OC(O)R11、-N(R11)C(O)OR11、-OC(O)N(R11)2、-N(R11)C(O)N(R11)2、-S(O)R11、-S(O)2R11、-S(O)2N(R11)2、-NO2、=O、=S、=N(R11) and-CN, and C 1-6 alkyl, C 2-6 alkenyl, and C 3-6 alkynyl, any of which is optionally substituted with one or more substituents independently selected from halogen 、-OR11、-SR11、-N(R11)2、-C(O)R11、-C(O)N(R11)2、-N(R11)C(O)R11、-C(O)OR11、-OC(O)R11、-N(R11)C(O)OR11、-OC(O)N(R11)2、-N(R11)C(O)N(R11)2、-S(O)R11、-S(O)2R11、-N(R11)S(O)2R11、-