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KR-102963519-B1 - MTORC1 MODULATORS AND USES THEREOF

KR102963519B1KR 102963519 B1KR102963519 B1KR 102963519B1KR-102963519-B1

Abstract

The disclosure provides compounds and salts exhibiting high selectivity and inhibitory activity against mTORC1, and their use for the treatment of diseases.

Inventors

  • 킨케이드 존

Assignees

  • 에오비안 파마슈티컬스, 인크.

Dates

Publication Date
20260511
Application Date
20210326
Priority Date
20200327

Claims (20)

  1. A compound represented by the structure of chemical formula X, or a pharmaceutically acceptable salt thereof: In the above formula, L is selected from unsubstituted C 2-4 alkylenes; R1 is selected from -S(O)OH, -S(O) 2OH , and -S(O)2C1-6 alkyl , wherein the C1-6 alkyl is optionally substituted with one or more substituents selected from halogens, -OH, -NO2 , =O, and -OC1-6 alkyl; R2 is selected from hydrogen and C1 - C3 alkoxy groups; R3 is selected from hydrogen and C1 - C3 alkoxy groups; R 4 is Selected from; z is 0, 1, 2, 3, 4, or 5; R5 is selected from hydrogen, hydroxy, and optionally substituted C1 - C6 alkoxy groups, wherein the substituent is independently selected in each case from hydroxy, halogen, -CN, -NO2 , C1 - C6 alkoxy groups, 3 to 10-membered heterocycles, and C3-10 carbocycles, wherein the 3 to 10-membered heterocycles and C3-10 carbocycles are each optionally substituted with one or more substituents independently selected from hydroxy, halogen, -CN, -NO2 , C1 - C6 alkyl, C1 - C6 haloalkyl, C1 - C6 hydroxyalkyl, C1 - C6 alkoxy, and C1- C6 alkoxy C1 -C6 alkyl; R 6 and R 7 together Forming; R 25 is independently selected in each case from hydrogen, optionally substituted C 1 -C 6 alkyl, -D-(CH 2 -CH 2 -G) y -V, optionally substituted C 3-20 carbocycle, and optionally substituted 3 to 20 heterocycle, and Here, where R 25 is an arbitrarily substituted C 1 -C 6 alkyl, the substituents on the C 1 -C 6 alkyl phase are independently, in each case, halogen, -OH, -CN, -NO 2 , -NH 2 , =O, =S, -C(O)N(R 31 ) 2 , Selected from -OC(O)N(R 31 ) 2 , -C(O)OR 31 , -P(O)(R 31 ) 2 , -C 1-10 haloalkyl , -OC 1-10 alkyl , -OC 1-10 alkyl-CN , -OC 1-10 alkyl-C(O)OR 31 , C 2-10 alkenyl , C 2-10 alkynyl , C 3-20 carbocycle , and 3 to 20 heterocycles; Here, where R 25 is an arbitrarily substituted C 3-20 carbocycle or an arbitrarily substituted 3 to 20-membered heterocycle, the substituents on the C 3-20 carbocycle and the 3 to 20-membered heterocycle are independently, in each case, a halogen, -OR 31 , -SR 31 , -N(R 31 ) 2 , -C(O)R 31 , -C(O)N(R 31 ) 2 , -N(R 31 )C(O)R 31 , -C(O)OR 31 , -OC(O)R 31 , -S(O)R 31 , -S(O) 2R 31 , Selected from -P(O)(OR 31 ) 2 , -OP(O)(OR 31 ) 2 , -NO 2 , =O, =S, =N(R 31 ), -CN, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, and C 2-6 alkynyl; Here, D is selected from bond and -O-; Each G is independently selected from -O-, -NR32- , -S-, and -SO2- ; Each y is selected from 1-20; Each V is selected from hydrogen and optionally substituted -C1 - C6 alkyl; R 30 is independently hydrogen in each case; selected from C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-10 carbocycle, and 3 to 10-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -OSi(C 1 -C 6 alkyl) 3 , -CN, -NO 2 , -NH 2 , =O, =S, C 1-10 alkyl, -C 1-10 haloalkyl, -OC 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-10 carbocycle, and 3 to 10-membered heterocycle; R' and R" are independently selected from C 1-8 alkyls optionally substituted with one or more substituents independently selected from hydrogen, halogen, -OR 31 , and halogen and -OR 31 in each case; R 31 is independently hydrogen in each case; and is selected from C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-12 carbocycle, and 3 to 12 heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -OSi(C 1 -C 6 alkyl) 3 , -CN, -NO 2 , -NH 2 , =O, = S, C 1-10 alkyl, -C 1-10 haloalkyl, -OC 1-10 alkyl, -OC 1-10 alkyl-OH, C 2-10 alkenyl, C 2-10 alkynyl, C 3-12 carbocycle, and 3 to 12 heterocycle; R 32 is independently hydrogen in each case; and is selected from C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-10 carbocycle, and 3 to 10-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NO 2 , -NH 2 , =O, =S, C 1-10 alkyl, -C 1-10 haloalkyl, -OC 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-10 carbocycle, and 3 to 10-membered heterocycle; Here, the substituents on V are independently assigned in each case. Halogen, -OR 30 , -N(R 30 ) 2 , -SR 30 , -C(O)R 30 , -C(O)N(R 30 ) 2 , -N(R 30 )C(O)R 30 , -C(O)OR 30 , -OC(O)R 30 , -S(O)R 30 , -S(O) 2R 30 , -P(O)(OR 30 ) 2 , -OP(O)(OR 30 ) 2 , -NO 2 , =S, =N(R 30 ), and -CN; Each halogen, -OR 30 , -SR 30 , -N(R 30 ) 2 , -C(O)R 30 , -C(O)N(R 30 ) 2 , -N(R 30 )C(O)R 30 , -C(O)OR 30 , -OC(O)R 30 , -S(O)R 30 , -S(O) 2 R 30 , -P(O)(OR 30 ) 2 , -OP(O)(OR 30 ) 2 , -NO 2 , =O, =S, =N(R 30 ), -CN, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl optionally substituted with one or more substituents independently selected from C 3-10 carbocycles and 3 to 10-membered heterocycles; and Each halogen, -OR 30 , -SR 30 , -N(R 30 ) 2 , -C(O)R 30 , -C(O)N(R 30 ) 2 , -N(R 30 )C(O)R 30 , -C(O)OR 30 , -OC(O)R 30 , -S(O)R 30 , -S(O) 2 R 30 , -P(O)(OR 30 ) 2 , -OP(O)(OR 30 ) 2 , -NO 2 , =O, =S, =N(R 30 ), -CN, C 3-10 carbocycles and 3 to 10 heterocycles optionally substituted with one or more substituents independently selected from C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, and C 2-6 alkynyl. Selected from.
  2. A compound or salt according to claim 1, wherein R1 is selected from -S(O)2OH and -S(O)2C1-6 alkyl , wherein the C1-6 alkyl is optionally substituted with one or more substituents selected from halogen, -OH, -NO2 , =O, and -OC1-6 alkyl.
  3. A compound or salt according to paragraph 2, wherein R1 is selected from -S(O) 2 C1-6 alkyl, wherein the C1-6 alkyl is optionally substituted with one or more substituents selected from halogen, -OH, -NO2 , =O, -OC1-6 alkyl.
  4. A compound or salt according to paragraph 3, wherein R1 is selected from -S(O) 2 C1-6 alkyl, wherein the C1-6 alkyl is an unsubstituted compound or salt.
  5. In paragraph 1, -OLR 1 is and A compound or salt selected from.
  6. In Paragraph 5, -OLR 1 is A compound or salt selected from.
  7. A compound or salt according to claim 1, wherein R 25 of R 4 is selected from hydrogen, optionally substituted C 1 -C 6 alkyl, -D-(CH 2 -CH 2 -G) y -V, optionally substituted 3 to 10-membered heterocycles, and optionally substituted C 3-10 carbocycles.
  8. A compound or salt according to claim 7, wherein the optionally substituted C1 - C6 alkyl of R25 is substituted with one or more substituents selected from C3-20 carbocycle, -OH, and -OC1-10 alkyl.
  9. A compound or salt according to claim 8, wherein the optionally substituted C1 - C6 alkyl of R25 is substituted with one or more substituents selected from -OH and -OC1-10 alkyl.
  10. A compound or salt according to claim 7, wherein D is -O-, G is -O-, y is 1-3, and V is selected from -C1 - C6 alkyl and hydrogen.
  11. A compound or salt according to claim 10, wherein R 25 is selected from hydrogen, and -D-(CH 2 -CH 2 -G) y -V, where D is -O-, G is -O-, y is 1-3, and V is selected from -C 1 -C 6 alkyl and hydrogen.
  12. In paragraph 1, R' and R" are compounds or salts that are independently selected from hydrogen in each case.
  13. In paragraph 1, z is a compound or salt selected from 1, 2, and 3.
  14. In paragraph 1, R 4 is , , , , , , , , and A compound or salt selected from.
  15. In paragraph 1, R 4 is , , , , , , , and A compound or salt selected from.
  16. In paragraph 1, R 4 is , , , and A compound or salt selected from.
  17. In paragraph 1, R 4 is , , , and A compound or salt selected from.
  18. In paragraph 17, R 4 is , and A compound or salt selected from.
  19. In paragraph 1, the compound is , , , , , , , , , , and , or a compound or salt selected from any one of these pharmaceutically acceptable salts.
  20. In paragraph 1, the compound is , , , , , , and , or a compound or salt selected from any one of these pharmaceutically acceptable salts.

Description

MTORC1 Modulatores and Uses Thereof Cross-reference The present application claims the benefit of U.S. provisional patent application No. 63/001,187 filed on March 27, 2020; No. 63/001,144 filed on March 27, 2020; No. 63/001,177 filed on March 27, 2020; No. 63/019,176 filed on May 1, 2020; No. 63/054,763 filed on July 21, 2020; No. 63/054,762 filed on July 21, 2020; and No. 63/054,768 filed on July 21, 2020; the full text of each of these is incorporated herein by reference. The therapeutic potential of rapamycin has been established for many chronic diseases, ranging from Alzheimer's and Parkinson's disease to diabetes and cardiovascular disease. However, the prohibitive safety profile of rapamycin for chronic treatment has limited its use in the treatment of various diseases. Rapamycin, an FDA-approved compound, inhibits mTOR signaling, which induces life extension in many species; however, it can cause side effects such as peripheral edema, hypercholesterolemia, mucosal ulcers, abdominal pain, headache, nausea, diarrhea, pain, constipation, hypertriglyceridemia, hypertension, elevated creatinine, fever, urinary tract infection, anemia, arthralgia, and thrombocytopenia. Given the complications associated with rapamycin, a new drug is needed. In a first aspect, the present disclosure provides a compound represented by the structure of Formula I, or a pharmaceutically acceptable salt thereof: In the above formula, R1 is -OH, Selected from , 3 to 10-membered heterocycles, and C3-10 carbocycles, wherein the 3 to 10-membered heterocycles and C3-10 carbocycles are each optionally substituted with one or more substituents independently selected from hydroxy, halogen, -CN, -NO2 , =O, C1 - C6 alkyl, C1 -C6 haloalkyl , C1 - C6 hydroxyalkyl, C1-C6 alkoxy, C1 - C6 alkoxy, 3 to 10-membered heterocycles, and C3-10 carbocycles, wherein the 3 to 10-membered heterocycles and C3-10 carbocycles are each hydroxy, halogen, -CN , -NO2 , C1- C6 alkyl, C1 - C6 haloalkyl, C1 - C6 hydroxyalkyl, and C1 - C6 arbitrarily substituted with one or more substituents independently selected from the alkoxy; R2 is selected from hydrogen and optionally substituted C1 - C6 alkoxy, wherein the substituent is independently selected in each case from hydroxy, halogen, -CN, -NO2 , C1 - C6 alkoxy, 3 to 10-membered heterocycles, and C3-10 carbocycles, wherein the 3 to 10-membered heterocycles and C3-10 carbocycles are each optionally substituted with one or more substituents independently selected from hydroxy, halogen, -CN, -NO2 , C1 - C6 alkyl, C1 - C6 haloalkyl, C1 - C6 hydroxyalkyl, and C1 - C6 alkoxy; R3 is selected from hydrogen and optionally substituted C1 - C6 alkoxy, wherein the substituent is independently selected in each case from hydroxy, halogen, -CN, -NO2 , C1 - C6 alkoxy, 3 to 10-membered heterocycles, and C3-10 carbocycles, wherein the 3 to 10-membered heterocycles and C3-10 carbocycles are each optionally substituted with one or more substituents independently selected from hydroxy, halogen, -CN, -NO2 , C1 - C6 alkyl, C1 - C6 haloalkyl, C1 - C6 hydroxyalkyl, and C1 - C6 alkoxy; R 4' is and Selected from; R5 is selected from hydrogen, hydroxy, and optionally substituted C1 - C6 alkoxy, wherein the substituent is independently selected in each case from hydroxy, halogen, -CN, -NO2 , C1 - C6 alkoxy, 3 to 10-membered heterocycles, and C3-10 carbocycles, wherein the 3 to 10-membered heterocycles and C3-10 carbocycles are each optionally substituted with one or more substituents independently selected from hydroxy, halogen, -CN, -NO2 , C1 - C6 alkyl, C1 - C6 haloalkyl, C1 - C6 hydroxyalkyl, and C1 - C6 alkoxy; R6 and R7 are each independently selected from hydrogen, hydroxy, and C1 - C6 alkoxy; or R6 and R7 together Forming; R 20 is selected from hydrogen and optionally substituted C 1 -C 6 alkyls; R 21 is selected from optionally substituted C 1 -C 6 alkyls, optionally substituted 3 to 10-membered heterocycles, and optionally substituted C 3-10 carbocycles; R 22 is selected from optionally substituted C 1 -C 6 alkyls, optionally substituted 3 to 10-membered heterocycles, optionally substituted C 3-10 carbocycles, and -P(=O)(R 24 ) 2 ; R 23 is selected from optionally substituted C 1 -C 6 alkyls, optionally substituted 3 to 10-membered heterocycles, and optionally substituted C 3-10 carbocycles; R 24 is an optionally substituted C 1 -C 6 alkyl; R 100 is Hydrogen and -( CH2 - CH2 -G) y -V; and Each halogen, -OR 31 , -SR 31 , -N(R 31 ) 2 , -C(O)R 31 , -C(O)N(R 31 ) 2 , -N(R 31 )C(O)R 31 , -C(O)OR 31 , -OC(O)R 31 , -S(O)R 31 , -S(O) 2 R 31 , -P(O)(OR 31 ) 2 , -OP(O)(OR 31 ) 2 , -NO 2 , -CN , C 3-20 carbocycle and 3 to 20-membered heterocycle, optionally substituted with one or more substituents; and Each halogen, -OR 31 , -SR 31 , -N(R 31 ) 2 , -C(O)R 31 , -C(O)N(R 31 ) 2 , -N(R 31 )C(O)R 31 , -C(O)OR 31 , -OC(O)R 31 , -S(O)R 31 , -S(O) 2 R 31 , -P(O)(OR 31 ) 2 , -OP(O)(OR 31 ) 2 , -NO 2 , =O, =S, =N(R 31 ), -CN, C 1-6 alkyl, C 1-6 alkyl-