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KR-20260068141-A - Conjugated pyridine for the treatment of cancer and other indications

KR20260068141AKR 20260068141 AKR20260068141 AKR 20260068141AKR-20260068141-A

Abstract

Compounds of Formula I'' and Formula II and compositions thereof are provided herein, which can interfere with, interrupt, and/or prevent the interaction between a small GTP degrading enzyme protein and a PI3K protein (e.g., PI3Ka). The present disclosure also provides methods for treating cancer and other indications with these compounds or compositions thereof.

Inventors

  • 쉬, 루이
  • 라이트스톤, 펠리스
  • 양, 위에
  • 왕, 빈
  • 월리스, 일라이
  • 웬, 폴
  • 시만슈, 디렌드라 쿠마르
  • 터너, 데이비드 마이클
  • 치지크, 다니엘 제이.
  • 싱, 스왑닐
  • 예라볼루, 자야수드한 레디

Assignees

  • 테라스, 인크.
  • 로렌스 리버모어 내쇼날 시큐리티, 엘엘시
  • 레이도스 바이오메디칼 리서치, 인크.

Dates

Publication Date
20260513
Application Date
20240807
Priority Date
20230808

Claims (20)

  1. Compound of the following chemical formula I'' I'' or as a salt thereof (e.g., a pharmaceutically acceptable salt), ester, tautomeric isomer, prodrug, amphoteric form, or stereoisomer, in the formula I'' above Ring A is a 9 to 10-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from phenyl, pyridine, or nitrogen, oxygen, and sulfur, and Ring B is a 5 to 6-membered heteroaryl ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5 to 6-membered heterocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 5 to 6-membered carboncyclic ring; and selected from phenyl, Ring C is selected from phenyl; a 9 to 10-membered dicyclic aryl ring; a 5 to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 9 to 10-membered dicyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3 to 7-membered carbon-cyclic ring; a 4 to 7-membered heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 6 to 11-membered dicyclic heterocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and a 12 to 13-membered polycyclic heterocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and Ring D is absent or selected from phenyl; a 5 to 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 9 to 10-membered dicyclic heteroaryl ring having 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur; a 3 to 7-membered carbon-cyclic ring; a 5 to 10-membered dicyclic or polycyclic carbon-cyclic ring; a 4 to 7-membered heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and a 6 to 11-membered dicyclic heterocyclic ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and L is a covalent or divalent linear or branched C1-6 hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced with -N(R)-, -N(R)C(O)-, -C(O)N(R)-, or -C(O)-, and If ring D is absent, L is also absent, and R1 is independently selected from halogen, optionally substituted C1-6 alkyl, cycloalkyl, -CN, -C(O)OR, -C(O) NR2 , -CH2NR2 , -N( R7 ) 2 , -N=S (R7)2 , -SR7 , -( C1-4 alkylene)OR, and -OR7 , wherein the sulfur atom of R1 may be oxidized, R7 is independently selected from hydrogen, optionally substituted C1-6 aliphatic, -( C1-4 alkylene)OR, -( C1-4 alkylene) NR2 , optionally substituted 3 to 6-membered carbon-cyclic rings, optionally substituted 4 to 7-membered heteroaryl rings having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and optionally substituted 4 to 7-membered heterocyclic rings having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, or Two R7 groups form a 4 to 6-membered heterocyclic ring having 0 to 1 additional heteroatom independently selected from nitrogen, oxygen, and sulfur, together with the atom(s) to which they are attached, and R2 is independently selected from halogens and arbitrarily substituted C1-6 aliphatic and -OR, respectively, and R3 is independently selected from oxo, halogen, -CN, -OR, -C(O)R, -C(O)N(R) 2 , -(CH 2 ) x C(O)OR, -(CH 2 ) x C(O)N(R) 2 , -(CH 2 ) x N(R)C(O)R, -(CH 2 ) x Cy, -O(CH 2 ) x Cy, -C(O)Cy, arbitrarily substituted carbon-cyclic rings and arbitrarily substituted C 1-6 aliphatic groups, respectively, and R 4 are each independently and arbitrarily substituted C 1-6 aliphatic, and R5 is absent or optionally substituted C1-6 aliphatic, -C(O) R9 , -( CH2 ) x N(R)C(O) R9 , or -CN, and R9 is an optionally substituted C2-6 alkyl, an optionally substituted C2-6 alkenyl, an optionally substituted C2-6 alkynyl, or a quaternary carbon-cyclic ring, and R6 and R6 ' are connected to an optionally substituted C4-8 hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced with -O- or -N(R)-, and m is 0, 1, 2, or 3, and n is 0, 1, or 2, and p is 0, 1, 2, or 3, and q is 0, 1, or 2, and r is 0 or 1, and x is independently 0, 1, or 2, and R is each independently hydrogen or an optionally substituted C 1-6 aliphatic, and Cy is independently selected from a 5 to 6-membered heteroaryl having 1 to 4 heteroatoms independently selected from phenyl, nitrogen, oxygen, and sulfur, a 3 to 7-membered carbon-cyclic ring, and a 4 to 7-membered heterocyclic ring having 1 to 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur, wherein Cy is substituted with 0 to 3 R8s ; R 8 are compounds independently selected from oxo, halogen, and optionally substituted C 1-6 aliphatic.
  2. In claim 1, the compound is a compound of the following chemical formula IC'. IC' A compound that is a salt of the compound (e.g., a pharmaceutically acceptable salt).
  3. In claim 1, the compound is a compound of the following chemical formula ID'. ID' or as a salt thereof (e.g., a pharmaceutically acceptable salt) in the above formula ID' A compound in which L is a divalent linear or branched C1-6 hydrocarbon chain, wherein one or more methylene units are optionally and independently replaced with -N(R)-, -N(R)C(O)-, -C(O)N(R)-, or -C(O)-.
  4. In claim 1, the compound is a compound of the following chemical formula IE'. IE' A compound that is a salt of the compound (e.g., a pharmaceutically acceptable salt).
  5. A compound according to any one of claims 1 to 4, wherein ring B is a 5-membered heteroaryl ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, and a 5-membered carbon-cyclic ring.
  6. A compound according to claim 5, wherein ring B is a pentagonal heteroaryl ring having 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  7. In paragraph 5, ring B is a compound that is a five-membered carbon-ring.
  8. In any one of paragraphs 1 through 4, the moiety Is , , , , , , , , , , , , , , , , , and A compound selected from.
  9. In paragraph 8, moiety Is , , and A compound selected from.
  10. In paragraph 9, moiety Is and A compound selected from.
  11. In claim 1 or 2, the compound is a compound of the following chemical formula IC3'-a, IC3'-b, IC3'-c, IC3'-d, IC3'-e, IC3'-f, IC3'-g, IC3'-h, IC3'-i, IC3'-j, IC3'-k, IC3'-l, or IC3'-m A compound that is a salt of the compound (e.g., a pharmaceutically acceptable salt).
  12. In claim 11, the compound is a compound of the chemical formula IC3'-a or a salt thereof (e.g., a pharmaceutically acceptable salt), provided that optionally the compound is not a compound selected from Table P1.
  13. In claim 11, the compound is a compound of the chemical formula IC3'-b or a salt thereof (e.g., a pharmaceutically acceptable salt), provided that optionally the compound is not a compound selected from Table P2.
  14. In claim 11, the compound is a compound of the chemical formula IC3'-c, or a salt thereof (e.g., a pharmaceutically acceptable salt).
  15. In paragraph 11, the compound is a compound of the chemical formula IC3'-d or a salt thereof (e.g., a pharmaceutically acceptable salt), provided that optionally the compound is not a compound selected from Table P3.
  16. In paragraph 11, the compound is a compound of the chemical formula IC3'-e or a salt thereof (e.g., a pharmaceutically acceptable salt), provided that optionally the compound is not a compound selected from Table P4.
  17. In claim 11, the compound is a compound of the chemical formula IC3'-f, or a salt thereof (e.g., a pharmaceutically acceptable salt).
  18. In claim 11, the compound is a compound of the chemical formula IC3'-g, or a salt thereof (e.g., a pharmaceutically acceptable salt).
  19. In paragraph 11, the compound is a compound of the chemical formula IC3'-h, or a salt thereof (e.g., a pharmaceutically acceptable salt).
  20. In claim 11, the compound is a compound of the chemical formula IC3'-i, or a salt thereof (e.g., a pharmaceutically acceptable salt).

Description

Conjugated pyridine for the treatment of cancer and other indications Government support The present invention was made with government support pursuant to 75N91019D00024 awarded by the National Institutes of Health and DE-AC52-07NA27344 awarded by the United States Department of Energy. The government holds specific rights to the present invention. Cross-reference of related applications This application claims priority and benefit to U.S. Application No. 63/518,242, filed August 8, 2023 and U.S. Application No. 63/666,479, filed July 1, 2024, the full contents of each of these applications are incorporated herein by reference. It is estimated that more than 600,000 Americans will die from cancer in 2021, which corresponds to over 1,600 deaths per day (Cancer Facts and Figures 2021). The leading causes of death are lung, prostate, and colorectal cancer for men, and lung, breast, and colorectal cancer for women. Nearly one-quarter of all cancer deaths are caused by lung cancer, 82% of which are directly caused by smoking. The five-year survival rate for lung cancer patients is only about 20%. Abnormal activation of phosphoinositide 3-kinase (PI3K) is one of the most frequent oncogenic events across human cancers, and inhibiting it is an attractive therapeutic approach for treating cancer. PI3K regulates numerous cellular activities, including metabolism, proliferation, and migration, by signaling downstream of receptor tyrosine kinase (RTK), G protein-coupled receptor (GPCR), and RAS proteins. The frequency of PI3K carcinogenic events has spurred the development and testing of PI3K inhibitors. To date, most PI3K inhibitors that have entered clinical development are reversible ATP-competitive kinase inhibitors. Despite significant efforts, clinical results for PI3K inhibitor-based therapies for solid tumors have been disappointing, primarily due to unbearable toxicity and drug resistance. The present disclosure provides a novel therapeutic mode for treating cancer and other indications (e.g., cancer and other indications associated with and/or characterized by abnormal activation of PI3K). The present disclosure includes the recognition that a therapeutic agent (e.g., a small molecule, e.g., a compound provided herein) that interferes with, inhibits, and/or prevents the interaction between a PI3K protein (e.g., PI3Kα) and a small GTP degrading enzyme (e.g., Rac1, CDC42, or RAS protein, such as KRAS, NRAS, HRAS, RRAS, RRAS2, MRAS, or RIT1) may be particularly useful for treating cancer and/or other indications (e.g., indications associated with and/or characterized by abnormal activation of PI3K), improving,/or delaying,/or improving or eliminating/or symptoms thereof, or inhibiting them. Although not intended to be bound by theory, the therapeutic agents provided herein (e.g., small molecules, e.g., therapeutic agents comprising the compounds provided herein) may bind to a PI3K protein (e.g., PI3Kα) while having (i) no or minimal binding to a small GTP degrading enzyme (e.g., Rac1, CDC42, or RAS protein, e.g., KRAS, NRAS, HRAS, RRAS, RRAS2, MRAS, or RIT1) and/or (ii) no substantial effect on the kinase activity of the PI3K protein (e.g., PI3Kα). In some embodiments, such therapeutic agents may provide benefits, such as improved efficacy or reduced side effects, compared to, for example, ATP-competitive PI3K kinase inhibitors, as described herein. For example, in some embodiments, such therapeutic agents may reduce the incidence of hyperglycemia and/or hyperinsulinemia compared to PI3K kinase inhibitors. The present disclosure provides a compound (including any available form, e.g., salt form) useful for interfering with, inhibiting, and/or preventing interactions between a PI3K protein (e.g., PI3Kα) and a small GTP degrading enzyme (e.g., Rac1, CDC42, or RAS protein, e.g., KRAS, NRAS, HRAS, RRAS, RRAS2, MRAS, or RIT1). In some embodiments, the present disclosure provides a compound capable of binding to a PI3Kα protein such that (i) interactions between a small GTP degrading enzyme (e.g., Rac1, CDC42, or RAS protein, e.g., KRAS, NRAS, HRAS, RRAS, RRAS2, MRAS, or RIT1) and the PI3Kα protein are interfering with, inhibiting, and/or prevented, or (ii) the phosphorylation activity of the PI3Kα protein is not inhibited. In some embodiments, such compounds are useful for treating cancer or other indications as described herein. In some embodiments, the present disclosure relates to a compound of the following formula I''. I" or provide a salt thereof (e.g., a pharmaceutically acceptable salt), wherein ring A, ring B, ring C, ring D, L, R 1 , R 2 , R 3 , R 4 , R 5 , R 6, R 6 ' , m, n, p, q, and r are as defined herein. In some embodiments, the present disclosure relates to a compound of the following formula I'. I' or provide a salt thereof (e.g., a pharmaceutically acceptable salt), wherein ring A, ring B, ring C, ring D, L, R 1 , R 2 , R 3 , R 4 , R 5 , R 6, R 6 ' , m, n, p, q, and r are as defined herein. In som