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CN-122029160-A - Method for preparing PI3K inhibitor

CN122029160ACN 122029160 ACN122029160 ACN 122029160ACN-122029160-A

Abstract

The present disclosure provides methods for preparing compounds of formula (I), such as (R) -1- (2-aminopyrimidin-5-yl) -3- (1- (5, 7-difluoro-3-methylbenzofuran-2-yl) -2, 2-trifluoroethyl) urea (compound 1), and salts and/or solvates thereof, that inhibit phosphatidylinositol 4, 5-bisphosphate 3-kinase (PI 3K) subtype α (PI 3K α).

Inventors

  • D. Little Saint Jean
  • A.D. JONES

Assignees

  • 蝎子疗法股份有限公司

Dates

Publication Date
20260512
Application Date
20240814
Priority Date
20230815

Claims (20)

  1. 1. A process for preparing a compound of formula (I) or a salt and/or solvate thereof: (I); comprising reacting a compound of formula (I-I): And (3) with (I) Carbonyl equivalent, and (Ii) Compounds of formula (I-ii) Contacting to form a compound of formula (I), wherein: z is O or NR x ; R x is hydrogen, C1-C6 alkyl or C3-C6 cycloalkyl; each R 1 is independently selected from halogen, hydroxy, cyano, C1-C6 alkyl optionally substituted with hydroxy, and C3-C6 cycloalkyl; m is 0, 1, 2 or 3; r 2 is halogen, hydroxy, C1-C6 alkyl optionally substituted with hydroxy, C1-C6 haloalkyl, C3-C6 cycloalkyl optionally substituted with 1 or 2 fluoro; R 3 is C1-C6 alkyl, C1-C6 haloalkyl or C3-C6 cycloalkyl optionally substituted with 1 or 2 substituents independently selected from fluoro and C1-C6 alkyl; ring A is a 6-10 membered aryl, C3-C8 cycloalkyl, 5-10 membered heteroaryl or 4-10 membered heterocyclyl; Each R 4 is independently selected from: (i) A halogen atom, (Ii) C1-C6 alkyl optionally substituted by 1 or 2 hydroxy groups or-NR A R B , (Iii) C1-C6 alkoxy optionally substituted with 1-2 substituents independently selected from hydroxy and C3-C6 cycloalkyl, (Iv) A C1-C6 haloalkyl group, (V) A hydroxyl group, (Vi) A cyano group, (vii) -CO 2 H, (viii) -NR A R B , (ix) =NR A2 , (x) -C(=O)NR C R D , (xi) -SO 2 (NR E R F ), (Xii) SO 2 (C1-C6 alkyl), (Xiii) S (=o) (=nh) (C1-C6 alkyl), (Xiv) C (=o) (C1-C6 alkyl), (Xv) CO 2 (C1-C6 alkyl), (Xvi) 5-6 membered heteroaryl optionally substituted by C1-C6 alkyl, (Xvii) A 3-9 membered heterocyclyl optionally substituted with 1 or 2 independently selected R G , and (Xviii) 3-6 membered cycloalkyl optionally substituted with 1 or 2 independently selected R G ; n is 0, 1 or 2; Each R A 、R A1 、R B 、R B1 、R C 、R C1 、R D 、R D1 、R E and R F is independently (I) The hydrogen is used to produce a hydrogen gas, (Ii) A hydroxyl group, (Iii) A 4-to 6-membered heterocyclic group, (Iv) A C1-C6 haloalkyl group, (V) C (=o) (C1-C6 alkyl), (Vi) C (=O) O (C1-C6 alkyl), (Vii) SO 2 (C1-C6 alkyl), (Viii) 3-6 membered cycloalkyl optionally substituted with hydroxy, or (Ix) C1-C6 alkyl optionally substituted with 1-2 substituents independently selected from hydroxy, -C (=O) NR B2 R C2 -6 membered heteroaryl, 3-6 membered cycloalkyl, -SO 2 (C1-C6 alkyl), -CO 2 H and-SO 2 (NH 2 , or R C and R D , together with the nitrogen atom to which they are attached, form a 4-10 membered heterocyclyl optionally substituted with 1-2 substituents independently selected from hydroxy, halogen, -C (=O) NR B1 R C1 、-SO 2 (C1-C6 alkyl), -CO 2 H, C1-C6 alkyl optionally substituted with hydroxy, C1-C6 alkoxy and C1-C6 haloalkoxy; Each R A2 、R B2 and R C2 is independently hydrogen or C1-C6 alkyl, and Each R G is independently selected from the group consisting of fluoro, cyano, hydroxy, C1-C6 alkyl optionally substituted with hydroxy, C1-C6 alkoxy, -NR A1 R B1 、=NR A2 、-C(=O)NR C1 R D1 、-CO 2 (C1-C6 alkyl), C1-C6 haloalkyl, C3-C6 cycloalkyl, C1-C6 haloalkoxy, -SO 2 (C1-C6 alkyl), and-CO 2 H.
  2. 2. A compound having the following structure is prepared 1 or a salt and/or solvate thereof: (1); Which comprises the steps of And (3) with (I) Carbonyl equivalent, and (Ii) Has the structure of Pyrimidine-2, 5-diamine; Contact to form compound 1.
  3. 3. The method of claim 2, wherein the method comprises preparing as follows Make (S) the Contact with acid to form 。
  4. 4. A process according to claim 3, wherein the process comprises preparing as follows Make (S) the Contact with a trifluoromethylating agent to form Wherein R '' is a C1-C6 alkyl group.
  5. 5. The method of claim 3 or 4, wherein the method comprises by causing And (3) with Contact to prepare 。
  6. 6. The method of claim 5, wherein the method comprises by causing Contact with acid to prepare 。
  7. 7. The method of claim 6, wherein the method comprises by causing And (3) with Contact to prepare Wherein LG is selected from chloro, bromo, iodo and trifluoromethanesulfonyl.
  8. 8. The method of claim 5, wherein the method comprises by causing Contact with acid to prepare Wherein Hal is selected from the group consisting of chloro, bromo, iodo and trifluoromethanesulfonyl.
  9. 9. The method of claim 8, wherein the method comprises by causing And (3) with Contact to prepare 。
  10. 10. A compound having the following structure is prepared 1 or a salt and/or solvate thereof: (1); Which comprises the steps of To form compound 1.
  11. 11. The method of claim 10, wherein the method comprises the steps of The reaction to form compound 1 comprises reacting And (3) with Contact to form Wherein R '' is a C1-C6 alkyl group.
  12. 12. The method of claim 11, wherein the method comprises the steps of The reaction to form compound 1 comprises reacting Contact with a trifluoromethylating agent to form Wherein R '' is a C1-C6 alkyl group.
  13. 13. The method of claim 12, wherein the method comprises the steps of The reaction to form compound 1 comprises reacting Contact with acid to form 。
  14. 14. The method of claim 10, wherein the method comprises the steps of The reaction to form compound 1 comprises reacting And (3) with (I) Carbonyl equivalent, and (Ii) Has the structure of Pyrimidine-2, 5-diamine; Contact to form compound 1.
  15. 15. A compound having the following structure is prepared 1 or a salt and/or solvate thereof: (1); Which comprises the steps of And (3) with Contact to form Wherein R '' is a C1-C6 alkyl group, and Make the following steps To form compound 1.
  16. 16. The method of claim 15, wherein the method comprises the steps of The reaction to form compound 1 includes the following preparation Make (S) the Contact with a trifluoromethylating agent to form Wherein R '' is a C1-C6 alkyl group.
  17. 17. The method of any one of claims 15-16, wherein the method is performed such that The reaction to form compound 1 includes the following preparation Make (S) the Contact with acid to form 。
  18. 18. The method of any one of claims 15-17, wherein the method is performed such that The reaction to form compound 1 comprises reacting And (3) with (I) Carbonyl equivalent, and (Ii) Has the structure of Pyrimidine-2, 5-diamine; Contact to form compound 1.
  19. 19. A compound having the following structure is prepared 1 or a salt and/or solvate thereof: (1); it comprises the following steps: (a) Make the following steps And (3) with Contact to form Wherein R '' is a C1-C6 alkyl group; (b) Make the following steps Contact with a trifluoromethylating agent to form ; (C) Make the following steps Contact with HCl to form And (C) sum (D) Make the following steps With (i) carbonyl equivalent, and (ii) having the structure Pyrimidine-2, 5-diamine contact; to form compound 1.
  20. 20. A compound having the following structure is prepared 1 or a salt and/or solvate thereof: (1); it comprises the following steps: (a) Make the following steps And (3) with Contact to form Wherein LG is selected from chloro, bromo, iodo and trifluoromethanesulfonyl; (b) Make the following steps Contact with acid to form ; (C) Make the following steps And (3) with Contact to form Wherein R '' is a C1-C6 alkyl group; (d) Make the following steps Contact with a trifluoromethylating agent to form ; (E) Make the following steps Contact with HCl to form And (C) sum (F) Make the following steps With (i) carbonyl equivalent, and (ii) having the structure Pyrimidine-2, 5-diamine contact; to form compound 1.

Description

Method for preparing PI3K inhibitor Cross Reference to Related Applications The present application claims priority from U.S. provisional application No. 63/532,695, filed 8/15 of 2023, which is incorporated herein by reference in its entirety. Technical Field The present disclosure provides methods for preparing compounds of formula (I), such as (R) -1- (2-aminopyrimidin-5-yl) -3- (1- (5, 7-difluoro-3-methylbenzofuran-2-yl) -2, 2-trifluoroethyl) urea (compound 1), and salts and/or solvates thereof, that inhibit phosphatidylinositol 4, 5-bisphosphate 3-kinase (PI 3K) subtype α (PI 3K α). Background Phosphatidylinositol 4, 5-bisphosphate 3-kinase (PI 3K) subtype α (PI 3kα) encoded by the PIK3CA gene is part of the PI3K/AKT/TOR signaling network and is altered in several human cancers. Some researchers have demonstrated a role for PI3K/AKT signaling in driving tumor progression, such as physiological and pathophysiological functions of metabolism, cell growth, proliferation, angiogenesis and metastasis. (see Fruman, d.a. The PI3K PATHWAY IN Human disease. Cell 2017, 170, 605-635 and Janku, inhibition of F et al ,Targeting the PI3K pathway in cancer: Are we making headwayNat. Rev. Clin. Oncol.2018, 15, 273–291.）PI3K/AKT/TOR signaling (e.g., pharmacological or genetic) may result in cancer cell death and regression of tumor growth. Certain compounds of formula (I) are described in WO 2022/265993, the entirety of which is incorporated herein by reference. An alternative synthetic procedure for the preparation of the compounds of formula (I) is needed. Such alternative synthetic procedures are disclosed herein. Disclosure of Invention Some embodiments provide a method of preparing a compound of formula (I): ; comprising reacting a compound of formula (I-I): And (3) with (I) Carbonyl equivalent, and (Ii) Compounds of formula (I-ii) Contacting to form a compound of formula (I), wherein: z is O or NR x; R x is hydrogen, C1-C6 alkyl or C3-C6 cycloalkyl; each R 1 is independently selected from halogen, hydroxy, cyano, C1-C6 alkyl optionally substituted with hydroxy, and C3-C6 cycloalkyl; m is 0, 1, 2 or 3; r 2 is halogen, hydroxy, C1-C6 alkyl optionally substituted with hydroxy, C1-C6 haloalkyl, C3-C6 cycloalkyl optionally substituted with 1 or 2 fluoro; R 3 is C1-C6 alkyl, C1-C6 haloalkyl or C3-C6 cycloalkyl optionally substituted with 1 or 2 substituents independently selected from fluoro and C1-C6 alkyl; ring A is a 6-10 membered aryl, C3-C8 cycloalkyl, 5-10 membered heteroaryl or 4-10 membered heterocyclyl; Each R 4 is independently selected from the group consisting of: (i) A halogen atom, (Ii) C1-C6 alkyl optionally substituted by 1 or 2 hydroxy groups or-NR ARB, (Iii) C1-C6 alkoxy optionally substituted with 1-2 substituents independently selected from hydroxy and C3-C6 cycloalkyl, (Iv) A C1-C6 haloalkyl group, (V) A hydroxyl group, (Vi) A cyano group, (vii) -CO2H, (viii) -NRARB, (ix) =NRA2, (x) -C(=O)NRCRD, (xi) -SO2(NRERF), (Xii) SO 2 (C1-C6 alkyl), (Xiii) S (=o) (=nh) (C1-C6 alkyl), (Xiv) C (=o) (C1-C6 alkyl), (Xv) CO 2 (C1-C6 alkyl), (Xvi) 5-6 membered heteroaryl optionally substituted by C1-C6 alkyl, (Xvii) A 3-9 membered heterocyclyl optionally substituted with 1 or 2 independently selected R G, and (Xviii) 3-6 membered cycloalkyl optionally substituted with 1 or 2 independently selected R G; n is 0, 1 or 2; Each R A、RA1、RB、RB1、RC、RC1、RD、RD1、RE and R F is independently (I) The hydrogen is used to produce a hydrogen gas, (Ii) A hydroxyl group, (Iii) A 4-to 6-membered heterocyclic group, (Iv) A C1-C6 haloalkyl group, (V) C (=o) (C1-C6 alkyl), (Vi) C (=O) O (C1-C6 alkyl), (Vii) SO 2 (C1-C6 alkyl), (Viii) 3-6 membered cycloalkyl optionally substituted with hydroxy, or (Ix) C1-C6 alkyl optionally substituted with 1-2 substituents independently selected from hydroxy, -C (=O) NR B2RC2 -6 membered heteroaryl, 3-6 membered cycloalkyl, -SO 2 (C1-C6 alkyl), -CO 2 H and-SO 2(NH2, or R C and R D, together with the nitrogen atom to which they are attached, form a 4-10 membered heterocyclyl optionally substituted with 1-2 substituents independently selected from hydroxy, halogen, -C (=O) NR B1RC1、-SO2 (C1-C6 alkyl), -CO 2 H, C1-C6 alkyl optionally substituted with hydroxy, C1-C6 alkoxy and C1-C6 haloalkoxy; Each R A2、RB2 and R C2 is independently hydrogen or C1-C6 alkyl, and Each R G is independently selected from the group consisting of fluoro, cyano, hydroxy, C1-C6 alkyl optionally substituted with hydroxy, C1-C6 alkoxy, -NR A1RB1、=NRA2、-C(=O)NRC1RD1、-CO2 (C1-C6 alkyl), C1-C6 haloalkyl, C3-C6 cycloalkyl, C1-C6 haloalkoxy, -SO 2 (C1-C6 alkyl), and-CO 2 H. Some embodiments provide a method of making a polymer having the structure a method of compound 1 or a salt and/or solvate thereof: ; Which comprises the steps of And (3) with (I) Carbonyl equivalent, and (Ii) Has the structure ofPyrimidine-2, 5-diamine; Contact to form compound 1. Some embodiments provide a method of making a polymer having the structure a method of