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US-20260125395-A1 - PROCESS FOR THE PREPARATION OF TRICYCLIC PI3K INHIBITOR COMPOUNDS AND METHODS FOR USING THE SAME FOR THE TREATMENT OF CANCER

US20260125395A1US 20260125395 A1US20260125395 A1US 20260125395A1US-20260125395-A1

Abstract

The present disclosure provides for methods for preparing tricyclic PI3K inhibitor compounds in high yield and purity in aqueous solvent systems.

Inventors

  • Andreas Stumpf
  • Remy Angelaud
  • Andrew McClory
  • Herbert Yajima
  • Chudi Ndubaku
  • Alan Olivero

Assignees

  • GENENTECH, INC.

Dates

Publication Date
20260507
Application Date
20250813

Claims (20)

  1. 1 . A process for preparing a compound of Formula III from a compound of Formula II in a reaction mixture according to the following reaction scheme: the process comprising: (i) forming a reaction mixture comprising the compound Formula II, organoboron-R 4 , the solvent system comprising at least 5 v/v % water, the base and the catalyst; (ii) reacting the reaction mixture at a temperature of less than 100° C. to form a reaction product mixture comprising compound Formula III; and (iii) isolating the compound Formula III, a stereoisomer, geometric isomer, tautomer, or a pharmaceutically acceptable salt thereof, from the reaction product mixture, wherein: the catalyst comprises palladium and the reaction mixture comprises less than 0.05 equivalents of catalyst per equivalent of compound Formula II; X 1 is S, O, N, NR 6 , CR 1 , C(R 1 ) 2 , or —C(R 1 ) 2 O—; X 2 is C, CR 2 or N; X 3 is C, CR 3 or N; X 4 is halogen; A is a 5, 6, or 7-membered carbocyclyl or heterocyclyl ring fused to X 2 and X 3 , optionally substituted with one or more R 5 , R 10 or R 15 groups; R 6 is H, C 1 -C 12 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, —(C 1 -C 12 alkylene)-(C 3 -C 12 carbocyclyl), —(C 1 -C 12 alkylene)(—C 2 -C 20 heterocyclyl), —(C 1 -C 12 alkylene)-C(═O)—(C 2 -C 20 heterocyclyl), (C 1 -C 12 alkylene)-(C 6 -C 20 aryl), and —(C 1 -C 12 alkylene)—(C 1 -C 20 heteroaryl), where alkyl, alkenyl, alkynyl, alkylene, carbocyclyl, heterocyclyl, aryl, and heteroaryl are optionally substituted with one or more groups independently selected from F, Cl, Br, I, —CH 3 , —CH 2 CH 3 , —C(CH 3 ) 3 , —CH 2 OH, —CH 2 CH 2 OH, —(CH 3 ) 2 OH, —CH 2 OCH 3 , —CN, —CO 2 H, —COCH 3 , —COC(CH 3 ) 3 , —CO 2 CH 3 , —CONH 2 , —CONHCH 3 , —CON(CH 3 ) 2 , —C(CH 3 ) 2 CONH 2 , —NO 2 , —NH 2 , —NHCH 3 , —N(CH 3 ) 2 , —NHCOCH 3 , —NHS(O) 2 CH 3 , —N(CH 3 )C(CH 3 ) 2 CONH 2 , —N(CH 3 )CH 2 CH 2 S(O) 2 CH 3 , ═O, —OH, —OCH 3 , —S(O) 2 N(CH 3 ) 2 , —SCH 3 , —S(O) 2 CH 3 , cyclopropyl, cyclobutyl, oxetanyl, morpholino, and 1,1-dioxo-thiopyran-4-yl; R 1 , R 2 , and R 3 are independently selected from H, F, Cl, Br, I, —CH 3 , —CH 2 CH 3 , —C(CH 3 ) 3 , —CH 2 OH, —CH 2 CH 2 OH, —C(CH 3 ) 2 OH, —CH 2 OCH 3 , —CN, —CF 3 , —CO 2 H, —COCH 3 , —COC(CH 3 ) 3 , —CO 2 CH 3 , —CONH 2 , —CONHCH 3 , —CON(CH 3 ) 2 , —C(CH 3 ) 2 , —CONH 2 , —NO 2 , —NH 2 , —NHCH 3 , —N(CH 3 ) 2 , —NHCOCH 3 , —NHS(O) 2 CH 3 , —N(CH 3 )C(CH 3 ) 2 CONH 2 , —N(CH 3 )CH 2 CH 2 S(O) 2 CH 3 , ═O, —OH, —OCH 3 , —S(O) 2 N(CH 3 ) 2 , —SCH 3 , —S(O) 2 CH 3 , cyclopropyl, cyclobutyl, oxetanyl, morpholino, and 1,1-dioxo-thiopyran-4-yl; R 4 is selected from C 6 -C 20 aryl, C 2 -C 20 heterocyclyl and C 1 -C 20 heteroaryl, each of which are optionally substituted with one or more groups independently selected from F, Cl, Br, I, —CH 3 , —CH 2 CH 3 , —CH(CH 3 ) 2 , —CH 2 CH(CH 3 ) 2 , —CH 2 CH 3 , —CH 2 CN, —CN, —CF 3 , —CH 2 OH, —CO 2 H, —CONH 2 , CONH(CH 3 ), —CON(CH 3 ) 2 , —NO 2 , —NH 2 , —NHCH 3 , —NHCOCH 3 , —OH, —OCH 3 , —OCH 2 CH 3 , —OCH(CH 3 ) 2 , —SH, —NHC(O)NHCH 3 , —NHC(O)NHCH 2 CH 3 , —NHS(O) 2 CH 3 , —N(CH 3 )C(O)OC(CH 3 ) 3 , —S(O) 2 CH 3 , benzyl, benzyloxy, morpholinyl, morpholinomethyl, and 4-methylpiperazin-1-yl; Each R 5 , R 10 and R 15 is independently selected from C 1 -C 12 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, —(C 1 -C 12 alkylene)-(C 3 -C 12 carbocyclyl), —(C 1 -C 12 alkylene)-(C 2 -C 20 heterocyclyl), —(C 1 -C 12 alkylene)—C(O)—(C 2 -C 20 heterocyclyl), —(C 1 -C 12 alkylene)-(C 6 -C 20 aryl), and —(C 1 -C 12 alkylene)-(C 1 -C 20 heteroaryl); or two geminal R 5 , R 10 and/or R 15 groups form a 3, 4, 5, or 6-membered carbocyclyl or heterocyclyl ring, where alkyl, alkenyl, alkynyl, alkylene, carbocyclyl, heterocyclyl, aryl, and heteroaryl are optionally substituted with one or more groups independently selected from F, Cl, Br, I, —CH 3 , —CH 2 CH 3 , —C(CH 3 ) 3 , —CH 2 OH, —CH 2 CH 2 OH, —C(CH 3 ) 2 OH, —CH 2 OCH 3 , —CN, —CH 2 F, —CHF 2 , —CF 3 , —CO 2 H, —COCH 3 , —COC(CH 3 ) 3 , —CO 2 CH 3 , —CONH 2 , —CONHCH 3 , —CON(CH 3 ) 2 , —C(CH 3 ) 2 CONH 2 , —NO 2 , —NH 2 , —NHCH 3 , —N(CH 3 ) 2 , —NH—COCH 3 , —NHS(O) 2 CH 3 , —N(CH 3 )C(CH 3 ) 2 CONH 2 , —N(CH 3 )CH 2 CH 2 S(O) 2 CH 3 , ═O, —OH, —OCH 3 , —S(O) 2 N(CH 3 ) 2 , —SCH 3 , —S(O) 2 CH 3 , cyclopropyl, cyclobutyl, oxetanyl, morpholino, and 1,1-dioxo-thiopyran-4-yl; and mor is selected from: wherein mor is optionally substituted with one or more R 7 groups independently selected from F, Cl, Br, I, —CH 3 , —CH 2 CH 3 , —CH 2 CH 2 CH 3 , —CH(CH 3 ) 2 , —C(CH 3 ) 3 , —CH 2 OCH 3 , —CHF 2 , —CN, —CF 3 , —CH 2 OH, —CH 2 OCH 3 , —CH 2 CH 2 OH, —CH 2 C(CH 3 ) 2 OH, —CH(CH 3 )OH, —CH(CH 2 CH 3 )OH, —CH 2 CH(OH)CH 3 , —C(CH 3 ) 2 OH, —C(CH 3 ) 2 OCH 3 , —CH(CH 3 )F, —C(CH 3 )F 2 , —CH(CH 2 CH 3 )F, —C(CH 2 CH 3 ) 2 F, —CO 2 H, —CONH 2 , —CON(CH 2 CH 3 ) 2 , —COCH 3 , —CON(CH 3 ) 2 , —NO 2 , —NH 2 , —NHCH 3 , —N(CH 3 ) 2 , —NHCH 2 CH 3 , —NHCH(CH 3 ) 2 , —NHCH 2 CH 2 OH, —NHCH 2 CH 2 OCH 3 , —NHCOCH 3 , —NHCOCH 2 CH 3 , —NHCOCH 2 OH, —NHS(O) 2 CH 3 , —N(CH 3 )S(O) 2 CH 3 , ═O, —OH, —OCH 3 , —OCH 2 CH 3 , —OCH(CH 3 ) 2 , —SH, —NHC(O)NHCH 3 , —NHC(O)NHCH 2 CH 3 , —S(O)CH 3 , —S(O)CH 2 CH 3 , —S(O) 2 CH 3 , —S(O) 2 NH 2 , —S(O) 2 NHCH 3 , —S(O) 2 N(CH 3 ) 2 , and —CH 2 S(O) 2 CH 3 .
  2. 2 . The process of claim 1 , wherein the solvent system further comprises at least one polar aprotic solvent selected from N-methylpyrrolidone, methyl isobutyl ketone, methyl ethyl ketone, tetrahydrofuran, dichloromethane, ethyl acetate, acetone, N,N-dimethylformamide, acetonitrile and dimethyl sulfoxide.
  3. 3 . The process of claim 2 , wherein the ratio of water to the at least one polar aprotic solvent is from about 1:10 v/v to about 5:1 v/v, from about 1:1 v/v to about 1:10 v/v, or from about 1:3 v/v to about 1:7 v/v.
  4. 4 . The process of claim 1 , wherein the solvent system comprises water and tetrahydrofuran.
  5. 5 . The process of claim 2 , wherein the solvent system consists essentially of water and the at least one polar aprotic solvent.
  6. 6 . The process of claim 1 , wherein the organoboron-R 4 is 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2 yl)-R 4 .
  7. 7 . The process of claim 1 , wherein the base is selected from K 3 PO 4 , Cs 2 CO 3 , and KOH.
  8. 8 . The process of claim 1 , wherein the base is K 3 PO 4 .
  9. 9 . The process of claim 1 , wherein the equivalent ratio of base to compound Formula II is at least 1:1, from about 1:1 to about 3:1, or about 2:1.
  10. 10 . The process of claim 1 , wherein the catalyst comprising palladium is selected from chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1, 1′-biphenyl)[2-(2-aminoethyl) phenyl)]palladium(II) (“Pd Xphos”); 1,1-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane (“PdCl 2 dppf CH 2 C 12 ”); Bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (“Pd(amphos)Cl 2 ”); dichlorobis(di-tert-butylphenylphosphine)palladium(II) (“Pd 122”); PdCl 2 (PPh 3 ) 2 ; Pd(t-Bu) 3 ; Pd(PPh 3 ) 4 ; Pd(Oac)/PPh 3 ; Cl 2 Pd[(Pet 3 )] 2 ; Pd(DIPHOS) 2 ; Cl 2 Pd(Bipy); [PdCl(Ph 2 PCH 2 PPh 2 )] 2 ; Cl 2 Pd[P(o-tol) 3 ] 2 ; Pd 2 (dba) 3 /P(o-tol) 3 ; Pd 2 (dba)/P(furyl) 3 ; Cl 2 Pd[P(furyl) 3 ] 2 ; Cl 2 Pd(PmePh 2 ) 2 ; Cl 2 Pd[P(4-F-Ph) 3 ] 2 ; Cl 2 Pd[P(C 6 F 6 ) 3 ] 2 ; Cl 2 Pd[P(2-COOH-Ph)(Ph) 2 ] 2 ; Cl 2 Pd[P(4-COOH-Ph)(Ph) 2 ] 2 ; palladium acetate, microencapsulated in a polyuria matrix, comprising 0.4 mmol/g Pd; palladium acetate and triphenylphosphine, microencapsulated in a polyuria matrix, comprising 0.4 mmol/g Pd and 0.3 mmol/g phosphorous; and palladium acetate and BINAP, microencapsulated in a polyuria matrix, comprising 0.4 mmol/g Pd.
  11. 11 . The process of claim 10 , wherein the catalyst comprising palladium is selected from chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2-aminoethyl) phenyl)]palladium(II) and 1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane, or is chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2-aminoethyl) phenyl)]palladium(II).
  12. 12 . The process of claim 1 , wherein the equivalent ratio of the catalyst comprising palladium to compound Formula II is between about 0.003:1 and 0.05:1, from about 0.003:1 to about 0.03:1 or from about 0.004:1 to about 0.02:1.
  13. 13 . The process of claim 1 , wherein the catalyst is chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2-aminoethyl) phenyl)]palladium(II) and the equivalent ratio of the catalyst comprising palladium to compound Formula II is from about 0.004:1 to about 0.015:1, from about 0.004:1 to about 0.01:1, from about 0.004:1 to about 0.007:1, or about 0.005:1.
  14. 14 . The process of claim 1 , wherein the catalyst is chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2-aminoethyl) phenyl)]palladium(II) or 1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex with dichloromethane and the equivalent ratio of the catalyst comprising palladium to compound Formula II is from about 0.005:1 to about 0.04:1, from about 0.005:1 to about 0.03:1, from about 0.01:1 to about 0.03:1, or about 0.02:1.
  15. 15 . The process of claim 1 , wherein the reaction temperature is between about 40° C. and 100° C., from about 40° C. to about 90° C., from about 40° C. to about 80° C., from about 50° C. to about 80° C. or from about 55° C. to about 75° C.
  16. 16 . The process of claim 1 , further comprising adding a polar protic solvent to the reaction product mixture to form an admixture comprising greater than 25 v/v % water and separating compound Formula III from the reaction product mixture by solid liquid separation.
  17. 17 . The process of claim 16 , wherein the polar protic solvent is selected from water, methanol, ethanol, isopropanol, n-propanol, and acetic acid.
  18. 18 . The process of claim 17 , wherein the polar protic solvent is water.
  19. 19 . The process of claim 18 , wherein the volume ratio of the solvent system to water added to the reaction product mixture is from about 1:5 v/v to about 5:1 v/v, from about 1:3 v/v to about 3:1 v/v, from about 1:2 v/v to about 2:1 v/v, from about 1:1.5 v/v to about 1.5:1 v/v, or about 1:1 v/v.
  20. 20 . A method for treating cancer in a patient wherein the cancer is characterized by the overexpression of PI3 kinase, the method comprising administering a therapeutically effective amount of a PI3 kinase inhibitor compound of Formula III according to claim 1 to a person in need of such treatment.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS The present disclosure is a continuation of U.S. Non-Provisional patent application Ser. No. 18/189,623, filed 24 Mar. 2023, which is a continuation of U.S. Non-Provisional patent application Ser. No. 17/115,095, filed 8 Dec. 2020 and now U.S. Pat. No. 11,643,421 B2, which is a continuation of U.S. Non-Provisional patent application Ser. No. 15/780,328, filed 31 May 2018 and now U.S. Pat. No. 10,906,981 B2, which claims priority to International Patent Application Serial No. PCT/US2016/067174, filed 16 Dec. 2016, and published as International Patent Application Publication No. WO 2017/106647, which claims the benefit of and priority to U.S. Provisional Application Ser. No. 62/291,248, filed 4 Feb. 2016, and U.S. Provisional Application Ser. No. 62/288,832, filed 29 Jan. 2016, and U.S. Provisional Application Ser. No. 62/268,149, filed 16 Dec. 2015, each of which is incorporated herein by reference in their entirety. FIELD OF THE DISCLOSURE The disclosure relates generally to methods for preparing compounds which inhibit PI3 kinase activity. The disclosure also relates to methods of using the compounds for in vitro, in situ, and in vivo diagnosis or treatment of mammalian cells, or associated pathological conditions. The disclosure also relates to methods of treating cancer characterized by the overexpression of PI3 kinase. BACKGROUND Any discussion of the prior art throughout the specification should in no way be considered as an admission that such prior art is widely known or forms part of the common general knowledge in the field. Phosphatidylinositol is one of a number of phospholipids found in cell membranes which play an important role in intracellular signal transduction. Cell signaling via 3′-phosphorylated phosphoinositides has been implicated in a variety of cellular processes, e.g., malignant transformation, growth factor signaling, inflammation, and immunity (Rameh et al. (1999) J. Biol Chem, 274:8347-8350). The enzyme responsible for generating these phosphorylated signaling products, phosphatidylinositol 3-kinase (also referred to as PI 3-kinase or PBK), was originally identified as an activity associated with viral oncoproteins and growth factor receptor tyrosine kinases that phosphorylate phosphatidylinositol (PI) and its phosphorylated derivatives at the 3′-hydroxyl of the inositol ring (Panayotou et al. (1992) Trends Cell Biol 2:358-60). Phosphoinositide 3-kinases (PI3K) are lipid kinases that phosphorylate lipids at the 3-hydroxyl residue of an inositol ring (Whitman et al. (1988) Nature, 332:664). The 3-phosphorylated phospholipids (PIP3s) generated by PI3-kinases act as second messengers recruiting kinases with lipid binding domains (including plekstrin homology (PH) regions), such as AKT and phosphoinositide-dependent kinase-1 (PDK1). Binding of AKT to membrane PIP3s causes the translocation of AKT to the plasma membrane, bringing AKT into contact with PDK1, which is responsible for activating AKT. The tumor-suppressor phosphatase, PTEN, dephosphorylates PIP3 and therefore acts as a negative regulator of AKT activation. The PI3-kinases AKT and PDK1 are important in the regulation of many cellular processes including cell cycle regulation, proliferation, survival, apoptosis and motility and are significant components of the molecular mechanisms of diseases such as cancer, diabetes and immune inflammation (Vivanco et al. (2002) Nature Rev. Cancer 2:489; Phillips et al. (1998) Cancer 83:41). The main PI3-kinase isoform in cancer is the Class I PI3-kinase, p110α (alpha) (see, e.g., U.S. Pat. Nos. 5,824,492; 5,846,824; 6,274,327). Other isoforms are implicated in cardiovascular and immune-inflammatory disease (Workman P (2004) Biochem Soc Trans 32:393-396; Patel et al. (2004) Proceedings of the American Association of Cancer Research (Abstract LB-247) 95th Annual Meeting, March 27-31, Orlando, Fla., USA; Ahmadi K and Waterfield M D (2004) Encyclopedia of Biological Chemistry (Lennarz W J, Lane M D eds) Elsevier/Academic Press). The PI3 kinase/Akt/PTEN pathway is an attractive target for cancer drug development since such modulating or inhibitory agents would be expected to inhibit proliferation, reverse the repression of apoptosis and surmount resistance to cytotoxic agents in cancer cells (Folkes et al. (2008) J. Med. Chem. 51:5522-5532; Yaguchi et al. (2006) Jour. of the Nat. Cancer Inst. 98(8):545-556). Malignant gliomas are the most common primary brain tumors in adults. In glioblastoma (GBM), the most aggressive glioma subtype, tumor formation and growth appear to be driven by amplification or overexpression of gene products involved in growth factor-initiated signal transduction acting in cooperation with genetic alterations disrupting cell-cycle control (Holland E C (2001) Nat Rev Genet 2:120-129). Of the genomic alterations described in GBM, PTEN mutation and/or deletion is the most common, with an estimated frequency of 70-90% (Nutt C, Louis