Granted Patent B2

US 12,522,589 · App. 18/252,695 · Granted Jan 13, 2026

Inventors: Kenneth Stauderman (San Diego, CA); Michael Dunn (La Jolla, CA); Kay Olmstead (San Diego, CA)

Assignee: CalciMedica, Inc.

C07D405/04

Abstract

Claims (47)

1 . A process of synthesizing CRAC channel inhibitors of Formula (I):

or a pharmaceutically acceptable salt thereof, wherein:

R 1 , R 2 , and R 3 are independently selected at each occurrence from hydrogen, halogen, and C 1 -C 3 alkyl optionally substituted with one or more substituents independently selected from hydrogen, halogen, —OH, —OR 4 , —CN, —N(R 4 ) 2 , and —NO 2 ;

or two R 1 groups are taken together with the atoms to which they are attached to form a carbocycle;

n is 0, 1, 2, or 3;

m is 0, 1, 2, 3, 4, or 5; and

R 4 is independently selected at each occurrence from hydrogen; and C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl, each of which may be optionally substituted at each occurrence by halogen, —CN, —NO 2 , —OH, —NH 2 , and OCH 3 ;

wherein the process comprises reacting a compound of Formula (I-A)

with a compound of Formula (I-B)

in the presence of a base, a catalyst, and a solvent, wherein:

X is selected from —B(OH) 2 , —BF 3 K,

 and

Y is selected from Cl, Br, and I.

2 . The process of claim 1 , wherein the base is selected from the group consisting of potassium carbonate, sodium carbonate, potassium bicarbonate, sodium bicarbonate, piperidine, pyridine, 1,8-diazabicyclo[5.4.0]undec-7-ene, sodium tert-butoxide, potassium tert-butoxide, cesium carbonate, potassium phosphate, sodium hydroxide, N,N-diisopropylethylamine, and triethylamine.

3 . The process of claim 1 , wherein the catalyst is selected from Pd(acac) 2 , [Pd(allyl)Cl] 2 , Pd(MeCN) 2 Cl 2 , Pd(dba) 2 , Pd(TFA) 2 , Pd 2 (dba) 3 , Pd 2 (dba) 3 ·CHCl 3 , Pd(PPh 3 ) 4 , Pd(OAc) 2 , Pd(PCy 3 ) 2 Cl 2 , Pd(PPh 3 ) 2 Cl 2 , Pd[P(o-tol) 3 ] 2 Cl 2 , Pd(amphos)Cl 2 , Pd(dppf)Cl 2 , Pd(dppf)Cl 2 ·CH 2 Cl 2 , Pd(dtbpf)Cl 2 , Pd(MeCN) 4 (BF 4 ) 2 , PdCl 2 , XPhos-Pd-G3, Pd-PEPPSI™-IPr, Pd—PEPPSI™-SIPr, and Pd-PEPPSI™-IPent.

4 . The process of claim 1 , wherein the solvent is selected from water, ethyl acetate, dichloromethane, tetrahydrofuran, diethyl ether, dimethylformamide, dimethylsulfoxide, methanol, ethanol, acetone, acetonitrile, 1,4-dioxane, hexane, and methyl tert-butyl ether.

5 . The process of claim 1 , wherein the process provides the compound of Formula (I) in a synthetic yield of greater than about 75%.

6 . The process of claim 1 , wherein the compound of Formula (I-A)

is synthesized by reacting a compound of Formula (I-C)

with a borylating agent in the presence of a second base and a second solvent.

7 . The process of claim 6 , wherein the borylating agent is selected from 2-isopropoxy-4,4,5,5,-tetramethyl-1,3,2-dioxaborolane, 2-methoxy-4,4,5,5,-tetramethyl-1,3,2-dioxaborolane, and 2-ethoxy-4,4,5,5,-tetramethyl-1,3,2-dioxaborolane.

8 . The process of claim 6 , wherein the second base is selected from isopropylmagnesium chloride, isopropylmagnesium lithium chloride, methylmagnesium bromide, methylmagnesium chloride, methylmagnesium iodide, ethylmagnesium chloride, ethylmagnesium bromide, isopropylmagnesium bromide, methyllithium, ethyllithium, isopropyllithium, n-butyllithium, and tert-butyllithium.

9 . The process of claim 6 , wherein the second solvent is selected from water, ethyl acetate, dichloromethane, tetrahydrofuran, diethyl ether, dimethylformamide, dimethylsulfoxide, methanol, ethanol, acetone, acetonitrile, 1,4-dioxane, hexane, and methyl tert-butyl ether.

10 . The process of claim 6 , wherein the process provides the compound of Formula (I-A) in a synthetic yield of greater than about 70%.

11 . The process of claim 6 , wherein the compound of Formula (I-C)

is synthesized by reacting a compound of Formula (I-D)

with a brominating agent in the presence of an acid and a third solvent.

12 . The process of claim 11 , wherein the brominating agent is selected from N-bromosuccinimide, tribromoisocyanuric acid, 1,3-dibromo-5,5-dimethylhydantoin, and bromine.

13 . The process of claim 11 , wherein the acid is selected from hydrochloric acid, sulfuric acid, nitric acid, acetic acid, hydrobromic acid, phosphoric acid, formic acid, and trifluoroacetic acid.

14 . The process of claim 11 , wherein the third solvent is selected from water, ethyl acetate, dichloromethane, tetrahydrofuran, diethyl ether, dimethylformamide, dimethylsulfoxide, methanol, ethanol, acetone, acetonitrile, 1,4-dioxane, hexane, and methyl tert-butyl ether.

15 . The process of claim 11 , wherein the process provides the compound of Formula (I-C) in a synthetic yield of greater than about 80%.

16 . The process of claim 1 , wherein the compound of Formula (I-B)

is synthesized by reacting a compound of Formula (I-E)

with a compound of Formula (I-F)

in the presence of a third base, wherein:

Z is selected from Cl, Br, and I.

17 . The process of claim 16 , wherein the third base is selected from the group consisting of potassium carbonate, sodium carbonate, potassium bicarbonate, sodium bicarbonate, piperidine, pyridine, 1,8-diazabicyclo[5.4.0]undec-7-ene, sodium tert-butoxide, potassium tert-butoxide, cesium carbonate, potassium phosphate, sodium hydroxide, N,N-diisopropylethylamine, and triethylamine.

18 . The process of claim 16 , wherein the process provides the compound of Formula (I-B) in a synthetic yield of greater than about 80%.

19 . The process of claim 16 , wherein the compound of Formula (I-F)

is synthesized by reacting a compound of Formula (I-G)

with an acyl halide preparation agent in the presence of a fourth solvent.

20 . The process of claim 19 , wherein the acyl halide preparation agent is selected from oxalyl chloride, thionyl chloride, phosphoryl chloride, phosphorous trichloride, phosphorous pentachloride, phosgene, diphosgene, triphosgene, and cyanuric chloride.

21 . The process of claim 19 , wherein the fourth solvent is selected from water, ethyl acetate, dichloromethane, tetrahydrofuran, diethyl ether, dimethylformamide, dimethylsulfoxide, methanol, ethanol, acetone, acetonitrile, 1,4-dioxane, hexane, and methyl tert-butyl ether.

22 . A process of synthesizing CRAC channel inhibitors of Formula (II):

or a pharmaceutically acceptable salt thereof, wherein the process comprises reacting a compound of Formula (II-A)

with a compound of Formula (II-B)

in the presence of a base, a catalyst, and a solvent.

Assignments (2)

Continuity (1)

References Cited (305)