IP Library › Granted Patent US 12679849

Granted Patent B2

US 12679849 · App. 17/598,524 · Granted Jul 14, 2026

Macrocyclic compounds as STING agonists

Inventors: Navnath Popat Karche (Taluka Mulshi, IN); Moloy Banerjee (Taluka Mulshi, IN); Pradeep Rangrao Patil (Taluka Mulshi, IN); Vinod Popatrao Vyavahare (Taluka Mulshi, IN); Deepak Sahebrao Walke (Taluka Mulshi, IN); Vaibhav Madhukar Kalhapure (Taluka Mulshi, IN); Vidya Ramdas (Taluka Mulshi, IN); Venkata P. Palle (Taluka Mulshi, IN); Rajender Kumar Kamboj (Taluka Mulshi, IN)

Assignee: LUPIN LIMITED

C07D498/16

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Quick Facts

Patent No.: US 12679849
App. No.: 17/598,524
Granted: Jul 14, 2026
Kind: B2

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Abstract

Disclosed are the macrocyclic compounds having the general Formula (I) and their tautomeric forms, stereoisomers, pharmaceutically acceptable salts, and their combination with suitable medicament, corresponding processes for the synthesis and pharmaceutical compositions and uses of compounds disclosed herein.

Claims (72)

1 . A compound of Formula (Ia), its stereoisomer, or its pharmaceutically acceptable salt,

wherein,

R 2 is independently selected from hydrogen, optionally substituted C 1 -C 6 alkyl, and optionally substituted C 3 -C 5 monocyclic cycloalkyl;

ring A is independently selected from optionally substituted heterocyclyl, and optionally substituted heteroaryl;

m is selected from 0, or 1;

n is selected from 0, 1, or 2;

when ‘alkyl’ is substituted, it is substituted with 1 to 4 substituents independently selected from halogen, alkyl, perhaloalkyl, cycloalkyl, heterocyclyl, —N(R 4 ) 2 , and —OR 4 ;

when ‘carbocycle’ or ‘cycloalkyl’ is substituted, it is substituted with 1 to 4 substituents independently selected from halogen, alkyl, perhaloalkyl, —N(R 4 ) 2 , and —OR 4 ;

when ‘heterocycle’ or ‘heterocyclyl’ is substituted, it is substituted with 1 to 4 substituents independently selected from oxo (═O), halogen, cyano, alkyl, perhaloalkyl, —OR 4 , —C(═O)OH, —OP(O)(OR 4 ) 2 , —P(O)(OR 4 ) 2 , —P(O)(OR 4 )R 4a , —SO 2 R 4a , —SO 2 NH 2 , —C(═O)N(H)R 4 , —C(═O)N(alkyl)R 4 , —N(H)C(═O)R 4a , —N(H)R 4 , and —N(alkyl)R 4 ;

when the ‘heteroaryl’ group is substituted, it is substituted with 1 to 4 substituents selected from halogen, cyano, alkyl, perhaloalkyl, —O-alkyl, —O-perhaloalkyl, —N(alkyl)alkyl, —N(H)R 4 , —SO 2 -alkyl, —N(alkyl)C(═O)alkyl, —N(H)C(═O)alkyl, —C(═O)N(alkyl)alkyl, —C(═O)N(H)alkyl, —C(═O)NH 2 , —SO 2 N(alkyl)alkyl, —SO 2 N(H)alkyl, —SO 2 NH 2 , —C(═O)OH, —OP(O)(OR 4 ) 2 , —P(O)(OR 4 ) 2 , and —P(O)(OR 4 )R 4a ;

each R 4 is independently selected from hydrogen, alkyl, and cycloalkyl; and

each R 4a is independently selected from alkyl, and cycloalkyl.

2 . The compound of Formula (Ia), its stereoisomer, or its pharmaceutically acceptable salt, as claimed in claim 1 , wherein, ring A is optionally substituted heterocyclyl or optionally substituted heteroaryl.

3 . The compound of Formula (Ia), its stereoisomer, or its pharmaceutically acceptable salt, as claimed in claim 1 , wherein, ring A is

4 . The compound of Formula (Ia), its stereoisomer, or its pharmaceutically acceptable salt, as claimed in claim 1 , wherein, R 2 is ethyl.

5 . The compound of Formula (Ia), its stereoisomer, or its pharmaceutically acceptable salt, as claimed in claim 1 , wherein, n is 0.

6 . The compound of Formula (Ia), its stereoisomer, or its pharmaceutically acceptable salt, as claimed in claim 1 , wherein, R 2 is C 1 -C 6 alkyl; n is 0, 1, or 2; and ring A is optionally substituted heterocyclyl or optionally substituted heteroaryl.

7 . The compound of Formula (Ia), its stereoisomer, or its pharmaceutically acceptable salt, as claimed in claim 1 , wherein, the compound is selected from:

(E)-8-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-1,15-bis(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-8,9,16,19-tetrahydro-7H-6,10-dioxa-2,14,15a, 19a-tetraazacyclopentadeca[3,2,1-cd:8,9,10-c′d′]diindene-4,12-dicarboxamide (Compound 1);

(E)-8-(3-oxa-8-azabicyclo[3.2.1]octan-8-yl)-1,15-bis(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-8,9,16,19-tetrahydro-7H-6,10-dioxa-2,14,15a, 19a-tetraazacyclopentadeca[3,2,1-cd:8,9,10-c′d′]diindene-4,12-dicarboxamide (Compound 2);

(E)-1,15-bis(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-8-morpholino-8,9,16,19-tetrahydro-7H-6,10-dioxa-2,14,15a, 19a-tetraazacyclopentadeca[3,2,1-cd:8,9,10-c′d′]diindene-4,12-dicarboxamide (Compound 3);

(E)-8-(4,4-difluoropiperidin-1-yl)-1,15-bis(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-8,9,16,19-tetrahydro-7H-6,10-dioxa-2,14,15a, 19a-tetraazacyclopentadeca[3,2,1-cd:8,9,10-c′d′]diindene-4,12-dicarboxamide (Compound 4);

(E)-8-((2S,6R)-2,6-dimethylmorpholino)-1,15-bis(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-8,9,16,19-tetrahydro-7H-6,10-dioxa-2,14,15a, 19a-tetraazacyclopentadeca[3,2,1-cd:8,9,10-c′d′]diindene-4,12-dicarboxamide (Compound 5);

(S,E)-1,15-bis(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-8-(3-methoxypyrrolidin-1-yl)-8,9,16,19-tetrahydro-7H-6,10-dioxa-2,14,15a, 19a-tetraazacyclopentadeca[3,2,1-cd:8,9,10-c′d′]diindene-4,12-dicarboxamide (Compound 6);

(E)-1,15-bis(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-8-(piperidin-1-yl)-8,9,16,19-tetrahydro-7H-6,10-dioxa-2,14,15a, 19a-tetraazacyclopentadeca[3,2,1-cd:8,9,10-c′d′]diindene-4,12-dicarboxamide (Compound 7);

(E)-8-(azetidin-1-yl)-1,15-bis(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-8,9,16,19-tetrahydro-7H-6,10-dioxa-2,14,15a, 19a-tetraazacyclopentadeca[3,2,1-cd:8,9,10-c′d′]diindene-4,12-dicarboxamide (Compound 8);

(E)-1,15-bis(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-8-(1-methylpiperidin-4-yl)-8,9,16,19-tetrahydro-7H-6,10-dioxa-2,14,15a, 19a-tetraazacyclopentadeca[3,2,1-cd:8,9,10-c′d′]diindene-4,12-dicarboxamide (Compound 9);

(E)-1,15-bis(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-8-(piperazin-1-yl)-8,9,16,19-tetrahydro-7H-6,10-dioxa-2,14,15a, 19a-tetraazacyclopentadeca[3,2,1-cd:8,9,10-c′d′]diindene-4,12-dicarboxamide (Compound 10);

(S,E)-1,15-bis(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-8-(3-hydroxypyrrolidin-1-yl)-8,9,16,19-tetrahydro-7H-6,10-dioxa-2,14,15a, 19a-tetraazacyclopentadeca[3,2,1-cd:8,9,10-c′d′]diindene-4,12-dicarboxamide (Compound 11);

(R,E)-1,15-bis(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-8-(3-hydroxypyrrolidin-1-yl)-8,9,16,19-tetrahydro-7H-6,10-dioxa-2,14,15a, 19a-tetraazacyclopentadeca[3,2,1-cd:8,9,10-c′d′]diindene-4,12-dicarboxamide (Compound 12);

(E)-1,15-bis(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-8-(2-morpholinoethyl)-8,9,16,19-tetrahydro-7H-6,10-dioxa-2,14,15a, 19a-tetraazacyclopentadeca[3,2,1-cd:8,9,10-c′d′]diindene-4,12-dicarboxamide (Compound 13);

(E)-1,15-bis(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-8-((1-methylazetidin-3-yl)methyl)-8,9,16,19-tetrahydro-7H-6,10-dioxa-2,14,15a, 19a-tetraazacyclopentadeca[3,2,1-cd:8,9,10-c′d′]diindene-4,12-dicarboxamide (Compound 14);

(E)-1,15-bis(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-8-((1-methylpiperidin-4-yl)methyl)-8,9,16,19-tetrahydro-7H-6,10-dioxa-2,14,15a, 19a-tetraazacyclopentadeca[3,2,1-cd:8,9,10-c′d′]diindene-4,12-dicarboxamide (Compound 15);

(E)-1,15-bis(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-8-(morpholinomethyl)-8,9,16,19-tetrahydro-7H-6,10-dioxa-2,14,15a, 19a-tetraazacyclopentadeca[3,2,1-cd:8,9,10-c′d′]diindene-4,12-dicarboxamide (Compound 16);

(E)-15-(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-1-(1-(2-fluoroethyl)-3-methyl-1H-pyrazole-5-carboxamido)-8-morpholino-8,9,16,19-tetrahydro-7H-6,10-dioxa-2,14,15a, 19a-tetraazacyclopentadeca[3,2,1-cd:8,9,10-c′d′]diindene-4,12-dicarboxamide (Compound 17);

(E)-1,15-bis(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-8-((4-methylpiperazin-1-yl)methyl)-8,9,16,19-tetrahydro-7H-6,10-dioxa-2,14,15a, 19a-tetraazacyclopentadeca[3,2,1-cd:8,9,10-c′d′]diindene-4,12-dicarboxamide (Compound 18);

(E)-1,15-bis(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-8-(1H-imidazol-1-yl)-8,9,16,19-tetrahydro-7H-6,10-dioxa-2,14,15a, 19a-tetraazacyclopentadeca[3,2,1-cd:8,9,10-c′d′]diindene-4,12-dicarboxamide (Compound 19);

(E)-1,15-bis(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-8-(4-hydroxypiperidin-1-yl)-8,9,16,19-tetrahydro-7H-6,10-dioxa-2,14,15a, 19a-tetraazacyclopentadeca[3,2,1-cd:8,9,10-c′d′]diindene-4,12-dicarboxamide (Compound 22);

(E)-8-(4-aminopiperidin-1-yl)-1,15-bis(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-8,9,16,19-tetrahydro-7H-6,10-dioxa-2,14,15a, 19a-tetraazacyclopentadeca[3,2,1-cd:8,9,10-c′d′]diindene-4,12-dicarboxamide (Compound 23);

(S,E)-1-(4,12-dicarbamoyl-1,15-bis(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-8,9,16,19-tetrahydro-7H-6,10-dioxa-2,14,15a, 19a-tetraazacyclopentadeca[3,2,1-cd:8,9,10-c′d′]diinden-8-yl) pyrrolidin-3-yl dihydrogen phosphate (Compound 24);

(E)-1-(4,12-dicarbamoyl-1,15-bis(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-8,9,16,19-tetrahydro-7H-6,10-dioxa-2,14,15a, 19a-tetraazacyclopentadeca[3,2,1-cd:8,9,10-c′d′]diinden-8-yl) piperidin-4-yl dihydrogen phosphate (Compound 25);

(E)-8-(3-cyanopyrrolidin-1-yl)-1,15-bis(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-8,9,16,19-tetrahydro-7H-6,10-dioxa-2,14,15a, 19a-tetraazacyclopentadeca[3,2,1-cd:8,9,10-c′d′]diindene-4,12-dicarboxamide (Compound 26);

(E)-8-(3-aminopyrrolidin-1-yl)-1,15-bis(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-8,9,16,19-tetrahydro-7H-6,10-dioxa-2,14,15a, 19a-tetraazacyclopentadeca[3,2,1-cd:8,9,10-c′d′]diindene-4,12-dicarboxamide (Compound 27);

(R,E)-1-(4,12-dicarbamoyl-1,15-bis(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-8,9,16,19-tetrahydro-7H-6,10-dioxa-2,14,15a, 19a-tetraazacyclopentadeca[3,2,1-cd:8,9,10-c′d′]diinden-8-yl) pyrrolidin-3-yl dihydrogen phosphate (Compound 28);

(E)-8-(4-cyanopiperidin-1-yl)-1,15-bis(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-8,9,16,19-tetrahydro-7H-6,10-dioxa-2,14,15a, 19a-tetraazacyclopentadeca[3,2,1-cd:8,9,10-c′d′]diindene-4,12-dicarboxamide (Compound 29);

(E)-8-(azetidin-3-yl)-1,15-bis(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-8,9,16,19-tetrahydro-7H-6,10-dioxa-2,14,15a, 19a-tetraazacyclopentadeca[3,2,1-cd:8,9,10-c′d′]diindene-4,12-dicarboxamide (Compound 30);

(E)-1,15-bis(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-8-(piperidin-4-yl)-8,9,16,19-tetrahydro-7H-6,10-dioxa-2,14,15a, 19a-tetraazacyclopentadeca[3,2,1-cd:8,9,10-c′d′]diindene-4,12-dicarboxamide (Compound 31);

(E)-1,15-bis(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-8-(1-methylazetidin-3-yl)-8,9,16,19-tetrahydro-7H-6,10-dioxa-2,14,15a, 19a-tetraazacyclopentadeca[3,2,1-cd:8,9,10-c′d′]diindene-4,12-dicarboxamide (Compound 34);

(R,E)-1,15-bis(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-8-(3-methoxypyrrolidin-1-yl)-8,9,16,19-tetrahydro-7H-6,10-dioxa-2,14,15a, 19a-tetraazacyclopentadeca[3,2,1-cd:8,9,10-c′d′]diindene-4,12-dicarboxamide (Compound 35); and

(E)-1,15-bis(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-8-(pyridin-2-yl)-8,9,16,19-tetrahydro-7H-6,10-dioxa-2,14,15a, 19a-tetraazacyclopentadeca[3,2,1-cd:8,9,10-c′d′]diindene-4,12-dicarboxamidexamide (Compound 36).

8 . The compound of Formula (Ia), its stereoisomer, or its pharmaceutically acceptable salt, as claimed in claim 1 , wherein, the compound is selected from:

(S,E)-1,15-bis(1-ethyl-3-methyl-1H-pyrazole-5-carboxamido)-8-(3-hydroxypyrrolidin-1-yl)-8,9,16,19-tetrahydro-7H-6, 10-dioxa-2,14,15a, 19a-tetraazacyclopentadeca[3,2,1-cd:8,9,10-c′d′]diindene-4,12-dicarboxamide (Compound 11);

9 . A pharmaceutical composition comprising the compound of Formula (Ia), or its pharmaceutically acceptable salt as claimed in claim 1 and at least one or more pharmaceutically acceptable excipient.

10 . A composition comprising a compound of Formula (Ia), or its pharmaceutically acceptable salt as claimed in claim 1 and an antigen or antigen composition.