IP Library › Granted Patent US 12,358,893
Granted Patent B2
US 12,358,893 · App. 17/421,567 · Granted Jul 15, 2025

Metalloenzyme inhibitor compounds

Inventors: Steven Sparks (Apex, NC); Christopher M. Yates (Raleigh, NC)
Assignee: Corxel Pharmaceuticals Hong Kong Limited
C07D403/04A61K45/06C07D471/04C07D519/00
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Quick Facts
Patent No.
US 12,358,893
App. No.
17/421,567
Granted
Jul 15, 2025
Kind
B2
Abstract

Provided are compounds having metalloenzyme modulating activity, and methods of treating diseases, disorders or symptoms thereof mediated by such metalloenzymes.

Claims (97)

1. A compound of Formula I:

or a pharmaceutically acceptable salt thereof; wherein

W, X, Y, and Z are each independently N or CR 1 ;

Q, T, U, and V are each independently N or CR 2 ;

A is N;

provided that no more than two of W, X, Y, and Z are N; and no more than two of Q, T, U, and V are N;

each R 1 is independently hydrogen, halogen, cyano, acyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, cycloalkyl, cycloalkoxy, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, heterocycloalkylalkyl, (CR e R f ) n NR a R b , (CR e R f ) n NR c S(O 2 )R d , (CR e R f ) n NR c CO 2 R d , CO 2 R e , COR f , or (CR e R f ) n OR f ; wherein at least one R 1 is halogen or cyano and any R 1 can be optionally substituted with 1-3 independent substituents R 7 ;

each R 2 is independently hydrogen, halogen, cyano, acyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, cycloalkyl, cycloalkoxy, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, heterocycloalkylalkyl, (CR e R f ) n NR a R b , (CR e R f ) n NR c S(O 2 )R d , (CR e R f ) n NR c CO 2 R d , N(S(O 2 )R d ) 2 , CO 2 R e , COR f , or (CR e R f ) n OR f ; wherein any R 2 can be optionally substituted with 1-3 independent substituents R 7 ;

R 3 is hydrogen, cyano, alkyl, haloalkyl, heteroalkyl, or cycloalkyl;

R 4 is alkyl, cycloalkyl, haloalkyl, or heteroalkyl;

each n is independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10;

each occurrence of R 7 is, independently, halogen, alkyl, alkoxy, haloalkyl, carboxyl, aryl, aryl substituted with 1-3 independent halogen, —(CR e R f ) n C(O)NR a R b , —S(O) 2 R d , —CO 2 R e , or NR a R b ; and

each occurrence of R a , R b , R e , R d , R e , and R f are, independently, hydrogen, acyl, alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkoxyalkyl, C(O)OC 1-6 alkyl, C(O)OH, C(O)C 1-6 alkyl, S(O2)C 1-6 alkyl, S(O2)aryl, S(O 2 )heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, or an oxygen protecting group when attached to an oxygen atom; or R a and R b together with the atoms to which they are attached form a heterocycloalkyl ring; or R e and R f together with the atoms to which they are attached form a cycloalkyl ring; or R c and R d together with the atoms to which they are attached form a heterocycloalkyl ring.

2. The compound of claim 1 , wherein the compound is of Formula I-a:

or a pharmaceutically acceptable salt thereof.

3. The compound of claim 1 , wherein the compound is of Formula I-b:

or a pharmaceutically acceptable salt thereof.

4. The compound of claim 1 , wherein the compound is of Formula I-c:

or a pharmaceutically acceptable salt thereof.

5. The compound of claim 1 , wherein the compound is of Formula I-d:

or a pharmaceutically acceptable salt thereof.

6. The compound of claim 1 , wherein the compound is of Formula I-e:

or a pharmaceutically acceptable salt thereof.

7. The compound of claim 1 , wherein the compound is of Formula I-f:

or a pharmaceutically acceptable salt thereof.

8. The compound of claim 1 , wherein the compound is of Formula I-g:

or a pharmaceutically acceptable salt thereof.

9. The compound of claim 1 , wherein the compound is of Formula I-h:

or a pharmaceutically acceptable salt thereof.

10. The compound of claim 1 , wherein the compound is of Formula I-i:

or a pharmaceutically acceptable salt thereof.

11. The compound of claim 1 , wherein the compound is of Formula I-j:

or a pharmaceutically acceptable salt thereof.

12. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein each R1 is independently hydrogen, halogen, cyano, alkyl, alkoxy, haloalkyl, or haloalkoxy.

13. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein each R 1 is independently hydrogen, halogen, or cyano.

14. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein each R 2 is independently hydrogen, halogen, cyano, acyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, haloalkoxy, cycloalkyl, cycloalkoxy, (CR e R f ) n NR a R b , (CR e R f ) n NR c S(O 2 )R d , (CR e R f ) n NR c CO 2 R d , CO 2 R e , COR f , (CR e R f ) n OR f , NHS(O 2 )R d , and R d is alkyl.

15. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein no more than one of W, X, Y, and Z is N.

16. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein W, X, Y, and Z are each CR 1 .

17. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein no more than one of Q, T, U, and Vis N, or wherein Q, T, U, and V are each CR 2 .

18. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein: each R 1 is independently hydrogen, halogen, or cyano; and R 4 is cyclopropyl.

19. The compound of claim 1 , wherein the compound is

1′-Cyclopropyl-6′-fluoro-1′H-1,2′-bibenzo[d]imidazole (1);

1′-Cyclopropyl-6′,7′-difluoro-1′H-1,2′-bibenzo[d]imidazole (2);

1′-Cyclopropyl-4,5,6′-trifluoro-1′H-1,2′-bibenzo[d]imidazole (3);

1′-Cyclopropyl-5,6,6′-trifluoro-1′H-1,2′-bibenzo[d]imidazole (4);

1′-Cyclopropyl-6′-fluoro-5,6-dimethoxy-1′H-1,2′-bibenzo [d] imidazole (5);

1′-Cyclopropyl-6′-fluoro-1′H-[1,2′-bibenzo[d]imidazole[-5-carbonitrile (6);

1′-Cyclopropyl-6′-fluoro-1′H-[1,2′-bibenzo[d]imidazole[-6-carbonitrile (7);

1′-Cyclopropyl-6′-fluoro-5-methyl-1′H-1,2′-bibenzo[d]imidazole (8);

1′-Cyclopropyl-6′-fluoro-6-methyl-1′H-1,2′-bibenzo[d]imidazole (9);

1′-Cyclopropyl-5-ethyl-6′-fluoro-1′H-1,2′-bibenzo[d]imidazole (10);

1′-Cyclopropyl-6-ethyl-6′-fluoro-1′H-1,2′-bibenzo[d]imidazole (11);

1′-Cyclopropyl-6′-fluoro-5-methoxy-1′H-1,2′-bibenzo[d]imidazole (12);

1′-Cyclopropyl-6′-fluoro-6-methoxy-1′H-1,2′-bibenzo[d]imidazole (13);

1′-Cyclopropyl-6′-fluoro-4-methyl-1′H-1,2′-bibenzo[d]imidazole (14);

1′-Cyclopropyl-5,6,6′,7′-tetrafluoro-1′H-1,2′-bibenzo[d]imidazole (15);

1′-Cyclopropyl-5′,6′-difluoro-1′H-1,2′-bibenzo[d]imidazole (16);

1′-Cyclopropyl-5,5′,6,6′-tetrafluoro-1′H-1,2′-bibenzo[d]imidazole (17);

1′-Cyclopropyl-5,6′-difluoro-1′H-1,2′-bibenzo[d]imidazole (18);

1′-Cyclopropyl-6,6′-difluoro-1′H-1,2′-bibenzo[d]imidazole (19);

1′-Cyclopropyl-6′-fluoro-5-(trifluoromethyl)-1′H-1,2′-bibenzo[d]imidazole (20);

1′-Cyclopropyl-6′-fluoro-6-(trifluoromethyl)-1′H-1,2′-bibenzo[d]imidazole (21);

1′-ethyl-5,6-difluoro-1′H-[1,2′-bibenzo[d]imidazole]-6′-carbonitrile (22);

1′-Cyclopropyl-5′,6′-difluoro-1′H-[1,2′-bibenzo[d]imidazole]-5-carbonitrile (23);

1′-Cyclopropyl-5′,6′-difluoro-1′H-[1,2′-bibenzo[d]imidazole]-6-carbonitrile (24);

1′-Cyclopropyl-5,6-difluoro-1′H-[1,2′-bibenzo[d]imidazole]-6′-carbonitrile (25);

6′-Chloro-1′-cyclopropyl-5,6-difluoro-1′H-1,2′-bibenzo [d] imidazole (26);

1′-Cyclopropyl-6′-fluoro-5-(trifluoromethoxy)-1′H-1,2′-bibenzo [d] imidazole (27);

1′-Cyclopropyl-6′-fluoro-6-(trifluoromethoxy)-1′H-1,2′-bibenzo [d] imidazole (28);

5-Chloro-3-cyclopropyl-2-(5,6-difluoro-1H-benzo [d] imidazol-1-yl)-3H-imidazo[4,5 b]pyridine (29);

N-(1′-cyclopropyl-6′,7′-difluoro-1′H-[1,2′-bibenzo [d]imidazol]-5-yl)-N (methylsulfonyl) methanesulfonamide (30);

N-(1′-cyclopropyl-6′,7′-difluoro-1′H-[1,2′-bibenzo[d]imidazol]-5-yl) methanesulfonamide (31);

3-Cyclopropyl-2-(5,6-difluoro-1H-benzo[d]imidazol-1-yl)-3H-imidaz[4,5-b]pyridine-5-carbonitrile (32);

N-(1′-cyclopropyl-6′,7′-difluoro-1′H-[1,2′-bibenzo[d]imidazol]-6-yl) methanesulfonamide (33);

1-(1-Cyclopropyl-5,6-difluoro-1H-benzo[d]imidazol-2-yl)-1H-imidazo[4,5-b]pyridine (34);

1-(1-Cyclopropyl-5,6-difluoro-1H-benzo [d]imidazol-2-yl)-1H-imidazo[4,5-c]pyridine (35);

3-(1-Cyclopropyl-5,6-difluoro-1H-benzo [d] imidazol-2-yl)-3H-imidazo[4,5-c]pyridine (36);

3-cyclopropyl-2-(3H-imidazo[4,5-c]pyridin-3-yl)-3H-imidazo[4,5-b]pyridine-5 carbonitrile (37); 3-cyclopropyl-2-(1H-imidazo[4,5-c]pyridin-1-yl)-3H-imidazo[4,5-b]pyridin 5-carbonitrile (38);

1-(1-Cyclopropyl-5,6-difluoro-1H-benzo [d] imidazol-2-yl)-1H-imidazo[4,5-c]pyridine 6-carboxylic acid (39);

1-(1-Cyclopropyl-5,6-difluoro-1H-benzo [d] imidazol-2-yl)-6-(difluoromethyl)-1H imidazo[4,5-c]pyridine (40);

3-(1-Cyclopropyl-5,6-difluoro-1H-benzo [d] imidazol-2-yl)-6-(difluoromethyl)-3H imidazo[4,5-c]pyridine (41);

1-Cyclopropyl-2-(3H-imidazo[4,5-c]pyridin-3-yl)-1H-benzo[d]imidazole-6 carbonitrile (42);

1-Cyclopropyl-2-(1H-imidazo[4,5-c]pyridin-1-yl)-1H-benzo[d]imidazole-6 carbonitrile (43);

1′-Cyclopropyl-5′,6′-difluoro-1′H-[1,2′-bibenzo[d]imidazole]-5-carboxylic acid (Ex. 44);

N-(1′-Cyclopropyl-5′,6′-difluoro-1′H-[1,2′-bibenzo[d] imidazol]-6 yl) methanesulfonamide (45);

N-(1′-Cyclopropyl-5′,6′-difluoro-1′H-[1,2′-bibenzo[d]imidazol]-5-yl) methanesulfonamide (46);

N-(6′-Cyano-1′-cyclopropyl-1′H-[1,2′-bibenzo[d] imidazol]-5-yl) methanesulfonamide (47);

N-(6′-Cyano-1′-cyclopropyl-1′H-[1,2′-bibenzo[d]imidazol]-6-yl) methanesulfonamide (48);

1′-Cyclopropyl-5-(difluoromethoxy)-1′H-[1,2′-bibenzo[d]imidazole]-6′-carbonitrile (49);

1′-Cyclopropyl-6-(difluoromethoxy)-1′H-[1,2′-bibenzo[d]imidazole]-6′-carbonitrile (50);

1′-Cyclopropyl-5′,6′-difluoro-1′H-[1,2′-bibenzo[d]imidazole]-6-carboxylic acid (51);

1′-Cyclopropyl-5-(difluoromethoxy)-5′,6′-difluoro-1′H-1,2′-bibenzo[d]imidazole (52);

1′-Cyclopropyl-6-(difluoromethoxy)-5′,6′-difluoro-1′H-1,2′-bibenzo[d]imidazole (53); or a pharmaceutically acceptable salt thereof.

20. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein:

each R 1 is independently hydrogen, halogen, or cyano; wherein at least one R 1 is halogen or cyano;

each R 2 is independently hydrogen, halogen, cyano, alkyl, haloalkyl, alkoxy, haloalkoxy, or (CR e R f ) n NR c S(O 2 )R d ; and

R 4 is cyclopropyl.

Assignments (11)
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Mar 3, 2026
From: CORXEL PHARMACEUTICALS HONG KONG LIMITED
To: CORXEL PHARMACEUTICALS LIMITED
Reel/Frame 073958/0018 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Mar 3, 2026
From: CORXEL PHARMACEUTICALS LIMITED
To: CORXEL PHARMACEUTICALS, INC.
Reel/Frame 073958/0129 →
CHANGE OF NAME Recorded Mar 14, 2025
From: JI XING PHARMACEUTICALS HONG KONG LIMITED
To: CORXEL PHARMACEUTICALS HONG KONG LIMITED
Reel/Frame 070523/0516 →
CORRECTION OF ERROR IN ASSIGNEE ADDRESS AS LISTED IN COVER SHEET PREVIOUSLY RECORDED AT REEL/FRAME 062691/0373 Recorded Jun 6, 2023
From: PHASEBIO PHARMACEUTICALS, INC.
To: JI XING PHARMACEUTICALS HONG KONG LIMITED
Reel/Frame 063873/0889 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Feb 14, 2023
From: PHASEBIO PHARMACEUTICALS, INC.
To: JI XING PHARMACEUTICALS HONG KONG LIMITED
Reel/Frame 062691/0373 →
RELEASE OF SECURITY INTEREST Recorded Jan 13, 2023
From: JMB CAPITAL PARTNERS LENDING, LLC
To: PHASEBIO PHARMACEUTICALS, INC.
Reel/Frame 062376/0850 →
SECURITY INTEREST Recorded Oct 31, 2022
From: PHASEBIO PHARMACEUTICALS, INC.
To: JMB CAPITAL PARTNERS LENDING, LLC
Reel/Frame 061601/0001 →
SECURITY INTEREST Recorded Oct 10, 2022
From: PHASEBIO PHARMACEUTICALS, INC.
To: JMB CAPITAL PARTNERS LENDING, LLC
Reel/Frame 061367/0674 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jul 8, 2021
From: SPARKS, STEVEN; YATES, CHRISTOPHER M.
To: SELENITY THERAPEUTICS, LLC
Reel/Frame 056794/0876 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jul 8, 2021
From: SELENITY THERAPEUTICS, LLC
To: SELENITY THERAPEUTICS (BERMUDA), LTD.
Reel/Frame 056794/0905 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jul 8, 2021
From: SELENITY THERAPEUTICS (BERMUDA), LTD.
To: PHASE BIO PHARMACEUTICALS, INC.
Reel/Frame 056794/0957 →
Continuity (2)
Provisional Application 62789832 · Jan 8, 2019
Related Publication 20220081420A1 · Mar 17, 2022
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