Process for preparing soluble guanylate cyclase stimulators

1. A process for preparing a compound represented by Formula (IA):

wherein:

(i) W is ring B;

ring B is phenyl or a 5- or 6-membered heteroaryl, wherein the 5- or 6-membered heteroaryl contains 1 or 2 N ring heteroatoms;

each J is independently H or CH 3 ;

each J B is independently halo, CN, C 1-6 aliphatic, OR B , or a C 3-8 cycloaliphatic ring, wherein each C 1-6 aliphatic and C 3-8 cycloaliphatic ring is optionally and independently substituted with 1, 2, or 3 independently selected R 3 substituents;

each R B is independently C 1-6 aliphatic or a C 3-8 cycloaliphatic ring, wherein each C 1-6 aliphatic and C 3-8 cycloaliphatic ring is optionally and independently substituted with 1, 2, or 3 independently selected R 3a substituents; and

each R 3a is independently halo, CN, C 1-4 alkyl, C 1-4 haloalkyl, OC 1-4 alkyl, or OC 1-4 haloalkyl; or

(ii) W is ring B;

ring B is C 3-7 cycloalkyl;

each J is independently H;

each J B is independently halo, CN, C 1-6 aliphatic, or OR B1 , wherein each C 1-6 aliphatic is optionally and independently substituted with 1, 2, or 3 independently selected R 3 substituents;

each R B1 is independently H, C 1-6 aliphatic, or a C 3-8 cycloaliphatic ring, wherein each C 1-6 aliphatic and C 3-8 cycloaliphatic ring is optionally and independently substituted with 1, 2, or 3 independently selected R 3b substituents; and

each R 3b is independently halo, CN, C 1-4 alkyl, C 1-4 haloalkyl, OC 1-4 alkyl, or OC 1-4 haloalkyl;

each J C is independently H, halo, CN, C 1-4 aliphatic, or OC 1-4 alkyl, wherein each C 1-4 aliphatic and OC 1-4 alkyl is optionally and independently substituted with 1, 2, or 3 substituents independently selected form the group consisting of halo, OH, OC 1-4 alkyl, and OC 1-4 haloalkyl;

each R 3 is independently halo, CN, C 1-4 alkyl, C 1-4 haloalkyl, OC 1-4 alkyl, or OC 1-4 haloalkyl;

R 11 is C 1-6 alkyl, C 2-6 alkenyl, or C 2-6 alkynyl, wherein the C 1-6 alkyl is optionally substituted with 1, 2, or 3 independently selected R 15 substituents, and further wherein the C 2-6 alkenyl or C 2-6 alkynyl is optionally substituted with 1 or 2 independently selected R b2 substituents;

each R 15 is independently halo, C(O)R b2 , C(O)NR a2 R b2 , NR a2 R b2 , C(O)OR b2 , OR b2 , OC 2-4 alkenyl, OC(O)NR a2 R b2 , SR b2 , C 3-4 cycloalkyl, 3- to 10-membered heterocyclyl, phenyl, or a 5- or 6-membered heteroaryl, wherein each 3- to 10-membered heterocyclyl and 5- or 6-membered heteroaryl independently contains 1, 2, or 3 ring heteroatoms independently selected from the group consisting of N, O, and S, and further wherein each C 3-4 cycloalkyl, 3- to 10-membered heterocyclyl, phenyl, and 5- or 6-membered heteroaryl is optionally and independently substituted with 1, 2, or 3 independently selected R 18 substituents;

each R 18 is independently halo, C 1-6 alkyl, C 1-6 haloalkyl, OH, OC 1-6 alkyl, or phenyl;

each R a2 is independently H, C 1-6 alkyl, C 1-6 haloalkyl, or C(O)R b2 ;

each R b2 is independently H, C 1-6 alkyl, or C 1-6 haloalkyl;

n is 0, 1, 2, or 3; and

p is 1 or 2;

wherein the process comprises the following step:

reacting a compound represented by Formula (IIA):

or a salt thereof,

wherein:

(i) W is ring B;

ring B is phenyl or a 5- or 6-membered heteroaryl, wherein the 5- or 6-membered heteroaryl contains 1 or 2 N ring heteroatoms;

each J is independently H or CH 3 ;

each J B is independently halo, CN, C 1-6 aliphatic, OR B , or a C 3-8 cycloaliphatic ring, wherein each C 1-6 aliphatic and C 3-8 cycloaliphatic ring is optionally and independently substituted with 1, 2, or 3 independently selected R 3 substituents;

each R B is independently C 1-6 aliphatic or a C 3-8 cycloaliphatic ring, wherein each C 1-6 aliphatic and C 3-8 cycloaliphatic ring is optionally and independently substituted with 1, 2, or 3 independently selected R 3a substituents; and

each R 3a is independently halo, CN, C 1-4 alkyl, C 1-4 haloalkyl, OC 1-4 alkyl, or OC 1-4 haloalkyl; or

(ii) W is ring B;

ring B is C 3-7 cycloalkyl;

each J is independently H;

each J B is independently halo, CN, C 1-6 aliphatic, or OR B1 , wherein each C 1-6 aliphatic is optionally and independently substituted with 1, 2, or 3 independently selected R 3 substituents;

each R B1 is independently H, C 1-6 aliphatic, or a C 3-8 cycloaliphatic ring, wherein each C 1-6 aliphatic and C 3-8 cycloaliphatic ring is optionally and independently substituted with 1, 2, or 3 independently selected R 3b substituents; and

each R 3b is independently halo, CN, C 1-4 alkyl, C 1-4 haloalkyl, OC 1-4 alkyl, or OC 1-4 haloalkyl;

each J C is independently H, halo, CN, C 1-4 aliphatic, or OC 1-4 alkyl, wherein each C 1-4 aliphatic and OC 1-4 alkyl is optionally and independently substituted with 1, 2, or 3 substituents independently selected form the group consisting of halo, OH, OC 1-4 alkyl, and OC 1-4 haloalkyl;

each R 3 is independently halo, CN, C 1-4 alkyl, C 1-4 haloalkyl, OC 1-4 alkyl, or OC 1-4 haloalkyl;

G 1 is CH 2 OCH 2 CH 2 Si(CH 3 ) 3 , CH 2 CH 2 Si(CH 3 ) 3 , CH 2 CH(Ph)Si(CH 3 ) 3 , C(O)CH 3 , C(O)CF 3 , C(O)CH 2 -phenyl, C(O)OCH 2 CCl 3 , C(O)OCH 2 -phenyl, C(O)OCH 2 -(9-fluorenyl), C(O)OCH 2 CH 2 Si(CH 3 ) 3 , C(O)OCH 2 CH═CH 2 , C(O)OC(CH 3 ) 3 , OSi[CH(CH 3 ) 2 ] 3 , S(O) 2 CH 3 , S(O) 2 -(4-bromophenyl), S(O) 2 -(4-methylphenyl), S(O) 2 -(2-nitrophenyl), or S(O) 2 -(4-nitrophenyl);

n is 0, 1, 2, or 3; and

p is 1 or 2;

with a compound of the following formula:

R 11 C(O)OE′,

wherein:

E′ is C 1-6 alkyl, C 1-6 haloalkyl, heterocyclyl, phenyl, or heteroaryl, wherein the heterocyclyl, phenyl, or heteroaryl is optionally substituted with 1, 2, 3, 4, 5, or 6 substituents independently selected from the group consisting of halo, CN, NO 2 , ═O, S(O) 2 OH, and S(O) 2 OC 1-6 alkyl; and

R 11 is C 1-6 alkyl, C 2-6 alkenyl, or C 2-6 alkynyl, wherein the C 1-6 alkyl is optionally substituted with 1, 2, or 3 independently selected R 15 substituents, and further wherein the C 2-6 alkenyl or C 2-6 alkynyl is optionally substituted with 1 or 2 independently selected R b2 substituents;

each R 15 is independently halo, C(O)R b2 , C(O)NR a2 R b2 , NR a2 R b2 , NR b2 C(O)OR b2 , OR b2 , OC 2-4 alkenyl, OC(O)NR a2 R b2 , SR b2 , C 3-4 cycloalkyl, 3- to 10-membered heterocyclyl, phenyl, or a 5- or 6-membered heteroaryl, wherein each 3- to 10-membered heterocyclyl and 5- or 6-membered heteroaryl independently contains 1, 2, or 3 ring heteroatoms independently selected from the group consisting of N, O, and S, and further wherein each C 3-4 cycloalkyl, 3- to 10-membered heterocyclyl, phenyl, and 5- or 6-membered heteroaryl is optionally and independently substituted with 1, 2, or 3 independently selected R 18 substituents;

each R 18 is independently halo, C 1-6 alkyl, C 1-6 haloalkyl, OH, OC 1-6 alkyl, or phenyl;

each R a2 is independently H, C 1-6 alkyl, C 1-6 haloalkyl, or C(O)R b2 ; and

each R b2 is independently H, C 1-6 alkyl, or C 1-6 haloalkyl;

in the presence of a base selected from the group consisting of LiOH, NaOH, KOH, NaOCH 3 , N(alkyl) 3 , 1,8-diazabicyclo(5.4.0)undec-7-ene (DBU), 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), guanidine, 1,1,3,3-tetramethylguanidine, 4-dimethylaminopyridine (DMAP), and 1,4-diazabicyclo[2.2.2]octane (DABCO).

2. The process of claim 1 , wherein G 1 is C(O)CH 3 , C(O)CF 3 , C(O)CH 2 -phenyl, C(O)OCH 2 CCl 3 , C(O)OCH 2 -phenyl, C(O)OCH 2 -(9-fluorenyl), C(O)OCH 2 CH═CH 2 , C(O)OC(CH 3 ) 3 , S(O) 2 CH 3 , S(O) 2 -(4-bromophenyl), S(O) 2 -(4-methylphenyl), S(O) 2 -(2-nitrophenyl), or S(O) 2 -(4-nitrophenyl).

3. The process of claim 2 , wherein G 1 is C(O)CH 3 , C(O)CF 3 , C(O)CH 2 -phenyl, C(O)OCH 2 CCl 3 , C(O)OCH 2 -phenyl, C(O)OCH 2 -(9-fluorenyl), C(O)OC(CH 3 ) 3 , S(O) 2 CH 3 , S(O) 2 -(4-bromophenyl), S(O) 2 -(4-methylphenyl), S(O) 2 -(2-nitrophenyl), or S(O) 2 -(4-nitrophenyl).

4. The process of claim 1 , wherein E′ is C 1-6 alkyl, C 1-6 haloalkyl, heterocyclyl, phenyl, or heteroaryl, wherein the heterocyclyl, phenyl, or heteroaryl is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halo, CN, NO 2 , ═O, S(O) 2 OH, and S(O) 2 OC 1-6 alkyl.

5. The process of claim 1 , wherein R 11 is C 1-6 alkyl, wherein the C 1-6 alkyl is optionally substituted with 1, 2, or 3 independently selected halo substituents.

6. The process of claim 1 , wherein the base is selected from the group consisting of N(alkyl) 3 , 1,8-diazabicyclo(5.4.0)undec-7-ene (DBU), 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), guanidine, 1,1,3,3-tetramethylguanidine, 4-dimethylaminopyridine (DMAP), and 1,4-diazabicyclo[2.2.2]octane (DABCO).

7. The process of claim 1 , wherein:

the compound represented by Formula (IA) is represented by Formula (ID):

the compound represented by Formula (IIA) is represented by Formula (IID):

or a salt thereof.

8. The process of claim 7 , wherein:

the compound represented by Formula (ID) is represented by Formula (IE):

the compound represented by Formula (IID) is represented by Formula (IIE):

or a salt thereof.

9. The process of claim 8 , wherein:

the compound represented by Formula (IE) is represented by Formula (IF):

the compound represented by Formula (IIE) is represented by Formula (IIF):

or a salt thereof.

10. The process of claim 1 , wherein the compound of Formula (IA) is represented by Formula (IF):

wherein the process comprises the following step:

reacting a compound represented by Formula (IIFa):

or a salt thereof;

with a compound of the following formula:

R 11 C(O)OE′,

wherein:

E′ is CH 2 CF 3 ; and

R 11 is CF 3 ;

in the presence of a base selected from the group consisting of N(alkyl) 3 , 1,8-diazabicyclo(5.4.0)undec-7-ene (DBU), 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), guanidine, 1,1,3,3-tetramethylguanidine, 4-dimethylaminopyridine (DMAP), and 1,4-diazabicyclo[2.2.2]octane (DABCO).

11. The process of claim 10 , wherein the base is 1,4-diazabicyclo[2.2.2]octane (DABCO).