Substituted amidrazones as intermediates in the process for preparing soluble guanylate cyclase stimulators

1. A compound represented by Formula (IIA):

or a salt thereof,

wherein:

(i) W is absent;

each J is independently H or CH 3 ;

J B is C 1-7 alkyl, wherein the C 1-7 alkyl is optionally substituted with 1, 2, 3, 4, 5, 6, 7, 8, or 9 F substituents; and

n is 1; or

(ii) W is ring B;

ring B is phenyl or a 5- or 6-membered heteroaryl, wherein the 5- or 6-membered heteroaryl contains one or two nitrogen 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;

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

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

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

(iii) 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;

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

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

n is 0, 1, 2, or 3;

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;

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)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 , C(O)phenyl, 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); and

p is 1 or 2.

2. The compound of claim 1 , or a salt thereof, wherein ring B is phenyl or a 5- or 6-membered heteroaryl, wherein the 5- or 6-membered heteroaryl contains one or two nitrogen ring heteroatoms.

3. The compound of claim 2 , or a salt thereof, wherein:

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

each R 3 is independently halo;

each J C is independently H, halo, CN, or C 1-4 alkyl, wherein each C 1-4 alkyl is optionally and independently substituted with 1, 2, or 3 independently selected halo substituents; and

p is 1 or 2.

4. The compound of claim 1 , or a salt thereof, wherein G 1 is C(O)CH 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 , C(O)phenyl, 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).

5. The compound of claim 4 , or a salt thereof, wherein G 1 is C(O)CH 3 , C(O)OCH 2 CCl 3 , C(O)OCH 2 -phenyl, C(O)OCH 2 -(9-fluorenyl), C(O)OC(CH 3 ) 3 , C(O)phenyl, 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).

6. The compound of claim 1 , wherein the compound represented by Formula (IIA) is represented by Formula (IIB):

or a salt thereof.

7. The compound of claim 6 , wherein the compound represented by Formula (IIB) is represented by Formula (IIC):

or a salt thereof.

8. The compound of claim 7 , wherein the compound represented by Formula (IIC) is represented by Formula (IID):

or a salt thereof.

9. The compound of claim 8 , wherein the compound represented by Formula (IID) is represented by Formula (IIE):

or a salt thereof.

10. The compound of claim 9 , wherein the compound represented by Formula (IIE) is represented by Formula (IIF):

or a salt thereof.

11. The compound of claim 1 , wherein the compound is:

or a salt thereof.

12. A process for preparing a compound represented by Formula (IIA):

or a salt thereof,

wherein:

(i) W is absent;

each J is independently H or CH 3 ;

J B is C 1-7 alkyl, wherein the C 1-7 alkyl is optionally substituted with 1, 2, 3, 4, 5, 6, 7, 8, or 9 F substituents; and

n is 1; or

(ii) W is ring B;

ring B is phenyl or a 5- or 6-membered heteroaryl, wherein the 5- or 6-membered heteroaryl contains one or two nitrogen 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;

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

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

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

(iii) 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;

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

each R 31 is independently halo, CN, C 1-4 alkyl, C 1-4 haloalkyl, OC 1-4 alkyl, or OC 1-4 haloalkyl; and

n is 0, 1, 2, or 3;

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;

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)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 , C(O)phenyl, 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); and

p is 1 or 2;

wherein the process comprises the following steps:

(1) reacting a compound represented by Formula (IIIA):

or a salt thereof,

wherein:

(i) W is absent;

each J is independently H or CH 3 ;

J B is C 1-7 alkyl, wherein the C 1-7 alkyl is optionally substituted with 1, 2, 3, 4, 5, 6, 7, 8, or 9 F substituents; and

n is 1; or

(ii) W is ring B;

ring B is phenyl or a 5- or 6-membered heteroaryl, wherein the 5- or 6-membered heteroaryl contains one or two nitrogen 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 3 , substituents;

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

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

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

(iii) 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 3A substituents;

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

each R 31 is independently halo, CN, C 1-4 alkyl, C 1-4 haloalkyl, OC 1-4 alkyl, or OC-4 haloalkyl; and

n is 0, 1, 2, or 3;

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; and

p is 1 or 2;

first with a base, and second with a compound represented by Formula H 2 NNHG 1 :

H 2 NNHG 1 ,

wherein:

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)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 , C(O)phenyl, 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);

in a reaction solvent, to provide the compound represented by Formula (IIA) above; and

(2) optionally reacting the compound represented by Formula (IIA) provided in step (1) above with an acid or a base, to provide a salt of the compound represented by Formula (IIA).