IP Library › Granted Patent US 9,622,991

Granted Patent B2

US 9,622,991 · App. 14/713,930 · Granted Apr 18, 2017

Hematopoietic growth factor mimetic small molecule compounds and their uses

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Patent No.: US 9,622,991
App. No.: 14/713,930
Granted: Apr 18, 2017
Kind: B2

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Abstract

The present embodiments relate to compounds with physiological effects, such as the activation of hematopoietic growth factor receptors. The present embodiments also relate to use of the compounds to treat a variety of conditions, diseases and ailments such as hematopoietic conditions and disorders.

Claims (185)

1. A compound of formula VIIIb:

and pharmaceutically acceptable salts thereof,

wherein:

A-J is

and Q-G is

or A-J is

and Q-G is

or A-J is

and Q-G is

or A-J is

and Q-G is

each E is separately selected from the group consisting of —CR 10a — and N (nitrogen);

each R 10a is separately selected from the group consisting of H (hydrogen), halogen, cyano, C 1 -C 6 alkyl optionally substituted with up to five fluoro, C 1 -C 6 alkoxy optionally substituted with up to five fluoro, C 2 -C 6 alkenyl optionally substituted with up to five fluoro, C 2 -C 6 alkynyl optionally substituted with up to five fluoro, C 3 -C 7 cycloalkyl optionally substituted with up to five fluoro, and C 3 -C 7 cycloalkenyl optionally substituted with up to five fluoro;

A 4 is selected from the group consisting of C 3 -C 7 cycloalkenyl, C 3 -C 7 cycloalkyl, C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, C 1 -C 6 alkoxy, —(CH 2 ) m NR P R L , heterocycle, polycyclic heterocyclyl, aryl, and heteroaryl, said C 3 -C 7 cycloalkenyl, C 3 -C 7 cycloalkyl, C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, heterocycle, polycyclic heterocyclyl, aryl, and heteroaryl, each optionally substituted with one or more substituents selected from the group consisting of R 1 , R 2 , and R 3 ;

G 4 is selected from the group consisting of polycyclic heterocyclyl, aryl, and heteroaryl, each optionally substituted with one or more substituents selected from the group consisting of R 4 , R 5 , and R 6 ;

A 5 is selected from the group consisting of polycyclic heterocyclyl, aryl and heteroaryl, each optionally substituted with one or more substituents selected from the group consisting of R 1 , R 2 , and R 3 ;

each R B is separately selected from the group consisting of hydrogen, an optionally substituted C 1 -C 6 alkyl, an optionally substituted C 2 -C 6 alkenyl, and an optionally substituted C 3 -C 7 cycloalkyl;

each —NR E R F is separately selected, wherein each R E is independently selected from the group consisting of hydrogen and an optionally C 1 -C 6 alkyl, and each R F is independently selected from the group consisting of aryl and heteroaryl, said aryl and heteroaryl in the definition of R F are each optionally substituted with halogen, cyano, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 3 -C 7 cycloalkyl, C 3 -C 7 cycloalkenyl, —C(═O)NR N R O , —OC(═O)NR N R O , —NHC(═O)NR N R O , —O(CH 2 ) q NR N R O , —NH(CH 2 ) q NR N R O —(CH 2 ) p NR N R O , an optionally substituted aryl and an optionally substituted heteroaryl, and said aryl and heteroaryl in the definition of R F are each further optionally fused with an optionally substituted nonaromatic heterocycle or an optionally substituted nonaromatic carbocycle;

R G is selected from the group consisting of C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 3 -C 8 cycloalkenyl, C 1 -C 6 heteroalkyl, C 2 -C 6 heteroalkenyl, C 2 -C 6 heteroalkynyl, heterocycle, aryl, and heteroaryl, each optionally substituted with one or more substituents selected from the group consisting of R 4 , R 5 , and R 6 , said aryl and heteroaryl in the definition of R G are each further optionally fused with an optionally substituted nonaromatic heterocycle or an optionally substituted nonaromatic carbocycle, or R G is —OR L or —NR P R L ;

R H is selected from the group consisting of hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 3 -C 7 cycloalkyl, and C 1 -C 3 haloalkyl, or —NR G R H is an optionally substituted non-aromatic heterocycle linked through a ring nitrogen atom;

each R 1 is separately selected from the group consisting of halogen, cyano, an optionally substituted C 1 -C 6 alkyl, an optionally substituted C 1 -C 6 alkoxy, an optionally substituted C 2 -C 6 alkenyl, an optionally substituted C 2 -C 6 alkynyl, an optionally substituted C 3 -C 7 cycloalkyl, optionally substituted C 3 -C 7 cycloalkenyl, an optionally substituted C 1 -C 6 haloalkyl, an optionally substituted C 1 -C 6 heteroalkyl, an optionally substituted aryl, and an optionally substituted heteroaryl;

each R 2 is separately selected from the group consisting of halogen, —O(CH 2 ) m OR I , —(CH 2 ) m OR I , —NR J R K , —(CH 2 ) m SR I , —C(═O)R L , —(CH 2 ) m R L , an optionally substituted C 1 -C 6 alkyl, an optionally substituted C 1 -C 6 alkoxy, an optionally substituted C 2 -C 6 alkenyl, an optionally substituted C 1 -C 6 haloalkyl, an optionally substituted C 1 -C 6 heteroalkyl, and an optionally substituted C 3 -C 7 cycloalkyl where said C 3 -C 7 cycloalkyl is further optionally fused with aryl or heteroaryl;

each R 3 is separately selected from the group consisting of halogen, —(CH 2 ) m OR G , —NR L C(═O)R M , —NR L C(═O)OR M , —NR L C(═O)NR N R O , —NR N R O , —(CH 2 ) m S(O) 0-2 R M , —(CH 2 ) m NHS(O) 0-2 R M , —(CH 2 ) m NO 2 , —(CH 2 ) m CN, —(CH 2 ) m R P , C 1 -C 6 alkyl C 1 -C 6 alkoxy, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 7 cycloalkyl, C 1 -C 6 haloalkyl, heterocycle, aryl, polycyclic heterocyclyl, and heteroaryl, said heterocycle, aryl polycyclic heterocyclyl, and heteroaryl in the definition of R 3 are each optionally substituted with halogen, hydroxy, cyano, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, —C(═O)OR M , or —NR J R K ;

each R 4 is separately selected from the group consisting of halogen, cyano, an optionally substituted C 1 -C 6 alkyl, an optionally substituted C 1 -C 6 alkoxy, an optionally substituted C 2 -C 6 alkenyl, an optionally substituted C 2 -C 6 alkynyl, an optionally substituted C 3 -C 7 cycloalkyl, an optionally substituted C 1 -C 6 haloalkyl, an optionally substituted C 1 -C 6 heteroalkyl, an optionally substituted aryl, and an optionally substituted heteroaryl;

each R 5 is separately selected from the group consisting of halogen, —O(CH 2 ) m OR I , —(CH 2 ) m OR I , —NR J R K , —(CH 2 ) m SR I , —(CH 2 ) m C(═O)R L , —(CH 2 ) m R L , an optionally substituted C 1 -C 6 alkyl, an optionally substituted C 1 -C 6 alkoxy, an optionally substituted C 2 -C 6 alkenyl, an optionally substituted C 3 -C 7 cycloalkyl, an optionally substituted C 1 -C 6 haloalkyl, and an optionally substituted C 1 -C 6 heteroalkyl;

each R 6 is separately selected from the group consisting of halogen, —(CH 2 ) m OR G , —NR L C(═O)R M , —NR L C(═O)OR M , —NR L C(═O)NR N R O , —NR N R O , —(CH 2 ) m S(O) 0-2 R M , —(CH 2 ) m NHS(O) 0-2 R M , —(CH 2 ) m NO 2 , —(CH 2 ) m CN, —(CH 2 ) m R P , C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 7 cycloalkyl, C 1 -C 6 haloalkyl, C 1 -C 6 heteroalkyl, heterocycle, aryl, polycyclic heterocyclyl, and heteroaryl, said heterocycle, aryl, polycyclic heterocyclyl, and heteroaryl in the definition of R 6 are each optionally substituted with halogen, cyano, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, —C(═O)OR M , or —NR J R K ;

each R I is separately selected from the group consisting of hydrogen, C 1 -C 6 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 3 -C 7 cycloalkyl, C 1 -C 6 haloalkyl, C 1 -C 6 heteroalkyl, and C 1 -C 6 heterohaloalkyl;

each —NR J R K is separately selected, wherein R J and R K are each independently selected from the group consisting of hydrogen, C 1 -C 6 alkyl optionally substituted with up to 5 fluoro, —(CH 2 ) m OR JA , —(CH 2 ) m NR JB R JC , —(CH 2 ) m R R , C 3 -C 7 cycloalkyl, heterocycle, aryl and heteroaryl, said C 3 -C 7 cycloalkyl, heterocycle, aryl and heteroaryl in the definition of R J and R K are each independently optionally substituted with one or more substituents selected from the group consisting of halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, aryl and heteroaryl, said aryl and heteroaryl substituent off of R J and R K are each optionally substituted with one or more halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, or —(CH 2 ) m NR KA R KB ; or —NR J R K is an optionally substituted non-aromatic heterocycle linked through a ring nitrogen atom;

each R JA is independently selected from the group consisting of hydrogen, C 1 -C 6 alkyl, and C 1 -C 6 haloalkyl;

each —NR JB R JC is separately selected, wherein R JB and R JC are each independently selected from the group consisting of hydrogen, C 1 -C 6 alkyl, and C 1 -C 6 haloalkyl;

each —NR KA R KB is separately selected, wherein R KA and R KB are each independently selected from the group consisting of hydrogen, C 1 -C 6 alkyl, and C 1 -C 6 haloalkyl;

each R M is independently selected from the group consisting of hydrogen, an optionally substituted C 1 -C 6 alkyl, an optionally substituted C 2 -C 4 alkenyl, an optionally substituted C 2 -C 4 alkynyl, an optionally substituted C 3 -C 7 cycloalkyl, an optionally substituted C 3 -C 7 cycloalkenyl, and —(CH 2 ) m R P ;

each —NR N R O is separately selected, wherein R N and R O are each independently selected from the group consisting of hydrogen, —(CH 2 ) m NR NA R NB , aryl and heteroaryl, said aryl and heteroaryl in the definition of R N and R O are each independently optionally substituted with one or more substituents selected from the group consisting of —(CH 2 ) m NR OA R OB , halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, aryl and heteroaryl, said aryl and heteroaryl substituent off of R N and R O are each optionally substituted with one or more halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, or —NR NA R NB ,

each —NR NA R NB is separately selected, wherein R NA and R NB are each independently selected from the group consisting of hydrogen, C 1 -C 6 alkyl, and C 1 -C 6 haloalkyl;

each —NR OA R OB is separately selected, wherein R OA and R OB are each independently selected from the group consisting of hydrogen, C 1 -C 6 alkyl, and C 1 -C 6 haloalkyl;

each R P is independently selected from the group consisting of hydrogen and C 1 -C 6 alkyl;

each R L is independently selected from the group consisting of C 3 -C 7 cycloalkyl, optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 alkoxy, —(CH 2 ) m OR LA , —(CH 2 ) m NR LB R LC aryl and heteroaryl, said aryl and heteroaryl in the definition of R L are each independently optionally substituted with one or more substituents selected from the group consisting of halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, —(CH 2 ) m NR LD R LE , aryl and heteroaryl, said aryl and heteroaryl substituent off of R L are each optionally substituted with one or more halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, or —(CH 2 ) m NR LF R LG ;

each R LA is independently selected from the group consisting of hydrogen, C 1 -C 6 alkyl, and C 1 -C 6 haloalkyl;

R LB and R LC are each independently selected from the group consisting of hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, and C 2 -C 6 heteroalkenyl, said C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, and C 2 -C 6 heteroalkenyl each optionally substituted with one or more halogen, cyano, or —(CH 2 ) m C(═O)OH; or —NR LB R LC is an optionally substituted non-aromatic heterocycle linked through a ring nitrogen atom;

each —NR LD R LE is separately selected, wherein R LD and R LE are each independently selected from the group consisting of hydrogen, aryl, heteroaryl, and optionally substituted C 1 -C 6 alkyl, said aryl and heteroaryl in the definition of R LD and R LE are each optionally substituted with C 1 -C 6 alkyl or C 1 -C 6 alkoxy; or —NR LD R LE is an optionally substituted non-aromatic heterocycle linked through a ring nitrogen atom;

each —NR LF R LG is separately selected, wherein R LF and R LG are each independently selected from the group consisting of hydrogen, and C 1 -C 6 alkyl; or —NR LF R LG is an optionally substituted non-aromatic heterocycle linked through a ring nitrogen atom;

R R is selected from the group consisting of C 1 -C 6 alkyl, an optionally substituted aryl, and an optionally substituted heteroaryl;

each m is independently 0, 1, 2, or 3;

each p is independently 0, 1, 2, 3, 4, 5, or 6; and

each q is independently 1, 2, 3, 4, 5, or 6;

L 5 is E 1 =E 1 or E 2 -E 2 ;

each E 1 is separately selected from the group consisting of —CR 10dd — and N (nitrogen);

each R 10dd is separately selected from the group consisting of H (hydrogen), halogen, cyano, C 1 -C 6 alkyl optionally substituted with up to five fluoro, C 1 -C 6 alkoxy optionally substituted with up to five fluoro, C 1 -C 6 alkylC(═O)— and C 3 -C 7 cycloalkylC(═O)—;

each E 2 is separately selected from the group consisting of —CR 7 R 8 — and NR 9 ;

R 7 and R 8 are each independently selected from the group consisting of hydrogen, —OH, and C 1 -C 6 alkyl optionally substituted with up to five fluoro, or optionally CR 7 R 8 is —C(═O)—; and,

R 9 is selected from the group consisting of hydrogen, C 3 -C 7 cycloalkylC(O)— and C 1 -C 6 alkylC(O)—, and C 1 -C 6 alkyl optionally substituted with up to five fluoro.

2. The compound of claim 1 , having the formula VIIIbb:

and pharmaceutically acceptable salts thereof,

wherein:

E 1A is N (nitrogen) and E 1B is —CH—,

or E 1A is —CH— and E 1B is —CH—,

or E 1A is —CH— and E 1B is N (nitrogen); and

A-J is

and Q-G is

or A-J is

and Q-G is

or A-J is

and Q-G is

3. The compound of claim 2 , having the formula VIIIbbb:

and pharmaceutically acceptable salts thereof,

wherein:

A-J is

and Q-G is

or A-J is

and Q-G is

or A-J is

and Q-G is

A 4 is selected from the group consisting of C 5 -C 7 cycloalkenyl, C 3 -C 6 cycloalkyl, C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, —NR P R L , heterocycle, aryl, and heteroaryl, said C 5 -C 7 cycloalkenyl, C 3 -C 6 cycloalkyl, C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, C 2 -C 6 alkenyl, heterocycle, aryl, and heteroaryl, each optionally substituted with one or more substituents selected from the group consisting of R 1 , R 2 , and R 3 ;

each R 2 is separately selected from the group consisting of —O(CH 2 ) m OR I , —(CH 2 ) m OR I , —NR J R K , —(CH 2 ) m SR I , —C(═O)R L , and —(CH 2 ) m R L ;

each R 3 is separately selected from the group consisting of —(CH 2 ) m OR G , —NR L C(═O)R M , —NR L C(═O)OR M , —NR L C(═O)NR N R O , —NR N R O , —(CH 2 ) m S(O) 0-2 R M , —(CH 2 ) m NHS(O) 0-2 R M , —(CH 2 ) m NO 2 , —(CH 2 ) m CN, —(CH 2 ) m R P , heterocycle, aryl, polycyclic heterocyclyl, and heteroaryl, said heterocycle, aryl polycyclic heterocyclyl, and heteroaryl in the definition of R 3 are each optionally substituted with halogen, hydroxy, cyano, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, —C(═O)OR M , or —NR J R K ;

G 4 is selected from the group consisting of aryl, and heteroaryl, each optionally substituted with one or more substituents selected from the group consisting of R 4 , R 5 , and R 6 ;

each R 4 is separately selected from the group consisting of halogen, cyano, an optionally substituted C 1 -C 6 alkyl, and an optionally substituted C 1 -C 6 heteroalkyl;

each R 5 is separately selected from the group consisting of halogen, —(CH 2 ) m OH, —NR J R K , and —(CH 2 ) m C(═O)R L ;

each R L is independently selected from the group consisting of —OH, C 1 -C 6 alkyl, and C 1 -C 6 alkoxy;

each R 6 is separately selected from the group consisting of —NR L C(═O)R M , —NR L C(═O)OR M , —NR L C(═O)NR N R O , —NR N R O , —(CH 2 ) m R P , heterocycle, aryl, polycyclic heterocyclyl, and heteroaryl, said heterocycle, aryl, polycyclic heterocyclyl, and heteroaryl in the definition of R 6 are each optionally substituted with halogen, cyano, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, —C(═O)OR M , or —NR J R K ;

R G within the definition of —NR G R H is heteroaryl optionally substituted with one or more substituents selected from the group consisting of R 4 , R 5 , and R 6 ; and,

R H within the definition of —NR G R H is hydrogen.

4. A compound of Formula IX:

and pharmaceutically acceptable salts thereof;

wherein:

Z is

or —C(=E 3 )-;

each E is separately selected from the group consisting of —CR 10a — and N (nitrogen);

each R 10a is separately selected from the group consisting of H (hydrogen), halogen, C 1 -C 6 alkyl optionally substituted with up to five fluoro, and C 1 -C 6 alkoxy optionally substituted with up to five fluoro;

E 3 is O (oxygen), N—NHR Q or N—OR Q where R Q in the definition of E 3 is selected from the group consisting of hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, —(CH 2 ) m R RA , and —C(═O)(CH 2 ) m R RA ;

R RA is selected from the group consisting of C 1 -C 6 alkyl, aryl, and heteroaryl;

A 9 is hydrogen or C 1 -C 6 alkyl;

A 10 is selected from the group consisting of C 1 -C 6 alkyl, C 2 -C 6 alkenyl, —C(═O)R A , —C(═O)C(═O)R A , —(CH 2 )R B , —(CH 2 )OR B ;

R A is selected from the group consisting of C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl, heterocycle, polycyclic heterocyclyl, aryl and heteroaryl, each optionally substituted with one or more substituents selected from the group consisting of R 1 , R 2 , and R 3 ;

R B is selected from the group consisting of hydrogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyl, C 3 -C 7 cycloalkyl, and heteroaryl;

G 4 is selected from the group consisting of polycyclic heterocyclyl, phenyl, and heteroaryl, each optionally substituted with one or more substituents selected from the group consisting of R 4 , R 5 , and R 6 ;

each R 1 is separately selected from the group consisting of halogen, cyano, C 1 -C 6 heteroalkyl, an optionally substituted C 1 -C 6 alkyl, an optionally substituted C 1 -C 6 alkoxy, an optionally substituted C 2 -C 6 alkenyl, an optionally substituted C 2 -C 6 alkynyl, an optionally substituted C 3 -C 7 cycloalkyl, optionally substituted C 3 -C 7 cycloalkenyl, an optionally substituted C 1 -C 6 haloalkyl, an optionally substituted aryl, and an optionally substituted heteroaryl;

each R 2 is separately selected from the group consisting of halogen, —O(CH 2 ) m OR I , —(CH 2 ) m OR I , —NR J R K , —(CH 2 ) m SR I , —C(═O)R L , —(CH 2 ) m R L , C 1 -C 6 heteroalkyl, an optionally substituted C 1 -C 6 alkyl, an optionally substituted C 1 -C 6 alkoxy, an optionally substituted C 2 -C 6 alkenyl, an optionally substituted C 1 -C 6 haloalkyl, and an optionally substituted C 3 -C 7 cycloalkyl where said C 3 -C 7 cycloalkyl is further optionally fused with aryl or heteroaryl;

each R 3 is separately selected from the group consisting of halogen, —(CH 2 ) m OR G , —NR L C(═O)R M , —NR L C(═O)OR M , —NR L C(═O)NR N R O , —NR N R O , —(CH 2 ) m S(O) 0-2 R M , —(CH 2 ) m NHS(O) 0-2 R M , —(CH 2 ) m CN, —(CH 2 ) m R P , C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 7 cycloalkyl, C 1 -C 6 haloalkyl, heterocycle, aryl, polycyclic heterocyclyl, and heteroaryl, said heterocycle, aryl polycyclic heterocyclyl, and heteroaryl in the definition of R 3 are each optionally substituted with halogen, hydroxy, cyano, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, —C(═O)OR M , or —NR J R K ;

each R 4 is separately selected from the group consisting of halogen, cyano, C 1 -C 6 heteroalkyl, an optionally substituted C 1 -C 6 alkyl, an optionally substituted C 1 -C 6 alkoxy, an optionally substituted C 2 -C 6 alkenyl, an optionally substituted C 2 -C 6 alkynyl, an optionally substituted C 3 -C 7 cycloalkyl, an optionally substituted C 1 -C 6 haloalkyl, an optionally substituted aryl, and an optionally substituted heteroaryl;

each R 5 is separately selected from the group consisting of halogen, —O(CH 2 ) m OR I , —(CH 2 ) m OR I , —NR J R K , —(CH 2 ) m SR I , —(CH 2 ) m C(═O)R L , —(CH 2 ) m R L , C 1 -C 6 heteroalkyl, an optionally substituted C 1 -C 6 alkyl, an optionally substituted C 1 -C 6 alkoxy, an optionally substituted C 2 -C 6 alkenyl, an optionally substituted C 3 -C 7 cycloalkyl, and an optionally substituted C 1 -C 6 haloalkyl;

each R 6 is separately selected from the group consisting of halogen, —(CH 2 ) m OR G , —NR L C(═O)R M , —NR L C(═O)OR M , —NR L C(═O)NR N R O , —NR N R O , —(CH 2 ) m S(O) 0-2 R M , —(CH 2 ) m NHS(O) 0-2 R M , —(CH 2 ) m CN, —(CH 2 ) m R P , C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 7 cycloalkyl, C 1 -C 6 haloalkyl, C 1 -C 6 heteroalkyl, heterocycle, aryl, polycyclic heterocyclyl, and heteroaryl, said heterocycle, aryl, polycyclic heterocyclyl, and heteroaryl in the definition of R 6 are each optionally substituted with halogen, cyano, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, —C(═O)OR M , or —NR J R K ;

each R JA is independently selected from the group consisting of hydrogen, C 1 -C 6 alkyl, and C 1 -C 6 haloalkyl;

each —NR JB R JC is separately selected, wherein R JB and R JC are each independently selected from the group consisting of hydrogen, C 1 -C 6 alkyl, and C 1 -C 6 haloalkyl;

each —NR KA R KB is separately selected, wherein R KA and R KB are each independently selected from the group consisting of hydrogen, C 1 -C 6 alkyl, and C 1 -C 6 haloalkyl;

each —NR NA R NB is separately selected, wherein R NA and R NB are each independently selected from the group consisting of hydrogen, C 1 -C 6 alkyl, and C 1 -C 6 haloalkyl;

each —NR OA R OB is separately selected, wherein R OA and R OB are each independently selected from the group consisting of hydrogen, C 1 -C 6 alkyl, and C 1 -C 6 haloalkyl;

R P is selected from the group consisting of hydrogen and C 1 -C 6 alkyl;

each R L is independently selected from the group consisting of C 3 -C 7 cycloalkyl, optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 alkoxy, —(CH 2 ) m OR LA , —(CH 2 ) m NR LB R LC , aryl and heteroaryl, said aryl and heteroaryl in the definition of R L are each independently optionally substituted with one or more substituents selected from the group consisting of halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, —(CH 2 ) m NR LD R LE , aryl and heteroaryl, said aryl and heteroaryl substituent off of R L are each optionally substituted with one or more halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, or —(CH 2 ) m NR LE R LG ;

each R LA is independently selected from the group consisting of hydrogen, C 1 -C 6 alkyl, and C 1 -C 6 haloalkyl;

R LB and R LC are each independently selected from the group consisting of hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, and C 1 -C 6 heteroalkenyl, said C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, and C 1 -C 6 heteroalkenyl each optionally substituted with one or more halogen, cyano, or —(CH 2 ) m C(═O)OH; or —NR LB R LC is an optionally substituted non-aromatic heterocycle linked through a ring nitrogen atom;

R R is selected from the group consisting of C 1 -C 6 alkyl, an optionally substituted aryl, and an optionally substituted heteroaryl; and

each m is independently 0, 1, 2, or 3, having the proviso that a compound of Formula IX is not selected from the group consisting of:

5. The compound of claim 4 , having the formula IXa:

and pharmaceutically acceptable salts thereof,

wherein:

Z is

or —C(═O)—;

R A is selected from the group consisting of heterocycle, polycyclic heterocyclyl, aryl and heteroaryl, each substituted with one or more substituents selected from the group consisting of R 1 , R 2 , and R 3 ;

each R 1 is separately selected from the group consisting of chloro, cyano, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 7 cycloalkyl, C 3 -C 7 cycloalkenyl, and C 1 -C 6 haloalkyl;

each R 2 is separately selected from the group consisting of —O(CH 2 ) m OR I , —(CH 2 ) m OR I , —NR J R K , —(CH 2 ) m SR I , —C(═O)R L , and —(CH 2 ) m R L ; and

each R 3 is separately selected from the group consisting of —(CH 2 ) m OR G , —NR L C(═O)R M , —NR L C(═O)OR M , —NR L C(═O)NR N R O , —NR N R O , —(CH 2 ) m S(O) 0-2 R M , —(CH 2 ) m NHS(O) 0-2 R M , —(CH 2 ) m CN, —(CH 2 ) m R P , heterocycle, aryl, polycyclic heterocyclyl, and heteroaryl, said heterocycle, aryl polycyclic heterocyclyl, and heteroaryl in the definition of R 3 are each optionally substituted with halogen, hydroxy, cyano, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, —C(═O)OR M , or —NR J R K .

6. A compound of formula IXaa:

and pharmaceutically acceptable salts thereof,

wherein:

each R 3 is separately selected from the group consisting of halogen, —(CH 2 ) m OR G , —NR L C(═O)R M , —NR L C(═O)OR M , —NR L C(═O)NR N R O , —NR N R O , —(CH 2 ) m S(O) 0-2 R M , —(CH 2 ) m NHS(O) 0-2 R M , —(CH 2 ) m CN, —(CH 2 ) m R P , C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 7 cycloalkyl, C 1 -C 6 haloalkyl, heterocycle, aryl, polycyclic heterocyclyl, and heteroaryl, said heterocycle, aryl polycyclic heterocyclyl, and heteroaryl in the definition of R 3 are each optionally substituted with halogen, hydroxy, cyano, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, —C(═O)OR M , or —NR J R K ;

G 4 is selected from the group consisting of polycyclic heterocyclyl, aryl, and heteroaryl, each substituted with one or more substituents selected from the group consisting of R 4 , R 5 , and R 6 ;

each R 4 is separately selected from the group consisting of chloro, cyano, an optionally substituted C 1 -C 6 alkyl, an optionally substituted C 1 -C 6 alkoxy, an optionally substituted C 2 -C 6 alkenyl, an optionally substituted C 2 -C 6 alkynyl, an optionally substituted C 3 -C 7 cycloalkyl, an optionally substituted C 1 -C 6 haloalkyl, an optionally substituted C 1 -C 6 heteroalkyl, an optionally substituted aryl, and an optionally substituted heteroaryl;

each R 5 is separately selected from the group consisting of —O(CH 2 ) m OR I , —(CH 2 ) m OR I , —NR J R K , —(CH 2 ) m SR I , —(CH 2 ) m C(═O)R L , —(CH 2 ) m R L , an optionally substituted C 1 -C 6 alkyl, an optionally substituted C 1 -C 6 alkoxy, an optionally substituted C 2 -C 6 alkenyl, an optionally substituted C 3 -C 7 cycloalkyl, an optionally substituted C 1 -C 6 haloalkyl, and an optionally substituted C 1 -C 6 heteroalkyl;

each R 6 is separately selected from the group consisting of —(CH 2 ) m OR G , —NR L C(═O)R M , —NR L C(═O)OR M , —NR L C(═O)NR N R O , —NR N R O , —(CH 2 ) m S(O) 0-2 R M , —(CH 2 ) m NHS(O) 0-2 R M , —(CH 2 ) m NO 2 , —(CH 2 ) m CN, (CH 2 ) m R P , C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 7 cycloalkyl, C 1 -C 6 haloalkyl, C 1 -C 6 heteroalkyl, heterocycle, aryl, polycyclic heterocyclyl, and heteroaryl, said heterocycle, aryl, polycyclic heterocyclyl, and heteroaryl in the definition of R 6 are each optionally substituted with halogen, cyano, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, —C(═O)OR M , or —NR J R K ;

each —NR J R K is separately selected, wherein R J and R K are each independently selected from the group consisting of hydrogen, C 1 -C 6 alkyl optionally substituted with up to 5 fluoro, —(CH 2 ) m OR JA , —(CH 2 ) m NR JB R JC , —(CH 2 ) m R R , C 3 -C 7 cycloalkyl, heterocycle, aryl and heteroaryl, said C 3 -C 7 cycloalkyl, heterocycle, aryl and heteroaryl in the definition of R J and R K are each independently optionally substituted with one or more substituents selected from the group consisting of halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, aryl and heteroaryl, said aryl and heteroaryl substituent off of R J and R K are each optionally substituted with one or more halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, or —(CH 2 ) m NR KA R KB , or —NR J R K is an optionally substituted non-aromatic heterocycle linked through a ring nitrogen atom;

each R JA is independently selected from the group consisting of hydrogen, C 1 -C 6 alkyl, and C 1 -C 6 haloalkyl;

each —NR JB R JC is separately selected, wherein R JB and R JC are each independently selected from the group consisting of hydrogen, C 1 -C 6 alkyl, and C 1 -C 6 haloalkyl;

each —NR KA R KB is separately selected, wherein R KA and R KB are each independently selected from the group consisting of hydrogen, C 1 -C 6 alkyl, and C 1 -C 6 haloalkyl;

each —NR N R O is separately selected, wherein R N and R O are each independently selected from the group consisting of hydrogen, —(CH 2 ) m NR NA R NB , aryl and heteroaryl, said and heteroaryl in the definition of R N and R O are each independently optionally substituted with one or more substituents selected from the group consisting of —(CH 2 ) m NR OA R OB , halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, aryl and heteroaryl, said aryl and heteroaryl substituent off of R N and R O are each optionally substituted with one or more halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, or —NR NA R NB ,

each —NR NA R NB is separately selected, wherein R NA and R NB are each independently selected from the group consisting of hydrogen, C 1 -C 6 alkyl, and C 1 -C 6 haloalkyl;

each —NR OA R OB is separately selected, wherein R OA and R OB are each independently selected from the group consisting of hydrogen, C 1 -C 6 alkyl, and C 1 -C 6 haloalkyl;

R P is selected from the group consisting of hydrogen and C 1 -C 6 alkyl;

each R L is independently selected from the group consisting of C 3 -C 7 cycloalkyl, optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 alkoxy, —(CH 2 ) m OR LA , —(CH 2 ) m NR LB R LC , aryl and heteroaryl, said aryl and heteroaryl in the definition of R L are each independently optionally substituted with one or more substituents selected from the group consisting of halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, —(CH 2 ) m NR LD R LE , aryl and heteroaryl, said aryl and heteroaryl substituent off of R L are each optionally substituted with one or more halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, or —(CH 2 ) m NR LF R LG ;

each R LA is independently selected from the group consisting of hydrogen, C 1 -C 6 alkyl, and C 1 -C 6 haloalkyl;

R LD and R LC are each independently selected from the group consisting of hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, and C 1 -C 6 heteroalkenyl, said C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, and C 1 -C 6 heteroalkenyl each optionally substituted with one or more halogen, cyano, or —(CH 2 ) m C(═O)OH; or —NR LD R LC is an optionally substituted non-aromatic heterocycle linked through a ring nitrogen atom;

R R is selected from the group consisting of C 1 -C 6 alkyl, an optionally substituted aryl, and an optionally substituted heteroaryl; and

each m is independently 0, 1, 2, or 3, having the proviso that the compound of Formula IXaa is not selected from the group consisting of:

7. The compound of claim 5 , wherein:

each R 1 is separately selected from the group consisting of cyano, an optionally substituted C 1 -C 6 alkyl, an optionally substituted C 1 -C 6 alkoxy, an optionally substituted C 1 -C 6 heteroalkyl, an optionally substituted aryl, and an optionally substituted heteroaryl;

each R 2 is separately selected from the group consisting of —O(CH 2 ) m OR I , —(CH 2 ) m OR I , —NR J R K , —(CH 2 ) m SR I , —C(═O)R L , and —(CH 2 ) m R L ;

each R 4 is separately selected from the group consisting of cyano, an optionally substituted C 1 -C 6 alkyl, and an optionally substituted C 1 -C 6 heteroalkyl;

each R 5 is separately selected from the group consisting of —(CH 2 ) m OH, —NR J R K , and —(CH 2 ) m C(═O)R L ;

each R L is independently selected from the group consisting of —OH, C 1 -C 6 alkyl, and C 1 -C 6 alkoxy; and

8. A compound of claim 1 that is an HGF mimetic, an HGF receptor agonist or an HGF receptor antagonist.

9. A compound of claim 1 that is a hematopoietic growth factor mimetic, a hematopoietic growth factor receptor agonist or a hematopoietic growth factor receptor antagonist.

10. A compound of claim 1 that is an EPO mimic.

11. A compound of claim 1 that is a selective EPO receptor agonist.

12. A compound of claim 1 to that is a selective EPO receptor partial agonist.

13. A compound of claim 1 that is a selective EPO receptor antagonist.

14. A compound of claim 1 that is a selective EPO receptor binding compound.

15. A method for modulating an EPO activity in a cell comprising contacting a cell with a compound of claim 1 .

16. A method for identifying a compound that modulates an EPO activity, comprising contacting a cell that expresses an EPO receptor with a compound of claim 1 ; and monitoring an effect of the compound on the cell.

17. A method of treating thrombocytopenia in a patient, comprising administering to the patient a therapeutically effective amount of a compound of claim 1 .

18. The method of claim 17 , wherein the thrombocytopenia results from radiation or chemotherapy.

19. The method of claim 18 , further comprising harvesting cells from the patient.

20. A method of treating a patient suffering from an anemia, a neutropenia, a cardiovascular disorder, an immune/autoimmune disorder, or a neurologic disorder, comprising administering to the patient a therapeutically effective amount of a compound of claim 1 .

21. A pharmaceutical composition comprising a physiologically acceptable carrier, diluent, or excipient; and a compound of claim 1 .

22. A compound of claim 1 selected from the group consisting of

or a pharmaceutically acceptable salt thereof.

23. A compound of claim 4 selected from the group consisting of

or a pharmaceutically acceptable salt thereof.

Assignments (2)

SECURITY INTEREST Recorded Oct 18, 2023

From: CYDEX PHARMACEUTICALS, INC.; LIGAND PHARMACEUTICALS INCORPORATED; METABASIS THERAPEUTICS, INC.; PFENEX INC.

To: CITIBANK, N.A., AS ADMINISTRATIVE AGENT

Reel/Frame 065271/0025 →

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jun 17, 2015

From: ZHI, LIN; HUDSON, ANDREW R.; VAN OEVEREN, CORNELIS A.; ROACH, STEVEN L.; PEDRAM, BIJAN; SHEN, YIXING; VALDEZ, LINO J.; BASINGER, JILLIAN; GRANT, VIRGINIA HEATHER SHARRON; PICKENS, JASON C.

To: LIGAND PHARMACEUTICALS INC.

Reel/Frame 035940/0961 →