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US 9,622,991 B2Granted
Hematopoietic growth factor mimetic small molecule compounds and their uses
AssigneeLigand Pharmaceuticals Incorporated
InventorsLin Zhi, Andrew R. Hudson, Cornelis A. Van Oeveren, Steven L. Roach, Bijan Pedram, Yixing Shen, Lino J. Valdez, Jillian Basinger, Virginia Heather Sharron Grant, Jason C. Pickens
Life of this patent
Estimating the term…
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.
Claims23
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 —CR10a— and N (nitrogen);
- each R10a is separately selected from the group consisting of H (hydrogen), halogen, cyano, C1-C6 alkyl optionally substituted with up to five fluoro, C1-C6 alkoxy optionally substituted with up to five fluoro, C2-C6 alkenyl optionally substituted with up to five fluoro, C2-C6 alkynyl optionally substituted with up to five fluoro, C3-C7 cycloalkyl optionally substituted with up to five fluoro, and C3-C7 cycloalkenyl optionally substituted with up to five fluoro;
- A4 is selected from the group consisting of C3-C7 cycloalkenyl, C3-C7 cycloalkyl, C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C1-C6 alkoxy, —(CH2)mNRPRL, heterocycle, polycyclic heterocyclyl, aryl, and heteroaryl, said C3-C7 cycloalkenyl, C3-C7 cycloalkyl, C1-C6 alkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, heterocycle, polycyclic heterocyclyl, aryl, and heteroaryl, each optionally substituted with one or more substituents selected from the group consisting of R1, R2, and R3;
- G4 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 R4, R5, and R6;
- A5 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 R1, R2, and R3;
- each RB is separately selected from the group consisting of hydrogen, an optionally substituted C1-C6 alkyl, an optionally substituted C2-C6 alkenyl, and an optionally substituted C3-C7 cycloalkyl;
- each —NRERF is separately selected, wherein each RE is independently selected from the group consisting of hydrogen and an optionally C1-C6 alkyl, and each RF is independently selected from the group consisting of aryl and heteroaryl, said aryl and heteroaryl in the definition of RF are each optionally substituted with halogen, cyano, C1-C6 alkyl, C1-C6 alkoxy, C3-C7 cycloalkyl, C3-C7 cycloalkenyl, —C(═O)NRNRO, —OC(═O)NRNRO, —NHC(═O)NRNRO, —O(CH2)qNRNRO, —NH(CH2)qNRNRO—(CH2)pNRNRO, an optionally substituted aryl and an optionally substituted heteroaryl, and said aryl and heteroaryl in the definition of RF are each further optionally fused with an optionally substituted nonaromatic heterocycle or an optionally substituted nonaromatic carbocycle;
- RG is selected from the group consisting of C1-C6 alkyl, C3-C6 cycloalkyl, C3-C8 cycloalkenyl, C1-C6 heteroalkyl, C2-C6 heteroalkenyl, C2-C6 heteroalkynyl, heterocycle, aryl, and heteroaryl, each optionally substituted with one or more substituents selected from the group consisting of R4, R5, and R6, said aryl and heteroaryl in the definition of RG are each further optionally fused with an optionally substituted nonaromatic heterocycle or an optionally substituted nonaromatic carbocycle, or RG is —ORL or —NRPRL;
- RH is selected from the group consisting of hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C3-C7 cycloalkyl, and C1-C3 haloalkyl, or —NRGRH is an optionally substituted non-aromatic heterocycle linked through a ring nitrogen atom;
- each R1 is separately selected from the group consisting of halogen, cyano, an optionally substituted C1-C6 alkyl, an optionally substituted C1-C6 alkoxy, an optionally substituted C2-C6 alkenyl, an optionally substituted C2-C6 alkynyl, an optionally substituted C3-C7 cycloalkyl, optionally substituted C3-C7 cycloalkenyl, an optionally substituted C1-C6 haloalkyl, an optionally substituted C1-C6 heteroalkyl, an optionally substituted aryl, and an optionally substituted heteroaryl;
- each R2 is separately selected from the group consisting of halogen, —O(CH2)mORI, —(CH2)mORI, —NRJRK, —(CH2)mSRI, —C(═O)RL, —(CH2)mRL, an optionally substituted C1-C6 alkyl, an optionally substituted C1-C6 alkoxy, an optionally substituted C2-C6 alkenyl, an optionally substituted C1-C6 haloalkyl, an optionally substituted C1-C6 heteroalkyl, and an optionally substituted C3-C7 cycloalkyl where said C3-C7 cycloalkyl is further optionally fused with aryl or heteroaryl;
- each R3 is separately selected from the group consisting of halogen, —(CH2)mORG, —NRLC(═O)RM, —NRLC(═O)ORM, —NRLC(═O)NRNRO, —NRNRO, —(CH2)mS(O)0-2RM, —(CH2)mNHS(O)0-2RM, —(CH2)mNO2, —(CH2)mCN, —(CH2)mRP, C1-C6 alkyl C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, C1-C6 haloalkyl, heterocycle, aryl, polycyclic heterocyclyl, and heteroaryl, said heterocycle, aryl polycyclic heterocyclyl, and heteroaryl in the definition of R3 are each optionally substituted with halogen, hydroxy, cyano, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, —C(═O)ORM, or —NRJRK;
- each R4 is separately selected from the group consisting of halogen, cyano, an optionally substituted C1-C6 alkyl, an optionally substituted C1-C6 alkoxy, an optionally substituted C2-C6 alkenyl, an optionally substituted C2-C6 alkynyl, an optionally substituted C3-C7 cycloalkyl, an optionally substituted C1-C6 haloalkyl, an optionally substituted C1-C6 heteroalkyl, an optionally substituted aryl, and an optionally substituted heteroaryl;
- each R5 is separately selected from the group consisting of halogen, —O(CH2)mORI, —(CH2)mORI, —NRJRK, —(CH2)mSRI, —(CH2)mC(═O)RL, —(CH2)mRL, an optionally substituted C1-C6 alkyl, an optionally substituted C1-C6 alkoxy, an optionally substituted C2-C6 alkenyl, an optionally substituted C3-C7 cycloalkyl, an optionally substituted C1-C6 haloalkyl, and an optionally substituted C1-C6 heteroalkyl;
- each R6 is separately selected from the group consisting of halogen, —(CH2)mORG, —NRLC(═O)RM, —NRLC(═O)ORM, —NRLC(═O)NRNRO, —NRNRO, —(CH2)mS(O)0-2RM, —(CH2)mNHS(O)0-2RM, —(CH2)mNO2, —(CH2)mCN, —(CH2)mRP, C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, C1-C6 haloalkyl, C1-C6 heteroalkyl, heterocycle, aryl, polycyclic heterocyclyl, and heteroaryl, said heterocycle, aryl, polycyclic heterocyclyl, and heteroaryl in the definition of R6 are each optionally substituted with halogen, cyano, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, —C(═O)ORM, or —NRJRK;
- each RI is separately selected from the group consisting of hydrogen, C1-C6 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C7 cycloalkyl, C1-C6 haloalkyl, C1-C6 heteroalkyl, and C1-C6 heterohaloalkyl;
- each —NRJRK is separately selected, wherein RJ and RK are each independently selected from the group consisting of hydrogen, C1-C6 alkyl optionally substituted with up to 5 fluoro, —(CH2)mORJA, —(CH2)mNRJBRJC, —(CH2)mRR, C3-C7 cycloalkyl, heterocycle, aryl and heteroaryl, said C3-C7 cycloalkyl, heterocycle, aryl and heteroaryl in the definition of RJ and RK are each independently optionally substituted with one or more substituents selected from the group consisting of halo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, aryl and heteroaryl, said aryl and heteroaryl substituent off of RJ and RK are each optionally substituted with one or more halo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, or —(CH2)mNRKARKB;
- or —NRJRK is an optionally substituted non-aromatic heterocycle linked through a ring nitrogen atom;
- each RJA is independently selected from the group consisting of hydrogen, C1-C6 alkyl, and C1-C6 haloalkyl;
- each —NRJBRJC is separately selected, wherein RJB and RJC are each independently selected from the group consisting of hydrogen, C1-C6 alkyl, and C1-C6 haloalkyl;
- each —NRKARKB is separately selected, wherein RKA and RKB are each independently selected from the group consisting of hydrogen, C1-C6 alkyl, and C1-C6 haloalkyl;
- each RM is independently selected from the group consisting of hydrogen, an optionally substituted C1-C6 alkyl, an optionally substituted C2-C4 alkenyl, an optionally substituted C2-C4 alkynyl, an optionally substituted C3-C7 cycloalkyl, an optionally substituted C3-C7 cycloalkenyl, and —(CH2)mRP;
- each —NRNRO is separately selected, wherein RN and RO are each independently selected from the group consisting of hydrogen, —(CH2)mNRNARNB, aryl and heteroaryl, said aryl and heteroaryl in the definition of RN and RO are each independently optionally substituted with one or more substituents selected from the group consisting of —(CH2)mNROAROB, halo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, aryl and heteroaryl, said aryl and heteroaryl substituent off of RN and RO are each optionally substituted with one or more halo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, or —NRNARNB,
- each —NRNARNB is separately selected, wherein RNA and RNB are each independently selected from the group consisting of hydrogen, C1-C6 alkyl, and C1-C6 haloalkyl;
- each —NROAROB is separately selected, wherein ROA and ROB are each independently selected from the group consisting of hydrogen, C1-C6 alkyl, and C1-C6 haloalkyl;
- each RP is independently selected from the group consisting of hydrogen and C1-C6 alkyl;
- each RL is independently selected from the group consisting of C3-C7 cycloalkyl, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy, —(CH2)mORLA, —(CH2)mNRLBRLC aryl and heteroaryl, said aryl and heteroaryl in the definition of RL are each independently optionally substituted with one or more substituents selected from the group consisting of halo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, —(CH2)mNRLDRLE, aryl and heteroaryl, said aryl and heteroaryl substituent off of RL are each optionally substituted with one or more halo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, or —(CH2)mNRLFRLG;
- each RLA is independently selected from the group consisting of hydrogen, C1-C6 alkyl, and C1-C6 haloalkyl;
- RLB and RLC are each independently selected from the group consisting of hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, and C2-C6 heteroalkenyl, said C1-C6 alkyl, C1-C6 haloalkyl, and C2-C6 heteroalkenyl each optionally substituted with one or more halogen, cyano, or —(CH2)mC(═O)OH;
- or —NRLBRLC is an optionally substituted non-aromatic heterocycle linked through a ring nitrogen atom;
- each —NRLDRLE is separately selected, wherein RLD and RLE are each independently selected from the group consisting of hydrogen, aryl, heteroaryl, and optionally substituted C1-C6 alkyl, said aryl and heteroaryl in the definition of RLD and RLE are each optionally substituted with C1-C6 alkyl or C1-C6 alkoxy;
- or —NRLDRLE is an optionally substituted non-aromatic heterocycle linked through a ring nitrogen atom;
- each —NRLFRLG is separately selected, wherein RLF and RLG are each independently selected from the group consisting of hydrogen, and C1-C6 alkyl;
- or —NRLFRLG is an optionally substituted non-aromatic heterocycle linked through a ring nitrogen atom;
- RR is selected from the group consisting of C1-C6 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;
- L5 is E1=E1 or E2-E2;
- each E1 is separately selected from the group consisting of —CR10dd— and N (nitrogen);
- each R10dd is separately selected from the group consisting of H (hydrogen), halogen, cyano, C1-C6 alkyl optionally substituted with up to five fluoro, C1-C6 alkoxy optionally substituted with up to five fluoro, C1-C6 alkylC(═O)— and C3-C7 cycloalkylC(═O)—;
- each E2 is separately selected from the group consisting of —CR7R8— and NR9;
- R7 and R8 are each independently selected from the group consisting of hydrogen, —OH, and C1-C6 alkyl optionally substituted with up to five fluoro, or optionally CR7R8 is —C(═O)—;
- and,
- R9 is selected from the group consisting of hydrogen, C3-C7cycloalkylC(O)— and C1-C6 alkylC(O)—, and C1-C6 alkyl optionally substituted with up to five fluoro.
53 more elements
A compound of Formula IX:
- and pharmaceutically acceptable salts thereof;
- wherein:
- Z is
- or —C(=E3)-;
- each E is separately selected from the group consisting of —CR10a— and N (nitrogen);
- each R10a is separately selected from the group consisting of H (hydrogen), halogen, C1-C6 alkyl optionally substituted with up to five fluoro, and C1-C6 alkoxy optionally substituted with up to five fluoro;
- E3 is O (oxygen), N—NHRQ or N—ORQ where RQ in the definition of E3 is selected from the group consisting of hydrogen, C1-C6 alkyl, C2-C6 alkenyl, —(CH2)mRRA, and —C(═O)(CH2)mRRA;
- RRA is selected from the group consisting of C1-C6 alkyl, aryl, and heteroaryl;
- A9 is hydrogen or C1-C6 alkyl;
- A10 is selected from the group consisting of C1-C6 alkyl, C2-C6 alkenyl, —C(═O)RA, —C(═O)C(═O)RA, —(CH2)RB, —(CH2)ORB;
- RA is selected from the group consisting of C1-C6 alkyl, C3-C7 cycloalkyl, heterocycle, polycyclic heterocyclyl, aryl and heteroaryl, each optionally substituted with one or more substituents selected from the group consisting of R1, R2, and R3;
- RB is selected from the group consisting of hydrogen, C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C3-C7 cycloalkyl, and heteroaryl;
- G4 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 R4, R5, and R6;
- each R1 is separately selected from the group consisting of halogen, cyano, C1-C6 heteroalkyl, an optionally substituted C1-C6 alkyl, an optionally substituted C1-C6 alkoxy, an optionally substituted C2-C6 alkenyl, an optionally substituted C2-C6 alkynyl, an optionally substituted C3-C7 cycloalkyl, optionally substituted C3-C7 cycloalkenyl, an optionally substituted C1-C6 haloalkyl, an optionally substituted aryl, and an optionally substituted heteroaryl;
- each R2 is separately selected from the group consisting of halogen, —O(CH2)mORI, —(CH2)mORI, —NRJRK, —(CH2)mSRI, —C(═O)RL, —(CH2)mRL, C1-C6 heteroalkyl, an optionally substituted C1-C6 alkyl, an optionally substituted C1-C6 alkoxy, an optionally substituted C2-C6 alkenyl, an optionally substituted C1-C6 haloalkyl, and an optionally substituted C3-C7 cycloalkyl where said C3-C7 cycloalkyl is further optionally fused with aryl or heteroaryl;
- each R3 is separately selected from the group consisting of halogen, —(CH2)mORG, —NRLC(═O)RM, —NRLC(═O)ORM, —NRLC(═O)NRNRO, —NRNRO, —(CH2)mS(O)0-2RM, —(CH2)mNHS(O)0-2RM, —(CH2)mCN, —(CH2)mRP, C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, C1-C6 haloalkyl, heterocycle, aryl, polycyclic heterocyclyl, and heteroaryl, said heterocycle, aryl polycyclic heterocyclyl, and heteroaryl in the definition of R3 are each optionally substituted with halogen, hydroxy, cyano, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, —C(═O)ORM, or —NRJRK;
- each R4 is separately selected from the group consisting of halogen, cyano, C1-C6 heteroalkyl, an optionally substituted C1-C6 alkyl, an optionally substituted C1-C6 alkoxy, an optionally substituted C2-C6 alkenyl, an optionally substituted C2-C6 alkynyl, an optionally substituted C3-C7 cycloalkyl, an optionally substituted C1-C6 haloalkyl, an optionally substituted aryl, and an optionally substituted heteroaryl;
- each R5 is separately selected from the group consisting of halogen, —O(CH2)mORI, —(CH2)mORI, —NRJRK, —(CH2)mSRI, —(CH2)mC(═O)RL, —(CH2)mRL, C1-C6 heteroalkyl, an optionally substituted C1-C6 alkyl, an optionally substituted C1-C6 alkoxy, an optionally substituted C2-C6 alkenyl, an optionally substituted C3-C7 cycloalkyl, and an optionally substituted C1-C6 haloalkyl;
- each R6 is separately selected from the group consisting of halogen, —(CH2)mORG, —NRLC(═O)RM, —NRLC(═O)ORM, —NRLC(═O)NRNRO, —NRNRO, —(CH2)mS(O)0-2RM, —(CH2)mNHS(O)0-2RM, —(CH2)mCN, —(CH2)mRP, C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, C1-C6 haloalkyl, C1-C6 heteroalkyl, heterocycle, aryl, polycyclic heterocyclyl, and heteroaryl, said heterocycle, aryl, polycyclic heterocyclyl, and heteroaryl in the definition of R6 are each optionally substituted with halogen, cyano, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, —C(═O)ORM, or —NRJRK;
- RG is selected from the group consisting of C1-C6 alkyl, C3-C6 cycloalkyl, C3-C8 cycloalkenyl, C1-C6 heteroalkyl, C2-C6 heteroalkenyl, C2-C6 heteroalkynyl, heterocycle, aryl, and heteroaryl, each optionally substituted with one or more substituents selected from the group consisting of R4, R5, and R6, said aryl and heteroaryl in the definition of RG are each further optionally fused with an optionally substituted nonaromatic heterocycle or an optionally substituted nonaromatic carbocycle, or RG is —ORL or —NRPRL;
- each RI is separately selected from the group consisting of hydrogen, C1-C6 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C7 cycloalkyl, C1-C6 haloalkyl, C1-C6 heteroalkyl, and C1-C6 heterohaloalkyl;
- each —NRJRK is separately selected, wherein RJ and RK are each independently selected from the group consisting of hydrogen, C1-C6 alkyl optionally substituted with up to 5 fluoro, —(CH2)mORJA, —(CH2)mNRJBRJC, —(CH2)mRR, C3-C7 cycloalkyl, heterocycle, aryl and heteroaryl, said C3-C7 cycloalkyl, heterocycle, aryl and heteroaryl in the definition of RJ and RK are each independently optionally substituted with one or more substituents selected from the group consisting of halo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, aryl and heteroaryl, said aryl and heteroaryl substituent off of RJ and RK are each optionally substituted with one or more halo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, or —(CH2)mNRKARKB;
- or —NRJRK is an optionally substituted non-aromatic heterocycle linked through a ring nitrogen atom;
- each RJA is independently selected from the group consisting of hydrogen, C1-C6 alkyl, and C1-C6 haloalkyl;
- each —NRJBRJC is separately selected, wherein RJB and RJC are each independently selected from the group consisting of hydrogen, C1-C6 alkyl, and C1-C6 haloalkyl;
- each —NRKARKB is separately selected, wherein RKA and RKB are each independently selected from the group consisting of hydrogen, C1-C6 alkyl, and C1-C6 haloalkyl;
- each RM is independently selected from the group consisting of hydrogen, an optionally substituted C1-C6 alkyl, an optionally substituted C2-C4 alkenyl, an optionally substituted C2-C4 alkynyl, an optionally substituted C3-C7 cycloalkyl, an optionally substituted C3-C7 cycloalkenyl, and —(CH2)mRP;
- each —NRNRO is separately selected, wherein RN and RO are each independently selected from the group consisting of hydrogen, —(CH2)mNRNARNB, aryl and heteroaryl, said aryl and heteroaryl in the definition of RN and RO are each independently optionally substituted with one or more substituents selected from the group consisting of —(CH2)mNROAROB, halo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, aryl and heteroaryl, said aryl and heteroaryl substituent off of RN and RO are each optionally substituted with one or more halo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, or —NRNARNB,
- each —NRNARNB is separately selected, wherein RNA and RNB are each independently selected from the group consisting of hydrogen, C1-C6 alkyl, and C1-C6 haloalkyl;
- each —NROAROB is separately selected, wherein ROA and ROB are each independently selected from the group consisting of hydrogen, C1-C6 alkyl, and C1-C6 haloalkyl;
- RP is selected from the group consisting of hydrogen and C1-C6 alkyl;
- each RL is independently selected from the group consisting of C3-C7 cycloalkyl, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy, —(CH2)mORLA, —(CH2)mNRLBRLC, aryl and heteroaryl, said aryl and heteroaryl in the definition of RL are each independently optionally substituted with one or more substituents selected from the group consisting of halo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, —(CH2)mNRLDRLE, aryl and heteroaryl, said aryl and heteroaryl substituent off of RL are each optionally substituted with one or more halo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, or —(CH2)mNRLERLG;
- each RLA is independently selected from the group consisting of hydrogen, C1-C6 alkyl, and C1-C6 haloalkyl;
- RLB and RLC are each independently selected from the group consisting of hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, and C1-C6 heteroalkenyl, said C1-C6 alkyl, C1-C6 haloalkyl, and C1-C6 heteroalkenyl each optionally substituted with one or more halogen, cyano, or —(CH2)mC(═O)OH;
- or —NRLBRLC is an optionally substituted non-aromatic heterocycle linked through a ring nitrogen atom;
- each —NRLDRLE is separately selected, wherein RLD and RLE are each independently selected from the group consisting of hydrogen, aryl, heteroaryl, and optionally substituted C1-C6 alkyl, said aryl and heteroaryl in the definition of RLD and RLE are each optionally substituted with C1-C6 alkyl or C1-C6 alkoxy;
- or —NRLDRLE is an optionally substituted non-aromatic heterocycle linked through a ring nitrogen atom;
- each —NRLFRLG is separately selected, wherein RLF and RLG are each independently selected from the group consisting of hydrogen, and C1-C6 alkyl;
- or —NRLFRLG is an optionally substituted non-aromatic heterocycle linked through a ring nitrogen atom;
- RR is selected from the group consisting of C1-C6 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:
39 more elements
A compound of formula IXaa:
- and pharmaceutically acceptable salts thereof,
- wherein:
- RA is selected from the group consisting of C1-C6 alkyl, C3-C7 cycloalkyl, heterocycle, polycyclic heterocyclyl, aryl and heteroaryl, each optionally substituted with one or more substituents selected from the group consisting of R1, R2, and R3;
- each R1 is separately selected from the group consisting of halogen, cyano, C1-C6 heteroalkyl, an optionally substituted C1-C6 alkyl, an optionally substituted C1-C6 alkoxy, an optionally substituted C2-C6 alkenyl, an optionally substituted C2-C6 alkynyl, an optionally substituted C3-C7 cycloalkyl, optionally substituted C3-C7 cycloalkenyl, an optionally substituted C1-C6 haloalkyl, an optionally substituted aryl, and an optionally substituted heteroaryl;
- each R2 is separately selected from the group consisting of halogen, —O(CH2)mORI, —(CH2)mORI, —NRJRK, —(CH2)mSRI, —C(═O)RL, —(CH2)mRL, C1-C6 heteroalkyl, an optionally substituted C1-C6 alkyl, an optionally substituted C1-C6 alkoxy, an optionally substituted C2-C6 alkenyl, an optionally substituted C1-C6 haloalkyl, and an optionally substituted C3-C7 cycloalkyl where said C3-C7 cycloalkyl is further optionally fused with aryl or heteroaryl;
- each R3 is separately selected from the group consisting of halogen, —(CH2)mORG, —NRLC(═O)RM, —NRLC(═O)ORM, —NRLC(═O)NRNRO, —NRNRO, —(CH2)mS(O)0-2RM, —(CH2)mNHS(O)0-2RM, —(CH2)mCN, —(CH2)mRP, C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, C1-C6 haloalkyl, heterocycle, aryl, polycyclic heterocyclyl, and heteroaryl, said heterocycle, aryl polycyclic heterocyclyl, and heteroaryl in the definition of R3 are each optionally substituted with halogen, hydroxy, cyano, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, —C(═O)ORM, or —NRJRK;
- G4 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 R4, R5, and R6;
- each R4 is separately selected from the group consisting of chloro, cyano, an optionally substituted C1-C6 alkyl, an optionally substituted C1-C6 alkoxy, an optionally substituted C2-C6 alkenyl, an optionally substituted C2-C6 alkynyl, an optionally substituted C3-C7 cycloalkyl, an optionally substituted C1-C6 haloalkyl, an optionally substituted C1-C6 heteroalkyl, an optionally substituted aryl, and an optionally substituted heteroaryl;
- each R5 is separately selected from the group consisting of —O(CH2)mORI, —(CH2)mORI, —NRJRK, —(CH2)mSRI, —(CH2)mC(═O)RL, —(CH2)mRL, an optionally substituted C1-C6 alkyl, an optionally substituted C1-C6 alkoxy, an optionally substituted C2-C6 alkenyl, an optionally substituted C3-C7 cycloalkyl, an optionally substituted C1-C6 haloalkyl, and an optionally substituted C1-C6 heteroalkyl;
- each R6 is separately selected from the group consisting of —(CH2)mORG, —NRLC(═O)RM, —NRLC(═O)ORM, —NRLC(═O)NRNRO, —NRNRO, —(CH2)mS(O)0-2RM, —(CH2)mNHS(O)0-2RM, —(CH2)mNO2, —(CH2)mCN, (CH2)mRP, C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, C1-C6 haloalkyl, C1-C6 heteroalkyl, heterocycle, aryl, polycyclic heterocyclyl, and heteroaryl, said heterocycle, aryl, polycyclic heterocyclyl, and heteroaryl in the definition of R6 are each optionally substituted with halogen, cyano, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, —C(═O)ORM, or —NRJRK;
- RG is selected from the group consisting of C1-C6 alkyl, C3-C6 cycloalkyl, C3-C8 cycloalkenyl, C1-C6 heteroalkyl, C2-C6 heteroalkenyl, C2-C6 heteroalkynyl, heterocycle, aryl, and heteroaryl, each optionally substituted with one or more substituents selected from the group consisting of R4, R5, and R6, said aryl and heteroaryl in the definition of RG are each further optionally fused with an optionally substituted nonaromatic heterocycle or an optionally substituted nonaromatic carbocycle, or RG is —ORL or —NRPRL;
- each RI is separately selected from the group consisting of hydrogen, C1-C6 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C7 cycloalkyl, C1-C6 haloalkyl, C1-C6 heteroalkyl, and C1-C6 heterohaloalkyl;
- each —NRJRK is separately selected, wherein RJ and RK are each independently selected from the group consisting of hydrogen, C1-C6 alkyl optionally substituted with up to 5 fluoro, —(CH2)mORJA, —(CH2)mNRJBRJC, —(CH2)mRR, C3-C7 cycloalkyl, heterocycle, aryl and heteroaryl, said C3-C7 cycloalkyl, heterocycle, aryl and heteroaryl in the definition of RJ and RK are each independently optionally substituted with one or more substituents selected from the group consisting of halo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, aryl and heteroaryl, said aryl and heteroaryl substituent off of RJ and RK are each optionally substituted with one or more halo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, or —(CH2)mNRKARKB, or —NRJRK is an optionally substituted non-aromatic heterocycle linked through a ring nitrogen atom;
- each RJA is independently selected from the group consisting of hydrogen, C1-C6 alkyl, and C1-C6 haloalkyl;
- each —NRJBRJC is separately selected, wherein RJB and RJC are each independently selected from the group consisting of hydrogen, C1-C6 alkyl, and C1-C6 haloalkyl;
- each —NRKARKB is separately selected, wherein RKA and RKB are each independently selected from the group consisting of hydrogen, C1-C6 alkyl, and C1-C6 haloalkyl;
- each RM is independently selected from the group consisting of hydrogen, an optionally substituted C1-C6 alkyl, an optionally substituted C2-C4 alkenyl, an optionally substituted C2-C4 alkynyl, an optionally substituted C3-C7 cycloalkyl, an optionally substituted C3-C7 cycloalkenyl, and —(CH2)mRP;
- each —NRNRO is separately selected, wherein RN and RO are each independently selected from the group consisting of hydrogen, —(CH2)mNRNARNB, aryl and heteroaryl, said and heteroaryl in the definition of RN and RO are each independently optionally substituted with one or more substituents selected from the group consisting of —(CH2)mNROAROB, halo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, aryl and heteroaryl, said aryl and heteroaryl substituent off of RN and RO are each optionally substituted with one or more halo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, or —NRNARNB,
- each —NRNARNB is separately selected, wherein RNA and RNB are each independently selected from the group consisting of hydrogen, C1-C6 alkyl, and C1-C6 haloalkyl;
- each —NROAROB is separately selected, wherein ROA and ROB are each independently selected from the group consisting of hydrogen, C1-C6 alkyl, and C1-C6 haloalkyl;
- RP is selected from the group consisting of hydrogen and C1-C6 alkyl;
- each RL is independently selected from the group consisting of C3-C7 cycloalkyl, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy, —(CH2)mORLA, —(CH2)mNRLBRLC, aryl and heteroaryl, said aryl and heteroaryl in the definition of RL are each independently optionally substituted with one or more substituents selected from the group consisting of halo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, —(CH2)mNRLDRLE, aryl and heteroaryl, said aryl and heteroaryl substituent off of RL are each optionally substituted with one or more halo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, or —(CH2)mNRLFRLG;
- each RLA is independently selected from the group consisting of hydrogen, C1-C6 alkyl, and C1-C6 haloalkyl;
- RLD and RLC are each independently selected from the group consisting of hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, and C1-C6 heteroalkenyl, said C1-C6 alkyl, C1-C6 haloalkyl, and C1-C6 heteroalkenyl each optionally substituted with one or more halogen, cyano, or —(CH2)mC(═O)OH;
- or —NRLDRLC is an optionally substituted non-aromatic heterocycle linked through a ring nitrogen atom;
- each —NRLDRLE is separately selected, wherein RLD and RLE are each independently selected from the group consisting of hydrogen, aryl, heteroaryl, and optionally substituted C1-C6 alkyl, said aryl and heteroaryl in the definition of RLD and RLE are each optionally substituted with C1-C6 alkyl or C1-C6 alkoxy;
- or —NRLDRLE is an optionally substituted non-aromatic heterocycle linked through a ring nitrogen atom;
- each —NRLFRLG is separately selected, wherein RLF and RLG are each independently selected from the group consisting of hydrogen, and C1-C6 alkyl;
- or —NRLFRLG is an optionally substituted non-aromatic heterocycle linked through a ring nitrogen atom;
- RR is selected from the group consisting of C1-C6 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:
29 more elements
Dependencies are inferred from the claim text.