WO2011050245A1 - Bicyclic heteroaryls as kinase inhibitors - Google Patents
Bicyclic heteroaryls as kinase inhibitors Download PDFInfo
- Publication number
- WO2011050245A1 WO2011050245A1 PCT/US2010/053690 US2010053690W WO2011050245A1 WO 2011050245 A1 WO2011050245 A1 WO 2011050245A1 US 2010053690 W US2010053690 W US 2010053690W WO 2011050245 A1 WO2011050245 A1 WO 2011050245A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- substituted
- compound
- kinase
- heteroaryl
- solvent
- Prior art date
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- NFZLIFXSPKYCCH-CYBMUJFWSA-N C[C@H](c1cc(OC)ccc1)NC(c([nH]c1c2)cc1ccc2-c1c[nH]nc1)=O Chemical compound C[C@H](c1cc(OC)ccc1)NC(c([nH]c1c2)cc1ccc2-c1c[nH]nc1)=O NFZLIFXSPKYCCH-CYBMUJFWSA-N 0.000 description 1
- APYUDFYJSWUTSN-UHFFFAOYSA-N C[n]1c2cc(-c3c[nH]nc3)ccc2c(C(NCCc2cc(OC)ccc2)=O)c1 Chemical compound C[n]1c2cc(-c3c[nH]nc3)ccc2c(C(NCCc2cc(OC)ccc2)=O)c1 APYUDFYJSWUTSN-UHFFFAOYSA-N 0.000 description 1
- WZDQKGHXNGWRRS-UHFFFAOYSA-N C[n]1c2cc(-c3ccncc3)ccc2cc1C(NCc1cc(OC)ccc1)=O Chemical compound C[n]1c2cc(-c3ccncc3)ccc2cc1C(NCc1cc(OC)ccc1)=O WZDQKGHXNGWRRS-UHFFFAOYSA-N 0.000 description 1
- OXSUIDKEACCIBW-UHFFFAOYSA-N Cc1c(C(NCc2cc(OC)ccc2)=O)[n](cc(cc2)-c3ccnc(N)n3)c2n1 Chemical compound Cc1c(C(NCc2cc(OC)ccc2)=O)[n](cc(cc2)-c3ccnc(N)n3)c2n1 OXSUIDKEACCIBW-UHFFFAOYSA-N 0.000 description 1
- YXFVVABEGXRONW-UHFFFAOYSA-N Cc1ccccc1 Chemical compound Cc1ccccc1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 1
- XHIGXQJTNWSSII-UHFFFAOYSA-N Cc1n[nH]cc1-c1ccc(cc(C(NCc2cccc(OC)c2)=O)[nH]2)c2n1 Chemical compound Cc1n[nH]cc1-c1ccc(cc(C(NCc2cccc(OC)c2)=O)[nH]2)c2n1 XHIGXQJTNWSSII-UHFFFAOYSA-N 0.000 description 1
- WGOLHUGPTDEKCF-UHFFFAOYSA-N Nc(nc1)ccc1Br Chemical compound Nc(nc1)ccc1Br WGOLHUGPTDEKCF-UHFFFAOYSA-N 0.000 description 1
- PEIRKBMFVHQQCS-UHFFFAOYSA-N O=C(c1c[nH]c2c1ccc(-c1c[nH]nc1)c2)NCc1cnccc1 Chemical compound O=C(c1c[nH]c2c1ccc(-c1c[nH]nc1)c2)NCc1cnccc1 PEIRKBMFVHQQCS-UHFFFAOYSA-N 0.000 description 1
- IGIQNYPVMJXZPI-UHFFFAOYSA-N O=C(c1c[nH]c2cc(-c3c[nH]nc3)ccc12)N(CC1)CC1c1ccccc1 Chemical compound O=C(c1c[nH]c2cc(-c3c[nH]nc3)ccc12)N(CC1)CC1c1ccccc1 IGIQNYPVMJXZPI-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/4025—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil not condensed and containing further heterocyclic rings, e.g. cromakalim
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/415—1,2-Diazoles
- A61K31/416—1,2-Diazoles condensed with carbocyclic ring systems, e.g. indazole
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
Definitions
- kinase enzymes There are believed to be in excess of 500 distinct kinase enzymes coded in the human genome. Kinases catalyze the phosphorylation of specific amino acid residues in specific protein substrates, and by doing so are believed to be key components of regulatory systems controlling cell proliferation, cell differentiation, cell death
- Rho kinases Protein Kinase B (also known as AKT), kinase p70S6K that acts on a ribosomal protein, LIM kinases, IKK kinases, an Fit kinases, Aurora kinases, and Src kinases.
- AKT Protein Kinase B
- LIM kinases kinase B
- IKK kinases an kinases
- Aurora kinases an Aurora kinases
- Src kinases Src kinases.
- Each of these subclasses can contain multiple forms, isozymes, protein sequences, and the like, and are characterized by structural and functional homologies.
- Rho kinases also known as Rho-associated kinases, are serine/threonine kinases that function downstream of Rho which is a low molecular GTP-binding protein.
- Rho kinase isoforms ROCK I and ROCK II.
- the enzymes are believed to be involved in a variety of biological events such as smooth muscle contraction, apoptosis, cell growth, cell migration, cell proliferation, cytokinesis, cytoskeletal control, and inflammation, and to be involved in pathology of various diseases including cardiovascular disease, tumor infiltration, osteogenesis, chondrocyte differentiation and neurogenic pain. See, e.g., H. Satoh, et al., Jpn. J.
- Rho kinase inhibitors See, e.g. WO98/06433; WO00/09162; WO00/78351; WO01/17562; WO02/076976; EP1256574; WO02/100833; WO03/082808; WO2004/009555; WO2004/024717;
- PKT Protein Kinase B
- AKT protein family a group of enzymes, also referred to as the AKT protein family, which are known to play a role in cellular signaling in mammals.
- Aktl is involved in cellular survival pathways, by inhibiting apoptotic processes.
- Aktl is also able to induce protein synthesis pathways, and is therefore a key signaling protein in the cellular pathways that lead to skeletal muscle hypertrophy, and general tissue growth. Since it can block apoptosis, and thereby promote cell survival, Aktl has been implicated as a major factor in many types of cancer. See, for example, published PCT patent application Pub. No. WO2008/110846 and documents cited therein.
- the protein kinase known as p70S6K a 70 kDa ribosomal protein kinase is a serine/threonine-specific protein kinase that is known to control or modulate protein synthesis on the ribosome through phosphorylation of a ribosomal protein S6.
- p70S6K is believed to be involved in cell cycle control, cell differentiation and motility, in the immune response, and in tissue repair. This kinase may block apoptosis in tumor cells and thus plays a role in cancer proliferation. See, for example, published PCT patent application Pub. No. WO2008/110846 and documents cited therein.
- LIM kinase including LIMK1 and LIMK2
- LIMK LIM kinase
- LIMK1 and LIMK2 are actin-binding kinases that may be involved in reorganization of the actin cytoskeleton, possibly by regulating Rho kinase dependent cytoskeletal rearrangement. See, for example, published patent application Pub. No. US2009/0042893 and documents cited therein.
- IKK kinases including IKKa (IKK1), ⁇ (IKK2) and IKKi ( ⁇ ) are regulatory signaling molecules that interact with ⁇ - ⁇ , a transcription factor that regulates the expression of many genes.
- ⁇ - ⁇ is believed to be involved in cellular and organismic processes including angiogenesis, inflammatory diseases, and
- IKK kinases are believed to activate ⁇ - ⁇ by phosphorylation in response to a variety of different biochemical signals. See, for example, published PCT patent application WO2009/089042; R. Agami (2007), Cell, 129, 1043; and J.S. Boehm, et al. (2007), Cell, 129, 1065.
- Fit kinases include Flt3, also known as FMS-like tyrosine kinase 3, is a cytokine- binding kinase, is a membrane-spanning receptor tyrosine kinase involved in
- Aurora kinases are a family of homologous serine/threonine protein kinases, include Aurora- A, Aurora-B, and Aurora-C kinase enzymes. They are involved in processes controlling cell mitosis, including chromosome condensation, centrosome maturation, and spindle formation, and perhaps cell meiosis include spermatogenesis. See for example D. Bebbington et al. (2009), “The Discovery of Potent Aurora Inhibitor MK 0457 (VX-680)", Biochem. Med. Chem. Lett., 19, 3856-3592; L. Garuti, et al.
- Src kinases are members of the cytoplasmic protein tyrosine kinase family, and the Src family includes members such as BLK, FGR, FYN, HCK, LCK, LYN, YES, SRC, AND YRK.
- Src is believed to be responsible for stimulation of VEGF, and is also involved in regulation of cell growth, migration, and survival. See for example K. Lee et al. (2009), "Structure-based Virtual Screening of Src Kinase Inhibitors," Bioorg. Med. Chem., 17, 3152-3161; H. Mukaiyama, et al. (2008), "Novel Pyrazolo[l,5-a]pyrimidines as c-SRc Kinase Inhibitors that Reduce Ikr Channel
- inhibition of one or more of these protein kinases could be therapeutically effective in the treatment of any of hypertension, atherosclerosis, angina, stroke, arterial obstruction, peripheral arterial disease, peripheral circulation disorder, erectile dysfunction, acute and chronic pain, dementia, Alzheimer's disease, Parkinson's disease, neuronal degeneration, asthma, amyotrophic lateral sclerosis, spinal cord injury, rheumatoid arthritis, osteoarthritis, osteoporosis, psoriasis, cerebral vasospasm, glaucoma, spinal cord injury, multiple sclerosis, pulmonary hypertension, acute respiratory distress syndrome, inflammation, diabetes, urinary organ diseases such as overactive bladder (OAB) and benign prostatic hypertrophy (BPH), metastasis, cancer, open angle glaucoma, ocular hypertension, retinopathy, autoimmune disease and viral infection, or in providing myocardial protection.
- OAB overactive bladder
- BPH benign prostatic hypertrophy
- the present invention is directed to heteroaryl compounds useful as inhibitors of various kinase enzymes.
- the invention provides a compound of the formula (I):
- X 1 and X 2 are each independently N, CR 1 ; and X 3 , X 4 , X 5 , or X 6 are each independently N, C-E, or CR , provided that ring B is substituted by only one E group, and provided that at least one of X 3 -X 6 is N, and no more than five of X x -X 6 are N;
- a dotted line indicates that a bond is either a single bond or a double bond
- R, R 1 and R 2 are each independently H, halo, (C 1 _C6)alkyl substituted with 0-2 R a , (C 2 -C 6 )alkenyl substituted with 0-2 R a , (C 2 _C 6 )alkynyl substituted with 0-2 R a , cycloalkyl substituted with 0-2 R a , cycloalkylalkyl substituted with 0-2 R a , heterocyclyl substituted with 0-2 R a , heterocyclylalkyl substituted with 0-2 R a , aryl substituted with 0-2 R a , aralkyl substituted with 0-2 R a , heteroaryl substituted with 0-2 R a , heteroarylalkyl substituted with 0-2 R a , heteroarylalkyl substituted with 0-2 R a , heteroarylalkyl substituted with 0-2 R a , heteroaryl
- nl plus the number of C-R groups comprised by X and X is 0-3;
- n2 plus the number of C-R 2 groups comprised X 3 -X 6 is 0-4;
- n3 plus the number of C-Ar 1 groups comprised by X 1 and X2 is 1-4, such that at least one Ar 1 is present on ring A;
- R a is halo, oxo, (C 1 _C 6 )alkyl substituted with 0-2 R a , (C 2 _C 6 )alkenyl substituted with 0-2 R a , (C 2 _C 6 )alkynyl substituted with 0-2 R a , cycloalkyl substituted with 0-2 R a , cycloalkylalkyl substituted with 0-2 R a , heterocyclyl substituted with 0-2 R a ,
- p 0, 1, 2, 3, or 4;
- Ar 1 is a 5 or 6 membered heteroaryl ring comprising at least one nitrogen atom, and 0-3 additional heteroatoms selected from O, S(0) m , and N; when Ar 1 is a 5- membered heteroaryl, the nitrogen atom is disposed two atoms away from a point of attachment of the heteroaryl to ring A, and when Ar 1 is a 6-membered heteroaryl, the nitrogen atom is disposed three atoms away from a point of attachment of the heteroaryl to ring A, wherein any 5-membered heteroaryl or 6-membered heteroaryl of Ar 1 is substituted with 0-3 R , and wherein any 5-membered heteroaryl or 6-membered heteroaryl can be fused with an aryl or heteroaryl ring that is substituted with 0-3 R 4 ;
- R 3 and R 4 are each independently (C 1 _C 6 )alkyl substituted with 0-2 R a ,
- Ar is unsubstituted aryl, unsubstituted heteroaryl, aryl substituted with one or more substituents selected from R 4 , or heteroaryl substituted with one or more
- n is an integer from 0 to about 2;
- G, J, and K are each independently CH 2 , O, S, NR 5 , or CHNHR 5 , provided that K can also be a bond;
- D is a 5- to 7-membered heterocyclyl comprising NR ;
- d is an integer from 0 to about 3;
- R h and R k are each independently at every occurrence selected from H,
- G 2 is a bond, O, NR 5 , or S;
- Y is at each occurrence independently selected from O, S, NR, and C(R b R d ), provided that no 0-0 bonds are present in Y c , or Y is absent;
- R b and R d are each independently at every occurrence H, halo, (C 1- C 6 )alkyl substituted with 0-2 R a , (C 2 -C 6 )alkenyl substituted with 0-2 R a , (C 2 -C 6 )alkynyl substituted with 0-2 R a , cycloalkyl substituted with 0-2 R a , heterocyclyl substituted with 0-2 R a , aryl substituted with 0-2 R a , aralkyl substituted with 0-2 R a , heteroaryl substituted with 0-2 R a , heteroarylalkyl substituted with 0-2 R a , (Q- haloalkyl, (Ci-C 6 )haloalkoxy,
- R 9 and R 9A are each independently at every occurrence H, halo, (C 1 _C 6 )alkyl substituted with 0-2 R a , (C 2 _C 6 )alkenyl substituted with 0-2 R a , (C 2 _C 6 )alkynyl substituted with 0-2 R a , cycloalkyl substituted with 0-2 R a , cycloalkylalkyl substituted with 0-2 R a , heterocyclyl substituted with 0-2 R a , heterocyclylalkyl substituted with 0-2 R a , heterocyclylalkyl substituted with 0-2 R a , aryl substituted with 0-2 R a , aralkyl substituted with 0-2 R a , heteroaryl substituted with 0-2 R a , heteroarylalkyl substituted with 0-2 R a , heteroarylalkyl substituted with 0-2 R
- compositions comprising a compound of the invention and a pharmaceutically acceptable excipient.
- Various embodiments of the invention provide a pharmaceutical combination comprising a compound of the invention and a second medicament.
- Various embodiments of the invention provide a method of inhibiting a Rho kinase, an AKT kinase, a p70S6K kinase, a LIM kinase, an IKK kinase, a Fit kinase, an Aurora kinase, or a Src kinase, or any combination thereof.
- a malcondition such as cancer, wherein inhibition of a Rho kinase, an AKT kinase, a p70S6K kinase, a LIM kinase, an IKK kinase, a Fit kinase, an Aurora kinase, or a Src kinase, or any combination thereof, is medically indicated.
- Various embodiments of the invention provide a use of a compound of the invention in manufacture of a medicament adapted to treat a malcondition, such as cancer.
- mammals as used herein, means both mammals and non-mammals.
- Mammals include, for example, humans; non-human primates, e.g. apes and monkeys; cattle; horses; sheep; and goats.
- Non-mammals include, for example, fish and birds.
- a kinase enzyme such as a Rho kinase, an AKT kinase, a p70S6K kinase, a LIM kinase, an IKK kinase, a Fit kinase, an Aurora kinase, or a Src kinase, or any combination thereof, plays a role in the biochemical mechanisms involved in the diseases such that a therapeutically beneficial effect can be achieved by acting on the kinase.
- a kinase enzyme such as a Rho kinase, an AKT kinase, a p70S6K kinase, a LIM kinase, an IKK kinase, a Fit kinase, an Aurora kinase, or a Src kinase, or any combination thereof, plays a role in the biochemical mechanisms involved in the diseases such that a therapeutically beneficial effect can be achieved by acting
- an effective amount when used to describe therapy to an individual suffering from a disorder, refers to the amount of a compound of the invention that is effective to inhibit or otherwise act on a kinase enzyme such as a Rho kinase, an an AKT kinase, a p70S6K kinase, a LIM kinase, an IKK kinase, a Fit kinase, an Aurora kinase, or a Src kinase, or any combination thereof in the individual's tissues wherein the kinase involved in the disorder is active, wherein such inhibition or other action occurs to an extent sufficient to produce a beneficial therapeutic effect.
- a kinase enzyme such as a Rho kinase, an an AKT kinase, a p70S6K kinase, a LIM kinase, an IKK kinase, a Fit kinase, an Aurora kina
- substantially as the term is used herein means completely or almost completely; for example, a composition that is "substantially free” of a component either has none of the component or contains such a trace amount that any relevant functional property of the composition is unaffected by the presence of the trace amount, or a compound is "substantially pure” is there are only negligible traces of impurities present.
- Treating refers to an alleviation of symptoms associated with a disorder or disease, or inhibition of further progression or worsening of those symptoms, or prevention or prophylaxis of the disease or disorder, or curing the disease or disorder.
- an "effective amount” or a “therapeutically effective amount” of a compound of the invention refers to an amount of the compound that alleviates, in whole or in part, symptoms associated with the disorder or condition, or halts or slows further progression or worsening of those symptoms, or prevents or provides prophylaxis for the disorder or condition.
- a therapeutically effective amount refers to an amount of the compound that alleviates, in whole or in part, symptoms associated with the disorder or condition, or halts or slows further progression or worsening of those symptoms, or prevents or provides prophylaxis for the disorder or condition.
- therapeutically effective amount refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired therapeutic result.
- a therapeutically effective amount is also one in which any toxic or detrimental effects of compounds of the invention are outweighed by the therapeutically beneficial effects.
- chemically feasible is meant a bonding arrangement or a compound where the generally understood rules of organic structure are not violated; for example a structure within a definition of a claim that would contain in certain situations a pentavalent carbon atom that would not exist in nature would be understood to not be within the claim.
- the structures disclosed herein, in all of their embodiments are intended to include only “chemically feasible” structures, and any recited structures that are not chemically feasible, for example in a structure shown with variable atoms or groups, are not intended to be disclosed or claimed herein.
- an isotopic form of one or more atoms in a molecule that is different from the naturally occurring isotopic distribution of the atom in nature is referred to as an "isotopically labeled form" of the molecule.
- All isotopic forms of atoms are included as options in the composition of any molecule, unless a specific isotopic form of an atom is indicated.
- any hydrogen atom or set thereof in a molecule can be any of the isotopic forms of hydrogen, i.e., protium ( 1 H), deuterium ( 2 H), or tritium ( H) in any combination.
- any carbon atom or set thereof in a molecule can be any of the isotopic form of carbons, such as U C, 12 C, 13 C, or 14 C, or any nitrogen atom or set thereof in a molecule can be any of the isotopic forms of nitrogen, such as 13 N, 14 N, or 15 N.
- a molecule can include any combination of isotopic forms in the component atoms making up the molecule, the isotopic form of every atom forming the molecule being independently selected. In a multi-molecular sample of a compound, not every individual molecule necessarily has the same isotopic composition.
- a sample of a compound can include molecules containing various different isotopic compositions, such as in a tritium or 14 C radiolabeled sample where only some fraction of the set of molecules making up the macroscopic sample contains a radioactive atom. It is also understood that many elements that are not artificially isotopically enriched themselves are mixtures of naturally occurring isotopic forms, such as 14 N and
- a molecule as recited herein is defined as including isotopic forms of all its constituent elements at each position in the molecule.
- isotopically labeled compounds can be prepared by the usual methods of chemical synthesis, except substituting an isotopically labeled precursor molecule.
- the isotopes, radiolabeled or stable can be obtained by any method known in the art, such as generation by neutron absorption of a precursor nuclide in a nuclear reactor, by cyclotron reactions, or by isotopic separation such as by mass spectrometry.
- the isotopic forms are incorporated into precursors as required for use in any particular synthetic route.
- 14 C and 3 H can be prepared using neutrons generated in a nuclear reactor. Following nuclear transformation, 14 C and 3 H are incorporated into precursor molecules, followed by further elaboration as needed.
- amino protecting group or "N-protected” as used herein refers to those groups intended to protect an amino group against undesirable reactions during synthetic procedures and which can later be removed to reveal the amine. Commonly used amino protecting groups are disclosed in Protective Groups in Organic Synthesis, Greene, T.W.; Wuts, P. G. M., John Wiley & Sons, New York, NY, (3rd Edition, 1999). Amino protecting groups include acyl groups such as formyl, acetyl, propionyl, pivaloyl, t- butylacetyl, 2-chloroacetyl, 2-bromoacetyl, trifluoroacetyl, trichloroacetyl,
- sulfonyl groups such as benzenesulfonyl, p-toluenesulfonyl and the like
- alkoxy- or aryloxy-carbonyl groups (which form urethanes with the protected amine) such as benzyloxycarbonyl (Cbz), p-chlorobenzyloxycarbonyl, p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl, p-bromobenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl,
- Amine protecting groups also include cyclic amino protecting groups such as phthaloyl and dithiosuccinimidyl, which incorporate the amino nitrogen into a heterocycle.
- amino protecting groups include formyl, acetyl, benzoyl, pivaloyl, t-butylacetyl, phenylsulfonyl, Alloc, Teoc, benzyl, Fmoc, Boc and Cbz. It is well within the skill of the ordinary artisan to select and use the appropriate amino protecting group for the synthetic task at hand.
- hydroxyl protecting group or "O-protected” as used herein refers to those groups intended to protect an OH group against undesirable reactions during synthetic procedures and which can later be removed to reveal the amine. Commonly used hydroxyl protecting groups are disclosed in Protective Groups in Organic Synthesis, Greene, T.W.; Wuts, P. G. M., John Wiley & Sons, New York, NY, (3rd Edition, 1999).
- Hydroxyl protecting groups include acyl groups such as formyl, acetyl, propionyl, pivaloyl, t-butylacetyl, 2-chloroacetyl, 2-bromoacetyl, trifluoroacetyl, trichloroacetyl, o-nitrophenoxyacetyl, a-chlorobutyryl, benzoyl, 4-chlorobenzoyl, 4-bromobenzoyl, 4-nitrobenzoyl, and the like; sulfonyl groups such as benzenesulfonyl, p-toluenesulfonyl and the like; acyloxy groups (which form urethanes with the protected amine) such as benzyloxycarbonyl (Cbz), p-chlorobenzyloxycarbonyl, p-methoxybenzyloxycarbonyl, p- nitrobenzyloxycarbonyl, 2-nitrobenzyl
- phenoxycarbonyl 4-nitrophenoxycarbonyl, fluorenyl-9-methoxycarbonyl (Fmoc), cyclopentyloxycarbonyl, adamantyloxycarbonyl, cyclohexyloxycarbonyl,
- phenylthiocarbonyl and the like phenylthiocarbonyl and the like; aralkyl groups such as benzyl, triphenylmethyl, benzyloxymethyl and the like; and silyl groups such as trimethylsilyl and the like. It is well within the skill of the ordinary artisan to select and use the appropriate hydroxyl protecting group for the synthetic task at hand.
- substituted refers to an organic group as defined herein in which one or more bonds to a hydrogen atom contained therein are replaced by one or more bonds to a non-hydrogen atom such as, but not limited to, a halogen (i.e., F, CI, Br, and I); an oxygen atom in groups such as hydroxyl groups, alkoxy groups, aryloxy groups, aralkyloxy groups, oxo(carbonyl) groups, carboxyl groups including carboxylic acids, carboxylates, and carboxylate esters; a sulfur atom in groups such as thiol groups, alkyl and aryl sulfide groups, sulfoxide groups, sulfone groups, sulfonyl groups, and sulfonamide groups; a nitrogen atom in groups such as amines, hydroxylamines, nitriles, nitro groups, N-oxides, hydrazides, azides, and enamines
- R' can be hydrogen or a carbon-based moiety, and wherein the carbon-based moiety can itself be further substituted.
- a substituent When a substituent is monovalent, such as, for example, F or CI, it is bonded to the atom it is substituting by a single bond.
- a divalent substituent such as O, S, C(O), S(O), or S(0) 2 can be connected by two single bonds to two different carbon atoms.
- O a divalent substituent
- any substituent can be bonded to a carbon or other atom by a linker, such as (CH 2 ) n or (CR' 2 ) n wherein n is 1, 2, 3, or more, and each R' is independently selected.
- Substituted alkyl, alkenyl, alkynyl, cycloalkyl, and cycloalkenyl groups as well as other substituted groups also include groups in which one or more bonds to a hydrogen atom are replaced by one or more bonds, including double or triple bonds, to a carbon atom, or to a heteroatom such as, but not limited to, oxygen in carbonyl (oxo), carboxyl, ester, amide, imide, urethane, and urea groups; and nitrogen in imines, hydroxyimines, oximes, hydrazones, amidines, guanidines, and nitriles.
- Substituted ring groups such as substituted cycloalkyl, aryl, heterocyclyl and heteroaryl groups also include rings and fused ring systems in which a bond to a hydrogen atom is replaced with a bond to a carbon atom. Therefore, substituted cycloalkyl, aryl, heterocyclyl and heteroaryl groups can also be substituted with alkyl, alkenyl, and alkynyl groups as defined herein.
- ring system as the term is used herein is meant a moiety comprising one, two, three or more rings, which can be substituted with non-ring groups or with other ring systems, or both, which can be fully saturated, partially unsaturated, fully unsaturated, or aromatic, and when the ring system includes more than a single ring, the rings can be fused, bridging, or spirocyclic.
- spirocyclic is meant the class of structures wherein two rings are fused at a single tetrahedral carbon atom, as is well known in the art.
- Alkyl groups include straight chain and branched alkyl groups and cycloalkyl groups having from 1 to about 20 carbon atoms, and typically from 1 to 12 carbons or, in some embodiments, from 1 to 8 carbon atoms.
- straight chain alkyl groups include those with from 1 to 8 carbon atoms such as methyl, ethyl, n-propyl, n-butyl, n- pentyl, n-hexyl, n-heptyl, and n-octyl groups.
- branched alkyl groups include, but are not limited to, isopropyl, iso-butyl, sec-butyl, t-butyl, neopentyl, isopentyl, and 2,2-dimethylpropyl groups.
- Representative substituted alkyl groups can be substituted one or more times with any of the groups listed above, for example, amino, hydroxy, cyano, carboxy, nitro, thio, alkoxy, and halogen groups.
- Cycloalkyl groups are cyclic alkyl groups such as, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl groups.
- the cycloalkyl group can have 3 to about 8-12 ring members, whereas in other embodiments the number of ring carbon atoms range from 3 to 5, 6, or 7.
- Cycloalkyl groups further include polycyclic cycloalkyl groups such as, but not limited to, norbornyl, adamantyl, bornyl, camphenyl, isocamphenyl, and carenyl groups, and fused rings such as, but not limited to, decalinyl, and the like. Cycloalkyl groups also include rings that are substituted with straight or branched chain alkyl groups as defined above.
- Representative substituted cycloalkyl groups can be mono-substituted or substituted more than once, such as, but not limited to, 2,2-, 2,3-, 2,4- 2,5- or 2,6- disubstituted cyclohexyl groups or mono-, di- or tri- substituted norbornyl or cycloheptyl groups, which can be substituted with, for example, amino, hydroxy, cyano, carboxy, nitro, thio, alkoxy, and halogen groups.
- cycloalkenyl alone or in combination denotes a cyclic alkenyl group.
- carbocyclic denotes a ring structure wherein the atoms of the ring are carbon, such as a cycloalkyl group or an aryl group.
- the carbocycle has 3 to 8 ring members, whereas in other words
- the number of ring carbon atoms is 4, 5, 6, or 7.
- the carbocyclic ring can be substituted with as many as N-l substituents wherein N is the size of the carbocyclic ring with, for example, alkyl, alkenyl, alkynyl, amino, aryl, hydroxy, cyano, carboxy, heteroaryl, heterocyclyl, nitro, thio, alkoxy, and halogen groups, or other groups as are listed above.
- a carbocyclyl ring can be a cycloalkyl ring, a cycloalkenyl ring, or an aryl ring.
- a carbocyclyl can be monocyclic or polycyclic, and if polycyclic each ring can be independently be a cycloalkyl ring, a cycloalkenyl ring, or an aryl ring.
- Cyclo alkyl alkyl groups also denoted cycloalkylalkyl, are alkyl groups as defined above in which a hydrogen or carbon bond of the alkyl group is replaced with a bond to a cycloalkyl group as defined above.
- Alkenyl groups include straight and branched chain and cyclic alkyl groups as defined above, except that at least one double bond exists between two carbon atoms.
- alkenyl groups have from 2 to about 20 carbon atoms, and typically from 2 to 12 carbons or, in some embodiments, from 2 to 8 carbon atoms.
- -C(CH 2 CH ) CH 2 , cyclohexenyl, cyclopentenyl, cyclohexadienyl, butadienyl, pentadienyl, and hexadienyl among others.
- Cycloalkenyl groups include cycloalkyl groups having at least one double bond between 2 carbons.
- cycloalkenyl groups include but are not limited to cyclohexenyl, cyclopentenyl, and cyclohexadienyl groups.
- Cycloalkenyl groups can have from 3 to about 8-12 ring members, whereas in other embodiments the number of ring carbon atoms range from 3 to 5, 6, or 7.
- Cycloalkyl groups further include polycyclic cycloalkyl groups such as, but not limited to, norbornyl, adamantyl, bornyl, camphenyl, isocamphenyl, and carenyl groups, and fused rings such as, but not limited to, decalinyl, and the like, provided they include at least one double bond within a ring.
- Cycloalkenyl groups also include rings that are substituted with straight or branched chain alkyl groups as defined above.
- (Cycloalkenyl)alkyl groups are alkyl groups as defined above in which a hydrogen or carbon bond of the alkyl group is replaced with a bond to a cycloalkenyl group as defined above.
- Alkynyl groups include straight and branched chain alkyl groups, except that at least one triple bond exists between two carbon atoms.
- alkynyl groups have from 2 to about 20 carbon atoms, and typically from 2 to 12 carbons or, in some embodiments, from 2 to 8 carbon atoms. Examples include, but are not limited to -C ⁇ CH, -C ⁇ C(CH ), -C ⁇ C(CH 2 CH 3 ), -CH 2 C ⁇ CH, -CH 2 C ⁇ C(CH 3 ), and -CH 2 C ⁇ C(CH 2 CH 3 ) among others.
- heteroalkyl by itself or in combination with another term means, unless otherwise stated, a stable straight or branched chain alkyl group consisting of the stated number of carbon atoms and one or two heteroatoms selected from the group consisting of O, N, and S, and wherein the nitrogen and sulfur atoms may be optionally oxidized and the nitrogen heteroatom may be optionally quaternized.
- the heteroatom(s) may be placed at any position of the heteroalkyl group, including between the rest of the heteroalkyl group and the fragment to which it is attached, as well as attached to the most distal carbon atom in the heteroalkyl group.
- Up to two heteroatoms may be consecutive, such as, for example, -CH 2 -NH-OCH 3 , or -CH 2 -CH 2 -S-S-CH 3 .
- a “cyclohetero alkyl” ring is a cycloalkyl ring containing at least one heteroatom.
- a cycloheteroalkyl ring can also be termed a “heterocyclyl,” described below.
- -CH CH-N(CH 3 )-CH 3
- -CH 2 -CH CH-CH 2 -SH
- -CH CH-0-CH 2 CH 2 -0-CH 3 .
- Aryl groups are cyclic aromatic hydrocarbons that do not contain heteroatoms.
- aryl groups include, but are not limited to, phenyl, azulenyl, heptalenyl, biphenyl, indacenyl, fluorenyl, phenanthrenyl, triphenylenyl, pyrenyl, naphthacenyl, chrysenyl, biphenylenyl, anthracenyl, and naphthyl groups.
- aryl groups contain about 6 to about 14 carbons in the ring portions of the groups.
- Aryl groups can be unsubstituted or substituted, as defined above.
- substituted aryl groups can be mono-substituted or substituted more than once, such as, but not limited to, 2-, 3-, 4-, 5-, or 6-substituted phenyl or 2-8 substituted naphthyl groups, which can be substituted with carbon or non-carbon groups such as those listed above.
- Aralkyl groups are alkyl groups as defined above in which a hydrogen or carbon bond of an alkyl group is replaced with a bond to an aryl group as defined above.
- Representative aralkyl groups include benzyl and phenylethyl groups and fused
- (cycloalkylaryl)alkyl groups such as 4-ethyl-indanyl.
- Aralkenyl group are alkenyl groups as defined above in which a hydrogen or carbon bond of an alkyl group is replaced with a bond to an aryl group as defined above.
- Heterocyclyl groups or the term "heterocyclyl” includes aromatic and non- aromatic ring compounds containing 3 or more ring members, of which, one or more is a heteroatom such as, but not limited to, N, O, and S.
- a heterocyclyl can be a cycloheteroalkyl, or a heteroaryl, or if polycyclic, any combination thereof.
- heterocyclyl groups include 3 to about 20 ring members, whereas other such groups have 3 to about 15 ring members.
- a heterocyclyl group designated as a C 2 - heterocyclyl can be a 5-ring with two carbon atoms and three heteroatoms, a 6-ring with two carbon atoms and four heteroatoms and so forth.
- a C 4 -heterocyclyl can be a 5-ring with one heteroatom, a 6-ring with two heteroatoms, and so forth.
- the number of carbon atoms plus the number of heteroatoms sums up to equal the total number of ring atoms.
- a heterocyclyl ring can also include one or more double bonds.
- a heteroaryl ring is an embodiment of a heterocyclyl group.
- the phrase "heterocyclyl group" includes fused ring species including those comprising fused aromatic and non-aromatic groups. For example, a dioxolanyl ring and a benzdioxolanyl ring system (methylenedioxyphenyl ring system) are both heterocyclyl groups within the meaning herein.
- Heterocyclyl groups can be unsubstituted, or can be substituted as discussed above.
- Heterocyclyl groups include, but are not limited to, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridinyl, thiophenyl, benzothiophenyl, benzofuranyl, dihydrobenzofuranyl, indolyl, dihydroindolyl, azaindolyl, indazolyl, benzimidazolyl, azabenzimidazolyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, imidazopyridiny
- Representative substituted heterocyclyl groups can be mono-substituted or substituted more than once, such as, but not limited to, piperidinyl or quinolinyl groups, which are 2-, 3-, 4-, 5-, or 6-substituted, or disubstituted with groups such as those listed above.
- Heteroaryl groups are aromatic ring compounds containing 5 or more ring members, of which, one or more is a heteroatom such as, but not limited to, N, O, and S; for instance, heteroaryl rings can have 5 to about 8-12 ring members.
- a heteroaryl group is a variety of a heterocyclyl group that possesses an aromatic electronic structure.
- a heteroaryl group designated as a C 2 -heteroaryl can be a 5-ring with two carbon atoms and three heteroatoms, a 6-ring with two carbon atoms and four heteroatoms and so forth.
- a C 4 -heteroaryl can be a 5-ring with one heteroatom, a 6-ring with two heteroatoms, and so forth.
- Heteroaryl groups include, but are not limited to, groups such as pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridinyl, thiophenyl, benzothiophenyl, benzofuranyl, indolyl, azaindolyl, indazolyl, benzimidazolyl, azabenzimidazolyl, benzoxazolyl, benzothiazolyl,
- heteroaryl groups can be unsubstituted, or can be substituted with groups as is discussed above.
- Representative substituted heteroaryl groups can be substituted one or more times with groups such as those listed above.
- aryl and heteroaryl groups include but are not limited to phenyl, biphenyl, indenyl, naphthyl (1-naphthyl, 2-naphthyl), N-hydroxytetrazolyl, N- hydroxytriazolyl, N-hydroxyimidazolyl, anthracenyl (1-anthracenyl, 2-anthracenyl, 3- anthracenyl), thiophenyl (2-thienyl, 3-thienyl), furyl (2-furyl, 3-furyl) , indolyl, oxadiazolyl, isoxazolyl, quinazolinyl, fluorenyl, xanthenyl, isoindanyl, benzhydryl, acridinyl, thiazolyl, pyrrolyl (2-pyrrolyl), pyrazolyl (3-pyrazolyl), imidazolyl (1- imidazolyl, 2-
- Heterocyclylalkyl groups are alkyl groups as defined above in which a hydrogen or carbon bond of an alkyl group as defined above is replaced with a bond to a heterocyclyl group as defined above.
- Representative heterocyclyl alkyl groups include, but are not limited to, furan-2-yl methyl, furan-3-yl methyl, pyridine-3-yl methyl, tetrahydrofuran-2-yl ethyl, and indol-2-yl propyl.
- Heteroarylalkyl groups are alkyl groups as defined above in which a hydrogen or carbon bond of an alkyl group is replaced with a bond to a heteroaryl group as defined above.
- alkoxy refers to an oxygen atom connected to an alkyl group, including a cycloalkyl group, as are defined above.
- linear alkoxy groups include but are not limited to methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, and the like.
- Examples of branched alkoxy include but are not limited to isopropoxy, sec-butoxy, tert-butoxy, isopentyloxy, isohexyloxy, and the like.
- cyclic alkoxy examples include but are not limited to cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, and the like.
- An alkoxy group can include one to about 12-20 carbon atoms bonded to the oxygen atom, and can further include double or triple bonds, and can also include heteroatoms.
- an allyloxy group is an alkoxy group within the meaning herein.
- a methoxyethoxy group is also an alkoxy group within the meaning herein.
- haloalkyl group includes mono-halo alkyl groups, poly-halo alkyl groups wherein all halo atoms can be the same or different, and per-halo alkyl groups, wherein all hydrogen atoms are replaced by halogen atoms, such as fluoro.
- haloalkyl include trifluoromethyl, 1,1-dichloroethyl, 1,2-dichloroethyl, l,3-dibromo-3,3- difluoropropyl, perfluorobutyl, and the like.
- haloalkoxy includes mono-halo alkoxy groups, poly-halo alkoxy groups wherein all halo atoms can be the same or different, and per-halo alkoxy groups, wherein all hydrogen atoms are replaced by halogen atoms, such as fluoro.
- haloalkoxy include trifluoromethoxy, 1,1-dichloroethoxy, 1,2-dichloroethoxy, 1,3- dibromo-3,3-difluoropropoxy, perfluorobutoxy, and the like.
- (C x -C y )perfluoroalkyl wherein x ⁇ y, means an alkyl group with a minimum of x carbon atoms and a maximum of y carbon atoms, wherein all hydrogen atoms are replaced by fluorine atoms.
- x ⁇ y means an alkyl group with a minimum of x carbon atoms and a maximum of y carbon atoms, wherein all hydrogen atoms are replaced by fluorine atoms.
- Preferred is -(C 1 -C6)perfluoroalkyl, more preferred is -(C 1 -C3)perfluoroalkyl, most preferred is -CF 3 .
- (C x -C y )perfluoroalkylene wherein x ⁇ y, means an alkyl group with a minimum of x carbon atoms and a maximum of y carbon atoms, wherein all hydrogen atoms are replaced by fluorine atoms.
- x ⁇ y means an alkyl group with a minimum of x carbon atoms and a maximum of y carbon atoms, wherein all hydrogen atoms are replaced by fluorine atoms.
- Preferred is -(C 1 -C6)perfluoroalkylene, more preferred is -(C 1 -C3)perfluoroalkylene, most preferred is -CF 2 -.
- aryloxy and arylalkoxy refer to, respectively, an aryl group bonded to an oxygen atom and an aralkyl group bonded to the oxygen atom at the alkyl moiety. Examples include but are not limited to phenoxy, naphthyloxy, and benzyloxy.
- acyl group refers to a group containing a carbonyl moiety wherein the group is bonded via the carbonyl carbon atom.
- the carbonyl carbon atom is also bonded to another carbon atom, which can be part of an alkyl, aryl, aralkyl cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl group or the like.
- the group is a "formyl” group, an acyl group as the term is defined herein.
- An acyl group can include 0 to about 12-20 additional carbon atoms bonded to the carbonyl group.
- An acyl group can include double or triple bonds within the meaning herein.
- An acryloyl group is an example of an acyl group.
- An acyl group can also include heteroatoms within the meaning here.
- a nicotinoyl group (pyridyl-3-carbonyl) group is an example of an acyl group within the meaning herein.
- Other examples include acetyl, benzoyl, phenylacetyl, pyridylacetyl, cinnamoyl, and acryloyl groups and the like.
- the group containing the carbon atom that is bonded to the carbonyl carbon atom contains a halogen, the group is termed a "haloacyl" group.
- An example is a trifluoroacetyl group.
- amine includes primary, secondary, and tertiary amines having, e.g., the formula N(group) 3 wherein each group can independently be H or non-H, such as alkyl, aryl, and the like.
- Amines include but are not limited to R-NH 2 , for example, alkylamines, arylamines, alkylarylamines; R 2 NH wherein each R is independently selected, such as dialkylamines, diarylamines, aralkylamines, heterocyclylamines and the like; and R 3 N wherein each R is independently selected, such as trialkylamines, dialkylarylamines, alkyldiarylamines, triarylamines, and the like.
- the term "amine” also includes ammonium ions as used herein.
- amino group is a substituent of the form -NH 2 , -NHR, -NR 2 , -NR 3 + , wherein each R is independently selected, and protonated forms of each. Accordingly, any compound substituted with an amino group can be viewed as an amine.
- An "ammonium” ion includes the unsubstituted ammonium ion NH 4 + , but unless otherwise specified, it also includes any protonated or quaternarized forms of amines. Thus, trimethylammonium hydrochloride and tetramethylammonium chloride are both ammonium ions, and amines, within the meaning herein.
- amide includes C- and N-amide groups, i.e., -C(0)NR 2 , and -NRC(0)R groups, respectively.
- Amide groups therefore include but are not limited to carbamoyl groups (-C(0)NH 2 ) and formamide groups (-NHC(O)H).
- a "carboxamido” group is a group of the formula C(0)NR 2 , wherein R can be H, alkyl, aryl, etc.
- urethane (or “carbamyl”) includes N- and O-urethane groups, i.e., -NRC(0)OR and -OC(0)NR 2 groups, respectively.
- sulfonamide includes S- and N-sulfonamide groups, i.e., -S0 2 NR 2 and -NRS0 2 R groups, respectively. Sulfonamide groups therefore include but are not limited to sulfamoyl groups (-S0 2 NH 2 ).
- An organosulfur structure represented by the formula -S(0)(NR)- is understood to refer to a sulfoximine, wherein both the oxygen and the nitrogen atoms are bonded to the sulfur atom, which is also bonded to two carbon atoms.
- amidine or “amidino” includes groups of the formula -C(NR)NR 2 .
- an amidino group is -C(NH)NH 2 .
- guanidine or “guanidino” includes groups of the formula
- a guanidino group is -NHC(NH)NH 2 .
- a “salt” as is well known in the art includes an organic compound such as a carboxylic acid, a sulfonic acid, or an amine, in ionic form, in combination with a counterion.
- acids in their anionic form can form salts with cations such as metal cations, for example sodium, potassium, and the like; with ammonium salts such as NH 4 + or the cations of various amines, including tetraalkyl ammonium salts such as tetramethylammonium, or other cations such as trimethylsulfonium, and the like.
- a “pharmaceutically acceptable” or “pharmacologically acceptable” salt is a salt formed from an ion that has been approved for human consumption and is generally non-toxic, such as a chloride salt or a sodium salt.
- a “zwitterion” is an internal salt such as can be formed in a molecule that has at least two ionizable groups, one forming an anion and the other a cation, which serve to balance each other. For example, amino acids such as glycine can exist in a zwitterionic form.
- a “zwitterion” is a salt within the meaning herein.
- the compounds of the present invention may take the form of salts.
- the term “salts" embraces addition salts of free acids or free bases which are compounds of the invention. Salts can be “pharmaceutically-acceptable salts.” The term
- “pharmaceutically-acceptable salt” refers to salts which possess toxicity profiles within a range that affords utility in pharmaceutical applications. Pharmaceutically unacceptable salts may nonetheless possess properties such as high crystallinity, which have utility in the practice of the present invention, such as for example utility in process of synthesis, purification or formulation of compounds of the invention.
- Suitable pharmaceutically-acceptable acid addition salts may be prepared from an inorganic acid or from an organic acid.
- inorganic acids include
- organic acids may be selected from aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic, carboxylic and sulfonic classes of organic acids, examples of which include formic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic, glucuronic, maleic, fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic, 4-hydroxybenzoic, phenylacetic, mandelic, embonic (pamoic),
- pharmaceutically unacceptable acid addition salts include, for example, perchlorates and tetrafluoroborates .
- Suitable pharmaceutically acceptable base addition salts of compounds of the invention include, for example, metallic salts including alkali metal, alkaline earth metal and transition metal salts such as, for example, calcium, magnesium, potassium, sodium and zinc salts.
- Pharmaceutically acceptable base addition salts also include organic salts made from basic amines such as, for example, N,A ⁇ -dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine
- salts examples include lithium salts and cyanate salts.
- pharmaceutically unacceptable salts are not generally useful as medicaments, such salts may be useful, for example as intermediates in the synthesis of Formula (I) compounds, for example in their purification by recrystallization.. All of these salts may be prepared by conventional means from the corresponding compound according to Formula (I) by reacting, for example, the appropriate acid or base with the compound according to Formula (I).
- pharmaceutically acceptable salts refers to nontoxic inorganic or organic acid and/or base addition salts, see, for example, Lit et al., Salt Selection for Basic Drugs (1986), Int J. Pharm., 33, 201-217, incorporated by reference herein.
- a “hydrate” is a compound that exists in a composition with water molecules.
- the composition can include water in stoichiometic quantities, such as a monohydrate or a dihydrate, or can include water in random amounts.
- a "hydrate” refers to a solid form, i.e., a compound in water solution, while it may be hydrated, is not a hydrate as the term is used herein.
- a “solvate” is a similar composition except that a solvent other that water replaces the water.
- a solvent other that water replaces the water.
- methanol or ethanol can form an "alcoholate", which can again be stoichiometic or non- stoichiometric.
- a “solvate” refers to a solid form, i.e., a compound in solution in a solvent, while it may be solvated, is not a solvate as the term is used herein.
- prodrug as is well known in the art is a substance that can be administered to a patient where the substance is converted in vivo by the action of biochemicals within the patients body, such as enzymes, to the active pharmaceutical ingredient.
- examples of prodrugs include esters of carboxylic acid groups, which can be hydrolyzed by endogenous esterases as are found in the bloodstream of humans and other mammals. Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in "Design of Prodrugs", ed. H. Bundgaard, Elsevier, 1985.
- the compound or set of compounds, such as are used in the inventive methods can be any one of any of the combinations and/or subcombinations of the above-listed embodiments.
- Provisos may apply to any of the disclosed categories or embodiments wherein any one or more of the other above disclosed embodiments or species may be excluded from such categories or embodiments.
- the present invention further embraces isolated compounds according to formula (I).
- isolated compound refers to a preparation of a compound of formula (I), or a mixture of compounds according to formula (I), wherein the isolated compound has been separated from the reagents used, and/or byproducts formed, in the synthesis of the compound or compounds. "Isolated” does not mean that the preparation is technically pure (homogeneous), but it is sufficiently pure to compound in a form in which it can be used therapeutically.
- an “isolated compound” refers to a preparation of a compound of formula (I) or a mixture of compounds according to formula (I), which contains the named compound or mixture of compounds according to formula (I) in an amount of at least 10 percent by weight of the total weight.
- the preparation contains the named compound or mixture of compounds in an amount of at least 50 percent by weight of the total weight; more preferably at least 80 percent by weight of the total weight; and most preferably at least 90 percent, at least 95 percent or at least 98 percent by weight of the total weight of the preparation.
- the compounds of the invention and intermediates may be isolated from their reaction mixtures and purified by standard techniques such as filtration, liquid-liquid extraction, solid phase extraction, distillation, recrystallization or chromatography, including flash column chromatography, or HPLC.
- a compound of the formula (I) or a salt thereof may exhibit the phenomenon of tautomerism whereby two chemical compounds that are capable of facile interconversion by exchanging a hydrogen atom between two atoms, to either of which it forms a covalent bond. Since the tautomeric compounds exist in mobile equilibrium with each other they may be regarded as different isomeric forms of the same compound. It is to be understood that the formulae drawings within this specification can represent only one of the possible tautomeric forms.
- the invention encompasses any tautomeric form, and is not to be limited merely to any one tautomeric form utilized within the formulae drawings.
- the formulae drawings within this specification can represent only one of the possible tautomeric forms and it is to be understood that the specification encompasses all possible tautomeric forms of the compounds drawn not just those forms which it has been convenient to show graphically herein.
- tautomerism may be exhibited by a pyrazolyl group bonded as indicated by the wavy line. While both substituents would be termed a 4-pyrazolyl group, it is evident that a different nitrogen atom bears the hydrogen atom in each structure.
- Such tautomerism can also occur with substituted pyrazoles such as 3-methyl, 5- methyl, or 3,5-dimethylpyrazoles, and the like.
- the isomers resulting from the presence of a chiral center comprise a pair of non-superimposable isomers that are called "enantiomers.”
- Single enantiomers of a pure compound are optically active, i.e., they are capable of rotating the plane of plane polarized light.
- Single enantiomers are designated according to the Cahn-Ingold-Prelog system.
- the present invention is meant to encompass diastereomers as well as their racemic and resolved, diastereomerically and enantiomerically pure forms and salts thereof. Diastereomeric pairs may be resolved by known separation techniques including normal and reverse phase chromatography, and crystallization.
- isolated optical isomer means a compound which has been substantially purified from the corresponding optical isomer(s) of the same formula.
- the isolated isomer is at least about 80%, more preferably at least 90% pure, even more preferably at least 98% pure, most preferably at least about 99% pure, by weight.
- Isolated optical isomers may be purified from racemic mixtures by well-known chiral separation techniques. According to one such method, a racemic mixture of a compound of the invention, or a chiral intermediate thereof, is separated into 99% wt.% pure optical isomers by HPLC using a suitable chiral column, such as a member of the series of DAICEL ® CHIRALPAK ® family of columns (Daicel Chemical Industries, Ltd., Tokyo, Japan). The column is operated according to the manufacturer's instructions. Rotational Isomerism
- the preferred compounds of the present invention have a particular spatial arrangement of substituents on the aromatic rings, which is related to the structure activity relationship demonstrated by the compound class. Often such substitution arrangement is denoted by a numbering system; however, numbering systems are often not consistent between different ring systems. In six-membered aromatic systems, the spatial arrangements are specified by the common nomenclature "para" for
- the invention provides a compound of the formula (I):
- X 1 and X 2 are each independently N, CR 1 ; and X 3 , X 4 , X 5 , or X 6 are each independently N, C-E, or CR , provided that ring B is substituted by only one E group, and provided that at least one of X 3 -X 6 is N, and no more than five of X x -X 6 are N;
- a dotted line indicates that a bond is either a single bond or a double bond
- R, R 1 and R 2 are each independently H, halo, (C 1 _C 6 )alkyl substituted with 0-2 R a ,
- nl plus the number of C-R groups comprised by X and X is 0-3;
- n2 plus the number of C-R 2 groups comprised X 3 -X 6 is 0-4;
- n3 plus the number of C-Ar 1 groups comprised by X 1 and X2 is 1-4, such that at least one Ar 1 is present on ring A;
- R a is halo, oxo, (C 1- C 6 )alkyl substituted with 0-2 R a , (C 2 _C 6 )alkenyl substituted with 0-2 R a , (C 2 _C 6 )alkynyl substituted with 0-2 R a , cycloalkyl substituted with 0-2 R a , cycloalkylalkyl substituted with 0-2 R a , heterocyclyl substituted with 0-2 R a , heterocyclylalkyl substituted with 0-2 R a , aryl substituted with 0-2 R a , aralkyl substituted with 0-2 R a , heteroaryl substituted with 0-2 R a , heteroarylalkyl substituted with 0-2 R a , heteroarylalkyl substituted with 0-2 R a , heteroarylalkyl substituted with 0-2 R a , heteroarylalkyl
- n 0, 1, or 2;
- p 0, 1, 2, 3, or 4;
- Ar 1 is a 5 or 6 membered heteroaryl ring comprising at least one nitrogen atom, and 0-3 additional heteroatoms selected from O, S(0) m , and N; when Ar 1 is a 5- membered heteroaryl, the nitrogen atom is disposed two atoms away from a point of attachment of the heteroaryl to ring A, and when Ar 1 is a 6-membered heteroaryl, the nitrogen atom is disposed three atoms away from a point of attachment of the heteroaryl to ring A, wherein any 5-membered heteroaryl or 6-membered heteroaryl of Ar 1 is substituted with 0-3 R , and wherein any 5-membered heteroaryl or 6-membered heteroaryl can be fused with an aryl or heteroaryl ring that is substituted with 0-3 R 4 ;
- R 3 and R 4 are each independently (C 1- C 6 )alkyl substituted with 0-2 R a ,
- E is any of the following, wherein a wavy line indicates a point of attachment to ring B:
- n is an integer from 0 to about 2;
- G, J, and K are each independently CH 2 , O, S, NR 5 , or CHNHR 5 , provided that K can also be a bond;
- D is a 5- to 7-membered heterocyclyl comprising NR ;
- d is an integer from 0 to about 3;
- R h and R k are each independently at every occurrence selected from H,
- Y is at each occurrence independently selected from O, S, NR, and C(R b R d ), provided that no 0-0 bonds are present in Y c , or Y is absent;
- R b and R d are each independently at every occurrence H, halo, (C 1 _C 6 )alkyl substituted with 0-2 R a , (C 2 _C 6 )alkenyl substituted with 0-2 R a , (C 2 _C 6 )alkynyl substituted with 0-2 R a , cycloalkyl substituted with 0-2 R a , heterocyclyl substituted with 0-2 R a , aryl substituted with 0-2 R a , aralkyl substituted with 0-2 R a , heteroaryl substituted with 0-2 R a , heteroarylalkyl substituted with 0-2 R a , heteroarylalkyl substituted with 0-2 R a , (C t - haloalkyl, (CiX ⁇ haloalkoxy,
- R 9 and R 9A are each independently at every occurrence H, halo, (C 1 _C 6 )alkyl substituted with 0-2 R a , (C 2 _C 6 )alkenyl substituted with 0-2 R a , (C 2 _C 6 )alkynyl substituted with 0-2 R a , cycloalkyl substituted with 0-2 R a , cycloalkylalkyl substituted with 0-2 R a , heterocyclyl substituted with 0-2 R a , heterocyclylalkyl substituted with 0-2 R a , heterocyclylalkyl substituted with 0-2 R a , aryl substituted with 0-2 R a , aralkyl substituted with 0-2 R a , heteroaryl substituted with 0-2 R a , heteroarylalkyl substituted with 0-2 R a , heteroarylalkyl substituted with 0-2 R
- Ar 1 can be a substituted or unsubstituted pyridyl, pyrazolyl, or pyrimidinyl.
- Ar 1 can be a substituted or unsubstituted bicyclic heteroaryl comprising any of the following ring systems, wherein a wavy line indicates a point of attachment:
- Ar is likewise so defined for any of formulas (IA), (IB), (IC), (ID), (IE), (IF), (IG), (IH), (IJ), (IK), and (IL).
- the compound of the invention can be a compound of formula (IA)
- one of X 1 1 and X2" can be N and the other of X 1 and X2 can be
- one of X 1 and X 2 can be CR 1 and the other of X 1 and X 2 can be C-Ar 1 .
- the compound of formula (IA) can be of any of the following formulas:
- R can be a substituted or unsubstituted aryl or heteroaryl
- Y can be C(R b R d )
- c can be 0, 1, or 2; or any combination thereof.
- the compound of formula (IA) can be any of the following structures:
- a compound of the invention can be a compound of formula (IB)
- a compound of the invention can be a compound of formula (IC)
- the compound of formula (IC) can comprise a compound of any of formulas:
- Y can be CR b R d , c can be 0, 1, or 2
- Ar can be any of following ring systems, wherein a wavy line indicates a point of attachment:
- the compound of formula (IC) can be any of the following structures:
- a compound of the invention can be a compound of formula (ID)
- a compound of the invention can be a compound of formula (IE)
- the compound of formula (IE) can comprise any of the formulas:
- the compound of formula (IE) can be any of the following structures:
- a compound of the invention can be a compound of formula (IF)
- the compound of formula (IF) can be any of the following:
- a compound of the invention can be a compound of formula (IG)
- the compound of formula (IG) can comprise any of the formulas:
- a compound of the invention can be a compound of formula (IH)
- a compound of the invention can be a compound of formula (IJ)
- a compound of the invention can be a compound of formula (IK)
- the compound of formula (IK) can be any of the following structures:
- a compound of the invention can be a compound of formula (IL)
- IL or any tautomer, salt, stereoisomer, hydrate, solvent, isotopically labeled form, or prodrug thereof.
- a compound of the invention can be a compound of any of the Examples 1-263, or any tautomer, salt, stereoisomer, hydrate, solvent, or prodrug thereof.
- compositions of the compounds of the invention alone or in combination with another medicament.
- compounds of the invention include stereoisomers, tautomers, solvates, prodrugs, pharmaceutically acceptable salts and mixtures thereof.
- Compositions containing a compound of the invention can be prepared by conventional techniques, e.g. as described in Remington: The Science and Practice of Pharmacy, 19th Ed., 1995, incorporated by reference herein.
- the compositions can appear in conventional forms, for example capsules, tablets, aerosols, solutions, suspensions or topical applications.
- compositions include a compound of the invention and a
- the active compound will usually be mixed with a carrier, or diluted by a carrier, or enclosed within a carrier which can be in the form of an ampoule, capsule, sachet, paper, or other container.
- a carrier or when the carrier serves as a diluent, it can be solid, semi- solid, or liquid material that acts as a vehicle, excipient, or medium for the active compound.
- the active compound can be adsorbed on a granular solid carrier, for example contained in a sachet.
- suitable carriers are water, salt solutions, alcohols, polyethylene glycols,
- polyhydroxyethoxylated castor oil peanut oil, olive oil, gelatin, lactose, terra alba, sucrose, dextrin, magnesium carbonate, sugar, cyclodextrin, amylose, magnesium stearate, talc, gelatin, agar, pectin, acacia, stearic acid or lower alkyl ethers of cellulose, silicic acid, fatty acids, fatty acid amines, fatty acid monoglycerides and diglycerides, pentaerythritol fatty acid esters, polyoxyethylene, hydroxymethylcellulose and polyvinylpyrrolidone.
- the carrier or diluent can include any sustained release material known in the art, such as glyceryl monostearate or glyceryl distearate, alone or mixed with a wax.
- the formulations can be mixed with auxiliary agents which do not deleteriously react with the active compounds.
- Such additives can include wetting agents, emulsifying and suspending agents, salt for influencing osmotic pressure, buffers and/or coloring substances preserving agents, sweetening agents or flavoring agents.
- the compositions can also be sterilized if desired.
- the route of administration can be any route which effectively transports the active compound of the invention to the appropriate or desired site of action, such as oral, nasal, pulmonary, buccal, subdermal, intradermal, transdermal or parenteral, e.g., rectal, depot, subcutaneous, intravenous, intraurethral, intramuscular, intranasal, ophthalmic solution or an ointment, the oral route being preferred.
- the preparation can be tabletted, placed in a hard gelatin capsule in powder or pellet form or it can be in the form of a troche or lozenge. If a liquid carrier is used, the preparation can be in the form of a syrup, emulsion, soft gelatin capsule or sterile injectable liquid such as an aqueous or non- aqueous liquid suspension or solution.
- Injectable dosage forms generally include aqueous suspensions or oil suspensions which can be prepared using a suitable dispersant or wetting agent and a suspending agent Injectable forms can be in solution phase or in the form of a suspension, which is prepared with a solvent or diluent.
- Acceptable solvents or vehicles include sterilized water, Ringer's solution, or an isotonic aqueous saline solution.
- sterile oils can be employed as solvents or suspending agents.
- the oil or fatty acid is non-volatile, including natural or synthetic oils, fatty acids, mono-, di- or tri-glycerides.
- the formulation can also be a powder suitable for reconstitution with an appropriate solution as described above. Examples of these include, but are not limited to, freeze dried, rotary dried or spray dried powders, amorphous powders, granules, precipitates, or particulates.
- the formulations can optionally contain stabilizers, pH modifiers, surfactants, bioavailability modifiers and combinations of these.
- the compounds can be formulated for parenteral administration by injection such as by bolus injection or continuous infusion.
- a unit dosage form for injection can be in ampoules or in multi-dose containers.
- the formulations of the invention can be designed to provide quick, sustained, or delayed release of the active ingredient after administration to the patient by employing procedures well known in the art. Thus, the formulations can also be formulated for controlled release or for slow release.
- compositions contemplated by the present invention can include, for example, micelles or liposomes, or some other encapsulated form, or can be administered in an extended release form to provide a prolonged storage and/or delivery effect. Therefore, the formulations can be compressed into pellets or cylinders and implanted
- Such implants can employ known inert materials such as silicones and biodegradable polymers, e.g., polylactide- polyglycolide.
- biodegradable polymers include poly(orthoesters) and poly(anhydrides) .
- the preparation can contain a compound of the invention, dissolved or suspended in a liquid carrier, preferably an aqueous carrier, for aerosol application.
- a liquid carrier preferably an aqueous carrier
- the carrier can contain additives such as solubilizing agents, e.g., propylene glycol, surfactants, absorption enhancers such as lecithin (phosphatidylcholine) or cyclodextrin, or preservatives such as parabens.
- injectable solutions or suspensions preferably aqueous solutions with the active compound dissolved in polyhydroxylated castor oil.
- Tablets, dragees, or capsules having talc and/or a carbohydrate carrier or binder or the like are particularly suitable for oral application.
- Preferable carriers for tablets, dragees, or capsules include lactose, corn starch, and/or potato starch.
- a syrup or elixir can be used in cases where a sweetened vehicle can be employed.
- a typical tablet that can be prepared by conventional tabletting techniques can contain: Core:
- Active compound 250 mg
- a typical capsule for oral administration contains compounds of the invention (250 mg), lactose (75 mg) and magnesium stearate (15 mg). The mixture is passed through a 60 mesh sieve and packed into a No. 1 gelatin capsule.
- a typical injectable preparation is produced by aseptically placing 250 mg of compounds of the invention into a vial, aseptically freeze-drying and sealing. For use, the contents of the vial are mixed with 2 mL of sterile physiological saline, to produce an injectable preparation.
- the compounds of the invention can be administered to a mammal, especially a human in need of such treatment, prevention, elimination, alleviation or amelioration of a malcondition.
- mammals include also animals, both domestic animals, e.g.
- the compounds of the invention are effective over a wide dosage range.
- dosages from about 0.05 to about 5000 mg, preferably from about 1 to about 2000 mg, and more preferably between about 2 and about 2000 mg per day can be used.
- a typical dosage is about 10 mg to about 1000 mg per day.
- the exact dosage will depend upon the activity of the compound, mode of administration, on the therapy desired, form in which administered, the subject to be treated and the body weight of the subject to be treated, and the preference and experience of the physician or veterinarian in charge.
- the compounds of the invention are dispensed in unit dosage form including from about 0.05 mg to about 1000 mg of active ingredient together with a pharmaceutically acceptable carrier per unit dosage.
- dosage forms suitable for oral, nasal, pulmonal or transdermal administration include from about 125 ⁇ g to about 1250 mg, preferably from about 250 ⁇ g to about 500 mg, and more preferably from about 2.5 mg to about 250 mg, of the compounds admixed with a pharmaceutically acceptable carrier or diluent.
- Dosage forms can be administered daily, or more than once a day, such as twice or thrice daily. Alternatively dosage forms can be administered less frequently than daily, such as every other day, or weekly, if found to be advisable by a prescribing physician.
- a pharmaceutical combination comprising a compound of the invention in a therapeutically effective dose and a second medicament in a therapeutically effective dose
- the second medicament can comprise an anti-proliferative agent, an anti-glaucoma agent, an anti-hypertensive agent, an anti- atherosclerotic agent, an anti-multiple sclerosis agent, an anti-angina agent, an anti-erectile dysfunction agent, an anti- stroke agent, or an anti-asthma agent.
- the anti-proliferative agent can comprise an alkylating agent, an anti-metabolite, a vinca alkaloid, a terpenoid, a topoisomerase inhibitor, a monoclonal antibody, a kinase inhibitor, carboplatin, cisplatin, taxol, leucovorin, 5-flurouracil, eloxatin,
- the anti- glaucoma agent can comprise a beta receptor-blocker, a prostaglandin, an alpha- adrenergic agonist, a parasympathomimetic (cholinergic agonist), or a carbonic anhydrase inhibitor.
- the anti-hypertensive agent can comprise a beta receptor-blocker, a calcium channel blocker, a diueretic, an angiotensin converting enzyme (ACE) inhibitor, a renin inhibitor, or an angiotensin receptor antagonist.
- ACE angiotensin converting enzyme
- the anti-atherosclerotic agent can comprise a 3-HMG-coA-reductase inhibitor, a statin, atorvastatin, simvastatin, niacin, or a combination drug such as vytorin.
- the anti-multiple sclerosis agent can comprise beta-inteferon, tysabri, or glatirimar acetate.
- the anti-angina agent can comprise a beta receptor- blocker, a calcium channel blocker, nitroglycerin, isosorbide mononitrate, nicorandil, or ranolanzine.
- the anti-erectile dysfunction agent can comprise a
- the anti-stroke agent can comprise tissue plasminogen activator.
- the anti-asthma agent can comprise a
- bronchodilator an inhaled corticosteroid, a leukotrine blockers, cromolyn, nedocromil, or theophylline.
- a pharmaceutical combination of the invention can further comprise a suitable excipient as outlined above to provide a pharmaceutical composition comprising both medicaments.
- a method of treatment of a malcondition comprising administering an effective amount of a compound of the invention and coadministering an effective amount of an additional medicament.
- the malcondition can comprise cardiovascular disease, neurogenic pain, hypertension, atherosclerosis, angina, stroke, arterial obstruction, peripheral arterial disease, peripheral circulation disorder, erectile dysfunction, acute and chronic pain, dementia, Alzheimer's disease, Parkinson's disease, neuronal degeneration, asthma, amyotrophic lateral sclerosis, spinal cord injury, rheumatoid arthritis, osteoarthritis, osteoporosis, psoriasis, cerebral vasospasm, open angle glaucoma, multiple sclerosis, pulmonary hypertension, acute respiratory distress syndrome, inflammation, diabetes, urinary organ diseases such as overactive bladder (OAB) and benign prostatic hypertrophy (BPH), metastasis, cancer, open angle glaucoma, ocular hypertension, retinopathy, autoimmune disease and viral infection, or myocardial pathology
- OAB
- the additional medicament that can be co-administered can comprise an anti-proliferative agent, an anti-glaucoma agent, an anti-hypertensive agent, an anti- atherosclerotic agent, an anti-multiple sclerosis agent, an anti-angina agent, an anti-erectile dysfunction agent, an anti-stroke agent, or an anti-asthma agent.
- coadministered is meant that the patient is provided with an effective dose of an inventive compound and with an effective dose of the second medicament during the course of treatment, such as concurrently, consecutively, intermittently, or in other regimens.
- the compound of the invention and the second medicament can be administered in separate dosage forms.
- the anti-proliferative agent can comprise an alkylating agent, an anti-metabolite, a vinca alkaloid, a terpenoid, a topoisomerase inhibitor, a monoclonal antibody, a kinase inhibitor, carboplatin, cisplatin, taxol, leucovorin, 5-flurouracil, eloxatin, cyclophosphamide, chlorambucil, avastin, or imatinib mesylate.
- an alkylating agent an anti-metabolite, a vinca alkaloid, a terpenoid, a topoisomerase inhibitor, a monoclonal antibody, a kinase inhibitor, carboplatin, cisplatin, taxol, leucovorin, 5-flurouracil, eloxatin, cyclophosphamide, chlorambucil, avastin, or imatinib mesylate.
- the anti-glaucoma agent can comprise a beta receptor-blocker, a prostaglandin, an alpha- adrenergic agonist, a parasympathomimetic (cholinergic agonist), or a carbonic anhydrase inhibitor.
- the anti-hypertensive agent can comprise a beta receptor-blocker, a calcium channel blocker, a diueretic, an angiotensin converting enzyme (ACE) inhibitor, a renin inhibitor, or an angiotensin receptor antagonist.
- ACE angiotensin converting enzyme
- the anti-atherosclerotic agent can comprise a 3-HMG-coA-reductase inhibitor, a statin, atorvastatin, simvastatin, niacin, or a combination drug such as vytorin.
- the anti-multiple sclerosis agent can comprise beta-inteferon, tysaberai, or glatirimar acetate.
- the anti-angina agent can comprise a beta receptor- blocker, a calcium channel blocker, nitroglycerin, isosorbide mononitrate, nicorandil, or ranolanzine.
- the anti-erectile dysfunction agent can comprise a
- the anti-stroke agent can comprise tissue plasminogen activator.
- the anti-asthma agent can comprise a
- bronchodilator an inhaled corticosteroid, a leukotrine blockers, cromolyn, nedocromil, or theophylline.
- the invention provides a method of inhibiting a kinase enzyme, comprising contacting the kinase enzyme and an effective amount of a compound of the invention.
- the kinase enzyme can comprise a Rho kinase, an AKT kinase, a p70S6K kinase, a LIM kinase, an IKK kinase, a Fit kinase, an Aurora kinase, or a Src kinase, or any combination thereof.
- the invention provides a method of treating a
- a kinase enzyme comprising a Rho kinase, an AKT kinase, a p70S6K kinase, a LIM kinase, an IKK kinase, a Fit kinase, an Aurora kinase, or a Src kinase, or any combination thereof, is medically indicated, the method comprising administering a compound of the invention to the patient in a dose, at a frequency, and for a duration to provide a beneficial effect to the patient.
- the malcondition can comprise hypertension, atherosclerosis, angina, stroke, arterial obstruction, peripheral arterial disease, peripheral circulation disorder, erectile dysfunction, acute and chronic pain, dementia, Alzheimer's disease, Parkinson's disease, neuronal degeneration, asthma, amyotrophic lateral sclerosis, spinal cord injury, rheumatoid arthritis, osteoarthritis, osteoporosis, psoriasis, cerebral vasospasm, open angle glaucoma, spinal cord injury, multiple sclerosis, pulmonary hypertension, acute respiratory distress syndrome, inflammation, diabetes, urinary organ diseases such as overactive bladder (OAB) and benign prostatic hypertrophy (BPH), metastasis, cancer, open angle glaucoma, ocular hypertension, retinopathy, autoimmune disease and viral infection.
- OAB overactive bladder
- BPH benign prostatic hypertrophy
- the invention provides the use of a compound of the invention in preparation of a medicament, such as where the medicament is adapted to inhibit a Rho kinase, an AKT kinase, a p70S6K kinase, a LIM kinase, an IKK kinase, a Fit kinase, an Aurora kinase, or a Src kinase, or any combination thereof, or the medicament is adapted to treat a malcondition wherein inhibition of the kinase is medically indicated.
- the malcondition can comprise hypertension, atherosclerosis, angina, stroke, arterial obstruction, peripheral arterial disease, peripheral circulation disorder, erectile dysfunction, acute and chronic pain, dementia, Alzheimer's disease, Parkinson's disease, neuronal degeneration, asthma, amyotrophic lateral sclerosis, spinal cord injury, rheumatoid arthritis, osteoarthritis, osteoporosis, psoriasis, cerebral vasospasm, open angle glaucoma, spinal cord injury, multiple sclerosis, pulmonary hypertension, acute respiratory distress syndrome, inflammation, diabetes, urinary organ diseases such as overactive bladder (OAB) and benign prostatic hypertrophy (BPH), metastasis, cancer, open angle glaucoma, ocular hypertension, retinopathy, autoimmune disease and viral infection.
- OAB overactive bladder
- BPH benign prostatic hypertrophy
- inhibition of one or more of these protein kinases could be therapeutically effective in the treatment of any of hypertension, atherosclerosis, angina, stroke, arterial obstruction, peripheral arterial disease, peripheral circulation disorder, erectile dysfunction, acute and chronic pain, dementia, Alzheimer's disease, Parkinson's disease, neuronal degeneration, asthma, amyotrophic lateral sclerosis, spinal cord injury, rheumatoid arthritis, osteoarthritis, osteoporosis, psoriasis, cerebral vasospasm, open angle glaucoma, spinal cord injury, multiple sclerosis, pulmonary hypertension, acute respiratory distress syndrome, inflammation, diabetes, urinary organ diseases such as overactive bladder (OAB) and benign prostatic hypertrophy (BPH), metastasis, cancer, open angle glaucoma, ocular hypertension, retinopathy, autoimmune disease and viral infection, or in providing myocardial protection
- OAB overactive bladder
- BPH benign prostatic hypertrophy
- a microwave pressure vial was charged with AcOH (0.25 M), formaldehyde (37% aqueous solution, 1.1 equiv) and the secondary amine (2.0 equiv). The solution was then stirred for 5 min at room temperature and then MeOH was added (6x volume of AcOH) followed by the indole (1.0 equiv). The pressure vial was sealed and warmed to 80 C in an oil bath. Upon completion by LC/MS, the solution was concentrated in vacuo. The residue was then purified on S1O 2 (Hex/EtOAc with an Et 3 N flushed column).
- the aryl bromide (1.0 equiv) was then combined with the pyrazoleboronate (1.30 equiv) and Na 2 C0 3 (3.0 equiv) in 20% aqueous dioxane in a microwave pressure tube at room temperature.
- PdCl 2 (PPh 3 ) 2 (0.10 equiv) and the solution was sparged with argon for 10 minutes.
- the reaction was subsequently heated in a microwave at 120 °C until the reaction was complete (-0.5-2 h).
- the solution was then concentrated in vacuo and purified on Si0 2 (CH 2 Cl 2 /MeOH + NH 4 OH) to give the pure product.
- Example 56 1 - (3 -hydroxypropyl)-N- (2-methoxybenzyl)-6- ( 1 H-pyrazol-4-yl)- 1 H-
- Example 65 N-(3-(dimethylamino)propyl)-N-(3-methoxybenzyl)-l-methyl-6-(lH- pyrazol-4-yl)- lH-indole-3-carboxamide
- Example 70 N-(3-methoxybenzyl)-N-methyl-6-( lH-pyrazol-4-yl)- 1 -(2-(pyrrolidin- 1- yl)ethyl)-lH-indole-3-carboxamide
- a microwave pressure vial was charged with finely ground K 3 P0 4 (2.1 equiv), the indole (1.0 equiv) and anhydrous dioxane. 1,2-trans-cyclohexyldiamine (0.2 equiv) and the aryl iodide (1.0 equiv) were then added. Cul (0.1 equiv) was lastly added and the sealed vial was sparged with argon for 10 minutes. The solution was then heated in a microwave reactor at 120 °C until the conversion was complete ( ⁇ 1 h). Upon completion the solution was diluted with CH 2 CI 2 and washed with an aqueous 1M HC1 solution.
- the aryl bromide (1.0 equiv) was combined with bis(pinacolato)boron (2.5 equiv), KOAc (5.0 equiv) and PdCl 2 (dppf) (0.1 equiv) under streaming argon in a microwave pressure tube. Dioxane was then added and the solution was sparged with argon for 10 minutes. The solution was then heated to 100 °C in a microwave until the conversion was complete (-60 min). To this solution was then added the arylchloride (1.0 equiv), Na 2 C0 3 (3.0 equiv) and
- Step B N-(3-methoxybenzyl)-6-(lH-pyrazol-4-yl)imidazorL2-alpyridine-2- carboxamide
- Step A To a solution of the bromide obtained in Scheme 8, Step A (75 mg, 0.21 mmol) in dioxane (1.5 mL) was added bis(pinacolato)diboron (133 mg, 0.52 mmol), potassium acetate (102 mg, 1.04 mmol), and PdCl 2 (dppf) (17 mg, 0.02 mmol).
- the reaction mixture was degassed, purged with argon, and heated to 100 °C for 1.5 h by microwave irradiation. After the reaction was determined to be complete by LC-MS, the mixture was diluted with ethyl acetate (25 mL) and washed with water (2 x 10 mL) and brine (10 mL).
- Step A 7-Chloro-N-(3-methoxybenzyl)imidazor 1 ,2-alpyridine-2-carboxamide
- Step B N-(3-methoxybenzyl)-7-(lH-pyrazol-4-yl)imidazorL2-alpyridine-2- carboxamide
- Oxalyl chloride (1.5 equiv) and dry DMF (4 drops) were added to the mixture of 6- methoxylchroman-3-carboxylic acid (1 equiv) in dry DCM (2 mL). After stirring 4 hours, the solvent was removed under reduced pressure and the remaining residue was resolved in dry DCM (2 mL) and added to the mixture of Meldrum's acid (1 equiv) and pyridine (3 equiv) in DCM (2 mL) at 0 °C.
- Example 110 7-(2-aminopyrimidin-4-yl)-2-(6-methoxychroman-3-yl)-4H-pyrido[l,2- a] pyrimidin-4- one
- compound 13-4 (0.73 mmol) was dissolved in anhydrous DMF and the reaction mixture was treated with HATU (1.3 equiv., 0.36 g, 0.95 mmol), a primary or a secondary amine NHRR' (1.3 equiv., 0.95 mmol) and triethyl amine (TEA) (5.0 equiv., 0.53 mL, 3.65 mmol).
- HATU 1.3 equiv., 0.36 g, 0.95 mmol
- a primary or a secondary amine NHRR' 1.3 equiv., 0.95 mmol
- TEA triethyl amine
- the reaction mixture was stirred overnight at room temperature.
- the reaction mixture was concentrated and the residue was diluted with EtOAc and washed with water.
- the aqueous layer was extracted with EtOAc (x3) and the combined organics were dried and concentrated. Purification by flash chromatography using Combiflash ® and employing a gradient
- alkyl halide (1.3 equiv.) was added and the reaction mixture was stirred at room temperature for 14 h. Upon completion, the solution was diluted with EtOAc and washed with water. The aqueous portion was extracted with EtOAc (x3) and the combined organics were dried and concentrated. Purification by flash chromatography using Combiflash ® and employing a gradient of 0-20% MeOH in DCM (+1% NH 3 ) afforded 14-8.
- EtOH/toluene (3:2 by volume) was sequentially treated with 2 M solution of K 2 C0 3 (9.0 equiv.) and the tetrakis palladium catalyst (10 mol%) and the tube was sealed and the solution degassed by passing a flow of argon.
- the mixture was heated at 145 °C for 1.0 h in a microwave reactor. After cooling to room temperature, the reaction was quenched with 10% TFA in water until evolution of gas was complete. The reaction mixture was concentrated and the residue was purified by preparative HPLC to give the target compounds.
- Example 150 l-(cyclopropylmethyl)-N-(3-(isopropylcarbamoyl)phenyl)-6-(5-methyl- 7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-indazole-3-carboxamide
- Example 151 l-(cyclopropylmethyl)-N-(3-(isopropylcarbamoyl)phenyl)-6-(7H- pyrrolo[2,3-d]pyrimidin-4-yl)-lH-indazole-3-carboxamide
- Example 153 1 -(cyclopropylmethyl)-N- (2- (dimethylamino)ethyl)-N- (3 - methoxybenzyl)-6-(lH-pyrazol-4-yl)-lH-indazole-3-carboxamide
Abstract
The invention is directed to heteroaryl compounds useful as inhibitors of various kinase enzymes. In various embodiments, the invention provides a heteroaryl compound having inhibitory bioactivity with respect to a Rho kinase, an AKT kinase, a p70S6K kinase, a LIM kinase, an IKK kinase, a Flt kinase, an Aurora kinase, or a Src kinase, or any combination thereof. Compounds of the invention include bicyclic heteroaryl compounds of formula (I), which can contain a bridging nitrogen atom at a ring junction. The invention further provides methods of synthesis of compounds of the invention, pharmaceutical compositions, pharmaceutical combinations, and methods of treatment of malconditions using compounds of the invention.
Description
BICYCLIC HETEROARYLS AS KINASE INHIBITORS
CROSS-REFERENCE TO RELATED APPLICATIONS
This application claims the priority of U.S. Ser. No. 61/254,218, filed Oct. 23, 2009, which is incorporated by reference herein in its entirety. BACKGROUND
There are believed to be in excess of 500 distinct kinase enzymes coded in the human genome. Kinases catalyze the phosphorylation of specific amino acid residues in specific protein substrates, and by doing so are believed to be key components of regulatory systems controlling cell proliferation, cell differentiation, cell death
(apoptosis), and tissue/organ organization. Among these many different kinase enzymes are subclasses known as Rho kinases, Protein Kinase B (also known as AKT), kinase p70S6K that acts on a ribosomal protein, LIM kinases, IKK kinases, an Fit kinases, Aurora kinases, and Src kinases. Each of these subclasses can contain multiple forms, isozymes, protein sequences, and the like, and are characterized by structural and functional homologies.
Rho kinases, also known as Rho-associated kinases, are serine/threonine kinases that function downstream of Rho which is a low molecular GTP-binding protein. Two Rho kinase isoforms, ROCK I and ROCK II, have been identified. The enzymes are believed to be involved in a variety of biological events such as smooth muscle contraction, apoptosis, cell growth, cell migration, cell proliferation, cytokinesis, cytoskeletal control, and inflammation, and to be involved in pathology of various diseases including cardiovascular disease, tumor infiltration, osteogenesis, chondrocyte differentiation and neurogenic pain. See, e.g., H. Satoh, et al., Jpn. J. Pharmacol., 1999, 79, Suppl I, 211, K. Kuwahara, et al, FEBS Lett., 1999, 452, 314-18; N. Sawada, et al., Circulation, 2000, 101, 2030-33; C. Kataoka, et al, Hypertension, 2002, 39(2), 245-50; F. Imamura, et al., Jpn. J. Cancer Res., 2000, 91, 811-16, K. Itoh et al, Nature Medicine, 1999, 5, 221-5, M. Nakajima, et al, Clin. Exp. Pharmacol. Physiol., 2003; 50(7): 457-63; W. Guoyan, et al., J. Biol. Chem., 2004, 279(13), 13205-14; S. Tatsumi, Neuroscience, 2005, 131(2) 491-98.
Various compounds have been described in the literature as Rho kinase inhibitors. See, e.g. WO98/06433; WO00/09162; WO00/78351; WO01/17562; WO02/076976; EP1256574; WO02/100833; WO03/082808; WO2004/009555; WO2004/024717;
WO2004/041813; WO2004/108724; WO2005/003101; WO2005/035501;
WO2005/035503; WO2005/035506; WO2005/037198; WO2005/058891;
WO2005/074642; WO2005/074643; WO2005/080934; WO2005/082367;
WO2005/082890; WO2005/097790; WO2005/100342; WO2005/103050;
WO2005/105780; WO2005/108397; WO2006/044753; WO2006/051311;
WO2006/057270; WO2006/058120; WO2006/065946; WO2006/099268;
WO2006/072792; WO2007/026920; WO2008/011557; WO2008/011560;
WO2008/036458; US2008/153813A; WO2009079008; WO2009079009;
WO2009079011; Takami, et al, Bioorg. Med. Chem., 2004, 12, 2115-37; M. Iwakubo, et al, Bioorg. Med. Chem., 2007, 15, 350-64; M. Iwakubo, et al., Bioorg. Med. Chem., 2007, 15, 1022-33.
Protein Kinase B (PKB) is a group of enzymes, also referred to as the AKT protein family, which are known to play a role in cellular signaling in mammals. In humans, there are at least three genes in the PCB/Akt family: Aktl, Akt2, and Akt3. These genes code for enzymes that are serine/threonine- specific protein kinases. Aktl is involved in cellular survival pathways, by inhibiting apoptotic processes. Aktl is also able to induce protein synthesis pathways, and is therefore a key signaling protein in the cellular pathways that lead to skeletal muscle hypertrophy, and general tissue growth. Since it can block apoptosis, and thereby promote cell survival, Aktl has been implicated as a major factor in many types of cancer. See, for example, published PCT patent application Pub. No. WO2008/110846 and documents cited therein.
The protein kinase known as p70S6K, a 70 kDa ribosomal protein kinase is a serine/threonine-specific protein kinase that is known to control or modulate protein synthesis on the ribosome through phosphorylation of a ribosomal protein S6. p70S6K is believed to be involved in cell cycle control, cell differentiation and motility, in the immune response, and in tissue repair. This kinase may block apoptosis in tumor cells and thus plays a role in cancer proliferation. See, for example, published PCT patent application Pub. No. WO2008/110846 and documents cited therein.
LIM kinase (LIMK) including LIMK1 and LIMK2, are actin-binding kinases that may be involved in reorganization of the actin cytoskeleton, possibly by regulating Rho kinase dependent cytoskeletal rearrangement. See, for example, published patent application Pub. No. US2009/0042893 and documents cited therein.
IKK kinases, including IKKa (IKK1), ΙΚΚβ (IKK2) and IKKi (ΙΚΚε) are regulatory signaling molecules that interact with ΝΚ-κΒ, a transcription factor that regulates the expression of many genes. ΝΚ-κΒ is believed to be involved in cellular and organismic processes including angiogenesis, inflammatory diseases, and
ischemic/reperfusion injury. The IKK kinases are believed to activate ΝΚ-κΒ by phosphorylation in response to a variety of different biochemical signals. See, for example, published PCT patent application WO2009/089042; R. Agami (2007), Cell, 129, 1043; and J.S. Boehm, et al. (2007), Cell, 129, 1065.
Fit kinases include Flt3, also known as FMS-like tyrosine kinase 3, is a cytokine- binding kinase, is a membrane-spanning receptor tyrosine kinase involved in
proliferation, differentiation, and apoptosis of cells in hematopoiesis. See for example US2006281788; Qi Chao, et al. (2009), J. Med. Chem., DOI: 10.1021/jm9007533, "Identification of N-5-iert-Butyl-isoxazol-3-yl)-N'-({4-[7-(2-morpholin-4-yl- ethoxy)imidazo-[2,l-b][l,3]benzothiazol-2-yl]phenyl}urea Dihydrochloride (AC220), a Uniquely Potent, Selective, and Efficacious FMS-Like Tyrosine Kinase-3 (FLT3) Inhibitor".
Aurora kinases are a family of homologous serine/threonine protein kinases, include Aurora- A, Aurora-B, and Aurora-C kinase enzymes. They are involved in processes controlling cell mitosis, including chromosome condensation, centrosome maturation, and spindle formation, and perhaps cell meiosis include spermatogenesis. See for example D. Bebbington et al. (2009), "The Discovery of Potent Aurora Inhibitor MK 0457 (VX-680)", Biochem. Med. Chem. Lett., 19, 3856-3592; L. Garuti, et al.
(2009), "Small Molecule Aurora Kinases Inhibitors," Curr. Med. Chem., 16, 1949-1963; M. Zhong et al. (2009), "2-Aminobenzimidazoles as Potent Aurora Kinase Inhibitors," Biochem. Med. Chem. Lett., 19, 5158-5161; WO2009114703; and WO2009111028.
Src kinases are members of the cytoplasmic protein tyrosine kinase family, and the Src family includes members such as BLK, FGR, FYN, HCK, LCK, LYN, YES,
SRC, AND YRK. Among other effects, Src is believed to be responsible for stimulation of VEGF, and is also involved in regulation of cell growth, migration, and survival. See for example K. Lee et al. (2009), "Structure-based Virtual Screening of Src Kinase Inhibitors," Bioorg. Med. Chem., 17, 3152-3161; H. Mukaiyama, et al. (2008), "Novel Pyrazolo[l,5-a]pyrimidines as c-SRc Kinase Inhibitors that Reduce Ikr Channel
Blockade," Bioorg. Med. Chem., 16, 909-921; N. Rucci et al. (2008), Anti-Cancer Agents in Medicinal Chemistry, 8, 342-349; and WO2008058341.
Thus, inhibition of one or more of these protein kinases could be therapeutically effective in the treatment of any of hypertension, atherosclerosis, angina, stroke, arterial obstruction, peripheral arterial disease, peripheral circulation disorder, erectile dysfunction, acute and chronic pain, dementia, Alzheimer's disease, Parkinson's disease, neuronal degeneration, asthma, amyotrophic lateral sclerosis, spinal cord injury, rheumatoid arthritis, osteoarthritis, osteoporosis, psoriasis, cerebral vasospasm, glaucoma, spinal cord injury, multiple sclerosis, pulmonary hypertension, acute respiratory distress syndrome, inflammation, diabetes, urinary organ diseases such as overactive bladder (OAB) and benign prostatic hypertrophy (BPH), metastasis, cancer, open angle glaucoma, ocular hypertension, retinopathy, autoimmune disease and viral infection, or in providing myocardial protection.
SUMMARY
The present invention is directed to heteroaryl compounds useful as inhibitors of various kinase enzymes. In various embodiments, the invention provides a compound of the formula (I):
wherein
X1 and X2 are each independently N,
CR1; and X3, X4, X5, or X6 are each independently N, C-E, or CR , provided that ring B is substituted by only one E group, and provided that at least one of X3-X6 is N, and no more than five of Xx-X6 are N;
Z is a bond between X3 and X4, or Z is C(=0) wherein X3 and X4 are each respectively connected to the C(=0) by a single bond;
a dotted line indicates that a bond is either a single bond or a double bond;
R, R1 and R2 are each independently H, halo, (C1_C6)alkyl substituted with 0-2 Ra, (C2-C6)alkenyl substituted with 0-2 Ra, (C2_C6)alkynyl substituted with 0-2 Ra, cycloalkyl substituted with 0-2 Ra, cycloalkylalkyl substituted with 0-2 Ra, heterocyclyl substituted with 0-2 Ra, heterocyclylalkyl substituted with 0-2 Ra, aryl substituted with 0-2 Ra, aralkyl substituted with 0-2 Ra, heteroaryl substituted with 0-2 Ra, heteroarylalkyl substituted with 0-2 Ra, (Ci-C¼)haloalkyl, (C1_C6)haloalkyl, (Ci-C6)haloalkoxy, (Ci- C6)hydroxyalkyl, (CH2)pN02, (CH2)PCN, (CH2)pOR, (CH2)PNR2, (CH2)pCOR,
(CH2)pOCOR, (CH2)pC02R, (CH2)pCONR2, (CH2)pOCONR2, (CH2)pNRCOR,
(CH2)pNRC02R, (CH2)pNRCONR2, (CH2)PC(=NH)NH2, (CH2)pS02R, (CH2)pS02NR2, (CH2)pNRS02R, or (CH2)pNRS02NR2;
1 1 2
nl plus the number of C-R groups comprised by X and X is 0-3;
n2 plus the number of C-R2 groups comprised X3-X6 is 0-4;
n3 plus the number of C-Ar 1 groups comprised by X 1 and X2 is 1-4, such that at least one Ar1 is present on ring A;
Ra is halo, oxo, (C1_C6)alkyl substituted with 0-2 Ra, (C2_C6)alkenyl substituted with 0-2 Ra, (C2_C6)alkynyl substituted with 0-2 Ra, cycloalkyl substituted with 0-2 Ra, cycloalkylalkyl substituted with 0-2 Ra, heterocyclyl substituted with 0-2 Ra,
heterocyclylalkyl substituted with 0-2 Ra, aryl substituted with 0-2 Ra, aralkyl substituted with 0-2 Ra, heteroaryl substituted with 0-2 Ra, heteroarylalkyl substituted with 0-2 Ra, (Ci_C6)haloalkyl, (Ci_C6)haloalkoxy, (CH2)pN02, (CH2)PCN, (CH2)pOR, (CH2)PNR2, (CH2)pCOR, (CH2)pOCOR, (CH2)pC02R, (CH2)pCONR2, (CH2)pOCONR2,
(CH2)pNRCOR, (CH2)pNRC02R, (CH2)pNRCONR2, (CH2)PC(=NH)NH2, (CH2)pS02R, (CH2)pS02NR2, (CH2)pNRS02R, or (CH2)pNRS02NR2;
m is 0, 1, or 2;
p is 0, 1, 2, 3, or 4;
Ar1 is a 5 or 6 membered heteroaryl ring comprising at least one nitrogen atom, and 0-3 additional heteroatoms selected from O, S(0)m, and N; when Ar1 is a 5- membered heteroaryl, the nitrogen atom is disposed two atoms away from a point of attachment of the heteroaryl to ring A, and when Ar1 is a 6-membered heteroaryl, the nitrogen atom is disposed three atoms away from a point of attachment of the heteroaryl to ring A, wherein any 5-membered heteroaryl or 6-membered heteroaryl of Ar1 is substituted with 0-3 R , and wherein any 5-membered heteroaryl or 6-membered heteroaryl can be fused with an aryl or heteroaryl ring that is substituted with 0-3 R4;
R3 and R4 are each independently (C1_C6)alkyl substituted with 0-2 Ra,
(C2-C6)alkenyl substituted with 0-2 Ra, (C2_C6)alkynyl substituted with 0-2 Ra, cycloalkyl substituted with 0-2 Ra, cycloalkylalkyl substituted with 0-2 Ra, heterocyclyl substituted with 0-2 Ra, heterocyclylalkyl substituted with 0-2 Ra, aryl substituted with 0-2 Ra, aralkyl substituted with 0-2 Ra, heteroaryl substituted with 0-2 Ra, heteroarylalkyl substituted with 0-2 Ra, (Ci-C¼)haloalkyl, (C1_C6)haloalkyl, (Ci-C6)haloalkoxy, (Ci- C6)hydroxyalkyl, halo, cyano, nitro, oxo, -C(=0)R, -C(=0)OR, (Cr
C6)alkylene-C(=0)OR, -C(=0)NR2, (Ci-C6)alkylene-C(=0)NR2, -C(=NR)NR2, -OR, (Ci-C6)alkylene-OR, -OC(=0)(Ci-C6)alkyl, -OC(=0)0(Ci-C6)alkyl, -OC(=0)NR2, -NR2, -NRC(=0)R, -NRC(=0)0(C1-C6)alkyl, -NRC(=0)NR2, -NR(C1-C6)alkylene-NR2, -NR(C1-C6)alkylene-OR, -NR(C1-C6)alkylene-Ar2, -NRS02R, -SR, -S(0)R, -S02R, -OS02(C1-C6)alkyl, -S02NR2, pyrazolyl, triazolyl, or tetrazolyl, provided that R4 can also be hydrogen; or two R4 groups taken together form a fused cycloalkyl, heterocyclyl, aryl or heteroaryl ring substituted with 0-4 Ra;
Ar is unsubstituted aryl, unsubstituted heteroaryl, aryl substituted with one or more substituents selected from R4, or heteroaryl substituted with one or more
substituents selected from R4;
R5 is hydrogen, (C1-C6)alkyl substituted with 0-2 Ra, (Cr alkenyl substituted with 0-2 Ra, C(=0)(Ci-C6)alkyl substituted with 0-2 Ra, C(=0)0(Ci-C6)alkyl substituted with 0-2 Ra, Ar2 wherein Ar2 is substituted with 0-2 R3; -(C1-C6)alkylene-Ar2 wherein Ar2 is substituted with 0-2 R3, -(C1-C6)alkylC(=0)OR, or -(C1-C6)alkylC(=0)NR2; and
E is any of the following, wherein a wavy line indicates a point of attachment to ring B:
(a) a group of the formula
wherein:
n is an integer from 0 to about 2;
G, J, and K are each independently CH2, O, S, NR5, or CHNHR5, provided that K can also be a bond;
or
wherein:
D is absent, or
D is
or D is a 5- to 7-membered heterocyclyl comprising NR ;
d is an integer from 0 to about 3;
Rh and Rk are each independently at every occurrence selected from H,
(Ci-C6)alkyl substituted with 0-2 Ra, NR2, and NRC(=0)-(C1_6)alkyl; or Rh and Rk taken together with a carbon atom to which they are attached form a (C3_C7)cycloalkyl ring substituted with 0-2 Ra;
R8 is H or C(=0)-(C1-C6)alkyl;
Gi is CH2, O, S, NR5, NR5C(=0), C(=0)NR5, NR5C(=0)NR5, or CHNHR5; and G2 is a bond, O, NR5, or S;
or
(c) a group of the formula
wherein
c is 0-3,
Y is at each occurrence independently selected from O, S, NR, and C(RbRd), provided that no 0-0 bonds are present in Yc, or Y is absent;
Rb and Rd are each independently at every occurrence H, halo, (C1-C6)alkyl substituted with 0-2 Ra, (C2-C6)alkenyl substituted with 0-2 Ra, (C2-C6)alkynyl substituted with 0-2 Ra, cycloalkyl substituted with 0-2 Ra, heterocyclyl substituted with 0-2 Ra, aryl substituted with 0-2 Ra, aralkyl substituted with 0-2 Ra, heteroaryl substituted with 0-2 Ra, heteroarylalkyl substituted with 0-2 Ra, (Q- haloalkyl, (Ci-C6)haloalkoxy,
(CH2)pN02, (CH2)PCN, (CH2)pOR, (CH2)PNR2, (CH2)pCOR, (CH2)pOCOR, (CH2)pC02R, (CH2)pCONR2, (CH2)pOCONR2, (CH2)pNRCOR, (CH2)pNRC02R, (CH2)pNRCONR2, (CH2)PC(=NH)NH2, (CH2)pS02R, (CH2)pS02NR2, (CH2)pNRS02R, or (CH2)pNRS02NR2 m is 0, 1, or 2; q is 1-5; and
R9 and R9A are each independently at every occurrence H, halo, (C1_C6)alkyl substituted with 0-2 Ra, (C2_C6)alkenyl substituted with 0-2 Ra, (C2_C6)alkynyl substituted with 0-2 Ra, cycloalkyl substituted with 0-2 Ra, cycloalkylalkyl substituted with 0-2 Ra, heterocyclyl substituted with 0-2 Ra, heterocyclylalkyl substituted with 0-2 Ra, aryl substituted with 0-2 Ra, aralkyl substituted with 0-2 Ra, heteroaryl substituted with 0-2 Ra, heteroarylalkyl substituted with 0-2 Ra, (Ci-C6)haloalkyl, (C1_C6)haloalkyl, (Ci_ C6)haloalkoxy, (Ci_C6)hydroxyalkyl, (CH2)pN02, (CH2)PCN, (CH2)pOR, (CH2)PNR2, (CH2)pCOR, (CH2)pOCOR, (CH2)pC02R, (CH2)pCONR2, (CH2)pOCONR2,
(CH2)pNRCOR, (CH2)pNRC02R, (CH2)pNRCONR2, (CH2)PC(=NH)NH2, (CH2)pS02R, (CH2)pS02NR2, (CH2)pNRS02R, (CH2)pNRS02NR2; or R9 and (Y)CR9A and the nitrogen
atom to which they are bonded can together form a heterocyclyl substituted with 0-2 Ra wherein the heterocyclyl can be fused with a substituted or unsubstituted cycloalkyl, heterocyclyl, aryl, or heteroaryl ring system;
or any tautomer, salt, stereoisomer, hydrate, solvent, isotopically labeled form, or prodrug thereof.
Various embodiments of the invention provide a pharmaceutical composition comprising a compound of the invention and a pharmaceutically acceptable excipient.
Various embodiments of the invention provide a pharmaceutical combination comprising a compound of the invention and a second medicament.
Various embodiments of the invention provide methods of synthesis of compounds of the invention.
Various embodiments of the invention provide a method of inhibiting a Rho kinase, an AKT kinase, a p70S6K kinase, a LIM kinase, an IKK kinase, a Fit kinase, an Aurora kinase, or a Src kinase, or any combination thereof.
Various embodiments of the invention provide a method of treating a
malcondition, such as cancer, wherein inhibition of a Rho kinase, an AKT kinase, a p70S6K kinase, a LIM kinase, an IKK kinase, a Fit kinase, an Aurora kinase, or a Src kinase, or any combination thereof, is medically indicated.
Various embodiments of the invention provide a use of a compound of the invention in manufacture of a medicament adapted to treat a malcondition, such as cancer.
DETAILED DESCRIPTION
Definitions
As used in the specification and the appended claims, the singular forms "a," "an" and "the" include plural referents unless the context clearly dictates otherwise.
As used herein, "individual" (as in the subject of the treatment) means both mammals and non-mammals. Mammals include, for example, humans; non-human primates, e.g. apes and monkeys; cattle; horses; sheep; and goats. Non-mammals include, for example, fish and birds.
The term "disease" or "disorder" or "malcondition" are used interchangeably, and are used to refer to diseases or conditions wherein a kinase enzyme such as a Rho kinase, an AKT kinase, a p70S6K kinase, a LIM kinase, an IKK kinase, a Fit kinase, an Aurora kinase, or a Src kinase, or any combination thereof, plays a role in the biochemical mechanisms involved in the diseases such that a therapeutically beneficial effect can be achieved by acting on the kinase.
The expression "effective amount", when used to describe therapy to an individual suffering from a disorder, refers to the amount of a compound of the invention that is effective to inhibit or otherwise act on a kinase enzyme such as a Rho kinase, an an AKT kinase, a p70S6K kinase, a LIM kinase, an IKK kinase, a Fit kinase, an Aurora kinase, or a Src kinase, or any combination thereof in the individual's tissues wherein the kinase involved in the disorder is active, wherein such inhibition or other action occurs to an extent sufficient to produce a beneficial therapeutic effect.
"Substantially" as the term is used herein means completely or almost completely; for example, a composition that is "substantially free" of a component either has none of the component or contains such a trace amount that any relevant functional property of the composition is unaffected by the presence of the trace amount, or a compound is "substantially pure" is there are only negligible traces of impurities present.
"Treating" or "treatment" within the meaning herein refers to an alleviation of symptoms associated with a disorder or disease, or inhibition of further progression or worsening of those symptoms, or prevention or prophylaxis of the disease or disorder, or curing the disease or disorder. Similarly, as used herein, an "effective amount" or a "therapeutically effective amount" of a compound of the invention refers to an amount of the compound that alleviates, in whole or in part, symptoms associated with the disorder or condition, or halts or slows further progression or worsening of those symptoms, or prevents or provides prophylaxis for the disorder or condition. In particular, a
"therapeutically effective amount" refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired therapeutic result. A therapeutically effective amount is also one in which any toxic or detrimental effects of compounds of the invention are outweighed by the therapeutically beneficial effects.
By "chemically feasible" is meant a bonding arrangement or a compound where the generally understood rules of organic structure are not violated; for example a structure within a definition of a claim that would contain in certain situations a pentavalent carbon atom that would not exist in nature would be understood to not be within the claim. The structures disclosed herein, in all of their embodiments are intended to include only "chemically feasible" structures, and any recited structures that are not chemically feasible, for example in a structure shown with variable atoms or groups, are not intended to be disclosed or claimed herein.
When a substituent is specified to be an atom or atoms of specified identity, "or a bond", a configuration is referred to when the substituent is "a bond" that the groups that are immediately adjacent to the specified substituent are directly connected to each other in a chemically feasible bonding configuration.
All chiral, diastereomeric, racemic forms of a structure are intended, unless a particular stereochemistry or isomeric form is specifically indicated. Compounds used in the present invention can include enriched or resolved optical isomers at any or all asymmetric atoms as are apparent from the depictions, at any degree of enrichment. Both racemic and diastereomeric mixtures, as well as the individual optical isomers can be isolated or synthesized so as to be substantially free of their enantiomeric or
diastereomeric partners, and these are all within the scope of the invention.
The inclusion of an isotopic form of one or more atoms in a molecule that is different from the naturally occurring isotopic distribution of the atom in nature is referred to as an "isotopically labeled form" of the molecule. All isotopic forms of atoms are included as options in the composition of any molecule, unless a specific isotopic form of an atom is indicated. For example, any hydrogen atom or set thereof in a molecule can be any of the isotopic forms of hydrogen, i.e., protium ( 1 H), deuterium ( 2 H), or tritium ( H) in any combination. Similarly, any carbon atom or set thereof in a molecule can be any of the isotopic form of carbons, such as UC, 12C, 13C, or 14C, or any nitrogen atom or set thereof in a molecule can be any of the isotopic forms of nitrogen, such as 13N, 14N, or 15N. A molecule can include any combination of isotopic forms in the component atoms making up the molecule, the isotopic form of every atom forming the molecule being independently selected. In a multi-molecular sample of a compound,
not every individual molecule necessarily has the same isotopic composition. For example, a sample of a compound can include molecules containing various different isotopic compositions, such as in a tritium or 14C radiolabeled sample where only some fraction of the set of molecules making up the macroscopic sample contains a radioactive atom. It is also understood that many elements that are not artificially isotopically enriched themselves are mixtures of naturally occurring isotopic forms, such as 14N and
15 N, 32 S and 34 S, and so forth. A molecule as recited herein is defined as including isotopic forms of all its constituent elements at each position in the molecule. As is well known in the art, isotopically labeled compounds can be prepared by the usual methods of chemical synthesis, except substituting an isotopically labeled precursor molecule. The isotopes, radiolabeled or stable, can be obtained by any method known in the art, such as generation by neutron absorption of a precursor nuclide in a nuclear reactor, by cyclotron reactions, or by isotopic separation such as by mass spectrometry. The isotopic forms are incorporated into precursors as required for use in any particular synthetic route. For example, 14C and 3H can be prepared using neutrons generated in a nuclear reactor. Following nuclear transformation, 14C and 3H are incorporated into precursor molecules, followed by further elaboration as needed.
The term "amino protecting group" or "N-protected" as used herein refers to those groups intended to protect an amino group against undesirable reactions during synthetic procedures and which can later be removed to reveal the amine. Commonly used amino protecting groups are disclosed in Protective Groups in Organic Synthesis, Greene, T.W.; Wuts, P. G. M., John Wiley & Sons, New York, NY, (3rd Edition, 1999). Amino protecting groups include acyl groups such as formyl, acetyl, propionyl, pivaloyl, t- butylacetyl, 2-chloroacetyl, 2-bromoacetyl, trifluoroacetyl, trichloroacetyl,
o-nitrophenoxyacetyl, a-chlorobutyryl, benzoyl, 4-chlorobenzoyl, 4-bromobenzoyl,
4-nitrobenzoyl, and the like; sulfonyl groups such as benzenesulfonyl, p-toluenesulfonyl and the like; alkoxy- or aryloxy-carbonyl groups (which form urethanes with the protected amine) such as benzyloxycarbonyl (Cbz), p-chlorobenzyloxycarbonyl, p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl, p-bromobenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl,
3,5-dimethoxybenzyloxycarbonyl, 2,4-dimethoxybenzyloxycarbonyl,
4-methoxybenzyloxycarbonyl, 2-nitro-4,5-dimethoxybenzyloxycarbonyl, 3,4,5-trimethoxybenzyloxycarbonyl, l-(p-biphenylyl)-l-methylethoxycarbonyl, a,a-dimethyl-3,5-dimethoxybenzyloxycarbonyl, benzhydryloxycarbonyl, t- butyloxycarbonyl (Boc), diisopropylmethoxycarbonyl, isopropyloxycarbonyl, ethoxycarbonyl, methoxycarbonyl, allyloxycarbonyl (Alloc), 2,2,2- trichloroethoxycarbonyl, 2-trimethylsilylethyloxycarbonyl (Teoc), phenoxycarbonyl, 4- nitrophenoxycarbonyl, fluorenyl-9-methoxycarbonyl (Fmoc), cyclopentyloxycarbonyl, adamantyloxycarbonyl, cyclohexyloxycarbonyl, phenylthiocarbonyl and the like; aralkyl groups such as benzyl, triphenylmethyl, benzyloxymethyl and the like; and silyl groups such as trimethylsilyl and the like. Amine protecting groups also include cyclic amino protecting groups such as phthaloyl and dithiosuccinimidyl, which incorporate the amino nitrogen into a heterocycle. Typically, amino protecting groups include formyl, acetyl, benzoyl, pivaloyl, t-butylacetyl, phenylsulfonyl, Alloc, Teoc, benzyl, Fmoc, Boc and Cbz. It is well within the skill of the ordinary artisan to select and use the appropriate amino protecting group for the synthetic task at hand.
The term "hydroxyl protecting group" or "O-protected" as used herein refers to those groups intended to protect an OH group against undesirable reactions during synthetic procedures and which can later be removed to reveal the amine. Commonly used hydroxyl protecting groups are disclosed in Protective Groups in Organic Synthesis, Greene, T.W.; Wuts, P. G. M., John Wiley & Sons, New York, NY, (3rd Edition, 1999). Hydroxyl protecting groups include acyl groups such as formyl, acetyl, propionyl, pivaloyl, t-butylacetyl, 2-chloroacetyl, 2-bromoacetyl, trifluoroacetyl, trichloroacetyl, o-nitrophenoxyacetyl, a-chlorobutyryl, benzoyl, 4-chlorobenzoyl, 4-bromobenzoyl, 4-nitrobenzoyl, and the like; sulfonyl groups such as benzenesulfonyl, p-toluenesulfonyl and the like; acyloxy groups (which form urethanes with the protected amine) such as benzyloxycarbonyl (Cbz), p-chlorobenzyloxycarbonyl, p-methoxybenzyloxycarbonyl, p- nitrobenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl, p-bromobenzyloxycarbonyl, 3,4- dimethoxybenzyloxycarbonyl, 3,5-dimethoxybenzyloxycarbonyl, 2,4- dimethoxybenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 2-nitro-4,5- dimethoxybenzyloxycarbonyl, 3,4,5-trimethoxybenzyloxycarbonyl, l-(p-biphenylyl)-l- methylethoxycarbonyl, a,a-dimethyl-3,5-dimethoxybenzyloxycarbonyl,
benzhydryloxycarbonyl, t-butyloxycarbonyl (Boc), diisopropylmethoxycarbonyl, isopropyloxycarbonyl, ethoxycarbonyl, methoxycarbonyl, allyloxycarbonyl (Alloc), 2,2,2-trichloroethoxycarbonyl, 2-trimethylsilylethyloxycarbonyl (Teoc),
phenoxycarbonyl, 4-nitrophenoxycarbonyl, fluorenyl-9-methoxycarbonyl (Fmoc), cyclopentyloxycarbonyl, adamantyloxycarbonyl, cyclohexyloxycarbonyl,
phenylthiocarbonyl and the like; aralkyl groups such as benzyl, triphenylmethyl, benzyloxymethyl and the like; and silyl groups such as trimethylsilyl and the like. It is well within the skill of the ordinary artisan to select and use the appropriate hydroxyl protecting group for the synthetic task at hand.
In general, "substituted" refers to an organic group as defined herein in which one or more bonds to a hydrogen atom contained therein are replaced by one or more bonds to a non-hydrogen atom such as, but not limited to, a halogen (i.e., F, CI, Br, and I); an oxygen atom in groups such as hydroxyl groups, alkoxy groups, aryloxy groups, aralkyloxy groups, oxo(carbonyl) groups, carboxyl groups including carboxylic acids, carboxylates, and carboxylate esters; a sulfur atom in groups such as thiol groups, alkyl and aryl sulfide groups, sulfoxide groups, sulfone groups, sulfonyl groups, and sulfonamide groups; a nitrogen atom in groups such as amines, hydroxylamines, nitriles, nitro groups, N-oxides, hydrazides, azides, and enamines; and other heteroatoms in various other groups. Non-limiting examples of substituents that can be bonded to a substituted carbon (or other) atom include F, CI, Br, I, OR', OC(0)N(R')2, CN, CF3,
OCF3, R', O (oxo), S (thiono), C(O), S(O), methylenedioxy, ethylenedioxy, N(R')2, SR', SOR', S02R', S02N(R')2, S03R', C(0)R', C(0)C(0)R', C(0)CH2C(0)R', C(S)R',
C(0)OR', OC(0)R', C(0)N(R')2, OC(0)N(R')2, C(S)N(R')2, (CH2)0_2NHC(O)R', (CH2)0_ 2N(R')N(R')2, N(R')N(R')C(0)R', N(R')N(R')C(0)OR', N(R')N(R')CON(R')2, N(R')S02R', N(R')S02N(R')2, N(R')C(0)OR', N(R')C(0)R', N(R')C(S)R', N(R')C(0)N(R')2,
N(R')C(S)N(R')2, N(COR')COR', N(OR')R', C(=NH)N(R')2, C(0)N(OR')R', or
C(=NOR')R' wherein R' can be hydrogen or a carbon-based moiety, and wherein the carbon-based moiety can itself be further substituted.
When a substituent is monovalent, such as, for example, F or CI, it is bonded to the atom it is substituting by a single bond. When a substituent is more than monovalent, such as O, which is divalent, it can be bonded to the atom it is substituting by more than
one bond, i.e., a divalent substituent is bonded by a double bond; for example, a C substituted with O forms a carbonyl group, C=0, which can also be written as "CO", "C(O)", or "C(=0)", wherein the C and the O are double bonded. When a carbon atom is substituted with a double-bonded oxygen (=0) group, the oxygen substituent is termed an "oxo" group. Alternatively, a divalent substituent such as O, S, C(O), S(O), or S(0)2 can be connected by two single bonds to two different carbon atoms. For example, O, a divalent substituent, can be bonded to each of two adjacent carbon atoms to provide an epoxide group, or the O can form a bridging ether group, termed an "oxy" group, between adjacent or non-adjacent carbon atoms, for example bridging the 1,4-carbons of a cyclohexyl group to form a [2.2.1]-oxabicyclo system. Further, any substituent can be bonded to a carbon or other atom by a linker, such as (CH2)n or (CR'2)n wherein n is 1, 2, 3, or more, and each R' is independently selected.
Substituted alkyl, alkenyl, alkynyl, cycloalkyl, and cycloalkenyl groups as well as other substituted groups also include groups in which one or more bonds to a hydrogen atom are replaced by one or more bonds, including double or triple bonds, to a carbon atom, or to a heteroatom such as, but not limited to, oxygen in carbonyl (oxo), carboxyl, ester, amide, imide, urethane, and urea groups; and nitrogen in imines, hydroxyimines, oximes, hydrazones, amidines, guanidines, and nitriles.
Substituted ring groups such as substituted cycloalkyl, aryl, heterocyclyl and heteroaryl groups also include rings and fused ring systems in which a bond to a hydrogen atom is replaced with a bond to a carbon atom. Therefore, substituted cycloalkyl, aryl, heterocyclyl and heteroaryl groups can also be substituted with alkyl, alkenyl, and alkynyl groups as defined herein.
By a "ring system" as the term is used herein is meant a moiety comprising one, two, three or more rings, which can be substituted with non-ring groups or with other ring systems, or both, which can be fully saturated, partially unsaturated, fully unsaturated, or aromatic, and when the ring system includes more than a single ring, the rings can be fused, bridging, or spirocyclic. By "spirocyclic" is meant the class of structures wherein two rings are fused at a single tetrahedral carbon atom, as is well known in the art.
Alkyl groups include straight chain and branched alkyl groups and cycloalkyl groups having from 1 to about 20 carbon atoms, and typically from 1 to 12 carbons or, in
some embodiments, from 1 to 8 carbon atoms. Examples of straight chain alkyl groups include those with from 1 to 8 carbon atoms such as methyl, ethyl, n-propyl, n-butyl, n- pentyl, n-hexyl, n-heptyl, and n-octyl groups. Examples of branched alkyl groups include, but are not limited to, isopropyl, iso-butyl, sec-butyl, t-butyl, neopentyl, isopentyl, and 2,2-dimethylpropyl groups. Representative substituted alkyl groups can be substituted one or more times with any of the groups listed above, for example, amino, hydroxy, cyano, carboxy, nitro, thio, alkoxy, and halogen groups.
Cycloalkyl groups are cyclic alkyl groups such as, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl groups. In some embodiments, the cycloalkyl group can have 3 to about 8-12 ring members, whereas in other embodiments the number of ring carbon atoms range from 3 to 5, 6, or 7.
Cycloalkyl groups further include polycyclic cycloalkyl groups such as, but not limited to, norbornyl, adamantyl, bornyl, camphenyl, isocamphenyl, and carenyl groups, and fused rings such as, but not limited to, decalinyl, and the like. Cycloalkyl groups also include rings that are substituted with straight or branched chain alkyl groups as defined above. Representative substituted cycloalkyl groups can be mono-substituted or substituted more than once, such as, but not limited to, 2,2-, 2,3-, 2,4- 2,5- or 2,6- disubstituted cyclohexyl groups or mono-, di- or tri- substituted norbornyl or cycloheptyl groups, which can be substituted with, for example, amino, hydroxy, cyano, carboxy, nitro, thio, alkoxy, and halogen groups. The term "cycloalkenyl" alone or in combination denotes a cyclic alkenyl group.
The terms "carbocyclic," "carbocyclyl," and "carbocycle" denote a ring structure wherein the atoms of the ring are carbon, such as a cycloalkyl group or an aryl group. In some embodiments, the carbocycle has 3 to 8 ring members, whereas in other
embodiments the number of ring carbon atoms is 4, 5, 6, or 7. Unless specifically indicated to the contrary, the carbocyclic ring can be substituted with as many as N-l substituents wherein N is the size of the carbocyclic ring with, for example, alkyl, alkenyl, alkynyl, amino, aryl, hydroxy, cyano, carboxy, heteroaryl, heterocyclyl, nitro, thio, alkoxy, and halogen groups, or other groups as are listed above. A carbocyclyl ring can be a cycloalkyl ring, a cycloalkenyl ring, or an aryl ring. A carbocyclyl can be
monocyclic or polycyclic, and if polycyclic each ring can be independently be a cycloalkyl ring, a cycloalkenyl ring, or an aryl ring.
(Cyclo alkyl) alkyl groups, also denoted cycloalkylalkyl, are alkyl groups as defined above in which a hydrogen or carbon bond of the alkyl group is replaced with a bond to a cycloalkyl group as defined above.
Alkenyl groups include straight and branched chain and cyclic alkyl groups as defined above, except that at least one double bond exists between two carbon atoms.
Thus, alkenyl groups have from 2 to about 20 carbon atoms, and typically from 2 to 12 carbons or, in some embodiments, from 2 to 8 carbon atoms. Examples include, but are not limited to vinyl, -CH=CH(CH3), -CH=C(CH3)2, -C(CH3)=CH2, -C(CH3)=CH(CH3),
-C(CH2CH )=CH2, cyclohexenyl, cyclopentenyl, cyclohexadienyl, butadienyl, pentadienyl, and hexadienyl among others.
Cycloalkenyl groups include cycloalkyl groups having at least one double bond between 2 carbons. Thus for example, cycloalkenyl groups include but are not limited to cyclohexenyl, cyclopentenyl, and cyclohexadienyl groups. Cycloalkenyl groups can have from 3 to about 8-12 ring members, whereas in other embodiments the number of ring carbon atoms range from 3 to 5, 6, or 7. Cycloalkyl groups further include polycyclic cycloalkyl groups such as, but not limited to, norbornyl, adamantyl, bornyl, camphenyl, isocamphenyl, and carenyl groups, and fused rings such as, but not limited to, decalinyl, and the like, provided they include at least one double bond within a ring. Cycloalkenyl groups also include rings that are substituted with straight or branched chain alkyl groups as defined above.
(Cycloalkenyl)alkyl groups are alkyl groups as defined above in which a hydrogen or carbon bond of the alkyl group is replaced with a bond to a cycloalkenyl group as defined above.
Alkynyl groups include straight and branched chain alkyl groups, except that at least one triple bond exists between two carbon atoms. Thus, alkynyl groups have from 2 to about 20 carbon atoms, and typically from 2 to 12 carbons or, in some embodiments, from 2 to 8 carbon atoms. Examples include, but are not limited to -C≡CH, -C≡C(CH ), -C≡C(CH2CH3), -CH2C≡CH, -CH2C≡C(CH3), and -CH2C≡C(CH2CH3) among others.
The term "heteroalkyl" by itself or in combination with another term means, unless otherwise stated, a stable straight or branched chain alkyl group consisting of the stated number of carbon atoms and one or two heteroatoms selected from the group consisting of O, N, and S, and wherein the nitrogen and sulfur atoms may be optionally oxidized and the nitrogen heteroatom may be optionally quaternized. The heteroatom(s) may be placed at any position of the heteroalkyl group, including between the rest of the heteroalkyl group and the fragment to which it is attached, as well as attached to the most distal carbon atom in the heteroalkyl group. Examples include: -O-CH2-CH2-CH3, -CH2-CH2CH2-OH, -CH2-CH2-NH-CH3, -CH2-S-CH2-CH3, -CH2CH2-S(=0)-CH3, and - CH2CH2-0-CH2CH2-0-CH3. Up to two heteroatoms may be consecutive, such as, for example, -CH2-NH-OCH3, or -CH2-CH2-S-S-CH3.
A "cyclohetero alkyl" ring is a cycloalkyl ring containing at least one heteroatom. A cycloheteroalkyl ring can also be termed a "heterocyclyl," described below.
The term "heteroalkenyl" by itself or in combination with another term means, unless otherwise stated, a stable straight or branched chain monounsaturated or di-unsaturated hydrocarbon group consisting of the stated number of carbon atoms and one or two heteroatoms selected from the group consisting of O, N, and S, and wherein the nitrogen and sulfur atoms may optionally be oxidized and the nitrogen heteroatom may optionally be quaternized. Up to two heteroatoms may be placed consecutively. Examples include -CH=CH-0-CH3, -CH=CH-CH2-OH, -CH2-CH=N-OCH3,
-CH=CH-N(CH3)-CH3, -CH2-CH=CH-CH2-SH, and and -CH=CH-0-CH2CH2-0-CH3.
Aryl groups are cyclic aromatic hydrocarbons that do not contain heteroatoms. Thus aryl groups include, but are not limited to, phenyl, azulenyl, heptalenyl, biphenyl, indacenyl, fluorenyl, phenanthrenyl, triphenylenyl, pyrenyl, naphthacenyl, chrysenyl, biphenylenyl, anthracenyl, and naphthyl groups. In some embodiments, aryl groups contain about 6 to about 14 carbons in the ring portions of the groups. Aryl groups can be unsubstituted or substituted, as defined above. Representative substituted aryl groups can be mono-substituted or substituted more than once, such as, but not limited to, 2-, 3-, 4-, 5-, or 6-substituted phenyl or 2-8 substituted naphthyl groups, which can be substituted with carbon or non-carbon groups such as those listed above.
Aralkyl groups are alkyl groups as defined above in which a hydrogen or carbon bond of an alkyl group is replaced with a bond to an aryl group as defined above.
Representative aralkyl groups include benzyl and phenylethyl groups and fused
(cycloalkylaryl)alkyl groups such as 4-ethyl-indanyl. Aralkenyl group are alkenyl groups as defined above in which a hydrogen or carbon bond of an alkyl group is replaced with a bond to an aryl group as defined above.
Heterocyclyl groups or the term "heterocyclyl" includes aromatic and non- aromatic ring compounds containing 3 or more ring members, of which, one or more is a heteroatom such as, but not limited to, N, O, and S. Thus a heterocyclyl can be a cycloheteroalkyl, or a heteroaryl, or if polycyclic, any combination thereof. In some embodiments, heterocyclyl groups include 3 to about 20 ring members, whereas other such groups have 3 to about 15 ring members. A heterocyclyl group designated as a C2- heterocyclyl can be a 5-ring with two carbon atoms and three heteroatoms, a 6-ring with two carbon atoms and four heteroatoms and so forth. Likewise a C4-heterocyclyl can be a 5-ring with one heteroatom, a 6-ring with two heteroatoms, and so forth. The number of carbon atoms plus the number of heteroatoms sums up to equal the total number of ring atoms. A heterocyclyl ring can also include one or more double bonds. A heteroaryl ring is an embodiment of a heterocyclyl group. The phrase "heterocyclyl group" includes fused ring species including those comprising fused aromatic and non-aromatic groups. For example, a dioxolanyl ring and a benzdioxolanyl ring system (methylenedioxyphenyl ring system) are both heterocyclyl groups within the meaning herein. The phrase also includes polycyclic ring systems containing a heteroatom such as, but not limited to, quinuclidyl. Heterocyclyl groups can be unsubstituted, or can be substituted as discussed above. Heterocyclyl groups include, but are not limited to, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridinyl, thiophenyl, benzothiophenyl, benzofuranyl, dihydrobenzofuranyl, indolyl, dihydroindolyl, azaindolyl, indazolyl, benzimidazolyl, azabenzimidazolyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, imidazopyridinyl, isoxazolopyridinyl, thianaphthalenyl, purinyl, xanthinyl, adeninyl, guaninyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, quinoxalinyl, and quinazolinyl groups. Representative substituted heterocyclyl groups can be mono-substituted or substituted more than once, such as, but
not limited to, piperidinyl or quinolinyl groups, which are 2-, 3-, 4-, 5-, or 6-substituted, or disubstituted with groups such as those listed above.
Heteroaryl groups are aromatic ring compounds containing 5 or more ring members, of which, one or more is a heteroatom such as, but not limited to, N, O, and S; for instance, heteroaryl rings can have 5 to about 8-12 ring members. A heteroaryl group is a variety of a heterocyclyl group that possesses an aromatic electronic structure. A heteroaryl group designated as a C2-heteroaryl can be a 5-ring with two carbon atoms and three heteroatoms, a 6-ring with two carbon atoms and four heteroatoms and so forth. Likewise a C4-heteroaryl can be a 5-ring with one heteroatom, a 6-ring with two heteroatoms, and so forth. The number of carbon atoms plus the number of heteroatoms sums up to equal the total number of ring atoms. Heteroaryl groups include, but are not limited to, groups such as pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridinyl, thiophenyl, benzothiophenyl, benzofuranyl, indolyl, azaindolyl, indazolyl, benzimidazolyl, azabenzimidazolyl, benzoxazolyl, benzothiazolyl,
benzothiadiazolyl, imidazopyridinyl, isoxazolopyridinyl, thianaphthalenyl, purinyl, xanthinyl, adeninyl, guaninyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl,
quinoxalinyl, and quinazolinyl groups. Heteroaryl groups can be unsubstituted, or can be substituted with groups as is discussed above. Representative substituted heteroaryl groups can be substituted one or more times with groups such as those listed above.
Additional examples of aryl and heteroaryl groups include but are not limited to phenyl, biphenyl, indenyl, naphthyl (1-naphthyl, 2-naphthyl), N-hydroxytetrazolyl, N- hydroxytriazolyl, N-hydroxyimidazolyl, anthracenyl (1-anthracenyl, 2-anthracenyl, 3- anthracenyl), thiophenyl (2-thienyl, 3-thienyl), furyl (2-furyl, 3-furyl) , indolyl, oxadiazolyl, isoxazolyl, quinazolinyl, fluorenyl, xanthenyl, isoindanyl, benzhydryl, acridinyl, thiazolyl, pyrrolyl (2-pyrrolyl), pyrazolyl (3-pyrazolyl), imidazolyl (1- imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl), triazolyl (1,2,3-triazol-l-yl, 1,2,3- triazol-2-yl l,2,3-triazol-4-yl, l,2,4-triazol-3-yl), oxazolyl (2-oxazolyl, 4-oxazolyl, 5- oxazolyl), thiazolyl (2-thiazolyl, 4-thiazolyl, 5-thiazolyl), pyridyl (2-pyridyl, 3-pyridyl, 4- pyridyl), pyrimidinyl (2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 6-pyrimidinyl), pyrazinyl, pyridazinyl (3- pyridazinyl, 4-pyridazinyl, 5-pyridazinyl), quinolyl (2-quinolyl, 3-quinolyl, 4-quinolyl, 5-quinolyl, 6-quinolyl, 7-quinolyl, 8-quinolyl), isoquinolyl (1-
isoquinolyl, 3-isoquinolyl, 4-isoquinolyl, 5-isoquinolyl, 6-isoquinolyl, 7-isoquinolyl, 8- isoquinolyl), benzo[b]furanyl (2-benzo[b]furanyl, 3-benzo[b]furanyl, 4-benzo[b]furanyl,
5- benzo[b]furanyl, 6-benzo[b]furanyl, 7-benzo[b]furanyl), 2,3-dihydro-benzo[b]furanyl (2-(2,3-dihydro-benzo[b]furanyl), 3-(2,3-dihydro-benzo[b]furanyl), 4-(2,3-dihydro- benzo[b]furanyl), 5-(2,3-dihydro-benzo[b]furanyl), 6-(2,3-dihydro-benzo[b]furanyl), 7- (2,3-dihydro-benzo[b]furanyl), benzo[b]thiophenyl (2-benzo[b]thiophenyl, 3- benzo[b]thiophenyl, 4-benzo[b]thiophenyl, 5-benzo[b]thiophenyl, 6-benzo[b]thiophenyl, 7-benzo[b]thiophenyl), 2,3-dihydro-benzo[b]thiophenyl, (2-(2,3-dihydro- benzo[b]thiophenyl), 3-(2,3-dihydro-benzo[b]thiophenyl), 4-(2,3-dihydro- benzo[b]thiophenyl), 5-(2,3-dihydro-benzo[b]thiophenyl), 6-(2,3-dihydro- benzo[b]thiophenyl), 7-(2,3-dihydro-benzo[b]thiophenyl), indolyl (1-indolyl, 2-indolyl,
3- indolyl, 4-indolyl, 5-indolyl, 6-indolyl, 7-indolyl), indazole (1-indazolyl, 3-indazolyl,
4- indazolyl, 5-indazolyl, 6-indazolyl, 7-indazolyl), benzimidazolyl (1-benzimidazolyl, 2-benzimidazolyl, 4-benzimidazolyl, 5-benzimidazolyl, 6-benzimidazolyl,
7-benzimidazolyl, 8 -benzimidazolyl), benzoxazolyl (1-benzoxazolyl, 2-benzoxazolyl), benzothiazolyl (1-benzothiazolyl, 2-benzothiazolyl, 4-benzothiazolyl, 5-benzothiazolyl,
6- benzothiazolyl, 7-benzothiazolyl), carbazolyl (1-carbazolyl, 2-carbazolyl, 3-carbazolyl, 4-carbazolyl), 5H-dibenz[b,f]azepine (5H-dibenz[b,f]azepin-l-yl, 5H-dibenz[b,f]azepine- 2-yl, 5H-dibenz[b,f]azepine-3-yl, 5H-dibenz[b,f]azepine-4-yl, 5H-dibenz[b,f]azepine-5- yl), 10,l l-dihydro-5H-dibenz[b,f]azepine (10,l l-dihydro-5H-dibenz[b,f]azepine-l-yl, 10,1 l-dihydro-5H-dibenz[b,f]azepine-2-yl, 10,1 l-dihydro-5H-dibenz[b,f]azepine-3-yl, 10,1 l-dihydro-5H-dibenz[b,f]azepine-4-yl, 10,1 l-dihydro-5H-dibenz[b,f]azepine-5-yl), and the like.
Heterocyclylalkyl groups are alkyl groups as defined above in which a hydrogen or carbon bond of an alkyl group as defined above is replaced with a bond to a heterocyclyl group as defined above. Representative heterocyclyl alkyl groups include, but are not limited to, furan-2-yl methyl, furan-3-yl methyl, pyridine-3-yl methyl, tetrahydrofuran-2-yl ethyl, and indol-2-yl propyl.
Heteroarylalkyl groups are alkyl groups as defined above in which a hydrogen or carbon bond of an alkyl group is replaced with a bond to a heteroaryl group as defined above.
The term "alkoxy" refers to an oxygen atom connected to an alkyl group, including a cycloalkyl group, as are defined above. Examples of linear alkoxy groups include but are not limited to methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, and the like. Examples of branched alkoxy include but are not limited to isopropoxy, sec-butoxy, tert-butoxy, isopentyloxy, isohexyloxy, and the like. Examples of cyclic alkoxy include but are not limited to cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, and the like. An alkoxy group can include one to about 12-20 carbon atoms bonded to the oxygen atom, and can further include double or triple bonds, and can also include heteroatoms. For example, an allyloxy group is an alkoxy group within the meaning herein. A methoxyethoxy group is also an alkoxy group within the meaning herein.
The terms "halo" or "halogen" or "halide" by themselves or as part of another substituent mean, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom, preferably, fluorine, chlorine, or bromine.
A "haloalkyl" group includes mono-halo alkyl groups, poly-halo alkyl groups wherein all halo atoms can be the same or different, and per-halo alkyl groups, wherein all hydrogen atoms are replaced by halogen atoms, such as fluoro. Examples of haloalkyl include trifluoromethyl, 1,1-dichloroethyl, 1,2-dichloroethyl, l,3-dibromo-3,3- difluoropropyl, perfluorobutyl, and the like.
A "haloalkoxy" group includes mono-halo alkoxy groups, poly-halo alkoxy groups wherein all halo atoms can be the same or different, and per-halo alkoxy groups, wherein all hydrogen atoms are replaced by halogen atoms, such as fluoro. Examples of haloalkoxy include trifluoromethoxy, 1,1-dichloroethoxy, 1,2-dichloroethoxy, 1,3- dibromo-3,3-difluoropropoxy, perfluorobutoxy, and the like.
The term "(Cx-Cy)perfluoroalkyl," wherein x < y, means an alkyl group with a minimum of x carbon atoms and a maximum of y carbon atoms, wherein all hydrogen atoms are replaced by fluorine atoms. Preferred is -(C1-C6)perfluoroalkyl, more preferred is -(C1-C3)perfluoroalkyl, most preferred is -CF3.
The term "(Cx-Cy)perfluoroalkylene," wherein x < y, means an alkyl group with a minimum of x carbon atoms and a maximum of y carbon atoms, wherein all hydrogen
atoms are replaced by fluorine atoms. Preferred is -(C1-C6)perfluoroalkylene, more preferred is -(C1-C3)perfluoroalkylene, most preferred is -CF2-.
The terms "aryloxy" and "arylalkoxy" refer to, respectively, an aryl group bonded to an oxygen atom and an aralkyl group bonded to the oxygen atom at the alkyl moiety. Examples include but are not limited to phenoxy, naphthyloxy, and benzyloxy.
An "acyl" group as the term is used herein refers to a group containing a carbonyl moiety wherein the group is bonded via the carbonyl carbon atom. The carbonyl carbon atom is also bonded to another carbon atom, which can be part of an alkyl, aryl, aralkyl cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl group or the like. In the special case wherein the carbonyl carbon atom is bonded to a hydrogen, the group is a "formyl" group, an acyl group as the term is defined herein. An acyl group can include 0 to about 12-20 additional carbon atoms bonded to the carbonyl group. An acyl group can include double or triple bonds within the meaning herein. An acryloyl group is an example of an acyl group. An acyl group can also include heteroatoms within the meaning here. A nicotinoyl group (pyridyl-3-carbonyl) group is an example of an acyl group within the meaning herein. Other examples include acetyl, benzoyl, phenylacetyl, pyridylacetyl, cinnamoyl, and acryloyl groups and the like. When the group containing the carbon atom that is bonded to the carbonyl carbon atom contains a halogen, the group is termed a "haloacyl" group. An example is a trifluoroacetyl group.
The term "amine" includes primary, secondary, and tertiary amines having, e.g., the formula N(group)3 wherein each group can independently be H or non-H, such as alkyl, aryl, and the like. Amines include but are not limited to R-NH2, for example, alkylamines, arylamines, alkylarylamines; R2NH wherein each R is independently selected, such as dialkylamines, diarylamines, aralkylamines, heterocyclylamines and the like; and R3N wherein each R is independently selected, such as trialkylamines, dialkylarylamines, alkyldiarylamines, triarylamines, and the like. The term "amine" also includes ammonium ions as used herein.
An "amino" group is a substituent of the form -NH2, -NHR, -NR2, -NR3 +, wherein each R is independently selected, and protonated forms of each. Accordingly, any compound substituted with an amino group can be viewed as an amine.
An "ammonium" ion includes the unsubstituted ammonium ion NH4 +, but unless otherwise specified, it also includes any protonated or quaternarized forms of amines. Thus, trimethylammonium hydrochloride and tetramethylammonium chloride are both ammonium ions, and amines, within the meaning herein.
The term "amide" (or "amido") includes C- and N-amide groups, i.e., -C(0)NR2, and -NRC(0)R groups, respectively. Amide groups therefore include but are not limited to carbamoyl groups (-C(0)NH2) and formamide groups (-NHC(O)H). A "carboxamido" group is a group of the formula C(0)NR2, wherein R can be H, alkyl, aryl, etc.
The term "urethane" (or "carbamyl") includes N- and O-urethane groups, i.e., -NRC(0)OR and -OC(0)NR2 groups, respectively.
The term "sulfonamide" (or "sulfonamido") includes S- and N-sulfonamide groups, i.e., -S02NR2 and -NRS02R groups, respectively. Sulfonamide groups therefore include but are not limited to sulfamoyl groups (-S02NH2). An organosulfur structure represented by the formula -S(0)(NR)- is understood to refer to a sulfoximine, wherein both the oxygen and the nitrogen atoms are bonded to the sulfur atom, which is also bonded to two carbon atoms.
The term "amidine" or "amidino" includes groups of the formula -C(NR)NR2. Typically, an amidino group is -C(NH)NH2.
The term "guanidine" or "guanidino" includes groups of the formula
-NRC(NR)NR2. Typically, a guanidino group is -NHC(NH)NH2.
A "salt" as is well known in the art includes an organic compound such as a carboxylic acid, a sulfonic acid, or an amine, in ionic form, in combination with a counterion. For example, acids in their anionic form can form salts with cations such as metal cations, for example sodium, potassium, and the like; with ammonium salts such as NH4 + or the cations of various amines, including tetraalkyl ammonium salts such as tetramethylammonium, or other cations such as trimethylsulfonium, and the like. A "pharmaceutically acceptable" or "pharmacologically acceptable" salt is a salt formed from an ion that has been approved for human consumption and is generally non-toxic, such as a chloride salt or a sodium salt. A "zwitterion" is an internal salt such as can be formed in a molecule that has at least two ionizable groups, one forming an anion and the other a cation, which serve to balance each other. For example, amino acids such as
glycine can exist in a zwitterionic form. A "zwitterion" is a salt within the meaning herein. The compounds of the present invention may take the form of salts. The term "salts" embraces addition salts of free acids or free bases which are compounds of the invention. Salts can be "pharmaceutically-acceptable salts." The term
"pharmaceutically-acceptable salt" refers to salts which possess toxicity profiles within a range that affords utility in pharmaceutical applications. Pharmaceutically unacceptable salts may nonetheless possess properties such as high crystallinity, which have utility in the practice of the present invention, such as for example utility in process of synthesis, purification or formulation of compounds of the invention.
Suitable pharmaceutically-acceptable acid addition salts may be prepared from an inorganic acid or from an organic acid. Examples of inorganic acids include
hydrochloric, hydrobromic, hydriodic, nitric, carbonic, sulfuric, and phosphoric acids. Appropriate organic acids may be selected from aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic, carboxylic and sulfonic classes of organic acids, examples of which include formic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic, glucuronic, maleic, fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic, 4-hydroxybenzoic, phenylacetic, mandelic, embonic (pamoic),
methanesulfonic, ethanesulfonic, benzenesulfonic, pantothenic, trifluoromethanesulfonic, 2-hydroxyethanesulfonic, p-toluenesulfonic, sulfanilic, cyclohexylaminosulfonic, stearic, alginic, β-hydroxybutyric, salicylic, galactaric and galacturonic acid. Examples of pharmaceutically unacceptable acid addition salts include, for example, perchlorates and tetrafluoroborates .
Suitable pharmaceutically acceptable base addition salts of compounds of the invention include, for example, metallic salts including alkali metal, alkaline earth metal and transition metal salts such as, for example, calcium, magnesium, potassium, sodium and zinc salts. Pharmaceutically acceptable base addition salts also include organic salts made from basic amines such as, for example, N,A^-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine
(N-methylglucamine) and procaine. Examples of pharmaceutically unacceptable base addition salts include lithium salts and cyanate salts. Although pharmaceutically unacceptable salts are not generally useful as medicaments, such salts may be useful, for
example as intermediates in the synthesis of Formula (I) compounds, for example in their purification by recrystallization.. All of these salts may be prepared by conventional means from the corresponding compound according to Formula (I) by reacting, for example, the appropriate acid or base with the compound according to Formula (I). The term "pharmaceutically acceptable salts" refers to nontoxic inorganic or organic acid and/or base addition salts, see, for example, Lit et al., Salt Selection for Basic Drugs (1986), Int J. Pharm., 33, 201-217, incorporated by reference herein.
A "hydrate" is a compound that exists in a composition with water molecules. The composition can include water in stoichiometic quantities, such as a monohydrate or a dihydrate, or can include water in random amounts. As the term is used herein a "hydrate" refers to a solid form, i.e., a compound in water solution, while it may be hydrated, is not a hydrate as the term is used herein.
A "solvate" is a similar composition except that a solvent other that water replaces the water. For example, methanol or ethanol can form an "alcoholate", which can again be stoichiometic or non- stoichiometric. As the term is used herein a "solvate" refers to a solid form, i.e., a compound in solution in a solvent, while it may be solvated, is not a solvate as the term is used herein.
A "prodrug" as is well known in the art is a substance that can be administered to a patient where the substance is converted in vivo by the action of biochemicals within the patients body, such as enzymes, to the active pharmaceutical ingredient. Examples of prodrugs include esters of carboxylic acid groups, which can be hydrolyzed by endogenous esterases as are found in the bloodstream of humans and other mammals. Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in "Design of Prodrugs", ed. H. Bundgaard, Elsevier, 1985.
In addition, where features or aspects of the invention are described in terms of
Markush groups, those skilled in the art will recognize that the invention is also thereby described in terms of any individual member or subgroup of members of the Markush group. For example, if X is described as selected from the group consisting of bromine, chlorine, and iodine, claims for X being bromine and claims for X being bromine and chlorine are fully described. Moreover, where features or aspects of the invention are described in terms of Markush groups, those skilled in the art will recognize that the
invention is also thereby described in terms of any combination of individual members or subgroups of members of Markush groups. Thus, for example, if X is described as selected from the group consisting of bromine, chlorine, and iodine, and Y is described as selected from the group consisting of methyl, ethyl, and propyl, claims for X being bromine and Y being methyl are fully described.
In various embodiments, the compound or set of compounds, such as are used in the inventive methods, can be any one of any of the combinations and/or subcombinations of the above-listed embodiments.
Provisos may apply to any of the disclosed categories or embodiments wherein any one or more of the other above disclosed embodiments or species may be excluded from such categories or embodiments.
The present invention further embraces isolated compounds according to formula (I). The expression "isolated compound" refers to a preparation of a compound of formula (I), or a mixture of compounds according to formula (I), wherein the isolated compound has been separated from the reagents used, and/or byproducts formed, in the synthesis of the compound or compounds. "Isolated" does not mean that the preparation is technically pure (homogeneous), but it is sufficiently pure to compound in a form in which it can be used therapeutically. Preferably an "isolated compound" refers to a preparation of a compound of formula (I) or a mixture of compounds according to formula (I), which contains the named compound or mixture of compounds according to formula (I) in an amount of at least 10 percent by weight of the total weight. Preferably the preparation contains the named compound or mixture of compounds in an amount of at least 50 percent by weight of the total weight; more preferably at least 80 percent by weight of the total weight; and most preferably at least 90 percent, at least 95 percent or at least 98 percent by weight of the total weight of the preparation.
The compounds of the invention and intermediates may be isolated from their reaction mixtures and purified by standard techniques such as filtration, liquid-liquid extraction, solid phase extraction, distillation, recrystallization or chromatography, including flash column chromatography, or HPLC.
Isomerism and Tautomerism in Compounds of the Invention
Tautomerism
Within the present invention it is to be understood that a compound of the formula (I) or a salt thereof may exhibit the phenomenon of tautomerism whereby two chemical compounds that are capable of facile interconversion by exchanging a hydrogen atom between two atoms, to either of which it forms a covalent bond. Since the tautomeric compounds exist in mobile equilibrium with each other they may be regarded as different isomeric forms of the same compound. It is to be understood that the formulae drawings within this specification can represent only one of the possible tautomeric forms.
However, it is also to be understood that the invention encompasses any tautomeric form, and is not to be limited merely to any one tautomeric form utilized within the formulae drawings. The formulae drawings within this specification can represent only one of the possible tautomeric forms and it is to be understood that the specification encompasses all possible tautomeric forms of the compounds drawn not just those forms which it has been convenient to show graphically herein. For example, tautomerism may be exhibited by a pyrazolyl group bonded as indicated by the wavy line. While both substituents would be termed a 4-pyrazolyl group, it is evident that a different nitrogen atom bears the hydrogen atom in each structure.
Such tautomerism can also occur with substituted pyrazoles such as 3-methyl, 5- methyl, or 3,5-dimethylpyrazoles, and the like.
Optical Isomerism
It will be understood that when compounds of the present invention contain one or more chiral centers, the compounds may exist in, and may be isolated as pure enantiomeric or diastereomeric forms or as racemic mixtures. The present invention therefore includes any possible enantiomers, diastereomers, racemates or mixtures thereof of the compounds of the invention.
The isomers resulting from the presence of a chiral center comprise a pair of non-superimposable isomers that are called "enantiomers." Single enantiomers of a pure compound are optically active, i.e., they are capable of rotating the plane of plane polarized light. Single enantiomers are designated according to the Cahn-Ingold-Prelog
system. Once the priority ranking of the four groups is determined, the molecule is oriented so that the lowest ranking group is pointed away from the viewer. Then, if the descending rank order of the other groups proceeds clockwise, the molecule is designated (R) and if the descending rank of the other groups proceeds counterclockwise, the molecule is designated (S). In the example in Scheme 14, the Cahn-Ingold-Prelog ranking is A > B > C > D. The lowest ranking atom, D is oriented away from the viewer.
(R) configuration (S) configuration
The present invention is meant to encompass diastereomers as well as their racemic and resolved, diastereomerically and enantiomerically pure forms and salts thereof. Diastereomeric pairs may be resolved by known separation techniques including normal and reverse phase chromatography, and crystallization.
"Isolated optical isomer" means a compound which has been substantially purified from the corresponding optical isomer(s) of the same formula. Preferably, the isolated isomer is at least about 80%, more preferably at least 90% pure, even more preferably at least 98% pure, most preferably at least about 99% pure, by weight.
Isolated optical isomers may be purified from racemic mixtures by well-known chiral separation techniques. According to one such method, a racemic mixture of a compound of the invention, or a chiral intermediate thereof, is separated into 99% wt.% pure optical isomers by HPLC using a suitable chiral column, such as a member of the series of DAICEL® CHIRALPAK® family of columns (Daicel Chemical Industries, Ltd., Tokyo, Japan). The column is operated according to the manufacturer's instructions. Rotational Isomerism
It is understood that due to chemical properties (i.e., resonance lending some double bond character to the C-N bond) of restricted rotation about the amide bond linkage (as illustrated below) it is possible to observe separate rotamer species and even, under some circumstances, to isolate such species (see below). It is further understood that certain structural elements, including steric bulk or substituents on the amide nitrogen, may enhance the stability of a rotamer to the extent that a compound may be
isolated as, and exist indefinitely, as a single stable rotamer. The present invention therefore includes any possible stable ro tamers of formula (I) which are biologically active in the treatment of cancer or other proliferative disease states.
Regioisomerism
The preferred compounds of the present invention have a particular spatial arrangement of substituents on the aromatic rings, which is related to the structure activity relationship demonstrated by the compound class. Often such substitution arrangement is denoted by a numbering system; however, numbering systems are often not consistent between different ring systems. In six-membered aromatic systems, the spatial arrangements are specified by the common nomenclature "para" for
1,4-substitution, "meta" for 1,3-substitution and "ortho" for 1,2-substitution as shown below.
"para-" "meta-" "ortho-"
Description
In various embodiments, the invention provides a compound of the formula (I):
(I),
wherein
X1 and X2 are each independently N,
CR1; and X3, X4, X5, or X6 are each independently N, C-E, or CR , provided that ring B is substituted by only one E group, and provided that at least one of X3-X6 is N, and no more than five of Xx-X6 are N;
Z is a bond between X3 and X4, or Z is C(=0) wherein X3 and X4 are each respectively connected to the C(=0) by a single bond;
a dotted line indicates that a bond is either a single bond or a double bond;
R, R1 and R2 are each independently H, halo, (C1_C6)alkyl substituted with 0-2 Ra,
(C2-C6)alkenyl substituted with 0-2 Ra, (C2_C6)alkynyl substituted with 0-2 Ra, cycloalkyl substituted with 0-2 Ra, cycloalkylalkyl substituted with 0-2 Ra, heterocyclyl substituted with 0-2 Ra, heterocyclylalkyl substituted with 0-2 Ra, aryl substituted with 0-2 Ra, aralkyl substituted with 0-2 Ra, heteroaryl substituted with 0-2 Ra, heteroarylalkyl substituted with 0-2 Ra, (Ci_C¼)haloalkyl, (Ci_C6)haloalkyl, (Ci_C¼)haloalkoxy, (Ci_ C6)hydroxyalkyl, (CH2)pN02, (CH2)PCN, (CH2)pOR, (CH2)PNR2, (CH2)pCOR,
(CH2)pOCOR, (CH2)pC02R, (CH2)pCONR2, (CH2)pOCONR2, (CH2)pNRCOR,
(CH2)pNRC02R, (CH2)pNRCONR2, (CH2)PC(=NH)NH2, (CH2)pS02R, (CH2)pS02NR2, (CH2)pNRS02R, or (CH2)pNRS02NR2;
1 1 2
nl plus the number of C-R groups comprised by X and X is 0-3;
n2 plus the number of C-R2 groups comprised X3-X6 is 0-4;
n3 plus the number of C-Ar 1 groups comprised by X 1 and X2 is 1-4, such that at least one Ar1 is present on ring A;
Ra is halo, oxo, (C1-C6)alkyl substituted with 0-2 Ra, (C2_C6)alkenyl substituted with 0-2 Ra, (C2_C6)alkynyl substituted with 0-2 Ra, cycloalkyl substituted with 0-2 Ra, cycloalkylalkyl substituted with 0-2 Ra, heterocyclyl substituted with 0-2 Ra,
heterocyclylalkyl substituted with 0-2 Ra, aryl substituted with 0-2 Ra, aralkyl substituted with 0-2 Ra, heteroaryl substituted with 0-2 Ra, heteroarylalkyl substituted with 0-2 Ra, (Ci_C6)haloalkyl, (Ci_C6)haloalkoxy, (CH2)pN02, (CH2)PCN, (CH2)pOR, (CH2)PNR2, (CH2)pCOR, (CH2)pOCOR, (CH2)pC02R, (CH2)pCONR2, (CH2)pOCONR2,
(CH2)pNRCOR, (CH2)pNRC02R, (CH2)pNRCONR2, (CH2)PC(=NH)NH2, (CH2)pS02R, (CH2)pS02NR2, (CH2)pNRS02R, or (CH2)pNRS02NR2;
m is 0, 1, or 2;
p is 0, 1, 2, 3, or 4;
Ar1 is a 5 or 6 membered heteroaryl ring comprising at least one nitrogen atom, and 0-3 additional heteroatoms selected from O, S(0)m, and N; when Ar1 is a 5- membered heteroaryl, the nitrogen atom is disposed two atoms away from a point of attachment of the heteroaryl to ring A, and when Ar1 is a 6-membered heteroaryl, the nitrogen atom is disposed three atoms away from a point of attachment of the heteroaryl to ring A, wherein any 5-membered heteroaryl or 6-membered heteroaryl of Ar1 is substituted with 0-3 R , and wherein any 5-membered heteroaryl or 6-membered heteroaryl can be fused with an aryl or heteroaryl ring that is substituted with 0-3 R4;
R3 and R4 are each independently (C1-C6)alkyl substituted with 0-2 Ra,
(C2_C6)alkenyl substituted with 0-2 Ra, (C2_C6)alkynyl substituted with 0-2 Ra, cycloalkyl substituted with 0-2 Ra, cycloalkylalkyl substituted with 0-2 Ra, heterocyclyl substituted with 0-2 Ra, heterocyclylalkyl substituted with 0-2 Ra, aryl substituted with 0-2 Ra, aralkyl substituted with 0-2 Ra, heteroaryl substituted with 0-2 Ra, heteroarylalkyl substituted with 0-2 Ra, (C1_C6)haloalkyl, (Ci_C6)haloalk l, (C1_C6)haloalkoxy, (Ci_ C6)hydroxyalkyl, halo, cyano, nitro, oxo, -C(=0)R, -C(=0)OR, (C - C6)alkylene-C(=0)OR, -C(=0)NR2, (C1-C6)alkylene-C(=0)NR2, -C(=NR)NR2, -OR, (C1-C6)alkylene-OR, -OC(=0)(C1-C6)alkyl, -OC(=0)0(C1-C6)alkyl, -OC(=0)NR2, -NR2, -NRC(=0)R, -NRC(=0)0(Ci-C6)alkyl, -NRC(=0)NR2, -NR(d-C6)alkylene-NR2, -NR(Ci-C6)alkylene-OR, -NR(Ci-C6)alkylene-Ar2, -NRS02R, -SR, -S(0)R, -S02R, -OS02(C1-C6)alkyl, -S02NR2, pyrazolyl, triazolyl, or tetrazolyl, provided that R4 can also be hydrogen; or two R4 groups taken together form a fused cycloalkyl, heterocyclyl, aryl or heteroaryl ring substituted with 0-4 Ra;
Ar is unsubstituted aryl, unsubstituted heteroaryl, aryl substituted with one or more substituents selected from R4, or heteroaryl substituted with one or more substituents selected from R4;
R5 is hydrogen, (C1-C6)alkyl substituted with 0-2 Ra, (C1-C6)alkenyl substituted with 0-2 Ra, C(=0)(C1-C6)alkyl substituted with 0-2 Ra, C(=0)0(C1-C6)alkyl substituted with 0-2 Ra, Ar2 wherein Ar2 is substituted with 0-2 R3; -(Q-Ce kylene-Ar2 wherein Ar2 is substituted with 0-2 R3, -(C1-C6)alkylC(=0)OR, or -(C1-C6)alkylC(=0)NR2; and
E is any of the following, wherein a wavy line indicates a point of attachment to ring B:
(a) a group of the formula
wherein:
n is an integer from 0 to about 2;
G, J, and K are each independently CH2, O, S, NR5, or CHNHR5, provided that K can also be a bond;
or
wherein:
D is absent, or
D is
or D is a 5- to 7-membered heterocyclyl comprising NR ;
d is an integer from 0 to about 3;
Rh and Rk are each independently at every occurrence selected from H,
(Ci-C6)alkyl substituted with 0-2 Ra, NR2, and NRC(=0)-(C1_6)alkyl; or Rh and Rk taken together with a carbon atom to which they are attached form a (C3_C7)cycloalkyl ring substituted with 0-2 Ra;
R8 is H or C(=0)-(Ci-C6)alkyl;
Gi is CH2, O, S, NR5, NR5C(=0), C(=0)NR5, NR5C(=0)NR5, or CHNHR5; and G2 is a bond, O, NR5, or S;
or
(c) a group of the formula
O R9
Y_ R9A
C
wherein
c is 0-3,
Y is at each occurrence independently selected from O, S, NR, and C(RbRd), provided that no 0-0 bonds are present in Yc, or Y is absent;
Rb and Rd are each independently at every occurrence H, halo, (C1_C6)alkyl substituted with 0-2 Ra, (C2_C6)alkenyl substituted with 0-2 Ra, (C2_C6)alkynyl substituted with 0-2 Ra, cycloalkyl substituted with 0-2 Ra, heterocyclyl substituted with 0-2 Ra, aryl substituted with 0-2 Ra, aralkyl substituted with 0-2 Ra, heteroaryl substituted with 0-2 Ra, heteroarylalkyl substituted with 0-2 Ra, (Ct- haloalkyl, (CiX^haloalkoxy,
(CH2)pN02, (CH2)PCN, (CH2)pOR, (CH2)PNR2, (CH2)pCOR, (CH2)pOCOR, (CH2)pC02R, (CH2)pCONR2, (CH2)pOCONR2, (CH2)pNRCOR, (CH2)pNRC02R, (CH2)pNRCONR2, (CH2)PC(=NH)NH2, (CH2)pS02R, (CH2)pS02NR2, (CH2)pNRS02R, or (CH2)pNRS02NR2 m is 0, 1, or 2; q is 1-5; and
R9 and R9A are each independently at every occurrence H, halo, (C1_C6)alkyl substituted with 0-2 Ra, (C2_C6)alkenyl substituted with 0-2 Ra, (C2_C6)alkynyl substituted with 0-2 Ra, cycloalkyl substituted with 0-2 Ra, cycloalkylalkyl substituted with 0-2 Ra, heterocyclyl substituted with 0-2 Ra, heterocyclylalkyl substituted with 0-2 Ra, aryl
substituted with 0-2 Ra, aralkyl substituted with 0-2 Ra, heteroaryl substituted with 0-2 Ra, heteroarylalkyl substituted with 0-2 Ra, (C1_C6)haloalkyl, (C1_C6)haloalkyl, (Q.
C6)haloalkoxy, (Ci_C6)hydroxyalkyl, (CH2)pN02, (CH2)PCN, (CH2)pOR, (CH2)PNR2, (CH2)pCOR, (CH2)pOCOR, (CH2)pC02R, (CH2)pCONR2, (CH2)pOCONR2,
(CH2)pNRCOR, (CH2)pNRC02R, (CH2)pNRCONR2, (CH2)PC(=NH)NH2, (CH2)pS02R, (CH2)pS02NR2, (CH2)pNRS02R, (CH2)pNRS02NR2; or R9 and (Y)CR9A and the nitrogen atom to which they are bonded can together form a heterocyclyl substituted with 0-2 Ra wherein the heterocyclyl can be fused with a substituted or unsubstituted cycloalkyl, heterocyclyl, aryl, or heteroaryl ring system;
or any tautomer, salt, stereoisomer, hydrate, solvent, isotopically labeled form, or prodrug thereof.
Compounds of the invention of formula (I) can include any and all combinations of defined substituents, provided the resulting structure is chemically feasible, as discussed above.
For example, Ar1 can be a substituted or unsubstituted pyridyl, pyrazolyl, or pyrimidinyl. Alternatively, Ar1 can be a substituted or unsubstituted bicyclic heteroaryl comprising any of the following ring systems, wherein a wavy line indicates a point of attachment:
In various embodiments, Ar is likewise so defined for any of formulas (IA), (IB), (IC), (ID), (IE), (IF), (IG), (IH), (IJ), (IK), and (IL).
In various embodiments, the compound of the invention can be a compound of formula (IA)
(IA)
or any tautomer, salt, stereoisomer, hydrate, solvent, isotopically labeled form, or prodrug thereof.
More specifically, one of X 11 and X2" can be N and the other of X 1 and X2 can be
C-Ar1.
Or, one of X1 and X2 can be CR1 and the other of X1 and X2 can be C-Ar1. In various embodiments, the compound of formula (IA) can be of any of the following formulas:
More specifically, R can be a substituted or unsubstituted aryl or heteroaryl, Y can be C(RbRd), and c can be 0, 1, or 2; or any combination thereof.
In various embodiments, the compound of formula (IA) can be any of the following structures:
or any tautomer, salt, stereoisomer, hydrate, solvent, isotopically labeled form, prodrug thereof.
In various embodiments, a compound of the invention can be a compound of formula (IB)
(IB)
or any tautomer, salt, stereoisomer, hydrate, solvent, isotopically labeled form, prodrug thereof.
In various embodiments, a compound of the invention can be a compound of formula (IC)
(IC)
or any tautomer, salt, stereoisomer, hydrate, solvent, isotopically labeled form, c prodrug thereof.
or any tautomer, salt, stereoisomer, hydrate, solvent, or prodrug thereof. More specifically, Y can be CRbRd, c can be 0, 1, or 2, Ar can be any of following ring systems, wherein a wavy line indicates a point of attachment:
For example, the compound of formula (IC) can be any of the following structures:
52
or any tautomer, salt, stereoisomer, hydrate, solvent, isotopically labeled form, prodrug thereof.
(ID)
or any tautomer, salt, stereoisomer, hydrate, solvent, isotopically labeled form, or prodrug thereof.
(IE)
or any tautomer, salt, stereoisomer, hydrate, solvent, isotopically labeled form, or prodrug thereof.
In various embodiments, the compound of formula (IE) can comprise any of the formulas:
or any tautomer, salt, stereoisomer, hydrate, solvent, or prodrug thereof.
For example, the compound of formula (IE) can be any of the following structures:
or any tautomer, salt, stereoisomer, hydrate, solvent, isotopically labeled form, or prodrug thereof.
(IF)
or any tautomer, salt, stereoisomer, hydrate, solvent, isotopically labeled form, or prodrug thereof.
For example, the compound of formula (IF) can be any of the following:
or any tautomer, salt, stereoisomer, hydrate, solvent, isotopically labeled form, or prodrug thereof.
(IG)
or any tautomer, salt, stereoisomer, hydrate, solvent, isotopically labeled form, or prodrug thereof.
In various embodiments, the compound of formula (IG) can comprise any of the formulas:
or any tautomer, salt, stereoisomer, hydrate, solvent, or prodrug thereof.
(IH)
or any tautomer, salt, stereoisomer, hydrate, solvent, isotopically labeled form, or prodrug thereof.
(U)
or any tautomer, salt, stereoisomer, hydrate, solvent, isotopically labeled form, or prodrug thereof.
In various embodiments, a compound of the invention can be a compound of formula (IK)
(R1 )m O
(IK)
or any tautomer, salt, stereoisomer, hydrate, solvent, isotopically labeled form, or prodrug thereof.
For example, the compound of formula (IK) can be any of the following structures:
or any tautomer, salt, stereoisomer, hydrate, solvent, isotopically labeled form, prodrug thereof.
(IL)
or any tautomer, salt, stereoisomer, hydrate, solvent, isotopically labeled form, or prodrug thereof.
In various embodiments, a compound of the invention can be a compound of any of the Examples 1-263, or any tautomer, salt, stereoisomer, hydrate, solvent, or prodrug thereof.
Another aspect of an embodiment of the invention provides compositions of the compounds of the invention, alone or in combination with another medicament. As set forth herein, compounds of the invention include stereoisomers, tautomers, solvates, prodrugs, pharmaceutically acceptable salts and mixtures thereof. Compositions containing a compound of the invention can be prepared by conventional techniques, e.g. as described in Remington: The Science and Practice of Pharmacy, 19th Ed., 1995, incorporated by reference herein. The compositions can appear in conventional forms, for example capsules, tablets, aerosols, solutions, suspensions or topical applications.
Typical compositions include a compound of the invention and a
pharmaceutically acceptable excipient which can be a carrier or a diluent. For example, the active compound will usually be mixed with a carrier, or diluted by a carrier, or enclosed within a carrier which can be in the form of an ampoule, capsule, sachet, paper, or other container. When the active compound is mixed with a carrier, or when the carrier serves as a diluent, it can be solid, semi- solid, or liquid material that acts as a vehicle, excipient, or medium for the active compound. The active compound can be adsorbed on a granular solid carrier, for example contained in a sachet. Some examples of suitable carriers are water, salt solutions, alcohols, polyethylene glycols,
polyhydroxyethoxylated castor oil, peanut oil, olive oil, gelatin, lactose, terra alba, sucrose, dextrin, magnesium carbonate, sugar, cyclodextrin, amylose, magnesium stearate, talc, gelatin, agar, pectin, acacia, stearic acid or lower alkyl ethers of cellulose, silicic acid, fatty acids, fatty acid amines, fatty acid monoglycerides and diglycerides, pentaerythritol fatty acid esters, polyoxyethylene, hydroxymethylcellulose and polyvinylpyrrolidone. Similarly, the carrier or diluent can include any sustained release material known in the art, such as glyceryl monostearate or glyceryl distearate, alone or mixed with a wax.
The formulations can be mixed with auxiliary agents which do not deleteriously react with the active compounds. Such additives can include wetting agents, emulsifying and suspending agents, salt for influencing osmotic pressure, buffers and/or coloring substances preserving agents, sweetening agents or flavoring agents. The compositions can also be sterilized if desired.
The route of administration can be any route which effectively transports the active compound of the invention to the appropriate or desired site of action, such as oral, nasal, pulmonary, buccal, subdermal, intradermal, transdermal or parenteral, e.g., rectal, depot, subcutaneous, intravenous, intraurethral, intramuscular, intranasal, ophthalmic solution or an ointment, the oral route being preferred.
If a solid carrier is used for oral administration, the preparation can be tabletted, placed in a hard gelatin capsule in powder or pellet form or it can be in the form of a troche or lozenge. If a liquid carrier is used, the preparation can be in the form of a syrup, emulsion, soft gelatin capsule or sterile injectable liquid such as an aqueous or non- aqueous liquid suspension or solution.
Injectable dosage forms generally include aqueous suspensions or oil suspensions which can be prepared using a suitable dispersant or wetting agent and a suspending agent Injectable forms can be in solution phase or in the form of a suspension, which is prepared with a solvent or diluent. Acceptable solvents or vehicles include sterilized water, Ringer's solution, or an isotonic aqueous saline solution. Alternatively, sterile oils can be employed as solvents or suspending agents. Preferably, the oil or fatty acid is non-volatile, including natural or synthetic oils, fatty acids, mono-, di- or tri-glycerides.
For injection, the formulation can also be a powder suitable for reconstitution with an appropriate solution as described above. Examples of these include, but are not limited to, freeze dried, rotary dried or spray dried powders, amorphous powders, granules, precipitates, or particulates. For injection, the formulations can optionally contain stabilizers, pH modifiers, surfactants, bioavailability modifiers and combinations of these. The compounds can be formulated for parenteral administration by injection such as by bolus injection or continuous infusion. A unit dosage form for injection can be in ampoules or in multi-dose containers.
The formulations of the invention can be designed to provide quick, sustained, or delayed release of the active ingredient after administration to the patient by employing procedures well known in the art. Thus, the formulations can also be formulated for controlled release or for slow release.
Compositions contemplated by the present invention can include, for example, micelles or liposomes, or some other encapsulated form, or can be administered in an extended release form to provide a prolonged storage and/or delivery effect. Therefore, the formulations can be compressed into pellets or cylinders and implanted
intramuscularly or subcutaneously as depot injections. Such implants can employ known inert materials such as silicones and biodegradable polymers, e.g., polylactide- polyglycolide. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides) .
For nasal administration, the preparation can contain a compound of the invention, dissolved or suspended in a liquid carrier, preferably an aqueous carrier, for aerosol application. The carrier can contain additives such as solubilizing agents, e.g., propylene glycol, surfactants, absorption enhancers such as lecithin (phosphatidylcholine) or cyclodextrin, or preservatives such as parabens.
For parenteral application, particularly suitable are injectable solutions or suspensions, preferably aqueous solutions with the active compound dissolved in polyhydroxylated castor oil.
Tablets, dragees, or capsules having talc and/or a carbohydrate carrier or binder or the like are particularly suitable for oral application. Preferable carriers for tablets, dragees, or capsules include lactose, corn starch, and/or potato starch. A syrup or elixir can be used in cases where a sweetened vehicle can be employed.
A typical tablet that can be prepared by conventional tabletting techniques can contain:
Core:
Active compound (as free compound or salt thereof) 250 mg
Colloidal silicon dioxide (Aerosil)® 1.5 mg Cellulose, microcryst. (Avicel)® 70 mg
Modified cellulose gum (Ac-Di-Sol)® 7.5 mg
Magnesium stearate Ad.
Coating:
HPMC approx. 9 mg *Mywacett 9-40 T approx. 0.9 mg
*Acylated monoglyceride used as plasticizer for film coating.
A typical capsule for oral administration contains compounds of the invention (250 mg), lactose (75 mg) and magnesium stearate (15 mg). The mixture is passed through a 60 mesh sieve and packed into a No. 1 gelatin capsule. A typical injectable preparation is produced by aseptically placing 250 mg of compounds of the invention into a vial, aseptically freeze-drying and sealing. For use, the contents of the vial are mixed with 2 mL of sterile physiological saline, to produce an injectable preparation.
The compounds of the invention can be administered to a mammal, especially a human in need of such treatment, prevention, elimination, alleviation or amelioration of a malcondition. Such mammals include also animals, both domestic animals, e.g.
household pets, farm animals, and non-domestic animals such as wildlife.
The compounds of the invention are effective over a wide dosage range. For example, in the treatment of adult humans, dosages from about 0.05 to about 5000 mg, preferably from about 1 to about 2000 mg, and more preferably between about 2 and about 2000 mg per day can be used. A typical dosage is about 10 mg to about 1000 mg per day. In choosing a regimen for patients it can frequently be necessary to begin with a higher dosage and when the condition is under control to reduce the dosage. The exact dosage will depend upon the activity of the compound, mode of administration, on the therapy desired, form in which administered, the subject to be treated and the body
weight of the subject to be treated, and the preference and experience of the physician or veterinarian in charge.
Generally, the compounds of the invention are dispensed in unit dosage form including from about 0.05 mg to about 1000 mg of active ingredient together with a pharmaceutically acceptable carrier per unit dosage.
Usually, dosage forms suitable for oral, nasal, pulmonal or transdermal administration include from about 125 μg to about 1250 mg, preferably from about 250 μg to about 500 mg, and more preferably from about 2.5 mg to about 250 mg, of the compounds admixed with a pharmaceutically acceptable carrier or diluent.
Dosage forms can be administered daily, or more than once a day, such as twice or thrice daily. Alternatively dosage forms can be administered less frequently than daily, such as every other day, or weekly, if found to be advisable by a prescribing physician.
Pharmaceutical Combinations
In various embodiments, a pharmaceutical combination comprising a compound of the invention in a therapeutically effective dose and a second medicament in a therapeutically effective dose is provided. More specifically, the second medicament can comprise an anti-proliferative agent, an anti-glaucoma agent, an anti-hypertensive agent, an anti- atherosclerotic agent, an anti-multiple sclerosis agent, an anti-angina agent, an anti-erectile dysfunction agent, an anti- stroke agent, or an anti-asthma agent. For example, the anti-proliferative agent can comprise an alkylating agent, an anti-metabolite, a vinca alkaloid, a terpenoid, a topoisomerase inhibitor, a monoclonal antibody, a kinase inhibitor, carboplatin, cisplatin, taxol, leucovorin, 5-flurouracil, eloxatin,
cyclophosphamide, chlorambucil, avastin, or imatinib mesylate. For example, the anti- glaucoma agent can comprise a beta receptor-blocker, a prostaglandin, an alpha- adrenergic agonist, a parasympathomimetic (cholinergic agonist), or a carbonic anhydrase inhibitor. For example, the anti-hypertensive agent can comprise a beta receptor-blocker, a calcium channel blocker, a diueretic, an angiotensin converting enzyme (ACE) inhibitor, a renin inhibitor, or an angiotensin receptor antagonist. For example, the anti-atherosclerotic agent can comprise a 3-HMG-coA-reductase inhibitor, a statin, atorvastatin, simvastatin, niacin, or a combination drug such as vytorin. For
example, the anti-multiple sclerosis agent can comprise beta-inteferon, tysabri, or glatirimar acetate. For example, the anti-angina agent can comprise a beta receptor- blocker, a calcium channel blocker, nitroglycerin, isosorbide mononitrate, nicorandil, or ranolanzine. For example, the anti-erectile dysfunction agent can comprise a
phosphodiesterase-5 inhibitor. For example, the anti-stroke agent can comprise tissue plasminogen activator. For example, the anti-asthma agent can comprise a
bronchodilator, an inhaled corticosteroid, a leukotrine blockers, cromolyn, nedocromil, or theophylline.
In various embodiments, a pharmaceutical combination of the invention can further comprise a suitable excipient as outlined above to provide a pharmaceutical composition comprising both medicaments.
In various embodiments, a method of treatment of a malcondition is provided comprising administering an effective amount of a compound of the invention and coadministering an effective amount of an additional medicament. The malcondition can comprise cardiovascular disease, neurogenic pain, hypertension, atherosclerosis, angina, stroke, arterial obstruction, peripheral arterial disease, peripheral circulation disorder, erectile dysfunction, acute and chronic pain, dementia, Alzheimer's disease, Parkinson's disease, neuronal degeneration, asthma, amyotrophic lateral sclerosis, spinal cord injury, rheumatoid arthritis, osteoarthritis, osteoporosis, psoriasis, cerebral vasospasm, open angle glaucoma, multiple sclerosis, pulmonary hypertension, acute respiratory distress syndrome, inflammation, diabetes, urinary organ diseases such as overactive bladder (OAB) and benign prostatic hypertrophy (BPH), metastasis, cancer, open angle glaucoma, ocular hypertension, retinopathy, autoimmune disease and viral infection, or myocardial pathology, or any combination thereof.
In various embodiments, the additional medicament that can be co-administered can comprise an anti-proliferative agent, an anti-glaucoma agent, an anti-hypertensive agent, an anti- atherosclerotic agent, an anti-multiple sclerosis agent, an anti-angina agent, an anti-erectile dysfunction agent, an anti-stroke agent, or an anti-asthma agent. By "coadministered" is meant that the patient is provided with an effective dose of an inventive compound and with an effective dose of the second medicament during the course of treatment, such as concurrently, consecutively, intermittently, or in other regimens. The
compound of the invention and the second medicament can be administered in separate dosage forms. For example, the anti-proliferative agent can comprise an alkylating agent, an anti-metabolite, a vinca alkaloid, a terpenoid, a topoisomerase inhibitor, a monoclonal antibody, a kinase inhibitor, carboplatin, cisplatin, taxol, leucovorin, 5-flurouracil, eloxatin, cyclophosphamide, chlorambucil, avastin, or imatinib mesylate. For example, the anti-glaucoma agent can comprise a beta receptor-blocker, a prostaglandin, an alpha- adrenergic agonist, a parasympathomimetic (cholinergic agonist), or a carbonic anhydrase inhibitor. For example, the anti-hypertensive agent can comprise a beta receptor-blocker, a calcium channel blocker, a diueretic, an angiotensin converting enzyme (ACE) inhibitor, a renin inhibitor, or an angiotensin receptor antagonist. For example, the anti-atherosclerotic agent can comprise a 3-HMG-coA-reductase inhibitor, a statin, atorvastatin, simvastatin, niacin, or a combination drug such as vytorin. For example, the anti-multiple sclerosis agent can comprise beta-inteferon, tysaberai, or glatirimar acetate. For example, the anti-angina agent can comprise a beta receptor- blocker, a calcium channel blocker, nitroglycerin, isosorbide mononitrate, nicorandil, or ranolanzine. For example, the anti-erectile dysfunction agent can comprise a
phosphodiesterase-5 inhibitor. For example, the anti-stroke agent can comprise tissue plasminogen activator. For example, the anti-asthma agent can comprise a
bronchodilator, an inhaled corticosteroid, a leukotrine blockers, cromolyn, nedocromil, or theophylline.
In various embodiments, the invention provides a method of inhibiting a kinase enzyme, comprising contacting the kinase enzyme and an effective amount of a compound of the invention. For example, the kinase enzyme can comprise a Rho kinase, an AKT kinase, a p70S6K kinase, a LIM kinase, an IKK kinase, a Fit kinase, an Aurora kinase, or a Src kinase, or any combination thereof.
In various embodiments, the invention provides a method of treating a
malcondition in a patient, wherein inhibition of a kinase enzyme comprising a Rho kinase, an AKT kinase, a p70S6K kinase, a LIM kinase, an IKK kinase, a Fit kinase, an Aurora kinase, or a Src kinase, or any combination thereof, is medically indicated, the method comprising administering a compound of the invention to the patient in a dose, at a frequency, and for a duration to provide a beneficial effect to the patient. More
specifically, the malcondition can comprise hypertension, atherosclerosis, angina, stroke, arterial obstruction, peripheral arterial disease, peripheral circulation disorder, erectile dysfunction, acute and chronic pain, dementia, Alzheimer's disease, Parkinson's disease, neuronal degeneration, asthma, amyotrophic lateral sclerosis, spinal cord injury, rheumatoid arthritis, osteoarthritis, osteoporosis, psoriasis, cerebral vasospasm, open angle glaucoma, spinal cord injury, multiple sclerosis, pulmonary hypertension, acute respiratory distress syndrome, inflammation, diabetes, urinary organ diseases such as overactive bladder (OAB) and benign prostatic hypertrophy (BPH), metastasis, cancer, open angle glaucoma, ocular hypertension, retinopathy, autoimmune disease and viral infection.
In various embodiments, the invention provides the use of a compound of the invention in preparation of a medicament, such as where the medicament is adapted to inhibit a Rho kinase, an AKT kinase, a p70S6K kinase, a LIM kinase, an IKK kinase, a Fit kinase, an Aurora kinase, or a Src kinase, or any combination thereof, or the medicament is adapted to treat a malcondition wherein inhibition of the kinase is medically indicated. More specifically, , the malcondition can comprise hypertension, atherosclerosis, angina, stroke, arterial obstruction, peripheral arterial disease, peripheral circulation disorder, erectile dysfunction, acute and chronic pain, dementia, Alzheimer's disease, Parkinson's disease, neuronal degeneration, asthma, amyotrophic lateral sclerosis, spinal cord injury, rheumatoid arthritis, osteoarthritis, osteoporosis, psoriasis, cerebral vasospasm, open angle glaucoma, spinal cord injury, multiple sclerosis, pulmonary hypertension, acute respiratory distress syndrome, inflammation, diabetes, urinary organ diseases such as overactive bladder (OAB) and benign prostatic hypertrophy (BPH), metastasis, cancer, open angle glaucoma, ocular hypertension, retinopathy, autoimmune disease and viral infection.
Thus, inhibition of one or more of these protein kinases could be therapeutically effective in the treatment of any of hypertension, atherosclerosis, angina, stroke, arterial obstruction, peripheral arterial disease, peripheral circulation disorder, erectile dysfunction, acute and chronic pain, dementia, Alzheimer's disease, Parkinson's disease, neuronal degeneration, asthma, amyotrophic lateral sclerosis, spinal cord injury, rheumatoid arthritis, osteoarthritis, osteoporosis, psoriasis, cerebral vasospasm, open
angle glaucoma, spinal cord injury, multiple sclerosis, pulmonary hypertension, acute respiratory distress syndrome, inflammation, diabetes, urinary organ diseases such as overactive bladder (OAB) and benign prostatic hypertrophy (BPH), metastasis, cancer, open angle glaucoma, ocular hypertension, retinopathy, autoimmune disease and viral infection, or in providing myocardial protection
EXAMPLES
The following abbreviations are used throughout the Examples:
DCM Dichloromethane
DMF N,N-Dimethylformamide
DMSO Dimethylsulfoxide
eq Equivalents
Et20 Diethyl ether
EtOAc Ethyl acetate
h Hours
mg Milligrams
min Minutes
mL Milliliters
μL· Microliters
mmole Millimoles
MS Mass spectroscopy
MeOH Methanol
rb Round-bottom
RT Room temperature
sat. Saturated
THF Tetrahydrofuran
~ to (range, e.g., X~Y = X to Y)
The following numbered Examples disclose compounds that have been prepared and characterized. Many have been evaluated as inhibitors of kinases. These compounds are examples only and in no way are limiting to the claims herein.
Scheme 1
A solution of 6-bromo-lH-indole-2-carboxylic acid (1.0 equiv), a primary or secondary amine (1.0 equiv) and Et3N (2.0 equiv) was prepared in anhydrous DMF at room temperature. To this solution was then added HATU (1.3 equiv). The solution was then stirred until the reaction was complete by LC/MS (-1-2 h). Upon completion, the solution was diluted with EtOAc and washed with H20. The aqueous portion was extracted with additional EtOAc and the combined organic portions were dried over MgS04. Purification on Si02 (Hexane/EtOAc or CH2Cl2/MeOH+NH4OH) gave the intermediate carboxamides. The aryl bromide (1.0 equiv) could then be combined with an arylboronate species (1.30 equiv) and Na2C03 (3.0 equiv) in 20% aqueous dioxane in a microwave pressure tube at room temperature. To this solution was added
PdCl2(PPh3)2 (0.10 equiv) and the solution was sparged with argon for 10 minutes. The reaction was subsequently heated in a microwave at 120 °C until the reaction was complete (-0.5-2 h). Alternatively, the aryl bromide (1.0 equiv) was combined with bis(pinacolato)boron (2.5 equiv), KOAc (5.0 equiv) and PdCl2(dppf) (0.1 equiv) under streaming argon in a microwave pressure tube. Dioxane was then added and the solution was sparged with argon for 10 minutes. The solution was then heated to 100 °C in a microwave until the conversion was complete (-60 min). Upon completion, the solution was diluted with EtOAc and washed with brine. The aqueous fraction was extracted with additional EtOAc and the combined organic portions were dried over MgS04 and concentrated. The unpurified arylboronate (1.0 equiv) was then combined with an arylchloride (1.0 equiv), Na2C03 (3.0 equiv) and PdCl2(PPh3)2 (0.1 equiv) under streaming argon. Aqueous dioxane (20%) was then added and the solution was sparged
with argon for 10 minutes. The solution was then heated to 120 °C in a microwave until complete (-30 min). Upon completion, the solution was purified via preparative HPLC to give the desired product.
Procedures in Scheme 1 were utilized to synthesize this compound. H-NMR (DMSO- d6, 400 MHz) δ 11.86 (1H, s), 9.12 (1H, t, J = 5.7 Hz), 8.64 (2H, m), 7.81 (1H, s), 7.78 (1H, d, J = 8.3 Hz), 7.71 (2H, m), 7.49 (1H, d, J = 8.6 Hz), 7.27 (2H, m), 6.94 (2H, m), 6.85 (1H, d, J = 8.1 Hz), 4.52 (2H, d, J = 6.0 Hz), 3.76 (3H, s). LC/MS: C22H19N302 (M+1) 358. Single peak at both 215 nm and 254 nm in analytical HPLC traces.
Procedures in Scheme 1 were utilized to synthesize this compound. H-NMR (DMSO- d6, 400 MHz) δ 12.90 (1H, s), 11.54 (1H, s), 8.97 (1H, t, J = 6.1 Hz), 8.14 (1H, s), 7.87 (1H, s), 7.60 (1H, d, J = 8.4 Hz), 7.56 (1H, s), 7.32 (1H, d, J = 8.3 Hz), 7.26 (1H, t, J = 8.1 Hz), 7.15 (1H, s), 6.92 (1H, m), 6.83 (1H, d, J = 8.0 Hz), 4.50 (2H, d, J = 6.0 Hz), 3.75 (3H, s). LC/MS: C2oHi8N402 (M+1) 347. Single peak at both 215 nm and 254 nm in analytical HPLC traces.
Procedures in Scheme 1 were utilized to synthesize this compound. LC/MS: C2iH2oN402 (M+1) 361. -95% pure at 254 nm in analytical HPLC traces.
Procedures in Scheme 1 were utilized to synthesize this compound. 1H-NMR (MeOD-d4, 400 MHz) δ 8.42 (1H, s), 8.24 (1H, d, J = 6.6 Hz), 7.97 (1H, d, J = 8.6 Hz), 7.78 (1H, d, J = 8.6 Hz), 7.54 (1H, d, J = 6.7 Hz), 7.25 (1H, t, J = 8.2 Hz), 7.19 (1H, s), 6.96 (2H, m), 6.83 (1H, m), 4.59 (2H, s), 3.78 (3H, s). LC/MS: C2iH19N502 (M+1) 374. Single peak at both 215 nm and 254 nm in analytical HPLC traces.
Procedures in Scheme 1 were utilized to synthesize this compound. 1H-NMR (MeOD-d4, 400 MHz) δ 7.93 (1H, d, J = 5.8 Hz), 7.76 (1H, s), 7.70 (1H, d, J = 8.4 Hz), 7.40 (1H, d, J = 8.4 Hz), 7.25 (1H, t, J = 8.1 Hz), 7.14 (1H, s), 6.95 (3H, m), 6.89 (1H, s), 6.82 (1H, d, J = 7.4 Hz), 4.58 (2H, s), 3.78 (3H, s). LC/MS: C22H2oN402 (M+1) 373. Single peak at both 215 nm and 254 nm in analytical HPLC traces.
Procedures in Scheme 1 were utilized to synthesize this compound. LC/MS: C23H21N302 (M+1) 372. Single peak at both 215 nm and 254 nm in analytical HPLC traces.
Procedures in Scheme 1 were utilized to synthesize this compound. LC/MS: C2iH2oN402 (M+1) 361. Single peak at both 215 nm and 254 nm in analytical HPLC traces.
Example 8. N-(3-(dimethylamino)propyl)-N-(3-methoxybenzyl)-6-(pyridin-4-yl)-lH-
Procedures in Scheme 1 were utilized to synthesize this compound. LC/MS: C27H30N4O2 (M+1) 443. Single peak at both 215 nm and 254 nm in analytical HPLC traces.
Example 9. N-(3-(dimethylamino)propyl)-N-(3-methoxybenzyl)-6-(lH-pyrazol-4-yl)- -indole-2-carboxamide
Procedures in Scheme 1 were utilized to synthesize this compound. 1H-NMR (MeOD-d4, 400 MHz) δ 8.05 (2H, s), 7.66 (1H, s), 7.53 (1H, d, J = 7.9 Hz), 7.33 (2H, m), 6.92 (3H, m), 6.72 (1H, s), 5.04 (2H, s), 3.80 (3H, s), 3.65 (2H, m), 3.18 (2H, t, J = 6.9 Hz), 2.93 (6H, s), 2.09 (2H, quin, J = 7.0 Hz). LC/MS: C25H29N5O2 (M+1) 432. Single peak at both 215 nm and 254 nm in analytical HPLC traces.
Example 10. N-(3-methoxybenzyl)-6-(lH-pyrazol-4-yl)-N-(2-(pyrrolidin- l-yl)ethyl)- lH-indole-2-carboxamide
Procedures in Scheme 1 were utilized to synthesize this compound. 1H-NMR (MeOD-d4, 400 MHz) δ 8.00 (2H, s), 7.65 (1H, s), 7.53 (1H, d, J = 8.3 Hz), 7.37 (1H, t, J = 7.8 Hz), 7.32 (1H, d, J = 8.3 Hz), 6.93 (3H, m), 6.75 (1H, s), 5.10 (2H, s), 3.87 (4H, m), 3.81 (3H, s), 3.49 (2H, t, J = 6.1 Hz), 3.16 (2H, m), 2.18 (2H, m), 2.06 (2H, m). LC/MS:
C26H29N5O2 (M+1) 444. Single peak at both 215 nm and 254 nm in analytical HPLC traces.
Example 11. N- (3-methoxybenzyl)-N- (3-morpholinopropyl)-6- ( 1 H-pyrazol-4-yl)- 1 H-
Procedures in Scheme 1 were utilized to synthesize this compound. 1H-NMR (MeOD-d4, 400 MHz) δ 8.00 (2H, s), 7.65 (1H, s), 7.53 (1H, d, J = 8.1 Hz), 7.36 (1H, t, J = 7.9 Hz), 7.32 (1H, d, J = 8.3 Hz), 6.91 (3H, m), 6.74 (1H, s), 5.05 (2H, s), 4.10 (2H, m), 3.84 (2H, m), 3.80 (3H, s), 3.69 (2H, m), 3.53 (2H, m), 3.19 (4H, m), 2.13 (2H, m, J = 7.2 Hz). LC/MS: C27H31N503 (M+1) 474. Single peak at both 215 nm and 254 nm in analytical HPLC traces.
Example 12. N-(3-methoxybenzyl)-N-(3-(4-methylpiperazin-l-yl)propyl)-6-(lH- pyrazol-4-yl)-lH-indole-2-carboxamide
Procedures in Scheme 1 were utilized to synthesize this compound. LC/MS: C28H34N602 (M+1) 487. Single peak at both 215 nm and 254 nm in analytical HPLC traces.
Example 13. (R)-N-(l-(3-methoxyphenyl)ethyl)-6-(lH-pyrazol-4-yl)-lH-indole-2- carboxamide
Procedures in Scheme 1 were utilized to synthesize this compound. 1H-NMR (MeOD-d4,
400 MHz) δ 7.96 (2H, s), 7.62 (1H, m), 7.33 (1H, d, J = 8.4 Hz), 7.25 (1H, t, J = 7.7 Hz), 7.17 (1H, s), 7.00 (2H, m), 6.80 (1H, m), 6.33 (1H, t, J = 2.0 Hz), 5.25 (1H, m), 3.78 (3H,
s), 1.58 (3H, d, J = 7.0 Hz). LC/MS: C21H20N4O2 (M+l) 361. Single peak at both 215 nm and 254 nm in analytical HPLC traces.
Example 14. (S)-N-(l-(3-methoxyphenyl)ethyl)-6-(lH-pyrazol-4-yl)-lH-indole-2- carboxamide
Procedures in Scheme 1 were utilized to synthesize this compound. LC/MS: C21H20N4O2
5 nm and 254 nm in analytical HPLC traces.
A solution of the indole carboxamide (1.0 equiv) and CS2CO3 (2.0 equiv) in anhydrous DMF was prepared at room temperature. To this solution was then added the alkyl halide (1.2 equiv). The resulting solution was stirred vigorously at room temperature until the alkylation was complete by LC/MS. The solution was then diluted with EtOAc and washed with brine. The aqueous portion was twice extracted with additional EtOAc and the combined organic portions were dried over MgS04. The resulting material was then used in the subsequent Suzuki coupling without purification. The aryl bromide (1.0 equiv) was then combined with an arylboronate species (1.30 equiv) and Na2C03 (3.0 equiv) in 20% aqueous dioxane in a microwave pressure tube at room temperature. To this solution was added PdCl2(PPh3)2 (0.10 equiv) and the solution was sparged with argon for 10 minutes. The reaction was subsequently heated in a microwave at 120 °C until the reaction was complete (-0.5-2 h). Purification via preparative HPLC gave the desired product (in the examples containing a TBS ether, the TBS group was removed by the TFA present in the HPLC eluent).
Procedures in Scheme 2 were utilized to synthesize this compound. 1H-NMR (MeOD-d4, 400 MHz) δ 8.77 (2H, d, J = 7.0 Hz), 8.42 (2H, d, J = 7.0 Hz), 8.17 (1H, s), 7.85 (1H, d, J = 8.4 Hz), 7.70 (1H, dd, J = 8.4 Hz, 1.7 Hz), 7.26 (1H, t, J = 8.0 Hz), 7.12 (1H, s), 6.97 (2H, m), 6.83 (1H, m), 4.56 (2H, s), 4.13 (3H, s), 3.79 (3H, s). LC/MS: C23H21N3O2 (M+1) 372. Single peak at both 215 nm and 254 nm in analytical HPLC traces.
Example 16. l-(3-hydroxypropyl)-N-(3-methoxybenzyl)-6-(pyridin-4-yl)- lH-indole-2- carboxamide
Procedures in Scheme 2 were utilized to synthesize this compound. LC/MS: C25H25N3O3 (M+1) 416. Single peak at both 215 nm and 254 nm in analytical HPLC traces.
Example 17. 1 - (3 -hydroxypropyl)-N- (3-methoxybenzyl)-6- ( 1 H-pyrazol-4-yl)- 1 H-
Procedures in Scheme 2 were utilized to synthesize this compound. 1H-NMR (MeOD-d4, 400 MHz) δ 8.10 (2H, s), 7.74 (1H, s), 7.62 (1H, d, J = 8.3 Hz), 7.37 (1H, dd, J = 8.3 Hz, 1.4 Hz), 7.24 (1H, t, J = 8.1 Hz), 7.06 (1H, s), 6.95 (2H, m), 6.82 (1H, dd, J = 7.9 Hz, 2.3 Hz), 4.69 (2H, t, J = 7.1 Hz), 4.54 (2H, s), 3.79 (3H, s), 3.54 (2H, t, J = 6.1 Hz), 2.04 (2H, m, J = 6.8 Hz). LC/MS: C23H24N403 (M+1) 405. Single peak at both 215 nm and 254 nm in analytical HPLC traces.
Example 18. l-(2-(dimethylamino)ethyl)-N-(3-methoxybenzyl)-6-(pyridin-4-yl)-lH- indole-2-carboxamide
Procedures in Scheme 2 were utilized to synthesize this compound. LC/MS: C26H28N4O2 (M+l) 429. Single peak at both 215 nm and 254 nm in analytical HPLC traces.
Example 19. l-(2-(dimethylamino)ethyl)-N-(3-methoxybenzyl)-6-(lH-pyrazol-4-yl)- -indole-2-carboxamide
Procedures in Scheme 2 were utilized to synthesize this compound. 1H-NMR (MeOD-d4, 400 MHz) δ 8.08 (2H, s), 7.76 (1H, s), 7.68 (1H, d, J = 8.1 Hz), 7.47 (1H, d, J = 7.9 Hz), 7.27 (1H, t, J = 7.8 Hz), 7.18 (1H, s), 6.96 (2H, m), 6.85 (1H, d, J = 6.5 Hz), 4.89 (2H, t, J = 6.0 Hz), 4.59 (2H, s), 3.80 (3H, s), 3.66 (2H, t, J = 6.1 Hz), 2.93 (6H, s). LC/MS:
C24H27N502 (M+l) 418. Single peak at both 215 nm and 254 nm in analytical HPLC traces.
Procedures in Scheme 2 were utilized to synthesize this compound. LC/MS: C24H23N302 (M+l) 386. Single peak at both 215 nm and 254 nm in analytical HPLC traces.
Procedures in Scheme 2 were utilized to synthesize this compound. LC/MS: C22H22N402 (M+l) 375. Single peak at both 215 nm and 254 nm in analytical HPLC traces.
Example 22. l-(2-(dimethylamino)ethyl)-N-(3-methoxybenzyl)-N-methyl-6-(pyridin-4- -lH-indole-2-carboxamide
Procedures in Scheme 2 were utilized to synthesize this compound. LC/MS: C27H30N4O2 (M+l) 443. Single peak at both 215 nm and 254 nm in analytical HPLC traces.
Example 23. l-(2-(dimethylamino)ethyl)-N-(3-methoxybenzyl)-N-methyl-6-(lH- pyrazol-4-yl)-lH-indole-2-carboxamide
Procedures in Scheme 2 were utilized to synthesize this compound. LC/MS: C25H29N5O2 (M+l) 432. Single peak at both 215 nm and 254 nm in analytical HPLC traces.
Scheme 3
A microwave pressure vial was charged with AcOH (0.25 M), formaldehyde (37% aqueous solution, 1.1 equiv) and the secondary amine (2.0 equiv). The solution was then stirred for 5 min at room temperature and then MeOH was added (6x volume of AcOH) followed by the indole (1.0 equiv). The pressure vial was sealed and warmed to 80 C in an oil bath. Upon completion by LC/MS, the solution was concentrated in vacuo. The residue was then purified on S1O2 (Hex/EtOAc with an Et3N flushed column). The aryl bromide (1.0 equiv) was then combined with the pyrazoleboronate (1.30 equiv) and Na2C03 (3.0 equiv) in 20% aqueous dioxane in a microwave pressure tube at room temperature. To this solution was added PdCl2(PPh3)2 (0.10 equiv) and the solution was sparged with argon for 10 minutes. The reaction was subsequently heated in a
microwave at 120 °C until the reaction was complete (-0.5-2 h). The solution was then concentrated in vacuo and purified on Si02 (CH2Cl2/MeOH + NH4OH) to give the pure product.
Example 24. N-(3-methoxybenzyl)-3-(morpholinomethyl)-6-(lH-pyrazol-4-yl)-lH-
Procedures in Scheme 3 were utilized to synthesize this compound. LC/MS: C25H27N5O3 (M+l) 446. Peak at both 215 nm and 254 nm in analytical HPLC traces with minor impurity.
Example 25. N-(3-methoxybenzyl)-3-((4-methylpiperazin-l-yl)methyl)-6-(lH-pyrazol- 4-yl)-lH-indole-2-carboxamide
Procedures in Scheme 3 were utilized to synthesize this compound. H-NMR (DMSO- d6, 400 MHz) δ 12.92 (1H, s), 11.62 (1H, s), 10.77 (1H, m), 8.14 (1H, s), 7.86 (1H, s), 7.66 (1H, d, J = 8.4 Hz), 7.54 (1H, s), 7.31 (2H, m), 6.99 (2H, m), 6.87 (1H, d, J = 6.6 Hz), 4.52 (2H, d, J = 5.1 Hz), 3.76 (3H, s), 3.74 (2H, s), 2.33 (6H, m, near solvent peak, should be 8H), 1.99 (3H, s). LC/MS: C26H30N6O2 (M+l) 459. Single peak at both 215 nm and 254 nm in analytical HPLC traces.
Example 26. 3-((benzyl(methyl)amino)methyl)-N-(3-methoxybenzyl)-6-(lH-pyrazol-4- yl)-lH-indole-2-carboxamide
Procedures in Scheme 3 were utilized to synthesize this compound. 1H-NMR (MeOD-d4, 400 MHz) δ 8.04 (2H, s), 7.77 (1H, d, J = 8.5 Hz), 7.68 (1H, s), 7.50 (6H, m), 7.30 (1H, t, J = 7.7 Hz), 7.01 (2H, m), 6.88 (1H, d, J = 8.3 Hz), 4.81 (1H, d, J = 13.5 Hz), 4.62 (4H, m), 4.34 (1H, d, J = 12.9 Hz), 3.80 (3H, s), 2.74 (3H, s). LC/MS: C29H29N5O2 (M+1) 480. Single peak at both 215 nm and 254 nm in analytical HPLC traces.
Example 27. 3-((dimethylamino)methyl)-N-(3-methoxybenzyl)-6-(lH-pyrazol-4-yl)- lH-indole-2-carboxamide
Procedures in Scheme 3 were utilized to synthesize this compound. 1H-NMR (MeOD-d4, 400 MHz) δ 8.02 (2H, s), 7.79 (1H, d, J = 8.5 Hz), 7.68 (1H, s), 7.52 (1H, d, J = 8.6 Hz), 7.29 (1H, t, J = 7.8 Hz), 7.00 (2H, m), 6.87 (1H, d, J = 8.5 Hz), 4.67 (2H, s), 4.64 (2H, s), 3.80 (3H, s), 2.93 (6H, s). LC/MS: C23H25N5O2 (M+1) 404. Single peak at both 215 nm and 254 nm in analytical HPLC traces.
Example 28. N-(3-methoxybenzyl)-3-((2-phenylpyrrolidin-l-yl)methyl)-6-(lH-pyrazol- -yl)-lH-indole-2-carboxamide
Procedures in Scheme 3 were utilized to synthesize this compound. 1H-NMR (MeOD-d4,
400 MHz) δ 8.01 (2H, s), 7.74 (1H, d, J = 8.4 Hz), 7.58 (1H, s), 7.51 (1H, d, J = 8.5 Hz), 7.28 (6H, m), 6.94 (2H, m), 6.89 (1H, d, J = 8.4 Hz), 4.74 (1H, d, J = 13.6 Hz), 4.65 (1H, d, J = 13.6 Hz), 4.60 (1H, d, J = 14.8 Hz), 4.54 (1H, m), 4.46 (1H, d, J = 14.7 Hz), 3.81
(4H, m), 3.46 (1H, m), 2.57 (1H, m), 2.31 (3H, m). LC/MS: C31H31N5O2 (M+l) 506.
Single peak at both 215 nm and 254 nm in analytical HPLC traces.
Example 29. 3-((l,4-diazepan-l-yl)methyl)-N-(3-methoxybenzyl)-6-(lH-pyrazol-4-yl)- -indole-2-carboxamide
Procedures in Scheme 3 were utilized to synthesize this compound. LC/MS: C26H30N6O2
(M+l) 459. Single peak at both 215 nm and 254 nm in analytical HPLC traces.
Example 30. 3-((3-aminoazetidin-l-yl)methyl)-N-(3-methoxybenzyl)-6-(lH-pyrazol-4- yl)-lH-indole-2-carboxamide
Procedures in Scheme 3 were utilized to synthesize this compound. LC/MS: C24H26N6O2 (M+l) 431. Single peak at both 215 nm and 254 nm in analytical HPLC traces.
Scheme 4
A dry flask was charged with 6-bromoindole (1.0 equiv, 10.2 mmol) and anhydrous (13 mL) and cooled to 0 °C. Trifluoroaceticanhydride (1.15 equiv, 11.7 mmol) was
added dropwise and stirred cold for 3 h. The solution was then poured into H20 and the resulting precipitate was collected by filtration. Dried in vacuo to give the
trifluoroacylketone (2.82 g, 95% yield). This ketone (1.0 equiv, 1.0 g) was then mixed with 20% aqueous NaOH (17 mL) and warmed to 100 °C. Stirring at this temperature was continued until the conversion was complete (-18 h). The solution was then cooled to room temperature and twice washed with CH2C12. The aqueous solution was then acidified with HC1 and the resulting precipitate was collected via filtration and dried in vacuo to give the corresponding carboxylic acid (715 mg, 87% yield). A solution of the carboxcylic acid (1.0 equiv), a primary or secondary amine (1.0 equiv) and Et3N (2.0 equiv) was prepared in anhydrous DMF at room temperature. To this solution was then added HATU (1.3 equiv). The solution was then stirred until the reaction was complete by LC/MS (-1-2 h). Upon completion, the solution was diluted with CH2C12 and washed with saturated NH4C1 solution. The aqueous portion was extracted with additional CH2C12 and the combined organic portions were dried over MgS04. Purification on Si02 (Hex/EtOAc) gave the desired carboxamides. The indolyl bromide (1.0 equiv) was then combined with an arylboronate (1.30 equiv) and Na2C03 (3.0 equiv) in 20% aqueous dioxane in a microwave pressure tube at room temperature. To this solution was added PdCl2(PPh3)2 (0.10 equiv) and the solution was sparged with argon for 10 minutes. The reaction was subsequently heated in a microwave at 120 °C until the reaction was complete (-0.5-2 h). The solution was then diluted with EtOAc and washed with brine. The aqueous portion was twice extracted with EtOAc and the combined organic portions were dried over MgS04 and concentrated. Purification either via preparatory HPLC or on Si02 (CH2Cl2/MeOH + NH4OH) gave the pure product.
Procedures in Scheme 4 were utilized to synthesize this compound. LC/MS: C22H19N302 (M+l) 358. Single peak at both 215 nm and 254 nm in analytical HPLC traces.
Procedures in Scheme 4 were utilized to synthesize this compound. H-NMR (MeOD-d4, 400 MHz) δ 11.16 (1H, s), 8.11 (1H, d, J = 8.4 Hz), 8.02 (2H, s), 7.90 (1H, m), 7.63 (1H, s), 7.42 (1H, d, J = 8.4 Hz), 7.24 (1H, t, J = 8.1 Hz), 6.96 (2H, m), 6.80 (1H, d, J = 8.3 Hz), 4.58 (2H, s), 3.78 (3H, s). LC/MS: C2oH18N402 (M+1) 347. Single peak at both 215 nm and 254 nm in analytical HPLC traces.
Procedures in Scheme 4 were utilized to synthesize this compound. H-NMR (MeOD-d4, 400 MHz) δ 8.18 (1H, d, J = 7.9 Hz), 8.06 (1H, d, J = 8.4 Hz), 7.95 (3H, m), 7.60 (1H, s), 7.39 (1H, d, J = 8.4 Hz), 7.24 (1H, t, J = 7.8 Hz), 7.01 (2H, m), 6.79 (1H, d, J = 7.3 Hz), 5.26 (1H, m), 3.78 (3H, s), 1.57 (3H, d, J = 7.0 Hz). LC/MS: C21H20N4O2 (M+1) 361. Single peak at both 215 nm and 254 nm in analytical HPLC traces.
Example 34. (S)-N-(l-(3-methoxyphenyl)ethyl)-6-(lH-pyrazol-4-yl)-lH-indole-3- carboxamide
Procedures in Scheme 4 were utilized to synthesize this compound. H-NMR (MeOD-d4,
400 MHz) δ 8.21 (1H, d, J = 7.9 Hz), 8.07 (1H, d, J = 8.3 Hz), 7.95 (3H, m), 7.60 (1H, s),
7.39 (1H, dd, J = 8.3 Hz, 1.5 Hz), 7.24 (1H, m), 7.01 (2H, m), 6.79 (1H, d, J = 8.3 Hz),
5.26 (1H, m), 3.78 (3H, s), 1.57 (1H, d, J = 7.0 Hz). LC/MS: C2iH20N4O2 (M+1) 361.
Single peak at both 215 nm and 254 nm in analytical HPLC traces.
Procedures in Scheme 4 were utilized to synthesize this compound. H-NMR (MeOD-d4, 400 MHz) δ 8.10 (2H, s), 7.80 (1H, d, J = 8.3 Hz), 7.65 (1H, s), 7.59 (1H, br), 7.42 (1H, dd, J = 8.3 Hz, 1.5 Hz), 7.28 (1H, m), 6.87 (3H, m), 4.81 (2H, s), 3.78 (3H, s), 3.12 (3H, s). LC MS: C21H20N4O2 (M+1) 361. Single peak at both 215 nm and 254 nm in analytical HPLC traces.
Procedures in Scheme 4 were utilized to synthesize this compound. H-NMR (MeOD-d4,
400 MHz) δ 8.07 (3H, m), 7.91 (1H, m), 7.64 (1H, s), 7.42 (1H, dd, J = 8.3 Hz, 1.5 Hz), 7.32 (1H, d, J = 7.5 Hz), 7.25 (1H, t, J = 7.6 Hz), 6.99 (1H, d, J = 8.3 Hz), 6.92 (1H, t, J = 7.6 Hz), 4.61 (2H, s), 3.90 (3H, s). LC/MS: C2oH18N402 (M+1) 347. Single peak at both 215 nm and 254 nm in analytical HPLC traces.
Procedures in Scheme 4 were utilized to synthesize this compound. H-NMR (MeOD-d4 400 MHz) δ 8.42 (2H, s), 8.17 (1H, d, J = 8.3 Hz), 7.93 (1H, m), 7.70 (1H, s), 7.46 (1H, dd, J = 8.4 Hz, 1.6 Hz), 7.31 (2H, d, J = 8.8 Hz), 6.89 (2H, d, J = 8.7 Hz), 4.53 (2H, s), 3.77 (3H, s). LC/MS: C20Hi8N4O2 (M+1) 347. Single peak at both 215 nm and 254 nm in analytical HPLC traces.
Example 38. 6-(lH-pyrazol-4-yl)-N-(3-(trifluoromethoxy)benzyl)- lH-indole-3- carboxamide
Procedures in Scheme 4 were utilized to synthesize this compound. H-NMR (MeOD-d4, 400 MHz) δ 8.10 (1H, d, J = 8.3 Hz), 8.00 (2H, s), 7.90 (1H, d, J = 2.9 Hz), 7.63 (1H, s), 7.42 (3H, m), 7.31 (1H, s), 7.16 (1H, d, J = 6.7 Hz), 4.63 (2H, s). LC/MS: C2oH15F3N402 (M+1) 401. Single peak at both 215 nm and 254 nm in analytical HPLC traces.
Procedures in Scheme 4 were utilized to synthesize this compound. H-NMR (MeOD-d4, 400 MHz) δ 8.33 (2H, s), 8.15 (1H, d, J = 8.4 Hz), 7.92 (1H, s), 7.68 (1H, s), 7.45 (1H, dd, J = 8.4 Hz, 1.5 Hz), 6.90 (1H, d, J = 1.5 Hz), 6.87 (1H, d, J = 7.9 Hz), 6.78 (1H, d, J = 7.9 Hz), 5.91 (2H, s), 4.50 (2H, s). LC/MS: C2oH16N403 (M+1) 361. Single peak at both 215 nm and 254 nm in analytical HPLC traces.
Procedures in Scheme 4 were utilized to synthesize this compound. 1H-NMR (MeOD-d4, 400 MHz) δ 8.07 (2H, s), 8.01 (1H, d, J = 8.3 Hz), 7.81 (1H, m), 7.63 (1H, s), 7.40 (1H, dd, J = 8.4 Hz, 1.3 Hz), 7.21 (1H, t, J = 8.0 Hz), 6.86 (2H, m), 6.78 (1H, d, J = 7.9 Hz), 3.76 (3H, s), 3.61 (2H, t, J = 7.4 Hz), 2.92 (2H, t, J = 7.4 Hz). LC/MS: C21H20N4O2 (M+1) 361. Single peak at both 215 nm and 254 nm in analytical HPLC traces.
Procedures in Scheme 4 were utilized to synthesize this compound. H-NMR (MeOD-d4, 400 MHz) δ 8.06 (1H, d, J = 8.3 Hz), 7.97 (2H, s), 7.85 (1H, m), 7.61 (1H, s), 7.40 (1H, dd, J = 8.4 Hz, 1.5 Hz), 3.24 (2H, d, J = 7.0 Hz), 1.85 (2H, m), 1.77 (2H, m), 1.66 (2H,
m), 1.28 (3H, m), 1.04 (2H, m). LC/MS: Q9H22N4O (M+l) 323. Single peak at both 215 nm and 254 nm in analytical HPLC traces.
Procedures in Scheme 4 were utilized to synthesize this compound. LC/MS: C22H20N4O (M+l) 357. Single peak at both 215 nm and 254 nm in analytical HPLC traces.
Procedures in Scheme 4 were utilized to synthesize this compound. H-NMR (MeOD-d4, 400 MHz) δ 8.10 (1H, d, J = 8.3 Hz), 8.00 (2H, s), 7.90 (1H, m), 7.63 (1H, s), 7.42 (1H, dd, J = 8.3 Hz, 1.5 Hz), 7.28 (1H, m), 7.21 (2H, m), 4.56 (2H, s). LC/MS: C19H14F2N4O (M+l) 353. Single peak at both 215 nm and 254 nm in analytical HPLC traces.
Example 44. N-(2,5-dimethoxybenzyl)-6-(lH-pyrazol-4-yl)-lH-indole-3-carboxamide
Procedures in Scheme 4 were utilized to synthesize this compound. LC/MS: C21H20N4O3 (M+l) 377. Single peak at both 215 nm and 254 nm in analytical HPLC traces.
Procedures in Scheme 4 were utilized to synthesize this compound. LC/MS: C2oH19NsO (M+l) 346. Single peak at both 215 nm and 254 nm in analytical HPLC traces.
Procedures in Scheme 4 were utilized to synthesize this compound. H-NMR (MeOD-d4, 400 MHz) δ 8.45 (2H, s), 8.11 (1H, d, J = 8.4 Hz), 7.88 (1H, m), 7.71 (1H, s), 7.46 (1H, dd, J = 8.4 Hz, 1.5 Hz), 7.22 (1H, dd, J = 5.0 Hz, 1.3 Hz), 6.94 (2H, m), 3.65 (2H, t, J = 7.2 Hz), 3.17 (2H, t, J = 7.2 Hz). LC/MS: C18Hi6N4OS (M+l) 337. Single peak at both 215 nm and 254 nm in analytical HPLC traces.
Procedures in Scheme 4 were utilized to synthesize this compound. H-NMR (MeOD-d4, 400 MHz) δ 8.81 (1H, s), 8.71 (1H, d, J = 5.7 Hz), 8.57 (1H, d, J = 8.1 Hz), 7.99 (4H, m), 7.80 (1H, m), 7.61 (1H, s), 7.40 (1H, dd, J = 8.4 Hz, 1.5 Hz), 3.76 (2H, t, J = 6.7 Hz), 3.20 (2H, t, J = 6.7 Hz). LC/MS: C19Hi7N50 (M+l) 332. Single peak at both 215 nm and 254 nm in analytical HPLC traces.
Scheme 5
A solution of the indole (1.0 equiv) and CS2CO3 (1.1 equiv) in anhydrous DMF was prepared at room temperature. To this solution was then added the alkyl halide (1.1 equiv). The resulting solution was stirred vigorously at room temperature until the alkylation was complete by LC/MS. The solution was then diluted with EtOAc and washed with brine. The aqueous portion was twice extracted with additional EtOAc and the combined organic portions were dried over MgS04. Purification on Si02
(Hexane/EtOAc or CH2Cl2/MeOH + NH4OH) gave the substituted indoles. The indolyl bromide (1.0 equiv) was then combined with an arylboronate (1.30 equiv) and Na2C03
(3.0 equiv) in 20% aqueous dioxane in a microwave pressure tube at room temperature. To this solution was added PdCl2(PPh3)2 (0.10 equiv) and the solution was sparged with argon for 10 minutes. The reaction was subsequently heated in a microwave at 120 °C until the reaction was complete (-0.5-2 h). The solution was then diluted with EtOAc and washed with brine. The aqueous portion was twice extracted with EtOAc and the combined organic portions were dried over MgS04 and concentrated. Purification on Si02 (CH2Cl2/MeOH + NH4OH) gave the biaryl product. The trifluormethylketone (1.0 equiv) was then dissolved in 50% aqueous dioxane. LiOH (2.0 equiv) was then added and stirred at 100 °C in a pressure tube until hydrolysis was complete. Upon completion, the solution was quenched with HC1 (4N in dioxane) and concentrated in vacuo. The residue was then used without purification in the subsequent peptide coupling. Thus, the carboxylic acid (1.0 equiv), a primary or secondary amine (1.0 equiv) and Et3N (2.0 equiv) were combined in anhydrous DMF at room temperature. To this solution was then added HATU (1.3 equiv). The solution was then stirred until the reaction was complete by LC/MS (-1-2 h). The crude reaction mixture was then purified directly via preparatory HPLC to give the final compounds.
Example 48. l-(2-(dimethylamino)ethyl)-N-(3-methoxybenzyl)-6-(lH-pyrazol-4-yl)- -indole-3-carboxamide
Procedures in Scheme 5 were utilized to synthesize this compound. LC/MS: C24H27N502 (M+l) 418. Single peak at both 215 nm and 254 nm in analytical HPLC traces.
Example 49. l-(2-(dimethylamino)ethyl)-N-(3-methoxybenzyl)-N-methyl-6-(lH- pyrazol-4-yl)-lH-indole-3-carboxamide
Procedures in Scheme 5 were utilized to synthesize this compound. LC/MS: C25H29Ns02 (M+l) 432. Single peak at both 215 nm and 254 nm in analytical HPLC traces.
Example 50. l-(2-(dimethylamino)ethyl)-N-(3-methoxyphenethyl)-6-(lH-pyrazol-4-yl)- -indole-3-carboxamide
Procedures in Scheme 5 were utilized to synthesize this compound. 1H-NMR (MeOD-d4, 400 MHz) δ 8.08 (2H, s), 7.98 (1H, d, J = 8.3 Hz), 7.83 (1H, s), 7.78 (1H, s), 7.49 (1H, dd, J = 8.4 Hz, 1.4 Hz), 7.21 (1H, t, J = 8.2 Hz), 6.87 (2H, m), 6.78 (1H, m), 4.70 (2H, t, J = 6.9 Hz), 3.76 (3H, s), 3.66 (4H, m), 2.97 (6H, s), 2.93 (2H, t, J = 7.3 Hz). LC/MS: C25H29N5O2 (M+1) 432. Single peak at both 215 nm and 254 nm in analytical HPLC traces.
Example 51. l-(3-hydroxypropyl)-N-(3-methoxybenzyl)-6-(lH-pyrazol-4-yl)-lH-
Procedures in Scheme 5 were utilized to synthesize this compound. 1H-NMR (MeOD-d4, 400 MHz) δ 8.11 (1H, d, J = 8.3 Hz), 8.01 (2H, s), 7.87 (1H, s), 7.71 (1H, s), 7.44 (1H, dd, J = 8.3 Hz, 1.4 Hz), 7.24 (1H, t, J = 8.1 Hz), 6.94 (2H, m), 6.81 (1H, d, J = 8.3 Hz), 4.57 (2H, s), 4.36 (2H, m), 3.78 (3H, s), 3.57 (2H, t, J = 6.0 Hz), 2.08 (2H, m). LC/MS: C23H24N403 (M+1) 405. Single peak at both 215 nm and 254 nm in analytical HPLC traces.
Example 52. l-(3-hydroxypropyl)-N-(3-methoxybenzyl)-N-methyl-6-(lH-pyrazol-4-yl)- -indole-3-carboxamide
Procedures in Scheme 5 were utilized to synthesize this compound. LC/MS: C24H26N403 (M+1) 419. Single peak at both 215 nm and 254 nm in analytical HPLC traces.
Example 53. l-(3-hydroxypropyl)-N-(3-methoxyphenethyl)-6-(lH-pyrazol-4-yl)-lH- indole-3-carboxamide
Procedures in Scheme 5 were utilized to synthesize this compound. LC/MS: C24H26N4O3 (M+1) 419. Single peak at both 215 nm and 254 nm in analytical HPLC traces.
Example 54. N-(4-fluorophenyl)- l-(3-hydroxypropyl)-6-(lH-pyrazol-4-yl)- lH-indole-3- carboxamide
Procedures in Scheme 5 were utilized to synthesize this compound. LC/MS:
C2iH19FN402 (M+1) 379. Single peak at both 215 nm and 254 nm in analytical HPLC traces.
Example 55. l-(3-hydroxypropyl)-6-(lH-pyrazol-4-yl)-N-(thiophen-2-ylmethyl)-lH- indole-3-carboxamide
Procedures in Scheme 5 were utilized to synthesize this compound. LC/MS:
C20H20N4O2S (M+1) 381. Single peak at both 215 nm and 254 nm in analytical HPLC traces.
Example 56. 1 - (3 -hydroxypropyl)-N- (2-methoxybenzyl)-6- ( 1 H-pyrazol-4-yl)- 1 H-
Procedures in Scheme 5 were utilized to synthesize this compound. LC/MS: C23H24N4O3 (M+l) 405. Single peak at both 215 nm and 254 nm in analytical HPLC traces.
Example 57. 1 - (3 -hydroxypropyl)-N- (4-methoxybenzyl)-6- ( 1 H-pyrazol-4-yl)- 1 H-
Procedures in Scheme 5 were utilized to synthesize this compound. LC/MS: C23H24N4O3 (M+l) 405. Single peak at both 215 nm and 254 nm in analytical HPLC traces.
Example 58. l-(3-hydroxypropyl)-6-(lH-pyrazol-4-yl)-N-(3-(trifluoromethyl)benzyl)- lH-indole-3-carboxamide
Procedures in Scheme 5 were utilized to synthesize this compound. LC/MS:
C23H21F3N4O2 (M+l) 443. Single peak at 254 nm in analytical HPLC trace.
Example 59. l-(3-hydroxypropyl)-6-(lH-pyrazol-4-yl)-N-(3- (trifluoromethyl)phenethyl)- 1 H-indole-3-carboxamide
Procedures in Scheme 5 were utilized to synthesize this compound. LC/MS:
C24H23F3N4O2 (M+l) 457. Single peak at 254 nm in analytical HPLC trace.
Example 60. N-(3-fluorophenethyl)- l-(3-hydroxypropyl)-6-(lH-pyrazol-4-yl)- 1H-
C23H23FN4O2 (M+1) 407. Single peak at both 215 nm and 254 nm in analytical HPLC traces.
Example 61. N-(3-methoxybenzyl)-l-methyl-6-(lH-pyrazol-4-yl)-lH-indole-3- carboxamide
Procedures in Scheme 5 were utilized to synthesize this compound. LC/MS: C21H20N4O2 (M+1) 163. Single peak at both 215 nm and 254 nm in analytical HPLC traces.
Example 62. N-(3-methoxybenzyl)-N,l-dimethyl-6-(lH-pyrazol-4-yl)-lH-indole-3- carboxamide
Procedures in Scheme 5 were utilized to synthesize this compound. 1H-NMR (MeOD-d4, 400 MHz) δ 8.14 (2H, s), 7.81 (1H, d, J = 8.4 Hz), 7.69 (1H, s), 7.56 (1H, br), 7.46 (1H, dd, J = 8.3 Hz, 1.5 Hz), 7.28 (1H, dd, J = 7.6 Hz, 8.6 Hz), 6.87 (3H, m), 4.81 (2H, s), 3.87 (3H, s), 3.78 (3H, s), 3.12 (3H, s). LC/MS: C22H22N4O2 (M+1) 375. Single peak at both 215 nm and 254 nm in analytical HPLC traces.
Example 63. N-(3-methoxyphenethyl)-l-methyl-6-(lH-pyrazol-4-yl)-lH-indole-3- carboxamide
Procedures in Scheme 5 were utilized to synthesize this compound. 1H-NMR (MeOD-d4, 400 MHz) δ 8.10 (2H, s), 8.01 (1H, d, J = 8.3 Hz), 7.72 (1H, s), 7.66 (1H, s), 7.44 (1H, dd, J = 8.3 Hz, 1.5 Hz), 7.21 (1H, t, J = 8.1 Hz), 6.86 (2H, m), 6.78 (1H, m), 3.88 (3H, s), 3.76 (3H, s), 3.61 (2H, m), 2.92 (2H, t, J = 7.4 Hz). LC/MS: C22H22N4O2 (M+1) 375. Single peak at both 215 nm and 254 nm in analytical HPLC traces.
Example 64. N-(2-(dimethylamino)ethyl)-N-(3-methoxybenzyl)-l-methyl-6-(lH- pyrazol-4-yl)-lH-indole-3-carboxamide
Procedures in Scheme 5 were utilized to synthesize this compound. 1H-NMR (MeOD-d4, 400 MHz) δ 8.04 (2H, s), 7.94 (1H, d, J = 8.4 Hz), 7.68 (1H, s), 7.48 (2H, m), 7.35 (1H, t, J = 7.8 Hz), 6.91 (2H, m), 6.84 (1H, s), 4.96 (2H, s), 3.85 (2H, t, J = 6.0 Hz), 3.83 (3H, s), 3.78 (3H, s), 3.35 (2H, m), 2.98 (6H,s). LC/MS: C25H29N5O2 (M+1) 432. Single peak at both 215 nm and 254 nm in analytical HPLC traces.
Example 65. N-(3-(dimethylamino)propyl)-N-(3-methoxybenzyl)-l-methyl-6-(lH- pyrazol-4-yl)- lH-indole-3-carboxamide
Procedures in Scheme 5 were utilized to synthesize this compound. 1H-NMR (MeOD-d4, 400 MHz) δ 8.05 (2H, s), 7.86 (1H, d, J = 8.3 Hz), 7.68 (1H, s), 7.47 (2H, m), 7.33 (1H, t, J = 7.9 Hz), 6.89 (2H, dd, J = 8.1 Hz, 2.2 Hz), 6.84 (1H, s), 4.92 (2H, s), 3.83 (3H, s), 3.77 (3H, s), 3.63 (2H, t, J = 6.8 Hz), 3.16 (2H, m), 2.92 (6H, s), 2.05 (2H, q, J = 7.1 Hz). LC/MS: C26H31N5O2 (M+1) 446. Single peak at both 215 nm and 254 nm in analytical HPLC traces.
Example 66. N- (3-methoxybenzyl)- 1 -methyl-N- (3-morpholinopropyl)-6- ( 1 H-pyrazol-4- - 1 H-indole- 3 -carboxamide
Procedures in Scheme 5 were utilized to synthesize this compound. LC/MS: C28H33N5O3 (M+l) 488. Minor impurity observed in analytical HPLC traces at both 215 nm and 254 nm.
Example 67. N-(3-methoxybenzyl)-l-methyl-N-(3-(4-methylpiperazin-l-yl)propyl)-6- -pyrazol-4-yl)-lH-indole-3-carboxamide
Procedures in Scheme 5 were utilized to synthesize this compound. LC/MS: C29H36N6O2 (M+l) 501. Single peak at both 215 nm and 254 nm in analytical HPLC traces.
Example 68. l-benzyl-N-(3-methoxybenzyl)-6-(lH-pyrazol-4-yl)-lH-indole-3- carboxamide
Procedures in Scheme 5 were utilized to synthesize this compound. LC/MS: C27H24N4O2 (M+l) 437. Single peak at both 215 nm and 254 nm in analytical HPLC traces.
Example 69. N-(3-methoxybenzyl)-6-(lH-pyrazol-4-yl)-l-(2-(pyrrolidin-l-yl)ethyl)-lH- indole-3-carboxamide
Procedures in Scheme 5 were utilized to synthesize this compound. LC/MS: C26H29N5O2 (M+l) 444. Single peak at both 215 nm and 254 nm in analytical HPLC traces.
Example 70. N-(3-methoxybenzyl)-N-methyl-6-( lH-pyrazol-4-yl)- 1 -(2-(pyrrolidin- 1- yl)ethyl)-lH-indole-3-carboxamide
Procedures in Scheme 5 were utilized to synthesize this compound. 1H-NMR (MeOD-d4, 400 MHz) δ 8.15 (2H, s), 7.80 (2H, m), 7.68 (1H, br), 7.52 (1H, dd, J = 8.3 Hz, 1.4 Hz), 7.28 (1H, t, J = 8.0 Hz), 6.86 (3H, m), 4.80 (2H, s), 4.67 (2H, m), 3.78 (3H, s), 3.75 (2H, t, J = 6.6 Hz), 3.61 (2H, br), 3.11 (5H, m), 2.11 (2H, br), 1.97 (2H, br). LC/MS:
C27H31N5O2 (M+1) 458. Single peak at both 215 nm and 254 nm in analytical HPLC traces.
Example 71. N-(2-(dimethylamino)ethyl)-N-(3-methoxybenzyl)-6-(lH-pyrazol-4-yl)-l- (2- (pyrrolidin- 1 - yl)ethyl) - 1 H-indole- 3 -carb oxamide
Procedures in Scheme 5 were utilized to synthesize this compound. LC/MS: C30H38N6O2 (M+1) 515. Single peak at both 215 nm and 254 nm in analytical HPLC traces.
Example 72. (R)-N-(l-(3-methoxyphenyl)ethyl)-6-(lH-pyrazol-4-yl)-l-(2-(pyrrolidin-l- yl)ethyl)-lH-indole-3-carboxamide
Procedures in Scheme 5 were utilized to synthesize this compound. 1H-NMR (MeOD-d4, 400 MHz) δ 8.15 (2H, s), 8.09 (1H, d, J = 8.3 Hz), 7.95 (1H, s), 7.77 (1H, s), 7.50 (1H, dd, J = 8.4 Hz, 1.4 Hz), 7.25 (1H, m), 7.01 (2H, m), 6.80 (1H, ddd, J = 8.3 Hz, 2.4 Hz, 1.0 Hz), 5.24 (1H, q, J = 7.0 Hz), 4.66 (2H, t, J = 6.5 Hz), 3.79 (3H, s), 3.77 (2H, t, J = 6.6 Hz), 3.64 (2H, br), 3.14 (2H, br), 2.14 (2H, br), 1.98 (2H, br), 1.58 (3H, d, J = 7.0 Hz). LC/MS: C27H31N502 (M+1) 458. Single peak at both 215 nm and 254 nm in analytical HPLC traces.
Example 73. (S)-N-(l-(3-methoxyphenyl)ethyl)-6-(lH-pyrazol-4-yl)-l-(2-(pyrrolidin-l- yl)ethyl)-lH-indole-3-carboxamide
Procedures in Scheme 5 were utilized to synthesize this compound. LC/MS: C27H31N502 (M+l) 458. Single peak at both 215 nm and 254 nm in analytical HPLC traces.
Example 74. l-(3-(dimethylamino)propyl)-N-(3-methoxybenzyl)-6-(lH-pyrazol-4-yl)- lH-indole-3-carboxamide
Procedures in Scheme 5 were utilized to synthesize this compound. LC/MS: C25H29N5O2 (M+l) 432. Single peak at both 215 nm and 254 nm in analytical HPLC traces.
Scheme 6
A microwave pressure vial was charged with finely ground K3P04 (2.1 equiv), the indole (1.0 equiv) and anhydrous dioxane. 1,2-trans-cyclohexyldiamine (0.2 equiv) and the aryl iodide (1.0 equiv) were then added. Cul (0.1 equiv) was lastly added and the sealed vial was sparged with argon for 10 minutes. The solution was then heated in a microwave reactor at 120 °C until the conversion was complete (~1 h). Upon completion the solution was diluted with CH2CI2 and washed with an aqueous 1M HC1 solution. The aqueous portion was twice extracted with additional CH2CI2 and the combined organic portions were dried over Na2S04. Purification on S1O2 (Hexane/EtOAc) gave the desired N-arylated indole. The indolyl bromide (1.0 equiv) was then combined with an arylboronate (1.30 equiv) and Na2C03 (3.0 equiv) in 20% aqueous dioxane in a
microwave pressure tube at room temperature. To this solution was added PdCl2(PPh3)2 (0.10 equiv) and the solution was sparged with argon for 10 minutes. The reaction was subsequently heated in a microwave reactor at 120 °C until the reaction was complete (-0.5-2 h). Upon completion, the solution was diluted with CH2C12 and washed with brine. The aqueous portion was twice extracted with additional CH2C12 and the combined organic portions were dried over Na2S04. Purification on Si02
(CH2Cl2/MeOH + NH4OH) gave the product.
Example 75. N-(3-methoxybenzyl)-l-phenyl-6-(lH-pyrazol-4-yl)-lH-indole-3- carboxamide
Procedures in Scheme 6 were utilized to synthesize this compound. 1H-NMR (CDC13, 400 MHz) δ 8.05 (1H, d, J = 8.4 Hz), 7.85 (1H, s), 7.83 (2H, s), 7.62 (1H, d, J = 2.1 Hz), 7.56 (3H, m), 7.50 (2H, m), 7.45 (2H, m), 7.29 (1H, d, J = 7.9 Hz), 7.00 (1H, d, J = 7.6 Hz), 6.96 (1H, s), 6.84 (1H, dd, J = 8.2 Hz, 0.7 Hz), 6.30 (1H, t, J = 5.5 Hz), 4.70 (2H, d, J = 5.6 Hz), 3.80 (3H, s). LC/MS: C26H22N402 (M+l) 423. Single peak at both 215 nm and 254 nm in analytical HPLC traces.
Example 76. N-(3-methoxybenzyl)-l-(3-methoxyphenyl)-6-(lH-pyrazol-4-yl)-lH-
Procedures in Scheme 6 were utilized to synthesize this compound. 1H-NMR (CDCI3
400 MHz) δ 8.05 (1H, d, J = 8.3 Hz), 7.85 (2H, s), 7.84 (1H, s), 7.63 (1H, m), 7.46 (2H, m), 7.29 (2H, m), 7.11 (1H, m), 7.04 (1H, t, J = 2.1 Hz), 7.01 (2H, m), 6.97 (1H, s), 6.85 (1H, dd, J = 8.3 Hz, 1.6 Hz), 6.21 (1H, m), 4.72 (2H, d, J = 5.7 Hz), 3.88 (3H, s), 3.82
(3H, s). LC/MS: C27H24N4O3 (M+l) 453. Single peak at both 215 nm and 254 nm in analytical HPLC traces.
Example 77. N-(3-methoxybenzyl)-6-(lH-pyrazol-4-yl)-l-(3-(trifluoromethyl)phenyl)- -indole-3-carboxamide
Procedures in Scheme 6 were utilized to synthesize this compound. 1H-NMR (CDCI3, 400 MHz) δ 10.60 (1H, br), 8.07 (1H, d, J = 8.4 Hz), 7.86 (1H, s), 7.84 (2H, s), 7.79 (1H, s), 7.72 (3H, m), 7.55 (1H, s), 7.47 (1H, dd, J = 8.3 Hz, 1.5 Hz), 7.29 (1H, t, J = 7.9 Hz), 7.0 (1H, d, J = 7.6 Hz), 6.96 (1H, s), 6.84 (1H, dd, J = 8.2 Hz, 2.5 Hz), 6.31 (1H, t, J = 5.6 Hz), 4.70 (2H, d, J = 5.6 Hz), 3.81 (3H, s). LC/MS: C27H21F3N402 (M+l) 491. Single peak at both 215 nm and 254 nm in analytical HPLC traces.
Scheme 7
A solution of 6-bromo-indazole-3-carboxylic acid (1.0 equiv), an amine(1.0 equiv) and Et3N (2.0 equiv) was prepared in anhydrous DMF at room temperature. To this solution was then added HATU (1.3 equiv). The solution was then stirred until the reaction was complete by LC/MS (-1-2 h). Upon completion, the solution was diluted with EtOAc and washed with H20. The aqueous portion was extracted with additional EtOAc and the combined organic portions were dried over MgS04. Purification on S1O2
(Hexane/EtOAc) gave the intermediate bromo-indazole carboxamide. The aryl bromide (1.0 equiv) was then combined with an arylboronate species (1.30 equiv) and Na2C03 (3.0 equiv) in 20% aqueous dioxane in a microwave pressure tube at room temperature. To this solution was added PdCl2(PPh3)2 (0.10 equiv) and the solution was sparged with argon for 10 minutes. The reaction was subsequently heated in a microwave at 120 °C until the reaction was complete (-0.5-2 h). Alternatively, the aryl bromide (1.0 equiv)
was combined with bis(pinacolato)boron (2.5 equiv), KOAc (5.0 equiv) and PdCl2(dppf) (0.1 equiv) under streaming argon in a microwave pressure tube. Dioxane was then added and the solution was sparged with argon for 10 minutes. The solution was then heated to 100 °C in a microwave until the conversion was complete (-60 min). To this solution was then added the arylchloride (1.0 equiv), Na2C03 (3.0 equiv) and
PdCl2(PPh3)2 (0.1 equiv) under streaming argon. The solution was sparged with argon for 10 minutes and then heated at 120 °C in a microwave until complete (-30 min). Upon completion, the solution was diluted with EtOAc and washed with brine. The aqueous portion was twice extracted with additional EtOAc and the combined organic portions were dried over Na2S04. Purification on Si02 (CH2Cl2/MeOH + NH OH) gave the shown products.
Procedures in Scheme 7 were utilized to synthesize this compound. LC/MS: C21H18N402 (M+1) 359. Single peak at both 215 nm and 254 nm in analytical HPLC traces.
Procedures in Scheme 7 were utilized to synthesize this compound. H-NMR (MeOD, 400 MHz) δ 8.41 (1H, s), 8.00 (2H, br), 7.69 (1H, dd, J = 8.7 Hz, 1.6 Hz), 7.59 (1H, dd, J = 8.7 Hz, 0.8 Hz), 7.24 (1H, t, J = 8.2 Hz), 6.98 (2H, m), 6.82 (1H, ddd, J = 8.3 Hz, 2.5 Hz, 0.9 Hz), 4.62 (2H, s), 3.31 (3H, s). LC/MS: Ci9H17N502 (M+1) 348. Single peak at both 215 nm and 254 nm in analytical HPLC traces.
Procedures in Scheme 7 were utilized to synthesize this compound. LC/MS: CioHigNeOi (M+l) 375. Single peak at both 215 nm and 254 nm in analytical HPLC traces.
dioxane
ii) ArCI, Pd(PPh3)4, K2C03,
H20, EtOH, toluene
Scheme 8
Ethyl 6-bromoimidazor 1 ,2-alpyridine-2-carboxylate
The title compound was prepared as described in Ito, et al. WO2006088246. 6-Bromoimidazor 1 ,2-alpyridine-2-carboxylic acid
To a solution of ethyl 6-bromoimidazo[l,2-a]pyridine-2-carboxylate (200 mg, 0.74 mmol) THF (2 mL) and methanol (2 mL) was added LiOH (42 mg 0.98 mmol) in water (2 mL) and stirred at 60 °C overnight. After removal of volatile solvent by rotary evaporation, the mixture was diluted with water and acidified to pH 4 with an aqueous solution of IN HC1. The resulting precipitate was collected by filtration, washed with water, and dried under vacuum to afford the title compound (0.125 g, 70%). This intermediate was used in subsequent reactions without further purification. LC-MS: single peak at 254 nm, MH+ calcd. for CgHeBrNiCh: 241, obtained: 241.
Example 81. N-(3-methoxybenzyl)-6-(lH-pyrazol-4-yl)imidazo[l,2-a]pyridine-2- carboxamide
Step A. 6-Bromo-N-(3-methoxybenzyl)imidazor 1 ,2-alpyridine-2-carboxamide
To a solution of 6-bromoimidazo[l,2-a]pyridine-2-carboxylic acid (100 mg, 0.41 mmol) in DMF (0.5 mL) was added 3-methoxybenzylamine (75 mg, 0.55 mmol) and HATU (190 mg, 0.50 mmol). The resulting mixture was stirred at room temperature overnight. After removal of solvent by rotary evaporation, the residue was dissolved in ethyl acetate (15 mL) and washed with a saturated aqueous Na2C03 solution (2 x 10 mL), and brine (10 mL), dried over Na2S04, and filtered. The solvent was removed in vacuo and the crude amide product was purified by flash column chromatography (10-65% ethyl acetate in hexanes) to afford the title compound (119 mg, 79%). LC-MS: single peak at 254 nm, MH+ calcd. for C16H15BrN302: 360, obtained: 360.
Step B. N-(3-methoxybenzyl)-6-(lH-pyrazol-4-yl)imidazorL2-alpyridine-2- carboxamide
To a solution of the bromide obtained in Step A (44 mg, 0.12 mmol) in a 3:2 mixture of ethanol: toluene (2 mL) was added lH-pyrazole-4-boronic acid pinacol ester (35 mg, 0.18 mmol), K2C03 (2 M aqueous solution, 0.18 mL), and
tetrakis(triphenylphosphine)palladium (0) (7 mg, 0.006 mmol). The reaction mixture was degassed, purged with argon, and heated to 140 °C for 1 h by microwave irradiation. After cooling to room temperature, the mixture was treated with an aqueous 10% solution of TFA (1 mL) and the solvent was removed by rotary evaporation. The residue was purified by preparative HPLC to afford the title compound (13 mg, 23%). 1H-NMR
(DMSO-d6, 400 MHz) δ 9.04 (br s, 1 H), 8.95 (s, 1 H), 8.35 (s, 1 H), 8.13 (s, 2 H), 7.78 (d, J = 9.6 Hz, 1 H), 7.65 (d, J = 9.2 Hz, 1 H), 7.24 (t, J = 8.0 Hz, 1 H), 6.91 (m, 2 H), 6.81 (m, 1 H), 4.46 (d, J = 6.4 Hz, 2 H), 3.73 (s, 3 H). LC-MS: single peak at 254 nm, MH+ calcd. for C19H18N502: 348, obtained: 348.
Example 82. 6-(2-aminopyrimidin-4-yl)-N-(3-methoxybenzyl)imidazo[l,2-a]pyridine-2- carboxamide
To a solution of the bromide obtained in Scheme 8, Step A (75 mg, 0.21 mmol) in dioxane (1.5 mL) was added bis(pinacolato)diboron (133 mg, 0.52 mmol), potassium
acetate (102 mg, 1.04 mmol), and PdCl2(dppf) (17 mg, 0.02 mmol). The reaction mixture was degassed, purged with argon, and heated to 100 °C for 1.5 h by microwave irradiation. After the reaction was determined to be complete by LC-MS, the mixture was diluted with ethyl acetate (25 mL) and washed with water (2 x 10 mL) and brine (10 mL). The organic layer was dried over Na2S04, filtered, and concentrated in vacuo to yield the crude aryl boronic ester. The residue was dissolved in a 3:2 mixture of ethanol: toluene (2.5 mL) and to this mixture was added 2-amino-4-chloro-pyrimidine (32 mg, 0.25 mmol), K2C03 (2 M aqueous solution, 0.3 mL), and
tetrakis(triphenylphosphine)palladium (0) (12 mg, 0.01 equiv). The reaction mixture was degassed, purged with argon, and heated to 140 °C for 1 h by microwave irradiation.
After cooling to room temperature, the mixture was treated with an aqueous 10% solution of TFA (1 mL) and the solvent was removed by rotary evaporation. The residue was purified by preparative HPLC to afford the desired final product (29 mg, 28%). 1H-NMR (DMSO-d6, 400 MHz) δ 9.41 (s, 1 H), 9.02 (t, J = 6.4 Hz, 1 H), 8.51 (s, 1 H), 8.40 (d, J = 5.2 Hz, 1 H), 8.03 (dd, J = 9.2, 1.6 Hz, 1 H), 7.73 (d, J = 9.6 Hz, 1 H), 7.23 (m, 2 H), 7.10 (br s, 2 H), 6.91 (m, 2 H), 6.81 (m, 1 H), 4.46 (d, J = 6.0 Hz, 2 H), 3.73 (s, 3 H). LC-MS: single peak at 254 nm, MH+ calcd. for C2oH19N602: 375, obtained: 375.
Example 83. 6-(2-aminopyrimidin-4-yl)-N-(3-fluorobenzyl)imidazo[ 1 ,2-a]pyridine-2- carboxamide
The title compound was prepared according to the procedure described in Scheme
8 (33 mg, 34%). 1H NMR (DMSO-d6, 400 MHz) δ 9.42 (s, 1 H), 9.14 (t, J = 6.0 Hz, 1 H), 8.51 (s, 1 H), 8.41 (d, J = 5.2 Hz, 1 H), 8.04 (dd, J = 9.6, 1.6 Hz, 1 H), 7.73 (d, J = 9.6 Hz, 1 H), 7.37 (dt, J = 8.0, 6.4 Hz, 1 H), 7.25 (d, J = 5.6 Hz, 1 H), 7.18 (d, J = 7.6 Hz, 1 H), 7.15 (br s, 2 H), 7.14 (d, J = 10.0, 1 H), 7.06 (td, J = 8.4, 2.4 Hz, 1 H), 4.50 (d, J = 6.4 Hz, 2 H). LC-MS: single peak at 254 nm, MH+ calcd. for C19H16FN60: 363, obtained: 363.
The title compound was prepared according to the procedure described in Scheme
8 (9 mg, 16%). 1H NMR (DMSO-d6, 400 MHz) δ 9.18 (t, J = 6.0 Hz, 1 H), 8.93 (s, 1 H), 8.35 (s, 1 H), 8.13 (s, 2 H), 7.76 (dd, J = 9.6, 1.6 Hz, 1 H), 7.65 (d, J = 9.6 Hz, 1 H), 7.10 (tt, J = 9.2, 2.4 Hz, 1 H), 7.04 (m, 2 H), 4.49 (d, J = 6.4 Hz, 2 H). LC-MS: single peak at 254 nm, MH+ calcd. for C18Hi4F2N50: 354, obtained: 354.
Example 85. 6-(2-aminopyrimidin-4-yl)-N-(3,5-difluorobenzyl)imidazo[l,2-a]pyridine- -carboxamide
The title compound was prepared according to the procedure described in Scheme
8 (22 mg, 38%). 1H NMR (DMSO-d6, 400 MHz) δ 9.38 (s, 1 H), 9.17 (t, J = 6.4 Hz, 1 H), 8.51 (s, 1 H), 8.39 (d, J = 5.2 Hz, 1 H), 8.02 (dd, J = 9.6, 1.6 Hz, 1 H), 7.72 (d, J = 9.6 Hz, 1 H), 7.21 (d, J = 5.2 Hz, 1 H), 7.09 (tt, J = 9.2, 2.4 Hz, 1 H), 7.02 (m, 4 H), 4.49 (d, J = 6.4 Hz, 2 H). LC-MS: single peak at 254 nm, MH+ calcd. for C19Hi5F2N60: 381, obtained: 381.
The title compound was prepared according to the procedure described in Scheme
8 (13 mg, 35%). 1H NMR (DMSO-d6, 400 MHz) δ 8.95 (s, 1 H), 8.55 (s, 1 H), 8.32 (s, 1 H), 8.13 (s, 2 H), 7.78 (d, J = 9.2 Hz, 1 H), 7.64 (d, J = 9.2 Hz, 1 H), 7.21 (t, J = 8.0 Hz, 1 H), 6.82 (m, 2 H), 6.77 (dd, J = 8.0, 2.4 Hz, 1 H), 3.73 (s, 3 H), 3.54 (q, J = 6.8 Hz, 2 H), 2.85 (t, J = 6.8 Hz, 2 H). LC-MS: single peak at 254 nm, MH+ calcd. for C2oH20N502: 362, obtained: 362.
Example 87. 6-(2-aminopyrimidin-4-yl)-N-(3-methoxyphenethyl)imidazo[ 1 ,2- a]pyridine-2-carboxamide.
The title compound was prepared according to the procedure described in Scheme 8 (24 mg, 35%). 1H NMR (DMSO-d6, 400 MHz) δ 9.40 (s, 1 H), 8.50 (t, J = 6.4 Hz, 1 H), 8.47 (s, 1 H), 8.40 (d, J = 5.6 Hz, 1 H), 8.03 (dd, J = 9.2, 2.0 Hz, 1 H), 7.71 (d, J = 9.6 Hz, 1 H), 7.23 (d, J = 5.6 Hz, 1 H), 7.21 (t, J = 8.4 Hz, 1 H), 7.08 (br s, 2 H), 6.82 (m, 2 H), 6.77 (dd, J = 7.6, 2.0 Hz, 1 H), 3.73 (s, 3 H), 3.54 (q, J = 6.8 Hz, 2 H), 2.85 (t, J = 6.8 Hz, 2 H). LC-MS: single peak at 254 nm, MH+ calcd. for C2iH21N602: 389, obtained: 389.
Example 88. 6-(2-aminopyrimidin-4-yl)-N-(2-(dimethylamino)ethyl)-N-(3- methoxybenzyl)imidazo[l,2-a]pyridine-2-carboxamide
The title compound was prepared according to the procedure described in Scheme 8 (16 mg, 26%). LC-MS: single peak at 254 nm, MH+ calcd. for C24H28N902: 446, obtained: 446.
Example 89. N-(2-(dimethylamino)ethyl)-N-(3-methoxybenzyl)-6-(lH-pyrazol-4- yl)imidazo[ 1 ,2-a]pyridine-2-carboxamide
The title compound was prepared according to the procedure described in Scheme
8 (15 mg, 38%). 1H NMR (DMSO-d6, 400 MHz) δ 13.05 (br s, 1 H), 8.87 (t, J = 1.2 Hz, 1 H), 8.29 (s, 1 H), 8.25 (s, 1 H), 7.94 (br s, 1 H), 7.62 (m, 2 H), 7.26 (dt, J = 8.8, 8.0 Hz, 1 H), 6.87 (m, 3 H), 5.40 (s, 1 H), 4.71 (s, 1 H), 4.02 (m, 1 H), 3.73 (d, J = 12.8 Hz, 3 H),
3.43 (m, 1 H), 2.22 (br s, 3 H), 2.16 (m, 3 H). LC-MS: single peak at 254 nm, MH+ calcd. for C23H27N6O2: 419, obtained: 419.
Example 90. N-(2-(dimethylamino)ethyl)-N-(3-methoxybenzyl)-6-(pyridin-4- yl)imidazo[ 1 ,2-a]pyridine-2-carboxamide
The title compound was prepared according to the procedure described in Scheme 8 (30 mg, 63%). 1H-NMR (DMSO-d6, 400 MHz) δ 13.06 (s, 1 H), 12.29 (s, 1 H), 8.40 (br s, 1 H), 8.30 (d, J = 2.0 Hz, 1 H), 8.09 (m, 2 H), 7.83 (s, 1 H), 7.66 (d, J = 8.4 Hz, 1 H), 7.28 (td, J = 7.6, 2.0 Hz, 1 H), 7.23 (t, J = 7.6 Hz, 1 H), 6.91 (d, J = 8.0 Hz, 1 H), 5.23 (s, 2 H). LC-MS: single peak at 254 nm, MH+ calcd. for C25H28N5O2: 430, obtained: 430.
ii) ArCI, Pd(PPh3)4, K2C03,
H20, EtOH, toluene
Scheme 9
To a solution of ethyl formylchloroacetate (prepared according to the procedure described by Plouvier et al. Heterocycles 1991, 32, 693) (2.41 g, 16.0 mmol) in ethanol (60 mL) was added 5-bromopyridin-2-amine (2.77 g, 16.0 mmol), and the mixture was
heated to reflux overnight. After cooling, the solvent was removed by rotary evaporation, and the residue was treated with CHCI3 (50 mL) and a saturated solution of aqueous NaHC03. The layers were separated and the aqueous layer was further extracted with CHC13 (2 x 30 mL). The combined organic layer was dried over Na2S04, filtered, and concentrated to dryness. Purification by flash column chromatography (20-35% ethyl acetate in hexane) gave the title compound (0.9 g, 21%). 1H-NMR (DMSO-d6, 400 MHz) δ 9.61 (s, 1 H), 8.32 (s, 1 H), 8.00 (d, J = 9.6 Hz, 1 H), 7.74 (d, J = 9.6 Hz, 1 H), 4.48 (q, J = 7.2 Hz, 2 H), 1.45 (t, J = 7.2 Hz, 3 H). LC-MS: single peak at 254 nm, MH+ calcd. for C10H10BrN2O2: 269, obtained: 269.
To a solution of ethyl 6-bromoimidazo[l,2-a]pyridine-3-carboxylate (180 mg, 0.67 mmol) THF (2 mL) and methanol (2 mL) was added LiOH (56 mg 1.34 mmol) in water (2 mL) and stirred at 60 °C overnight. After removal of volatile solvent by rotary evaporation, the mixture was diluted with water and acidified to pH 4 with an aqueous solution of IN HC1. The resulting precipitate was collected by filtration, washed with water, and dried under vacuum to afford the title compound (108 mg, 67%). This intermediate was used in subsequent reactions without further purification. LC-MS: single peak at 254 nm, MH+ calcd. for C8H6BrN202: 241, obtained: 241.
Step A. 6-bromo-N-(3-methoxybenzyl)imidazorL2-alpyridine-3-carboxamide
To a solution of 6-bromoimidazo[l,2-a]pyridine-3-carboxylic acid (50 mg, 0.21 mmol) in DMF (0.5 mL) was added 3-methoxybenzylamine (37 mg, 0.27 mmol) and HATU (95 mg, 0.25 mmol). The resulting mixture was stirred at room temperature overnight. After removal of solvent by rotary evaporation, the residue was dissolved in ethyl acetate (15
mL) and washed with a saturated aqueous Na2C03 solution (2 x 10 mL), and brine (10 mL), dried over Na2S04, and filtered. The solvent was removed in vacuo and the crude amide product was purified by flash chromatography on silica gel to afford the title compound (52 mg, 70%). LC-MS: single peak at 254 nm, MH+ calcd. for C16H15BrN302: 360, obtained: 360.
Step B. N-(3-methoxybenzyl)-6-(lH-pyrazol-4-yl)imidazorL2-alpyridine-3- carboxamide
The title compound was prepared according to the procedure described in Scheme
9, Step B (13 mg, 23%). 1H-NMR (DMSO-d6, 400 MHz) δ 9.75 (s, 1 H), 9.22 (t, J = 6.0 Hz, 1 H), 8.56 (s, 1 H), 8.16 (s, 2 H), 8.00 (d, J = 9.6 Hz, 1 H), 7.89 (d, J = 9.2 Hz, 1 H), 7.27 (t, J = 7.2 Hz, 1 H), 7.27 (t, J = 7.2 Hz, 1 H), 6.95 (m, 2 H), 6.84 (m, 1 H), 4.53 (d, J = 6.0 Hz, 2 H), 3.74 (s, 3 H). LC-MS: single peak at 254 nm, MH+ calcd. for
C19Hi8N502: 348, obtained: 348.
Example 92. N-(2-(dimethylamino)ethyl)-N-(3-methoxybenzyl)-6-(lH-pyrazol-4- yl)imidazo[ 1 ,2-a]pyridine-3-carboxamide
The title compound was prepared according to the procedure described in Scheme
9 (9 mg, 44%). LC-MS: single peak at 254 nm, MH+ calcd. for C23H27N602: 419, obtained: 419.
To a solution of ethyl 2-chloroacetoacetate (1.64 g, 10.0 mmol) in ethanol (60 mL) was added 5-bromopyridin-2-amine (1.73 g, 10.0 mmol), and the mixture was heated to reflux overnight. After cooling, the solvent was removed by rotary evaporation, and the residue was treated with CHC13 (50 mL) and a saturated solution of aqueous NaHC03. The layers were separated and the aqueous layer was further extracted with CHC13 (2 x 30 mL). The combined organic layer was dried over Na2S04, filtered, and
concentrated to dryness. Purification by flash column chromatography (15-40% ethyl acetate in hexane) gave the title compound (0.59 g, 21%). LC-MS: single peak at 254 nm, MH+ calcd. for CuHi2BrN202: 283, obtained: 283.
To a solution of ethyl 6-bromoimidazo[l,2-a]pyridine-3-carboxylate (140 mg, 0.49 mmol) THF (2 mL) and methanol (2 mL) was added LiOH (42 mg 0.99 mmol) in water (2 mL) and stirred at 60 °C overnight. After removal of volatile solvent by rotary evaporation, the mixture was diluted with water and acidified to pH 4 with an aqueous solution of IN HCl. The resulting precipitate was collected by filtration, washed with water, and dried under vacuum to afford the title compound (93 mg, 74%). This intermediate was used in subsequent reactions without further purification. LC-MS: single peak at 254 nm, MH+ calcd. for C9H8BrN202: 255, obtained: 255.
The title compound was prepared according to the procedure described in Scheme 9 (30 mg, 46%). 1H-NMR (DMSO-d6, 400 MHz) δ 9.23 (s, 1 H), 8.84 (t, J = 5.6 Hz, 1 H), 8.18 (s, 2 H), 8.08 (d, J = 9.2 Hz, 1 H), 7.87 (d, J = 9.2 Hz, 1 H), 7.28 (t, J = 8.0 Hz, 1 H), 6.98 (m, 2 H), 6.85 (m, 1 H), 4.56 (d, J = 6.0 Hz, 2 H), 3.75 (s, 3 H), 2.66 (s, 3 H). LC-MS: single peak at 254 nm, MH+ calcd. for C20H20N5O2: 362, obtained: 362.
Example 94. 6-(2-aminopyrimidin-4-yl)-N-(3-methoxybenzyl)-2-methylimidazo[ 1 ,2- a]pyridine-3-carboxamide
The title compound was prepared according to the procedure described in Scheme 9 (30 mg, 46%). 1H-NMR (DMSO-d6, 400 MHz) δ 9.83 (d, J = 0.8 Hz, 1 H), 8.72 (t, J = 6.0 Hz, 1 H), 8.42 (d, J = 5.6 Hz, 1 H), 8.23 (dd, J = 9.6, 1.6 Hz, 1 H), 7.85 (d, J = 9.2 Hz, 1 H), 7.28 (m, 4 H), 6.98 (m, 2 H), 6.85 (dd, J = 7.6, 2.0 Hz, 1 H), 4.56 (d, J = 6.0 Hz, 2 H), 3.75 (s, 3 H), 2.67 (s, 3 H). LC-MS: single peak at 254 nm, MH+ calcd. for
C20H20N5O2: 362, obtained: 362.
ii) ArCI, Pd(PPh3)4, K2C03,
H20, EtOH, toluene Scheme 10
Ethyl 7-chloroimidazor 1 ,2-alpyridine-2-carboxylate
To a solution of 2-amino-4-chloropyridine (1.28 g, 10 mmol) in DME (20 mL) was added ethyl bromopyruvate (90%, 2.17 g, 10 mmol) and the mixture was stirred at room temperature for 1 h. After the solvent was removed, the residue was treated with ethanol (70 mL) and heated to reflux for 3 h. The mixture was cooled and concentrated to dryness by rotary evaporation. The residue was treated with water (50 mL) and a saturated aqueous NaHC03 solution (25 mL), and extracted with CH2CI2 (3 x 50 mL). The organic layers were combined, washed with brine (50 mL), dried over Na2S04, and filtered. The solvent was removed in vacuo and the residue was purified by flash column chromatography (10-60% ethyl acetate in hexanes) to afford the title compound (1.30 g, 58%). LC-MS: single peak at 254 nm, MH+ calcd. for C10HioClN202: 225, obtained: 225.
7-Chloroimidazor 1 ,2-alpyridine-2-carboxylic acid
To a solution of ethyl 7-chloroimidazo[l,2-a]pyridine-2-carboxylate (240 mg, 1.07 mmol) THF (5 mL) and methanol (5 mL) was added LiOH (69 mg 1.60 mmol) in water (5 mL) and stirred at 60 °C overnight. After removal of volatile solvent by rotary evaporation, the mixture was diluted with water and acidified to pH 4 with an aqueous solution of IN HC1. The resulting precipitate was collected by filtration, washed with water, and dried under vacuum to afford the title compound (0.125 g, 70%). This intermediate was used in subsequent reactions without further purification. LC-MS: single peak at 254 nm, MH+ calcd. for C8H6C1N202: 197, obtained: 197.
Example 95. N-(3-methoxybenzyl)-7-(lH-pyrazol-4-yl)imidazo[l,2-a]pyridine-2- carboxamide
Step A. 7-Chloro-N-(3-methoxybenzyl)imidazor 1 ,2-alpyridine-2-carboxamide
To a solution of 7-chloroimidazo[l,2-a]pyridine-2-carboxylic acid (78 mg, 0.40 mmol) in
DMF (0.5 mL) was added 3-methoxybenzylamine (75 mg, 0.55 mmol) and HATU (180 mg, 0.48 mmol). The resulting mixture was stirred at room temperature overnight. After removal of solvent by rotary evaporation, the residue was dissolved in ethyl acetate (15 mL) and washed with a saturated aqueous NaHC03 solution (2 x 10 mL), and brine (10 mL), dried over Na2S04, and filtered. The solvent was removed in vacuo and the crude amide product was purified by flash chromatography on silica gel to afford the title compound (120 mg, 96%). LC-MS: single peak at 254 nm, MH+ calcd. for
C16Hi5ClN302: 316, obtained: 316.
Step B. N-(3-methoxybenzyl)-7-(lH-pyrazol-4-yl)imidazorL2-alpyridine-2- carboxamide
To a solution of the chloride obtained in Step A (32 mg, 0.10 mmol) in a 3:2 mixture of ethanol: toluene (2 mL) was added lH-pyrazole-4-boronic acid pinacol ester (30 mg, 0.15 mmol), K2C03 (2 M aqueous solution, 0.15 mL), and
tetrakis(triphenylphosphine)palladium (0) (6 mg, 0.005 mmol). The reaction mixture was degassed, purged with argon, and heated to 95 °C for 16 h. After cooling to room temperature, the solvent was removed and the residue was treated with ethyl acetate (25
mL) and a saturated aqueous NaHC03 solution (10 mL). The layers were separated and the organic layer was washed with brine, dried over Na2S04, and filtered. The solvent was removed by rotary evaporation and the residue was purified by flash column chromatography (0.5-20% MeOH in CH2C12 with 0.1% NH4OH) to yield the title compound (17 mg, 48%). 1H-NMR (DMSO-d6, 400 MHz) δ 9.04 (br s, 1 H), 8.95 (s, 1 H), 8.35 (s, 1 H), 8.13 (s, 2 H), 7.78 (d, J = 9.6 Hz, 1 H), 7.65 (d, J = 9.2 Hz, 1 H), 7.24 (t, J = 8.0 Hz, 1 H), 6.91 (m, 2 H), 6.81 (m, 1 H), 4.46 (d, J = 6.4 Hz, 2 H), 3.73 (s, 3 H). LC-MS: single peak at 254 nm, MH+ calcd. for C19Hi8N502: 348, obtained: 348.
Example 96. N-(2-(dimethylamino)ethyl)-N-(3-methoxybenzyl)-7-(lH-pyrazol-4- yl)imidazo[ 1 ,2-a]pyridine-2-carboxamide
The title compound was prepared according to the procedure described in Scheme 10 (23 mg, 35%). LC-MS: single peak at 254 nm, MH+ calcd. for C23H27N602: 419, obtained: 419.
Example 97. N-(2-(dimethylamino)ethyl)-N-(3-methoxybenzyl)-7-(pyridin-4- yl)imidazo[ 1 ,2-a]pyridine-2-carboxamide
The title compound was prepared according to the procedure described in Scheme
10 (21 mg, 55%). 1H-NMR (DMSO-d6, 400 MHz) δ 8.71 (d, J = 7.2 Hz, 1 H), 8.67 (d, J = 8.8, 5.2, Hz, 2 H), 8.46 (s, 1 H), 8.15 (s, 1 H), 7.88 (m, 2 H), 7.49 (d, J = 7.2 Hz, 1 H), 7.29 (q, J = 8.4 Hz, 1 H), 6.91-6.86 (m, 3 H), 5.41 (s, 1 H), 4.73 (s, 1 H), 4.00 (m, 1 H), 3.73 (d, J = 12.8 Hz, 3 H), 3.43 (m, 1 H), 3.54 (m, 1 H), 3.32 (m, 1 H), 2.92 (s, 3 H), 2.85 (s, 3 H). LC-MS: single peak at 254 nm, MH+ calcd. for C25H28N502: 430, obtained: 430. Example 98. N-(3-methoxybenzyl)-7-(pyridin-4-yl)imidazo[ 1 ,2-a]pyridine-2- carboxamide
The title compound was prepared according to the procedure described in Scheme 10 (11 mg, 32%). 1H-NMR (DMSO-d6, 400 MHz) δ 8.94 (t, J = 6.4 Hz, 1 H), 8.72 (dd, J = 7.2, 0.8 Hz, 1 H), 8.70 (dd, J = 6.0, 1.6 Hz, 2 H), 8.45 (d, J = 0.4 Hz, 1 H), 8.07 (d, J = 0.8 Hz, 1 H), 7.87 (dd, J = 6.0 Hz, 1.6 Hz, 2 H), 7.49 (dd, J = 7.2, 2.0 Hz, 1 H), 7.23 (t, J = 8.0 Hz, 1 H), 6.91 (m, 2 H), 6.81 (m, 1 H), 4.46 (d, J = 6.4 Hz, 2 H), 3.73 (s, 3 H). LC- MS: single peak at 254 nm, MH+ calcd. for C2iH19N402: 359, obtained: 359.
ii) ArCI, Pd(PPh3)4, K2C03,
H20, EtOH, toluene Scheme 11
Ethyl 7-chloroimidazor 1 ,2-alpyridine-3-carboxylate
To a solution of ethyl formylchloroacetate (2.23 g, 14.8 mmol) in ethanol (60 mL) was added 5-bromopyridin-2-amine (1.90 g, 14.8 mmol), and the mixture was heated to reflux overnight. After cooling, the solvent was removed by rotary evaporation, and the residue was treated with CHC13 (50 mL) and a saturated solution of aqueous NaHC03. The layers were separated and the aqueous layer was further extracted with CHC13 (2 x 30 mL). The combined organic layer was dried over Na2S04, filtered, and concentrated to dryness. Purification by flash column chromatography (20-35% ethyl acetate in hexane) gave the title compound (0.60 g, 18%). LC-MS: single peak at 254 nm, MH+ calcd. for C10H10ClN2O2: 225, obtained: 225.
7-Chloroimidazor 1 ,2-alpyridine-3-carboxylic acid
To a solution of ethyl 7-chloroimidazo[l,2-a]pyridine-3-carboxylate (600 mg, 2.67 mmol) THF (10 mL) and methanol (10 mL) was added LiOH (280 mg 6.51 mmol) in water (10 mL) and stirred at 60 °C overnight. After removal of volatile solvent by rotary evaporation, the mixture was diluted with water and acidified to pH 4 with an aqueous solution of IN HCl. The resulting precipitate was collected by filtration, washed with water, and dried under vacuum to afford the title compound (360 mg, 69%). This intermediate was used in subsequent reactions without further purification. LC-MS: single peak at 254 nm, MH+ calcd. for C8H6C1N202: 197, obtained: 197.
The title compound was prepared according to the procedure described in Scheme 11 (14 mg, 42%). 1H-NMR (DMSO-d6, 400 MHz) δ 13.12 (br s, 1 H), 9.40 (dd, J = 7.2, 0.8 Hz, 1 H), 8.96 (t, J = 6.0 Hz, 1 H), 8.45 (br s, 1 H), 8.35 (s, 1 H), 8.15 (s, 1 H), 7.96 (dd, J = 2.0, 0.8 Hz, 1 H), 7.44 (dd, J = 7.2, 1.6 Hz, 1 H), 7.26 (t, J = 8.0 Hz, 1 H), 6.93 (m, 2 H), 6.83 (m, 1 H), 4.49 (d, J = 6.0 Hz, 2 H), 3.74 (s, 3 H). LC-MS: single peak at 254 nm, MH+ calcd. for C19Hi8N502: 348, obtained: 348.
The title compound was prepared according to the procedure described in Scheme 11 (21 mg, 61%). 1H-NMR (DMSO-d6, 400 MHz) δ 9.56 (dd, J = 7.2, 0.8 Hz, 1 H), 9.10 (t, J = 6.0 Hz, 1 H), 8.70 (dd, J = 6.4, 1.6 Hz, 2 H), 8.48 (s, 1 H), 8.28 (dd, J = 2.0, 0.8 Hz, 1 H), 7.92 (dd, J = 6.0, 1.6 Hz, 2 H), 7.63 (dd, J = 7.2, 1.6 Hz, 1 H), 7.26 (t, J = 8.0 Hz, 1 H), 6.94 (m, 2 H), 6.83 (m, 1 H), 4.51 (d, J = 6.0 Hz, 2 H), 3.74 (s, 3 H). LC-MS: single peak at 254 nm, MH+ calcd. for C21H19N402: 359, obtained: 359.
Example 101. N-(2-(dimethylamino)ethyl)-N-(3-methoxybenzyl)-7-(lH-pyrazol-4- yl)imidazo[ 1 ,2-a]pyridine-3-carboxamide
The title compound was prepared according to the procedure described in Scheme 11 (22 mg, 57%). 1H-NMR (DMSO-d6, 400 MHz) δ 13.14 (br s, 1 H), 8.93 (m, 1 H), 8.46 (s, 1 H), 8.16 (s, 1 H), 8.16 (s, 1 H), 7.96 (s, 1 H), 7.43 (t, J = 8.0 Hz, 1 H), 6.88 (m, 3 H), 4.84 (s, 2 H), 3.75 (s, 3 H), 3.61 (t, J = 6.0 Hz, 2 H), 2.08 (br s, 6 H). LC-MS: single peak at 254 nm, MH+ calcd. for C23H27N6O2: 419, obtained: 419.
Example 102. N-(2-(dimethylamino)ethyl)-N-(3-methoxybenzyl)-7-(pyridin-4- yl)imidazo[ 1 ,2-a]pyridine-3-carboxamide
The title compound was prepared according to the procedure described in Scheme
11 (30 mg, 78%). 1H-NMR (DMSO-d6, 400 MHz) δ 9.02 (br s, 1 H), 8.70 (dd, J = 6.0,
1.6 Hz, 2 H), 8.28 (dd, J = 2.0, 0.8 Hz, 1 H), 7.92 (dd, J = 6.4, 1.6 Hz, 2 H), 7.92 (dd, J =
7.6, 2.0 Hz, 1 H), 7.31 (t, J = 8.0 Hz, 1 H), 6.92 (m, 2 H), 6.87 (dd, J = 8.0, 2.0 Hz, 1 H),
4.85 (s, 2 H), 3.75 (s, 3 H), 3.62 (t, J = 6.0 Hz, 2 H), 2.05 (br s, 6 H). LC-MS: single peak at 254 nm, MH+ calcd. for C25H28N5O2: 430, obtained: 430.
The title compound was prepared according to the procedure described in Scheme
11 (22 mg, 51%). 1H-NMR (DMSO-d6, 400 MHz) δ 13.13 (br s, 1 H), 9.07 (dd, J = 7.2 Hz, 1 H), 8.46 (br s, 1 H), 8.16 (s, 1 H), 7.92 (t, J = 0.8 Hz, 1 H), 7.44 (dd, J = 7.2, 1.6 Hz, 1 H), 7.31 (dd, J = 8.4, 7.6 Hz, 1 H), 6.91-6.87 (m, 3 H), 4.78 (s, 2 H), 3.75 (s, 3 H),
3.19 (s, 3 H). LC-MS: single peak at 254 nm, MH+ calcd. for C20H20N5O2: 362, obtained: 362.
The title compound was prepared according to the procedure described in Scheme
11 (14 mg, 42%). 1H-NMR (DMSO-d6, 400 MHz) δ 13.12 (br s, 1 H), 9.40 (dd, J = 7.2, 0.8 Hz, 1 H), 8.98 (t, J = 6.0 Hz, 1 H), 8.45 (br s, 1 H), 8.35 (s, 1 H), 8.15 (s, 1 H), 7.96 (dd, J = 2.0, 0.8 Hz, 1 H), 7.44 (dd, J = 7.2, 2.0 Hz, 1 H), 7.35 (m, 5 H), 4.52 (d, J = 6.0 Hz, 2 H). LC-MS: single peak at 254 nm, MH+ calcd. for C18H16N50: 318, obtained: 318.
Example 105. N-(3,5-dimethoxybenzyl)-7-(lH-pyrazol-4-yl)imidazo[l,2-a]pyridine-3- carboxamide
The title compound was prepared according to the procedure described in Scheme 11 (8 mg, 21%). 1H-NMR (DMSO-d6, 400 MHz) δ 13.13 (br s, 1 H), 9.39 (dd, J = 7.2, 0.8 Hz, 1 H), 8.94 (t, J = 6.0 Hz, 1 H), 8.45 (br s, 1 H), 8.35 (s, 1 H), 8.16 (dd, J = 1.6, 0.8 Hz, 1 H), 7.45 (dd, J = 7.6, 1.6 Hz, 1 H), 6.52 (t, J = 2.4 Hz, 2 H), 6.39 (t, J = 6.0 Hz, 1 H), 4.44 (d, J = 6.0 Hz, 2 H), 3.72 (s, 6 H). LC-MS: single peak at 254 nm, MH+ calcd. for C20H20N5O3: 378, obtained: 378.
Example 106. N-(3-methoxybenzyl)-2-methyl-7-(lH-pyrazol-4-yl)imidazo[l,2- a]pyridine-3-carboxamide
The title compound was prepared according to the procedure described in Scheme mg, 42%). 1H-NMR (DMSO-d6, 400 MHz) δ 13.11 (br s, 1 H), 8.97 (dd, J = 7.2,
0.8 Hz, 1 H), 8.41 (s, 1 H), 8.26 (t, J = 6.0 Hz, 1 H), 8.12 (s, 1 H), 7.81 (dd, J = 1.6, 0.8 Hz, 1 H), 7.33 (dd, J = 7.2, 2.0 Hz, 1 H), 7.27 (t, J = 8.0 Hz, 1 H), 6.96 (m, 2 H), 6.82 (m, 1 H), 4.51 (d, J = 6.0 Hz, 2 H), 3.74 (s, 3 H), 2.59 (s, 3 H). LC-MS: single peak at 254 nm, MH+ calcd. for C20H20N5O2: 362, obtained: 362.
Example 107. N-(3-methoxybenzyl)-7-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)imidazo[l,2- a]pyridine-3-carboxamide
The title compound was prepared according to the procedure described in Scheme 10 (4 mg, 8%). 1H-NMR (DMSO-d6, 400 MHz) δ 12.44 (br s, 1 H), 9.66 (d, J = 7.6 Hz, 1 H), 9.17 (t, J = 6.0 Hz, 1 H), 8.92 (s, 1 H), 8.57 (br s, 1 H), 8.50 (br s, 1 H), 8.02 (d, J = 7.2 Hz, 1 H), 7.78 (m, 1 H), 7.27 (t, J = 8.0 Hz, 1 H), 7.07 (m, 1 H), 6.96 (m, 2 H), 6.84 (m, 1 H), 4.53 (d, J = 5.6 Hz, 2 H), 3.75 (s, 3 H). LC-MS: single peak at 254 nm, MH+ calcd. for CiiHigNeCh: 399, obtained: 399.
Example 108: 2-(6-Methoxychroman-3-yl)-7-(lH-pyrazol-4-yl)-4H-pyrido[l,2- a]pyrimidin-4-one
Scheme 12
Oxalyl chloride (1.5 equiv) and dry DMF (4 drops) were added to the mixture of 6- methoxylchroman-3-carboxylic acid (1 equiv) in dry DCM (2 mL). After stirring 4 hours, the solvent was removed under reduced pressure and the remaining residue was resolved in dry DCM (2 mL) and added to the mixture of Meldrum's acid (1 equiv) and pyridine (3 equiv) in DCM (2 mL) at 0 °C. After stirring at room temperature for 30 min, the reaction was quenched with water and the organic phase was extract with DCM, dried over anhydrous Na2S04, concentrated under reduced pressure, and purified over silica gel to give 5-(6-Methoxychroman-3-carbonyl)-2, 2-dimethyl-l, 3-dioxane-4, 6 -dione in 72% yield. 1H-NMR (DMSO-d6, 400MHz) δ 6.68 (d, J=8.8 Hz, 1H), 6.60 (dd, J=8.8, 2.4 Hz, 1H), 6.54 (d, J=2.4 Hz, 1H), 4.38-4.32 (m, 1H), 4.27-4.25 (m, 1H), 4.14 (s, 1H), 4.12- 4.11 (m, 1H), 3.69 (s, 3H), 3.05-2.92 (m, 2H).
A mixture of 5-(6-Methoxychroman-3-carbonyl)-2, 2-dimethyl-l, 3-dioxane-4, 6 - dione (1 equiv) in ethanol (2 mL) was heated to reflux for 70 min. then the solvent was removed under reduced pressure and 12-2 was obtained through purification over silica gel in 81% yield. 1H-NMR (DMSO-d6, 400MHz) δ 6.65 (d, J=8.8 Hz, 1H), 6.58 (dd, J=8.8, 2.8 Hz, 1H), 6.52 (d, J=2.8 Hz, 1H), 4.31-4.21 (m, 1H), 4.10 (q, J=7.2 Hz, 2H), 3.98-3.93 (m, 1H), 3.65 (s, 3H), 3.50 (s, 2H), 3.14-3.08 (m, 1H), 3.00-2.89 (m, 1H), 2.86- 2.81 (m, 1H), 1.19 (t, J=7.2 Hz, 3H).
A mixture of 5-bromopyridin-2-amine (0.1 equiv)and 12-2 (0.1 equiv) in HOAc (1 mL) was heated at 80 °C until the complete disappearance of 5-bromopyridin-2-amine by LC-MS, then acetic acid was removed under reduced pressure to give a tar residue. The residue was then washed with saturated NaHC03 and the organic phase was extracted with EtOAc, dried over anhydrous Na2S04, and concentrated under reduced pressure to give crude bromide. The crude bromide was mixed with 4-(4,4,5,5-tetramethyl- 1,3,2- dioxaborolan-2-yl)-lH-pyrazole (0.1 equiv), Ph(PPh3)4 (0.01 equiv), 2N K2C03 solution(0.3 equiv), Dioxane/H20 (V:V=5: 1, 1 mL) under argon protection. Then the mixture was then heated at 90 °C for 3 hours and purified over reverse HPLC to give the title compound (12-4) in 41% yield as a white solid. 1H-NMR (DMSO-d6, 400MHz) δ 9.12 (d, J=2.0 Hz, 1H), 8.30 (dd, J=9.2, 2.0 Hz, , 2H), 7.73 (d, J=9.2 Hz, 1H), 6.75 (m,
1H), 6.72-6.68 (m, 2H), 6.43 (s, 1H), 4.41-4.38 (m, 1H), 4.17-4.12 (m, 1H), 3.69 (s, 3H),
3.25-3.16 (m, 2H), 3.05-3.02 (m, IH); LC/MS: C2iHi8N403 (M+l) 375. Single peak in analytic HPLC traces as monitored at both 215 nm and 254 nm.
Procedures as in Scheme 12 were utilized to synthesize this compound. H-NMR (DMSO-d6, 400MHz) δ 9.31 (d, J=2.4 Hz, IH), 8.77 (d, J=6.0 Hz, 2H), 8.43 (dd, J=9.2, 2.4 Hz, IH), 7.97 (d, J=6.0 Hz, 2H), 7.83 (d, J=9.2 Hz, IH), 6.77-6.76 (m, IH), 6.73-6.71 (m, 2H), 6.52 (s, IH), 4.43 (m, IH), 4.20-4.15 (m, IH), 3.70 (s, 3H), 3.33-3.25 (m, IH), 3.23-3.18 (m, IH), 3.09-3.04 (m, IH); LC/MS: C23Hi9N303 (M+l) 386. Single peak in analytic HPLC traces as monitored at both 215 nm and 254 nm.
Procedures as in Scheme 12 were utilized to synthesize this compound. LC/MS:
C22H19N503 (M+l) 402. Single peak in analytic HPLC traces as monitored at both 215 nm and 254 nm.
1) HCI.dioxane, 72 °C, 6 h,
NRR' 72% HATU, DMF, TEA,
2) pyruvic acid, DABCO, DMF, Cl N H ° NHRR' Cl N H °
°C, 3.5 h, 13 4 13-5
Scheme 13
To a suspension of 6-chloro-pyridin-2-ylamine 13-1 (0.30 g, 2.33 mmol) and triethlyamine (0.41 mL, 2.92 mmol) in anhydrous methylene chloride at 0 °C was added a solution of trichloromethylacetyl chloride (0.32 mL, 2.57 mmol) in anhydrous methylene chloride. The mixture was stirred at 0 °C for 50 min, before allowing it to gradually warm up to room temperature. After 5 h, the reaction mixture was poured into water and the organic phase separated. The aqueous layer was extracted with methylene chloride and the combined organic phases were dried and concentrated. The product was purified by flash chromatography using Combiflash® employing a gradient of 0-15% EtOAc in Hexanes to afford 0.48 g (2.28 mmol, 98% yield) of 13-2 as a white solid.
A solution of iert-BuLi (1.7 M in pentane) was slowly added over half hour to a solution of compound 13-2 (1.25 g, 5.91 mmol) in anhydrous THF at -78 °C. After the reaction was stirred for 3 h at -78 °C, a solution of iodine (1.8 g, 7.09 mmol, 1.2 equiv.) in THF was added and the reaction mixture was allowed to warm up to room temperature and stirred for 14 h. The reaction was concentrated and the residue diluted with methylene chloride. The organic layer was washed sequentially with 10% aqueous
Na2S203 and NaHC03 and concentrated under reduced pressure. The product was purified by flash chromatography using Combiflash® and employing a gradient of 0-20% EtOAc in Hexanes to afford 1.50 g (4.45 mmol, 73% yield) of 13-3.
Compound 13-3 (0.18 g, 0.54 mmol) was dissolved in 1 M HCl/dioxane and the reaction mixture was heated at 72 °C for 3h. LC-MS showed the presence of some
starting material. Additional 2.0 mL of 1 M of HCl/dioxane was added and heating continued for another 3 hours. Upon completion, the reaction was concentrated and the residue was purified using flash chromatography using Combiflash® and employing a gradient of 0-2% MeOH in DCM (+1% NH3) to afford 6-chloro-3-iodo-pyridin-2-ylamine as white solid (0.10 g, 0.39 mmol, 72% yield).
A solution of 6-chloro-3-iodo-pyridin-2-ylamine (0.73 mmol), pyruvic acid (3.2 equiv., 2.32 mmol, 161.5 ^L) and DABCO (3.0 equiv., 0.27 g, 2.18 mmol) in anhydrous DMF was taken in a sealed tube and the solution was purged with Argon for 3 minutes. Pd(OAc)2 (10 mol%, 18.5 mg) was next added and the system was again purged with Argon for 3 minutes. The reaction mixture was heated at 105 °C for 3.5 h in an oil bath. The solution was allowed to cool down to room temperature, diluted with EtOAc and filtered through Celite. The filtrate was concentrated under reduced pressure and the residue was taken up in EtOAc. The organic layer was washed with water and was dried and concentrated. The crude acid 13-4 was forwarded to the next step without further purification.
In a typical example, compound 13-4 (0.73 mmol) was dissolved in anhydrous DMF and the reaction mixture was treated with HATU (1.3 equiv., 0.36 g, 0.95 mmol), a primary or a secondary amine NHRR' (1.3 equiv., 0.95 mmol) and triethyl amine (TEA) (5.0 equiv., 0.53 mL, 3.65 mmol). The reaction mixture was stirred overnight at room temperature. Upon completion, the reaction mixture was concentrated and the residue was diluted with EtOAc and washed with water. The aqueous layer was extracted with EtOAc (x3) and the combined organics were dried and concentrated. Purification by flash chromatography using Combiflash® and employing a gradient of 0-50% MeOH in DCM (+1% NH3) afforded 13-5.
In a typical example, a solution of 13-5 (0.12 mmol) and boronic acid ester (1.5 equiv.) in EtOH/toluene (3:2 by volume) was treated with 2 M solution of K2C03 (3.0 equiv.). The tetrakis palladium catalyst (10 mol%) was added, the tube sealed, and the solution degassed by a flow of argon. The mixture was heated at 145 °C for 1.0 h in a microwave reactor. After cooling to room temperature, the reaction was quenched with 10% TFA in water until evolution of gas was complete. The reaction mixture was concentrated and the residue purified by preparative HPLC to give the target compounds.
Example 111. 6-(lH-Pyrazol-4-yl)-lH-pyrrolo[2,3-b]pyridine-2-carboxylic acid 4- methoxy-benzylamide
Procedures in Scheme 13 were utilized to synthesize this compound. 1Η NMR (400 MHz, MeOH-d4) δ ppm 8.33-8.27 (bs, 2H), 8.16 (d, J = 8 Hz, 1H), 7.57 (d, J = 8 Hz, 1H), 7.33 (d, J = 9 Hz, 2H), 7.16 (s, 1H), 6.92 (d, J = 9 Hz, 2H), 4.55 (s, 2H), 3.79 (s, 3H). LC/MS: C23H19N3O3 (M+1) 386. LC/MS: C19Hi8N502 (M+1) 348. Single peak observed at 254 and 215 nm in analytical HPLC traces.
Procedures in Scheme 13 were utilized to synthesize this compound. LC/MS:
C19H18N502 (M+1) 348. Single peak observed at 254 and 215 nm in analytical HPLC traces.
Example 113. 6-(3-Methyl-lH-pyrazol-4-yl)-lH-pyrrolo[2,3-b]pyridine-2-carboxylic acid 3-methoxy-benzylamide
Procedures in Scheme 13 were utilized to synthesize this compound. LC/MS:
C20H20N5O2 (M+1) 362. Single peak observed at 254 and 215 nm in analytical HPLC traces.
Example 114. 6-Pyridin-4-yl-lH-pyrrolo[2,3-b]pyridine-2-carboxylic acid 3-methoxy- benzylamide
Procedures in Scheme 13 were utilized to synthesize this compound. LC/MS:
C2iH19N402 (M+1) 359. Single peak observed at 254 and 215 nm in analytical HPLC traces.
Example 115. 6-(lH-Pyrazol-4-yl)-lH-pyrrolo[2,3-b]pyridine-2-carboxylic acid (3- methoxy-benzyl)-[3-(4-methyl-piperazin-l-yl)-propyl]-amide
Procedures in Scheme 13 were utilized to synthesize this compound. LC/MS:
C27H34N702 (M+1) 488. Single peak observed at 254 and 215 nm in analytical HPLC traces.
Example 116. 6-(lH-Pyrazol-4-yl)-lH-pyrrolo[2,3-b]pyridine-2-carboxylic acid (3- methoxy-benzyl)-(2-methoxy-ethyl)-amide
Procedures in Scheme 13 were utilized to synthesize this compound. LC/MS:
C22H24N503 (M+1) 406. Single peak observed at 254 and 215 nm in analytical HPLC traces.
Example 117. 6-(lH-Pyrazol-4-yl)-lH-pyrrolo[2,3-b]pyridine-2-carboxylic acid (3- methoxy-benzyl)-methyl-amide
Procedures in Scheme 13 were utilized to synthesize this compound. LC/MS:
C20H20N5O2 (M+1) 362. Single peak observed at 215 and 254 nm in analytical HPLC traces.
Example 118. 6-(lH-Pyrazol-4-yl)-lH-pyrrolo[2,3-b]pyridine-2-carboxylic acid (3- methoxy-benzyl)-(2-pyrrolidin-l-yl-ethyl)-amide
Procedures in Scheme 13 were utilized to synthesize this compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.10 (s, 1H), 9.62-9.46 (bs, 1H), 8.20 (s, 2H), 7.99 (d, J = 8 Hz, 1H), 7.48 (d, J = 8 Hz, 1H), 7.35 (t, J = 8 Hz, 1H), 6.94-6.82 (m, 3H), 6.74-6.60 (bs, 1H), 5.00-4.85 (bs, 2H), 3.80-3.55 (m, 7H), 3.52-3.41 (m, 2H), 3.16-3.00 (m, 2H), 2.09- 1.95 (m, 2H), 1.95-1.79 (m, 2H). LC/MS: C25H29N6O2 (M+l) 445. Single peak observed at 215 and 254 nm in analytical HPLC traces.
Example 119. 6-(lH-Pyrazol-4-yl)-lH-pyrrolo[2,3-b]pyridine-2-carboxylic acid isopropyl- (3 -methoxy-benzyl)-amide
Procedures in Scheme 13 were utilized to synthesize this compound. LC/MS:
C22H24N5O2 (M+l) 390. Single peak at 215 and 254 nm in analytical HPLC traces.
Example 120. 6-(lH-Pyrazol-4-yl)-lH-pyrrolo[2,3-b]pyridine-2-carboxylic acid (3- methoxy-benzyl)-ethyl-amide
Procedures in Scheme 13 were utilized to synthesize this compound. LC/MS:
C21H22N5O2 (M+l) 376. Single peak observed at 215 and 254 nm in analytical HPLC traces.
Example 121. N-cyclopropyl-N-(3-methoxybenzyl)-6-(lH-pyrazol-4-yl)-lH-pyrrolo[2,3- b]pyridine-2-carboxamide
Procedures in Scheme 13 were utilized to synthesize this compound. LC/MS:
C22H22N5O2 (M+1) 388. Single peak observed at 215 and 254 nm in analytical HPLC traces.
Example 122. 6-(lH-Pyrazol-4-yl)-lH-pyrrolo[2,3-b]pyridine-2-carboxylic acid cyclopropyl- (3 -hydroxy-benzyl)-amide
Procedures in Scheme 13 were utilized to synthesize this compound. LC/MS:
C23H24N5O2 (M+1) 402. Single peak observed at 215 and 254 nm in analytical HPLC traces.
Example 123. 6-(lH-Pyrazol-4-yl)-lH-pyrrolo[2,3-b]pyridine-2-carboxylic acid (2- dimethylamino-ethyl)-(3-methoxy-benzyl)-amide
Procedures in Scheme 13 were utilized to synthesize this compound. LC/MS:
C23H27N6O2 (M+1) 419. Single peak observed at 215 and 254 nm in analytical HPLC traces.
Example 124. 6-(lH-Pyrazol-4-yl)-lH-pyrrolo[2,3-b]pyridine-2-carboxylic acid (3- dimethylamino-propyl)-(3-methoxy-benzyl)-amide
C24H29N6O2 (M+l) 433. Single peak observed at 215 and 254 nm in analytical HPLC traces.
Scheme 14
An alkyl halide (1.5 equiv) was added to a solution of compound 14-7 (1.0 equiv.) and CS2CO3 (2.0 equiv) in anhydrous DMF and the solution was stirred at 45 °C for 14 h. Upon completion, the solution was diluted with EtOAc and washed with water. The aqueous portion was extracted with EtOAc (x3) and the combined organic phases were dried and concentrated. The crude product was forwarded to the next step without further purification. Alternatively, compound 14-7 (76 mg, 0.24 mmol) was dissolved in anhydrous DMF and treated with NaH (2.0 equiv, 65% dispersion in oil) at room temperature. After 30 minutes, alkyl halide (1.3 equiv.) was added and the reaction mixture was stirred at room temperature for 14 h. Upon completion, the solution was diluted with EtOAc and washed with water. The aqueous portion was extracted with EtOAc (x3) and the combined organics were dried and concentrated. Purification by flash chromatography using Combiflash® and employing a gradient of 0-20% MeOH in DCM (+1% NH3) afforded 14-8.
A solution of 14-8 (1.0 equiv.) and boronic acid ester (1.5 equiv.) in
EtOH/toluene (3:2 by volume) was sequentially treated with 2 M solution of K2C03 (9.0 equiv.) and the tetrakis palladium catalyst (10 mol%) and the tube was sealed and the solution degassed by passing a flow of argon. The mixture was heated at 145 °C for 1.0 h in a microwave reactor. After cooling to room temperature, the reaction was quenched with 10% TFA in water until evolution of gas was complete. The reaction mixture was
concentrated and the residue was purified by preparative HPLC to give the target compounds.
Example 125. N-(3-methoxybenzyl)-l-methyl-6-(lH-pyrazol-4-yl)- lH-pyrrolo[2,3- b]pyridine-2-carboxamide
Procedures in Scheme 14 were utilized to synthesize this compound. LC/MS:
C20H20N5O2 (M+1) 362. Single peak observed at 254 and 215 nm in analytical HPLC traces.
Example 126. N,l-bis(3-methoxybenzyl)-6-(lH-pyrazol-4-yl)- lH-pyrrolo[2,3- b]pyridine-2-carboxamide
Procedures in Scheme 14 were utilized to synthesize this compound. LC/MS:
C27H26N5O3 (M+1) 468. Single peak observed at 254 and 215 nm in analytical HPLC traces.
Example 127. l-ethyl-N-(3-methoxybenzyl)-6-(lH-pyrazol-4-yl)-lH-pyrrolo[2,3- b]pyridine-2-carboxamide
Procedures in Scheme 14 were utilized to synthesize this compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 9.10 (t, J = 6 Hz, 1H), 8.24 (s, 2H), 8.05 (d, J = 8 Hz, 1H), 7.52 (d, J = 8 Hz, 1H), 7.27 (t, J = 7 Hz, 1H), 7.12 (s, 1H), 6.96-6.90 (m, 2H), 6.86-6.79 (m, 1H), 4.71 (q, J = 7 Hz, 2H), 4.48 (d, J =6 Hz, 2H), 3.75 (s, 3H), 1.31 (t, J = 7 Hz, 3H). LC/MS: C21H22N5O2 (M+1) 376. Single peak observed at 254 and 215 nm in analytical HPLC traces.
Example 128. N-(3-methoxybenzyl)-6-(lH-pyrazol-4-yl)- l-(2-(pyrrolidin-l-yl)ethyl)- -pyrrolo[2,3-b]pyridine-2-carboxamide
Procedures in Scheme 14 were utilized to synthesize this compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 9.73-9.63 (bs, 1H), 9.26 (t, J = 7 Hz, 1H), 8.31 (s, 2H), 8.12 (d, J = 8 Hz, 1H), 7.60 (d, J = 8 Hz, 1H), 7.30 (s, 1H), 7.27 (t, J = 8 Hz, 1H), 6.96-6.91 (m, 2H), 6.86-6.82 (m, 1H), 4.96 (t, J = 6 Hz, 2H), 4.50 (d, J =6 Hz, 2H), 3.80-3.72 (m, 5H), 3.69 (q, J = 6 Hz, 2H), 3.22-3.11 (m, 2H), 2.09- 1.99 (m, 2H), 1.86-1.76 (m, 2H).
LC/MS: C25H29N6O2 (M+1) 445. Single peak observed at 254 and 215 nm in analytical HPLC traces.
Example 129. l-(2-hydroxyethyl)-N-(3-methoxybenzyl)-6-(lH-pyrazol-4-yl)- lH- pyrrolo[2,3-b]pyridine-2-carboxamide
Procedures in Scheme 14 were utilized to synthesize this compound. LC/MS:
C21H22N5O3 (M+1) 392. Single peak observed at 254 and 215 nm in analytical HPLC traces.
Example 130. l-(2-(dimethylamino)ethyl)-N-(3-methoxybenzyl)-6-(lH-pyrazol-4-yl)- -pyrrolo[2,3-b]pyridine-2-carboxamide
Procedures in Scheme 14 were utilized to synthesize this compound. LC/MS:
C23H27N6O2 (M+1) 419. Single peak observed at 254 and 215 nm in analytical HPLC traces.
Example 131. l-(cyclopropylmethyl)-N-(3-methoxybenzyl)-6-(lH-pyrazol-4-yl)-lH- pyrrolo[2,3-b]pyridine-2-carboxamide
Procedures in Scheme 14 were utilized to synthesize this compound. LC/MS:
C23H24N5O2 (M+1) 402. Single peak observed at 254 and 215 nm in analytical HPLC traces.
15-10 15-11
Scheme 15
Compound 15-10 (25 mg, 0.05 mmol; prepared according to procedures in
Scheme 14) was treated with TFA/DCM (1: 1) at room temperature for 1 h. LC-MS showed complete conversion of the starting material. The reaction mixture was concentrated under vacuo to afford compound 15-11.
Example 132. l-(3-hydroxypropyl)-N-(3-methoxybenzyl)-6-(lH-pyrazol-4-yl)-lH- pyrrolo[2,3-b]pyridine-2-carboxamide
Procedures in Scheme 15 were utilized to synthesize this compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 9.12 (t, J = 6 Hz, 1H), 8.25 (s, 2H), 8.06 (d, J = 8 Hz, 1H), 7.52 (d, J = 8 Hz, 1H), 7.26 (t, J = 8 Hz, 1H), 7.14 (s, 1H), 6.95-6.90 (m, 2H), 6.85-6.81 (m, 1H), 4.71 (t, J = 7 Hz, 2H), 4.47 (d, J =6 Hz, 2H), 3.75 (s, 3H), 3.37 (t, J = 7 Hz, 2H), 1.91 (p, J =7 Hz, 2H). LC/MS: C22H24N5O3 (M+1) 406. Single peak observed at 254 and 215 nm in analytical HPLC traces.
133 134
Scheme 16
A degassed solution of 14-7 (0.28 mmol), iodobenzene (1.0 equiv., 32 μί), Cul (0.5 mg), ligand (3 mg), and K3PO4 (111 mg) in 1 mL of anhydrous dioxane was heated at 120 °C for 5 h in an oil bath. LC-MS showed incomplete conversion of the starting material. Additional iodobenzene (32 μ¾, Cul (2.0 mg), K3PO4 (50 mg) were added and the reaction mixture was purged with argon and heated at 120 °C for 16 h. LC-MS showed complete conversion of the starting material and the presence of mono and bis arylated products. The solution was allowed to cool down to room temperature, diluted with EtOAc and filtered through Celite. The filtrate was concentrated under reduced pressure and the residue was taken up into EtOAc. The organic layer was washed with water and was dried and concentrated. The crude products were used in the next step without isolation and purification.
A solution of the halide substrates (0.28 equiv.), boronic acid ester (1.3 equiv., 71 mg) in 1.75 mL EtOH/toluene (3:2 by volume) was sequentially treated with 2 M solution of K2CO3 (1.3 mL) and the tetrakis palladium catalyst (10 mol , 29 mg) and the tube was sealed. The mixture was heated at 145 °C for 1.0 h in a microwave reactor.
After cooling to room temperature, the reaction was quenched with 10% TFA in water until evolution of gas was complete. The reaction mixture was concentrated and the residue was purified by preparative HPLC to give the target compounds 133 and 134. Example 133. N-(3-methoxybenzyl)-l-phenyl-6-(lH-pyrazol-4-yl)-lH-pyrrolo[2,3- b]pyridine-2-carboxamide
Procedures in Scheme 16 were utilized to synthesize this compound. 1H NMR (400 MHz, MeOH-d4) δ ppm 8.06-7.98 (bs, 2H), 7.96 (d, J = 8 Hz, 1H), 7.44 (d, J = 8 Hz, 1H), 7.42-7.27 (m, 5H), 7.13 (t, J = 8 Hz, 1H), 6.98 (s, 1H), 6.77-6.72 (m, 3H), 4.37 (s, 2H), 3.69 (s, 3H). LC/MS: C25H22N5O2 (M+1) 424. Single peak observed at 254 and 215 nm in analytical HPLC traces.
Example 134. N-(3-methoxybenzyl)-l,3-diphenyl-6-(lH-pyrazol-4-yl)-lH-pyrrolo[2,3- b]pyridine-2-carboxamide
Procedures in Scheme 16 were utilized to synthesize this compound. LC/MS:
C31H26N5O2 (M+1) 500. Single peak observed at 254 and 215 nm in analytical HPLC traces.
17-3 17-4
Scheme 17
General procedures: The conversion of substituted isatins to substituted Indazole-3- carboxylic acids is essentially the same methods as described by Snyder, H. R. et al. Thus, the substituted isatin (17-1) was suspended in IN NaOH and was heated at 50°C for 30 min. The burgundy solution was allowed to cool to room temperature and was maintained for an additional one hour. The reaction mixture was cooled to 0 °C and was treated with a solution of NaN02 (22 mmol) in water. This solution was added through a pipet submerged below the surface of H2S04 in water at 0°c in 15 min. The reaction was maintained for an additional 30 min. A cold solution of Tin(II) chloride in con. HC1 was added to the reaction mixture over 10 min and the reaction mixture was stirred at the same temperature for an additional 2h. The solid filtered and washed with water several times and dried in vacuo to give quantitative mass balance of the product (17-2) with 80% NMR purity.
To a stirred solution of acid (1 eq), amine (1.2 eq) and DIPEA (3 eq) in DMF was added HATU (1.3 eq) and the reaction mixture was stirred for 3-5 h. After completion of reaction (monitored by LCMS) DMF was removed by rotovapor, residue was suspended in ethyl acetate and washed with saturated solution of NaHC03. Solvent removed by rotovapor and the crude product (17-3) was directly used for Suzuki reaction without further purification.
To a solution of the crude (17-3) in a 4: 1 mixture of dioxane/water were added K2C03 (4 equiv) and a boronic acid ester (1.4 equiv). The mixture was degassed and Pd(PPh )4 (0.1 eq) was added. After sealing, the reaction mixture was heated at 90oC for 3 hours. The solvent was removed by rotovapor, the crude was dissolved in ethyl acetate,
washed with saturated solution of NaHC03. The solvent was removed by rotovapor and the crude was purified by preparative HPLC to give the final product (17-4).
Example 135. N-(2-methylbenzyl)-6-(lH-pyrazol-4-yl)-lH-indazole-3-carboxamide
Procedures described in Scheme 17 were used to prepare this compound. H NMR (DMSO, 400MHz) 13.48 (1H, s), 12.89 (1H, s), 8.71-8.68 (1H, m), 8.03-8.01 (2H, m), 7.67 (1H, s), 7.46-7.44 (1H, m), 7.22-7.19 (1H, m), 7.08-7.05 (3H, m), 4.40 (2H, d, J= 6), 2.26 (3H, s). LC/MS: C19H17N05 (M+1) 332. Single peak in analytic HPLC at both 215 nm and 254 nm.
Example 136. N-(2-methoxybenzyl)-6-(lH-pyrazol-4-yl)-lH-indazole-3-carboxamide
Procedures described in Scheme 17 were used to prepare this compound. H NMR (DMSO, 400MHz) 13.1 (1H, s), 12.81 (s, 1H), 8.53-8.51 (1H, s), 8.01 (2H, d, J= 8.4), 7.66 (1H, s), 7.46-7.44 (1H, m), 6.93-6.79 (4H, m), 4.40 (2H, d, J= 6.4), 3.77 (3H, s). LC/MS: C19H17N502 (M+1) 348. Single peak in analytical HPLC traces at 215 nm and 254 nm.
Example 137. N-(3-methoxyphenethyl)-6-(lH-pyrazol-4-yl)-lH-indazole-3-carboxamide
Procedures described in Scheme 17 were used to prepare this compound. LC/MS:
C20H19N5O2 (M+1) 362. Single peak in analytic HPLC traces at 215 nm and 254 nm. Example 138. N-(3-methoxybenzyl)-6-(lH-pyrazol-4-yl)-lH-indazole-3-carboxamide
Procedures described in Scheme 17 were used to prepare this compound. LC/MS:
-(3-methoxybenzyl)-6-(pyridin-4-yl)- lH-indazole-3-carboxamide
Procedures described in Scheme 17 were used to prepare this compound. LC/MS:
C2iH18N402 (M+1) 359. Single peak in analytic HPLC traces as monitored at 215 nm and 254 nm.
Example 140. N-benzyl-N-(cyclopropylmethyl)-6-(lH-pyrazol-4-yl)-lH-indazole-3- carboxamide
Procedures described in Scheme 17 were used to prepare this compound. LC/MS:
C22H21N5O (M+1) 372. Single peak in analytic HPLC traces as monitored at 215 nm and 254 nm.
Example 141. N-(3-methoxybenzyl)-N-methyl-6-(lH-pyrazol-4-yl)-lH-indazole-3- carboxamide
Procedures described in Scheme 17 were used to prepare this compound. LC/MS:
C2oH19N5C, 2 (M+1) 362. Single peak in analytic HPLC traces as monitored at 215 nm and 254 nm.
Example 142. N-(2-(dimethylamino)ethyl)-N-(3-methoxybenzyl)-6-(lH-pyrazol-4-yl)- lH-indazole-3-carboxamide
Procedures described in Scheme 17 were used to prepare this compound. LC/MS:
C2oH19N502 (M+1) 419.03. Single peak in analytic HPLC traces as monitored at 215 nm and 254 nm.
Example 143. 6-(7-ethyl-8-oxo-8,9-dihydro-7H-purin-6-yl)-N-(3-methoxybenzyl)- 1H- indazole- 3 -carboxamide
Procedures described in Scheme 17 were used to prepare this compound. LC/MS:
C23H21N703 (M+1) 444. Single peak in analytic HPLC traces as monitored at 215 nm and 254 nm.
Example 144. N-(3-methoxybenzyl)-6-(lH-pyrrolo[2,3-b]pyridin-4-yl)-lH-indazole-3- carboxamide
Procedures described in Scheme 17 were used to prepare this compound. LC/MS:
C23H19Ns02 (M+1) 398. Single peak in analytic HPLC traces as monitored at 215 nm and 254 nm.
Procedures described in Scheme 17 were used to prepare this compound. LC/MS:
C22H18N602 (M+1) 399. Single peak in analytic HPLC traces as monitored at 215 nm and 254 nm.
7
Scheme 18
Catalytical amount of con. H2S04 was added to a stirred solution of 6- bromoindazole-3-carboxylic acid (lg) in MeOH. The reaction mixture was heated to reflux for 22h. After completion of reaction (monitored by LCMS) the solvent was removed by rotovapor and the residue was dissolved in dichloromethane (25 mL). The organic layer was washed successively with saturated solution of NaHC03 and brine
followed by drying over anhydrous Na2S04. The solvent was removed by rotovapor and the residue was purified by flash chromatography to yield the desired ester (18-1) in 51% yield.
To a solution of the indazole ester (18-1, 1 equiv) was added K2C03 (1.2 equiv) and the alkyl halide (1 equiv). The reaction mixture was stirred overnight at room temperature (the reaction afforded two regioisomers in 1: 1 ratio). After completion of reaction, K2C03 was filtered by sintered funnel, the solvent was removed by rotovapor, and the residue was dissolved in ethyl acetate and the combined organic phase was washed with saturated NaHC03 followed by brine, dried over anhydrous Na2S04. The solvent was removed by rotovapor and the crude was purified by flash chromatography to afford the two regioisomers (18-2a and 18-2b).
After standard procedures of basic hydrolysis, the resulting acids (18-3a and 18- 3b)were subjected to amide formations and Suzuki couplings as described in Scheme 17 to afford the final products (18-4a and 18-4b).
Example 146. 2-(cyclopropylmethyl)-6-(7-ethyl-8-oxo-8,9-dihydro-7H-purin-6-yl)-N-(3- (isopropylcarbamoyl)phenyl)-2H-indazole-3-carboxamide
Procedures described in Scheme 18 were used to prepare this compound. LC/MS:
C29H30N8O3 (M+1) 539. Single peak in analytic HPLC traces at both 215 nm and 254 nm. Example 147. N-(3-methoxybenzyl)-l-methyl-6-(lH-pyrazol-4-yl)-lH-indazole-3- carboxamide
Procedures described in Scheme 18 were used to prepare this compound. 1H NMR (DMSO, 400MHz) 8.88-8.85 (1H, m), 8.21-7.96 (3H, m), 7.58-7.56 (1H, m), 7.26-7.21 (2H, m), 6.94-6.92 (3H, m), 6.88-6.79 (1H, m), 4.46 (2H, d, J= 6), 4.15 (3H, s), 3.74 (3H,
s). LC/MS: C2oH19N502 (M+l) 362. Single peak in analytical HPLC traces at both 215 nm and 254 nm.
Example 148. 6-(2-aminopyrimidin-4-yl)- 1 -(cyclopropylmethyl)-N-(3-methoxybenzyl)- -indazole-3-carboxamide
Procedures described in Scheme 18 were used to prepare this compound. H NMR (DMSO, 400MHz) 8.87-8.84 (IH, m), 8.34 (IH, s), 8.34 (IH, d, J= 5.6), 8.21-8.19 (IH, m), 7.98-7.97 (IH, m), 7.53- 7.35 (3H, br), 7.19-7.15 (IH, m), 7.13-7.09 (IH, m), 6.88- 6.87 (2H, m), 6.74-6.73 (IH, m), 4.42-4.40 (4H, m), 3.66 (3H, s), 1.63-1.54 (IH, m), 0.81-0.69 (4H, m). LC/MS: C24H24N6O2 (M+l) 429. Single peak in analytical HPLC traces at both 215 nm and 254 nm.
Example 149. l-(2-(dimethylamino)ethyl)-N-(3-methoxybenzyl)-6-(lH-pyrazol-4-yl)- -indazole-3-carboxamide
Procedures described in Scheme 18 were used to prepare this compound. H NMR
(DMSO, 400MHz) 9.13 (IH, s), 8.81-8.78 (IH, m), 8.08-8.06 (IH, m), 7.97 (IH, s), 7.86- 7.84 (IH, m), 7.66-7.54 (2H, m), 7.57-7.54 (IH, m), 7.20-7.15 (IH, m), 6.88-6.74 (m, 2H0, 4.82-4.79 (2H, m), 4.46-4.43 (2H, m), 2.92-2.84 (5H, m), 2.36 (6H, s). LC/MS: C23H26N6O2 (M+l) 419. Single peak in analytical HPLC traces at both 215 nm and 254 nm.
Example 150. l-(cyclopropylmethyl)-N-(3-(isopropylcarbamoyl)phenyl)-6-(5-methyl- 7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-indazole-3-carboxamide
Procedures described in Scheme 18 were used to prepare this compound. H NMR (DMSO, 400MHz) 12.32 (IH, s), 10.36 (IH, s), 8.85 (s, 1H0, 8.43-8.34 (2H, m), 8.32- 7.96 (3H, m), 7.59-7.29 (4H, m), 4.89-4.47 (3H, m), 4.07-4.03 (2H, m), 1.95 (3H, s), 1.46-1.43 (IH, m), 1.129 (3H, s), 1.11 (3H, s), 0.89-0.86 (4H, m). LC/MS: C29H29N7O2 (M+1) 508. Single peak in analytical HPLC traces at both 215 nm and 254 nm.
Example 151. l-(cyclopropylmethyl)-N-(3-(isopropylcarbamoyl)phenyl)-6-(7H- pyrrolo[2,3-d]pyrimidin-4-yl)-lH-indazole-3-carboxamide
Procedures described in Scheme 18 were used to prepare this compound. H NMR
(DMSO, 400MHz) 12.32 (IH, s), 10.43 (IH, s), 8.93 (s, IH), 8.43-8.34 (3H, m), 8.32- 7.96 (3H, m), 7.59-7.29 (4H, m), 4.89-4.47 (3H, m), 4.07-4.03 (2H, m), 1.46-1.43 (IH, m), 1.129 (3H, s), 1.11 (3H, s), 0.89-0.86 (4H, m). LC/MS: C28H27N7O2 (M+1) 494. Single peak in analytic HPLC traces at both 215 nm and 254 nm.
Example 152. N-(3-methoxybenzyl)-l-propyl-6-(lH-pyrazol-4-yl)-lH-indazole-3- carboxamide
Procedures described in Scheme 18 were used to prepare this compound. H NMR (DMSO, 400MHz) 8.76-8.75 (IH, m), 8.14 (IH, s), 8.03 (IH, d, J= 8.4), 7.92 (IH, s), 7.48-7.47 (IH, m), 7.19-7.15 (IH, m), 6.88-6.86 (2H, m), 6.73-6.72 (IH, m), 4.39-4.38 (4H, m), 3.66 (3H, s), 1.88-1.83 (2H, m), 0.82 (3H, t, J= 7.2). LC/MS: C22H23N5O2 (M+1) 390. Single peak in analytic HPLC traces at both 215 nm and 254 nm.
Example 153. 1 -(cyclopropylmethyl)-N- (2- (dimethylamino)ethyl)-N- (3 - methoxybenzyl)-6-(lH-pyrazol-4-yl)-lH-indazole-3-carboxamide
Procedures described in Scheme 18 were used to prepare this compound. H NMR (DMSO, 400MHz) 9.14 (1H, s), 7.97-7.79 (4H, m), 7.35-7.33 (1H, m), 7.09-7.01 (1H, m), 6.73-6.60 (3H, m), 5.04 (1H, m), 4.53-4.07 (3H, m), 3.472-3.46 (4H, m), 3.32- 3.18(2H, m), 2.65-2.64 (6H, m), 2.36 (6H, s), 1.31-1.28 (1H, m), 0.47-0.41 (4H, m). LCMS: C27H32N6O2 (M+1) 473. Single peak in analytic HPLC traces at both 215 nm and 254 nm.
Example 154. l-(cyclopropylmethyl)-N-(3-methylbenzyl)-6-(lH-pyrazol-4-yl)-lH-
Procedures described in Scheme 18 were used to prepare this compound. LC/MS:
C23H23N5O (M+1) 386. Single peak in analytic HPLC traces at both 215 nm and 254 nm. Example 155. l-(cyclopropylmethyl)-N-(4-methoxybenzyl)-6-(lH-pyrazol-4-yl)-lH-
Procedures described in Scheme 18 were used to prepare this compound. LC/MS:
C23H23N5O2 (M+1) 402. Single peak in analytic HPLC traces at both 215 nm and 254 nm. Example 156. l-(cyclopropylmethyl)-N-(2-fluorobenzyl)-6-(lH-pyrazol-4-yl)-lH- indazole- 3 -carboxamide
Procedures described in Scheme 18 were used to prepare this compound. LC/MS:
C22H20FN5O (M+1) 390. Single peak in analytic HPLC traces at both 215 nm and 254 nm.
Example 157. 6-(2-aminopyrimidin-4-yl)-2-(cyclopropylmethyl)-N-(3-methoxybenzyl)- -indazole-3-carboxamide
Procedures described in Scheme 18 were used to prepare this compound. LC/MS:
C24H24N6O2 (M+1) 429. Single peak in analytic HPLC traces at both 215 nm and 254 nm. Example 158. 2-(cyclopropylmethyl)-N-(3-methoxybenzyl)-6-(lH-pyrazol-4-yl)-2H-
Procedures described in Scheme 18 were used to prepare this compound. LC/MS:
C23H23N5O2 (M+1) 402. Single peak in analytic HPLC traces at both 215 nm and 254 nm. Example 159. 2-(cyclopropylmethyl)-N-(3-(isopropylcarbamoyl)phenyl)-6-(5-methyl- -pyrrolo[2,3-d]pyrimidin-4-yl)-2H-indazole-3-carboxamide
Procedures described in Scheme 18 were used to prepare this compound. LC/MS:
C29H29N7O2 (M+1) 508. Single peak in analytic HPLC traces at both 215 nm and 254 nm.
Example 160. 2-(cyclopropylmethyl)-N- (2- (dimethylamino)ethyl)-N- (3 - methoxybenzyl)-6-(lH-pyrazol-4-yl)-2H-indazole-3-carboxamide
Procedures described in Scheme 18 were used to prepare this compound. LC/MS:
C27H32N6O2 (M+1) 473. Single peak in analytic HPLC traces at both 215 nm and 254 nm.
Example 161. l-(cyclopropylmethyl)-N-(3-(isopropylcarbamoyl)phenyl)-6-(5-methyl- 7H-pyrrolo[2,3-d]pyrimidin-4-yl)-lH-indazole-3-carboxamide
Procedures described in Scheme 18 were used to prepare this compound. LC/MS:
C29H29N7O2 (M+1) 508. Single peak in analytic HPLC traces at both 215 nm and 254 nm. Example 162. l-(cyclopropylmethyl)-N-(3-(isopropylcarbamoyl)phenyl)-6-(7H- pyrrolo[2,3-d]pyrimidin-4-yl)-lH-indazole-3-carboxamide
Procedures described in Scheme 18 were used to prepare this compound. LC/MS:
C28H27N7O2 (M+1) 494. Single peak in analytic HPLC traces at both 215 nm and 254 nm. Example 163. 1 -(cyclopropylmethyl)-N- (2- (dimethylamino)ethyl)-N- (3 - methoxybenzyl)-6-(lH-pyrazol-4-yl)-lH-indazole-3-carboxamide
Procedures described in Scheme 18 were used to prepare this compound. LC/MS:
C27H32N6O2 (M+1) 473.07. Single peak in analytic HPLC traces at both 215 nm and 254 nm.
Example 164. l-(2-(dimethylamino)ethyl)-N-(3-methoxybenzyl)-6-(pyridin-3-yl)-lH- indazole- 3 -carboxamide
Procedures described in Scheme 18 were used to prepare this compound. LC/MS:
C25H27N5O2 (M+1) 430. Single peak in analytic HPLC traces at both 215 nm and 254 nm. Example 165. l-(2-(dimethylamino)ethyl)-N-(3-methoxybenzyl)-6-(pyridin-4-yl)-lH- indazole- 3 -carboxamide
Procedures described in Scheme 18 were used to prepare this compound. LC/MS:
C25H27N5O2 (M+1) 430. Single peak in analytic HPLC traces at both 215 nm and 254 nm. Example 166. l-(2-(dimethylamino)ethyl)-N-(3-methoxybenzyl)-6-(lH-pyrazol-4-yl)- lH-indazole-3-carboxamide
C23H26N6O2 (M+1) 419. Single peak in analytic HPLC traces at both 215 nm and 254 nm. Example 167. 2-(cyclopropylmethyl)-N-(2-fluorobenzyl)-6-(lH-pyrazol-4-yl)-2H- indazole- 3 -carboxamide
Procedures described in Scheme 18 were used to prepare this compound. LC/MS:
C22H20FN5O (M+1) 390. Single peak in analytic HPLC traces at both 215 nm and 254 nm.
Example 168. 2-(cyclopropylmethyl)-N-(3-methylbenzyl)-6-(lH-pyrazol-4-yl)-2H- indazole- 3 -carboxamide
Procedures described in Scheme 18 were used to prepare this compound. LC/MS:
C23H23N5O (M+1) 386. Single peak in analytic HPLC traces at both 215 nm and 254 nm. Example 169. 2-(cyclopropylmethyl)-N-(3-methoxyphenyl)-6-(lH-pyrazol-4-yl)-2H-
Procedures described in Scheme 18 were used to prepare this compound. LC/MS:
C22H21N5O2 (M+1) 388.20. Single peak in analytic HPLC traces at both 215 nm and nm.
Example 170. 2-(cyclopropylmethyl)-N-(2-methylbenzyl)-6-( lH-pyrazol-4-yl)-2H- indazole- 3 -carboxamide
Procedures described in Scheme 18 were used to prepare this compound. LC/MS:
C23H23N5O (M+1) 386. Single peak in analytic HPLC traces at both 215 nm and 254 nm. Example 171. 6-(2-aminopyrimidin-4-yl)-N-(3-methoxybenzyl)-2-methyl-2H-indazole- -carboxamide
Procedures described in Scheme 18 were used to prepare this compound. LC/MS:
C21H20N6O2 (M+1) 389. Single peak in analytic HPLC traces at both 215 nm and 254 nm. Example 172. N-(3-methoxybenzyl)-2-methyl-6-(lH-pyrazol-4-yl)-2H-indazole-3- carboxamide
Procedures described in Scheme 18 were used to prepare this compound. LC/MS:
C2oH19N502 (M+1) 362. Single peak in analytic HPLC traces at both 215 nm and 254 nm.
Example 173. l-(cyclopropylmethyl)-N-(3-methoxybenzyl)-6-(lH-pyrazol-4-yl)-lH-
Procedures described in Scheme 18 were used to prepare this compound. LC/MS:
C23H23N5O2 (M+1) 402. Single peak in analytic HPLC traces at both 215 nm and 254 nm. Example 174. l-(cyclopropylmethyl)-N-(3-fluorobenzyl)-6-(lH-pyrazol-4-yl)-lH- indazole- 3 -carboxamide
Procedures described in Scheme 18 were used to prepare this compound. LC/MS:
C22H20N5O (M+1) 390. Single peak in analytic HPLC traces at both 215 nm and 254 nm. Example 175. l-(cyclopropylmethyl)-N-(3-methoxyphenyl)-6-(lH-pyrazol-4-yl)- 1H-
Procedures described in Scheme 18 were used to prepare this compound. LC/MS:
C22H21N5O2 (M+1) 388. Single peak in analytic HPLC traces at both 215 nm and 254 nm.
Scheme 19
19-4
Compound 13-3 (0.89 mmol), TMS-acetylene (1.5 equiv), Cul (15 mol ) were charged in a reactor. THF and triethylamine were added and the system was sealed and purged with argon for 3 minutes. Pd(PPh3)2Cl2 (10 mol ) was added and the system was again degassed by passing a stream of argon. The reaction mixture was heated at 150 °C for 1 h. Upon cooling down to the room temperature, the reaction mixture was diluted with DCM and filtered through Celite®. The filtrate was concentrated and again diluted with EtOAc. The organic layer was washed with water, and the aqueous layer extracted
with EtOAc (x3), dried and concentrated under vacuo. Purification by flash chromatography using Combiflash afforded 19-1.
Compound 19-1 (0.22 g, 0.72 mmol) was taken up in THF and treated with a solution of tetrabutylammonium fluoride in THF (TBAF, 1 M in THF). The resulting mixture was refluxed for 1 h and then cooled down to room temperature. The residue dissolved in EtOAc, and washed with water, dried and concentrated under reduced pressure. The crude product was dissolved in anhydrous DMF and cooled down to 0 °C.
Trifluoroacetic anhydride (TFAA, 0.12 mL) was next added. After 2 h, the reaction mixture was poured in to water and extracted with EtOAc (x3). The combined organics dried and concentrated. NaOH (2 M) was added to the residue and refluxed overnight. The resulting solution was acidified and extracted with EtOAc (x5). The combined organic layer was dried and concentrated to afford acid 19-2. The acid was utilized to make the target compounds 19-4, using the procedures described in Scheme 13.
Example 176. N-(3-methoxybenzyl)-6-(lH-pyrazol-4-yl)-lH-pyrrolo[2,3-b]pyridine-3- carboxamide
Procedures described in Scheme 19 were used to prepare this compound. LC/MS:
C19H17N502 (M+1) 348. Single peak in analytic HPLC traces at both 215 nm and 254 nm. Example 177. 6-(2-aminopyrimidin-4-yl)-N-(3-methoxybenzyl)- lH-pyrrolo[2,3- b]pyridine-3-carboxamide
Procedures described in Scheme 19 were used to prepare this compound. LC/MS:
C2oH18N602 (M+1) 375. Single peak in analytic HPLC traces at both 215 nm and 254 nm.
Scheme 20
The free acid intermediates 20-3a and 20-3b were prepared according to procedures described in WO2006059164. Products 20-5a and 20-5b were then obtained via the amide formation and the Suzuki coupling sequences using procedures described in
Scheme 13.
Example 178. N-(3-methoxybenzyl)-6-(lH-pyrazol-4-yl)-lH-pyrrolo[3,2-c]pyridine-3- carboxamide
Procedures described in Scheme 20 were used to prepare this compound. LC/MS:
C19H17N502 (M+1) 348. Single peak in analytic HPLC traces at both 215 nm and 254 nm. Example 179. 6-(2-aminopyrimidin-4-yl)-N-(3-methoxybenzyl)- lH-pyrrolo[3,2- c]pyridine-3-carboxamide
Procedures described in Scheme 20 were used to prepare this compound. LC/MS:
C2oH18N602 (M+1) 375. Single peak in analytic HPLC traces at both 215 nm and 254 nm.
Example 180. N-(3-methoxybenzyl)-6-(lH-pyrazol-4-yl)-lH-pyrrolo[3,2-c]pyridine-2- carboxamide
Procedures described in Scheme 20 were used to prepare this compound. LC/MS:
C19H17N502 (M+1) 348. Single peak in analytic HPLC traces at both 215 nm and 254 nm. Example 181. 6-(2-aminopyrimidin-4-yl)-N-(3-methoxybenzyl)- lH-pyrrolo[3,2- c]pyridine-2-carboxamide
Procedures described in Scheme 20 were used to prepare this compound. LC/MS:
C2oH18N602 (M+1) 375. Single peak in analytic HPLC traces at both 215 nm and 254 nm.
Scheme 21
Hydroxylamine sulfonic acid (21-1, 3 eq) in water was added to a solution of 3- bromopyridine (1 equiv) in DCM. The reaction mixture was heated to 50°C for lh then K2C03 was added, the heating was continued for additional 2h. K2C03 was removed by filtration and the solvent was removed by rotovapor. The residue was dissolved in EtOH, and KI was added to the solution. The mixture was kept in a refrigerator to crystallize the desired compound (21-2).
A mixture of the N-amino salt (21-2, 3eq), the alkyne (1 eq), and K2CO3 in anhydrous DMF was stirred at room temperature for 20h. After the completion of reaction (monitored by LCMS), the residue was dissolved in ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate. The solvent was removed under vacuo and the residue was subjected to flash chromatography to afford the desired compound (21-3). Compound 21-3 was then subjected to a sequence of hydrolysis, amide formation, and Suzuki coupling reactions to afford the final product (21-5) following the procedures described in Scheme 13.
Example 182. N-(3-methoxybenzyl)-6-(lH-pyrazol-4-yl)pyrazolo[l,5-a]pyridine-3- carboxamide
Procedures in Scheme 21 were utilized to synthesize this compound. LC/MS:
C19H17N502 (M+1) 348. Single peak in analytic HPLC traces at both 215 nm and 254 nm.
Example 183. N-(2-(dimethylamino)ethyl)-N-(3-methoxybenzyl)-6-(lH-pyrazol-4- yl)pyrazolo[ 1 ,5-a]pyridine-3-carboxamide
Procedures in Scheme 21 were utilized to synthesize this compound. LC/MS:
C23H26N6O2 (M+1) 419. Single peak in analytic HPLC traces at both 215 nm and 254 nm. Example 184. N-(2-(dimethylamino)ethyl)-N-(3-methoxybenzyl)-6-(pyridin-4- yl)pyrazolo[ 1 ,5-a]pyridine-3-carboxamide
C25H27N5O2 (M+1) 430. Single peak in analytic HPLC traces at both 215 nm and 254 nm. Example 185. N-(3-methoxybenzyl)-6-(pyridin-4-yl)pyrazolo[l,5-a]pyridine-3- carboxamide
Procedures in Scheme 21 were utilized to synthesize this compound. LC/MS:
C2iH18N402 (M+1) 359. Single peak in analytic HPLC traces at both 215 nm and 254 nm.
The following compounds are prepared based on procedures described
Schemes 1-21.
carboxamide
0 N-cyclopropyl-6-(lH-pyrazol- C20H18N6O 247 4-yl) -Ν- (pyridin- 3 -ylmethyl) - lH-pyrrolo[2,3-b]pyridine-3- carboxamide
Η
N-cyclopropyl-N-(pyridin-3- C24H20N6O 248 ylmethyl)-lH,l'H-4,6'- bipyrrolo[2,3-b]pyridine-3'- carboxamide
Η
0 N-cyclopropyl-N-(pyridin-3- C24H20N6O 249 ylmethyl)-6-(lH-pyrrolo[2,3- b]pyridin-4-yl)-lH- pyrrolo[3,2-c]pyridine-3-
Η carboxamide
0 N-cyclopropyl-6-(lH-pyrazol- C20H18N6O 250
4-yl) -N- (pyridin- 3 -ylmethyl) - lH-pyrrolo[3,2-c]pyridine-3- carboxamide
Η
6-(lH-pyrazol-4-yl)-N- C17H14N60 251 (pyridin-2-ylmethyl)- 1H- pyrrolo[3,2-c]pyridine-2- carboxamide
Η 0
6-(lH-pyrazol-4-yl)-N- C17H14N60 252 (pyridin-3-ylmethyl)- 1H- pyrrolo[3,2-c]pyridine-2- carboxamide
Η 0
N,l-diethyl-6-(lH-pyrazol-4- C21H22N60 253 yl)-N-(pyridin-3-ylmethyl)- 1 H-pyrrolo [3 ,2-c]pyridine-2- carboxamide
k °
N-cyclopropyl-6-(lH-pyrazol- C20H18N6O 254 4-yl) -N- (pyridin- 3 -ylmethyl) - 1 H-pyrrolo [3 ,2-c]pyridine-2- carboxamide
Η 0
N-cyclopropyl-6-(lH-pyrazol- C20H18N6O 255 4-yl) -N- (pyridin- 3 -ylmethyl) - lH-pyrrolo[2,3-b]pyridine-2- carboxamide
Η 0
Enzymatic RhoK2 (ROCK I and ROCK II) Assays.
Assays were performed using the STK2 kinase system from Cisbio. 5 μΐ mixture of a 1 μΜ STK2 substrate and ATP (ROCK-I: 4 μΜ; ROCK-II: 20 μΜ) in STK-buffer was added to the wells using a BioRAPTR FRD™ Workstation (Aurora Discovery). 20 nl of test compounds was dispensed. Reaction was started by addition of 5 μΐ of 2.5 nM ROCK-I or 0.5 nM ROCK-II in STK-buffer. After 4 h at RT the reaction was stopped by addition of 10 μΐ of lx antibody and 62.5 nM Sa-XL in detection buffer. After 1 h at RT the plates were read on the Viewlux in HTRF mode. The IC50s of all examples were in the range of 0.25 nM - 10 μΜ.
Myosin Light Chain Double Phosphorylation Assays (ppMLC, cell assay).
Serum starved smooth muscle cells were incubated with compound for lh before induction of myosin light chain phosphorylation by LPA for 30 min. Cells were washed and fixed before staining for phosphorylated myosin light chain and DNA.
Phosphorylation status was quantitated with the LI-COR Odyssey Imager.
Neurite Length Assay (N2a, cell assay).
N2a cells are maintained in DMEM/FBS at 37 °C and 5% C02. For the experiment the cells were plated on a poly-D-lysine coated 96-well tissue culture plate. After attachment, cell differentiation was induced for 2 days by addition of lOuM retinoic acid. Cells were treated for lh with a dilution of compounds in 0.3% DMSO final concentration before neurite retraction was induced by 5uM LPA. Cells were stained for tubulin and nuclei and images were acquired on a INCell 1000 workstation. Images were analyzed using the developer toolbox and neurite length was quantitated. The IC50s of all examples selected for testing were in the range of 1 nM - 20 μΜ.
Inhibitory potency for exemplary compounds:
* < 100 nM
** 100 nM - 1000 nM
*** > 1000 nM
N-(3-methoxybenzyl)-6-(lH-pyrazol-4-yl)-l-(2- *
(pyrrolidin- 1 -yl)ethyl)- 1 H-indole-3-carboxamide
N-(2-(dimethylamino)ethyl)-N-(3- ***
methoxybenzyl)-6-(lH-pyrazol-4-yl)-l-(2- (pyrrolidin- 1 -yl)ethyl)- 1 H-indole-3-carboxamide
(R)-N-(l-(3-methoxyphenyl)ethyl)-6-(lH- *
pyrazol-4-yl)- l-(2-(pyrrolidin- l-yl)ethyl)- 1H- indole-3-carboxamide
N-(3-methoxybenzyl)-6-(lH-pyrazol-4-yl)-l-(3- **
(trifluoromethyl)phenyl)-lH-indole-3- carboxamide
N-(3-methoxybenzyl)-6-(lH-pyrazol-4- ** *** yl)imidazo[ 1 ,2-a]pyridine-2-carboxa
6-(2-aminopyrimidin-4-yl)-N-(3- ** *** methoxybenzyl)imidazo[l,2-a]pyridine-2- carboxamide
N-(2-(dimethylamino)ethyl)-N-(3-methoxybenzyl)-6-(lH- *
pyrazol-4-yl)imidazo[ 1 ,2-a]pyridine-2-carboxamide
N-(3-methoxybenzyl)-6-(lH-pyrazol-4- ** *** yl)imidazo[ 1 ,2-a]pyridine-3-carboxamide
N-(3-methoxybenzyl)-2-methyl-6-(lH-pyrazol-4- *** *** yl)imidazo[ 1 ,2-a]pyridine-3-carboxamide
N-(3-methoxybenzyl)-7-(lH-pyrazol-4-yl)imidazo[l,2- * * a]pyridine-3-carboxamide
N-(2-(dimethylamino)ethyl)-N-(3- * ** methoxybenzyl)-7-(lH-pyrazol-4-yl)imidazo[l,2- a]pyridine-3-carboxamide
N-benzyl-7-(lH-pyrazol-4-yl)imidazo[l,2-a]pyridine-3- *
carboxamide
2-(6-Methoxychroman-3-yl)-7-(lH-pyrazol-4-yl)- * ** 4H-pyrido[ 1 ,2-a]pyrimidin-4-one
2-(6-Methoxychroman-3-yl)-7-(pyridin-4-yl)-4H- **
pyrido[ 1 ,2-a]pyrimidin-4-one
6-(lH-Pyrazol-4-yl)-lH-pyrrolo[2,3-b]pyridine- *
2-carboxylic acid 3-methoxy-benzylamide
6-(3-Methyl-lH-pyrazol-4-yl)-lH-pyrrolo[2,3- *
b]pyridine-2-carboxylic acid 3-methoxy- benzylamide
N-(3-methoxybenzyl)-l-methyl-6-(lH-pyrazol-4- * * yl)-lH-pyrrolo[2,3-b]pyridine-2-carboxamide
6-(lH-Pyrazol-4-yl)-lH-pyrrolo[2,3-b]pyridine- * ** 2-carboxylic acid (3-methoxy-benzyl)-methyl- amide
N-(3-methoxybenzyl)-6-(lH-pyrazol-4-yl)-l-(2- *
(pyrrolidin-l-yl)ethyl)-lH-pyrrolo[2,3-
b]pyridine-2-carboxamide
132 l-(3-hydroxypropyl)-N-(3-methoxybenzyl)-6- *
(lH-pyrazol-4-yl)-lH-pyrrolo[2,3-b]pyridine-2- carboxamide
121 N-cyclopropyl-N- (3 -methoxybenzyl)-6- ( 1 H- *
pyrazol-4-yl)-lH-pyrrolo[2,3-b]pyridine-2- carboxamide
123 6-(lH-Pyrazol-4-yl)-lH-pyrrolo[2,3-b]pyridine- *
2-carboxylic acid (2-dimethylamino-ethyl)-(3- methoxy-benzyl)-amide
115 6-(lH-Pyrazol-4-yl)-lH-pyrrolo[2,3-b]pyridine- *
2-carboxylic acid (3-methoxy-benzyl)-[3-(4- methyl-piperazin- 1 -yl)-propyl] -amide
118 6-(lH-Pyrazol-4-yl)-lH-pyrrolo[2,3-b]pyridine- *
2-carboxylic acid (3-methoxy-benzyl)-(2- pyrrolidin- 1 -yl-ethyl)-amide
138 N-(3-methoxybenzyl)-6-(lH-pyrazol-4-yl)-lH- * * indazole-3-carboxamide
142 N- (2- (dimethylamino)ethyl)-N- (3 - *
methoxybenzyl)-6-(lH-pyrazol-4-yl)-lH- indazole-3-carboxamide
136 N-(2-methoxybenzyl)-6-(lH-pyrazol-4-yl)-lH- *
indazole-3-carboxamide
141 N-(3-methoxybenzyl)-N-methyl-6-(lH-pyrazol- * *
4-yl)- lH-indazole-3-carboxamide
140 N-(cyclopropylmethyl)-N-(3-methoxybenzyl)-6- *
(lH-pyrazol-4-yl)-lH-indazole-3-carboxamide
135 N- (2-methylbenzyl)-6- ( 1 H-pyrazol-4-yl)- 1 H- *
indazole-3-carboxamide
137 N-(3-methoxyphenethyl)-6-(lH-pyrazol-4-yl)- *
lH-indazole-3-carboxamide
152 N-(3-methoxybenzyl)- 1 -propyl-6-( lH-pyrazol-4- *
yl)- lH-indazole-3-carboxamide
149 1 - (2- (dimethylamino)ethyl)-N- (3 - *
methoxybenzyl)-6-(lH-pyrazol-4-yl)-lH- indazole-3-carboxamide
165 1 - (2- (dimethylamino)ethyl)-N- (3 - *
methoxybenzyl)-6-(pyridin-4-yl)-lH-indazole-3- carboxamide
164 1 - (2- (dimethylamino)ethyl)-N- (3 - ***
methoxybenzyl)-6-(pyridin-3-yl)-lH-indazole-3- carboxamide
163 l-(cyclopropylmethyl)-N-(2- *
(dimethylamino)ethyl)-N-(3-methoxybenzyl)-6-
(lH-pyrazol-4-yl)-lH-indazole-3-carboxamide
143 6-(7-ethyl-8-oxo-8,9-dihydro-7H-purin-6-yl)-N- ***
(3 -methoxybenzyl) - 1 H-indazole- 3 -carboxamide
148 6-(2-aminopyrimidin-4-yl)- 1- *
(cyclopropylmethyl)-N-(3-methoxybenzyl)-lH- indazole-3-carboxamide
135 N-(3-methoxybenzyl)-l-methyl-6-(lH-pyrazol-4- *
yl)- lH-indazole-3-carboxamide
157 6-(2-aminopyrimidin-4-yl)-2- **
(cyclopropylmethyl)-N-(3-methoxybenzyl)-2H- indazole-3-carboxamide
158 2-(cyclopropylmethyl)-N-(3-methoxybenzyl)-6- **
(lH-pyrazol-4-yl)-2H-indazole-3-carboxamide
Evaluations
It is within ordinary skill to evaluate any compound disclosed and claimed herein for effectiveness in inhibition of a kinase enzyme such as a Rho kinase, AKT kinase, a p70S6K kinase, a LIM kinase, an IKK kinase, a Fit kinase, an Aurora kinase, or a Src kinase, or any combination thereof, and in the various cellular assays using the procedures described above. Accordingly, the person of ordinary skill can prepare and evaluate any of the claimed compounds without undue experimentation.
Any compound found to be an effective inhibitor of a kinase can likewise be tested in animal models and in human clinical studies using the skill and experience of the investigator to guide the selection of dosages and treatment regimens.
While the invention has been described and exemplified in sufficient detail for those skilled in this art to make and use it, various alternatives, modifications, and improvements will be apparent to those skilled in the art without departing from the spirit and scope of the claims.
All patents and publications are herein incorporated by reference to the same extent as if each individual publication was specifically and individually indicated to be incorporated by reference.
The terms and expressions which have been employed are used as terms of description and not of limitation, and there is no intention that in the use of such terms and expressions of excluding any equivalents of the features shown and described or portions thereof, but it is recognized that various modifications are possible within the
scope of the invention claimed. Thus, it should be understood that although the present invention has been specifically disclosed by preferred embodiments and optional features, modification and variation of the concepts herein disclosed may be resorted to by those skilled in the art, and that such modifications and variations are considered to be within the scope of this invention as defined by the appended claims.
Claims
What is claimed is:
1. A compound of the formula (I):
(I),
wherein
X1 and X2 are each independently N,
CR1; and X3, X4, X5, or X6 are each independently N, C-E, or CR , provided that ring B is substituted by only one E group, and provided that at least one of X3-X6 is N, and no more than five of Xx-X6 are N;
Z is a bond between X3 and X4, or Z is C(=0) wherein X3 and X4 are each respectively connected to the C(=0) by a single bond;
a dotted line indicates that a bond is either a single bond or a double bond;
R, R1 and R2 are each independently H, halo, (C1_C6)alkyl substituted with 0-2 Ra, (C2-C6)alkenyl substituted with 0-2 Ra, (C2_C6)alkynyl substituted with 0-2 Ra, cycloalkyl substituted with 0-2 Ra, cycloalkylalkyl substituted with 0-2 Ra, heterocyclyl substituted with 0-2 Ra, heterocyclylalkyl substituted with 0-2 Ra, aryl substituted with 0-2 Ra, aralkyl substituted with 0-2 Ra, heteroaryl substituted with 0-2 Ra, heteroarylalkyl substituted with 0-2 Ra, (Ci-C¼)haloalkyl, (Ci-C6)haloalkyl, (Ci-C¼)haloalkoxy, (Ci- C6)hydroxyalkyl, (CH2)pN02, (CH2)PCN, (CH2)pOR, (CH2)PNR2, (CH2)pCOR,
(CH2)pOCOR, (CH2)pC02R, (CH2)pCONR2, (CH2)pOCONR2, (CH2)pNRCOR,
(CH2)pNRC02R, (CH2)pNRCONR2, (CH2)PC(=NH)NH2, (CH2)pS02R, (CH2)pS02NR2, (CH2)pNRS02R, or (CH2)pNRS02NR2;
1 1 2
nl plus the number of C-R groups comprised by X and X is 0-3;
n2 plus the number of C-R2 groups comprised X3-X6 is 0-4;
1 1 2
n3 plus the number of C-Ar groups comprised by X and X is 1-4, such that at least one Ar1 is present on ring A;
Ra is halo, oxo, (C1-C6)alkyl substituted with 0-2 Ra, (C2-C6)alkenyl substituted with 0-2 Ra, (C2_C6)alkynyl substituted with 0-2 Ra, cycloalkyl substituted with 0-2 Ra, cycloalkylalkyl substituted with 0-2 Ra, heterocyclyl substituted with 0-2 Ra,
heterocyclylalkyl substituted with 0-2 Ra, aryl substituted with 0-2 Ra, aralkyl substituted with 0-2 Ra, heteroaryl substituted with 0-2 Ra, heteroarylalkyl substituted with 0-2 Ra, (Ci_C6)haloalkyl, (Ci_C6)haloalkoxy, (CH2)pN02, (CH2)PCN, (CH2)pOR, (CH2)PNR2, (CH2)pCOR, (CH2)pOCOR, (CH2)pC02R, (CH2)pCONR2, (CH2)pOCONR2,
(CH2)pNRCOR, (CH2)pNRC02R, (CH2)pNRCONR2, (CH2)PC(=NH)NH2, (CH2)pS02R, (CH2)pS02NR2, (CH2)pNRS02R, or (CH2)pNRS02NR2;
m is 0, 1, or 2;
p is 0, 1, 2, 3, or 4;
Ar1 is a 5 or 6 membered heteroaryl ring comprising at least one nitrogen atom, and 0-3 additional heteroatoms selected from O, S(0)m, and N; when Ar1 is a 5- membered heteroaryl, the nitrogen atom is disposed two atoms away from a point of attachment of the heteroaryl to ring A, and when Ar1 is a 6-membered heteroaryl, the nitrogen atom is disposed three atoms away from a point of attachment of the heteroaryl to ring A, wherein any 5-membered heteroaryl or 6-membered heteroaryl of Ar1 is substituted with 0-3 R , and wherein any 5-membered heteroaryl or 6-membered heteroaryl can be fused with an aryl or heteroaryl ring that is substituted with 0-3 R4;
R3 and R4 are each independently (C1_C6)alkyl substituted with 0-2 Ra,
(C2_C6)alkenyl substituted with 0-2 Ra, (C2_C6)alkynyl substituted with 0-2 Ra, cycloalkyl substituted with 0-2 Ra, cycloalkylalkyl substituted with 0-2 Ra, heterocyclyl substituted with 0-2 Ra, heterocyclylalkyl substituted with 0-2 Ra, aryl substituted with 0-2 Ra, aralkyl substituted with 0-2 Ra, heteroaryl substituted with 0-2 Ra, heteroarylalkyl substituted with 0-2 Ra, (Ci-C¼)haloalkyl, (C1_C6)haloalkyl, (Ci-C6)haloalkoxy, (Ci- C6)hydroxyalkyl, halo, cyano, nitro, oxo, -C(=0)R, -C(=0)OR, (C - C6)alkylene-C(=0)OR, -C(=0)NR2, (Ci-C6)alkylene-C(=0)NR2, -C(=NR)NR2, -OR,
(C1-C6)alkylene-OR, -OC(=0)(C1-C6)alkyl, -OC(=0)0(C1-C6)alkyl, -OC(=0)NR2, -NR2, -NRC(=0)R, -NRC(=0)0(C1-C6)alkyl, -NRC(=0)NR2, -NR(C1-C6)alkylene-NR2, -NR(Ci-C6)alkylene-OR, -NR(Ci-C6)alkylene-Ar2, -NRS02R, -SR, -S(0)R, -S02R, -OS02(C1-C6)alkyl, -S02NR2, pyrazolyl, triazolyl, or tetrazolyl, provided that R4 can also be hydrogen; or two R4 groups taken together form a fused cycloalkyl, heterocyclyl, aryl or heteroaryl ring substituted with 0-4 Ra;
Ar is unsubstituted aryl, unsubstituted heteroaryl, aryl substituted with one or more substituents selected from R4, or heteroaryl substituted with one or more
substituents selected from R4;
R5 is hydrogen, (C Ce kyl substituted with 0-2 Ra, (C Ce kenyl substituted with 0-2 Ra, C(=0)(C1-C6)alkyl substituted with 0-2 Ra, C(=0)0(C1-C6)alkyl substituted with 0-2 Ra, Ar2 wherein Ar2 is substituted with 0-2 R3; -(C1-C6)alkylene-Ar2 wherein Ar2 is substituted with 0-2 R3, -(Ci-C6)alkylC(=0)OR, or -(Ci-C6)alkylC(=0)NR2; and
E is any of the following, wherein a wavy line indicates a point of attachment to ring B:
(a) a group of the formula
wherein:
n is an integer from 0 to about 2;
G, J, and K are each independently CH2, O, S, NR5, or CHNHR5, provided that K can also be a bond;
or
wherein:
D is absent, or
D is
or D is a 5- to 7-membered heterocyclyl comprising NR ;
d is an integer from 0 to about 3;
Rh and Rk are each independently at every occurrence selected from H,
(Ci-C6)alkyl substituted with 0-2 Ra, NR2, and NRC(=0)-(C1_6)alkyl; or Rh and Rk taken together with a carbon atom to which they are attached form a (C3_C7)cycloalkyl ring substituted with 0-2 Ra;
R8 is H or C(=0)-(Ci-C6)alkyl;
Gi is CH2, O, S, NR5, NR5C(=0), C(=0)NR5, NR5C(=0)NR5, or CHNHR5; and G2 is a bond, O, NR5, or S;
or
(c) a group of the formula
wherein
c is 0-3,
Y is at each occurrence independently selected from O, S, NR, and C(RbRd), provided that no 0-0 bonds are present in Yc, or Y is absent;
Rb and Rd are each independently at every occurrence H, halo, (C1_C6)alkyl substituted with 0-2 Ra, (C2-C6)alkenyl substituted with 0-2 Ra, (C2-C6)alkynyl substituted with 0-2 Ra, cycloalkyl substituted with 0-2 Ra, heterocyclyl substituted with 0-2 Ra, aryl substituted with 0-2 Ra, aralkyl substituted with 0-2 Ra, heteroaryl substituted with 0-2 Ra, heteroarylalkyl substituted with 0-2 Ra, (Ci-Ce^aloalkyl, (CiX^haloalkoxy,
(CH2)pN02, (CH2)PCN, (CH2)pOR, (CH2)PNR2, (CH2)pCOR, (CH2)pOCOR, (CH2)pC02R,
(CH2)pCONR2, (CH2)pOCONR2, (CH2)pNRCOR, (CH2)pNRC02R, (CH2)pNRCONR2, (CH2)PC(=NH)NH2, (CH2)pS02R, (CH2)pS02NR2, (CH2)pNRS02R, or (CH2)pNRS02NR2 m is 0, 1, or 2; q is 1-5; and
R9 and R9A are each independently at every occurrence H, halo, (C1_C6)alkyl substituted with 0-2 Ra, (C2_C6)alkenyl substituted with 0-2 Ra, (C2_C6)alkynyl substituted with 0-2 Ra, cycloalkyl substituted with 0-2 Ra, cycloalkylalkyl substituted with 0-2 Ra, heterocyclyl substituted with 0-2 Ra, heterocyclylalkyl substituted with 0-2 Ra, aryl substituted with 0-2 Ra, aralkyl substituted with 0-2 Ra, heteroaryl substituted with 0-2 Ra, heteroarylalkyl substituted with 0-2 Ra, (C1_C6)haloalkyl, (C1_C6)haloalkyl, (Q.
C6)haloalkoxy, (Ci_C6)hydroxyalkyl, (CH2)pN02, (CH2)PCN, (CH2)pOR, (CH2)PNR2, (CH2)pCOR, (CH2)pOCOR, (CH2)pC02R, (CH2)pCONR2, (CH2)pOCONR2,
(CH2)pNRCOR, (CH2)pNRC02R, (CH2)pNRCONR2, (CH2)PC(=NH)NH2, (CH2)pS02R, (CH2)pS02NR2, (CH2)pNRS02R, (CH2)pNRS02NR2; or R9 and (Y)CR9A and the nitrogen atom to which they are bonded can together form a heterocyclyl substituted with 0-2 Ra wherein the heterocyclyl can be fused with a substituted or unsubstituted cycloalkyl, heterocyclyl, aryl, or heteroaryl ring system;
or any tautomer, salt, stereoisomer, hydrate, solvent, isotopically labeled form, or prodrug thereof.
2. The compound of claim 1 wherein each independently selected Ar1 is substituted or unsubstituted pyridyl, pyrazolyl, or pyrimidinyl.
3. The compound of claim 1 wherein each independently selected Ar1 is a substituted or unsubstituted bicyclic heteroaryl comprising any of the following ring systems, wherein a wavy line indicates a point of attachment:
4. The compound of claim 1, comprising a compound of formula (IA)
(IA)
or any tautomer, salt, stereoisomer, hydrate, solvent, isotopically labeled form, or prodrug thereof.
The compound of claim 4 wherein one of X1 and X' is N and the other of X1 and C-Ar1.
1 2 1 1
6. The compound of claim 4 wherein one of X1 and X is CR and the other of X1 and X2 is C-Ar1.
7. The compound of claim 4 comprising a compound of the formula
8. The compound of claim 7 wherein R is a substituted or unsubstituted aryl or heteroaryl, Y is C(RbRd), and c = 0, 1, or 2.
9. The compound of claim 7 wherein Ar is substituted or unsubstituted pyridyl, pyrazolyl, or pyrimidinyl, or is a substituted or unsubstituted bicyclic heteroaryl comprising any of the following ring systems, wherein a wavy line indicates a point of attachment:
The compound of claim 4, comprising any of the following structures:
174
or any tautomer, salt, stereoisomer, hydrate, solvent, isotopically labeled form, or prodrug thereof.
(IB)
or any tautomer, salt, stereoisomer, hydrate, solvent, isotopically labeled form, or prodrug thereof.
12. The compound of claim 11 wherein Ar1 is substituted or unsubstituted pyridyl, pyrazolyl, or pyrimidinyl, or is a substituted or unsubstituted bicyclic heteroaryl comprising any of the following ring systems, wherein a wavy line indicates a point of attachment:
(IC)
or any tautomer, salt, stereoisomer, hydrate, solvent, isotopically labeled form, or prodrug thereof.
The compound of claim 13, comprising a compound of any of formulas:
or any tautomer, salt, stereoisomer, hydrate, solvent, isotopically labeled form, or prodrug thereof.
15. The compound of claim 13, wherein Y is CRbRd; c is 0, 1, or 2; or Ar1 is any of the following ring systems, wherein a wavy line indicates a point of attachment:
any combination thereof.
The compound of claim 13, comprising any of the following structures:
187
or any tautomer, salt, stereoisomer, hydrate, solvent, isotopically labeled form, or prodrug thereof.
The compound of claim 1, comprising a compound of formula (ID)
(ID)
or any tautomer, salt, stereoisomer, hydrate, solvent, isotopically labeled form, or prodrug thereof.
18. The compound of claim 17 wherein Ar1 is substituted or unsubstituted pyridyl, pyrazolyl, or pyrimidinyl, or is a substituted or unsubstituted bicyclic heteroaryl comprising any of the following ring systems, wherein a wavy line indicates a point of attachment:
(IE)
or any tautomer, salt, stereoisomer, hydrate, solvent, isotopically labeled form, or prodrug thereof.
The com ound of claim 19, comprising a compound of any of the formulas:
or any tautomer, salt, stereoisomer, hydrate, solvent, isotopically labeled form, or prodrug thereof.
21. The compound of claim 19 wherein Ar1 is substituted or unsubstituted pyridyl, pyrazolyl, or pyrimidinyl, or is a substituted or unsubstituted bicyclic heteroaryl comprising any of the following ring systems, wherein a wavy line indicates a point of attachment:
or any tautomer, salt, stereoisomer, hydrate, solvent, isotopically labeled form, or prodrug thereof.
(IF)
or any tautomer, salt, stereoisomer, hydrate, solvent, isotopically labeled form, or prodrug thereof.
24. The compound of claim 23 wherein Ar1 is substituted or unsubstituted pyridyl, pyrazolyl, or pyrimidinyl, or is a substituted or unsubstituted bicyclic heteroaryl comprising any of the following ring systems, wherein a wavy line indicates a point of attachment:
The compound of claim 23 comprising any of the following:
or any tautomer, salt, stereoisomer, hydrate, solvent, isotopically labeled form, or prodrug thereof.
(IG)
or any tautomer, salt, stereoisomer, hydrate, solvent, isotopically labeled form, or prodrug thereof.
The compound of claim 26, comprising any of the formulas:
or any tautomer, salt, stereoisomer, hydrate, solvent, or prodrug thereof.
28. The compound of claim 26 wherein Ar1 is substituted or unsubstituted pyridyl, pyrazolyl, or pyrimidinyl, or is a substituted or unsubstituted bicyclic heteroaryl comprising any of the following ring systems, wherein a wavy line indicates a point of attachment:
(IH)
or any tautomer, salt, stereoisomer, hydrate, solvent, isotopically labeled form, or prodrug thereof.
30. The compound of claim 29 wherein Ar1 is substituted or unsubstituted pyridyl, pyrazolyl, or pyrimidinyl, or is a substituted or unsubstituted bicyclic heteroaryl comprising any of the following ring systems, wherein a wavy line indicates a point of attachment:
(D)
or any tautomer, salt, stereoisomer, hydrate, solvent, isotopically labeled form, or prodrug thereof.
32. The compound of claim 31 wherein Ar1 is substituted or unsubstituted pyridyl, pyrazolyl, or pyrimidinyl, or is a substituted or unsubstituted bicyclic heteroaryl comprising any of the following ring systems, wherein a wavy line indicates a point of attachment:
or any tautomer, salt, stereoisomer, hydrate, solvent, isotopically labeled form, or prodrug thereof.
34. The compound of claim 33 wherein Ar1 is substituted or unsubstituted pyridyl, pyrazolyl, or pyrimidinyl, or is a substituted or unsubstituted bicyclic heteroaryl comprising any of the following ring systems, wherein a wavy line indicates a point of attachment:
or any tautomer, salt, stereoisomer, hydrate, solvent, isotopically labeled form, or prodrug thereof.
36. The compound of claim 1 com rising a compound of formula (IL)
or any tautomer, salt, stereoisomer, hydrate, solvent, isotopically labeled form, or prodrug thereof.
37. The compound of claim 36 wherein Ar1 is substituted or unsubstituted pyridyl, pyrazolyl, or pyrimidinyl, or is a substituted or unsubstituted bicyclic heteroaryl comprising any of the following ring systems, wherein a wavy line indicates a point of attachment:
202
203
204
207
208
209
210
211
212
213
214
215
216
39. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable excipient.
40. A pharmaceutical combination comprising a compound of claim 1 and a second medicament.
41. A pharmaceutical composition comprising the combination of claim 40 and a pharmaceutically acceptable excipient.
42. A method of inhibiting a kinase enzyme, comprising contacting the kinase enzyme and an effective amount of a compound of claim 1.
43. The method of claim 42 wherein the kinase enzyme comprises a Rho kinase, an AKT kinase, a p70S6K kinase, a LIM kinase, an IKK kinase, a Fit kinase, an Aurora kinase, or a Src kinase, or any combination thereof.
44. A method of treating a malcondition in a patient, wherein inhibition of a kinase enzyme comprising a Rho kinase, an AKT kinase, a p70S6K kinase, a LIM kinase, an IKK kinase, a Fit kinase, an Aurora kinase, or a Src kinase, or any combination thereof, is medically indicated, the method comprising administering a compound of claim 1 to the patient in a dose, at a frequency, and for a duration to provide a beneficial effect to the patient.
45. The method of claim 44 wherein the malcondition comprises hypertension, atherosclerosis, angina, stroke, arterial obstruction, peripheral arterial disease, peripheral circulation disorder, erectile dysfunction, acute and chronic pain, dementia, Alzheimer's disease, Parkinson's disease, neuronal degeneration, asthma, amyotrophic lateral sclerosis, spinal cord injury, rheumatoid arthritis, osteoarthritis, osteoporosis, psoriasis, cerebral vasospasm, glaucoma, spinal cord injury, multiple sclerosis, pulmonary hypertension, acute respiratory distress syndrome, inflammation, diabetes, urinary organ diseases such as overactive bladder (OAB) and benign prostatic hypertrophy (BPH),
metastasis, cancer, open angle glaucoma, ocular hypertension, retinopathy, autoimmune disease or viral infection.
46. Use of a compound of claim 1 in preparation of a medicament.
47. The use of claim 46 wherein the medicament is adapted to inhibit a Rho kinase, an AKT kinase, a p70S6K kinase, a LIM kinase, an IKK kinase, a Fit kinase, an Aurora kinase, or a Src kinase, or any combination thereof, or the medicament is adapted to treat a malcondition wherein inhibition of the kinase is medically indicated.
48. The use of claim 47 wherein the malcondition comprises hypertension, atherosclerosis, angina, stroke, arterial obstruction, peripheral arterial disease, peripheral circulation disorder, erectile dysfunction, acute and chronic pain, dementia, Alzheimer's disease, Parkinson's disease, neuronal degeneration, asthma, amyotrophic lateral sclerosis, spinal cord injury, rheumatoid arthritis, osteoarthritis, osteoporosis, psoriasis, cerebral vasospasm, glaucoma, spinal cord injury, multiple sclerosis, pulmonary hypertension, acute respiratory distress syndrome, inflammation, diabetes, urinary organ diseases such as overactive bladder (OAB) and benign prostatic hypertrophy (BPH), metastasis, cancer, open angle glaucoma, ocular hypertension, retinopathy, autoimmune disease or viral infection.
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Cited By (180)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
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US8232294B2 (en) | 2009-03-21 | 2012-07-31 | Ning Xi | Amino ester derivatives, sailts thereof and methods of use |
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US8916555B2 (en) | 2012-03-16 | 2014-12-23 | Axikin Pharmaceuticals, Inc. | 3,5-diaminopyrazole kinase inhibitors |
US9073921B2 (en) | 2013-03-01 | 2015-07-07 | Novartis Ag | Salt forms of bicyclic heterocyclic derivatives |
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US9309238B2 (en) | 2009-11-05 | 2016-04-12 | University Of Notre Dame Du Lac | Imidazo [1,2-a]pyridine compounds, synthesis thereof, and methods of using same |
US9388185B2 (en) | 2012-08-10 | 2016-07-12 | Incyte Holdings Corporation | Substituted pyrrolo[2,3-b]pyrazines as FGFR inhibitors |
WO2016133838A1 (en) | 2015-02-20 | 2016-08-25 | Rigel Pharmaceuticals, Inc. | Gdf-8 inhibitors |
US20160257679A1 (en) * | 2013-09-26 | 2016-09-08 | Janssen Pharmaceutica Nv | NEW 1-(4-PYRIMIDINYL)-1H-PYRROLO[3,2-c]PYRIDINE DERIVATIVES AS NIK INHIBITORS |
JP2016169241A (en) * | 2012-07-27 | 2016-09-23 | 佐藤製薬株式会社 | Difluoromethylene compound |
US9475825B2 (en) | 2014-09-08 | 2016-10-25 | Samumed, Llc | 3-(3H-imidazo[4,5-C]pyridin-2-yl)-1H-pyrazolo[3,4-C]pyridine and therapeutic uses thereof |
US9475807B2 (en) | 2014-09-08 | 2016-10-25 | Samumed, Llc | 2-(1H-indazol-3-yl)-1H-imidazo[4,5-C]pyridine and therapeutic uses thereof |
US9493442B2 (en) | 2014-02-13 | 2016-11-15 | Incyte Corporation | Cyclopropylamines as LSD1 inhibitors |
US9493450B2 (en) | 2014-02-13 | 2016-11-15 | Incyte Corporation | Cyclopropylamines as LSD1 inhibitors |
US9493487B2 (en) | 2014-09-08 | 2016-11-15 | Samumed, Llc | 3-(1H-imidazo[4,5-C]pyridin-2-YL)-1H-pyrazolo[3,4-B]pyridine and therapeutic uses thereof |
US9527835B2 (en) | 2014-02-13 | 2016-12-27 | Incyte Corporation | Cyclopropylamines as LSD1 inhibitors |
US9533954B2 (en) | 2010-12-22 | 2017-01-03 | Incyte Corporation | Substituted imidazopyridazines and benzimidazoles as inhibitors of FGFR3 |
US9533984B2 (en) | 2013-04-19 | 2017-01-03 | Incyte Holdings Corporation | Bicyclic heterocycles as FGFR inhibitors |
US9540398B2 (en) | 2014-09-08 | 2017-01-10 | Samumed, Llc | 3-(1h-imidazo[4,5-C]pyridin-2-yl)-1h-pyrazolo[3,4-C]pyridine and therapeutic uses thereof |
US9540351B2 (en) | 2013-09-18 | 2017-01-10 | Axikin Pharmaceuticals, Inc. | Pharmaceutically acceptable salts of 3,5-diaminopyrazole kinase inhibitors |
US9546185B2 (en) | 2014-09-08 | 2017-01-17 | Samumed, Llc | 3-(3H-imidazo[4,5-B]pyridin-2-yl)-1H-pyrazolo[3,4-C]pyridine and therapeutic uses thereof |
US9546163B2 (en) | 2014-12-23 | 2017-01-17 | Axikin Pharmaceuticals, Inc. | 3,5-diaminopyrazole kinase inhibitors |
US9580423B2 (en) | 2015-02-20 | 2017-02-28 | Incyte Corporation | Bicyclic heterocycles as FGFR4 inhibitors |
US9611267B2 (en) | 2012-06-13 | 2017-04-04 | Incyte Holdings Corporation | Substituted tricyclic compounds as FGFR inhibitors |
KR101727650B1 (en) | 2009-05-14 | 2017-04-17 | 얀센 파마슈티카 엔.브이. | Compounds with two fused bicyclic heteroaryl moieties as modulators of leukotriene a4 hydrolase |
US9657016B2 (en) | 2014-09-08 | 2017-05-23 | Samumed, Llc | 3-(1h-benzo[d]imidazol-2-yl)-1h-pyrazolo[3,4-c]pyridine and therapeutic uses thereof |
US9670210B2 (en) | 2014-02-13 | 2017-06-06 | Incyte Corporation | Cyclopropylamines as LSD1 inhibitors |
US9695180B2 (en) | 2014-07-10 | 2017-07-04 | Incyte Corporation | Substituted imidazo[1,2-a]pyrazines as LSD1 inhibitors |
US9695168B2 (en) | 2014-07-10 | 2017-07-04 | Incyte Corporation | Substituted imidazo[1,5-α]pyridines and imidazo[1,5-α]pyrazines as LSD1 inhibitors |
US9695167B2 (en) | 2014-07-10 | 2017-07-04 | Incyte Corporation | Substituted triazolo[1,5-a]pyridines and triazolo[1,5-a]pyrazines as LSD1 inhibitors |
US9708318B2 (en) | 2015-02-20 | 2017-07-18 | Incyte Corporation | Bicyclic heterocycles as FGFR4 inhibitors |
US9738638B2 (en) | 2014-09-08 | 2017-08-22 | Samumed, Llc | 2-(1H-indazol-3-yl)-3H-imidazo[4,5-B]pyridine and therapeutic uses thereof |
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US9758523B2 (en) | 2014-07-10 | 2017-09-12 | Incyte Corporation | Triazolopyridines and triazolopyrazines as LSD1 inhibitors |
AU2015239886B2 (en) * | 2014-04-04 | 2018-02-01 | Iomet Pharma Ltd | Indole derivatives for use in medicine |
US9890156B2 (en) | 2015-02-20 | 2018-02-13 | Incyte Corporation | Bicyclic heterocycles as FGFR4 inhibitors |
US9908867B2 (en) | 2013-01-08 | 2018-03-06 | Samumed, Llc | 3-(benzoimidazol-2-yl)-indazole inhibitors of the Wnt signaling pathway and therapeutic uses thereof |
US9944647B2 (en) | 2015-04-03 | 2018-04-17 | Incyte Corporation | Heterocyclic compounds as LSD1 inhibitors |
US9981962B2 (en) | 2014-10-23 | 2018-05-29 | Janssen Pharmaceutica Nv | Pyrazole derivatives as NIK inhibitors |
US9981963B2 (en) | 2013-09-26 | 2018-05-29 | Janssen Pharmaceutica Nv | 3-(1H-pyrazol-4-yl)-1H-pyrrolo[2,3-c]pyridine derivatives as NIK inhibitors |
WO2018108156A1 (en) * | 2016-12-16 | 2018-06-21 | 成都先导药物开发有限公司 | Rock inhibitor and application thereof |
US10005776B2 (en) | 2014-10-23 | 2018-06-26 | Janssen Pharmaceutica Nv | Compounds as NIK inhibitors |
US10072004B2 (en) | 2016-06-01 | 2018-09-11 | Samumed, Llc | Process for preparing N-(5-(3-(7-(3-fluorophenyl)-3H-imidazo [4,5-C]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)-3-methylbutanamide |
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US10155756B2 (en) * | 2014-10-21 | 2018-12-18 | Guangzhou Eggbio Co., Ltd. | Pyrazolo[1,5-A]pyridine compounds and use thereof |
US10166218B2 (en) | 2015-08-03 | 2019-01-01 | Samumed, Llc | 3-(1H-indol-2-yl)-1H-pyrazolo[3,4-C]pyridines and therapeutic uses thereof |
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US10206908B2 (en) | 2015-08-03 | 2019-02-19 | Samumed, Llc | 3-(1H-pyrrolo[3,2-C]pyridin-2-YL)-1H-pyrazolo[3,4-C]pyridines and therapeutic uses thereof |
US10221180B2 (en) | 2014-10-23 | 2019-03-05 | Janssen Pharmaceutica Nv | Pyrazolopyrimidine derivatives as NIK inhibitors |
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US10226453B2 (en) | 2015-08-03 | 2019-03-12 | Samumed, Llc | 3-(1H-indol-2-yl)-1H-pyrazolo[4,3-B]pyridines and therapeutic uses thereof |
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US10266530B2 (en) | 2016-09-09 | 2019-04-23 | Incyte Corporation | Pyrazolopyridine compounds and uses thereof |
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US10285982B2 (en) | 2015-08-03 | 2019-05-14 | Samumed, Llc | 3-(1H-pyrrolo[2,3-B]pyridin-2-yl)-1H-pyrazolo[3,4-C]pyridines and therapeutic uses thereof |
US10285983B2 (en) | 2015-08-03 | 2019-05-14 | Samumed, Llc | 3-(1H-pyrrolo[2,3-B]pyridin-2-yl)-1H-pyrazolo[3,4-B] pyridines and therapeutic uses thereof |
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WO2019121159A1 (en) | 2017-12-21 | 2019-06-27 | Basf Se | Pesticidal compounds |
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WO2019129025A1 (en) * | 2017-12-26 | 2019-07-04 | 迈第康(上海)生物医药科技有限公司 | Tetrahydropyrrole compound, preparation method therefor, pharmaceutical composition containing same, and use thereof |
US10350199B2 (en) | 2015-08-03 | 2019-07-16 | Samumed, Llc | 3-(1h-pyrrolo[2,3-b]pyridin-2-yl)-1h-indazoles and therapeutic uses thereof |
US10383861B2 (en) | 2015-08-03 | 2019-08-20 | Sammumed, LLC | 3-(1H-pyrrolo[2,3-C]pyridin-2-yl)-1H-pyrazolo[3,4-C]pyridines and therapeutic uses thereof |
US10392383B2 (en) | 2015-08-03 | 2019-08-27 | Samumed, Llc | 3-(1H-benzo[d]imidazol-2-yl)-1H-pyrazolo[4,3-b]pyridines and therapeutic uses thereof |
WO2019201297A1 (en) * | 2018-04-18 | 2019-10-24 | 南京明德新药研发有限公司 | Benzopyrazole compound used as rho kinase inhibitor |
US10463651B2 (en) | 2015-08-03 | 2019-11-05 | Samumed, Llc | 3-(1H-pyrrolo[3,2-C]pyridin-2-YL)-1H-indazoles and therapeutic uses thereof |
US10519169B2 (en) | 2015-08-03 | 2019-12-31 | Samumed, Llc | 3-(1H-pyrrolo[2,3-C]pyridin-2-yl)-1 H-pyrazolo[4,3-B]pyridines and therapeutic uses thereof |
US10544139B2 (en) | 2015-11-06 | 2020-01-28 | Samumed, Llc | Treatment of osteoarthritis |
US10588900B2 (en) | 2016-02-09 | 2020-03-17 | Pharmakea, Inc. | Quinolinone lysyl oxidase-like 2 inhibitors and uses thereof |
US10604512B2 (en) | 2015-08-03 | 2020-03-31 | Samumed, Llc | 3-(1H-indol-2-yl)-1H-indazoles and therapeutic uses thereof |
US10611762B2 (en) | 2017-05-26 | 2020-04-07 | Incyte Corporation | Crystalline forms of a FGFR inhibitor and processes for preparing the same |
US10618916B2 (en) | 2018-05-11 | 2020-04-14 | Incyte Corporation | Heterocyclic compounds as immunomodulators |
EP3643705A1 (en) | 2018-10-24 | 2020-04-29 | Basf Se | Pesticidal compounds |
US10668171B2 (en) | 2015-05-30 | 2020-06-02 | Ptc Therapeutics, Inc. | Methods for modulating RNA splicing |
US10669271B2 (en) | 2018-03-30 | 2020-06-02 | Incyte Corporation | Heterocyclic compounds as immunomodulators |
US10669240B2 (en) | 2014-03-20 | 2020-06-02 | Samumed, Llc | 5-substituted indazole-3-carboxamides and preparation and use thereof |
US10722495B2 (en) | 2017-09-08 | 2020-07-28 | Incyte Corporation | Cyanoindazole compounds and uses thereof |
US10745388B2 (en) | 2018-02-20 | 2020-08-18 | Incyte Corporation | Indazole compounds and uses thereof |
US10752635B2 (en) | 2018-02-20 | 2020-08-25 | Incyte Corporation | Indazole compounds and uses thereof |
US10758523B2 (en) | 2016-11-07 | 2020-09-01 | Samumed, Llc | Single-dose, ready-to-use injectable formulations |
US10793565B2 (en) | 2016-12-22 | 2020-10-06 | Incyte Corporation | Heterocyclic compounds as immunomodulators |
US10800761B2 (en) | 2018-02-20 | 2020-10-13 | Incyte Corporation | Carboxamide compounds and uses thereof |
US10800782B2 (en) | 2016-08-31 | 2020-10-13 | Agios Pharmaceutical, Inc. | Inhibitors of cellular metabolic processes |
US10806785B2 (en) | 2016-12-22 | 2020-10-20 | Incyte Corporation | Immunomodulator compounds and methods of use |
US10806726B2 (en) | 2016-10-21 | 2020-10-20 | Samumed, Llc | Methods of using indazole-3-carb oxamides and their use as Wnt/B-catenin signaling pathway inhibitors |
US10851105B2 (en) | 2014-10-22 | 2020-12-01 | Incyte Corporation | Bicyclic heterocycles as FGFR4 inhibitors |
CN112020501A (en) * | 2018-02-23 | 2020-12-01 | 萨穆梅德有限公司 | 5-heteroaryl substituted indazol-3-yl carboxamides, their preparation and use |
WO2020242946A1 (en) | 2019-05-24 | 2020-12-03 | Fmc Corporation | Pyrazole-substituted pyrrolidinones as herbicides |
US10858319B2 (en) | 2016-10-03 | 2020-12-08 | Iomet Pharma Ltd. | Indole derivatives for use in medicine |
US10874672B2 (en) | 2015-12-10 | 2020-12-29 | Ptc Therapeutics, Inc. | Methods for treating Huntington's disease |
EP3766879A1 (en) | 2019-07-19 | 2021-01-20 | Basf Se | Pesticidal pyrazole derivatives |
US10899755B2 (en) | 2018-08-08 | 2021-01-26 | Incyte Corporation | Benzothiazole compounds and uses thereof |
US10919888B2 (en) | 2015-09-17 | 2021-02-16 | University Of Notre Dame Du Lac | Benzyl amine-containing heterocyclic compounds and compositions useful against mycobacterial infection |
US10968200B2 (en) | 2018-08-31 | 2021-04-06 | Incyte Corporation | Salts of an LSD1 inhibitor and processes for preparing the same |
WO2021093795A1 (en) * | 2019-11-15 | 2021-05-20 | 武汉朗来科技发展有限公司 | Rock inhibitor, preparation method therefor and use thereof |
US11014929B2 (en) | 2016-09-09 | 2021-05-25 | Incyte Corporation | Pyrazolopyrimidine compounds and uses thereof |
US11066404B2 (en) | 2018-10-11 | 2021-07-20 | Incyte Corporation | Dihydropyrido[2,3-d]pyrimidinone compounds as CDK2 inhibitors |
US11066394B2 (en) | 2019-08-06 | 2021-07-20 | Incyte Corporation | Solid forms of an HPK1 inhibitor |
US11111247B2 (en) | 2018-09-25 | 2021-09-07 | Incyte Corporation | Pyrazolopyrimidine compounds and uses thereof |
US11174257B2 (en) | 2018-05-04 | 2021-11-16 | Incyte Corporation | Salts of an FGFR inhibitor |
US11242343B2 (en) | 2016-09-09 | 2022-02-08 | Incyte Corporation | Pyrazolopyridine compounds and uses thereof |
WO2022052861A1 (en) * | 2020-09-09 | 2022-03-17 | 成都奥睿药业有限公司 | 5-substituted indole 3-amide derivative, preparation method and use thereof |
US11299473B2 (en) | 2018-04-13 | 2022-04-12 | Incyte Corporation | Benzimidazole and indole compounds and uses thereof |
US11306088B2 (en) | 2016-06-21 | 2022-04-19 | X4 Pharmaceuticals, Inc. | CXCR4 inhibitors and uses thereof |
WO2022101453A1 (en) * | 2020-11-12 | 2022-05-19 | Conservatoire National des Arts et Métiers | Compounds and methods for treating a cytokine-mediated disease |
US11352328B2 (en) | 2016-07-12 | 2022-06-07 | Arisan Therapeutics Inc. | Heterocyclic compounds for the treatment of arenavirus |
WO2022140326A1 (en) * | 2020-12-22 | 2022-06-30 | Gilead Sciences, Inc. | Substituted indole compounds |
US11384083B2 (en) | 2019-02-15 | 2022-07-12 | Incyte Corporation | Substituted spiro[cyclopropane-1,5′-pyrrolo[2,3-d]pyrimidin]-6′(7′h)-ones as CDK2 inhibitors |
US11382918B2 (en) | 2017-06-28 | 2022-07-12 | Ptc Therapeutics, Inc. | Methods for treating Huntington's Disease |
US11395822B2 (en) | 2017-06-28 | 2022-07-26 | Ptc Therapeutics, Inc. | Methods for treating Huntington's disease |
US11401279B2 (en) | 2019-09-30 | 2022-08-02 | Incyte Corporation | Pyrido[3,2-d]pyrimidine compounds as immunomodulators |
US11407750B2 (en) | 2019-12-04 | 2022-08-09 | Incyte Corporation | Derivatives of an FGFR inhibitor |
US11407749B2 (en) | 2015-10-19 | 2022-08-09 | Incyte Corporation | Heterocyclic compounds as immunomodulators |
US11406624B2 (en) | 2017-02-15 | 2022-08-09 | Incyte Corporation | Pyrazolopyridine compounds and uses thereof |
US11407753B2 (en) | 2017-06-05 | 2022-08-09 | Ptc Therapeutics, Inc. | Compounds for treating Huntington's disease |
US11427567B2 (en) | 2019-08-14 | 2022-08-30 | Incyte Corporation | Imidazolyl pyrimidinylamine compounds as CDK2 inhibitors |
US11440914B2 (en) | 2019-05-01 | 2022-09-13 | Incyte Corporation | Tricyclic amine compounds as CDK2 inhibitors |
US11447494B2 (en) | 2019-05-01 | 2022-09-20 | Incyte Corporation | Tricyclic amine compounds as CDK2 inhibitors |
US11465981B2 (en) | 2016-12-22 | 2022-10-11 | Incyte Corporation | Heterocyclic compounds as immunomodulators |
US11466004B2 (en) | 2018-05-04 | 2022-10-11 | Incyte Corporation | Solid forms of an FGFR inhibitor and processes for preparing the same |
US11472791B2 (en) | 2019-03-05 | 2022-10-18 | Incyte Corporation | Pyrazolyl pyrimidinylamine compounds as CDK2 inhibitors |
WO2022237878A1 (en) * | 2021-05-14 | 2022-11-17 | 武汉朗来科技发展有限公司 | Crystal form of compound, composition containing crystal form, preparation method therefor and use thereof |
WO2022237892A1 (en) * | 2021-05-14 | 2022-11-17 | 武汉朗来科技发展有限公司 | Acid addition salt of rock inhibitor, and crystal form, composition and pharmaceutical use thereof |
US11535615B2 (en) | 2015-12-22 | 2022-12-27 | Incyte Corporation | Heterocyclic compounds as immunomodulators |
US11566028B2 (en) | 2019-10-16 | 2023-01-31 | Incyte Corporation | Bicyclic heterocycles as FGFR inhibitors |
US11572366B2 (en) | 2015-11-19 | 2023-02-07 | Incyte Corporation | Heterocyclic compounds as immunomodulators |
US11591329B2 (en) | 2019-07-09 | 2023-02-28 | Incyte Corporation | Bicyclic heterocycles as FGFR inhibitors |
US11608501B2 (en) | 2017-06-14 | 2023-03-21 | Ptc Therapeutics, Inc. | Methods for modifying RNA splicing |
US11608337B2 (en) | 2016-05-06 | 2023-03-21 | Incyte Corporation | Heterocyclic compounds as immunomodulators |
US11607416B2 (en) | 2019-10-14 | 2023-03-21 | Incyte Corporation | Bicyclic heterocycles as FGFR inhibitors |
US11613536B2 (en) | 2016-08-29 | 2023-03-28 | Incyte Corporation | Heterocyclic compounds as immunomodulators |
US11628162B2 (en) | 2019-03-08 | 2023-04-18 | Incyte Corporation | Methods of treating cancer with an FGFR inhibitor |
US11661431B2 (en) | 2021-04-16 | 2023-05-30 | Gilead Sciences, Inc. | Thienopyrrole compounds |
US11661422B2 (en) | 2020-08-27 | 2023-05-30 | Incyte Corporation | Tricyclic urea compounds as JAK2 V617F inhibitors |
US11673883B2 (en) | 2016-05-26 | 2023-06-13 | Incyte Corporation | Heterocyclic compounds as immunomodulators |
US11685746B2 (en) | 2018-06-27 | 2023-06-27 | Ptc Therapeutics, Inc. | Heteroaryl compounds for treating Huntington's disease |
US11691971B2 (en) | 2020-06-19 | 2023-07-04 | Incyte Corporation | Naphthyridinone compounds as JAK2 V617F inhibitors |
US11702646B2 (en) | 2016-11-28 | 2023-07-18 | Ptc Therapeutics, Inc. | Methods for modulating RNA splicing |
US11718605B2 (en) | 2016-07-14 | 2023-08-08 | Incyte Corporation | Heterocyclic compounds as immunomodulators |
US11725010B2 (en) | 2019-12-02 | 2023-08-15 | Storm Therapeutics Limited | Polyheterocyclic compounds as METTL3 inhibitors |
US11753406B2 (en) | 2019-08-09 | 2023-09-12 | Incyte Corporation | Salts of a PD-1/PD-L1 inhibitor |
US11753413B2 (en) | 2020-06-19 | 2023-09-12 | Incyte Corporation | Substituted pyrrolo[2,1-f][1,2,4]triazine compounds as JAK2 V617F inhibitors |
US11760756B2 (en) | 2020-11-06 | 2023-09-19 | Incyte Corporation | Crystalline form of a PD-1/PD-L1 inhibitor |
US11767323B2 (en) | 2020-07-02 | 2023-09-26 | Incyte Corporation | Tricyclic pyridone compounds as JAK2 V617F inhibitors |
US11780840B2 (en) | 2020-07-02 | 2023-10-10 | Incyte Corporation | Tricyclic urea compounds as JAK2 V617F inhibitors |
US11780836B2 (en) | 2020-11-06 | 2023-10-10 | Incyte Corporation | Process of preparing a PD-1/PD-L1 inhibitor |
US11780839B2 (en) | 2018-03-27 | 2023-10-10 | Ptc Therapeutics, Inc. | Compounds for treating Huntington's disease |
WO2023196538A1 (en) * | 2022-04-07 | 2023-10-12 | Crossignal Therapeutics, Inc. | Gpr35 modulators and uses thereof |
US11786528B2 (en) | 2018-06-04 | 2023-10-17 | Exscientia Ltd. | Pyrazolopyrimidine compounds as adenosine receptor antagonists |
US11827640B2 (en) | 2020-10-23 | 2023-11-28 | Ildong Pharmaceutical Co., Ltd. | Substituted pyrazolo[1,5-a]pyrimidines as CFTR modulators |
US11851426B2 (en) | 2019-10-11 | 2023-12-26 | Incyte Corporation | Bicyclic amines as CDK2 inhibitors |
US11858941B2 (en) | 2018-06-27 | 2024-01-02 | Ptc Therapeutics, Inc. | Heterocyclic and heteroaryl compounds for treating Huntington's disease |
US11866434B2 (en) | 2020-11-06 | 2024-01-09 | Incyte Corporation | Process for making a PD-1/PD-L1 inhibitor and salts and crystalline forms thereof |
US11866451B2 (en) | 2019-11-11 | 2024-01-09 | Incyte Corporation | Salts and crystalline forms of a PD-1/PD-L1 inhibitor |
EP4076444A4 (en) * | 2019-12-18 | 2024-01-10 | Merck Sharp & Dohme Llc | Indazole derivatives and methods of use thereof for the treatment of herpes viruses |
US11873309B2 (en) | 2016-06-20 | 2024-01-16 | Incyte Corporation | Heterocyclic compounds as immunomodulators |
WO2024028243A1 (en) | 2022-08-02 | 2024-02-08 | Basf Se | Pyrazolo pesticidal compounds |
US11897891B2 (en) | 2019-12-04 | 2024-02-13 | Incyte Corporation | Tricyclic heterocycles as FGFR inhibitors |
US11919908B2 (en) | 2020-12-21 | 2024-03-05 | Incyte Corporation | Substituted pyrrolo[2,3-d]pyrimidine compounds as JAK2 V617F inhibitors |
US11919904B2 (en) | 2019-03-29 | 2024-03-05 | Incyte Corporation | Sulfonylamide compounds as CDK2 inhibitors |
US11939331B2 (en) | 2021-06-09 | 2024-03-26 | Incyte Corporation | Tricyclic heterocycles as FGFR inhibitors |
WO2024061768A1 (en) | 2022-09-19 | 2024-03-28 | Basf Se | Azole pesticidal compounds |
US11958861B2 (en) | 2022-02-24 | 2024-04-16 | Incyte Corporation | Spirocyclic lactams as JAK2 V617F inhibitors |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6858638B2 (en) * | 2002-03-11 | 2005-02-22 | Aventis Pharma S.A. | Substituted indazoles, compositions containing them, method of production and use |
US20050282814A1 (en) * | 2002-10-03 | 2005-12-22 | Targegen, Inc. | Vasculostatic agents and methods of use thereof |
US20070049600A1 (en) * | 1999-09-15 | 2007-03-01 | Warner-Lambert Company | Pteridinones as kinase inhibitors |
-
2010
- 2010-10-22 WO PCT/US2010/053690 patent/WO2011050245A1/en active Application Filing
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20070049600A1 (en) * | 1999-09-15 | 2007-03-01 | Warner-Lambert Company | Pteridinones as kinase inhibitors |
US6858638B2 (en) * | 2002-03-11 | 2005-02-22 | Aventis Pharma S.A. | Substituted indazoles, compositions containing them, method of production and use |
US20050282814A1 (en) * | 2002-10-03 | 2005-12-22 | Targegen, Inc. | Vasculostatic agents and methods of use thereof |
Cited By (338)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US8232294B2 (en) | 2009-03-21 | 2012-07-31 | Ning Xi | Amino ester derivatives, sailts thereof and methods of use |
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US10016406B2 (en) | 2009-08-10 | 2018-07-10 | Samumed, Llc | Indazole inhibitors of the WNT signal pathway and therapeutic uses thereof |
US9309238B2 (en) | 2009-11-05 | 2016-04-12 | University Of Notre Dame Du Lac | Imidazo [1,2-a]pyridine compounds, synthesis thereof, and methods of using same |
US9908876B2 (en) | 2009-11-05 | 2018-03-06 | University Of Notre Dame Du Lac | Imidazo [1,2-a]pyridine compounds, synthesis thereof, and methods of using same |
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US9067939B2 (en) | 2009-12-21 | 2015-06-30 | Samumed, Llc | 1H-pyrazolo[3,4-b]pyridines and therapeutic uses thereof |
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US10813930B2 (en) | 2010-12-22 | 2020-10-27 | Incyte Corporation | Substituted imidazopyridazines and benzimidazoles as inhibitors of FGFR3 |
US10213427B2 (en) | 2010-12-22 | 2019-02-26 | Incyte Corporation | Substituted imidazopyridazines and benzimidazoles as inhibitors of FGFR3 |
US9533954B2 (en) | 2010-12-22 | 2017-01-03 | Incyte Corporation | Substituted imidazopyridazines and benzimidazoles as inhibitors of FGFR3 |
US8883819B2 (en) | 2011-09-01 | 2014-11-11 | Irm Llc | Bicyclic heterocycle derivatives for the treatment of pulmonary arterial hypertension |
US9751876B2 (en) | 2011-09-01 | 2017-09-05 | Novartis Ag | Bicyclic heterocycle derivatives for the treatment of pulmonary arterial hypertension |
US11780823B2 (en) | 2011-09-14 | 2023-10-10 | Biosplice Therapeutics, Inc. | Indazole-3-carboxamides and their use as Wnt/β-catenin signaling pathway inhibitors |
US9802916B2 (en) | 2011-09-14 | 2017-10-31 | Samumed, Llc | Indazole-3-carboxamides and their use as Wnt/beta-catenin signaling pathway inhibitors |
US20130079329A1 (en) * | 2011-09-14 | 2013-03-28 | John Hood | INDAZOLE-3-CARBOXAMIDES AND THEIR USE AS WNT/Beta-CATENIN SIGNALING PATHWAY INHIBITORS |
US8697887B2 (en) | 2011-09-14 | 2014-04-15 | Samumed, Llc | Indazole-3-carboxamides and their use as Wnt/β-catenin signaling pathway inhibitors |
US10464924B2 (en) | 2011-09-14 | 2019-11-05 | Samumed, Llc | Indazole-3-carboxamides and their use as Wnt/β-catenin signaling pathway inhibitors |
US9221793B2 (en) * | 2011-09-14 | 2015-12-29 | Samumed, Llc | Indazole-3-carboxamides and their use as Wnt/β-catenin signaling pathway inhibitors |
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US11066388B2 (en) | 2011-09-14 | 2021-07-20 | Biosplice Therapeutics, Inc. | Indazole-3-carboxamides and their use as WNT/B-catenin signaling pathway inhibitors |
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KR20140121482A (en) * | 2012-02-10 | 2014-10-15 | 피티씨 테라퓨틱스, 인크. | Compounds for treating spinal muscular atrophy |
US11753407B2 (en) | 2012-02-10 | 2023-09-12 | Ptc Therapeutics, Inc. | Compounds for treating spinal muscular atrophy |
US10851101B2 (en) | 2012-02-10 | 2020-12-01 | Ptc Therapeutics, Inc. | Compounds for treating spinal muscular atrophy |
US9879007B2 (en) | 2012-02-10 | 2018-01-30 | Ptc Therapeutics, Inc. | Compounds for treating spinal muscular atrophy |
KR102341596B1 (en) * | 2012-02-10 | 2021-12-21 | 피티씨 테라퓨틱스, 인크. | Compounds for treating spinal muscular atrophy |
JP2017122097A (en) * | 2012-02-10 | 2017-07-13 | ピーティーシー セラピューティクス, インコーポレイテッド | Compounds for treating spinal muscular atrophy |
TWI585085B (en) * | 2012-02-10 | 2017-06-01 | Ptc治療公司 | Compounds for treating spinal muscular atrophy |
KR20200093066A (en) * | 2012-02-10 | 2020-08-04 | 피티씨 테라퓨틱스, 인크. | Compounds for treating spinal muscular atrophy |
JP2015508075A (en) * | 2012-02-10 | 2015-03-16 | ピーティーシー セラピューティクス, インコーポレイテッド | Compounds for treating spinal muscular atrophy |
CN104349777A (en) * | 2012-02-10 | 2015-02-11 | Ptc医疗公司 | Compounds for treating spinal muscular atrophy |
US9586955B2 (en) | 2012-02-10 | 2017-03-07 | Ptc Therapeutics, Inc. | Compounds for treating spinal muscular atrophy |
US20150005289A1 (en) * | 2012-02-10 | 2015-01-01 | Ptc Therapeutics Inc. | Compounds for treating spinal muscular atrophy |
KR102137087B1 (en) * | 2012-02-10 | 2020-07-24 | 피티씨 테라퓨틱스, 인크. | Compounds for treating spinal muscular atrophy |
US8916555B2 (en) | 2012-03-16 | 2014-12-23 | Axikin Pharmaceuticals, Inc. | 3,5-diaminopyrazole kinase inhibitors |
US9346792B2 (en) | 2012-03-16 | 2016-05-24 | Axikin Pharmaceuticals, Inc. | 3,5-diaminopyrazole kinase inhibitors |
US9382237B2 (en) | 2012-03-16 | 2016-07-05 | Axikin Pharmaceuticals, Inc. | 3,5-diaminopyrazole kinase inhibitors |
US9365556B2 (en) | 2012-03-16 | 2016-06-14 | Axikin Pharmaceuticals, Inc. | 3,5-diaminopyrazole kinase inhibitors |
US10947228B2 (en) | 2012-04-04 | 2021-03-16 | Samumed, Llc | Indazole inhibitors of the Wnt signal pathway and therapeutic uses thereof |
US8987298B2 (en) | 2012-04-04 | 2015-03-24 | Samumed, Llc | Indazole inhibitors of the Wnt signal pathway and therapeutic uses thereof |
US11697649B2 (en) | 2012-04-04 | 2023-07-11 | Biosplice Therapeutics, Inc. | Indazole inhibitors of the Wnt signal pathway and therapeutic uses thereof |
US8664241B2 (en) | 2012-04-04 | 2014-03-04 | Samumed, Llc | Indazole inhibitors of the Wnt signal pathway and therapeutic uses thereof |
US9199991B2 (en) | 2012-04-04 | 2015-12-01 | Samumed, Llc | Indazole inhibitors of the WNT signal pathway and therapeutic uses thereof |
US10407425B2 (en) | 2012-04-04 | 2019-09-10 | Samumed, Llc | Indazole inhibitors of the Wnt signal pathway and therapeutic uses thereof |
US8673936B2 (en) | 2012-04-04 | 2014-03-18 | Samumed, Llc | Indazole inhibitors of the Wnt signal pathway and therapeutic uses thereof |
US9994563B2 (en) | 2012-04-04 | 2018-06-12 | Samumed, Llc | Indazole inhibitors of the wnt signal pathway and therapeutic uses thereof |
US10342788B2 (en) | 2012-05-04 | 2019-07-09 | Samumed, Llc | 1H-pyrazolo[3,4-b]pyridines and therapeutic uses thereof |
US9233104B2 (en) | 2012-05-04 | 2016-01-12 | Samumed, Llc | 1H-pyrazolo[3,4-B]pyridines and therapeutic uses thereof |
US9586977B2 (en) | 2012-05-04 | 2017-03-07 | Samumed, Llc | 1H-pyrazolo[3,4-b]pyridines and therapeutic uses thereof |
US8883822B2 (en) | 2012-05-04 | 2014-11-11 | Samumed, Llc | 1H-pyrazolo[3,4-B]pyridines and therapeutic uses thereof |
US9012472B2 (en) | 2012-05-04 | 2015-04-21 | Samumed, Llc | 1H-pyrazolo[3,4-B]pyridines and therapeutic uses thereof |
US10071086B2 (en) | 2012-05-04 | 2018-09-11 | Samumed, Llc | 1H-pyrazolo[3,4-b]pyridines and therapeutic uses thereof |
US8618128B1 (en) | 2012-05-04 | 2013-12-31 | Samumed, Llc | 1H-pyrazolo[3,4-b]pyridines and therapeutic uses thereof |
US9611267B2 (en) | 2012-06-13 | 2017-04-04 | Incyte Holdings Corporation | Substituted tricyclic compounds as FGFR inhibitors |
US11053246B2 (en) | 2012-06-13 | 2021-07-06 | Incyte Corporation | Substituted tricyclic compounds as FGFR inhibitors |
US11840534B2 (en) | 2012-06-13 | 2023-12-12 | Incyte Corporation | Substituted tricyclic compounds as FGFR inhibitors |
US10131667B2 (en) | 2012-06-13 | 2018-11-20 | Incyte Corporation | Substituted tricyclic compounds as FGFR inhibitors |
JP2016169241A (en) * | 2012-07-27 | 2016-09-23 | 佐藤製薬株式会社 | Difluoromethylene compound |
US9540366B2 (en) | 2012-07-31 | 2017-01-10 | Kyowa Hakko Kirin Co., Ltd. | Ring-fused heterocyclic compound |
WO2014021383A1 (en) * | 2012-07-31 | 2014-02-06 | 協和発酵キリン株式会社 | Condensed ring heterocyclic compound |
JPWO2014021383A1 (en) * | 2012-07-31 | 2016-07-21 | 協和発酵キリン株式会社 | Fused heterocyclic compounds |
US9745311B2 (en) | 2012-08-10 | 2017-08-29 | Incyte Corporation | Substituted pyrrolo[2,3-b]pyrazines as FGFR inhibitors |
US9388185B2 (en) | 2012-08-10 | 2016-07-12 | Incyte Holdings Corporation | Substituted pyrrolo[2,3-b]pyrazines as FGFR inhibitors |
WO2014026984A1 (en) | 2012-08-17 | 2014-02-20 | Bayer Cropscience Ag | Azaindole carboxylic acid amides and azaindole thiocarboxylic acid amides for use as insecticides and acaricides |
US9266892B2 (en) | 2012-12-19 | 2016-02-23 | Incyte Holdings Corporation | Fused pyrazoles as FGFR inhibitors |
US10654832B2 (en) | 2013-01-08 | 2020-05-19 | Samumed, Llc | 3-(benzoimidazol-2-YL)-indazole inhibitors of the Wnt signaling pathway and therapeutic uses thereof |
US10183929B2 (en) | 2013-01-08 | 2019-01-22 | Samumed, Llc | 3-(benzoimidazol-2-yl)-indazole inhibitors of the Wnt signaling pathway and therapeutic uses thereof |
US9908867B2 (en) | 2013-01-08 | 2018-03-06 | Samumed, Llc | 3-(benzoimidazol-2-yl)-indazole inhibitors of the Wnt signaling pathway and therapeutic uses thereof |
US9073921B2 (en) | 2013-03-01 | 2015-07-07 | Novartis Ag | Salt forms of bicyclic heterocyclic derivatives |
US11530214B2 (en) | 2013-04-19 | 2022-12-20 | Incyte Holdings Corporation | Bicyclic heterocycles as FGFR inhibitors |
US10040790B2 (en) | 2013-04-19 | 2018-08-07 | Incyte Holdings Corporation | Bicyclic heterocycles as FGFR inhibitors |
US10450313B2 (en) | 2013-04-19 | 2019-10-22 | Incyte Holdings Corporation | Bicyclic heterocycles as FGFR inhibitors |
US10947230B2 (en) | 2013-04-19 | 2021-03-16 | Incyte Corporation | Bicyclic heterocycles as FGFR inhibitors |
US9533984B2 (en) | 2013-04-19 | 2017-01-03 | Incyte Holdings Corporation | Bicyclic heterocycles as FGFR inhibitors |
US9540351B2 (en) | 2013-09-18 | 2017-01-10 | Axikin Pharmaceuticals, Inc. | Pharmaceutically acceptable salts of 3,5-diaminopyrazole kinase inhibitors |
US20160257679A1 (en) * | 2013-09-26 | 2016-09-08 | Janssen Pharmaceutica Nv | NEW 1-(4-PYRIMIDINYL)-1H-PYRROLO[3,2-c]PYRIDINE DERIVATIVES AS NIK INHIBITORS |
US10005773B2 (en) * | 2013-09-26 | 2018-06-26 | Janssen Pharmaceutica Nv | 1-(4-pyrimidinyl)-1H-pyrrolo[3,2-c]pyridine derivatives as NIK inhibitors |
US9981963B2 (en) | 2013-09-26 | 2018-05-29 | Janssen Pharmaceutica Nv | 3-(1H-pyrazol-4-yl)-1H-pyrrolo[2,3-c]pyridine derivatives as NIK inhibitors |
US10195202B2 (en) | 2013-12-19 | 2019-02-05 | Ptc Therapeutics, Inc. | Methods for modulating the amount of RNA transcripts |
US10688099B2 (en) | 2013-12-19 | 2020-06-23 | Ptc Therapeutics, Inc. | Methods for modulating the amount of RNA transcripts |
US9493450B2 (en) | 2014-02-13 | 2016-11-15 | Incyte Corporation | Cyclopropylamines as LSD1 inhibitors |
US10300051B2 (en) | 2014-02-13 | 2019-05-28 | Incyte Corporation | Cyclopropylamines as LSD1 inhibitors |
US10174030B2 (en) | 2014-02-13 | 2019-01-08 | Incyte Corporation | Cyclopropylamines as LSD1 inhibitors |
US10513493B2 (en) | 2014-02-13 | 2019-12-24 | Incyte Corporation | Cyclopropylamines as LSD1 inhibitors |
US10676457B2 (en) | 2014-02-13 | 2020-06-09 | Incyte Corporation | Cyclopropylamines as LSD1 inhibitors |
US11247992B2 (en) | 2014-02-13 | 2022-02-15 | Incyte Corporation | Cyclopropylamines as LSD1 inhibitors |
US9994546B2 (en) | 2014-02-13 | 2018-06-12 | Incyte Corporation | Cyclopropylamines as LSD1 inhibitors |
US10717737B2 (en) | 2014-02-13 | 2020-07-21 | Incyte Corporation | Cyclopropylamines as LSD1 inhibitors |
US9493442B2 (en) | 2014-02-13 | 2016-11-15 | Incyte Corporation | Cyclopropylamines as LSD1 inhibitors |
US11155532B2 (en) | 2014-02-13 | 2021-10-26 | Incyte Corporation | Cyclopropylamines as LSD1 inhibitors |
US9670210B2 (en) | 2014-02-13 | 2017-06-06 | Incyte Corporation | Cyclopropylamines as LSD1 inhibitors |
US9527835B2 (en) | 2014-02-13 | 2016-12-27 | Incyte Corporation | Cyclopropylamines as LSD1 inhibitors |
US10669240B2 (en) | 2014-03-20 | 2020-06-02 | Samumed, Llc | 5-substituted indazole-3-carboxamides and preparation and use thereof |
US10167257B2 (en) | 2014-04-04 | 2019-01-01 | Iomet Pharma Ltd. | Indole derivatives for use in medicine |
AU2015239886B2 (en) * | 2014-04-04 | 2018-02-01 | Iomet Pharma Ltd | Indole derivatives for use in medicine |
US9695180B2 (en) | 2014-07-10 | 2017-07-04 | Incyte Corporation | Substituted imidazo[1,2-a]pyrazines as LSD1 inhibitors |
US10112950B2 (en) | 2014-07-10 | 2018-10-30 | Incyte Corporation | Substituted imidazo[1,2-a]pyrazines as LSD1 inhibitors |
US10125133B2 (en) | 2014-07-10 | 2018-11-13 | Incyte Corporation | Substituted [1,2,4]triazolo[1,5-a]pyridines and substituted [1,2,4]triazolo[1,5-a]pyrazines as LSD1 inhibitors |
US9758523B2 (en) | 2014-07-10 | 2017-09-12 | Incyte Corporation | Triazolopyridines and triazolopyrazines as LSD1 inhibitors |
US10047086B2 (en) | 2014-07-10 | 2018-08-14 | Incyte Corporation | Imidazopyridines and imidazopyrazines as LSD1 inhibitors |
US10138249B2 (en) | 2014-07-10 | 2018-11-27 | Incyte Corporation | Triazolopyridines and triazolopyrazines as LSD1 inhibitors |
US9695168B2 (en) | 2014-07-10 | 2017-07-04 | Incyte Corporation | Substituted imidazo[1,5-α]pyridines and imidazo[1,5-α]pyrazines as LSD1 inhibitors |
US10640503B2 (en) | 2014-07-10 | 2020-05-05 | Incyte Corporation | Imidazopyridines and imidazopyrazines as LSD1 inhibitors |
US9695167B2 (en) | 2014-07-10 | 2017-07-04 | Incyte Corporation | Substituted triazolo[1,5-a]pyridines and triazolo[1,5-a]pyrazines as LSD1 inhibitors |
US10968221B2 (en) | 2014-07-10 | 2021-04-06 | Incyte Corporation | Substituted [1,2,4]triazolo[1,5-a]pyrazines as LSD1 inhibitors |
US10556908B2 (en) | 2014-07-10 | 2020-02-11 | Incyte Corporation | Substituted imidazo[1,2-a]pyrazines as LSD1 inhibitors |
US10206929B2 (en) | 2014-09-08 | 2019-02-19 | Samumed, Llc | 3-(1H-imidazo[4,5-c]pyridin-2-yl)-1H-pyrazolo[3,4-b]pyridine and therapeutic uses thereof |
US9546185B2 (en) | 2014-09-08 | 2017-01-17 | Samumed, Llc | 3-(3H-imidazo[4,5-B]pyridin-2-yl)-1H-pyrazolo[3,4-C]pyridine and therapeutic uses thereof |
US10596154B2 (en) | 2014-09-08 | 2020-03-24 | Samumed, Llc | 3-(1H-imidazo[4,5-C]pyridin-2-yl)-1H-pyrazolo[3,4-C]pyridine and therapeutic uses thereof |
US10533020B2 (en) | 2014-09-08 | 2020-01-14 | Samumed, Llc | 3-(3H-imidazo[4,5-B]pyridin-2-yl)-1 H-pyrazolo[3,4-C]pyridine and therapeutic uses thereof |
US10202377B2 (en) | 2014-09-08 | 2019-02-12 | Samumed, Llc | 3-(1H-benzo[D]imidazol-2-yl)-1H-pyrazolo[3,4-C]pyridine and therapeutic uses thereof |
US10526347B2 (en) | 2014-09-08 | 2020-01-07 | Samumed, Llc | 3-(3H-imidazo[4,5-B]pyridin-2-yl)-1H-pyrazolo[3,4-B]pyridine and therapeutic uses thereof |
US9889140B2 (en) | 2014-09-08 | 2018-02-13 | Samumed, Llc | 3-(1H-imidazo[4,5-C]pyridin-2-yl)-1H-pyrazolo[3,4-B]pyridine and therapeutic uses thereof |
US9475825B2 (en) | 2014-09-08 | 2016-10-25 | Samumed, Llc | 3-(3H-imidazo[4,5-C]pyridin-2-yl)-1H-pyrazolo[3,4-C]pyridine and therapeutic uses thereof |
US9844536B2 (en) | 2014-09-08 | 2017-12-19 | Samumed, Llc | 3-(1H-imidazo[4,5-C]pyridin-2-yl)-1H-pyrazolo[3,4-C]pyridine and therapeutic uses thereof |
US9475807B2 (en) | 2014-09-08 | 2016-10-25 | Samumed, Llc | 2-(1H-indazol-3-yl)-1H-imidazo[4,5-C]pyridine and therapeutic uses thereof |
US10023572B2 (en) | 2014-09-08 | 2018-07-17 | Samumed, Llc | 2-(1h-indazol-3-yl)-3h-imidazo[4,5-b]pyridine and therapeutic uses thereof |
US10131677B2 (en) | 2014-09-08 | 2018-11-20 | Samumed, Llc | 3-(3H-imidazo[4,5-B]pyridin-2-yl)-1H-pyrazolo[3,4-B]pyridine and therapeutic uses thereof |
US9738638B2 (en) | 2014-09-08 | 2017-08-22 | Samumed, Llc | 2-(1H-indazol-3-yl)-3H-imidazo[4,5-B]pyridine and therapeutic uses thereof |
US9758531B2 (en) | 2014-09-08 | 2017-09-12 | Samumed, Llc | 3-(3H-imidazo[4,5-B]pyridin-2-yl)-1H-pyrazolo[3,4-B]pyridine and therapeutic uses thereof |
US10052331B2 (en) | 2014-09-08 | 2018-08-21 | Samumed, Llc | 3-(3H-imidazo[4,5-C]pyridin-2-yl)-1H-pyrazolo[3,4-C]pyridine and therapeutic uses thereof |
US9493487B2 (en) | 2014-09-08 | 2016-11-15 | Samumed, Llc | 3-(1H-imidazo[4,5-C]pyridin-2-YL)-1H-pyrazolo[3,4-B]pyridine and therapeutic uses thereof |
US10280166B2 (en) | 2014-09-08 | 2019-05-07 | Samumed, Llc | 2-(1H-indazol-3-yl)-3H-imidazo[4,5-B]pyridine and therapeutic uses thereof |
US9763951B2 (en) | 2014-09-08 | 2017-09-19 | Samumed, Llc | 3-(3H-imidazo[4,5-C]pyridin-2-yl)-1H-pyrazolo[3,4-C]pyridine and therapeutic uses thereof |
US9657016B2 (en) | 2014-09-08 | 2017-05-23 | Samumed, Llc | 3-(1h-benzo[d]imidazol-2-yl)-1h-pyrazolo[3,4-c]pyridine and therapeutic uses thereof |
US9540398B2 (en) | 2014-09-08 | 2017-01-10 | Samumed, Llc | 3-(1h-imidazo[4,5-C]pyridin-2-yl)-1h-pyrazolo[3,4-C]pyridine and therapeutic uses thereof |
US10081631B2 (en) | 2014-09-08 | 2018-09-25 | Samumed, Llc | 2-(1H-indazol-3-yl)-1H-imidazo[4,5-C]pyridine and therapeutic uses thereof |
US10155756B2 (en) * | 2014-10-21 | 2018-12-18 | Guangzhou Eggbio Co., Ltd. | Pyrazolo[1,5-A]pyridine compounds and use thereof |
US10851105B2 (en) | 2014-10-22 | 2020-12-01 | Incyte Corporation | Bicyclic heterocycles as FGFR4 inhibitors |
US10221180B2 (en) | 2014-10-23 | 2019-03-05 | Janssen Pharmaceutica Nv | Pyrazolopyrimidine derivatives as NIK inhibitors |
US10323045B2 (en) | 2014-10-23 | 2019-06-18 | Janssen Pharmaceutica Nv | Thienopyrimidine derivatives as NIK inhibitors |
US10822342B2 (en) | 2014-10-23 | 2020-11-03 | Janssen Pharmaceutica Nv | Pyrazolopyrimidine derivatives as NIK inhibitors |
US10005776B2 (en) | 2014-10-23 | 2018-06-26 | Janssen Pharmaceutica Nv | Compounds as NIK inhibitors |
US9981962B2 (en) | 2014-10-23 | 2018-05-29 | Janssen Pharmaceutica Nv | Pyrazole derivatives as NIK inhibitors |
US9730914B2 (en) | 2014-12-23 | 2017-08-15 | Axikin Pharmaceuticals | 3,5-diaminopyrazole kinase inhibitors |
US9546163B2 (en) | 2014-12-23 | 2017-01-17 | Axikin Pharmaceuticals, Inc. | 3,5-diaminopyrazole kinase inhibitors |
US11173162B2 (en) | 2015-02-20 | 2021-11-16 | Incyte Corporation | Bicyclic heterocycles as FGFR4 inhibitors |
US9580423B2 (en) | 2015-02-20 | 2017-02-28 | Incyte Corporation | Bicyclic heterocycles as FGFR4 inhibitors |
US9801889B2 (en) | 2015-02-20 | 2017-10-31 | Incyte Corporation | Bicyclic heterocycles as FGFR4 inhibitors |
US11014923B2 (en) | 2015-02-20 | 2021-05-25 | Incyte Corporation | Bicyclic heterocycles as FGFR4 inhibitors |
US10214528B2 (en) | 2015-02-20 | 2019-02-26 | Incyte Corporation | Bicyclic heterocycles as FGFR4 inhibitors |
US10738048B2 (en) | 2015-02-20 | 2020-08-11 | Incyte Corporation | Bicyclic heterocycles as FGFR4 inhibitors |
US10016438B2 (en) | 2015-02-20 | 2018-07-10 | Incyte Corporation | Bicyclic heterocycles as FGFR4 inhibitors |
US11667635B2 (en) | 2015-02-20 | 2023-06-06 | Incyte Corporation | Bicyclic heterocycles as FGFR4 inhibitors |
WO2016133838A1 (en) | 2015-02-20 | 2016-08-25 | Rigel Pharmaceuticals, Inc. | Gdf-8 inhibitors |
US10251892B2 (en) | 2015-02-20 | 2019-04-09 | Incyte Corporation | Bicyclic heterocycles as FGFR4 inhibitors |
US9708318B2 (en) | 2015-02-20 | 2017-07-18 | Incyte Corporation | Bicyclic heterocycles as FGFR4 inhibitors |
US10632126B2 (en) | 2015-02-20 | 2020-04-28 | Incyte Corporation | Bicyclic heterocycles as FGFR4 inhibitors |
US9890156B2 (en) | 2015-02-20 | 2018-02-13 | Incyte Corporation | Bicyclic heterocycles as FGFR4 inhibitors |
US11401272B2 (en) | 2015-04-03 | 2022-08-02 | Incyte Corporation | Heterocyclic compounds as LSD1 inhibitors |
US10800779B2 (en) | 2015-04-03 | 2020-10-13 | Incyte Corporation | Heterocyclic compounds as LSD1 inhibitors |
US9944647B2 (en) | 2015-04-03 | 2018-04-17 | Incyte Corporation | Heterocyclic compounds as LSD1 inhibitors |
US10668171B2 (en) | 2015-05-30 | 2020-06-02 | Ptc Therapeutics, Inc. | Methods for modulating RNA splicing |
US11602567B2 (en) | 2015-05-30 | 2023-03-14 | Ptc Therapeutics, Inc. | Methods for modulating RNA splicing |
US10604512B2 (en) | 2015-08-03 | 2020-03-31 | Samumed, Llc | 3-(1H-indol-2-yl)-1H-indazoles and therapeutic uses thereof |
US10519169B2 (en) | 2015-08-03 | 2019-12-31 | Samumed, Llc | 3-(1H-pyrrolo[2,3-C]pyridin-2-yl)-1 H-pyrazolo[4,3-B]pyridines and therapeutic uses thereof |
US10231956B2 (en) | 2015-08-03 | 2019-03-19 | Samumed, Llc | 3-(1H-pyrrolo[3,2-C]pyridin-2-YL)-1 H-pyrazolo[4,3-B]pyridines and therapeutic uses thereof |
US10226453B2 (en) | 2015-08-03 | 2019-03-12 | Samumed, Llc | 3-(1H-indol-2-yl)-1H-pyrazolo[4,3-B]pyridines and therapeutic uses thereof |
US10285982B2 (en) | 2015-08-03 | 2019-05-14 | Samumed, Llc | 3-(1H-pyrrolo[2,3-B]pyridin-2-yl)-1H-pyrazolo[3,4-C]pyridines and therapeutic uses thereof |
US10285983B2 (en) | 2015-08-03 | 2019-05-14 | Samumed, Llc | 3-(1H-pyrrolo[2,3-B]pyridin-2-yl)-1H-pyrazolo[3,4-B] pyridines and therapeutic uses thereof |
US10226448B2 (en) | 2015-08-03 | 2019-03-12 | Samumed, Llc | 3-(1H-pyrrolo[3,2-C]pyridin-2-yl)-1H-pyrazolo[3,4-B]pyridines and therapeutic uses thereof |
US10206909B2 (en) | 2015-08-03 | 2019-02-19 | Samumed, Llc | 3-(1H-pyrrolo[2,3-B]pyridin-2-yl)-1H-pyrazolo[4,3-B]pyridines and therapeutic uses thereof |
US10195185B2 (en) | 2015-08-03 | 2019-02-05 | Samumed, Llc | 3-(1H-imidazo[4,5-C]pyridin-2-yl)-1H-pyrazolo[4,3-B]pyridines and therapeutic uses thereof |
US10329309B2 (en) | 2015-08-03 | 2019-06-25 | Samumed, Llc | 3-(3H-imidazo[4,5-B]pyridin-2-yl)-1H-pyrazolo[4,3-B]pyridines and therapeutic uses thereof |
US10463651B2 (en) | 2015-08-03 | 2019-11-05 | Samumed, Llc | 3-(1H-pyrrolo[3,2-C]pyridin-2-YL)-1H-indazoles and therapeutic uses thereof |
US10166218B2 (en) | 2015-08-03 | 2019-01-01 | Samumed, Llc | 3-(1H-indol-2-yl)-1H-pyrazolo[3,4-C]pyridines and therapeutic uses thereof |
US10206908B2 (en) | 2015-08-03 | 2019-02-19 | Samumed, Llc | 3-(1H-pyrrolo[3,2-C]pyridin-2-YL)-1H-pyrazolo[3,4-C]pyridines and therapeutic uses thereof |
US10392383B2 (en) | 2015-08-03 | 2019-08-27 | Samumed, Llc | 3-(1H-benzo[d]imidazol-2-yl)-1H-pyrazolo[4,3-b]pyridines and therapeutic uses thereof |
US10350199B2 (en) | 2015-08-03 | 2019-07-16 | Samumed, Llc | 3-(1h-pyrrolo[2,3-b]pyridin-2-yl)-1h-indazoles and therapeutic uses thereof |
US10188634B2 (en) | 2015-08-03 | 2019-01-29 | Samumed, Llc | 3-(3H-imidazo[4,5-C]pyridin-2-yl)-1 H-pyrazolo[4,3-B]pyridines and therapeutic uses thereof |
US10383861B2 (en) | 2015-08-03 | 2019-08-20 | Sammumed, LLC | 3-(1H-pyrrolo[2,3-C]pyridin-2-yl)-1H-pyrazolo[3,4-C]pyridines and therapeutic uses thereof |
US10723700B2 (en) | 2015-08-12 | 2020-07-28 | Incyte Corporation | Salts of an LSD1 inhibitor |
US11498900B2 (en) | 2015-08-12 | 2022-11-15 | Incyte Corporation | Salts of an LSD1 inhibitor |
US10329255B2 (en) | 2015-08-12 | 2019-06-25 | Incyte Corporation | Salts of an LSD1 inhibitor |
US11820767B2 (en) | 2015-09-17 | 2023-11-21 | University Of Notre Dame Du Lac | Benzyl amine-containing heterocyclic compounds and compositions useful against mycobacterial infection |
US10919888B2 (en) | 2015-09-17 | 2021-02-16 | University Of Notre Dame Du Lac | Benzyl amine-containing heterocyclic compounds and compositions useful against mycobacterial infection |
US11407749B2 (en) | 2015-10-19 | 2022-08-09 | Incyte Corporation | Heterocyclic compounds as immunomodulators |
US11667632B2 (en) | 2015-11-06 | 2023-06-06 | Biosplice Therapeutics, Inc. | 2-(1H-indazol-3-yl)-3H-imidazo[4,5-C]pyridines and their anti-inflammatory uses thereof |
US10899757B2 (en) | 2015-11-06 | 2021-01-26 | Samumed, Llc | 2-(1H-indazol-3-yl)-3H-imidazo[4,5-C]pyridines and their anti-inflammatory uses thereof |
US10882860B2 (en) | 2015-11-06 | 2021-01-05 | Samumed, Llc | Treatment of osteoarthritis |
US11560378B2 (en) | 2015-11-06 | 2023-01-24 | Biosplice Therapeutics, Inc. | Treatment of osteoarthritis |
US10544139B2 (en) | 2015-11-06 | 2020-01-28 | Samumed, Llc | Treatment of osteoarthritis |
US11572366B2 (en) | 2015-11-19 | 2023-02-07 | Incyte Corporation | Heterocyclic compounds as immunomodulators |
CN105294688A (en) * | 2015-12-02 | 2016-02-03 | 北京工业大学 | 6-chlorine-N-(substituted benzyl)-1H-pyrrolo[2,3-b]pyridine-2-amide compound and preparation method as well as application thereof |
US10881658B2 (en) | 2015-12-10 | 2021-01-05 | Ptc Therapeutics, Inc. | Methods for treating Huntington's disease |
US11638706B2 (en) | 2015-12-10 | 2023-05-02 | Ptc Therapeutics, Inc. | Methods for treating Huntington's disease |
US10874672B2 (en) | 2015-12-10 | 2020-12-29 | Ptc Therapeutics, Inc. | Methods for treating Huntington's disease |
US11535615B2 (en) | 2015-12-22 | 2022-12-27 | Incyte Corporation | Heterocyclic compounds as immunomodulators |
US11866435B2 (en) | 2015-12-22 | 2024-01-09 | Incyte Corporation | Heterocyclic compounds as immunomodulators |
US11058676B2 (en) | 2016-02-09 | 2021-07-13 | Pharmakea, Inc. | Quinolinone lysyl oxidase-like 2 inhibitors and uses thereof |
US10588900B2 (en) | 2016-02-09 | 2020-03-17 | Pharmakea, Inc. | Quinolinone lysyl oxidase-like 2 inhibitors and uses thereof |
US10166221B2 (en) | 2016-04-22 | 2019-01-01 | Incyte Corporation | Formulations of an LSD1 inhibitor |
US11608337B2 (en) | 2016-05-06 | 2023-03-21 | Incyte Corporation | Heterocyclic compounds as immunomodulators |
US11673883B2 (en) | 2016-05-26 | 2023-06-13 | Incyte Corporation | Heterocyclic compounds as immunomodulators |
US10072004B2 (en) | 2016-06-01 | 2018-09-11 | Samumed, Llc | Process for preparing N-(5-(3-(7-(3-fluorophenyl)-3H-imidazo [4,5-C]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)-3-methylbutanamide |
US10633380B2 (en) | 2016-06-01 | 2020-04-28 | Samumed, Llc | Process for preparing N-(5-(3-(7-(3-fluorophenyl)-3H-imidazo[4,5-C]pyridin-2-yl)-1H-indazol-5-yl)pyridin-3-yl)-3-methylbutanamide |
US11873309B2 (en) | 2016-06-20 | 2024-01-16 | Incyte Corporation | Heterocyclic compounds as immunomodulators |
JP6994767B2 (en) | 2016-06-21 | 2022-01-14 | エックス4 ファーマシューティカルズ, インコーポレイテッド | CXCR4 inhibitor and its use |
US11306088B2 (en) | 2016-06-21 | 2022-04-19 | X4 Pharmaceuticals, Inc. | CXCR4 inhibitors and uses thereof |
US11780837B2 (en) | 2016-06-21 | 2023-10-10 | X4 Pharmaceuticals, Inc. | CXCR4 inhibitors and uses thereof |
JP2019518768A (en) * | 2016-06-21 | 2019-07-04 | エックス4 ファーマシューティカルズ, インコーポレイテッド | CXCR4 inhibitors and uses thereof |
US11352328B2 (en) | 2016-07-12 | 2022-06-07 | Arisan Therapeutics Inc. | Heterocyclic compounds for the treatment of arenavirus |
US11718605B2 (en) | 2016-07-14 | 2023-08-08 | Incyte Corporation | Heterocyclic compounds as immunomodulators |
US11613536B2 (en) | 2016-08-29 | 2023-03-28 | Incyte Corporation | Heterocyclic compounds as immunomodulators |
US10800782B2 (en) | 2016-08-31 | 2020-10-13 | Agios Pharmaceutical, Inc. | Inhibitors of cellular metabolic processes |
US11325914B1 (en) | 2016-08-31 | 2022-05-10 | Servier Pharmaceuticals Llc | Inhibitors of cellular metabolic processes |
US10266530B2 (en) | 2016-09-09 | 2019-04-23 | Incyte Corporation | Pyrazolopyridine compounds and uses thereof |
US11014929B2 (en) | 2016-09-09 | 2021-05-25 | Incyte Corporation | Pyrazolopyrimidine compounds and uses thereof |
US11542265B2 (en) | 2016-09-09 | 2023-01-03 | Incyte Corporation | Pyrazolopyrimidine compounds and uses thereof |
US11891388B2 (en) | 2016-09-09 | 2024-02-06 | Incyte Corporation | Pyrazolopyridine compounds and uses thereof |
US10280164B2 (en) | 2016-09-09 | 2019-05-07 | Incyte Corporation | Pyrazolopyridone compounds and uses thereof |
US10435405B2 (en) | 2016-09-09 | 2019-10-08 | Incyte Corporation | Pyrazolopyridine compounds and uses thereof |
US11242343B2 (en) | 2016-09-09 | 2022-02-08 | Incyte Corporation | Pyrazolopyridine compounds and uses thereof |
US11795166B2 (en) | 2016-09-09 | 2023-10-24 | Incyte Corporation | Pyrazolopyridine compounds and uses thereof |
US10934288B2 (en) | 2016-09-09 | 2021-03-02 | Incyte Corporation | Pyrazolopyridine compounds and uses thereof |
US10858319B2 (en) | 2016-10-03 | 2020-12-08 | Iomet Pharma Ltd. | Indole derivatives for use in medicine |
US11684615B2 (en) | 2016-10-21 | 2023-06-27 | Biosplice Therapeutics, Inc. | Methods of using indazole-3-carboxamides and their use as Wnt/β-catenin signaling pathway inhibitors |
US10806726B2 (en) | 2016-10-21 | 2020-10-20 | Samumed, Llc | Methods of using indazole-3-carb oxamides and their use as Wnt/B-catenin signaling pathway inhibitors |
US10758523B2 (en) | 2016-11-07 | 2020-09-01 | Samumed, Llc | Single-dose, ready-to-use injectable formulations |
US11819499B2 (en) | 2016-11-07 | 2023-11-21 | Biosplice Therapeutics, Inc. | Single-dose, ready-to-use injectable formulations |
US11446288B2 (en) | 2016-11-07 | 2022-09-20 | Biosplice Therapeutics, Inc. | Single-dose, ready-to-use injectable formulations |
US11702646B2 (en) | 2016-11-28 | 2023-07-18 | Ptc Therapeutics, Inc. | Methods for modulating RNA splicing |
WO2018108156A1 (en) * | 2016-12-16 | 2018-06-21 | 成都先导药物开发有限公司 | Rock inhibitor and application thereof |
CN108203433A (en) * | 2016-12-16 | 2018-06-26 | 成都先导药物开发有限公司 | A kind of ROCK inhibitor and its application |
US11465981B2 (en) | 2016-12-22 | 2022-10-11 | Incyte Corporation | Heterocyclic compounds as immunomodulators |
US11566026B2 (en) | 2016-12-22 | 2023-01-31 | Incyte Corporation | Heterocyclic compounds as immunomodulators |
US11339149B2 (en) | 2016-12-22 | 2022-05-24 | Incyte Corporation | Heterocyclic compounds as immunomodulators |
US10806785B2 (en) | 2016-12-22 | 2020-10-20 | Incyte Corporation | Immunomodulator compounds and methods of use |
US10308644B2 (en) | 2016-12-22 | 2019-06-04 | Incyte Corporation | Heterocyclic compounds as immunomodulators |
US11787793B2 (en) | 2016-12-22 | 2023-10-17 | Incyte Corporation | Heterocyclic compounds as immunomodulators |
US10800768B2 (en) | 2016-12-22 | 2020-10-13 | Incyte Corporation | Heterocyclic compounds as immunomodulators |
US10793565B2 (en) | 2016-12-22 | 2020-10-06 | Incyte Corporation | Heterocyclic compounds as immunomodulators |
US11406624B2 (en) | 2017-02-15 | 2022-08-09 | Incyte Corporation | Pyrazolopyridine compounds and uses thereof |
WO2018177781A1 (en) | 2017-03-28 | 2018-10-04 | Basf Se | Pesticidal compounds |
US10611762B2 (en) | 2017-05-26 | 2020-04-07 | Incyte Corporation | Crystalline forms of a FGFR inhibitor and processes for preparing the same |
US11472801B2 (en) | 2017-05-26 | 2022-10-18 | Incyte Corporation | Crystalline forms of a FGFR inhibitor and processes for preparing the same |
US11407753B2 (en) | 2017-06-05 | 2022-08-09 | Ptc Therapeutics, Inc. | Compounds for treating Huntington's disease |
US11608501B2 (en) | 2017-06-14 | 2023-03-21 | Ptc Therapeutics, Inc. | Methods for modifying RNA splicing |
US11395822B2 (en) | 2017-06-28 | 2022-07-26 | Ptc Therapeutics, Inc. | Methods for treating Huntington's disease |
US11382918B2 (en) | 2017-06-28 | 2022-07-12 | Ptc Therapeutics, Inc. | Methods for treating Huntington's Disease |
US10722495B2 (en) | 2017-09-08 | 2020-07-28 | Incyte Corporation | Cyanoindazole compounds and uses thereof |
WO2019121159A1 (en) | 2017-12-21 | 2019-06-27 | Basf Se | Pesticidal compounds |
WO2019129025A1 (en) * | 2017-12-26 | 2019-07-04 | 迈第康(上海)生物医药科技有限公司 | Tetrahydropyrrole compound, preparation method therefor, pharmaceutical composition containing same, and use thereof |
US11731958B2 (en) | 2018-02-20 | 2023-08-22 | Incyte Corporation | Carboxamide compounds and uses thereof |
US10745388B2 (en) | 2018-02-20 | 2020-08-18 | Incyte Corporation | Indazole compounds and uses thereof |
US10752635B2 (en) | 2018-02-20 | 2020-08-25 | Incyte Corporation | Indazole compounds and uses thereof |
US10800761B2 (en) | 2018-02-20 | 2020-10-13 | Incyte Corporation | Carboxamide compounds and uses thereof |
US11492354B2 (en) | 2018-02-20 | 2022-11-08 | Incyte Corporation | Indazole compounds and uses thereof |
US11713320B2 (en) | 2018-02-23 | 2023-08-01 | Biosplice Therapeutics, Inc. | 5-heteroaryl substituted indazole-3-carboxamides and preparation and use thereof |
CN112020501A (en) * | 2018-02-23 | 2020-12-01 | 萨穆梅德有限公司 | 5-heteroaryl substituted indazol-3-yl carboxamides, their preparation and use |
US11780839B2 (en) | 2018-03-27 | 2023-10-10 | Ptc Therapeutics, Inc. | Compounds for treating Huntington's disease |
US10669271B2 (en) | 2018-03-30 | 2020-06-02 | Incyte Corporation | Heterocyclic compounds as immunomodulators |
US11124511B2 (en) | 2018-03-30 | 2021-09-21 | Incyte Corporation | Heterocyclic compounds as immunomodulators |
US11299473B2 (en) | 2018-04-13 | 2022-04-12 | Incyte Corporation | Benzimidazole and indole compounds and uses thereof |
WO2019201297A1 (en) * | 2018-04-18 | 2019-10-24 | 南京明德新药研发有限公司 | Benzopyrazole compound used as rho kinase inhibitor |
US11345678B2 (en) | 2018-04-18 | 2022-05-31 | Medshine Discovery Inc. | Benzopyrazole compound used as RHO kinase inhibitor |
US11466004B2 (en) | 2018-05-04 | 2022-10-11 | Incyte Corporation | Solid forms of an FGFR inhibitor and processes for preparing the same |
US11174257B2 (en) | 2018-05-04 | 2021-11-16 | Incyte Corporation | Salts of an FGFR inhibitor |
US10906920B2 (en) | 2018-05-11 | 2021-02-02 | Incyte Corporation | Heterocyclic compounds as immunomodulators |
US11414433B2 (en) | 2018-05-11 | 2022-08-16 | Incyte Corporation | Heterocyclic compounds as immunomodulators |
US10618916B2 (en) | 2018-05-11 | 2020-04-14 | Incyte Corporation | Heterocyclic compounds as immunomodulators |
US11786528B2 (en) | 2018-06-04 | 2023-10-17 | Exscientia Ltd. | Pyrazolopyrimidine compounds as adenosine receptor antagonists |
US11685746B2 (en) | 2018-06-27 | 2023-06-27 | Ptc Therapeutics, Inc. | Heteroaryl compounds for treating Huntington's disease |
US11858941B2 (en) | 2018-06-27 | 2024-01-02 | Ptc Therapeutics, Inc. | Heterocyclic and heteroaryl compounds for treating Huntington's disease |
US11866426B2 (en) | 2018-08-08 | 2024-01-09 | Incyte Corporation | Benzothiazole compounds and uses thereof |
US10899755B2 (en) | 2018-08-08 | 2021-01-26 | Incyte Corporation | Benzothiazole compounds and uses thereof |
US10968200B2 (en) | 2018-08-31 | 2021-04-06 | Incyte Corporation | Salts of an LSD1 inhibitor and processes for preparing the same |
US11512064B2 (en) | 2018-08-31 | 2022-11-29 | Incyte Corporation | Salts of an LSD1 inhibitor and processes for preparing the same |
US11111247B2 (en) | 2018-09-25 | 2021-09-07 | Incyte Corporation | Pyrazolopyrimidine compounds and uses thereof |
US11066404B2 (en) | 2018-10-11 | 2021-07-20 | Incyte Corporation | Dihydropyrido[2,3-d]pyrimidinone compounds as CDK2 inhibitors |
US11866432B2 (en) | 2018-10-11 | 2024-01-09 | Incyte Corporation | Dihydropyrido[2,3-d]pyrimidinone compounds as CDK2 inhibitors |
EP3643705A1 (en) | 2018-10-24 | 2020-04-29 | Basf Se | Pesticidal compounds |
WO2020083733A1 (en) | 2018-10-24 | 2020-04-30 | Basf Se | Pesticidal compounds |
US11384083B2 (en) | 2019-02-15 | 2022-07-12 | Incyte Corporation | Substituted spiro[cyclopropane-1,5′-pyrrolo[2,3-d]pyrimidin]-6′(7′h)-ones as CDK2 inhibitors |
US11472791B2 (en) | 2019-03-05 | 2022-10-18 | Incyte Corporation | Pyrazolyl pyrimidinylamine compounds as CDK2 inhibitors |
US11628162B2 (en) | 2019-03-08 | 2023-04-18 | Incyte Corporation | Methods of treating cancer with an FGFR inhibitor |
US11919904B2 (en) | 2019-03-29 | 2024-03-05 | Incyte Corporation | Sulfonylamide compounds as CDK2 inhibitors |
US11447494B2 (en) | 2019-05-01 | 2022-09-20 | Incyte Corporation | Tricyclic amine compounds as CDK2 inhibitors |
US11440914B2 (en) | 2019-05-01 | 2022-09-13 | Incyte Corporation | Tricyclic amine compounds as CDK2 inhibitors |
WO2020242946A1 (en) | 2019-05-24 | 2020-12-03 | Fmc Corporation | Pyrazole-substituted pyrrolidinones as herbicides |
US11591329B2 (en) | 2019-07-09 | 2023-02-28 | Incyte Corporation | Bicyclic heterocycles as FGFR inhibitors |
WO2021013561A1 (en) | 2019-07-19 | 2021-01-28 | Basf Se | Pesticidal pyrazole and triazole derivatives |
EP3766879A1 (en) | 2019-07-19 | 2021-01-20 | Basf Se | Pesticidal pyrazole derivatives |
US11787784B2 (en) | 2019-08-06 | 2023-10-17 | Incyte Corporation | Solid forms of an HPK1 inhibitor |
US11066394B2 (en) | 2019-08-06 | 2021-07-20 | Incyte Corporation | Solid forms of an HPK1 inhibitor |
US11753406B2 (en) | 2019-08-09 | 2023-09-12 | Incyte Corporation | Salts of a PD-1/PD-L1 inhibitor |
US11427567B2 (en) | 2019-08-14 | 2022-08-30 | Incyte Corporation | Imidazolyl pyrimidinylamine compounds as CDK2 inhibitors |
US11401279B2 (en) | 2019-09-30 | 2022-08-02 | Incyte Corporation | Pyrido[3,2-d]pyrimidine compounds as immunomodulators |
US11851426B2 (en) | 2019-10-11 | 2023-12-26 | Incyte Corporation | Bicyclic amines as CDK2 inhibitors |
US11607416B2 (en) | 2019-10-14 | 2023-03-21 | Incyte Corporation | Bicyclic heterocycles as FGFR inhibitors |
US11566028B2 (en) | 2019-10-16 | 2023-01-31 | Incyte Corporation | Bicyclic heterocycles as FGFR inhibitors |
US11866451B2 (en) | 2019-11-11 | 2024-01-09 | Incyte Corporation | Salts and crystalline forms of a PD-1/PD-L1 inhibitor |
EP4059928A4 (en) * | 2019-11-15 | 2023-11-15 | Wuhan LL Science and Technology Development Co., Ltd. | Rock inhibitor, preparation method therefor and use thereof |
WO2021093795A1 (en) * | 2019-11-15 | 2021-05-20 | 武汉朗来科技发展有限公司 | Rock inhibitor, preparation method therefor and use thereof |
CN114728926A (en) * | 2019-11-15 | 2022-07-08 | 武汉朗来科技发展有限公司 | ROCK inhibitor and preparation method and application thereof |
US11725010B2 (en) | 2019-12-02 | 2023-08-15 | Storm Therapeutics Limited | Polyheterocyclic compounds as METTL3 inhibitors |
US11897891B2 (en) | 2019-12-04 | 2024-02-13 | Incyte Corporation | Tricyclic heterocycles as FGFR inhibitors |
US11407750B2 (en) | 2019-12-04 | 2022-08-09 | Incyte Corporation | Derivatives of an FGFR inhibitor |
EP4076444A4 (en) * | 2019-12-18 | 2024-01-10 | Merck Sharp & Dohme Llc | Indazole derivatives and methods of use thereof for the treatment of herpes viruses |
US11753413B2 (en) | 2020-06-19 | 2023-09-12 | Incyte Corporation | Substituted pyrrolo[2,1-f][1,2,4]triazine compounds as JAK2 V617F inhibitors |
US11691971B2 (en) | 2020-06-19 | 2023-07-04 | Incyte Corporation | Naphthyridinone compounds as JAK2 V617F inhibitors |
US11767323B2 (en) | 2020-07-02 | 2023-09-26 | Incyte Corporation | Tricyclic pyridone compounds as JAK2 V617F inhibitors |
US11780840B2 (en) | 2020-07-02 | 2023-10-10 | Incyte Corporation | Tricyclic urea compounds as JAK2 V617F inhibitors |
US11661422B2 (en) | 2020-08-27 | 2023-05-30 | Incyte Corporation | Tricyclic urea compounds as JAK2 V617F inhibitors |
CN114230565A (en) * | 2020-09-09 | 2022-03-25 | 成都奥睿药业有限公司 | 5-substituted indole 3-amide derivative and preparation method and application thereof |
WO2022052861A1 (en) * | 2020-09-09 | 2022-03-17 | 成都奥睿药业有限公司 | 5-substituted indole 3-amide derivative, preparation method and use thereof |
CN114230565B (en) * | 2020-09-09 | 2023-10-27 | 成都奥睿药业有限公司 | 5-substituted indole 3-amide derivative, preparation method and application thereof |
US11827640B2 (en) | 2020-10-23 | 2023-11-28 | Ildong Pharmaceutical Co., Ltd. | Substituted pyrazolo[1,5-a]pyrimidines as CFTR modulators |
US11780836B2 (en) | 2020-11-06 | 2023-10-10 | Incyte Corporation | Process of preparing a PD-1/PD-L1 inhibitor |
US11760756B2 (en) | 2020-11-06 | 2023-09-19 | Incyte Corporation | Crystalline form of a PD-1/PD-L1 inhibitor |
US11866434B2 (en) | 2020-11-06 | 2024-01-09 | Incyte Corporation | Process for making a PD-1/PD-L1 inhibitor and salts and crystalline forms thereof |
WO2022101453A1 (en) * | 2020-11-12 | 2022-05-19 | Conservatoire National des Arts et Métiers | Compounds and methods for treating a cytokine-mediated disease |
US11919908B2 (en) | 2020-12-21 | 2024-03-05 | Incyte Corporation | Substituted pyrrolo[2,3-d]pyrimidine compounds as JAK2 V617F inhibitors |
WO2022140326A1 (en) * | 2020-12-22 | 2022-06-30 | Gilead Sciences, Inc. | Substituted indole compounds |
US11661431B2 (en) | 2021-04-16 | 2023-05-30 | Gilead Sciences, Inc. | Thienopyrrole compounds |
WO2022237892A1 (en) * | 2021-05-14 | 2022-11-17 | 武汉朗来科技发展有限公司 | Acid addition salt of rock inhibitor, and crystal form, composition and pharmaceutical use thereof |
WO2022237878A1 (en) * | 2021-05-14 | 2022-11-17 | 武汉朗来科技发展有限公司 | Crystal form of compound, composition containing crystal form, preparation method therefor and use thereof |
US11939331B2 (en) | 2021-06-09 | 2024-03-26 | Incyte Corporation | Tricyclic heterocycles as FGFR inhibitors |
US11958861B2 (en) | 2022-02-24 | 2024-04-16 | Incyte Corporation | Spirocyclic lactams as JAK2 V617F inhibitors |
WO2023196538A1 (en) * | 2022-04-07 | 2023-10-12 | Crossignal Therapeutics, Inc. | Gpr35 modulators and uses thereof |
WO2024028243A1 (en) | 2022-08-02 | 2024-02-08 | Basf Se | Pyrazolo pesticidal compounds |
WO2024061768A1 (en) | 2022-09-19 | 2024-03-28 | Basf Se | Azole pesticidal compounds |
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