ZA200507979B - Quinazolines useful as modulators of ion channels - Google Patents
Quinazolines useful as modulators of ion channels Download PDFInfo
- Publication number
- ZA200507979B ZA200507979B ZA200507979A ZA200507979A ZA200507979B ZA 200507979 B ZA200507979 B ZA 200507979B ZA 200507979 A ZA200507979 A ZA 200507979A ZA 200507979 A ZA200507979 A ZA 200507979A ZA 200507979 B ZA200507979 B ZA 200507979B
- Authority
- ZA
- South Africa
- Prior art keywords
- optionally substituted
- ring
- compound
- och
- phenyl
- Prior art date
Links
- 102000004310 Ion Channels Human genes 0.000 title description 15
- 150000003246 quinazolines Chemical class 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims description 536
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 452
- 229910052757 nitrogen Inorganic materials 0.000 claims description 285
- -1 hexahydro-1H-1,4-diazepin-1-yl Chemical group 0.000 claims description 257
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 241
- 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 claims description 186
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 176
- 229910052760 oxygen Chemical group 0.000 claims description 164
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 163
- 239000001301 oxygen Chemical group 0.000 claims description 163
- 125000005842 heteroatom Chemical group 0.000 claims description 162
- 229910052717 sulfur Inorganic materials 0.000 claims description 160
- 229910052731 fluorine Inorganic materials 0.000 claims description 159
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 158
- 239000011593 sulfur Chemical group 0.000 claims description 158
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 155
- 229910052801 chlorine Inorganic materials 0.000 claims description 146
- 125000002950 monocyclic group Chemical group 0.000 claims description 145
- 229920000728 polyester Polymers 0.000 claims description 145
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 142
- 125000003118 aryl group Chemical group 0.000 claims description 140
- 229910052794 bromium Inorganic materials 0.000 claims description 130
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 130
- 125000004194 piperazin-1-yl group Chemical group [H]N1C([H])([H])C([H])([H])N(*)C([H])([H])C1([H])[H] 0.000 claims description 121
- 229910052739 hydrogen Inorganic materials 0.000 claims description 118
- 229920006395 saturated elastomer Polymers 0.000 claims description 116
- 239000001257 hydrogen Substances 0.000 claims description 114
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 claims description 112
- 229910052736 halogen Inorganic materials 0.000 claims description 105
- 150000002367 halogens Chemical class 0.000 claims description 105
- 125000002619 bicyclic group Chemical group 0.000 claims description 101
- 125000001931 aliphatic group Chemical group 0.000 claims description 94
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 claims description 93
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 86
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 84
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 75
- 125000004566 azetidin-1-yl group Chemical group N1(CCC1)* 0.000 claims description 74
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 73
- 125000000587 piperidin-1-yl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 63
- 150000002431 hydrogen Chemical group 0.000 claims description 60
- 208000002193 Pain Diseases 0.000 claims description 59
- 125000001072 heteroaryl group Chemical group 0.000 claims description 58
- 125000004076 pyridyl group Chemical group 0.000 claims description 58
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 claims description 57
- 125000004214 1-pyrrolidinyl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 52
- 238000000034 method Methods 0.000 claims description 49
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 43
- 229910052799 carbon Inorganic materials 0.000 claims description 37
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 36
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 35
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 34
- 125000004434 sulfur atom Chemical group 0.000 claims description 32
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 30
- 125000004429 atom Chemical group 0.000 claims description 28
- 208000004296 neuralgia Diseases 0.000 claims description 28
- 230000036407 pain Effects 0.000 claims description 28
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 26
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims description 25
- 239000011734 sodium Substances 0.000 claims description 25
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 24
- 125000000623 heterocyclic group Chemical group 0.000 claims description 23
- 230000000694 effects Effects 0.000 claims description 22
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 claims description 22
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 22
- 208000021722 neuropathic pain Diseases 0.000 claims description 21
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 20
- 125000005322 morpholin-1-yl group Chemical group 0.000 claims description 20
- 125000004368 propenyl group Chemical group C(=CC)* 0.000 claims description 20
- 108010053752 Voltage-Gated Sodium Channels Proteins 0.000 claims description 19
- 102000016913 Voltage-Gated Sodium Channels Human genes 0.000 claims description 19
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 18
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 18
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 claims description 17
- 125000001118 alkylidene group Chemical group 0.000 claims description 17
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 claims description 16
- 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 claims description 15
- 201000010099 disease Diseases 0.000 claims description 15
- 208000035475 disorder Diseases 0.000 claims description 15
- 206010015037 epilepsy Diseases 0.000 claims description 14
- 150000003839 salts Chemical class 0.000 claims description 14
- 208000005298 acute pain Diseases 0.000 claims description 13
- 125000000335 thiazolyl group Chemical group 0.000 claims description 13
- 208000000094 Chronic Pain Diseases 0.000 claims description 11
- JWVCLYRUEFBMGU-UHFFFAOYSA-N quinazoline Chemical compound N1=CN=CC2=CC=CC=C21 JWVCLYRUEFBMGU-UHFFFAOYSA-N 0.000 claims description 11
- 125000004182 2-chlorophenyl group Chemical group [H]C1=C([H])C(Cl)=C(*)C([H])=C1[H] 0.000 claims description 10
- 102000003922 Calcium Channels Human genes 0.000 claims description 10
- 206010065390 Inflammatory pain Diseases 0.000 claims description 10
- 230000001154 acute effect Effects 0.000 claims description 10
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 claims description 10
- 101100113485 Neurospora crassa (strain ATCC 24698 / 74-OR23-1A / CBS 708.71 / DSM 1257 / FGSC 987) chs-3 gene Proteins 0.000 claims description 9
- 230000004913 activation Effects 0.000 claims description 9
- 239000000203 mixture Substances 0.000 claims description 9
- 230000002981 neuropathic effect Effects 0.000 claims description 9
- KHBQMWCZKVMBLN-UHFFFAOYSA-N Benzenesulfonamide Chemical compound NS(=O)(=O)C1=CC=CC=C1 KHBQMWCZKVMBLN-UHFFFAOYSA-N 0.000 claims description 8
- 108090000312 Calcium Channels Proteins 0.000 claims description 8
- 125000003545 alkoxy group Chemical group 0.000 claims description 8
- 125000000217 alkyl group Chemical group 0.000 claims description 8
- 230000001684 chronic effect Effects 0.000 claims description 8
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 8
- 208000008035 Back Pain Diseases 0.000 claims description 7
- 208000004404 Intractable Pain Diseases 0.000 claims description 7
- DTQVDTLACAAQTR-UHFFFAOYSA-M Trifluoroacetate Chemical compound [O-]C(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-M 0.000 claims description 7
- 206010003119 arrhythmia Diseases 0.000 claims description 7
- 125000003386 piperidinyl group Chemical group 0.000 claims description 7
- 125000004198 2-fluorophenyl group Chemical group [H]C1=C([H])C(F)=C(*)C([H])=C1[H] 0.000 claims description 6
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 claims description 6
- 125000004800 4-bromophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Br 0.000 claims description 6
- 206010058019 Cancer Pain Diseases 0.000 claims description 6
- 206010019233 Headaches Diseases 0.000 claims description 6
- 208000016285 Movement disease Diseases 0.000 claims description 6
- 208000009935 visceral pain Diseases 0.000 claims description 6
- 125000004201 2,4-dichlorophenyl group Chemical group [H]C1=C([H])C(*)=C(Cl)C([H])=C1Cl 0.000 claims description 5
- 206010061533 Myotonia Diseases 0.000 claims description 5
- 206010028836 Neck pain Diseases 0.000 claims description 5
- 208000004550 Postoperative Pain Diseases 0.000 claims description 5
- 206010059604 Radicular pain Diseases 0.000 claims description 5
- 208000008765 Sciatica Diseases 0.000 claims description 5
- 239000003814 drug Substances 0.000 claims description 5
- 201000006417 multiple sclerosis Diseases 0.000 claims description 5
- 229940037201 oris Drugs 0.000 claims description 5
- KPKNTUUIEVXMOH-UHFFFAOYSA-N 1,4-dioxa-8-azaspiro[4.5]decane Chemical compound O1CCOC11CCNCC1 KPKNTUUIEVXMOH-UHFFFAOYSA-N 0.000 claims description 4
- IANQTJSKSUMEQM-UHFFFAOYSA-N 1-benzofuran Chemical compound C1=CC=C2OC=CC2=C1 IANQTJSKSUMEQM-UHFFFAOYSA-N 0.000 claims description 4
- 125000001462 1-pyrrolyl group Chemical group [*]N1C([H])=C([H])C([H])=C1[H] 0.000 claims description 4
- 125000005809 3,4,5-trimethoxyphenyl group Chemical group [H]C1=C(OC([H])([H])[H])C(OC([H])([H])[H])=C(OC([H])([H])[H])C([H])=C1* 0.000 claims description 4
- 125000004189 3,4-dichlorophenyl group Chemical group [H]C1=C([H])C(Cl)=C(Cl)C([H])=C1* 0.000 claims description 4
- 125000001541 3-thienyl group Chemical group S1C([H])=C([*])C([H])=C1[H] 0.000 claims description 4
- RAUWPNXIALNKQM-UHFFFAOYSA-N 4-nitro-1,2-phenylenediamine Chemical compound NC1=CC=C([N+]([O-])=O)C=C1N RAUWPNXIALNKQM-UHFFFAOYSA-N 0.000 claims description 4
- VRJHQPZVIGNGMX-UHFFFAOYSA-N 4-piperidinone Chemical group O=C1CCNCC1 VRJHQPZVIGNGMX-UHFFFAOYSA-N 0.000 claims description 4
- 208000019901 Anxiety disease Diseases 0.000 claims description 4
- 206010003591 Ataxia Diseases 0.000 claims description 4
- 208000006561 Cluster Headache Diseases 0.000 claims description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 4
- 230000036506 anxiety Effects 0.000 claims description 4
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 claims description 4
- 208000002551 irritable bowel syndrome Diseases 0.000 claims description 4
- 125000000040 m-tolyl group Chemical group [H]C1=C([H])C(*)=C([H])C(=C1[H])C([H])([H])[H] 0.000 claims description 4
- 125000001624 naphthyl group Chemical group 0.000 claims description 4
- 125000004193 piperazinyl group Chemical group 0.000 claims description 4
- 206010044652 trigeminal neuralgia Diseases 0.000 claims description 4
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 claims description 3
- 125000004939 6-pyridyl group Chemical group N1=CC=CC=C1* 0.000 claims description 3
- 208000000003 Breakthrough pain Diseases 0.000 claims description 3
- 208000032131 Diabetic Neuropathies Diseases 0.000 claims description 3
- 206010021639 Incontinence Diseases 0.000 claims description 3
- 208000001294 Nociceptive Pain Diseases 0.000 claims description 3
- 206010036376 Postherpetic Neuralgia Diseases 0.000 claims description 3
- 206010003246 arthritis Diseases 0.000 claims description 3
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 3
- 208000015122 neurodegenerative disease Diseases 0.000 claims description 3
- 208000015706 neuroendocrine disease Diseases 0.000 claims description 3
- 201000008482 osteoarthritis Diseases 0.000 claims description 3
- 208000020016 psychiatric disease Diseases 0.000 claims description 3
- NGXSWUFDCSEIOO-SCSAIBSYSA-N (3r)-pyrrolidin-3-amine Chemical compound N[C@@H]1CCNC1 NGXSWUFDCSEIOO-SCSAIBSYSA-N 0.000 claims description 2
- FTNJQNQLEGKTGD-UHFFFAOYSA-N 1,3-benzodioxole Chemical compound C1=CC=C2OCOC2=C1 FTNJQNQLEGKTGD-UHFFFAOYSA-N 0.000 claims description 2
- IZXIZTKNFFYFOF-UHFFFAOYSA-N 2-Oxazolidone Chemical compound O=C1NCCO1 IZXIZTKNFFYFOF-UHFFFAOYSA-N 0.000 claims description 2
- 125000002941 2-furyl group Chemical group O1C([*])=C([H])C([H])=C1[H] 0.000 claims description 2
- 125000000175 2-thienyl group Chemical group S1C([*])=C([H])C([H])=C1[H] 0.000 claims description 2
- 125000003762 3,4-dimethoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C(OC([H])([H])[H])C([H])=C1* 0.000 claims description 2
- BXDZOYLPNAIDOC-UHFFFAOYSA-N N-[5-[(5-tert-butyl-1,3-oxazol-2-yl)methylsulfanyl]-1,3-thiazol-2-yl]-1-[2-[2-[2-[2-[2-[[2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl]amino]ethoxy]ethoxy]ethoxy]ethylamino]-2-oxoethyl]piperidine-4-carboxamide Chemical compound CC(C)(C)c1cnc(CSc2cnc(NC(=O)C3CCN(CC(=O)NCCOCCOCCOCCNc4cccc5C(=O)N(C6CCC(=O)NC6=O)C(=O)c45)CC3)s2)o1 BXDZOYLPNAIDOC-UHFFFAOYSA-N 0.000 claims description 2
- RFRXIWQYSOIBDI-UHFFFAOYSA-N benzarone Chemical compound CCC=1OC2=CC=CC=C2C=1C(=O)C1=CC=C(O)C=C1 RFRXIWQYSOIBDI-UHFFFAOYSA-N 0.000 claims description 2
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 claims description 2
- 125000002962 imidazol-1-yl group Chemical group [*]N1C([H])=NC([H])=C1[H] 0.000 claims description 2
- 125000003037 imidazol-2-yl group Chemical group [H]N1C([*])=NC([H])=C1[H] 0.000 claims description 2
- HDOWRFHMPULYOA-UHFFFAOYSA-N piperidin-4-ol Chemical group OC1CCNCC1 HDOWRFHMPULYOA-UHFFFAOYSA-N 0.000 claims description 2
- 125000004482 piperidin-4-yl group Chemical group N1CCC(CC1)* 0.000 claims description 2
- PBMFSQRYOILNGV-UHFFFAOYSA-N pyridazine Chemical group C1=CC=NN=C1 PBMFSQRYOILNGV-UHFFFAOYSA-N 0.000 claims description 2
- NGXSWUFDCSEIOO-UHFFFAOYSA-N pyrrolidin-3-amine Chemical compound NC1CCNC1 NGXSWUFDCSEIOO-UHFFFAOYSA-N 0.000 claims description 2
- 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 2
- 125000005505 thiomorpholino group Chemical group 0.000 claims description 2
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 claims description 2
- 230000002401 inhibitory effect Effects 0.000 claims 15
- 101100271014 Bacillus subtilis (strain 168) asnO gene Proteins 0.000 claims 4
- 208000013403 hyperactivity Diseases 0.000 claims 4
- 239000012472 biological sample Substances 0.000 claims 2
- ULUJSOKAYRGZQV-UHFFFAOYSA-N 2,5-diazabicyclo[2.2.1]heptane;2,2,2-trifluoroacetic acid Chemical compound C1NC2CNC1C2.OC(=O)C(F)(F)F.OC(=O)C(F)(F)F ULUJSOKAYRGZQV-UHFFFAOYSA-N 0.000 claims 1
- IQFIFBLWZFRCCZ-UHFFFAOYSA-N 4-(3-benzyl-3,8-diazabicyclo[3.2.1]octan-8-yl)-2-phenylquinazoline Chemical compound C=1C=CC=CC=1CN(C1)CC2CCC1N2C(C1=CC=CC=C1N=1)=NC=1C1=CC=CC=C1 IQFIFBLWZFRCCZ-UHFFFAOYSA-N 0.000 claims 1
- 101100043731 Caenorhabditis elegans syx-3 gene Proteins 0.000 claims 1
- 101000634404 Datura stramonium Tropinone reductase 1 Proteins 0.000 claims 1
- 101100535673 Drosophila melanogaster Syn gene Proteins 0.000 claims 1
- 101100368134 Mus musculus Syn1 gene Proteins 0.000 claims 1
- 241000218657 Picea Species 0.000 claims 1
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims 1
- 101000848007 Saccharomyces cerevisiae (strain ATCC 204508 / S288c) Thioredoxin-1 Proteins 0.000 claims 1
- ATJFFYVFTNAWJD-UHFFFAOYSA-N Tin Chemical compound [Sn] ATJFFYVFTNAWJD-UHFFFAOYSA-N 0.000 claims 1
- 240000003834 Triticum spelta Species 0.000 claims 1
- 235000015107 ale Nutrition 0.000 claims 1
- 239000003085 diluting agent Substances 0.000 claims 1
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 claims 1
- 239000003937 drug carrier Substances 0.000 claims 1
- 239000003981 vehicle Substances 0.000 claims 1
- 125000004093 cyano group Chemical group *C#N 0.000 description 42
- 239000003112 inhibitor Substances 0.000 description 35
- 108091006146 Channels Proteins 0.000 description 22
- 102000018674 Sodium Channels Human genes 0.000 description 18
- 108010052164 Sodium Channels Proteins 0.000 description 18
- 125000001424 substituent group Chemical group 0.000 description 17
- 108090000862 Ion Channels Proteins 0.000 description 14
- 210000002569 neuron Anatomy 0.000 description 14
- 125000006297 carbonyl amino group Chemical group [H]N([*:2])C([*:1])=O 0.000 description 13
- 210000003594 spinal ganglia Anatomy 0.000 description 11
- 239000011575 calcium Substances 0.000 description 8
- 210000003169 central nervous system Anatomy 0.000 description 8
- 210000005036 nerve Anatomy 0.000 description 8
- 210000001044 sensory neuron Anatomy 0.000 description 8
- CFMYXEVWODSLAX-QOZOJKKESA-N tetrodotoxin Chemical compound O([C@@]([C@H]1O)(O)O[C@H]2[C@@]3(O)CO)[C@H]3[C@@H](O)[C@]11[C@H]2[C@@H](O)N=C(N)N1 CFMYXEVWODSLAX-QOZOJKKESA-N 0.000 description 8
- 229950010357 tetrodotoxin Drugs 0.000 description 8
- CFMYXEVWODSLAX-UHFFFAOYSA-N tetrodotoxin Natural products C12C(O)NC(=N)NC2(C2O)C(O)C3C(CO)(O)C1OC2(O)O3 CFMYXEVWODSLAX-UHFFFAOYSA-N 0.000 description 8
- 241000282414 Homo sapiens Species 0.000 description 7
- 230000002757 inflammatory effect Effects 0.000 description 7
- 230000035772 mutation Effects 0.000 description 7
- 102000004129 N-Type Calcium Channels Human genes 0.000 description 6
- 108090000699 N-Type Calcium Channels Proteins 0.000 description 6
- 239000001961 anticonvulsive agent Substances 0.000 description 6
- 230000009977 dual effect Effects 0.000 description 6
- XEEYBQQBJWHFJM-UHFFFAOYSA-N iron Substances [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 6
- ONIKNECPXCLUHT-UHFFFAOYSA-N 2-chlorobenzoyl chloride Chemical compound ClC(=O)C1=CC=CC=C1Cl ONIKNECPXCLUHT-UHFFFAOYSA-N 0.000 description 5
- 230000036982 action potential Effects 0.000 description 5
- 239000005557 antagonist Substances 0.000 description 5
- 230000000692 anti-sense effect Effects 0.000 description 5
- 238000010304 firing Methods 0.000 description 5
- 229910052698 phosphorus Inorganic materials 0.000 description 5
- 108090000623 proteins and genes Proteins 0.000 description 5
- 239000004215 Carbon black (E152) Substances 0.000 description 4
- 208000002091 Febrile Seizures Diseases 0.000 description 4
- 208000004454 Hyperalgesia Diseases 0.000 description 4
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 4
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 4
- 210000004556 brain Anatomy 0.000 description 4
- YKPUWZUDDOIDPM-SOFGYWHQSA-N capsaicin Chemical compound COC1=CC(CNC(=O)CCCC\C=C\C(C)C)=CC=C1O YKPUWZUDDOIDPM-SOFGYWHQSA-N 0.000 description 4
- 125000004122 cyclic group Chemical group 0.000 description 4
- 238000001514 detection method Methods 0.000 description 4
- 229930195733 hydrocarbon Natural products 0.000 description 4
- 230000002779 inactivation Effects 0.000 description 4
- 229910052740 iodine Inorganic materials 0.000 description 4
- 230000003040 nociceptive effect Effects 0.000 description 4
- 239000011574 phosphorus Substances 0.000 description 4
- 229910052708 sodium Inorganic materials 0.000 description 4
- 230000008685 targeting Effects 0.000 description 4
- BPKIMPVREBSLAJ-QTBYCLKRSA-N ziconotide Chemical compound C([C@H]1C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H]2C(=O)N[C@@H]3C(=O)N[C@H](C(=O)NCC(=O)N[C@@H](CO)C(=O)N[C@H](C(N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CO)C(=O)NCC(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CSSC2)C(N)=O)=O)CSSC[C@H](NC(=O)[C@H](CCCCN)NC(=O)[C@H](C)NC(=O)CNC(=O)[C@H](CCCCN)NC(=O)CNC(=O)[C@H](CCCCN)NC(=O)[C@@H](N)CSSC3)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@H](C(N1)=O)CCSC)[C@@H](C)O)C1=CC=C(O)C=C1 BPKIMPVREBSLAJ-QTBYCLKRSA-N 0.000 description 4
- 229960002811 ziconotide Drugs 0.000 description 4
- 206010001497 Agitation Diseases 0.000 description 3
- 101150065749 Churc1 gene Proteins 0.000 description 3
- 208000035154 Hyperesthesia Diseases 0.000 description 3
- NNJVILVZKWQKPM-UHFFFAOYSA-N Lidocaine Chemical compound CCN(CC)CC(=O)NC1=C(C)C=CC=C1C NNJVILVZKWQKPM-UHFFFAOYSA-N 0.000 description 3
- 208000028389 Nerve injury Diseases 0.000 description 3
- 102100038239 Protein Churchill Human genes 0.000 description 3
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical compound [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 description 3
- 125000003342 alkenyl group Chemical group 0.000 description 3
- 229940125681 anticonvulsant agent Drugs 0.000 description 3
- 125000006615 aromatic heterocyclic group Chemical group 0.000 description 3
- 230000005540 biological transmission Effects 0.000 description 3
- 150000001721 carbon Chemical group 0.000 description 3
- 210000004027 cell Anatomy 0.000 description 3
- 125000000753 cycloalkyl group Chemical group 0.000 description 3
- 208000002173 dizziness Diseases 0.000 description 3
- 125000005678 ethenylene group Chemical group [H]C([*:1])=C([H])[*:2] 0.000 description 3
- 125000005843 halogen group Chemical group 0.000 description 3
- 229960004194 lidocaine Drugs 0.000 description 3
- 230000008764 nerve damage Effects 0.000 description 3
- 230000000955 neuroendocrine Effects 0.000 description 3
- 230000003957 neurotransmitter release Effects 0.000 description 3
- 230000002093 peripheral effect Effects 0.000 description 3
- 230000004044 response Effects 0.000 description 3
- 229910052710 silicon Inorganic materials 0.000 description 3
- 239000010703 silicon Substances 0.000 description 3
- 210000000427 trigeminal ganglion Anatomy 0.000 description 3
- 206010008025 Cerebellar ataxia Diseases 0.000 description 2
- 206010008072 Cerebellar syndrome Diseases 0.000 description 2
- 206010010904 Convulsion Diseases 0.000 description 2
- UGJMXCAKCUNAIE-UHFFFAOYSA-N Gabapentin Chemical compound OC(=O)CC1(CN)CCCCC1 UGJMXCAKCUNAIE-UHFFFAOYSA-N 0.000 description 2
- 241000282412 Homo Species 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- 208000001089 Multiple system atrophy Diseases 0.000 description 2
- 241000699670 Mus sp. Species 0.000 description 2
- 208000005890 Neuroma Diseases 0.000 description 2
- 206010031127 Orthostatic hypotension Diseases 0.000 description 2
- 206010039897 Sedation Diseases 0.000 description 2
- 238000013019 agitation Methods 0.000 description 2
- VREFGVBLTWBCJP-UHFFFAOYSA-N alprazolam Chemical compound C12=CC(Cl)=CC=C2N2C(C)=NN=C2CN=C1C1=CC=CC=C1 VREFGVBLTWBCJP-UHFFFAOYSA-N 0.000 description 2
- 125000003710 aryl alkyl group Chemical group 0.000 description 2
- 125000005160 aryl oxy alkyl group Chemical group 0.000 description 2
- 210000003050 axon Anatomy 0.000 description 2
- 229960002504 capsaicin Drugs 0.000 description 2
- 235000017663 capsaicin Nutrition 0.000 description 2
- 210000005056 cell body Anatomy 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 230000006735 deficit Effects 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 230000004064 dysfunction Effects 0.000 description 2
- 125000004475 heteroaralkyl group Chemical group 0.000 description 2
- 125000005114 heteroarylalkoxy group Chemical group 0.000 description 2
- 210000003630 histaminocyte Anatomy 0.000 description 2
- 150000002430 hydrocarbons Chemical class 0.000 description 2
- 230000002055 immunohistochemical effect Effects 0.000 description 2
- 238000007913 intrathecal administration Methods 0.000 description 2
- 229910052742 iron Inorganic materials 0.000 description 2
- 229960001848 lamotrigine Drugs 0.000 description 2
- PYZRQGJRPPTADH-UHFFFAOYSA-N lamotrigine Chemical compound NC1=NC(N)=NN=C1C1=CC=CC(Cl)=C1Cl PYZRQGJRPPTADH-UHFFFAOYSA-N 0.000 description 2
- 230000002045 lasting effect Effects 0.000 description 2
- 230000028161 membrane depolarization Effects 0.000 description 2
- BQJCRHHNABKAKU-KBQPJGBKSA-N morphine Chemical compound O([C@H]1[C@H](C=C[C@H]23)O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O BQJCRHHNABKAKU-KBQPJGBKSA-N 0.000 description 2
- 210000003205 muscle Anatomy 0.000 description 2
- 230000004770 neurodegeneration Effects 0.000 description 2
- 206010029864 nystagmus Diseases 0.000 description 2
- 230000001575 pathological effect Effects 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- 230000003518 presynaptic effect Effects 0.000 description 2
- 210000000063 presynaptic terminal Anatomy 0.000 description 2
- 230000036280 sedation Effects 0.000 description 2
- 230000020341 sensory perception of pain Effects 0.000 description 2
- 239000003195 sodium channel blocking agent Substances 0.000 description 2
- 241000894007 species Species 0.000 description 2
- 210000000278 spinal cord Anatomy 0.000 description 2
- 230000002459 sustained effect Effects 0.000 description 2
- 210000000225 synapse Anatomy 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- 238000002560 therapeutic procedure Methods 0.000 description 2
- 125000004001 thioalkyl group Chemical group 0.000 description 2
- 210000001519 tissue Anatomy 0.000 description 2
- 230000000451 tissue damage Effects 0.000 description 2
- 231100000827 tissue damage Toxicity 0.000 description 2
- 239000003053 toxin Substances 0.000 description 2
- 231100000765 toxin Toxicity 0.000 description 2
- 210000001170 unmyelinated nerve fiber Anatomy 0.000 description 2
- 108091023044 voltage-gated calcium channel activity Proteins 0.000 description 2
- 125000006570 (C5-C6) heteroaryl group Chemical group 0.000 description 1
- AVGHIQUXSVAJBC-UHFFFAOYSA-N 1,2-diazabicyclo[2.2.1]heptane Chemical compound C1C2CCN1NC2 AVGHIQUXSVAJBC-UHFFFAOYSA-N 0.000 description 1
- LEBVLXFERQHONN-UHFFFAOYSA-N 1-butyl-N-(2,6-dimethylphenyl)piperidine-2-carboxamide Chemical compound CCCCN1CCCCC1C(=O)NC1=C(C)C=CC=C1C LEBVLXFERQHONN-UHFFFAOYSA-N 0.000 description 1
- UUFQTNFCRMXOAE-UHFFFAOYSA-N 1-methylmethylene Chemical compound C[CH] UUFQTNFCRMXOAE-UHFFFAOYSA-N 0.000 description 1
- 101100309713 Arabidopsis thaliana SD129 gene Proteins 0.000 description 1
- 241000272875 Ardeidae Species 0.000 description 1
- 208000032116 Autoimmune Experimental Encephalomyelitis Diseases 0.000 description 1
- 101800004538 Bradykinin Proteins 0.000 description 1
- 101100167062 Caenorhabditis elegans chch-3 gene Proteins 0.000 description 1
- 108090000932 Calcitonin Gene-Related Peptide Proteins 0.000 description 1
- 102100025588 Calcitonin gene-related peptide 1 Human genes 0.000 description 1
- 229940127291 Calcium channel antagonist Drugs 0.000 description 1
- 208000031976 Channelopathies Diseases 0.000 description 1
- 102000004127 Cytokines Human genes 0.000 description 1
- 108090000695 Cytokines Proteins 0.000 description 1
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 description 1
- BWGNESOTFCXPMA-UHFFFAOYSA-N Dihydrogen disulfide Chemical compound SS BWGNESOTFCXPMA-UHFFFAOYSA-N 0.000 description 1
- 101000941893 Felis catus Leucine-rich repeat and calponin homology domain-containing protein 1 Proteins 0.000 description 1
- QXZGBUJJYSLZLT-UHFFFAOYSA-N H-Arg-Pro-Pro-Gly-Phe-Ser-Pro-Phe-Arg-OH Natural products NC(N)=NCCCC(N)C(=O)N1CCCC1C(=O)N1C(C(=O)NCC(=O)NC(CC=2C=CC=CC=2)C(=O)NC(CO)C(=O)N2C(CCC2)C(=O)NC(CC=2C=CC=CC=2)C(=O)NC(CCCN=C(N)N)C(O)=O)CCC1 QXZGBUJJYSLZLT-UHFFFAOYSA-N 0.000 description 1
- 206010019280 Heart failures Diseases 0.000 description 1
- 101000631760 Homo sapiens Sodium channel protein type 1 subunit alpha Proteins 0.000 description 1
- 206010020751 Hypersensitivity Diseases 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 102100035792 Kininogen-1 Human genes 0.000 description 1
- 102000004016 L-Type Calcium Channels Human genes 0.000 description 1
- 108090000420 L-Type Calcium Channels Proteins 0.000 description 1
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 1
- 101100400546 Mus musculus Matn1 gene Proteins 0.000 description 1
- 208000012905 Myotonic disease Diseases 0.000 description 1
- 102000004194 NAV1.8 Voltage-Gated Sodium Channel Human genes 0.000 description 1
- 108010056565 NAV1.8 Voltage-Gated Sodium Channel Proteins 0.000 description 1
- 206010028813 Nausea Diseases 0.000 description 1
- 208000007256 Nevus Diseases 0.000 description 1
- 101000870363 Oryctolagus cuniculus Glutathione S-transferase Yc Proteins 0.000 description 1
- 206010061334 Partial seizures Diseases 0.000 description 1
- 102000003728 Peroxisome Proliferator-Activated Receptors Human genes 0.000 description 1
- 108090000029 Peroxisome Proliferator-Activated Receptors Proteins 0.000 description 1
- CXOFVDLJLONNDW-UHFFFAOYSA-N Phenytoin Chemical compound N1C(=O)NC(=O)C1(C=1C=CC=CC=1)C1=CC=CC=C1 CXOFVDLJLONNDW-UHFFFAOYSA-N 0.000 description 1
- 102000001708 Protein Isoforms Human genes 0.000 description 1
- 108010029485 Protein Isoforms Proteins 0.000 description 1
- 102100028910 Sodium channel protein type 1 subunit alpha Human genes 0.000 description 1
- 102100033974 Sodium channel protein type 11 subunit alpha Human genes 0.000 description 1
- 101710102203 Sodium channel protein type 11 subunit alpha Proteins 0.000 description 1
- 206010042674 Swelling Diseases 0.000 description 1
- 108010057722 Synaptosomal-Associated Protein 25 Proteins 0.000 description 1
- 102000004183 Synaptosomal-Associated Protein 25 Human genes 0.000 description 1
- 102000013265 Syntaxin 1 Human genes 0.000 description 1
- 108010090618 Syntaxin 1 Proteins 0.000 description 1
- 229940123445 Tricyclic antidepressant Drugs 0.000 description 1
- YZCKVEUIGOORGS-NJFSPNSNSA-N Tritium Chemical compound [3H] YZCKVEUIGOORGS-NJFSPNSNSA-N 0.000 description 1
- 206010046543 Urinary incontinence Diseases 0.000 description 1
- 206010047513 Vision blurred Diseases 0.000 description 1
- 208000027418 Wounds and injury Diseases 0.000 description 1
- 230000001594 aberrant effect Effects 0.000 description 1
- 238000009825 accumulation Methods 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 125000002015 acyclic group Chemical group 0.000 description 1
- 230000003044 adaptive effect Effects 0.000 description 1
- 208000026802 afebrile Diseases 0.000 description 1
- 210000003766 afferent neuron Anatomy 0.000 description 1
- 125000000304 alkynyl group Chemical group 0.000 description 1
- 206010053552 allodynia Diseases 0.000 description 1
- 230000036592 analgesia Effects 0.000 description 1
- 230000000202 analgesic effect Effects 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 230000006472 autoimmune response Effects 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 238000004166 bioassay Methods 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- QXZGBUJJYSLZLT-FDISYFBBSA-N bradykinin Chemical compound NC(=N)NCCC[C@H](N)C(=O)N1CCC[C@H]1C(=O)N1[C@H](C(=O)NCC(=O)N[C@@H](CC=2C=CC=CC=2)C(=O)N[C@@H](CO)C(=O)N2[C@@H](CCC2)C(=O)N[C@@H](CC=2C=CC=CC=2)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O)CCC1 QXZGBUJJYSLZLT-FDISYFBBSA-N 0.000 description 1
- 229960003150 bupivacaine Drugs 0.000 description 1
- 239000000480 calcium channel blocker Substances 0.000 description 1
- 230000009460 calcium influx Effects 0.000 description 1
- 229960000623 carbamazepine Drugs 0.000 description 1
- FFGPTBGBLSHEPO-UHFFFAOYSA-N carbamazepine Chemical compound C1=CC2=CC=CC=C2N(C(=O)N)C2=CC=CC=C21 FFGPTBGBLSHEPO-UHFFFAOYSA-N 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 229910002091 carbon monoxide Inorganic materials 0.000 description 1
- 230000022900 cardiac muscle contraction Effects 0.000 description 1
- 229940113118 carrageenan Drugs 0.000 description 1
- 235000010418 carrageenan Nutrition 0.000 description 1
- 229920001525 carrageenan Polymers 0.000 description 1
- 239000000679 carrageenan Substances 0.000 description 1
- 230000002490 cerebral effect Effects 0.000 description 1
- 229910052729 chemical element Inorganic materials 0.000 description 1
- 208000018912 cluster headache syndrome Diseases 0.000 description 1
- 210000001072 colon Anatomy 0.000 description 1
- 229940126214 compound 3 Drugs 0.000 description 1
- 239000013256 coordination polymer Substances 0.000 description 1
- 229940111134 coxibs Drugs 0.000 description 1
- 125000000392 cycloalkenyl group Chemical group 0.000 description 1
- 125000001316 cycloalkyl alkyl group Chemical group 0.000 description 1
- 239000003255 cyclooxygenase 2 inhibitor Substances 0.000 description 1
- 230000001086 cytosolic effect Effects 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 229910052805 deuterium Inorganic materials 0.000 description 1
- 231100000673 dose–response relationship Toxicity 0.000 description 1
- 230000007831 electrophysiology Effects 0.000 description 1
- 238000002001 electrophysiology Methods 0.000 description 1
- 230000008519 endogenous mechanism Effects 0.000 description 1
- 230000001747 exhibiting effect Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000003517 fume Substances 0.000 description 1
- 230000006870 function Effects 0.000 description 1
- 230000004927 fusion Effects 0.000 description 1
- 229960002870 gabapentin Drugs 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 238000003209 gene knockout Methods 0.000 description 1
- 229930195712 glutamate Natural products 0.000 description 1
- PCHJSUWPFVWCPO-UHFFFAOYSA-N gold Chemical compound [Au] PCHJSUWPFVWCPO-UHFFFAOYSA-N 0.000 description 1
- 229910052737 gold Inorganic materials 0.000 description 1
- 239000010931 gold Substances 0.000 description 1
- 230000036433 growing body Effects 0.000 description 1
- 125000000262 haloalkenyl group Chemical group 0.000 description 1
- 125000004438 haloalkoxy group Chemical group 0.000 description 1
- 125000001188 haloalkyl group Chemical group 0.000 description 1
- 231100000869 headache Toxicity 0.000 description 1
- 125000001183 hydrocarbyl group Chemical group 0.000 description 1
- 238000003365 immunocytochemistry Methods 0.000 description 1
- 238000007901 in situ hybridization Methods 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 230000004941 influx Effects 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 230000000977 initiatory effect Effects 0.000 description 1
- 208000014674 injury Diseases 0.000 description 1
- 230000009545 invasion Effects 0.000 description 1
- 238000011813 knockout mouse model Methods 0.000 description 1
- 229910052746 lanthanum Inorganic materials 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 239000003589 local anesthetic agent Substances 0.000 description 1
- 229960005015 local anesthetics Drugs 0.000 description 1
- 210000004962 mammalian cell Anatomy 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 230000025350 membrane depolarization involved in regulation of action potential Effects 0.000 description 1
- CWWARWOPSKGELM-SARDKLJWSA-N methyl (2s)-2-[[(2s)-2-[[2-[[(2s)-2-[[(2s)-2-[[(2s)-5-amino-2-[[(2s)-5-amino-2-[[(2s)-1-[(2s)-6-amino-2-[[(2s)-1-[(2s)-2-amino-5-(diaminomethylideneamino)pentanoyl]pyrrolidine-2-carbonyl]amino]hexanoyl]pyrrolidine-2-carbonyl]amino]-5-oxopentanoyl]amino]-5 Chemical compound C([C@@H](C(=O)NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCSC)C(=O)OC)NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CCCCN)NC(=O)[C@H]1N(CCC1)C(=O)[C@@H](N)CCCN=C(N)N)C1=CC=CC=C1 CWWARWOPSKGELM-SARDKLJWSA-N 0.000 description 1
- VLPIATFUUWWMKC-UHFFFAOYSA-N mexiletine Chemical compound CC(N)COC1=C(C)C=CC=C1C VLPIATFUUWWMKC-UHFFFAOYSA-N 0.000 description 1
- 230000004784 molecular pathogenesis Effects 0.000 description 1
- 229960005181 morphine Drugs 0.000 description 1
- 230000000869 mutational effect Effects 0.000 description 1
- 210000000107 myocyte Anatomy 0.000 description 1
- 208000029264 myotonic syndrome Diseases 0.000 description 1
- 230000008693 nausea Effects 0.000 description 1
- 230000008035 nerve activity Effects 0.000 description 1
- 210000001640 nerve ending Anatomy 0.000 description 1
- 210000000653 nervous system Anatomy 0.000 description 1
- 230000001537 neural effect Effects 0.000 description 1
- 210000004412 neuroendocrine cell Anatomy 0.000 description 1
- 230000008587 neuronal excitability Effects 0.000 description 1
- 230000004112 neuroprotection Effects 0.000 description 1
- 239000002858 neurotransmitter agent Substances 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 229940021182 non-steroidal anti-inflammatory drug Drugs 0.000 description 1
- 229940046166 oligodeoxynucleotide Drugs 0.000 description 1
- 229940005483 opioid analgesics Drugs 0.000 description 1
- 125000004430 oxygen atom Chemical group O* 0.000 description 1
- 230000008052 pain pathway Effects 0.000 description 1
- 230000008058 pain sensation Effects 0.000 description 1
- 244000052769 pathogen Species 0.000 description 1
- 230000001717 pathogenic effect Effects 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 230000000737 periodic effect Effects 0.000 description 1
- 210000001428 peripheral nervous system Anatomy 0.000 description 1
- 230000002085 persistent effect Effects 0.000 description 1
- 238000001050 pharmacotherapy Methods 0.000 description 1
- 229960002036 phenytoin Drugs 0.000 description 1
- 239000011148 porous material Substances 0.000 description 1
- 210000004044 posterior horn cell Anatomy 0.000 description 1
- 150000003180 prostaglandins Chemical class 0.000 description 1
- 230000009993 protective function Effects 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 230000004850 protein–protein interaction Effects 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 210000000449 purkinje cell Anatomy 0.000 description 1
- 238000011552 rat model Methods 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 230000002829 reductive effect Effects 0.000 description 1
- 238000007634 remodeling Methods 0.000 description 1
- 230000008521 reorganization Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000036390 resting membrane potential Effects 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- 239000000523 sample Substances 0.000 description 1
- RPQXVSUAYFXFJA-HGRQIUPRSA-N saxitoxin Chemical compound NC(=O)OC[C@@H]1N=C(N)N2CCC(O)(O)[C@@]22N=C(N)N[C@@H]12 RPQXVSUAYFXFJA-HGRQIUPRSA-N 0.000 description 1
- RPQXVSUAYFXFJA-UHFFFAOYSA-N saxitoxin hydrate Natural products NC(=O)OCC1N=C(N)N2CCC(O)(O)C22NC(N)=NC12 RPQXVSUAYFXFJA-UHFFFAOYSA-N 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 230000009528 severe injury Effects 0.000 description 1
- 238000009097 single-agent therapy Methods 0.000 description 1
- 210000002027 skeletal muscle Anatomy 0.000 description 1
- 210000002460 smooth muscle Anatomy 0.000 description 1
- 150000003385 sodium Chemical class 0.000 description 1
- 235000014347 soups Nutrition 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 230000008961 swelling Effects 0.000 description 1
- 230000002889 sympathetic effect Effects 0.000 description 1
- 210000000331 sympathetic ganglia Anatomy 0.000 description 1
- 230000000946 synaptic effect Effects 0.000 description 1
- 102000003137 synaptotagmin Human genes 0.000 description 1
- 108060008004 synaptotagmin Proteins 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 230000010989 thermoception Effects 0.000 description 1
- 239000003029 tricyclic antidepressant agent Substances 0.000 description 1
- 229910052722 tritium Inorganic materials 0.000 description 1
- 230000025102 vascular smooth muscle contraction Effects 0.000 description 1
- 102000008538 voltage-gated sodium channel activity proteins Human genes 0.000 description 1
- 108040002416 voltage-gated sodium channel activity proteins Proteins 0.000 description 1
- 239000002023 wood Substances 0.000 description 1
- UHVMMEOXYDMDKI-JKYCWFKZSA-L zinc;1-(5-cyanopyridin-2-yl)-3-[(1s,2s)-2-(6-fluoro-2-hydroxy-3-propanoylphenyl)cyclopropyl]urea;diacetate Chemical compound [Zn+2].CC([O-])=O.CC([O-])=O.CCC(=O)C1=CC=C(F)C([C@H]2[C@H](C2)NC(=O)NC=2N=CC(=CC=2)C#N)=C1O UHVMMEOXYDMDKI-JKYCWFKZSA-L 0.000 description 1
Description
VPU/02-138 WO
QUINAZOLINES USEFUL AS MODULATORS OF ION CHANNELS
PRIORITY INFORMATION
[0001] The present application claims priority under 35 U.S.C. §119 to U.S. Provisional
Application numbers: 60/451,458 filed March 3, 2003, entitled “Compositions Useful as
Inhibitors of Voltage-Gated Sodium Channels”, and 60/463,797, filed April 18, 2003, entitled “Compositions Useful as Inhibitors of Voltage-Gated Sodium Channels”, and the entire contents of each of these applications is hereby incorporated by reference.
[0002] The present invention relates to compounds useful as inhibitors of ion channels.
The invention also provides pharmaceutically acceptable compositions comprising the compounds of the invention and methods of using the compositions in the treatment of various disorders.
[0003] Na channels are central to the generation of action potentials in all excitable cells such as neurons and myocytes. They play key roles in excitable tissue including brain, smooth muscles of the gastrointestinal tract, skeletal muscle, the peripheral nervous system, spinal cord and airway. As such they play key roles in a variety of disease states such as epilepsy (See, Moulard, B. and D. Bertrand (2002) “Epilepsy and sodium channel blockers”
Expert Opin. Ther. Patents 12(1): 85-91)), pain (See, Waxman, S. G., S. Dib-Hajj, et al. (1999) “Sodium channels and pain” Proc Natl Acad Sci U S A 96(14): 7635-9 and Waxman,
S. G.,, T. R. Cummins, et al. (2000) “Voltage-gated sodium channels and the molecular pathogenesis of pain: a review” J Rehabil Res Dev 37(5): 517-28), myotonia (See, Meola, G. and V. Sansone (2000) “Therapy in myotonic disorders and in muscle channelopathies”
Neurol Sci 21(5): $953-61 and Mankodi, A. and C. A. Thomton (2002) “Myotonic syndromes” Curr Opin Neurol 15(5): 545-52), ataxia (See, Meisler, M. H., J. A. Kearney, et al. (2002) “Mutations of voltage-gated sodium channels in movement disorders and epilepsy”
Novartis Found Symp 241: 72-81), multiple sclerosis (See, Black, J. A., S. Dib-Hajj, et al. (2000) “Sensory neuron-specific sodium channel SNS is abnormally expressed in the brains of mice with experimental allergic encephalomyelitis and humans with multiple sclerosis”
Proc Natl Acad Sci U S A 97(21): 11598-602, and Renganathan, M., M. Gelderblom, et al. (2003) “Expression of Na(v)1.8 sodium channels perturbs the firing patterns of cerebellar purkinje cells” Brain Res 959(2): 235-42), irritable bowel (See. Su, X., R. E. Wachtel, et al. (1999) “Capsaicin sensitivity and voltage-gated sodium currents in colon sensory neurons from rat dorsal root ganglia” Am J Physiol 277(6 Pt 1): G1180-8, and Laird, J. M., V.
Souslova, et al. (2002) “Deficits in visceral pain and referred hyperalgesia in Navl.8 (SNS/PN3)- null mice” J Neurosci 22(19): 8352-6), urinary incontinence and visceral pain (See,Yoshimura, N., S. Seki, et al. (2001) “The involvement of the tetrodotoxin-resistant sodium channel Na(v)1.8 (PN3/SNS) in a rat model of visceral pain” J Neurosci 21(21): 8690-6), as well as an array of psychiatry dysfunctions such as anxiety and depression (See,
Hurley, S. C. (2002) “Lamotrigine update and its use in mood disorders” Ann Pharmacother 36(5): 860-73).
[0004] Voltage gated Na channels comprise a gene family consisting of 9 different subtypes (NaV1.1-NaV1.9). As shown in Table 1, these subtypes show tissue specific localization and functional differences (See, Goldin, A. L. (2001) “Resurgence of sodium channel research” Annu Rev Physiol 63: 871-94). Three members of the gene family (NaVv1.8, 1.9, 1.5) are resistant to block by the well-known Na channel blocker TTX, demonstrating subtype specificity within this gene family. Mutational analysis has identified glutamate 387 as a critical residue for TTX binding (See, Noda, M., H. Suzuki, et al. (1989) “A single point mutation confers tetrodotoxin and saxitoxin insensitivity on the sodium channel II” FEBS Lett 259(1): 213-6).
[6005] Table 1 (Abbreviations: CNS = central nervous system, PNS = peripheral nervous sytem, DRG = dorsal root ganglion, TG = Trigeminal ganglion): isoform
NaVv1l.l | CNS, PNS 10nM Pain, Epilepsy, soma of neurodegeneration neurons
NaV1.2 | CNS, highin 10nM Neurodegeneration axons Epileps
NaV1.3 | CNS, 15nM embryonic, injured nerves muscle
NaVl.5 | Heart 2uM Arrythmia, long QT
NaV1.6 | CNS 6nM Pain, movement disorders widespread, most abuntant
NaV1l.7 | PNS, DRG, 25nM Pain, Neuroendocrine terminals disorders neuroendocrine
NaV1.8 | PNS, small >50uM neurons in
DRG & TG
NaV1.9 [| PNS, small pM neurons in
DRG & TG
[0006] In general, voltage-gated sodium channels (NaVs) are responsible for initiating the rapid upstroke of action potentials in excitable tissue in nervous system, which transmit the electrical signals that compose and encode normal and aberrant pain sensations.
Antagonists of NaV channels can attenuate these pain signals and are useful for treating a variety of pain conditions, including but not limited to acute, chronic, inflammatory, and neuropathic pain. Known NaV antagonists, such as TTX, lidocaine (See, Mao, J. and L. L.
Chen (2000) “Systemic lidocaine for neuropathic pain relief” Pain 87(1): 7-17.) bupivacaine, phenytoin (See, Jensen, T. S. (2002) “Anticonvulsants in neuropathic pain: rationale and clinical evidence” Eur J Pain 6 (Suppl A): 61-8), lamotrigine (See. Rozen, T. D. (2001) “Antiepileptic drugs in the management of cluster headache and trigeminal neuralgia”
Headache 41 Suppl 1: 525-32 and Jensen, T. S. (2002) “Anticonvulsants in neuropathic pain: rationale and clinical evidence” Eur J Pain 6 (Suppl A): 61-8.), and carbamazepine (See,
Backonja, M. M. (2002) “Use of anticonvulsants for treatment of neuropathic pain”
Neurology 59(5 Suppl 2): S14-7), have been shown to be useful attenuating pain in humans and animal models.
[0007] Hyperalgesia (extreme sensitivity to something painful) that develops in the presence of tissue injury or inflammation reflects, at least in part, an increase in the excitability of high-threshold primary afferent neurons innervating the site of injury. Voltage sensitive sodium channels activation is critical for the generation and propagation of neuronal action potentials. There is a growing body of evidence indicating that modulation of NaV currents is an endogenous mechanism used to control neuronal excitability (See, Goldin, A.
L. (2001) “Resurgence of sodium channel research” Annu Rev Physiol 63: 871-94). Several kinetically and pharmacologically distinct voltage-gated sodium channels are found in dorsal root ganglion (DRG) neurons. The TTX-resistant current is insensitive to micromolar concentrations of tetrodotoxin, and displays slow activation and inactivation kinetics and a more depolarized activation threshold when compared to other voltage-gated sodium channels. TTX-resistant sodium currents are primarily restricted to a subpopulation of sensory neurons likely to be involved in nociception. Specifically, TTX-resistant sodium currents are expressed almost exclusively in neurons that have a small cell-body diameter; and give rise to small-diameter slow-conducting axons and that are responsive to capsaicin. A large body of experimental evidence demonstrates that TTX-resistant sodium channels are expressed on C-fibers and are important in the transmission of nociceptive information to the spinal cord.
[0008] Intrathecal administration of antisense oligo-deoxynucleotides targeting a unique region of the TTX-resistant sodium channel (NaV1.8) resulted in a significant reduction in
PGEz-induced hyperalgesia (See, Khasar, S. G., M. S. Gold, et al. (1998) “A tetrodotoxin- resistant sodium current mediates inflammatory pain in the rat” Neurosci Lett 256(1): 17-20).
More recently, a knockout mouse line was generated by Wood and colleagues, which lacks functional NaV1.8. The mutation has an analgesic effect in tests assessing the animal’s response to the inflammatory agent carrageenan (See, Akopian, A. N., V. Souslova, et al. (1999) “The tetrodotoxin-resistant sodium channel SNS has a specialized function in pain pathways” Nat Neurosci 2(6): 541-8.). In addition, deficit in both mechano- and thermoreception were observed in these animals. The analgesia shown by the Navl.8 knockout mutants is consistent with observations about the role of TTX-resistant currents in nociception.
[0009] Immunohistochemical, in-situ hybridization and in-vitro electrophysiology experiments have all shown that the sodium channel NaV1.8 is selectively localized to the small sensory neurons of the dorsal root ganglion and trigeminal ganglion (See, Akopian, A.
N., L. Sivilotti, et al. (1996) “A tetrodotoxin-resistant voltage-gated sodium channel expressed by sensory neurons” Nature 379(6562): 257-62.). The primary role of these neurons is the detection and transmission of nociceptive stimuli. Antisense and immunohistochemical evidence also supports a role for NaV1.8 in neuropathic pain (See, Lai,
J., M. S. Gold, et al. (2002) “Inhibition of neuropathic pain by decreased expression of the tetrodotoxin-resistant sodium channel, NaV1.8” Pain 95(1-2): 143-52, and Lai, J, J. C.
Hunter, et al. (2000) “Blockade of neuropathic pain by antisense targeting of tetrodotoxin- resistant sodium channels in sensory neurons” Methods Enzymol 314: 201-13.). NaV1.8 protein is upregulated along uninjured C-fibers adjacent to the nerve injury. Antisense treatment prevents the redistribution of NaV1.8 along the nerve and reverses neuropathic pain. Taken together the gene-knockout and antisense data support a role for NaV1.8 in the detection and transmission of inflammatory and neuropathic pain.
[0010] In neuropathic pain states there is a remodeling of Na channel distribution and subtype. In the injured nerve, expression of NaV1.8 and NaV1.9 are greatly reduced whereas expression of the TTX sensitive subunit NaV1.3 is 5-10 fold upregulated (See, Dib-Hajj, S.
D., J. Fjell, et al. (1999) “Plasticity of sodium channel expression in DRG neurons in the chronic constriction injury model of neuropathic pain.” Pain 83(3): 591-600.) The timecourse of the increase in NaV1.3 parallels the appearance of allodynia in animal models subsequent to nerve injury. The biophysics of the NaV1.3 channel is distinctive in that it shows very fast repriming after inactivation following an action potential. This allows for sustained rates of high firing as is often seen in the injured nerve (See, Cummins, T. R., F.
Aglieco, et al. (2001) “Navl.3 sodium channels: rapid repriming and slow closed-state inactivation display quantitative differences after expression in a mammalian cell line and in spinal sensory neurons” J Neurosci 21(16): 5952-61.). NaV1.3 is expressed in the central and peripheral systems of man. NaV1.9 is similar to NaV1.8 as it is selectively localized to small sensory neurons of the dorsal root ganglion and trigeminal ganglion (See, Fang, X., L.
Djouhri, et al. (2002). “The presence and role of the tetrodotoxin-resistant sodium channel
Na(v)1.9 (NaN) in nociceptive primary afferent neurons.” J Neurosci 22(17): 7425-33.). It has a slow rate of inactivation and left-shifted voltage dependence for activation (See, Dib-
Hajj, S., J. A. Black, et al. (2002) “NaN/Nav1.9: a sodium channel with unique properties”
Trends Neurosci 25(5): 253-9.). These two biophysical properties allow NaV1.9 to play a role in establishing the resting membrane potential of nociceptive neurons. The resting membrane potential of NaV1.9 expressing cells is in the 55 to —=50mV range compared to — 65mV for most other peripheral and central neurons. This persistent depolarization is in large part due to the sustained low-level activation of NaV1.9 channels. This depolarization allows the neurons to more easily reach the threshold for firing action potentials in response to nociceptive stimuli. Compounds that block the NaV1.9 channel may play an important role in establishing the set point for detection of painful stimuli. In chronic pain states, nerve and nerve ending can become swollen and hypersensitive exhibiting high frequency action potential firing with mild or even no stimulation. These pathologic nerve swellings are termed neuromas and the primary Na channels expressed in them are NaV1.8 and NaV1.7 (See, Kretschmer, T., L. T. Happel, et al. (2002) “Accumulation of PN1 and PN3 sodium channels in painful human neuroma- evidence from immunocytochemistry” Acta Neurochir (Wien) 144(8): 803-10; discussion 810.). NaV1.6 and NaV1.7 are also expressed in dorsal root ganglion neurons and contribute to the small TTX sensitive component seen in these cells. NaV1.7 in particular my therefore be a potential pain target in addition to it’s role in neuroendocrine excitability (See, Klugbauer, N., L. Lacinova, et al. (1995) “Structure and functional expression of a new member of the tetrodotoxin- sensitive voltage-activated sodium channel family from human neuroendocrine cells” Embo J 14(6): 1084-90).
[0011] NaV1.1 (See, Sugawara, T., E. Mazaki-Miyazaki, et al. (2001) “Nav1.1 mutations cause febrile seizures associated with afebrile partial seizures.” Neurology 57(4): 703-5.) and
NaV1.2 (See, Sugawara, T., Y. Tsurubuchi, et al. (2001) “A missense mutation of the Na+ channel alpha II subunit gene Na(v)1.2 in a patient with febrile and afebrile seizures causes channel dysfunction” Proc Natl Acad Sci U S A 98(11): 6384-9) have been linked to epilepsy conditions including febrile seizures. There are over 9 genetic mutations in NaV1.l associated with febrile seizures (See, Meisler, M. H., J. A. Kearney, et al. (2002) “Mutations of voltage-gated sodium channels in movement disorders and epilepsy” Novartis Found
Symp 241: 72-81)
[0012] Antagonists for NaV1.5 have been developed and used to treat cardiac arrhythmias. A gene defect in NaV1.5 that produces a larger noninactivating component to the current has been linked to long QT in man and the orally available local anesthetic mexilitine has been used to treat this condition (See, Wang, D. W., K. Yazawa, et al. (1997) “Pharmacological targeting of long QT mutant sodium channels.” J Clin Invest 99(7): 1714- 20).
[0013] Several Na channel blockers are currently used or being tested in the clinic to treat epilepsy (See, Moulard, B. and D. Bertrand (2002) “Epilepsy and sodium channel] blockers”
Expert Opin. Ther. Patents 12(1): 85-91.); acute (See, Wiffen, P., S. Collins, et al. (2000) “Anticonvulsant drugs for acute and chronic pain” Cochrane Database Syst Rev 3), chronic (See. Wiffen, P., S. Collins, et al. (2000) “Anticonvulsant drugs for acute and chronic pain”
Cochrane Database Syst Rev 3, and Guay, D. R. (2001) “Adjunctive agents in the management of chronic pain” Pharmacotherapy 21(9): 1070-81), inflammatory (See, Gold,
M. S. (1999) “Tetrodotoxin-resistant Na+ currents and inflammatory hyperalgesia.” Proc Natl
Acad Sci U S A 96(14): 7645-9), and neuropathic pain (See, Strichartz, G. R., Z. Zhou, et al. (2002) “Therapeutic concentrations of local anaesthetics unveil the potential role of sodium channels in neuropathic pain” Novartis Found Symp 241: 189-201, and Sandner-Kiesling, A.,
G. Rumpold Seitlinger, et al. (2002) “Lamotrigine monotherapy for control of neuralgia after nerve section” Acta Anaesthesiol Scand 46(10): 1261-4); cardiac arrhythmias (See, An, R.
H., R. Bangalore, et al. (1996) “Lidocaine block of LQT-3 mutant human Na+ channels” Circ
Res 79(1): 103-8, and Wang, D. W., K. Yazawa, et al. (1997) “Pharmacological targeting of long QT mutant sodium channels” J Clin Invest 99(7): 1714-20); neuroprotection (See.
Taylor, C. P. and L. S. Narasimhan (1997) “Sodium channels and therapy of central nervous system diseases” Adv Pharmacol 39: 47-98) and as anesthetics (See, Strichartz, G. R., Z.
Zhou, et al. (2002) “Therapeutic concentrations of local anaesthetics unveil the potential role of sodium channels in neuropathic pain.” Novartis Found Symp 241: 189-201)
[0014] Calcium channels are membrane-spanning, multi-subunit proteins that allow Ca entry from the external milieu and concurrent depolarization of the cell’s membrane potential. ‘Traditionally calcium channels have been classified based on their functional characteristics such as low voltage or high voltage activated and their kinetics (L,T,N,P,Q).
The ability to clone and express the calcium channel subunits has lead to an increased understanding of the channel composition that produces these functional responses. There are three primary subunit types that make up calcium channels - al, ¢29, and PB. The al is the subunit containing the channel pore and voltage sensor, 02 is primarily extracellular and is disulfide linked to the transmembrane J subunit, B is nonglycosylated subunit found bound to the cytoplasmic region of the al subunit of the Ca channel. Currently the various calcium channel subtypes are believed to made up of the following specific subunits: e L-type, comprising subunits 04cOupOyp, OF Os, 028 and Bsa e N-Type, comprising subunits 04g, 028 , Bip ¢ P-Type, comprising subunits 04a, 028 , Baa ¢ Q-Type, comprising subunits 0,4 (splice variant) 028 , Baa e R-Type, comprising subunits oy, 023 , Bip eo T-Type, comprising subunits 04g, Ou, OT Oh
[0015] Calcium channels play a central role in neurotransmitter release. Ca influx into the presynaptic terminal of a nerve process binds to and produces a cascade of protein-protein interactions (syntaxin 1A, SNAP-25 and synaptotagmin) that ultimately ends with the fusion of a synaptic vesical and release of the neurotransmitter packet. Blockade of the presynaptic calcium channels reduces the influx of Ca and produces a cubic X? decrease in neurotransmitter release.
[0016] The N type Ca channel (CaV2.2) is highly expressed at the presynaptic nerve terminals of the dorsal root ganglion as it forms a synapse with the dorsal horn neurons in lamina I and XI. These neurons in turn have large numbers of N type Ca channels at their presynaptic terminals as they synapse onto second and third order neurons. This pathway is very important in relaying pain information to the brain.
[0017] Pain can be roughly divided into three different types: acute, inflammatory, and neuropathic. Acute pain serves an important protective function in keeping the organism safe from stimuli that may produce tissue damage. Severe thermal, mechanical, or chemical inputs have the potential to cause severe damage to the organism if unheeded. Acute pain serves to quickly remove the individual from the damaging environment. Acute pain by its very nature generally is short lasting and intense. Inflammatory pain on the other had may last for much longer periods of time and it’s intensity is more graded. Inflammation may occur for many reasons including tissue damage, autoimmune response, and pathogen invasion. Inflammatory pain is mediated by an “inflammatory soup” that consists of substance P, histamines, acid, prostaglandin, bradykinin, CGRP, cytokines, ATP, and neurotransmitter release. The third class of pain is neuropathic and involves nerve damage that results in reorganization of neuronal proteins and circuits yielding a pathologic “sensitized” state that can produce chronic pain lasting for years. This type of pain provides no adaptive benefit and is particularly difficult to treat with existing therapies.
[0018] Pain, particularly neuropathic and intractable pain is a large unmet medical need.
Millions of individuals suffer from severe pain that is not well controlled by current therapeutics. The current drugs used to treat pain include NSAIDS, COX2 inhibitors, opioids, tricyclic antidepressants, and anticonvulsants. Neuropathic pain has been particularly difficult to treat as it does not respond well to opiods until high doses are reached. Gabapentin is currently the favored therapeutic for the treatment of neuropathic pain although it works in only 60% of patients where it shows modest efficacy. The drug is however very safe and side effects are generally tolerable although sedation is an issue at higher doses.
[0019] The N type Ca channel has been validated in man by intrathecal infusion of the toxin Ziconotide for the treatment of intractable pain, cancer pain, opioid resistant pain, and neuropathic and severe pain. The toxin has an 85% success rate for the treatment of pain in humans with a greater potency than morphine. An orally available N type Ca channel antagonist would garner a much larger share of the pain market. Ziconotide causes mast cell degranulation and produces dose-dependent central side effects. These include dizziness, nystagmus, agitation, and dysmetria. There is also orthostatic hypotension in some patients at high doses. The primary risk for this target involves the CNS side effects seen with
Ziconotide at high dosing. These include dizziness, nystagmus, agitation, and dysmetria.
There is also orthostatic hypotension in some patients at high doses. It is believed that this may be due to Ziconotide induced mast cell degranulation and/or its effects on the sympathetic ganglion that like the dorsal root ganglion also expresses the N type Ca channel.
Use-dependent compounds that block preferentially in the higher frequency range >10Hz should be helpful in minimizing these potential side-effect issues. The firing rate in man of the sympathetic efferents is in the 0.3 Hz range. CNS neurons can fire at high frequencies but generally only do so in short bursts of action potentials. Even with the selectivity imparted by use-dependence intrinsic selectivity against the L type calcium channel is still necessary as it is involved in cardiac and vascular smooth muscle contraction.
[0020] Unfortunately, as described above, the efficacy of currently used sodium channel blockers and calcium channel blockers for the disease states described above has been to a large extent limited by a number of side effects. These side effects include various CNS disturbances such as blurred vision, dizziness, nausea, and sedation as well more potentially life threatening cardiac arrhythmias and cardiac failure. Accordingly, there remains a need to develop additional Na channel and Ca channel antagonists, preferably those with higher potency and fewer side effects.
[0021] It has now been found that compounds of this invention, and pharmaceutically acceptable compositions thereof, are useful as inhibitors of voltage-gated sodium channels and calcium channels. These compounds have the general formula i:
RL, 3° ~N pS . or a pharmaceutically acceptable derivative thereof, wherein R', X, R3, x, and ring A are as defined below.
[0022] These compounds and pharmaceutically acceptable compositions are useful for treating or lessening the severity of a variety of diseases, disorders, or conditions, including, but not limited to, acute, chronic, neuropathic, or inflammatory pain, arthritis, migrane, cluster headaches, trigeminal neuralgia, herpetic neuralgia, general neuralgias, epilepsy or epilepsy conditions, neurodegenerative disorders, psychiatric disorders such as anxiety and depression, myotonia, arrythmia, movement disorders, neuroendocrine disorders, ataxia, multiple sclerosis, irritable bowel syndrome, incontinence, visceral pain, osteoarthritis pain, postherpetic neuralgia, diabetic neuropathy, radicular pain, sciatica, back pain, head or neck pain, severe or intractable pain, nociceptive pain, breakthrough pain, postsurgical pain, or cancer pain.
[0023] I General Description of Compounds of the Invention: : [0024] The present invention relates to compounds of formula I useful as inhibitors of voltage-gated sodium channels and calcium channels:
RL,
Se
N
1 or a pharmaceutically acceptable salt thereof, wherein:
X is O or NR% wherein R' and R? are each independently an optionally substituted group selected from hydrogen, C).¢aliphatic, or Cy', wherein Cy' is a 5-7-membered monocyclic aryl ring or an 3-10-membered bicyclic aryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or is a 3-12-membered saturated, or partially unsaturated monocyclic or bicyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein Cy' is bonded directly to the nitrogen atom or is bonded through an optionally substituted C,4aliphatic group, wherein one or more methylene units in the C,. saliphatic group are optionally replaced with -NR-, -O-, -COO, -0CO-, -NRCO-, -CONR-, -
SO,NR-, or -NRSO,-; or R! and R?, taken together with the nitrogen atom to which they are bound, form an optionally substituted 3-12-membered monocyclic or bicyclic saturated, partially unsaturated, or fully unsaturated ring having 0-3 additional heteroatoms independently selected from nitrogen, sulfur, or oxygen; wherein R' and R?, or the ring formed by R! and R? taken together, are each optionally and independently substituted at one or more substitutable carbon, nitrogen, or sulfur atoms with z independent occurrences of —
R*, wherein z is 0-5;
Ring A is a 5-7-membered monocyclic aryl ring or an 8-10-membered bicyclic aryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, oris a 3-12-membered monocyclic or bicyclic saturated or partially unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein ring
A is optionally substituted with y independent occurrences of —R®, wherein y is 0-5, and is additionally optionally substituted with q independent occurrences of R>, wherein q is 0-2; x is 0-4; each occurrence of R3 R% and R’ is independently Q-R%; wherein Q is a bond or is a
C;-C alkylidene chain wherein up to two non-adjacent methylene units of Q are optionally and independently replaced by -NR-, -S-, -O-, -CS-, -CO»-, -0CO-, -CO-, -COCO-, -CONR-, _NRCO-, -NRCO,-, -SO;NR-, -NRSO;-, -CONRNR-, -NRCONR-, -OCONR-, -NRNR-, -
NRSO,NR-, -SO-, -SO;-, -PO-, -PO;-, -OP(O)(OR)-, or -POR-; and each occurrence of R*is independently selected from -R’, =0, =NR’, halogen, -NO3, -CN, -OR’, -SR’, -N(R’)a, -
NR’COR’, -NR’CON(R’),, -NR’CO2R’, -COR’, -CO:R’, -OCOR’, -CON(R"),, -
OCON(R’), -SOR’, -SO,R’, -SO,N(R’)z, -NR’SO;R’, -NR’SO:NR)z, -COCOR’, -
COCH,COR’, -OP(O)(OR’),, -P(O)(OR’),, -OP(0),0R’, -P(O),0R’, -POR’ )2, OF -
OPOR)2; each occurrence of R* is independently an optionally substituted C;-Cealiphatic group, halogen, -OR’, -SR’, -N(R");, -NR’COR’, -NR’CON(R’);, -NR’ COR’, -COR’, -
CO,R’, -OCOR’, -CON(R)z, -OCON(R’)z, -SOR’, -SO2R’, -SOz2N(R")2, -NR’SO2R’, -
NR’SO5N(R”),, -COCOR’, -COCH,COR’, -OP(O)(OR)2, -P(O)(OR’),, -OP(O),0R’, -
P(0),0R’, -PO(R"),, or -OPO(R’); and each occurrence of R is independently hydrogen or an optionally substituted Cy. aliphatic group; and each occurrence of R’ is independently hydrogen or an optionally substituted Cy.¢ aliphatic group, a 3-8-membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-12 membered saturated, partially unsaturated, or fully unsaturated bicyclic ring system having 0-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or R and R’, two occurrences of R, or two occurrences of R’, are taken together with the atom(s) to which they are bound to form an optionally substituted 3-12 membered saturated, partially unsaturated, or fully unsaturated monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
[0025] In certain embodiments for compounds described directly above:
i) when x is 1 and R? is optionally substituted 6-phenyl or 6-pyridyl, and R'is hydrogen, then R? is not Cy';and ii) Piperazine, 1-(4-amino-6,7-dimethoxy-2-quinazolinyl)-4(2-furanylcarbonyl)- monohydrochloride and Piperazine, 1-(4-amino-6,7-dimethoxy-2-quinazolinyl)-4{(2,3- dihydro-1,4-benzodioxin-2-yl)carbonyl}- are excluded.
[0026] 2. Compounds and Definitions:
[0027] Compounds of this invention include those described generally above, and are further illustrated by the classes, subclasses, and species disclosed herein. As used herein, the following definitions shall apply unless otherwise indicated. For purposes of this invention, the chemical elements are identified in accordance with the Periodic Table of the Elements,
CAS version, Handbook of Chemistry and Physics, 75" Ed. Additionally, general principles of organic chemistry are described in “Organic Chemistry”, Thomas Sorrell, University
Science Books, Sausalito: 1999, and “March’s Advanced Organic Chemistry”, 5" Ed., Ed.:
Smith, M.B. and March, J., John Wiley & Sons, New York: 2001, the entire contents of which are hereby incorporated by reference.
[0028] As described herein, compounds of the invention may optionally be substituted with one or more substituents, such as are illustrated generally above, or as exemplified by particular classes, subclasses, and species of the invention. It will be appreciated that the phrase “optionally substituted” is used interchangeably with the phrase “substituted or unsubstituted.” In general, the term “substituted”, whether preceded by the term “optionally” or not, refers to the replacement of hydrogen radicals in a given structure with the radical of a specified substituent. Unless otherwise indicated, an optionally substituted group may have a substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at every position.
Combinations of substituents envisioned by this invention are preferably those that result in the formation of stable or chemically feasible compounds. The term “stable”, as used herein, refers to compounds that are not substantially altered when subjected to conditions to allow for their production, detection, and preferably their recovery, purification, and use for one or more of the purposes disclosed herein. In some embodiments, a stable compound or chemically feasible compound is one that is not substantially altered when kept at a temperature of 40°C or less, in the absence of moisture or other chemically reactive conditions, for at least a week.
[0029] The term “aliphatic” or “aliphatic group”, as used herein, means a straight-chain (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is completely saturated or that contains one or more units of unsaturation, or a monocyclic hydrocarbon or bicyclic hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic (also referred to herein as “carbocycle" “cycloaliphatic” or “cycloalkyl”, that has a single point of attachment to the rest of the molecule. Unless otherwise specified, aliphatic groups contain 1-20 aliphatic carbon atoms.
In some embodiments, aliphatic groups contain 1-10 aliphatic carbon atoms. In other embodiments, aliphatic groups contain 1-8 aliphatic carbon atoms. In still other embodiments, aliphatic groups contain 1-6 aliphatic carbon atoms, and in yet other embodiments aliphatic groups contain 1-4 aliphatic carbon atoms. In some embodiments, “cycloaliphatic” (or “carbocycle” or “cycloalkyl”) refers to a monocyclic C3-Cg hydrocarbon or bicyclic Cg-Cj2 hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic, that has a single point of attachment to the rest of the molecule wherein any individual ring in said bicyclic ring system has 3-7 members.
Suitable aliphatic groups include, but are not limited to, linear or branched, substituted or unsubstituted alkyl, alkenyl, alkynyl groups and hybrids thereof such as (cycloalkylalkyl, (cycloalkenyl)alkyl or (cycloalkyl)alkenyl.
[0030] The term “heteroaliphatic”, as used herein, means aliphatic groups wherein one or two carbon atoms are independently replaced by one or more of oxygen, sulfur, nitrogen, phosphorus, or silicon. Heteroaliphatic groups may be substituted or unsubstituted, branched or unbranched, cyclic or acyclic, and include “heterocycle”, “heterocyclyl”, “heterocycloaliphatic”, or “heterocyclic” groups.
[0031] The term “heterocycle”, “heterocyclyl”, “heterocycloaliphatic”, or “heterocyclic” as used herein means non-aromatic, monocyclic, bicyclic, or tricyclic ring systems in which one or more ring members are an independently selected heteroatom. In some embodiments, the “heterocycle”, “heterocyclyl”, “heterocycloaliphatic”, or “heterocyclic” group has three to fourteen ring members in which one or more ring members is a heteroatom independently selected from oxygen, sulfur, nitrogen, or phosphorus, and each ring in the system contains 3 to 7 ring members.
[0032] The term “heteroatom” means one or more of oxygen, sulfur, nitrogen, phosphorus, or silicon (including, any oxidized form of nitrogen, sulfur, phosphorus, or silicon; the quaternized form of any basic nitrogen or; a substitutable nitrogen of a heterocyclic ting, for example N (as in 3 4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) or
NR (as in N-substituted pyrrolidinyl)).
[0033] The term "unsaturated", as used herein, means that a moiety has one or more units of unsaturation.
[0034] The term “alkoxy”, or “thioalkyl”, as used herein, refers to an alkyl group, as previously defined, attached to the principal carbon chain through an oxygen (“alkoxy”) or sulfur (“thioalkyl”) atom.
[0035] The terms “haloalkyl”, “haloalkenyl” and “haloalkoxy” means alkyl, alkenyl or alkoxy, as the case may be, substituted with one or more halogen atoms. The term “halogen” means F, Cl, Br, or L.
[0036] . The term “aryl” used alone or as part of a larger moiety as in “aralkyl”, “aralkoxy”, or “aryloxyalkyl”, refers to monocyclic, bicyclic, and tricyclic ring systems having a total of five to fourteen ring members, wherein at least one ring in the system is aromatic and wherein each ring in the system contains 3 to 7 ring members. The term “aryl” may be used interchangeably with the term “aryl ring”. The term "aryl" also refers to heteroaryl ring systems as defined hereinbelow.
[0037] The term “heteroaryl”, used alone or as part of a larger moiety as in “heteroaralkyl” or “heteroarylalkoxy”, refers to monocyclic, bicyclic, and tricyclic ring systems having a total of five to fourteen ring members, wherein at least one ring in the system is aromatic, at least one ring in the system contains one or more heteroatoms, and wherein each ring in the system contains 3 to 7 ring members. The term “heteroaryl” may be used interchangeably with the term “heteroaryl ring” or the term “heteroaromatic”.
[0038] An aryl (including aralkyl, aralkoxy, aryloxyalkyl and the like) or heteroaryl (including heteroaralkyl and heteroarylalkoxy and the like) group may contain one or more substituents and thus may be “optionally substituted”. Unless otherwise defined above and herein, suitable substituents on the unsaturated carbon atom of an aryl or heteroaryl group are generally selected from halogen; -R°; -OR®; -SR°; phenyl (Ph) optionally substituted with R®; -O(Ph) optionally substituted with R% -(CHp).2(Ph), optionally substituted with R% -
CH=CH(Ph), optionally substituted with R% -NOz; -CN; -N(R°)z; -NR°C(O)R% -
NRCC(S)R®; -NR°C(ON(R®);; -NR°C(S)N(R®); -NR°CO.R°; -NR°NR°C(O)R®;
-NR°NR°C(O)N(R®); -NR°NR°CO:R®; -C(0)C(O)R® -C(O)CH,C(O)R®; -CO;R%; -
C(O)R®; -C(S)R®; -C(O)N(R®)z; -C(S)N(R®)z; -OC(OIN(R")2; -OC(O)R®; -C(O)N(OR°) R%;
C(NOR®) R° -S(O);R% -S(O):R° -SONR®): SOR? “NR°SO;N(R®);; -NR°SO2R;
N(OR®)R®; -C(=NH)-N(R°); -P(O):R°; POR); -OPOR"); -(CH2)0.2NHC(O)R?; phenyl (Ph) optionally substituted with R% -O(Ph) optionally substituted with R®% -(CHy)12(Ph), optionally substituted with R®; or -CH=CH(Ph), optionally substituted with R°; wherein each independent occurrence of R° is selected from hydrogen, optionally substituted C,-¢ aliphatic, an unsubstituted 5-6 membered heteroaryl or heterocyclic ring, phenyl, -O(Ph), or -CHa(Ph), or, notwithstanding the definition above, two independent occurrences of R°, on the same substituent or different substituents, taken together with the atom(s) to which each R°® group is bound, to form an optionally substituted 3-12 membered saturated, partially unsaturated, or fully unsaturated monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
[0039] . Optional substituents on the aliphatic group of R° are selected from NH,
NH(C;4aliphatic), N(C4aliphatic),, halogen, C,.aliphatic, OH, O(C; aliphatic), NO, CN,
CO,H, CO,(C.qaliphatic), O(haloCy.4 aliphatic), or haloC)4aliphatic, wherein each of the foregoing C;aliphatic groups of R° is unsubstituted.
[0040] An aliphatic or heteroaliphatic group, or a non-aromatic heterocyclic ring may contain one or more substituents and thus may be “optionally substituted”. Unless otherwise defined above and herein, suitable substituents on the saturated carbon of an aliphatic or heteroaliphatic group, or of a non-aromatic heterocyclic ring are selected from those listed above for the unsaturated carbon of an aryl or heteroaryl group and additionally include the following: =O, =S, =NNHR', =NNQRY), =NNHC(O)R", =NNHCO(alkyl), =NNHSO,(alkyl), or =NR’, where each R" is independently selected from hydrogen or an optionally substituted C6 aliphatic group.
[0041] Unless otherwise defined above and herein, optional substituents on the nitrogen of a non-aromatic heterocyclic ring are generally selected from -R’, NR", -C(O)RY, -COR*, -C(O)C(O)R*, -C(O)CH,C(O)R", -SO.RY, -SONRM),, -C(=S)NR™),, -C(=NH)-
N(R*)2, or -NR*SO;R"; wherein R* is hydrogen, an optionally substituted Cy.¢ aliphatic, optionally substituted phenyl, optionally substituted -O(Ph), optionally substituted -CHz(Ph), optionally substituted -(CH,),.2(Ph); optionally substituted -CH=CH(Ph); or an unsubstituted 5.6 membered heteroaryl or heterocyclic ring having one to four heteroatoms independently selected from oxygen, nitrogen, or sulfur, or, notwithstanding the definition above, two independent occurrences of R’, on the same substituent or different substituents, taken together with the atom(s) to which each R* group is bound, form an optionally substituted 3- 12 membered saturated, partially unsaturated, or fully unsaturated monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
[0042] Optional substituents on the aliphatic group or the phenyl ring of R" are selected from -NH,, -NH(C;.4 aliphatic), -N(Ci4 aliphatic), halogen, C4 aliphatic, -OH, -O(Ci4 aliphatic), -NO,, -CN, -CO,H, -CO5(C,4 aliphatic), -O(halo C.4 aliphatic), or halo(Ci4 aliphatic), wherein each of the foregoing Cialiphatic groups of R* is unsubstituted.
[0043] The term “alkylidene chain” refers to a strai ght or branched carbon chain that may be fully saturated or have one or more units of unsaturation and has two points of attachment to the rest of the molecule.
[0044] As detailed above, in some embodiments, two independent occurrences of R° (or
R*, R, R’ or any other variable similarly defined herein), are taken together with the atom(s) to which they are bound to form an optionally substituted 3-12 membered saturated, partially unsaturated, or fully unsaturated monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
[0045] Exemplary rings that are formed when two independent occurrences of R® (or RY,
R, R’ or any other variable similarly defined herein), are taken together with the atom(s) to which each variable is bound include, but are not limited to the following: a) two independent occurrences of R° (or R*, R, R’ or any other variable similarly defined herein) that are bound to the same atom and are taken together with that atom to form a ring, for example, N(R), where both occurrences of R° are taken together with the nitrogen atom to form a piperidin-1-yl, piperazin-1-yl, or morpholin-4-yl group; and b) two independent occurrences of R® (or R*, R, R’ or any other variable similarly defined herein) that are bound to different atoms and are taken together with both of those atoms to form a ring, for example
Ce where a phenyl group is substituted with two occurrences of OR® % OR® these two occurrences of R° are taken together with the oxygen atoms to which they are bound to form jou a fused 6-membered oxygen containing ring: % O” . 1t will be appreciated that a variety of other rings can be formed when two independent occurrences of R® (or R*,R,R’ or any other variable similarly defined herein) are taken together with the atom(s) to which each variable is bound and that the examples detailed above are not intended to be limiting.
Unless otherwise stated, structures depicted herein are also meant to include all isomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational)) forms of the structure; for example, the R and S configurations for each asymmetric center, (Z) and (E) double bond isomers, and (Z) and (E) conformational isomers. Therefore, single stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the present compounds are within the scope of the invention.
Unless otherwise stated, all tautomeric forms of the compounds of the invention are within the scope of the invention. Additionally, unless otherwise stated, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures except for the replacement of hydrogen by deuterium or tritium, or the replacement of a carbon by a 13. or "“C-enriched carbon are within the scope of this invention. Such compounds are useful, for example, as analytical tools or probes in biological assays.
[0046] 3. Description of Exemplary Compounds:
[0047] As described generally above, for compounds of the invention, X is O or NR>.
Accordingly, in certain embodiments, X is NR? and compounds have the structure of formula I-A: 1 m2
RnR
XN
N
I-A
[0048] In other embodiments, X is O, and compounds have the structure of formula I-B: 1
Rx 0
XIN
N
1-B
[0049] In certain embodiments for compounds of general formula I-A, one of R! or R* is hydrogen, and the other of R' and R is selected from an optionally substituted C; aliphatic group, wherein one or more methylene units in the C}.qaliphatic group are optionally replaced with -NR-, -O-, -COO, -OCO-, -NRCO-, -CONR-, -SO;NR-, or -NRSOy-, or is Cy, wherein
Cy' is a 5-7-membered monocyclic aryl ring or an 8-10-membered bicyclic aryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, Of sulfur, or is a 3-12- membered saturated, or partially unsaturated monocyclic or bicyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein Cy’ is bonded directly to the nitrogen atom or is bonded through an optionally substituted Ci4aliphatic group, wherein one or more methylene units in the C;.saliphatic group are optionally replaced with -NR-, -O-, -COO, -OCO-, -NRCO-, -CONR-, -SO2NR-, or -NRSO;-.
[0050] In still other embodiments, R' and R? are each independently selected from Cy’, wherein Cy' is a 5-7-membered monocyclic aryl ring or an 8-10-membered bicyclic aryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or is a 3-12- membered saturated, or partially unsaturated monocyclic or bicyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein Cy' is bonded directly to the nitrogen atom or is bonded through an optionally substituted C;4aliphatic group, wherein one or more methylene units in the Cialiphatic group are optionally replaced with -NR-, -O-, -COO, -OCO-, -NRCO-, -CONR-, -SO;NR-, or -NRSO;-; or from an optionally substituted C_saliphatic group, wherein one or more methylene units in the C;. saliphatic group are optionally replaced with -NR-, -0-, -COO0-, -0CO-, -NRCO-, -CONR-, -
SO;NR-, or -NRSO>-.
[0051] In other embodiments, for compounds of formula I-A, one of R! or R? is hydrogen, and the other of R or R? is an optionally substituted Cy.4aliphatic group, wherein one or more methylene units in the Cy saliphatic group are optionally replaced with -NR-, -O- , -CO0-, -OCO-, -NRCO-, -CONR-, -SO,NR-~, or -NRSO,-. In still other embodiments, the optionally substituted C,.aliphatic group is substituted with Cy', wherein Cy' is 5-7- membered monocyclic aryl ring or an 8-10-membered bicyclic aryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or is a 3-12 membered saturated or partially unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein Cy’ is optionally substituted with 0-5 . independent occurrences of -R®. In yet other embodiments, one of R! or R? is hydrogen or
C,-Caalkyl, and the other of R! or R? is -CH,-Cy'.
[0052] In yet other embodiments, for compounds of formula I-B, R! is an optionally substituted Cj4aliphatic group, wherein one or more methylene units in the C,4aliphatic group are optionally replaced with -NR-, -O-, .COO-, -0CO, -NRCO-, -CONR-, -SO;NR-, or -NRSO-.
[0053] In still other embodiments, for compounds of formula I-A, neither R! nor R? is hydrogen, and R' and R? are each independently selected from Cy', wherein Cy' is a 5-7- membered monocyclic aryl ring or an 8-10-membered bicyclic aryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, Of sulfur, or is a 3-12-membered saturated, or partially unsaturated monocyclic or bicyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein Cy' is bonded directly to the nitrogen atom or is bonded through an optionally substituted Cy-saliphatic group, wherein one or more methylene units in the Cj.saliphatic group are optionally replaced with -NR-, -O- , -COO0, -0CO-, -NRCO-, -CONR-, -SO,NR-, or -NRSO»-; or from an optionally substituted
C4aliphatic group, wherein one or more methylene units in the Cj 4aliphatic group are optionally replaced with NR-, -O-, -CO0O-, -OCO-, -NRCO-, -CONR-, SO;NR-, or -NRSO;
In other embodiments, both R' and R? are an optionally substituted C4aliphatic group, wherein one or more methylene units in the C;4aliphatic group are optionally replaced with —
NR-, -O-, -COO-, -OCO-, -NRCO-, -CONR-, -SO;NR-, or -NRSO;..
[0054] In some embodiments, for compounds of formula I, I-A or I-B, Cy' is selected from:
TN TA NZD ay PO g nd Ny 4 oe ST C7 ER a b c d (R*), (R*) __ (RY, (R*
N” N* “o 4 e f g h
H
NN Sik — RY, we, ‘al Aye HS i J k 1
R4 R* R*
R¢
L's )z NN NY, .
S ve O Jy J=n “, hn, m n o p
R4 Rr? Rr § A A >= ! pe Nd Fe "hn N wl a (RF) q r ] t d 0
TUNE T FUME Tas FUSE
NG Qn NE SSA (RY); N N (RY)
H H u \{ w x
H
N Sn, oN ON, 2 (Re
EC INRY, TINE, Uwe, < ( )z y z aa bb wherein R* is previously defined and z is 0-4. Other exemplary rings include those shown below in Table 2.
[0055] In yet other embodiments, for compounds of formula I, I-A, and I-B, exemplary
R! and R? groups are optionally substituted methyl, ethyl, cyclopropyl, n-propyl, propenyl, cyclobutyl, (CO)OCH:CH;, (CH,);0CH;, CHx(CO)OCH,CHj, CH2(CO)OCHGs,
CH(CHs3)CH,CHs, or n-butyl. Other exemplary R! and R? groups include those shown below in Table 2.
[0056] In still other embodiments, for compounds of formula I-A, R' and R?, taken together with the nitrogen atom to which they are bound, form an optionally substituted 3-12 membered heterocyclyl ring having 1-3 heteroatoms independently selected from nitrogen, sulfur, or oxygen. In certain preferred embodiments, R! and R? are taken together with the nitrogen atom to which they are bound and form a group selected from:
A” A AT A
LN $$ Lo cc dd ee en yo Ne
Cr™ (oy
INRY, ff gg hh 4 ed ™ £0 A & § os RY <X
AR%) ii ii kk 1 T y po % @ wh GY y ) (R9; (R%): n mm an 00 wherein the ring formed by R! and R? taken together, is optionally substituted at one or more substitutable carbon, nitrogen, or sulfur atoms with z independent occurrences of -
R* and zis 0-5.
[0057] In other embodiments, for compounds of formula I-A, R! and R? taken together are optionally substituted azetidin-1-yl (jj), pyrrolidin-1-yl (ff), piperidin1-yl (dd), piperazin- 1-yl (cc), or morpholin-4-yl (ee). In other embodiments, for compounds of formula I-A, R! and R? taken together are optionally substituted azetidin-1-yl (i), pyrrolidin-1-yl (ff), piperidinl-yl (dd), or piperazin-1-yl (cc). In yet other embodiments, for compounds of formula I-A, R! and R?, taken together is optionally substituted azetidin-1-yl (jj). In yet other embodiments, for compounds of formula I-A, R' and R? taken together is optionally substituted pyrrolidin-1-yl (ff). In still other embodiments, for compounds of formula I-A, R! and R?, taken together is optionally substituted piperidinl-yl (dd). In yet other embodiments,
for compounds of formula I-A, R! and R?, taken together is optionally substituted piperazin- 1-yl (cc).
[0058] In certain embodiments, z is 0-2. In other embodiments, z is 0 and the ring is unsubstituted. Preferred R* groups, when present, are each independently halogen, CN, NO»,
N(R’)z, -CHN(R’),, -OR’, -CH,OR’, -SR’, -CH,SR’, -COOR’, -NRCOR’, -CON(R")2, -
OCON(R’),;, COR’, -NHCOOR’, -SO2R’, -SO,N(R’), or an optionally substituted group selected from C;.Cealiphatic, aryl, heteroaryl, cycloaliphatic, heterocycloaliphatic, arylC,-
Cealkyl, heteroarylC,-Cealkyl, cycloaliphaticC;-Cealkyl, or heterocycloaliphaticC;-Cealkyl.
Other exemplary R* groups are Cl, Br, F, CFs, CHs, -CH;CH;, CN, -COOH, -N(CHs)y, -
N(Et);, -N(@iPr);, -O(CH,),OCH3, -CONH,, -COOCH;, -OH, -CH,OH, -NHCOCH;, -
SO,NH,, -SOx(CH,);CHs, -SO,CH(CHs),, -SO,N(CH3);, -SO.CH,CH;, -
C(O)OCH,CH(CH3);, -C(O)NHCH,CH(CHa)z, -NHCOOCH;, -C(O)C(CHs);, -
COO(CH,),CHj;, -C(O)NHCH(CHj3)s, -C(O)CH,CHj, or an optionally substituted group selected from -piperidinyl, piperizinyl, morpholino, C.4alkoxy, phenyl, phenyloxy, benzyl, benzyloxy, -CHxcyclohexyl, pyridyl, -CH,pyridyl, or -CHathiazolyl. Still other exemplary R* groups include those shown below in Table 2.
[0059] In certain embodiments, for compounds of formula I-A, R! and R?, taken together is optionally substituted azetidin-1-yl (jj), wherein z is 1 or 2 and at least one occurrence of
R* is -NRSO;R’, -NRCOOR?’, or -NRCOR’. In certain other embodiments, for compounds of formula I-A, R! and R? taken together is optionally substituted azetidin-1-y1 (jj), wherein 2 is 1 and R* is -=NRSO,R’. In other embodiments, for compounds of formula I-A, R! and
R?, taken together is optionally substituted azetidin-1-yl (jj), wherein z is 1 and R* is -
NRCOOR’. In certain other embodiments, for compounds of formula I-A, R! and R?, taken together is optionally substituted azetidin-1-yl (jj), wherein z is 1 and R*is -NRCOR’. In yet other embodiments, for compounds of formula I-A, R' and R?, taken together is optionally substituted pyrrolidin-1-yl (ff), wherein z is 1 or 2 and R* is Cl, Br, F, CFs, CHa, -CH,CHs, -
OR’, or -CH,OR’. In still other embodiments, for compounds of formula I-A, R! and R?, taken together is optionally substituted piperidin-1-yl (dd), wherein z is 1 or 2 and at least one occurrence of R* is Cl, Br, F, CFs, CHs, -CH,CHj3, -OR’, or -CHOR’, ~NRSOR’, -
NRCOOR’, or -OCON(R’);. In certain other embodiments, for compounds of formula I-A,
R' and R?, taken together is optionally substituted piperidin-1-yl (dd), wherein z is 1 and R* is F, CFs, CHs, -CH,CH;, -OR’, or -CH,OR’. In other embodiments, for compounds of formula I-A, R' and R?, taken together is optionally substituted piperidin-1-yl (dd), wherein z is 1 and R* is —NRSO,R’,. In certain other embodiments, for compounds of formula I-A, R! _22-
and R?, taken together is optionally substituted piperidin-1-yl (dd), wherein z is 1 and R* is -
NRCOOR’. In yet other embodiments, for compounds of formula I-A, R' and R?, taken together is optionally substituted piperazin-1-yl (cc), wherein z is 1 or 2 and at least one occurrence of R? is —SOR’, <CON(R’)z, -SO,N(R")2, COR’, or -COOR’. In certain other embodiments, for compounds of formula I-A, R! and R? taken together is optionally substituted piperazin-1-yl (cc), wherein z is 1 and R* is —=SOR’. In certain other embodiments, for compounds of formula I-A, R' and R?, taken together is optionally substituted piperazin-1-yl (cc), wherein z is 1 and R* is -COOR’. In certain other embodiments, for compounds of formula I-A, R! and R? taken together is optionally substituted piperazin-1-yl (cc), wherein z is 1 and R* is -CON(R’),. In certain other embodiments, for compounds of formula I-A, R! and R? taken together is optionally substituted piperazin-1-yl (cc), wherein z is 1 and R* is -SO,N(R’),. In certain other embodiments, for compounds of formula I-A, R! and R? taken together is optionally substituted piperazin-1-yl (cc), wherein z is 1 and R'is -COR’.
[0060] As described generally above, for compounds of formulas I, I-A, or I-B, the quinazoline ring can be substituted with up to four independent occurrences of R®. In certain embodiments, x is 0-2. In other embodiments, x is 1 or 2. In still other embodiments x is 1 and R? is substituted at the 6- or 7-position of the quinazoline ring. When the quinazoline ring is substituted (x is 1-4), rR? groups are halogen, CN, NO, -NR’),, -CH2N(R"),, -OR’, -
CH,OR’, -SR’, -CH,SR’, -COOR’, -NRCOR’, -CON(R’);, -OCON(R’),, COR’, -
NHCOOR’, -SO;R’, -SO,N(R’);, or an optionally substituted group selected from Ci.
Cealiphatic, aryl, heteroaryl, cycloaliphatic, heterocycloaliphatic, arylC;-Cealkyl, heteroarylC;-Cealkyl, cycloaliphaticC;-Csalkyl, or heterocycloaliphaticCy-Cealkyl. In still other embodiments, each occurrence of R3 is independently Cl, Br, F, CF;, -OCFs, Me, Et,
CN, -COOH, -NH;, -N(CHj),, -N(Bt)z, -N(iPr),, -O(CH3),0CH3, -CONH,, -COOCHj, -OH, -OCH;, -OCH;CHs;, -CH;OH, -NHCOCH;, -NHCOCH(CHz);, -SONH; -
CONH(cyclopropyl), -CONHCH3, -CONHCH,CH3, or an optionally substituted group selected from -piperidinyl, piperizinyl, morpholino, phenyl, phenyloxy, benzyl, or benzyloxy.
In still other embodiments, x is 1 or 2 and each R® group is independently halogen, CN, optionally substituted Ci-Cealkyl, OR’, N(R’);, CON(R’);, or NRCOR’. In yet other embodiments, x is 1 or 2, and each R3 group is -Cl, -CHs, -CH,CHj, -F, -CF;, -OCF;, -
CONHCHj;, -CONHCH,CH3, -CONH(cyclopropyl), -OCHs, -NH;, -OCH;CHj, or -CN. In still other embodiments, x is 1 and R® is at the 6-position of the quinazoline ring and is -Cl, -
CH,, -CH,CH;, -F, -CF3, -OCF;, -CONHCH3, -CONHCH,CHj, -CONH(cyclopropyl), -
OCHs, -NH,, -OCH,CHa, or -CN. IN yet other embodiments, x is 1 and R3 is at the 7- position of the quinazoline ring and is -Cl, -CHs, -CH,CHs, -F, -CFs, -OCF;, -CONHCH;, -
CONHCH,CH;, -CONH(cyclopropyl), -OCHs, -NH,, -OCHCHs, or -CN. In other embodiments, x is 1 and R’ is at the 6-position of the quinazoline ring and is -Cl, -CHj, -
CH,CHa, -F, -CFs, -OCFs, -OCH, or -OCH;CH;. In still other embodiments, x is 1 and Ris at the 7-position of the quinazoline ring and is -Cl, -CHj, -CH,CHj, -F, -CF3, -OCF;3, -OCHs, or -OCH,CHs. In other embodiments, X is 1 and R? is at the 6-position of the quinazoline ring and is -CON(R’),, or NRCOR’. In yet other embodiments, x is 1 and R? is at the 7- position of the quinazoline ring and is -CON(R’),, or NRCOR’. Other exemplary R? groups include those shown below in Table 2.
[0061] As described generally above, for compounds of formula I, I-A, or I-B, Ring A is a 5-7-membered monocyclic aryl ring or an 8-10-membered bicyclic aryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or is a 3-12-membered saturated or partially unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein ring A is optionally substituted with y independent occurrences of -R®, wherein y is 0-5, and is additionally optionally substituted with q independent occurrences of R*, wherein q is 0-2.
[0062] In certain embodiments, ring A is selected from:
SN Lee He, ht wy i ii iii iv [> (F* § (ZF HA JN v vi vit viii
N-NH RE) NRF 0 (Fo, NK
Lz LN i, °N i 2-(R*) wf RACY LNRE2), 4 N $s” ix x xi xii
(R°) (Ry (RS), (RS) { y
NF mo, Arye, RE = YR
O N 0] S
H xiii xiv XV xvi 5 RO (R%)
RU (R*®)q q y (R52) A RN Gal ' AON ol s oL xvii xviii xix XX 5 (R)y (R%)y (RF
Nea I N—” 4 al I HI
O (R53), N (R%)q (R%3), xxi xxii xxiii 5 5 (RS)
LIS NS MY ’ w=) = 1) i J
N (R%?)q S (R%)q (R%9)q xxiv XXV xxvi (RS)y H (R®) (RS
N s N. y 0. ly
SC) HY He HOR
NN fe pT SI a
WL, Ba my BP x N xxvii xxviii xxix XXX (RO) (R%) (R) (RS
S. y y ly
A A / / — (R52 C0 Ne N_ 5a ie 3
NE NG, SPINE ei CN
H (R%3)q q xxxi xxxii xxxiii xxxiv
AN fh A 5) 0) \__/m5a
CI wm, YE y= (R%3)q
XXXV XXXVi xxxvii
[0063] In certain other embodiments, fing A is selected from optionally substituted phenyl, 2-pyridyl, 3-pyridyl, or 4-pyridyl, or pyrrol-1-yL
[0064] In some embodiments, y is 0-5, is 0-2, and R® and R* groups, when present, are each independently halogen, CN, NO,;, -NR’)a2, -CH,N(R’);, -OR’, -CH,0R’, -SR’, -
CH,SR’, - -NRCOR’, -CON(R")2, -S(0)2NR)z, -OCOR’, -COR’, -CO,R’, -OCONR’),, -
NR’SO,R’, -OP(0)(OR’),, -P(O)(OR’)2, -OP(0),0R’, -P(0),0R’, -POR’)2, -OPOR’),, or an optionally substituted group selected from C;.Cgaliphatic, aryl, heteroaryl, cycloaliphatic, heterocycloaliphatic, arylC;-Csalkyl, heteroarylC;-Cealkyl, cycloaliphaticC;-Cealkyl, or heterocycloaliphaticC;-Cealkyl.
[0065] In yet other embodiments, y is 0-5, and q is 1 or 2, and each occurrence of Ris independently Cl, Br, F, CF;, Me, Et, CN, -COOH, -NH,, -N(CHs),, -N(Et)z, -N(Pr)2, -
O(CH,);OCH;, -CONH,, -COOCH;, -OH, -OCHs, -OCH,CH;, -CH,OH, -NHCOCH;, -
SO,NH,, -SO,NHC(CH3),, ~-OCOC(CHs)s, -OCOCH,C(CH3)3, -O(CH2);N(CH3),, 4-CHs- piperazin-1-yl, OCOCH(CHs)z, OCO(cyclopentyl), -COCHj, optionally substituted phenoxy, or optionally substituted benzyloxy.
[0066] In still other embodiments, y is 0, and q is 1 and R* is F. In yet other embodiments, v is 0, q is 1, and R* is OR’. In still other embodiments, y is 0, q is 1 and R* is OH. In yet other embodiments, y is 0, q is 2 and one occurrence of R* is OR’ and the other occurrence of R* is F. In yet other embodiments, y is 0, q is 2 and one occurrence of
R%® is OH and the other occurrence of R* is F.
[0067] In still other embodiments, ring A is phenyl, y is 0, and q is 1 and R® is F substituted at the 2-position of the phenyl ring. In yet other embodiments, ring A is phenyl, y is 0, gis 1, and R*® is OR’ substituted at the 2-position of the phenyl ring. In still other embodiments, ring A is phenyl, y is 0, gis 1 and R> is OH substituted at the 2-position of the phenyl ring. In yet other embodiments, ring A is phenyl, y is 0, q is 2 and one occurrence of
R>® is OR’ and the other occurrence of Ris F, wherein OR’ is substituted at the 2-position of the phenyl ring and F is substituted at the 6-position of the phenyl ring. In yet other embodiments, ring A is phenyl, y is 0, q is 2 and one occurrence of R* is OH and the other occurrence of R* is F, wherein OH is substituted at the 2-position of the phenyl ring and F is substituted at the 6-position of the phenyl ring. [00681 Other exemplary R® and R*® groups include those shown below in Table 2.
[0069] For compounds described in this section above, in general, compounds are useful as inhibitors of ion channels, preferably voltage gated sodium channels and N-type calcium channels. In certain exemplary embodiments, compounds of the invention are useful as inhibitors of NaV1.8. In other embodiments, compounds of the invention are useful as inhibitors of NaV1.8 and CaV2.2. In still other embodiments, compounds of the invention are useful as inhibitors of CaV2.2. In yet other embodiments, compounds of the invention are useful as dual inhibitors of NaV1.8 and a TTX-sensitive ion channel such as NaVv1l.3 or
NaVv1.7.
[0070] Certain additional embodiments of compounds described generally above are described in more detail below. For example:
[0071] I. Compounds of formula IA:
RL A? wr) 0)
IA or a pharmaceutically acceptable salt thereof, wherein:
R! and R?, taken together with the nitrogen atom to which they are bound, form an optionally substituted 3-12-membered monocyclic or bicyclic saturated, partially unsaturated, or fully unsaturated ring having 0-3 additional heteroatoms independently selected from nitrogen, sulfur, or oxygen; wherein the ring formed by R' and R? taken together, is optionally substituted at one or more substitutable carbon, nitrogen, or sulfur atoms with z independent occurrences of —R*, wherein z is 0-5;
Ring A is a 5-7-membered monocyclic aryl ring or an 8-10-membered bicyclic aryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, oris a 3-12-membered saturated or partially unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein ring A is optionally substituted with y independent occurrences of —R5, wherein y is 0-5, and is additionally optionally substituted with q independent occurrences of R*, wherein q is 0-2; x is 0-4; each occurrence of R®, R*, and R® is independently Q-R*; wherein Q is a bond or is a
C,-C alkylidene chain wherein up to two non-adjacent methylene units of Q are optionally and independently replaced by -NR-, -S-, -O-, -CS-, -COz-, -0CO-, -CO-, -COCO-, -CONR-, -NRCO-, -NRCO,-, -SO,NR-, -NRSO;-, -CONRNR-, -NRCONR-, -OCONR-, -NRNR-, -
NRSO,NR-, -SO-, -SO,-, -PO-, -PO2-, -OP(O)(OR)-, or -POR+; and each occurrence of R%is independently selected from -R’, halogen, =O, =NR’, -NO, -CN, -OR’, -SR’, NR")2, -
NR’COR’, -NR’CON(R’),, -NR’COR’, -COR’, -CO;R’, -OCOR’, -CONR’),, -
OCON(R")z, -SOR’, -SO;R’, -SO2N(R")2, -NR’SOR’, -NR’SO;N(R’),, -COCOR’, -
COCH,COR’, -OP(O)(OR"),, -P(0)(OR’);, -OP(0):0R’, -P(0),0R’, -POR’),, or -
OPOR); each occurrence of R* is independently an optionally substituted C,-Cealiphatic group, halogen, -OR’, -SR’, -N(R’),, -NR’COR’, -NR’CON(R’),, -NR’CO;R’, -COR’, -
CO,R’, -OCOR’, -CONR"), -OCON(R)2, -SOR’, -SO2R’, -SO,N(R’),, -NR’SO;R’, -
NR’SO,N(R’), -COCOR’, -COCH,COR’, -OP(O)(OR’),, -P(O)(OR’)z, -OP(0),0OR’, -
P(0),0R’, -PO(R’),, or -OPO(R’),; and each occurrence of R is independently hydrogen or an optionally substituted Ci. aliphatic group; and each occurrence of R'is independently hydrogen or an optionally substituted Cy. aliphatic group, a 3-8-membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-12 membered saturated, partially unsaturated, or fully unsaturated bicyclic ring system having 0-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or R and R’, two occurrences of R, or two occurrences of R, are taken together with the atom(s) to which they are bound to form an optionally substituted 3-12 membered saturated, partially unsaturated, or fully unsaturated monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
[0072] In certain embodiments, for compounds described directly above: a. when R! and R?, taken together with the nitrogen atom to which they are bound, form an optionally substituted 4-membered monocyclic saturated or partially unsaturated ring having 0-3 additional heteroatoms independently selected from nitrogen, sulfur, or oxygen, then 2-Oxazolidinone, 3-[(3R 4R)-2-0x0-1-(2-phenyl-4-quinazolinyl)-4-[2-(3- pyridinyl)ethenyl]-3-azetidinyl}-4-phenyl-, (45)- is excluded; b. when R! and R?, taken together with the nitrogen atom to which they are bound, form an optionally substituted 5-membered monocyclic saturated or partially unsaturated ring having 0-3 additional heteroatoms independently selected from nitrogen, sulfur, or oxygen; then: i. ring A is not optionally substituted hexahydro-1H-1,4-diazepin-1-yl; and il. Benzenesulfonamide, 2-methoxy-5-[2-[[1-(2-phenyl-4-quinazoliny})-3- pyrrolidinylJamino]ethyl]-, (R)-, bis(trifluoroacetate), and Benzenesulfonamide, 2-methoxy- 5-[2-[[1-(2-phenyl-4-quinazolinyl)-3-pyrrolidinylJamino]ethyl]-, (S)-, bis(trifluoroacetate) are excluded; iii. 3-Pyrrolidinamine, 1-(2-phenyl-4-quinazolinyl)-, and (R)- 3-Pyrrolidinamine, 1- (2-phenyl-4-quinazolinyl)-, (S)- are excluded, iv. when R! and R?, taken together are unsubstituted pyrrolidin-1-yl, ring A is unsubstituted phenyl, and x is 1, then R3 is not 6-OMe or 6-OH; v. when R! and R?, taken together are unsubstituted pyrrolidin-1-yl, ring A is unsubstituted phenyl, and x is 2, then the two R? groups are not 6-OMe and 7-OMe; vi. when R! and R?, taken together are unsubstituted pyrrolidin-1-yl, then ring A is not unsubstituted pyrrolidin-1-yl, optionally substituted piperazin-1-yl, unsubstituted morpholin-1-yl; or unsubstituted piperidin-1-yl; vii. when R! and R?, taken together are pyrrolidin-1-yl, x is 0 and ring A is unsubstituted phenyl, then the pyrrolidin-1-yl group is not substituted at the 3-position with —
OH or 2-methoxy-phenoxy; viii. when R' and R?, taken together are unsubstituted pyrrolidin-1-yl, and x is 0, then ring A is not 2,3-xylyl, 3-methylphenyl, unsubstituted phenyl, 4-bromo-phenyl, 4- chloro-phenyl, 3-nitro-phenyl, unsubstituted pyrid-3-yl, 2,4-dichlorophenyl, 3,4- dichlorophenyl, 4-propoxyphenyl, 3-methylphenyl, 3,4,5-trimethoxyphenyl, 2-chlorophenyl, unsubstituted pyrid-4-yl, 2-hydroxyphenyl, or 4-(1,1-dimethylethyl)phenyl; c. when R! and R?, taken together with the nitrogen atom to which they are bound, form an optionally substituted 6-membered monocyclic or bicyclic saturated or partially unsaturated ring having 0-3 additional heteroatoms independently selected from nitrogen, sulfur, or oxygen; then: i. when R' and R?, taken together form an unsubstituted morpholino ring, and ring A is unsubstituted phenyl, then x is not 0, or if x is 1 or 2, then R? is not: 6-fluoro, 6,7- dimethoxy, 6-nitro, 6-AcHN-, 6-methox, 6-NH2, 6-OCHN-, 6-OH, 6-AcMeN-, 6-TsHN-, 6-
Me2N-, 7-OH, 6-amino-thiazol-2-yl, 6-NHCOCOOEt, or 6~(4-phenyl-amino-thiazol-2-yl); ii. when R' and R?, taken together form an unsubstituted morpholino ring, and ring A is unsubstituted cyclohexyl, unsubstituted pyrid-3-yl, unsubstituted 2-furyl, 2-fluorophenyl, 3-thienyl, benzofuran, pyridazine, phenyl substituted in one or more of the 3, 4, or 5-position of the phenyl ring, and x is 1 or 2, then R3 is not 6-NH,, 6-OHCHN-, 6-OH, 7-OH, 6-MsHN-, 6-AcHN-, 6-fluoro, or 6-OMe;
iii. when R! and R?, taken together, form a piperid-4-one, piperid-4-ol, or thiomorpholino, or a dimethyl substituted morpholino ring, ring A is unsubstituted phenyl, and x is 1, then R? is not 6-OH; iv. when x is 0 and A is unsubstituted phenyl, 3,4,5-trimethoxyphenyl, or 3,4- dimethoxyphenyl, then R" and R?, taken together is not optionally substituted piperidinyl or optionally substituted piperazinyl; v. when x is 2 or 3, and R3 is 6,7-diOMe, or 6,7,8-triOMe, then R! and R?, taken together is not optionally substituted piperidin-1-yl, piperazin-1-yl, or morpholin-1-yl; vi. when x is 0 and ring A is unsubstituted phenyl, then R! and R,, taken together is not optionally substituted or fused piperazinyl; vii. when x is 0 and ring A is phenyl optionally substituted in one or more of the 3-4- ,or 5-positions of the phenyl ring, then R! and R?, taken together is not optionally substituted piperazin-1-yl, or morpholin-1-yl; viii. when x is 0 and ring A is 2-F-phenyl, then R! and R?, taken together is not 4-(2-
Cl-phenyl)-piperazin-1-yl, 4-(3-Cl-phenyl)-piperazin-1-yl, or unsubstituted morpholin-1-yl; ix. when x is 0 and ring A is 2-Cl-phenyl, then R' and R?, taken together is not unsubstituted morpholin-1-yl, 4-Me-piperazin-1-yl, 4-Et-piperazin-1-yl, 4-phenyl-piperazin- 1-y1, or 4-CH,Ph;-piperazin-1-yl; x. when x is 0 and ring A is 2-OH-phenyl, then R1 and R2, taken together is not unsubstituted morpholin-1-yl, 4-(2-OMe-phenyl)-piperazin-1-yl, 4-CH2Ph-piperazin-1-yl, 4-
Et-piperazin-1-yl, or 4-Me-piperazin-1-yl; xi. whenxis0,xis1 and R?is 6-Br, or x is 2 and R3 is 6-7-diOMe, and ring A is optionally substituted 2- or 3-thienyl, then R! and R?, taken together is not 4-Ph-piperazin-1- yl, 4-(3-CF3-phenyl)-piperazin-1-yl, 4-(2-OEt-phenyl)-piperazin-1-yl, 4-Me-piperazinyl, or unsubstituted morpholin-1-yl; xii when x is 0, and ring A is unsubstituted pyrid-3-yl or pyrid-4-yl, then R' and R%, taken together is not optionally substituted morpholin-1-yl, or optionally substituted piperazin-1-yl; xiii. when x is 0, and ring A is optionally substituted 1H-imidazol-2-yl or 1H- imidazol-1-yl, then R' and R? taken together is not unsubstituted morpholin-1-yl, 4-Me- piperazin-1-yl, or 4-CH,CH,OH-piperazin-1-yl; xiv. when x is 0 and ring A is 5-NO,-thiazol-2-yl, then R! and R?, taken together is not 4-Me-piperazin-1-yl; xv. when x is 0 and ring A is 5-NO,-2-furanyl, then R! and R?, taken together is not 4-
CH,CH,OH-piperazin-1-yl, 4-Me-piperazin-1-yl, or unsubstituted morpholin-1-yl; xvi. when xis 1, R®is 6-OH and ring A is unsubstituted phenyl, then R! and R?, taken together is not unsubstituted morpholin-1-yl, or 4-Me-piperazin-1-yl; xvii. when x is 0 and R' and R?, taken together is unsubstituted piperidinyl, then ring A is not 2-OH-phenyl, 4-OMe-phenyl, 4-F-phenyl, 4-NO,-phenyl, pyrid-3-yl, pyrid-4-yl, 2-Cl-phenyl, 4-O,Pr-phenyl, 3 4-dichlorophenyl, 2-F-phenyl, 4-Br-phenyl, 4-Cl-phenyl, 3-
NO,-phenyl, or 2,4-dichlorophenyl; xviii. when x is 0, ring A is 4-Br-phenyl, 2-F-phenyl, 2-Cl-phenyl, 4-Cl-phenyl, 4-
OnPr-phenyl, 2,4-dichlorophenyl, 3 4-dichlorophenyl, 4-Me-phenyl, 3-Me-phenyl, pyrid-3- yl, pyrid-4-yl, 2-OH-pheny}, 4-NO,-phenyl, 4-tBu-phenyl, then R! and R?, taken together is not 2-Me-piperidin-1-yl, 4-CH,-Ph-piperidin-1-yl, 4-Me-piperidin-1-yl, 3-COOEt-piperidin- 1-yl, 4-COOEt-piperidin-1-yl, 2-Et-piperidin-1-yl, 3-Me-piperidin-1-yl, 3,5-diMe-piperidin- 1-yl, 4-CONH,-piperidin-1-yl, (4-piperidinyl, 4-carboxamide)-piperidin-1-yl, 1,4-dioxa-8- azaspiro[4.5]decane, 3,4-dihydro-2(1H)-isoquinolinyl,or piperidin-4-one; xix. when x is 1, R? is 6-Br, 6-Cl, 6-OH, 6-OMe, or 6-Me and ring A is 4- bromophenyl, 4-CH,P(O)(OH)(OEt)phenyl, or unsubstituted phenyl, then R! and R?, taken together, is not optionally substituted piperidinyl; xx.when x is 2, and R® is 6,7-dimethoxy, and A is unsubstituted phenyl, then R! and
R?, taken together is not 1,4-dioxa-8-azaspiro[4.5)decane or 3,4-dihydro-2(1H)-isoquinolinyl; xxi. when x is 3, and the three occurrences of R3 are 5-OAc, 6-OAc, and 8- piperidinyl , and ring A is unsubstituted phenyl, then R! and R?, taken together is not an unsubstituted piperidinyl ring; xxii. when x is 3 and the three occurrences of R3 are 6-Me, 7-COOEt, and 8-Me, and ring A is 2-Cl-phenyl, then R! and R?, taken together, is not 4-phenyl-piperidin-1-y1, 4- (4-Cl-phenyl)-piperazin-1-yl, unsubstituted piperazin-1-yl, 4-CH,Ph-piperazin-1-yl, 4(2-Cl- phenyl)piperazin-1-yl, or 4-COOEt-piperazin-1-yl; c. when R! and R?, taken together with the nitrogen atom to which they are bound, form an optionally substituted 7-membered monocyclic or bicyclic saturated or partially unsaturated ring having 0-3 additional heteroatoms independently selected from nitrogen, sulfur, or oxygen; then: i. Benzenesulfonamide, 2-methoxy-5-[2-[5-(2-phenyl-4-quinazolinyl)-2,5- diazabicyclo[2.2.1]hept-2-yl]ethyl}-, and bis(trifluoroacetate) 2,5-
Diazabicyclo[2.2.1]heptane, 2-(2-phenyl-4-quinazolinyl)- are excluded; ii. when x is 2 and both occurrences of R> are OMe, and ring A is 4-Cl-phenyl,
then R! and R?, taken together is not unsubstituted hexahydro-1H-azepin-1-yl; iii. when x is 0 and R! and R?, taken together is unsubstituted hexahydro-1H- azepin-1-yl, then ring A is not unsubstituted phenyl, 4-F-phenyl, 4-NO2-phenyl, pyrid-4-yl, 3,4-diCl-phenyl, 2-Cl-phenyl, 2,4-diCl-phenyl, 2,4-diCl-phenyl, 3-NO-phenyl, 4-Cl-phenyl, 4-O,Pr-phenyl, 3-Me-phenyl, 3 4-OMe-phenyl, 3,4,5-OMe-phenyl, pyrid-3-yl, or 2-OH- phenyl; d. when R" and R?, taken together with the nitrogen atom to which they are bound, form an optionally substituted 8-membered monocyclic or bicyclic saturated or partially unsaturated ring having 0-3 additional heteroatoms independently selected from nitrogen, sulfur, or oxygen; then: i. Benzenesulfonamide, 2-methoxy-5-[2-[8-(2-phenyl-4-quinazolinyl)-3,8- diazabicyclo[3.2.1]Joct-3-ylJethyl}-, bis(trifluoroacetate) 3,8-Diazabicyclo[3.2. 1]Joctane, 3- (phenylmethyl)-8-(2-phenyl-4-quinazolinyl)- 3,8-Diazabicyclo[3.2.1]Joctane, 8-(2-phenyl-4- quinazolinyl)-; Quinazoline, 2-(3-methylphenyl)-4-(1,3,3-trimethyl-6-azabicyclo[3.2.1]oct-6- yl)-, monohydrochloride; Quinazoline, 2-(4-nitrophenyl)-4-(1,3,3-trimethyl-6- azabicyclo[3.2.1joct-6-yl)-, monohydrochloride; Quinazoline, 2-(3-methylphenyl)-4-(1,3,3- trimethyl-6-azabicyclo[3.2.1Joct-6-yl)-; Quinazoline, 2-(4-methylphenyl)-4-(1,3,3-trimethyl- 6-azabicyclo[3.2.1]oct-6-yl)-; and Quinazoline, 2-(4-nitrophenyl)-4-(1,3,3-trimethyl-6- azabicyclo[3.2.1]oct-6-yl)-are excluded; and e. when R' and R?, taken together with the nitrogen atom to which they are bound, form an optionally substituted 9-membered monocyclic or bicyclic saturated or partially unsaturated ring having 0-3 additional heteroatoms independently selected from nitrogen, sulfur, or oxygen; then:
Piperazine, 1-[4-(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)-6,7-dimethoxy-2- quinazolinyl]-4-(2-furanylcarbonyl)- is excluded.
[0073] In other embodiments, for compounds described directly above, the ring formed by R! and R? taken together is selected from:
AA AAT A
LNH J Ne cc dd ee pe iN 1 ™ (r™ (Cy (RY), ff gg hh
Lo 2 I) ; os Re <2 : 2R%) ii Ji kk
Tk y poR % @
I GN J ) (R): (RY): 11 mm nn 00 wherein the ring formed by R' and R* taken together, is optionally substituted at one or more substitutable carbon, nitrogen, or sulfur atoms with z independent occurrences of —
R*, and z is 0-5.
[0074] In other embodiments, for compounds of formula I-A, R! and R? taken together are optionally substituted azetidin-1-yl (ij), pyrrolidin-1-yl (ff), piperidinl-yl (dd), piperazin- 1-y1 (eg), or morpholin-4-yl (ee). In other embodiments, for compounds of formula I-A, R! and R? taken together are optionally substituted azetidin-1-yl (ij), pyrrolidin-1-yl (ff), piperidinl-yl (dd), or piperazin-1-yl (ce). In yet other embodiments, for compounds of formula I-A, R' and R?, taken together is optionally substituted azetidin-1-yI (jj). In yet other embodiments, for compounds of formula I-A, R! and R? taken together is optionally substituted pyrrolidin-1-yl (ff). In still other embodiments, for compounds of formula I-A, R! and R?, taken together is optionally substituted piperidinl-yl (dd). In yet other embodiments, for compounds of formula I-A, R! and R? taken together is optionally substituted piperazin- 1-yl (cc).
[0075] For compounds described directly above, z is 0-5, and R* groups, when present, are each independently halogen, CN, NO, -N(R’);, -CH,N(R’),, -OR’, -CH20R’, -SR’, -
CH,SR’, -COOR’, -NRCOR’, -CON(R’);, -OCON(R’);, COR’, -NHCOOR’, -SO,R’, -
SO,N(R’),, or an optionally substituted group selected from C,.Cealiphatic, aryl, heteroaryl,
cycloaliphatic, heterocycloaliphatic, arylC,-Cealkyl, heteroarylC,-Cgalkyl, cycloaliphaticCy-
Cealkyl, or heterocycloaliphaticCi-Cealkyl.
[0076] In still other embodiments, z is 0-5 and R* groups are each independently Cl, Br,
F, CFs, CHa, -CH,CHj, CN, -COOH, —N(CHa)z, -N(E)2, -N(Pr)s, -O(CH2),0CHs, -CONH, -COOCH;, -OH, -CH,OH, -NHCOCH;, -SO:NH, -SO,(CH,);CH3, -SO,CH(CHz),, -
SO,N(CHa),, -SO;CH,CHj, -C(O)OCH;CH(CHs),, -C(O)NHCH;CH(CH3),, -NHCOOCH3, -
C(O)C(CHs);, -COO(CH,),CH;, -C(O)NHCH(CHa)z, -C(O)CH,CHj;, or an optionally substituted group selected from -piperidinyl, piperizinyl, morpholino, C;4alkoxy, phenyl, phenyloxy, benzyl, benzyloxy, -CHycyclohexyl, pyridyl, -CHzpyridyl, or -CH;thiazolyl.
[0077] In certain embodiments, for compounds of formula I-A, R! and R?, taken together is optionally substituted azetidin-1-yl (3j), wherein z is 1 or 2 and at least one occurrence of
R* is -NRSO,R’, -NRCOOR’, or -NRCOR’. In certain other embodiments, for compounds of formula I-A, R! and R?, taken together is optionally substituted azetidin-1-yl (jj), wherein zis 1 and R* is -NRSO,R’. In other embodiments, for compounds of formula I-A, R! and
R?, taken together is optionally substituted azetidin-1-yl (jj), wherein z is 1 and R* is -
NRCOOR’. In certain other embodiments, for compounds of formula I-A, R! and R?, taken together is optionally substituted azetidin-1-y! (jj), wherein z is 1 and R* is -NRCOR’. In yet other embodiments, for compounds of formula I-A, R! and R?, taken together is optionally substituted pyrrolidin-1-yl (ff), wherein z is 1 or 2 and R* is Cl, Br, F, CFs, CHs, -CH,CHj, -
OR’, or -CH,OR’. In still other embodiments, for compounds of formula I-A, R! and R?, taken together is optionally substituted piperidin-1-yl (dd), wherein z is 1 or 2 and at least one occurrence of R* is Cl, Br, F, CF;, CHj, -CH,CHj, -OR’, or -CH,0R’, -NRSO;R’, -
NRCOOR’, or -OCON(R’),. In certain other embodiments, for compounds of formula I-A,
R! and R?, taken together is optionally substituted piperidin-1-yl (dd), wherein z is 1 and R* is F, CFs, CHa, -CH,CHj, -OR’, or -CH,0R’. In other embodiments, for compounds of formula I-A, R! and R?, taken together is optionally substituted piperidin-1-yl (dd), wherein z is 1 and R* is —NRSO,R’,. In certain other embodiments, for compounds of formula I-A, R! and R?, taken together is optionally substituted piperidin-1-yl (dd), wherein z is 1 and R'is -
NRCOOR’. In yet other embodiments, for compounds of formula I-A, R' and R?, taken together is optionally substituted piperazin-1-yl (cc), wherein z is 1 or 2 and at least one occurrence of R* is -SOR’, -CON(R’),, -SO.N(R’);, COR’, or -COOR’. In certain other embodiments, for compounds of formula I-A, R' and R?, taken together is optionally substituted piperazin-1-yl (cc), wherein z is 1 and R* is -SOR’. In certain other embodiments, for compounds of formula I-A, R! and R? taken together is optionally substituted piperazin-1-yl (cc), wherein z is 1 and R* is -COOR’. In certain other embodiments, for compounds of formula I-A, R! and R?, taken together is optionally substituted piperazin-1-yl (cc), wherein z is 1 and R* is -CONR”)2. In certain other embodiments, for compounds of formula I-A, R! and RZ, taken together is optionally substituted piperazin-1-yl (cc), wherein z is 1 and R* is -SO;N(QR’).. In certain other embodiments, for compounds of formula I-A, R! and R? taken together is optionally substituted piperazin-1-yl (cc), wherein z is 1 and R* is -COR’.
[0078] For compounds described directly above, in some embodiments, x is 0-4, and R® groups, when present, are each independently halogen, CN, NO, -NR’)2, -CH;N(R’),, -OR’, _CH,OR’, -SR’, -CH,SR’, -COOR’, -NRCOR’, -CON(QR’);, -OCON(R’);, COR’, -
NHCOOR’, -SO;R’, -SO;N(R)2, or an optionally substituted group selected from Ci.
Cealiphatic, aryl, heteroaryl, cycloaliphatic, heterocycloaliphatic, arylC;-Cealkyl, heteroarylC,;-Csalkyl, cycloaliphaticC;-Cealkyl, or heterocycloaliphaticCq-Csalkyl.
[0079] In yet other embodiments, x is 1 or 2, and each occurrence of R® is independently
Cl, Br, F, CFs, -OCFs, Me, Et, CN, -COOH, -NHa, —N(CHz);, -N(Et);, -N(iPr), -
O(CH,),OCH3, -CONH,, -COOCH3, -OH, -OCHs, -OCH,CH;, -CH,OH, -NHCOCH;, -
NHCOCH(CHs)2, -SO2NH,, -CONH(cyclopropyl), -CONHCH;, -CONHCH,CH3, or an optionally substituted group selected from -piperidinyl, piperizinyl, morpholino, phenyl, phenyloxy, benzyl, or benzyloxy.
[0080] In still other embodiments, x is 1 or 2 and each R> group is independently halogen, CN, optionally substituted C:-Cealkyl, OR’, N(R’);, CON(R’)2, or NRCOR’.
[0081] In yet other embodiments, x is 1 or 2, and each rR? group is -Cl, -CHs, -CH,CHj, -
F, -CFs;, -OCF;, -CONHCH;, -CONHCH,CHj, -CONH(cyclopropyl), -OCH;, -NH,, -
OCH,CHj, or -CN.
[0082] In still other embodiments, x is 1 and R? is at the 6-position of the quinazoline ring and is -Cl, -CHs, -CH,CH;, -F, -CF -OCF;, -CONHCH;, -CONHCH,CH;3, -
CONH(cyclopropyl), -OCHs, -NH,, -OCH,CHj, or -CN.
[0083] In yet other embodiments, x is 1 and R? is at the 7-position of the quinazoline ring and is -Cl, -CHs;, -CH,CH;, -F, -CF;, -OCF;, -CONHCH; -CONHCH;CHj, -
CONH(cyclopropyl), -OCHj, -NH, -OCH,CHj, or -CN.
[0084] In still other embodiments, x is 1 and R® is at the 6-position of the quinazoline ring and is -Cl, -CH3;, -CH,CH;, -F, -CF;, -OCF;, -OCH;, or -OCH,CHs.
[0085] In yet other embodiments, x is 1 and R? is at the 7-position of the quinazoline ring and is -Cl, -CHs, -CH,CH, -F, -CF3, -OCF3, -OCHj, or -OCH,CHs.
[0086] In still other embodiments, Xx is 1 and R’ is at the 6-position of the quinazoline ring and is -CON(R"),, or NRCOR".
[0087] In yet other embodiments, x is 1 and R3 is at the 7-position of the quinazoline ring and is -Cl, -CHs, -CH,CH3, -F, -CF;3, -OCF3, -OCHj3, or -OCH,CHs.
[0088] For compounds described directly above, in certain embodiments, ring A is a group selected from:
RS), JR) (R%)q y(RY) JR)
A NT nN YSN
He be A 3 (R%)q = 5 (R%)q wd N° av N i ii iii iv (R) (R) (RS) (goa (Fy ; NA fo : NAN y . 3 nl Ja hy FE
J (R*)q —i _—(R%) — any “7 “NZ q Cy N wf N v vi vii viii
N-NH (R® NAR Np Rs a W
IL A LSA wf NR), LORE, “ N s ix X xi xii y hi y (5) ig
Ma (rsa NARI NR (Roe NR _(RS?)
Ni Sa TE 4 TE = 8 SLI Sa
O N Oo S
H xiii xiv Xv xvi (R®) 5a (RS) (RY) 5a (R%) 5a y y R y wg Fa he RS 0 . NY k -~ — N \o/= { [ 4
J o § Cg IN vj N xvii xviii xix XX
(RS), Ir (RO) Fy eS N Re
N— 1) 1 + | J N, 5 NT PN 0 Ns Nes (R%) (R*)q H (Aq a (RS)
A vs —_—
Nol a ® 1
HN, ~~ XK S Xo N N Sa
N (RS), (R82), (R°%)q xxiv XXV Xxvi (Ry H (RY) (RS) 00 DE Ey SR Ty MN Fe SS 'N X R5a SR 5a : Sn” lit “Nv Fs wl, ( )q y(R%) (R Ng H H xxvii xxviii xxix XXX (R%)y (B®) (RS) (R%)
S, y y y
C7 Fo CN 5 —_— (R53) _C _r ~—(R%2) Lb bi
NN a Cd TJ Tg N(R),
H (R%%)q xxxi xxxii xxxiii xxxiv
NR Po ay ne ' CAE L(A), [— (R%3¥)q YY (R ly (R%3)q
XXXV XXXVi Xxxvii
[0089] In other embodiments, ring A is optionally substituted phenyl, 2-pyridyl, 3- pyridyl, or 4-pyridyl, or pyrrol-1-yl.
[0090] For compounds described directly above, in some embodiments, y is 0-5, q is 0-2, and R® and R® groups, when present, are each independently halogen, CN, NO, -N(R’),, -
CH,N(R’);, -OR’, -CH;OR’, -SR’, -CH;SR’, - -NRCOR’, -CONR’), -S(O)NR’)2, -
OCOR’, -COR’, -COR’, -OCON(R’);, -NR’SO;R’, -OP(O)}OR’);, -P(O)OR’)2, -
OP(0),0R’, -P(0),0R’, -POR’), -OPO(R’)2, or an optionally substituted group selected from C;.Cgaliphatic, aryl, heteroaryl, cycloaliphatic, heterocycloaliphatic, arylC;-Csalkyl, heteroarylC,-Cealkyl, cycloaliphaticCi-Cealkyl, or heterocycloaliphaticCi-Cealkyl.
[0091] In still other embodiments, y is 0-5, and q is 1 or 2, and each occurrence of Ris independently Cl, Br, F, CFs, Me, Et, CN, COOH, -NH,, -N(CHa),, -N(Et)z, -NGP1)2, -
O(CH,),0CHs, -CONH,, -COOCH;, -OH, -OCHj;, -OCH,CH;, -CH,OH, -NHCOCH;, -
SO,NH,, -SO,NHC(CH3);, -OCOC(CHa)s, -OCOCH,C(CHs)s, -O(CH;),N(CH3)z, 4-CHs- piperazin-1-yl, OCOCH(CH;), OCO(cyclopentyl), -COCHj, optionally substituted phenoxy, or optionally substituted benzyloxy.
[0092] In still other embodiments, y is 0, and q is 1 and R®® is F. In yet other embodiments, y is 0, q is 1, and Ris OR’. In still other embodiments, y is 0, q is 1 and R*® is OH. In yet other embodiments, y is 0, q is 2 and one occurrence of R* is OR’ and the other occurrence of R* is F. In yet other embodiments, y is 0, q is 2 and one occurrence of
Ris OH and the other occurrence of R™®isF.
[0093] In yet other embodiments, ring A is optionally substituted phenyl and compounds have the structure IA-i:
RL -R?
Noe: (RO) ay oy
FA-i wherein: y is 0-5; q is 0-2; and each occurrence of R* is independently an optionally substituted C;-Cealiphatic group, halogen, -OR’, -SR’, -N(R”)2, -NR’COR”, -NR’CON(R),, -NR’CO2.R’, -COR’, -
CO,R’, -OCOR’, -CON(R’),, -OCON(R’)2, -SOR’, -SOzR’, -SO:2N(R’), -NR’SO;R’, -
NR’SO,N(R’);, -COCOR’, -COCH;COR’, -OP(O}(OR"),, -P(O)(OR’), -OP(O);0R’, -
P(0);0R’, -PO(R’),, or -OPO(R’)>.
[0094] In certain exemplary embodiments, the ring formed by R! and R? taken together is selected from:
4 R* (RY) £ RB )2 Lo ) A ‘
NT ) @
L_NH © cc dd ee “ ou N
N
Ny (Fe (ye
Re (RY) ff £8 hh
Lom
N" 2 ) os GLY / (R*) ii Ji kk
T T 7 3
N N N N i» ) a $; XN 4 NERY x (R*),
AR") z 4 (RY): i mm nn 00 wherein the ring formed by R! and R? taken together, is optionally substituted at one or more substitutable carbon, nitrogen, or sulfur atoms with z independent occurrences of —
R*, and z is 0-5.
[0095] In other embodiments, for compounds of formula IA-i, R' and R? taken together are optionally substituted azetidin-1-yl (jj), pyrrolidin-1-yl (ff), piperidin1-yl (dd), piperazin- 1-y1 (cc), or morpholin-4-yl (ee). In other embodiments, for compounds of formula I-A, R! and R? taken together are optionally substituted azetidin-1-yl (Gi), pyrrolidin-1-yl (ff), piperidinl-yl (dd), or piperazin-1-yl (cc). In yet other embodiments, for compounds of formula JA-i, R! and RZ, taken together is optionally substituted azetidin-1-yl (jj). In yet other embodiments, for compounds of formula IA-i, R! and R?, taken together is optionally substituted pyrrolidin-1-y1 (ff). In still other embodiments, for compounds of formula IA-i,
R' and R? taken together is optionally substituted piperidinl-yl (dd). In yet other embodiments, for compounds of formula 1A-i, R! and RZ, taken together is optionally substituted piperazin-1-yl (cc).
[0096] For compounds of formula IA-j, z is 0-5, and R* groups, when present, are each independently halogen, CN, NO, -N(R’)z, -CHN(R’),, -OR’, -CH0R", -SR’, -CHzSR’, -
COOR’, -NRCOR’, -CON(R’),, -OCON(R");, COR’, NHCOOR’, -SO,R’, -SO2N(R’),, or an optionally substituted group selected from C,.Cealiphatic, aryl, heteroaryl, cycloaliphatic, heterocycloaliphatic, arylC;-Csalkyl, heteroarylCy-Cealkyl, cycloaliphaticCy-Cealkyl, or heterocycloaliphaticC;-Cealkyl. In other embodiments, z is 0-5 and R* groups are each independently Cl, Br, F, CFs, CH;, -CH,CHs, CN, -COOH, -N(CH3),, -N(Et)2, -N(GPr)2, -
O(CH,),0CHj3, -CONH,, -COOCH;3, -OH, -CH,0H, -NHCOCH3, -SO,NH,, -SO2(CH3)sCHs, -SO,CH(CHas), -SO,N(CHs),, -SO,CH,CHj, -C(O)OCH,CH(CHs), -
C(O)NHCH,CH(CHas)s, -NHCOOCHS3, -C(O)C(CHs)s, -COO(CH,).CHs, -
C(O)NHCH(CHj3),, -C(O)CH,CHj;, or an optionally substituted group selected from - piperidinyl, piperizinyl, morpholino, Ci4alkoxy, phenyl, phenyloxy, benzyl, benzyloxy, -
CHacyclohexyl, pyridyl, -CHypyridyl, or -CHathiazolyl.
[0097] In certain embodiments, for compounds of formula A-i, R! and R?, taken together is optionally substituted azetidin-1-yl (J), wherein z is 1 or 2 and at least one occurrence of
R* is -NRSO,R’, -NRCOOR’, or -NRCOR’. In certain other embodiments, for compounds of formula IA-i, R! and R?, taken together is optionally substituted azetidin-1-yl (jj), wherein zis 1 and R? is -NRSO;R’. In other embodiments, for compounds of formula IA-i, R! and
R?, taken together is optionally substituted azetidin-1-yl (jj), wherein z is 1 and R* is -
NRCOOR’. In certain other embodiments, for compounds of formula XA-i, R! and R?, taken together is optionally substituted azetidin-1-yl (jj), wherein z is 1 and R* is -NRCOR’. In yet other embodiments, for compounds of formula IA-i, R! and R?, taken together is optionally substituted pyrrolidin-1-yl (ff), wherein z is 1 or 2 and R* is C), Br, F, CFs, CH3, -CH,CHj, -
OR’, or -CH,OR’. In still other embodiments, for compounds of formula JA-i, R! and R?, taken together is optionally substituted piperidin-1-yl (dd), wherein z is 1 or 2 and at least one occurrence of R* is Cl, Br, F, CFs, CH, -CH,CHjs, -OR’, or -CH,0OR’, -NRSO2R’, -
NRCOOR’, or -OCON(R’),. In certain other embodiments, for compounds of formula IA-i,
R! and R?, taken together is optionally substituted piperidin-1-yl (dd), wherein z is 1 and R* is F, CFs, CHjs, -CH,CHj, -OR’, or -CH,OR’. In other embodiments, for compounds of formula IA-i, R! and R?, taken together is optionally substituted piperidin-1-yl (dd), wherein zis 1 and R* is —NRSO2R’,. In certain other embodiments, for compounds of formula IA-i,
R! and R?, taken together is optionally substituted piperidin-1-yl (dd), wherein z is 1 and R* _40-
is -NRCOOR’. In yet other embodiments, for compounds of formula IA-i, R! and R?, taken together is optionally substituted piperazin-1-yl (cc), wherein z is 1 or 2 and at least one occurrence of R? is —SOR’, -CON(R"),, -SO.N(R")2, COR’, or —COOR’. In certain other embodiments, for compounds of formula IA-i, R! and R?, taken together is optionally substituted piperazin-1-yl (cc), wherein z is 1 and R* is SOR’. In certain other embodiments, for compounds of formula IA-i, R' and R? taken together is optionally substituted piperazin-1-yl (ce), wherein z is 1 and R* is —COOR’. In certain other embodiments, for compounds of formula IA-i, R' and R? taken together is optionally substituted piperazin-1-yl (ec), wherein z is 1 and R* is -CON(R");. In certain other embodiments, for compounds of formula IA-i, R! and R?, taken together is optionally substituted piperazin-1-yl (cc), wherein z is 1 and R* is -SO,N(R’),. In certain other embodiments, for compounds of formula IA-i, R! and R? taken together is optionally substituted piperazin-1-yl (cc), wherein z is 1 and R*is -COR’.
[0098] In some embodiments for compounds of formula IA-i, x is 0-4, and R® groups, when present, are each independently halogen, CN, NO, -N(R’), -CH,N(R),, -OR’, -
CH,OR’, -SR’, -CH,SR’, -COOR’, -NRCOR’, -CON(R’);, -OCON(RR’);, COR’, -
NHCOOR’, -SO,R’, -SO,N(R’),, or an optionally substituted group selected from Ci.
Cealiphatic, aryl, heteroaryl, cycloaliphatic, heterocycloaliphatic, arylCy-Cealkyl, heteroarylC,-Cgalkyl, cycloaliphaticC,-Cealkyl, or heterocycloaliphaticC-Cgalkyl.
[0099] In still other embodiments, x is 1 or 2, and each occurrence of R3is independently
Cl, Br, F, CFs, -OCFs, Me, Et, CN, -COOH, -INH,, -N(CHs);, -N(Et);, -N(Pr),, -
O(CH,),0CH;, -CONH,, -COOCH;, -OH, -OCHs, -OCH,CH;, -CH,OH, -NHCOCH;, -
NHCOCH(CH;);, -SO,NH,, -CONH(cyclopropyl), -CONHCH;, -CONHCH,CHs, or an optionally substituted group selected from -piperidinyl, piperizinyl, morpholino, phenyl, phenyloxy, benzyl, or benzyloxy.
[00100] In yet other embodiments, x is 1 or 2 and each R? group is independently halogen,
CN, optionally substituted C;-Cealkyl, OR’, N(R’)2, CON(R’)z, or NRCOR’.
[00101] In still other embodiments, X is 1 or 2, and each rR? group is -Cl, -CHj, -CH,CHj, -
F, -CF;, -OCFs;, -CONHCH3, -CONHCH,CHs, -CONH(cyclopropyl), -OCHs, -NHa, -
OCH,CHs;, or -CN.
[00102] In yet other embodiments x is 1 and R? is at the 6-position of the quinazoline ring and is -Cl, -CH;, -CH,CH3, -F, -CF;, -OCF;, -CONHCH; -CONHCH;CHs, -
CONH(cyclopropyl), -OCHj3, -NH,, -OCH,CHj, or -CN.
[00103] In still other embodimenst, x is 1 and R3 is at the 7-position of the quinazoline ring and is -Cl, -CHs;, -CHCHs, -F, -CF;, -OCF,;, -CONHCH;, ~-CONHCH,CHs, -
CONH(cyclopropyl), -OCHs, -NHa, -OCH,CHj, or -CN.
[00104] In yet other embodiments, x is 1 and R? is at the 6-position of the quinazoline ring and is -Cl, -CH3, -CH,CHj, -F, -CF3, -OCF3, -OCHs, or -OCH,CHs.
[00105] In still other embodiments, x is 1 and R? is at the 7-position of the quinazoline ring and is -Cl, -CHs, -CH,CHs, -F, -CF3, -OCF;, -OCHj, or -OCH,CHs.
[00106] In yet other embodiments, x is 1 and R3 is at the 6-position of the quinazoline ring and is <=CON(R’),, or NRCOR’.
[00107] In still other embodiments, x is 1 and R® is at the 7-position of the quinazoline ring and is -CON(R’),, or NRCOR’.
[00108] In some embodiments for compounds of formula JAA, y is 0-5, q is 0-2, and R’ and R® groups, when present, are each independently halogen, CN, NO;, -NR’}),, -
CH,N(R’)z, -OR’, -CH,OR’, -SR’, -CH,;SR’, - -NRCOR’, -CONR’)2, -S(0)NR’),, -
OCOR’, -COR’, -CO,R’, -OCON(R’),, -NR’SO:R’, -OP(O}OR’), -P(O)(OR’)s, -
OP(0O),0R’, -P(0),0R’, -PO(R’),, -OPO(R’), or an optionally substituted group selected from C,.Cealiphatic, aryl, heteroaryl, cycloaliphatic, heterocycloaliphatic, arylC;-Csalkyl, heteroarylC;-Csalkyl, cycloaliphaticC,-Cealkyl, or heterocycloaliphaticC;-Csalkyl.
[00109] In yet other embodiments, y is 0-5, and q is 1 or 2, and each occurrence of R* is independently Cl, Br, F, CF;, Me, Et, CN, -COOH, -NH;, -N(CHa),, -N(Et),, -N@Pr),, -
O(CH,),0CH3, -CONH,, -COOCH;, -OH, -OCHs, -OCH,CHs, -CH;OH, -NHCOCH;, -
SO,NH,, -SO,NHC(CHs);, -OCOC(CH3)s3, -OCOCH;C(CHs), -O(CH2),N(CHz),, 4-CHs- piperazin-1-yl, OCOCH(CHz),, OCO(cyclopentyl), -COCH, optionally substituted phenoxy, or optionally substituted benzyloxy.
[00110] In still other embodiments, when ring A is phenyl, y is 0, and q is 1 and R*® is F substituted at the 2-position of the phenyl ring. In yet other embodiments, when ring Ais phenyl, y is 0, q is 1, and R* is OR’ substituted at the 2-position of the phenyl ring. In still other embodiments, when ring A is phenyl, y is 0, q is 1 and R>® is OH substituted at the 2- position of the phenyl ring. In yet other embodiments, when ring A is phenyl, yis 0, q is 2 and one occurrence of R>® is OR’ and the other occurrence of R*® is F, wherein OR’ is substituted at the 2-position of the phenyl ring and F is substituted at the 6-position of the phenyl ring. In yet other embodiments, when ring A is phenyl, y is 0, q is 2 and one occurrence of R* is OH and the other occurrence of R* is F, wherein OH is substituted at the 2-position of the phenyl ring and F is substituted at the 6-position of the phenyl ring.
[00111] In still other embodiments, for compounds of formula IA-i, q is 1 and R* is at the 2-position of the phenyl ring, and compounds have the structure TA-ii: 1 2
RAR afi TN R52
ART oe
N = 2X (Roy
IA-ii wherein: a) the ring formed by R! and R? taken together is selected from: 4 R4 (R* £ JR ) £ NS )z A )z ig $ )
L_NH L_o cc dd ee r Jy ny > (3 Cy
TNRY, fr gg hh
A (R%: Tr T ) 2 ) ~s GY / ’ AR) ii ii kk " N N N (RY RY, 8 . (RY): (R%)
Il mm nn 00 and the ring formed by R! and R? taken together, is optionally substituted at one or more substitutable carbon, nitrogen, or sulfur atoms with z independent occurrences of -R*, and z is 0-5;
b) wherein z is 0-5, and R* groups, when present, are each independently halogen,
CN, NO,, -N(R’);, -CHoN(R")2, -OR’, -CHOR’, -SR’, -CH,SR’, -COOR’, -NRCOR’, -
CON(R’);, -OCON(R’);, COR’, -NHCOOR’, -SO,R’, -SO;N(R’);, or an optionally substituted group selected from Ci.Cealiphatic, aryl, heteroaryl, cycloaliphatic, heterocycloaliphatic, arylC;-Csalkyl, heteroarylC;-Cealkyl, cycloaliphaticC;-Cealkyl, or heterocycloaliphaticC;-Cgalkyl. c) wherein x is 0-4, and R? groups, when present, are each independently halogen,
CN, NO,, -NR’)z, -CH:N®R’)z, -OR’, -CH,OR’, -SR’, -CH,SR’, -COOR’, -NRCOR’, -
CON(R’);, -OCON(R’);, COR’, -NHCOOR’, -SOzR’, -SO;N(R’);, or an optionally substituted group selected from Ci Cealiphatic, aryl, heteroaryl, cycloaliphatic, heterocycloaliphatic, arylC;-Cealkyl, heteroarylC;-Cealkyl, cycloaliphaticCy-Cgalkyl, or heterocycloaliphaticC;-Cealkyl. d) wherein y is 0-5, and R® groups, when present, are each independently halogen,
CN, NO, -N(R’);, -CHN(R’)2, -OR’, -CH,OR’, -SR’, -CH,SR’, - -NRCOR’, -CONR’),, -
S(O)N(R’);, -OCOR’, -COR’, -CO;R’, -OCON(R’);, -NR’SO:R’, -OP(O)(OR’), -
P(O)(OR"),, -OP(O),0R’, -P(O),,0R’, -POR’);, -OPO(R’), or an optionally substituted group selected from C;.Csaliphatic, aryl, heteroaryl, cycloaliphatic, heterocycloaliphatic, arylC;-Cealkyl, heteroarylC;-Cealkyl, cycloaliphaticC,-Cealkyl, or heterocycloaliphaticC;-
Cealkyl; and e) R* is Cl, Br, F, CF;, Me, Et, CN, -COOH, -NHp, —N(CHs)z, -N(Et)2, -N(@iPr),, -
O(CH,),OCHs, -CONH,, -COOCH;, -OH, -OCHs, -OCH;CHs, -CH,OH, -NHCOCH;, -
SO,NH,, -SO,NHC(CHs);, -OCOC(CHs)s, -OCOCH,C(CHs)s, -O(CH2)N(CHs),, 4-CHs- piperazin-1-yl, OCOCH(CHz),, OCO(cyclopentyl), -COCHs, optionally substituted phenoxy, or optionally substituted benzyloxy.
[00112] In still other embodiments, for compounds of formula IA-ii: q is 1 and R® is at the 2-position of the phenyl ring, and compounds have the structure TA-ii:
RL, -R?
Se N R92 0) “FO
TA-ii wherein:
a) R! and R? taken together is an optionally substituted ring selected from azetidin-1- v1 (jj), pyrrolidin-1-y1 (ff), piperidin1-yl (dd), or piperazin-1-yl (cc); b) z is 0-5 and R* groups are each independently Cl, Br, F, CFs, CHj, -CH,CHs, CN, -
COOH, —-N(CHa),, -N(Et), -N(iPr)2, -O(CH;);OCHs, -CONH,, -COOCHj3, -OH, -CH,OH, -
NHCOCH;, -SO:NH;, -SO2(CH:):CHs, -SO,CH(CHz),, -SO,N(CHz);, -SOCH,CHs, -
C(O)OCH,CH(CHz),, -C(O)NHCH,CH(CHs),, NHCOOCH;, -C(O)C(CH3);, -
COO(CH,),CHs, -C(O)NHCH(CHs)z, -C(O)CH,CHs, or an optionally substituted group selected from -piperidinyl, piperizinyl, morpholino, Ciaalkoxy, phenyl, phenyloxy, benzyl, benzyloxy, -CHacyclohexyl, pyridyl, -CH,pyridyl, or -CHathiazoly}; c) x is 1 or 2, and each occurrence of R? is independently Cl, Br, F, CFs, -OCFs, Me,
Et, CN, -COOH, -NH,, -N(CHa)s, -N(Et);, -N(iPr)z, -O(CH,),OCHj, -CONH;,, -COOCH3, -
OH, -OCH,;, -OCH,CH,; -CH,OH, -NHCOCH;, -NHCOCH(CHs3);, -SO:NH;, -
CONH(cyclopropyl), -CONHCH;, -CONHCH,CHs, or an optionally substituted group selected from -piperidinyl, piperizinyl, morpholino, phenyl, phenyloxy, benzyl, or benzyloxy; d) wherein y is 0-4, and R’ groups, when present, are each independently Cl, Br, F,
CF;, Me, Et, CN, -COOH, -NH;, -N(CHz);, -N(Et)z, -N(iPr)s, -O(CH,),OCH3, -CONHy, -
COOCHS;, -OH, -OCHs, -OCH,CHj3, -CH,0H, -NHCOCH;, -SO2NH;, -SO,NHC(CHz),, -
OCOC(CHjz)s, -OCOCH,C(CHz)s, -O(CH,),N(CH3),, 4-CH;-piperazin-1-yl, OCOCH(CHs),,
OCO(cyclopentyl), -COCHs, optionally substituted phenoxy, or optionally substituted benzyloxy; and e) R® is Cl, F, CFs, Me, Et, -OH, -OCH;, -OCH,CH;, -CH,OH, -SO,NHy, -
SO,NHC(CH3),, -OCOC(CH3);, -OCOCH,C(CHs)s, -O(CHz)2N(CHs)s, 4-CHj-piperazin-1- yl, OCOCH(CHa)>, OCO(cyclopentyl), or -COCHs.
[00113] In still other embodiments, for compounds of formula IA-ii x is 1 and R? is at the 6-position of the quinazoline ring and is -Cl, -CHj3, -CH,CHs, -F, -CF3, -OCF;, -CONHCH;3, -
CONHCH,CHs;, -CONH(cyclopropyl), -OCH3, -NH,, -OCH,CHj3, or -CN. In yet other embodiments, x is 1 and R? is at the 7-position of the quinazoline ring and is Cl, -CH,, -
CH,CH, -F, -CFs, -OCF;, -CONHCH3, -CONHCH,CHj3, -CONH(cyclopropyl), -OCH;, -
NH,, -OCH,CHa, or -CN. In still other embodiments, x is 1 and R? is at the 6-position of the quinazoline ring and is -Cl, -CHj, -CH,CHj, -F, -CF3, -OCF;, -OCHj, or -OCH;CH;. In yet other embodiments, x is 1 and R? is at the 7-position of the quinazoline ring and is -Cl, -CHs, -CH,CHs, -F, -CF3, -OCF3, -OCHj, or -OCH;CH3. In still other embodiments, x is 1 and R® is at the 6-position of the quinazoline ring and is -CON(R’),, or NRCOR’.
[00114] In yet other embodiments, x is 1 and R’ is at the 7-position of the quinazoline ring and is -CON(R’),, or NRCOR’.
[00115] In still other embodiments, R* is Cl, F, CFs, Me, Et, OR’,-OH, -OCHs, -
OCH,CHs.
[00116] In yet other embodiments, R* is OR’. In still other embodiments, R®isF.
[00117] In still other exemplary embodiments compounds have formula IA-ii:
RL -R®
In Noe N R% 0 “Fo,
TA-ii wherein: a) R! and R? taken together is an optionally substituted ring selected from azetidin-1- yl (jj), pyrrolidin-1-yl (ff), piperidin1-yl (dd), or piperazin-1-yl (cc); b) z is 0-5 and R* groups are each independently Cl, Br, F, CFs, CH;, -CH,CH3, CN, -
COOH, —-N(CHa),, -N(Et)z, -N(iPr),, -O(CH,),OCHj3, -CONH2, -COOCH;, -OH, -CHOH, -
NHCOCH;, -SO,NH,, -SO,(CH3):CHs, -SO,CH(CHs);, -SO,N(CH3)s, -SO,CH,CHs, -
C(O)OCH,CH(CHa);, -C(O)NHCH,CH(CH3);, -NHCOOCH;, -C(O)C(CH3);, -
COO(CH,),CHs, -C(O)NHCH(CH3),, -C(O)CHCH3, or an optionally substituted group selected from -piperidinyl, piperizinyl, morpholino, C;salkoxy, phenyl, phenyloxy, benzyl, benzyloxy, -CHacyclohexyl, pyridyl, -CHapyridyl, or -CHathiazolyl; ¢) x is 1, and each occurrence of R% is independently Cl, Br, F, CFs, -OCF;, Me, Et,
CN, -COOH, -OH, or -OCHj; d) yis O or 1, and R® groups, when present, are each independently Cl, Br, F, CFs,
Me, -OH, -OCH3, -OCH,CH3, -CH,OH, -NHCOCH3, -SO,NH2, -SO,NHC(CHs),; and e) Ris F, -OR’, or NHSO;R".
[00118] In some embodiments for compounds described directly above, x is 1 and R® is at the 6-position of the quinazoline ring and is -Cl, -CHs, -CH,CHjs, -F, -CF;, -OCF;, -
CONHCH;, -CONHCH,CHj3, -CONH(cyclopropyl), -OCHj3, -NH,, -OCH,CHjs, or -CN. In still other embodiments, x is 1 and R? is at the 7-position of the quinazoline ring and is -ClI, -
CH, -CH,CH;, -F, -CF;, -OCF;, -CONHCH;, -CONHCH,CH3, -CONH(cyclopropyl), -
OCH;, -NH,, -OCH,CH,, or -CN. In yet other embodiments, x is 1 and R3 is at the 6- position of the quinazoline ring and is -Cl, -CHa, -CH,CHj, -F, -CFs, -OCF3, -OCH;, or -
OCH,CHs. In still other embodiments, x is 1 and R® is at the 7-position of the quinazoline ring and is -Cl, -CHj3, -CH,CHj3, -F, -CF;, -OCF;, -OCH;, or -OCH,CH;. In yet other embodiments, x is 1 and R? is at the 6-position of the quinazoline ring and is —CON(R’),, or
NRCOR’. In still other embodiments, x is 1 and R3 is at the 7-position of the quinazoline ring and is -CON(R’),, or NRCOR’.
[00119] In yet other embodiments, R%® is OR’ and x is 1 and R? is at the 6-position of the quinazoline ring and is -Cl, -CHs, -CH,CHj, -F, -CF3, ~OCF;, -OCH;, or -OCH,CH;, In yet other embodiments, R* is OR’ and x is 1 and R® is at the 7-position of the quinazoline ring and is -Cl, -CHjs, -CH,CH, -F, -CF;, -OCFs, -OCH3, or -OCH,CHs.
[00120] In yet other embodiments, R* is OH and x is 1 and R® is at the 6-position of the quinazoline ring and is -Cl, -CHj3, -CH,CHj, -F, -CF3, -OCF;, -OCHj, or -OCH,CH;, In yet other embodiments, R* is OH and x is 1 and R? is at the 7-position of the quinazoline ring and is -Cl, -CHj3, -CH,CHj, -F, -CF3, -OCF3, -OCH3, or -OCH;CH3.
[00121] In yet other embodiments, R* is F and x is 1 and R? is at the 6-position of the quinazoline ring and is -Cl, -CHs, -CH>CHs, -F, -CF3, -OCF;, -OCHjs, or -OCH,CHj;, In yet other embodiments, R* is F and x is 1 and R? is at the 7-position of the quinazoline ring and is -Cl, -CHj3, -CH,CHj, -F, -CF3, -OCF;3, -OCHj, or -OCH,CH;,
[00122] In still other embodiments, for compounds of formula TA-ii, R! and R?, taken together is optionally substituted azetidin-1-yl (jj). In yet other embodiments, for compounds of formula FA-ii, R! and R? taken together is optionally substituted pyrrolidin-1-yl (ff). In still other embodiments, for compounds of formula IA-ii, R' and R?, taken together is optionally substituted piperidinl-yl (dd). In yet other embodiments, for compounds of formula IA-ii, R! and R? taken together is optionally substituted piperazin-1-yl (cc).
[00123] In certain embodiments, for compounds of formula XA-ii, R' and R?, taken together is optionally substituted azetidin-1-yl (jj), wherein z is 1 or 2 and at least one occurrence of R* is -NRSO,R’, -NRCOOR’, or -NRCOR’. In certain other embodiments, for compounds of formula IA-ii, R' and R?, taken together is optionally substituted azetidin-1-yl (jj), wherein z is 1 and R*is -NRSO,R’. In other embodiments, for compounds of formula
IA-ii, R' and R?, taken together is optionally substituted azetidin-1-y1 (jj), wherein z is 1 and
R* is -NRCOOR’. In certain other embodiments, for compounds of formula IA-ii, R! and R?, taken together is optionally substituted azetidin-1-yl (jj), wherein z is 1 and R* is -NRCOR’.
In yet other embodiments, for compounds of formula IA-ii, R! and R?, taken together is _47 -
optionally substituted pyrrolidin-1-yl (ff), wherein z is 1 or 2 and R* is Cl, Br, F, CFs, CH, -
CH,CH;, -OR’, or -CH;0R’. In still other embodiments, for compounds of formula 1A-ii, R! and R?, taken together is optionally substituted piperidin-1-yl (dd), wherein z is 1 or 2 and at least one occurrence of R* is Cl, Br, F, CFs, CHs, -CH,CHs, -OR’, or -CH;0R’, -NRSO.R’, -
NRCOOR’, or -OCON(R’). In certain other embodiments, for compounds of formula IA-ii,
R! and R?, taken together is optionally substituted piperidin-1-yl (dd), wherein z is 1 and R* is F, CFs, CH3, -CH,CHj, -OR’, or -CHOR'. In other embodiments, for compounds of formula IA-ii, R' and R?, taken together is optionally substituted piperidin-1-yl (dd), wherein zis 1 and R* is —NRSO,R’,. In certain other embodiments, for compounds of formula TA-ii,
R! and R?, taken together is optionally substituted piperidin-1-yl (dd), wherein z is 1 and R* is -NRCOOR’. In yet other embodiments, for compounds of formula JA-ii, R! and R?, taken together is optionally substituted piperazin-1-yl (cc), wherein z is 1 or 2 and at least one occurrence of R? is —SOR’, -CON(R"), -SO:N(R’),, -COR’, or -COOR’. In certain other embodiments, for compounds of formula IA-ii, R! and R? taken together is optionally substituted piperazin-1-yl (cc), wherein z is 1 and R* is —=SOR’. In certain other embodiments, for compounds of formula IA-ii, R! and R? taken together is optionally substituted piperazin-1-yl (cc), wherein z is 1 and R* is -COOR’. In certain other embodiments, for compounds of formula TA-ii, R! and R? taken together is optionally substituted piperazin-1-yl (cc), wherein z is 1 and R* is -CON(R’);. In certain other embodiments, for compounds of formula JA-ii, R! and R? taken together is optionally substituted piperazin-1-yl (ce), wherein z is 1 and R* is -SO,M(R’),. In certain other embodiments, for compounds of formula IA-ii, R! and R? taken together is optionally substituted piperazin-1-yl (cc), wherein z is 1 and R*is -COR’.
[00124] For compounds described in this section above, in general, compounds are useful as inhibitors of ion channels, preferably voltage gated sodium channels and N-type calcium channels. In certain exemplary embodiments, compounds of the invention are useful as inhibitors of NaV1.8. In other embodiments, compounds of the invention are useful as inhibitors of NaV1.8 and CaV2.2. In still other embodiments, compounds of the invention are useful as inhibitors of CaV2.2. In yet other embodiments, compounds of the invention are useful as dual inhibitors of NaV1.8 and a TTX-sensitive ion channel such as NaV1.3 or
NaVvl.7.
[00125] II. Compounds of formula IA-ii:
RL -R?
NSE. me
Sm
FZ
IA-ii wherein R! and R? are each independently an optionally substituted group selected from C,aliphatic, Cy, wherein Cy! is a 5-7-membered monocyclic aryl ring or an 8-10- membered bicyclic aryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or is a 3.12-membered saturated or partially unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, Or sulfur, wherein Cy’ is bonded directly to the nitrogen atom or is bonded through an optionally substituted Cj. saliphatic group, wherein one or more methylene units in the C, aliphatic group are optionally replaced with -NR-, -O-, -COO, -OCO-, -NRCO-, -CONR-, -SO;NR-, or -
NRSO,-: wherein R! and R? are each optionally and independently substituted at one or more substitutable carbon, nitrogen, or sulfur atoms with z independent occurrences of -R%, wherein z is 0-5; x is 0-4; y is 0-4; each occurrence of R?, R?, and R’ is independently Q-R*; wherein Q is a bond or is a
C,-C; alkylidene chain wherein up to two non-adjacent methylene units of Q are optionally and independently replaced by -NR-, -S-, -0-, -CS-, -C0O,-, -0CO-, -CO-, -COCO-, -CONR-, _NRCO-, -NRCO,-, -SO;NR-, -NRSO,-, -CONRNR-, -NRCONR-, -OCONR-, -NRNR-, -
NRSO,NR-, -SO-, -SO3-, -PO-, -PO»-, -OP(0)(OR)-, or -POR-; and each occurrence of R¥is independently selected from -R’, =O, =NR’, halogen, -NO2, -CN, -OR’, -SR’, -N(R’)2, -
NR’COR’, -NR’CON(R’),, -NR’CO;R’, -COR’, -CO;R’, -OCOR’, -CONR)2, -
OCON(R’);, -SOR’, -SO,R’, -SO.N(R’),, -NR’SOR’, -NR’SO;N(R’),, -COCOR’, -
COCH,COR’, -OP(O)(OR’),, -P(O)(OR’),, -OP(0)0R’, -P(0);0R’, -PO(R’),, oF -
OPO(R")z;
R>? is an optionally substituted C,-Cealiphatic group, halogen, -OR’, -SR’, -N(R’)2, -
NR’COR’, -NR’CON(R’);, -NR’CO;R’, -COR’, -COzR’, -OCOR’, -CON(R™), -
OCON(R’), -SOR’, -SO;R’, -SO,N(R’);, -NR’SO:R’, -NR’SO;N[R’),, -COCOR’, -
COCH,COR’, -OP(Q)(OR")z, -P(O)(OR"), -OP(0);0R’, -P(0):0R’, POR’ )z, OF -
OPO(R’),; and each occurrence of R is independently hydrogen or an optionally substituted Ci.6 aliphatic group; and each occurrence of R'is independently hydrogen or an optionally substituted C;.¢ aliphatic group, a 3.8-membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-12 membered saturated, partially unsaturated, or fully unsaturated bicyclic ring system having 0-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or R and R’, two occurrences of R, or two occurrences of R, are taken together with the atom(s) to which they are bound to form an optionally substituted 3-12 membered saturated, partially unsaturated, or fully unsaturated monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
[00126] In certain embodiments, for compounds described directly above, a. when x is 0, R! is hydrogen, and R* is Cl, Me, CF;, Br, or F, then R? is not — (CH,),4-Cy', -SO,CH,CyY", or —CH,SO,Cy, wherein Cy! is a 5-7-membered monocyclic aryl ring or an 8-10-membered bicyclic aryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or is a 3.8-membered saturated or partially unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; b. when x is 0, and R* is Cl, Me, NO, or OH, then: i. when R! is hydrogen, R? is not Me, iBu, nBu, -COCHs, -CH,COOE, -
CH,COOMe, -CH,CH,OH, iPr, -CH,-pyridyl, -CH,Ph, -(CHz);sNH,, - (CHa),-moropholinyl, or -CHCHoPh; ii. R!and R? are not simultaneously Et or Me; and iii. when R! is Et, then R? is not 4-Me-phenyl, 4-OMe-phenyl, or 2-Me- phenyl; c. whenxis land R3? is 6-Cl, or 7-F, or x is 0 and R’? is —OPr, or Cl, then when
R! is hydrogen, R? is not —(CHz),-morpholino, or —CH,(benzofuran); and d. when x is 2 and one occurrence of R3 is 6-OMe and the other occurrence of rR? is 7-OMe, and R* is F, then when R! is hydrogen, R? is not -(CHz)sN(CHs)z;
[00127] In certain other embodiments, for compounds described directly above, a) one of R! or R? is hydrogen, and the other of R! and R? is selected from:
i) Cy' wherein Cy' is bonded directly to the nitrogen atom or is bonded through an optionally substituted Cy.saliphatic group, wherein one or more methylene units in the C,_aliphatic group are optionally replaced with -NR-, -O-, -COO, -0CO-, -NRCO-, -CONR-, -SO;NR-, or -NRSO,-; or ii) an optionally substituted C;4aliphatic group, wherein one or more methylene units in the Cialiphatic group are optionally replaced with -NR-, -O-, -
C00, -0CO-, -NRCO-, -CONR-, -SO,NR-, or -NRSO»-; or b) R! and R? are each independently selected from cy, wherein Cy’ is bonded directly to the nitrogen atom or is bonded through an optionally substituted Ci. saliphatic group, wherein one or more methylene units in the Cj4aliphatic group are optionally replaced with -NR-, -0-, -C0O0, -0CO-, -NRCO-, -CONR-, -SO,NR-, or -
NRSO,-; or an optionally substituted C)saliphatic group, wherein one or more methylene units in the Cyaliphatic group are optionally replaced with -NR-, -O-, -
COO-, -OCO-, -NRCO-, -CONR-, -SO;NR-, or -NRSO»-.
[00128] In other embodiments Cy' is: 4 +1 Jw 3m, ey 1
Zh be) > oR a N a b c d (R*): (RY), (RY, RY
N° N “ 4 e f g h . — ”
He al Ay 251 i J k 1
R4 A Rr Rt : 2 )2 » \ = o A,
Ss nf ve g J=n en m n 0 p
R* Rr R4 <n No Ns £0) — od 7 NC a wf Ve N (RY), q r S t
N 0
HOE He HO HOT
SNR, “Sy N (Re),
H H u v w X
H
N So,
IN AN] zs \_(R*
CRY, CRY, LA ey, — we y z aa bb
[00129] In still other embodiments, for compounds described directly above, R! is hydrogen or an optionally substituted C,-Caaliphatic group and R?is ~-CHR-Cy', wherein R is hydrogen or C;-Cjalkyl, and Cy' is: (R* 0 Ne) Ey CN 2 (RY) lJ z u Pp 2 J (RY), “yl, N N a b e d (RY), (RY. (RY (R%
Z/ Ya N= 2
HO Lh 7
N” N* wt, “i e f g h
H 4
NN nc (Fz "
N JN mY £ N— (RY):
Ag N ye TT "e (RY), 4H J Ty i J k 1
. R# R* R4
R
HET fa
S o] g =N =, , Mon, m n o p
R* R* R*
PN A A
= ! el en Fl a Va wg R, q r Ss t
N 0
HO iL 3s, HC Ten HY
NG NE 2 ope (RY), N N (R%),
H H u v w X
H
N Sr, ay cy A (Re lm, i , Les, + (RY), y z aa bb
[00130] In yet other embodiments, R! and R? groups are each independently an optionally substituted Cj4aliphatic group and are each independently selected from optionally substituted methyl, ethyl, cyclopropyl, n-propyl, propenyl, cyclobutyl, (CO)OCH,CHj, (CH,);0CH3, CH,CO)OCH,CH3, CHz(CO)OCH3, CH(CH3)CH,CHj, or n-butyl.
[00131] For compounds described directly above, z is 0-5, and R* groups, when present, are each independently halogen, CN, NO;, -N(R");, -CH;N(R’),, -OR’, -CH,OR’, -SR’, -
CH,SR’, -COOR’, -NRCOR’, -CON(R’);, -OCON(R’);, COR’, -NHCOOR’, -SO.R’, -
SO,N(R’),, or an optionally substituted group selected from C,.Cealiphatic, aryl, heteroaryl, cycloaliphatic, heterocycloaliphatic, arylC;-Cgalkyl, heteroarylC;-Cealkyl, cycloaliphaticC;-
Cgalkyl, or heterocycloaliphaticCy-Csalkyl.
[00132] In other embodiments, z is 0-5 and R* groups are each independently Cl, Br, F,
CF;, CH,, -CH,CHs, CN, -COOH, -N(CHs),, -N(Et),, -N(iPr)z, -O(CH;),OCH3, -CONH,, -
COOCH;, -OH, -CH,OH, -NHCOCH;, -SO,NH;, -SO;(CH);CHs;, -SO,CH(CHj)., -
SO,N(CH3),, -SO,CH,CH3, -C(O)OCH,CH(CHj3),, -C(O)NHCH,CH(CHs)o, -NHCOOCH;, -
C(O)C(CH3)s, -COO(CH,):CHs, -C(O)NHCH(CH3);, -C(O)CHCHs, or an optionally substituted group selected from -piperidinyl, piperizinyl, morpholino, Cysalkoxy, phenyl, phenyloxy, benzyl, benzyloxy, -CHycyclohexyl, pyridyl, -CH,pyridyl, or -CHythiazolyl.
[00133] In still other embodiments, for compounds described directly above, x is 0-4, and
R? groups, when present, are each independently halogen, CN, NO, -N(R’),, -CH.NR)z, -
OR’, -CH,OR’, -SR’, -CH,;SR’, -COOR’, _NRCOR’, -CON(R’);, -OCON(R’);, COR’, -
NHCOOR’, -SO;R’, -SO:N(R’),, or an optionally substituted group selected from C;.
Cealiphatic, aryl, heteroaryl, cycloaliphatic, heterocycloaliphatic, arylC,-Cealkyl, heteroarylC;-Cealkyl, cycloaliphaticC;-Cealkyl, or heterocycloaliphaticC;-Cealkyl.
[00134] In yet other embodients, for compounds described directly above, x is 1 or 2, and each occurrence of R® is independently Cl, Br, F, CF3, -OCF3, Me, Et, CN, -COOH, -NH3, —
N(CHa),, -N(Et)z, -N(iPr),, -O(CH;),0CH;, -CONH, -COOCH;, -OH, -OCHj3, -OCH,CHs, -
CH,OH, -NHCOCH;, -NHCOCH(CHa),, -SONHa, -CONH(cyclopropyl), -CONHCH3, -
CONHCH,CH;, or an optionally substituted group selected from -piperidinyl, piperizinyl, morpholino, phenyl, phenyloxy, benzyl, or benzyloxy.
[00135] In still other embodiments, x is 1 or 2 and each R® group is independently halogen, CN, optionally substituted C;-Cealkyl, OR’, N(R’), CONR”),, or NRCOR’.
[00136] In yet other embodiments, x is 1 or 2, and each R® group is -Cl, -CHjs, -CH,CHs, -
F, -CFs, -OCF;, -CONHCH;, -CONHCH,CHs, -CONH(cyclopropyl), -OCHs, -NHp, -
QCH,CHj, or -CN.
[00137] In still other embodiments, X is 1 and R? is at the 6-position of the quinazoline ring and is -Cl, -CHs;, -CH,CHj;, -F, -CF, -OCF;, -CONHCH;, -CONHCH,CH3, -
CONH (cyclopropyl), -OCHj, -NH;, -OCH,CHj, or -CN.
[00138] In yet other embodiments, x is 1 and R3 is at the 7-position of the quinazoline ring and is -Cl, -CH;, -CH,CHs;, -F, -CF;, -OCF;, -CONHCH;, -CONHCH,CHs, -
CONH(cyclopropyl), -OCHj3, -NHo, -OCH,CHs, or -CN.
[00139] In still other embodiments, x is 1 and R? is at the 6-position of the quinazoline ring and is -Cl, -CHj, -CH,CHj, -F, -CF3, -OCFs, -OCHs, or -OCH,CHs.
[00140] In other embodiments, x is 1 and R3 is at the 7-position of the quinazoline ring and is -Cl, -CHs, -CH,CH3, -F, -CF;, -OCF3, -OCHj3, or -OCH,CHs.
[00141] In yet other embodiments, R3 is at the 6-position of the quinazoline ring and is -
CON(R’),, or NRCOR’.
[00142] In still other embodiments, x is 1 and R3 is at the 7-position of the quinazoline ring and is -CON(R”),, or NRCOR’.
[00143] For compounds described directly above, y is 0-4, q is 0-2, and R® and R*® groups, when present, are each independently halogen, CN, NO,, -NR’)2, -CH,NR)2, -OR’, -
CH,OR’, -SR’, -CH,SR’, - -NRCOR’, -CON(R)2, -S(0),N(R’),, -OCOR’, -COR’, -CO2R’, -
OCON(R’), -NR’SO;R’, -OP(O)(OR")2, -P(O)(OR")z, -OP(0O),0R’, -P(0),0R’, -POR’)s, -
OPO(R’),, or an optionally substituted group selected from C;.Cgaliphatic, aryl, heteroaryl, cycloaliphatic, heterocycloaliphatic, arylC1-Cealkyl, heteroarylC,-Cealkyl, cycloaliphaticC;-
Cialkyl, or heterocycloaliphaticCi-Cealkyl.
[00144] In other embodiments, y is 0-4, and q is 1 or 2, and each occurrence of R* is independently Cl, Br, F, CFs, Me, Et, CN, -COOH, -NH;, -N(CHzs),, -N(Et),, -N(@iPr)2, -
O(CH,),OCH3, -CONH,, -COOCH;, -OH, -OCHs, -OCH,CHs, -CH,OH, -NHCOCH3, -
SO,NH,, -SO,NHC(CH3);, -OCOC(CHa)s, -OCOCH2C(CHs)s, -O(CH,);N(CHs),, 4-CHs- piperazin-1-yl, OCOCH(CHs)z, OCO(cyclopentyl), -COCHs, optionally substituted phenoxy, or optionally substituted benzyloxy.
[00145] In still other embodiments, y is 0, and R*?isF. In yet other embodimentsy is 0,q is 1, and R*® is OR’. In still other embodiments, y is 0, q is 1 and R*® is OH. In yet other embodiments, v is 1, Ris OR’ and R® is F, wherein OR’ is substituted at the 2-position of the phenyl ring and F is substituted at the 6-position of the phenyl ring. In yet other embodiments, y is 1, R3* is OH and R is F, wherein OH is substituted at the 2-position of the phenyl ring and F is substituted at the 6-position of the phenyl ring.
[00146] In still other embodiments for compounds of formula IA-ii described directly above: a) one of R! or R? is hydrogen, and the other of R! and R? is selected from Cy’, wherein Cy’ is bonded directly to the nitrogen atom or is bonded through an optionally substituted C;.saliphatic group, wherein one or more methylene units in the Ci aliphatic group are optionally replaced with -NR-, -O-, -COO, -OCO-, -NRCO-, -CONR-, -SO;NR-, or -NRSO,-, or an optionally substituted C,saliphatic group, wherein one or more methylene units in the Cjaliphatic group are optionally replaced with -NR-, -O-, -COO, -OCO-, -
NRCO-, -CONR-, -SO,NR-, or -NRSO,-; or R! and R? are each independently selected from an optionally substituted C;_aliphatic group, wherein one or more methylene units in the C,. saliphatic group are optionally replaced with -NR-, -O-, -COO, -OCO-, -NRCO-, -CONR-, -
SO,NR-, or -NRSO2-; or Cy' wherein Cy' is bonded to the nitrogen atom directly or is bonded through an optionally substituted Cy4aliphatic group. wherein one or more methylene units in the Cj4aliphatic group are optionally replaced with -NR-, -O-, -COO, -OCO-, -
NRCO-, -CONR-, -SO,NR-, or -NRSO2-; b) z is 0-5 and R* groups are each independently Cl, Br, F, CFs, CH, -CH,CHj3, CN, -
COOH, —N(CHa),, -N(Et)2, -N(iP1)2, -O(CH2),OCHs, -CONH,, -COOCHj;, -OH, -CH;OH, -
NHCOCH;, -SO:NH,, -SO2(CH:);CHs, -SO,CH(CH3)2, -SON(CH3);, -SO,CHCHs, -
C(O)OCH,CH(CHs);, -C(O)NHCH,CH(CHs)y, -NHCOOCH3;, -C(O)C(CHs);, -
COO(CH>),CHs, -C(O)NHCH(CHs),, -C(O)CH,CH3, or an optionally substituted group selected from -piperidinyl, piperizinyl, morpholino, Cialkoxy, phenyl, phenyloxy, benzyl, benzyloxy, -CHacyclohexyl, pyridyl, -CHypyridyl, or -CHsthiazolyl; c) x is 0, 1, or 2, and each occurrence of R? is independently Cl, Br, F, CFs, -OCFs,
Me, Et, CN, -COOH, -NH;, -N(CHs),, -N(Et)2, -N(iPr)z, -O(CH,),0CH3, -CONHa, -
COOCHS, -OH, -OCHs, -OCH,CHjs, -CH,OH, -NHCOCHS, -NHCOCH(CH3), -SO;NH;, -
CONH(cyclopropyl), -CONHCH;, -CONHCH,CH3, or an optionally substituted group selected from -piperidinyl, piperizinyl, morpholino, phenyl, phenyloxy, benzyl, or benzyloxy; d) wherein y is 0-4, and R’ groups, when present, are each independently Cl, Br, F,
CFs, Me, Et, CN, -COOH, -NH,, —N(CHz),, -N(Et), -N(iPr)s, -O(CH,),0CHj3, -CONH,, -
COOCH;, -OH, -OCH3, -OCH,CHj;, -CH,OH, -NHCOCH3, -SO2NH,, ~-SO,NHC(CHjs),, -
OCOC(CHs)3, -OCOCH,C(CH3)s, -O(CH)N(CHa)y, 4-CHs-piperazin-1-yl, OCOCH(CHs)s,
OCO(cyclopentyl), -COCHj, optionally substituted phenoxy, or optionally substituted benzyloxy; and e) R® is Cl, F, CF;, Me, Et, -OH, -OCHj, -OCH,CHs, -CH,OH, -SO;NH,, -
SO,NHC(CHs);, -OCOC(CHs)s, -OCOCH,C(CH3)s, -O(CH2)N(CHa), 4-CHj;-piperazin-1- yl, OCOCH(CH3)y, OCO(cyclopentyl), or -COCHs.
[00147] In other embodiments, for compounds described directly above, x is 1 and R3is at the 6-position of the quinazoline ring and is -Cl, -CHs, -CH2CHs, -F, -CFs;, -OCHF;, -
CONHCH;, -CONHCH,CH;, -CONH(cyclopropyl), -OCHj, -NH;, -OCH;CHs, or —CN. In yet other embodiments, X is 1 and R3 is at the 7-position of the quinazoline ring and is -Cl, -
CH, -CH,CH;, -F, -CF3, -OCF;, -CONHCHj, -CONHCH,CHj;, -CONH(cyclopropyl), -
OCH;, -NH,, -OCH,CHjs, or -CN. In still other embodiments, x is 1 and R? is at the 6- position of the quinazoline ring and is -Cl, -CHs, -CH,CHj, -F, -CF3, -OCFs, -OCH3, or -
OCH,CHs. In still other embodiments, x is 1 and R® is at the 7-position of the quinazoline ring and is -Cl, -CHs, -CH;CH;, -F, -CF;, -OCF;, -OCHj3, or -OCH,CHs. In yet other embodiments, x is 1 and R3 is at the 6-position of the quinazoline ring and is -CON(R’);, or
NRCOR’.
[00148] In still other embodiments, x is 1 and R? is at the 7-position of the quinazoline ring and is -CON(R’), or NRCOR’.
[00149] In vet other embodiments, Ris Cl, F, CFs, Me, Et, -OH, -OCH;, -OCH,CHs.
[00150] In still other embodiments, y is 0, and R%is F. In yet other embodimentsy is 0, q is 1, and R3® is OR’. In still other embodiments, y is 0,qis 1 and Ris OH. In yet other embodiments, y is 1, Ris OR’ and R3 is F, wherein OR’ is substituted at the 2-position of the phenyl ring and F is substituted at the 6-position of the phenyl ring. In yet other embodiments, y is 1, R** is OH and R’ is F, wherein OH is substituted at the 2-position of the phenyl ring and F is substituted at the 6-position of the phenyl ring.
[00151] In still other embodiments for compounds of formula IA-ii described above: a): one of R! or R? is hydrogen, and the other of R! and R? is selected from Cy', wherein Cy' is bonded directly to the nitrogen atom or is bonded through an optionally substituted C,.qaliphatic group, wherein one or more methylene units in the C,.4aliphatic group are optionally replaced with -NR-, -O-, -C0OO, -OCO-, -NRCO-, -CONR-, -SO,NR-, or -NRSO,-, or an optionally substituted Cj4aliphatic group, wherein one or more methylene units in the C,4aliphatic group are optionally replaced with -NR-, -O-, -COO, -0CO-, -
NRCO-, -CONR-, -SO,NR-, or -NRSO»-; or R! and R? are each independently selected from an optionally substituted C;.saliphatic group, wherein one or more methylene units in the Cy. saliphatic group are optionally replaced with -NR-, -O-, -COO, -OCO-, -NRCO-, -CONR-, -
SO,NR-, or -NRSO;-; or Cy' wherein Cy! is bonded to the nitrogen atom directly or is bonded through an optionally substituted Cy 4aliphatic group, wherein one or more methylene units in the Cj.saliphatic group are optionally replaced with -NR-, -O-, -COO, -0CO-, -
NRCO-, -CONR-, -SO;NR-, or -NRSO»-; and Cy' is selected from:
Z UN N
He, ve HC By HE Je. a b c d (RY), (RY), (RY), Ré
SUI A
N™ N° “wh 4 e f g h
H 4
N- NC (RY .N | N Arh, . Nx z
HE, “oN cs J Ly i J k 1
R4 Re R*
R4
Lee )z NN a. oN
Ma, m n o p
R* R4 R4 wd, wg, wf (RY): q r Ss t
N 0
Ni a IIA i 2 RY C9
NP Nw z LJ NG (RY); N N (R%);
H H u v w pi
H
N Sn,
SN CQ 29 A(R y 4 aa bb or R! and R? are each independently an optionally substituted C,_4aliphatic group and are each independently selected from optionally substituted methyl, ethyl, cyclopropyl, n-propyl, propenyl, cyclobutyl, (CO)OCH;CHj3, (CH2);0CH3, CH;CO)OCH,CHs, CH,(CO)OCHg,
CH(CH3)CH,CHs, or n-butyl; b) zis 0-5 and R* groups are each independently Cl, Br, F, CF3, CH, -CH,CH;, CN, -
COOH, —N(CHj3),, -N(Et),, -N(iPr),, -O(CH;),0CHj3, -CONH,, -COOCH;3, -OH, -CH,0H, -
NHCOCH;, -SO,NH;, -SO,(CH2);CHs, -SO,CH(CHs)., -SO,N(CHz);, -SO.CH,CHj, -
C(O)OCH,CH(CH3);, -C(O)NHCH,CH(CH3);, -NHCOOCH;, -C(O)C(CHa)s, -
COO(CH,),CH3, -C(O)NHCH(CH3),, -C(O)CH>CHj, or an optionally substituted group selected from -piperidinyl, piperizinyl, morpholino, C, alkoxy, phenyl, phenyloxy, benzyl, benzyloxy, -CHacyclohexyl, pyridyl, -CHzpyridyl, or -CHthiazolyl; c) x is 0, 1, or 2, and each occurrence of R? is independently Cl, Br, F, CFs, -OCF5,
Me, Bt, CN, -COOH, -NH,, -N(CHs), -N(Bt)s, -N(Pr), -O(CHz);0CHs, -CONH, -
COOCH;, -OH, -OCH3, -OCH,CH3, -CHOH, -NHCOCH;, -NHCOCH(CHz),, -SO,NH, -
CONH(cyclopropyl), -CONHCH3, -CONHCH,CH3, or an optionally substituted group selected from -piperidinyl, piperizinyl, morpholino, phenyl, phenyloxy, benzyl, or benzyloxy; d) wherein y is 0-4, and R® groups, when present, are each independently Cl, Br, F,
CFs, Me, Et, CN, -COOH, -NH,, -N(CH3),, -N(Et)2, -N(iPr);, -O(CH,),OCH3, -CONH,, -
COOCH,, -OH, -OCH;, -OCH,CH;, -CH,0H, -NHCOCHS, -SO;NH,, -SO,NHC(CHs),, -
OCOC(CHs)3, -OCOCHC(CHa)s, -O(CH2):N(CHaz)2, 4-CHi-piperazin-1-yl, OCOCH(CHs),
OCO(cyclopentyl), -COCHjs, optionally substituted phenoxy, or optionally substituted benzyloxy; and e) R® is Cl, F, CFs, Me, Et, -OH, -OCH;, -OCH:CHs, -CH,OH, -SO;NH,, -
SO,NHC(CHs),, -OCOC(CHs)s, -OCOCH,C(CHs)s, -O(CHz)2N(CHa)z, 4-CH;-piperazin-1- yl, OCOCH(CHj3),,0CO(cyclopentyl), or -COCHj.
[00152] In yet other embodiments for compounds described directly above, x is 1 and R’is at the 6-position of the quinazoline ring and is -Cl, -CH;, -CH,CH;, -F, -CF3, -OCF;, -
CONHCH;, -CONHCH,CH;, -CONH(cyclopropyl), -OCH;, -NH,, -OCH,CHj, or -CN. In still other embodiments, x is 1 and R? is at the 7-position of the quinazoline ring and is -Cl, -
CH;, -CH.CHj, -F, -CF;, -OCF;, -CONHCH;, -CONHCH,CHs, -CONH(cyclopropyl), -
OCH, -NH,, -OCH,CHs, or -CN. In still other embodiments, x is 1 and R? is at the 6- position of the quinazoline ring and is -Cl, -CH;, -CH,CH;, -F, -CFs, -OCF;, -OCHj, or -
OCH,CH;. In yet other embodiments, x is 1 and R? is at the 7-position of the quinazoline ring and is -Cl, -CHs, -CH.CHs, -F, -CFs, -OCFs, -OCHs, or -OCH,CH;. In still other embodiments, x is 1 and R® is at the 6-position of the quinazoline ring and is ~CON(R™),, or
NRCOR’. In yet other embodiments, x is 1 and R? is at the 7-position of the quinazoline ring and is —CON(R");, or NRCOR’. In still other embodiments, R* is Cl, F, CFs, Me, Et, -OH, -
OCH;, -OCH,CH;.
[00153] In still other embodiments, y is 0, and R* is F. In yet other embodimentsy is 0, q is 1, and R* is OR’. In still other embodiments, y is 0, q is 1 and R* is OH. In yet other embodiments, y is 1, Ris OR’ and R® is F, wherein OR’ is substituted at the 2-position of the phenyl ring and F is substituted at the 6-position of the phenyl ring. In yet other embodiments, y is 1, R> is OH and RS is F, wherein OH is substituted at the 2-position of the phenyl ring and F is substituted at the 6-position of the phenyl ring.
[00154] For compounds described in this section above, in general, compounds are useful as inhibitors of ion channels, preferably voltage gated sodium channels and N-type calcium channels. In certain exemplary embodiments, compounds of the invention are useful as inhibitors of NaV1.8. In other embodiments, compounds of the invention are useful as inhibitors of NaV1.8 and CaV2.2. In still other embodiments, compounds of the invention are useful as inhibitors of CaV2.2. In yet other embodiments, compounds of the invention are useful as dual inhibitors of NaV1.8 and a TTX-sensitive ion channel such as NaVl.3 or
NaV1.7.
[00155] III. Compounds of formula IA-i:
RY, -R?
Nee JRO ag
RE),
TA-i or a pharmaceutically acceptable salt thereof, wherein R! and R? are each independently an optionally substituted group selected from Ci.saliphatic, Cy’, wherein Cy' is a 5-7-membered monocyclic aryl ring or an 8-10- membered bicyclic aryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or is a 3-12-membered saturated or partially unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein Cy' is bonded directly to the nitrogen atom or is bonded through an optionally substituted C,. saliphatic group, wherein one or more methylene units in the Caliphatic group are optionally replaced with -NR-, -O-, -C00, -0CO-, -NRCO-, -CONR-, -SO,NR-, or -NRSO,- . wherein R! and RZ, are each optionally and independently substituted at one or more substitutable carbon, nitrogen, or sulfur atoms with z independent occurrences of -R%, wherein z is 0-5; x is 1 and R? is substituted at either the 6- or 7-position of the quinazoline ring; y is 0-4; qis 0,1 or2;
cach occurrence of R?, R*, and R’ is independently Q-R%; wherein Q is abond or is a
C;-Cs alkylidene chain wherein up to two non-adjacent methylene units of Q are optionally and independently replaced by -NR-, -S-, -O-, -CS-, -CO2-, -0CO-, -CO-, -COCO-, -CONR-, _NRCO-, -NRCO;-, -SO;NR-, -NRSO,-, -CONRNR-, NRCONR-, -OCONR-, -NRNR-, -
NRSO,NR-, -SO-, -SO2-, -PO-, -PO2-, -OP(O)(OR)-, or -POR-; and each occurrence of R* is independently selected from -R’, =0, =NR’, halogen, -NOa, -CN, -OR’, -SR’, -N(R’)2, -
NR’COR’, -NR’CON(R’),, -NR’CO2R’, -COR’, -CO,R’, -OCOR’, -CON(R")z, -
OCON(R’)z, -SOR’, -SO2R’, -SO2N(R)2, _NR’SO,R’, -NR’SO,N(R")2, -COCOR’, -
COCH,COR’, -OP(O)(OR’);, -P(O)(OR’), -OP(0),0R’, -P(0),0R’, -POR’),, or -
OPO(R’)z; each occurrence of R> is independently an optionally substituted C;-Cgaliphatic group, halogen, -OR’, -SR’, NR’), NR’COR’, -NR'CON(R’),, -NR’CO:R’, -COR’, -
CO,R’, -OCOR’, -CON(R’),, -OCON(R");, -SOR’, -SO2R’, -SO,N(R’),, -NR’SO2R’, -
NR’SO,NR’)2, -COCOR’, -COCH,COR’, -OP(O)(OR")2, -P(O)(OR’),, -OP(0),0R’, -
P(0),0R’, -PO(R’),, or -OPO(R"),; and each occurrence of R is independently hydrogen or an optionally substituted C;.¢ aliphatic group; and each occurrence of R'is independently hydrogen or an optionally substituted Ci. aliphatic group, a 3-8-membered saturated, partially unsaturated, or tully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-12 membered saturated, partially unsaturated, or fully unsaturated bicyclic ring system having 0-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or R and R’, two occurrences of R, or two occurrences of R, are taken together with the atom(s) to which they are bound to form an optionally substituted 3-12 membered saturated, partially unsaturated, or fully unsaturated monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
[00156] In certain embodiments, for compounds described directly above: a) when R® is at the 7-position of the quinazoline ring then: i) when R? is Cl or Me, ring A is unsubstituted naphthyl, and R! is hydrogen, then R? is not «(CH,;):NMe;; ii) when R? is Cl, the sum of q and y is 1 and the phenyl ring is substituted at the 4-position with Br, and R! is hydrogen, then R? is not Cy', wherein Cy' is bonded to the nitrogen atom through an optionally substituted Cy saliphatic group, wherein one or more methylene units in the C;qaliphatic group are optionally replaced with -NR-, -O-, -COO, -
OCO-, -NRCO-, -CONR-, -SO,NR-, or -NRSO,-;
iii) when R® is Cl or OMe, the sum of q and y is 1 and the phenyl ring is substituted at the 4-position with either OMe or Cl, and R' is hydrogen, then R? is not —
CH(CH3)}(CH2)sN(Et)z; iv) when R® is Me, OMe, or NO?, and q and y are 0, then R! and R? are not both methyl; v) when R? is OMe, q and y are 0, and R! is hydrogen, then R? is not —SO,(4-
Me-phenyl); vi) when R? is F, the sum of g and y is 1 and the phenyl ring is substituted at the 2-position with Cl, and R! is hydrogen, then R? is not ~(CH;)morpholino; and b) a) when R? is at the 6-position of the quinazoline ring then: i) when R? is NHz, Me, Cl, Br, -NHAc, the sum of gq and y is 1 and the phenyl ring is substituted at the 4-position with F, or ring A is naphthyl, and Ris hydrogen, then R? is not (CH3)3-4N(R)2; ii) when R3 is -OCH,Ph, or OH, and q and y are 0, then when R is hydrogen,
R? is not Me, nBu, or —-(CH;),morpholino, or R! and R? are not simultaneously Me or Et; iii) when R® is Me or Cl, and the sum of q and y are 1, then the phenyl ring is not substituted in the 4-position with Br; iv) when R*is Cl, q and y are 0, and R! is hydrogen, then R? is not -SO,(4-
Me-phenyl); v) when R? is OMe, and q and y are 0, and R'is hydrogen, then R? is not —
CH,CH,0H or —~CH,CH,pyrrolidinyl; vi) when R? is Cl or Br, the sum of q and y is 1, and the phenyl ring is substituted in the 4-position with -CH,PO(OR’)2, then R! is not hydrogen when R? is Me, or
R! and R? are not simultaneously Me or Et; ‘ vii) when R? is OH and q and y are 0, then R! and R? are not simultaneously -
CH,CH,OMe;, viii) when Rs is Cl, the sum of q and y is 1 and the phenyl ring is substituted in the 2-position with OnPr, and R! is hydrogen, then R? is not —CHa(1,3-benzodioxol); ix) when R® is OMe, OH, Br, Cl, NO,, Me, and q and y are 0, then when R'is hydrogen, R? is not Me, -CH,CH,COOMe, -CH,COOMe, or (CH,);CH, or R' and R? are not simultaneously Me; and x) when R? is CI, the sum of q and y is 1 and the phenyl ring is substituted in the 4-position with Cl, then R! and R? are not simultaneously Me or iPr.
[00157] In certain other embodiments, for compounds described directly above: a) one of R' or R? is hydrogen, and the other of R' and R? is selected from: i) Cy' wherein Cy' is bonded directly to the nitrogen atom or is bonded through an optionally substituted C;.saliphatic group, wherein one or more methylene units in the Cy_4aliphatic group are optionally replaced with -NR-, -O-, -C00, -0OCO-, -NRCO-, -CONR-, -SO,NR-~, or -NRSO,-; or ii) an optionally substituted Cj4aliphatic group, wherein one or more methylene units in the Cjaliphatic group are optionally replaced with -NR-, -O-, -
COO, -OCO-, -NRCO-, -CONR-, -SO,NR-, or -NRSO,-; or i b) R! and R? are each independently selected from Cy', wherein Cy' is bonded directly to the nitrogen atom or is bonded through an optionally substituted Ci. : saliphatic group, wherein one or more methylene units in the C;4aliphatic group are optionally replaced with -NR-, -O-, -COO, -OCO-, -NRCO-, -CONR-, -SO,NR-, or -
NRSO,-; or an optionally substituted C;.qaliphatic group, wherein one or more methylene units in the Cj.4aliphatic group are optionally replaced with -NR-, -O-, -
COO-, -OCO-, -NRCO-, -CONR-, -SO;NR-, or -NRSO»-.
[00158] In still other embodiments, Cy' is: 2 IN N
SET Le HE JB) HL Se. a b € d (R, (A): _ RY, Ré
LG eT
N” N* “a 4 e f g h
NN NR i”
WE 3 SA Sa i i k 1
R* Re R R : e's 2 NN N .
S a ve J=n
Te,
m n o P
R* R* BR? eN A A oN N" 0 NE gy
CSE Ee wo: q r S t
NH CY on er 0 ~£) EGRET Ei J
SSVI Se Sy VN u v w X
H oN} ey A \(R*
CN RY, CNR, Te, +4 )z y z aa bb
[00159] In yet other embodiments, R! is hydrogen or an optionally substituted C;-
C,aliphatic group and R? is -CHR-Cy', wherein R is hydrogen or C-Caalkyl, and Cy' is: (RY) © NY PPAR NS = RY Sal a J SER ad, N a b ¢ d (RY): (RY), (RY, (RY,
LG gt i, e f g h
H 4
Nn-N Nx (R )z 4
N | 'N Fd 7 (RY), . N—~(R )z “WE, “ kS:3 4 Tp i J k I
Ré R* R* ; Ne TH NA on
S 4 o Se Ya m n 0 p
R4 Ré Re i" Oy Os HO) ve ra ve Eo 9 r s t
H
HO HE de FOr HES “me, NZI NP Nog,
H H u v w X
H
N
Fe, he, 5 i y z aa bb
[00160] In yet other embodiments, R! and R? groups are each independently an optionally substituted C.qaliphatic group and are each independently selected from optionally substituted methyl, ethyl, cyclopropyl, n-propyl, propenyl, cyclobutyl, (CO)OCH,CHj, (CH,),OCH3, CH,CO)OCH,CHj3, CH,(CO)OCH3;, CH(CH3)CH>CHj, or n-butyl.
[00161] In still other embodiments, for compounds described directly above, z is 0-5, and
R* groups, when present, are each independently halogen, CN, NO, -N(R’),, -CH,NRR’),, -
OR’, -CH,0R’, -SR’, -CH,SR’, -COOR’, -NRCOR’, -CON(R’),;, -OCON(R’);, COR’, -
NHCOOR’, -SO;R’, -SO;N(R’),, or an optionally substituted group selected from Ci.
Cealiphatic, aryl, heteroaryl, cycloaliphatic, heterocycloaliphatic, arylC;-Csalkyl, heteroarylC;-Csalkyl, cycloaliphaticC,-Csalkyl, or heterocycloaliphaticC;-Cgalkyl.
[00162] In yet other embodiments, z is 0-5 and R* groups are each independently Cl, Br, F,
CFs, CHj, -CH,CHj3, CN, -COOH, ~N(CHs)a, -N(Et),, -N(iPr),, -O(CH;);OCHj3, -CONH,, -
COOCH;, -OH, -CH,OH, -NHCOCH;, -SO,NH,, -SO;(CH,);CHs;, -SO,CH(CHj3),, -
SO,N(CH3),, -SO,CH;CH3, -C(O)OCH,CH(CH3),, -C(O)NHCH,CH(CH3),, -NHCOOCHj, -
C(O)C(CHz)s, -COO(CH,)CHs, -C(O)NHCH(CHz), -C(O)CHCHs, or an optionally substituted group selected from -piperidinyl, piperizinyl, morpholino, C,.4alkoxy, phenyl, phenyloxy, benzyl, benzyloxy, -CHacyclohexyl, pyridyl, -CHopyridyl, or -CH;thiazolyl.
[00163] In still other embodiments, for compounds described directly above, R® is halogen, CN, NO, -N(R’), -CH2N(R’);, -OR’, -CH,OR’, -SR’, -CH,SR’, -COOR’, -
NRCOR’, -CON(R’),, -OCON(R);, COR’, -NHCOOR’, -SO;R’, -SON(R’),, or an optionally substituted group selected from C,.Cgaliphatic, aryl, heteroaryl, cycloaliphatic, heterocycloaliphatic, arylC;-Cealkyl, heteroarylC;-Cealkyl, cycloaliphaticC,-Csalkyl, or heterocycloaliphaticC,-Cgalkyl.
[00164] In yet other embodiments, R? is Cl, Br, F, CFs, -OCF;, Me, Et, CN, -COOH, -
NH,, -N(CHa),, -N(Et);, -N(iPr);, -O(CH;),0CH3, -CONHb, -COOCH;, -OH, -OCHj, -
OCH,CH;, -CH,OH, -NHCOCH;, -NHCOCH(CHs), -SO.NH, -CONH(cyclopropyl), -
CONHCHs;, -CONHCH,CHs, or an optionally substituted group selected from -piperidinyl, piperizinyl, morpholino, phenyl, phenyloxy, benzyl, or benzyloxy.
[00165] In still other embodiments, R? is halogen, CN, optionally substituted C;-Cealkyl,
OR’, N(R’)2, CON(R"),, or NRCOR’. In yet other embodiments, R3 is -Cl, -CHj, -CH,CHj, -
F, -CFs;, -OCF,;, -CONHCH;, -CONHCH,CH;, -CONH(cyclopropyl), -OCHs, -NHz, -
OCH,CHa, or -CN. In still other embodiments, R3 is at the 6-position of the quinazoline ring and is -Cl, -CHs;, -CH,CHs, -F, -CF;, -OCF;, -CONHCH;, -CONHCHCHs, -
CONH(cyclopropyl), -OCHj, -NH,, -OCH,CHj, or -CN. In yet other embodiments, R? is at the 7-position of the quinazoline ring and is -Cl, -CH,, -CH,CH;, -F, -CF;, -OCE;, -
CONHCHj;, -CONHCH,CHs, -CONH(cyclopropyl), ~-OCHs, -NHa, -OCH;CHs, or -CN. In still other embodiments, R® is at the 6-position of the quinazoline ring and is Cl, -CH;, -
CH,CHj, -F, -CF3, -OCF;, -OCHj3, or -OCH,CH;. In yet other embodiments, R? is at the 7- position of the quinazoline ring and is -Cl, -CHs, -CH,CH3, -F, -CFs, -OCF;, -OCHj, or -
OCH,CHs. In still other embodiments, R%is at the 6-position of the quinazoline ring and is ~
CON(R’)2, or NRCOR’. In still other embodiments, R’ is at the 7-position of the quinazoline ring and is -CON(R’),, or NRCOR’.
[00166] In still other embodiments for compounds described directly above, y is 0-5, q is 0-2, and R® and R® groups, when present, are each independently halogen, CN, NO;, -
N(R’)2, -CHzN(R’),, -OR’, -CH0R’, -SR’, -CH;SR’, - -NRCOR’, -CON(R’)z, -S(O)2N(R’)z, -OCOR’, -COR’, -CO;R’, -OCON(R’);, -NR'SO;R’, -OP(O)OR’);, -P(O)OR’);, -
OP(0);0R’, -P(0),0R’, -PO(R’),, -OPO(R’),, or an optionally substituted group selected from C,Cealiphatic, aryl, heteroaryl, cycloaliphatic, heterocycloaliphatic, arylC;-Cealkyl, heteroarylC,-Cealkyl, cycloaliphaticC;-Cealkyl, or heterocycloaliphaticCi-Cealkyl.
[00167] In yet other embodiments, y is 0-5, and q is 1 or 2, and each occurrence of Ris independently Cl, Br, F, CFs, Me, Et, CN, -COOH, -NH;, ~N(CHa)s, -N(Et)2, -N(iPr), -
O(CH,),OCH;, -CONH,, -COOCH3, -OH, -OCHj, -OCH,CHs, -CH,OH, -NHCOCH;, -
SO,NH,, -SO,NHC(CHs),, -OCOC(CHz)s, -OCOCHC(CHz)s, -O(CH2),N(CH3),, 4-CHs- piperazin-1-yl, OCOCH(CHjs),, OCO(cyclopentyl), -COCHj, optionally substituted phenoxy, or optionally substituted benzyloxy.
[00168] In still other embodiments, y is 0, and Ris F. In yet other embodiments y is 0, q is 1, and R® is OR’. In still other embodiments, y is 0, q is 1 and R* is OH. In yet other embodiments, y is 1, Ris OR’ and R® is F, wherein OR’ is substituted at the 2-position of the phenyl ring and F is substituted at the 6-position of the phenyl ring. In yet other embodiments, y is 1, R** is OH and R’ is F, wherein OH is substituted at the 2-position of the phenyl ring and F is substituted at the 6-position of the phenyl ring.
[00169] In still other embodiments, R? is substituted at the 6-position of the quinazoline ring, q is 1, and y is 0, and compounds have formula I1X:
RL -R? 0
I
[00170] In certain embodiments, for compounds described above, a) R! and R? are each independently an optionally substituted group selected from Ci. ealiphatic, Cy', wherein Cy! is a 5-7-membered monocyclic aryl ring or an 8-10-membered bicyclic aryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or is a 3-12-membered saturated or partially unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein Cy' is bonded directly to the nitrogen atom or is bonded through an optionally substituted Cj.saliphatic group, wherein one or more methylene units in the Cj_4aliphatic group are optionally replaced with -NR-, -O-, -COO, -OCO-, -NRCO-, -CONR-, -SO;NR-, or -NRSO:-; wherein R! and
R?, are each optionally and independently substituted at one or more substitutable carbon, nitrogen, or sulfur atoms with z independent occurrences of -R*, wherein z is 0-5; b) z is 0-5 and R* groups are each independently Cl, Br, F, CFs, CH, -CH,CH;s, CN, -
COOH, —-N(CHs),, -N(Et),, -N(iPr),, -O(CH;);0CH;, -CONH,, -COOCH3, -OH, -CH,;0H, -
NHCOCH;, -SO,NH,, -SO»(CH;);CHj, -SO,CH(CHs), -SO.N(CHa), -SO,CH,CH3, -
C(O)OCH,CH(CH3);, -C(O)NHCHCH(CH3);, -NHCOOCH;, -C(O)C(CH3)3, -
COO(CH,),CH3, -C(O)NHCH(CHs),, -C(O)CH,CHj, or an optionally substituted group selected from -piperidinyl, piperizinyl, morpholino, Ci4alkoxy, phenyl, phenyloxy, benzyl, benzyloxy, -CHacyclohexyl, pyridyl, -CHzpyridyl, or -CH;thiazolyl; ¢) R® is Ql, Br, F, CFs, -OCF3, Me, Et, CN, -COOH, -NH,, -N(CHs),, -N(Et),, -
N(iPr);, -O(CH,),OCHs, -CONH;, -COOCH;, -OH, -OCH;, -OCH.CH;, -CH:OH, -
NHCOCH;, -NHCOCH(CH3);, -SO,NH,;, -CONH(cyclopropyl), -CONHCHs;, -
CONHCH,CH;, or an optionally substituted group selected from -piperidinyl, piperizinyl, morpholino, phenyl, phenyloxy, benzyl, or benzyloxy; and d) R® is Cl, F, CF;, Me, Et, -OH, -OCHj, -OCH,CH3, -CHOH, -SO:NH;, -
SO,NHC(CH3),, -OCOC(CHs)3, -OCOCH,C(CH3)s, -O(CH3);N(CH3),, 4-CHs-piperazin-1- yl, OCOCH(CH3),, OCO(cyclopentyl), or -COCHa.
[00171] In certain other embodiments, for compounds described directly above R? is -C}, -
CH;, -CH,CHs, -F, -CFs, -OCF;, -CONHCH;, -CONHCH.CHs, -CONH(cyclopropyl), -
OCH3;, -NH,, -OCH,CHs, or -CN. In still other embodiments, R3 is -Cl, -CH3, -CH,CHj, -F, -CFs, -OCF;, -OCHs, or -OCH,CH;. In yet other embodiments, R? is is -CON(R),, or
NRCOR’. In still other embodiments, R* is Cl, FE, CF, Me, Et, -OH, -OCH3, -OCH,CHs.
[00172] In still other embodiments, y is 0, and R?isF. In yet other embodimentsy is 0, q is 1, and R* is OR’. In still other embodiments, y is 0, q is 1 and R* is OH.
[00173] In certain other embodiments, for compounds described directly above: a) Cy' is:
Tg I NZD qe LE g 0 NS 4
ZA 5 : op SPR a b c d
(RY, (RY), RY, SRY);
NY 0 gt WY, 4! 4 bss NI
N” N” es Ho e f g h
H 4 -N — AR);
NT" NT (RY
IN IN Arr, PRL a “l Nod i J k 1
R4 R4 R4
R4
ESA'S TEE 5 WE. a
Ss ve o Mg J=N ~ a, m n 0 p
R* R4 R¢
A A A
= N No N” S FL =N 7 —
Wh, mg N d= N RY, q r 4] t
N 0
UY, SNCRLCIEE ENGEL ENV (R%), N N (R%); u v w xX
H
N Sa, oN CQ AK A(R
YOR) ONE, Lm, 0 y z aa bb or R! and R? are each independently an optionally substituted C_aliphatic group and are each independently selected from optionally substituted methyl, ethyl, cyclopropyl, n-propyl, propenyl, cyclobutyl, (CO)OCH,CHj, (CH,);OCH3, CH,CO)OCH,;CH3;, CH,(CO)OCH3,
CH(CH;)CH,CHj, or n-butyl; b) z is 0-5 and R* groups are each independently Cl, Br, F, CF;, CH3, -CH,CH3, CN, -
COOH, —N(CHz),, -N(Et),, -N(iPr),, -O(CH;),OCHj3, -CONHj,, -COOCHj3, -OH, -CH,0H, -
NHCOCH;, -SO;NH,, -SO»(CH2);CHs, -SO,CH(CHs);, -SO:N(CHs), -SO;CH:CHj, -
C(O)OCH,CH(CH3);, -C(O)NHCHCH(CHs),, -NHCOOCH;, -C(O)C(CH3);, -
COO(CHy),CH3, -C(O)NHCH(CHs);, -C(O)CH,CHs, or an optionally substituted group selected from -piperidinyl, piperizinyl, morpholino, C;.4alkoxy, phenyl, phenyloxy, benzyl, benzyloxy, -CH,cyclohexyl, pyridyl, -CHzpyridyl, or -CHathiazolyl; ¢) R? is Cl, Br, F, CFs, -OCFs, Me, Et, CN, -COOH, -NH,, -N(CHa)z, -N(Et),, -
N(iPr);, -O(CH,),OCH;, -CONH,, -COOCH;, -OH, -OCHs;, -OCH;CHs, -CH0H, -
NHCOCHs, -NHCOCH(CH:);, -SO,NH, -CONH(cyclopropyl), -CONHCHs, -
CONHCH,CHs, or an optionally substituted group selected from -piperidinyl, piperizinyl, morpholino, phenyl, phenyloxy, benzyl, or benzyloxy; and d) R* is Cl, F, CFs, Me, Et, -OH, -OCH;, -OCH,CH;, -CH;OH, -SO;NH,, -
SO,NHC(CHs),, -OCOC(CHz);, -OCOCH,C(CHs)s, -O(CH2)2N(CH3),, 4-CHs-piperazin-1- yl, OCOCH(CH3),,0CO(cyclopentyl), or -COCHs.
[00174] In certain embodiments, for compounds described directly above R3is -Cl, -CHs, -
CH,CHj, -F, -CFs, -OCF;, -CONHCH;, -CONHCH,CH3, -CONH(cyclopropyl), -OCHs, -
NH, -OCH,CHj, or -CN. In other embodiments, R® is -Cl, -CH3, -CH.CHs, -F, -CF3, -OCF;, -OCHs;, or -OCH,;CH;. In still other embodiments, R? is-CON(R");, or NRCOR’. In yet other embodiments, R*® is Cl, F, CFs, Me, Et, -OH, -OCH;, -OCH,CH;. In still other embodiments, y is 0, and R* is F. In yet other embodiments y is 0, q is 1, and R*®is OR’. In still other embodiments, y is 0, q is 1 and R> is OH.
[00175] In yet other embodiments, R? is substituted at the 7-position of the quinazoline ring, q is 1, and y is 0, and compounds have formula IV:
RL, -R? 508
Re 0
Iv a) wherein R! and R? are each independently an optionally substituted group selected from C,.aliphatic, Cy, wherein Cy' is a 5-7-membered monocyclic aryl ring or an 8-10- membered bicyclic aryl ring having 0-3 heteroatoms independently selected from nitrogen,
oxygen, or sulfur, or is a 3-12-membered saturated or partially unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein Cy! is bonded directly to the nitrogen atom or is bonded through an optionally substituted C;- saliphatic group, wherein one or more methylene units in the Cijaliphatic group are optionally replaced with -NR-, -O-, -COO, -OCO-, -NRCO-, -CONR-, -SO,NR-, or -NRSO>- : wherein R' and R?, are each optionally and independently substituted at one or more substitutable carbon, nitrogen, or sulfur atoms with z independent occurrences of —R%, wherein z is 0-5; b) z is 0-5 and R* groups are each independently Cl, Br, F, CF3, CH, -CH,CH;, CN, -
COOH, -N(CHs),, -N(Et),, -N(iPr),, -O(CH2);OCH3, -CONH3, -COOCH;, -OH, -CH,OH, -
NHCOCH;, -SO;NH,, -SO2(CH;);CHs, -SO,CH(CH3);, -SO.N(CH3);, -SO,CH,CHs, -
C(O)OCH,CH(CHs);, -C(O)NHCH,CH(CH3);, -NHCOOCH;, -C(O)C(CHs)s, -
COO(CH,),CHs, -C(O)NHCH(CH,);, -C(O)CH,CHs, or an optionally substituted group selected from -piperidinyl, piperizinyl, morpholino, Cj4alkoxy, phenyl, phenyloxy, benzyl, benzyloxy, -CHacyclohexyl, pyridyl, -CHapyridyl, or -CHythiazolyl; ¢) R? is Cl, Br, F, CFs, -OCF;, Me, Et, CN, -COOH, -NH;, -N(CHs)2, -N(Et),, -
N(iPr);, -O(CH,),OCH3, -CONH,, -COOCH3;, -OH, -OCH;, -OCH,CH,;, -CH,OH, -
NHCOCH;, -NHCOCH(CHs);, -SO,NH,;, -CONH(cyclopropyl), -CONHCH;, -
CONHCH,CHj, or an optionally substituted group selected from -piperidinyl, piperizinyl, morpholino, phenyl, phenyloxy, benzyl, or benzyloxy; and d) R® is Cl, F, CFs, Me, Et, -OH, -OCH3, -OCH,CH;, -CH,OH, -SO:NH;, -
SO,NHC(CHj3)2, -OCOC(CH3);, -OCOCH,C(CH3)s, -O(CH,):N(CH3),, 4-CHs-piperazin-1- yl, OCOCH(CHj3),, OCO(cyclopentyl), or -COCHs.
[00176] In certain embodiments, for compounds described directly above, R3 is -Cl, -CHj, -CH,CH;, -F, -CF;, -OCF;, -CONHCH;, -CONHCH,CHj3, -CONH(cyclopropyl), -OCHs, -
NH,, -OCH,CHj, or -CN. In other embodiments, R3 is -Cl, -CH3, -CH,CHa, -F, -CF, -
OCF;, -OCH;, or -OCH,CHj. In still other embodiments, R? is is -CON(R),, or NRCOR’.
In yet other embodiments, R>® is Cl, F, CFs, Me, Et, -OH, -OCHj3, -OCH,CHs. In still other embodiments, y is 0, and R* is F. In yet other embodiments y is 0, q is 1, and R* is OR’. In still other embodiments, y is 0, q is 1 and R> is OH.
[00177] In certain other embodiments, for compounds described directly above: a) Cy' is:
RO N
ON TA "Ne 2 (RY), NZ (R%)2 § 7 2 7 (R*), a b c d
Rk bike ny Fe (AF ~ a —N =
TOT bow
N° Ni a ed e f g h
H 4
N-N N(R )z Ré
IN NM N Ara (RY FN )z
Nod N 3 3 z 7 \ " (R*), he H AW Ty i j kK 1
N—~ (RY), oy Tl T i > po NN 0 N
S “ o Pe g d= , Mon, m n © P
R4 R4 R4
ETS
=n =N J=nN NX ne hn, oe (R%)z q r Ss t
H
NH NN ON No
TL J IN ——(R%); TL -—RY, — J
NNR, : Nw “\ pe
H H u v w X
AN] ¢ iN Ne PRG oT (RY), OEY, \__INRY), % ? y Zz aa bb or R! and R? are each independently an optionally substituted C; 4aliphatic group and are each independently selected from optionally substituted methyl, ethyl, cyclopropyl, n-propyl, propenyl, cyclobutyl, (CO)OCHCH3, (CHz),OCHs, CH,CO)OCH,CHj3;, CH;(CO)OCHs,
CH(CH3)CH,CH3, or n-butyl; b) z is 0-5 and R* groups are each independently Cl, Br, F, CFs, CH;, -CH,CHj3, CN, -
COOH, —N(CHs), -N(Et)y, -N(iPr),, -O(CH,),OCH3, -CONH,, -COOCH;, -OH, -CH,OH, -
NHCOCH;, -SO;NH,, -SO,(CH,)sCH;, -SO,CH(CHs),, -SO:N(CHs),, -SOCH,CHs, -
C(O)OCH,CH(CH3);, -C(O)NHCH,CH(CH;);, -NHCOOCH;, -C(O)C(CHs)s, -
COO(CH,),CHs, -C(O)NHCH(CH3;),, -C(O)CH,CHj;, or an optionally substituted group selected from -piperidinyl, piperizinyl, morpholino, Cj.alkoxy, phenyl, phenyloxy, benzyl, benzyloxy, -CHacyclohexyl, pyridyl, -CH,pyridyl, or -CHsthiazolyl; ¢) R? is Cl, Br, F, CFs, -OCF;, Me, Et, CN, -COOH, -NH;, -N(CH3),, -N(Et)2, -
N(@Pr),, -O(CH,),OCH;, -CONH;, -COOCH;, -OH, -OCHs, -OCH,CH;, -CH,OH, -
NHCOCH;, -NHCOCH(CHj3);, -SO,NH,;, -CONH(cyclopropyl), -CONHCH;, -
CONHCH,CHj, or an optionally substituted group selected from -piperidinyl, piperizinyl, morpholino, phenyl, phenyloxy, benzyl, or benzyloxy; and d) R® is Cl, F, CFs, Me, Bt, -OH, -OCHj;, -OCH,CH;, -CH;OH, -SO,NH,, -
SO,NHC(CHz),, -OCOC(CH3)3, -OCOCH,C(CHs);, -O(CH2),N(CH3),, 4-CHs-piperazin-1- yl, OCOCH(CH3;),,0CO(cyclopentyl), or -COCHs.
[00178] In certain other embodiments, for compounds described directly above R?is -Cl, -
CHs, -CH,CH;, -F, -CF;, -OCF;, -CONHCH;, -CONHCH>CH;, -CONH(cyclopropyl), -
OCH, -NHa, -OCH,CHs, or -CN. In other embodiments, R® is -Cl, -CHj, -CH,CHj, -F, -
CF3;, -OCF3, -OCH3, or -OCH,CH;. In still other embodiments, Rr? is—CON(R’);, or
NRCOR’. In yet other embodiments, R* is Cl, F, CFs, Me, Et, -OH, -OCHj, or -OCH,CHs.
In still other embodiments, y is 0, and R* is F. In yet other embodiments y is 0, q is 1, and
Ris OR’. In still other embodiments, y is 0, q is 1 and R** is OH.
[00179] For compounds described in this section above, in general, compounds are useful as inhibitors of ion channels, preferably voltage gated sodium channels and N-type calcium channels. In certain exemplary embodiments, compounds of the invention are useful as inhibitors of NaV1.8. In other embodiments, compounds of the invention are useful as inhibitors of NaV1.8 and CaV2.2. In still other embodiments, compounds of the invention are useful as inhibitors of CaV2.2. In yet other embodiments, compounds of the invention are useful as dual inhibitors of NaV1.8 and a TTX-sensitive ion channel such as NaV1.3 or
NaVl.7. } [00180] IV. Compounds of formula V:
RL -R?
NSN wm OC BN a (> (RO)
A wherein R' and R? are each independently an optionally substituted group selected from C,aliphatic, Cy!, wherein Cy' is a 5-7-membered monocyclic aryl ring or an 8-10- membered bicyclic aryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or is a 3-12-membered saturated or partially unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein Cy’ is bonded directly to the nitrogen atom or is bonded through an optionally substituted C;. saliphatic group, wherein one or more methylene units in the C;4aliphatic group are optionally replaced with -NR-, -O-, -COO, -OCO-, -NRCO-, -CONR-, -SO;NR-, or -
NRSO,-; or R' and R?, taken together with the nitrogen atom to which they are bound, form an optionally substituted 3-12-membered monocyclic or bicyclic saturated or partially unsaturated ring having 0-3 additional heteroatoms independently selected from nitrogen, sulfur, or oxygen; wherein R! and R?, or the ring formed by R! and R? taken together, are each optionally and independently substituted at one or more substitutable carbon, nitrogen, or sulfur atoms with z independent occurrences of —R*, wherein z is 0-5; x is 0-4; y is 0-2; each occurrence of R®, R®, and R® is independently Q-R*; wherein Q is abond or is a
C,-Cg alkylidene chain wherein up to two non-adjacent methylene units of Q are optionally and independently replaced by —NR-, -S-, -O-, -CS-, -CO,-, -0CO-, -CO-, -COCO-, -CONR-, -NRCO-, -NRCO;-, -SO,NR-, -NRSO;-, -CONRNR-, -NRCONR-, -OCONR-, -NRNR-, -
NRSO;NR-, -SO-, -SO2-, -PO-, -PO,-, -OP(O)(OR)-, or -POR-; and each occurrence of R* is independently selected from -R’, =O, =NR’, halogen, -NO3, -CN, -OR’, -SR’, -N(R")a, -
NR’COR’, -NR'CON(R’),, -NR’CO,R’, -COR’, -COzR’, -OCOR’, -CON(R’),, -
OCON(R’),, -SOR’, -SO;R’, -SO2N(R’)2, -NR’SO2R’, -NR’SO;N(R")2, -COCOR’, -
COCH,COR’, -OP(O)(OR’),, -P(O)XOR’),, -OP(0)0R’, -P(O), OR’, -PO(R™),, or -
OPO);
R* is an optionally substituted C;-Cealiphatic group, halogen, -OR’, -SR’, -N(R’),, -
NR’COR’, -NR’CON(R’),, -NR’CO;R’, -COR’, -COR’, -OCOR’, -CONR),, -
OCON(R’),, -SOR’, -SO,R’, -SON(R’)2, -NR’SO,R’, -NR’SO;N(R’)2, -COCOR’, -
COCH,COR’, -OP(O)(OR’),, -P(O)(OR’),, -OP(0),0R’, -P(0).0R’, -PO(R’),, or -
OPO(R’);; and each occurrence of R is independently hydrogen or an optionally substituted Ci. aliphatic group; and each occurrence of R’ is independently hydrogen or an optionally substituted C,_¢ aliphatic group, a 3-8-membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-12 membered saturated, partially unsaturated, or fully unsaturated bicyclic ring system having 0-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or R and R’, two occurrences of R, or two occurrences of R', are taken together with the atom(s) to which they are bound to form an optionally substituted 3-12 membered saturated, partially unsaturated, or fully unsaturated monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
[00181] In certain embodiments, for compounds described directly above, when x is 1 and
R? is 6-OMe, R' is hydrogen, and y and q are both 0, then R is not ~CH,CH,OCH,CH,0H or the monomethanesulfonate salt.
[00182] In certain other embodiments, for compounds described directly above, a) one of R! or R? is hydrogen, and the other of R! and R? is selected from: ij) Cy! wherein Cy' is bonded directly to the nitrogen atom or is bonded through an optionally substituted C,saliphatic group, wherein one or more methylene units in the C4aliphatic group are optionally replaced with -NR-, -O-, -COO, -OCO-, -NRCO-, -CONR-, -SO;NR-, or -NRSO,-; or ii) an optionally substituted Ci4aliphatic group, wherein one or more methylene units in the C)4aliphatic group are optionally replaced with -NR-, -O-, -
COO, -OCO-, -NRCO-, -CONR-, -SO;NR-, or -NRSO,-; or b) R! and R? are each independently selected from Cy', wherein Cy' is bonded directly to the nitrogen atom or is bonded through an optionally substituted C;. saliphatic group, wherein one or more methylene units in the Cj.4aliphatic group are optionally replaced with -NR-, -0-, -COO0, -OCO-, -NRCO-, -CONR-, -SO,;NR-, or -
NRSO,-; or an optionally substituted C,.qaliphatic group, wherein one or more methylene units in the Cyaliphatic group are optionally replaced with -NR-, -O-, -
COO-, -OCO-, -NRCO-, -CONR-, -SO,NR-, or -NRSO;-.
[00183] In other embodiments, Cy is: (RY). (N Nn s EVN PUN
Hi SRY 7 ®Y): oy $I (RY
J WW CP (Fo a b c d (RY; (R), (RY (RY 2% pA N=" % 22 2 HO XD
N” N* “th “g, e f g h
H 4
N-N N— (R )z 4 .N pu N £ Yr 4 . N(R )z
Nad { N43 (RY), fn \
R N 4 \ 1
Wf (A), “ N £5 T i J k (RY 7 A wt ~
LY ’ a NA oy
S ve Ve J=N
Mn, m n [1] P
R? R4 Ré
ST TEE SE
= i; 3 ~, ve N ve N Se, q r s t
N 0
N
HO) " . = Jr a Jr, = (R%)z N N (RY),
u v w X
H
N J, oN PN ed (RY) y z aa bb
[00184] In still other embodiments, R! is hydrogen or an optionally substituted Ci-
Cjaliphatic group and R? is -CHR-Cy', wherein R is hydrogen or C;-Caalkyl, and Cy! is: (R%)
Y 4 NT R4 fA NS 4
LJ ®: al CJ RY wd, N a b c d (R% R4 4 4
I
SULT Gow \
N’ Nig wd, “of e f g h
H
-N — (RY
NN NV" 72 4 { .N Ps N Lm (RY § N—~(R )z
AN 1 J nT z ~~ AN
R N \
Wf (R%), “ N S&F Ty i J k 1 4 R4 R* R*
R
Le js = oy
S 4 o Se = N ih, m n 0 p
R4 R4 R4 o~ No NP +L) =p 4 = "a, WN wl N SNR, q r Ss t
N 0
HOY pee HO HE
Zz
SNR, “y” N oi"
H H u v Ww x
H
N Sa, oN AN] > (AR),
CNR, CINRY, Xa a, +L y z aa bb
[00185] In still other embodiments, R! and R? groups are each independently an optionally substituted Cjaliphatic group and are each independently selected from optionally substituted methyl, ethyl, cyclopropyl, n-propyl, propenyl, cyclobutyl, (CO)OCH,CHs, (CH,),OCH3, CH,CO)OCH,CH;, CH2(CO)OCHs, CH(CH3)CH,CHj, or n-butyl.
[00186] In yet other embodiments for compounds described directly above, R! and R?, taken together with the nitrogen atom to which they are bound, form an optionally substituted 3-12 membered heterocyclyl ring having 1-3 heteroatoms independently selected from nitrogen or oxygen and form a 3-12 membered heterocyclyl group selected from: 4 4
Lom AA AA \ J .
L_NH L_o ce dd ee pee ry
N
MS (ye (ye
INRA, ff gg hh
A AR T i ~~ Y- N N 7 2 )
Ls NAY) /. : R?) ii jj kk
] \ \ N a A 7 J § :
RY “RY, NY, (RY), (BR) 11 mm nn 00 wherein the ring formed by R! and R? taken together, is optionally substituted at one or more substitutable carbon, nitrogen, or sulfur atoms with z independent occurrences of —
R*, and z is 0-5.
[00187] In other embodiments, for compounds of formula I-A, R! and R? taken together are optionally substituted azetidin-1-yl (jj), pyrrolidin-1-yl (ff), piperidinl-yl (dd), piperazin- 1-yl (ce), or morpholin-4-yl (ee). In other embodiments, for compounds of formula I-A, R! and R® taken together are optionally substituted azetidin-1-yl (jj), pyrrolidin-1-yl1 (ff), piperidinl-yl (dd), or piperazin-1-yl (cc). In yet other embodiments, for compounds of formula I-A, R! and R?, taken together is optionally substituted azetidin-1-yl (jj). In yet other embodiments, for compounds of formula I-A, R' and R? taken together is optionally substituted pyrrolidin-1-yl (ff). In still other embodiments, for compounds of formula I-A, R! and R?, taken together is optionally substituted piperidinl-yl (dd). In yet other embodiments, for compounds of formula I-A, R! and R?, taken together is optionally substituted piperazin- 1-yl (cc).
[00188] In still other embodiments, for compounds described directly above, z is 0-5, and
R* groups, when present, are each independently halogen, CN, NO,, -N(R’),, -CH2NR™),, -
OR’, -CH,OR’, -SR’, -CH,SR’, -COOR’, -NRCOR’, -CON(R’);, -OCON(R’)2, COR’, -
NHCOOR’, -SO;R’, -SO,N(R’);, or an optionally substituted group selected from C;.
Cealiphatic, aryl, heteroaryl, cycloaliphatic, heterocycloaliphatic, arylC;-Csalkyl, heteroarylC;-Csalkyl, cycloaliphaticC,-Cealkyl, or heterocycloaliphaticC;-Csalkyl.
[00189] In yet other embodiments, z is 0-5 and R* groups are each independently Cl, Br, F,
CFs, CHs, -CH,CHs, CN, -COOH, ~N(CHs),, -N(Et)2, -N(iPr)2, -O(CH2);0CHs, -CONH_y, -
COOCH;, -OH, -CH,OH, -NHCOCH;, -SO,NH, -SO»(CH);CHs, -SO.CH(CH3), -
SO,N(CHs),, -SO,CH,CH;, -C(O)OCH,CH(CH3),, -C(O)NHCH,CH(CHs)s, -NHCOOCHg3, -
C(O)C(CHa)s, -COO(CH,),CHs, -C(O)NHCH(CH3);, -C(O)CH,CH3, or an optionally substituted group selected from -piperidinyl, piperizinyl, morpholino, C,4alkoxy, phenyl, phenyloxy, benzyl, benzyloxy, -CHxcyclohexyl, pyridyl, -CH,pyridyl, or -CHjthiazolyl.
[00190] In certain embodiments, for compounds of formula I-A, R! and R?, taken together is optionally substituted azetidin-1-yl (jj), wherein z is 1 or 2 and at least one occurrence of
R* is -NRSO,R’, -NRCOOR’, or -NRCOR’. In certain other embodiments, for compounds of formula I-A, R! and R?, taken together is optionally substituted azetidin-1-yl (jj), wherein zis 1 and R* is -NRSO,R’. In other embodiments, for compounds of formula I-A, R' and
R?, taken together is optionally substituted azetidin-1-yl (jj), wherein z is 1 and R* is -
NRCOOR’. In certain other embodiments, for compounds of formula I-A, R' and R?, taken together is optionally substituted azetidin-1-yl (jj), wherein z is 1 and R*is -NRCOR’. In yet other embodiments, for compounds of formula I-A, R! and R?, taken together is optionally substituted pyrrolidin-1-yl (ff), wherein z is 1 or 2 and R*is Cl, Br, F, CFs, CHs, -CH,CH3, -
OR’, or -CH,OR’. In still other embodiments, for compounds of formula I-A, R! and R?, - taken together is optionally substituted piperidin-1-yl (dd), wherein z is 1 or 2 and at least one occurrence of R* is Cl, Br, F, CFs, CHs, -CH,CHj3, -OR’, or -CH,0R’, -NRSO:R’, -
NRCOOR’, or -OCON(R’),. In certain other embodiments, for compounds of formula I-A,
R! and R?, taken together is optionally substituted piperidin-1-yl (dd), wherein z is 1 and R* is F, CF;, CHs, -CH,CH3, -OR’, or -CH,OR’. In other embodiments, for compounds of formula I-A, R! and R?, taken together is optionally substituted piperidin-1-yl (dd), wherein z is 1 and R* is —NRSO,R’,. In certain other embodiments, for compounds of formula I-A, R! and RZ, taken together is optionally substituted piperidin-1-yl (dd), wherein z is 1 and Ris -
NRCOOR’. In yet other embodiments, for compounds of formula I-A, R! and R?, taken together is optionally substituted piperazin-1-yl (cc), wherein z is 1 or 2 and at least one occurrence of R* is =SOR’, -CON(R’)z, -SO2N(R’)2, COR’, or -COOR’. In certain other embodiments, for compounds of formula I-A, R! and R? taken together is optionally substituted piperazin-1-yl (cc), wherein z is 1 and R* is -SOR’. In certain other embodiments, for compounds of formula I-A, R! and R?, taken together is optionally substituted piperazin-1-yl (cc), wherein z is 1 and R* is -COOR’. In certain other embodiments, for compounds of formula I-A, R! and RZ taken together is optionally substituted piperazin-1-yl (cc), wherein z is 1 and R* is -CON(R’),. In certain other embodiments, for compounds of formula I-A, R' and R?, taken together is optionally substituted piperazin-1-yl (cc), wherein z is 1 and R* is -SO,N(R’);. In certain other embodiments, for compounds of formula I-A, R' and R? taken together is optionally substituted piperazin-1-yl (cc), wherein z is 1 and R* is -COR’.
[00191] In still other embodiments, x is 0-4, and R? groups, when present, are each independently halogen, CN, NO2, -N(R’), -CHoN(®R)2, -OR’, -CH,0R’, -SR’, -CH;SR’, -
COOR’, -NRCOR’, -CON(R’), -OCON(R");, COR’, -NHCOOR’, -SO;R’, -SO2N(R’)z, or an optionally substituted group selected from C;.Cealiphatic, aryl, heteroaryl, cycloaliphatic, heterocycloaliphatic, arylCj-Cealkyl, heteroarylCi-Cealkyl, cycloaliphaticCi-Cealkyl, or heterocycloaliphaticC;-Cgalkyl. In yet other embodiments, x is 1 or 2, and each occurrence of R%is independently Cl, Br, F, CFs, -OCF;, Me, Et, CN, -COOH, -NH,, —N(CHj3)s, -N(Et)2,
N(iPr);, -O(CH,),OCH;, -CONH;, -COOCH;, -OH, -OCHj;, -OCHCH;, -CH;OH, -
NHCOCH;, -NHCOCH(CHs);, -SO,NH,, -CONH(cyclopropyl), -CONHCHsz;, -
CONHCH,CHs, or an optionally substituted group selected from -piperidinyl, piperizinyl, morpholino, phenyl, phenyloxy, benzyl, or benzyloxy.
[00192] In still other embodiments, x is 1 or 2 and each R® group is independently halogen, CN, optionally substituted C;-Cgalkyl, OR’, N(R’)2, CON(R’);, or NRCOR’. In yet other embodiments, x is 1 or 2, and each rR? group is -Cl, -CHjs, -CH,CHs, -F, -CF3, -OCF;, -
CONHCHs;, -CONHCH,CHa;, -CONH(cyclopropyl), -OCH3, -NH,, -OCH,CHjs, or -CN. In still other embodiments, x is 1 and R? is at the 6-position of the quinazoline ring and is -Cl, -
CH;, -CH,CHa, -F, -CF;, -OCF;, -CONHCH;, -CONHCH,;CHs, -CONH(cyclopropyl), -
OCH3;, -NH,, -OCH,CHj, or -CN. In yet other embodiments, x is 1 and R3 is at the 7- position of the quinazoline ring and is -Cl, -CHs, -CH,CHj, -F, -CFs, -OCF3, -CONHCH3, -
CONHCH,CH3;, -CONH(cyclopropyl), -OCHj, -MH,, -OCH,CHj3, or -CN. In still other embodiments, x is 1 and R® is at the 6-position of the quinazoline ring and is -Cl, -CHj, -
CH,CHs, -F, -CF3, -OCF;, -OCH3, or -OCH,CHj3. In yet other embodiments, x is 1 and R’is at the 7-position of the quinazoline ring and is -Cl, -CHs, -CH,CHj, -F, -CF;, -OCF;3, -OCHs3, or -OCH,CH. In still other embodiments, x is 1 and R’ is at the 6-position of the quinazoline ring and is -CON(R’),, or NRCOR’. In yet other embodiments, x is 1 and R? is at the 7- position of the quinazoline ring and is -CON(R’),, or NRCOR’.
[00193] In still other embodiments for compounds described directly above, y is 0-2, q is 0-2, and R® and R® groups, when present, are each independently halogen, CN, NO,, -
NR’),, -CH2N(R)2, -OR’, -CH,0R’, -SR’, -CH,SR’, - -NRCOR’, -CON(R’)y, -S(0):N(R’), -OCOR’, -COR’, -COs;R’, -OCON(R’);, -NR’SO.R’, -OP(O)OR’);, -P(O)(OR’),, -
OP(0),0R’, -P(O);0R’, -PO(R’);, -OPO(R’),, or an optionally substituted group selected from C;.Cgaliphatic, aryl, heteroaryl, cycloaliphatic, heterocycloaliphatic, arylC;-Cgalkyl, heteroarylC;-Cealky), cycloaliphaticC;-Cgalkyl, or heterocycloaliphaticC;-Cealkyl.
[00194] In yet other embodiments, y is 0-2, and q is 1 or 2, and each occurrence of R¥®is independently Cl, Br, F, CFs, Me, Et, CN, -COOH, -NH;, -N(CHz),, -N(Et),, -N(Pr)z, -
O(CH;),0CH;, -CONH,, -COOCHj3, -OH, -OCHj, -OCH,CH;, -CH,OH, -NHCOCH;, -
SO.NH,, -SO;NHC(CHz);, -OCOC(CHs)s, -OCOCH,C(CHs)s, -O(CH2),N(CHs),, 4-CHs- ~ piperazin-1-yl, OCOCH(CH3)2, OCO(cyclopentyl), -COCHj, optionally substituted phenoxy, or optionally substituted benzyloxy.
[00195] In still other embodiments, y is 0, and q is 1 and R® is F. In yet other embodiments, y is 0, q is 1, and R53 is OR’. In still other embodiments, yis 0,qis 1 and R*® is OH. In yet other embodiments, y is 0, q is 2 and one occurrence of R* is OR’ and the other occurrence of R* is F. In yet other embodiments, y is 0, q is 2 and one occurrence of
Ris OH and the other occurrence of R* is F.
[00196] In still other embodiments: a) R' and R? taken together is an optionally substituted ring selected from azetidin-1- yl (J), pyrrolidin-1-yl (ff), piperidinl-yl (dd), or piperazin-1-yl (cc); one of R! or R? is hydrogen, and the other of R' and R? is selected from Cy!, wherein Cy' is bonded directly to the nitrogen atom or is bonded through an optionally substituted C;.4aliphatic group, wherein one or more methylene units in the C, 4aliphatic group are optionally replaced with -NR-, -O- , “COO, -OCO-, -NRCO-, -CONR-, -SO;NR-, or -NRSO,-, or an optionally substituted C;. qaliphatic group, wherein one or more methylene units in the Cj.jaliphatic group are optionally replaced with -NR-, -O-, -COO, -0CO-, -NRCO-, -CONR-, -SO,NR-, or -
NRSO;-; or R! and R? are each independently selected from an optionally substituted C;. saliphatic group, wherein one or more methylene units in the C,4aliphatic group are optionally replaced with -NR-, -O-, -COO, -OCO-, -NRCO-, -CONR-, -SO,NR-, or -
NRSO;-; or Cy’ wherein Cy’ is bonded to the nitrogen atom directly or is bonded through an optionally substituted C,;_saliphatic group, wherein one or more methylene units in the C,. saliphatic group are optionally replaced with -NR-, -O-, -COQ, -OCO-, -NRCO-, -CONR-, -
SO,NR-, or -NRSO»-; b) z is 0-5 and R* groups are each independently Cl, Br, F, CFs, CH3, -CH,CH;, CN, -
COOH, -N(CH3),, -N(Et)2, -N(iPr),, -O(CH,),OCHj3, ~-CONH;, -COOCHj3, -OH, -CH,OH, -
NHCOCH;, -SO,NH;, -SO(CH2);CHs, -SO,CH(CHs),, -SO,N(CHj)z, -SO,CH,CH;, -
C(O)OCHCH(CH3);, -C(O)NHCH,CH(CH3);, -NHCOOCH;, -C(O)C(CHj);, -
COO(CH,),CHj, -C(O)NHCH(CHjs);, -C(O)CH,CHs, or an optionally substituted group selected from -piperidinyl, piperizinyl, morpholino, Cy4alkoxy, phenyl, phenyloxy, benzyl, benzyloxy, -CHacyclohexyl, pyridyl, -CHopyridyl, or -CHathiazolyl; c) x is 0, 1, or 2, and each occurrence of Riis independently Cl, Br, F, CF;, -OCF;,
Me, Et, CN, -COOH, -NH,, -N(CH;);, -N(Et);, -N(@iPr);, -O(CH2)0CHs, -CONHa, -
COOCH;, -OH, -OCHj, -OCH,CHj3, -CH,0H, -NHCOCH;, -NHCOCH(CH3)2, -SO,NH,, -
CONH(cyclopropyl), -CONHCH;, -CONHCH,CH3, or an optionally substituted group selected from -piperidinyl, piperizinyl, morpholino, phenyl, phenyloxy, benzyl, or benzyloxy; d) wherein y is 0-2, and R’ groups, when present, are each independently Cl, Br, F,
CFs, Me, Et, CN, -COOH, -NH,, -N(CH3),, -N(Et);, -N(iPr), -O(CH,);OCH3;, -CONHy, -
COOCH;, -OH, -OCH;, -OCH,;CH;, -CH,0H, -NHCOCH;3;, -SO,NH;, -SO,NHC(CHs),, -
OCOC(CH3);, -OCOCH,C(CHs)3, -O(CH;),N(CH3),, 4-CHj3-piperazin-1-yl, OCOCH(CHs),,
OCO(cyclopentyl), -COCH3, optionally substituted phenoxy, or optionally substituted benzyloxy; and e) R*® is Cl, F, CFs, Me, Et, -OH, -OCHs, -OCH,CHs, -CHOH, -SO,NHy, -
SO,NHC(CHj3),, -OCOC(CHj3)3, -OCOCH,C(CHjs)s, -O(CH_);N(CH3);, 4-CH;-piperazin-1- yl, OCOCH(CH3),, OCO(cyclopentyl), or -COCHs.
[00197] In yet other embodiments, for compounds of formula I-A, R! and RZ, taken together is optionally substituted azetidin-1-yl (jj). In yet other embodiments, for compounds of formula I-A, R” and R?, taken together is optionally substituted pyrrolidin-1-yl (ff). In still other embodiments, for compounds of formula I-A, R' and R? taken together is optionally substituted piperidinl-yl (dd). In yet other embodiments, for compounds of formula I-A, R! and R?, taken together is optionally substituted piperazin-1-yl (cc).
[00198] In certain embodiments, for compounds of formula I-A, R! and R?, taken together is optionally substituted azetidin-1-yl (jj), wherein z is 1 or 2 and at least one occurrence of
R* is -NRSO;R’, -NRCOOR’, or -NRCOR’. In certain other embodiments, for compounds of formula I-A, R! and R?, taken together is optionally substituted azetidin-1-yl (jj), wherein z is 1 and R* is -NRSO,R’. In other embodiments, for compounds of formula I-A, R! and
R?, taken together is optionally substituted azetidin-1-yl (jj), wherein z is 1 and R* is -
NRCOOR’. In certain other embodiments, for compounds of formula I-A, R! and R?, taken together is optionally substituted azetidin-1-yl (jj), wherein z is 1 and R* is -NRCOR’. In yet other embodiments, for compounds of formula I-A, R' and R?, taken together is optionally substituted pyrrolidin-1-yl (ff), wherein z is 1 or 2 and R*is C1, Br, F, CFs, CHs, -CH,CH;, -
OR’, or -CH,OR’. In still other embodiments, for compounds of formula I-A, R! and R?,
taken together is optionally substituted piperidin-1-yl (dd), wherein z is 1 or 2 and at least one occurrence of R? is Cl, Br, F, CFs, CH;, -CH,CHjs, -OR’, or -CHOR’, -NRSO,R’, -
NRCOOR’, or -OCON(R’),. In certain other embodiments, for compounds of formula I-A,
R! and R?, taken together is optionally substituted piperidin-1-yl (dd), wherein z is 1 and R* is F, CFs, CHs, -CH,CHj, -OR’, or -CH,OR’. In other embodiments, for compounds of formula I-A, R! and R?, taken together is optionally substituted piperidin-1-yl (dd), wherein z is 1 and R* is —NRSO,R’,. In certain other embodiments, for compounds of formula I-A, R! and R?, taken together is optionally substituted piperidin-1-yl (dd), wherein z is 1 and R* is -
NRCOOR’. In yet other embodiments, for compounds of formula I-A, R! and R?, taken together is optionally substituted piperazin-1-yl (cc), wherein z is 1 or 2 and at least one occurrence of R* is —SOR’, -CONR),, -SO,N(R’),, -COR’, or -COOR’. In certain other embodiments, for compounds of formula I-A, R! and R? taken together is optionally substituted piperazin-1-yl (cc), wherein z is 1 and R* is —-SOR’. In certain other embodiments, for compounds of formula I-A, R! and R? taken together is optionally substituted piperazin-1-yl (ec), wherein z is 1 and R* is -COOR’. In certain other embodiments, for compounds of formula I-A, R' and R? taken together is optionally substituted piperazin-1-yl (ce), wherein z is 1 and R* is -CON(R’);. In certain other embodiments, for compounds of formula I-A, R' and R? taken together is optionally substituted piperazin-1-yl (cc), wherein z is 1 and R* is -SO,N(R’);. In certain other embodiments, for compounds of formula I-A, R' and R? taken together is optionally substituted piperazin-1-yl (ee), wherein z is 1 and R*is-COR’.
[00199] In yet other embodiments for compounds described directly above, x is 1 and Ris at the 6-position of the quinazoline ring and is -Cl, -CHs, -CH,CH;, -F, -CF;, -OCF3, -
CONHCH;, -CONHCH,CH3;, -CONH(cyclopropyl), -OCHs, -NH3, -OCH,CHj, or -CN. In still other embodiments, x is 1 and R? is at the 7-position of the quinazoline ring and is -Cl, -
CH;, -CH,CH;, -F, -CF;, -OCF;, -CONHCH;, -CONHCH;CH3, -CONH(cyclopropyl), -
OCH, -NH,, -OCH,CH3, or -CN. In yet other embodiments, x is 1 and R? is at the 6- position of the quinazoline ring and is -Cl, -CHj, -CH,CH3, -F, -CF;, -OCF,, -OCHj3, or -
OCH,CHj;. In still other embodiments, x is 1 and R3 is at the 7-position of the quinazoline ring and is -Cl, -CHs, -CH;CHj3, -F, -CFs, -OCF;, -OCH;, or -OCH,;CH;. In yet other embodiments, x is 1 and R> is at the 6-position of the quinazoline ring and is -CON(R’),, or
NRCOR’. In yet other embodiments, x is 1 and R3 is at the 7-position of the quinazoline ring and is -CON(R’);, or NRCOR’. In yet other embodiments, Ris Cl, F, CFs, Me, Et, -OH, -
OCH;, -OCH,CHs. In still other embodiments, y is 0, and q is 1 and R*¥isF. In yet other embodiments, y is 0, q is 1, and Ris OR’. In still other embodiments, y is 0, q is 1 and R*® is OH. In yet other embodiments, y is 0, q is 2 and one occurrence of R* is OR’ and the other occurrence of R* is F. In yet other embodiments, y is 0, q is 2 and one occurrence of
R* is OH and the other occurrence of Ris F.
[00200] In certain embodiments, for compounds described directly above, a) Cy' is: (R* 0 R4 NZD ca LES eS 4
PZ (R%)z lye J z CA FU JR )z “wf N a b [ d (R%) (R%), R4 Rr?
BN HE) Ge NH 7
N” N* “a 4 e f g h
H
-N — (RY
N7 NV" /z 4
IN | N & a 4 . N—~(R )z
SIN ON
R N ~ /
Wf (R*), oN LS TS i J k 1 4 R4 R* R?
R
ES = NA NA oA
Cg PS , RY N an, m n 0 p
R? R4 R4 sy PN A
J=N = 1 J EN on we, N Ve N (R%), q r Ss t
H
HO HE Fe Hoye HED
SN mh, NE Nw NR,
H H u v w X
N >
Ep, te, Le, a y z aa bb or R! and R? are each independently an optionally substituted C;4aliphatic group and are each independently selected from optionally substituted methyl, ethyl, cyclopropyl, n-propyl, propenyl, cyclobutyl, (CO)OCH,CH;3, (CH,),OCH3, CH,CO)OCH,CHj3;, CH(CO)OCHs3,
CH(CH3)CH,CHj, or n-butyl; b) z is 0-5 and R* groups are each independently Cl, Br, F, CFs, CHs, -CH,CH, CN, -
COOH, -N(CHjs),, -N(Et)2, -N(iPr);, -O(CH;),OCHj3, -CONH;, -COOCH3, -OH, -CH,0H, -
NHCOCH;, -SO;NH,, -SO,(CH;);CH;, -SO,CH(CHj);, -SO,N(CHj3);, -SO.CH,CHs, -
C(O)OCH,CH(CH3);, -C(O)NHCH,CH(CH;);, -NHCOOCH;, -C(O)C(CH3);, -
COO(CH,),CHs, -C(O)NHCH(CHj3),, -C(O)CH,CHs, or an optionally substituted group selected from -piperidinyl, piperizinyl, morpholino, C;salkoxy, phenyl, phenyloxy, benzyl, benzyloxy, -CH,cyclohexyl, pyridyl, -CHopyridyl, or -CHjthiazolyl; ¢) x is 0, 1, or 2, and each occurrence of R? is independently Cl, Br, F, CFs, -OCF;,
Me, Et, CN, -COOH, -NH;, -N(CHjs),, -N(Et);, -N(iPr);, -O(CH2);OCH3, -CONH;, -
COOCH;3;, -OH, -OCHs, -OCH,;CH;j, -CH;0H, -NHCOCH3;3, -NHCOCH(CHs),, -SO,NHy, -
CONH(cyclopropyl), -CONHCHj3;, -CONHCH,CH3;, or an optionally substituted group selected from -piperidinyl, piperizinyl, morpholino, phenyl, phenyloxy, benzyl, or benzyloxy; d) wherein y is 0-5, and R® groups, when present, are each independently Cl, Br, F,
CFs, Me, Et, CN, -COOH, -NH;, -N(CHj3),, -N(Et),, -N(iPr)2, -O(CH;),OCH3;, -CONH,, -
COOCH;, -OH, -OCHj;, -OCH,CHj;, -CH,OH, -NHCOCH;, -SO,NH,, -SO,NHC(CHj),, -
OCOC(CHs3);, -OCOCH,C(CHa)s, -O(CH,).N(CH3),, 4-CH;-piperazin-1-yl, OCOCH(CHj3),,
OCO(cyclopentyl), -COCHaj, optionally substituted phenoxy, or optionally substituted benzyloxy; and e) R® is Cl, F, CFs, Me, Et, -OH, -OCHj, -OCH,CH;, -CH,OH, -SO,NH,, -
SO,NHC(CH3),, -OCOC(CHjs)s, -OCOCH,C(CHs)s, -O(CH2):N(CH3),, 4-CHs-piperazin-1- yl, OCOCH(CHs),,0CO(cyclopentyl), or -COCHjs.
[00201] In yet other embodiments for compounds described directly above, x is 1 and R? is at the 6-position of the quinazoline ring and is -Cl, -CH3, -CH,CHs, -F, -CF;, -OCF;, -
CONHCH3;, -CONHCH,CH3;, -CONH(cyclopropyl), -OCHs, -NH,, -OCH,CHs, or -CN. In still other embodiments, x is 1 and R is at the 7-position of the quinazoline ring and is -Cl, -
CHj;, -CHCH;, -F, -CF;, -OCF;, -CONHCH;, -CONHCH,CHj, -CONH(cyclopropyl), - : OCH, -NH,, -OCH,CHs, or -CN. In yet other embodiments, x is 1 and R? is at the 6- position of the quinazoline ring and is -Cl, -CH;, -CH,CH;3, -F, -CF;, -OCF;, -OCHs, or -
OCH,CH;. In still other embodiments, x is 1 and R? is at the 7-position of the quinazoline ring and is -Cl, -CHs, -CH,CHj3, -F, -CF3, -OCF3, -OCHjs, or -OCH,CH;. In yet other embodiments, x is 1 and R® is at the 6-position of the quinazoline ring and is ~CON(R),, or
NRCOR’. In yet other embodiments, x is 1 and R? is at the 7-position of the quinazoline ring and is -CON(R’),, or NRCOR’. In yet other embodiments, Ris Cl, F, CFs, Me, Et, -OH, -
OCHs, -OCH,CHs. In still other embodiments, y is 0, and q is 1 and R®isF. In yet other embodiments, y is 0, q is 1, and R*® is OR’. In still other embodiments, y is 0, q is 1 and R® is OH. In yet other embodiments, y is 0, q is 2 and one occurrence of R> is OR’ and the other occurrence of R*® is F. In yet other embodiments, y is 0, q is 2 and one occurrence of
Ris OH and the other occurrence of R* is F.
[00202] For compounds described in this section above, in general, compounds are useful as inhibitors of ion channels, preferably voltage gated sodium channels and N-type calcium channels. In certain exemplary embodiments, compounds of the invention are useful as inhibitors of NaV1.8. In other embodiments, compounds of the invention are useful as inhibitors of NaV1.8 and CaV2.2. In still other embodiments, compounds of the invention are useful as inhibitors of CaV2.2. In yet other embodiments, compounds of the invention are useful as dual inhibitors of NaV1.8 and a TTX-sensitive ion channel such as NaV1.3 or
NaV1l.7.
[00203] V. Compounds of formula I-B-i:
RL, } or N R% re =
I-B-i or a pharmaceutically acceptable salt thereof, wherein R! is selected from C,-¢aliphatic, Cy', wherein Cy' is a 5-7-membered monocyclic aryl ring or an 8-10-membered bicyclic aryl ring having 0-3 heteroatoms : independently selected from nitrogen, oxygen, or sulfur, or is a 3-12-membered saturated or partially unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein Cy! is bonded directly to the nitrogen atom or is bonded through an optionally substituted C.4aliphatic group, wherein one or more methylene units in the C)4aliphatic group are optionally replaced with -NR-, -O-, -COO, -OCO-, -NRCO-, -
CONR-, -SO;NR-, or -NRSO,-; wherein R! is optionally substituted at one or more substitutable carbon, nitrogen, or sulfur atoms with z independent occurrences of RR, wherein z is 0-5; x is 0-4; y is 0-4; each occurrence of R®, R®, and R’ is independently Q-R; wherein Q is a bond or is a
C;-Cs alkylidene chain wherein up to two non-adjacent methylene units of Q are optionally and independently replaced by -NR-, -S-, -O-, -CS-, -CO,-, -OCO-, -CO-, -COCO-, -CONR-, -NRCO-, -NRCO5-, -SO;NR-, -NRSO;3-, -CONRNR-, -NRCONR-, -OCONR-, -NRNR-, -
NRSO,;NR-, -SO-, -SO5-, -PO-, -PO,-, -OP(O)(OR)-, or -POR-; and each occurrence of R*is independently selected from -R’, =O, =NR’, halogen, -NO,, -CN, -OR’, -SR’, -N(R’),, -
NR’COR’, -NR’CON(R’),, -NR’CO;R’, -COR’, -CO,R’, -OCOR’, -CON(R’)2, -
OCON(R)z, -SOR’, -SO,R’, -SO;N(R’),, -NR’SO,R’, -NR’SO,N(R’),, -COCOR’, -
COCH,;COR’, -OP(O)(OR’),, -P(0O)(OR’);, -OP(0),0R’, -P(O);0R’, -PO(R’),, or -
OPO); each occurrence of R* is independently an optionally substituted C,-Csaliphatic group, halogen, -OR’, -SR’, -N(R’);, -NR’COR’, -NR’CON(R’),, -NR’CO2R’, -COR’, -
COR’, -OCOR’, -CON(R’), -OCON(R")3, -SOR’, -SO4R’, -SO,N(R’),, -NR’SOsR’, -
NR’SO;N(R’),, -COCOR’, -COCH,COR’, -OP(O)(OR"),, -P(O)(OR’),, -OP(O), OR’, -
P(0);0R’, -PO(R’),, or -OPO(R’),; and each occurrence of R is independently hydrogen or an optionally substituted Cj. aliphatic group; and each occurrence of R'is independently hydrogen or an optionally substituted C;.¢ aliphatic group, a 3-8-membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-12 membered saturated, partially unsaturated, or fully unsaturated bicyclic ring system having 0-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or R and R’, two occurrences of R, or two occurrences of R’, are taken together with the atom(s) to which they are bound to form an optionally substituted 3-12 membered saturated, partially unsaturated, or fully unsaturated monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
[00204] For compounds described directly above, in certain embodiments, a) when R>? is Me, Cl, or OMe, and x is 0, then R! is not Et or Me; b) when Ris Cl, x is 3, and the three occurrences of R3 are 6-Me, 7-COOEt, and 8-
Me, then R! is not «(CH,),piperidin-1-yl; c) when R* is Me, x is 1 and R’ is NO, or NH, then R' is not Et; d) when R* is OH, NHMe, or N(NO)Me, and x is 0, then R' is not Et, Me or —
CH,CH=CHy; e) when R™ is NHZ, and x is 0, then R' is not ~COCH; f) when R* is Cl or Me, and y is O or 1 and when y is 1, R® is 4-C}, and x is 0, then R' is not 4-CN-phenyl, 4-Me-phenyl, 4-OMe-phenyl, 4-Cl-phenyl, 4-NO,-phenyl, -
CH,CH,NHMe, Et, Me, 4-COOMe-phenyl, -CH,Ph, iPr, 2-Me-phenyl, 4-phenyl-phenyl, or —-
CH,CH=CHo.
[00205] For compounds described directly above, in certain other embodiments, a) R! is selected from: i) Cy' wherein Cy' is bonded directly to the nitrogen atom or is bonded through an optionally substituted C,.saliphatic group, wherein one or more methylene units in the C;4aliphatic group are optionally replaced with -NR-, -O-, -COO, -OCO-, -NRCO-, -CONR-, -SO,NR-, or -NRSO»-; or ii) an optionally substituted Cj.saliphatic group, wherein one or more methylene units in the C;4aliphatic group are optionally replaced with -NR-, -O-, -
COO, -OCO-, -NRCO-, -CONR-, -SO,NR-, or -NRSO,-.
[00206] For compounds described directly above, in certain embodiments Cy! is,
oN NP APN Ns =r, RY i A
J he z C7 >> a b c d (RY (R%). R4 - (R?
PL pe y © )2 y 54 )2 g SN Le wad ve e f g h § (RY)
NS Nx z 4 .N J N La (RY fF NF )z
AN 7 z 7 ON " (RY), “NY LS Tp i j k 1 \ - x | R4 =%4 hE)
Ry po. a on
Ao A he, m n [1] | YJ
R4 R4 R4
Se IEE c SS va Ve N SNE, q r Ss t a A Oo
NH CY CN me 0
J —- S(R%, - TR): —C
NEVI ANP Co NEV
H H z u Vv w X
A N >
AN) 2:4 (Re
EC INRY, TNR, Lr, + (R%); y z aa bb
[00207] In other embodiments, R! is~-CHR-Cy’, wherein R is hydrogen or C;-Cjalkyl, and
Cy' is: 7 NZ A NS
J (I m4 ik Sl ( =: 5J (RY; J : Co a b c d (RY), (RY); _ RY, (RY)
LYS gt ND
NY SN vi “ e f g h
WN Nc Fe Ss § N (R% i oN Po] 72 -(RY, . ad z “NE, “N 3 Tp i J k 1 i” R4 R4 R4
AEN TS 5 To
S o g =\ hs *, va m n o p
R4 Rt R4
Co Wo Ws +)
Mo, MG, g, (R%)2 q r Ss t a N oO _
CNH eM 0 WINE Wel
J Cw, FC Te. FE “Xa, : ' Sy “Re, u v w p.
A ; >
AN AK (RY),
CRY, CNR), THs 5, +4 R)
y Zz aa bb
[00208] In still other embodiments, R’ is an optionally substituted C, aliphatic group and are each independently selected from optionally substituted methyl, ethyl, cyclopropyl, n- propyl, propenyl, cyclobutyl, (CO)OCH,CH;, (CH,),OCHS,, CH,CO)OCH,CHs,
CH,(CO)OCH;3, CH(CH;3)CH,CHj, or n-butyl.
[00209] In yet other embodiments, z is 0-5, and R* groups, when present, are each independently halogen, CN, NO,, -N(R’);, -CH,N(R’),, -OR’, -CH,0R’, -SR’, -CH,SR’, -
COOR’, -NRCOR’, -CON(R’)2, -OCON(R’),, COR’, -NHCOOR’, -SO,R’, -SO,N(R’),, or an optionally substituted group selected from C; Csaliphatic, aryl, heteroaryl, cycloaliphatic, heterocycloaliphatic, arylC,-Cgalkyl, heteroarylC;-Csalkyl, cycloaliphaticC;-Cgalkyl, or heterocycloaliphaticC-Cealkyl.
[00210] In still other embodiments, z is 0-5 and R* groups are each independently Cl, Br,
F, CFs, CHa, -CH,CHs, CN, -COOH, ~N(CHa),, -N(Et),, -N(iPr),, -O(CH,), OCH, -CONH,, -COOCH;3, -OH, -CH,OH, -NHCOCH;, -SO,NH,, -SOxCH,):CHs, -SO.CH(CHs),, -
SO2N(CHj),, -SO2CH,CH, -C(O)OCH,CH(CHs),, -C(O)NHCH,CH(CH;),, -NHCOOCH;, -
C(O)C(CHs);, -COO(CH),CH;, -C(O)NHCH(CHs),, -C(O)CH,CH;, or an optionally substituted group selected from -piperidinyl, piperizinyl, morpholino, Cisalkoxy, phenyl, phenyloxy, benzyl, benzyloxy, -CHacyclohexyl, pyridyl, -CH,pyridyl, or -CH;thiazolyl.
[00211] In yet other embodiments, R® is halogen, CN, NO,, -N(R’);, -CH,NR’),, -OR’, -
CH:OR’, -SR’, -CH,SR’, -COOR’, -NRCOR’, -CON(R’); -OCON(R’), COR’, -
NHCOOR’, -SO;R’, -SO;N(R’),, or an optionally substituted group selected from C;.
Cealiphatic, aryl, heteroaryl, cycloaliphatic, heterocycloaliphatic, arylC,-Cgalkyl, heteroarylC;-Cgalkyl, cycloaliphaticC;-Cealkyl, or heterocycloaliphaticC;-Cgalkyl.
[00212] In still other embodiments, R3 is Cl, Br, F, CFs, -OCF;, Me, Et, CN, -COOH, -
NH, -N(CHz);, -N(Et)z, -N(iPr),, -O(CH;),0CH3, -CONH,, -COOCHj3, -OH, -OCHs, -
OCH;CHj;, -CH,OH, -NHCOCH;, -NHCOCH(CH:),, -SO,NH,, -CONH(cyclopropyl), -
CONHCHj3, -CONHCH,CHj, or an optionally substituted group selected from -piperidinyl, piperizinyl, morpholino, phenyl, phenyloxy, benzyl, or benzyloxy.
[00213] In yet other embodiments, R® is halogen, CN, optionally substituted C;-Cealkyl,
OR’, N(R’), CON(R’);, or NRCOR’. In still other embodiments, R? is -Cl, -CHs;, -CH,CH;, -F, -CFs, -OCF;, -CONHCH;, -CONHCH,CH;, -CONH(cyclopropyl), -OCHi, -NH,, -
OCH,CHj, or -CN. In yet other embodiments, R? is at the 6-position of the quinazoline ring and is -Cl, -CHs, -CH,CH;, -F, -CFs;, -OCF;, -CONHCHs;, -CONHCH,CH;, -
CONH(cyclopropyl), -OCH;, -NH;, -OCH,CH3, or -CN. In still other embodiments, R is at the 7-position of the quinazoline ring and is -Cl, -CHs, -CH,CHj, -F, -CFs, -OCF;, -
CONHCH3;, -CONHCH,CHj3;, -CONH(cyclopropyl), ~-OCH3, -NH,, -OCH,CH3, or -CN. In yet other embodiments, R® is at the 6-position of the quinazoline ring and is -Cl, -CH, -
CH,CHj, -F, -CF;, -OCF3, -OCHs, or -OCH,CH;. In still other embodiments, R? is at the 7- position of the quinazoline ring and is -Cl, -CH3, -CH,CHj, -F, -CFs, -OCF;, -OCHj, or -
OCH,CH3. In other embodiments, R? is at the 6-position of the quinazoline ring and is —
CON(R’),, or NRCOR’. In yet other embodiments, R3 is at the 7-position of the quinazoline ring and is -CON(R’),, or NRCOR”.
[00214] In yet other embodiments, for compounds described directly above, y is 0-5, q is 0-2, and R® and R® groups, when present, are each independently halogen, CN, NO,, -
NR"),, -CHoN(R’),, -OR’, -CH,0R’, -SR’, -CH,SR’, - -NRCOR’, -CON(R’),, -S(0),N(R’),, -OCOR’, -COR’, -COzR’, -OCON(R’)2, -NR’SO:R’, -OP(O)(OR’),, -P(O)(OR’),, -
OP(O),0R’, -P(O).0R’, -POR’);, -OPO(R’);, or an optionally substituted group selected from Ci.Cealiphatic, aryl, heteroaryl, cycloaliphatic, heterocycloaliphatic, arylC;-Csalkyl, heteroarylC;-Csalkyl, cycloaliphaticC;-Csalkyl, or heterocycloaliphaticC;-Csalkyl.
[00215] In still other embodiments, y is 0-5, and q is 1 or 2, and each occurrence of Ris independently Cl, Br, F, CF;, Me, Et, CN, -COOH, -NH,, -N(CHs),, -N(Et),, -N(iPr),, -
O(CH;)0CHj3, -CONH;, -COOCH3, -OH, -OCH;, -OCH,CHj;, -CH,OH, -NHCOCH;, -
SO2NH;, -SO;NHC(CH3);, -OCOC(CHs)s, -OCOCH,C(CHj3);, -O(CH,);N(CH3),, 4-CH;- piperazin-1-yl, OCOCH(CHjs),;, OCO(cyclopentyl), -COCHj, optionally substituted phenoxy, or optionally substituted benzyloxy.
[00216] In still other embodiments, y is 0, and R™ is FE. In yet other embodimentsy is 0, q is 1, and R* is OR’. In still other embodiments, yis 0,qis 1 and R® is OH. In yet other embodiments, y is 1, R* is OR’ and R® is F, wherein OR’ is substituted at the 2-position of the phenyl ring and F is substituted at the 6-position of the phenyl ring. In yet other embodiments, y is 1, R>®is OH and R’ is F, wherein OH is substituted at the 2-position of the phenyl ring and F is substituted at the 6-position of the phenyl ring. {00217] For compounds described in this section above, in general, compounds are useful as inhibitors of ion channels, preferably voltage gated sodium channels and N-type calcium channels. In certain exemplary embodiments, compounds of the invention are useful as inhibitors of NaV1.8. In other embodiments, compounds of the invention are useful as inhibitors of NaV1.8 and CaV2.2. In still other embodiments, compounds of the invention are useful as inhibitors of CaV2.2. In yet other embodiments, compounds of the invention are useful as dual inhibitors of NaV1.8 and a TTX-sensitive ion channel such as NaV1.3 or
NaV1.7.
[00218] Representative examples of compounds as described above and herein are set forth below in Table 2.
[00219] Table 2. Examples of Compounds of Formula I:
DR ECR
$$ " PRL
N
[Taga
Za"! 1 | PP 3 x N
N ou
HO
CHy C
A J
= H 2 Nal 4
A N wo”
d
IN
(JJ Le]
CJ J
4 5 Ne 7
N N
Cl Br r £4
Uj
LL] CJ aS Ni x & “CL
ZN a
"Co Ea oe® oe 11 xy Ny =
SPL
CH,
A uM, ( J Za"
I Se 12 a
H
Cr rs 3] Hn el )
d
NH, 0) ~]" N g\
N @ 13 4 ! 15
N N hi x a
NZ
HO
0 os
SA Ny 14 oQ 16
QC is
HO
Cm] cH, . iY (J @
N
= 19 2 yy od 17 oe x 2e “Cu
N ou ; r 0 MN N = LJ A 20 74 \ N “O ee TF
CHy p<] \
J 2 uN iy: "
HN N LJ ob 21 Nu 23
Pp cl a . o cu,
EN wr b§'
H MN N
= 22 AY 24
Cmpd
CH, CHy gt 03 4 "N d
HN bY I]
NIT 25 ~y 27
QL “CL
N
Nh cHy CH,
CH, CH,
Is! 7s
HN a HH i
ZZ A " “N PN 0 “N
L_ ug Ls on
Ea re cH, oH, \ 3
Js , Js d
HY N HN N oC 29 CC N 31 “0 “CO om cu, cd
Js > / uN N "
Cr i Cry i
A
ZN OO) iF SS lL
0
Hye : Ia EN © Hi oP 3 ay 35 { N
PA
} r
Jog r yr H 2 HH 34 36
A, AN Ny
IN
’ 1] { he
HY N
( ) 37 id 39
I] Ny
OC “QL ae
N cHy 0 jas CHy
HN I
SA 2 xn
Br
[eo] “0 &
N NH
HH KJ 41 CL | 43 a I OH LE 0 on
Hye
Za | ey 42 TL We : 44
Hl NS uy 4
CO ae
Cmpd
HO
I CHy r I
HR 45 JGR NZ” NH 47 7 SN Re 0 ; :
N “4 cH,
Sy
W cH, ony
PY ° cy
JQ 5 ha 46 ° “7 48 ae eu, N 0)
Br d [
J, n J “0 PP
N a a
H
) i © ; xu 50 TL sy 52 2¢ 0)
H q
Os eu Nn
Cmpd
IR es G. [ g © a 53 ZN 35
Ja : UN
L'} [] oS I
ZZ HN CHy & NNN 54 oP 56
Al “.
H el d
SA ct
N NH
Pa 57 Zz 59
OH LW
HyC
Hye aH, IN
TQ =
HH N x
Lh a 58 XY ’ gel
H
Br
IN = NN i & el
LP ke [7]
SPL! — of [']
A ® uN CH, = “0 ae 2]
Cmpd i cy i Pen
[7] en 67
WN N p> 65
N ~~
SP | l =
CH, o
XO A
2
A =
N IAN
8 Ne
ZH .
= [XN o Is " uy i
MN
\ 7) “ =
N
0 eng cu, \
HN ul J
CCL 70 ou 7
WF u PN 1) on eu
BB [>
Vd HN N
HN h H a. 73 CCL 75 oH
Ny | 2 a
OH
Hy
IN ps CS
H
HR 4
Cr 74 76
Ny
Js CC
M ~ oe A
Crapd Cmpd
ARTY ie —_I { NH
HN a Sa " 77 _ 79
Ny N
AN,
Hye ~°
Pa HH ° °
H.C eI LAA,
HH bh 3 seSUNLN Noe i
ECR
“
CH, of
Jy! wg 3)
HN N
SH 81 83 = ry
H
Zz [*] fe)
CH, cy cH, \
Vd Hy N
HN u H = 0 0
Hye pp
N o eww [eww FF
N
<7) & A
HN "
Ny
Lr ae
H 7) i A uN A aw Sw
H oC 88
EN
WF 1] N
4N a HK pH
A AN, om cH, ° / d
IN
4 I A
Sa 5
HN h
Ny” Nw 92
Az Ny
N RN | J
Sr “O - rs ¥F
’ Cm cH 9
W H— CHy N,
HN 1 »
N = rE 93 \ 95 or OO 0 ® { (. w= N a oN
Xu e0 “0 “0 we
ICN
[e]
O
New, \ R Ln
Vd HH d 97 ® Pi
A WZ
N N
@ : v ) [e)
N
Jo?
HR
IN
N xT no N 100
A F Z
F
F
Cm, ©, HH,
LLJY
\ A
A Ng
HN N
C J ry
Noy
SEIN 20 3
NH
HN N HK wv a] a Ny
PN P
0 “0 a”
a | [ewe FF
Hu NH
A u 2
HH
Nu ony oP
So 0) “Cr CH, o
CHy
I] NE uN N 106 AN,
C1 §
A 0 SCH,
d Cmpd ¥ [3
NH " Va ~H = NS
HR W
[3 1
SR ey r
LZ WF
N
F
[3 3
PE i. — .
HH
HM ~ x. / EL N we 110 112 = ow C “OO = N i) ~~
F v
C Cmpd
Compound op Compound #
F
= | . -— \; HN N oO IY
HC TL LL] Nn
N o 2 J ! h “en, (2 13
T
. (= \Y y/, a ~/ ci a) N 16
LL] = A
N 2 0 ZN { N CL
F NH,
C Cmpd ra
Sa NH " ! HK ~y/
Cr s
NZ "x WZ
FP cH, j C 13 ~
NH ad | WM
HN N - =, /
CL 118 120 _R
WF "S | A z
Pr
F ody
Cmpd d Cmpd
Compound # Compoun 8
F
F : ~ / LL]
I NF i” :
W
HN N \,
Cia ~ 5
L] =
L}
F g o r
F Sl,
HH
: / | NH a h He ~ wn oC Mer a b | Ry 0 ’ 0
F x
Q ~
Fo
Sh, F F
I i I= NN i &, Q ~~ 7 —
WN N NH
Sd uy N ay]
Z =u
N
3 2 ) 0
A ® i.
Pa
J»,
S a
HR 3 ~ Pla
HN N
SN
P “ 126 Xu 128
H AN
WZ AS
> ) =
ZZ r Coy 3 oO, O pa /
HH Co " r v oO
WZ NF
0” CH, we” ©
H
&
XN o TT
NH
HN Cry
Sy WF ~
N ey
Cmpd
I) XX cH,
NH
CL ig
WZ " SN
HN
Hy ° o cH,
NZ TN 'T} a SN or a Le
Y
CH,
d Cmpd 3
NH WH or cy oy ue” °
HC
0 h@ cHy
NH
NH
138 — = NNN xy RN
Xx. xy
Ps cH,
C Cmpd “N HH,
C J HM
[]
CC C0
Qu 0
H
1) ey 2 iy pe = ¢ -
Jt HM all] uN 144
SAS i Ny ct
LN,
BN “CL cl
004/006451
Cmpd ; uN
J — o —
N
I 4 ) = _ om i HN 4 0 |) e 7
Cl r .
F
H
OC) " iN [] —N
HN =
HN
Hye 146 SW 148 ~ =X No
H
AS WE N# en,
CH o Lo] re hey ba
006451
Cmpd ; [] ¥ H H
IRON IRSW
ZZ
HN F EH HN NY se CC
Pp “CO ge
F
= " n
N N N
CL aol = y=
CL] ES HN N oe 150 CY 152
F SD “OL "*<o Pe . ;
d Cmpd
WH
] 4 N
N N
J JO
= an ZZ ~~
LL x _
Ny AN
WF $ WZ “! \_4 ct
LL
N n i RS y "N is
I HR a SN uN ZF 2 Ny 154 156
NY]
W7 A) ® g Z u Ng z
C Cmpd
QL
> N CH
HN i a 0” 3
Cr Ie
AA i. ©
H o ~H [+]
No OO —~—
CL HN
N 158 ° : 160 a SN © 2.
CH, CH, o
ES i EN i
H
0) 1X NM SON ) =
HN [e] CH, N So
CO 161 N 163 “Ol.
On 0)
H H o °
CL CL a ~
J 162 9 164 ne NX S$
CH,
Cmpd * Cl ¢ Cl
N N r=
NZ 165 LN 167
N
O Q o [ad]
Cl Cl
TL TL
N =
N
J
() JL ° [
CH, cu,
Cmpd Cmpd
Compound Te Compound 3
Cl
A
= =z oq \ XJ
N N
@ @
Hye J cy a i.
H H
7 | x
Nas Nn _~
H MN
PO cy
Cropd
Br Pe a : og N
CY -
CHy CH 0, > 13
Th 49 4
N
N 174 XN 176 0 O
Cy
A.
N ad
H oe CL
N "x a cHy CM
Hye ©
N
N AN
JS I
NF 178 ul # 180
N
C @
Cmpd
Cmpd
H
S [} >d
N ’
Zz \
Han CL
Na
N
CJ
CJ
O N ue” ® i. ] o
CL A x 182 Ny
Re @
Cc Cmpd fo}
I
N- 0 rd
Za z
Ha Ha
JN
CJ [e] (e]
Pp ba, La,
Hye [+]
I
H, ©” "
H 2 = Na
Nay 186 188
N en, ( ) tl or" J y
Hie
Cmpd Cmpd
A Hie
NF Pp ! og
Sh cy we”
La CMs cH,
QL he
H |S “ u a a X ] 190 og 192
Sen, H
LI
Cropd
EN coy . 4 <¥ N=] i] 0] » 193 “= ° 195 hd PN [] | o
J
N
\ cH,
H nH
Mp ou
HY
Ny HN
CL o o. »
NZ H Na 7 © He” ° i
Cmpd
EN
FC . rv hs)
CL. ; x = =
Ne 2 I
H we” Sey r Ns
F
CL x
Z
N = el 200 cl M ts ue” Sew, )
06451
Cmpd Cmpd
Compound ¥ Compound 4
J
Cl CL
NF
“ "5 ¢) 203
LT ! 4
Hy 1 3 Fv
C}
Cl CL “FF cl 202 = c) 204
N EN @
Cmpd Cmpd
Compound © Compound u
F v _N x 3 . CL
H x Br N ue” i oH, ( / r
M N
~
Nan
INF Br ’
H ( M @ ne
LR
ECT
F
" HC dd
Has, ) =
HyC N N= - ou "
N
= 210 ,
Nao = 212
Ha tm = Cl
He :
He” Seu
Cmpd em FF cH r i : eu, "
N >
Fo Ny
LN
¢! NH ae” cu r
Br
Br ve CL.
Zz Zz 9¢ 2 XJ 216
N LN
He” cy r hl cH, CH
Cm
Br Br
N
Cn
LI a
O “O v Be 0)
CL ) g
N
ANC 218 X 220 |’ @ @ oy
Cm
PF
CL
KR
= i eS
LNG ~
N
HH xX
IF ¢l
Hye” is cH we $ (J
CG 222 CG 224
SN cl x cl
H N ne Tew, ae” ew
Cmpd
ECR o
L
Ne rs 7S ne” ° NF ZF Nt
CG O i = o
H ~o
N (TY
N
Han =
H Ux ue” US eu,
Cm)
ER oe o ° uu ° )
LT} “
CL Ya o \
LC He” Seng ne” IR
LLP r
N Hn
Na ba we” Sen, ae”
r
F
L]
N | = = Li “a
H
Hye” US en, /
F F
H
CL CC 2
Na 234 aN 236 a
CH, La @
Cmopd
Cmpd
F
>d
N
A se CL
LIN” ZZ
Nv ee ¢ LL] cn, 3
CL
CC
H Zz ~ H
N oq 238 JK 240
LEN
He ¢ LL] \@ cH,
Cy
CN
[2 . CL = hp ~ 0 ad H py ue” "~ cHy @
G
H ~
S TN I
NF h 244
H
J] C h »; P eu,
Cmpd
F
CL i
N
AS
OC |S
HN 2 ~
HM od
IT
CH, v on
H
Nan 246 AEN 248
Hye ~ um Js Hy cu, 0
Cmpd
EC om oN [ =
N
= be
N . Be ['] iy rr) cHy CH ne
OH A
<
N
CL JO
N
He Ha CH, M ’ i He? ew
Cmpd oe : J
CL CL x cl ian
AN N
Hye cH, ae” cn, ay CH,
M J
CC 254 CC 256
Na bee ae” ~ eu PLN * * Hye cy
4 A ! ]
Na ] we” en, He” ed
CH, I cu, °
N
SN 5
AAS i
Hye oy ae en,
FF o” CHy ‘ 3 o
NH
N
N 261 Be Z 263 . 2 te
BS (od ] AN ~
Hye cH, ] ue Seu, 2 i cs
Ne ° z N 262 4 264
Nao . nN
H ue” Neu, ae” cu
EN o oH
CL CL
~ =
N cH N oQy 3 SQ UN ony we” uy ae Seu, ou oH
H N
AC a6 CC he ha 268
N ™N
H AN ~ l_s
Ne” Sed, HC cH,
Cmpd
Le cH 0
H o “ i d Zz 271
Na or le
LI N
" Hy ne” Ney
Ps Fs © °
I
N o "
H >, ys 0 CH, N oN k u ue” Seu, we” eu,
Cmpd
EN r on i jo ° CL al [< ‘
CL cts XJ ue” ony ae” en, oH . eu,
CL q¢ 4 [3 7d od og CL CHy 1] H ne” “ew, ae” “en d F RT
CL CL - z M,C = 0 XJ
A N
Hye cy ue Seay i o .
N
~~ NN
Na 278 280 = | “ < i ) = Ae ™ cH,
C Cmpd
L : ~ on od 4 n=" i ] i <aol <pe eH, 1 on
NZ i WP
N | NY CH,
NL
NS) CHy
C
:
Ps oH w
NF TN JER
To " ™
CHy
N
( ) = \ NZ" HN 2
Gon | oo
He” Ny [<} we
Cmpd a i i NT i
H N Pa Na Ng CH, et o HH,
NZ TN Ne i = nN Ha J,
Sa en, cy
EN
# # ci pS CHy om
NF i
N N cH ’ SN - CHy
CR cM
J HC 3
CH, Fay
OL cM, euly 13 we o” CH, or cn,
Re i We : 206
Nn 4 Cy a o en, 4g CH He Hy 0 °~ cu, on ey
I vs i IN
Ea ® aes
Hye CH, - .
A y an ye Ss | h 1 x N on on 3 cH, =
Chon
ED
N._~# iz 298 WP 300
NI I xy ne CM rn
Cmpd
Cmpd mp . RG 3 3 - 13
NF NN nN h . | we CH, NN > CH, } ony cy
HyC o
T or cy 302 a
HZ ON
[| x 84 CH,
Na Ay CH b p CHy
Z bY
Cm)
CHy
HC —
HN / 7
N “| H I x Ne CH, A we CH, ony CHy
CH, —
HN
Hye CH, 2 h 306 WP 308
Nx we CH, So | en, ex 3 > | CH, yr
¢ « QL
SZ
NT i 2 )
H > NZ” SN
CH ax. PLN tu,
QL x 0 c N 310 | oA x
Nn" i i]
NN CH o cH we A 3
So cH,
Compound ng Compound 4 oH 3 x CC
N = x
C0 0
N
LL] 1
PRN
0” RN 4 —_ any oH
OM
I")
N x2
CL oe
NZ
N 316
H_
I tC, . ¢ ! . CHy —
Cmpd ou on
H
CL SON
Hae oe
US en, ~~ M 7 No Cr oH oH
N
CC. >
No NF
NM HY
~ L = NM
Cm; om 6
N
= N cl
CL
LN
Nas
NH
N
S J o yr N
OH
[eo]
NA
Na a
LRN ol 324
N cn, !
EN C J
9 “
Cmpd ;
OH [4 es
N [o] N oO 7 7 [a8
NK NG o” CHy Raa oo” Hy ®
CJ fo] on ) 3 [e]
H Hs ~ N Oo
Haw o” CH, “ad
L] cH
LU] NY 0” 3 @®
CH,
Cmpd oo » . : 5
Zz
N eH WN.
IL 3 OV
N Na $ cu, ¢ CL o ~
J JO
Zz
J a
[1] ® . 0
Claims (3)
1. A compound of formula IA: RL -R? a fi ON IA or a pharmaceutically acceptable salt thereof, wherein: R! and R? taken together with the nitrogen atom to which they are bound, form an optionally substituted 3-12-membered monocyclic or bicyclic saturated, partially unsaturated, or fully unsaturated ring having 0-3 additional heteroatoms independently selected from nitrogen, sulfur, or oxygen; wherein the ring formed by R! and R? taken together, is optionally substituted at one or more substitutable carbon, nitrogen, or sulfur atoms with z independent occurrences of ~R*, wherein z is 0-5; Ring A is a 5-7-membered monocyclic aryl ring or an 8-10-membered bicyclic aryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or is a 3-12- membered saturated or partially unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein ring A is optionally substituted with y independent occurrences of —R>, wherein y is 0-3, and is additionally optionally substituted with q independent occurrences of R*®, wherein qis 0-2; x is 0-4; each occurrence of R?, R%, and R® is independently Q-R%; wherein Q is a bond or is a Cy- Cs alkylidene chain wherein up to two non-adjacent methylene units of Q are optionally and independently replaced by -NR-, -S-, -O-, -CS-, -CO;-, -OCO-, -CO-, -COCO-, -CONR-, - NRCO-, -NRCO;-, -SO;NR-, -NRSO,-, -CONRNR-, -NRCONR-, -OCONR-, -NRNR-, - NRSO,NR-, -SO-, -8O,-, -PO-, -PO,-, -OP(O)(OR)-, or -POR-; and each occurrence of RX is independently selected from -R’, halogen, =0, =NR’, -NO,, -CN, -OR’, -SR’, -N(R’),, - NR’COR’, -NR’CON(R’);, -NR’CO,R’, -COR’, -CO,R’, -OCOR’, -CON(R’);, -OCON(R")s, - SOR’, -SO:R’, -SO;N(R”), -NR’SO2R’, -NR’SO,N(R’),, ~COCOR’, -COCH,COR’, - OP(O)(OR’);, -P(O)(OR’);, -OP(O),0R’, -P(0),0R’, -PO(R’),, or -OPOR’),;
each occurrence of R* is independently an optionally substituted C;-Csaliphatic group, halogen, -OR’, -SR’, -N(R"), -NR’COR’, -NR’CON(R"),, -NR’ COzR’, -COR’, -COR’, - OCOR’, -CON(R’), -OCON(R’)z, -SOR’, -SO,R’, -SO;N(R")2, -NR’SO2R’, -NR'SO,NR™),, - COCOR’, -COCH,COR’, -OP(O)(OR’)z, -P(O)(OR’),, -OP(0),0R’, -P(0),0R’, -PO(R’),, or - OPOR’),; and each occurrence of R is independently hydrogen or an optionally substituted Ci. aliphatic group; and each occurrence of R'is independently hydrogen or an optionally substituted C6 aliphatic group, a 3-8-membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-12 membered saturated, partially unsaturated, or fully unsaturated bicyclic ring system having 0-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or R and R, two occurrences of R, or two occurrences of R, are taken together with the atom(s) to which they are bound to form an optionally substituted 3-12 membered saturated, partially unsaturated, or fully unsaturated monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; provided that:
a. when R' and R?, taken together with the nitrogen atom to which they are bound, form an optionally substituted 4-membered monocyclic saturated or partially unsaturated ring having 0-3 additional heteroatoms independently selected from nitrogen, sulfur, or oxygen; then 2- Oxazolidinone, 3-[(3R 4R)-2-0x0-1-(2-phenyl-4-quinazolinyl)-4-[2-(3-pyridinyl)ethenyl}-3- azetidinyl]-4-phenyl-, (4S)- is excluded;
b. when R' and R?, taken together with the nitrogen atom to which they are bound, form an optionally substituted S-membered monocyclic saturated or partially unsaturated ring having 0-3 additional heteroatoms independently selected from nitrogen, sulfur, or oxygen; then:
i. ring A is not optionally substituted hexahydro-1H-1,4-diazepin-1-yl; and ii. Benzenesulfonamide, 2-methoxy-5-[2-[[1-(2-phenyl-4-quinazolinyl)-3- pyrrolidinylJamino]ethyl]-, (R)-, bis(trifluoroacetate), and Benzenesulfonamide, 2-methoxy-5-[2- [[1-(2-phenyl-4-quinazolinyl)-3-pyrrolidinylJamino]ethyl]-, (S)-, bis(trifluoroacetate) are excluded;
iii. 3-Pyrrolidinamine, 1-(2-phenyl-4-quinazolinyl)-, and (R)- 3-Pyrrolidinamine, 1-(2- phenyl-4-quinazolinyl)-, (S)- are excluded;
iv. when R! and R?, taken together are unsubstituted pyrrolidin-1-yl, ring A is unsubstituted phenyl, and x is 1, then R? is not 6-OMe or 6-OH;
v. when R' and R?, taken together are unsubstituted pyrrolidin-1-yl, ring A is unsubstituted phenyl, and x is 2, then the two rR? groups are not 6-OMe and 7-OMe;
vi. when R! and R?, taken together are unsubstituted pyrrolidin-1-yl, then ring A is not unsubstituted pyrrolidin-1-yl, optionally substituted piperazin-1-yl, unsubstituted morpholin-1- yl; or unsubstituted piperidin-1-yl;
vii. when R! and R?, taken together are pyrrolidin-1-yl, x is 0 and ring A is unsubstituted phenyl, then the pyrrolidin-1-y! group is not substituted at the 3-position with -OH or 2- methoxy-phenoxy; viii. when R! and R?, taken together are unsubstituted pyrrolidin-1-yl, and x is 0, then ring A is not 2,3-xylyl, 3-methylphenyl, unsubstituted phenyl, 4-bromo-phenyl, 4-chloro-phenyl, 3-nitro-phenyl, unsubstituted pyrid-3-yl, 2,4-dichlorophenyl, 3,4-dichlorophenyl, 4- propoxyphenyl, 3-methylphenyl, 3,4,5-trimethoxyphenyl, 2-chlorophenyl, unsubstituted pyrid- 4-yl, 2-hydroxyphenyl, or 4-(1,1-dimethylethyl)phenyl;
c. when R! and R?, taken together with the nitrogen atom to which they are bound, form an optionally substituted 6-membered monocyclic or bicyclic saturated or partially unsaturated ring having 0-3 additional heteroatoms independently selected from nitrogen, sulfur, or oxygen; then:
i. when R! and R?, taken together form an unsubstituted morpholino ring, and ring A is unsubstituted phenyl, then x is not 0, or if x is 1 or 2, then R? is not: 6-fluoro, 6,7-dimethoxy, 6- nitro, 6-AcHN-, 6-methox, 6-NH2, 6-OCHN-, 6-OH, 6-AcMeN-, 6-TsHN-, 6-Me2N-, 7-OH, 6- amino-thiazol-2-yl, 6-NHCOCOOE:t, or 6-(4-phenyl-amino-thiazol-2-yl);
ii. when R' and R? taken together form an unsubstituted morpholino ring, and ring A is unsubstituted cyclohexyl, unsubstituted pyrid-3-yl, unsubstituted 2-furyl, 2-fluorophenyl, 3- thienyl, benzofuran, pyridazine, phenyl substituted in one or more of the 3, 4, or 5-position of the phenyl ring, and x is 1 or 2, then R? is not 6-NH,, 6-OHCHN-, 6-OH, 7-OH, 6-MsHN-, 6-AcHN- , 6-fluoro, or 6-OMe;
iii. when R' and R?, taken together, form a piperid-4-one, piperid-4-ol, or thiomorpholino, or a dimethyl substituted morpholino ring, ring A is unsubstituted phenyl, and x is 1, then R? is not 6-OH;
iv. when x is 0 and A is unsubstituted phenyl, 3,4,5-trimethoxyphenyl, or 3,4- dimethoxyphenyl, then R! and R?, taken together is not optionally substituted piperidinyl or optionally substituted piperazinyl;
v. when x is 2 or 3, and R® is 6,7-diOMe, or 6,7,8-triOMe, then R' and R, taken together is not optionally substituted piperidin-1-yl, piperazin-1-yl, or morpholin-1-yl;
vi. when x is 0 and ring A is unsubstituted phenyl, then R! and Ry, taken together is not optionally substituted or fused piperazinyl;
vii. when x is 0 and ring A is phenyl optionally substituted in one or more of the 3-,4-,0r S-positions of the phenyl ring, then R! and R?, taken together is not optionally substituted piperazin-1-yl, or morpholin-1-yl; viii. when x is 0 and ring A is 2-F-phenyl, then R! and R?, taken together is not 4-(2-Cl- phenyl)-piperazin-1-yl, 4-(3-Cl-phenyl)-piperazin-1-yl, or unsubstituted morpholin-1-yl;
ix. when x is 0 and ring A is 2-Cl-phenyl, then R! and R?, taken together is not unsubstituted morpholin-1-yl, 4-Me-piperazin-1-yl, 4-Et-piperazin-1-yl, 4-phenyl-piperazin-1-yl, or 4-CH,Ph,-piperazin-1-yl;
x. when x is 0 and ring A is 2-OH-phenyl, then R1 and R2, taken together is not unsubstituted morpholin-1-yl, 4-(2-OMe-phenyl)-piperazin-1-yl, 4-CH2Ph-piperazin-1-yl, 4-Et- piperazin-1-yl, or 4-Me-piperazin-1-yl;
xi. when xis 0, x is 1 and R% is 6-Br, or x is 2 and R? is 6-7-diOMe, and ring A is optionally substituted 2- or 3-thienyl, then R' and R?, taken together is not 4-Ph-piperazin-1-yl, 4-(3-CFs-phenyl)-piperazin-1-yl, 4-(2-OEt-phenyl)-piperazin-1-yl, 4-Me-piperazinyl, or unsubstituted morpholin-1-yl; xii when x is 0, and ring A is unsubstituted pyrid-3-yl or pyrid-4-yl, then R! and R?, taken together is not optionally substituted morpholin-1-yl, or optionally substituted piperazin-1- yh; xiii. when x is 0, and ring A is optionally substituted 1H-imidazol-2-yl or 1H-imidazol-1- yl, then R' and R? taken together is not unsubstituted morpholin-1-yl, 4-Me-piperazin-1-yl, or 4- CH,CH,;OH-piperazin-1-yl;
xiv. when x is 0 and ring A is 5-NO,-thiazol-2-yl, then R* and R?, taken together is not 4- Me-piperazin-1-yl;
xv. when x is 0 and ring A is 5-NO,-2-furanyl, then R! and R?, taken together is not 4-
' CH,CH,OH-piperazin-1-yl, 4-Me-piperazin-1-yl, or unsubstituted morpholin-1-yl;
xvi. when xis 1, Ris 6-OH and ring A is unsubstituted phenyl, then R! and R?, taken together is not unsubstituted morpholin-1-yl, or 4-Me-piperazin- 1-yl; xvii. when x is 0 and R' and R?, taken together is unsubstituted piperidinyl, then ring A is not 2-OH-phenyl, 4-OMe-phenyl, 4-F-phenyl, 4-NO,-phenyl, pyrid-3-yl, pyrid-4-yl, 2-Cl- phenyl, 4-O,Pr-phenyl, 3,4-dichlorophenyl, 2-F-phenyl, 4-Br-phenyl, 4-Cl-phenyl, 3-NO,- phenyl, or 2,4-dichlorophenyl; xviii. when x is 0, ring A is 4-Br-phenyl, 2-F-phenyl, 2-Cl-phenyl, 4-Cl-phenyl, 4- OnPr-phenyl, 2,4-dichlorophenyl, 3,4-dichlorophenyl, 4-Me-phenyl, 3-Me-phenyl, pyrid-3-yl, pyrid-4-yl, 2-OH-phenyl, 4-NO2-phenyl, 4-tBu-phenyl, then R! and R?, taken together is not 2- Me-piperidin-1-yl, 4-CH2-Ph-piperidin-1-y}, 4-Me-piperidin-1-yl, 3-COOEt-piperidin-1-yl, 4- COOEt-piperidin-1-yl, 2-Et-piperidin-1-y}, 3-Me-piperidin-1-yl, 3,5-diMe-piperidin-1-yl, 4- CONH,-piperidin-1-yl, (4-piperidinyl, 4-carboxamide)-piperidin-1-yl, 1,4-dioxa-8- azaspiro[4.5]decane, 3,4-dihydro-2(1H)-isoquinolinyl,or piperidin-4-one;
xix. when x is 1, R? is 6-Br, 6-Cl, 6-OH, 6-OMe, or 6-Me and ring A is 4- bromophenyl, 4-CH,P(O)(OH)(OEt)phenyl, or unsubstituted phenyl, then R! and R?, taken together, is not optionally substituted piperidinyl;
xx.when x is 2, and R® is 6,7-dimethoxy, and A is unsubstituted phenyl, then R' and R?, taken together is not 1,4-dioxa-8-azaspiro[4.5]decane or 3,4-dihydro-2(1H)-isoquinolinyl;
xxi. when x is 3, and the three occurrences of R? are 5-OAc, 6-OAc, and 8-piperidinyl , and ring A is unsubstituted phenyl, then R! and R?, taken together is not an unsubstituted piperidinyl ring; xxii. when x is 3 and the three occurrences of R3 are 6-Me, 7-COOEt, and 8-Me, and ring A is 2-Cl-phenyl, then R! and R?, taken together, is not 4-phenyl-piperidin-1-y}, 4-(4-Cl- phenyl)-piperazin-1-yl, unsubstituted piperazin-1-yl, 4-CH,Ph-piperazin-1-y}, 4(2-Cl- phenyl)piperazin-1-yl, or 4-COOEt-piperazin-1-yl;
c. when R! and R?, taken together with the nitrogen atom to which they are bound, form an optionally substituted 7-membered monocyclic or bicyclic saturated or partially unsaturated ring having 0-3 additional heteroatoms independently selected from nitrogen, sulfur, or oxygen; then:
i. Benzenesulfonamide, 2-methoxy-5-[2-[5-(2-phenyl-4-quinazolinyl)-2,5- diazabicyclo[2.2.1]hept-2-yl]Jethyl]-, and bis(trifluoroacetate) 2,5-Diazabicyclo[2.2.1]heptane, 2-
(2-phenyl-4-quinazolinyl)- are excluded;
ii. when x is 2 and both occurrences of R> are OMe, and ring A is 4-Cl-phenyl, then R! and R?, taken together is not unsubstituted hexahydro-1H-azepin-1-yl;
iii. when x is 0 and R! and R?, taken together is unsubstituted hexahydro-1H-azepin- 1-yl, then ring A is not unsubstituted phenyl, 4-F-phenyl, 4-NO2-phenyl, pyrid-4-yl, 3,4-diCl- phenyl, 2-Cl-phenyl, 2,4-diCl-phenyl, 2,4-diCl-phenyl, 3-NO2-phenyl, 4-Cl-phenyl, 4-O,Pr- phenyl, 3-Me-phenyl, 3,4-OMe-phenyl, 3,4,5-OMe-pheny}, pyrid-3-yl, or 2-OH-phenyl;
d. when R' and R?, taken together with the nitrogen atom to which they are bound, form an optionally substituted 8-membered monocyclic or bicyclic saturated or partially unsaturated ring having 0-3 additional heteroatoms independently selected from nitrogen, sulfur, or oxygen; then:
i. Benzenesulfonamide, 2-methoxy-5-[2-[8-(2-phenyl-4-quinazolinyl)-3,8- diazabicyclo[3.2.1Joct-3-yl]Jethyl]-, bis(trifluoroacetate) 3,8-Diazabicyclo[3 .2.1Joctane, 3- (phenylmethyl)-8-(2-phenyl-4-quinazolinyl)- 3,8-Diazabicyclo[3.2.1]octane, 8-(2-phenyl-4- quinazolinyl)-; Quinazoline, 2-(3-methylphenyl)-4-(1,3,3-trimethyl-6-azabicyclof3.2.1Joct-6-y1)- , monohydrochloride; Quinazoline, 2-(4-nitrophenyl)-4-(1,3,3-trimethyl-6-azabicyclo[3.2.1]oct- 6-yl)-, monohydrochloride; Quinazoline, 2-(3-methylphenyl)-4-(1,3,3-trimethyl-6- azabicyclo[3.2.1]oct-6-yl)-; Quinazoline, 2-(4-methylphenyl)-4-(1,3,3-trimethyl-6- azabicyclo[3.2.1]oct-6-yl)-; and Quinazoline, 2-(4-nitrophenyl)-4-(1,3,3-trimethyl-6- azabicyclo[3.2.1]oct-6-y})-are excluded; and e. when R! and R?, taken together with the nitrogen atom to which they are bound, form an optionally substituted 9-membered monocyclic or bicyclic saturated or partially unsaturated ring having 0-3 additional heteroatoms independently selected from nitrogen, sulfur, or oxygen; then: Piperazine, 1-[4-(1,3-dihydro-1,3-dioxo-2H-isoindol-2-y1)-6,7-dimethoxy-2- quinazolinyl]-4-(2-furanylcarbonyl)- is excluded.
2. The compound of claim 1, wherein the ring formed by R! and R? taken together is selected from: A Ad AS L_NH J Lo cc dd ee
“Tm iY N N Ny (rm (or (x 4 (R"); ff gg hh (RY) T hy FP N ‘ NS \ Ls Ra <X z 2(R%) ii i kk J ™ “ N N N N » ) a ¢ N ; Fi RY N Gy AR) z 4 (R%), Ii mm nn 00 wherein the ring formed by R! and R? taken together, is optionally substituted at one or more substitutable carbon, nitrogen, or sulfur atoms with z independent occurrences of —R*, and z is 0-5.
3. The compound of claim 2, wherein R! and R? taken together is an optionally substituted ring selected from azetidin-1-yl (jj), pyrrolidin-1-yl (ff), piperidinl-yl (dd), piperazin-1-yl (cc), or morpholin-4-yl (ee).
4. The compound of claim 2, wherein R! and R? taken together is an optionally substituted ring selected from azetidin-1-yl (jj), pyrrolidin-1-yl (ff), piperidinl-yl (dd), or piperazin-1-yl (cc).
5. The compound of claim 2, wherein R! and RZ taken together is selected from:
a. optionally substituted azetidin-1-yl (jj), wherein z is 1 or 2 and at least one occurrence of R* is -NRSO,R’, -NRCOOR’, or -NRCOR’;
b. optionally substituted azetidin-1-yl (jj), wherein z is 1 and R* is -NRSO,R’;
c. optionally substituted azetidin-1-yl (ij), wherein z is 1 and R* is -NRCOOR’;
d. optionally substituted azetidin-1-y1 (jj), wherein z is 1 and Ris -NRCOR’;
e. optionally substituted pyrrolidin-1-yl (ff), wherein z is 1 or 2 and R*is C1, Br, F, CFs, CH;, -CHCHj3, -OR’, or -CH,0R’;
f. optionally substituted piperidin-1-yl (dd), wherein z is 1 or 2 and at least one occurrence of R* is Cl, Br, F, CFs, CHs, -CH,CHj, -OR’, or -CH,0R’, -NRSO:R’, -NRCOOR’, or -OCON(R’);
g. optionally substituted piperidin-1-yl (dd), wherein z is 1 and R*is F, CFs, CHa, - CH,CHj3, -OR’, or -CH,0R’;
h. optionally substituted piperidin-1-yl (dd), wherein z is 1 and R*is -—NRSO,R’;
i. optionally substituted piperidin-1-yl (dd), wherein z is 1 and R* is -NRCOOR'; Je optionally substituted piperazin-1-yl (cc), wherein z is 1 or 2 and at least one occurrence of R* is ~SOR’, -CON(R’),, -SO,N(R’),, -COR’, or -COOR’;
k. optionally substituted piperazin-1-yl (cc), wherein z is 1 and R*is —SOR’ L optionally substituted piperazin-1-yl (cc), wherein z is 1 and R*is -COOR’;
m. optionally substituted piperazin-1-yl (cc), wherein z is 1 and R*is -CONR’);
n. optionally substituted piperazin-1-yl (cc), wherein z is 1 and R*is -SO,N(R’)y; or o. optionally substituted piperazin-1-yl (cc), wherein z is 1 and R* is -COR’.
6. The compound of claim 1, wherein z is 0-5, and R* groups, when present, are each independently halogen, CN, NO, -N(R");, -CH,N(R’),, -OR’, -CH,OR’, -SR’, -CH,SR’, - COOR’, -NRCOR’, -CON(R’),;, -OCON(R’),, COR’, -NHCOOR’, -SO2R’, -SON(R’),, or an optionally substituted group selected from C,.Cealiphatic, aryl, heteroaryl, cycloaliphatic, heterocycloaliphatic, arylC;-Cgalkyl, heteroarylC,-Csalkyl, cycloaliphaticCy-Cgalkyl, or heterocycloaliphaticC;-Cgalkyl.
7. The compound of claim 1, wherein z is 0-5 and R* groups are each independently Cl, Br, F, CF;, CHs, -CH,CHj3, CN, -COOH, —N(CHz);, -N(Et)2, -N(iPr),, -O(CH,)OCHj3;, -CONH,, - COOCH;, -OH, -CH,OH, -NHCOCH; -SO;NH;, -SO,(CH,);CHjs, -SO,CH(CHs);, - SO,;N(CHj3),;, -SO.CH2CHj3, -C(O)OCH,CH(CHj3),;, -C(O)NHCH,CH(CH3),, -NHCOOCH;, - C(O)C(CH3)3, -COO(CHz).CH3, -C(O)NHCH(CHs)2, -C(O)CH:CHs3, or an optionally substituted group selected from -piperidinyl, piperizinyl, morpholino, Ci.alkoxy, phenyl, phenyloxy, benzyl, benzyloxy, -CHacyclohexyl, pyridyl, -CHapyridyl, or -CHythiazolyl.
8. The compound of claim 1, wherein x is 0-4, and R® groups, when present, are each independently halogen, CN, NO, -N(R’);, -CH;N(R’),, -OR’, -CH,0OR’, -SR’, -CH:SR’, - COOR’, -NRCOR’, -CON(R’)2, -OCON(R’),, COR’, -NHCOOR’, -SO2R’, -SO2N(R’),, or an optionally substituted group selected from C;.Cealiphatic, aryl, heteroaryl, cycloaliphatic, heterocycloaliphatic, arylC,-Cgalkyl, heteroarylC;-Cealkyl, cycloaliphaticC,-Cgalkyl, or heterocycloaliphaticC;-Cgalkyl.
9. The compound of claim 1, wherein x is 1 or 2, and each occurrence of R? is independently Cl, Br, F, CF;, -OCF;, Me, Et, CN, -COOH, -NH,, -N(CHas),, -N(Et);, -N(GPr),, - O(CHy);OCH;, -CONH,, -COOCH;, -OH, -OCH; -OCH,CHs;, -CH,OH, -NHCOCH;, - NHCOCH(CH3), -SO;NH,, -CONH(cyclopropyl), -CONHCH;, -CONHCH,CH;, or an optionally substituted group selected from -piperidinyl, piperizinyl, morpholino, phenyl, phenyloxy, benzyl, or benzyloxy.
10. The compound of claim 1, wherein x is 1 or 2 and each R® group is independently halogen, CN, optionally substituted C;-Cgalkyl, OR’, NR’);, CON(R’);, or NRCOR’.
11. The compound of claim 1, wherein x is 1 or 2, and each R® group is -Cl, -CHj3, -CH,CHj, -F, -CF;, -OCF;, -CONHCH;, -CONHCH,CH;, -CONH(cyclopropyl), -OCHj;, -NHj, - OCH,CHs, or -CN.
12. The compound of claim 1, wherein x is 1 and R? is at the 6-position of the quinazoline ring and is -Cl, -CH;, -CH,CH;, -F, -CF;, -OCF;, -CONHCH;, -CONHCH,CH;, - CONH(cyclopropyl), -OCH3, -NH,, -OCH,CHj, or -CN.
13. The compound of claim 1, wherein x is 1 and R? is at the 7-position of the quinazoline ring and is -Cl, -CH,, -CH,CHs;, -F, -CF;, -OCF;, -CONHCHi, -CONHCH,CH,, - CONH(cyclopropyl), -OCHs, -NH;, -OCH,CHj, or -CN.
15. The compound of claim 1, wherein x is 1 and R3 is at the 6-position of the quinazoline ring and is -Cl, -CHj3, -CH,CHj, -F, -CF3, -OCF;, -OCHj, or -OCH;CHs.
15. The compound of claim 1, wherein x is 1 and R? is at the 7-position of the quinazoline ring and is -Cl, -CHjs, -CH,CHj, -F, -CF;, -OCF;, -OCHj, or -OCH;CHa.
16. The compound of claim 1, wherein x is 1 and R? is at the 6-position of the quinazoline ring and is -CON(R’);, or NRCOR’.
17. The compound of claim 1, wherein x is 1 and R? is at the 7-position of the quinazoline ring and is -Cl, -CH;, -CH,CH3;, -F, -CF;, -OCF;, -OCHs;, or -OCH,CH;.
18. The compound of claim 1, wherein ring A is a group selected from: (RS), y(RY) (Rg y(RY) J(R) «Yq NA NY PSN FUR bn LT Fe Fu Rr nf N af N i ii iii iv
RS). (RS) (R%)y (R®) (rsa (R=) een, A a ng Ja q —5 S—(R%), —i . N n SNe of N v vi vii viii H yB) os RS N-NH_ qs) NN nF a | y JZ Hye ~ I~ ~ WN wse, LER, “ N s ix x xi xii
RS) Roy (B® (Roy ¥ y i frhomen Arms, TNE, ENR), Ce TFT RY £ J H xiii xiv XV xvi (RS) 5a (RY NG (R52) y(R ) (R5%) 'N \n ol )q sh FS qn a Si N q Yd He N JN iN d, “ho xvii xviii xix XX 1] (R%)y (RS) bk ly Nea PL Ne” a Sa he! SS) Tree, NT ree, (RE#)q xd xxii xxii 5 (R%) me SQ N S43 ly Nee” y wn) + | Jo) = N™ trea), S (R5%)q (R53) xiv TRY xvi (RS) H (RS). (RS) ve N. y oO. y ‘a P (pm LL 1 ree LC AT NTN gee Se 5 “Sn” Fa “N° (R*)q do my BM H N xxvii xxvii xxix ox (RS), (RS) (R%) (RS)
S. y y y >A ho IN A RM + A Ga) J “Nn q : Ld . { NG q Cro, H (RS?) xxxi Xxxii xxxiii XXXiV
N, 4% AO 0 A sa < es) ys (R%)q (R)q | y (R%®)q
19. The compound of claim 17, wherein ring A is optionally substituted phenyl, 2-pyridyl, 3- pyridyl, or 4-pyridyl, or pyrroi-1-yl.
20. The compound of claim 1, wherein y is 0-5, q is 0-2, and R’ and R™® groups, when present, are each independently halogen, CN, NO,, -N(R"),, -CH:N(R'),, -OR’, -CH,0R’, -SR’, -CH,SR’, - -NRCOR’, -CONR’),, -S(0);N(R’),;, -OCOR’, -COR’, -CO2R’, -OCON(R’),, - NR’SO;R’, -OP(0)(OR"),, -P(O)(OR’),, -OP(0)0R’, -P(O),OR’, -PO(R’),, -OPO(R’),, or an optionally substituted group selected from C,.Cealiphatic, aryl, heteroaryl, cycloaliphatic, heterocycloaliphatic, arylC;-Csalkyl, heteroarylC,-Cgalkyl, cycloaliphaticC,-Csalkyl, or heterocycloaliphaticC-Cgalkyl.
21. The compound of claim 1, wherein y is 0-5, and q is 1 or 2, and each occurrence of R* is independently Cl, Br, F, CF;, Me, Et, CN, -COOH, -NH;, -N(CHz),, -N(Et)2, -N(iPr),, - O(CH,;),OCH3, -CONH,, -COOCHj3, -OH, -OCH3;, -OCH,CHj3, -CH,0H, -NHCOCHj3, -SO,NH,, -SO,NHC(CH3),, -OCOC(CH3)3, -OCOCH,C(CH3)3, -O(CH3)>N(CH3),, 4-CH3-piperazin-1-yl, OCOCH(CHs3),, OCO(cyclopentyl), -COCH3, optionally substituted phenoxy, or optionally substituted benzyloxy.
22. The compound of claim 1, wherein:
a. yis0,andqis1and R®isF;
b. yisO,qis1,and R¥is OR’;
c. yis0,qis1andR®is OH;
d. yisO, qis 2 and one occurrence of R> is OR’ and the other occurrence of R® is F;or e. yis0,qis?2 and one occurrence of R* is OH and the other occurrence of R* is F.
23. The compound of claim 1, wherein ring A is optionally substituted phenyl and compounds have the structure IA~i: 1 2 Rin PR Xr SN Ne SFO N 7a J (R%%)q IA-i wherein: y is 0-5; q is 0-2; and each occurrence of R* is independently an optionally substituted C;-Csaliphatic group, halogen, -OR’, -SR’, -N(R’),, -NR’COR’, -NR’CON(R"),, -NR’CO,R’, -COR’, -CO;R’, - OCOR’, -CON(R),, -OCON(R’)2, -SOR’, -SO2R’, -SO;N(R’),, -NR’SO,R’, -NR’SO,N(R’)s, - COCOR’, -COCH,;COR’, -OP(0)(OR’),, -P(O)(OR’);, -OP(0),0R’, -P(0), OR’, -PO(R’), or - OPO(R’),.
24. The compound of claim 23, wherein the ring formed by R! and R? taken together is selected from: RY), (RY) (R*) L_NH Lo cc dd ee wo i N A (3 (Ce TRY), ff gg hh Fat i ~aS N NT N ) ~ ) _s N (RY /. : RY)
ii ij kk “ wan T™ wave N N N N J ) 7 ¢ N ; wh “RY. N RY; z (RY), mm nn 00 wherein the ring formed by R! and R® taken together, is optionally substituted at one or more substitutable carbon, nitrogen, or sulfur atoms with z independent occurrences of -R*, and zis 0-5.
25. The compound of claim 24, wherein R' and R* taken together is an optionally substituted ring selected from azetidin-1-yl (jj), pyrrolidin-1-yl (ff), piperidinl-yl (dd), piperazin-1-yl (cc), or morpholin-4-yl (ee).
26. The compound of claim 24, wherein R! and R? taken together is an optionally substituted ring selected from azetidin-1-yl (jj), pyrrolidin-1-yl (ff), piperidinl-yl (dd), or piperazin-1-yl (cc).
27. The compound of claim 23, wherein z is 0-5, and R* groups, when present, are each independently halogen, CN, NO;, -N(R’),, -CH:N(R’);, -OR’, -CH;0R’, -SR’, -CH,SR’, - COOR’, -NRCOR’, -CON(R’),, -OCON(R’),, COR’, -NHCOOR’, -SO2R’, -SO,NR’),, or an optionally substituted group selected from C;Cgaliphatic, aryl, heteroaryl, cycloaliphatic, heterocycloaliphatic, arylC;-Cealkyl, heteroarylC;-Cealkyl, cycloaliphaticC;-Cgalkyl, or heterocycloaliphaticC;-Csalkyl.
28. The compound of claim 23, wherein z is 0-5 and R* groups are each independently Cl, Br, F, CF;, CH3, -CH,CH;3, CN, -COOH, -N(CH3),, -N(Et),, -N(iPr),, -O(CH,);OCHj3, -CONH,, -COOCH;, -OH, -CH;OH, -NHCOCHj3; -SO;NH,, -SO,(CH,);CH;, -SO,CH(CHj);, - SO;N(CH3),, -SO2CH,CH3, -C(O)OCH,CH(CH3),;, -C(O)NHCH,CH(CH3),, -NHCOOCH;, - C(O)C(CH3);, -COO(CH2),CH;, -C(O)NHCH(CH3);, -C(O)CHCHj;, or an optionally substituted group selected from -piperidinyl, piperizinyl, morpholino, C;.4alkoxy, phenyl, phenyloxy, benzyl, benzyloxy, -CHocyclohexyl, pyridyl, -CH,pyridyl, or -CHjythiazolyl.
29. The compound of claim 23, wherein R! and R?, taken together is selected from:
a. optionally substituted azetidin-1-yl (jj), wherein z is 1 or 2 and at least one occurrence of R* is -NRSO,R’, -NRCOOR’, or -NRCOR’;
b. optionally substituted azetidin-1-yl (jj), wherein z is 1 and R*is -NRSO,R’;
Cc. optionally substituted azetidin-1-y} (35), wherein z is 1 and R* is -NRCOOR’;
d. optionally substituted azetidin-1-yl (§j), wherein z is 1 and R*is -NRCOR’;
e. optionally substituted pyrrolidin-1-yl (ff), wherein z is 1 or 2 and R*is Cl, Br, F, CF;, CH3, -CH,CHj, -OR’, or -CH,0R’;
f. optionally substituted piperidin-1-yl (dd), wherein z is 1 or 2 and at least one occurrence of R* is Cl, Br, F, CFs, CH;, -CH,CHj, -OR’, or -CH,0R’, -NRSO,R’, -NRCOOR’, or -OCONR),;
g. optionally substituted piperidin-1-yl (dd), wherein z is 1 and R* is F, CF3, CH, - CH,CHj, -OR’, or -CH,0R’;
h. optionally substituted piperidin-1-yl (dd), wherein z is 1 and R* is —NRSO,R’;
i. optionally substituted piperidin-1-yl (dd), wherein z is 1 and R* is -NRCOOR’; j- optionally substituted piperazin-1-yl (ee), wherein z is 1 or 2 and at least one occurrence of R* is —SOR’, -CON(R’),, -SO;N(R"),, -COR’, or -COOR’;
k. optionally substituted piperazin-1-yl (cc), wherein z is 1 and R* is ~SOR’
1. optionally substituted piperazin-1-yl (cc), wherein z is 1 and R* is -COOR’;
m. optionally substituted piperazin-1-yl (cc), wherein z is 1 and R* is -CON(R”),;
n. optionally substituted piperazin-1-yl (cc), wherein z is 1 and R* is -SO,NR"),; or o. optionally substituted piperazin-1-yl (cc), wherein z is 1 and R* is -COR’.
30. The compound of claim 23, wherein x is 0-4, and R® groups, when present, are each independently halogen, CN, NO,, -N(R"),, -CH>N(R’);, -OR’, -CH,0R’, -SR’, -CH,SR’, - COOR’, -NRCOR’, -CON(R’);, -OCON(R’);, COR’, -NHCOOR’, -SO;R’, -SO;N(R’),, or an optionally substituted group selected from C;.Cealiphatic, aryl, heteroaryl, cycloaliphatic,
heterocycloaliphatic, arylC;-Cealkyl, heteroarylCi-Csalkyl, ~cycloaliphaticCy-Cealkyl, or heterocycloaliphaticC,-Cgalkyl.
31. The compound of claim 23, wherein x is 1 or 2, and each occurrence of R’ is independently Cl, Br, F, CFs, -OCF;, Me, Et, CN, -COOH, -NH3, -N(CH3),, -N(Et), -N(iPr),, - O(CH,),OCH3;, -CONH,, -COOCHi, -OH, -OCH;, -OCH,CHj;, -CH,OH, -NHCOCHj;, - NHCOCH(CH3);, -SO;NH;, -CONH(cyclopropyl), -CONHCH3;, -CONHCH,CH3, or an optionally substituted group selected from -piperidinyl, piperizinyl, morpholino, phenyl, phenyloxy, benzyl, or benzyloxy.
32. The compound of claim 23 wherein x is 1 or 2 and each rR} group is independently halogen, CN, optionally substituted C;-Cgalkyl, OR’, N(R’), CON(R’),, or NRCOR’.
33. The compound of claim 23, wherein x 1s 1 or 2, and each R3 group is -Cl, -CHj, - CH,CHj, -F, -CF3, -OCF;, -CONHCHj3, -CONHCH,CH3, -CONH(cyclopropyl), -OCHj3, -NH,, - OCH,CHs;, or -CN.
34. The compound of claim 23, wherein x is 1 and R? is at the 6-position of the quinazoline ring and is -Cl, -CHj, -CH,CHj;, -F, -CF;, -OCF; -CONHCH;, -CONHCH,CH;, - CONH(cyclopropyl), -OCHj3, -NH,, -OCH,CHj, or -CN.
35. The compound of claim 23, wherein x is 1 and R? is at the 7-position of the quinazoline ring and is -Cl, -CHs;, -CH,CHj;, -F, -CF; -OCF;, -CONHCH;, -CONHCH,CHj;, - CONH(cyclopropyl), -OCHj3, -NH,, -OCH;CHj3, or -CN.
36. The compound of claim 23, wherein x is 1 and R? is at the 6-position of the quinazoline ring and is -Cl, -CHs, -CH,CH;, -F, -CF;, -OCF;, -OCHs;, or -OCH,CHs.
37. The compound of claim 23, wherein x is 1 and R? is at the 7-position of the quinazoline ring and is -Cl, -CHj3, -CH,CHj, -F, -CF3, -OCF;, -OCH3, or -OCH,CHj.
38. The compound of claim 23, wherein x is 1 and R3 is at the 6-position of the quinazoline ring and is -CON(R’),, or NRCOR’.
39. The compound of claim 23, wherein x is 1 and R3 is at the 7-position of the quinazoline ring and is -CON(R’),, or NRCOR’. :
40. The compound of claim 23, wherein y is 0-5, q is 0-2, and R’ and R® groups, when present, are each independently halogen, CN, NO,, -N(R’);, -CHN(QR’),, -OR’, -CH,0R’, -SR’, -CH,SR’, - -NRCOR’, -CON(R’);, -S(O);N(R’),, -OCOR’, -COR’, -COzR’, -OCONR’),, - NR’SOzR’, -OP(O)(OR’),, -P(O)(OR’),, -OP(0),0R’, -P(0),OR’, -PO(R’),, -OPO(R’),, or an optionally substituted group selected from C;Csaliphatic, aryl, heteroaryl, cycloaliphatic, heterocycloaliphatic, arylC,-Cgalkyl, heteroarylC;-Cealkyl, cycloaliphaticC;-Cgalkyl, or heterocycloaliphaticC;-Cgalkyl.
41. The compound of claim 23, wherein y is 0-5, and q is 1 or 2, and each occurrence of R> is independently Cl, Br, F, CF;, Me, Et, CN, -COOH, -NH,, -N(CH3),, -N(Et);, -N(GPr),, - O(CH_),0OCHj3, -CONH,, -COOCHj3;, -OH, -OCHj3, -OCH,CHj3, -CH,0H, -NHCOCH3, -SO,NH,, -SO:NHC(CHj3),, -OCOC(CH3);, -OCOCH,C(CHj3)3, -O(CH,),N(CH3),, 4-CH;-piperazin-1-yl, OCOCH(CHz);, OCO(cyclopentyl), -COCHs, optionally substituted phenoxy, or optionally substituted benzyloxy. 42, The compound of claim 23, wherein:
f. yis0, and qis 1 and R® is F substituted at the 2-position of the phenyl ring;
g. yisO0,qis 1, and R*is OR’ substituted at the 2-position of the phenyl ring;
h. yisO,qis 1 and R> is OH substituted at the 2-position of the phenyl ring;
i. yisO0,qis2 and one occurrence of R* is OR’ substituted at the 2-position of the phenyl ring and the other occurrence of R>* is F substituted at the 6-position of the phenyl ring;or j. yisO,qis 2 and one occurrence of R* is OH substituted at the 2-position of the phenyl ring, and the other occurrence of R*® is F substituted at the 6-position of the phenyl ring.
43. The compound of claim 23, wherein q is 1 and Ris at the 2-position of the phenyl ring, and compounds have the structure JA-ii:
1 2 RiP XIN Roa N = 2X (R%)y TA-ii wherein: a) the ring formed by R! and R® taken together is selected from: 4 (RY (R*) A A2 - Ay : A ‘ ig J ). L_nH L_o cc dd ee ™ wo i N (ye (ye TNR), ff gg hh Faas i “NT N N ~~ AGN ’ AR*) ii Ji kk N N N » ! a N 3 N (RY GLY N (RY: (R*), Il mm nn 00 and the ring formed by R' and R? taken together, is optionally substituted at one or more substitutable carbon, nitrogen, or sulfur atoms with z independent occurrences of -R*, and z is O- 5; b) wherein z is 0-5, and R* groups, when present, are each independently halogen, CN, NO,, -N(R’),, -CH;N(R’),, -OR’, -CH,OR’, -SR’, -CH,SR’, -COOR’, -NRCOR’, -CONR’),, - OCON(R’),, COR’, -NHCOOR’, -SO;R’, -SO;N(R’),, or an optionally substituted group selected from C;Cgaliphatic, aryl, heteroaryl, cycloaliphatic, heterocycloaliphatic, arylC;- Cealkyl, heteroarylC;-Cgalkyl, cycloaliphaticC;-Csalkyl, or heterocycloaliphaticC;-Cealkyl. c) wherein x is 0-4, and R> groups, when present, are each independently halogen, CN, NO,, -N(R’),, -CH2N(R’),, -OR’, -CH,0R’, -SR’, -CH,SR’, -COOR’, -NRCOR’, -CON(R’},, - OCON(R’);, COR’, -NHCOOR’, -SO;R’, -SO;N(R’)2, or an optionally substituted group selected from C;.Cealiphatic, aryl, heteroaryl, cycloaliphatic, heterocycloaliphatic, arylC;- Cealkyl, heteroarylC;-Cgalkyl, cycloaliphaticC;-Cgalkyl, or heterocycloaliphaticCy-Cgalkyl. d) wherein y is 0-5, and R’ groups, when present, are each independently halogen, CN, NO, -N(R’);, -CHoN(RR’);, -OR’, -CH,OR’, -SR’, -CH,SR’, - -NRCOR’, -CON(R’),, - S(O)N(R’),, -OCOR’, -COR’, -CO3R’, -OCON(R’),, -NR’SO,R’, -OP(0)(OR’),, -P(O)(OR’),, -OP(0),0R’, -P(0)20R’, -PO(R’),, -OPO(R"),, or an optionally substituted group selected from
Ci.Cealiphatic, aryl, heteroaryl, cycloaliphatic, heterocycloaliphatic, arylC;-Cealkyl, heteroarylC;-Csalkyl, cycloaliphaticC;-Cealkyl, or heterocycloaliphaticC,-Cgalkyl; and e) R*® is Cl, Br, F, CF;, Me, Et, CN, -COOH, -NH,, -N(CHy),, -N(Et)z, -N@GPr),, - O(CH:);OCH3, -CONH,, -COOCHj3, -OH, -OCHj3;, -OCH>CHj, -CH,OH, -NHCOCH3, -SO,NHS, -SO;NHC(CH3);, -OCOC(CH3);, -OCOCH,C(CH3)s, -O(CH2),N(CH3),, 4-CH3-piperazin-1-yl, OCOCH(CHs;);, OCO(cyclopentyl), -COCHj;, optionally substituted phenoxy, or optionally substituted benzyloxy.
44. The compound of claim 23, wherein q is 1 and R* is at the 2-position of the phenyl ring, and compounds have the structure IA-ii:
RL, -R? NN 5a “iF, 1A-ii wherein:
a) R! and R? taken together is an optionally substituted ring selected from azetidin-1-yl (jj), pyrrolidin-1-yl (ff), piperidin1-yl (dd), or piperazin-1-yl (cc);
b) z is 0-5 and R* groups are each independently Cl, Br, F, CF3;, CH3, -CH;CH;, CN, - COOH, —N(CH3),, -N(Et);, -N(iPr);, -O(CH;),;OCH3, -CONH,, -COOCHj3, -OH, -CH;OH, - NHCOCH;, -SO;NH,, -SO,(CH,);CH;, -SO,CH(CHs);, -SO,N(CH3);, -SO.CHoCHj;, - C(O)OCH,CH(CHs),, -C(O)NHCH,CH(CH3),, -NHCOOCH;, -C(O)C(CH3)s, -COO(CH2),CH3, -C(O)NHCH(CHj3);, -C(O)CH,CH3, or an optionally substituted group selected from - piperidinyl, piperizinyl, morpholino, C,4alkoxy, phenyl, phenyloxy, benzyl, benzyloxy, - CHacyclohexyl, pyridyl, -CH,pyridyl, or -CHzthiazolyl;
c) x is 1 or 2, and each occurrence of R3is independently Cl, Br, F, CF3, -OCF3, Me, Et, CN, -COOH, -NH,, -N(CH3),, -N(Et);, -N(iPr),, -O(CH,),OCH3, -CONH;, -COOCHj3, -OH, - OCH3, -OCH,CH3, -CH,0H, -NHCOCH3;, -NHCOCH(CHj3),, -SO.NH,, -CONH(cyclopropyl), - CONHCHj3;, -CONHCH,CHj3, or an optionally substituted group selected from -piperidinyl, piperizinyl, morpholino, phenyl, phenyloxy, benzyl, or benzyloxy;
d) wherein y is 04, and R® groups, when present, are each independently Cl, Br, F, CF, Me, Et, CN, -COOH, -NH,, -N(CH3),, -N(Et),, -N(iPr),, -O(CH,),OCH3, -CONH,, -COOCHj3, - OH, -OCHj;, -OCH,CHj, -CH,OH, -NHCOCHj3;, -SO,NH,, -SO,NHC(CHj3),, -OCOC(CHa)s, - OCOCHC(CH3s)3, -O(CH,),N(CH3),, 4-CHj;-piperazin-1-yl, OCOCH(CHj3),, OCO(cyclopentyl), -COCH;, optionally substituted phenoxy, or optionally substituted benzyloxy; and e) R® is Cl, F, CF;, Me, Et, -OH, -OCHs, -OCH,CH;, -CH,0H, -SO,NH,, - SO,NHC(CH3),, -OCOC(CHj3);, -OCOCH,;C(CHj3)3, -O(CH2),N(CH3),;, 4-CHj3-piperazin-1-yl, OCOCH(CH3),, OCO(cyclopentyl), or -COCHs.
45. The compound of claim 44, wherein x is 1 and R3 is at the 6-position of the quinazoline ring and is -Cl, -CH;, -CH,CH,, -F, -CF;, -OCF;, -CONHCH;, -CONHCH.CHs, - CONH(cyclopropyl), -OCHj, -NHj;, -OCH,;CHj, or -CN.
46. The compound of claim 44, wherein x is 1 and R® is at the 7-position of the quinazoline ring and is -Cl, -CHs, -CH,CHs, -F, -CFs;, -OCF;, -CONHCH;, -CONHCH:CHs, - CONH(cyclopropyl), -OCHj3, -NH,, -OCH,CH3, or -CN.
47. The compound of claim 44, wherein x is 1 and R? is at the 6-position of the quinazoline Ting and is -Cl, -CHj3, -CH,CH3, -F, -CF;, -OCPF;, -OCHs, or -OCH,CHsj.
48. The compound of claim 44 wherein x is 1 and R® is at the 7-position of the quinazoline ring and is -Cl, -CHj3, -CH,CHj, -F, -CF3, -OCF;, -OCHj3, or -OCH,;CHj.
49. The compound of claim 44, wherein x is 1 and R? is at the 6-position of the quinazoline ring and is -CON(R’);, or NRCOR’.
50. The compound of claim 44, wherein x is 1 and R® is at the 7-position of the quinazoline ring and is “CON(R’),, or NRCOR’.
51. The compound of claim 44, wherein R* is Cl, F, CFs, Me, Et, -OH, OR’, -OCH;, - OCH,CHs.
52. The compound of claim 44, wherein R* is OR’.
53. The compound of claim 44, wherein R* is OH.
54. The compound of claim 44, wherein R® is F.
55. The compound of claim 23, wherein q is 1 and R* is at the 2-position of the phenyl ring, and compounds have the structure JA -ii:
RL, -R? XIN RSa N = =X (R%)y : IA-ii wherein: a) R! and R? taken together is an optionally substituted ring selected from azetidin-1-yl (ij), pyrrolidin-1-y1 (ff), piperidinl-y! (dd), or piperazin-1-yl (cc); b) z is 0-5 and R* groups are each independently Cl, Br, F, CF;, CH3, -CH,CHj, CN, - COOH, -N(CH3),, -N(Et),, -N(iPr),, -O(CH;),OCHj, -CONH,, -COOCH;, -OH, -CH,0H, - NHCOCH;, -SO;NH;, -SO,(CH,);CH;, -SO,CH(CHj);, -SO,N(CHs),;, -SO,CH:CHs, - C(O)OCH,CH(CHs),, -C(O)NHCH,CH(CH3),, -NHCOOCH;3, -C(O)C(CH3)3, -COO(CH,),CHs, -C(O)NHCH(CH3;);, -C(O)CH,CH;, or an optionally substituted group selected from - piperidinyl, piperizinyl, morpholino, C;salkoxy, phenyl, phenyloxy, benzyl, benzyloxy, - CHscyclohexyl, pyridyl, -CH;pyridyl, or -CH;thiazolyl; ¢) x is 1, and each occurrence of R3is independently Cl, Br, F, CF;, -OCF;, Me, Et, CN, - COOH, -OH, or -OCH3; d)yisOor 1, and R® groups, when present, are each independently Cl, Br, F, CF;, Me, - OH, -OCHj3;, -OCH,CHj;, -CH,0H, -NHCOCHj3;, -SO,NH,, -SO,NHC(CH3),; and e) R®is F, -OR’, or NHSO,R’.
56. The compound of claim 55, wherein x is 1 and R® is at the 6-position of the quinazoline ring and is -Cl, -CH3, -CH,CH;, -F, -CF;, -OCF;, -CONHCH;, -CONHCH,CH;, - CONH( (cyclopropyl), -OCHj, -NH;, -OCH,CHj, or -CN.
57. The compound of claim 55, wherein x is 1 and R? is at the 7-position of the quinazoline ring and is -Cl, -CHs;, -CH,CHi, -F, -CF;, -OCF;, -CONHCH;, -CONHCH,CHj;, - CONH(cyclopropyl), -OCHj;, -NH,, -OCH,CHj, or -CN.
58. The compound of claim 55, wherein x is 1 and R? is at the 6-position of the quinazoline ring and is -Cl, -CHs, -CH,CHj, -F, -CF3, -OCF;, -OCHa, or -OCH2CHa.
59. The compound of claim 55, wherein x is 1 and R3 is at the 7-position of the quinazoline ring and is -Cl, -CHs,, -CH,CHs;, -F, -CF,, -OCFs, -OCHs;, or -OCH,CHs.
60. The compound of claim 55, wherein x is 1 and R3 is at the 6-position of the quinazoline ring and is —-CON(R’),, or NRCOR’.
61. The compound of claim 55, wherein x is 1 and R? is at the 7-position of the quinazoline ring and is ~-CON(R’)z, or NRCOR’.
62. The compound of claim 55, wherein Ris OR’ and x is 1 and R® is at the 6-position of the quinazoline ring and is -Cl, -CHj, -CH,CHjs, -F, -CF;, -OCF;s, -OCH;, or -OCH,CHj,
63. The compound of claim 55, wherein R*® is OR’ and x is 1 and R® is at the 7-position of the quinazoline ring and is -Cl, -CHs, -CH,CHj, -F, -CF;, -OCF;, -OCH3, or -OCH,CH3
64. The compound of claim 55, wherein R! and R?, taken together is selected from:
a. optionally substituted azetidin-1-yl (§j), wherein z is 1 or 2 and at least one occurrence of R* is -NRSO,R’, -NRCOOR’, or -NRCOR’;
b. optionally substituted azetidin-1-y (jj), wherein z is 1 and R* is -NRSO,R’;
c. optionally substituted azetidin-1-yl (jj), wherein z is 1 and R* is -NRCOOR’;
d. optionally substituted azetidin-1-yl (jj), wherein z is 1 and R* is -NRCOR’;
e. optionally substituted pyrrolidin-1-y! (ff), wherein z is 1 or 2 and R* is Cl, Br, F, CF;, CH3, -CH,CH3, -OR’, or -CH,OR’;
f. optionally substituted piperidin-1-yl (dd), wherein z is 1 or 2 and at least one occurrence of R* is Cl, Br, F, CFs, CH;, -CH,CH;, -OR’, or -CH,OR’, -NRSO,R’, -NRCOOR’, or -OCON(R’)2;
g. optionally substituted piperidin-1-yl (dd), wherein z is 1 and R* is F, CF;, CH;, - CH,CH3, -OR’, or -CH,0R’;
+h. optionally substituted piperidin-1-yl (dd), wherein z is 1 and R* is —NRSO,R’; i optionally substituted piperidin-1-yl (dd), wherein z is 1 and R* is -NRCOOR’; Je optionally substituted piperazin-1-yl (ec), wherein z is 1 or 2 and at least one occurrence of R* is ~SOR’, -CON(R"),, -SO;N(R”), -COR’, or -COOR’;
k. optionally substituted piperazin-1-yl (cc), wherein z is 1 and R*is SOR’
1. optionally substituted piperazin-1-yl (cc), wherein z is 1 and R*is -COOR’;
m. optionally substituted piperazin-1-yl (cc), wherein z is 1 and R* is -CONR’)z;
n. optionally substituted piperazin-1-yl (cc), wherein z is 1 and R* is -SO,N(R"),; or
0. optionally substituted piperazin-1-yl (cc), wherein z is 1 and R*is -COR’.
65. A compound of formula IA-ii: RY, -R? we) ee N AS IA-ii wherein R' and R? are each independently an optionally substituted group selected from
C.¢aliphatic, Cy', wherein Cy' is a 5-7-membered monocyclic aryl ring or an 8-10-membered bicyclic aryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or is a 3-12-membered saturated or partially unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein Cy! is bonded directly to the nitrogen atom or is bonded through an optionally substituted C,4aliphatic group, wherein one or more methylene units in the C, 4aliphatic group are optionally replaced with -NR- , -O-, -COO, -OCO-, -NRCO-, -CONR-, -SO;NR-, or -NRSO;-; wherein R' and R? are each optionally and independently substituted at one or more substitutable carbon, nitrogen, or sulfur atoms with z independent occurrences of —-R*, wherein z is 0-5; x is 0-4; y is 0-4; each occurrence of R3, R*, and R® is independently Q-R¥; wherein Qis abond oris a C;- Cs alkylidene chain wherein up to two non-adjacent methylene units of Q are optionally and independently replaced by ~-NR-, -S-, -O-, -CS-, -CO;-, -OCO-, -CO-~, -COCO-, -CONR-, - NRCO-, -NRCO3-, -SO;NR-, -NRSO,-, -CONRNR-, -NRCONR-, -OCONR-, -NRNR-, - NRSO,NR-, -SO-, -SO3-, -PO-, -POy-, -OP(O)(OR)-, or -POR-; and each occurrence of R* is independently selected from -R’, =0, =NR’, halogen, -NO;, CN, -OR’, -SR’, -N([R’)3, - NR’COR’, -NR’CON(R’),, -NR’CO;R’, -COR’, -CO,R’, -OCOR’, -CON(R’),, -OCON(R’)2, - SOR’, -SO,R’, -SO,;N(R’),, -NR’SO,R’, -NR’SO;N(R’),, -COCOR’, -COCH,COR’, - OP(O)(OR’),, -P(O)(OR’),, -OP(0),0R’, -P(O),0R’, -PO(R’)z, or -OPO(R’),; R’® is an optionally substituted C,-Csaliphatic group, halogen, -OR’, -SR’, -N(R"),, - : NR’COR’, -NR’CON(R’),, -NR’CO,R’, -COR’, -COzR’, -OCOR’, -CON(R’)2, ~OCON(R’),, - SOR’, -SO,R’, -SO,N(R'),, -NR’SO;R’, -NR’SO,;N(R’),, -COCOR’, -COCH,COR’, - OP(O)(OR’),, -P(O)(OR’),, -OP(0),0R’, -P(0)%,0R’, -PO(R’);, or -OPO(R’); and each occurrence of R is independently hydrogen or an optionally substituted C6 aliphatic group; and each occurrence of R'is independently hydrogen or an optionally substituted Cy. aliphatic group, a 3-8-membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-12 membered saturated, partially unsaturated, or fully unsaturated bicyclic ring system having 0-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or R and R’, two occurrences of R, or two occurrences of R, are taken together with the atom(s) to which they are bound to form an optionally substituted 3-12 membered saturated, partially unsaturated, or fully unsaturated monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; provided that:
a. when x is 0, R' is hydrogen, and R* is Cl, Me, CF, Br, or F, then R? is not - (CH,),-4-Cy', -SO,CH,Cy!, or —~CH,SO,Cy', wherein Cy' is a 5-7-membered monocyclic aryl ring or an 8-10-membered bicyclic aryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or is a 3-8-membered saturated or partially unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur;
b. when x is 0, and R* is Cl, Me, NO, or OH, then:
i. when R! is hydrogen, R? is not Me, iBu, nBu, -COCH;, -CH,COOEt, - CH,COOMe, -CH,CH,0H, iPr, -CH;,-pyridyl, -CH,Ph, -(CH;);NH;, -(CH,),- moropholinyl, or -CH,CH,Ph;
ii. R! and R? are not simultaneously Et or Me; and iii. when R! is Et, then R? is not 4-Me-phenyl, 4-OMe-phenyl, or 2-Me-phenyl;
c. when x is 1 and R® is 6-Cl, or 7-F, or x is 0 and R® is ~OPr, or Cl, then when R’ is hydrogen, R? is not —~(CHa),-morpholino, or -CH,(benzofuran); and d. when x is 2 and one occurrence of R? is 6-OMe and the other occurrence of Ris 7-OMe, and R* is F, then when R! is hydrogen, R? is not -(CH2)sN(CHa);
66. The compound of claim 65, wherein a) one of R! or R? is hydrogen, and the other of R! and R? is selected from: i) Cy' wherein Cy’ is bonded directly to the nitrogen atom or is bonded through an optionally substituted C;.aliphatic group, wherein one or more methylene units in the C4aliphatic group are optionally replaced with -NR-, -O-, -COO, -OCO-, -NRCO-, - CONR-, -SO;NR-, or -NRSO,-; or ii) an optionally substituted C,4aliphatic group, wherein one or more methylene units in the C;4aliphatic group are optionally replaced with -NR-, -O-, -COO, -OCO-, - NRCO-, -CONR-, -SO;NR-, or -NRSO;-; or b) R! and R? are each independently selected from Cy', wherein Cy' is bonded directly to the nitrogen atom or is bonded through an optionally substituted Cj4aliphatic group, wherein one or more methylene units in the C;4aliphatic group are optionally replaced with -NR-, -O-, -COO, -OCO-, -NRCO-, -CONR-, -SO,NR-, or -NRSO;-; or an optionally substituted C;4aliphatic group, wherein one or more methylene units in the C;. saliphatic group are optionally replaced with -NR-, -O-, -COO-, -OCO-, -NRCO-, - CONR-, -SO;NR-, or -NRSO,-.
67. The compound of claim 65, wherein Cy" is: R? ee ey ES NN J “7 2 a b c d
(R%), (RY), _ (RY, RY, Ys RN FU _N Vo N— Ng N* a , e f g h H 4 NN N—x B )z (RY IN IN Le (RY SN 2 i “CN J : Ty i J k 1 Rr R4 R4 : RA : Sy! )z NY N + o Ay S ve ve s J=N Mh, m n o p R* R4 Re $y NN A d= pn po FTL, “, td ng N (R), q r Ss t _ NH ‘a rN C0 a SSSR 35 2 aN (RY), N N (R*), un v w EE < H N on SN lo) (RY) y z aa bb
68. The compound of claim 65, wherein R' is hydrogen or an optionally substituted C;- Caliphatic group and R?is ~CHR-Cy', wherein R is hydrogen or C,-Calkyl, and Cy’ is:
RY IAN NN NSN N 12 m, UIE) SL gh I (of LD HJ Hg a b c d (RY), (RY, RY Ré 24 2 N=} Z 2 )z 24 1 £07 a gy N ¥ N~ SN ad N 4 e f g h H 4 on jn tg {Nm SRY), N NERY: ~ 5 wR) “HN > Tp i j Kk 1 Ri R4 Rr4 R4 Sg l N N “N oO N o! Se =n a, m n 0 p R* R4 4 PY R SE * SS en ~ dN SR, q r Ss t a N 0 _£ NH CY CY ne J aN (RY, Ny (RY, “ XR, : 7 Sy : me, u Vv w x NN N , IN A TOR, Ow, Ty, LB:
H H y z aa bb
69. The compound of claim 65, wherein R! and R? groups are each independently an optionally substituted C,.aliphatic group and are each independently selected from optionally substituted methyl, ethyl, cyclopropyl, n-propyl, propenyl, cyclobutyl, (CO)OCH.CHs, (CH,),OCH3;, CH,CO)OCH,CH3, CH»(CO)OCH3, CH(CH3)CH2CHs, or n-butyl.
70. The compound of claim 65, wherein z is 0-5, and R* groups, when present, are each independently halogen, CN, NO,, -N(R’),, -CH,N(R’);, -OR’, -CH,OR’, -SR’, -CH,SR’, - COOR’, -NRCOR’, -CON(R’)z, -OCON(R’);, COR’, -NHCOOR’, -SO4R’, -SO2N(R’)2, or an optionally substituted group selected from C;.Cealiphatic, aryl, heteroaryl, cycloaliphatic, heterocycloaliphatic, arylC;-Cgalkyl, heteroarylC,-Cealkyl, cycloaliphaticC;-Cealkyl, or heterocycloaliphaticC,-Cgalkyl.
71. The compound of claim 65, wherein z is 0-5 and R* groups are each independently Cl, Br, F, CF, CHs, -CH,CHj3, CN, -COOH, —N(CHja),, -N(Et), -N(iPr),, -O(CH;),OCH3, -CONHa, -COOCHj;, -OH, -CH,OH, -NHCOCH;, -SO,NH;, -SO2(CH,);CHi, -SO,CH(CHjs),, - SO,;N(CH3);, -SO,CH,CHj3, -C(O)OCH,CH(CH3),, -C(O)NHCH,CH(CH3),, -NHCOOCHS, - C(O)C(CH3)3, -COO(CH»);CHj;, -C(O)NHCH(CHj), -C(O)CH,CHj;, or an optionally substituted group selected from -piperidinyl, piperizinyl, morpholino, C;alkoxy, phenyl, phenyloxy, benzyl, benzyloxy, -CH;cyclohexyl, pyridyl, -CH,pyridyl, or -CH,thiazolyl.
72. The compound of claim 65, wherein x is 0-4, and R® groups, when present, are each independently halogen, CN, NO,, -N(R’);, -CH,N(R’),, -OR’, -CH,0R’, -SR’, -CH,SR’, - COOR’, -NRCOR’, -CON(R’)2, -OCON(R’);, COR’, -NHCOOR’, -SO;R’, -SO,N(R)2, or an optionally substituted group selected from C;Cealiphatic, aryl, heteroaryl, cycloaliphatic, heterocycloaliphatic, arylC,-Cgalkyl, heteroarylC,-Cgalkyl, cycloaliphaticC;-Cealkyl, or heterocycloaliphaticC;-Cgalkyl.
73. The compound of claim 65, wherein x is 1 or 2, and each occurrence of R® is independently CI, Br, F, CF;, -OCF;, Me, Et, CN, -COOH, -NH,, -N(CH3),, -N(Et),, -N(iPr),, -
O(CH;),0CH;, -CONH,, -COOCH;, -OH, -OCHj;, -OCH,CH;, -CH,OH, -NHCOCH;, - NHCOCH(CH3),, -SO;NH,, -CONH(cyclopropyl), -CONHCH;, -CONHCH,CH;, or an optionally substituted group selected from -piperidinyl, piperizinyl, morpholino, phenyl, phenyloxy, benzyl, or benzyloxy.
74. The compound of claim 65, wherein x is 1 or 2 and each R’ group is independently halogen, CN, optionally substituted C;-Cesalkyl, OR’, N(R”), CON(R’);, or NRCOR”.
75. The compound of claim 65, wherein x is 1 or 2, and each R® group is -Cl, -CHs, - CH,CHj3, -F, -CF3, -OCF3;, -CONHCH3;, -CONHCH,CHj3;, -CONH(cyclopropyl), -OCH3, -NHj, - OCH,CH;, or -CN.
76. The compound of claim 65, wherein x is 1 and R? is at the 6-position of the quinazoline ring and is -Cl, -CHj;, -CH,CH;, -F, -CF;, -OCF;, -CONHCHj;, -CONHCH,CH;, - CONH(cyclopropyl), -OCHj3, -NH;, -OCH,CH3, or -CN.
77. The compound of claim 65, wherein x is 1 and R? is at the 7-position of the quinazoline ring and is -Cl, -CHj;, -CH,CH;, -F, -CF;, -OCF;, -CONHCH;, -CONHCH,CH;, - CONH( (cyclopropyl), -OCH3, -NH3, -OCH,CH3, or -CN.
78. The compound of claim 65, wherein x is 1 and R? is at the 6-position of the quinazoline ring and is -Cl, -CH3, -CH,CHj3, -F, -CF3, -OCF3, -OCH3, or -OCH,CH3.
79. The compound of claim 65, wherein x is 1 and R? is at the 7-position of the quinazoline ring and is -Cl, -CHj3, -CH,CH3, -F, -CF3, -OCF;3, -OCH3, or -OCH,CHi.
80. The compound of claim 65, wherein x is 1 and R’ is at the 6-position of the quinazoline ring and is -CON(R”),, or NRCOR’.
81. The compound of claim 65, wherein x is 1 and R? is at the 7-position of the quinazoline ring and is -CON(R’),, or NRCOR’. - 500 - Amended sheet: 29 September 2006
82. The compound of claim 65, wherein y is 0-4, q is 0-2, and R® and R*® groups, when present, are each independently halogen, CN, NO,, -N(R”),, -CH,;N(R’),, -OR’, -CH,0R’, -SR”’, - CH,SR’, - -NRCOR’, -CON(R"),, -S(O),N(R”);, -OCOR’, -COR’, -CO,R’, -OCON(R’),, - NR’SO;R’, -OP(O)(OR’),, -P(O}(OR’);, -OP(0),0R’, -P(0),0R’, -PO(R’);, -OPO(R’),, or an optionally substituted group selected from C,.Cealiphatic, aryl, heteroaryl, cycloaliphatic, heterocycloaliphatic, arylC,-Cealkyl, heteroarylC;-Cealkyl, cycloaliphaticC;-Cgalkyl, or heterocycloaliphaticC,-Cealkyl.
83. The compound of claim 65, wherein y is 0-4, and q is 1 or 2, and each occurrence of R* is independently Cl, Br, F, CF;, Me, Et, CN, -COOH, -NH,, -N(CH3),, -N(Et),, -N(iPr),, - O(CH;),0OCH3s, -CONHj,, -COOCHj3, -OH, -OCH3, -OCH;CH3, -CH,OH, -NHCOCH;3, -SO,;NH,, -SO;NHC(CH3)2, -OCOC(CH3)3, -OCOCH,C(CH3)3, -O(CH;)N(CH3);, 4-CH;-piperazin-1-yl, OCOCH(CHj3),, OCO(cyclopentyl), -COCHj3, optionally substituted phenoxy, or optionally substituted benzyloxy.
84. The compound of claim 65, wherein: yis0,qis 1,and R*isF; yis 0, qis 1, and R* is OR’; y is 0, q is 1 and R*® is OH; y is 1, R® is OR’ and R® is F, wherein OR’ is substituted at the 2-position of the phenyl ring and F is substituted at the 6-position of the phenyl ring; or y is 1, R*® is OH and R® is F, wherein OH is substituted at the 2-position of the phenyl ring and F is substituted at the 6-position of the phenyl ring.
85. The compound of claim 65, wherein: a) one of R' or R? is hydrogen, and the other of R' and R? is selected from Cy', wherein Cy' is bonded directly to the nitrogen atom or is bonded through an optionally substituted C;. saliphatic group, wherein one or more methylene units in the C4aliphatic group are optionally replaced with -NR-, -O-, -COO, -OCO-, -NRCO-, -CONR-, -SO;NR-, or -NRSO,-, or an optionally substituted Cj4aliphatic group, wherein one or more methylene units in the C,. saliphatic group are optionally replaced with -NR-, -O-, -COO, -OCO-, -NRCO-, -CONR-, - - 501 - Amended sheet: 29 September 2006
SO;NR-, or -NRSO,-; or R' and R? are each independently selected from an optionally substituted C, aliphatic group, wherein one or more methylene units in the C)_aliphatic group are optionally replaced with -NR-, -O-, -COO, -OCO-, -NRCO-, -CONR-, -SO;NR-, or -NRSO;-; or Cy' wherein Cy' is bonded to the nitrogen atom directly or is bonded through an optionally substituted Cj.jaliphatic group, wherein one or more methylene units in the C,. saliphatic group are optionally replaced with -NR-, -O-, -COO, -OCO-, -NRCO-, -CONR-, -SO;NR-, or -NRSO;-; b) z is 0-5 and R* groups are each independently Cl, Br, F, CF3, CHj, -CH,CH3, CN, - COOH, -N(CHj),, -N(Et)2, -N(iPr),, -O(CH,),OCH3, -CONH,, -COOCHj3, -OH, -CH,OH, - NHCOCH;, -SO;NH,;, -SO,(CH»);CHs3, -SO,CH(CHj;);, -SO;N(CHj);, -SO,CH,CHj, - C(O)OCH,CH(CH3),, -C(O)NHCH,CH(CH3),, -NHCOOCH;, -C(O)C(CH3)3, -COO(CH,),CH3, -C(O)NHCH(CH3),, -C(O)CH,CHj3, or an optionally substituted group selected from -piperidinyl, piperizinyl, morpholino, C;4alkoxy, phenyl, phenyloxy, benzyl, benzyloxy, -CH,cyclohexyl, pyridyl, -CH,pyridyl, or -CH,thiazolyl; ¢) xis 0, 1, or 2, and each occurrence of R® is independently Cl, Br, F, CF;, -OCF;, Me, Et, CN, -COOH, -NH,, -N(CHj3),, -N(Et)3, -N(iPr),, -O(CH,),OCHj3;, -CONH,, -COOCH3, -OH, -OCH3, -OCH,CH3, -CH,OH, -NHCOCH3, -NHCOCH(CH3),, -SO;NH,, -CONH(cyclopropyl), -CONHCH3;, -CONHCH,CH3, or an optionally substituted group selected from -piperidinyl, piperizinyl, morpholino, phenyl, phenyloxy, benzyl, or benzyloxy; d) wherein y is 0-4, and R® groups, when present, are each independently Cl, Br, F, CF3, Me, Et, CN, -COOH, -NH,, -N(CH3), -N(Et),, -N(iPr),, -O(CH;),OCHj3, -CONH,, -COOCHj, - OH, -OCHj3;, -OCH,CH3, -CH;OH, -NHCOCHj3;, -SO,NH;, -SO;NHC(CH3),, -OCOC(CHa3);, - OCOCH;,C(CH3)3, -O(CH,),N(CH3),, 4-CH;-piperazin-1-yl, OCOCH(CHj3),, OCO(cyclopentyl), -COCHs3, optionally substituted phenoxy, or optionally substituted benzyloxy; and e) R® is Cl, F, CF;, Me, Et, -OH, -OCH;, -OCH,CH;, -CH,OH, -SO,NH,, - SO,NHC(CHj3),;, -OCOC(CHj3)3, -OCOCH,C(CH3);3, -O(CH;);N(CH3),, 4-CHjs-piperazin-1-yl, OCOCH(CH3),, OCO(cyclopentyl), or -COCH3.
86. The compound of claim 85, wherein x is 1 and R? is at the 6-position of the quinazoline ring and is -Cl, -CHj;, -CH)CHj;, -F, -CF3;, -OCF;, -CONHCH;, -CONHCH,CH;, - CONH(cyclopropyl), -OCH3, -NH,, -OCH,CHj3, or -CN. -502- Amended sheet: 29 September 2006
87. The compound of claim 85 wherein x is 1 and R> is at the 7-position of the quinazoline ring and is -Cl, -CH;, -CH,CHs;, -F, -CF;, -OCFs;, -CONHCH; -CONHCH,CH;, - CONH(cyclopropyl), -OCH3, -NH,, -OCH,CHj3, or -CN.
88. The compound of claim 85, wherein x is 1 and R? is at the 6-position of the quinazoline ring and is -Cl, -CHs, -CH,CH;, -F, -CF;3, -OCF;, -OCH;, or -OCH,CH;.
89. The compound of claim 85, wherein x is 1 and R? is at the 7-position of the quinazoline ring and is -Cl, -CH3, -CH,CH3, -F, -CF;, -OCF3, -OCHj3, or -OCH,CH3.
90. The compound of claim 85, wherein x is 1 and R? is at the 6-position of the quinazoline ring and is -CON(R’);, or NRCOR’.
91. The compound of claim 85, wherein x is 1 and R? is at the 7-position of the quinazoline ring and is -CON(R’),, or NRCOR".
92. The compound of claim 85, wherein Ris CI, F, CF3, Me, Et, -OH, -OCH3, -OCH,CHj.
93. The compound of claim 85, wherein: yis 0, qis 1, and R®isF; yis 0, qis 1, and R®is OR’; yis 0, qis 1 and Ris OH; yis 1, R*®is OR’ and R® is F, wherein OR’ is substituted at the 2-position of the phenyl ring and F is substituted at the 6-position of the phenyl ring; or y is 1, R® is OH and R® is F, wherein OH is substituted at the 2-position of the phenyl ring and F is substituted at the 6-position of the phenyl ring. 94, The compound of claim 85, wherein: a): one of R' or R? is hydrogen, and the other of R! and R? is selected from Cy', wherein Cy' is bonded directly to the nitrogen atom or is bonded through an optionally substituted C,. saliphatic group, wherein one or more methylene units in the C,aliphatic group are optionally -503 - Amended sheet: 29 September 2006 replaced with -NR-, -O-, -COO, -OCO-, -NRCO-, -CONR-, -SO;NR-, or -NRSO,-, or an optionally substituted Cj.jaliphatic group, wherein one or more methylene units in the Ci. saliphatic group are optionally replaced with -NR-, -O-, -COO, -OCO-, -NRCO-, -CONR-, - SO;NR-, or -NRSO;-; or R' and R? are each independently selected from an optionally substituted C).4aliphatic group, wherein one or more methylene units in the C) aliphatic group are optionally replaced with -NR-, -O-, -COO, -OCO-, -NRCO-, -CONR-, -SO,NR-, or -NRSO,-; or Cy" wherein Cy! is bonded to the nitrogen atom directly or is bonded through an optionally substituted Cj4aliphatic group, wherein one or more methylene units in the C,. aliphatic group are optionally replaced with -NR-, -O-, -COOQ, -OCO-, -NRCO-, -CONR-, - SO;NR-, or -NRSO»-; and Cy' is selected from: RY N I NZ ee AN CN ca 1 (RY: LTR J 1 RY: A Se Ne QA va N a b c d (R%) (RY), (R%) (R%) 2% PA N=X z NZX z SET bow JT N” Na h “ e f g h H N — (RY), N~'™ N= RY) N J N KRY FN (RY.
AN 4 N ’ \ Zz i \ i (RY), =H NS TS i j k 1 R4 R4 R4 > (RY HTT on S hd od , s J=N m n 0 Pp -504 - Amended sheet: 29 September 2006
R4 R4 R4 SE vs 0) =N J he wg N wf ~o (RY), q r $ t N 0 OF He Fe HOS (RY), N N (RY), H H u v w Xx H N a SN CY ~~ ” y z aa bb or R' and R? are each independently an optionally substituted Ci.saliphatic group and are each independently selected from optionally substituted methyl, ethyl, cyclopropyl, n-propyl, propenyl, cyclobutyl, (CO)OCH,CHj3, (CH;);OCH;, CH,CO)OCH,CHj3, CH,(CO)OCH3, CH(CHj3)CH,CHjs, or n-butyl;
b) z is 0-5 and R* groups are each independently Cl, Br, F, CF3;, CHj;, -CH,CHj;, CN, - COOH, -N(CH3),, -N(Et),, -N(iPr),, -O(CH;);OCH3s, -CONH,, -COOCH3;, -OH, -CH,0H, - NHCOCH;3;, -SO;NHj;, -SOy(CH3);CHj;, -SO,CH(CHs);, -SO;N(CHj3),, -SO,CH,CHs, - C(0O)OCH;CH(CH3),, -C(O)NHCH,CH(CH3),;, -NHCOOCH3;, -C(O)C(CH3)3, -COO(CH;),CHj, -C(O)NHCH(CH3),, -C(O)CH,CH3, or an optionally substituted group selected from -piperidinyl, piperizinyl, morpholino, Ci4alkoxy, phenyl, phenyloxy, benzyl, benzyloxy, -CH,cyclohexyl, pyridyl, -CH,pyridyl, or -CHzthiazolyl;
¢) xis 0, 1, or 2, and each occurrence of R? is independently Cl, Br, F, CF;, -OCF;, Me, Et, CN, -COOH, -NH;, -N(CH3),, -N(Et);, -N(iPr),, -O(CH,),OCH3, -CONH,, -COOCH3, -OH, -OCH3, -OCH,CH3, -CH>OH, -NHCOCH3, -NHCOCH(CH3),, -SO,NH;, -CONH(cyclopropyl), -CONHCH;, -CONHCH,CH3, or an optionally substituted group selected from -piperidinyl, piperizinyl, morpholino, phenyl, phenyloxy, benzyl, or benzyloxy;
- 505 - Amended sheet: 29 September 2006 d) wherein y is 0-4, and R® groups, when present, are each independently Cl, Br, F, CF; Me, Et, CN, -COOH, -NH;, -N(CH3),, -N(Et),, -N(iPr),, -O(CH;),OCH3;, -CONH,, -COOCHj3, - OH, -OCHj3;, -OCH,CHj3;, -CH,OH, -NHCOCH;, -SO,NH,, -SO,NHC(CH3),, -OCOC(CHs)s, - OCOCH,;C(CH3)3, -O(CH,):N(CH3)a, 4-CHs-piperazin-1-yl, OCOCH(CH3),, OCO(cyclopentyl), -COCH3, optionally substituted phenoxy, or optionally substituted benzyloxy; and e) R® is Cl, F, CF;, Me, Et, -OH, -OCHj, -OCH,CHj;, -CH,OH, -SO,NH,, - SO; NHC(CH3),, -OCOC(CHj3);, -OCOCH,C(CH3);3, -O(CH;)2N(CH3),, 4-CHjs-piperazin-1-yl, OCOCH(CH3),,0CO(cyclopentyl), or -COCH3.
95. The compound of claim 94, wherein x is 1 and R? is at the 6-position of the quinazoline ring and is -Cl, -CH;, -CH,CH;, -F, -CF;, -OCF; -CONHCHj;, -CONHCH,CHj;, - CONH(cyclopropyl), -OCH3, -NH,, -OCH,CHj, or -CN.
96. The compound of claim 94 wherein x is 1 and R? is at the 7-position of the quinazoline ring and is -Cl, -CH;, -CH,CH;, -F, -CFi;, -OCF;, -CONHCH;, -CONHCH;CH;, - CONH(cyclopropyl), -OCH3, -NH,, -OCH,CHj, or -CN.
97. The compound of claim 94, wherein x is 1 and R? is at the 6-position of the quinazoline ring and is -Cl, -CH3, -CH,CHjs, -F, -CF3, -OCF3, -OCH3, or -OCH,CH.
98. The compound of claim 94, wherein x is 1 and R? is at the 7-position of the quinazoline ring and is -Cl, -CH3, -CH,CH3, -F, -CF3, -OCF;, -OCH3, or -OCH;CHi.
99. The compound of claim 94, wherein x is 1 and R? is at the 6-position of the quinazoline ring and is -CON(R”),, or NRCOR’.
100. The compound of claim 94, wherein x is 1 and R? is at the 7-position of the quinazoline ring and is -CON(R’),, or NRCOR’.
101. The compound of claim 94, wherein Ris Cl, F, CF;, Me, Et, -OH, -OCH3, -OCH,CH;. - 506 - Amended sheet: 29 September 2006
102. The compound of claim 94, wherein: yis 0, qis 1, and R® is F; yis0, qis 1, and Ris OR’; yis 0, q is 1 and R* is OH; yis 1, R® is OR’ and R® is F, wherein OR’ is substituted at the 2-position of the phenyl ring and F is substituted at the 6-position of the phenyl ring; or y is 1, R*® is OH and R® is F, wherein OH is substituted at the 2-position of the phenyl ring and F is substituted at the 6-position of the phenyl ring.
103. A compound of formula IA-i: RR? wo) JSR ag “R), IA-i or a pharmaceutically acceptable salt thereof, wherein R' and R? are each independently an optionally substituted group selected from C,aliphatic, Cy', wherein Cy' is a 5-7-membered monocyclic aryl ring or an 8-10-membered bicyclic aryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or is a 3-12-membered saturated or partially unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein Cy' is bonded directly to the nitrogen atom or is bonded through an optionally substituted C,4aliphatic group, wherein one or more methylene units in the C,4aliphatic group are optionally replaced with -NR- , -0-, -CO0, -0OCO-, -NRCO-, -CONR-, -SO;NR-, or -NRSO;-~; wherein R! and R?, are each optionally and independently substituted at one or more substitutable carbon, nitrogen, or sulfur atoms with z independent occurrences of -R* wherein z is 0-5; x is 1 and R? is substituted at either the 6- or 7-position of the quinazoline ring; y is 0-4; qis0,1or2; - 507 - Amended sheet: 29 September 2006 each occurrence of R®, RY, and R® is independently Q-R*; wherein Q is a bond or is a C- Cs alkylidene chain wherein up to two non-adjacent methylene units of Q are optionally and independently replaced by —-NR-, -S-, -O-, -CS-, -CO,-, -OCO-, -CO-, -COCO-, -CONR-, - NRCO-, -NRCO,-, -SO;NR-, -NRSO;-, -CONRNR-, -NRCONR-, -OCONR-, -NRNR-, - NRSO;NR-, -SO-, -SO;-, -PO-, -PO;-, -OP(O)(OR)-, or -POR-; and each occurrence of R¥ is independently selected from -R’, =0, =NR’, halogen, -NO,, -CN, -OR’, -SR’, -N(R"),, - NR’COR’, -NR’CON(R’),, -NR’CO,R’, -COR’, -CO2R’, -OCOR’, -CON(R’);, -OCON(R’),, - SOR’, -SO3R’, -SO;N(R’),, -NR’SO2R’, -NR’SO,N(R’),, -COCOR’, -COCH,COR’, - OP(O)(OR),, -P(O)(OR™),, -OP(0),0R’, -P(0),0R’, -PO(R’),, or -OPO(R’),;
each occurrence of R* is independently an optionally substituted C-Cgaliphatic group, halogen, -OR’, -SR’, -N(R’),, -NR’COR’, -NR’CON(R’);, -NR’CO;R’, -COR’, -CO,R’, - OCOR’, -CON(R’);, -OCON(R)2, -SOR’, -SOzR”’, -SO;N(R’)2, -NR’SO,R’, -NR’SO;N(R’),, - COCOR’, -COCH,COR’, -OP(0)(OR’),, -P(O)(OR’),, -OP(O),0R’, -P(0),0R’, -PO(R’),, or - OPO(R’),; and each occurrence of R is independently hydrogen or an optionally substituted C,.¢ aliphatic group; and each occurrence of Ris independently hydrogen or an optionally substituted C4 aliphatic group, a 3-8-membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-12 membered saturated, partially unsaturated, or fully unsaturated bicyclic ring system having 0-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or R and R’, two occurrences of R, or two occurrences of R’, are taken together with the atom(s) to which they are bound to form an optionally substituted 3-12 membered saturated, partially unsaturated, or fully unsaturated monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; provided that:
a) when R? is at the 7-position of the quinazoline ring then:
i) when R® is Cl or Me, ring A is unsubstituted naphthyl, and R'is hydrogen, then R? is not (CH;)3sNMey;
ii) when R? is Cl, the sum of q and y is 1 and the phenyl ring is substituted at the 4-position with Br, and R'is hydrogen, then R? is not Cy', wherein Cy' is bonded to the nitrogen atom through an optionally substituted C,.4aliphatic group, wherein one or more methylene units
-508 - Amended sheet: 29 September 2006 in the Cj_saliphatic group are optionally replaced with -NR-, -O-, -COO, -OCO-, -NRCO-, - CONR-, -SO;NR-, or -NRSO,-;
iii) when R? is Cl or OMe, the sum of q and y is 1 and the phenyl ring is substituted at the 4-position with either OMe or Cl, and R! is hydrogen, then R? is not — CH(CH3)(CH2)sN(Et);
iv) when R? is Me, OMe, or NO?, and q and y are 0, then R! and R? are not both methyl;
v) when R? is OMe, q and y are 0, and R' is hydrogen, then R? is not —SO,(4-Me- phenyl);
vi) when R? is F, the sum of q and y is 1 and the phenyl ring is substituted at the 2-position with Cl, and R' is hydrogen, then R? is not (CH,)morpholino; and b) a) when R? is at the 6-position of the quinazoline ring then:
i) when R3is NH,, Me, CI, Br, -NHAc, the sum of q and y is 1 and the phenyl ring is substituted at the 4-position with F, or ring A is naphthyl, and R' is hydrogen, then R? is not |(CH;3)3-4N(R”)y;
ii) when R? is —OCH,Ph, or OH, and q and y are 0, then when R' is hydrogen, R? is not Me, nBu, or (CHa);morpholino, or R' and R? are not simultaneously Me or Et;
iii) when R? is Me or Cl, and the sum of q and y are 1, then the phenyl ring is not substituted in the 4-position with Br;
iv) when R? is Cl, q andy are 0, and R' is hydrogen, then R? is not —SO,(4-Me- phenyl);
v) when R? is OMe, and q and y are 0, and R! is hydrogen, then R? is not — CH,CH,0H or —CH,CH,pyrrolidinyl;
vi) when R? is Cl or Br, the sum of q and y is 1, and the phenyl ring is substituted in the 4-position with ~-CH,PO(OR’),, then R! is not hydrogen when R? is -Me, or R' and R? are not simultaneously Me or Et;
vii) when R? is OH and q and y are 0, then R' and R? are not simultaneously — CH,CH,0OMe;
viii) when Rj is Cl, the sum of q and y is 1 and the phenyl ring is substituted in the 2-position with OnPr, and R'is hydrogen, then R? is not —CHjs(1,3-benzodioxol);
- 509 - Amended sheet: 29 September 2006 ix) when Ris OMe, OH, Br, Cl, NO,, Me, and q and y are 0, then when R!is hydrogen, R? is not Me, -CH,CH,COOMe, -CH,COOMe, or (CH,);CH3, or R! and R? are not simultaneously Me; and x) when R? is Cl, the sum of q and y is | and the phenyl ring is substituted in the 4-position with Cl, then R' and R? are not simultaneously Me or iPr.
104. The compound of claim 103, wherein a) one of R' or R? is hydrogen, and the other of R' and R? is selected from: i) Cy! wherein Cy' is bonded directly to the nitrogen atom or is bonded through an optionally substituted C,4aliphatic group, wherein one or more methylene units in the C4aliphatic group are optionally replaced with -NR-, -O-, -COO, -OCO-, -NRCO-, - CONR-, -SO;NR-, or -NRSO;-; or ii) an optionally substituted C;4aliphatic group, wherein one or more methylene units in the C;4aliphatic group are optionally replaced with -NR-, -O-, -COO, -OCO-, - NRCO-, -CONR-, -SO;NR-, or -NRSO;-; or b) R' and R? are each independently selected from Cy’, wherein Cy' is bonded directly to the nitrogen atom or is bonded through an optionally substituted Cj.4aliphatic group, wherein one or more methylene units in the C,4aliphatic group are optionally replaced with -NR-, -O-, -COO, -OCO-, -NRCO-, -CONR-, -SO;NR-, or -NRSO;-; or an optionally substituted C,_4aliphatic group, wherein one or more methylene units in the C;. saliphatic group are optionally replaced with -NR-, -O-, -COO-, -OCO-, -NRCO-, - CONR-, -SO;NR-, or -NRSO;-.
105. The compound of claim 103, wherein Cy'is: 1 CN NT ey PA g NS R4 J z J z Cy » C (RY); a b ¢ d -510- Amended sheet: 29 September 2006
(RY), (RY), (RY), (RY) 24 A N=X N= z ST [Zh \7 N” NN “h 4 e f g h H -N (RY N \ N > z R%) N Ps N Army FN (RY): IN pd N ~ oA z TN " (RY), = Ne TS i j k R* R* R4 R4 SES )z NA NA . S nO 'e a m n 0 Pp R* R? R4 CO EO “me q r Ss t N 0 gy SNSRUCIIE SPRUCE RV (RY), N N (R%); u v w xX H N So ON IN 5 1 (RY CNRS, CNR, re, + z y z aa bb
106. The compound of claim 103, wherein R' is hydrogen or an optionally substituted C;- Caliphatic group and R? is -CHR-Cy', wherein R is hydrogen or C,-Csalkyl, and Cy" is: -511- Amended sheet: 29 September 2006
TN NZ A NS — RY, (RY, T Lr, = TR I'S J ali a b c d (R%), (RY), (R%), (RY), N77 A ga NZ Sg So GN Ja N N he 0, e f g h H 4 N-N N—x (R )z R4 .N Pe N La (R%) § NA )z XN h 1 rd 7 \ (RY, oN No TS i i k 1 R4 R4 R4 4 Pa: a NA oN CD Pa N | 'N N S EO Hs J=N hd a, m n 0 p rR? rR R4 SE SEE SEE =N =N =N ox 4 “h, ve Ve (RY), q r S t H 0 > NH YY CY 4 0 ny, — RY; -C RY, FC “Re, : pe Sy NXRé, u \ 4 \i4 X -512- Amended sheet: 29 September 2006
N > Xe, po Ae, SE i y z aa bb
107. The compound of claim 103, wherein R' and R? groups are each independently an optionally substituted C,4aliphatic group and are each independently selected from optionally substituted methyl, ethyl, cyclopropyl, n-propyl, propenyl, cyclobutyl, (CO)OCH,CHj3, (CH;),0CHj3, CH,CO)OCH,CH;, CH(CO)OCH3, CH(CH;)CH,CH3, or n-butyl.
108. The compound of claim 103, wherein z is 0-5, and R* groups, when present, are each independently halogen, CN, NO,, -N(R’);, -CH;N(R’),, -OR’, -CH,0OR’, -SR’, -CH,SR’, - COOR’, -NRCOR’, -CON(R’);, -OCON(R’);, COR’, -NHCOOR’, -SO;R’, -SO;N(R’),, or an optionally substituted group selected from C;.Cealiphatic, aryl, heteroaryl, cycloaliphatic, heterocycloaliphatic, arylC,-Cealkyl, heteroarylC-Cealkyl, cycloaliphaticC,-Cealkyl, or heterocycloaliphaticC,-Cgalkyl.
109. The compound of claim 103, wherein z is 0-5 and R* groups are each independently CI, Br, F, CF3;, CH3, -CH,CHj3, CN, -COOH, —N(CH3),, -N(Et)2, -N(iPr), -O(CH,);OCHj3, -CONH,, -COOCHj;, -OH, -CH,OH, -NHCOCH;, -SO;NH,;, -SO;(CH;);CHs, -SO,CH(CHj3),, - SO;N(CH3);, -SO,CH,CH3, -C(O)OCH,CH(CH3),, -C(O)NHCH,CH(CH3),;, -NHCOOCH;, - C(0O)C(CH3);, -COO(CH,),CHj3, -C(O)NHCH(CHj3),, -C(O)CH,CHj3;, or an optionally substituted group selected from -piperidinyl, piperizinyl, morpholino, Ci.salkoxy, phenyl, phenyloxy, benzyl, benzyloxy, -CHacyclohexyl, pyridyl, -CH,pyridyl, or -CH,thiazolyl.
110. The compound of claim 103, R® is halogen, CN, NO,, -N(R’);, -CH;N(R’),, -OR’, - CH,0R’, -SR’, -CH,SR’, -COOR’, -NRCOR’, -CON(R’),, -OCON(R”),, COR’, -NHCOOR’, - SOR’, -SO;N(R’);, or an optionally substituted group selected from C;.Cealiphatic, aryl, heteroaryl, cycloaliphatic, heterocycloaliphatic, arylC,-Csalkyl, heteroarylC,-Cgalkyl, cycloaliphaticC;-Cealkyl, or heterocycloaliphaticC,-Cgalkyl.
111. The compound of claim 105, wherein R? is Cl, Br, F, CF;, -OCF3;, Me, Et, CN, -COOH, - NH,, —N(CH3)2, -N(Et)2, -N(iPr);, -O(CH;);OCH3;, -CONH,;, -COOCHj;, -OH, -OCH;, - -513- Amended sheet: 29 September 2006
OCH,CH3, -CH,OH, -NHCOCH;, -NHCOCH(CH;);, -SO,NH,, -CONH(cyclopropyl), - CONHCHj3;, -CONHCH,CHj3;, or an optionally substituted group selected from -piperidinyl, piperizinyl, morpholino, phenyl, phenyloxy, benzyl, or benzyloxy.
112. The compound of claim 103, wherein R® is halogen, CN, optionally substituted C;- Csalkyl, OR’, N(R”), CON(R”);, or NRCOR”’.
113. The compound of claim 103, wherein R? is -Cl, -CH;, -CH,CHs, -F, -CF3, -OCF;, - CONHCHj3;, -CONHCH;,CH3, -CONH(cyclopropyl), -OCHj3, -NH,, -OCH,CH3, or -CN.
114. The compound of claim 103, wherein R? is at the 6-position of the quinazoline ring and is -Cl, -CH3s, -CH,CH3, -F, -CF;, -OCF;, -CONHCHj3;, -CONHCH,CH3, -CONH(cyclopropyl), - OCH;, -NH,, -OCH,CHs, or -CN.
115. The compound of claim 103, R? is at the 7-position of the quinazoline ring and is -ClI, - CH;, -CH,CHs, -F, -CF3, -OCF3, -CONHCH3, -CONHCH,CH3, -CONH(cyclopropyl), -OCH3, - NH,, -OCH,CH3, or -CN.
116. The compound of claim 103, wherein R? is at the 6-position of the quinazoline ring and is -Cl, -CHs, -CH,CHj3, -F, -CF;, -OCF;, -OCH3s, or -OCH,CHjs.
117. The compound of claim 103, wherein R? is at the 7-position of the quinazoline ring and is -Cl, -CH3, -CH,CHGs, -F, -CF3, -OCFj3, -OCHj3, or -OCH,CHi.
118. The compound of claim 103, wherein R? is at the 6-position of the quinazoline ring and is —CON(R’)2, or NRCOR’.
119. The compound of claim 103, wherein R? is at the 7-position of the quinazoline ring and is —CON(R’),;, or NRCOR’. -514- Amended sheet: 29 September 2006
120. The compound of claim 103, wherein y is 0-5, q is 0-2, and R> and R® groups, when present, are each independently halogen, CN, NO,, -N(R?),, -CH>N(R),, -OR’, -CH,0R’, -SR”, -CH,;SR’, - -NRCOR’, -CON(R’);, -S(0);N(R”);, -OCOR’, -COR’, -CO,R’, -OCON(R’),, - NR’SOzR’, -OP(O)(OR’),, -P(O)(OR’);, -OP(0),0R’, -P(0),0R’, -PO(R’),;, -OPO(R’),, or an optionally substituted group selected from C,.Cealiphatic, aryl, heteroaryl, cycloaliphatic, heterocycloaliphatic, arylC;-Cgalkyl, heteroarylC;-Cgalkyl, cycloaliphaticC;-Cgalkyl, or heterocycloaliphaticC;-Cgalkyl.
121. The compound of claim 103, wherein y is 0-5, and q is 1 or 2, and each occurrence of R>® is independently CI, Br, F, CF;, Me, Et, CN, -COOH, -NH;, -N(CH3),, -N(Et)2, -N(iPr),, - O(CH,),0CH3j, -CONH,, -COOCHj3;, -OH, -OCH3, -OCH,CH3, -CH,0H, -NHCOCH;, -SO;NH,, -SO;NHC(CH3),, -OCOC(CH3);, -OCOCH,C(CHz3)3, -O(CH2);N(CH3),, 4-CHj-piperazin-1-yl, OCOCH(CH3);, OCO(cyclopentyl), -COCHj, optionally substituted phenoxy, or optionally substituted benzyloxy.
122. The compound of claim 103, wherein: y is 0, and R* is F; yis 0, qis 1, and R*is OR’; y is 0, q is 1 and R* is OH; yis 1, R* is OR’ and R’ is F, wherein OR” is substituted at the 2-position of the phenyl ring and F is substituted at the 6-position of the phenyl ring; or y is 1, R* is OH and R’ is F, wherein OH is substituted at the 2-position of the phenyl ring and F is substituted at the 6-position of the phenyl ring.
123. The compound of claim 103, wherein R’ is substituted at the 6-position of the quinazoline ring, q is 1, and y is 0, and compounds have formula III: RY, -R® ae -515- Amended sheet: 29 September 2006
III
124. The compound of claim 123, wherein: a) wherein R' and R? are each independently an optionally substituted group selected from Cjgaliphatic, Cy', wherein Cy' is a 5-7-membered monocyclic aryl ring or an 8-10- membered bicyclic aryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or is a 3-12-membered saturated or partially unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein Cy' is bonded directly to the nitrogen atom or is bonded through an optionally substituted C,aliphatic group, wherein one or more methylene units in the C;4aliphatic group are optionally replaced with -NR-, -O-, -COO, -OCO-, -NRCO-, -CONR-, -SO,NR-, or -NRSO,-; wherein R' and R?, are each optionally and independently substituted at one or more substitutable carbon, nitrogen, or sulfur atoms with z independent occurrences of -R*, wherein z is 0-5; b) z is 0-5 and R* groups are each independently Cl, Br, F, CF;, CHs, -CH,CH3, CN, - COOH, -N(CH3)2, -N(Et);, -N(iPr);, -O(CH,);OCH3;, -CONH,, -COOCH3;, -OH, -CH,OH, - NHCOCH;, -SO;NH,, -SO,(CH;,);CHi;, -SO,CH(CHj);, -SO,N(CHj),, -SO,CH,CH;, - C(O)OCH,CH(CH3s),, -C(O)NHCH,CH(CH3),, -NHCOOCH3;, -C(O)C(CH3);, -COO(CH,),CH3, -C(O)NHCH(CH3),;, -C(O)CH,CHj;, or an optionally substituted group selected from - piperidinyl, piperizinyl, morpholino, C;4alkoxy, phenyl, phenyloxy, benzyl, benzyloxy, - CHjcyclohexyl, pyridyl, -CH,pyridyl, or -CH,thiazoly],; ¢) R* is Cl, Br, F, CFs, -OCF;, Me, Et, CN, -COOH, -NH,, -N(CH3),, -N(Et),, -N(iPr),, - O(CH,),0CH3, -CONH,;, -COOCH;, -OH, -OCHs, -OCH,CHj;, -CH,OH, -NHCOCH;, - NHCOCH(CH3;),;, -SO;NH;, -CONH(cyclopropyl), -CONHCH;, -CONHCH,CHj;, or an optionally substituted group selected from -piperidinyl, piperizinyl, morpholino, phenyl, phenyloxy, benzyl, or benzyloxy; and d) R® is Cl, F, CF;, Me, Et, -OH, -OCHs, -OCH,CH;, -CH,OH, -SO,NH,, - SO,NHC(CHj3)2, -OCOC(CHs)s, -OCOCH,C(CH3)3, -O(CH;),N(CH3),, 4-CH;-piperazin-1-yl, OCOCH(CH3)2, OCO(cyclopentyl), or -COCH3;.
125. The compound of claim 123, wherein R® is -Cl, -CH;, -CH,CHs, -F, -CF;, -OCF;, - CONHCH3;, -CONHCH,CH3, -CONH(cyclopropyl), -OCH3, -NH,, -OCH,CHj3, or -CN. -516- Amended sheet: 29 September 2006
126. The compound of claim 123, wherein R3is -Cl, -CHj3, -CH,CH3, -F, -CF3, -OCF;, -OCH3, or -OCH,CH;.
127. The compound of claim 123, wherein Ris —CON(R’),, or NRCOR’.
128. The compound of claim 123, wherein Ris Cl, F, CF;, Me, Et, -OH, -OCH3, -OCH,CH3s.
129. The compound of claim 123, wherein: Ris F; R>*is OR’; or Ris OH.
130. The compound of claim 123, wherein: a) Cy' is: 2R*) N Mig I NT ge g 0 ~N s 1 Dry Ch 7 RA a b c d (R*), (R), (R%) (RY) 2 WAN N=X z NZX z Lig ig \ N” NN ho “ e f g h H 4 -N —(R%) N-™N NT (RY N J N £ “2 (RY FN z AN 4 N h T r4 7 \\ "e (R%); oN NN TS i i k 1 -517- Amended sheet: 29 September 2006
4 R4 R4 R4 R « NA , | N N S £4 0] My J=N he The, m n 0 P R4 R4 R4 j= p= j=, ., on “i, wy, (RY); q r S t N 0 Cod x oR: CJR od, (R%), N N (R%), H H u v w x H N Su, SN SN] AA (R%) po 0 A TOR, ORY, ER y z aa bb or R' and R? are each independently an optionally substituted C,_saliphatic group and are each independently selected from optionally substituted methyl, ethyl, cyclopropyl, n-propyl, propenyl, cyclobutyl, (CO)OCH,CH3, (CH,),OCH;, CH,CO)OCH,CHj3, CH»(CO)OCH;, CH(CH3)CH,CHs, or n-butyl;
b) z is 0-5 and R* groups are each independently Cl, Br, F, CF;, CH3, -CH,CHj3, CN, - COOH, —N(CHs),, -N(Et),, -N(iPr);, -O(CH;);OCH3, -CONH,, -COOCH;, -OH, -CH,0OH, - NHCOCH;, -SO;NH;, -SO,(CH;);CH;, -SO,CH(CHj3);, -SO,N(CHj);, -SO,CH,CHj;, - C(O)OCH,CH(CH3),, -C(O)NHCH,CH(CH3),, -NHCOOCH;3;, -C(O)C(CH3);, -COO(CH,),CHs, -C(O)NHCH(CH3),, -C(O)CH,CHj3, or an optionally substituted group selected from - piperidinyl, piperizinyl, morpholino, Cj4alkoxy, phenyl, phenyloxy, benzyl, benzyloxy, - CHscyclohexyl, pyridyl, -CH,pyridyl, or -CHjthiazolyl;
-518- Amended sheet: 29 September 2006
¢) Ris Cl, Br, F, CFs, -OCF3, Me, Et, CN, -COOH, -NH,, —-N(CHj3), -N(Et),, -N(iPr), - O(CH;),0CH3, -CONH,, -COOCH;, -OH, -OCHj;, -OCH,CH;, -CH,OH, -NHCOCH;, - NHCOCH(CH3),, -SO,NH,, -CONH(cyclopropyl), -CONHCH;, -CONHCH,CHj;, or an optionally substituted group selected from -piperidinyl, piperizinyl, morpholino, phenyl, phenyloxy, benzyl, or benzyloxy; and d) R™® is Cl, F, CF;, Me, Et, -OH, -OCHj;, -OCH,CHs, -CH,OH, -SO,NH,, - SO;NHC(CH3),, -OCOC(CH3);, -OCOCH;C(CH3)3, -O(CH»),N(CH3),, 4-CH;-piperazin-1-yl, OCOCH(CH3),,0CO(cyclopentyl), or -COCHs.
131. The compound of claim 123, wherein R} is -Cl, -CH;, -CH,CHs, -F, -CF;, -OCF;, - CONHCH3;, -CONHCH,CHs, -CONH(cyclopropyl), -OCH3, -NH,, -OCH,CH3, or -CN.
132. The compound of claim 123, wherein Ris -Cl, -CH;, -CH,CHas, -F, -CF3, -OCF;, -OCHs, or -OCH,CHs.
133. The compound of claim 123, wherein R} is—CON(R’),, or NRCOR".
134. The compound of claim 123, wherein R¥ is Cl, F, CF;, Me, Et, -OH, -OCH,;, -OCH,CHas.
135. The compound of claim 123, wherein: R® is F; R%® is OR’; or Ris OH.
136. The compound of claim 103, wherein R® is substituted at the 7-position of the quinazoline ring, q is 1, and y is 0, and compounds have formula I'V: 1 2 RNR Ory RSa aac IV -519- Amended sheet: 29 September 2006
137. The compound of claim 136, wherein: a) wherein R' and R? are each independently an optionally substituted group selected from Cjealiphatic, Cy', wherein Cy' is a 5-7-membered monocyclic aryl ring or an 8-10- membered bicyclic aryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or is a 3-12-membered saturated or partially unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein Cy' is bonded directly to the nitrogen atom or is bonded through an optionally substituted C,4aliphatic group, wherein one or more methylene units in the C;4aliphatic group are optionally replaced with -NR-, -O-, -COO, -OCO-, -NRCO-, -CONR-, -SO,NR-, or -NRSO,-; wherein R' and R?, are each optionally and independently substituted at one or more substitutable carbon, nitrogen, or sulfur atoms with z independent occurrences of —R*, wherein z is 0-5; b) z is 0-5 and R* groups are each independently Cl, Br, F, CF;, CHs, -CH,CHj3;, CN, - COOH, —-N(CH3),, -N(Et),, -N(iPr),;, -O(CH,),OCH3;, -CONH,, -COOCHj;, -OH, -CH,OH, - NHCOCH;, -SO;NH;, -SO(CH;);CHs3, -SO,CH(CH3);, -SO,N(CHj),, -SO,CH,CHs, - C(O)OCH,CH(CH3),, -C(O)NHCH,CH(CH3),, -NHCOOCH3;, -C(O)C(CH3);, -COO(CH,),CH3, -C(O)NHCH(CH3j),;, -C(O)CH,CHs, or an optionally substituted group selected from - piperidinyl, piperizinyl, morpholino, C;4alkoxy, phenyl, phenyloxy, benzyl, benzyloxy, - CHycyclohexyl, pyridyl, -CH;pyridyl, or -CH,thiazolyl, ¢) R? is Cl, Br, F, CF, -OCF3, Me, Et, CN, -COOH, -NH,, -N(CH3),, -N(Et),, -N(iPr),, - O(CH,),OCHj;, -CONH,, -COOCH;, -OH, -OCHj;, -OCH,CHj;, -CH,OH, -NHCOCH;, - NHCOCH(CH3);, -SO;NH,, -CONH(cyclopropyl), -CONHCH;, -CONHCH,CH;, or an optionally substituted group selected from -piperidinyl, piperizinyl, morpholino, phenyl, phenyloxy, benzyl, or benzyloxy; and d) R® is Cl, F, CF;, Me, Et, -OH, -OCHj, -OCH,CHj;, -CH,OH, -SO,NH,, - SO,NHC(CH3),, -OCOC(CHj3);, -OCOCH,C(CH3);3, -O(CH,)N(CH3),, 4-CHjs-piperazin-1-yl, OCOCH(CH3;),, OCO(cyclopentyl), or -COCH3.
138. The compound of claim 136, wherein R? is -Cl, -CHj;, -CH,CHjs, -F, -CFs, -OCF;, - CONHCHj3;, -CONHCH,CH3, -CONH(cyclopropyl), -OCH3, -NH,, -OCH,CHj3, or -CN. -520- Amended sheet: 29 September 2006
139. The compound of claim 136, wherein R} is -Cl, -CH3s, -CH,CH;, -F, -CF;, -OCF;, -OCHjs, or -OCH,CHs.
140. The compound of claim 136, wherein R® is —CON(R’)3, or NRCOR’.
141. The compound of claim 136, wherein R® is Cl, F, CFs, Me, Et, -OH, -OCH3;, -OCH,CH;.
142. The compound of claim 136, wherein: R*isF; Ris OR’; or R* is OH.
143. The compound of claim 136, wherein: a) Cy' is: 2R*) N ON ge) NZ ee 1 ~N g al R4 A z J z (7 >” (R%), “, N a b c d (R)2 (R*), (R%) (RY) ~ N=x r4 = r4 2 [hv 7 N” NN “ 4 e f g h H 4 -N —(R%) N \ N x z R4 .N Ps N KRY § NA )z Nod N / \ z i \ 0 (RY), = N NN Ty i j k - 521 - Amended sheet: 29 September 2006
4 R4 R4 R4 y~(R UY on NA . S £4 0] 'e we m n ) p R4 RY Rr va ve N ve N ~~ (RY), q r Ss t N 0 FC rr hl R4 ad 2 RY Ha NS fo oR: C, J Fo od, (RY), N N (R%), H H u v w x H N on AN; AN ~~ RY) ~ Oo) i OONRY, CORY, LX ge, 4 i y z aa bb or R! and R? are each independently an optionally substituted C_saliphatic group and are each independently selected from optionally substituted methyl, ethyl, cyclopropyl, n-propyl, propenyl, cyclobutyl, (CO)YOCH,CH3, (CH2),OCH3, CH,CO)OCH,CH3, CH,(CO)OCH3, CH(CH3)CH,CHs, or n-butyl;
b) z is 0-5 and R* groups are each independently Cl, Br, F, CFs, CH3, -CH,CH3, CN, - COOH, —-N(CH3), -N(Et)z, -N(iPr),, -O(CH,);OCH;, -CONH,, -COOCHj;, -OH, -CH,OH, - NHCOCH;, -SO;NH,, -SOy(CH,);CHs, -SO,CH(CHs;);, -SO;N(CH;);, -SO,CH,CH;, - C(0O)OCH,CH(CH3s),, -C(O)NHCH,CH(CH3),, -NHCOOCH3;, -C(O)C(CH3)3, -COO(CH,),CHs, -C(O)NHCH(CH3);, -C(O)CH,CHs, or an optionally substituted group selected from - piperidinyl, piperizinyl, morpholino, C,salkoxy, phenyl, phenyloxy, benzyl, benzyloxy, - CHjcyclohexyl, pyridyl, -CHapyridyl, or -CHathiazolyl;
-522- Amended sheet: 29 September 2006
¢) Ris Cl, Br, F, CFs, -OCF3, Me, Et, CN, -COOH, -NH,, -N(CHjs),, -N(Et),, -N(@iPr)a, - O(CH,);0CH;, -CONH,, -COOCH;, -OH, -OCH;, -OCH,CH;, -CH,OH, -NHCOCH;, - NHCOCH(CH3);, -SO;NH;, -CONH(cyclopropyl), -CONHCHj;, -CONHCH,CH;, or an optionally substituted group selected from -piperidinyl, piperizinyl, morpholino, phenyl, phenyloxy, benzyl, or benzyloxy; and d) R® is Cl, F, CF;, Me, Et, -OH, -OCHs3, -OCH,CHj;, -CH,OH, -SO,NH,, - SO,NHC(CH3j),, -OCOC(CHs);, -OCOCH,C(CHj3)3, -O(CH3)>N(CHjs),, 4-CHjs-piperazin-1-yl, OCOCH(CH3),,0CO(cyclopentyl), or -COCHs.
144. The compound of claim 136, wherein R® is -Cl, -CH3, -CH,CHj3, -F, -CF;, -OCF;, - CONHCH3;, -CONHCH,CHj3;, -CONH(cyclopropyl), -OCHj3, -NH,, -OCH,CH3, or -CN.
145. The compound of claim 136, wherein Ris -Cl, -CHs, -CH,CH3;, -F, -CF3, -OCF;, -OCH3, or -OCH,CHs.
146. The compound of claim 136, wherein R} is=CON(R’),, or NRCOR’.
147. The compound of claim 136, wherein Ris Cl, F, CF;, Me, Et, -OH, -OCH,, -OCH,CHs.
148. The compound of claim 136, wherein: R*is F; Ris OR’: or R*is OH.
149. A compound of formula V: 1 2 Ri y-R TN we L * LL ~ NNR LD (R%y \% -523- Amended sheet: 29 September 2006 wherein R' and R? are each independently an optionally substituted group selected from Cialiphatic, Cy', wherein Cy' is a 5-7-membered monocyclic aryl ring or an 8-10-membered bicyclic aryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or is a 3-12-membered saturated or partially unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein Cy' is bonded directly to the nitrogen atom or is bonded through an optionally substituted C, aliphatic group, wherein one or more methylene units in the C,4aliphatic group are optionally replaced with -NR- , -0-, -CO0, -OCO-, -NRCO-, -CONR-, -SO3;NR-, or -NRSO»-; or R' and R?, taken together with the nitrogen atom to which they are bound, form an optionally substituted 3-12-membered monocyclic or bicyclic saturated or partially unsaturated ring having 0-3 additional heteroatoms independently selected from nitrogen, sulfur, or oxygen; wherein R! and R?, or the ring formed by R! and R? taken together, are each optionally and independently substituted at one or more substitutable carbon, nitrogen, or sulfur atoms with z independent occurrences of —R*, wherein z is 0-5;
x is 0-4;
y is 0-2;
each occurrence of R?, R%, and R® is independently Q-R*; wherein Q is a bond or is a C;- Cs alkylidene chain wherein up to two non-adjacent methylene units of Q are optionally and independently replaced by -NR-, -S-, -O-, -CS-, -CO,-, -OCO-, -CO-, -COCO-, -CONR-, - NRCO-, -NRCO;-, -SO;NR-, -NRSO;-, -CONRNR-, -NRCONR-, -OCONR-, -NRNR-, - NRSO;NR-, -SO-, -SO;-, -PO-, -PO,-, -OP(O)(OR)-, or -POR-; and each occurrence of RX is independently selected from -R’, =O, =NR’, halogen, -NO,, -CN, -OR’, -SR’, -N(R’)a, - NR’COR’, -NR’CON(R);, -NR’CO;R’, -COR’, -CO;R’, -OCOR’, -CON(R’),, -OCON(R’),, - SOR’, -SO,R’, -SO;N(R’),, -NR’SO,R’, -NR’SO;N(R),, -COCOR’, -COCH,COR’, - OP(O)(OR),, -P(O)(OR’),, -OP(0),;0R”’, -P(0);0R”’, -PO(R’),, or -OPO(R’),;
R> is an optionally substituted C,-Csaliphatic group, halogen, -OR’, -SR”’, -N(R"),, - NR’COR’, -NR’CON(R’),, -NR’CO;R’, -COR’, -CO,R’, -OCOR’, -CON(R’);, -OCON(R’),, - SOR’, -SO,R’, -SO;N(R’),, -NR’SO2R’, -NR’SO,N(R),, -COCOR’, -COCH,COR’, - OP(O)(OR’)z, -P(O)}(OR’);, -OP(0); OR’, -P(0)0R’, -PO(R’)2, or -OPO(R’),; and
-524 - Amended sheet: 29 September 2006 each occurrence of R is independently hydrogen or an optionally substituted C,. aliphatic group; and each occurrence of Ris independently hydrogen or an optionally substituted C6 aliphatic group, a 3-8-membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-12 membered saturated, partially unsaturated, or fully unsaturated bicyclic ring system having 0-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or R and R, two occurrences of R, or two occurrences of R, are taken together with the atom(s) to which they are bound to form an optionally substituted 3-12 membered saturated, partially unsaturated, or fully unsaturated monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; provided that when x is 1 and R? is 6-OMe, R! is hydrogen, and y and q are both 0, then R? is not —CH,CH,0OCH,CH,0H or the monomethanesulfonate salt.
150. The compound of claim 149, wherein a) one of R' or R? is hydrogen, and the other of R' and R? is selected from: i) Cy' wherein Cy' is bonded directly to the nitrogen atom or is bonded through an optionally substituted C4aliphatic group, wherein one or more methylene units in the Cj4aliphatic group are optionally replaced with -NR-, -O-, -COO, -OCO-, -NRCO-, - CONR-, -SO;NR-, or -NRSO»-; or ii) an optionally substituted C,4aliphatic group, wherein one or more methylene units in the C,4aliphatic group are optionally replaced with -NR-, -O-, -COO, -OCO-, - NRCO-, -CONR-, -SO;NR-, or -NRSO,-; or b) R! and R? are each independently selected from Cy', wherein Cy' is bonded directly to the nitrogen atom or is bonded through an optionally substituted C;4aliphatic group, wherein one or more methylene units in the C,aliphatic group are optionally replaced with -NR-, -O-, -COO, -OCO-, -NRCO-, -CONR-, -SO;NR-, or -NRSO;-; or an optionally substituted C,_4aliphatic group, wherein one or more methylene units in the C,. saliphatic group are optionally replaced with —NR-, -O-, -COO-, -OCO-, -NRCO-, - CONR-, -SO;NR-, or -NRSO;-. - 525 - Amended sheet: 29 September 2006
151. The compound of claim 149, wherein Cy" is: Ny 2 APA NS i NZ AN Fo uo R4 z i (R* z ag —- TT (R* z HR SI J oR a b c d (R%), (R*), (RY), (RY) = > N= = z NZ A = NZX ES Jl HL bo NH Nr N N’ ho Ed e f g h H 4 -N — (RY), N \ N 4 R% .N | N a ®Y, . N—( z — “) gC 3 i i Kk 1 R* R* R? 3 R* r4 i yf NN NA oy S eS Pa J=N hs Tn, m : n 0 p R4 R4 R4 _— No Ng 0) LN a “LN SNR, q r Ss t H (0) ‘ a NH CN CY oa 0 T J — SRY, i 5 (RY, = J Hod, Se Wy Code, u v w X - 526 - Amended sheet: 29 September 2006
H N on SN} AN; XK (RY TIN RY, TNR, ey —& 2 y z aa bb
152. The compound of claim 149, wherein R' is hydrogen or an optionally substituted C;- Caliphatic group and R? is —CHR-Cy', wherein R is hydrogen or C;-Caalkyl, and Cy is: ARYL N FY 4 NZ 4 ne =N fn x 4 1 RY, LR: FT) 1 RY: “, N N a b c d (R%), (R%), (R%) (RY) = SA N=" NZX 2 Sl! Lh Dw J Ng Nh h , e f g h H -N — RY N~™, NV" /z R%) .N pa N La (R% § NA z AN 4 N h \ z l} \ ®e ON $0 Ty i j k 1 R4 Rr R4 R4 yt )z NN N A, oN s nf 0 Pa J=N hd Tha, m n 0 Pp R4 R* R* BY ro rg 0) a ve N w= N SNR, q r Ss t - 527 - Amended sheet: 29 September 2006
N 0 FO He He HO (Ne QJ Rk CJ Cod, (R%), N N (R%), H H u v w xX H ) >, oN; EN A (R%) SN 0 i RY, re, { po, RE z y z aa bb
153. The compound of claim 149, wherein R' and R* groups are each independently an optionally substituted Cj4aliphatic group and are each independently selected from optionally substituted methyl, ethyl, cyclopropyl, n-propyl, propenyl, cyclobutyl, (CO)OCH,CHj, (CH,);0CH3, CH,CO)OCH,CHj3;, CH,(CO)OCH;, CH(CH3)CH,CH3, or n-butyl.
154. The compound of claim 149, wherein R' and R?, taken together with the nitrogen atom to which they are bound, form an optionally substituted 3-12 membered heterocyclyl ring having 1- 3 heteroatoms independently selected from nitrogen or oxygen and form a 3-12 membered heterocyclyl group selected from: R* (R%) (R%) A )2 A ? A ‘ L_NH NG cc dd ee y N iN (5 (Cy (2 4 (RY), ff gg hh £ RY, T jo CNT N 2 ) (_s “RY /. ’ 2R% ii ii kk - 528 - Amended sheet: 29 September 2006
: I) I Tv KoRn & pe Ri, Q . i) (RY), 1} mm nn 00 wherein the ring formed by R! and R? taken together, is optionally substituted at one or more substitutable carbon, nitrogen, or sulfur atoms with z independent occurrences of -R*, and zis 0-S.
155. The compound of claim 149, wherein R' and R? taken together is an optionally substituted ring selected from pyrrolidin-1-yl (ff), piperidinl-yl (dd), piperazin-1-yl (cc), or morpholin-4-yl (ee).
156. The compound of claim 149, wherein R' and R? taken together is an optionally substituted ring selected from pyrrolidin-1-yl (ff), piperidin!-yl (dd), or piperazin-1-yl (ce).
157. The compound of claim 149, wherein z is 0-5, and R* groups, when present, are each independently halogen, CN, NO,, -N(R’),, -CH,N(R’),;, -OR’, -CH,0R’, -SR’, -CH,SR’, - COOR’, -NRCOR’, -CON(R’);, -OCON(R’);, COR’, -NHCOOR’, -SO;R’, -SO;N(R’),, or an optionally substituted group selected from C,.Cqaliphatic, aryl, heteroaryl, cycloaliphatic, heterocycloaliphatic, arylC,-Csalkyl, heteroarylC;-Cealkyl, cycloaliphaticC,-Cgalkyl, or heterocycloaliphaticC;-Cealkyl.
158. The compound of claim 149, wherein z is 0-5 and R* groups are each independently Cl, Br, F, CF3;, CHjs, -CH,CH3, CN, -COOH, —-N(CH3),, -N(Et),, -N(iPr),, -O(CH;),OCH3, -CONH,, © -COOCH;, -OH, -CH,OH, -NHCOCH;, -SO,;NH,, -SO,(CH,);CH;, -SO,CH(CHs),, - SO;N(CH3),, -SO,CH,CHj3, -C(O)OCH;CH(CH3),, -C(O)NHCH,CH(CH3),, -NHCOOCH;, - C(O)C(CH3)3, -COO(CH;),CH;, -C(O)NHCH(CH3;);, -C(O)CH,CH3, or an optionally substituted group selected from -piperidinyl, piperizinyl, morpholino, Cj.salkoxy, phenyl, phenyloxy, benzyl, benzyloxy, -CHacyclohexyl, pyridyl, -CHpyridyl, or -CH,thiazolyl. - 529 - Amended sheet: 29 September 2006
159. The compound of claim 149, wherein x is 0-4, and rR? groups, when present, are each independently halogen, CN, NO,, -N(R”);, -CH;N(R’);, -OR’, -CH,OR’, -SR’, -CH,SR’, - COOR’, -NRCOR’, -CON(R”);, -OCON(R’);, COR’, -NHCOOR’, -SO;R’, -SO;N(R’),, or an optionally substituted group selected from C,Cgaliphatic, aryl, heteroaryl, cycloaliphatic, heterocycloaliphatic, arylC|-Cealkyl, heteroarylC,;-Cealkyl, cycloaliphaticC,-Cgalkyl, or heterocycloaliphaticC,-Cealkyl.
160. The compound of claim 149, wherein R' and RZ, taken together is selected from:
a. optionally substituted azetidin-1-yl (jj), wherein z is 1 or 2 and at least one occurrence of R* is -NRSO,R’, -NRCOOR’, or -NRCOR’;
b. optionally substituted azetidin-1-yl (jj), wherein z is I and R* is -NRSO,R’;
c. optionally substituted azetidin-1-yl (jj), wherein z is 1 and R* is -NRCOOR’;
d. optionally substituted azetidin-1-yl (jj), wherein z is 1 and R* is -NRCOR’;
e. optionally substituted pyrrolidin-1-yl (ff), wherein z is 1 or 2 and R* is CI, Br, F, CF;, CH3;, -CH,CH3, -OR’, or -CH,OR’;
f. optionally substituted piperidin-1-yl (dd), wherein z is 1 or 2 and at least one occurrence of R* is Cl, Br, F, CF3, CH3, -CH,CHj, -OR’, or -CH,OR’, -NRSO;R’, -NRCOOR”, or —-OCON(R’)3;
g. optionally substituted piperidin-1-yl (dd), wherein z is 1 and R* is F, CFs, CH;, - CH,CHj, -OR’, or -CH,0OR’;
h. optionally substituted piperidin-1-yl (dd), wherein z is | and R* is —NRSO,R’;
i. optionally substituted piperidin-1-yl (dd), wherein z is 1 and R* is -NRCOOR’; Je optionally substituted piperazin-1-yl (cc), wherein z is 1 or 2 and at least one occurrence of R* is —=SOR’, -CON(R”),, -SO;N(R?),, -COR’, or -COOR’;
k. optionally substituted piperazin-1-yl (cc), wherein z is | and R* is ~-SOR’
1. optionally substituted piperazin-1-yl (ec), wherein zis 1 and R* is —COOR’;
m. optionally substituted piperazin-1-yl (ce), wherein z is 1 and R* is -CON(R’);
n. optionally substituted piperazin-1-yl (ec), wherein z is 1 and R* is -SO,N(R),; or
0. optionally substituted piperazin-1-yl (cc), wherein z is 1 and R*is -COR’. -530- Amended sheet: 29 September 2006
161. The compound of claim 149, wherein x is 1 or 2, and each occurrence of R? is independently Cl, Br, F, CF;, -OCF3, Me, Et, CN, -COOH, -NH;, —-N(CH3),, -N(Et),, -N(iPr)y, - O(CH,),0CH;, -CONH,;, -COOCHj;, -OH, -OCHs;, -OCH,CH;, -CH,OH, -NHCOCH;, - NHCOCH(CH3);, -SO.NH,;, -CONH(cyclopropyl), -CONHCH;, -CONHCH,CHs3;, or an optionally substituted group selected from -piperidinyl, piperizinyl, morpholino, phenyl, phenyloxy, benzyl, or benzyloxy.
162. The compound of claim 149, wherein x is 1 or 2 and each R® group is independently halogen, CN, optionally substituted C,-Cealkyl, OR’, N(R’),, CON(R"),, or NRCOR”.
163. The compound of claim 149, wherein x is 1 or 2, and each R® group is -Cl, -CHj3, - CH,CHj, -F, -CF3, -OCF3, -CONHCHj3;, -CONHCH,CHj3, -CONH(cyclopropyl), -OCHs, -NH,, - OCH,CHjs;, or -CN.
164. The compound of claim 149, wherein x is 1 and R® is at the 6-position of the quinazoline ring and is -Cl, -CHj;, -CH,CHj;, -F, -CF;, -OCF;, -CONHCH;, -CONHCH,CHs;, - CONH(cyclopropyl), -OCH3, -NH,, -OCH,CHj3, or -CN.
165. The compound of claim 149, wherein x is 1 and R? is at the 7-position of the quinazoline ring and is -Cl, -CHs, -CH,CHs;, -F, -CF; -OCF; -CONHCHj;, -CONHCH,CHj;, - CONH(cyclopropyl), -OCHj, -NH,, -OCH,CH3, or -CN.
166. The compound of claim 149, wherein x is 1 and R? is at the 6-position of the quinazoline ring and is -Cl, -CH;, -CH,CH3s, -F, -CF;, -OCF;, -OCHjs, or -OCH,CHj;.
167. The compound of claim 149, wherein x is 1 and R? is at the 7-position of the quinazoline ring and is -Cl, -CH3, -CH,CHj, -F, -CF3, -OCF3, -OCH3, or -OCH,CH3.
168. The compound of claim 149, wherein x is 1 and R? is at the 6-position of the quinazoline ring and is “CON(R’),, or NRCOR". -531- Amended sheet: 29 September 2006
169. The compound of claim 149, wherein x is 1 and R? is at the 7-position of the quinazoline ring and is -CON(R”),, or NRCOR".
170. The compound of claim 149, wherein y is 0-2, q is 0-2, and R’ and R> groups, when present, are each independently halogen, CN, NO,, -N(R”),, -CH,N(R’),, -OR’, -CH,OR”’, -SR”, -CH,SR’, - -NRCOR’, -CON(R’),, -S(0);N(R’);, -OCOR’, -COR’, -CO;R’, -OCON(R’),, - NR’SO,;R’, -OP(O)(OR’),, -P(O)(OR’),, -OP(0),0R’, -P(0),0R’, -PO(R’),, -OPO(R’),, or an optionally substituted group selected from C,.Cqaliphatic, aryl, heteroaryl, cycloaliphatic, heterocycloaliphatic, arylC,-Cealkyl, heteroarylC,-Cealkyl, cycloaliphaticC,-Cealkyl, or heterocycloaliphaticC;-Cesalkyl.
171. The compound of claim 149, wherein y is 0-2, and q is 1 or 2, and each occurrence of R> is independently Cl, Br, F, CF;, Me, Et, CN, -COOH, -NH;, -N(CH3),, -N(Et)2, -N(iPr),, - O(CH;),0CH3, -CONH;, -COOCHj3, -OH, -OCH3, -OCH,CH3, -CH,OH, -NHCOCH3, -SO;NHs, -SO,NHC(CH3),, -OCOC(CH3)3, -OCOCH,;C(CH3)3, -O(CH3),N(CH3),, 4-CHj-piperazin-1-yl, OCOCH(CH3),, OCO(cyclopentyl), -COCHs, optionally substituted phenoxy, or optionally substituted benzyloxy.
172. The compound of claim 149, wherein: a) yis0,and q is | and R®is F; b)yis 0, qis 1, and R* is OR’; c)yis 0, qis 1 and R* is OH; d) y is 0, q is 2 and one occurrence of Ris OR’ and the other occurrence of R* is F, or e) y is 0, q is 2 and one occurrence of R® is OH and the other occurrence of R* is F.
173. The compound of claim 149, wherein: a) R! and R? taken together is an optionally substituted ring selected from azetidin-1-yl (ji), pyrrolidin-1-yl (ff), piperidinl-yl (dd), or piperazin-1-yl (cc); one of R! or R? is hydrogen, and the other of R' and R? is selected from Cy', wherein Cy' is bonded directly to the nitrogen atom or is bonded through an optionally substituted C,4aliphatic group, wherein one or more -532- Amended sheet: 29 September 2006 methylene units in the C,4aliphatic group are optionally replaced with -NR-, -O-, -COO, -0OCO-, -NRCO-, -CONR-, -SO;NR-, or -NRSO;-, or an optionally substituted C)4aliphatic group, wherein one or more methylene units in the C4aliphatic group are optionally replaced with -NR- , -0-, -CO0, -OCO-, -NRCO-, -CONR-, -SO;NR-, or -NRSO;-; or R! and R? are each independently selected from an optionally substituted C,4aliphatic group, wherein one or more methylene units in the C,4aliphatic group are optionally replaced with -NR-, -O-, -COO, -OCO-, -NRCO-, -CONR-, -SO,NR-, or -NRSO,-; or Cy’ wherein Cy' is bonded to the nitrogen atom directly or is bonded through an optionally substituted C;aliphatic group, wherein one or more methylene units in the C,4aliphatic group are optionally replaced with -NR-, -O-, -COO, -OCO-, -NRCO-, -CONR-, -SO;NR-, or -NRSO;-;
b) z is 0-5 and R* groups are each independently Cl, Br, F, CF;, CH3;, -CH,CHj3, CN, - COOH, —-N(CH3),, -N(Et);, -N(iPr),;, -O(CH;),0OCHj3;, -CONH,, -COOCH3;, -OH, -CH,OH, - NHCOCH;, -SO;NH;, -SO,(CH;);CHj;, -SO,CH(CHs),, -SO,N(CHs),, -SO,CH,CHj, - C(O)OCH,CH(CH3),, -C(O)NHCH,CH(CH3),, -NHCOOCH3, -C(O)C(CH3)3, -COO(CH;3),CH3, -C(O)NHCH(CH3),2, -C(O)CH,CHj;, or an optionally substituted group selected from - piperidinyl, piperizinyl, morpholino, C;4alkoxy, phenyl, phenyloxy, benzyl, benzyloxy, - CHacyclohexyl, pyridyl, -CH,pyridyl, or -CHathiazolyl;
¢) xis 0, 1, or 2, and each occurrence of Ris independently Cl, Br, F, CF;, -OCF;, Me, Et, CN, -COOH, -NHj, -N(CH3),, -N(Et),, -N(iPr),, -O(CH,);OCHj3;, -CONH,, -COOCH3, -OH, -OCHj3;, -OCH,CHj3;, -CH,0H, -NHCOCHj;, -NHCOCH(CH3),, -SO,NH,, -CONH(cyclopropyl), -CONHCHj;, -CONHCH,CH3, or an optionally substituted group selected from -piperidinyl, piperizinyl, morpholino, phenyl, phenyloxy, benzyl, or benzyloxy;
d) wherein y is 0-2, and R’ groups, when present, are each independently CI, Br, F, CF;, Me, Et, CN, -COOH, -NH;, -N(CH3),, -N(Et),, -N(iPr),, -O(CH,),OCHj3, -CONH,, -COOCHj;, - OH, -OCHj;, -OCH,CHj3;, -CH,0H, -NHCOCHs;, -SO;NH;, -SO,NHC(CHj3),, -OCOC(CHs)s, - OCOCH,C(CH3)s, -O(CH,);N(CH3),, 4-CH;-piperazin-1-yl, OCOCH(CH3),;, OCO(cyclopentyl), -COCH3, optionally substituted phenoxy, or optionally substituted benzyloxy; and e) R*® is Cl, F, CF;, Me, Et, -OH, -OCHs3, -OCH,CHs, -CH,0OH, -SO,NH,, - SO,NHC(CH3);, -OCOC(CH3);, -OCOCH,C(CH3)3, -O(CH;):N(CH3),, 4-CHjs-piperazin-1-yl, OCOCH(CH3),, OCO(cyclopentyl), or -COCHs.
-533- Amended sheet: 29 September 2006
174. The compound of claim 173, wherein x is 1 and R? is at the 6-position of the quinazoline ring and is -Cl, -CHj;, -CH,CHj;, -F, -CF;, -OCF;, -CONHCH; -CONHCH,CHj;, - CONH( (cyclopropyl), -OCH3, -NH,, -OCH,CH3, or -CN.
175. The compound of claim 173 wherein x is 1 and R® is at the 7-position of the quinazoline ring and is -Cl, -CHs;, -CH,CHs;, -F, -CF;, -OCF;, -CONHCHj;, -CONHCH,CH;, - CONH(cyclopropyl), -OCH3, -NH,, -OCH,CH3, or -CN.
176. The compound of claim 173, wherein x is 1 and R’ is at the 6-position of the quinazoline ring and is -Cl, -CH3, -CH,CHj3, -F, -CF3, -OCF3, -OCHj3, or -OCH,CHs.
177. The compound of claim 173, wherein x is 1 and R? is at the 7-position of the quinazoline ring and is -Cl, -CHj3, -CH,CH3, -F, -CF3, -OCF;3, -OCH3, or -OCH,CH3.
178. The compound of claim 173, wherein x is 1 and R? is at the 6-position of the quinazoline ring and is -CON(R’),, or NRCOR’.
179. The compound of claim 173, wherein x is 1 and R? is at the 7-position of the quinazoline ring and is -CON(R’);, or NRCOR”.
180. The compound of claim 173, wherein R3*is Cl, F, CFs, Me, Et, -OH, -OCHj3, -OCH,CHj.
181. The compound of claim 173, wherein: a) yis 0, and q is 1 and R®is F; b)yis 0, q is 1, and R* is OR’; ¢)yis0,qis 1 and R* is OH; d) y is 0, q is 2 and one occurrence of R*® is OR’ and the other occurrence of R* is F; or e) y is 0, q is 2 and one occurrence of R*® is OH and the other occurrence of Ris F. -534 - Amended sheet: 29 September 2006
182. The compound of claim 173, wherein: a) Cy' is: Ny NT A 7 try, TRY; = ££ Sry, RY 5 CJ oR a b c d (R%) (R%); (R%) (RY) = < N= z oN z AH [wn 7 N~ SN “ad, 4 e f g h H -N — (RY N \ N > 2 R4
] .N J N Sry f NA )z AN 4 N h 3 ra 7 \ "e (R%), wg N No Ty i i k 1 . R4 R4 R4 R%)z ee Ny NA . S w/ Pa J=N 4, a, m n |] Pp R4 R4 R4 SE JE BE =N =N =N N04 “4, wg Ve (RY), q r S t N 0 SR, “NT Sy “RE, H H u v w X -535- Amended sheet: 29 September 2006
N > eC Xn, mo, Se, LR y z aa bb or R! and R? are each independently an optionally substituted C,_saliphatic group and are each independently selected from optionally substituted methyl, ethyl, cyclopropyl, n-propyl, propenyl, cyclobutyl, (CO)OCH,CH3, (CH,),OCH3, CH,CO)OCH,CH3, CH2(CO)OCH3, CH(CH3)CH,CH3, or n-butyl; b) z is 0-5 and R* groups are each independently Cl, Br, F, CF;, CH3, -CH,CH3, CN, - COOH, —-N(CH3)2, -N(Et);, -N(iPr),;, -O(CH,);OCHj3, -CONH,, -COOCHj3;, -OH, -CH,0H, - NHCOCH;, -SO;NH,, -SO,(CH;);CHj3;, -SO,CH(CHj3),, -SO;N(CHs);, -SO,CH,CH;, - C(0)OCH,CH(CHs),, -C(O)NHCH,CH(CH3s),, -NHCOOCH3;, -C(O)C(CH3)3, -COO(CH;),CH3, -C(O)NHCH(CH3);, -C(O)CH,CHs, or an optionally substituted group selected from - piperidinyl, piperizinyl, morpholino, Cjalkoxy, phenyl, phenyloxy, benzyl, benzyloxy, - CHacyclohexyl, pyridyl, -CH;pyridyl, or -CHsthiazolyl; ¢) xis 0, 1, or 2, and each occurrence of R? is independently Cl, Br, F, CF;, -OCF;, Me, Et, CN, -COOH, -NH,, -N(CHj3),, -N(Et)2, -N(iPr),, -O(CH,),OCH3, -CONH;, -COOCH3, -OH, -OCHj3;, -OCH,CHj3;, -CH,0OH, -NHCOCHj;, -NHCOCH(CH3),, -SO,NH;, -CONH(cyclopropyl), -CONHCHj;, -CONHCH,CH3, or an optionally substituted group selected from -piperidinyl, piperizinyl, morpholino, phenyl, phenyloxy, benzyl, or benzyloxy; d) wherein y is 0-5, and R® groups, when present, are each independently Cl, Br, F, CF3, Me, Et, CN, -COOH, -NH;, -N(CH3),, -N(Et),, -N(iPr),, -O(CH;),OCH3s, -CONH;, -COOCHy3, - OH, -OCHs;, -OCH,CHj;, -CH;OH, -NHCOCHj;, -SO;NH;, -SO,NHC(CHj3),, -OCOC(CH3);, - OCOCH,C(CH3)3, -O(CH,),N(CH3),, 4-CHjs-piperazin-1-yl, OCOCH(CHj;),, OCO(cyclopentyl), -COCH3, optionally substituted phenoxy, or optionally substituted benzyloxy; and e) R® is Cl, F, CF;, Me, Et, -OH, -OCHs, -OCH,CH3, -CH,OH, -SO,NH,, - SO,NHC(CH3)2, -OCOC(CH3)3, -OCOCH,C(CH3)3, -O(CH2);N(CH3),, 4-CHj;-piperazin-1-yl, OCOCH(CH3)2,0CO(cyclopentyl), or -COCH3.
183. The compound of claim 173, wherein x is | and R’ is at the 6-position of the quinazoline ring and is -Cl, -CH;, -CH,CH;, -F, -CF;, -OCF;, -CONHCH;, -CONHCH,CH;, - CONH(cyclopropyl), ~OCH3, -NH;, -OCH,CH3, or -CN. - 536 - Amended sheet: 29 September 2006
184. The compound of claim 173 wherein x is 1 and R? is at the 7-position of the quinazoline ring and is -Cl, -CH;, -CH,CHj;, -F, -CF3;, -OCF;, -CONHCH;, -CONHCH)CH;, - CONH(cyclopropyl), -OCH3, -NH,, -OCH,CH3, or -CN.
185. The compound of claim 173, wherein x is 1 and R? is at the 6-position of the quinazoline ring and is -Cl, -CH3;, -CH,CH3, -F, -CF3, -OCF;, -OCH3, or -OCH,CH;.
186. The compound of claim 173, wherein x is | and R? is at the 7-position of the quinazoline ring and is -Cl, -CH;, -CH,CH3, -F, -CF;, -OCF;, -OCHs;, or -OCH,CHj;.
187. The compound of claim 173, wherein x is 1 and R? is at the 6-position of the quinazoline ring and is -CON(R”),, or NRCOR".
188. The compound of claim 173, wherein x is | and R? is at the 7-position of the quinazoline ring and is -CON(R”),, or NRCOR’.
189. The compound of claim 173, wherein Ris Cl, F, CFs, Me, Et, -OH, -OCH3, -OCH,CHj.
190. The compound of claim 173, wherein R* is OR’.
191. The compound of claim 173, wherein R* is OH.
192. The compound of claim 173, wherein R* is F.
193. A compound of formula I-B-i: 1 R30 XY SN RSa N N 5 Ry I-B-i -537- Amended sheet: 29 September 2006 or a pharmaceutically acceptable salt thereof,
wherein R' is selected from C,saliphatic, Cy', wherein Cy' is a 5-7-membered monocyclic aryl ring or an 8-10-membered bicyclic aryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or is a 3-12-membered saturated or partially unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein Cy' is bonded directly to the nitrogen atom or is bonded through an optionally substituted C;4aliphatic group, wherein one or more methylene units in the Cialiphatic group are optionally replaced with -NR-, -O-, -COO, -OCO-, -NRCO-, -CONR-, - SO,NR-, or -NRSO,-; wherein R! is optionally substituted at one or more substitutable carbon, nitrogen, or sulfur atoms with z independent occurrences of -RY, wherein z is 0-5;
x is 0-4;
y is 0-4;
each occurrence of R?, R*, and R® is independently Q-R*; wherein Q is a bond or is a C;- Ce alkylidene chain wherein up to two non-adjacent methylene units of Q are optionally and independently replaced by —NR-, -S-, -O-, -CS-, -CO;-, -OCO-, -CO-, -COCO-, -CONR-, - NRCO-, -NRCO;-, -SO,NR-, -NRSO;-, -CONRNR-, -NRCONR-, -OCONR-, -NRNR-, - NRSO;NR-, -SO-, -S0;-, -PO-, -PO,-, -OP(O)(OR)-, or -POR-; and each occurrence of RX is independently selected from -R’, =0, =NR’, halogen, -NO,, -CN, -OR’, -SR’, -N(R’),, - NR’COR’, -NR’CON(R’),, -NR’CO3R’, -COR”’, -COzR’, -OCOR’, -CON(R’), -OCON(R’),, - SOR’, -SO,R’, -SO;N(R),, -NR’SO5R’, -NR’SO,;N(R’),, -COCOR’, -COCH,COR’, - OP(O)(OR’),, -P(O)(OR’),, -OP(0); OR’, -P(0),0R’, -PO(R’);, or -OPO(R’);
each occurrence of R* is independently an optionally substituted C,-Cgaliphatic group, halogen, -OR’, -SR”’, -N(R’),, -NR’COR’, -NR’CON(R’);, -NR’CO,R’, -COR”’, -CO,R’, - OCOR’, -CON(R’),, -OCON(R’)3, -SOR’, -SO2R’, -SO,N(R’)2, -NR’SO3R’, -NR’SO;N(R’),, - COCOR’, -COCH,COR’, -OP(O)(OR’),, -P(O)(OR’),, -OP(O),0R’, -P(0),0R’, -PO(R’),, or - OPO(R’),; and each occurrence of R is independently hydrogen or an optionally substituted C,.¢ aliphatic group; and each occurrence of R’ is independently hydrogen or an optionally substituted C. aliphatic group, a 3-8-membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-12 membered saturated, partially unsaturated, or fully unsaturated bicyclic ring system having 0-5
-538- Amended sheet: 29 September 2006 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or R and R, two occurrences of R, or two occurrences of R , are taken together with the atom(s) to which they are bound to form an optionally substituted 3-12 membered saturated, partially unsaturated, or fully unsaturated monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; provided that: a) when R¥ is Me, Cl, or OMe, and x is 0, then R! is not Et or Me; b) when R¥ is Cl, x is 3, and the three occurrences of R® are 6-Me, 7-COQEt, and 8-Me, then R' is not (CHa),piperidin-1-yl; ¢) when R* is Me, x is | and R® is NO, or NHa, then R! is not Et; d) when R¥is OH, NHMe, or N(NO)Me, and x is 0, then R! is not Et, Me or — CH,CH=CHy,; e) when R* is NH?, and x is 0, then R' is not -COCHj; f) when R* is Cl or Me, and y is 0 or 1 and when y is 1, R® is 4-Cl, and x is 0, then R' is not 4-CN-phenyl, 4-Me-phenyl, 4-OMe-phenyl, 4-Cl-phenyl, 4-NO,-phenyl, -CH,CH,NHMe, Et, Me, 4-COOMe-phenyl, -CH,Ph, iPr, 2-Me-phenyl, 4-phenyl-phenyl, or -CH,CH=CHS,.
194. The compound of claim 193, wherein a) R' is selected from: i) Cy! wherein Cy' is bonded directly to the nitrogen atom or is bonded through an optionally substituted C,.saliphatic group, wherein one or more methylene units in the C)4aliphatic group are optionally replaced with -NR-, -O-, -COO, -OCO-, -NRCO-, - CONR-, -SO;NR-, or -NRSO»-; or ii) an optionally substituted C,4aliphatic group, wherein one or more methylene units in the Cj4aliphatic group are optionally replaced with -NR-, -O-, -COO, -OCO-, - NRCO-, -CONR-, -SO;NR-, or -NRSO;-.
195. The compound of claim 193, wherein Cy' is:
AR. N +0) re, Ire, 0 Bi 0 re) NZ J “NF ZC a b ¢ d -539- Amended sheet: 29 September 2006
(RY), (RY), (R%), (RY) NT A N=X NZX O° Lg 07 LO NH WW Sy CN ad “ e f g h H 4 N-N N(R )z RY .N ps N KRY § N= )z INpd N / \ z / \ " (RY), ON NN Ty i j k 1 a R4 R4 R4 © )z Ny nA oN s eS pi =n hd Ta, m n 0 pP R* R4 R4 SEE Os) =N =N =N : Xa wd wg ve (RY), q r S t rn H oO a NH CO CN oa iC o gy + F®), FT TRY: J SRY, “NT | Sy re, H H u \J Ww X H oN ¢ aN IE \_(R%) CNR, CNR, Lr, 1 z y z aa bb - 540 - Amended sheet: 29 September 2006
196. The compound of claim 193, wherein R' is<CHR-Cy', wherein R is hydrogen or C;- Caalkyl, and Cy is: 2R*) N 1 we, EY He) 3m ! ~ | Zz A J NZ 7 a b c d (RY), (RY), (R%) (R%) ~ \ N= z 2 z A HO [hn 7 N” SN wi, Ee e f g h H -N — (RY) NN NT 72 R4 ] N ] N Lr . NA )z ww “) NEI f Ty i j k . R* R4 R4 R yt )z NN NA oN s ve Pa J=N hd Ta, m n 0 p R4 R* R4 sn No Ne +) =N —! va ve § ve N SRY, q r S t N 0 GV a ialL USA ae (RY), N N (RY); u v w xX - 541 - Amended sheet: 29 September 2006
N > hen, 1 SE , Rn, SE y z aa bb
197. The compound of claim 193, wherein R! is an optionally substituted C,aliphatic group and are each independently selected from optionally substituted methyl, ethyl, cyclopropyl, n- propyl, propenyl, cyclobutyl, (CO)OCH,CHj3, (CH;);OCH3;, CH,CO)OCH,CHj3;, CH(CO)OCH;, CH(CH3)CH,CH3, or n-butyl.
198. The compound of claim 193, wherein z is 0-5, and R* groups, when present, are each independently halogen, CN, NO;, -N(R’);, -CH:N(R"),, -OR’, -CH,0R’, -SR’, -CH,SR’, - COOR’, -NRCOR”’, -CON(R’);, -OCON(R’),, COR’, -NHCOOR’, -SO;R’, -SO;N(R’), or an optionally substituted group selected from C;.Cealiphatic, aryl, heteroaryl, cycloaliphatic, heterocycloaliphatic, arylC,-Cealkyl, heteroarylC,-Cealkyl, cycloaliphaticC,-Cealkyl, or heterocycloaliphaticC,-Cealkyl.
199. The compound of claim 193, wherein z is 0-5 and R* groups are each independently Cl, Br, F, CF;, CHj3, -CH>CH3, CN, -COOH, —N(CH3),, -N(Et)2, -N(iPr),, -O(CH,),OCH3;, -CONH,, -COOCH;, -OH, -CH,OH, -NHCOCHj;, -SO;NH;, -SO2(CH,);CH;, -SO,CH(CH3),, - SO,;N(CHj3),, -SO,CH,CHj;, -C(O)OCH,CH(CH3),, -C(O)NHCH,CH(CH3),, -NHCOOCH;, - C(O)C(CH3);, -COO(CH,),CHj;, -C(O)NHCH(CHj3);, -C(O)CH,CHs, or an optionally substituted group selected from -piperidinyl, piperizinyl, morpholino, C,4alkoxy, phenyl, phenyloxy, benzyl, benzyloxy, -CHycyclohexyl, pyridyl, -CH,pyridyl, or -CH,thiazolyl.
200. The compound of claim 193, R® is halogen, CN, NO,, -N(R’),, -CH;N(R’);, -OR’, - CH,OR’, -SR’, -CH,SR’, -COOR’, -NRCOR’, -CON(R’);, -OCON(R”),, COR’, -NHCOOR’, - SO,R’, -SO;N(R’),, or an optionally substituted group selected from C,.Cealiphatic, aryl, heteroaryl, cycloaliphatic, heterocycloaliphatic, arylC;-Cealkyl, heteroarylC,-Cealkyl, cycloaliphaticC;-Cealkyl, or heterocycloaliphaticC;-Cealkyl. -542 - Amended sheet: 29 September 2006
201. The compound of claim 193, wherein R? is Cl, Br, F, CFs, -OCF;3, Me, Et, CN, -COOH, - NH;, -N(CHj3);, -N(Et);, -N(iPr);, -O(CH,),0OCHj;, -CONH,, -COOCHj;, -OH, -OCHjs, - OCH,CH;, -CH,OH, -NHCOCH;, -NHCOCH(CHj3);, -SO;NH,;, -CONH(cyclopropyl), - CONHCHj;, -CONHCH,CHs, or an optionally substituted group selected from -piperidinyl, piperizinyl, morpholino, phenyl, phenyloxy, benzyl, or benzyloxy.
202. The compound of claim 193, wherein R? is halogen, CN, optionally substituted C;- Cealkyl, OR’, N(R’);, CON(R’),, or NRCOR’.
203. The compound of claim 193, wherein R® is -Cl, -CHs, -CH,CHs, -F, -CFs, -OCF;, - CONHCH3, -CONHCH,CH3, -CONH(cyclopropyl), -OCHj3, -NH;, -OCH,CH3, or -CN.
204. The compound of claim 193, wherein R? is at the 6-position of the quinazoline ring and is -Cl, -CH3, -CH,CHjs, -F, -CF;, -OCF;, -CONHCHj3;, -CONHCH,CH3, -CONH(cyclopropyl), - OCH3;, -NH,, -OCH,CHj3, or -CN.
205. The compound of claim 193, R? is at the 7-position of the quinazoline ring and is -Cl, - CH;, -CH,CH3, -F, -CF3, -OCF;, -CONHCHj;, -CONHCH,CH3, -CONH(cyclopropyl), -OCH3, - NH, -OCH,CH;, or -CN.
206. The compound of claim 193, wherein R® is at the 6-position of the quinazoline ring and is -Cl, -CH3j, -CH,CHas, -F, -CF;, -OCFs3, -OCH;, or -OCH,CH;.
207. The compound of claim 193, wherein R? is at the 7-position of the quinazoline ring and is -Cl, -CH;, -CH,CH3, -F, -CF;, -OCF;, -OCH;, or -OCH,CH;.
208. The compound of claim 193, wherein R? is at the 6-position of the quinazoline ring and is ~CON(R’);, or NRCOR”.
209. The compound of claim 193, wherein R? is at the 7-position of the quinazoline ring and is ~CON(R”),, or NRCOR”. -543 - Amended sheet: 29 September 2006
210. The compound of claim 193, wherein y is 0-5, q is 0-2, and R® and R* groups, when present, are each independently halogen, CN, NO,, -N(R’),, -CH,N(R’),, -OR”’, -CH,0R’, -SR’, -CH,SR’, - -NRCOR’, -CON(R’);, -S(0);N(R’),, -OCOR’, -COR’, -COzR’, -OCON(R),, - NR’SO;R’, -OP(O)(OR’),, -P(O)(OR”),, -OP(0),0R’, -P(0),0R’, -PO(R’);, -OPO(R’),, or an optionally substituted group selected from C,Cgaliphatic, aryl, heteroaryl, cycloaliphatic, heterocycloaliphatic, arylC;-Cgalkyl, heteroarylC;-Cealkyl, cycloaliphaticC-Cealkyl, or heterocycloaliphaticC,-Cealkyl.
211. The compound of claim 193, wherein y is 0-5, and q is | or 2, and each occurrence of rR is independently Cl, Br, F, CFs, Me, Et, CN, -COOH, -NH,, -N(CHj3),, -N(Et);, -N(iPr),, - O(CH;);0CHj3;, -CONH,, -COOCHj3, -OH, -OCHj3;, -OCH,CH3, -CH,OH, -NHCOCH;3, -SO,;NH,, -SO,NHC(CH3),, -OCOC(CH3)3, -OCOCH,C(CH3)s, -O(CH,),N(CH3);, 4-CHj-piperazin-1-yl, OCOCH(CH3;),;, OCO(cyclopentyl), -COCH3, optionally substituted phenoxy, or optionally substituted benzyloxy.
212. The compound of claim 193, wherein: a) yis0,qis land R®isF; b) yis 0, q is 1, and R*is OR’; ¢) yis0,qis 1 and R*is OH; d) yis 1, R® is OR’ and R® is F, wherein OR’ is substituted at the 2-position of the phenyl ring and F is substituted at the 6-position of the phenyl ring; or e) yis 1, R% is OH and R® is F, wherein OH is substituted at the 2-position of the phenyl ring and F is substituted at the 6-position of the phenyl ring.
213. A composition comprising a compound of any one of claims 1-212; and a pharmaceutically acceptable carrier, vehicle, or diluent.
214. A compound of formula I: -544 - Amended sheet: 29 September 2006
RL, OC : N I or a pharmaceutically acceptable salt thereof, wherein:
X is O or NR;
wherein R! and R? are each independently an optionally substituted group selected from hydrogen, C,.¢aliphatic, or Cy', wherein Cy' is a 5-7-membered monocyclic aryl ring or an 8-10- membered bicyclic aryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or is a 3-12-membered saturated, or partially unsaturated monocyclic or bicyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein Cy' is bonded directly to the nitrogen atom or is bonded through an optionally substituted C,.saliphatic group, wherein one or more methylene units in the C4aliphatic group are optionally replaced with -NR-, -O-, -COO, -OCO-, -NRCO-, -CONR-, -SO2NR-, or -NRSO;-; or R! and R?, taken together with the nitrogen atom to which they are bound, form an optionally substituted 3-12-membered monocyclic or bicyclic saturated, partially unsaturated, or fully unsaturated ring having 0-3 additional heteroatoms independently selected from nitrogen, sulfur, or oxygen; wherein R' and R?, or the ring formed by R' and R? taken together, are each optionally and independently substituted at one or more substitutable carbon, nitrogen, or sulfur atoms with z independent occurrences of —R*, wherein z is 0-5;
Ring A is a 5-7-membered monocyclic aryl ring or an 8-10-membered bicyclic aryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or is a 3-12- membered monocyclic or bicyclic saturated or partially unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein ring A is optionally substituted with y independent occurrences of —R®, wherein y is 0-5, and is additionally optionally substituted with q independent occurrences of R, wherein q is 0-2;
x is 0-4;
each occurrence of R?, R* and R’ is independently Q-R%; wherein Q is a bond orisa Ci- Cs alkylidene chain wherein up to two non-adjacent methylene units of Q are optionally and independently replaced by -NR-, -S-, -O-, -CS-, -CO,-, -OCO-, -CO-, -COCO-, -CONR-, -
- 545 - Amended sheet: 29 September 2006
NRCO-, -NRCO;-, -SO,NR-, -NRSO;-, -CONRNR-, -NRCONR-, -OCONR-, -NRNR-, - NRSO;NR-, -SO-, -SO,-, -PO-, -PO;-, -OP(O)(OR)-, or -POR-; and each occurrence of RX is independently selected from -R’, =0, =NR’, halogen, -NO,, -CN, -OR’, -SR’, -N(R’),, - NR’COR’, -NR’CON(R’),, -NR’CO;R’, -COR’, -CO;R’, -OCOR’, -CON(R’);, -OCON(R’),, - SOR’, -SO;R’, -SO,N(R’),, -NR’SO,R’, -NR’SO,N(R),, -COCOR’, -COCH,COR’, - OP(O)(OR’),, -P(0)(OR’),, -OP(0),0R”’, -P(0),0R’, -PO(R”),, or -OPO(R’);
each occurrence of R* is independently an optionally substituted C,-Cgaliphatic group, halogen, -OR’, -SR’, -N(R’),, -NR’COR’, -NR’CON(R’),, -NR’CO;R’, -COR’, -CO;R’, - OCOR’, -CON(R’);, -OCON(R’),, -SOR’, -SO2R’, -SO;N(R’),, -NR’SO2R’, -NR’SO,;N(R’),, - COCOR’, -COCH,COR’, -OP(0)(OR’),, -P(O)(OR),, -OP(0),0R’, -P(O),OR’, -PO(R™),, or - OPO(R’);; and each occurrence of R is independently hydrogen or an optionally substituted C,¢ aliphatic group; and each occurrence of R is independently hydrogen or an optionally substituted C,¢ aliphatic group, a 3-8-membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-12 membered saturated, partially unsaturated, or fully unsaturated bicyclic ring system having 0-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or R and R’, two occurrences of R, or two occurrences of R, are taken together with the atom(s) to which they are bound to form an optionally substituted 3-12 membered saturated, partially unsaturated, or fully unsaturated monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur provided that:
i) when x is 1 and R’ is optionally substituted 6-phenyl or 6-pyridyl, and R' is hydrogen, then R? is not Cy';and ii) Piperazine, 1-(4-amino-6,7-dimethoxy-2-quinazolinyl)-4(2-furanylcarbonyl)- monohydrochloride and Piperazine, 1-(4-amino-6,7-dimethoxy-2-quinazolinyl)-4[(2,3-dihydro- 1,4-benzodioxin-2-yl)carbonyl]- are excluded,
for use in a method of treating or lessening the severity of a disease, disorder, or condition selected from acute, chronic, neuropathic, or inflammatory pain, arthritis, migrane, cluster headaches, trigeminal neuralgia, herpetic neuralgia, general neuralgias, epilepsy or epilepsy conditions, neurodegenerative disorders, psychiatric disorders including anxiety and depression, myotonia, arrythmia, movement disorders, neuroendocrine disorders, ataxia, multiple sclerosis,
- 546 - Amended sheet: 29 September 2006 irritable bowel syndrome, incontinence, visceral pain, osteoarthritis pain, postherpetic neuralgia, diabetic neuropathy, radicular pain, sciatica, back pain, head or neck pain, severe or intractable pain, nociceptive pain, breakthrough pain, postsurgical pain, or cancer pain.
215. The compound of claim 214, wherein the disease, condition, or disorder is implicated in the activation or hyperactivity of voltage-gated sodium channels.
216. The compound of claim 214, wherein the disease, condition, or disorder is implicated in the activation or hyperactivity of calcium channels.
217. The compound of claim 214, wherein the disease, condition, or disorder is acute, chronic, neuropathic, or inflammatory pain.
218. The compound of claim 214, wherein the disease, condition, or disorder is radicular pain, sciatica, back pain, head pain, or neck pain.
219. The compound of claim 214, wherein the disease, condition, or disorder is severe or intractable pain, acute pain, postsurgical pain, back pain, or cancer pain.
220. The use of a compound of formula I: RL X = SN N I or a pharmaceutically acceptable salt thereof, wherein: X is O or NR? wherein R' and R? are each independently an optionally substituted group selected from hydrogen, Caliphatic, or Cy', wherein Cy' is a 5-7-membered monocyclic aryl ring or an 8-10- membered bicyclic aryl ring having 0-3 heteroatoms independently selected from nitrogen, -547 - Amended sheet: 29 September 2006 oxygen, or sulfur, or is a 3-12-membered saturated, or partially unsaturated monocyclic or bicyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein Cy' is bonded directly to the nitrogen atom or is bonded through an optionally substituted C,.4aliphatic group, wherein one or more methylene units in the C,aliphatic group are optionally replaced with -NR-, -O-, -COQO, -OCO-, -NRCO-, -CONR-, -SO,NR-, or -NRSO;-; or R! and R?, taken together with the nitrogen atom to which they are bound, form an optionally substituted 3-12-membered monocyclic or bicyclic saturated, partially unsaturated, or fully unsaturated ring having 0-3 additional heteroatoms independently selected from nitrogen, sulfur, or oxygen; wherein R' and R?, or the ring formed by R' and R? taken together, are each optionally and independently substituted at one or more substitutable carbon, nitrogen, or sulfur atoms with z independent occurrences of —-R*, wherein z is 0-5;
Ring A is a 5-7-membered monocyclic aryl ring or an 8-10-membered bicyclic aryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or is a 3-12- membered monocyclic or bicyclic saturated or partially unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein ring A is optionally substituted with y independent occurrences of —R’, wherein y is 0-5, and is additionally optionally substituted with q independent occurrences of R*, wherein q is 0-2;
x is 0-4;
each occurrence of R®, RY, and R’ is independently Q-R%; wherein Q is a bond or is a C;- Ce alkylidene chain wherein up to two non-adjacent methylene units of Q are optionally and independently replaced by -NR-, -S-, -O-, -CS-, -CO,-, -OCO-, -CO-, -COCO-, -CONR-, - NRCO-, -NRCO,-, -SO;NR-, -NRSO;-, -CONRNR-, -NRCONR-, -OCONR-, -NRNR-, - NRSO,;NR-, -SO-, -SO;-, -PO-, -PO,-, -OP(0O)(OR)-, or -POR-; and each occurrence of R* is independently selected from -R’, =O, =NR’, halogen, -NO,, -CN, -OR’, -SR’, -N(R’),, - NR’COR’, -NR’CON(R’);, -NR’CO;R’, -COR’, -CO,R’, -OCOR’, -CON(R’),, -OCON(R’),, - SOR’, -SO;R’, -SO;N(R*)2, -NR’SO2R’, -NR’SO;N(R*),, -COCOR’, -COCH,COR”, - OP(O)(OR), -P(O)(OR’),, -OP(O);0R’, -P(0),0R’, -PO(R’),, or -OPO(R’);
each occurrence of R* is independently an optionally substituted C,-Cgaliphatic group, halogen, -OR’, -SR’, -N(R”)2, -NR’COR’, -NR’CON(R’),, -NR’CO;R’, -COR’, -CO;R’, - OCOR?’, -CON(R’),, -OCON(R’)3, -SOR’, -SO,R’, -SO,N(R’)2, -NR’SO2R’, -NR’SO,N(R’),, -
- 548 - Amended sheet: 29 September 2006
COCOR’, -COCH,COR’, -OP(0)(OR),, -P(O)(OR’),, -OP(0), OR’, -P(0),0R’, -PO(R*),, or - OPO(R’),; and each occurrence of R is independently hydrogen or an optionally substituted C,.¢ aliphatic group; and each occurrence of Ris independently hydrogen or an optionally substituted C5 aliphatic group, a 3-8-membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-12 membered saturated, partially unsaturated, or fully unsaturated bicyclic ring system having 0-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or R and R, two occurrences of R, or two occurrences of R, are taken together with the atom(s) to which they are bound to form an optionally substituted 3-12 membered saturated, partially unsaturated, or fully unsaturated monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur provided that: i) when x is 1 and R? is optionally substituted 6-phenyl or 6-pyridyl, and R' is hydrogen, then R? is not Cy';and ii) Piperazine, 1-(4-amino-6,7-dimethoxy-2-quinazolinyl)-4(2-furanylcarbonyl)- monohydrochloride and Piperazine, 1-(4-amino-6,7-dimethoxy-2-quinazolinyl)-4[(2,3-dihydro- 1,4-benzodioxin-2-yl)carbonyl]- are excluded, in the manufacture of a medicament for use in a method of treating or lessening the severity of a disease, disorder, or condition selected from acute, chronic, neuropathic, or inflammatory pain, arthritis, migrane, cluster headaches, trigeminal neuralgia, herpetic neuralgia, general neuralgias, epilepsy or epilepsy conditions, neurodegenerative disorders, psychiatric disorders including anxiety and depression, myotonia, arrythmia, movement disorders, neuroendocrine disorders, ataxia, multiple sclerosis, irritable bowel syndrome, incontinence, visceral pain, osteoarthritis pain, postherpetic neuralgia, diabetic neuropathy, radicular pain, sciatica, back pain, head or neck pain, severe or intractable pain, nociceptive pain, breakthrough pain, postsurgical pain, or cancer pain.
221. The use of claim 220, wherein the disease, condition, or disorder is implicated in the activation or hyperactivity of voltage-gated sodium channels. - 549 - Amended sheet: 29 September 2006
222. The use of claim 220, wherein the disease, condition, or disorder is implicated in the activation or hyperactivity of calcium channels.
223. The use of claim 220, wherein the disease, condition, or disorder is acute, chronic, neuropathic, or inflammatory pain.
224. The use of claim 220, wherein the disease, condition, or disorder is radicular pain, sciatica, back pain, head pain, or neck pain.
225. The use of claim 220, wherein the disease, condition, or disorder is severe or intractable pain, acute pain, postsurgical pain, back pain, or cancer pain.
226. A method of inhibiting one or more of NaV1.1, NaV1.
2, NaV1.
3, NaV1.4,NaVl.5, NaV1.6,NaV1.7, NaV1.8, NaV1.9, or CaV2.2 activity in: a biological sample, which method comprises contacting said biological sample with a compound of formula I: 1 Rx x = SN N I or a pharmaceutically acceptable salt thereof, wherein: X is O or NR? wherein R' and R? are each independently an optionally substituted group selected from hydrogen, C,saliphatic, or Cy', wherein Cy' is a 5-7-membered monocyclic aryl ring or an 8-10- membered bicyclic aryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or is a 3-12-membered saturated, or partially unsaturated monocyclic or bicyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein Cy' is bonded directly to the nitrogen atom or is bonded through an optionally substituted C,4aliphatic group, wherein one or more methylene units in the C,.aliphatic group are optionally replaced with -NR-, -O-, -COO, -OCO-, -NRCO-, -CONR-, -SO;NR-, or -NRSO,- -550- Amended sheet: 29 September 2006
; or R' and R?, taken together with the nitrogen atom to which they are bound, form an optionally substituted 3-12-membered monocyclic or bicyclic saturated, partially unsaturated, or fully unsaturated ring having 0-3 additional heteroatoms independently selected from nitrogen, sulfur, or oxygen; wherein R' and R%, or the ring formed by R' and R? taken together, are each optionally and independently substituted at one or more substitutable carbon, nitrogen, or sulfur atoms with z independent occurrences of —R*, wherein z is 0-5;
Ring A is a 5-7-membered monocyclic aryl ring or an 8-10-membered bicyclic aryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or is a 3-12- membered monocyclic or bicyclic saturated or partially unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein ring A is optionally substituted with y independent occurrences of —R>, wherein y is 0-5, and is additionally optionally substituted with q independent occurrences of R*®, wherein q is 0-2;
x is 0-4;
each occurrence of R* s RY and R® is independently Q-R%, wherein Q is a bond oris a C;- Cs alkylidene chain wherein up to two non-adjacent methylene units of Q are optionally and independently replaced by -NR-, -S-, -O-, -CS-, -CO;-, -OCO-, -CO-, -COCO-, -CONR-, - NRCO-, -NRCO;-, -SO,NR-, -NRSO;-, -CONRNR-, -NRCONR-, -OCONR-, -NRNR-, - NRSO,;NR-, -SO-, -SO;-, -PO-, -PO,-, -OP(O)(OR)-, or -POR-; and each occurrence of Ris independently selected from -R’, =O, =NR’, halogen, -NO,, -CN, -OR”’, -SR’, -N(R’),, - NR’COR’, -NR’CON(R’),, -NR’CO,R’, -COR”, -CO3R’, -OCOR’, -CON(R’),, -OCON(R),, - SOR’, -SO;R’, -SO;N(R’)2, -NR’SO2R’, -NR’SO,;N(R’),, -COCOR’, -COCH,COR’, - OP(O)(OR’);, -P(O)(OR’)2, -OP(0);0R’, -P(0),0R”’, -PO(R’),, or -OPO(R’);
each occurrence of R* is independently an optionally substituted C,-Cealiphatic group, halogen, -OR’, -SR’, -N(R’),, -NR’COR’, -NR’CON(R’),, -NR’CO;R’, -COR’, -CO3R’, - OCOR’, -CON(R’),, -OCON(R’),, -SOR’, -SO,R’, -SO;N(R’)2, -NR’SO2R’, -NR’SO;N(R’),, - COCOR’, -COCH,COR’, -OP(O)(OR’),, -P(O)(OR’),, -OP(0),0R’, -P(0),0R’, -PO(R’)3, or - OPO(R’),; and each occurrence of R is independently hydrogen or an optionally substituted C;.¢ aliphatic group; and each occurrence of R’ is independently hydrogen or an optionally substituted C; aliphatic group, a 3-8-membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-12
- 551 - Amended sheet: 29 September 2006 membered saturated, partially unsaturated, or fully unsaturated bicyclic ring system having 0-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or R and R, two occurrences of R, or two occurrences of R , are taken together with the atom(s) to which they are bound to form an optionally substituted 3-12 membered saturated, partially unsaturated, or fully unsaturated monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
227. The method of claim 226, wherein X is NR?, and compounds have the structure of formula I-A: 1 2 RNR Xr IN N I-A
228. The method of claim 226, wherein X is O, and compounds have the structure of formula I-B: RY o Xr IN N I-B
229. The method of claim 226, wherein a) one of R' or R? is hydrogen, and the other of R' and R? is selected from: i) an optionally substituted C,.saliphatic group, wherein one or more methylene units in the C aliphatic group are optionally replaced with -NR-, -O-, -COO, -OCO-, - NRCO-, -CONR-, -SO,NR-, or -NRSO»-; or Cy', wherein Cy! is a S-7-membered monocyclic aryl ring or an 8-10-membered bicyclic aryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or is a 3-12-membered saturated, or partially unsaturated monocyclic or bicyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein Cy' is bonded directly to the nitrogen -552- Amended sheet: 29 September 2006 atom or is bonded through an optionally substituted C,4aliphatic group, wherein one or more methylene units in the C,4aliphatic group are optionally replaced with -NR-, -O-, - COO, -OCO-, -NRCO-, -CONR-, -SO,NR-, or -NRSO;-; or ii) an optionally substituted C,aliphatic group, wherein one or more methylene units in the Cj4aliphatic group are optionally replaced with -NR-, -O-, -COO, -OCO-, - NRCO-, -CONR-, -SO;NR-, or -NRSO;-; or b) R' and R? are each independently selected from Cy', wherein Cy' is a 5-7-membered monocyclic aryl ring or an 8-10-membered bicyclic aryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or is a 3-12-membered saturated, or partially unsaturated monocyclic or bicyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein Cy' is bonded directly to the nitrogen atom or is bonded through an optionally substituted Cj4aliphatic group, wherein one or more methylene units in the C_4aliphatic group are optionally replaced with -NR-, -O-, -COOQ, -OCO-, -NRCO-, - CONR-, -SO;NR-, or -NRSO;-; or from an optionally substituted C,.saliphatic group, wherein one or more methylene units in the C4aliphatic group are optionally replaced with —NR-, -O-, - COO-, -OCO-, -NRCO-, -CONR-, -SO;NR-, or -NRSO;-.
230. The method of claim 226, wherein Cy' is: 2R*) N HE PUN UCU SA) 1 (re, A J “NF “\\* a b c d (R*); (RY); _(R%; (RY), SOT SN N” N* wh, , e f g h NR Ne (Re (RY) A US 5 ALES 5 i i k -553- Amended sheet: 29 September 2006
‘ R4 R4 R4 R : NA )z NA N A o A gD NM N | N N hd Tn, m n 0 P R4 R4 R% § 0 No NA — Jon j= pe ANE he “, wf N (R%)z q r $ t N 0 FOr He Hm HO (RY), N N (RY), H H u v w xX H N Jr oN IN 23 (RY TNR, TRY, LR re, + z y z aa bb
231. The method of claim 226, wherein R' is hydrogen or an optionally substituted C,- Caaliphatic group and R? is -CH,-Cy', wherein Cy' is: 2(RY) N IP NZ ns iN ro = TR: JR: IP HL RY: 2 : : a b ¢ d (RY), (RY), (RY) (RY) 2 S N=" = LG Ie [he "7 N” NN wh 4 e f g h -554 - Amended sheet: 29 September 2006
H -N — (RY NH [NR 4 N HN r/R § NR: AN N ~ oy 2 TT (RY), wg N NN. TS i 1] k R* R4 Rr R4 Hy ” NY NA oN S nf 'S va m n ° [1] R4 R4 R? =N — 1 — 7 \¢ q r ] t N 0 £m AY iC Fo, 3 (RY), N N (RY), H H u v w xX H N pu oN CJ ed (RY) YOR OONR, Le, a y z aa bb
232. The method of claim 226, wherein R' and R? groups are each independently an optionally substituted C,4aliphatic group and are each independently selected from optionally substituted methyl, ethyl, cyclopropyl, n-propyl, propenyl, cyclobutyl, (CO)OCH,CHs, (CH,);OCHs, CH,CO)OCH,CH3;, CH,(CO)OCH3, CH(CH3)CH,CHs, or n-butyl. - 555 - Amended sheet: 29 September 2006
233. The method of claim 226, wherein R' and R?, taken together with the nitrogen atom to which they are bound, form an optionally substituted 3-12 membered heterocyclyl ring having 1-3 heteroatoms independently selected from nitrogen or oxygen and form a 3-12 membered heterocyclyl group selected from: 4 (R%) (R*) AT An Aye ig J ) L_NH NF cc dd ee “ Ne N N Ny (3 (ye TRS (RY), ff gg hh A i N a. 2 ) _s “RY /. ? 2(R*) ii ji kk N IN T T N N N i» ) a ¢ N 4 (RY N (RY), 2(R%) z 4 (RY), 1] mm nn 00 wherein the ring formed by R' and R? taken together, is optionally substituted at one or more substitutable carbon, nitrogen, or sulfur atoms with z independent occurrences of -R*, and zis 0-5.
234. The method of claim 226, wherein R' and R? taken together is an optionally substituted ring selected from azetidin-1-yl (jj), pyrrolidin-1-yl (ff), piperidinl-yl (dd), piperazin-1-yl (cc), or morpholin-4-yl (ee). - 556 - Amended sheet: 29 September 2006
235. The method of claim 226, wherein R' and R? taken together is an optionally substituted ring selected from azetidin-1-yl (jj), pyrrolidin-1-yl (ff), piperidinl-yl (dd), or piperazin-1-yl (cc).
236. The method of claim 226, wherein z is 0-5, and R* groups, when present, are each independently halogen, CN, NO, -N(R’);, -CH;N(R’),, -OR’, -CH,OR’, -SR’, -CH,SR’, - COOR’, -NRCOR”’, -CON(R’),;, -OCON(R’);, COR’, -NHCOOR’, -SO;R’, -SO>N(R’);, or an optionally substituted group selected from C,.Cgqaliphatic, aryl, heteroaryl, cycloaliphatic, heterocycloaliphatic, arylC,-Ce¢alkyl, heteroarylC,-Cealkyl, cycloaliphaticC,-Cg¢alkyl, or heterocycloaliphaticC;-Cgalkyl.
237. The method of claim 226, wherein z is 0-5 and R* groups are each independently Cl, Br, F, CF3, CHj3, -CH2CH3, CN, -COOH, —-N(CHj3)z, -N(Et),, -N(iPr);, -O(CH2),0CH3;, -CONHa, -COOCH;, -OH, -CH,OH, -NHCOCH;, -SO;NH;, -SO(CH;);CH;, -SO,CH(CHs),, -SO;N(CH3)2, -SO,CH,CH3, -C(O)OCH,CH(CH3),;, -C(O)NHCH,CH(CH3);, -NHCOOCH;, -C(O)C(CH3)3, -COO(CH,).CH3, -C(O)NHCH(CHj3);, -C(O)CH,CHs;, or an optionally substituted group selected from -piperidinyl, piperizinyl, morpholino, C,alkoxy, phenyl, phenyloxy, benzyl, benzyloxy, -CH,cyclohexyl, pyridyl, -CH,pyridyl, or -CH;thiazolyl.
238. The method of claim 226, wherein R! and RZ, taken together is selected from:
a. optionally substituted azetidin-1-yl (jj), wherein z is 1 or 2 and at least one occurrence of R* is -NRSO,R’, -NRCOOR’, or -NRCOR’;
b. optionally substituted azetidin-1-yl (jj), wherein z is 1 and R* is -NRSO,R’;
c. optionally substituted azetidin-1-yl (jj), wherein z is 1 and R* is -NRCOOR’;
d. optionally substituted azetidin-1-yl (jj), wherein z is 1 and R* is -NRCOR’;
e. optionally substituted pyrrolidin-1-yl (ff), wherein z is 1 or 2 and R* is Cl, Br, F, CF;, CH3, -CH,CH3, -OR’, or -CH,0OR’;
f. optionally substituted piperidin-1-yl (dd), wherein z is 1 or 2 and at least one occurrence of R* is Cl, Br, F, CF;, CH3;, -CH,CH3, -OR’, or -CH,0R’, -NRSO,R’, -NRCOOR’, or —OCON(R); - 557 - Amended sheet: 29 September 2006 g. optionally substituted piperidin-1-yl (dd), wherein z is 1 and R'is F, CFs, CHj, - CH,CHj3, -OR’, or -CH,0R’;
h. optionally substituted piperidin-1-yl (dd), wherein z is 1 and R* is —NRSO,R’;
i. optionally substituted piperidin-1-yl (dd), wherein z is 1 and R* is -NRCOOR’; Je optionally substituted piperazin-1-yl (ec), wherein z is 1 or 2 and at least one occurrence of R* is —SOR’, -CON(R?)3, -SO;N(R*);, -COR”’, or —-COOR’;
k. optionally substituted piperazin-1-yl (cc), wherein z is 1 and R* is -SOR’
l. optionally substituted piperazin-1-yl (cc), wherein z is 1 and R* is <COOR?;
m. optionally substituted piperazin-1-yl (cc), wherein z is 1 and R* is -CON(R’)z;
n. optionally substituted piperazin-1-yl (ec), wherein zis 1 and R* is -SO;N(R’),; or
0. optionally substituted piperazin-1-yl (ec), wherein z is 1 and R*is -COR’.
239. The method of claim 226, wherein x is 0-4, and rR} groups, when present, are each independently halogen, CN, NO, -N(R’);, -CH,N(R’)2, -OR’, -CH,OR’, -SR’, -CH,SR’, - COOR’, -NRCOR’, -CON(R’);, -OCON(R");, COR’, -NHCOOR’, -SOzR’, -SO;N(R’),, or an optionally substituted group selected from C,.Cealiphatic, aryl, heteroaryl, cycloaliphatic, heterocycloaliphatic, arylC,-Cgalkyl, heteroarylC,-Cealkyl, cycloaliphaticC,-Csalkyl, or heterocycloaliphaticC;-Cealkyl.
240. The method of claim 226, wherein x is 1 or 2, and each occurrence of R? is independently Cl, Br, F, CF;, -OCF;3, Me, Et, CN, -COOH, -NH,, -N(CH3)3, -N(Et),, -N(iPr),, -O(CH,),OCH3, -CONH,, -COOCH;, -OH, -OCHj;, -OCH,CHs;, -CH,OH, -NHCOCHj3;, -NHCOCH(CHjs),, -SO;NH,, -CONH(cyclopropyl), -CONHCH3;, -CONHCH,CH3, or an optionally substituted group selected from -piperidinyl, piperizinyl, morpholino, phenyl, phenyloxy, benzyl, or benzyloxy.
241. The method of claim 226, wherein x is 1 or 2 and each R® group is independently halogen, CN, optionally substituted C;-Csalkyl, OR’, N(R”), CON(R’),, or NRCOR’. - 558 - Amended sheet: 29 September 2006
242. The method of claim 226, wherein x is 1 or 2, and each R? group is -Cl, -CHj3, -CH,CH3, -F, -CF3, -OCF3, -CONHCH3, -CONHCH,CH;, -CONH(cyclopropyl), -OCHj3, -NH,, -OCH,CH3, or -CN.
243. The method of claim 226, wherein x is 1 and R? is at the 6-position of the quinazoline ring and is -Cl, -CH; -CH,CHs;, -F, -CF;, -OCF;, -CONHCH;, -CONHCH,CH;, - CONH(cyclopropyl), -OCHj3, -NH,, -OCH,CH3, or -CN.
244. The method of claim 226, wherein x is 1 and R® is at the 7-position of the quinazoline ring and is -Cl, -CH;, -CH,CH;, -F, -CF;, -OCF;, -CONHCHj;, -CONHCH,CH;, - CONH(cyclopropyl), -OCH3, -NH,, -OCH,CH3, or -CN.
245. The method of claim 226, wherein x is 1 and R? is at the 6-position of the quinazoline ring and is -Cl, -CHj3, -CH,CH3, -F, -CF3, -OCF3, -OCHj3, or -OCH,CHs.
246. The method of claim 226, wherein x is 1 and R® is at the 7-position of the quinazoline ring and is -Cl, -CHj3, -CH,CH3, -F, -CF3, -OCF3, -OCH3, or -OCH,CH3.
247. The method of claim 226, wherein x is 1 and R® is at the 6-position of the quinazoline ring and is “CON(R’),, or NRCOR’.
248. The method of claim 226, wherein x is 1 and R? is at the 7-position of the quinazoline ring and is “CON(R”),, or NRCOR’.
249. The method of claim 226, wherein y is 0-5, q is 0-2, and R3 and R® groups, when present, are each independently halogen, CN, NO,;, -N(R’);, -CH;N(R’),, -OR’, -CH,0R’, -SR’, -CH,SR’, -NRCOR’, -CON(R’);, -S(O):N(R’);, -OCOR’, -COR’, -CO,R’, -OCON(R’),, -NR’SO;R’, -OP(O)(OR’),, -P(O)(OR’),, -OP(0),0R’, -P(0),;0R’, -PO(R’);, -OPO(R’),, or an optionally substituted group selected from C,.Cealiphatic, aryl, heteroaryl, cycloaliphatic, heterocycloaliphatic, arylC,-Csalkyl, heteroarylC,-Cealkyl, cycloaliphaticC,-Cealkyl, or heterocycloaliphaticC;-Cgalkyl. - 559 - Amended sheet: 29 September 2006
250. The method of claim 226, wherein q is 1 and y is 0 or 1, and R* is F, OR’, or OH.
251. The method of claim 226, wherein ring A is selected from: 5 (RS), y(R%) (R%)q y(RY y(R®) . BOA Ne NR CN (R52), v I RE 1 ro, NN wd N° ad N i ii iii iv (R%) uf Be wn (JY, OA sa NTN a 0S 1 —(R®), 1 _(R% so 4 vy vi vii viii (RY) 5 _NH ; x (R), y \n (R53), gi ly NR UN oN Ho 2 (R%) & X “N (LS wf NRE, A (R32), oN Cs” ix X xi xii RS § ily & Fo Ny y A Cs NY (R53) si Y—(R%) ~ITR(R%) N(R), — 5 (R%) ~ a (ye a. » H xiii xiv Xv xvi 5 (R%) (RY) 5 (RS) y(R®) (roa y RSa Ie LE oy Nk I N _ “N = 4 \s): { Ss Su /=N JN xvii xviii xix XX - 560 - Amended sheet: 29 September 2006
RY) (RO), (R9) (R°)y N—5 #L Nor ’ N BN — | J NS ) + R 0) X 5a N N 5 N (R53) (R>)q H (R¥)q q xxi xxii xxiii RS (RS) (R%)y SN S: N RB ’ ~ HN _ J + \ A No xX NT TRS), (R%)q (R%)q XXiv XXV xxvi (RY) H (RS RS Nee i Nf ly Lo (RO NL) J iT —(R%) rs) NTN ges AT “SN ) SN” ) wd (R>%)q y(R%) (R*)q H H xxvii xxviii xxix XXX (R%)y (R%) (R%) (R%) S, y y y _ 5— (R53), _r _r T—(R%), bv Ni “N : Cd § NG % (R59), H (R53), xxxi xxxii xxxiii XXxiv H RS RS NR Py RY £2 rs YR) (R%)q XXXV XXXVi XXXVvii
252. The method of claim 226, wherein ring A is selected from optionally substituted phenyl, 2-pyridyl, 3-pyridyl, or 4-pyridyl, or pyrrol-1-yl.
253. The method of claim 226, comprising administering a compound of any one of claims 1-
211. - 561 - Amended sheet: 29 September 2006
254. The method of claim 226 or 253, comprising inhibiting NaV 1.3 or NaV1.8 activity.
255. The method of claim 226 or 253, comprising inhibiting CaV2.2 activity.
256. The method of claim 226 or 253, comprising inhibiting NaV1.8 and CaV2.2 activity.
257. The method of claim 226 or 253, comprising inhibiting NaV 1.8 activity.
258. A compound of formula I: 4 Rx x = SN N I or a pharmaceutically acceptable salt thereof, wherein: XisOor NR? wherein R' and R? are each independently an optionally substituted group selected from hydrogen, C,saliphatic, or Cy', wherein Cy' is a 5-7-membered monocyclic aryl ring or an 8-10- membered bicyclic aryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or is a 3-12-membered saturated, or partially unsaturated monocyclic or bicyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein Cy' is bonded directly to the nitrogen atom or is bonded through an optionally substituted Cj.4aliphatic group, wherein one or more methylene units in the Cj4aliphatic group are optionally replaced with -NR-, -O-, -COO, -OCO-, -NRCO-, -CONR-, -SO;NR-, or -NRSO,-; or R! and R?, taken together with the nitrogen atom to which they are bound, form an optionally substituted 3-12-membered monocyclic or bicyclic saturated, partially unsaturated, or fully unsaturated ring having 0-3 additional heteroatoms independently selected from nitrogen, sulfur, or oxygen; wherein R! and R?, or the ring formed by R' and R? taken together, are each optionally and independently substituted at one or more substitutable carbon, nitrogen, or sulfur atoms with z independent occurrences of -R*, wherein z is 0-5; - 562 - Amended sheet: 29 September 2006
Ring A is a 5-7-membered monocyclic aryl ring or an 8-10-membered bicyclic aryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or is a 3-12- membered monocyclic or bicyclic saturated or partially unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein ring A is optionally substituted with y independent occurrences of —R>, wherein y is 0-5, and is additionally optionally substituted with q independent occurrences of R*, wherein q is 0-2;
x is 0-4;
each occurrence of R?, R*, and R® is independently Q-R¥; wherein Q is a bond or is a Ci- Cs alkylidene chain wherein up to two non-adjacent methylene units of Q are optionally and independently replaced by -NR-, -S-, -O-, -CS-, -CO,-, -OCO-, -CO-, -COCO-, -CONR-, - NRCO-, -NRCOs-, -SO;NR-, -NRSO,-, -CONRNR-, -NRCONR-, -OCONR-, -NRNR-, - NRSO;NR-, -SO-, -SO;-, -PO-, -PO,-, -OP(O)(OR)-, or -POR-; and each occurrence of R¥ is independently selected from -R’, =O, =NR’, halogen, -NO,, -CN, -OR’, -SR’, -N(R’),, - NR’COR’, -NR’CON(R’),, -NR’CO;R’, -COR’, -COzR’, -OCOR’, -CON(R’),, -OCON(R’),, - SOR’, -SO3R’, -SO;N(R’),, -NR’SO;R’, -NR’SO;N(R*),, -COCOR?, -COCH,COR’, - OP(O)(OR”),, -P(O)(OR’),, -OP(0),OR’, -P(0),0R’, -PO(R’),, or -OPO(R’),;
each occurrence of R* is independently an optionally substituted C,-Csaliphatic group, halogen, -OR’, -SR’, -N(R’),;, -NR’COR’, -NR’CON(R’),, -NR’CO;R’, -COR’, -CO;R’, - OCOR’, -CON(R’),, -OCON(R’),, -SOR’, -SO;R”’, -SO;N(R’)2, -NR’SO2R’, -NR’SO;N(R’),, - COCOR’, -COCH,COR’, -OP(O)(OR’),, -P(O)(OR”),, -OP(O),0OR’, -P(0), OR’, -PO(R’),, or - OPO(R’);; and each occurrence of R is independently hydrogen or an optionally substituted C,.¢ aliphatic group; and each occurrence of R'is independently hydrogen or an optionally substituted C, aliphatic group, a 3-8-membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-12 membered saturated, partially unsaturated, or fully unsaturated bicyclic ring system having 0-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or R and R’, two occurrences of R, or two occurrences of R | are taken together with the atom(s) to which they are bound to form an optionally substituted 3-12 membered saturated, partially unsaturated, or fully unsaturated monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur,
- 563 - Amended sheet: 29 September 2006 for use in a method of inhibiting one or more of NaV1.1, NaV1.2,NaV1.3, NaV1.4,NaV1.5, NaV1.6, NaV1.7, NaV1.8, NaV1.9, or CaV2.2 activity in a patient.
259. The compound of claim 214 or 258, wherein X is NR?, and compounds have the structure of formula I-A: 1 2 RNR Xr IN N I-A
260. The compound of claim 214 or 258, wherein X is O, and compounds have the structure of formula I-B: RY 0 Xr IN N I-B
261. The compound of claim 214 or 258, wherein a) one of R' or R? is hydrogen, and the other of R' and R? is selected from: i) an optionally substituted C;4aliphatic group, wherein one or more methylene units in the Cj4aliphatic group are optionally replaced with -NR-, -O-, -COO, -OCO-, - NRCO-, -CONR-, -SO;NR-, or -NRSO;-; or Cy', wherein Cy! is a S5-7-membered monocyclic aryl ring or an 8-10-membered bicyclic aryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or is a 3-12-membered saturated, or partially unsaturated monocyclic or bicyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein Cy' is bonded directly to the nitrogen atom or is bonded through an optionally substituted C, 4aliphatic group, wherein one or - 564 - Amended sheet: 29 September 2006 more methylene units in the C,4aliphatic group are optionally replaced with -NR-, -O-, -COOQ, -0CO-, -NRCO-, -CONR-, -SO;NR-, or -NRSO,-; or ii) an optionally substituted C4aliphatic group, wherein one or more methylene units in the C;4aliphatic group are optionally replaced with -NR-, -O-, -COQ, -OCO-, - NRCO-, -CONR-, -SO;NR-, or -NRSO,-; or b) R' and R? are each independently selected from Cy', wherein Cy’ is a 5-7-membered monocyclic aryl ring or an 8-10-membered bicyclic aryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or is a 3-12-membered saturated, or partially unsaturated monocyclic or bicyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein Cy' is bonded directly to the nitrogen atom or is bonded through an optionally substituted C;4aliphatic group, wherein one or more methylene units in the C,_4aliphatic group are optionally replaced with -NR-, -O-, -COOQ, -OCO-, -NRCO-, - CONR-, -SO;NR-, or -NRSO;-; or from an optionally substituted C;4aliphatic group, wherein one or more methylene units in the C4aliphatic group are optionally replaced with —-NR-, -O-, - COO-, -OCO-, -NRCO-, -CONR-, -SO,NR-, or -NRSO;-.
262. The compound of claim 214 or 258, wherein Cy' is:
AR). N re, re, He) 0 rR, % J NG “\* a b c d 4 4 Wh § LON le no " oi SN | Se Nad of e f g h NN NT (R%), 4 VEN ES a i i k 1 - 565 - Amended sheet: 29 September 2006
R4 R* R* R4 SES " N NA oy S ve a J=N , Tn, m n 0] p R4 R4 R? )=N J= = AN ih, “wg nf N (R%), q r s t N 0 (od FC oR: CL J Rk od, (R%); N N (R%); u v Ww X H N py SN, AN; aK A(R) TNR, $C NRY, Ure, 5 z y z aa bb
263. The compound of claim 214 or 258, wherein R'is hydrogen or an optionally substituted C,-Csaliphatic group and R? is —CH,-Cy', wherein Cy' is: RY) N FY 4 NZ 4 NSN 4 x 4 1 (Re, LR: TJ 1 RY: A ys “N* (7 2d, N N a b c d (RY), (RY), (R%) (RY Zz) A N=¢ 2 NEY 2 ST [hw 7 N” NN 4 e f g h - 566 - Amended sheet: 29 September 2006
H -N —(R% N7N NN" z —_ R4 Mg =i AT = ¥' " i j k I R4 R4 R4 R4 : Np )z NA N A o A <_D pi IN N hd Th, m n 0 p R4 R? R4 )= N = N J= > AN 4 d, wd wg (R%), q r ] t N 0 HC NH I i (RY 9 Ld, RY LJ Nk Lod, (R%), N N (R%), H H u v w X H N Su, ON C3 o XK \_(R%) TNR, TNR, re, — z y z aa bb
264. The compound of claim 214 or 258, wherein R' and R? groups are each independently an optionally substituted C4aliphatic group and are each independently selected from optionally substituted methyl, ethyl, cyclopropyl, n-propyl, propenyl, cyclobutyl, (CO)OCH,CHj;, (CH;),0CH3;, CH,CO)OCH,CH3, CHy(CO)OCH;, CH(CH3)CH,CHj, or n-butyl. - 567 - Amended sheet: 29 September 2006
265. The compound of claim 214 or 258, wherein R! and R?, taken together with the nitrogen atom to which they are bound, form an optionally substituted 3-12 membered heterocyclyl ring having 1-3 heteroatoms independently selected from nitrogen or oxygen and form a 3-12 membered heterocyclyl group selected from: 4 (RY) (RY) LS ~R )2 ESP ? LA ’ i J ) L_NH Fe cc dd ee “ oy WN N iN (re (ye TNR4 (R%); ff gg hh A i N 7 » ) (_s “RY /. ? 2(R%) ii ji kk N Tr IN * N N N » a ¢ N i RY N (R). 2(R%) z 4 (RY), Il mm nn 00 wherein the ring formed by R' and R? taken together, is optionally substituted at one or more substitutable carbon, nitrogen, or sulfur atoms with z independent occurrences of RY, and zis 0-5.
266. The compound of claim 214 or 258, wherein R' and R? taken together is an optionally substituted ring selected from azetidin-1-yl (jj), pyrrolidin-1-yl (ff), piperidinl-yl (dd), piperazin- 1-yl (cc), or morpholin-4-yl (ee). - 568 - Amended sheet: 29 September 2006
267. The compound of claim 214 or 258, wherein R' and R? taken together is an optionally substituted ring selected from azetidin-1-yl (jj), pyrrolidin-1-yl (ff), piperidinl-yl (dd), or piperazin-1-yl (cc).
268. The compound of claim 214 or 258, wherein z is 0-5, and R* groups, when present, are each independently halogen, CN, NO,, -N(R’),, -CH,N(R’),, -OR’, -CH,0R”, -SR”’, -CH,SR’, - COOR’, -NRCOR’, -CON(R’);, -OCON(R’),, COR’, -NHCOOR’, -SO;R’, -SO,N(R’);, or an optionally substituted group selected from C,.Cealiphatic, aryl, heteroaryl, cycloaliphatic, heterocycloaliphatic, arylC;-Cealkyl, heteroarylC,;-Csalkyl, cycloaliphaticC;-Cgsalkyl, or heterocycloaliphaticC,-Cealkyl.
269. The compound of claim 214 or 258, wherein z is 0-5 and R* groups are each independently Cl, Br, F, CF;, CHj;, -CH,CHs;, CN, -COOH, —-N(CHj),, -N(Et);, -N(iPr),, -O(CH3),OCH3s, -CONH,, -COOCH3;, -OH, -CH,0OH, -NHCOCHj3;, -SO;NH,, -SO,(CH;);CHj3, -SO,CH(CH3),, -SO,N(CH3),, -SO,CH,CH3, -C(O)OCH,CH(CH3);, -C(O)NHCH,CH(CHz),, -NHCOOCH;, -C(O)C(CH3);, -COO(CH;),CHs3, -C(O)NHCH(CH3),, -C(O)CHCHj;, or an optionally substituted group selected from -piperidinyl, piperizinyl, morpholino, C;4alkoxy, phenyl, phenyloxy, benzyl, benzyloxy, -CHcyclohexyl, pyridyl, -CH,pyridyl, or -CH,thiazolyl.
270. The compound of claim 214 or 258, wherein R! and R?, taken together is selected from:
a. optionally substituted azetidin-1-yl (jj), wherein z is 1 or 2 and at least one occurrence of R* is —-NRSO,R’, -NRCOOR’, or -NRCOR’;
b. optionally substituted azetidin-1-yl (jj), wherein z is 1 and R* is -NRSO,R”;
C. optionally substituted azetidin-1-yl (jj), wherein z is 1 and R* is -NRCOOR’;
d. optionally substituted azetidin-1-yl (jj), wherein z is 1 and R* is -NRCOR’;
e. optionally substituted pyrrolidin-1-yl (ff), wherein z is 1 or 2 and R* is Cl, Br, F, CF;, CHs, -CH,CH3, -OR’, or -CH,0R’;
f. optionally substituted piperidin-1-yl (dd), wherein z is 1 or 2 and at least one occurrence of R? is Cl, Br, F, CF;, CHs, -CH,CHj3, -OR’, or -CH,0R’, -NRSO,R’, -NRCOOR’, or —-OCON(R’)y; - 569 - Amended sheet: 29 September 2006 g. optionally substituted piperidin-1-yl (dd), wherein z is 1 and R* is F, CFs, CH;, - CH,CH3, -OR’, or -CH,OR’;
h. optionally substituted piperidin-1-yl (dd), wherein z is | and R* is —NRSO,R’;
i. optionally substituted piperidin-1-yl (dd), wherein z is | and R* is -NRCOOR’; J- optionally substituted piperazin-1-yl (ec), wherein z is 1 or 2 and at least one occurrence of R* is —SOR’, -CON(R’),, -SO;N(R’),, -COR’, or —COOR’;
k. optionally substituted piperazin-1-yl (cc), wherein z is 1 and R* is —SOR’
1. optionally substituted piperazin-1-yl (cc), wherein z is | and R* is -COOR’;
m. optionally substituted piperazin-1-yl (ce), wherein z is 1 and R* is -CON(R’)y;
n. optionally substituted piperazin-1-yl (cc), wherein z is 1 and R* is -SO,N(R*),; or
0. optionally substituted piperazin-1-yl (cc), wherein z is 1 and R* is -COR”.
271. The compound of claim 214 or 258, wherein x is 0-4, and Rr? groups, when present, are each independently halogen, CN, NO, -N(R’),, -CHaN(R’),, -OR’, -CH,OR’, -SR’, -CH,SR’, - COOR’, -NRCOR’, -CON(R’);, -OCON(R’);, COR’, -NHCOOR’, -SO;R’, -SO;N(R’);, or an optionally substituted group selected from C,Cgaliphatic, aryl, heteroaryl, cycloaliphatic, heterocycloaliphatic, arylC;-Cgalkyl, heteroarylC,-Cealkyl, cycloaliphaticC,-Csalkyl, or heterocycloaliphaticC,-Cgalkyl.
272. The compound of claim 214 or 258, wherein x is | or 2, and each occurrence of R® is independently Cl, Br, F, CFs, -OCF;, Me, Et, CN, -COOH, -NH;, -N(CH3),, -N(Et);, -N(iPr),, - O(CH,),OCH;, -CONH,, -COOCH3;, -OH, -OCHs, -OCH,CHj;, -CH,OH, -NHCOCH;, - NHCOCH(CHj3);, -SO;NH,, -CONH(cyclopropyl), -CONHCHj;, -CONHCH,CHj;, or an optionally substituted group selected from -piperidinyl, piperizinyl, morpholino, phenyl, phenyloxy, benzyl, or benzyloxy.
273. The compound of claim 214 or 258, wherein x is 1 or 2 and each R* group is independently halogen, CN, optionally substituted C,;-Cealkyl, OR’, N(R’);, CON(R’),, or NRCOR’. -570- Amended sheet: 29 September 2006
274. The compound of claim 214 or 258, wherein x is 1 or 2, and each R? group is -Cl, -CHj, - CH,CHj, -F, -CF3, -OCF3;, -CONHCH3, -CONHCH,CH3, -CONH(cyclopropyl), -OCHj3, -NH,, - OCH,CHs, or -CN.
275. The compound of claim 214 or 258, wherein x is 1 and R? is at the 6-position of the quinazoline ring and is -Cl, -CHj, -CH,CH3, -F, -CF3, -OCF;, -CONHCH3, -CONHCH,CH3, - CONH(cyclopropyl), -OCH3, -NH,, -OCH,CH3, or -CN.
276. The compound of claim 214 or 258, wherein x is 1 and R? is at the 7-position of the quinazoline ring and is -Cl, -CHs, -CH,CHj, -F, -CF;, -OCF;, -CONHCHj;, -CONHCH,CHj3, - CONH(cyclopropyl), -OCH3;, -NH,, -OCH,CH3, or -CN.
277. The compound of claim 214 or 258, wherein x is 1 and R® is at the 6-position of the quinazoline ring and is -Cl, -CH3, -CH,CH3, -F, -CF3, -OCF;, -OCHj, or -OCH2CH3.
278. The compound of claim 214 or 258, wherein x is 1 and R® is at the 7-position of the quinazoline ring and is -Cl, -CH3, -CH,CHjs, -F, -CF3, -OCF3, -OCHj, or -OCH,CH.
279. The compound of claim 214 or 258, wherein x is 1 and R? is at the 6-position of the quinazoline ring and is -CON(R’),, or NRCOR”.
280. The compound of claim 214 or 258, wherein x is 1 and R? is at the 7-position of the quinazoline ring and is -CON(R);, or NRCOR’.
281. The compound of claim 214 or 258, wherein y is 0-5, q is 0-2, and R® and R® groups, when present, are each independently halogen, CN, NO,, -N(R’),, -CHaN(R’),, -OR’, -CH,0R”, -SR’, -CH,SR’, - -NRCOR’, -CON(R’),, -S(0):N(R"),, -OCOR’, -COR’, -CO;R’, -OCON(R’),, -NR’SO;R’, -OP(O)(OR’)2, -P(O)(OR’),, -OP(0);0R’, -P(0),0R’, -PO(R’),, -OPO(R’),, or an optionally substituted group selected from C,.Cealiphatic, aryl, heteroaryl, cycloaliphatic, heterocycloaliphatic, arylCi-Cealkyl, heteroarylC,-Cealkyl, cycloaliphaticC,;-Cealkyl, or heterocycloaliphaticC;-Csalkyl. -571- Amended sheet: 29 September 2006
282. The compound of claim 214 or 258, wherein q is | and y is 0 or 1, and R¥ is F, OR’, or
OH.
283. The compound of claim 214 or 258, wherein ring A is selected from: 5 (RS), yR) (R%®), y(RY) JR) rad NP NN ee en LA LI He, 7 N° wd) N i ii iii iv 5 RS (R) RS) (RS (Ry ug RF)g i _—(R%), — oN v vi vii viii (RY) 5 -NH 5 N (R%)y ’ SY (R%2)q i § NER) UN NON aa “2 NX ony TN wf ONRE), LR, a s ix X xi xii 5 (R%) (RS) (R%) (Ry y Lah ’ (R53) Arh me Nh (roe), roo, pul 7 \ q Uv hy : y H xiii xiv Xv xvi 5 (RY) (goa (R%) yR% (RS?) WR) say y R y ~ a Aa )q Joy (RE) oN %N q AY N q Ul N N N (Wy (EY / 0 $ “g IN /'N wd, “a, xvii xviii xix XX -572- Amended sheet: 29 September 2006
(RY), (RS), (R®)y S S Ne” al 1 — 1) = XX N, XX N 2 0 (R52), N (R59), (R52), xxi xxii xxiii RS) (RS), (R%), Ry Ro " N Ks a HN, Ld AL NAR N™ (Ra), (R%)q (R53), xxiv XXV XXVvi (R%), H (RS RS N ¥ “NH NL ly 04 ly N, \ ~ — J i 5— (R58), — ——(R%) NTN Rea PS “nN NW q oL (Ra (RS) (Ra H H xxvii xxviii XXix XXX (Ro) (RS) (RS) (R%)
S. bf y y 7 To CN 4 a. ——(R%®), _r _r T—(R%), _L bi “Sn SY CU) Nw, H (R33), Xxxi xxxii xxxiii XXXiv N(R PON y(RS) EAN % [S—) (R53), I~ (R Jy (R53), XXXV XXxvi XXXVii
284. The compound of claim 214 or 258, wherein ring A is selected from optionally substituted phenyl, 2-pyridyl, 3-pyridyl, or 4-pyridyl, or pyrrol-1-yl.
285. The compound of claim 214 or 258, wherein the method comprises administering a compound of any one of claims 1-212. -573 - Amended sheet: 29 September 2006
286. The compound of claim 214 or 285, wherein the method comprises inhibiting NaV1.3 or NaV1.8 activity.
287. The compound of claim 214 or 285, wherein the method comprises inhibiting CaV2.2 activity.
288. The compound of claim 214 or 285, wherein the method comprises inhibiting NaV1.8 and CaV2.2 activity.
289. The compound of claim 214 or 285, wherein the method comprises inhibiting NaV1.8 activity.
290. The use of a compound of formula I: 1 Rx x Haas I or a pharmaceutically acceptable salt thereof, wherein: XisOor NR? wherein R' and R? are each independently an optionally substituted group selected from hydrogen, C, aliphatic, or Cy', wherein Cy' is a 5-7-membered monocyclic aryl ring or an 8-10- membered bicyclic aryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or is a 3-12-membered saturated, or partially unsaturated monocyclic or bicyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein Cy' is bonded directly to the nitrogen atom or is bonded through an optionally substituted C,4aliphatic group, wherein one or more methylene units in the C,4aliphatic group are optionally replaced with -NR-, -O-, -COO, -OCO-, -NRCO-, -CONR-, -SO;NR-, or -NRSO;-; or R! and R?, taken together with the nitrogen atom to which they are bound, form an optionally substituted 3-12-membered monocyclic or bicyclic saturated, partially unsaturated, or fully unsaturated ring having 0-3 additional heteroatoms independently selected from nitrogen, -574 - Amended sheet: 29 September 2006 sulfur, or oxygen; wherein R' and R?, or the ring formed by R' and R? taken together, are each optionally and independently substituted at one or more substitutable carbon, nitrogen, or sulfur atoms with z independent occurrences of —-R*, wherein z is 0-5;
Ring A is a 5-7-membered monocyclic aryl ring or an 8-10-membered bicyclic aryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or is a 3-12- membered monocyclic or bicyclic saturated or partially unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein ring A is optionally substituted with y independent occurrences of —R’, wherein y is 0-5, and is additionally optionally substituted with q independent occurrences of R*, wherein q is 0-2;
x is 0-4;
each occurrence of R* ,R* and R® is independently Q-R%; wherein Q is a bond oris a C;- Cs alkylidene chain wherein up to two non-adjacent methylene units of Q are optionally and independently replaced by -NR-, -S-, -O-, -CS-, -CO,-, -OCO-, -CO-, -COCO-, -CONR-, - NRCO-, -NRCO;-, -SO,NR-, -NRSO;-, -CONRNR-, -NRCONR-, -OCONR-, -NRNR-, - NRSO;NR-, -SO-, -SO;-, -PO-, -PO,-, -OP(O)(OR)-, or -POR-; and each occurrence of R¥ is independently selected from -R’, =O, =NR’, halogen, -NO,, -CN, -OR’, -SR’, -N(R’),, - NR’COR’, -NR’CON(R’),, -NR’CO2R’, -COR’, -CO,R’, -OCOR?’, -CON(R),, -OCON(R’),, - SOR’, -SO,R’, -SO;N(R’),, -NR’SO4R’, -NR’SO;N(R’),, -COCOR’, -COCH,COR’, - OP(O)(OR’),, -P(O}(OR’),, -OP(0);0R’, -P(0),OR’, -PO(R’),, or -OPO(R’),;
each occurrence of R*® is independently an optionally substituted C,-Cqaliphatic group, halogen, -OR’, -SR’, -N(R’),, -NR’COR’, -NR’CON(R’),, -NR’CO;R’, -COR’, -COzR’, - OCOR’, -CON(R’);, -OCON(R’),, -SOR’, -SO;R”’, -SO;N(R’)2, -NR’SO,R’, -NR’SO2N(R),, - COCOR’, -COCH,COR’, -OP(O)(OR”),, -P(O)(OR’),, -OP(O),0OR’, -P(0);OR’, -PO(R’),, or - OPO(R’); and each occurrence of R is independently hydrogen or an optionally substituted C,.¢ aliphatic group; and each occurrence of R'is independently hydrogen or an optionally substituted C, aliphatic group, a 3-8-membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-12 membered saturated, partially unsaturated, or fully unsaturated bicyclic ring system having 0-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or R and R’, two occurrences of R, or two occurrences of R', are taken together with the atom(s) to which they are
-575- Amended sheet: 29 September 2006 bound to form an optionally substituted 3-12 membered saturated, partially unsaturated, or fully unsaturated monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, in the manufacture of a medicament for use in a method of inhibiting one or more of NaVl1.1,NaV1.2,NaV1.3,NaV1.4,NaV1.5,NaV1.6,NaV1.7, NaV1.8, NaV1.9, or CaV2.2 activity in a patient.
291. The use of claim 220 or 290, wherein X is NR?, and compounds have the structure of formula I-A: RL? XN N I-A
292. The use of claim 220 or 290, wherein X is O, and compounds have the structure of formula I-B: RY o XY” SN N I-B
293. The use of claim 220 or 290, wherein a) one of R' or R? is hydrogen, and the other of R' and R? is selected from: i) an optionally substituted C,4aliphatic group, wherein one or more methylene units in the Cj4aliphatic group are optionally replaced with -NR-, -O-, -COO, -OCO-, - NRCO-, -CONR-, -SO,NR-, or -NRSO,-; or Cy', wherein Cy' is a 5-7-membered monocyclic aryl ring or an 8-10-membered bicyclic aryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or is a 3-12-membered saturated, or partially unsaturated monocyclic or bicyclic ring having 0-3 heteroatoms independently - 576 - Amended sheet: 29 September 2006 selected from nitrogen, oxygen, or sulfur, wherein Cy' is bonded directly to the nitrogen atom or is bonded through an optionally substituted C,4aliphatic group, wherein one or more methylene units in the C)4aliphatic group are optionally replaced with -NR-, -O-, -COO, -OCO-, -NRCO-, -CONR-, -SO,NR-, or -NRSO;-; or ii) an optionally substituted C,4aliphatic group, wherein one or more methylene units in the C;4aliphatic group are optionally replaced with -NR-, -O-, -COO, -OCO-, - NRCO-, -CONR-, -SO;NR-, or -NRSO,-; or b) R! and R? are each independently selected from Cy', wherein Cy' is a 5-7-membered monocyclic aryl ring or an 8-10-membered bicyclic aryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or is a 3-12-membered saturated, or partially unsaturated monocyclic or bicyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein Cy' is bonded directly to the nitrogen atom or is bonded through an optionally substituted C,4aliphatic group, wherein one or more methylene units in the C_4aliphatic group are optionally replaced with -NR-, -O-, -COOQO, -OCO-, -NRCO-, - CONR-, -SO;NR-, or -NRSO»-; or from an optionally substituted C4aliphatic group, wherein one or more methylene units in the C, aliphatic group are optionally replaced with —-NR-, -O-, - COO-, -OCO-, -NRCO-, -CONR-, -SO;NR-, or -NRSO;-.
294. The use of claim 220 or 290, wherein Cy' is:
oR . + re, VIR, Ho) 0 re, NZ J nN? 7 a b c d = noe yf SOT a WJ N N h, wy e f g h NN Nx (Re RY, Le GE Am Hy i j k 1 -577- Amended sheet: 29 September 2006
. R4 R R R 2 SASS TEE TE S wf Mg J=N hd Th, m n 1] Pp R* R4 Re sn NN Ns -C =N —! — Lo ve " ve N SNR, q r $ t N 0 NSS” FC oR: NZ od, (R%), N N (R™), H H u v w xX H N Pa SN SN] aK A(R) y z aa bb
295. The use of claim 220 or 290, wherein R' is hydrogen or an optionally substituted C,- Caaliphatic group and R? is —-CH,-Cy', wherein Cy’ is: ZRH N No NZ ca A oN = TR: IR: Sq HL RY, 2 : : a b c d -578 - Amended sheet: 29 September 2006
(RY); (R); (R) (RY) 22, S N= z = 7 LT [he 0 N" SN “4, “ e f g h H -N — (RY N D NT z RY IN pd N 7 \ z TN “ (RY), ON NN TS i i k R4 rR? R4 3 (RY) s no pw =n hd Ta, m n 0 p R4 R4 R4 LN WN wl N SR, q r s t N 0 Ld, RY: J Re Lod, (R%); N N (R%); u v w X H N on IN IN. oR (RY) y z aa bb
296. The use of claim 220 or 290, wherein R' and R? groups are each independently an optionally substituted C;4aliphatic group and are each independently selected from optionally -579 - Amended sheet: 29 September 2006 substituted methyl, ethyl, cyclopropyl, n-propyl, propenyl, cyclobutyl, (CO)OCH,CHs, (CH,),0CH3;, CH,CO)OCH,CH3, CH2(CO)OCHj3, CH(CH3)CH,CH3, or n-butyl.
297. The use of claim 220 or 290, wherein R' and R?, taken together with the nitrogen atom to which they are bound, form an optionally substituted 3-12 membered heterocyclyl ring having 1-3 heteroatoms independently selected from nitrogen or oxygen and form a 3-12 membered heterocyclyl group selected from: 4 (RY) (R%) ES ~R )2 Ls ‘ LQ : 7 J ) L_NH Lo cc dd ee “ Ne N N 2X 4 (R%), ff gg hh A I \ a 2 ) _s “RY /. ’ 2(R*) ii ii kk or T ™ N N N N ) ) a ( N\ RY ORY, N (R), i (RY), mm nn 00 wherein the ring formed by R' and R? taken together, is optionally substituted at one or more substitutable carbon, nitrogen, or sulfur atoms with z independent occurrences of -RY, and zis 0-5. - 580 - Amended sheet: 29 September 2006
298. The use of claim 220 or 290, wherein R' and R* taken together is an optionally substituted ring selected from azetidin-1-yl (jj), pyrrolidin-1-yl (ff), piperidinl-yl (dd), piperazin-1-yl (cc), or morpholin-4-yl (ee).
299. The use of claim 220 or 290, wherein R' and R? taken together is an optionally substituted ring selected from azetidin-1-yl (jj), pyrrolidin-1-y! (ff), piperidinl-yl (dd), or piperazin-1-yl (cc).
300. The use of claim 220 or 290, wherein z is 0-5, and R* groups, when present, are each independently halogen, CN, NO,, -N(R’);, -CH>N(R”),, -OR’, -CH,0OR”’, -SR’, -CH,SR’, - COOR’, -NRCOR’, -CON(R’);, -OCON(R’),, COR’, -NHCOOR’, -SO;R’, -SO,;N(R’),, or an optionally substituted group selected from C,;.Cealiphatic, aryl, heteroaryl, cycloaliphatic, heterocycloaliphatic, arylC;-Cgalkyl, heteroarylC;-Cealkyl, cycloaliphaticC,-Cgalkyl, or heterocycloaliphaticC,-Cealkyl.
301. The use of claim 220 or 290, wherein z is 0-5 and R* groups are each independently Cl, Br, F, CF3, CHs, -CH,CH3, CN, -COOH, —-N(CH3),, -N(Et),, -N(iPr),, -O(CH;);OCH3, -CONH,, -COOCH;, -OH, -CH,OH, -NHCOCH;, -SO;NH,;, -SO,(CH,);CHj;, -SO,CH(CHj),, - SO;N(CH3),, -SO,CH,CH3, -C(O)OCH,CH(CH3)2, -C(O)NHCH;CH(CH3),, -NHCOOCHs3;, - C(0)C(CHa)3, -COO(CH,),CHj3, -C(O)NHCH(CHy3),, -C(O)CH,CHj3, or an optionally substituted group selected from -piperidinyl, piperizinyl, morpholino, Ci 4alkoxy, phenyl, phenyloxy, benzyl, benzyloxy, -CHacyclohexyl, pyridyl, -CH,pyridyl, or -CHathiazolyl.
302. The use of claim 220 or 290, wherein R! and R?, taken together is selected from:
a. optionally substituted azetidin-1-yl (jj), wherein z is 1 or 2 and at least one occurrence of R* is -NRSO,R’, -NRCOOR’, or -NRCOR’;
b. optionally substituted azetidin-1-yl (jj), wherein z is 1 and R* is -NRSOR’;
C. optionally substituted azetidin-1-yl (jj), wherein z is 1 and R* is -NRCOOR’;
d. optionally substituted azetidin-1-yl (jj), wherein z is 1 and R* is -NRCOR’;
e. optionally substituted pyrrolidin-1-yl (ff), wherein z is 1 or 2 and R'is Cl, Br, F, CF;, CHj, -CH,CH3, -OR’, or -CH,OR’; - 581 - Amended sheet: 29 September 2006 f. optionally substituted piperidin-1-yl (dd), wherein z is 1 or 2 and at least one occurrence of R* is Cl, Br, F, CF3, CH;, -CH,CHj;, -OR’, or -CH,OR’, -NRSO;R’, -NRCOOR’, or -OCON(R’),;
g. optionally substituted piperidin-1-yl (dd), wherein z is 1 and R* is F, CFs, CH3, - CH,CH3, -OR’, or -CH,0OR’;
h. optionally substituted piperidin-1-yl (dd), wherein z is 1 and R* is —NRSO,R’;
i. optionally substituted piperidin-1-yl (dd), wherein z is 1 and R* is -NRCOOR’;
J. optionally substituted piperazin-1-yl (ec), wherein z is 1 or 2 and at least one occurrence of R* is =SOR’, -CON(R),, -SO,N(R”),, -COR’, or -COOR’;
k. optionally substituted piperazin-1-yl (cc), wherein z is 1 and R* is ~SOR’
1. optionally substituted piperazin-1-yl (cc), wherein z is 1 and R* is -COOR’;
m. optionally substituted piperazin-1-yl (cc), wherein z is 1 and R* is -CON(R’)y;
n. optionally substituted piperazin-1-yl (ec), wherein z is 1 and R* is -SO;N(R’),; or
0. optionally substituted piperazin-1-yl (cc), wherein z is 1 and R* is -COR’.
303. The use of claim 220 or 290, wherein x is 0-4, and R® groups, when present, are each independently halogen, CN, NO;, -N(R’);, -CH,N(R’)2, -OR’, -CH,0R’, -SR’, -CH,SR’, - COOR’, -NRCOR’, -CON(R’);, -OCON(R’),, COR’, -NHCOOR’, -SO,R’, -SO,N(R’),, or an optionally substituted group selected from C,.Cealiphatic, aryl, heteroaryl, cycloaliphatic, heterocycloaliphatic, arylC,-Cealkyl, heteroarylC;-Cealkyl, cycloaliphaticC,-Cgalkyl, or heterocycloaliphaticC,-Csalkyl.
304. The use of claim 220 or 290, wherein x is 1 or 2, and each occurrence of R® is independently Cl, Br, F, CF;, -OCF3, Me, Et, CN, -COOH, -NH;, -N(CH3),, -N(Et),, -N(iPr),, - O(CH,),0CH;, -CONH;, -COOCHj;, -OH, -OCHj;, -OCH,CHs;, -CH,OH, -NHCOCH;, - NHCOCH(CH3),;, -SO;NH,, -CONH(cyclopropyl), -CONHCH;, -CONHCH,CHj;, or an optionally substituted group selected from -piperidinyl, piperizinyl, morpholino, phenyl, phenyloxy, benzyl, or benzyloxy.
305. The use of claim 220 or 290, wherein x is 1 or 2 and each R* group is independently halogen, CN, optionally substituted C,-Cealkyl, OR’, N(R’);, CON(R’),, or NRCOR’. - 582 - Amended sheet: 29 September 2006
306. The use of claim 220 or 290, wherein x is 1 or 2, and each R® group is -Cl, -CHj, - CH,CHj, -F, -CF3, -OCF3;, -CONHCHj3, -CONHCH,CHj, -CONH(cyclopropyl), -OCHj3, -NHa, - OCH,CHjs, or -CN.
307. The use of claim 220 or 290, wherein x is 1 and R? is at the 6-position of the quinazoline ring and is -Cl, -CH;, -CH,CH;, -F, -CF;, -OCF; -CONHCHj;, -CONHCH,CH;, - CONH(cyclopropyl), -OCH3, -NH,, -OCH,;CH3, or -CN.
308. The use of claim 220 or 290, wherein x is 1 and R3 is at the 7-position of the quinazoline ring and is -Cl, -CH; -CH;CH;, -F, -CF; -OCF;, -CONHCH; -CONHCH,CH;, - CONH(cyclopropyl), -OCH3, -NH,, -OCH,CHs, or -CN.
309. The use of claim 220 or 290, wherein x is 1 and R? is at the 6-position of the quinazoline ring and is -Cl, -CH;, -CH,CH;, -F, -CF3, -OCFs3, -OCH;, or -OCH,CH3.
310. The use of claim 220 or 290, wherein x is 1 and R’ is at the 7-position of the quinazoline ring and is -Cl, -CH;, -CH,CH;, -F, -CF3, -OCF;, -OCHs, or -OCH,CHas.
311. The use of claim 220 or 290, wherein x is | and R? is at the 6-position of the quinazoline ring and is -CON(R’),, or NRCOR”.
312. The use of claim 220 or 290, wherein x is 1 and R? is at the 7-position of the quinazoline ring and is “CON(R’),, or NRCOR’.
313. The use of claim 220 or 290, wherein y is 0-5, q is 0-2, and R® and R*® groups, when present, are each independently halogen, CN, NO, -N(R’),, -CH,N(R’), -OR’, -CH,OR’, -SR”’, - CH,SR’, - -NRCOR’, -CON(R’),, -S(O);N(R”),, -OCOR’, -COR’, -CO;R’, -OCON(R’),, - NR’SOzR’, -OP(O)(OR’),, -P(O)(OR’);, -OP(0),0R’, -P(O),0R’, -PO(R’),, -OPO(R’)2, or an optionally substituted group selected from C,.Cealiphatic, aryl, heteroaryl, cycloaliphatic, -583- Amended sheet: 29 September 2006 heterocycloaliphatic, arylC,-Cgalkyl, heteroarylC,-Cgalkyl, cycloaliphaticC;-Cgalkyl, or heterocycloaliphaticC,-Cealkyl.
314. The use of claim 220 or 290, wherein q is 1 and y is 0 or 1, and Ris F, OR’, or OH.
315. The use of claim 220 or 290, wherein ring A is selected from: 5 (RS), y(R%) (R33) y(RY) y(R%) HER, LN bo R®a Eg (Ry = and SN wd N i ii iii iv (R9) (R%), RY) (RS?) RY OY en, Ley “1 J (R?), —T _—(R%), —i NG v vi vii viii 5 H yR) os RS N-NH i” n-NRy nN a ( | ly I CT AC Ro), LR) “HN S ix X xi xii 5 (RS), (RY), (R%)y il Lh ree Arh re), hw, & 3 (R%, HR q rq ' p : H xiii Xiv XV xvi 5 RS) (R%) 5a (RS) y(R®) (R53) yl (R58) y R M ~ ES Na nr Ra oy SYN 1] N = “N \: =N = ‘N /© ~g ve / wd, wy xvii xviii xix XX -584 - Amended sheet: 29 September 2006
(Ro), Py (RY), Ry N— "a No N BD s—¢ | J NS 3 = <_ 0 (R53), N (R53), (R53) xxi xxii xxiii RY) (RS) (R%) Ry wl) a 3 TN XX N (R59), (R%3), (R53), XXiv XXV xxvi (Ry H (RS RS N 7 NH NL ly 04 ly Ne = J FL —(R%), — — (R52) NTN Ra IN sa “nN SN” ! we (Rg JRS (R%q H H xxvii xxviii XXix XXX (R%)y (RS) (R%) (R%)
S. y y y A to CN Kk iC (R53), _r _r (R32), _b bi Sn =U =) CNR, H (R59), XXXi XXxxii xxxiii XXXiv NR A 0 C7 0’ _ N(R [gia R52 (RS) ¥ a ( )q y (R53), XXXV XXXVi XXXxvii
316. The use of claim 220 or 290, wherein ring A is selected from optionally substituted phenyl, 2-pyridyl, 3-pyridyl, or 4-pyridyl, or pyrrol-1-yl.
317. The use of claim 220 or 290, wherein the method comprises administering a compound of any one of claims 1-212. - 585 - Amended sheet: 29 September 2006
318. The use of claim 220 or 317, wherein the method comprises inhibiting NaV1.3 or NaV1.8 activity.
319. The use of claim 220 or 317, wherein the method comprises inhibiting CaV2.2 activity.
320. The use of claim 220 or 317, wherein the method comprises inhibiting NaV1.8 and CaV2.2 activity.
321. The use of claim 220 or 317, wherein the method comprises inhibiting NaV1.8 activity.
322. Compounds according to claim 1 as specifically described herein.
323. Compounds according to claim 103 as specifically described herein.
324. Compounds according to claim 149 as specifically described herein.
325. Compounds according to claim 193 as specifically described herein. - 586 - ) Amended sheet: 29 September 2006
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US45145803P | 2003-03-03 | 2003-03-03 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| ZA200507979B true ZA200507979B (en) | 2007-03-28 |
Family
ID=36773809
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| ZA200507979A ZA200507979B (en) | 2003-03-03 | 2004-03-03 | Quinazolines useful as modulators of ion channels |
Country Status (2)
| Country | Link |
|---|---|
| CN (1) | CN1784391B (en) |
| ZA (1) | ZA200507979B (en) |
Families Citing this family (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CA2772642C (en) * | 2009-09-03 | 2017-08-29 | Bristol-Myers Squibb Company | Quinazolines as potassium ion channel inhibitors |
| KR20130095772A (en) * | 2010-10-05 | 2013-08-28 | 퍼듀 퍼머 엘피 | Quinazoline compounds as sodium channel blockers |
| BR112014030147B1 (en) * | 2012-06-22 | 2019-10-15 | Sumitomo Chemical Company, Limited | Fused Heterocyclic Compounds, Composition and Method to Control Pests |
| CN103819467B (en) * | 2014-02-27 | 2019-03-08 | 中国科学院福建物质结构研究所 | The preparation method and its usage of quinazoline derivant |
| CA2943011A1 (en) * | 2014-04-04 | 2015-10-08 | H. Lundbeck A/S | Halogenated quinazolin-thf-amines as pde1 inhibitors |
| JP2022538588A (en) * | 2019-06-27 | 2022-09-05 | グラクソスミスクライン、インテレクチュアル、プロパティー、ディベロップメント、リミテッド | 2,3-dihydroquinazoline compounds as NaV1.8 inhibitors |
| CN117412752A (en) * | 2021-05-12 | 2024-01-16 | 广东众生药业股份有限公司 | Application of 4-arylaminoquinazoline hydroxamic acid compound in preparation of pain medicines |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3340260A (en) * | 1962-12-03 | 1967-09-05 | Ciba Geigy Corp | 4-amino-pyrimidines |
| US3637693A (en) * | 1968-07-12 | 1972-01-25 | Du Pont | Hydroxyarylquinazolines and their use as uv-absorbers |
| DE69425804T2 (en) * | 1993-06-17 | 2001-02-08 | Otsuka Pharma Co Ltd | PHOSPHONIC ACID SERIES DERIVATIVES |
-
2004
- 2004-03-03 ZA ZA200507979A patent/ZA200507979B/en unknown
- 2004-03-03 CN CN200480011981.4A patent/CN1784391B/en not_active Expired - Fee Related
Also Published As
| Publication number | Publication date |
|---|---|
| CN1784391B (en) | 2010-06-09 |
| CN1784391A (en) | 2006-06-07 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| AU2004217891B2 (en) | Quinazolines useful as modulators of ion channels | |
| JP6670885B2 (en) | Compositions containing thienopyrimidine and thienopyridine compounds and methods of using them | |
| JP4808156B2 (en) | Condensed pyrimidine compounds as inhibitors of voltage-gated ion channels | |
| ES2680246T3 (en) | Pyrimidinecarboxamides as sodium channel blockers | |
| JP6186494B2 (en) | Carboxamide derivatives and uses thereof | |
| JP6337124B2 (en) | Indazole and its use | |
| CN101238109B (en) | Indane derivatives as modulator of ion channels | |
| DE60103935T2 (en) | IMIDAZOLE-5-YL-2-ANILINO-PYRIMIDINE AS INHIBITORS OF CELL PROLIFERATION | |
| ES2327945T3 (en) | USEFUL KINAZOLINS AS MODULATORS OF ION CHANNELS. | |
| MXPA06000051A (en) | Pyrimidines useful as modulators of voltage-gated ion channels. | |
| US20100249100A1 (en) | Quinazolines useful as modulators of ion channels | |
| ZA200507979B (en) | Quinazolines useful as modulators of ion channels | |
| CN101406469B (en) | Use of GAL3 receptor antagonists for the treatment of depression and/or anxiety and compounds useful in such methods | |
| ZA200600197B (en) | Pyrimidines useful as modulators of voltage-gated ion channels |