PYRIDO-/AZEPINO-BENZOFURAN AND PYRIDO-/AZEPINO-BENZOTHIOPHENE MCH-1 ANTAGONISTS, METHODS OF MAKING, AND USE THEREOF
Novel MCH-1 receptor antagonists are disclosed. These compounds are used in the treatment of various disorders, including obesity, anxiety, depression, non-alcoholic fatty liver disease, and psychiatric disorders. Methods of making these compounds are also described.
1 . A compound of formula (I):
wherein
R 2 -R 5 and R 9 -R 12 are each, independently, selected from the group consisting of H, halogen, —OR 13 , —NR 13 R 14 , —NR 13 C(O)R 14 , —NR 13 C(O) 2 R 14 , —NR 15 C(O)NR 14 R 15 , —S(O) q R 14 , —CN, —C(O)R 14 , —C(O)NR 13 R 14 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, C 4 -C 7 cycloalkylalkyl, heterocyclyl, aryl, and heteroaryl, wherein each of C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, C 4 -C 7 cycloalkylalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with from 1 to 3 substituents independently selected at each occurrence thereof from C 1 -C 3 alkyl, halogen, —CN, —OR 16 , —NR 16 R 17 , and phenyl which is optionally substituted 1-3 times with halogen, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, —CN, —OR 16 , or —NR 16 R 17 ; or R 2 and R 3 or R 4 and R 5 can combine to form an oxo, thio, imine, cycloalkyl, or heterocycle group containing from 1 to 5 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur; or any one of R 2 , R 3 , R 4 , or R 5 can combine with any one of R 9 , R 10 , R 11 , or R 12 to form —(CH 2 ) r —;
R 6 is independently selected at each location from the group consisting of H, halogen, —OR 13 , —NR 13 C(O)R 14 , —NR 13 C(O) 2 R 14 , —NR 15 C(O)NR 14 R 15 , —S(O) q R 14 , —CN, —C(O)R 14 , —C(O)NR 13 R 14 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, C 4 -C 7 cycloalkylalkyl, heterocyclyl, aryl, and heteroaryl, wherein each of C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, C 4 -C 7 cycloalkylalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with from 1 to 3 substituents independently selected at each occurrence thereof from C 1 -C 3 alkyl, halogen, —CN, —OR 6 , —NR 16 R 17 , and phenyl which is optionally substituted 1-3 times with halogen, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, —CN, —OR 16 , or NR 16 R 17 ;
R 7 is optionally present and, if present, is selected from the group consisting of H, halogen, —OR 13 , —NR 13 R 14 , —NR 13 C(O)R 14 , —NR 13 C(O) 2 R 14 , —NR 15 C(O)NR 14 R 15 , —S(O) q R 14 , —CN, —C(O)R 14 , —C(O)NR 13 R 14 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, C 4 -C 7 cycloalkylalkyl, heterocyclyl, aryl, and heteroaryl, wherein each of C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, C 4 -C 7 cycloalkylalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with from 1 to 3 substituents independently selected at each occurrence thereof from C 1 -C 3 alkyl, halogen, —CN, —OR 16 , —NR 16 R 17 , and phenyl which is optionally substituted 1-3 times with halogen, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, —CN, —OR 16 , or —NR 16 R 17 ;
R 8 is selected from the group consisting of H, —S(O) q R 14 , —C(O)R 14 , —C(O)NR 13 R 14 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, C 4 -C 7 cycloalkylalkyl, heterocyclyl, and heteroaryl, wherein each of C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, C 4 -C 7 cycloalkylalkyl, heterocyclyl, and heteroaryl is optionally substituted with from 1 to 3 substituents independently selected at each occurrence thereof from C 1 -C 3 alkyl, halogen, —CN, —OR 16 , —NR 16 R 17 , and phenyl which is optionally substituted 1-3 times with halogen, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, —CN, —OR 16 , or NR 16 R 17 ; or
R 8 and one of R 2 , R 3 , R 4 , and R 5 can combine to form a 3- to 7-membered heterocycle, wherein the 3- to 7-membered heterocycle includes from 1 to 2 heteroatoms selected from the group consisting of N, O, and S and is optionally substituted with from 1 to 10 substituents independently selected at each occurrence thereof from H, halogen, —OR 13 , —NR 13 R 14 , —NR 13 C(O)R 14 , —NR 13 C(O) 2 R 14 , —NR 15 C(O)NR 14 R 15 , —S(O) q R 14 , —CN, —C(O)R 14 , —C(O)NR 13 R 14 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, C 4 -C 7 cycloalkylalkyl, heterocyclyl, aryl, and heteroaryl, wherein each of C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, C 4 -C 7 cycloalkylalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with from 1 to 3 substituents independently selected at each occurrence thereof from C 1 -C 3 alkyl, halogen, —CN, —OR 16 , —NR 16 R 17 , and phenyl which is optionally substituted 1-3 times with halogen, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, —CN, —OR 16 , or —NR 16 R 17 ;
R 13 is H, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxyalkyl, C 3 -C 6 cycloalkyl, C 4 -C 7 cycloalkylalkyl, —C(O)R 15 , phenyl, or benzyl, wherein phenyl or benzyl is optionally substituted 1 to 3 times with halogen, cyano, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, or C 1 -C 4 alkoxy;
R 14 is H, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxyalkyl, C 3 -C 6 cycloalkyl, C 4 -C 7 cycloalkylalkyl, phenyl, or benzyl, wherein phenyl or benzyl is optionally substituted 1 to 3 times with halogen, cyano, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, or C 1 -C 4 alkoxy;
R 15 is C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, or phenyl;
R 16 and R 17 are each independently H, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxyalkyl, C 3 -C 6 cycloalkyl, C 4 -C 7 cycloalkylalkyl, —C(O)R 15 , phenyl, or benzyl, wherein phenyl or benzyl is optionally substituted from 1 to 3 times with a substituent selected independently at each occurrence thereof from the group consisting of halogen, cyano, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, and C 1 -C 4 alkoxy;
R 18 is selected from the group consisting of H, halogen, —OR 13 , —NR 13 R 14 —NR 13 C(O)R 14 , —NR 13 C(O) 2 R 14 , —NR 14 C(O)NR 14 R 15 , —S(O) q R 14 , —CN, —C(O)R 14 , —C(O)NR 13 R 14 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, C 4 -C 7 cycloalkylalkyl, heterocyclyl, aryl, and heteroaryl, wherein each of C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, C 4 -C 7 cycloalkylalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with from 1 to 3 substituents independently selected at each occurrence thereof from C 1 -C 3 alkyl, halogen, —CN, —OR 16 , —NR 16 R 17 , and phenyl which is optionally substituted 1-3 times with halogen, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, —CN, —OR 8 , or —NR 8 R 9 ;
G is —NR 8 —CR 9 R 10 —, —CR 9 R 10 —NR 8 —, —NR 8 —CR 9 R 10 —CR 11 R 12 —, —CR 9 R 10 —NR 8 —CR 11 R 12 —, or —CR 9 R 10 —CR 11 R 12 —NR 8 —;
X is CR 18 , C(R 18 ) 2 , N, or NR 18 ;
Y is CR 18 , C, or N;
Z is O or S;
L is —(CH 2 ) p —O—, —(CH 2 ) p —, —CH═CH—, or a bond;
A is C, CH, or N;
B is aryl, heteroaryl, heterocyclyl, or cycloalkyl, wherein each of the aryl, heteroaryl, heterocyclyl, or cycloalkyl is optionally substituted with from 1 to 3 substituents selected from the group consisting of H, alkoxy, —S-alkyl, optionally substituted C 1 -C 6 alkyl, halogen, —CF 3 , —OCF 3 , and —CN;
n is 0, 1, 2, or 3;
p is from 1 to 4;
q is 0, 1, or 2;
r is from 1 to 4; and
represents an optional double bond,
or an oxide thereof, a pharmaceutically acceptable salt thereof, a solvate thereof, or prodrug thereof.
2 . The compound according to claim 1 , wherein G is —NR 8 —CR 9 R 10 —.
3 . The compound according to claim 1 , wherein G is —CR 9 R 10 —NR 8 —.
4 . The compound according to claim 1 , wherein G is —NR 8 —CR 9 R 10 —CR 11 R 12 —.
5 . The compound according to claim 1 , wherein G is —CR 9 R 10 —NR 8 —CR 11 R 12 —.
6 . The compound according to claim 1 , wherein G is —CR 9 R 10 —CR 11 R 12 —NR 8 —.
7 . The compound according to claim 1 , wherein R 2 to R 5 are each independently selected from the group consisting of H and optionally substituted C 1 -C 6 alkyl.
8 . The compound according to claim 1 , wherein R 6 is H, halogen, or optionally substituted C 1 -C 6 alkyl.
9 . The compound according to claim 1 , wherein R 7 is H, halogen, or optionally substituted C 1 -C 6 alkyl.
10 . The compound according to claim 1 , wherein R 8 is H or C 1 -C 6 alkyl and R 9 -R 12 are H.
11 . The compound according to claim 1 , wherein R 8 and one of R 2 , R 3 , R 4 , and R 5 combine to form a 3- to 7-membered heterocycle.
12 . The compound according to claim 1 , wherein any one of R 2 , R 3 , R 4 , or R 5 combine with any one of R 9 , R 10 , R 1 , or R 12 to form —(CH 2 ) r — and r is from 1 to 4.
13 . The compound according to claim 1 , wherein R 8 is H or C 1 -C 6 alkyl.
14 . The compound according to claim 1 , wherein R 8 is —C(O)R 14 .
15 . The compound according to claim 1 , wherein Z is O.
16 . The compound according to claim 1 , wherein Z is S.
17 . The compound according to claim 1 , wherein X is N, CH, or CH 2 .
18 . The compound according to claim 1 , wherein Y is N or C.
19 . The compound according to claim 1 , wherein L is a bond.
20 . The compound according to claim 1 , wherein L is —CH 2 —O—.
21 . The compound according to claim 1 , wherein L is —CH 2 —CH 2 —.
22 . The compound according to claim 1 , wherein B is phenyl or pyridinyl.
23 . The compound according to claim 1 , wherein B is unsubstituted.
24 . The compound according to claim 1 , wherein B is substituted with at least one substituent selected from trifluoromethyl, chloro, fluoro, and methyl.
25 . The compound according to claim 1 , wherein B is selected from the group consisting of phenyl, 4-(trifluoromethyl)phenyl, pyridin-2-yl, 5-(trifluoromethyl)pyridin-2-yl, 5-fluoro-pyridin-2-yl, 6-methylpyridin-3-yl, 6-(trifluoromethyl)pyridin-2-yl, 6-(trifluoromethyl)pyridin-3-yl, 5-chloro-pyridin-2-yl, and 4-chloro-phenyl.
26 . The compound according to claim 1 , wherein B is selected from the group consisting of 6-(trifluoromethyl)pyridazin-3-yl, 2-fluoro-4-methoxyphenyl, 2-chloro-4-methoxyphenyl, and 2-methyl-4-(trifluoromethoxy)phenyl.
27 . The compound according to claim 1 , wherein the compound has the structure:
28 . The compound according to claim 1 , wherein the compound is selected from the group consisting of
29 . The compound according to claim 1 , wherein the compound is selected from the group consisting of
30 . The compound according to claim 1 , wherein the compound is an HCl salt.
31 . A pharmaceutical composition comprising a therapeutically effective amount of the compound according to claim 1 and a pharmaceutically acceptable carrier.
32 . A method of treating a disease or condition which is susceptible to treatment with a MCH-1 receptor antagonist comprising:
selecting a patient with a disease or condition which is susceptible to treatment with a MCH-1 antagonist, and
administering to the patient a therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof.
33 . The method according to claim 32 , wherein the disease or condition is selected from the group consisting of obesity, general anxiety disorders, inflammatory bowel disease, social phobias, vertigo, obsessive-compulsive disorders, panic disorders, post-traumatic stress disorders, Parkinson's Disease Psychosis, schizophrenia, cognitive decline and defects in schizophrenia, presenile dementias, Alzheimer's Disease, psychological disorders, depression, substance abuse disorders, dementia associated with neurodegenerative disease, cognition deficits, and epilepsy.
34 . The method according to claim 32 further comprising:
administering to the patient a therapeutically effective amount of a therapeutic adjunct.
35 . The method according to claim 34 , wherein the therapeutic adjunct is selected from the group consisting of phenylpropanolamine, ephedrine, pseudoephedrine, phentermine, a cholecystokinin-A agonist, a monoamine reuptake inhibitor, a sympathomimetic agent, a serotonergic agent, a dopamine agonist, a melanocyte-stimulating hormone receptor agonist or mimetic, a melanocyte-stimulating hormone analog, a cannabinoid receptor antagonist or inverse agonist, a melanin concentrating hormone receptor antagonist, a serotonin 5-HT 6 receptor antagonist, a serotonin 5-HT 2C receptor agonist, leptin, a leptin analog, a leptin receptor agonist, amylin peptide, an amylin analog, an amylin receptor agonist, a neuropeptide Y receptor modulator, a galanin antagonist, a GI lipase inhibitor or decreaser, a bombesin agonist, dehydroepiandrosterone or analogs thereof, a glucocorticoid receptor agonist, a glucocorticoid receptor antagonist, an orexin receptor antagonist, an urocortin binding protein antagonist, an agonist of the glucagon-like peptide-1 receptor, a ciliary neurotrophic factor, an allosteric modulator of the GABA A receptor, a serotonin 5-HT 1A receptor partial agonist, a selective serotonin reuptake inhibitor, a serotonin-norepinephrine reuptake inhibitor, a monoamine neurotransmitter reuptake inhibitor of tricyclic antidepressant class, a combined serotonin reuptake inhibitor and 5-HT 2C antagonist, an H 1 receptor antagonist, a noradrenergic and specific serotonergic antidepressant, a norepinephrine reuptake inhibitor, a norepinephrine-dopamine reuptake inhibitor, a monoamine oxidase inhibitor, an AMP-activated protein kinase agonist, a peroxisome proliferator-activated receptor gamma activator, a HMG-CoA reductase inhibitor, a PDE4 inhibitor, and combinations thereof.
36 . A method of treating obesity in a subject in need of weight loss comprising:
selecting a patient in need of weight loss, and
administering to the patient a therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof.
37 . The method according to claim 36 further comprising:
administering to the patient a therapeutically effective amount of an anti-obesity adjunct.
38 . The method according to claim 37 , wherein the anti-obesity adjunct is selected from the group consisting of phenylpropanolamine, ephedrine, pseudoephedrine, phentermine, a cholecystokinin-A agonist, a monoamine reuptake inhibitor, a sympathomimetic agent, a serotonergic agent, a dopamine agonist, a melanocyte-stimulating hormone receptor agonist or mimetic, a melanocyte-stimulating hormone analog, a cannabinoid receptor antagonist or inverse agonist, a melanin concentrating hormone receptor antagonist, a serotonin 5-HT 6 receptor antagonist, a serotonin 5-HT 2C receptor agonist, leptin, a leptin analog, a leptin receptor agonist, amylin peptide, an amylin analog, an amylin receptor agonist, a neuropeptide Y receptor modulator, a galanin antagonist, a GI lipase inhibitor or decreaser, a bombesin agonist, dehydroepiandrosterone or analogs thereof, a glucocorticoid receptor agonist, a glucocorticoid receptor antagonist, an orexin receptor antagonist, an urocortin binding protein antagonist, an agonist of the glucagon-like peptide-1 receptor, a ciliary neurotrophic factor, and combinations thereof.
39 . A method of treating obesity in a subject who has experienced weight loss comprising:
selecting a patient who has experienced weight loss, and
administering to the patient a therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof.
40 . A method of treating anxiety comprising:
selecting a patient with anxiety, and
administering to the patient a therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof.
41 . The method according to claim 40 further comprising:
administering to the patient a therapeutically effective amount of a anti-anxiety adjunct.
42 . The method according to claim 41 , wherein the anti-anxiety adjunct is selected from the group consisting of an allosteric modulator of the GABA A receptor, a serotonin 5-HT 1A receptor partial agonist, a selective serotonin reuptake inhibitor, a serotonin-norepinephrine reuptake inhibitor, a monoamine neurotransmitter reuptake inhibitor of tricyclic antidepressant class, a combined serotonin reuptake inhibitor and 5-HT 2C antagonist, an H 1 receptor antagonist, and combinations thereof.
43 . A method of treating depression comprising:
selecting a patient with depression, and
administering to the patient a therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof.
44 . The method according to claim 43 further comprising:
administering to the patient a therapeutically effective amount of an anti-depression adjunct.
45 . The method according to claim 44 , wherein the anti-depression adjunct is selected from the group consisting of a serotonin 5-HT 1A receptor partial agonist, a selective serotonin reuptake inhibitor, a serotonin-norepinephrine reuptake inhibitor, a monoamine neurotransmitter reuptake inhibitor of tricyclic antidepressant class, a combined serotonin reuptake inhibitor and 5-HT 2C antagonist, a noradrenergic and specific serotonergic antidepressant, a norepinephrine reuptake inhibitor, a norepinephrine-dopamine reuptake inhibitor, a monoamine oxidase inhibitor, and combinations thereof.
46 . A method of treating non-alcoholic fatty liver disease comprising:
selecting a patient who has non-alcoholic fatty liver disease, and
administering to the patient a therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof.
47 . The method according to claim 46 further comprising:
administering to the patient a therapeutically effective amount of an anti-non-alcoholic fatty liver disease adjunct.
48 . The method according to claim 47 , wherein the anti-non-alcoholic fatty liver disease adjunct is selected from the group consisting of an AMP-activated protein kinase agonist, a peroxisome proliferator-activated receptor gamma activator, a HMG-CoA reductase inhibitor, a PDE4 inhibitor, and combinations thereof.
49 . A method of treating inflammatory bowel disease comprising:
selecting a patient with inflammatory bowel disease, and
administering to the patient a therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof.
50 . A process for the preparation of a product compound of formula (I):
wherein
R 2 -R 5 and R 9 -R 12 are each, independently, selected from the group consisting of H, halogen, —OR 13 , —NR 13 R 14 , —NR 13 C(O)R 14 , —NR 13 C(O) 2 R 14 , —NR 15 C(O)NR 14 R 15 , —S(O) q R 14 , —CN, —C(O)R 14 , —C(O)NR 13 R 14 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, C 4 -C 7 cycloalkylalkyl, heterocyclyl, aryl, and heteroaryl, wherein each of C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, C 4 -C 7 cycloalkylalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with from 1 to 3 substituents independently selected at each occurrence thereof from C 1 -C 3 alkyl, halogen, —CN, —OR 16 , —NR 16 R 17 , and phenyl which is optionally substituted 1-3 times with halogen, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, —CN, —OR 16 , or —NR 16 R 17 ; or R 2 and R 3 or R 4 and R 5 can combine to form an oxo, thio, imine, cycloalkyl, or heterocycle group containing from 1 to 5 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur; or any one of R 2 , R 3 , R 4 , or R 5 can combine with any one of R 9 , R 10 , R 11 , or R 12 to form —(CH 2 ) r —;
R 6 is independently selected at each location from the group consisting of H, halogen, —OR 13 , —NR 13 C(O)R 14 , —NR 13 C(O) 2 R 14 , —NR 15 C(O)NR 14 R 15 , —S(O) q R 14 , —CN, —C(O)R 14 , —C(O)NR 13 R 14 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, C 4 -C 7 cycloalkylalkyl, heterocyclyl, aryl, and heteroaryl, wherein each of C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, C 4 -C 7 cycloalkylalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with from 1 to 3 substituents independently selected at each occurrence thereof from C 1 -C 3 alkyl, halogen, —CN, —OR 6 , —NR 16 R 17 , and phenyl which is optionally substituted 1-3 times with halogen, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, —CN, —OR 16 , or NR 16 R 17 ;
R 7 is optionally present and, if present, is selected from the group consisting of H, halogen, —OR 13 , —NR 13 R 14 , —NR 13 C(O)R 14 , —NR 13 C(O) 2 R 14 , —NR 15 C(O)NR 14 R 15 , —S(O) q R 14 , —CN, —C(O)R 14 , —C(O)NR 13 R 14 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, C 4 -C 7 cycloalkylalkyl, heterocyclyl, aryl, and heteroaryl, wherein each of C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, C 4 -C 7 cycloalkylalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with from 1 to 3 substituents independently selected at each occurrence thereof from C 1 -C 3 alkyl, halogen, —CN, —OR 16 , —NR 16 R 17 , and phenyl which is optionally substituted 1-3 times with halogen, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, —CN, —OR 16 , or —NR 16 R 17 ;
R 8 is selected from the group consisting of H, —S(O) q R 14 , —C(O)R 14 , —C(O)NR 13 R 14 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, C 4 -C 7 cycloalkylalkyl, heterocyclyl, and heteroaryl, wherein each of C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, C 4 -C 7 cycloalkylalkyl, heterocyclyl, and heteroaryl is optionally substituted with from 1 to 3 substituents independently selected at each occurrence thereof from C 1 -C 3 alkyl, halogen, —CN, —OR 16 , —NR 16 R 17 , and phenyl which is optionally substituted 1-3 times with halogen, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, —CN, —OR 16 , or NR 16 R 17 ; or
R 8 and one of R 2 , R 3 , R 4 , and R 5 can combine to form a 3- to 7-membered heterocycle, wherein the 3- to 7-membered heterocycle includes from 1 to 2 heteroatoms selected from the group consisting of N, O, and S and is optionally substituted with from 1 to 10 substituents independently selected at each occurrence thereof from H, halogen, —OR 13 , —NR 13 R 14 , —NR 13 C(O)R 14 , —NR 13 C(O) 2 R 14 , —NR 15 C(O)NR 14 R 15 , —S(O) q R 14 , —CN, —C(O)R 14 , —C(O)NR 13 R 14 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, C 4 -C 7 cycloalkylalkyl, heterocyclyl, aryl, and heteroaryl, wherein each of C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, C 4 -C 7 cycloalkylalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with from 1 to 3 substituents independently selected at each occurrence thereof from C 1 -C 3 alkyl, halogen, —CN, —OR 16 , —NR 16 R 17 , and phenyl which is optionally substituted 1-3 times with halogen, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, —CN, —OR 16 , or —NR 16 R 17 ;
R 13 is H, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxyalkyl, C 3 -C 6 cycloalkyl, C 4 -C 7 cycloalkylalkyl, —C(O)R 15 , phenyl, or benzyl, wherein phenyl or benzyl is optionally substituted 1 to 3 times with halogen, cyano, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, or C 1 -C 4 alkoxy;
R 14 is H, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxyalkyl, C 3 -C 6 cycloalkyl, C 4 -C 7 cycloalkylalkyl, phenyl, or benzyl, wherein phenyl or benzyl is optionally substituted 1 to 3 times with halogen, cyano, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, or C 1 -C 4 alkoxy;
R 15 is C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, or phenyl;
R 16 and R 17 are each independently H, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxyalkyl, C 3 -C 6 cycloalkyl, C 4 -C 7 cycloalkylalkyl, —C(O)R 15 , phenyl, or benzyl, wherein phenyl or benzyl is optionally substituted from 1 to 3 times with a substituent selected independently at each occurrence thereof from the group consisting of halogen, cyano, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, and C 1 -C 4 alkoxy;
R 18 is selected from the group consisting of H, halogen, —OR 13 , —NR 13 R 14 —NR 13 C(O)R 14 , —NR 13 C(O) 2 R 14 , —NR 14 C(O)NR 14 R 15 , —S(O) q R 14 , —CN, —C(O)R 14 , —C(O)NR 13 R 14 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, C 4 -C 7 cycloalkylalkyl, heterocyclyl, aryl, and heteroaryl, wherein each of C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, C 4 -C 7 cycloalkylalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with from 1 to 3 substituents independently selected at each occurrence thereof from C 1 -C 3 alkyl, halogen, —CN, —OR 16 , —NR 16 R 17 , and phenyl which is optionally substituted 1-3 times with halogen, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy, —CN, —OR 8 , or —NR 8 R 9 ;
G is —NR 8 —CR 9 R 10 —, —CR 9 R 10 —NR 8 —, —NR 8 —CR 9 R 10 —CR 11 R 12 —, —CR 9 R 10 —NR 8 —CR 11 R 12 —, or —CR 9 R 10 —CR 11 R 12 —NR 8 —;
X is CR 18 , C(R 18 ) 2 , N, or NR 18 ;
Y is CR 18 , C, or N;
Z is O or S;
L is —(CH 2 ) p —O—, —(CH 2 ) p —, —CH═CH—, or a bond;
A is C, CH, or N;
B is aryl, heteroaryl, heterocyclyl, or cycloalkyl, wherein each of the aryl, heteroaryl, heterocyclyl, or cycloalkyl is optionally substituted with from 1 to 3 substituents selected from the group consisting of H, alkoxy, —S-alkyl, optionally substituted C 1 -C 6 alkyl, halogen, —CF 3 , —OCF 3 , and —CN;
n is 0, 1, 2, or 3;
p is from 1 to 4;
q is 0, 1, or 2;
r is from 1 to 4; and
represents an optional double bond,
said process comprising:
treating a first intermediate of formula (II):
wherein Q is a halogen, under conditions effective to form the compound of formula (I).
51 . The process according to claim 50 , wherein treating comprises:
reacting the first intermediate with a second intermediate of formula (III):
52 . The process according to claim 50 further comprising:
treating a third intermediate of formula (IV):
under conditions effective to form the first intermediate compound.
53 . The process according to claim 52 further comprising:
reacting
under conditions effective to form a fourth intermediate of formula (V):
and
treating the fourth intermediate compound under conditions effective to form the third intermediate compound.