Compounds as autotaxin inhibitors and pharmaceutical compositions comprising the same
The present invention relates to novel compounds as autotoxin inhibitors for treatment and prophylaxis of conditions or a disorder caused by autotaxin activation or increased concentration of lysophosphatidic acid, and also a pharmaceutical composition containing the same. The novel compounds of the present invention are autotoxin inhibitors, and by inhibiting the production of lysophosphatidic acid, they are useful for treatment or prophylaxis of cardiovascular disorder, cancer, metabolic disorder, kidney disorder, liver disorder, inflammatory disorder, nervous system disorder, respiratory system disorder, fibrotic disease, ocular disorder, cholestatic and other forms of chronic pruritus, or acute or chronic organ transplant rejection.
1. A compound represented by the chemical formula 1, or a pharmaceutically acceptable salt thereof:
wherein:
X is CH and Y is N;
R is indanyl;
A is
or a ring selected from:
wherein
R a is hydrogen, carboxyl, carbamoyl, C1-C10 alkylsulfonylamino, aminosulfonylamino (—NHSO 2 NH 2 ), or amino;
R b is hydrogen, carboxyl, or aminosulfonyl;
m is an integer of 0, 1, or 2;
p is 0;
L is —(CR 3 R 4 ) a C(═O)—, —C(═O)—(CR 3 R 4 ) a —, —C(═O)—(CR 5 R 6 ) b —NH—(CR 7 R 8 ) c —, —NH—(CR 7 R 8 ) c —C(═O)—(CR 5 R 6 ) b —, or —C(═NR 9 )—(CR 3 R 4 ) a —;
R 3 to R 8 are each independently hydrogen or C1-C10 alkyl;
R 9 is hydroxy;
a is an integer of from 1 to 5;
b and c are each independently an integer of from 0 to 5;
Q is a five-membered heteroarylene having 2 or 3 heteroatoms selected from nitrogen, oxygen and sulfur;
said heteroarylene of above Q may be further substituted with one or more substituents that are selected from C1-C10 alkyl, halo-substituted C1-C10 alkyl, hydroxy C1-C10 alkyl, C3-C10 cycloalkyl, C6-C12 aryl, C2-C12 heteroaryl, carboxyl, NR 11 R 12 , —O(CH 2 ) e R 13 , —(CH 2 ) f R 14 , and —C(═O)R 15 , in which said alkyl, cycloalkyl, aryl, and heteroaryl may be further substituted with NR 11 R 12 or carboxyl;
R 11 and R 12 are each independently hydrogen, C1-C10 alkyl, C6-C12 aryl, C2-C12 heteroaryl, or C3-C10 cycloalkyl;
e and f are each independently an integer of from 0 to 5;
R 13 is hydrogen, C1-C10 alkyl, C6-C12 aryl, C2-C12 heterocycloalkyl, or carboxyl, in which said aryl and heterocycloalkyl of above R 13 may be further substituted with one or more substituents that are selected from C1-C10 alkyl, halo-substituted C1-C10 alkyl, and carboxyl;
R 14 and R 15 are each independently C2-C12 heterocycloalkyl, in which said heterocycloalkyl of R 14 and R 15 may be a single ring, a fused ring, or a spiro ring that is either saturated or unsaturated, in which a CH 2 in the ring may be substituted with oxo and also in which said heterocycloalkyl of R 14 and R 15 may be substituted with or further substituted with one or more substituents that are selected from halogen, C1-C10 alkyl, halo-substituted C1-C10 alkyl, and C6-C12 aryl; and
said heteroaryl and heterocycloalkyl contain at least one heteroatom that is selected from nitrogen, oxygen, and sulfur.
2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein A is selected from the following structures:
wherein
R c is C1-C7 alkyl, or amino;
p is 0; and
m is an integer of 0, 1, or 2.
3. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein L is selected from:
wherein
R d and R e are each independently hydrogen or C1-C7 alkyl;
R f is hydroxy;
s is an integer of from 0 to 3; and
t is an integer of from 1 to 3.
4. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein the Q is selected from:
wherein
R g is hydrogen or C1-C7 alkyl;
R h is hydrogen, hydroxy, NR 11 R 12 , C1-C7 alkoxy, C1-C7 alkyl, hydroxy C1-C7 alkyl, C3-C7 cycloalkyl, C6-C12 aryl, C2-C12 heteroaryl, carboxyl, —O(CH 2 ) e R 13 , —(CH2) f R 14 , or —C(═O)R 15 , in which said alkyl, cycloalkyl, aryl, and heteroaryl of R h may be further substituted with NR 11 R 12 or carboxyl;
R 11 and R 12 are each independently hydrogen, C1-C7 alkyl, C6-C12 aryl, C2-C12 heteroaryl, or C3-C7 cycloalkyl;
R 13 is C6-C12 aryl, C3-C9 heterocycloalkyl, or carboxyl, in which said aryl and heterocycloalkyl of R 13 may be further substituted with one or more substituents that are selected from C1-C7 alkyl, halo-substituted C1-C7 alkyl, and carboxyl;
R 14 and R 15 are each independently C3-C9 heterocycloalkyl, in which said heterocycloalkyl of R 14 and R 15 may be a single ring, a fused ring, or a spiro ring that is either saturated or unsaturated, in which a CH 2 in the ring may be substituted with oxo, and also in which said heterocycloalkyl of R 14 and R 15 may be substituted with or further substituted with one or more substituents that are selected from halogen, C1-C7 alkyl, halo-substituted C1-C7 alkyl, and C6-C12 aryl;
R i is hydrogen, C1-C7 alkyl, or halo-substituted C1-C7 alkyl;
R j is hydrogen, C1-C7 alkyl, halo-substituted C1-C7 alkyl, C3-C7 cycloalkyl, or C6-C12 aryl;
e is an integer of from 0 to 3; and
f is an integer of from 0 to 3.
5. The compound according to claim 4 , or a pharmaceutically acceptable salt thereof, wherein the R h is hydrogen, hydroxy, NR 11 R 12 , C1-C7 alkoxy, C1-C7 alkyl, hydroxy C1-C7 alkyl, C3-C7 cycloalkyl, C6-C12 aryl, C2-C12 heteroaryl, or carboxyl, or selected from:
wherein
R 11 and R 12 are each independently hydrogen, C1-C7 alkyl, C6-C12 aryl, or C3-C7 cycloalkyl;
R k is hydrogen or carboxyl;
R l is hydrogen, C1-C7 alkyl, or halo-substituted C1-C7 alkyl;
R m and R n are each independently hydrogen, C1-C7 alkyl, or halogen;
R o is hydrogen or C1-C7 alkyl;
R p is C6-C12 aryl; and
w is an integer of from 0 to 3.
6. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein the compound is a compound represented by the following chemical formula 2;
wherein
R is indanyl;
A is selected from the following structures;
R c is C1-C7 alkyl or amino;
p is 0;
m is an integer of 0, 1, or 2;
L is selected from:
R d and R e are each independently hydrogen or C1-C7 alkyl;
R f is hydroxy;
s is an integer of from 0 to 3;
t is an integer of from 1 to 3;
Q is selected from the following structures:
R g is hydrogen or C1-C7 alkyl;
R h is hydrogen, hydroxy, NR 11 R 12 , C1-C7 alkoxy, C1-C7 alkyl, hydroxy C1-C7 alkyl, C3-C7 cycloalkyl, C6-C12 aryl, C2-C12 heteroaryl, or carboxyl, or selected from:
said alkyl, cycloalkyl, aryl, and heteroaryl of R h may be further substituted with NR 11 R 12 or carboxyl;
R i is hydrogen, C1-C7 alkyl, or halo-substituted C1-C7 alkyl;
R j is hydrogen, C1-C7 alkyl, halo-substituted C1-C7 alkyl, C3-C7 cycloalkyl, or C6-C12 aryl;
R 11 and R 12 are each independently hydrogen, C1-C7 alkyl, C6-C12 aryl, or C3-C7 cycloalkyl;
R k is hydrogen or carboxyl;
R l is hydrogen, C1-C7 alkyl, or halo-substituted C1-C7 alkyl;
R m and R n are each independently hydrogen, C1-C7 alkyl, or halogen;
R o is hydrogen or C1-C7 alkyl;
R p is C6-C12 aryl; and
w is an integer of from 0 to 3.
7. The compound according to claim 6 , or a pharmaceutically acceptable salt thereof, wherein
R is indanyl;
A is selected from:
p is 0;
m is an integer of 0, 1, or 2;
L is selected from:
R d and R e are each independently hydrogen or C1-C7 alkyl;
s is an integer of from 0 to 3;
t is an integer of from 1 to 3;
Q is selected from the following structures;
R g is hydrogen or C1-C7 alkyl;
R i is hydrogen, C1-C7 alkyl, or halo-substituted C1-C7 alkyl;
R j is hydrogen, C1-C7 alkyl, halo-substituted C1-C7 alkyl, C3-C7 cycloalkyl, or C6-C12 aryl;
R h is hydrogen, hydroxy, NR 11 R 12 , C1-C7 alkoxy, C1-C7 alkyl, hydroxy C1-C7 alkyl, C3-C7 cycloalkyl, C6-C12 aryl, C2-C12 heteroaryl, or carboxyl, or selected from:
R 11 and R 12 are each independently hydrogen C1-C7 alkyl, C6-C12 aryl, or C3-C7 cycloalkyl;
R k is hydrogen or carboxyl;
R l is hydrogen, C1-C7 alkyl, or halo-substituted C1-C7 alkyl;
R m and R n are each independently hydrogen, C1-C7 alkyl, or halogen;
R o is hydrogen or C1-C7 alkyl;
R p is C6-C12 aryl; and
w is an integer of from 0 to 3.
8. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein the compound is selected from:
9. A compound selected from:
or a pharmaceutically acceptable salt thereof.
10. A compound of formula 2.1
or a pharmaceutically acceptable salt thereof.
11. A compound of formula 2.3
or a pharmaceutically acceptable salt thereof.
12. A compound of formula 3.3
or a pharmaceutically acceptable salt thereof.
13. A compound of formula 4.1
or a pharmaceutically acceptable salt thereof.
14. A compound of formula 4.3
or a pharmaceutically acceptable salt thereof.
15. A compound of formula 5.2
or a pharmaceutically acceptable salt thereof.
16. A compound of formula 6.1
or a pharmaceutically acceptable salt thereof.
17. A pharmaceutical composition comprising a compound of claim 1 , or a hydrate, solvate, or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
18. A method of prophylaxis or treatment of a disorder, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein the disorder is selected from the group consisting of cardiovascular disorder, cancer, obesity, diabetes mellitus, acute kidney failure, chronic kidney disease, diabetic nephropathy, acute kidney transplant rejection, chronic allograft nephropathy, liver cirrhosis, hepatic congestion, pruritus, nonalcoholic steatohepatitis, acute and chronic liver transplant rejection, arthritis, atopic dermatitis, asthma, neuropathic pain, schizophrenia, neuro-inflammation, peripheral neuropathy, autonomic neuropathy, systemic disease, vasculitides, sarcoidosis, hypersensitivity pneumonia, alveolar proteinosis, langerhans cell granulomatosis, lymphangioleiomyomatosis, radiation induced fibrosis, silicosis, asbestos induced pulmonary fibrosis, acute respiratory distress syndrome (ARDS), myocardial and vascular fibrosis, kidney fibrosis, liver fibrosis, pulmonary fibrosis, skin fibrosis, scleroderma, encapsulating peritonitis, renal tubulo-interstitial fibrosis, glomerulosclerosis, non-alcoholic liver steatosis, idiopathic pulmonary fibrosis, proliferative and non-proliferative retinopathy, dry and wet age-related macular degeneration (AMD), macular edema, central arterial/venous occlusion, traumatic injury, glaucoma, chronic pruritus of cholestatic form, and acute or chronic organ transplant rejection.
19. A pharmaceutical composition comprising a compound of claim 9 , or a hydrate, solvate, or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
20. A method of prophylaxis or treatment of a disorder, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound according to claim 9 , or a pharmaceutically acceptable salt thereof, wherein the disorder is selected from the group consisting of cardiovascular disorder, cancer, obesity, diabetes mellitus, acute kidney failure, chronic kidney disease, diabetic nephropathy, acute kidney transplant rejection, chronic allograft nephropathy, liver cirrhosis, hepatic congestion, pruritus, nonalcoholic steatohepatitis, acute and chronic liver transplant rejection, arthritis, atopic dermatitis, asthma, neuropathic pain, schizophrenia, neuro-inflammation, peripheral neuropathy, autonomic neuropathy, systemic disease, vasculitides, sarcoidosis, hypersensitivity pneumonia, alveolar proteinosis, langerhans cell granulomatosis, lymphangioleiomyomatosis, radiation induced fibrosis, silicosis, asbestos induced pulmonary fibrosis, acute respiratory distress syndrome (ARDS), myocardial and vascular fibrosis, kidney fibrosis, liver fibrosis, pulmonary fibrosis, skin fibrosis, scleroderma, encapsulating peritonitis, renal tubulo-interstitial fibrosis, glomerulosclerosis, non-alcoholic liver steatosis, idiopathic pulmonary fibrosis, proliferative and non-proliferative retinopathy, dry and wet age-related macular degeneration (AMD), macular edema, central arterial/venous occlusion, traumatic injury, glaucoma, chronic pruritus of cholestatic form, and acute or chronic organ transplant rejection.
21. A compound selected from:
or a hydrate, solvate, or pharmaceutically acceptable salt thereof.
22. A compound of formula 2.1
or a hydrate, solvate, or pharmaceutically acceptable salt thereof.
23. A compound of formula 2.3
or a hydrate, solvate, or pharmaceutically acceptable salt thereof.
24. A compound of formula 3.3
or a hydrate, solvate, or pharmaceutically acceptable salt thereof.
25. A compound of formula 4.1
or a hydrate, solvate, or pharmaceutically acceptable salt thereof.
26. A compound of formula 4.3
or a hydrate, solvate, or pharmaceutically acceptable salt thereof.
27. A compound of formula 5.2
or a hydrate, solvate, or pharmaceutically acceptable salt thereof.
28. A compound of formula 6.1
or a hydrate, solvate, or pharmaceutically acceptable salt thereof.