US2022135598A1PendingUtilityA1
Ectonucleotide pyrophosphatase-phosphodiesterase-1 (enpp1) inhibitors and uses thereof
Assignee: INTEGRAL BIOSCIENCES PRIVATE LTDPriority: Oct 30, 2020Filed: Nov 1, 2021Published: May 5, 2022
Est. expiryOct 30, 2040(~14.3 yrs left)· nominal 20-yr term from priority
Inventors:Brahmam PujalaAmantullah AnsariShreya SapraPradeep S. JadhavarDhananjay PendharkarSreekanth A. RamachandranUzma SaeedAbhinandan DanodiaFarha KhanSagar PatniSanjeev SoniAshu GuptaSarvajit ChakravartyBalaji Dashrath Sathe
C07F 9/65583C07F 5/025C07D 495/04C07D 401/04C07D 491/056C07D 403/04C07D 401/14C07D 487/04C07D 403/14C07D 471/04
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Claims
Abstract
The present invention discloses compounds useful in treatment of conditions associated with dysfunction of ectonucleotide pyrophosphatase/phosphodiesterase-1 (ENPP1) enzyme. Specifically, the present invention discloses compound of formula (J) which exhibit inhibitory activity against ENPP1. Method of treating conditions associated with over-expression of ENPP1 gene with such compound is disclosed. Uses thereof, pharmaceutical composition, and kits are also disclosed.
Claims
exact text as granted — not AI-modifiedWhat is claimed is:
1 . A compound of formula (J)
or a salt thereof, wherein
C is 5- to 6-membered heteroaryl optionally substituted with R 1 ;
D is C 6 -aryl or 5- to 6-membered heteroaryl, each of which is optionally substituted with R 2 , wherein D is fused to C;
A is hydrogen, C 1 -C 6 alkyl, or C 6 -aryl, each of which is optionally substituted with halogen;
G is a bond, —CH 2 — or —CH 2 —CH 2 —;
R a and R b are independently hydrogen or C 1 -C 6 alkyl;
or R a and R b are taken together with the atoms to which they are attached to form a C 3 -C 6 cycloalkyl ring;
or any one of R a and R b , and A are taken together along with the atoms to which they are attached to form a C 4 -C 6 cycloalkyl ring;
L is a bond, linear or branched C 1 -C 6 alkylene or linear or branched C 2 -C 6 alkenylene;
t is 0 or 1;
provided that when t is 0 then L is linear or branched C 2 -C 6 alkenylene;
Z is —NR c S(O) 2 NH 2 , —NR c S(O) 2 CH 3 , —SO 2 NH 2 , —NR c C(O)CH 3 , —C(O)OH, —CONH 2 , NR c CONH 2 , —CONH(OH), —B(OH) 2 —P(O)(OH) 2 , —SO 2 OH, —NR c S(O) 2 CF 3 , —NR c S(O) 2 NHCH 3 , or —NR 1 CH 2 C 6 -aryl-S(O) 2 NH 2 .
each R 1 and R 2 are independently hydrogen, oxo, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, adamantly, 3- to 6-membered heterocyclyl, C 6 -aryl, 5- to 6-membered heteroaryl, —CN, halogen, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, —OR 10 , —SR 10 , —S(O) 2 R 10 , —S(O) 2 NR 11 R 12 , —NR 10 S(O) 2 R 11 , —NR 11 R 12 , —C(O)R 10 , —NR 10 C(O)R 11 , —NR 10 C(O)NR 11 R 12 , —C(O)OR 10 , —C(O)ONR 11 R 12 , —C(O)NR 11 R 12 , wherein each of which is optionally substituted by R 9 ;
or any two of R 2 are taken together with the atoms to which they attached to form a C 5 -C 6 cycloalkyl, 5- to 6-membered heterocyclyl, C 6 -aryl or 5- to 6-membered heteroaryl, wherein each of which is optionally substituted by R 9 ;
R 9 is oxo, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, 3- to 6-membered heterocyclyl, C 6 -aryl, 5- to 6-membered heteroaryl, —CN, halogen, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, C 1 -C 6 haloalkyl, —OR 13 , —SR 13 , —S(O) 2 R 13 , —S(O) 2 NR 14 R 15 , —NR 13 S(O) 2 R 14 , —NR 14 R 15 , —C(O)R 13 , —NR 13 C(O)R 14 , —NR 13 C(O)NR 14 R 15 , —C(O)OR 13 , —C(O)ONR 14 R 15 , —C(O)NR 14 R 15 or C 1 -C 6 alkyl optionally substituted by oxo, OH or halogen;
R c is hydrogen, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, —(C 1 -C 6 alkylene)C 3 -C 6 cycloalkyl, 3- to 6-membered heterocyclyl, —(C 1 -C 6 alkylene) 3 - to 6-membered heterocyclyl, —(C 1 -C 6 alkylene)C 6 -aryl, 5- to 6-membered heteroaryl, —(C 1 -C 6 alkylene) 5 - to 6-membered heteroaryl, C 1 -C 6 haloalkyl, —(C 1 -C 6 alkylene)OR 13 , —(C 1 -C 6 alkylene)SR 13 , —(C 1 -C 6 alkylene)S(O) 2 R 13 , —(C 1 -C 6 alkylene)S(O) 2 NR 14 R 15 , —(C 1 -C 6 alkylene)NR 13 S(O) 2 R 14 , —(C 1 -C 6 alkylene)NR 14 R 15 , —(C 1 -C 6 alkylene)C(O)R 13 , —(C 1 -C 6 alkylene)NR 13 C(O)R 14 , —(C 1 -C 6 alkylene)NR 13 C(O)NR 14 R 15 , —(C 1 -C 6 alkylene)C(O)OR 13 , —(C 1 -C 6 alkylene) C(O)ONR 14 R 15 or —(C 1 -C 6 alkylene)-C(O)NR 14 R 15 , each of which is optionally substituted with R d ;
R d is hydrogen, halogen, —OH, oxo, —CN, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, —COOH or C 1 -C 6 alkyl optionally substituted with —OH, halogen, CN or oxo;
each R 10 , R 11 and R 12 is independently hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, —(C 1 -C 6 alkylene)C 3 -C 6 cycloalkyl-, 3- to 6-membered heterocyclyl or, —(C 1 -C 6 alkylene) 3 - to 6-membered heterocyclyl, wherein each of R 10 , R 11 and R 12 is independently optionally substituted by oxo, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, —CN, halogen, C 1 -C 6 alkoxy or C 1 -C 6 alkyl optionally substituted by oxo, OH, halogen;
or R 11 and R 12 are taken together with the atoms to which they attached to form a 3-6 membered heterocyclyl optionally substituted by oxo, OH, halogen or C 1 -C 6 alkyl optionally substituted by oxo, OH or halogen;
each R 13 , R 14 and R 15 is independently hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 3 -C 6 cycloalkyl or 3- to 6-membered heterocyclyl, wherein each of R 10 , R 11 and R 12 is independently optionally substituted by oxo, —OH, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, —CN, halogen or C 1 -C 6 alkyl optionally substituted by oxo, OH, halogen;
or R 14 and R 15 are taken together with the atoms to which they attached to form a 3-6 membered heterocyclyl optionally substituted by oxo, OH, halogen, or C 1 -C 6 alkyl optionally substituted by oxo, OH or halogen;
m is 0, 1 or 2; and
n is 0, 1, 2, 3 or 4;
provided that when Z is —NR c S(O) 2 CH 3 , —CONH 2 or —C(O)OH, G is a bond and t is 1 then L is not a bond; and
the compound is not:
1-[7-(4-Bromo-2,6-dimethylphenyl)-2,5-dimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-3-azetidinebutanoic acid;
1-[7-(4-Bromo-2,6-dimethylphenyl)-2,5-dimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-3-azetidinepentanoic acid; or
Acetamide, N-[[1-(6-fluoro-2-benzoxazolyl)-3-azetidinyl]methyl]-N-methyl.
2 . The compound of claim 1 , wherein A is selected from hydrogen, C 1 -C 6 alkyl or C 6 -aryl, each of which is optionally substituted with halogen.
3 . The compound of claim 2 , wherein A is hydrogen.
4 . The compound of claim 2 , wherein A is methyl.
5 . The compound of claim 2 , wherein A is —CF 3 .
6 . The compound of claim 2 , wherein A is phenyl.
7 . The compound of claim 1 , wherein G is selected from a bond, —CH 2 — or —CH 2 —CH 2 —.
8 . The compound of claim 7 , wherein G is a bond.
9 . The compound of claim 7 , wherein G is —CH 2 —.
10 . The compound of claim 7 , wherein G is —CH 2 —CH 2 —.
11 . The compound of claim 1 , wherein R a and R b are independently selected from hydrogen or C 1 -C 6 alkyl.
12 . The compound of claim 11 , wherein R a and R b both are hydrogen.
13 . The compound of claim 11 , wherein any one of R a and R b is hydrogen and other one is C 1 -C 6 alkyl.
14 . The compound of claim 11 , wherein R a and R b both are C 1 -C 6 alkyl.
15 . The compound of claim 13 , wherein any one of R a and R b is hydrogen and other one is methyl.
16 . The compound of claim 13 , wherein any one of R a and R b is hydrogen and other one is ethyl.
17 . The compound of claim 14 , wherein R a and R b both are methyl.
18 . The compound of claim 1 , wherein R a and R b are taken together with the atoms to which they attached to form a C 3 -C 6 cycloalkyl ring.
19 . The compound of claim 18 , wherein R a and R b are taken together with the atoms to which they attached to form a cycloproplyl ring.
20 . The compound of claim 1 , wherein any one of R a and R b , and A are taken together along with the atoms to which they are attached to form a C 4 -C 6 cycloalkyl.
21 . The compound of claim 20 , wherein any one of R a and R b , and A are taken together along with the atoms to which they are attached to form a cyclobutyl ring.
22 . The compound of claim 20 , wherein any one of R a and R b , and A are taken together along with the atoms to which they are attached to form a cyclopentyl ring.
23 . The compound of claim 20 , wherein any one of R a and R b , and A are taken together along with the atoms to which they are attached to form a cyclohexyl ring.
24 . The compound of claim 1 , wherein L is selected from a bond, linear or branched C 1 -C 6 alkylene, or linear or branched C 2 -C 6 alkenylene.
25 . The compound of claim 24 , wherein L is a bond.
26 . The compound of claim 24 , wherein L is —CH 2 —.
27 . The compound of claim 24 , wherein L is —C 2 H 4 —.
28 . The compound of claim 24 , wherein L is —C 3 H 6 —.
29 . The compound of claim 24 , wherein L is —CH(CH 3 )—.
30 . The compound of claim 24 , wherein L is —C(CH 3 ) 2 —.
31 . The compound of claim 24 , wherein L is —CH(CH 3 )—CH 2 —.
32 . The compound of claim 24 , wherein L is —CH 2 CH(CH 3 )—.
33 . The compound of claim 24 , wherein L is —C(CH 3 ) 2 —CH 2 —.
34 . The compound of claim 24 , wherein L is —CH 2 C(CH 3 ) 2 —.
35 . The compound of claim 24 , wherein L is —CH(C 2 H 5 )—CH 2 —.
36 . The compound of claim 24 , wherein L is —CH═CH—.
37 . The compound of claim 1 , wherein t is 0 or 1.
38 . The compound of claim 37 , wherein t is 0.
39 . The compound of claim 37 , wherein t is 1.
40 . The compound of claim 1 , wherein Z is selected from —NR c SO 2 NH 2 , —NR c S(O) 2 CH 3 , —SO 2 NH 2 , —NR c C(O)CH 3 , —C(O)OH, —CONH 2 , NR c CONH 2 , —CONH(OH), —B(OH) 2 , —P(O)(OH) 2 , —SO 2 OH, —NR c S(O) 2 CF 3 , —NR c S(O) 2 NHCH 3 or —NR c CH 2 C 6 -aryl-S(O) 2 NH 2 .
41 . The compound of claim 40 , wherein Z is NR c SO 2 NH 2 .
42 . The compound of claim 40 , wherein Z is —NHS(O) 2 CH 3 .
43 . The compound of claim 40 , wherein Z is —SO 2 NH 2 .
44 . The compound of claim 40 , wherein Z is —NHC(O)CH 3 .
45 . The compound of claim 40 , wherein Z is —C(O)OH.
46 . The compound of claim 40 , wherein Z is —CONH 2 .
47 . The compound of claim 40 , wherein Z is —NHCONH 2 .
48 . The compound of claim 40 , wherein Z is —CONH(OH).
49 . The compound of claim 40 , wherein Z is —B(OH) 2 .
50 . The compound of claim 40 , wherein Z is —P(O)(OH) 2 .
51 . The compound of claim 40 , wherein Z is —S(O) 20 H.
52 . The compound of claim 40 , wherein Z is —NR c S(O) 2 CF 3 .
53 . The compound of claim 40 , wherein Z is —NR c S(O) 2 NHCH 3 .
54 . The compound of claim 40 , wherein Z is —NR c CH 2 C 6 -aryl-S(O) 2 NH 2 .
55 . The compound of claim 1 , wherein R c is hydrogen, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, —(C 1 -C 6 alkylene)C 3 -C 6 cycloalkyl, 3- to 6-membered heterocyclyl, —(C 1 -C 6 alkylene) 3- to 6-membered heterocyclyl, —(C 1 -C 6 alkylene)C 6 -aryl, 5- to 6-membered heteroaryl, —(C 1 -C 6 alkylene) 5- to 6-membered heteroaryl, C 1 -C 6 haloalkyl, —(C 1 -C 6 alkylene)OR 13 , —(C 1 -C 6 alkylene)SR 13 , —(C 1 -C 6 alkylene)S(O) 2 R 13 , —(C 1 -C 6 alkylene)S(O) 2 NR 14 R 15 , —(C 1 -C 6 alkylene)NR 13 S(O) 2 R 14 , —(C 1 -C 6 alkylene)NR 14 R 15 , —(C 1 -C 6 alkylene)C(O)R 13 , —(C 1 -C 6 alkylene)NR 13 C(O)R 14 , —(C 1 -C 6 alkylene)NR 13 C(O)NR 14 R 15 , —(C 1 -C 6 alkylene)C(O)OR 13 , —(C 1 -C 6 alkylene) C(O)ONR 14 R 15 or —(C 1 -C 6 alkylene)-C(O)NR 14 R 15 , each of which is optionally substituted with R d .
56 . The compound of claim 55 , wherein R c is selected from the group consisting of methyl, ethyl, isopropyl, n-propyl, n-butyl, cyclopropyl, cyclobutyl, cyclopentyl,
57 . The compound of claim 1 , wherein Z is selected from the group consisting of
58 . The compound of claim 1 , wherein G, R a , R b , L, t and Z together is selected from the group consisting of
59 . The compound of claim 20 , wherein L and Z together is selected from the group consisting of
60 . The compound of claim 1 , wherein C is 5- to 6-membered heteroaryl optionally substituted with R 1 .
61 . The compound of claim 60 , wherein C is selected from the group consisting of imidazole, pyrazzole, pyrrole, pyridine, pyrimidine, pyridone, pyrimidone, pyridazine, pyridazinone and triazine, wherein each of which is optionally substituted with oxo, methyl, ethyl, ethylene, propynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, adamantly, oxetanyl, tetrahydropyranyl, pyrazolyl, pyridyl, pyrimidyl, phenyl, —Cl, —CONH 2 , —NH 2 , —CHF 2 , —CF 3 and —CN; wherein each of which is optionally further substituted with pyridyl, F, CF 3 and CHF 2 .
62 . The compound of claim 1 , wherein D is is C 6 -aryl or 5- to 6-membered heteroaryl, each of which is optionally substituted with R 2 .
63 . The compound of claim 62 , wherein D is selected from the group consisting of phenyl, pyrrole, pyrazole, imidazole, pyridine, thiophene and pyrimidine; wherein each of which is optionally substituted with fluorine, bromine, chloro, oxo, methyl, ethyl, isopropyl, methoxy, ethoxy, propoxy, phenyl, 4-methoxypheyl, —CN, —OCH 2 F, —OCH 2 OCH 3 , —(OCH 2 CH 2 )morpholine, 4-hydroxycyclohexyl, —CF 3 , cyclopropyl and phenyl.
64 . The compound of claim 1 , wherein any two of R 2 are taken together with the atoms to which they attached to form a C 5 -C 6 cycloalkyl, 5- to 6-membered heterocyclyl, C 6 -aryl or 5- to 6-membered heteroaryl, wherein each of which is optionally substituted by R 9 .
65 . The compound of claim 64 , wherein any two of R 2 are taken together with the atoms to which they attached to form imidazole, dioxole and dihydro dioxine, wherein each of which is optionally substituted with methyl.
66 . The compound of any of the claim 1 , wherein m is any of the 0 to 2.
67 . The compound of any of the claim 1 , wherein n is any of the 0 to 4.
68 . The compound of any of the claim 1 , wherein C, D, R 1 and R 2 together is selected from the group consisting of
69 . The compound of claim 68 , wherein C, D, R 1 and R 2 together is selected from the group consisting of
70 . The compound of claim 1 , wherein the compound is a compound of formula (I):
or a salt thereof, wherein A, G, R a , R b , L, Z, C, D, R 1 , R 2 , m and n are as detailed herein.
71 . The compound of claim 1 , wherein the compound is a compound of formula (II):
or a salt thereof, wherein A, R a , R b , L, Z, C, D, R 1 , R 2 m and n are as detailed herein.
72 . The compound of claim 1 , wherein the compound is a compound of formula (III):
or a salt thereof, wherein L, Z, C, D, R 1 , R 2 , m and n are as detailed herein.
73 . The compound of claim 1 , wherein the compound is a compound of formula (IV):
or a salt thereof, wherein
X is N or CR 1 ;
Y is N or CR 1 ; provided that at same time both X and Y are not N;
and A, G, R a , R b , L, Z, D, R 1 , R 2 , n and t are as detailed herein.
74 . The compound of claim 71 , wherein the compound is any of the compound of formula (IV-1) to (IV-11):
or a salt thereof, wherein
X 1 , X 2 and X 3 are independently N, NR 2 or CR 2 ;
provided that any one of X 1 , X 2 and X 3 is NR 2 and others are N or CR 2 ;
and A, G, R a , R b , L, Z, R 1 , R 2 and t are as detailed herein.
75 . The compound of claim 1 , wherein the compound is a compound of formula (V):
or a salt thereof, wherein
X is N or CR 1 ;
Y is N or CR 1 ; provided that at same time both X and Y are not N;
and L, Z, D, R 1 , R 2 and n are as detailed herein.
76 . The compound of claim 73 , wherein the compound is any of the compound of formula (V-1) to (V-11):
or a salt thereof, wherein
X 1 , X 2 and X 3 are independently N, NR 2 or CR 2 ;
provided that any one of X 1 , X 2 and X 3 is NR 2 and others are N or CR 2 ;
and L, Z, R 1 and R 2 are as detailed herein.
77 . The compound of claim 1 , wherein the compound is a compound of formula (VI):
or a salt thereof, wherein
Y 1 is N or NR 1 ;
Y 2 is N, NR 1 or CR 1 ; provided that any one of Y 1 and Y 2 is NR 1 and other one is other than NR 1 ;
and A, G, R a , R b , L, Z, R 1 , R 2 and t are as detailed herein.
78 . The compound of claim 1 , wherein the compound is a compound of formula (VII):
or a salt thereof, wherein
Z 1 is N or CR 1 ;
and A, G, R a , R b , L, Z, R 1 , R 2 and t are as detailed herein.
79 . The compound of claim 1 , wherein the compound is a compound of formula (VIII):
or a salt thereof, wherein A, G, R a , R b , L, Z, R 1 , R 2 and t are as detailed herein.
80 . The compound of claim 1 , wherein the compound is a compound of formula (IX):
or a salt thereof, wherein
Y 1 is N or NR 1 ;
Y 2 is N, NR 1 or CR 1 ; provided that one of Y 1 and Y 2 is NR 1 and other one is other than NR 1 ;
and L, Z, R 1 and R 2 are as detailed herein.
81 . The compound of claim 1 , wherein the compound is a compound of formula (X):
or a salt thereof, wherein
Z 1 is N or CR 1 ;
and L, Z, Rand R 2 are as detailed herein.
82 . The compound of claim 1 , wherein the compound is a compound of formula (XI):
or a salt thereof, wherein L, Z, Rand R 2 are as detailed herein.
83 . The compound of claim 1 , wherein the compound is a compound of formula (XII):
or a salt thereof, wherein,
X is N or CR 1 ;
X 4 and X 5 is independently N or CR 2 ; provided that at same time both are not N;
and A, G, R a , R b , L, Z, R 1 , R 2 and t are as detailed herein.
84 . The compound of claim 81 , wherein the compound is any of the compound of formula (XII-1) to (XII-6):
or a salt thereof, wherein A, G, R a , R b , L, Z, R 1 , R 2 , R c and t are as detailed herein.
85 . The compound of claim 1 , wherein the compound is a compound of formula (XIII):
or a salt thereof, wherein,
X is N or CR 1 ;
X 4 and X 5 is independently N or CR 2 ; provided that at same time both are not N; and
L, Z, R 1 and R 2 are as detailed herein.
86 . The compound of claim 83 , wherein the compound is any of the compound of formula (XIII-1) to (XIII-9):
or a salt thereof, wherein L, Z, R 1 , R 2 and R c are as detailed herein.
87 . The compound of claim 1 , wherein the compound is selected from the compound No. 1.1 to 1.135 as mentioned in table-1.
88 . The compound of claim 1 , wherein the compound is selected from the compound No. 2.1 to 2.362 as mentioned in table-2.
89 . A method of treating a disease or disorder associated with ENPP1 enzyme in an individual in need thereof, wherein the method comprises administering to the individual an effective amount of the compound of claim 1 .
90 . A method of treating cancer in an individual in need thereof, wherein the method comprises administering to the individual an effective amount of the compound of claim 1 .
91 . A method of inhibiting ENPP1 enzyme in an individual in need thereof, wherein the method comprises administering to the individual an effective amount of the compound of claim 1 .
92 . A method of treating a disease or disorder associated with ENPP1 enzyme in an individual in need thereof, wherein the method comprises administering to the individual an effective amount of the compound of claim 1 in combination with other therapeutic agents.
93 . A pharmaceutical composition, comprising the compound of claim 1 , and atleast one pharmaceutically acceptable excipient.
94 . A method of treating a disease or disorder associated with ENPP1 enzyme in an individual in need thereof, wherein the method comprises administering to the individual a pharmaceutical composition comprising an effective amount of the compound of claim 1 .
95 . Use of the compound of claim 1 in the manufacture of the medicament for treatment of a disease or disorder associated with this ENPP1 gene.Join the waitlist — get patent alerts
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