1-aryl-4-substituted isoquinolines
First Claim
2. A compound according to Formula II:
- or a pharmaceutically acceptable salt thereof, wherein;
Ar is substituted phenyl, optionally substituted naphthyl, or optionally substituted heteroaryl;
A is OR4, NR4R5, or CR4(XRy)2;
R1 is chosen from;
(i) hydrogen, halogen, amino, and cyano; and
(ii) C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, C1-C4haloalkyl, C1-C4haloalkoxy, mono- and di-(C1-C6alkyl)amino, (C3-C7cycloalkyl)C0-C4alkyl, (3- to 7-membered heterocycloalkyl)C0-C4alkyl and —
S(On)C1-C4alkyl, each of which is substituted with from 0 to 4 substituents independently chosen from Rx;
R3 represents between 0 and 4 substituents, each of which is independently selected from hydrogen, halogen, hydroxy, amino, cyano, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted alkoxy, optionally substituted alkoxyalkyl, optionally substituted hydroxyalkyl, optionally substituted mono- and di-alkylamino, optionally substituted aminoalkyl, optionally substituted cycloalkyloxy, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted aryloxy, optionally substituted arylalkyloxy, optionally substituted heterocycle, optionally substituted heterocycle-oxy, -E-(CRCRD)m-Z, -E-(CRCRD)m—
XRA;
R4 is;
(i) C2-C8alkyl, C2-C8alkenyl, C2-C8alkynyl, (C3-C7cycloalkyl)C0-C4alkyl, mono- or di-(C1-C4alkylamino)C2-C4alkyl, (3- to 7-membered heterocycloalkyl)C0-C4alkyl, arylC0-C4alkyl, or heteroarylC0-4alkyl, each of which is substituted with from 0 to 4 substituents independently chosen from Rx, C2-C4alkanoyl, mono- and di-(C1-C4alkyl)amino(C1-C4alkyl), mono- and di-C1-C4alkylamino(C1-C4alkoxy), (3- to 7-membered heterocycloalkyl)C0-C4alkyl and XRy;
or (ii) joined to R5 to form, with the nitrogen to which R4 and R5 are bound, a heterocycle having from 1 to 3 rings, 5 to 7 ring members in each ring, wherein the heterocycle is substituted with from 0 to 4 substituents independently chosen from Rx, oxo and W-Z;
R5 is;
(i) hydrogen;
(ii) C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, (C3-C7carbocycle)C0-C4alkyl, each of which is substituted with from 0 to 3 substituents independently chosen from halogen, hydroxy, amino, cyano, C1-C4alkyl, C1-C4alkoxy, methylamino, dimethylamino, trifluoromethyl and trifluoromethoxy;
or (iii) joined to R4 to form an optionally substituted heterocycle;
R8 and R9 are independently selected from;
(i) hydrogen, halogen, hydroxy, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, C1-C6alkylamino or C3-C7cycloalkyl C0-C4alkyl;
E is a single covalent bond, oxygen, or NRA;
X is a single covalent bond, —
CRARB—
, —
O—
, —
C(═
O)—
, —
C(═
O)O—
, —
S(O)n—
or —
NRB—
; and
Ry is;
(i) hydrogen;
or (ii) C1-C10alkyl, C2-C10alkenyl, C2-C10alkynyl, C3-C10carbocycleC0-C4alkyl or (3- to 10-membered heterocycle)C0-C4alkyl, each of which is substituted with from 0 to 6 substituents independently selected from Rx, oxo, —
NH(C1-C6alkanoyl), —
N(C1-C6alkyl)C1-C6alkanoyl, —
NHS(On)C1-C6alkyl, —
N(S(On)C1-C6alkyl)2, —
S(On)NHC1-C6alkyl and —
S(On)N(C1-C6alkyl)2;
W is a single covalent bond, —
CRARB—
, —
NRB—
or —
O—
;
Z is independently selected at each occurrence from 3- to 7-membered carbocycles and heterocycles, each of which is substituted with from 0 to 4 substituents independently selected from halogen, oxo, —
COOH, hydroxy, amino, cyano, C1-C6alkyl, C1-C6alkoxy, C1-C6haloalkyl, C1-C6haloalkoxy, mono- and di-(C1-C6alkyl)amino and —
S(On) C1-C6alkyl; and
RA and RB are independently selected at each occurrence from;
(i) hydrogen; and
(ii) C1-C10alkyl, C2-C10alkenyl, C2-C10alkynyl, saturated or partially saturated (C3-C10carbocycle)C0-C4alkyl and saturated or partially saturated (3- to 10-membered heterocycle)C0-C4alkyl, each of which is substituted with from 0 to 6 substituents independently selected from oxo, hydroxy, halogen, cyano, amino, C1-C6alkoxy, mono- and di-(C1-C4alkyl)amino, —
COOH, —
C(═
O)NH2, —
NHC(═
O)(C1-C6alkyl), —
N(C1-C6alkyl)C(═
O)(C1-C6alkyl), —
NHS(On)C1-C6alkyl, SO3H, —
S(On)C1-C6alkyl, —
S(On)NHC1-C6alkyl, —
S(On)N(C1-C6alkyl)C1-C6alkyl and Z;
RC and RD are independently selected from RA, hydroxy, C1-6alkoxy, and oxo;
Rx is independently chosen at each occurrence from halogen, hydroxy, amino, cyano, nitro, —
COOH, —
C(═
O)NH2, C1-C6alkoxycarbonyl, mono- and di-(C1-6alkyl)aminocarbonyl, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, mono- and di-(C1-C6alkyl)amino, C1-C6alkoxy, C1-C2hydroxyalkyl, C1-C2haloalkyl, C1-C2haloalkoxy, (C3-C7cycloalkyl)C0-C4alkyl, and —
S(On)C1-C6alkyl;
m is an integer independently selected at each occurrence from 0-8; and
n is an integer independently selected at each occurrence from 0, 1 and 2.
1 Assignment
0 Petitions
Accused Products
Abstract
1-aryl-4-substituted isoquinoline or 1-aryl-3,4-disubstituted isoquinoline analogues of Formula I and Formula II, as follows:
wherein R1, R2, R3, R8, R9, A and Ar are defined herein. Such compounds are ligands of C5a receptors. Preferred compounds of Formula I and II bind to C5a receptors with high affinity and exhibit neutral antagonist or inverse agonist activity at C5a receptors. The present invention also relates to pharmaceutical compositions comprising such compounds, and to the use of such compounds in treating a variety of inflammatory, cardiovascular, and immune system disorders. In addition, the present invention provides labeled 1-aryl-4-substituted isoquinolines or 1-aryl-3,4-disubstituted isoquinolines, which are useful as probes for the localization of C5a receptors.
-
Citations
111 Claims
-
2. A compound according to Formula II:
-
or a pharmaceutically acceptable salt thereof, wherein;
Ar is substituted phenyl, optionally substituted naphthyl, or optionally substituted heteroaryl;
A is OR4, NR4R5, or CR4(XRy)2;
R1 is chosen from;
(i) hydrogen, halogen, amino, and cyano; and
(ii) C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, C1-C4haloalkyl, C1-C4haloalkoxy, mono- and di-(C1-C6alkyl)amino, (C3-C7cycloalkyl)C0-C4alkyl, (3- to 7-membered heterocycloalkyl)C0-C4alkyl and —
S(On)C1-C4alkyl, each of which is substituted with from 0 to 4 substituents independently chosen from Rx;
R3 represents between 0 and 4 substituents, each of which is independently selected from hydrogen, halogen, hydroxy, amino, cyano, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted alkoxy, optionally substituted alkoxyalkyl, optionally substituted hydroxyalkyl, optionally substituted mono- and di-alkylamino, optionally substituted aminoalkyl, optionally substituted cycloalkyloxy, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted aryloxy, optionally substituted arylalkyloxy, optionally substituted heterocycle, optionally substituted heterocycle-oxy, -E-(CRCRD)m-Z, -E-(CRCRD)m—
XRA;
R4 is;
(i) C2-C8alkyl, C2-C8alkenyl, C2-C8alkynyl, (C3-C7cycloalkyl)C0-C4alkyl, mono- or di-(C1-C4alkylamino)C2-C4alkyl, (3- to 7-membered heterocycloalkyl)C0-C4alkyl, arylC0-C4alkyl, or heteroarylC0-4alkyl, each of which is substituted with from 0 to 4 substituents independently chosen from Rx, C2-C4alkanoyl, mono- and di-(C1-C4alkyl)amino(C1-C4alkyl), mono- and di-C1-C4alkylamino(C1-C4alkoxy), (3- to 7-membered heterocycloalkyl)C0-C4alkyl and XRy;
or(ii) joined to R5 to form, with the nitrogen to which R4 and R5 are bound, a heterocycle having from 1 to 3 rings, 5 to 7 ring members in each ring, wherein the heterocycle is substituted with from 0 to 4 substituents independently chosen from Rx, oxo and W-Z;
R5 is;
(i) hydrogen;
(ii) C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, (C3-C7carbocycle)C0-C4alkyl, each of which is substituted with from 0 to 3 substituents independently chosen from halogen, hydroxy, amino, cyano, C1-C4alkyl, C1-C4alkoxy, methylamino, dimethylamino, trifluoromethyl and trifluoromethoxy;
or(iii) joined to R4 to form an optionally substituted heterocycle;
R8 and R9 are independently selected from;
(i) hydrogen, halogen, hydroxy, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, C1-C6alkylamino or C3-C7cycloalkyl C0-C4alkyl;
E is a single covalent bond, oxygen, or NRA;
X is a single covalent bond, —
CRARB—
, —
O—
, —
C(═
O)—
, —
C(═
O)O—
, —
S(O)n—
or —
NRB—
; and
Ry is;
(i) hydrogen;
or(ii) C1-C10alkyl, C2-C10alkenyl, C2-C10alkynyl, C3-C10carbocycleC0-C4alkyl or (3- to 10-membered heterocycle)C0-C4alkyl, each of which is substituted with from 0 to 6 substituents independently selected from Rx, oxo, —
NH(C1-C6alkanoyl), —
N(C1-C6alkyl)C1-C6alkanoyl, —
NHS(On)C1-C6alkyl, —
N(S(On)C1-C6alkyl)2, —
S(On)NHC1-C6alkyl and —
S(On)N(C1-C6alkyl)2;
W is a single covalent bond, —
CRARB—
, —
NRB—
or —
O—
;
Z is independently selected at each occurrence from 3- to 7-membered carbocycles and heterocycles, each of which is substituted with from 0 to 4 substituents independently selected from halogen, oxo, —
COOH, hydroxy, amino, cyano, C1-C6alkyl, C1-C6alkoxy, C1-C6haloalkyl, C1-C6haloalkoxy, mono- and di-(C1-C6alkyl)amino and —
S(On) C1-C6alkyl; and
RA and RB are independently selected at each occurrence from;
(i) hydrogen; and
(ii) C1-C10alkyl, C2-C10alkenyl, C2-C10alkynyl, saturated or partially saturated (C3-C10carbocycle)C0-C4alkyl and saturated or partially saturated (3- to 10-membered heterocycle)C0-C4alkyl, each of which is substituted with from 0 to 6 substituents independently selected from oxo, hydroxy, halogen, cyano, amino, C1-C6alkoxy, mono- and di-(C1-C4alkyl)amino, —
COOH, —
C(═
O)NH2, —
NHC(═
O)(C1-C6alkyl), —
N(C1-C6alkyl)C(═
O)(C1-C6alkyl), —
NHS(On)C1-C6alkyl, SO3H, —
S(On)C1-C6alkyl, —
S(On)NHC1-C6alkyl, —
S(On)N(C1-C6alkyl)C1-C6alkyl and Z;
RC and RD are independently selected from RA, hydroxy, C1-6alkoxy, and oxo;
Rx is independently chosen at each occurrence from halogen, hydroxy, amino, cyano, nitro, —
COOH, —
C(═
O)NH2, C1-C6alkoxycarbonyl, mono- and di-(C1-6alkyl)aminocarbonyl, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, mono- and di-(C1-C6alkyl)amino, C1-C6alkoxy, C1-C2hydroxyalkyl, C1-C2haloalkyl, C1-C2haloalkoxy, (C3-C7cycloalkyl)C0-C4alkyl, and —
S(On)C1-C6alkyl;
m is an integer independently selected at each occurrence from 0-8; and
n is an integer independently selected at each occurrence from 0, 1 and 2. - View Dependent Claims (1, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111)
or a pharmaceutically acceptable salt thereof, wherein: -
R1 is selected from hydrogen, halogen, cyano, amino, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted haloalkyl, optionally substituted haloalkoxy, optionally substituted alkoxy, optionally substituted cycloalkoxy, optionally substituted (cycloalkyl)alkoxy, or optionally substituted heterocycloalkyl;
R2 is selected from the group consisting of —
NR4R5, —
(CRARB)OR4, —
CRARBNR4R5, —
C(RA′
)═
CRARB, and —
CRARBQ;
R3 represents between 0 and 4 substituents, each of which is independently selected from halogen, hydroxy, amino, cyano, optionally substituted alkyl, optionally substituted haloalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted alkoxy, optionally substituted haloalkoxy, optionally substituted hydroxyalkyl, optionally substituted alkoxyalkyl, optionally substituted mono- and di-alkylamino, optionally substituted aminoalkyl, -E-(CRCRD)m-Z, and -E-(CRCRD)m—
XRA;
R4 is;
(i) C2-C8alkyl, C2-C8alkenyl, C2-C8alkynyl, (C3-C7cycloalkyl)C0-C4alkyl, mono- or di-(C1-C4alkylamino)C2-C4alkyl, (3- to 7-membered heterocycloalkyl)C0-C4alkyl, arylC0-C4alkyl, or (heteroaryl)C0-4alkyl, each of which is substituted with from 0 to 4 substituents independently chosen from Rx, C2-C4alkanoyl, mono- and di-(C1-C4alkyl)amino(C1-C4alkyl), mono- and di-C1-C4alkylamino(C1-C4alkoxy), (3- to 7-membered heterocycloalkyl)C0-C4alkyl and XRy;
or(ii) joined to R5 to form, with the nitrogen to which R4 and R5 are bound, a heterocycle having from 1 to 3 rings, 5 to 7 ring members in each ring, wherein the heterocycle is substituted with from 0 to 4 substituents independently chosen from Rx, oxo and W-Z;
R5 is;
(i) hydrogen;
(ii) C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, (C3-C7carbocycle)C0-C4alkyl, each of which is substituted with from 0 to 3 substituents independently chosen from halogen, hydroxy, amino, cyano, C1-C4alkyl, C1-C4alkoxy, methylamino, dimethylamino, trifluoromethyl and trifluoromethoxy;
or(iii) joined to R4 to form an optionally substituted heterocycle;
Ar is mono-, di-, or tri-substituted phenyl, optionally substituted naphthyl, or optionally substituted heteroaryl, wherein Ar is optionally substituted heteroaryl when R2 is —
NR4R5;
RA, RA′
, and RB, which may be the same or different, are independently selected at each occurrence from;
(i) hydrogen and hydroxy, and (ii) alkyl groups, cycloalkyl groups, and (cycloalkyl)alkyl groups, each of which is optionally substituted with one or more substituent(s) independently selected from oxo, hydroxy, halogen, cyano, amino, C1-6alkoxy, —
NH(C1-6alkyl), —
N(C1-6alkyl)(C1-6alkyl), —
NHC(═
O)(C1-6alkyl), —
N(C1-6alkyl)C(═
O)(C1-6alkyl), —
NHS(O)n(C1-6alkyl), —
S(O)n(C1-6 alkyl), —
S(O)nNH(C1-6alkyl), —
S(O)nN(C1-6 alkyl)(C1-6alkyl), and Z;
E is a single covalent bond, oxygen, or NRA;
X is independently selected at each occurrence from the group consisting of —
CH2—
, —
CHRB—
, —
O—
, —
C(═
O)—
, —
C(═
O)O—
, —
S(O)n—
, —
NH—
, —
NRB—
, —
C(═
O)NH—
, —
C(═
O)NRB—
, —
S(O)nNH—
, —
S(O)nNRB—
, —
NHC(═
O)—
, —
NRBC(═
O)—
, —
NHS(O)n—
, and —
NRBS(O)n—
;
Y and Z are independently selected at each occurrence from 3- to 7-membered carbocyclic or heterocyclic groups which are saturated, unsaturated, or aromatic, which are optionally substituted with one or more substituents independently selected from halogen, oxo, hydroxy, amino, cyano, C1-4alkyl, —
O(C1-4alkyl), —
NH(C1-4alkyl), —
N(C1-4alkyl)(C1-4alkyl), and —
S(O)n(alkyl);
Q is an optionally substituted carbocyclic or optionally substituted heterocyclic group which are saturated, unsaturated or aromatic and comprises between 3 and 18 ring atoms arranged in 1, 2, or 3 rings which are fused, spiro or coupled by a bond;
m is independently selected at each occurrence from integers ranging from 0 to 8; and
n is an integer independently selected at each occurrence from 0, 1, and 2.
-
3. A compound or pharmaceutically acceptable salt thereof according to claim 2, wherein R3 is absent.
-
4. A compound or pharmaceutically acceptable salt thereof according to claim 2, wherein R1 is hydrogen, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, C1-C6haloalkyl, C1-C6haloalkoxy, (C3-C7cycloalkyl)-C0-C4alkyl.
-
5. A compound or pharmaceutically acceptable salt thereof according to claim 4, wherein R1 is hydrogen, C1-C4alkyl or C1-C4alkoxy.
-
6. A compound or pharmaceutically acceptable salt thereof according to claim 5, wherein R1 is hydrogen, methyl, ethyl, or methoxy.
-
7. A compound or pharmaceutically acceptable salt thereof according to claim 2, wherein R3 represents between 0 and 2 substituents, each of which is independently selected from C1-6alkyl, C1-6alkoxy, C1-6haloalkyl, C1-6haloalkoxy, mono- and di-(C1-6alkyl)amino, (amino)C0-6alkyl.
-
8. A compound or pharmaceutically acceptable salt thereof according to claim 7, wherein R3 represents between 0 and 2 substituents, each of which is independently selected from C1-6alkyl, and C1-6alkoxy.
-
9. A compound or pharmaceutically acceptable salt thereof according to claim 2, wherein Ar is mono-, di-, or tri-substituted phenyl, optionally substituted naphthyl, or optionally substituted heteroaryl.
-
10. A compound or pharmaceutically acceptable salt thereof according to claim 9, wherein Ar is mono-, di-, or tri-substituted phenyl, or Ar is 1-naphthyl, 2-naphthyl, pyridyl, pyrimidinyl, pyrazinyl, pyridizinyl, thienyl, thiazolyl, pyrazolyl, imidazolyl, tetrazolyl, oxazolyl, isoxazolyl, indazolyl, indolyl, pyrrolyl, furanyl, or triazolyl, each of which is optionally mono-, di-, or tri-substituted.
-
11. A compound or pharmaceutically acceptable salt thereof according to claim 10, wherein Ar is phenyl substituted with between 1 and 3 residues independently selected from the group consisting of optionally substituted C1-6alkyl, optionally substituted C2-6alkenyl, optionally substituted C2-6alkynyl, optionally substituted C1-6alkoxy, optionally substituted (C1-6alkoxy)C1-6alkyl, optionally substituted (amino)C1-6alkyl, optionally substituted mono- and di-(C1-6alkyl)amino.
-
12. A compound or pharmaceutically acceptable salt thereof according to claim 2, wherein
R4 is: -
(i) C2-C8alkyl, C2-C8alkenyl, C2-C8alkynyl, (C3-C7cycloalkyl)C0-C4alkyl, mono- or di-(C1-C4alkylamino)C2-C4alkyl, (3- to 7-membered heterocycloalkyl)C0-C4alkyl, phenylC0-C4alkyl, pyridylC0-C4alkyl, pyrimidinylC0-C4alkyl, thienylC0-C4alkyl, imidazolylC0-C4alkyl, pyrrolylC0-C4alkyl, pyrazolylC0-C4alkyl, benzoisothiazolyl or tetrahydronapthyl, each of which is substituted with from 0 to 4 substituents independently chosen from Rx, C2-C4alkanoyl, mono- and di-(C1-C4alkyl)amino(C1-C4alkyl), mono- and di-C1-C4alkylamino(C1-C4alkoxy), (3- to 7-membered heterocycloalkyl)C0-C4alkyl and XRy;
or(ii) joined to R5 to form, with the nitrogen to which R4 and R5 are bound, a heterocycle having from 1 to 3 rings, 5 to 7 ring members in each ring, wherein the heterocycle is substituted with from 0 to 4 substituents independently chosen from Rx, oxo and W-Z; and
R5 is;
(i) hydrogen;
(ii) C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, (C3-C7carbocycle)C0-C4alkyl, each of which is substituted with from 0 to 3 substituents independently chosen from halogen, hydroxy, amino, cyano, C1-C4alkyl, C1-C4alkoxy, methylamino, dimethylamino, trifluoromethyl and trifluoromethoxy;
or(iii) joined to R4 to form an optionally substituted heterocycle.
-
-
13. A compound or pharmaceutically acceptable salt thereof according to claim 2, wherein A is NR4R5.
-
14. A compound or pharmaceutically acceptable salt thereof according to claim 13, wherein:
-
R4 is chosen from (C3-C7cycloalkyl)C0-C4alkyl, phenylC0-C4alkyl, pyridylC0-C4alkyl, pyrimidinylC0-C4alkyl, thienylC0-C4alkyl, imidazolylC0-C4alkyl, pyrrolylC0-C4alkyl, pyrazolylC0-C4alkyl, indolylC0-C4alkyl, indazolylC0-C4alkyl, benzocycloalkenylC0-C4alkyl, decahydronaphthylC0-C4alkyl, benzoisothiazolylC0-C4alkyl, tetrahydroquinolinylC0-C4alkyl and tetrahydronaphthylC0-C4alkyl, each of which is substituted with from 0 to 4 groups independently chosen from Rx, mono- and di-C1-C4alkylamino(C1-C4alkyl), mono- and di-C1-C4alkylamino(C1-C4alkoxy), (3- to 7-membered heterocycloalkyl)C0-C4alkyl, C2-C4alkanoyl and C2-C4alkanoyloxy; and
R5 is C1-C6alkyl, C2-C6alkenyl or (C3-C7carbocycle)C0-C4alkyl.
-
-
15. A compound or pharmaceutically acceptable salt thereof according to claim 13, wherein R4 and R5 are joined to form a saturated or partially saturated heterocycle containing 1 or 2 fused or spiro rings;
- wherein the heterocycle is substituted with from 0 to 4 substituents independently chosen from halogen, hydroxy, amino, cyano, —
COOH, —
CH2COOH, C1-6alkoxycarbonyl, —
CH2CO2—
C1-6alkyl, —
C(═
O)NH2, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, mono- and di-(C1-C6alkyl)amino, C1-C6alkoxy, C1-C2haloalkyl, C1-C2haloalkoxy, (C3-C7cycloalkyl)C0-C4alkyl, —
S(On)C1-C6alkyl, SO3H, and phenyl.
- wherein the heterocycle is substituted with from 0 to 4 substituents independently chosen from halogen, hydroxy, amino, cyano, —
-
16. A compound or pharmaceutically acceptable salt thereof according to claim 15, wherein R4 and R5 are joined to form a saturated 4- to 7-membered heterocyclic ring that is substituted with from 0 to 3 substituents independently chosen from halogen, hydroxy, amino, cyano, C1-C2alkyl, C1-C2alkoxy, trifluoromethyl, difluoromethyl, trifluoromethoxy difluoromethoxy, —
- COOH, —
CH2COOH, C1-2alkoxycarbonyl, and —
CH2CO2—
C1-2alkyl.
- COOH, —
-
17. A compound or pharmaceutically acceptable salt thereof according to claim 16, wherein the heterocyclic ring is azepanyl, morpholinyl, homomorpholinyl, pyrrolidinyl, piperazinyl, homopiperazinyl, piperidinyl, or homopiperidinyl.
-
18. A compound or pharmaceutically acceptable salt thereof according to claim 15, wherein R4 and R5 are joined to form a heterocycle containing 2 rings;
- wherein each of the rings is substituted with from 0 to 3 substituents independently selected from the group consisting of halogen, hydroxy, amino, cyano, C1-C2alkyl, C1-C2alkoxy, trifluoromethyl, difluoromethyl, trifluoromethoxy, and difluoromethoxy.
-
19. A compound or pharmaceutically acceptable salt thereof according to claim 18, wherein the heterocycle is tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, decahydroisoquinolinyl, indazolyl, indolinyl, phenylimidazolyl, pyridooxazinyl, or benzoxazinyl.
-
20. A compound or pharmaceutically acceptable salt thereof according to claim 13, wherein the compound is according to Formula III:
-
wherein;
R3 and R3a are independently selected from hydrogen, C1-6alkyl, C1-6alkoxy, C1-6haloalkyl, C1-6haloalkoxy, COOH, CONH2, SO2NH2, hydroxy, halogen, or amino;
R13 represents from 0 to 3 substituents independently chosen from;
(i) Rx; and
(ii) phenyl and pyridyl, each of which is substituted with from 0 to 4 substituents independently chosen from halogen, hydroxy, amino, cyano, C1-C4alkyl, C1-C4alkoxy, (C3-C7cycloalkyl)C0-C4alkyl, C1-C2haloalkyl, C1-C2haloalkoxy, and mono- and di-(C1-C4alkyl)amino; and
G is CH2, sulfur, oxygen or NRE;
wherein RE is;
(i) hydrogen;
or(ii) C1-C6alkyl, (C3-C7cycloalkyl)C0-C4alkyl, phenyl or a 5- or 6-membered heteroaryl ring, each of which is substituted with from 0 to 3 substituents independently chosen from Rx.
-
-
21. A compound or pharmaceutically acceptable salt thereof according to claim 20, wherein G is oxygen.
-
22. A compound or pharmaceutically acceptable salt thereof according to claim 20, wherein R13 represents from 0 to 2 substituents independently chosen from halogen, methyl, methoxy, ethyl, phenyl, and phenoxy, wherein each phenyl or phenoxy group is substituted with between 0 and 3 substituents chosen from Rx.
-
23. A compound or pharmaceutically acceptable salt thereof according to claim 20, wherein:
-
R1 is hydrogen, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, C1-C6haloalkyl, C1-C6haloalkoxy, (C3-C7cycloalkyl)-C0-C4alkyl R8 and R9 are independently chosen from hydrogen, halogen, hydroxy, C1-C6alkyl, C1-C6alkenyl, (C3-C6cycloalkyl)C0-C4alkyl and C1-C6alkoxy; and
Ar is phenyl, 1-naphthyl, 2-naphthyl, pyridyl, pyrimidinyl, pyrazinyl, pyridizinyl, thienyl, thiazolyl, pyrazolyl, imidazolyl, tetrazolyl, oxazolyl, isoxazolyl, indazolyl, indolyl, pyrrolyl, furanyl, or triazolyl, each of which is optionally mono-, di-, or tri-substituted.
-
-
24. A compound or pharmaceutically acceptable salt thereof according to claim 23, wherein R3 represents between 0 and 2 substituents, each of which is independently selected from hydroxy, methyl, ethyl, or methoxy.
-
25. A compound or pharmaceutically acceptable salt thereof according to claim 23, wherein Ar is mono-, di-, or tri-substituted phenyl, optionally substituted naphthyl, or optionally substituted heteroaryl.
-
26. A compound or pharmaceutically acceptable salt thereof according to claim 25, wherein Ar is mono-, di-, or tri-substituted phenyl, or Ar is 1-naphthyl, 2-naphthyl, pyridyl, pyrimidinyl, pyrazinyl, pyridizinyl, thienyl, thiazolyl, pyrazolyl, imidazolyl, tetrazolyl, oxazolyl, isoxazolyl, indazolyl, indolyl, pyrrolyl, furanyl, or triazolyl, each of which is optionally mono-, di-, or tri-substituted.
-
27. A compound or pharmaceutically acceptable salt thereof according to claim 25, wherein Ar is phenyl substituted with between 1 and 3 residues independently selected from the group consisting of optionally substituted C1-6alkyl, optionally substituted C2-6alkenyl, optionally substituted C2-6alkynyl, optionally substituted C1-6alkoxy, optionally substituted (C1-6alkoxy)C1-6alkyl, optionally substituted (amino)C1-6alkyl, optionally substituted mono- and di-(C1-6alkyl)amino.
-
28. A compound or pharmaceutically acceptable salt thereof according to claim 13, wherein the compound has the formula:
-
wherein;
R3 and R3a are independently selected from the group consisting of hydrogen, C1-6alkyl, C1-6alkoxy, C1-6haloalkyl, C1-6haloalkoxy, COOH, CONH2, SO2NH2, hydroxy, halogen, and amino;
R10 and R11 are independently chosen from hydrogen, C1-C6alkyl, C1-C2haloalkyl and C3-C7cycloalkyl(C0-C2alkyl); and
R12 represents from 0 to 3 substituents independently chosen from Rx, mono- and di-(C1-C4alkyl)amino(C1-C4alkyl), mono- and di-(C1-C4alkyl)amino(C1-C4alkoxy) and YZ;
or two adjacent R12 groups are joined to form a fused 5- to 7-membered carbocyclic or heterocyclic ring.
-
-
29. A compound or pharmaceutically acceptable salt thereof according to claim 28, wherein R12 represents from 0 to 3 substituents independently chosen from halogen, hydroxy, amino, cyano, C1-C4alkyl, mono- and di-(C1-C2alkyl)amino, C1-C4alkoxy, C1-C2haloalkyl, C1-C2haloalkoxy and (C3-C7cycloalkyl)C0-C2alkyl.
-
30. A compound or pharmaceutically acceptable salt thereof according to claim 28, wherein:
-
R1 is hydrogen, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, C1-C6haloalkyl, C1-C6haloalkoxy, (C3-C7cycloalkyl)-C0-C4alkyl;
R8 and R9 are independently chosen from hydrogen, halogen, hydroxy, C1-C6alkyl, C1-C6alkenyl, (C3-C6cycloalkyl)C0-C4alkyl and C1-C6alkoxy; and
Ar is phenyl, 1-naphthyl, 2-naphthyl, pyridyl, pyrimidinyl, pyrazinyl, pyridizinyl, thienyl, thiazolyl, pyrazolyl, imidazolyl, tetrazolyl, oxazolyl, isoxazolyl, indazolyl, indolyl, pyrrolyl, furanyl, and triazolyl, each of which is optionally mono-, di-, or tri-substituted.
-
-
31. A compound or pharmaceutically acceptable salt thereof according to claim 28, wherein Ar is mono-, di-, or tri-substituted phenyl, optionally substituted naphthyl, or optionally substituted heteroaryl.
-
32. A compound or pharmaceutically acceptable salt thereof according to claim 31, wherein Ar is mono-, di-, or tri-substituted phenyl, or Ar is 1-naphthyl, 2-naphthyl, pyridyl, pyrimidinyl, pyrazinyl, pyridizinyl, thienyl, thiazolyl, pyrazolyl, imidazolyl, tetrazolyl, oxazolyl, isoxazolyl, indazolyl, indolyl, pyrrolyl, furanyl, or triazolyl, each of which is optionally mono-, di-, or tri-substituted.
-
33. A compound or pharmaceutically acceptable salt thereof according to claim 31, wherein Ar is phenyl substituted with between 1 and 3 residues independently selected from the group consisting of optionally substituted C1-6alkyl, optionally substituted C2-6alkenyl, optionally substituted C2-6alkynyl, optionally substituted C1-6alkoxy, optionally substituted (C1-6alkoxy)C1-6alkyl, optionally substituted (amino)C1-6alkyl, optionally substituted mono- and di-(C1-6alkyl)amino.
-
34. A compound or pharmaceutically acceptable salt thereof according to claim 13, wherein the compound has the formula:
-
wherein;
R3 and R3a are independently selected from the group consisting of hydrogen, C1-6alkyl, C1-6alkoxy, C1-6haloalkyl, C1-6haloalkoxy, COOH, CONH2, SO2NH2, hydroxy, halogen, and amino;
R12 and R13 independently represent from 0 to 3 substituents independently chosen from Rx;
R14 is hydrogen, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C2haloalkyl or (C3-C7cycloalkyl)C0-C2alkyl, COOH, CONH2, CH2COOH, CH2CONH2, C1-6alkoxycarbonyl, CH2CO2—
C1-6alkyl, or SO3H; and
x is 0, 1 or2.
-
-
35. A compound or pharmaceutically acceptable salt thereof according to claim 34, wherein x is 1.
-
36. A compound or pharmaceutically acceptable salt thereof according to claim 34, wherein:
-
R12 and R13 independently represent from 0 to 2 substituents independently chosen from halogen, methyl, methoxy and ethyl; and
R14 is hydrogen, C1-C6alkyl, C2-C6alkenyl or C3-C7cycloalkyl(C0-C2alkyl).
-
-
37. A compound or pharmaceutically acceptable salt thereof according to claim 34, wherein:
-
R1 is hydrogen, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, C1-C6haloalkyl, C1-C6haloalkoxy, (C3-C7cycloalkyl)-C0-C4alkyl;
R8 and R9 are independently chosen from hydrogen, halogen, hydroxy, C1-C6alkyl, C1-C6alkenyl, (C3-C6cycloalkyl)C0-C4alkyl and C1-C6alkoxy; and
Ar is phenyl which is mono-, di-, or tri-substituted, or 1-naphthyl, 2-naphthyl, pyridyl, pyrimidinyl, pyrazinyl, pyridizinyl, thienyl, thiazolyl, pyrazolyl, imidazolyl, tetrazolyl, oxazolyl, isoxazolyl, indolyl, indazolyl, pyrrolyl, furanyl, indolyl, indazolyl and triazolyl, each of which is optionally mono-, di-, or tri-substituted.
-
-
38. A compound or pharmaceutically acceptable salt thereof according to claim 34, wherein Ar is mono-, di-, or tri-substituted phenyl, optionally substituted naphthyl, or optionally substituted heteroaryl.
-
39. A compound or pharmaceutically acceptable salt thereof according to claim 38, wherein Ar is mono-, di-, or tri-substituted phenyl, or Ar is 1-naphthyl, 2-naphthyl, pyridyl, pyrimidinyl, pyrazinyl, pyridizinyl, thienyl, thiazolyl, pyrazolyl, imidazolyl, tetrazolyl, oxazolyl, isoxazolyl, indazolyl, indolyl, pyrrolyl, furanyl, or triazolyl, each of which is optionally mono-, di-, or tri-substituted.
-
40. A compound or pharmaceutically acceptable salt thereof according to claim 38, wherein Ar is phenyl substituted with between 1 and 3 residues independently selected from the group consisting of optionally substituted C1-6alkyl, optionally substituted C2-6alkenyl, optionally substituted C2-6alkynyl, optionally substituted C1-6alkoxy, optionally substituted (C1-6alkoxy)C1-6alkyl, optionally substituted (amino)C1-6alkyl, optionally substituted mono- and di-(C1-6alkyl)amino.
-
41. A compound or pharmaceutically acceptable salt thereof according to claim 13, wherein the compound has the formula:
-
wherein;
R3 and R3a are independently selected from the group consisting of hydrogen, C1-6alkyl, C1-6alkoxy, C1-6haloalkyl, C1-6haloalkoxy, COOH, CONH2, SO2NH2, hydroxy, halogen, and amino;
R12 and R13 represent from 0 to 3 substituents independently chosen from Rx;
G is CH2, NH, sulfur or oxygen;
G3 is N, CH, or CRx and x is 0, 1 or 2.
-
-
42. A compound or pharmaceutically acceptable salt thereof according to claim 41, wherein x is 1.
-
43. A compound or pharmaceutically acceptable salt thereof according to claim 41, wherein R12 and R13 independently represent from 0 to 2 substituents independently chosen from halogen, methyl, methoxy and ethyl.
-
44. A compound or pharmaceutically acceptable salt thereof according to claim 41, wherein:
-
R1 is hydrogen, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, C1-C6haloalkyl, C1-C6haloalkoxy, (C3-C7cycloalkyl)-C0-C4alkyl;
R8 and R9 are independently chosen from hydrogen, halogen, hydroxy, C1-C6alkyl, C1-C6alkenyl, (C3-C6cycloalkyl)C0-C4alkyl and C1-C6alkoxy; and
Ar is phenyl which is mono-, di-, or tri-substituted, or 1-naphthyl, 2-naphthyl, pyridyl, pyrimidinyl, pyrazinyl, pyridizinyl, thienyl, thiazolyl, pyrazolyl, imidazolyl, tetrazolyl, oxazolyl, isoxazolyl, indolyl, indazolyl, pyrrolyl, furanyl, indolyl, indazolyl and triazolyl, each of which is optionally mono-;
di-, or tri-substituted.
-
-
45. A compound or pharmaceutically acceptable salt thereof according to claim 41, wherein Ar is mono-, di-, or tri-substituted phenyl, optionally substituted naphthyl, or optionally substituted heteroaryl.
-
46. A compound or pharmaceutically acceptable salt thereof according to claim 45, wherein Ar is mono-, di-, or tri-substituted phenyl, or Ar is 1-naphthyl, 2-naphthyl, pyridyl, pyrimidinyl, pyrazinyl, pyridizinyl, thienyl, thiazolyl, pyrazolyl, imidazolyl, tetrazolyl, oxazolyl, isoxazolyl, indazolyl, indolyl, pyrrolyl, furanyl, or triazolyl, each of which is optionally mono-, di-, or tri-substituted.
-
47. A compound or pharmaceutically acceptable salt thereof according to claim 45, wherein Ar is phenyl substituted with between 1 and 3 residues independently selected from the group consisting of optionally substituted C1-6alkyl, optionally substituted C2-6alkenyl, optionally substituted C2-6alkynyl, optionally substituted C1-6alkoxy, optionally substituted (C1-6alkoxy)C1-6alkyl, optionally substituted (amino)C1-6-alkyl, optionally substituted mono- and di-(C1-6alkyl)amino.
-
48. A compound or pharmaceutically acceptable salt thereof according to claim 13, wherein the compound has the formula:
-
wherein R3 and R3a are independently selected from the group consisting of hydrogen, C1-6alkyl, C1-6alkoxy, C1-6haloalkyl, C1-6haloalkoxy, COOH, CONH2, SO2NH2, hydroxy, halogen, and amino;
R12 and R13 independently represent from 0 to 3 substituents independently chosen from Rx;
G is CH2, NH or oxygen; and
x is 0, 1 or 2.
-
-
49. A compound or pharmaceutically acceptable salt thereof according to claim 48, wherein x is 1.
-
50. A compound or pharmaceutically acceptable salt thereof according to claim 48, wherein G is CH2.
-
51. A compound or pharmaceutically acceptable salt thereof according to claim 48, wherein R12 and R13 independently represent from 0 to 3 substituents independently chosen from halogen, hydroxy, amino, cyano, C1-C4alkyl, mono- and di-(C1-C2alkyl)amino, C1-C4alkoxy, C1-C2haloalkyl, C1-C2haloalkoxy, and (C3-C7cycloalkyl)C0-C2alkyl.
-
52. A compound or pharmaceutically acceptable salt thereof according to claim 51, wherein R12 and R13 independently represent from 0 to 2 substituents independently chosen from halogen, C1-C2alkyl and C1-C2alkoxy.
-
53. A compound or pharmaceutically acceptable salt thereof according to claim 51, wherein:
-
R5 is C1-C6alkyl; and
R12 and R13 each represent from 0 to 2 substituents independently chosen from halogen, methyl, methoxy and ethyl.
-
-
54. A compound or pharmaceutically acceptable salt thereof according to claim 51, wherein:
-
R1 is hydrogen, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, C1-C6haloalkyl, C1-C6haloalkoxy, (C3-C7cycloalkyl)-C0-C4alkyl;
R8 and R9 are independently chosen from hydrogen, halogen, hydroxy, C1-C6alkyl, C1-C6alkenyl, (C3-C6cycloalkyl)C0-C4alkyl and C1-C6alkoxy; and
Ar is phenyl which is mono-, di-, or tri-substituted, or 1-naphthyl, 2-naphthyl, pyridyl, pyrimidinyl, pyrazinyl, pyridizinyl, thienyl, thiazolyl, pyrazolyl, imidazolyl, tetrazolyl, oxazolyl, isoxazolyl, pyrrolyl, furanyl, indolyl, indazolyl, and triazolyl, each of which is optionally mono-, di-, or tri-substituted.
-
-
55. A compound or pharmaceutically acceptable salt thereof according to claim 48, wherein Ar is mono-, di-, or tri-substituted phenyl, optionally substituted naphthyl, or optionally substituted heteroaryl.
-
56. A compound or pharmaceutically acceptable salt thereof according to claim 55, wherein Ar is mono-, di-, or tri-substituted phenyl, or Ar is 1-naphthyl, 2-naphthyl, pyridyl, pyrimidinyl, pyrazinyl, pyridizinyl, thienyl, thiazolyl, pyrazolyl, imidazolyl, tetrazolyl, oxazolyl, isoxazolyl, indazolyl, indolyl, pyrrolyl, furanyl, or triazolyl, each of which is optionally mono-, di-, or tri-substituted.
-
57. A compound or pharmaceutically acceptable salt thereof according to claim 55, wherein Ar is phenyl substituted with between 1 and 3 residues independently selected from the group consisting of optionally substituted C1-6alkyl, optionally substituted C2-6alkenyl, optionally substituted C2-6alkynyl, optionally substituted C1-6alkoxy, optionally substituted (C1-6alkoxy)C1-6alkyl, optionally substituted (amino)C1-6alkyl, optionally substituted mono- and di-(C1-6alkyl)amino.
-
58. A compound or pharmaceutically acceptable salt thereof according to claim 2, wherein:
-
A is OR4; and
R4 is C2-C6alkyl, C2-C6alkenyl, phenylC0-C4alkyl, naphthylC0-C4alkyl, pyridylC0-C4alkyl, pyrimidinylC0-C4alkyl, thienylC0-C4alkyl, imidazolylC0-C4alkyl or pyrrolylC0-C4alkyl, each of which is substituted with from 0 to 4 substituents independently chosen from Rx, mono- and di-(C1-C4alkyl)amino(C1-C4alkyl), mono- and di-C1-C4alkylamino(C1-C4alkoxy), (3- to 7-membered heterocycloalkyl)C0-C4alkyl and C2-C4alkanoyl.
-
-
59. A compound or pharmaceutically acceptable salt thereof according to claim 58, wherein R4 is phenyl, benzyl, pyridyl or pyridylmethyl, each of which is substituted with from 0 to 4 substituents independently chosen from Rx, mono- and di-C1-C4alkylamino(C0-C4alkyl), mono- and di-C1-C4alkylamino(C1-C4alkoxy), (3- to 7-membered heterocycloalkyl)C0-C4alkyl and C2-C4alkanoyl.
-
60. A compound or pharmaceutically acceptable salt thereof according to claim 58, wherein:
-
R1 is hydrogen, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, C1-C6haloalkyl, C1-C6haloalkoxy, (C3-C7cycloalkyl)-C0-C4alkyl R3 represents between 0 and 2 substituents, each of which is independently selected from C1-6alkyl, C1-6alkoxy, C1-6haloalkyl, C1-6haloalkoxy, mono- and di-(C1-6alkyl)amino, (amino)C0-6alkyl;
R8 and R9 are independently chosen from hydrogen, halogen, hydroxy, C1-C6alkyl, C1-C6alkenyl, (C3-C6cycloalkyl)C0-C4alkyl and C1-C6alkoxy; and
Ar is phenyl which is mono-, di-, or tri-substituted, or 1-naphthyl, 2-naphthyl, pyridyl, pyrimidinyl, pyrazinyl, pyridizinyl, thienyl, thiazolyl, pyrazolyl, imidazolyl, tetrazolyl, oxazolyl, isoxazolyl, pyrrolyl, furanyl, indolyl, indazolyl, and triazolyl, each of which is optionally mono-, di-, or tri-substituted.
-
-
61. A compound or pharmaceutically acceptable salt thereof according to claim 58, wherein Ar is mono-, di-, or tri-substituted phenyl, optionally substituted naphthyl, or optionally substituted heteroaryl.
-
62. A compound or pharmaceutically acceptable salt thereof according to claim 61, wherein Ar is mono-, di-, or tri-substituted phenyl, or Ar is 1-naphthyl, 2-naphthyl, pyridyl, pyrimidinyl, pyrazinyl, pyridizinyl, thienyl, thiazolyl, pyrazolyl, imidazolyl, tetrazolyl, oxazolyl, isoxazolyl, indazolyl, indolyl, pyrrolyl, furanyl, or triazolyl, each of which is optionally mono-, di-, or tri-substituted.
-
63. A compound or pharmaceutically acceptable salt thereof according to claim 61, wherein Ar is phenyl substituted with between 1 and 3 residues independently selected from the group consisting of optionally substituted C1-6alkyl, optionally substituted C2-6alkenyl, optionally substituted C2-6alkynyl, optionally substituted C1-6alkoxy, optionally substituted (C1-6alkoxy)C1-6alkyl, optionally substituted (amino)C1-6alkyl, optionally substituted mono- and di-(C1-6alkyl)amino.
-
64. A compound or pharmaceutically acceptable salt thereof according to claim 58, wherein the compound has the formula:
-
wherein;
D is CH or N;
R3 and R3a are independently selected from the group consisting of hydrogen, C1-6alkyl, C1-6alkoxy, C1-6haloalkyl, C1-6haloalkoxy, COOH, CONH2, SO2NH2, hydroxy, halogen, and amino;
R21 represents from 0 to 3 substituents independently chosen from Rx and LRd;
or two adjacent R21 groups are joined to form a fused 5- to 7-membered carbocyclic or heterocyclic ring that is substituted with from 0 to 3 substituents independently chosen from Rx;
L is a single covalent bond or —
CH2—
; and
Rd is piperazinyl, morpholinyl, piperidinyl or pyrrolidinyl.
-
-
65. A compound or pharmaceutically acceptable salt thereof according to claim 64, wherein:
-
R21 represents from 0 to 3 substituents independently chosen from Rx and LRd;
R1 is hydrogen, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, C1-C6haloalkyl, C1-C6haloalkoxy, (C3-C7cycloalkyl)-C0-C4alkyl;
R8 and R9 are independently chosen from hydrogen, halogen, hydroxy, C1-C6alkyl, C1-C6alkenyl, (C3-C6cycloalkyl)C0-C4alkyl and C1-C6alkoxy; and
Ar is phenyl which is mono-, di-, or tri-substituted, or 1-naphthyl, 2-naphthyl, pyridyl, pyrimidinyl, pyrazinyl, pyridizinyl, thienyl, thiazolyl, pyrazolyl, imidazolyl, tetrazolyl, oxazolyl, isoxazolyl, pyrrolyl, furanyl, indolyl, indazolyl, and triazolyl, each of which is optionally mono-, di-, or tri-substituted.
-
-
66. A compound or pharmaceutically acceptable salt thereof according to claim 64, wherein Ar is mono-, di-, or tri-substituted phenyl, optionally substituted naphthyl, or optionally substituted heteroaryl.
-
67. A compound or pharmaceutically acceptable salt thereof according to claim 66, wherein Ar is mono-, di-, or tri-substituted phenyl, or Ar is 1-naphthyl, 2-naphthyl, pyridyl, pyrimidinyl, pyrazinyl, pyridizinyl, thienyl, thiazolyl, pyrazolyl, imidazolyl, tetrazolyl, oxazolyl, isoxazolyl, indazolyl, indolyl, pyrrolyl, furanyl, or triazolyl, each of which is optionally mono-, di-, or tri-substituted.
-
68. A compound or pharmaceutically acceptable salt thereof according to claim 66, wherein Ar is phenyl substituted with between 1 and 3 residues independently selected from the group consisting of optionally substituted C1-6alkyl, optionally substituted C2-6alkenyl, optionally substituted C2-6alkynyl, optionally substituted C1-6alkoxy, optionally substituted (C1-6alkoxy)C1-6alkyl, optionally substituted (amino)C1-6alkyl, optionally substituted mono- and di-(C1-6alkyl)amino.
-
69. A compound or pharmaceutically acceptable salt thereof according to claim 64, wherein the group designated:
-
is chosen from naphthyl, tetrahydronaphthyl, benzofuranyl, benzodioxolyl, indanyl, indolyl, indazolyl, benzodioxolyl, benzo[1,4]dioxanyl and benzoxazolyl, each of which is substituted with from 0 to 3 substituents independently chosen from Rx.
-
-
70. A compound or pharmaceutically acceptable salt thereof according to claim 1, wherein R2 is —
- NR4R5; and
Ar is heteroaryl.
- NR4R5; and
-
71. A compound or pharmaceutically acceptable salt thereof according to claim 70, wherein R3 is absent.
-
72. A compound or pharmaceutically acceptable salt thereof according to claim 70, wherein R1 is hydrogen, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C1-C6alkoxy, C1-C6haloalkyl, C1-C6haloalkoxy, (C3-C7cycloalkyl)-C0-C4alkyl.
-
73. A compound or pharmaceutically acceptable salt thereof according to claim 72, wherein R1 is hydrogen, C1-C4alkyl or C1-C4alkoxy.
-
74. A compound or pharmaceutically acceptable salt thereof according to claim 73, wherein R1 is hydrogen, methyl, ethyl, or methoxy.
-
75. A compound or pharmaceutically acceptable salt thereof according to claim 70, wherein R3 represents between 0 and 2 substituents, each of which is independently selected from C1-6alkyl, C1-6alkoxy, C1-6haloalkyl, C1-6haloalkoxy, mono- and di-(C1-6alkyl)amino, (amino)C0-6alkyl.
-
76. A compound or pharmaceutically acceptable salt thereof according to claim 75, wherein R3 represents between 0 and 2 substituents, each of which is independently selected from C1-6alkyl, and C1-6alkoxy.
-
77. A compound or pharmaceutically acceptable salt thereof according to claim 70, wherein Ar is pyridyl, pyrimidinyl, pyrazinyl, pyridizinyl, thienyl, thiazolyl, pyrazolyl, imidazolyl, tetrazolyl, oxazolyl, isoxazolyl, indazolyl, indolyl, pyrrolyl, furanyl, or triazolyl, each of which is optionally mono-, di-, or tri-substituted.
-
78. A compound or pharmaceutically acceptable salt thereof according to claim 77, wherein Ar is substituted with between 1 and 3 residues independently selected from the group consisting of optionally substituted C1-6alkyl, optionally substituted C2-6alkenyl, optionally substituted C2-6alkynyl, optionally substituted C1-6alkoxy, optionally substituted (C1-6alkoxy)C1-6alkyl, optionally substituted (amino)C1-6alkyl, optionally substituted mono- and di-(C1-6alkyl)amino.
-
79. A compound or pharmaceutically acceptable salt thereof according to claim 70, wherein
R4 is: -
(i) C2-C8alkyl, C2-C8alkenyl, C2-C8alkynyl, (C3-C7cycloalkyl)C0-C4alkyl, mono- or di-(C1-C4alkylamino)C2-C4alkyl, (3- to 7-membered heterocycloalkyl)C0-C4alkyl, phenylC0-C4alkyl, pyridylC0-C4alkyl, pyrimidinylC0-C4alkyl, thienylC0-C4alkyl, imidazolylC0-C4alkyl, pyrrolylC0-C4alkyl, pyrazolylC0-C4alkyl, benzoisothiazolyl or tetrahydronapthyl, each of which is substituted with from 0 to 4 substituents independently chosen from Rx, C2-C4alkanoyl, mono- and di-(C1-C4alkyl)amino(C1-C4alkyl), mono- and di-C1-C4alkylamino(C1-C4alkoxy), (3- to 7-membered heterocycloalkyl)C0-C4alkyl and XRy;
or(ii) joined to R5 to form, with the nitrogen to which R4 and R5 are bound, a heterocycle having from 1 to 3 rings, 5 to 7 ring members in each ring, wherein the heterocycle is substituted with from 0 to 4 substituents independently chosen from Rx, oxo and W-Z; and
R5 is;
(i) hydrogen;
(ii) C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, (C3-C7carbocycle)C0-C4alkyl, each of which is substituted with from 0 to 3 substituents independently chosen from halogen, hydroxy, amino, cyano, C1-C4alkyl, C1-C4alkoxy, methylamino, dimethylamino, trifluoromethyl and trifluoromethoxy;
or(iii) joined to R4 to form an optionally substituted heterocycle.
-
-
80. A compound or pharmaceutically acceptable salt thereof according to claim 70, wherein:
-
R4 is chosen from (C3-C7cycloalkyl)C0-C4alkyl, phenylC0-C4alkyl, pyridylC0-C4alkyl, pyrimidinylC0-C4alkyl, thienylC0-C4alkyl, imidazolylC0-C4alkyl, pyrrolylC0-C4alkyl, pyrazolylC0-C4alkyl, indolylC0-C4alkyl, indazolylC0-C4alkyl, benzocycloalkenylC0-C4alkyl, decahydronaphthylC0-C4alkyl, benzoisothiazolylC0-C4alkyl, tetrahydroquinolinylC0-C4alkyl and tetrahydronaphthylC0-C4alkyl, each of which is substituted with from 0 to 4 groups independently chosen from Rx, mono- and di-C1-C4alkylamino(C1-C4alkyl), mono- and di-C1-C4alkylamino(C1-C4alkoxy), (3- to 7-membered heterocycloalkyl)C0-C4alkyl, C2-C4alkanoyl and C2-C4alkanoyloxy; and
R5 is C1-C6alkyl, C2-C6alkenyl or (C3-C7carbocycle)C0-C4alkyl.
-
-
81. A compound or pharmaceutically acceptable salt thereof according to claim 70, wherein R4 and R5 are joined to form a saturated or partially saturated heterocycle containing 1 or 2 fused or spiro rings;
- wherein the heterocycle is substituted with from 0 to 4 substituents independently chosen from halogen, hydroxy, amino, cyano, —
COOH, —
CH2COOH, C1-6alkoxycarbonyl, —
CH2CO2—
C1-6alkyl, —
C(═
O)NH2, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, mono- and di-(C1-C6alkyl)amino, C1-C6alkoxy, C1-C2haloalkyl, C1-C2haloalkoxy, (C3-C7cycloalkyl)C0-C4alkyl, —
S(On)C1-C6alkyl, SO3H, and phenyl.
- wherein the heterocycle is substituted with from 0 to 4 substituents independently chosen from halogen, hydroxy, amino, cyano, —
-
82. A compound or pharmaceutically acceptable salt thereof according to claim 81, wherein R4 and R5 are joined to form a saturated 4- to 7-membered heterocyclic ring that is substituted with from 0 to 3 substituents independently chosen from halogen, hydroxy, amino, cyano, C1-C2alkyl, C1-C2alkoxy, trifluoromethyl, difluoromethyl, trifluoromethoxy difluoromethoxy, —
- COOH, —
CH2COOH, C1-2alkoxycarbonyl, and —
CH2CO2—
C1-2alkyl.
- COOH, —
-
83. A compound or pharmaceutically acceptable salt thereof according to claim 82, wherein the heterocyclic ring is azepanyl, morpholinyl, homomorpholinyl, pyrrolidinyl, piperazinyl, homopiperazinyl, piperidinyl, or homopiperidinyl.
-
92. A compound or pharmaceutically acceptable salt thereof according to claim 91, wherein the heterocyclic ring is azepanyl, morpholinyl, homomorpholinyl, pyrrolidinyl, piperazinyl, homopiperazinyl, piperidinyl, or homopiperidinyl.
-
93. A compound or salt thereof according to any one of claims 1, 2, or 84, wherein the compound exhibits an IC50 of 25 nM or less in a standard in vitro C5a receptor-mediated chemotaxis or calcium mobilization assay.
-
94. A compound or salt thereof according to any one of claims 1, 2, or 84, wherein the compound exhibits less than 5% agonist activity in a GTP binding assay.
-
95. A pharmaceutical composition comprising at least one compound or salt thereof according to any one of claims 1, 2, or 84, in combination with a physiologically acceptable carrier or excipient.
-
96. A pharmaceutical composition according to claim 95, wherein the pharmaceutical composition is formulated as an injectable fluid, an aerosol, a cream, a gel, a pill, a capsule, a syrup, or a transdermal patch.
-
97. A method for inhibiting signal-transducing activity of a cellular C5a receptor, comprising contacting a cell expressing C5a receptor with at least one compound or salt thereof according to any one of claims 1, 2, or 84, and thereby reducing signal transduction by C5a receptor.
-
98. A method according to claim 97, wherein the cell is contacted in vivo in an animal.
-
99. A method according to claim 97, wherein the animal is a human.
-
100. A method of inhibiting binding of C5a to C5a receptor in vitro, the method comprising contacting C5a receptor with at least one compound or salt thereof according to any one of claims 1, 2, or 84, under conditions and in an amount sufficient to detectably inhibit C5a binding to C5a receptor.
-
101. A method of inhibiting binding of C5a to C5a receptor in a human patient, comprising contacting cells expressing C5a receptor with at least one compound or salt thereof according to any one of claims 1, 2, or 84, in an amount sufficient to detectably inhibit C5a binding to cells expressing a cloned C5a receptor in vitro, and thereby inhibiting binding of C5a to C5a receptor in the patient.
-
102. A method for treating a patient suffering from rheumatoid arthritis, psoriasis, cardiovascular disease, reperfusion injury, or bronchial asthma comprising administering to the patient a therapeutically effective amount of a compound or salt thereof according to any one of claims 1, 2, or 84.
-
103. A method for treating a patient suffering from stroke, myocardial infarction, atherosclerosis, ischemic heart disease, fibrosis, cardiac fibrosis, or ischemia-reperfusion injury comprising administering to the patient a therapeutically effective amount of a compound or salt thereof according to any one of claims 1, 2, or 84.
-
104. A method for treating a patient suffering from cystic fibrosis, comprising administering to a patient in need of such treatment a therapeutically effective amount of a compound or salt thereof according to any one of claims 1, 2, or 84.
-
105. A method for treating a patient suffering from inflammation, comprising administering to a patient in need of such treatment a therapeutically effective amount of a compound or salt thereof according to any one of claims 1, 2, or 84.
-
106. A method for inhibiting C5a receptor-mediated cellular chemotaxis, comprising contacting mammalian white blood cells with a therapeutically effective amount of a compound or salt thereof according to any one of claims 1, 2, or 84.
-
107. A method for localizing C5a receptor in a tissue sample, comprising:
-
(a) contacting the tissue sample containing C5a receptor with a detectably labeled compound according to any one of claims 1, 2, or 84 under conditions that permit binding of the compound to C5a receptors; and
(b) detecting the bound compound.
-
-
108. A method according to claim 107, wherein the compound is radiolabeled.
-
109. A packaged pharmaceutical preparation, comprising:
-
(a) a pharmaceutical composition according to claim 96 in a container; and
(b) instructions for using the composition to treat a patient suffering from inflammation.
-
-
110. A packaged pharmaceutical preparation, comprising:
-
(a) a pharmaceutical composition according to claim 96 in a container; and
(b) instructions for using the composition to treat a patient suffering from rheumatoid arthritis, psoriasis, cardiovascular disease, reperfusion injury, or bronchial asthma.
-
-
111. A packaged pharmaceutical preparation, comprising:
-
(a) a pharmaceutical composition according to claim 96 in a container; and
(b) instructions for using the composition to treat stroke, myocardial infarction, atherosclerosis, ischemic heart disease, or ischemia-reperfusion injury.
-
-
-
84. A compound according to Formula IX:
-
or a pharmaceutically acceptable salt thereof, wherein;
R1 is selected from the group consisting of hydrogen, halogen, cyano, amino, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted haloalkyl, optionally substituted haloalkoxy, optionally substituted alkoxy, optionally substituted cycloalkoxy, optionally substituted (cycloalkyl)alkoxy, and optionally substituted heterocycloalkyl;
R3 represents between 0 and 4 substituents, each of which is independently selected from optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkoxy, optionally substituted hydroxyalkyl, optionally substituted aminoalkyl, optionally substituted mono- and di-alkylamino, —
O—
(CRARB)m—
XRA, —
O—
(CRARB)m—
Y, —
N(RB)—
(CRARB)m—
XRA, —
N(RB)—
(CRARB)m—
Y;
R4 is;
(i) C2-C8alkyl, C2-C8alkenyl, C2-C8alkynyl, (C3-C7cycloalkyl)C0-C4alkyl, mono- or di-(C1-C4alkylamino)C2-C4alkyl, (3- to 7-membered heterocycloalkyl)C0-C4alkyl, arylC0-C4alkyl, or (heterocycle)C0-4alkyl, each of which is substituted with from 0 to 4 substituents independently chosen from Rx, C2-C4alkanoyl, mono- and di-(C1-C4alkyl)amino(C1-C4alkyl), mono- and di-C1-C4alkylamino(C1-C4alkoxy), (3- to 7-membered heterocycloalkyl)C0-C4alkyl and XRy;
or(ii) joined to R5 to form, with the nitrogen to which R4 and R5 are bound, a heterocycle having from 1 to 3 rings, 5 to 7 ring members in each ring, wherein the heterocycle is substituted with from 0 to 4 substituents independently chosen from Rx, oxo and W-Z;
R5 is;
(i) hydrogen;
(ii) C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, (C3-C7carbocycle)C0-C4alkyl, each of which is substituted with from 0 to 3 substituents independently chosen from halogen, hydroxy, amino, cyano, C1-C4alkyl, C1-C4alkoxy, methylamino, dimethylamino, trifluoromethyl and trifluoromethoxy;
or(iii) joined to R4 to form an optionally substituted heterocycle;
Ar is optionally substituted naphthyl or optionally substituted heteroaryl;
RA and RB, which may be the same or different, are independently selected at each occurrence from;
hydrogen, hydroxy, and straight or branched alkyl groups, cycloalkyl groups, (cycloalkyl)alkyl groups and are optionally further substituted with one or more substituent(s) independently selected from oxo, hydroxy, halogen, cyano, amino, C1-6alkoxy, —
NH(C1-6alkyl), —
N(C1-6alkyl)(C1-6alkyl), —
NHC(═
O)(C1-6alkyl), —
N(C1-6alkyl)C(═
O)(C1-6alkyl), —
NHS(O)n(C1-6alkyl), —
S(O)n(C1-6 alkyl), —
S(O)nNH(C1-6alkyl), —
S(O)nN(C1-6 alkyl)(C1-6alkyl), and Z;
X is independently selected at each occurrence from the group consisting of —
CH2—
, —
CHRB—
, —
O—
, —
C(═
O)—
, —
C(═
O)O—
, —
S(O)n—
, —
NH—
, —
NRB—
, —
C(═
O)NH—
, —
C(═
O)NRB—
, —
S(O)nNH—
, —
S(O)nNRB—
, —
NHC(═
O)—
, —
NRBC(═
O)—
, —
NHS(O)n—
, and —
NRBS(O)n—
;
Y and Z are independently selected at each occurrence from 3- to 7-membered carbocyclic or heterocyclic groups which are saturated, unsaturated, or aromatic, which are optionally substituted with one or more substituents independently selected from halogen, oxo, hydroxy, amino, cyano, C1-4alkyl, —
O(C1-4alkyl), —
NH(C1-4alkyl), —
N(C1-4alkyl)(C1-4alkyl), and —
S(O)n(alkyl),m is an integer independently selected at each occurrence from integers in range of 0-8; and
n is an integer independently selected at each occurrence from 0, 1, and 2. - View Dependent Claims (85, 86, 87, 88, 89, 90, 91)
R3 represents between 0 and 2 substituents, each of which is independently selected from C1-6alkyl, C1-6alkoxy, C1-6haloalkyl, C1-6haloalkoxy, mono- and di-(C1-6alkyl)amino, (amino)C0-6alkyl.
-
-
89. A compound or pharmaceutically acceptable salt thereof according to claim 84, wherein:
-
R4 is chosen from (C3-C7cycloalkyl)C0-C4alkyl, phenylC0-C4alkyl, pyridylC0-C4alkyl, pyrimidinylC0-C4alkyl, thienylC0-C4alkyl, imidazolylC0-C4alkyl, pyrrolylC0-C4alkyl, pyrazolylC0-C4alkyl, indolylC0-C4alkyl, indazolylC0-C4alkyl, benzocycloalkenylC0-C4alkyl, decahydronaphthylC0-C4alkyl, benzoisothiazolylC0-C4alkyl, tetrahydroquinolinylC0-C4alkyl and tetrahydronaphthylC0-C4alkyl, each of which is substituted with from 0 to 4 groups independently chosen from Rx, mono- and di-C1-C4alkylamino(C1-C4alkyl), mono- and di-C1-C4alkylamino(C1-C4alkoxy), (3- to 7-membered heterocycloalkyl)C0-C4alkyl, C2-C4alkanoyl and C2-C4alkanoyloxy; and
R5 is C1-C6alkyl, C2-C6alkenyl or (C3-C7carbocycle)C0-C4alkyl.
-
-
90. A compound or pharmaceutically acceptable salt thereof according to claim 84, wherein R4 and R5 are joined to form a saturated or partially saturated heterocycle containing 1 or 2 fused or spiro rings;
- wherein the heterocycle is substituted with from 0 to 4 substituents independently chosen from halogen, hydroxy, amino, cyano, —
COOH, —
CH2COOH, C1-6alkoxycarbonyl, —
CH2CO2—
C1-6alkyl, —
C(═
O)NH2, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, mono- and di-(C1-C6alkyl)amino, C1-C6alkoxy, C1-C2haloalkyl, C1-C2haloalkoxy, (C3-C7cycloalkyl)C0-C4alkyl, —
S(On)C1-C6alkyl, SO3H, and phenyl.
- wherein the heterocycle is substituted with from 0 to 4 substituents independently chosen from halogen, hydroxy, amino, cyano, —
-
91. A compound or pharmaceutically acceptable salt thereof according to claim 90, wherein R4 and R5 are joined to form a saturated 4- to 7-membered heterocyclic ring that is substituted with from 0 to 3 substituents independently chosen from halogen, hydroxy, amino, cyano, C1-C2alkyl, C1-C2alkoxy, trifluoromethyl, difluoromethyl, trifluoromethoxy difluoromethoxy, —
- COOH, —
CH2COOH, C1-2alkoxycarbonyl, and —
CH2CO2—
C1-2alkyl.
- COOH, —
-
92-1. A compound or salt thereof according to any one of claims 1, 2, or 84, wherein the compound exhibits an IC50 of 500 nM or less in a standard in vitro C5a receptor-mediated chemotaxis or calcium mobilization assay.
Specification