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Msg  10135 of 10313  at  8/11/2022 1:08:56 AM  by

JBWIN


Building IP: BMY Patent Application re "IMMUNOMODULATORS"

 
United States Patent Application20220251141
Kind CodeA1
WANG; Tao ; et al.August 11, 2022

IMMUNOMODULATORS

Abstract

In accordance with the present disclosure, macrocyclic compounds have been discovered that bind to PD-L1 and are capable of inhibiting the interaction of PD-L1 with PD-1 and CD80. These macrocyclic compounds exhibit in vitro immunomodulatory efficacy thus making them therapeutic candidates for the treatment of various diseases including cancer and infectious diseases.


Inventors:WANG; Tao; (Farmington, CT) ; SUN; Li-Qiang; (Glastonbury, CT) ; MENG; Zhaoxing; (Pennington, NJ) ; SCOLA; Paul; (Glastonbury, CT)
Applicant:
NameCityStateCountryType

Bristol-Myers Squibb Company

Princeton

NJ

US
Appl. No.:17/612915
Filed:May 21, 2020
PCT Filed:May 21, 2020
PCT NO:PCT/US2020/034053
371 Date:November 19, 2021

Related U.S. Patent Documents

Application NumberFiling DatePatent Number
62850622May 21, 2019

International Class:C07K 7/52 20060101 C07K007/52

Claims



1. A compound of formula (I) ##STR00098## or a pharmaceutically acceptable salt thereof, wherein: A is selected from a bond, ##STR00099## wherein: denotes the point of attachment to the carbonyl group and denotes the point of attachment to the nitrogen atom; z is 0, 1, or 2; w is 1 or 2; n is 0 or 1; m is 1 or 2; m' is 0 or 1; p is 0, 1, or 2; R.sup.x is hydrogen, amino, hydroxy, or methyl; R.sup.14 and R.sup.15 are independently hydrogen or methyl; and R.sup.z is hydrogen or --C(O)NHR.sup.16; wherein R.sup.16 is hydrogen, --CHR.sup.17C(O)NH.sub.2, --CHR.sup.17C(O)NHCHR.sup.18C(O)NH.sub.2, or --CHR.sup.17C(O)NHCHR.sup.18C(O)NHCH.sub.2C(O)NH.sub.2; wherein R.sup.17 is hydrogen or --CH.sub.2OH and wherein R.sup.18 is hydrogen or methyl; R.sup.v is hydrogen or a natural amino acid side chain; R.sup.c, R.sup.f, R.sup.h, R.sup.i, and R.sup.m are hydrogen; R.sup.n is hydrogen or methyl or, when p is 0, R.sup.v and R.sup.n, together with the atoms to which they are attached, can form a pyrrolidine ring; R.sup.a, R.sup.e, and R.sup.j are each independently hydrogen or methyl; R.sup.5 is --(CH.sub.2).sub.qNR.sup.50R.sup.51, a natural amino acid side chain, or an unnatural amino acid side chain; R.sup.9 is --(CH.sub.2).sub.q'NR.sup.50R.sup.51', a natural amino acid side chain, or an unnatural amino acid side chain; provided that at least one of R.sup.5 and R.sup.9 is other than a natural amino acid side chain or an unnatural amino acid side chain; q and q' are each independently 1 or 2; R.sup.50, R.sup.51, R.sup.50', and R.sup.51' are each independently hydrogen, C.sub.1-C.sub.13alkoxycarbonyl, C.sub.4-C.sub.13alkylcarbonyl, C.sub.1-C.sub.13alkylsulfanylcarbonyl, C.sub.1-C.sub.13haloalkoxycarbonyl, C.sub.1-C.sub.13haloalkylcarbonyl, --CN, --C(N--CN)C.sub.1-C.sub.13alkyl, --C(O)NR.sup.70R.sup.71, --C(S)NR.sup.90R.sup.91, or --SO.sub.2NR.sup.90R.sup.91; R.sup.70 and R.sup.71 are independently hydrogen, C.sub.1-C.sub.13alkoxy, C.sub.1-C.sub.13alkyl, C.sub.1-C.sub.13alkylcarbonyl, C.sub.3-C.sub.14cycloalkyl, or phenylC.sub.1-C.sub.3alkyl wherein the phenyl part of the phenylC.sub.1-C.sub.3alkyl is optionally substituted with one, two, or three groups wherein each group is independently C.sub.1-C.sub.3alkoxy, C.sub.1-C.sub.3alkyl, or C.sub.1-C.sub.3alkylcarbonyl, and wherein the phenyl part of the phenylC.sub.1-C.sub.3alkyl is optionally fused to a dioxolanyl ring; R.sup.90 and R.sup.91 are independently hydrogen or C.sub.1-C.sub.6alkyl; provided that when R.sup.5 is --(CH.sub.2).sub.qNR.sup.50R.sup.51 and R.sup.9 is an amino acid side chain or an unnatural amino acid side chain, at least one of R.sup.50 and R.sup.51 is other than hydrogen; provided that when R.sup.9 is --(CH.sub.2).sub.q'NR.sup.50'R.sup.51' and R.sup.5 is an amino acid side chain or an unnatural amino acid side chain, at least one of R.sup.50' and R.sup.51' is other than hydrogen; and provided that when R.sup.5 is --(CH.sub.2).sub.q'NR.sup.50'R.sup.51' and R.sup.9 is --(CH.sub.2).sub.q'NR.sup.50'R.sup.51'; at least one of R.sup.50, R.sup.51, R.sup.50' and R.sup.51' is other than hydrogen; R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.6, R.sup.7, R.sup.8, R.sup.10, R.sup.11, R.sup.12, and R.sup.13 are each independently a natural amino acid side chain or an unnatural amino acid side chain; or R.sup.2, R.sup.4, R.sup.6, R.sup.7, R.sup.8, R.sup.10, R.sup.11, R.sup.12, and R.sup.13 can each independently form a ring with the corresponding vicinal R group as described below; R.sup.b is methyl or R.sup.b and R.sup.2, together with the atoms to which they are attached, form an azetidine, pyrrolidine, morpholine, piperidine, piperazine, or tetrahydrothiazole ring; wherein each ring is optionally substituted with one to four groups wherein each group is independently amino, cyano, methyl, halo, or hydroxy; R.sup.d is hydrogen or methyl, or R.sup.d and R.sup.4, together with the atoms to which they are attached, can form an azetidine, pyrrolidine, morpholine, piperidine, piperazine, or tetrahydrothiazole ring; wherein each ring is optionally substituted with one to four groups wherein each group is independently amino, cyano, methyl, halo, hydroxy, or phenyl; R.sup.g is hydrogen or methyl, or R.sup.g and R.sup.7, together with the atoms to which they are attached, can form an azetidine, pyrrolidine, morpholine, piperidine, piperazine, or tetrahydrothiazole ring; wherein each ring is optionally substituted with one to four groups wherein each group is independently amino, benzyl optionally substituted with a halo group, benzyloxy, cyano, cyclohexyl, methyl, halo, hydroxy, isoquinolinyloxy optionally substituted with a methoxy group, quinolinyloxy optionally substituted with a halo group, or tetrazolyl; and wherein the pyrrolidine ring and the piperidine ring are optionally fused to a cyclohexyl, phenyl, or indole group; R.sup.k is hydrogen or methyl, or R.sup.k and R.sup.11, together with the atoms to which they are attached, can form an azetidine, pyrrolidine, morpholine, piperidine, piperazine, or tetrahydrothiazole ring; wherein each ring is optionally substituted with one to four groups wherein each group is independently amino, cyano, methyl, halo, and hydroxy; R.sup.L is methyl or R.sup.L and R.sup.12, together with the atoms to which they are attached, form an azetidine or pyrrolidine ring, wherein each ring is optionally substituted with one to four groups wherein each group is independently amino, cyano, methyl, halo, or hydroxy; provided that the compound of formula (I) contains at least one carbon on the backbone of the ring that has four substituents other than hydrogen and is not an alpha-methyl-substituted ring.

2. A compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein A is ##STR00100##

3. A compound of claim 2, or a pharmaceutically acceptable salt thereof, wherein: z is 0; w is 1; and R.sup.z is --C(O)NHR.sup.16.

4. A compound of claim 3, or a pharmaceutically acceptable salt thereof, wherein R.sup.16 is hydrogen or CHR.sup.17C(O)NH.sub.2, wherein R.sup.17 is hydrogen.

5. A compound of any one of claims 1-4, or a pharmaceutically acceptable salt thereof, wherein: R.sup.d is methyl, or R.sup.d and R.sup.4, together with the atoms to which they are attached, can form an azetidine, pyrrolidine, morpholine, piperidine, piperazine, or tetrahydrothiazole ring; wherein each ring is optionally substituted with one to four groups wherein each group is independently amino, cyano, methyl, halo, hydroxy, or phenyl; R.sup.g is methyl, or R.sup.g and R.sup.7, together with the atoms to which they are attached, can form an azetidine, pyrrolidine, morpholine, piperidine, piperazine, or tetrahydrothiazole ring; wherein each ring is optionally substituted with one to four groups wherein each group is independently amino, benzyl optionally substituted with a halo group, benzyloxy, cyano, cyclohexyl, methyl, halo, hydroxy, isoquinolinyloxy optionally substituted with a methoxy group, quinolinyloxy optionally substituted with a halo group, or tetrazolyl; and wherein the pyrrolidine ring and the piperidine ring are optionally fused to a cyclohexyl, phenyl, or indole group; and R.sup.k is methyl, or R.sup.k and R.sup.11, together with the atoms to which they are attached, can form an azetidine, pyrrolidine, morpholine, piperidine, piperazine, or tetrahydrothiazole ring; wherein each ring is optionally substituted with one to four groups wherein each group is independently amino, cyano, methyl, halo, and hydroxy.

6. A compound of any one of claims 1-4, or a pharmaceutically acceptable salt thereof, wherein: R.sup.d and R.sup.4, together with the atoms to which they are attached, form an azetidine, pyrrolidine, morpholine, piperidine, piperazine, or tetrahydrothiazole ring; wherein each ring is optionally substituted with one to four groups wherein each group is independently amino, cyano, methyl, halo, hydroxy, or phenyl; R.sup.g and R.sup.7, together with the atoms to which they are attached, can form an azetidine, pyrrolidine, morpholine, piperidine, piperazine, or tetrahydrothiazole ring; wherein each ring is optionally substituted with one to four groups wherein each group is independently amino, benzyl optionally substituted with a halo group, benzyloxy, cyano, cyclohexyl, methyl, halo, hydroxy, isoquinolinyloxy optionally substituted with a methoxy group, quinolinyloxy optionally substituted with a halo group, or tetrazolyl; and wherein the pyrrolidine ring and the piperidine ring are optionally fused to a cyclohexyl, phenyl, or indole group; and R.sup.k is methyl.

7. A compound of any one of claims 1-4, or a pharmaceutically acceptable salt thereof, wherein: R.sup.1 is biphenylC.sub.1-C.sub.3alkyl wherein the biphenyl is optionally substituted with a methyl group, diphenylmethyl, naphthylC.sub.1-C.sub.3alkyl, phenoxyC.sub.1-C.sub.3alkyl wherein the phenoxy part of the phenoxyC.sub.1-C.sub.3alkyl is optionally substituted with a C.sub.1-C.sub.3alkyl group, or phenylC.sub.1-C.sub.3alkyl wherein the phenyl part of the phenylC.sub.1-C.sub.3alkyl is optionally substituted with one, two, three, four, or five groups wherein each group is independently C.sub.1-C.sub.4alkoxy, C.sub.1-C.sub.4alkyl, C.sub.1-C.sub.3alkylsulfonylamino, amido, amino, aminoC.sub.1-C.sub.3alkyl, aminosulfonyl, carboxy, cyano, halo, haloC.sub.1-C.sub.3alkyl, hydroxy, --NC(NH.sub.2).sub.2, nitro, or --OP(O)(OH).sub.2; R.sup.2 is C.sub.1-C.sub.7alkyl, C.sub.2-C.sub.7alkenyl, C.sub.1-C.sub.3alkoxyC.sub.1-C.sub.3alkyl, or C.sub.1-C.sub.3alkylsulfanylC.sub.1-C.sub.3alkyl, or, R.sup.2 and R.sup.b, together with the atoms to which they are attached, form an azetidine, pyrrolidine, morpholine, piperidine, piperazine, or tetrahydrothiazole ring; wherein each ring is optionally substituted with one to four groups wherein each group is independently amino, cyano, methyl, halo, or hydroxyl; R.sup.3 is C.sub.1-C.sub.6alkoxycarbonylC.sub.1-C.sub.3alkyl, carboxyC.sub.1-C.sub.3alkyl, or NR.sup.tR.sup.ucarbonylC.sub.1-C.sub.3alkyl, wherein R.sup.t and R.sup.u are independently hydrogen, C.sub.1-C.sub.3alkyl, or triphenylmethyl; R.sup.4 and R.sup.d, together with the atoms to which they are attached, form an azetidine, pyrrolidine, morpholine, piperidine, piperazine, or tetrahydrothiazole ring; wherein each ring is optionally substituted with one to four groups wherein each group is independently amino, cyano, methyl, halo, hydroxy, or phenyl; R.sup.5 is --(CH.sub.2).sub.qNR.sup.50R.sup.51; R.sup.6 is C.sub.1-C.sub.7alkyl, C.sub.2-C.sub.7alkenyl, C.sub.1-C.sub.3alkoxyC.sub.1-C.sub.3alkyl, or C.sub.1-C.sub.3alkylsulfanylC.sub.1-C.sub.3alkyl; R.sup.7 and R.sup.g, together with the atoms to which they are attached, can form an azetidine, pyrrolidine, morpholine, piperidine, piperazine, or tetrahydrothiazole ring; wherein each ring is optionally substituted with one to four groups wherein each group is independently amino, benzyl optionally substituted with a halo group, benzyloxy, cyano, cyclohexyl, methyl, halo, hydroxy, isoquinolinyloxy optionally substituted with a methoxy group, quinolinyloxy optionally substituted with a halo group, or tetrazolyl; and wherein the pyrrolidine ring and the piperidine ring are optionally fused to a cyclohexyl, phenyl, or indole group; R.sup.8 and R.sup.10 are each independently azaindolylC.sub.1-C.sub.3alkyl, benzothiazolylC.sub.1-C.sub.3alkyl, benzothienylC.sub.1-C.sub.3alkyl, benzyloxyC.sub.1-C.sub.3alkyl, C.sub.3-C.sub.14cycloalkylC.sub.1-C.sub.3alkyl, furanylC.sub.1-C.sub.3alkyl, imidazolylC.sub.1-C.sub.3alkyl, pyridinylC.sub.1-C.sub.3alkyl, thiazolylC.sub.1-C.sub.3alkyl, thienylC.sub.1-C.sub.3alkyl, or indolylC.sub.1-C.sub.3alkyl, wherein the indolyl part of the indolylC.sub.1-C.sub.3alkyl is optionally substituted with one group which is C.sub.1-C.sub.6alkoxycarbonyl, C.sub.1-C.sub.6alkoxycarbonylC.sub.1-C.sub.3alkyl, C.sub.1-C.sub.3alkyl, carboxyC.sub.1-C.sub.3alkyl, halo, haloC.sub.1-C.sub.3alkoxycarbonyl, hydroxy, or phenyl, wherein the phenyl is further optionally substituted by one, two, or three groups wherein each group is independently C.sub.1-C.sub.3alkoxy, C.sub.1-C.sub.3alkyl, or halo; R.sup.9 is --(CH.sub.2).sub.qNR.sup.50'R.sup.51'; and R.sup.11, R.sup.12, and R.sup.13 are each independently C.sub.1-C.sub.7alkyl, C.sub.2-C.sub.7alkenyl, C.sub.1-C.sub.3alkoxyC.sub.1-C.sub.3alkyl, or C.sub.1-C.sub.3alkylsulfanylC.sub.1-C.sub.3alkyl.

8. A compound of claim 7, or a pharmaceutically acceptable salt thereof, wherein: R.sup.1 is phenylC.sub.1-C.sub.3alkyl wherein the phenyl part of the phenylC.sub.1-C.sub.3alkyl is optionally substituted with one, two, three, four, or five groups wherein each group is independently C.sub.1-C.sub.4alkoxy, C.sub.1-C.sub.4alkyl, amino, aminoC.sub.1-C.sub.3alkyl, carboxy, cyano, halo, haloC.sub.1-C.sub.3alkyl, hydroxy, or --OP(O)(OH).sub.2; R.sup.2 is C.sub.1-C.sub.7alkyl, or, R.sup.2 and R.sup.b, together with the atoms to which they are attached, form piperidine ring; R.sup.3 is NR.sup.tR.sup.ucarbonylC.sub.1-C.sub.3alkyl, wherein R.sup.t and R.sup.u are independently hydrogen or C.sub.1-C.sub.3alkyl; R.sup.4 and R.sup.d, together with the atoms to which they are attached, form a pyrrolidine, morpholine, piperidine, or piperazine ring, wherein each ring is optionally substituted with one to four groups wherein each group is independently amino, cyano, methyl, halo, or hydroxy; R.sup.5 is --(CH.sub.2).sub.qNR.sup.50R.sup.51; R.sup.6 is C.sub.1-C.sub.7alkyl; R.sup.7 and R.sup.g, together with the atoms to which they are attached, form a pyrrolidine, morpholine, piperidine, or piperazine ring, wherein each ring is optionally substituted with one to four groups wherein each group is independently amino, cyano, methyl, halo, or hydroxy; R.sup.8 and R.sup.10 are each independently azaindolylC.sub.1-C.sub.3alkyl or indolylC.sub.1-C.sub.3alkyl, wherein the indolyl part of the indolylC.sub.1-C.sub.3alkyl is optionally substituted with one group which is C.sub.1-C.sub.3alkoxycarbonylC.sub.1-C.sub.3alkyl, C.sub.1-C.sub.3alkyl, carboxyC.sub.1-C.sub.3alkyl, halo, or hydroxy; R.sup.9 is --(CH.sub.2).sub.q'NR.sup.50'R.sup.51'; and R.sup.11, R.sup.12, and R.sup.13 are each independently C.sub.1-C.sub.7alkyl.

9. A compound of any one of claims 1-4, or a pharmaceutically acceptable salt thereof, wherein: R.sup.5 is --(CH.sub.2).sub.qNR.sup.50R.sup.51; R.sup.9 is --(CH.sub.2).sub.q'NR.sup.50'R.sup.51'; and R.sup.50, R.sup.51, R.sup.50', and R.sup.51' are each independently hydrogen, C.sub.1-C.sub.13alkylsulfanylcarbonyl, C.sub.1-C.sub.13haloalkoxycarbonyl, --CN, --C(N--CN)C.sub.1-C.sub.13alkyl, --C(O)NR.sup.70R.sup.71, --C(S)NR.sup.90R.sup.91, or --SO.sub.2NR.sup.90R.sup.91; provided that when R.sup.50 and R.sup.51 are each hydrogen, at least one of R.sup.50' and R.sup.51' is other than hydrogen.

10. A compound of any one of claims 1-4, or a pharmaceutically acceptable salt thereof, wherein: R.sup.5 is --(CH.sub.2).sub.qNR.sup.50R.sup.51; R.sup.9 is --(CH.sub.2).sub.q'NR.sup.50'R.sup.51'; and R.sup.50, R.sup.51, R.sup.50', and R.sup.51' are each independently hydrogen, C.sub.1-C.sub.13alkoxycarbonyl, C.sub.4-C.sub.13alkylcarbonyl, or C.sub.1-C.sub.13haloalkylcarbonyl; provided that when R.sup.50 and R.sup.51 are each hydrogen, at least one of R.sup.50' and R.sup.51' is other than hydrogen.

11. A compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein: A is ##STR00101## z is 0; w is 1; R.sup.z is --C(O)NHR.sup.16; R.sup.16 is hydrogen or CHR.sup.17C(O)NH.sub.2, wherein R.sup.17 is hydrogen; R.sup.1 is phenylC.sub.1-C.sub.3alkyl wherein the phenyl part of the phenylC.sub.1-C.sub.3alkyl is optionally substituted with one, two, three, four, or five groups wherein each group is independently C.sub.1-C.sub.4alkoxy, C.sub.1-C.sub.4alkyl, amino, aminoC.sub.1-C.sub.3alkyl, carboxy, cyano, halo, haloC.sub.1-C.sub.3alkyl, hydroxy, or --OP(O)(OH).sub.2; R.sup.2 is C.sub.1-C.sub.7alkyl, or, R.sup.2 and R.sup.b, together with the atoms to which they are attached, form piperidine ring; R.sup.3 is NR.sup.tR.sup.ucarbonylC.sub.1-C.sub.3alkyl, wherein R.sup.t and R.sup.u are independently hydrogen or C.sub.1-C.sub.3alkyl; R.sup.4 and R.sup.d, together with the atoms to which they are attached, form a pyrrolidine, morpholine, piperidine, or piperazine ring, wherein each ring is optionally substituted with one to four groups wherein each group is independently amino, cyano, methyl, halo, or hydroxy; R.sup.5 is --(CH.sub.2).sub.qNR.sup.50R.sup.51; R.sup.6 is C.sub.1-C.sub.7alkyl; R.sup.7 and R.sup.g, together with the atoms to which they are attached, form a pyrrolidine, morpholine, piperidine, or piperazine ring, wherein each ring is optionally substituted with one to four groups wherein each group is independently amino, cyano, methyl, halo, or hydroxy; R.sup.8 and R.sup.10 are each independently azaindolylC.sub.1-C.sub.3alkyl or indolylC.sub.1-C.sub.3alkyl, wherein the indolyl part of the indolylC.sub.1-C.sub.3alkyl is optionally substituted with one group which is C.sub.1-C.sub.3alkoxycarbonylC.sub.1-C.sub.3alkyl, C.sub.1-C.sub.3alkyl, carboxyC.sub.1-C.sub.3alkyl, halo, or hydroxy; R.sup.9 is --(CH.sub.2).sub.q'NR.sup.50'R.sup.51'; and R.sup.11, R.sup.12, and R.sup.13 are each independently C.sub.1-C.sub.7alkyl.

12. A compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein: A is ##STR00102## z is 0; w is 1; R.sup.z is --C(O)NHR.sup.16; R.sup.16 is hydrogen or CHR.sup.17C(O)NH.sub.2, wherein R.sup.17 is hydrogen; R.sup.1 is phenylC.sub.1-C.sub.3alkyl wherein the phenyl part of the phenylC.sub.1-C.sub.3alkyl is optionally substituted with one, two, three, four, or five groups wherein each group is independently C.sub.1-C.sub.4alkoxy, C.sub.1-C.sub.4alkyl, amino, aminoC.sub.1-C.sub.3alkyl, carboxy, cyano, halo, haloC.sub.1-C.sub.3alkyl, hydroxy, or --OP(O)(OH).sub.2; R.sup.2 is C.sub.1-C.sub.7alkyl, or, R.sup.2 and R.sup.b, together with the atoms to which they are attached, form piperidine ring; R.sup.3 is NR.sup.tR.sup.ucarbonylC.sub.1-C.sub.3alkyl, wherein R.sup.t and R.sup.u are independently hydrogen or C.sub.1-C.sub.3alkyl; R.sup.4 and R.sup.d, together with the atoms to which they are attached, form a pyrrolidine, morpholine, piperidine, or piperazine ring, wherein each ring is optionally substituted with one to four groups wherein each group is independently amino, cyano, methyl, halo, or hydroxy; R.sup.5 is --(CH.sub.2).sub.qNR.sup.50R.sup.51; wherein R.sup.50 and R.sup.51 are each independently hydrogen, C.sub.1-C.sub.13alkylsulfanylcarbonyl, C.sub.1-C.sub.13haloalkoxycarbonyl, --CN, --C(N--CN)C.sub.1-C.sub.13alkyl, --C(O)NR.sup.70R.sup.71, --C(S)NR.sup.90R.sup.91, or --SO.sub.2NR.sup.90R.sup.91; R.sup.6 is C.sub.1-C.sub.7alkyl; R.sup.7 and R.sup.g, together with the atoms to which they are attached, form a pyrrolidine, morpholine, piperidine, or piperazine ring, wherein each ring is optionally substituted with one to four groups wherein each group is independently amino, cyano, methyl, halo, or hydroxy; R.sup.8 and R.sup.10 are each independently azaindolylC.sub.1-C.sub.3alkyl or indolylC.sub.1-C.sub.3alkyl, wherein the indolyl part of the indolylC.sub.1-C.sub.3alkyl is optionally substituted with one group which is C.sub.1-C.sub.3alkoxycarbonylC.sub.1-C.sub.3alkyl, C.sub.1-C.sub.3alkyl, carboxyC.sub.1-C.sub.3alkyl, halo, or hydroxy; R.sup.9 is --(CH.sub.2).sub.q'NR.sup.50'R.sup.51'; wherein R.sup.50' and R.sup.51' are each independently hydrogen, C.sub.1-C.sub.13alkylsulfanylcarbonyl, C.sub.1-C.sub.13haloalkoxycarbonyl, --CN, --C(N--CN)C.sub.1-C.sub.13alkyl, --C(O)NR.sup.70R.sup.71, --C(S)NR.sup.90R.sup.91, or --SO.sub.2NR.sup.90R.sup.91; provided that when R.sup.50 and R.sup.51 are each hydrogen, at least one of R.sup.50' and R.sup.51' is other than hydrogen; and R.sup.11, R.sup.12, and R.sup.13 are each independently C.sub.1-C.sub.7alkyl.

13. A compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein: A is ##STR00103## z is 0; w is 1; R.sup.z is --C(O)NHR.sup.16; R.sup.16 is CHR.sup.17C(O)NH.sub.2, wherein R.sup.17 is hydrogen; R.sup.1 is phenylC.sub.1-C.sub.3alkyl wherein the phenyl part of the phenylC.sub.1-C.sub.3alkyl is optionally substituted with one, two, three, four, or five groups wherein each group is independently C.sub.1-C.sub.4alkoxy, C.sub.1-C.sub.4alkyl, amino, aminoC.sub.1-C.sub.3alkyl, carboxy, cyano, halo, haloC.sub.1-C.sub.3alkyl, hydroxy, or --OP(O)(OH).sub.2; R.sup.2 is C.sub.1-C.sub.7alkyl, or, R.sup.2 and R.sup.b, together with the atoms to which they are attached, form piperidine ring; R.sup.3 is NR.sup.tR.sup.ucarbonylC.sub.1-C.sub.3alkyl, wherein R.sup.t and R.sup.u are independently hydrogen or C.sub.1-C.sub.3alkyl; R.sup.4 and R.sup.d, together with the atoms to which they are attached, form a pyrrolidine, morpholine, piperidine, or piperazine ring, wherein each ring is optionally substituted with one to four groups wherein each group is independently amino, cyano, methyl, halo, or hydroxy; R.sup.5 is --(CH.sub.2).sub.qNR.sup.50R.sup.51; wherein R.sup.50 and R.sup.51 are each independently hydrogen, C.sub.1-C.sub.13alkoxycarbonyl, C.sub.4-C.sub.13alkylcarbonyl, or C.sub.1-C.sub.13haloalkylcarbonyl; R.sup.6 is C.sub.1-C.sub.7alkyl; R.sup.7 and R.sup.g, together with the atoms to which they are attached, form a pyrrolidine, morpholine, piperidine, or piperazine ring, wherein each ring is optionally substituted with one to four groups wherein each group is independently amino, cyano, methyl, halo, or hydroxy; R.sup.8 and R.sup.10 are each independently azaindolylC.sub.1-C.sub.3alkyl or indolylC.sub.1-C.sub.3alkyl, wherein the indolyl part of the indolylC.sub.1-C.sub.3alkyl is optionally substituted with one group which is C.sub.1-C.sub.3alkoxycarbonylC.sub.1-C.sub.3alkyl, C.sub.1-C.sub.3alkyl, carboxyC.sub.1-C.sub.3alkyl, halo, or hydroxy; R.sup.9 is --(CH.sub.2).sub.qNR.sup.50'R.sup.51'; wherein R.sup.50' and R.sup.51' are each independently hydrogen, C.sub.1-C.sub.13alkoxycarbonyl, C.sub.4-C.sub.13alkylcarbonyl, or C.sub.1-C.sub.13haloalkylcarbonyl; provided that when R.sup.50 and R.sup.51 are each hydrogen, at least one of R.sup.50' and R.sup.51' is other than hydrogen; and R.sup.11, R.sup.12, and R.sup.13 are each independently C.sub.1-C.sub.7alkyl.

14. A compound of formula (II) ##STR00104## or a pharmaceutically acceptable salt thereof, wherein: A is selected from a bond, ##STR00105## and; wherein: denotes the point of attachment to the carbonyl group and denotes the point of attachment to the nitrogen atom; n is 0 or 1; m is 1 or 2; R.sup.14 and R.sup.15 are independently hydrogen or methyl; and R.sup.16 is hydrogen, --CHR.sup.17C(O)NH.sub.2, --CHR.sup.17C(O)NHCHR.sup.18C(O)NH.sub.2, or --CHR.sup.17C(O)NHCHR.sup.18C(O)NHCH.sub.2C(O)NH.sub.2; wherein R.sup.17 is hydrogen or --CH.sub.2OH and wherein R.sup.18 is hydrogen or methyl; R.sup.c, R.sup.f, R.sup.h, R.sup.i, and R.sup.m are hydrogen; R.sup.n is methyl; R.sup.a and R.sup.j, are each independently hydrogen or methyl; q and q' are each independently 1 or 2; R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7, R.sup.8, R.sup.9, R.sup.10, R.sup.11, R.sup.12, and R.sup.13 are each independently a natural amino acid side chain or an unnatural amino acid side chain; or form a ring with the corresponding vicinal R group as described below; R.sup.b is methyl or R.sup.b and R.sup.2, together with the atoms to which they are attached, form an azetidine, pyrrolidine, morpholine, piperidine, piperazine, or tetrahydrothiazole ring; wherein each ring is optionally substituted with one to four groups wherein each group is independently amino, cyano, methyl, halo, or hydroxy; R.sup.d is hydrogen or methyl, or R.sup.d and R.sup.4, together with the atoms to which they are attached, can form an azetidine, pyrrolidine, morpholine, piperidine, piperazine, or tetrahydrothiazole ring; wherein each ring is optionally substituted with one to four groups wherein each group is independently amino, cyano, methyl, halo, hydroxy, or phenyl; R.sup.k is hydrogen or methyl, or R.sup.k and R.sup.11, together with the atoms to which they are attached, can form an azetidine, pyrrolidine, morpholine, piperidine, piperazine, or tetrahydrothiazole ring; wherein each ring is optionally substituted with one to four groups wherein each group is independently amino, cyano, methyl, halo, and hydroxy; R.sup.e is hydrogen or methyl, or R.sup.e and R.sup.5, together with the atoms to which they are attached, can form an azetidine, pyrrolidine, morpholine, piperidine, piperazine, or tetrahydrothiazole ring; wherein each ring is optionally substituted with one to four groups wherein each group is independently amino, benzyl optionally substituted with a halo group, benzyloxy, cyano, cyclohexyl, methyl, halo, hydroxy, isoquinolinyloxy optionally substituted with a methoxy group, quinolinyloxy optionally substituted with a halo group, or tetrazolyl; and wherein the pyrrolidine ring and the piperidine ring are optionally fused to a cyclohexyl, phenyl, or indole group; R.sup.k is hydrogen or methyl, or R.sup.k and R.sup.11, together with the atoms to which they are attached, can form an azetidine, pyrrolidine, morpholine, piperidine, piperazine, or tetrahydrothiazole ring; wherein each ring is optionally substituted with one to four groups wherein each group is independently amino, cyano, methyl, halo, and hydroxy; R.sup.L is methyl or R.sup.L and R.sup.12, together with the atoms to which they are attached, form an azetidine or pyrrolidine ring, wherein each ring is optionally substituted with one to four groups wherein each group is independently amino, cyano, methyl, halo, or hydroxy; provided that the compound of formula (I) contains at least one carbon on the backbone of the ring that has four substituents other than hydrogen and is not an alpha-methyl-substituted ring.

15. A method of enhancing, stimulating, and/or increasing an immune response in a subject in need thereof, wherein the method comprises administering to the subject a therapeutically effective amount of a compound of any one of claims 1-14, or a pharmaceutically acceptable salt thereof.

16. A method of blocking the interaction of PD-L1 with PD-1 and/or CD80 in a subject, wherein the method comprises administering to the subject a therapeutically effective amount of a compound of any one of claims 1-14 or a pharmaceutically acceptable salt thereof.
Description



CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This PCT application claims the priority benefit of U.S. Provisional Application No. 62/850,622, filed May 21, 2019, which is incorporated herein by reference in its entirety.

REFERENCE TO SEQUENCE LISTING SUBMITTED ELECTRONICALLY

[0002] The content of the electronically submitted sequence listing in ASCII text file (Name 3338_149PC01_SL_ST25; Size: 5736 bytes; and Date of Creation: May 20, 2020) filed with the application is incorporated herein by reference in its entirety.

FIELD

[0003] The present disclosure provides macrocyclic compounds that bind to PD-L1 and are capable of inhibiting the interaction of PD-L1 with PD-1 and CD80. These macrocyclic compounds exhibit in vitro immunomodulatory efficacy thus making them therapeutic candidates for the treatment of various diseases including cancer and infectious diseases.

BACKGROUND

[0004] The protein Programmed Death 1 (PD-1) is an inhibitory member of the CD28 family of receptors, that also includes CD28, CTLA-4, ICOS and BTLA. PD-1 is expressed on activated B cells, T cells, and myeloid cells (Agata et al., supra; Okazaki et al., Curr. Opin. Immunol., 14:779-782 (2002); Bennett et al., J. Immunol., 170:711-718 (2003)).

[0005] The PD-1 protein is a 55 kDa type I transmembrane protein that is part of the Ig gene superfamily (Agata et al., Int. Immunol., 8:765-772 (1996)). PD-1 contains a membrane proximal immunoreceptor tyrosine inhibitory motif (ITIM) and a membrane distal tyrosine-based switch motif (ITSM) (Thomas, M. L., J. Exp. Med., 181:1953-1956 (1995); Vivier, E. et al., Immunol. Today, 18:286-291 (1997)). Although structurally similar to CTLA-4, PD-1 lacks the MYPPY motif that is critical for CD80 CD86 (B7-2) binding. Two ligands for PD-1 have been identified, PD-L1 (B7-H1) and PD-L2 (b7-DC). The activation of T cells expressing PD-1 has been shown to be downregulated upon interaction with cells expressing PD-L1 or PD-L2 (Freeman et al., J. Exp. Med., 192:1027-1034 (2000); Latchman et al., Nat. Immunol., 2:261-268 (2001); Carter et al., Eur. J. Immunol., 32:634-643 (2002)). Both PD-L1 and PD-L2 are B7 protein family members that bind to PD-1, but do not bind to other CD28 family members. The PD-L1 ligand is abundant in a variety of human cancers (Dong et al., Nat. Med., 8:787-789 (2002)). The interaction between PD-1 and PD-L1 results in a decrease in tumor infiltrating lymphocytes, a decrease in T-cell receptor mediated proliferation, and immune evasion by the cancerous cells (Dong et al., J. Mol. Med., 81:281-287 (2003); Blank et al., Cancer Immunol. Immunother., 54:307-314 (2005); Konishi et al., Clin. Cancer Res., 10:5094-5100 (2004)). Immune suppression can be reversed by inhibiting the local interaction of PD-1 with PD-L1, and the effect is additive when the interaction of PD-1 with PD-L2 is blocked as well (Iwai et al., Proc. Natl. Acad. Sci. USA, 99:12293-12297 (2002); Brown et al., J. Immunol., 170:1257-1266 (2003)).

[0006] PD-L1 has also been shown to interact with CD80 (Butte M J et al, Immunity; 27:111-122 (2007)). The interaction of PD-L1/CD80 on expressing immune cells has been shown to be an inhibitory one. Blockade of this interaction has been shown to abrogate this inhibitory interaction (Paterson A M, et al., J Immunol., 187:1097-1105 (2011); Yang J, et al. J Immunol. August 1; 187(3):1113-9 (2011)).

[0007] When PD-1 expressing T cells contact cells expressing its ligands, functional activities in response to antigenic stimuli, including proliferation, cytokine secretion, and cytotoxicity, are reduced. PD-1/PD-L1 or PD-L2 interactions down regulate immune responses during resolution of an infection or tumor, or during the development of self tolerance (Keir, M. E. et al., Annu. Rev. Immunol., 26: Epub (2008)). Chronic antigen stimulation, such as that which occurs during tumor disease or chronic infections, results in T cells that express elevated levels of PD-1 and are dysfunctional with respect to activity towards the chronic antigen (reviewed in Kim et al., Curr. Opin. Imm. (2010)). This is termed "T cell exhaustion". B cells also display PD-1/PD-ligand suppression and "exhaustion".

[0008] Blockade of PD-1/PD-L1 ligation using antibodies to PD-L1 has been shown to restore and augment T cell activation in many systems. Patients with advanced cancer benefit from therapy with a monoclonal antibody to PD-L1 (Brahmer et al., New Engl. J. Med. (2012)). Preclinical animal models of tumors and chronic infections have shown that blockade of the PD-1/PD-L1 pathway by monoclonal antibodies can enhance an immune response and result in tumor rejection or control of infection. Antitumor immunotherapy via PD-1/PD-L1 blockade can augment therapeutic immune response to a number of histologically distinct tumors (Dong, H. et al., "B7-H1 pathway and its role in the evasion of tumor immunity", J. Mol. Med., 81(5):281-287 (2003); Dong, H. et al., "Tumor-associated B7-H1 promotes T-cell apoptosis: a potential mechanism of immune evasion", Nat. Med., 8(8):793-800 (2002)).

[0009] Interference with the PD-1/PD-L1 interaction causes enhanced T cell activity in systems with chronic infection. Blockade of PD-L1 caused improved viral clearance and restored immunity in mice with chromoic lymphocytic chorio meningitis virus infection (Barber, D. L. et al., "Restoring function in exhausted CD8 T cells during chronic viral infection", Nature, 439(7077):682-687 (2006)). Humanized mice infected with HIV-1 show enhanced protection against viremia and viral depletion of CD4+ T cells (Palmer et al., J. Immunol. (2013)). Blockade of PD-1/PD-L1 through monoclonal antibodies to PD-L1 can restore in vitro antigen-specific functionality to T cells from HIV patients (Day, Nature (2006); Petrovas, J. Exp. Med. (2006); Trautman, Nature Med. (2006); D'Souza, J. Immunol. (2007); Zhang, Blood (2007); Kaufmann, Nature Imm. (2007); Kasu, J. Immunol. (2010); Porichis, Blood (2011)), HCV patients (Golden-Mason, J. Virol. (2007); Jeung, J. Leuk. Biol. (2007); Urbani, J. Hepatol. (2008); Nakamoto, PLoS Path. (2009); Nakamoto, Gastroenterology (2008)) and HBV patients (Boni, J. Virol. (2007); Fisicaro, Gastro. (2010); Fisicaro et al., Gastroenterology (2012); Boni et al., Gastro. (2012); Penna et al., J. Hep. (2012); Raziorrough, Hepatology (2009); Liang, World J. Gastro. (2010); Zhang, Gastro. (2008)).

[0010] Blockade of the PD-L1/CD80 interaction has also been shown to stimulate immunity (Yang J., et al., J Immunol. August 1; 187(3):1113-9 (2011)). Immune stimulation resulting from blockade of the PD-L1/CD80 interaction has been shown to be enhanced through combination with blockade of further PD-1/PD-L1 or PD-1/PD-L2 interactions.

[0011] Alterations in immune cell phenotypes are hypothesized to be an important factor in septic shock (Hotchkiss, et al., Nat Rev Immunol (2013)). These include increased levels of PD-1 and PD-L1 (Guignant, et al, Crit. Care (2011)). Cells from septic shock patients with increased levels of PD-1 and PD-L1 exhibit an increased level of T cell apoptosis. Antibodies directed to PD-L1, can reduce the level of immune cell apoptosis (Zhang et al, Crit. Care (2011)). Furthermore, mice lacking PD-1 expression are more resistant to septic shock symptoms than wildtype mice. Yang J., et al.. J Immunol. August 1; 187(3):1113-9 (2011)). Studies have revealed that blockade of the interactions of PD-L1 using antibodies can suppress inappropriate immune responses and ameliorate disease signs.

[0012] In addition to enhancing immunologic responses to chronic antigens, blockade of the PD-1/PD-L1 pathway has also been shown to enhance responses to vaccination, including therapeutic vaccination in the context of chronic infection (Ha, S. J. et al., "Enhancing therapeutic vaccination by blocking PD-1-mediated inhibitory signals during chronic infection", J. Exp. Med., 205(3):543-555 (2008); Finnefrock, A. C. et al., "PD-1 blockade in rhesus macaques: impact on chronic infection and prophylactic vaccination", J. Immunol., 182(2):980-987 (2009); Song, M.-Y. et al., "Enhancement of vaccine-induced primary and memory CD8+t-cell responses by soluble PD-1", J. Immunother., 34(3):297-306 (2011)).

[0013] The PD-1 pathway is a key inhibitory molecule in T cell exhaustion that arises from chronic antigen stimulation during chronic infections and tumor disease. Blockade of the PD-1/PD-L1 interaction through targeting the PD-L1 protein has been shown to restore antigen-specific T cell immune functions in vitro and in vivo, including enhanced responses to vaccination in the setting of tumor or chronic infection. Accordingly, agents that block the interaction of PD-L1 with either PD-1 or CD80 are desired.

SUMMARY

[0014] The present disclosure provides macrocyclic compounds which inhibit the PD-1/PD-L1 and CD80/PD-L1 protein/protein interaction, and are thus useful for the amelioration of various diseases, including cancer and infectious diseases.

[0015] In a first aspect the present disclosure provides a compound of formula (I)

##STR00001##

or a pharmaceutically acceptable salt thereof, wherein:

[0016] A is selected from a bond,

##STR00002##

wherein: [0017] denotes the point of attachment to the carbonyl group and denotes the point of attachment to the nitrogen atom; [0018] z is 0, 1, or 2; [0019] w is 1 or 2; [0020] n is 0 or 1; [0021] m is 1 or 2; [0022] m' is 0 or 1; [0023] p is 0, 1, or 2; [0024] R.sup.x is hydrogen, amino, hydroxy, or methyl; [0025] R.sup.14 and R.sup.15 are independently hydrogen or methyl; and [0026] R.sup.z is hydrogen or --C(O)NHR.sup.16; wherein R.sup.16 is hydrogen, --CHR.sup.17C(O)NH.sub.2, --CHR.sup.17C(O)NHCHR.sup.18C(O)NH.sub.2, or --CHR.sup.17C(O)NHCHR.sup.18C(O)NHCH.sub.2C(O)NH.sub.2; wherein R.sup.17 is hydrogen or --CH.sub.2OH and wherein R.sup.18 is hydrogen or methyl; [0027] R.sup.v is hydrogen or a natural amino acid side chain; [0028] R.sup.c, R.sup.f, R.sup.h, R.sup.i, and R.sup.m are hydrogen; [0029] R.sup.n is hydrogen or methyl or, when p is 0, R.sup.v and R.sup.n, together with the atoms to which they are attached, can form a pyrrolidine ring; [0030] R.sup.a, R.sup.e, and R.sup.j are each independently hydrogen or methyl; [0031] R.sup.5 is --(CH.sub.2).sub.qNR.sup.50R.sup.51, a natural amino acid side chain, or an unnatural amino acid side chain; [0032] R.sup.9 is --(CH.sub.2).sub.q'NR.sup.50'R.sup.51', a natural amino acid side chain, or an unnatural amino acid side chain; [0033] provided that at least one of R.sup.5 and R.sup.9 is other than a natural amino acid side chain or an unnatural amino acid side chain; [0034] q and q' are each independently 1 or 2; [0035] R.sup.50, R.sup.51, R.sup.50', and R.sup.51' are each independently hydrogen, C.sub.1-C.sub.13alkoxycarbonyl, C.sub.4-C.sub.13alkylcarbonyl, C.sub.1-C.sub.13alkylsulfanylcarbonyl, C.sub.1-C.sub.13haloalkoxycarbonyl, C.sub.1-C.sub.13haloalkylcarbonyl, --CN, --C(N--CN)C.sub.1-C.sub.13alkyl, --C(O)NR.sup.70R.sup.71, --C(S)NR.sup.90R91, or --SO.sub.2NR.sup.90R.sup.91; [0036] R.sup.70 and R.sup.71 are independently hydrogen, C.sub.1-C.sub.13alkoxy, C.sub.1-C.sub.13alkyl, C.sub.1-C.sub.13alkylcarbonyl, C3-C.sub.14cycloalkyl, or phenylC.sub.1-C.sub.3alkyl wherein the phenyl part of the phenylC.sub.1-C.sub.3alkyl is optionally substituted with one, two, or three groups wherein each group is independently C.sub.1-C.sub.3alkoxy, C.sub.1-C.sub.3alkyl, or C.sub.1-C.sub.3alkylcarbonyl, and wherein the phenyl part of the phenylC.sub.1-C.sub.3alkyl is optionally fused to a dioxolanyl ring; [0037] R.sup.90 and R.sup.91 are independently hydrogen or C.sub.1-C.sub.6alkyl; [0038] provided that when R.sup.5 is --(CH.sub.2)qNR.sup.50R.sup.51 and R.sup.9 is an amino acid side chain or an unnatural amino acid side chain, at least one of R.sup.50 and R.sup.51 is other than hydrogen; [0039] provided that when R.sup.9 is --(CH.sub.2).sub.q'NR.sup.50'R.sup.51' and R.sup.5 is an amino acid side chain or an unnatural amino acid side chain, at least one of R.sup.50' and R.sup.51' is other than hydrogen; and [0040] provided that when R.sup.5 is --(CH.sub.2).sub.q'NR.sup.50'R.sup.51' and R.sup.9 is --(CH.sub.2).sub.q'NR.sup.50'R.sup.51'; at least one of R.sup.50, R.sup.51, R.sup.50' and R.sup.51' is other than hydrogen;

[0041] R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.6, R.sup.7, R.sup.8, R.sup.10, R.sup.11, R.sup.12, and R.sup.13 are each independently a natural amino acid side chain or an unnatural amino acid side chain; or

[0042] R.sup.2, R.sup.4, R.sup.6, R.sup.7, R.sup.8, R.sup.10, R.sup.11, R.sup.12, and R.sup.13 can each independently form a ring with the corresponding vicinal R group as described below;

[0043] R.sup.b is methyl or R.sup.b and R.sup.2, together with the atoms to which they are attached, form an azetidine, pyrrolidine, morpholine, piperidine, piperazine, or tetrahydrothiazole ring; wherein each ring is optionally substituted with one to four groups wherein each group is independently amino, cyano, methyl, halo, or hydroxy;

[0044] R.sup.d is hydrogen or methyl, or R.sup.d and R.sup.4, together with the atoms to which they are attached, can form an azetidine, pyrrolidine, morpholine, piperidine, piperazine, or tetrahydrothiazole ring; wherein each ring is optionally substituted with one to four groups wherein each group is independently amino, cyano, methyl, halo, hydroxy, or phenyl;

[0045] R.sup.g is hydrogen or methyl, or R.sup.g and R.sup.7, together with the atoms to which they are attached, can form an azetidine, pyrrolidine, morpholine, piperidine, piperazine, or tetrahydrothiazole ring; wherein each ring is optionally substituted with one to four groups wherein each group is independently amino, benzyl optionally substituted with a halo group, benzyloxy, cyano, cyclohexyl, methyl, halo, hydroxy, isoquinolinyloxy optionally substituted with a methoxy group, quinolinyloxy optionally substituted with a halo group, or tetrazolyl; and wherein the pyrrolidine ring and the piperidine ring are optionally fused to a cyclohexyl, phenyl, or indole group;

[0046] R.sup.k is hydrogen or methyl, or R.sup.k and R.sup.11, together with the atoms to which they are attached, can form an azetidine, pyrrolidine, morpholine, piperidine, piperazine, or tetrahydrothiazole ring; wherein each ring is optionally substituted with one to four groups wherein each group is independently amino, cyano, methyl, halo, and hydroxy; and

[0047] R.sup.L is methyl or R.sup.L and R.sup.12, together with the atoms to which they are attached, form an azetidine or pyrrolidine ring, wherein each ring is optionally substituted with one to four groups wherein each group is independently amino, cyano, methyl, halo, or hydroxy;

[0048] provided that the compound of formula (I) contains at least one carbon on the backbone of the ring that has four substituents other than hydrogen and is not an alpha-methyl-substituted ring.

[0049] In a first embodiment of the first aspect, the present disclosure provides a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein A is

##STR00003##

[0050] In a second embodiment of the first aspect, z is 0; w is 1; and R.sup.z is --C(O)NHR.sup.16. In a third embodiment of the first aspect, R.sup.16 is hydrogen or CHR.sup.17C(O)NH.sub.2, wherein R.sup.17 is hydrogen.

[0051] In a fourth embodiment of the first aspect, the present disclosure provides a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein:

[0052] R.sup.d is methyl, or R.sup.d and R.sup.4, together with the atoms to which they are attached, can form an azetidine, pyrrolidine, morpholine, piperidine, piperazine, or tetrahydrothiazole ring; wherein each ring is optionally substituted with one to four groups wherein each group is independently amino, cyano, methyl, halo, hydroxy, or phenyl;

[0053] R.sup.g is methyl, or R.sup.g and R.sup.7, together with the atoms to which they are attached, can form an azetidine, pyrrolidine, morpholine, piperidine, piperazine, or tetrahydrothiazole ring; wherein each ring is optionally substituted with one to four groups wherein each group is independently amino, benzyl optionally substituted with a halo group, benzyloxy, cyano, cyclohexyl, methyl, halo, hydroxy, isoquinolinyloxy optionally substituted with a methoxy group, quinolinyloxy optionally substituted with a halo group, or tetrazolyl; and wherein the pyrrolidine ring and the piperidine ring are optionally fused to a cyclohexyl, phenyl, or indole group; and

[0054] R.sup.k is methyl, or R.sup.k and R.sup.11, together with the atoms to which they are attached, can form an azetidine, pyrrolidine, morpholine, piperidine, piperazine, or tetrahydrothiazole ring; wherein each ring is optionally substituted with one to four groups wherein each group is independently amino, cyano, methyl, halo, and hydroxy.

[0055] In a fifth embodiment of the first aspect, the present disclosure provides a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein:

[0056] R.sup.d and R.sup.4, together with the atoms to which they are attached, form an azetidine, pyrrolidine, morpholine, piperidine, piperazine, or tetrahydrothiazole ring; wherein each ring is optionally substituted with one to four groups wherein each group is independently amino, cyano, methyl, halo, hydroxy, or phenyl;

[0057] R.sup.g and R.sup.7, together with the atoms to which they are attached, can form an azetidine, pyrrolidine, morpholine, piperidine, piperazine, or tetrahydrothiazole ring; wherein each ring is optionally substituted with one to four groups wherein each group is independently amino, benzyl optionally substituted with a halo group, benzyloxy, cyano, cyclohexyl, methyl, halo, hydroxy, isoquinolinyloxy optionally substituted with a methoxy group, quinolinyloxy optionally substituted with a halo group, or tetrazolyl; and wherein the pyrrolidine ring and the piperidine ring are optionally fused to a cyclohexyl, phenyl, or indole group; and

[0058] R.sup.k is methyl.

[0059] In a sixth embodiment of the first aspect, the present disclosure provides a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein:

[0060] R.sup.1 is biphenylC.sub.1-C.sub.3alkyl wherein the biphenyl is optionally substituted with a methyl group, diphenylmethyl, naphthylC.sub.1-C.sub.3alkyl, phenoxyC.sub.1-C.sub.3alkyl wherein the phenoxy part of the phenoxyC.sub.1-C.sub.3alkyl is optionally substituted with a C.sub.1-C.sub.3alkyl group, or phenylC.sub.1-C.sub.3alkyl wherein the phenyl part of the phenylC.sub.1-C.sub.3alkyl is optionally substituted with one, two, three, four, or five groups wherein each group is independently C.sub.1-C.sub.4alkoxy, C.sub.1-C.sub.4alkyl, C.sub.1-C.sub.3alkylsulfonylamino, amido, amino, aminoC.sub.1-C.sub.3alkyl, aminosulfonyl, carboxy, cyano, halo, haloC.sub.1-C.sub.3alkyl, hydroxy, --NC(NH.sub.2).sub.2, nitro, or --OP(O)(OH).sub.2;

[0061] R.sup.2 is C.sub.1-C.sub.7alkyl, C.sub.2-C.sub.7alkenyl, C.sub.1-C.sub.3alkoxyC.sub.1-C.sub.3alkyl, or C.sub.1-C.sub.3alkylsulfanylC.sub.1-C.sub.3alkyl, or, R.sup.2 and R.sup.b, together with the atoms to which they are attached, form an azetidine, pyrrolidine, morpholine, piperidine, piperazine, or tetrahydrothiazole ring; wherein each ring is optionally substituted with one to four groups wherein each group is independently amino, cyano, methyl, halo, or hydroxyl;

[0062] R.sup.3 is C.sub.1-C.sub.6alkoxycarbonylC.sub.1-C.sub.3alkyl, carboxyC.sub.1-C.sub.3alkyl, or NR.sup.tR.sup.ucarbonylC.sub.1-C.sub.3alkyl, wherein R.sup.t and R.sup.u are independently hydrogen, C.sub.1-C.sub.3alkyl, or triphenylmethyl;

[0063] R.sup.4 and R.sup.d, together with the atoms to which they are attached, form an azetidine, pyrrolidine, morpholine, piperidine, piperazine, or tetrahydrothiazole ring; wherein each ring is optionally substituted with one to four groups wherein each group is independently amino, cyano, methyl, halo, hydroxy, or phenyl;

[0064] R.sup.5 is --(CH.sub.2).sub.qNR.sup.50R.sup.51;

[0065] R.sup.6 is C.sub.1-C.sub.7alkyl, C.sub.2-C.sub.7alkenyl, C.sub.1-C.sub.3alkoxyC.sub.1-C.sub.3alkyl, or C.sub.1-C.sub.3alkylsulfanylC.sub.1-C.sub.3alkyl;

[0066] R.sup.7 and R.sup.g, together with the atoms to which they are attached, can form an azetidine, pyrrolidine, morpholine, piperidine, piperazine, or tetrahydrothiazole ring; wherein each ring is optionally substituted with one to four groups wherein each group is independently amino, benzyl optionally substituted with a halo group, benzyloxy, cyano, cyclohexyl, methyl, halo, hydroxy, isoquinolinyloxy optionally substituted with a methoxy group, quinolinyloxy optionally substituted with a halo group, or tetrazolyl; and wherein the pyrrolidine ring and the piperidine ring are optionally fused to a cyclohexyl, phenyl, or indole group;

[0067] R.sup.8 and R.sup.10 are each independently azaindolylC.sub.1-C.sub.3alkyl, benzothiazolylC.sub.1-C.sub.3alkyl, benzothienylC.sub.1-C.sub.3alkyl, benzyloxyC.sub.1-C.sub.3alkyl, C.sub.3-C.sub.14cycloalkylC.sub.1-C.sub.3alkyl, furanylC.sub.1-C.sub.3alkyl, imidazolylC.sub.1-C.sub.3alkyl, pyridinylC.sub.1-C.sub.3alkyl, thiazolylC.sub.1-C.sub.3alkyl, thienylC.sub.1-C.sub.3alkyl, or indolylC.sub.1-C.sub.3alkyl, wherein the indolyl part of the indolylC.sub.1-C.sub.3alkyl is optionally substituted with one group which is C.sub.1-C.sub.6alkoxycarbonyl, C.sub.1-C.sub.6alkoxycarbonylC.sub.1-C.sub.3alkyl, C.sub.1-C.sub.3alkyl, carboxyC.sub.1-C.sub.3alkyl, halo, haloC.sub.1-C.sub.3alkoxycarbonyl, hydroxy, or phenyl, wherein the phenyl is further optionally substituted by one, two, or three groups wherein each group is independently C.sub.1-C.sub.3alkoxy, C.sub.1-C.sub.3alkyl, or halo;

[0068] R.sup.9 is --(CH.sub.2).sub.q'NR.sup.50'R.sup.51'; and

[0069] R.sup.11, R.sup.12, and R.sup.13 are each independently C.sub.1-C.sub.7alkyl, C.sub.2-C.sub.7alkenyl, C.sub.1-C.sub.3alkoxyC.sub.1-C.sub.3alkyl, or C.sub.1-C.sub.3alkylsulfanylC.sub.1-C.sub.3alkyl.

[0070] In a seventh embodiment of the first aspect, the present disclosure provides a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein:

[0071] R.sup.1 is phenylC.sub.1-C.sub.3alkyl wherein the phenyl part of the phenylC.sub.1-C.sub.3alkyl is optionally substituted with one, two, three, four, or five groups wherein each group is independently C.sub.1-C.sub.4alkoxy, C.sub.1-C.sub.4alkyl, amino, aminoC.sub.1-C.sub.3alkyl, carboxy, cyano, halo, haloC.sub.1-C.sub.3alkyl, hydroxy, or --OP(O)(OH).sub.2;

[0072] R.sup.2 is C.sub.1-C.sub.7alkyl, or, R.sup.2 and R.sup.b, together with the atoms to which they are attached, form piperidine ring;

[0073] R.sup.3 is NR.sup.tR.sup.ucarbonylC.sub.1-C.sub.3alkyl, wherein R.sup.t and R.sup.u are independently hydrogen or C.sub.1-C.sub.3alkyl;

[0074] R.sup.4 and R.sup.d, together with the atoms to which they are attached, form a pyrrolidine, morpholine, piperidine, or piperazine ring, wherein each ring is optionally substituted with one to four groups wherein each group is independently amino, cyano, methyl, halo, or hydroxy;

[0075] R.sup.5 is --(CH.sub.2).sub.qNR.sup.50R.sup.51;

[0076] R.sup.6 is C.sub.1-C.sub.7alkyl;

[0077] R.sup.7 and R.sup.g, together with the atoms to which they are attached, form a pyrrolidine, morpholine, piperidine, or piperazine ring, wherein each ring is optionally substituted with one to four groups wherein each group is independently amino, cyano, methyl, halo, or hydroxy;

[0078] R.sup.8 and R.sup.10 are each independently azaindolylC.sub.1-C.sub.3alkyl or indolylC.sub.1-C.sub.3alkyl, wherein the indolyl part of the indolylC.sub.1-C.sub.3alkyl is optionally substituted with one group which is C.sub.1-C.sub.3alkoxycarbonylC.sub.1-C.sub.3alkyl, C.sub.1-C.sub.3alkyl, carboxyC.sub.1-C.sub.3alkyl, halo, or hydroxy;

[0079] R.sup.9 is --(CH.sub.2).sub.q'NR.sup.50'R.sup.51'; and

[0080] R.sup.11, R.sup.12, and R.sup.13 are each independently C.sub.1-C.sub.7alkyl.

[0081] In an eighth embodiment of the first aspect, the present disclosure provides a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein:

[0082] R.sup.5 is --(CH.sub.2).sub.qNR.sup.50R.sup.51;

[0083] R.sup.9 is --(CH.sub.2).sub.q'NR.sup.50'R.sup.51'; and

[0084] R.sup.50, R.sup.51, R.sup.50', and R.sup.51' are each independently hydrogen, C.sub.1-C.sub.13alkylsulfanylcarbonyl, C.sub.1-C.sub.13haloalkoxycarbonyl, --CN, --C(N--CN)C.sub.1-C.sub.13alkyl, --C(O)NR.sup.70R.sup.71, --C(S)NR.sup.90R.sup.91, or --SO.sub.2NR.sup.90R.sup.91; provided that when R.sup.50 and R.sup.51 are each hydrogen, at least one of R.sup.50' and R.sup.51' is other than hydrogen.

[0085] In a ninth embodiment of the first aspect, the present disclosure provides a compound of formula (I) wherein:

[0086] R.sup.5 is --(CH.sub.2).sub.qNR.sup.50R.sup.51;

[0087] R.sup.9 is --(CH.sub.2).sub.q'NR.sup.50'R.sup.51'; and

[0088] R.sup.50, R.sup.51, R.sup.50', and R.sup.51' are each independently hydrogen, C.sub.1-C.sub.13alkoxycarbonyl, C.sub.4-C.sub.13alkylcarbonyl, or C.sub.1-C.sub.13haloalkylcarbonyl; provided that when R.sup.50 and R.sup.51 are each hydrogen, at least one of R.sup.50' and R.sup.51' is other than hydrogen.

[0089] In a tenth embodiment of the first aspect, the present disclosure provides a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein:

[0090] A is

##STR00004##

[0091] z is 0;

[0092] w is 1;

[0093] R.sup.z is --C(O)NHR.sup.16;

[0094] R.sup.16 is hydrogen or CHR.sup.17C(O)NH.sub.2, wherein R.sup.17 is hydrogen;

[0095] R.sup.1 is phenylC.sub.1-C.sub.3alkyl wherein the phenyl part of the phenylC.sub.1-C.sub.3alkyl is optionally substituted with one, two, three, four, or five groups wherein each group is independently C.sub.1-C.sub.4alkoxy, C.sub.1-C.sub.4alkyl, amino, aminoC.sub.1-C.sub.3alkyl, carboxy, cyano, halo, haloC.sub.1-C.sub.3alkyl, hydroxy, or --OP(O)(OH).sub.2;

[0096] R.sup.2 is C.sub.1-C.sub.7alkyl, or, R.sup.2 and R.sup.b, together with the atoms to which they are attached, form piperidine ring;

[0097] R.sup.3 is NR.sup.tR.sup.ucarbonylC.sub.1-C.sub.3alkyl, wherein R.sup.t and R.sup.u are independently hydrogen or C.sub.1-C.sub.3alkyl;

[0098] R.sup.4 and R.sup.d, together with the atoms to which they are attached, form a pyrrolidine, morpholine, piperidine, or piperazine ring, wherein each ring is optionally substituted with one to four groups wherein each group is independently amino, cyano, methyl, halo, or hydroxy;

[0099] R.sup.5 is --(CH.sub.2).sub.qNR.sup.50R.sup.51;

[0100] R.sup.6 is C.sub.1-C.sub.7alkyl;

[0101] R.sup.7 and R.sup.g, together with the atoms to which they are attached, form a pyrrolidine, morpholine, piperidine, or piperazine ring, wherein each ring is optionally substituted with one to four groups wherein each group is independently amino, cyano, methyl, halo, or hydroxy;

[0102] R.sup.8 and R.sup.10 are each independently azaindolylC.sub.1-C.sub.3alkyl or indolylC.sub.1-C.sub.3alkyl, wherein the indolyl part of the indolylC.sub.1-C.sub.3alkyl is optionally substituted with one group which is C.sub.1-C.sub.3alkoxycarbonylC.sub.1-C.sub.3alkyl, C.sub.1-C.sub.3alkyl, carboxyC.sub.1-C.sub.3alkyl, halo, or hydroxy;

[0103] R.sup.9 is --(CH.sub.2).sub.q'NR.sup.50'R.sup.51'; and

[0104] R.sup.11, R.sup.12, and R.sup.13 are each independently C.sub.1-C.sub.7alkyl.

[0105] In an eleventh embodiment of the first aspect, the present disclosure provides a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein:

[0106] A is

##STR00005##

[0107] z is 0;

[0108] w is 1;

[0109] R.sup.z is --C(O)NHR.sup.16;

[0110] R.sup.16 is hydrogen or CHR.sup.17C(O)NH.sub.2, wherein R.sup.17 is hydrogen;

[0111] R.sup.1 is phenylC.sub.1-C.sub.3alkyl wherein the phenyl part of the phenylC.sub.1-C.sub.3alkyl is optionally substituted with one, two, three, four, or five groups wherein each group is independently C.sub.1-C.sub.4alkoxy, C.sub.1-C.sub.4alkyl, amino, aminoC.sub.1-C.sub.3alkyl, carboxy, cyano, halo, haloC.sub.1-C.sub.3alkyl, hydroxy, or --OP(O)(OH).sub.2;

[0112] R.sup.2 is C.sub.1-C.sub.7alkyl, or, R.sup.2 and R.sup.b, together with the atoms to which they are attached, form piperidine ring;

[0113] R.sup.3 is NR.sup.tR.sup.ucarbonylC.sub.1-C.sub.3alkyl, wherein R.sup.t and R.sup.u are independently hydrogen or C.sub.1-C.sub.3alkyl;

[0114] R.sup.4 and R.sup.d, together with the atoms to which they are attached, form a pyrrolidine, morpholine, piperidine, or piperazine ring, wherein each ring is optionally substituted with one to four groups wherein each group is independently amino, cyano, methyl, halo, or hydroxy;

[0115] R.sup.5 is --(CH.sub.2).sub.qNR.sup.50R.sup.51; wherein R.sup.50 and R.sup.51 are each independently hydrogen, C.sub.1-C.sub.13alkylsulfanylcarbonyl, C.sub.1-C.sub.13haloalkoxycarbonyl, --CN, --C(N--CN)C.sub.1-C.sub.13alkyl, --C(O)NR.sup.70R.sup.71, --C(S)NR.sup.90R.sup.91, or --SO.sub.2NR.sup.90R.sup.91;

[0116] R.sup.6 is C.sub.1-C.sub.7alkyl;

[0117] R.sup.7 and R.sup.g, together with the atoms to which they are attached, form a pyrrolidine, morpholine, piperidine, or piperazine ring, wherein each ring is optionally substituted with one to four groups wherein each group is independently amino, cyano, methyl, halo, or hydroxy;

[0118] R.sup.8 and R.sup.10 are each independently azaindolylC.sub.1-C.sub.3alkyl or indolylC.sub.1-C.sub.3alkyl, wherein the indolyl part of the indolylC.sub.1-C.sub.3alkyl is optionally substituted with one group which is C.sub.1-C.sub.3alkoxycarbonylC.sub.1-C.sub.3alkyl, C.sub.1-C.sub.3alkyl, carboxyC.sub.1-C.sub.3alkyl, halo, or hydroxy;

[0119] R.sup.9 is --(CH.sub.2).sub.q'NR.sup.50'R.sup.51'; wherein R.sup.50' and R.sup.51' are each independently hydrogen, C.sub.1-C.sub.13alkylsulfanylcarbonyl, C.sub.1-C.sub.13haloalkoxycarbonyl, --CN, --C(N--CN)C.sub.1-C.sub.13alkyl, --C(O)NR.sup.70R.sup.71, --C(S)NR.sup.90R.sup.91, or --SO.sub.2NR.sup.90R.sup.91; provided that when R.sup.50 and R.sup.51 are each hydrogen, at least one of R.sup.50' and R.sup.51' is other than hydrogen; and

[0120] R.sup.11, R.sup.12, and R.sup.13 are each independently C.sub.1-C.sub.7alkyl.

[0121] In a twelfth embodiment of the first aspect, the present disclosure provides a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein:

[0122] A is

##STR00006##

[0123] z is 0;

[0124] w is 1;

[0125] R.sup.z is --C(O)NHR.sup.16;

[0126] R.sup.16 is CHR.sup.17C(O)NH.sub.2, wherein R.sup.17 is hydrogen;

[0127] R.sup.1 is phenylC.sub.1-C.sub.3alkyl wherein the phenyl part of the phenylC.sub.1-C.sub.3alkyl is optionally substituted with one, two, three, four, or five groups wherein each group is independently C.sub.1-C.sub.4alkoxy, C.sub.1-C.sub.4alkyl, amino, aminoC.sub.1-C.sub.3alkyl, carboxy, cyano, halo, haloC.sub.1-C.sub.3alkyl, hydroxy, or --OP(O)(OH).sub.2;

[0128] R.sup.2 is C.sub.1-C.sub.7alkyl, or, R.sup.2 and R.sup.b, together with the atoms to which they are attached, form piperidine ring;

[0129] R.sup.3 is NR.sup.tR.sup.ucarbonylC.sub.1-C.sub.3alkyl, wherein R.sup.t and R.sup.u are independently hydrogen or C.sub.1-C.sub.3alkyl;

[0130] R.sup.4 and R.sup.d, together with the atoms to which they are attached, form a pyrrolidine, morpholine, piperidine, or piperazine ring, wherein each ring is optionally substituted with one to four groups wherein each group is independently amino, cyano, methyl, halo, or hydroxy;

[0131] R.sup.5 is --(CH.sub.2).sub.qNR.sup.50R.sup.51; wherein R.sup.50 and R.sup.51 are each independently hydrogen, C.sub.1-C.sub.13alkoxycarbonyl, C.sub.4-C.sub.13alkylcarbonyl, or C.sub.1-C.sub.13haloalkylcarbonyl;

[0132] R.sup.6 is C.sub.1-C.sub.7alkyl;

[0133] R.sup.7 and R.sup.g, together with the atoms to which they are attached, form a pyrrolidine, morpholine, piperidine, or piperazine ring, wherein each ring is optionally substituted with one to four groups wherein each group is independently amino, cyano, methyl, halo, or hydroxy;

[0134] R.sup.8 and R.sup.10 are each independently azaindolylC.sub.1-C.sub.3alkyl or indolylC.sub.1-C.sub.3alkyl, wherein the indolyl part of the indolylC.sub.1-C.sub.3alkyl is optionally substituted with one group which is C.sub.1-C.sub.3alkoxycarbonylC.sub.1-C.sub.3alkyl, C.sub.1-C.sub.3alkyl, carboxyC.sub.1-C.sub.3alkyl, halo, or hydroxy;

[0135] R.sup.9 is --(CH.sub.2).sub.q'NR.sup.50'R.sup.51'; wherein R.sup.50' and R.sup.51' are each independently hydrogen, C.sub.1-C.sub.13alkoxycarbonyl, C.sub.4-C.sub.13alkylcarbonyl, or C.sub.1-C.sub.13haloalkylcarbonyl; provided that when R.sup.50 and R.sup.51 are each hydrogen, at least one of R.sup.50' and R.sup.51' is other than hydrogen; and

[0136] R.sup.11, R.sup.12, and R.sup.13 are each independently C.sub.1-C.sub.7alkyl.

[0137] In a second aspect, the present disclosure provides a compound of formula (II)

##STR00007##

or a pharmaceutically acceptable salt thereof, wherein:

[0138] A is selected from a bond,

##STR00008##

and; wherein: denotes the point of attachment to the carbonyl group and denotes the point of attachment to the nitrogen atom;

[0139] n is 0 or 1;

[0140] m is 1 or 2;

[0141] R.sup.14 and R.sup.15 are independently hydrogen or methyl; and

[0142] R.sup.16 is hydrogen, --CHR.sup.17C(O)NH.sub.2, --CHR.sup.17C(O)NHCHR.sup.18C(O)NH.sub.2, or

[0143] --CHR.sup.17C(O)NHCHR.sup.18C(O)NHCH.sub.2C(O)NH.sub.2; wherein R'.sup.7 is hydrogen or --CH.sub.2OH and wherein R.sup.18 is hydrogen or methyl;

[0144] R.sup.f, R.sup.h, R.sup.i, and R.sup.m are hydrogen;

[0145] R.sup.n is methyl;

[0146] R.sup.a and R.sup.j are each independently hydrogen or methyl;

[0147] q and q' are each independently 1 or 2;

[0148] R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7, R.sup.8, R.sup.9, R.sup.10, R.sup.11, R.sup.12, and R.sup.13 are each independently a natural amino acid side chain or an unnatural amino acid side chain; or form a ring with the corresponding vicinal R group as described below;

[0149] R.sup.b is methyl or R.sup.b and R.sup.2, together with the atoms to which they are attached, form an azetidine, pyrrolidine, morpholine, piperidine, piperazine, or tetrahydrothiazole ring; wherein each ring is optionally substituted with one to four groups wherein each group is independently amino, cyano, methyl, halo, or hydroxy;

[0150] R.sup.d is hydrogen or methyl, or R.sup.d and R.sup.4, together with the atoms to which they are attached, can form an azetidine, pyrrolidine, morpholine, piperidine, piperazine, or tetrahydrothiazole ring; wherein each ring is optionally substituted with one to four groups wherein each group is independently amino, cyano, methyl, halo, hydroxy, or phenyl;

[0151] R.sup.k is hydrogen or methyl, or R.sup.k and R.sup.11, together with the atoms to which they are attached, can form an azetidine, pyrrolidine, morpholine, piperidine, piperazine, or tetrahydrothiazole ring; wherein each ring is optionally substituted with one to four groups wherein each group is independently amino, cyano, methyl, halo, and hydroxy;

[0152] R.sup.e is hydrogen or methyl, or R.sup.e and R.sup.5, together with the atoms to which they are attached, can form an azetidine, pyrrolidine, morpholine, piperidine, piperazine, or tetrahydrothiazole ring; wherein each ring is optionally substituted with one to four groups wherein each group is independently amino, benzyl optionally substituted with a halo group, benzyloxy, cyano, cyclohexyl, methyl, halo, hydroxy, isoquinolinyloxy optionally substituted with a methoxy group, quinolinyloxy optionally substituted with a halo group, or tetrazolyl; and wherein the pyrrolidine ring and the piperidine ring are optionally fused to a cyclohexyl, phenyl, or indole group;

[0153] R.sup.k is hydrogen or methyl, or R.sup.k and R.sup.11, together with the atoms to which they are attached, can form an azetidine, pyrrolidine, morpholine, piperidine, piperazine, or tetrahydrothiazole ring; wherein each ring is optionally substituted with one to four groups wherein each group is independently amino, cyano, methyl, halo, and hydroxy;

[0154] R.sup.L is methyl or R.sup.L and R.sup.12, together with the atoms to which they are attached, form an azetidine or pyrrolidine ring, wherein each ring is optionally substituted with one to four groups wherein each group is independently amino, cyano, methyl, halo, or hydroxy;

[0155] provided that the compound of formula (I) contains at least one carbon on the backbone of the ring that has four substituents other than hydrogen and is not an alpha-methyl-substituted ring.

[0156] In a third aspect, the present disclosure provides a method of enhancing, stimulating, and/or increasing an immune response in a subject in need thereof, wherein the method comprises administering to the subject a therapeutically effective amount of a compound of formula (I) or formula (II), or a pharmaceutically acceptable salt thereof.

[0157] In a fourth aspect, the present disclosure provides a method of blocking the interaction of PD-L1 with PD-1 and/or CD80 in a subject, wherein the method comprises administering to the subject a therapeutically effective amount of a compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof.

[0158] In a fifth aspect the present disclosure provides a method of enhancing, stimulating, and/or increasing an immune response in a subject in need thereof, said method comprising administering to the subject a therapeutically effective amount of a compound of formula (I) or formula (II), or a pharmaceutically acceptable salt thereof. In a first embodiment of the second aspect the method further comprises administering an additional agent prior to, after, or simultaneously with the compound of formula (I), compound of formula (I)), or a pharmaceutically acceptable salt thereof. In a second embodiment the additional agent is selected from an antimicrobial agent, an antiviral agent, a cytotoxic agent, a TLR7 agonist, a TLR8 agonist, an HDAC inhibitor, and an immune response modifier.

[0159] In a sixth aspect the present disclosure provides a method of inhibiting growth, proliferation, or metastasis of cancer cells in a subject in need thereof, said method comprising administering to the subject a therapeutically effective amount a compound of formula (I) or formula (II), or a pharmaceutically acceptable salt thereof. In a first embodiment of the third aspect the cancer is selected from melanoma, renal cell carcinoma, squamous non-small cell lung cancer (NSCLC), non-squamous NSCLC, colorectal cancer, castration-resistant prostate cancer, ovarian cancer, gastric cancer, hepatocellular carcinoma, pancreatic carcinoma, squamous cell carcinoma of the head and neck, carcinomas of the esophagus, gastrointestinal tract and breast, and hematological malignancies.

[0160] In a seventh aspect the present disclosure provides a method of treating an infectious disease in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of formula (I) or formula (II), or a pharmaceutically acceptable salt thereof. In a first embodiment of the fourth aspect the infectious disease is caused by a virus. In a second embodiment the virus is selected from HIV, Hepatitis A, Hepatitis B, Hepatitis C, herpes viruses, and influenza.

[0161] In an eighth aspect the present disclosure provides a method of treating septic shock in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of formula (I) or formula (II), or a pharmaceutically acceptable salt thereof.

[0162] In a ninth aspect the present disclosure provides a method of blocking the interaction of PD-L1 with PD-1 and/or CD80 in a subject, said method comprising administering to the subject a therapeutically effective amount of a compound of formula (I) or formula (II), or a pharmaceutically acceptable salt thereof.


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