http://rdf.ncbi.nlm.nih.gov/pubchem/patent/AR-108186-A1
Outgoing Links
| Predicate | Object |
|---|---|
| assignee | http://rdf.ncbi.nlm.nih.gov/pubchem/patentassignee/MD5_42e94091a4fc81b8d0237117707cc7ee |
| classificationCPCAdditional | http://rdf.ncbi.nlm.nih.gov/pubchem/patentcpc/A61K38-00 http://rdf.ncbi.nlm.nih.gov/pubchem/patentcpc/Y02A50-30 |
| classificationCPCInventive | http://rdf.ncbi.nlm.nih.gov/pubchem/patentcpc/C07K7-64 http://rdf.ncbi.nlm.nih.gov/pubchem/patentcpc/C07K7-56 http://rdf.ncbi.nlm.nih.gov/pubchem/patentcpc/C07K7-54 http://rdf.ncbi.nlm.nih.gov/pubchem/patentcpc/A61P37-04 http://rdf.ncbi.nlm.nih.gov/pubchem/patentcpc/C07K7-08 http://rdf.ncbi.nlm.nih.gov/pubchem/patentcpc/A61K38-12 http://rdf.ncbi.nlm.nih.gov/pubchem/patentcpc/A61P35-04 http://rdf.ncbi.nlm.nih.gov/pubchem/patentcpc/A61P35-00 http://rdf.ncbi.nlm.nih.gov/pubchem/patentcpc/A61P31-00 http://rdf.ncbi.nlm.nih.gov/pubchem/patentcpc/A61P31-12 http://rdf.ncbi.nlm.nih.gov/pubchem/patentcpc/A61P31-04 |
| classificationIPCInventive | http://rdf.ncbi.nlm.nih.gov/pubchem/patentipc/A61K31-438 http://rdf.ncbi.nlm.nih.gov/pubchem/patentipc/A61K38-12 http://rdf.ncbi.nlm.nih.gov/pubchem/patentipc/A61K31-416 http://rdf.ncbi.nlm.nih.gov/pubchem/patentipc/C07D519-00 http://rdf.ncbi.nlm.nih.gov/pubchem/patentipc/A61K31-41 http://rdf.ncbi.nlm.nih.gov/pubchem/patentipc/C07K7-54 http://rdf.ncbi.nlm.nih.gov/pubchem/patentipc/C07D513-14 http://rdf.ncbi.nlm.nih.gov/pubchem/patentipc/A61K31-437 |
| filingDate | 2017-04-05-04:00^^<http://www.w3.org/2001/XMLSchema#date> |
| inventor | http://rdf.ncbi.nlm.nih.gov/pubchem/patentinventor/MD5_e6880bf0c37bf4077ae4985b31bb6586 http://rdf.ncbi.nlm.nih.gov/pubchem/patentinventor/MD5_836ca1b8d1c98b73721fafe41203f053 http://rdf.ncbi.nlm.nih.gov/pubchem/patentinventor/MD5_09de3efe5c479530a6a3f235304cf5a2 http://rdf.ncbi.nlm.nih.gov/pubchem/patentinventor/MD5_253fc860c10d9b807c1da047174dfca6 http://rdf.ncbi.nlm.nih.gov/pubchem/patentinventor/MD5_7cd7a781633518e703cb7e78935a5a55 http://rdf.ncbi.nlm.nih.gov/pubchem/patentinventor/MD5_6e8d21a02dc1f5c91489591fc82da1e8 http://rdf.ncbi.nlm.nih.gov/pubchem/patentinventor/MD5_dcb6a331935095f8a8de57ed28c67970 http://rdf.ncbi.nlm.nih.gov/pubchem/patentinventor/MD5_da8fa5793783b9adcdf22d2abae22564 http://rdf.ncbi.nlm.nih.gov/pubchem/patentinventor/MD5_31211bae2a262eb4cb629a99aef28862 http://rdf.ncbi.nlm.nih.gov/pubchem/patentinventor/MD5_dbe8dc04241d4ed47d74dcaae607b097 |
| publicationDate | 2018-07-25-04:00^^<http://www.w3.org/2001/XMLSchema#date> |
| publicationNumber | AR-108186-A1 |
| titleOfInvention | MACROCYCLIC PEPTIDES THAT INHIBIT THE PROTEIN / PROTEIN INTERACTIONS, PROGRAMMED DEATH PROTEIN 1 (PD-1) / PD-1 (PD-L1) AND PD-L1 / CD80 |
| abstract | Macrocyclic peptides that inhibit PD-1/PD-L1 and PD-L1/CD80 protein/protein interactions, and thus are useful for the improvement of various diseases, including cancer and infectious diseases. Claim 1: A compound characterized by formula (1), or a pharmaceutically acceptable salt thereof, wherein: A is selected from a bond, or a compound from the group of formulas (2); where: "the wavy line *" indicates the point of attachment to the carbonyl group and "the wavy line" indicates 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; Rˣ is selected from hydrogen, amino, hydroxy and methyl; R¹⁴ and R¹⁵ are independently selected from hydrogen and methyl; and Rᶻ is selected from hydrogen and -C(O)NHR¹⁶; wherein R¹⁶ is selected from hydrogen, -CHR¹⁷C(O)NH₂, -CHR¹⁷C(O)NHCHR¹⁸C(O)NH₂, and -CHR¹⁷C(O)NHCHR¹⁸C(O)NHCH₂C(O)NH₂; where R¹⁷ is selected from hydrogen and -CH₂OH, and where R¹⁸ is selected from hydrogen and methyl; Rᵛ is hydrogen or a natural amino acid side chain; "the wavy line *" indicates the point of attachment to the carbonyl group and "the wavy line" indicates the point of attachment to the nitrogen atom; Rᶜ, Rᶠ, Rʰ, Rⁱ, Rᵐ and Rⁿ are hydrogen; Rᵃ, Rᵉ, Rʲ and Rᵏ are each independently selected from hydrogen and methyl; R¹⁰ is indolylC₁₋₃alkyl, wherein the indolyl moiety is optionally substituted with a group selected from C₁₋₆alkoxy, C₁₋₆alkoxycarbonyl, C₁₋₆alkoxycarbonylC₁₋₃alkyl, (C₁₋₆alkyl)S(O)₂NHC(O)C₃alkyl , arylS(O)₂NHC(O)C₁₋₃alkyl, arylC₁₋₃alkylS(O)₂NHC(O)C₁₋₃alkyl, C₃₋₆cycloalkylS(O)₂NHC(O)C₁₋₃alkyl, C₃₋₆cycloalkylC₁₋)₃CalkylS(O (O)C₁₋₃alkyl, heteroarylC₁₋₃alkylS(O)₂NHC(O)C₁₋₃alkyl, -NRᵖRq, (NRᵖRq)C₁₋₃alkyl and tetrazolylC₁₋₃alkyl, or with two groups selected from C₁₋₆alkoxy, C₁₋carbonyl₆ ₋₆alkoxycarbonylC₁₋₃alkyl, C₁₋₃alkyl, (C₁₋₆alkyl)S(O)₂NHC(O)C₁₋₃alkyl, arylS(O)₂NHC(O)C₁₋₃alkyl, arylC₁₋₃alkylS(O)₂NHC(O)C₋ ₃alkyl, carboxy, carboxyC₁₋₃alkyl, cyano, C₃₋₆cycloalkylS(O)₂NHC(O)C₁₋₃alkyl, C₃₋₆cycloalkylC₁₋₃alkylS(O)₂NHC(O)C₁₋₃alkyl, halo, haloC₁₋coalkyl,halo₃C₁₋,halo₋ heteroarylS(O)₂NHC(O)C₁₋₃alkyl, heteroarylC₁₋₃alkylS(O)₂NHC(O)C₁₋₃alkyl, hydroxy, -NRᵖRq, (NRᵖRq)C₁₋₃alkyl, tetrazolyl, tetrazolylC₁₋₃alkyl and phenyl, and n where phenyl is also optionally substituted with 1, 2 or 3 groups independently selected from C₁₋₃alkoxy, C₁₋₃alkyl and halo; or R¹⁰ is azaindolylC₁₋₃alkyl, wherein the azaindolyl part of azaindolylC₁₋₃alkyl is substituted with 1 or 2 different groups independently selected from C₁₋₆alkoxy, C₁₋₆alkoxycarbonyl, C₁₋₆alkoxycarbonylC₁₋₋,C₋₋alkyl, C₁₋₋alkyl, )S(O)₂NHC(O)C₁₋₃alkyl, arylS(O)₂NHC(O)C₁₋₃alkyl, arylC₁₋₃alkylS(O)₂NHC(O)C₁₋₃alkyl, carboxy, carboxyC₁₋₃alkyl, cyano, C₃₋₆cycloalkylS (O)₂NHC(O)C₁₋₃alkyl, C₃₋₆cycloalkylC₁₋₃alkylS(O)₂NHC(O)C₁₋₃alkyl, halo, haloC₁₋₃alkoxy, haloC₁₋₃alkyl, heteroarylS(O)₂NHC(O)C₁₋alkyl, heteroaryl₋ ₋₃alkylS(O)₂NHC(O)C₁₋₃alkyl, hydroxy, -NRᵖRq, (NRᵖRq)C₁₋₃alkyl, tetrazolyl, tetrazolylC₁₋₃alkyl and phenyl, wherein phenyl is also optionally substituted with 1, 2 or 3 independently selected groups from C₁₋₃alkoxy, C₁₋₃alkyl and halo; or R¹⁰ is -(CH₂)ₙQ’ is a saturated or unsaturated 5,6-fused ring system containing 1, 2, 3 or 4 nitrogen atoms, wherein the ring system is optionally substituted with 1, 2 or 3 groups selected from C₁₋₆alkoxy, C₁₋₆alkoxycarbonyl, C₁₋₆alkoxycarbonylC₁₋₃alkyl, C₁₋₃alkyl, (C₁₋₆alkyl)S(O)₂NHC(O)C₁₋₃alkyl, arylS(O)₂NHC(O)₁C₃alkyl ₋₃alkylS(O)₂NHC(O)C₁₋₃alkyl, carboxy, carboxyC₁₋₃alkyl, cyano, C₃₋₆cycloalkylS(O)₂NHC(O)C₁₋₃alkyl, C₃₋₆cycloalkylC₁₋₃alkylS(O)₋NHC₁alkyl(O)₋NHC₁alkyl , halo, haloC₁₋₃alkoxy, haloC₁₋₃alkyl, heteroarylS(O)₂NHC(O)C₁₋₃alkyl, heteroarylC₁₋₃alkylS(O)₂NHC(O)C₁₋₃alkyl, hydroxy, -NRᵖRq, (NRᵖRq)C₁₋alkyl, tetrazolyl₋ , tetrazolylC₁₋₃alkyl and phenyl, wherein the phenyl is also optionally substituted with 1, 2 or 3 groups independently selected from C₁₋₃alkoxy, C₁₋₃alkyl and halo; provided that Q' is not azaindolyl or indolyl; or R¹⁰ is -(CH₂)ₙZ’, where n is 1-3 and Z’ is a saturated or unsaturated 6,6-fused ring system containing 1, 2, 3 or 4 nitrogen atoms, where the ring system rings is optionally substituted with 1, 2 or 3 groups selected from C₁₋₆alkoxy, C₁₋₆alkoxycarbonyl, C₁₋₆alkoxycarbonylC₁₋₃alkyl, C₁₋₃alkyl, (C₁₋₆alkyl)S(O)₂NHC(O)C₁₋₃(arylS O)₂NHC(O)C₁₋₃alkyl, arylC₁₋₃alkylS(O)₂NHC(O)C₁₋₃alkyl, carboxy, carboxyC₁₋₃alkyl, cyano, C₃₋₆cycloalkylS(O)₂NHC(O)C₁₋₃alkyl, C₃₋C₋₆ ₃alkylS(O)NHC(O)C₁₋₃alkyl, halo, haloC₁₋₃alkoxy, haloC₁₋₃alkyl, heteroarylS(O)₂NHC(O)C₁₋₃alkyl, heteroarylC₁₋₃alkylS(O)₂NHC(O)C₁₋₃alkyl, hydroxy, -NRᵖRq, (NRᵖRq)C₁₋₃alkyl, tetrazolyl, tetrazolylC₁₋₃alkyl and phenyl, wherein phenyl is also optionally substituted with 1, 2 or 3 groups independently selected from C₁₋₃alkoxy, C₁₋₃alkyl and halo; Rᵖ and Rq are independently selected from hydrogen and C₁₋₆ alkyl; R¹³ is selected from a natural amino acid side chain, an unnatural amino acid side chain, and -(C(R¹⁷ᵃ)₂)₂-X-R³⁰; -C(R¹⁷ᵃ)₂C(O)N(R¹⁶ᵃ)C(R¹⁷ᵃ)₂-X’-R³¹; -C(R¹⁷ᵃ)₂[C(O)N(R¹⁶ᵃ)C(R¹⁷ᵃ)₂]ʷ’-X-R³¹; -(C(R¹⁷ᵃ)(R¹⁷)C(O)NR¹⁶ᵃ)ₙ’-H; and -(C(R¹⁷ᵃ)(R¹⁷)C(O)NR¹⁶ᵃ)ₘ’-C(R¹⁷ᵃ)(R¹⁷)-CO₂H; w' is 2 or 3; n' is 1-6; m' is 0-5; X is a chain of 1 to 172 atoms, where the atoms are selected from carbon and oxygen, and where the chain may contain 1, 2, 3 or 4 groups selected from -NHC(O)NH- and -C(O )NH- embedded; and wherein the chain is optionally substituted with 1 to 6 groups independently selected from -CO₂H, -C(O)NH₂, -CH₂C(O)NH₂, and -(CH₂)CO₂H; X' is a chain of 1 to 172 atoms, where the atoms are selected from carbon and oxygen, and where the chain may contain 1, 2, 3 or 4 groups selected from -NHC(O)NH- and -C( O)NH-embedded; and wherein the chain is optionally substituted with 1 to 6 groups independently selected from -CO₂H, -C(O)NH₂ and -CH₂CO₂H, provided that X' is not unsubstituted PEG; R³⁰ is selected from -CO₂H, -C(O)NRʷRˣ and -CH₃, where Rʷ and Rˣ are independently selected from hydrogen and C₁₋₆alkyl, provided that when X is carbon, R³⁰ is not -CH₃; R³¹ is -CO₂H, -C(O)NRʷRˣ, -CH₃, alexa-5-SDP, and biotin; each R¹⁷ᵃ is independently selected from hydrogen, C₁₋₆alkyl, -CH₂OH, -CH₂CO₂H, -(CH₂)₂CO₂H; each R¹⁷ is independently selected from hydrogen, -CH₃, (CH₂)ᶻN₃, -(CH₂)ᶻNH₂, -X-R³¹, -(CH₂)ᶻCO₂H, -CH₂OH, CH₂CCºCCH and -(CH₂)ᶻ-triazolyl-X-R³⁵, where z is 1-6, and R³⁵ is selected from -CO₂H, -C(O)NRʷRˣ, CH₃, biotin, -2-fluoropyridine, -C(O)-(CH₂)₂-C(O)O-vitamin E, -C(O)O-vitamin E; and the compound of formula (3) provided that at least one R¹⁷ is not hydrogen, -CH₃ or -CH₂OH; R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹¹ and R¹² are independently selected from one natural amino acid side chain and one unnatural amino acid side chain, or form a ring with the corresponding proximal R group, as described below; Rᵉ and Rᵏ can each form a ring with the corresponding proximal R group and the atoms to which they are attached, selected from azetidine, pyrrolidine, morpholine, piperidine, piperazine and tetrahydrothiazole; wherein each ring is optionally substituted with one to four groups independently selected from amino, cyano, methyl, halo, and hydroxy; Rᵇ is methyl, or Rᵇ and R², together with the atoms to which they are attached, form a ring selected from azetidine, pyrrolidine, morpholine, piperidine, piperazine, and tetrahydrothiazole; wherein each ring is optionally substituted with 1 to 4 groups independently selected from amino, cyano, methyl, halo, and hydroxy; Rᵈ is hydrogen or methyl, or Rᵈ and R⁴, together with the atoms to which they are attached, may form a ring selected from azetidine, pyrrolidine, morpholine, piperidine, piperazine and tetrahydrothiazole; wherein each ring is optionally substituted with 1 to 4 groups independently selected from amino, cyano, methyl, halo, hydroxy, and phenyl; Rᵍ is hydrogen or methyl, or Rᵍ and R⁷, together with the atoms to which they are attached, may form a ring selected from azetidine, pyrrolidine, morpholine, piperidine, piperazine and tetrahydrothiazole; wherein each ring is optionally substituted with one to four groups independently selected from amino, benzyl optionally substituted with a halo, benzyloxy, cyano, cyclohexyl, methyl, halo, hydroxy, isoquinolinyloxy optionally substituted with a methoxy group, quinolinyloxy optionally substituted with a halo group, and tetrazolyl; and wherein the pyrrolidine and piperidine rings are optionally fused with a cyclohexyl, phenyl or indole group; and RL is methyl, or RL and R¹², together with the atoms to which they are attached, form a ring selected from azetidine and pyrrolidine, wherein each ring is optionally substituted with one to four groups independently selected from amino, cyano, methyl, halo and hydroxy. |
| priorityDate | 2016-04-05-04:00^^<http://www.w3.org/2001/XMLSchema#date> |
| type | http://data.epo.org/linked-data/def/patent/Publication |
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Total number of triples: 70.