Patent Application
20250127790
This application contains a Sequence Listing which has been submitted electronically in XML format. The Sequence Listing XML is incorporated herein by reference. Said XML file, created on Aug. 10, 2022, is named DCP-109WO_SL.xml and is 20,390 bytes in size.
Autophagy is a cellular process enabling the recycling of cytoplasmic components via the formation of double-membraned vesicles termed autophagosomes. In addition to autophagy-mediated vesicular trafficking, the endosomal vesicular trafficking process also enables the sequestration and destruction/recycling of cellular components. Upon fusion with lysosomes, the cargo of the autophagosome or the late-stage endosome is degraded and released back into the cell, fueling cellular metabolism. Due to its cytoprotective role, defective autophagy has been implicated in several human pathologies including cancer. Cancer cells have been shown to upregulate autophagy in response to stress factors present in the tumor microenvironment (TME) such as hypoxia, nutrient deprivation, as well as a resistance mechanism to anti-cancer therapy. Recently it has become known that the autophagy pathway and/or the endosomal pathway can be upregulated in various cancers to degrade proteins that would otherwise trigger a productive anti-tumor immune response. In certain cases, autophagy or endosomal trafficking in tumor cells leads to immune evasion by destroying the release of proinflammatory mediators, reducing immune cell recognition via MHC-I, and limiting T and natural killer (NK) cell-mediated cell death. Thus, there is a need to block the immunosuppressive effects of autophagy and endosomal trafficking in the tumor environment as a potential therapeutic strategy to improve cancer immunotherapy.
Innate immune sensing in the tumor environment is a critical for promoting spontaneous tumor-initiated T cell priming and tumor infiltration. Transcriptional profiling analyses of melanoma patients have revealed that tumors containing infiltrating activated T cells are characterized by a type I IFN signature. Murine studies have demonstrated that type I IFN signaling plays a critical role in tumor-initiated T cell priming. These findings in humans and in mice indicate that the innate immune system is defective in non-T-cell-inflamed tumors. Thus, strategies to induce type I IFN signaling and antigen-presenting cell activation in the tumor environment to bridge the innate and adaptive immune responses may have therapeutic utility in treating cancer patients. Recent work has demonstrated that activation of the STING pathway in the innate tumor environment is required for induction of a productive CD8+ T cell response against tumor-derived antigens in vivo. STING (stimulator of interferon genes) is a transmembrane protein localized to the endoplasmic reticulum that is activated in response to binding of cyclic dinucleotides (CDNs), resulting in a downstream signaling cascade involving TBK1 kinase activation, IRF-3 phosphorylation, and production of IFN-b and other cytokines. IFN-b is the major cytokine induced in response to activating STING, either by exogenous CDNs produced by bacterial infection or through binding of a structurally distinct endogenous CDNs produced by a host cyclic GMPAMP synthetase (cGAS). These observations suggest that direct activation of the STING pathway in the tumor environment by specific agonists could be an effective therapeutic strategy to promote broad tumor-initiated T cell priming against an individual's tumor antigen repertoire.
Exogenously administered STING agonists are being developed as vaccine adjuvants, as well as direct anti-tumor therapeutic effects. In addition to the administration of exogenous STING agonists, an alternative approach that modulates and upregulates endogenous STING signaling in the tumor environment may be a more preferred method of treatment. The lipid kinase vacuolar protein sorting 34 (VPS34) is a promising target for blocking autophagy- or endosomal pathway-mediated immunosuppression. VPS34, also known as class III phosphoinositide 3-kinase (PIK3C3), regulates autophagy initiation and other vesicular trafficking processes, including playing a key role in endosomal trafficking. Therefore, there is a need for therapeutics that directly activate the STING pathway for use in the treatment of disorders such as cancer.
The present disclosure, in part, is drawn to a method of treating cancers in a patient in need thereof, comprising administering to the patient a VPS34 inhibitor. It has been found that VPS34 inhibitors stimulate the endogenous CGAS/STING pathway in cancer cells or other cells in the tumor environment. Mechanistically, it has been found that VPS34 inhibition triggers an interferon (IFN) response by upregulating the cGAS-STING pathway in various cancers. The present disclosure also provides a method for turning cold tumors (tumor that evade the immune system) into hot tumors (tumors that are recognized and destroyed by the immune system) by administration of a VPS34 inhibitor. The present disclosure is further drawn to a method of the use of VPS34 inhibitors to synergize with exogenous STING agonists in increasing STING-dependent IFN response in vitro and in vivo and further converting cold tumors into hot tumors. These findings identify VPS34 inhibitors as a therapeutic strategy to activate the endogenous cGAS-STING pathway, resulting in a proinflammatory IFN response in the tumor environment and a productive anti-tumor immune response. Further, administration of a VPS34 inhibitor to a cancer patient in need of treatment could be beneficial in combination with other immunostimulatory therapeutics, such as a STING agonist, to improve the outcome of cancer immunotherapy.
In an aspect, provided herein is a method of treating cancer in a patient in need thereof, comprising: (i) administering to the patient a therapeutically effective amount of a compound represented by Formula I:
or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein: R1, R2, and R3 are independently selected from the group consisting of H, C1-C3haloalkyl, and C1-C3alkyl; A represents:
is a single bond or a double bond; X is selected from the group consisting of CH2, S, SO, SO2, NR5, NCOR5, NCOR9, NCOCH2R9, O, and a bond; Y is selected from the group consisting of N, CH, and C, provided that, when Y is CH,
is a single bond; n is selected from 1, 2, 3 and 4; R4 is selected from the group consisting of H, halogen, COR6, C1-C6alkyl, C1-C3alkoxyC1-C3alkyl, C1-C6alkoxy, C3-C6cycloalkyl, C3-C6heterocyclyl, C1-C3cyanoalkyl, C1-C3haloalkyl, aryl, and heteroaryl, wherein said aryl and said heteroaryl are optionally substituted with one or more R7; R5 is selected from the group consisting of H, C1-C3fluoroalkyl, C1-C3alkyl, C1-C3alkoxyC1-C3alkyl, and C3-C6cycloalkyl; R6 is selected from the group consisting of C1-C3alkoxy, N—C1-C3alkylamino, N,N-diC1-C3alkylamino, 1-pyrrolidinyl, 1-piperidinyl, and 1-azetidinyl; each R7 is independently selected from the group consisting of C1-C6alkyl, C3-C6cycloalkyl, C1-C3alkoxyC1-C3alkyl, C1-C3haloalkyl, halogen, N—C1-C3alkylamino, N,N-diC1-C3alkylamino, C1-C3haloalkoxy and C1-C3alkoxy; R9 is selected from the group consisting of C1-C3alkyl, C1-C3alkoxy, C3-C6cycloalkyl, heterocyclyl, phenyl and a monocyclic heteroaryl, wherein said heterocyclyl, said phenyl and said monocyclic heteroaryl are optionally substituted with one or two R8; and each R8 is independently selected from the group consisting of halogen, C1-C3haloalkyl and C1-C3alkyl; and (ii) administering to the patient a therapeutically effective amount of a STING agonist; wherein administering the therapeutically effective amount of the STING agonist and the compound results in an increased expression level of at least one chemokine in the patient as compared to any increase in the expression level of the at least one chemokine resulting from administering the compound alone to the patient.
In an aspect, provided herein is a method of upregulating at least one chemokine in a cell comprising: contacting the cell sample with: (i) a compound represented by:
or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein: R1, R2, and R3 are independently selected from the group consisting of H, C1-C3haloalkyl, and C1-C3alkyl; A represents:
is a single bond or a double bond; X is selected from the group consisting of CH2, S, SO, SO2, NR5, NCOR5, NCOR9, NCOCH2R9, O, and a bond; Y is selected from the group consisting of N, CH, and C, provided that, when Y is CH,
is a single bond; n is selected from 1, 2, 3 and 4; R4 is selected from the group consisting of H, halogen, COR6, C1-C6alkyl, C1-C3alkoxyC1-C3alkyl, C1-C6alkoxy, C3-C6cycloalkyl, C3-C6heterocyclyl, C1-C3cyanoalkyl, C1-C3haloalkyl, aryl, and heteroaryl, wherein said aryl and said heteroaryl are optionally substituted with one or more R7; R5 is selected from the group consisting of H, C1-C3fluoroalkyl, C1-C3alkyl, C1-C3alkoxyC1-C3alkyl, and C3-C6cycloalkyl; R6 is selected from the group consisting of C1-C3alkoxy, N—C1-C3alkylamino, N,N-diC1-C3alkylamino, 1-pyrrolidinyl, 1-piperidinyl, and 1-azetidinyl; each R7 is independently selected from the group consisting of C1-C6alkyl, C3-C6cycloalkyl, C1-C3alkoxyC1-C3alkyl, C1-C3haloalkyl, halogen, N—C1-C3alkylamino, N,N-diC1-C3alkylamino, C1-C3haloalkoxy and C1-C3alkoxy; R9 is selected from the group consisting of C1-C3alkyl, C1-C3alkoxy, C3-C6cycloalkyl, heterocyclyl, phenyl and a monocyclic heteroaryl, wherein said heterocyclyl, said phenyl and said monocyclic heteroaryl are optionally substituted with one or two R8; and each R8 is independently selected from the group consisting of halogen, C1-C3haloalkyl and C1-C3alkyl; in an amount sufficient to induce a Type I interferon response by the cell; and
In an aspect, provided herein is a method of treating cancer in a patient in need thereof, comprising administering to the patient: (i) a therapeutically effective amount of a compound represented by Formula II:
or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein: R1 is selected from the group consisting of aryl and heteroaryl, wherein said aryl and said heteroaryl being mono- or bicyclic and each of aryl and heteroaryl is optionally substituted with one or more independent occurrences of a substituent selected from the group consisting of R5, R6, R7 and R8; each of R2, R3, R4 is independently selected from the group consisting of H, C1-C3haloalkyl, and C1-C3alkyl; each of R5, R6, R7, and R8 is independently selected from the group consisting of halogen, C1-C6alkyl, C1-C6alkoxy, C1-C6haloalkyl, amino, —NHSO2R9, hydroxy, phenyl, and a monocyclic heteroaryl; and R9 is selected from C1-C3haloalkyl and C1-C3alkyl; and (ii) a therapeutically effective amount of a STING agonist; wherein administering the therapeutically effective amount of the STING agonist and the compound results in an increased expression level of at least one chemokine in the patient as compared to any increase in the expression level of the at least one chemokine resulting from administering the compound alone to the patient.
In an aspect, provided herein is a method of upregulating at least one chemokine in a cell comprising: contacting the cell sample with: (i) a compound represented by:
or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein: R1 is selected from the group consisting of aryl and heteroaryl, wherein said aryl and said heteroaryl being mono- or bicyclic and each of aryl and heteroaryl is optionally substituted with one or more independent occurrences of a substituent selected from the group consisting of R5, R6, R7 and R8; each of R2, R3, R4 is independently selected from the group consisting of H, C1-C3haloalkyl, and C1-C3alkyl; each of R5, R6, R7, and R8 is independently selected from the group consisting of halogen, C1-C6alkyl, C1-C6alkoxy, C1-C6haloalkyl, amino, —NHSO2R9, hydroxy, phenyl, and a monocyclic heteroaryl; and R9 is selected from C1-C3haloalkyl and C1-C3alkyl; in an amount sufficient to induce a Type I interferon response by the cell; and (ii) a STING agonist in an amount sufficient to increase the expression level of the at least one chemokine in the cell.
In an aspect, provided herein is a method of treating cancer in a patient in need thereof, comprising administering to the patient: (i) a therapeutically effective amount of a compound represented by Formula III:
or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein: X is selected from N and CR1; R1 is selected from the group consisting of H, C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxyC1-C3alkyl, C3-C6cycloalkyl, cyano, phenyl, and monocyclic heteroaryl, wherein each of phenyl and monocyclic heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of halo, N—C1-C3alkylamino, N,N-diC1-C3alkylamino, C3-C6cycloalkyl, C1-C3alkoxyC1-C3alkyl, C1-C3haloalkyl, C1-C3haloalkoxy, C1-C3alkoxy, and C1-C3alkyl; R2 is selected from the group consisting of H, C1-C3haloalkyl, and C1-C3alkyl; R3 is selected from the group consisting of A, phenyl, and monocyclic heteroaryl, wherein each of phenyl and monocyclic heteroaryl is optionally substituted with one or more occurrences of R4; each R4 is independently selected from the group consisting of COR5, halogen, C1-C6alkyl, C1-C6alkoxy, C1-C6haloalkoxy, amino N—C1-C3alkylamino, N,N-diC1-C3alkylamino, 1-pyrrolidinyl, 1-piperidinyl, 1-azetidinyl, NHSO2R6, SO2R7, hydroxy, C3-C6cycloalkyl, C1-C3alkoxyC1-C3alkyl, C1-C3cyanoalkyl and C1-C6haloalkyl; R5 is selected from the group consisting of C1-C3alkoxy, N—C1-C3alkylamino, N,N-diC1-C3alkylamino, 1-pyrrolidinyl, 1-piperidinyl, and 1-azetidinyl; R6 is selected from C1-C3haloalkyl and C1-C3alkyl; each R7 is independently selected from the group consisting of R8, C1-C6alkyl, N—C1-C3alkylamino, N,N-diC1-C3alkylamino and C1-C3alkoxyC1-C3alkyl, wherein each of C1-C6alkyl and C1-C3alkoxyC1-C3alkyl is optionally substituted with one occurrence of R8, and each of C1-C6alkyl and C1-C3alkoxyC1-C3alkyl is optionally substituted with or one or more independent occurrences of halogen; each R8 is independently selected from the group consisting of phenyl, monocyclic heteroaryl, C3-C6cycloalkyl, and heterocyclyl, wherein each of phenyl, monocyclic heteroaryl, C3-C6cycloalkyl, and heterocyclyl is optionally substituted with one or more occurrences of R9; each R9 is independently selected from the group consisting of halo, N—C1-C3alkylamino, N,N-diC1-C3alkylamino, C1-C3alkoxyC1-C3alkyl, amino, C1-C3haloalkyl, C1-C3alkoxy, C1-C3haloalkoxy, C3-C6cycloalkyl and C1-C3alkyl; A is
R10 is selected from the group consisting of H, halogen, COR11, C1-C6alkyl, C1-C3alkoxyC1-C3alkyl, C1-C6alkoxy, C3-C6cycloalkyl, C1-C3cyanoalkyl, C1-C3haloalkyl, phenyl, and heteroaryl, wherein each of phenyl and heteroaryl is optionally substituted with one or more occurrences of R12, and provided that when R10 is phenyl or heteroaryl, then X is N or CH; each R11 is independently selected from the group consisting of C1-C3alkoxy, N—C1-C3alkylamino, N,N-diC1-C3alkylamino, 1-pyrrolidinyl, 1-piperidinyl, and 1-azetidinyl; Y is selected from the group consisting of CH2, S, SO, SO2, NR13, NCOR7, NCOOR14, NSO2R7, NCOCH2R7, O, and a bond; R12 is selected from the group consisting of C1-C6alkyl, C3-C6cycloalkyl, C1-C3alkoxyC1-C3alkyl, C1-C3haloalkyl, halogen, N—C1-C3alkylamino, N,N-diC1-C3alkylamino, C1-C3haloalkoxy, and C1-C3alkoxy; R13 is selected from H, C1-C3haloalkyl, C1-C3alkoxyC1-C3alkyl, C1-C3alkyl, C3-C6cycloalkyl; and R14 is selected from R8, C1-C6alkyl, C1-C3alkoxyC1-C3alkyl, wherein each of C1-C6alkyl and C1-C3alkoxyC1-C3alkyl is optionally substituted with one occurrence of R8, and each of C1-C6alkyl and C1-C3alkoxyC1-C3alkyl is optionally substituted with or one or more independent occurrences of halogen; and (ii) a therapeutically effective amount of a STING agonist; wherein administering the therapeutically effective amount of the STING agonist and the compound results in an increased expression level of at least one chemokine in the patient as compared to any increase in the expression level of the at least one chemokine resulting from administering the compound alone to the patient.
In an aspect, provided herein is a method of upregulating at least one chemokine in a cell comprising: contacting the cell sample with: (i) a compound represented by:
or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein: X is selected from N and CR1; R1 is selected from the group consisting of H, C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxyC1-C3alkyl, C3-C6cycloalkyl, cyano, phenyl, and monocyclic heteroaryl, wherein each of phenyl and monocyclic heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of halo, N—C1-C3alkylamino, N,N-diC1-C3alkylamino, C3-C6cycloalkyl, C1-C3alkoxyC1-C3alkyl, C1-C3haloalkyl, C1-C3haloalkoxy, C1-C3alkoxy, and C1-C3alkyl; R2 is selected from the group consisting of H, C1-C3haloalkyl, and C1-C3alkyl; R3 is selected from the group consisting of A, phenyl, and monocyclic heteroaryl, wherein each of phenyl and monocyclic heteroaryl is optionally substituted with one or more occurrences of R4; each R4 is independently selected from the group consisting of COR5, halogen, C1-C6alkyl, C1-C6alkoxy, C1-C6haloalkoxy, amino N—C1-C3alkylamino, N,N-diC1-C3alkylamino, 1-pyrrolidinyl, 1-piperidinyl, 1-azetidinyl, NHSO2R6, SO2R7, hydroxy, C3-C6cycloalkyl, C1-C3alkoxyC1-C3alkyl, C1-C3cyanoalkyl and C1-C6haloalkyl; R5 is selected from the group consisting of C1-C3alkoxy, N1-C3alkylamino, N,N-diC1-C3alkylamino, 1-pyrrolidinyl, 1-piperidinyl, and 1-azetidinyl; R6 is selected from C1-C3haloalkyl and C1-C3alkyl; each R7 is independently selected from the group consisting of R8, C1-C6alkyl, N—C1-C3alkylamino, N,N-diC1-C3alkylamino and C1-C3alkoxyC1-C3alkyl, wherein each of C1-C6alkyl and C1-C3alkoxyC1-C3alkyl is optionally substituted with one occurrence of R8, and each of C1-C6alkyl and C1-C3alkoxyC1-C3alkyl is optionally substituted with or one or more independent occurrences of halogen; each R8 is independently selected from the group consisting of phenyl, monocyclic heteroaryl, C3-C6cycloalkyl, and heterocyclyl, wherein each of phenyl, monocyclic heteroaryl, C3-C0cycloalkyl, and heterocyclyl is optionally substituted with one or more occurrences of R9; each R9 is independently selected from the group consisting of halo, N—C1-C3alkylamino, N,N-diC1-C3alkylamino, C1-C3alkoxyC1-C3alkyl, amino, C1-C3haloalkyl, C1-C3alkoxy, C1-C3haloalkoxy, C3-C6cycloalkyl and C1-C3alkyl; A is
R10 is selected from the group consisting of H, halogen, CORDI, C1-C6alkyl, C1-C3alkoxyC1-C3alkyl, C1-C6alkoxy, C3-C6cycloalkyl, C1-C3cyanoalkyl, C1-C3haloalkyl, phenyl, and heteroaryl, wherein each of phenyl and heteroaryl is optionally substituted with one or more occurrences of R12, and provided that when R10 is phenyl or heteroaryl, then X is N or CH; each R11 is independently selected from the group consisting of C1-C3alkoxy, N—C1-C3alkylamino, N,N-diC1-C3alkylamino, 1-pyrrolidinyl, 1-piperidinyl, and 1-azetidinyl; Y is selected from the group consisting of CH2, S, SO, SO2, NR13, NCOR7, NCOOR14, NSO2R7, NCOCH2R7, O, and a bond; R12 is selected from the group consisting of C1-C6alkyl, C3-C6cycloalkyl, C1-C3alkoxyC1-C3alkyl, C1-C3haloalkyl, halogen, N—C1-C3alkylamino, N,N-diC1-C3alkylamino, C1-C3haloalkoxy, and C1-C3alkoxy; R13 is selected from H, C1-C3haloalkyl, C1-C3alkoxyC1-C3alkyl, C1-C3alkyl, C3-C6cycloalkyl; and R14 is selected from R8, C1-C5alkyl, C1-C3alkoxyC1-C3alkyl, wherein each of C1-C6alkyl and C1-C3alkoxyC1-C3alkyl is optionally substituted with one occurrence of R8, and each of C1-C6alkyl and C1-C3alkoxyC1-C3alkyl is optionally substituted with or one or more independent occurrences of halogen; and in an amount sufficient to induce a Type I interferon response by the cell; and (ii) a STING agonist in an amount sufficient to increase the expression level of the at least one chemokine in the cell.
In an aspect, provided herein is a method of treating cancer in a patient in need thereof, comprising: (i) administering to the patient a therapeutically effective amount of a compound represented by Formula IV:
or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein: X is selected from —C(═O)— and a bond; R1 is selected from the group consisting of H, C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxyC1-C3alkyl, C3-C6cycloalkyl, C3-C6cyclohaloalkyl, C1-C3alkoxy, C1-C3haloalkoxy, C3-C6cycloalkoxymethyl, N—C1-C3alkylamino, N,N-diC1-C3alkylamino, 1-pyrrolidinyl, 1-piperidinyl and 1-azetidinyl, provided that when R1 is selected from the group consisting of C1-C3alkoxy, C1-C3haloalkoxy, N—C1-C3alkylamino, N,N-diC1-C3alkylamino, 1-pyrrolidinyl, 1-piperidinyl, and 1-azetidinyl, then X is C═O; R2 is selected from the group consisting of H, C1-C3haloalkyl, and C1-C3alkyl; R3 is selected from the group consisting of A, phenyl and monocyclic heteroaryl, wherein each of phenyl and monocyclic heteroaryl is optionally substituted with one or more occurrences of a substituent independently selected from the group consisting of R4, R5, R6 and R7; each R4, R5, R6, and R7 is independently selected from the group consisting of halo, C1-C6alkyl, C3-C6cycloalkyl, C1-C6alkoxy, C1-C3haloalkoxy, N,N-diC1-C3alkylamino, N—C1-C3alkylamino, 1-azetidinyl, C1-C6haloalkyl, amino, NHSO2R8, SO2R9, and hydroxy; R8 is selected from C1-C3haloalkyl and C1-C3alkyl; each R9 is independently selected from the group consisting of R10, C1-C6alkyl, amino, N—C1-C3alkylamino, N,N-di-C1-C3alkylamino and C1-C3alkoxyC1-C3alkyl, wherein each of C1-C6alkyl and C1-C3alkoxyC1-C3alkyl is optionally substituted with one occurrence of R10, and each of C1-C6alkyl and C1-C3alkoxyC1-C3alkyl is optionally substituted with or one or more independent occurrences of halogen; each R10 is independently selected from the group consisting of phenyl, monocyclic heteroaryl, C3-C6cycloalkyl, and heterocyclyl, wherein each phenyl, monocyclic heteroaryl, C3-C6cycloalkyl, and heterocyclyl is optionally substituted with one or more occurrences of R11; each R11 is independently selected from the group consisting of halo, C1-C3alkoxyC1-C3alkyl, amino, N—C1-C3alkylamino, N,N-diC1-C3alkylamino, C1-C3haloalkoxy, C1-C3alkoxy, C3-C6cycloalkyl, C1-C3haloalkyl, and C1-C3alkyl; A is:
R12 is selected from the group consisting of H, halo, COR13, C1-C6alkyl, C1-C3alkoxyC1-C3alkyl, C1-C6alkoxy, C3-C6cycloalkyl, C1-C3cyanoalkyl, and C1-C3haloalkyl; R13 is selected from the group consisting of C1-C3alkoxy, N—C1-C3alkylamino, N,N-diC1-C3alkylamino, 1-pyrrolidinyl, 1-piperidinyl, and 1-azetidinyl; Y is selected from the group consisting of CH2, S, SO, SO2, NR14, NCOR9, NCOOR15, NSO2R9, NCOCH2R9, O, and a bond; R14 is selected from the group consisting of H, C1-C3haloalkyl, C1-C3alkoxyC1-C3alkyl, C1-C3alkyl, and C3-C6cycloalkyl; and R15 is selected from the group consisting of R10, C1-C6alkyl and C1-C3alkoxyC1-C3alkyl, wherein each of C1-C6alkyl and C1-C3alkoxyC1-C3alkyl is optionally substituted with one occurrence of R10, and each of C1-C6alkyl and C1-C3alkoxyC1-C3alkyl is optionally substituted with or one or more independent occurrences of halogen; and (ii) administering to the patient a therapeutically effective amount of a STING agonist; wherein administering the therapeutically effective amount of the STING agonist and the compound results in an increased expression level of at least one chemokine in the patient as compared to any increase in the expression level of the at least one chemokine resulting from administering the compound alone to the patient.
In an aspect, provided herein is a method of upregulating at least one chemokine in a cell comprising: contacting the cell sample with: (i) a compound represented by:
or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein: X is selected from —C(═O)— and a bond; R1 is selected from the group consisting of H, C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxyC1-C3alkyl, C3-C6cycloalkyl, C3-C6cyclohaloalkyl, C1-C3alkoxy, C1-C3haloalkoxy, C3-C6cycloalkoxymethyl, N—C1-C3alkylamino, N,N-diC1-C3alkylamino, 1-pyrrolidinyl, 1-piperidinyl and 1-azetidinyl, provided that when R1 is selected from the group consisting of C1-C3alkoxy, C1-C3haloalkoxy, N—C1-C3alkylamino, N,N-diC1-C3alkylamino, 1-pyrrolidinyl, 1-piperidinyl, and 1-azetidinyl, then X is C═O; R2 is selected from the group consisting of H, C1-C3haloalkyl, and C1-C3alkyl; R3 is selected from the group consisting of A, phenyl and monocyclic heteroaryl, wherein each of phenyl and monocyclic heteroaryl is optionally substituted with one or more occurrences of a substituent independently selected from the group consisting of R4, R5, R6 and R7; each R4, R5, R6, and R7 is independently selected from the group consisting of halo, C1-C6alkyl, C3-C6cycloalkyl, C1-C6alkoxy, C1-C3haloalkoxy, N,N-diC1-C3alkylamino, N—C1-C3alkylamino, 1-azetidinyl, C1—C haloalkyl, amino, NHSO2R8, SO2R9, and hydroxy; R8 is selected from C1-C3haloalkyl and C1-C3alkyl; each R9 is independently selected from the group consisting of R10, C1-C6alkyl, amino, N—C1-C3alkylamino, N,N-di-C1-C3alkylamino and C1-C3alkoxyC1-C3alkyl, wherein each of C1-C6alkyl and C1-C3alkoxyC1-C3alkyl is optionally substituted with one occurrence of R10, and each of C1-C6alkyl and C1-C3alkoxyC1-C3alkyl is optionally substituted with or one or more independent occurrences of halogen; each R10 is independently selected from the group consisting of phenyl, monocyclic heteroaryl, C3-C6cycloalkyl, and heterocyclyl, wherein each phenyl, monocyclic heteroaryl, C3-C6cycloalkyl, and heterocyclyl is optionally substituted with one or more occurrences of R11; each R11 is independently selected from the group consisting of halo, C1-C3alkoxyC1-C3alkyl, amino, N—C1-C3alkylamino, N,N-diC1-C3alkylamino, C1-C3haloalkoxy, C1-C3alkoxy, C3-C6cycloalkyl, C1-C3haloalkyl, and C1-C3alkyl; A is:
R12 is selected from the group consisting of H, halo, COR13, C1-C6alkyl, C1-C3alkoxyC1-C3alkyl, C1-C6alkoxy, C3-C6cycloalkyl, C1-C3cyanoalkyl, and C1-C3haloalkyl; R13 is selected from the group consisting of C1-C3alkoxy, N—C1-C3alkylamino, N,N-diC1-C3alkylamino, 1-pyrrolidinyl, 1-piperidinyl, and 1-azetidinyl; Y is selected from the group consisting of CH2, S, SO, SO2, NR14, NCOR9, NCOOR15, NSO2R9, NCOCH2R9, O, and a bond; R14 is selected from the group consisting of H, C1-C3haloalkyl, C1-C3alkoxyC1-C3alkyl, C1-C3alkyl, and C3-C6cycloalkyl; and R15 is selected from the group consisting of R10, C1-C6alkyl and C1-C3alkoxyC1-C3alkyl, wherein each of C1-C6alkyl and C1-C3alkoxyC1-C3alkyl is optionally substituted with one occurrence of R10, and each of C1-C6alkyl and C1-C3alkoxyC1-C3alkyl is optionally substituted with or one or more independent occurrences of halogen; and in an amount sufficient to induce a Type I interferon response by the cell; and (ii) a STING agonist in an amount sufficient to increase the expression level of the at least one chemokine in the cell.
In an aspect, provided herein is a method of treating cancer in a patient in need thereof, comprising: (i) administering to the patient a therapeutically effective amount of a compound represented by Formula V:
or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein: R1 is selected from phenyl and monocyclic 5-6 membered heteroaryl, wherein each of phenyl and monocyclic 5-6 membered heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, C1-C6alkyl, C3-C4cycloalkyl, C1-C6alkoxy, C1-C6haloalkyl, C1-C6haloalkoxy, amino, N—C1-C3alkylamino and N,N-diC1-C3alkylamino; R2 is selected from the group consisting of H, C1-C3haloalkyl, and C1-C3alkyl; R3 is selected from the group consisting of A, phenyl, and monocyclic heteroaryl, wherein each of phenyl and heteroaryl is optionally substituted with one or more occurrences of a substituent independently selected from the group consisting of R4, R5, R6, and R7; each of R4, R5, R6, and R7 is independently selected from the group consisting of halogen, C1-C6alkyl, C3-C4cycloalkyl, C1-C6alkoxy, C1-C6haloalkyl, C1-C6haloalkoxy, azetidine, amino, N—C1-C3alkylamino, N,N-diC1-C3alkylamino, NHSO2R8, SO2R9, and hydroxy; R8 is selected from C1-C3haloalkyl and C1-C3alkyl; each R9 is independently selected from the group consisting of R10, C1-C6alkyl, amino, N—C1-C3alkylamino, N,N-diC1-C3alkylamino, and C1-C3alkoxyC1-C3alkyl, wherein each of C1-C6alkyl and C1-C3alkoxyC1-C3alkyl is optionally substituted with one occurrence of R10, and each of C1-C6alkyl and C1-C6alkoxyC1-C3alkyl is optionally substituted with or one or more independent occurrences of halogen; each R10 is independently selected from the group consisting of phenyl, benzyl, monocyclic heteroaryl, C3-C6cycloalkyl, and heterocyclyl, wherein each of phenyl, benzyl, monocyclic heteroaryl, C3-C6cycloalkyl, and heterocyclyl is optionally substituted with one or more occurrences of R11; each R11 is independently selected from the group consisting of halogen, C1-C3haloalkyl, C3-C4cycloalkyl, C1-C3alkyl, amino, N—C1-C3alkylamino, N,N-diC1-C3alkylamino, and C1-C3alkoxyC1-C3alkyl; A is
R2 is selected from the group consisting of H, halogen, COR13, C1-C5alkyl, C3-C6cycloalkyl, C1-C3alkoxyC1-C3alkyl, C1-C6alkoxy, C3-C6cycloalkyl, C1-C3cyanoalkyl, and C1-C3haloalkyl; R13 is selected from the group consisting of C1-C3alkoxy, N—C1-C3alkylamino, N,N-diC1-C3alkylamino, 1-pyrrolidinyl, 1-piperidinyl, and 1-azetidinyl; Y is selected from the group consisting of CH2, S, SO, SO2, NR14, NCOR9, NCOOR15, NSO2R9, NCOCH2R9, O, and a bond; R14 is selected from H, C1-C3haloalkyl, C1-C3alkoxyC1-C3alkyl, C1-C3alkyl, and C3-C6cycloalkyl; and R15 is selected from R10, C1-C6alkyl, and C1-C3alkoxyC1-C3alkyl, wherein each of C1-C6alkyl and C1-C3alkoxyC1-C3alkyl is optionally substituted with one occurrence of R10, and each of C1-C6alkyl and C1-C3alkoxyC1-C3alkyl is optionally substituted with or one or more independent occurrences of halogen; and Z is selected from CH and N; and (ii) administering to the patient a therapeutically effective amount of a STING agonist; wherein administering the therapeutically effective amount of the STING agonist and the compound results in an increased expression level of at least one chemokine in the patient as compared to any increase in the expression level of the at least one chemokine resulting from administering the compound alone to the patient.
In an aspect, provided herein is a method of upregulating at least one chemokine in a cell comprising: contacting the cell sample with: (i) a compound represented by:
or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein: R1 is selected from phenyl and monocyclic 5-6 membered heteroaryl, wherein each of phenyl and monocyclic 5-6 membered heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, C1-C6alkyl, C3-C4cycloalkyl, C1-C6alkoxy, C1-C6haloalkyl, C1-C6haloalkoxy, amino, N—C1-C3alkylamino and N,N-diC1-C3alkylamino; R2 is selected from the group consisting of H, C1-C3haloalkyl, and C1-C3alkyl; R3 is selected from the group consisting of A, phenyl, and monocyclic heteroaryl, wherein each of phenyl and heteroaryl is optionally substituted with one or more occurrences of a substituent independently selected from the group consisting of R4, R5, R6, and R7; each of R4, R5, R6, and R7 is independently selected from the group consisting of halogen, C1-C6alkyl, C3-C4cycloalkyl, C1-C6alkoxy, C1-C6haloalkyl, C1-C6haloalkoxy, azetidine, amino, N—C1-C3alkylamino, N,N-diC1-C3alkylamino, NHSO2R8, SO2R9, and hydroxy; R8 is selected from C1-C3haloalkyl and C1-C3alkyl; each R9 is independently selected from the group consisting of R10, C1-C6alkyl, amino, N—C1-C3alkylamino, N,N-diC1-C3alkylamino, and C1-C3alkoxyC1-C3alkyl, wherein each of C1-C6alkyl and C1-C3alkoxyC1-C3alkyl is optionally substituted with one occurrence of R10, and each of C1-C6alkyl and C1-C3alkoxyC1-C3alkyl is optionally substituted with or one or more independent occurrences of halogen; each R10 is independently selected from the group consisting of phenyl, benzyl, monocyclic heteroaryl, C3-C6cycloalkyl, and heterocyclyl, wherein each of phenyl, benzyl, monocyclic heteroaryl, C3-C6cycloalkyl, and heterocyclyl is optionally substituted with one or more occurrences of R11; each R11 is independently selected from the group consisting of halogen, C1-C3haloalkyl, C3-C4cycloalkyl, C1-C3alkyl, amino, N—C1-C3alkylamino, N,N-diC1-C3alkylamino, and C1-C3alkoxyC1-C3alkyl; A is
R12 is selected from the group consisting of H, halogen, COR13, C1-C6alkyl, C3-C6cycloalkyl, C1-C3alkoxyC1-C3alkyl, C1-C6alkoxy, C3-C6cycloalkyl, C1-C3cyanoalkyl, and C1-C3haloalkyl; R13 is selected from the group consisting of C1-C3alkoxy, N—C1-C3alkylamino, N,N-diC1-C3alkylamino, 1-pyrrolidinyl, 1-piperidinyl, and 1-azetidinyl; Y is selected from the group consisting of CH2, S, SO, SO2, NR14, NCOR9, NCOOR15, NSO2R9, NCOCH2R9, O, and a bond; R14 is selected from H, C1-C3haloalkyl, C1-C3alkoxyC1-C3alkyl, C1-C3alkyl, and C3-C6cycloalkyl; and R15 is selected from R10, C1-C6alkyl, and C1-C3alkoxyC1-C3alkyl, wherein each of C1-C6alkyl and C1-C3alkoxyC1-C3alkyl is optionally substituted with one occurrence of R10, and each of C1-C6alkyl and C1-C3alkoxyC1-C3alkyl is optionally substituted with or one or more independent occurrences of halogen; and Z is selected from CH and N; and in an amount sufficient to induce a Type I interferon response by the cell; and (ii) a STING agonist in an amount sufficient to increase the expression level of the at least one chemokine in the cell.
In an aspect, provided herein is a method of treating cancer in a patient in need thereof, comprising: (i) administering to the patient a therapeutically effective amount of a compound represented by Formula VI:
or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein: R1 is selected from C1-C3alkyl and cyclopropyl; R2 is selected from the group consisting of H, C1-C3haloalkyl, and C1-C3alkyl; A is selected from:
each R3 is independently selected from the group consisting of R6, C1-C6alkyl, amino N—C1-C3alkylamino, N,N-diC1-C3alkylamino, and C1-C3alkoxyC1-C3alkyl, wherein each of C1-C6alkyl and C1-C3alkoxyC1-C3alkyl is optionally substituted with one occurrence of R6, and each of C1-C6alkyl and C1-C3alkoxyC1-C3alkyl is optionally substituted with or one or more independent occurrences of halogen; R4 is selected from the group consisting of C1-C6alkyl, C1-C6alkoxy, C1-C6haloalkyl, C3-C6cycloalkyl, and phenyl, wherein phenyl is optionally substituted with one or more occurrences of a substituent independently selected from the group consisting of fluoro, chloro, methyl, methoxy, dimethylamino, trifluoromethoxy, trifluoromethyl, and cyclopropyl; R5 is selected from the group consisting of halogen, C1-C6alkyl, C1-C6alkoxy, C1-C6haloalkyl, and C3-C6cycloalkyl; each R6 is independently selected from the group consisting of phenyl, monocyclic heteroaryl, C3-C6cycloalkyl, and heterocyclyl, wherein each of phenyl, monocyclic heteroaryl, C3-C6cycloalkyl, and heterocyclyl is optionally substituted with one or more occurrences of R7; and each R7 is independently selected from the group consisting of halogen, amino, N—C1-C3alkylamino, N,N-diC1-C3alkylamino and C1-C3alkoxyC1-C3alkyl, C1-C3alkoxy, C1-C3haloalkoxy, C3-C6cycloalkyl, C1-C3haloalkyl, and C1-C3alkyl; and (ii) administering to the patient a therapeutically effective amount of a STING agonist; wherein administering the therapeutically effective amount of the STING agonist and the compound results in an increased expression level of at least one chemokine in the patient as compared to any increase in the expression level of the at least one chemokine resulting from administering the compound alone to the patient.
In an aspect, provided herein is a method of upregulating at least one chemokine in a cell comprising: contacting the cell sample with: (i) a compound represented by:
or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein: R1 is selected from C1-C3alkyl and cyclopropyl; R2 is selected from the group consisting of H, C1-C3haloalkyl, and C1-C3alkyl; A is selected from:
each R3 is independently selected from the group consisting of R6, C1-C6alkyl, amino N—C1-C3alkylamino, N, N-diC1-C3alkylamino, and C1-C3alkoxyC1-C3alkyl, wherein each of C1-C6alkyl and C1-C3alkoxyC1-C3alkyl is optionally substituted with one occurrence of R6, and each of C1-C6alkyl and C1-C3alkoxyC1-C3alkyl is optionally substituted with or one or more independent occurrences of halogen; R4 is selected from the group consisting of C1-C6alkyl, C1-C6alkoxy, C1-C6haloalkyl, C3-C6cycloalkyl, and phenyl, wherein phenyl is optionally substituted with one or more occurrences of a substituent independently selected from the group consisting of fluoro, chloro, methyl, methoxy, dimethylamino, trifluoromethoxy, trifluoromethyl, and cyclopropyl; R5 is selected from the group consisting of halogen, C1-C6alkyl, C1-C6alkoxy, C1-C6haloalkyl, and C3-C6cycloalkyl; each R6 is independently selected from the group consisting of phenyl, monocyclic heteroaryl, C3-C6cycloalkyl, and heterocyclyl, wherein each of phenyl, monocyclic heteroaryl, C3-C6cycloalkyl, and heterocyclyl is optionally substituted with one or more occurrences of R7; and each R7 is independently selected from the group consisting of halogen, amino, N—C1-C3alkylamino, N,N-diC1-C3alkylamino and C1-C3alkoxyC1-C3alkyl, C1-C3alkoxy, C1-C3haloalkoxy, C3-C6cycloalkyl, C1-C3haloalkyl, and C1-C3alkyl; in an amount sufficient to induce a Type I interferon response by the cell; and (ii) a STING agonist in an amount sufficient to increase the expression level of the at least one chemokine in the cell.
In an aspect, provided herein is a method of treating cancer in a patient in need thereof, comprising: (i) means for inducing a Type I interferon response in a cancerous cell in the patient; and (ii) administering a therapeutically effective amount of a STING agonist to the patient;
wherein the therapeutically effective amount of the STING agonist results in an increased expression level of at least one chemokine in the patient as compared to any increase in the expression level of the at least one chemokine resulting from administering the compound to the patient.
The definitions set forth in this application are intended to clarify terms used throughout this application. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of skill in art to which the subject matter herein belongs. As used in the specification and the appended claims, unless specified to the contrary, the following terms have the meaning indicated in order to facilitate the understanding of the present disclosure. When a substituent is listed without indicating the atom via which such substituent is bonded to the rest of the compound of a given formula, then such substituent may be bonded via any atom in such substituent. Combinations of substituents, positions of substituents and/or variables are permissible only if such combinations result in stable compounds. It is understood that substituents and substitution patterns on the compounds of the present disclosure can be selected by one of ordinary skilled person in the art to result chemically stable compounds which can be readily synthesized by techniques known in the art, as well as those methods set forth below, from readily available starting materials. If a substituent is itself substituted with more than one group, it is understood that these multiple groups may be on the same carbon or on different carbons, so long as a stable structure results.
It has been found that VPS34 inhibitors can activate a type I IFN signaling in a through activation of the cGAS/STING pathway. In some embodiments, both pharmacological and siRNA-mediated VPS34 inhibition increases signaling of the cGAS-STING pathway. In some embodiments, an increase in signaling of the cGAS-STING pathway leads to expression and secretion of IFNβ, CCL5, and CXCL10. In some embodiments, a combination of VPS34 inhibitor and a STING agonist further induces cytokine release in both human and murine cancer cells. In other embodiments, the VPS34 inhibitor Compound 1 treatment sensitizes Renca and B16-F10 tumor-bearing mice to STING agonist treatment and significantly improved mice survival.
As used herein, “Compound 1” refers to a compound having the structure:
and having the name 4-((R)-3-methylmorpholino)-6-((R)-2-(trifluoromethyl)piperidin-1-yl)pyridin-2(1H)-one.
As used herein, “Compound 2” refers to a compound having the structure:
and having the name (S)-9-((5-chloropyridin-3-yl)methyl)-2-((R)-3-methylmorpholino)-8-(trifluoromethyl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one.
As used herein, the term “C1-C6alkyl” means both linear and branched chain saturated hydrocarbon groups with 1 to 6 carbon atoms. Examples of C1-C6alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl, sec-butyl, t-butyl, n-pentyl, 4-methyl-butyl, n-hexyl, 2-ethyl-butyl groups. Among unbranched C1-C6alkyl groups, typical ones are methyl, ethyl, n-propyl, n-butyl, n-pentyl and n-hexyl groups. Among branched alkyl groups, there may be mentioned iso-propyl, iso-butyl, sec-butyl, t-butyl, 4-methyl-butyl and 2-ethyl-butyl groups.
As used herein, the term “C1-C3alkyl” means both linear and branched chain saturated hydrocarbon groups with 1 to 3 carbon atoms. Examples of C1-C3alkyl groups include methyl, ethyl, n-propyl and isopropyl groups.
As used herein, the term “C1-C6alkoxy” means the group O-alkyl, where “C1-C6alkyl” is used as described above. Examples of C1-C6alkoxy groups include, but are not limited to, methoxy, ethoxy, isopropoxy, n-propoxy, n-butoxy, n-hexoxy, 3-methyl-butoxy groups.
As used herein, the term “C1-C3alkoxy” means the group O-alkyl, where “C1-C3alkyl” is used as described above. Examples of C1-C3alkoxy groups include, but are not limited to, methoxy, ethoxy, isopropoxy and n-propoxy.
As used herein, the term “C1-C6haloalkyl” means both linear and branched chain saturated hydrocarbon groups, with 1 to 6 carbon atoms and with 1 to all hydrogens substituted by a halogen of different or same type. Examples of C1-C6haloalkyl groups include methyl substituted with 1 to 3 halogen atoms, ethyl substituted with 1 to 5 halogen atoms, n-propyl or iso-propyl substituted with 1 to 7 halogen atoms, n-butyl or iso-butyl substituted with 1 to 9 halogen atoms, and sec-butyl or t-butyl groups substituted with 1 to 9 halogen atoms.
As used herein, the term “C1-C3haloalkyl” means both linear and branched chain saturated hydrocarbon groups, with 1 to 3 carbon atoms and with 1 to all hydrogens substituted by a halogen of different or same type. Examples of C1-C3haloalkyl groups include methyl substituted with 1 to 3 halogen atoms, ethyl substituted with 1 to 5 halogen atoms, and n-propyl or iso-propyl substituted with 1 to 7 halogen atoms.
As used herein, the term “C1-C3haloalkoxy” means both linear and branched chain saturated alkoxy groups, with 1 to 3 carbon atoms and with 1 to all hydrogen atoms substituted by a halogen atom of different or same type. Examples of C1-C3haloalkoxy groups include methoxy substituted with 1 to 3 halogen atoms, ethoxy substituted with 1 to 5 halogen atoms, and n-propoxy or iso-propoxy substituted with 1 to 7 halogen atoms.
As used herein, the term “C1-C3fluorooalkyl” means both linear and branched chain saturated hydrocarbon groups, with 1 to 3 carbon atoms and with 1 to all hydrogen atoms substituted by a fluorine atom. Examples of C1-C3fluoroalkyl groups include methyl substituted with 1 to 3 fluorine atoms, ethyl substituted with 1 to 5 fluorine atoms, and n-propyl or iso-propyl substituted with 1 to 7 fluorine atoms.
As used herein, the term “C1-C3fluorooalkoxy” means both linear and branched chain saturated alkoxy groups, with 1 to 3 carbon atoms and with 1 to all hydrogen atoms substituted by a fluorine atom. Examples of C1-C3fluoroalkoxy groups include methoxy substituted with 1 to 3 fluorine atoms, ethoxy substituted with 1 to 5 fluorine atoms, and n-propoxy or iso-propoxy substituted with 1 to 7 fluorine atoms.
As used herein, the term “C3-C6cycloalkyl” means a cyclic saturated hydrocarbon group, with 3 to 6 carbon atoms. Examples of C3-C6cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
As used herein, the term “C1-C3alkoxyC1-C3alkyl” means both a both linear and branched chain saturated hydrocarbon group, with 1 to 3 carbon atoms, substituted with an alkoxy group with 1 to 3 carbon atoms. Examples of C1-C3alkoxyC1-C3alkyl groups are drawn below.
As used herein, the term “C1-C3cyanoalkyl” means both a linear and branched chain cyano (CN) derivative, with one to three carbon atoms including the carbon atom that is part of the cyano group. Examples of C1-C3cyanoalkyl groups are drawn below.
As used herein, the term “halogen” means fluorine, fluoro, chloro, bromine, bromo, iodine, or iodine.
As used herein, the term “aryl” means a monocyclic or bicyclic aromatic carbocyclic group. Examples of aryl groups include phenyl and naphthyl. A naphthyl group may be attached through the 1 or the 2 position. In a bicyclic aryl, one of the rings may be partially saturated. Examples of such groups include indanyl and tetrahydronaphthyl.
As used herein, the term “monocyclic aryl” means a monocyclic aromatic carbocyclic group. Examples of monocyclic aryl groups include phenyl.
As used herein, the term “heteroaryl” means a monocyclic or bicyclic aromatic group of carbon atoms wherein from one to three of the carbon atoms is/are replaced by one or more heteroatoms independently selected from nitrogen, oxygen or sulfur. In a bicyclic aryl, one of the rings may be partially saturated. Examples of such groups include indolinyl, dihydrobenzofuran and 1,3-benzodioxolyl.
As used herein, the term “monocyclic heteroaryl” means a monocyclic aromatic group of carbon atoms wherein from one to three of the carbon atoms is/are replaced by one or more heteroatoms independently selected from nitrogen, oxygen or sulfur.
Examples of monocyclic heteroaryl groups include, but are not limited to, furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, pyridyl, triazolyl, triazinyl, pyridazyl, isothiazolyl, isoxazolyl, pyrazinyl, pyrazolyl, and pyrimidinyl.
Examples of bicyclic heteroaryl groups include, but are not limited to, quinoxalinyl, quinazolinyl, pyridopyrazinyl, benzoxazolyl, benzothiophenyl, benzimidazolyl, naphthyridinyl, quinolinyl, benzofuryl, indolyl, indazolyl, benzothiazolyl,
pyridopyrimidinyl, and isoquinolinyl.
As used herein, the term “heterocyclyl” means a cyclic group of carbon atoms wherein from one to three of the carbon atoms is/are replaced by one or more heteroatoms independently selected from nitrogen, oxygen and sulfur. Examples of heterocyclyl groups include, but are not limited to, tetrahydrofuryl, tetrahydropyranyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl and dioxanyl.
A “combination therapy” is a treatment that includes the administration of two or more therapeutic agents, e.g., a compound of Formula I and an antibiotic, a viral protease inhibitor, or an anti-viral nucleoside anti-metabolite, to a patient in need thereof.
“Disease,” “disorder,” and “condition” are used interchangeably herein.
“Individual,” “patient,” or “subject” are used interchangeably and include any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses, or primates, and most preferably humans. The compounds described herein can be administered to a mammal, such as a human, but can also be administered to other mammals such as an animal in need of veterinary treatment, e.g., domestic animals (e.g., dogs, cats, and the like), farm animals (e.g., cows, sheep, pigs, horses, and the like) and laboratory animals (e.g., rats, mice, guinea pigs, and the like).
“Pharmaceutically or pharmacologically acceptable” include molecular entities and compositions that do not produce an adverse, allergic or other untoward reaction when administered to an animal, or a human, as appropriate. For human administration, preparations should meet sterility, pyrogenicity, and general safety and purity standards as required by FDA Office of Biologics standards.
The term “pharmaceutically acceptable carrier” or “pharmaceutically acceptable excipient” as used herein refers to any and all solvents, dispersion media, coatings, isotonic and absorption delaying agents, and the like, that are compatible with pharmaceutical administration. The use of such media and agents for pharmaceutically active substances is well known in the art. The compositions may also contain other active compounds providing supplemental, additional, or enhanced therapeutic functions.
The term “pharmaceutical composition” as used herein refers to a composition comprising at least one compound as disclosed herein formulated together with one or more pharmaceutically acceptable carriers.
The term “pharmaceutically acceptable salt(s)” as used herein refers to salts of acidic or basic groups that may be present in compounds used in the compositions. Compounds included in the present compositions that are basic in nature are capable of forming a wide variety of salts with various inorganic and organic acids. The acids that may be used to prepare pharmaceutically acceptable acid addition salts of such basic compounds are those that form non-toxic acid addition salts, i.e., salts containing pharmacologically acceptable anions, including, but not limited to, malate, oxalate, chloride, bromide, iodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate, citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate and pamoate (i.e., 1,1′-methylene-bis-(2-hydroxy-3-naphthoate)) salts. Compounds included in the present compositions that are acidic in nature are capable of forming base salts with various pharmacologically acceptable cations. Examples of such salts include alkali metal or alkaline earth metal salts, particularly calcium, magnesium, sodium, lithium, zinc, potassium, and iron salts. Compounds included in the present compositions that include a basic or acidic moiety may also form pharmaceutically acceptable salts with various amino acids. The compounds of the disclosure may contain both acidic and basic groups; for example, one amino and one carboxylic acid group. In such a case, the compound can exist as an acid addition salt, a zwitterion, or a base salt.
The compounds of the disclosure may contain one or more chiral centers and, therefore, exist as stereoisomers. The term “stereoisomers” when used herein consist of all enantiomers or diastereomers. These compounds may be designated by the symbols “(+),” “(−),” “R” or “S,” depending on the configuration of substituents around the stereogenic carbon atom, but the skilled artisan will recognize that a structure may denote a chiral center implicitly. The presently described compounds encompasses various stereoisomers of these compounds and mixtures thereof. Mixtures of enantiomers or diastereomers may be designated “(±)” in nomenclature, but the skilled artisan will recognize that a structure may denote a chiral center implicitly.
In the present specification, the term “therapeutically effective amount” means the amount of the subject compound that will elicit the biological or medical response of a tissue, system or animal, (e.g., mammal or human) that is being sought by the researcher, veterinarian, medical doctor or other clinician. The compounds described herein are administered in therapeutically effective amounts to treat a disorder.
“Treating” includes any effect, e.g., lessening, reducing, modulating, or eliminating, that results in the improvement of the condition, disease, disorder and the like.
The disclosure also embraces isotopically labeled compounds which are identical to those recited herein, except that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds of the present disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine, such as 2H, 3H, 13C, 14C, 15N, 18O, 17O, 31P, 32P, 35S, 18F, and 36Cl, respectively. For example, a compound of the disclosure may have one or more H atom replaced with deuterium.
Individual enantiomers and diastereomers of compounds of the present disclosure can be prepared synthetically from commercially available starting materials that contain asymmetric or stereogenic centers, or by preparation of racemic mixtures followed by resolution methods well known to those of ordinary skill in the art. These methods of resolution are exemplified by (1) attachment of a mixture of enantiomers to a chiral auxiliary, separation of the resulting mixture of diastereomers by recrystallization or chromatography and liberation of the optically pure product from the auxiliary, (2) salt formation employing an optically active resolving agent, (3) direct separation of the mixture of optical enantiomers on chiral liquid chromatographic columns or (4) kinetic resolution using stereoselective chemical or enzymatic reagents. Racemic mixtures can also be resolved into their component enantiomers by well-known methods, such as chiral-phase liquid chromatography or crystallizing the compound in a chiral solvent. Stereoselective syntheses, a chemical or enzymatic reaction in which a single reactant forms an unequal mixture of stereoisomers during the creation of a new stereocenter or during the transformation of a pre-existing one, are well known in the art. Stereoselective syntheses encompass both enantio- and diastereoselective transformations, and may involve the use of chiral auxiliaries. For examples, see Carreira and Kvaerno, Classics in Stereoselective Synthesis, Wiley-VCH: Weinheim, 2009.
In some embodiments, described herein is a compound of Formula I:
or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein: R1, R2, and R3 are independently selected from the group consisting of H, C1-C3haloalkyl, and C1-C3alkyl; A represents:
is a single bond or a double bond; X is selected from the group consisting of CH2, S, SO, SO2, NR5, NCOR5, NCOR9, NCOCH2R9, O, and a bond; Y is selected from the group consisting of N, CH, and C, provided that, when Y is CH,
is a single bond; n is selected from 1, 2, 3 and 4; R4 is selected from the group consisting of H, halogen, COR6, C1-C6alkyl, C1-C3alkoxyC1-C3alkyl, C1-C6alkoxy, C3-C6cycloalkyl, C3-C6heterocyclyl, C1-C3cyanoalkyl, C1-C3haloalkyl, aryl, and heteroaryl, wherein said aryl and said heteroaryl are optionally substituted with one or more R7; R5 is selected from the group consisting of H, C1-C3fluoroalkyl, C1-C3alkyl, C1-C3alkoxyC1-C3alkyl, and C3-C6cycloalkyl; R6 is selected from the group consisting of C1-C3alkoxy, N—C1-C3alkylamino, N,N-diC1-C3alkylamino, 1-pyrrolidinyl, 1-piperidinyl, and 1-azetidinyl; each R7 is independently selected from the group consisting of C1-C6alkyl, C3-C6cycloalkyl, C1-C3alkoxyC1-C3alkyl, C1-C3haloalkyl, halogen, N—C1-C3alkylamino, N,N-diC1-C3alkylamino, C1-C3haloalkoxy and C1-C3alkoxy; R9 is selected from the group consisting of C1-C3alkyl, C1-C3alkoxy, C3-C6cycloalkyl, heterocyclyl, phenyl and a monocyclic heteroaryl, wherein said heterocyclyl, said phenyl and said monocyclic heteroaryl are optionally substituted with one or two R8; and each R8 is independently selected from the group consisting of halogen, C1-C3haloalkyl and C1-C3alkyl.
In some embodiments, R1 is H. In some embodiments, R2 is H. In some embodiments, R3 is C1-C3alkyl. In some embodiments, A is piperidinyl. In some embodiments, R4 is C1-C3haloalkyl.
In some embodiments, R4 is selected from the group consisting of hydrogen, halogen, COR6, C1-C6alkyl, C1-C3alkoxyC1-C3alkyl, C1-C6alkoxy, C3-C6cycloalkyl, C1-C3cyanoalkyl, C1-C3haloalkyl, aryl and heteroaryl, wherein said aryl and said heteroaryl are optionally substituted with one or more R7.
In some embodiments, Y is N. In some embodiments of this aspect, R1 and re are independently selected from hydrogen and methyl. In some embodiments, R2 is hydrogen. In some embodiments, R1 is hydrogen. In some embodiments, R3 is methyl. In some embodiments, R3 is hydrogen. In some embodiments, R5 is C1-C3alkyl. In some embodiments, R6 is N—C1-C3alkylamino or N,N-diC1-C3alkylamino, such as N,N-diC1-C3alkylamino. In some embodiments, R6 is dimethylamino. In some embodiments, R7 is selected from the group consisting of halogen, C1-C3fluoroalkyl, C1-C3fluoroalkoxy, C1-C3alkoxy, C1-C3alkyl, C3-C6cycloalkyl and N,N-diC1-C3alkylamino. In some embodiments, R7 is selected from the group consisting of fluoro, chloro, trifluoromethyl, trifluoromethoxy, methoxy, methyl, ethyl, cyclopropyl and dimethylamino. In some embodiments, R9 is selected from the group consisting of C1-C3alkoxy, heterocyclyl, phenyl and a monocyclic heteroaryl, wherein said heterocyclyl, said phenyl and said nonocyclic heteroaryl are optionally substituted with one or two R8. In some embodiments, R9 is selected from the group consisting of heterocyclyl, phenyl and a monocyclic heteroaryl, wherein said heterocyclyl, said phenyl and said monocyclic heteroaryl are optionally substituted with one or two R8. In some embodiments, R9 is selected from the group consisting of tetrahydrofuryl, phenyl and pyridyl, each optionally substituted with one or two R8. In some embodiments, R8 is halogen. In some embodiments, said monocyclic heteroaryl in R4 is selected from the group consisting of pyridyl, furyl, isoxasolyl, pyrazolyl and thiazolyl, each optionally substituted with one or more R7.
In some embodiments R4 selected from the group consisting of:
In some embodiments R7 is selected from the group consisting of fluoro, chloro, C1-C3alkoxy, C1-C3fluoroalkoxy, C1-C3fluoroalkyl, C3-C6cycloalkyl, N,N-diC1-C3alkylamino. In some embodiments, R7 is selected from the group consisting of fluoro, chloro, methyl, ethyl, methoxy, trifluoromethoxy, trifluoromethyl, cyclopropyl and N,N-dimethylamino. In some embodiments, X represents a bond. In some embodiments, R4 is selected from the group consisting of:
In some embodiments, A is selected from the group consisting of:
In some embodiments, X is selected from the group consisting of CH2, SO, SO2, NR5, NCOR5, NCOR9, NCOCH2R9 and O; and R5 is C1-C3alkyl.
In some embodiments, R4 is selected from the group consisting of hydrogen, C1-C6alkyl, C3-C6cycloalkyl, C1-C3haloalkyl and phenyl, wherein phenyl is optionally substituted with one, or more R7.
In some embodiments, A is selected from the group consisting of:
In some embodiments, X is selected from the group consisting of CH2, SO, SO2, NR5, NCOR5, NCOR9, NCOCH2R9, O, and a bond; R4 is selected from the group consisting of hydrogen, COR6, C1-C3alkyl, methoxyC1-C3alkyl, C3-C6cycloalkyl, C1-C3fluoroalkyl, phenyl and a monocyclic heteroaryl, wherein said phenyl and said monocyclic heteroaryl are optionally substituted with one or two R7; R3 is C1-C3alkyl; R6 is N,N-diC1-C3alkylamino; and R7 is selected from fluoro, chloro, C1-C3alkyl, C1-C3alkoxy, C1-C3fluoroalkoxy, C1-C3fluoroalkyl, C3-C6cycloalkyl and N,N-diC1-C3alkylamino.
In some embodiments, Y is CH or C; X is O; and R4 is hydrogen. In some embodiments, R1 and R2 are hydrogen; R3 is methyl; X is selected from the group consisting of CH2, O, NCOR5, NCOR9, NCOCH2R9, and a bond; Y is N; R4 is selected from the group consisting of hydrogen, phenyl, and trifluoromethyl; R3 is methyl; R7 is methoxy; R9 is selected from the group consisting of pyridyl, phenyl; and R8 is fluoro. In some embodiments, R1 and R2 are hydrogen; R3 is methyl; X is selected from the group consisting of CH2, O, NCOR5, NCOCH2R9, and a bond; Y is N; R4 is phenyl or trifluoromethyl, said phenyl being substituted with one or more R7; R5 is methyl; R7 is methoxy or halogen, such as methoxy or chloro; R9 is phenyl, said phenyl being optionally substituted by one or more R8; and R8 is halogen, such as fluoro. In some embodiments, R4 is selected from trifluoromethyl and phenyl, said phenyl being meta-substituted with methoxy or chloro. In some embodiments, R7 is methoxy or chloro; and R8 is fluoro.
In some embodiments, A represents
In some embodiments, A represents
In some embodiments, R1 and R2 are hydrogen; R3 is methyl; X is selected from NCOR9 and NCOCH2R9; R4 is selected from trifluoromethyl and phenyl, said phenyl being optionally substituted with methoxy or chloro; R9 is selected from the group consisting of C1-C3alkyl, C1-C3alkoxy, C3-C6cycloalkyl, heterocyclyl, phenyl and a monocyclic heteroaryl, wherein said heterocyclyl, said phenyl and said monocyclic heteroaryl are optionally substituted with one or two R8; and R8 is selected from the group consisting of fluoro, chloro, C1-C3haloalkyl and C1-C3alkyl.
In some embodiments, R1 and R2 are hydrogen; R3 is methyl; X represents NCOR9 or NCOCH2R9; R4 is trifluoromethyl; R9 is selected from the group consisting of C1-C3alkyl, C1-C3alkoxy, C3-C6cycloalkyl, oxazolyl, tetrahydrofuryl, morpholinyl, pyridyl and phenyl, wherein said oxazolyl, said tetrahydrofuryl, said morpholinyl, said pyridyl and said phenyl are optionally substituted with one or two R8; and R8 is selected from the group consisting of fluoro, chloro, C1-C3haloalkyl and C1-C3alkyl.
In some embodiments, X represents Cl2, SO, SO2, NR5, NCOR5, NCOR9, NCOCH2R9 or O; R1 and R3 are independently selected from hydrogen and methyl; R2 is hydrogen; R4 is selected from the group consisting of:
F3C—R5 is C1-C3alkyl; R7 is selected from the group consisting of fluoro chloro, methyl, ethyl, methoxy, trifluoromethoxy, trifluoromethyl, cyclopropyl and N,N-dimethylamino; R9 is selected from the group consisting of tetrahydrofuryl, phenyl and pyridyl, each optionally substituted with one or two R8; and R8 is halogen.
In some embodiments, R1, R2 and R3 are independently selected from hydrogen and methyl; and A is selected from the group consisting of:
In some embodiments, the compound is selected from the group consisting of: 4-morpholino-6-(2-phenylpyrrolidin-1-yl)-1H-pyridin-2-one; 1-methyl-4-morpholino-6-(2-phenylpyrrolidin-1-yl)pyridin-2-one; 4-morpholino-6-[(2S)-2-phenylpyrrolidin-1-yl]-1H-pyridin-2-one; 4-morpholino-6-[(2R)-2-phenylpyrrolidin-1-yl]-1H-pyridin-2-one; 6-(3,6-dihydro-2H-pyran-4-yl)-4-(3-methylmorpholin-4-yl)-1H-pyridin-2-one; 4-(3-methylmorpholin-4-yl)-6-tetrahydropyran-4-yl-1H-pyridin-2-one; 6-[2-(3-methoxyphenyl)pyrrolidin-1-yl]-4-(3-methylmorpholin-4-yl)-1H-pyridin-2-one; 4-(3-methylmorpholin-4-yl)-6-[2-(3-pyridyl)pyrrolidin-1-yl]-1H-pyridin-2-one; 4-(3-methylmorpholin-4-yl)-6-(2-phenylpyrrolidin-1-yl)-1H-pyridin-2-one; N,N-dimethyl-1-[4-[(3R)-3-methylmorpholin-4-yl]-6-oxo-1H-pyridin-2-yl]pyrrolidine-2-carboxamide; 6-[2-(1-methoxy-1-methyl-ethyl)pyrrolidin-1-yl]-4-[(3R)-3-methylmorpholin-4-yl]-1H-pyridin-2-one; 6-(2-cyclohexylpyrrolidin-1-yl)-4-[(3R)-3-methylmorpholin-4-yl]-1H-pyridin-2-one; 6-[2-(3-fluorophenyl)pyrrolidin-1-yl]-4-[(3R)-3-methylmorpholin-4-yl]-1H-pyridin-2-one; 6-[2-(2,5-difluorophenyl)pyrrolidin-1-yl]-4-[(3R)-3-methylmorpholin-4-yl]-1H-pyridin-2-one; 4-[(3R)-3-methylmorpholin-4-yl]-6-[2-[3-(trifluoromethoxy)phenyl]pyrrolidin-1-yl]-1H-pyridin-2-one; 4-[(3R)-3-methylmorpholin-4-yl]-6-[2-[3-(trifluoromethyl)phenyl]pyrrolidin-1-yl]-1H-pyridin-2-one; 6-[2-(3-methoxyphenyl)pyrrolidin-1-yl]-4-[(3R)-3-methylmorpholin-4-yl]-1H-pyridin-2-one; 4-[(3R)-3-methylmorpholin-4-yl]-6-(2-phenylpyrrolidin-1-yl)-1H-pyridin-2-one; 4-[(3R)-3-methylmorpholin-4-yl]-6-[2-(1-methylpyrazol-4-yl)pyrrolidin-1-yl]-1H-pyridin-2-one; 6-[2-(1,5-dimethylpyrazol-3-yl)pyrrolidin-1-yl]-4-[(3R)-3-methylmorpholin-4-yl]-1H-pyridin-2-one; 6-[2-(1-ethylpyrazol-3-yl)pyrrolidin-1-yl]-4-[(3R)-3-methylmorpholin-4-yl]-1H-pyridin-2-one; 6-[2-(5-methyl-2-furyl)pyrrolidin-1-yl]-4-[(3R)-3-methylmorpholin-4-yl]-1H-pyridin-2-one; 6-[2-[3-(dimethylamino)phenyl]pyrrolidin-1-yl]-4-[(3R)-3-methylmorpholin-4-yl]-1H-pyridin-2-one; 4-[(3R)-3-methylmorpholin-4-yl]-6-(3-methylmorpholin-4-yl)-1H-pyridin-2-one; 4-[(3R)-3-methylmorpholin-4-yl]-6-[2-(trifluoromethyl)-1-piperidyl]-1H-pyridin-2-one; 4-[(3R)-3-methylmorpholin-4-yl]-6-(3-phenylmorpholin-4-yl)-1H-pyridin-2-one; 4-[(3R)-3-methylmorpholin-4-yl]-6-(1-oxo-1,4-thiazinan-4-yl)-1H-pyridin-2-one; 6-(1,1-dioxo-1,4-thiazinan-4-yl)-4-[(3R)-3-methylmorpholin-4-yl]-1H-pyridin-2-one; 6-(4-acetylpiperazin-1-yl)-4-[(3R)-3-methylmorpholin-4-yl]-1H-pyridin-2-one; 4-[(3R)-3-methylmorpholin-4-yl]-6-[(2R)-2-phenyl-1-piperidyl]-1H-pyridin-2-one; 4-[(3R)-3-methylmorpholin-4-yl]-6-(4-methyl-2-phenyl-piperazin-1-yl)-1H-pyridin-2-one; 4-[(3R)-3-methylmorpholin-4-yl]-6-[3-(trifluoromethyl)morpholin-4-yl]-1H-pyridin-2-one; 6-(3-cyclopropylmorpholin-4-yl)-4-[(3R)-3-methylmorpholin-4-yl]-1H-pyridin-2-one; 4-[(3R)-3-methylmorpholin-4-yl]-6-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]-1H-pyridin-2-one; 4-[(3R)-3-methylmorpholin-4-yl]-6-[(2R)-2-(trifluoromethyl)pyrrolidin-1-yl]-1H-pyridin-2-one; 6-[2-(3-chlorophenyl)pyrrolidin-1-yl]-4-[(3R)-3-methylmorpholin-4-yl]-1H-pyridin-2-one; 6-[2-(3-cyclopropylphenyl)pyrrolidin-1-yl]-4-[(3R)-3-methylmorpholin-4-yl]-1H-pyridin-2-one; 4-[(3R)-3-methylmorpholin-4-yl]-6-[2-(2-pyridyl)pyrrolidin-1-yl]-1H-pyridin-2-one; 4-[(3R)-3-methylmorpholin-4-yl]-6-(2-thiazol-2-ylpyrrolidin-1-yl)-1H-pyridin-2-one; 6-[2-(5-methylisoxazol-3-yl)pyrrolidin-1-yl]-4-[(3R)-3-methylmorpholin-4-yl]-1H-pyridin-2-one; 1-methyl-4-[(3R)-3-methylmorpholin-4-yl]-6-[(2R)-2-(trifluoromethyl)-1-piperidyl]pyridin-2-one; 4-[(3R)-3-methylmorpholin-4-yl]-6-(8-oxa-5-azaspiro[3.5]nonan-5-yl)-1H-pyridin-2-one; 6-[2-(3-methoxyphenyl)-1-piperidyl]-4-[(3R)-3-methylmorpholin-4-yl]-1H-pyridin-2-one; 6-[4-acetyl-2-(trifluoromethyl)piperazin-1-yl]-4-[(3R)-3-methylmorpholin-4-yl]-1H pyridin-2-one; 6-[4-(5-fluoropyridine-3-carbonyl)-2-(trifluoromethyl)piperazin-1-yl]-4-[(3R)-3-methylmorpholin-4-yl]-1H-pyridin-2-one; 6-[4-[2-(4-fluorophenyl)acetyl]-2-(trifluoromethyl)piperazin-1-yl]-4-[(3R)-3-methylmorpholin-4-yl]-1H-pyridin-2-one; 4-[(3R)-3-methylmorpholin-4-yl]-6-[4-(tetrahydrofuran-2-carbonyl)-2-(trifluoromethyl)piperazin-1-yl]-1H-pyridin-2-one; 4-[(3R)-3-methylmorpholin-4-yl]-6-[4-methyl-2-(trifluoromethyl)piperazin-1-yl]-1H-pyridin-2-one; and pharmaceutically acceptable salts, tautomers, and stereoisomers thereof.
In some embodiments, the compound is selected from the group consisting of:
and pharmaceutically acceptable salts, stereoisomers, and tautomers thereof.
In some embodiments, the compound is selected from the group consisting of:
and pharmaceutically acceptable salts thereof.
In some embodiments, the compound is selected from the group consisting of:
and pharmaceutically acceptable salts thereof.
In some embodiments, the compound is selected from the group consisting of:
and pharmaceutically acceptable salts thereof.
In another embodiment, described herein is a compound of Formula II:
or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein: R1 is selected from the group consisting of aryl and heteroaryl, wherein said aryl and said heteroaryl being mono- or bicyclic and each of aryl and heteroaryl is optionally substituted with one or more independent occurrences of a substituent selected from the group consisting of R5, R6, R7 and R8; each of R2, R3, R4 is independently selected from the group consisting of H, C1-C3haloalkyl, and C1-C3alkyl; each of R5, R6, R7, and R8 is independently selected from the group consisting of halogen, C1-C6alkyl, C1-C6alkoxy, C1-C6haloalkyl, amino, —NHSO2R9, hydroxy, phenyl, and a monocyclic heteroaryl; and R9 is selected from C1-C3haloalkyl and C1-C3alkyl.
In some embodiments, R1 is aryl. In some embodiments, R1 is phenyl. In some embodiments, R1 is phenyl substituted with one occurrence of C1-C3haloalkyl. In some embodiments, R1 is phenyl substituted with one occurrence of trifluoromethyl.
In some embodiments, R3 is H. In some embodiments, R4 is C1-C3alkyl. In some embodiments, R4 is —CH3.
In some embodiments, R4 is C1-C3alkyl.
In some embodiments, R2 is selected from hydrogen and methyl.
In some embodiments, R3 is hydrogen.
In some embodiments, R4 is methyl.
In some embodiments, R2 is hydrogen.
In some embodiments, R1 is selected from the group consisting of phenyl, furyl, thienyl, pyridyl, pyrimidinyl, naphtyl, quinolinyl, indazolyl, indolyl, 4-azaindolyl, benzoxazolyl, benzimidazolyl, benzothiophenyl, each optionally substituted with one or more of R5, R6, R7 and R8.
In some embodiments, R5, R6, R7 and R8 are independently selected from the group consisting of chloro, fluoro, C1-C3alkyl. C1-C3fluoroalkyl, phenyl, amino, —NHSO2CH3, hydroxy, imidazolyl and pyrazolyl.
In some embodiments, R1 is selected from the group consisting of phenyl, furyl, thienyl, pyridyl, pyrimidinyl, naphtyl, quinolinyl, indazolyl, indolyl, 4-azaindolyl, benzoxazolyl, benzimidazolyl, benzothiophenyl, each optionally substituted with one or more of R5, R6, R7 and R8; and R5, R6, R7 and R8 are independently selected from the group consisting of halogen, C1-C3alkyl, C1-C3haloalkyl, phenyl, amino, —NHSO2CH3, hydroxy, imidazolyl and pyrazolyl.
In some embodiments, R1 is selected from the group consisting of phenyl, furyl, thienyl, pyridyl, pyrimidinyl and quinolinyl.
In some embodiments, R5 and R6 are independently selected from the group consisting of chloro, fluoro, trifluoromethyl, methyl, phenyl, —NHSO2CH3 and pyrazolyl.
In some embodiments, R1 is selected from the group consisting of phenyl, furyl, thienyl, pyridyl, pyrimidinyl and quinolinyl.
In some embodiments, R1 is selected from the group consisting of phenyl, furyl, thienyl, pyridyl, pyrimidinyl and quinolinyl, each optionally substituted with R5 and/or R6; and R5 and R6 are independently selected from the group consisting of chloro, fluoro, trifluoromethyl, methyl, phenyl, —NHSO2CH3 and pyrazolyl.
In some embodiments R1 is selected from the group consisting of:
wherein R5 and R6 are independently selected from the group consisting of halogen, C1-C3alkyl, C1-C3haloalkyl, phenyl, pyrazolyl, and —NHSO2CH3.
In some embodiments, R1 is a monocyclic aryl or heteroaryl.
In some embodiments, R1 is selected from phenyl and pyridyl.
In some embodiments, R5 and R6 are independently selected from the group consisting of chloro, fluoro and trifluoromethyl, such as chloro and trifluoromethyl.
In some embodiments, R1 is selected from phenyl and pyridyl, each optionally substituted with R5 and/or R6; and R5 and R6 are independently selected from the group consisting of chloro, fluoro and trifluoromethyl.
In some embodiments, R1 is selected from the group consisting of:
R4 is C1-C3alkyl; and R5 and R6 are independently selected from the group consisting of chloro, fluoro, and trifluoromethyl.
In some embodiments, R1 is selected from the group consisting of:
In some embodiments, R1 is selected from:
R2 is hydrogen; and R5 is selected from chloro and trifluoromethyl.
In some embodiments, R1 is selected from the group consisting of:
R2 is hydrogen; R4 is C1-C3alkyl; and R5 and R0 are independently selected from chloro, fluoro and trifluoromethyl.
In some embodiments, R1 is selected from the group consisting of:
R2 is hydrogen or methyl; R3 is hydrogen; R4 is methyl; R5 and R6 selected from the group consisting of chloro, fluoro, trifluoromethyl, methyl, phenyl pyrazolyl and —NHSO2CH3; and pharmaceutically acceptable salts and stereoisomers thereof.
In some embodiments, the compound is selected from the group consisting of:
and pharmaceutically acceptable salts, stereoisomers, and tautomers thereof.
In some embodiments, the compound is selected from the group consisting of:
and pharmaceutically acceptable salts thereof.
In some embodiments, the compound is selected from the group consisting of: 6-(2-chlorophenyl)-4-morpholino-1H-pyridin-2-one; 6-(2-chlorophenyl)-1-methyl-4-morpholino-pyridin-2-one; 6-(2-chlorophenyl)-4-(3-methylmorpholin-4-yl)-1H-pyridin-2-one; 6-(2-chlorophenyl)-1-methyl-4-(3-methylmorpholin-4-yl)pyridin-2-one; 4-(3-methylmorpholin-4-yl)-6-(4-methyl-3-pyridyl)-1H-pyridin-2-one; 4-(3-methylmorpholin-4-yl)-6-pyrimidin-5-yl-1H-pyridin-2-one; 4-(3-methylmorpholin-4-yl)-6-(2-phenylphenyl)-1H-pyridin-2-one; 6-(2-chloro-5-fluoro-phenyl)-4-[(3R)-3-methylmorpholin-4-yl]-1H-pyridin-2-one; 4-[(3R)-3-methylmorpholin-4-yl]-6-(o-tolyl)-1H-pyridin-2-one; 4-[(3R)-3-methylmorpholin-4-yl]-6-[2-(trifluoromethyl)-3-pyridyl]-1H-pyridin-2-one; 6-(2-chlorophenyl)-4-[(3R)-3-methylmorpholin-4-yl]-1H-pyridin-2-one; 4-[(3R)-3-methylmorpholin-4-yl]-6-[2-(trifluoromethyl)phenyl]-1H-pyridin-2-one; 6-(3-furyl)-4-[(3R)-3-methylmorpholin-4-yl]-1H-pyridin-2-one; 4-[(3R)-3-methylmorpholin-4-yl]-6-(4-methyl-3-thienyl)-1H-pyridin-2-one; N-[2-[4-[(3R)-3-methylmorpholin-4-yl]-6-oxo-1H-pyridin-2-yl]phenyl]methanesulfonamide; 4-[(3R)-3-methylmorpholin-4-yl]-6-(4-(methylsulfonyl)-2-(trifluoromethyl)phenyl)-1H-pyridin-2-one; 4-[(3R)-3-methylmorpholin-4-yl]-6-(6-methyl-5-quinolyl)-1H-pyridin-2-one; 4-[(3R)-3-methylmorpholin-4-yl]-6-[4-(1H-pyrazol-5-yl)phenyl]-1H-pyridin-2-one; N,N-dimethyl-[4[4-[(3R)-3-methylmorpholin-4-yl]-6-oxo-1H-pyridin-2-yl]-3-(trifluoromethyl)]benzenesulfonamide; and pharmaceutically acceptable salts, tautomers, and stereoisomers thereof.
In some embodiments, described herein is a compound of Formula III:
or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein: X is selected from N and CR1; R1 is selected from the group consisting of H, C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxyC1-C3alkyl, C3-C6cycloalkyl, cyano, phenyl, and monocyclic heteroaryl, wherein each of phenyl and monocyclic heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of halo, N—C1-C3alkylamino, N,N-diC1-C3alkylamino, C3-C6cycloalkyl, C1-C3alkoxyC1-C3alkyl, C1-C3haloalkyl, C1-C3haloalkoxy, C1-C3alkoxy, and C1-C3alkyl; R2 is selected from the group consisting of H, C1-C3haloalkyl, and C1-C3alkyl; R3 is selected from the group consisting of A, phenyl, and monocyclic heteroaryl, wherein each of phenyl and monocyclic heteroaryl is optionally substituted with one or more occurrences of R4; each R4 is independently selected from the group consisting of COR5, halogen, C1-C6alkyl, C1-C6alkoxy, C1-C6haloalkoxy, amino N—C1-C3alkylamino, N,N-diC1-C3alkylamino, 1-pyrrolidinyl, 1-piperidinyl, 1-azetidinyl, NHSO2R6, SO2R7, hydroxy, C3-C6cycloalkyl, C1-C3alkoxyC1-C3alkyl, C1-C3cyanoalkyl and C1-C6haloalkyl; R5 is selected from the group consisting of C1-C3alkoxy, N—C1-C3alkylamino, N,N-diC1-C3alkylamino, 1-pyrrolidinyl, 1-piperidinyl, and 1-azetidinyl; R6 is selected from C1-C3haloalkyl and C1-C3alkyl; each R7 is independently selected from the group consisting of R8, C1-C6alkyl, N—C1-C3alkylamino, N,N-diC1-C3alkylamino and C1-C3alkoxyC1-C3alkyl, wherein each of C1-C6alkyl and C1-C3alkoxyC1-C3alkyl is optionally substituted with one occurrence of R8, and each of C1-C6alkyl and C1-C3alkoxyC1-C3alkyl is optionally substituted with or one or more independent occurrences of halogen; each R8 is independently selected from the group consisting of phenyl, monocyclic heteroaryl, C3-C6cycloalkyl, and heterocyclyl, wherein each of phenyl, monocyclic heteroaryl, C3-C6cycloalkyl, and heterocyclyl is optionally substituted with one or more occurrences of R9; each R9 is independently selected from the group consisting of halo, N—C1-C3alkylamino, N,N-diC1-C3alkylamino, C1-C3alkoxyC1-C3alkyl, amino, C1-C3haloalkyl, C1-C3alkoxy, C1-C3haloalkoxy, C3-C6cycloalkyl and C1-C3alkyl; A is
R10 is selected from the group consisting of H, halogen, COR11, C1-C6alkyl, C1-C3alkoxyC1-C3alkyl, C1-C6alkoxy, C3-C6cycloalkyl, C1-C3cyanoalkyl, C1-C3haloalkyl, phenyl, and heteroaryl, wherein each of phenyl and heteroaryl is optionally substituted with one or more occurrences of R12, and provided that when R10 is phenyl or heteroaryl, then X is N or CH; each R11 is independently selected from the group consisting of C1-C3alkoxy, N—C1-C3alkylamino, N,N-diC1-C3alkylamino, 1-pyrrolidinyl, 1-piperidinyl, and 1-azetidinyl; Y is selected from the group consisting of CH2, S, SO, SO2, NR13, NCOR7, NCOOR14, NSO2R7, NCOCH2R7, O, and a bond; R12 is selected from the group consisting of C1-C6alkyl, C3-C6cycloalkyl, C1-C3alkoxyC1-C3alkyl, C1-C3haloalkyl, halogen, N—C1-C3alkylamino, N,N-diC1-C3alkylamino, C1-C3haloalkoxy, and C1-C3alkoxy; R13 is selected from H, C1-C3haloalkyl, C1-C3alkoxyC1-C3alkyl, C1-C3alkyl, C3-C6cycloalkyl; and R14 is selected from R8, C1-C6alkyl, C1-C3alkoxyC1-C3alkyl, wherein each of C1-C6alkyl and C1-C3alkoxyC1-C3alkyl is optionally substituted with one occurrence of R8, and each of C1-C6alkyl and C1-C3alkoxyC1-C3alkyl is optionally substituted with or one or more independent occurrences of halogen.
In some embodiments, R2 is H. In some embodiments, R3 is A. In some embodiments, Y is CH2. In some embodiments, X is N. In some embodiments, R10 is C1-C3haloalkyl.
In some embodiments, R2 is hydrogen or C1-C3alkyl.
In some embodiments, R1 is selected from the group consisting of H, C1-C3alkyl, C1-C3haloalkyl, C3-C6cycloalkyl, cyano, phenyl, heteroaryl, wherein said phenyl and said heteroaryl are optionally and independently substituted with one or more substituents selected from the group consisting of C1-C3haloalkyl, halo, C3-C6cycloalkyl and C1-C3alkyl.
In some embodiments, R2 is hydrogen.
In some embodiments, said heteroaryl in R1 is selected from the group consisting of pyridyl, oxazolyl, thienyl, and pyrimidinyl, each optionally and independently substituted with one or more substituents selected from halo, cyclopropyl, C1-C3fluoroalkyl and C1-C3alkyl.
In some embodiments, R1 is selected from the group consisting of:
In some embodiments R1 is selected from the group consisting of:
In some embodiments, R3 is selected from the group consisting of A, phenyl and monocyclic heteroaryl selected from pyridyl, thienyl, furyl, pyrimidinyl and pyrazolyl, wherein said phenyl and said heteroaryl are optionally and independently substituted with one or two R4.
In some embodiments, R3 is selected from the group consisting of A, phenyl and monocyclic heteroaryl selected from pyridyl, thienyl and pyrazolyl, wherein said phenyl and said heteroaryl are optionally and independently substituted with one or two R4.
In some embodiments, R3 is selected from the group consisting of A, phenyl and pyridyl, wherein said phenyl and said pyridyl are optionally substituted with one R4.
In some embodiments, R3 is selected from the group consisting of A, phenyl and pyridyl, wherein said phenyl and said pyridyl are optionally and independently substituted with one or two R4.
In some embodiments, R4 is selected from the group consisting of fluoro, chloro, C1-C3alkyl, C3-C6cycloalkyl, C1-C3fluoroalkyl and SO2R7.
In some embodiments, R4 is selected from the group consisting of chloro, C1-C3alkyl, C1-C3fluoroalkyl and SO2R7.
In some embodiments, Y is selected from the group consisting of CH2, NSO2R7, O and a bond.
In some embodiments, R1 is selected from the group consisting of hydrogen, C1-C3alkyl, C3-C6cycloalkyl, phenyl, monocyclic heteroaryl and C1-C3haloalkyl, wherein said phenyl and said heteroaryl are optionally and independently substituted with one R12; and
R12 is selected from the group consisting of C1-C3alkyl, cyclopropyl, CF3, halogen, C1-C3haloalkoxy and C1-C3alkoxy.
In some embodiments, R10 is selected from the group consisting of hydrogen, C1-C3alkyl, phenyl, C1-C3haloalkyl.
In some embodiments, R7 is selected from the group consisting of R5, N,N-diC1-C3alkylamino, C1-C3alkyl and methoxyC1-C3alkyl, said C1-C3alkyl being optionally substituted with one R8.
In some embodiments, R7 is selected from C1-C3alkyl and fluorophenyl.
In some embodiments, R7 is selected from C1-C3alkyl and fluorobenzyl.
In some embodiments, R8 is selected from the group consisting of phenyl, pyridyl, imidazolyl, isoxazolyl, oxazolyl, cyclopropyl, cyclopentyl, pyrrolidinyl, tetrahydrofuryl, each optionally substituted with one or more substituents selected from cyclopropyl, methyl and fluoro.
In some embodiments, R3 is selected from the group consisting of:
In some embodiments, R3 is selected from the group consisting of:
In some embodiments R3 is selected from the group consisting of:
wherein Y is selected from the group consisting of CH2, O and a bond; R4 is selected from CF3, fluoro and chloro, cyclopropyl and methyl; and R10 is selected from the group consisting of cyclopropyl, methyl, fluorophenyl, chlorophenyl, methoxyphenyl and CF3.
In some embodiments R3 is selected from the group consisting of:
wherein Y is selected from the group) consisting of CH2, O and a bond; R4 is selected from CF3, chloro, and methyl; and R10 is selected from methyl, phenyl and CF3.
In some embodiments, R3 is selected from the group consisting of:
wherein Y is selected from CH2, O, NSO2R7 and a bond; R4 is selected from CF3, fluoro, cyclopropyl and methyl; and R1 is selected from hydrogen, phenyl, cyclopropyl, methyl, and CF3.
In some embodiments, R3 is selected from the group consisting of:
wherein Y is selected from the group consisting of CH2, O, NSO2R7 and a bond; R4 is selected from the group consisting of CF3, chloro and methyl; and R10 is selected from hydrogen, phenyl, methyl, and CF3.
In some embodiments, R3 is selected from the group consisting of:
wherein Y is selected from the group consisting of CH2, O and a bond; R4 is selected from the group consisting of CF3, cyclopropyl, fluoro and chloro; and R10 is CF3 or cyclopropyl.
In some embodiments, R3 is selected from
wherein Y is selected from the group consisting of CH, O and a bond; R4 is selected from the group consisting of CF3 and chloro; and R10 is CF3.
In some embodiments, X is N.
In some embodiments, X is CR1.
In some embodiments, R1 is selected from the group consisting of:
R2 is hydrogen; and R3 is selected from the group consisting of:
In some embodiments R1 is selected from the group consisting of:
R2 is hydrogen and R3 is selected from the group consisting of:
In some embodiments, R1 is selected from the group consisting of:
R2 is hydrogen; and R3 is selected from the group consisting of:
In some embodiments, X is N; R2 is hydrogen; and R3 is selected from the group consisting of:
In some embodiments, the compound is selected from the group consisting of
and pharmaceutically acceptable salts, stereoisomers, and tautomers thereof.
In some embodiments, the compound is selected from the group consisting of:
and pharmaceutically acceptable salts, stereoisomers, and tautomers thereof.
In some embodiments, the compound is selected from the group consisting of
and pharmaceutically acceptable salts thereof.
In some embodiments, the compound is selected from the group consisting of:
and pharmaceutically acceptable salts thereof.
In some embodiments, the compound is selected from the group consisting of: 4-(1H-pyrrolo[2,3-b]pyridin-4-yl)-6-[2-(trifluoromethyl)phenyl]-1H-pyridin-2-one; 6-(3-Methyl-4-pyridyl)-4-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyridin-2-one; 6-(2-phenylpyrrolidin-1-yl)-4-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyridin-2-one; 4-(2-Methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-6-(3-pyridyl)-1H-pyridin-2-one; 4-(2-Methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-6-morpholino-1H-pyridin-2-one; 6-(2-Chlorophenyl)-4-(2-oxazol-5-yl-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyridin-2-one; 6-(2-Chlorophenyl)-4-[2-(3-pyridyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]-1H-pyridin-2-one; 6-(2-Chlorophenyl)-4-(2-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyridin-2-one; 4-(2-Methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-6-[2-(trifluoromethyl)-1-piperidyl]-1H-pyridin-2-one; 4-(1H-pyrrolo[2,3-b]pyridin-4-yl)-6-[2-(trifluoromethyl)-1-piperidyl]-1H-pyridin-2-one; 4-(1H-pyrrolo[2,3-b]pyridin-4-yl)-6-[3-(trifluoromethyl)morpholin-4-yl]-1H-pyridin-2-one; 6-[3-(Trifluoromethyl)morpholin-4-yl]-4-[2-[3-(trifluoromethyl)phenyl]-1H-pyrrolo[2,3-b]pyridin-4-yl]-1H-pyridin-2-one; 4-[2-(5-Methyl-2-thienyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]-6-[3-(trifluoromethyl)morpholin-4-yl]-1H-pyridin-2-one; 4-(1H-pyrazolo[3,4-b]pyridin-4-yl)-6-[2-(trifluoromethyl)-1-piperidyl]-1H-pyridin-2-one; 6-[2-(Trifluoromethyl)-1-piperidyl]-4-yl]-1H-pyrrolo[2,3-b]pyridin-4-yl]-1H-pyridin-2-one; 6-[2-(Trifluoromethyl)-1-piperidyl]-4-[2-[6-(trifluoromethyl)-3-pyridyl]-1H-pyrrolo[2,3-b]pyridin-4-yl]-1H-pyridin-2-one; 6-[2-(Trifluoromethyl)-1-piperidyl]-4-[2-[5-(trifluoromethyl)-3-pyridyl]-1H-pyrrolo[2,3-b]pyridin-4-yl]-1H-pyridin-2-one; 4-(2-cyclopropyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-6-[4-ethylsulfonyl-2-(trifluoromethyl)piperazin-1-yl]-1H-pyridin-2-one; 6-[4-ethylsulfonyl-2-(trifluoromethyl)piperazin-1-yl]-4-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyridin-2-one; 6-[4-[(4-fluorophenyl)methylsulfonyl]-2-(trifluoromethyl)piperazin-1-yl]-4-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyridin-2-one; 6-[4-Ethylsulfonyl-2-(trifluoromethyl)piperazin-1-yl]-4-(2-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyridin-2-one; 4-[2-[4-Ethylsulfonyl-2-(trifluoromethyl)piperazin-1-yl]-6-oxo-1H-pyridin-4-yl]-1H-pyrrolo[2,3-b]pyridine-2-carbonitrile; 4-(2-cyclopropyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-6-[2-(trifluoromethyl)phenyl]-1H-pyridin-2-one; 4-[2-Oxo-6-[2-(trifluoromethyl)phenyl]-1H-pyridin-4-yl]-1H-pyrrolo[2,3-b]pyridine-2-carbonitrile; 4-(1H-pyrazolo[3,4-b]pyridin-4-yl)-6-[2-(trifluoromethyl)phenyl]-1H-pyridin-2-one; 4-(6-(2-chlorophenyl)-2-oxo-1,2-dihydropyridin-4-yl)-N-ethyl-1H-pyrrolo[2,3-b]pyridine-2-carboxamide; 6-[4-Methylsulfonyl-2-(trifluoromethyl)piperazin-1-yl]-4-(1H-pyrazolo[3,4-b]pyridin-4-yl)-1H-pyridin-2-one; and pharmaceutically acceptable salts, stereoisomers, and tautomers thereof.
In some embodiments, the compound is selected from the group consisting of: 4-(1H-pyrrolo[2,3-b]pyridin-4-yl)-6-[2-(trifluoromethyl)phenyl]-1H-pyridin-2-one; 6-(3-Methyl-4-pyridyl)-4-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyridin-2-one; 6-(2-phenylpyrrolidin-1-yl)-4-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyridin-2-one; 4-(2-Methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-6-(3-pyridyl)-1H-pyridin-2-one; 4-(2-Methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-6-morpholino-1H-pyridin-2-one; 6-(2-Chlorophenyl)-4-(2-oxazol-5-yl-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyridin-2-one; 6-(2-Chlorophenyl)-4-[2-(3-pyridyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]-1H-pyridin-2-one; 6-(2-Chlorophenyl)-4-(2-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyridin-2-one; 4-(2-Methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-6-[2-(trifluoromethyl)-1-piperidyl]-1H-pyridin-2-one; 4-(1H-pyrrolo[2,3-b]pyridin-4-yl)-6-[2-(trifluoromethyl)-1-piperidyl]-1H-pyridin-2-one; 4-(1H-pyrrolo[2,3-b]pyridin-4-yl)-6-[3-(trifluoromethyl)morpholin-4-yl]-1H-pyridin-2-one; 6-[3-(Trifluoromethyl)morpholin-4-yl]-4-[2-[3-(trifluoromethyl)phenyl]-1H-pyrrolo[2,3-b]pyridin-4-yl]-1H-pyridin-2-one; 4-[2-(5-Methyl-2-thienyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]-6-[3-(trifluoromethyl)morpholin-4-yl]-1H-pyridin-2-one; 4-(1H-pyrazolo[3,4-b]pyridin-4-yl)-6-[2-(trifluoromethyl)-1-pipendyl]-1H-pyridin-2-one; 6-[2-(Trifluoromethyl)-1-piperidyl]-4-yl]-1H-pyrrolo[2,3-b]pyridin-4-yl]-1H-pyridin-2-one; 6-[2-(Trifluoromethyl)-1-piperidyl]-4-[2-[6-(trifluoromethyl)-3-pyridyl]-1H-pyrrolo[2,3-b]pyridin-4-yl]-1H-pyridin-2-one; 6-[2-(Trifluoromethyl)-1-piperidyl]-4-[2-[5-(trifluoromethyl)-3-pyridyl]-1H-pyrrolo[2,3-b]pyridin-4-yl]-1H-pyridin-2-one; 4-(2-cyclopropyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-6-[4-ethylsulfonyl-2-(trifluoromethyl)piperazin-1-yl]-1H-pyridin-2-one; 6-[4-ethylsulfonyl-2-(trifluoromethyl)piperazin-1-yl]-4-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyridin-2-one; 6-[4-[(4-fluorophenyl)methylsulfonyl]-2-(trifluoromethyl)piperazin-1-yl]-4-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyridin-2-one; and pharmaceutically acceptable salts, stereoisomers, and tautomers thereof.
In some embodiments, described herein is a compound of Formula IV:
or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein: X is selected from —C(═O)— and a bond; R1 is selected from the group consisting of H, C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxyC1-C3alkyl, C3-C6cycloalkyl, C3-C6cyclohaloalkyl, C1-C3alkoxy, C1-C3haloalkoxy, C3-C6cycloalkoxymethyl, N—C1-C3alkylamino, N,N-diC1-C3alkylamino, 1-pyrrolidinyl, 1-piperidinyl and 1-azetidinyl, provided that when R1 is selected from the group consisting of C1-C3alkoxy, C1-C3haloalkoxy, N—C1-C3alkylamino, N,N-diC1-C3alkylamino, 1-pyrrolidinyl, 1-piperidinyl, and 1-azetidinyl, then X is C═O; R2 is selected from the group consisting of H, C1-C3haloalkyl, and C1-C3alkyl; R3 is selected from the group consisting of A, phenyl and monocyclic heteroaryl, wherein each of phenyl and monocyclic heteroaryl is optionally substituted with one or more occurrences of a substituent independently selected from the group consisting of R4, R5, R6 and R7; each R4, R5, R6, and R7 is independently selected from the group consisting of halo, C1-C6alkyl, C3-C6cycloalkyl, C1-C6alkoxy, C1-C3haloalkoxy, N,N-diC1-C3alkylamino, N—C1-C3alkylamino, 1-azetidinyl, C1-C6haloalkyl, amino, NHSO2R8, SO2R9, and hydroxy; R8 is selected from C1-C3haloalkyl and C1-C3alkyl; each R9 is independently selected from the group consisting of R10, C1-C6alkyl, amino, N—C1-C3alkylamino, N,N-di-C1-C3alkylamino and C1-C3alkoxyC1-C3alkyl, wherein each of C1-C6alkyl and C1-C3alkoxyC1-C3alkyl is optionally substituted with one occurrence of R10, and each of C1-C6alkyl and C1-C3alkoxyC1-C3alkyl is optionally substituted with or one or more independent occurrences of halogen; each R10 is independently selected from the group consisting of phenyl, monocyclic heteroaryl, C3-C6cycloalkyl, and heterocyclyl, wherein each phenyl, monocyclic heteroaryl, C3-C6cycloalkyl, and heterocyclyl is optionally substituted with one or more occurrences of R11; each R11 is independently selected from the group consisting of halo, C1-C3alkoxyC1-C3alkyl, amino, N—C1-C3alkylamino, N,N-diC1-C3alkylamino, C1-C3haloalkoxy, C1-C3alkoxy, C3-C6cycloalkyl, C1-C3haloalkyl, and C1-C3alkyl; A is:
R12 is selected from the group consisting of H, halo, COR13, C1-C6alkyl, C1-C3alkoxyC1-C3alkyl, C1-C6alkoxy, C3-C6cycloalkyl, C1-C3cyanoalkyl, and C1-C3haloalkyl; R13 is selected from the group consisting of C1-C3alkoxy, N—C1-C3alkylamino, N,N-diC1-C3alkylamino, 1-pyrrolidinyl, 1-piperidinyl, and 1-azetidinyl; Y is selected from the group consisting of CH2, S, SO, SO2, NR14, NCOR9, NCOOR15, NSO2R9, NCOCH2R9, O, and a bond; R14 is selected from the group consisting of H, C1-C3haloalkyl, C1-C3alkoxyC1-C3alkyl, C1-C3alkyl, and C3-C6cycloalkyl; and R15 is selected from the group consisting of R10, C1-C6alkyl and C1-C3alkoxyC1-C3alkyl, wherein each of C1-C6alkyl and C1-C3alkoxyC1-C3alkyl is optionally substituted with one occurrence of R10, and each of C1-C6alkyl and C1-C3alkoxyC1-C3alkyl is optionally substituted with or one or more independent occurrences of halogen.
In some embodiments, X is —C(═O)—. In some embodiments, R1 is C1-C3alkoxy. In some embodiments, R3 is aryl. In some embodiments, R3 is phenyl. In some embodiments, R3 is phenyl substituted with one occurrence of halo (e.g., chloro).
In some embodiments, R2 is hydrogen or C1-C3alkyl, such as hydrogen or methyl, such as hydrogen.
In some embodiments, R1 is selected from the group consisting of H, C1-C3alkyl, C1-C3alkoxy, C1-C3haloalkoxy, C1-C3alkoxyC1-C3alkyl, N,N-diC1-C3alkylamino, 1-pyrrolidinyl and C3-C6cycloalkyl.
In some embodiments, R1 is selected from the group consisting of H, methyl, methoxy, methoxymethyl, N,N-dimethylamino, 1-pyrrolidinyl and cyclopropyl.
In some embodiments, R1 is selected from the group consisting of H, methyl, methoxymethyl, N,N-dimethylamino, 1-pyrrolidinyl and cyclopropyl.
In some embodiments, R3 is selected from the group consisting of A, phenyl and monocyclic heteroaryl selected from pyridyl, thienyl, furyl, pyrimidinyl and pyrazolyl, wherein said phenyl and said heteroaryl are optionally substituted with R4 and/or R5.
In some embodiments, R3 is selected from the group consisting of A, phenyl and pyridyl, wherein said phenyl and said pyridyl are optionally and independently substituted with R4 and/or R5.
In some embodiments, R4, R5, R6 and R7 are independently selected from the group consisting of fluoro, chloro, C1-C3alkyl, C3-C6cycloalkyl, C1-C3fluoroalkyl and SO2R9.
In some embodiments, Y is selected from the group consisting of CH2, NSO2R9, O and a bond.
In some embodiments, Y is selected from the group consisting of CH2, O and a bond.
In some embodiments, R12 is selected from the group consisting of hydrogen, C1-C3alkyl, C1-C3alkoxyC1-C3alkyl, C1-C3haloalkyl and C3-C6cycloalkyl.
In some embodiments, R12 is selected from the group consisting of hydrogen, C1-C3alkyl, C1-C3haloalkyl and C3-C6cycloalkyl.
In some embodiments, R9 is selected from the group consisting of R10, N,N-diC1-C3alkylamino and methoxyC1-C3alkyl, said C1-C3alkyl being optionally substituted with one R10.
In some embodiments, R10 is selected from the group consisting of phenyl, pyridyl, imidazolyl, isoxazolyl, oxazolyl, cyclopropyl, cyclopentyl, pyrrolidinyl, tetrahydrofuryl, each optionally substituted with one or more methyl and/or fluoro.
In some embodiments, R3 is selected from the group consisting of:
In some embodiments, R3 is selected from the group consisting of:
In some embodiments, R3 is selected from the group consisting of:
In some embodiments, R3 is selected from the group consisting of:
wherein Y is selected from the group consisting of CH2, O and a bond; R4 is selected from CF3, chloro, cyclopropyl and methyl; R5 is fluoro; and R12 is selected from hydrogen, cyclopropyl, methyl, 1-methoxy-1-methyl-ethyl and CF3.
In some embodiments, R3 is selected from the group consisting of:
wherein Y is selected from the group consisting of CH2, O and a bond; R4 is selected from the group consisting of CF3, chloro, cyclopropyl and methyl; R5 is fluoro; and R12 is selected from hydrogen, cyclopropyl, methyl and CF3.
In some embodiments, R3 is selected from the group consisting of:
wherein Y is selected from CH2 and O; R4 is selected from the group consisting of CF3, chloro cyclopropyl and chloro; R5 is fluoro; and R12 is CF3 and cyclopropyl.
In some embodiments, R1 is selected from the group consisting of H, methyl, methoxy, methoxymethyl, N,N-dimethylamino, 1-pyrrolidinyl and cyclopropyl; R2 is hydrogen; and R3 is selected from the group consisting of:
In some embodiments, R1 is selected from the group consisting of H, methyl, methoxy, methoxymethyl, N,N-dimethylamino, 1-pyrrolidinyl and cyclopropyl; R2 is hydrogen; and R3 is selected from the group consisting of:
In some embodiments, R1 is selected from the group consisting of H, methyl, methoxymethyl N,N-dimethylamino, 1-pyrrolidinyl and cyclopropyl; R2 is hydrogen; and R3 is selected from the group consisting of:
In some embodiments, the compound is selected from the group consisting of: N-[4-[2-(2-chlorophenyl)-6-oxo-1H-pyridin-4-yl]-2-pyridyl]acetamide; 4-(2-Amino-4-pyridyl)-6-(3-pyridyl)-1H-pyridin-2-one; 4-(2-Amino-4-pyridyl)-6-(2-chlorophenyl)-1H-pyridin-2-one; N-[4-[2-(2-chlorophenyl)-6-oxo-1H-pyridin-4-yl]-2-pyridyl]-2-methoxy-acetamide; N-[4-[2-oxo-6-[2-(trifluoromethyl)-1-piperidyl]-1H-pyridin-4-yl]-2-pyridyl]acetamide; N-[4-[2-oxo-6-[2-(trifluoromethyl)-1-piperidyl]-1H-pyridin-4-yl]-2-pyridyl]cyclopropanecarboxamide; N-[4-[2-oxo-6-[3-(trifluoromethyl)morpholin-4-yl]-1H-pyridin-4-yl]-2-pyridyl]acetamide; methyl N-[4-[2-(2-chlorophenyl)-6-oxo-1H-pyridin-4-yl]-2-pyridyl]carbamate; methyl N-[4-[2-[1-ethyl-3-(trifluoromethyl)pyrazol-4-yl]-6-oxo-1H-pyridin-4-yl]-2-pyridyl]carbamate; methyl N-[4-[2-oxo-6-[2-(trifluoromethyl)-3-pyridyl]-1H-pyridin-4-yl]-2-pyridyl]carbamate; methyl N-[4-[2-oxo-6-[2-(trifluoromethyl)phenyl]-1H-pyridin-4-yl]-2-pyridyl]carbamate; N-[4-[2-oxo-6-[2-(trifluoromethyl)phenyl]-1H-pyridin-4-yl]-2-pyridyl]acetamide; N-[4-[2-(4-methyl-3-pyridyl)-6-oxo-1H-pyridin-4-yl]-2-pyridyl]acetamide; N-[4-[2-oxo-6-[2-(trifluoromethyl)-3-pyridyl]-1H-pyridin-4-yl]-2-pyridyl]acetamide; N-[4-[2-[1-ethyl-3-(trifluoromethyl)pyrazol-4-yl]-6-oxo-1H-pyridin-4-yl]-2-pyridyl]acetamide; methyl N-[4-[2-oxo-6-[3-(trifluoromethyl)morpholin-4-yl]-1H-pyridin-4-yl]-2-pyridyl]carbamate; methyl N-[4-[2-oxo-6-[2-(trifluoromethyl)-1-piperidyl]-1H-pyridin-4-yl]-2-pyridyl]carbamate; N-[4-[2-(3-cyclopropylmorpholin-4-yl)-6-oxo-1H-pyridin-4-yl]-2-pyridyl]acetamide; N-[4-[2-[4-ethylsulfonyl-2-(trifluoromethyl)piperazin-1-yl]-6-oxo-1H-pyridin-4-yl]-2-pyridyl]acetamide; N-[4-[2-(2-methyl-3-pyridyl)-6-oxo-1H-pyridin-4-yl]-2-pyridyl]acetamide; N-[4-[2-oxo-6-[4-(trifluoromethyl)-3-thienyl]-1H-pyridin-4-yl]-2-pyridyl]acetamide; 1,1-Dimethyl-3-[4-[2-oxo-6-[2-(trifluoromethyl)phenyl]-1H-pyridin-4-yl]-2-pyridyl]urea; N-[4-[2-oxo-6-[2-(trifluoromethyl)phenyl]-1H-pyridin-4-yl]-2-pyridyl]pyrrolidine-1-carboxamide; N-[4-[2-[2-(1-methoxy-1-methyl-ethyl)pyrrolidin-1-yl]-6-oxo-1H-pyridin-4-yl]-2-pyridyl]acetamide; and pharmaceutically acceptable salts, tautomers, and stereoisomers thereof.
In some embodiments, the compound is selected from the group consisting of: 4-(2-Amino-4-pyridyl)-6-(3-pyridyl)-1H-pyridin-2-one; 4-(2-Amino-4-pyridyl)-6-(2-chlorophenyl)-1H-pyridin-2-one; N-[4-[2-(2-chlorophenyl)-6-oxo-1H-pyridin-4-yl]-2-pyridyl]-2-methoxy acetamide; N-[4-[2-oxo-6-[2-(trifluoromethyl)-1-piperidyl]-1H-pyridin-4-yl]-2-pyridyl]acetamide; N-[4-[2-oxo-6-[2-(trifluoromethyl)-1-piperidyl]-1H-pyridin-4-yl]-2-pyridyl]cyclopropanecarboxamide; N-[4-[2-oxo-6-[3-(trifluoromethyl)morpholin-4-yl]-1H-pyridin-4-yl]-2-pyridyl]acetamide; methyl N-[4-[2-(2-chlorophenyl)-6-oxo-1H-pyridin-4-yl]-2-pyridyl]carbamate; methyl N-[4-[2-[1-ethyl-3-(trifluoromethyl)pyrazol-4-yl]-6-oxo-1H-pyridin-4-yl]-2-pyridyl]carbamate; methyl N-[4-[2-oxo-6-[2-(trifluoromethyl)-3-pyridyl]-1H-pyridin-4-yl]-2 pyridyl]carbamate; methyl N-[4-[2-(4-methyl-3-pyridyl)-6-oxo-1H-pyridin-4-yl]-2-pyridyl]carbamate; methyl N-[4-[2-oxo-6-[2-(trifluoromethyl)phenyl]-1H-pyridin-4-yl]-2-pyridyl]carbamate; N-[4-[2-oxo-6-[2-(trifluoromethyl)phenyl]-1H-pyridin-4-yl]-2-pyridyl]acetamide; N-[4-[2-(4-methyl-3-pyridyl)-6-oxo-1H-pyridin-4-yl]-2-pyridyl]acetamide; N-[4-[2-oxo-6-[2-(trifluoromethyl)-3-pyridyl]-1H-pyridin-4-yl]-2-pyridyl]acetamide; N-[4-[2-[1-ethyl-3-(trifluoromethyl)pyrazol-4-yl]-6-oxo-1H-pyridin-4-yl]-2-pyridyl]acetamide; methyl N-[4-[2-oxo-6-[3-(trifluoromethyl)morpholin-4-yl]-1H-pyridin-4-yl]-2-pyridyl]carbamate; methyl N-[4-[2-oxo-6-[2-(trifluoromethyl)-1-piperidyl]-1H-pyridin-4-yl]-2-pyridyl]carbamate; methyl N-[4-[2-[4-ethylsulfonyl-2-(trifluoromethyl)piperazin-1-yl]-6-oxo-1H-pyridin-4-yl]-2-pyridyl]carbamate; methyl N-[4-[2-(3-cyclopropylmorpholin-4-yl)-6-oxo-1H-pyridin-4-yl]-2-pyridyl]carbamate; N-[4-[2-(3-cyclopropylmorpholin-4-yl)-6-oxo-1H-pyridin-4-yl]-2-pyridyl]acetamide; N-[4-[2-[4-ethylsulfonyl-2-(trifluoromethyl)piperazin-1-yl]-6-oxo-1H-pyridin-4-yl]-2-pyridyl]acetamide; 3-[4-[2-(2-chlorophenyl)-6-oxo-1H-pyridin-4-yl]-2-pyridyl]-1,1-dimethyl-urea; N-[4-[2-(2-chlorophenyl)-6-oxo-1H-pyridin-4-yl]-2-pyridyl]pyrrolidine-1-carboxamide; and pharmaceutically acceptable salts, tautomers, and stereoisomers thereof.
In some embodiments, the compound is selected from the group consisting of: N-[4-[2-(2-chlorophenyl)-6-oxo-1H-pyridin-4-yl]-2-pyridyl]acetamide; 4-(2-Amino-4-pyridyl)-6-(3-pyridyl)-1H-pyridin-2-one; 4-(2-Amino-4-pyridyl)-6-(2-chlorophenyl)-1H-pyridin-2-one; N-[4-[2-(2-chlorophenyl)-6-oxo-1H-pyridin-4-yl]-2-pyridyl]-2-methoxy-acetamide; N-[4-[2-oxo-6-[2-(trifluoromethyl)-1-piperidyl]-1H-pyridin-4-yl]-2-pyridyl]acetamide; N-[4-[2-oxo-6-[2-(trifluoromethyl)-1-piperidyl]-1H-pyridin-4-yl]-2-pyridyl]cyclopropanecarboxamide; N-[4-[2-oxo-6-[3-(trifluoromethyl)morpholin-4-yl]-1H-pyridin-4-yl]-2-pyridyl]acetamide; methyl N-[4-[2-(2-chlorophenyl)-6-oxo-1H-pyridin-4-yl]-2-pyridyl]carbamate; methyl N-[4-[2-[1-ethyl-3-(trifluoromethyl)pyrazol-4-yl]-6-oxo-1H-pyridin-4-yl]-2-pyridyl]carbamate; methyl N-[4-[2-oxo-6-[2-(trifluoromethyl)-3-pyridyl]-1H-pyridin-4-yl]-2-pyridyl]carbamate; methyl N-[4-[2-oxo-6-[2-(trifluoromethyl)phenyl]-1H-pyridin-4-yl]-2-pyridyl]carbamate; N-[4-[2-oxo-6-[2-(trifluoromethyl)phenyl]-1H-pyridin-4-yl]-2-pyridyl]acetamide; N-[4-[2-(4-methyl-3-pyridyl)-6-oxo-1H-pyridin-4-yl]-2-pyridyl]acetamide; N-[4-[2-oxo-6-[2-(trifluoromethyl)-3-pyridyl]-1H-pyridin-4-yl]-2-pyridyl]acetamide; N-[4-[2-[1-ethyl-3-(trifluoromethyl)pyrazol-4-yl]-6-oxo-1H-pyridin-4-yl]-2-pyridyl]acetamide; methyl N-[4-[2-oxo-6-[3-(trifluoromethyl)morpholin-4-yl]-1H-pyridin-4-yl]-2-pyridyl]carbamate; methyl N-[4-[2-oxo-6-[2-(trifluoromethyl)-1-piperidyl]-1H-pyridin-4-yl]-2-pyridyl]carbamate; N-[4-[2-(3-cyclopropylmorpholin-4-yl)-6-oxo-1H-pyridin-4-yl]-2-pyridyl]acetamide; N-[4-[2-[4-ethylsulfonyl-2-(trifluoromethyl)piperazin-1-yl]-6-oxo-1H-pyridin-4-yl]-2-pyridyl]acetamide; and pharmaceutically acceptable salts, tautomers, and stereoisomers thereof.
In some embodiments, the compound is selected from the group consisting of:
and pharmaceutically acceptable salts and tautomers thereof.
In some embodiments, the compound is selected from the group consisting of:
and pharmaceutically acceptable salts thereof.
In some embodiments, described herein is a compound of Formula V:
or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein: R1 is selected from phenyl and monocyclic 5-6 membered heteroaryl, wherein each of phenyl and monocyclic 5-6 membered heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, C1-C6alkyl, C3-C4cycloalkyl, C1-C6alkoxy, C1-C6haloalkyl, C1-C6haloalkoxy, amino, N—C1-C3alkylamino and N,N-diC1-C3alkylamino; R2 is selected from the group consisting of H, C1-C3haloalkyl, and C1-C3alkyl; R3 is selected from the group consisting of A, phenyl, and monocyclic heteroaryl, wherein each of phenyl and heteroaryl is optionally substituted with one or more occurrences of a substituent independently selected from the group consisting of R4, R5, R6, and R7; each of R4, R5, R6, and R7 is independently selected from the group consisting of halogen, C1-C6alkyl, C3-C4cycloalkyl, C1-C6alkoxy, C1-C6haloalkyl, C1-C6haloalkoxy, azetidine, amino, N—C1-C3alkylamino, N,N-diC1-C3alkylamino, NHSO2R8, SO2R9, and hydroxy; R8 is selected from C1-C3haloalkyl and C1-C3alkyl; each R9 is independently selected from the group consisting of R10, C1-C6alkyl, amino, N—C1-C3alkylamino, N,N-diC1-C3alkylamino, and C1-C3alkoxyC1-C3alkyl, wherein each of C1-C6alkyl and C1-C3alkoxyC1-C3alkyl is optionally substituted with one occurrence of R10, and each of C1-C6alkyl and C1-C3alkoxyC1-C3alkyl is optionally substituted with or one or more independent occurrences of halogen; each R10 is independently selected from the group consisting of phenyl, benzyl, monocyclic heteroaryl, C3-C6cycloalkyl, and heterocyclyl, wherein each of phenyl, benzyl, monocyclic heteroaryl, C3-C6cycloalkyl, and heterocyclyl is optionally substituted with one or more occurrences of R11; each R11 is independently selected from the group consisting of halogen, C1-C3haloalkyl, C3-C4cycloalkyl, C1-C3alkyl, amino, N—C1-C3alkylamino, N,N-diC1-C3alkylamino, and C1-C3alkoxyC1-C3alkyl; A is
R12 is selected from the group consisting of H, halogen, COR13, C1-C6alkyl, C3-C6cycloalkyl, C1-C3alkoxyC1-C3alkyl, C1-C6alkoxy, C3-C6cycloalkyl, C1-C3cyanoalkyl, and C1-C3haloalkyl; R13 is selected from the group consisting of C1-C3alkoxy, N—C1-C3alkylamino, N,N-diC1-C3alkylamino, 1-pyrrolidinyl, 1-piperidinyl, and 1-azetidinyl; Y is selected from the group consisting of CH2, S, SO, SO2, NR14, NCOR9, NCOOR15, NSO2R9, NCOCH2R9, O, and a bond; R14 is selected from H, C1-C3haloalkyl, C1-C3alkoxyC1-C3alkyl, C1-C3alkyl, and C3-C6cycloalkyl; and R15 is selected from R10, C1-C6alkyl, and C1-C3alkoxyC1-C3alkyl, wherein each of C1-C6alkyl and C1-C3alkoxyC1-C3alkyl is optionally substituted with one occurrence of R10, and each of C1-C6alkyl and C1-C3alkoxyC1-C3alkyl is optionally substituted with or one or more independent occurrences of halogen; and Z is selected from CH and N.
In some embodiments, R2 is selected from hydrogen and C1-C3alkyl.
In some embodiments, R2 is hydrogen.
In some embodiments, R1 is selected from phenyl and a monocyclic 5-6 membered heteroaryl, each optionally substituted with one or more substituents selected from the group consisting of halogen, C1-C6alkyl, C3-C4cycloalkyl, C1-C6haloalkyl, C1-C6alkoxy, C1-C6haloalkoxy, amino, —N—C1-C3alkylamino, N,N-di-C1-C3alkylamino and halogen.
In some embodiments, R1 is selected from phenyl and a monocyclic 5-6 membered heteroaryl, each optionally substituted with one or more substituents selected from the group consisting of C1-C6alkyl, C3-C4cycloalkyl, and halogen.
In some embodiments, R3 is selected from the group consisting of:
In some embodiments, R3 is selected from the group consisting of:
In some embodiments, R3 is selected from the group consisting of:
Y is selected from the group consisting of CH2, NSO2R9, O and a bond; R4 is selected from the group consisting of CF3, fluoro, cyclopropyl and methyl; R5 is fluoro; R9 is selected from the group consisting of C1-C6alkyl, phenyl, and benzyl, each optionally substituted with one or more halogen; and R12 is selected from the group consisting of hydrogen, methyl, cyclopropyl and CF3.
In some embodiments, R3 is selected from the group consisting of:
Y is selected from the group consisting of NSO2R9, CH2 and O; R4 is selected from the group consisting of cyclopropyl, CF3 and chloro; R5 is fluoro; R9 is selected from the group consisting of C1-C6alkyl, phenyl, and benzyl, each optionally substituted with one or more halogen; and R12 is selected from cyclopropyl and CF3.
In some embodiments, R3 is
R9 is selected from the group consisting of C1-C6alkyl, phenyl, and benzyl, wherein said phenyl and benzyl group may optionally be substituted with one or more halogen, C1-C6alkyl, C1-C6haloalkyl and C3-C4cycloalkyl; and R12 is selected from the group consisting of halogen, C1-C6alkyl, C1-C6haloalkyl and C3-C4cycloalkyl.
In some embodiments, R1 is selected from the group consisting of phenyl, pyrimidinyl, oxazolyl, imidazolyl, pyrazolyl and thiazolyl, each optionally substituted with one or more substituents selected from halogen, C1-C6alkyl, C3-C4cycloalkyl, and C1-C6haloalkyl.
In some embodiments, R1 is selected from the group consisting of phenyl, pyrimidinyl, oxazolyl, imidazolyl, and thiazolyl, each optionally substituted with one or more substituents selected from halogen, C1-C6alkyl, C3-C4cycloalkyl, and C1-C6haloalkyl.
In some embodiments, R3 is selected from the group consisting of A, phenyl, pyridyl, thienyl, furyl, pyrimidinyl and pyrazolyl, each optionally and independently substituted with one or more R4 or R5.
In some embodiments, R3 is selected from the group consisting of A, phenyl and pyridyl, each optionally and independently substituted with one or more R4 or R5.
In some embodiments, R3 is selected from the group consisting of phenyl, pyridyl, morpholinyl, piperidyl, pyrrolidinyl, thienyl, and piperazinyl, each optionally substituted with one or more substituents selected from halogen, C1-C6alkyl, C1-C6haloalkyl and C3-C4cycloalkyl.
In some embodiments, R4, R5, R6 and R7 are independently selected from the group consisting of fluoro, chloro, C1-C3alkyl. C1-C3fluoroalkyl, cyclopropyl and SO2R9.
In some embodiments, Y is selected from the group consisting of CH2, O and a bond. In some embodiments, R12 is selected from the group consisting of hydrogen, CON(CH3)2, C1-C3alkyl, CF3 and cyclopropyl.
In some embodiments, R9 is selected from the group consisting of R10, N,N-diC1-C3alkylamino and methoxyC1-C3alkyl, said C1-C3alkyl being optionally substituted with one R10.
In some embodiments, R10 is selected from the group consisting of phenyl, benzyl, pyridyl, imidazolyl, isoxazolyl, oxazolyl, cyclopropyl, cyclopentyl, pyrrolidinyl, and tetrahydrofuryl, each optionally substituted with one or more methyl and/or fluoro.
In some embodiments, R3 is selected from the group consisting of phenyl, pyridyl, pyrrolidinyl and thienyl, each optionally substituted with one or more substituents selected from the group consisting of halogen, C1-C6alkyl, C1-C6haloalkyl and C3-C4cycloalkyl; or A; Y is CH2, O, NSO2-C1-C6alkyl or NSO2-benzyl, wherein said benzyl is optionally substituted by one or more halogen; and R12 is selected from C1-C6alkyl and C1-C6haloalkyl.
In some embodiments, R1 is selected from phenyl and a monocyclic 5-6 membered heteroaryl each optionally substituted with one or more substituents selected from the group consisting of halogen, C1-C6alkyl, C3-C4cycloalkyl, C1-C6haloalkyl, C1-C6alkoxy, C1-C6haloalkoxy, amino, N—C1-C3alkylamino, N,N-di-C1-C3alkylamino and halogen; R2 is hydrogen; R3 is selected from phenyl and a monocyclic 5-6 membered heteroaryl each optionally substituted with one or more substituents selected from the group consisting of halogen, C1-C6alkyl, C1-C6haloalkyl and C3-C4cycloalkyl.
In some embodiments, R1 is selected from phenyl and a monocyclic 5-6 membered heteroaryl each optionally substituted with one or more substituents selected from the group consisting of halogen, C1-C6alkyl, C1-C6haloalkyl, and C3-C4cycloalkyl; R2 is hydrogen; and R3 is selected from phenyl and monocyclic 5-6 membered heteroaryl each optionally substituted with one or more substituents selected from the group consisting of halogen, C1-C6alkyl, C1-C6haloalkyl and C3-C4cycloalkyl.
In some embodiments, R1 is selected from the group consisting of phenyl, pyrimidinyl, oxazolyl, imidazolyl, or thiazolyl, each optionally substituted with one or more substituents selected from the group consisting of halogen, C1-C6alkyl, C1-C6haloalkyl, and C3-C4cycloalkyl; R2 is hydrogen; R3 is selected from the group consisting of the group consisting of phenyl, pyridyl, pyrazolyl pyrrolidinyl, and thienyl, each optionally substituted with one or more substituents selected from the group consisting of halogen, C1-C6alkyl, C1-C6haloalkyl, C3-C4cycloalkyl; or A; Y is CH2, O, NSO2—C1-C6alkyl or NSO2-benzyl, wherein said benzyl is optionally substituted by one or more halogen; and R12 is C1-C6alkyl or C1-C6haloalkyl.
In some embodiments, R1 is selected from the group consisting of phenyl, 4-pyrimidinyl, 2-methylpyrimidin-4-yl, 2-cyclopropyl-pyrimidin-4-yl, 2-oxazolyl, 1-methyl-imidazol-4-yl, 2-methyl-thiazol-4-yl, 3,5-difluorophenyl and 2-methylpyrazol-3-yl; R2 is hydrogen; and R3 is selected from the group consisting of 2-chlorophenyl, 3-pyridyl, 4-pyridyl, 4-morpholinyl, 3-(trifluoromethyl)morpholin-4-yl, 2-(trifluoromethyl)-piperidin-1-yl, 2-(trifluoromethyl)phenyl, 4-methyl-pyridin-3-yl, 2-(trifluoromethyl)-pyridin-3-yl, 1-ethyl-3-(trifluoromethyl)pyrazol-4-yl, 3-cyclopropyl-morpholin-4-yl, 4-[(4-fluorophenyl)methylsulfonyl]-2-(trifluoromethyl)piperazin-1-yl, 4-ethylsulfonyl-2-(trifluoromethyl)piperazin-1-yl, 2-(trifluoromethyl)-pyrrolidin-1-yl, 2-chloro-5-fluorophenyl, 3-(trifluoromethyl)-pyrazolin-4-yl, 2-(trifluoromethyl)-pyridin-3-yl, 3-methyl-thien-4-yl, 2-methyl phenyl, 1-acetyl-3-trifluoromethyl-piperazin-4-yl, 2-methyl-piperidin-1-yl, 2-cyclopropyl-piperidin-1-yl, 2-methyl-morpholin-4-yl, 2-trifluoromethyl-morpholin-4-yl, and 2-cyclopropyl-morpholin-4-yl.
In some embodiments, R1 is selected from the group consisting of phenyl, 4-pyrimidinyl, 2-methylpyrimidin-4-yl, 2-cyclopropyl-pyrimidin-4-yl, 2-oxazolyl, 1-methyl-imidazol-4-yl, 2-methyl-thiazol-4-yl, and 3,5-difluorophenyl; R2 is hydrogen; and R3 is selected from the group consisting of 2-chlorophenyl, 3-pyridyl, 4-pyridyl, 4-morpholinyl, 3-(trifluoromethyl)morpholin-4-yl, 2-(trifluoromethyl)-piperidin-1-yl, 2-(trifluoromethyl)phenyl, 4-methyl-pyridin-3-yl, 2-(trifluoromethyl)-pyridin-3-yl, 1-ethyl-3-(trifluoromethyl)pyrazol-4-yl, 3-cyclopropyl-morpholin-4-yl, 4-[(4-fluorophenyl)methylsulfonyl-]2-(trifluoromethyl)piperazin-1-yl, 4-ethylsulfonyl-2-(trifluoromethyl)-piperazin-1-yl, 2-(trifluoromethyl)-pyrrolidin-1-yl, 2-chloro-5-fluorophenyl, 3-(trifluoromethyl)-pyrazolin-4-yl, 2-(trifluoromethyl)-pyridin-3-yl, 3-methyl-thien-4-yl, 2-methyl phenyl, 1-acetyl-3-trifluoromethyl-piperazin-4-yl, 2-methyl-piperidin-1-yl, 2-cyclopropyl-piperidin-1-yl, 2-methyl-morpholin-4-yl, 2-trifluoromethyl-morpholin-4-yl, and 2-cyclopropyl-morpholin-4-yl.
In some embodiments, R1 is selected from phenyl and monocyclic 5-6 membered heteroaryl, each optionally substituted with one or more substituents selected from the group consisting of halogen, C1-C6alkyl, C1-C6haloalkyl, and C3-C4cycloalkyl; R2 is hydrogen; R3 is selected from phenyl and a monocyclic 5-6 membered heteroaryl, each optionally substituted with one or more substituents selected from the group consisting of halogen, C1-C6alkyl, C1-C6haloalkyl, and C3-C4cycloalkyl; and Z is CH or N; or a pharmaceutically acceptable salt thereof.
In some embodiments, R1 is selected from phenyl and pyrimidinyl, each optionally substituted with one or more substituents selected from the group consisting of halogen, C1-C6alkyl, C1-C6haloalkyl, or C3-C4cycloalkyl; R2 is hydrogen; R3 is selected from the group consisting of phenyl, pyridyl and pyrazolyl, each optionally substituted with one or more substituents selected from halogen, C1-C6alkyl, C1-C6haloalkyl, and C3-C4cycloalkyl; or A; Y is selected from the group consisting of CH2, O, NSO2—C1-C6alkyl and NSO7-benzyl, wherein said benzyl is optionally substituted by one or more halogen; R12 is selected from C1-C6alkyl and C1-C6haloalkyl; and Z is selected from CH and N; or a pharmaceutically acceptable salt thereof.
In some embodiments, R1 is selected from phenyl, 3,5-difluorophenyl and 2-methylpyrimidin-4-yl; R2 is hydrogen; R3 is selected from the group consisting of 2-chlorophenyl, 3-pyridyl, 4-pyridyl, 1-morpholinyl, 2-(trifluoromethyl)-1-piperidyl, 3-(trifluoromethyl)morpholin-4-yl, 4-[(4-fluorophenyl)methylsulfonyl]-2-(trifluoromethyl)piperazin-1-yl, 4-ethylsulfonyl-2-(trifluoromethyl)piperazin-1-yl, 2-(trifluoromethyl)phenyl, 4-methyl-3-pyridyl, 2-(trifluoromethyl)-3-pyridyl, 1-ethyl-3-(trifluoromethyl)pyrazol-4-yl, and 3-cyclopropylmorpholin-4-yl; and Z is selected from CH and N; or a pharmaceutically acceptable salt thereof.
In some embodiments, R1 is selected from phenyl and monocyclic 5-6 membered heteroaryl, each optionally substituted with one or more substituents selected from the group consisting of halogen, C1-C6alkyl, C1-C6haloalkyl, and C3-C4cycloalkyl; R2 is hydrogen; R3 is selected from phenyl and a monocyclic 5-6 membered heteroaryl, each optionally substituted with one or more substituents selected from the group consisting of halogen, C1-C6alkyl, C1-C6haloalkyl, and C3-C4cycloalkyl; and Z is CH or N; or a pharmaceutically acceptable salt thereof.
In some embodiments, R1 is selected from phenyl and pyrimidinyl, each optionally substituted with one or more substituents selected from the group consisting of halogen, C1-C6alkyl, C1-C6haloalkyl, and C3-C4cycloalkyl; R2 is hydrogen; R3 is selected from phenyl and pyridyl, each optionally substituted with one or more substituents selected from the group consisting of halogen, C1-C6alkyl, C1-C6haloalkyl, and C3-C4cycloalkyl; or A; Y is selected from the group consisting of CH2, O, NSO2—C1-C6alkyl and NSO2-benzyl, wherein said benzyl is optionally substituted by one or more halogen; R12 is selected from C1-C6alkyl and C1-C6haloalkyl; and Z is selected from CH and N; or a pharmaceutically acceptable salt thereof.
In some embodiments, R1 is selected from the group consisting of phenyl, 2-methylpyrimidin-4-yl, oxazol-2yl, 2-methylthiazol-4-yl, 2-methylpyrazol-3-yl, and 1-methyl imidazol-4-yl; R2 is hydrogen; R3 is selected from the group consisting of 2-chlorophenyl, 3-pyridyl, 4-pyridyl, 1-morpholinyl, 2-(trifluoromethyl)-1-piperidyl, 3-(trifluoromethyl)morpholin-4-yl, 4-[(4-fluorophenyl)methylsulfonyl]-2-(trifluoromethyl)piperazin-1-yl, 4-ethylsulfonyl-2-(trifluoromethyl)piperazin-1-yl; 2-(trifluoromethyl)phenyl, 4-methyl-pyridin-3-yl, 2-(trifluoromethyl)-pyridin-3-yl, and 1-ethyl-3-(trifluoromethyl)pyrazol-4-yl; and Z is selected from CH and N; or a pharmaceutically acceptable salt thereof.
In some embodiments, R1 is selected from phenyl and 2-methylpyrimidin-4-yl; R2 is hydrogen; R3 is selected from the group consisting of 2-chlorophenyl, 3-pyridyl, 4-pyridyl, 1-morpholinyl, 2-(trifluoromethyl)-1-piperidyl, 3-(trifluoromethyl)morpholin-4-yl, 4-[(4-fluorophenyl)methylsulfonyl]-2-(trifluoromethyl)piperazin-1-yl, and 4-ethylsulfonyl-2-(trifluoromethyl)piperazin-1-yl; and Z is selected from CH and N; or a pharmaceutically acceptable salt thereof.
In some embodiments, the compound is selected from the group consisting of: 4-(2-anilinopyrimidin-4-yl)-6-(2-chlorophenyl)-1H-pyridin-2-one; 4-(2-anilinopyrimidin-4-yl)-6-(3-pyridyl)-1H-pyridin-2-one; 4-(2-anilinopyrimidin-4-yl)-6-(4-pyridyl)-1H-pyridin-2-one; 4-(2-anilinopyrimidin-4-yl)-6-morpholino-1H-pyridin-2-one; 4-[2-[(2-Methylpyrimidin-4-yl)amino]-4-pyridyl]-6-[2-(trifluoromethyl)-1-piperidyl]-1H-pyridin-2-one; 4-(2-anilinopyrimidin-4-yl)-6-[2-(trifluoromethyl)-1-piperidyl]-1H-pyridin-2-one; 4-[2-[(2-Methylpyrimidin-4-yl)amino]-4-pyridyl]-6-[3-(trifluoromethyl)morpholin-4-yl]-1H-pyridin-2-one; 4-(2-anilinopyrimidin-4-yl)-6-[3-(trifluoromethyl)morpholin-4-yl]-1H-pyridin-2-one; 6-[4-[(4-Fluorophenyl)methylsulfonyl]-2-(trifluoromethyl)piperazin-1-yl]-4-[2-[(2-methylpyrimidin-4-yl)amino]-4-pyridyl]-1H-pyridin-2-one; 6-[4-Ethylsulfonyl-2-(trifluoromethyl)piperazin-1-yl]-4-[2-[(2-methylpyrimidin-4-yl)amino]-4-pyridyl]-1H-pyridin-2-one; 4-[2-(Oxazol-2-ylamino)-4-pyridyl]-6-[3-(trifluoromethyl)morpholin-4-yl]-1H-pyridin-2-one; 4-[2-[(2-Methylthiazol-4-yl)amino]-4-pyridyl]-6-[3-(trifluoromethyl)morpholin-4-yl]-1H-pyridin-2-one; 4-[2-[(2-methylpyrimidin-4-yl)amino]-4-pyridyl]-6-[2-(trifluoromethyl)-phenyl]-1H-pyridin-2-one; 4-[2-[(2-Methylpyrazol-3-yl)amino]-4-pyridyl]-6-[2-(trifluoromethyl)phenyl]-1H-pyridin-2-one; 4-[2-[(2-Methylthiazol-4-yl)amino]-4-pyridyl]-6-[2-(trifluoromethyl)phenyl]-1H-pyridin-2-one; 6-(4-methyl-3-pyridyl)-4-[2-[(2-methylpyrimidin-4-yl)amino]-4-pyridyl]-1H-pyridin-2-one; 4-[2-[(2-methylpyrimidin-4-yl)amino]-4-pyridyl]-6-[2-(trifluoromethyl)-3-pyridyl]-1H-pyridin-2-one; 6-[1-ethyl-3-(trifluoromethyl)pyrazol-4-yl]-4-[2-[(2-methylpyrimidin-4-yl)am 4-pyridyl]-1H-pyridin-2-one; 4-[2-[(1-Methylimidazol-4-yl)amino]-4-pyridyl]-6-[2-(trifluoromethyl)phenyl pyridin-2-one; 6-(2-chlorophenyl)-4-[2-[(2-methylpyrimidin-4-yl)amino]-4-pyridyl]-1H-pyridin-2-one, and pharmaceutically acceptable salts, stereoisomers, and tautomers thereof.
In some embodiments, the compound is selected from the group consisting of: 4-(2-anilinopyrimidin-4-yl)-6-(2-chlorophenyl)-1H-pyridin-2-one; 4-(2-anilinopyrimidin-4-yl)-6-(3-pyridyl)-1H-pyridin-2-one; 4-(2-anilinopyrimidin-4-yl)-6-(4-pyridyl)-1H-pyridin-2-one; 4-(2-anilinopyrimidin-4-yl)-6-morpholino-1H-pyridin-2-one; 4-[2-[(2-Methylpyrimidin-4-yl)amino]-4-pyridyl]-6-[2-(trifluoromethyl)-1-piperidyl]-1H-pyridin-2-one; 4-(2-anilinopyrimidin-4-yl)-6-[2-(trifluoromethyl)-1-piperidyl]-1H-pyridin-2-one; 4-[2-[(2-Methylpyrimidin-4-yl)amino]-4-pyridyl]-6-[3-(trifluoromethyl)morpholin-4-yl]-1H-pyridin-2-one; 4-(2-anilinopyrimidin-4-yl)-6-[3-(trifluoromethyl)morpholin-4-yl]-1H-pyridin-2-one; 6-[4-[(4-Fluorophenyl)methylsulfonyl]-2-(trifluoromethyl)piperazin-1-yl]-4-[2-[(2-methylpyrimidin-4-yl)amino]-4-pyridyl]-1H-pyridin-2-one; 6-[4-Ethylsulfonyl-2-(trifluoromethyl)piperazin-1-yl]-4-[2-[(2-methylpyrimidin-4-yl)amino]-4-pyridyl]-1H-pyridin-2-one; 4-[2-[(2-methylpyrimidin-4-yl)amino]-4-pyridyl]-6-[2-(trifluoromethyl)-phenyl]-1H-pyridin-2-one; 6-(4-methyl-3-pyridyl)-4-[2-[(2-methylpyrimidin-4-yl)amino]-4-pyridyl]-1H-pyridin-2-one; 4-[2-[(2-methylpyrimidin-4-yl)amino]-4-pyridyl]-6-[2-(trifluoromethyl)-3-pyridyl]-1H-pyridin-2-one; 6-[1-ethyl-3-(trifluoromethyl)pyrazol-4-yl]-4-[2-[(2-methylpyrimidin-4-yl)am 4-pyridyl]-1H-pyridin-2-one; 6-(2-chlorophenyl)-4-[2-[(2-methylpyrimidin-4-yl)amino]-4-pyridyl]-1H-pyridin-2-one; 6-(3-cyclopropylmorpholin-4-yl)-4-[2-[(2-methylpyrimidin-4-yl)amino]-4-pyridyl]-1H-pyridin-2-one, and pharmaceutically acceptable salts, stereoisomers, and tautomers thereof.
In some embodiments, the compound is selected from the group consisting of: 4-(2-anilinopyrimidin-4-yl)-6-(2-chlorophenyl)-1H-pyridin-2-one; 4-(2-anilinopyrimidin-4-yl)-6-(3-pyridyl)-1H-pyridin-2-one; 4-(2-anilinopyrimidin-4-yl)-6-(4-pyridyl)-1H-pyridin-2-one 4-(2-anilinopyrimidin-4-yl)-6-morpholino-1H-pyridin-2-one; 4-[2-[(2-Methylpyrimidin-4-yl)amino]-4-pyridyl]-6-[2-(trifluoromethyl)-1-piperidyl]-1H-pyridin-2-one; 4-(2-anilinopyrimidin-4-yl)-6-[2-(trifluoromethyl)-1-piperidyl]-1H-pyridin-2-one; 4-[2-[(2-Methylpyrimidin-4-yl)amino]-4-pyridyl]-6-[3-(trifluoromethyl)morpholin-4-yl]-1H-pyridin-2-one; 4-(2-anilinopyrimidin-4-yl)-6-[3-(trifluoromethyl)morpholin-4-yl]-1H-pyridin-2-one; 6-[4-[(4-Fluorophenyl)methylsulfonyl]-2-(trifluoromethyl)piperazin-1-yl]-4-[2-[(2-methylpyrimidin-4-yl)amino]-4-pyridyl]-1H-pyridin-2-one; 6-[4-Ethylsulfonyl-2-(trifluoromethyl)piperazin-1-yl]-4-[2-[(2-methylpyrimidin-4-yl)amino]-4-pyridyl]-1H-pyridin-2-one; 4-[2-[(2-methylpyrimidin-4-yl)amino]-4-pyridyl]-6-[2-(trifluoromethyl)-phenyl]-1H-pyridin-2-one; 6-(4-methyl-3-pyridyl)-4-[2-[(2-methylpyrimidin-4-yl)amino]-4-pyridyl]-1H-pyridin-2-one; 4-[2-[(2-methylpyrimidin-4-yl)amino]-4-pyridyl]-6-[2-(trifluoromethyl)-3-pyridyl]-1H-pyridin-2-one; 6-[1-ethyl-3-(trifluoromethyl)pyrazol-4-yl]-4-[2-[(2-methylpyrimidin-4-yl)amino]-4-pyridyl]-1H-pyridin-2-one; 6-(2-chlorophenyl)-4-[2-[(2-methylpyrimidin-4-yl)amino]-4-pyhdyl]-1H-pyridin-2-one, and pharmaceutically acceptable salts, stereoisomers, and tautomers thereof.
In some embodiments, described herein is a compound of Formula VI:
or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein: R1 is selected from C1-C3alkyl and cyclopropyl; R2 is selected from the group consisting of H, C1-C3haloalkyl, and C1-C3alkyl; A is selected from:
each R3 is independently selected from the group consisting of R6, C1-C6alkyl, amino N—C1-C3alkylamino, N, N-diC1-C3alkylamino, and C1-C3alkoxyC1-C3alkyl, wherein each of C1-C6alkyl and C1-C3alkoxyC1-C3alkyl is optionally substituted with one occurrence of R6, and each of C1-C6alkyl and C1-C3alkoxyC1-C3alkyl is optionally substituted with or one or more independent occurrences of halogen; R4 is selected from the group consisting of C1-C6alkyl, C1-C6alkoxy, C1-C6haloalkyl, C3-C6cycloalkyl, and phenyl, wherein phenyl is optionally substituted with one or more occurrences of a substituent independently selected from the group consisting of fluoro, chloro, methyl, methoxy, dimethylamino, trifluoromethoxy, trifluoromethyl, and cyclopropyl; R5 is selected from the group consisting of halogen, C1-C6alkyl, C1-C6alkoxy, C1-C6haloalkyl, and C3-C6cycloalkyl; each R6 is independently selected from the group consisting of phenyl, monocyclic heteroaryl, C3-C6Cycloalkyl, and heterocyclyl, wherein each of phenyl, monocyclic heteroaryl, C3-C6cycloalkyl, and heterocyclyl is optionally substituted with one or more occurrences of R7; and each R7 is independently selected from the group consisting of halogen, amino, N—C1-C3alkylamino, N,N-diC1-C3alkylamino and C1-C3alkoxyC1-C3alkyl, C1-C3alkoxy, C1-C3haloalkoxy, C3-C6cycloalkyl, C1-C3haloalkyl, and C1-C3alkyl.
In some embodiments, R2 is selected from hydrogen and C1-C3alkyl.
In some embodiments, R1 is methyl.
In some embodiments, R7 is selected from the group consisting of fluoro, cyclopropyl and methyl.
In some embodiments, R7 is fluoro or methyl.
In some embodiments, R4 is selected from the group consisting of methyl, trifluoromethyl, cyclopropyl and phenyl, said phenyl being optionally meta-substituted with one of fluoro, chloro, methyl, methoxy, dimethylamino, trifluoromethoxy, trifluoromethyl and cyclopropyl; and
R5 is selected from the group consisting of chloro, cyclopropyl, methyl and trifluoromethyl.
In some embodiments, R4 and R5 are independently selected from the group consisting of C1-C3haloalkyl, such as C1-C3fluorooalkyl, such as monofluoromethyl, difluoromethyl, and trifluoromethyl.
In some embodiments, R4 is selected from the group consisting of methyl, trifluoromethyl and cyclopropyl; and R5 is selected from the group consisting of chloro, cyclopropyl, methyl and trifluoromethyl.
In some embodiments, R3 is selected from the group consisting of R6, C1-C3alkyl, N,N-diC1-C3alkylamino and methoxyC1-C3alkyl, said C1-C3alkyl being optionally substituted with one R6.
In some embodiments, R6 is selected from the group consisting of phenyl, pyridyl, morpholinyl, imidazolyl, isoxazolyl, pyrazolyl, oxazolyl, cyclopropyl, cyclopentyl, pyrrolidinyl and tetrahydrofuryl, each optionally substituted with one or more R7.
In some embodiments, R6 is selected from the group consisting of phenyl, pyridyl, morpholinyl, imidazolyl, pyrazolyl, cyclopropyl, pyrrolidinyl, piperidinyl, and tetrahydrofuryl, each optionally substituted with one or more R7
In some embodiments, R6 is selected from the group consisting of phenyl, pyridyl, pyrrolidinyl, pyrazolyl, tetrahydrofuryl, each optionally substituted with one or more R7.
In some embodiments, R6 is selected from the group consisting of:
In some embodiments, R6 is selected from the group consisting of:
In some embodiments R6 is selected from the group consisting of:
In some embodiments, R3 is selected from the group consisting of:
In some embodiments, R3 is selected from the group consisting of:
In some embodiments, R3 is selected from the group consisting of:
In some embodiments, A is
In some embodiments, A is
In some embodiments, R1 is selected from the group consisting of methyl and cyclopropyl; R2 is selected from the group consisting of hydrogen,
and R3 is selected from the group consisting of:
In some embodiments, R1 is methyl; R2 is hydrogen; R4 and R5 are CF3; A is selected from:
and R3 is selected from the group consisting of:
In some embodiments, R1 is methyl; R2 is hydrogen; R4 is CF3; A is
and
R3 is selected from the group consisting of:
In some embodiments, R1 is methyl or cyclopropyl; R2 is hydrogen; R and R5 are CF3; A is selected from:
and R3 is selected from the group consisting of:
In some embodiments, the compound is selected from the group consisting of: 4-(3-methylmorpholin-4-yl)-6-[4-methylsulfonyl-2-(trifluoromethyl)piperazin-1-yl]-1H-pyridin-2-one; 6-[4-[(4-Fluorophenyl)methylsulfonyl]-2-(trifluoromethyl)piperazin-1-yl]-4-(3-methylmorpholin-4-yl)-1H-pyridin-2-one; 6-[4-[(5-Fluoro-3-pyridyl)sulfonyl]-2-(trifluoromethyl)piperazin-1-yl]-4-(3-methylmorpholin-4-yl)-1H-pyridin-2-one; 4-(3-methylmorpholin-4-yl)-6-[4-tetrahydrofuran-3-ylsulfonyl-2-(trifluoromethyl)piperazin-1-yl]-1H-pyridin-2-one; 4-(3-methylmorpholin-4-yl)-6-[4-pyrrolidin-1-ylsulfonyl-2-(trifluoromethyl)piperazin-1-yl]-1H-pyridin-2-one; N,N-dimethyl-4-[4-(3-methylmorpholin-4-yl)-6-oxo-1H-pyridin-2-yl]-3-(trifluoromethyl)piperazine-1-sulfonamide; 6-[4-(2-methoxyethylsulfonyl)-2-(trifluoromethyl)piperazin-1-yl]-4-(3-methylmorpholin-4-yl)-1H-pyridin-2-one; 6-[4-(4-fluorophenyl)sulfonyl-2-(trifluoromethyl)piperazin-1-yl]-4-(3-methylmorpholin-4-yl)-1H-pyridin-2-one; 4-(3-methylmorpholin-4-yl)-6-[4-(2-methylpyrazol-3-yl)sulfonyl-2-(trifluoromethyl)piperazin-1-yl]-1H-pyridin-2-one; 6-[4-Cyclopropylsulfonyl-2-(trifluoromethyl)piperazin-1-yl]-4-(3-methylmorpholin-4-yl)-1H-pyridin-2-one; 4-(3-methylmorpholin-4-yl)-6-[4-(1-piperidylsulfonyl)-2-(trifluoromethyl)piperazin-1-yl]-1H-pyridin-2-one; 4-(3-methylmorpholin-4-yl)-6-[4-morpholinosulfonyl-2-(trifluoromethyl)piperazin-1-yl]-1H-pyridin-2-one; 6-[4-(1,2-Dimethylimidazol-4-yl)sulfonyl-2-(trifluoromethyl)piperazin-1-yl]-4-(3-methylmorpholin-4-yl)-1H-pyridin-2-one; 6-[4-(1-methylcyclopropyl)sulfonyl-2-(trifluoromethyl)piperazin-1-yl]-4-(3-methylmorpholin-4-yl)-1H-pyridin-2-one; 4-(3-methylmorpholin-4-yl)-6-[4-methylsulfonyl-2-(trifluoromethyl)phenyl]-1H-pyridin-2-one; N,N-dimethyl-4-[4-(3-methylmorpholin-4-yl)-6-oxo-1H-pyridin-2-yl]-3-(trifluoromethyl)benzenesulfonamide; and pharmaceutically acceptable salts, stereoisomers, and tautomers thereof.
In some embodiments, the compound is selected from the group consisting of: 4-(3-methylmorpholin-4-yl)-6-[4-methylsulfonyl-2-(trifluoromethyl)piperazin-1-yl]-1H-pyridin-2-one; 6-[4-[(4-Fluorophenyl)methylsulfonyl]-2-(trifluoromethyl)piperazin-1-yl]-4-(3-methylmorpholin-4-yl)-1H-pyridin-2-one; 6-[4-[(5-Fluoro-3-pyridyl)sulfonyl]-2-(trifluoromethyl)piperazin-1-yl]-4-(3-methylmorpholin-4-yl)-1H-pyridin-2-one; 4-(3-methylmorpholin-4-yl)-6-[4-tetrahydrofuran-3-ylsulfonyl-2-(trifluoromethyl)piperazin-1-yl]-H-pyridin-2-one; 4-(3-methylmorpholin-4-yl)-6-[4-pyrrolidin-1-ylsulfonyl-2-(trifluoromethyl)piperazin-1-yl]-1H-pyridin-2-one; N,N-dimethyl-4-[4-(3-methylmorpholin-4-yl)-6-oxo-1H-pyridin-2-yl]-3-(trifluoromethyl)piperazine-1-sulfonamide; 6-[4-(2-methoxyethylsulfonyl)-2-(trifluoromethyl)piperazin-1-yl]-4-(3-methylmorpholin-4-yl)-1H-pyhdin-2-one; 6-[4-(4-fluorophenyl)sulfonyl-2-(trifluoromethyl)piperazin-1-yl]-4-(3-methylmorpholin-4-yl)-1H-pyridin-2-one; 4-(3-methylmorpholin-4-yl)-6-[4-(2-methylpyrazol-3-yl)sulfonyl-2-(trifluoromethyl)piperazin-1-yl]-1H-pyridin-2-one; and pharmaceutically acceptable salts, stereoisomers, and tautomers thereof.
Described herein, in another embodiment, is a method of treating a disorder in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a VPS34 inhibitor and one or more additional therapeutic agents. The disorder may be cancer.
Described herein, in another embodiment, is a method of treating a disorder in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound described herein and one or more additional therapeutic agents. The disorder may be cancer.
Non-limiting examples of cancers of the present disclosure include gastrointestinal stromal tumors, a esophageal cancer, a gastric cancer, a melanoma, a glioma, a glioblastoma, an ovarian cancer, a bladder cancer, a head cancer, a neck cancer, a urothelial cancer, a uterine cancer, a pancreatic cancer, a prostate cancer, a lung cancer, a breast cancer, a renal cancer, a hepatic cancer, an osteosarcoma, a sarcoma, a multiple myeloma, a cervical carcinoma, a cancer that is metastatic to bone, a papillary thyroid carcinoma, a non-small cell lung cancer, a lymphoma, a leukemia, and a colorectal cancer.
In some embodiments, the cancerous cell is of a cancer is selected from the group consisting of gastrointestinal stromal tumors, a esophageal cancer, a gastric cancer, a melanoma, a glioma, a glioblastoma, an ovarian cancer, a bladder cancer, a head cancer, a neck cancer, a urothelial cancer, a uterine cancer, a pancreatic cancer, a prostate cancer, a lung cancer, a breast cancer, a renal cancer, a hepatic cancer, an osteosarcoma, a sarcoma, a multiple myeloma, a cervical carcinoma, a cancer that is metastatic to bone, a papillary thyroid carcinoma, a non-small cell lung cancer, a lymphoma, a leukemia, and a colorectal cancer.
In some embodiments, the cancer is selected from the group consisting of a renal cancer and a melanoma. In some embodiments, the renal cancer is renal cell carcinoma such as clear-cell renal cell carcinoma.
In an aspect, provided herein is a method of treating cancer in a patient in need thereof, comprising: (i) administering to the patient a therapeutically effective amount of a compound represented by Formula I:
or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein: R1, R2, and R3 are independently selected from the group consisting of H, C1-C3haloalkyl, and C1-C3alkyl; A represents:
is a single bond or a double bond; X is selected from the group consisting of CH2, S, SO, SO2, NR5, NCOR5, NCOR9, NCOCH2R9, O, and a bond; Y is selected from the group consisting of N, CH, and C, provided that, when Y is CH,
is a single bond; n is selected from 1, 2, 3 and 4; R4 is selected from the group consisting of H, halogen, COR6, C1-C6alkyl, C1-C3alkoxyC1-C3alkyl, C1-C6alkoxy, C3-C6cycloalkyl, C3-C6heterocyclyl, C1-C3cyanoalkyl, C1-C3haloalkyl, aryl, and heteroaryl, wherein said aryl and said heteroaryl are optionally substituted with one or more R7; R5 is selected from the group consisting of H, C1-C3fluoroalkyl, C1-C3alkyl, C1-C3alkoxyC1-C3alkyl, and C3-C6cycloalkyl; R6 is selected from the group consisting of C1-C3alkoxy, N—C1-C3alkylamino, N,N-diC1-C3alkylamino, 1-pyrrolidinyl, 1-piperidinyl, and 1-azetidinyl; each R7 is independently selected from the group consisting of C1-C6alkyl, C3-C6cycloalkyl, C1-C3alkoxyC1-C3alkyl, C1-C3haloalkyl, halogen, N—C1-C3alkylamino, N,N-diC1-C3alkylamino, C1-C3haloalkoxy and C1-C3alkoxy; R9 is selected from the group consisting of C1-C3alkyl, C1-C3alkoxy, C3-C6cycloalkyl, heterocyclyl, phenyl and a monocyclic heteroaryl, wherein said heterocyclyl, said phenyl and said monocyclic heteroaryl are optionally substituted with one or two R8; and each R8 is independently selected from the group consisting of halogen, C1-C3haloalkyl and C1-C3alkyl; and (ii) administering to the patient a therapeutically effective amount of a STING agonist; wherein administering the therapeutically effective amount of the STING agonist and the compound results in an increased expression level of at least one chemokine in the patient as compared to any increase in the expression level of the at least one chemokine resulting from administering the compound alone to the patient.
In an aspect, provided herein is a method of upregulating at least one chemokine in a cell comprising: contacting the cell sample with: (i) a compound represented by:
or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein: R1, R2, and R3 are independently selected from the group consisting of H, C1-C3haloalkyl, and C1-C3alkyl; A represents:
is a single bond or a double bond; X is selected from the group consisting of CH2, S, SO, SO2, NR5, NCOR5, NCOR9, NCOCH2R9, O, and a bond; Y is selected from the group consisting of N, CH, and C, provided that, when Y is CH,
is a single bond; n is selected from 1, 2, 3 and 4; R4 is selected from the group consisting of H, halogen, COR6, C1-C6alkyl, C1-C3alkoxyC1-C3alkyl, C1-C6alkoxy, C3-C6cycloalkyl, C3-C6heterocyclyl, C1-C3cyanoalkyl, C1-C3haloalkyl, aryl, and heteroaryl, wherein said aryl and said heteroaryl are optionally substituted with one or more R7; R5 is selected from the group consisting of H, C1-C3fluoroalkyl, C1-C3alkyl, C1-C3alkoxyC1-C3alkyl, and C3-C6cycloalkyl; R6 is selected from the group consisting of C1-C3alkoxy, N—C1-C3alkylamino, N,N-diC1-C3alkylamino, 1-pyrrolidinyl, 1-piperidinyl, and 1-azetidinyl; each R7 is independently selected from the group consisting of C1-C6alkyl, C3-C6cycloalkyl, C1-C3alkoxyC1-C3alkyl, C1-C3haloalkyl, halogen, N—C1-C3alkylamino, N,N-diC1-C3alkylamino, C1-C3haloalkoxy and C1-C3alkoxy; R9 is selected from the group consisting of C1-C3alkyl, C1-C3alkoxy, C3-C6cycloalkyl, heterocyclyl, phenyl and a monocyclic heteroaryl, wherein said heterocyclyl, said phenyl and said monocyclic heteroaryl are optionally substituted with one or two R8; and each R8 is independently selected from the group consisting of halogen, C1-C3haloalkyl and C1-C3alkyl; in an amount sufficient to induce a Type I interferon response by the cell; and
In some embodiments, R1 is H. In some embodiments, R2 is H. In some embodiments, R3 is C1-C3alkyl. In some embodiments, A is piperidinyl. In some embodiments, R4 is C1-C3haloalkyl.
In some embodiments, the compound is selected from the group consisting of: 4-morpholino-6-(2-phenylpyrrolidin-1-yl)-1H-pyridin-2-one; 1-methyl-4-morpholino-6-(2-phenylpyrrolidin-1-yl)pyridin-2-one; 4-morpholino-6-[(2S)-2-phenylpyrrolidin-1-yl]-1H-pyridin-2-one; 4-morpholino-6-[(2R)-2-phenylpyrrolidin-1-yl]-1H-pyridin-2-one; 6-(3,6-dihydro-2H-pyran-4-yl)-4-(3-methylmorpholin-4-yl)-1H-pyridin-2-one; 4-(3-methylmorpholin-4-yl)-6-tetrahydropyran-4-yl-1H-pyridin-2-one; 6-[2-(3-methoxyphenyl)pyrrolidin-1-yl]-4-(3-methylmorpholin-4-yl)-1H-pyridin-2-one; 4-(3-methylmorpholin-4-yl)-6-[2-(3-pyridyl)pyrrolidin-1-yl]-1H-pyridin-2-one; 4-(3-methylmorpholin-4-yl)-6-(2-phenylpyrrolidin-1-yl)-1H-pyridin-2-one; N,N-dimethyl-1-[4-[(3R)-3-methylmorpholin-4-yl]-6-oxo-1H-pyridin-2-yl]pyrrolidine-2-carboxamide; 6-[2-(1-methoxy-1-methyl-ethyl)pyrrolidin-1-yl]-4-[(3R)-3-methylmorpholin-4-yl]-1H-pyridin-2-one; 6-(2-cyclohexylpyrrolidin-1-yl)-4-[(3R)-3-methylmorpholin-4-yl]-1H-pyridin-2-one; 6-[2-(3-fluorophenyl)pyrrolidin-1-yl]-4-[(3R)-3-methylmorpholin-4-yl]-1H-pyridin-2-one; 6-[2-(2,5-difluorophenyl)pyrrolidin-1-yl]-4-[(3R)-3-methylmorpholin-4-yl]-1H-pyridin-2-one; 4-[(3R)-3-methylmorpholin-4-yl]-6-[2-[3-(trifluoromethoxy)phenyl]pyrrolidin-1-yl]-1H-pyridin-2-one; 4-[(3R)-3-methylmorpholin-4-yl]-6-[2-[3-(trifluoromethyl)phenyl]pyrrolidin-1-yl]-1H-pyridin-2-one; 6-[2-(3-methoxyphenyl)pyrrolidin-1-yl]-4-[(3R)-3-methylmorpholin-4-yl]-1H-pyridin-2-one; 4-[(3R)-3-methylmorpholin-4-yl]-6-(2-phenylpyrrolidin-1-yl)-1H-pyridin-2-one; 4-[(3R)-3-methylmorpholin-4-yl]-6-[2-(1-methylpyrazol-4-yl)pyrrolidin-1-yl]-1H-pyridin-2-one; 6-[2-(1,5-dimethylpyrazol-3-yl)pyrrolidin-1-yl]-4-[(3R)-3-methylmorpholin-4-yl]-1H-pyridin-2-one; 6-[2-(1-ethylpyrazol-3-yl)pyrrolidin-1-yl]-4-[(3R)-3-methylmorpholin-4-yl]-1H-pyridin-2-one; 6-[2-(5-methyl-2-furyl)pyrrolidin-1-yl]-4-[(3R)-3-methylmorpholin-4-yl]-1H-pyridin-2-one; 6-[2-[3-(dimethylamino)phenyl]pyrrolidin-1-yl]-4-[(3R)-3-methylmorpholin-4-yl]-1H-pyridin-2-one; 4-[(3R)-3-methylmorpholin-4-yl]-6-(3-methylmorpholin-4-yl)-1H-pyridin-2-one; 4-[(3R)-3-methylmorpholin-4-yl]-6-[2-(trifluoromethyl)-1-piperidyl]-1H-pyridin-2-one; 4-[(3R)-3-methylmorpholin-4-yl]-6-(3-phenylmorpholin-4-yl)-1H-pyridin-2-one; 4-[(3R)-3-methylmorpholin-4-yl]-6-(1-oxo-1,4-thiazinan-4-yl)-1H-pyridin-2-one; 6-(1,1-dioxo-1,4-thiazinan-4-yl)-4-[(3R)-3-methylmorpholin-4-yl]-1H-pyridin-2-one; 6-(4-acetylpiperazin-1-yl)-4-[(3R)-3-methylmorpholin-4-yl]-1H-pyridin-2-one; 4-[(3R)-3-methylmorpholin-4-yl]-6-[(2R)-2-phenyl-1-piperidyl]-1H-pyridin-2-one; 4-[(3R)-3-methylmorpholin-4-yl]-6-(4-methyl-2-phenyl-piperazin-1-yl)-1H-pyridin-2-one; 4-[(3R)-3-methylmorpholin-4-yl]-6-[3-(trifluoromethyl)morpholin-4-yl]-1H-pyridin-2-one; 6-(3-cyclopropylmorpholin-4-yl)-4-[(3R)-3-methylmorpholin-4-yl]-1H-pyridin-2-one; 4-[(3R)-3-methylmorpholin-4-yl]-6-[(2S)-2-(trifluoromethyl)pyrrolidin-1-yl]-1H-pyridin-2-one; 4-[(3R)-3-methylmorpholin-4-yl]-6-[(2R)-2-(trifluoromethyl)pyrrolidin-1-yl]-1H-pyridin-2-one; 6-[2-(3-chlorophenyl)pyrrolidin-1-yl]-4-[(3R)-3-methylmorpholin-4-yl]-1H-pyridin-2-one; 6-[2-(3-cyclopropylphenyl)pyrrolidin-1-yl]-4-[(3R)-3-methylmorpholin-4-yl]-1H-pyridin-2-one; 4-[(3R)-3-methylmorpholin-4-yl]-6-[2-(2-pyridyl)pyrrolidin-1-yl]-1H-pyridin-2-one; 4-[(3R)-3-methylmorpholin-4-yl]-6-(2-thiazol-2-ylpyrrolidin-1-yl)-1H-pyridin-2-one; 6-[2-(5-methylisoxazol-3-yl)pyrrolidin-1-yl]-4-[(3R)-3-methylmorpholin-4-yl]-1H-pyridin-2-one; 1-methyl-4-[(3R)-3-methylmorpholin-4-yl]-6-[(2R)-2-(trifluoromethyl)-1-piperidyl]pyridin-2-one; 4-[(3R)-3-methylmorpholin-4-yl]-6-(8-oxa-5-azaspiro[3.5]nonan-5-yl)-1H-pyridin-2-one; 6-[2-(3-methoxyphenyl)-1-piperidyl]-4-[(3R)-3-methylmorpholin-4-yl]-1H-pyridin-2-one; 6-[4-acetyl-2-(trifluoromethyl)piperazin-1-yl]-4-[(3R)-3-methylmorpholin-4-yl]-1H pyridin-2-one; 6-[4-(5-fluoropyridine-3-carbonyl)-2-(trifluoromethyl)piperazin-1-yl]-4-[(3R)-3-methylmorpholin-4-yl]-1H-pyridin-2-one; 6-[4-[2-(4-fluorophenyl)acetyl]-2-(trifluoromethyl)piperazin-1-yl]-4-[(3R)-3-methylmorpholin-4-yl]-1H-pyridin-2-one; 4-[(3R)-3-methylmorpholin-4-yl]-6-[4-(tetrahydrofuran-2-carbonyl)-2-(trifluoromethyl)piperazin-1-yl]-1H-pyridin-2-one; 4-[(3R)-3-methylmorpholin-4-yl]-6-[4-methyl-2-(trifluoromethyl)piperazin-1-yl]-1H-pyridin-2-one; and pharmaceutically acceptable salts, tautomers, and stereoisomers thereof.
In some embodiments, the compound is selected from the group consisting of:
and pharmaceutically acceptable salts thereof.
In some embodiments, the compound is selected from the group consisting of:
and pharmaceutically acceptable salts thereof.
In some embodiments, the compound is selected from the group consisting of:
and pharmaceutically acceptable salts thereof.
In some embodiments, the at least one chemokine is selected from the group consisting of CCL5 and CXCL10.
In an aspect, provided herein is a method of treating cancer in a patient in need thereof, comprising administering to the patient: (i) a therapeutically effective amount of a compound represented by Formula II:
or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein: R1 is selected from the group consisting of aryl and heteroaryl, wherein said aryl and said heteroaryl being mono- or bicyclic and each of aryl and heteroaryl is optionally substituted with one or more independent occurrences of a substituent selected from the group consisting of R5, R6, R7 and R8; each of R2, R3, R4 is independently selected from the group consisting of H, C1-C3haloalkyl, and C1-C3alkyl; each of R5, R6, R7, and R8 is independently selected from the group consisting of halogen, C1-C6alkyl, C1-C6alkoxy, C1-C6haloalkyl, amino, —NHSO2R9, hydroxy, phenyl, and a monocyclic heteroaryl; and R9 is selected from C1-C3haloalkyl and C1-C3alkyl; and (ii) a therapeutically effective amount of a STING agonist; wherein administering the therapeutically effective amount of the STING agonist and the compound results in an increased expression level of at least one chemokine in the patient as compared to any increase in the expression level of the at least one chemokine resulting from administering the compound alone to the patient.
In an aspect, provided herein is a method of upregulating at least one chemokine in a cell comprising: contacting the cell sample with: (i) a compound represented by:
or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein: R1 is selected from the group consisting of aryl and heteroaryl, wherein said aryl and said heteroaryl being mono- or bicyclic and each of aryl and heteroaryl is optionally substituted with one or more independent occurrences of a substituent selected from the group consisting of R5, R6, R7 and R8; each of R2, R3, R4 is independently selected from the group consisting of H, C1-C3haloalkyl, and C1-C3alkyl; each of R5, R6, R7, and R8 is independently selected from the group consisting of halogen, C1-C6alkyl, C1-C6alkoxy, C1-C6haloalkyl, amino, —NHSO2R9, hydroxy, phenyl, and a monocyclic heteroaryl; and R9 is selected from C1-C3haloalkyl and C1-C3alkyl; in an amount sufficient to induce a Type I interferon response by the cell; and (ii) a STING agonist in an amount sufficient to increase the expression level of the at least one chemokine in the cell.
In some embodiments, the compound is selected from the group consisting of:
and pharmaceutically acceptable salts thereof.
In some embodiments, the compound is selected from the group consisting of: 6-(2-chlorophenyl)-4-morpholino-1H-pyridin-2-one; 6-(2-chlorophenyl)-1-methyl-4-morpholino-pyridin-2-one; 6-(2-chlorophenyl)-4-(3-methylmorpholin-4-yl)-1H-pyridin-2-one; 6-(2-chlorophenyl)-1-methyl-4-(3-methylmorpholin-4-yl)pyridin-2-one; 4-(3-methylmorpholin-4-yl)-6-(4-methyl-3-pyridyl)-1H-pyridin-2-one; 4-(3-methylmorpholin-4-yl)-6-pyrimidin-5-yl-1H-pyridin-2-one; 4-(3-methylmorpholin-4-yl)-6-(2-phenylphenyl)-1H-pyridin-2-one; 6-(2-chloro-5-fluoro-phenyl)-4-[(3R)-3-methylmorpholin-4-yl]-1H-pyridin-2-one; 4-[(3R)-3-methylmorpholin-4-yl]-6-(o-tolyl)-1H-pyridin-2-one; 4-[(3R)-3-methylmorpholin-4-yl]-6-[2-(trifluoromethyl)-3-pyridyl]-1H-pyridin-2-one; 6-(2-chlorophenyl)-4-[(3R)-3-methylmorpholin-4-yl]-1H-pyridin-2-one; 4-[(3R)-3-methylmorpholin-4-yl]-6-[2-(trifluoromethyl)phenyl]-1H-pyridin-2-one; 6-(3-furyl)-4-[(3R)-3-methylmorpholin-4-yl]-1H-pyridin-2-one; 4-[(3R)-3-methylmorpholin-4-yl]-6-(4-methyl-3-thienyl)-1H-pyridin-2-one; N-[2-[4-[(3R)-3-methylmorpholin-4-yl]-6-oxo-1H-pyridin-2-yl]phenyl]methanesulfonamide; 4-[(3R)-3-methylmorpholin-4-yl]-6-(4-(methylsulfonyl)-2-(trifluoromethyl)phenyl)-1H-pyridin-2-one; 4-[(3R)-3-methylmorpholin-4-yl]-6-(6-methyl-5-quinolyl)-1H-pyridin-2-one; 4-[(3R)-3-methylmorpholin-4-yl]-6-[4-(1H-pyrazol-5-yl)phenyl]-1H-pyridin-2-one; N,N-dimethyl-[4[4-[(3R)-3-methylmorpholin-4-yl]-6-oxo-1H-pyridin-2-yl]-3-(trifluoromethyl)]benzenesulfonamide; and pharmaceutically acceptable salts, tautomers, and stereoisomers thereof.
In some embodiments, the at least one chemokine is selected from the group consisting of CCL5 and CXCL10.
In an aspect, provided herein is a method of treating cancer in a patient in need thereof, comprising administering to the patient: (i) a therapeutically effective amount of a compound represented by Formula III:
or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein: X is selected from N and CR1; R1 is selected from the group consisting of H, C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxyC1-C3alkyl, C3-C6cycloalkyl, cyano, phenyl, and monocyclic heteroaryl, wherein each of phenyl and monocyclic heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of halo, N—C1-C3alkylamino, N,N-diC1-C3alkylamino, C3-C6cycloalkyl, C1-C3alkoxyC1-C3alkyl, C1-C3haloalkyl, C1-C3haloalkoxy, C1-C3alkoxy, and C1-C3alkyl; R2 is selected from the group consisting of H, C1-C3haloalkyl, and C1-C3alkyl; R3 is selected from the group consisting of A, phenyl, and monocyclic heteroaryl, wherein each of phenyl and monocyclic heteroaryl is optionally substituted with one or more occurrences of R4; each R4 is independently selected from the group consisting of COR5, halogen, C1-C6alkyl, C1-C6alkoxy, C1-C6haloalkoxy, amino N—C1-C3alkylamino, N,N-diC1-C3alkylamino, 1-pyrrolidinyl, 1-piperidinyl, 1-azetidinyl, NHSO2R6, SO2R7, hydroxy, C3-C6cycloalkyl, C1-C3alkoxyC1-C3alkyl, C1-C3cyanoalkyl and C1-C6haloalkyl; R5 is selected from the group consisting of C1-C3alkoxy, N—C1-C3alkylamino, N,N-diC1-C3alkylamino, 1-pyrrolidinyl, 1-piperidinyl, and 1-azetidinyl; R6 is selected from C1-C3haloalkyl and C1-C3alkyl; each R7 is independently selected from the group consisting of R8, C1-C6alkyl, N—C1-C3alkylamino, N,N-diC1-C3alkylamino and C1-C3alkoxyC1-C3alkyl, wherein each of C1-C6alkyl and C1-C3alkoxyC1-C3alkyl is optionally substituted with one occurrence of R8, and each of C1-C6alkyl and C1-C3alkoxyC1-C3alkyl is optionally substituted with or one or more independent occurrences of halogen; each R8 is independently selected from the group consisting of phenyl, monocyclic heteroaryl, C3-C6cycloalkyl, and heterocyclyl, wherein each of phenyl, monocyclic heteroaryl, C3-C6cycloalkyl, and heterocyclyl is optionally substituted with one or more occurrences of R9; each R9 is independently selected from the group consisting of halo, N—C1-C3alkylamino, N,N-diC1-C3alkylamino, C1-C3alkoxyC1-C3alkyl, amino, C1-C3haloalkyl, C1-C3alkoxy, C1-C3haloalkoxy, C3-C6cycloalkyl and C1-C3alkyl; A is
R10 is selected from the group consisting of H, halogen, COR11, C1-C6alkyl, C1-C3alkoxyC1-C3alkyl, C1-C6alkoxy, C3-C6cycloalkyl, C1-C3cyanoalkyl, C1-C3haloalkyl, phenyl, and heteroaryl, wherein each of phenyl and heteroaryl is optionally substituted with one or more occurrences of R12, and provided that when R10 is phenyl or heteroaryl, then X is N or CH; each R11 is independently selected from the group consisting of C1-C3alkoxy, N—C1-C3alkylamino, N,N-diC1-C3alkylamino, 1-pyrrolidinyl, 1-piperidinyl, and 1-azetidinyl; Y is selected from the group consisting of CH2, S, SO, SO2, NR13, NCOR7, NCOOR14, NSO2R7, NCOCH2R7, O, and a bond; R12 is selected from the group consisting of C1-C6alkyl, C3-C6cycloalkyl, C1-C3alkoxyC1-C3alkyl, C1-C3haloalkyl, halogen, N—C1-C3alkylamino, N,N-diC1-C3alkylamino, C1-C3haloalkoxy, and C1-C3alkoxy; R13 is selected from H, C1-C3haloalkyl, C1-C3alkoxyC1-C3alkyl, C1-C3alkyl, C3-C6cycloalkyl; and R14 is selected from R8, C1-C6alkyl, C1-C3alkoxyC1-C3alkyl, wherein each of C1-C3alkyl and C1-C3alkoxyC1-C3alkyl is optionally substituted with one occurrence of R8, and each of C1-C6alkyl and C1-C3alkoxyC1-C3alkyl is optionally substituted with or one or more independent occurrences of halogen; and (ii) a therapeutically effective amount of a STING agonist; wherein administering the therapeutically effective amount of the STING agonist and the compound results in an increased expression level of at least one chemokine in the patient as compared to any increase in the expression level of the at least one chemokine resulting from administering the compound alone to the patient.
In an aspect, provided herein is a method of upregulating at least one chemokine in a cell comprising: contacting the cell sample with: (i) a compound represented by:
or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein: X is selected from N and CR1; R1 is selected from the group consisting of H, C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxyC1-C3alkyl, C3-C6cycloalkyl, cyano, phenyl, and monocyclic heteroaryl, wherein each of phenyl and monocyclic heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of halo, N—C1-C3alkylamino, N,N-diC1-C3alkylamino, C3-C6cycloalkyl, C1-C3alkoxyC1-C3alkyl, C1-C3haloalkyl, C1-C3haloalkoxy, C1-C3alkoxy, and C1-C3alkyl; R2 is selected from the group consisting of H, C1-C3haloalkyl, and C1-C3alkyl; R3 is selected from the group consisting of A, phenyl, and monocyclic heteroaryl, wherein each of phenyl and monocyclic heteroaryl is optionally substituted with one or more occurrences of R4; each R4 is independently selected from the group consisting of COR5, halogen, C1-C6alkyl, C1-C6alkoxy, C1-C6haloalkoxy, amino N—C1-C3alkylamino, N,N-diC1-C3alkylamino, 1-pyrrolidinyl, 1-piperidinyl, 1-azetidinyl, NHSO2R6, SO2R7, hydroxy, C3-C6cycloalkyl, C1-C3alkoxyC1-C3alkyl, C1-C3cyanoalkyl and C1-C6haloalkyl; R5 is selected from the group consisting of C1-C3alkoxy, N—C1-C3alkylamino, N,N-diC1-C3alkylamino, 1-pyrrolidinyl, 1-piperidinyl, and 1-azetidinyl; R6 is selected from C1-C3haloalkyl and C1-C3alkyl; each R7 is independently selected from the group consisting of R8, C1-C6alkyl, N—C1-C3alkylamino, N,N-diC1-C3alkylamino and C1-C3alkoxyC1-C3alkyl, wherein each of C1-C6alkyl and C1-C3alkoxyC1-C3alkyl is optionally substituted with one occurrence of R8, and each of C1-C6alkyl and C1-C3alkoxyC1-C3alkyl is optionally substituted with or one or more independent occurrences of halogen; each R8 is independently selected from the group consisting of phenyl, monocyclic heteroaryl, C3-C6cycloalkyl, and heterocyclyl, wherein each of phenyl, monocyclic heteroaryl, C3-C6cycloalkyl, and heterocyclyl is optionally substituted with one or more occurrences of R9; each R9 is independently selected from the group consisting of halo, N—C1-C3alkylamino, N,N-diC1-C3alkylamino, C1-C3alkoxyC1-C3alkyl, amino, C1-C3haloalkyl, C1-C3alkoxy, C1-C3haloalkoxy, C3-C6cycloalkyl and C1-C3alkyl; A is
R10 is selected from the group consisting of H, halogen, COR11, C1-C6alkyl, C1-C3alkoxyC1-C3alkyl, C1-C6alkoxy, C3-C6cycloalkyl, C1-C3cyanoalkyl, C1-C3haloalkyl, phenyl, and heteroaryl, wherein each of phenyl and heteroaryl is optionally substituted with one or more occurrences of R12, and provided that when R10 is phenyl or heteroaryl, then X is N or CH; each R11 is independently selected from the group consisting of C1-C3alkoxy, N—C1-C3alkylamino, N,N-diC1-C3alkylamino, 1-pyrrolidinyl, 1-piperidinyl, and 1-azetidinyl; Y is selected from the group consisting of CH2, S, SO, SO2, NR13, NCOR7, NCOOR14, NSO2R7, NCOCH2R7, O, and a bond; R12 is selected from the group consisting of C1-C6alkyl, C3-C6cycloalkyl, C1-C3alkoxyC1-C3alkyl, C1-C3haloalkyl, halogen, N—C1-C3alkylamino, N,N-diC1-C3alkylamino, C1-C3haloalkoxy, and C1-C3alkoxy; R13 is selected from H, C1-C3haloalkyl, C1-C3alkoxyC1-C3alkyl, C1-C3alkyl, C3-C6cycloalkyl; and R14 is selected from R8, C1-C6alkyl, C1-C3alkoxyC1-C3alkyl, wherein each of C1-C6alkyl and C1-C3alkoxyC1-C3alkyl is optionally substituted with one occurrence of R8, and each of C1-C6alkyl and C1-C3alkoxyC1-C3alkyl is optionally substituted with or one or more independent occurrences of halogen; and in an amount sufficient to induce a Type I interferon response by the cell; and (ii) a STING agonist in an amount sufficient to increase the expression level of the at least one chemokine in the cell.
In some embodiments, the compound is selected from the group consisting of:
and pharmaceutically acceptable salts thereof.
In some embodiments, the compound is selected from the group consisting of: 4-(1H-pyrrolo[2,3-b]pyridin-4-yl)-6-[2-(trifluoromethyl)phenyl]-1H-pyridin-2-one; 6-(3-Methyl-4-pyridyl)-4-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyridin-2-one; 6-(2-phenylpyrrolidin-1-yl)-4-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyridin-2-one; 4-(2-Methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-6-(3-pyridyl)-1H-pyridin-2-one; 4-(2-Methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-6-morpholino-1H-pyridin-2-one; 6-(2-Chlorophenyl)-4-(2-oxazol-5-yl-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyridin-2-one; 6-(2-Chlorophenyl)-4-[2-(3-pyridyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]-1H-pyridin-2-one; 6-(2-Chlorophenyl)-4-(2-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyridin-2-one; 4-(2-Methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-6-[2-(trifluoromethyl)-1-piperidyl]-1H-pyridin-2-one; 4-(1H-pyrrolo[2,3-b]pyridin-4-yl)-6-[2-(trifluoromethyl)-1-piperidyl]-1H-pyridin-2-one; 4-(1H-pyrrolo[2,3-b]pyridin-4-yl)-6-[3-(trifluoromethyl)morpholin-4-yl]-1H-pyridin-2-one; 6-[3-(Trifluoromethyl)morpholin-4-yl]-4-[2-[3-(trifluoromethyl)phenyl]-1H-pyrrolo[2,3-b]pyridin-4-yl]-1H-pyridin-2-one; 4-[2-(5-Methyl-2-thienyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]-6-[3-(trifluoromethyl)morpholin-4-yl]-1H-pyridin-2-one; 4-(1H-pyrazolo[3,4-b]pyridin-4-yl)-6-[2-(trifluoromethyl)-1-piperidyl]-1H-pyridin-2-one; 6-[2-(Trifluoromethyl)-1-piperidyl]-4-yl]-1H-pyrrolo[2,3-b]pyridin-4-yl]-1H-pyridin-2-one; 6-[2-(Trifluoromethyl)-1-piperidyl]-4-[2-[6-(trifluoromethyl)-3-pyridyl]-1H-pyrrolo[2,3-b]pyridin-4-yl]-1H-pyridin-2-one; 6-[2-(Trifluoromethyl)-1-piperidyl]-4-[2-[5-(trifluoromethyl)-3-pyridyl]-1H-pyrrolo[2,3-b]pyridin-4-yl]-1H-pyridin-2-one; 4-(2-cyclopropyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-6-[4-ethylsulfonyl-2-(trifluoromethyl)piperazin-1-yl]-1H-pyridin-2-one; 6-[4-ethylsulfonyl-2-(trifluoromethyl)piperazin-1-yl]-4-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyridin-2-one; 6-[4-[(4-fluorophenyl)methylsulfonyl]-2-(trifluoromethyl)piperazin-1-yl]-4-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyridin-2-one; 6-[4-Ethylsulfonyl-2-(trifluoromethyl)piperazin-1-yl]-4-(2-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyridin-2-one; 4-[2-[4-Ethylsulfonyl-2-(trifluoromethyl)piperazin-1-yl]-6-oxo-1H-pyridin-4-yl]-1H-pyrrolo[2,3-b]pyridine-2-carbonitrile; 4-(2-cyclopropyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-6-[2-(trifluoromethyl)phenyl]-1H-pyridin-2-one; 4-[2-Oxo-6-[2-(trifluoromethyl)phenyl]-1H-pyridin-4-yl]-1H-pyrrolo[2,3-b]pyridine-2-carbonitrile; 4-(1H-pyrazolo[3,4-b]pyridin-4-yl)-6-[2-(trifluoromethyl)phenyl]-1H-pyridin-2-one; 4-(6-(2-chlorophenyl)-2-oxo-1,2-dihydropyridin-4-yl)-N-ethyl-1H-pyrrolo[2,3-b]pyridine-2-carboxamide; 6-[4-Methylsulfonyl-2-(trifluoromethyl)piperazin-1-yl]-4-(1H-pyrazolo[3,4-b]pyridin-4-yl)-1H-pyridin-2-one; and pharmaceutically acceptable salts, stereoisomers, and tautomers thereof.
In some embodiments, the compound is selected from the group consisting of: 4-(1H-pyrrolo[2,3-b]pyridin-4-yl)-6-[2-(trifluoromethyl)phenyl]-1H-pyridin-2-one; 6-(3-Methyl-4-pyridyl)-4-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyridin-2-one; 6-(2-phenylpyrrolidin-1-yl)-4-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyridin-2-one; 4-(2-Methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-6-(3-pyridyl)-1H-pyridin-2-one; 4-(2-Methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-6-morpholino-1H-pyridin-2-one; 6-(2-Chlorophenyl)-4-(2-oxazol-5-yl-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyridin-2-one; 6-(2-Chlorophenyl)-4-[2-(3-pyridyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]-1H-pyridin-2-one; 6-(2-Chlorophenyl)-4-(2-methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyridin-2-one; 4-(2-Methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-6-[2-(trifluoromethyl)-1-piperidyl]-1H-pyridin-2-one; 4-(1H-pyrrolo[2,3-b]pyridin-4-yl)-6-[2-(trifluoromethyl)-1-piperidyl]-1H-pyridin-2-one; 4-(1H-pyrrolo[2,3-b]pyridin-4-yl)-6-[3-(trifluoromethyl)morpholin-4-yl]-1H-pyridin-2-one; 6-[3-(Trifluoromethyl)morpholin-4-yl]-4-[2-[3-(trifluoromethyl)phenyl]-1H-pyrrolo[2,3-b]pyridin-4-yl]-1H-pyridin-2-one; 4-[2-(5-Methyl-2-thienyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]-6-[3-(trifluoromethyl)morpholin-4-yl]-1H-pyridin-2-one; 4-(1H-pyrazolo[3,4-b]pyridin-4-yl)-6-[2-(trifluoromethyl)-1-pipendyl]-1H-pyridin-2-one; 6-[2-(Trifluoromethyl)-1-piperidyl]-4-yl]-1H-pyrrolo[2,3-b]pyridin-4-yl]-1H-pyridin-2-one; 6-[2-(Trifluoromethyl)-1-piperidyl]-4-[2-[6-(trifluoromethyl)-3-pyridyl]-1H-pyrrolo[2,3-b]pyridin-4-yl]-1H-pyridin-2-one; 6-[2-(Trifluoromethyl)-1-piperidyl]-4-[2-[5-(trifluoromethyl)-3-pyridyl]-1H-pyrrolo[2,3-b]pyridin-4-yl]-1H-pyridin-2-one; 4-(2-cyclopropyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-6-[4-ethylsulfonyl-2-(trifluoromethyl)piperazin-1-yl]-1H-pyridin-2-one; 6-[4-ethylsulfonyl-2-(trifluoromethyl)piperazin-1-yl]-4-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyridin-2-one; 6-[4-[(4-fluorophenyl)methylsulfonyl]-2-(trifluoromethyl)piperazin-1-yl]-4-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyridin-2-one; and pharmaceutically acceptable salts, stereoisomers, and tautomers thereof.
In some embodiments, the at least one chemokine is selected from the group consisting of CCL5 and CXCL10.
In an aspect, provided herein is a method of treating cancer in a patient in need thereof, comprising: (i) administering to the patient a therapeutically effective amount of a compound represented by Formula IV:
or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein: X is selected from —C(═O)— and a bond; R1 is selected from the group consisting of H, C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxyC1-C3alkyl, C3-C6cycloalkyl, C3-C6cyclohaloalkyl, C1-C3alkoxy, C1-C3haloalkoxy, C3-C6cycloalkoxymethyl, N—C1-C3alkylamino, N,N-diC1-C3alkylamino, 1-pyrrolidinyl, 1-piperidinyl and 1-azetidinyl, provided that when R1 is selected from the group consisting of C1-C3alkoxy, C1-C3haloalkoxy, N—C1-C3alkylamino, N,N-diC1-C3alkylamino, 1-pyrrolidinyl, 1-piperidinyl, and 1-azetidinyl, then X is C═O; R2 is selected from the group consisting of H, C1-C3haloalkyl, and C1-C3alkyl; R3 is selected from the group consisting of A, phenyl and monocyclic heteroaryl, wherein each of phenyl and monocyclic heteroaryl is optionally substituted with one or more occurrences of a substituent independently selected from the group consisting of R4, R5, R6 and R7; each R4, R5, R6, and R7 is independently selected from the group consisting of halo, C1-C6alkyl, C3-C6cycloalkyl, C1-C6alkoxy, C1-C3haloalkoxy, N,N-diC1-C3alkylamino, N—C1-C3alkylamino, 1-azetidinyl, C1-C6haloalkyl, amino, NHSO2R8, SO2R9, and hydroxy; R8 is selected from C1-C3haloalkyl and C1-C3alkyl; each R9 is independently selected from the group consisting of R10, C1-C6alkyl, amino, N—C1-C3alkylamino, N,N-di-C1-C3alkylamino and C1-C3alkoxyC1-C3alkyl, wherein each of C1-C6alkyl and C1-C3alkoxyC1-C3alkyl is optionally substituted with one occurrence of R10, and each of C1-C6alkyl and C1-C3alkoxyC1-C3alkyl is optionally substituted with or one or more independent occurrences of halogen; each R10 is independently selected from the group consisting of phenyl, monocyclic heteroaryl, C3-C6cycloalkyl, and heterocyclyl, wherein each phenyl, monocyclic heteroaryl, C3-C6cycloalkyl, and heterocyclyl is optionally substituted with one or more occurrences of R11; each R11 is independently selected from the group consisting of halo, C1-C3alkoxyC1-C3alkyl, amino, N—C1-C3alkylamino, N,N-diC1-C3alkylamino, C1-C3haloalkoxy, C1-C3alkoxy, C3-C6cycloalkyl, C1-C3haloalkyl, and C1-C3alkyl; A is:
R12 is selected from the group consisting of H, halo, COR13, C1-C6alkyl, C1-C3alkoxyC1-C3alkyl, C1-C6alkoxy, C3-C6cycloalkyl, C1-C3cyanoalkyl, and C1-C3haloalkyl; R13 is selected from the group consisting of C1-C3alkoxy, N—C1-C3alkylamino, N,N-diC1-C3alkylamino, 1-pyrrolidinyl, 1-piperidinyl, and 1-azetidinyl; Y is selected from the group consisting of CH2, S, SO, SO2, NR14, NCOR9, NCOOR15, NSO2R9, NCOCH2R9, O, and a bond; R14 is selected from the group consisting of H, C1-C3haloalkyl, C1-C3alkoxyC1-C3alkyl, C1-C3alkyl, and C3-C6cycloalkyl; and R15 is selected from the group consisting of R10, C1-C6alkyl and C1-C3alkoxyC1-C3alkyl, wherein each of C1-C6alkyl and C1-C3alkoxyC1-C3alkyl is optionally substituted with one occurrence of R10, and each of C1-C6alkyl and C1-C3alkoxyC1-C3alkyl is optionally substituted with or one or more independent occurrences of halogen; and (ii) administering to the patient a therapeutically effective amount of a STING agonist; wherein administering the therapeutically effective amount of the STING agonist and the compound results in an increased expression level of at least one chemokine in the patient as compared to any increase in the expression level of the at least one chemokine resulting from administering the compound alone to the patient.
In an aspect, provided herein is a method of upregulating at least one chemokine in a cell comprising: contacting the cell sample with: (i) a compound represented by:
or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein: X is selected from —C(═O)— and a bond; R1 is selected from the group consisting of H, C1-C3alkyl, C1-C3haloalkyl, C1-C3alkoxyC1-C3alkyl, C3-C6cycloalkyl, C3-C6cyclohaloalkyl, C1-C3alkoxy, C1-C3haloalkoxy, C3-C6cycloalkoxymethyl, N—C1-C3alkylamino, N,N-diC1-C3alkylamino, 1-pyrrolidinyl, 1-piperidinyl and 1-azetidinyl, provided that when R1 is selected from the group consisting of C1-C3alkoxy, C1-C3haloalkoxy, N—C1-C3alkylamino, N,N-diC1-C3alkylamino, 1-pyrrolidinyl, 1-piperidinyl, and 1-azetidinyl, then X is C═O; R2 is selected from the group consisting of H, C1-C3haloalkyl, and C1-C3alkyl; R3 is selected from the group consisting of A, phenyl and monocyclic heteroaryl, wherein each of phenyl and monocyclic heteroaryl is optionally substituted with one or more occurrences of a substituent independently selected from the group consisting of R4, R5, R6 and R7; each R4, R5, R6, and R7 is independently selected from the group consisting of halo, C1-C6alkyl, C3-C6cycloalkyl, C1-C6alkoxy, C1-C3haloalkoxy, N,N-diC1-C3alkylamino, N—C1-C3alkylamino, 1-azetidinyl, C1-C6haloalkyl, amino, NHSO2R8, SO2R9, and hydroxy; R8 is selected from C1-C3haloalkyl and C1-C3alkyl; each R9 is independently selected from the group consisting of R10, C1-C6alkyl, amino, N—C1-C3alkylamino, N,N-di-C1-C3alkylamino and C1-C3alkoxyC1-C3alkyl, wherein each of C1-C6alkyl and C1-C3alkoxyC1-C3alkyl is optionally substituted with one occurrence of R10, and each of C1-C6alkyl and C1-C3alkoxyC1-C3alkyl is optionally substituted with or one or more independent occurrences of halogen; each R10 is independently selected from the group consisting of phenyl, monocyclic heteroaryl, C3-C6cycloalkyl, and heterocyclyl, wherein each phenyl, monocyclic heteroaryl, C3-C6cycloalkyl, and heterocyclyl is optionally substituted with one or more occurrences of R11; each R11 is independently selected from the group consisting of halo, C1-C3alkoxyC1-C3alkyl, amino, N—C1-C3alkylamino, N,N-diC1-C3alkylamino, C1-C3haloalkoxy, C1-C3alkoxy, C3-C6cycloalkyl, C1-C3haloalkyl, and C1-C3alkyl; A is:
R12 is selected from the group consisting of H, halo, COR13, C1-C6alkyl, C1-C3alkoxyC1-C3alkyl, C1-C6alkoxy, C3-C0cycloalkyl, C1-C3cyanoalkyl, and C1-C3haloalkyl; R13 is selected from the group consisting of C1-C3alkoxy, N—C1-C3alkylamino, N,N-diC1-C3alkylamino, 1-pyrrolidinyl, 1-piperidinyl, and 1-azetidinyl; Y is selected from the group consisting of CH2, S, SO, SO2, NR14, NCOR9, NCOOR15, NSO2R9, NCOCH2R9, O, and a bond; R14 is selected from the group consisting of H, C1-C3haloalkyl, C1-C3alkoxyC1-C3alkyl, C1-C3alkyl, and C3-C6cycloalkyl; and R15 is selected from the group consisting of R10, C1-C6alkyl and C1-C3alkoxyC1-C3alkyl, wherein each of C1-C6alkyl and C1-C3alkoxyC1-C3alkyl is optionally substituted with one occurrence of R10, and each of C1-C6alkyl and C1-C3alkoxyC1-C3alkyl is optionally substituted with or one or more independent occurrences of halogen; and in an amount sufficient to induce a Type I interferon response by the cell; and (ii) a STING agonist in an amount sufficient to increase the expression level of the at least one chemokine in the cell.
In some embodiments, the compound is selected from the group consisting of:
and pharmaceutically acceptable salts thereof.
In some embodiments, the compound is selected from the group consisting of: N-[4-[2-(2-chlorophenyl)-6-oxo-1H-pyridin-4-yl]-2-pyridyl]acetamide; 4-(2-Amino-4-pyridyl)-6-(3-pyridyl)-1H-pyridin-2-one; 4-(2-Amino-4-pyridyl)-6-(2-chlorophenyl)-1H-pyridin-2-one; N-[4-[2-(2-chlorophenyl)-6-oxo-1H-pyridin-4-yl]-2-pyridyl]-2-methoxy-acetamide; N-[4-[2-oxo-6-[2-(trifluoromethyl)-1-piperidyl]-1H-pyridin-4-yl]-2-pyridyl]acetamide; N-[4-[2-oxo-6-[2-(trifluoromethyl)-1-piperidyl]-1H-pyridin-4-yl]-2-pyridyl]cyclopropanecarboxamide; N-[4-[2-oxo-6-[3-(trifluoromethyl)morpholin-4-yl]-1H-pyridin-4-yl]-2-pyridyl]acetamide; methyl N-[4-[2-(2-chlorophenyl)-6-oxo-1H-pyridin-4-yl]-2-pyridyl]carbamate; methyl N-[4-[2-[1-ethyl-3-(trifluoromethyl)pyrazol-4-yl]-6-oxo-1H-pyridin-4-yl]-2-pyridyl]carbamate; methyl N-[4-[2-oxo-6-[2-(trifluoromethyl)-3-pyridyl]-1H-pyridin-4-yl]-2-pyridyl]carbamate; methyl N-[4-[2-oxo-6-[2-(trifluoromethyl)phenyl]-1H-pyridin-4-yl]-2-pyridyl]carbamate; N-[4-[2-oxo-6-[2-(trifluoromethyl)phenyl]-1H-pyridin-4-yl]-2-pyridyl]acetamide; N-[4-[2-(4-methyl-3-pyridyl)-6-oxo-1H-pyridin-4-yl]-2-pyridyl]acetamide; N-[4-[2-oxo-6-[2-(trifluoromethyl)-3-pyridyl]-1H-pyridin-4-yl]-2-pyridyl]acetamide; N-[4-[2-[1-ethyl-3-(trifluoromethyl)pyrazol-4-yl]-6-oxo-1H-pyridin-4-yl]-2-pyridyl]acetamide; methyl N-[4-[2-oxo-6-[3-(trifluoromethyl)morpholin-4-yl]-1H-pyridin-4-yl]-2-pyridyl]carbamate; methyl N-[4-[2-oxo-6-[2-(trifluoromethyl)-1-piperidyl]-1H-pyridin-4-yl]-2-pyridyl]carbamate; N-[4-[2-(3-cyclopropylmorpholin-4-yl)-6-oxo-1H-pyridin-4-yl]-2-pyridyl]acetamide; N-[4-[2-[4-ethylsulfonyl-2-(trifluoromethyl)piperazin-1-yl]-6-oxo-1H-pyridin-4-yl]-2-pyridyl]acetamide; N-[4-[2-(2-methyl-3-pyridyl)-6-oxo-1H-pyridin-4-yl]-2-pyridyl]acetamide; N-[4-[2-oxo-6-[4-(trifluoromethyl)-3-thienyl]-1H-pyridin-4-yl]-2-pyridyl]acetamide; 1,1-Dimethyl-3-[4-[2-oxo-6-[2-(trifluoromethyl)phenyl]-1H-pyridin-4-yl]-2-pyridyl]urea; N-[4-[2-oxo-6-[2-(trifluoromethyl)phenyl]-1H-pyridin-4-yl]-2-pyridyl]pyrrolidine-1-carboxamide; N-[4-[2-[2-(1-methoxy-1-methyl-ethyl)pyrrolidin-1-yl]-6-oxo-1H-pyridin-4-yl]-2-pyridyl]acetamide; and pharmaceutically acceptable salts, tautomers, and stereoisomers thereof.
In some embodiments, the compound is selected from the group consisting of: 4-(2-Amino-4-pyridyl)-6-(3-pyridyl)-1H-pyridin-2-one; 4-(2-Amino-4-pyridyl)-6-(2-chlorophenyl)-1H-pyridin-2-one; N-[4-[2-(2-chlorophenyl)-6-oxo-1H-pyridin-4-yl]-2-pyridyl]-2-methoxy acetamide; N-[4-[2-oxo-6-[2-(trifluoromethyl)-1-piperidyl]-1H-pyridin-4-yl]-2-pyridyl]acetamide; N-[4-[2-oxo-6-[2-(trifluoromethyl)-1-piperidyl]-1H-pyridin-4-yl]-2-pyridyl]cyclopropanecarboxamide; N-[4-[2-oxo-6-[3-(trifluoromethyl)morpholin-4-yl]-1H-pyridin-4-yl]-2-pyridyl]acetamide; methyl N-[4-[2-(2-chlorophenyl)-6-oxo-1H-pyridin-4-yl]-2-pyridyl]carbamate; methyl N-[4-[2-[1-ethyl-3-(trifluoromethyl)pyrazol-4-yl]-6-oxo-1H-pyridin-4-yl]-2-pyridyl]carbamate; methyl N-[4-[2-oxo-6-[2-(trifluoromethyl)-3-pyridyl]-1H-pyridin-4-yl]-2 pyridyl]carbamate; methyl N-[4-[2-(4-methyl-3-pyridyl)-6-oxo-1H-pyridin-4-yl]-2-pyridyl]carbamate; methyl N-[4-[2-oxo-6-[2-(trifluoromethyl)phenyl]-1H-pyridin-4-yl]-2-pyridyl]carbamate; N-[4-[2-oxo-6-[2-(trifluoromethyl)phenyl]-1H-pyridin-4-yl]-2-pyridyl]acetamide; N-[4-[2-(4-methyl-3-pyridyl)-6-oxo-1H-pyridin-4-yl]-2-pyridyl]acetamide; N-[4-[2-oxo-6-[2-(trifluoromethyl)-3-pyridyl]-1H-pyridin-4-yl]-2-pyridyl]acetamide; N-[4-[2-[1-ethyl-3-(trifluoromethyl)pyrazol-4-yl]-6-oxo-1H-pyridin-4-yl]-2-pyridyl]acetamide; methyl N-[4-[2-oxo-6-[3-(trifluoromethyl)morpholin-4-yl]-1H-pyridin-4-yl]-2-pyridyl]carbamate; methyl N-[4-[2-oxo-6-[2-(trifluoromethyl)-1-piperidyl]-1H-pyridin-4-yl]-2-pyridyl]carbamate; methyl N-[4-[2-[4-ethylsulfonyl-2-(trifluoromethyl)piperazin-1-yl]-6-oxo-1H-pyridin-4-yl]-2-pyridyl]carbamate; methyl N-[4-[2-(3-cyclopropylmorpholin-4-yl)-6-oxo-1H-pyridin-4-yl]-2-pyridyl]carbamate; N-[4-[2-(3-cyclopropylmorpholin-4-yl)-6-oxo-1H-pyridin-4-yl]-2-pyridyl]acetamide; N-[4-[2-[4-ethylsulfonyl-2-(trifluoromethyl)piperazin-1-yl]-6-oxo-1H-pyridin-4-yl]-2-pyridyl]acetamide; 3-[4-[2-(2-chlorophenyl)-6-oxo-1H-pyridin-4-yl]-2-pyridyl]-1,1-dimethyl-urea; N-[4-[2-(2-chlorophenyl)-6-oxo-1H-pyridin-4-yl]-2-pyridyl]pyrrolidine-1-carboxamide; and pharmaceutically acceptable salts, tautomers, and stereoisomers thereof.
In some embodiments, the compound is selected from the group consisting of: N-[4-[2-(2-chlorophenyl)-6-oxo-1H-pyridin-4-yl]-2-pyridyl]acetamide; 4-(2-Amino-4-pyridyl)-6-(3-pyridyl)-1H-pyridin-2-one; 4-(2-Amino-4-pyridyl)-6-(2-chlorophenyl)-1H-pyridin-2-one; N-[4-[2-(2-chlorophenyl)-6-oxo-1H-pyridin-4-yl]-2-pyridyl]-2-methoxy-acetamide; N-[4-[2-oxo-6-[2-(trifluoromethyl)-1-piperidyl]-1H-pyridin-4-yl]-2-pyridyl]acetamide; N-[4-[2-oxo-6-[2-(trifluoromethyl)-1-piperidyl]-1H-pyridin-4-yl]-2-pyridyl]cyclopropanecarboxamide; N-[4-[2-oxo-6-[3-(trifluoromethyl)morpholin-4-yl]-1H-pyridin-4-yl]-2-pyridyl]acetamide; methyl N-[4-[2-(2-chlorophenyl)-6-oxo-1H-pyridin-4-yl]-2-pyridyl]carbamate; methyl N-[4-[2-[1-ethyl-3-(trifluoromethyl)pyrazol-4-yl]-6-oxo-1H-pyridin-4-yl]-2-pyridyl]carbamate; methyl N-[4-[2-oxo-6-[2-(trifluoromethyl)-3-pyridyl]-1H-pyridin-4-yl]-2-pyridyl]carbamate; methyl N-[4-[2-oxo-6-[2-(trifluoromethyl)phenyl]-1H-pyridin-4-yl]-2-pyridyl]carbamate; N-[4-[2-oxo-6-[2-(trifluoromethyl)phenyl]-1H-pyridin-4-yl]-2-pyridyl]acetamide; N-[4-[2-(4-methyl-3-pyridyl)-6-oxo-1H-pyridin-4-yl]-2-pyridyl]acetamide; N-[4-[2-oxo-6-[2-(trifluoromethyl)-3-pyridyl]-1H-pyridin-4-yl]-2-pyridyl]acetamide; N-[4-[2-[1-ethyl-3-(trifluoromethyl)pyrazol-4-yl]-6-oxo-1H-pyridin-4-yl]-2-pyridyl]acetamide; methyl N-[4-[2-oxo-6-[3-(trifluoromethyl)morpholin-4-yl]-1H-pyridin-4-yl]-2-pyridyl]carbamate; methyl N-[4-[2-oxo-6-[2-(trifluoromethyl)-1-piperidyl]-1H-pyridin-4-yl]-2-pyridyl]carbamate; N-[4-[2-(3-cyclopropylmorpholin-4-yl)-6-oxo-1H-pyridin-4-yl]-2-pyridyl]acetamide; N-[4-[2-[4-ethylsulfonyl-2-(trifluoromethyl)piperazin-1-yl]-6-oxo-1H-pyridin-4-yl]-2-pyridyl]acetamide; and pharmaceutically acceptable salts, tautomers, and stereoisomers thereof.
In some embodiments, the at least one chemokine is selected from the group consisting of CCL5 and CXCL10.
In an aspect, provided herein is a method of treating cancer in a patient in need thereof, comprising: (i) administering to the patient a therapeutically effective amount of a compound represented by Formula V:
or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein: R1 is selected from phenyl and monocyclic 5-6 membered heteroaryl, wherein each of phenyl and monocyclic 5-6 membered heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, C1-C6alkyl, C3-C4cycloalkyl, C1-C6alkoxy, C1-C6haloalkyl, C1-C6haloalkoxy, amino, N—C1-C3alkylamino and N,N-diC1-C3alkylamino; R2 is selected from the group consisting of H, C1-C3haloalkyl, and C1-C3alkyl; R3 is selected from the group consisting of A, phenyl, and monocyclic heteroaryl, wherein each of phenyl and heteroaryl is optionally substituted with one or more occurrences of a substituent independently selected from the group consisting of R4, R5, R6, and R7; each of R4, R5, R6, and R7 is independently selected from the group consisting of halogen, C1-C6alkyl, C3-C4cycloalkyl, C1-C6alkoxy, C1-C6haloalkyl, C1-C6haloalkoxy, azetidine, amino, N—C1-C3alkylamino, N,N-diC1-C3alkylamino, NHSO2R8, SO2R9, and hydroxy; R8 is selected from C1-C3haloalkyl and C1-C3alkyl; each R9 is independently selected from the group consisting of R10, C1-C6alkyl, amino, N—C1-C3alkylamino, N,N-diC1-C3alkylamino, and C1-C3alkoxyC1-C3alkyl, wherein each of C1-C6alkyl and C1-C3alkoxyC1-C3alkyl is optionally substituted with one occurrence of R10, and each of C1-C6alkyl and C1-C3alkoxyC1-C3alkyl is optionally substituted with or one or more independent occurrences of halogen; each R10 is independently selected from the group consisting of phenyl, benzyl, monocyclic heteroaryl, C3-C6cycloalkyl, and heterocyclyl, wherein each of phenyl, benzyl, monocyclic heteroaryl, C3-C6cycloalkyl, and heterocyclyl is optionally substituted with one or more occurrences of R11; each R11 is independently selected from the group consisting of halogen, C1-C3haloalkyl, C3-C4cycloalkyl, C1-C3alkyl, amino, N—C1-C3alkylamino, N,N-diC1-C3alkylamino, and C1-C3alkoxyC1-C3alkyl; A is
R12 is selected from the group consisting of H, halogen, COR13, C1-C6alkyl, C3-C6cycloalkyl, C1-C3alkoxyC1-C3alkyl, C1-C6alkoxy, C3-C6cycloalkyl, C1-C3cyanoalkyl, and C1-C3haloalkyl; R13 is selected from the group consisting of C1-C3alkoxy, N—C1-C3alkylamino, N,N-diC1-C3alkylamino, 1-pyrrolidinyl, 1-piperidinyl, and 1-azetidinyl; Y is selected from the group consisting of CH2, S, SO, SO2, NR14, NCOR9, NCOOR15, NSO2R9, NCOCH2R9, O, and a bond; R14 is selected from H, C1-C3haloalkyl, C1-C3alkoxyC1-C3alkyl, C1-C3alkyl, and C3-C6cycloalkyl; and R15 is selected from R10, C1-C6alkyl, and C1-C3alkoxyC1-C3alkyl, wherein each of C1-C6alkyl and C1-C3alkoxyC1-C3alkyl is optionally substituted with one occurrence of R10, and each of C1-C6alkyl and C1-C3alkoxyC1-C3alkyl is optionally substituted with or one or more independent occurrences of halogen; and Z is selected from CH and N; and (ii) administering to the patient a therapeutically effective amount of a STING agonist; wherein administering the therapeutically effective amount of the STING agonist and the compound results in an increased expression level of at least one chemokine in the patient as compared to any increase in the expression level of the at least one chemokine resulting from administering the compound alone to the patient.
In an aspect, provided herein is a method of upregulating at least one chemokine in a cell comprising: contacting the cell sample with: (i) a compound represented by:
or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein: R1 is selected from phenyl and monocyclic 5-6 membered heteroaryl, wherein each of phenyl and monocyclic 5-6 membered heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, C1-C6alkyl, C3-C4cycloalkyl, C1-C6alkoxy, C1-C6haloalkyl, C1-C6haloalkoxy, amino, N—C1-C3alkylamino and N,N-diC1-C3alkylamino; R2 is selected from the group consisting of H, C1-C3haloalkyl, and C1-C3alkyl; R3 is selected from the group consisting of A, phenyl, and monocyclic heteroaryl, wherein each of phenyl and heteroaryl is optionally substituted with one or more occurrences of a substituent independently selected from the group consisting of R4, R5, R6, and R7; each of R4, R5, R6, and R7 is independently selected from the group consisting of halogen, C1-C6alkyl, C3-C4cycloalkyl, C1-C6alkoxy, C1-C6haloalkyl, C1-C6haloalkoxy, azetidine, amino, N—C1-C3alkylamino, N,N-diC1-C3alkylamino, NHSO2R8, SO2R9, and hydroxy; R8 is selected from C1-C3haloalkyl and C1-C3alkyl; each R9 is independently selected from the group consisting of R10, C1-C6alkyl, amino, N—C1-C3alkylamino, N,N-diC1-C3alkylamino, and C1-C3alkoxyC1-C3alkyl, wherein each of C1-C6alkyl and C1-C3alkoxyC1-C3alkyl is optionally substituted with one occurrence of R10, and each of C1-C6alkyl and C1-C3alkoxyC1-C3alkyl is optionally substituted with or one or more independent occurrences of halogen; each R10 is independently selected from the group consisting of phenyl, benzyl, monocyclic heteroaryl, C3-C6cycloalkyl, and heterocyclyl, wherein each of phenyl, benzyl, monocyclic heteroaryl, C3-C6cycloalkyl, and heterocyclyl is optionally substituted with one or more occurrences of R11; each R11 is independently selected from the group consisting of halogen, C1-C3haloalkyl, C3-C4cycloalkyl, C1-C3alkyl, amino, N—C1-C3alkylamino, N,N-diC1-C3alkylamino, and C1-C3alkoxyC1-C3alkyl; A is
R12 is selected from the group consisting of H, halogen, COR13, C1-C6alkyl, C3-C6cycloalkyl, C1-C3alkoxyC1-C3alkyl, C1-C6alkoxy, C3-C6cycloalkyl, C1-C3cyanoalkyl, and C1-C3haloalkyl; R13 is selected from the group consisting of C1-C3alkoxy, N—C1-C3alkylamino, N,N-diC1-C3alkylamino, 1-pyrrolidinyl, 1-piperidinyl, and 1-azetidinyl; Y is selected from the group consisting of CH2, S, SO, SO2, NR14, NCOR9, NCOOR15, NSO2R9, NCOCH2R9, O, and a bond; R14 is selected from H, C1-C3haloalkyl, C1-C3alkoxyC1-C3alkyl, C1-C3alkyl, and C3-C6cycloalkyl; and R15 is selected from R10, C1-C6alkyl, and C1-C3alkoxyC1-C3alkyl, wherein each of C1-C6alkyl and C1-C3alkoxyC1-C3alkyl is optionally substituted with one occurrence of R10, and each of C1-C6alkyl and C1-C3alkoxyC1-C3alkyl is optionally substituted with or one or more independent occurrences of halogen; and Z is selected from CH and N; and in an amount sufficient to induce a Type I interferon response by the cell; and (ii) a STING agonist in an amount sufficient to increase the expression level of the at least one chemokine in the cell.
In some embodiments, the compound is selected from the group consisting of: 4-(2-anilinopyrimidin-4-yl)-6-(2-chlorophenyl)-1H-pyridin-2-one; 4-(2-anilinopyrimidin-4-yl)-6-(3-pyridyl)-1H-pyridin-2-one; 4-(2-anilinopyrimidin-4-yl)-6-(4-pyridyl)-1H-pyridin-2-one; 4-(2-anilinopyrimidin-4-yl)-6-morpholino-1H-pyridin-2-one; 4-[2-[(2-Methylpyrimidin-4-yl)amino]-4-pyridyl]-6-[2-(trifluoromethyl)-1-piperidyl]-1H-pyridin-2-one; 4-(2-anilinopyrimidin-4-yl)-6-[2-(trifluoromethyl)-1-piperidyl]-1H-pyridin-2-one; 4-[2-[(2-Methylpyrimidin-4-yl)amino]-4-pyridyl]-6-[3-(trifluoromethyl)morpholin-4-yl]-1H-pyridin-2-one; 4-(2-anilinopyrimidin-4-yl)-6-[3-(trifluoromethyl)morpholin-4-yl]-1H-pyridin-2-one; 6-[4-[(4-Fluorophenyl)methylsulfonyl]-2-(trifluoromethyl)piperazin-1-yl]-4-[2-[(2-methylpyrimidin-4-yl)amino]-4-pyridyl]-1H-pyridin-2-one; 6-[4-Ethylsulfonyl-2-(trifluoromethyl)piperazin-1-yl]-4-[2-[(2-methylpyrimidin-4-yl)amino]-4-pyridyl]-1H-pyridin-2-one; 4-[2-(Oxazol-2-ylamino)-4-pyridyl]-6-[3-(trifluoromethyl)morpholin-4-yl]-1H-pyridin-2-one; 4-[2-[(2-Methylthiazol-4-yl)amino]-4-pyridyl]-6-[3-(trifluoromethyl)morpholin-4-yl]-1H-pyridin-2-one; 4-[2-[(2-methylpyrimidin-4-yl)amino]-4-pyridyl]-6-[2-(trifluoromethyl)-phenyl]-1H-pyridin-2-one; 4-[2-[(2-Methylpyrazol-3-yl)amino]-4-pyridyl]-6-[2-(trifluoromethyl)phenyl]-1H-pyridin-2-one; 4-[2-[(2-Methylthiazol-4-yl)amino]-4-pyridyl]-6-[2-(trifluoromethyl)phenyl]-1H-pyridin-2-one; 6-(4-methyl-3-pyridyl)-4-[2-[(2-methylpyrimidin-4-yl)amino]-4-pyridyl]-1H-pyridin-2-one; 4-[2-[(2-methylpyrimidin-4-yl)amino]-4-pyridyl]-6-[2-(trifluoromethyl)-3-pyridyl]-1H-pyridin-2-one; 6-[1-ethyl-3-(trifluoromethyl)pyrazol-4-yl]-4-[2-[(2-methylpyrimidin-4-yl)am 4-pyridyl]-1H-pyridin-2-one; 4-[2-[(1-Methylimidazol-4-yl)amino]-4-pyridyl]-6-[2-(trifluoromethyl)phenyl pyridin-2-one; 6-(2-chlorophenyl)-4-[2-[(2-methylpyrimidin-4-yl)amino]-4-pyridyl]-1H-pyridin-2-one, and pharmaceutically acceptable salts, stereoisomers, and tautomers thereof.
In some embodiments, the compound is selected from the group consisting of: 4-(2-anilinopyrimidin-4-yl)-6-(2-chlorophenyl)-1H-pyridin-2-one; 4-(2-anilinopyrimidin-4-yl)-6-(3-pyridyl)-1H-pyridin-2-one; 4-(2-anilinopyrimidin-4-yl)-6-(4-pyridyl)-1H-pyridin-2-one; 4-(2-anilinopyrimidin-4-yl)-6-morpholino-1H-pyridin-2-one; 4-[2-[(2-Methylpyrimidin-4-yl)amino]-4-pyridyl]-6-[2-(trifluoromethyl)-1-piperidyl]-1H-pyridin-2-one; 4-(2-anilinopyrimidin-4-yl)-6-[2-(trifluoromethyl)-1-piperidyl]-1H-pyridin-2-one; 4-[2-[(2-Methylpyrimidin-4-yl)amino]-4-pyridyl]-6-[3-(trifluoromethyl)morpholin-4-yl]-1H-pyridin-2-one; 4-(2-anilinopyrimidin-4-yl)-6-[3-(trifluoromethyl)morpholin-4-yl]-1H-pyridin-2-one; 6-[4-[(4-Fluorophenyl)methylsulfonyl]-2-(trifluoromethyl)piperazin-1-yl]-4-[2-[(2-methylpyrimidin-4-yl)amino]-4-pyridyl]-1H-pyridin-2-one; 6-[4-Ethylsulfonyl-2-(trifluoromethyl)piperazin-1-yl]-4-[2-[(2-methylpyrimidin-4-yl)amino]-4-pyridyl]-1H-pyridin-2-one; 4-[2-[(2-methylpyrimidin-4-yl)amino]-4-pyridyl]-6-[2-(trifluoromethyl)-phenyl]-1H-pyridin-2-one; 6-(4-methyl-3-pyridyl)-4-[2-[(2-methylpyrimidin-4-yl)amino]-4-pyridyl]-1H-pyridin-2-one; 4-[2-[(2-methylpyrimidin-4-yl)amino]-4-pyridyl]-6-[2-(trifluoromethyl)-3-pyridyl]-1H-pyridin-2-one; 6-[1-ethyl-3-(trifluoromethyl)pyrazol-4-yl]-4-[2-[(2-methylpyrimidin-4-yl)am 4-pyridyl]-1H-pyridin-2-one; 6-(2-chlorophenyl)-4-[2-[(2-methylpyrimidin-4-yl)amino]-4-pyridyl]-1H-pyridin-2-one; 6-(3-cyclopropylmorpholin-4-yl)-4-[2-[(2-methylpyrimidin-4-yl)amino]-4-pyridyl]-1H-pyridin-2-one, and pharmaceutically acceptable salts, stereoisomers, and tautomers thereof.
In some embodiments, the compound is selected from the group consisting of: 4-(2-anilinopyrimidin-4-yl)-6-(2-chlorophenyl)-1H-pyridin-2-one; 4-(2-anilinopyrimidin-4-yl)-6-(3-pyridyl)-1H-pyridin-2-one; 4-(2-anilinopyrimidin-4-yl)-6-(4-pyridyl)-1H-pyridin-2-one 4-(2-anilinopyrimidin-4-yl)-6-morpholino-1H-pyridin-2-one; 4-[2-[(2-Methylpyrimidin-4-yl)amino]-4-pyridyl]-6-[2-(trifluoromethyl)-1-piperidyl]-1H-pyridin-2-one; 4-(2-anilinopyrimidin-4-yl)-6-[2-(trifluoromethyl)-1-piperidyl]-1H-pyridin-2-one; 4-[2-[(2-Methylpyrimidin-4-yl)amino]-4-pyridyl]-6-[3-(trifluoromethyl)morpholin-4-yl]-1H-pyridin-2-one; 4-(2-anilinopyrimidin-4-yl)-6-[3-(trifluoromethyl)morpholin-4-yl]-1H-pyridin-2-one; 6-[4-[(4-Fluorophenyl)methylsulfonyl]-2-(trifluoromethyl)piperazin-1-yl]-4-[2-[(2-methylpyrimidin-4-yl)amino]-4-pyridyl]-1H-pyridin-2-one; 6-[4-Ethylsulfonyl-2-(trifluoromethyl)piperazin-1-yl]-4-[2-[(2-methylpyrimidin-4-yl)amino]-4-pyridyl]-1H-pyridin-2-one; 4-[2-[(2-methylpyrimidin-4-yl)amino]-4-pyridyl]-6-[2-(trifluoromethyl)-phenyl]-1H-pyridin-2-one; 6-(4-methyl-3-pyridyl)-4-[2-[(2-methylpyrimidin-4-yl)amino]-4-pyridyl]-1H-pyridin-2-one; 4-[2-[(2-methylpyrimidin-4-yl)amino]-4-pyridyl]-6-[2-(trifluoromethyl)-3-pyridyl]-1H-pyridin-2-one; 6-[1-ethyl-3-(trifluoromethyl)pyrazol-4-yl]-4-[2-[(2-methylpyrimidin-4-yl)amino]-4-pyridyl]-1H-pyridin-2-one; 6-(2-chlorophenyl)-4-[2-[(2-methylpyrimidin-4-yl)amino]-4-pyhdyl]-1H-pyridin-2-one, and pharmaceutically acceptable salts, stereoisomers, and tautomers thereof.
In some embodiments, the at least one chemokine is selected from the group consisting of CCL5 and CXCL10.
In an aspect, provided herein is a method of treating cancer in a patient in need thereof, comprising: (i) administering to the patient a therapeutically effective amount of a compound represented by Formula VI:
or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein: R1 is selected from C1-C3alkyl and cyclopropyl; R2 is selected from the group consisting of H, C1-C3haloalkyl, and C1-C3alkyl; A is selected from:
each R3 is independently selected from the group consisting of R6, C1-C6alkyl, amino N—C1-C3alkylamino, N, N-diC1-C3alkylamino, and C1-C3alkoxyC1-C3alkyl, wherein each of C1-C6alkyl and C1-C3alkoxyC1-C3alkyl is optionally substituted with one occurrence of R6, and each of C1-C6alkyl and C1-C3alkoxyC1-C3alkyl is optionally substituted with or one or more independent occurrences of halogen; R4 is selected from the group consisting of C1-C6alkyl, C1-C6alkoxy, C1-C6haloalkyl, C3-C6cycloalkyl, and phenyl, wherein phenyl is optionally substituted with one or more occurrences of a substituent independently selected from the group consisting of fluoro, chloro, methyl, methoxy, dimethylamino, trifluoromethoxy, trifluoromethyl, and cyclopropyl; R5 is selected from the group consisting of halogen, C1-C6alkyl, C1-C6alkoxy, C1-C6haloalkyl, and C3-C6cycloalkyl; each R6 is independently selected from the group consisting of phenyl, monocyclic heteroaryl, C3-C6cycloalkyl, and heterocyclyl, wherein each of phenyl, monocyclic heteroaryl, C3-C6cycloalkyl, and heterocyclyl is optionally substituted with one or more occurrences of R7; and each R7 is independently selected from the group consisting of halogen, amino, N—C1-C3alkylamino, N,N-diC1-C3alkylamino and C1-C3alkoxyC1-C3alkyl, C1-C3alkoxy, C1-C3haloalkoxy, C3-C6cycloalkyl, C1-C3haloalkyl, and C1-C3alkyl; and (ii) administering to the patient a therapeutically effective amount of a STING agonist; wherein administering the therapeutically effective amount of the STING agonist and the compound results in an increased expression level of at least one chemokine in the patient as compared to any increase in the expression level of the at least one chemokine resulting from administering the compound alone to the patient.
In an aspect, provided herein is a method of upregulating at least one chemokine in a cell comprising: contacting the cell sample with: (i) a compound represented by:
or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein: R1 is selected from C1-C3alkyl and cyclopropyl; R2 is selected from the group consisting of H, C1-C3haloalkyl, and C1-C3alkyl; A is selected from:
each R3 is independently selected from the group consisting of R6, C1-C6alkyl, amino N—C1-C3alkylamino, N, N-diC1-C3alkylamino, and C1-C3alkoxyC1-C3alkyl, wherein each of C1-C6alkyl and C1-C3alkoxyC1-C3alkyl is optionally substituted with one occurrence of R6, and each of C1-C6alkyl and C1-C3alkoxyC1-C3alkyl is optionally substituted with or one or more independent occurrences of halogen; R4 is selected from the group consisting of C1-C6alkyl, C1-C6alkoxy, C1-C6haloalkyl, C3-C6cycloalkyl, and phenyl, wherein phenyl is optionally substituted with one or more occurrences of a substituent independently selected from the group consisting of fluoro, chloro, methyl, methoxy, dimethylamino, trifluoromethoxy, trifluoromethyl, and cyclopropyl; R5 is selected from the group consisting of halogen, C1-C6alkyl, C1-C6alkoxy, C1-C6haloalkyl, and C3-C6cycloalkyl; each R6 is independently selected from the group consisting of phenyl, monocyclic heteroaryl, C3-C6cycloalkyl, and heterocyclyl, wherein each of phenyl, monocyclic heteroaryl, C3-C6cycloalkyl, and heterocyclyl is optionally substituted with one or more occurrences of R7; and each R7 is independently selected from the group consisting of halogen, amino, N—C1-C3alkylamino, N,N-diC1-C3alkylamino and C1-C3alkoxyC1-C3alkyl, C1-C3alkoxy, C1-C3haloalkoxy, C3-C6cycloalkyl, C1-C3haloalkyl, and C1-C3alkyl; in an amount sufficient to induce a Type I interferon response by the cell; and (ii) a STING agonist in an amount sufficient to increase the expression level of the at least one chemokine in the cell.
In some embodiments, the compound is selected from the group consisting of: 4-(3-methylmorpholin-4-yl)-6-[4-methylsulfonyl-2-(trifluoromethyl)piperazin-1-yl]-1H-pyridin-2-one; 6-[4-[(4-Fluorophenyl)methylsulfonyl]-2-(trifluoromethyl)piperazin-1-yl]-4-(3-methylmorpholin-4-yl)-1H-pyridin-2-one; 6-[4-[(5-Fluoro-3-pyridyl)sulfonyl]-2-(trifluoromethyl)piperazin-1-yl]-4-(3-methylmorpholin-4-yl)-1H-pyridin-2-one; 4-(3-methylmorpholin-4-yl)-6-[4-tetrahydrofuran-3-ylsulfonyl-2-(trifluoromethyl)piperazin-1-yl]-1H-pyridin-2-one; 4-(3-methylmorpholin-4-yl)-6-[4-pyrrolidin-1-ylsulfonyl-2-(trifluoromethyl)piperazin-1-yl]-1H-pyridin-2-one; N,N-dimethyl-4-[4-(3-methylmorpholin-4-yl)-6-oxo-1H-pyridin-2-yl]-3-(trifluoromethyl)piperazine-1-sulfonamide; 6-[4-(2-methoxyethylsulfonyl)-2-(trifluoromethyl)piperazin-1-yl]-4-(3-methylmorpholin-4-yl)-1H-pyridin-2-one; 6-[4-(4-fluorophenyl)sulfonyl-2-(trifluoromethyl)piperazin-1-yl]-4-(3-methylmorpholin-4-yl)-1H-pyridin-2-one; 4-(3-methylmorpholin-4-yl)-6-[4-(2-methylpyrazol-3-yl)sulfonyl-2-(trifluoromethyl)piperazin-1-yl]-1H-pyridin-2-one; 6-[4-Cyclopropylsulfonyl-2-(trifluoromethyl)piperazin-1-yl]-4-(3-methylmorpholin-4-yl)-1H-pyridin-2-one; 4-(3-methylmorpholin-4-yl)-6-[4-(1-piperidylsulfonyl)-2-(trifluoromethyl)piperazin-1-yl]-1H-pyridin-2-one; 4-(3-methylmorpholin-4-yl)-6-[4-morpholinosulfonyl-2-(trifluoromethyl)piperazin-1-yl]-1H-pyridin-2-one; 6-[4-(1,2-Dimethylimidazol-4-yl)sulfonyl-2-(trifluoromethyl)piperazin-1-yl]-4-(3-methylmorpholin-4-yl)-1H-pyridin-2-one; 6-[4-(1-methylcyclopropyl)sulfonyl-2-(trifluoromethyl)piperazin-1-yl]-4-(3-methylmorpholin-4-yl)-1H-pyridin-2-one; 4-(3-methylmorpholin-4-yl)-6-[4-methylsulfonyl-2-(trifluoromethyl)phenyl]-1H-pyridin-2-one; N,N-dimethyl-4-[4-(3-methylmorpholin-4-yl)-6-oxo-1H-pyridin-2-yl]-3-(trifluoromethyl)benzenesulfonamide; and pharmaceutically acceptable salts, stereoisomers, and tautomers thereof.
In some embodiments, the compound is selected from the group consisting of: 4-(3-methylmorpholin-4-yl)-6-[4-methylsulfonyl-2-(trifluoromethyl)piperazin-1-yl]-1H-pyridin-2-one; 6-[4-[(4-Fluorophenyl)methylsulfonyl]-2-(trifluoromethyl)piperazin-1-yl]-4-(3-methylmorpholin-4-yl)-1H-pyridin-2-one; 6-[4-[(5-Fluoro-3-pyridyl)sulfonyl]-2-(trifluoromethyl)piperazin-1-yl]-4-(3-methylmorpholin-4-yl)-1H-pyridin-2-one; 4-(3-methylmorpholin-4-yl)-6-[4-tetrahydrofuran-3-ylsulfonyl-2-(trifluoromethyl)piperazin-1-yl]-H-pyridin-2-one; 4-(3-methylmorpholin-4-yl)-6-[4-pyrrolidin-1-ylsulfonyl-2-(trifluoromethyl)piperazin-1-yl]-1H-pyridin-2-one; N,N-dimethyl-4-[4-(3-methylmorpholin-4-yl)-6-oxo-1H-pyridin-2-yl]-3-(trifluoromethyl)piperazine-1-sulfonamide; 6-[4-(2-methoxyethylsulfonyl)-2-(trifluoromethyl)piperazin-1-yl]-4-(3-methylmorpholin-4-yl)-1H-pyhdin-2-one; 6-[4-(4-fluorophenyl)sulfonyl-2-(trifluoromethyl)piperazin-1-yl]-4-(3-methylmorpholin-4-yl)-1H-pyridin-2-one; 4-(3-methylmorpholin-4-yl)-6-[4-(2-methylpyrazol-3-yl)sulfonyl-2-(trifluoromethyl)piperazin-1-yl]-1H-pyridin-2-one; and pharmaceutically acceptable salts, stereoisomers, and tautomers thereof.
In some embodiments, the at least one chemokine is selected from the group consisting of CCL5 and CXCL10.
In an aspect, provided herein is a method of treating cancer in a patient in need thereof, comprising: (i) means for inducing a Type I interferon response in a cancerous cell in the patient; and (ii) administering a therapeutically effective amount of a STING agonist to the patient;
In some embodiments, the methods described herein may further comprise administering an additional therapeutic agent to the patient. In some embodiments, the additional therapeutic agent is selected from the group consisting of a PD-1 pathway antagonist, a TIM-3 pathway antagonist, a Vista pathway antagonist, a BTLA pathway antagonist, a LAG-3 pathway antagonist, a TIGIT pathway antagonist, and a CTLA4 pathway antagonist.
In some embodiments, the STING agonist is selected from the group consisting of 5,6-dimethylxanthenone-4-acetic acid (DMXAA), ADU-S100, MK-1454, MK-2118, BMS-986301, GSK3745417, SB-11285, BI1387446 (BI-STING), E7766, TAK-676, SNX281, SYNB1891, JNJ-67544412, JNJ-′6196, GSK532, TTI-10001, ALG-031048, MSA-1, MSA-2, CRD-5500, MV-626, SR-8314, SR-8291, SR8541A, SR-717, STING antibody-drug conjugates (ADC), and IMSA-101, and pharmaceutically acceptable salts thereof. In some embodiments, the STING agonist is selected from the group consisting of ADU-S100, MK-1454, MK-2118, BMS-986301, GSK3745417, SB-11285, B11387446 (BI-STING), E7766, TAK-676, SNX281, SYNB1891, and IMSA-101, and pharmaceutically acceptable salts thereof. In some embodiments, the STING agonist is selected from ADU-S100 and pharmaceutically acceptable salts thereof.
Compounds described herein, e.g., a compound of Formula I, Formula II, Formula III, Formula IV, Formula V, or Formula VI as defined herein, can be administered in combination with one or more additional therapeutic agents (e.g., one or more other additional agents described herein) to treat a disorder described herein, such as a cancer described herein. For example, provided in the present disclosure is a pharmaceutical composition comprising a compound described herein, e.g., a compound of Formula I, Formula II, Formula III, Formula IV, Formula V, or Formula VI as defined herein, one or more additional therapeutic agents, and a pharmaceutically acceptable excipient. In some embodiments, a compound of Formula I, Formula II, Formula III, Formula IV, Formula V, or Formula VI as defined herein and one additional therapeutic agent is administered. In some embodiments, a compound of Formula I, Formula II, Formula III, Formula IV, Formula V, or Formula VI as defined herein and two additional therapeutic agents are administered. In some embodiments, a compound of Formula I, Formula II, Formula III, Formula IV, Formula V, or Formula VI as defined herein and three additional therapeutic agents are administered. Combination therapy can be achieved by administering two or more therapeutic agents, each of which is formulated and administered separately. For example, a compound of Formula I, Formula II, Formula III, Formula IV, Formula V, or Formula VI as defined herein and an additional therapeutic agent can be formulated and administered separately. Combination therapy can also be achieved by administering two or more therapeutic agents in a single formulation, for example a pharmaceutical composition comprising a compound of Formula I, Formula II, Formula III, Formula IV, Formula V, or Formula VI as one therapeutic agent and one or more additional therapeutic agents such as an antibiotic, a viral protease inhibitor, or an anti-viral nucleoside anti-metabolite. For example, a compound of Formula I, Formula II, Formula III, Formula IV, Formula V, or Formula VI as defined herein and an additional therapeutic agent can be administered in a single formulation. Other combinations are also encompassed by combination therapy. While the two or more agents in the combination therapy can be administered simultaneously, they need not be. For example, administration of a first agent (or combination of agents) can precede administration of a second agent (or combination of agents) by minutes, hours, days, or weeks. Thus, the two or more agents can be administered within minutes of each other or within 1, 2, 3, 6, 9, 12, 15, 18, or 24 hours of each other or within 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 14 days of each other or within 2, 3, 4, 5, 6, 7, 8, 9, or weeks of each other. In some cases even longer intervals are possible. While in many cases it is desirable that the two or more agents used in a combination therapy be present in within the patient's body at the same time, this need not be so.
Combination therapy can also include two or more administrations of one or more of the agents used in the combination using different sequencing of the component agents. For example, if agent X and agent Y are used in a combination, one could administer them sequentially in any combination one or more times, e.g., in the order X-Y-X, X-X-Y, Y-X-Y, Y-Y-X, X-X-Y-Y, etc.
Examples of additional therapeutics agents that can be used in combination with a VPS34 inhibitor such as a compound of Formula I, Formula II, Formula III, Formula IV, Formula V, or Formula VI as defined herein, includes, but not limited to, a STING agonist (e.g., DMXAA, ADU-S100, or pharmaceutically acceptable salt thereof), an anti-PD-1 therapeutic, an anti PD-L1 therapeutic, or a CTLA4 inhibitor.
Another aspect of this disclosure provides pharmaceutical compositions comprising compounds as disclosed herein formulated together with a pharmaceutically acceptable carrier. In particular, the present disclosure provides pharmaceutical compositions comprising compounds as disclosed herein formulated together with one or more pharmaceutically acceptable carriers. These formulations include those suitable for oral, rectal, topical, buccal, parenteral (e.g., subcutaneous, intramuscular, intradermal, or intravenous) rectal, vaginal, or aerosol administration, although the most suitable form of administration in any given case will depend on the degree and severity of the condition being treated and on the nature of the particular compound being used. For example, disclosed compositions may be formulated as a unit dose, and/or may be formulated for oral or subcutaneous administration.
Exemplary pharmaceutical compositions may be used in the form of a pharmaceutical preparation, for example, in solid, semisolid or liquid form, which contains one or more of the compounds described herein, as an active ingredient, in admixture with an organic or inorganic carrier or excipient suitable for external, enteral or parenteral applications. The active ingredient may be compounded, for example, with the usual non-toxic, pharmaceutically acceptable carriers for tablets, pellets, capsules, suppositories, solutions, emulsions, suspensions, and any other form suitable for use. The active object compound is included in the pharmaceutical composition in an amount sufficient to produce the desired effect upon the process or condition of the disease.
For preparing solid compositions such as tablets, the principal active ingredient may be mixed with a pharmaceutical carrier, e.g., conventional tableting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate or gums, and other pharmaceutical diluents, e.g., water, to form a solid preformulation composition containing a homogeneous mixture of a compound provided herein, or a non-toxic pharmaceutically acceptable salt thereof. When referring to these preformulation compositions as homogeneous, it is meant that the active ingredient is dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules.
In solid dosage forms for oral administration (capsules, tablets, pills, dragees, powders, granules and the like), the subject composition is mixed with one or more pharmaceutically acceptable carriers, such as sodium citrate or dicalcium phosphate, and/or any of the following: (1) fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and/or silicic acid; (2) binders, such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and/or acacia; (3) humectants, such as glycerol; (4) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (5) solution retarding agents, such as paraffin; (6) absorption accelerators, such as quaternary ammonium compounds; (7) wetting agents, such as, for example, acetyl alcohol and glycerol monostearate; (8) absorbents, such as kaolin and bentonite clay; (9) lubricants, such a talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof; and (10) coloring agents. In the case of capsules, tablets and pills, the compositions may also comprise buffering agents. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugars, as well as high molecular weight polyethylene glycols and the like.
A tablet may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared using binder (for example, gelatin or hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant (for example, sodium starch glycolate or cross-linked sodium carboxymethyl cellulose), surface-active or dispersing agent. Molded tablets may be made by molding in a suitable machine a mixture of the subject composition moistened with an inert liquid diluent. Tablets, and other solid dosage forms, such as dragees, capsules, pills and granules, may optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical-formulating art.
Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable, aqueous or organic solvents, or mixtures thereof, and powders. Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the subject composition, the liquid dosage forms may contain inert diluents commonly used in the art, such as, for example, water or other solvents, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, cyclodextrins and mixtures thereof.
Suspensions, in addition to the subject composition, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.
Formulations for rectal or vaginal administration may be presented as a suppository, which may be prepared by mixing a subject composition with one or more suitable non-irritating excipients or carriers comprising, for example, cocoa butter, polyethylene glycol, a suppository wax or a salicylate, and which is solid at room temperature, but liquid at body temperature and, therefore, will melt in the body cavity and release the active agent.
Dosage forms for transdermal administration of a subject composition include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants. The active component may be mixed under sterile conditions with a pharmaceutically acceptable carrier, and with any preservatives, buffers, or propellants which may be required.
The ointments, pastes, creams and gels may contain, in addition to a subject composition, excipients, such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.
Powders and sprays may contain, in addition to a subject composition, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances. Sprays may additionally contain customary propellants, such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane.
Compositions and compounds of the present disclosure may alternatively be administered by aerosol. This is accomplished by preparing an aqueous aerosol, liposomal preparation or solid particles containing the compound. A non-aqueous (e.g., fluorocarbon propellant) suspension could be used. Sonic nebulizers may be used because they minimize exposing the agent to shear, which may result in degradation of the compounds contained in the subject compositions. Ordinarily, an aqueous aerosol is made by formulating an aqueous solution or suspension of a subject composition together with conventional pharmaceutically acceptable carriers and stabilizers. The carriers and stabilizers vary with the requirements of the particular subject composition, but typically include non-ionic surfactants (Tweens, Pluronics, or polyethylene glycol), innocuous proteins like serum albumin, sorbitan esters, oleic acid, lecithin, amino acids such as glycine, buffers, salts, sugars or sugar alcohols. Aerosols generally are prepared from isotonic solutions.
Pharmaceutical compositions of the present disclosure suitable for parenteral administration comprise a subject composition in combination with one or more pharmaceutically-acceptable sterile isotonic aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, or sterile powders which may be reconstituted into sterile injectable solutions or dispersions just prior to use, which may contain antioxidants, buffers, bacteriostats, solutes which render the formulation isotonic with the blood of the intended recipient or suspending or thickening agents.
Examples of suitable aqueous and non-aqueous carriers which may be employed in the pharmaceutical compositions provided herein include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils, such as olive oil, and injectable organic esters, such as ethyl oleate and cyclodextrins. Proper fluidity may be maintained, for example, by the use of coating materials, such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.
In another aspect, provided are enteral pharmaceutical formulations including a disclosed compound and an enteric material; and a pharmaceutically acceptable carrier or excipient thereof. Enteric materials refer to polymers that are substantially insoluble in the acidic environment of the stomach, and that are predominantly soluble in intestinal fluids at specific pHs. The small intestine is the part of the gastrointestinal tract (gut) between the stomach and the large intestine, and includes the duodenum, jejunum, and ileum. The pH of the duodenum is about 5.5, the pH of the jejunum is about 6.5 and the pH of the distal ileum is about 7.5.
Accordingly, enteric materials are not soluble, for example, until a pH of about 5.0, of about 5.2, of about 5.4, of about 5.6, of about 5.8, of about 6.0, of about 6.2, of about 6.4, of about 6.6, of about 6.8, of about 7.0, of about 7.2, of about 7.4, of about 7.6, of about 7.8, of about 8.0, of about 8.2, of about 8.4, of about 8.6, of about 8.8, of about 9.0, of about 9.2, of about 9.4, of about 9.6, of about 9.8, or of about 10.0. Exemplary enteric materials include cellulose acetate phthalate (CAP), hydroxypropyl methylcellulose phthalate (HPMCP), polyvinyl acetate phthalate (PVAP), hydroxypropyl methylcellulose acetate succinate (HPMCAS), cellulose acetate trimellitate, hydroxypropyl methylcellulose succinate, cellulose acetate succinate, cellulose acetate hexahydrophthalate, cellulose propionate phthalate, cellulose acetate maleate, cellulose acetate butyrate, cellulose acetate propionate, copolymer of methylmethacrylic acid and methyl methacrylate, copolymer of methyl acrylate, methylmethacrylate and methacrylic acid, copolymer of methylvinyl ether and maleic anhydride (Gantrez ES series), ethyl methyacrylate-methylmethacrylate-chlorotrimethylammonium ethyl acrylate copolymer, natural resins such as zein, shellac and copal collophorium, and several commercially available enteric dispersion systems (e.g., Eudragit L30D55, Eudragit FS30D, Eudragit L100, Eudragit S100, Kollicoat EMM30D, Estacryl 30D, Coateric, and Aquateric). The solubility of each of the above materials is either known or is readily determinable in vitro. The foregoing is a list of possible materials, but one of skill in the art with the benefit of the disclosure would recognize that it is not comprehensive and that there are other enteric materials that would meet the objectives described herein.
Advantageously, provided herein are kits for use by a e.g. a consumer in need of treatment of a disease or disorder described herein, such as an infection caused by a pathogen described herein, e.g., a virus, fungus, or protozoan. Such kits include a suitable dosage form such as those described above and instructions describing the method of using such dosage form to mediate, reduce or prevent inflammation. The instructions would direct the consumer or medical personnel to administer the dosage form according to administration modes known to those skilled in the art. Such kits could advantageously be packaged and sold in single or multiple kit units. An example of such a kit is a so-called blister pack. Blister packs are well known in the packaging industry and are being widely used for the packaging of pharmaceutical unit dosage forms (tablets, capsules, and the like). Blister packs generally consist of a sheet of relatively stiff material covered with a foil of a preferably transparent plastic material. During the packaging process recesses are formed in the plastic foil. The recesses have the size and shape of the tablets or capsules to be packed. Next, the tablets or capsules are placed in the recesses and the sheet of relatively stiff material is sealed against the plastic foil at the face of the foil which is opposite from the direction in which the recesses were formed. As a result, the tablets or capsules are sealed in the recesses between the plastic foil and the sheet. Preferably the strength of the sheet is such that the tablets or capsules can be removed from the blister pack by manually applying pressure on the recesses whereby an opening is formed in the sheet at the place of the recess. The tablet or capsule can then be removed via said opening.
It may be desirable to provide a memory aid on the kit, e.g., in the form of numbers next to the tablets or capsules whereby the numbers correspond with the days of the regimen which the tablets or capsules so specified should be ingested. Another example of such a memory aid is a calendar printed on the card, e.g., as follows “First Week, Monday, Tuesday, . . . etc. . . . Second Week, Monday, Tuesday, . . . ” etc. Other variations of memory aids will be readily apparent. A “daily dose” can be a single tablet or capsule or several pills or capsules to be taken on a given day. Also, a daily dose of a first compound can consist of one tablet or capsule while a daily dose of the second compound can consist of several tablets or capsules and vice versa. The memory aid should reflect this.
The compounds described herein can be prepared in a number of ways based on the teachings contained herein and disclosures of synthetic procedures in the art. In the description of the synthetic methods described below, it is to be understood that all proposed reaction conditions, including choice of solvent, reaction atmosphere, reaction temperature, duration of the experiment and workup procedures, can be chosen to be the conditions standard for that reaction, unless otherwise indicated. It is understood by one skilled in the art of organic synthesis that the functionality present on various portions of the molecule should be compatible with the reagents and reactions proposed. Substituents not compatible with the reaction conditions will be apparent to one skilled in the art, and alternate methods are therefore indicated. The starting materials for the examples are either commercially available or are readily prepared by standard methods from known materials.
Compound 1 was prepared according to synthetic procedures described in WO 2017/140843.
A498 cells were grown in Minimal Essential Medium containing 10% fetal bovine serum. Cells were then incubated for 2 days at 37 degrees Celsius, 5% CO2, and 95% humidity. A498 cells were incubated with 2 μM of compound 1 for 24 hr. Cells were washed with PBS and RNA was isolated using the PureLink RNA kit (#12183018A, Thermo Fisher Scientific) according to the manufacturer's protocol. Genomic DNA was removed using DNA-binding columns (RNeasy plus kit, #74134, Qiagen) and/or DNase treatment (#12185010, Thermo Fisher Scientific). RNA was quantified using NanoDrop (Thermo Fisher Scientific) and 50 ng/μL RNA was used for cDNA synthesis with SuperScript IV VILO Master Mix (#11756050, Thermo Fisher Scientific). Quantitative RT-PCR (qRT-PCR) was run with diluted cDNA (1:25 or 1:12.5), PowerUp SYBR Green Master Mix (#A25741, Thermo Fisher Scientific), and 200 nM primers (see below) on a CFX Connect RT-PCR system (BioRad). Data was analyzed using the ΔΔCT method. Results are mean±SEM of three independent experiments.
A study was performed to test whether Compound 1 or Compound 2 activated the STING pathway through increased Type 1 Interferon pathway genes in A-498 renal cell carcinoma cells.
786-O cells were grown in RPMI-1640 medium containing 10% fetal bovine serum. Cells were then incubated for 2 days at 37 degrees Celsius, 5% CO2, and 95% humidity. 786-O cells were incubated with 2 μM of compound 1 for 24 hr. Cells were washed with PBS and RNA was isolated using the PureLink RNA kit (#12183018A, Thermo Fisher Scientific) according to the manufacturer's protocol. Genomic DNA was removed using DNA-binding columns (RNeasy plus kit, #74134, Qiagen) and/or DNase treatment (#12185010, Thermo Fisher Scientific). RNA was quantified using NanoDrop (Thermo Fisher Scientific) and 50 ng/μL RNA was used for cDNA synthesis with SuperScript IV VILO Master Mix (#11756050, Thermo Fisher Scientific). Quantitative RT-PCR (qRT-PCR) was run with diluted cDNA (1:25 or 1:12.5), PowerUp SYBR Green Master Mix (#A25741, Thermo Fisher Scientific), and 200 nM primers (see below) on a CFX Connect RT-PCR system (BioRad). Data was analyzed using the ΔΔCT method. Results are mean±SEM of three independent experiments.
A study was performed to test whether Compound 1 or Compound 2 activated the STING pathway through increased Type 1 Interferon pathway genes in 786-O renal cell carcinoma cells.
A-498 cells were seeded at 1.5×105 cells/well in 6-well plates and cultured overnight. Cells were treated with 10 μg/mL mouse monoclonal antibody to human interferon α/β receptor chain 2 (α-IFNAR2) (clone: MMHAR-2, #21385-1, PBL Assay Science) or 10 μg/mL mouse IgG2a isotype control antibody (clone: eBM2a, #16-4724-81, Thermo Fisher Scientific). After 1 h, DMSO or 2 μM Compound 1 was added and cells were incubated for another 24 h. Treatment with 5 ng/mL recombinant IFNβ (#300-02BC, PeproTech) was used as a positive control. A-498 cells were washed in PBS and lysed in RIPA buffer (50 mM Tris HCl pH=7.4, 150 mM NaCl, 1% Triton X-100, 0.5% Na-deoxycholate, 0.1% SDS) containing protease inhibitor cocktail (#11836170001, Roche), and phosphatase inhibitor (#11836170001, Roche) for 10 min at 4° C. After centrifugation at 15000 rpm for 10 min at 4° C., the supernatant was obtained, and protein concentration was quantified using BCA assay (#23225, Thermo Fisher). Equal amounts were mixed with 0.1 M DTT and LDS Sample Buffer (#84788, Thermo Fisher), heated for 5 min at 90° C. before loading onto 4-12% Bis-Tris gels. Proteins were transferred to nitrocellulose membranes. Membranes were blocked in 5% non-fat dry milk in TBS with 0.05% Tween (TBS-T) for 1 h at RT, washed in TBS-T, and probed with primary antibodies shaking overnight at 4° C. After washing in TBS-T, membranes were incubated with IRDye 800CW goat anti-rabbit or IRDye 680RD donkey anti-mouse IgG (H+L) (#926-32211 and #926-68072, respectively, LI-COR, 1:10,000 dilution) secondary antibody in Intercept blocking buffer (#927-60001, LI-COR) for 1 h at RT. After washing in TBS-T, membranes were imaged using the Odyssey CLx (LI-COR). Band intensities were quantified using Image Studio Lite software version 5.2.5 (LI-COR).
A study was performed to test whether Compound 1 activated the STING pathway through increased STAT1 phosphorylation.
A-498 cells were transfected with scrambled siRNA control (siSCR) or siRNA targeting TBK1 (siTBK1), STING (siSTING) or CGAS (siCGAS). After 48 h cells were treated with DMSO or 2 μM of VPS34 inhibitor (Compound 1 or Compound 2) for 24 h. A-498 cells were washed in PBS and lysed in RIPA buffer (50 mM Tris HCl pH=7.4, 150 mM NaCl, 1% Triton X-100, 0.5% Na-deoxycholate, 0.1% SDS) containing protease inhibitor cocktail (#11836170001, Roche), and phosphatase inhibitor (#11836170001, Roche) for 10 min at 4° C. After centrifugation at 15000 rpm for 10 min at 4° C., the supernatant was obtained, and protein concentration was quantified using BCA assay (#23225, Thermo Fisher). Equal amounts were mixed with 0.1 M DTT and LDS Sample Buffer (#84788, Thermo Fisher), heated for 5 min at 90° C. before loading onto 4-12% Bis-Tris gels. Proteins were transferred to nitrocellulose membranes. Membranes were blocked in 5% non-fat dry milk in TBS with 0.05% Tween (TBS-T) for 1 h at RT, washed in TBS-T, and probed with primary antibodies shaking overnight at 4° C. After washing in TBS-T, membranes were incubated with IRDye 800CW goat anti-rabbit or IRDye 680RD donkey anti-mouse IgG (H+L) (#926-32211 and #926-68072, respectively, LI-COR, 1:10,000 dilution) secondary antibody in Intercept blocking buffer (#927-60001, LI-COR) for 1 h at RT. After washing in TBS-T, membranes were imaged using the Odyssey CLx (LI-COR). Band intensities were quantified using Image Studio Lite software version 5.2.5 (LI-COR).
A study was performed to test whether Compound 1 or Compound 2 increased activation of the STING pathway in A-498 renal cell carcinoma cells. Levels of phosphorylated TBK1, IRF3, and STAT1, downstream of STING and CGAS, were measured by Western blot.
Lanes 5-8 show the effects of Compound 1 either alone or in conjunction with siRNA knockdown of STING pathway genes. Lane 5 shows the effect of Compound 1 which results in an increase in p-TKB1, increase in STING in comparison to DMSO alone (lane 1), a mild increase in CGAS and strong increases in p-IRF3 and p-STAT1 in comparison to DMSO alone, demonstrating an effect of Compound 1 on stimulation of the STING pathway. Lane 6 shows the effect of Compound 1 in conjunction with siRNA knockdown of TBK1 which results in complete loss of p-TBK1 and total TBK1, and an increase in STING, similar to that of Compound 1 alone (lane 5), an increase in CGAS compared to DMSO Lanes 1 and 2 and to Compound 1 alone (lane 5). Lane 6 also shows similar levels of p-IRF3 and p-STAT1 as Compound 1 alone (lane 5), indicating that Compound 1 can still activate downstream STING pathway signaling through p-IRF3 and p-STAT1. Lane 7 shows the effect of Compound 1 in conjunction with siRNA knockdown of STING which results in nearly complete loss of STING in addition to a decrease in p-TBK1 in comparison to Compound 1 alone (lane 5). Lane 7 also shows complete loss of p-IRF3 and p-STAT1 in comparison to Compound 1 alone (lane 5), demonstrating that the effects of Compound 1 to increase p-IRF3 and p-STAT1 levels are mediated through STING. Lane 8 shows the effect of Compound 1 in conjunction with siRNA knockdown of CGAS which results in a complete loss of CGAS, a decrease in p-TKB1, and complete loss of p-IRF3 and p-STAT1 in comparison to Compound 1 alone (lane 5), again confirming that the effects of Compound 1 to stimulate p-IRF3 and p-STAT1 are mediated through the CGAS/STING pathway.
Lanes 9-12 show the effects of Compound 2 either alone or in conjunction with siRNA knockdown of STING pathway genes. Lane 9 shows the effect of Compound 2 which results in an increase in p-TKB1, increase in STING, a mild increase in CGAS and strong increases in p-IRF3 and p-STAT1 in comparison to DMSO alone (lane 1), demonstrating an effect of Compound 2 on stimulation of the STING pathway. Lane 10 shows the effect of Compound 2 in conjunction with siRNA knockdown of TBK1 which results in complete loss of p-TBK1 and total TBK1 and an increase in STING in comparison to DMSO alone (lane 1), similar to that of Compound 2 alone (lane 9), an increase in CGAS compared to DMSO Lane 1 and similar to Compound 2 alone (lane 9). Lane 10 also shows similar levels of p-IRF3 and p-STAT1 as Compound 2 alone (lane 9), indicating that Compound 2 can still activate downstream STING pathway signaling through p-IRF3 and p-STAT1. Lane 11 shows the effect of Compound 2 in conjunction with siRNA knockdown of STING which results in complete loss of STING in addition to a decrease in p-TBK1 in comparison to Compound 2 alone (lane 9). Lane 11 also shows complete loss of p-IRF3 and p-STAT1 in comparison to Compound 2 alone (lane 9), demonstrating that the effects of Compound 2 to increase p-IRF3 and p-STAT1 levels are mediated through STING. Lane 12 shows the effect of Compound 2 in conjunction with siRNA knockdown of CGAS which results in a complete loss of CGAS, a decrease in p-TKB1, and complete loss of p-IRF3 and p-STAT1 in comparison to Compound 2 alone (lane 9), again confirming that the effects of Compound 2 to stimulate p-IRF3 and p-STAT1 are mediated through the CGAS/STING pathway.
786-O cells were transfected with scrambled siRNA control (siSCR) or siRNA targeting TBK1 (siTBK1), STING (siSTING) or CGAS (siCGAS). After 48 h cells were treated with DMSO or 2 μM of VPS34 inhibitor (Compound 1 or Compound 2) for 24 h. 786-O cells were washed in PBS and lysed in RIPA buffer (50 mM Tris HCl pH=7.4, 150 mM NaCl, 1% Triton X-100, 0.5% Na-deoxycholate, 0.1% SDS) containing protease inhibitor cocktail (#11836170001, Roche), and phosphatase inhibitor (#11836170001, Roche) for 10 min at 4° C. After centrifugation at 15000 rpm for 10 min at 4° C., the supernatant was obtained, and protein concentration was quantified using BCA assay (#23225, Thermo Fisher). Equal amounts were mixed with 0.1 M DTT and LDS Sample Buffer (#84788, Thermo Fisher), heated for 5 min at 90° C. before loading onto 4-12% Bis-Tris gels. Proteins were transferred to nitrocellulose membranes. Membranes were blocked in 5% non-fat dry milk in TBS with 0.05% Tween (TBS-T) for 1 h at RT, washed in TBS-T, and probed with primary antibodies shaking overnight at 4° C. After washing in TBS-T, membranes were incubated with IRDye 800CW goat anti-rabbit or IRDye 680RD donkey anti-mouse IgG (H+L) (#926-32211 and #926-68072, respectively, LI-COR, 1:10,000 dilution) secondary antibody in Intercept blocking buffer (#927-60001, LI-COR) for 1 h at RT. After washing in TBS-T, membranes were imaged using the Odyssey CLx (LI-COR). Band intensities were quantified using Image Studio Lite software version 5.2.5 (LI-COR).
A study was performed to test whether Compound 1 or Compound 2 increased activation of the STING pathway in 786-O renal cell carcinoma cells. Levels of phosphorylated TBK1, IRF3, and STAT1, downstream of STING and CGAS were measured by Western blot.
Lanes 5-8 show the effects of Compound 1 either alone or in conjunction with siRNA knockdown of STING pathway genes. Lane 5 shows the effect of Compound 1 which results in an increase in p-TKB1, increase in STING in comparison to DMSO alone (lane 1), a mild increase in CGAS and strong increases in p-IRF3 and p-STAT1 in comparison to DMSO alone, demonstrating an effect of Compound 1 on stimulation of the STING pathway. Lane 6 shows the effect of Compound 1 in conjunction with siRNA knockdown of TBK1 which results in complete loss of p-TBK1 and total TBK1 and an increase in STING, similar to that of Compound 1 alone (lane 5), an increase in CGAS compared to DMSO Lane 1 and 2 and to Compound 1 alone (lane 5). Lane 6 also shows similar levels of p-IRF3 and p-STAT1 as Compound 1 alone (lane 5), indicating that Compound 1 can still activate downstream STING pathway signaling through p-IRF3 and p-STAT1. Lane 7 shows the effect of Compound 1 in conjunction with siRNA knockdown of STING which results in nearly complete loss of STING in addition to a decrease in p-TBK1 in comparison to Compound 1 alone (lane 5). Lane 7 also shows complete loss of p-IRF3 and p-STAT1 in comparison to Compound 1 alone (lane 5), demonstrating that the effects of Compound 1 to increase p-IRF3 and p-STAT1 levels are mediated through STING. Lane 8 shows the effect of Compound 1 in conjunction with siRNA knockdown of CGAS which results in a complete loss of CGAS, a decrease in p-TKB1, and complete loss of p-IRF3 and p-STAT1 in comparison to Compound 1 alone (lane 5), again confirming that the effects of Compound 1 to stimulate p-IRF3 and p-STAT1 are mediated through the CGAS/STING pathway.
Lanes 9-12 show the effects of Compound 2 either alone or in conjunction with siRNA knockdown of STING pathway genes. Lane 9 shows the effect of Compound 2 which results in an increase in p-TKB1, increase in STING, a mild increase in CGAS and strong increases in p-IRF3 and p-STAT1 in comparison to DMSO alone, demonstrating an effect of Compound 2 on stimulation of the STING pathway. Lane 10 shows the effect of Compound 2 in conjunction with siRNA knockdown of TBK1 which results in complete loss of p-TBK1 and total TBK1 and an increase in STING in comparison to DMSO alone (lane 1), similar to that of Compound 2 alone (lane 9), an increase in CGAS compared to DMSO Lane 1 and similar to Compound 2 alone (lane 9). Lane 10 also shows similar levels of p-IRF3 and p-STAT1 as Compound 2 alone (lane 9), indicating that Compound 2 can still activate downstream STING pathway signaling through p-IRF3 and p-STAT1. Lane 11 shows the effect of Compound 2 in conjunction with siRNA knockdown of STING which results in complete loss of STING in addition to a decrease in p-TBK1 in comparison to Compound 2 alone (lane 9). Lane 11 also shows complete loss of p-IRF3 and p-STAT1 in comparison to Compound 2 alone (lane 9), demonstrating that the effects of Compound 2 to increase p-IRF3 and p-STAT1 levels are mediated through STING. Lane 12 shows the effect of Compound 2 in conjunction with siRNA knockdown of CGAS which results in a complete loss of CGAS, a decrease in p-TKB1, and complete loss of p-IRF3 and p-STAT1 in comparison to Compound 2 alone (lane 9), again confirming that the effects of Compound 1 to stimulate p-IRF3 and p-STAT1 are mediated through the CGAS/STING pathway.
A-498 cells were grown in Minimal Essential Medium containing 10% fetal bovine serum. Cells were then incubated for 2 days at 37 degrees Celsius, 5% CO2, and 95% humidity. A498 cells were transfected with scrambled siRNA control (siSCR) or siRNA targeting TBK1 (siTBK1), STING (siSTING) or CGAS (siCGAS). After 48 h cells were treated with DMSO or 2 μM of VPS34 inhibitor (Compound 1 or Compound 2) for 24 h. Cells were washed with PBS and RNA was isolated using the PureLink RNA kit (#12183018A, Thermo Fisher Scientific) according to the manufacturer's protocol. Genomic DNA was removed using DNA-binding columns (RNeasy plus kit, #74134, Qiagen) and/or DNase treatment (#12185010, Thermo Fisher Scientific). RNA was quantified using NanoDrop (Thermo Fisher Scientific) and 50 ng/μL RNA was used for cDNA synthesis with SuperScript IV VILO Master Mix (#11756050, Thermo Fisher Scientific). Quantitative RT-PCR (qRT-PCR) was run with diluted cDNA (1:25 or 1:12.5), PowerUp SYBR Green Master Mix (#A25741, Thermo Fisher Scientific), and 200 nM primers (see below) on a CFX Connect RT-PCR system (BioRad). Data was analyzed using the ΔΔCT method. Results are mean±SEM of three independent experiments.
A study was performed to test whether Compound 1 or Compound 2 activated the STING pathway in A-498 renal cell carcinoma cells through increased Type 1 Interferon pathway genes and whether this is ablated through the siRNA knockdown of STING pathway genes.
Compound 1 increases mRNA expression of IFNB1 (>5-fold), IRF7 (˜4-fold), CCL5 (>4-fold) and CXCL10 (>5-fold). Compound 2 increases mRNA expression of IFNB1 (>10-fold), IRF7 (˜7-fold), CCL5 (˜8-fold) and CXCL10 (˜10-fold). siRNA knockdown of TBK1 (filled squares) in combination with Compound 1 or Compound 2 results in moderate or negligible changes in IFNB1, IRF7, CCL5 or CXCL10 in comparison to Compound 1 or Compound 2 alone. siRNA knockdown of STING (filled triangles) in combination with Compound 1 or Compound 2 results in complete ablation of IFNB1, IRF7, CCL5 and CXCL10 expression in comparison to Compound 1 or Compound 2 alone. siRNA knockdown of CGAS (cross) in combination with Compound 1 or Compound 2 results in complete ablation of IFNB1, IRF7, CCL5 and CXCL10 expression in comparison to Compound 1 or Compound 2 alone. In composite, these data demonstrate that Compound 1 and Compound 2 mediate the increase in type 1 interferon response genes through activation of the CGAS/STING pathway.
Quantitative reverse-transcriptase polymerase chain reaction (RT-PCR) assay 786-O cells were grown in RPMI-1640 medium containing 10% fetal bovine serum. Cells were then incubated for 2 days at 37 degrees Celsius, 5% CO2, and 95% humidity. A498 cells were transfected with scrambled siRNA control (siSCR) or siRNA targeting TBK1 (siTBK1), STING (siSTING) or CGAS (siCGAS). After 48 h cells were treated with DMSO or 2 μM of VPS34 inhibitor (Compound 1 or Compound 2) for 24 h. Cells were washed with PBS and RNA was isolated using the PureLink RNA kit (#12183018A, Thermo Fisher Scientific) according to the manufacturer's protocol. Genomic DNA was removed using DNA-binding columns (RNeasy plus kit, #74134, Qiagen) and/or DNase treatment (#12185010, Thermo Fisher Scientific). RNA was quantified using NanoDrop (Thermo Fisher Scientific) and 50 ng/μL RNA was used for cDNA synthesis with SuperScript IV VILO Master Mix (#11756050, Thermo Fisher Scientific). Quantitative RT-PCR (qRT-PCR) was run with diluted cDNA (1:25 or 1:12.5), PowerUp SYBR Green Master Mix (#A25741, Thermo Fisher Scientific), and 200 nM primers (see below) on a CFX Connect RT-PCR system (BioRad). Data was analyzed using the ΔΔCT method. Results are mean±SEM of three independent experiments.
A study was performed to test whether Compound 1 or Compound 2 activated the STING pathway in 786-O renal cell carcinoma cells through increased Type 1 Interferon pathway genes and whether this is ablated through the siRNA knockdown of STING pathway genes.
Compound 1 increases mRNA expression of IFNB1 (>5-fold), IRF7 (>2-fold), CCL5 (>3-fold) and CXCL10 (˜5-fold). Compound 2 increases mRNA expression of IFNB1 (˜4-fold), IRF7 (˜3-fold), CCL5 (˜4-fold) and CXCL10 (˜5-fold). siRNA knockdown of TBK1 (filled squares) in combination with Compound 1 or Compound 2 results in near complete ablation of IFNB1, and modest decreases in IRF7, CCL5 and CXCL10 in comparison to Compound 1 or Compound 2 alone. siRNA knockdown of STING (filled triangles) in combination with Compound 1 or Compound 2 results in complete ablation of IFNB1, CCL5 and CXCL10 expression and significant decreases in IRF7 (similar to DMSO controls) expression in comparison to Compound 1 or Compound 2 alone. siRNA knockdown of CGAS (cross) in combination with Compound 1 or Compound 2 results in complete ablation of IFNB1, CCL5 and CXCL10 expression and significant decreases in IRF7 (similar to DMSO controls) expression in comparison to Compound 1 or Compound 2 alone. In composite, these data demonstrate that Compound 1 and Compound 2 mediate the increase in type 1 interferon response genes through activation of the CGAS/STING pathway.
A-498 cells were transfected with scrambled siRNA control (siSCR) or siRNA targeting TBK1 (siTBK1), STING (siSTING) or CGAS (siCGAS). After 48 h cells were treated with DMSO or 2 μM of VPS34 inhibitor (Compound 1 or Compound 2) for 24 h. Cell culture medium was centrifuged at 1600 rpm for 10 min at 4° C. and obtained supernatant stored at −80° C. Cytokine levels were quantified using following Meso Scale Discovery (MSD) assays: human R-PLEX RANTES/CCL5 (#F21ZN), U-PLEX CXCL10/IP-10 (#K151UFK). Assays were run on the SECTOR Quickplex Imager and analyzed using Discovery Workbench version 4.0 (MSD).
A study was performed to test whether Compound 1 or Compound 2 increased the secretion of CCL5 and CXCL10 in A-498 renal cell carcinoma cells and whether this is ablated through siRNA knockdown of STING pathway proteins.
Compound 1 and Compound 2 increased CCL5 and CXCL10 protein secretion ˜2-fold in combination with siRNA against non-specific controls (filled circles). siRNA knockdown of TBK1 (filled squares) in combination with Compound 1 or Compound 2 resulted in non-significant changes CCL5 or CXCL10 protein secretion in comparison to Compound 1 or Compound 2 alone. siRNA knockdown of STING (filled triangles) in combination with Compound 1 or Compound 2 resulted in decreases in CCL5 and CXCL10 protein secretion down to the levels of DMSO controls in comparison to Compound 1 or Compound 2 alone. siRNA knockdown of CGAS (cross) in combination with Compound 1 or Compound 2 resulted in decreased CCL5 and CXCL10 secretion down to the levels of DMSO controls in comparison to Compound 1 or Compound 2 alone. In composite, these data demonstrate that Compound 1 and Compound 2 mediate the increase in CCL5 and CXCL10 cytokines through activation of the CGAS/STING pathway.
786-O cells were transfected with scrambled siRNA control (siSCR) or siRNA targeting TBK1 (siTBK1), STING (siSTING) or CGAS (siCGAS). After 48 h cells were treated with DMSO or 2 μM of VPS34 inhibitor (Compound 1 or Compound 2) for 24 h. Cell culture medium was centrifuged at 1600 rpm for 10 min at 4° C. and obtained supernatant stored at −80° C. Cytokine levels were quantified using following Meso Scale Discovery (MSD) assays: human R-PLEX RANTES/CCL5 (#F21ZN), U-PLEX CXCL10/IP-10 (#K151UFK). Assays were run on the SECTOR Quickplex Imager and analyzed using Discovery Workbench version 4.0 (MSD).
A study was performed to test whether Compound 1 or Compound 2 increased the secretion of CCL5 and CXCL10 in 786-O renal cell carcinoma cells and whether this is ablated through the siRNA knockdown of STING pathway proteins.
Compound 1 and Compound 2 increased CCL5 and CXCL10 protein secretion ˜2-fold in combination with siRNA against non-specific controls (filled circles). siRNA knockdown of TBK1 (filled squares) in combination with Compound 1 or Compound 2 results in decreased secretion of CCL5 or CXCL10 in comparison to Compound 1 or Compound 2 alone. siRNA knockdown of STING (filled triangles) in combination with Compound 1 or Compound 2 resulted in near complete ablation of CCL5 and CXCL10 protein secretion in comparison to Compound 1 or Compound 2 alone. siRNA knockdown of CGAS (cross) in combination with Compound 1 or Compound 2 resulted in near complete ablation of CCL5 and CXCL10 secretion in comparison to Compound 1 or Compound 2 alone. In composite, these data demonstrate that Compound 1 and Compound 2 mediate the increase in CCL5 and CXCL10 cytokines through activation of the CGAS/STING pathway.
A-498 cells were reversely transfected with scrambled siRNA control (siSCR) or siRNA targeting STING (siSTING) or cGAS (siCGAS). After 24 h, cells were forwardly transfected with siSCR control or siRNA targeting VPS34 (siVPS34) for 48 h. A-498 cells were washed in PBS and lysed in RIPA buffer (50 mM Tris HCl pH=7.4, 150 mM NaCl, 1% Triton X-100, 0.5% Na-deoxycholate, 0.1% SDS) containing protease inhibitor cocktail (#11836170001, Roche), and phosphatase inhibitor (#11836170001, Roche) for 10 min at 4° C. After centrifugation at 15000 rpm for 10 min at 4° C., the supernatant was obtained, and protein concentration was quantified using BCA assay (#23225, Thermo Fisher). Equal amounts were mixed with 0.1 M DTT and LDS Sample Buffer (#84788, Thermo Fisher), heated for 5 min at 90° C. before loading onto 4-12% Bis-Tris gels. Proteins were transferred to nitrocellulose membranes. Membranes were blocked in 5% non-fat dry milk in TBS with 0.05% Tween (TBS-T) for 1 h at RT, washed in TBS-T, and probed with primary antibodies shaking overnight at 4° C. After washing in TBS-T, membranes were incubated with IRDye 800CW goat anti-rabbit or IRDye 680RD donkey anti-mouse IgG (H+L) (#926-32211 and #926-68072, respectively, LI-COR, 1:10,000 dilution) secondary antibody in Intercept blocking buffer (#927-60001, LI-COR) for 1 h at RT. After washing in TBS-T, membranes were imaged using the Odyssey CLx (LI-COR). Band intensities were quantified using Image Studio Lite software version 5.2.5 (LI-COR).
A study was performed to test whether siRNA knockdown of VPS34 mimicked the effects of Compound 1 or Compound 2 in activating the STING pathway in A-498 renal cell carcinoma cells.
In
A-498 cells were grown in Minimal Essential Medium containing 10% fetal bovine serum. Cells were then incubated for 2 days at 37 degrees Celsius, 5% CO2, and 95% humidity. A-498 cells were reversely transfected with scrambled siRNA control (siSCR) or siRNA targeting STING (siSTING) or cGAS (siCGAS). After 24 h, cells were forwardly transfected with siSCR control or siRNA targeting VPS34 (siVPS34) for 48 h. Cells were washed with PBS and RNA was isolated using the PureLink RNA kit (#12183018A, Thermo Fisher Scientific) according to the manufacturer's protocol. Genomic DNA was removed using DNA-binding columns (RNeasy plus kit, #74134, Qiagen) and/or DNase treatment (#12185010, Thermo Fisher Scientific). RNA was quantified using NanoDrop (Thermo Fisher Scientific) and 50 ng/μL RNA was used for cDNA synthesis with SuperScript IV VILO Master Mix (#11756050, Thermo Fisher Scientific). Quantitative RT-PCR (qRT-PCR) was run with diluted cDNA (1:25 or 1:12.5), PowerUp SYBR Green Master Mix (#A25741, Thermo Fisher Scientific), and 200 nM primers (see below) on a CFX Connect RT-PCR system (BioRad). Data was analyzed using the ΔΔCT method. Results are mean±SEM of three independent experiments.
A study was performed to test whether siRNA knockdown of VPS34 increased the mRNA expression of Type 1 interferon genes IFNB1 and IRF7, as well as CCL5 and CXCL10 and whether knockdown of STING pathway genes modulated that increase in A-498 renal cell carcinoma cells.
In
A-498 cells were reversely transfected with scrambled siRNA control (siSCR) or siRNA targeting STING (siSTING) or cGAS (siCGAS). After 24 h, cells were forwardly transfected with siSCR control or siRNA targeting VPS34 (siVPS34) for 48 h. Cell culture medium was centrifuged at 1600 rpm for 10 min at 4° C. and obtained supernatant stored at −80° C. Cytokine levels were quantified using following Meso Scale Discovery (MSD) assays: human R-PLEX RANTES/CCL5 (#F21ZN), U-PLEX CXCL10/IP-10 (#K151UFK), U-PLEX IFNβ (#K151VIK). Assays were run on the SECTOR Quickplex Imager and analyzed using Discovery Workbench version 4.0 (MSD).
A study was performed to test whether siRNA knockdown of VPS34 increased the secretion of IFNβ, CCL5, and CXCL10 and whether knockdown of STING pathway genes abolished that increase in A-498 renal cell carcinoma cells.
In
A-498 cells were grown in Minimal Essential Medium containing 10% fetal bovine serum. Cells were then incubated for 2 days at 37 degrees Celsius, 5% CO2, and 95% humidity. A-498 cells were treated with DMSO control, 2 μM Compound 1 or 2 μM Compound 2 in combination with 50 μM STING agonist ADU-S100 for 24 h. Cells were washed with PBS and RNA was isolated using the PureLink RNA kit (#12183018A, Thermo Fisher Scientific) according to the manufacturer's protocol. Genomic DNA was removed using DNA-binding columns (RNeasy plus kit, #74134, Qiagen) and/or DNase treatment (#12185010, Thermo Fisher Scientific). RNA was quantified using NanoDrop (Thermo Fisher Scientific) and 50 ng/μL RNA was used for cDNA synthesis with SuperScript IV VILO Master Mix (#11756050, Thermo Fisher Scientific). Quantitative RT-PCR (qRT-PCR) was run with diluted cDNA (1:25 or 1:12.5), PowerUp SYBR Green Master Mix (#A25741, Thermo Fisher Scientific), and 200 nM primers (see below) on a CFX Connect RT-PCR system (BioRad). Data was analyzed using the ΔΔCT method. Results are mean±SEM of three independent experiments.
A study was performed to test whether Compound 1 or Compound 2 would augment the mRNA expression of STING pathway gene IFNB1 and CCL5 and CXCL10 expression in combination with the STING agonist, ADU-S100, in A-498 renal cell carcinoma cells.
Compound 1 mildly increased IFNB1, CCL5 and CXCL10 expression. Compound 2 mildly increased IFNB1, CCL5 and CXCL10 expression. ADU-S100 has no effect on IFNB1 expression, and increased CCL5 and CXCL10 expression. The combination of Compound 1 and ADU-S100 synergistically increased the expression of IFNB1, CCL5 and CXCL10 in comparison to single agents alone (compare bar 5 to bars 2 and 4). The combination of Compound 2 and ADU-S100 synergistically increased the expression of IFNB1, CCL5 and CXCL10 in comparison to single agents alone (compare bar 6 to bars 3 and 4).
786-O cells were grown in RPMI-1640 medium containing 10% fetal bovine serum. Cells were then incubated for 2 days at 37 degrees Celsius, 5% CO2, and 95% humidity. A-498 cells were treated with DMSO control, 2 μM Compound 1 or 2 μM Compound 2 in combination with 50 μM STING agonist ADU-S100 for 24 h. Cells were washed with PBS and RNA was isolated using the PureLink RNA kit (#12183018A, Thermo Fisher Scientific) according to the manufacturer's protocol. Genomic DNA was removed using DNA-binding columns (RNeasy plus kit, #74134, Qiagen) and/or DNase treatment (#12185010, Thermo Fisher Scientific). RNA was quantified using NanoDrop (Thermo Fisher Scientific) and 50 ng/μL RNA was used for cDNA synthesis with SuperScript IV VILO Master Mix (#11756050, Thermo Fisher Scientific). Quantitative RT-PCR (qRT-PCR) was run with diluted cDNA (1:25 or 1:12.5), PowerUp SYBR Green Master Mix (#A25741, Thermo Fisher Scientific), and 200 nM primers (see below) on a CFX Connect RT-PCR system (BioRad). Data was analyzed using the ΔΔCT method. Results are mean±SEM of three independent experiments.
A study was performed to test whether Compound 1 or Compound 2 would augment the mRNA expression of STING pathway gene IFNB1 and CCL5 and CXCL10 expression in combination with the STING agonist, ADU-S100 in 786-O renal cell carcinoma cells.
Compound 1 as a single agent increased IFNB1, CCL5 and CXCL10 expression. Compound 2 as a single agent increased IFNB1, CCL5 and CXCL10 expression. ADU-S100 had no effect on IFNB1 and CXCL10 expression, and increased CCL5 expression. The combination of Compound 1 and ADU-S100 synergistically increased the expression of IFNB1, CCL5 and CXCL10 in comparison to single agents alone (compare bar 5 to bars 2 and 4). The combination of Compound 2 and ADU-S100 synergistically increased the expression of IFNB1, CCL5 and CXCL10 in comparison to single agents alone (compare bar 6 to bars 3 and 4).
A-498 cells were treated with DMSO control, 2 μM Compound 1 or 2 μM Compound 2 in combination with 50 μM STING agonist ADU-S100 for 24 h. Cell culture medium was centrifuged at 1600 rpm for 10 min at 4° C. and obtained supernatant stored at −80° C. Cytokine levels were quantified using following Meso Scale Discovery (MSD) assays: human R-PLEX RANTES/CCL5 (#F21ZN), U-PLEX CXCL10/IP-10 (#K151UFK). Assays were run on the SECTOR Quickplex Imager and analyzed using Discovery Workbench version 4.0 (MSD). Low concentrations of human IFNβ were determined using High Sensitivity IFN Beta ELISA Kit, (PBL assay science, #41415-1).
A study was performed to test whether Compound 1 or Compound 2 would augment the STING pathway and CCL5 and CXCL10 secretion in combination with the STING agonist, ADU-S100 in A-498 renal cell carcinoma cells.
Compound 1 as a single agent increased IFNβ, CCL5 and CXCL10 secretion. Compound 2 as a single agent increased IFNβ, CCL5 and CXCL10 secretion. ADU-S100 had no effect on IFNβ secretion, and mildly increased CCL5 and CXCL10 secretion. The combination of Compound 1 and ADU-S100 synergistically increased the secretion of IFNβ, CCL5 and CXCL10 in comparison to single agents alone (compare bar 5 to bars 2 and 4). The combination of Compound 2 and ADU-S100 synergistically increased the secretion of IFNβ, CCL5 and CXCL10 in comparison to single agents alone (compare bar 6 to bars 3 and 4).
786-O cells were treated with DMSO control, 2 μM Compound 1 or 2 μM Compound 2 in combination with 50 μM STING agonist ADU-S100 for 24 h. Cell culture medium was centrifuged at 1600 rpm for 10 min at 4° C. and obtained supernatant stored at −80° C. Cytokine levels were quantified using following Meso Scale Discovery (MSD) assays: human R-PLEX RANTES/CCL5 (#F21ZN), U-PLEX CXCL10/IP-10 (#K151UFK). Assays were run on the SECTOR Quickplex Imager and analyzed using Discovery Workbench version 4.0 (MSD). Low concentrations of human IFNβ were determined using High Sensitivity IFN Beta ELISA Kit, (PBL assay science, #41415-1).
A study was performed to test whether Compound 1 or Compound 2 would augment the STING pathway and CCL5 and CXCL10 secretion in combination with the STING agonist, ADU-S100 in 786-O renal cell carcinoma cells.
Compound 1 as a single agent increased IFNβ, CCL5 and CXCL10 secretion. Compound 2 as a single agent increased IFNβ, CCL5 and CXCL10 secretion. ADU-S100 had a mild effect on IFNβ secretion, and significantly increased CCL5 and CXCL10 secretion. The combination of Compound 1 and ADU-S100 further increased the secretion of IFNβ, CCL5, and CXCL10 in comparison to single agents alone (compare bar 5 to bars 2 and 4). The combination of Compound 2 and ADU-S100 increased the secretion of IFNβ, CCL5 and CXCL10 in comparison to single agents alone (compare bar 6 to bars 3 and 4).
Renca cells were grown in RPMI-1640 medium containing 10% fetal bovine serum. Cells were then incubated for 2 days at 37 degrees Celsius, 5% CO2, and 95% humidity. Renca cells were reversely transfected with scrambled siRNA control (siSCR) or siRNA targeting STING (siSTING). After transfection for 48 h, cells were treated with DMSO control, 2 μM Compound 1 or 2 μM Compound 2 in combination with 10 μM ADU-S100 for 4 h (for Ifnb1) or 24 h (Ccl5 and Cxcl10). Cells were washed with PBS and RNA was isolated using the PureLink RNA kit (#12183018A, Thermo Fisher Scientific) according to the manufacturer's protocol. Genomic DNA was removed using DNA-binding columns (RNeasy plus kit, #74134, Qiagen) and/or DNase treatment (#12185010, Thermo Fisher Scientific). RNA was quantified using NanoDrop (Thermo Fisher Scientific) and 50 ng/μL RNA was used for cDNA synthesis with SuperScript IV VILO Master Mix (#11756050, Thermo Fisher Scientific). Quantitative RT-PCR (qRT-PCR) was run with diluted cDNA (1:25 or 1:12.5), PowerUp SYBR Green Master Mix (#A25741, Thermo Fisher Scientific), and 200 nM primers (see below) on a CFX Connect RT-PCR system (BioRad). Data was analyzed using the ΔΔCT method. Results are mean±SEM of three independent experiments.
A study was performed to test whether combining Compound 1 with a STING agonist, ADU-S100 would increase the mRNA expression of IFNB1, CCL5 and CXCL10 and if siRNA knockdown of STING would abolish that increase in Renca renal cell carcinoma cells.
Compound 1 as a single agent did not significantly increase IFNB1 expression but did increase CCL5 and CXCL10 expression. ADU-S100 as a single agent increased the expression of IFNB1, CCL5 and CXCL10. The combination of Compound 1 and ADU-S100 further increased IFNB1, and synergistically increased CCL5 and CXCL10 expression.
SiRNA knockdown of STING blocked the increase in IFNB1, CCL5 and CXCL10 by Compound 1, ADU-S100, and the combination in all cases.
B16-F10 cells were grown in DMEM/F12 medium containing 10% fetal bovine serum. Cells were then incubated for 2 days at 37 degrees Celsius, 5% CO2, and 95% humidity. Renca cells were reversely transfected with scrambled siRNA control (siSCR) or siRNA targeting STING (siSTING). After transfection for 48 h, cells were treated with DMSO control, 2 μM Compound 1 or 2 μM Compound 2 in combination with 10 μM ADU-S100 for 4 h (for Ifnb1) or 24 h (Ccl5 and Cxcl10). Cells were washed with PBS and RNA was isolated using the PureLink RNA kit (#12183018A, Thermo Fisher Scientific) according to the manufacturer's protocol. Genomic DNA was removed using DNA-binding columns (RNeasy plus kit, #74134, Qiagen) and/or DNase treatment (#12185010, Thermo Fisher Scientific). RNA was quantified using NanoDrop (Thermo Fisher Scientific) and 50 ng/μL RNA was used for cDNA synthesis with SuperScript IV VILO Master Mix (#11756050, Thermo Fisher Scientific). Quantitative RT-PCR (qRT-PCR) was run with diluted cDNA (1:25 or 1:12.5), PowerUp SYBR Green Master Mix (#A25741, Thermo Fisher Scientific), and 200 nM primers (see below) on a CFX Connect RT-PCR system (BioRad). Data was analyzed using the ΔΔCT method. Results are mean±SEM of three independent experiments.
A study was performed to test whether Compound 1 or Compound 2 upregulated IFNB1, CCL5 and CXCL10 in combination with a STING agonist, ADU-S100, in B16-F10 melanoma cells.
Compound 1 as a single agent did not increase IFNB1 expression but did mildly increase CCL5 and CXCL10 expression. Compound 2 as a single agent did not increase IFNB1 expression but did mildly increase CCL5 and CXCL10 expression. ADU-S100 did not increase the expression of IFNB1 but did increase the expression of CCL5 and CXCL10. The combination of Compound 1 and ADU-S100 synergistically increased IFNB1, CCL5 and CXCL10 expression. The combination of Compound 2 and ADU-S100 synergistically increased IFNB1, CCL5 and CXCL10 expression.
Renca cells were treated with a combination of DMSO or 2 μM Compound 1 alone or in combination with STING agonist ADU-S100 for 24 hours. Treatment with 1 μM staurosporine was used as a positive control for apoptosis induction. To assess cell proliferation, 1000 cells/well were plated in 96-well plates. After 24 h, cells were treated with compounds in 100 μL complete medium. Phase-contrast images (10×) were acquired every 3 h for 24-72 h and cell confluence (%) was calculated using the IncuCyte S3 live-cell analysis system (Sartorius). For monitoring apoptosis, 5 μM of IncuCyte Caspase-3/7 Green Dye (#4440, Sartorius) was added to the medium at the time of treatment. Both phase-contrast and green fluorescent images were captured. Caspase 3/7 induction was calculated by counting green fluorescent objects per mm2 and dividing it by the percentage of cell confluency.
A study was performed to test whether Compound 1, in combination with a STING agonist, ADU-S100, would inhibit cell growth and induce apoptosis in Renca renal cell carcinoma cells.
In
Me30966 cells were transfected with siSCR or siSTING. After 48 h, cells were treated with DMSO or 2 μM of VPS34 inhibitors (Compound 1 or Compound 2) for 24 h. Cells were washed with PBS and RNA was isolated using the PureLink RNA kit (#12183018A, Thermo Fisher Scientific) according to the manufacturer's protocol. Genomic DNA was removed using DNA-binding columns (RNeasy plus kit, #74134, Qiagen) and/or DNase treatment (#12185010, Thermo Fisher Scientific). RNA was quantified using NanoDrop (Thermo Fisher Scientific) and 50 ng/μL RNA was used for cDNA synthesis with SuperScript IV VILO Master Mix (#11756050, Thermo Fisher Scientific). Quantitative RT-PCR (qRT-PCR) was run with diluted cDNA (1:25 or 1:12.5), PowerUp SYBR Green Master Mix (#A25741, Thermo Fisher Scientific), and 200 nM primers (see below) on a CFX Connect RT-PCR system (BioRad). Data was analyzed using the ΔΔCT method. Results are mean±SEM of three independent experiments.
A study was performed to test whether Compound 1 (Compound 1) or Compound 2 (Compound 2) increased IFNB1, CCL5 and CXCL10 mRNA expression and if siRNA knockdown of STING would reverse that effect in Me30966 melanoma cells.
In
CT26 cells were treated for 24 hours with DMSO or VPS34 inhibitors (5 μM Compound 1 or 10 μM Compound 2) in combination with 10 mg/mL STING agonist cGAMP (green bars). Cells were washed with PBS and RNA was isolated using the PureLink RNA kit (#12183018A, Thermo Fisher Scientific) according to the manufacturer's protocol. Genomic DNA was removed using DNA-binding columns (RNeasy plus kit, #74134, Qiagen) and/or DNase treatment (#12185010, Thermo Fisher Scientific). RNA was quantified using NanoDrop (Thermo Fisher Scientific) and 50 ng/μL RNA was used for cDNA synthesis with SuperScript IV VILO Master Mix (#11756050, Thermo Fisher Scientific). Quantitative RT-PCR (qRT-PCR) was run with diluted cDNA (1:25 or 1:12.5), PowerUp SYBR Green Master Mix (#A25741, Thermo Fisher Scientific), and 200 nM primers (see below) on a CFX Connect RT-PCR system (BioRad). Data was analyzed using the ΔΔCT method. Results are mean±SEM of three independent experiments.
Cell culture medium was centrifuged at 1600 rpm for 10 min at 4° C. and obtained supernatant stored at −80° C. Cytokine levels were quantified using following Meso Scale Discovery (MSD) assays: mouse U-PLEX RANTES/CCL5 (#K152A2K) and U-PLEX IP-10/CXCL10 (#K152UFK). Assays were run on the SECTOR Quickplex Imager and analyzed using Discovery Workbench version 4.0 (MSD).
A study was performed to test whether Compound 1 or Compound 2 increase CCL5 and CXCL10 gene expression alone and in combination with an endogenous STING agonist, cGAMP.
In
4T1 cells were treated for 24 hours with DMSO or VPS34 inhibitors (5 μM Compound 1 or 10 μM Compound 2) in combination with 10 mg/ml STING agonist cGAMP (green bars). Cells were washed with PBS and RNA was isolated using the PureLink RNA kit (#12183018A, Thermo Fisher Scientific) according to the manufacturer's protocol. Genomic DNA was removed using DNA-binding columns (RNeasy plus kit, #74134, Qiagen) and/or DNase treatment (#12185010, Thermo Fisher Scientific). RNA was quantified using NanoDrop (Thermo Fisher Scientific) and 50 ng/μL RNA was used for cDNA synthesis with SuperScript IV VILO Master Mix (#11756050, Thermo Fisher Scientific). Quantitative RT-PCR (qRT-PCR) was run with diluted cDNA (1:25 or 1:12.5), PowerUp SYBR Green Master Mix (#A25741, Thermo Fisher Scientific), and 200 nM primers (see below) on a CFX Connect RT-PCR system (BioRad). Data was analyzed using the ΔΔCT method. Results are mean±SEM of three independent experiments.
Cell culture medium was centrifuged at 1600 rpm for 10 min at 4° C. and obtained supernatant stored at −80° C. Cytokine levels were quantified using following Meso Scale Discovery (MSD) assays: mouse U-PLEX RANTES/CCL5 (#K152A2K) and U-PLEX IP-10/CXCL10 (#K152UFK). Assays were run on the SECTOR Quickplex Imager and analyzed using Discovery Workbench version 4.0 (MSD).
A study was performed to test whether Compound 1 or Compound 2 increase CCL5 and CXCL10 gene expression alone and in combination with a STING agonist, ADU-S100 in addition to enhancing the effects of an endogenous STING agonist, cGAMP.
In
YUMM1.7 cells were treated for 24 hours with DMSO or VPS34 inhibitors (5 μM Compound 1 or 10 μM Compound 2) in combination with 10 mg/ml STING agonist cGAMP (green bars). Cells were washed with PBS and RNA was isolated using the PureLink RNA kit (#12183018A, Thermo Fisher Scientific) according to the manufacturer's protocol. Genomic DNA was removed using DNA-binding columns (RNeasy plus kit, #74134, Qiagen) and/or DNase treatment (#12185010, Thermo Fisher Scientific). RNA was quantified using NanoDrop (Thermo Fisher Scientific) and 50 ng/μL RNA was used for cDNA synthesis with SuperScript IV VILO Master Mix (#11756050, Thermo Fisher Scientific). Quantitative RT-PCR (qRT-PCR) was run with diluted cDNA (1:25 or 1:12.5), PowerUp SYBR Green Master Mix (#A25741, Thermo Fisher Scientific), and 200 nM primers (see below) on a CFX Connect RT-PCR system (BioRad). Data was analyzed using the ΔΔCT method. Results are mean±SEM of three independent experiments.
Cell culture medium was centrifuged at 1600 rpm for 10 min at 4° C. and obtained supernatant stored at −80° C. Cytokine levels were quantified using following Meso Scale Discovery (MSD) assays: mouse U-PLEX RANTES/CCL5 (#K152A2K) and U-PLEX IP-10/CXCL10 (#K152UFK). Assays were run on the SECTOR Quickplex Imager and analyzed using Discovery Workbench version 4.0 (MSD).
A study was performed to test whether Compound 1 or Compound 2 increase CCL5 and CXCL10 gene expression alone and in combination with an endogenous STING agonist, cGAMP.
In
B16-F10, CT26, DC2.4 or Renca cells were seeded at 1×106 cells/well in 6-well plates and cultured overnight. Cells were treated with DMSO, 10 μg/mL ADU-S100, 2 μM Compound 1 or the combination for the times indicated in the figure. Cells were washed in PBS and lysed in RIPA buffer (#89901, Pierce) containing protease inhibitor cocktail (#78401, Pierce), phosphatase inhibitor (#78420, Pierce), and 0.5M EDTA solution (#1861276, Thermo Fisher) for 10 min at 4° C. After centrifugation at 21000 rpm for 10 min at 4° C., the supernatant was obtained, and protein concentration was quantified using BCA assay (#23225, Thermo Fisher). Equal amounts were mixed with Sample Reducing agent (#NP0009, Thermo Fisher) and LDS Sample Buffer (#NP0007, Thermo Fisher), heated for 15 min at 90° C. before loading onto 10% Bis-Tris Midi gels. Proteins were transferred to polyvinylidene fluoride (PVDF) membranes. Membranes were blocked with 5% BSA in 1×TBS solution for 1 h at RT, washed in TBS-T, and probed with primary antibodies shaking overnight at 4° C. After washing in TBS-T, membranes were incubated with IRDye 800CW Goat anti-Rabbit (#926-32211, LI-COR, 1:10,000 dilution) secondary antibody in Intercept Blocking Buffer (#927-70001, LI-COR) for 1 h at RT. After washing in TBS-T, membranes were imaged using the Odyssey CLx (LI-COR). Band intensities were quantified using Image Studio software version 5.2.5 (LI-COR).
THP1-Dual™ Cells lines were purchased from InvivoGen (WT (thpd-nfis) and STING-KO (thpd-kostg)) and cultured as recommended by manufacturer: in RPMI media (Gibco 22400-071) supplemented with 10% heat-inactivated Fetal Bovine Serum (FBS) (Gibco A38400-02) and 1× Pen-Strep-Glutamine (Gibco 10378-016). Cells were treated with selective antibiotic every other passage using 100 μg/ml Normocin™ (InvivoGen ant-nr-1), 10 μg/ml of blasticidin (InvivoGen ant-bl-05) and 100 μg/ml of Zeocin™ (InvivoGen ant-zn-05). THP1-Dual™ Cells (wild-type or STING-KO) were seeded at 1.5×105 cells/well in 96-well plates. Cells were treated with DMSO, 5 μg/mL ADU-S100, 2 μM Compound 1 or 2 or the combinations overnight. The next day, 10 μL of the media from the treated cells were mixed with 50 μL of QUANTI-Luc™ Gold (Invivogen rep-qlcg2) in a white 96-well plate (Thermo Scientific 9502887) to measure the interferon-sensitive response element (ISRE) promoter activity through Luciferase signal using a plate reader. For measuring NF-κB promoter activity, 10 μL of the media from the treated cells were mixed with 90 μL of QUANTI-Blue™ (Invivogen rep-qbs3) in white-96-well plates (Corning-Costar 3610), then incubated at 37° C. for one hour. The signal was then measured using a plate reader with detection at 640 nm wavelength.
This study was performed to identify whether the combination of a STING agonist and a VPS34 inhibitor resulted in enhanced activation of STING due to the delayed degradation of activated STING in multiple cancer cell lines.
B16-F10 tumor-bearing C57BI/6 mice were treated with vehicle or 20 mg/kg Compound 1 p.o. (daily from day 7-16) in combination with PBS or 10 μg ADU-S100 i.t. (on days 9, 11, 13, and 15).
While specific embodiments have been discussed, the above specification is illustrative and not restrictive. Many variations of the embodiments will become apparent to those skilled in the art upon review of this specification. The full scope of what is disclosed should be determined by reference to the claims, along with their full scope of equivalents, and the specification, along with such variations.
Unless otherwise indicated, all numbers expressing quantities of ingredients, reaction conditions, and so forth used in the specification and claims are to be understood as being modified in all instances by the term “about.” Accordingly, unless indicated to the contrary, the numerical parameters set forth in this specification and attached claims are approximations that may vary depending upon the desired properties sought to be obtained.
This application is a U.S. National Stage application filed under 35 U.S.C. § 371 claiming benefit to International Patent Application No. PCT/US2022/074925 filed Aug. 12, 2022, which claims priority to U.S. Provisional Application No. 63/232,983 filed Aug. 13, 2021, and U.S. Provisional Application No. 63/317,500 filed Mar. 7, 2022, the contents of each of which are incorporated herein by reference.
| Filing Document | Filing Date | Country | Kind |
|---|---|---|---|
| PCT/US2022/074925 | 8/12/2022 | WO |
| Number | Date | Country | |
|---|---|---|---|
| 63317500 | Mar 2022 | US | |
| 63232983 | Aug 2021 | US |
