Therapeutic heterocyclic compounds

Abstract

The present application discloses compounds having the following formula (I), or pharmaceutically acceptable salts thereof, and their uses and preparation methods.

Description

[0001] Cross - Reference to Related Applications

[0002] This application claims the benefit of priority of U.S. Provisional Application No. 62 / 694,926, filed on Jul. 6, 2018. The content of this application is incorporated herein by reference. Technical Field

[0003] The present disclosure generally relates to inhibitors of indoleamine 2,3 - dioxygenase 1 (IDO1) activity, and methods of using and making the same. Background Art

[0004] The inducible heme - containing enzyme indoleamine 2,3 - dioxygenase 1 (IDO1) catabolism of the essential amino acid tryptophan is a major pathway for maintaining an immunosuppressive microenvironment in many cancers. IDO1 catalyzes the degradation of tryptophan to kynurenine, and its immunosuppressive effects are attributed to reduced tryptophan availability and the production of tryptophan metabolites, resulting in multiple negative effects on cytotoxic T lymphocytes and the expansion of immunosuppressive regulatory T cells. IDO1 is elevated in a variety of cancers and is induced by chemotherapy, targeted therapy, or immunotherapy. Expression of IDO1 in the tumor microenvironment is associated with poor prognosis in a variety of cancers. IDO1 inhibitors can enhance the efficacy of a variety of cancer therapies, including immunotherapy, targeted drugs, and chemotherapy. Moreover, epacadostat (INCB24360) is a potent and selective IDO1 inhibitor that has entered clinical trials and has shown activity in combination with ipilimumab (anti - CTLA4) in melanoma.

[0005] In addition to the above, IDO1 has been shown to play a role in chronic infections, HIV and AIDS, autoimmune diseases or disorders (such as rheumatoid arthritis), and immune tolerance such as preventing the rejection of the fetus in utero. Inhibiting IDO1 may also be an important therapeutic strategy for patients suffering from a neurological or neuropsychiatric disease or disorder (such as depression).

[0006] There remains a need for additional therapeutic agents for treating IDO1 - mediated proliferative diseases or disorders. Summary of the Invention

[0007] The present disclosure provides compounds having IDO1 inhibitor function. The present disclosure also provides compositions (including pharmaceutical compositions), kits comprising the compounds, and methods of using and making the compounds. The compounds provided herein are suitable for treating diseases, disorders, or conditions mediated by IDO1. The present disclosure also provides compounds for use in therapy. The present disclosure further provides compounds for use in methods of treating diseases, disorders, or conditions mediated by IDO1. In addition, the present disclosure provides the use of the compounds in the manufacture of a medicament for treating diseases, disorders, or conditions mediated by IDO1.

[0008] In some embodiments, there are provided compounds having the structure of Formula I, or pharmaceutically acceptable salts or pharmaceutically acceptable tautomers thereof:

[0009]

[0010] Wherein:

[0011] Y 1 is O or N;

[0012] ______ is a single bond that is present or absent,

[0013] wherein when Y 1 is O, ______ is absent, and when Y 1 is N, ______ is present;

[0014] When ______ is absent, it indicates that the ring containing X 5 、X 6 、X 7 and X 8 is a monocyclic aryl or heteroaryl ring, and when ______ is present, it indicates that the ring containing X 5 、X 6 、X 7 and X 8 forms a bicyclic heteroaryl together with the ring containing Y 1 ;

[0015] X 1 、X 2 、and X 4 are each independently N or CH;

[0016] X 3 is N or CR a ,

[0017] wherein R a is H, halogen, or C 1-4 alkyl;

[0018] X 5 is N, C or CR b ,

[0019] provided that when Y 1 is O, X 5 is N or CR b , and when Y 1 is N, X 5 is C;

[0020] X 6 is N or CR c ;

[0021] X 7 is N or CR d ;

[0022] X 8 is N or CR e ;

[0023] wherein R b , R c , R d , and R e are each independently H, halogen, or CN;

[0024] R 1 is H, halogen, or CN;

[0025] R 2 is C 1-6 alkyl, C 1-6 haloalkyl, or C 1-6 haloalkoxy;

[0026] R 3 is C 1-3 alkyl, 6 - 12 - membered aryl or 5 - 12 - membered heteroaryl, wherein the C 3 alkyl, 6 - 12 - membered aryl, or 5 - 12 - membered heteroaryl of R 1-3 is unsubstituted or substituted with one, two, or three substituents independently selected from: halogen, CN, C 1-6 alkyl, C 1-6 haloalkyl, phenyl, or 5 - 6 - membered heteroaryl; and

[0027] Z is C(Z a )(Z b ), OC(Z a )(Z b ), NH, or O,

[0028] wherein Z a and Z b are independently H or C 1-4 alkyl, or

[0029] Z a and Z b together with the carbon atoms to which they are attached form 3- to 5-membered carbon rings.

[0030] Another embodiment provides a compound of formula Ia below, or a pharmaceutically acceptable salt or pharmaceutically acceptable tautomer thereof:

[0031]

[0032] wherein

[0033] X 1 , X 2 , and X 4 are each independently N or CH;

[0034] X 3 is N or CR a ,

[0035] wherein R a is H, halogen, or C 1-4 alkyl;

[0036] X 5 is N or CH;

[0037] X 6 is N or CH;

[0038] X 8 is N or CH;

[0039] R d is H, halogen, or CN;

[0040] R 2 is C 1-3 alkyl, C 1-3 haloalkyl, or C 1-3 haloalkoxy; and

[0041] R 3 is C 1-3 alkyl, 6- to 12-membered aryl, or 5- to 12-membered heteroaryl, wherein the C 3 alkyl, 6- to 12-membered aryl, or 5- to 12-membered heteroaryl of R 1-3 is unsubstituted or substituted with one, two, or three substituents independently selected from: halogen, CN, C 1-6 alkyl, C 1-6 haloalkyl, phenyl, or 5- to 6-membered heteroaryl.

[0042] Another embodiment provides a compound of formula Ib below, or a pharmaceutically acceptable salt or pharmaceutically acceptable tautomer thereof:

[0043]

[0044] Wherein:

[0045] X 1 、X 2 、and X 4 are each independently N or CH;

[0046] X 3 is N or CR a ;

[0047] Wherein R a is H, halogen, or C 1-4 alkyl;

[0048] X 5 is N or CH;

[0049] X 6 is N or CH;

[0050] R d and R e are each independently H, halogen, or CN;

[0051] R 2 is C 1-3 alkyl, C 1-3 haloalkyl, or C 1-3 haloalkoxy; and

[0052] R 3 is C 1-3 alkyl, 6 - to 12 - membered aryl, or 5 - to 12 - membered heteroaryl, wherein the C 3 alkyl, 6 - to 12 - membered aryl, or 5 - to 12 - membered heteroaryl of R 1-3 is unsubstituted or substituted with one, two, or three substituents independently selected from: halogen, CN, C 1-6 alkyl, C 1-6 haloalkyl, phenyl, or 5 - to 6 - membered heteroaryl.

[0053] Another embodiment provides a compound of formula Ic below, or a pharmaceutically acceptable salt or pharmaceutically acceptable tautomer thereof:

[0054]

[0055] Wherein:

[0056] X 1 、X 2 、and X 4 are each independently N or CH;

[0057] X 3is N or CR a ;

[0058] wherein R a is H, a halogen, or C 1-4 alkyl;

[0059] X 5 is N or CH;

[0060] X 8 is N or CH;

[0061] R c and R d are each independently H, a halogen, or CN;

[0062] R 2 is C 1-3 alkyl, C 1-3 haloalkyl, or C 1-3 haloalkoxy; and

[0063] R 3 is C 1-3 alkyl, a 6 - 12 - membered aryl, or a 5 - 12 - membered heteroaryl, wherein the C 3 alkyl, 6 - 12 - membered aryl, or 5 - 12 - membered heteroaryl of R 1-3 is unsubstituted or substituted with one, two, or three substituents independently selected from: a halogen, CN, C 1-6 alkyl, C 1-6 haloalkyl, phenyl, or a 5 - 6 - membered heteroaryl.

[0064] Another embodiment provides a compound of formula Id, or a pharmaceutically acceptable salt or pharmaceutically acceptable tautomer thereof:

[0065]

[0066] wherein:

[0067] X 1 、X 2 、and X 4 are each independently N or CH;

[0068] X 3 is N or CR a ;

[0069] wherein R a is H, a halogen, or C 1-4 alkyl;

[0070] X 7 is N or CH;

[0071] R b 、Rc and R e are each independently H, halogen, or CN;

[0072] R 2 is C 1-6 alkyl, C 1-6 haloalkyl, or C 1-6 haloalkoxy; and

[0073] R 3 is C 1-3 alkyl, 6 - to 12 - membered aryl, or 5 - to 12 - membered heteroaryl, where the C 3 alkyl, 6 - to 12 - membered aryl, or 5 - to 12 - membered heteroaryl of R 1-3 is unsubstituted or substituted with one, two, or three substituents independently selected from: halogen, CN, C 1-6 alkyl, C 1-6 haloalkyl, phenyl, or 5 - to 6 - membered heteroaryl.

[0074] Another embodiment provides a compound of formula Ie, or a pharmaceutically acceptable salt or pharmaceutically acceptable tautomer thereof:

[0075]

[0076] wherein:

[0077] X 1 , X 2 , and X 4 are each independently N or CH;

[0078] X 3 is N or CR a ;

[0079] where R a is H, halogen, or C 1-4 alkyl;

[0080] X 7 is N or CH;

[0081] X 8 is N or CH;

[0082] R b and R c are each independently H, halogen, or CN;

[0083] R 2 is C 1-6 alkyl, C 1-6 haloalkyl, or C 1-6 haloalkoxy; and

[0084] R3 is C 1-3 alkyl, 6- to 12-membered aryl, or 5- to 12-membered heteroaryl, wherein R 3 of said C 1-3 alkyl, 6- to 12-membered aryl, or 5- to 12-membered heteroaryl is unsubstituted or substituted with one, two, or three substituents independently selected from: halogen, CN, C 1-6 alkyl, C 1-6 haloalkyl, phenyl, or 5- to 6-membered heteroaryl.

[0085] Another embodiment provides a compound having the following formula If, or a pharmaceutically acceptable salt or pharmaceutically acceptable tautomer thereof:

[0086]

[0087] wherein:

[0088] X 1 , X 2 , and X 4 are each independently N or CH;

[0089] X 3 is N or CR a ;

[0090] wherein R a is H, halogen, or C 1-4 alkyl;

[0091] X 5 is N or CH;

[0092] X 7 is N or CH;

[0093] R c and R e are each independently H, halogen, or CN;

[0094] R 2 is C 1-6 alkyl, C 1-6 haloalkyl, or C 1-6 haloalkoxy; and

[0095] R 3 is C 1-3 alkyl, 6- to 12-membered aryl, or 5- to 12-membered heteroaryl, wherein R 3 of said C 1-3 alkyl, 6- to 12-membered aryl, or 5- to 12-membered heteroaryl is unsubstituted or substituted with one, two, or three substituents independently selected from: halogen, CN, C 1-6 alkyl, C 1-6haloalkyl, phenyl, or 5- to 6-membered heteroaryl.

[0096] Another embodiment provides a compound of formula Ig below, or a pharmaceutically acceptable salt or pharmaceutically acceptable tautomer thereof:

[0097]

[0098] wherein

[0099] X 1 and X 2 and X 4 are each independently N or CH;

[0100] X 3 is N or CR a ,

[0101] wherein R a is H, halogen, or C 1-4 alkyl;

[0102] X 5 is N or CR b ;

[0103] X 6 is N or CR c ;

[0104] X 7 is N or CR d ;

[0105] X 8 is N or CR e ;

[0106] wherein R b R c R d and R e are each independently H, halogen, or CN;

[0107] R 1 is H, halogen, or CN;

[0108] R 2 is C 1-3 alkyl, C 1-3 haloalkyl, or C 1-3 haloalkoxy; and

[0109] R 3 is C 1-3 alkyl, 6- to 12-membered aryl or 5- to 12-membered heteroaryl, wherein the C of R 3 of 1-3The alkyl group, 6- to 12-membered aryl group, or 5- to 12-membered heteroaryl group is unsubstituted or substituted with one, two, or three substituents independently selected from the following: halogen, CN, C 1-6 alkyl group, C 1-6 haloalkyl group, or phenyl group or 5- to 6-membered heteroaryl group.

[0110] Another embodiment provides a compound of formula Ih below, or a pharmaceutically acceptable salt or pharmaceutically acceptable tautomer thereof:

[0111]

[0112] wherein

[0113] X 1 、X 2 、and X 4 are each independently N or CH;

[0114] X 3 is N or CR a ,

[0115] wherein R a is H, halogen, or C 1-4 alkyl group;

[0116] X 5 is N or CR b ;

[0117] X 6 is N or CR c ;

[0118] X 7 is N or CR d ;

[0119] X 8 is N or CR e ;

[0120] wherein R b 、R c 、R d 、and R e are each independently H, halogen, or CN;

[0121] R 1 is H, halogen, or CN;

[0122] R 2 is C 1-3 alkyl group, C 1-3 haloalkyl group or C 1-3 haloalkoxy group; and

[0123] R 3 is C 1-3An alkyl group, a 6- to 12-membered aryl group, or a 5- to 12-membered heteroaryl group, wherein R 3 of said C 1-3 The alkyl group, 6- to 12-membered aryl group, or 5- to 12-membered heteroaryl group is unsubstituted or substituted with one, two, or three substituents independently selected from the following: halogen, CN, C 1-6 alkyl group, C 1-6 haloalkyl group, phenyl group, or 5- to 6-membered heteroaryl group.

[0124] Another embodiment provides a compound of formula Ii below, or a pharmaceutically acceptable salt or pharmaceutically acceptable tautomer thereof:

[0125]

[0126] wherein

[0127] X 1 , X 2 , and X 4 are each independently N or CH;

[0128] X 3 is N or CR a ,

[0129] wherein R a is H, halogen, or C 1-4 alkyl group;

[0130] X 5 is N or CR b ;

[0131] X 6 is N or CR c ;

[0132] X 7 is N or CR d ;

[0133] X 8 is N or CR e ;

[0134] wherein R b , R c , R d , and R e are each independently H, halogen, or CN;

[0135] R 1 is H, halogen, or CN;

[0136] R 2 is C 1-3 alkyl group, C 1-3 haloalkyl group or C 1-3 haloalkoxy group;

[0137] R 3 is C 1-3 alkyl, 6- to 12-membered aryl or 5- to 12-membered heteroaryl, wherein R 3 said C 1-3 alkyl, 6- to 12-membered aryl, or 5- to 12-membered heteroaryl is unsubstituted or substituted with one, two or three substituents independently selected from the following: halogen, CN, C 1-6 alkyl, C 1-6 haloalkyl, phenyl, or 5- to 6-membered heteroaryl; and

[0138] Z a and Z b are independently H or C 1-4 alkyl, or

[0139] Z a and Z b together with the carbon to which they are each attached form a 3- to 5-membered carbocycle.

[0140] Another embodiment provides a compound having the following formula Ij:

[0141]

[0142] wherein

[0143] X 1 、X 2 、and X 4 are each independently N or CH;

[0144] X 3 is N or CR a ,

[0145] wherein R a is H, halogen, or C 1-4 alkyl;

[0146] X 6 is N or CR c ;

[0147] X 7 is N or CR d ;

[0148] X 8 is N or CR e ;

[0149] wherein R c 、R d 、and R e are each independently H, halogen, or CN;

[0150] R 1is H, a halogen, or CN;

[0151] R 2 is C 1-3 alkyl, C 1-3 haloalkyl, or C 1-3 haloalkoxy;

[0152] R 3 is C 1-3 alkyl, a 6- to 12-membered aryl, or a 5- to 12-membered heteroaryl, where the C 3 alkyl, 6- to 12-membered aryl, or 5- to 12-membered heteroaryl of R 1-3 is unsubstituted or substituted with one, two, or three substituents independently selected from: halogen, CN, C 1-6 alkyl, C 1-6 haloalkyl, phenyl, or a 5- to 6-membered heteroaryl; and

[0153] Z is C(Z a )(Z b ), OC(Z a )(Z b ), NH, or O,

[0154] where Z a and Z b are independently H or C 1-4 alkyl, or

[0155] Z a and Z b together with the carbon to which they are each attached form a 3- to 5-membered carbocyclic ring.

[0156] In some embodiments, provided is a method of treating a subject having a disease or disorder responsive to inhibition of IDO1 activity with a pharmaceutical composition comprising a compound of formula I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, or Ij, or a pharmaceutically acceptable salt or pharmaceutically acceptable tautomer thereof.

[0157] In some embodiments, provided is a method of treating a subject having a disease or disorder responsive to inhibition of IDO1 activity with a pharmaceutical composition comprising a compound of formula I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, or Ij, or a pharmaceutically acceptable salt or pharmaceutically acceptable tautomer thereof.

[0158] In some embodiments, provided is a method of inhibiting the activity of IDO1 protein by contacting the protein with a compound of formula I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, or Ij, or a pharmaceutically acceptable salt or pharmaceutically acceptable tautomer thereof.

[0159] In some embodiments, methods for inhibiting the activity of IDO1 protein are provided, which are carried out by contacting said protein with a compound of formula I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii or Ij, or a pharmaceutically acceptable salt or pharmaceutically acceptable tautomer thereof.

[0160] In some embodiments, methods for inhibiting the growth or proliferation of cancer cells are provided, which are carried out by administering a therapeutically effective amount of any compound of formula I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii or Ij, or a pharmaceutically acceptable salt or pharmaceutically acceptable tautomer thereof.

[0161] In some embodiments, methods for inhibiting immunosuppression in a subject are provided, which are carried out by administering a therapeutically effective amount of any compound of formula I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii or Ij, or a pharmaceutically acceptable salt or pharmaceutically acceptable tautomer thereof.

[0162] In some embodiments, methods for treating cancer or viral infection in a subject are provided, which are carried out by administering a therapeutically effective amount of any compound of formula I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii or Ij, or a pharmaceutically acceptable salt or pharmaceutically acceptable tautomer thereof. In some embodiments, the viral infection is hepatitis B virus (HBV) and human immunodeficiency virus (HIV). In some embodiments, the cancer is selected from melanoma, non-small cell lung cancer, colorectal cancer, pancreatic cancer, and bladder cancer.

[0163] In some embodiments, the method for inhibiting IDO1 protein activity, the method for inhibiting the growth or proliferation of cancer cells, the method for inhibiting immunosuppression, the method for treating cancer, or the method for treating viral infection further comprises administering to the subject a therapeutically effective amount of an antiviral agent, chemotherapeutic agent, immunosuppressive agent, radiation, anti-tumor vaccine, antiviral vaccine, cytokine therapy, checkpoint inhibitor, or tyrosine kinase inhibitor.

[0164] In some embodiments, the method for inhibiting IDO1 protein activity, the method for inhibiting the growth or proliferation of cancer cells, the method for inhibiting immunosuppression, the method for treating cancer, or the method for treating viral infection further comprises administering to the subject a therapeutically effective amount of an HBV inhibitor or an HIV inhibitor.

[0165] In some embodiments, a method of inhibiting IDO1 protein activity, a method of inhibiting the growth or proliferation of cancer cells, a method of inhibiting immunosuppression, a method of treating cancer, or a method of treating a viral infection further comprises administering to a subject a therapeutically effective amount of a checkpoint inhibitor, wherein the checkpoint inhibitor is a PD1 inhibitor, a PD-L1 inhibitor, a PD1 and PD-L1 inhibitor, a TIM-3 inhibitor, a TIM-3 and PD1 inhibitor, a LAG-3 inhibitor, or a LAG-3 and PD-1 inhibitor. In some embodiments, the checkpoint inhibitor is a monoclonal antibody. In some embodiments, the checkpoint inhibitor is a small molecule. In some embodiments, the checkpoint inhibitor is nivolumab, pembrolizumab, lambrolizumab, pidilizumab, durvalumab, avelumab, atezolizumab, PDR001, TSR-042, or BMS-986016 or a pharmaceutically acceptable salt or solvate of any of the foregoing.

[0166] In some embodiments, a method of inhibiting IDO1 protein activity, a method of inhibiting the growth or proliferation of cancer cells, a method of inhibiting immunosuppression, a method of treating cancer, or a method of treating a viral infection further comprises administering to a subject a therapeutically effective amount of at least one additional therapeutic agent selected from the group consisting of inducible T cell co-stimulator (ICOS) agonists, cytotoxic T lymphocyte antigen 4 (CTLA-4) blocking antibodies, PD1 and / or PD-L1 inhibitors, cluster of differentiation 47 (CD47) inhibitors, hematopoietic progenitor kinase (HPK1) inhibitors, Toll-like receptor 7 (TLR7) agonists, OX40 agonists, GITR agonists, CD40 agonists, CD137 agonists, indoleamine-pyrrole-2,3-dioxygenase (IDO1) inhibitors, Toll-like receptor 8 (TLR8) agonists, T cell immunoglobulin and mucin domain-3 (TIM-3) inhibitors, lymphocyte activation gene 3 (LAG-3) inhibitors, CEACAM1 inhibitors, T cell immunoreceptor with Ig and ITIM domains (TIGIT) inhibitors, T cell activation containing V domain immunoglobulin (Ig) (VISTA) inhibitors, anti-killer IgG-like receptor (KIR) inhibitors, STING agonists, C-X-C chemokine receptor type 4 (CXCR-4) inhibitors, B7-H3 inhibitors, and CD73 inhibitors.

[0167] In some embodiments, a method of inhibiting IDO1 protein activity, a method of inhibiting the growth or proliferation of cancer cells, a method of inhibiting immunosuppression, a method of treating cancer, or a method of treating a viral infection further comprises administering to a subject a therapeutically effective amount of at least one additional therapeutic agent selected from the following: PD1 inhibitors: nivolumab, lambrolizumab, pembrolizumab, pidilizumab, PDR001, or TSR-001, or a pharmaceutically acceptable salt or solvate of any of the foregoing.

[0168] In some embodiments, a method of inhibiting IDO1 protein activity, a method of inhibiting the growth or proliferation of cancer cells, a method of inhibiting immunosuppression, a method of treating cancer, or a method of treating a viral infection further comprises administering to a subject a therapeutically effective amount of at least one additional therapeutic agent selected from the following: PD-L1 inhibitors: atezolizumab, durvalumab, or avelumab, or a pharmaceutically acceptable salt or solvate of any of the foregoing.

[0169] In some embodiments, a method of inhibiting IDO1 protein activity, a method of inhibiting the growth or proliferation of cancer cells, a method of inhibiting immunosuppression, a method of treating cancer, or a method of treating a viral infection further comprises administering to a subject a therapeutically effective amount of a Toll-like receptor 7 (TLR7) agonist. In some embodiments, the Toll-like receptor 7 (TLR7) agonist is vesatolimod.

[0170] In some embodiments, a method of inhibiting IDO1 protein activity, a method of inhibiting the growth or proliferation of cancer cells, a method of inhibiting immunosuppression, a method of treating cancer, or a method of treating a viral infection further comprises administering to a subject a therapeutically effective amount of a Toll-like receptor 8 (TLR8) agonist. In some embodiments, a method of inhibiting IDO1 protein activity, a method of inhibiting the growth or proliferation of cancer cells, a method of inhibiting immunosuppression, a method of treating cancer, or a method of treating a viral infection further comprises administering to a subject a therapeutically effective amount of a Toll-like receptor 8 (TLR8) agonist and a therapeutically effective amount of a programmed death 1 (PD-1) inhibitor and / or a programmed death ligand 1 (PD-L1) inhibitor.

[0171] In some embodiments, a method of inhibiting IDO1 protein activity, a method of inhibiting the growth or proliferation of cancer cells, a method of inhibiting immunosuppression, a method of treating cancer, or a method of treating a viral infection further comprises administering to a subject a therapeutically effective amount of an additional therapeutic agent selected from T cell immunomodulators and a compound of formula I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, or Ij, or a pharmaceutically acceptable salt or pharmaceutically acceptable tautomer thereof. In some embodiments, the T cell immunomodulators are selected from: inhibitory RNAs, HPK1 inhibitors, IL2 / 15 / 17 fusion proteins, OX40 agonists, CD27 agonists, MKNK1 / 2 inhibitors, CD40 agonists, CD137 agonists, CD28 agonists, and GITR agonists.

[0172] Some embodiments provide methods for treating a disease or disorder in a mammal, particularly a human, which disease or disorder is amenable to treatment via an IDO1 inhibitor (e.g., cancer, HBV, etc.), using a compound of formula I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, or Ij, or a compound of other general formulas described throughout the text.

[0173] Some embodiments provide methods for treating a disease or disorder in a mammal, particularly a human, which disease or disorder is amenable to treatment via an IDO1 inhibitor (e.g., cancer, HBV, etc.), using a compound of formula I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, or Ij, or a compound of other general formulas described throughout the text, or a pharmaceutically acceptable salt or pharmaceutically acceptable tautomer thereof.

[0174] In some embodiments, the present disclosure provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of the present disclosure (e.g., formula I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, or Ij, or a compound of other general formulas described throughout the text), or a pharmaceutically acceptable salt or pharmaceutically acceptable tautomer thereof, and at least one pharmaceutically acceptable excipient.

[0175] In some embodiments, the present disclosure provides an article of manufacture comprising a unit dose of a compound of the present disclosure (e.g., formula I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, or Ij, or a compound of other general formulas described throughout the text), or a pharmaceutically acceptable salt or pharmaceutically acceptable tautomer thereof.

[0176] In some embodiments, the disclosure herein provides compounds of the disclosure (e.g., of Formula I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, or Ij, or compounds of other general formulas described throughout the text), which are used in medical therapies.

[0177] In some embodiments, the disclosure herein provides the compounds of the disclosure (e.g., of Formula I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, or Ij, or compounds of other general formulas described throughout the text), or pharmaceutically acceptable salts or pharmaceutically acceptable tautomers thereof, for use in the manufacture of a medicament for treating a disease or disorder in a mammal, particularly a human, which disease or disorder is amenable to treatment via an IDO1 inhibitor (e.g., cancer, HBV, etc.).

[0178] The invention of the disclosure is described throughout the specification. In addition, specific embodiments of the invention are disclosed herein. Detailed Description of the Invention

[0180] Definitions and General Parameters

[0181] The following description sets forth exemplary methods, parameters, etc. However, it should be recognized that such description is not intended to limit the scope of the invention, but rather is provided as a description of exemplary embodiments.

[0182] As used in this specification, the following words, phrases and symbols generally are intended to have the meanings as set forth below, unless the context in which they are used indicates otherwise.

[0183] A dash (“-”) not between two letters or symbols is used to indicate the point of attachment of a substituent. For example, -CONH 2 is attached through a carbon atom. Dashes in front of or behind a chemical group are for convenience; a chemical group may be depicted with or without one or more dashes without losing its usual meaning. A wavy line drawn through a line in a structure indicates the point of attachment of a group. Unless chemically or structurally required, the order in which a chemical group is written or named does not indicate or imply directionality.

[0184] The prefix “C u-v ” indicates that the group following has from u to v carbon atoms. For example, “C 1-6 alkyl” indicates that the alkyl has from 1 to 6 carbon atoms.

[0185] As used herein, the term "about" in reference to a value or parameter includes (and describes) embodiments that involve that value or parameter per se. In some embodiments, the term "about" includes the indicated amount ± 10%. In other embodiments, the term "about" includes the indicated amount ± 5%. In some other embodiments, the term "about" includes the indicated amount ± 1%. In addition, the term "about X" includes the description of "X". Further, the singular forms "a" and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "the compound" includes a plurality of such compounds, and reference to "the assay" includes reference to one or more assays known to those of skill in the art and their equivalents.

[0186] "Alkyl" refers to a non-branched or branched saturated hydrocarbon chain. Alkyl as used herein has from 1 to 20 carbon atoms (i.e., C 1-20 alkyl), from 1 to 8 carbon atoms (i.e., C 1-8 alkyl), from 1 to 6 carbon atoms (i.e., C 1-6 alkyl), or from 1 to 4 carbon atoms (i.e., C 1-4 alkyl). Examples of alkyl include methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl, and 3-methylpentyl. When an alkyl residue having a specific number of carbon atoms is named by a chemical name or determined by a molecular formula, it may include all positional isomers having that number of carbon atoms; thus, for example, "butyl" includes n-butyl (i.e., -(CH 2 ) 3 CH 3 )), sec-butyl (i.e., -CH(CH 3 )CH 2 CH 3 )), isobutyl (i.e., -CH 2 CH(CH 3 ) 2 ) and tert-butyl (i.e., -C(CH 3 ) 3 )), and "propyl" includes n-propyl (i.e., -(CH 2 ) 2 CH 3 ) and isopropyl (i.e., -CH(CH 3 ) 2 ).

[0187] "Alkenyl" refers to an aliphatic group that contains at least one carbon-carbon double bond and has from 2 to 20 carbon atoms (i.e., C 2-20 alkenyl), from 2 to 8 carbon atoms (i.e., C 2-8 alkenyl), from 2 to 6 carbon atoms (i.e., C 2-6(alkenyl), or 2 to 4 carbon atoms (i.e., C 2-4 (alkenyl). Examples of alkenyl include vinyl, propenyl, butadienyl (including 1,2-butadienyl and 1,3-butadienyl).

[0188] "Alkynyl" refers to an aliphatic group that contains at least one carbon-carbon triple bond and has 2 to 20 carbon atoms (i.e., C 2-20 (alkynyl), 2 to 8 carbon atoms (i.e., C 2-8 (alkynyl), 2 to 6 carbon atoms (i.e., C 2-6 (alkynyl), or 2 to 4 carbon atoms (i.e., C 2-4 (alkynyl). The term "alkynyl" also includes those groups having one triple bond and one double bond.

[0189] "Alkoxy" refers to the group "alkyl-O-". Examples of alkoxy include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentyloxy, n-hexyloxy, and 1,2-dimethylbutoxy. "Halogenated alkoxy" refers to the alkoxy as defined above, where one or more hydrogen atoms are replaced by halogen.

[0190] "Acyl" refers to the group -C(=O)R, where R is hydrogen, alkyl, cycloalkyl, heterocyclic group, aryl, heteroalkyl, or heteroaryl; each of which may be optionally substituted as defined herein. Examples of acyl include formyl, acetyl, cyclohexylcarbonyl, cyclohexylmethyl-carbonyl, and benzoyl.

[0191] "Acylamino" refers to the "C-acylamino" group (which refers to the group -C(=O)NR y R z ) and the "N-acylamino" group (which refers to the group -NR y C(=O)R z ), where R y and R z are independently selected from hydrogen, alkyl, aryl, halogenated alkyl, or heteroaryl; each of which may be optionally substituted.

[0192] "Amino" refers to the group -NR y R z , where R y and R z are independently selected from hydrogen, alkyl, halogenated alkyl, aryl, or heteroaryl; each of which may be optionally substituted.

[0193] "Aryl" refers to an aromatic carbocyclic group having a single ring (e.g., monocyclic) or multiple rings (e.g., bicyclic or tricyclic) (including fused systems). Aryl as used herein has 6 to 20 ring carbon atoms (i.e., C 6-20(aryl), 6 to 12 carbon ring atoms (i.e., C 6-12 (aryl), or 6 to 10 carbon ring atoms (i.e., C 6-10 (aryl). Examples of aryl include phenyl, naphthyl, fluorenyl, and anthracenyl. However, aryl does not include heteroaryl as defined below or overlap with heteroaryl as defined below in any way. If one or more aryl groups are fused to a heteroaryl ring, the resulting ring system is heteroaryl.

[0194] "Cyano" or "nitrile" means the group -CN.

[0195] "Cycloalkyl" means a saturated or partially saturated cyclic alkyl group having a monocyclic or polycyclic (including fused, bridged, and spiro ring systems). The term "cycloalkyl" includes cycloalkenyl (i.e., the cyclic group has at least one double bond). Cycloalkyl as used herein has 3 to 20 ring carbon atoms (i.e., C 3-20 cycloalkyl), 3 to 12 ring carbon atoms (i.e., C 3-12 cycloalkyl), 3 to 10 ring carbon atoms (i.e., C 3-10 cycloalkyl), 3 to 8 ring carbon atoms (i.e., C 3-8 cycloalkyl), or 3 to 6 ring carbon atoms (i.e., C 3-6 cycloalkyl). Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0196] "Bridged" means ring fusion where non-adjacent atoms on the ring are connected by a divalent substituent such as an alkylene or heteroalkylene or a single heteroatom. Quinuclidinyl and adamantyl are examples of bridged ring systems.

[0197] The term "fused" means a ring that is joined to an adjacent ring.

[0198] "Spiro" means a ring substituent that is connected by two bonds to the same carbon atom. Examples of spiro groups include 1,1-diethylcyclopentane, dimethyl-dioxolane, and 4-benzyl-4-methylpiperidine, where cyclopentane and piperidine are spiro substituents respectively.

[0199] "Halogen" or "halo" includes fluorine, chlorine, bromine, and iodine. "Haloalkyl" means an unbranched or branched alkyl group as defined above, where one or more hydrogen atoms are replaced by halogen. For example, when a residue is substituted with more than one halogen, it may be referred to by using a prefix corresponding to the number of attached halogen moieties. Dihaloalkyl and trihaloalkyl mean an alkyl group substituted with two ("di") or three ("tri") halogen groups, which may be, but need not be, the same halogen. Examples of haloalkyl include difluoromethyl (-CHF 2 ) and trifluoromethyl (-CF 3 ).

[0200] "Heteroalkyl" means an alkyl group in which one or more carbon atoms (and any associated hydrogen atoms) are each independently replaced by the same or different heteroatom groups. The term "heteroalkyl" includes non-branched or branched saturated chains having carbon and heteroatoms. By way of example, 1, 2, or 3 carbon atoms may be independently replaced by the same or different heteroatom groups. Heteroatom groups include, but are not limited to, -NR-, -O-, -S-, -S(O)-, -S(O) 2 -, etc., where R is H, alkyl, aryl, cycloalkyl, heteroalkyl, heteroaryl, or heterocyclic group, each of which may be optionally substituted. Examples of heteroalkyl include -OCH 3 -, -CH 2 OCH 3 -, -SCH 3 -, -CH 2 SCH 3 -, -NRCH 3 -, and -CH 2 NRCH 3 -, where R is hydrogen, alkyl, aryl, arylalkyl, heteroalkyl, or heteroaryl, each of which may be optionally substituted. As used herein, heteroalkyl contains 1-10 carbon atoms, 1-8 carbon atoms, or 1-4 carbon atoms; and 1-3 heteroatoms, 1-2 heteroatoms, or 1 heteroatom.

[0201] "Heteroaryl" means an aromatic group having a single ring, multiple rings, or multiple fused rings, wherein one or more ring heteroatoms are independently selected from nitrogen, oxygen, and sulfur. As described herein, heteroaryl includes 1 to 20 ring carbon atoms (i.e., C 1-20 heteroaryl), 3 to 12 ring carbon atoms (i.e., C 3-12 heteroaryl), or 3 to 8 carbon ring atoms (i.e., C 3-8 heteroaryl); and 1 to 5 heteroatoms, 1 to 4 heteroatoms, 1 to 3 ring heteroatoms, 1 to 2 ring heteroatoms, or 1 ring heteroatom, said ring heteroatoms being independently selected from nitrogen, oxygen, and sulfur. Examples of heteroaryl include pyrimidinyl, purinyl, pyridyl, pyridazinyl, benzothiazolyl, and pyrazolyl. Heteroaryl does not include aryl as defined above or overlap therewith.

[0202] "Heterocyclic group" or "heterocycle" (heterocyclic ring or heterocycle) refers to an unsaturated non-aromatic cyclic alkyl group having one or more ring heteroatoms independently selected from nitrogen, oxygen, and sulfur. The "heterocyclic group" or "heterocycle" used herein refers to a saturated or partially saturated ring, unless otherwise specified. For example, in some embodiments, the "heterocyclic group" or "heterocycle" refers to a partially saturated ring in the specified case. The term "heterocyclic group" or "heterocycle" includes heteroalkenyl (i.e., a heterocyclic group having at least one double bond). The heterocyclic group can be monocyclic or polycyclic, where the polycycle can be fused, bridged, or spiro. The heterocyclic group used herein has 2 to 20 ring carbon atoms (i.e., C 2-20 heterocyclic group), 2 to 12 ring carbon atoms (i.e., C 2-12 heterocyclic group), 2 to 10 ring carbon atoms (i.e., C 2-10 heterocyclic group), 2 to 8 ring carbon atoms (i.e., C 2-8 heterocyclic group), 3 to 12 ring carbon atoms (i.e., C 3-12 heterocyclic group), 3 to 8 ring carbon atoms (i.e., C 3-8 heterocyclic group), or 3 to 6 ring carbon atoms (i.e., C 3-6 heterocyclic group); having 1 to 5 ring heteroatoms, 1 to 4 ring heteroatoms, 1 to 3 ring heteroatoms, 1 to 2 ring heteroatoms, or 1 ring heteroatom, and the ring heteroatoms are independently selected from nitrogen, sulfur, or oxygen. Examples of heterocyclic groups include pyrrolidinyl, piperidinyl, piperazinyl, oxetanyl, dioxolanyl, azetidinyl, and morpholinyl. The term "bridged-heterocyclic group" used herein refers to a 4- to 10-membered cyclic moiety that is connected at two non-adjacent atoms of the heterocyclic group to one or more (e.g., 1 or 2) 4- to 10-membered cyclic moieties having at least one heteroatom, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur. The "bridged-heterocyclic group" used herein includes bicyclic and tricyclic ring systems. In addition, the term "spiro-heterocyclic group" used herein refers to a ring system in which a 3- to 10-membered heterocyclic group has one or more additional rings, where the one or more additional rings are 3- to 10-membered cycloalkyl groups or 3- to 10-membered heterocyclic groups, and a single atom of the one or more additional rings is also an atom of the 3- to 10-membered heterocyclic group. Examples of spiro-heterocyclic groups include bicyclic and tricyclic ring systems, such as 2-oxa-7-azaspiro[3.5]nonyl, 2-oxa-6-azaspiro[3.4]octyl, and 6-oxa-1-azaspiro[3.3]heptyl. As used herein, the terms "heterocycle" and "heterocyclic group" are used interchangeably.

[0203] "Hydroxy" refers to the group -OH.

[0204] "Oxo" refers to the group (=O) or (O).

[0205] "Sulfonyl" means the group -S(O) 2 R, where R is alkyl, haloalkyl, heterocyclic group, cycloalkyl, heteroaryl, or aryl. Examples of sulfonyl groups are methylsulfonyl, ethylsulfonyl, phenylsulfonyl, and toluenesulfonyl.

[0206] Whenever the graphical representation of a group terminates at a single-bonded nitrogen atom, unless otherwise specified, the group represents an -NH group. Similarly, unless otherwise specified, a hydrogen atom is implied or considered to be present according to the knowledge of those skilled in the art to complete the valence or provide stability.

[0207] Some common alternative chemical names may be used. For example, divalent groups such as divalent "alkyl", divalent "aryl", etc. may also be referred to as "alkylene (or alkylenyl)", "arylene (or arylenyl)", respectively. Additionally, unless otherwise defined, in cases where a combination of groups is referred to herein as a moiety (e.g., arylalkyl), the last-mentioned group contains the atom that attaches the moiety to the rest of the molecule.

[0208] The term "optionally" or "optionally" means that the subsequent described event or circumstance may or may not occur, and the description includes the case where the event or circumstance occurs and the case where the event or circumstance does not occur. In addition, the term "optionally substituted" means that any one or more hydrogen atoms on a specified atom or group may be replaced with or without a moiety other than hydrogen.

[0209] The term "substituted" means that any one or more hydrogen atoms on a specified atom or group are replaced by a moiety other than hydrogen, provided that the normal valence of the specified atom is not exceeded. The one or more substituents include, but are not limited to, alkyl, alkenyl, alkynyl, alkoxy, acyl, amino, amido, amidino, aryl, azido, carbamoyl, carboxy, carboxyester, cyano, guanidino, halogen, haloalkyl, heteroalkyl, heteroaryl, heterocyclic, hydroxy, hydrazino, imino, oxo, nitro, alkanesulfinyl, sulfonic acid, alkanesulfonyl, thiocyanate, mercapto, thione, or combinations thereof. Polymers or similar indefinite structures obtained by further defining substituents infinitely with the appended substituents are not contemplated herein (e.g., a substituted aryl having a substituted alkyl, the substituted alkyl itself being substituted with a substituted aryl, the substituted aryl further substituted with a substituted heteroalkyl, etc.). Unless otherwise stated, the maximum number of consecutive substitutions in the compounds described herein is 3. For example, consecutive substitution of a substituted aryl by two other substituted aryls is limited to (substituted aryl)(substituted aryl)substituted aryl. Similarly, the above definitions are not intended to include non-permitted modes of substitution (e.g., a methyl substituted with 5 fluorines or a heteroaryl having two adjacent oxygen ring atoms). These non-permitted modes of substitution are well known to those skilled in the art. When used to modify a chemical group, the term "substituted" may describe other chemical groups defined herein. For example, the term "substituted aryl" includes, but is not limited to, "alkylaryl". Unless otherwise stated, when a group is described as optionally substituted, any substituent of the group is itself unsubstituted.

[0210] In some embodiments, the term "substituted alkyl" refers to an alkyl having one or more substituents, the substituents including hydroxy, halogen, alkoxy, cycloalkyl, heterocyclic, aryl, and heteroaryl. In other embodiments, "substituted cycloalkyl" refers to a cycloalkyl having one or more substituents, the substituents including alkyl, haloalkyl, cycloalkyl, heterocyclic, aryl, heteroaryl, alkoxy, halogen, oxo, and hydroxy; "substituted heterocyclic" refers to a heterocyclic having one or more substituents, the substituents including alkyl, haloalkyl, heterocyclic, cycloalkyl, aryl, heteroaryl, alkoxy, halogen, oxo, and hydroxy; "substituted aryl" refers to an aryl having one or more substituents, the substituents including halogen, alkyl, haloalkyl, cycloalkyl, heterocyclic, heteroaryl, alkoxy, and cyano; "substituted heteroaryl" refers to a heteroaryl having one or more substituents, the substituents including halogen, alkyl, haloalkyl, heterocyclic, heteroaryl, alkoxy, and cyano, and "substituted sulfonyl" refers to the group -S(O) 2R, wherein R is substituted by one or more substituents, said substituents including alkyl, cycloalkyl, heterocyclic group, aryl and heteroaryl. In other embodiments, the one or more substituents may be further substituted by halogen, alkyl, haloalkyl, hydroxy, alkoxy, cycloalkyl, heterocyclic group, aryl or heteroaryl, each of the above groups being substituted. In other embodiments, the substituents may be further substituted by halogen, alkyl, haloalkyl, alkoxy, hydroxy, cycloalkyl, heterocyclic group, aryl or heteroaryl, each of the above groups being unsubstituted.

[0211] Some compounds exist as "tautomers". Tautomers are in equilibrium with each other. For example, a compound containing an amide may exist in equilibrium with an imino acid tautomer. Regardless of which tautomer is shown and regardless of the nature of the equilibrium between the tautomers, one of ordinary skill in the art understands that the compound includes both the amide and imino acid tautomers. Thus, a compound containing an amide should be understood to include its imino acid tautomers. Similarly, a compound containing an imino acid should be understood to include its amide tautomers.

[0212] Any general formula or structure given herein is also intended to represent both the unlabeled form and the isotopically labeled form of the compound. The isotopically labeled compound has the structure described by the general formula given herein, except that one or more atoms are replaced by atoms having a selected atomic mass or mass number. Examples of isotopes that can be incorporated into the compounds of the present disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine, such as, but not limited to 2 H (deuterium, D), 3 H (tritium), 11 C, 13 C, 14 C, 15 N, 18 F, 31 P, 32 P, 35 S, 36 Cl and 125 I. The present invention includes various isotopically labeled compounds of the present invention, such as those compounds incorporating radioactive isotopes such as 3 H, 13 C and 14 C. Such isotopically labeled compounds can be used in metabolic studies, reaction kinetics studies, detection or imaging techniques, such as positron emission tomography (PET) or single photon emission computed tomography (SPECT), including determination of drug or substrate tissue distribution or for radioactive treatment of patients.

[0213] The present disclosure also includes compounds of formula I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, or Ij, wherein 1 to n hydrogens attached to carbon atoms are replaced by deuterium, where n is the number of hydrogen atoms in the molecule. When administered to mammals, especially humans, these compounds exhibit increased antimetabolism, and thus they can be used to increase the half-life of any compound of formula I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, or Ij. See, e.g., Foster, “Deuterium Isotope Effects in Studies of Drug Metabolism,” Trends Pharmacol. Sci. 5(12):524-527 (1984). These compounds can be synthesized by methods known in the art, e.g., by using starting materials in which one or more hydrogens have been replaced by deuterium.

[0214] Deuterium-labeled or -substituted therapeutic compounds of the invention can have improved DMPK (drug metabolism and pharmacokinetics) properties, which relate to absorption, distribution, metabolism, and excretion (ADME). Substitution with a heavier isotope (e.g., deuterium) can provide some therapeutic advantages based on greater metabolic stability, such as increased in vivo half-life, reduced dose requirements, and / or improved therapeutic index. 18 F-labeled compounds can be used for PET or SPECT studies. Isotope-labeled compounds of the invention and their prodrugs are generally prepared by utilizing the procedures or examples described hereinafter and the steps described in the preparations, where the non-isotope-labeled reagents are replaced by readily available isotope-labeled reagents. It is understood that deuterium herein can be regarded as a substituent of the compounds of formula I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, or Ij.

[0215] The concentration of such heavier isotopes (specifically deuterium) can be defined by the isotope enrichment factor. In the compounds of the invention, any atom not specifically designated as a particular isotope means that it represents any stable isotope of that atom. Unless otherwise specified, when a position is specifically designated as "H" or "hydrogen," it should be understood that the position is hydrogen with its natural abundance isotope composition. Thus, in the compounds of the invention, any atom specifically designated as deuterium (D) means deuterium.

[0216] In many cases, due to the presence of amino and / or carboxyl or similar groups, the compounds of the invention are capable of forming acid and / or base salts.

[0217] The term "pharmaceutically acceptable salt" of a given compound refers to salts that retain the biological effectiveness and properties of the given compound and are not biologically or otherwise undesirable. Pharmaceutically acceptable base addition salts can be prepared from inorganic and organic bases. Salts derived from inorganic bases include (by way of example only) sodium, potassium, lithium, ammonium, calcium, and magnesium salts. Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, such as alkyl amines, dialkyl amines, trialkyl amines, substituted alkyl amines, bis(substituted alkyl) amines, tris(substituted alkyl) amines, alkenyl amines, dialkenyl amines, trialkenyl amines, substituted alkenyl amines, bis(substituted alkenyl) amines, tris(substituted alkenyl) amines, monocyclic alkyl amines, bicyclic alkyl amines or tricyclic alkyl amines, monoaryl amines, diaryl amines or triaryl amines, or mixed amines, etc. Specific examples of suitable amines include (by way of example only) isopropylamine, trimethylamine, diethylamine, tris(isopropyl)amine, tris(n-propyl)amine, ethanolamine, 2-dimethylaminoethanol, piperazine, piperidine, morpholine, N-ethylpiperidine, etc.

[0218] Pharmaceutically acceptable acid addition salts can be prepared from inorganic and organic acids. Inorganic acids from which salts can be derived include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc. Organic acids from which salts can be derived include acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, etc.

[0219] As used in the present invention, "pharmaceutically acceptable carrier" or "pharmaceutically acceptable excipient" includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, etc. Such media and agents are well known in the art for use with pharmaceutical active substances. Unless any conventional media or agent is incompatible with the active ingredient, its use in the therapeutic compositions can be expected. Auxiliary active ingredients can also be incorporated into the compositions.

[0220] "Treatment" or "therapy" refers to a method for obtaining a beneficial or desired result, including a clinical result. Beneficial or desired clinical results can include one or more of the following: a) inhibiting a disease or disorder (e.g., reducing one or more symptoms caused by the disease or disorder and / or alleviating the severity of the disease or disorder); b) slowing or preventing the development of one or more clinical symptoms associated with a disease or disorder (e.g., stabilizing the disease or disorder, preventing or delaying the worsening or progression of the disease or disorder, and / or preventing or delaying the spread (e.g., metastasis) of the disease or disorder); and / or c) alleviating the disease, i.e., causing the clinical symptoms to subside (e.g., improving the disease state, providing partial or complete remission of the disease or disorder, enhancing the effectiveness of other drug therapies, delaying disease progression, improving quality of life, and / or prolonging survival).

[0221] "Prevention" or "prophylaxis" refers to any treatment of a disease or disorder that prevents the clinical symptoms of the disease or disorder from occurring. In some embodiments, the compound can be administered to a subject (including a human) at risk of a disease or disorder or having a family history of the disease or disorder.

[0222] "Subject" refers to an animal, such as a mammal (including a human), that has been or will be the subject of treatment, observation, or experimentation. The methods described herein can be used for human therapy and veterinary applications. In some embodiments, the subject is a mammal. In one embodiment, the subject is a human.

[0223] The term "therapeutically effective amount" or "effective amount" of a compound or a pharmaceutically acceptable salt, isomer, or mixture thereof described herein, refers to an amount sufficient to effect treatment when administered to a subject to provide a therapeutic benefit, such as improving symptoms or slowing disease progression. For example, a therapeutically effective amount can be an amount sufficient to reduce the symptoms of a disease or disorder responsive to inhibition of IDO1 activity. The therapeutically effective amount can vary depending on the subject and the disease or disorder being treated, the weight and age of the subject, the severity of the disease or disorder, and the mode of administration, and can be readily determined by one of ordinary skill in the art.

[0224] The term "inhibition" indicates a decrease in the baseline activity of a biological activity or process. "Inhibition of the activity of IDO1" or a variant thereof refers to a decrease in the activity of IDO1 in direct or indirect response to the presence of a compound of the present application relative to the activity of IDO1 in the absence of the compound of the present application. "Inhibition of IDO1" refers to a decrease in the activity of IDO1 in direct or indirect response to the presence of a compound described herein relative to the activity of IDO1 in the absence of the compound described herein. In some embodiments, the inhibition of IDO1 activity can be compared to the same subject prior to treatment or to other subjects not receiving the treatment.

[0225] Compound

[0226] Compounds are provided herein that are useful as IDO1 inhibitors. In one aspect, compounds having the structure of formula (I) are provided:

[0227]

[0228] or a pharmaceutically acceptable salt or pharmaceutically acceptable tautomer thereof.

[0229] In some embodiments, the compound of formula (I) is a compound of formula (Ia):

[0230]

[0231] or a pharmaceutically acceptable salt or pharmaceutically acceptable tautomer thereof.

[0232] In some embodiments, the compound of formula (I) is a compound of formula (Ib):

[0233]

[0234] or a pharmaceutically acceptable salt or pharmaceutically acceptable tautomer thereof.

[0235] In some embodiments, the compound of formula (I) is a compound of formula (Ic):

[0236]

[0237] or a pharmaceutically acceptable salt or pharmaceutically acceptable tautomer thereof.

[0238] In some embodiments, the compound of formula (I) is a compound of formula (Id):

[0239]

[0240] or a pharmaceutically acceptable salt or pharmaceutically acceptable tautomer thereof.

[0241] In some embodiments, the compound of formula (I) is a compound of formula (Ie):

[0242]

[0243] or a pharmaceutically acceptable salt or pharmaceutically acceptable tautomer thereof.

[0244] In some embodiments, the compound of formula (I) is a compound of formula (If):

[0245]

[0246] or a pharmaceutically acceptable salt or pharmaceutically acceptable tautomer thereof.

[0247] In some embodiments, the compound of formula (I) is a compound of formula (Ig):

[0248]

[0249] or a pharmaceutically acceptable salt or pharmaceutically acceptable tautomer thereof.

[0250] In some embodiments, the compound of formula (I) is a compound of formula (Ih):

[0251]

[0252] or a pharmaceutically acceptable salt or pharmaceutically acceptable tautomer thereof.

[0253] In some embodiments, the compound of formula (I) is a compound of formula (Ii):

[0254]

[0255] or a pharmaceutically acceptable salt or pharmaceutically acceptable tautomer thereof.

[0256] In some embodiments, the compound of formula (I) is a compound of formula (Ij):

[0257]

[0258] or a pharmaceutically acceptable salt or pharmaceutically acceptable tautomer thereof.

[0259] The following specific values are values for the compounds of formula (I) and all related general formulas (e.g., Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, and Ij). The following specific values are for the compounds of formula (I) and all related general formulas (e.g., Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, and Ij), or pharmaceutically acceptable salts thereof. It should be understood that two or more values can be combined. Thus, it should be understood that any variable of the compound of formula I can be combined with any other variable of the compound of formula (I), as if each and every combination of the variables was specifically and individually listed. For example, it should be understood that any specific value of R 1 of the compounds of formula (I) described in detail herein can be combined with one or more of the variables X 1 、X 2 、X 3 、X 4 、X 5 、X6 , X 7 , X 8 , Y 1 , Z, R 2 , or R 3 or any other specific combination of values, as if each and all combinations were specifically and individually listed.

[0260] In some embodiments of Formula I, Y 1 is O, and the ring containing X 5 , X 6 , X 7 and X 8 is a monocyclic aryl ring, and ______ is absent. In some embodiments of Formula I, Y 1 is O, and the ring containing X 5 , X 6 , X 7 and X 8 is a monocyclic heteroaryl ring, and ______ is absent. In other embodiments of Formula I, Y 1 is N, and the ring containing X 5 , X 6 , X 7 and X 8 and the ring containing Y 1 together form a bicyclic heteroaryl ring, and ______ represents a single bond.

[0261] In some embodiments of Formula I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, or Ij, X 1 is N. In other embodiments, X 1 is CH. In some embodiments of Formula I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, or Ij, X 2 is N. In other embodiments, X 2 is CH. In some embodiments of Formula I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, or Ij, X 4 is N. In other embodiments, X 4 is CH. In some embodiments of Formula I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, or Ij, X 1 is CH, and X 2 is CH. In some embodiments of Formula I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, or Ij, X 1 is CH, X 2 is CH, and X 4is CH. In some embodiments of Formula I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, or Ij, X 1 is CH, X 2 is CH, and X 4 is N. In some embodiments of Formula I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, or Ij, X 1 is N, X 2 is CH, and X 4 is CH. In some embodiments of Formula I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, or Ij, X 1 is CH, X 2 is N, and X 4 is CH. In some embodiments of Formula I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, or Ij, X 1 is N, X 2 is CH, and X 4 is N. In some embodiments of Formula I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, or Ij, X 1 、X 2 and X 4 both are N, and X 1 、X 2 and X 4 one of them is CH. In some embodiments of Formula I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, or Ij, X 1 、X 2 and X 4 both are CH, and X 1 、X 2 and X 4 one of them is N.

[0262] In some embodiments of Formula I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, or Ij, X 3 is N. In other embodiments, X 3 is CR a where R a is H, halogen, or C 1-4 alkyl. In some embodiments, X 3 is CH. In some embodiments, X 3 is CR a and R a is halogen. For example, in some embodiments, X 3 is C(F), C(Cl), C(Br), or C(I). In some embodiments, X3 is CR a , and R a is C 1-4 alkyl. For example, in some embodiments, X 3 is C(CH 3 ), C(CH 2 CH 3 ), C(CH 2 CH 2 CH 3 ), C(CH(CH 3 )) 2 ), C(CH 2 CH 2 CH 2 CH 3 ), C(CH 2 CH(CH 3 )) 2 ), C(CH(CH 3 )CH 2 CH 3 ), or C(C(CH 3 )) 3 ).

[0263] It should be understood that the description of each X 1 can be combined with the description of each R 1 , R 2 , R 3 , X 2 , X 3 , X 4 , X 5 , X 6 , X 7 , X 8 , Z, and / or Y 1 as if every and all combinations were specifically and individually listed. The description of each X 2 can be combined with the description of each R 1 , R 2 , R 3 , X 1 , X 3 , X 4 , X 5 , X 6 , X 7 , X 8 , Z, and / or Y 1 as if every and all combinations were specifically and individually listed. The description of each X 3 can be combined with the description of each R 1 , R 2 , R 3 , X 1 , X 2 ​4 , X 5 , X 6 , X 7 , X 8 , Z, and / or Y 1 The description combinations of are as if each and all combinations were specifically and individually listed. It should be understood similarly that each X 4 The description of can be combined with each R 1 , R 2 , R 3 , X 1 , X 2 , X 3 , X 5 , X 6 , X 7 , X 8 , Z, and / or Y 1 The description combinations of are as if each and all combinations were specifically and individually listed.

[0264] In some embodiments of Formula I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, or Ij, X 1 is CH, X 2 is CH, and X 3 is CR a , where R a is H, halogen, or C 1-4 alkyl. In some embodiments, X 1 , X 2 , and X 3 are each CH. In some embodiments, X 1 and X 2 are each CH, and X 3 is C(F), C(Cl), C(Br), or C(I). In other embodiments, X 1 and X 2 are each CH, and X 3 is CR a , and R a is C 1-4 alkyl. In some embodiments of Formula I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, or Ij, X 1 is N, X 2 is CH, and X 3 is CR a , where R a is H, halogen, or C 1-4 alkyl. In some embodiments, X 1 is N, X 2 is CH, and X 3 is CH. In some embodiments, X1 is N, X 2 is CH, and X 3 is C(F), C(Cl), C(Br), or C(I). In other embodiments, X 1 is N, X 2 is CH, and X 3 is CR a and R a is C 1-4 alkyl. In some embodiments of Formula I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, or Ij, X 1 is CH, X 2 is N, and X 3 is CR a wherein R a is H, halogen, or C 1-4 alkyl. In some embodiments, X 1 is CH, X 2 is N, and X 3 is CH. In some embodiments, X 1 is CH, X 2 is N, and X 3 is C(F), C(Cl), C(Br), or C(I). In other embodiments, X 1 is CH, X 2 is N, and X 3 is CR a and R a is C 1-4 alkyl. In some embodiments of Formula I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, or Ij, X 1 is N, X 2 is N, and X 3 is CR a wherein R a is H, halogen, or C 1-4 alkyl. In some embodiments, X 1 is N, X 2 is N, and X 3 is CH. In some embodiments, X 1 and X 2 are each N, and X 3 is C(F), C(Cl), C(Br), or C(I). In other embodiments, X 1 and X 2 are each N, and X 3 is CR a and R a is C 1-4 alkyl.

[0265] In some embodiments of Formula I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, or Ij, X 1 is CH, X 2 is CH, and X 3 is N. In some embodiments, X 1 is N, X 2 is CH, and X 3 is N. In some embodiments, X 1 is CH, X 2 is N, and X 3 is N. In some embodiments, X 1 、X 2 、and X 3 are each N.

[0266] In some embodiments of Formula I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, or Ij, X 1 is CH, X 2 is CH, X 4 is CH, and X 3 is CR a , where R a is H, halogen, or C 1-4 alkyl. In some embodiments, X 1 、X 2 、X 4 、and X 3 are each CH. In some embodiments, X 1 is CH, X 2 is CH, X 4 is CH, and X 3 is C(F), C(Cl), C(Br), or C(I). In other embodiments, X 1 is CH, X 2 is CH, X 4 is CH, and X 3 is CR a , and R a is C 1-4 alkyl. In some embodiments of Formula I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, or Ij, X 1 is N, X 2 is CH, X 4 is CH, and X 3 is CR a , where R a is H, halogen, or C 1-4 alkyl. In some embodiments, X 1 is N, X 2is CH, X 4 is CH, and X 3 is CH.

[0267] In some embodiments, X 1 is N, X 2 is CH, X 4 is CH, and X 3 is C(F), C(Cl), C(Br), or C(I). In other embodiments, X 1 is N, X 2 is CH, X 4 is CH, and X 3 is CR a , and R a is C 1-4 alkyl.

[0268] In some embodiments of Formulae I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, or Ij, X 1 is CH, X 2 is N, X 4 is CH, and X 3 is CR a , where R a is H, halogen, or C 1-4 alkyl. In some embodiments, X 1 is CH, X 2 is N, X 4 is CH, and X 3 is CH. In some embodiments, X 1 is CH, X 2 is N, X 4 is CH, and X 3 is C(F), C(Cl), C(Br), or C(I). In other embodiments, X 1 is CH, X 2 is N, X 4 is CH, and X 3 is CR a , and R a is C 1-4 alkyl.

[0269] In some embodiments of Formulae I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, or Ij, X 1 is CH, X 2 is CH, X 4 is N, and X 3 is CR a , where R a is H, halogen, or C 1-4Alkyl. In some embodiments, X 1 is CH, X 2 is CH, X 4 is N, and X 3 is CH. In some embodiments, X 1 is CH, X 2 is CH, X 4 is N, and X 3 is C(F), C(Cl), C(Br), or C(I). In other embodiments, X 1 is CH, X 2 is CH, X 4 is N, and X 3 is CR a , and R a is C 1-4 alkyl.

[0270] In some embodiments of Formula I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, or Ij, X 1 is N, X 2 is N, X 4 is CH, and X 3 is CR a , where R a is H, halogen, or C 1-4 alkyl. In some embodiments, X 1 is N, X 2 is N, X 4 is CH, and X 3 is CH. In some embodiments, X 1 is N, X 2 is N, X 4 is CH, and X 3 is C(F), C(Cl), C(Br), or C(I). In other embodiments, X 1 is N, X 2 is N, X 4 is CH, and X 3 is CR a , and R a is C 1-4 alkyl.

[0271] In some embodiments of Formula I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, or Ij, X 1 is N, X 2 is CH, X 4 is N, where R a is H, halogen, or C 1-4 alkyl. In some embodiments, X 1 is N, X2 is CH, X 4 is N, and X 3 is CH. In some embodiments, X 1 is N, X 2 is CH, X 4 is N, and X 3 is C(F), C(Cl), C(Br), or C(I). In other embodiments, X 1 is N, X 2 is CH, X 4 is N, and X 3 is CR a , and R a is C 1-4 alkyl.

[0272] In some embodiments of Formulae I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, or Ij, X 1 is CH, X 2 is N, X 4 is N, and X 3 is CR a , where R a is H, halogen, or C 1-4 alkyl. In some embodiments, X 1 is CH, X 2 is N, X 4 is N, and X 3 is CH. In some embodiments, X 1 is CH, X 2 is N, X 4 is N, and X 3 is C(F), C(Cl), C(Br), or C(I). In other embodiments, X 1 is CH, X 2 is N, X 4 is N, and X 3 is CR a , and R a is C 1-4 alkyl.

[0273] In some embodiments of Formulae I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, or Ij, X 1 is CH, X 2 is CH, X 4 is CH, and X 3 is N. In some embodiments, X 1 is N, X 2 is CH, X 4 is CH, and X 3is N. In some embodiments, X 1 is CH, X 2 is N, X 4 is CH, and X 3 is N. In some embodiments, X 1 is CH, X 2 is CH, X 4 is N, and X 3 is N. In some embodiments, X 1 is N, X 2 is N, X 4 is CH, and X 3 is N. In some embodiments, X 1 is N, X 2 is CH, X 4 is N, and X 3 is N. In some embodiments, X 1 is CH, X 2 is N, X 4 is N, and X 3 is N. In some embodiments, X 1 , X 2 , X 4 , and X 3 are each N.

[0274] In some embodiments of Formula I, Ia, Ib, Ic, If, Ig, Ih, or Ii, X 5 is N. In some embodiments, X 5 is C. In some embodiments, X 5 is CR b , where R b is H, a halogen, or CN. In some embodiments, X 5 is CH. In some embodiments, X 5 is CR b , and R b is a halogen. For example, in some embodiments, X 5 is C(F), C(Cl), C(Br), or C(I). In other embodiments, X 5 is C(CN). In some embodiments of Formula I, X 5 is C and Y 1 is N. In some embodiments of Formula I, X 5 is N and Y 1 is O. In some embodiments of Formula I, X 5 is CR b and Y 1 is O. In certain embodiments of Formula I, X 5 is CH and Y1 is O. In some embodiments of Formula I, X 5 is C(F) and Y 1 is O. In some embodiments of Formula I, X 5 is C(Cl) and Y 1 is O. In some embodiments of Formula I, X 5 is C(Br) and Y 1 is O. In some embodiments of Formula I, X 5 is C(I) and Y 1 is O. In other embodiments of Formula I, X 5 is C(CN) and Y 1 is O.

[0275] In some embodiments of Formula I, Ia, Ib, Ig, Ih, Ii, or Ij, X 6 is N. In some embodiments, X 6 is CR c where R c is H, halogen, or CN. In some embodiments, X 6 is CH. In some embodiments, X 6 is CR c and R c is halogen. For example, in some embodiments, X 6 is C(F), C(Cl), C(Br), or C(I). In other embodiments, X 6 is C(CN).

[0276] In some embodiments of Formula I, Id, Ie, If, Ig, Ih, Ii, or Ij, X 7 is N. In some embodiments, X 7 is CR d where R d is H, halogen, or CN. In some embodiments, X 7 is CH. In some embodiments, X 7 is CR d and R d is halogen. For example, in some embodiments, X 7 is C(F), C(Cl), C(Br), or C(I). In other embodiments, X 7 is C(CN).

[0277] In some embodiments of Formula I, Ia, Ic, Ie, Ig, Ih, Ii, or Ij, X 8 is N. In some embodiments, X 8 is CR e where Re is H, a halogen, or CN. In some embodiments, X 8 is CH. In some embodiments, X 8 is CR e , and R e is a halogen. For example, in some embodiments, X 8 is C(F), C(Cl), C(Br), or C(I). In other embodiments, X 8 is C(CN).

[0278] In some embodiments of Formula I, Ig, Ih, Ii, or Ij, R 1 is H. In some embodiments, R 1 is a halogen. For example, in some embodiments, R 1 is F. In some embodiments, R 1 is Cl. In some embodiments, R 1 is Br. In other embodiments, R 1 is I. In some embodiments, R 1 is CN.

[0279] In some embodiments of Formula I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, or Ij, R 2 is C 1-6 alkyl. For example, in some embodiments, R 2 is methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, sec-butyl, or tert-butyl. In some embodiments, R 2 is C 1-6 haloalkyl. For example, in some embodiments, R 2 is fluoromethyl, fluoroethyl, trifluoromethyl, difluoromethyl, or trifluoromethyl. In other embodiments, R 2 is C 1-6 haloalkoxy. For example, in some embodiments, R 2 is fluoromethoxy, fluoroethoxy, trifluoromethoxy, difluoromethoxy, or trifluoromethoxy.

[0280] In some embodiments of Formula I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, or Ij, R 3 is C 1-6 alkyl, wherein the C 1-6 alkyl is unsubstituted or substituted with one, two, or three substituents independently selected from: halogen, CN, C 1-6 alkyl, C 1-6 haloalkyl, phenyl, or 5- to 6-membered heteroaryl. In some embodiments, R 3is an unsubstituted C 1-6 alkyl group. For example, in some embodiments, R 3 is methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, sec-butyl, or tert-butyl. In some embodiments, R 3 is a 6- to 12-membered aryl group, wherein the 6- to 12-membered aryl group is unsubstituted or substituted with one, two, or three substituents independently selected from the following: halogen, CN, C 1-6 alkyl, C 1-6 haloalkyl, phenyl, or a 5- to 6-membered heteroaryl group. In some embodiments, R 3 is an unsubstituted 6- to 12-membered aryl group. For example, in some embodiments, R 3 is phenyl or naphthyl. In some embodiments, R 3 is phenyl or naphthyl, substituted with one, two, or three substituents independently selected from the following: halogen, CN, C 1-6 alkyl, C 1-6 haloalkyl, phenyl, or a 5- to 6-membered heteroaryl group. In some embodiments, R 3 is a 5- to 6-membered heteroaryl group, wherein the 5- to 6-membered heteroaryl group is unsubstituted or substituted with one, two, or three substituents independently selected from the following: halogen, CN, C 1-6 alkyl, C 1-6 haloalkyl, phenyl, or a 5- to 6-membered heteroaryl group. For example, in some embodiments, R 3 is pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furyl, isoxazolyl, oxazolyl, oxadiazolyl, thienyl, isothiazolyl, thiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, or tetrazinyl. In some embodiments, R 3 is a 5- to 6-membered heteroaryl group, substituted with one, two, or three substituents independently selected from the following: halogen, CN, C 1-6 alkyl, C 1-6 haloalkyl, phenyl, or a 5- to 6-membered heteroaryl group. In other embodiments, R 3 is a 5- to 12-membered heteroaryl group, wherein the 5- to 12-membered heteroaryl group is unsubstituted or substituted with one, two, or three substituents independently selected from the following: halogen, CN, C 1-6 alkyl, C 1-6 haloalkyl, phenyl, or a 5- to 6-membered heteroaryl group. For example, in some embodiments, R 3is pyridyl, quinolinyl, isoquinolinyl, quinoxalinyl, cinnolinyl, quinazolinyl, phthalazinyl, benzoxazolyl, benzothiazolyl, benzimidazolyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furyl, isoxazolyl, oxazolyl, oxadiazolyl, thienyl, isothiazolyl, thiazolyl, thiadiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, tetrazinyl, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzofuryl, benzoisoxazolyl, benzoxadiazolyl, benzothienyl, benzoisothiazolyl, benzothiadiazolyl, pyrrolopyridyl, pyrazolopyridyl, imidazolopyridyl, triazolopyridyl, furanopyridyl, oxazolopyridyl, isoxazolopyridyl, oxadiazolopyridyl, thienopyridyl, thiazolopyridyl, isothiazolopyridyl, thiadiazolopyridyl, thienopyridyl, phthalazinyl, pyrazolothiazolyl, pyrazolothiazolyl, or imidazolothiazolyl. In some embodiments, R 3 is a 5- to 12-membered heteroaryl, substituted with one, two, or three substituents independently selected from: halogen, CN, C 1-6 alkyl, C 1-6 haloalkyl, phenyl, or 5- to 6-membered heteroaryl.

[0281] In some embodiments of Formula I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, or Ij, R 3 is selected from:

[0282] It should be understood that the description of each R 1 can be combined with the description of each R 2 , R 3 , X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , X 7 , X 8 , Z, and / or Y 1 as if each and every combination was specifically and individually listed. The description of each R 2 can be combined with the description of each R 1 , R 3 , X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , X 7 , X 8 , Z, and / or Y 1The description of the combinations is as if each and all combinations were specifically and individually listed. Each R 3 description can be combined with each R 1 、R 2 、X 1 、X 2 、X 3 、X 4 、X 5 、X 6 、X 7 、X 8 、Z、and / or Y 1 The description of the combinations is as if each and all combinations were specifically and individually listed. It should be similarly understood that the description of each Z can be combined with each R 1 、R 2 、R 3 、X 1 、X 2 、X 3 、X 4 、X 5 、X 6 、X 7 、X 8 、and / or Y 1 The description of the combinations is as if each and all combinations were specifically and individually listed.

[0283] In some embodiments of Formula I, Ig, Ih, Ii, or Ij, R 1 is H and R 2 is C 1-6 alkyl. For example, in some embodiments, R 1 is H and R 2 is methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, sec-butyl, or tert-butyl. In some embodiments, R 1 is H and R 2 is C 1-6 haloalkyl. For example, in some embodiments, R 1 is H and R 2 is fluoromethyl, fluoroethyl, trifluoromethyl, difluoromethyl, or trifluoromethyl. In other embodiments, R 1 is H and R 2 is C 1-6 haloalkoxy. For example, in some embodiments, R 1 is H and R 2 is fluoromethoxy, fluoroethoxy, trifluoromethoxy, difluoromethoxy, or trifluoromethoxy. In some embodiments, R 1 is halogen or CN; and R 2 is C 1-6 alkyl. In some embodiments, R 1is halogen or CN; and R 2 is C 1-6 haloalkyl. In other embodiments, R 1 is halogen or CN; and R 2 is C 1-6 haloalkoxy.

[0284] In some embodiments of Formula I, Ig, Ih, Ii, or Ij, R 1 is H, R 2 is C 1-6 alkyl, and R 3 is C 1-3 alkyl, wherein the C 3 alkyl of R 1-3 is unsubstituted or substituted with one, two, or three substituents independently selected from: halogen, CN, C 1-6 alkyl, C 1-6 haloalkyl, phenyl, or 5- to 6-membered heteroaryl. In some embodiments, R 1 is H, R 2 is C 1-6 alkyl, and R 3 is 6- to 12-membered aryl, wherein the 6- to 12-membered aryl of R 3 is unsubstituted or substituted with one, two, or three substituents independently selected from: halogen, CN, C 1-6 alkyl, C 1-6 haloalkyl, phenyl, or 5- to 6-membered heteroaryl. In some embodiments, R 1 is H, R 2 is C 1-6 alkyl, and R 3 is 5- to 12-membered heteroaryl, wherein the 5- to 12-membered heteroaryl of R 3 is unsubstituted or substituted with one, two, or three substituents independently selected from: halogen, CN, C 1-6 alkyl, C 1-6 haloalkyl, phenyl, or 5- to 6-membered heteroaryl.

[0285] In some embodiments of Formula I, Ig, Ih, Ii, or Ij, R 1 is H, R 2 is C 1-6 haloalkyl, and R 3 is C 1-3 alkyl, wherein the C 3 alkyl of R 1-3 is unsubstituted or substituted with one, two, or three substituents independently selected from: halogen, CN, C 1-6 alkyl, C 1-6Halogenoalkyl, phenyl, or 5- to 6-membered heteroaryl. In some embodiments, R 1 is H, R 2 is C 1-6 halogenoalkyl, and R 3 is 6- to 12-membered aryl, wherein said 6- to 12-membered aryl of R 3 is unsubstituted or substituted with one, two, or three substituents independently selected from: halogen, CN, C 1-6 alkyl, C 1-6 halogenoalkyl, phenyl, or 5- to 6-membered heteroaryl. In some embodiments, R 1 is H, R 2 is C 1-6 halogenoalkyl, and R 3 is 5- to 12-membered heteroaryl, wherein said 5- to 12-membered heteroaryl of R 3 is unsubstituted or substituted with one, two, or three substituents independently selected from: halogen, CN, C 1-6 alkyl, C 1-6 halogenoalkyl, phenyl, or 5- to 6-membered heteroaryl.

[0286] In some embodiments of Formula I, Ig, Ih, Ii, or Ij, R 1 is H, R 2 is C 1-6 halogenoalkoxy, and R 3 is C 1-3 alkyl, wherein said C 3 alkyl of R 1-3 is unsubstituted or substituted with one, two, or three substituents independently selected from: halogen, CN, C 1-6 alkyl, C 1-6 halogenoalkyl, phenyl, or 5- to 6-membered heteroaryl. In some embodiments, R 1 is H, R 2 is C 1-6 halogenoalkoxy, and R 3 is 6- to 12-membered aryl, wherein said 6- to 12-membered aryl of R 3 is unsubstituted or substituted with one, two, or three substituents independently selected from: halogen, CN, C 1-6 alkyl, C 1-6 halogenoalkyl, phenyl, or 5- to 6-membered heteroaryl. In some embodiments, R 1 is H, R 2 is C 1-6 halogenoalkoxy, and R 3 is 5- to 12-membered heteroaryl, wherein said R 3The 5- to 12-membered heteroaryl is unsubstituted or substituted with one, two or three substituents independently selected from the following: halogen, CN, C 1-6 alkyl, C 1-6 haloalkyl, phenyl, or 5- to 6-membered heteroaryl.

[0287] In some embodiments of Formula I, Ig, Ih, Ii, or Ij, R 1 is halogen or CN; R 2 is C 1-6 alkyl; and R 3 is C 1-3 alkyl, where the C 3 alkyl of R 1-3 is unsubstituted or substituted with one, two or three substituents independently selected from the following: halogen, CN, C 1-6 alkyl, C 1-6 haloalkyl, phenyl, or 5- to 6-membered heteroaryl. In some embodiments, R 1 is halogen or CN, R 2 is C 1-6 alkyl, and R 3 is 6- to 12-membered aryl, where the 6- to 12-membered aryl of R 3 is unsubstituted or substituted with one, two or three substituents independently selected from the following: halogen, CN, C 1-6 alkyl, C 1-6 haloalkyl, phenyl, or 5- to 6-membered heteroaryl. In some embodiments, R 1 is halogen or CN, R 2 is C 1-6 alkyl, and R 3 is 5- to 12-membered heteroaryl, where the 5- to 12-membered heteroaryl of R 3 is unsubstituted or substituted with one, two or three substituents independently selected from the following: halogen, CN, C 1-6 alkyl, C 1-6 haloalkyl, phenyl, or 5- to 6-membered heteroaryl. In some embodiments of Formula I, Ig, Ih, Ii, or Ij, R 1 is halogen or CN; R 2 is C 1-6 haloalkyl; and R 3 is C 1-3 alkyl, where the C 3 alkyl of R 1-3 is unsubstituted or substituted with one, two or three substituents independently selected from the following: halogen, CN, C 1-6 alkyl, C 1-6 haloalkyl, phenyl, or 5- to 6-membered heteroaryl. In some embodiments, R 1 is halogen or CN, R2 is C 1-6 haloalkyl, and R 3 is a 6- to 12-membered aryl, wherein the R 3 of said 6- to 12-membered aryl is unsubstituted or substituted with one, two or three substituents independently selected from the following: halogen, CN, C 1-6 alkyl, C 1-6 haloalkyl, phenyl, or 5- to 6-membered heteroaryl. In some embodiments, R 1 is halogen or CN, R 2 is C 1-6 haloalkyl, and R 3 is a 5- to 12-membered heteroaryl, wherein the R 3 of said 5- to 12-membered heteroaryl is unsubstituted or substituted with one, two or three substituents independently selected from the following: halogen, CN, C 1-6 alkyl, C 1-6 haloalkyl, phenyl, or 5- to 6-membered heteroaryl. In some embodiments of Formula I, Ig, Ih, Ii, or Ij, R 1 is halogen or CN; R 2 is C 1-6 haloalkoxy; and R 3 is C 1-3 alkyl, wherein the R 3 of said C 1-3 alkyl is unsubstituted or substituted with one, two or three substituents independently selected from the following: halogen, CN, C 1-6 alkyl, C 1-6 haloalkyl, phenyl, or 5- to 6-membered heteroaryl. In some embodiments, R 1 is halogen or CN, R 2 is C 1-6 haloalkoxy, and R 3 is a 6- to 12-membered aryl, wherein the R 3 of said 6- to 12-membered aryl is unsubstituted or substituted with one, two or three substituents independently selected from the following: halogen, CN, C 1-6 alkyl, C 1-6 haloalkyl, phenyl, or 5- to 6-membered heteroaryl. In some embodiments, R 1 is halogen or CN, R 2 is C 1-6 haloalkoxy, and R 3 is a 5- to 12-membered heteroaryl, wherein the R 3 of said 5- to 12-membered heteroaryl is unsubstituted or substituted with one, two or three substituents independently selected from the following: halogen, CN, C 1-6 alkyl, C 1-6 haloalkyl, phenyl, or 5- to 6-membered heteroaryl.

[0288] In some embodiments of Formula I, Ia, Ib, Ic, Id, If, Ig, Ih, Ii, or Ij, R 2 is C 1-6 alkyl and R 3 is C 1-6 alkyl, wherein the C 1-6 alkyl is unsubstituted or substituted with one, two or three substituents independently selected from: halogen, CN, C 1-6 alkyl, C 1-6 haloalkyl, phenyl, or 5-6 membered heteroaryl. In some embodiments, R 2 is C 1-6 alkyl and R 3 is methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, sec-butyl, or tert-butyl. In some embodiments, R 2 is C 1-6 alkyl and R 3 is a 6-12 membered aryl, wherein the 6-12 membered aryl is unsubstituted or substituted with one, two or three substituents independently selected from: halogen, CN, C 1-6 alkyl, C 1-6 haloalkyl, phenyl, or 5-6 membered heteroaryl. In some embodiments, R 2 is C 1-6 alkyl and R 3 is phenyl or naphthyl, wherein the phenyl or naphthyl is unsubstituted or substituted with one, two or three substituents independently selected from: halogen, CN, C 1-6 alkyl, C 1-6 haloalkyl, phenyl, or 5-6 membered heteroaryl. In some embodiments, R 2 is C 1-6 alkyl and R 3 is a 5-6 membered heteroaryl, wherein the 5-6 membered heteroaryl is unsubstituted or substituted with one, two or three substituents independently selected from: halogen, CN, C 1-6 alkyl, C 1-6 haloalkyl, phenyl, or 5-6 membered heteroaryl. In some embodiments, R 2 is C 1-6 alkyl and R 3 is pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furyl, isoxazolyl, oxazolyl, oxadiazolyl, thienyl, isothiazolyl, thiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, or tetrazinyl, each of which is unsubstituted or substituted with one, two or three substituents independently selected from: halogen, CN, C 1-6 alkyl, C 1-6A haloalkyl group, a phenyl group, or a 5- or 6-membered heteroaryl group. In some embodiments, R 2 is C 1-6 alkyl and R 3 is a 5- or 6-membered heteroaryl group, substituted with one, two, or three substituents independently selected from: halogen, CN, C 1-6 alkyl, C 1-6 haloalkyl, phenyl, or a 5- or 6-membered heteroaryl group. In other embodiments, R 2 is C 1-6 alkyl and R 3 is a 5- to 12-membered heteroaryl group, wherein the 5- to 12-membered heteroaryl group is unsubstituted or substituted with one, two, or three substituents independently selected from: halogen, CN, C 1-6 alkyl, C 1-6 haloalkyl, phenyl, or a 5- or 6-membered heteroaryl group. In some embodiments, R 2 is C 1-6 alkyl and R 3 is pyridyl, quinolinyl, isoquinolinyl, quinoxalinyl, cinnolinyl, quinazolinyl, phthalazinyl, benzoxazolyl, benzothiazolyl, benzimidazolyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furyl, isoxazolyl, oxazolyl, oxadiazolyl, thienyl, isothiazolyl, thiazolyl, thiadiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, tetrazinyl, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzofuryl, benzoisoxazolyl, benzoxadiazolyl, benzothienyl, benzoisothiazolyl, benzothiadiazolyl, pyrrolopyridyl, pyrazolopyridyl, imidazolopyridyl, triazolopyridyl, furanopyridyl, oxazolopyridyl, isoxazolopyridyl, oxadiazolopyridyl, thienopyridyl, thiazolopyridyl, isothiazolopyridyl, thiadiazolopyridyl, thienopyridyl, phthalazinyl, pyrazolothiazolyl, pyrazolothiazolyl, or imidazolothiazolyl, each of which is unsubstituted or substituted with one, two, or three substituents independently selected from: halogen, CN, C 1-6 alkyl, C 1-6 haloalkyl, phenyl, or a 5- or 6-membered heteroaryl group. In some embodiments, R 2 is selected from: methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, sec-butyl, and tert-butyl; and R 3 is selected from:

[0289] In some embodiments of Formula I, Ia, Ib, Ic, Id, If, Ig, Ih, Ii, or Ij, R 2 is C 1-6 haloalkyl and R3 is C 1-6 alkyl, wherein said C 1-6 alkyl is unsubstituted or substituted with one, two or three substituents independently selected from: halogen, CN, C 1-6 alkyl, C 1-6 haloalkyl, phenyl, or 5-6 membered heteroaryl. In some embodiments, R 2 is C 1-6 haloalkyl and R 3 is methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, sec-butyl, or tert-butyl. In some embodiments, R 2 is C 1-6 haloalkyl and R 3 is a 6-12 membered aryl, wherein said 6-12 membered aryl is unsubstituted or substituted with one, two or three substituents independently selected from: halogen, CN, C 1-6 alkyl, C 1-6 haloalkyl, phenyl, or 5-6 membered heteroaryl. In some embodiments, R 2 is C 1-6 haloalkyl and R 3 is phenyl or naphthyl, wherein said phenyl or naphthyl is unsubstituted or substituted with one, two or three substituents independently selected from: halogen, CN, C 1-6 alkyl, C 1-6 haloalkyl, phenyl, or 5-6 membered heteroaryl. In some embodiments, R 2 is C 1-6 haloalkyl and R 3 is a 5-6 membered heteroaryl, wherein said 5-6 membered heteroaryl is unsubstituted or substituted with one, two or three substituents independently selected from: halogen, CN, C 1-6 alkyl, C 1-6 haloalkyl, phenyl, or 5-6 membered heteroaryl. In some embodiments, R 2 is C 1-6 haloalkyl and R 3 is pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furyl, isoxazolyl, oxazolyl, oxadiazolyl, thienyl, isothiazolyl, thiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, or tetrazinyl, each of these substituents being unsubstituted or substituted with one, two or three substituents independently selected from: halogen, CN, C 1-6 alkyl, C 1-6 haloalkyl, phenyl, or 5-6 membered heteroaryl. In some embodiments, R 2 is C 1-6 haloalkyl and R 3is a 5- or 6-membered heteroaryl, substituted with one, two or three substituents independently selected from: halogen, CN, C 1-6 alkyl, C 1-6 haloalkyl, phenyl, or 5- or 6-membered heteroaryl. In other embodiments, R 2 is C 1-6 haloalkyl and R 3 is a 5- to 12-membered heteroaryl, wherein the 5- to 12-membered heteroaryl is unsubstituted or substituted with one, two or three substituents independently selected from: halogen, CN, C 1-6 alkyl, C 1-6 haloalkyl, phenyl, or 5- or 6-membered heteroaryl. In some embodiments, R 2 is C 1-6 haloalkyl and R 3 is pyridyl, quinolinyl, isoquinolinyl, quinoxalinyl, cinnolinyl, quinazolinyl, phthalazinyl, benzoxazolyl, benzothiazolyl, benzimidazolyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furyl, isoxazolyl, oxazolyl, oxadiazolyl, thienyl, isothiazolyl, thiazolyl, thiadiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, tetrazinyl, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzofuryl, benzisoxazolyl, benzoxadiazolyl, benzothienyl, benzisothiazolyl, benzothiadiazolyl, pyrrolopyridyl, pyrazolopyridyl, imidazolopyridyl, triazolopyridyl, furanopyridyl, oxazolopyridyl, isoxazolopyridyl, oxadiazolopyridyl, thienopyridyl, thiazolopyridyl, isothiazolopyridyl, thiadiazolopyridyl, thienopyridyl, phthalazinyl, pyrazolothiazolyl, pyrazolothiazolyl, or imidazolothiazolyl, each of these substituents being unsubstituted or substituted with one, two or three substituents independently selected from: halogen, CN, C 1-6 alkyl, C 1-6 haloalkyl, phenyl, or 5- or 6-membered heteroaryl. In some embodiments, R 2 is selected from: fluoromethyl, fluoroethyl, trifluoromethyl, difluoromethyl, and trifluoromethyl; and R 3 is selected from:

[0290] In some embodiments of formula I, Ia, Ib, Ic, Id, If, Ig, Ih, Ii, or Ij, R 2 is C 1-6 haloalkoxy and R 3 is C 1-6 alkyl, wherein the C 1-6The alkyl group is unsubstituted or substituted with one, two or three substituents independently selected from the following: halogen, CN, C 1-6 alkyl, C 1-6 haloalkyl, phenyl, or 5- or 6-membered heteroaryl. In some embodiments, R 2 is C 1-6 haloalkoxy and R 3 is methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, sec-butyl, or tert-butyl. In some embodiments, R 2 is C 1-6 haloalkoxy and R 3 is a 6- to 12-membered aryl group, wherein the 6- to 12-membered aryl group is unsubstituted or substituted with one, two or three substituents independently selected from the following: halogen, CN, C 1-6 alkyl, C 1-6 haloalkyl, phenyl, or 5- or 6-membered heteroaryl. In some embodiments, R 2 is C 1-6 haloalkoxy and R 3 is phenyl or naphthyl, wherein the phenyl or naphthyl is unsubstituted or substituted with one, two or three substituents independently selected from the following: halogen, CN, C 1-6 alkyl, C 1-6 haloalkyl, phenyl, or 5- or 6-membered heteroaryl. In some embodiments, R 2 is C 1-6 haloalkoxy and R 3 is a 5- or 6-membered heteroaryl group, wherein the 5- or 6-membered heteroaryl group is unsubstituted or substituted with one, two or three substituents independently selected from the following: halogen, CN, C 1-6 alkyl, C 1-6 haloalkyl, phenyl, or 5- or 6-membered heteroaryl. In some embodiments, R 2 is C 1-6 haloalkoxy and R 3 is pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furyl, isoxazolyl, oxazolyl, oxadiazolyl, thienyl, isothiazolyl, thiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, or tetrazinyl, each of these substituents being unsubstituted or substituted with one, two or three substituents independently selected from the following: halogen, CN, C 1-6 alkyl, C 1-6 haloalkyl, phenyl, or 5- or 6-membered heteroaryl. In some embodiments, R 2 is C 1-6 haloalkoxy and R 3 is a 5- or 6-membered heteroaryl group, substituted with one, two or three substituents independently selected from the following: halogen, CN, C 1-6 alkyl, C1-6 a haloalkyl, phenyl, or 5- to 6-membered heteroaryl. In other embodiments, R 2 is C 1-6 a haloalkoxy and R 3 is a 5- to 12-membered heteroaryl, wherein the 5- to 12-membered heteroaryl is unsubstituted or substituted with one, two, or three substituents independently selected from: halogen, CN, C 1-6 alkyl, C 1-6 a haloalkyl, phenyl, or 5- to 6-membered heteroaryl. In some embodiments, R 2 is C 1-6 a haloalkoxy and R 3 is pyridyl, quinolinyl, isoquinolinyl, quinoxalinyl, cinnolinyl, quinazolinyl, phthalazinyl, benzoxazolyl, benzothiazolyl, benzimidazolyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furyl, isoxazolyl, oxazolyl, oxadiazolyl, thienyl, isothiazolyl, thiazolyl, thiadiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, tetrazinyl, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzofuryl, benzoisoxazolyl, benzoxadiazolyl, benzothienyl, benzoisothiazolyl, benzothiadiazolyl, pyrrolopyridyl, pyrazolopyridyl, imidazolopyridyl, triazolopyridyl, furanopyridyl, oxazolopyridyl, isoxazolopyridyl, oxadiazolopyridyl, thienopyridyl, thiazolopyridyl, isothiazolopyridyl, thiadiazolopyridyl, thienopyridyl, phthalazinyl, pyrazolothiazolyl, pyrazolothiazolyl, or imidazolothiazolyl, each of which is unsubstituted or substituted with one, two, or three substituents independently selected from: halogen, CN, C 1-6 alkyl, C 1-6 a haloalkyl, phenyl, or 5- to 6-membered heteroaryl. In some embodiments, R 2 is selected from: fluoromethoxy, fluoroethoxy, trifluoromethoxy, difluoromethoxy, and trifluoromethoxy; and R 3 is selected from:

[0291] In some embodiments of Formula I or Ij, Z is C(Z a )(Z b )(e.g., ), wherein Z a and Z b are independently H or C 1-4 alkyl. In some embodiments, Z is C(Z a )(Z b ), wherein Z a and Z bOne of them is H and the other is C 1-4 alkyl. For example, in some embodiments, Z is C(Z a )(Z b ), where one of Z a and Z b is H and the other is methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, sec-butyl, or tert-butyl. In some embodiments, Z is C(Z a )(Z b ), where Z a and Z b are each C 1-4 alkyl. For example, in some embodiments, Z is C(Z a )(Z b ), where Z a and Z b are each independently methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, sec-butyl, or tert-butyl. In some embodiments, Z is CH 2 . In some embodiments, Z is C(Z a )(Z b ), where Z a and Z b together with the carbon to which they are attached form a 3- to 5-membered carbon ring. For example, in some embodiments, Z is C(Z a )(Z b ), where Z a and Z b together with the carbon to which they are attached form a 3-membered carbon ring, 4-membered carbon ring, or 5-membered carbon ring.

[0292] In some embodiments of Formula I or Ij, Z is OC(Z a )(Z b ) (for example, ), where Z a and Z b are independently H or C 1-4 alkyl. In some embodiments, Z is OC(Z a )(Z b ), where one of Z a and Z b is H and the other is C 1-4 alkyl. For example, in some embodiments, Z is OC(Z a )(Z b ), where one of Z a and Z b is H and the other is methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, sec-butyl, or tert-butyl. In some embodiments, Z is OC(Z a )(Zb ), wherein Z a and Z b are each C 1-4 alkyl. For example, in some embodiments, Z is OC(Z a )(Z b ), wherein Z a and Z b are each independently methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, sec-butyl, or tert-butyl. In some embodiments, Z is CH 2 . In some embodiments, Z is OC(Z a )(Z b ), wherein Z a and Z b together with the carbon to which they are attached form a 3- to 5-membered carbon ring. For example, in some embodiments, Z is OC(Z a )(Z b ), wherein Z a and Z b together with the carbon to which they are attached form a 3-membered carbon ring, a 4-membered carbon ring, or a 5-membered carbon ring.

[0293] In some embodiments of Formula I or Ij, Z is NH. In other embodiments, Z is O.

[0294] In one embodiment, the compounds of the present disclosure are selected from the following compounds or pharmaceutically acceptable salts or pharmaceutically acceptable tautomers thereof:

[0295]

[0296]

[0297]

[0298]

[0299] The compounds or pharmaceutically acceptable salts or pharmaceutically acceptable tautomers thereof may also be included in the compositions or kits described herein, or used in any of the methods described herein.

[0300] In one embodiment, the compounds of the present disclosure are selected from the following compounds or pharmaceutically acceptable salts or pharmaceutically acceptable tautomers thereof:

[0301]

[0302]

[0303]

[0304] The compound or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable tautomer thereof may also be included in the compositions or kits described herein or used in any method described herein.

[0305] In one embodiment, the compounds of the present disclosure are selected from the following compounds or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable tautomer thereof:

[0306]

[0307]

[0308] The compound or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable tautomer thereof may also be included in the compositions or kits described herein or used in any method described herein.

[0309] In one embodiment, the compounds of the present disclosure are selected from the following compounds or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable tautomer thereof:

[0310]

[0311] The compound or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable tautomer thereof may also be included in the compositions or kits described herein or used in any method described herein.

[0312] In one embodiment, the compounds of the present disclosure are selected from the following compounds or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable tautomer thereof:

[0313]

[0314] The compound or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable tautomer thereof may also be included in the compositions or kits described herein or used in any method described herein.

[0315] In one embodiment, the compounds of the present disclosure are selected from the following compounds or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable tautomer thereof:

[0316]

[0317] The compound or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable tautomer thereof may also be included in the compositions or kits described herein or used in any method described herein.

[0318] In one embodiment, the compounds of the present disclosure are selected from the following compounds or pharmaceutically acceptable salts or pharmaceutically acceptable tautomers thereof:

[0319]

[0320]

[0321]

[0322] The compounds or pharmaceutically acceptable salts or pharmaceutically acceptable tautomers thereof may also be included in the compositions or kits described herein or used in any of the methods described herein.

[0323] In one embodiment, the compounds of the present disclosure are selected from the following compounds or pharmaceutically acceptable salts or pharmaceutically acceptable tautomers thereof:

[0324]

[0325] The compounds or pharmaceutically acceptable salts or pharmaceutically acceptable tautomers thereof may also be included in the compositions or kits described herein or used in any of the methods described herein.

[0326] In one embodiment, the compounds of the present disclosure are selected from the following compounds or pharmaceutically acceptable salts or pharmaceutically acceptable tautomers thereof:

[0327]

[0328] The compounds or pharmaceutically acceptable salts or pharmaceutically acceptable tautomers thereof may also be included in the compositions or kits described herein or used in any of the methods described herein.

[0329] In one embodiment, the compounds of the present disclosure are selected from the following compounds or pharmaceutically acceptable salts or pharmaceutically acceptable tautomers thereof:

[0330]

[0331]

[0332]

[0333] The compounds or pharmaceutically acceptable salts or pharmaceutically acceptable tautomers thereof may also be included in the compositions or kits described herein or used in any of the methods described herein.

[0334] In one embodiment, the compounds of the present disclosure are selected from the following compounds or pharmaceutically acceptable salts or pharmaceutically acceptable tautomers thereof:

[0335]

[0336] The compound or its pharmaceutically acceptable salt or its pharmaceutically acceptable tautomer may also be included in the compositions or kits described herein, or used in any method described herein.

[0337] In one embodiment, the compounds of the present disclosure are selected from the following compounds or pharmaceutically acceptable salts or pharmaceutically acceptable tautomers thereof:

[0338]

[0339] The compound or its pharmaceutically acceptable salt or its pharmaceutically acceptable tautomer may also be included in the compositions or kits described herein, or used in any method described herein.

[0340] In some embodiments, the compounds of the present disclosure are the following compounds, or pharmaceutically acceptable salts or pharmaceutically acceptable tautomers thereof:

[0341]

[0342] The compound or its pharmaceutically acceptable salt or its pharmaceutically acceptable tautomer may also be included in the compositions or kits described herein, or used in any method described herein.

[0343] In some embodiments, the compounds of the present disclosure are the following compounds, or pharmaceutically acceptable salts or pharmaceutically acceptable tautomers thereof:

[0344]

[0345] The compound or its pharmaceutically acceptable salt or its pharmaceutically acceptable tautomer may also be included in the compositions or kits described herein, or used in any method described herein.

[0346] In some embodiments, the compounds of the present disclosure are the following compounds, or pharmaceutically acceptable salts or pharmaceutically acceptable tautomers thereof:

[0347]

[0348] The compound or its pharmaceutically acceptable salt or its pharmaceutically acceptable tautomer may also be included in the compositions or kits described herein, or used in any method described herein.

[0349] In some embodiments, the compounds of the present disclosure are the following compounds, or pharmaceutically acceptable salts or pharmaceutically acceptable tautomers thereof:

[0350]

[0351] The compound or its pharmaceutically acceptable salt or its pharmaceutically acceptable tautomer may also be included in the compositions or kits described herein, or used in any of the methods described herein.

[0352] In some embodiments, the compounds of the present disclosure are the following compounds, or pharmaceutically acceptable salts or pharmaceutically acceptable tautomers thereof:

[0353]

[0354] The compound or its pharmaceutically acceptable salt or its pharmaceutically acceptable tautomer may also be included in the compositions or kits described herein, or used in any of the methods described herein.

[0355] In some embodiments, the compounds of the present disclosure are the following compounds, or pharmaceutically acceptable salts or pharmaceutically acceptable tautomers thereof:

[0356]

[0357] The compound or its pharmaceutically acceptable salt or its pharmaceutically acceptable tautomer may also be included in the compositions or kits described herein, or used in any of the methods described herein.

[0358] Also provided herein are the compounds or pharmaceutically acceptable salts, isomers or mixtures thereof described herein, wherein 1 - n hydrogen atoms attached to carbon atoms may be replaced by deuterium atoms or D, where n is the number of hydrogen atoms on the molecule. As is known in the art, deuterium atoms are non-radioactive isotopes of hydrogen atoms. Such compounds can increase antimetabolism and, thus, when administered to a mammal, can be used to increase the half-life of the compounds or pharmaceutically acceptable salts, isomers or mixtures thereof described herein. See, e.g., Foster, “Deuterium Isotope Effects in Studies of Drug Metabolism”, Trends Pharmacol. Sci., 5(12):524 - 527(1984). Such compounds are synthesized by means well known in the art, such as by using starting materials in which one or more hydrogen atoms have been replaced by deuterium.

[0359] Also provided are pharmaceutically acceptable salts, hydrates, solvates, tautomeric forms, polymorphs, and prodrugs of the compounds described herein. "Pharmaceutically acceptable" or "physiologically acceptable" refers to compounds, salts, compositions, dosage forms, and other substances that are suitable for the preparation of pharmaceutical compositions for veterinary or human medical use. "Pharmaceutically acceptable salts" or "physiologically acceptable salts" include, for example, salts formed with inorganic acids and salts formed with organic acids. Further, if the compounds described herein are obtained in the form of acid addition salts, the free base can be obtained by alkalizing the acid salt solution. Conversely, if the product is a free base, an addition salt, specifically a pharmaceutically acceptable addition salt, can be produced by dissolving the free base in a suitable organic solvent and treating the solution with an acid according to conventional procedures for preparing acid addition salts from basic compounds. Those skilled in the art will appreciate the various synthetic methods available for preparing non-toxic pharmaceutically acceptable addition salts.

[0360] "Solvates" are formed by the interaction of a solvent and a compound. Solvates of salts of the compounds described herein are also provided. Hydrates of the compounds are also provided.

[0361] "Prodrug" is a biologically inactive derivative of a drug that is converted into a biologically active parent drug in the body after administration by some chemical or enzymatic pathway.

[0362] In some embodiments, provided are optical isomers, racemates, or other mixtures of the compounds described herein or their pharmaceutically acceptable salts or mixtures thereof. In those cases, the single enantiomers or diastereomers (i.e., the optically active forms) can be obtained by asymmetric synthesis or by resolution of the racemate. Resolution of the racemate can be achieved by, for example, conventional methods such as crystallization in the presence of a resolving agent, or chromatography, using, for example, a chiral high performance liquid chromatography (HPLC) column. Further, the Z- and E-forms (or cis- and trans-forms) of the hydroxyamidine compounds described herein are also provided. Specifically, even if only one name is given for the carbon-carbon double bond as well as the hydroxyamidine bond, both the Z- and E-forms are included.

[0363] In cases where chirality is not specified but chirality is present, it is understood that the embodiment is directed to a specific diastereomeric or enantiomerically enriched form; or a racemic or scalemic mixture of such compounds.

[0364] "Enantiomers" are a pair of stereoisomers that are non-superimposable mirror images of each other. A 1:1 mixture of a pair of enantiomers is a "racemic" mixture. A mixture in which the ratio of enantiomers is not 1:1 is a "scalemic" mixture.

[0365] "Diastereomers" are stereoisomers that have at least two asymmetric atoms and are not mirror images of each other.

[0366] The compositions provided herein that contain a compound described herein or a pharmaceutically acceptable salt, isomer, or mixture thereof can include a racemic mixture, a mixture with an enantiomeric excess of one enantiomer, or a single diastereomer or a mixture of diastereomers. All such isomeric forms of these compounds are expressly included herein as if each and every isomeric form were specifically and individually recited.

[0367] In some embodiments, crystalline and amorphous forms of the compounds described herein or pharmaceutically acceptable salts, isomers, or mixtures thereof are also provided herein.

[0368] In some embodiments, chelates, non-covalent complexes, and mixtures thereof of the compounds described herein or pharmaceutically acceptable salts, isomers, or mixtures thereof are also provided. A "chelate" is formed by coordinating a compound to a metal ion at two (or more) points. A "non-covalent complex" is formed by the interaction of a compound with another molecule, where no covalent bond is formed between the compound and the molecule. For example, complexation can occur through van der Waals interactions, hydrogen bonding, and electrostatic interactions (also referred to as ionic bonding).

[0369] Therapeutic Uses of Compounds

[0370] The methods described herein can be applied to in vivo or ex vivo cell populations. "In vivo" means within a living individual, such as in an animal or a human. In context, the methods described herein can be used therapeutically in an individual. "Ex vivo" means outside of a living individual. Examples of ex vivo cell populations include in vitro cell cultures and biological samples, including fluid or tissue samples obtained from an individual. Such samples can be obtained by methods well known in the art. Exemplary biological fluid samples include blood, cerebrospinal fluid, urine, and saliva. Exemplary tissue samples include tumors and biopsy samples thereof. In context, the present invention can be used for various purposes, including therapeutic and experimental purposes. For example, the present invention can be used ex vivo to determine the optimal dosing schedule and / or dose of an IDO1 inhibitor for a specified indication, cell type, individual, and other parameters. Information gathered from such uses can be used for experimental purposes or in the clinic to establish an in vivo treatment regimen. Other ex vivo uses to which the present invention can be adapted are described below or should be apparent to those skilled in the art. The selected compounds can be further characterized to examine safety or tolerable doses in human or non-human subjects. Such properties can be examined using methods generally known to those skilled in the art.

[0371] In some embodiments, the compounds described herein can be used to treat subjects having or suspected of having a disease state, disorder, and condition (collectively also referred to as "indications") that respond or are thought to respond to inhibition of IDO1 activity. In some embodiments, the compounds described herein can be used to inhibit the activity of IDO1 polypeptides. In some embodiments, the compounds described herein can be used to inhibit an excessive or destructive immune response or the growth or proliferation of cells (such as cancer cells), or to inhibit immunosuppression.

[0372] Exemplary indications suitable for treatment with the compounds described herein include, but are not limited to, cancer, viral infections such as HIV infection, HBV infection, HCV infection, other infections (e.g., skin infections, gastrointestinal infections, urinary tract infections, genitourinary infections, and systemic infections), depression, neurodegenerative disorders such as Alzheimer's disease and Huntington's disease, trauma, age-related cataracts, organ transplantation (e.g., organ transplant rejection), and autoimmune diseases.

[0373] Examples of autoimmune diseases include, but are not limited to, asthma, collagen diseases such as rheumatoid arthritis, lupus (e.g., systemic lupus erythematosus), Sharp syndrome, CREST syndrome (calcinosis, Raynaud's syndrome, esophageal dysmotility, sclerodactyly, telangiectasia), dermatomyositis, vasculitis (Wegener's disease), and Sjogren's syndrome, kidney diseases such as Goodpasture's syndrome, rapidly progressive glomerulonephritis, and membranoproliferative glomerulonephritis type II, endocrine diseases such as type I diabetes, autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED), autoimmune parathyroid disease, pernicious anemia, gonadal insufficiency, idiopathic Addison's disease, hyperthyroidism, Hashimoto's thyroiditis, and primary myxedema, skin diseases such as pemphigus vulgaris, bullous pemphigoid, herpes gestationis, epidermolysis bullosa, and Stevens-Johnson syndrome, liver diseases such as primary biliary cirrhosis, autoimmune cholangitis, autoimmune hepatitis type 1, autoimmune hepatitis type 2, and primary sclerosing cholangitis, neuronal diseases such as multiple sclerosis, myasthenia gravis, Lambert-Eaton myasthenic syndrome, acquired neuromyotomy, Guillain-Barré syndrome (Miller-Fisher syndrome), stiff-person syndrome, cerebellar degeneration, ataxia, opsoclonus, sensory neuropathy, and achalasia, blood diseases such as autoimmune hemolytic anemia, idiopathic thrombocytopenic purpura (Werlhof's disease), infectious diseases associated with autoimmune responses such as AIDS, allergic inflammation, inflammatory bowel disease, psoriasis, and systemic lupus erythematosus, malaria, and Chagas disease.

[0374] In some embodiments, the compounds described herein can be used to treat cancer, viral infections, depression, neurodegenerative disorders, trauma, age-related cataracts, organ transplant rejection, or autoimmune diseases.

[0375] In other embodiments, the disease being treated is a solid tumor. In a specific embodiment, the solid tumor is pancreatic cancer, bladder cancer, colorectal cancer, breast cancer, prostate cancer, kidney cancer, hepatocellular carcinoma, lung cancer, ovarian cancer, cervical cancer, gastric cancer, esophageal cancer, head and neck cancer, melanoma, neuroendocrine cancer, CNS cancer, brain tumor (e.g., glioma, anaplastic oligodendroglioma, adult glioblastoma multiforme, and adult anaplastic astrocytoma), bone cancer, or soft tissue sarcoma. In some embodiments, the solid tumor is non-small cell lung cancer, small cell lung cancer, colon cancer, CNS cancer, melanoma, ovarian cancer, kidney cancer, prostate cancer, or breast cancer.

[0376] In some embodiments, the disease to be treated is leukemia or lymphoma. In some embodiments, the disease to be treated is diffuse large B-cell lymphoma (DLBCL), mediastinal B-cell lymphoma, high-grade B-cell lymphoma, follicular lymphoma, lymphocytic leukemia (ALL), such as B-cell acute lymphoblastic leukemia (BALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), or hairy cell leukemia (HCL).

[0377] In some embodiments, the disease is an autoimmune disease. In specific embodiments, the autoimmune disease is lupus (e.g., systemic lupus erythematosus (SLE)), myasthenia gravis, rheumatoid arthritis (RA), acute disseminated encephalomyelitis, idiopathic thrombocytopenic purpura, multiple sclerosis (MS), psoriasis, Sjogren's syndrome, psoriasis, autoimmune hemolytic anemia, asthma, or chronic obstructive pulmonary disease (COPD). In other embodiments, the disease is an inflammation. In other embodiments, the disease is an excessive or destructive immune response, such as asthma, rheumatoid arthritis, multiple sclerosis, chronic obstructive pulmonary disease (COPD), and lupus.

[0378] Provided are methods for treating a subject having or suspected of having a disease or disorder responsive to or believed to be responsive to inhibition of IDO1 activity, which are treated by administering to the subject a compound or a pharmaceutically acceptable salt, isomer, or mixture thereof described herein. Also provided are methods for inhibiting the kinase activity of an IDO1 polypeptide, which are by contacting the polypeptide with a compound or a pharmaceutically acceptable salt, isomer, or mixture thereof described herein. Also provided are methods for inhibiting the growth or proliferation of cancer cells of a hematopoietic organ, which include contacting the cancer cells with an effective amount of a compound or a pharmaceutically acceptable salt, isomer, or mixture thereof described herein.

[0379] In one embodiment, the compounds of the present invention can be used in combination with one or more other therapeutic agents that are being used and / or developed to treat cancer or inflammatory diseases. The one or more additional therapeutic agents can be chemotherapeutic agents, immunotherapeutic agents, radiotherapeutic agents, anti-tumor agents, anti-cancer agents, anti-proliferative agents, anti-fibrotic agents, anti-angiogenic agents, therapeutic antibodies, or any combination thereof.

[0380] The one or more other therapeutic agents can be inhibitors against: PI3K (such as PI3Kγ, PI3Kβ, PI3Kδ, and / or PI3Kα), Janus kinase (JAK) (such as JAK1, JAK2, and / or JAK3), spleen tyrosine kinase (SYK), Bruton's tyrosine kinase (BTK), bromodomain-containing protein inhibitor (BRD) (such as BRD4), lysyl oxidase protein (LOX), lysyl oxidase-like protein (LOXL) (such as LOXL1-5), matrix metalloproteinase (MMP) (such as MMP 1-10), adenosine A2B receptor (A2B), isocitrate dehydrogenase (IDH) (such as IDH1), apoptosis signal-regulating kinase (ASK) (such as ASK1), serine / threonine kinase TPL2, discoidin domain receptor (DDR) (such as DDR1 and DDR2), histone deacetylase (HDAC), protein kinase C (PKC), or any combination thereof.

[0381] The compounds described herein can be used or combined with one or more of the following: chemotherapeutic agents, anti-cancer agents, anti-angiogenic agents, anti-fibrotic agents, immunotherapeutic agents, therapeutic antibodies, bispecific antibodies, and "antibody-like" therapeutic proteins (such as Fab derivatives), antibody-drug conjugates (ADCs), radiotherapeutic agents, anti-tumor agents, anti-proliferative agents, oncolytic viruses, gene modifiers or editors such as CRISPR (including CRISPR Cas9), zinc finger nucleases, or synthetic nucleases (TALEN), chimeric antigen receptor (CAR) T cell immunotherapeutic agents, T cell receptor (TCR) immunotherapeutic agents, immune checkpoint inhibitors, immune checkpoint-stimulating protein agonists, or any combination thereof. These therapeutic agents can be in the form of compounds, antibodies, polypeptides, or polynucleotides. In one embodiment, the present application provides a product comprising the compounds described herein and an additional therapeutic agent as a combined preparation for simultaneous, separate, or sequential use in therapy.

[0382] In some embodiments, the compounds disclosed herein can be used or combined with one or more of the following: chemotherapeutic agents, anti-cancer agents, anti-angiogenic agents, anti-fibrotic agents, immunotherapeutic agents, therapeutic antibodies, bispecific antibodies, and "antibody-like" therapeutic proteins (such as Fab derivatives, antibody-drug conjugates (ADCs), radiotherapeutic agents, anti-tumor therapeutic agents, anti-proliferative agents, oncolytic viruses, gene modifiers or editors such as CRISPR (including CRISPR Cas9), zinc finger nucleases or synthetic nucleases (TALENs), chimeric antigen receptors (CARs), T cell immunotherapeutic agents, T-cell receptor (TCR) immunotherapeutic agents, or any combination thereof. These therapeutic agents can be in the form of compounds, antibodies, polypeptides, live cells (such as cell therapy), or polynucleotides. In some embodiments, the present application provides a product comprising a compound described herein and an additional therapeutic agent, the product being a combination preparation for simultaneous, separate, or sequential use in therapy.

[0383] In some embodiments, the chimeric antigen receptor (CAR) T cell immunotherapeutic agent is selected from Yescarta TM (axicabtagene ciloleucel) and KYMRIAH TM (tisagenlecleucel).

[0384] In some embodiments, the chimeric antigen receptor (CAR) T cell immunotherapeutic agent is YESCARTA TM (axicabtagene ciloleucel).

[0385] In some embodiments, the compound is administered to a subject before, after, or simultaneously with the administration of one or more additional therapeutic agents. In some embodiments, the compound is administered to the subject about 30 minutes or more, about 1 hour or more, about 2 hours or more, about 4 hours or more, about 6 hours or more, about 12 hours or more, about 24 hours or more, about 48 hours or more, or about 72 hours or more before or after the administration of one or more additional therapeutic agents. In some embodiments, the compound is administered to the subject about 30 minutes or less, about 1 hour or less, about 2 hours or less, about 4 hours or less, about 6 hours or less, about 12 hours or less, about 24 hours, about 48 hours or less, about 48 hours or less, or about 72 hours or less before or after the administration of one or more additional therapeutic agents.

[0386] In some embodiments, a method of treating a disease in a subject comprises administering to the subject a combination of a therapeutically effective amount of any of the compounds described herein (e.g., of formula I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii or Ij or a pharmaceutically acceptable salt or pharmaceutically acceptable tautomer thereof) and one or more additional therapeutic agents. In some embodiments, the one or more additional therapeutic agents comprise immunotherapeutic agents, such as, for example, immune checkpoint inhibitors, hematopoietic progenitor kinase 1 (HPK1) inhibitors, immune checkpoint stimulating protein agonists, or engineered immune cells (e.g., T cells having a chimeric antigen receptor (i.e., CAR T cells) or T cells having an engineered T cell receptor (TCR)). In some embodiments, the compound is administered to the subject before, after, or simultaneously with the administration of one or more immunotherapeutic agents. In some embodiments, the compound is administered to the subject about 30 minutes or more, about 1 hour or more, about 2 hours or more, about 4 hours or more, about 6 hours or more, about 12 hours or more, about 24 hours or more, about 48 hours or more, or about 72 hours or more before or after the administration of one or more immunotherapeutic agents. In some embodiments, the compound is administered to the subject about 30 minutes or less, about 1 hour or less, about 2 hours or less, about 4 hours or less, about 6 hours or less, about 12 hours or less, about 24 hours or less, about 48 hours or less, or about 72 hours or less before or after the administration of one or more immunotherapeutic agents.

[0387] In some embodiments, a method of treating a disease in a subject comprises administering to the subject a combination of a therapeutically effective amount of any of the compounds described herein (e.g., of formula I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii or Ij or a pharmaceutically acceptable salt or pharmaceutically acceptable tautomer thereof) and a therapeutically effective amount of one or more immune checkpoint inhibitors. In some embodiments, the compound is administered to the subject before, after, or simultaneously with the administration of the immune checkpoint inhibitor. In some embodiments, the immune checkpoint inhibitor is a small molecule inhibitor. In some embodiments, the immune checkpoint inhibitor is an antibody or a fragment thereof. In some embodiments, the immune checkpoint inhibitor inhibits adenosine A 2AReceptors (A2aR), B7-H3, V-set domain-containing T cell activation inhibitor 1 (VTCN1, also known as B7-H4), B and T lymphocyte attenuator (BTLA), cytotoxic T lymphocyte-associated protein 4 (CTLA-4), killer cell immunoglobulin-like receptor (KIR), lymphocyte activation gene 3 (LAG3), programmed death 1 (PD-1), programmed death ligand 1 (PD-L1), programmed death ligand 2 (PD-L2), T cell immunoreceptor with Ig and ITIM domains (TIGIT), T cell immunoglobulin and mucin domain 3 (TIM-3), or V-domain Ig inhibitor of T cell activation (VISTA). Exemplary immune checkpoint inhibitors include, but are not limited to, avelumab, atezolizumab, durvalumab, nivolumab, pembrolizumab, ipilimumab, PDR001, TSR-042, and BMS-986016.

[0388] In some embodiments, a method of treating a subject's disease comprises administering to the subject a combination of a therapeutically effective amount of any of the compounds described herein (e.g., of formula I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, or Ij or a pharmaceutically acceptable salt or pharmaceutically acceptable tautomer thereof) and a therapeutically effective amount of one or more immune checkpoint stimulating protein agonists. In some embodiments, the compound is administered to the subject before, after, or simultaneously with the administration of the immune checkpoint stimulating protein agonist. In some embodiments, the immune checkpoint stimulating protein agonist is an antibody or a fragment thereof. In some embodiments, the immune checkpoint stimulating protein agonist is an agonist of CD27, CD28, CD40, CD122, 4-1BB, OX40, glucocorticoid-induced TNFR family-related protein (GITR), or inducible T cell co-stimulator molecule (ICOS).

[0389] In some embodiments, a method of treating a disease in a subject comprises administering to the subject a combination of a therapeutically effective amount of any of the compounds described herein (e.g., a compound of Formula I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, or Ij or a pharmaceutically acceptable salt or pharmaceutically acceptable tautomer thereof) and a therapeutically effective amount of engineered immune cells, such as CAR T cells or T cells having an engineered TCR. In some embodiments, the compound is administered to the subject before, after, or simultaneously with the administration of the engineered immune cells. In some embodiments, the engineered immune cells are heterologous engineered immune cells, such as heterologous engineered T cells (e.g., CAR T cells or T cells having an engineered TCR). In some embodiments, the engineered immune cells are autologous engineered immune cells, such as autologous engineered T cells (e.g., CAR T cells or T cells having an engineered TCR).

[0390] In some embodiments, a method of treating a disease in a subject comprises administering to the subject a combination of a therapeutically effective amount of any of the compounds described herein (e.g., a compound of Formula I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, or Ij or a pharmaceutically acceptable salt or pharmaceutically acceptable tautomer thereof) and a therapeutically effective amount of axicabtagene ciloleucel (which is sold under the trade name YESCARTA TM ). In some embodiments, a method of treating a disease in a subject comprises administering to the subject a combination of a therapeutically effective amount of any of the compounds described herein (e.g., a compound of Formula I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, or Ij or a pharmaceutically acceptable salt or pharmaceutically acceptable tautomer thereof) and a therapeutically effective amount of tisagenlecleucel (which is sold under the trade name KYMRIAH TM ).

[0391] In some embodiments, a method of treating a disease in a subject comprises administering to the subject a combination of a therapeutically effective amount of any of the compounds described herein (e.g., a compound of Formula I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, or Ij or a pharmaceutically acceptable salt or pharmaceutically acceptable tautomer thereof) and (1) a therapeutically effective amount of engineered immune cells, such as CAR T cells or T cells having an engineered TCR, and (2) a therapeutically effective amount of an immune checkpoint inhibitor or an immune checkpoint stimulating protein agonist.

[0392] In some embodiments, a method of treating cancer or a proliferative disorder in a subject comprises administering to the subject a therapeutically effective amount of any of the compounds described herein (e.g., of formula I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, or Ij or a pharmaceutically acceptable salt or pharmaceutically acceptable tautomer thereof) in combination with one or more additional therapeutic agents. In some embodiments, the one or more additional therapeutic agents include immunotherapeutic agents such as immune checkpoint inhibitors, hematopoietic progenitor kinase 1 (HPK1) inhibitors, immune checkpoint stimulating protein agonists, or engineered immune cells (e.g., T cells having a chimeric antigen receptor (i.e., CAR T cells) or T cells having an engineered T cell receptor (TCR). In some embodiments, the compound is administered to the subject before, after, or simultaneously with the administration of one or more immunotherapeutic agents. In some embodiments, the compound is administered to the subject about 30 minutes or more, about 1 hour or more, about 2 hours or more, about 4 hours or more, about 6 hours or more, about 12 hours or more, about 24 hours or more, about 48 hours or more, or about 72 hours or more before or after the administration of one or more additional immunotherapeutic agents. In some embodiments, the compound is administered to the subject about 30 minutes or less, about 1 hour or less, about 2 hours or less, about 4 hours or less, about 6 hours or less, about 12 hours or less, about 24 hours or less, about 48 hours or less, or about 72 hours or less before or after the administration of one or more additional immunotherapeutic agents.

[0393] In some embodiments, a method of treating cancer or a proliferative disease in a subject comprises administering to the subject a therapeutically effective amount of any of the compounds described herein (e.g., of formula I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, or Ij or a pharmaceutically acceptable salt or pharmaceutically acceptable tautomer thereof) in combination with a therapeutically effective amount of one or more immune checkpoint inhibitors. In some embodiments, the compound is administered to the subject before, after, or simultaneously with the administration of the immune checkpoint inhibitor. In some embodiments, the immune checkpoint inhibitor is a small molecule inhibitor. In some embodiments, the immune checkpoint inhibitor is an antibody or a fragment thereof. In some embodiments, the immune checkpoint inhibitor inhibits adenosine A 2AReceptors (A2aR), B7-H3, V-set domain-containing T cell activation inhibitor 1 (VTCN1, also known as B7-H4), B and T lymphocyte attenuator (BTLA), cytotoxic T lymphocyte-associated protein 4 (CTLA-4), killer cell immunoglobulin-like receptor (KIR), lymphocyte activation gene 3 (LAG3), programmed death 1 (PD-1), programmed death ligand 1 (PD-L1), programmed death ligand 2 (PD-L2), T cell immunoreceptor with Ig and ITIM domains (TIGIT), T cell immunoglobulin and mucin domain 3 (TIM-3), or V-domain Ig inhibitor of T cell activation (VISTA). Exemplary immune checkpoint inhibitors include, but are not limited to, avelumab, atezolizumab, durvalumab, nivolumab, pembrolizumab, ipilimumab, PDR001, TSR-042, and BMS-986016.

[0394] In some embodiments, a method of treating cancer or a proliferative disease in a subject comprises administering to the subject a combination of a therapeutically effective amount of any of the compounds described herein (e.g., Formula I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, or Ij or a pharmaceutically acceptable salt or pharmaceutically acceptable tautomer thereof) and a therapeutically effective amount of one or more immune checkpoint stimulating protein agonists. In some embodiments, the compound is administered to the subject before, after, or simultaneously with the administration of the immune checkpoint stimulating protein agonist. In some embodiments, the immune checkpoint stimulating protein agonist is an antibody or a fragment thereof. In some embodiments, the immune checkpoint stimulating protein agonist is an agonist of CD27, CD28, CD40, CD122, 4-1BB, OX40, glucocorticoid-induced TNFR family-related protein (GITR), or inducible T cell co-stimulator molecule (ICOS).

[0395] In some embodiments, methods of treating cancer or a proliferative disease in a subject comprise administering to the subject a therapeutically effective amount of any of the compounds described herein (e.g., of formula I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, or Ij or a pharmaceutically acceptable salt or pharmaceutically acceptable tautomer thereof) in combination with a therapeutically effective amount of engineered immune cells, such as CAR T cells or T cells having an engineered TCR. In some embodiments, the compound is administered to the subject before, after, or simultaneously with the engineered immune cells. In some embodiments, the engineered immune cells are heterologous engineered immune cells, such as heterologous engineered T cells (e.g., CAR T cells or T cells having an engineered TCR). In some embodiments, the engineered immune cells are autologous engineered immune cells, such as autologous engineered T cells (e.g., CAR T cells or T cells having an engineered TCR). In some embodiments, the engineered immune cells (e.g., engineered T cells) target a tumor antigen. In some embodiments, the engineered immune cells (e.g., engineered T cells) target CD7, CD19, CD22, CD30, CD33, CD70, CD123, GD2, HER2, EpCAM, PSA, MUC1, CEA, B cell maturation antigen (BCMA), glypican 3, mesothelin, or EGFRvIII.

[0396] In some embodiments, methods of treating cancer or a proliferative disease in a subject comprise administering to the subject a therapeutically effective amount of any of the compounds described herein (e.g., of formula I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, or Ij or a pharmaceutically acceptable salt or pharmaceutically acceptable tautomer thereof) in combination with a therapeutically effective amount of axicabtagene ciloleucel (which is sold under the trade name YESCARTA TM ). In some embodiments, methods of treating cancer or a proliferative disease in a subject comprise administering to the subject a therapeutically effective amount of any of the compounds described herein (e.g., of formula I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, or Ij or a pharmaceutically acceptable salt or pharmaceutically acceptable tautomer thereof) in combination with a therapeutically effective amount of tisagenlecleucel (which is sold under the trade name KYMRIAH TM ).

[0397] In some embodiments, a method of treating cancer or a proliferative disease in a subject comprises administering to the subject a therapeutically effective amount of any of the compounds described herein (e.g., of formula I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, or Ij or a pharmaceutically acceptable salt or pharmaceutically acceptable tautomer thereof) in combination with (1) a therapeutically effective amount of engineered immune cells, such as CAR T cells or T cells having an engineered TCR, and (2) a therapeutically effective amount of an immune checkpoint inhibitor or an immune checkpoint stimulating protein agonist. In some embodiments, a method of treating cancer or a proliferative disease in a subject comprises administering to the subject a therapeutically effective amount of any of the compounds described herein (e.g., of formula I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, or Ij or a pharmaceutically acceptable salt or pharmaceutically acceptable tautomer thereof) in combination with (1) a therapeutically effective amount of engineered immune cells, such as CAR T cells or T cells having an engineered TCR, and (2) a therapeutically effective amount of a chemotherapeutic agent. In some embodiments, a method of treating cancer or a proliferative disease in a subject comprises administering to the subject a therapeutically effective amount of any of the compounds described herein (e.g., of formula I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, or Ij or a pharmaceutically acceptable salt or pharmaceutically acceptable tautomer thereof) in combination with (1) a therapeutically effective amount of an immune checkpoint inhibitor or an immune checkpoint stimulating protein agonist, and (2) a therapeutically effective amount of a chemotherapeutic agent. In some embodiments, a method of treating cancer or a proliferative disease in a subject comprises administering to the subject a therapeutically effective amount of any of the compounds described herein (e.g., of formula I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, or Ij or a pharmaceutically acceptable salt or pharmaceutically acceptable tautomer thereof) in combination with (1) a therapeutically effective amount of engineered immune cells, such as CAR T cells or T cells having an engineered TCR, (2) a therapeutically effective amount of an immune checkpoint inhibitor or an immune checkpoint stimulating protein agonist, and (3) a therapeutically effective amount of a chemotherapeutic agent.

[0398] Phosphoinositide 3-kinase inhibitors (PI3K inhibitors) act by inhibiting one or more phosphoinositide 3-kinases, including but not limited to PI3Kγ, PI3Kβ, PI3Kδ, and PI3Ka. Non-limiting examples of PI3K inhibitors include wortmannin, demethoxyviridin, LY294002, idelalisib, perifosine, PX-866, IPI-145, BAY 80-6946, BEZ235, RP6530, TGR 1202, INK1117, GDC-0941, BKM120, XL147 (also known as SAR245408), XL765 (also known as SAR245409), Palomid 529, GSK1059615, ZSTK474, PWT33597, IC87114, CAL263, RP6503, PI-103, GNE-477, CUDC-907, and AEZS-136. In some embodiments, the PI3K inhibitor is a PI3Kδ inhibitor, such as idelalisib, IPI-145, RP6530, and RP6503, and those disclosed in U.S. Patent 8,569,296, and PCT Publications WO 2014 / 006572 and WO 2015 / 001491.

[0399] In some embodiments, the one or more additional therapeutic agents can be an MMP9 inhibitor, or an agent that inhibits the expression and / or activity of MMP9. A representative protein sequence of MMP9 is GenBank accession number NP_004985. The inhibitor can be small molecule or biological. For example, Gu et al., The Journal of Neuroscience, 25(27):6401-6408 (2005) disclose a specific MMP9 inhibitor, SB-3CT (CAS 292605-14-2). In addition, siRNA, antisense RNA, and antibodies have also been shown to inhibit the expression or activity of MMP9 and are within the scope of the present invention. In one embodiment, the MMP9 inhibitor is a monoclonal anti-MMP9 antibody. In some embodiments, the one or more additional therapeutic agents include an MMP9 inhibitor and a nucleoside analogue such as gemcitabine.

[0400] One, two, three, or more of the therapeutic agents (e.g., PI3K inhibitor, JAK inhibitor, SYK inhibitor, BTK inhibitor, BRD4 inhibitor, LOXL2 inhibitor, MMP9 inhibitor, A2B inhibitor, IDH inhibitor, ASK inhibitor, TPL2 inhibitor, DDR1 inhibitor, TBK inhibitor, HDAC inhibitor, PKC inhibitor) may further be used or combined with chemotherapeutic agents, immunotherapeutic agents, radiotherapeutic agents, anti-tumor agents, anti-cancer agents, anti-fibrotic agents, anti-angiogenic agents, therapeutic antibodies, or any combination thereof.

[0401] Chemotherapeutic agents can be classified by their mechanism of action into the following groups: antimetabolite / anticancer agents, such as pyrimidine analogs (fluorouracil, capecitabine, and cytarabine); and purine analogs, folic acid antagonists, and related inhibitors; antiproliferative / antimitotic agents, including natural products such as vinca alkaloids (vinblastine, vincristine), and tubulin inhibitors such as taxanes (paclitaxel, docetaxel), vinblastine, nocodazole, epothilones, and navelbine, epidipodophyllotoxins (etoposide, teniposide); DNA-damaging agents (actinomycin, amsacrine, busulfan, carboplatin, chlorambucil, cisplatin, cyclophosphamide, Cytoxan, actinomycin D, daunorubicin, doxorubicin, epirubicin, ifosfamide, melphalan, mechlorethamine, mitomycin, mitoxantrone, nitrosoureas, procarbazine, taxol, taxotere, teniposide, etoposide, thiotepa); antibiotics such as dactinomycin (actinomycin D), daunorubicin, doxorubicin (adriamycin), idarubicin, anthracyclines, mitoxantrone, bleomycin, plicamycin (mithramycin), and mitomycin; enzymes (L-asparaginase, which metabolizes L-asparagine systemically and kills cells that are unable to synthesize their own asparagine); antiplatelet agents; antiproliferative / antimitotic alkylating agents, such as nitrogen mustard cyclophosphamide and analogs, melphalan, chlorambucil), and (hexamethylmelamine and thiotepa), alkyl nitrosoureas (BCNU) and analogs, streptozocin), triazenes - dacarbazine (DTIC); antiproliferative / antimitotic antimetabolites, such as folic acid analogs (methotrexate); platinum coordination complexes (cisplatin, oxaliplatinim, carboplatin), procarbazine, hydroxyurea, mitotane, aminoglutethimide; hormones, hormone analogs (estrogen, tamoxifen, goserelin, bicalutamide, nilutamide), and aromatase inhibitors (letrozole, anastrozole); anticoagulants (heparin, synthetic heparin salts, and other thrombin inhibitors); fibrinolytic agents (such as tissue plasminogen activator, streptokinase, and urokinase), aspirin, dipyridamole, ticlopidine, clopidogrel; antimetastatic agents; secretory inhibitors (breveldin); immunosuppressive agents, tacrolimus, sirolimus, azathioprine, mycophenolate mofetil; compounds (TNP-470, genistein) and growth factor inhibitors (vascular endothelial growth factor inhibitors, fibroblast growth factor inhibitors); angiotensin receptor blockers, nitric oxide donors; antisense oligonucleotides; antibodies (trastuzumab, rituximab); cell cycle inhibitors and differentiation inducers (retinoic acid);Inhibitors, topoisomerase inhibitors (doxorubicin (adriamycin), daunorubicin, dactinomycin, teniposide, epirubicin, etoposide, idarubicin, irinotecan and mitoxantrone, topotecan, irinotecan, camptothecin), corticosteroids (cortisone, dexamethasone, hydrocortisone, methylprednisolone, prednisone and prednisolone); growth factor signal transduction kinase inhibitors; dysfunction inducers, toxins such as cholera toxin, ricin, Pseudomonas exotoxin, Bordetella pertussis adenylate cyclase toxin, or diphtheria toxin, and caspase activators; and chromatin.;

[0402] As used herein, the term "chemotherapeutic agent" or "chemotherapeutic" (or "chemotherapy" in the case of treatment with a chemotherapeutic agent) refers to any non-proteinaceous (i.e., non-peptide) chemical compound that is used for treating cancer. Examples of chemotherapeutic agents include alkylating agents such as thiotepa and cyclophosphamide (CYTOXAN); alkyl sulfonates such as busulfan, improsulfan, and piposulfan; aziridines such as benzodopa, carboquone, meturedopa, and uredopa; ethylenimine and methylamelamine, including hexamethylmelamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide, and trimethylolmelamine; acetogenins (especially bullatacin and bullatacinone); camptothecin (including the synthetic analog topotecan); bryostatin; callystatin; CC-1065 (including its synthetic analogs adozelesin, carzelesin, and bizelesin); cryptophycins (especially cryptophycin 1 and cryptophycin 8); dolastatin; duocarmycin (including the synthetic analogs KW-2189 and CB1-TM1); eleutherobin; pancratistatin; sarcodictyin; spongistatin; nitrogen mustards such as chlorambucil, chlornaphazine, chlorophosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novembichin, phenesterine, prednimustine, trofosfamide, uracil mustard; nitrosoureas such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, and ranimustine;Antibiotics such as enediyne antibiotics (e.g., calicheamicin, especially calicheamicin γ1I, calicheamicin phiI1 (see, e.g., Agnew, Chem. Intl. Ed. Engl, 33:183-186 (1994)); dynemicin antibiotics, including dynemicin A; bisphosphonates such as clodronate; esperamicin; and neocarzinostatin chromophore and related chromoprotein enediyne antibiotic chromophores, aclacinomysin, actinomycin, authramycin, azaserine, bleomycin, cactinomycin, carabicin, carminomycin, carzinophilin, chromomycin, dactinomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, doxorubicin (including morpholino-doxorubicin, cyano-morpholino-doxorubicin, 2-pyrrolino-doxorubicin, and deoxy-doxorubicin), epirubicin, esorubicin, idarubicin, marcellomycin, mitomycins such as mitomycin C, mycophenolic acid, nogalamycin, olivomycins, peplomycin, porfiromycin, puromycin, quelamycin, rodorubicin, streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin, zorubicin; antimetabolites such as methotrexate and 5-fluorouracil (5-FU); folic acid analogs such as dimethylfolate, methotrexate, pteropterin, trimetrexate;Purine analogues such as fludarabine, 6-mercaptopurine, thiamiprine, thioguanine; pyrimidine analogues such as ancitabine, azacytidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, floxuridine; androgens such as calusterone, dromostanolone propionate, epitiostanol, mepitiostane, testolactone; anti-adrenal agents such as aminoglutethimide, mitotane, trilostane; folic acid replenishers such as folinic acid; aceglatone; aldophosphamide glycoside; aminolevulinic acid; eniluracil; amsacrine; hestrabucil; bisantrene; edatraxate; defofamine; demecolcine; diaziquone; elfornithine; elliptinium acetate; epothilone; etoglucid; gallium nitrate; hydroxyurea; lentinan; leucovorin; lonidainine; maytansinoids such as maytansine and ansamitocin; mitoguazone; mitoxantrone; mopidanmol; nitraerine; pentostatin; phenamet; pirarubicin;Losoxantrone; fluoropyrimidine; folinic acid; podophyllinic acid; 2-ethylhydrazine; procarbazine; PSK(r); razoxane; rhizoxin; sizofiran; spirogermanium; tenuazonic acid; triaziquone; 2,2',2"-trichloroethylamine; trichothecene (especially T-2 toxin, verracurin A, bacitracin A and anguidine); urethane; vindesine; dacarbazine; mannomustine; mitobronitol; mitolactol; pipobroman; gacytosine; arabinoside ("Ara-C"); cyclophosphamide; thiotepa; taxane, such as paclitaxel (TAXOL(r)) and docetaxel (TAXOTERE(r)); chlorambucil; gemcitabine (Gemzar(r)); 6-thioguanine; mercaptopurine; methotrexate; platinum analogs, such as cisplatin and carboplatin; vinblastine; platinum; etoposide (VP-16); ifosfamide; mitoxantrone; vincristine; vinorelbine (Navelbine(r)); novantrone; teniposide; edatrexate; daunorubicin; aminopterin; capecitabine; ibandronate; CPT-11; topoisomerase inhibitor RFS 2000; difluoromethylornithine (DMFO); retinoid such as retinoic acid; capecitabine; FOLFIRI (fluorouracil, leucovorin and irinotecan), and pharmaceutically acceptable salts, acids or derivatives of any of the foregoing. One or more chemotherapeutic agents are used or included in the present application. For example, gemcitabine, nab-paclitaxel and gemcitabine / nab-paclitaxel are used in combination with JAK inhibitors and / or PI3Kδ inhibitors for the treatment of hyperproliferative disorders.;

[0403] The definition of "chemotherapeutic agent" also includes antihormonal agents for modulating or inhibiting the action of hormones on tumors, such as antiestrogens and selective estrogen receptor modulators (SERMs), including, for example, tamoxifen (including NolvadexTM), raloxifene, droloxifene, 4-hydroxytamoxifen, trioxifene, keoxifene, LY117018, onapristone, and toremifene (Fareston(r)); aromatase inhibitors, which modulate the production of estrogen in the adrenal gland, such as 4(5)-imidazoles, aminoglutethimide, megestrol acetate (Megace(r)), exemestane, formestane, fadrozole, vorozole (Rivisor(r)), letrozole (Femara(r)), and anastrozole (Arimidex(r)); and antiandrogens, such as flutamide, nilutamide, bicalutamide, leuprolide, and goserelin; and pharmaceutically acceptable salts, acids, or derivatives of any of the foregoing.

[0404] Examples of anti-angiogenic agents include, but are not limited to, retinoic acid and its derivatives, 2-methoxyestradiol, angiostatin(r), endostatin(r), suramin, squalamine, tissue inhibitor of metalloproteinase-1, tissue inhibitor of metalloproteinase-2, plasminogen activator inhibitor-1, plasminogen activator inhibitor-2, cartilage-derived inhibitor, paclitaxel (albumin-bound paclitaxel), platelet factor 4, protamine sulfate (salmin), sulfated chitin derivative (prepared from snow crab shell), sulfated polysaccharide peptide polysaccharide complex (sp-pg), staurosporine, matrix metabolic regulators, including, for example, proline analogs ((1-azetidine-2-carboxylic acid (LACA), cis-hydroxyproline, D,L-3,4-dehydroproline, thiaproline, α-bipyridine, β-aminopropionitrile fumarate, 4-propyl-5-(4-pyridyl)-2(3H)-oxazolone); methotrexate, mitoxantrone, heparin, interferon, serum of 2-macroglobulin, chimp-3, chymostatin, β-cyclodextrin tetradecasulfate, eponemycin; fumagillin, gold sodium thiomalate, d-penicillamine (CDPT), β-1-anticollagenase-serum, α-2-antiplasmin, bisantrene, clobenzarit disodium, disodium n-2-carboxyphenyl-4-chloroanthranilate or "CCA", thalidomide; angiostatic steroids, carboxynaminolmidazole; metalloproteinase inhibitors such as BB94. Other anti-angiogenic agents include antibodies, preferably monoclonal antibodies against the following angiogenic growth factors: β-FGF, α-FGF, FGF-5, VEGF isoforms, VEGF-C, HGF / SF and Ang-1 / Ang-2. See Ferrara N. and Alitalo, K. "Clinical application of angiogenic growth factors and their inhibitors" (1999) Nature Medicine 5:1359-1364.

[0405] Antifibrotic agents include, but are not limited to, compounds such as β-aminopropionitrile (BAPN), and the compounds disclosed below: the compounds disclosed in U.S. Patent No. 4,965,288, entitled "inhibitors of lysyl oxidase", issued to Palfreyman et al. on October 23, 1990, which relates to lysyl oxidase inhibitors and their use in treating diseases and disorders associated with abnormal collagen deposition; the compounds in U.S. Patent No. 4,997,854, entitled "Anit-fibrotic agents and methods for inhibiting the activity of lysyl oxidase in situ using adjacently positioned diamine analogue substrate", issued to Kagan et al. on March 5, 1991, which relates to compounds for inhibiting LOX to treat various pathological fibrotic conditions, which is incorporated herein by reference. Other exemplary inhibitors are described in the compounds in U.S. Patent No. 4,943,593, entitled "inhibitors of lysyloxidase", issued to Palfreyman et al. on July 24, 1990, which relates to compounds such as 2-isobutyl-3-fluoro-, chloro-, or bromo-allylamine; and, for example, U.S. Patent No. 5,021,456; U.S. Patent No. 5,5059,714; U.S. Patent No. 5,120,764; U.S. Patent No. 5,182,297; the compounds in U.S. Patent No. 5,252,608 (relating to 2-(1-naphthyloxymethyl)-3-fluoroallylamine); and U.S. Patent Application No. 2004 / 0248871, which is incorporated herein by reference. Exemplary antifibrotic agents also include primary amines that react with the carbonyl group at the active site of lysyl oxidase, and more specifically those primary amines that produce resonance-stabilized products after binding to the carbonyl group, such as the following primary amines: ethylenediamine, hydrazine, phenylhydrazine, and their derivatives, semicarbazide, and urea derivatives, aminonitriles, such as β-aminopropionitrile (BAPN), or 2-nitroethylamine, unsaturated or saturated haloamines, such as 2-bromo-ethylamine, 2-chloroethylamine, 2-trifluoroethylamine, 3-bromopropylamine, p-halobenzylamine, selenohomocysteine lactone. In addition, the antifibrotic agent is a copper chelator, cell-permeable or non-cell-permeable.Exemplary compounds include indirect inhibitors such as compounds that block aldehyde derivatives (derived from the oxidative deamination of lysyl and hydroxylysyl residues by lysyl oxidase), such as thiolamines, in particular D-penicillamine, or analogs thereof such as 2-amino-5-mercapto-5-methylhexanoic acid, D-2-amino-3-methyl-3-((2-acetamidoethyl)disulfanyl)butanoic acid, p-2-amino-3-methyl-3-((2-aminoethyl)disulfanyl)butanoic acid, sodium 4-((p-1-dimethyl-2-amino-2-carboxyethyl)disulfanyl)butane sulphurate, 2-acetamidoethyl 2-acetamidoethane thiolsulfonate, and sodium 4-mercaptobutanesulfinate trihydrate.

[0406] Immunotherapeutic agents include, but are not limited to, therapeutic antibodies suitable for treating patients; such as abagovomab, adecatumumab, afutuzumab, alemtuzumab, altumomab, amatuximab, anatumomab, arcitumomab, bavituximab, bectumomab, bevacizumab, bivatuzumab, blinatumomab, brentuximab, cantuzumab, catumaxomab, cetuximab, citatuzumab, cixutumumab, clivatuzumab, conatumumab, daratumumab, drozitumab, duligotumab, dusigitumab, detumomab, dacetuzumab, dalotuzumab, ecromeximab, elotuzumab, ensituximab, ertumaxomab, etaracizumab, farietuzumab, ficlatuzumab, figitumumab, flanvotumab, futuximab, ganitumab, gemtuzumab, girentuximab, glembatumumab, ibritumomab, igovomab, imgatuzumab, indatuximab, inotuzumab, intetumumab, ipilimumab, iratumumab, labetuzumab, lexatumumab,Lintuzumab, Lorvotuzumab, Lucatumumab, Mapatumumab, Matuzumab, Milatuzumab, Minretumomab, Mitumomab, Moxetumomab, Narnatumab, Naptumomab, Necitumumab, Nimotuzumab, Nofetumomabn, Ocaratuzumab, Ofatumumab, Olaratumab, Onartuzumab, Oportuzumab, Oregovomab, Panitumumab, Parsatuzumab, Patritumab, Pemtumomab, Pertuzumab, Pintumomab, Pritumumab, Racotumomab, Radretumab, Rilotumumab, Rituximab, Robatumumab, Satumomab, Sibrotuzumab, Siltuximab, Simtuzumab, Solitomab, Tacatuzumab, Taplitumomab, Tenatumomab, Teprotumumab, Tigatuzumab, Tositumomab, Trastuzumab, Tucotuzumab, Ublituximab, Veltuzumab, Vorsetuzumab, Votumumab, Zalutumumab, CC49 and 3F8. The exemplified therapeutic antibodies can be further labeled or combined with radioactive isotope particles such as indium In 111, yttrium Y 90,Iodine-131.

[0407] The present application also provides methods for treating a subject who is undergoing one or more standard treatments, such as chemotherapy, radiotherapy, immunotherapy, surgery, or a combination thereof. Accordingly, one or more therapeutic agents or inhibitors can be administered before, during, or after administration of chemotherapy, radiotherapy, immunotherapy, surgery, or a combination thereof.

[0408] In some embodiments, the subject can be a human who is (i) substantially refractory to treatment with at least one chemotherapy, or (ii) has relapsed after treatment with chemotherapy, or both (i) and (ii). In some embodiments, the subject is refractory to at least two, at least three, or at least four chemotherapy treatments (including standard or experimental chemotherapy).

[0409] In some embodiments, the subject is refractory to at least one, at least two, at least three, or at least four chemotherapy treatments (including standard or experimental chemotherapy), the chemotherapy treatments selected from fludarabine, rituximab, ofatumumab, alkylating agents, alemtuzumab, and other chemotherapy treatments such as CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone); R-CHOP (rituximab-CHOP); hyperCVAD (hyperfractionated cyclophosphamide, vincristine, doxorubicin, dexamethasone, methotrexate, cytarabine); R-hyperCVAD (rituximab-hyperCVAD); FCM (fludarabine, cyclophosphamide, mitoxantrone); R-FCM (rituximab, fludarabine, cyclophosphamide, mitoxantrone); bortezomib and rituximab; temsirolimus and rituximab; temsirolimus and Iodine-131 tositumomab and CHOP; CVP (cyclophosphamide, vincristine, prednisone); R-CVP (rituximab-CVP); ICE (ifosfamide, carboplatin, etoposide); R-ICE (rituximab-ICE); FCR (fludarabine, cyclophosphamide, rituximab); FR (fludarabine, rituximab); and D.T.PACE (dexamethasone, thalidomide, cisplatin, cyclophosphamide, etoposide).

[0410] Other examples of chemotherapy treatments (including standard or experimental chemotherapy) are described below. In addition, the treatment of some lymphomas can be found in Cheson, B.D., Leonard, J.P., “Monoclonal Antibody Therapy for B-Cell Non-Hodgkin’s Lymphoma” The New England Journal of Medicine 2008, 359(6), p. 613-626; and Wierda, W.G., “Current and Investigational Therapies for Patients with CLL” Hematology 2006, pp. 285-294. The lymphoma incidence patterns in the United States were analyzed in Morton, L.M. et al. “Lymphoma Incidence Patterns by WHO Subtype in the United States, 1992-2001” Blood 2006, 107(1), pp. 265-276.

[0411] Examples of immunotherapeutic agents for treating lymphoma or leukemia include, but are not limited to, rituximab (such as Rituxan), alemtuzumab (such as Campath, MabCampath), anti-CD19 antibody, anti-CD20 antibody, anti-MN-14 antibody, anti-TRAIL, anti-TRAIL DR4 and DR5 antibodies, anti-CD74 antibody, obinutuzumab, bevacizumab, CHIR-12.12, epratuzumab (hLL2 - anti-CD22 humanized antibody), galiximab, ha20, ibritumomab tiuxetan, lumiliximab, miralumumab, ofatumumab, PRO131921, SGN-40, WT-1 analog peptide vaccine, WT1 126-134 peptide vaccine, tositumomab, autologous human tumor-derived HSPPC-96, and vitespen. Other immunotherapeutic agents include cancer vaccines using the genetic makeup of an individual patient's tumor, such as the lymphoma vaccine example GTOP-99

[0412] Examples of chemotherapeutic agents for treating lymphoma or leukemia include aldesleukin, alvocidib, antineoplaston AS2-1, antineoplaston A10, antithymocyte globulin, amifostine trihydrate, aminocamptothecin, arsenic trioxide, βalethine, Bcl-2 family protein inhibitor ABT-263, BMS-345541, bortezomib Bryostatin 1, Busulfan, Carboplatin, Campath-1H, CC-5103, Carmustine, Caspofungin Acetate, Clofarabine, Cisplatin, Cladribine (Leustarin), Chlorambucil (Leukeran), Curcumin, Cyclosporine, Cyclophosphamide (Cyloxan, Endoxan, Endoxana, Cyclostin), Cytarabine, Denileukin, Dexamethasone, DTPACE, Docetaxel, Dolastatin 10, Doxorubicin( Adriblastine), Doxorubicin Hydrochloride, Enzastaurin, Epoetin Alfa, Etoposide, Everolimus (RAD001), Fenretinide, Filgrastim, Melphalan, Mesna, Flavopiridol, Fludarabine (Fludara), Geldanamycin (17-AAG), Ifosfamide, Irinotecan Hydrochloride, Ixabepilone, Lenalidomide( CC-5013), Lymphokine-Activated Killer Cells, Melphalan, Methotrexate, Mitoxantrone Hydrochloride, Gadolinium Motexafin, Mycophenolate Mofetil, Nelarabine, Oligomycin (Genasense) Obatoclax (GX15-070), Oligomycin, Octreotide Acetate, ω-3 Fatty Acids, Oxaliplatin, Paclitaxel, PD0332991, PEGylated Liposomal Doxorubicin Hydrochloride, Pegfilgrastim, Pentostatin (Nipent), Perifosine, Prednisolone, Prednisone, R-roscovitine (Selicilib, CYC202), Recombinant Interferon α, Recombinant Interleukin-12, Recombinant Interleukin-11, Recombinant flt3 Ligand, Recombinant Human Thrombopoietin, Rituximab, Sargramostim, Sildenafil Citrate, Simvastatin, Sirolimus, Styryl Sulfone, Tacrolimus, Tanshinone, Temsirolimus (CCl-779), Thalidomide, Therapeutic Allogeneic Lymphocytes, Thiotepa, Tipifarnib, (Bortezomib or PS-341), vincristine (Oncovin), vincristine sulfate, vinorelbine ditartrate, vorinostat (SAHA), vorinostat, and FR (fludarabine, rituximab), CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone), CVP (cyclophosphamide, vincristine, and prednisone), FCM (fludarabine, cyclophosphamide, mitoxantrone), FCR (fludarabine, cyclophosphamide, rituximab), hyperCVAD (hyperfractionated cyclophosphamide, vincristine, doxorubicin, dexamethasone, methotrexate, cytarabine), ICE (ifosfamide, carboplatin, and etoposide), MCP (mitoxantrone, chlorambucil, and prednisolone), R-CHOP (rituximab plus CHOP), R-CVP (rituximab plus CVP), R-FCM (rituximab plus FCM), R-ICE (rituximab-ICE), and R-MCP (rituximab-MCP).

[0413] In some embodiments, the cancer is melanoma. Suitable agents for use in combination with the compounds described herein include, but are not limited to, dacarbazine (DTIC), optionally, together with other chemotherapeutic agents such as carmustine (BCNU) and cisplatin; the "Dartmouth regimen" consisting of DTIC, BCNU, cisplatin, and tamoxifen; combinations of cisplatin, vinblastine, and DTIC, temozolomide, or YERVOY TM According to the compounds of the present invention, in the treatment of melanoma, it can also be combined with immunotherapy drugs, and the immunotherapy drugs include cytokines such as interferon α, interleukin 2, and tumor necrosis factor (TNF).

[0414] The compounds described herein can also be combined with vaccine therapy for the treatment of melanoma. In some aspects, anti-melanoma vaccines are similar to antiviral vaccines used to prevent diseases caused by viruses such as polio, measles, and mumps. Weakened melanoma cells or parts of melanoma cells, known as antigens, can be injected into a patient's body to stimulate the body's immune system to destroy melanoma cells.

[0415] Melanomas confined to the arm or leg can also be treated with a combination of agents including one or more of the compounds described herein using the hyperthermic isolated limb perfusion technique. This treatment protocol temporarily separates the circulation of the involved limb from the rest of the body and injects high doses of chemotherapy drugs into the artery supplying the limb, thereby delivering a high dose to the tumor area without exposing the internal organs to these doses, which could otherwise cause severe side effects. Typically the fluid is heated to 102° to 104°F. Melphalan is the drug most commonly used in this chemotherapy process. This can be administered together with another drug called tumor necrosis factor (TNF).

[0416] The treatment can be supplemented with or combined with any of the above treatments with stem cell transplantation or processing. An example of a modified method is radioimmunotherapy, in which monoclonal antibodies are combined with radioactive isotope particles such as indium In 111, yttrium Y 90, iodine I-131. Examples of combination therapies include, but are not limited to, iodine-131 tositumomab yttrium-90 ibritumomab and CHOP.

[0417] Other treatment procedures include peripheral blood stem cell transplantation, autologous hematopoietic stem cell transplantation, autologous bone marrow transplantation, antibody therapy, biotherapy, enzyme inhibitor therapy, total body irradiation, stem cell infusion, stem cell-supported bone marrow ablation, ex vivo processed peripheral blood stem cell transplantation, cord blood transplantation, immunoenzymatic techniques, pharmacological research, low-LET cobalt-60 γ-ray therapy, bleomycin, conventional surgery, radiotherapy, and non-myeloablative allogeneic hematopoietic stem cell transplantation.

[0418] Anti-HBV combination therapy

[0419] In certain embodiments, methods of treating or preventing HBV infection in a person having or at risk of having HBV infection are provided, which comprise administering to the person a therapeutically effective amount of a compound disclosed herein or a pharmaceutically acceptable salt thereof, in combination with a therapeutically effective amount of one or more (e.g., one, two, three, four, one or two, or one to three, or one to four) additional therapeutic agents. In one embodiment, a method of treating HBV infection in a person having or at risk of having HBV infection is provided, which comprises administering to the person a therapeutically effective amount of a compound disclosed herein or a pharmaceutically acceptable salt thereof, in combination with a therapeutically effective amount of one or more (e.g., one, two, three, four, one or two, or one to three, or one to four) additional therapeutic agents.

[0420] In certain embodiments, the present disclosure provides methods for treating HBV infection, the methods comprising administering to a patient in need thereof a therapeutically effective amount of a compound disclosed herein or a pharmaceutically acceptable salt thereof, in combination with a therapeutically effective amount of one or more additional therapeutic agents suitable for treating HBV infection.

[0421] In one embodiment, there is provided a pharmaceutical composition comprising a compound disclosed herein or a pharmaceutically acceptable salt thereof, and one or more (e.g., one, two, three, four, one or two, or one to three, or one to four) additional therapeutic agents, and a pharmaceutically acceptable carrier, diluent or excipient.

[0422] In one embodiment, there is provided a kit comprising a combination of a compound disclosed herein or a pharmaceutically acceptable salt thereof and one or more (e.g., one, two, three, four, one or two, or one to three, or one to four) additional therapeutic agents.

[0423] In the above embodiments, the additional therapeutic agent can be an anti-HBV agent. For example, in some embodiments, the additional therapeutic agent is selected from HBV combination drugs, HBV DNA polymerase inhibitors, immunomodulators, toll-like receptor modulators (modulators of tlr1, tlr2, tlr3, tlr4, tlr5, tlr6, tlr7, tlr8, tlr9, tlr10, tlr11, tlr12, and tlr13), interferon α receptor ligands, hyaluronidase inhibitors, recombinant IL-7, hepatitis B surface antigen (HBsAg) inhibitors, compounds targeting hepatitis B core antigen (HbcAg), cyclophilin inhibitors, HBV therapeutic vaccines, HBV prophylactic vaccines, HBV virus entry inhibitors, NTCP (Na+-taurocholate cotransporting polypeptide) inhibitors, antisense oligonucleotides targeting viral mRNA, short interfering RNA (siRNA), miRNA gene therapy agents, endonuclease modulators, ribonucleotide reductase inhibitors, hepatitis B virus e antigen inhibitors, recombinant scavenger receptor A (SRA) protein, Src kinase inhibitors, HBx inhibitors, cccDNA inhibitors, short synthetic hairpin RNA (sshRNA), HBV antibodies and "antibody-like" therapeutic proteins including HBV antibodies targeting hepatitis B virus surface antigen and bispecific antibodies (e.g. Fab derivatives, CC R2 chemokine antagonists, thymosin agonists, cytokines, nucleoprotein inhibitors (HBV core or capsid protein inhibitors), stimulators of retinoic acid-inducible gene 1, stimulators of NOD2, stimulators of NOD1, arginase-1 inhibitors, STING agonists, PI3K inhibitors, lymphotoxin β receptor activators, natural killer cell receptor 2B4 inhibitors, lymphocyte activation gene 3 inhibitors, CD160 inhibitors, cytotoxic T lymphocyte-associated protein 4 inhibitors, CD137 inhibitors, killer cell lectin-like receptor subfamily G member 1 inhibitors, TIM-3 inhibitors, B and T lymphocyte attenuator inhibitors, CD305 inhibitors, PD-1 inhibitors, PD-L1 inhibitors, PEG-interferon λ, recombinant thymosin α-1, BTK inhibitors, TIGIT modulators, CD47 modulators, SIRPα modulators, ICOS modulators, CD27 modulators, CD70 modulators, OX40 modulators, NKG2D modulators, Tim-4 modulators, B7-H4 modulators, B7-H3 modulators, NKG2A modulators, GITR modulators, CD160 modulators, HEVEM modulators, CD161 modulators, Axl modulators, Mer modulators, Tyro modulators, gene modifiers or editors such as CRISPR (including CRISPR Cas9), zinc finger nucleases or synthetic nucleases (TALEN), hepatitis B virus replication inhibitor compounds, such as the compounds disclosed in the following documents: US20100143301 (Gilead Sciences), US20110098248 (Gilead Sciences), US20090047249 (Gilead Sciences), US8722054 (Gilead Sciences), US20140045849 (Janssen), US20140073642 (Janssen), WO2014 / 056953 (Janssen), WO2014 / 076221 (Janssen), WO2014 / 128189 (Janssen), US20140350031 (Janssen), WO2014 / 023813 (Janssen), US20080234251 (Array Biopharma), US20080306050 (Array Biopharma), US20100029585 (Ventirx Pharma), US20110092485 (VentirxPharma), US20110118235 (Ventirx Pharma), US20120082658 (Ventirx(Pharma), US20120219615 (Ventirx Pharma), US20140066432 (Ventirx Pharma), US20140088085 (Ventirx Pharma), US20140275167 (Novira therapeutics), US20130251673 (No viratherapeutics), US8513184 (Gilead Sciences), US20140030221 (Gilead S ciences), US20130344030 (Gilead Sciences), US20130344029 (Gilead Scien ces), US20140343032 (Roche), WO2014037480 (Roche), US20130267517 (Roche), WO2014131847 (Janssen), WO2014033176 (Janssen), WO2014033170 (Janssen), WO2014033167 (Janssen), US20140330015 (Ono pharmace utical), US20130079327 (Ono pharmaceutical), US20130217880 (Ono phar maceutical), and other drugs for the treatment of HBV, and combinations thereof.

[0424] In some embodiments, one or more other therapeutic agents include Toll-like receptor 8 (TLR8) modulators. In some embodiments, the Toll-like receptor 8 (TLR8) modulator is a Toll-like receptor 8 (TLR8) agonist. In some embodiments, the Toll-like receptor 8 (TLR8) agonist is a compound disclosed in U.S. Patent No. 9,670,205, which is incorporated herein by reference in its entirety, and particularly with respect to the disclosed compounds (e.g., but not limited to, the compounds of Examples 59, 61, 62, 63, 65, 66, 80, 98, 101, 114, and 116, or pharmaceutically acceptable salts thereof) and methods for their preparation and use. In some embodiments, the Toll-like receptor 8 (TLR8) agonist is selected from:

[0425] or a pharmaceutically acceptable salt thereof. In some embodiments, the Toll-like receptor 8 (TLR8) agonist is selected from:

[0426] or a pharmaceutically acceptable salt thereof.

[0427] In some embodiments, the Toll-like receptor 8 (TLR8) agonist is selected from:

[0428] or a pharmaceutically acceptable salt thereof.

[0429] In some embodiments, the Toll-like receptor 8 (TLR8) agonist is:

[0430] or a pharmaceutically acceptable salt thereof.

[0431] In some embodiments, the Toll-like receptor 8 (TLR8) agonist is:

[0432] or a pharmaceutically acceptable salt thereof.

[0433] In some embodiments, the Toll-like receptor 8 (TLR8) agonist is:

[0434] or a pharmaceutically acceptable salt thereof.

[0435] In some embodiments, the one or more additional therapeutic agents further comprise a programmed death 1 (PD-1) inhibitor and / or a programmed death ligand 1 (PD-L1) inhibitor. In some embodiments, the programmed death 1 (PD-1) inhibitor is selected from nivolumab, lambrolizumab, pembrolizumab, pidilizumab, PDR001, and TSR-001, or a pharmaceutically acceptable salt or solvate of any of the foregoing. In some embodiments, the programmed death ligand 1 (PD-L1) inhibitor is selected from atezolizumab, durvalumab, or avelumab, or a pharmaceutically acceptable salt or solvate of any of the foregoing.

[0436] In certain embodiments, there is provided a method of treating HBV infection in a human having the infection, the method comprising administering to the human:

[0437] (i) a therapeutically effective amount of a compound of formula I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, or Ij disclosed herein, or a pharmaceutically acceptable salt or pharmaceutically acceptable tautomer thereof, in combination with:

[0438] (ii) a therapeutically effective amount of a Toll-like receptor 8 (TLR8) agonist, the TLR8 agonist being selected from:

[0439] or a pharmaceutically acceptable salt thereof, and

[0440] (iii) optionally, a PD-1 inhibitor and / or a PD-L1 inhibitor. In one such method, the optional PD-1 inhibitor and / or PD-L1 inhibitor is not administered. In another such method, the optional PD-1 inhibitor and / or PD-L1 inhibitor is administered. In one such method, a PD-1 inhibitor is administered. In another such method, a PD-L1 inhibitor is administered. In another such method, a PD-1 inhibitor and a PD-L1 inhibitor are administered.

[0441] In certain embodiments, there is provided a method of treating HBV infection in a human having the infection, the method comprising administering to the human:

[0442] (i) a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt or pharmaceutically acceptable tautomer thereof, said compound selected from:

[0443]

[0444]

[0445]

[0446] and in combination with:

[0447] (ii) a therapeutically effective amount of a Toll-like receptor 8 (TLR8) agonist, selected from:

[0448] or a pharmaceutically acceptable salt thereof, and

[0449] (iii) optionally, a PD-1 inhibitor and / or a PD-L1 inhibitor. In one such method, the optional PD-1 inhibitor and / or PD-L1 inhibitor is not administered. In another such method, the optional PD-1 inhibitor and / or PD-L1 inhibitor is administered. In one such method, a PD-1 inhibitor is administered. In another such method, a PD-L1 inhibitor is administered. In another such method, a PD-1 inhibitor and a PD-L1 inhibitor are administered.

[0450] In certain embodiments, there is provided a method of treating HBV infection in a human having the infection, the method comprising administering to the human:

[0451] (i) A therapeutically effective amount of a compound, or a pharmaceutically acceptable salt or pharmaceutically acceptable tautomer thereof, said compound selected from:

[0452] In combination with:

[0453] (ii) A therapeutically effective amount of a Toll-like receptor 8 (TLR8) agonist, selected from:

[0454] or a pharmaceutically acceptable salt thereof; and

[0455] (iii) Optionally, a PD-1 inhibitor and / or a PD-L1 inhibitor. In one such method, the optional PD-1 inhibitor and / or PD-L1 inhibitor is not administered. In another such method, the optional PD-1 inhibitor and / or PD-L1 inhibitor is administered. In one such method, a PD-1 inhibitor is administered. In another such method, a PD-L1 inhibitor is administered. In another such method, a PD-1 inhibitor and a PD-L1 inhibitor are administered.

[0456] In certain embodiments, a method of treating HBV infection in a human having the infection is provided, comprising administering to the human:

[0457] (i) A therapeutically effective amount of a compound, or a pharmaceutically acceptable salt or pharmaceutically acceptable tautomer thereof, said compound selected from:

[0458] In combination with:

[0459] (ii) A therapeutically effective amount of a Toll-like receptor 8 (TLR8) agonist, said TLR8 agonist selected from:

[0460] or a pharmaceutically acceptable salt thereof, and

[0461] (iii) Optionally, a PD-1 inhibitor and / or a PD-L1 inhibitor. In one such method, the optional PD-1 inhibitor and / or PD-L1 inhibitor is not administered. In another such method, the optional PD-1 inhibitor and / or PD-L1 inhibitor is administered. In one such method, a PD-1 inhibitor is administered. In another such method, a PD-L1 inhibitor is administered. In another such method, a PD-1 inhibitor and a PD-L1 inhibitor are administered.

[0462] In certain embodiments, there is provided a method of treating HBV infection in a human having the infection, the method comprising administering to the human:

[0463] (i) a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt or pharmaceutically acceptable tautomer thereof, the compound selected from:

[0464] in combination with:

[0465] (ii) a therapeutically effective amount of a Toll-like receptor 8 (TLR8) agonist, the TLR8 agonist selected from:

[0466] or a pharmaceutically acceptable salt thereof, and

[0467] (iii) optionally, a PD-1 inhibitor and / or a PD-L1 inhibitor. In one such method, the optional PD-1 inhibitor and / or PD-L1 inhibitor is not administered. In another such method, the optional PD-1 inhibitor and / or PD-L1 inhibitor is administered. In one such method, a PD-1 inhibitor is administered. In another such method, a PD-L1 inhibitor is administered. In another such method, a PD-1 inhibitor and a PD-L1 inhibitor are administered.

[0468] In certain embodiments, there is provided a method of treating HBV infection in a human having the infection, the method comprising administering to the human:

[0469] (i) a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt or pharmaceutically acceptable tautomer thereof, the compound selected from:

[0470] in combination with:

[0471] (ii) a therapeutically effective amount of a Toll-like receptor 8 (TLR8) agonist, the TLR8 agonist selected from:

[0472] or a pharmaceutically acceptable salt thereof, and

[0473] (iii) optionally, a PD-1 inhibitor and / or a PD-L1 inhibitor. In one such method, the optional PD-1 inhibitor and / or PD-L1 inhibitor is not administered. In another such method, the optional PD-1 inhibitor and / or PD-L1 inhibitor is administered. In one such method, a PD-1 inhibitor is administered. In another such method, a PD-L1 inhibitor is administered. In another such method, a PD-1 inhibitor and a PD-L1 inhibitor are administered.

[0474] In certain embodiments, a method of treating an HBV infection in a human having the infection is provided, which comprises administering to the human:

[0475] (i) a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt or pharmaceutically acceptable tautomer thereof, said compound selected from:

[0476] in combination with:

[0477] (ii) a therapeutically effective amount of a Toll-like receptor 8 (TLR8) agonist, said TLR8 agonist selected from:

[0478] or a pharmaceutically acceptable salt thereof, and

[0479] (iii) optionally, a PD-1 inhibitor and / or a PD-L1 inhibitor. In one such method, the optional PD-1 inhibitor and / or PD-L1 inhibitor is not administered. In another such method, the optional PD-1 inhibitor and / or PD-L1 inhibitor is administered. In one such method, a PD-1 inhibitor is administered. In another such method, a PD-L1 inhibitor is administered. In another such method, a PD-1 inhibitor and a PD-L1 inhibitor are administered.

[0480] In certain embodiments, a method of treating an HBV infection in a human having the infection is provided, which comprises administering to the human:

[0481] (i) a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt or pharmaceutically acceptable tautomer thereof, said compound selected from:

[0482] in combination with:

[0483] (ii) a therapeutically effective amount of a Toll-like receptor 8 (TLR8) agonist, said TLR8 agonist selected from:

[0484] or a pharmaceutically acceptable salt thereof, and

[0485] (iii) optionally, a PD-1 inhibitor and / or a PD-L1 inhibitor. In one such method, the optional PD-1 inhibitor and / or PD-L1 inhibitor is not administered. In another such method, the optional PD-1 inhibitor and / or PD-L1 inhibitor is administered. In one such method, a PD-1 inhibitor is administered. In another such method, a PD-L1 inhibitor is administered. In another such method, a PD-1 inhibitor and a PD-L1 inhibitor are administered.

[0486] In certain embodiments, there is provided a method of treating an HBV infection in a human having the infection, the method comprising administering to the human:

[0487] (i) a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt or pharmaceutically acceptable tautomer thereof, the compound selected from:

[0488] in combination with:

[0489] (ii) a therapeutically effective amount of a Toll-like receptor 8 (TLR8) agonist, the TLR8 agonist selected from:

[0490] or a pharmaceutically acceptable salt thereof, and

[0491] (iii) optionally, a PD-1 inhibitor and / or a PD-L1 inhibitor. In one such method, the optional PD-1 inhibitor and / or PD-L1 inhibitor is not administered. In another such method, the optional PD-1 inhibitor and / or PD-L1 inhibitor is administered. In one such method, a PD-1 inhibitor is administered. In another such method, a PD-L1 inhibitor is administered. In another such method, a PD-1 inhibitor and a PD-L1 inhibitor are administered.

[0492] There are also provided compositions and kits for combination therapy. In some embodiments, there are provided herein compositions comprising:

[0493] (i) a compound of formula I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii or Ij disclosed herein, or a pharmaceutically acceptable salt or pharmaceutically acceptable tautomer thereof; and

[0494] (ii) a Toll-like receptor 8 (TLR8) agonist selected from:

[0495]

[0496] or a pharmaceutically acceptable salt thereof. In some embodiments, the composition further comprises a PD-1 inhibitor and / or a PD-L1 inhibitor.

[0497] In some embodiments, there are provided herein compositions comprising

[0498] (i) a compound disclosed herein, or a pharmaceutically acceptable salt or pharmaceutically acceptable tautomer thereof, the compound selected from:

[0499]

[0500]

[0501]

[0502]

[0503] and

[0504] (ii) a Toll-like receptor 8 (TLR8) agonist selected from:

[0505]

[0506] or a pharmaceutically acceptable salt thereof. In some embodiments, the composition further comprises a PD-1 inhibitor and / or a PD-L1 inhibitor.

[0507] In some embodiments, provided herein is a composition comprising

[0508] (i) a compound disclosed herein, or a pharmaceutically acceptable salt or pharmaceutically acceptable tautomer thereof, said compound selected from:

[0509]

[0510] (ii) a Toll-like receptor 8 (TLR8) agonist selected from:

[0511] or a pharmaceutically acceptable salt thereof. In some embodiments, the composition further comprises a PD-1 inhibitor and / or a PD-L1 inhibitor.

[0512] In some embodiments, provided herein is a composition comprising

[0513] (i) a compound disclosed herein, or a pharmaceutically acceptable salt or pharmaceutically acceptable tautomer thereof, said compound selected from:

[0514] and

[0515] (ii) a Toll-like receptor 8 (TLR8) agonist selected from:

[0516] or a pharmaceutically acceptable salt thereof. In some embodiments, the composition further comprises a PD-1 inhibitor and / or a PD-L1 inhibitor.

[0517] In certain embodiments, provided herein is a composition comprising

[0518] (i) A compound disclosed herein, or a pharmaceutically acceptable salt or pharmaceutically acceptable tautomer thereof, wherein the compound is selected from:

[0519] and

[0520] (ii) A Toll-like receptor 8 (TLR8) agonist, which is selected from:

[0521] or a pharmaceutically acceptable salt thereof. In some embodiments, the composition further comprises a PD-1 inhibitor and / or a PD-L1 inhibitor.

[0522] In certain embodiments, the present disclosure provides a composition comprising

[0523] (i) A compound disclosed herein, or a pharmaceutically acceptable salt or pharmaceutically acceptable tautomer thereof, wherein the compound is selected from:

[0524] and

[0525] (ii) A Toll-like receptor 8 (TLR8) agonist, which is selected from:

[0526] or a pharmaceutically acceptable salt thereof. In some embodiments, the composition further comprises a PD-1 inhibitor and / or a PD-L1 inhibitor.

[0527] In certain embodiments, the present disclosure provides a composition comprising

[0528] (i) A compound disclosed herein, or a pharmaceutically acceptable salt or pharmaceutically acceptable tautomer thereof, wherein the compound is selected from:

[0529] and

[0530] (ii) A Toll-like receptor 8 (TLR8) agonist, which is selected from:

[0531] or a pharmaceutically acceptable salt thereof. In some embodiments, the composition further comprises a PD-1 inhibitor and / or a PD-L1 inhibitor.

[0532] In certain embodiments, the present disclosure provides a composition comprising

[0533] (i) A compound disclosed herein, or a pharmaceutically acceptable salt or pharmaceutically acceptable tautomer thereof, wherein the compound is selected from:

[0534] and

[0535] (ii) Toll-like receptor 8 (TLR8) agonists, selected from:

[0536] or a pharmaceutically acceptable salt thereof. In some embodiments, the composition further comprises a PD-1 inhibitor and / or a PD-L1 inhibitor.

[0537] In certain embodiments, the present disclosure provides a composition comprising

[0538] (i) a compound disclosed herein, or a pharmaceutically acceptable salt or pharmaceutically acceptable tautomer thereof, said compound selected from:

[0539] and

[0540] (ii) Toll-like receptor 8 (TLR8) agonists, selected from:

[0541] or a pharmaceutically acceptable salt thereof. In some embodiments, the composition further comprises a PD-1 inhibitor and / or a PD-L1 inhibitor.

[0542] In certain embodiments, the present disclosure provides a composition comprising

[0543] (i) a compound disclosed herein, or a pharmaceutically acceptable salt or pharmaceutically acceptable tautomer thereof, said compound selected from:

[0544] and

[0545] (ii) Toll-like receptor 8 (TLR8) agonists, selected from:

[0546] or a pharmaceutically acceptable salt thereof. In some embodiments, the composition further comprises a PD-1 inhibitor and / or a PD-L1 inhibitor.

[0547] In certain embodiments, the present disclosure provides a composition comprising

[0548] (i) a compound disclosed herein, or a pharmaceutically acceptable salt or pharmaceutically acceptable tautomer thereof, said compound selected from:

[0549] and

[0550] (ii) Toll-like receptor 8 (TLR8) agonists, selected from:

[0551] or a pharmaceutically acceptable salt thereof. In some embodiments, the composition further comprises a PD-1 inhibitor and / or a PD-L1 inhibitor.

[0552] In some embodiments, provided herein are kits that comprise:

[0553] (i) a compound of Formula I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, or Ij disclosed herein, or a pharmaceutically acceptable salt or pharmaceutically acceptable tautomer thereof; and

[0554] (ii) a Toll-like receptor 8 (TLR8) agonist selected from:

[0555] or a pharmaceutically acceptable salt thereof. In some embodiments, the kit further comprises a PD-1 inhibitor and / or a PD-L1 inhibitor. In some embodiments, the kit further comprises instructions indicating use for treating HBV infection in a human.

[0556] In some embodiments, provided herein are kits that comprise:

[0557] (i) a compound disclosed herein, or a pharmaceutically acceptable salt or pharmaceutically acceptable tautomer thereof, said compound selected from:

[0558]

[0559]

[0560]

[0561] and

[0562] (ii) a Toll-like receptor 8 (TLR8) agonist selected from:

[0563] or a pharmaceutically acceptable salt thereof. In some embodiments, the kit further comprises a PD-1 inhibitor and / or a PD-L1 inhibitor. In some embodiments, the kit further comprises instructions indicating use for treating HBV infection in a human.

[0564] In certain embodiments, the additional therapeutic agent is selected from HBV combination drugs, HBV DNA polymerase inhibitors, toll-like receptor 7 modulators, toll-like receptor 8 modulators, toll-like receptor 7 and 8 modulators, toll-like receptor 3 modulators, interferon alpha receptor ligands, HBsAg inhibitors, compounds targeting HbcAg, cyclophilin inhibitors, HBV therapeutic vaccines, HBV prophylactic vaccines, HBV viral entry inhibitors, NTCP inhibitors, antisense oligonucleotides targeting viral mRNA, short interfering RNAs (siRNAs), hepatitis B virus e antigen inhibitors, HBx inhibitors, cccDNA inhibitors, HBV antibodies including HBV antibodies targeting the surface antigen of hepatitis B virus, thymosin agonists, cytokines, nucleoprotein inhibitors (HBV nuclear or capsid protein inhibitors), stimulator of interferon genes 1, stimulator of NOD2, stimulator of NOD1, recombinant thymosin alpha-1, BTK inhibitors, and hepatitis B virus replication inhibitors, and combinations thereof.

[0565] In certain embodiments, the compounds disclosed herein are formulated into tablets, which may optionally contain one or more other compounds useful for the treatment of HBV. In certain embodiments, the tablets may contain another active ingredient for the treatment of HBV, such as an HBV DNA polymerase inhibitor, an immunomodulator, a toll-like receptor modulator (modulators of tlr1, tlr2, tlr3, tlr4, tlr5, tlr6, tlr7, tlr8, tlr9, tlr10, tlr11, tlr12, and tlr13), a modulator of tlr7, a modulator of tlr8, a modulator of tlr7 and tlr8, an interferon α receptor ligand, a hyaluronidase inhibitor, a hepatitis B surface antigen (HBsAg) inhibitor, a compound targeting hepatitis B core antigen (HbcAg), a cyclophilin inhibitor, an HBV virus entry inhibitor, an NTCP (Na+-taurocholate cotransporting polypeptide) inhibitor, an endonuclease modulator, a ribonucleotide reductase inhibitor, a hepatitis B virus e antigen inhibitor, an Src kinase inhibitor, an HBx inhibitor, a cccDNA inhibitor, a CCR2 chemokine antagonist, a thymosin agonist, a nucleoprotein inhibitor (HBV nuclear or capsid protein inhibitor), a stimulator of retinoic acid-inducible gene 1, a stimulator of NOD2, a stimulator of NOD1, an arginase-1 inhibitor, a STING agonist, a PI3K inhibitor, a lymphotoxin β receptor activator, a natural killer cell receptor 2B4 inhibitor, a lymphocyte activation gene 3 inhibitor, a CD160 inhibitor, a cytotoxic T lymphocyte-associated protein 4 inhibitor, a CD137 inhibitor, a killer cell lectin-like receptor subfamily G member 1 inhibitor, a TIM-3 inhibitor, a B and T lymphocyte attenuator inhibitor, a CD305 inhibitor, a PD-1 inhibitor, a PD-L1 inhibitor, a BTK inhibitor, a TIGIT modulator, a CD47 modulator, an SIRPα modulator, an ICOS modulator, a CD27 modulator, a CD70 modulator, an OX40 modulator, an NKG2D modulator, a Tim-4 modulator, a B7-H4 modulator, a B7-H3 modulator, an NKG2A modulator, a GITR modulator, a CD160 modulator, a HEVEM modulator, a CD161 modulator, an Axl modulator, a Mer modulator, a Tyro modulator, and a hepatitis B virus replication inhibitor, and combinations thereof.

[0566] In some embodiments, methods of treating HBV in a subject include administering to the subject a therapeutically effective amount of any of the compounds described herein (e.g., of formula I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, or Ij or a pharmaceutically acceptable salt or pharmaceutically acceptable tautomer thereof) in combination with an immunotherapeutic agent, such as an immune checkpoint inhibitor, a hematopoietic progenitor kinase 1 (HPK1) inhibitor, an immune checkpoint stimulating protein agonist, or an engineered immune cell (e.g., a T cell having a chimeric antigen receptor (i.e., a CAR T cell) or a T cell having an engineered T cell receptor (TCR)). In some embodiments, the compound is administered to the subject before, after, or simultaneously with the administration of one or more immunotherapeutic agents. In some embodiments, the compound is administered to the subject about 30 minutes or more, about 1 hour or more, about 2 hours or more, about 4 hours or more, about 6 hours or more, about 12 hours or more, about 24 hours or more, about 48 hours or more, or about 72 hours or more before or after the administration of one or more additional immunotherapeutic agents. In some embodiments, the compound is administered to the subject about 30 minutes or less, about 1 hour or less, about 2 hours or less, about 4 hours or less, about 6 hours or less, about 12 hours or less, about 24 hours or less, about 48 hours or less, or about 72 hours or less before or after the administration of one or more additional immunotherapeutic agents.

[0567] In some embodiments, methods of treating HBV in a subject include administering to the subject a therapeutically effective amount of any of the compounds described herein (e.g., of formula I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, or Ij or a pharmaceutically acceptable salt or pharmaceutically acceptable tautomer thereof) in combination with one or more immune checkpoint inhibitors. In some embodiments, the compound is administered to the subject before, after, or simultaneously with the administration of the immune checkpoint inhibitor. In some embodiments, the immune checkpoint inhibitor is a small molecule inhibitor. In some embodiments, the immune checkpoint inhibitor is an antibody or a fragment thereof. In some embodiments, the immune checkpoint inhibitor inhibits adenosine A 2AReceptors (A2aR), B7-H3, V-set domain-containing T cell activation inhibitor 1 (VTCN1, also known as B7-H4), B and T lymphocyte attenuator (BTLA), cytotoxic T lymphocyte-associated protein 4 (CTLA-4), killer cell immunoglobulin-like receptor (KIR), lymphocyte activation gene 3 (LAG3), programmed death 1 (PD-1), programmed death ligand 1 (PD-L1), programmed death ligand 2 (PD-L2), T cell immunoreceptor with Ig and ITIM domains (TIGIT), T cell immunoglobulin and mucin domain 3 (TIM-3), or V-domain Ig inhibitor of T cell activation (VISTA). Exemplary immune checkpoint inhibitors include, but are not limited to, avelumab, atezolizumab, durvalumab, nivolumab, pembrolizumab, ipilimumab, PDR001, TSR-042, and BMS-986016.

[0568] In some embodiments, a method of treating HBV in a subject comprises administering to the subject a therapeutically effective amount of any of the compounds described herein (e.g., of formula I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, or Ij or a pharmaceutically acceptable salt or pharmaceutically acceptable tautomer thereof) in combination with one or more immune checkpoint-stimulating protein agonists. In some embodiments, the compound is administered to the subject before, after, or simultaneously with the administration of the immune checkpoint-stimulating protein agonist. In some embodiments, the immune checkpoint-stimulating protein agonist is an antibody or a fragment thereof. In some embodiments, the immune checkpoint-stimulating protein agonist is an agonist of CD27, CD28, CD40, CD122, 4-1BB, OX40, glucocorticoid-induced TNFR family-related protein (GITR), or inducible T cell co-stimulator molecule (ICOS).

[0569] In some embodiments, a method of treating HBV in a subject comprises administering to the subject a combination of a therapeutically effective amount of any of the compounds described herein (e.g., of formula I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii or Ij or a pharmaceutically acceptable salt or pharmaceutically acceptable tautomer thereof) and a therapeutically effective amount of engineered immune cells, such as CAR T cells or T cells having an engineered TCR. In some embodiments, the compound is administered to the subject before, after or simultaneously with the administration of the engineered immune cells. In some embodiments, the engineered immune cells are heterologous engineered immune cells, such as heterologous engineered T cells (e.g., CAR T cells or T cells having an engineered TCR). In some embodiments, the engineered immune cells are autologous engineered immune cells, such as autologous engineered T cells (e.g., CAR T cells or T cells having an engineered TCR). In some embodiments, the engineered immune cells (e.g., engineered T cells) target HBV antigens, such as hepatitis B surface antigen (HBsAg) or hepatitis B core antigen (HBcAg).

[0570] In some embodiments, methods of treating HBV in a subject include administering to the subject a therapeutically effective amount of any of the compounds described herein (e.g., Formula I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, or Ij or a pharmaceutically acceptable salt or pharmaceutically acceptable tautomer thereof) in combination with (1) a therapeutically effective amount of engineered immune cells, such as CAR T cells or T cells having an engineered TCR, and (2) a therapeutically effective amount of an immune checkpoint inhibitor or an immune checkpoint stimulating protein agonist. In some embodiments, methods of treating HBV in a subject include administering to the subject a therapeutically effective amount of any of the compounds described herein (e.g., Formula I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, or Ij or a pharmaceutically acceptable salt or pharmaceutically acceptable tautomer thereof) in combination with (1) a therapeutically effective amount of engineered immune cells, such as CAR T cells or T cells having an engineered TCR, and (2) a therapeutically effective amount of an antiviral agent (e.g., an anti-HBV agent). In some embodiments, methods of treating HBV in a subject include administering to the subject a therapeutically effective amount of any of the compounds described herein (e.g., Formula I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, or Ij or a pharmaceutically acceptable salt or pharmaceutically acceptable tautomer thereof) in combination with (1) a therapeutically effective amount of an immune checkpoint inhibitor or an immune checkpoint stimulating protein agonist, and (2) a therapeutically effective amount of an antiviral agent (e.g., an anti-HBV agent). In some embodiments, methods of treating HBV in a subject include administering to the subject a therapeutically effective amount of any of the compounds described herein (e.g., Formula I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, or Ij or a pharmaceutically acceptable salt or pharmaceutically acceptable tautomer thereof) in combination with (1) a therapeutically effective amount of engineered immune cells, such as CAR T cells or T cells having an engineered TCR, (2) a therapeutically effective amount of an immune checkpoint inhibitor or an immune checkpoint stimulating protein agonist, and (3) a therapeutically effective amount of an antiviral agent (e.g., an anti-HBV agent).

[0571] In certain embodiments, such tablets are suitable for once-daily dosing.

[0572] In some embodiments, the additional therapeutic agent is selected from one or more of the following:

[0573] (1)Combination drugs, which are selected from tenofovir disoproxil fumarate + emtricitabine (TRUVADA); adefovir + clevudine, ABX-203 + lamivudine + PEG-IFNα, ABX-203 + adefovir + PEG-IFNα and GBV-015;

[0574] (2)HBV DNA polymerase inhibitors, which are selected from besifovir, entecavir adefovir tenofovir disoproxil fumarate tenofoviralafenamide, tenofovir, tenofovir disoproxil, tenofoviralafenamide fumarate, tenofoviralafenamide semi-fumarate, tenofovir bis-pivalate, tenofovir bis-pivalate fumarate, tenofovir octadecyl oxyethyl ester, telbivudine paritaprevir, clevudine, emtricitabine ribavirin, lamivudine phosphazide, famciclovir, SNC-019754, FMCA, fusolin, AGX-1009 and metacavir;

[0575] (3)Immunomodulators, which are selected from resiquimod, emedastine dihydrochloride, ingaron, dermaVir, plaquenil (hydroxychloroquine), aldesleukin, hydroxyurea, mycophenolate mofetil (MPA) and its ester derivative mycophenolate mofetil (MMF), WF-10, ribavirin, IL-12, polymer polyethyleneimine (PEI), Gepon, VGV-1, MOR-22, BMS-936559 and IR-103;

[0576] (4)Toll-like receptor 7 modulators, which are selected from GS-9620, GSK-2245035, imiquimod, resiquimod, DSR-6434, DSP-3025, IMO-4200, MCT-465, 3M-051, SB-9922, 3M-052, Limtop, TMX-30X, TMX-202RG-7863 and RG-7795;

[0577] (5)Toll-like receptor 8 modulators, which are selected from motolimod, resiquimod, 3M-051, 3M-052, MCT-465, IMO-4200, VTX-763, VTX-1463;

[0578] (6) Toll-like receptor 3 modulators selected from resiquimod, poly-ICLC, MCT-465, MCT-475, Riboxxon, Riboxxim, and ND-1.1;

[0579] (7) Interferon α receptor ligands selected from interferon α-2b Pegylated interferon α-2a Interferon α1b Veldona, Infradure, Roferon-A, YPEG-interferon α-2a (YPEG-rhIFNα-2a), P-1101, Algeron, Alfarona, Ingaron (interferon γ), rSIFN-co (recombinant super interferon), Ypeg interferon α-2b (YPEG-rhIFNα-2b), MOR-22, peg interferon α-2b Bioferon, Novaferon, Inmutag (Inferon), Interferon α-n1 Interferon β-1a Shaferon, interferon α-2b (AXXO), Alfaferone, interferon α-2b (BioGeneric Pharma), interferon-α2 (CJ), Laferonum, VIPEG, BLAUFERON-B, BLAUFERON-A, Intermaxα, Realdiron, Lanstion, Pegaferon, PDFERON-B PDFERON-B, interferon α-2b (IFN, Laboratorios Bioprofarma), alfainterferona 2b, Kalferon, Pegnano, Feronsure, PegiHep, interferon α2b (Zydus-Cadila), Optipeg A, Reα2b, Reliferon, interferon α-2b (Amega), interferon α-2b (Virchow), peg interferon α-2b (Amega), Reaferon-EC, Proquiferon, Uniferon, Urifron, interferon α-2b (Changchun Institute of Biological Products), Andafen, Shanferon, Layfferon, Shang Sheng Lei Tai, INTEFEN, SINOGEN, Fukangtai, Pegstat, rHSA-IFNα-2b, and Interapo (Interapa);

[0580] (8) A hyaluronidase inhibitor selected from astodrimer;

[0581] (9) A modulator of IL-10;

[0582] (10) An HBsAg inhibitor selected from HBF-0259, PBHBV-001, PBHBV-2-15, PBHBV-2-1, REP9AC, REP-9C and REP 9AC';

[0583] (11) A Toll-like receptor 9 modulator selected from CYT003;

[0584] (12) A cyclophilin inhibitor selected from OCB-030, SCY-635 and NVP-018;

[0585] (13) An HBV prophylactic vaccine selected from Hexaxim, Heplisav, Mosquirix, DTwP-HBV vaccine, Bio-Hep-B, D / T / P / HBV / M (LBVP-0101; LBVW-0101), DTwP-Hepb-Hib-IPV vaccine, Heberpenta L, DTwP-HepB-Hib, V-419, CVI-HBV-001, Tetrabhay, hepatitis B prophylactic vaccine (Advax Super D), Hepatrol-07, GSK-223192A, Recombinant hepatitis B vaccine (intramuscular, Kangtai Biological Products), recombinant hepatitis B vaccine (Hansenula polymorpha, intramuscular, Hualan Biological Engineering), Bimmugen, Euforavac, Eutravac, anrix-DTaP-IPV-Hep B, Infanrix-DTaP-IPV-Hep B-Hib, Pentabio Vaksin DTP-HB-Hib, Comvac 4, Twinrix, Euvax-B, Tritanrix HB, Infanrix Hep B, Kenweis, DTP-Hib-HBV vaccine, DTP-HBV vaccine, Yi Tai, Heberbiovac HB, Trivac HB, GerVax, DTwP-Hep B-Hib vaccine, Bilive, Hepavax-Gene, SUPERVAX, Comvac5, Shanvac-B, Hebsulin, Recombivax HB, Revac B mcf, Revac B+, Fendrix, DTwP-HepB-Hib, DNA-001, Shan6, rhHBsAG vaccine, and DTaP-rHB-Hib vaccine;

[0586] (14) HBV therapeutic vaccines, selected from HBsAG-HBIG complex, Bio-Hep-B, NASVAC, abi-HB (intravenous), ABX-203, Tetrabhay, GX-110E, GS-4774, peptide vaccine (epsilonPA-44), Hepatrol-07, NASVAC (NASTERAP), IMP-321, BEVAC, Revac B mcf, Revac B+, MGN-1333, KW-2, CVI-HBV-002, AltraHepB, VGX-6200, FP-02, TG-1050, NU-500, HBVax, im / TriGrid / antigen vaccine, Mega-CD40L-adjuvant vaccine, HepB-v, NO-1800, recombinant VLP-based therapeutic vaccine (HBV infection, VLP Biotech), AdTG-17909, AdTG-17910AdTG-18202, CHronVac-B, and Lm HBV;

[0587] (15) HBV virus entry inhibitors, selected from Myrcludex B;

[0588] (16) Antisense oligonucleotides targeting viral mRNA, selected from ISIS-HBVRx;

[0589] (17) Short interfering RNA (siRNA), which is selected from TKM-HBV (TKM-HepB), ALN-HBV, SR-008, ddRNAi, and ARC-520;

[0590] (18) Endonuclease modulator, which is selected from PGN-514;

[0591] (19) Ribonucleotide reductase inhibitor, which is selected from Trimidox;

[0592] (20) Hepatitis B virus e antigen inhibitor, which is selected from wogonin;

[0593] (21) HBV antibody targeting hepatitis B virus surface antigen, which is selected from GC-1102, XTL-17, XTL-19, XTL-001, KN-003, and fully human monoclonal antibody therapy (hepatitis B virus infection, Humabs BioMed);

[0594] (22) HBV antibodies including monoclonal antibodies and polyclonal antibodies, which are selected from Zutectra, Shang Sheng Gan Di, Uman Big (hepatitis B hyperimmune), Omri-Hep-B, Nabi-HB, Hepatect CP, HepaGam B, igantibe, Niuliva, CT-P24, hepatitis B immunoglobulin (intravenous, pH4, hepatitis B virus infection, ShanghaiRAAS Blood Products), and Fovepta (BT-088);

[0595] (23) CCR2 chemokine antagonist, which is selected from propizide;

[0596] (24) Thymosin agonist, which is selected from thymalfasin;

[0597] (25) Cytokines, which are selected from recombinant IL-7, CYT-107, interleukin-2 (IL-2, Immunex); recombinant human interleukin-2 (Shenzhen Neptunus, Shenzhen Neptunus), and simotil;

[0598] (26) Nucleoprotein inhibitor (hepatitis B virus core or capsid protein inhibitor), which is selected from NVR-1221, NVR-3778, BAY41-4109, morphothiadine mesilate, and DVR-23;

[0599] (27) Stimulants of retinoic acid-inducible gene 1, selected from SB-9200, SB-40, SB-44, ORI-7246, ORI-9350, ORI-7537, ORI-9020, ORI-9198, and ORI-7170;

[0600] (28) Stimulants of NOD2, selected from SB-9200;

[0601] (29) Recombinant thymosin α-1, selected from NL-004 and pegylated thymosin α1;

[0602] (30) Hepatitis B virus replication inhibitors, selected from isothiocyanic acid fluorine, IQP-HBV, RM-5038, and Xingantie;

[0603] (31) PI3K inhibitors, selected from idelalisib, AZD-8186, buparlisib, CLR-457, pictilisib, neratinib, rigosertib, rigosertib sodium, EN-3342, TGR-1202, alpelisib, duvelisib, UCB-5857, taselisib, XL-765, gedatolisib, VS-5584, copanlisib, CAI oramid, perifosine, RG-7666, GSK-2636771, DS-7423, panulisib, GSK-2269557, GSK-2126458, CUDC-907, PQR-309, INCB-040093, pilaralisib, BAY-1082439, pquitinib mesylate, SAR-245409, AMG-319, RP-6530, ZSTK-474, MLN-1117, SF-1126, RV-1729, sonolisib, LY-3023414, SAR-260301, and CLR-1401;

[0604] (32) cccDNA inhibitors, selected from BSBI-25;

[0605] (33) PD-L1 inhibitors, selected from MEDI-0680, RG-7446, durvalumab, KY-1003, KD-033, MSB-0010718C, TSR-042, ALN-PDL, STI-A1014, and BMS-936559;

[0606] (34) PD-1 inhibitors, selected from nivolumab, pembrolizumab, pidilizumab, BGB-108, and mDX-400;

[0607] (35) BTK inhibitors, which are selected from ACP-196, dasatinib, ibrutinib, PRN-1008, SNS-062, ONO-4059, BGB-3111, MSC-2364447, X-022, spebrutinib, TP-4207, HM-71224, KBP-7536, and AC-0025;

[0608] (36) Other drugs for the treatment of HBV, which are selected from gentiopicroside, nitazoxanide, birinapant, NOV-205 (Molixan; BAM-205), Oligotide, miltefosine, human fibroblast interferon, levamisole, kassinin, Alloferon, WS-007, Y-101 (tifentine), rSIFN-co, PEG-IIFNm, KW-3, BP-Inter-014, oleanolic acid, HepB-nRNA, cTP-5 (rTP-5), HSK-II-2, HEISCO-106-1, HEISCO-106, Hepbarna, IBPB-006IA, Hepuyinfen, DasKloster 0014-01, Jiangantai (Ganxikang), picroside II, GA5 NM-HBV, DasKloster-0039, hepulantai, IMB-2613, TCM-800B, reduced glutathione, and ZH-2N; and

[0609] (37) Compounds disclosed in the following documents: US20100143301 (Gilead Sciences), US20110098248 (Gilead Sciences), US20090047249 (Gilead Sciences), US8722054 (Gilead Sciences), US20140045849 (Janssen), US20140073642 (Janssen), WO2014 / 056953 (Janssen), WO2014 / 076221 (Janssen), WO2014 / 128189 (Janssen), US20140350031 (Janssen), WO2014 / 023813 (Janssen), US20080234251 (Array Biopharma), US20080306050 (Array Biopharma), US20100029585 (Ventirx Pharma), US20110092485 (Ventirx Pharma), US20110118235 (Ventirx Pharma), US20120082658 (Ventirx Pharma), US20120219615 (Ventirx Pharma), US20140066432 (Ventirx Pharma), US20140088085 (Ventirx Pharma), US20140275167 (Novira therapeutics), US20130251673 (Novira therapeutics), US8513184 (Gilead Sciences), US20140030221 (Gilead Sciences), US20130344030 (Gilead Sciences), US20130344029 (Gilead Sciences), US20140343032 (Roche), WO2014037480 (Roche), US20130267517 (Roche), WO2014131847 (Janssen), WO2014033176 (Janssen), WO2014033170 (Janssen), WO2014033167 (Janssen), US20140330015 (Ono pharmaceutical), US20130079327 (Ono pharmaceutical) and US20130217880 (Onopharmaceutical).

[0610] In some embodiments, the compounds or pharmaceutically acceptable salts thereof disclosed herein are combined with 1, 2, 3, 4 or more additional therapeutic agents. In some embodiments, the compounds or pharmaceutically acceptable salts thereof disclosed herein are combined with 2 additional therapeutic agents. In other embodiments, the compounds or pharmaceutically acceptable salts thereof disclosed herein are combined with 3 additional therapeutic agents. In other embodiments, the compounds or pharmaceutically acceptable salts thereof disclosed herein are combined with 4 additional therapeutic agents. The 1, 2, 3, 4 or more additional therapeutic agents can be different therapeutic agents selected from the same class of therapeutic agents, and / or they can be selected from different classes of therapeutic agents.

[0611] In one specific embodiment, the compounds or pharmaceutically acceptable salts thereof disclosed herein are combined with an HBV DNA polymerase inhibitor. In another specific embodiment, the compounds or pharmaceutically acceptable salts thereof disclosed herein are combined with an HBV DNA polymerase inhibitor and at least one additional therapeutic agent selected from: immunomodulators, toll-like receptor modulators (modulators of tlr1, tlr2, tlr3, tlr4, tlr5, tlr6, tlr7, tlr8, tlr9, tlr10, tlr11, tlr12 and tlr13), interferon α receptor ligands, hyaluronidase inhibitors, recombinant IL-7, HBsAg inhibitors, compounds targeting HbcAg, cyclophilin inhibitors, HBV therapeutic vaccines, HBV prophylactic vaccines, HBV viral entry inhibitors, NTCP inhibitors, antisense oligonucleotides targeting viral mRNA, short interfering RNAs (siRNAs), miRNA gene therapy agents, endonuclease modulators, ribonucleotide reductase inhibitors, hepatitis B virus e antigen inhibitors, recombinant scavenger receptor A (SRA) protein, src kinase inhibitors, HBx inhibitors, cccDNA inhibitors, short synthetic hairpin RNAs (sshRNAs), HBV antibodies including HBV antibodies targeting hepatitis B virus surface antigen and bispecific antibodies, and "antibody-like" therapeutic proteins (e.g. Fab derivatives), CCR2 chemokine antagonists, thymosin agonists, cytokines, nucleoprotein inhibitors (HBV core or capsid protein inhibitors), stimulators of retinoic acid-inducible gene 1, stimulators of NOD2, stimulators of NOD1, arginase-1 inhibitors, STING agonists, PI3K inhibitors, lymphotoxin β receptor activators, natural killer cell receptor 2B4 inhibitors, lymphocyte activation gene 3 inhibitors, CD160 inhibitors, cytotoxic T-lymphocyte-associated protein 4 inhibitors, CD137 inhibitors, killer cell lectin-like receptor subfamily G member 1 inhibitors, TIM-3 inhibitors, B- and T-lymphocyte attenuator inhibitors, CD305 inhibitors, PD-1 inhibitors, PD-L1 inhibitors, PEG-interferon λ, recombinant thymosin α-1, BTK inhibitors, TIGIT modulators, CD47 modulators, SIRPα modulators, ICOS modulators, CD27 modulators, CD70 modulators, OX40 modulators, NKG2D modulators, Tim-4 modulators, B7-H4 modulators, B7-H3 modulators, NKG2A modulators, GITR modulators, CD160 modulators, HEVEM modulators, CD161 modulators, Axl modulators, Mer modulators, Tyro modulators, gene modifiers or editors such as CRISPR (including CRISPR Cas9), zinc finger nucleases or synthetic nucleases (TALEN), and HBV replication inhibitors.

[0612] In another specific embodiment, the compounds or pharmaceutically acceptable salts thereof disclosed herein are combined with an HBV DNA polymerase inhibitor and at least a second additional therapeutic agent selected from: immunomodulators, toll-like receptor modulators (modulators of tlr1, tlr2, tlr3, tlr4, tlr5, tlr6, tlr7, tlr8, tlr9, tlr10, tlr11, tlr12, and tlr13), HBsAg inhibitors, HBV therapeutic vaccines, HBV antibodies and "antibody-like" therapeutic proteins including HBV antibodies and bispecific antibodies targeting hepatitis B virus surface antigen (e.g. Fab derivatives), cyclophilin inhibitors, stimulators of retinoic acid-inducible gene 1, PD-1 inhibitors, PD-L1 inhibitors, arginase-1 inhibitors, PI3K inhibitors, and stimulators of NOD2.

[0613] In another specific embodiment, the compounds disclosed herein or pharmaceutically acceptable salts thereof are combined with an HBV DNA polymerase inhibitor and at least a second additional therapeutic agent selected from: HBV virus entry inhibitors, NTCP inhibitors, HBx inhibitors, cccDNA inhibitors, HBV antibodies targeting hepatitis B virus surface antigen, short interfering RNAs (siRNAs), miRNA gene therapy agents, short synthetic hairpin RNAs (sshRNAs), and nucleoprotein inhibitors (HBV core or capsid protein inhibitors).

[0614] In another specific embodiment, the compounds disclosed herein or pharmaceutically acceptable salts thereof are combined with: an HBV DNA polymerase inhibitor; one or two additional therapeutic agents selected from: immunomodulators, toll-like receptor modulators (modulators of tlr1, tlr2, tlr3, tlr4, tlr5, tlr6, tlr7, tlr8, tlr9, tlr10, tlr11, tlr12, and tlr13), HBsAg inhibitors, HBV therapeutic vaccines, HBV antibodies and "antibody-like" therapeutic proteins including HBV antibodies targeting hepatitis B virus surface antigen and bispecific antibodies (e.g. Fab derivatives), cyclophilin inhibitors, stimulators of retinoic acid-inducible gene 1, PD-1 inhibitors, PD-L1 inhibitors, arginase-1 inhibitors, PI3K inhibitors, and stimulators of NOD2; and one or two additional therapeutic agents selected from: HBV virus entry inhibitors, NTCP inhibitors, HBx inhibitors, cccDNA inhibitors, HBV antibodies targeting hepatitis B virus surface antigen, short interfering RNAs (siRNAs), miRNA gene therapy agents, short synthetic hairpin RNAs (sshRNAs), and nucleoprotein inhibitors (HBV core or capsid protein inhibitors).

[0615] In one specific embodiment, the compounds disclosed herein or pharmaceutically acceptable salts thereof are combined with one, two, three, four or more additional therapeutic agents selected from adefovir tenofovir disoproxil fumarate + emtricitabine tenofovir disoproxil fumarate entecavir lamivudine tenofovir alafenamide, tenofovir, tenofovir disoproxil, tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, telbivudine emtricitabine peg interferon α-2b interferon α1b Interferon α-2b Pegylated interferon α-2a Interferon α-n1 Ribavirin, Interferon β-1a Bioferon, Ingaron, Inmutag (Inferon), Algeron, Roferon-A, Oligotide, Zutectra, Shaferon, Interferon α-2b (AXXO), Alfaferone, Interferon α-2b (BioGeneric Pharma), Human fibroblast interferon, Interferon-α2 (CJ), BEVAC, Laferonum, VIPEG, BLAUFERON-B, BLAUFERON-A, Intermaxα, Realdiron, Lanstion, Pegaferon, PDferon-B, Interferon α-2b (IFN, Laboratorios Bioprofarma), alfainterferona 2b, Kalferon, Pegnano, Feronsure, PegiHep, Interferon α2b (Zydus-Cadila), Optipeg A, Reα2b, Reliferon, Interferon α-2b (Amega), Interferon α-2b (Virchow), peginterferon α-2b (Amega), Reaferon-EC, Proquiferon, Uniferon, Urifron, Interferon α-2b (Changchun Institute of Biological Products), Andafen, Shanferon, MOR-22, Interleukin-2 (IL-2, Immunex), Recombinant human interleukin-2 (Shenzhen Hepalink), Layfferon, Kashing, ShangSheng LeiTai, Intron A, Sai Ruojin, Fukangtai, Alloferon and Simu interleukin.

[0616] In one specific embodiment, the compounds or pharmaceutically acceptable salts thereof disclosed herein are combined with the following: Entecavir Adefovir Tenofovir disoproxil fumarate Tenofovir alafenamide, Tenofovir, Tenofovir disoproxil, Tenofovir alafenamide fumarate, Tenofovir alafenamide semi-fumarate, Telbivudine Or Lamivudine

[0617] In a specific embodiment, the compounds disclosed herein or pharmaceutically acceptable salts thereof are combined with: entecavir adefovir tenofovir disoproxil fumarate tenofovir alafenamide hemifumarate, telbivudine or lamivudine

[0618] In a specific embodiment, the compounds disclosed herein or pharmaceutically acceptable salts thereof are combined with a first additional therapeutic agent and at least a second additional therapeutic agent, wherein the first additional therapeutic agent is selected from entecavir adefovir tenofovir disoproxil fumarate tenofovir alafenamide, tenofovir, tenofovir disoproxil, tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, telbivudine or lamivudine The second additional therapeutic agent is selected from immunomodulators, toll-like receptor modulators (modulators of tlr1, tlr2, tlr3, tlr4, tlr5, tlr6, tlr7, tlr8, tlr9, tlr10, tlr11, tlr12 and tlr13), interferon α receptor ligands, hyaluronidase inhibitors, recombinant IL-7, HBsAg inhibitors, compounds targeting HbcAg, cyclophilin inhibitors, HBV therapeutic vaccines, HBV prophylactic vaccines, HBV virus entry inhibitors, NTCP inhibitors, antisense oligonucleotides targeting viral mRNA, short interfering RNA (siRNA), miRNA gene therapy agents, endonuclease modulators, ribonucleotide reductase inhibitors, hepatitis B virus e antigen inhibitors, recombinant scavenger receptor A (SRA) protein, src kinase inhibitors, HBx inhibitors, cccDNA inhibitors, short synthetic hairpin RNA (sshRNA), HBV antibodies including HBV antibodies targeting hepatitis B virus surface antigen and bispecific antibodies, and "antibody-like" therapeutic proteins (e.g. Fab derivatives, CCR2 chemokine antagonists, thymosin agonists, cytokines, nucleoprotein inhibitors (HBV core or capsid protein inhibitors), stimulators of retinoic acid-inducible gene 1, stimulators of NOD2, stimulators of NOD1, recombinant thymosin α-1, arginase-1 inhibitors, STING agonists, PI3K inhibitors, lymphotoxin β receptor activators, natural killer cell receptor 2B4 inhibitors, lymphocyte activation gene 3 inhibitors, CD160 inhibitors, cytotoxic T-lymphocyte-associated protein 4 inhibitors, CD137 inhibitors, killer cell lectin-like receptor subfamily G member 1 inhibitors, TIM-3 inhibitors, B- and T-lymphocyte attenuator inhibitors, CD305 inhibitors, PD-1 inhibitors, PD-L1 inhibitors, PEG-interferon λ, BTK inhibitors, TIGIT modulators, CD47 modulators, SIRPα modulators, ICOS modulators, CD27 modulators, CD70 modulators, OX40 modulators, NKG2D modulators, Tim-4 modulators, B7-H4 modulators, B7-H3 modulators, NKG2A modulators, GITR modulators, CD160 modulators, HEVEM modulators, CD161 modulators, Axl modulators, Mer modulators, Tyro modulators, gene modifiers or editors such as CRISPR (including CRISPR Cas9), zinc finger nucleases or synthetic nucleases (TALEN), and hepatitis B virus replication inhibitors.

[0619] In one specific embodiment, a compound or a pharmaceutically acceptable salt thereof disclosed herein is combined with a first additional therapeutic agent and at least a second additional therapeutic agent, wherein the first additional therapeutic agent is selected from entecavir adefovir tenofovir disoproxil fumarate tenofovir alafenamide, tenofovir, tenofovir disoproxil, tenofovir alafenamide fumarate, tenofovir alafenamide semi-fumarate, telbivudine or lamivudine and the second additional therapeutic agent is selected from peg interferon α-2b interferon α1b interferon α-2b peginterferon α-2a interferon α-n1 ribavirin, interferon β-1a Bioferon, Ingaron, Inmutag (Inferon), Algeron, Roferon-A, Oligotide, Zutectra, Shaferon, interferon alpha-2b (AXXO), Alfaferone, interferon alpha-2b (BioGeneric Pharma), human fibroblast interferon, interferon-alpha2 (CJ), BEVAC, Laferonum, VIPEG, BLAUFERON-B, BLAUFERON-A, Intermaxα, Realdiron, Lanstion, Pegaferon, PDFERON-B, interferon alpha-2b (IFN, Laboratorios Bioprofarma), alfainterferona 2b, Kalferon, Pegnano, Feronsure, PegiHep, interferon alpha2b (Zydus-Cadila), Optipeg A, Reα2b, Reliferon, interferon alpha-2b (Amega), interferon alpha-2b (Virchow), peg interferon alpha-2b (Amega), Reaferon-EC, Proquiferon, Uniferon, Urifron, interferon alpha-2b (Changchun Institute of Biological Products), Andafen, Shanferon, MOR-22, interleukin-2 (IL-2, Immunex), recombinant human interleukin-2 (Shenzhen Hepalink), Layfferon, Kashing, Shanghai Roche, Intron A, Sai Ruojin, Fukangtai, Alloferon and Simotil.

[0620] In one specific embodiment, a compound or a pharmaceutically acceptable salt thereof disclosed herein is combined with a first additional therapeutic agent and at least a second additional therapeutic agent, wherein the first additional therapeutic agent is selected from entecavir adefovir tenofovir disoproxil fumarate tenofovir alafenamide, tenofovir, tenofovir disoproxil, tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, telbivudine or lamivudine The second additional therapeutic agent is selected from immunomodulators, toll-like receptor modulators (modulators of tlr1, tlr2, tlr3, tlr4, tlr5, tlr6, tlr7, tlr8, tlr9, tlr10, tlr11, tlr12, and tlr13), HBsAg inhibitors, HBV therapeutic vaccines, HBV antibodies and "antibody-like" therapeutic proteins including HBV antibodies targeting hepatitis B virus surface antigen and bispecific antibodies (e.g., Fab derivatives), cyclophilin inhibitors, stimulators of retinoic acid-inducible gene 1, arginase-1 inhibitors, PI3K inhibitors, PD-1 inhibitors, PD-L1 inhibitors, and stimulators of NOD2.

[0621] In one specific embodiment, the compound or a pharmaceutically acceptable salt thereof disclosed herein is combined with a first additional therapeutic agent and at least a second additional therapeutic agent, the first additional therapeutic agent being selected from entecavir adefovir tenofovir disoproxil fumarate tenofovir alafenamide, tenofovir, tenofovir disoproxil, tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, telbivudine or lamivudine The second additional therapeutic agent is selected from HBV virus entry inhibitors, NTCP inhibitors, HBx inhibitors, cccDNA inhibitors, HBV antibodies targeting hepatitis B virus surface antigen, short interfering RNA (siRNA), miRNA gene therapy agents, short synthetic hairpin RNA (sshRNA), and nucleoprotein inhibitors (HBV core or capsid protein inhibitors).

[0622] In one specific embodiment, the compound or a pharmaceutically acceptable salt thereof disclosed herein is combined with: a first additional therapeutic agent selected from the group consisting of entecavir adefovir tenofovir disoproxil fumarate tenofovir alafenamide, tenofovir, tenofovir disoproxil, tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, telbivudine or lamivudine One or two additional therapeutic agents selected from the following: immunomodulators, toll-like receptor modulators (modulators of tlr1, tlr2, tlr3, tlr4, tlr5, tlr6, tlr7, tlr8, tlr9, tlr10, tlr11, tlr12, and tlr13), HBsAg inhibitors, HBV therapeutic vaccines, HBV antibodies and "antibody-like" therapeutic proteins including HBV antibodies and bispecific antibodies targeting hepatitis B virus surface antigen (e.g., Fab derivatives), cyclophilin inhibitors, stimulators of retinoic acid-inducible gene 1, PD-1 inhibitors, PD-L1 inhibitors, arginase-1 inhibitors, PI3K inhibitors, and stimulators of NOD2, and one or two additional therapeutic agents selected from the following: HBV virus entry inhibitors, NTCP inhibitors, HBx inhibitors, cccDNA inhibitors, HBV antibodies targeting hepatitis B virus surface antigen, short interfering RNA (siRNA), miRNA gene therapy agents, short synthetic hairpin RNA (sshRNA), and nucleoprotein inhibitors (HBV core or capsid protein inhibitors).

[0623] In some embodiments, the compounds or pharmaceutically acceptable salts thereof disclosed herein are combined with 5 - 30 mg of tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, or tenofovir alafenamide. In some embodiments, the compounds or pharmaceutically acceptable salts thereof disclosed herein are combined with 5 - 10; 5 - 15; 5 - 20; 5 - 25; 25 - 30; 20 - 30; 15 - 30; or 10 - 30 mg of tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, or tenofovir alafenamide. In some embodiments, the compounds or pharmaceutically acceptable salts thereof disclosed herein are combined with 10 mg of tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, or tenofovir alafenamide. In some embodiments, the compounds or pharmaceutically acceptable salts thereof disclosed herein are combined with 25 mg of tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, or tenofovir alafenamide. The compounds disclosed herein (e.g., compounds of formula (I)) can be combined with the agents provided herein at any dose of the compound (e.g., 50 mg to 500 mg of the compound) as if each dose combination was specifically and individually listed.

[0624] In some embodiments, the compounds disclosed herein or pharmaceutically acceptable salts thereof are combined with 100 - 400 mg of tenofovir disoproxil fumarate, tenofovir disoproxil semi - fumarate, or tenofovir disoproxil. In some embodiments, the compounds disclosed herein or pharmaceutically acceptable salts thereof are combined with 100 - 150; 100 - 200; 100 - 250; 100 - 300; 100 - 350; 150 - 200; 150 - 250; 150 - 300; 150 - 350; 150 - 400; 200 - 250; 200 - 300; 200 - 350; 200 - 400; 250 - 350; 250 - 400; 350 - 400 or 300 - 400 mg of tenofovir disoproxil fumarate, tenofovir disoproxil semi - fumarate, or tenofovir disoproxil. In some embodiments, the compounds disclosed herein or pharmaceutically acceptable salts thereof are combined with 300 mg of tenofovir disoproxil fumarate, tenofovir disoproxil semi - fumarate, or tenofovir disoproxil. In some embodiments, the compounds disclosed herein or pharmaceutically acceptable salts thereof are combined with 250 mg of tenofovir disoproxil fumarate, tenofovir disoproxil semi - fumarate, or tenofovir disoproxil. In some embodiments, the compounds disclosed herein or pharmaceutically acceptable salts thereof are combined with 150 mg of tenofovir disoproxil fumarate, tenofovir disoproxil semi - fumarate, or tenofovir disoproxil. The compounds disclosed herein (e.g., compounds of formula (I)) can be combined with the agents provided herein in any dose of the compound (e.g., 50 mg to 500 mg of the compound) as if each dose combination were specifically and individually listed.

[0625] In some embodiments, when the compounds disclosed herein are combined with one or more additional therapeutic agents as described above, the components of the composition are administered in a simultaneous or sequential regimen. When administered sequentially, the combination can be administered in two or more administrations.

[0626] In some embodiments, the compounds disclosed herein are combined with one or more additional therapeutic agents in a single dosage form for simultaneous administration to a patient, such as a solid dosage form for oral administration.

[0627] In some embodiments, the compounds disclosed herein are co - administered with one or more additional therapeutic agents. Co - administration of the compounds disclosed herein and one or more additional therapeutic agents generally refers to the simultaneous or sequential administration of the compounds disclosed herein and one or more additional therapeutic agents such that a therapeutically effective amount of the compounds disclosed herein and one or more additional therapeutic agents are present in the patient.

[0628] Co - administration includes administering a unit dose of a compound disclosed herein before or after administering a unit dose of one or more additional therapeutic agents, e.g., administering a compound disclosed herein within seconds, minutes, or hours of administering one or more additional therapeutic agents. For example, in some embodiments, a unit dose of a compound disclosed herein is administered first, followed by a unit dose of one or more additional therapeutic agents within seconds or minutes. Alternatively, in other embodiments, a unit dose of one or more additional therapeutic agents is administered first, and then a unit dose of a compound disclosed herein is administered within seconds or minutes. In some embodiments, a unit dose of a compound disclosed herein is administered first, and then a unit dose of one or more additional therapeutic agents is administered after several hours (e.g., 1 - 12 hours). In other embodiments, a unit dose of one or more additional therapeutic agents is administered first, and then a unit dose of a compound disclosed herein is administered after several hours (e.g., 1 - 12 hours).

[0629] Anti - HIV combination therapy

[0630] In some embodiments, provided is a method of treating or preventing HIV infection in a human who has the infection or is at risk of having the infection, the method comprising administering to the human a therapeutically effective amount of a compound disclosed herein or a pharmaceutically acceptable salt thereof, in combination with a therapeutically effective amount of one or more (e.g., 1, 2, 3, 4, 1 or 2, or 1 - 3, or 1 - 4) additional therapeutic agents. In one embodiment, provided is a method of treating HIV infection in a human who has the infection or is at risk of having the infection, the method comprising administering to the human a therapeutically effective amount of a compound disclosed herein or a pharmaceutically acceptable salt thereof, in combination with a therapeutically effective amount of one or more (e.g., 1, 2, 3, 4, 1 or 2, or 1 - 3, or 1 - 4) additional therapeutic agents.

[0631] In some embodiments, the present invention provides a method of treating HIV infection, which comprises administering to a patient in need a therapeutically effective amount of a compound disclosed herein or a pharmaceutically acceptable salt thereof, in combination with a therapeutically effective amount of one or more additional therapeutic agents suitable for treating HIV infection.

[0632] In one embodiment, provided is a pharmaceutical composition comprising a compound disclosed herein or a pharmaceutically acceptable salt thereof, in combination with one or more (e.g., 1, 2, 3, 4, 1 or 2, or 1 - 3, or 1 - 4) additional therapeutic agents, and a pharmaceutically acceptable carrier, diluent, or excipient.

[0633] In one embodiment, there is provided a kit comprising a compound disclosed herein or a pharmaceutically acceptable salt thereof, in combination with one or more (e.g., 1, 2, 3, 4, 1 or 2, or 1 - 3, or 1 - 4) additional therapeutic agents.

[0634] In the above embodiment, the additional therapeutic agent can be an anti - HIV agent. For example, in some embodiments, the additional therapeutic agent is selected from HIV protease inhibitors, HIV non - nucleoside inhibitors of reverse transcriptase, HIV nucleoside or nucleotide inhibitors of reverse transcriptase, HIV integrase inhibitors, HIV non - catalytic site (or allosteric) integrase inhibitors, entry inhibitors (e.g., CCR5 inhibitors, gp41 inhibitors (i.e., fusion inhibitors) and CD4 attachment inhibitors), CXCR4 inhibitors, gp120 inhibitors, G6PD and NADH - oxidase inhibitors, compounds targeting the HIV capsid ("capsid inhibitors"; e.g., capsid polymerization inhibitors or capsid - disrupting compounds such as those disclosed in WO 2013 / 006738 (Gilead Sciences), US 2013 / 0165489 (University of Pennsylvania), and WO 2013 / 006792 (Pharma Resources)), pharmacokinetic enhancers, and other drugs for the treatment of HIV, and combinations thereof.

[0635] In other embodiments, the additional therapeutic agent is selected from one or more of the following:

[0636] (1) HIV protease inhibitors, which are selected from amprenavir, atazanavir, fosamprenavir, indinavir, lopinavir, ritonavir, nelfinavir, saquinavir, tipranavir, brecanavir, darunavir, TMC - 126, TMC - 114, mozenavir (DMP - 450), JE - 2147 (AG1776), L - 756423, RO0334649, KNI - 272, DPC - 681, DPC - 684, GW640385X, DG17, PPL - 100, DG35, and AG 1859;

[0637] (2) Non-nucleoside or non-nucleotide inhibitors of HIV reverse transcriptase, which are selected from capravirine, emivirine, delavirdine, efavirenz, nevirapine, (+)-calanolide A, etravirine, GW5634, DPC-083, DPC-961, DPC-963, MIV-150, TMC-120, rilpivirene, BILR 355BS, VRX840773, lersivirine (UK-453061), RDEA806, KM023 and MK-1439;

[0638] (3) Nucleoside or nucleotide inhibitors of HIV reverse transcriptase, which are selected from zidovudine, emtricitabine, didanosine, stavudine, zalcitabine, lamivudine, abacavir, abacavir sulfate, amdoxovir, elvucitabine, alovudine, MIV-210, ±-FTC, D-d4FC, emtricitabine, phosphazide, foztivudine tidoxil, apricitibine (AVX754), KP-1461, GS-9131 (Gilead Sciences) and fosalvudine tidoxil (formerly known as HDP99.0003), tenofovir, tenofovir disoproxil fumarate, tenofovir alafenamide (Gilead Sciences), tenofovir alafenamide hemifumarate (Gilead Sciences), GS-9148 (Gilead Sciences), adefovir, adefovir dipivoxil, CMX-001 (Chimerix) or CMX-157 (Chimerix);

[0639] (4) HIV integrase inhibitors, which are selected from curcumin, curcumin derivatives, chlorogenic acid, chlorogenic acid derivatives, 3,5-dicaffeoylquinic acid, 3,5-dicaffeoylquinic acid derivatives, aurintricarboxylic acid, aurintricarboxylic acid derivatives, caffeic acid phenethyl ester, caffeic acid phenethyl ester derivatives, tyrphostin, tyrphostin derivatives, quercetin, quercetin derivatives, S-1360, AR-177, L-870812, and L-870810, raltegravir, BMS-538158, GSK364735C, BMS-707035, MK-2048, BA 011, elvitegravir, dolutegravir and GSK-744;

[0640] (5)HIV non-catalytic site, or allosteric integrase inhibitor (NCINI), including but not limited to BI-224436, CX0516, CX05045, CX14442, compounds disclosed in the following documents: WO 2009 / 062285 (Boehringer Ingelheim), WO 2010 / 130034 (Boehringer Ingelheim), WO 2013 / 159064 (Gilead Sciences), WO 2012 / 145728 (Gilead Sciences), WO 2012 / 003497 (Gilead Sciences), WO 2012 / 003498 (Gilead Sciences), each of which is incorporated herein by reference in its entirety;

[0641] (6) gp41 inhibitor, selected from enfuvirtide, T-20, alovudine, FB006M, and TRI-1144;

[0642] (7) CXCR4 inhibitor AMD-070;

[0643] (8) Entry inhibitor SP01A;

[0644] (9) gp120 inhibitor BMS-488043;

[0645] (10) G6PD and NADH-oxidase inhibitor immunitin;

[0646] (11) CCR5 inhibitor, selected from aplaviroc, vicriviroc, maraviroc, cenicriviroc, PRO-140, INCB15050, PF-232798 (Pfizer), and CCR5 mAb004;

[0647] (12) CD4 attachment inhibitor, selected from ibalizumab (TMB-355) and BMS-068 (BMS-663068);

[0648] (13) Pharmacokinetic enhancer, selected from cobicistat and SPI-452; and

[0649] (14) Other drugs for treating HIV, selected from BAS-100, SPI-452, REP 9, SP-01A, TNX-355, DES6, ODN-93, ODN-112, VGV-1, PA-457 (bevirimat), HRG214, VGX-410, KD-247, AMZ 0026, CYT 99007A-221HIV, DEBIO-025, BAY 50-4798, MDX010 (ipilimumab), PBS 119, ALG 889, and PA-1050040 (PA-040), and combinations thereof.

[0650] In some embodiments, the additional therapeutic agent is a Toll-like receptor 8 modulator selected from motolimod, resiquimod, 3M-051, 3M-052, MCT-465, IMO-4200, VTX-763, VTX-1463, and those disclosed in the following: US20140045849 (Janssen), US20140073642 (Janssen), WO2014 / 056953 (Janssen), WO2014 / 076221 (Janssen), WO2014 / 128189 (Janssen), US20140350031 (Janssen), WO2014 / 023813 (Janssen), US20080234251 (Array Biopharma), US20080306050 (Array Biopharma), US20100029585 (Ventirx Pharma), US20110092485 (Ventirx Pharma), US20110118235 (Ventirx Pharma), US20120082658 (Ventirx Pharma), US20120219615 (Ventirx Pharma), US20140066432 (Ventirx Pharma), US20140088085 (Ventirx Pharma), US20140275167 (Novira therapeutics), US20130251673 (Novira therapeutics), U.S. Patent No. 9,670,205 (Gilead Sciences Inc.), US20160289229 (Gilead Sciences Inc.), U.S. Patent Application 15 / 692161 (Gilead Sciences Inc.), and U.S. Patent Application 15 / 692093 (Gilead Sciences Inc.).

[0651] In some embodiments, one or more additional therapeutic agents include a Toll-like receptor 8 (TLR8) modulator. In some embodiments, the Toll-like receptor 8 (TLR8) modulator is a Toll-like receptor 8 (TLR8) agonist. In some embodiments, the Toll-like receptor 8 (TLR8) agonist is the compound disclosed in U.S. Patent No. 9,670,205 or a pharmaceutically acceptable salt thereof.

[0652] In some embodiments, the compounds disclosed herein or pharmaceutically acceptable salts thereof are combined with one, two, three, four or more additional therapeutic agents. In some embodiments, the compounds disclosed herein or pharmaceutically acceptable salts thereof are combined with two additional therapeutic agents. In other embodiments, the compounds disclosed herein or pharmaceutically acceptable salts thereof are combined with three additional therapeutic agents. In other embodiments, the compounds disclosed herein or pharmaceutically acceptable salts thereof are combined with four additional therapeutic agents. The two, three, four or more additional therapeutic agents may be different therapeutic agents selected from the same class of therapeutic agents, or they may be selected from different classes of therapeutic agents. In one specific embodiment, the compounds disclosed herein or pharmaceutically acceptable salts thereof are combined with an HIV nucleoside or nucleotide inhibitor of reverse transcriptase and an HIV non-nucleoside inhibitor of reverse transcriptase. In another specific embodiment, the compounds disclosed herein or pharmaceutically acceptable salts thereof are combined with an HIV nucleoside or nucleotide inhibitor of reverse transcriptase, and an HIV protease inhibitory compound. In yet another embodiment, the compounds disclosed herein or pharmaceutically acceptable salts thereof are combined with an HIV nucleoside or nucleotide inhibitor of reverse transcriptase, an HIV non-nucleoside inhibitor of reverse transcriptase and an HIV protease inhibitory compound. In an additional embodiment, the compounds disclosed herein or pharmaceutically acceptable salts thereof are combined with an HIV nucleoside or nucleotide inhibitor of reverse transcriptase, an HIV non-nucleoside inhibitor of reverse transcriptase and a pharmacokinetic enhancer. In another embodiment, the compounds disclosed herein or pharmaceutically acceptable salts thereof are combined with two HIV nucleoside or nucleotide inhibitors of reverse transcriptase.

[0653] In one specific embodiment, the compounds disclosed herein or pharmaceutically acceptable salts thereof are combined with abacavir sulfate, tenofovir, tenofovir disoproxil fumarate, tenofovir alafenamide, or tenofovir alafenamide hemifumarate.

[0654] In one specific embodiment, the compounds disclosed herein or pharmaceutically acceptable salts thereof are combined with tenofovir, tenofovir disoproxil fumarate, tenofovir alafenamide, or tenofovir alafenamide hemifumarate.

[0655] In a specific embodiment, the compounds disclosed herein or pharmaceutically acceptable salts thereof are combined with a first additional therapeutic agent selected from abacavir sulfate, tenofovir, tenofovir disoproxil fumarate, tenofovir alafenamide, and tenofovir alafenamide hemifumarate and a second additional therapeutic agent selected from emtricitabine and lamivudine. In a specific embodiment, the compounds disclosed herein or pharmaceutically acceptable salts thereof are combined with a first additional therapeutic agent and a second additional therapeutic agent, the first additional therapeutic agent being selected from tenofovir, tenofovir disoproxil fumarate, tenofovir alafenamide, and tenofovir alafenamide hemifumarate, and the second additional therapeutic agent being emtricitabine.

[0656] In some embodiments, a method of treating HIV in a subject comprises administering to the subject a therapeutically effective amount of any of the compounds described herein (e.g., of formula I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii or Ij or a pharmaceutically acceptable salt or pharmaceutically acceptable tautomer thereof) in combination with an immunotherapeutic agent, such as an immune checkpoint inhibitor, a hematopoietic progenitor kinase 1 (HPK1) inhibitor, an immune checkpoint stimulating protein agonist or an engineered immune cell (e.g., a T cell having a chimeric antigen receptor (i.e., a CAR T cell) or a T cell having an engineered T cell receptor (TCR)). In some embodiments, the compound is administered to the subject before, after or simultaneously with the administration of one or more immunotherapeutic agents. In some embodiments, the compound is administered about 30 minutes or more, about 1 hour or more, about 2 hours or more, about 4 hours or more, about 6 hours or more, about 12 hours or more, about 24 hours or more, about 48 hours or more or about 72 hours or more before or after the administration of one or more additional immunotherapeutic agents. In some embodiments, the compound is administered about 30 minutes or less, about 1 hour or less, about 2 hours or less, about 4 hours or less, about 6 hours or less, about 12 hours or less, about 24 hours or less, about 48 hours or less or about 72 hours or less before or after the administration of one or more additional immunotherapeutic agents.

[0657] In some embodiments, a method of treating HIV in a subject comprises administering to the subject a combination of a therapeutically effective amount of any of the compounds described herein (e.g., of formula I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, or Ij or a pharmaceutically acceptable salt or pharmaceutically acceptable tautomer thereof) and a therapeutically effective amount of one or more immune checkpoint inhibitors. In some embodiments, the compound is administered to the subject before, after, or simultaneously with the administration of the immune checkpoint inhibitor. In some embodiments, the immune checkpoint inhibitor is a small molecule inhibitor. In some embodiments, the immune checkpoint inhibitor is an antibody or a fragment thereof. In some embodiments, the immune checkpoint inhibitor inhibits adenosine A 2A receptor (A2aR), B7-H3, V-set domain-containing T cell activation inhibitor 1 (VTCN1, also known as B7-H4), B and T lymphocyte attenuator (BTLA), cytotoxic T lymphocyte-associated protein 4 (CTLA-4), killer cell immunoglobulin-like receptor (KIR), lymphocyte activation gene 3 (LAG3), programmed death 1 (PD-1), programmed death ligand 1 (PD-L1), programmed death ligand 2 (PD-L2), T cell immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domain-containing receptor (TIGIT), T cell immunoglobulin and mucin domain 3 (TIM-3), or V-domain Ig inhibitor of T cell activation (VISTA). Exemplary immune checkpoint inhibitors include, but are not limited to, avelumab, atezolizumab, durvalumab, nivolumab, pembrolizumab, ipilimumab, PDR001, TSR-042, and BMS-986016.

[0658] In some embodiments, a method of treating HIV in a subject comprises administering to the subject a combination of a therapeutically effective amount of any of the compounds described herein (e.g., of formula I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, or Ij or a pharmaceutically acceptable salt or pharmaceutically acceptable tautomer thereof) and a therapeutically effective amount of one or more immune checkpoint stimulating protein agonists. In some embodiments, the compound is administered to the subject before, after, or simultaneously with the administration of the immune checkpoint stimulating protein agonist. In some embodiments, the immune checkpoint stimulating protein agonist is an antibody or a fragment thereof. In some embodiments, the immune checkpoint stimulating protein agonist is an agonist of CD27, CD28, CD40, CD122, 4-1BB, OX40, glucocorticoid-induced TNFR family-related protein (GITR), or inducible T cell co-stimulator (ICOS).

[0659] In some embodiments, a method of treating HIV in a subject comprises administering to the subject a combination of a therapeutically effective amount of any of the compounds described herein (e.g., of Formula I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii or Ij or a pharmaceutically acceptable salt or pharmaceutically acceptable tautomer thereof) and a therapeutically effective amount of engineered immune cells, such as CAR T cells or T cells having an engineered TCR. In some embodiments, the compound is administered to the subject before, after or simultaneously with the administration of the engineered immune cells. In some embodiments, the engineered immune cells are heterologous engineered immune cells, such as heterologous engineered T cells (e.g., CAR T cells or T cells having an engineered TCR). In some embodiments, the engineered immune cells are autologous engineered immune cells, such as autologous engineered T cells (e.g., CAR T cells or T cells having an engineered TCR).

[0660] In some embodiments, methods of treating HIV in a subject include administering to the subject a therapeutically effective amount of any of the compounds described herein (e.g., of formula I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, or Ij or a pharmaceutically acceptable salt or pharmaceutically acceptable tautomer thereof) in combination with (1) a therapeutically effective amount of engineered immune cells, such as CAR T cells or T cells having an engineered TCR, and (2) a therapeutically effective amount of an immune checkpoint inhibitor or immune checkpoint stimulating protein agonist. In some embodiments, methods of treating HIV in a subject include administering to the subject a therapeutically effective amount of any of the compounds described herein (e.g., of formula I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, or Ij or a pharmaceutically acceptable salt or pharmaceutically acceptable tautomer thereof) in combination with (1) a therapeutically effective amount of engineered immune cells, such as CAR T cells or T cells having an engineered TCR, and (2) a therapeutically effective amount of an antiviral agent (e.g., an anti-HIV agent). In some embodiments, methods of treating HIV in a subject include administering to the subject a therapeutically effective amount of any of the compounds described herein (e.g., of formula I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, or Ij or a pharmaceutically acceptable salt or pharmaceutically acceptable tautomer thereof) in combination with (1) a therapeutically effective amount of an immune checkpoint inhibitor or immune checkpoint stimulating protein agonist and (2) a therapeutically effective amount of an antiviral agent (e.g., an anti-HIV agent). In some embodiments, methods of treating HIV in a subject include administering to the subject a therapeutically effective amount of any of the compounds described herein (e.g., of formula I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, or Ij or a pharmaceutically acceptable salt or pharmaceutically acceptable tautomer thereof) in combination with (1) a therapeutically effective amount of engineered immune cells, such as CAR T cells or T cells having an engineered TCR, (2) a therapeutically effective amount of an immune checkpoint inhibitor or immune checkpoint stimulating protein agonist, and (3) a therapeutically effective amount of an antiviral agent (e.g., an anti-HIV agent).

[0661] In some embodiments, when the compounds disclosed herein are combined with one or more additional therapeutic agents as described above, the components of the composition are administered in a simultaneous or sequential regimen. When administered sequentially, the combination may be administered in two or more administrations.

[0662] In certain embodiments, the compounds disclosed herein are combined with one or more additional therapeutic agents in a single dosage form for simultaneous administration to a patient, such as a solid dosage form for oral administration.

[0663] In some embodiments, the compounds disclosed herein are co-administered with one or more additional therapeutic agents. Co-administration of the compounds disclosed herein with one or more additional therapeutic agents generally refers to the administration of the compounds disclosed herein and one or more additional therapeutic agents either simultaneously or sequentially such that a therapeutically effective amount of both the compounds disclosed herein and one or more additional therapeutic agents are present in the patient.

[0664] Co-administration includes administering a unit dose of the compounds disclosed herein before or after administering a unit dose of one or more additional therapeutic agents, such as administering the compounds disclosed herein within seconds, minutes, or hours of administering one or more additional therapeutic agents. For example, in some embodiments, a unit dose of the compounds disclosed herein is administered first, followed by a unit dose of one or more additional therapeutic agents within seconds or minutes. Alternatively, in other embodiments, a unit dose of one or more additional therapeutic agents is administered first, followed by a unit dose of the compounds disclosed herein within seconds or minutes. In some embodiments, a unit dose of the compounds disclosed herein is administered first, followed by a unit dose of one or more additional therapeutic agents after several hours (e.g., 1 - 12 hours). In other embodiments, a unit dose of one or more additional therapeutic agents is administered first, followed by a unit dose of the compounds disclosed herein after several hours (e.g., 1 - 12 hours).

[0665] Kit

[0666] The present disclosure also provides kits that include a compound of Formula I or a pharmaceutically acceptable salt, stereoisomer, prodrug, or solvate thereof, and a suitable package. In one embodiment, the kit further includes instructions for use. In one aspect, the kit includes a compound of Formula I or a pharmaceutically acceptable salt, stereoisomer, prodrug, or solvate thereof, and a label and / or instructions that indicate the use of the compound for treating the indications (including diseases or disorders) described herein.

[0667] The present disclosure also provides kits that include a compound of Formula I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, or Ij or a pharmaceutically acceptable salt, stereoisomer, prodrug, or solvate thereof, and a suitable package. In one embodiment, the kit further includes instructions for use. In one aspect, the kit includes a compound of Formula I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii, or Ij or a pharmaceutically acceptable salt, stereoisomer, prodrug, or solvate thereof, and a label and / or instructions that indicate the use of the compound for treating the indications (including diseases or disorders) described herein.

[0668] The present invention also provides articles of manufacture that include a compound described herein, or a pharmaceutically acceptable salt, isomer, or mixture thereof, in a suitable container. The container can be a vial, can, ampule, prefilled syringe, and intravenous bag.

[0669] Pharmaceutical Compositions and Modes of Administration

[0670] The compounds provided herein are generally administered in the form of pharmaceutical compositions. Accordingly, the present invention also provides pharmaceutical compositions that include one or more compounds described herein, or a pharmaceutically acceptable salt, isomer, or mixture thereof, and one or more pharmaceutically acceptable vehicles selected from carriers, excipients, and diluents. Suitable pharmaceutically acceptable vehicles can include, for example, inert solid diluents and fillers, diluents (including sterile aqueous solutions and a variety of organic solvents), penetration enhancers, solubilizers, and excipients. Such compositions are prepared in a manner well known in the pharmaceutical art. See, e.g., Remington’s Pharmaceutical Sciences, Mace Publishing Co., Philadelphia, Pa. 17th Ed. (1985); and Modern Pharmaceutics, Marcel Dekker, Inc. 3rd Ed., (G.S. Banker & C.T. Rhodes, Eds.).

[0671] The pharmaceutical compositions can be administered in single-dose or multi-dose forms. The pharmaceutical compositions can be administered by a variety of methods, including, for example, rectal, buccal, intranasal, and transdermal routes. In some embodiments, the pharmaceutical compositions can be administered by intraarterial injection, intravenous, intraperitoneal, parenteral, intramuscular, subcutaneous, oral, topical, or in the form of an inhalant.

[0672] One mode of administration is parenteral, such as by injection. Forms that can be incorporated into the pharmaceutical compositions provided herein for administration by injection include, for example, aqueous or oily suspensions or emulsions containing sesame oil, corn oil, cottonseed oil, or peanut oil, and elixirs, mannitol, dextrose, or sterile aqueous solutions, and similar pharmaceutical vehicles.

[0673] Oral administration can be another route for administering the compounds described herein. For example, it can be administered by capsules or enteric-coated tablets. In the manufacture of a pharmaceutical composition comprising at least one compound described herein or a pharmaceutically acceptable salt, isomer or mixture thereof, the active ingredient is usually diluted with an excipient and / or enclosed within a carrier that can be in the form of a capsule, sachet, paper or other container. When an excipient is used as a diluent, it can be in the form of a solid, semi-solid or liquid material that acts as a vehicle, carrier or medium for the active ingredient. Thus, the compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (in solid form or in a liquid medium), ointments containing, for example, up to 10% by weight of the active compound, soft and hard gelatin capsules, sterile injectable solutions and sterile packaged powders.

[0674] Some examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starch, acacia, calcium phosphate, alginate, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, sterile water, syrup, and methyl cellulose. The formulations can additionally include: lubricants such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifying and suspending agents; preservatives such as methyl hydroxybenzoate and propyl hydroxybenzoate; sweetening agents; and flavoring agents.

[0675] Compositions comprising at least one compound described herein or a pharmaceutically acceptable salt, isomer or mixture thereof can be formulated to provide rapid, sustained or delayed release of the active ingredient after administration to a subject by procedures known in the art. Controlled release drug delivery systems for oral administration include osmotic pump systems and dissolution systems that contain polymer-coated reservoirs or drug-polymer matrix formulations. Examples of controlled release systems are given in U.S. Patents 3,845,770, 4,326,525, 4,902,514 and 5,616,345. Another formulation for use in the methods of the present invention employs a transdermal delivery device (“patch”). Such transdermal patches can be used to provide continuous or discontinuous infusion of the compounds described herein in a controlled amount. The construction and use of transdermal patches for delivering agents are well known in the art. See, for example, U.S. Patents 5,023,252, 4,992,445 and 5,001,139. Such patches can be constructed to deliver the agent continuously, pulsatilely or on demand.

[0676] For the preparation of solid compositions such as tablets, the active ingredient may be mixed with a pharmaceutical excipient to form a solid pre-formulated composition that is a homogeneous mixture containing the compounds described herein or pharmaceutically acceptable salts, isomers, or mixtures thereof. When referring to these pre-formulated compositions as homogeneous compositions, the active ingredient may be uniformly dispersed throughout the composition so that the composition can be easily re-divided into equally effective unit dosage forms such as tablets, pills, and capsules.

[0677] Tablets or pills of the compounds described herein may be coated or otherwise compounded to provide dosage forms that have the advantage of extended action or protection against the acidic conditions of the stomach. For example, a tablet or pill may include an inner dose and an outer dose component, the latter being in the form of an envelope over the former. The two components may be separated by an enteric layer to resist disintegration in the stomach and permit the inner component to pass intact into the duodenum or to be released therein in a delayed manner. Many materials may be used for such enteric layers or coatings, including many polymeric acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol, and cellulose acetate.

[0678] Compositions for inhalation or insufflation may include solutions and suspensions in pharmaceutically acceptable aqueous or organic solvents or mixtures thereof, as well as powders. The liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described above. In some embodiments, the compositions are administered by the oral or nasal respiratory route for local or systemic effect. In other embodiments, the compositions in pharmaceutically acceptable solvents may be nebulized by the use of an inert gas. The nebulized solution may be inhaled directly from the nebulizing device or the nebulizing device may be connected to a face mask adapter or to an intermittent positive pressure breathing machine. The solution, suspension, or powder compositions may be administered in a suitable manner, preferably orally or nasally, from a device that delivers the formulation.

[0679] Dosage

[0680] For any particular subject, the specific dosage level of the compounds of the present application will depend on a variety of factors, including the activity of the specific compound employed in the subject undergoing the therapy, age, body weight, general health, sex, diet, time of administration, route of administration, and rate of excretion, drug combination, and the severity of the particular disease. For example, the dosage may be expressed as milligrams of the compound described herein per kilogram of the subject's body weight (mg / kg). A dosage of about 0.1 to 150 mg / kg may be appropriate. In some embodiments, about 0.1 to 100 mg / kg may be appropriate. In other embodiments, a dosage of 0.5 to 60 mg / kg may be appropriate. When adjusting the dosage between subjects of widely different body sizes, such as when using a drug in children and adults or when converting an effective dosage in a non-human subject (e.g., a dog) to a dosage suitable for a human subject, standardization based on the body weight of the subject is particularly applicable.

[0681] The daily dose can also be described as the total amount of the compound described herein administered per dose or per day. The daily dose of a compound of formula I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii or Ij, or a pharmaceutically acceptable salt or pharmaceutically acceptable tautomer thereof, can be between about 1 mg and 4000 mg, between about 2000 and 4000 mg / day, between about 1 and 2000 mg / day, between about 1 and 1000 mg / day, between about 10 and 500 mg / day, between about 20 and 500 mg / day, between about 50 and 300 mg / day, between about 75 and 200 mg / day, or between about 15 and 150 mg / day.

[0682] When administered orally, the total daily dose for a human subject can be between 1 mg - 1000 mg, between about 10 - 500 mg / day, between about 50 - 300 mg / day, between about 75 - 200 mg / day, or between about 100 - 150 mg / day.

[0683] In some embodiments, the daily dose (which may be an oral dose) of a compound of formula I, Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii or Ij, or a pharmaceutically acceptable salt or pharmaceutically acceptable tautomer thereof, is from about 40 mg / day to about 120 mg / day, from about 60 mg / day to about 100 mg / day, or about 80 mg / day.

[0684] The compounds or their compositions of the present application can be administered once, twice, three times, or four times a day using any suitable mode described above. Additionally, the administration or treatment with the compound can continue for multiple days; for example, for one treatment cycle, the treatment will typically continue for at least 7 days, 14 days, or 28 days. Treatment cycles are well-known in cancer chemotherapy and are often alternated with a rest period of about 1 to 28 days, typically about 7 days or about 14 days, between multiple cycles. In other embodiments, the treatment cycles can also be continuous.

[0685] In one specific embodiment, the method includes administering an initial daily dose of about 1 to 500 mg of the compound described herein to a subject and increasing the dose in certain increments until clinical efficacy is achieved. Increments of about 5, 10, 25, 50, or 100 mg can be used to increase the dose. The dose can be increased daily, every other day, twice a week, or once a week.

[0686] Synthesis of Compounds of Formula I

[0687] The compounds can be prepared using the methods disclosed herein and their conventional modifications, which will be apparent in view of the disclosure herein and methods well-known in the art. In addition to the teachings herein, conventional and well-known synthetic methods can be used. The synthesis of the exemplary compounds described herein can be carried out as described in the following examples. Reagents can be purchased from Sigma Aldrich or other chemical suppliers if available.

[0688] General Synthetic Methods

[0689] Exemplary embodiments of the compounds of the present invention can be synthesized using the general reaction schemes described below. It will be apparent in view of the description of the present application that the general reaction schemes can be varied by substituting the starting materials with other starting materials having similar structures, thereby obtaining corresponding different products. The following synthetic descriptions give multiple examples of how the starting materials can be varied to obtain the corresponding products. In the case of a given desired product with defined substituents, the required starting materials can generally be determined by inspection. The starting materials are typically obtained from commercial sources or synthesized using published methods. To synthesize the compounds as the embodiments described in the present invention, examining the structure of the compound to be synthesized will provide the identification of each substituent. Considering the examples given in the text, by simple inspection methods, the determination of the final product usually makes the determination of the required starting materials clear. Generally, the compounds described herein are typically stable and separable at room temperature and room pressure.

[0690] Synthesis Reaction Parameters

[0691] The compounds of the present invention can be prepared from readily available starting materials using, for example, the general methods and procedures described below. It should be understood that other process conditions may also be used when typical or preferred process conditions (i.e., reaction temperature, time, molar ratio of reactants, solvent, pressure, etc.) are given, unless otherwise stated. The optimal reaction conditions may vary depending on the specific reactants or solvents used, but can be determined by those skilled in the art through routine optimization procedures.

[0692] In addition, as will be apparent to those skilled in the art, conventional protecting groups may be necessary to prevent undesired reactions of some functional groups. Suitable protecting groups for various functional groups and suitable conditions for protecting and deprotecting specific functional groups are well known in the art. For example, many protecting groups are described in T.W. Greene and G.M. Wuts (1999) Protecting Groups in Organic Synthesis, 3rd edition, Wiley, New York and the references cited therein.

[0693] Furthermore, the compounds of the present invention may contain one or more chiral centers. Therefore, if desired, the compound can be prepared as a pure stereoisomer or separated into pure stereoisomers, i.e., as individual enantiomers or diastereomers or as a stereoisomer-enriched mixture. Unless otherwise stated, all such stereoisomers (and enriched mixtures) are included within the scope of the present invention. Pure stereoisomers (or enriched mixtures) can be prepared using, for example, optically active starting materials or stereoselective reagents well known in the art. Alternatively, the racemic mixture of the compound can be separated using, for example, chiral column chromatography, chiral resolving agents, etc.

[0694] The starting materials for the following reactions are generally known compounds or can be prepared by known methods or obvious modifications thereof. For example, many starting materials are available from commercial suppliers such as Aldrich Chemical Co. (Milwaukee, Wisconsin, USA), Bachem (Torrance, California, USA), Emka-Chemce or Sigma (St. Louis, Missouri, USA). Others can be prepared by the procedures described in standard reference works or obvious modifications thereof, such as Fieser and Fieser's Reagents for Organic Synthesis, Volumes 1-15 (John Wiley and Sons, 1991), Rodd's Chemistry of Carbon Compounds, Volumes 1-5 and Supplements (Elsevier Science Publishers, 1989), Organic Reactions, Volumes 1-40 (John Wiley and Sons, 1991), March's Advanced Organic Chemistry, (John Wiley and Sons, 5th Edition, 2001) and Larock's Comprehensive Organic Transformations (VCH Publishers Inc., 1989).

[0695] The term "solvent", "inert organic solvent" or "inert solvent" refers to a solvent that is inert under the reaction conditions described therewith (including, for example, benzene, toluene, acetonitrile, tetrahydrofuran ("THF"), dimethylformamide ("DMF"), chloroform, dichloromethane, diethyl ether, methanol, etc.). Unless otherwise specified, the solvent used in the reactions of the present invention is an inert organic solvent and the reaction is carried out under an inert gas, preferably nitrogen.

[0696] The term "q.s." means an amount sufficient to effect the stated function, e.g., to bring a solution to the desired volume (i.e., 100%).

[0697] The compound of formula I

[0698] The compound of formula I can be prepared by the scheme shown below.

[0699] Each intermediate in the following scheme can be isolated and / or purified before the subsequent step or used in the next step without purification and / or isolation. It should also be understood that the addition of any substituent may result in the formation of many isomeric products, and any or all of said isomeric products can be separated and purified using conventional techniques. Examples

[0700] The following examples are included to illustrate specific embodiments of the present invention. Those skilled in the art will understand that the techniques disclosed in the following examples represent representative techniques discovered by the inventors that can be well implemented for the present invention, and thus can be understood as constituting specific ways for its implementation. However, those skilled in the art will understand that based on the disclosure of the present invention, many variations can be made in the disclosed specific embodiments, and still the same or similar results can be obtained without departing from the spirit and scope of the present invention.

[0701] List of Abbreviations and Acronyms

[0702] Abbreviation Meaning

[0703] % Percent

[0704] °C Degrees Celsius

[0705] A2B Adenosine A2B Receptor

[0706] Ac Acetyl

[0707] ACN / CH 3 CN / MeCN Acetonitrile

[0708] ADME Absorption, Distribution, Metabolism, and Excretion

[0709] APECED Autoimmune Polyendocrinopathy - Candidiasis - Ectodermal Dystrophy

[0710] ASK Apoptosis Signal - Regulating Kinase

[0711] BAPN β - Aminopropionitrile

[0712] BCNU Carmustine

[0713] Bicarb Bicarbonate

[0714] Bpin Pinacolborane

[0715] br Broad

[0716] BRD Bromodomain - Containing Protein Inhibitor

[0717] BTK Bruton's Tyrosine Kinase

[0718] CAS Chemical Abstracts Service

[0719] CD Cluster of Differentiation

[0720] CHOP Cyclophosphamide

[0721] CNS Central Nervous System

[0722] COPD Chronic Obstructive Pulmonary Disease

[0723] CREST Calcinosis, Raynaud's syndrome, Esophageal dysmotility, Sclerodactyly, and Telangiectasia

[0724] CRISPR Clustered Regularly Interspaced Short Palindromic Repeats

[0725] CVP Cyclophosphamide, Vincristine, Prednisone

[0726] d Doublet

[0727] D Deuterium

[0728] D.T.PACE Dexamethasone, Thalidomide, Cisplatin, Cyclophosphamide, Etoposide

[0729] D / d Deuterium

[0730] 1,4 - Diazabicyclo[2.2.2]octane

[0731] DCE Dichloroethane

[0732] DCM / CH 2 Cl 2 Dichloromethane / Methylene Chloride

[0733] dd Double doublet

[0734] DDR Discoidin Domain Receptor

[0735] DIPEA / DIEA N,N - Diisopropylethylamine

[0736] DMF Dimethylformamide

[0737] DMFO Difluoromethylornithine

[0738] DMPK Drug Metabolism and Pharmacokinetics

[0739] DMSO Dimethyl Sulfoxide

[0740] DTIC Dacarbazine

[0741] EC 50 Half maximal effective concentration

[0742] equiv / eq Equivalent

[0743] Et Ethyl

[0744] EtOAc / AcOEt Ethyl acetate

[0745] EtOH Ethanol

[0746] F Fahrenheit

[0747] Fab fragment antigen binding

[0748] FBS Fetal bovine serum

[0749] FCM Fludarabine, cyclophosphamide, mitoxantrone

[0750] FCR Fludarabine, cyclophosphamide, rituximab

[0751] FOLFIRI Fluorouracil, leucovorin, and irinotecan

[0752] FR Fludarabine, rituximab

[0753] g Gram

[0754] GITR Glucocorticoid-induced TNFR-related protein

[0755] Gp Glycoprotein

[0756] h / hr Hour

[0757] HATU (1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate)

[0758] HbcAg Hepatitis B core antigen

[0759] HBsAg Hepatitis B surface antigen

[0760] HBV Hepatitis B virus

[0761] HBx Hepatitis B virus protein

[0762] HDAC Histone deacetylase

[0763] hex Hexane

[0764] HPLC High performance liquid chromatography

[0765] hyperCVAD Hyperfractionated cyclophosphamide, vincristine, doxorubicin, dexamethasone, methotrexate, cytarabine

[0766] Hz Hertz

[0767] ICE Ifosfamide, carboplatin, etoposide

[0768] ICOS Inducible T-cell Costimulator

[0769] IDH Isocitrate Dehydrogenase

[0770] IDO1 Indoleamine 2,3-Dioxygenase 1

[0771] IL Interleukin

[0772] INCB24360 Epacadostat

[0773] IUPAC International Union of Pure and Applied Chemistry

[0774] J Coupling Constant (MHz)

[0775] JAK Janus Kinase

[0776] Kg / kg Kilogram

[0777] LACA 1-Azetidine-2-carboxylic Acid

[0778] LCMS / LC-MS Liquid Chromatography-Mass Spectrometry

[0779] LOX Lysyl Oxidase Protein

[0780] LOXL Lysyl Oxidase-Like Protein

[0781] M Molar Concentration

[0782] m Multiplet

[0783] M+ Proton Peak

[0784] M+H Proton Peak Plus Hydrogen

[0785] MCP Mitoxantrone, Chlorambucil, and Prednisolone

[0786] Me Methyl

[0787] mg Milligram

[0788] MHz Megahertz

[0789] min / m Minute

[0790] miRNA MicroRNA

[0791] ml / mL Milliliter

[0792] mM Millimolar Concentration

[0793] MMF Mycophenolate Mofetil Ester Derivative

[0794] mmol Millimole

[0795] MMP matrix metalloproteinase

[0796] mol mole

[0797] MS mass spectrometry

[0798] MS multiple sclerosis

[0799] N normal concentration

[0800] NADH reduced form of nicotinamide adenine dinucleotide

[0801] NCINI non-catalytic site, or allosteric integrase inhibitor

[0802] ng nanogram

[0803] nM nanomolar concentration

[0804] NMR nuclear magnetic resonance

[0805] NTCP Na + -taurocholate cotransporting polypeptide

[0806] PD-L programmed death ligand

[0807] PEG polyethylene glycol

[0808] PEI polymer polyethyleneimine

[0809] PET positron emission tomography

[0810] Ph phenyl

[0811] PI3K phosphoinositide 3-kinase

[0812] PKC protein kinase C

[0813] prep preparative

[0814] q.s. quantity sufficient to effect the function

[0815] RA rheumatoid arthritis

[0816] R-CHOP rituximab-CHOP (rituximab + CHOP)

[0817] R-CVP rituximab-CVP (rituximab + CVP)

[0818] Rf retention factor

[0819] R-FCM rituximab + FCM

[0820] R-hyperCVAD rituximab-hyperCVAD

[0821] R-ICE Rituximab-ICE

[0822] R-MCP Rituximab-MCP

[0823] RPM Revolutions Per Minute

[0824] rSIFN-co Recombinant Highly Potent Composite Interferon

[0825] RT / rt Room Temperature

[0826] s Second

[0827] s Singlet

[0828] SAHA Vorinostat

[0829] sat. Saturated

[0830] SERMs Selective Estrogen Receptor Modulators

[0831] siRNA Small Interfering RNA

[0832] SIRP Signal Regulatory Protein

[0833] SLE Systemic Lupus Erythematosus

[0834] SPECT Single Photon Emission Computed Tomography

[0835] SRA Scavenger Receptor A

[0836] Src Proto-Oncogene Tyrosine-Protein Kinase

[0837] sshRNA Short Synthetic Hairpin RNA

[0838] STING Sequence To and withIN Graphics

[0839] SYK Spleen Tyrosine Kinase

[0840] t Triplet

[0841] TALEN Transcription Activator-Like Effector Nuclease

[0842] TCA Trichloroacetic Acid

[0843] TEA Triethylamine

[0844] temp. Temperature

[0845] TFA Trifluoroacetic Acid

[0846] THF Tetrahydrofuran

[0847] T cell immunoreceptor with Ig and ITIM domains

[0848] TIM T cell immunoglobulin and mucin domains

[0849] TKM-HBV TKM-HepB

[0850] Tlr Toll-like receptor modulator

[0851] TNF Tumor necrosis factor

[0852] TPL2 Serine / threonine kinase

[0853] Vac Vacuum

[0854] w / v Weight / volume

[0855] w / w Weight / weight

[0856] YPEG-rhIFNα-2a PEG-interferon α-2a

[0857] YPEG-rhIFNα-2b Ypeg interferon α-2b

[0858] δ Chemical shift (ppm)

[0859] μg Microgram

[0860] μL / μl Microliter

[0861] μM Micromolar concentration

[0862] μm Micrometer

[0863] μmol Micromole

[0864] General synthesis sequence of Formula I

[0865] General synthesis of Formula I

[0866] In some embodiments, the compounds of formula (I) can be synthesized according to Scheme 1.

[0867] Scheme 1.

[0868]

[0869] Wherein X 1 、X 2 、X 3 、X 4 、X 5 、X 6 、X 7 、X 8 、Y 1, ______, Z, R 1 , R 2 , and R 3 as defined by formula (I) or any of its variables as detailed herein, and each X is a halogen.

[0870] In some embodiments, the compounds of formula (I) can be synthesized according to Scheme 2.

[0871] Scheme 2.

[0872]

[0873] wherein X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , X 7 , X 8 , Y 1 , ______, Z, R 1 , R 2 , and R 3 as defined by formula (I) or any of its variables as detailed herein, and each X is a halogen.

[0874] In some embodiments, the compounds of formula (I) can be synthesized according to Scheme 3.

[0875] Scheme 3.

[0876]

[0877] wherein X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , X 7 , X 8 , Y 1 , ______, Z, R 1 , R 2 , and R 3 as defined by formula (I) or any of its variables as detailed herein, and each X is a halogen.

[0878] In some embodiments, the compounds of formula (I) can be synthesized according to Scheme 4.

[0879] Scheme 4.

[0880]

[0881] wherein X 1 、X 2 、X 3 、X 4 、X 5 、X 6 、X 7 、X 8 、Y 1 、______、 Z, R 1 、R 2 、and R 3 as defined by formula (I) or any of its variables as detailed herein, and each X is a halogen.

[0882] In some embodiments, the compounds of formula (I) can be synthesized according to Scheme 5.

[0883] Scheme 5.

[0884]

[0885] wherein X 1 、X 2 、X 3 、X 4 、X 5 、X 6 、X 7 、X 8 、Y 1 、Z, R 1 、R 2 、and R 3 as defined by formula (I) or any of its variables as detailed herein, and each X is a halogen.

[0886] In some embodiments, the compounds of formula (I) can be synthesized according to Scheme 6.

[0887] Scheme 6.

[0888]

[0889] wherein X 1 、X 2 、X 3 、X 4 、X 5 、X 6 、X 7 、X 8 、Y 1 、______、 Z, R 1 、R 2 、and R 3 as defined by formula (I) or any of its variables as detailed herein, and each X is a halogen.

[0890] Examples

[0891] Example 1: 5-(3,3-Dimethyl-2-oxo-1-(pyrimidin-2-yl)indoline-4-yl)-N-(4-fluorophenyl)-2-(trifluoromethyl)benzamide, Compound 1

[0892]

[0893] 1. Synthesis of 4-bromo-3,3-dimethyl-1-(pyrimidin-2-yl)indoline-2-one (Intermediate 1-1)

[0894]

[0895] A suspension of 4-bromo-3,3-dimethylindoline-2-one (500 mg, 2.1 mmol) and 2-bromopyrimidine (331 mg, 2.1 mmol) in acetonitrile (5 mL) was degassed with nitrogen, then potassium carbonate (576 mg, 4.1 mmol), copper(I) iodide (4 mg, 0.2 mmol) and N,N'-dimethylethylenediamine (18 mg, 0.2 mmol) were added, and the reaction mixture was stirred in a microwave reactor at 120 °C for 1.5 h. The reaction mixture was partitioned between water and EtOAc, and the organic layer was dried over MgSO 4 dried, filtered, concentrated in vacuo, and the resulting residue was purified by flash chromatography (silica gel, 30% to 100% EtOAc in hexane). The fractions containing the desired compound were evaporated to give Intermediate 1-1.

[0896] 2. Synthesis of Compound 1

[0897] To a suspension of 4-bromo-3,3-dimethyl-1-(pyrimidin-2-yl)indoline-2-one (50 mg, 0.2 mmol), N-(4-fluorophenyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(trifluoromethyl)benzamide (62 mg, 0.2 mmol), potassium carbonate (27 mg, 0.2 mmol) in DMF / water (9:1), Pd(dppf) 2 Cl 2 (5 mol%) was added. The reaction mixture was stirred in a microwave reactor at 120 °C for 15 minutes. The reaction mixture was diluted with ethyl acetate, filtered through celite and concentrated in vacuo. The resulting residue was purified by HPLC (CAN / water containing 0.1% TFA) to give the title compound. 11H NMR (400 MHz, chloroform-d) δ 8.93 (s, 1H), 7.83 (d, J = 8.1 Hz, 1H), 7.67 (dd, J = 8.1, 1.0 Hz, 1H), 7.65–7.51 (m, 4H), 7.46 (s, 1H), 7.32 (dd, J = 10.7, 5.1 Hz, 2H), 7.19–7.03 (m, 3H), 6.91 (dd, J = 7.7, 1.0 Hz, 1H), 1.34 (s, 6H).

[0898] C 28 H 20 F 4 N 4 O 2。 521.1 (M+H).

[0899] Example 2: 5-(3,3-Dimethyl-2-oxo-1-(pyridin-2-yl)indolin-4-yl)-N-(4-fluorophenyl)-2-(trifluoromethyl)benzamide, Compound 2

[0900]

[0901] Compound 2 was prepared in a manner similar to that applied in the synthesis of Compound 1 (described in Example 1), but using 4-bromo-3,3-dimethyl-1-(pyridin-2-yl)indolin-2-one in place of 4-bromo-3,3-dimethyl-1-(pyrimidin-2-yl)indolin-2-one. 1 1H NMR (400 MHz, chloroform-d) δ 8.63 (ddd, J = 4.9, 2.0, 0.9 Hz, 1H), 8.00–7.69 (m, 3H), 7.70–7.39 (m, 5H), 7.40–7.23 (m, 3H), 7.14–7.00 (m, 2H), 6.88 (dd, J = 7.7, 1.0 Hz, 1H), 1.32 (s, 6H). C 29 H 21 F 4 N 3 O 2。 520.1 (M+H).

[0902] The preparation of 4-bromo-3,3-dimethyl-1-(pyridin-2-yl)indolin-2-one was similar to that of 4-bromo-3,3-dimethyl-1-(pyrimidin-2-yl)indolin-2-one, but using 2-bromopyridine in place of 2-bromopyrimidine (75%). LC-MS (m / z): 318.1 (M+1). 4-Bromo-3,3-dimethyl-1-(pyridin-2-yl)indolin-2-one has the following structure:

[0903]

[0904] Example 3: 5-(3,3-Dimethyl-2-oxo-1-(pyrimidin-4-yl)-2,3-dihydro-1H-indol-4-yl)-N-(4-fluorophenyl)-2-(trifluoromethyl)benzamide, Compound 3

[0905]

[0906] Compound 3 was prepared in a manner similar to that applied in the synthesis of Compound 1, but using 4-bromo-3,3-dimethyl-1-(pyrimidin-4-yl)-2,3-dihydro-1H-indol-2-one in place of 4-bromo-3,3-dimethyl-1-(pyrimidin-2-yl)-2,3-dihydro-1H-indol-2-one. 1 HNMR(400MHz, chloroform-d) δ8.93(dd, J = 4.8, 3.0Hz, 2H), 7.83(d, J = 8.1Hz, 1H), 7.74–7.39(m, 6H), 7.40–7.26(m, 2H), 7.17–7.01(m, 2H), 6.92(dd, J = 7.7, 1.0Hz, 1H), 1.34(s, 6H). C 28 H 20 F 4 N 4 O 2 .521.1(M+H).

[0907] The preparation of 4-bromo-3,3-dimethyl-1-(pyrimidin-4-yl)-2,3-dihydro-1H-indol-2-one was similar to the preparation of 4-bromo-3,3-dimethyl-1-(pyrimidin-2-yl)-2,3-dihydro-1H-indol-2-one, but using 4-bromopyrimidine in place of 2-bromopyrimidine. LC-MS(m / z): 319.0(M+1). 4-Bromo-3,3-dimethyl-1-(pyrimidin-4-yl)-2,3-dihydro-1H-indol-2-one has the following structure:

[0908]

[0909] Example 4: 5-(3,3-Dimethyl-2-oxo-1-(pyrazin-2-yl)-2,3-dihydro-1H-indol-4-yl)-N-(4-fluorophenyl)-2-(trifluoromethyl)benzamide, Compound 4

[0910]

[0911] Compound 4 was prepared in a manner similar to that applied in the synthesis of Compound 1, but using 4-bromo-3,3-dimethyl-1-(pyrazin-2-yl)-2,3-dihydro-1H-indol-2-one in place of 4-bromo-3,3-dimethyl-1-(pyrimidin-2-yl)-2,3-dihydro-1H-indol-2-one. 1HNMR (400 MHz, chloroform-d) δ 9.21 (d, J = 1.5 Hz, 1H), 8.70–8.45 (m, 2H), 7.98–7.72 (m, 2H), 7.71–7.41 (m, 5H), 7.33 (t, J = 7.9 Hz, 1H), 7.07 (t, J = 8.6 Hz, 2H), 6.93 (dd, J = 7.8, 1.0 Hz, 1H), 1.33 (s, 6H).

[0912] C 28 H 20 F 4 N 4 O 2 .521.1 (M+H).

[0913] The preparation of 4-bromo-3,3-dimethyl-1-(pyrazin-2-yl)indolin-2-one is similar to that of 4-bromo-3,3-dimethyl-1-(pyrimidin-2-yl)indolin-2-one, but using 2-bromopyrazine instead of 2-bromopyrimidine. LC-MS (m / z): 319.0 (M+1). 4-Bromo-3,3-dimethyl-1-(pyrazin-2-yl)indolin-2-one has the following structure:

[0914]

[0915] Example 5: 5-(3,3-Dimethyl-2-oxo-1-(1H-pyrazol-3-yl)indolin-4-yl)-N-(4-fluorophenyl)-2-(trifluoromethyl)benzamide, Compound 5

[0916]

[0917] 5-(3,3-Dimethyl-2-oxo-1-(1H-pyrazol-3-yl)indolin-4-yl)-N-(4-fluorophenyl)-2-(trifluoromethyl)benzamide C 27 H 20 F 4 N 4 O 2 .509.3 (M+1). 1 H NMR (400 MHz, methanol-d4) δ 7.90 (d, J = 8.0 Hz, 1H), 7.81 (d, J = 2.4 Hz, 1H), 7.68-7.61 (m, 4H), 7.41 (dd, J = 8.4, 1.2 Hz, 1H), 7.34 (t, J = 7.6 Hz, 1H), 7.12-7.08 (m, 2H), 6.94 (dd, J = 7.6, 1.2 Hz, 1H), 6.57 (d, J = 2.4 Hz, 1H), 1.30 (s, 6H).

[0918] Example 6: 5-(3,3-Dimethyl-1-(1-methyl-1H-pyrazol-4-yl)-2-oxodihydroindol-4-yl)-N-(4-fluorophenyl)-2-(trifluoromethyl)benzamide, Compound 6

[0919]

[0920] 5-(3,3-Dimethyl-1-(1-methyl-1H-pyrazol-4-yl)-2-oxodihydroindol-4-yl)-N-(4-fluorophenyl)-2-(trifluoromethyl)benzamide was prepared analogously to Example 1, using 4-iodo-1-methyl-1H-pyrazole in place of tert-butyl 3-iodo-1H-pyrazole-1-carboxylate. C 28 H 22 F 4 N 4 O 2 .523.3 (M+1). 1 1H NMR (400 MHz, methanol-d4) δ 7.90 (d, J = 8.0 Hz, 1H), 7.71 (d, J = 2.4 Hz, 1H), 7.68 - 7.61 (m, 4H), 7.47 (dd, J = 8.2, 1.0 Hz, 1H), 7.34 (t, J = 8.0 Hz, 1H), 7.12 - 7.08 (m, 2H), 6.94 (dd, J = 7.6, 1.2 Hz, 1H), 6.53 (d, J = 2.4 Hz, 1H), 3.96 (s, 3H), 1.29 (s, 6H).

[0921] Example 7: 5-(3,3-Dimethyl-2-oxo-1-(pyridin-3-yl)dihydroindol-4-yl)-N-(4-fluorophenyl)-2-(trifluoromethyl)benzamide, Compound 7

[0922]

[0923] Compound 7 was prepared in a manner analogous to that applied in the synthesis of Compound 1, but using 4-bromo-3,3-dimethyl-1-(pyridin-3-yl)dihydroindol-2-one in place of 4-bromo-3,3-dimethyl-1-(pyrimidin-2-yl)dihydroindol-2-one. 1 1H NMR (400 MHz, chloroform-d) δ 9.52 (s, 1H), 9.18–8.97 (m, 1H), 8.80 (d, J = 5.2 Hz, 1H), 8.39 (d, J = 8.3 Hz, 1H), 8.02–7.77 (m, 2H), 7.75–7.41 (m, 5H), 7.34 (t, J = 7.9 Hz, 1H), 7.18–6.88 (m, 3H), 1.34 (s, 6H). C 29 H21 F 4 N 3 O 2 .520.1 (M+H).

[0924] The preparation of 4-bromo-3,3-dimethyl-1-(pyridin-3-yl)indolin-2-one is similar to the preparation of 4-bromo-3,3-dimethyl-1-(pyrimidin-2-yl)indolin-2-one, but 3-bromopyridine is used instead of 2-bromopyrimidine. 318.0 (M+1). 4-bromo-3,3-dimethyl-1-(pyridin-3-yl)indolin-2-one has the following structure:

[0925]

[0926] Example 8: 5-(3,3-dimethyl-2-oxo-1-(pyridin-4-yl)indolin-4-yl)-N-(4-fluorophenyl)-2-(trifluoromethyl)benzamide, Compound 8

[0927]

[0928] Compound 8 was prepared in a manner similar to that applied in the synthesis of Compound 1, but 4-bromo-3,3-dimethyl-1-(pyridin-4-yl)indolin-2-one was used instead of 4-bromo-3,3-dimethyl-1-(pyrimidin-2-yl)indolin-2-one. 1 HNMR (400 MHz, chloroform-d) δ 9.05 (d, J = 57.2 Hz, 2H), 8.14 (d, J = 5.3 Hz, 2H), 7.86 (d, J = 8.1 Hz, 1H), 7.66 (d, J = 1.6 Hz, 1H), 7.56 (td, J = 7.2, 3.7 Hz, 4H), 7.50–7.28 (m, 2H), 7.15–6.87 (m, 3H), 1.35 (s, 6H). C 29 H 21 F 4 N 3 O 2 .520.1 (M+H).

[0929] The preparation of 4-bromo-3,3-dimethyl-1-(pyridin-4-yl)indolin-2-one is similar to the preparation of 4-bromo-3,3-dimethyl-1-(pyrimidin-2-yl)indolin-2-one, but 4-bromopyridine is used instead of 2-bromopyrimidine. 318.1 (M+1). 4-bromo-3,3-dimethyl-1-(pyridin-4-yl)indolin-2-one has the following structure:

[0930]

[0931] Example 9: 5-(3,3-Dimethyl-2-oxo-1-(pyrimidin-2-yl)-2,3-dihydro-1H-indol-4-yl)-N-(4-fluorophenyl)-2-methylbenzamide, Compound 9

[0932]

[0933] Compound 9 was prepared in a manner similar to that applied in the synthesis of Compound 1, but using 5-(3,3-dimethyl-2-oxo-2,3-dihydro-1H-indol-4-yl)-N-(4-fluorophenyl)-2-methylbenzamide instead of 5-(3,3-dimethyl-2-oxo-2,3-dihydro-1H-indol-4-yl)-N-(4-fluorophenyl)-2-(trifluoromethyl)benzamide.

[0934] 1 H NMR (400 MHz, chloroform-d) δ 8.91 (d, J = 4.9 Hz, 2H), 7.75–7.50 (m, 3H), 7.43 (d, J = 8.5 Hz, 2H), 7.41–7.20 (m, 4H), 7.06 (t, J = 8.5 Hz, 2H), 6.93 (d, J = 7.7 Hz, 1H), 2.59 (s, 3H), 1.34 (s, 6H). C 29 H 24 FN 4 O 2 .467.2 (M+H).

[0935] Example 10: 5-(3,3-Dimethyl-2-oxo-1-(pyridin-2-yl)-2,3-dihydro-1H-indol-4-yl)-N-(4-fluorophenyl)-2-methylbenzamide, Compound 10

[0936]

[0937] Compound 10 was prepared in a manner similar to that applied in the synthesis of Compound 1, but using 2-bromopyridine instead of 2-bromopyrimidine and 5-(3,3-dimethyl-2-oxo-2,3-dihydro-1H-indol-4-yl)-N-(4-fluorophenyl)-2-methylbenzamide instead of 5-(3,3-dimethyl-2-oxo-2,3-dihydro-1H-indol-4-yl)-N-(4-fluorophenyl)-2-(trifluoromethyl)benzamide.

[0938] 11H NMR (400 MHz, chloroform-d) δ 8.63 (dd, J = 5.0, 1.8 Hz, 1H), 7.91 (td, J = 7.8, 1.9 Hz, 1H), 7.73 (d, J = 8.1 Hz, 1H), 7.66–7.38 (m, 5H), 7.41–7.15 (m, 3H), 7.06 (t, J = 8.4 Hz, 2H), 6.90 (d, J = 7.7 Hz, 1H), 2.59 (s, 3H), 1.31 (s, 6H).

[0939] C 29 H 24 FN 3 O 2 .466.2 (M+H).

[0940] Example 11: 5-(1-(1H-Imidazol-4-yl)-3,3-dimethyl-2-oxodihydroindol-4-yl)-N-(4-fluorophenyl)-2-(trifluoromethyl)benzamide, Compound 11

[0941]

[0942] The preparation of Compound 11, 5-(1-(1H-imidazol-4-yl)-3,3-dimethyl-2-oxodihydroindol-4-yl)-N-(4-fluorophenyl)-2-(trifluoromethyl)benzamide is similar to that of Compound 5, 5-(3,3-dimethyl-2-oxo-1-(1H-pyrazol-3-yl)dihydroindol-4-yl)-N-(4-fluorophenyl)-2-(trifluoromethyl)benzamide, but using 4-iodo-1H-imidazole instead of tert-butyl 3-iodo-1H-pyrazole-1-carboxylate.

[0943] 5-(1-(1H-Imidazol-4-yl)-3,3-dimethyl-2-oxodihydroindol-4-yl)-N-(4-fluorophenyl)-2-(trifluoromethyl)benzamide C 27 H 20 F 4 N 4 O 2 .509.3 (M+1). 1 1H NMR (400 MHz, methanol-d4) δ 8.39 (s, 1H), 7.91 (d, J = 8.4 Hz, 1H), 7.68 - 7.60 (m, 5H), 7.36 (t, J = 8.0 Hz, 1H), 7.12 - 7.07 (m, 3H), 6.97 (dd, J = 7.6, 1.0 Hz, 1H), 1.31 (s, 6H).

[0944] Example 12: 5-(3,3-Dimethyl-2-oxo-1-(pyridin-2-yl)-2,3-dihydro-1H-indol-4-yl)-N-(4-fluorophenyl)-2-methylnicotinamide, Compound 12

[0945]

[0946] Compound 12 was prepared in a manner similar to that applied in the synthesis of Compound 1, but using 2-bromopyridine instead of 2-bromopyrimidine and 5-(3,3-dimethyl-2-oxo-1-(pyridin-2-yl)-2,3-dihydro-1H-indol-4-yl)-N-(4-fluorophenyl)-2-methylnicotinamide instead of 5-(3,3-dimethyl-2-oxo-2,3-dihydro-1H-indol-4-yl)-N-(4-fluorophenyl)-2-(trifluoromethyl)benzamide.

[0947] 1 H NMR (400 MHz, chloroform-d) δ 9.47 (s, 1H), 8.62 (ddd, J = 5.0, 2.0, 0.9 Hz, 1H), 8.52 (d, J = 2.0 Hz, 1H), 8.24 (d, J = 1.9 Hz, 1H), 7.92 (td, J = 7.8, 2.0 Hz, 1H), 7.82–7.53 (m, 4H), 7.49–7.26 (m, 2H), 7.07 (t, J = 8.6 Hz, 2H), 6.91 (d, J = 7.7 Hz, 1H), 2.96 (s, 3H), 1.30 (s, 6H). C 28 H 23 FN 4 O 2 . 467.2 (M+H).

[0948] Example 13: 5-(3,3-Dimethyl-2-oxo-1-(pyridin-3-yl)-2,3-dihydro-1H-indol-4-yl)-N-(4-fluorophenyl)-2-methylnicotinamide, Compound 13

[0949]

[0950] Compound 13 was prepared in a manner similar to that applied in the synthesis of Compound 1, but using 3-bromopyridine instead of 2-bromopyrimidine and 5-(3,3-dimethyl-2-oxo-1-(pyridin-3-yl)-2,3-dihydro-1H-indol-4-yl)-N-(4-fluorophenyl)-2-methylnicotinamide instead of 5-(3,3-dimethyl-2-oxo-2,3-dihydro-1H-indol-4-yl)-N-(4-fluorophenyl)-2-(trifluoromethyl)benzamide.

[0951] 11H NMR (400 MHz, chloroform-d) δ 9.06–8.79 (m, 2H), 8.75 (dd, J = 5.2, 1.4 Hz, 1H), 8.62 (d, J = 1.9 Hz, 1H), 8.32–8.05 (m, 2H), 7.81 (dd, J = 8.3, 5.2 Hz, 1H), 7.66 (dd, J = 8.8, 4.8 Hz, 2H), 7.37 (t, J = 7.8 Hz, 1H), 7.20–6.90 (m, 4H), 2.97 (s, 3H), 1.34 (s, 6H). C 28 H 23 FN 4 O 2 . 467.2 (M+H).

[0952] Example 14: 5-(3,3-Dimethyl-2-oxo-1-(pyrimidin-2-yl)indolin-4-yl)-N-(4-fluorophenyl)-2-methylnicotinamide, Compound 14

[0953]

[0954] Compound 14 was prepared in a manner similar to that applied in the synthesis of Compound 1, but using 5-(3,3-dimethyl-2-oxo-1-(pyridin-2-yl)indolin-4-yl)-N-(4-fluorophenyl)-2-methylnicotinamide instead of 5-(3,3-dimethyl-2-oxoindolin-4-yl)-N-(4-fluorophenyl)-2-(trifluoromethyl)benzamide.

[0955] 1 1H NMR (400 MHz, chloroform-d) δ 9.51 (s, 1H), 8.89 (d, J = 4.9 Hz, 2H), 8.54 (d, J = 2.0 Hz, 1H), 8.23 (d, J = 2.0 Hz, 1H), 7.86–7.56 (m, 3H), 7.47–7.26 (m, 2H), 7.07 (t, J = 8.6 Hz, 2H), 7.00–6.85 (m, 1H), 2.96 (s, 3H), 1.30 (s, 6H).

[0956] C 27 H 22 FN 5 O 2 . 468.1 (M+H).

[0957] Example 15: 5-(3,3-Dimethyl-2-oxo-1-(pyrazin-2-yl)indolin-4-yl)-N-(4-fluorophenyl)-2-methylnicotinamide, Compound 15

[0958]

[0959] Compound 15 was prepared in a manner similar to that applied in the synthesis of Compound 1, but using 2-bromopyrazine instead of 2-bromopyrimidine and 5-(3,3-dimethyl-2-oxo-1-(pyridin-2-yl)dihydroindol-4-yl)-N-(4-fluorophenyl)-2-methylnicotinamide instead of 5-(3,3-dimethyl-2-oxodihydroindol-4-yl)-N-(4-fluorophenyl)-2-(trifluoromethyl)benzamide.

[0960] 1 H NMR (400 MHz, chloroform-d) δ 9.48 (s, 1H), 8.91 (d, J = 4.9 Hz, 2H), 8.54 (d, J = 2.0 Hz, 1H), 8.23 (d, J = 2.0 Hz, 1H), 7.86–7.56 (m, 3H), 7.47–7.26 (m, 2H), 7.07 (t, J = 8.6 Hz, 2H), 7.00–6.85 (m, 1H), 2.96 (s, 3H), 1.30 (s, 6H).

[0961] C 27 H 22 FN 5 O 2 .468.1 (M+H).

[0962] Example 16: 5-(3,3-Dimethyl-2-oxo-1-(pyrimidin-2-ylmethyl)dihydroindol-4-yl)-N-(4-fluorophenyl)-2-(trifluoromethyl)benzamide, Compound 16

[0963]

[0964] To a solution of 4-bromo-3,3-dimethylindolin-2-one (I, 0.1 g, 0.4 mmol) and 2-(chloromethyl)pyrimidine in 2 mL of DMF was added K 2 CO 3 (0.115, 0.8 mmol), and the mixture was stirred at 80 °C for 4 hours. 5 mL of water was added to the mixture, and the mixture was extracted with 2x5 EtOAc. The organic solvents were separated, dried over MgSO 4 . The solvent was evaporated and purified using preparative HPLC, which used Gilson reverse phase eluted with ACN and water containing 0.1% TFA, using a Luna column, to obtain the title compound. C 15 H 14 BrN 3 .333.0 (M+1).

[0965] To a suspension of 4-bromo-3,3-dimethyl-1-(pyrimidin-2-ylmethyl)-2,3-dihydroindol-2-one (30 mg, 0.1 mmol), N-(4-fluorophenyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(trifluoromethyl)benzamide (30 mg, 0.1 mmol), and sodium bicarbonate (84 mg, 0.2 mmol) in DMF / water (9:1) was added a palladium catalyst (5 mol%). The reaction mixture was subjected to microwave irradiation at 120 °C for 15 minutes. The reaction mixture was diluted with ethyl acetate, filtered through diatomaceous earth and concentrated. The residue was purified by preparative HPLC using a Gilson reverse phase with elution by ACN and water containing 0.1% TFA, using a Luna column to afford the title compound. 1 H NMR (400 MHz, chloroform-d) δ 8.82 (d, J = 5.4 Hz, 1H), 8.07 (td, J = 7.9, 1.4 Hz, 1H), 7.82 (d, J = 8.1 Hz, 1H), 7.69–7.44 (m, 6H), 7.17–7.03 (m, 2H), 6.98 (dd, J = 8.0, 1.0 Hz, 1H), 6.84 (dd, J = 7.8, 1.0 Hz, 1H), 5.34 (s, 2H), 1.27 (s, 6H). C 29 H 22 F 4 N 4 O 2 .534.2 (M+H).

[0966] Example 17: 5-(3,3-Dimethyl-2-oxo-1-(pyridin-2-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-N-(4-fluorophenyl)-2-(trifluoromethyl)benzamide, Compound 17

[0967]

[0968] 1. Synthesis of 4-bromo-1-(pyridin-2-yl)-1H-pyrrolo[2,3-b]pyridine

[0969]

[0970] To 4-bromo-1H-pyrrolo[2,3-b]pyridine (1.0 g, 5.08 mmol, 1 equiv), 2-iodopyridine (1.56 g, 7.61 mmol, 1.5 equiv), Cu 2 O (73 mg, 0.51 mmol, 10 mol%) and Cs 2 CO 3DMSO (5 mL) was added to a mixture of (3.31 g, 10 mmol, 2 equiv). The reaction mixture was stirred at 100 °C for 12 h. The reaction mixture was diluted with water and extracted twice with EtOAc. The combined organic layers were dried over MgSO 4

[0971] 2. Synthesis of methyl 5-(1-(pyridin-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-(trifluoromethyl)benzoate

[0972]

[0973] To a mixture of methyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(trifluoromethyl)benzoate (500 mg, 1.52 mmol, 1 equiv), 4-bromo-1-(pyridin-2-yl)-1H-pyrrolo[2,3-b]pyridine (540 mg, 1.97 mmol, 1.3 equiv), PdCl 2 (dppf) (46 mg, 0.076 mmol, 5 mol%) and K 2 CO 3 (419 mg, 3.03 mmol, 2 equiv) in degassed DMF / water (5.5 mL, 10:1) was added. The reaction mixture was stirred at 100 °C for 16 h. The reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were dried over MgSO 4 and filtered and concentrated in vacuo. The crude product was purified by silica gel column chromatography (0 - 100% EtOAc / hexane) to afford methyl 5-(1-(pyridin-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-(trifluoromethyl)benzoate (LC-MS m / z: 398.5 (M + 1)).

[0974] 3. Synthesis of methyl 5-(2-oxo-1-(pyridin-2-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-(trifluoromethyl)benzoate

[0975]

[0976] To a solution of methyl 5-(1-(pyridin-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-(trifluoromethyl)benzoate (0.184 g, 0.463 mmol, 1 equiv) in tBuOH / H2O (3.85 mL, 10:1) was added pyridinium tribromide (444 mg, 1.39 mmol, 3 equiv). The reaction mixture was stirred at room temperature for 3 h. The reaction mixture was concentrated in vacuo, diluted with water, extracted twice with EtOAc, and the combined organic layers were dried over MgSO 4 4, filtered, and concentrated in vacuo. The reaction gave a mixture of methyl 5-(2-oxo-1-(pyridin-2-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-(trifluoromethyl)benzoate, methyl 5-(3-bromo-2-oxo-1-(pyridin-2-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-(trifluoromethyl)benzoate, and methyl 5-(3,3-dibromo-2-oxo-1-(pyridin-2-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-(trifluoromethyl)benzoate. The mixture was dissolved in AcOH (2.5 mL) and zinc powder (0.245 g, 0.429 mmol, 1 equiv) was added. The reaction mixture was stirred at room temperature for 4 h. The reaction mixture was concentrated in vacuo and purified via silica gel column chromatography (0-100% EtOAc / hexanes) to afford methyl 5-(1-(pyridin-2-yl)-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-(trifluoromethyl)benzoate. LC-MS m / z: 414.5 (M+1).

[0977] 4. Synthesis of methyl 5-(3,3-dimethyl-2-oxo-1-(pyridin-2-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-(trifluoromethyl)benzoate

[0978]

[0979] At 0 °C, to a solution of methyl 5-(2-oxo-1-(pyridin-2-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-(trifluoromethyl)benzoate (50 mg, 0.121 mmol, 1 equiv) in DMF (0.75 mL) was added NaH (11 mg, 0.266 mmol, 2.2 equiv). The reaction mixture was stirred at 0 °C for 5 min before the addition of MeI (0.017 mL, 38 mg, 0.266 mmol, 2.2 equiv). The reaction was warmed to room temperature and stirred for 3 h. The reaction was quenched with water, extracted twice with EtOAc, and the combined organic layers were dried over MgSO 4Dry, filter, and concentrate in vacuo to afford the title compound. LC-MS m / z: 442.6 (M+1).

[0980] 5. Synthesis of 5-(3,3-Dimethyl-2-oxo-1-(pyridin-2-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-(trifluoromethyl)benzoic acid

[0981]

[0982] Dissolve methyl 5-(3,3-dimethyl-2-oxo-1-(pyridin-2-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-(trifluoromethyl)benzoate in a mixture of THF / MeOH / 2N LiOH (1.6 mL, 2:1:1), and stir at room temperature for 12 h. Neutralize the reaction mixture with 2N HCl, dilute with water, extract twice with EtOAc, and dry the combined organic layers over MgSO 4 Dry, filter, and concentrate in vacuo to afford the title compound. LC-MS m / z: 428.5 (M+1).

[0983] Example 18: 5-(3,3-Dimethyl-2-oxo-1-(1H-pyrazol-4-yl)indolin-4-yl)-N-(4-fluorophenyl)-2-(trifluoromethyl)benzamide, Compound 18

[0984]

[0985] The preparation of Compound 18, 5-(3,3-dimethyl-2-oxo-1-(1H-pyrazol-4-yl)indolin-4-yl)-N-(4-fluorophenyl)-2-(trifluoromethyl)benzamide is similar to that of Compound 5, 5-(3,3-dimethyl-2-oxo-1-(1H-pyrazol-3-yl)indolin-4-yl)-N-(4-fluorophenyl)-2-(trifluoromethyl)benzamide, but using 4-iodo-1H-pyrazole instead of tert-butyl 3-iodo-1H-pyrazole-1-carboxylate.

[0986] 5-(3,3-Dimethyl-2-oxo-1-(1H-pyrazol-4-yl)indolin-4-yl)-N-(4-fluorophenyl)-2-(trifluoromethyl)benzamide C 27 H 20 F 4 N 4 O 2 . 509.1 (M+1). 11H NMR (400 MHz, methanol-d4) δ 8.00 - 7.79 (m, 3H), 7.67 - 7.60 (m, 4H), 7.35 (t, J = 7.8 Hz, 1H), 7.13 - 7.06 (m, 2H), 7.03 (dd, J = 8.0, 1.2 Hz, 1H), 6.93 (dd, J = 7.8, 1.0 Hz, 1H), 1.28 (s, 6H).

[0987] Example 19: N-(5-Cyanopyridin-2-yl)-5-(3,3-dimethyl-2-oxo-1-(pyridin-3-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-(trifluoromethyl)benzamide, Compound 19

[0988]

[0989] The preparation of Compound 19 was similar to Example 17, using 6-aminopyridine-3-carbonitrile (25 mg, 0.211 mmol, 5 equiv) instead of 4-fluoroaniline. The reaction mixture was stirred overnight at 50 °C. Compound 19 was isolated. C 28 H 19 F 3 N 6 O 2 . 529.7 (M+1). 1 1H NMR (400 MHz, DMSO-d6) δ 11.85 (s, 1H), 8.88 – 8.74 (m, 1H), 8.64 (dd, J = 4.8, 1.5 Hz, 2H), 8.21 (dd, J = 7.0, 5.3 Hz, 2H), 8.08 – 7.99 (m, 2H), 7.74 (m, 1H), 7.70 – 7.59 (m, 2H), 7.02 (d, J = 5.3 Hz, 2H), 1.30 (s, 6H). 19 19F NMR (376 MHz, DMSO-d6) δ -58.31 (s, 2F), -58.77 (s, 1F), -74.90 (s, 3F).

[0990] Example 20: N-(4-Fluorophenyl)-5-(1-(5-fluoropyridin-3-yl)-3,3-dimethyl-2-oxoindolin-4-yl)-2-(trifluoromethyl)nicotinamide, Compound 20

[0991]

[0992] The preparation of Compound 20 was similar to that of Example 36, 5-(3,3-dimethyl-2-oxo-1-(pyridin-3-yl)indoline-4-yl)-N-(4-fluorophenyl)-2-(trifluoromethyl)nicotinamide, using 4-bromo-1-(5-fluoropyridin-3-yl)-3,3-dimethylindolin-2-one instead of 4-bromo-3,3-dimethyl-1-(pyridin-3-yl)indoline-2-one (mono-TFA salt). C 28 H 19 F 5 N 4 O 2 .539.7 (M+1). 1 1H NMR (400 MHz, DMSO-d6) δ 10.79 (s, 1H), 8.85 (d, J = 1.9 Hz, 1H), 8.73 (d, J = 2.6 Hz, 1H), 8.64 (t, J = 1.6 Hz, 1H), 8.23 (d, J = 2.0 Hz, 1H), 8.09 (ddd, J = 9.7, 2.7, 1.9 Hz, 1H), 7.71–7.63 (m, 2H), 7.39 (t, J = 7.9 Hz, 1H), 7.25–7.16 (m, 2H), 7.04–6.96 (m, 2H), 1.23 (s, 6H). 19 19F NMR (376 MHz, DMSO-d6) δ -63.49, -75.34, -118.50 (td, J = 8.8, 4.2 Hz), -125.71 (d, J = 9.6 Hz).

[0993]

[0994] Example 21: 5-(3,3-Dimethyl-2-oxo-1-(pyrimidin-2-yl)indoline-4-yl)-N-(pyridin-3-yl)-2-(trifluoromethyl)benzamide, Compound 21

[0995]

[0996] Compound 21 was prepared in a similar manner to that used in Synthesis Example 47, but using 3-aminopyridine instead of 5-aminopyrimidine.

[0997] 1 1H NMR (400 MHz, chloroform-d) δ 9.54 (d, J = 14.3 Hz, 2H), 9.03 (dd, J = 21.3, 4.8 Hz, 3H), 8.33 (t, J = 5.9 Hz, 1H), 8.01–7.71 (m, 4H), 7.71–7.25 (m, 3H), 7.21–6.97 (m, 1H), 1.35 (s, 6H). C 27 H20 F 3 N 5 O 2 .504.1 (M+H).

[0998] Example 22: 5-(1-(2,3-difluorophenyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)-N-(4-fluorophenyl)-2-methylbenzamide, Compound 22

[0999]

[1000] To a stirred solution of N-(4-fluorophenyl)-2-methyl-5-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)benzamide (30 mg, 0.083 mmol) in CH 2 Cl 2 (5 mL) was added (2,3-difluorophenyl)boronic acid (17.0 mg, 0.108 mmol), copper(II) acetate anhydrous (30.2 mg, 0.166 mmol), 4A activated molecular sieves, and triethylamine (25.2 mg, 0.249 mmol). The resulting mixture was stirred overnight at room temperature. The reaction mixture was filtered through celite and washed with MeOH. The filtrate was concentrated and purified by preparative HPLC to afford 5-(1-(2,3-difluorophenyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)-N-(4-fluorophenyl)-2-methylbenzamide.

[1001] 5-(1-(2,3-difluorophenyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-4-yl)-N-(4-fluorophenyl)-2-methylbenzamide C 27 H 18 F 3 N 3 O 2 .474.2 (M+1). 1 H NMR (400 MHz, methanol-d 4 ) δ 7.78 (s, 1H), 7.55 - 7.51 (m, 2H), 7.43 (d, J = 1.2 Hz, 2H), 7.21 - 7.42 (m, 3H), 7.00 - 6.93 (m, 3H), 6.78 (d, J = 7.6 Hz, 1H), 2.61 (s, 3H).

[1002] Example 23: 5-(3,3-dimethyl-1-(1-methyl-1H-pyrazol-4-yl)-2-oxoindolin-4-yl)-N-(4-fluorophenyl)-2-(trifluoromethyl)benzamide, Compound 23

[1003]

[1004] The compound of Example 23 has the following experimental data: C 28 H 22 F 4 N 4 O 2 .523.3 (M+1). 1 1H NMR (400 MHz, methanol-d 4 ) δ 7.83 (d, J = 8.0 Hz, 1H), 7.74 (d, J = 5.2 Hz, 2H(m, 2H), 7.65 (d, J = 1.6 Hz, 1H), 7.58 - 7.54 (m, 3H), 7.45 (s, 1H), 7.30 (t, J = 7.8 Hz, 1H), 7.10 - 7.05 (m, 3H), 6.86 (dd, J = 7.8, 1.0 Hz, 1H), 4.00 (s, 3H), 1.29 (s, 6H).

[1005] Example 24: 5-(3,3-Dimethyl-2-oxo-1-(pyrimidin-2-yl)indolin-4-yl)-N-(4-fluorophenyl)-2-(trifluoromethoxy)benzamide, Compound 24

[1006]

[1007] The preparation of 5-(3,3-dimethyl-2-oxo-1-(pyrimidin-2-yl)indolin-4-yl)-N-(4-fluorophenyl)-2-(trifluoromethoxy)benzamide is similar to that of Compound 46, 6-(3,3-dimethyl-2-oxo-1-(pyrimidin-2-yl)indolin-4-yl)-N-(4-fluorophenyl)-3-(trifluoromethyl)pyridine-2-carboxamide, but using 5-bromo-N-(4-fluorophenyl)-2-(trifluoromethoxy)benzamide in place of 6-bromo-N-(4-fluorophenyl)-3-(trifluoromethyl)pyridine-2-carboxamide.

[1008] C 28 H 20 F 4 N 4 O 3 .537.1 (M+1). 1 1H NMR (400 MHz, methanol-d4) δ 8.95 (d, J = 4.8 Hz, 2H), 7.70 - 7.65 (m, 3H), 7.62 (dd, J = 8.4, 2.0 Hz, 1H), 7.56 - 7.51 (m, 3H), 7.34 (t, J = 8.0 Hz, 1H), 7.12 - 7.08 (m, 2H), 7.00 (dd, J = 7.8, 1.2 Hz, 1H), 1.32 (s, 6H).

[1009] Example 25: 2-(3,3-Dimethyl-2-oxo-1-(pyrimidin-2-yl)-2,3-dihydro-1H-indol-4-yl)-N-(4-fluorophenyl)-5-(trifluoromethyl)isonicotinamide, Compound 25

[1010]

[1011] The preparation of Compound 25, 2-(3,3-dimethyl-2-oxo-1-(pyrimidin-2-yl)-2,3-dihydro-1H-indol-4-yl)-N-(4-fluorophenyl)-5-(trifluoromethyl)isonicotinamide, is similar to that of Compound 46, 6-(3,3-dimethyl-2-oxo-1-(pyrimidin-2-yl)-2,3-dihydro-1H-indol-4-yl)-N-(4-fluorophenyl)-3-(trifluoromethyl)picolinamide, but uses 2-bromo-N-(4-fluorophenyl)-5-(trifluoromethyl)isonicotinamide in place of 6-bromo-N-(4-fluorophenyl)-3-(trifluoromethyl)picolinamide.

[1012] 2-(3,3-Dimethyl-2-oxo-1-(pyrimidin-2-yl)-2,3-dihydro-1H-indol-4-yl)-N-(4-fluorophenyl)-5-(trifluoromethyl)isonicotinamide C 27 H 19 F 4 N 5 O 2 .522.1 (M+1). 1 1H NMR (400 MHz, methanol-d4) δ 9.13 (s, 1H), 8.96 (d, J = 4.8 Hz, 2H), 7.86 (s, 1H), 7.69 - 7.62 (m, 3H), 7.53 (t, J = 5.0 Hz, 1H), 7.43 (t, J = 8.0 Hz, 1H), 7.30 (dd, J = 7.8, 1.0 Hz, 1H), 7.15 - 7.09 (m, 2H), 1.50 (s, 6H).

[1013] Example 26: 5-(3,3-Dimethyl-2-oxo-1-(pyrimidin-2-yl)-2,3-dihydro-1H-indol-4-yl)-N-(pyridin-4-yl)-2-(trifluoromethyl)benzamide, Compound 26

[1014]

[1015] Compound 26 is prepared in a manner similar to that applied in the synthesis of Compound 49, but uses 4-aminopyridine in place of 5-aminopyrimidine. 11H NMR (400 MHz, chloroform-d) δ 11.45 (s, 1H), 8.94 (dd, J = 13.0, 4.8 Hz, 2H), 8.49 (d, J = 42.9 Hz, 3H), 7.98–7.50 (m, 4H), 7.45–7.24 (m, 3H), 7.02 (d, J = 7.6 Hz, 1H), 1.25 (s, 6H). C 27 H 20 F 3 N 5 O.504.1 (M + H).

[1016] Example 27: N-(3,4-Difluorophenyl)-5-(3,3-dimethyl-2-oxo-1-(pyridin-2-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-2-(trifluoromethyl)benzamide, Compound 27

[1017]

[1018] The preparation of Compound 27 was similar to that of Compound 17, using 3,4-difluoroaniline (21 mg, 0.164 mmol, 2.5 equiv) instead of 4-fluoroaniline. Compound 27 was isolated. C 28 H 19 F 5 N 4 O 2 .539.7 (M + 1). 1 1H NMR (400 MHz, DMSO-d6) δ 10.87 (s, 1H), 8.65 (ddd, J = 4.9, 2.0, 0.9 Hz, 1H), 8.18 (d, J = 5.3 Hz, 1H), 8.11–8.00 (m, 2H), 7.83 (ddd, J = 12.7, 7.4, 2.3 Hz, 1H), 7.79–7.73 (m, 2H), 7.59 (dt, J = 7.9, 1.0 Hz, 1H), 7.54 (ddd, J = 7.5, 4.8, 1.1 Hz, 1H), 7.50–7.37 (m, 2H), 6.98 (d, J = 5.3 Hz, 1H), 1.28 (s, 6H). 19F NMR (376 MHz, DMSO-d6) δ -58.42 (s, 3F), -75.35 (s, 3F), -137.50 (ddd, J = 22.3, 12.8, 8.1 Hz, 1F), -144.21 (m, 1F).

[1019] Example 28: 5-(3,3-Dimethyl-2-oxo-1-(pyridin-2-yl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-4-yl)-N-(5-fluoropyridin-2-yl)-2-(trifluoromethyl)benzamide, Compound 28

[1020]

[1021] The preparation of Compound 28 was similar to that of Compound 17, using 5-fluoropyridin-2-amine (18 mg, 0.164 mmol, 2.5 equiv) in place of 4-fluoroaniline. The reaction mixture was stirred at 50 °C overnight. The title compound was then isolated. C 27 H 19 F 4 N 5 O 2 .522.7 (M+1). 1 1H NMR (400 MHz, DMSO-d6) δ 11.41 (s, 1H), 8.65 (ddd, J = 4.9, 1.9, 0.9 Hz, 1H), 8.38 (d, J = 2.9 Hz, 1H), 8.22 (d, J = 7.9 Hz, 1H), 8.17 (d, J = 5.4 Hz, 1H), 8.06 (td, J = 7.7, 1.9 Hz, 1H), 7.98 (d, J = 8.2 Hz, 1H), 7.82 (td, J = 8.7, 3.1 Hz, 1H), 7.76–7.66 (m, 2H), 7.58 (dt, J = 8.0, 1.0 Hz, 1H), 7.53 (ddd, J = 7.5, 4.8, 1.1 Hz, 1H), 6.99 (d, J = 5.3 Hz, 1H), 1.29 (s, 6H). 19 19F NMR (376 MHz, DMSO-d6) δ -58.36 (s, 3F), -75.30 (s, 3F), -132.82 (...

Claims

1. A compound of formula (Ii), or a pharmaceutically acceptable salt or pharmaceutically acceptable tautomer thereof wherein X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , X 7 , and X 8 are each independently CH; R 1 is H; R 2 is C 1-3 alkyl, C 1-3 haloalkyl or C 1-3 haloalkoxy; R 3 Selected from: Z a and Z b are independently H or C 1-4 alkyl groups.

2. A compound of formula (Ij), or a pharmaceutically acceptable salt or pharmaceutically acceptable tautomer thereof wherein X 1 、X 2 、X 3 、X 4 、X 6 、X 7 and X 8 are each independently CH; R 1 is H, a halogen, or CN; R 2 is C 1-3 alkyl, C 1-3 haloalkyl or C 1-3 haloalkoxy; R 3 Selected from: and Z is CH 2 .

3. The compound according to claim 1, or a pharmaceutically acceptable salt or pharmaceutically acceptable tautomer thereof, wherein R 2 is methyl, CF 3 , CHF 2 , or OCF 3 .

4. The compound according to claim 1, or a pharmaceutically acceptable salt or pharmaceutically acceptable tautomer thereof, wherein R 2 is methyl.

5. The compound according to claim 1, or a pharmaceutically acceptable salt or pharmaceutically acceptable tautomer thereof, wherein R 2 is CF 3 .

6. A compound, or a pharmaceutically acceptable salt or pharmaceutically acceptable tautomer thereof, selected from:

7. A pharmaceutical composition comprising a compound according to any one of claims 1 - 6, or a pharmaceutically acceptable salt or pharmaceutically acceptable tautomer thereof, and at least one pharmaceutically acceptable carrier.

8. Use of a compound according to any one of claims 1 - 6, or a pharmaceutically acceptable salt or pharmaceutically acceptable tautomer thereof, in the manufacture of a medicament for treating a disease or disorder in a subject responsive to inhibition of IDO1 activity.

9. Use of a compound according to any one of claims 1 - 6 or a pharmaceutically acceptable salt or pharmaceutically acceptable tautomer thereof in the manufacture of a medicament for inhibiting the activity of IDO1 protein.

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