Antiviral pyrazolopyridone compounds

Abstract

The present invention provides compounds of formula (I) as described herein, as well as pharmaceutically acceptable salts, pharmaceutical compositions containing such compounds, and methods of using these compounds, salts, and compositions to treat viral infections, particularly infections caused by herpes viruses. #imgabs0#

Description

[0001] Related applications

[0002] This application claims priority to U.S. Provisional Application No. 62 / 906,664, filed September 26, 2019, the contents of which are hereby incorporated by reference herein. Technical Field

[0003] The present invention relates to novel bicyclic pyrazolopyridone compounds that are inhibitors of herpes virus replication and are therefore useful in treating herpes virus infections. The compounds inhibit the viral DNA polymerases of various herpes viruses, including cytomegalovirus (CMV), herpes simplex virus, and the like. The present invention provides novel bicyclic pyrazolopyridone compounds as disclosed herein, pharmaceutical compositions containing such compounds, and methods of using these compounds and compositions to treat and prevent herpes virus diseases. Background Art

[0004] Human CMV (also known as human herpesvirus 5 (HHV-5)) is a beta-herpesvirus that affects all populations worldwide, including adults and children with normal or compromised immune systems. Although usually asymptomatic in healthy individuals, CMV can become life-threatening in immunocompromised individuals. CMV is also a concern during pregnancy because it can be transmitted from mother to fetus and cause serious birth defects. There is no approved treatment to prevent or treat congenital CMV infection. In the transplant setting, current anti-CMV therapies include the nucleoside analogs valganciclovir (valGCV), ganciclovir (GCV) and cidofovir (CDV) and the pyrophosphate analog foscarnet (FOS). Each of these therapeutic agents inhibits CMV DNA polymerase, a protein encoded by the UL54 gene, which is an enzyme essential for viral replication (PNAS 2003, 100(24), 14223-14228; WO 2013 / 152063; WO 2005 / 012545). In solid organ transplant recipients, first-line therapy consists of prophylaxis or prior treatment with GCV or the orally bioavailable prodrug valGCV. GCV significantly reduces the risk of disease and is effective in treating active CMV infection. However, drug tolerance is poor. GCV and valGCV can cause severe bone marrow suppression, which puts patients at risk of graft failure in stem cell transplant recipients. Second-line therapies such as CDV and FOS are associated with severe nephrotoxicity. In addition, resistance to current anti-CMV nucleoside analogs is a significant cause of treatment failure. Therefore, there is a need for new classes of CMV therapeutics, particularly non-nucleoside compounds, to provide safer CMV treatment and combat herpes viruses that are resistant to known classes of antivirals.

[0005] In addition to CMV, herpes viruses that cause a wide range of human viral infections include Epstein-Barr virus (EBV), varicella-zoster virus (VZV), and herpes simplex viruses HSV-1 and HSV-2. Other herpes viruses that cause human disease include human herpes virus 6, human herpes virus 7, and Kaposi's sarcoma-associated herpes virus.

[0006] Herpes virus infection is not only widely spread, and also continues lifelong in its host of latent period. It is estimated that more than 90% of adults are potentially infected with at least one herpes virus, and the herpes virus may reactivate after a few years. For example, when varicella zoster virus (VZV) is reactivated from latent period, usually many years after the original infection (chickenpox) has been controlled, it will cause herpes zoster (Zoster / Shingles). Herpes zoster is the painful condition that mainly affects the elderly and the individual with immune dysfunction. Complications include postherpetic neuralgia, potential debilitating and chronic pain syndrome, and anti-VZV inhibitors (nucleosides) only have a slight effect on it.

[0007] The individual of immune disability is in herpes virus reactivation, such as transplant patient, and is at high risk such as CMV, HSV or VZV.Therefore, the safe and effective virus inhibitor with extensive herpes virus activity will be extremely valuable.The invention provides to several herpes viruses, comprise that CMV, HSV, VZV and EBV have active novel compound. Summary of the Invention

[0008] The present invention provides novel non-nucleoside compounds that inhibit herpesvirus DNA polymerase, which have effective antiviral activity in vitro. The compound is active against several herpesviruses, including CMV, HSV, VZV and EBV. Effective non-nucleoside polymerase inhibitors have significant advantages over current anti-CMV agents. First, unlike nucleoside analogs, the compound is not incorporated by human polymerase and is therefore expected to have better safety than current anti-CMV drugs. Secondly, the compound as described herein is active against GCV-resistant viruses and therefore has the potential for rescue therapy in patients with cross-resistance to nucleoside analogs. Finally, the compound is active against several human herpesviruses, providing opportunities for a wide range of clinical uses. The present invention also provides pharmaceutical compositions containing novel compounds and methods for using the compound and composition to inhibit herpesvirus replication or reactivation and treat disease symptoms associated with or caused by herpesviruses. Other objects of the present invention are described in the following description and examples.

[0009] In one aspect, the present invention provides compounds of formula (I):

[0010]

[0011] in:

[0012] X is 5-6 membered heteroaryl having 1 to 4 heteroatoms independently selected from N, O and S as ring members; containing 1 to 4 heteroatoms independently selected from N, NH, NR 17 , O or S ring members; or containing 1 to 4 independently selected from N, NH, NR 17 , O or S as ring members;

[0013] Y is a bond, -O- or Where * in Y indicates the point of attachment to X and ** in Y indicates the point of attachment to R B attachment points;

[0014] q is 0 or 1;

[0015] When q is 1, then L MC Yes*-((CR 11 R 12 ) n O) m (CR 11 R 12 ) p -**、*-C(=O)NR 15 ((CR 11 R 12 ) n O) m (CR 11 R 12 ) p -**、*-(CR 11 R 12 ) n NR 15 ((CR 11 R 12 ) n O) m (CR 11 R 12 ) p -**、*-(CR 11 R 12 ) n -**、*-((CR 11 R 12 ) n NR 15 ) m (CR 11 R 12 ) p -**、*-(CR 11 R 12)C(=O)NR 15 (CR 11 R 12 ) n -**、*-C(=O)NR 15 (CR 11 R 12 ) n -**、*-O(CR 11 R 12 ) n -** or *-NR 15 (CR 11 R 12 ) n -**, where L MC The * indicates the attachment point with Z and L MC The ** indicates the attachment point with A;

[0016] When q is 1, then L MC exists, A is a bond and Z is Where * of Z indicates the point of attachment to LMC and ** of Z indicates the point of attachment to L;

[0017] m is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10;

[0018] Each n is independently selected from 1, 2, 3, 4, 5, 7, 8, 9 and 10;

[0019] p is 1, 2, 3, 4, 5, or 6;

[0020] When q is 0, then L MC does not exist, and Z is W, and A is R 4 ;

[0021] R B is H, C1-C6 alkyl, phenyl, pyridyl, phenylthio, pyrimidinyl or 5-8 membered cycloalkyl, wherein R B Optionally 1 to 3 R 5 group substitution;

[0022] R 1 Selected from H, C 1- C3 alkyl and C substituted with 1 to 3 -OH groups 1- C3 alkyl;

[0023] R 2 Selected from H, C 1- C3 alkyl and C substituted with 1 to 3 -OH groups 1- C3 alkyl;

[0024] or R 1 and R2 Together with the carbon atoms to which they are attached, they can form a 3-6 membered cycloalkyl ring;

[0025] t is 0, 1, or 2;

[0026] Each R 3 , when present, is a substituent on the ring to which -LZ is directly attached, wherein each R 3 independently selected from halogen, CN, C 1- C3 alkoxy, C 1- C3 alkyl, C(=O)OR 10 and C(=O)NR 13 R 14 ;

[0027] R 4 It is H, C 1- C3 alkyl, C 3- C6 cycloalkyl, -(CH2)2O(CH2)2Br or 1 to 2 independently selected from -OH, -C(=O)R 15 and R 10 C 1- C3 alkyl;

[0028] Each R 5 are independently selected from halo, -CN, hydroxy, -NR 13 R 14 、C 3- C6 cycloalkyl, C 1- C3 alkoxy, C 1- C3 haloalkyl and optionally 1 to 3 R 6 C 1- C3 alkyl, where R B By two R 5 Replace and each R 5 is optionally replaced by 1 to 3 R 6 C 1- C3 alkyl, when directly attached to the same carbon atom, can be taken together with the carbon atoms to which the two are directly attached to form a C3 alkyl group optionally substituted by 1 to 3 R 6 a 3-5 membered cycloalkyl ring substituted with a group;

[0029] Each R 6 Independently selected from halo, hydroxy, CN, C 1- C3 alkoxy, C 1- C3 alkyl and C 3- C5 cycloalkyl,

[0030] Or two R 6The group together with the carbon atom to which they are directly attached can form a 3-5 membered cycloalkyl ring or a 4-6 membered heterocyclic ring containing O, N or S as ring members and optionally substituted by 1 to 2 groups independently selected from oxo and C 1- C3 alkyl group substitution;

[0031] L is a C1-C4 straight or branched chain alkylene linker, or when W is an optionally substituted ring, L can be a C1-C4 straight or branched chain alkylene linker or bond;

[0032] W is H; -OH; -OR 10 ;-C(=O)NR 13 R 14 ;-C(=O)OR 13 ;-NR 13 R 14 ;-NR 13 C(=O)OR 10 ;-NR 13 C(=O)R 10 ;-SO2R 10 ;-SO2NR 13 R 14 ;-NR 13 SO2R 10 ;-P(=O)(OR 13 )2;-S(=O)R 10 ;-S(=O)(=NR 13 )R 10 ;-CR 11 R 12 C(=O)NR 13 R 14 ;-CR 11 R 12 C(=O)OR 13 ;-CR 11 R 12 NR 13 R 14 ;-CR 11 R 12 NR 13 C(=O)OR 10 ;-CR 11 R 12 NR 13 C(=O)R 10 ;-CR 11 R 12 SO2R 10 ;-CR 11 R 12 SO2NR 13 R 14 ;-CR 11 R12 NR 13 SO2R 10 ;-CR 11 R 12 P(=O)(OR 13 )2;-CR 11 R 12 S(=O)R 10 ;-CR 11 R 12 S(=O)(=NR 13 )R 10 ; 3-6 membered cycloalkyl; phenyl; containing one or two independently selected from N, NH, NR 17 , O or S ring members of the 5-6 membered heterocycloalkyl; containing one or two independently selected from N, NH, NR 17 , O or S as ring members; or a 5-membered heteroaryl group having 1 to 4 heteroatoms selected from N, O and S as ring members, which is optionally fused to a phenyl group,

[0033] wherein the 3-6 membered cycloalkyl, the phenyl, the 5-6 membered heterocycloalkyl, the 5-6 membered heterocyclyl and the 5 membered heteroaryl of W are each optionally substituted by 1 to 3 groups independently selected from the following: 1- C3 alkyl, oxo, halogen, C 1- C3 haloalkyl, –L 2 OH, –L 2 OR 10 ,–L 2 OC(=O)NR 13 R 14 ,–L 2 SO2R 10 ,–L 2 SO2NR 14 R 10 ,–L 2 SO2NR 13 R 14 ,–L 2 SO2N=CR 13 NR 13 R 14 ,–L 2 SO2NR 13 C(=O)R 10 ,–L 2 C(=O)NR 13 SO2R 10 ,–L 2 S(=O)R 10 ,–L 2 S(=O)(=NR 13 )R 10 ,–L2 NR 13 SO2NR 13 R 14 ,–L 2 NR 13 SO2R 10 ,–L 2 NR 13 R 14 ,–L 2 NR 13 C(=O)R 13 ,–L 2 NR 13 C(=O)OR 10 ,–L 2 C(=O)NR 13 R 14 and –L 2 C(=O)OR 13 ;

[0034] R 10 Selected from C 1- C5 alkyl; C 1- C3 haloalkyl; 3-6 membered cycloalkyl; phenyl; 5-6 membered heteroaryl having 1 to 4 heteroatoms independently selected from N, O and S as ring members; containing one or two independently selected from N, NH, NR 17 , O or S ring members; and containing 1 to 2 independently selected from N, NH, NR 17 , O or S ring members of the 4-6 membered heterocyclic group,

[0035] Each R 10 Optionally substituted with 1 to 5 groups independently selected from: C 1- C4 alkyl, deuterium, C 1- C4 haloalkoxy, –L 3 OH, –L 3 CN, -L 3 OC(=O)R 14 、-L 3 OR 13 、C 1- C3 haloalkyl, oxo, -L 3 Halogen, –L 3 C 1- C3 alkoxy, –L 3 OC(=O)NR 13 R 14 ,–L 3 SO2R 13 ,–L 3 SO2NR 13 R 14 ,–L 3SO2NR 13 C(=O)R 13 ,–L 3 C(=O)NR 13 SO2R 13 ,–L 3 S(=O)R 13 ,–L 3 S(=O)(=NR 14 )R 13 ,–L 3 NR 13 SO2NR 13 R 14 ,–L 3 NR 13 SO2R 13 ,–L 3 NR 13 R 14 ,–L 3 NR 14 C(=O)R 13 ,–L 3 NR 14 C(=O)OR 13 ,–L 3 C(=O)NR 13 R 14 ,–L 3 C(=O)OR 13 、-L 3 -(containing 1 to 2 independently selected from N, NH, NR 17 , O or S as ring members of the 4-7 membered heterocycloalkyl group), -L 3 -(containing 1 to 2 independently selected from N, NH, NR 17 , O or S ring member 4-7 membered heterocyclic group), -L 3 -C 3- C5 cycloalkyl and -L 3 -(a 5-6 membered heteroaryl ring having 1 to 4 heteroatoms containing 1 to 4 nitrogen atoms, 0 or 1 oxygen atoms and 0 or 1 sulfur atoms as ring members), wherein said C 1- C4 alkyl, 4-7 membered heterocycloalkyl, 4-7 membered heterocyclyl, C 3- The C5 cycloalkyl and 5-6 membered heteroaryl rings are each optionally further substituted by 1 to 3 groups independently selected from halo, C 1- C3 alkyl, C 1- C3 haloalkyl, -L 4 OR 13 、-L 4 CN and –L 4 NR 13 R 14 The group substitution;

[0036] R 11 and R 12 Each independently selected from H and C 1- C4 alkyl;

[0037] Each R 13 Independently selected from H; C 1- C4 alkyl; containing 1 to 2 independently selected from N, NH, NR 17 , O or S ring members; containing 1 to 2 independently selected from N, NH, NR 17 , O or S as ring members; and C 3- C6 cycloalkyl, wherein the C 1- C4 alkyl, heterocycloalkyl, heterocyclyl and C 3- C6 cycloalkyl is optionally substituted by 1 to 3 independently selected 1- C4 alkyl, halogen, -OH, -NR 15 R 16 、-C(=O)OR 15 , C1-C2 alkoxy and C1-C2 substituted by 1 to 2 hydroxyl groups 1- C4 alkyl group substitution;

[0038] R 14 Selected from H, C 1- C4 alkyl and C 3- C6 cycloalkyl, wherein the C 1- C4 alkyl and C 3- C6 cycloalkyl is optionally substituted by 1 to 3 independently selected 1- C4 alkyl, halogen, -OH, -NR 15 R 16 、C 1- C2 alkoxy and C substituted by 1 to 2 hydroxyl groups 1- C4 alkyl group substitution;

[0039] or R 13 and R 14 Together with the nitrogen atom to which they are directly attached, they are capable of forming a 4-6 membered ring optionally containing additional N, O or S as ring members and optionally substituted by one to three selected from C 1- C2 alkyl, C 1- C2 alkoxy, oxo and hydroxy group substitution;

[0040] R 15 and R 16 Each independently selected from H and C 1- C4 alkyl;

[0041] Each R 17 Independently selected from H, C 1-C4 alkyl and C3-C8 cycloalkyl;

[0042] or R 17 is a C that, together with the nitrogen atom to which it is directly attached and the nitrogen atom from the pyrazole ring, is capable of forming a 5-8 membered ring fused to the pyrazole ring. 1- C4 alkyl;

[0043] Each L 2 and L 3 and L 4 are independently a bond or a straight or branched C 1- C3 alkylene;

[0044] and

[0045] Indicates a single bond or a double bond.

[0046] Another aspect of the present invention is a pharmaceutical composition comprising a compound of the present invention or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. In one embodiment of this aspect, the pharmaceutical composition according to the present invention further comprises a therapeutically effective amount of at least one other antiviral agent.

[0047] Another aspect of the present invention relates to a method of treating or preventing herpes virus diseases and / or infections in humans by administering to a human an antivirally effective amount of a compound of the present invention, a pharmaceutically acceptable salt thereof, or a composition as described above, alone or in combination with at least one other antiviral agent administered together or separately.

[0048] Another aspect of the present invention relates to a method of treating or preventing herpes virus diseases and / or infections in humans by administering to a human a compound of the present invention, a pharmaceutically acceptable salt thereof, or a composition as described above, alone or in combination with at least one other antiviral agent administered together or separately.

[0049] Yet another aspect of the present invention relates to a method of inhibiting the replication of CMV or another herpes virus, the method comprising exposing the virus to an effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof under conditions that inhibit viral replication. The method can be implemented in vitro or in vivo.

[0050] Another aspect of the present invention is the use of a compound of the present invention or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating or preventing herpes virus diseases and / or infections (including CMV) in humans.

[0051] Another embodiment of the present invention provides a compound as described above or a pharmaceutically acceptable salt thereof as a medicament.

[0052] Another aspect of the invention is the use of a pharmaceutical composition as described above for treating CMV infection or other herpes virus in a human suffering from or at risk of suffering from the infection.

[0053] Another aspect of the present invention is the use of a pharmaceutical composition as described above for treating CMV disease or other herpes virus infection in a human suffering from or at risk of suffering from the disease.

[0054] Another aspect of the present invention relates to a method for treating a viral disease and / or infection in a human, which method comprises administering to a human an antivirally effective amount of a compound of the present invention, a pharmaceutically acceptable salt thereof, or a composition as described above, alone or in combination with at least one other antiviral agent administered together or separately, wherein the viral disease or infection is selected from CMV infection in immunocompromised patients (e.g., transplant recipients), congenital CMV, genital herpes, oral herpes (cold sores), herpetic keratitis, neonatal herpes, herpes encephalitis, varicella (chickenpox), herpes zoster, infectious mononucleosis, post-transplant lymphoproliferative disorder (PTLD), Castelman's disease, and hemophagocytic lymphohistiocytosis.

[0055] Another aspect of the present invention relates to a method for treating a condition in a human that can be induced / exacerbated / accelerated by a herpes virus infection, which method comprises administering to the human an effective amount of a compound of the present invention, a pharmaceutically acceptable salt thereof, or a composition as described above, alone or in combination with at least one other antiviral agent administered together or separately, wherein the condition is selected from Alzheimer's disease, chronic fatigue syndrome (CFS), systemic lupus erythematosus (SLE), multiple sclerosis (MS), rheumatoid arthritis (RA), juvenile idiopathic arthritis (JIA), inflammatory bowel disease (IBD), celiac disease, and type 1 diabetes.

[0056] Another aspect of the present invention relates to a method for treating a condition in a human that can be induced / exacerbated / accelerated by a herpes virus infection, which method comprises administering to the human an effective amount of a compound of the present invention, a pharmaceutically acceptable salt thereof, or a composition as described above, alone or in combination with at least one other antiviral agent administered together or separately, wherein the condition is selected from Alzheimer's disease, chronic fatigue syndrome (CFS), systemic lupus erythematosus (SLE), multiple sclerosis (MS), rheumatoid arthritis (RA), juvenile idiopathic arthritis (JIA), inflammatory bowel disease (IBD), atherosclerosis (AS), celiac disease, and type 1 diabetes.

[0057] Another aspect of the present invention is the use of a compound of the present invention or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment or prevention of a condition that may be induced / exacerbated / accelerated by a herpes virus infection, wherein the condition is selected from Alzheimer's disease, chronic fatigue syndrome (CFS), systemic lupus erythematosus (SLE), multiple sclerosis (MS), rheumatoid arthritis (RA), juvenile idiopathic arthritis (JIA), inflammatory bowel disease (IBD), celiac disease and type 1 diabetes.

[0058] Another aspect of the present invention is the use of a compound of the present invention or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment or prevention of a condition that may be induced / exacerbated / accelerated by a herpes virus infection, wherein the condition is selected from Alzheimer's disease, chronic fatigue syndrome (CFS), systemic lupus erythematosus (SLE), multiple sclerosis (MS), rheumatoid arthritis (RA), juvenile idiopathic arthritis (JIA), inflammatory bowel disease (IBD), atherosclerosis (AS), celiac disease and type 1 diabetes.

[0059] Another aspect of the present invention is the use of a pharmaceutical composition as described herein for the treatment of a viral disease and / or infection in a human, wherein the viral disease or infection is selected from CMV infection in an immunocompromised patient (e.g., a transplant recipient), congenital CMV, genital herpes, oral herpes (cold sores), herpetic keratitis, neonatal herpes, herpes encephalitis, varicella, herpes zoster, infectious mononucleosis, post-transplant lymphoproliferative disorder (PTLD), Castleman's disease, and hemophagocytic lymphohistiocytosis.

[0060] Another aspect of the present invention is the use of a pharmaceutical composition as described herein for the treatment of a condition that can be induced / exacerbated / accelerated by a herpes virus infection, wherein the condition is selected from Alzheimer's disease, chronic fatigue syndrome (CFS), systemic lupus erythematosus (SLE), multiple sclerosis (MS), rheumatoid arthritis (RA), juvenile idiopathic arthritis (JIA), inflammatory bowel disease (IBD), celiac disease and type 1 diabetes.

[0061] Another aspect of the present invention is the use of a pharmaceutical composition as described herein for the treatment of a condition that can be induced / exacerbated / accelerated by a herpes virus infection, wherein the condition is selected from Alzheimer's disease, chronic fatigue syndrome (CFS), systemic lupus erythematosus (SLE), multiple sclerosis (MS), rheumatoid arthritis (RA), juvenile idiopathic arthritis (JIA), inflammatory bowel disease (IBD), atherosclerosis (AS), celiac disease and type 1 diabetes. DETAILED DESCRIPTION

[0062] Various enumerated embodiments of the present invention are described herein. It will be appreciated that features specified within each embodiment can be combined with other specified features to provide further embodiments of the present invention.

[0063] definition

[0064] For the purpose of interpreting this specification, the following definitions shall apply and, whenever appropriate, terms used in the singular shall also include the plural. Unless the context clearly indicates otherwise, the terms used in the specification shall have the following meanings:

[0065] As used herein, the term "alkyl" refers to a fully saturated branched or straight chain hydrocarbon. In certain embodiments, the alkyl group is "C1-C2 alkyl," "C1-C3 alkyl," "C1-C4 alkyl," "C1-C5 alkyl," "C1-C6 alkyl," "C1-C7 alkyl," "C1-C8 alkyl," "C1-C9 alkyl," or "C1-C 10 C1-C2 alkyl group, C1-C3 alkyl group, C1-C4 alkyl group, C1-C5 alkyl group, C1-C6 alkyl group, C1-C7 alkyl group, C1-C8 alkyl group, C1-C9 alkyl group and C1-C 10 "Alkyl" refers to an alkyl group containing at least 1 and at most 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms, respectively. Non-limiting examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, 3-methylhexyl, 2,2-dimethylpentyl, 2,3-dimethylpentyl, n-heptyl, n-octyl, n-nonyl, and n-decyl.

[0066] As used herein, the term "alkoxy" refers to -O-alkyl or -alkyl-O-, wherein the "alkyl" group is as defined herein. In certain embodiments, the alkoxy group is a "C1-C2 alkoxy," "C1-C3 alkoxy," "C1-C4 alkoxy," "C1-C5 alkoxy," "C1-C6 alkoxy," "C1-C7 alkoxy," "C1-C8 alkoxy," "C1-C9 alkoxy," or "C1-C 10 Alkoxy", wherein as used herein, the terms "C1-C2 alkoxy", "C1-C3 alkoxy", "C1-C4 alkoxy", "C1-C5 alkoxy", "C1-C6 alkoxy", "C1-C7 alkoxy", "C1-C8 alkoxy", "C1-C9 alkoxy" and "C1-C 10"Alkoxy" refers to -O-C1-C2 alkyl, -O-C1-C3 alkyl, -O-C1-C4 alkyl, -O-C1-C5 alkyl, -O-C1-C6 alkyl, -O-C1-C7 alkyl, -O-C1-C8 alkyl, -O-C1-C9 alkyl or -O-C1-C 10 Non-limiting examples of "alkoxy" groups include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, n-pentoxy, isopentoxy, hexyloxy, heptyloxy, octyloxy, nonyloxy, decyloxy, and the like.

[0067] As used herein, the term "alkylene" refers to a saturated branched or straight-chain divalent hydrocarbon radical derived from an alkyl group as defined herein. In certain embodiments, the alkylene group is "C1-C3 alkylene," "C1-C4 alkylene," "C1-C5 alkylene," "C1-C6 alkylene," "C1-C7 alkylene," "C1-C8 alkylene," "C1-C9 alkylene," or "C1-C 10 "C1-C3 alkylene", "C1-C4 alkylene", "C1-C5 alkylene", "C1-C6 alkylene", "C1-C7 alkylene" and "C1-C8 alkylene" as used herein refer to alkylene groups containing at least 1 and at most 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms, respectively. Non-limiting examples of alkylene groups as used herein include methylene, ethylene, n-propylene, isopropylene, n-butylene, isobutylene, sec-butylene, tert-butylene, n-pentylene, isopentylene, hexylene, heptylene, octylene, nonylene, decylene and the like.

[0068] In certain embodiments, an alkylene group is a "C1-C2 alkylene," which refers to an alkylene group containing at least 1 and at most 2 carbon atoms, respectively.

[0069] As used herein, the term "C3-C8 cycloalkyl" refers to a fully saturated monocyclic hydrocarbon ring system having 3 to 8 carbon atoms as ring members. Non-limiting examples of such "C3-C8 cycloalkyl" groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl groups.

[0070] As used herein, the term "C3-C6 cycloalkyl" refers to a fully saturated monocyclic hydrocarbon ring system having 3 to 6 carbon atoms as ring members. Non-limiting examples of such "C3-C8 cycloalkyl" groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl groups.

[0071] As used herein, the term "C5-C8 cycloalkyl" refers to a fully saturated monocyclic hydrocarbon ring system having 5 to 8 carbon atoms as ring members. Non-limiting examples of such "C5-C8 cycloalkyl" groups include cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl groups.

[0072] As used herein, the term "haloalkyl" refers to an alkyl as defined herein, wherein at least one hydrogen atom of the alkyl is replaced by a halogen group as defined herein. A haloalkyl group can be a monohaloalkyl, a dihaloalkyl, a trihaloalkyl, or a polyhaloalkyl group including a perhaloalkyl group. A monohaloalkyl group can have one iodine, bromine, chlorine, or fluorine in the alkyl group. A dihaloalkyl group can have two and a polyhaloalkyl group can have two or more identical halogen atoms or a combination of different halogen groups in the alkyl group. Typically, a polyhaloalkyl group contains up to 6, or 4, or 3, or 2 halogen groups. Non-limiting examples of haloalkyl groups include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl, and dichloropropyl. A perhaloalkyl group refers to an alkyl group (e.g., trifluoromethyl) in which all hydrogen atoms are replaced by halogen atoms. Unless otherwise indicated, representative haloalkyl groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl, wherein at least one hydrogen is replaced by a halogen, such as, for example, CF3CF2-, (CF3)2CH-, CH3-CF2-, CF3CF2-, CF3, CF2H-, CF3CF2CH(CF3)-, or CF3CF2CF2CF2-, wherein the halogen is fluorine.

[0073] As used herein, the term "C1-C3 haloalkyl" refers to the corresponding "C1-C3 alkyl" as defined herein, wherein at least one hydrogen atom of the "C1-C3 alkyl" is replaced by a halogen atom. The C1-C3 haloalkyl group may be a mono-C1-C3 haloalkyl group, wherein such C1-C3 haloalkyl group has one iodine, one bromine, one chlorine or one fluorine. Additionally, the C1-C3 haloalkyl group may be a di-C1-C3 haloalkyl group, wherein such C1-C3 haloalkyl group may have two halogen atoms independently selected from iodine, bromine, chlorine or fluorine. Furthermore, the C1-C3 haloalkyl group may be a poly-C1-C3 haloalkyl group, wherein such C1-C3 haloalkyl group may have two or more identical halogen atoms or a combination of two or more different halogen atoms. Such poly C1-C3 haloalkyl groups may be perhalogenated C1-C3 haloalkyl groups, wherein all hydrogen atoms of the corresponding C1-C3 alkyl group have been replaced by halogen atoms, and the halogen atoms may be a combination of the same or different halogen atoms. Non-limiting examples of "C1-C3 haloalkyl" groups include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, difluoropropyl, dichloroethyl, and dichloropropyl.

[0074] As used herein, the term "haloalkoxy" refers to a radical -O-alkyl, wherein an "alkyl" group is as defined herein, and wherein at least one hydrogen atom of the alkyl group is replaced by a halogen group as defined herein for "haloalkyl". A haloalkoxy group can be a monohaloalkoxy, a dihaloalkoxy, a trihaloalkoxy or a polyhaloalkoxy group comprising a perhaloalkoxy group. A monohaloalkoxy group can have an iodine, bromine, chlorine or fluorine in the alkyl group. A dihaloalkoxy group can have two and a polyhaloalkoxy group can have two or more identical halogen atoms or a combination of different halogen groups in the alkyl group. Typically, a polyhaloalkoxy group contains up to 6, or 4, or 3, or 2 halogen groups. The non-limiting example of haloalkoxy comprises fluoromethoxy, difluoromethoxy, trifluoromethoxy, chloromethoxy, dichloromethoxy, trichloromethoxy, pentafluoroethoxy, heptafluoropropoxy, difluorochloromethoxy, dichlorofluoromethoxy, difluoroethoxy, difluoropropoxy, dichloroethoxy and dichloropropoxy.Perhaloalkoxy refers to the alkoxy (for example, trifluoromethoxy) that all hydrogen atoms are replaced by halogen atoms.Unless otherwise indicated, representative haloalkoxy groups include methoxy and the ethoxy groups substituted by single fluorine, difluoro and trifluoro, for example-OCF ,-OCHF ,-OCH F,-OCH CHF and-OCH CF .

[0075] As used herein, the term "C1-C4 haloalkoxy" refers to the group -O-C1-C4 alkyl, wherein the "alkyl" group is as defined herein, and wherein at least one hydrogen atom of the "C1-C4 alkyl" group is replaced by a halogen atom as defined herein for "haloalkyl." The C1-C4 haloalkoxy group may be a mono-C1-C4 haloalkoxy group, wherein such C1-C4 haloalkoxy group has one iodine, one bromine, one chlorine, or one fluorine. Additionally, the C1-C4 haloalkoxy group may be a di-C1-C4 haloalkoxy group, wherein such C1-C4 haloalkoxy group may have two halogen atoms independently selected from iodine, bromine, chlorine, or fluorine. Furthermore, the C1-C4 haloalkoxy group may be a poly-C1-C4 haloalkoxy group, wherein such C1-C4 haloalkoxy group may have two or more of the same halogen atoms or a combination of two or more different halogen atoms. Such poly-C1-C4 haloalkoxy groups may be perhalogenated C1-C4 haloalkoxy groups, wherein all hydrogen atoms of the corresponding C1-C4 alkoxy group have been replaced by halogen atoms, and the halogen atoms may be a combination of the same or different halogen atoms. Non-limiting examples of "C1-C4 haloalkoxy" groups include fluoromethoxy, difluoromethoxy, trifluoromethoxy, chloromethoxy, dichloromethoxy, trichloromethoxy, pentafluoroethoxy, heptafluoropropoxy, difluorochloromethoxy, dichlorofluoromethoxy, fluoroethoxy, difluoroethoxy, trifluoroethoxy, difluoropropoxy, dichloroethoxy, and dichloropropoxy.

[0076] As used herein, the term "halo" or "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br), or iodine (I).

[0077] As used herein, the term "heteroaryl" refers to

[0078] i) 5-6 membered heteroaryl having 1 to 4 heteroatoms independently selected from heteroatoms N, O and S as ring members, which refers to an aromatic 5-6 membered monocyclic ring system having 1 to 4 heteroatoms independently selected from heteroatoms N, O and S as ring members, although usually the heteroaryl ring contains not more than one divalent O or S in the ring,

[0079] ii) 5-6 membered heteroaryl having 1 to 3 heteroatoms independently selected from heteroatoms N, O and S as ring members, which refers to an aromatic 5-6 membered monocyclic ring system having 1 to 3 heteroatoms independently selected from heteroatoms N, O and S as ring members,

[0080] iii) 5-6 membered heteroaryl having 1 to 2 heteroatoms independently selected from heteroatoms N, O and S as ring members, which refers to an aromatic 5-6 membered monocyclic ring system having 1 to 2 heteroatoms independently selected from heteroatoms N, O and S as ring members,

[0081] iv) 5-membered heteroaryl having 1 to 4 heteroatoms independently selected from heteroatoms N, O and S as ring members, which refers to an aromatic 5-membered monocyclic ring system having 1 to 4 heteroatoms independently selected from heteroatoms N, O and S as ring members,

[0082] v) 6-membered heteroaryl having 1 to 4 heteroatoms independently selected from the group consisting of heteroatoms N, O and S as ring members, which refers to an aromatic 6-membered monocyclic ring system having 1 to 4 heteroatoms independently selected from the group consisting of heteroatoms N, O and S as ring members,

[0083] vi) 5- to 6-membered heteroaryl having 1 to 4 nitrogen atoms as ring members, which refers to aromatic 5- to 6-membered monocyclic ring systems having 1 to 4 nitrogen atoms as ring members,

[0084] vii) 9-10 membered bicyclic heteroaryl having 1 to 2 heteroatoms independently selected from heteroatoms N, O and S as ring members, which refers to an aromatic 9-10 membered fused bicyclic ring system having 1 to 2 heteroatoms independently selected from heteroatoms N, O and S as ring members,

[0085] as well as

[0086] viii) 9-10 membered bicyclic heteroaryl having 1 to 3 heteroatoms independently selected from heteroatoms N, O and S as ring members, which refers to an aromatic 9-10 membered fused bicyclic ring system having 1 to 3 heteroatoms independently selected from heteroatoms N, O and S as ring members,

[0087] Non-limiting examples of heteroaryl groups as used herein include benzofuranyl, benzo[c]thienyl, benzothienyl, benzo oxazolyl, benzothiazolyl, benzimidazolyl, cinnolinyl, furazolinyl, furanyl, imidazolyl, indolyl, indolizinyl, indazolyl, isoindolyl, isoquinolinyl, iso Azolyl, isothiazolyl, Azolyl, oxaindolyl, oxadiazolyl, pyrazolyl, pyrrolyl, phthalazinyl, pyridinyl, pyridazinyl, pyrazinyl, pyrimidinyl, quinoxalinyl, quinolinyl, quinazolinyl, tetrazolyl, thiazolyl, thiadiazolyl, thienyl, triazinyl, and triazolyl.

[0088] As used herein, the term "heteroatoms" or "hetero atoms" refers to nitrogen (N), oxygen (O), or sulfur (S) atoms.

[0089] As used herein, the term "heterocycloalkyl" refers to a ring structure in which one to two carbon atoms are replaced by one to two independently selected groups consisting of N, NH, NR, 17 , O or -S-, wherein R17 is H, C1-C6 alkyl or C3-C8 cycloalkyl. Specifically, heterocycloalkyl can be

[0090] i) contains one to two independently selected from N, NH, NR 17 , O or -S- ring members, which refers to a 4 to 6-membered heterocycloalkyl group having a fully saturated monocyclic hydrocarbon ring structure with 4 to 6 ring members, wherein one to two ring members are independently selected from N, NH, NR 17 , O or -S-, where R 17 is H, C1-C6 alkyl or C3-C8 cycloalkyl,

[0091] ii) contains one to two independently selected from N, NH, NR 17 , O or -S- ring members, which refers to a 5- to 6-membered heterocycloalkyl group having a fully saturated monocyclic hydrocarbon ring structure with 5 to 6 ring members, wherein one to two ring members are independently selected from N, NH, NR 17 , O or -S-, where R 17 is H, C1-C6 alkyl or C3-C8 cycloalkyl,

[0092] as well as

[0093] iii) contains one to two independently selected from N, NH, NR 17 , O or -S-, which refers to an 8- to 10-membered heterocycloalkyl group having a fully saturated fused bicyclic ring structure with 8 to 10 ring members, wherein one to two ring members are independently selected from N, NH, NR 17 , O or -S-, where R 17 It is a C1-C6 alkyl group or a C3-C8 cycloalkyl group.

[0094] As used herein, non-limiting examples of heterocycloalkyl groups include azetidinyl, azetidin-1-yl, azetidin-2-yl, azetidin-3-yl, oxetane, oxetane-2-yl, oxetane-3-yl, oxetane-4-yl, thiocyclobutane, thiocyclobutane-2-yl, thiocyclobutane-3-yl, thiocyclobutane-4-yl, pyrrolidinyl, pyrrolidin-1-yl, pyrrolidin-2-yl, pyrrolidin-3-yl, pyrrolidin-4-yl. yl, pyrrolidin-5-yl, tetrahydrofuranyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrofuran-4-yl, tetrahydrofuran-5-yl, tetrahydrothiophene-2-yl, tetrahydrothiophene-3-yl, tetrahydrothiophene-4-yl, tetrahydrothiophene-5-yl, piperidinyl, piperidin-1-yl, piperidin-2-yl, piperidin-3-yl, piperidin-4-yl, piperidin-5-yl, piperidin-6-yl, tetrahydropyranyl, tetrahydropyran-2-yl, tetrahydropyran-3-yl, tetrahydropyran-4-yl, tetrahydropyran-5-yl, tetrahydrothiophene-2-yl, tetrahydrothiophene-3-yl, tetrahydrothiophene-4-yl, tetrahydrothiophene-5-yl, piperidinyl, piperidin-1-yl, piperidin-2-yl, piperidin-3-yl, piperidin-4-yl, piperidin-5-yl, piperidin-6-yl, tetrahydropyranyl, tetrahydropyran-2-yl, tetrahydropyran-3-yl, tetrahydropyran- pyran-4-yl, tetrahydropyran-5-yl, tetrahydropyran-6-yl, tetrahydrothiopyran-2-yl, tetrahydrothiopyran-3-yl, tetrahydrothiopyran-4-yl, tetrahydrothiopyran-5-yl, tetrahydrothiopyran-6-yl, piperazinyl, piperazin-1-yl, piperazin-2-yl, piperazin-3-yl, piperazin-4-yl, piperazin-5-yl, piperazin-6-yl, morpholinyl, morpholin-2-yl, morpholin-3-yl, morpholin-4-yl, morpholin-5-yl, morpholin-6-yl, thiomorpholinyl, thiomorpholinyl, thiomorpholinyl thiomorpholin-2-yl, thiomorpholin-3-yl, thiomorpholin-4-yl, thiomorpholin-5-yl, thiomorpholin-6-yl, oxathianyl, oxathianyl-2-yl, oxathianyl-3-yl, oxathianyl-5-yl, oxathianyl-6-yl, dithianyl, dithianyl-2-yl, dithianyl-3-yl, dithianyl-5-yl, dithianyl-6-yl, dioxolanyl, dioxolan-2-yl, dioxolan-4-yl, dioxolan-5-yl, thiomorpholin-6-yl, Alkyl, thiol Alkyl-2-yl, thiol Alkyl-3-yl, thiol Alkyl-4-yl, thiol alkyl-5-yl, dithiolane, dithiolane-2-yl, dithiolane-4-yl, dithiolane-5-yl, pyrazolidin-1-yl, pyrazolidin-2-yl, pyrazolidin-3-yl, pyrazolidin-4-yl, pyrazolidin-5-yl, 2-azabicyclo[4.2.0]octyl, octahydro-1H-cyclopenta[b]pyridine, and decahydroquinoline.

[0095] The term "hydroxy" or "hydroxyl" refers to the group -OH.

[0096] As used herein, the term "oxo" refers to a "=0" group.

[0097] As used herein, the term "heterocyclyl" refers to a heterocyclic group having 1 to 7, 1 to 5, 1 to 3, or 1 to 2 groups independently selected from N, NH, NR, 36 , O or S ring members of the 4 to 14-membered saturated or partially saturated hydrocarbon ring structure, wherein R 36 is a C1-C6 alkyl or C3-C8 cycloalkyl. The term "heterocyclic group" includes monocyclic groups, bicyclic groups, fused ring groups, spirocyclic groups and bridged ring groups. A heterocyclic group may be attached to another group at a nitrogen or carbon atom. Specifically, a heterocyclic group may be

[0098] i) contains 1 to 2 independently selected from N, NH, NR 17 , O or S ring members of the 4-6 membered heterocyclic group, wherein R 17 is H, C1-C6 alkyl or C3-C8 cycloalkyl,

[0099] ii) contains 1 to 2 independently selected from N, NH, NR 17 , O or S ring members of the 4-7 membered heterocyclic group, wherein R 17 is H, C1-C6 alkyl or C3-C8 cycloalkyl,

[0100] iii) contains 1 to 4 independently selected from N, NH, NR 17 , O or S ring members of the 5-6 membered heterocyclic group, wherein R 17 is H, C1-C6 alkyl or C3-C8 cycloalkyl,

[0101] iv) contains 1 to 2 independently selected from N, NH, NR 17 , O or S ring members of the 5-6 membered heterocyclic group, wherein R 17 is H, C1-C6 alkyl or C3-C8 cycloalkyl,

[0102] v) contains 1 to 3 independently selected from N, NH, NR 17 , O or S ring members, wherein R 17 is H, C1-C6 alkyl or C3-C8 cycloalkyl,

[0103] as well as

[0104] vi) contains 1 to 4 independently selected from N, NH, NR 17 , O or S ring members, wherein R 17 It is H, C1-C6 alkyl or C3-C8 cycloalkyl.

[0105] Non-limiting examples of heterocycloalkyl groups as used herein include dihydrobenzofuranyl, dihydrobenzo[c]thienyl, dihydrobenzothienyl, dihydrobenzo oxazolyl, dihydrobenzothiazolyl, dihydrobenzimidazolyl, dihydrocinnolinyl, dihydrofurazolyl, dihydrofuranyl, dihydroimidazolyl, dihydroindolyl, dihydroindolizinyl, dihydroindazolyl, dihydroisoindolyl, dihydroisoquinolinyl, dihydroisoquinolinyl Azolyl, dihydroisothiazolyl, dihydro Azolyl, dihydrooxindolyl, dihydro oxadiazolyl, dihydropyrazolyl, dihydropyrrolyl, dihydrophthalazinyl, dihydropyridinyl, dihydropyridazinyl, dihydropyrazinyl, dihydropyrimidinyl, dihydroquinoxalinyl, dihydroquinolinyl, dihydroquinazolinyl, dihydrotetrazolyl, dihydrothiazolyl, dihydrothiadiazolyl, dihydrothiophenyl, dihydrotriazinyl, dihydrotriazolyl, tetrahydrobenzofuranyl, tetrahydrobenzo[c]thiophenyl, tetrahydrobenzothiophenyl, tetrahydrobenzo oxazolyl, tetrahydrobenzothiazolyl, tetrahydrobenzimidazolyl, tetrahydrocinnolinyl, tetrahydroindolyl, tetrahydroindolizinyl, tetrahydroindazolyl, tetrahydroisoindolyl, tetrahydroisoquinolinyl, tetrahydrooxindolyl, tetrahydrophthalazinyl, tetrahydropyridinyl, tetrahydropyridazinyl, tetrahydropyrazinyl, tetrahydropyrimidinyl, tetrahydroquinoxalinyl, tetrahydroquinolinyl, tetrahydroquinazolinyl, tetrahydrotriazinyl, hexahydrobenzofuranyl, hexahydrobenzo[c]thienyl, hexahydrobenzothienyl, hexahydrobenzo oxazolyl, hexahydrobenzothiazolyl, hexahydrobenzimidazolyl, hexahydrocinnolinyl, hexahydroindolyl, hexahydroindolizinyl, hexahydroindazolyl, hexahydroisoindolyl, hexahydroisoquinolinyl, hexahydrooxaindolyl, hexahydrophthalazinyl, hexahydroquinoxalinyl, hexahydroquinolinyl, hexahydroquinazolinyl, octahydrocinnolinyl, octahydroisoquinolinyl, octahydrophthalazinyl, octahydroquinoxalinyl, octahydroquinolinyl, and octahydroquinazolinyl.

[0106] As used herein, the term "subject" refers to an animal. In some aspects, the animal is a mammal. A subject also refers to, for example, a primate (e.g., human), cattle, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds, etc. In certain embodiments, the subject is a human. As used herein, "patient" refers to a human subject.

[0107] As used herein, the term "linker" refers to a divalent chemical moiety capable of covalently linking two spaced chemical moieties together.

[0108] As used herein, the term "inhibition" or "inhibiting" refers to a reduction or suppression of a given condition, symptom or disorder or disease, or a decrease in the baseline activity of a biological activity or process.

[0109] The term "optical isomer" or "stereoisomer" refers to any of the various stereoisomeric configurations that can exist for a given compound of the present invention and includes geometric isomers. It should be understood that substituents can be attached to the chiral center of a carbon atom. The term "chirality" refers to a molecule that has non-superimposability on its mirror image partner, while the term "achiral" refers to a molecule that is superimposable on its mirror image partner. Therefore, the present invention includes enantiomers, diastereomers, or racemates of a compound. An "enantiomer" is 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. This term is used to represent a racemic mixture when appropriate. A "diastereomer" is a stereoisomer that has at least two asymmetric atoms but is not a mirror image of each other. Absolute stereochemistry is specified according to the Cahn-Ingold-Prelog RS system. When a compound is a pure enantiomer, the stereochemistry of each chiral carbon can be specified by R or S. Resolved compounds whose absolute configuration is unknown can be designated as (+) or (-) according to the direction (dextrorotatory or levorotatory) in which they rotate plane-polarized light at the wavelength of the sodium D line. Certain compounds described herein contain one or more asymmetric centers or axes and can thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that can be defined, in terms of absolute stereochemistry, as (R)- or (S)-.

[0110] As used herein, the terms "treating" or "treatment" of any disease or condition refer, in one embodiment, to ameliorating the disease or condition (i.e., slowing or arresting or reducing the development of the disease or at least one clinical symptom thereof). In another embodiment, "treating" or "treatment" refers to alleviating or improving at least one physical parameter, including those that the patient may not be able to discern. In another embodiment, "treating" or "treatment" refers to modulating the disease or condition physically (e.g., stabilizing discernible symptoms), physiologically (e.g., stabilizing physical parameters), or both. In another embodiment, "treating" or "treatment" refers to preventing or delaying the onset or development or progression of a disease or condition.

[0111] The compound names provided in this article were generated using ChemDraw Ultra version 12.0. or JChem version 5.3.1 (ChemAxon).

[0112] Unless otherwise indicated herein or otherwise clearly contradictory to the context, all methods described herein can be performed in any suitable order. The use of any and all embodiments or exemplary language (e.g., "such as") provided herein is intended only to better illustrate the present invention and is not intended to limit the scope of the present invention as otherwise claimed.

[0113] "Optionally substituted" means that the group indicated may be substituted at one or more positions with any one or any combination of the groups listed thereafter. The number, position, and choice of substituents should be understood to encompass only those substitutions that a skilled chemist would expect to be reasonably stable; thus, 'oxo' is not a substituent on an aryl or heteroaryl ring, for example, and a single carbon atom does not have three hydroxy or amino substituents.

[0114] Groups may be substituted at the same position at which they are attached to the rest of the molecule being defined. For example, a group may be substituted with a cyclopropyl group, which in turn may be substituted with another group at the same carbon at which it is attached to the rest of the molecule.

[0115] Unless otherwise indicated, the terms “compounds of the present invention,” “compounds of the invention,” or “compounds provided herein” refer to compounds of Formula (A)-(C), (IIa)-(IIb), (IIId)-(IIIc), (IVa)-(IVb), (IVc)-(IVd), (Va)-(Vb), (Vc)-(VI), (VII) and (VIII), and pharmaceutically acceptable salts, stereoisomers (including diastereomers and enantiomers), rotamers, tautomers, and isotopically labeled compounds (including deuterium substitution), as well as inherently occurring moieties.

[0116] As used herein, the terms "a," "an," "the" and similar terms used in the context of the invention (especially in the context of the claims) are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context.

[0117] Unless otherwise indicated herein or otherwise clearly contradictory to the context, all methods described herein can be performed in any suitable order. The use of any and all embodiments or exemplary language (e.g., "such as") provided herein is intended only to better illustrate the present invention and is not intended to limit the scope of the present invention as otherwise claimed.

[0118] Compounds of the present invention

[0119] The present invention provides a compound having a structure of formula (I) or a pharmaceutically acceptable salt thereof:

[0120]

[0121] in:

[0122] X is 5-6 membered heteroaryl having 1 to 4 heteroatoms independently selected from N, O and S as ring members; containing 1 to 4 heteroatoms independently selected from N, NH, NR 17 , O or S ring members; or containing 1 to 4 independently selected from N, NH, NR 17 , O or S as ring members;

[0123] Y is a bond, -O- or Where * in Y indicates the point of attachment to X and ** in Y indicates the point of attachment to R B attachment points;

[0124] q is 0 or 1;

[0125] When q is 1, then L MC Yes*-((CR 11 R 12 ) n O) m (CR 11 R 12 ) p -**、*-C(=O)NR 15 ((CR 11 R 12 ) n O) m (CR 11 R 12 ) p -**、*-(CR 11 R 12 ) n NR 15 ((CR 11 R 12 ) n O) m (CR 11 R 12 ) p -**、*-(CR 11 R 12 ) n -**、*-((CR 11 R 12 ) n NR 15 ) m (CR11 R 12 ) p -**、*-(CR 11 R 12 )C(=O)NR 15 (CR 11 R 12 ) n -**、*-C(=O)NR 15 (CR 11 R 12 ) n -**、*-O(CR 11 R 12 ) n -** or *-NR 15 (CR 11 R 12 ) n -**, where L MC The * indicates the attachment point with Z and L MC The ** indicates the attachment point with A;

[0126] When q is 1, then L MC exists, A is a bond and Z is Where * of Z indicates the point of attachment to LMC and ** of Z indicates the point of attachment to L;

[0127] m is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10;

[0128] Each n is independently selected from 1, 2, 3, 4, 5, 7, 8, 9 and 10;

[0129] p is 1, 2, 3, 4, 5, or 6;

[0130] When q is 0, then L MC does not exist, and Z is W, and A is R 4 ;

[0131] R B is H, C1-C6 alkyl, phenyl, pyridyl, phenylthio, pyrimidinyl or 5-8 membered cycloalkyl, wherein R B Optionally 1 to 3 R 5 group substitution;

[0132] R 1 Selected from H, C 1- C3 alkyl and C substituted with 1 to 3 -OH groups 1- C3 alkyl;

[0133] R 2 Selected from H, C 1-C3 alkyl and C substituted with 1 to 3 -OH groups 1- C3 alkyl;

[0134] or R 1 and R 2 Together with the carbon atoms to which they are attached, they can form a 3-6 membered cycloalkyl ring;

[0135] t is 0, 1, or 2;

[0136] Each R 3 , when present, is a substituent on the ring to which -LZ is directly attached, wherein each R 3 independently selected from halogen, CN, C 1- C3 alkoxy, C 1- C3 alkyl, C(=O)OR 10 and C(=O)NR 13 R 14 ;

[0137] R 4 It is H, C 1- C3 alkyl, C 3- C6 cycloalkyl, -(CH2)2O(CH2)2Br or 1 to 2 independently selected from -OH, -C(=O)R 15 and R 10 C1-C3 alkyl substituted with a group;

[0138] Each R 5 are independently selected from halo, -CN, hydroxy, -NR 13 R 14 、C 3- C6 cycloalkyl, C 1- C3 alkoxy, C 1- C3 haloalkyl and optionally 1 to 3 R 6 C 1- C3 alkyl, where R B By two R 5 Replace and each R 5 is optionally replaced by 1 to 3 R 6 C 1- C3 alkyl, when directly attached to the same carbon atom, can be taken together with the carbon atoms to which the two are directly attached to form a C3 alkyl group optionally substituted by 1 to 3 R 6 a 3-5 membered cycloalkyl ring substituted with a group;

[0139] Each R 6 Independently selected from halo, hydroxy, CN, C 1- C3 alkoxy, C 1- C3 alkyl and C 3- C5 cycloalkyl,

[0140] Or two R 6 The group together with the carbon atom to which they are directly attached can form a 3-5 membered cycloalkyl ring or a 4-6 membered heterocyclic ring containing O, N or S as ring members and optionally substituted by 1 to 2 groups independently selected from oxo and C 1- C3 alkyl group substitution;

[0141] L is a C1-C4 straight or branched chain alkylene linker, or when W is an optionally substituted ring, L can be a C1-C4 straight or branched chain alkylene linker or bond;

[0142] W is H; -OH; –OR 10 ;-C(=O)NR 13 R 14 ;-C(=O)OR 13 ;-NR 13 R 14 ;-NR 13 C(=O)OR 10 ;-NR 13 C(=O)R 10 ;-SO2R 10 ;-SO2NR 13 R 14 ;-NR 13 SO2R 10 ;-P(=O)(OR 13 )2;-S(=O)R 10 ;-S(=O)(=NR 13 )R 10 ;-CR 11 R 12 C(=O)NR 13 R 14 ;-CR 11 R 12 C(=O)OR 13 ;-CR 11 R 12 NR 13 R 14 ;-CR 11 R 12 NR 13 C(=O)OR 10 ;-CR 11 R 12 NR 13 C(=O)R 10 ;-CR 11 R 12 SO2R 10 ;-CR 11 R 12 SO2NR 13 R 14;-CR 11 R 12 NR 13 SO2R 10 ;-CR 11 R 12 P(=O)(OR 13 )2;-CR 11 R 12 S(=O)R 10 ;-CR 11 R 12 S(=O)(=NR 13 )R 10 ; 3-6 membered cycloalkyl; phenyl; containing one or two independently selected from N, NH, NR 17 , O or S ring members of the 5-6 membered heterocycloalkyl; containing one or two independently selected from N, NH, NR 17 , O or S as ring members; or a 5-membered heteroaryl group having 1 to 4 heteroatoms selected from N, O and S as ring members, which is optionally fused to a phenyl group,

[0143] wherein the 3-6 membered cycloalkyl, the phenyl, the 5-6 membered heterocycloalkyl, the 5-6 membered heterocyclyl and the 5 membered heteroaryl of W are each optionally substituted by 1 to 3 groups independently selected from the following: 1- C3 alkyl, oxo, halogen, C 1- C3 haloalkyl, –L 2 OH, –L 2 OR 10 ,–L 2 OC(=O)NR 13 R 14 ,–L 2 SO2R 10 ,–L 2 SO2NR 14 R 10 ,–L 2 SO2NR 13 R 14 ,–L 2 SO2N=CR 13 NR 13 R 14 ,–L 2 SO2NR 13 C(=O)R 10 ,–L 2 C(=O)NR 13 SO2R 10 ,–L 2 S(=O)R 10 ,–L 2 S(=O)(=NR 13)R 10 ,–L 2 NR 13 SO2NR 13 R 14 ,–L 2 NR 13 SO2R 10 ,–L 2 NR 13 R 14 ,–L 2 NR 13 C(=O)R 13 ,–L 2 NR 13 C(=O)OR 10 ,–L 2 C(=O)NR 13 R 14 and –L 2 C(=O)OR 13 ;

[0144] R 10 Selected from C 1- C5 alkyl; C 1- C3 haloalkyl; 3-6 membered cycloalkyl; phenyl; 5-6 membered heteroaryl having 1 to 4 heteroatoms independently selected from N, O and S as ring members; containing one or two independently selected from N, NH, NR 17 , O or S ring members; and containing 1 to 2 independently selected from N, NH, NR 17 , O or S ring members of the 4-6 membered heterocyclic group,

[0145] Each R 10 Optionally substituted with 1 to 5 groups independently selected from: C 1- C4 alkyl, deuterium, C 1- C4 haloalkoxy, –L 3 OH, –L 3 CN, -L 3 OC(=O)R 14 、-L 3 OR 13 、C 1- C2 haloalkyl, oxo, -L 3 Halogen, –L 3 C 1- C3 alkoxy, –L 3 OC(=O)NR 13 R 14 ,–L 3 SO2R 13 ,–L 3 SO2NR 13 R14 ,–L 3 SO2NR 13 C(=O)R 13 ,–L 3 C(=O)NR 13 SO2R 13 ,–L 3 S(=O)R 13 ,–L 3 S(=O)(=NR 14 )R 13 ,–L 3 NR 13 SO2NR 13 R 14 ,–L 3 NR 13 SO2R 13 ,–L 3 NR 13 R 14 ,–L 3 NR 14 C(=O)R 13 ,–L 3 NR 14 C(=O)OR 13 ,–L 3 C(=O)NR 13 R 14 ,–L 3 C(=O)OR 13 、-L 3 -(containing 1 to 2 independently selected from N, NH, NR 17 , O or S as ring members of the 4-7 membered heterocycloalkyl group), -L 3 -(containing 1 to 2 independently selected from N, NH, NR 17 , O or S ring member 4-7 membered heterocyclic group)), -L 3 -C 3- C5 cycloalkyl and -L 3 -(a 5-6 membered heteroaryl ring having 1 to 4 heteroatoms containing 1 to 4 nitrogen atoms, 0 or 1 oxygen atoms and 0 or 1 sulfur atoms as ring members), wherein said C 1- C4 alkyl, 4-7 membered heterocycloalkyl, 4-7 membered heterocyclyl, C 3- The C5 cycloalkyl and 5-6 membered heteroaryl rings are each optionally further substituted by 1 to 3 groups independently selected from halo, C 1- C3 alkyl, C 1- C3 haloalkyl, -L 4 OR 13 、-L 4 CN and –L 4 NR 13 R14 The group substitution;

[0146] R 11 and R 12 Each independently selected from H and C 1- C4 alkyl;

[0147] Each R 13 Independently selected from H; C 1- C4 alkyl; containing 1 to 2 independently selected from N, NH, NR 17 , O or S ring members; containing 1 to 2 independently selected from N, NH, NR 17 , O or S as ring members; and C 3- C6 cycloalkyl, wherein the C 1- C4 alkyl, heterocycloalkyl, heterocyclyl and C 3- C6 cycloalkyl is optionally substituted by 1 to 3 independently selected 1- C4 alkyl, halogen, -OH, -NR 15 R 16 、-C(=O)OR 15 , C1-C2 alkoxy and C1-C2 substituted by 1 to 2 hydroxyl groups 1- C4 alkyl group substitution;

[0148] R 14 Selected from H, C 1- C4 alkyl and C 3- C6 cycloalkyl, wherein the C 1- C4 alkyl and C 3- C6 cycloalkyl is optionally substituted by 1 to 3 independently selected 1- C4 alkyl, halogen, -OH, -NR 15 R 16 、C 1- C2 alkoxy and C substituted by 1 to 2 hydroxyl groups 1- C4 alkyl group substitution;

[0149] or R 13 and R 14 Together with the nitrogen atom to which they are directly attached, they are capable of forming a 4-6 membered ring optionally containing additional N, O or S as ring members and optionally substituted by one to three selected from C 1- C2 alkyl, C 1- C2 alkoxy, oxo and hydroxy group substitution;

[0150] R 15 and R 16 Each independently selected from H and C 1- C4 alkyl;

[0151] Each L2 and L 3 and L 4 are independently a bond or a straight or branched C 1- C3 alkylene;

[0152] and

[0153] Indicates a single bond or a double bond.

[0154] Various embodiments of the compounds of the present invention are described herein. It will be appreciated that the features specified in each embodiment can be combined with other specified features to provide additional embodiments. The embodiments listed below represent compounds of formula (I) of the present invention:

[0155] Embodiment 1. A compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein X is

[0156] Embodiment 2. A compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein X is

[0157] Embodiment 3. A compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein X is

[0158] Embodiment 4. A compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein X is

[0159] Embodiment 5. A compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein X is a 5-6 membered heteroaryl group having 1 to 4 heteroatoms independently selected from N, O and S as ring members.

[0160] Embodiment 6. A compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein X is a 1 to 4 independently selected from N, NH, NR 17 , O or S as ring members.

[0161] Embodiment 7. A compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein X is a 1 to 4 moieties independently selected from N, NH, NR 17 , O or S as ring members.

[0162] Embodiment 8. A compound of formula (I), or a compound according to any one of Embodiments 1 to 7, or a pharmaceutically acceptable salt thereof, wherein Y is

[0163] Embodiment 9. A compound of formula (I), or a compound according to any one of Embodiments 1 to 7, or a pharmaceutically acceptable salt thereof, wherein Y is Where * in Y indicates the point of attachment to X and ** in Y indicates the point of attachment to R B attachment point.

[0164] Embodiment 10. A compound of formula (I), or a compound according to any one of Embodiments 1 to 7, or a pharmaceutically acceptable salt thereof, wherein Y is -O-.

[0165] Embodiment 11. A compound of formula (I), or a compound according to any one of Embodiments 1 to 7, or a pharmaceutically acceptable salt thereof, wherein Y is Where * in Y indicates the point of attachment to X and ** in Y indicates the point of attachment to R B attachment point.

[0166] Embodiment 12. A compound of formula (I), or a compound according to any one of Embodiments 1 to 7, or a pharmaceutically acceptable salt thereof, wherein Y is a bond.

[0167] Embodiment 13. A compound of formula (I), or a compound according to any one of Embodiments 1 to 12, or a pharmaceutically acceptable salt thereof, wherein q is 1, L MC exists and A is a key.

[0168] Embodiment 14. A compound of formula (I), or a compound according to any one of Embodiments 1 to 13, or a pharmaceutically acceptable salt thereof, wherein q is 1, A is a bond, and L MC Yes*-((CR 11 R 12 ) n O) m (CR 11 R 12 ) p -**、*-C(=O)NR 15 ((CR 11 R 12 ) n O) m (CR 11 R 12 ) p -**or*-(CR 11 R 12 ) n NR 15 ((CR 11 R 12 ) n O) m (CR 11 R 12 ) p -**, where L MC The * indicates the attachment point with Z and L MCThe ** indicates the attachment point to A.

[0169] Embodiment 15. A compound of formula (I), or a compound according to any one of Embodiments 1 to 14, or a pharmaceutically acceptable salt thereof, wherein q is 1, A is a bond, and L MC yes

[0170] Among them L MC The * indicates the attachment point with Z and L MC The ** indicates the attachment point to A.

[0171] Embodiment 16. A compound of formula (I), or a compound according to any one of Embodiments 1 to 14, or a pharmaceutically acceptable salt thereof, wherein q is 1, A is a bond, and L MC yes

[0172] Among them L MC The * indicates the attachment point with Z and L MC The ** indicates the attachment point to A.

[0173] Embodiment 17. A compound of formula (I), or a compound according to any one of Embodiments 1 to 14, or a pharmaceutically acceptable salt thereof, wherein q is 1, A is a bond, and L MC yes

[0174] Among them L MC The * indicates the attachment point with Z and L MC The ** indicates the attachment point to A.

[0175] Embodiment 18. A compound of formula (I), or a compound according to any one of Embodiments 1 to 17, or a pharmaceutically acceptable salt thereof, wherein q is 1 and Z is The * of Z indicates that MC and the ** of Z indicates the attachment point with L.

[0176] Embodiment 19. A compound of formula (I), or a compound according to any one of Embodiments 1 to 17, or a pharmaceutically acceptable salt thereof, wherein q is 1 and Z is The * of Z indicates that MC and the ** of Z indicates the attachment point with L.

[0177] Embodiment 20. A compound of formula (I), or a compound according to any one of Embodiments 1 to 12, or a pharmaceutically acceptable salt thereof, wherein q is 0, L MC does not exist and Z is W.

[0178] Embodiment 21. A compound of formula (I) having a structure of formula (II) or a pharmaceutically acceptable salt thereof,

[0179]

[0180] Where W, L, t, R 1 、R 2 、R 3 、R 4 and R B As defined in formula (I).

[0181] Embodiment 22. A compound of formula (II) according to any one of Embodiments 1 to 21, or a pharmaceutically acceptable salt thereof,

[0182] in:

[0183] R B is phenyl, pyridyl, phenylthio, pyrimidinyl or 5-8 membered cycloalkyl, wherein R B Optionally 1 to 3 R 5 group substitution;

[0184] R 1 Selected from H, C 1- C3 alkyl and C substituted with 1 to 3 -OH groups 1- C3 alkyl;

[0185] R 2 Selected from H, C 1- C3 alkyl and C substituted with 1 to 3 -OH groups 1- C3 alkyl;

[0186] or R 1 and R 2 Together with the carbon atoms to which they are attached, they can form a 3-6 membered cycloalkyl ring;

[0187] t is 0, 1, or 2;

[0188] Each R 3 , when present, is a substituent on the ring to which –LW is directly attached, wherein each R 3 independently selected from halogen, CN, C1-C3 alkoxy, C1-C3 alkyl, C(=O)OR 10 and C(=O)NR 13 R 14 ;

[0189] R 4 It is H, C1-C3 alkyl, C 3- C6 cycloalkyl, -(CH2)2O(CH2)2Br or 1 to 2 independently selected from -OH, -C(=O)R 15 and R10 C 1- C3 alkyl;

[0190] Each R 5 are independently selected from halo, -CN, hydroxy, -NR 13 R 14 、C 3- C6 cycloalkyl, C 1- C3 alkoxy, C 1- C3 haloalkyl and optionally 1 to 3 R 6 C 1- C3 alkyl, where R B By two R 5 Replace and each R 5 is optionally replaced by 1 to 3 R 6 C 1- C3 alkyl, when directly attached to the same carbon atom, can be taken together with the carbon atoms to which the two are directly attached to form a C3 alkyl group optionally substituted by 1 to 3 R 6 a 3-5 membered cycloalkyl ring substituted with a group;

[0191] Each R 6 independently selected at each occurrence from halo, hydroxy, CN, C 1- C3 alkoxy, C 1- C3 alkyl and C 3- C5 cycloalkyl,

[0192] Or two R 6 The group together with the carbon atom to which they are directly attached can form a 3-5 membered cycloalkyl ring or a 4-6 membered heterocyclic ring containing O, N or S as ring members and optionally substituted by 1 to 2 groups independently selected from oxo and C 1- C3 alkyl group substitution;

[0193] L is a C1-C4 straight or branched chain alkylene linker, or when W is an optionally substituted ring, L can be a C1-C4 straight or branched chain alkylene linker or bond;

[0194] W is H; -OH; -OR 10 ;-C(=O)NR 13 R 14 ;-C(=O)OR 13 ;-NR 13 R 14 ;-NR 13 C(=O)OR 10 ;-NR 13 C(=O)R 10 ;-SO2R 10 ;-SO2NR 13 R 14;-NR 13 SO2R 10 ;-P(=O)(OR 13 )2;-S(=O)R 10 ;-S(=O)(=NR 13 )R 10 ;-CR 11 R 12 C(=O)NR 13 R 14 ;-CR 11 R 12 C(=O)OR 13 ;-CR 11 R 12 NR 13 R 14 ;-CR 11 R 12 NR 13 C(=O)OR 10 ;-CR 11 R 12 NR 13 C(=O)R 10 ;-CR 11 R 12 SO2R 10 ;-CR 11 R 12 SO2NR 13 R 14 ;-CR 11 R 12 NR 13 SO2R 10 ;-CR 11 R 12 P(=O)(OR 13 )2;-CR 11 R 12 S(=O)R 10 ;-CR 11 R 12 S(=O)(=NR 13 )R 10 ; 3-6 membered cycloalkyl; phenyl; containing one or two independently selected from N, NH, NR 17 , O or S ring members of the 5-6 membered heterocycloalkyl; containing one or two independently selected from N, NH, NR 17 , O or S as ring members; or a 5-membered heteroaryl group having 1 to 4 heteroatoms selected from N, O and S as ring members, which is optionally fused to a phenyl group,

[0195] wherein the 3-6 membered cycloalkyl, the phenyl, the 5-6 membered heterocycloalkyl, the 5-6 membered heterocyclyl and the 5 membered heteroaryl of W are each optionally substituted by 1 to 3 groups independently selected from the following: 1- C3 alkyl, oxo, halogen, C 1- C3 haloalkyl, -OH, -OR 10 、–OC(=O)NR 13 R 14 ,–SO2R 10 , –SO2NR 14 R 10 , –SO2NR 13 R 14 、–SO2N=CR 13 NR 13 R 14 , –SO2NR 13 C(=O)R 10 、–C(=O)NR 13 SO2R 10 、–S(=O)R 10 、–S(=O)(=NR 13 )R 10 ,–NR 13 SO2NR 13 R 14 ,–NR 13 SO2R 10 ,–NR 13 R 14 ,–NR 13 C(=O)R 13 ,–NR 13 C(=O)OR 10 、–C(=O)NR 13 R 14 and –C(=O)OR 13 ;

[0196] R 10 Selected from C 1- C5 alkyl; C 1- C3 haloalkyl; 3-6 membered cycloalkyl; phenyl; 5-6 membered heteroaryl having 1 to 4 heteroatoms independently selected from N, O and S as ring members; containing one or two independently selected from N, NH, NR 17 , O or S ring members; and containing 1 to 2 independently selected from N, NH, NR 17 , O or S ring members of the 4-6 membered heterocyclic group,

[0197] Each R 10 Optionally substituted with 1 to 5 groups independently selected from: C 1-C4 alkyl, deuterium, C 1- C4 haloalkoxy, -OH, -CN, -OC(=O)R 14 、-L 3 OR 13 、C 1- C2 haloalkyl, oxo, -halo, –C 1- C3 alkoxy, –OC(=O)NR 13 R 14 ,–SO2R 13 , –SO2NR 13 R 14 , –SO2NR 13 C(=O)R 13 、–C(=O)NR 13 SO2R 13 、–S(=O)R 13 、–S(=O)(=NR 14 )R 13 ,–NR 13 SO2NR 13 R 14 ,–NR 13 SO2R 13 ,–NR 13 R 14 ,–NR 14 C(=O)R 13 ,–NR 14 C(=O)OR 13 、–C(=O)NR 13 R 14 、–C(=O)OR 13 、-(containing 1 to 2 independently selected from N, NH, NR 17 , O or S), -(containing 1 to 2 independently selected from N, NH, NR 17 , O or S as ring members), -C 3- C5 cycloalkyl and -(a 5-6 membered heteroaryl ring having 1 to 4 heteroatoms containing 1 to 4 nitrogen atoms, 0 or 1 oxygen atoms and 0 or 1 sulfur atoms as ring members), wherein said C 1- C4 alkyl, 4-7 membered heterocycloalkyl, 4-7 membered heterocyclyl, C 3- The C5 cycloalkyl and 5-6 membered heteroaryl rings are each optionally further substituted by 1 to 3 groups independently selected from halo, C 1- C3 alkyl, C 1- C3 haloalkyl, -OR 13 , -CN and –NR 13 R 14 The group substitution;

[0198] R 11 and R 12 Each independently selected from H and C 1- C4 alkyl;

[0199] Each R 13 Independently selected from H; C 1- C4 alkyl; containing 1 to 2 independently selected from N, NH, NR 17 , O or S ring members; containing 1 to 2 independently selected from N, NH, NR 17 , O or S as ring members; and C 3- C6 cycloalkyl, wherein the C 1- C4 alkyl, heterocyclic and C 3- C6 cycloalkyl is optionally substituted by 1 to 3 independently selected 1- C4 alkyl, halogen, -OH, -NR 15 R 16 、-C(=O)OR 15 、C 1- C2 alkoxy and C substituted by 1 to 2 hydroxyl groups 1- C4 alkyl group substitution;

[0200] R 14 Selected from H, C 1- C4 alkyl and C 3- C6 cycloalkyl, wherein the C 1- C4 alkyl and C 3- C6 cycloalkyl is optionally substituted by 1 to 3 independently selected 1- C4 alkyl, halogen, -OH, -NR 15 R 16 、C 1- C2 alkoxy and C substituted by 1 to 2 hydroxyl groups 1- C4 alkyl group substitution;

[0201] or R 13 and R 14 Together with the nitrogen atom to which they are directly attached, they are capable of forming a 4-6 membered ring optionally containing additional N, O or S as ring members and optionally substituted by one to three selected from C 1- C2 alkyl, C 1- C2 alkoxy, oxo and hydroxy group substitution;

[0202] R 15 and R 16 Each independently selected from H and C 1- C4 alkyl;

[0203] L 3 Is a bond or a straight chain or branched chain C 1-C3 alkylene;

[0204] and

[0205] Indicates a single bond or a double bond.

[0206] Embodiment 23. A compound of formula (II) according to any one of Embodiments 1 to 22, or a pharmaceutically acceptable salt thereof, wherein:

[0207] R B is phenyl, pyridyl, phenylthio or 5-8 membered cycloalkyl, wherein R B Optionally 1 to 3 R 5 group substitution;

[0208] R 1 Selected from H, C 1- C3 alkyl and C substituted with 1 to 3 -OH groups 1- C3 alkyl;

[0209] R 2 It is H;

[0210] t is 0, 1, or 2;

[0211] Each R 3 , when present, is a substituent on the ring to which -LW is directly attached, wherein each R 3 Independently selected from C 1- C3 alkyl;

[0212] R 4 It is H, C 1- C3 alkyl, C 3- C6 cycloalkyl, -(CH2)2O(CH2)2Br or 1 to 2 independently selected from -OH, -C(=O)R 15 and R 10 C 1- C3 alkyl;

[0213] Each R 5 independently selected from halogen, -CN, C 1- C3 alkoxy and C 1- C3 alkyl;

[0214] L is a C1-C4 straight or branched chain alkylene linker, or when W is an optionally substituted ring, L can be a C1-C4 straight or branched chain alkylene linker or bond;

[0215] W is a 3-6 membered cycloalkyl group, wherein the 3-6 membered cycloalkyl group is substituted by 1 to 3 independently selected -SO2R 10 , –SO2NR 14 R 10 , –SO2NR13 R 14 and –SO2N=CR 13 NR 13 R 14 The group substitution;

[0216] R 10 Selected from C 1- C5 alkyl; C 1- C3 haloalkyl; 3-6 membered cycloalkyl; phenyl; 5-6 membered heteroaryl having 1 to 4 heteroatoms independently selected from N, O and S as ring members; containing one or two independently selected from N, NH, NR 17 , O or S ring members; and containing 1 to 2 independently selected from N, NH, NR 17 , O or S ring members of the 4-6 membered heterocyclic group,

[0217] Each R 10 Optionally substituted with 1 to 5 groups independently selected from: C 1- C4 alkyl, deuterium, C 1- C4 haloalkoxy, -OH, -CN, -OC(=O)R 14 、-L 3 OR 13 、-NR 13 R 14 ,–NR 14 C(=O)R 13 ,–NR 14 C(=O)OR 13 、–C(=O)NR 13 R 14 、–C(=O)OR 13 、(containing 1 to 2 independently selected from N, NH, NR 17 , O or S ring members), (containing 1 to 2 independently selected from N, NH, NR 17 , O or S as ring members) and -C 3- C5 cycloalkyl, wherein the C 1- C4 alkyl, 4-7 membered heterocycloalkyl, 4-7 membered heterocyclyl and C 3- Each C5 cycloalkyl group is optionally further substituted by 1 to 3 groups independently selected from halogen, -OR 13 and –NR 13 R 14 The group substitution;

[0218] R 11 and R 12 Each independently selected from H and C 1- C4 alkyl;

[0219] Each R 13 Independently selected from H; C 1- C4 alkyl; containing 1 to 2 independently selected from N, NH, NR 17 , O or S ring members; containing 1 to 2 independently selected from N, NH, NR 17 , O or S as ring members; and C 3- C6 cycloalkyl, wherein the C 1- C4 alkyl, heterocyclic and C 3- C6 cycloalkyl is optionally substituted by 1 to 3 independently selected 1- C4 alkyl, halogen, -OH, -NR 15 R 16 、-C(=O)OR 15 and C substituted with 1 to 2 hydroxyl groups 1- C4 alkyl group substitution;

[0220] R 14 Selected from H and C 1- C4 alkyl;

[0221] R 15 and R 16 Each independently selected from H and C 1- C4 alkyl;

[0222] L 3 Is a bond or a straight chain or branched chain C 1- C3 alkylene;

[0223] and

[0224] Indicates a single bond or a double bond.

[0225] Embodiment 24. A compound of Formula (I) or Formula (II) having the structure of Formula (IIIa), Formula (IIIb) or Formula (IIIc), or a pharmaceutically acceptable salt thereof:

[0226]

[0227] in:

[0228] W, L, t, R 1 、R 3 and R 5 As defined in formula (I);

[0229] or W, L, t, R 1 、R 3 and R 5 As defined in embodiment 22,

[0230] or W, L, t, R1 、R 3 and R 5 As defined in embodiment 23.

[0231] Embodiment 25. A compound of Formula (I) or Formula (II) having the structure of Formula (IIIa), or a pharmaceutically acceptable salt thereof:

[0232]

[0233] in:

[0234] W, L, t, R 1 、R 3 and R 5 As defined in formula (I);

[0235] or W, L, t, R 1 、R 3 and R 5 As defined in embodiment 22,

[0236] or W, L, t, R 1 、R 3 and R 5 As defined in embodiment 23.

[0237] Embodiment 26. The compound of any one of Embodiments 1 to 25, or a pharmaceutically acceptable salt thereof, wherein:

[0238] R 1 Selected from H, C 1- C3 alkyl and C substituted with one -OH group 1- C3 alkyl;

[0239] t is 0, 1, or 2;

[0240] Each R 3 , when present, is a substituent on the ring to which –LW is directly attached, wherein each R 3 independently selected from halogen, CN, C 1- C3 alkoxy, C 1- C3 alkyl, C(=O)OR 10 and C(=O)NR 13 R 14 ;

[0241] Each R 5 independently selected from halogen, CN, C 1- C3 alkyl and C 1- C3 alkoxy;

[0242] L is a C1-C4 straight or branched alkylene linker;

[0243] W is -SO2R 10 、-SO2NR 13 R 14 、-NR 14 SO2R 10 、-CR 11 R 12 SO2R 10 、-CR 11 R 12 SO2NR 13 R 14 、-CR 11 R 12 NR 14 SO2R 10 or an optionally substituted 3-6 membered cycloalkyl;

[0244] wherein the optional substituents of the optionally substituted cycloalkyl group are 1 to 3 independently selected from C 1- C3 alkyl, oxo, halogen, -OH, -SO2R 10 、-SO2NR 13 R 14 、-SO2NR 14 R 10 、-NR 13 SO2NR 13 R 14 、-NR 13 SO2R 10 、-NR 13 R 14 、-OR 10 、-NR 13 C(=O)OR 10 、-C(=O)NR 13 R 14 and C(=O)OR 13 The group,

[0245] R 10 Selected from C 1- C5 alkyl; 3-6 membered cycloalkyl; phenyl; 5-6 membered heteroaryl having 1 to 4 heteroatoms independently selected from N, O and S as ring members; containing one or two independently selected from N, NH, NR 17 , O or S as ring members;

[0246] and containing 1 to 2 independently selected from N, NH, NR 17 , O or S ring members of the 4-6 membered heterocyclic group,

[0247] Each R 10 Optionally 1 to 4 selected from C 1- C3 alkyl, oxo, CN, halogen, C1- C3 alkoxy, OH and C 3- C5 cycloalkyl group substitution;

[0248] R 11 and R 12 Each independently selected from H and C 1- C4 alkyl;

[0249] Each R 13 independently selected from H and optionally substituted by halo, -OH or C 1- C2 alkoxy substituted C 1- C4 alkyl;

[0250] R 14 Selected from H and C 1- C4 alkyl;

[0251] or R 13 and R 14 Together with the nitrogen atom to which they are directly attached, they are capable of forming a 4-6 membered ring optionally containing additional N, O or S as ring members and optionally substituted by one to two selected from C 1- C2 alkyl, C 1- C2 alkoxy, oxo and hydroxy groups are substituted.

[0252] Embodiment 27. The compound of any one of Embodiments 1 to 25, or a pharmaceutically acceptable salt thereof, wherein:

[0253] R 1 is H, methyl, or methyl substituted by a -OH group;

[0254] t is 0, 1, or 2;

[0255] Each R 3 , when present, is a substituent on the ring to which -LW is directly attached, wherein each R 3 independently selected from methyl;

[0256] Each R 5 Independently selected from Cl, F, -CN, methyl and -OCH3;

[0257] L is -CH2- or -CH2CH2-;

[0258] W is -SO2R 10 、-SO2NR 13 R 14 or -SO2NR 14 R 10 substituted cyclopropyl;

[0259] R 10Selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, cyclopropyl, cyclobutyl, pyridyl, pyrazolyl, isopropyl oxetane, tetrahydrofuranyl, tetrahydropyranyl, morpholinyl, piperidinyl, piperazinyl, pyrrolidinyl and azetidinyl,

[0260] Each R 10 Optionally substituted with 1 to 4 groups independently selected from the group consisting of methyl, ethyl, deuterium, -OCH3, -OH, -OCHF2, -CN, -NH2, -NHCH3, -N(CH3)2, -NHR 13 , -NHCH(=O), -NHC(=O)CH3, -NHC(=O)OCH3, -NHC(=O)CH2NH2, -NHC(=O)CH2N(CH3)2, -NHC(=O)CH(CH3)NH2, -NHC(=O)C(CH3)2NH2, -OC H2CH2OH, -OCH2CH(CH3)OH, -OCH2CH(CH3)2OH, -OCH(F)CH2OH, -OCF2CH2OH, -OCH2CH2NH2, -OCH2CH(CH3)NH2, -OCH2C(CH3)2NH2, -OCH 2CH2NHCH3, -OCH2CH2N(CH3)2, -OCH(F)CH2NH2, -OCF2CH2NH2, -CH2OCH2CH2NH2, -CH2CH2OH, -CH2OH, -CH2NH2, -O-azetidinyl, -C(=O)NH2, -C(=O)NHCH3, -OC(=O)CH3, cyclopropyl, azetidinyl, pyrrolidinyl, morpholinyl, 6-oxa-3-azabicyclo[3.1.1]heptyl, 2-oxa-5-azabicyclo[2.2.1]heptyl, 2-oxa-6-azaspiro[3.3]heptyl and 4,5-dihydroisopropyl azole group,

[0261] wherein the methyl, ethyl, cyclopropyl, azetidinyl, pyrrolidinyl, morpholinyl, 6-oxa-3-azabicyclo[3.1.1]heptyl, 2-oxa-5-azabicyclo[2.2.1]heptyl, 2-oxa-6-azaspiro[3.3]heptyl and 4,5-dihydroisoxyl are Each oxazolyl group is optionally further substituted with 1 to 3 groups independently selected from F, -OH, -OCH3, -NH2 and methyl;

[0262] R 13 is selected from H, methyl, ethyl, isopropyl, propyl, butyl, isobutyl, pentyl, a 4-7 membered heterocyclic group containing 1 to 2 heteroatoms independently selected from N, O or S as ring members, and C 3- C6 cycloalkyl,

[0263] wherein the methyl, ethyl, isopropyl, propyl, butyl, isobutyl, pentyl, heterocyclic and C 3- C6 cycloalkyl is optionally substituted by 1 to 3 independently selected from methyl, ethyl, propyl, isopropyl, F, -OH, -NH2, -N(CH3)2, -C(=O)OH, C 1- C2 alkoxy and C substituted by 1 to 2 hydroxyl groups 1- C4 alkyl group substitution,

[0264] and

[0265] R 14 Selected from H and methyl.

[0266] Embodiment 28. A compound of Formula (I) or Formula (II) having the structure of Formula (IVa), Formula (IVb) or Formula (IVc), or a pharmaceutically acceptable salt thereof:

[0267]

[0268] in:

[0269] L, R 1 、R 5 、R 10 、R 11 and R 12 As defined in formula (I);

[0270] or L, R 1 、R 5 、R 10 、R 11 and R 12 As defined in embodiment 22;

[0271] or L, R 1 、R 5 、R 10 、R 11 and R 12 As defined in embodiment 23;

[0272] or L, R 1 、R 5 、R 10 、R 11 and R 12 As defined in embodiment 26,

[0273] or L, R 1 、R 5 、R 10 、R 11 and R 12 As defined in embodiment 27.

[0274] Embodiment 29. A compound of Formula (I) or Formula (II) having the structure of Formula (IVa), or a pharmaceutically acceptable salt thereof:

[0275]

[0276] in:

[0277] L, R 1 、R 5 、R 10 、R 11 and R 12 As defined in formula (I);

[0278] or L, R 1 、R 5 、R 10 、R 11 and R 12 As defined in embodiment 22;

[0279] or L, R 1 、R 5 、R 10 、R 11 and R 12 As defined in embodiment 23;

[0280] or L, R 1 、R 5 、R 10 、R 11 and R 12 As defined in embodiment 26,

[0281] or L, R 1 、R 5 、R 10 、R 11 and R 12 As defined in embodiment 27.

[0282] Embodiment 30. A compound of Formula (I) or Formula (II) having the structure of Formula (Va), Formula (Vb), or Formula (Vc), or a pharmaceutically acceptable salt thereof:

[0283]

[0284] in:

[0285] L, R 1 、R 5 and R 10 As defined in formula (I);

[0286] or L, R 1 、R 5 and R 10As defined in embodiment 22;

[0287] or L, R 1 、R 5 and R 10 As defined in embodiment 23;

[0288] or L, R 1 、R 5 and R 10 As defined in embodiment 26,

[0289] or L, R 1 、R 5 and R 10 As defined in embodiment 27.

[0290] Embodiment 31. A compound of Formula (I) or Formula (II) having the structure of Formula (Va), or a pharmaceutically acceptable salt thereof:

[0291]

[0292] in:

[0293] L, R 1 、R 5 and R 10 As defined in formula (I);

[0294] or L, R 1 、R 5 and R 10 As defined in embodiment 22;

[0295] or L, R 1 、R 5 and R 10 As defined in embodiment 23;

[0296] or L, R 1 、R 5 and R 10 As defined in embodiment 26,

[0297] or L, R 1 、R 5 and R 10 As defined in embodiment 27.

[0298] Embodiment 32. The compound of any one of Embodiments 1 to 31, or a pharmaceutically acceptable salt thereof, wherein:

[0299] R 1 is H, methyl, or methyl substituted by a -OH group;

[0300] Each R 5independently selected from Cl, F and -CN;

[0301] L is a bond or CH2 or CH2CH2;

[0302] R 10 Selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, cyclopropyl, cyclobutyl, pyridyl, pyrazolyl, isopropyl oxetane, tetrahydrofuranyl, tetrahydropyranyl, morpholinyl, piperidinyl, piperazinyl, pyrrolidinyl and azetidinyl,

[0303] Each R 10 Optionally substituted with 1 to 4 groups independently selected from the group consisting of methyl, ethyl, deuterium, -OCH3, -OH, -OCHF2, -CN, -NH2, -NHCH3, -N(CH3)2, -NHR 13 , -NHCH(=O), -NHC(=O)CH3, -NHC(=O)OCH3, -NHC(=O)CH2NH2, -NHC(=O)CH2N(CH3)2, -NHC(=O)CH(CH3)NH2, -NHC(=O)C(CH3)2NH2, -OC H2CH2OH, -OCH2CH(CH3)OH, -OCH2CH(CH3)2OH, -OCH(F)CH2OH, -OCF2CH2OH, -OCH2CH2NH2, -OCH2CH(CH3)NH2, -OCH2C(CH3)2NH2, -OCH 2CH2NHCH3, -OCH2CH2N(CH3)2, -OCH(F)CH2NH2, -OCF2CH2NH2, -CH2OCH2CH2NH2, -CH2CH2OH, -CH2OH, -CH2NH2, -O-azetidinyl, -C(=O)NH2, -C(=O)NHCH3, -OC(=O)CH3, cyclopropyl, azetidinyl, pyrrolidinyl, morpholinyl, 6-oxa-3-azabicyclo[3.1.1]heptyl, 2-oxa-5-azabicyclo[2.2.1]heptyl, 2-oxa-6-azaspiro[3.3]heptyl and 4,5-dihydroisopropyl azole group,

[0304] wherein the methyl, ethyl, cyclopropyl, azetidinyl, pyrrolidinyl, morpholinyl, 6-oxa-3-azabicyclo[3.1.1]heptyl, 2-oxa-5-azabicyclo[2.2.1]heptyl, 2-oxa-6-azaspiro[3.3]heptyl and 4,5-dihydroisoxyl are Each oxazolyl group is optionally further substituted by 1 to 3 groups independently selected from F, -OH, -OCH3, -NH2

[0305] and

[0306] R 11 and R 12 Each independently represents H or methyl.

[0307] Embodiment 33. The compound of any one of Embodiments 1 to 32, or a pharmaceutically acceptable salt thereof, wherein:

[0308] R 1 is H, methyl, or methyl substituted by a -OH group;

[0309] Each R 5 independently selected from Cl, F and -CN;

[0310] L is a bond or CH2 or CH2CH2;

[0311] and

[0312] R 10 Selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, cyclopropyl, cyclobutyl, pyridyl, pyrazolyl, isopropyl oxetane, tetrahydrofuranyl, tetrahydropyranyl, morpholinyl, piperidinyl, piperazinyl, pyrrolidinyl and azetidinyl,

[0313] Each R 10 Optionally substituted with 1 to 4 groups independently selected from the group consisting of methyl, ethyl, deuterium, -OCH3, -OH, -OCHF2, -CN, -NH2, -NHCH3, -N(CH3)2, -NHR 13, -NHCH(=O), -NHC(=O)CH3, -NHC(=O)OCH3, -NHC(=O)CH2NH2, -NHC(=O)CH2N(CH3)2, -NHC(=O)CH(CH3)NH2, -NHC(=O)C(CH3)2NH2, -OC H2CH2OH, -OCH2CH(CH3)OH, -OCH2CH(CH3)2OH, -OCH(F)CH2OH, -OCF2CH2OH, -OCH2CH2NH2, -OCH2CH(CH3)NH2, -OCH2C(CH3)2NH2, -OCH 2CH2NHCH3, -OCH2CH2N(CH3)2, -OCH(F)CH2NH2, -OCF2CH2NH2, -CH2OCH2CH2NH2, -CH2CH2OH, -CH2OH, -CH2NH2, -O-azetidinyl, -C(=O)NH2, -C(=O)NHCH3, -OC(=O)CH3, cyclopropyl, azetidinyl, pyrrolidinyl, morpholinyl, 6-oxa-3-azabicyclo[3.1.1]heptyl, 2-oxa-5-azabicyclo[2.2.1]heptyl, 2-oxa-6-azaspiro[3.3]heptyl and 4,5-dihydroisopropyl azole group,

[0314] wherein the methyl, ethyl, cyclopropyl, azetidinyl, pyrrolidinyl, morpholinyl, 6-oxa-3-azabicyclo[3.1.1]heptyl, 2-oxa-5-azabicyclo[2.2.1]heptyl, 2-oxa-6-azaspiro[3.3]heptyl and 4,5-dihydroisoxyl are Each oxazolyl group is optionally further substituted with 1 to 3 groups independently selected from F, -OH, -OCH3, -NH2.

[0315] Embodiment 34. A compound of formula (I) having the structure of formula (VI) or a pharmaceutically acceptable salt thereof,

[0316]

[0317] in:

[0318] W, L, t, R 3 、R 4 and R B As defined in formula (I).

[0319] Embodiment 35. A compound of formula (VII) or a pharmaceutically acceptable salt thereof,

[0320]

[0321] in:

[0322] R C is H or optionally 1 to 3 R 6 a C1-C6 alkyl group substituted with a group;

[0323] t is 0, 1, or 2;

[0324] Each R 3 , when present, is a substituent on the ring to which –LW is directly attached, wherein each R 3 independently selected from halogen, CN, C 1- C3 alkoxy, C 1- C3 alkyl, C(=O)OR 10 and C(=O)NR 13 R 14 ;

[0325] R 4 is H, halogen or C 1-3 alkyl;

[0326] L is a C1-C4 straight or branched alkylene linker or bond;

[0327] W is H; -OH; -OR 10 ;-C(=O)NR 13 R 14 ;-C(=O)OR 13 ;-NR 13 R 14 ;-NR 13 C(=O)OR 10 ;-NR 13 C(=O)R 10 ;-SO2R 10 ;-SO2NR 13 R 14 ;-NR 13 SO2R 10 ;-P(=O)(OR 13 )2;-S(=O)R 10 ;-S(=O)(=NR 13 )R 10 ;-CR 11 R 12 C(=O)NR 13 R 14 ;-CR 11 R 12 C(=O)OR 13 ;-CR 11 R 12 NR 13 R 14 ;-CR 11 R 12 NR 13 C(=O)OR10 ;-CR 11 R 12 NR 13 C(=O)R 10 ;-CR 11 R 12 SO2R 10 ;-CR 11 R 12 SO2NR 13 R 14 ;-CR 11 R 12 NR 13 SO2R 10 ;-CR 11 R 12 P(=O)(OR 13 )2;-CR 11 R 12 S(=O)R 10 ;-CR 11 R 12 S(=O)(=NR 13 )R 10 ; 3-6 membered cycloalkyl; phenyl; containing one or two independently selected from N, NH, NR 17 , O or S ring members of the 5-6 membered heterocycloalkyl; containing one or two independently selected from N, NH, NR 17 , O or S as ring members; or a 5-membered heteroaryl group having 1 to 4 heteroatoms selected from N, O and S as ring members, which is optionally fused to a phenyl group,

[0328] wherein the 3-6 membered cycloalkyl, the phenyl, the 5-6 membered heterocycloalkyl, the 5-6 membered heterocyclyl and the 5 membered heteroaryl of W are each optionally substituted by 1 to 3 groups independently selected from the following: 1- C3 alkyl, oxo, halogen, C 1- C3 haloalkyl, -OH, -OR 10 、–OC(=O)NR 13 R 14 ,–SO2R 10 , –SO2NR 14 R 10 , –SO2NR 13 R 14 、–SO2N=CR 13 NR 13 R 14 , –SO2NR 13 C(=O)R 10 、–C(=O)NR 13 SO2R 10 、–S(=O)R10 、–S(=O)(=NR 13 )R 10 ,–NR 13 SO2NR 13 R 14 ,–NR 13 SO2R 10 ,–NR 13 R 14 ,–NR 13 C(=O)R 13 ,–NR 13 C(=O)OR 10 、–C(=O)NR 13 R 14 and –C(=O)OR 13 ;

[0329] R 10 Selected from C 1- C5 alkyl; C 1- C3 haloalkyl; 3-6 membered cycloalkyl; phenyl; 5-6 membered heteroaryl having 1 to 4 heteroatoms independently selected from N, O and S as ring members; containing one or two independently selected from N, NH, NR 17 , O or S ring members; and containing 1 to 2 independently selected from N, NH, NR 17 , O or S ring members of the 4-6 membered heterocyclic group,

[0330] Each R 10 Optionally substituted with 1 to 5 groups independently selected from: C 1- C4 alkyl, deuterium, C 1- C4 haloalkoxy, -OH, -CN, -OC(=O)R 14 、-L 3 OR 13 、C 1- C2 haloalkyl, oxo, -halo, –C 1- C3 alkoxy, –OC(=O)NR 13 R 14 ,–SO2R 13 , –SO2NR 13 R 14 , –SO2NR 13 C(=O)R 13 、–C(=O)NR 13 SO2R 13 、–S(=O)R 13 、–S(=O)(=NR 14 )R 13 ,–NR 13 SO2NR13 R 14 ,–NR 13 SO2R 13 ,–NR 13 R 14 ,–NR 14 C(=O)R 13 ,–NR 14 C(=O)OR 13 、–C(=O)NR 13 R 14 、–C(=O)OR 13 、(containing 1 to 2 independently selected from N, NH, NR 17 , O or S ring members), (containing 1 to 2 independently selected from N, NH, NR 17 , O or S as ring members), -C 3- C5 cycloalkyl and -(a 5-6 membered heteroaryl ring having 1 to 4 heteroatoms containing 1 to 4 nitrogen atoms, 0 or 1 oxygen atoms and 0 or 1 sulfur atoms as ring members), wherein said C 1- C4 alkyl, 4-7 membered heterocycloalkyl, 4-7 membered heterocyclyl, C 3- The C5 cycloalkyl and 5-6 membered heteroaryl rings are each optionally further substituted by 1 to 3 groups independently selected from halo, C 1- C3 alkyl, C 1- C3 haloalkyl, -OR 13 , -CN and –NR 13 R 14 The group substitution;

[0331] R 11 and R 12 Each independently selected from H and C 1- C4 alkyl;

[0332] Each R 13 independently selected from H; optionally substituted by halo, -OH, amino or C 1-2 Alkoxy-substituted C 1-4 Alkyl; and optionally substituted by halo, -OH, amino or C 1-2 Alkoxy-substituted C 3-6 alkyl;

[0333] R 14 independently selected from H; optionally substituted by halo, -OH, amino or C 1-2 Alkoxy-substituted C 1-4 Alkyl; and optionally substituted by halo, -OH, amino or C 1-2 Alkoxy-substituted C 3-6 alkyl

[0334] or R13 and R 14 Together with the nitrogen atom to which they are directly attached, they are capable of forming a 4-6 membered ring optionally containing additional N, O or S as ring members and optionally substituted by one to three selected from C 1-2 Alkyl, C 1-2 Alkoxy, oxo and hydroxy group substitution;

[0335] L 3 Is a bond or a straight chain or branched chain C 1-3 alkylene;

[0336] Each R 6 independently selected at each occurrence from halo, hydroxy, CN, C 1- C3 alkoxy, C 1- C3 alkyl and C 3- C5 cycloalkyl,

[0337] or

[0338] Two R's 6 The group together with the carbon atom to which they are directly attached can form a 3-5 membered cycloalkyl ring or a 4-6 membered heterocyclic ring containing O, N or S as ring members and optionally substituted by 1 to 2 groups independently selected from oxo and C 1- The residue is substituted with a C3 alkyl group.

[0339] Embodiment 36. The compound of formula (VII) according to embodiment 35, or a pharmaceutically acceptable salt thereof, wherein R C is H, methyl, ethyl, propyl, isopropyl, tert-butyl or n-butyl.

[0340] Embodiment 37. The compound of any one of Embodiments 34 to 36, or a pharmaceutically acceptable salt thereof, wherein:

[0341] L is a C1-C4 straight or branched alkylene linker;

[0342] W is -SO2R 10 、-SO2NR 13 R 14 、-NR 14 SO2R 10 、-CR 11 R 12 SO2R 10 、-CR 11 R 12 SO2NR 13 R 14 、-CR 11 R 12 NR 14 SO2R 10, or an optionally substituted C1-C3 alkyl group, or an optionally substituted 3-6 membered cycloalkyl group;

[0343] wherein the optional substituents of the optionally substituted C1-C3 alkyl and optionally substituted cycloalkyl are 1 to 3 independently selected 1- C3 alkyl, oxo, halogen, -OH, -SO2R 10 、-SO2NR 13 R 14 、-SO2NR 14 R 10 、-NR 13 SO2NR 13 R 14 、-NR 13 SO2R 10 、-NR 13 R 14 、-OR 10 、-NR 13 C(=O)OR 10 、-C(=O)NR 13 R 14 and C(=O)OR 13 Groups;

[0344] R 10 Selected from C 1- C5 alkyl; 3-6 membered cycloalkyl; phenyl; 5-6 membered heteroaryl having 1 to 4 heteroatoms independently selected from N, O and S as ring members; containing one or two independently selected from N, NH, NR 17 , O or S as ring members;

[0345] and containing 1 to 2 independently selected from N, NH, NR 17 , O or S ring members of the 4-6 membered heterocyclic group,

[0346] Each R 10 Optionally 1 to 4 selected from C 1- C3 alkyl, oxo, CN, halogen, C 1- C3 alkoxy, OH and C 3- C5 cycloalkyl group substitution;

[0347] R 11 and R 12 Each independently selected from H and C 1- C4 alkyl;

[0348] Each R 13 independently selected from H and optionally substituted by halo, -OH or C 1- C2 alkoxy substituted C 1- C4 alkyl;

[0349] R 14 Selected from H and C 1- C4 alkyl;

[0350] or R 13 and R 14 Together with the nitrogen atom to which they are directly attached, they are capable of forming a 4-6 membered ring optionally containing additional N, O or S as ring members and optionally substituted by one to two selected from C 1- C2 alkyl, C 1- C2 alkoxy, oxo and hydroxy groups are substituted.

[0351] Embodiment 38. A compound of formula (I), or a compound according to any one of Embodiments 1 to 34, or a pharmaceutically acceptable salt thereof, wherein R B is selected from phenyl, pyridyl, phenylthio and cyclohexyl, each of which is optionally substituted by 1 to 3 R 5 Group substitution.

[0352] Embodiment 39. A compound of formula (I), or a compound according to any one of Embodiments 1 to 34, or a pharmaceutically acceptable salt thereof, wherein R B is optionally replaced by 1 to 3 R 5 A pyridyl group substituted with a group.

[0353] Embodiment 40. A compound of formula (I), or a compound according to any one of Embodiments 1 to 34, or a pharmaceutically acceptable salt thereof, wherein R B is optionally replaced by 1 to 3 R 5 A pyridin-3-yl group substituted with a group.

[0354] Embodiment 41. A compound of formula (I), or a compound according to any one of Embodiments 1 to 34, or a pharmaceutically acceptable salt thereof, wherein R B is optionally replaced by 1 to 3 R 5 A pyridin-2-yl group substituted with a group.

[0355] Embodiment 42. A compound of formula (I), or a compound according to any one of Embodiments 1 to 34, or a pharmaceutically acceptable salt thereof, wherein R B is optionally replaced by 1 to 3 R 5 A phenylthio group substituted with a group.

[0356] Embodiment 43. A compound of formula (I), or a compound according to any one of Embodiments 1 to 34, or a pharmaceutically acceptable salt thereof, wherein R B is optionally replaced by 1 to 3 R 5 A phenylthio-2-yl group substituted with a group.

[0357] Embodiment 44. A compound of formula (I), or a compound according to any one of Embodiments 1 to 34, or a pharmaceutically acceptable salt thereof, wherein R B is optionally replaced by 1 to 3 R 5 A cyclohexyl group substituted with a group.

[0358] Embodiment 45. A compound of formula (I), or a compound according to any one of Embodiments 1 to 34, or a pharmaceutically acceptable salt thereof, wherein R B is optionally replaced by 1 to 3 R 5 substituted phenyl groups.

[0359] Embodiment 46. A compound of formula (I), or a compound according to any one of Embodiments 1 to 34, or a pharmaceutically acceptable salt thereof, wherein R B is selected from phenyl, pyridyl, phenylthio and cyclohexyl, each of which is optionally substituted by 1 to 3 independently selected from halo, C 1- C3 alkoxy, C 1- C3 alkyl and -CN R 5 Group substitution.

[0360] Embodiment 47. A compound of formula (I), or a compound according to any one of Embodiments 1 to 34, or a pharmaceutically acceptable salt thereof, wherein R B is optionally replaced by 1 to 3 R 5 A pyridin-3-yl group substituted with a group.

[0361] Embodiment 48. A compound of formula (I), or a compound according to any one of Embodiments 1 to 34, or a pharmaceutically acceptable salt thereof, wherein R B is optionally substituted by 1 to 3 independently selected from halo, C 1- C3 alkoxy, C 1- C3 alkyl and -CN R 5 A pyridin-2-yl group substituted with a group.

[0362] Embodiment 49. A compound of formula (I), or a compound according to any one of Embodiments 1 to 34, or a pharmaceutically acceptable salt thereof, wherein R B is optionally substituted by 1 to 3 independently selected from halo, C 1- C3 alkoxy, C 1- C3 alkyl and -CN R 5 A phenylthio group substituted with a group.

[0363] Embodiment 50. A compound of formula (I), or a compound according to any one of Embodiments 1 to 34, or a pharmaceutically acceptable salt thereof, wherein R B is optionally substituted by 1 to 3 independently selected from halo, C1- C3 alkoxy, C 1- C3 alkyl and -CN R 5 A phenylthio-2-yl group substituted with a group.

[0364] Embodiment 51. A compound of formula (I), or a compound according to any one of Embodiments 1 to 34, or a pharmaceutically acceptable salt thereof, wherein R B is optionally substituted by 1 to 3 independently selected from halo, C 1- C3 alkoxy, C 1- C3 alkyl and -CN R 5 A cyclohexyl group substituted with a group.

[0365] Embodiment 52. A compound of formula (I), or a compound according to any one of Embodiments 1 to 34, or a pharmaceutically acceptable salt thereof, wherein R B is optionally substituted by 1 to 3 independently selected from halo, C 1- C3 alkoxy, C 1- C3 alkyl and -CN R 5 substituted phenyl groups.

[0366] Embodiment 53. A compound of formula (I), or a compound according to any one of Embodiments 1 to 34, or a pharmaceutically acceptable salt thereof, wherein R B is selected from phenyl, pyridyl, phenylthio and cyclohexyl, each of which is optionally substituted by 1 to 3 R independently selected from Cl, F, -OCH3, methyl and -CN 5 Group substitution.

[0367] Embodiment 54. A compound of formula (I), or a compound according to any one of Embodiments 1 to 34, or a pharmaceutically acceptable salt thereof, wherein R B is optionally substituted by 1 to 3 R independently selected from Cl, F, -OCH3, methyl and -CN 5 A pyridin-2-yl group substituted with a group.

[0368] Embodiment 55. A compound of formula (I), or a compound according to any one of Embodiments 1 to 34, or a pharmaceutically acceptable salt thereof, wherein R B is optionally substituted by 1 to 3 R independently selected from Cl, F, -OCH3, methyl and -CN 5 A phenylthio group substituted with a group.

[0369] Embodiment 56. A compound of formula (I), or a compound according to any one of Embodiments 1 to 34, or a pharmaceutically acceptable salt thereof, wherein R B is optionally substituted by 1 to 3 R independently selected from Cl, F, -OCH3, methyl and -CN5 A phenylthio-2-yl group substituted with a group.

[0370] Embodiment 57. A compound of formula (I), or a compound according to any one of Embodiments 1 to 34, or a pharmaceutically acceptable salt thereof, wherein R B is optionally substituted by 1 to 3 R independently selected from Cl, F, -OCH3, methyl and -CN 5 A cyclohexyl group substituted with a group.

[0371] Embodiment 58. A compound of formula (I), or a compound according to any one of Embodiments 1 to 34, or a pharmaceutically acceptable salt thereof, wherein R B is optionally substituted by 1 to 3 R independently selected from Cl, F, -OCH3, methyl and -CN 5 substituted phenyl groups.

[0372] Embodiment 59. A compound of formula (I), or a compound according to any one of Embodiments 1 to 34, or a pharmaceutically acceptable salt thereof, wherein R B is selected from phenyl, pyridyl, phenylthio and cyclohexyl, each of which is optionally substituted by 1 to 2 independently selected from halo, C 1- C3 alkoxy, C 1- C3 alkyl and -CN R 5 Group substitution.

[0373] Embodiment 60. A compound of formula (I), or a compound according to any one of Embodiments 1 to 34, or a pharmaceutically acceptable salt thereof, wherein R B is optionally replaced by 1 to 2 R 5 A pyridin-3-yl group substituted with a group.

[0374] Embodiment 61. A compound of formula (I), or a compound according to any one of Embodiments 1 to 34, or a pharmaceutically acceptable salt thereof, wherein R B is optionally substituted by 1 to 2 independently selected from halogen, C 1- C3 alkoxy, C 1- C3 alkyl and -CN R 5 A pyridin-2-yl group substituted with a group.

[0375] Embodiment 62. A compound of formula (I), or a compound according to any one of Embodiments 1 to 34, or a pharmaceutically acceptable salt thereof, wherein R B is optionally substituted by 1 to 2 independently selected from halogen, C 1- C3 alkoxy, C 1- C3 alkyl and -CN R 5 A phenylthio group substituted with a group.

[0376] Embodiment 63. A compound of formula (I), or a compound according to any one of Embodiments 1 to 34, or a pharmaceutically acceptable salt thereof, wherein R B is optionally substituted by 1 to 2 independently selected from halogen, C 1- C3 alkoxy, C 1- C3 alkyl and -CN R 5 A phenylthio-2-yl group substituted with a group.

[0377] Embodiment 64. A compound of formula (I), or a compound according to any one of Embodiments 1 to 34, or a pharmaceutically acceptable salt thereof, wherein R B is optionally substituted by 1 to 2 independently selected from halogen, C 1- C3 alkoxy, C 1- C3 alkyl and -CN R 5 A cyclohexyl group substituted with a group.

[0378] Embodiment 65. A compound of formula (I), or a compound according to any one of Embodiments 1 to 34, or a pharmaceutically acceptable salt thereof, wherein R B is optionally substituted by 1 to 2 independently selected from halogen, C 1- C3 alkoxy, C 1- C3 alkyl and -CN R 5 substituted phenyl groups.

[0379] Embodiment 66. A compound of formula (I), or a compound according to any one of Embodiments 1 to 34, or a pharmaceutically acceptable salt thereof, wherein R B is optionally substituted by 1 to 2 R independently selected from Cl, F, -OCH3, methyl and -CN 5 A pyridin-2-yl group substituted with a group.

[0380] Embodiment 67. A compound of formula (I), or a compound according to any one of Embodiments 1 to 34, or a pharmaceutically acceptable salt thereof, wherein R B is optionally substituted by 1 to 2 R independently selected from Cl, F, -OCH3, methyl and -CN 5 A phenylthio group substituted with a group.

[0381] Embodiment 68. A compound of formula (I), or a compound according to any one of Embodiments 1 to 34, or a pharmaceutically acceptable salt thereof, wherein R B is optionally substituted by 1 to 2 R independently selected from Cl, F, -OCH3, methyl and -CN 5 A phenylthio-2-yl group substituted with a group.

[0382] Embodiment 69. A compound of formula (I), or a compound according to any one of Embodiments 1 to 34, or a pharmaceutically acceptable salt thereof, wherein R B is optionally substituted by 1 to 2 R independently selected from Cl, F, -OCH3, methyl and -CN 5 A cyclohexyl group substituted with a group.

[0383] Embodiment 70. A compound of formula (I), or a compound according to any one of Embodiments 1 to 34, or a pharmaceutically acceptable salt thereof, wherein R B is optionally substituted by 1 to 2 R independently selected from Cl, F, -OCH3, methyl and -CN 5 substituted phenyl groups.

[0384] Embodiment 71. A compound according to any one of embodiments 38, 45, 46, 52, 53, 58, 59, 65 or 70, or a pharmaceutically acceptable salt thereof, wherein the phenyl ring R B The substituents are located at the meta and / or para position of the benzene ring.

[0385] Embodiment 72. A compound according to any one of Embodiments 1 to 34, 38, 45, 46, 52, 53, 58, 59, 65 or 70, or a pharmaceutically acceptable salt thereof, wherein R B Selected from:

[0386]

[0387] Embodiment 73. A compound according to any one of Embodiments 1 to 34, 38, 45, 46, 52, 53, 58, 59, 65 or 70, or a pharmaceutically acceptable salt thereof, wherein R B Selected from:

[0388]

[0389] Embodiment 74. A compound of formula (I), or a compound according to any one of Embodiments 1 to 73, or a pharmaceutically acceptable salt thereof, wherein R 1 It’s H.

[0390] Embodiment 75. A compound of formula (I), or a compound according to any one of Embodiments 1 to 73, or a pharmaceutically acceptable salt thereof, wherein R 1 It is C 1- C3 alkyl.

[0391] Embodiment 76. A compound of formula (I), or a compound according to any one of Embodiments 1 to 73, or a pharmaceutically acceptable salt thereof, wherein R 1 It's methyl.

[0392] Embodiment 77. A compound of formula (I), or a compound according to any one of Embodiments 1 to 73, or a pharmaceutically acceptable salt thereof, wherein R 1 is a C substituted with 1 to 3 -OH groups 1- C3 alkyl.

[0393] Embodiment 78. A compound of formula (I), or a compound according to any one of Embodiments 1 to 73, or a pharmaceutically acceptable salt thereof, wherein R 1 It is –CH2OH.

[0394] Embodiment 79. A compound of formula (I) or a compound according to any one of Embodiments 1 to 78, or a pharmaceutically acceptable salt thereof, wherein R 2 It’s H.

[0395] Embodiment 80. A compound of formula (I), or a compound according to any one of Embodiments 1 to 78, or a pharmaceutically acceptable salt thereof, wherein R 2 It is C 1- C3 alkyl.

[0396] Embodiment 81. A compound of formula (I), or a compound according to any one of Embodiments 1 to 78, or a pharmaceutically acceptable salt thereof, wherein R 2 It's methyl.

[0397] Embodiment 82. A compound of formula (I), or a compound according to any one of Embodiments 1 to 78, or a pharmaceutically acceptable salt thereof, wherein R 2 is a C substituted with 1 to 3 -OH groups 1- C3 alkyl.

[0398] Embodiment 83. A compound of formula (I), or a compound according to any one of Embodiments 1 to 78, or a pharmaceutically acceptable salt thereof, wherein R 2 It is –CH2OH.

[0399] Embodiment 84. A compound of formula (I), or a compound according to any one of Embodiments 1 to 83, or a pharmaceutically acceptable salt thereof, wherein each R 3 independently selected from halogen, CN, C 1- C3 alkoxy, C 1- C3 alkyl, C(=O)OR 10 and C(=O)NR 13 R 14 .

[0400] Embodiment 85. A compound of formula (I), or a compound according to any one of Embodiments 1 to 83, or a pharmaceutically acceptable salt thereof, wherein each R 3 independently selected from halogen, CN, C 1- C3 alkoxy and C 1- C3 alkyl.

[0401] Embodiment 86. A compound of formula (I), or a compound according to any one of Embodiments 1 to 83, or a pharmaceutically acceptable salt thereof, wherein each R 3 Independently selected from Cl, F, CN, -OCH3 and methyl.

[0402] Embodiment 87. A compound of formula (I), or a compound according to any one of Embodiments 1 to 83, or a pharmaceutically acceptable salt thereof, wherein R 3 It's methyl.

[0403] Embodiment 88. A compound of formula (I), or a compound according to any one of Embodiments 1 to 83, or a pharmaceutically acceptable salt thereof, wherein R 3 Does not exist.

[0404] Embodiment 89. A compound of formula (I), or a compound according to any one of Embodiments 1 to 88, or a pharmaceutically acceptable salt thereof, wherein R 4 It is H, C 1- C3 alkyl, C 3- C6 cycloalkyl or 1 to 2 independently selected from -OH, -C(=O)R 15 and R 10 C 1- C3 alkyl.

[0405] Embodiment 90. A compound of formula (I), or a compound according to any one of Embodiments 1 to 88, or a pharmaceutically acceptable salt thereof, wherein R 4 is H, methyl, cyclopropyl,

[0406]

[0407] Embodiment 91. A compound of formula (I), or a compound according to any one of Embodiments 1 to 88, or a pharmaceutically acceptable salt thereof, wherein R 4 Is H or C 1- C3 alkyl.

[0408] Embodiment 92. A compound of formula (I), or a compound according to any one of Embodiments 1 to 88, or a pharmaceutically acceptable salt thereof, wherein R 4 It is H or methyl.

[0409] Embodiment 93. A compound of formula (I) or a compound according to any one of Embodiments 1 to 88, or a pharmaceutically acceptable salt thereof, wherein R 4 It’s H.

[0410] Embodiment 94. A compound of formula (I) or a compound according to any one of Embodiments 1 to 88, or a pharmaceutically acceptable salt thereof, wherein R 4 It's methyl.

[0411] Embodiment 95. A compound of formula (I), or a compound according to any one of Embodiments 1 to 88, or a pharmaceutically acceptable salt thereof, wherein R 4 is 1 to 2 independently selected from -OH, -C(=O)R 15 and R 10 C 1- C3 alkyl.

[0412] Embodiment 96. A compound of formula (I), or a compound according to any one of Embodiments 1 to 88, or a pharmaceutically acceptable salt thereof, wherein R 4 yes

[0413] Embodiment 97. A compound of formula (I), or a compound according to any one of Embodiments 1 to 88, or a pharmaceutically acceptable salt thereof, wherein R 4 It is C 3- C6 cycloalkyl.

[0414] Embodiment 98. A compound of formula (I), or a compound according to any one of Embodiments 1 to 87, or a pharmaceutically acceptable salt thereof, wherein R 4 It is cyclopropyl.

[0415] Embodiment 99. A compound of formula (I), or a compound according to any one of Embodiments 1 to 98, or a pharmaceutically acceptable salt thereof, wherein each R 5 are independently selected from halo, -CN, hydroxy, -NR 13 R 14 、C 3- C6 cycloalkyl, C 1- C3 alkoxy, C 1- C3 haloalkyl and optionally 1 to 3 R 6 C 1- C3 alkyl, which, when directly attached to the same carbon atom, is optionally substituted by 1 to 3 R 6 The C 1- Two of the C3 alkyl groups can be taken together with the carbon to which they are attached to form a C3 alkyl group optionally substituted by 1 to 3 R6 A 3- to 5-membered cycloalkyl ring substituted with a group.

[0416] Embodiment 100. A compound of formula (I), or a compound according to any one of Embodiments 1 to 98, or a pharmaceutically acceptable salt thereof, wherein each R 5 independently selected from halogen, -CN, C 1- C3 alkoxy and C 1- C3 alkyl.

[0417] Embodiment 101. A compound of formula (I), or a compound according to any one of Embodiments 1 to 98, or a pharmaceutically acceptable salt thereof, wherein each R 5 Independently selected from Cl, F, -CN, -OCH3 and methyl.

[0418] Embodiment 102. A compound of formula (I), or a compound according to any one of Embodiments 1 to 98, or a pharmaceutically acceptable salt thereof, wherein each R 5 Independently selected from Cl and -CN.

[0419] Embodiment 103. A compound of formula (I), or a compound according to any one of Embodiments 1 to 102, or a pharmaceutically acceptable salt thereof, wherein each R 6 independently selected at each occurrence from halo, hydroxy, CN, C 1- C3 alkoxy, C 1- C3 alkyl and C 3- C5 cycloalkyl.

[0420] Embodiment 104. A compound of formula (I), or a compound according to any one of Embodiments 1 to 102, or a pharmaceutically acceptable salt thereof, wherein each R 6 It is a hydroxyl group.

[0421] Embodiment 105. A compound of formula (I) or a compound according to any one of Embodiments 1 to 104, or a pharmaceutically acceptable salt thereof, wherein

[0422] W is H; -OH; -OR; -C(=O)NR 13 R 14 ;-C(=O)OR 13 ;-NR 13 R 14 ;-NR 13 C(=O)OR 10 ;-NR 13 C(=O)R 10 ;-SO2R 10 ;-SO2NR 13 R 14 ;-NR13 SO2R 10 ;-P(=O)(OR 13 )2;-S(=O)R 10 ;-S(=O)(=NR 13 )R 10 ;-CR 11 R 12 C(=O)NR 13 R 14 ;-CR 11 R 12 C(=O)OR 13 ;-CR 11 R 12 NR 13 R 14 ;-CR 11 R 12 NR 13 C(=O)OR 10 ;-CR 11 R 12 NR 13 C(=O)R 10 ;-CR 11 R 12 SO2R 10 ;-CR 11 R 12 SO2NR 13 R 14 ;-CR 11 R 12 NR 13 SO2R 10 ;-CR 11 R 12 P(=O)(OR 13 )2;-CR 11 R 12 S(=O)R 10 ;-CR 11 R 12 S(=O)(=NR 13 )R 10 ; 3-6 membered cycloalkyl; phenyl; containing one or two independently selected from N, NH, NR 17 , O or S ring members of the 5-6 membered heterocycloalkyl; containing one or two independently selected from N, NH, NR 17 , O or S as ring members; or a 5-membered heteroaryl group having 1 to 4 heteroatoms selected from N, O and S as ring members, which is optionally fused to a phenyl group,

[0423] wherein the 3-6 membered cycloalkyl, the phenyl, the 5-6 membered heterocycloalkyl, the 5-6 membered heterocyclyl and the 5 membered heteroaryl of W are each optionally substituted by 1 to 3 groups independently selected from the following: 1- C3 alkyl, oxo, halogen, C 1- C3 haloalkyl, –L 2 OH, –L 2 OR 10 ,–L 2 OC(=O)NR 13 R 14 ,–L 2 SO2R 10 ,–L 2 SO2NR 14 R 10 ,–L 2 SO2NR 13 R 14 ,–L 2 SO2N=CR 13 NR 13 R 14 ,–L 2 SO2NR 13 C(=O)R 10 ,–L 2 C(=O)NR 13 SO2R 10 ,–L 2 S(=O)R 10 ,–L 2 S(=O)(=NR 13 )R 10 ,–L 2 NR 13 SO2NR 13 R 14 ,–L 2 NR 13 SO2R 10 ,–L 2 NR 13 R 14 ,–L 2 NR 13 C(=O)R 13 ,–L 2 NR 13 C(=O)OR 10 ,–L 2 C(=O)NR 13 R 14 and –L 2 C(=O)OR 13 .

[0424] Embodiment 106. A compound of formula (I) or a compound according to any one of Embodiments 1 to 104, or a pharmaceutically acceptable salt thereof, wherein

[0425] W is H, -OH, –OR, -C(=O)NR 13 R 14 、-C(=O)OR 13 、-NR 13 R 14 、-NR 13 C(=O)OR 10 、-NR 13 C(=O)R 10 、-SO2R 10 、-SO2NR 13 R 14 、-NR 13 SO2R 10 、-P(=O)(OR 13 )2、-S(=O)R 10 、-S(=O)(=NR 13 )R 10 、-CR 11 R 12 C(=O)NR 13 R 14 、-CR 11 R 12 C(=O)OR 13 、-CR 11 R 12 NR 13 R 14 、-CR 11 R 12 NR 13 C(=O)OR 10 、-CR 11 R 12 NR 13 C(=O)R 10 、-CR 11 R 12 SO2R 10 、-CR 11 R 12 SO2NR 13 R 14 、-CR 11 R 12 NR 13 SO2R 10 、-CR 11 R 12 P(=O)(OR 13 )2. -CR 11 R 12 S(=O)R10 or -CR 11 R 12 S(=O)(=NR 13 )R 10 .

[0426] Embodiment 107. A compound of formula (I) or a compound according to any one of Embodiments 1 to 104, or a pharmaceutically acceptable salt thereof, wherein

[0427] W is a 3-6 membered cycloalkyl group; a phenyl group; and one or two independently selected from N, NH, NR 17 , O or S ring members of the 5-6 membered heterocycloalkyl; containing one or two independently selected from N, NH, NR 17 , O or S as ring members; or a 5-membered heteroaryl group having 1 to 4 heteroatoms selected from N, O and S as ring members, which is optionally fused to a phenyl group,

[0428] wherein the 3-6 membered cycloalkyl, the phenyl, the 5-6 membered heterocycloalkyl, the 5-6 membered heterocyclyl and the 5 membered heteroaryl of W are each optionally substituted by 1 to 3 groups independently selected from the following: 1- C3 alkyl, oxo, halogen, C 1- C3 haloalkyl, –L 2 OH, –L 2 OR 10 ,–L 2 OC(=O)NR 13 R 14 ,–L 2 SO2R 10 ,–L 2 SO2NR 14 R 10 ,–L 2 SO2NR 13 R 14 ,–L 2 SO2N=CR 13 NR 13 R 14 ,–L 2 SO2NR 13 C(=O)R 10 ,–L 2 C(=O)NR 13 SO2R 10 ,–L 2 S(=O)R 10 ,–L 2 S(=O)(=NR 13 )R 10 ,–L 2 NR 13SO2NR 13 R 14 ,–L 2 NR 13 SO2R 10 ,–L 2 NR 13 R 14 ,–L 2 NR 13 C(=O)R 13 ,–L 2 NR 13 C(=O)OR 10 ,–L 2 C(=O)NR 13 R 14 and –L 2 C(=O)OR 13 .

[0429] Embodiment 108. A compound of formula (I) or a compound according to any one of Embodiments 1 to 104, or a pharmaceutically acceptable salt thereof, wherein

[0430] W is a 3-6 membered cycloalkyl group optionally substituted by 1 to 3 groups independently selected from the group consisting of: C 1- C3 alkyl, oxo, halogen, C 1- C3 haloalkyl, –L 2 OH, –L 2 OR 10 ,–L 2 OC(=O)NR 13 R 14 ,–L 2 SO2R 10 ,–L 2 SO2NR 14 R 10 ,–L 2 SO2NR 13 R 14 ,–L 2 SO2N=CR 13 NR 13 R 14 ,–L 2 SO2NR 13 C(=O)R 10 ,–L 2 C(=O)NR 13 SO2R 10 ,–L 2 S(=O)R 10 ,–L 2 S(=O)(=NR 13 )R 10 ,–L 2 NR13 SO2NR 13 R 14 ,–L 2 NR 13 SO2R 10 ,–L 2 NR 13 R 14 ,–L 2 NR 13 C(=O)R 13 ,–L 2 NR 13 C(=O)OR 10 ,–L 2 C(=O)NR 13 R 14 and –L 2 C(=O)OR 13 .

[0431] Embodiment 109. A compound of formula (I) or a compound according to any one of Embodiments 1 to 104, or a pharmaceutically acceptable salt thereof, wherein

[0432] W is O2R 10 , –SO2NR 14 R 10 , –SO2NR 13 R 14 , or –SO2N=CR 13 NR 13 R 14 , –SO2NR 13 C(=O)R 10 、–C(=O)NR 13 SO2R 10 、–S(=O)R 10 、–S(=O)(=NR 13 )R 10 ,–NR 13 SO2NR 13 R 14 ,–NR 13 SO2R 10 ,–NR 13 R 14 ,–NR 13 C(=O)R 13 ,–NR 13 C(=O)OR 10 、–C(=O)NR 13 R 14 and –C(=O)OR 13 Substituted cyclopropyl.

[0433] Embodiment 110. A compound of formula (I) or a compound according to any one of Embodiments 1 to 104, or a pharmaceutically acceptable salt thereof, wherein

[0434] W is -SO2R 10 , –SO2NR 14 R 10 , –SO2NR 13 R 14 or –SO2N=CR 13 NR 13 R 14 Substituted cyclopropyl.

[0435] Embodiment 111. A compound of formula (I) or any one of embodiments 1 to 104, or a pharmaceutically acceptable salt thereof, wherein the moiety W—L— is selected from:

[0436]

[0437] Embodiment 112. A compound of formula (I) or any one of embodiments 1 to 104, or a pharmaceutically acceptable salt thereof, wherein W is selected from:

[0438]

[0439]

[0440]

[0441]

[0442] Embodiment 113. A compound of formula (I), or a compound according to any one of Embodiments 1 to 112, or a pharmaceutically acceptable salt thereof, wherein R 10 Selected from C 1- C4 alkyl; C 1- C3 haloalkyl; 3-6 membered cycloalkyl; phenyl; 5-6 membered heteroaryl having 1 to 4 heteroatoms independently selected from N, O and S as ring members; containing one or two independently selected from N, NH, NR 17 , O or S ring members; and containing 1 to 2 independently selected from N, NH, NR 17 , O or S ring members of the 4-6 membered heterocyclic group,

[0443] Each R 10 Optionally substituted with 1 to 5 groups independently selected from: C 1- C4 alkyl, deuterium, C 1- C4 haloalkoxy, -OH, -CN, -OC(=O)R14 、-L 3 OR 13 、C 1- C2 haloalkyl, oxo, -halo, –C 1- C3 alkoxy, –OC(=O)NR 13 R 14 ,–SO2R 13 , –SO2NR 13 R 14 , –SO2NR 13 C(=O)R 13 、–C(=O)NR 13 SO2R 13 、–S(=O)R 13 、–S(=O)(=NR 14 )R 13 ,–NR 13 SO2NR 13 R 14 ,–NR 13 SO2R 13 ,–NR 13 R 14 ,–NR 14 C(=O)R 13 ,–NR 14 C(=O)OR 13 、–C(=O)NR 13 R 14 、–C(=O)OR 13 , -(a 4-7 membered heterocyclic group containing one to two heteroatoms independently selected from N, O or S as ring members), -C 3- C5 cycloalkyl and -(a 5-6 membered heteroaryl ring having 1 to 4 heteroatoms containing 1 to 4 nitrogen atoms, 0 or 1 oxygen atoms and 0 or 1 sulfur atoms as ring members), wherein said C 1- C4 alkyl, 4-7 membered heterocycloalkyl, 4-7 membered heterocyclyl, C 3- The C5 cycloalkyl and 5-6 membered heteroaryl rings are each optionally further substituted by 1 to 3 groups independently selected from halo, C 1- C3 alkyl, C 1- C3 haloalkyl, -L 4 OR 13 、-L 4 CN and –L 4 NR 13 R 14 substituted by a group.

[0444] Embodiment 114. A compound of formula (I), or a compound according to any one of Embodiments 1 to 112, or a pharmaceutically acceptable salt thereof, wherein R 10Selected from C 1- C4 alkyl; C 1- C3 haloalkyl; 3-6 membered cycloalkyl; 5-6 membered heteroaryl having 1 to 4 heteroatoms independently selected from N, O and S as ring members; containing one or two independently selected from N, NH, NR 17 , O or S ring members; and containing 1 to 2 independently selected from N, NH, NR 17 , O or S ring members of the 4-6 membered heterocyclic group,

[0445] Each R 10 Optionally substituted with 1 to 5 groups independently selected from: C 1- C4 alkyl, deuterium, C 1- C4 haloalkoxy, -OH, -CN, -OC(=O)R 14 、-L 3 OR 13 、-NR 13 R 14 ,–NR 14 C(=O)R 13 ,–NR 14 C(=O)OR 13 、–C(=O)NR 13 R 14 、–C(=O)OR 13 、(containing 1 to 2 independently selected from N, NH, NR 17 , O or S), -(containing 1 to 2 independently selected from N, NH, NR 17 , O or S as ring members) and -C 3- C5 cycloalkyl, wherein the C 1- C4 alkyl, 4-7 membered heterocycloalkyl, 4-7 membered heterocyclyl and C 3- Each C5 cycloalkyl group is optionally further substituted by 1 to 3 groups independently selected from halogen, -OR 13 , -CN and –NR 13 R 14 substituted by a group.

[0446] Embodiment 115. A compound of formula (I), or a compound according to any one of Embodiments 1 to 110, or a pharmaceutically acceptable salt thereof, wherein

[0447] R 10 Selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, cyclopropyl, cyclobutyl, pyridyl, pyrazolyl, isopropyl oxetane, tetrahydrofuranyl, tetrahydropyranyl, morpholinyl, piperidinyl, piperazinyl, pyrrolidinyl and azetidinyl,

[0448] Each R 10 Optionally substituted with 1 to 4 groups independently selected from the group consisting of methyl, ethyl, deuterium, -OCH3, -OH, -OCHF2, -CN, -NH2, -NHCH3, -N(CH3)2, -NHR 13 , -NHCH(=O), -NHC(=O)CH3, -NHC(=O)OCH3, -NHC(=O)CH2NH2, -NHC(=O)CH2N(CH3)2, -NHC(=O)CH(CH3)NH2, -NHC(=O)C(CH3)2NH2, -OC H2CH2OH, -OCH2CH(CH3)OH, -OCH2CH(CH3)2OH, -OCH(F)CH2OH, -OCF2CH2OH, -OCH2CH2NH2, -OCH2CH(CH3)NH2, -OCH2C(CH3)2NH2, -OCH 2CH2NHCH3, -OCH2CH2N(CH3)2, -OCH(F)CH2NH2, -OCF2CH2NH2, -CH2OCH2CH2NH2, -CH2CH2OH, -CH2OH, -CH2NH2, -O-azetidinyl, -C(=O)NH2, -C(=O)NHCH3, -OC(=O)CH3, cyclopropyl, azetidinyl, pyrrolidinyl, morpholinyl, 6-oxa-3-azabicyclo[3.1.1]heptyl, 2-oxa-5-azabicyclo[2.2.1]heptyl, 2-oxa-6-azaspiro[3.3]heptyl and 4,5-dihydroisopropyl azole group,

[0449] wherein the methyl, ethyl, cyclopropyl, azetidinyl, pyrrolidinyl, morpholinyl, 6-oxa-3-azabicyclo[3.1.1]heptyl, 2-oxa-5-azabicyclo[2.2.1]heptyl, 2-oxa-6-azaspiro[3.3]heptyl and 4,5-dihydroisoxyl are Each oxazolyl group is optionally further substituted with 1 to 3 groups independently selected from F, -OH, -OCH3, -NH2 and methyl.

[0450] Embodiment 116. A compound of formula (I), or a compound according to any one of Embodiments 1 to 112, or a pharmaceutically acceptable salt thereof, wherein

[0451] R 10 is selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, isobutyl and pentyl,

[0452] Each R 10Optionally substituted with 1 to 4 groups independently selected from the group consisting of methyl, ethyl, deuterium, -OCH3, -OH, -OCHF2, -CN, -NH2, -NHCH3, -N(CH3)2, -NHR 13 , -NHCH(=O), -NHC(=O)CH3, -NHC(=O)OCH3, -NHC(=O)CH2NH2, -NHC(=O)CH2N(CH3)2, -NHC(=O)CH(CH3)NH2, -NHC(=O)C(CH3)2NH2, -OC H2CH2OH, -OCH2CH(CH3)OH, -OCH2CH(CH3)2OH, -OCH(F)CH2OH, -OCF2CH2OH, -OCH2CH2NH2, -OCH2CH(CH3)NH2, -OCH2C(CH3)2NH2, -OCH 2CH2NHCH3, -OCH2CH2N(CH3)2, -OCH(F)CH2NH2, -OCF2CH2NH2, -CH2OCH2CH2NH2, -CH2CH2OH, -CH2OH, -CH2NH2, -O-azetidinyl, -C(=O)NH2, -C(=O)NHCH3, -OC(=O)CH3, cyclopropyl, azetidinyl, pyrrolidinyl, morpholinyl, 6-oxa-3-azabicyclo[3.1.1]heptyl, 2-oxa-5-azabicyclo[2.2.1]heptyl, 2-oxa-6-azaspiro[3.3]heptyl and 4,5-dihydroisopropyl azole group,

[0453] wherein the methyl, ethyl, cyclopropyl, azetidinyl, pyrrolidinyl, morpholinyl, 6-oxa-3-azabicyclo[3.1.1]heptyl, 2-oxa-5-azabicyclo[2.2.1]heptyl, 2-oxa-6-azaspiro[3.3]heptyl and 4,5-dihydroisoxyl are Each oxazolyl group is optionally further substituted with 1 to 3 groups independently selected from F, -OH, -OCH3, -NH2 and methyl.

[0454] Embodiment 117. A compound of formula (I), or a compound according to any one of Embodiments 1 to 112, or a pharmaceutically acceptable salt thereof, wherein

[0455] R 10 is selected from cyclopropyl and cyclobutyl,

[0456] Each R 10 Optionally substituted with 1 to 4 groups independently selected from the group consisting of methyl, ethyl, deuterium, -OCH3, -OH, -OCHF2, -CN, -NH2, -NHCH3, -N(CH3)2, -NHR 13, -NHCH(=O), -NHC(=O)CH3, -NHC(=O)OCH3, -NHC(=O)CH2NH2, -NHC(=O)CH2N(CH3)2, -NHC(=O)CH(CH3)NH2, -NHC(=O)C(CH3)2NH2, -OC H2CH2OH, -OCH2CH(CH3)OH, -OCH2CH(CH3)2OH, -OCH(F)CH2OH, -OCF2CH2OH, -OCH2CH2NH2, -OCH2CH(CH3)NH2, -OCH2C(CH3)2NH2, -OCH 2CH2NHCH3, -OCH2CH2N(CH3)2, -OCH(F)CH2NH2, -OCF2CH2NH2, -CH2OCH2CH2NH2, -CH2CH2OH, -CH2OH, -CH2NH2, -O-azetidinyl, -C(=O)NH2, -C(=O)NHCH3, -OC(=O)CH3, cyclopropyl, azetidinyl, pyrrolidinyl, morpholinyl, 6-oxa-3-azabicyclo[3.1.1]heptyl, 2-oxa-5-azabicyclo[2.2.1]heptyl, 2-oxa-6-azaspiro[3.3]heptyl and 4,5-dihydroisopropyl azole group,

[0457] wherein the methyl, ethyl, cyclopropyl, azetidinyl, pyrrolidinyl, morpholinyl, 6-oxa-3-azabicyclo[3.1.1]heptyl, 2-oxa-5-azabicyclo[2.2.1]heptyl, 2-oxa-6-azaspiro[3.3]heptyl and 4,5-dihydroisoxyl are Each oxazolyl group is optionally further substituted with 1 to 3 groups independently selected from F, -OH, -OCH3, -NH2 and methyl.

[0458] Embodiment 118. A compound of formula (I), or a compound according to any one of Embodiments 1 to 112, or a pharmaceutically acceptable salt thereof, wherein

[0459] R 10 Selected from pyridyl, pyrazolyl and iso azole group,

[0460] Each R 10 Optionally substituted with 1 to 4 groups independently selected from the group consisting of methyl, ethyl, deuterium, -OCH3, -OH, -OCHF2, -CN, -NH2, -NHCH3, -N(CH3)2, -NHR 13, -NHCH(=O), -NHC(=O)CH3, -NHC(=O)OCH3, -NHC(=O)CH2NH2, -NHC(=O)CH2N(CH3)2, -NHC(=O)CH(CH3)NH2, -NHC(=O)C(CH3)2NH2, -OC H2CH2OH, -OCH2CH(CH3)OH, -OCH2CH(CH3)2OH, -OCH(F)CH2OH, -OCF2CH2OH, -OCH2CH2NH2, -OCH2CH(CH3)NH2, -OCH2C(CH3)2NH2, -OCH 2CH2NHCH3, -OCH2CH2N(CH3)2, -OCH(F)CH2NH2, -OCF2CH2NH2, -CH2OCH2CH2NH2, -CH2CH2OH, -CH2OH, -CH2NH2, -O-azetidinyl, -C(=O)NH2, -C(=O)NHCH3, -OC(=O)CH3, cyclopropyl, azetidinyl, pyrrolidinyl, morpholinyl, 6-oxa-3-azabicyclo[3.1.1]heptyl, 2-oxa-5-azabicyclo[2.2.1]heptyl, 2-oxa-6-azaspiro[3.3]heptyl and 4,5-dihydroisopropyl azole group,

[0461] wherein the methyl, ethyl, cyclopropyl, azetidinyl, pyrrolidinyl, morpholinyl, 6-oxa-3-azabicyclo[3.1.1]heptyl, 2-oxa-5-azabicyclo[2.2.1]heptyl, 2-oxa-6-azaspiro[3.3]heptyl and 4,5-dihydroisoxyl are Each oxazolyl group is optionally further substituted with 1 to 3 groups independently selected from F, -OH, -OCH3, -NH2 and methyl.

[0462] Embodiment 119. A compound of formula (I), or a compound according to any one of Embodiments 1 to 112, or a pharmaceutically acceptable salt thereof, wherein

[0463] R 10 is selected from the group consisting of oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, morpholinyl, piperidinyl, piperazinyl, pyrrolidinyl and azetidinyl,

[0464] Each R 10 Optionally substituted with 1 to 4 groups independently selected from the group consisting of methyl, ethyl, deuterium, -OCH3, -OH, -OCHF2, -CN, -NH2, -NHCH3, -N(CH3)2, -NHR 13, -NHCH(=O), -NHC(=O)CH3, -NHC(=O)OCH3, -NHC(=O)CH2NH2, -NHC(=O)CH2N(CH3)2, -NHC(=O)CH(CH3)NH2, -NHC(=O)C(CH3)2NH2, -OC H2CH2OH, -OCH2CH(CH3)OH, -OCH2CH(CH3)2OH, -OCH(F)CH2OH, -OCF2CH2OH, -OCH2CH2NH2, -OCH2CH(CH3)NH2, -OCH2C(CH3)2NH2, -OCH 2CH2NHCH3, -OCH2CH2N(CH3)2, -OCH(F)CH2NH2, -OCF2CH2NH2, -CH2OCH2CH2NH2, -CH2CH2OH, -CH2OH, -CH2NH2, -O-azetidinyl, -C(=O)NH2, -C(=O)NHCH3, -OC(=O)CH3, cyclopropyl, azetidinyl, pyrrolidinyl, morpholinyl, 6-oxa-3-azabicyclo[3.1.1]heptyl, 2-oxa-5-azabicyclo[2.2.1]heptyl, 2-oxa-6-azaspiro[3.3]heptyl and 4,5-dihydroisopropyl azole group,

[0465] wherein the methyl, ethyl, cyclopropyl, azetidinyl, pyrrolidinyl, morpholinyl, 6-oxa-3-azabicyclo[3.1.1]heptyl, 2-oxa-5-azabicyclo[2.2.1]heptyl, 2-oxa-6-azaspiro[3.3]heptyl and 4,5-dihydroisoxyl are Each oxazolyl group is optionally further substituted with 1 to 3 groups independently selected from F, -OH, -OCH3, -NH2 and methyl.

[0466] Embodiment 120. A compound of formula (I), or a compound according to any one of Embodiments 1 to 112, or a pharmaceutically acceptable salt thereof, wherein R 10 Selected from:

[0467]

[0468]

[0469] Embodiment 121. A compound of formula (I), or a compound according to any one of Embodiments 1 to 120, or a pharmaceutically acceptable salt thereof, wherein R 11 and R 12 are each independently selected from H and methyl.

[0470] Embodiment 122. A compound of formula (I), or a compound according to any one of Embodiments 1 to 121, or a pharmaceutically acceptable salt thereof, wherein each R 13 Independently selected from H; C 1- C4 alkyl; containing 1 to 2 independently selected from N, NH, NR 17 , O or S ring members; containing 1 to 2 independently selected from N, NH, NR 17 , O or S as ring members; and C 3- C6 cycloalkyl, wherein the C 1- C4 alkyl, heterocyclic and C 3- C6 cycloalkyl is optionally substituted by 1 to 3 independently selected 1- C4 alkyl, halogen, -OH, -NR 15 R 16 、-C(=O)OR 15 、C 1- C2 alkoxy and C substituted by 1 to 2 hydroxyl groups 1- The residue is substituted with a C4 alkyl group.

[0471] Embodiment 123. A compound of formula (I), or a compound according to any one of Embodiments 1 to 121, or a pharmaceutically acceptable salt thereof, wherein each R 13 Independently selected from H; C 1- C4 alkyl; containing 1 to 2 independently selected from N, NH, NR 17 , O or S ring members; containing 1 to 2 independently selected from N, NH, NR 17 , O or S as ring members; and C 3- C6 cycloalkyl, wherein the C 1- C4 alkyl, heterocyclic and C 3- C6 cycloalkyl is optionally substituted by 1 to 3 independently selected 1- C4 alkyl, halogen, -OH, -NR 15 R 16 、-C(=O)OR 15 and C substituted with 1 to 2 hydroxyl groups 1- The residue is substituted with a C4 alkyl group.

[0472] Embodiment 124. A compound of formula (I), or a compound according to any one of Embodiments 1 to 121, or a pharmaceutically acceptable salt thereof, wherein each R 13 Independently selected from H or C 1- C4 alkyl, wherein the C 1- C4 alkyl is optionally substituted by 1 to 3 independently selected 1-C4 alkyl, halogen, -OH, -NR 15 R 16 、-C(=O)OR 15 and C substituted with 1 to 2 hydroxyl groups 1- The residue is substituted with a C4 alkyl group.

[0473] Embodiment 125. A compound of formula (I), or a compound according to any one of Embodiments 1 to 121, or a pharmaceutically acceptable salt thereof, wherein each R 13 independently selected from the group consisting of 1 to 2 independently selected from N, NH, NR 17 , O or S ring members; containing 1 to 2 independently selected from N, NH, NR 17 , O or S as ring members; and C 3- C6 cycloalkyl, wherein the heterocyclyl and C3-C6 cycloalkyl are optionally substituted by 1 to 3 independently selected C 1- C4 alkyl, halogen, -OH, -NR 15 R 16 、-C(=O)OR 15 and C substituted with 1 to 2 hydroxyl groups 1- The residue is substituted with a C4 alkyl group.

[0474] Embodiment 126. A compound of formula (I), or a compound according to any one of Embodiments 1 to 121, or a pharmaceutically acceptable salt thereof, wherein each R 13 Independently selected from H, methyl, -CHF2,

[0475] Embodiment 127. A compound of formula (I), or a compound according to any one of Embodiments 1 to 126, or a pharmaceutically acceptable salt thereof, wherein R 14 Selected from H, C 1- C4 alkyl and C 3- C6 cycloalkyl, wherein the C 1- C4 alkyl and C 3- C6 cycloalkyl is optionally substituted by 1 to 3 independently selected 1- C4 alkyl, halogen, -OH, -NR 15 R 16 、C 1- C2 alkoxy and C substituted by 1 to 2 hydroxyl groups 1- The residue is substituted with a C4 alkyl group.

[0476] Embodiment 128. A compound of formula (I), or a compound according to any one of Embodiments 1 to 126, or a pharmaceutically acceptable salt thereof, wherein R 14 Selected from H and C 1- C4 alkyl.

[0477] Embodiment 129. A compound of formula (I), or a compound according to any one of Embodiments 1 to 126, or a pharmaceutically acceptable salt thereof, wherein R 14 It is H or methyl.

[0478] Embodiment 130. A compound of formula (I), or a compound according to any one of Embodiments 1 to 130, or a pharmaceutically acceptable salt thereof, wherein R 15 Selected from H and C 1- C4 alkyl.

[0479] Embodiment 131. A compound of formula (I), or a compound according to any one of Embodiments 1 to 130, or a pharmaceutically acceptable salt thereof, wherein R 15 It is H or methyl.

[0480] Embodiment 132. A compound of formula (I), or a compound according to any one of Embodiments 1 to 131, or a pharmaceutically acceptable salt thereof, wherein R 16 Selected from H and C 1- C4 alkyl.

[0481] Embodiment 133. A compound of formula (I), or a compound according to any one of Embodiments 1 to 131, or a pharmaceutically acceptable salt thereof, wherein R 16 It is H or methyl.

[0482] Embodiment 134. A compound of formula (I), or a compound according to any one of Embodiments 1 to 133, or a pharmaceutically acceptable salt thereof, wherein L 2 Is a bond or a straight chain or branched chain C 1- C3 alkylene.

[0483] Embodiment 135. A compound of formula (I), or a compound according to any one of Embodiments 1 to 133, or a pharmaceutically acceptable salt thereof, wherein L 2 It is a bond, -CH2- or -CH2CH2-.

[0484] Embodiment 136. A compound of formula (I), or a compound according to any one of Embodiments 1 to 133, or a pharmaceutically acceptable salt thereof, wherein L 2 It is a key.

[0485] Embodiment 137. A compound of formula (I), or a compound according to any one of Embodiments 1 to 136, or a pharmaceutically acceptable salt thereof, wherein L 3 Is a bond or a straight chain or branched chain C 1- C3 alkylene.

[0486] Embodiment 138. A compound of formula (I), or a compound according to any one of Embodiments 1 to 136, or a pharmaceutically acceptable salt thereof, wherein L 3 It is a bond, -CH2- or -CH2CH2-.

[0487] Embodiment 139. A compound of formula (I), or a compound according to any one of Embodiments 1 to 136, or a pharmaceutically acceptable salt thereof, wherein L 3 It is a key.

[0488] Embodiment 140. A compound of formula (I), or a compound according to any one of Embodiments 1 to 139, or a pharmaceutically acceptable salt thereof, wherein L 4 Is a bond or a straight chain or branched chain C 1- C3 alkylene.

[0489] Embodiment 141. A compound of formula (I), or a compound according to any one of Embodiments 1 to 139, or a pharmaceutically acceptable salt thereof, wherein L 4 It is a bond, -CH2- or -CH2CH2-.

[0490] Embodiment 142. A compound of formula (I), or a compound according to any one of Embodiments 1 to 139, or a pharmaceutically acceptable salt thereof, wherein L 4 It is a key.

[0491] Embodiment 143. A compound of formula (I), or a compound according to any one of Embodiments 1 to 142, wherein when W is an optionally substituted ring, L can be a C1-C4 straight or branched chain alkylene linker or bond.

[0492] Embodiment 144. A compound of formula (I), or a compound according to any one of Embodiments 1 to 142, wherein L is a C1-C4 straight or branched chain alkylene linker.

[0493] Embodiment 145. A compound of formula (I), or a compound according to any one of Embodiments 1 to 142, wherein L is -CH2- or -CH2CH2-.

[0494] Embodiment 146. A compound of formula (I), or a compound according to any one of Embodiments 1 to 142, wherein L is -CH2-.

[0495] Embodiment 147. A compound of formula (I), or a compound according to any one of Embodiments 1 to 111, wherein when W is an optionally substituted ring, L is a bond.

[0496] Embodiment 148. A compound of formula (I) having a structure of formula (II) or a pharmaceutically acceptable salt thereof,

[0497]

[0498] in

[0499] W is -SO2R 10 、-SO2NR 13 R 14 or -SO2NR 14 R 10 substituted cyclopropyl;

[0500] R 10 is selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, isobutyl, cyclopropyl and pyridyl; wherein said R 10 optionally substituted with 1 to 4 groups independently selected from methyl, ethyl, -OH, -NH2, -CH2OH and -CH2NH2;

[0501] L is a C1-C4 straight or branched alkylene linker;

[0502] R 1 Selected from H and C 1- C3 alkyl;

[0503] R 2 It is H;

[0504] t is 0 and R 3 does not exist;

[0505] R 4 It is H, C 1- C3 alkyl or C3 substituted by 1 to 2 groups independently selected from -OH and methyl 1- C3 alkyl;

[0506] Each R 13 and R 14 Independently selected from H and C 1-4 alkyl;

[0507] And R B is optionally replaced by 1 to 3 R 5 phenyl substituted with a group; and each R 5 are independently halogen, -CN, C 1- C3 alkoxy or C 1- C3 alkyl.

[0508] Embodiment 149. A compound of formula (I) having the structure of formula (II) or a pharmaceutically acceptable salt thereof,

[0509]

[0510] in

[0511] W is -SO2R 10 or -SO2NR 14 R 10 substituted cyclopropyl;

[0512] R 10 is selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, cyclopropyl and pyridyl; wherein said R 10 optionally substituted with 1 to 2 groups independently selected from methyl, -OH, -NH2, -CH2OH and -CH2NH2;

[0513] L is -CH2- or -CH2CH2;

[0514] R 1 Selected from H and C 1- C3 alkyl;

[0515] R 2 It is H;

[0516] t is 0 and R 3 does not exist;

[0517] R 4 It is H, C 1- C3 alkyl or C3 substituted by 1 to 2 groups independently selected from -OH and methyl 1- C3 alkyl;

[0518] R 14 It is H;

[0519] And R B is optionally replaced by 1 R 5 phenyl substituted with a group; and R 5 is halo or -CN. Embodiment 150. A compound of formula (I) having a structure of formula (II) or a pharmaceutically acceptable salt thereof,

[0520]

[0521] in

[0522] W is -SO2R 10 or -SO2NR 14 R 10 substituted cyclopropyl;

[0523] R10 is selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, cyclopropyl and pyridyl; wherein said R 10 optionally substituted with 1 to 2 groups independently selected from methyl, -OH, -NH2, -CH2OH and -CH2NH2;

[0524] L is –CH2-;

[0525] R 1 、R 2 and R 14 Each is hydrogen;

[0526] t is 0 and R 3 does not exist;

[0527] R 4 It is H, C 1- C3 alkyl or C3 substituted by 1 to 2 groups independently selected from -OH and methyl 1- C3 alkyl;

[0528] And R B is optionally replaced by 1 R 5 phenyl substituted with a group; and R 5 is halogen or -CN.

[0529] Embodiment 151. A compound of formula (I), or a pharmaceutically acceptable salt thereof, selected from any one of Examples 1 to 242. This embodiment includes each of the Examples presented in the Biological Activity Data Table provided herein.

[0530] Embodiment 152. A compound of formula (I) or a pharmaceutically acceptable salt thereof selected from:

[0531] N-(4-cyanobenzyl)-6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-6,7-dihydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide;

[0532] N-(4-cyanobenzyl)-1-methyl-6-((1-(methylsulfonyl)cyclopropyl)methyl)-7-oxo-6,7-dihydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide;

[0533] N-(4-cyanobenzyl)-6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide;

[0534] N-(4-chlorobenzyl)-6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide;

[0535] 6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-N-(4-fluorobenzyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide;

[0536] N-(4-cyanobenzyl)-6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-N,1-dimethyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide;

[0537] N-((6-chloropyridin-3-yl)methyl)-6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide;

[0538] 6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-1-methyl-N-(4-methylbenzyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide;

[0539] N-(4-cyano-3-fluorobenzyl)-6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide;

[0540] N-((5-chlorothien-2-yl)methyl)-6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide;

[0541] N-(4-cyano-3-methylbenzyl)-6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide;

[0542] N-(4-cyano-2-methylbenzyl)-6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide;

[0543] N-(4-cyano-2-fluorobenzyl)-6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide;

[0544] N-((5-cyanopyridin-2-yl)methyl)-6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide;

[0545] N-(4-cyano-3-methoxybenzyl)-6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide;

[0546] (S)-N-(1-(4-cyanophenyl)ethyl)-6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide;

[0547] (R)-N-(1-(4-cyanophenyl)ethyl)-6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide;

[0548] (R)-N-(1-(4-chlorophenyl)-2-hydroxyethyl)-6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide;

[0549] (S)-N-(1-(4-chlorophenyl)-2-hydroxyethyl)-6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide;

[0550] N-(4-cyanobenzyl)-6-((1-(ethylsulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide;

[0551] N-(4-cyanobenzyl)-1-methyl-6-((1-(methylsulfonyl)cyclopropyl)methyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide;

[0552] N-(4-chlorobenzyl)-1-methyl-6-((1-(methylsulfonyl)cyclopropyl)methyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide;

[0553] N-(4-cyano-3-fluorobenzyl)-1-methyl-6-((1-(methylsulfonyl)cyclopropyl)methyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide;

[0554] 4-Cyanobenzyl 6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylate;

[0555] 4-(2-(6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridin-3-yl)-2-oxoethoxy)benzonitrile;

[0556] 4-((5-(6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridin-3-yl)-1,3,4- oxadiazol-2-yl)methyl)benzonitrile;

[0557] 4-((5-(6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridin-3-yl)-1,2,4- oxadiazol-3-yl)methyl)benzonitrile;

[0558] 4-((3-(6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridin-3-yl)-1,2,4- oxadiazol-5-yl)methyl)benzonitrile;

[0559] 4-((5-(6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridin-3-yl)-2H-tetrazol-2-yl)methyl)benzonitrile;

[0560] 4-((5-(6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridin-3-yl)-1H-tetrazol-1-yl)methyl)benzonitrile;

[0561] 4-(3-(6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridin-3-yl)-4,5-dihydroisoxo- oxazol-5-yl)benzonitrile;

[0562] (R)-4-(3-(6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridin-3-yl)-4,5-dihydroisoxo- oxazol-5-yl)benzonitrile;

[0563] (S)-4-(3-(6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridin-3-yl)-4,5-dihydroisoxo- oxazol-5-yl)benzonitrile;

[0564] 4-((3-(6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridin-3-yl)isothiazolinone oxazol-5-yl)methyl)benzonitrile;

[0565] 4-((4-(6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridin-3-yl)-1H-1,2,3-triazol-1-yl)methyl)benzonitrile;

[0566] 6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-3-(1-((4,4-difluorocyclohexyl)methyl)-1H-1,2,3-triazol-4-yl)-1-methyl-5,6-dihydro-1H-pyrazolo[3,4-c]pyridin-7(4H)-one;

[0567] N-(4-chlorophenoxy)-1-methyl-6-((1-((1-methylcyclopropyl)sulfonyl)cyclopropyl)methyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide;

[0568] N-(4-cyanobenzyl)-6-((1-((difluoromethyl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide;

[0569] N-(4-chlorobenzyl)-6-((1-((difluoromethyl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide;

[0570] N-(4-cyanobenzyl)-1,5-dimethyl-6-((1-(methylsulfonyl)cyclopropyl)methyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide;

[0571] (R)-N-(4-cyanobenzyl)-1,5-dimethyl-6-((1-(methylsulfonyl)cyclopropyl)methyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide;

[0572] (S)-N-(4-cyanobenzyl)-1,5-dimethyl-6-((1-(methylsulfonyl)cyclopropyl)methyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide;

[0573] N-(4-cyanobenzyl)-1-cyclopropyl-6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide;

[0574] N-(4-chlorobenzyl)-6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide;

[0575] N-(4-cyanobenzyl)-6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide;

[0576] 4-((8-((1-(methylsulfonyl)cyclopropyl)methyl)-1,7-dioxo-3,4,7,8,9,10-hexahydropyrido[3′,4′:3,4]pyrazolo[1,5-a]pyrazin-2(1H)-yl)methyl)benzonitrile;

[0577] N-(4-cyanobenzyl)-6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-1-((1-(hydroxymethyl)cyclopropyl)methyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide;

[0578] N-(4-cyanobenzyl)-1-((1-(hydroxymethyl)cyclopropyl)methyl)-6-((1-(methylsulfonyl)cyclopropyl)methyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide;

[0579] N-(4-cyanobenzyl)-6-((1-((1-hydroxy-2-methylpropan-2-yl)sulfonyl)cyclopropyl)methyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide;

[0580] N-(4-chlorobenzyl)-6-((1-((1-hydroxy-2-methylpropan-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide;

[0581] N-((6-chloropyridin-3-yl)methyl)-6-((1-((1-hydroxy-2-methylpropan-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide;

[0582] N-(4-cyanobenzyl)-6-((1-((1-hydroxy-2-methylpropan-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide;

[0583] N-(4-fluorobenzyl)-6-((1-((1-hydroxy-2-methylpropan-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide;

[0584] (S)-N-(1-(4-cyanophenyl)ethyl)-6-((1-((1-hydroxy-2-methylpropan-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide;

[0585] (R)-N-(1-(4-cyanophenyl)ethyl)-6-((1-((1-hydroxy-2-methylpropan-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide;

[0586] N-(4-cyanobenzyl)-6-((1-((1-hydroxy-2-methylpropan-2-yl-1,1-d2)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide;

[0587] 2-((1-((3-((4-cyanobenzyl)carbamoyl)-1-methyl-7-oxo-4,5-dihydro-1H-pyrazolo[3,4-c]pyridin-6(7H)-yl)methyl)cyclopropyl)sulfonyl)-2-methylpropyl acetate;

[0588] N-(4-cyanobenzyl)-6-((1-((1-(difluoromethoxy)-2-methylpropan-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide;

[0589] N-(4-cyanobenzyl)-6-((1-((2-cyanopropan-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide;

[0590] N-(4-cyanobenzyl)-6-((1-((1-(3-fluoroazetidin-1-yl)-2-methylpropan-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide;

[0591] N-(4-cyanobenzyl)-1-methyl-6-((1-((2-methyl-1-morpholinopropan-2-yl)sulfonyl)cyclopropyl)methyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide;

[0592] (R)-N-(4-cyanobenzyl)-6-((1-((1-(3-methoxypyrrolidin-1-yl)-2-methylpropan-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide;

[0593] 6-((1-((1-(6-oxa-3-azabicyclo[3.1.1]heptan-3-yl)-2-methylpropan-2-yl)sulfonyl)cyclopropyl)methyl)-N-(4-cyanobenzyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide;

[0594] 6-((1-((1-(2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-2-methylpropan-2-yl)sulfonyl)cyclopropyl)methyl)-N-(4-cyanobenzyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide;

[0595] N-(4-cyanobenzyl)-6-((1-((1-(3-hydroxyazetidin-1-yl)-2-methylpropan-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide;

[0596] N-(4-cyanobenzyl)-6-((1-((1-(3-methoxyazetidin-1-yl)-2-methylpropan-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide;

[0597] N-(4-cyanobenzyl)-1-methyl-6-((1-((2-methyl-1-(2-oxa-6-azaspiro[3.3]heptan-6-yl)propan-2-yl)sulfonyl)cyclopropyl)methyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide;

[0598] N-(4-cyanobenzyl)-6-((1-((1-(3-hydroxypyrrolidin-1-yl)-2-methylpropan-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide;

[0599] N-(4-cyanobenzyl)-6-((1-((1-((2-hydroxyethyl)amino)-2-methylpropan-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide;

[0600] 6-((1-((1-amino-2-methylpropan-2-yl)sulfonyl)cyclopropyl)methyl)-N-(4-cyanobenzyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide;

[0601] N-(4-cyanobenzyl)-6-((1-((1-formamido-2-methylpropan-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide;

[0602] 6-((1-((1-acetamido-2-methylpropan-2-yl)sulfonyl)cyclopropyl)methyl)-N-(4-cyanobenzyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide;

[0603] Methyl (2-((1-((3-((4-cyanobenzyl)carbamoyl)-1-methyl-7-oxo-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)methyl)cyclopropyl)sulfonyl)-2-methylpropyl)carbamate;

[0604] 6-((1-((1-(2-aminoacetamido)-2-methylpropan-2-yl)sulfonyl)cyclopropyl)methyl)-N-(4-cyanobenzyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide;

[0605] (R)-6-((1-((1-(2-aminopropionamido)-2-methylpropan-2-yl)sulfonyl)cyclopropyl)methyl)-N-(4-cyanobenzyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide;

[0606] (S)-6-((1-((1-(2-aminopropionamido)-2-methylpropan-2-yl)sulfonyl)cyclopropyl)methyl)-N-(4-cyanobenzyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide;

[0607] 6-((1-((1-(2-amino-2-methylpropionamido)-2-methylpropan-2-yl)sulfonyl)cyclopropyl)methyl)-N-(4-cyanobenzyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide;

[0608] N-(4-cyanobenzyl)-6-((1-((1-(2-(dimethylamino)acetamido)-2-methylpropan-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide;

[0609] N-(4-cyanobenzyl)-6-((1-((1-(1-fluoro-2-hydroxyethoxy)-2-methylpropan-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide;

[0610] (R)-N-(4-cyanobenzyl)-6-((1-((1-(1-fluoro-2-hydroxyethoxy)-2-methylpropan-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide;

[0611] (S)-N-(4-cyanobenzyl)-6-((1-((1-(1-fluoro-2-hydroxyethoxy)-2-methylpropan-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide;

[0612] (R)-6-((1-((1-(2-amino-1-fluoroethoxy)-2-methylpropan-2-yl)sulfonyl)cyclopropyl)methyl)-N-(4-cyanobenzyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide;

[0613] (S)-6-((1-((1-(2-amino-1-fluoroethoxy)-2-methylpropan-2-yl)sulfonyl)cyclopropyl)methyl)-N-(4-cyanobenzyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide;

[0614] N-(4-cyanobenzyl)-6-((1-((1-(1,1-difluoro-2-hydroxyethoxy)-2-methylpropan-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide;

[0615] 6-((1-((1-(2-amino-1,1-difluoroethoxy)-2-methylpropan-2-yl)sulfonyl)cyclopropyl)methyl)-N-(4-cyanobenzyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide;

[0616] N-(4-cyanobenzyl)-6-((1-((1-(2-hydroxy-2-methylpropoxy)-2-methylpropan-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide;

[0617] N-(4-cyanobenzyl)-6-((1-((1-(2-hydroxyethoxy)-2-methylpropan-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide;

[0618] N-(4-chlorobenzyl)-6-((1-((1-(2-hydroxyethoxy)-2-methylpropan-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide;

[0619] N-(4-cyanobenzyl)-6-((1-((1-(2-hydroxypropoxy)-2-methylpropan-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide;

[0620] (R)-N-(4-cyanobenzyl)-6-((1-((1-(2-hydroxypropoxy)-2-methylpropan-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide;

[0621] (S)-N-(4-cyanobenzyl)-6-((1-((1-(2-hydroxypropoxy)-2-methylpropan-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide;

[0622] 6-((1-((1-(2-aminoethoxy)-2-methylpropan-2-yl)sulfonyl)cyclopropyl)methyl)-N-(4-cyanobenzyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide;

[0623] 6-((1-((1-(2-aminoethoxy)-2-methylpropan-2-yl)sulfonyl)cyclopropyl)methyl)-N-(4-chlorobenzyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide;

[0624] 6-((1-((1-(2-aminoethoxy)-2-methylpropan-2-yl)sulfonyl)cyclopropyl)methyl)-N-(4-fluorobenzyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide;

[0625] 6-((1-((1-((2-aminoethoxy)methyl)cyclopropyl)sulfonyl)cyclopropyl)methyl)-N-(4-chlorobenzyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide;

[0626] 6-((1-((1-((2-aminoethoxy)methyl)cyclopropyl)sulfonyl)cyclopropyl)methyl)-N-(4-cyanobenzyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide;

[0627] (R)-6-((1-((1-(2-aminopropoxy)-2-methylpropan-2-yl)sulfonyl)cyclopropyl)methyl)-N-(4-chlorobenzyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide;

[0628] (S)-6-((1-((1-(2-aminopropoxy)-2-methylpropan-2-yl)sulfonyl)cyclopropyl)methyl)-N-(4-chlorobenzyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide;

[0629] (R)-6-((1-((1-(2-aminopropoxy)-2-methylpropan-2-yl)sulfonyl)cyclopropyl)methyl)-N-(4-cyanobenzyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide;

[0630] (S)-6-((1-((1-(2-aminopropoxy)-2-methylpropan-2-yl)sulfonyl)cyclopropyl)methyl)-N-(4-cyanobenzyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide;

[0631] N-(4-cyanobenzyl)-1-methyl-6-((1-((2-methyl-1-(2-(methylamino)ethoxy)propan-2-yl)sulfonyl)cyclopropyl)methyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide;

[0632] 6-((1-((1-(azetidin-3-yloxy)-2-methylpropan-2-yl)sulfonyl)cyclopropyl)methyl)-N-(4-cyanobenzyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide;

[0633] 6-((1-((1-(2-amino-2-methylpropoxy)-2-methylpropan-2-yl)sulfonyl)cyclopropyl)methyl)-N-(4-cyanobenzyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide;

[0634] N-(4-cyanobenzyl)-6-((1-((1-(2-(dimethylamino)ethoxy)-2-methylpropan-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide;

[0635] 4-((4-(6-((1-((1-hydroxy-2-methylpropan-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridin-3-yl)-1H-1,2,3-triazol-1-yl)methyl)benzonitrile;

[0636] 4-(3-(6-((1-((1-hydroxy-2-methylpropane-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridin-3-yl)-4,5-dihydroisoxo- oxazol-5-yl)benzonitrile;

[0637] (R)-4-(3-(6-((1-((1-hydroxy-2-methylpropane-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridin-3-yl)-4,5-dihydroisoxo- oxazol-5-yl)benzonitrile;

[0638] (S)-4-(3-(6-((1-((1-hydroxy-2-methylpropane-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridin-3-yl)-4,5-dihydroisoxo- oxazol-5-yl)benzonitrile;

[0639] 6-((1-((1-amino-2-methyl-1-oxopropan-2-yl)sulfonyl)cyclopropyl)methyl)-N-(4-chlorobenzyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide;

[0640] N-(4-chlorobenzyl)-1-methyl-6-((1-((2-methyl-1-(methylamino)-1-oxopropan-2-yl)sulfonyl)cyclopropyl)methyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide;

[0641] (R)-N-(4-cyanobenzyl)-1-methyl-6-((1-((2-(3-methyl-4,5-dihydroisothiazolinone) oxazol-5-yl)propan-2-yl)sulfonyl)cyclopropyl)methyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide;

[0642] (S)-N-(4-Cyanobenzyl)-1-methyl-6-((1-((2-(3-methyl-4,5-dihydroisothiazolinone) oxazol-5-yl)propan-2-yl)sulfonyl)cyclopropyl)methyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide;

[0643] N-(4-cyanobenzyl)-6-((1-((4-hydroxy-2-methylbutan-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide;

[0644] N-(4-cyanobenzyl)-6-((1-((4-hydroxy-2-methylpentan-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide;

[0645] (R)-N-(4-cyanobenzyl)-6-((1-((4-hydroxy-2-methylpentan-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide;

[0646] (S)-N-(4-cyanobenzyl)-6-((1-((4-hydroxy-2-methylpentan-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide;

[0647] N-(4-cyanobenzyl)-6-((1-((1-(2-hydroxyethyl)cyclopropyl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide;

[0648] N-(4-cyanobenzyl)-6-((1-((2-hydroxy-2-methylpropyl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide;

[0649] N-(4-cyanobenzyl)-6-((1-(((1s,3s)-3-hydroxycyclobutyl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide;

[0650] N-(4-cyanobenzyl)-6-((1-(((1r,3r)-3-hydroxycyclobutyl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide;

[0651] N-(4-chlorobenzyl)-1-methyl-7-oxo-6-((1-sulfamoylcyclopropyl)methyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide;

[0652] (E)-N-(4-chlorobenzyl)-6-((1-(N-((dimethylamino)methylene)sulfamoyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide;

[0653] N-(4-cyanobenzyl)-1-methyl-6-((1-(N-methylsulfamoyl)cyclopropyl)methyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide;

[0654] N-(4-cyanobenzyl)-1-methyl-6-((1-(morpholinylsulfonyl)cyclopropyl)methyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide;

[0655] N-(4-cyanobenzyl)-6-((1-((4-hydroxypiperidin-1-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide;

[0656] (R)-N-(4-cyanobenzyl)-6-((1-((3-hydroxypyrrolidin-1-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide;

[0657] (S)-N-(4-cyanobenzyl)-6-((1-((3-hydroxypyrrolidin-1-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide;

[0658] N-(4-cyanobenzyl)-6-((1-((3-hydroxyazetidin-1-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide;

[0659] N-(4-cyanobenzyl)-6-((1-(N-cyclopropylsulfamoyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide;

[0660] (S)-N-(4-cyanobenzyl)-6-((1-((3-hydroxy-3-methylpyrrolidin-1-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide;

[0661] (R)-N-(4-cyanobenzyl)-6-((1-((3-hydroxy-3-methylpyrrolidin-1-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide;

[0662] N-(4-cyanobenzyl)-1-methyl-6-((1-(N-(oxetan-3-yl)sulfamoyl)cyclopropyl)methyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide;

[0663] N-(4-cyanobenzyl)-1-methyl-7-oxo-6-((1-(piperazin-1-ylsulfonyl)cyclopropyl)methyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide;

[0664] 6-((1-(N-(3-aminopropyl)sulfamoyl)cyclopropyl)methyl)-N-(4-cyanobenzyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide;

[0665] 6-((1-(N-(2-aminoethyl)sulfamoyl)cyclopropyl)methyl)-N-(4-cyanobenzyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide;

[0666] N-(4-cyanobenzyl)-1-methyl-6-((1-((4-methylpiperazin-1-yl)sulfonyl)cyclopropyl)methyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide;

[0667] N-(4-cyanobenzyl)-1-methyl-7-oxo-6-((1-(N-(piperidin-4-yl)sulfamoyl)cyclopropyl)methyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide;

[0668] 6-((1-((4-aminopiperidin-1-yl)sulfonyl)cyclopropyl)methyl)-N-(4-cyanobenzyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide;

[0669] 6-((1-(((3R,4R)-3-amino-4-hydroxypyrrolidin-1-yl)sulfonyl)cyclopropyl)methyl)-N-(4-cyanobenzyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide;

[0670] 6-((1-(((3S,4S)-3-amino-4-hydroxypyrrolidin-1-yl)sulfonyl)cyclopropyl)methyl)-N-(4-cyanobenzyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide;

[0671] (R)-6-((1-((3-aminopyrrolidin-1-yl)sulfonyl)cyclopropyl)methyl)-N-(4-cyanobenzyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide;

[0672] (S)-6-((1-((3-aminopyrrolidin-1-yl)sulfonyl)cyclopropyl)methyl)-N-(4-cyanobenzyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide;

[0673] N-(4-chlorobenzyl)-6-((1-(N-(2-hydroxyethyl)sulfamoyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide;

[0674] N-(4-chlorobenzyl)-6-((1-(N-(2-hydroxyethyl)-N-methylsulfamoyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide;

[0675] N-(4-cyanobenzyl)-6-((1-(N-(2-hydroxyethyl)sulfamoyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide;

[0676] N-(4-cyanobenzyl)-6-((1-(N-(2-hydroxyethyl)-N-methylsulfamoyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide;

[0677] N-(4-cyanobenzyl)-6-((1-(N-(1,3-dihydroxypropan-2-yl)-N-methylsulfamoyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide;

[0678] N-(4-chlorobenzyl)-6-((1-(N-(1-hydroxy-2-methylpropan-2-yl)sulfamoyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide;

[0679] N-(4-cyanobenzyl)-6-((1-(N-(1-hydroxy-2-methylpropan-2-yl)sulfamoyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide;

[0680] N-(4-chlorobenzyl)-6-((1-((3-hydroxyazetidin-1-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide;

[0681] N-(4-chlorobenzyl)-1-methyl-6-((1-(N-methylsulfamoyl)cyclopropyl)methyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide;

[0682] N-(4-chlorobenzyl)-6-((1-(N-(2-hydroxy-2-methylpropyl)sulfamoyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide;

[0683] N-(4-chlorobenzyl)-6-((1-(N-(1,3-dihydroxy-2-methylpropan-2-yl)sulfamoyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide;

[0684] N-(4-chlorobenzyl)-6-((1-(N-(1,3-dihydroxy-2-methylpropan-2-yl)-N-methylsulfamoyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide;

[0685] N-(4-cyanobenzyl)-1-methyl-7-oxo-6-((1-(N-(pyridin-2-yl)sulfamoyl)cyclopropyl)methyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide;

[0686] N-(4-cyanobenzyl)-1-methyl-6-((1-(N-(1-methyl-1H-pyrazol-3-yl)sulfamoyl)cyclopropyl)methyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide;

[0687] N-(4-cyanobenzyl)-1-methyl-6-((1-(N-(6-methylpyridin-2-yl)sulfamoyl)cyclopropyl)methyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide;

[0688] N-(4-chlorobenzyl)-1-methyl-7-oxo-6-((1-(N-(pyridin-2-yl)sulfamoyl)cyclopropyl)methyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide;

[0689] N-(4-cyanobenzyl)-6-((1-(N-(3-methoxypyridin-2-yl)sulfamoyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide;

[0690] N-(4-cyanobenzyl)-6-((1-(N-(3-methoxy-6-methylpyridin-2-yl)sulfamoyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide;

[0691] N-(4-cyanobenzyl)-1-methyl-6-((1-(N-(2-methylpyridin-3-yl)sulfamoyl)cyclopropyl)methyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide;

[0692] N-(4-cyanobenzyl)-6-((1-(N-(2-methoxypyridin-3-yl)sulfamoyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide;

[0693] N-(4-cyanobenzyl)-6-((1-(N-(6-methoxypyridin-2-yl)sulfamoyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide;

[0694] N-(4-cyanobenzyl)-1-methyl-6-((1-(N-(3-methylpyridin-2-yl)sulfamoyl)cyclopropyl)methyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide;

[0695] N-(4-cyanobenzyl)-1-methyl-6-((1-(N-(5-methylisothiazolinone) oxazol-3-yl)sulfamoyl)cyclopropyl)methyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide;

[0696] N-(4-chlorobenzyl)-1-methyl-6-((1-(N-(5-methylisothiazolyl) oxazol-3-yl)sulfamoyl)cyclopropyl)methyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide;

[0697] N-(4-cyanobenzyl)-6-((1-(N-(5-cyclopropylisothiazolinone)) oxazol-3-yl)sulfamoyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide;

[0698] N-(4-cyanobenzyl)-1-methyl-6-((1-(oxetan-3-ylsulfonyl)cyclopropyl)methyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide;

[0699] N-(4-cyanobenzyl)-1-methyl-7-oxo-6-((1-((tetrahydro-2H-pyran-4-yl)sulfonyl)cyclopropyl)methyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide;

[0700] (S)-N-(4-cyanobenzyl)-1-methyl-7-oxo-6-((1-((tetrahydrofuran-3-yl)sulfonyl)cyclopropyl)methyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide;

[0701] (R)-N-(4-cyanobenzyl)-1-methyl-7-oxo-6-((1-((tetrahydrofuran-3-yl)sulfonyl)cyclopropyl)methyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide;

[0702] N-(4-cyanobenzyl)-1-methyl-6-((1-((3-methyloxetan-3-yl)sulfonyl)cyclopropyl)methyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide;

[0703] N-(4-cyanobenzyl)-6-((1-((3-(hydroxymethyl)oxetan-3-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide;

[0704] 6-((1-((3-(aminomethyl)oxetan-3-yl)sulfonyl)cyclopropyl)methyl)-N-(4-cyanobenzyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide;

[0705] N-(4-chlorobenzyl)-6-((1-((1,3-dihydroxy-2-methylpropan-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide;

[0706] N-(4-cyanobenzyl)-6-((1-((1,3-dihydroxy-2-methylpropan-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide;

[0707] (S)-N-(1-(4-chlorophenyl)ethyl)-6-((1-((1,3-dihydroxy-2-methylpropan-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide;

[0708] (R)-N-(1-(4-chlorophenyl)ethyl)-6-((1-((1,3-dihydroxy-2-methylpropan-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide;

[0709] N-(4-cyanobenzyl)-6-((1-((1,3-dimethoxy-2-methylpropan-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide;

[0710] N-(4-cyanobenzyl)-6-((1-((1-hydroxy-3-methoxy-2-methylpropan-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide;

[0711] (R)-N-(4-cyanobenzyl)-6-((1-((1-hydroxy-3-methoxy-2-methylpropan-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide;

[0712] (S)-N-(4-cyanobenzyl)-6-((1-((1-hydroxy-3-methoxy-2-methylpropan-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide;

[0713] 6-((1-((1-amino-3-hydroxy-2-methylpropan-2-yl)sulfonyl)cyclopropyl)methyl)-N-(4-cyanobenzyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide;

[0714] (S)-6-((1-((1-amino-3-hydroxy-2-methylpropan-2-yl)sulfonyl)cyclopropyl)methyl)-N-(4-cyanobenzyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide;

[0715] (R)-6-((1-((1-amino-3-hydroxy-2-methylpropan-2-yl)sulfonyl)cyclopropyl)methyl)-N-(4-cyanobenzyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide;

[0716] 6-((1-((1-amino-3-hydroxy-2-methylpropan-2-yl)sulfonyl)cyclopropyl)methyl)-N-(4-chlorobenzyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide;

[0717] (S)-6-((1-((1-amino-3-hydroxy-2-methylpropan-2-yl)sulfonyl)cyclopropyl)methyl)-N-(4-chlorobenzyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide;

[0718] (R)-6-((1-((1-amino-3-hydroxy-2-methylpropan-2-yl)sulfonyl)cyclopropyl)methyl)-N-(4-chlorobenzyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide;

[0719] N-(4-chlorobenzyl)-6-((1-((3,4-dihydroxy-2-methylbutan-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide;

[0720] (S)-N-(4-chlorobenzyl)-6-((1-((3,4-dihydroxy-2-methylbutan-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide;

[0721] (R)-N-(4-chlorobenzyl)-6-((1-((3,4-dihydroxy-2-methylbutan-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide;

[0722] (S)-N-(4-cyanobenzyl)-6-((1-((3,4-dihydroxy-2-methylbutan-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide;

[0723] (R)-N-(4-cyanobenzyl)-6-((1-((3,4-dihydroxy-2-methylbutan-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide;

[0724] (S)-N-(4-cyanobenzyl)-6-((1-((1-(1,2-dihydroxyethyl)cyclopropyl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide;

[0725] (R)-N-(4-cyanobenzyl)-6-((1-((1-(1,2-dihydroxyethyl)cyclopropyl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide;

[0726] (S)-N-(4-chlorobenzyl)-6-((1-((1-(1,2-dihydroxyethyl)cyclopropyl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide;

[0727] (R)-N-(4-chlorobenzyl)-6-((1-((1-(1,2-dihydroxyethyl)cyclopropyl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide;

[0728] (R)-6-((1-((4-amino-3-hydroxy-2-methylbutan-2-yl)sulfonyl)cyclopropyl)methyl)-N-(4-cyanobenzyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide;

[0729] (S)-6-((1-((4-amino-3-hydroxy-2-methylbutan-2-yl)sulfonyl)cyclopropyl)methyl)-N-(4-cyanobenzyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide;

[0730] (S)-6-((1-((4-amino-3-hydroxy-2-methylbutan-2-yl)sulfonyl)cyclopropyl)methyl)-N-(4-chlorobenzyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide;

[0731] (R)-6-((1-((4-amino-3-hydroxy-2-methylbutan-2-yl)sulfonyl)cyclopropyl)methyl)-N-(4-chlorobenzyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide;

[0732] (R)-N-(4-cyanobenzyl)-6-((1-((3-hydroxy-2-methyl-4-(methylamino)butan-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide;

[0733] (S)-N-(4-cyanobenzyl)-6-((1-((3-hydroxy-2-methyl-4-(methylamino)butan-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide;

[0734] (R)-N-(4-chlorobenzyl)-6-((1-((3-hydroxy-2-methyl-4-(methylamino)butan-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide;

[0735] (S)-N-(4-chlorobenzyl)-6-((1-((3-hydroxy-2-methyl-4-(methylamino)butan-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide;

[0736] (R)-N-(4-chlorobenzyl)-6-((1-((4-(dimethylamino)-3-hydroxy-2-methylbutan-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide;

[0737] (S)-N-(4-chlorobenzyl)-6-((1-((4-(dimethylamino)-3-hydroxy-2-methylbutan-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide;

[0738] 6-((1-((1-(2-amino-1-hydroxyethyl)cyclopropyl)sulfonyl)cyclopropyl)methyl)-N-(4-cyanobenzyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide;

[0739] 6-((1-((1-(2-amino-1-hydroxyethyl)cyclopropyl)sulfonyl)cyclopropyl)methyl)-N-(4-chlorobenzyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide;

[0740] 6-((1-((4-amino-3-hydroxy-2,4-dimethylpentan-2-yl)sulfonyl)cyclopropyl)methyl)-N-(4-cyanobenzyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide;

[0741] (R)-6-((1-((4-amino-3-hydroxy-2,4-dimethylpentan-2-yl)sulfonyl)cyclopropyl)methyl)-N-(4-cyanobenzyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide;

[0742] (S)-6-((1-((4-amino-3-hydroxy-2,4-dimethylpentan-2-yl)sulfonyl)cyclopropyl)methyl)-N-(4-cyanobenzyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide;

[0743] (R)-6-((1-((3-amino-4-hydroxy-2-methylbutan-2-yl)sulfonyl)cyclopropyl)methyl)-N-(4-cyanobenzyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide;

[0744] (R)-6-((1-((3-amino-4-hydroxy-2-methylbutan-2-yl)sulfonyl)cyclopropyl)methyl)-N-(4-chlorobenzyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide hydrochloride;

[0745] ((1-((3-((4-chlorobenzyl)carbamoyl)-1-methyl-7-oxo-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)methyl)cyclopropyl)sulfonyl)-D-valine;

[0746] N-(4-cyanobenzyl)-6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-1-(2-hydroxyethyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide;

[0747] N-(4-cyanobenzyl)-1-(2-hydroxyethyl)-6-((1-((1-methylcyclopropyl)sulfonyl)cyclopropyl)methyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide;

[0748] N-(4-chlorobenzyl)-6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-1-(2-hydroxyethyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide;

[0749] N-(4-chlorobenzyl)-1-(2-hydroxyethyl)-6-((1-(methylsulfonyl)cyclopropyl)methyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide;

[0750] N-(4-cyanobenzyl)-6-((1-((1-hydroxy-2-methylpropan-2-yl)sulfonyl)cyclopropyl)methyl)-1-(2-hydroxyethyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide;

[0751] N-(4-chlorobenzyl)-6-((1-((1-hydroxy-2-methylpropan-2-yl)sulfonyl)cyclopropyl)methyl)-1-(2-hydroxyethyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide;

[0752] N-(4-chlorobenzyl)-1-(2-(2-hydroxyethoxy)ethyl)-6-((1-((1-methylcyclopropyl)sulfonyl)cyclopropyl)methyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide;

[0753] 1-(2-(2-aminoethoxy)ethyl)-N-(4-chlorobenzyl)-6-((1-((1-methylcyclopropyl)sulfonyl)cyclopropyl)methyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide;

[0754] N-(4-cyanobenzyl)-6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-1-(2-hydroxypropyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide;

[0755] (S)-N-(4-cyanobenzyl)-6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-1-(2-hydroxypropyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide;

[0756] (R)-N-(4-cyanobenzyl)-6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-1-(2-hydroxypropyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide;

[0757] N-(4-cyanobenzyl)-6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-7-oxo-1-(2-oxobutyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide;

[0758] N-(4-cyanobenzyl)-6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-1-((1-hydroxycyclopropyl)methyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide;

[0759] N-(4-chlorobenzyl)-6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-1-(2-hydroxy-2-methylpropyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide;

[0760] N-(4-cyanobenzyl)-6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-1-(2-hydroxy-2-methylpropyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide;

[0761] N-(4-chlorobenzyl)-1-(2-hydroxy-2-methylpropyl)-6-((1-(methylsulfonyl)cyclopropyl)methyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide;

[0762] N-(4-cyanobenzyl)-1-(2-hydroxy-2-methylpropyl)-6-((1-(methylsulfonyl)cyclopropyl)methyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide;

[0763] N-(4-cyanobenzyl)-6-((1-(ethylsulfonyl)cyclopropyl)methyl)-1-(2-hydroxy-2-methylpropyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide;

[0764] N-(4-cyanobenzyl)-1-(2-hydroxy-2-methylpropyl)-6-((1-((1-(hydroxymethyl)cyclopropyl)sulfonyl)cyclopropyl)methyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide;

[0765] N-(4-cyanobenzyl)-6-((1-((1-hydroxy-2-methylpropan-2-yl)sulfonyl)cyclopropyl)methyl)-1-(2-hydroxy-2-methylpropyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide;

[0766] N-(4-cyanobenzyl)-6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-1-(3-hydroxypropyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide;

[0767] N-(4-cyanobenzyl)-1-(3-hydroxypropyl)-6-((1-((1-methylcyclopropyl)sulfonyl)cyclopropyl)methyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide;

[0768] Ethylene glycol macrocyclic N-(4-cyanobenzyl)carboxamide;

[0769] Ethylene glycol macrocyclic N-(4-chlorobenzyl)formamide;

[0770] lactam macrocyclic N-(4-cyanobenzyl)carboxamide; and

[0771] Amine macrocycle N-(4-cyanobenzyl)carboxamide.

[0772] Embodiment 153. A compound of formula (I) or a pharmaceutically acceptable salt thereof selected from:

[0773] N-(4-chlorobenzyl)-6-((1-((1,3-dihydroxy-2-methylpropan-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide;

[0774] N-(4-cyanobenzyl)-6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-1-(2-hydroxyethyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide;

[0775] N-(4-cyanobenzyl)-6-((1-((1,3-dihydroxy-2-methylpropan-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide;

[0776] (R)-6-((1-((4-amino-3-hydroxy-2-methylbutan-2-yl)sulfonyl)cyclopropyl)methyl)-N-(4-cyanobenzyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide;

[0777] (S)-6-((1-((4-amino-3-hydroxy-2-methylbutan-2-yl)sulfonyl)cyclopropyl)methyl)-N-(4-cyanobenzyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide;

[0778] N-(4-cyanobenzyl)-1-(2-hydroxyethyl)-6-((1-((1-methylcyclopropyl)sulfonyl)cyclopropyl)methyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide;

[0779] N-(4-cyanobenzyl)-6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-1-(2-hydroxy-2-methylpropyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide;

[0780] N-(4-cyanobenzyl)-6-((1-((1-hydroxy-2-methylpropan-2-yl)sulfonyl)cyclopropyl)methyl)-1-(2-hydroxy-2-methylpropyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide;

[0781] N-(4-chlorobenzyl)-6-((1-((1-hydroxy-2-methylpropan-2-yl)sulfonyl)cyclopropyl)methyl)-1-(2-hydroxyethyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide;

[0782] (R)-N-(4-cyanobenzyl)-6-((1-((3,4-dihydroxy-2-methylbutan-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide;

[0783] N-(4-cyanobenzyl)-1-(2-hydroxy-2-methylpropyl)-6-((1-((1-(hydroxymethyl)cyclopropyl)sulfonyl)cyclopropyl)methyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide;

[0784] as well as

[0785] N-(4-cyanobenzyl)-1-methyl-7-oxo-6-((1-(N-(pyridin-2-yl)sulfamoyl)cyclopropyl)methyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide.

[0786] Embodiment 154. A compound of formula (II) according to any one of embodiments 21 to 23, or a pharmaceutically acceptable salt thereof, wherein the compound has the structure of formula (IIa):

[0787]

[0788] Among them, L, R 1 、R 2 、R B 、R 4 、R 10 、R 11 and R 12 As defined in formula (I);

[0789] or L, R 1 、R 2 、R B 、R 4 、R 10 、R 11 and R 12 As defined in embodiment 21;

[0790] or L, R 1 、R 2 、R B 、R 4 、R 10 、R 11 and R 12 As defined in embodiment 22;

[0791] or L, R 1 、R 2 、R B 、R 4 、R 10 、R 11 and R 12 As defined in embodiment 23.

[0792] Embodiment 155. A compound of formula (II) according to any one of embodiments 21 to 23, or a pharmaceutically acceptable salt thereof, wherein the compound has the structure of formula (IIb):

[0793]

[0794] Among them, L, R 1 、R 4 、R 5 、R 10 、R 11 and R 12 As defined in formula (I);

[0795] or L, R 1 、R 4 、R 5 、R 10 、R 11 and R 12 As defined in embodiment 21;

[0796] or L, R 1 、R 4 、R 5 、R 10 、R 11 and R 12 As defined in embodiment 22;

[0797] or L, R 1 、R 4 、R 5 、R 10 、R 11 and R 12 As defined in embodiment 23.

[0798] Embodiment 156. The compound according to embodiment 155, or a pharmaceutically acceptable salt thereof, wherein R 5 It is –CN or a halide.

[0799] Embodiment 157. A compound according to any one of Embodiments 154 to 156, or a pharmaceutically acceptable salt thereof, wherein R 4 It's methyl.

[0800] Embodiment 158. A compound of formula (IVa) having the structure of formula (IVd)

[0801]

[0802] Among them, L, R 1 、R 5 and R 10 As defined in formula (I);

[0803] or L, R 1 、R 5 and R 10 As defined in embodiment 22;

[0804] or L, R 1 、R 4 、R 5 、R 10 、R 11 and R 12 As defined in embodiment 23.

[0805] Embodiment 159. The compound according to embodiment 158, or a pharmaceutically acceptable salt thereof, wherein R 5 It is –CN or a halide.

[0806] Embodiment 160. A compound of formula (Vc) according to embodiment 30, or a pharmaceutically acceptable salt thereof, wherein each R 5 is a halogen group, and R 10 It is two-L 3 OH-substituted C 1- C5 alkyl, of which L 3 As defined in formula (I).

[0807] Embodiment 161. A compound of formula (Va) according to embodiment 30, or a pharmaceutically acceptable salt thereof, wherein R 5 is a halogen group, and R 10 It is two-L 3 OH-substituted C 1- C5 alkyl, of which L 3 As defined in formula (I).

[0808] Embodiment 162. A compound of formula (Va) according to embodiment 30, or a pharmaceutically acceptable salt thereof, wherein R 5 is -CN, and R 10 It is two-L 3 OH-substituted C 1- C5 alkyl, of which L 3 As defined in formula (I).

[0809] Embodiment 163. A compound of formula (I), or a pharmaceutically acceptable salt thereof, having a structure of formula (VIII),

[0810]

[0811] where R 10 Selected from:

[0812] Phenyl, which is unsubstituted or substituted with one -CN;

[0813] unsubstituted or replaced by a single moiety selected from -L 3 Halogen, -L 3 OH or -L 3 NHC(=O)R 13 A 6-membered heteroaryl group substituted with 1-2 heteroatoms, each heteroatom being N, wherein L 3 is a bond or a linear or branched C1-C3 alkylene group, and R 13 is C1-C4 alkyl; and

[0814] By a –L 3 C(=O)NR13R14 or 2 or 3 –L 3 OH-substituted C1-C5 alkyl, wherein L 3 is a bond or a straight or branched C1-C3 alkylene group, R 13 is H or C1-C4 alkyl, and R 14 is H or C1-C4 alkyl.

[0815] Embodiment 164. The compound according to embodiment 163, or a pharmaceutically acceptable salt thereof, wherein L 3 Yes key.

[0816] Embodiment 165. The compound according to embodiment 163 or 164, or a pharmaceutically acceptable salt thereof, wherein R 10 is an unsubstituted 6-membered heteroaryl group having 1-2 heteroatoms, each of which is nitrogen.

[0817] Embodiment 166. A compound according to any one of Embodiments 163 to 165, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from: N-(4-cyanobenzyl)-6-((1-(N-(6-(hydroxymethyl)pyridin-2-yl)sulfamoyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide;

[0818] 6-((1-(N-(6-acetylaminopyridin-2-yl)sulfamoyl)cyclopropyl)methyl)-N-(4-cyanobenzyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide;

[0819] N-(4-cyanobenzyl)-1-methyl-7-oxo-6-((1-(N-(pyrazin-2-yl)sulfamoyl)cyclopropyl)methyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide;

[0820] N-(4-cyanobenzyl)-1-methyl-7-oxo-6-((1-(N-phenylsulfamoyl)cyclopropyl)methyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide;

[0821] N-(4-cyanobenzyl)-6-((1-(N-(3-fluoropyridin-2-yl)sulfamoyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide;

[0822] N-(4-cyanobenzyl)-6-((1-(N-(2-cyanophenyl)sulfamoyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide;

[0823] N-(4-chloro-3-fluorobenzyl)-6-((1-((3,4-dihydroxy-2-methylbutan-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide;

[0824] (R)-N-(4-chloro-3-fluorobenzyl)-6-((1-((3,4-dihydroxy-2-methylbutan-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide;

[0825] (S)-N-(4-chloro-3-fluorobenzyl)-6-((1-((3,4-dihydroxy-2-methylbutan-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide;

[0826] N-(4-cyanobenzyl)-6-((1-((3,4-dihydroxy-2-methylbutan-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide;

[0827] 6-((1-(N-(4-amino-2-methyl-4-oxobutan-2-yl)sulfamoyl)cyclopropyl)methyl)-N-(4-cyanobenzyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide;

[0828] N-(4-cyanobenzyl)-6-((1-(N-(3-(dimethylamino)-3-oxopropyl)sulfamoyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide;

[0829] N-(4-cyanobenzyl)-6-((1-(((3S,4S)-3,4-dihydroxypyrrolidin-1-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide;

[0830] N-(4-cyanobenzyl)-1-methyl-7-oxo-6-((1-(N-(1-(pyridazin-3-yl)cyclopropyl)sulfamoyl)cyclopropyl)methyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide;

[0831] N-(4-cyanobenzyl)-6-((1-(N-(1,3-dihydroxy-2-methylpropan-2-yl)sulfamoyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide;

[0832] N-(4-cyanobenzyl)-1-methyl-7-oxo-6-((1-(N-(pyrimidin-2-ylmethyl)sulfamoyl)cyclopropyl)methyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide;

[0833] N-(4-cyanobenzyl)-1-methyl-7-oxo-6-((1-(N-(1-(pyrazin-2-yl)ethyl)sulfamoyl)cyclopropyl)methyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide;

[0834] N-(4-cyanobenzyl)-1-methyl-7-oxo-6-((1-(N-(pyrazin-2-ylmethyl)sulfamoyl)cyclopropyl)methyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide;

[0835] N-(4-cyanobenzyl)-6-((1-(N-(1,3-dihydroxy-2-(hydroxymethyl)propan-2-yl)sulfamoyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide; and

[0836] N-(4-cyanobenzyl)-1-methyl-7-oxo-6-((1-sulfamoylcyclopropyl)methyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide.

[0837] Embodiment 167. A compound according to any one of Embodiments 1 to 150, or a pharmaceutically acceptable salt thereof, wherein R 4 is composed of 1 to 2 independently selected from -OH and R 10 A C2-C3 alkyl group substituted with a group.

[0838] Embodiment 168. A compound according to any one of claims 1 to 150 and 167, or a pharmaceutically acceptable salt thereof, wherein R 4 Substituted with -OH, and optionally substituted with methyl.

[0839] Embodiment 169. A compound according to any one of claims 1 to 150 and 167 to 168, or a pharmaceutically acceptable salt thereof, wherein W is L 2 SO2R 10 .

[0840] Embodiment 170. A compound according to any one of claims 1 to 150 and 167 to 169, or a pharmaceutically acceptable salt thereof, wherein L 2 is a key and R 10 It is a C1-C4 alkyl group substituted by 1 to 3 groups selected from C1-C4 alkyl and -OH.

[0841] Compounds of formula (VII) are novel and are useful as intermediates in the preparation of compounds of formula (I) to formula (VI) described herein.

[0842] Compounds of formula (VII) are novel and are useful as intermediates in the preparation of compounds of formula (VIII) described herein.

[0843] General synthesis procedures

[0844] The compounds of the present invention can be prepared by organic synthesis methods known to those of ordinary skill in the art, with reference to the following general synthetic schemes of the reactions hereinbelow and in more detail in the Examples.

[0845] All starting materials, building blocks, reagents, acids, bases, dehydrating agents, solvents and catalysts used in the synthesis of the compounds of the present invention are commercially available or can be prepared by organic synthesis methods known to those skilled in the art (Houben-Weyl 4th edition 1952, Methods of Organic Synthesis, Thieme, Vol. 21).

[0846] Within the scope of this text, only readily removable groups which are not a component of the specific desired end product of the compounds of the invention are designated as "protecting groups", unless the context indicates otherwise. Functional groups are protected by such protecting groups, the protecting groups themselves and their cleavage reactions being described, for example, in standard reference works, such as Science of Synthesis: Houben-Weyl Methods of Molecular Transformation. Georg Thieme Verlag, Stuttgart, Germany. 2005. 41627 pages (URL: http: / / www.science-of-synthesis.com (electronic version, Vol. 48)); JFW McOmie, "Protective Groups in Organic Chemistry", Plenum Press, London and New York 1973, TW Greene and PGM Wuts, "Protective Groups in Organic Synthesis", 3rd edition, Wiley, New York 1999, "The Peptides"; Vol. 3 (Editors: E. Gross and J. Meienhofer), Academic Press, London and New York 1981, "Methoden der Organischen Chemie" (Methods of Organic Chemistry), Houben Weyl, 4th edition, Vol. 15 / 1, Georg Thieme Verlag, Stuttgart 1974, H.-D. Jakubke and H. Jeschkeit, " Peptide, Protein" (Amino acids, Peptides, Proteins), Verlag Chemie, Weinheim, Deerfield Beach, and Basel 1982, and Jochen Lehmann, "Chemie der Kohlenhydrate: Monosaccharide und Derivate" (Chemistry of Carbohydrates: Monosaccharides and Derivatives), Georg Thieme Verlag, Stuttgart 1974. Protecting groups are characterized in that they can be easily removed (i.e., without undesired side reactions), for example, by solvolysis, reduction, photolysis, or alternatively under physiological conditions (e.g., by enzymatic cleavage).

[0847] The following provides general methods for synthesizing compounds of formula (I) in Schemes I to VI. Specifically, Schemes I to III show general methods 1 to 14 for synthesizing compounds of formula (I) wherein Z is W and LMC is absent, and wherein R 1 、R 2 、R 3 、R 4 、R 15 、R B , t, L and W are as defined herein for compounds of formula (I).

[0848] Plan I

[0849]

[0850] Scheme 1 shows General Methods 1 to 7 for the synthesis of compounds of formula (I) wherein X is and Y is a bond, -O- or Bicyclic intermediates (e.g., intermediate I-1) can be N-alkylated to attach the WL- moiety of interest, for example, where L is attached via -CH2-. WL-X1 represents a suitable alkylating agent for such a reaction, where X1 is a leaving group such as a halide (e.g., Br or I) or a sulfonic acid leaving group such as a mesylate, tosylate, or triflate. The WL- moiety may of course contain functional groups that can be further modified in the product of formula (I), such as hydroxyl groups or amine groups, for example in protected form, which can be deprotected and further derivatized.

[0851] R Ccan be a simple alkyl ester such as methyl, ethyl, propyl, isopropyl, tert-butyl or n-butyl; and if WL- contains an ester, then R C can be a different ester, such as a benzyl group which can be easily distinguished from the ester in WL-, so R C The selective hydrolysis can be used for the coupling reaction in Scheme 1. In some examples, R C is an ester that hydrolyzes under alkylation reaction conditions, possibly due to the presence of adventitious water or hydroxide; in other instances, a separate hydrolysis step is used, such as the addition of lithium hydroxide, sodium hydroxide, or potassium hydroxide and water. The resulting free carboxylate compound is then readily reacted with a molecule containing the desired R using standard amide bond forming conditions and appropriate reagents. B The suitable amine coupling of the group. This can be the direct amidation of carboxylic esters (method 1 and method 2), or it can be realized by carboxylic acid being converted into an activated intermediate (acyl chlorides, acyl anhydrides etc.) (method 4) as known in the art and illustrated by the accompanying examples. The example of the amide coupling reagent used in methods 1, 2, 4 and 5 includes but is not limited to EDCI, HATU, HBTU, TBTU and T3P. In addition, carboxylic acid can be converted into an activated intermediate (method 5), which undergoes subsequent etherification. Typical etherification occurs in the presence of alkali such as KCO3 or KOH using alkyl halides (Cl, Br, I).

[0852] Alternatively, the carboxylic acid is esterified using Lewis acid or Bronsted acid catalyzed esterification of the carboxylic acid with an alcohol (Method 6), although examples of other esterification reagents include diethyl azodicarboxylate (DEAD) or diisopropyl azodicarboxylate (DIAD), di-tert-butyl azodicarboxylate (DTBAD), dicyclohexylcarbodiimide (DCC) / 4-N,N-dimethylaminopyridine (DMAP), and 2,4,6-trichlorobenzoyl chloride / 4-N,N-dimethylaminopyridine (DMAP).

[0853] Finally, for R 4 is H and R 15 In compounds of formula (I) containing an alkyl halide moiety, the secondary amine on the pyrazolyl ring can be alkylated (Method 7) to form a third fused ring. 15 Hydroamination and amine alkylation of alcohols can be used when appropriate reactive groups are included.

[0854] Option II

[0855]

[0856] Scheme II shows a general method for synthesizing compounds of formula (I) wherein X is a 5-6 membered heteroaryl group and Y is Using the carboxylic acid intermediate described in Scheme (I), it is easy to obtain In method 8, the diazole is condensed with a carboxylic acid and then subjected to dehydration cyclization of the resulting diacylhydrazide intermediate. Alternatively, in method 9, the oxadiazole synthesis is carried out by condensation of a carboxylic acid and an amidine oxime followed by cyclization. Finally, in method 10, the carboxylic acid intermediate is converted to an amide and then to a nitrile, which is then used to form the amidinoxime intermediate. The oxadiazole is then formed by condensation of the carboxylic acid and amidinoxime followed by cyclization. The reagents used in such methods are known in the art and are illustrated by the accompanying examples.

[0857] Option III

[0858]

[0859] Scheme III shows a general method for synthesizing compounds of formula (I) wherein X is a 5-6 membered heteroaryl or a 5-6 membered heterocyclyl, and Y is a bond or Using the carboxylic acid intermediate or the corresponding ester intermediate described in Scheme (I), a product containing triazole, tetrazole, isocyanate, azole or dihydroisoxazole In method 11, the aldehyde intermediate formed from the ester is used to form a nitrile intermediate. Subsequent copper-catalyzed "click" chemistry using the nitrile intermediate and the azide intermediate leads to triazole formation. Additionally, in method 12, the aldehyde intermediate formed from the ester is used to form an oxime intermediate, which is subsequently converted to a carbonimido chloride derivative. The reaction of the carbonimido chloride derivative with an olefin yields a dihydroisoquinoline. Alternatively, the reaction of a carbonimido chloride derivative with a nitrile intermediate (Method 13) affords the isocyanate. Finally, in Method 14, the carboxylic acid intermediate is converted to an amide, followed by formation of a nitrile and subsequently a tetrazole intermediate, which is then N-alkylated using an alkyl halide.

[0860] Scheme IV shows a general method for synthesizing compounds of formula (I) wherein LMC is present and wherein R 1 、R 2 、R 3 、R 4 、R 15 、R B , t and L are as defined herein for compounds of formula (I).

[0861] Option IV

[0862]

[0863] In Scheme (IV), the amine-protected bicyclic intermediate described in Scheme (I) (e.g., intermediate I-1) is used to obtain the macrocyclic compound of Formula (I). Here, the bicyclic intermediate can be N-alkylated as described in Scheme I to attach the OH-ZL- moiety of interest, for example, where L is attached via -CH2-. The hydroxyl group of the OH-ZL group is alkylated to attach the linker moiety, which is further attached after amine deprotection by N-alkylation of the deprotected amine. The ester is converted to the corresponding carboxylic acid, which is then amidated with the desired amine intermediate.

[0864] Scheme V shows a general method for synthesizing compounds of formula (I) wherein LMC is present and wherein R 1 、R 2 、R 3 、R 4 、R 15 、R B , t and L are as defined herein for compounds of formula (I).

[0865] Plan V

[0866]

[0867] In Scheme (V), the amine-protected bicyclic intermediate described in Scheme (I) (e.g., intermediate I-1) is used to obtain the macrocyclic compound of Formula (I). Here, the bicyclic intermediate can be N-alkylated as described in Scheme I to attach the OH-ZL- moiety of interest, particularly where L is attached via -CH2-. The ester is then converted to the corresponding carboxylic acid, which is then amidated with the desired amine intermediate. After deprotection, the amine is alkylated to attach the linker, which is then activated with the azide moiety. The hydroxyl group of the OH-ZL group is converted to a carboxylic acid, which is then amidated via the azide moiety to attach the linker and complete the macrocycle formation.

[0868] Scheme VI shows a general method for synthesizing compounds of formula (I) wherein LMC is present and wherein R 1 、R 2 、R 3 、R 4 、R 15 、R B , t and L are as defined herein for compounds of formula (I).

[0869] Plan VI

[0870]

[0871] In Scheme (VI), the amine-protected bicyclic intermediate described in Scheme (I) (e.g., intermediate I-1) is used to obtain the macrocyclic compound of Formula (I). Here, the bicyclic intermediate can be N-alkylated as described in Scheme I to attach the OH-ZL- moiety of interest, for example, where L is attached via -CH2-. The ester is then converted to the corresponding carboxylic acid, which is then amidated with the desired amine intermediate. After deprotection, the amine is alkylated to attach the linker, which is then activated with the azide moiety. The hydroxyl group of the OH-ZL group is converted to an aldehyde, which is then amidated via the azide moiety to attach the linker and complete the macrocycle formation.

[0872] While Schemes IV-VI illustrate general methods for synthesizing macrocyclic compounds of formula (I), wherein X is and Y is a bond, But this method can be used where X is 5-6 membered heteroaryl, 5-6 membered heterocycloalkyl or 5-6 membered heterocyclyl, and Y is a bond, -O- or implementation plan.

[0873] Using the methods described above, as well as additional extensions, modifications, and variations illustrated by the following examples, one skilled in the art can readily prepare various compounds of Formula (I)-Formula (VI).

[0874] Intermediates and final products can be processed and / or purified according to suitable methods, for example using chromatographic methods, distribution methods, (re-)crystallization and the like.

[0875] Depending on the choice of starting materials and procedures, the compound can be present in the form of one possible isomer or as a mixture thereof, for example as a pure optical isomer, or as a mixture of isomers, such as a racemate and a diastereomeric mixture, depending on the number of asymmetric carbon atoms. The present invention is intended to include all such possible stereoisomers, including racemic mixtures, diastereomeric mixtures and optically pure forms. Optically active (R)-isomers and (S)-isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. If the compound contains a double bond, the substituent can be in E or Z configuration. If the compound contains a disubstituted cycloalkyl, the cycloalkyl substituent can have a cis configuration or a trans configuration. All tautomeric forms are also intended to be included.

[0876] Any resulting isomeric mixtures can be separated on the basis of the physicochemical differences of the constituents, into the pure or substantially pure geometric or optical isomers or diastereomers, for example, by chromatography and / or fractional crystallization.

[0877] The mixtures of isomers obtainable according to the invention can be separated into the individual isomers in a manner known per se; diastereomers can be separated, for example, by partitioning between heterogeneous solvent mixtures, recrystallization and / or chromatography (for example on silica gel) or by medium-pressure liquid chromatography, for example on reverse-phase columns, and racemates can be separated, for example, by salt formation with optically pure salt-forming reagents and separation of the diastereomeric mixtures thus obtainable, for example by means of fractional crystallization, or by chromatography on optically active column materials.

[0878] Any resulting racemate of the final product or intermediate can be resolved into optical antipodes by known methods, for example, by separating the diastereomeric salts obtained with optically active acids or bases, and releasing the optically active acidic or basic compounds. Specifically, the basic moiety can therefore be used to resolve the compounds of the present invention into their optical antipodes, for example, by fractional crystallization of salts formed with optically active acids (e.g., tartaric acid, dibenzoyltartaric acid, diacetyltartaric acid, di-O,O'-p-toluoyltartaric acid, mandelic acid, malic acid, or camphor-10-sulfonic acid). The racemic product can also be resolved by chiral chromatography, for example, using high pressure liquid chromatography (HPLC) using a chiral adsorbent.

[0879] Many compounds of the present invention contain one or more chiral centers. These compounds can be prepared and used as a single isomer or as a mixture of isomers. Methods for separating isomers (including diastereomers and enantiomers) are known in the art, and examples of suitable methods are described herein. In certain embodiments, the compounds of the present invention are used as single substantially pure isomers, meaning that at least 90% of the sample of the compound is the specified isomer, and less than 10% of the sample is any other isomer or mixture of isomers. For example, at least 95% of the sample is a single isomer. In view of the present disclosure, the selection of suitable isomers is within the ordinary technical level. For example, one isomer may be more active in the herpes virus DNA polymerase in vitro assay described herein. In cases where the difference in in vitro activity between the isomers is relatively small, for example less than about 4 times, a single isomer can be selected based on the activity level for viral replication in cell culture using methods such as those described herein: for example, IC 50 or EC 50 Lower isomers.

[0880] In addition, the compounds of the present invention (including their salts) can also be obtained in the form of their hydrates, or include other solvents for their crystallization. The compounds of the present invention can inherently or by design form solvates with pharmaceutically acceptable solvents (including water); therefore, the present invention is intended to cover solvated and non-solvated forms. The term "solvate" refers to a molecular complex of a compound of the present invention (including its pharmaceutically acceptable salt) and one or more solvent molecules. Such solvent molecules are those commonly used in the field of medicine that are known to be harmless to the recipient, for example, water, ethanol, etc. The term "hydrate" refers to a complex in which the solvent molecule is water.

[0881] The compounds of the present invention (including their salts, hydrates and solvates) may inherently or by design form polymorphs.

[0882] As used herein, the term "salt" or "salts" refers to acid addition salts or base addition salts of the compounds of the present invention. "Salts" specifically include "pharmaceutically acceptable salts". The term "pharmaceutically acceptable salts" refers to salts that retain the biological effectiveness and properties of the compounds of the present invention and are generally not biologically or otherwise undesirable. In many cases, the compounds of the present invention are capable of forming acid and / or base salts by means of amino groups and / or carboxyl groups or groups similar thereto.

[0883] Pharmaceutically acceptable acid addition salts can be formed with inorganic and organic acids, for example, acetate, aspartate, benzoate, benzenesulfonate, bromide / hydrobromide, bicarbonate / carbonate, bisulfate / sulfate, camphorsulfonate, chloride / hydrochloride, chlortheophyllonate, citrate, edisylate, fumarate, gluconate, glucuronate, hippurate, hydroiodide / iodide, isethionate, lactate, lactobionate, lauryl sulfate, malate, maleate, malonate, mandelate, methanesulfonate, methylsulfate, naphthoate, naphthylate, nicotinate, nitrate, octadecanoate, oleate, oxalate, palmitate, pamoate, phosphate / hydrogenphosphate / dihydrogenphosphate, polygalacturonate, propionate, stearate, succinate, sulfosalicylate, tartrate, toluenesulfonate, and trifluoroacetate.

[0884] Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like.

[0885] Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, sulfosalicylic acid, etc. Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases.

[0886] Inorganic bases from which salts can be derived include, for example, ammonium salts and metals from columns I to XII of the periodic table. In certain embodiments, the salts are derived from sodium, potassium, ammonium, calcium, magnesium, iron, silver, zinc, and copper; particularly suitable salts include ammonium, potassium, sodium, calcium, and magnesium salts.

[0887] Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like. Certain organic amines include isopropylamine, benzathine, choline salts, diethanolamine, diethylamine, lysine, meglumine, piperazine, and tromethamine.

[0888] The pharmaceutically acceptable salts of the present invention can be synthesized by alkaline or acidic moieties by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid forms of these compounds with a stoichiometric amount of a suitable base (such as sodium hydroxide, calcium hydroxide, magnesium hydroxide, potassium hydroxide, sodium carbonate, calcium carbonate, magnesium carbonate, potassium carbonate, sodium bicarbonate or potassium bicarbonate, etc.), or by reacting the free base forms of these compounds with a stoichiometric amount of a suitable acid. Such reactions are generally carried out in water or in an organic solvent, or in a mixture of the two. Generally, where feasible, it is necessary to use a non-aqueous medium such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile. A list of other suitable salts can be found, for example, in "Remington's Pharmaceutical Sciences", 20th edition, Mack Publishing Company, Easton, Pa., (1985); and in "Handbook of Pharmaceutical Salts: Properties, Selection, and Use" (Wiley-VCH, Weinheim, Germany, 2002) by Stahl and Wermuth.

[0889] The salt of the compounds of this invention with at least one salt-forming group can be prepared in a manner known per se.For example, the salt of the compounds of this invention with an acid group can be, for example, by using a metallic compound, such as an alkali metal salt of a suitable organic carboxylic acid, for example, the sodium salt of 2-ethylhexanoic acid, with an organic alkali metal or alkaline earth metal compound, such as corresponding hydroxide, carbonate or bicarbonate, such as sodium hydroxide or potassium hydroxide, sodium carbonate or potassium carbonate, sodium bicarbonate or potassium bicarbonate, with corresponding calcium compound or with ammonia or suitable organic amine to process the compound to form, stoichiometric or only a small amount of excessive salt-forming agent can be used. The acid-addition salts of the compounds of this invention are obtained in a conventional manner, for example, by processing compound with acid or a suitable anion exchange reagent. The inner salt of the compounds of this invention containing acid and alkaline salt-forming groups (for example, free carboxyl groups and free amino groups) can be, for example, by, for example, neutralizing salt (such as acid-addition salts) to isoelectric point with a weak base, or formed by processing with an ion exchanger.

[0890] Salts can be converted into the free compounds in a customary manner; metal and ammonium salts can be converted, for example, by treatment with suitable acids, and acid addition salts can be converted, for example, by treatment with suitable basic agents.

[0891] Any chemical formula given herein is intended to represent unlabeled forms as well as isotopically labeled forms of the compounds of the invention having up to three atoms with unnatural isotopic distributions, e.g., deuterium-enriched or 13 C or 15 Isotopically labeled compounds have structures depicted by the formulas given herein except that one or more atoms are replaced by atoms having a selected atomic mass or mass number other than the naturally abundant mass distribution. Examples of isotopes that may be usefully incorporated into the compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine, such as 2 H. 3 H. 11 C. 13 C. 14 C. 15 N. 18 F. 31 P. 32 P. 35 S. 36 Cl, 125 I. The present invention includes various isotopically labeled compounds of the present invention, for example, those in which radioactive isotopes such as 3 H and 14 C, or non-radioactive isotopes thereof such as 2 H and 13 C is present at a level substantially above the normal isotopic distribution. Such isotopically labeled compounds are useful in metabolic studies (e.g., 14 C), reaction kinetics studies (e.g.2 H or 3 H), detection or imaging techniques, such as positron emission tomography (PET) or single photon emission computed tomography (SPECT), including tissue distribution assays of drugs or substrates, or radiation therapy that may be used for patients. Specifically, 18 F-labeled compounds of the invention may be particularly desirable for PET or SPECT studies. Isotopically labeled compounds of the invention can generally be prepared by conventional techniques known to those skilled in the art or by methods analogous to those described in the accompanying examples and preparations, using appropriate isotopically labeled reagents in place of the normally employed non-labeled reagents. Labeled samples can be used for relatively low isotope incorporation, such as where the radiolabel is used to detect trace amounts of the compound.

[0892] In addition, the use of heavier isotopes, especially deuterium (i.e. 2 More extensive substitution with H or D) can provide certain therapeutic advantages resulting from greater metabolic stability, such as increased half-life in vivo or reduced dosage requirements or improved therapeutic index. It should be understood that deuterium herein is considered to be a substituent of the compounds of the present invention, and that samples of compounds having deuterium as a substituent typically have at least 50% deuterium incorporation at the labeled position. The concentration of such heavier isotopes (particularly deuterium) can be defined by an isotopic enrichment factor. As used herein, the term "isotopic enrichment factor" refers to the ratio between the isotopic abundance of a particular isotope and its natural abundance. Where a substituent in a compound of the invention is represented as deuterium, such compound has an isotopic enrichment factor per designated deuterium atom of at least 3500 (52.5% deuterium incorporation at each designated deuterium atom), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium incorporation), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation).

[0893] Pharmaceutically acceptable solvates according to the present invention include those wherein the solvent of crystallization may be isotopically substituted, for example D2O, d 6 -acetone, d 6 -DMSO.

[0894] Compounds of the invention containing groups capable of acting as hydrogen bond donors and / or acceptors may be capable of forming co-crystals with suitable co-crystal formers. These co-crystals may be prepared from compounds of the invention by known co-crystal formation procedures. Such procedures include grinding, heating, co-subliming, co-melting, or contacting a compound of the invention with a co-crystal former in solution under crystallization conditions, and isolating the co-crystals thus formed. Suitable co-crystal formers include those described in WO 2004 / 078163. Accordingly, the present invention further provides co-crystals comprising compounds of the invention.

[0895] Unless otherwise indicated herein or otherwise clearly contradictory to the context, all methods described herein can be performed in any suitable order. The use of any and all embodiments or exemplary language (e.g., "such as") provided herein is intended only to better illustrate the present invention and is not intended to limit the scope of the present invention as otherwise claimed.

[0896] The present invention also provides a method for preparing a compound of formula I as described herein and an intermediate useful for preparing a compound of formula (I). Accordingly, the present invention also includes a method for preparing a compound of formula (I), comprising:

[0897] The compound of formula (A)

[0898]

[0899] in:

[0900] X1 represents -OH or a leaving group;

[0901] t is 0, 1, or 2;

[0902] Each R 3 , when present, is a substituent on the ring to which –LW is directly attached, wherein each R 3 independently selected from halogen, CN, C 1- C3 alkoxy, C 1- C3 alkyl, C(=O)OR 10 and C(=O)NR 13 R 14 ;

[0903] R 4 It is H, C 1- C3 alkyl, C 3- C6 cycloalkyl or 1 to 2 independently selected from -OH, -C(=O)R 15 and R 10 C 1- C3 alkyl;

[0904] L is a C1-C4 straight or branched alkylene linker or bond;

[0905] W is H; -OH; –OR 10 ; -C(=O)NR 13 R 14 ; -C(=O)OR 13 ; -NR 13 R 14 ; -NR 13 C(=O)OR 10 ; -NR 13 C(=O)R 10 ; -SO2R 10 ; -SO2NR 13 R 14 ; -NR 13 SO2R 10 ; -P(=O)(OR 13 )2; -S(=O)R 10 ; -S(=O)(=NR 13 )R 10 ; -CR 11 R 12 C(=O)NR 13 R 14 ; -CR 11 R 12 C(=O)OR 13 ; -CR 11 R 12 NR 13 R 14 ; -CR 11 R 12 NR 13 C(=O)OR 10 ; -CR 11 R 12 NR 13 C(=O)R 10 ; -CR 11 R 12 SO2R 10 ; -CR 11 R 12 SO2NR 13 R 14 ; -CR 11 R 12 NR 13 SO2R 10 ; -CR 11 R 12 P(=O)(OR 13 )2; -CR 11 R 12 S(=O)R 10 ; -CR 11 R 12S(=O)(=NR 13 )R 10 ; 3-6 membered cycloalkyl; phenyl; containing one or two independently selected from N, NH, NR 17 , O or S ring members of the 5-6 membered heterocycloalkyl; containing one or two independently selected from N, NH, NR 17 , O or S as ring members; or a 5-membered heteroaryl group having 1 to 4 heteroatoms selected from N, O and S as ring members, which is optionally fused to a phenyl group,

[0906] wherein the 3-6 membered cycloalkyl, the phenyl, the 5-6 membered heterocycloalkyl, the 5-6 membered heterocyclyl and the 5 membered heteroaryl of W are each optionally substituted by 1 to 3 groups independently selected from the following: 1- C3 alkyl, oxo, halogen, C 1- C3 haloalkyl, –L 2 OH, –L 2 OR 10 ,–L 2 OC(=O)NR 13 R 14 ,–L 2 SO2R 10 ,–L 2 SO2NR 14 R 10 ,–L 2 SO2NR 13 R 14 ,–L 2 SO2N=CR 13 NR 13 R 14 ,–L 2 SO2NR 13 C(=O)R 10 ,–L 2 C(=O)NR 13 SO2R 10 ,–L 2 S(=O)R 10 ,–L 2 S(=O)(=NR 13 )R 10 ,–L 2 NR 13 SO2NR 13 R 14 ,–L 2 NR 13 SO2R 10 ,–L 2 NR 13 R 14 ,–L 2 NR13 C(=O)R 13 ,–L 2 NR 13 C(=O)OR 10 ,–L 2 C(=O)NR 13 R 14 and –L 2 C(=O)OR 13 ;

[0907] R 10 In each occurrence, independently selected from C 1- C4 alkyl; C 1- C3 haloalkyl; 3-6 membered cycloalkyl; phenyl; 5-6 membered heteroaryl having 1 to 4 heteroatoms independently selected from N, O and S as ring members; containing one or two independently selected from N, NH, NR 17 , O or S ring members; and containing 1 to 2 independently selected from N, NH, NR 17 , O or S ring members of the 4-6 membered heterocyclic group,

[0908] Each R 10 Optionally substituted with 1 to 5 groups independently selected from: C 1- C4 alkyl, deuterium, C 1- C4 haloalkoxy, –L 3 OH, –L 3 CN, -L 3 OC(=O)R 14 、-L 3 OR 13 、C 1- C2 haloalkyl, oxo, -L 3 Halogen, –L 3 C 1- C3 alkoxy, –L 3 OC(=O)NR 13 R 14 ,–L 3 SO2R 13 ,–L 3 SO2NR 13 R 14 ,–L 3 SO2NR 13 C(=O)R 13 ,–L 3 C(=O)NR 13 SO2R 13 ,–L 3 S(=O)R 13 ,–L 3 S(=O)(=NR 14)R 13 ,–L 3 NR 13 SO2NR 13 R 14 ,–L 3 NR 13 SO2R 13 ,–L 3 NR 13 R 14 ,–L 3 NR 14 C(=O)R 13 ,–L 3 NR 14 C(=O)OR 13 ,–L 3 C(=O)NR 13 R 14 ,–L 3 C(=O)OR 13 、-L 3 -(containing 1 to 2 independently selected from N, NH, NR 17 , O or S as ring members of the 4-7 membered heterocycloalkyl group), -L 3 -(containing 1 to 2 independently selected from N, NH, NR 17 , O or S ring member 4-7 membered heterocyclic group), -L 3 -C 3- C5 cycloalkyl and -L 3 -(a 5-6 membered heteroaryl ring having 1 to 4 heteroatoms containing 1 to 4 nitrogen atoms, 0 or 1 oxygen atoms and 0 or 1 sulfur atoms as ring members), wherein said C 1- C4 alkyl, 4-7 membered heterocycloalkyl, 4-7 membered heterocyclyl, C 3- The C5 cycloalkyl and 5-6 membered heteroaryl rings are each optionally further substituted by 1 to 3 groups independently selected from halo, C 1- C3 alkyl, C 1- C3 haloalkyl, -L 4 OR 13 、-L 4 CN and –L 4 NR 13 R 14 The group substitution;

[0909] R 11 and R 12 Each independently selected from H and C 1- C4 alkyl;

[0910] Each R 13 Independently selected from H; C 1- C4 alkyl; containing 1 to 2 independently selected from N, NH, NR17 , O or S ring members; containing 1 to 2 independently selected from N, NH, NR 17 , O or S as ring members; and C 3- C6 cycloalkyl, wherein the C 1- C4 alkyl, heterocyclic and C 3- C6 cycloalkyl is optionally substituted by 1 to 3 independently selected 1- C4 alkyl, halogen, -OH, -NR 15 R 16 、-C(=O)OR 15 、C 1- C2 alkoxy and C substituted by 1 to 2 hydroxyl groups 1- C4 alkyl group substitution;

[0911] R 14 Selected from H, C 1- C4 alkyl and C 3- C6 cycloalkyl, wherein the C 1- C4 alkyl and C 3- C6 cycloalkyl is optionally substituted by 1 to 3 independently selected 1- C4 alkyl, halogen, -OH, -NR 15 R 16 、C 1- C2 alkoxy and C substituted by 1 to 2 hydroxyl groups 1- C4 alkyl group substitution;

[0912] or R 13 and R 14 Together with the nitrogen atom to which they are directly attached, they are capable of forming a 4-6 membered ring optionally containing additional N, O or S as ring members and optionally substituted by one to three selected from C 1- C2 alkyl, C 1- C2 alkoxy, oxo and hydroxy group substitution;

[0913] Each L 2 and L 3 and L 4 are independently a bond or a straight or branched C 1- C3 alkylene,

[0914] and

[0915] represents a single bond or a double bond;

[0916] Contact with a compound of formula (I-2):

[0917]

[0918] in:

[0919] R B is phenyl, pyridyl, phenylthio, pyrimidinyl or 5-8 membered cycloalkyl, wherein R B Optionally 1 to 3 R 5 group substitution;

[0920] R 1 Selected from H, C 1- C3 alkyl and C substituted with 1 to 3 -OH groups 1- C3 alkyl;

[0921] R 2 Selected from H, C 1- C3 alkyl and C substituted with 1 to 3 -OH groups 1- C3 alkyl;

[0922] or R 1 and R 2 Together with the carbon atoms to which they are attached, they can form a 3-6 membered cycloalkyl ring;

[0923] Each R 5 are independently selected from halo, -CN, hydroxy, -NR 13 R 14 、C 3- C6 cycloalkyl, C 1- C3 alkoxy, C 1- C3 haloalkyl and optionally 1 to 3 R 6 C 1- C3 alkyl, where R B By two R 5 Replace and each R 5 is optionally replaced by 1 to 3 R 6 C 1- C3 alkyl, when directly attached to the same carbon atom, can be taken together with the carbon atoms to which the two are directly attached to form a C3 alkyl group optionally substituted by 1 to 3 R 6 a 3-5 membered cycloalkyl ring substituted with a group;

[0924] Each R 6 Independently selected from halo, hydroxy, CN, C 1- C3 alkoxy, C 1- C3 alkyl and C 3- C5 cycloalkyl,

[0925] Or two R 6 The group together with the carbon atom to which they are directly attached can form a 3-5 membered cycloalkyl ring or a 4-6 membered heterocyclic ring containing O, N or S as ring members and optionally substituted by 1 to 2 groups independently selected from oxo and C 1- C3 alkyl group substitution;

[0926] Each R 13 Independently selected from H; C 1- C4 alkyl; containing 1 to 2 independently selected from N, NH, NR 17 , O or S ring members; containing 1 to 2 independently selected from N, NH, NR 17 , O or S as ring members; and C 3- C6 cycloalkyl, wherein the C 1- C4 alkyl, heterocyclic and C 3- C6 cycloalkyl is optionally substituted by 1 to 3 independently selected 1- C4 alkyl, halogen, -OH, -NR 15 R 16 、-C(=O)OR 15 、C 1- C2 alkoxy and C substituted by 1 to 2 hydroxyl groups 1- C4 alkyl group substitution;

[0927] R 14 Selected from H, C 1- C4 alkyl and C 3- C6 cycloalkyl, wherein the C 1- C4 alkyl and C 3- C6 cycloalkyl is optionally substituted by 1 to 3 independently selected 1- C4 alkyl, halogen, -OH, -NR 15 R 16 、C 1- C2 alkoxy and C substituted by 1 to 2 hydroxyl groups 1- C4 alkyl group substitution;

[0928] or R 13 and R 14 Together with the nitrogen atom to which they are directly attached, they are capable of forming a 4-6 membered ring optionally containing additional N, O or S as ring members and optionally substituted by one to three selected from C 1- C2 alkyl, C 1- C2 alkoxy, oxo and hydroxy group substitution;

[0929] R 15 and R 16 Each independently selected from H and C 1- C4 alkyl,

[0930] and

[0931] Each R 17 Independently selected from H, C 1- C4 alkyl and C3-C8 cycloalkyl.

[0932] Typically, for these methods, compounds of formula (A) and formula (I-2) are brought together or mixed in the presence of an inert solvent under conditions suitable for forming an amide bond (including known methods for peptide synthesis). For example, where X represents -OH, any of the various dehydrating agents suitable for forming an amide bond from an amine and a carboxylic acid can be used. Some of these are illustrated by the examples herein and include carbodiimides (e.g., dicyclohexylcarbodiimide; diisopropylcarbodiimide; EDC; etc.). Optionally, the reaction with the carbodiimide can be promoted by the presence of an activator (such as HOBt, HOAt, N-hydroxysuccinimide, etc.). Alternatively, prior to contact with the amine compound of formula (I-2), the acid of formula (A) or a salt thereof can be activated by reacting with an activator (such as HATU, HBTU, BOP, PyBOP, PyBrOP, TBTU, COMU or TFFH) optionally in the presence of a base (such as triethylamine, DIPEA, DMAP, pyridine, etc.). Where X represents a leaving group, it may be a halide (e.g. Cl) or an acyl group (such as -OC(O)-OR*), wherein R* represents an acyl group optionally substituted by up to three halide or C 1-3 Alkoxy-substituted C1-C6 alkyl.

[0933] In certain embodiments, the compound of formula (A) is a compound of formula (VII):

[0934]

[0935] where R C is H; L is –CH2-; and W is –SO2R 10 , –SO2NR 14 R 10 or –SO2NR 13 R 14 Substituted cyclopropyl, wherein t, R 10 、R 13 and R 14 As defined in formula (A).

[0936] The compounds of formula (A) and (I-2) as described above and methods of using them to prepare the compounds of the present invention are also aspects of the present invention.

[0937] The invention also comprises any variant of the process in which intermediate products obtainable at any stage thereof are used as starting materials and the remaining steps are carried out, or in which the starting materials are formed in situ under the reaction conditions, or in which the reaction components are used in the form of their salts or optically pure materials.

[0938] The invention also relates to those versions of the process in which compounds which are obtainable as intermediates at any stage of the process are used as starting materials and the remaining process steps are carried out, or in which the starting materials are formed under the reaction conditions or used in the form of derivatives, for example in protected form or in the form of salts, or in which compounds obtainable by the process according to the invention are prepared under the process conditions and further processed in situ.

[0939] Pharmaceutical compositions and routes of administration

[0940] Included within the scope of the present invention are pharmaceutical compositions comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

[0941] According to another aspect of this embodiment, the pharmaceutical composition according to the present invention further comprises a therapeutically effective amount of at least one other antiviral agent.

[0942] The compounds of the present invention can be administered by known methods, including oral, parenteral, inhalation, and the like. In certain embodiments, the compounds of the present invention are administered orally in the form of pills, lozenges, tablets, capsules, solutions, or suspensions. In other embodiments, the compounds of the present invention are administered by injection or infusion. Infusion is typically performed intravenously, typically over a period of about 15 minutes to 4 hours. In other embodiments, the compounds of the present invention are administered intranasally or by inhalation; inhalation methods are particularly useful for treating respiratory tract infections. The compounds of the present invention exhibit oral bioavailability and can be administered by oral administration.

[0943] The term "pharmaceutical composition" includes formulations suitable for administration to mammals, such as humans. When the compounds of the present invention are administered to mammals (e.g., humans) as pharmaceuticals, they can be administered per se or as a pharmaceutical composition comprising, for example, 0.1% to 99.5% (e.g., 0.5% to 90%) of at least one compound of formula (I) or any subgenus thereof as an active ingredient in combination with a pharmaceutically acceptable carrier, or optionally a combination of two or more pharmaceutically acceptable carriers.

[0944] The phrase "pharmaceutically acceptable carrier" is art-recognized and includes pharmaceutically acceptable materials, compositions, or vehicles suitable for administering a compound of the invention to a mammal. Carriers include liquid or solid fillers, diluents, excipients, solvents, or encapsulating materials involved in carrying or transporting the subject agent from one organ or part of the body to another organ or part of the body. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient. Some examples of materials that can serve as pharmaceutically acceptable carriers include: sugars such as lactose, glucose, and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethylcellulose, ethylcellulose, and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; glycols such as propylene glycol; polyols such as glycerol, sorbitol, mannitol, and polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffers such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethanol; phosphate buffered saline; and other nontoxic, compatible substances employed in pharmaceutical formulations. Typically, pharmaceutically acceptable carriers are sterile and / or substantially free of pyrogens.

[0945] Wetting agents, emulsifiers and lubricants, such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, release agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the compositions.

[0946] Examples of pharmaceutically acceptable antioxidants include: water-soluble antioxidants such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite, etc.; oil-soluble antioxidants such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, α-tocopherol, etc.; and metal chelators such as citric acid, ethylenediaminetetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, etc.

[0947] The preparations of the present invention include those suitable for oral, nasal, inhalation, topical, transdermal, buccal, sublingual, rectal, vaginal and / or parenteral administration. The preparations can be conveniently present in unit dosage form and can be prepared by suitable methods. The amount of active ingredient that can be combined with a carrier material to produce a single dosage form will generally be the amount of the compound that produces the therapeutic effect. Typically, out of 100%, this amount will be in the range of about 1% to about 99%, for example, about 5% to about 70%, or about 10% to about 30% of the active ingredient.

[0948] The methods for preparing these formulations or compositions include the step of bringing into association the compound of the present invention with a carrier and, optionally, one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association the compound of the present invention with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product.

[0949] Formulations of the present invention suitable for oral administration may be in the form of capsules, cachets, pills, tablets, lozenges (using a flavored base, for example, typically sucrose and acacia or tragacanth), powders, granules, or in the form of a solution or suspension in an aqueous or non-aqueous liquid, or in the form of an oil-in-water or water-in-oil liquid emulsion, or in the form of an elixir or syrup, or in the form of a lozenge (using an inert base such as gelatin and glycerin, or sucrose and acacia) and / or in the form of a mouthwash, etc., each containing a predetermined amount of a compound of the present invention as the active ingredient. The compounds of the present invention may also be administered as a bolus, electuary, or paste.

[0950] In solid dosage forms of the invention for oral administration (capsules, tablets, pills, dragees, powders, granules, etc.), the active ingredient is mixed with one or more pharmaceutically acceptable carriers (such as sodium citrate or dicalcium phosphate) and / or any of the following: fillers or extenders such as starch, lactose, sucrose, glucose, mannitol and / or silicic acid; binders such as carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and / or acacia; humectants such as glycerol; disintegrants such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates and sodium carbonate; solution retarding agents such as paraffin; absorption accelerators such as quaternary ammonium compounds; wetting agents such as cetyl alcohol and glyceryl monostearate; absorbents such as kaolin and bentonite; lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate and mixtures thereof; and coloring agents. In the case of capsules, tablets and pills, the pharmaceutical composition may also contain a buffer. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using excipients such as lactose (milk sugar) and high molecular weight polyethylene glycols.

[0951] Tablets can be prepared by compression or molding, optionally with one or more auxiliary ingredients. Compressed tablets can be prepared using a binder (e.g., gelatin or hydroxypropyl methylcellulose), a lubricant, an inert diluent, a preservative, a disintegrant (e.g., sodium starch glycolate or cross-linked sodium carboxymethyl cellulose), a surfactant, or a dispersant. Molded tablets can be prepared by molding a mixture of powdered compounds moistened with an inert liquid diluent in a suitable machine.

[0952] The tablets and other solid dosage forms (such as dragees, capsules, pills and granules) of the pharmaceutical composition of the present invention can optionally be scored or prepared with coatings and shells such as enteric coatings and other coatings. Hydroxypropyl methylcellulose, for example, in different proportions, can also be used to formulate them so as to provide a slow or controlled release of the active ingredient therein to provide a desired release profile, other polymer matrices, liposomes and / or microspheres. They can be sterilized by, for example, filtering through a bacteria-retaining filter, or by incorporating a sterilizing agent in the form of a sterile solid composition, which can be dissolved in sterile water or some other sterile injectable media immediately before use. These compositions can also optionally contain an opacifier and can be compositions that release the active ingredient only in or preferentially in a certain part of the gastrointestinal tract in a delayed manner. Examples of usable embedding compositions include polymeric substances and waxes. If appropriate, the active ingredient can also be in a microencapsulated form with one or more of the above-mentioned excipients.

[0953] Liquid dosage forms for oral administration of the compounds of the invention include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active ingredient, the liquid dosage form may also contain inert diluents commonly used in the art, for example, water or other solvents, solubilizers and emulsifiers, such as ethanol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (particularly cottonseed oil, peanut oil, corn, germ oil, olive oil, castor oil and sesame oil), glycerol, tetrahydrofuranyl alcohol, polyethylene glycol and fatty acid esters of sorbitan, and mixtures thereof.

[0954] Besides inert diluents, the oral compositions may also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming and preservative agents.

[0955] Suspensions, in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.

[0956] Formulations of the pharmaceutical compositions of the present invention for rectal or vaginal administration may be presented in the form of suppositories, which may be prepared by mixing one or more compounds of the present invention with one or more suitable non-irritating excipients or carriers, including, for example, cocoa butter, polyethylene glycol, suppository waxes or salicylates, which are solid at room temperature but liquid at body temperature and therefore will melt in the rectum or vaginal cavity and release the active compound.

[0957] Formulations of the present invention suitable for vaginal administration also include pessaries, tampons, creams, gels, pastes, foams or spray formulations containing such carriers as are known in the art to be appropriate.

[0958] Dosage forms for topical or transdermal administration of the compounds of this invention include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants. The active compound may be mixed under sterile conditions with a pharmaceutically acceptable carrier and with any preservatives, buffers or propellants that may be required.

[0959] Ointments, pastes, creams and gels may contain, in addition to the active compounds of this invention, excipients such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.

[0960] In addition to the compounds of this invention, powders and sprays may contain excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicate and polyamide powder, or mixtures of these substances. Sprays may additionally contain conventional propellants, such as chlorofluorocarbons and volatile unsubstituted hydrocarbons, such as butane and propane.

[0961] Transdermal patches have the additional advantage of providing controlled delivery of the compounds of the present invention to the body. Such dosage forms can be prepared by dissolving or dispersing the compound in an appropriate medium. Absorption enhancers can also be used to increase the flux of the compound through the skin. The rate of such flux can be controlled by providing a rate-controlling membrane or by dispersing the active compound in a polymer matrix or gel.

[0962] Ophthalmic formulations, eye ointments, powders, solutions, etc. are also contemplated as being within the scope of this invention.

[0963] Pharmaceutical compositions of the present invention suitable for parenteral administration may comprise one or more compounds of the present invention in combination with one or more pharmaceutically acceptable carriers, such as sterile isotonic aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, or sterile powders that can be reconstituted into sterile injectable solutions or dispersions just before use, which may contain antioxidants, buffers, bacteriostats, solutes that render the formulation isotonic with the blood of the intended recipient, or suspending or thickening agents.

[0964] Examples of suitable aqueous and non-aqueous carriers that can be used in the pharmaceutical compositions of the present invention include water, ethanol, glycol ethers, polyols (such as glycerol, propylene glycol, polyethylene glycol, etc.), and suitable mixtures thereof, vegetable oils (such as olive oil), and injectable organic esters (such as ethyl oleate). Suitable fluidity can be maintained, for example, by the use of coating materials (such as lecithin), by maintaining the desired particle size in the case of dispersions, and by the use of surfactants.

[0965] These compositions can also contain adjuvants, such as preservatives, wetting agents, emulsifiers and dispersants. Can ensure to prevent the effect of microorganisms by including various antibacterials and antifungals (for example parabens, chlorobutanol, phenol, sorbic acid etc.). It is also possible to expect that in these compositions, isotonic agents, such as sugar, sodium chloride etc., are included. In addition, the extended absorption of injectable drug forms can be realized by including the reagent that delays absorption, such as aluminum monostearate and gelatin.

[0966] In some cases, in order to prolong the effect of the drug, it may be necessary to slow down the absorption of the drug from subcutaneous or intramuscular injection. This can be achieved by using a liquid suspension of a crystalline or amorphous material with poor water solubility. The absorption rate of the drug depends on its dissolution rate, which in turn can depend on crystal size and crystalline form. Alternatively, delayed absorption of a drug form administered parenterally can be achieved by dissolving or suspending the drug in an oil vehicle.

[0967] Injectable long-acting forms are prepared by forming a microcapsule matrix of the subject compound in a biodegradable polymer (such as polylactide-polyglycolide). Depending on the ratio of the drug to the polymer and the properties of the specific polymer employed, the drug release rate can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Long-acting injectable formulations are also prepared by embedding the drug in liposomes or microemulsions compatible with body tissues.

[0968] The preparations of the present invention can be administered orally, parenterally, topically or rectally. They are of course administered in a form suitable for each route of administration. For example, they are administered in tablet or capsule form, by injection, inhalation, eye lotion, ointment, suppository, etc., by injection, infusion or inhalation; topically by lotion or ointment; and rectally by suppository.

[0969] As used herein, the phrases "parenteral administration" and "administered parenterally" mean modes of administration other than enteral and topical administration (typically by injection), and include, but are not limited to, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcutaneous, intraarticular, subcapsular, subarachnoid, intraspinal, and intrasternal injection and infusion. In some embodiments, the compounds of the invention are administered by intravenous infusion. Infusion can be used to deliver a single daily dose or multiple doses. In some embodiments, the compounds of the invention are administered by infusion at intervals between 15 minutes and 4 hours, typically between 0.5 hours and 3 hours. Such infusions can be used once a day, twice a day, or up to three times a day.

[0970] As used herein, the phrases "systemic administration," "administered systemically," "peripheral administration," and "administered peripherally" mean that a compound, drug, or other material is not administered directly into the central nervous system such that it enters the patient's system and thereby undergoes metabolism and other similar processes, e.g., subcutaneous administration.

[0971] These compounds can be administered to humans and other animals for therapeutic use by any suitable route of administration, including orally, nasally (e.g., by spray), rectal, vaginal, parenteral, intracisternal, and topically, such as by powders, ointments, or drops, including buccal and sublingual.

[0972] Regardless of the route of administration selected, the compounds of the present invention and / or the pharmaceutical compositions of the present invention, which can be used in a suitable hydrated form, are formulated into pharmaceutically acceptable dosage forms by conventional methods known to those skilled in the art.

[0973] Actual dosage levels of the active ingredients in the pharmaceutical compositions of the present invention may be varied so as to obtain an amount of the active ingredient which is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient.

[0974] The selected dosage level will depend upon a variety of factors, including the activity of the particular compound of the present invention being employed, or its ester, salt or amide; the route of administration; the time of administration; the rate of excretion of the particular compound being employed; the duration of the treatment; other drugs, compounds and / or materials used in combination with the particular compound being employed; and the age, sex, weight, condition, general health and prior medical history of the patient being treated, among other factors.

[0975] A physician or veterinarian having ordinary skill in the art can determine and prescribe the effective amount of the pharmaceutical composition required. For example, a physician or veterinarian can start the dosage of the compound of the invention employed in the pharmaceutical composition at a level lower than that required to achieve the desired therapeutic effect, and gradually increase the dosage until the desired effect is achieved.

[0976] Typically, the suitable daily dose of the compound of the present invention will be the amount of the compound of the minimum dose that effectively produces therapeutic effect.This effective dose will generally depend on the above-mentioned factors.Usually, when used for indicating effect, the intravenous and subcutaneous dose of the compound of the present invention of the patient will be in the range of about 0.0001 to about 100mg / kg body weight / day, more for example about 0.01 to about 50mg / kg / day, or every day about 0.1 to about 20mg / kg / day.Effective dose is the amount of preventing or treating viral infection (such as CMV or another herpes virus).

[0977] If desired, the effective daily dose of the active compound can be administered in a single dose every day or in two, three, four, five, six or more sub-doses administered separately at appropriate intervals throughout the day, optionally in unit dosage form. The compound delivered orally or by inhalation is typically administered in a dose of once to four times a day. The compound delivered by injection is typically administered once a day, or is administered once every other day. The compound delivered by infusion is typically administered in a dose of once to three times a day. When multiple doses are administered in one day, the dosage can be administered at intervals of about 4 hours, about 6 hours, about 8 hours or about 12 hours.

[0978] Although the compounds of the present invention can be administered alone, they are typically administered as pharmaceutical compositions, such as those described herein. Accordingly, methods of using the compounds of the present invention include administering the compounds as pharmaceutical compositions, wherein at least one compound of the present invention is mixed with a pharmaceutically acceptable carrier prior to administration.

[0979] Various embodiments of the pharmaceutical compositions of the present invention are described herein. It will be appreciated that the features specified in each embodiment can be combined with other specified features to provide additional embodiments. The examples listed below represent pharmaceutical compositions of the present invention.

[0980] Embodiment 171. A pharmaceutical composition comprising a compound of formula (I) or a compound according to any one of Embodiments 1 to 153, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.

[0981] Embodiment 172. The pharmaceutical composition of Embodiment 154, further comprising at least one additional antiviral agent.

[0982] Embodiment 173. The pharmaceutical composition of embodiment 155, wherein the at least one additional antiviral agent is selected from the group consisting of herpes virus entry inhibitors; herpes virus early transcription event inhibitors; herpes virus helicase-primase inhibitors; herpes virus DNA polymerase inhibitors such as ganciclovir Valganciclovir Cidofovir Foscarnet CMX001, cyclopropavir (MBX-400), and valaciclovir Inhibitors of UL97 kinase, such as Maribavir; Herpes virus protease inhibitors; Herpes virus terminal enzyme inhibitors, such as AIC246 (Letermovir); Herpes virus maturation inhibitors; other inhibitors, such as artesunate; CMV vaccines, such as TransVax, and herpes virus biopharmaceuticals, such as Cytogam

[0983] Embodiment 174. A pharmaceutical composition comprising a compound of formula (I) or a compound according to any one of Embodiments 154 to 170, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.

[0984] Embodiment 175. The pharmaceutical composition of Embodiment 174, further comprising at least one additional antiviral agent.

[0985] Embodiment 176. The pharmaceutical composition of embodiment 175, wherein the at least one additional antiviral agent is selected from the group consisting of herpes virus entry inhibitors; herpes virus early transcription event inhibitors; herpes virus helicase-primase inhibitors; herpes virus DNA polymerase inhibitors such as ganciclovir Valganciclovir Cidofovir Foscarnet CMX001, cyclopropavir (MBX-400), and valaciclovir Inhibitors of UL97 kinase, such as Maribavir; Herpes virus protease inhibitors; Herpes virus terminal enzyme inhibitors, such as AIC246 (Letermovir); Herpes virus maturation inhibitors; other inhibitors, such as artesunate; CMV vaccines, such as TransVax, and herpes virus biopharmaceuticals, such as Cytogam

[0986] Pharmacology and efficacy

[0987] Another aspect of the present invention relates to a method of treating or preventing herpes virus diseases and / or infections in humans by administering to a human an antivirally effective amount of a compound of the present invention, a pharmaceutically acceptable salt thereof, or a composition as described above, alone or in combination with at least one other antiviral agent administered together or separately.

[0988] Yet another aspect of the present invention relates to a method for inhibiting the replication of CMV or another herpes virus, the method comprising exposing the virus to an effective amount of a compound of formula (I) or a salt thereof under conditions that inhibit viral replication. The method can be implemented in vitro or in vivo.

[0989] Also within the scope of the present invention is the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating or preventing herpes virus diseases and / or infections (including CMV) in humans.

[0990] Another embodiment of the present invention provides a compound as described above or a pharmaceutically acceptable salt thereof as a medicament.

[0991] The present invention also provides the use of a pharmaceutical composition as described herein for treating CMV infection or other herpes virus infection in a human suffering from or at risk of suffering from the infection.

[0992] The present invention also provides the use of a pharmaceutical composition as described herein for treating CMV disease or other herpes virus infection in a human having or at risk of having the disease.

[0993] Another aspect of the present invention is a product comprising a composition effective for treating herpes virus diseases and / or infections; and packaging material comprising a label indicating that the composition can be used to treat diseases and / or infections caused by herpes viruses such as CMV; wherein the composition comprises a compound of formula (I) according to the present invention or a pharmaceutically acceptable salt thereof.

[0994] Also within the scope of the present invention is the use of a compound of formula (I) or a salt thereof for inhibiting the replication of CMV.

[0995] The dosage range of the compounds of the invention for use per day is generally 0.01 mg / kg to 100 mg / kg of body weight, for example 0.1 mg / kg to 50 mg / kg of body weight. Each dosage unit may conveniently contain 5% to 95% active compound (w / w). For example, such formulations contain 20% to 80% active compound.

[0996] The actual pharmaceutically effective amount or therapeutic dose will of course depend on factors known to those skilled in the art, such as the patient's age and weight, route of administration, and severity of the disease. In any case, the combination will be administered in a dosage and manner that allows a pharmaceutically effective amount to be delivered based on the patient's unique condition.

[0997] The " effective amount " of a compound is the amount necessary or sufficient for treating or preventing viral infections and / or diseases or conditions described herein. In one example, the effective amount of a herpes virus or CMV DNA polymerase inhibitor of Formula I is an amount sufficient to treat the viral infection of a subject. In another example, the effective amount of a DNA polymerase inhibitor is an amount sufficient to treat the viral infection (such as, but not limited to, CMV, VZV, or EBV) of a subject in need of such treatment. The effective amount can vary according to factors such as the size and weight of the subject, the type of disease, or the specific compound of the present invention. For example, the selection of the compound of the present invention can affect the composition of the " effective amount ". One of ordinary skill in the art will be able to study the factors contained herein and determine the effective amount of the compound of the present invention without excessive experimentation.

[0998] The administration regimen can affect what constitutes an effective amount. The compounds of the present invention can be administered to the subject before or after the onset of viral infection. In addition, several divided doses and staggered doses can be administered daily or sequentially, or the dose can be a continuous infusion or a bolus injection. Furthermore, the dose of the compounds of the present invention can be proportionally increased or decreased as indicated by the urgency of the therapeutic or preventive situation.

[0999] The compounds of the present invention are useful for treating conditions, disorders, or diseases as described herein, or for the manufacture of pharmaceutical compositions for the treatment of these diseases. The present invention provides methods of using the compounds of the present invention to treat these diseases or to prepare pharmaceutical compositions containing the compounds of the present invention for the treatment of these diseases.

[1000] Another aspect of the present invention relates to a method for treating a viral disease and / or infection in a human, which method comprises administering to a human an antivirally effective amount of a compound of the present invention, a pharmaceutically acceptable salt thereof, or a composition as described above, alone or in combination with at least one other antiviral agent administered together or separately, wherein the viral disease or infection is selected from CMV infection in immunocompromised patients (e.g., transplant recipients), congenital CMV, genital herpes, oral herpes (cold sores), herpetic keratitis, neonatal herpes, herpes encephalitis, varicella (chickenpox), herpes zoster, infectious mononucleosis, post-transplant lymphoproliferative disorder (PTLD), Castelman's disease, and hemophagocytic lymphohistiocytosis.

[1001] Another aspect of the present invention relates to a method for treating a condition in a human that can be induced / exacerbated / accelerated by a herpes virus infection, which method comprises administering to the human an effective amount of a compound of the present invention, a pharmaceutically acceptable salt thereof, or a composition as described above, alone or in combination with at least one other antiviral agent administered together or separately, wherein the condition is selected from Alzheimer's disease, chronic fatigue syndrome (CFS), systemic lupus erythematosus (SLE), multiple sclerosis (MS), rheumatoid arthritis (RA), juvenile idiopathic arthritis (JIA), inflammatory bowel disease (IBD), celiac disease, and type 1 diabetes.

[1002] Another aspect of the present invention relates to a method for treating a condition in a human that can be induced / exacerbated / accelerated by a herpes virus infection, which method comprises administering to the human an effective amount of a compound of the present invention, a pharmaceutically acceptable salt thereof, or a composition as described above, alone or in combination with at least one other antiviral agent administered together or separately, wherein the condition is selected from Alzheimer's disease, chronic fatigue syndrome (CFS), systemic lupus erythematosus (SLE), multiple sclerosis (MS), rheumatoid arthritis (RA), juvenile idiopathic arthritis (JIA), inflammatory bowel disease (IBD), atherosclerosis (AS), celiac disease, and type 1 diabetes.

[1003] Another aspect of the present invention is the use of a compound of the present invention or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment or prevention of a condition that may be induced / exacerbated / accelerated by a herpes virus infection, wherein the condition is selected from Alzheimer's disease, chronic fatigue syndrome (CFS), systemic lupus erythematosus (SLE), multiple sclerosis (MS), rheumatoid arthritis (RA), juvenile idiopathic arthritis (JIA), inflammatory bowel disease (IBD), celiac disease and type 1 diabetes.

[1004] Another aspect of the present invention is the use of a compound of the present invention or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment or prevention of a condition that may be induced / exacerbated / accelerated by a herpes virus infection, wherein the condition is selected from Alzheimer's disease, chronic fatigue syndrome (CFS), systemic lupus erythematosus (SLE), multiple sclerosis (MS), rheumatoid arthritis (RA), juvenile idiopathic arthritis (JIA), inflammatory bowel disease (IBD), atherosclerosis (AS), celiac disease and type 1 diabetes.

[1005] Another aspect of the present invention is the use of a pharmaceutical composition as described herein for the treatment of a viral disease and / or infection in a human, wherein the viral disease or infection is selected from CMV infection in an immunocompromised patient (e.g., a transplant recipient), congenital CMV, genital herpes, oral herpes (cold sores), herpetic keratitis, neonatal herpes, herpes encephalitis, varicella, herpes zoster, infectious mononucleosis, post-transplant lymphoproliferative disorder (PTLD), Castleman's disease, and hemophagocytic lymphohistiocytosis.

[1006] Another aspect of the present invention is the use of a pharmaceutical composition as described herein for the treatment of a condition that can be induced / exacerbated / accelerated by a herpes virus infection, wherein the condition is selected from Alzheimer's disease, chronic fatigue syndrome (CFS), systemic lupus erythematosus (SLE), multiple sclerosis (MS), rheumatoid arthritis (RA), juvenile idiopathic arthritis (JIA), inflammatory bowel disease (IBD), celiac disease and type 1 diabetes.

[1007] Another aspect of the present invention is the use of a pharmaceutical composition as described herein for the treatment of a condition that can be induced / exacerbated / accelerated by a herpes virus infection, wherein the condition is selected from Alzheimer's disease, chronic fatigue syndrome (CFS), systemic lupus erythematosus (SLE), multiple sclerosis (MS), rheumatoid arthritis (RA), juvenile idiopathic arthritis (JIA), inflammatory bowel disease (IBD), atherosclerosis (AS), celiac disease and type 1 diabetes.

[1008] Various embodiments of the methods of treatment and uses of the compounds of this invention are described herein. It will be appreciated that the features specified in each embodiment can be combined with other specified features to provide additional embodiments. The embodiments listed below represent methods of treatment and uses of the compounds of this invention.

[1009] Embodiment 177. A method of treating a herpes virus infection, the method comprising administering to a patient suffering from a herpes virus infection a compound of formula (I) according to any one of Embodiments 1 to 153, or a pharmaceutical composition comprising a compound of formula (I) or a compound according to any one of Embodiments 1 to 153.

[1010] Embodiment 178. The method of embodiment 177, wherein the herpes virus is selected from the group consisting of cytomegalovirus (CMV), Epstein-Barr virus (EBV), varicella-zoster virus (VZV), herpes simplex viruses including HSV-1 and HSV-2, herpes virus 6, human herpes virus 7, and Kaposi's sarcoma-associated herpes virus.

[1011] Embodiment 179. A method of treating a herpes virus infection, comprising administering to a patient suffering from a herpes virus infection a compound of formula (I) according to any one of embodiments 154 to 170, or a pharmaceutical composition comprising a compound of formula (I) or a compound according to any one of embodiments 154 to 170.

[1012] Embodiment 180. The method of embodiment 179, wherein the herpes virus is selected from the group consisting of cytomegalovirus (CMV), Epstein-Barr virus (EBV), varicella-zoster virus (VZV), herpes simplex viruses including HSV-1 and HSV-2, herpes virus 6, human herpes virus 7, and Kaposi's sarcoma-associated herpes virus.

[1013] Embodiment 181. Use of a compound according to any one of Embodiments 1 to 170, or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for the treatment of a viral infection.

[1014] Embodiment 182. A compound for use in treating a viral infection in a patient in need thereof, the compound comprising a compound according to any one of Embodiments 1 to 170.

[1015] Embodiment 183. A compound as disclosed in Examples 1 to 262.

[1016] Embodiment 184. Use of a compound according to any one of Embodiments 1 to 170 and 183 for treating a viral infection.

[1017] Combination therapy

[1018] In some embodiments, a compound of formula (I) is co-administered with at least one additional agent selected from the group consisting of a herpesvirus entry inhibitor, an inhibitor of herpesvirus early transcriptional events, a herpesvirus helicase-primase inhibitor, another herpesvirus DNA polymerase inhibitor, a UL97 kinase inhibitor, a herpesvirus protease inhibitor, a herpesvirus terminase inhibitor, a herpesvirus maturation inhibitor, another targeted inhibitor in the herpesvirus life cycle, a herpesvirus vaccine, and a herpesvirus biologic. In some embodiments, the herpesvirus is CMV.

[1019] These additional agents can be combined with the compounds of the present invention to produce a single pharmaceutical dosage form. Alternatively, these additional agents can be administered to the patient separately as part of a multiple dosage form, for example, using a kit. Such additional agents can be administered to the patient before, simultaneously with, or after administration of the compounds of the present invention or a pharmaceutically acceptable salt thereof.

[1020] When the compositions of the invention comprise a combination of a compound of the invention and one or more additional therapeutic or prophylactic agents, both the compound and the additional agent should be present at dosage levels of between about 10% to 100%, e.g., between about 10% to 80%, of the dosage normally administered in a monotherapy regimen.

[1021] Antiviral agents contemplated for use in such combination therapies include agents (compounds or biological agents) that effectively inhibit the formation and / or replication of viruses in humans, including but not limited to agents that interfere with host or viral mechanisms necessary for the formation and / or replication of viruses in humans. Such agents may be selected from: herpes virus entry inhibitors; herpes virus early transcription event inhibitors; herpes virus helicase-primase inhibitors; herpes virus DNA polymerase inhibitors, such as ganciclovir Valganciclovir Cidofovir Foscarnet CMX001, cyclopropavir (MBX-400), and valaciclovir Inhibitors of UL97 kinase, such as Maribavir; Herpes virus protease inhibitors; Herpes virus terminal enzyme inhibitors, such as AIC246 (Letermovir); Herpes virus maturation inhibitors; other inhibitors, such as artesunate; CMV vaccines, such as TransVax, and herpes virus biopharmaceuticals, such as Cytogam

[1022] The compounds of the invention may also be used in combination with other agents (combination partners) (eg, additional antiviral agents of Formula I or not) for treating a viral infection in a subject.

[1023] The term "combination" is intended to mean a fixed combination in the form of one dosage unit, as separate dosage forms suitable for simultaneous or sequential use, or as a kit for combined administration, wherein the compound of the present invention and the combination partner can be administered independently simultaneously or separately within a time interval which, inter alia, allows the combination partners to exhibit a synergistic, e.g., synergistic, effect or any combination thereof.

[1024] In certain embodiments of the present invention, the compounds of the present invention are used in combination with a second antiviral agent, such as those named herein.

[1025] A second antiviral agent can be administered in combination with a compound of the invention, wherein the second antiviral agent is administered before, simultaneously with, or after one or more compounds of the invention. When it is desired to administer a compound of the invention and a second agent simultaneously and by the same route of administration, the compound of the invention and the second agent can be formulated into the same dosage form. Examples of dosage forms containing a compound of the invention and a second agent are tablets or capsules.

[1026] In some embodiments, the combination of a compound of the invention and a second antiviral agent can provide synergistic activity.The compound of the invention and the second antiviral agent can be administered together, separately but simultaneously, or sequentially.

[1027] Use of the compound of the present invention in combination with an immunomodulator

[1028] Compounds and compositions described herein can be used in combination with one or more therapeutic agents (such as activators of costimulatory molecules, or inhibitors of immunosuppressive molecules, or vaccines) serving as immunomodulators or administered. Programmed death 1 (PD-1) protein is an inhibitory member (Okazaki et al. (2002) Curr Opin Immunol 14:391779-82 of the extended CD28 / CTLA4 family of T cell regulators; Bennett et al. (2003) J. Immunol. 170:711-8). PD-1 is expressed on activated B cells, T cells, and monocytes. PD-1 is a negative regulator of TCR signaling (Ishida, Y. et al. (1992) EMBO J. 11: 3887-3895; Blank, C. et al. (Epub December 29, 2006) Immunol. Immunother. 56 (5): 739-745), and an immunosuppressive protein that is upregulated in chronic infection. The interaction between PD-1 and PD-L1 can serve as an immune checkpoint, which can lead to, for example, a decrease in infiltrating lymphocytes, a decrease in T cell receptor-mediated proliferation, and / or immune escape of cancer cells or infected cells (Dong et al. (2003) J. Mol. Med. 81: 281-7; Blank et al. (2005) Cancer Immunol. Immunother. 54: 307-314; Konishi et al. (2004) Clin. Cancer Res. 10: 5094-100). Immune suppression can be reversed by inhibiting the local interaction of PD-1 with PD-L1 or PD-L2; when the interaction of PD-1 with PD-L2 is also blocked, the effect is additive (Iwai et al. (2002) Proc. Nat'l. Acad. Sci. USA 99: 12293-7; Brown et al. (2003) J. Immunol. 170: 1257-66). Immune regulation can be achieved by binding to immunosuppressive proteins (e.g., PD-1) or to binding proteins that regulate inhibitory proteins (e.g., PD-L1, PD-L2).

[1029] In one embodiment, the combination therapy of the present invention includes an immunomodulator that is an inhibitor or antagonist of an inhibitory molecule of an immune checkpoint molecule. In another embodiment, the immunomodulator binds to a protein that naturally inhibits an immune checkpoint molecule. When used in combination with an antiviral compound, these immunomodulators can enhance the antiviral response and thus enhance the efficacy relative to treatment with an antiviral compound alone.

[1030] The term "immune checkpoint" refers to a group of molecules on the cell surface of CD4 and CD8 T cells. These molecules can be effectively used as "brakes" to lower or inhibit adaptive immune responses. Immune checkpoint molecules include but are not limited to programmed death 1 (PD-1), cytotoxic T lymphocyte antigen 4 (CTLA-4), B7H1, B7H4, OX-40, CD137, CD40 and LAG3, which directly inhibit immune cells. Immunotherapeutics that can serve as immune checkpoint inhibitors that can be used in the methods of the present invention include but are not limited to inhibitors of PD-L1, PD-L2, CTLA4, TIM3, LAG3, VISTA, BTLA, TIGIT, LAIR1, CD160, 2B4 and / or TGFRβ. The inhibition of inhibitory molecules can be carried out by inhibition at the DNA, RNA or protein levels. In some embodiments, inhibitory nucleic acids (e.g., dsRNA, siRNA or shRNA) can be used to inhibit the expression of inhibitory molecules. In other embodiments, the inhibitor of the inhibitory signal is a polypeptide that is bound to the inhibitory molecule, such as a soluble ligand, or an antibody or its antigen-binding fragment.

[1031] "In combination with" is not intended to imply that the therapies or therapeutic agents must be administered simultaneously and / or formulated for delivery together, although such methods of delivery are within the scope described herein. The immunomodulator can be administered simultaneously with, before, or after one or more compounds of the invention and optionally one or more additional therapies or therapeutic agents. The therapeutic agents in the combination can be administered in any order. Generally, each agent will be administered at a dose and / or schedule determined for that agent. It will also be understood that the therapeutic agents used in the combination can be administered together in a single composition or separately in different compositions. Generally, it is contemplated that the level of use of each therapeutic agent used in combination will not exceed the level at which it is used alone. In some embodiments, the level used in combination will be lower than the level used alone.

[1032] In certain embodiments, the antiviral compounds described herein are administered in combination with one or more immunomodulators that are inhibitors of PD-1, PD-L1, and / or PD-L2. Each such inhibitor can be an antibody, an antigen-binding fragment thereof, an immunoadhesin, a fusion protein, or an oligopeptide. Examples of such immunomodulators are known in the art.

[1033] In some embodiments, the immunomodulator is an anti-PD-1 antibody selected from MDX-1106, Merck 3475, or CT-011.

[1034] In some embodiments, the immunomodulator is an immunoadhesin (e.g., an immunoadhesin comprising the extracellular or PD-1 binding portion of PD-L1 or PD-L2 fused to a constant region (e.g., an Fc region of an immunoglobulin sequence)).

[1035] In some embodiments, the immunomodulator is a PD-1 inhibitor, such as AMP-224.

[1036] In some embodiments, the immunomodulator is a PD-L1 inhibitor, such as an anti-PD-L1 antibody.

[1037] In some embodiments, the immunomodulator is an anti-PD-L1 binding antagonist selected from YW243.55.S70, MPDL3280A, MEDI-4736, MSB-0010718C, or MDX-1105. MDX-1105 (also known as BMS-936559) is an anti-PD-L1 antibody described in WO2007 / 005874. Antibody YW243.55.S70 is an anti-PD-L1 antibody described in WO2010 / 077634.

[1038] In some embodiments, the immunomodulator is nivolumab (CAS Reg. No. 946414-94-4). Alternative names for nivolumab include MDX-1106, MDX-1106-04, ONO-4538, or BMS-936558. Nivolumab is a fully human IgG4 monoclonal antibody that specifically blocks PD-1. Nivolumab (clone 5C4) and other human monoclonal antibodies that specifically bind to PD-1 are disclosed in US 8,008,449, EP 2161336, and WO 2006 / 121168.

[1039] In some embodiments, the immunomodulator is the anti-PD-1 antibody pembrolizumab. Pembrolizumab (also known as lambrolizumab, MK-3475, MK03475, SCH-900475, or Merck) is a humanized IgG4 monoclonal antibody that binds to PD-1. Pembrolizumab and other humanized anti-PD-1 antibodies are disclosed in Hamid, O. et al. (2013) New England Journal of Medicine 369(2):134–44, US 8,354,509, WO2009 / 114335, and WO2013 / 079174.

[1040] In some embodiments, the immunomodulator is Pidilizumab (CT-011; CureTech), a humanized IgG1k monoclonal antibody that binds to PD 1. Pidilizumab and other humanized anti-PD-1 monoclonal antibodies are disclosed in WO 2009 / 101611.

[1041] Other anti-PD1 antibodies that can be used as immunomodulators in the methods disclosed herein include AMP 514 (Amplimmune) and anti-PD1 antibodies disclosed in US 8,609,089, US 2010028330, and / or US 20120114649. In some embodiments, the anti-PD-L1 antibody is MSB0010718C. MSB0010718C (also known as A09-246-2; Merck Serono) is a monoclonal antibody that binds to PD-L1.

[1042] In some embodiments, the immunomodulator is MDPL3280A (Genentech / Roche), a human Fc-optimized IgG1 monoclonal antibody that binds to PD-L1. MDPL3280A and other human monoclonal antibodies against PD-L1 are disclosed in U.S. Patent No. 7,943,743 and U.S. Publication No. 20120039906. Other anti-PD-L1 binding agents that can be used as immunomodulators in the methods of the present invention include YW243.55.S70 (see WO2010 / 077634), MDX-1105 (also known as BMS-936559), and the anti-PD-L1 binding agents disclosed in WO2007 / 005874.

[1043] In some embodiments, the immunomodulator is AMP-224 (B7-DCIg; Amplimmune; disclosed, e.g., in WO 2010 / 027827 and WO 2011 / 066342), a PD-L2 Fc fusion soluble receptor that blocks the interaction between PD1 and B7-H1.

[1044] In some embodiments, the immunomodulator is an anti-LAG-3 antibody, such as BMS-986016. BMS-986016 (also referred to as BMS986016) is a monoclonal antibody that binds to LAG-3. BMS-986016 and other humanized anti-LAG-3 antibodies are disclosed in US 2011 / 0150892, WO 2010 / 019570, and WO 2014 / 008218.

[1045] In certain embodiments, the combination therapies disclosed herein include a co-stimulatory molecule or an inhibitory molecule, such as a modulator of a co-inhibitory ligand or receptor.

[1046] In one embodiment, the co-stimulatory modulator (e.g., agonist) of a co-stimulatory molecule is selected from an agonist (e.g., an agonist antibody or antigen-binding fragment thereof, or a soluble fusion thereof) of OX40, CD2, CD27, CDS, ICAM-1, LFA-1 (CD11a / CD18), ICOS (CD278), 4-1BB (CD137), GITR, CD30, CD40, BAFFR, HVEM, CD7, LIGHT, NKG2C, SLAMF7, NKp80, CD160, B7-H3, or a CD83 ligand.

[1047] In another embodiment, the combination therapies disclosed herein include an immunomodulatory agent that is a costimulatory molecule, such as an agonist associated with positive signaling including the costimulatory domains of CD28, CD27, ICOS, and / or GITR.

[1048] Exemplary GITR agonists include, for example, GITR fusion proteins and anti-GITR antibodies (e.g., bivalent anti-GITR antibodies), such as the GITR fusion proteins described in U.S. Pat. No. 6,111,090, European Patent No. 090505B1, U.S. Pat. No. 8,586,023, PCT Publication Nos. WO 2010 / 003118 and 2011 / 090754, or, for example, U.S. Pat. No. 7,025,962, European Patent No. 1947183B1, U.S. Pat. No. 7,812,135, U.S. Pat. No. 8,388,967, U.S. Pat. No. 8,591,886, European Patent No. EP 1866339, PCT Publication No. WO 2011 / 028683, PCT Publication No. WO 2013 / 039954, PCT Publication No. WO 2005 / 007190, PCT Publication No. WO 2007 / 133822, PCT Publication No. WO 2005 / 055808, PCT Publication No. WO 99 / 40196, PCT Publication No. WO 2001 / 03720, PCT Publication No. WO 99 / 20758, PCT Publication No. WO 2006 / 083289, PCT Publication No. WO 2005 / 115451, U.S. Patent No. 7,618,632, and PCT Publication No. WO 2011 / 051726.

[1049] In one embodiment, the immunomodulator used is a soluble ligand (e.g., CTLA-4-Ig), or an antibody or antibody fragment that binds to PD-L1, PD-L2, or CTLA4. For example, an anti-PD-1 antibody molecule can be administered in combination with an anti-CTLA-4 antibody (e.g., ipilimumab). Exemplary anti-CTLA4 antibodies include Tremelimumab (an IgG2 monoclonal antibody available from Pfizer, formerly known as ticilimumab, CP-675,206); and Ipilimumab (CTLA-4 antibody, also known as MDX-010, CAS No. 477202-00-9).

[1050] In one embodiment, the anti-PD-1 antibody molecule is administered following treatment with a compound of the invention as described herein.

[1051] In another embodiment, an anti-PD-1 or PD-L1 antibody molecule is administered in combination with an anti-LAG-3 antibody or an antigen-binding fragment thereof. In another embodiment, an anti-PD-1 or PD-L1 antibody molecule is administered in combination with an anti-TIM-3 antibody or an antigen-binding fragment thereof. In yet other embodiments, an anti-PD-1 or PD-L1 antibody molecule is administered in combination with an anti-LAG-3 antibody and an anti-TIM-3 antibody or an antigen-binding fragment thereof. The combination of antibodies described herein can be administered, for example, as a single antibody alone, or, for example, as a bispecific or trispecific antibody molecule. In one embodiment, a bispecific antibody comprising an anti-PD-1 or PD-L1 antibody molecule and an anti-TIM-3 or anti-LAG-3 antibody or an antigen-binding fragment thereof is administered. In certain embodiments, the combination of antibodies described herein is used to treat cancer, for example, a cancer as described herein (e.g., a solid tumor). The efficacy of the above combination can be tested in animal models known in the art. For example, an animal model for testing the synergistic effect of anti-PD-1 and anti-LAG-3 is described, for example, in Woo et al. (2012) Cancer Res. 72 (4): 917-27).

[1052] Exemplary immunomodulators that can be used in combination therapy include, but are not limited to, afutuzumab (available from ); pegfilgrastim Lenalidomide (CC-5013, ); thalidomide Pomalidomide (actimid) (CC4047); and cytokines, such as IL-21 or IRX-2 (a mixture of human cytokines including interleukin 1, interleukin 2, and interferon gamma, CAS 951209-71-5, available from IRX Therapeutics).

[1053] Exemplary dosages of such immunomodulators that can be used in combination with the antiviral compounds of the invention include a dose of about 1 mg / kg to 10 mg / kg, e.g., 3 mg / kg, of an anti-PD-1 antibody molecule, and a dose of about 3 mg / kg of an anti-CTLA-4 antibody (e.g., ipilimumab).

[1054] Examples of embodiments of methods of using the antiviral compounds of the present invention in combination with immunomodulators include these, which can be used with compounds of Formula I disclosed herein, or any subgenus or species thereof:

[1055] i. A method of treating a viral infection in a subject, comprising administering to the subject a compound of formula (I) as described herein and an immunomodulatory agent.

[1056] ii. The method according to embodiment i, wherein the immunomodulator is an activator of a co-stimulatory molecule or an inhibitor of an immune checkpoint molecule.

[1057] iii. A method according to any one of embodiments i and ii, wherein the activator of the co-stimulatory molecule is an agonist of one or more of OX40, CD2, CD27, CDS, ICAM-1, LFA-1 (CD11a / CD18), ICOS (CD278), 4-1BB (CD137), GITR, CD30, CD40, BAFFR, HVEM, CD7, LIGHT, NKG2C, SLAMF7, NKp80, CD160, B7-H3 and CD83 ligand.

[1058] iv. A method according to any one of embodiments i to iii above, wherein the inhibitor of the immune checkpoint molecule is selected from PD-1, PD-L1, PD-L2, CTLA4, TIM3, LAG3, VISTA, BTLA, TIGIT, LAIR1, CD160, 2B4 and TGFRβ.

[1059] v. The method according to any one of embodiments i to iii, wherein the inhibitor of the immune checkpoint molecule is selected from an inhibitor of PD-1, PD-L1, LAG-3, TIM-3 or CTLA4, or any combination thereof.

[1060] vi. The method according to any one of embodiments i to v, wherein the inhibitor of the immune checkpoint molecule is a soluble ligand or an antibody or antigen-binding fragment thereof that binds to the immune checkpoint molecule.

[1061] vii. The method according to any one of embodiments i to vi, wherein the antibody or antigen-binding fragment thereof is from IgG1 or IgG4 (eg, human IgG1 or IgG4).

[1062] viii. The method of any one of embodiments i to vii, wherein the antibody or antigen-binding fragment thereof is altered (e.g., mutated) to increase or decrease one or more of the following: Fc receptor binding, antibody glycosylation, the number of cysteine residues, effector cell function, or complement function.

[1063] ix. The method of any one of embodiments i to viii, wherein the antibody molecule is a bispecific or multispecific antibody molecule having a first binding specificity for PD-1 or PD-L1 and a second binding specificity for TIM-3, LAG-3, or PD-L2. x. The method of any one of embodiments i to ix, wherein the immunomodulator is an anti-PD-1 antibody selected from nivolumab, pembrolizumab, or pidilizumab.

[1064] xi. The method according to any one of embodiments i to x, wherein the immunomodulator is an anti-PD-L1 antibody selected from YW243.55.S70, MPDL3280A, MEDI-4736, MSB-0010718C or MDX-1105.

[1065] xii. The method according to any one of embodiments i to x, wherein the immunomodulatory agent is an anti-LAG-3 antibody molecule.

[1066] xiii. The method of embodiment xii, wherein the anti-LAG-3 antibody molecule is BMS-986016.

[1067] xiv. The method of any one of embodiments i to x, wherein the immunomodulator is an anti-PD-1 antibody molecule administered by injection (e.g., subcutaneously or intravenously) at a dose of about 1 mg / kg to 30 mg / kg, e.g., about 5 mg / kg to 25 mg / kg, about 10 mg / kg to 20 mg / kg, about 1 mg / kg to 5 mg / kg, or about 3 mg / kg, e.g., once a week to once every 2, 3, or 4 weeks.

[1068] xv. The method according to embodiment xiv, wherein the anti-PD-1 antibody molecule is administered at a dose of about 10 mg / kg to 20 mg / kg every other week.

[1069] xvi. The method of embodiment xv, wherein the anti-PD-1 antibody molecule (eg, nivolumab) is administered intravenously every two weeks at a dose of about 1 mg / kg to 3 mg / kg, eg, about 1 mg / kg, 2 mg / kg, or 3 mg / kg.

[1070] xvii. The method according to embodiment xv, wherein the anti-PD-1 antibody molecule (eg, nivolumab) is administered intravenously at a dose of about 2 mg / kg at intervals of 3 weeks.

[1071] Example

[1072] The invention is further illustrated by the following examples, which should not be construed as limiting.The assays used throughout the examples are well established in the art: demonstration of efficacy in these assays is generally considered predictive of efficacy in subjects.

[1073] List of abbreviations

[1074] Ac acetyl

[1075] ACN or MeCN Acetonitrile

[1076] AcOEt / EtOAc Ethyl acetate

[1077] AcOH acetic acid

[1078] aq water-based

[1079] Bn benzyl

[1080] Bu butyl (nBu = n-butyl, tBu = tert-butyl)

[1081] CDI Carbonyldiimidazole

[1082] CH3CN acetonitrile

[1083] DBU 1,8-diazabicyclo[5.4.0]-undec-7-ene

[1084] Boc2O Di-tert-butyl dicarbonate

[1085] DCE 1,2-dichloroethane

[1086] DCM dichloromethane

[1087] DIAD Diisopropyl azodicarboxylate

[1088] DiBAl-H Diisobutylaluminum hydride

[1089] DIPEA or DIEA N-ethyldiisopropylamine

[1090] DMA N,N-dimethylacetamide

[1091] DMAP dimethylaminopyridine

[1092] DMF N,N-dimethylformamide

[1093] DMSO dimethyl sulfoxide

[1094] EDC 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide

[1095] ESI electrospray ionization

[1096] Et2O diethyl ether

[1097] Et3N triethylamine

[1098] Ether

[1099] EtOAc

[1100] EtOH

[1101] FC flash chromatography

[1102] h hour

[1103] HATU O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate

[1104] HBTU O-(Benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate

[1105] HCl

[1106] HMPA Hexamethylphosphoramide

[1107] HOBt 1-Hydroxybenzotriazole

[1108] HPLC high-performance liquid chromatography

[1109] H2O water

[1110] IPA Isopropyl alcohol

[1111] L liter

[1112] LC-MS liquid chromatography-mass spectrometry

[1113] LiHMDS Lithium bis(trimethylsilyl)amide

[1114] MgSO4 magnesium sulfate

[1115] Me methyl

[1116] MeI iodomethane

[1117] MeOH methanol

[1118] mg milligrams

[1119] min

[1120] mL milliliters

[1121] MS

[1122] MsCl methanesulfonyl chloride

[1123] NaHCO3 sodium bicarbonate

[1124] Na2SO4 sodium sulfate

[1125] NBS N-bromosuccinimide

[1126] NCS N-chlorosuccinimide

[1127] NH2OH Hydroxylamine

[1128] NMO 4-Methylmorpholine N-oxide

[1129] Pd / C Palladium / Carbon

[1130] Pd(OH)2 Palladium Hydroxide

[1131] PG protecting group

[1132] Ph Phenyl

[1133] Ph3P triphenylphosphine

[1134] Prep

[1135] Rf ratio shift value

[1136] RP Inverter

[1137] Rt retention time

[1138] RT Room temperature

[1139] SFC Supercritical Fluid Chromatography

[1140] SiO2 silica gel

[1141] SOCl2 thionyl chloride

[1142] Propylphosphonic anhydride

[1143] TBAF Tetrabutylammonium fluoride

[1144] TBDMS tert-butyldimethylsilyl

[1145] TBDPS tert-butyldiphenylsilyl

[1146] TBTU O-(Benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate

[1147] TEA triethylamine

[1148] TFA trifluoroacetic acid

[1149] THF Tetrahydrofuran

[1150] TIPS triisopropylsilyl

[1151] TLC thin layer chromatography

[1152] TPAP Tetrapropylammonium perruthenate

[1153] TsCl Tosyl chloride

[1154] TsOH Toluenesulfonic acid

[1155] Preparation of key intermediates

[1156] Intermediate 1

[1157] 1-(Bromomethyl)-1-(cyclopropylsulfonyl)cyclopropane(int-1)

[1158]

[1159] Step 1: To a slurry of sodium cyclopropanesulfinate (5.79 g, 45.2 mmol, 1.2 eq) in DMF (30 mL) was added benzyl 2-bromoacetate (5.97 mL, 37.7 mmol, 1.0 eq). The resulting mixture was stirred at room temperature overnight and then diluted with H2O and Et2O. The layers were separated and the aqueous layer was extracted with Et2O. The combined organic extracts were washed with brine, dried over Na2SO4, filtered and concentrated to afford benzyl 2-(cyclopropylsulfonyl)acetate (ii-a). 1 H NMR (400MHz, CDCl3) δ7.44–7.34(m,5H),5.26(s,2H),4.09–4.03(m,2H),2.76–2.67(m,1H),1.31–1.24(m,2H),1.09–1.02(m,2H).

[1160] Step 2: To a solution of 2-(cyclopropylsulfonyl)benzyl acetate (i1-a) (9.37 g, 36.8 mmol, 2.0 equiv) in DMF (350 mL) was added K2CO3 (10.18 g, 73.7 mmol, 1.0 equiv) and 1,2-dibromoethane (3.81 mL, 44.2 mmol, 1.2 equiv). The resulting mixture was stirred at 60 ° C for 12 h, then cooled to room temperature and diluted with Et2O. The solid was removed by filtration, the filtrate was washed with water, and the aqueous layer was extracted with Et2O. The combined organic extracts were washed with brine, dried over Na2SO4, filtered and concentrated. The oil was purified by column chromatography (SiO2, 0-100% DCM / heptane) to give 1-(cyclopropylsulfonyl)cyclopropanecarboxylic acid benzyl ester (i1-b). 1 H NMR (400MHz, CDCl3) δ7.41–7.32(m,5H),5.26–5.22(m,2H),3.00(tt,J=8.09,4.90H z,1H),1.78–1.72(m,2H),1.68–1.63(m,2H),1.25–1.20(m,2H),1.01–0.95(m,2H).

[1161] Step 3: To a solution of benzyl 1-(cyclopropylsulfonyl)cyclopropanecarboxylate (i1-b) (6.53 g, 23.29 mmol) in THF (50 mL) was added LiBH4 (2.0 M in THF, 11.65 mL, 23.29 mmol). The resulting solution was stirred at room temperature overnight, and the reaction mixture was then added to a 2M HCl / ice mixture. The biphasic mixture was extracted with DCM, and the combined organic extracts were dried over Na2SO4, filtered and concentrated. The oil was purified by column chromatography (SiO2, 0-100% EtOAc / heptane) to give (1-(cyclopropylsulfonyl)cyclopropyl)methanol (i1-c). TLC R f =0.2 (1:3 EtOAc / petroleum ether). 1 HNMR (400MHz, CDCl3) δ3.92 (d, J = 6.11Hz, 2H), 2.59–2.50 (m, 2H), 1.52–1.47 (m, 2H), 1.29–1.23 (m, 2H), 1.10–1.01 (m, 4H). MS(ESI): m / z 177.1[M+H]+.

[1162] Step 4: A solution of (1-(cyclopropylsulfonyl)cyclopropyl)methanol (ii-c) (10.0 g, 56.7 mmol, 1.0 equiv) and DPPE (16.0 g, 39.7 mmol, 0.7 equiv) in THF (100 mL) was cooled to 0 ° C., and then a solution of CBr4 (38.0 g, 113.5 mmol, 2.0 equiv) in THF (20 mL) was added over 0.5 h. After 90 min at 25 ° C., the solids were removed by filtration and the filtrate was concentrated. The residue was purified by column chromatography (SiO2, 10-25% EtOAc / petroleum ether) to give 1-(bromomethyl)-1-(cyclopropylsulfonyl)cyclopropane (int-1). TLC R f = 0.5 (25% EtOAc / petroleum ether). 1 H NMR (400MHz, CDCl3) δ3.89(s,2H),2.66(m,1H),1.78–1.69(m,2H),1.33–1.26(m,2H),1.23–1.18(m,2H),1.16–1.09(m,2H).

[1163] Intermediate 2

[1164] 1-(Bromomethyl)-1-((1-methylcyclopropyl)sulfonyl)cyclopropane(int-2)

[1165]

[1166] Step 1: A solution of (1-(cyclopropylsulfonyl)cyclopropyl)methanol (30 g, 170 mmol, 1.0 equiv) in DMF (300 mL) was cooled to 0°C and NaH (60% in mineral oil, 13.6 g, 341 mmol, 2.0 equiv) was added portionwise (gas evolution). The reaction mixture was stirred at 0°C for 0.5 h and then NaI (1.7 g, 17.0 mmol, 0.1 equiv) and BnBr (29 g, 170 mmol, 1.0 equiv) were added at 0°C. The reaction mixture was stirred at 0°C for 3 h and then poured into saturated NH4Cl (300 mL) and extracted with EtOAc (3 x 100 mL). The combined organic extracts were dried over Na2SO4, filtered and concentrated. The material was purified by trituration from EtOAc / petroleum ether to afford (((1-(cyclopropylsulfonyl)cyclopropyl)methoxy)methyl)benzene (i2-a). 1 H NMR (400MHz, CDCl3) δ7.38–7.32(m,5H),4.59(s,2H),3.82(s,2H),2.70(m,1H),1.51–1.49(m,2H),1.22–1.20(m,2H),1.03–0.98(m,4H).

[1167] Step 2: n-BuLi (2.5 M in hexanes, 2.16 mL, 5.40 mmol, 1.2 eq) was added dropwise to a solution of (((1-(cyclopropylsulfonyl)cyclopropyl)methoxy)methyl)benzene (i2-a) (1.2 g, 4.50 mmol, 1.0 eq) in THF (20 mL) at -60 °C. The reaction was stirred at 0 °C for 30 min, then MeI (0.84 mL, 13.5 mmol, 3.0 eq) was added at 0 °C. The reaction was stirred at 25 °C for 1 h, then quenched with water (20 mL) and extracted with EtOAc (3 x 10 mL). The combined organic extracts were washed with brine (20 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by RP-HPLC to give (((1-((1-methylcyclopropyl)sulfonyl)cyclopropyl)methoxy)methyl)benzene (i2-b). TLC R f =0.4 (1:5 EtOAc / petroleum ether). MS (ESI): m / z 281.0 [M+H] + .

[1168] Step 3: A mixture of (((1-((1-methylcyclopropyl)sulfonyl)cyclopropyl)methoxy)methyl)benzene (i2-b) (900 mg, 2.71 mmol, 1.0 equiv) and Pd / C (200 mg) in MeOH (10 mL) and AcOH (10 mL) was stirred at 20 °C under a hydrogen atmosphere for 12 h. The solid was removed by filtration and the filtrate was concentrated. The residue was diluted with water (10 mL), neutralized with saturated Na2CO3, and extracted with EtOAc (3×5 mL). The combined organic extracts were dried over Na2SO4, filtered and concentrated to give (1-((1-methylcyclopropyl)sulfonyl)cyclopropyl)methanol (i2-c). TLC R f =0.1 (1:5 EtOAc / petroleum ether). 1 H NMR (400MHz, MeOH-d4) δ3.78(s,2H),1.43(s,3H),1.30–1.29(m,2H),1.24–1.22(m,2H),1.00–0.98(m,2H),0.78–0.76(m,2H).

[1169] Step 4: A solution of (1-((1-methylcyclopropyl)sulfonyl)cyclopropyl)methanol) (i2-c) (220 mg, 1.16 mmol, 1.0 equiv) in THF (4 mL) was cooled to -40 ° C, and then Et3N (234 mg, 2.32 mmol, 2.0 equiv) and MsCl (199 mg, 1.73 mmol, 1.5 equiv) were added. The mixture was stirred at -40 ° C for 1 h, then placed in an ice bath and LiBr (502 mg, 5.78 mmol, 5.0 equiv) was added in one portion. The mixture was stirred at 25 ° C for 1 h, then diluted with water (20 mL) and extracted with EtOAc (3×20 mL). The combined organic extracts were washed with brine (20 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography (SiO2, 10-25% EtOAc / petroleum ether) to give 1-(bromomethyl)-1-((1-methylcyclopropyl)sulfonyl)cyclopropane (int-2). TLC R f = 0.8 (25% EtOAc / petroleum ether). 1 H NMR (400MHz, MeOH-d4) δ3.95(s,2H),1.70–1.65(m,2H),1.58(s,3H),1.51–1.46(m,2H),1.33–1.27(m,3H),1.01–0.95(m,2H).

[1170] Intermediate 3

[1171] 1-(Bromomethyl)-1-(ethylsulfonyl)cyclopropane(int-3)

[1172]

[1173] Step 1: Ethyl 1-(ethylsulfonyl)cyclopropanecarboxylate (i3-a) was obtained using the method described for the synthesis of intermediate (i1-b), except that ethyl 2-(ethylsulfonyl)acetate was used instead of benzyl 2-(cyclopropylsulfonyl)acetate (i1-a). TLC R f = 0.5 (33% EtOAc / petroleum ether). 1 H NMR (400MHz, CDCl3) δ4.23(q,J=7.2Hz,2H),3.45(q,J=7.5Hz,2H),2.02(s,1H),1 .78–1.72(m,2H),1.66–1.60(m,2H),1.38(t,J=7.5Hz,3H),1.28(t,J=7.2Hz,3H).

[1174] Step 2: A solution of ethyl 1-(ethylsulfonyl)cyclopropanecarboxylate (i3-a) (15 g, 72.7 mmol, 1.0 equiv) in THF (150 mL) was cooled to 0 ° C., and LiAlH4 (3.3 g, 87.2 mmol, 1.2 equiv) was added in portions. The mixture was allowed to warm to room temperature and stirred at this temperature for 3 h, and then quenched with a solution of sodium hydroxide (3.3 g) in water (10 mL). The solid was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, 15-50% EtOAc / petroleum ether) to give (1-(ethylsulfonyl)cyclopropyl)methanol (i3-b). TLC R f = 0.1 (33% EtOAc / petroleum ether). 1 H NMR (400MHz, CDCl3) δ3.82(s,2H),3.15(q,J=7.6Hz,2H),2.56(s,1H),1.44–1.40(m,2H),1.34(t,J=7.6Hz,3H),0.97–0.93(m,2H).

[1175] Step 3: 1-(bromomethyl)-1-(ethylsulfonyl)cyclopropane (int-3) is obtained using the method described for the synthesis of intermediate (int-1) in step 4, except that (1-(ethylsulfonyl)cyclopropyl)methanol (i3-b) is used instead of (1-(cyclopropylsulfonyl)cyclopropyl)methanol (i1-c). 1 H NMR (400MHz, CDCl3) δ3.79 (s, 2H), 3.28–3.16 (m, 2H), 1.74–1.66 (m, 2H), 1.36 (t, J = 7.5Hz, 3H), 1.16–1.08 (m, 2H).

[1176] Intermediate 4

[1177] 1-(Bromomethyl)-1-(methylsulfonyl)cyclopropane(int-4)

[1178]

[1179] Step 1: Methyl 1-(methylsulfonyl)cyclopropanecarboxylate (i4-a) was obtained using the method described for the synthesis of intermediate (i1-b) except that methyl 2-(methylsulfonyl)acetate was used in place of benzyl 2-(cyclopropylsulfonyl)acetate (i1-a). 1 H NMR (400MHz, CDCl3) δ3.81(s,3H),3.20(s,3H),1.84–1.79(m,2H),1.70–1.65(m,2H).

[1180] Step 2: (1-(methylsulfonyl)cyclopropyl)methanol (i4-b) is obtained using the method described for the synthesis of intermediate (i1-c), except that 1-(methylsulfonyl)cyclopropanecarboxylic acid methyl ester (i4-a) is used to replace 1-(cyclopropylsulfonyl)cyclopropanecarboxylic acid benzyl ester (i1-b). 1 H NMR (400MHz, CDCl3) δ3.92 (d, J = 5.53Hz, 2H), 3.04 (s, 3H), 2.48 (t, J = 5.45Hz, 1H), 1.54–1.48 (m, 2H), 1.08–1.01 (m, 2H).

[1181] Step 3: 1-(bromomethyl)-1-(methylsulfonyl)cyclopropane (int-4) was obtained using the method described for the synthesis of intermediate (int-1) in step 4, except that (1-(methylsulfonyl)cyclopropyl)methanol (i4-b) was used instead of (1-(cyclopropylsulfonyl)cyclopropyl)methanol (i1-c). 1 H NMR (400MHz, CDCl3) δ3.86(s,1H),3.10(s,3H),1.79–1.76(m,2H),1.23–1.19(m,2H).

[1182] Intermediate 5

[1183] 1-Methyl-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid ethyl ester (int-5)

[1184]

[1185] Step 1: To a solution of 3-iodo-1H-pyrazolo[3,4-c]pyridine (7.2 g, 29.4 mmol, 1.0 eq) in DMF (160 mL) was added NaH (60% in mineral oil, 2.4 g, 58.8 mmol, 2.0 eq) in portions at 0°C (gas evolution). The mixture was stirred for 30 min, then CH3I (8.7 g, 61.3 mmol, 2.1 eq) was added at 0°C. After the reaction mixture was stirred at 0°C for 30 min and at 15°C for 1 h, the mixture was diluted with H2O (300 mL) and neutralized to pH 7 with 1M HCl. The aqueous layer was extracted with EtOAc (3×200 mL), and the combined organic extracts were dried over Na2SO4, filtered, and concentrated. The crude solid was purified by RP-HPLC to give 3-iodo-1-methyl-1H-pyrazolo[3,4-c]pyridine (i5-a). 1H NMR (400MHz, CDCl3) δ8.86 (s, 1H), 8.31 (d, J = 5.6Hz, 1H), 7.30 (d, J = 5.6Hz, 1H), 4.15 (s, 3H). MS(ESI):m / z 260.1[M+H] + .

[1186] Step 2: To a solution of 3-iodo-1-methyl-1H-pyrazolo[3,4-c]pyridine (i5-a) (4.0 g, 15.4 mmol, 1.0 equiv) in EtOH (150 mL) was added Pd(dppf)Cl2 (3.95 g, 5.41 mmol, 0.35 equiv) and Et3N (6.44 mL, 46.3 mmol, 3.0 equiv). The mixture was stirred at 40 ° C. for 24 h under a CO atmosphere (50 psi) and then concentrated. The residue was dry loaded onto silica gel and purified by column chromatography (SiO2, 20-75% EtOAc / petroleum ether) to give 1-methyl-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid ethyl ester (i5-b). 1 H NMR (400MHz, CDCl3) δ 8.97 (d, J = 1.0 Hz, 1H), 8.40 (d, J = 5.6 Hz, 1H), 7.98 (dd, J = 1.2, 5.6 Hz, 1H), 4.46 (q, J = 7.2 Hz, 2H), 4.22 (s, 3H), 1.42 (t, J = 7.2 Hz, 3H). MS(ESI):m / z 206.3[M+H] + .

[1187] Step 3: TFAA (1.5 mL) was added dropwise to a solution of N-oxide × (221 mg, 1.0 mmol, 1.0 equiv) in DMF (3 mL) at 20 ° C. The reaction mixture was stirred for 18 h and then diluted with ice water (10 mL). The mixture was neutralized with 10% Na2CO3 and extracted with EtOAc (4 × 3 mL). The combined organic extracts were dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography (SiO2, 50% EtOAc / petroleum ether) to give 1-methyl-7-oxo-6,7-dihydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid ethyl ester (int-5). 1 H NMR (400MHz, MeOH-d4) δ7.08 (d, J = 7.1 Hz, 1H), 6.95 (d, J = 7.1 Hz, 1H), 4.45 (q, J = 7.1 Hz, 2H), 4.41 (s, 3H), 1.45 (t, J = 7.2 Hz, 3H). MS(ESI):m / z 222.1[M+H] + .

[1188] Intermediate 6

[1189] 6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-6,7-dihydro-1H-pyrazolo[3, 4-c]pyridine-3-carboxylic acid ethyl ester (int-6)

[1190]

[1191] A mixture of ethyl 1-methyl-7-oxo-6,7-dihydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylate (int-5) (80 mg, 0.37 mmol, 1.0 equiv), CsCO (620 mg, 1.9 mmol, 5.0 equiv) and 1-(bromomethyl)-1-(cyclopropylsulfonyl)cyclopropane (int-1) (177 mg, 0.74 mmol, 2.0 equiv) in DMF (2 mL) was stirred at 50 ° C for 12 h, then diluted with water (2 mL) and extracted with EtOAc (3×2 mL). The combined organic extracts were washed with water (4 mL) and brine (2×4 mL), dried over NaSO, filtered and concentrated. The re...

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof, in: X is 5-6 membered heteroaryl having 1 to 4 heteroatoms independently selected from N, O and S as ring members; or containing 1 to 4 heteroatoms independently selected from N, NH, NR 17 , O or S as ring members; Y is a bond, -O- or Where * in Y indicates the point of attachment to X and ** in Y indicates the point of attachment to R B attachment points; q is 0; L MC does not exist; Z is W; A is for R 4 ; R B is H, C1-C6 alkyl, phenyl, pyridyl, phenylthio, pyrimidinyl or 5-8 membered cycloalkyl, wherein R B Optionally 1 to 3 R 5 group substitution; R 1 Selected from H, C 1- C3 alkyl and C substituted with 1 to 3 -OH groups 1- C3 alkyl; R 2 Selected from H, C 1- C3 alkyl and C substituted with 1 to 3 -OH groups 1- C3 alkyl; or R 1 and R 2 Together with the carbon atoms to which they are attached, they can form a 3-6 membered cycloalkyl ring; t is 0 or 1; Each R 3 , when present, is a substituent on the ring to which –LZ is directly attached, wherein each R 3 Independently selected from C 1- C3 alkyl; R 4 It is H, C 1- C3 alkyl, C 3- C6 cycloalkyl, -(CH2)2O(CH2)2Br, (CH2)2O(CH2)2OH or 1 or 2 independently selected from -OH, -C(=O)R 15 and R 10 C 1- C3 alkyl; Each R 5 are independently selected from halo, -CN, hydroxy, -NR 13 R 14 、C 3- C6 cycloalkyl, C 1- C3 alkoxy, C 1- C3 haloalkyl and optionally 1 to 3 R 6 C 1- C3 alkyl, where R B By two R 5 Replace and each R 5 is optionally replaced by 1 to 3 R 6 C 1- C3 alkyl, when directly attached to the same carbon atom, can be taken together with the carbon atoms to which the two are directly attached to form a C3 alkyl group optionally substituted by 1 to 3 R 6 a 3-5 membered cycloalkyl ring substituted with a group; Each R 6 Independently selected from halo, hydroxy, CN, C 1- C3 alkoxy, C 1- C3 alkyl and C 3- C5 cycloalkyl, Or two R 6 The group together with the carbon atom to which they are directly attached can form a 3-5 membered cycloalkyl ring or a 4-6 membered heterocyclic ring containing O, N or S as ring members and optionally substituted by 1 to 2 groups independently selected from oxo and C 1- C3 alkyl group substituted; L is -CH2-; W is cyclopropyl, wherein the cyclopropyl group is optionally substituted by 1 to 3 groups independently selected from the group consisting of: C 1- C3 alkyl, oxo, halogen, C 1- C3 haloalkyl, –L 2 OH, –L 2 OR 10 ,–L 2 OC(=O)NR 13 R 14 ,–L 2 SO2R 10 ,–L 2 SO2NR 14 R 10 ,–L 2 SO2NR 13 R 14 ,–L 2 SO2N=CR 13 NR 13 R 14 ,–L 2 SO2NR 13 C(=O)R 10 ,–L 2 C(=O)NR 13 SO2R 10 ,–L 2 S(=O)R 10 ,–L 2 S(=O)(=NR 13 )R 10 ,–L 2 NR 13 SO2NR 13 R 14 ,–L 2 NR 13 SO2R 10 ,–L 2 NR 13 R 14 ,–L 2 NR 13 C(=O)R 13 ,–L 2 NR 13 C(=O)OR 10 ,–L 2 C(=O)NR 13 R 14 and –L 2 C(=O)OR 13 ; R 10 Selected from C 1- C5 alkyl; C 1- C3 haloalkyl; and 3-6 membered cycloalkyl; Each R 10 Optionally substituted with 1 to 5 groups independently selected from: C 1- C4 alkyl, deuterium, C 1- C4 haloalkoxy, –L 3 OH, –L 3 CN, -L 3 OC(=O)R 14 、-L 3 OR 13 、C 1- C2 haloalkyl, oxo, -L 3 Halogen, –L 3 C 1- C3 alkoxy, –L 3 OC(=O)NR 13 R 14 ,–L 3 SO2R 13 ,–L 3 SO2NR 13 R 14 ,–L 3 SO2NR 13 C(=O)R 13 ,–L 3 C(=O)NR 13 SO2R 13 ,–L 3 S(=O)R 13 ,–L 3 S(=O)(=NR 14 )R 13 ,–L 3 NR 13 SO2NR 13 R 14 ,–L 3 NR 13 SO2R 13 ,–L 3 NR 13 R 14 ,–L 3 NR 14 C(=O)R 13 ,–L 3 NR 14 C(=O)OR 13 ,–L 3 C(=O)NR 13 R 14 ,–L 3 C(=O)OR 13 、-L 3 -(containing 1 to 2 independently selected from N, NH, NR 17 , O or S ring member 4-7 membered heterocyclic group), -L 3 -C 3- C5 cycloalkyl and -L 3 -(a 5-6 membered heteroaryl ring having 1 to 4 heteroatoms containing 1 to 4 nitrogen atoms, 0 or 1 oxygen atoms and 0 or 1 sulfur atoms as ring members), wherein said C 1- C4 alkyl, 4-7 membered heterocyclic group, C 3- The C5 cycloalkyl and 5-6 membered heteroaryl rings are each optionally further substituted by 1 to 3 groups independently selected from halo, C 1- C3 alkyl, C 1- C3 haloalkyl, -L 4 OR 13 、-L 4 CN and –L 4 NR 13 R 14 The group substitution; Each R 13 Independently selected from H; C 1- C4 alkyl; containing 1 to 2 independently selected from N, NH, NR 17 , O or S as ring members; and C 3- C6 cycloalkyl, wherein the C 1- C4 alkyl, heterocyclic and C 3- C6 cycloalkyl is optionally substituted by 1 to 3 independently selected 1- C4 alkyl, halogen, -OH, -NR 15 R 16 、-C(=O)OR 15 、C 1- C2 alkoxy and C substituted by 1 to 2 hydroxyl groups 1- C4 alkyl group substitution; R 14 Selected from H, C 1- C4 alkyl and C 3- C6 cycloalkyl, wherein the C 1- C4 alkyl and C 3- C6 cycloalkyl is optionally substituted by 1 to 3 independently selected 1- C4 alkyl, halogen, -OH, -NR 15 R 16 、C 1- C2 alkoxy and C substituted by 1 to 2 hydroxyl groups 1- C4 alkyl group substitution; or R 13 and R 14 Together with the nitrogen atom to which they are directly attached, they are capable of forming a 4-6 membered ring optionally containing additional N, O or S as ring members and optionally substituted by one to three selected from C 1- C2 alkyl, C 1- C2 alkoxy, oxo and hydroxy group substitution; R 15 and R 16 Each independently selected from H and C 1- C4 alkyl; Each R 17 Independently selected from H, C 1- C4 alkyl and C3-C8 cycloalkyl, or R 17 is a C that, together with the nitrogen atom to which it is directly attached and the nitrogen atom from the pyrazole ring, is capable of forming a 5-8 membered ring fused to the pyrazole ring. 1- C4 alkyl; Each L 2 and L 3 and L 4 are independently a bond or a straight or branched C 1- C3 alkylene; and Indicates a single bond or a double bond.

2. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound has a structure of formula (II), Among them, W, L, R 1 、R 2 、R 3 、R 4 and R B As defined in claim 1.

3. The compound according to claim 1 or claim 2, wherein R B is phenyl or 6-membered cycloalkyl, where R B Optionally 1 to 3 R 5 group substitution; R 1 Selected from H, C 1- C3 alkyl and C substituted with 1 to 3 -OH groups 1- C3 alkyl; R 2 It is H; t is 0; R 4 It is H, C 1- C3 alkyl, C 3- C6 cycloalkyl, -(CH2)2O(CH2)2Br, (CH2)2O(CH2)2OH or 1 to 2 independently selected -OH, -C(=O)R 15 and R 10 C 1- C3 alkyl; Each R 5 Independently selected from halo, -CN, hydroxy, C 1- C3 alkoxy, and C 1- C3 haloalkyl; L is -CH2-; W is cyclopropyl, wherein the cyclopropyl group is optionally substituted by 1 to 3 groups independently selected from the group consisting of: C 1- C3 alkyl, oxo, halogen, C 1- C3 haloalkyl, -OH, -OR 10 、–OC(=O)NR 13 R 14 ,–SO2R 10 , –SO2NR 14 R 10 , –SO2NR 13 R 14 、–SO2N=CR 13 NR 13 R 14 , –SO2NR 13 C(=O)R 10 、–C(=O)NR 13 SO2R 10 、–S(=O)R 10 、–S(=O)(=NR 13 )R 10 ,–NR 13 SO2NR 13 R 14 ,–NR 13 SO2R 10 ,–NR 13 R 14 ,–NR 13 C(=O)R 13 ,–NR 13 C(=O)OR 10 、–C(=O)NR 13 R 14 and –C(=O)OR 13 ; R 10 Selected from C 1- C5 alkyl; C 1- C3 haloalkyl; 3-6 membered cycloalkyl; phenyl; 5-6 membered heteroaryl having 1 to 4 heteroatoms independently selected from N, O and S as ring members; and containing 1 to 2 heteroatoms independently selected from N, NH, NR 17 , O or S ring members of the 4-6 membered heterocyclic group, Each R 10 Optionally substituted with 1 to 5 groups independently selected from: C 1- C4 alkyl, deuterium, C 1- C4 haloalkoxy, -OH, -CN, -OC(=O)R 14 、-L 3 OR 13 、C 1- C2 haloalkyl, oxo, -halo, –C 1- C3 alkoxy, –OC(=O)NR 13 R 14 ,–SO2R 13 , –SO2NR 13 R 14 , –SO2NR 13 C(=O)R 13 、–C(=O)NR 13 SO2R 13 、–S(=O)R 13 、–S(=O)(=NR 14 )R 13 ,–NR 13 SO2NR 13 R 14 ,–NR 13 SO2R 13 ,–NR 13 R 14 ,–NR 14 C(=O)R 13 ,–NR 14 C(=O)OR 13 、–C(=O)NR 13 R 14 、–C(=O)OR 13 , containing 1 to 2 independently selected from N, NH, NR 17 , O or S ring member 4-7 membered heterocyclic group, -C 3- C5 cycloalkyl and -5-6 membered heteroaryl ring having 1 to 4 heteroatoms containing 1 to 4 nitrogen atoms, 0 or 1 oxygen atoms and 0 or 1 sulfur atoms as ring members, wherein said C 1- C4 alkyl, 4-7 membered heterocyclic group, C 3- The C5 cycloalkyl and 5-6 membered heteroaryl rings are each optionally further substituted by 1 to 3 groups independently selected from halo, C 1- C3 alkyl, C 1- C3 haloalkyl, -OR 13 , -CN and –NR 13 R 14 The group substitution; Each R 13 Independently selected from H; C 1- C4 alkyl; containing 1 to 2 independently selected from N, NH, NR 17 , O or S as ring members; and C 3- C6 cycloalkyl, wherein the C 1- C4 alkyl, heterocyclic and C 3- C6 cycloalkyl is optionally substituted by 1 to 3 independently selected 1- C4 alkyl, halogen, -OH, -NR 15 R 16 、-C(=O)OR 15 、C 1- C2 alkoxy and C substituted by 1 to 2 hydroxyl groups 1- C4 alkyl group substitution; R 14 Selected from H, C 1- C4 alkyl and C 3- C6 cycloalkyl, wherein the C 1- C4 alkyl and C 3- C6 cycloalkyl is optionally substituted by 1 to 3 independently selected 1- C4 alkyl, halogen, -OH, -NR 15 R 16 、C 1- C2 alkoxy and C substituted by 1 to 2 hydroxyl groups 1- C4 alkyl group substitution; or R 13 and R 14 Together with the nitrogen atom to which they are directly attached, they are capable of forming a 4-6 membered ring optionally containing additional N, O or S as ring members and optionally substituted by one to three selected from C 1- C2 alkyl, C 1- C2 alkoxy, oxo and hydroxy group substitution; R 15 and R 16 Each independently selected from H and C 1- C4 alkyl; L 3 Is a bond or a straight chain or branched chain C 1- C3 alkylene; and Indicates a single bond or a double bond.

4. The compound according to any one of claims 1 to 3, wherein R B is phenyl or 6-membered cycloalkyl, where R B Optionally 1 to 3 R 5 group substitution; R 1 Selected from H, C 1- C3 alkyl and C substituted with 1 to 3 -OH groups 1- C3 alkyl; R 2 It is H; t is 0; R 4 It is H, C 1- C3 alkyl, C 3- C6 cycloalkyl, -(CH2)2O(CH2)2Br, (CH2)2O(CH2)2OH or 1 to 2 independently selected -OH, -C(=O)R 15 and R 10 C 1- C3 alkyl; Each R 5 independently selected from halogen, -CN, C 1- C3 alkoxy and C 1- C3 alkyl; L is -CH2-; W is cyclopropyl; R 10 Selected from C 1- C5 alkyl; C 1- C3 haloalkyl; 3-6 membered cycloalkyl; 5-6 membered heteroaryl having 1 to 4 heteroatoms independently selected from N, O and S as ring members; and 1 to 2 heteroatoms independently selected from N, NH, NR 17 , O or S ring members of the 4-6 membered heterocyclic group, Each R 10 Optionally substituted with 1 to 5 groups independently selected from: C 1- C4 alkyl, deuterium, C 1- C4 haloalkoxy, -OH, -CN, -OC(=O)R 14 、-L 3 OR 13 、-NR 13 R 14 ,–NR 14 C(=O)R 13 ,–NR 14 C(=O)OR 13 、–C(=O)NR 13 R 14 、–C(=O)OR 13 , containing 1 to 2 independently selected from N, NH, NR 17 , O or S ring members of the 4-7 membered heterocyclic group and -C 3- C5 cycloalkyl, wherein the C 1- C4 alkyl, 4-7 membered heterocyclic group and C 3- Each C5 cycloalkyl group is optionally further substituted by 1 to 3 groups independently selected from halogen, -OR 13 and –NR 13 R 14 The group substitution; Each R 13 Independently selected from H; C 1- C4 alkyl; containing 1 to 2 independently selected from N, NH, NR 17 , O or S as ring members; and C 3- C6 cycloalkyl, wherein the C 1- C4 alkyl, heterocyclic and C 3- C6 cycloalkyl is optionally substituted by 1 to 3 independently selected 1- C4 alkyl, halogen, -OH, -NR 15 R 16 、-C(=O)OR 15 、C 1- C2 alkoxy and C substituted by 1 to 2 hydroxyl groups 1- C4 alkyl group substitution; R 14 Selected from H and C 1- C4 alkyl; R 15 and R 16 Each independently selected from H and C 1- C4 alkyl; L 3 Is a bond or a straight chain or branched chain C 1- C3 alkylene; and Indicates a single bond or a double bond.

5. The compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein the compound has the structure of Formula (IIIa), Formula (IIIb) or Formula (IIIc):

6. The compound according to any one of claims 1 to 5, wherein the moiety W—L— is selected from: as well as 7. The compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, which has a structure of Formula (Va) or Formula (Vc):

8. The compound according to claim 7, or a pharmaceutically acceptable salt thereof, (a) wherein the compound is of formula (Va) or formula (Vc), or a pharmaceutically acceptable salt thereof, where R 5 or each R 5 is a halogen, and R 10 For the two-L 3 OH-substituted C1-C5 alkyl, wherein L 3 As defined in formula (I); or (b) wherein the compound is of formula (Va), or a pharmaceutically acceptable salt thereof, wherein R 5 is -CN, and R 10 For the two-L 3 OH-substituted C1-C5 alkyl, wherein L 3 As defined in formula (I).

9. The compound according to any one of claims 1 to 6 or the compound having the structure of formula (Va) according to claim 7, or a pharmaceutically acceptable salt thereof, wherein: R 1 is H, methyl, or methyl substituted by a -OH group; Each R 5 independently selected from Cl, F and -CN; L is CH2; and R 10 Selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, cyclopropyl, cyclobutyl, pyridyl, pyrazolyl, isopropyl oxetane, tetrahydrofuranyl, tetrahydropyranyl, morpholinyl, piperidinyl, piperazinyl, pyrrolidinyl and azetidinyl, Each R 10 Optionally substituted with 1 to 4 groups independently selected from the group consisting of methyl, ethyl, deuterium, -OCH3, -OH, -OCHF2, -CN, -NH2, -NHCH3, -N(CH3)2, -NHR 13 , -NHCH(=O), -NHC(=O)CH3, -NHC(=O)OCH3, -NHC(=O)CH2NH2, -NHC(=O)CH2N(CH3)2, -NHC(=O)CH(CH3)NH2, -NHC(=O) C(CH3)2NH2, -OCH2CH2OH, -OCH2CH(CH3)OH, -OCH2CH(CH3)2OH, -OCH(F)CH2OH, -OCF2CH2OH, -OCH2CH2NH2, -OCH2CH( -OCH3)NH2、-OCH2C(CH3)2NH2、-OCH2CH2NHCH3、-OCH2CH2N(CH3)2、-OCH(F)CH2NH2、-OCF2CH2NH2、-CH2OCH2CH2NH2、-CH2CH2OH、-CH2OH、-CH2NH2、-O-azetidinyl、-C(=O)NH2、-C(=O)NHCH3、-OC(=O)CH3、cyclopropyl, azetidinyl, pyrrolidinyl, morpholinyl, 6-oxa-3-azabicyclo[ 3.1.1]heptyl, 2-oxa-5-azabicyclo[2.2.1]heptyl, 2-oxa-6-azaspiro[3.3]heptyl and 4,5-dihydroisoxyl azole group, wherein the methyl, ethyl, cyclopropyl, azetidinyl, pyrrolidinyl, morpholinyl, 6-oxa-3-azabicyclo[ 3.1.1]heptyl, 2-oxa-5-azabicyclo[2.2.1]heptyl, 2-oxa-6-azaspiro[3.3]heptyl and 4,5-dihydroisoxyl Each oxazolyl group is optionally further substituted with 1 to 3 groups independently selected from F, -OH, -OCH3, -NH2.

10. A compound according to any one of claims 1 to 6 or a compound having a structure of formula (Va) according to claim 7 or claim 9, or a pharmaceutically acceptable salt thereof, wherein R 10 Selected from:

11. A compound, or a pharmaceutically acceptable salt thereof, selected from 12. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound has the structure of formula (VIII), where R 10 Selected from: Phenyl, which is unsubstituted or substituted with one -CN; unsubstituted or replaced by a single moiety selected from -L 3 Halogen, -L 3 OH or -L 3 NHC(=O)R 13 A 6-membered heteroaryl group substituted with 1-2 heteroatoms, each heteroatom being N, wherein L 3 is a bond or a linear or branched C1-C3 alkylene group, and R 13 is C1-C4 alkyl; and By a –L 3 C(=O)NR 13 R 14 or 2 or 3 – L 3 OH-substituted C1-C5 alkyl, wherein L 3 is a bond or a straight or branched C1-C3 alkylene group, R 13 is H or C1-C4 alkyl, and R 14 is H or C1-C4 alkyl.

13. The compound according to claim 1, wherein the compound contains 1 to 4 independently selected from N, NH, NR 17 , O or S ring members of the 5-6 membered heterocyclic group is a ring containing 1 to 4 independently selected from N, NH, NR 17 , O or S as ring members.

14. The compound according to claim 1, wherein the -L 3 -(containing 1 to 2 independently selected from N, NH, NR 17 , O or S) is a 4-7 membered heterocyclic group 3 -(containing 1 to 2 independently selected from N, NH, NR 17 , O or S as ring members).

15. The compound according to claim 1, wherein the compound contains 1 to 2 independently selected from N, NH, NR 17 , O or S ring members of the 4-7 membered heterocyclic group is a ring containing 1 to 2 independently selected from N, NH, NR 17 , O or S as ring members.

16. The compound according to claim 3, wherein the compound contains 1 to 2 independently selected from N, NH, NR 17 , O or S ring members of the 4-6 membered heterocyclic group is a ring containing one or two independently selected from N, NH, NR 17 , O or S as ring members.

17. The compound according to claim 3, wherein For R 10 , containing 1 to 2 independently selected from N, NH, NR 17 , O or S ring members of the 4-7 membered heterocyclic group is a ring containing 1 to 2 independently selected from N, NH, NR 17 , O or S as ring members.

18. The compound according to claim 3, wherein For R 13 , containing 1 to 2 independently selected from N, NH, NR 17 , O or S ring members of the 4-7 membered heterocyclic group is a ring containing 1 to 2 independently selected from N, NH, NR 17 , O or S as ring members.

19. The compound according to claim 4, wherein the compound contains 1 to 2 independently selected from N, NH, NR 17 , O or S ring members of the 4-6 membered heterocyclic group is a ring containing one or two independently selected from N, NH, NR 17 , O or S as ring members.

20. The compound according to claim 4, wherein For R 10 , containing 1 to 2 independently selected from N, NH, NR 17 , O or S ring members of the 4-7 membered heterocyclic group is a ring containing 1 to 2 independently selected from N, NH, NR 17 , O or S as ring members.

21. The compound according to claim 4, wherein For R 13 , containing 1 to 2 independently selected from N, NH, NR 17 , O or S ring members of the 4-7 membered heterocyclic group is a ring containing 1 to 2 independently selected from N, NH, NR 17 , O or S as ring members.

22. A pharmaceutical composition comprising a compound according to any one of claims 1 to 21 and at least one pharmaceutically acceptable carrier.

23. according to the compound described in any one of claims 1 to 21 or the pharmaceutical composition comprising the compound described in any one of claims 1 to 21 in the preparation of a medicine for the treatment of herpes virus infection, wherein the herpes virus is selected from cytomegalovirus (CMV), Epstein-Barr virus (EBV), varicella-zoster virus (VZV), herpes simplex virus including HSV-1 and HSV-2, herpes virus 6, human herpes virus 7 and Kaposi's sarcoma-associated herpes virus.

24. The method of claim 23, wherein the method comprises treating a condition induced, exacerbated or accelerated by the herpes virus infection, wherein the condition is selected from the group consisting of: Alzheimer's disease, chronic fatigue syndrome (CFS), systemic lupus erythematosus (SLE), multiple sclerosis (MS), rheumatoid arthritis (RA), juvenile idiopathic arthritis (JIA), inflammatory bowel disease (IBD), atherosclerosis (AS), celiac disease and type 1 diabetes.

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