Heterocyclic compounds for the treatment of diseases

Abstract

Described herein are heterocyclic compounds, compositions, and methods of use thereof for treating disease.

Description

[0001] This application is a divisional application of the Chinese patent application with the application date of November 11, 2016, application number 201680078856.8, and invention name “Heterocyclic compounds for treating diseases” (the application date of the corresponding PCT application is November 11, 2016, and the application number is PCT / US2016 / 061676).

[0002] Cross-references

[0003] This application claims the benefit of U.S. Provisional Application No. 62 / 255,041, filed November 13, 2015, which is incorporated herein by reference in its entirety. Background Art

[0004] Sphingosine-1-phosphate (S1P) receptors are a class of G protein-coupled receptors that are targets of the lipid signaling molecule sphingosine-1-phosphate. Sphingosine-1-phosphate (S1P) is a bioactive sphingolipid that has been shown to induce many cellular processes, including those leading to platelet aggregation, cell proliferation, cell morphology, tumor cell invasion, endothelial cell chemotaxis and angiogenesis, cytoskeletal rearrangements in many cell types to regulate immune cell trafficking, vascular homeostasis, and cell communication in the central nervous system (CNS) and peripheral organ systems. S1P is able to bind to members of the endothelial differentiation gene family of G protein-coupled receptors localized to the plasma membrane (EDG receptors). To date, five members of this family have been identified as S1P receptors in different cell types: S1P1 (EDG-1), S1P2 (EDG-5), S1P3 (EDG-3), S1P4 (EDG-6), and S1P5 (EDG-8). S1P receptor modulators are compounds that signal at one or more S1P receptors as agonists or antagonists. Because S1P mediates numerous cellular responses, S1P receptor modulators are promising targets for a variety of therapeutic indications. Summary of the invention

[0005] Described herein are compounds of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (II), (IIa), (IIb), (IIc), (IId), or (IIe), pharmaceutical compositions comprising such compounds, and methods of use thereof for modulating S1P receptors. In one aspect, a therapeutically effective amount of at least one S1P receptor modulator described herein is administered to a mammal to treat a disease, disorder, or condition that would benefit from S1P receptor modulation.

[0006] In one aspect, provided herein is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof:

[0007]

[0008] in:

[0009] X1, X2, X3 and X4 are each CR1; or

[0010] X1 is N; X2, X3 and X4 are each CR1; or

[0011] X2 is N; X1, X3 and X4 are each CR1; or

[0012] X3 is N; X1, X2 and X4 are each CR1; or

[0013] X4 is N; X1, X2 and X3 are each CR1;

[0014] Selected from

[0015] Z is -O-, -S-, -N(R4)-, -CH2-, -OCH2- or -CH2O-;

[0016] Each R1 is independently selected from hydrogen, halogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted C3-C8 cycloalkyl, optionally substituted -(C1-C2 alkylene)-(C3-C8 cycloalkyl), optionally substituted C2-C9 heterocycloalkyl, optionally substituted -(C1-C2 alkylene)-(C2-C9 heterocycloalkyl), optionally substituted -(C1-C2 alkylene)-(aryl), optionally substituted -(C1-C2 alkylene)-(heteroaryl), -CF3, -OR 10 、-SR 10 、-N(R 11 )R 12 、-N(R 11 )S(O)2R 15 ;-N(R 13 )N(R 11 )R 12 、-N(R 13 )N(R 11 )S(O)2R 15 、-C(O)R 14 、-C(O)OR 10 、-C(S)OR 10 、-C(O)SR 10 、-C(O)N(R 11 )R 12 、-C(S)N(R 11 )R12 、-C(O)N(R 11 )S(O)2R 15 、-C(S)N(R 11 )S(O)2R 15 、-C(O)N(R 13 )N(R 11 )R 12 、-C(S)N(R 13 )N(R 11 )R 12 and -C(O)N(R 13 )N(R 11 )S(O)2R 15 ;

[0017] Each R2 is independently selected from halogen, optionally substituted C1-C6 alkyl, -OR 20 、-SR 20 、-N(R 21 )R 22 、-C(O)R 20 、-C(O)N(R 21 )R 22 and -N(R 23 )C(O)R 20 ;

[0018] R3 is selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C8 cycloalkyl, optionally substituted aryl, optionally substituted -(C1-C2 alkylene)-(aryl), optionally substituted heteroaryl, and optionally substituted -(C1-C2 alkylene)-(heteroaryl);

[0019] R4 is hydrogen or an optionally substituted C1-C6 alkyl group,

[0020] R 10 , R 13 and R 14 each independently selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C8 cycloalkyl, optionally substituted aryl, optionally substituted -(C1-C2 alkylene)-(aryl), optionally substituted C2-C9 heterocycloalkyl, optionally substituted heteroaryl, and optionally substituted -(C1-C2 alkylene)-(heteroaryl);

[0021] R 11 and R 12R is each independently selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C8 cycloalkyl, optionally substituted aryl, optionally substituted -(C1-C2 alkylene)-(aryl), optionally substituted C2-C9 heterocycloalkyl, optionally substituted heteroaryl, and optionally substituted -(C1-C2 alkylene)-(heteroaryl); or optionally R 11 and R 12 Together with the nitrogen atom to which they are attached, they form an optionally substituted C2-C9 heterocycloalkyl ring;

[0022] R 15 is selected from optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C8 cycloalkyl, optionally substituted aryl, optionally substituted -(C1-C2 alkylene)-(aryl), optionally substituted C2-C9 heterocycloalkyl, optionally substituted heteroaryl, and optionally substituted -(C1-C2 alkylene)-(heteroaryl);

[0023] R 20 and R 23 each independently selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C8 cycloalkyl, optionally substituted aryl, optionally substituted -(C1-C2 alkylene)-(aryl), optionally substituted C2-C9 heterocycloalkyl, optionally substituted heteroaryl, and optionally substituted -(C1-C2 alkylene)-(heteroaryl);

[0024] R 21 and R 22 R is each independently selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C8 cycloalkyl, optionally substituted aryl, optionally substituted -(C1-C2 alkylene)-(aryl), optionally substituted C2-C9 heterocycloalkyl, optionally substituted heteroaryl, and optionally substituted -(C1-C2 alkylene)-(heteroaryl); or optionally R 21 and R 22 Together with the nitrogen atom to which they are attached, they form an optionally substituted C2-C9 heterocycloalkyl ring;

[0025] n is 0-4; and

[0026] p is 0 or 1.

[0027] In one embodiment is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein X1, X2, X3 and X4 are each CR1. In another embodiment is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein X1 is N; X2, X3 and X4 are each CR1. In another embodiment is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein X2 is N; and X1, X3 and X4 are each CR1. In another embodiment is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein X3 is N; and X1, X2 and X4 are each CR1. In another embodiment is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein X4 is N; and X1, X2 and X3 are each CR1. In another embodiment is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein each R1 is independently selected from hydrogen, halogen, optionally substituted C1-C6 alkyl, -CF3, -OR 10 、-N(R 11 )R 12 、-C(O)R 14 、-C(O)OR 10 and -C(O)N(R 11 )R 12 In another embodiment is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein each R1 is independently selected from hydrogen, halogen, and -CF3. In another embodiment is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein each R2 is independently selected from halogen, optionally substituted C1-C6 alkyl, -OR 20 and -N(R 21 )R 22 In another embodiment is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein each R2 is independently selected from halogen and optionally substituted C1-C6 alkyl. In another embodiment is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is selected from hydrogen and optionally substituted C1-C6 alkyl. In another embodiment is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein for In another embodiment is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein for In another embodiment is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein for In another embodiment is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein for In another embodiment is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein for In another embodiment is a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein for In another embodiment is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein Z is -O-, -OCH2- or -CH2O-. In another embodiment is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein Z is -O-. In another embodiment is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein Z is -OCH2-. In another embodiment is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein p is 0. In another embodiment is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein p is 1. In another embodiment is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 0. In another embodiment is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 1. In another embodiment is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein n is 2.

[0028] Any combination of the groups described above or below for the various variables is contemplated herein. Throughout the specification, groups and substituents thereof are selected by one skilled in the art to provide stable moieties and compounds.

[0029] On the other hand, a pharmaceutical composition is provided herein, comprising a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable diluent, excipient or adhesive. In one embodiment, the pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof is formulated for administration selected from oral administration, parenteral administration, buccal administration, nasal administration, topical administration or rectal administration.

[0030] In another aspect is a method of treating a disease, disorder or condition in a mammal that would benefit from S1P receptor modulation, comprising administering to the mammal a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof.

[0031] In another embodiment is a method of treating a disease, disorder or condition in a mammal that would benefit from S1P receptor modulation, comprising administering to the mammal a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof; wherein the disease, disorder or condition in the mammal is selected from multiple sclerosis, ulcerative colitis and Crohn's disease. In another embodiment is a method of treating a disease, disorder or condition in a mammal that would benefit from S1P receptor modulation, comprising administering to the mammal a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof; wherein the disease, disorder or condition in the mammal is multiple sclerosis. In another embodiment is a method of treating a disease, disorder or condition in a mammal that would benefit from S1P receptor modulation, comprising administering to the mammal an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof; wherein the disease, disorder or condition in the mammal is ulcerative colitis. In another embodiment is a method of treating a disease, disorder or condition in a mammal that would benefit from S1P receptor modulation, comprising administering to the mammal a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof; wherein the disease, disorder or condition in the mammal is Crohn's disease.

[0032] In a further embodiment is a method of treating a disease, disorder or condition in a mammal that would benefit from S1P receptor modulation, comprising administering to the mammal a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof; wherein the disease, disorder or condition in the mammal is rejection of a transplanted organ or tissue; graft-versus-host disease resulting from transplantation; autoimmune syndromes including rheumatoid arthritis, multiple sclerosis, myasthenia gravis; pollen allergy; type I diabetes; prevention of psoriasis; Crohn's disease; ulcerative colitis, acute respiratory distress syndrome; adult respiratory distress syndrome; influenza; post-infectious autoimmune diseases including rheumatic fever and post-infectious glomerulonephritis; and cancer metastasis.

[0033] In another embodiment is the use of a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (II), (IIa), (IIb), (IIc), (IId) or (IIe) in the preparation of a medicament for treating a disease, disorder or condition that would benefit from S1P receptor modulation. In another embodiment is the use of an S1P receptor modulator in the preparation of a medicament for treating a disease, disorder or condition in a mammal, wherein the disease, disorder or condition in the mammal is transplant organ or tissue rejection; graft-versus-host disease caused by transplantation; autoimmune syndromes including rheumatoid arthritis, multiple sclerosis, myasthenia gravis; pollen allergy; type I diabetes; prevention of psoriasis; Crohn's disease; ulcerative colitis, acute respiratory distress syndrome; adult respiratory distress syndrome; influenza; post-infectious autoimmune diseases including rheumatic fever and post-infectious glomerulonephritis; and cancer metastasis.

[0034] In another aspect is a method of modulating S1P receptor activity comprising contacting the S1P receptor or a portion thereof with a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof.

[0035] Incorporation by reference

[0036] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference. BRIEF DESCRIPTION OF THE DRAWINGS

[0037] Figure 1 It is shown that the compounds of formula (I) described herein are 2+ Cell potency in throughput assays.

[0038] Figure 2 The compounds of formula (I) described herein show a reduction in lymphocyte counts at four hours. DETAILED DESCRIPTION

[0039] Sphingosine-1-phosphate receptors regulate fundamental biological processes such as cell proliferation, angiogenesis, migration, cytoskeletal organization, endothelial cell chemotaxis, immune cell trafficking, and mitogenesis. Sphingosine-1-phosphate receptors are also involved in immunoregulation and are directly involved in the inhibition of innate immune responses from T cells. Sphingosine-1-phosphate (S1P) receptors are divided into five subtypes: S1PR1, S1PR2, S1PR3, S1PR4, and S1PR5. They are expressed in numerous tissues, and each subtype displays different cell specificity, although they are found at the highest density on leukocytes.

[0040] Described herein are compounds of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (II), (IIa), (IIb), (IIc), (IId), or (IIe), pharmaceutical compositions comprising such compounds, and methods of use thereof for modulating S1P receptors. In some embodiments, described herein are compounds of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (II), (IIa), (IIb), (IIc), (IId), or (IIe), pharmaceutical compositions comprising such compounds, and methods of use thereof for selectively modulating S1P receptor subtypes. In some embodiments, described herein are compounds of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (II), (IIa), (IIb), (IIc), (IId), or (IIe), pharmaceutical compositions comprising such compounds, and methods of use thereof for selectively modulating two S1P receptor subtypes. In some embodiments, described herein are compounds of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (II), (IIa), (IIb), (IIc), (IId), or (IIe), pharmaceutical compositions comprising such compounds, and methods of use thereof for selectively modulating one S1P receptor subtype. In some embodiments, described herein are compounds of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (II), (IIa), (IIb), (IIc), (IId), or (IIe), pharmaceutical compositions comprising such compounds, and methods of use thereof for selectively modulating S1P receptor subtype 1. In some embodiments, described herein are compounds of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (II), (IIa), (IIb), (IIc), (IId), or (IIe), pharmaceutical compositions comprising such compounds, and methods of use thereof for selectively modulating S1P receptor subtype 2. In some embodiments, described herein are compounds of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (II), (IIa), (IIb), (IIc), (IId), or (IIe), pharmaceutical compositions comprising such compounds, and methods of use thereof for selectively modulating S1P receptor subtype 3. In some embodiments, described herein are compounds of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (II), (IIa), (IIb), (IIc), (IId), or (IIe), pharmaceutical compositions comprising such compounds, and methods of use thereof for selectively modulating S1P receptor subtype 4.In some embodiments, described herein are compounds of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (II), (IIa), (IIb), (IIc), (IId), or (IIe), pharmaceutical compositions comprising such compounds, and methods of use thereof for selectively modulating S1P receptor subtype 5.

[0041] In another aspect, at least one S1P receptor modulator described herein is administered to a mammal to treat a disease, disorder, or condition that would benefit from S1P receptor modulation. In some embodiments, at least one S1P receptor modulator described herein is administered to a mammal to treat a disease, disorder, or condition that would benefit from selective modulation of an S1P receptor subtype. In some embodiments, at least one S1P receptor modulator described herein is administered to a mammal to treat a disease, disorder, or condition that would benefit from selective modulation of two S1P receptor subtypes. In some embodiments, at least one S1P receptor modulator described herein is administered to a mammal to treat a disease, disorder, or condition that would benefit from selective modulation of one S1P receptor subtype. In some embodiments, at least one S1P receptor modulator described herein is administered to a mammal to treat a disease, disorder, or condition that would benefit from selective modulation of S1P receptor subtype 1. In some embodiments, at least one S1P receptor modulator described herein is administered to a mammal to treat a disease, disorder, or condition that would benefit from selective modulation of S1P receptor subtype 2. In some embodiments, at least one S1P receptor modulator described herein is administered to a mammal to treat a disease, disorder, or condition that would benefit from selective modulation of S1P receptor subtype 3. In some embodiments, at least one S1P receptor modulator described herein is administered to a mammal to treat a disease, disorder, or condition that would benefit from selective modulation of S1P receptor subtype 4. In some embodiments, at least one S1P receptor modulator described herein is administered to a mammal to treat a disease, disorder, or condition that would benefit from selective modulation of S1P receptor subtype 5.

[0042] In some embodiments are methods of modulating S1P receptor activity comprising contacting a S1P receptor or a portion thereof with a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (II), (IIa), (IIb), (IIc), (IId), or (IIe) or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (II), (IIa), (IIb), (IIc), (IId), or (IIe) or a pharmaceutically acceptable salt or solvate thereof is an S1P receptor agonist. In some embodiments, a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (II), (IIa), (IIb), (IIc), (IId), or (IIe) or a pharmaceutically acceptable salt or solvate thereof is an S1P receptor subtype 1 agonist. In some embodiments, the compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (II), (IIa), (IIb), (IIc), (IId) or (IIe), or a pharmaceutically acceptable salt or solvate thereof, is an S1P receptor subtype 2 agonist. In some embodiments, the compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (II), (IIa), (IIb), (IIc), (IId) or (IIe), or a pharmaceutically acceptable salt or solvate thereof, is an S1P receptor subtype 3 agonist. In some embodiments, the compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (II), (IIa), (IIb), (IIc), (IId) or (IIe), or a pharmaceutically acceptable salt or solvate thereof, is an S1P receptor subtype 4 agonist. In some embodiments, the compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (II), (IIa), (IIb), (IIc), (IId) or (IIe), or a pharmaceutically acceptable salt or solvate thereof, is an S1P receptor subtype 5 agonist. In some embodiments, the compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (II), (IIa), (IIb), (IIc), (IId) or (IIe), or a pharmaceutically acceptable salt or solvate thereof, is an S1P receptor partial agonist. In some embodiments, the compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (II), (IIa), (IIb), (IIc), (IId) or (IIe), or a pharmaceutically acceptable salt or solvate thereof, is an S1P receptor subtype 1 partial agonist.In some embodiments, the compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (II), (IIa), (IIb), (IIc), (IId) or (IIe), or a pharmaceutically acceptable salt or solvate thereof, is a S1P receptor subtype 2 partial agonist. In some embodiments, the compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (II), (IIa), (IIb), (IIc), (IId) or (IIe), or a pharmaceutically acceptable salt or solvate thereof, is a S1P receptor subtype 3 partial agonist. In some embodiments, the compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (II), (IIa), (IIb), (IIc), (IId) or (IIe), or a pharmaceutically acceptable salt or solvate thereof, is a S1P receptor subtype 4 partial agonist. In some embodiments, the compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (II), (IIa), (IIb), (IIc), (IId) or (IIe) or a pharmaceutically acceptable salt or solvate thereof is an S1P receptor subtype 5 partial agonist. In some embodiments, the compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (II), (IIa), (IIb), (IIc), (IId) or (IIe) or a pharmaceutically acceptable salt or solvate thereof is an S1P receptor antagonist. In some embodiments, the compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (II), (IIa), (IIb), (IIc), (IId) or (IIe) or a pharmaceutically acceptable salt or solvate thereof is an S1P receptor subtype 1 antagonist. In some embodiments, the compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (II), (IIa), (IIb), (IIc), (IId) or (IIe), or a pharmaceutically acceptable salt or solvate thereof, is an S1P receptor subtype 2 antagonist. In some embodiments, the compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (II), (IIa), (IIb), (IIc), (IId) or (IIe), or a pharmaceutically acceptable salt or solvate thereof, is an S1P receptor subtype 3 antagonist. In some embodiments, the compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (II), (IIa), (IIb), (IIc), (IId) or (IIe), or a pharmaceutically acceptable salt or solvate thereof, is an S1P receptor subtype 4 antagonist.In some embodiments, the compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (II), (IIa), (IIb), (IIc), (IId) or (IIe), or a pharmaceutically acceptable salt or solvate thereof, is an S1P receptor subtype 5 antagonist.

[0043] Compound

[0044] In one aspect, provided herein is a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof:

[0045]

[0046] in:

[0047] X1, X2, X3 and X4 are each CR1; or

[0048] X1 is N; X2, X3 and X4 are each CR1; or

[0049] X2 is N; X1, X3 and X4 are each CR1; or

[0050] X3 is N; X1, X2 and X4 are each CR1; or

[0051] X4 is N; X1, X2 and X3 are each CR1;

[0052] Selected from

[0053] Z is -O-, -S-, -N(R4)-, -CH2-, -OCH2- or -CH2O-;

[0054] Each R1 is independently selected from hydrogen, halogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted C3-C8 cycloalkyl, optionally substituted -(C1-C2 alkylene)-(C3-C8 cycloalkyl), optionally substituted C2-C9 heterocycloalkyl, optionally substituted -(C1-C2 alkylene)-(C2-C9 heterocycloalkyl), optionally substituted -(C1-C2 alkylene)-(aryl), optionally substituted -(C1-C2 alkylene)-(heteroaryl), -CF3, -OR 10 、-SR 10 、-N(R 11 )R 12 、-N(R 11 )S(O)2R 15 ;-N(R 13 )N(R 11 )R12 、-N(R 13 )N(R 11 )S(O)2R 15 、-C(O)R 14 、-C(O)OR 10 、-C(S)OR 10 、-C(O)SR 10 、-C(O)N(R 11 )R 12 、-C(S)N(R 11 )R 12 、-C(O)N(R 11 )S(O)2R 15 、-C(S)N(R 11 )S(O)2R 15 、-C(O)N(R 13 )N(R 11 )R 12 、-C(S)N(R 13 )N(R 11 )R 12 and -C(O)N(R 13 )N(R 11 )S(O)2R 15 ;

[0055] Each R2 is independently selected from halogen, optionally substituted C1-C6 alkyl, -OR 20 、-SR 20 、-N(R 21 )R 22 、-C(O)R 20 、-C(O)N(R 21 )R 22 and -N(R 23 )C(O)R 20 ;

[0056] R3 is selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C8 cycloalkyl, optionally substituted aryl, optionally substituted -(C1-C2 alkylene)-(aryl), optionally substituted heteroaryl, and optionally substituted -(C1-C2 alkylene)-(heteroaryl);

[0057] R4 is hydrogen or an optionally substituted C1-C6 alkyl group,

[0058] R 10 , R 13 and R 14each independently selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C8 cycloalkyl, optionally substituted aryl, optionally substituted -(C1-C2 alkylene)-(aryl), optionally substituted C2-C9 heterocycloalkyl, optionally substituted heteroaryl, and optionally substituted -(C1-C2 alkylene)-(heteroaryl);

[0059] R 11 and R 12 R is each independently selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C8 cycloalkyl, optionally substituted aryl, optionally substituted -(C1-C2 alkylene)-(aryl), optionally substituted C2-C9 heterocycloalkyl, optionally substituted heteroaryl, and optionally substituted -(C1-C2 alkylene)-(heteroaryl); or optionally R 11 and R 12 Together with the nitrogen atom to which they are attached, they form an optionally substituted C2-C9 heterocycloalkyl ring;

[0060] R 15 is selected from optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C8 cycloalkyl, optionally substituted aryl, optionally substituted -(C1-C2 alkylene)-(aryl), optionally substituted C2-C9 heterocycloalkyl, optionally substituted heteroaryl, and optionally substituted -(C1-C2 alkylene)-(heteroaryl);

[0061] R 20 and R 23 each independently selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C8 cycloalkyl, optionally substituted aryl, optionally substituted -(C1-C2 alkylene)-(aryl), optionally substituted C2-C9 heterocycloalkyl, optionally substituted heteroaryl, and optionally substituted -(C1-C2 alkylene)-(heteroaryl);

[0062] R 21 and R 22 R is each independently selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C8 cycloalkyl, optionally substituted aryl, optionally substituted -(C1-C2 alkylene)-(aryl), optionally substituted C2-C9 heterocycloalkyl, optionally substituted heteroaryl, and optionally substituted -(C1-C2 alkylene)-(heteroaryl); or optionally R 21 and R 22Together with the nitrogen atom to which they are attached, they form an optionally substituted C2-C9 heterocycloalkyl ring;

[0063] n is 0-4; and

[0064] p is 0 or 1.

[0065] In one embodiment is a compound of formula (I), wherein X1, X2, X3 and X4 are each CR1. In another embodiment is a compound of formula (I), wherein X1, X2, X3 and X4 are each CR1; and each R1 is independently selected from hydrogen, halogen, optionally substituted C1-C6 alkyl, -CF3, -OR 10 、-N(R 11 )R 12 、-C(O)R 14 、-C(O)OR 10 and -C(O)N(R 11 )R 12 In another embodiment is a compound of formula (I), wherein X1, X2, X3 and X4 are each CR1; and each R1 is independently selected from hydrogen, halogen, optionally substituted C1-C6 alkyl, -CF3, -OR 10 and -N(R 11 )R 12 In another embodiment is a compound of Formula (I), wherein X1, X2, X3 and X4 are each CR1; and each R1 is independently selected from hydrogen, halogen and -CF3.

[0066] In another embodiment is a compound of formula (I) wherein X1 is N; and X2, X3 and X4 are each CR1. In another embodiment is a compound of formula (I) wherein X1 is N; and X2, X3 and X4 are each CR1; and each R1 is independently selected from hydrogen, halogen, optionally substituted C1-C6 alkyl, -CF3, -OR 10 、-N(R 11 )R 12 、-C(O)R 14 、-C(O)OR 10 and -C(O)N(R 11 )R 12 In another embodiment is a compound of formula (I), wherein X1 is N; and X2, X3 and X4 are each CR1; and each R1 is independently selected from hydrogen, halogen, optionally substituted C1-C6 alkyl, -CF3, -OR 10 and -N(R 11 )R 12 In another embodiment is a compound of Formula (I), wherein X1 is N; and X2, X3, and X4 are each CR1; and each R1 is independently selected from hydrogen, halogen, and -CF3.

[0067] In another embodiment is a compound of formula (I) wherein X2 is N; and X1, X3 and X4 are each CR1. In another embodiment is a compound of formula (I) wherein X2 is N; and X1, X3 and X4 are each CR1; and each R1 is independently selected from hydrogen, halogen, optionally substituted C1-C6 alkyl, -CF3, -OR 10 、-N(R 11 )R 12 、-C(O)R 14 、-C(O)OR 10 and -C(O)N(R 11 )R 12 In another embodiment is a compound of formula (I), wherein X2 is N; and X1, X3 and X4 are each CR1; and each R1 is independently selected from hydrogen, halogen, optionally substituted C1-C6 alkyl, -CF3, -OR 10 and -N(R 11 )R 12 In another embodiment is a compound of Formula (I), wherein X2 is N; and X1, X3, and X4 are each CR1; and each R1 is independently selected from hydrogen, halogen, and -CF3.

[0068] In another embodiment is a compound of formula (I) wherein X3 is N; and X1, X2 and X4 are each CR1. In another embodiment is a compound of formula (I) wherein X3 is N; and X1, X2 and X4 are each CR1; and each R1 is independently selected from hydrogen, halogen, optionally substituted C1-C6 alkyl, -CF3, -OR 10 、-N(R 11 )R 12 、-C(O)R 14 、-C(O)OR 10 and -C(O)N(R 11 )R 12 In another embodiment is a compound of formula (I), wherein X3 is N; and X1, X2 and X4 are each CR1; and each R1 is independently selected from hydrogen, halogen, optionally substituted C1-C6 alkyl, -CF3, -OR 10 and -N(R 11 )R 12 In another embodiment is a compound of Formula (I), wherein X3 is N; and X1, X2, and X4 are each CR1; and each R1 is independently selected from hydrogen, halogen, and -CF3.

[0069] In another embodiment is a compound of formula (I) wherein X4 is N; and X1, X2 and X3 are each CR1. In another embodiment is a compound of formula (I) wherein X4 is N; and X1, X2 and X3 are each CR1; and each R1 is independently selected from hydrogen, halogen, optionally substituted C1-C6 alkyl, -CF3, -OR 10 、-N(R 11 )R 12 、-C(O)R 14 、-C(O)OR 10 and -C(O)N(R 11 )R 12 In another embodiment is a compound of formula (I), wherein X4 is N; and X1, X2 and X3 are each CR1; and each R1 is independently selected from hydrogen, halogen, optionally substituted C1-C6 alkyl, -CF3, -OR 10 and -N(R 11 )R 12 In another embodiment is a compound of Formula (I), wherein X4 is N; and X1, X2, and X3 are each CR1; and each R1 is independently selected from hydrogen, halogen, and -CF3.

[0070] In another embodiment is a compound of Formula (I), wherein n is 3 and each R2 is independently selected from halogen, optionally substituted C1-C6 alkyl, -OR 20 and -N(R 21 )R 22 In another embodiment is a compound of formula (I) wherein n is 3 and each R2 is independently selected from halogen and optionally substituted C1-C6 alkyl. In another embodiment is a compound of formula (I) wherein n is 2 and each R2 is independently selected from halogen, optionally substituted C1-C6 alkyl, -OR 20 and -N(R 21 )R 22 In another embodiment is a compound of formula (I) wherein n is 2 and each R2 is independently selected from halogen and optionally substituted C1-C6 alkyl. In another embodiment is a compound of formula (I) wherein n is 1 and R2 is selected from halogen, optionally substituted C1-C6 alkyl, -OR 20 and -N(R 21 )R 22 In another embodiment is a compound of formula (I) wherein n is 1 and R2 is selected from halogen and optionally substituted C1-C6 alkyl. In another embodiment is a compound of formula (I) wherein n is 0.

[0071] In another embodiment, it is a compound of formula (I) wherein R3 is selected from hydrogen and optionally substituted C1-C6 alkyl. In another embodiment, it is a compound of formula (I) wherein R3 is hydrogen. In another embodiment, it is a compound of formula (I) wherein R3 is optionally substituted C1-C6 alkyl. In another embodiment, it is a compound of formula (I) wherein R3 is methyl.

[0072] In another embodiment is a compound of formula (I), wherein for In another embodiment is a compound of formula (I), wherein for In another embodiment is a compound of formula (I), wherein for In another embodiment is a compound of formula (I), wherein for In another embodiment is a compound of formula (I), wherein for In another embodiment is a compound of formula (I), wherein

[0073] In another embodiment is a compound of formula (I) wherein Z is -O-, -OCH2- or -CH2O-. In another embodiment is a compound of formula (I) wherein Z is -O-. In another embodiment is a compound of formula (I) wherein Z is -OCH2-. In another embodiment is a compound of formula (I) wherein Z is -CH2O-. In another embodiment is a compound of formula (I) wherein Z is -S-. In another embodiment is a compound of formula (I) wherein Z is -CH2-. In another embodiment is a compound of formula (I) wherein Z is -N(R4)-. In another embodiment is a compound of formula (I) wherein Z is -N(H)-. In another embodiment is a compound of formula (I) wherein Z is -N(CH3)-.

[0074] In another embodiment is a compound of Formula (I) wherein p is 0. In another embodiment is a compound of Formula (I) wherein p is 1.

[0075] In some embodiments provided herein, the compound of Formula (I) has the structure of Formula (Ia), or a pharmaceutically acceptable salt or solvate thereof:

[0076]

[0077] in:

[0078] Selected from

[0079] Z is -O-, -S-, -N(R4)-, -CH2-, -OCH2- or -CH2O-;

[0080] Each R1 is independently selected from hydrogen, halogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted C3-C8 cycloalkyl, optionally substituted -(C1-C2 alkylene)-(C3-C8 cycloalkyl), optionally substituted C2-C9 heterocycloalkyl, optionally substituted -(C1-C2 alkylene)-(C2-C9 heterocycloalkyl), optionally substituted -(C1-C2 alkylene)-(aryl), optionally substituted -(C1-C2 alkylene)-(heteroaryl), -CF3, -OR 10 、-SR 10 、-N(R 11 )R 12 、-N(R 11 )S(O)2R 15 ;-N(R 13 )N(R 11 )R 12 、-N(R 13 )N(R 11 )S(O)2R 15 、-C(O)R 14 、-C(O)OR 10 、-C(S)OR 10 、-C(O)SR 10 、-C(O)N(R 11 )R 12 、-C(S)N(R 11 )R 12 、-C(O)N(R 11 )S(O)2R 15 、-C(S)N(R 11 )S(O)2R 15 、-C(O)N(R 13 )N(R 11 )R 12 、-C(S)N(R 13 )N(R 11 )R 12 and -C(O)N(R 13 )N(R 11 )S(O)2R 15 ;

[0081] Each R2 is independently selected from halogen, optionally substituted C1-C6 alkyl, -OR20 、-SR 20 、-N(R 21 )R 22 、-C(O)R 20 、-C(O)N(R 21 )R 22 and -N(R 23 )C(O)R 20 ;

[0082] R3 is selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C8 cycloalkyl, optionally substituted aryl, optionally substituted -(C1-C2 alkylene)-(aryl), optionally substituted heteroaryl, and optionally substituted -(C1-C2 alkylene)-(heteroaryl);

[0083] R4 is hydrogen or an optionally substituted C1-C6 alkyl group,

[0084] R 10 , R 13 and R 14 each independently selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C8 cycloalkyl, optionally substituted aryl, optionally substituted -(C1-C2 alkylene)-(aryl), optionally substituted C2-C9 heterocycloalkyl, optionally substituted heteroaryl, and optionally substituted -(C1-C2 alkylene)-(heteroaryl);

[0085] R 11 and R 12 R is each independently selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C8 cycloalkyl, optionally substituted aryl, optionally substituted -(C1-C2 alkylene)-(aryl), optionally substituted C2-C9 heterocycloalkyl, optionally substituted heteroaryl, and optionally substituted -(C1-C2 alkylene)-(heteroaryl); or optionally R 11 and R 12 Together with the nitrogen atom to which they are attached, they form an optionally substituted C2-C9 heterocycloalkyl ring;

[0086] R 15 is selected from optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C8 cycloalkyl, optionally substituted aryl, optionally substituted -(C1-C2 alkylene)-(aryl), optionally substituted C2-C9 heterocycloalkyl, optionally substituted heteroaryl, and optionally substituted -(C1-C2 alkylene)-(heteroaryl);

[0087] R 20 and R 23 each independently selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C8 cycloalkyl, optionally substituted aryl, optionally substituted -(C1-C2 alkylene)-(aryl), optionally substituted C2-C9 heterocycloalkyl, optionally substituted heteroaryl, and optionally substituted -(C1-C2 alkylene)-(heteroaryl);

[0088] R 21 and R 22 R is each independently selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C8 cycloalkyl, optionally substituted aryl, optionally substituted -(C1-C2 alkylene)-(aryl), optionally substituted C2-C9 heterocycloalkyl, optionally substituted heteroaryl, and optionally substituted -(C1-C2 alkylene)-(heteroaryl); or optionally R 21 and R 22 Together with the nitrogen atom to which they are attached, they form an optionally substituted C2-C9 heterocycloalkyl ring;

[0089] n is 0-4; and

[0090] p is 0 or 1.

[0091] In one embodiment is a compound of Formula (Ia), wherein each R1 is independently selected from hydrogen, halogen, optionally substituted C1-C6 alkyl, -CF3, -OR 10 、-N(R 11 )R 12 、-C(O)R 14 、-C(O)OR 10 and -C(O)N(R 11 )R 12 In another embodiment is a compound of formula (Ia), wherein each R1 is independently selected from hydrogen, halogen, optionally substituted C1-C6 alkyl, -CF3, -OR 10 and -N(R 11 )R 12 In another embodiment is a compound of Formula (Ia), wherein each R1 is independently selected from hydrogen, halogen and -CF3.

[0092] In another embodiment is a compound of Formula (Ia), wherein n is 3 and each R2 is independently selected from halogen, optionally substituted C1-C6 alkyl, -OR 20 and -N(R 21 )R 22In another embodiment is a compound of formula (Ia), wherein n is 3 and each R2 is independently selected from halogen and optionally substituted C1-C6 alkyl. In another embodiment is a compound of formula (Ia), wherein n is 2 and each R2 is independently selected from halogen, optionally substituted C1-C6 alkyl, -OR 20 and -N(R 21 )R 22 In another embodiment is a compound of formula (Ia), wherein n is 2 and each R2 is independently selected from halogen and optionally substituted C1-C6 alkyl. In another embodiment is a compound of formula (Ia), wherein n is 1 and R2 is selected from halogen, optionally substituted C1-C6 alkyl, -OR 20 and -N(R 21 )R 22 In another embodiment is a compound of Formula (Ia) wherein n is 1 and R2 is selected from halogen and optionally substituted C1-C6 alkyl. In another embodiment is a compound of Formula (Ia) wherein n is 0.

[0093] In another embodiment, it is a compound of formula (Ia), wherein R3 is selected from hydrogen and optionally substituted C1-C6 alkyl. In another embodiment, it is a compound of formula (Ia), wherein R3 is hydrogen. In another embodiment, it is a compound of formula (Ia), wherein R3 is optionally substituted C1-C6 alkyl. In another embodiment, it is a compound of formula (Ia), wherein R3 is methyl.

[0094] In another embodiment is a compound of Formula (Ia) wherein for In another embodiment is a compound of Formula (Ia) wherein for In another embodiment is a compound of Formula (Ia) wherein for In another embodiment is a compound of Formula (Ia) wherein for In another embodiment is a compound of Formula (Ia) wherein for In another embodiment is a compound of Formula (Ia) wherein for

[0095] In another embodiment, there is a compound of formula (Ia), wherein Z is -O-, -OCH2- or -CH2O-. In another embodiment, there is a compound of formula (Ia), wherein Z is -O-. In another embodiment, there is a compound of formula (Ia), wherein Z is -OCH2-. In another embodiment, there is a compound of formula (Ia), wherein Z is -CH2O-. In another embodiment, there is a compound of formula (Ia), wherein Z is -S-. In another embodiment, there is a compound of formula (Ia), wherein Z is -CH2-. In another embodiment, there is a compound of formula (Ia), wherein Z is -N(R4)-. In another embodiment, there is a compound of formula (Ia), wherein Z is -N(H)-. In another embodiment, there is a compound of formula (Ia), wherein Z is -N(CH3)-.

[0096] In another embodiment is a compound of Formula (Ia) wherein p is 0. In another embodiment is a compound of Formula (Ia) wherein p is 1.

[0097] In some embodiments provided herein, the compound of Formula (I) has the structure of Formula (Ib), or a pharmaceutically acceptable salt or solvate thereof:

[0098]

[0099]

[0100] in:

[0101] Selected from

[0102] Z is -O-, -S-, -N(R4)-, -CH2-, -OCH2- or -CH2O-;

[0103] Each R1 is independently selected from hydrogen, halogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted C3-C8 cycloalkyl, optionally substituted -(C1-C2 alkylene)-(C3-C8 cycloalkyl), optionally substituted C2-C9 heterocycloalkyl, optionally substituted -(C1-C2 alkylene)-(C2-C9 heterocycloalkyl), optionally substituted -(C1-C2 alkylene)-(aryl), optionally substituted -(C1-C2 alkylene)-(heteroaryl), -CF3, -OR 10 、-SR 10 、-N(R 11 )R 12 、-N(R 11 )S(O)2R 15;-N(R 13 )N(R 11 )R 12 、-N(R 13 )N(R 11 )S(O)2R 15 、-C(O)R 14 、-C(O)OR 10 、-C(S)OR 10 、-C(O)SR 10 、-C(O)N(R 11 )R 12 、-C(S)N(R 11 )R 12 、-C(O)N(R 11 )S(O)2R 15 、-C(S)N(R 11 )S(O)2R 15 、-C(O)N(R 13 )N(R 11 )R 12 、-C(S)N(R 13 )N(R 11 )R 12 and -C(O)N(R 13 )N(R 11 )S(O)2R 15 ;

[0104] Each R2 is independently selected from halogen, optionally substituted C1-C6 alkyl, -OR 20 、-SR 20 、-N(R 21 )R 22 、-C(O)R 20 、-C(O)N(R 21 )R 22 and -N(R 23 )C(O)R 20 ;

[0105] R3 is selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C8 cycloalkyl, optionally substituted aryl, optionally substituted -(C1-C2 alkylene)-(aryl), optionally substituted heteroaryl, and optionally substituted -(C1-C2 alkylene)-(heteroaryl);

[0106] R4 is hydrogen or an optionally substituted C1-C6 alkyl group,

[0107] R 10 , R 13 and R 14each independently selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C8 cycloalkyl, optionally substituted aryl, optionally substituted -(C1-C2 alkylene)-(aryl), optionally substituted C2-C9 heterocycloalkyl, optionally substituted heteroaryl, and optionally substituted -(C1-C2 alkylene)-(heteroaryl);

[0108] R 11 and R 12 R is each independently selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C8 cycloalkyl, optionally substituted aryl, optionally substituted -(C1-C2 alkylene)-(aryl), optionally substituted C2-C9 heterocycloalkyl, optionally substituted heteroaryl, and optionally substituted -(C1-C2 alkylene)-(heteroaryl); or optionally R 11 and R 12 Together with the nitrogen atom to which they are attached, they form an optionally substituted C2-C9 heterocycloalkyl ring;

[0109] R 15 is selected from optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C8 cycloalkyl, optionally substituted aryl, optionally substituted -(C1-C2 alkylene)-(aryl), optionally substituted C2-C9 heterocycloalkyl, optionally substituted heteroaryl, and optionally substituted -(C1-C2 alkylene)-(heteroaryl);

[0110] R 20 and R 23 each independently selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C8 cycloalkyl, optionally substituted aryl, optionally substituted -(C1-C2 alkylene)-(aryl), optionally substituted C2-C9 heterocycloalkyl, optionally substituted heteroaryl, and optionally substituted -(C1-C2 alkylene)-(heteroaryl);

[0111] R 21 and R 22 R is each independently selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C8 cycloalkyl, optionally substituted aryl, optionally substituted -(C1-C2 alkylene)-(aryl), optionally substituted C2-C9 heterocycloalkyl, optionally substituted heteroaryl, and optionally substituted -(C1-C2 alkylene)-(heteroaryl); or optionally R 21 and R 22Together with the nitrogen atom to which they are attached, they form an optionally substituted C2-C9 heterocycloalkyl ring;

[0112] n is 0-4; and

[0113] p is 0 or 1.

[0114] In one embodiment is a compound of formula (Ib), wherein each R1 is independently selected from hydrogen, halogen, optionally substituted C1-C6 alkyl, -CF3, -OR 10 、-N(R 11 )R 12 、-C(O)R 14 、-C(O)OR 10 and -C(O)N(R 11 )R 12 In another embodiment is a compound of formula (Ib), wherein each R1 is independently selected from hydrogen, halogen, optionally substituted C1-C6 alkyl, -CF3, -OR 10 and -N(R 11 )R 12 In another embodiment is a compound of Formula (Ib), wherein each R1 is independently selected from hydrogen, halogen and -CF3.

[0115] In another embodiment is a compound of Formula (Ib) wherein n is 3 and each R2 is independently selected from halogen, optionally substituted C1-C6 alkyl, -OR 20 and -N(R 21 )R 22 In another embodiment is a compound of formula (Ib) wherein n is 3 and each R2 is independently selected from halogen and optionally substituted C1-C6 alkyl. In another embodiment is a compound of formula (Ib) wherein n is 2 and each R2 is independently selected from halogen, optionally substituted C1-C6 alkyl, -OR 20 and -N(R 21 )R 22 In another embodiment is a compound of formula (Ib) wherein n is 2 and each R2 is independently selected from halogen and optionally substituted C1-C6 alkyl. In another embodiment is a compound of formula (Ib) wherein n is 1 and R2 is selected from halogen, optionally substituted C1-C6 alkyl, -OR 20 and -N(R 21 )R 22 In another embodiment is a compound of Formula (Ib) wherein n is 1 and R2 is selected from halogen and optionally substituted C1-C6 alkyl. In another embodiment is a compound of Formula (Ib) wherein n is 0.

[0116] In another embodiment, it is a compound of formula (Ib), wherein R3 is selected from hydrogen and optionally substituted C1-C6 alkyl. In another embodiment, it is a compound of formula (Ib), wherein R3 is hydrogen. In another embodiment, it is a compound of formula (Ib), wherein R3 is optionally substituted C1-C6 alkyl. In another embodiment, it is a compound of formula (Ib), wherein R3 is methyl.

[0117] In another embodiment is a compound of Formula (Ib) wherein for In another embodiment is a compound of Formula (Ib) wherein for In another embodiment is a compound of Formula (Ib) wherein for In another embodiment is a compound of Formula (Ib) wherein for In another embodiment is a compound of Formula (Ib) wherein for In another embodiment is a compound of Formula (Ib) wherein for

[0118] In another embodiment, there is a compound of formula (Ib), wherein Z is -O-, -OCH2- or -CH2O-. In another embodiment, there is a compound of formula (Ib), wherein Z is -O-. In another embodiment, there is a compound of formula (Ib), wherein Z is -OCH2-. In another embodiment, there is a compound of formula (Ib), wherein Z is -CH2O-. In another embodiment, there is a compound of formula (Ib), wherein Z is -S-. In another embodiment, there is a compound of formula (Ib), wherein Z is -CH2-. In another embodiment, there is a compound of formula (Ib), wherein Z is -N(R4)-. In another embodiment, there is a compound of formula (Ib), wherein Z is -N(H)-. In another embodiment, there is a compound of formula (Ib), wherein Z is -N(CH3)-.

[0119] In another embodiment is a compound of Formula (Ib) wherein p is 0. In another embodiment is a compound of Formula (Ib) wherein p is 1.

[0120] In some embodiments provided herein, the compound of Formula (I) has the structure of Formula (Ic), or a pharmaceutically acceptable salt or solvate thereof:

[0121]

[0122] in:

[0123] Selected from

[0124] Z is -O-, -S-, -N(R4)-, -CH2-, -OCH2- or -CH2O-;

[0125] Each R1 is independently selected from hydrogen, halogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted C3-C8 cycloalkyl, optionally substituted -(C1-C2 alkylene)-(C3-C8 cycloalkyl), optionally substituted C2-C9 heterocycloalkyl, optionally substituted -(C1-C2 alkylene)-(C2-C9 heterocycloalkyl), optionally substituted -(C1-C2 alkylene)-(aryl), optionally substituted -(C1-C2 alkylene)-(heteroaryl), -CF3, -OR 10 、-SR 10 、-N(R 11 )R 12 、-N(R 11 )S(O)2R 15 ;-N(R 13 )N(R 11 )R 12 、-N(R 13 )N(R 11 )S(O)2R 15 、-C(O)R 14 、-C(O)OR 10 、-C(S)OR 10 、-C(O)SR 10 、-C(O)N(R 11 )R 12 、-C(S)N(R 11 )R 12 、-C(O)N(R 11 )S(O)2R 15 、-C(S)N(R 11 )S(O)2R 15 、-C(O)N(R 13 )N(R 11 )R 12 、-C(S)N(R 13 )N(R 11 )R 12 and -C(O)N(R 13 )N(R 11 )S(O)2R 15 ;

[0126] Each R2 is independently selected from halogen, optionally substituted C1-C6 alkyl, -OR 20 、-SR 20 、-N(R 21 )R 22 、-C(O)R 20 、-C(O)N(R 21 )R 22 and -N(R 23 )C(O)R 20 ;

[0127] R3 is selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C8 cycloalkyl, optionally substituted aryl, optionally substituted -(C1-C2 alkylene)-(aryl), optionally substituted heteroaryl, and optionally substituted -(C1-C2 alkylene)-(heteroaryl);

[0128] R4 is hydrogen or an optionally substituted C1-C6 alkyl group,

[0129] R 10 , R 13 and R 14 each independently selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C8 cycloalkyl, optionally substituted aryl, optionally substituted -(C1-C2 alkylene)-(aryl), optionally substituted C2-C9 heterocycloalkyl, optionally substituted heteroaryl, and optionally substituted -(C1-C2 alkylene)-(heteroaryl);

[0130] R 11 and R 12 R is each independently selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C8 cycloalkyl, optionally substituted aryl, optionally substituted -(C1-C2 alkylene)-(aryl), optionally substituted C2-C9 heterocycloalkyl, optionally substituted heteroaryl, and optionally substituted -(C1-C2 alkylene)-(heteroaryl); or optionally R 11 and R 12 Together with the nitrogen atom to which they are attached, they form an optionally substituted C2-C9 heterocycloalkyl ring;

[0131] R 15is selected from optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C8 cycloalkyl, optionally substituted aryl, optionally substituted -(C1-C2 alkylene)-(aryl), optionally substituted C2-C9 heterocycloalkyl, optionally substituted heteroaryl, and optionally substituted -(C1-C2 alkylene)-(heteroaryl);

[0132] R 20 and R 23 each independently selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C8 cycloalkyl, optionally substituted aryl, optionally substituted -(C1-C2 alkylene)-(aryl), optionally substituted C2-C9 heterocycloalkyl, optionally substituted heteroaryl, and optionally substituted -(C1-C2 alkylene)-(heteroaryl);

[0133] R 21 and R 22 R is each independently selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C8 cycloalkyl, optionally substituted aryl, optionally substituted -(C1-C2 alkylene)-(aryl), optionally substituted C2-C9 heterocycloalkyl, optionally substituted heteroaryl, and optionally substituted -(C1-C2 alkylene)-(heteroaryl); or optionally R 21 and R 22 Together with the nitrogen atom to which they are attached, they form an optionally substituted C2-C9 heterocycloalkyl ring;

[0134] n is 0-4; and

[0135] p is 0 or 1.

[0136] In one embodiment is a compound of formula (Ic), wherein each R1 is independently selected from hydrogen, halogen, optionally substituted C1-C6 alkyl, -CF3, -OR 10 、-N(R 11 )R 12 、-C(O)R 14 、-C(O)OR 10 and -C(O)N(R 11 )R 12 In another embodiment is a compound of formula (Ic), wherein each R1 is independently selected from hydrogen, halogen, optionally substituted C1-C6 alkyl, -CF3, -OR 10 and -N(R 11 )R 12 In another embodiment is a compound of Formula (Ic), wherein each R1 is independently selected from hydrogen, halogen and -CF3.

[0137] In another embodiment is a compound of Formula (Ic), wherein n is 3 and each R2 is independently selected from halogen, optionally substituted C1-C6 alkyl, -OR 20 and -N(R 21 )R 22 In another embodiment is a compound of formula (Ic) wherein n is 3 and each R2 is independently selected from halogen and optionally substituted C1-C6 alkyl. In another embodiment is a compound of formula (Ic) wherein n is 2 and each R2 is independently selected from halogen, optionally substituted C1-C6 alkyl, -OR 20 and -N(R 21 )R 22 In another embodiment is a compound of formula (Ic), wherein n is 2 and each R2 is independently selected from halogen and optionally substituted C1-C6 alkyl. In another embodiment is a compound of formula (Ic), wherein n is 1 and R2 is selected from halogen, optionally substituted C1-C6 alkyl, -OR 20 and -N(R 21 )R 22 In another embodiment is a compound of formula (Ic) wherein n is 1 and R2 is selected from halogen and optionally substituted C1-C6 alkyl. In another embodiment is a compound of formula (Ic) wherein n is 0.

[0138] In another embodiment, a compound of formula (Ic) wherein R3 is selected from hydrogen and optionally substituted C1-C6 alkyl. In another embodiment, a compound of formula (Ic) wherein R3 is hydrogen. In another embodiment, a compound of formula (Ic) wherein R3 is optionally substituted C1-C6 alkyl. In another embodiment, a compound of formula (Ic) wherein R3 is methyl.

[0139] In another embodiment is a compound of formula (Ic), wherein for In another embodiment is a compound of formula (Ic), wherein for In another embodiment is a compound of formula (Ic), wherein for In another embodiment is a compound of formula (Ic), wherein for In another embodiment is a compound of formula (Ic), wherein for In another embodiment is a compound of formula (Ic), wherein for

[0140] In another embodiment is a compound of formula (Ic), wherein Z is -O-, -OCH2- or -CH2O-. In another embodiment is a compound of formula (Ic), wherein Z is -O-. In another embodiment is a compound of formula (Ic), wherein Z is -OCH2-. In another embodiment is a compound of formula (Ic), wherein Z is -CH2O-. In another embodiment is a compound of formula (Ic), wherein Z is -S-. In another embodiment is a compound of formula (Ic), wherein Z is -CH2-. In another embodiment is a compound of formula (Ic), wherein Z is -N(R4)-. In another embodiment is a compound of formula (Ic), wherein Z is -N(H)-. In another embodiment is a compound of formula (Ic), wherein Z is -N(CH3)-.

[0141] In another embodiment is a compound of Formula (Ic) wherein p is 0. In another embodiment is a compound of Formula (Ic) wherein p is 1.

[0142] In some embodiments provided herein, the compound of Formula (I) has the structure of Formula (Id), or a pharmaceutically acceptable salt or solvate thereof:

[0143]

[0144] in:

[0145] Selected from

[0146] Z is -O-, -S-, -N(R4)-, -CH2-, -OCH2- or -CH2O-;

[0147] Each R1 is independently selected from hydrogen, halogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted C3-C8 cycloalkyl, optionally substituted -(C1-C2 alkylene)-(C3-C8 cycloalkyl), optionally substituted C2-C9 heterocycloalkyl, optionally substituted -(C1-C2 alkylene)-(C2-C9 heterocycloalkyl), optionally substituted -(C1-C2 alkylene)-(aryl), optionally substituted -(C1-C2 alkylene)-(heteroaryl), -CF3, -OR 10 、-SR 10 、-N(R 11 )R 12 、-N(R 11 )S(O)2R 15 ;-N(R 13 )N(R 11 )R12 、-N(R 13 )N(R 11 )S(O)2R 15 、-C(O)R 14 、-C(O)OR 10 、-C(S)OR 10 、-C(O)SR 10 、-C(O)N(R 11 )R 12 、-C(S)N(R 11 )R 12 、-C(O)N(R 11 )S(O)2R 15 、-C(S)N(R 11 )S(O)2R 15 、-C(O)N(R 13 )N(R 11 )R 12 、-C(S)N(R 13 )N(R 11 )R 12 and -C(O)N(R 13 )N(R 11 )S(O)2R 15 ;

[0148] Each R2 is independently selected from halogen, optionally substituted C1-C6 alkyl, -OR 20 、-SR 20 、-N(R 21 )R 22 、-C(O)R 20 、-C(O)N(R 21 )R 22 and -N(R 23 )C(O)R 20 ;

[0149] R3 is selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C8 cycloalkyl, optionally substituted aryl, optionally substituted -(C1-C2 alkylene)-(aryl), optionally substituted heteroaryl, and optionally substituted -(C1-C2 alkylene)-(heteroaryl);

[0150] R4 is hydrogen or an optionally substituted C1-C6 alkyl group,

[0151] R 10 , R 13 and R 14each independently selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C8 cycloalkyl, optionally substituted aryl, optionally substituted -(C1-C2 alkylene)-(aryl), optionally substituted C2-C9 heterocycloalkyl, optionally substituted heteroaryl, and optionally substituted -(C1-C2 alkylene)-(heteroaryl);

[0152] R 11 and R 12 R is each independently selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C8 cycloalkyl, optionally substituted aryl, optionally substituted -(C1-C2 alkylene)-(aryl), optionally substituted C2-C9 heterocycloalkyl, optionally substituted heteroaryl, and optionally substituted -(C1-C2 alkylene)-(heteroaryl); or optionally R 11 and R 12 Together with the nitrogen atom to which they are attached, they form an optionally substituted C2-C9 heterocycloalkyl ring;

[0153] R 15 is selected from optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C8 cycloalkyl, optionally substituted aryl, optionally substituted -(C1-C2 alkylene)-(aryl), optionally substituted C2-C9 heterocycloalkyl, optionally substituted heteroaryl, and optionally substituted -(C1-C2 alkylene)-(heteroaryl);

[0154] R 20 and R 23 each independently selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C8 cycloalkyl, optionally substituted aryl, optionally substituted -(C1-C2 alkylene)-(aryl), optionally substituted C2-C9 heterocycloalkyl, optionally substituted heteroaryl, and optionally substituted -(C1-C2 alkylene)-(heteroaryl);

[0155] R 21 and R 22 R is each independently selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C8 cycloalkyl, optionally substituted aryl, optionally substituted -(C1-C2 alkylene)-(aryl), optionally substituted C2-C9 heterocycloalkyl, optionally substituted heteroaryl, and optionally substituted -(C1-C2 alkylene)-(heteroaryl); or optionally R 21 and R 22Together with the nitrogen atom to which they are attached, they form an optionally substituted C2-C9 heterocycloalkyl ring;

[0156] n is 0-4; and

[0157] p is 0 or 1.

[0158] In one embodiment is a compound of formula (Id), wherein each R1 is independently selected from hydrogen, halogen, optionally substituted C1-C6 alkyl, -CF3, -OR 10 、-N(R 11 )R 12 、-C(O)R 14 、-C(O)OR 10 and -C(O)N(R 11 )R 12 In another embodiment is a compound of formula (Id), wherein each R1 is independently selected from hydrogen, halogen, optionally substituted C1-C6 alkyl, -CF3, -OR 10 and -N(R 11 )R 12 In another embodiment is a compound of Formula (Id), wherein each R1 is independently selected from hydrogen, halogen and -CF3.

[0159] In another embodiment is a compound of Formula (Id) wherein n is 3 and each R2 is independently selected from halogen, optionally substituted C1-C6 alkyl, -OR 20 and -N(R 21 )R 22 In another embodiment is a compound of formula (Id) wherein n is 3 and each R2 is independently selected from halogen and optionally substituted C1-C6 alkyl. In another embodiment is a compound of formula (Id) wherein n is 2 and each R2 is independently selected from halogen, optionally substituted C1-C6 alkyl, -OR 20 and -N(R 21 )R 22 In another embodiment is a compound of formula (Id) wherein n is 2 and each R2 is independently selected from halogen and optionally substituted C1-C6 alkyl. In another embodiment is a compound of formula (Id) wherein n is 1 and R2 is selected from halogen, optionally substituted C1-C6 alkyl, -OR 20 and -N(R 21 )R 22 In another embodiment is a compound of formula (Id) wherein n is 1 and R2 is selected from halogen and optionally substituted C1-C6 alkyl. In another embodiment is a compound of formula (Id) wherein n is 0.

[0160] In another embodiment, it is a compound of formula (Id), wherein R3 is selected from hydrogen and optionally substituted C1-C6 alkyl. In another embodiment, it is a compound of formula (Id), wherein R3 is hydrogen. In another embodiment, it is a compound of formula (Id), wherein R3 is optionally substituted C1-C6 alkyl. In another embodiment, it is a compound of formula (Id), wherein R3 is methyl.

[0161] In another embodiment is a compound of Formula (Id), wherein for In another embodiment is a compound of Formula (Id), wherein for In another embodiment is a compound of Formula (Id), wherein for In another embodiment is a compound of Formula (Id), wherein for In another embodiment is a compound of Formula (Id), wherein for In another embodiment is a compound of Formula (Id), wherein for

[0162] In another embodiment is a compound of formula (Id) wherein Z is -O-, -OCH2- or -CH2O-. In another embodiment is a compound of formula (Id) wherein Z is -O-. In another embodiment is a compound of formula (Id) wherein Z is -OCH2-. In another embodiment is a compound of formula (Id) wherein Z is -CH2O-. In another embodiment is a compound of formula (Id) wherein Z is -S-. In another embodiment is a compound of formula (Id) wherein Z is -CH2-. In another embodiment is a compound of formula (Id) wherein Z is -N(R4)-. In another embodiment is a compound of formula (Id) wherein Z is -N(H)-. In another embodiment is a compound of formula (Id) wherein Z is -N(CH3)-.

[0163] In another embodiment is a compound of Formula (Id) wherein p is 0. In another embodiment is a compound of Formula (Id) wherein p is 1.

[0164] In some embodiments provided herein, the compound of Formula (I) has the structure of Formula (Ie), or a pharmaceutically acceptable salt or solvate thereof:

[0165]

[0166] in:

[0167] Selected from

[0168] Z is -O-, -S-, -N(R4)-, -CH2-, -OCH2- or -CH2O-;

[0169] Each R1 is independently selected from hydrogen, halogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted C3-C8 cycloalkyl, optionally substituted -(C1-C2 alkylene)-(C3-C8 cycloalkyl), optionally substituted C2-C9 heterocycloalkyl, optionally substituted -(C1-C2 alkylene)-(C2-C9 heterocycloalkyl), optionally substituted -(C1-C2 alkylene)-(aryl), optionally substituted -(C1-C2 alkylene)-(heteroaryl), -CF3, -OR 10 、-SR 10 、-N(R 11 )R 12 、-N(R 11 )S(O)2R 15 ;-N(R 13 )N(R 11 )R 12 、-N(R 13 )N(R 11 )S(O)2R 15 、-C(O)R 14 、-C(O)OR 10 、-C(S)OR 10 、-C(O)SR 10 、-C(O)N(R 11 )R 12 、-C(S)N(R 11 )R 12 、-C(O)N(R 11 )S(O)2R 15 、-C(S)N(R 11 )S(O)2R 15 、-C(O)N(R 13 )N(R 11 )R 12 、-C(S)N(R 13 )N(R 11 )R 12 and -C(O)N(R 13 )N(R 11 )S(O)2R 15 ;

[0170] Each R2 is independently selected from halogen, optionally substituted C1-C6 alkyl, -OR 20 、-SR 20 、-N(R 21 )R 22 、-C(O)R 20 、-C(O)N(R 21 )R 22 and -N(R 23 )C(O)R 20 ;

[0171] R3 is selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C8 cycloalkyl, optionally substituted aryl, optionally substituted -(C1-C2 alkylene)-(aryl), optionally substituted heteroaryl, and optionally substituted -(C1-C2 alkylene)-(heteroaryl);

[0172] R4 is hydrogen or an optionally substituted C1-C6 alkyl group,

[0173] R 10 , R 13 and R 14 each independently selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C8 cycloalkyl, optionally substituted aryl, optionally substituted -(C1-C2 alkylene)-(aryl), optionally substituted C2-C9 heterocycloalkyl, optionally substituted heteroaryl, and optionally substituted -(C1-C2 alkylene)-(heteroaryl);

[0174] R 11 and R 12 R is each independently selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C8 cycloalkyl, optionally substituted aryl, optionally substituted -(C1-C2 alkylene)-(aryl), optionally substituted C2-C9 heterocycloalkyl, optionally substituted heteroaryl, and optionally substituted -(C1-C2 alkylene)-(heteroaryl); or optionally R 11 and R 12 Together with the nitrogen atom to which they are attached, they form an optionally substituted C2-C9 heterocycloalkyl ring;

[0175] R 15is selected from optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C8 cycloalkyl, optionally substituted aryl, optionally substituted -(C1-C2 alkylene)-(aryl), optionally substituted C2-C9 heterocycloalkyl, optionally substituted heteroaryl, and optionally substituted -(C1-C2 alkylene)-(heteroaryl);

[0176] R 20 and R 23 each independently selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C8 cycloalkyl, optionally substituted aryl, optionally substituted -(C1-C2 alkylene)-(aryl), optionally substituted C2-C9 heterocycloalkyl, optionally substituted heteroaryl, and optionally substituted -(C1-C2 alkylene)-(heteroaryl);

[0177] R 21 and R 22 R is each independently selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C8 cycloalkyl, optionally substituted aryl, optionally substituted -(C1-C2 alkylene)-(aryl), optionally substituted C2-C9 heterocycloalkyl, optionally substituted heteroaryl, and optionally substituted -(C1-C2 alkylene)-(heteroaryl); or optionally R 21 and R 22 Together with the nitrogen atom to which they are attached, they form an optionally substituted C2-C9 heterocycloalkyl ring;

[0178] n is 0-4; and

[0179] p is 0 or 1.

[0180] In one embodiment is a compound of formula (Ie), wherein each R1 is independently selected from hydrogen, halogen, optionally substituted C1-C6 alkyl, -CF3, -OR 10 、-N(R 11 )R 12 、-C(O)R 14 、-C(O)OR 10 and -C(O)N(R 11 )R 12 In another embodiment is a compound of formula (Ie), wherein each R1 is independently selected from hydrogen, halogen, optionally substituted C1-C6 alkyl, -CF3, -OR 10 and -N(R 11 )R 12 In another embodiment is a compound of Formula (Ie), wherein each R1 is independently selected from hydrogen, halogen and -CF3.

[0181] In another embodiment is a compound of Formula (Ie), wherein n is 3 and each R2 is independently selected from halogen, optionally substituted C1-C6 alkyl, -OR 20 and -N(R 21 )R 22 In another embodiment is a compound of formula (Ie) wherein n is 3 and each R2 is independently selected from halogen and optionally substituted C1-C6 alkyl. In another embodiment is a compound of formula (Ie) wherein n is 2 and each R2 is independently selected from halogen, optionally substituted C1-C6 alkyl, -OR 20 and -N(R 21 )R 22 In another embodiment is a compound of formula (Ie), wherein n is 2 and each R2 is independently selected from halogen and optionally substituted C1-C6 alkyl. In another embodiment is a compound of formula (Ie), wherein n is 1 and R2 is selected from halogen, optionally substituted C1-C6 alkyl, -OR 20 and -N(R 21 )R 22 In another embodiment is a compound of formula (Ie) wherein n is 1 and R2 is selected from halogen and optionally substituted C1-C6 alkyl. In another embodiment is a compound of formula (Ie) wherein n is 0.

[0182] In another embodiment, there is a compound of formula (Ie), wherein R3 is selected from hydrogen and optionally substituted C1-C6 alkyl. In another embodiment, there is a compound of formula (Ie), wherein R3 is hydrogen. In another embodiment, there is a compound of formula (Ie), wherein R3 is optionally substituted C1-C6 alkyl. In another embodiment, there is a compound of formula (Ie), wherein R3 is methyl.

[0183] In another embodiment is a compound of Formula (Ie), wherein for In another embodiment is a compound of Formula (Ie), wherein for In another embodiment is a compound of Formula (Ie), wherein for In another embodiment is a compound of Formula (Ie), wherein for In another embodiment is a compound of Formula (Ie), wherein for In another embodiment is a compound of Formula (Ie), wherein for

[0184] In another embodiment is a compound of formula (Ie) wherein Z is -O-, -OCH2- or -CH2O-. In another embodiment is a compound of formula (Ie) wherein Z is -O-. In another embodiment is a compound of formula (Ie) wherein Z is -OCH2-. In another embodiment is a compound of formula (Ie) wherein Z is -CH2O-. In another embodiment is a compound of formula (Ie) wherein Z is -S-. In another embodiment is a compound of formula (Ie) wherein Z is -CH2-. In another embodiment is a compound of formula (Ie) wherein Z is -N(R4)-. In another embodiment is a compound of formula (Ie) wherein Z is -N(H)-. In another embodiment is a compound of formula (Ie) wherein Z is -N(CH3)-.

[0185] In another embodiment is a compound of Formula (Ie) wherein p is 0. In another embodiment is a compound of Formula (Ie) wherein p is 1.

[0186] In one aspect, provided herein is a compound of formula (II), or a pharmaceutically acceptable salt or solvate thereof:

[0187]

[0188] in:

[0189] X1, X2, X3 and X4 are each CR1; or

[0190] X1 is N; X2, X3 and X4 are each CR1; or

[0191] X2 is N; X1, X3 and X4 are each CR1; or

[0192] X3 is N; X1, X2 and X4 are each CR1; or

[0193] X4 is N; X1, X2 and X3 are each CR1;

[0194] Selected from

[0195] Z is -O-, -S-, -N(R4)-, -CH2-, -OCH2- or -CH2O-;

[0196] Each R1 is independently selected from hydrogen, halogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted C3-C8 cycloalkyl, optionally substituted -(C1-C2 alkylene)-(C3-C8 cycloalkyl), optionally substituted C2-C9 heterocycloalkyl, optionally substituted -(C1-C2 alkylene)-(C2-C9 heterocycloalkyl), optionally substituted -(C1-C2 alkylene)-(aryl), optionally substituted -(C1-C2 alkylene)-(heteroaryl), -CF3, -OR 10 、-SR 10 、-N(R 11 )R 12 、-N(R 11 )S(O)2R 15 ;-N(R 13 )N(R 11 )R 12 、-N(R 13 )N(R 11 )S(O)2R 15 、-C(O)R 14 、-C(O)OR 10 、-C(S)OR 10 、-C(O)SR 10 、-C(O)N(R 11 )R 12 、-C(S)N(R 11 )R 12 、-C(O)N(R 11 )S(O)2R 15 、-C(S)N(R 11 )S(O)2R 15 、-C(O)N(R 13 )N(R 11 )R 12 、-C(S)N(R 13 )N(R 11 )R 12 and -C(O)N(R 13 )N(R 11 )S(O)2R 15 ;

[0197] Each R2 is independently selected from halogen, optionally substituted C1-C6 alkyl, -OR 20 、-SR 20 、-N(R 21 )R 22 、-C(O)R 20 、-C(O)N(R 21 )R 22and -N(R 23 )C(O)R 20 ;

[0198] R3 is selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C8 cycloalkyl, optionally substituted aryl, optionally substituted -(C1-C2 alkylene)-(aryl), optionally substituted heteroaryl, and optionally substituted -(C1-C2 alkylene)-(heteroaryl);

[0199] R4 is hydrogen or an optionally substituted C1-C6 alkyl group,

[0200] R 10 , R 13 and R 14 each independently selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C8 cycloalkyl, optionally substituted aryl, optionally substituted -(C1-C2 alkylene)-(aryl), optionally substituted C2-C9 heterocycloalkyl, optionally substituted heteroaryl, and optionally substituted -(C1-C2 alkylene)-(heteroaryl);

[0201] R 11 and R 12 R is each independently selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C8 cycloalkyl, optionally substituted aryl, optionally substituted -(C1-C2 alkylene)-(aryl), optionally substituted C2-C9 heterocycloalkyl, optionally substituted heteroaryl, and optionally substituted -(C1-C2 alkylene)-(heteroaryl); or optionally R 11 and R 12 Together with the nitrogen atom to which they are attached, they form an optionally substituted C2-C9 heterocycloalkyl ring;

[0202] R 15 is selected from optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C8 cycloalkyl, optionally substituted aryl, optionally substituted -(C1-C2 alkylene)-(aryl), optionally substituted C2-C9 heterocycloalkyl, optionally substituted heteroaryl, and optionally substituted -(C1-C2 alkylene)-(heteroaryl);

[0203] R 20 and R 23each independently selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C8 cycloalkyl, optionally substituted aryl, optionally substituted -(C1-C2 alkylene)-(aryl), optionally substituted C2-C9 heterocycloalkyl, optionally substituted heteroaryl, and optionally substituted -(C1-C2 alkylene)-(heteroaryl);

[0204] R 21 and R 22 R is each independently selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C8 cycloalkyl, optionally substituted aryl, optionally substituted -(C1-C2 alkylene)-(aryl), optionally substituted C2-C9 heterocycloalkyl, optionally substituted heteroaryl, and optionally substituted -(C1-C2 alkylene)-(heteroaryl); or optionally R 21 and R 22 Together with the nitrogen atom to which they are attached, they form an optionally substituted C2-C9 heterocycloalkyl ring;

[0205] n is 0-4; and

[0206] p is 0 or 1.

[0207] In one embodiment, it is a compound of formula (II), wherein X1, X2, X3 and X4 are each CR1. In another embodiment, it is a compound of formula (II), wherein X1, X2, X3 and X4 are each CR1; and each R1 is independently selected from hydrogen, halogen, optionally substituted C1-C6 alkyl, -CF3, -OR 10 、-N(R 11 )R 12 、-C(O)R 14 、-C(O)OR 10 and -C(O)N(R 11 )R 12 In another embodiment is a compound of formula (II), wherein X1, X2, X3 and X4 are each CR1; and each R1 is independently selected from hydrogen, halogen, optionally substituted C1-C6 alkyl, -CF3, -OR 10 and -N(R 11 )R 12 .

[0208] In another embodiment is a compound of Formula (II), wherein X1, X2, X3 and X4 are each CR1; and each R1 is independently selected from hydrogen, halogen and -CF3.

[0209] In another embodiment is a compound of formula (II), wherein X1 is N; and X2, X3 and X4 are each CR1. In another embodiment is a compound of formula (II), wherein X1 is N; and X2, X3 and X4 are each CR1; and each R1 is independently selected from hydrogen, halogen, optionally substituted C1-C6 alkyl, -CF3, -OR 10 、-N(R 11 )R 12 、-C(O)R 14 、-C(O)OR 10 and -C(O)N(R 11 )R 12 In another embodiment is a compound of formula (II), wherein X1 is N; and X2, X3 and X4 are each CR1; and each R1 is independently selected from hydrogen, halogen, optionally substituted C1-C6 alkyl, -CF3, -OR 10 and -N(R 11 )R 12 In another embodiment is a compound of formula (II), wherein X1 is N; and X2, X3, and X4 are each CR1; and each R1 is independently selected from hydrogen, halogen, and -CF3.

[0210] In another embodiment is a compound of formula (II), wherein X2 is N; and X1, X3 and X4 are each CR1. In another embodiment is a compound of formula (II), wherein X2 is N; and X1, X3 and X4 are each CR1; and each R1 is independently selected from hydrogen, halogen, optionally substituted C1-C6 alkyl, -CF3, -OR 10 、-N(R 11 )R 12 、-C(O)R 14 、-C(O)OR 10 and -C(O)N(R 11 )R 12 In another embodiment is a compound of formula (II), wherein X2 is N; and X1, X3 and X4 are each CR1; and each R1 is independently selected from hydrogen, halogen, optionally substituted C1-C6 alkyl, -CF3, -OR 10 and -N(R 11 )R 12 In another embodiment is a compound of formula (II), wherein X2 is N; and X1, X3, and X4 are each CR1; and each R1 is independently selected from hydrogen, halogen, and -CF3.

[0211] In another embodiment is a compound of formula (II), wherein X3 is N; and X1, X2 and X4 are each CR1. In another embodiment is a compound of formula (II), wherein X3 is N; and X1, X2 and X4 are each CR1; and each R1 is independently selected from hydrogen, halogen, optionally substituted C1-C6 alkyl, -CF3, -OR 10 、-N(R 11 )R 12 、-C(O)R 14 、-C(O)OR 10 and -C(O)N(R 11 )R 12 In another embodiment is a compound of formula (II), wherein X3 is N; and X1, X2 and X4 are each CR1; and each R1 is independently selected from hydrogen, halogen, optionally substituted C1-C6 alkyl, -CF3, -OR 10 and -N(R 11 )R 12 In another embodiment is a compound of formula (II), wherein X3 is N; and X1, X2, and X4 are each CR1; and each R1 is independently selected from hydrogen, halogen, and -CF3.

[0212] In another embodiment is a compound of formula (II), wherein X4 is N; and X1, X2 and X3 are each CR1. In another embodiment is a compound of formula (II), wherein X4 is N; and X1, X2 and X3 are each CR1; and each R1 is independently selected from hydrogen, halogen, optionally substituted C1-C6 alkyl, -CF3, -OR 10 、-N(R 11 )R 12 、-C(O)R 14 、-C(O)OR 10 and -C(O)N(R 11 )R 12 In another embodiment is a compound of formula (II), wherein X4 is N; and X1, X2 and X3 are each CR1; and each R1 is independently selected from hydrogen, halogen, optionally substituted C1-C6 alkyl, -CF3, -OR 10 and -N(R 11 )R 12 In another embodiment is a compound of formula (II), wherein X4 is N; and X1, X2, and X3 are each CR1; and each R1 is independently selected from hydrogen, halogen, and -CF3.

[0213] In another embodiment is a compound of formula (II), wherein n is 3 and each R2 is independently selected from halogen, optionally substituted C1-C6 alkyl, -OR 20 and -N(R 21)R 22 In another embodiment is a compound of formula (II), wherein n is 3 and each R2 is independently selected from halogen and optionally substituted C1-C6 alkyl. In another embodiment is a compound of formula (II), wherein n is 2 and each R2 is independently selected from halogen, optionally substituted C1-C6 alkyl, -OR 20 and -N(R 21 )R 22 In another embodiment is a compound of formula (II), wherein n is 2 and each R2 is independently selected from halogen and optionally substituted C1-C6 alkyl. In another embodiment is a compound of formula (II), wherein n is 1 and R2 is selected from halogen, optionally substituted C1-C6 alkyl, -OR 20 and -N(R 21 )R 22 In another embodiment is a compound of formula (II) wherein n is 1 and R2 is selected from halogen and optionally substituted C1-C6 alkyl. In another embodiment is a compound of formula (II) wherein n is 0.

[0214] In another embodiment, it is a compound of formula (II), wherein R3 is selected from hydrogen and optionally substituted C1-C6 alkyl. In another embodiment, it is a compound of formula (II), wherein R3 is hydrogen. In another embodiment, it is a compound of formula (II), wherein R3 is optionally substituted C1-C6 alkyl. In another embodiment, it is a compound of formula (II), wherein R3 is methyl.

[0215] In another embodiment is a compound of formula (II), wherein for In another embodiment is a compound of formula (II), wherein for In another embodiment is a compound of formula (II), wherein for In another embodiment is a compound of formula (II), wherein for In another embodiment is a compound of formula (II), wherein for In another embodiment is a compound of formula (II), wherein for

[0216] In another embodiment, a compound of formula (II) wherein Z is -O-, -OCH2- or -CH2O-. In another embodiment, a compound of formula (II) wherein Z is -O-. In another embodiment, a compound of formula (II) wherein Z is -OCH2-. In another embodiment, a compound of formula (II) wherein Z is -CH2O-. In another embodiment, a compound of formula (II) wherein Z is -S-. In another embodiment, a compound of formula (II) wherein Z is -CH2-. In another embodiment, a compound of formula (II) wherein Z is -N(R4)-. In another embodiment, a compound of formula (II) wherein Z is -N(H)-. In another embodiment, a compound of formula (II) wherein Z is -N(CH3)-.

[0217] In another embodiment is a compound of Formula (II) wherein p is 0. In another embodiment is a compound of Formula (II) wherein p is 1.

[0218] In some embodiments provided herein, the compound of formula (II) has the structure of formula (IIa), or a pharmaceutically acceptable salt or solvate thereof:

[0219]

[0220] in:

[0221] Selected from

[0222] Z is -O-, -S-, -N(R4)-, -CH2-, -OCH2- or -CH2O-;

[0223] Each R1 is independently selected from hydrogen, halogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted C3-C8 cycloalkyl, optionally substituted -(C1-C2 alkylene)-(C3-C8 cycloalkyl), optionally substituted C2-C9 heterocycloalkyl, optionally substituted -(C1-C2 alkylene)-(C2-C9 heterocycloalkyl), optionally substituted -(C1-C2 alkylene)-(aryl), optionally substituted -(C1-C2 alkylene)-(heteroaryl), -CF3, -OR 10 、-SR 10 、-N(R 11 )R 12 、-N(R 11 )S(O)2R 15 ;-N(R 13 )N(R 11 )R12 、-N(R 13 )N(R 11 )S(O)2R 15 、-C(O)R 14 、-C(O)OR 10 、-C(S)OR 10 、-C(O)SR 10 、-C(O)N(R 11 )R 12 、-C(S)N(R 11 )R 12 、-C(O)N(R 11 )S(O)2R 15 、-C(S)N(R 11 )S(O)2R 15 、-C(O)N(R 13 )N(R 11 )R 12 、-C(S)N(R 13 )N(R 11 )R 12 and -C(O)N(R 13 )N(R 11 )S(O)2R 15 ;

[0224] Each R2 is independently selected from halogen, optionally substituted C1-C6 alkyl, -OR 20 、-SR 20 、-N(R 21 )R 22 、-C(O)R 20 、-C(O)N(R 21 )R 22 and -N(R 23 )C(O)R 20 ;

[0225] R3 is selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C8 cycloalkyl, optionally substituted aryl, optionally substituted -(C1-C2 alkylene)-(aryl), optionally substituted heteroaryl, and optionally substituted -(C1-C2 alkylene)-(heteroaryl);

[0226] R4 is hydrogen or an optionally substituted C1-C6 alkyl group,

[0227] R 10 , R 13 and R 14each independently selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C8 cycloalkyl, optionally substituted aryl, optionally substituted -(C1-C2 alkylene)-(aryl), optionally substituted C2-C9 heterocycloalkyl, optionally substituted heteroaryl, and optionally substituted -(C1-C2 alkylene)-(heteroaryl);

[0228] R 11 and R 12 R is each independently selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C8 cycloalkyl, optionally substituted aryl, optionally substituted -(C1-C2 alkylene)-(aryl), optionally substituted C2-C9 heterocycloalkyl, optionally substituted heteroaryl, and optionally substituted -(C1-C2 alkylene)-(heteroaryl); or optionally R 11 and R 12 Together with the nitrogen atom to which they are attached, they form an optionally substituted C2-C9 heterocycloalkyl ring;

[0229] R 15 is selected from optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C8 cycloalkyl, optionally substituted aryl, optionally substituted -(C1-C2 alkylene)-(aryl), optionally substituted C2-C9 heterocycloalkyl, optionally substituted heteroaryl, and optionally substituted -(C1-C2 alkylene)-(heteroaryl);

[0230] R 20 and R 23 each independently selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C8 cycloalkyl, optionally substituted aryl, optionally substituted -(C1-C2 alkylene)-(aryl), optionally substituted C2-C9 heterocycloalkyl, optionally substituted heteroaryl, and optionally substituted -(C1-C2 alkylene)-(heteroaryl);

[0231] R 21 and R 22 R is each independently selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C8 cycloalkyl, optionally substituted aryl, optionally substituted -(C1-C2 alkylene)-(aryl), optionally substituted C2-C9 heterocycloalkyl, optionally substituted heteroaryl, and optionally substituted -(C1-C2 alkylene)-(heteroaryl); or optionally R 21 and R 22Together with the nitrogen atom to which they are attached, they form an optionally substituted C2-C9 heterocycloalkyl ring;

[0232] n is 0-4; and

[0233] p is 0 or 1.

[0234] In one embodiment is a compound of formula (IIa), wherein each R1 is independently selected from hydrogen, halogen, optionally substituted C1-C6 alkyl, -CF3, -OR 10 、-N(R 11 )R 12 、-C(O)R 14 、-C(O)OR 10 and -C(O)N(R 11 )R 12 In another embodiment is a compound of formula (IIa), wherein each R1 is independently selected from hydrogen, halogen, optionally substituted C1-C6 alkyl, -CF3, -OR 10 and -N(R 11 )R 12 In another embodiment is a compound of Formula (IIa), wherein each R1 is independently selected from hydrogen, halogen and -CF3.

[0235] In another embodiment is a compound of Formula (IIa), wherein n is 3 and each R2 is independently selected from halogen, optionally substituted C1-C6 alkyl, -OR 20 and -N(R 21 )R 22 In another embodiment is a compound of formula (IIa) wherein n is 3 and each R2 is independently selected from halogen and optionally substituted C1-C6 alkyl. In another embodiment is a compound of formula (IIa) wherein n is 2 and each R2 is independently selected from halogen, optionally substituted C1-C6 alkyl, -OR 20 and -N(R 21 )R 22 In another embodiment is a compound of formula (IIa), wherein n is 2 and each R2 is independently selected from halogen and optionally substituted C1-C6 alkyl. In another embodiment is a compound of formula (IIa), wherein n is 1 and R2 is selected from halogen, optionally substituted C1-C6 alkyl, -OR 20 and -N(R 21 )R 22 In another embodiment is a compound of formula (IIa) wherein n is 1 and R2 is selected from halogen and optionally substituted C1-C6 alkyl. In another embodiment is a compound of formula (IIa) wherein n is 0.

[0236] In another embodiment, it is a compound of formula (IIa), wherein R3 is selected from hydrogen and optionally substituted C1-C6 alkyl. In another embodiment, it is a compound of formula (IIa), wherein R3 is hydrogen. In another embodiment, it is a compound of formula (IIa), wherein R3 is optionally substituted C1-C6 alkyl. In another embodiment, it is a compound of formula (IIa), wherein R3 is methyl.

[0237] In another embodiment is a compound of formula (IIa), wherein for In another embodiment is a compound of formula (IIa), wherein for In another embodiment is a compound of formula (IIa), wherein for In another embodiment is a compound of formula (IIa), wherein for In another embodiment is a compound of formula (IIa), wherein for In another embodiment is a compound of formula (IIa), wherein for

[0238] In another embodiment, a compound of formula (IIa) wherein Z is -O-, -OCH2- or -CH2O-. In another embodiment, a compound of formula (IIa) wherein Z is -O-. In another embodiment, a compound of formula (IIa) wherein Z is -OCH2-. In another embodiment, a compound of formula (IIa) wherein Z is -CH2O-. In another embodiment, a compound of formula (IIa) wherein Z is -S-. In another embodiment, a compound of formula (IIa) wherein Z is -CH2-. In another embodiment, a compound of formula (IIa) wherein Z is -N(R4)-. In another embodiment, a compound of formula (IIa) wherein Z is -N(H)-. In another embodiment, a compound of formula (IIa) wherein Z is -N(CH3)-.

[0239] In another embodiment is a compound of Formula (IIa) wherein p is 0. In another embodiment is a compound of Formula (IIa) wherein p is 1.

[0240] In some embodiments provided herein, the compound of Formula (II) has the structure of Formula (IIb), or a pharmaceutically acceptable salt or solvate thereof:

[0241]

[0242] in:

[0243] Selected from

[0244] Z is -O-, -S-, -N(R4)-, -CH2-, -OCH2- or -CH2O-;

[0245] Each R1 is independently selected from hydrogen, halogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted C3-C8 cycloalkyl, optionally substituted -(C1-C2 alkylene)-(C3-C8 cycloalkyl), optionally substituted C2-C9 heterocycloalkyl, optionally substituted -(C1-C2 alkylene)-(C2-C9 heterocycloalkyl), optionally substituted -(C1-C2 alkylene)-(aryl), optionally substituted -(C1-C2 alkylene)-(heteroaryl), -CF3, -OR 10 、-SR 10 、-N(R 11 )R 12 、-N(R 11 )S(O)2R 15 ;-N(R 13 )N(R 11 )R 12 、-N(R 13 )N(R 11 )S(O)2R 15 、-C(O)R 14 、-C(O)OR 10 、-C(S)OR 10 、-C(O)SR 10 、-C(O)N(R 11 )R 12 、-C(S)N(R 11 )R 12 、-C(O)N(R 11 )S(O)2R 15 、-C(S)N(R 11 )S(O)2R 15 、-C(O)N(R 13 )N(R 11 )R 12 、-C(S)N(R 13 )N(R 11 )R 12 and -C(O)N(R 13 )N(R 11 )S(O)2R 15 ;

[0246] Each R2 is independently selected from halogen, optionally substituted C1-C6 alkyl, -OR 20 、-SR 20 、-N(R 21 )R 22 、-C(O)R 20 、-C(O)N(R 21 )R 22 and -N(R 23 )C(O)R 20 ;

[0247] R3 is selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C8 cycloalkyl, optionally substituted aryl, optionally substituted -(C1-C2 alkylene)-(aryl), optionally substituted heteroaryl, and optionally substituted -(C1-C2 alkylene)-(heteroaryl);

[0248] R4 is hydrogen or an optionally substituted C1-C6 alkyl group,

[0249] R 10 , R 13 and R 14 each independently selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C8 cycloalkyl, optionally substituted aryl, optionally substituted -(C1-C2 alkylene)-(aryl), optionally substituted C2-C9 heterocycloalkyl, optionally substituted heteroaryl, and optionally substituted -(C1-C2 alkylene)-(heteroaryl);

[0250] R 11 and R 12 R is each independently selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C8 cycloalkyl, optionally substituted aryl, optionally substituted -(C1-C2 alkylene)-(aryl), optionally substituted C2-C9 heterocycloalkyl, optionally substituted heteroaryl, and optionally substituted -(C1-C2 alkylene)-(heteroaryl); or optionally R 11 and R 12 Together with the nitrogen atom to which they are attached, they form an optionally substituted C2-C9 heterocycloalkyl ring;

[0251] R 15is selected from optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C8 cycloalkyl, optionally substituted aryl, optionally substituted -(C1-C2 alkylene)-(aryl), optionally substituted C2-C9 heterocycloalkyl, optionally substituted heteroaryl, and optionally substituted -(C1-C2 alkylene)-(heteroaryl);

[0252] R 20 and R 23 each independently selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C8 cycloalkyl, optionally substituted aryl, optionally substituted -(C1-C2 alkylene)-(aryl), optionally substituted C2-C9 heterocycloalkyl, optionally substituted heteroaryl, and optionally substituted -(C1-C2 alkylene)-(heteroaryl);

[0253] R 21 and R 22 R is each independently selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C8 cycloalkyl, optionally substituted aryl, optionally substituted -(C1-C2 alkylene)-(aryl), optionally substituted C2-C9 heterocycloalkyl, optionally substituted heteroaryl, and optionally substituted -(C1-C2 alkylene)-(heteroaryl); or optionally R 21 and R 22 Together with the nitrogen atom to which they are attached, they form an optionally substituted C2-C9 heterocycloalkyl ring;

[0254] n is 0-4; and

[0255] p is 0 or 1.

[0256] In one embodiment is a compound of formula (IIb), wherein each R1 is independently selected from hydrogen, halogen, optionally substituted C1-C6 alkyl, -CF3, -OR 10 、-N(R 11 )R 12 、-C(O)R 14 、-C(O)OR 10 and -C(O)N(R 11 )R 12 In another embodiment is a compound of formula (IIb), wherein each R1 is independently selected from hydrogen, halogen, optionally substituted C1-C6 alkyl, -CF3, -OR 10 and -N(R 11 )R 12 In another embodiment is a compound of Formula (IIb), wherein each R1 is independently selected from hydrogen, halogen and -CF3.

[0257] In another embodiment is a compound of formula (IIb), wherein n is 3 and each R2 is independently selected from halogen, optionally substituted C1-C6 alkyl, -OR 20 and -N(R 21 )R 22 In another embodiment is a compound of formula (IIb), wherein n is 3 and each R2 is independently selected from halogen and optionally substituted C1-C6 alkyl. In another embodiment is a compound of formula (IIb), wherein n is 2 and each R2 is independently selected from halogen, optionally substituted C1-C6 alkyl, -OR 20 and -N(R 21 )R 22 In another embodiment is a compound of formula (IIb), wherein n is 2 and each R2 is independently selected from halogen and optionally substituted C1-C6 alkyl. In another embodiment is a compound of formula (IIb), wherein n is 1 and R2 is selected from halogen, optionally substituted C1-C6 alkyl, -OR 20 and -N(R 21 )R 22 In another embodiment is a compound of formula (IIb) wherein n is 1 and R2 is selected from halogen and optionally substituted C1-C6 alkyl. In another embodiment is a compound of formula (IIb) wherein n is 0.

[0258] In another embodiment, it is a compound of formula (IIb), wherein R3 is selected from hydrogen and optionally substituted C1-C6 alkyl. In another embodiment, it is a compound of formula (IIb), wherein R3 is hydrogen. In another embodiment, it is a compound of formula (IIb), wherein R3 is optionally substituted C1-C6 alkyl. In another embodiment, it is a compound of formula (IIb), wherein R3 is methyl.

[0259] In another embodiment is a compound of formula (IIb), wherein for In another embodiment is a compound of formula (IIb), wherein for In another embodiment is a compound of formula (IIb), wherein for In another embodiment is a compound of formula (IIb), wherein for In another embodiment is a compound of formula (IIb), wherein for In another embodiment is a compound of formula (IIb), wherein for

[0260] In another embodiment, there is a compound of formula (IIb), wherein Z is -O-, -OCH2- or -CH2O-. In another embodiment, there is a compound of formula (IIb), wherein Z is -O-. In another embodiment, there is a compound of formula (IIb), wherein Z is -OCH2-. In another embodiment, there is a compound of formula (IIb), wherein Z is -CH2O-. In another embodiment, there is a compound of formula (IIb), wherein Z is -S-. In another embodiment, there is a compound of formula (IIb), wherein Z is -CH2-. In another embodiment, there is a compound of formula (IIb), wherein Z is -N(R4)-. In another embodiment, there is a compound of formula (IIb), wherein Z is -N(H)-. In another embodiment, there is a compound of formula (IIb), wherein Z is -N(CH3)-.

[0261] In another embodiment is a compound of Formula (IIb) wherein p is 0. In another embodiment is a compound of Formula (IIb) wherein p is 1.

[0262] In some embodiments provided herein, the compound of formula (II) has the structure of formula (IIc), or a pharmaceutically acceptable salt or solvate thereof:

[0263]

[0264] in:

[0265] Selected from

[0266] Z is -O-, -S-, -N(R4)-, -CH2-, -OCH2- or -CH2O-;

[0267] Each R1 is independently selected from hydrogen, halogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted C3-C8 cycloalkyl, optionally substituted -(C1-C2 alkylene)-(C3-C8 cycloalkyl), optionally substituted C2-C9 heterocycloalkyl, optionally substituted -(C1-C2 alkylene)-(C2-C9 heterocycloalkyl), optionally substituted -(C1-C2 alkylene)-(aryl), optionally substituted -(C1-C2 alkylene)-(heteroaryl), -CF3, -OR 10 、-SR 10 、-N(R 11 )R 12 、-N(R 11 )S(O)2R 15 ;-N(R 13 )N(R11 )R 12 、-N(R 13 )N(R 11 )S(O)2R 15 、-C(O)R 14 、-C(O)OR 10 、-C(S)OR 10 、-C(O)SR 10 、-C(O)N(R 11 )R 12 、-C(S)N(R 11 )R 12 、-C(O)N(R 11 )S(O)2R 15 、-C(S)N(R 11 )S(O)2R 15 、-C(O)N(R 13 )N(R 11 )R 12 、-C(S)N(R 13 )N(R 11 )R 12 and -C(O)N(R 13 )N(R 11 )S(O)2R 15 ;

[0268] Each R2 is independently selected from halogen, optionally substituted C1-C6 alkyl, -OR 20 、-SR 20 、-N(R 21 )R 22 、-C(O)R 20 、-C(O)N(R 21 )R 22 and -N(R 23 )C(O)R 20 ;

[0269] R3 is selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C8 cycloalkyl, optionally substituted aryl, optionally substituted -(C1-C2 alkylene)-(aryl), optionally substituted heteroaryl, and optionally substituted -(C1-C2 alkylene)-(heteroaryl);

[0270] R4 is hydrogen or an optionally substituted C1-C6 alkyl group,

[0271] R 10 , R 13 and R 14each independently selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C8 cycloalkyl, optionally substituted aryl, optionally substituted -(C1-C2 alkylene)-(aryl), optionally substituted C2-C9 heterocycloalkyl, optionally substituted heteroaryl, and optionally substituted -(C1-C2 alkylene)-(heteroaryl);

[0272] R 11 and R 12 R is each independently selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C8 cycloalkyl, optionally substituted aryl, optionally substituted -(C1-C2 alkylene)-(aryl), optionally substituted C2-C9 heterocycloalkyl, optionally substituted heteroaryl, and optionally substituted -(C1-C2 alkylene)-(heteroaryl); or optionally R 11 and R 12 Together with the nitrogen atom to which they are attached, they form an optionally substituted C2-C9 heterocycloalkyl ring;

[0273] R 15 is selected from optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C8 cycloalkyl, optionally substituted aryl, optionally substituted -(C1-C2 alkylene)-(aryl), optionally substituted C2-C9 heterocycloalkyl, optionally substituted heteroaryl, and optionally substituted -(C1-C2 alkylene)-(heteroaryl);

[0274] R 20 and R 23 each independently selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C8 cycloalkyl, optionally substituted aryl, optionally substituted -(C1-C2 alkylene)-(aryl), optionally substituted C2-C9 heterocycloalkyl, optionally substituted heteroaryl, and optionally substituted -(C1-C2 alkylene)-(heteroaryl);

[0275] R 21 and R 22 R is each independently selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C8 cycloalkyl, optionally substituted aryl, optionally substituted -(C1-C2 alkylene)-(aryl), optionally substituted C2-C9 heterocycloalkyl, optionally substituted heteroaryl, and optionally substituted -(C1-C2 alkylene)-(heteroaryl); or optionally R 21 and R 22Together with the nitrogen atom to which they are attached, they form an optionally substituted C2-C9 heterocycloalkyl ring;

[0276] n is 0-4; and

[0277] p is 0 or 1.

[0278] In one embodiment is a compound of formula (IIc), wherein each R1 is independently selected from hydrogen, halogen, optionally substituted C1-C6 alkyl, -CF3, -OR 10 、-N(R 11 )R 12 、-C(O)R 14 、-C(O)OR 10 and -C(O)N(R 11 )R 12 In another embodiment is a compound of formula (IIc), wherein each R1 is independently selected from hydrogen, halogen, optionally substituted C1-C6 alkyl, -CF3, -OR 10 and -N(R 11 )R 12 In another embodiment is a compound of Formula (IIc), wherein each R1 is independently selected from hydrogen, halogen and -CF3.

[0279] In another embodiment is a compound of formula (IIc), wherein n is 3 and each R2 is independently selected from halogen, optionally substituted C1-C6 alkyl, -OR 20 and -N(R 21 )R 22 In another embodiment is a compound of formula (IIc), wherein n is 3 and each R2 is independently selected from halogen and optionally substituted C1-C6 alkyl. In another embodiment is a compound of formula (IIc), wherein n is 2 and each R2 is independently selected from halogen, optionally substituted C1-C6 alkyl, -OR 20 and -N(R 21 )R 22 In another embodiment is a compound of formula (IIc), wherein n is 2 and each R2 is independently selected from halogen and optionally substituted C1-C6 alkyl. In another embodiment is a compound of formula (IIc), wherein n is 1 and R2 is selected from halogen, optionally substituted C1-C6 alkyl, -OR 20 and -N(R 21 )R 22 In another embodiment is a compound of formula (IIc) wherein n is 1 and R2 is selected from halogen and optionally substituted C1-C6 alkyl. In another embodiment is a compound of formula (IIc) wherein n is 0.

[0280] In another embodiment, it is a compound of formula (IIc), wherein R3 is selected from hydrogen and optionally substituted C1-C6 alkyl. In another embodiment, it is a compound of formula (IIc), wherein R3 is hydrogen. In another embodiment, it is a compound of formula (IIc), wherein R3 is optionally substituted C1-C6 alkyl. In another embodiment, it is a compound of formula (IIc), wherein R3 is methyl.

[0281] In another embodiment is a compound of formula (IIc), wherein for In another embodiment is a compound of formula (IIc), wherein for In another embodiment is a compound of formula (IIc), wherein for In another embodiment is a compound of formula (IIc), wherein for In another embodiment is a compound of formula (IIc), wherein for In another embodiment is a compound of formula (IIc), wherein for

[0282] In another embodiment, a compound of formula (IIc) wherein Z is -O-, -OCH2- or -CH2O-. In another embodiment, a compound of formula (IIc) wherein Z is -O-. In another embodiment, a compound of formula (IIc) wherein Z is -OCH2-. In another embodiment, a compound of formula (IIc) wherein Z is -CH2O-. In another embodiment, a compound of formula (IIc) wherein Z is -S-. In another embodiment, a compound of formula (IIc) wherein Z is -CH2-. In another embodiment, a compound of formula (IIc) wherein Z is -N(R4)-. In another embodiment, a compound of formula (IIc) wherein Z is -N(H)-. In another embodiment, a compound of formula (IIc) wherein Z is -N(CH3)-.

[0283] In another embodiment is a compound of Formula (IIc) wherein p is 0. In another embodiment is a compound of Formula (IIc) wherein p is 1.

[0284] In some embodiments provided herein, the compound of Formula (II) has the structure of Formula (IId), or a pharmaceutically acceptable salt or solvate thereof:

[0285]

[0286] in:

[0287] Selected from

[0288] Z is -O-, -S-, -N(R4)-, -CH2-, -OCH2- or -CH2O-;

[0289] Each R1 is independently selected from hydrogen, halogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted C3-C8 cycloalkyl, optionally substituted -(C1-C2 alkylene)-(C3-C8 cycloalkyl), optionally substituted C2-C9 heterocycloalkyl, optionally substituted -(C1-C2 alkylene)-(C2-C9 heterocycloalkyl), optionally substituted -(C1-C2 alkylene)-(aryl), optionally substituted -(C1-C2 alkylene)-(heteroaryl), -CF3, -OR 10 、-SR 10 、-N(R 11 )R 12 、-N(R 11 )S(O)2R 15 ;-N(R 13 )N(R 11 )R 12 、-N(R 13 )N(R 11 )S(O)2R 15 、-C(O)R 14 、-C(O)OR 10 、-C(S)OR 10 、-C(O)SR 10 、-C(O)N(R 11 )R 12 、-C(S)N(R 11 )R 12 、-C(O)N(R 11 )S(O)2R 15 、-C(S)N(R 11 )S(O)2R 15 、-C(O)N(R 13 )N(R 11 )R 12 、-C(S)N(R 13 )N(R 11 )R 12 and -C(O)N(R 13 )N(R 11 )S(O)2R 15 ;

[0290] Each R2 is independently selected from halogen, optionally substituted C1-C6 alkyl, -OR 20 、-SR 20 、-N(R 21 )R 22 、-C(O)R 20 、-C(O)N(R 21 )R 22 and -N(R 23 )C(O)R 20 ;

[0291] R3 is selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C8 cycloalkyl, optionally substituted aryl, optionally substituted -(C1-C2 alkylene)-(aryl), optionally substituted heteroaryl, and optionally substituted -(C1-C2 alkylene)-(heteroaryl);

[0292] R4 is hydrogen or an optionally substituted C1-C6 alkyl group,

[0293] R 10 , R 13 and R 14 each independently selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C8 cycloalkyl, optionally substituted aryl, optionally substituted -(C1-C2 alkylene)-(aryl), optionally substituted C2-C9 heterocycloalkyl, optionally substituted heteroaryl, and optionally substituted -(C1-C2 alkylene)-(heteroaryl);

[0294] R 11 and R 12 R is each independently selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C8 cycloalkyl, optionally substituted aryl, optionally substituted -(C1-C2 alkylene)-(aryl), optionally substituted C2-C9 heterocycloalkyl, optionally substituted heteroaryl, and optionally substituted -(C1-C2 alkylene)-(heteroaryl); or optionally R 11 and R 12 Together with the nitrogen atom to which they are attached, they form an optionally substituted C2-C9 heterocycloalkyl ring;

[0295] R 15is selected from optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C8 cycloalkyl, optionally substituted aryl, optionally substituted -(C1-C2 alkylene)-(aryl), optionally substituted C2-C9 heterocycloalkyl, optionally substituted heteroaryl, and optionally substituted -(C1-C2 alkylene)-(heteroaryl);

[0296] R 20 and R 23 each independently selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C8 cycloalkyl, optionally substituted aryl, optionally substituted -(C1-C2 alkylene)-(aryl), optionally substituted C2-C9 heterocycloalkyl, optionally substituted heteroaryl, and optionally substituted -(C1-C2 alkylene)-(heteroaryl);

[0297] R 21 and R 22 R is each independently selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C8 cycloalkyl, optionally substituted aryl, optionally substituted -(C1-C2 alkylene)-(aryl), optionally substituted C2-C9 heterocycloalkyl, optionally substituted heteroaryl, and optionally substituted -(C1-C2 alkylene)-(heteroaryl); or optionally R 21 and R 22 Together with the nitrogen atom to which they are attached, they form an optionally substituted C2-C9 heterocycloalkyl ring;

[0298] n is 0-4; and

[0299] p is 0 or 1.

[0300] In one embodiment is a compound of formula (IId), wherein each R1 is independently selected from hydrogen, halogen, optionally substituted C1-C6 alkyl, -CF3, -OR 10 、-N(R 11 )R 12 、-C(O)R 14 、-C(O)OR 10 and -C(O)N(R 11 )R 12 In another embodiment is a compound of formula (IId), wherein each R1 is independently selected from hydrogen, halogen, optionally substituted C1-C6 alkyl, -CF3, -OR 10 and -N(R 11 )R 12 In another embodiment is a compound of Formula (IId), wherein each R1 is independently selected from hydrogen, halogen and -CF3.

[0301] In another embodiment is a compound of formula (IId), wherein n is 3 and each R2 is independently selected from halogen, optionally substituted C1-C6 alkyl, -OR 20 and -N(R 21 )R 22 In another embodiment is a compound of formula (IId) wherein n is 3 and each R2 is independently selected from halogen and optionally substituted C1-C6 alkyl. In another embodiment is a compound of formula (IId) wherein n is 2 and each R2 is independently selected from halogen, optionally substituted C1-C6 alkyl, -OR 20 and -N(R 21 )R 22 In another embodiment is a compound of formula (IId) wherein n is 2 and each R2 is independently selected from halogen and optionally substituted C1-C6 alkyl. In another embodiment is a compound of formula (IId) wherein n is 1 and R2 is selected from halogen, optionally substituted C1-C6 alkyl, -OR 20 and -N(R 21 )R 22 In another embodiment is a compound of formula (IId) wherein n is 1 and R2 is selected from halogen and optionally substituted C1-C6 alkyl. In another embodiment is a compound of formula (IId) wherein n is 0.

[0302] In another embodiment, it is a compound of formula (IId), wherein R3 is selected from hydrogen and optionally substituted C1-C6 alkyl. In another embodiment, it is a compound of formula (IId), wherein R3 is hydrogen. In another embodiment, it is a compound of formula (IId), wherein R3 is optionally substituted C1-C6 alkyl. In another embodiment, it is a compound of formula (IId), wherein R3 is methyl.

[0303] In another embodiment is a compound of formula (IId), wherein for In another embodiment is a compound of formula (IId), wherein for In another embodiment is a compound of formula (IId), wherein for In another embodiment is a compound of formula (IId), wherein for In another embodiment is a compound of formula (IId), wherein for In another embodiment is a compound of formula (IId), wherein for

[0304] In another embodiment, there is a compound of formula (IId), wherein Z is -O-, -OCH2- or -CH2O-. In another embodiment, there is a compound of formula (IId), wherein Z is -O-. In another embodiment, there is a compound of formula (IId), wherein Z is -OCH2-. In another embodiment, there is a compound of formula (IId), wherein Z is -CH2O-. In another embodiment, there is a compound of formula (IId), wherein Z is -S-. In another embodiment, there is a compound of formula (IId), wherein Z is -CH2-. In another embodiment, there is a compound of formula (IId), wherein Z is -N(R4)-. In another embodiment, there is a compound of formula (IId), wherein Z is -N(H)-. In another embodiment, there is a compound of formula (IId), wherein Z is -N(CH3)-.

[0305] In another embodiment is a compound of Formula (IId) wherein p is 0. In another embodiment is a compound of Formula (IId) wherein p is 1.

[0306] In some embodiments provided herein, the compound of Formula (II) has the structure of Formula (IIe), or a pharmaceutically acceptable salt or solvate thereof:

[0307]

[0308] in:

[0309] Selected from

[0310] Z is -O-, -S-, -N(R4)-, -CH2-, -OCH2- or -CH2O-;

[0311] Each R1 is independently selected from hydrogen, halogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted C3-C8 cycloalkyl, optionally substituted -(C1-C2 alkylene)-(C3-C8 cycloalkyl), optionally substituted C2-C9 heterocycloalkyl, optionally substituted -(C1-C2 alkylene)-(C2-C9 heterocycloalkyl), optionally substituted -(C1-C2 alkylene)-(aryl), optionally substituted -(C1-C2 alkylene)-(heteroaryl), -CF3, -OR 10 、-SR 10 、-N(R 11 )R 12 、-N(R 11 )S(O)2R 15 ;-N(R 13 )N(R11 )R 12 、-N(R 13 )N(R 11 )S(O)2R 15 、-C(O)R 14 、-C(O)OR 10 、-C(S)OR 10 、-C(O)SR 10 、-C(O)N(R 11 )R 12 、-C(S)N(R 11 )R 12 、-C(O)N(R 11 )S(O)2R 15 、-C(S)N(R 11 )S(O)2R 15 、-C(O)N(R 13 )N(R 11 )R 12 、-C(S)N(R 13 )N(R 11 )R 12 and -C(O)N(R 13 )N(R 11 )S(O)2R 15 ;

[0312] Each R2 is independently selected from halogen, optionally substituted C1-C6 alkyl, -OR 20 、-SR 20 、-N(R 21 )R 22 、-C(O)R 20 、-C(O)N(R 21 )R 22 and -N(R 23 )C(O)R 20 ;

[0313] R3 is selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C8 cycloalkyl, optionally substituted aryl, optionally substituted -(C1-C2 alkylene)-(aryl), optionally substituted heteroaryl, and optionally substituted -(C1-C2 alkylene)-(heteroaryl);

[0314] R4 is hydrogen or an optionally substituted C1-C6 alkyl group,

[0315] R 10 , R 13 and R 14each independently selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C8 cycloalkyl, optionally substituted aryl, optionally substituted -(C1-C2 alkylene)-(aryl), optionally substituted C2-C9 heterocycloalkyl, optionally substituted heteroaryl, and optionally substituted -(C1-C2 alkylene)-(heteroaryl);

[0316] R 11 and R 12 R is each independently selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C8 cycloalkyl, optionally substituted aryl, optionally substituted -(C1-C2 alkylene)-(aryl), optionally substituted C2-C9 heterocycloalkyl, optionally substituted heteroaryl, and optionally substituted -(C1-C2 alkylene)-(heteroaryl); or optionally R 11 and R 12 Together with the nitrogen atom to which they are attached, they form an optionally substituted C2-C9 heterocycloalkyl ring;

[0317] R 15 is selected from optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C8 cycloalkyl, optionally substituted aryl, optionally substituted -(C1-C2 alkylene)-(aryl), optionally substituted C2-C9 heterocycloalkyl, optionally substituted heteroaryl, and optionally substituted -(C1-C2 alkylene)-(heteroaryl);

[0318] R 20 and R 23 each independently selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C8 cycloalkyl, optionally substituted aryl, optionally substituted -(C1-C2 alkylene)-(aryl), optionally substituted C2-C9 heterocycloalkyl, optionally substituted heteroaryl, and optionally substituted -(C1-C2 alkylene)-(heteroaryl);

[0319] R 21 and R 22 R is each independently selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C8 cycloalkyl, optionally substituted aryl, optionally substituted -(C1-C2 alkylene)-(aryl), optionally substituted C2-C9 heterocycloalkyl, optionally substituted heteroaryl, and optionally substituted -(C1-C2 alkylene)-(heteroaryl); or optionally R 21 and R 22Together with the nitrogen atom to which they are attached, they form an optionally substituted C2-C9 heterocycloalkyl ring;

[0320] n is 0-4; and

[0321] p is 0 or 1.

[0322] In one embodiment is a compound of formula (IIe), wherein each R1 is independently selected from hydrogen, halogen, optionally substituted C1-C6 alkyl, -CF3, -OR 10 、-N(R 11 )R 12 、-C(O)R 14 、-C(O)OR 10 and -C(O)N(R 11 )R 12 In another embodiment is a compound of formula (IIe), wherein each R1 is independently selected from hydrogen, halogen, optionally substituted C1-C6 alkyl, -CF3, -OR 10 and -N(R 11 )R 12 In another embodiment is a compound of Formula (IIe), wherein each R1 is independently selected from hydrogen, halogen and -CF3.

[0323] In another embodiment is a compound of formula (IIe), wherein n is 3 and each R2 is independently selected from halogen, optionally substituted C1-C6 alkyl, -OR 20 and -N(R 21 )R 22 In another embodiment is a compound of formula (IIe) wherein n is 3 and each R2 is independently selected from halogen and optionally substituted C1-C6 alkyl. In another embodiment is a compound of formula (IIe) wherein n is 2 and each R2 is independently selected from halogen, optionally substituted C1-C6 alkyl, -OR 20 and -N(R 21 )R 22 In another embodiment is a compound of formula (IIe), wherein n is 2 and each R2 is independently selected from halogen and optionally substituted C1-C6 alkyl. In another embodiment is a compound of formula (IIe), wherein n is 1 and R2 is selected from halogen, optionally substituted C1-C6 alkyl, -OR 20 and -N(R 21 )R 22 In another embodiment is a compound of formula (IIe) wherein n is 1 and R2 is selected from halogen and optionally substituted C1-C6 alkyl. In another embodiment is a compound of formula (IIe) wherein n is 0.

[0324] In another embodiment, there is a compound of formula (IIe), wherein R3 is selected from hydrogen and optionally substituted C1-C6 alkyl. In another embodiment, there is a compound of formula (IIe), wherein R3 is hydrogen. In another embodiment, there is a compound of formula (IIe), wherein R3 is optionally substituted C1-C6 alkyl. In another embodiment, there is a compound of formula (IIe), wherein R3 is methyl.

[0325] In another embodiment is a compound of formula (IIe), wherein for In another embodiment is a compound of formula (IIe), wherein for In another embodiment is a compound of formula (IIe), wherein for In another embodiment is a compound of formula (IIe), wherein for In another embodiment is a compound of formula (IIe), wherein for In another embodiment is a compound of formula (IIe), wherein for

[0326] In another embodiment is a compound of formula (IIe) wherein Z is -O-, -OCH2- or -CH2O-. In another embodiment is a compound of formula (IIe) wherein Z is -O-. In another embodiment is a compound of formula (IIe) wherein Z is -OCH2-. In another embodiment is a compound of formula (IIe) wherein Z is -CH2O-. In another embodiment is a compound of formula (IIe) wherein Z is -S-. In another embodiment is a compound of formula (IIe) wherein Z is -CH2-. In another embodiment is a compound of formula (IIe) wherein Z is -N(R4)-. In another embodiment is a compound of formula (IIe) wherein Z is -N(H)-. In another embodiment is a compound of formula (IIe) wherein Z is -N(CH3)-.

[0327] In another embodiment is a compound of Formula (IIe) wherein p is 0. In another embodiment is a compound of Formula (IIe) wherein p is 1.

[0328] Any combination of the groups described above or below for the various variables is contemplated herein. Throughout the specification, groups and substituents thereof are selected by one skilled in the art to provide stable moieties and compounds.

[0329] In some embodiments is a compound selected from the group consisting of:

[0330] or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof.

[0331] In some embodiments is a compound selected from the group consisting of:

[0332] or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof.

[0333] In some embodiments is a compound selected from the group consisting of:

[0334]

[0335] or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof.

[0336] In some embodiments is a compound selected from the group consisting of:

[0337] or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof.

[0338] In some embodiments is a compound selected from the group consisting of:

[0339]

[0340] or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof.

[0341] In some embodiments is a compound selected from the group consisting of:

[0342] or a pharmaceutically acceptable salt or a pharmaceutically acceptable solvate thereof.

[0343] In some embodiments, the therapeutic agent (e.g., a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (II), (IIa), (IIb), (IIc), (IId), or (IIe)) is present in the pharmaceutical composition as a pharmaceutically acceptable salt. In some embodiments, any of the above compounds are suitable for use in any of the methods or compositions described herein.

[0344] In certain embodiments, the compounds presented herein have one or more stereocenters, and each center exists independently in the R or S configuration. The compounds described herein include all diastereoisomers, enantiomers, atropisomers and epimeric forms, and appropriate mixtures thereof. If desired, stereoisomers are obtained by methods such as stereoselective synthesis and / or separation of stereoisomers via chiral chromatographic columns. In some embodiments, formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (II), (IIa), (IIb), (IIc), (IId) or (IIe) compounds are used as single enantiomers. In some embodiments, formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (II), (IIa), (IIb), (IIc), (IId) or (IIe) compounds are used as racemic mixtures. In some embodiments, compounds of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (II), (IIa), (IIb), (IIc), (IId), or (IIe) have hindered rotation about a single bond, resulting in atropisomers.

[0345] The methods and formulations described herein include the use of N-oxides (where appropriate), crystalline forms (also known as polymorphs), or pharmaceutically acceptable salts of the compounds having the structures described herein, as well as active metabolites of these compounds having the same type of activity.

[0346] In some cases, compounds may exist as tautomers. All tautomers are included within the scope of the compounds presented herein.

[0347] In some embodiments, the compounds described herein are prepared as prodrugs. "Prodrug" refers to a medicament that is converted into a parent drug in vivo. Prodrugs are generally useful because, in some cases, they may be easier to administer than the parent drug. For example, they may be bioavailable by oral administration, while the parent drug is not. Prodrugs may also have improved solubility than the parent drug in a pharmaceutical composition. In some embodiments, the design of the prodrug increases effective water solubility. In certain embodiments, via in vivo administration, the prodrug is chemically converted into a biologically active, pharmaceutically active, or therapeutically active form of the compound. In certain embodiments, the prodrug is enzymatically metabolized into a biologically active, pharmaceutically active, or therapeutically active form of the compound by one or more steps or processes.

[0348] Prodrugs of the compounds described herein include, but are not limited to, esters, ethers, carbonates, thiocarbonates, N-acyl derivatives, N-acyloxyalkyl derivatives, quaternary ammonium derivatives of tertiary amines, N-Mannich bases, Schiff bases, amino acid conjugates, phosphates and sulfonates. See, for example, Design of Prodrugs, Bundgaard, A., ed., Elseview, 1985 and Method in Enzymology, Widder, K. et al., ed.; Academic, 1985, vol. 42, p. 309-396; Bundgaard, H. "Design and Application of Prodrugs" in A Textbook of Drug Design and Development, Krosgaard-Larsen and H. Bundgaard, ed., 1991, Chapter 5, p. 113-191; and Bundgaard, H., Advanced Drug Delivery Review, 1992, 8, 1-38, each of which is incorporated herein by reference. In some embodiments, the hydroxyl group in the compounds disclosed herein is used to form a prodrug, wherein the hydroxyl group is introduced into an acyloxyalkyl ester, an alkoxycarbonyloxyalkyl ester, an alkyl ester, an aryl ester, a phosphate ester, a sugar ester, an ether, and the like.

[0349] Pharmaceutical forms of the compounds described herein are included within the scope of the claims, wherein the prodrug is metabolized in vivo as described herein to produce a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (II), (IIa), (IIb), (IIc), (IId), or (IIe). In some cases, some of the compounds described herein may be a prodrug of another derivative or active compound.

[0350] In certain embodiments, the compounds described herein exist in solvated forms with pharmaceutically acceptable solvents such as water, ethanol, etc. In other embodiments, the compounds described herein exist in unsolvated forms.

[0351] In some embodiments, the compounds of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (II), (IIa), (IIb), (IIc), (IId) or (IIe) described herein include solvent addition forms or their crystal forms, in particular solvates or polymorphs. Solvates contain stoichiometric or non-stoichiometric amounts of solvents and can be formed during crystallization with pharmaceutically acceptable solvents such as water, ethanol, etc. When the solvent is water, hydrates are formed, or when the solvent is alcohol, alcoholates are formed.

[0352] In some embodiments, sites on the compounds of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (II), (IIa), (IIb), (IIc), (IId), or (IIe) disclosed herein are susceptible to various metabolic reactions. Therefore, the introduction of appropriate substituents at the sites of metabolic reactions will reduce, minimize, or eliminate metabolic pathways. In specific embodiments, by way of example only, suitable substituents that reduce or eliminate the susceptibility of the aromatic ring to metabolic reactions are halogens, deuterium, or alkyl groups.

[0353] In some embodiments, the compounds of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (II), (IIa), (IIb), (IIc), (IId) or (IIe) disclosed herein are isotopically labeled and are identical to those compounds recited in the various formulae and structures presented herein, except that one or more atoms are replaced by atoms having an atomic mass or mass number different from the atomic mass or mass number typically found in nature. In some embodiments, one or more hydrogen atoms are replaced by deuterium. In some embodiments, metabolic sites on the compounds described herein are deuterated. In some embodiments, substitution with deuterium results in certain therapeutic advantages resulting from greater metabolic stability, for example, prolonged in vivo half-life or reduced dosage requirements.

[0354] In some embodiments, the compounds described herein, such as compounds of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (II), (IIa), (IIb), (IIc), (IId), or (IIe), are in various forms, including but not limited to amorphous forms, ground forms, and nanoparticle forms. In addition, the compounds described herein include crystalline forms, also known as polymorphs. Polymorphs include different crystal packing arrangements of compounds of the same elemental composition. Polymorphs typically have different X-ray diffraction patterns, melting points, density, hardness, crystal shape, optical properties, stability, and solubility. Various factors such as recrystallization solvent, crystallization rate, and storage conditions can cause a single crystalline form to predominate.

[0355] The screening and characterization of pharmaceutically acceptable salts, polymorphs and / or solvates can be completed using a variety of techniques, including but not limited to thermal analysis, X-ray diffraction, spectroscopy, vapor adsorption and microscopy. Thermal analysis methods are directed to thermochemical degradation or thermophysical processes, including but not limited to polymorphic transitions, and such methods are used to analyze the relationship between polymorphic forms, determine weight loss, find glass transition temperatures, or for excipient compatibility studies. Such methods include but are not limited to differential scanning calorimetry (DSC), modulation differential scanning calorimetry (MDCS), thermogravimetric analysis (TGA) and thermogravimetric measurement and infrared analysis (TG / IR). X-ray diffraction methods include but are not limited to single crystal and powder diffractometers and synchrotron sources. The various spectral techniques used include but are not limited to Raman, FTIR, UV-VIS and NMR (liquid and solid). Various microscopy techniques include, but are not limited to, polarized light microscopy, scanning electron microscopy (SEM) with energy dispersive X-ray analysis (EDX), environmental scanning electron microscopy (in a gas or water vapor atmosphere) with EDX, IR microscopy, and Raman microscopy.

[0356] Throughout the specification, groups and substituents thereof may be chosen to provide stable moieties and compounds.

[0357] Synthesis of compounds

[0358] In some embodiments, the synthesis of the compounds described herein is achieved by using means described in the chemical literature, using the methods described herein, or by a combination thereof. Additionally, solvents, temperatures, and other reaction conditions presented herein may be varied.

[0359] In other embodiments, starting materials and reagents used to synthesize compounds described herein are synthesized or obtained from commercial sources such as, but not limited to, Sigma-Aldrich, Fischer Scientific (Fischer Chemicals), and Acros Organics. In further embodiments, the compounds described herein and other related compounds having different substituents are synthesized using the techniques and materials described herein as well as those recognized in the art, such as described in Fieser and Fieser, Reagents for Organic Synthesis, Volumes 1-17 (John Wiley and Sons, 1991); Rodd, Chemistry of Carbon Compounds, Volumes 1-5 and Supplements (Elsevier Science Publishers, 1989); Organic Reactions, Volumes 1-40 (John Wiley and Sons, 1991), Larock, Comprehensive Organic Transformations (VCH Publishers Inc., 1989), March, Advanced Organic Chemistry 4th Edition, (Wiley 1992); Carey and Sundberg, Advanced Organic Chemistry 4th Edition, Volumes A and B (Plenum 2000, 2001), and Green and Wuts, Protective Groups in Organic Synthesis 3rd Edition, (Wiley 1999) (for which disclosures are incorporated herein by reference in their entirety). General methods for preparing compounds disclosed herein can be derived from the reactions and the reactions can be modified by using appropriate reagents and conditions to introduce the various moieties found in the general formulas provided herein.

[0360] Use of protecting groups

[0361] In the described reaction, in the case where reactive functional groups are required in the final product, it may be necessary to protect the reactive functional groups, such as hydroxyl, amino, imino, thio or carboxyl groups, to prevent them from undesirably participating in the reaction. Protective groups are used to block some or all reactive moieties and prevent these groups from participating in chemical reactions until the protective groups are removed. Preferably, each protective group can be removed by different means. Protective groups that cleave under completely different reaction conditions meet the requirements for differential removal.

[0362] Protecting groups can be removed by acid, base, reducing conditions (e.g., hydrogenolysis), and / or oxidative conditions. Groups such as trityl, dimethoxytrityl, acetal, and tert-butyldimethylsilyl are acid labile and can be used to protect carboxyl and hydroxy reactive moieties in the presence of amino groups protected with Cbz groups (removable by hydrogenolysis) and Fmoc groups (base labile). Carboxylic acid and hydroxy reactive moieties can be blocked with base labile groups such as, but not limited to, methyl, ethyl, and acetyl in the presence of amines blocked with acid labile groups such as tert-butyl carbamate or with carbamates that are both stable to acid and base but can be removed by hydrolysis.

[0363] Carboxylic acid and hydroxyl reactive moieties may also be blocked with hydrolytically removable protecting groups such as benzyl, while amine groups capable of hydrogen bonding with acids may be blocked with base labile groups such as Fmoc. Carboxylic acid reactive moieties may be protected by conversion to simple ester compounds as exemplified herein, including conversion to alkyl esters, or they may be blocked with oxidatively removable protecting groups such as 2,4-dimethoxybenzyl, while coexisting amino groups may be blocked with fluoride-labile silylcarbamates.

[0364] Allyl blocking groups are useful in the presence of acid protecting groups and base protecting groups because the former are stable and can be subsequently removed by metal or π-acid catalysts. For example, allyl-blocked carboxylic acids can be deprotected by Pd0-catalyzed reactions in the presence of acid-labile tert-butyl carbamate or base-labile acetate amine protecting groups. Another form of protecting group is a resin to which a compound or intermediate can be attached. As long as the residue is attached to the resin, the functional group will be blocked and cannot react. Once released from the resin, the functional group can react.

[0365] In general, blocking / protecting groups can be selected from:

[0366]

[0367] Other protecting groups, as well as a detailed description of techniques suitable for creating protecting groups and their removal, are described in Greene and Wuts, Protective Groups in Organic Synthesis, 3rd ed., John Wiley & Sons, New York, NY, 1999, and Kocienski, Protective Groups, Thieme Verlag, New York, NY, 1994, which are incorporated herein by reference for such disclosures.

[0368] Certain terms

[0369] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as the general understanding to which the claimed subject matter belongs. If a term herein has multiple definitions, the definitions in this section shall prevail. All patents, patent applications, publications, and disclosed nucleotide and amino acid sequences (e.g., sequences available in GenBank or other databases) mentioned herein are incorporated herein by reference. Where a URL or other such identifier or address is mentioned, it is to be understood that such identifiers may change, and specific information on the Internet may be available from time to time, but equivalent information may be found by searching the Internet. Reference to it proves the availability and public dissemination of such information.

[0370] It should be understood that the foregoing general description and the following detailed description are exemplary and illustrative only and are not intended to limit any subject matter for which protection is sought. In this application, unless otherwise specifically stated, the use of the singular includes the plural. It must be noted that the singular forms "a", "an", and "the" used in this specification and the appended claims include plural referents unless the context clearly indicates otherwise. In this application, the use of "or" means "and / or" unless otherwise stated. In addition, the use of the term "includes" and other forms such as "includes", "contains", and "has" is not restrictive.

[0371] The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described.

[0372] Definitions of standard chemical terms may be found in reference books, including but not limited to Carey and Sundberg "Advanced Organic Chemistry 4th Edition" Volume A (2000) and Volume B (2001), Plenum Press, New York. Unless otherwise indicated, conventional methods of mass spectroscopy, NMR, HPLC, protein chemistry, biochemistry, recombinant DNA techniques, and pharmacology are used.

[0373] Unless specific definitions are provided, the nomenclature and laboratory procedures and techniques used in analytical chemistry, synthetic organic chemistry, and drugs and medicinal chemistry described herein are those recognized in the art. Standard techniques can be used for chemical synthesis, chemical analysis, drug preparation, preparation and delivery, and the treatment of patients. Standard techniques can be used for recombinant DNA, oligonucleotide synthesis, and tissue culture and transformation (e.g., electroporation, lipofection). Reaction and purification techniques can be carried out, for example, using manufacturer's kit instructions, or as generally implemented in the art or as described herein. The aforementioned techniques and procedures can be generally carried out by conventional methods, and are carried out as described in various general references and more specific references cited and discussed throughout this specification.

[0374] It should be understood that the methods and compositions described herein are not limited to the specific methods, protocols, cell lines, constructs and reagents described herein, but may vary. It should also be understood that the terms used herein are only for the purpose of describing specific embodiments and are not intended to limit the scope of the methods, compounds, compositions described herein.

[0375] As used herein, C1-C x Including C1-C2, C1-C3...C1-C x C1-C x refers to the number of carbon atoms that make up the moiety to which it refers (excluding optional substituents).

[0376] An "alkyl" group refers to an aliphatic hydrocarbon group. An alkyl group may or may not include unsaturated units. An alkyl moiety may be a "saturated alkyl" group, which means that it does not contain any unsaturated units (i.e., carbon-carbon double bonds or carbon-carbon triple bonds). An alkyl group may also be an "unsaturated alkyl" moiety, which means that it contains at least one unsaturated unit. An alkyl moiety, whether saturated or unsaturated, may be branched, straight chain, or cyclic.

[0377] "Alkyl" groups can have 1-6 carbon atoms (whenever they appear in this document, a numerical range such as "1-6" refers to each integer in the given range; for example, "1-6 carbon atoms" means that the alkyl group can be composed of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 6 carbon atoms, although the present definition also covers the presence of the term "alkyl" without specifying a numerical range). The alkyl group of the compounds described herein can be designated as "C1-C6 alkyl" or a similar designation. By way of example only, "C1-C6 alkyl" means that there are 1-6 carbon atoms in the alkyl chain, i.e., the alkyl chain is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, hexyl, propen-3-yl (allyl), cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl. Alkyl groups can be substituted or unsubstituted. Depending on the structure, alkyl groups can be monovalent or divalent (i.e., alkylene).

[0378] "Alkoxy" means an "O-alkyl" group where alkyl is as defined herein.

[0379] The term "alkenyl" refers to a class of alkyl groups in which two atoms of the alkyl group form a double bond that is not part of an aromatic group. Non-limiting examples of alkenyl groups include -CH=CH2, -C(CH3)=CH2, -CH=CHCH3, -CH=C(CH3)2, and -C(CH3)=CHCH3. The alkenyl moiety may be branched, straight-chain, or cyclic (in which case it may also be referred to as a "cycloalkenyl"). The alkenyl group may have 2-6 carbons. The alkenyl group may be substituted or unsubstituted. Depending on the structure, the alkenyl group may be monovalent or divalent (i.e., alkenylene).

[0380] The term "alkynyl" refers to a class of alkyl groups in which two atoms of the alkyl group form a triple bond. Non-limiting examples of alkynyl groups include -C≡CH, -C≡CCH3, -C≡CCH2CH3, and -C≡CCH2CH2CH3. The "R" portion of the alkynyl moiety can be branched, straight chain, or cyclic. The alkynyl group can have 2-6 carbons. The alkynyl group can be substituted or unsubstituted. Depending on the structure, the alkynyl group can be monovalent or divalent (i.e., alkynylene).

[0381] "Amino" refers to the -NH2 group.

[0382] The term "alkylamine" or "alkylamino" refers to an -N(alkyl) x H y A group wherein alkyl is as defined herein, and x and y are selected from the group consisting of x=1, y=1 and x=2, y=0. When x=2, the alkyl groups together with the nitrogen to which they are attached may optionally form a cyclic ring system. "Dialkylamino" refers to a -N(alkyl)2 group wherein alkyl is as defined herein.

[0383] The term "aromatic" refers to a planar ring having a delocalized π-electron system containing 4n+2 π electrons, where n is an integer. The aromatic ring can be composed of five, six, seven, eight, nine or more atoms. The aromatic ring can be optionally substituted. The term "aromatic" includes aryl (e.g., phenyl, naphthyl) and heteroaryl (e.g., pyridyl, quinolinyl).

[0384] As used herein, the term "aryl" refers to an aromatic ring in which each atom forming the ring is a carbon atom. The aryl ring can be composed of five, six, seven, eight, nine or more carbon atoms. The aryl group can be optionally substituted. Examples of aryl groups include, but are not limited to, phenyl and naphthyl. Depending on the structure, the aryl group can be monovalent or divalent (i.e., arylene).

[0385] "Carboxyl" refers to -CO2H. In some embodiments, the carboxyl moiety can be replaced with a "carboxylic acid bioisostere," which refers to a functional group or moiety that exhibits similar physical and / or chemical properties as a carboxylic acid moiety. A carboxylic acid bioisostere has similar biological properties as a carboxylic acid group. A compound having a carboxylic acid moiety can have the carboxylic acid moiety replaced with a carboxylic acid bioisostere and have similar physical and / or biological properties when compared to the carboxylic acid-containing compound. For example, in one embodiment, a carboxylic acid bioisostere will ionize at a physical pH to approximately the same extent as a carboxylic acid group. Examples of carboxylic acid bioisosteres include, but are not limited to wait.

[0386] The term "cycloalkyl" refers to a monocyclic or polycyclic non-aromatic group in which each atom (i.e., backbone atom) constituting the ring is a carbon atom. The cycloalkyl group may be saturated or partially unsaturated. The cycloalkyl group may be fused to an aromatic ring (in which case the cycloalkyl group is bonded via a non-aromatic ring carbon atom). Cycloalkyl groups include groups having 3 to 10 ring atoms. Illustrative examples of cycloalkyl groups include, but are not limited to, the following moieties:

[0387] wait.

[0388] The term "heteroaryl" or alternatively "heteroaromatic" refers to an aromatic group containing one or more ring heteroatoms selected from nitrogen, oxygen and sulfur. An N-containing "heteroaromatic" or "heteroaryl" moiety refers to an aromatic group in which at least one skeletal atom on the ring is a nitrogen atom. Polycyclic heteroaryl groups may be fused or non-fused. Illustrative examples of heteroaryl groups include the following moieties:

[0389] wait.

[0390] A "heterocycloalkyl" group or "heteroalicyclic" group refers to a cycloalkyl group in which at least one backbone ring atom is a heteroatom selected from nitrogen, oxygen and sulfur. The group may be fused to an aryl or heteroaryl group. Illustrative examples of heterocycloalkyl groups (also known as non-aromatic heterocycles) include:

[0391] etc. The term heteroalicyclic also includes all cyclic carbohydrates, including but not limited to monosaccharides, disaccharides and oligosaccharides. Unless otherwise specified, heterocycloalkyl has 2 to 10 carbons in the ring. It should be understood that when referring to the number of carbon atoms in heterocycloalkyl, the number of carbon atoms in heterocycloalkyl is different from the total number of atoms (including heteroatoms) constituting the heterocycloalkyl (i.e., the backbone atoms of the heterocycloalkyl ring).

[0392] The term "halo" or alternatively "halogen" refers to fluoro, chloro, bromo and iodo.

[0393] The term "haloalkyl" refers to an alkyl group substituted with one or more halogens. These halogens may be identical, or they may be different. Non-limiting examples of haloalkyl include -CH2Cl, -CF3, -CHF2, -CH2CF3, -CF2CF3, -CF(CH3)2, etc.

[0394] The terms "fluoroalkyl" and "fluoroalkoxy" include alkyl and alkoxy groups substituted with one or more fluorine atoms, respectively. Non-limiting examples of fluoroalkyl groups include -CF3, -CHF2, -CH2F, -CH2CF3, -CF2CF3, -CF2CF2CF3, -CF(CH3)3, etc. Non-limiting examples of fluoroalkoxy groups include -OCF3, -OCHF2, -OCH2F, -OCH2CF3, -OCF2CF3, -OCF2CF2CF3, -OCF(CH3)2, etc.

[0395] The term "heteroalkyl" refers to an alkyl group in which one or more backbone chain atoms are selected from atoms other than carbon, for example, oxygen, nitrogen, sulfur, phosphorus, silicon or a combination thereof. The heteroatom may be located at any internal position of the heteroalkyl group. Examples include, but are not limited to, -CH2-O-CH3, -CH2-CH2-O-CH3, -CH2-NH-CH3, -CH2-CH2-NH-CH3, -CH2-N(CH3)-CH3, -CH2-CH2-NH-CH3, -CH2-CH2-N(CH3)-CH3, -CH2-S-CH2-CH3, -CH2-CH2, -S(O)-CH3, -CH2-CH2-S(O)2-CH3, -CH2-NH-OCH3, -CH2-O-Si(CH3)3, -CH2-CH=N-OCH3 and -CH=CH-N(CH3)-CH3. Additionally, up to two heteroatoms may be consecutive, such as, for example, -CH2-NH-OCH3 and -CH2-O-Si(CH3)3. Regardless of the number of heteroatoms, a "heteroalkyl" group may have 1 to 6 carbon atoms.

[0396] The term "bond" or "single bond" refers to a chemical bond between two atoms, or between two moieties when the atoms connected by the bond are viewed as part of a larger substructure.

[0397] The term "moiety" refers to a specific segment or functional group of a molecule. A chemical moiety is generally considered to be a chemical entity embedded in or attached to a molecule.

[0398] As used herein, the substituent "R", when occurring alone and without a designated number, refers to a substituent selected from alkyl, haloalkyl, heteroalkyl, alkenyl, cycloalkyl, aryl, heteroaryl (bonded through a ring carbon), and heterocycloalkyl.

[0399] The term "optionally substituted" or "substituted" means that the referenced group may be substituted with one or more additional groups, each and independently selected from the group consisting of alkyl, cycloalkyl, aryl, heteroaryl, heterocycloalkyl, -OH, alkoxy, aryloxy, alkylthio, arylthio, alkyl sulfoxide, aryl sulfoxide, alkyl sulfone, aryl sulfone, -CN, alkyne, C1-C6 alkylalkyne, halo, acyl, acyloxy, -CO2H, -CO2-alkyl, nitro, haloalkyl, fluoroalkyl, and amino, including mono- and di-substituted amino (e.g., -NH2, -NHR, -N(R)2), and protected derivatives thereof. In some embodiments, optional substituents are independently selected from halogen, -CN, -NH2, -NH(CH3), -N(CH3)2, -OH, -CO2H, -CO2alkyl, -C(=O)NH2, -C(=O)NH(alkyl), -C(=O)N(alkyl)2, -S(=O)2NH2, -S(=O)2NH(alkyl), -S(=O)2N(alkyl)2, alkyl, cycloalkyl, fluoroalkyl, heteroalkyl, alkoxy, fluoroalkoxy, heterocycloalkyl, aryl, heteroaryl, aryloxy, alkylthio, arylthio, alkyl sulfoxide, aryl sulfoxide, alkyl sulfone and aryl sulfone. In some embodiments, optional substituents are independently selected from halogen, -CN, -NH2, -OH, -NH(CH3), -N(CH3)2, -CH3, -CH2CH3, -CF3, -OCH3 and -OCF3. In some embodiments, the substituted groups are substituted with one or two of the aforementioned groups. In some embodiments, optional substituents on aliphatic carbon atoms (acyclic or cyclic, saturated or unsaturated carbon atoms, excluding aromatic carbon atoms) include oxo (=0).

[0400] The methods and formulations described herein include the use of crystalline forms (also known as polymorphs) or pharmaceutically acceptable salts of compounds having the structure of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (II), (IIa), (IIb), (IIc), (IId) or (IIe), as well as active metabolites of these compounds having the same type of activity.

[0401] As used herein, the term "about" or "approximately" means within 20%, preferably within 10%, and more preferably within 5% of a given value or range.

[0402] As used herein, the term "therapeutically effective amount" refers to an amount of an S1P receptor modulator that, when administered to a mammal in need thereof, is effective to at least partially alleviate or at least partially prevent a disease, disorder or condition described herein.

[0403] As used herein, the term "expression" includes the process by which a polynucleotide is transcribed into mRNA and translated into a peptide, polypeptide or protein.

[0404] The term "activator" is used in this specification to denote any molecular species that results in activation of the indicated receptor, whether the species itself binds to the receptor or a metabolite of the species binds to the receptor. Thus, an activator may be a ligand for the receptor, or it may be an activator that is metabolized to a ligand for the receptor (i.e., a metabolite that is formed in the tissue and is the actual ligand).

[0405] As used herein, the term "antagonist" refers to a small molecule agent that binds to a receptor and subsequently reduces agonist-induced transcriptional activity of the receptor.

[0406] As used herein, the term "agonist" refers to a small molecule agent that binds to a receptor and subsequently increases the transcriptional activity of the receptor in the absence of a known agonist.

[0407] As used herein, the term "inverse agonist" refers to a small molecule agent that binds to a receptor and subsequently reduces the basal level of receptor transcriptional activity that is present in the absence of a known agonist.

[0408] As used herein, the term "modulate" means interacting directly or indirectly with a target to change the activity of the target, including, by way of example only, enhancing the activity of the target, inhibiting the activity of the target, limiting the activity of the target, or extending the activity of the target.

[0409] The term "S1P receptor modulator" includes S1P receptor agonists, partial agonists, antagonists and tissue selective S1P receptor modulators.

[0410] The term "subject" or "patient" includes mammals. Examples of mammals include, but are not limited to, any member of the class Mammalia: humans, non-human primates, such as chimpanzees and other apes and monkey species; farm animals, such as cattle, horses, sheep, goats, pigs; domestic animals, such as rabbits, dogs and cats; laboratory animals, including rodents, such as rats, mice and guinea pigs, etc. In one aspect, the mammal is a human. One skilled in the art will recognize that a therapy that reduces the severity of a pathology in one species of mammal may predict the effect of the therapy on another species of mammal.

[0411] As used herein, the terms "treat" or "treatment" include prophylactically and / or therapeutically alleviating, eliminating or ameliorating at least one symptom of a disease or condition, preventing additional symptoms, inhibiting the disease or condition, such as arresting the development of the disease or condition, relieving the disease or condition, causing regression of the disease or condition, relieving conditions caused by the disease or condition, or halting symptoms of the disease or condition.

[0412] Route of administration

[0413] Suitable routes of administration include, but are not limited to, oral, intravenous, rectal, aerosol, parenteral, ophthalmic, pulmonary, transmucosal, transdermal, vaginal, auricular, nasal, and topical administration. In addition, parenteral delivery includes, by way of example only, intramuscular, subcutaneous, intravenous, intramedullary injection, as well as intrathecal, direct intraventricular, intraperitoneal, intralymphatic, and intranasal injection.

[0414] In certain embodiments, the compound as described herein is applied in a local rather than systemic manner, for example, by injecting the compound directly into an organ, usually in the form of a long-acting preparation or a sustained-release preparation. In a specific embodiment, the long-acting preparation is applied by implantation (e.g., subcutaneous or intramuscular) or by intramuscular injection. In addition, in other embodiments, the drug is delivered in a targeted drug delivery system, for example, in a liposome coated with an organ-specific antibody. In such an embodiment, the liposome is targeted to the organ and selectively absorbed by the organ. In other other embodiments, the compound as described herein is provided in the form of a quick-release preparation, in the form of an extended-release preparation, or in the form of an intermediate-release preparation. In other other embodiments, the compound as described herein is applied topically.

[0415] Pharmaceutical compositions and administration methods of SIP receptor modulators

[0416] Administration of a SIP receptor modulator as described herein may be in any pharmacological form, including a therapeutically effective amount of a SIP receptor modulator alone or in combination with a pharmaceutically acceptable carrier.

[0417] Pharmaceutical compositions can be formulated in a conventional manner using one or more physiologically acceptable carriers, which include excipients and adjuvants that facilitate processing of the active compound into a pharmaceutically acceptable preparation. Suitable formulations depend on the selected route of administration. Additional details on suitable excipients for the pharmaceutical compositions described herein can be found in, for example, Remington: The Science and Practice of Pharmacy, 19th Edition (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, HA and Lachman, L., eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, NY, 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, 7th Edition (Lippincott Williams & Wilkins 1999), which are incorporated herein by reference for these disclosures.

[0418] As used herein, a pharmaceutical composition refers to a mixture of a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (II), (IIa), (IIb), (IIc), (IId), or (IIe) as described herein with other chemical components such as carriers, stabilizers, diluents, dispersants, suspending agents, thickeners, and / or excipients. A pharmaceutical composition facilitates administration of a compound to an organism. In the practice of the methods of treatment or uses provided herein, a therapeutically effective amount of a compound described herein is administered in a pharmaceutical composition to a mammal suffering from a disease, disorder, or condition to be treated. In some embodiments, the mammal is a human. A therapeutically effective amount can vary widely depending on the severity of the disease, the age and relative health of the subject, the potency of the compound used, and other factors.

[0419] In another aspect, provided herein are pharmaceutical compositions comprising a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (II), (IIa), (IIb), (IIc), (IId), or (IIe), or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable diluent, excipient, or binder. In one embodiment, the pharmaceutical composition comprising a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (II), (IIa), (IIb), (IIc), (IId), or (IIe), or a pharmaceutically acceptable salt or solvate thereof, is formulated for a route of administration selected from oral, parenteral, buccal, nasal, topical, or rectal administration.

[0420] In another aspect is a method of treating a disease, disorder or condition in a mammal that would benefit from S1P receptor modulation, comprising administering to the mammal a therapeutically effective amount of a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (II), (IIa), (IIb), (IIc), (IId) or (IIe), or a pharmaceutically acceptable salt or solvate thereof.

[0421] In another embodiment is a method of treating a disease, disorder or condition in a mammal that would benefit from S1P receptor modulation, comprising administering to the mammal a therapeutically effective amount of a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (II), (IIa), (IIb), (IIc), (IId) or (IIe), or a pharmaceutically acceptable salt or solvate thereof; wherein the disease, disorder or condition in the mammal is selected from multiple sclerosis, ulcerative colitis and Crohn's disease. In another embodiment is a method of treating a disease, disorder or condition in a mammal that would benefit from S1P receptor modulation, comprising administering to the mammal a therapeutically effective amount of a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (II), (IIa), (IIb), (IIc), (IId) or (IIe), or a pharmaceutically acceptable salt or solvate thereof; wherein the disease, disorder or condition in the mammal is multiple sclerosis. In another embodiment is a method of treating a disease, disorder or condition in a mammal that would benefit from S1P receptor modulation, comprising administering to the mammal a therapeutically effective amount of a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (II), (IIa), (IIb), (IIc), (IId) or (IIe), or a pharmaceutically acceptable salt or solvate thereof; wherein the disease, disorder or condition in the mammal is ulcerative colitis. In another embodiment is a method of treating a disease, disorder or condition in a mammal that would benefit from S1P receptor modulation, comprising administering to the mammal a therapeutically effective amount of a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (II), (IIa), (IIb), (IIc), (IId) or (IIe), or a pharmaceutically acceptable salt or solvate thereof; wherein the disease, disorder or condition in the mammal is Crohn's disease.

[0422] In a further embodiment is a method of treating a disease, disorder or condition in a mammal that would benefit from S1P receptor modulation, comprising administering to the mammal a therapeutically effective amount of a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (II), (IIa), (IIb), (IIc), (IId) or (IIe), or a pharmaceutically acceptable salt or solvate thereof; wherein the disease, disorder or condition in the mammal is rejection of a transplanted organ or tissue; graft-versus-host disease resulting from transplantation; autoimmune syndromes including rheumatoid arthritis, multiple sclerosis, myasthenia gravis; pollen allergy; type I diabetes; prevention of psoriasis; Crohn's disease; ulcerative colitis, acute respiratory distress syndrome; adult respiratory distress syndrome; influenza; post-infectious autoimmune diseases including rheumatic fever and post-infectious glomerulonephritis; and cancer metastasis.

[0423] In some embodiments, a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (II), (IIa), (IIb), (IIc), (IId), or (IIe) is used alone or in combination with one or more therapeutic agents as components of a mixture (e.g., in a combination therapy). In some embodiments, a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (II), (IIa), (IIb), (IIc), (IId), or (IIe) is used alone. In some embodiments, a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (II), (IIa), (IIb), (IIc), (IId), or (IIe) is used in combination with another S1P receptor modulator or another type of therapeutic agent, or both. In some embodiments, a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (II), (IIa), (IIb), (IIc), (IId), or (IIe) is used in combination with another S1P receptor modulator. In some embodiments, a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (II), (IIa), (IIb), (IIc), (IId), or (IIe) is used in combination with another type of therapeutic agent. In some embodiments, a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (II), (IIa), (IIb), (IIc), (IId), or (IIe) is used in combination with another S1P receptor modulator and another type of therapeutic agent.

[0424] The pharmaceutical formulations described herein can be administered to a subject by a variety of routes of administration, including, but not limited to, oral, parenteral (e.g., intravenous, subcutaneous, intramuscular), intranasal, buccal, topical, rectal, or transdermal routes of administration. In addition, the pharmaceutical compositions described herein comprising a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (II), (IIa), (IIb), (IIc), (IId), or (IIe) described herein can be formulated into any suitable dosage form, including, but not limited to, aqueous oral dispersions, liquids, gels, syrups, elixirs, slurries, suspensions, aerosols, controlled release formulations, fast melt formulations, effervescent formulations, lyophilized formulations, tablets, powders, pills, dragees, capsules, delayed release formulations, extended release formulations, pulsatile release formulations, multiparticulate formulations, and mixed immediate and controlled release formulations.

[0425] Pharmaceutical compositions comprising the compounds described herein may be manufactured in a conventional manner, such as, by way of example only, by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, encapsulating or compression processes.

[0426] Dosage administration may be repeated depending on the pharmacokinetic parameters of the dosage formulation and the route of administration utilized.

[0427] It is particularly advantageous to formulate the composition in dosage unit form for ease of administration and uniformity of dosage. As used herein, dosage unit form refers to physically discrete units suitable as unit dosages for mammalian subjects to be treated; each unit contains a predetermined amount of active compound calculated to produce the desired therapeutic effect together with the required pharmaceutical carrier. The specifications for the dosage unit form are dictated by and directly dependent on (a) the unique characteristics of the SIP receptor modulator and the specific therapeutic effect to be achieved, and (b) the limitations inherent in the art of compounding such active compounds for the treatment of individual sensitivity. A person of ordinary skill in the art can readily calculate the specific dosage, for example, based on the approximate body weight or body surface area of ​​the patient or the volume of body space to be occupied. The dosage will also be calculated based on the specific route of administration selected. Further refinement of the calculations necessary to determine the appropriate therapeutic dose is routinely performed by a person of ordinary skill in the art. Such calculations can be performed by a person of ordinary skill in the art without undue experimentation based on the activity of the S1P receptor modulator disclosed herein in the formulation by assaying target cells. The exact dosage is determined in conjunction with standard dose response studies. It will be understood that the actual amount of composition administered will be determined by the practitioner according to the relevant circumstances, including the disease or condition to be treated, the choice of composition to be administered, the age, weight and response of the individual patient, the severity of the patient's symptoms, and the selected route of administration.

[0428] The toxicity and therapeutic efficacy of such S1P receptor modulators can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, for example, to determine the LD 50 (50% lethal dose in a population) and ED 50 (the dose that is therapeutically effective in 50% of the population). The dose ratio between toxic and therapeutic effects is the therapeutic index, and it can be expressed as LD 50 / ED 50 S1P receptor modulators that exhibit high therapeutic indices are preferred. Although S1P receptor modulators that exhibit toxic side effects may be used, delivery systems that target such modulators to the affected tissue site should be carefully designed to minimize potential damage to non-infected cells, thereby reducing side effects.

[0429] The data obtained from cell culture assays and animal studies can be used in formulating a range of dosage for use in humans. The dosage of such S1P receptor modulators is preferably within the range of ED 50 The dosage may vary within this range depending on the dosage form employed and the route of administration utilized. For any S1P receptor modulator used in the methods described herein, the therapeutically effective dose can be estimated initially from cell culture assays. A dose can be formulated in animal models to achieve an IC determined in cell culture. 50 (ie, the concentration of the S1P receptor modulator that achieves a half-maximal inhibition of symptoms). Such information can be used to more accurately determine useful doses in humans. Levels in plasma can be measured, for example, by high performance liquid chromatography.

[0430] Dosage and treatment regimen

[0431] The compounds described herein can be used to prepare a medicament for modulating S1P receptors or treating a disease or condition that would benefit, at least in part, from S1P receptor modulation. In addition, a method of treating any disease or condition described herein in a subject in need of such treatment comprises administering to the subject a pharmaceutical composition containing at least one compound described herein or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate or hydrate thereof, in a therapeutically effective amount.

[0432] The compositions containing the compounds described herein can be administered for preventive and / or therapeutic treatment. In therapeutic applications, the compositions are administered to a patient already suffering from a disease or condition in an amount sufficient to cure or at least partially arrest the symptoms of the disease or condition. Amounts effective for this use will depend on the severity and course of the disease or condition, previous treatments, the patient's health status, weight, and response to the drugs, and the judgment of the treating physician.

[0433] In preventive applications, compositions containing the compounds described herein are administered to a patient susceptible to or at risk of a particular disease, disorder or condition. Such an amount is defined as a "prophylactically effective amount or dose". In this application, the precise amount also depends on the patient's health, weight, etc. When used in a patient, an amount effective for this application will depend on the severity and course of the disease, disorder or condition, previous treatment, the patient's health status and response to drugs, and the judgment of the treating physician.

[0434] In the event that the patient's condition does not improve, at the physician's discretion, administration of the compound may be given chronically, i.e., for an extended period of time, including throughout the patient's life, in order to alleviate or otherwise control or limit the symptoms of the patient's disease or condition.

[0435] In the event that the patient's condition does improve, at the discretion of the physician, the administration of the compound may be continued; alternatively, the administered drug dose may be temporarily reduced or temporarily suspended for a period of time (i.e., a "drug holiday"). The length of the drug holiday may vary from 2 days to 1 year, including, by way of example only, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 10 days, 12 days, 15 days, 20 days, 28 days, 35 days, 50 days, 70 days, 100 days, 120 days, 150 days, 180 days, 200 days, 250 days, 280 days, 300 days, 320 days, 350 days, or 365 days. The dosage reduction during the drug holiday can be from about 10% to about 100%, including, by way of example only, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or about 100%.

[0436] Once the patient's condition improves, a maintenance dose is administered, if necessary. Subsequently, the dose or frequency of administration, or both, may be reduced, depending on changes in symptoms, to a level at which the improvement in the disease, disorder or condition is maintained. However, the patient may require intermittent treatment on a long-term basis upon any recurrence of symptoms.

[0437] The amount of a given agent corresponding to this amount will vary according to factors such as the specific compound, the disease or condition and its severity, the characteristics of the subject or host to be treated (e.g., body weight), but can still be determined in a manner recognized in the art according to the specific circumstances of the case, including, for example, the specific agent administered, the route of administration, the condition to be treated, and the subject or host to be treated. However, in general, the dosage used for adult treatment will generally be in the range of about 0.01 mg / day to about 5000 mg / day, in some embodiments, in the range of about 1 mg / day to about 1500 mg / day. The desired dosage may be conveniently presented in a single dose or as divided doses, which are administered simultaneously (or over a short period of time) or at appropriate intervals, for example, in two, three, four or more sub-doses per day.

[0438] The pharmaceutical compositions described herein can be in a unit dosage form suitable for single administration of precise doses. In a unit dosage form, the preparation is divided into unit doses containing an appropriate amount of one or more compounds. The unit dose can be in the form of a package containing a discrete amount of preparation. Non-limiting examples are packaged tablets or capsules and powders in vials or ampoules. Aqueous suspension compositions can be packaged in single-dose containers that cannot be reclosed. Alternatively, a recloseable multi-dose container can be used, in which case a preservative is generally included in the composition. For example only, preparations for parenteral injection can be presented in a unit dosage form including but not limited to ampoules, or in a multi-dose container with a preservative added.

[0439] The daily dose suitable for the compounds described herein is about 0.01 mg / kg to about 30 mg / kg. In one embodiment, the daily dose is about 0.01 mg / kg to about 10 mg / kg. The daily dose indicated in larger mammals (including but not limited to humans) is in the range of about 0.1 mg to about 1000 mg, conveniently administered in single doses or divided doses, including but not limited to, up to four times a day or in an extended release form. Suitable oral unit dosage forms contain about 1 to about 500 mg of active ingredient. In one embodiment, the unit dose is about 1 mg, about 5 mg, about 10 mg, about 20 mg, about 50 mg, about 100 mg, about 200 mg, about 250 mg, about 400 mg or about 500 mg. The aforementioned ranges are only suggestive, because the number of variables about individual treatment regimens is large, and considerable deviations from these recommended values ​​are not uncommon. Such dosage may vary according to many variables including but not limited to the activity of the compound employed, the disease or condition being treated, the mode of administration, the requirements of the subject, the severity of the disease or condition being treated, and the judgment of the practitioner.

[0440] Toxicity and therapeutic efficacy of such treatment regimens can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, including but not limited to determining the LD 50 (50% lethal dose in a population) and ED 50 (the dose that is therapeutically effective in 50% of the population). The dose ratio between toxic and therapeutic effects is the therapeutic index, and it can be expressed as LD 50 With ED 50 Compounds that exhibit high therapeutic indices are preferred. Data obtained from cell culture assays and animal studies can be used to formulate a dosage range for use in humans. The dosage of such compounds is preferably within the range that includes the ED 50 The dosage may vary within this range depending upon the dosage form employed and the route of administration utilized.

[0441] The present invention provides embodiments including but not limited to the following:

[0442] 1. A compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof:

[0443]

[0444] in:

[0445] X1, X2, X3 and X4 are each CR1; or

[0446] X1 is N; X2, X3 and X4 are each CR1; or

[0447] X2 is N; X1, X3 and X4 are each CR1; or

[0448] X3 is N; X1, X2 and X4 are each CR1; or

[0449] X4 is N; X1, X2 and X3 are each CR1;

[0450] Selected from

[0451] Z is -O-, -S-, -N(R4)-, -CH2-, -OCH2- or -CH2O-;

[0452] Each R1 is independently selected from hydrogen, halogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted C3-C8 cycloalkyl, optionally substituted -(C1-C2 alkylene)-(C3-C8 cycloalkyl), optionally substituted C2-C9 heterocycloalkyl, optionally substituted -(C1-C2 alkylene)-(C2-C9 heterocycloalkyl), optionally substituted -(C1-C2 alkylene)-(aryl), optionally substituted -(C1-C2 alkylene)-(heteroaryl), -CF3, -OR 10 、-SR 10 、-N(R 11 )R 12 、-N(R 11 )S(O)2R 15 ;-N(R 13 )N(R 11 )R 12 、-N(R 13 )N(R 11 )S(O)2R 15 、-C(O)R 14 、-C(O)OR 10 、-C(S)OR 10 、-C(O)SR 10 、-C(O)N(R 11 )R 12 、-C(S)N(R 11 )R 12 、-C(O)N(R 11 )S(O)2R 15 、-C(S)N(R 11 )S(O)2R 15 、-C(O)N(R 13 )N(R 11 )R 12 、-C(S)N(R 13 )N(R 11 )R 12 and -C(O)N(R 13 )N(R 11 )S(O)2R 15 ;

[0453] Each R2 is independently selected from halogen, optionally substituted C1-C6 alkyl, -OR 20 、-SR 20 、-N(R 21 )R 22 、-C(O)R 20 、-C(O)N(R 21 )R 22and -N(R 23 )C(O)R 20 ;

[0454] R3 is selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C8 cycloalkyl, optionally substituted aryl, optionally substituted -(C1-C2 alkylene)-(aryl), optionally substituted heteroaryl, and optionally substituted -(C1-C2 alkylene)-(heteroaryl);

[0455] R4 is hydrogen or an optionally substituted C1-C6 alkyl group,

[0456] R 10 , R 13和 R 14 each independently selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C8 cycloalkyl, optionally substituted aryl, optionally substituted -(C1-C2 alkylene)-(aryl), optionally substituted C2-C9 heterocycloalkyl, optionally substituted heteroaryl, and optionally substituted -(C1-C2 alkylene)-(heteroaryl);

[0457] R 11 and R 12 R is each independently selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C8 cycloalkyl, optionally substituted aryl, optionally substituted -(C1-C2 alkylene)-(aryl), optionally substituted C2-C9 heterocycloalkyl, optionally substituted heteroaryl, and optionally substituted -(C1-C2 alkylene)-(heteroaryl); or optionally R 11 and R 12 Together with the nitrogen atom to which they are attached, they form an optionally substituted C2-C9 heterocycloalkyl ring;

[0458] R 15 is selected from optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C8 cycloalkyl, optionally substituted aryl, optionally substituted -(C1-C2 alkylene)-(aryl), optionally substituted C2-C9 heterocycloalkyl, optionally substituted heteroaryl, and optionally substituted -(C1-C2 alkylene)-(heteroaryl);

[0459] R 20 and R 23each independently selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C8 cycloalkyl, optionally substituted aryl, optionally substituted -(C1-C2 alkylene)-(aryl), optionally substituted C2-C9 heterocycloalkyl, optionally substituted heteroaryl, and optionally substituted -(C1-C2 alkylene)-(heteroaryl);

[0460] R 21 and R 22 R is each independently selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C8 cycloalkyl, optionally substituted aryl, optionally substituted -(C1-C2 alkylene)-(aryl), optionally substituted C2-C9 heterocycloalkyl, optionally substituted heteroaryl, and optionally substituted -(C1-C2 alkylene)-(heteroaryl); or optionally R 21 and R 22 Together with the nitrogen atom to which they are attached, they form an optionally substituted C2-C9 heterocycloalkyl ring;

[0461] n is 0-4; and

[0462] p is 0 or 1.

[0463] 2. The compound as described in embodiment 1, or a pharmaceutically acceptable salt or solvate thereof, wherein X1, X2, X3 and X4 are each CR1.

[0464] 3. The compound as described in embodiment 1, or a pharmaceutically acceptable salt or solvate thereof, wherein X1 is N; and X2, X3 and X4 are each CR1.

[0465] 4. The compound as described in embodiment 1, or a pharmaceutically acceptable salt or solvate thereof, wherein X2 is N; X1, X3 and X4 are each CR1.

[0466] 5. The compound as described in embodiment 1, or a pharmaceutically acceptable salt or solvate thereof, wherein X3 is N; X1, X2 and X4 are each CR1.

[0467] 6. The compound of embodiment 1, or a pharmaceutically acceptable salt or solvate thereof, wherein X4 is N; and X1, X2 and X3 are each CR1.

[0468] 7. A compound as described in any one of embodiments 1-6, or a pharmaceutically acceptable salt or solvate thereof, wherein each R1 is independently selected from hydrogen, halogen, optionally substituted C1-C6 alkyl, -CF3, -OR 10 、-N(R 11 )R 12、-C(O)R 14 、-C(O)OR 10 and -C(O)N(R 11 )R 12 .

[0469] 8. A compound as described in any one of embodiments 1-7, or a pharmaceutically acceptable salt or solvate thereof, wherein each R1 is independently selected from hydrogen, halogen and -CF3.

[0470] 9. A compound as described in any one of embodiments 1-8, or a pharmaceutically acceptable salt or solvate thereof, wherein each R2 is independently selected from halogen, optionally substituted C1-C6 alkyl, -OR 20 and -N(R 21 )R 22 .

[0471] 10. A compound as described in any one of embodiments 1-9, or a pharmaceutically acceptable salt or solvate thereof, wherein each R2 is independently selected from halogen and optionally substituted C1-C6 alkyl.

[0472] 11. A compound as described in any one of embodiments 1-10, or a pharmaceutically acceptable salt or solvate thereof, wherein R3 is selected from hydrogen and optionally substituted C1-C6 alkyl.

[0473] 12. A compound as described in any one of embodiments 1-11, or a pharmaceutically acceptable salt or solvate thereof, wherein for

[0474] 13. A compound as described in any one of embodiments 1-11, or a pharmaceutically acceptable salt or solvate thereof, wherein for

[0475] 14. A compound as described in any one of embodiments 1-11, or a pharmaceutically acceptable salt or solvate thereof, wherein for

[0476] 15. A compound as described in any one of embodiments 1-11, or a pharmaceutically acceptable salt or solvate thereof, wherein for

[0477] 16. A compound as described in any one of embodiments 1-11, or a pharmaceutically acceptable salt or solvate thereof, wherein for

[0478] 17. A compound as described in any one of embodiments 1-11, or a pharmaceutically acceptable salt or solvate thereof, wherein for

[0479] 18. The compound of any one of embodiments 1-17, or a pharmaceutically acceptable salt or solvate thereof, wherein Z is -O-, -OCH2-, or -CH2O-.

[0480] 19. The compound of any one of embodiments 1-17, or a pharmaceutically acceptable salt or solvate thereof, wherein Z is -O-.

[0481] 20. The compound of any one of embodiments 1-17, or a pharmaceutically acceptable salt or solvate thereof, wherein Z is -OCH2-.

[0482] 21. A compound as described in any one of embodiments 1-20, or a pharmaceutically acceptable salt or solvate thereof, wherein p is 0.

[0483] 22. A compound as described in any one of embodiments 1-20, or a pharmaceutically acceptable salt or solvate thereof, wherein p is 1.

[0484] 23. A compound as described in any one of embodiments 1-22, or a pharmaceutically acceptable salt or solvate thereof, wherein n is 0.

[0485] 24. The compound of any one of embodiments 1-22, or a pharmaceutically acceptable salt or solvate thereof, wherein n is 1.

[0486] 25. A compound as described in any one of embodiments 1-22, or a pharmaceutically acceptable salt or solvate thereof, wherein n is 2.

[0487] 26. A pharmaceutical composition comprising a pharmaceutically acceptable diluent, excipient or binder, and a compound according to any one of embodiments 1 to 25; or a pharmaceutically acceptable salt or solvate thereof.

[0488] 27. A method of modulating sphingosine-1-phosphate (S1P) receptor activity, comprising contacting the S1P receptor or a portion thereof with a compound according to any one of embodiments 1-25, or a pharmaceutically acceptable salt or solvate thereof.

[0489] 28. A method of treating a disease, disorder or condition in a mammal that would benefit from modulation of a sphingosine-1-phosphate (S1P) receptor, comprising administering to the mammal a therapeutically effective amount of a compound according to any one of embodiments 1-25, or a pharmaceutically acceptable salt or solvate thereof.

[0490] 29. The method of embodiment 28, wherein the disease, disorder or condition in the mammal is selected from multiple sclerosis, ulcerative colitis and Crohn's disease.

[0491] Example

[0492] The following examples are provided for illustrative purposes and are not intended to limit the scope of the claims provided herein. All documents cited in these examples and throughout the specification are incorporated herein by reference for all legal purposes provided thereby. The starting materials and reagents used to synthesize the compounds described herein can be synthesized or can be obtained from commercial sources such as, but not limited to, Sigma-Aldrich, Acros Organics, Fluka, and Fischer Scientific.

[0493] Example 1: Synthesis of (S)-5-((2,5-dichloro-4-(5-(8-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)-1,2,4-oxadiazol-3-yl)phenoxy)methyl)pyrrolidin-2-one (11)

[0494]

[0495] At room temperature, cuprous cyanide (101.5 g, 1.13 mmol) was added to a stirred solution of 2,5-dichloro-4-bromophenol (1) (210.0 g, 0.86 mol) in DMF (1000 mL). The reaction mixture was stirred at 150 ° C for 4 h. The mixture was concentrated under vacuum. Water and EtOAc were added to the residue and then filtered through a celite pad. The filtrate was extracted with EtOAc, and the combined organic layers were dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was recrystallized from petroleum ether / EtOAc (10: 1, 1400 mL) to obtain 2,5-dichloro-4-hydroxybenzonitrile (2) (93.0 g, 57%) as a white solid.

[0496] At 0°C, NaH (13.7 g, 347 mmol) was added to a stirred solution of 2,5-dichloro-4-hydroxybenzonitrile (2) (35.0 g, 186 mmol) in DMF (150 mL) in small batches, and the mixture was stirred at 0°C for 30 min. Methyl iodide (35 mL, 560 mmol) was added dropwise, and the reaction mixture was warmed to room temperature and stirred for 3 h. The mixture was cooled to 0°C, and ice water was carefully added. The resulting precipitate was collected by filtration, washed with water, and dried to give compound (3) (29 g, 78%) as a white solid.

[0497] Triethylamine (160.0 g, 1.27 mol) was added to a stirred solution of hydroxylamine hydrochloride (3) (64.0 g, 0.5 mol) in EtOH (500 mL), and the mixture was stirred at room temperature for 30 min. Compound 2 was added, and the reaction mixture was stirred at 80 ° C for 4 h. The mixture was concentrated, and the residue was dissolved in EtOAc. The resulting solution was washed with water, dried over anhydrous Na2SO4, and concentrated in vacuo to give a mixture of off-white solids (60.0 g, compound (4) and 2,5-dichloro-4-methoxybenzamide, 1: 2). The solid was slurried in MBTE and then filtered. The filtrate was concentrated under vacuum to give a solid (40.1 g, 28%, compound (4) and 2,5-dichloro-4-methoxybenzamide, 1: 1).

[0498] At room temperature, ethyl bromopyruvate (80.0 mL, 0.64 mol) was added to a stirred solution of 2-amino-3-chloro-5-trifluoromethylpyridine (5) (50.0 g, 0.25 mmol) in EtOH (500 mL). The reaction mixture was heated at 80 ° C for 48 h and then cooled to room temperature. The mixture was concentrated and the residue was suspended in diethyl ether. The resulting precipitate was collected by filtration and dried in vacuo to obtain 8-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridine-2-carboxylic acid ethyl ester (6) (64.0 g, 86%) as an off-white solid.

[0499] 1M NaOH aqueous solution (640.0 mL) was added to a stirred solution of 8-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridine-2-carboxylic acid ethyl ester (6) (64.0 g, 0.22 mol) in MeOH (64.0 mL). The reaction mixture was heated at 50 ° C for 1 h and then cooled to room temperature. The mixture was concentrated under vacuum. Water was added to the residue, and the mixture was acidified to pH = 4 with AcOH. The resulting precipitate was collected by filtration, washed with water, and dried in vacuo to obtain compound (7) (24.0 g) as an off-white solid. The filtrate was extracted with EtOAc, and the combined organic layer was dried over anhydrous Na2SO4 and concentrated in vacuo to obtain another portion of compound (7) (20.0 g) as an off-white solid (combined yield 77%).

[0500] To a stirred solution of compound (7) (26.5 g, 100 mmol) in DMF (50.0 mL) was added EDCI-HCl (19.2 g, 100 mmol) and HOBt (13.5 g, 100 mmol). The mixture was stirred for 15 min, and hydroxyimidate (4) (36 g, purity of about 54%, 100 mmol) was added. The reaction mixture was stirred at 100 ° C for 12 h. The mixture was concentrated under vacuum, and the residue was purified by silica gel flash column chromatography (petroleum ether / EtOAc=10:1) to give compound (8) (12.6 g, 33%) as a white solid.

[0501] Under N2, AlCl3 (23 g, 172.5 mmol) was added in small batches to a cold solution of compound (8) (16 g, 34.5 mmol) in DCM (110 mL), keeping the temperature below 10°C. The light brown suspension was stirred for 10 min, and then EtSH (12.8 mL, 172.5 mmol) was added dropwise, keeping the temperature below 5°C. The reaction mixture was stirred for 2.5 h at less than 10°C, and then slowly poured into ice water under vigorous stirring. The organic layer was separated, and the aqueous layer was extracted with DCM. The combined DCM layers were washed with water, dried over anhydrous Na2SO4, and concentrated. The residue was azeotroped with toluene to obtain compound (9) (15.5 g, 100%) as an off-white solid.

[0502] At 0 ° C, DMAP (446 mg, 3.65 mmol) and Et3N (369 mg, 3.65 mmol) were added to a solution of (S)-5-(hydroxymethyl)-2-pyrrolidone (10) (420 mg, 3.65 mmol) and p-toluenesulfonyl chloride (696 mg, 3.65 mmol) in DCM (20 mL). The reaction mixture was warmed to room temperature and stirred overnight. The reaction was quenched with 20 mL of water, and the aqueous layer was extracted with DCM. The combined organic extracts were washed with 1N HCl aqueous solution, dried over anhydrous Na2SO4, and concentrated in vacuo. The residue was recrystallized from petroleum ether / DCM (20: 1, 30 mL) to obtain (S)-(5-oxopyrrolidin-2-yl)methyl 4-methylbenzenesulfonate (700 mg, 71%) as a white solid.

[0503] To a solution of compound (9) (300 mg, 0.67 mmol) and (S)-(5-oxopyrrolidin-2-yl)methyl 4-methylbenzenesulfonate (199 mg, 0.74 mmol) in acetonitrile (25 mL) was added potassium carbonate (185 mg, 1.34 mmol). The reaction mixture was heated at 76 ° C for 13 h and then cooled to room temperature. The mixture was diluted with water (20 mL) and extracted with DCM (25 mL×2). The combined organic phases were washed with brine, dried over anhydrous Na2SO4, and concentrated in vacuo. The residue was purified by silica gel flash column chromatography and then recrystallized from EtOAc to give compound (11) (30 mg, 8%). 1 H NMR (400 MHz, DMSO-d6) δ9.33 (s, 1H), 9.08 (s, 1H), 8.12 (s, 1H), 8.07 (s, 1H), 7.82 (s, 1H), 7.56 (s, 1H), 4.20-4.18 (m, 2H), 3.97-3.95 (m, 1H), 2.44-2.33 (m, 1H), 2.27-2.12 (m, 2H), 1.99-1.96 (m, 1H). LC-MS (ESI): for C 21 H 13 m / z calculated for Cl3F3N5O3: 545.00, found: 546.73 [M+H] + Example 2: Synthesis of (R)-5-((2,5-dichloro-4-(5-(8-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)-1,2,4-oxadiazol-3-yl)phenoxy)methyl)pyrrolidin-2-one (13)

[0504]

[0505] At 0 ° C, DMAP (339 mg, 2.78 mmol) and Et3N (280 mg, 2.78 mmol) were added to a solution of (R)-5-(hydroxymethyl)-2-pyrrolidone (12) (320 mg, 2.78 mmol) and p-toluenesulfonyl chloride (530 mg, 2.78 mmol) in DCM (20 mL). The reaction mixture was warmed to room temperature and stirred overnight. The reaction was quenched with 20 mL of water, and the aqueous layer was extracted with DCM. The combined organic extracts were washed with 1N HCl aqueous solution, dried over anhydrous Na2SO4, and concentrated in vacuo. The residue was recrystallized from petroleum ether / DCM (20: 1, 25 mL) to obtain (R)-(5-oxopyrrolidin-2-yl)methyl 4-methylbenzenesulfonate (400 mg, 53.4% ​​yield) as a white solid.

[0506] To a solution of compound (9) (300 mg, 0.67 mmol) and (R)-(5-oxopyrrolidin-2-yl)methyl 4-methylbenzenesulfonate (199 mg, 0.74 mmol) in acetonitrile (25 mL) was added potassium carbonate (185 mg, 1.34 mmol). The reaction mixture was heated at 76 ° C for 13 h and then cooled to room temperature. The mixture was diluted with water (20 mL) and extracted with DCM (25 mL×2). The combined organic phases were washed with brine, dried over anhydrous Na2SO4, and concentrated in vacuo. The residue was purified by silica gel flash column chromatography and then recrystallized from EtOAc to give compound (13) (40.3 mg, 11%). 1 H NMR (400 MHz, DMSO-d6): δ9.33 (s, 1H), 9.07 (s, 1H), 8.12 (s, 1H), 8.07 (s, 1H), 7.81 (s, 1H), 7.56 (s, 1H), 4.22-4.16 (m, 2H), 3.98-3.95 (m, 1H), 2.41-2.33 (m, 1H), 2.29-2.16 (m, 2H), 1.99-1.96 (m, 1H). LC-MS (ESI): for C 21 H 13 m / z calculated for Cl3F3N5O3: 545.00, found: 546.58 [M+H] + Example 3: Synthesis of (R)-5-((2,5-dichloro-4-(5-(8-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)-1,2,4-oxadiazol-3-yl)phenoxy)methyl)pyrrolidin-2-one (15)

[0507]

[0508] At 0 ° C, DMAP (530 mg, 4.34 mmol) and Et3N (438 mg, 4.34 mmol) were added to a solution of (R)-5-hydroxypiperidin-2-one (14) (500 mg, 4.34 mmol) and p-toluenesulfonyl chloride (827 mg, 4.34 mmol) in DCM (20 mL). The reaction mixture was warmed to room temperature and stirred overnight. The reaction was quenched with 20 mL of water, and the aqueous layer was extracted with DCM. The combined organic extracts were washed with 1N HCl aqueous solution, dried over anhydrous Na2SO4, and concentrated in vacuo. The residue was recrystallized from petroleum ether / DCM (20: 1, 30 mL) to obtain (R)-6-oxopiperidin-3-yl 4-methylbenzenesulfonate (670 mg, 57% yield) as a white solid.

[0509] Potassium carbonate (461 mg, 3.34 mmol) was added to a solution of compound (9) (750 mg, 1.67 mmol) and (R)-6-oxopiperidin-3-yl 4-methylbenzenesulfonate (450 mg, 1.67 mmol) in acetonitrile (40 mL). The reaction mixture was heated at 76 ° C for 18 h and then cooled to room temperature. The mixture was diluted with water (50 mL) and extracted with DCM (45 mL×2). The combined organic phases were washed with brine, dried over anhydrous Na2SO4, and concentrated in vacuo. The residue was purified by silica gel flash column chromatography and then recrystallized from EtOAc to obtain compound (15) (130 mg, 14% yield). 1 H NMR (400 MHz, DMSO-d6): δ9.33 (s, 1H), 9.07 (s, 1H), 8.12 (s, 1H), 8.07 (s, 1H), 7.73 (s, 1H), 7.47 (s, 1H), 5.17-5.15 (m, 1H), 3.53-3.49 (m, 1H), 3.39-3.34 (m, 1H), 2.36-2.21 (m, 2H), 2.12-2.08 (m, 2H). LC-MS (ESI): for C 21 H 13 m / z calculated for Cl3F3N5O3: 545.00, found: 546.65 [M+H] + .

[0510] Example 4: Synthesis of (S)-5-(2,5-dichloro-4-(5-(8-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)-1,2,4-oxadiazol-3-yl)phenoxy)-1-methylpiperidin-2-one (16)

[0511]

[0512] To a solution of compound (15) (100 mg, 0.18 mmol) in THF (75 mL) was added NaH (15 mg, 0.37 mmol) at 0°C, and the mixture was stirred at 0°C for 30 min. Methyl iodide (129 mg, 0.91 mmol) was added dropwise, and the reaction mixture was warmed to room temperature and stirred for 3 h. The mixture was cooled to 0°C, and ice water was added carefully. The resulting mixture was extracted with EtOAc. The combined extracts were washed with brine, dried over anhydrous Na2SO4, and concentrated in vacuo. The residue was purified by silica gel flash column chromatography and then recrystallized from EtOAc to give compound (16) (21.7 mg, 21%). 1H NMR (400 MHz, DMSO-d6): δ9.33 (s, 1H), 9.07 (s, 1H), 8.12 (s, 1H), 8.08 (s, 1H), 7.75 (s, 1H), 5.21 (s, 1H), 3.72-3.67 (m, 1H), 3.50-3.46 (m, 1H), 2.83 (s, 3H), 2.43-2.29 (m, 2H), 2.11 (m, 2H). LC-MS (ESI): for C 22 H 15 m / z calculated for Cl3F3N5O3: 559.02, found: 560.55 [M+H] + .

[0513] Example 5: Synthesis of (R)-5-(2,5-dichloro-4-(5-(8-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)-1,2,4-oxadiazol-3-yl)phenoxy)piperidin-2-one (18)

[0514]

[0515] At 0 ° C, DMAP (530 mg, 4.34 mmol) and Et3N (438 mg, 4.34 mmol) were added to a solution of (S)-5-hydroxypiperidin-2-one (500 mg, 4.34 mmol) and p-toluenesulfonyl chloride (17) (827 mg, 4.34 mmol) in DCM (20 mL). The reaction mixture was warmed to room temperature and stirred overnight. The reaction was quenched with 20 mL of water, and the aqueous layer was extracted with DCM. The combined organic extracts were washed with 1N HCl aqueous solution, dried over anhydrous Na2SO4, and concentrated in vacuo. The residue was recrystallized from petroleum ether / DCM (20: 1, 30 mL) to obtain (S)-6-oxopiperidin-3-yl 4-methylbenzenesulfonate (700 mg, 60%) as a white solid.

[0516] To a solution of compound (9) (750 mg, 1.67 mmol) and (S)-6-oxopiperidin-3-yl 4-methylbenzenesulfonate (450 mg, 1.67 mmol) in acetonitrile (40 mL) was added potassium carbonate (461 mg, 3.34 mmol). The reaction mixture was heated at 76 ° C for 18 h and then cooled to room temperature. The mixture was diluted with water (50 mL) and extracted with DCM (45 mL×2). The combined organic phases were washed with brine, dried over anhydrous Na2SO4, and concentrated in vacuo. The residue was purified by silica gel flash column chromatography and then recrystallized from EtOAc to obtain compound (18) (134 mg, yield 15%). 1H NMR (400 MHz, DMSO-d6) δ9.33 (s, 1H), 9.07 (s, 1H), 8.12 (s, 1H), 8.08 (s, 1H), 7.74 (s, 1H), 7.48 (s, 1H), 5.17-5.15 (m, 1H), 3.53-3.49 (m, 1H), 3.39-3.34 (m, 1H), 2.36-2.22 (m, 2H), 2.11-2.08 (m, 2H). LC-MS (ESI): for C 21 H 13 m / z calculated for Cl3F3N5O3: 545.00, found: 546.51 [M+H] + .

[0517] Example 6: Synthesis of (R)-5-(2,5-dichloro-4-(5-(8-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)-1,2,4-oxadiazol-3-yl)phenoxy)-1-methylpiperidin-2-one (19)

[0518]

[0519] To a solution of compound (18) (100 mg, 0.18 mmol) in THF (75 mL) was added NaH (15 mg, 0.37 mmol) at 0°C, and the mixture was stirred at 0°C for 30 min. Methyl iodide (129 mg, 0.91 mmol) was added dropwise, and the reaction mixture was warmed to room temperature and stirred for 3 h. The mixture was cooled to 0°C, and ice water was added carefully. The mixture was extracted with EtOAc. The combined extracts were washed with brine, dried over anhydrous Na2SO4, and concentrated in vacuo. The residue was purified by silica gel flash column chromatography and then recrystallized from EtOAc to give compound (19) (27.7 mg, 27%). 1 H NMR (400 MHz, DMSO-d6) δ9.34 (s, 1H), 9.07 (s, 1H), 8.13 (s, 1H), 8.09 (s, 1H), 7.76 (s, 1H), 5.22 (m, 1H), 3.71-3.67 (m, 1H), 3.50-3.46 (m, 1H), 2.83 (s, 3H), 2.43-2.28 (m, 2H), 2.11 (m, 2H). LC-MS (ESI): for C 22 H 15 C l3 m / z calculated for F3N5O3: 559.02, found: 560.47 [M+H] + .

[0520] Embodiment 7-9

[0521] The following compounds were prepared in a similar manner as described above.

[0522]

[0523] Examples 10-16

[0524] The following compounds were prepared in a similar manner as described above.

[0525]

[0526]

[0527] Example 17: GTPγS binding assay

[0528] S1P1 membranes were prepared from CHO-K1 Gαqi5 cells expressing full-length human S1P1. 35 Scintillation proximity assay (SPA) was performed by incubating S with various concentrations of compounds for 60 minutes. SPA beads coated with wheat germ agglutinin were added and incubated for 60 minutes, followed by centrifugation and scintillation counting. The EC values ​​of the exemplary compounds are shown in Table 1 below. 50 data.

[0529] Table 1

[0530] Example <![CDATA[EC 50 (μM)]]> 1 A 5 A 6 A

[0531] A=EC 50 <1μM

[0532] Example 18: Ca 2+ Flux experiment

[0533] Cells were quickly thawed by removing them from liquid nitrogen and immediately immersing them in a 37°C water bath. After the ice melted, the outside of the vials was sterilized immediately with 70% ethanol. 1 mL of pre-warmed culture medium components were added to each cell vial. The contents from two vials were placed in a 15 mL conical tube and the volume was brought to 10 mL of culture medium components. The cell suspension was centrifuged at 190 x g for 4 minutes. The supernatant was removed and 10.5 mL of pre-warmed culture medium components were added to resuspend the cell pellet. The cell suspension was inoculated into a suitable assay microplate (100 μL / well for 96-well plates and 25 μL / well for 384-well plates). When the inoculation was complete, the assay plate was kept at room temperature for 30 minutes and then moved to a humid 37°C 5% CO2 incubator for 24 hours. After 24 hours of incubation, the assay plate was removed from the incubator and washed extensively with Hank's balanced salt solution (HBSS) supplemented with 20 mM HEPES, 2.5 mM probenecid (pH 7.4) to remove all traces of culture medium components. Fluo-8, AM (AAT Bioquest: 21080) Ca was prepared by dissolving 1 mg Fluo-8 NW Fluo-8 in 200 μL DMSO. 2+ Once dissolved, add 10 μL Fluo-8 NW Ca 2+ The dye solution was placed in 10 mL of HBSS 20 mM HEPES, 2.5 mM probenecid (pH 7.4) buffer and applied to the assay microplate (10 μL / 10 mL of Ca 2+ The dye is sufficient to load one (1) microplate). Set up the FLIPR to dispense the 3x ligand into the appropriate wells in the assay plate. Set the excitation wavelength to 470-495 nm (FLIPRTETRA) or 485 nm (FLIPR1, FLIPR2, FLIPR3) and the emission wavelength to 515-565 nm (FLIPRTETRA) or 515-565 nm for Ca 2+ Emission filters for the dye (FLIPR1, FLIPR2, FLIPR3). Set the pipette tip height to 5 μL below the liquid surface and set the dispensing rate to 75 μL / sec (96-well format) or 50 μL / sec (384-well format). Set the plate layout and tip layout for each individual experiment. Set the time course to 180 seconds and add ligand at 10 seconds. Prepare the ligand in a non-binding surface Corning plate (Corning3605-96-well or Corning 3574-384-well). After the run is completed, apply negative controls for correction and use the maximum statistical value to analyze the data. Figure 1 As shown in FIG. 1 , the compounds of formula (I) described herein exhibit cellular potency (EC 50 ~200nM).

[0534] Example 19: Pk test and lymphocyte count

[0535] In this study, a total of 6 mice were used for each compound (Examples 1-6) and divided into two groups: Group 1 (vehicle, dose: 10 mL / kg) and Group 2 (compound, dose: 10 mg / kg, oral). The vehicle was administered to the animals in Group 1. The 10 mg / kg dose of PTC1566-1 solution formulation was administered to the animals in Group 2 by oral route. Blood samples for Group 2 were collected from a group of three mice under mild isoflurane anesthesia at 1 hour and 4 hours (oral), and blood samples for Group 1 were collected at 4 hours. Plasma was harvested by centrifugation of the blood and stored at -70°C until analysis. Brains were collected from the animals in Group 2 at 4 hours, weighed, and transferred to polypropylene tubes. Two volumes of PBS buffer (pH 7.4) were added and homogenized to obtain 3 times the final volume and stored at less than -70°C until bioanalysis. The 4-hour blood samples of both groups were used for lymphocyte counting. Plasma and brain sample analysis was quantified by a fit-for-purpose LCMS / MS method (LLOQ: 4.91 ng / mL for plasma and 14.73 ng / g for brain). For each of the six compounds tested, plasma concentrations were greater than 2600 ng / mL at 1 hour and greater than 2100 ng / mL at 4 hours. For each of the six compounds tested, brain concentrations were less than 200 ng / g. For each of the six compounds tested (Compound 15, Compound 18, Compound 19, Compound 16, Compound 11, and Compound 13), lymphocyte counts were less than 45% of the control ( Figure 2 ).

[0536] Example 20: Phase 3 Study to Evaluate the Safety and Efficacy of a Compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (II), (IIa), (IIb), (IIc), (IId) or (IIe) in Patients with Relapsing Multiple Sclerosis (MS)

[0537] The primary objective of this study is to evaluate the tolerability, safety, and health outcomes in patients with relapsing MS taking a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (II), (IIa), (IIb), (IIc), (IId), or (IIe).

[0538] patient: Eligible patients were males and females aged 18 to 65 years.

[0539] standard:

[0540] Inclusion criteria:

[0541] Patients must be 18-65 years old and have relapsing forms of MS

[0542] Exclusion criteria:

[0543] People with non-relapsing forms of MS

[0544] Patients with a history of chronic immune disease

[0545] Patients with a history of certain cancers

[0546] Diabetic patients with certain eye conditions

[0547] Patients receiving certain immunosuppressive medications or cardiac medications

[0548] Patients with certain heart conditions

[0549] Patients with certain lung conditions

[0550] Type of study: Interventional

[0551] Study Design: Intervention mode: Single group allocation

[0552] Masking: Open label

[0553] Main purpose: Treatment

[0554] Main outcome measures:

[0555] The primary objective of this study is to evaluate the safety and tolerability profile of a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (Ie), (II), (IIa), (IIb), (IIc), (IId) or (IIe) in patients with relapsing MS.

[0556] Secondary outcome measures:

[0557] The incidence of macular edema.

[0558] The incidence of bradyarrhythmias on the electrocardiogram.

[0559] Patient-Reported Outcomes Index for Multiple Sclerosis (PRIMUS), the Brief Health Survey-12, and the Medication Satisfaction Questionnaire.

[0560]

Claims

1. A method for preparing (R)-5-(2,5-dichloro-4-(5-(8-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)-1,2,4-oxadiazol-3-yl)phenoxy)piperidin-2-one: (1) reacting (S)-5-hydroxypiperidin-2-one and p-toluenesulfonyl chloride to produce (S)-6-oxopiperidin-3-yl 4-methylbenzenesulfonate; and (2) reacting a compound having the following structure, potassium carbonate, and (S)-6-oxopiperidin-3-yl 4-methylbenzenesulfonate to produce (R)-5-(2,5-dichloro-4-(5-(8-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)-1,2,4-oxadiazol-3-yl)phenoxy)piperidin-2-one:

2. A method for preparing (R)-5-(2,5-dichloro-4-(5-(8-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)-1,2,4-oxadiazol-3-yl)phenoxy)-1-methylpiperidin-2-one: (1) reacting (S)-5-hydroxypiperidin-2-one and p-toluenesulfonyl chloride to produce (S)-6-oxopiperidin-3-yl 4-methylbenzenesulfonate; (2) reacting A compound of the structure, potassium carbonate and (S)-6-oxopiperidin-3-yl 4-methylbenzenesulfonate are reacted to produce (R)-5-(2,5-dichloro-4-(5-(8-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)-1,2,4-oxadiazol-3-yl)phenoxy)piperidin-2-one: and (3) Reaction with sodium hydride and methyl iodide to produce (R)-5-(2,5-dichloro-4-(5-(8-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)-1,2,4-oxadiazol-3-yl)phenoxy)-1-methylpiperidin-2-one having the following structure:

3. A method for preparing (S)-5-(2,5-dichloro-4-(5-(8-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)-1,2,4-oxadiazol-3-yl)phenoxy)piperidin-2-one: (1) reacting (R)-5-hydroxypiperidin-2-one and p-toluenesulfonyl chloride to produce (R)-6-oxopiperidin-3-yl 4-methylbenzenesulfonate; and (2) reacting a compound having the following structure, potassium carbonate, and (R)-6-oxopiperidin-3-yl 4-methylbenzenesulfonate to produce (S)-5-(2,5-dichloro-4-(5-(8-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)-1,2,4-oxadiazol-3-yl)phenoxy)piperidin-2-one:

4. A method for preparing (S)-5-(2,5-dichloro-4-(5-(8-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)-1,2,4-oxadiazol-3-yl)phenoxy)-1-methylpiperidin-2-one: (1) reacting (R)-5-hydroxypiperidin-2-one and p-toluenesulfonyl chloride to produce (R)-6-oxopiperidin-3-yl 4-methylbenzenesulfonate; (2) reacting A compound of the structure, potassium carbonate and (R)-6-oxopiperidin-3-yl 4-methylbenzenesulfonate are reacted to produce (S)-5-(2,5-dichloro-4-(5-(8-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)-1,2,4-oxadiazol-3-yl)phenoxy)piperidin-2-one: and (3) Reaction with sodium hydride and methyl iodide to produce (S)-5-(2,5-dichloro-4-(5-(8-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl)-1,2,4-oxadiazol-3-yl)phenoxy)-1-methylpiperidin-2-one having the following structure:

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