Alpha V Beta 6 and Alpha V Beta 1 Integrin Inhibitors and Uses Thereof - Patent application

Abstract

Provided are alpha V beta6 and alpha V beta 1 integrin inhibitors, methods of making such alpha V beta6 and alpha V beta 1 integrin inhibitors, pharmaceutical compositions of alpha V beta6 and alpha V beta 1 integrin inhibitors and methods of treating and / or preventing various medical disorders in subjects in need of treatment by administration of alpha V beta6 and alpha V beta 1 integrin inhibitors.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Application No. 63 / 159,063, filed March 10, 2021, which is incorporated herein by reference in its entirety.

[0002] Field Provided herein are αVβ6 and αVβ1 integrin inhibitors, methods for producing such αVβ6 and αVβ1 integrin inhibitors, pharmaceutical compositions of αVβ6 and αVβ1 integrin inhibitors, and methods for treating and / or preventing various medical disorders in subjects in need of treatment by administering αVβ6 and αVβ1 integrin inhibitors. [Background technology]

[0003] background Integrins are α / β heterodimeric transmembrane proteins involved in cell adhesion to a wide range of extracellular matrix proteins, mediating cell-cell interactions, cell migration, cell proliferation, cell survival, and tissue integrity (Barczyk et al., Cell and Tissue Research 2010, 339, 269). Mammals have 24 α / β integrin heterodimers derived from combinations of 18 alpha and 8 beta subunits. Transforming growth factor β (TGFβ) plays a central role in driving several pathological processes, including fibrosis, cell proliferation, and the underlying causes of autoimmune diseases. Alpha V (αV) integrins, including αVβ1, αVβ3, αVβ5, αVβ6, and αVβ8, are involved in the critical pathway leading to the conversion of latent TGFβ to its active form (Henderson, NC; Sheppard, D. Biochim, Biophys. Acta 2013, 1832, 891). Therefore, antagonism of this αV integrin-mediated activation of latent TGFβ provides a viable therapeutic approach to intervene in TGFβ-driven pathological conditions (Sheppard, D. Eur. Resp. Rev. 2008, 17, 157; Goodman, SL; Picard, M. Trends Pharmacol. Sciences 2012, 33(7), 405; Hinz, B., Nature Medicine 2013, 19(12), 1567; Pozzi, A.; Zent, ​​RJ Am. Soc. Nephrol. 2013, 24(7), 1034). All five αV integrins belong to a small subset (8 of 24) of integrins that recognize the arginine-glycine-aspartic acid (RGD) motif present in natural ligands such as fibronectin, vitronectin, and latency-associated peptide (LAP).

[0004] Integrins are expressed on the surface of most human cells. For example, αVβ6 and αVβ1 integrins are expressed at very low levels on epithelial cells in healthy tissues, but are significantly upregulated during inflammation and wound healing. Integrin pathology contributes to a diverse group of human diseases, including, for example, platelet disorders, atherosclerosis, cancer, osteoporosis, fibrosis, renal diabetic neuropathy, macular degeneration, and various autoimmune and chronic inflammatory diseases. Summary of the Invention [Problem to be solved by the invention]

[0005] Thus, although αVβ6 and αVβ1 integrin inhibitors have been extensively tested, therapeutic success has been limited despite significant efforts. Thus, in certain embodiments, there is a need for αVβ6 and αVβ1 integrin inhibitors that are orally deliverable and can treat and / or prevent, for example, platelet disorders, atherosclerosis, cancer, osteoporosis, fibrosis, renal diabetic neuropathy, macular degeneration, and various autoimmune and chronic inflammatory diseases. [Means for solving the problem]

[0006] overview In some embodiments, compounds of formula (I) that meet this and other needs are [ka] [During the ceremony, each R1 is independently hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, arylalkenyl, substituted arylalkenyl, arylalkynyl, substituted arylalkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, cycloheteroalkyl, substituted cycloheteroalkyl, cycloheteroalkenyl or substituted cycloheteroalkenyl, heteroalkyl, substituted heteroalkyl, heteroalkenyl, substituted heteroalkenyl, heteroalkynyl, substituted heteroalkynyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heteroarylalkenyl, substituted heteroarylalkenyl, heteroarylalkynyl, substituted heteroarylalkynyl, halo, -C(O)NR8R9, -C(O)OR 10 , -NR 11 C(O)OR 12 , -NR 13 C(O)OR 14 , -OC(O)OR 15 , -CN, -CF3, -NR 16 SO2R 17 -OR 18 m is 0, 1, 2, or 3; each R2 is independently hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, arylalkenyl, substituted arylalkenyl, arylalkynyl, substituted arylalkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, cycloheteroalkyl, substituted cycloheteroalkyl, cycloheteroalkenyl, substituted cycloheteroalkenyl, heteroalkyl, substituted heteroalkyl, heteroalkenyl, substituted heteroalkenyl, heteroalkynyl, substituted heteroalkynyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heteroarylalkenyl, substituted heteroarylalkenyl, heteroarylalkynyl, substituted heteroarylalkynyl, halo, -C(O)NR 19 R 20, -C(O)OR 21 , -NR 22 C(O)OR 23 , -NR 24 C(O)OR 25 , -OC(O)OR 26 , -CN, -CF3, -NR 27 SO2R 28 -OR 29 n is 0, 1, or 2; each R3 is independently hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, arylalkenyl, substituted arylalkenyl, arylalkynyl, substituted arylalkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, cycloheteroalkyl, substituted cycloheteroalkyl, cycloheteroalkenyl, substituted cycloheteroalkenyl, heteroalkyl, substituted heteroalkyl, heteroalkenyl, substituted heteroalkenyl, heteroalkynyl, substituted heteroalkynyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heteroarylalkenyl, substituted heteroarylalkenyl, heteroarylalkynyl, substituted heteroarylalkynyl, halo, -C(O)NR 30 R 31 , -C(O)OR 32 , -NR 33 C(O)OR 34 , -NR 35 C(O)OR 36 , -OC(O)OR 37 , -CN, -CF3, -NR 38 SO2R 39 -OR 40when q is 1, o is 0, 1, 2, or 3; when q is 2, o is 0, 1, 2, 3, or 4; when q is 3, o is 0, 1, 2, 3, 4, or 5; R4 is hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, arylalkenyl, substituted arylalkenyl, arylalkynyl, substituted arylalkynyl, cycloalkyl, substituted substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, cycloheteroalkyl, substituted cycloheteroalkyl, cycloheteroalkenyl, substituted cycloheteroalkenyl, heteroalkyl, substituted heteroalkyl, heteroalkenyl, substituted heteroalkenyl, heteroalkynyl, substituted heteroalkynyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heteroarylalkenyl, substituted heteroarylalkenyl, heteroarylalkynyl, substituted heteroarylalkynyl, -F, -C(O)NR 41 R 42 , -C(O)R 43 , -C(O)OR 44 , -CN, -CF3, or R4 and R5 together with the atoms to which they are attached form a C4-C8 cycloalkyl ring; E is -CH2- or -CH2Z-; Z is -NR 46 -, -S-, -SO2- or -O-; when E is -CH2-, D is -(CH2)2-, -(CH2)3-, -CH=CHCH2-, -C(O)-, -C≡CCH2-, phenyl, cyclohexyl or cyclopentyl; Z is NR 45 or -O-, then D is -(CH2)2-, -(CH2)3-, -C(O)-, phenyl, cyclohexyl, or cyclopentyl; when Z is -SO2- or -S-, then D is -(CH2)2-, -(CH2)3-, phenyl, cyclohexyl, or cyclopentyl; XY is -C(O)NR 46 -, -NR 47C(O)-, -C(O)O-, -CH2CH2-, -CH=CH-, -C≡C-, -NR 48 CH2-, -CH2NR 49 -, -O-CH2-, -CH2-O-, -SO2NR 50 -, -NR 51 SO2- or cyclopropyl; A is hydrogen, -OR 52 , alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, arylalkenyl, substituted arylalkenyl, arylalkynyl, substituted arylalkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, cycloheteroalkyl, substituted cycloheteroalkyl, cycloheteroalkenyl, substituted cycloheteroalkenyl, heteroalkyl, substituted heteroalkyl, heteroalkenyl, substituted heteroalkenyl, heteroalkynyl, substituted heteroalkynyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heteroarylalkenyl, substituted heteroarylalkenyl, heteroarylalkynyl, substituted heteroarylalkynyl, substituted heteroaryl B is hydrogen, aryl, substituted aryl, arylalkyl, substituted arylalkyl, arylalkenyl, substituted arylalkenyl, arylalkynyl, substituted arylalkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, cycloheteroalkyl, substituted cycloheteroalkyl, cycloheteroalkenyl, substituted cycloheteroalkenyl, heteroalkyl, substituted heteroalkyl, heteroalkenyl, substituted heteroalkenyl, heteroalkynyl, substituted heteroalkynyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heteroarylalkenyl, substituted heteroarylalkenyl, heteroarylalkynyl, substituted heteroarylalkynyl, halo, -NR 53 R 54 , -OR 55 , -SR 56 or -SO2-R 57 and;R8~R 53 and R 58 ~R64 is independently hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, arylalkenyl, substituted arylalkenyl, arylalkynyl, substituted arylalkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, cycloheteroalkyl, substituted cycloheteroalkyl, cycloheteroalkenyl, substituted cycloheteroalkenyl, heteroalkyl, substituted heteroalkyl, heteroalkenyl, substituted heteroalkenyl, heteroalkynyl, substituted heteroalkynyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heteroarylalkenyl, substituted heteroarylalkenyl, heteroarylalkynyl, or substituted heteroarylalkynyl; R 54 is alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, arylalkenyl, substituted arylalkenyl, arylalkynyl, substituted arylalkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, cycloheteroalkyl, substituted cycloheteroalkyl, cycloheteroalkenyl, substituted cycloheteroalkenyl, heteroalkyl, substituted heteroalkyl, heteroalkenyl, substituted heteroalkenyl, heteroalkynyl, substituted heteroalkynyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heteroarylalkenyl, substituted heteroarylalkenyl, heteroarylalkynyl, substituted heteroarylalkynyl, -C(O)R 58 , -C(O)OR 59 , -C(O)NR 60 R 61 or -SO2R 62 and; R 55 ~R 57is alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, arylalkenyl, substituted arylalkenyl, arylalkynyl, substituted arylalkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, cycloheteroalkyl, substituted cycloheteroalkyl, cycloheteroalkenyl, substituted cycloheteroalkenyl, heteroalkyl, substituted heteroalkyl, heteroalkenyl, substituted heteroalkenyl, heteroalkynyl, substituted heteroalkynyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heteroarylalkenyl, substituted heteroarylalkenyl, heteroarylalkynyl, or substituted heteroarylalkynyl; R5 is hydrogen or -F; R6 is hydrogen, -F, or -OR 63 and R7 is hydrogen, -F or -OR 64 where R4 is -C(O)NR 41 R 42 , -C(O)R 43 , -C(O)OR 44 or -CN, then R5 is hydrogen; provided that when B is hydrogen or halo, then A is hydrogen, halo, or -OR 52 except that A is hydrogen, halo, or -OR 52 when B is not hydrogen or halo; provided that B is not halo, -NR 53 R 54 , -OR 55 , -SR 56 or -SO2R 57 R7 is hydrogen when XY is -CH2CH2-, -CH=CH-, -C≡C-, or cyclopropyl, but only when R6 is -OR 63 where R6 is -OR 63 When A is -OR 52 with the proviso that when R6 is -F, then A is not -Cl, -Br, or -I. or a pharmaceutically acceptable salt, hydrate or solvate thereof.

[0007] In other aspects, provided are derivatives, including salts, esters, enol ethers, enol esters, solvates, hydrates, metabolites, and prodrugs, of the compounds of Formula (I) described herein. Also provided are pharmaceutical compositions comprising a compound of Formula (I) provided herein and a pharmaceutically acceptable vehicle.

[0008] Provided herein are methods for treating, preventing, or alleviating symptoms of medical disorders such as platelet disorders, atherosclerosis, cancer, osteoporosis, fibrosis, renal diabetic neuropathy, macular degeneration, and various autoimmune and chronic inflammatory diseases. In practicing the method, a therapeutically effective amount of a compound of formula (I) or a pharmaceutical composition thereof is administered to a patient having the disorder or condition.

[0009] Described herein are methods for inhibiting αVβ6 integrin in a patient. In practicing the method, a therapeutically effective amount of a compound of formula (I) or a pharmaceutical composition thereof is administered to the patient.

[0010] Described herein are methods for inhibiting αVβ1 integrin in a patient. In practicing the method, a therapeutically effective amount of a compound of formula (I) or a pharmaceutical composition thereof is administered to the patient.

[0011] Provided herein is a method for inhibiting TGFβ activation in a cell, in which an effective amount of a compound of formula (I) or a pharmaceutical composition thereof is administered to the cell.

[0012] In some embodiments, compounds of formula (Ia) that meet this and other needs are [ka] {In the formula, q is 1, 2 or 3; R 1 and R 3 are each independently halogen in each occurrence, C 1-4 Alkyl, C 1-4 Haloalkyl, -OR 11 , -SR 11 , -N(R 11)2, -C(O)N(R 11 )2, -C(O)OR 11 , ═O, ═S and —CN; m is selected from 0, 1, 2, 3, 4, 5 and 6; o is selected from 0, 1, 2, 3, 4, 5, 6, 7 and 8; R 2 are independently halogen in each occurrence, C 1-4 Alkyl, C 1-4 Haloalkyl, -OR 12 , -SR 12 , -N(R 12 )2, -CN and -NO2; n is 0, 1 or 2; R 4 and R 5 are each independently hydrogen, halogen, or C 1-4 Alkyl, C 1-4 Haloalkyl, -OR 13 , -SR 13 , -N(R 13 )2 and -CN; or R 4 and R 5 Together, =O, =S and =N(R 13 ) forming a double bond substituent selected from; D is selected from a bond, —C(O)—, —C≡CCH2—, and —CH═CHCH2—; E is C 1-4 selected from alkylene and —(CH)Z—; wherein Z is selected from -NH-, -S-, -SO2-, and -O-; XY is λ -C(O)N(R 14 )-, λ -N(R 14 )C(O)-, λ -N(R 14 )C(O)C(R 15 )2-, λ -C(O)O-, λ -C(R 15 )2C(R 15 )2-, λ -CH=CH-, λ -C≡C-, λ -N(R14 )C(R 15 )2-, λ -C(R 15 )2N(R 14 )-, λ -O-, λ -OC(R 15 )2-, λ -C(R 15 )2O-, λ -SO2N(R 14 )-and λ -N(R 14 )SO2-; where: λ is from XY [ka] means bonding to; R 6 and R 7 are each independently hydrogen, halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, -OR 16 and -CN; A is (i) and (ii): (i) Hydrogen, halogen and -CN or A and R 6 C 3-6 Forms a carbocyclic or 3- to 6-membered heterocyclic ring; (ii)-OR 17 , -SR 17 , -N(R 17 )2, -N(R 17 )C(O)R 17 , -N(R 17 )C(O)OR 17 , -N(R 17 )C(O)N(R 17 )2, -N(R 17 )C(S)N(R 17 )2, -N(R 17 )S(O)2(R 17 ), -C(O)R 17 , -C(O)OR 17 , -OC(O)R 17 , -OC(O)N(R 17 )2, -C(O)N(R 17 )2, -S(O)R17 , -S(O)2R 17 and -S(O)N(R 17 )2; C 1-6 Alkyl (optionally Halogen, -OR 17 , -SR 17 , -N(R 17 )2, -C(O)R 17 , -C(O)OR 17 , -OC(O)R 17 , -OC(O)N(R 17 )2, -C(O)N(R 17 )2, -N(R 17 )C(O)R 17 , -N(R 17 )C(O)OR 17 , -N(R 17 )C(O)N(R 17 )2, -N(R 17 )C(S)N(R 17 )2, -N(R 17 )S(O)2(R 17 ), -S(O)R 17 , -S(O)2R 17 , -S(O)2N(R 17 )2, -NO2, =O, =S, =N(R 17 ), -N3 and -CN, C 3-10 Carbocyclic and 3- to 10-membered heterocyclic rings and is substituted with one or more substituents independently selected from where C 3-10 The carbocyclic ring and the 3- to 10-membered heterocyclic ring each optionally contain halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR 17 , -SR 17 , -N(R 17 )2, -C(O)R 17 , -C(O)OR 17 , -OC(O)R 17 , -OC(O)N(R 17 )2, -C(O)N(R 17 )2, -N(R 17 )C(O)R 17 , -N(R 17 )C(O)OR 17 , -N(R17 )C(O)N(R 17 )2, -N(R 17 )C(S)N(R 17 )2, -N(R 17 )S(O)2(R 17 ), -S(O)R 17 , -S(O)2R 17 , -S(O)2N(R 17 )2, -NO2, =O, =S, =N(R 17 ), -N3 and -CN; and C 3-12 Carbocyclic rings and 3- to 12-membered heterocyclic rings (both optionally: Halogen, -OR 17 , -SR 17 , -N(R 17 )2, -C(O)R 17 , -C(O)OR 17 , -OC(O)R 17 , -OC(O)N(R 17 ) 2、 -C(O)N(R 17 )2, -N(R 17 )C(O)R 17 , -N(R 17 )C(O)OR 17 , -N(R 17 )C(O)N(R 17 )2, -N(R 17 )C(S)N(R 17 )2, -N(R 17 )S(O)2(R 17 ), -S(O)R 17 , -S(O)2R 17 , -S(O)2N(R 17 )2, -NO2, =O, =S, =N(R 17 ), -N3 and -CN; Possibly halogen, -OR 17 , -SR 17 , -N(R 17 )2, -C(O)R 17 , -C(O)OR 17 , -OC(O)R 17 , -OC(O)N(R 17 ) 2、 -C(O)N(R 17)2, -N(R 17 )C(O)R 17 , -N(R 17 )C(O)OR 17 , -N(R 17 )C(O)N(R 17 )2, -N(R 17 )C(S)N(R 17 )2, -N(R 17 )S(O)2(R 17 ), -S(O)R 17 , -S(O)2R 17 , -S(O)2N(R 17 )2, -NO2, =O, =S, =N(R 17 ), -N3 and -CN, and C substituted with one or more substituents independently selected from 1-6 alkyl; and Both may contain halogen, C 1-4 Alkyl, C 1-4 C substituted with one or more substituents independently selected from haloalkyl and =O 3-10 Carbocyclic and 3- to 10-membered heterocyclic rings and substituted with one or more substituents independently selected from Selected from; When A is selected from (ii), B is selected from (I); or When A is selected from (i), B is selected from (II): (I) Hydrogen, halogen and -CN or B and R 7 C 3-6 Forms a carbocyclic or 3- to 6-membered heterocyclic ring; (II)-OR 18 , -SR 18 , -N(R 18 )2, -C(O)R 18 , -C(O)OR 18 , -OC(O)R 18 , -OC(O)N(R 18 )2, -C(O)N(R 18 )2, -N(R 18 )C(O)R 18 , -N(R 18 )C(O)OR 18 , -N(R 18 )C(O)N(R18 )2, -N(R 18 )C(S)N(R 18 )2, -N(R 18 )S(O)2(R 18 ), -S(O)R 18 , -S(O)2R 18 and -S(O)N(R 18 )2; C 1-6 Alkyl (optionally: Halogen, -OR 18 , -SR 18 , -N(R 18 )2, -C(O)R 18 , -C(O)OR 18 , -OC(O)R 18 , -OC(O)N(R 18 )2, -C(O)N(R 18 )2, -N(R 18 )C(O)R 18 , -N(R 18 )C(O)OR 18 , -N(R 18 )C(O)N(R 18 )2, -N(R 18 )C(S)N(R 18 )2, -N(R 18 )S(O)2(R 18 ), -S(O)R 18 , -S(O)2R 18 , -S(O)2N(R 18 )2, -NO2, =O, =S, =N(R 18 ), -N3, -CN, C 3-10 substituted with one or more substituents independently selected from a carbocycle and a 3- to 10-membered heterocycle; where C 3-10 Carbocyclic rings and 3- to 10-membered heterocyclic rings may optionally contain halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR 18 , -SR 18 , -N(R 18 )2, -C(O)R 18 , -C(O)OR 18 , -OC(O)R 18 , -OC(O)N(R 18 )2, -C(O)N(R 18)2, -N(R 18 )C(O)R 18 , -N(R 18 )C(O)OR 18 , -N(R 18 )C(O)N(R 18 )2, -N(R 18 )C(S)N(R 18 )2, -N(R 18 )S(O)2(R 18 ), -S(O)R 18 , -S(O)2R 18 , -S(O)2N(R 18 )2, -NO2, =O, =S, =N(R 18 ), -N3 and -CN; and C 3-12 Carbocyclic rings and 3- to 12-membered heterocyclic rings (each optionally: Halogen, -OR 18 , -SR 18 , -N(R 18 )2, -C(O)R 18 , -C(O)OR 18 , -OC(O)R 18 , -OC(O)N(R 18 )2, -C(O)N(R 18 )2, -N(R 18 )C(O)R 18 , -N(R 18 )C(O)OR 18 , -N(R 18 )C(O)N(R 18 )2, -N(R 18 )C(S)N(R 18 )2, -N(R 18 )S(O)2(R 18 ), -S(O)R 18 , -S(O)2R 18 , -S(O)2N(R 18 )2, -NO2, =O, =S, =N(R 18 ), -N3 and -CN; C 1-6 Alkyl (optionally: Halogen, -OR 18 , -SR 18 , -N(R 18 )2, -C(O)R 18, -C(O)OR 18 , -OC(O)R 18 , -OC(O)N(R 18 )2, -C(O)N(R 18 )2, -N(R 18 )C(O)R 18 , -N(R 18 )C(O)OR 18 , -N(R 18 )C(O)N(R 18 )2, -N(R 18 )C(S)N(R 18 )2, -N(R 18 )S(O)2(R 18 ), -S(O)R 18 , -S(O)2R 18 , -S(O)2N(R 18 )2, -NO2, =O, =S, =N(R 18 ), -N3, -CN, C 3-6 Carbocyclic and 3- to 6-membered heterocyclic rings and is substituted with one or more substituents independently selected from where C 3-6 The carbocyclic ring and the 3- to 6-membered heterocyclic ring each optionally contain halogen, C 1-4 Alkyl, C 1-4 substituted with one or more substituents independently selected from haloalkyl and ═O); and Both may contain halogen, C 1-4 Alkyl, C 1-4 C substituted with one or more substituents independently selected from haloalkyl and =O 3-10 Carbocyclic and 3- to 10-membered heterocyclic rings and substituted with one or more substituents independently selected from: R 11 , R 12 , R 13 , R 14 and R 16 are each independently hydrogen in each occurrence, C 1-4 Alkyl and C 1-4 haloalkyl; R 15 are independently hydrogen, halogen, C 1-4 Alkyl and C 1-4 haloalkyl; R 17 Independently in each case: hydrogen; Possibly halogen, -OR 21 , -SR 21 , -N(R 21 )2, -C(O)R 21 , -C(O)OR 21 , -OC(O)R 21 , -OC(O)N(R 21 )2, -C(O)N(R 21 )2, -N(R 21 )C(O)R 21 , -NO2, =O, =S, =N(R 21 ), -N3 and -CN, and C substituted with one or more substituents independently selected from 1-6 alkyl; and Both may contain halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, -OR 21 , -SR 21 , -N(R 21 )2, -C(O)R 21 , -C(O)OR 21 , -OC(O)R 21 , -OC(O)N(R 21 )2, -C(O)N(R 21 )2, -N(R 21 )C(O)R 21 , -N(R 21 )C(O)OR 21 , -N(R 21 )C(O)N(R 21 )2, -N(R 21 )C(S)N(R 21 )2, -N(R 21 )S(O)2(R 21 ), -S(O)R 21 , -S(O)2R 21 , -S(O)2N(R 21 )2, -NO2, =O, =S, =N(R 21 ), -N3 and -CN, and C substituted with one or more substituents independently selected from 3-6 Carbocyclic and 3- to 6-membered heterocyclic rings Selected from; R 18Independently in each case: hydrogen; C 1-6 Alkyl (optionally Halogen, -OR 22 , -SR 22 , -N(R 22 )2, -C(O)R 22 , -C(O)OR 22 , -OC(O)R 22 , -OC(O)N(R 22 )2, -C(O)N(R 22 )2, -N(R 22 )C(O)R 22 , -NO2, =O, =S, =N(R 22 ), -N3, -CN, C 3-10 Carbocyclic and 3- to 10-membered heterocyclic rings and is substituted with one or more substituents independently selected from where C 3-10 The carbocyclic ring and the 3- to 10-membered heterocyclic ring each optionally contain halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR 22 , -SR 22 and -N(R 22 ) substituted with one or more substituents independently selected from 2); and C 3-10 Carbocycles and 3- to 10-membered heterocycles (both optionally: Halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR 22 , -SR 22 , -N(R 22 )2, -C(O)R 22 , -C(O)OR 22 , -OC(O)R 22 , -OC(O)N(R 22 )2, -C(O)N(R 22 )2, -N(R 22 )C(O)R 22 , -N(R 22 )C(O)OR 22 , -N(R 22 )C(O)N(R 22 )2, -N(R 22 )C(S)N(R 22)2, -N(R 22 )S(O)2(R 22 ), -S(O)R 22 , -S(O)2R 22 , -S(O)2N(R 22 )2, -NO2, =O, =S, =N(R 22 ), -N3, -CN, C 3-6 Carbocyclic and 3- to 6-membered heterocyclic rings and is substituted with one or more substituents independently selected from: where C 3-6 The carbocyclic ring and the 3- to 6-membered heterocyclic ring each optionally contain halogen, C 1-4 Alkyl and C 1-4 substituted with one or more substituents independently selected from haloalkyl Selected from; R 21 and R 22 are each independently in each case: hydrogen; Optionally halogen, hydroxyl, C 3-6 C substituted with one or more substituents independently selected from carbocycles and 3- to 6-membered heterocycles 1-4 Alkyl (wherein each C 3-6 Carbocyclic and 3- to 6-membered heterocyclic rings are optionally C 1-4 Alkyl, -N(R 23 )2 and -C(O)N(R 23 ) substituted with one or more substituents independently selected from 2); and Both may contain halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 C substituted with one or more substituents independently selected from alkoxy and =O 3-6 Carbocyclic and 3- to 12-membered heterocyclic rings is selected from; and R 23 are independently hydrogen and C in each case 1-4 alkyl.} or a pharmaceutically acceptable salt thereof.

[0013] In one embodiment, the present invention provides a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound or salt of Formula (Ia).

[0014] In certain aspects, the present invention provides a method of modulating alpha V integrin in a subject in need thereof, comprising administering to the subject a compound or salt of Formula (Ia) or a pharmaceutical composition of Formula (Ia).

[0015] In certain embodiments, the alpha V integrin is alpha V beta 1 integrin.

[0016] In certain embodiments, the alpha V integrin is alpha V beta 6 integrin.

[0017] In certain embodiments, the present invention provides a method of treating a disease or condition, comprising administering to a subject in need thereof a compound or salt of Formula (Ia) or a pharmaceutical composition comprising a compound or salt of Formula (Ia).

[0018] In certain embodiments, the disease or condition is selected from idiopathic pulmonary fibrosis, systemic lupus erythematosus-associated interstitial lung disease, rheumatoid arthritis, diabetic nephropathy, focal segmental glomerulosclerosis, chronic kidney disease, nonalcoholic steatohepatitis, primary biliary cirrhosis, primary sclerosing cholangitis, solid tumors, hematologic malignancies, organ transplantation, Alport syndrome, interstitial lung disease, radiation-induced fibrosis, bleomycin-induced fibrosis, asbestos-induced fibrosis, influenza-induced fibrosis, coagulation-induced fibrosis, vascular injury-induced fibrosis, aortic stenosis, and cardiac fibrosis. [Brief explanation of the drawings]

[0019] [Figure 1] Scheme 1 showing the synthesis of intermediate 10 is shown.

[0020] [Figure 2] Scheme 2 is shown illustrating the synthesis of compounds of formula (VII).

[0021] [Figure 3] Scheme 4 is shown showing another synthesis of compounds of formula (VII).

[0022] [Figure 4] Scheme 6 is shown illustrating the synthesis of compounds of formula (VIII).

[0023] [Figure 5] Scheme 10 is shown showing another synthesis of compounds of formula (VIII).

[0024] [Figure 6] Scheme 12 is shown illustrating the synthesis of amides and sulfonamides of formula (VIII).

[0025] [Figure 7] Scheme 14 is shown illustrating the synthesis of compounds where the central piperidine ring is substituted and / or where ED is not propyl. DETAILED DESCRIPTION OF THE INVENTION

[0026] Incorporation by Citation 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.

[0027] Detailed Description of the Invention definition Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. In the event that there are multiple definitions for a term, those in this section prevail unless stated otherwise.

[0028] As used herein and unless otherwise specified, the terms "about" and "approximately," when used in connection with a numerical value or numerical range characteristic, indicate that the value or numerical range may deviate to an extent that would be considered reasonable by one of ordinary skill in the art while still describing the particular property. Specifically, the terms "about" and "approximately," when used in this context, indicate that the numerical value or numerical range may vary by 5%, 4%, 3%, 2%, 1%, 0.9%, 0.8%, 0.7%, 0.6%, 0.5%, 0.4%, 0.3%, 0.2%, or 0.1% from the stated value or numerical range.

[0029] "Alkyl" by itself or as part of another substituent refers to a saturated, branched, or straight-chain monovalent hydrocarbon radical derived by the removal of one hydrogen atom from a single carbon atom of a parent alkane. Typical alkyl groups include, but are not limited to, methyl; ethyl; propyl, such as propan-1-yl, propan-2-yl; butyl, such as butan-1-yl, butan-2-yl, 2-methyl-propan-1-yl, 2-methyl-propan-2-yl; and the like. In certain embodiments, an alkyl group is an alkyl group having 1 to 20 carbon atoms (C1-C6). 20 In other embodiments, an alkyl group contains 1 to 10 carbon atoms (C-C 10 In yet other embodiments, the alkyl group contains 1 to 6 carbon atoms (C1-C6 alkyl).

[0030] "Alkenyl" by itself or as part of another substituent refers to a branched or straight-chain alkyl group having at least one carbon-carbon double bond. The radical is derived from the removal of a hydrogen atom from a single carbon atom of a parent alkene. The group may be in either the cis or trans conformation about the double bond. Typical alkenyl groups include, but are not limited to, ethenyl; propenyl such as prop-1-en-1-yl, prop-1-en-2-yl, prop-2-en-1-yl (allyl), prop-2-en-2-yl, cycloprop-1-en-1-yl; cycloprop-2-en-1-yl; butenyl such as but-1-en-1-yl, but-1-en-2-yl, 2-methyl-prop-1-en-1-yl, but-2-en-1-yl, but-2-en-1-yl, but-2-en-2-yl, but-1,3-dien-1-yl, buta-1,3-dien-2-yl, cyclobut-1-en-1-yl, cyclobut-1-en-3-yl, cyclobuta-1,3-dien-1-yl; and the like. In some embodiments, an alkenyl group has 1 to 20 carbon atoms (C-C 20 In other embodiments, an alkenyl group contains 1 to 10 carbon atoms (C-C 10 In yet other embodiments, the alkenyl group contains 1 to 6 carbon atoms (C1-C6 alkenyl).

[0031] "Alkynyl" by itself or as part of another substituent refers to a branched or straight-chain alkyl group having at least one carbon-carbon triple bond. The radical is derived from the removal of one hydrogen atom from a single carbon atom of a parent alkyne. Typical alkynyl groups include, but are not limited to, ethynyl; propynyl, such as prop-1-yn-1-yl, prop-2-yn-1-yl; butynyl, such as but-1-yn-1-yl, but-1-yn-3-yl, but-3-yn-1-yl; and the like. In certain embodiments, an alkynyl group is an alkyl group having 1 to 20 carbon atoms (C1-C6). 20 In other embodiments, an alkynyl group contains 1 to 10 carbon atoms (C-C 10In still other embodiments, the alkynyl group contains 1 to 6 carbon atoms (C1-C6 alkynyl).

[0032] "Aryl," by itself or as part of another substituent, refers to a monovalent aromatic hydrocarbon radical derived by the removal of one hydrogen atom from a single carbon atom of a parent aromatic ring system, as defined herein. Typical aryl groups include, but are not limited to, radicals derived from aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, coronene, fluoranthene, fluorene, hexacene, hexaphene, hexalene, as-indacene, s-indacene, indane, indene, naphthalene, octacene, octaphene, octalene, ovalene, penta-2,4-diene, pentacene, pentalene, pentaphene, perylene, phenalene, phenanthrene, picene, pleiadene, pyrene, pyranthrene, rubicene, triphenylene, trinaphthalene, and the like. In certain embodiments, an aryl group is an aryl group having 6 to 20 carbon atoms (C6-C6). 20 In other embodiments, the aryl group contains 6 to 15 carbon atoms (C-C 15 In yet other embodiments, the aryl group contains 6 to 10 carbon atoms (C-C 10 aryl).

[0033] "Arylalkyl" by itself or as part of another substituent means an alkyl group having a carbon atom, typically a terminal or sp 3 This refers to an acyclic alkyl group in which one of the hydrogen atoms bonded to a carbon atom is replaced with an aryl group, as described herein. Exemplary arylalkyl groups include, but are not limited to, benzyl, 2-phenylethan-1-yl, 2-phenylethen-1-yl, naphthylmethyl, 2-naphthylethan-1-yl, 2-naphthylethene-1-yl, naphthobenzyl, 2-naphthophenylethan-1-yl, and the like. In some embodiments, an arylalkyl group is (C6-C 30 ) arylalkyl, e.g., the alkyl portion of the arylalkyl group is (C1-C 10 ) alkyl, and the aryl moiety is (C6-C20 In other embodiments, the arylalkyl group is (C-C 20 ) arylalkyl, e.g., the alkyl portion of the arylalkyl group is (C1-C8) alkyl and the aryl portion is (C6-C 12 In yet another embodiment, the arylalkyl group is (C-C 15 ) arylalkyl, e.g., the alkyl portion of the arylalkyl group is (C1-C5) alkyl and the aryl portion is (C6-C 10 ) aryl.

[0034] "Arylalkenyl" by itself or as part of another substituent refers to an acyclic alkenyl group in which one of the hydrogen atoms bonded to a carbon atom is replaced with an aryl group, as defined herein. In certain embodiments, an arylalkenyl group is (C-C 30 ) arylalkenyl, for example, the alkenyl portion of the arylalkenyl group is (C1-C 10 ) alkenyl, and the aryl moiety is (C6-C 20 In other embodiments, the arylalkenyl group is (C-C 20 ) arylalkenyl, for example, the alkenyl portion of the arylalkenyl group is (C1-C8) alkenyl and the aryl portion is (C6-C 12 In yet other embodiments, the arylalkenyl group is (C-C 15 ) arylalkenyl, for example, the alkenyl portion of the arylalkenyl group is (C1-C5) alkenyl and the aryl portion is (C6-C 10 ) aryl.

[0035] "Arylalkynyl" by itself or as part of another substituent refers to an acyclic alkynyl group in which one of the hydrogen atoms bonded to a carbon atom is replaced with an aryl group, as defined herein. In certain embodiments, an arylalkynyl group is a (C-C 30 ) arylalkynyl, for example, the alkynyl portion of the arylalkynyl group is (C1-C 10) alkynyl, and the aryl moiety is (C6-C 20 In other embodiments, the arylalkynyl group is (C-C 20 ) arylalkynyl, for example, the alkynyl portion of the arylalkynyl group is (C1-C8) alkynyl and the aryl portion is (C6-C 12 In yet other embodiments, the arylalkynyl group is (C-C 15 ) arylalkynyl, for example, the alkynyl portion of the arylalkynyl group is (C1-C5) alkynyl and the aryl portion is (C6-C 10 ) aryl.

[0036] As used herein, "carbocycle" refers to a saturated, unsaturated, or aromatic ring in which each atom of the ring is carbon. Carbocycles include 3- to 10-membered monocyclic rings and 6- to 12-membered bicyclic rings. Each ring of a bicyclic carbocycle can be selected from saturated, unsaturated, and aromatic rings. A bicyclic carbocycle can be a fused, bridged, or spiro ring system. In some embodiments, a carbocycle is an aryl. In some embodiments, a carbocycle is a cycloalkyl. In some embodiments, a carbocycle is a cycloalkenyl. In exemplary embodiments, an aromatic ring, such as phenyl, can be fused to a saturated or unsaturated ring, such as cyclohexane, cyclopentane, or cyclohexene. Any combination of saturated, unsaturated, and aromatic bicyclic rings, as permitted by valence, is included in the definition of carbocycle. Examples of carbocycles include cyclopentyl, cyclohexyl, cyclohexenyl, adamantyl, phenyl, indanyl, and naphthyl. Carbocycles may be optionally substituted with one or more substituents such as those described herein.

[0037] "Cycloalkyl" by itself or as part of another substituent refers to a saturated cyclic monovalent hydrocarbon radical derived from the removal of one hydrogen atom from a single carbon atom of a parent cycloalkane. Exemplary cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, and the like. In certain embodiments, cycloalkyl groups have from 3 to 15 carbon atoms (C3-C4). 15In other embodiments, the cycloalkyl group contains 3 to 10 carbon atoms (C-C 10 In yet other embodiments, cycloalkyl groups contain 3 to 8 carbon atoms (C3-C8 cycloalkyl). The term "cycloalkyl" also includes single radicals and polycyclic hydrocarbon ring systems having 5 to 15 carbon atoms. Examples of polycyclic cycloalkyl rings include bridged, fused, and spirocycloalkyl ring systems, including, for example, norbornyl, vinyl, and adamantyl.

[0038] "Cycloalkenyl" by itself or as part of another substituent refers to an unsaturated cyclic monovalent hydrocarbon radical derived from the removal of one hydrogen atom from a single carbon atom of a parent cycloalkene. Exemplary cycloalkenyl groups include, but are not limited to, cyclopropene, cyclobutene, cyclopentene, and the like. In certain embodiments, a cycloalkenyl group has from 3 to 15 carbon atoms (C3-C4). 15 In other embodiments, a cycloalkenyl group contains 3 to 10 carbon atoms (C-C 10 In yet other embodiments, cycloalkenyl groups contain 3 to 8 carbon atoms (C3-C8 cycloalkenyl). The term "cycloalkenyl" also includes single radical and multicyclic hydrocarbon ring systems having 5 to 15 carbon atoms and alkenyl groups.

[0039] "Cycloheteroalkyl," by itself or as part of another substituent, refers to a cycloalkyl group in which one or more of the carbon atoms (and optionally any associated hydrogen atoms) are each, independently of one another, replaced with the same or different heteroatoms or heteroatom groups defined below under "heteroalkyl." In certain embodiments, a cycloheteroalkyl group is a group of 3 to 15 carbon atoms (C3-C6). 15 In other embodiments, the cycloheteroalkyl group contains 3 to 10 carbon atoms (C-C 10In yet other embodiments, the cycloheteroalkyl group contains 3 to 8 carbon atoms (C3-C8 cycloheteroalkyl). The term "cycloheteroalkyl" also includes polycyclic hydrocarbon ring systems having a single radical and at least one heteroatom, having 5 to 15 carbon atoms.

[0040] "Cycloheteroalkenyl," by itself or as part of another substituent, refers to a cycloalkenyl group in which one or more of the carbon atoms (and optionally any associated hydrogen atoms) are each, independently of one another, replaced with the same or different heteroatoms or heteroatom groups defined below under "heteroalkenyl." In certain embodiments, a cycloheteroalkenyl group is a cycloheteroalkenyl group having 3 to 15 carbon atoms (C3-C4). 15 In other embodiments, the cycloheteroalkyl group contains 3 to 10 carbon atoms (C-C 10 In yet other embodiments, the cycloheteroalkyl group contains 3 to 8 carbon atoms (C3-C8 cycloheteroalkenyl). The term "cycloheteroalkenyl" also includes polycyclic hydrocarbon ring systems having a single radical and at least one heteroatom and one alkenyl group, having 5 to 15 carbon atoms.

[0041] "Compound" refers to a compound contained within the structural formulae disclosed herein, including any specific compounds within those formulae whose structures are specifically disclosed herein. Compounds are identified by their chemical structure and / or chemical name. The compounds described herein may contain one or more chiral centers and / or double bonds and, therefore, may exist as stereoisomers, such as double bond isomers (i.e., geometric isomers), enantiomers, or diastereomers. Thus, the chemical structures described herein include stereomerically pure forms (e.g., geometrically pure, enantiomerically pure, or diastereomerically pure) depicted in the structure. The chemical structures described herein also include enantiomeric and stereoisomeric derivatives of the depicted compounds. Enantiomeric and stereoisomeric mixtures can be resolved into the component enantiomers or stereoisomers using separation or chiral synthesis techniques well known to those skilled in the art. Compounds may also exist in several tautomeric forms, including enol forms, keto forms, and mixtures thereof. Thus, the chemical structures described herein encompass all possible tautomeric forms of the depicted compounds. The compounds described include isotopically labeled compounds where one or more atoms have an atomic mass different from the atomic mass conventionally found in nature. Examples of isotopes that can be incorporated into compounds disclosed herein include: 2 H, 3 H, 11 C. 13 C. 14 C. 15 N, 18 O. 17 Compounds may exist in unsolvated and solvated forms, including hydrated forms. In general, compounds may be hydrated or solvated. A compound may exist in multiple crystalline or amorphous forms. In general, all physical forms are equivalent for the uses contemplated herein and are intended to be within the scope of the present invention. Furthermore, when a substructure of a compound is described, a wavy line should be understood to indicate the point of attachment of the substructure to the remainder of the molecule.

[0042] "Halo" by itself or as part of another substituent refers to the radicals -F, -Cl, -Br, or -I.

[0043] "Heteroalkyl" by itself or as part of another substituent refers to an alkyl group in which one or more of the carbon atoms (and optionally any associated hydrogen atoms) are each, independently of one another, replaced with the same or different heteroatoms or heteroatomic groups. Typical heteroatoms or heteroatomic groups that can replace a carbon atom include, but are not limited to, -O-, -S-, -N-, -Si-, -NH-, -S(O)-, -S(O)2-, -S(O)NH-, -S(O)2NH-, and the like, and combinations thereof. The heteroatom or heteroatomic group can be located at any interior position of the alkyl group. Typical heteroatom groups that can be included in these groups include -O-, -S-, -OO-, -SS-, -OS-, -NR 501 R 502 , =NN=, -N=N-, -N=N-NR 503 R 504 , -PR 505 -, -P(O)2-, -POR 506 -, -OP(O)2-, -SO-, -SO2-, -SnR 507 R 508 Including, but not limited to, R 501 , R 502 , R 503 , R 504 , R 505 , R 506 , R 507 and R 508 is independently hydrogen, alkyl, alkenyl, alkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl, or heteroarylalkynyl and substituted counterparts thereof.

[0044] "Heteroalkenyl" refers to an alkenyl group in which one or more of the carbon atoms (and optionally any associated hydrogen atoms) are each, independently of one another, replaced with the same or different heteroatoms or heteroatomic groups. Typical heteroatoms or heteroatomic groups that can replace a carbon atom include, but are not limited to, -O-, -S-, -N-, -Si-, -NH-, -S(O)-, -S(O)2-, -S(O)NH-, -S(O)2NH-, etc., and combinations thereof. The heteroatom or heteroatomic group can be located at any interior position of the alkenyl group. Typical heteroatom groups that can be included in these groups include -O-, -S-, -OO-, -SS-, -OS-, -NR 509 R 510 , =NN=, -N=N-, -N=N-NR 511 R 512 , -PR 514 -, -P(O)2-, -POR 514 -, -OP(O)2-, -SO-, -SO2-, -SnR 515 R 516 Including, but not limited to, R 509 , R 510 , R 511 , R 512 , R 513 , R 514 , R 515 and R 516 is independently hydrogen, alkyl, aryl, substituted aryl, heteroalkyl, heteroaryl, or substituted heteroaryl.

[0045] "Heteroalkynyl" by itself or as part of another substituent refers to an alkynyl group in which one or more of the carbon atoms (and optionally any associated hydrogen atoms) are each, independently of one another, replaced with the same or different heteroatoms or heteroatomic groups. Typical heteroatoms or heteroatomic groups that can replace a carbon atom include, but are not limited to, -O-, -S-, -N-, -Si-, -NH-, -S(O)-, -S(O)2-, -S(O)NH-, -S(O)2NH-, and the like, and combinations thereof. The heteroatom or heteroatomic group can be located at any interior position of the alkynyl group. Typical heteroatom groups that can be included in these groups include -O-, -S-, -OO-, -SS-, -OS-, -NR 517 R 518 , =NN=, -N=N-, -N=N-NR 519 R 520 , -PR 521 -, -P(O)2-, -POR 52 2 -, -OP(O)2-, -SO-, -SO2-, -SnR 523 R 524 Including, but not limited to, R 517 , R 518 , R 519 , R 520 , R 521 , R 522 , R 523 and R 524 is independently hydrogen, alkyl, aryl, substituted aryl, heteroalkyl, heteroaryl, or substituted heteroaryl.

[0046] "Heteroaryl" by itself or as part of another substituent refers to a monovalent heteroaromatic radical derived from the removal of one hydrogen atom from a single atom of a parent heteroaromatic ring system, as defined above. Typical heteroaryl groups include, but are not limited to, groups derived from acridine, β-carboline, chromane, chromene, cinnoline, furan, imidazole, indazole, indole, indoline, indolizine, isobenzofuran, isochromene, isoindole, isoindoline, isoquinoline, isothiazole, isoxazole, naphthyridine, oxadiazole, oxazole, perimidine, phenanthridine, phenanthroline, phenazine, phthalazine, pteridine, purine, pyran, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole, pyrrolidine, quinazoline, quinoline, quinolizine, quinoxaline, tetrazole, thiadiazole, thiazole, thiophene, triazole, xanthene, and the like. In some embodiments, heteroaryl groups contain 5 to 20 ring atoms (5-20 membered heteroaryl). In other embodiments, heteroaryl groups contain 5 to 10 ring atoms (5-10 membered heteroaryl). Exemplary heteroaryl groups include those derived from furan, thiophene, pyrrole, benzothiophene, benzofuran, benzimidazole, indole, pyridine, pyrazole, quinoline, imidazole, oxazole, isoxazole, and pyrazine.

[0047] "Heteroarylalkyl" by itself or as part of another substituent means an alkyl group containing a carbon atom, typically a terminal or sp 3 "Heteroarylalkyl" refers to an acyclic alkyl group in which one of the hydrogen atoms bonded to a carbon atom is replaced with a heteroaryl group. In some embodiments, the heteroarylalkyl group is a 6- to 21-membered heteroarylalkyl, e.g., the alkyl portion of the heteroarylalkyl is (C1-C6) alkyl and the heteroaryl portion is a 5- to 15-membered heteroaryl. In other embodiments, the heteroarylalkyl group is a 6- to 13-membered heteroarylalkyl, e.g., the heteroalkyl portion is (C1-C3) alkyl and the heteroaryl portion is a 5- to 10-membered heteroaryl.

[0048] "Heteroarylalkenyl" by itself or as part of another substituent refers to an acyclic alkenyl group in which one of the hydrogen atoms bonded to a carbon atom is replaced with a heteroaryl group. In certain embodiments, the heteroarylalkenyl group is a 5- to 21-membered heteroarylalkenyl, e.g., the alkenyl moiety of the heteroarylalkenyl is a (C2-C6)alkenyl and the heteroaryl moiety is a 3- to 15-membered heteroaryl. In other embodiments, the heteroarylalkenyl is a 6- to 13-membered heteroarylalkenyl, e.g., the alkenyl moiety is a (C3)alkenyl and the heteroaryl moiety is a 3- to 10-membered heteroaryl.

[0049] "Heteroarylalkynyl" by itself or as part of another substituent refers to an acyclic alkynyl group in which one of the hydrogen atoms bonded to a carbon atom is replaced with a heteroaryl group. In certain embodiments, the heteroarylalkynyl group is a 5- to 21-membered heteroarylalkynyl, e.g., the alkynyl moiety of the heteroarylalkynyl is (C2-C6)alkynyl and the heteroaryl moiety is a 3- to 15-membered heteroaryl. In other embodiments, the heteroarylalkynyl is a 6- to 13-membered heteroarylalkynyl, e.g., the alkynyl moiety is (C3)alkynyl and the heteroaryl moiety is a 3- to 10-membered heteroaryl.

[0050] As used herein, a "heterocycle" refers to a saturated, unsaturated, non-aromatic, or aromatic ring containing one or more heteroatoms. Heteroatoms include N, O, Si, P, B, and S atoms. Examples of heterocycles include 3- to 10-membered monocyclic rings and 6- to 12-membered bicyclic rings. Each ring of a bicyclic heterocycle can be selected from saturated, unsaturated, and aromatic rings. In certain embodiments, a heterocycle contains at least one heteroatom selected from oxygen, nitrogen, sulfur, or any combination thereof. In certain embodiments, a heterocycle contains at least one heteroatom selected from oxygen, nitrogen, or any combination thereof. In certain embodiments, a heterocycle contains at least one heteroatom selected from oxygen, sulfur, or any combination thereof. In certain embodiments, a heterocycle contains at least one heteroatom selected from nitrogen, sulfur, or any combination thereof. A heterocycle can be attached to the remainder of the molecule through any atom of the heterocycle, as allowed by valence, such as a carbon or nitrogen atom of the heterocycle. In certain embodiments, a heterocycle is heteroaryl. In certain embodiments, a heterocycle is heterocycloalkyl. Examples of heterocycles include pyrrolidinyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, piperidinyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, thiophenyl, oxazolyl, thiazolyl, morpholinyl, indazolyl, indolyl, and quinolinyl. Bicyclic heterocycles can be fused, bridged, or spiro ring systems. In exemplary embodiments, heterocycles, such as pyridyl, can be fused to saturated or unsaturated rings, such as cyclohexane, cyclopentane, or cyclohexene. Heterocycles can be optionally substituted with one or more substituents, such as those described herein.

[0051] "Hydrate" refers to the incorporation of water into the crystal lattice of a compound described herein in a stoichiometric ratio, resulting in the formation of an adduct. Hydrated forms of the compounds described herein are also considered to be disclosed herein. Methods for producing hydrates include, but are not limited to, storage in a water vapor-containing atmosphere, a dosage form containing water, or routine pharmaceutical processing steps such as crystallization (i.e., from water or a mixed aqueous solvent), lyophilization, wet granulation, aqueous film coating, or spray drying. Hydrates can also form from crystalline solvates under certain circumstances by exposure to water vapor or suspension of the anhydrous material in water. Hydrates can also crystallize into more than one form, resulting in hydrate polymorphs. See, for example, (Guillory, K., Chapter 5, pp. 2022-205 in Polymorphism in Pharmaceutical Solids, (Brittain, H. ed.), Marcel Dekker, Inc., New York, NY, 1999). The above-described methods for preparing hydrates are well within the skill of those in the art, are completely routine, and do not require any experimentation beyond that typical in the art. Hydrates can be characterized and / or analyzed by methods well known to those skilled in the art, such as single crystal X-ray diffraction, X-ray powder diffraction, polarized light microscopy, thermal microscopy, thermogravimetric analysis, differential thermal analysis, differential scanning calorimetry, IR spectroscopy, Raman spectroscopy, and NMR spectroscopy. (Brittain, H., Chapter 6, pp. 205-208 in Polymorphism in Pharmaceutical Solids, (Brittain, H. ed.), Marcel Dekker, Inc. New York, 1999). Furthermore, many commercial companies, such as HOLODIAG, Pharmaparc II, Voie de l'Innovation, 27 100 Val de Reuil, France (http: / / www.holodiag.com), routinely provide services that include the preparation and / or characterization of hydrates.

[0052] "Parent aromatic ring system" refers to an unsaturated cyclic or polycyclic ring system having a conjugated π-electron system. Specifically included within the definition of "parent aromatic ring system" are fused ring systems in which one or more of the rings are aromatic and one or more of the rings are saturated or unsaturated, such as, for example, fluorene, indane, indene, phenalene, etc. Exemplary parent aromatic ring systems include, but are not limited to, aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, coronene, fluoranthene, fluorene, hexacene, hexaphene, hexalene, as-indacene, s-indacene, indane, indene, naphthalene, octacene, octaphene, octalene, ovalene, penta-2,4-diene, pentacene, pentalene, pentaphene, perylene, phenalene, phenanthrene, picene, pleiadene, pyrene, pyranthrene, rubicene, triphenylene, trinaphthalene, etc. Saturated ring systems may contain one or more heteroatoms.

[0053] "Parent heteroaromatic ring system" refers to a parent aromatic ring system in which one or more carbon atoms (and optionally any associated hydrogen atoms) are each independently replaced with the same or different heteroatom. Typical heteroatoms replacing carbon atoms include, but are not limited to, N, P, O, S, Si, etc. Specifically included within the definition of "parent heteroaromatic ring system" are ring systems in which one or more of the rings is aromatic, one or more of the rings is saturated or unsaturated, and fused ring systems, such as, for example, benzodioxane, benzofuran, chromane, chromene, indole, indoline, xanthene, etc. Exemplary parent heteroaromatic ring systems include, but are not limited to, arsindole, carbazole, β-carboline, chroman, chromene, cinnoline, furan, imidazole, indazole, indole, indoline, indolizine, isobenzofuran, isochromene, isoindole, isoindoline, isoquinoline, isothiazole, isoxazole, naphthyridine, oxadiazole, oxazole, perimidine, phenanthridine, phenanthroline, phenazine, phthalazine, pteridine, purine, pyran, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole, pyrrolidine, quinazoline, quinoline, quinolizine, quinoxaline, tetrazole, thiadiazole, thiazole, thiophene, triazole, xanthene, etc. Saturated ring systems may contain one or more heteroatoms.

[0054] "Pharmaceutically acceptable salt" refers to a salt of a compound that possesses the desired pharmacological activity of the parent compound. Such salts include (1) salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or salts formed with acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4-hydroxybenzoylbenzoic acid, ... or (2) acid addition salts formed with organic acids such as 1-methylbicyclo[2.2.2]-oct-2-ene-1-carboxylic acid, glucoheptonic acid, 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, etc.; or (3) base addition salts formed when an acidic proton present in the parent compound is replaced by a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion; or coordinated with organic bases such as ethanolamine, diethanolamine, triethanolamine, N-methylglucamine, etc.

[0055] "Preventing" or "prevention" refers to a reduction in the risk of acquiring a disease or disorder (i.e., the arrest of the development of at least one clinical symptom of the disease in a patient who may be exposed to or predisposed to the disease, but who has not yet experienced or displayed symptoms of the disease). The application of prophylactic or preventative treatment to a disease or disorder is known as 'prophylaxis'. In certain embodiments, the compounds provided herein provide superior prophylaxis due to low long-term side effects over an extended period of time.

[0056] A "protecting group" refers to a group of atoms that, when attached to a reactive functional group in a molecule, masks, reduces, or prevents the reactivity of that functional group during chemical synthesis. Examples of protecting groups are described in Green et al., "Protective Groups in Organic Chemistry," (Wiley, 2009). nd ed. 1991) and Harrison et al., "Compendium of Synthetic Organic Methods", Vol. 18 (John Wiley and Sons, 1971-1996). Representative amino-protecting groups include, but are not limited to, formyl, acetyl, trifluoroacetyl, benzyl, benzyloxycarbonyl ("CBZ"), tert-butoxycarbonyl ("Boc"), trimethylsilyl ("TMS"), 2-trimethylsilyl-ethanesulfonyl ("SES"), trityl and substituted trityl groups, allyloxycarbonyl, 9-fluorenylmethyloxycarbonyl ("FMOC"), nitro-veratryloxycarbonyl ("NVOC"), and the like. Representative hydroxy-protecting groups include, but are not limited to, benzyl and trityl ethers, as well as those in which the hydroxy group is acylated or alkylated, such as alkyl ethers, tetrahydropyranyl ethers, trialkylsilyl ethers, and allyl ethers.

[0057] A "solvate" refers to a solvent in the crystalline lattice of a compound described herein in a stoichiometric ratio, resulting in the formation of an adduct. Additionally, the compounds described herein can exist in unsolvated and solvated forms with pharmaceutically acceptable solvents, such as water, ethanol, and the like. Solvated forms of the compounds described herein are also considered to be disclosed herein. Methods for producing solvates include, but are not limited to, storage in a solvent-containing atmosphere, a solvent-containing dosage form, or routine pharmaceutical processing steps, such as crystallization (i.e., from a solvent or solvent mixture), vapor diffusion, and the like. Solvates may, under certain circumstances, form from other crystalline solvates or hydrates by exposure to a solvent or suspension of a substance in a solvent. Solvates may also crystallize in more than one form, resulting in solvate polymorphism. See, for example, (Guillory, K., Chapter 5, pp. 205-208 in Polymorphism in Pharmaceutical Solids, (Brittain, H. ed.), Marcel Dekker, Inc., New York, NY, 1999). The above-mentioned methods for preparing solvates are well within the scope of those skilled in the art, are completely routine, and do not require any experimentation beyond that routine in the art. Solvates can be characterized and / or analyzed by methods well known to those skilled in the art, such as single crystal X-ray diffraction, X-ray powder diffraction, polarized light microscopy, thermal microscopy, thermogravimetry, differential thermal analysis, differential scanning calorimetry, IR spectroscopy, Raman spectroscopy, and NMR spectroscopy. (Brittain, H., Chapter 6, pp. 205208 in Polymorphism in Pharmaceutical Solids, (Brittain, H. ed.), Marcel Dekker, Inc. New York, 1999). In addition, many commercial companies, such as HOLODIAG, Pharmaparc II, Voie de l'Innovation, 27 100 Val de Reuil, France (http: / / www.holodiag.com), routinely provide services that include the preparation and / or characterization of solvates.

[0058] "Substituted," when used to modify a particular group or radical, means that one or more of the hydrogen atoms of the particular group or radical are each, independently of one another, replaced with the same or different substituents. Substituents useful for replacing saturated carbon atoms in the particular group or radical include R a , halo, -O - , =O, -OR b , -SR b , -S - , =S, -NR c R c , =NR b , =N-OR b , trihalomethyl, -CF3, -CN, -OCN, -SCN, -NO, -NO2, -N-OR b , -N-NR c R c , -NR b S(O)2R b , =N2, -N3, -S(O)2R b , -S(O)NR b R b , -S(O)2O - , -S(O)2OR b , -OS(O)2R b , -OS(O)2O - , -OS(O)2OR b , -OS(O)2NR c NR c , -P(O)(O - )2, -P(O)(OR b )(O - ), -P(O)(OR b )(OR b ), -C(O)R b , -C(O)NR b -OR b , -C(S)R b , -C(NR b )R b , -C(O)O - , -C(O)OR b , -C(S)OR b , -C(O)NR c R c , -C(NR b )NR c R c , -OC(O)R b, -OC(S)R b , -OC(O)O - , -OC(O)OR b , -OC(O)NR c R c , -OC(NCN)NR c R c , -OC(S)OR b , -NR b C(O)R b , -NR b C(S)R b , -NR b C(O)O - , -NR b C(O)OR b , -NR b C(NCN)OR b , -NR b S(O)NR c R c , -NR b C(S)OR b , -NR b C(O)NR c R c , -NR b C(S)NR c R c , -NR b C(S)NR b C(O)R a , -NR b S(O)2OR b , -NR b S(O)2R b , -NR b C(NCN)NR c R c , -NR b C(NR b )R b and -NR b C(NR b )NR c R c where each R ais independently aryl, substituted aryl, arylalkenyl, substituted arylalkenyl, arylalkynyl, substituted arylalkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, cycloheteroalkyl, substituted cycloheteroalkyl, cycloheteroalkenyl, substituted cycloheteroalkenyl, heteroalkyl, substituted heteroalkyl, heteroalkenyl, substituted heteroalkenyl, heteroalkynyl, substituted heteroalkynyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heteroarylalkenyl, substituted heteroarylalkenyl, heteroarylalkynyl, or substituted heteroarylalkynyl; each R b is independently hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, cycloheteroalkyl, substituted cycloheteroalkyl, cycloheteroalkenyl, substituted cycloheteroalkenyl, heteroalkyl, substituted heteroalkyl, heteroalkenyl, substituted heteroalkenyl, heteroalkynyl, substituted heteroalkynyl, arylalkyl, substituted arylalkyl, arylalkenyl, substituted arylalkenyl, arylalkynyl, substituted arylalkynyl, heteroarylalkyl, substituted heteroarylalkyl, heteroarylalkenyl, substituted heteroarylalkenyl, heteroarylalkynyl, or substituted heteroarylalkynyl; and each R c is independently R b or two R c together with the nitrogen atom to which they are attached form a 4-, 5-, 6-, or 7-membered cycloheteroalkyl, substituted cycloheteroalkyl, cycloheteroalkenyl, substituted cycloheteroalkenyl, or cycloheteroalkyl or fused to an aryl group, which optionally contains 1 to 4 identical or different additional heteroatoms selected from the group consisting of O, N, and S. Specific examples include -NR c R cis intended to include -NH, -NH-alkyl, N-alkenyl, N-pyrrolidinyl, and N-morpholinyl. In other embodiments, substituents useful for replacing saturated carbon atoms in the specified groups or radicals are R a , halo, -OR b , -NR c R c , trihalomethyl, =N-OR b , -CN, -NR b S(O)2R b , -C(O)R b , -C(O)OR b , -C(O)NR c R c , -OC(O)R b , -OC(O)OR b , -S(O)2R b , -S(O)NR c NR c , -OC(O)NR c R c and -NR b C(O)OR b where R a , R b and R c is as previously defined above.

[0059] Useful substituents for replacing unsaturated carbon atoms in the particular groups or radicals are -R a , halo, -O - , -OR b , -SR b , -S - , -NR c R c , trihalomethyl, -CF3, -CN, -OCN, -SCN, -NO, -NO2, -N3, -S(O)2O - , -S(O)2OR b , -OS(O)2R b , -OS(O)2OR b , -OS(O)2O - , -P(O)(O - )2, -P(O)(OR b )(O - ), -P(O)(OR b )(OR b ), -C(O)Rb , -C(S)R b , -C(NR b )R b , -C(O)O - , -C(O)OR b , -C(S)OR b , -C(O)NR c R c , -C(NR b )NR c R c , -OC(O)R b , -OC(S)R b , -OC(O)O - , -OC(O)OR b , -OC(S)OR b , -OC(O)NR c R c , -OS(O)2NR c NR c , -NR b C(O)R b , -NR b C(S)R b , -NR b C(O)O - , -NR b C(O)OR b , -NR b S(O)2OR a , -NR b S(O)2R a , -NR b C(S)OR b , -NR b C(O)NR c R c , -NR b C(NR b )R b and -NR b C(NR b )NR c R c where R a , R b and R c is as defined above. In other embodiments, a substituent useful for replacing an unsaturated carbon atom in said particular group or radical is -R a , halo, -OR b , -SR b , -NR c R c, trihalomethyl, -CN, -S(O)2OR b , -C(O)R b , -C(O)OR b , -C(O)NR c R c , -OC(O)R b , -OC(O)OR b , -S(O)NR c NR c , -NR b C(O)R b and -NR b C(O)OR b where R a , R b and R c is as defined above.

[0060] Useful substituents for substituting nitrogen atoms in heteroalkyl and cycloheteroalkyl groups are -R a , -O - , -OR b , -SR b , -S - , -NR c R c , trihalomethyl, -CF3, -CN, -NO, -NO2, -S(O)2R b , -S(O)2O - , -S(O)2OR b , -OS(O)2R b , -OS(O)2O - , -OS(O)2OR b , -P(O)(O - )2, -P(O)(OR b )(O - ), -P(O)(OR b )(OR b ), -C(O)R b , -C(S)R b , -C(NR b )R b , -C(O)OR b , -C(S)OR b , -C(O)NR c R c , -C(NR b )NR c R c , -OC(O)R b, -OC(S)R b , -OC(O)OR b , -OC(S)OR b , -NR b C(O)R b , -NR b C(S)R b , -NR b C(O)OR b , -NR b C(S)OR b , -NR b C(O)NR c R c , -NR b C(NR b )R b and -NR b C(NR b )NR c R c where R a , R b and R c is as defined above in the first embodiment of "substituted" above. In certain embodiments, substituents useful for substituting nitrogen atoms in heteroalkyl, heteroalkenyl, cycloheteroalkyl, and cycloheteroalkenyl groups are R a , -OR b , -NR c R c , trihalomethyl, -CN, -S(O)2OR b , -OS(O)2R b , -OS(O)2OR b , -C(O)R b , -C(NR b )R b , -C(O)OR b , -C(O)NR c R c , -OC(O)R b , -OC(O)OR b , -OS(O)2NR c NR c , -NR b C(O)R b and -NR b C(O)OR b where R a , R b and R cis as defined above in the first embodiment of "substituted" above.

[0061] In certain embodiments, substituents useful for replacing saturated carbon atoms in the particular groups or radicals are R a , halo, -OR b , -NR c R c , trihalomethyl, =N-OR b , -CN, -NR b S(O)2R b , -C(O)R b , -C(O)OR b , -C(O)NR c R c , -OC(O)R b , -OC(O)OR b , -S(O)2R b , -S(O)NR c NR c , -OC(O)NR c R c and -NR b C(O)OR b and useful substituents for replacing unsaturated carbon atoms in said particular groups or radicals include -R a , halo, -OR b , -SR b , -NR c R c , trihalomethyl, -CN, -S(O)2OR b , -C(O)R b , -C(O)OR b , -C(O)NR c R c , -OC(O)R b , -OC(O)OR b , -S(O)NR c NR c , -NR b C(O)R b and -NR b C(O)OR b and heteroalkyl, and useful substituents for replacing a nitrogen atom in a heteroalkenyl, cycloheteroalkyl, or cycloheteroalkenyl group are R a , -OR b , -NR c Rc , trihalomethyl, -CN, -S(O)2OR b , -OS(O)2R b , -OS(O)2OR b , -C(O)R b , -C(NR b )R b , -C(O)OR b , -C(O)NR c R c , -OC(O)R b , -OC(O)OR b , -OS(O)2NR c NR c , -NR b C(O)R b and -NR b C(O)OR b where each R a is independently aryl, arylalkenyl, arylalkynyl, cycloalkyl, cycloalkenyl, cycloheteroalkyl, cycloheteroalkenyl, heteroalkyl, heteroalkenyl, heteroalkynyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl, or heteroarylalkynyl; R b are independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloheteroalkyl, cycloheteroalkenyl, heteroalkyl, heteroalkenyl, substituted heteroalkynyl, arylalkyl, arylalkenyl, arylalkynyl, heteroarylalkyl, heteroarylalkenyl, or heteroarylalkynyl; and each R c is independently R b or two R c together with the nitrogen atom to which they are attached form a 4-, 5-, 6-, or 7-membered cycloheteroalkyl or cycloheteroalkenyl ring.

[0062] Substituents used to substitute a particular group may, in certain embodiments, be further substituted with one or more of the same or different groups typically selected from the various groups identified above.

[0063] The terms "subject," "individual," or "patient" are used interchangeably herein and refer to a vertebrate, preferably a mammal, including, but not limited to, murines, rodents, apes, humans, farm animals, sport animals, and pets.

[0064] "Treating" or "treatment" of any disease or disorder, in certain embodiments, refers to ameliorating the disease or disorder (i.e., halting or reducing the progression of the disease or at least one of its clinical symptoms). Treatment may also be considered to include preemptive or prophylactic administration to ameliorate, halt, or prevent the progression of at least one of the disease or clinical symptoms. In a further aspect, treatment reduces the likelihood of long-term side effects over several years. In other embodiments, "treating" or "treatment" refers to the improvement of at least one physical parameter, which may not be discernible by the patient. In yet other embodiments, "treating" or "treatment" refers to the prevention of the disease or disorder physically (e.g., stabilization of discernible symptoms), physiologically (e.g., stabilization of physical parameters), or both. In yet other embodiments, "treating" or "treatment" refers to the delay in the onset of the disease or disorder.

[0065] A "therapeutically effective amount" means the amount of a compound that, when administered to a patient for treating a disease, is sufficient to treat the disease. The "therapeutically effective amount" will vary depending on the compound, the disease and its severity, and the age, weight, absorption, distribution, metabolism, and excretion of the patient being treated.

[0066] "Vehicle" refers to a diluent, excipient, or carrier with which a compound is administered to a subject. In certain embodiments, the vehicle is pharmaceutically acceptable.

[0067] compound Provided is a compound of formula (I): [ka] [During the ceremony, each R1 is independently hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, arylalkenyl, substituted arylalkenyl, arylalkynyl, substituted arylalkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, cycloheteroalkyl, substituted cycloheteroalkyl, cycloheteroalkenyl or substituted cycloheteroalkenyl, heteroalkyl, substituted heteroalkyl, heteroalkenyl, substituted heteroalkenyl, heteroalkynyl, substituted heteroalkynyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heteroarylalkenyl, substituted heteroarylalkenyl, heteroarylalkynyl, substituted heteroarylalkynyl, halo, -C(O)NR8R9, -C(O)OR 10 , -NR 11 C(O)OR 12 , -NR 13 C(O)OR 14 , -OC(O)OR 15 , -CN, -CF3, -NR 16 SO2R 17 -OR 18 m is 0, 1, 2, or 3; each R2 is independently hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, arylalkenyl, substituted arylalkenyl, arylalkynyl, substituted arylalkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, cycloheteroalkyl, substituted cycloheteroalkyl, cycloheteroalkenyl, substituted cycloheteroalkenyl, heteroalkyl, substituted heteroalkyl, heteroalkenyl, substituted heteroalkenyl, heteroalkynyl, substituted heteroalkynyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heteroarylalkenyl, substituted heteroarylalkenyl, heteroarylalkynyl, substituted heteroarylalkynyl, halo, -C(O)NR 19 R 20, -C(O)OR 21 , -NR 22 C(O)OR 23 , -NR 24 C(O)OR 25 , -OC(O)OR 26 , -CN, -CF3, -NR 27 SO2R 28 -OR 29 n is 0, 1, or 2; each R3 is independently hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, arylalkenyl, substituted arylalkenyl, arylalkynyl, substituted arylalkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, cycloheteroalkyl, substituted cycloheteroalkyl, cycloheteroalkenyl, substituted cycloheteroalkenyl, heteroalkyl, substituted heteroalkyl, heteroalkenyl, substituted heteroalkenyl, heteroalkynyl, substituted heteroalkynyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heteroarylalkenyl, substituted heteroarylalkenyl, heteroarylalkynyl, substituted heteroarylalkynyl, halo, -C(O)NR 30 R 31 , -C(O)OR 32 , -NR 33 C(O)OR 34 , -NR 35 C(O)OR 36 , -OC(O)OR 37 , -CN, -CF3, -NR 38 SO2R 39 -OR 40when q is 1, o is 0, 1, 2, or 3; when q is 2, o is 0, 1, 2, 3, or 4; when q is 3, o is 0, 1, 2, 3, 4, or 5; R4 is hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, arylalkenyl, substituted arylalkenyl, arylalkynyl, substituted arylalkynyl, cycloalkyl, substituted substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, cycloheteroalkyl, substituted cycloheteroalkyl, cycloheteroalkenyl, substituted cycloheteroalkenyl, heteroalkyl, substituted heteroalkyl, heteroalkenyl, substituted heteroalkenyl, heteroalkynyl, substituted heteroalkynyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heteroarylalkenyl, substituted heteroarylalkenyl, heteroarylalkynyl, substituted heteroarylalkynyl, -F, -C(O)NR 41 R 42 , -C(O)R 43 , -C(O)OR 44 , -CN, -CF3, or R4 and R5 together with the atoms to which they are attached form a C4-C8 cycloalkyl ring; E is -CH2- or -CH2Z-; Z is -NR 46 -, -S-, -SO2- or -O-; when E is -CH2-, D is -(CH2)2-, -(CH2)3-, -CH=CHCH2-, -C(O)-, -C≡CCH2-, phenyl, cyclohexyl or cyclopentyl; Z is NR 45 or -O-, then D is -(CH2)2-, -(CH2)3-, -C(O)-, phenyl, cyclohexyl, or cyclopentyl; when Z is -SO2- or -S-, then D is -(CH2)2-, -(CH2)3-, phenyl, cyclohexyl, or cyclopentyl; XY is -C(O)NR 46 -, -NR 47C(O)-, -C(O)O-, -CH2CH2-, -CH=CH-, -C≡C-, -NR 48 CH2-, -CH2NR 49 -, -O-CH2-, -CH2-O-, -SO2NR 50 -, -NR 51 SO2- or cyclopropyl; A is hydrogen, -OR 52 , alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, arylalkenyl, substituted arylalkenyl, arylalkynyl, substituted arylalkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, cycloheteroalkyl, substituted cycloheteroalkyl, cycloheteroalkenyl, substituted cycloheteroalkenyl, heteroalkyl, substituted heteroalkyl, heteroalkenyl, substituted heteroalkenyl, heteroalkynyl, substituted heteroalkynyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heteroarylalkenyl, substituted heteroarylalkenyl, heteroarylalkynyl, substituted heteroarylalkynyl, substituted heteroaryl B is hydrogen, aryl, substituted aryl, arylalkyl, substituted arylalkyl, arylalkenyl, substituted arylalkenyl, arylalkynyl, substituted arylalkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, cycloheteroalkyl, substituted cycloheteroalkyl, cycloheteroalkenyl, substituted cycloheteroalkenyl, heteroalkyl, substituted heteroalkyl, heteroalkenyl, substituted heteroalkenyl, heteroalkynyl, substituted heteroalkynyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heteroarylalkenyl, substituted heteroarylalkenyl, heteroarylalkynyl, substituted heteroarylalkynyl, halo, -NR 53 R 54 , -OR 55 , -SR 56 or -SO2-R 57 and;R8~R 53 and R 58 ~R64 is independently hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, arylalkenyl, substituted arylalkenyl, arylalkynyl, substituted arylalkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, cycloheteroalkyl, substituted cycloheteroalkyl, cycloheteroalkenyl, substituted cycloheteroalkenyl, heteroalkyl, substituted heteroalkyl, heteroalkenyl, substituted heteroalkenyl, heteroalkynyl, substituted heteroalkynyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heteroarylalkenyl, substituted heteroarylalkenyl, heteroarylalkynyl, or substituted heteroarylalkynyl; R 54 is alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, arylalkenyl, substituted arylalkenyl, arylalkynyl, substituted arylalkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, cycloheteroalkyl, substituted cycloheteroalkyl, cycloheteroalkenyl, substituted cycloheteroalkenyl, heteroalkyl, substituted heteroalkyl, heteroalkenyl, substituted heteroalkenyl, heteroalkynyl, substituted heteroalkynyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heteroarylalkenyl, substituted heteroarylalkenyl, heteroarylalkynyl, substituted heteroarylalkynyl, -C(O)R 58 , -C(O)OR 59 , -C(O)NR 60 R 61 or -SO2R 62 and; R 55 ~R 57is alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, arylalkenyl, substituted arylalkenyl, arylalkynyl, substituted arylalkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, cycloheteroalkyl, substituted cycloheteroalkyl, cycloheteroalkenyl, substituted cycloheteroalkenyl, heteroalkyl, substituted heteroalkyl, heteroalkenyl, substituted heteroalkenyl, heteroalkynyl, substituted heteroalkynyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, heteroarylalkenyl, substituted heteroarylalkenyl, heteroarylalkynyl, or substituted heteroarylalkynyl; R5 is hydrogen or -F; R6 is hydrogen, -F, or -OR 63 and R7 is hydrogen, -F or -OR 64 where R4 is -C(O)NR 41 R 42 , -C(O)R 43 , -C(O)OR 44 or -CN, then R5 is hydrogen; provided that when B is hydrogen or halo, then A is hydrogen, halo, or -OR 52 except that A is hydrogen, halo, or -OR 52 when B is not hydrogen or halo; provided that B is halo, -NR 53 R 54 , -OR 55 , -SR 56 or -SO2R 57 R7 is hydrogen when XY is -CH2CH2-, -CH=CH-, -C≡C-, or cyclopropyl, but only when R6 is -OR 63 where R6 is -OR 63 When A is -OR 52 with the proviso that when R6 is -F, then A is not -Cl, -Br, or -I. or a pharmaceutically acceptable salt, hydrate or solvate thereof.

[0068]

[0023] In certain embodiments, in the compound of Formula (I), each R is independently hydrogen, alkyl, alkenyl, alkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, cycloalkyl, cycloalkenyl, cycloheteroalkyl, cycloheteroalkenyl, heteroalkyl, heteroalkenyl, heteroalkynyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, halo, -C(O)NR8R9, -C(O)OR 10 , -NR 11 C(O)OR 12 , -NR 13 C(O)OR 14 , -OC(O)OR 15 , -CN, -CF3, -NR 16 SO2R 17 -OR 18 m is 0, 1, 2, or 3; each R2 is independently hydrogen, alkyl, alkenyl, alkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, cycloalkyl, cycloalkenyl, cycloheteroalkyl, cycloheteroalkenyl, heteroalkyl, heteroalkenyl, heteroalkynyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, halo, -C(O)NR 19 R 20 , -C(O)OR 21 , -NR 22 C(O)OR 23 , -NR 24 C(O)OR 25 , -OC(O)OR 26 , -CN, -CF3, -NR 27 SO2R 28 -OR 29n is 0, 1, or 2; each R3 is independently hydrogen, alkyl, alkenyl, alkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, cycloalkyl, cycloalkenyl, substituted cycloalkenyl, cycloheteroalkyl, cycloheteroalkenyl, heteroalkyl, heteroalkenyl, heteroalkynyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, halo, -C(O)NR 30 R 31 , -C(O)OR 32 , -NR 33 C(O)OR 34 , -NR 35 C(O)OR 36 , -OC(O)OR 37 , -CN, -CF3, -NR 38 SO2R 39 -OR 40 and q is 0, 1, 2, or 3; when q is 0, o is 0, 1, or 2; when q is 1, o is 0, 1, 2, or 3; when q is 2, o is 0, 1, 2, 3, or 4; when q is 3, o is 0, 1, 2, 3, 4, or 5; and R4 is hydrogen, alkyl, alkenyl, alkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, cycloalkyl, cycloalkenyl, substituted cycloalkenyl, cycloheteroalkyl, cycloheteroalkenyl, heteroalkyl, heteroalkenyl, heteroalkynyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, halo, -C(O)NR 41 R 42 , -C(O)R 43 , -C(O)OR 44 , -CN, -CF3, or R4 and R5 together with the atoms to which they are attached form a C4-C8 cycloalkyl ring; R5 is hydrogen, -F, -CF3, or alkyl; E is -CH2-, -CH2Z-, and Z is -NR 46 E is -, -S-, -SO2-, or -O-; E is -CH2-, -CH2Z, and Z is -NR 45-, -S-, -SO2- or -O-; when E is -CH2-, D is -(CH2)2-, -(CH2)3-, -CH=CHCH2-, -C(O)-, -C≡CCH2-, phenyl, cyclohexyl or cyclopentyl; Z is NR 45 or -O-, then D is -(CH2)2-, -(CH2)3-, -C(O)-, phenyl, cyclohexyl, or cyclopentyl; when Z is -SO2- or -S-, then D is -(CH2)2-, -(CH2)3-, phenyl, cyclohexyl, or cyclopentyl; XY is -C(O)NR 46 -, -NR 47 C(O)-, -C(O)O-, -CH2CH2-, -CH=CH-, -C≡C-, -NR 48 CH2-, -CH2NR 49 -, -O-CH2-, -CH2-O-, -SO2NR 50 -, -NR 51 SO2- or cyclopropyl; A is hydrogen, -OR 52 , alkyl, alkenyl, alkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, cycloalkyl, cycloalkenyl, cycloheteroalkyl, cycloheteroalkenyl, heteroalkyl, heteroalkenyl, heteroalkynyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, or halo; B is hydrogen, aryl, arylalkyl, arylalkenyl, arylalkynyl, cycloalkyl, cycloalkenyl, cycloheteroalkyl, cycloheteroalkenyl, heteroalkyl, heteroalkenyl, heteroalkynyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, halo, -NR 53 R 54 , -OR 55 , -SR 56 or -SO2-R 57 and;R8~R 53 and R 58 ~R 64are independently hydrogen, alkyl, alkenyl, alkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, cycloalkyl, cycloalkenyl, cycloheteroalkyl, cycloheteroalkenyl, heteroalkyl, heteroalkenyl, heteroalkynyl, heteroaryl, heteroarylalkyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, cycloalkyl, cycloalkenyl, cycloheteroalkyl, cycloheteroalkenyl, heteroalkyl, heteroalkenyl, heteroalkynyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, -C(O)R 58 , -C(O)OR 59 , -C(O)NR 60 R 61 or -SO2R 62 and;R 55 ~R 57 is alkyl, alkenyl, alkynyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, cycloalkyl, cycloalkenyl, cycloheteroalkyl, cycloheteroalkenyl, heteroalkyl, heteroalkenyl, heteroalkynyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl, or heteroarylalkynyl; R5 is hydrogen or fluoro; R6 is hydrogen, fluoro, or -OR 63 and R7 is hydrogen, fluoro, or -OR 64 is.

[0069] In still other embodiments, in the compound of Formula (I), each R is independently hydrogen, alkyl, alkenyl, aryl, arylalkyl, arylalkenyl, cycloalkyl, cycloalkenyl, cycloheteroalkyl, cycloheteroalkenyl, heteroalkyl, heteroalkenyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl, halo, —C(O)NR8R9, —C(O)OR 10 , -NR 11 C(O)OR 12 , -NR 13 C(O)OR 14 , -OC(O)OR15 , -CN, -CF3, -NR 16 SO2R 17 -OR 18 m is 0 or 1; each R2 is independently hydrogen, alkyl, alkenyl, alkynyl, aryl, arylalkyl, arylalkenyl, cycloalkyl, cycloalkenyl, cycloheteroalkyl, cycloheteroalkenyl, heteroalkyl, heteroalkenyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl, halo, -C(O)NR 19 R 20 , -C(O)OR 21 , -NR 22 C(O)OR 23 , -NR 24 C(O)OR 25 , -OC(O)OR 26 , -CN, -CF3, -NR 27 SO2R 28 -OR 29 n is 0, 1, or 2; and each R3 is independently hydrogen, alkyl, alkenyl, aryl, arylalkyl, arylalkenyl, cycloalkyl, cycloalkenyl, cycloheteroalkyl, cycloheteroalkenyl, heteroalkyl, heteroalkenyl, heteroalkynyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl, halo, -C(O)NR 30 R 31 , -C(O)OR 32 , -NR 33 C(O)OR 34 , -NR 35 C(O)OR 36 , -OC(O)OR 37 , -CN, -CF3, -NR 38 SO2R 39 -OR 40when q is 1, o is 0, 1, 2, or 3; when q is 2, o is 0, 1, 2, 3, or 4; when q is 3, o is 0, 1, 2, 3, 4, or 5; R4 is hydrogen, alkyl, alkenyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, cycloalkyl, cycloalkenyl, cycloheteroalkyl, cycloheteroalkenyl, heteroalkyl, heteroalkenyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl, halo, -C(O)NR 41 R 42 , -C(O)R 43 , -C(O)OR 44 , -CN, -CF3, or R4 and R5 together with the atoms to which they are attached form a C4-C8 cycloalkyl ring; R5 is hydrogen, -F, -CF3, or alkyl; E is -CH2-, -CH2Z-, and Z is -NR 46 E is -, -S-, -SO2-, or -O-; E is -CH2-, -CH2Z, and Z is -NR 45 -, -S-, -SO2- or -O-; when E is -CH2-, D is -(CH2)2-, -(CH2)3-, -CH=CHCH2-, -C(O)-, -C≡CCH2-, phenyl, cyclohexyl or cyclopentyl; Z is NR 45 or -O-, then D is -(CH2)2-, -(CH2)3-, -C(O)-, phenyl, cyclohexyl, or cyclopentyl; when Z is -SO2- or -S-, then D is -(CH2)2-, -(CH2)3-, phenyl, cyclohexyl, or cyclopentyl; XY is -C(O)NR 46 -, -NR 47 C(O)-, -C(O)O-, -CH2CH2-, -CH=CH-, -C≡C-, -NR 48 CH2-, -CH2NR 49 -, -O-CH2-, -CH2-O-, -SO2NR 50 -, -NR 51 SO2- or cyclopropyl; A is hydrogen, -OR 52, alkyl, alkenyl, aryl, arylalkyl, arylalkenyl, cycloalkyl, cycloalkenyl, cycloalkenyl, cycloheteroalkyl, cycloheteroalkenyl, heteroalkyl, heteroalkenyl, heteroalkynyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl, or halo; B is hydrogen, aryl, arylalkyl, arylalkenyl, arylalkynyl, cycloalkyl, cycloalkenyl, cycloheteroalkyl, cycloheteroalkenyl, heteroalkyl, heteroalkenyl, heteroalkynyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl, halo, -NR 53 R 54 , -OR 55 , -SR 56 or -SO2-R 57 and;R8~R 53 and R 58 ~R 64 are independently hydrogen, alkyl, alkenyl, aryl, arylalkyl, arylalkenyl, cycloalkyl, cycloalkenyl, cycloheteroalkyl, cycloheteroalkenyl, heteroalkyl, heteroalkenyl, heteroaryl, heteroarylalkyl, aryl, arylalkyl, arylalkenyl, cycloalkyl, cycloalkenyl, cycloheteroalkyl, cycloheteroalkenyl, heteroalkyl, heteroalkenyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, -C(O)R 58 , -C(O)OR 59 , -C(O)NR 60 R 61 or -SO2R 62 and;R 55 ~R 57 is alkyl, alkenyl, aryl, arylalkyl, arylalkenyl, cycloalkyl, cycloalkenyl, cycloheteroalkyl, cycloheteroalkenyl, heteroalkyl, heteroalkenyl, heteroaryl, heteroarylalkyl, or heteroarylalkenyl; R5 is hydrogen or fluoro; R6 is hydrogen, fluoro, or -OR 63and R7 is hydrogen, fluoro, or -OR 64 is.

[0070] In still other embodiments, in the compound of Formula (I), each R is independently hydrogen, alkyl, alkenyl, aryl, arylalkyl, arylalkenyl, cycloalkyl, cycloalkenyl, cycloheteroalkyl, cycloheteroalkenyl, heteroalkyl, heteroalkenyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl, halo, —C(O)NR8R9, —C(O)OR 10 , -NR 11 C(O)OR 12 , -NR 13 C(O)OR 14 , -OC(O)OR 15 , -CN, -CF3, -NR 16 SO2R 17 -OR 18 m is 0 or 1; each R2 is independently hydrogen, alkyl, alkenyl, aryl, arylalkyl, arylalkenyl, cycloalkyl, cycloalkenyl, cycloheteroalkyl, cycloheteroalkenyl, heteroalkyl, heteroalkenyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl, halo, -C(O)NR 19 R 20 , -C(O)OR 21 , -NR 22 C(O)OR 23 , -NR 24 C(O)OR 25 , -OC(O)OR 26 , -CN, -CF3, -NR 27 SO2R 28 -OR 29 n is 0, 1, or 2; and each R3 is independently hydrogen, alkyl, alkenyl, aryl, arylalkyl, arylalkenyl, cycloalkyl, cycloalkenyl, cycloheteroalkyl, cycloheteroalkenyl, heteroalkyl, heteroalkenyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl, halo, -C(O)NR 30 R 31 , -C(O)OR32 , -NR 33 C(O)OR 34 , -NR 35 C(O)OR 36 , -OC(O)OR 37 , -CN, -CF3, -NR 38 SO2R 39 -OR 40 when q is 1, o is 0, 1, 2, or 3; when q is 2, o is 0, 1, 2, 3, or 4; when q is 3, o is 0, 1, 2, 3, 4, or 5; R4 is hydrogen, alkyl, alkenyl, aryl, arylalkyl, arylalkenyl, cycloalkyl, cycloalkenyl, cycloheteroalkyl, cycloheteroalkenyl, heteroalkyl, heteroalkenyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl, halo, -C(O)NR 41 R 42 , -C(O)R 43 , -C(O)OR 44 , -CN, -CF3, or R4 and R5 together with the atoms to which they are attached form a C4-C8 cycloalkyl ring; R5 is hydrogen, -F, -CF3, or alkyl; E is -CH2-, -CH2Z-, and Z is -NR 46 E is -, -S-, -SO2-, or -O-; E is -CH2-, -CH2Z, and Z is -NR 45 -, -S-, -SO2- or -O-; when E is -CH2-, D is -(CH2)2-, -(CH2)3-, -CH=CHCH2-, -C(O)-, -C≡CCH2-, phenyl, cyclohexyl or cyclopentyl; Z is NR 45 or -O-, then D is -(CH2)2-, -(CH2)3-, -C(O)-, phenyl, cyclohexyl, or cyclopentyl; when Z is -SO2- or -S-, then D is -(CH2)2-, -(CH2)3-, phenyl, cyclohexyl, or cyclopentyl; XY is -C(O)NR 46 -, -NR 47C(O)-, -C(O)O-, -CH2CH2-, -CH=CH-, -C≡C-, -NR 48 CH2-, -CH2NR 49 -, -O-CH2-, -CH2-O-, -SO2NR 50 -, -NR 51 SO2- or cyclopropyl; A is hydrogen, -OR 52 , alkyl, alkenyl, aryl, arylalkyl, arylalkenyl, cycloalkyl, cycloalkenyl, cycloalkenyl, cycloheteroalkyl, cycloheteroalkenyl, heteroalkyl, heteroalkenyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl, or halo; B is hydrogen, aryl, arylalkyl, arylalkenyl, arylalkynyl, cycloalkyl, cycloalkenyl, cycloheteroalkyl, cycloheteroalkenyl, heteroalkyl, heteroalkenyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl, halo, -NR 53 R 54 , -OR 55 , -SR 56 or -SO2-R 57 and;R8~R 53 and R 58 ~R 64 are independently hydrogen, alkyl, alkenyl, aryl, arylalkyl, arylalkenyl, cycloalkyl, cycloalkenyl, cycloheteroalkyl, cycloheteroalkenyl, heteroalkyl, heteroalkenyl, heteroaryl, heteroarylalkyl, aryl, arylalkyl, arylalkenyl, cycloalkyl, cycloalkenyl, cycloheteroalkyl, cycloheteroalkenyl, heteroalkyl, heteroalkenyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl, -C(O)R 58 , -C(O)OR 59 , -C(O)NR 60 R 61 or -SO2R 62 and;R 55 ~R 57is alkyl, alkenyl, aryl, arylalkyl, arylalkenyl, cycloalkyl, cycloalkenyl, cycloheteroalkyl, cycloheteroalkenyl, heteroalkyl, heteroalkenyl, heteroaryl, heteroarylalkyl, or heteroarylalkenyl; R5 is hydrogen or fluoro; R6 is hydrogen, fluoro, or -OR 63 and R7 is hydrogen, fluoro, or -OR 64 is.

[0071] In still other embodiments, in the compound of Formula (I), each R is independently hydrogen, alkyl, aryl, arylalkyl, cycloalkyl, cycloheteroalkyl, heteroalkyl, heteroaryl, halo, —C(O)NR, —C(O)OR 10 , -NR 11 C(O)OR 12 , -NR 13 C(O)OR 14 , -OC(O)OR 15 , -CN, -CF3, -NR 16 SO2R 17 -OR 18 m is 0 or 1; and each R2 is independently hydrogen, alkyl, aryl, arylalkyl, cycloalkyl, cycloheteroalkyl, heteroalkyl, heteroaryl, heteroarylalkyl, halo, -C(O)NR 19 R 20 , -C(O)OR 21 , -NR 22 C(O)OR 23 , -NR 24 C(O)OR 25 , -OC(O)OR 26 , -CN, -CF3, -NR 27 SO2R 28 -OR 29 n is 0, 1, or 2; and each R3 is independently hydrogen, alkyl, alkenyl, aryl, arylalkyl, cycloalkyl, cycloheteroalkyl, heteroalkyl, heteroalkynyl, heteroaryl, heteroarylalkyl, halo, -C(O)NR 30 R 31 , -C(O)OR32 , -NR 33 C(O)OR 34 , -NR 35 C(O)OR 36 , -OC(O)OR 37 , -CN, -CF3, -NR 38 SO2R 39 -OR 40 when q is 1, o is 0, 1, 2, or 3; when q is 2, o is 0, 1, 2, 3, or 4; when q is 3, o is 0, 1, 2, 3, 4, or 5; R4 is hydrogen, alkyl, alkenyl, aryl, arylalkyl, cycloalkyl, cycloheteroalkyl, cycloheteroalkenyl, heteroalkyl, heteroaryl, heteroarylalkyl, halo, -C(O)NR 41 R 42 , -C(O)R 43 , -C(O)OR 44 , -CN, -CF3, or R4 and R5 together with the atoms to which they are attached form a C4-C8 cycloalkyl ring; R5 is hydrogen, -F, -CF3, or alkyl; E is -CH2-, -CH2Z-, and Z is -NR 46 E is -, -S-, -SO2-, or -O-; E is -CH2-, -CH2Z, and Z is -NR 45 -, -S-, -SO2- or -O-; when E is -CH2-, D is -(CH2)2-, -(CH2)3-, -CH=CHCH2-, -C(O)-, -C≡CCH2-, phenyl, cyclohexyl or cyclopentyl; Z is NR 45 or -O-, then D is -(CH2)2-, -(CH2)3-, -C(O)-, phenyl, cyclohexyl, or cyclopentyl; when Z is -SO2- or -S-, then D is -(CH2)2-, -(CH2)3-, phenyl, cyclohexyl, or cyclopentyl; XY is -C(O)NR 46 -, -NR 47 C(O)-, -C(O)O-, -CH2CH2-, -CH=CH-, -C≡C-, -NR 48CH2-, -CH2NR 49 -, -O-CH2-, -CH2-O-, -SO2NR 50 -, -NR 51 SO2- or cyclopropyl; A is hydrogen, -OR 52 , alkyl, alkenyl, aryl, arylalkyl, cycloalkyl, cycloalkenyl, cycloheteroalkyl, heteroalkyl, heteroalkenyl, heteroaryl, heteroarylalkyl, or halo; B is hydrogen, aryl, arylalkyl, cycloalkyl, cycloheteroalkyl, heteroalkyl, heteroaryl, heteroarylalkyl, halo, -NR 53 R 54 , -OR 55 , -SR 56 or -SO2-R 57 and;R8~R 53 and R 58 ~R 64 are independently hydrogen, alkyl, aryl, arylalkyl, cycloalkyl, cycloheteroalkyl, heteroalkyl, heteroaryl, aryl, arylalkyl, cycloalkyl, cycloheteroalkyl, heteroalkyl, heteroaryl, heteroarylalkyl, -C(O)R 58 , -C(O)OR 59 , -C(O)NR 60 R 61 or -SO2R 62 and;R 55 ~R 57 is alkyl, aryl, arylalkyl, cycloalkyl, cycloheteroalkyl, heteroalkyl, heteroaryl, or heteroarylalkyl; R5 is hydrogen or fluoro; R6 is hydrogen, fluoro, or -OR 63 and R7 is hydrogen, fluoro, or -OR 64 is.

[0072] In certain embodiments, a compound of formula (II) [ka] The compound of formula (I) is provided.

[0073] In other embodiments, the compound of formula (III) [ka] The compound of formula (I) is provided.

[0074] In yet another embodiment, a compound of formula (IV) [ka] The compound of formula (I) is provided.

[0075] In yet another embodiment, a compound of formula (V) [ka] The compound of formula (I) is provided.

[0076] In yet another embodiment, a compound of formula (VI) [ka] The compound of formula (I) is provided.

[0077] In certain embodiments of compounds of Formulas (I-VI), each R is independently alkyl, substituted alkyl, alkenyl, substituted alkenyl, phenyl, substituted phenyl, cycloalkyl, heteroalkyl, cycloheteroalkyl, —F, —C(O)NRR, —C(O)OR 10 , -OC(O)OR 15 , -CF3 or -OR 18 In other embodiments, each R is independently (C-C) alkyl, (C-C) alkenyl, phenyl, substituted phenyl, (C-C) cycloalkyl, (C-C) cycloheteroalkyl, -F, or -CF.

[0078] In certain embodiments of compounds of Formulae (I-VI), m is 0 or 1. In other embodiments, n is 0 or 1.

[0079] In certain embodiments of compounds of Formulae (I-VI), each R2 is independently alkyl, substituted alkyl, alkenyl, substituted alkenyl, phenyl, substituted phenyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroalkyl, cycloheteroalkyl, or cycloheteroalkenyl, halo, -C(O)NR 19 R 20 , -C(O)OR 21 , -NR 22 C(O)OR 23 , -NR 24 C(O)OR 25 , -OC(O)OR 26 , -CN, -CF3, -NR 27 SO2R 28 -OR 29 In other embodiments, each R2 is independently (C1-C4) alkyl, (C2-C4) alkenyl, phenyl, substituted phenyl, (C5-C7) cycloalkyl, (C5-C7) cycloheteroalkyl, halo, C(O)NR 19 R 20 , -C(O)OR 21 , -NR 22 C(O)OR 23 , -NR 24 C(O)OR 25 , -OC(O)OR 26 , -CN, -CF3, -NR 27 SO2R 28 -OR 29 is.

[0080] In certain embodiments of compounds of Formulae (I-VI), each R3 is independently alkyl, substituted alkyl, alkenyl, substituted alkenyl, phenyl, substituted phenyl, cycloalkyl, heteroalkyl, cycloheteroalkyl, -F, -C(O)NR 30 R 31 , -C(O)OR 32 , -OC(O)OR 37 , -CF3 or -OR 40 is 。In other embodiments, each R3 is independently (C1-C4) alkyl, (C2-C4) alkenyl, phenyl, substituted phenyl, (C5-C7) cycloalkyl, (C5-C7) cycloheteroalkyl, -F, or -CF3.

[0081] In some embodiments of compounds of Formulae (I-VI), o is 0 or 1. In other embodiments, o is 0, 1, 2, or 3. In some embodiments, o is 1, 2, or 3. In some embodiments, o is 1 or 2.

[0082] In certain embodiments of compounds of Formulae (I-VI), R4 is hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, -F, -C(O)NR 41 R 42 , -C(O)R 43 , -C(O)OR 44 Or -CF3. In other embodiments of compounds of Formulae (I-VI), R4 is hydrogen, (C1-C4) alkyl, (C2-C4) alkenyl, -F, or -CF3.

[0083] In certain embodiments of Formulae (I-VI), R5 is hydrogen or -F.

[0084] In certain embodiments of compounds of Formulas (I-VI), R8-R 53 and R 58 ~R 64 are independently hydrogen, alkyl, alkenyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl, heteroalkyl, heteroalkenyl, heteroaryl, substituted heteroaryl, cycloheteroalkyl, or substituted cycloheteroalkyl. 53 and R 58 ~R 64 are independently hydrogen, (C1-C4) alkyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, cycloheteroalkyl, or substituted cycloheteroalkyl.

[0085] In certain embodiments of compounds of Formulas (I-VI), R 55 ~R 57 is independently alkyl, alkenyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl, heteroalkyl, heteroalkenyl, heteroaryl, substituted heteroaryl, cycloheteroalkyl, or substituted cycloheteroalkyl. 55 ~R 57 is independently (C1-C4) alkyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, cycloheteroalkyl, or substituted cycloheteroalkyl.

[0086] In certain embodiments of compounds of Formulas (I-VI), each R is independently alkyl, substituted alkyl, alkenyl, substituted alkenyl, phenyl, substituted phenyl, cycloalkyl, heteroalkyl, cycloheteroalkyl, —F, —C(O)NRR, —C(O)OR 10 , -OC(O)OR 15 , -CF3 or -OR 18 wherein m is 0 or 1, and each R2 is independently alkyl, substituted alkyl, alkenyl, substituted alkenyl, phenyl, substituted phenyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroalkyl, cycloheteroalkyl, halo, or —C(O)NR 19 R 20 , -C(O)OR 21 , -NR 22 C(O)OR 23 , -NR 24 C(O)OR 25 , -OC(O)OR 26 , -CN, -CF3, -NR 27 SO2R 28 -OR 29 wherein n is 0 or 1, and each R3 is independently alkyl, substituted alkyl, alkenyl, substituted alkenyl, phenyl, substituted phenyl, cycloalkyl, heteroalkyl, cycloheteroalkyl, -F -C(O)NR 30 R 31, -C(O)OR 32 , -OC(O)OR 37 , -CF3 or -OR 40 wherein o is 0, 1, 2, or 3, and R4 is hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, -F, or -C(O)NR 41 R 42 , -C(O)OR 43 , -C(O)OR 44 or -CF3, R8 to R 53 and R 58 ~R 64 is independently hydrogen, alkyl, alkenyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl, heteroalkyl, heteroalkenyl, heteroaryl, substituted heteroaryl, cycloheteroalkyl, or substituted cycloheteroalkyl. In other embodiments, R is independently (C-C)alkyl, (C-C)alkenyl, phenyl, substituted phenyl, (C-C)cycloalkyl, (C-C)cycloheteroalkyl, -F, or -CF; m is 0 or 1; and each R is independently (C-C)alkyl, (C-C)alkenyl, phenyl, substituted phenyl, (C-C)cycloalkyl, (C-C)cycloheteroalkyl, halo, C(O)NR 19 R 20 , -C(O)OR 21 , -NR 22 C(O)OR 23 , -NR 24 C(O)OR 25 , -OC(O)OR 26 , -CN, -CF3, -NR 27 SO2R 28 -OR 29 is 0 or 1; each R3 is independently (C1-C4)alkyl, (C2-C4)alkenyl, phenyl, substituted phenyl, (C5-C7)cycloalkyl, (C5-C7)cycloheteroalkyl, -F, or -CF3; o is 0 or 1; R4 is hydrogen, (C1-C4)alkyl, (C2-C4)alkenyl, -F, or -CF3; and R8 to R 53 and R 58 ~R 64are independently hydrogen, (C1-C4) alkyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, cycloheteroalkyl, or substituted cycloheteroalkyl.

[0087] In some embodiments of the compounds of Formula (I, II, IV and V), A is aryl, substituted aryl, aryl alkyl, substituted aryl alkyl, aryl alkenyl, substituted aryl alkenyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heteroaryl alkyl, substituted heteroaryl alkyl, heteroaryl alkenyl, substituted heteroaryl alkenyl, cycloheteroalkyl, substituted cycloheteroalkyl, cycloheteroalkenyl or substituted cycloheteroalkenyl. In other embodiments, A is aryl, substituted aryl, aryl alkyl, substituted aryl alkyl, heteroaryl, substituted heteroaryl, heteroaryl alkyl or substituted heteroaryl alkyl. In still other embodiments of the compounds of Formula (I, II, IV and V), A is aryl, substituted aryl, heteroaryl or substituted heteroaryl.

[0088] In some embodiments of compounds of Formula (I, III, IV, and VI), B is aryl, substituted aryl, aryl alkyl, substituted aryl alkyl, aryl alkenyl, substituted aryl alkenyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heteroaryl alkyl, substituted heteroaryl alkyl, heteroaryl alkenyl, substituted heteroaryl alkenyl, cycloheteroalkyl, substituted cycloheteroalkyl, cycloheteroalkenyl, or substituted cycloheteroalkenyl. In other embodiments, B is aryl, substituted aryl, aryl alkyl, substituted aryl alkyl, heteroaryl, substituted heteroaryl, heteroaryl alkyl, or substituted heteroaryl alkyl. In yet other embodiments, B is aryl, substituted aryl, heteroaryl, or substituted heteroaryl. In yet other embodiments, B is -NR 53 R 54 In still other embodiments, B is -NHR 54 , R 54 is aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, or substituted heteroarylalkyl-C(O)R 58 , -C(O)OR 59 or -SO2R 62 In still other embodiments, B is -NHR 54 and R 54 is aryl, substituted aryl, heteroaryl, substituted heteroaryl, -C(O)R 58 , -C(O)OR 59 or -SO2R 62 That is true.

[0089] In some embodiments of compounds of Formula (I) and (IV), A is aryl, substituted aryl, heteroaryl, or substituted heteroaryl, and B is aryl, substituted aryl, heteroaryl, or substituted heteroaryl. In other embodiments of Formula (I) and (IV), A is aryl, substituted aryl, heteroaryl, or substituted heteroaryl, and B is -NR53 R 54 In still other embodiments of formula (I) and (IV), A is aryl, substituted aryl, heteroaryl, or substituted heteroaryl, and B is -NHR 54 and R 54 is aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, or substituted heteroarylalkyl-C(O)R 58 , -C(O)OR 59 or -SO2R 62 In still other embodiments of formula (I) and (IV), A is aryl, substituted aryl, heteroaryl, or substituted heteroaryl, and B is -NHR 54 and R 54 is aryl, substituted aryl, heteroaryl, substituted heteroaryl, -C(O)R 58 , -C(O)OR 59 or -SO2R 62 is.

[0090] In certain embodiments, a compound of formula (VII) [ka] The compound of formula (I) is provided.

[0091] In some embodiments, A is aryl, substituted aryl, heteroaryl, or substituted heteroaryl. In other embodiments, A is aryl, substituted phenyl, heteroaryl, or substituted heteroaryl.

[0092] In certain embodiments, a compound of formula (VIIII) [ka] The compound of formula (I) is provided.

[0093] In some embodiments, B is aryl, substituted aryl, heteroaryl, or substituted heteroaryl. In other embodiments, B is aryl, substituted phenyl, heteroaryl, or substituted heteroaryl. In yet other embodiments, B is -NHR 54 and R 54 is aryl, substituted aryl, heteroaryl, substituted heteroaryl, -C(O)R 58 , -C(O)OR 59 or -SO2R 62 is.

[0094] In some embodiments, the compound of formula (IX) [ka] The compound of formula (I) is provided.

[0095] In certain embodiments, A is phenyl or substituted phenyl.

[0096] In certain embodiments, a compound of formula (Ia) [ka] or a pharmaceutically acceptable salt thereof, q is 1, 2 or 3; R 1 and R 3 are each independently halogen in each occurrence, C 1-4 Alkyl, C 1-4 Haloalkyl, -OR 11 , -SR 11 , -N(R 11 )2, -C(O)N(R 11 )2, -C(O)OR 11 , ═O, ═S and —CN; m is selected from 0, 1, 2, 3, 4, 5 and 6; o is selected from 0, 1, 2, 3, 4, 5, 6, 7 and 8; R 2 are independently halogen in each occurrence, C 1-4 Alkyl, C 1-4 Haloalkyl, -OR12 , -SR 12 , -N(R 12 )2, -CN and -NO2; n is 0, 1 or 2; R 4 and R 5 are each independently hydrogen, halogen, or C 1-4 Alkyl, C 1-4 Haloalkyl, -OR 13 , -SR 13 , -N(R 13 )2 and -CN; or R 4 and R 5 Together, =O, =S and =N(R 13 ) forming a double bond substituent selected from; D is selected from a bond, —C(O)—, —C≡CCH2—, and —CH═CHCH2—; E is C 1-4 selected from alkylene and —(CH)Z—; wherein Z is selected from -NH-, -S-, -SO2-, and -O-; XY is λ -C(O)N(R 14 )-, λ -N(R 14 )C(O)-, λ -N(R 14 )C(O)C(R 15 )2-, λ -C(O)O-, λ -C(R 15 )2C(R 15 )2-, λ -CH=CH-, λ -C≡C-, λ -N(R 14 )C(R 15 )2-, λ -C(R 15 )2N(R 14 )-, λ -O-, λ -OC(R 15 )2-, λ -C(R 15 )2O-, λ -SO2N(R 14 )-and λ -N(R14 )SO2-; where: λ is from XY [ka] means bonding to; R 6 and R 7 are each independently hydrogen, halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, -OR 16 and -CN; A is (i) and (ii): (i) Hydrogen, halogen and -CN or A and R 6 C 3-6 Forms a carbocyclic or 3- to 6-membered heterocyclic ring; (ii)-OR 17 , -SR 17 , -N(R 17 )2, -N(R 17 )C(O)R 17 , -N(R 17 )C(O)OR 17 , -N(R 17 )C(O)N(R 17 )2, -N(R 17 )C(S)N(R 17 )2, -N(R 17 )S(O)2(R 17 ), -C(O)R 17 , -C(O)OR 17 , -OC(O)R 17 , -OC(O)N(R 17 )2, -C(O)N(R 17 )2, -S(O)R 17 , -S(O)2R 17 and -S(O)N(R 17 )2; C 1-6 Alkyl (optionally: Halogen, -OR 17 , -SR 17 , -N(R 17 )2, -C(O)R 17 , -C(O)OR 17 , -OC(O)R 17, -OC(O)N(R 17 )2, -C(O)N(R 17 )2, -N(R 17 )C(O)R 17 , -N(R 17 )C(O)OR 17 , -N(R 17 )C(O)N(R 17 )2, -N(R 17 )C(S)N(R 17 )2, -N(R 17 )S(O)2(R 17 ), -S(O)R 17 , -S(O)2R 17 , -S(O)2N(R 17 )2, -NO2, =O, =S, =N(R 17 ), -N3 and -CN, C 3-10 Carbocyclic and 3- to 10-membered heterocyclic rings and is substituted with one or more substituents independently selected from where C 3-10 The carbocyclic ring and the 3- to 10-membered heterocyclic ring each optionally contain halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR 17 , -SR 17 , -N(R 17 )2, -C(O)R 17 , -C(O)OR 17 , -OC(O)R 17 , -OC(O)N(R 17 )2, -C(O)N(R 17 )2, -N(R 17 )C(O)R 17 , -N(R 17 )C(O)OR 17 , -N(R 17 )C(O)N(R 17 )2, -N(R 17 )C(S)N(R 17 )2, -N(R 17 )S(O)2(R 17 ), -S(O)R 17 , -S(O)2R 17 , -S(O)2N(R 17 )2, -NO2, =O, =S, =N(R 17), -N3 and -CN; and C 3-12 Carbocyclic rings and 3- to 12-membered heterocyclic rings (both optionally: Halogen, -OR 17 , -SR 17 , -N(R 17 )2, -C(O)R 17 , -C(O)OR 17 , -OC(O)R 17 , -OC(O)N(R 17 ) 2、 -C(O)N(R 17 )2, -N(R 17 )C(O)R 17 , -N(R 17 )C(O)OR 17 , -N(R 17 )C(O)N(R 17 )2, -N(R 17 )C(S)N(R 17 )2, -N(R 17 )S(O)2(R 17 ), -S(O)R 17 , -S(O)2R 17 , -S(O)2N(R 17 )2, -NO2, =O, =S, =N(R 17 ), -N3 and -CN; Possibly halogen, -OR 17 , -SR 17 , -N(R 17 )2, -C(O)R 17 , -C(O)OR 17 , -OC(O)R 17 , -OC(O)N(R 17 ) 2、 -C(O)N(R 17 )2, -N(R 17 )C(O)R 17 , -N(R 17 )C(O)OR 17 , -N(R 17 )C(O)N(R 17 )2, -N(R 17 )C(S)N(R 17 )2, -N(R 17 )S(O)2(R 17 ), -S(O)R17 , -S(O)2R 17 , -S(O)2N(R 17 )2, -NO2, =O, =S, =N(R 17 ), -N3 and -CN, and C substituted with one or more substituents independently selected from 1-6 alkyl; and Both may contain halogen, C 1-4 Alkyl, C 1-4 C substituted with one or more substituents independently selected from haloalkyl and =O 3-10 Carbocyclic and 3- to 10-membered heterocyclic rings and substituted with one or more substituents independently selected from Selected from; When A is selected from (ii), B is selected from (I) or when A is selected from (i), B is selected from (II): (I) Hydrogen, halogen and -CN or B and R 7 C 3-6 Forms a carbocyclic or 3- to 6-membered heterocyclic ring; (II)-OR 18 , -SR 18 , -N(R 18 )2, -C(O)R 18 , -C(O)OR 18 , -OC(O)R 18 , -OC(O)N(R 18 )2, -C(O)N(R 18 )2, -N(R 18 )C(O)R 18 , -N(R 18 )C(O)OR 18 , -N(R 18 )C(O)N(R 18 )2, -N(R 18 )C(S)N(R 18 )2, -N(R 18 )S(O)2(R 18 ), -S(O)R 18 , -S(O)2R 18 and -S(O)N(R 18 )2; C 1-6 Alkyl (optionally: Halogen, -OR18 , -SR 18 , -N(R 18 )2, -C(O)R 18 , -C(O)OR 18 , -OC(O)R 18 , -OC(O)N(R 18 )2, -C(O)N(R 18 )2, -N(R 18 )C(O)R 18 , -N(R 18 )C(O)OR 18 , -N(R 18 )C(O)N(R 18 )2, -N(R 18 )C(S)N(R 18 )2, -N(R 18 )S(O)2(R 18 ), -S(O)R 18 , -S(O)2R 18 , -S(O)2N(R 18 )2, -NO2, =O, =S, =N(R 18 ), -N3, -CN, C 3-10 Carbocyclic and 3- to 10-membered heterocyclic rings and is substituted with one or more substituents independently selected from where C 3-10 Carbocyclic rings and 3- to 10-membered heterocyclic rings may optionally contain halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR 18 , -SR 18 , -N(R 18 )2, -C(O)R 18 , -C(O)OR 18 , -OC(O)R 18 , -OC(O)N(R 18 )2, -C(O)N(R 18 )2, -N(R 18 )C(O)R 18 , -N(R 18 )C(O)OR 18 , -N(R 18 )C(O)N(R 18 )2, -N(R 18 )C(S)N(R 18 )2, -N(R 18 )S(O)2(R 18 ), -S(O)R18 , -S(O)2R 18 , -S(O)2N(R 18 )2, -NO2, =O, =S, =N(R 18 ), -N3 and -CN; and C 3-12 Carbocyclic rings and 3- to 12-membered heterocyclic rings (each optionally: C 3-6 Carbocyclic and 3- to 6-membered heterocyclic rings (both optionally containing halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, -OR 21 , -SR 21 , -N(R 21 )2, -C(O)R 21 , -C(O)OR 21 , -OC(O)R 21 , -OC(O)N(R 21 )2, -C(O)N(R 21 )2, -N(R 21 )C(O)R 21 , -N(R 21 )C(O)OR 21 , -N(R 21 )C(O)N(R 21 )2, -N(R 21 )C(S)N(R 21 )2, -N(R 21 )S(O)2(R 21 ), -S(O)R 21 , -S(O)2R 21 , -S(O)2N(R 21 )2, -NO2, =O, =S, =N(R 21 ), -N3 and -CN, each of which is substituted with one or more substituents independently selected from and substituted with one or more substituents independently selected from: R 11 , R 12 , R 13 , R 14 and R 16 are each independently hydrogen in each occurrence, C 1-4 Alkyl and C 1-4 haloalkyl; R 15are independently hydrogen, halogen, C 1-4 Alkyl and C 1-4 haloalkyl; R 17 Independently in each case: hydrogen; Possibly halogen, -OR 21 , -SR 21 , -N(R 21 )2, -C(O)R 21 , -C(O)OR 21 , -OC(O)R 21 , -OC(O)N(R 21 )2, -C(O)N(R 21 )2, -N(R 21 )C(O)R 21 , -NO2, =O, =S, =N(R 21 ), -N3 and -CN, and C substituted with one or more substituents independently selected from 1-6 alkyl; and Both may contain halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, -OR 21 , -SR 21 , -N(R 21 )2, -C(O)R 21 , -C(O)OR 21 , -OC(O)R 21 , -OC(O)N(R 21 )2, -C(O)N(R 21 )2, -N(R 21 )C(O)R 21 , -N(R 21 )C(O)OR 21 , -N(R 21 )C(O)N(R 21 )2, -N(R 21 )C(S)N(R 21 )2, -N(R 21 )S(O)2(R 21 ), -S(O)R 21 , -S(O)2R 21 , -S(O)2N(R 21 )2, -NO2, =O, =S, =N(R 21 ), -N3 and -CN, and C substituted with one or more substituents independently selected from 3-6Carbocyclic and 3- to 6-membered heterocyclic rings Selected from; R 18 Independently in each case: hydrogen; C 1-6 Alkyl (optionally: Halogen, -OR 22 , -SR 22 , -N(R 22 )2, -C(O)R 22 , -C(O)OR 22 , -OC(O)R 22 , -OC(O)N(R 22 )2, -C(O)N(R 22 )2, -N(R 22 )C(O)R 22 , -NO2, =O, =S, =N(R 22 ), -N3, -CN, C 3-10 substituted with one or more substituents independently selected from a carbocycle and a 3- to 10-membered heterocycle; where C 3-10 The carbocyclic ring and the 3- to 10-membered heterocyclic ring each optionally contain halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR 22 , -SR 22 and -N(R 22 ) substituted with one or more substituents independently selected from 2); and C 3-10 Carbocycles and 3- to 10-membered heterocycles (both optionally: Halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR 22 , -SR 22 , -N(R 22 )2, -C(O)R 22 , -C(O)OR 22 , -OC(O)R 22 , -OC(O)N(R 22 )2, -C(O)N(R 22 )2, -N(R 22 )C(O)R 22 , -N(R 22 )C(O)OR 22 , -N(R 22 )C(O)N(R22 )2, -N(R 22 )C(S)N(R 22 )2, -N(R 22 )S(O)2(R 22 ), -S(O)R 22 , -S(O)2R 22 , -S(O)2N(R 22 )2, -NO2, =O, =S, =N(R 22 ), -N3, -CN, C 3-6 Carbocyclic and 3- to 6-membered heterocyclic rings and is substituted with one or more substituents independently selected from: where C 3-6 The carbocyclic ring and the 3- to 6-membered heterocyclic ring each optionally contain halogen, C 1-4 Alkyl and C 1-4 substituted with one or more substituents independently selected from haloalkyl Selected from; R 21 and R 22 are each independently in each case: hydrogen; C 1-4 Alkyl (optionally halogen, hydroxyl, C 3-6 substituted with one or more substituents independently selected from a carbocycle and a 3- to 6-membered heterocycle, wherein each C 3-6 Carbocyclic and 3- to 6-membered heterocyclic rings are optionally C 1-4 Alkyl, -N(R 23 )2 and -C(O)N(R 23 ) substituted with one or more substituents independently selected from 2); and Both may contain halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 C substituted with one or more substituents independently selected from alkoxy and =O 3-6 Carbocyclic and 3- to 12-membered heterocyclic rings is selected from; and R 23 are independently hydrogen and C in each case 1-4 alkyl.

[0097] In certain embodiments, a compound of formula (IIa) [ka] or a pharmaceutically acceptable salt thereof, wherein: q is 1, 2 or 3; R 1 and R 3 are each independently halogen in each occurrence, C 1-4 Alkyl, C 1-4 Haloalkyl, -OR 11 , -SR 11 , -N(R 11 )2, -C(O)N(R 11 )2, -C(O)OR 11 , ═O, ═S and —CN; m is selected from 0, 1, 2, 3, 4, 5 and 6; o is selected from 0, 1, 2, 3, 4, 5, 6, 7 and 8; R 2 are independently halogen in each occurrence, C 1-4 Alkyl, C 1-4 Haloalkyl, -OR 12 , -SR 12 , -N(R 12 )2, -CN and -NO2; n is 0, 1 or 2; R 4 and R 5 are each independently hydrogen, halogen, or C 1-4 Alkyl, C 1-4 Haloalkyl, -OR 13 , -SR 13 , -N(R 13 )2 and -CN; or R 4 and R 5 Together, =O, =S and =N(R 13 ) forming a double bond substituent selected from; D is selected from a bond, —C(O)—, —C≡CCH2—, and —CH═CHCH2—; E is C 1-4 selected from alkylene and —(CH)Z—; wherein Z is selected from -NH-, -S-, -SO2-, and -O-; XY is λ -C(O)N(R 14 )-, λ -N(R 14 )C(O)-, λ -N(R 14 )C(O)C(R 15 )2-, λ -C(O)O-, λ -C(R 15 )2C(R 15 )2-, λ -CH=CH-, λ -C≡C-, λ -N(R 14 )C(R 15 )2-, λ -C(R 15 )2N(R 14 )-, λ -O-, λ -OC(R 15 )2-, λ -C(R 15 )2O-, λ -SO2N(R 14 )-and λ -N(R 14 )SO2-; where: λ is from XY [ka] means bonding to; R 6 and R 7 are each independently hydrogen, halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, -OR 16 and -CN; A is -OR 17 , -SR 17 , -N(R 17 )2, -N(R 17 )C(O)R 17 , -N(R 17 )C(O)OR 17 , -N(R 17 )C(O)N(R 17)2, -N(R 17 )C(S)N(R 17 )2, -N(R 17 )S(O)2(R 17 ), -C(O)R 17 , -C(O)OR 17 , -OC(O)R 17 , -OC(O)N(R 17 )2, -C(O)N(R 17 )2, -S(O)R 17 , -S(O)2R 17 and -S(O)N(R 17 )2; C 1-6 Alkyl (optionally: Halogen, -OR 17 , -SR 17 , -N(R 17 )2, -C(O)R 17 , -C(O)OR 17 , -OC(O)R 17 , -OC(O)N(R 17 )2, -C(O)N(R 17 )2, -N(R 17 )C(O)R 17 , -N(R 17 )C(O)OR 17 , -N(R 17 )C(O)N(R 17 )2, -N(R 17 )C(S)N(R 17 )2, -N(R 17 )S(O)2(R 17 ), -S(O)R 17 , -S(O)2R 17 , -S(O)2N(R 17 )2, -NO2, =O, =S, =N(R 17 ), -N3 and -CN, C 3-10 Carbocyclic and 3- to 10-membered heterocyclic rings and is substituted with one or more substituents independently selected from where C 3-10 The carbocyclic ring and the 3- to 10-membered heterocyclic ring each optionally contain halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR 17 , -SR 17 , -N(R17 )2, -C(O)R 17 , -C(O)OR 17 , -OC(O)R 17 , -OC(O)N(R 17 )2, -C(O)N(R 17 )2, -N(R 17 )C(O)R 17 , -N(R 17 )C(O)OR 17 , -N(R 17 )C(O)N(R 17 )2, -N(R 17 )C(S)N(R 17 )2, -N(R 17 )S(O)2(R 17 ), -S(O)R 17 , -S(O)2R 17 , -S(O)2N(R 17 )2, -NO2, =O, =S, =N(R 17 ), -N3 and -CN; and C 3-12 Carbocyclic rings and 3- to 12-membered heterocyclic rings (both optionally: Halogen, -OR 17 , -SR 17 , -N(R 17 )2, -C(O)R 17 , -C(O)OR 17 , -OC(O)R 17 , -OC(O)N(R 17 ) 2、 -C(O)N(R 17 )2, -N(R 17 )C(O)R 17 , -N(R 17 )C(O)OR 17 , -N(R 17 )C(O)N(R 17 )2, -N(R 17 )C(S)N(R 17 )2, -N(R 17 )S(O)2(R 17 ), -S(O)R 17 , -S(O)2R 17 , -S(O)2N(R 17 )2, -NO2, =O, =S, =N(R 17), -N3 and -CN; Possibly halogen, -OR 17 , -SR 17 , -N(R 17 )2, -C(O)R 17 , -C(O)OR 17 , -OC(O)R 17 , -OC(O)N(R 17 ) 2、 -C(O)N(R 17 )2, -N(R 17 )C(O)R 17 , -N(R 17 )C(O)OR 17 , -N(R 17 )C(O)N(R 17 )2, -N(R 17 )C(S)N(R 17 )2, -N(R 17 )S(O)2(R 17 ), -S(O)R 17 , -S(O)2R 17 , -S(O)2N(R 17 )2, -NO2, =O, =S, =N(R 17 ), -N3 and -CN, and C substituted with one or more substituents independently selected from 1-6 alkyl; and Both may contain halogen, C 1-4 Alkyl, C 1-4 C substituted with one or more substituents independently selected from haloalkyl and =O 3-10 Carbocyclic and 3- to 10-membered heterocyclic rings and substituted with one or more substituents independently selected from Selected from; R 11 , R 12 , R 13 , R 14 and R 16 are each independently hydrogen in each occurrence, C 1-4 Alkyl and C 1-4 haloalkyl; R 15 are independently hydrogen, halogen, C 1-4 Alkyl and C 1-4 haloalkyl; R17 Independently in each case: hydrogen; Possibly halogen, -OR 21 , -SR 21 , -N(R 21 )2, -C(O)R 21 , -C(O)OR 21 , -OC(O)R 21 , -OC(O)N(R 21 )2, -C(O)N(R 21 )2, -N(R 21 )C(O)R 21 , -NO2, =O, =S, =N(R 21 ), -N3 and -CN, and C substituted with one or more substituents independently selected from 1-6 alkyl; and Both may contain halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, -OR 21 , -SR 21 , -N(R 21 )2, -C(O)R 21 , -C(O)OR 21 , -OC(O)R 21 , -OC(O)N(R 21 )2, -C(O)N(R 21 )2, -N(R 21 )C(O)R 21 , -N(R 21 )C(O)OR 21 , -N(R 21 )C(O)N(R 21 )2, -N(R 21 )C(S)N(R 21 )2, -N(R 21 )S(O)2(R 21 ), -S(O)R 21 , -S(O)2R 21 , -S(O)2N(R 21 )2, -NO2, =O, =S, =N(R 21 ), -N3 and -CN, and C substituted with one or more substituents independently selected from 3-6 Carbocyclic and 3- to 6-membered heterocyclic rings Selected from; R 21 Independently in each case: hydrogen; Optionally halogen, hydroxyl, C 3-6 C substituted with one or more substituents independently selected from carbocycles and 3- to 6-membered heterocycles 1-4 Alkyl (wherein each C 3-6 Carbocyclic and 3- to 6-membered heterocyclic rings are optionally C 1-4 Alkyl, -N(R 23 )2 and -C(O)N(R 23 ) substituted with one or more substituents independently selected from 2); and Both may contain halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 C substituted with one or more substituents independently selected from alkoxy and =O 3-6 Carbocyclic and 3- to 12-membered heterocyclic rings is selected from; and R 23 are independently hydrogen and C in each case 1-4 alkyl.

[0098] In other embodiments, the compound of formula (IIIa) [ka] or a pharmaceutically acceptable salt thereof, wherein: q is 1, 2 or 3; R 1 and R 3 are each independently halogen in each occurrence, C 1-4 Alkyl, C 1-4 Haloalkyl, -OR 11 , -SR 11 , -N(R 11 )2, -C(O)N(R 11 )2, -C(O)OR 11 , ═O, ═S and —CN; m is selected from 0, 1, 2, 3, 4, 5 and 6; o is selected from 0, 1, 2, 3, 4, 5, 6, 7 and 8; R 2 are independently halogen in each occurrence, C1-4 Alkyl, C 1-4 Haloalkyl, -OR 12 , -SR 12 , -N(R 12 )2, -CN and -NO2; n is 0, 1 or 2; R 4 and R 5 are each independently hydrogen, halogen, or C 1-4 Alkyl, C 1-4 Haloalkyl, -OR 13 , -SR 13 , -N(R 13 )2 and -CN; or R 4 and R 5 Together, =O, =S and =N(R 13 ) forming a double bond substituent selected from; D is selected from a bond, —C(O)—, —C≡CCH2—, and —CH═CHCH2—; E is C 1-4 selected from alkylene and —(CH)Z—; wherein Z is selected from -NH-, -S-, -SO2-, and -O-; XY is λ -C(O)N(R 14 )-, λ -N(R 14 )C(O)-, λ -N(R 14 )C(O)C(R 15 )2-, λ -C(O)O-, λ -C(R 15 )2C(R 15 )2-, λ -CH=CH-, λ -C≡C-, λ -N(R 14 )C(R 15 )2-, λ -C(R 15 )2N(R 14 )-, λ -O-, λ -OC(R 15 )2-, λ -C(R 15 )2O-, λ-SO2N(R 14 )-and λ -N(R 14 )SO2-; where: λ is from XY [ka] means bonding to; R 6 and R 7 are each independently hydrogen, halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, -OR 16 and -CN; B is: -OR 18 , -SR 18 , -N(R 18 )2, -C(O)R 18 , -C(O)OR 18 , -OC(O)R 18 , -OC(O)N(R 18 )2, -C(O)N(R 18 )2, -N(R 18 )C(O)R 18 , -N(R 18 )C(O)OR 18 , -N(R 18 )C(O)N(R 18 )2, -N(R 18 )C(S)N(R 18 )2, -N(R 18 )S(O)2(R 18 ), -S(O)R 18 , -S(O)2R 18 and -S(O)N(R 18 )2; C 1-6 Alkyl (optionally: Halogen, -OR 18 , -SR 18 , -N(R 18 )2, -C(O)R 18 , -C(O)OR 18 , -OC(O)R 18 , -OC(O)N(R 18 )2, -C(O)N(R 18 )2, -N(R18 )C(O)R 18 , -N(R 18 )C(O)OR 18 , -N(R 18 )C(O)N(R 18 )2, -N(R 18 )C(S)N(R 18 )2, -N(R 18 )S(O)2(R 18 ), -S(O)R 18 , -S(O)2R 18 , -S(O)2N(R 18 )2, -NO2, =O, =S, =N(R 18 ), -N3, -CN, C 3-10 Carbocyclic and 3- to 10-membered heterocyclic rings and is substituted with one or more substituents independently selected from where C 3-10 Carbocyclic rings and 3- to 10-membered heterocyclic rings may optionally contain halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR 18 , -SR 18 , -N(R 18 )2, -C(O)R 18 , -C(O)OR 18 , -OC(O)R 18 , -OC(O)N(R 18 )2, -C(O)N(R 18 )2, -N(R 18 )C(O)R 18 , -N(R 18 )C(O)OR 18 , -N(R 18 )C(O)N(R 18 )2, -N(R 18 )C(S)N(R 18 )2, -N(R 18 )S(O)2(R 18 ), -S(O)R 18 , -S(O)2R 18 , -S(O)2N(R 18 )2, -NO2, =O, =S, =N(R 18 ), -N3 and -CN; and C 3-12Carbocyclic rings and 3- to 12-membered heterocyclic rings (both optionally: Both may contain halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, -OR 21 , -SR 21 , -N(R 21 )2, -C(O)R 21 , -C(O)OR 21 , -OC(O)R 21 , -OC(O)N(R 21 )2, -C(O)N(R 21 )2, -N(R 21 )C(O)R 21 , -N(R 21 )C(O)OR 21 , -N(R 21 )C(O)N(R 21 )2, -N(R 21 )C(S)N(R 21 )2, -N(R 21 )S(O)2(R 21 ), -S(O)R 21 , -S(O)2R 21 , -S(O)2N(R 21 )2, -NO2, =O, =S, =N(R 21 ), -N3 and -CN, and C substituted with one or more substituents independently selected from 3-6 Carbocyclic and 3- to 6-membered heterocyclic rings and substituted with one or more substituents independently selected from Selected from; R 11 , R 12 , R 13 , R 14 and R 16 are each independently hydrogen in each occurrence, C 1-4 Alkyl and C 1-4 haloalkyl; R 15 are independently hydrogen, halogen, C 1-4 Alkyl and C 1-4 haloalkyl; R 18 Independently in each case: hydrogen; C 1-6Alkyl (optionally: Halogen, -OR 22 , -SR 22 , -N(R 22 )2, -C(O)R 22 , -C(O)OR 22 , -OC(O)R 22 , -OC(O)N(R 22 )2, -C(O)N(R 22 )2, -N(R 22 )C(O)R 22 , -NO2, =O, =S, =N(R 22 ), -N3, -CN, C 3-10 Carbocyclic and 3- to 10-membered heterocyclic rings and is substituted with one or more substituents independently selected from where C 3-10 The carbocyclic ring and the 3- to 10-membered heterocyclic ring each optionally contain halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR 22 , -SR 22 and -N(R 22 ) substituted with one or more substituents independently selected from 2); and C 3-10 Carbocycles and 3- to 10-membered heterocycles (both optionally: Halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR 22 , -SR 22 , -N(R 22 )2, -C(O)R 22 , -C(O)OR 22 , -OC(O)R 22 , -OC(O)N(R 22 )2, -C(O)N(R 22 )2, -N(R 22 )C(O)R 22 , -N(R 22 )C(O)OR 22 , -N(R 22 )C(O)N(R 22 )2, -N(R 22 )C(S)N(R 22 )2, -N(R 22 )S(O)2(R 22 ), -S(O)R22 , -S(O)2R 22 , -S(O)2N(R 22 )2, -NO2, =O, =S, =N(R 22 ), -N3, -CN, C 3-6 Carbocyclic and 3- to 6-membered heterocyclic rings and is substituted with one or more substituents independently selected from: where C 3-6 The carbocyclic ring and the 3- to 6-membered heterocyclic ring each optionally contain halogen, C 1-4 Alkyl and C 1-4 substituted with one or more substituents independently selected from haloalkyl Selected from; R 22 Independently in each case: hydrogen; C 1-4 Alkyl (optionally halogen, hydroxyl, C 3-6 substituted with one or more substituents independently selected from a carbocycle and a 3- to 6-membered heterocycle, wherein each C 3-6 Carbocyclic and 3- to 6-membered heterocyclic rings are optionally C 1-4 Alkyl, -N(R 23 )2 and -C(O)N(R 23 ) substituted with one or more substituents independently selected from 2); and Both may contain halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 C substituted with one or more substituents independently selected from alkoxy and =O 3-6 Carbocyclic and 3- to 12-membered heterocyclic rings is selected from; and R 23 are independently hydrogen and C in each case 1-4 alkyl.

[0099] In certain embodiments, for a compound or salt of Formula (Ia), (IIa), or (IIIa), q is 1, 2, or 3. In certain embodiments, q is selected from 1, 2, and 3. In certain embodiments, q is selected from 1 and 2. In certain embodiments, q is selected from 2 and 3. In certain embodiments, q is 1. In certain embodiments, q is 2. In certain embodiments, q is 3.

[0100] In certain embodiments, for a compound or salt of Formula (Ia), (IIa), or (IIIa), R 1 and R 3 are each independently halogen in each occurrence, C 1-4 Alkyl, C 1-4 Haloalkyl, -OR 11 , -N(R 11 )2, -C(O)N(R 11 )2, -C(O)OR 11 , ═O, and —CN. In some embodiments, R 1 and R 3 are each independently halogen in each occurrence, C 1-4 Alkyl, C 1-4 Haloalkyl, -OR 11 , -N(R 11 )2, -C(O)N(R 11 )2, -C(O)OR 11 and ═O. In some embodiments, R 1 and R 3 are each independently halogen in each occurrence, C 1-4 Alkyl, C 1-4 Haloalkyl, -OR 11 , -N(R 11 )2, -C(O)N(R 11 )2, -C(O)OR 11 and -CN. In some embodiments, R 1 and R 3 are each independently halogen in each occurrence, C 1-4 Alkyl, C 1-4 Haloalkyl, -OR 11 , -N(R 11 )2, -C(O)N(R 11)2 and -C(O)OR 11 In some embodiments, R 1 and R 3 are each independently halogen in each occurrence, C 1-4 Alkyl, C 1-4 Haloalkyl, -OR 11 , -C(O)N(R 11 )2 and -C(O)OR 11 In some embodiments, R 1 and R 3 are each independently halogen in each occurrence, C 1-4 Alkyl, C 1-4 Haloalkyl, -C(O)N(R 11 )2 and -C(O)OR 11 In some embodiments, R 1 and R 3 are each independently halogen in each occurrence, C 1-4 Alkyl, C 1-4 Haloalkyl and -C(O)N(R 11 In some embodiments, R 1 and R 3 are each independently halogen in each occurrence, C 1-4 Alkyl, -C(O)N(R 11 )2 and -C(O)OR 11 In some embodiments, R 1 and R 3 are each independently halogen in each occurrence, C 1-4 Alkyl and -C(O)N(R 11 )2 is selected.

[0101] In certain embodiments, for a compound or salt of Formula (Ia), (IIa), or (IIIa), m is selected from 0, 1, 2, 3, 4, 5, and 6. In certain embodiments, m is selected from 0, 1, 2, 3, 4, and 5. In certain embodiments, m is selected from 0, 1, 2, 3, and 4. In certain embodiments, m is selected from 1, 2, 3, and 4. In certain embodiments, m is selected from 0, 1, 2, and 3. In certain embodiments, m is selected from 0, 1, and 2. In certain embodiments, m is selected from 0 and 1. In certain embodiments, m is 1. In certain embodiments, m is 2. In certain embodiments, m is 3. In certain embodiments, m is 4. In certain embodiments, m is 5. In certain embodiments, m is 6.

[0102] In certain embodiments, for a compound or salt of Formula (Ia), (IIa), or (IIIa), o is selected from 0, 1, 2, 3, 4, 5, 6, 7, and 8. In certain embodiments, o is selected from 0, 1, 2, 3, 4, 5, 6, and 7. In certain embodiments, o is selected from 0, 1, 2, 3, 4, 5, and 6. In certain embodiments, o is selected from 0, 1, 2, 3, 4, and 5. In certain embodiments, o is selected from 0, 1, 2, 3, and 4. In certain embodiments, o is selected from 1, 2, 3, and 4. In certain embodiments, o is selected from 0, 1, 2, and 3. In certain embodiments, o is selected from 0, 1, and 2. In certain embodiments, o is selected from 0 and 1. In certain embodiments, o is 0. In certain embodiments, o is 1. In certain embodiments, o is 2. In certain embodiments, o is 3. In certain embodiments, o is 4. In certain embodiments, o is 5. In certain embodiments, o is 6. In certain embodiments, o is 7. In some embodiments, o is 8.

[0103] In certain embodiments, for a compound or salt of Formula (Ia), (IIa), or (IIIa), R 2are independently halogen in each occurrence, C 1-4 Alkyl, C 1-4 Haloalkyl, -OR 12 , -SR 12 , -N(R 12 )2 and -CN. In some embodiments, R 2 are independently halogen in each occurrence, C 1-4 Alkyl, C 1-4 Haloalkyl, -OR 12 , -N(R 12 )2 and -CN. In some embodiments, R 2 are independently halogen in each occurrence, C 1-4 Alkyl, C 1-4 Haloalkyl, -OR 12 and -CN. In some embodiments, R 2 are independently halogen in each occurrence, C 1-4 Alkyl, C 1-4 Haloalkyl, -N(R 12 )2 and -CN. In some embodiments, R 2 are independently halogen in each occurrence, C 1-4 Alkyl, C 1-4 Haloalkyl, -OR 12 and -N(R 12 In some embodiments, R 2 are independently halogen in each occurrence, C 1-4 Alkyl, C 1-4 In some embodiments, R is selected from haloalkyl and —CN. 2 are independently halogen in each occurrence, C 1-4 Alkyl, C 1-4 Haloalkyl and -N(R 12 In some embodiments, R 2 are independently halogen in each occurrence, C 1-4 Alkyl, C 1-4 Haloalkyl and -OR 12 In some embodiments, R 2 are independently halogen in each occurrence, C 1-4 Alkyl and C 1-4 In some embodiments, R2 is independently selected at each occurrence from halogen. In certain embodiments, R 2 is independent in each case C 1-4 In some embodiments, R 2 is independent in each case C 1-4 haloalkyl.

[0104] In certain embodiments, for a compound or salt of Formula (Ia), (IIa), or (IIIa), n is 0, 1, or 2. In certain embodiments, n is selected from 0, 1, and 2. In certain embodiments, n is selected from 0 and 1. In certain embodiments, n is selected from 1 and 2. In certain embodiments, n is 0. In certain embodiments, n is 1. In certain embodiments, n is 2.

[0105] In certain embodiments, for a compound or salt of Formula (Ia), (IIa), or (IIIa), R 4 and R 5 are each independently hydrogen, halogen, or C 1-4 Alkyl, C 1-4 Haloalkyl, -OR 13 , -SR 13 , -N(R 13 )2 and -CN; or R 4 and R 5 Together, =O, =S and =N(R 13 In one embodiment, R 4 and R 5 are each independently hydrogen, halogen, or C 1-4 Alkyl, C 1-4 Haloalkyl, -OR 13 , -N(R 13 )2 and -CN; or R 4 and R 5 are combined with =O and =N(R 13 In one embodiment, R 4 and R 5 are each independently hydrogen, halogen, or C1-4 Alkyl, C 1-4 Haloalkyl, -OR 13 , -N(R 13 )2 and -CN; or R 4 and R 5 together form =O. In some embodiments, R 4 and R 5 are each independently hydrogen, halogen, or C 1-4 Alkyl, C 1-4 Haloalkyl, -OR 13 , and-N(R 13 )2; or R 4 and R 5 are combined with =O and =N(R 13 In one embodiment, R 4 and R 5 are each independently hydrogen, halogen, or C 1-4 Alkyl, C 1-4 Haloalkyl, -OR 13 , and-N(R 13 )2; or R 4 and R 5 together form =O. In some embodiments, R 4 and R 5 are each independently hydrogen, halogen, or C 1-4 Alkyl, C 1-4 Haloalkyl and -OR 13 or R 4 and R 5 together form =O. In some embodiments, R 4 and R 5 are each independently hydrogen, halogen, or C 1-4 Alkyl, C 1-4 Haloalkyl and -N(R 13 )2; or R 4 and R 5 together form =O. In some embodiments, R 4 and R 5 are each independently hydrogen, halogen, or C 1-4 Alkyl and C 1-4haloalkyl; or R 4 and R 5 together form =O. In some embodiments, R 4 and R 5 are each independently hydrogen, halogen, and C 1-4 alkyl; or R 4 and R 5 come together to form =O.

[0106] In certain embodiments, for a compound or salt of Formula (Ia), (IIa), or (IIIa), R 4 and R 5 are each independently hydrogen, halogen, or C 1-4 Alkyl, C 1-4 Haloalkyl, -OR 13 , -SR 13 , -N(R 13 )2 and -CN. In some embodiments, R 4 and R 5 are each independently hydrogen, halogen, or C 1-4 Alkyl, C 1-4 Haloalkyl, -OR 13 , -N(R 13 )2 and -CN. In some embodiments, R 4 and R 5 are each independently hydrogen, halogen, or C 1-4 Alkyl, C 1-4 Haloalkyl, -OR 13 and -N(R 13 In some embodiments, R 4 and R 5 are each independently hydrogen, halogen, or C 1-4 Alkyl, C 1-4 Haloalkyl, -OR 13 and -CN. In some embodiments, R 4 and R 5 are each independently hydrogen, halogen, or C 1-4 Alkyl, C 1-4 Haloalkyl, -N(R 13 )2 and -CN. In some embodiments, R 4and R 5 are each independently hydrogen, halogen, or C 1-4 Alkyl, C 1-4 In some embodiments, R is selected from haloalkyl and —CN. 4 and R 5 are each independently hydrogen, halogen, or C 1-4 Alkyl and C 1-4 In some embodiments, R 4 and R 5 are each independently hydrogen, halogen, and C 1-4 In some embodiments, R 4 and R 5 are each independently selected from hydrogen and halogen. 4 and R 5 are each hydrogen.

[0107] In certain embodiments, for a compound or salt of Formula (Ia), (IIa), or (IIIa), R 4 and R 5 Together, =O, =S and =N(R 13 In one embodiment, R 4 and R 5 are combined with =O and =N(R 13 In certain embodiments, for a compound or salt of Formula (I), R 4 and R 5 together form a double bond substituent selected from =O and =S. In certain embodiments, R 4 and R 5 come together to form =O.

[0108] In certain embodiments, for a compound or salt of Formula (Ia), (IIa), or (IIIa), D is selected from a bond, -C(O)-, and -C≡CCH2-. In certain embodiments, D is selected from a bond, -C(O)-, and -CH=CHCH2-. In certain embodiments, D is selected from a bond and -C(O)-. In certain embodiments, D is a bond. In certain embodiments, D is -C(O)-.

[0109] In certain embodiments, for compounds or salts of Formula (Ia), (IIa), or (IIIa), E is C 1-4 In some embodiments, E is selected from -(CH2)Z-, where Z is selected from -NH-, -S-, -SO2-, and -O-. In some embodiments, E is selected from -(CH2)Z-, where Z is selected from -NH-, -S-, -SO2-, and -O-. 1-4 In some embodiments, E is selected from alkylene and -(CH2)Z-, where Z is selected from -NH-, -S-, and -O-. 1-4 In some embodiments, E is selected from alkylene and -(CH2)Z-, where Z is selected from -NH-, -SO2-, and -O-. 1-4 It is selected from alkylene and -(CH2)Z-, where Z is selected from -NH- and -O-.

[0110] In certain embodiments, for compounds or salts of Formula (Ia), (IIa), or (IIIa), D is selected from a bond and —C(O)—; and E is C 1-4 In some embodiments, D is a bond; and E is C 1-4 In some embodiments, D is -C(O)-; and E is C 1-4 alkylene.

[0111] In certain embodiments, for a compound or salt of Formula (Ia), (IIa) or (IIIa), XY is: λ -C(O)N(R 14 )-, λ -N(R14 )C(O)-, λ -N(R 14 )C(O)C(R 15 )2-, λ -C(O)O-, λ -C(R 15 )2C(R 15 )2-, λ -N(R 14 )C(R 15 )2-, λ -C(R 15 )2N(R 14 )-, λ -O-, λ -OC(R 15 )2-, λ -C(R 15 )2O-, λ -SO2N(R 14 )-and λ -N(R 14 )SO2-; wherein λ is from XY [ka] In some embodiments, XY is λ -C(O)N(R 14 )-, λ -N(R 14 )C(O)-, λ -N(R 14 )C(O)C(R 15 )2-, λ -C(O)O-, λ -C(R 15 )2C(R 15 )2-, λ -CH=CH-, λ -C≡C-, λ -N(R 14 )C(R 15 )2-, λ -C(R 15 )2N(R 14 )-, λ -O-, λ -OC(R 15 )2- and λ -C(R 15 In some embodiments, XY is selected from: λ-C(O)N(R 14 )-, λ -N(R 14 )C(O)-, λ -N(R 14 )C(O)C(R 15 )2-, λ -C(R 15 )2C(R 15 )2-, λ -CH=CH-, λ -C≡C-, λ -N(R 14 )C(R 15 )2-, λ -C(R 15 )2N(R 14 )-, λ -O-, λ -OC(R 15 )2-, λ -C(R 15 )2O-, λ -SO2N(R 14 )-and λ -N(R 14 In some embodiments, XY is selected from: λ -C(O)N(R 14 )-, λ -N(R 14 )C(O)-, λ -N(R 14 )C(O)C(R 15 )2-, λ -C(O)O-, λ -C(R 15 )2C(R 15 )2-, λ -N(R 14 )C(R 15 )2-, λ -C(R 15 )2N(R 14 )-, λ -O-, λ -OC(R 15 )2- and λ -C(R 15 In some embodiments, XY is selected from: λ -C(O)N(R 14 )-, λ -N(R 14 )C(O)-, λ -N(R14 )C(O)C(R 15 )2-, λ -C(R 15 )2C(R 15 )2-, λ -N(R 14 )C(R 15 )2-, λ -C(R 15 )2N(R 14 )-, λ -O-, λ -OC(R 15 )2-, λ -C(R 15 )2O-, λ -SO2N(R 14 )-and λ -N(R 14 In some embodiments, XY is selected from: λ -C(O)N(R 14 )-, λ -N(R 14 )C(O)-, λ -N(R 14 )C(O)C(R 15 )2-, λ -C(R 15 )2C(R 15 )2-, λ -CH=CH-, λ -C≡C-, λ -N(R 14 )C(R 15 )2-, λ -C(R 15 )2N(R 14 )-, λ -O-, λ -OC(R 15 )2- and λ -C(R 15 )2O-.

[0112] In certain embodiments, for compounds or salts of Formula (Ia), (IIa), or (IIIa), XY is λ -C(O)N(R 14 )-, λ -N(R 14 )C(O)-, λ -C(R 15 )2C(R 15)2-, λ -N(R 14 )C(R 15 )2-, λ -C(R 15 )2N(R 14 )-, λ -O-, λ -OC(R 15 )2- and λ -C(R 15 In some embodiments, XY is selected from: λ -C(O)N(R 14 )-, λ -N(R 14 )C(O)-, λ -N(R 14 )C(R 15 )2-, λ -C(R 15 )2N(R 14 )-, λ -O-, λ -OC(R 15 )2- and λ -C(R 15 In some embodiments, XY is selected from: λ -C(O)N(R 14 )-, λ -N(R 14 )C(O)-, λ -N(R 14 )C(R 15 )2-, λ -C(R 15 )2N(R 14 )-, λ -OC(R 15 )2- and λ -C(R 15 In some embodiments, XY is selected from: λ -C(O)N(R 14 )-, λ -N(R 14 )C(O)-, λ -OC(R 15 )2- and λ -C(R 15 In some embodiments, XY is selected from: λ -C(O)N(R 14 )-, λ -N(R14 )C(O)-, λ -OC(R 15 )2- and λ -C(R 15 In some embodiments, XY is selected from: λ -C(O)N(R 14 )-and λ -N(R 14 )C(O)—. In some embodiments, XY is λ -OC(R 15 )2- and λ -C(R 15 In some embodiments, XY is selected from: λ -C(O)N(R 14 )-, and in some embodiments, XY is λ -N(R 14 )C(O)—. In some embodiments, XY is λ -C(R 15 )2C(R 15 In some embodiments, XY is λ -N(R 14 )C(R 15 In some embodiments, XY is λ -C(R 15 )2N(R 14 In some embodiments, XY is λ In some embodiments, XY is -O-. λ -OC(R 15 In some embodiments, XY is λ -C(R 15 )2O-.

[0113] In certain embodiments, for compounds or salts of Formula (Ia), (IIa), or (IIIa), XY is λ -C(O)N(R 14 )-, λ -N(R 14 )C(O)-, λ -N(R 14 )C(O)CH2-, λ -CH2CH2-, λ -N(R14 )CH2-, λ -CH2N(R 14 )-, λ -O-, λ -OCH2- and λ -CH2O-; and R 14 In each case, hydrogen and C 1-4 In some embodiments, XY is λ -C(O)N(R 14 )-, λ -N(R 14 )C(O)-, λ -N(R 14 )C(R 15 )2-, λ -C(R 15 )2N(R 14 )-, λ -OC(R 15 )2- and λ -C(R 15 )2O-; R 14 In each case, hydrogen and C 1-4 In some embodiments, XY is selected from alkyl. λ -C(O)N(R 14 )-, λ -N(R 14 )C(O)-, λ -OC(R 15 )2- and λ -C(R 15 )2O-; R 14 In each case, hydrogen and C 1-4 In some embodiments, XY is selected from alkyl. λ -C(O)N(R 14 )-, λ -N(R 14 )C(O)-, λ -OC(R 15 )2- and λ -C(R 15 )2O-; R 14 In each case, hydrogen and C 1-4 In some embodiments, XY is selected from alkyl. λ -C(O)N(R 14 )-and λ -N(R 14)C(O)-; R 14 In each case, hydrogen and C 1-4 alkyl.

[0114] In certain embodiments, for compounds or salts of Formula (Ia), (IIa), or (IIIa), XY is λ -C(O)N(H)-, λ -N(H)C(O)-, λ -CH2CH2-, λ -N(H)CH2-, λ -CH2N(H)-, λ -O-, λ -OCH2- and λ In some embodiments, XY is selected from -CH2O-. λ -C(O)N(H)-, λ -N(H)C(O)-, λ -N(H)CH2-, λ -CH2N(H)-, λ -O-, λ -OCH2- and λ In some embodiments, XY is selected from -CH2O-. λ -C(O)N(H)-, λ -N(H)C(O)-, λ -N(H)CH2-, λ -CH2N(H)-, λ -OCH2- and λ In some embodiments, XY is selected from -CH2O-. λ -C(O)N(H)-, λ -N(H)C(O)-, λ -OCH2- and λ In some embodiments, XY is selected from -CH2O-. λ -C(O)N(H)-, λ -N(H)C(O)-, λ -OCH2- and λ In some embodiments, XY is selected from -CH2O-. λ -C(O)N(H)- and λ In some embodiments, XY is selected from -N(H)C(O)-. λ -OCH2- andλ In some embodiments, XY is selected from -CH2O-. λ In some embodiments, XY is -C(O)N(H)-. λ In some embodiments, XY is -N(H)C(O)-. λ In some embodiments, XY is -CHCH-. λ In some embodiments, XY is -N(H)CH-. λ In some embodiments, XY is -CHN(H)-. λ In some embodiments, XY is -O-. λ In some embodiments, XY is -OCH2-. λ -CH2O-.

[0115] In certain embodiments, for a compound or salt of Formula (Ia), (IIa), or (IIIa), R 6 and R 7 are each independently hydrogen, halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, -OR 16 , -N(R 16 )2 and -CN. In some embodiments, R 6 and R 7 are each independently hydrogen, halogen, C 1-4 Alkyl, C 1-4 Haloalkyl and -OR 16 In some embodiments, R 6 and R 7 are each independently hydrogen, halogen, C 1-4 Alkyl and -OR 16 In some embodiments, R 6 and R 7 are each independently hydrogen, halogen and -OR 16 In some embodiments, R 6 and R 7 is independently selected at each occurrence from hydrogen and halogen. 6 and R 7are each independently hydrogen and -OR 16 In some embodiments, R 6 and R 7 are each hydrogen.

[0116] In certain embodiments, for a compound or salt of Formula (Ia), (IIa), or (IIIa), A is selected from (i) and (ii): (i) Hydrogen, halogen and -CN or A and R 6 C 3-6 forming a carbocyclic ring or a 3- to 6-membered heterocyclic ring; and (ii) C 3-12 Carbocyclic rings and 3- to 12-membered heterocyclic rings (both optionally: Halogen, -OR 17 , -SR 17 , -N(R 17 )2, -C(O)R 17 , -C(O)OR 17 , -OC(O)R 17 , -OC(O)N(R 17 ) 2、 -C(O)N(R 17 )2, -N(R 17 )C(O)R 17 , -N(R 17 )C(O)OR 17 , -N(R 17 )C(O)N(R 17 )2, -N(R 17 )C(S)N(R 17 )2, -N(R 17 )S(O)2(R 17 ), -S(O)R 17 , -S(O)2R 17 , -S(O)2N(R 17 )2, -NO2, =O, =S, =N(R 17 ), -N3 and -CN; Possibly halogen, -OR 17 , -SR 17 , -N(R 17 )2, -C(O)R 17 , -C(O)OR 17 , -OC(O)R 17 , -OC(O)N(R 17 )2、 -C(O)N(R 17 )2, -N(R 17 )C(O)R 17 , -N(R 17 )C(O)OR 17 , -N(R 17 )C(O)N(R 17 )2, -N(R 17 )C(S)N(R 17 )2, -N(R 17 )S(O)2(R 17 ), -S(O)R 17 , -S(O)2R 17 , -S(O)2N(R 17 )2, -NO2, =O, =S, =N(R 17 ), -N3 and -CN, and C substituted with one or more substituents independently selected from 1-6 alkyl; and Both may contain halogen, C 1-4 Alkyl, C 1-4 C substituted with one or more substituents independently selected from haloalkyl and =O 3-10 Carbocyclic and 3- to 10-membered heterocyclic rings and substituted with one or more substituents independently selected from is selected from.

[0117] In certain embodiments, for a compound or salt of Formula (Ia), (IIa), or (IIIa), A is selected from (i) and (ii): (i) hydrogen; and (ii) C 3-12 Carbocyclic rings and 3- to 12-membered heterocyclic rings (both optionally: Halogen, -OR 17 , -N(R 17 )2, -C(O)R 17 , -C(O)OR 17 , -OC(O)R 17 , -OC(O)N(R 17 ) 2、 -C(O)N(R 17 )2, -N(R 17 )C(O)R 17 , -N(R 17 )C(O)OR 17 , -N(R17 )C(O)N(R 17 )2, -N(R 17 )S(O)2(R 17 ), -S(O)R 17 , -S(O)2R 17 , -S(O)2N(R 17 )2, -NO2, =O and -CN; Possibly halogen, -OR 17 , -N(R 17 )2, -C(O)R 17 , -C(O)OR 17 , -OC(O)R 17 , -OC(O)N(R 17 ) 2、 -C(O)N(R 17 )2, -N(R 17 )C(O)R 17 , -N(R 17 )C(O)OR 17 , -N(R 17 )C(O)N(R 17 )2, -N(R 17 )S(O)2(R 17 ), -S(O)R 17 , -S(O)2R 17 , -S(O)2N(R 17 )2, -NO2, =O, C substituted with one or more substituents independently selected from -CN 1-6 alkyl; and Both may contain halogen, C 1-4 Alkyl, C 1-4 C substituted with one or more substituents independently selected from haloalkyl and =O 3-10 Carbocyclic and 3- to 10-membered heterocyclic rings and substituted with one or more substituents independently selected from is selected from.

[0118] In certain embodiments, for a compound or salt of Formula (Ia), (IIa), or (IIIa), A is selected from (i) and (ii): (i) hydrogen; and (ii) C 3-12 Carbocyclic rings and 3- to 12-membered heterocyclic rings (both optionally: Halogen, -OR17 , -N(R 17 )2, -C(O)R 17 , -C(O)OR 17 , -OC(O)R 17 , -C(O)N(R 17 )2, -N(R 17 )C(O)R 17 , -N(R 17 )S(O)2(R 17 ), -S(O)R 17 , -S(O)2N(R 17 )2, -NO2, =O and -CN; Possibly halogen, -OR 17 , -N(R 17 )2, -C(O)R 17 , -C(O)OR 17 , -OC(O)R 17 , -C(O)N(R 17 )2, -N(R 17 )C(O)R 17 , -N(R 17 )S(O)2(R 17 ), -S(O)R 17 , -S(O)2N(R 17 )2, -NO2, =O, C substituted with one or more substituents independently selected from -CN 1-6 alkyl; and Both may contain halogen, C 1-4 Alkyl, C 1-4 C substituted with one or more substituents independently selected from haloalkyl and =O 3-10 Carbocyclic and 3- to 10-membered heterocyclic rings and substituted with one or more substituents independently selected from is selected from.

[0119] In certain embodiments, for a compound or salt of Formula (Ia), (IIa), or (IIIa), A is selected from (i) and (ii): (i) hydrogen; and (ii) C 3-12 Carbocyclic rings and 3- to 12-membered heterocyclic rings (both optionally: Halogen, -OR 17 , -N(R 17)2, -C(O)R 17 , -C(O)OR 17 , -OC(O)R 17 , -C(O)N(R 17 )2, -N(R 17 )C(O)R 17 , -NO2, =O and -CN; Possibly halogen, -OR 17 , -N(R 17 )2, -C(O)R 17 , -C(O)OR 17 , -OC(O)R 17 , -C(O)N(R 17 )2, -N(R 17 )C(O)R 17 C substituted with one or more substituents independently selected from -NO2, =O, and -CN 1-6 alkyl; and Both may contain halogen, C 1-4 Alkyl, C 1-4 C substituted with one or more substituents independently selected from haloalkyl and =O 3-10 Carbocyclic and 3- to 10-membered heterocyclic rings and substituted with one or more substituents independently selected from is selected from.

[0120] In certain embodiments, for a compound or salt of Formula (Ia), (IIa), or (IIIa), A is selected from (i) and (ii): (i) hydrogen; and (ii) C 3-12 Carbocyclic and 3- to 12-membered heterocyclic rings (each optionally halogenated; -OR 17 C optionally substituted with one or more substituents independently selected from halogen 1-6 alkyl; and each optionally halogen, C 1-4 Alkyl, C 1-4 C substituted with one or more substituents independently selected from haloalkyl and =O 3-10 substituted with one or more substituents independently selected from a carbocycle and a 3- to 10-membered heterocycle; 17 are independently hydrogen in each occurrence, C 1-6Alkyl, C 3-6 selected from carbocyclic rings and 3- to 6-membered heterocyclic rings is selected from.

[0121] In certain embodiments, for compounds or salts of Formula (Ia), (IIa), or (IIIa), A is selected from hydrogen, halogen, and —CN, or A and R 6 C 3-6 In some embodiments, A is selected from hydrogen and halogen, or A and R 6 C 3-6 In some embodiments, A is hydrogen or A and R 6 C 3-6 In some embodiments, A is selected from hydrogen, halogen, and -CN. In some embodiments, A is selected from hydrogen and halogen. In some embodiments, A is selected from hydrogen and -CN. In some embodiments, A is hydrogen. In some embodiments, A and R 6 C 3-6 In one embodiment, A and R form a carbocyclic ring or a 3- to 6-membered heterocyclic ring. 6 C 3-6 Forms a carbocyclic ring.

[0122] In certain embodiments, for compounds or salts of Formula (Ia), (IIa), or (IIIa), A is C 3-12 selected from carbocycles and 3- to 12-membered heterocycles, each optionally being: Halogen, -OR 17 , -SR 17 , -N(R 17 )2, -C(O)R 17 , -C(O)OR 17 , -OC(O)R 17 , -OC(O)N(R 17 ) 2、 -C(O)N(R 17 )2, -N(R 17 )C(O)R 17 , -N(R 17)C(O)OR 17 , -N(R 17 )C(O)N(R 17 )2, -N(R 17 )C(S)N(R 17 )2, -N(R 17 )S(O)2(R 17 ), -S(O)R 17 , -S(O)2R 17 , -S(O)2N(R 17 )2, -NO2, =O, =S, =N(R 17 ), -N3 and -CN; Possibly halogen, -OR 17 , -SR 17 , -N(R 17 )2, -C(O)R 17 , -C(O)OR 17 , -OC(O)R 17 , -OC(O)N(R 17 ) 2、 -C(O)N(R 17 )2, -N(R 17 )C(O)R 17 , -N(R 17 )C(O)OR 17 , -N(R 17 )C(O)N(R 17 )2, -N(R 17 )C(S)N(R 17 )2, -N(R 17 )S(O)2(R 17 ), -S(O)R 17 , -S(O)2R 17 , -S(O)2N(R 17 )2, -NO2, =O, =S, =N(R 17 ), -N3 and -CN, and C substituted with one or more substituents independently selected from 1-6 alkyl; and Both may contain halogen, C 1-4 Alkyl, C 1-4 C substituted with one or more substituents independently selected from haloalkyl and =O 3-10 Carbocyclic and 3- to 10-membered heterocyclic rings is substituted with one or more substituents independently selected from

[0123] In certain embodiments, for compounds or salts of Formula (Ia), (IIa), or (IIIa), A is C 3-12 selected from carbocycles and 3- to 12-membered heterocycles, each optionally being: Halogen, -OR 17 , -N(R 17 )2, -C(O)R 17 , -C(O)OR 17 , -OC(O)R 17 , -OC(O)N(R 17 ) 2、 -C(O)N(R 17 )2, -N(R 17 )C(O)R 17 , -N(R 17 )C(O)OR 17 , -N(R 17 )C(O)N(R 17 )2, -N(R 17 )S(O)2(R 17 ), -S(O)R 17 , -S(O)2R 17 , -S(O)2N(R 17 )2, -NO2, =O and -CN; Possibly halogen, -OR 17 , -N(R 17 )2, -C(O)R 17 , -C(O)OR 17 , -OC(O)R 17 , -OC(O)N(R 17 ) 2、 -C(O)N(R 17 )2, -N(R 17 )C(O)R 17 , -N(R 17 )C(O)OR 17 , -N(R 17 )C(O)N(R 17 )2, -N(R 17 )S(O)2(R 17 ), -S(O)R 17 , -S(O)2R 17 , -S(O)2N(R 17 )2, -NO2, =O, C substituted with one or more substituents independently selected from -CN 1-6 alkyl; and Both may contain halogen, C1-4 Alkyl, C 1-4 C substituted with one or more substituents independently selected from haloalkyl and =O 3-10 Carbocyclic and 3- to 10-membered heterocyclic rings is substituted with one or more substituents independently selected from

[0124] In certain embodiments, for compounds or salts of Formula (Ia), (IIa), or (IIIa), A is C 3-12 selected from carbocycles and 3- to 12-membered heterocycles, each optionally being: Halogen, -OR 17 , -N(R 17 )2, -C(O)R 17 , -C(O)OR 17 , -OC(O)R 17 , -C(O)N(R 17 )2, -N(R 17 )C(O)R 17 , -NO2, =O and -CN; Possibly halogen, -OR 17 , -N(R 17 )2, -C(O)R 17 , -C(O)OR 17 , -OC(O)R 17 , -C(O)N(R 17 )2, -N(R 17 )C(O)R 17 C substituted with one or more substituents independently selected from -NO2, =O, and -CN 1-6 alkyl; and Both may contain halogen, C 1-4 Alkyl, C 1-4 C substituted with one or more substituents independently selected from haloalkyl and =O 3-10 Carbocyclic and 3- to 10-membered heterocyclic rings is substituted with one or more substituents independently selected from

[0125] In certain embodiments, for compounds or salts of Formula (Ia), (IIa), or (IIIa), A is C 3-12selected from carbocycles and 3- to 12-membered heterocycles, each optionally containing halogen; -OR 17 C optionally substituted with one or more substituents independently selected from halogen 1-6 alkyl; and each optionally halogen, C 1-4 Alkyl, C 1-4 C substituted with one or more substituents independently selected from haloalkyl and =O 3-10 It is substituted with one or more substituents independently selected from a carbocycle and a 3- to 10-membered heterocycle.

[0126] In certain embodiments, for a compound or salt of Formula (Ia), (IIa), or (IIIa), R 17 Independently in each case: hydrogen; Possibly halogen, -OR 21 , -N(R 21 )2, -C(O)R 21 , -C(O)OR 21 , -OC(O)R 21 , -OC(O)N(R 21 )2, -C(O)N(R 21 )2, -N(R 21 )C(O)R 21 C substituted with one or more substituents independently selected from -NO, -O, and -CN 1-6 alkyl; and Both may contain halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, -OR 21 , -N(R 21 )2, -C(O)R 21 , -C(O)OR 21 , -OC(O)R 21 , -OC(O)N(R 21 )2, -C(O)N(R 21 )2, -N(R 21 )C(O)R 21 , -N(R 21 )C(O)OR 21 , -N(R 21 )C(O)N(R 21 )2, -N(R 21 )C(S)N(R21 )2, -N(R 21 )S(O)2(R 21 ), -S(O)R 21 , -S(O)2R 21 , -S(O)2N(R 21 C substituted with one or more substituents independently selected from -NO, -O, and -CN 3-6 Carbocyclic and 3- to 6-membered heterocyclic rings is selected from.

[0127] In certain embodiments, for a compound or salt of Formula (Ia), (IIa), or (IIIa), R 17 Independently in each case: hydrogen; Possibly halogen, -OR 21 , -N(R 21 )2, -C(O)OR 21 , -OC(O)R 21 , -C(O)N(R 21 )2, -N(R 21 )C(O)R 21 C substituted with one or more substituents independently selected from ═O and —CN 1-6 alkyl; and Both may contain halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, -OR 21 , -N(R 21 )2, -C(O)R 21 , -C(O)OR 21 , -OC(O)R 21 , -C(O)N(R 21 )2, -N(R 21 )C(O)R 21 , -N(R 21 )S(O)2(R 21 ), -S(O)R 21 , -S(O)2N(R 21 )2, C substituted with one or more substituents independently selected from ═O and —CN 3-6 Carbocyclic and 3- to 6-membered heterocyclic rings is selected from.

[0128] In certain embodiments, for a compound or salt of Formula (Ia), (IIa), or (IIIa), R 17 is independently in each occurrence hydrogen; optionally halogen, -OR 21 , -N(R 21 )2, -C(O)N(R 21 )2, -N(R 21 )C(O)R 21 C substituted with one or more substituents independently selected from ═O and —CN 1-6 Alkyl; and halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, -OR 21 , -N(R 21 )2, -C(O)R 21 , -C(O)N(R 21 )2, -N(R 21 )C(O)R 21 , =O and -CNC 3-6 In one embodiment, R 17 are independently hydrogen in each occurrence, C 1-6 Alkyl, C 3-6 It is selected from carbocycles and 3- to 6-membered heterocycles.

[0129] In certain embodiments, for a compound or salt of Formula (Ia), (IIa), or (IIIa), R 21 Independently in each case: hydrogen; C 1-4 Alkyl (optionally halogen, hydroxyl, C 3-6 substituted with one or more substituents independently selected from a carbocycle and a 3- to 6-membered heterocycle, wherein each C 3-6 Carbocyclic and 3- to 6-membered heterocyclic rings may optionally contain halogen, C 1-4 Alkyl and -C(O)N(R 23 ) substituted with one or more substituents independently selected from 2); and Both may contain halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 C substituted with one or more substituents independently selected from alkoxy and =O3-6 Carbocyclic and 3- to 12-membered heterocyclic rings is selected from; and R 23 are independently hydrogen and C in each case 1-4 alkyl.

[0130] In certain embodiments, for a compound or salt of Formula (Ia), (IIa), or (IIIa), R 21 are independently hydrogen in each occurrence, C 1-4 Alkyl, C 3-6 selected from carbocycles and 3- to 6-membered heterocycles, 3-6 The carbocyclic ring and the 3- to 6-membered heterocyclic ring may each optionally be C 1-4 Alkyl and C 1-4 substituted with one or more substituents independently selected from alkoxy; and R 23 are independently hydrogen and C in each case 1-4 alkyl.

[0131] In certain embodiments, for compounds or salts of Formula (Ia), (IIa), or (IIIa), A is C 3-12 In one embodiment, C of A is selected from a carbocycle and a 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents. 3-12 The carbocycle and 3- to 12-membered heterocycle are selected from phenyl; pyridine; indane; chroman; benzodioxole; 2,3-dihydrobenzofuran; quinoline; 1,2,3,4-tetrahydronaphthalene; naphthalene; quinoxaline; 2',3'-dihydrospiro[cyclopropane-1,1'-indene]; and pyrazole, each of which is optionally substituted with one or more substituents.

[0132] In certain embodiments, for a compound or salt of Formula (Ia), (IIa), or (IIIa), C of A 3-12 Carbocycles and 3- to 12-membered heterocycles are monocyclic C 3-6In some embodiments, for a compound or salt of Formula (Ia), (IIa), or (IIIa), C of A is selected from a carbocycle and a 3- to 7-membered monocyclic heterocycle, each of which is optionally substituted with one or more substituents. 3-12 The carbocycle and 3- to 12-membered heterocycle are selected from phenyl, pyridine and pyrazole, each of which is optionally substituted with one or more substituents.

[0133] In certain embodiments, for a compound or salt of Formula (Ia), (IIa), or (IIIa), C of A 3-12 Carbocycles and 3- to 12-membered heterocycles are polycyclic C 7-12 In some embodiments, for a compound or salt of Formula (Ia), (IIa), or (IIIa), C of A is selected from a carbocycle and a 7- to 12-membered monocyclic heterocycle, each of which is optionally substituted with one or more substituents. 3-12 The carbocycle and 3- to 12-membered heterocycle are selected from indane; chroman; benzodioxole; 2,3-dihydrobenzofuran; quinoline; 1,2,3,4-tetrahydronaphthalene; naphthalene; quinoxaline; and 2',3'-dihydrospiro[cyclopropane-1,1'-indene], each optionally substituted with one or more substituents.

[0134] In certain embodiments, for compounds or salts of Formula (Ia), (IIa), or (IIIa), one or more optional substituents of A are Halogen, -OR 17 , -N(R 17 )2, -C(O)R 17 , -C(O)OR 17 , -OC(O)R 17 , -OC(O)N(R 17 ) 2、 -C(O)N(R 17 )2, -N(R 17 )C(O)R 17 , -N(R 17 )C(O)OR 17 , -N(R 17 )C(O)N(R 17 )2, -N(R 17 )S(O)2(R 17), -S(O)R 17 , -S(O)2R 17 , -S(O)2N(R 17 )2, -NO2, =O and -CN; Possibly halogen, -OR 17 , -N(R 17 )2, -C(O)R 17 , -C(O)OR 17 , -OC(O)R 17 , -OC(O)N(R 17 ) 2、 -C(O)N(R 17 )2, -N(R 17 )C(O)R 17 , -N(R 17 )C(O)OR 17 , -N(R 17 )C(O)N(R 17 )2, -N(R 17 )S(O)2(R 17 ), -S(O)R 17 , -S(O)2R 17 , -S(O)2N(R 17 )2, -NO2, =O, C substituted with one or more substituents independently selected from -CN 1-6 alkyl; and Both may contain halogen, C 1-4 Alkyl, C 1-4 C substituted with one or more substituents independently selected from haloalkyl and =O 3-10 Carbocyclic and 3- to 10-membered heterocyclic rings is selected from.

[0135] In certain embodiments, for compounds or salts of Formula (Ia), (IIa), or (IIIa), one or more optional substituents of A are Halogen, -OR 17 , -N(R 17 )2, -C(O)R 17 , -C(O)OR 17 , -OC(O)R 17 , -C(O)N(R 17 )2, -N(R 17 )C(O)R 17 , -NO2, =O and -CN; Possibly halogen, -OR 17 , -N(R 17 )2, -C(O)R 17 , -C(O)OR 17 , -OC(O)R 17 , -C(O)N(R 17 )2, -N(R 17 )C(O)R 17 C substituted with one or more substituents independently selected from -NO2, =O, and -CN 1-6 alkyl; and Both may contain halogen, C 1-4 Alkyl, C 1-4 C substituted with one or more substituents independently selected from haloalkyl and =O 3-10 Carbocyclic and 3- to 10-membered heterocyclic rings is selected from.

[0136] In certain embodiments, for compounds or salts of Formula (Ia), (IIa), or (IIIa), one or more optional substituents of A are: Halogen, -OR 17 , N(R 17 )2, -C(O)R 17 , -N(R 17 )C(O)R 17 , -N(R 17 )S(O)2(R 17 ), =O, =S and -CN; C 1-6 Alkyl (optionally halogen, -OR 17 , -N(R 17 )2, -N(R 17 )C(O)R 17 , -N(R 17 )S(O)2(R 17 ), -S(O)R 17 , ═O, and —CN; and Both may contain halogen, C 1-4 Alkyl, C 1-4 C substituted with one or more substituents independently selected from haloalkyl and =O 3-10 Carbocyclic and 3- to 10-membered heterocyclic rings is selected from.

[0137] In certain embodiments, for compounds or salts of Formula (Ia), (IIa), or (IIIa), one or more optional substituents of A are halogen, —OR 17 , C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 Carbocyclic and 3- to 10-membered heterocyclic rings (wherein C 3-10 The carbocyclic ring and the 3- to 10-membered heterocyclic ring may each optionally be C 1-4 Alkyl, C 1-4 substituted with one or more substituents independently selected from haloalkyl and ═O.

[0138] In certain embodiments, for compounds or salts of Formula (Ia), (IIa), or (IIIa), A is C 3-12 selected from carbocycles and 3- to 12-membered heterocycles, each of which is optionally Halogen, -OR 17 , -N(R 17 )2, -C(O)R 17 , -C(O)OR 17 , -OC(O)R 17 , -OC(O)N(R 17 ) 2、 -C(O)N(R 17 )2, -N(R 17 )C(O)R 17 , -N(R 17 )C(O)OR 17 , -N(R 17 )C(O)N(R 17 )2, -N(R 17 )S(O)2(R 17 ), -S(O)R 17 , -S(O)2R 17 , -S(O)2N(R 17 )2, -NO2, =O and -CN; Possibly halogen, -OR 17 , -N(R 17 )2, -C(O)R 17 , -C(O)OR 17 , -OC(O)R 17 , -OC(O)N(R17 ) 2、 -C(O)N(R 17 )2, -N(R 17 )C(O)R 17 , -N(R 17 )C(O)OR 17 , -N(R 17 )C(O)N(R 17 )2, -N(R 17 )S(O)2(R 17 ), -S(O)R 17 , -S(O)2R 17 , -S(O)2N(R 17 )2, -NO2, =O, C substituted with one or more substituents independently selected from -CN 1-6 alkyl; and Both may contain halogen, C 1-4 Alkyl, C 1-4 C substituted with one or more substituents independently selected from haloalkyl and =O 3-10 Carbocyclic and 3- to 10-membered heterocyclic rings is substituted with one or more substituents selected from

[0139] In certain embodiments, for compounds or salts of Formula (Ia), (IIa), or (IIIa), A is C 3-12 selected from carbocycles and 3- to 12-membered heterocycles, each optionally containing halogen; -OR 17 C optionally substituted with one or more substituents independently selected from halogen 1-6 alkyl; and each optionally halogen, C 1-4 Alkyl, C 1-4 C substituted with one or more substituents independently selected from haloalkyl and =O 3-10 In one embodiment, A is substituted with one or more substituents selected from a carbocycle and a 3- to 10-membered heterocycle. 3-12 a carbocycle and a 3- to 12-membered heterocycle, each of which may optionally contain halogen, -OR 17 , C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 Carbocyclic and 3- to 10-membered heterocyclic rings (wherein C 3-10The carbocyclic ring and the 3- to 10-membered heterocyclic ring may each optionally be C 1-4 Alkyl, C 1-4 In certain embodiments, R is substituted with one or more substituents selected from haloalkyl and ═O. 17 is independently in each occurrence hydrogen; optionally halogen, -OR 21 , -N(R 21 )2, -C(O)N(R 21 )2, -N(R 21 )C(O)R 21 C substituted with one or more substituents independently selected from ═O and —CN 1-6 Alkyl; and halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, -OR 21 , -N(R 21 )2, -C(O)R 21 , -C(O)N(R 21 )2, -N(R 21 )C(O)R 21 , =O and -CNC 3-6 In one embodiment, R 17 are independently hydrogen in each occurrence, C 1-6 Alkyl, C 3-6 It is selected from carbocycles and 3- to 6-membered heterocycles.

[0140] In certain embodiments, for compounds or salts of Formula (Ia), (IIa), or (IIIa), A is C 3-12 carbocycle and 3- to 12-membered heterocycle, each of which optionally contains halogen, hydroxyl, methoxy, trifluoromethyl, propyl, cyclopropyl, cyclopentyl, phenyl, phenoxy, [ka] is substituted with one or more substituents selected from

[0141] In certain embodiments, for compounds or salts of Formula (Ia), (IIa), or (IIIa), A is C 3-12carbocycle and 3- to 12-membered heterocycle, each of which optionally contains halogen, hydroxyl, methoxy, trifluoromethyl, propyl, cyclopropyl, cyclopentyl, phenyl, phenoxy, [ka] is substituted with one or more substituents selected from

[0142] In certain embodiments, for a compound or salt of Formula (Ia), (IIa), or (IIIa), A is selected from phenyl; pyridine; indane; chroman; benzodioxole; 2,3-dihydrobenzofuran; quinoline; 1,2,3,4-tetrahydronaphthalene; naphthalene; quinoxaline; 2',3'-dihydrospiro[cyclopropane-1,1'-indene]; and pyrazole, each optionally Halogen, -OR 17 , -N(R 17 )2, -C(O)R 17 , -C(O)OR 17 , -OC(O)R 17 , -OC(O)N(R 17 ) 2、 -C(O)N(R 17 )2, -N(R 17 )C(O)R 17 , -N(R 17 )C(O)OR 17 , -N(R 17 )C(O)N(R 17 )2, -N(R 17 )S(O)2(R 17 ), -S(O)R 17 , -S(O)2R 17 , -S(O)2N(R 17 )2, -NO2, =O and -CN; Possibly halogen, -OR 17 , -N(R 17 )2, -C(O)R 17 , -C(O)OR 17 , -OC(O)R 17 , -OC(O)N(R 17 ) 2、 -C(O)N(R 17)2, -N(R 17 )C(O)R 17 , -N(R 17 )C(O)OR 17 , -N(R 17 )C(O)N(R 17 )2, -N(R 17 )S(O)2(R 17 ), -S(O)R 17 , -S(O)2R 17 , -S(O)2N(R 17 )2, -NO2, =O, C substituted with one or more substituents independently selected from -CN 1-6 alkyl; and Both may contain halogen, C 1-4 Alkyl, C 1-4 C substituted with one or more substituents independently selected from haloalkyl and =O 3-10 Carbocyclic and 3- to 10-membered heterocyclic rings is substituted with one or more substituents independently selected from

[0143] In certain embodiments, for a compound or salt of Formula (Ia), (IIa), or (IIIa), A is selected from phenyl; pyridine; indane; chroman; benzodioxole; 2,3-dihydrobenzofuran; quinoline; 1,2,3,4-tetrahydronaphthalene; naphthalene; quinoxaline; 2',3'-dihydrospiro[cyclopropane-1,1'-indene]; and pyrazole, each optionally Halogen, -OR 17 , -N(R 17 )2, -C(O)R 17 , -C(O)OR 17 , -OC(O)R 17 , -C(O)N(R 17 )2, -N(R 17 )C(O)R 17 , -NO2, =O and -CN; Possibly halogen, -OR 17 , -N(R 17 )2, -C(O)R 17 , -C(O)OR 17 , -OC(O)R 17 , -C(O)N(R17 )2, -N(R 17 )C(O)R 17 C substituted with one or more substituents independently selected from -NO2, =O, and -CN 1-6 alkyl; and Both may contain halogen, C 1-4 Alkyl, C 1-4 C substituted with one or more substituents independently selected from haloalkyl and =O 3-10 Carbocyclic and 3- to 10-membered heterocyclic rings is substituted with one or more substituents independently selected from

[0144] In certain embodiments, for a compound or salt of Formula (Ia), (IIa), or (IIIa), A is selected from phenyl; pyridine; indane; chroman; benzodioxole; 2,3-dihydrobenzofuran; quinoline; 1,2,3,4-tetrahydronaphthalene; naphthalene; quinoxaline; 2',3'-dihydrospiro[cyclopropane-1,1'-indene]; and pyrazole, each optionally containing halogen; -OR 17 C optionally substituted with one or more substituents independently selected from halogen 1-6 alkyl; and each optionally halogen, C 1-4 Alkyl, C 1-4 C substituted with one or more substituents independently selected from haloalkyl and =O 3-10 Carbocyclic and 3- to 10-membered heterocyclic rings is substituted with one or more substituents independently selected from

[0145] In certain embodiments, for a compound or salt of Formula (Ia), (IIa), or (IIIa), A is selected from phenyl; pyridine; indane; chroman; benzodioxole; 2,3-dihydrobenzofuran; quinoline; 1,2,3,4-tetrahydronaphthalene; naphthalene; quinoxaline; 2',3'-dihydrospiro[cyclopropane-1,1'-indene]; and pyrazole, each of which optionally contains halogen, -OR 17 , C 1-6 Alkyl, C1-6 Haloalkyl, C 3-10 Carbocyclic and 3- to 10-membered heterocyclic rings (wherein C 3-10 The carbocyclic ring and the 3- to 10-membered heterocyclic ring may each optionally be C 1-4 Alkyl, C 1-4 substituted with one or more substituents independently selected from haloalkyl and =O is substituted with one or more substituents independently selected from

[0146] In certain embodiments, for a compound or salt of Formula (Ia), (IIa), or (IIIa), A is selected from phenyl; pyridine; indane; chroman; benzodioxole; 2,3-dihydrobenzofuran; quinoline; 1,2,3,4-tetrahydronaphthalene; naphthalene; quinoxaline; 2',3'-dihydrospiro[cyclopropane-1,1'-indene]; and pyrazole, each optionally containing halogen, hydroxyl, methoxy, trifluoromethyl, propyl, cyclopropyl, cyclopentyl, phenyl, phenoxy, [ka] is substituted with one or more substituents independently selected from

[0147] In certain embodiments, for a compound or salt of Formula (Ia), (IIa), or (IIIa), A is selected from phenyl; pyridine; indane; chroman; benzodioxole; 2,3-dihydrobenzofuran; quinoline; 1,2,3,4-tetrahydronaphthalene; naphthalene; quinoxaline; 2',3'-dihydrospiro[cyclopropane-1,1'-indene]; and pyrazole, each optionally containing halogen, hydroxyl, methoxy, trifluoromethyl, propyl, cyclopropyl, cyclopentyl, phenyl, phenoxy, [ka] is substituted with one or more substituents independently selected from

[0148] In certain embodiments, for a compound or salt of Formula (Ia), (IIa), or (IIIa), C of A 3-12 Carbocycles and 3- to 12-membered heterocycles are monocyclic C 3-6 selected from carbocycles and 3- to 7-membered monocyclic heterocycles, each of which is optionally Halogen, -OR 17 , -N(R 17 )2, -C(O)R 17 , -C(O)OR 17 , -OC(O)R 17 , -OC(O)N(R 17 ) 2、 -C(O)N(R 17 )2, -N(R 17 )C(O)R 17 , -N(R 17 )C(O)OR 17 , -N(R 17 )C(O)N(R 17 )2, -N(R 17 )S(O)2(R 17 ), -S(O)R 17 , -S(O)2R 17 , -S(O)2N(R 17 )2, -NO2, =O and -CN; Possibly halogen, -OR 17 , -N(R 17 )2, -C(O)R 17 , -C(O)OR 17 , -OC(O)R 17 , -OC(O)N(R 17 ) 2、 -C(O)N(R 17 )2, -N(R 17 )C(O)R 17 , -N(R 17 )C(O)OR 17 , -N(R 17 )C(O)N(R 17 )2, -N(R 17 )S(O)2(R 17 ), -S(O)R 17 , -S(O)2R 17 , -S(O)2N(R 17 )2, -NO2, =O, C substituted with one or more substituents independently selected from -CN1-6 alkyl; and Both may contain halogen, C 1-4 Alkyl, C 1-4 C substituted with one or more substituents independently selected from haloalkyl and =O 3-10 Carbocyclic and 3- to 10-membered heterocyclic rings is substituted with one or more substituents independently selected from

[0149] In certain embodiments, for a compound or salt of Formula (Ia), (IIa), or (IIIa), C of A 3-12 Carbocycles and 3- to 12-membered heterocycles are monocyclic C 3-6 selected from carbocycles and 3- to 7-membered monocyclic heterocycles, each of which is optionally Halogen, -OR 17 , -N(R 17 )2, -C(O)R 17 , -C(O)OR 17 , -OC(O)R 17 , -C(O)N(R 17 )2, -N(R 17 )C(O)R 17 , -NO2, =O and -CN; Possibly halogen, -OR 17 , -N(R 17 )2, -C(O)R 17 , -C(O)OR 17 , -OC(O)R 17 , -C(O)N(R 17 )2, -N(R 17 )C(O)R 17 C substituted with one or more substituents independently selected from -NO2, =O, and -CN 1-6 alkyl; and Both may contain halogen, C 1-4 Alkyl, C 1-4 C substituted with one or more substituents independently selected from haloalkyl and =O 3-10 Carbocyclic and 3- to 10-membered heterocyclic rings is substituted with one or more substituents independently selected from

[0150] In certain embodiments, for a compound or salt of Formula (Ia), (IIa), or (IIIa), C of A 3-12 Carbocycles and 3- to 12-membered heterocycles are monocyclic C 3-6 Carbocycle and 3- to 7-membered monocyclic heterocycle, each of which may optionally contain halogen, -OR 17 , C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 Carbocyclic and 3- to 10-membered heterocyclic rings (wherein C 3-10 The carbocyclic ring and the 3- to 10-membered heterocyclic ring may each optionally be C 1-4 Alkyl, C 1-4 substituted with one or more substituents independently selected from haloalkyl and ═O).

[0151] In certain embodiments, for a compound or salt of Formula (Ia), (IIa), or (IIIa), C of A 3-12 Carbocycles and 3- to 12-membered heterocycles are monocyclic C 3-6 carbocycle and 3- to 7-membered monocyclic heterocycle, each of which optionally contains halogen, hydroxyl, methoxy, trifluoromethyl, propyl, cyclopropyl, cyclopentyl, phenyl, phenoxy, [ka] is substituted with one or more substituents independently selected from

[0152] In certain embodiments, for a compound or salt of Formula (Ia), (IIa), or (IIIa), C of A 3-12 The carbocycle and 3- to 12-membered heterocycle are selected from phenyl, pyridine, and pyrazole, each of which is optionally Halogen, -OR 17 , -N(R 17 )2, -C(O)R 17 , -C(O)OR 17 , -OC(O)R 17 , -OC(O)N(R 17 ) 2、 -C(O)N(R 17)2, -N(R 17 )C(O)R 17 , -N(R 17 )C(O)OR 17 , -N(R 17 )C(O)N(R 17 )2, -N(R 17 )S(O)2(R 17 ), -S(O)R 17 , -S(O)2R 17 , -S(O)2N(R 17 )2, -NO2, =O and -CN; Possibly halogen, -OR 17 , -N(R 17 )2, -C(O)R 17 , -C(O)OR 17 , -OC(O)R 17 , -OC(O)N(R 17 ) 2、 -C(O)N(R 17 )2, -N(R 17 )C(O)R 17 , -N(R 17 )C(O)OR 17 , -N(R 17 )C(O)N(R 17 )2, -N(R 17 )S(O)2(R 17 ), -S(O)R 17 , -S(O)2R 17 , -S(O)2N(R 17 )2, -NO2, =O, C substituted with one or more substituents independently selected from -CN 1-6 alkyl; and Both may contain halogen, C 1-4 Alkyl, C 1-4 C substituted with one or more substituents independently selected from haloalkyl and =O 3-10 Carbocyclic and 3- to 10-membered heterocyclic rings is substituted with one or more substituents independently selected from

[0153] In certain embodiments, for a compound or salt of Formula (Ia), (IIa), or (IIIa), C of A 3-12The carbocycle and 3- to 12-membered heterocycle are selected from phenyl, pyridine, and pyrazole, each of which is optionally Halogen, -OR 17 , -N(R 17 )2, -C(O)R 17 , -C(O)OR 17 , -OC(O)R 17 , -C(O)N(R 17 )2, -N(R 17 )C(O)R 17 , -NO2, =O and -CN; Possibly halogen, -OR 17 , -N(R 17 )2, -C(O)R 17 , -C(O)OR 17 , -OC(O)R 17 , -C(O)N(R 17 )2, -N(R 17 )C(O)R 17 C substituted with one or more substituents independently selected from -NO2, =O, and -CN 1-6 alkyl; and Both may contain halogen, C 1-4 Alkyl, C 1-4 C substituted with one or more substituents independently selected from haloalkyl and =O 3-10 Carbocyclic and 3- to 10-membered heterocyclic rings is substituted with one or more substituents independently selected from

[0154] In certain embodiments, for a compound or salt of Formula (Ia), (IIa), or (IIIa), C of A 3-12 The carbocycle and 3- to 12-membered heterocycle are selected from phenyl, pyridine and pyrazole, each of which may optionally contain halogen, -OR 17 , C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 Carbocyclic and 3- to 10-membered heterocyclic rings (wherein C 3-10 The carbocyclic ring and the 3- to 10-membered heterocyclic ring may each optionally be C 1-4 Alkyl, C 1-4 substituted with one or more substituents independently selected from haloalkyl and =O is substituted with one or more substituents independently selected from

[0155] In certain embodiments, for a compound or salt of Formula (Ia), (IIa), or (IIIa), C of A 3-12 The carbocycle and 3- to 12-membered heterocycle are selected from phenyl, pyridine and pyrazole, each of which optionally contains halogen, hydroxyl, methoxy, trifluoromethyl, propyl, cyclopropyl, cyclopentyl, phenyl, phenoxy, [ka] is substituted with one or more substituents independently selected from

[0156] In certain embodiments, for a compound or salt of Formula (Ia), (IIa), or (IIIa), C of A 3-12 Carbocycles and 3- to 12-membered heterocycles are polycyclic C 7-12 selected from carbocycles and 7- to 12-membered polycyclic heterocycles, each of which is optionally Halogen, -OR 17 , -N(R 17 )2, -C(O)R 17 , -C(O)OR 17 , -OC(O)R 17 , -OC(O)N(R 17 ) 2、 -C(O)N(R 17 )2, -N(R 17 )C(O)R 17 , -N(R 17 )C(O)OR 17 , -N(R 17 )C(O)N(R 17 )2, -N(R 17 )S(O)2(R 17 ), -S(O)R 17 , -S(O)2R 17 , -S(O)2N(R 17 )2, -NO2, =O and -CN; Possibly halogen, -OR 17 , -N(R 17 )2, -C(O)R 17, -C(O)OR 17 , -OC(O)R 17 , -OC(O)N(R 17 ) 2、 -C(O)N(R 17 )2, -N(R 17 )C(O)R 17 , -N(R 17 )C(O)OR 17 , -N(R 17 )C(O)N(R 17 )2, -N(R 17 )S(O)2(R 17 ), -S(O)R 17 , -S(O)2R 17 , -S(O)2N(R 17 )2, -NO2, =O, C substituted with one or more substituents independently selected from -CN 1-6 alkyl; and Both may contain halogen, C 1-4 Alkyl, C 1-4 C substituted with one or more substituents independently selected from haloalkyl and =O 3-10 Carbocyclic and 3- to 10-membered heterocyclic rings is substituted with one or more substituents independently selected from

[0157] In certain embodiments, for a compound or salt of Formula (Ia), (IIa), or (IIIa), C of A 3-12 Carbocycles and 3- to 12-membered heterocycles are polycyclic C 7-12 selected from carbocycles and 7- to 12-membered polycyclic heterocycles, each of which is optionally Halogen, -OR 17 , -N(R 17 )2, -C(O)R 17 , -C(O)OR 17 , -OC(O)R 17 , -C(O)N(R 17 )2, -N(R 17 )C(O)R 17 , -NO2, =O and -CN; Possibly halogen, -OR 17 , -N(R 17 )2, -C(O)R 17 , -C(O)OR17 , -OC(O)R 17 , -C(O)N(R 17 )2, -N(R 17 )C(O)R 17 C substituted with one or more substituents independently selected from -NO2, =O, and -CN 1-6 alkyl; and Both may contain halogen, C 1-4 Alkyl, C 1-4 C substituted with one or more substituents independently selected from haloalkyl and =O 3-10 Carbocyclic and 3- to 10-membered heterocyclic rings is substituted with one or more substituents independently selected from

[0158] In certain embodiments, for a compound or salt of Formula (Ia), (IIa), or (IIIa), C of A 3-12 Carbocycles and 3- to 12-membered heterocycles are polycyclic C 7-12 Carbocycle and 7- to 12-membered polycyclic heterocycle, each of which may optionally contain halogen, -OR 17 , C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 Carbocyclic and 3- to 10-membered heterocyclic rings (wherein C 3-10 The carbocyclic ring and the 3- to 10-membered heterocyclic ring may each optionally be C 1-4 Alkyl, C 1-4 substituted with one or more substituents independently selected from haloalkyl and =O is substituted with one or more substituents independently selected from

[0159] In certain embodiments, for a compound or salt of Formula (Ia), (IIa), or (IIIa), C of A 3-12 Carbocycles and 3- to 12-membered heterocycles are polycyclic C 7-12 carbocycle and 7- to 12-membered polycyclic heterocycle, each of which optionally contains halogen, hydroxyl, methoxy, trifluoromethyl, propyl, cyclopropyl, cyclopentyl, phenyl, phenoxy, [ka] is substituted with one or more substituents independently selected from

[0160] In certain embodiments, for a compound or salt of Formula (Ia), (IIa), or (IIIa), C of A 3-12 The carbocycle and 3- to 12-membered heterocycle are selected from indane; chroman; benzodioxole; 2,3-dihydrobenzofuran; quinoline; 1,2,3,4-tetrahydronaphthalene; naphthalene; quinoxaline; and 2',3'-dihydrospiro[cyclopropane-1,1'-indene], each optionally selected from: Halogen, -OR 17 , -N(R 17 )2, -C(O)R 17 , -C(O)OR 17 , -OC(O)R 17 , -OC(O)N(R 17 ) 2、 -C(O)N(R 17 )2, -N(R 17 )C(O)R 17 , -N(R 17 )C(O)OR 17 , -N(R 17 )C(O)N(R 17 )2, -N(R 17 )S(O)2(R 17 ), -S(O)R 17 , -S(O)2R 17 , -S(O)2N(R 17 )2, -NO2, =O and -CN; Possibly halogen, -OR 17 , -N(R 17 )2, -C(O)R 17 , -C(O)OR 17 , -OC(O)R 17 , -OC(O)N(R 17 ) 2、 -C(O)N(R 17 )2, -N(R 17 )C(O)R 17 , -N(R 17 )C(O)OR 17 , -N(R 17 )C(O)N(R 17)2, -N(R 17 )S(O)2(R 17 ), -S(O)R 17 , -S(O)2R 17 , -S(O)2N(R 17 )2, -NO2, =O, C substituted with one or more substituents independently selected from -CN 1-6 alkyl; and Both may contain halogen, C 1-4 Alkyl, C 1-4 C substituted with one or more substituents independently selected from haloalkyl and =O 3-10 Carbocyclic and 3- to 10-membered heterocyclic rings is substituted with one or more substituents independently selected from

[0161] In certain embodiments, for a compound or salt of Formula (Ia), (IIa), or (IIIa), C of A 3-12 The carbocycle and 3- to 12-membered heterocycle are selected from indane; chroman; benzodioxole; 2,3-dihydrobenzofuran; quinoline; 1,2,3,4-tetrahydronaphthalene; naphthalene; quinoxaline; and 2',3'-dihydrospiro[cyclopropane-1,1'-indene], each of which is optionally Halogen, -OR 17 , -N(R 17 )2, -C(O)R 17 , -C(O)OR 17 , -OC(O)R 17 , -C(O)N(R 17 )2, -N(R 17 )C(O)R 17 , -NO2, =O and -CN; Possibly halogen, -OR 17 , -N(R 17 )2, -C(O)R 17 , -C(O)OR 17 , -OC(O)R 17 , -C(O)N(R 17 )2, -N(R 17 )C(O)R 17 C substituted with one or more substituents independently selected from -NO2, =O, and -CN 1-6alkyl; and Both may contain halogen, C 1-4 Alkyl, C 1-4 C substituted with one or more substituents independently selected from haloalkyl and =O 3-10 It is substituted with one or more substituents independently selected from a carbocycle and a 3- to 10-membered heterocycle.

[0162] In certain embodiments, for a compound or salt of Formula (Ia), (IIa), or (IIIa), C of A 3-12 The carbocycle and 3- to 12-membered heterocycle are selected from indane; chroman; benzodioxole; 2,3-dihydrobenzofuran; quinoline; 1,2,3,4-tetrahydronaphthalene; naphthalene; quinoxaline; and 2',3'-dihydrospiro[cyclopropane-1,1'-indene], each of which optionally contains halogen, -OR 17 , C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-10 Carbocyclic and 3- to 10-membered heterocyclic rings (wherein C 3-10 The carbocyclic ring and the 3- to 10-membered heterocyclic ring may each optionally be C 1-4 Alkyl, C 1-4 substituted with one or more substituents independently selected from haloalkyl and ═O).

[0163] In certain embodiments, for a compound or salt of Formula (Ia), (IIa), or (IIIa), C of A 3-12 The carbocycle and 3- to 12-membered heterocycle are selected from indane; chroman; benzodioxole; 2,3-dihydrobenzofuran; quinoline; 1,2,3,4-tetrahydronaphthalene; naphthalene; quinoxaline; and 2',3'-dihydrospiro[cyclopropane-1,1'-indene], each of which optionally contains halogen, hydroxyl, methoxy, trifluoromethyl, propyl, cyclopropyl, cyclopentyl, phenyl, phenoxy, [ka] is substituted with one or more substituents independently selected from

[0164] In certain embodiments, for compounds or salts of Formula (Ia), (IIa), or (IIIa), A is [ka] [ka] is selected from.

[0165] In certain embodiments, for compounds or salts of Formula (Ia), (IIa), or (IIIa), A is [ka] [ka] is selected from.

[0166] In certain embodiments, for compounds or salts of Formula (Ia), (IIa), or (IIIa), when A is selected from (ii), B is selected from (I), or when A is selected from (i), B is selected from (II): (I) Hydrogen, halogen and -CN or B and R 7 C 3-6 Forms a carbocyclic or 3- to 6-membered heterocyclic ring; (II)-OR 18 , -SR 18 , -N(R 18 )2, -C(O)R 18 , -C(O)OR 18 , -OC(O)R 18 , -OC(O)N(R 18 )2, -C(O)N(R 18 )2, -N(R 18 )C(O)R 18 , -N(R 18 )C(O)OR 18 , -N(R 18 )C(O)N(R 18 )2, -N(R18 )C(S)N(R 18 )2, -N(R 18 )S(O)2(R 18 ), -S(O)R 18 , -S(O)2R 18 and -S(O)N(R 18 )2; C 3-12 Carbocyclic rings and 3- to 12-membered heterocyclic rings (both may be Halogen, -OR 18 , -SR 18 , -N(R 18 )2, -C(O)R 18 , -C(O)OR 18 , -OC(O)R 18 , -OC(O)N(R 18 )2, -C(O)N(R 18 )2, -N(R 18 )C(O)R 18 , -N(R 18 )C(O)OR 18 , -N(R 18 )C(O)N(R 18 )2, -N(R 18 )C(S)N(R 18 )2, -N(R 18 )S(O)2(R 18 ), -S(O)R 18 , -S(O)2R 18 , -S(O)2N(R 18 )2, -NO2, =O, =S, =N(R 18 ), -N3 and -CN; C 1-6 Alkyl (optionally: Halogen, -OR 18 , -SR 18 , -N(R 18 )2, -C(O)R 18 , -C(O)OR 18 , -OC(O)R 18 , -OC(O)N(R 18 )2, -C(O)N(R 18 )2, -N(R 18 )C(O)R 18 , -N(R 18 )C(O)OR 18 , -N(R 18 )C(O)N(R18 )2, -N(R 18 )C(S)N(R 18 )2, -N(R 18 )S(O)2(R 18 ), -S(O)R 18 , -S(O)2R 18 , -S(O)2N(R 18 )2, -NO2, =O, =S, =N(R 18 ), -N3, -CN, C 3-6 Carbocyclic and 3- to 6-membered heterocyclic rings and is substituted with one or more substituents independently selected from where C 3-6 The carbocyclic ring and the 3- to 6-membered heterocyclic ring each optionally contain halogen, C 1-4 Alkyl, C 1-4 substituted with one or more substituents independently selected from haloalkyl and ═O); and Both may contain halogen, C 1-4 Alkyl, C 1-4 C substituted with one or more substituents independently selected from haloalkyl and =O 3-10 Carbocyclic and 3- to 10-membered heterocyclic rings and substituted with one or more substituents independently selected from:

[0167] In certain embodiments, for compounds or salts of Formula (Ia), (IIa), or (IIIa), when A is selected from (ii), B is selected from (I), or when A is selected from (i), B is selected from (II): (I) Hydrogen, halogen and -CN or B and R 7 C 3-6 Forms a carbocyclic or 3- to 6-membered heterocyclic ring; (II)-OR 18 , -N(R 18 )2, -C(O)R 18 , -C(O)OR 18 , -OC(O)R 18 , -OC(O)N(R 18 )2, -C(O)N(R 18 )2, -N(R 18 )C(O)R 18, -N(R 18 )C(O)OR 18 , -N(R 18 )C(O)N(R 18 )2, -N(R 18 )S(O)2(R 18 ), -S(O)R 18 and -S(O)N(R 18 )2; C 3-12 Carbocyclic rings and 3- to 12-membered heterocyclic rings (each optionally: Halogen, -OR 18 , -N(R 18 )2, -C(O)R 18 , -C(O)OR 18 , -OC(O)R 18 , -OC(O)N(R 18 )2, -C(O)N(R 18 )2, -N(R 18 )C(O)R 18 , -N(R 18 )C(O)OR 18 , -N(R 18 )C(O)N(R 18 )2, -N(R 18 )S(O)2(R 18 ), -S(O)R 18 , -S(O)2R 18 , -S(O)2N(R 18 )2, =O and -CN; C 1-6 Alkyl (optionally: Halogen, -OR 18 , -N(R 18 )2, -C(O)R 18 , -C(O)OR 18 , -OC(O)R 18 , -OC(O)N(R 18 )2, -C(O)N(R 18 )2, -N(R 18 )C(O)R 18 , -N(R 18 )C(O)OR 18 , -N(R 18 )C(O)N(R 18 )2, -N(R 18 )S(O)2(R 18 ), -S(O)R 18, -S(O)2R 18 , -S(O)2N(R 18 )2, =O-CN, C 3-6 Carbocyclic and 3- to 6-membered heterocyclic rings and is substituted with one or more substituents independently selected from where C 3-6 The carbocyclic ring and the 3- to 6-membered heterocyclic ring each optionally contain halogen, C 1-4 Alkyl, C 1-4 substituted with one or more substituents independently selected from haloalkyl and ═O); and Both may contain halogen, C 1-4 Alkyl, C 1-4 C substituted with one or more substituents independently selected from haloalkyl and =O 3-10 and substituted with one or more substituents independently selected from a carbocycle and a 3- to 10-membered heterocycle.

[0168] In certain embodiments, for compounds or salts of Formula (Ia), (IIa), or (IIIa), when A is selected from (ii), B is selected from (I), or when A is selected from (i), B is selected from (II): (I) Hydrogen and halogens; (II)-N(R 18 )2, -C(O)R 18 , -C(O)OR 18 , -OC(O)N(R 18 )2, -C(O)N(R 18 )2, -N(R 18 )C(O)R 18 , -N(R 18 )C(O)OR 18 , -N(R 18 )C(O)N(R 18 )2, -N(R 18 )S(O)2(R 18 ); C 3-12 Carbocyclic rings and 3- to 12-membered heterocyclic rings (each optionally: Halogen, -OR 18 , -N(R 18 )2, -C(O)R 18 , -C(O)OR 18, -C(O)N(R 18 )2, -N(R 18 )C(O)R 18 , -N(R 18 )S(O)2(R 18 ), -S(O)R 18 , =O and -CN; C 1-6 Alkyl (optionally: Halogen, -OR 18 , -N(R 18 )2, -C(O)R 18 , -C(O)OR 18 , -C(O)N(R 18 )2, -N(R 18 )C(O)R 18 , -N(R 18 )S(O)2(R 18 ), -S(O)R 18 , =O, -CN and optionally halogen, C 1-4 Alkyl, C 1-4 C substituted with one or more substituents independently selected from haloalkyl and =O 3-6 carbocyclic ring and Both may contain halogen, C 1-4 Alkyl, C 1-4 C substituted with one or more substituents independently selected from haloalkyl and =O 3-10 Carbocyclic and 3- to 10-membered heterocyclic rings and substituted with one or more substituents independently selected from:

[0169] In certain embodiments, for compounds or salts of Formula (Ia), (IIa), or (IIIa), when A is selected from (ii), B is selected from (I), or when A is selected from (i), B is selected from (II): (I) Hydrogen and halogens; (II)-N(R 18 )2, -N(R 18 )C(O)R 18 , -N(R 18 )C(O)OR 18 , -N(R 18)C(O)N(R 18 )2, -N(R 18 )S(O)2(R 18 ); and C 3-12 Carbocyclic rings and 3- to 12-membered heterocyclic rings (both optionally: Halogen; -OR 18 ; optionally halogen, -OR 18 and C 3-6 C substituted with one or more substituents independently selected from carbocycles 1-6 alkyl; and both optionally halogen and C 1-4 C substituted with one or more substituents independently selected from alkyl 3-10 Carbocyclic and 3- to 10-membered heterocyclic rings and substituted with one or more substituents independently selected from:

[0170] In certain embodiments, for compounds or salts of Formula (Ia), (IIa), or (IIIa), when A is selected from (ii), B is selected from (I), or when A is selected from (i), B is selected from (II): (I) Hydrogen and halogens; (II)-N(R 18 )2, -N(R 18 )C(O)R 18 , -N(R 18 )C(O)OR 18 , -N(R 18 )C(O)N(R 18 )2 and -N(R 18 )S(O)2(R 18 ).

[0171] In certain embodiments, for compounds or salts of Formula (Ia), (IIa), or (IIIa), when A is selected from (ii), B is selected from (I), or when A is selected from (i), B is selected from (II): (I) Hydrogen and halogens; (II)C 3-12 Carbocyclic rings and 3- to 12-membered heterocyclic rings (both optionally: Halogen; -OR 18; optionally halogen, -OR 18 and C 3-6 C substituted with one or more substituents independently selected from carbocycles 1-6 alkyl; and both optionally halogen and C 1-4 C substituted with one or more substituents independently selected from alkyl 3-10 Carbocyclic and 3- to 10-membered heterocyclic rings and substituted with one or more substituents independently selected from:

[0172] In certain embodiments, for compounds or salts of Formula (Ia), (IIa), or (IIIa), B is selected from hydrogen, halogen, and —CN, or B and R 7 C 3-6 In some embodiments, B is selected from hydrogen and halogen, or B and R 7 C 3-6 In some embodiments, B is selected from hydrogen and halogen, or B and R 7 C 3-6 In some embodiments, B is selected from hydrogen, halogen, and -CN. In some embodiments, B is selected from hydrogen and halogen. In some embodiments, B is selected from hydrogen and halogen. In some embodiments, B is selected from hydrogen. In some embodiments, B is selected from halogen. In some embodiments, B and R 7 C 3-6 Forms a carbocyclic ring.

[0173] In certain embodiments, for compounds or salts of Formula (Ia), (IIa), or (IIIa), B is C 3-12 It is selected from a carbocycle and a 3- to 12-membered heterocycle, either of which is optionally substituted with one or more substituents.

[0174] In certain embodiments, for compounds or salts of Formula (Ia), (IIa), or (IIIa), C of B3-12 Carbocyclic rings and 3- to 12-membered heterocyclic rings are each optionally Halogen, -OR 18 , -N(R 18 )2, -C(O)R 18 and =O; Possibly halogen, -OR 18 , -N(R 18 )2, =O, -CN, C 3-6 C substituted with one or more substituents independently selected from carbocycles and 3- to 6-membered heterocycles 1-6 Alkyl (where C 3-6 The carbocyclic ring and the 3- to 6-membered heterocyclic ring each optionally contain halogen, C 1-4 Alkyl, C 1-4 substituted with one or more substituents independently selected from haloalkyl and ═O); and Both may contain halogen, C 1-4 Alkyl, C 1-4 C substituted with one or more substituents independently selected from haloalkyl and =O 3-10 It is substituted with one or more substituents independently selected from a carbocycle and a 3- to 10-membered heterocycle.

[0175] In certain embodiments, for compounds or salts of Formula (Ia), (IIa), or (IIIa), C of B 3-12 Carbocyclic rings and 3- to 12-membered heterocyclic rings are each optionally halogenated; -OR 18 ; possibly halogen, OR 18 and C 3-6 C substituted with one or more substituents independently selected from carbocycles 1-6 alkyl; and C 3-10 Carbocycles and 3- to 10-membered heterocycles, where C 3-10 The carbocyclic ring and the 3- to 10-membered heterocyclic ring each optionally contain halogen and C 1-4 substituted with one or more substituents independently selected from alkyl;

[0176] In certain embodiments, for compounds or salts of Formula (Ia), (IIa), or (IIIa), B is C3-12 selected from carbocycles and 3- to 12-membered heterocycles, each of which is optionally Halogen, -OR 18 , -N(R 18 )2, -C(O)R 18 , =O and -CN; Possibly halogen, -OR 18 , -SR 18 , -N(R 18 )2, -C(O)R 18 , =O, -CN, C 3-6 C substituted with one or more substituents independently selected from carbocycles and 3- to 6-membered heterocycles 1-6 Alkyl (where C 3-6 The carbocyclic ring and the 3- to 6-membered heterocyclic ring each optionally contain halogen, C 1-4 Alkyl, C 1-4 substituted with one or more substituents independently selected from haloalkyl and ═O); and Both may contain halogen, C 1-4 Alkyl, C 1-4 C substituted with one or more substituents independently selected from haloalkyl and =O 3-10 Carbocyclic and 3- to 10-membered heterocyclic rings is substituted with one or more substituents independently selected from

[0177] In certain embodiments, for compounds or salts of Formula (Ia), (IIa), or (IIIa), B is C 3-12 selected from carbocycles and 3- to 12-membered heterocycles, each optionally containing halogen; -OR 18 ; optionally halogen, -OR 18 and C 3-6 C substituted with one or more substituents independently selected from carbocycles 1-6 alkyl; and C 3-10 Carbocyclic and 3- to 10-membered heterocyclic rings (wherein C 3-10 The carbocyclic ring and the 3- to 10-membered heterocyclic ring each optionally contain halogen and C 1-4 In some embodiments, B is substituted with one or more substituents independently selected from C3-12 selected from carbocycles and 3- to 12-membered heterocycles, both optionally halogen; optionally halogen and C 3-6 C substituted with one or more substituents independently selected from carbocycles 1-6 alkyl; and C 3-10 Carbocyclic and 3- to 10-membered heterocyclic rings (wherein C 3-10 The carbocyclic ring and the 3- to 10-membered heterocyclic ring each optionally contain halogen and C 1-4 substituted with one or more substituents independently selected from alkyl is substituted with one or more substituents independently selected from

[0178] In certain embodiments, for a compound or salt of Formula (Ia), (IIa), or (IIIa), R 18 Independently in each case: hydrogen; C 1-6 Alkyl (optionally: Halogen, -OR 22 , -SR 22 , -N(R 22 )2, -C(O)R 22 , -C(O)OR 22 , -OC(O)R 22 , -OC(O)N(R 22 )2, -C(O)N(R 22 )2, -N(R 22 )C(O)R 22 , -NO2, =O, =S, =N(R 22 ), -N3, -CN, C 3-10 Carbocyclic and 3- to 10-membered heterocyclic rings and is substituted with one or more substituents independently selected from where C 3-10 The carbocyclic ring and the 3- to 10-membered heterocyclic ring each optionally contain halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR 22 , -SR 22 and -N(R 22 ) substituted with one or more substituents independently selected from 2); and Both may contain halogen, C 1-6Alkyl, C 1-6 C substituted with one or more substituents independently selected from haloalkyl 3-10 Carbocyclic and 3- to 10-membered heterocyclic rings is selected from.

[0179] In certain embodiments, for a compound or salt of Formula (Ia), (IIa), or (IIIa), R 18 is independently in each occurrence hydrogen; optionally halogen and C 3-6 C substituted with one or more substituents independently selected from carbocycles 1-6 alkyl; and each optionally halogen, C 1-6 Alkyl, C 1-6 C substituted with one or more substituents independently selected from haloalkyl 3-10 It is selected from carbocycles and 3- to 10-membered heterocycles.

[0180] In certain embodiments, for a compound or salt of Formula (Ia), (IIa), or (IIIa), R 22 Independently in each case: hydrogen; C 1-4 Alkyl (optionally halogen, hydroxyl, C 3-6 substituted with one or more substituents independently selected from a carbocycle and a 3- to 6-membered heterocycle, wherein each C 3-6 Carbocyclic and 3- to 6-membered heterocyclic rings may optionally contain halogen, C 1-4 Alkyl and -C(O)N(R 23 ) substituted with one or more substituents independently selected from 2); and Both may contain halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 C substituted with one or more substituents independently selected from alkoxy and =O 3-6 Carbocyclic and 3- to 12-membered heterocyclic rings is selected from; and R 23 are independently hydrogen and C in each case 1-4 alkyl.

[0181] In certain embodiments, for a compound or salt of Formula (Ia), (IIa), or (IIIa), R 22 are independently hydrogen in each occurrence, C 1-4 Alkyl, C 3-6 selected from carbocycles and 3- to 6-membered heterocycles, 3-6 The carbocyclic ring and the 3- to 6-membered heterocyclic ring may each optionally be C 1-4 Alkyl and C 1-4 substituted with one or more substituents independently selected from alkoxy; and R 23 are independently hydrogen and C in each case 1-4 alkyl.

[0182] In certain embodiments, for compounds or salts of Formula (Ia), (IIa), or (IIIa), C of B 3-12 The carbocycle and 3- to 12-membered heterocycle are selected from phenyl; pyridinyl, naphthyl; 1,2,3,4-tetrahydronaphthalene; indane; 7-azaindole; indazole; and chroman, each optionally substituted with one or more substituents.

[0183] In certain embodiments, for compounds or salts of Formula (Ia), (IIa), or (IIIa), C of B 3-12 Carbocycles and 3- to 12-membered heterocycles are monocyclic C 3-6 and a 3- to 7-membered monocyclic heterocycle, each optionally substituted with one or more substituents. In some embodiments, B is selected from phenyl and pyridinyl, each optionally substituted with one or more substituents.

[0184] In certain embodiments, for compounds or salts of Formula (Ia), (IIa), or (IIIa), B is a bicyclic C 6-12and a bicyclic 6- to 12-membered bicyclic heterocycle, each optionally substituted with one or more substituents. In some embodiments, B is selected from naphthyl; 1,2,3,4-tetrahydronaphthalene; indane; 7-azaindole; indazole; and chroman, each optionally substituted with one or more substituents.

[0185] In certain embodiments, for compounds or salts of Formula (Ia), (IIa), or (IIIa), one or more optional substituents of B are independently: Halogen, -OR 18 , -SR 18 , -N(R 18 )2, -C(O)R 18 , -C(O)OR 18 , -OC(O)R 18 , -OC(O)N(R 18 )2, -C(O)N(R 18 )2, -N(R 18 )C(O)R 18 , -N(R 18 )C(O)OR 18 , -N(R 18 )C(O)N(R 18 )2, -N(R 18 )C(S)N(R 18 )2, -N(R 18 )S(O)2(R 18 ), -S(O)R 18 , -S(O)2R 18 , -S(O)2N(R 18 )2, -NO2, =O, =S, =N(R 18 ), -N3 and -CN; C 1-6 Alkyl (optionally: Halogen, -OR 18 , -SR 18 , -N(R 18 )2, -C(O)R 18 , -C(O)OR 18 , -OC(O)R 18 , -OC(O)N(R 18 )2, -C(O)N(R 18 )2, -N(R 18 )C(O)R 18, -N(R 18 )C(O)OR 18 , -N(R 18 )C(O)N(R 18 )2, -N(R 18 )C(S)N(R 18 )2, -N(R 18 )S(O)2(R 18 ), -S(O)R 18 , -S(O)2R 18 , -S(O)2N(R 18 )2, -NO2, =O, =S, =N(R 18 ), -N3, -CN, C 3-6 substituted with one or more substituents independently selected from a carbocycle and a 3- to 6-membered heterocycle; where C 3-6 The carbocyclic ring and the 3- to 6-membered heterocyclic ring each optionally contain halogen, C 1-4 Alkyl, C 1-4 substituted with one or more substituents independently selected from haloalkyl and ═O); and Both may contain halogen, C 1-4 Alkyl, C 1-4 C substituted with one or more substituents independently selected from haloalkyl and =O 3-10 It is selected from carbocycles and 3- to 10-membered heterocycles.

[0186] In certain embodiments, for compounds or salts of Formula (Ia), (IIa), or (IIIa), one or more optional substituents of B are independently: Halogen, -OR 18 , -N(R 18 )2, -C(O)R 18 , =O and -CN; Possibly halogen, -OR 18 , -SR 18 , -N(R 18 )2, -C(O)R 18 , =O, -CN, C 3-6 C substituted with one or more substituents independently selected from carbocycles and 3- to 6-membered heterocycles 1-6 Alkyl (where C 3-6 The carbocyclic ring and the 3- to 6-membered heterocyclic ring each optionally contain halogen, C1-4 Alkyl, C 1-4 substituted with one or more substituents independently selected from haloalkyl and ═O); and Both may contain halogen, C 1-4 Alkyl, C 1-4 C substituted with one or more substituents independently selected from haloalkyl and =O 3-10 Carbocyclic and 3- to 10-membered heterocyclic rings is selected from.

[0187] In certain embodiments, for compounds or salts of Formula (Ia), (IIa), or (IIIa), one or more optional substituents of B are independently Halogen and -OR 18 ; Possibly halogen, OR 18 and C 3-6 C substituted with one or more substituents independently selected from carbocycles 1-6 alkyl; and C 3-10 Carbocyclic and 3- to 10-membered heterocyclic rings (wherein C 3-10 The carbocyclic ring and the 3- to 10-membered heterocyclic ring each optionally contain halogen and C 1-4 substituted with one or more substituents independently selected from alkyl is selected from.

[0188] In certain embodiments, for compounds or salts of Formula (Ia), (IIa), or (IIIa), B is C 3-12 selected from carbocycles and 3- to 12-membered heterocycles, each optionally containing halogen; -OR 18 ; optionally halogen, -OR 18 and C 3-6 C substituted with one or more substituents independently selected from carbocycles 1-6 alkyl; and C 3-10 substituted with one or more substituents independently selected from a carbocycle and a 3- to 10-membered heterocycle, wherein C 3-10 The carbocyclic ring and the 3- to 10-membered heterocyclic ring each optionally contain halogen and C 1-4substituted with one or more substituents independently selected from alkyl; 18 are independently hydrogen in each occurrence, C 1-6 Alkyl and optionally halogen, C 1-6 Alkyl, C 1-6 C substituted with one or more substituents independently selected from haloalkyl 3-10 Carbocycles are selected from:

[0189] In certain embodiments, for compounds or salts of Formula (Ia), (IIa), or (IIIa), B is C 3-12 a carbocycle and a 3- to 12-membered heterocycle, each of which optionally contains halogen, trifluoromethyl, cyclopropyl, phenyl, [ka] is substituted with one or more substituents independently selected from

[0190] In certain embodiments, for compounds or salts of Formula (Ia), (IIa), or (IIIa), B is C 3-12 a carbocycle and a 3- to 12-membered heterocycle, each of which optionally contains halogen, trifluoromethyl, cyclopropyl, phenyl, [ka] is substituted with one or more substituents independently selected from

[0191] In certain embodiments, for compounds or salts of Formula (Ia), (IIa), or (IIIa), B is selected from phenyl; pyridinyl, naphthyl; 1,2,3,4-tetrahydronaphthalene; indane; 7-azaindole; indazole; and chroman, each optionally selected from: Halogen, -OR 18 , -N(R 18 )2, -C(O)R 18 and =O; Possibly halogen, -OR 18 , -N(R 18 )2, =O, -CN, C3-6 C substituted with one or more substituents independently selected from carbocycles and 3- to 6-membered heterocycles 1-6 Alkyl (where C 3-6 The carbocyclic ring and the 3- to 6-membered heterocyclic ring each optionally contain halogen, C 1-4 Alkyl, C 1-4 substituted with one or more substituents independently selected from haloalkyl and ═O); and Both may contain halogen, C 1-4 Alkyl, C 1-4 C substituted with one or more substituents independently selected from haloalkyl and =O 3-10 Carbocyclic and 3- to 10-membered heterocyclic rings is substituted with one or more substituents independently selected from

[0192] In certain embodiments, for compounds or salts of Formula (Ia), (IIa), or (IIIa), B is selected from phenyl; pyridinyl, naphthyl; 1,2,3,4-tetrahydronaphthalene; indane; 7-azaindole; indazole; and chroman, each optionally containing halogen; -OR 18 ; optionally halogen, -OR 18 and C 3-6 C substituted with one or more substituents independently selected from carbocycles 1-6 alkyl; and C 3-10 Carbocyclic and 3- to 10-membered heterocyclic rings (wherein C 3-10 The carbocyclic ring and the 3- to 10-membered heterocyclic ring each optionally contain halogen and C 1-4 substituted with one or more substituents independently selected from alkyl is substituted with one or more substituents independently selected from

[0193] In certain embodiments, for compounds or salts of Formula (Ia), (IIa), or (IIIa), B is selected from phenyl; pyridinyl, naphthyl; 1,2,3,4-tetrahydronaphthalene; indane; 7-azaindole; indazole; and chroman, each optionally containing halogen; and optionally containing halogen and C 3-6C substituted with one or more substituents independently selected from carbocycles 1-6 alkyl; and C 3-10 Carbocyclic and 3- to 10-membered heterocyclic rings (wherein C 3-10 The carbocyclic ring and the 3- to 10-membered heterocyclic ring each optionally contain halogen and C 1-4 substituted with one or more substituents independently selected from alkyl is substituted with one or more substituents independently selected from

[0194] In certain embodiments, for compounds or salts of Formula (Ia), (IIa), or (IIIa), B is selected from phenyl; pyridinyl, naphthyl; 1,2,3,4-tetrahydronaphthalene; indane; 7-azaindole; indazole; and chroman, each optionally containing halogen; -OR 18 ; optionally halogen, -OR 18 and C 3-6 C substituted with one or more substituents independently selected from carbocycles 1-6 alkyl; and C 3-10 Carbocyclic and 3- to 10-membered heterocyclic rings (wherein C 3-10 The carbocyclic ring and the 3- to 10-membered heterocyclic ring each optionally contain halogen and C 1-4 substituted with one or more substituents independently selected from alkyl; 18 are independently hydrogen in each occurrence, C 1-6 Alkyl and optionally halogen, C 1-6 Alkyl, C 1-6 C substituted with one or more substituents independently selected from haloalkyl 3-10 Carbocycles are selected from:

[0195] In certain embodiments, for compounds or salts of Formula (Ia), (IIa), or (IIIa), B is selected from phenyl; pyridinyl, naphthyl; 1,2,3,4-tetrahydronaphthalene; indane; 7-azaindole; indazole; and chroman, each optionally containing halogen, trifluoromethyl, cyclopropyl, phenyl, [ka] is substituted with one or more substituents independently selected from

[0196] In certain embodiments, for compounds or salts of Formula (Ia), (IIa), or (IIIa), B is selected from phenyl; pyridinyl, naphthyl; 1,2,3,4-tetrahydronaphthalene; indane; 7-azaindole; indazole; and chroman, each optionally containing halogen, trifluoromethyl, cyclopropyl, phenyl, [ka] is substituted with one or more substituents independently selected from

[0197] In certain embodiments, for compounds or salts of Formula (Ia), (IIa), or (IIIa), C of B 3-12 Carbocycles and 3- to 12-membered heterocycles are monocyclic C 3-6 selected from carbocycles and 3- to 7-membered monocyclic heterocycles, each of which is optionally Halogen, -OR 18 , -N(R 18 )2, -C(O)R 18 and =O; Possibly halogen, -OR 18 , -N(R 18 )2, =O, -CN, C 3-6 C substituted with one or more substituents independently selected from carbocycles and 3- to 6-membered heterocycles 1-6 Alkyl (where C 3-6 The carbocyclic ring and the 3- to 6-membered heterocyclic ring each optionally contain halogen, C 1-4 Alkyl, C 1-4 substituted with one or more substituents independently selected from haloalkyl and ═O); and Both may contain halogen, C 1-4 Alkyl, C 1-4 C substituted with one or more substituents independently selected from haloalkyl and =O 3-10 Carbocyclic and 3- to 10-membered heterocyclic rings is substituted with one or more substituents independently selected from

[0198] In certain embodiments, for compounds or salts of Formula (Ia), (IIa), or (IIIa), C of B 3-12 Carbocycles and 3- to 12-membered heterocycles are monocyclic C 3-6 selected from carbocycles and 3- to 7-membered monocyclic heterocycles, each optionally containing halogen; -OR 18 ; optionally halogen, -OR 18 and C 3-6 C substituted with one or more substituents independently selected from carbocycles 1-6 alkyl; and C 3-10 Carbocyclic and 3- to 10-membered heterocyclic rings (wherein C 3-10 The carbocyclic ring and the 3- to 10-membered heterocyclic ring each optionally contain halogen and C 1-4 substituted with one or more substituents independently selected from alkyl;

[0199] In certain embodiments, for compounds or salts of Formula (Ia), (IIa), or (IIIa), C of B 3-12 Carbocycles and 3- to 12-membered heterocycles are monocyclic C 3-6 selected from carbocycles and 3- to 7-membered monocyclic heterocycles, both optionally halogen; optionally halogen and C 3-6 C substituted with one or more substituents independently selected from carbocycles 1-6 alkyl; and C 3-10 Carbocyclic and 3- to 10-membered heterocyclic rings (wherein C 3-10 The carbocyclic ring and the 3- to 10-membered heterocyclic ring each optionally contain halogen and C 1-4 substituted with one or more substituents independently selected from alkyl;

[0200] In certain embodiments, for compounds or salts of Formula (Ia), (IIa), or (IIIa), C of B 3-12 Carbocycles and 3- to 12-membered heterocycles are monocyclic C 3-6selected from carbocycles and 3- to 7-membered monocyclic heterocycles, each optionally containing halogen; -OR 18 ; optionally halogen, -OR 18 and C 3-6 C substituted with one or more substituents independently selected from carbocycles 1-6 alkyl; and C 3-10 Carbocyclic and 3- to 10-membered heterocyclic rings (wherein C 3-10 The carbocyclic ring and the 3- to 10-membered heterocyclic ring each optionally contain halogen and C 1-4 substituted with one or more substituents independently selected from alkyl; 18 are independently hydrogen in each occurrence, C 1-6 Alkyl and optionally halogen, C 1-6 Alkyl, C 1-6 C substituted with one or more substituents independently selected from haloalkyl 3-10 The ring is selected from carbocycles.

[0201] In certain embodiments, for compounds or salts of Formula (Ia), (IIa), or (IIIa), C of B 3-12 Carbocycles and 3- to 12-membered heterocycles are monocyclic C 3-6 carbocycle and 3- to 7-membered monocyclic heterocycle, each of which is optionally substituted with halogen, trifluoromethyl, cyclopropyl, phenyl, [ka] is substituted with one or more substituents independently selected from

[0202] In certain embodiments, for compounds or salts of Formula (Ia), (IIa), or (IIIa), B is selected from phenyl and pyridinyl, each optionally Halogen, -OR 18 , -N(R 18 )2, -C(O)R 18 and =O; Possibly halogen, -OR 18 , -N(R 18 )2, =O, -CN, C3-6 C substituted with one or more substituents independently selected from carbocycles and 3- to 6-membered heterocycles 1-6 Alkyl (where C 3-6 The carbocyclic ring and the 3- to 6-membered heterocyclic ring each optionally contain halogen, C 1-4 Alkyl, C 1-4 substituted with one or more substituents independently selected from haloalkyl and ═O); and Both may contain halogen, C 1-4 Alkyl, C 1-4 C substituted with one or more substituents independently selected from haloalkyl and =O 3-10 Carbocyclic and 3- to 10-membered heterocyclic rings is substituted with one or more substituents independently selected from

[0203] In certain embodiments, for compounds or salts of Formula (Ia), (IIa), or (IIIa), B is selected from phenyl and pyridinyl, each of which is optionally halogen; —OR 18 ; optionally halogen, -OR 18 and C 3-6 C substituted with one or more substituents independently selected from carbocycles 1-6 alkyl; and C 3-10 Carbocyclic and 3- to 10-membered heterocyclic rings (wherein C 3-10 The carbocyclic ring and the 3- to 10-membered heterocyclic ring each optionally contain halogen and C 1-4 substituted with one or more substituents independently selected from alkyl;

[0204] In certain embodiments, for compounds or salts of Formula (Ia), (IIa), or (IIIa), B is selected from phenyl and pyridinyl, both optionally halogen; optionally halogen and C 3-6 C substituted with one or more substituents independently selected from carbocycles 1-6 alkyl; and C 3-10 Carbocyclic and 3- to 10-membered heterocyclic rings (wherein C 3-10The carbocyclic ring and the 3- to 10-membered heterocyclic ring each optionally contain halogen and C 1-4 substituted with one or more substituents independently selected from alkyl;

[0205] In certain embodiments, for compounds or salts of Formula (Ia), (IIa), or (IIIa), B is selected from phenyl and pyridinyl, each of which is optionally halogen; —OR 18 ; optionally halogen, -OR 18 and C 3-6 C substituted with one or more substituents independently selected from carbocycles 1-6 alkyl; and C 3-10 Carbocyclic and 3- to 10-membered heterocyclic rings (wherein C 3-10 The carbocyclic ring and the 3- to 10-membered heterocyclic ring each optionally contain halogen and C 1-4 substituted with one or more substituents independently selected from alkyl; 18 are independently hydrogen in each occurrence, C 1-6 Alkyl and optionally halogen, C 1-6 Alkyl, C 1-6 C substituted with one or more substituents independently selected from haloalkyl 3-10 Carbocycles are selected from:

[0206] In certain embodiments, for compounds or salts of Formula (Ia), (IIa), or (IIIa), B is selected from phenyl and pyridinyl, each of which is optionally halogen, trifluoromethyl, cyclopropyl, phenyl, [ka] is substituted with one or more substituents independently selected from

[0207] In certain embodiments, for compounds or salts of Formula (Ia), (IIa), or (IIIa), B is a bicyclic C 6-12selected from carbocycles and bicyclic 6- to 12-membered bicyclic heterocycles, each optionally Halogen, -OR 18 , -N(R 18 )2, -C(O)R 18 and =O; Possibly halogen, -OR 18 , -N(R 18 )2, =O, -CN, C 3-6 C substituted with one or more substituents independently selected from carbocycles and 3- to 6-membered heterocycles 1-6 Alkyl (where C 3-6 The carbocyclic ring and the 3- to 6-membered heterocyclic ring each optionally contain halogen, C 1-4 Alkyl, C 1-4 substituted with one or more substituents independently selected from haloalkyl and ═O); and Both may contain halogen, C 1-4 Alkyl, C 1-4 C substituted with one or more substituents independently selected from haloalkyl and =O 3-10 Carbocyclic and 3- to 10-membered heterocyclic rings is substituted with one or more substituents independently selected from

[0208] In certain embodiments, for compounds or salts of Formula (Ia), (IIa), or (IIIa), B is a bicyclic C 6-12 selected from carbocycles and bicyclic 6- to 12-membered bicyclic heterocycles, each optionally containing halogen; -OR 18 ; optionally halogen, -OR 18 and C 3-6 C substituted with one or more substituents independently selected from carbocycles 1-6 alkyl; and C 3-10 Carbocyclic and 3- to 10-membered heterocyclic rings (wherein C 3-10 The carbocyclic ring and the 3- to 10-membered heterocyclic ring each optionally contain halogen and C 1-4 substituted with one or more substituents independently selected from alkyl;

[0209] In certain embodiments, for compounds or salts of Formula (Ia), (IIa), or (IIIa), B is a bicyclic C 6-12 Carbocycles and bicyclic 6- to 12-membered bicyclic heterocycles, both optionally halogen; optionally halogen and C 3-6 C substituted with one or more substituents independently selected from carbocycles 1-6 alkyl; and C 3-10 Carbocyclic and 3- to 10-membered heterocyclic rings (wherein C 3-10 The carbocyclic ring and the 3- to 10-membered heterocyclic ring each optionally contain halogen and C 1-4 substituted with one or more substituents independently selected from alkyl;

[0210] In certain embodiments, for compounds or salts of Formula (Ia), (IIa), or (IIIa), B is a bicyclic C 6-12 selected from carbocycles and bicyclic 6- to 12-membered bicyclic heterocycles, each optionally containing halogen; -OR 18 ; optionally halogen, -OR 18 and C 3-6 C substituted with one or more substituents independently selected from carbocycles 1-6 alkyl; and C 3-10 Carbocyclic and 3- to 10-membered heterocyclic rings (wherein C 3-10 The carbocyclic ring and the 3- to 10-membered heterocyclic ring each optionally contain halogen and C 1-4 substituted with one or more substituents independently selected from alkyl; 18 are independently hydrogen in each occurrence, C 1-6 Alkyl and optionally halogen, C 1-6 Alkyl, C 1-6 C substituted with one or more substituents independently selected from haloalkyl 3-10 Carbocycles are selected from:

[0211] In certain embodiments, for compounds or salts of Formula (Ia), (IIa), or (IIIa), B is a bicyclic C 6-12selected from carbocycles and bicyclic 6- to 12-membered bicyclic heterocycles, each optionally containing halogen, trifluoromethyl, cyclopropyl, phenyl, [ka] is substituted with one or more substituents independently selected from

[0212] In certain embodiments, for compounds or salts of Formula (Ia), (IIa), or (IIIa), B is selected from naphthyl; 1,2,3,4-tetrahydronaphthalene; indane; 7-azaindole; indazole; and chroman, each optionally Halogen, -OR 18 , -N(R 18 )2, -C(O)R 18 and =O; Possibly halogen, -OR 18 , -N(R 18 )2, =O, -CN, C 3-6 C substituted with one or more substituents independently selected from carbocycles and 3- to 6-membered heterocycles 1-6 Alkyl (where C 3-6 The carbocyclic ring and the 3- to 6-membered heterocyclic ring each optionally contain halogen, C 1-4 Alkyl, C 1-4 substituted with one or more substituents independently selected from haloalkyl and ═O); and Both may contain halogen, C 1-4 Alkyl, C 1-4 C substituted with one or more substituents independently selected from haloalkyl and =O 3-10 Carbocyclic and 3- to 10-membered heterocyclic rings is substituted with one or more substituents independently selected from

[0213] In certain embodiments, for compounds or salts of Formula (Ia), (IIa), or (IIIa), B is selected from naphthyl; 1,2,3,4-tetrahydronaphthalene; indane; 7-azaindole; indazole; and chroman, each optionally containing a halogen; -OR 18; optionally halogen, -OR 18 and C 3-6 C substituted with one or more substituents independently selected from carbocycles 1-6 alkyl; and C 3-10 Carbocyclic and 3- to 10-membered heterocyclic rings (wherein C 3-10 The carbocyclic ring and the 3- to 10-membered heterocyclic ring each optionally contain halogen and C 1-4 substituted with one or more substituents independently selected from alkyl;

[0214] In certain embodiments, for compounds or salts of Formula (Ia), (IIa), or (IIIa), B is selected from naphthyl; 1,2,3,4-tetrahydronaphthalene; indane; 7-azaindole; indazole; and chroman, each optionally containing halogen and C 3-6 carbocyclic; and C 3-10 Carbocyclic and 3- to 10-membered heterocyclic rings (wherein C 3-10 The carbocyclic ring and the 3- to 10-membered heterocyclic ring each optionally contain halogen and C 1-4 substituted with one or more substituents independently selected from alkyl;

[0215] In certain embodiments, for compounds or salts of Formula (Ia), (IIa), or (IIIa), B is selected from naphthyl; 1,2,3,4-tetrahydronaphthalene; indane; 7-azaindole; indazole; and chroman; each optionally and independently selected from halogen, -OR 18 and C 3-6 carbocyclic; and C 3-10 Carbocyclic and 3- to 10-membered heterocyclic rings (wherein C 3-10 The carbocyclic ring and the 3- to 10-membered heterocyclic ring each optionally contain halogen and C 1-4 substituted with one or more substituents independently selected from alkyl; 18 are independently hydrogen in each occurrence, C 1-6 Alkyl and optionally halogen, C 1-6Alkyl, C 1-6 C substituted with one or more substituents independently selected from haloalkyl 3-10 Carbocycles are selected from:

[0216] In certain embodiments, for compounds or salts of Formula (Ia), (IIa), or (IIIa), B is selected from naphthyl; 1,2,3,4-tetrahydronaphthalene; indane; 7-azaindole; indazole; and chroman, each optionally containing halogen, trifluoromethyl, cyclopropyl, phenyl, [ka] is substituted with one or more substituents independently selected from

[0217] In certain embodiments, for compounds or salts of Formula (Ia), (IIa), or (IIIa), B is: [ka] is selected from.

[0218] In certain embodiments, for compounds or salts of Formula (Ia), (IIa), or (IIIa), B is [ka] is selected from.

[0219] In certain embodiments, for compounds or salts of Formula (Ia), (IIa), or (IIIa), B is -OR 18 , -SR 18 , -N(R 18 )2, -C(O)R 18 , -C(O)OR 18 , -OC(O)R 18 , -OC(O)N(R 18 )2, -C(O)N(R 18 )2, -N(R 18 )C(O)R 18 , -N(R 18 )C(O)OR 18, -N(R 18 )C(O)N(R 18 )2, -N(R 18 )C(S)N(R 18 )2, -N(R 18 )S(O)2(R 18 ), -S(O)R 18 , -S(O)2R 18 and -S(O)N(R 18 )2. In some embodiments, B is selected from -OR 18 , -N(R 18 )2, -C(O)R 18 , -C(O)OR 18 , -OC(O)R 18 , -OC(O)N(R 18 )2, -C(O)N(R 18 )2, -N(R 18 )C(O)R 18 , -N(R 18 )C(O)OR 18 , -N(R 18 )C(O)N(R 18 )2, -N(R 18 )C(S)N(R 18 )2 and -N(R 18 )S(O)2(R 18 In some embodiments, B is selected from -OR 18 , -N(R 18 )2, -OC(O)R 18 , -OC(O)N(R 18 )2, -C(O)N(R 18 )2, -N(R 18 )C(O)R 18 , -N(R 18 )C(O)OR 18 , -N(R 18 )C(O)N(R 18 )2, -N(R 18 )C(S)N(R 18 )2 and -N(R 18 )S(O)2(R 18 In some embodiments, B is selected from -OR 18 , -N(R 18 )2, -OC(O)R 18 , -OC(O)N(R 18 )2, -N(R18 )C(O)R 18 , -N(R 18 )C(O)OR 18 , -N(R 18 )C(O)N(R 18 )2, -N(R 18 )C(S)N(R 18 )2 and -N(R 18 )S(O)2(R 18 ) is selected.

[0220] In certain embodiments, for compounds or salts of Formula (Ia), (IIa), or (IIIa), B is -OR 18 , -N(R 18 )2, -N(R 18 )C(O)R 18 , -N(R 18 )C(O)OR 18 , -N(R 18 )C(O)N(R 18 )2, -N(R 18 )C(S)N(R 18 )2 and -N(R 18 )S(O)2(R 18 In some embodiments, B is selected from -N(R 18 )2, -N(R 18 )C(O)R 18 , -N(R 18 )C(O)OR 18 , -N(R 18 )C(O)N(R 18 )2, -N(R 18 )C(S)N(R 18 )2 and -N(R 18 )S(O)2(R 18 In some embodiments, B is selected from -N(R 18 )2, -N(R 18 )C(O)R 18 , -N(R 18 )C(O)OR 18 , -N(R 18 )C(O)N(R 18 )2 and -N(R 18 )S(O)2(R 18 In some embodiments, B is selected from -N(R 18)2, -N(R 18 )C(O)R 18 , -N(R 18 )C(O)N(R 18 )2 and -N(R 18 )S(O)2(R 18 In some embodiments, B is selected from -N(R 18 )2. In some embodiments, B is —N(R 18 )C(O)R 18 In some embodiments, B is —N(R 18 )C(O)N(R 18 )2. In some embodiments, B is —N(R 18 )S(O)2(R 18 )

[0221] In certain embodiments, for a compound or salt of Formula (Ia), (IIa), or (IIIa), R 18 Independently in each case: hydrogen; C 1-6 Alkyl (optionally: Halogen, -OR 22 , -SR 22 , -N(R 22 )2, -C(O)R 22 , -C(O)OR 22 , -OC(O)R 22 , -OC(O)N(R 22 )2, -C(O)N(R 22 )2, -N(R 22 )C(O)R 22 , -NO2, =O, =S, =N(R 22 ), -N3, -CN, C 3-10 substituted with one or more substituents independently selected from a carbocycle and a 3- to 10-membered heterocycle; where C 3-10 The carbocyclic ring and the 3- to 10-membered heterocyclic ring each optionally contain halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR 22 , -SR 22 and -N(R 22 ) substituted with one or more substituents independently selected from 2); and C 3-10 Carbocycles and 3- to 10-membered heterocycles (both optionally: Halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR 22 , -SR 22 , -N(R 22 )2, -C(O)R 22 , -C(O)OR 22 , -OC(O)R 22 , -OC(O)N(R 22 )2, -C(O)N(R 22 )2, -N(R 22 )C(O)R 22 , -N(R 22 )C(O)OR 22 , -N(R 22 )C(O)N(R 22 )2, -N(R 22 )C(S)N(R 22 )2, -N(R 22 )S(O)2(R 22 ), -S(O)R 22 , -S(O)2R 22 , -S(O)2N(R 22 )2, -NO2, =O, =S, =N(R 22 ), -N3, -CN, C 3-6 substituted with one or more substituents independently selected from a carbocycle and a 3- to 6-membered heterocycle; where C 3-6 The carbocyclic ring and the 3- to 6-membered heterocyclic ring each optionally contain halogen, C 1-4 Alkyl and C 1-4 substituted with one or more substituents independently selected from haloalkyl is selected from.

[0222] In certain embodiments, for a compound or salt of Formula (Ia), (IIa), or (IIIa), R 18 are independently hydrogen and C in each case 1-6 Alkyl (optionally: Halogen, -OR 22 , -SR 22 , -N(R 22 )2, -C(O)R 22, -C(O)OR 22 , -OC(O)R 22 , -OC(O)N(R 22 )2, -C(O)N(R 22 )2, -N(R 22 )C(O)R 22 , -NO2, =O, =S, =N(R 22 ), -N3, -CN, C 3-10 substituted with one or more substituents independently selected from a carbocycle and a 3- to 10-membered heterocycle; where C 3-10 The carbocyclic ring and the 3- to 10-membered heterocyclic ring each optionally contain halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR 22 , -SR 22 and -N(R 22 ) substituted with one or more substituents independently selected from 2).

[0223] In certain embodiments, for a compound or salt of Formula (Ia), (IIa), or (IIIa), R 18 independently in each occurrence hydrogen and optionally halogen, -OR 22 , -N(R 22 )2, =O, -CN, C 3-10 C substituted with one or more substituents independently selected from carbocycles and 3- to 10-membered heterocycles 1-6 alkyl; 3-10 The carbocyclic ring and the 3- to 10-membered heterocyclic ring each optionally contain halogen and C 1-6 and substituted with one or more substituents independently selected from alkyl.

[0224] In certain embodiments, for a compound or salt of Formula (Ia), (IIa), or (IIIa), R 22 Independently in each case: hydrogen; C 1-4 Alkyl (optionally halogen, hydroxyl, C 3-6 substituted with one or more substituents independently selected from a carbocycle and a 3- to 6-membered heterocycle, wherein each C 3-6Carbocyclic and 3- to 6-membered heterocyclic rings may optionally contain halogen, C 1-4 Alkyl and -C(O)N(R 23 ) substituted with one or more substituents independently selected from 2); and C 3-6 Carbocyclic rings and 3- to 12-membered heterocyclic rings (both optionally containing halogen, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 substituted with one or more substituents independently selected from alkoxy and ═O is selected from; and R 23 are independently hydrogen and C in each case 1-4 alkyl.

[0225] In certain embodiments, for a compound or salt of Formula (Ia), (IIa), or (IIIa), R 22 are independently hydrogen in each occurrence, C 1-4 Alkyl, C 3-6 selected from carbocycles and 3- to 6-membered heterocycles, wherein C 3-6 The carbocyclic ring and the 3- to 6-membered heterocyclic ring may each optionally be C 1-4 Alkyl and C 1-4 substituted with one or more substituents independently selected from alkoxy; and R 23 are independently hydrogen and C in each case 1-4 alkyl.

[0226] In certain embodiments, for a compound or salt of Formula (Ia), (IIa), or (IIIa), R 18 is independently in each case: hydrogen, C 3-10 selected from carbocycles and 3- to 10-membered heterocycles, wherein R 18 Each C 3-10 The carbocycle and 3- to 10-membered heterocycle are optionally substituted with one or more substituents. In certain embodiments, R 18 Each C 3-10The carbocycle and 3- to 10-membered heterocycle are independently selected in each occurrence from hydrogen; and pyrrolidine, piperidine, phenyl, indoline, bicyclo[2.2.2]octane, cyclohexane, tetrahydropyran, pyridine, oxadiazole, pyrimidine, quinazoline, naphthalene, quinoline, thieno[3,2-d]pyrimidine, thieno[2,3-d]pyrimidine, benzothiazole, indane, thieno[2,3-d]pyrimidine oxide, and cyclopropyl, any of which is optionally substituted by one or more substituents.

[0227] In certain embodiments, for a compound or salt of Formula (Ia), (IIa), or (IIIa), R 18 Each C 3-10 The carbocyclic ring and the 3- to 10-membered heterocyclic ring are independently in each case monocyclic C 3-6 In one embodiment, R is selected from a carbocycle and a 3- to 7-membered monocyclic heterocycle, each of which is optionally substituted with one or more substituents. 18 Each C 3-10 The carbocycle and the 3- to 10-membered heterocycle are independently selected at each occurrence from pyrrolidine, piperidine, phenyl, cyclohexane, tetrahydropyran, pyridine, oxadiazole, pyrimidine, and cyclopropyl, any of which is optionally substituted with one or more substituents. 18 is independently selected at each occurrence from hydrogen; and pyrrolidine, piperidine, phenyl, cyclohexane, tetrahydropyran, pyridine, oxadiazole, pyrimidine, and cyclopropyl, any of which is optionally substituted with one or more substituents.

[0228] In certain embodiments, for a compound or salt of Formula (Ia), (IIa), or (IIIa), R 18 Each C 3-10 Carbocycles and 3- to 10-membered heterocycles are independently in each case bicyclic C 6-10 In one embodiment, R is selected from a carbocycle and a bicyclic 6- to 10-membered bicyclic heterocycle, each of which is optionally substituted with one or more substituents. 18 Each C 3-10The carbocycle and the 3- to 10-membered heterocycle are independently selected in each occurrence from indoline, bicyclo[2.2.2]octane, quinazoline, naphthalene, quinoline, thieno[3,2-d]pyrimidine, thieno[2,3-d]pyrimidine, benzothiazole, indane, and thieno[2,3-d]pyrimidine oxide, each of which is optionally substituted with one or more substituents. In certain embodiments, R 18 is independently selected at each occurrence from hydrogen; and indoline, bicyclo[2.2.2]octane, quinazoline, naphthalene, quinoline, thieno[3,2-d]pyrimidine, thieno[2,3-d]pyrimidine, benzothiazole, indane, and thieno[2,3-d]pyrimidine oxide, each of which is optionally substituted with one or more substituents.

[0229] In certain embodiments, for a compound or salt of Formula (Ia), (IIa), or (IIIa), R 18 C 3-10 The carbocyclic ring and the 3- to 10-membered heterocyclic ring each independently represent halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR 22 , -N(R 22 )2, -C(O)R 22 , -C(O)N(R 22 )2, -N(R 22 )C(O)R 22 , -S(O)2R 22 , =O, -CN, C 3-6 Carbocyclic and 3- to 6-membered heterocyclic rings (where C 3-6 The carbocyclic ring and the 3- to 6-membered heterocyclic ring each optionally contain halogen, C 1-4 Alkyl and C 1-4 In certain embodiments, R is optionally substituted with one or more substituents selected from haloalkyl. 18 C 3-10 The carbocyclic ring and the 3- to 10-membered heterocyclic ring each independently represent halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, -N(R 22 )2, -C(O)R 22 , -C(O)N(R 22)2, -S(O)2R 22 , =O, C 3-6 Carbocyclic and 3- to 6-membered heterocyclic rings (where C 3-6 The carbocyclic ring and the 3- to 6-membered heterocyclic ring each optionally contain halogen and C 1-4 and optionally substituted with one or more substituents selected from haloalkyl).

[0230] In certain embodiments, for a compound or salt of Formula (Ia), (IIa), or (IIIa), R 18 C 3-10 The carbocyclic ring and the 3- to 10-membered heterocyclic ring are each independently selected from halogen, methyl, trifluoromethyl, cyclopropyl, phenyl, -NH2, =O, [ka] In certain embodiments, R 18 C 3-10 The carbocyclic ring and the 3- to 10-membered heterocyclic ring are each independently selected from halogen, methyl, trifluoromethyl, cyclopropyl, phenyl, -NH2, =O, [ka] and optionally substituted with one or more substituents selected from:

[0231] In certain embodiments, for a compound or salt of Formula (Ia), (IIa), or (IIIa), R 18 Independently in each case: Hydrogen, C 3-10 Carbocyclic and 3- to 10-membered heterocyclic rings where R 18 Each C 3-10 Carbocyclic rings and 3- to 10-membered heterocyclic rings are each: Halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR 22 , -SR 22 , -N(R 22 )2, -C(O)R22 , -C(O)OR 22 , -OC(O)R 22 , -OC(O)N(R 22 )2, -C(O)N(R 22 )2, -N(R 22 )C(O)R 22 , -N(R 22 )C(O)OR 22 , -N(R 22 )C(O)N(R 22 )2, -N(R 22 )C(S)N(R 22 )2, -N(R 22 )S(O)2(R 22 ), -S(O)R 22 , -S(O)2R 22 , -S(O)2N(R 22 )2, -NO2, =O, =S, =N(R 22 ), -N3, -CN, C 3-6 optionally substituted with one or more substituents independently selected from carbocycles and 3- to 6-membered heterocycles; where C 3-6 The carbocyclic ring and the 3- to 6-membered heterocyclic ring each optionally contain halogen, C 1-4 Alkyl and C 1-4 and substituted with one or more substituents independently selected from haloalkyl.

[0232] In certain embodiments, for a compound or salt of Formula (Ia), (IIa), or (IIIa), R 18 Independently in each case: Hydrogen, C 3-10 Carbocyclic and 3- to 10-membered heterocyclic rings where R 18 Each C 3-10 Carbocyclic rings and 3- to 10-membered heterocyclic rings are each: Halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR 22 , -N(R 22 )2, -C(O)R 22 , -C(O)OR 22 , -OC(O)R 22 , -OC(O)N(R 22)2, -C(O)N(R 22 )2, -N(R 22 )C(O)R 22 , -N(R 22 )C(O)OR 22 , -S(O)2R 22 , -S(O)2N(R 22 )2, =O, -CN, C 3-6 optionally substituted with one or more substituents independently selected from carbocycles and 3- to 6-membered heterocycles; where C 3-6 The carbocyclic ring and the 3- to 6-membered heterocyclic ring each optionally contain halogen, C 1-4 Alkyl and C 1-4 and substituted with one or more substituents independently selected from haloalkyl.

[0233] In certain embodiments, for a compound or salt of Formula (Ia), (IIa), or (IIIa), R 18 is independently in each case: hydrogen, C 3-10 selected from carbocycles and 3- to 10-membered heterocycles, wherein R 18 Each C 3-10 Carbocyclic rings and 3- to 10-membered heterocyclic rings are each: Halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, -N(R 22 )2, -C(O)R 22 , -C(O)N(R 22 )2, -S(O)2R 22 , C 3-6 optionally substituted with one or more substituents independently selected from carbocycles and 3- to 6-membered heterocycles; where C 3-6 The carbocyclic ring and the 3- to 6-membered heterocyclic ring each optionally contain halogen, C 1-4 Alkyl and C 1-4 and substituted with one or more substituents independently selected from haloalkyl.

[0234] In certain embodiments, for a compound or salt of Formula (Ia), (IIa), or (IIIa), R 18 is independently in each case: hydrogen, C 3-10selected from carbocycles and 3- to 10-membered heterocycles, wherein R 18 Each C 3-10 The carbocycle and 3- to 10-membered heterocycle are selected from pyrrolidine, piperidine, phenyl, indoline, bicyclo[2.2.2]octane, cyclohexane, tetrahydropyran, pyridine, oxadiazole, pyrimidine, quinazoline, naphthalene, quinoline, thieno[3,2-d]pyrimidine, thieno[2,3-d]pyrimidine, benzothiazole, indane, thieno[2,3-d]pyrimidine oxide, and cyclopropyl, each of which is optionally Halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR 22 , -SR 22 , -N(R 22 )2, -C(O)R 22 , -C(O)OR 22 , -OC(O)R 22 , -OC(O)N(R 22 )2, -C(O)N(R 22 )2, -N(R 22 )C(O)R 22 , -N(R 22 )C(O)OR 22 , -N(R 22 )C(O)N(R 22 )2, -N(R 22 )C(S)N(R 22 )2, -N(R 22 )S(O)2(R 22 ), -S(O)R 22 , -S(O)2R 22 , -S(O)2N(R 22 )2, -NO2, =O, =S, =N(R 22 ), -N3, -CN, C 3-6 Carbocyclic and 3- to 6-membered heterocyclic rings and is substituted with one or more substituents independently selected from: where C 3-6 The carbocyclic ring and the 3- to 6-membered heterocyclic ring each optionally contain halogen, C 1-4 Alkyl and C 1-4 and substituted with one or more substituents independently selected from haloalkyl.

[0235] In certain embodiments, for a compound or salt of Formula (Ia), (IIa), or (IIIa), R 18 Each C 3-10 The carbocycle and 3- to 10-membered heterocycle are selected from pyrrolidine, piperidine, phenyl, indoline, bicyclo[2.2.2]octane, cyclohexane, tetrahydropyran, pyridine, oxadiazole, pyrimidine, quinazoline, naphthalene, quinoline, thieno[3,2-d]pyrimidine, thieno[2,3-d]pyrimidine, benzothiazole, indane, thieno[2,3-d]pyrimidine oxide, and cyclopropyl, each of which is optionally Halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR 22 , -N(R 22 )2, -C(O)R 22 , -C(O)OR 22 , -OC(O)R 22 , -OC(O)N(R 22 )2, -C(O)N(R 22 )2, -N(R 22 )C(O)R 22 , -N(R 22 )C(O)OR 22 , -S(O)2R 22 , -S(O)2N(R 22 )2, =O, -CN, C 3-6 Carbocyclic and 3- to 6-membered heterocyclic rings and is substituted with one or more substituents independently selected from: where C 3-6 The carbocyclic ring and the 3- to 6-membered heterocyclic ring each optionally contain halogen, C 1-4 Alkyl and C 1-4 and substituted with one or more substituents independently selected from haloalkyl.

[0236] In certain embodiments, for a compound or salt of Formula (Ia), (IIa), or (IIIa), R 18 Each C 3-10The carbocycle and 3- to 10-membered heterocycle are selected from pyrrolidine, piperidine, phenyl, indoline, bicyclo[2.2.2]octane, cyclohexane, tetrahydropyran, pyridine, oxadiazole, pyrimidine, quinazoline, naphthalene, quinoline, thieno[3,2-d]pyrimidine, thieno[2,3-d]pyrimidine, benzothiazole, indane, thieno[2,3-d]pyrimidine oxide, and cyclopropyl, each of which is optionally Halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, -N(R 22 )2, -C(O)R 22 , -C(O)N(R 22 )2, -S(O)2R 22 , C 3-6 Carbocyclic and 3- to 6-membered heterocyclic rings and is substituted with one or more substituents independently selected from: where C 3-6 The carbocyclic ring and the 3- to 6-membered heterocyclic ring each optionally contain halogen, C 1-4 Alkyl and C 1-4 and substituted with one or more substituents independently selected from haloalkyl.

[0237] In certain embodiments, for a compound or salt of Formula (Ia), (IIa), or (IIIa), R 18 Each C 3-10 The carbocycle and 3- to 10-membered heterocycle are selected from pyrrolidine, piperidine, phenyl, indoline, bicyclo[2.2.2]octane, cyclohexane, tetrahydropyran, pyridine, oxadiazole, pyrimidine, quinazoline, naphthalene, quinoline, thieno[3,2-d]pyrimidine, thieno[2,3-d]pyrimidine, benzothiazole, indane, thieno[2,3-d]pyrimidine oxide, and cyclopropyl, each of which optionally contains halogen, methyl, trifluoromethyl, cyclopropyl, phenyl, -NH, =O, [ka] is substituted with one or more substituents independently selected from

[0238] In certain embodiments, for a compound or salt of Formula (Ia), (IIa), or (IIIa), R 18 Each C 3-10 The carbocyclic ring and the 3- to 10-membered heterocyclic ring are independently in each case monocyclic C 3-6 Carbocycle and 3- to 7-membered monocyclic heterocycle, Hydrogen, C 3-10 optionally substituted with one or more substituents independently selected from carbocycles and 3- to 10-membered heterocycles, wherein R 18 Each C 3-10 Carbocyclic rings and 3- to 10-membered heterocyclic rings are each: Halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR 22 , -N(R 22 )2, -C(O)R 22 , -C(O)OR 22 , -OC(O)R 22 , -OC(O)N(R 22 )2, -C(O)N(R 22 )2, -N(R 22 )C(O)R 22 , -N(R 22 )C(O)OR 22 , -S(O)2R 22 , -S(O)2N(R 22 )2, =O, -CN, C 3-6 Carbocyclic and 3- to 6-membered heterocyclic rings optionally substituted with one or more substituents independently selected from: where C 3-6 The carbocyclic ring and the 3- to 6-membered heterocyclic ring each optionally contain halogen, C 1-4 Alkyl and C 1-4 and substituted with one or more substituents independently selected from haloalkyl.

[0239] In certain embodiments, for a compound or salt of Formula (Ia), (IIa), or (IIIa), R 18 Each C 3-10 The carbocyclic ring and the 3- to 10-membered heterocyclic ring are independently in each case monocyclic C 3-6Carbocycle and 3- to 7-membered monocyclic heterocycle, Halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, -N(R 22 )2, -C(O)R 22 , -C(O)N(R 22 )2, -S(O)2R 22 , C 3-6 Carbocyclic and 3- to 6-membered heterocyclic rings optionally substituted with one or more substituents independently selected from: where C 3-6 The carbocyclic ring and the 3- to 6-membered heterocyclic ring each optionally contain halogen, C 1-4 Alkyl and C 1-4 and substituted with one or more substituents independently selected from haloalkyl.

[0240] In certain embodiments, for a compound or salt of Formula (Ia), (IIa), or (IIIa), R 18 Each C 3-10 The carbocyclic ring and the 3- to 10-membered heterocyclic ring are independently in each case monocyclic C 3-6 carbocycle and 3- to 7-membered monocyclic heterocycle, each of which in each case is selected from halogen, methyl, trifluoromethyl, cyclopropyl, phenyl, -NH2, =O, [ka] and optionally substituted with one or more substituents independently selected from:

[0241] In certain embodiments, for a compound or salt of Formula (Ia), (IIa), or (IIIa), R 18 Each C 3-10 The carbocycle and the 3- to 10-membered heterocycle are independently selected in each occurrence from pyrrolidine, piperidine, phenyl, cyclohexane, tetrahydropyran, pyridine, oxadiazole, pyrimidine, and cyclopropyl; Hydrogen, C 3-10 optionally substituted with one or more substituents independently selected from carbocycles and 3- to 10-membered heterocycles, wherein R 18Each C 3-10 Carbocyclic rings and 3- to 10-membered heterocyclic rings are each: Halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR 22 , -N(R 22 )2, -C(O)R 22 , -C(O)OR 22 , -OC(O)R 22 , -OC(O)N(R 22 )2, -C(O)N(R 22 )2, -N(R 22 )C(O)R 22 , -N(R 22 )C(O)OR 22 , -S(O)2R 22 , -S(O)2N(R 22 )2, =O, -CN, C 3-6 Carbocyclic and 3- to 6-membered heterocyclic rings optionally substituted with one or more substituents independently selected from: where C 3-6 The carbocyclic ring and the 3- to 6-membered heterocyclic ring each optionally contain halogen, C 1-4 Alkyl and C 1-4 and substituted with one or more substituents independently selected from haloalkyl.

[0242] In certain embodiments, for a compound or salt of Formula (Ia), (IIa), or (IIIa), R 18 Each C 3-10 The carbocycle and the 3- to 10-membered heterocycle are independently selected in each occurrence from pyrrolidine, piperidine, phenyl, cyclohexane, tetrahydropyran, pyridine, oxadiazole, pyrimidine, and cyclopropyl; Halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, -N(R 22 )2, -C(O)R 22 , -C(O)N(R 22 )2, -S(O)2R 22 , C 3-6 Carbocyclic and 3- to 6-membered heterocyclic rings optionally substituted with one or more substituents independently selected from: where C 3-6 The carbocyclic ring and the 3- to 6-membered heterocyclic ring each optionally contain halogen, C 1-4 Alkyl and C 1-4 and substituted with one or more substituents independently selected from haloalkyl.

[0243] In certain embodiments, for a compound or salt of Formula (Ia), (IIa), or (IIIa), R 18 Each C 3-10 The carbocycle and the 3- to 10-membered heterocycle are independently selected in each occurrence from pyrrolidine, piperidine, phenyl, cyclohexane, tetrahydropyran, pyridine, oxadiazole, pyrimidine, and cyclopropyl, each of which is independently selected in each occurrence from halogen, methyl, trifluoromethyl, cyclopropyl, phenyl, -NH, =O, [ka] and optionally substituted with one or more substituents independently selected from:

[0244] In certain embodiments, for a compound or salt of Formula (Ia), (IIa), or (IIIa), R 18 Each C 3-10 Carbocycles and 3- to 10-membered heterocycles are independently in each case bicyclic C 6-10 Carbocycle and bicyclic 6- to 10-membered bicyclic heterocycle, each in each case Hydrogen, C 3-10 optionally substituted with one or more substituents independently selected from carbocycles and 3- to 10-membered heterocycles, wherein R 18 Each C 3-10 Carbocyclic rings and 3- to 10-membered heterocyclic rings are each: Halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR 22 , -N(R 22 )2, -C(O)R 22 , -C(O)OR 22 , -OC(O)R 22 , -OC(O)N(R 22 )2, -C(O)N(R 22)2, -N(R 22 )C(O)R 22 , -N(R 22 )C(O)OR 22 , -S(O)2R 22 , -S(O)2N(R 22 )2, =O, -CN, C 3-6 Carbocyclic and 3- to 6-membered heterocyclic rings optionally substituted with one or more substituents independently selected from: where C 3-6 The carbocyclic ring and the 3- to 6-membered heterocyclic ring each optionally contain halogen, C 1-4 Alkyl and C 1-4 and substituted with one or more substituents independently selected from haloalkyl.

[0245] In certain embodiments, for a compound or salt of Formula (Ia), (IIa), or (IIIa), R 18 Each C 3-10 Carbocycles and 3- to 10-membered heterocycles are independently in each case bicyclic C 6-10 Carbocycle and bicyclic 6- to 10-membered bicyclic heterocycle, each in each case Halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, -N(R 22 )2, -C(O)R 22 , -C(O)N(R 22 )2, -S(O)2R 22 , C 3-6 Carbocyclic and 3- to 6-membered heterocyclic rings optionally substituted with one or more substituents independently selected from: where C 3-6 The carbocyclic ring and the 3- to 6-membered heterocyclic ring each optionally contain halogen, C 1-4 Alkyl and C 1-4 and substituted with one or more substituents independently selected from haloalkyl.

[0246] In certain embodiments, for a compound or salt of Formula (Ia), (IIa), or (IIIa), R 18 Each C 3-10 Carbocycles and 3- to 10-membered heterocycles are independently in each case bicyclic C6-10 carbocycle and bicyclic 6- to 10-membered bicyclic heterocycle, each of which in each case is selected from halogen, methyl, trifluoromethyl, cyclopropyl, phenyl, -NH2, =O, [ka] and optionally substituted with one or more substituents independently selected from:

[0247] In certain embodiments, for a compound or salt of Formula (Ia), (IIa), or (IIIa), R 18 Each C 3-10 The carbocycle and the 3- to 10-membered heterocycle are independently selected in each occurrence from indoline, bicyclo[2.2.2]octane, quinazoline, naphthalene, quinoline, thieno[3,2-d]pyrimidine, thieno[2,3-d]pyrimidine, benzothiazole, indane, and thieno[2,3-d]pyrimidine oxide, each optionally selected from: Hydrogen, C 3-10 substituted with one or more substituents independently selected from a carbocycle and a 3- to 10-membered heterocycle, wherein R 18 Each C 3-10 Carbocyclic rings and 3- to 10-membered heterocyclic rings are each: Halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, -OR 22 , -N(R 22 )2, -C(O)R 22 , -C(O)OR 22 , -OC(O)R 22 , -OC(O)N(R 22 )2, -C(O)N(R 22 )2, -N(R 22 )C(O)R 22 , -N(R 22 )C(O)OR 22 , -S(O)2R 22 , -S(O)2N(R 22 )2, =O, -CN, C 3-6 Carbocyclic and 3- to 6-membered heterocyclic rings optionally substituted with one or more substituents independently selected from: where C3-6 The carbocyclic ring and the 3- to 6-membered heterocyclic ring each optionally contain halogen, C 1-4 Alkyl and C 1-4 and substituted with one or more substituents independently selected from haloalkyl.

[0248] In certain embodiments, for a compound or salt of Formula (Ia), (IIa), or (IIIa), R 18 Each C 3-10 The carbocycle and the 3- to 10-membered heterocycle are independently selected in each occurrence from indoline, bicyclo[2.2.2]octane, quinazoline, naphthalene, quinoline, thieno[3,2-d]pyrimidine, thieno[2,3-d]pyrimidine, benzothiazole, indane, and thieno[2,3-d]pyrimidine oxide, each optionally selected from: Halogen, C 1-6 Alkyl, C 1-6 Haloalkyl, -N(R 22 )2, -C(O)R 22 , -C(O)N(R 22 )2, -S(O)2R 22 , C 3-6 Carbocyclic and 3- to 6-membered heterocyclic rings and is substituted with one or more substituents independently selected from: where C 3-6 The carbocyclic ring and the 3- to 6-membered heterocyclic ring each optionally contain halogen, C 1-4 Alkyl and C 1-4 and substituted with one or more substituents independently selected from haloalkyl.

[0249] In certain embodiments, for a compound or salt of Formula (Ia), (IIa), or (IIIa), R 18 Each C 3-10 The carbocycle and the 3- to 10-membered heterocycle are independently selected in each occurrence from indoline, bicyclo[2.2.2]octane, quinazoline, naphthalene, quinoline, thieno[3,2-d]pyrimidine, thieno[2,3-d]pyrimidine, benzothiazole, indane, and thieno[2,3-d]pyrimidine oxide, each of which is optionally selected from halogen, methyl, trifluoromethyl, cyclopropyl, phenyl, -NH, =O, [ka] is substituted with one or more substituents independently selected from

[0250] In certain embodiments, for compounds or salts of Formula (Ia), (IIa), or (IIIa), B is [ka] [ka] is selected from.

[0251] In certain embodiments, for compounds or salts of Formula (Ia), (IIa), or (IIIa), B is [ka] [ka] is selected from.

[0252] In certain embodiments, the compound or salt of Formula (I), (II), or (III) is selected from the compounds in Table 1 below. [Table 1] [Table 2] [Table 3] [Table 4] [Table 5] [Table 6] [Table 7] Table 8 Table 9

Table 10

Table 19

[0253] Synthesis method Figure 1 shows the synthesis of intermediate 10. Condensation of pyridyl aldehyde 1 with ketoester 2 in the presence of pyrrolidine in sulfuric acid gives cyclic ester 3, which is reduced under conventional conditions to give crude pyridyl ester 4. Protection of the free amine gives Boc derivative 5, which is reduced with lithium borohydride to give alcohol 6. Barrick-Döring oxidation of alcohol 6 gives crude aldehyde 7, which is condensed with amine 8 under reducing conditions to give 3-pyridyl ester 9. Hydrolysis of ester 9 gives crude lithium salt 10.

[0254] Figure 2 shows the synthesis of compounds of formula (VII), in which aldehyde 11 is condensed with malonic acid 12 in the presence of ammonium formate to give β-amino acid 13, which is then esterified to give β-amino ester 14. Reaction of β-amino ester 14 with compound 10 gives β-amino ester amide 15, which is globally deprotected to give compounds of formula (VII).

[0255] FIG. 3 shows an alternative synthesis of compound of formula (VII), in which compound 21 is obtained by cross-coupling an aryl halide with a transition metal compound, which is then acid-deprotected and reacted with compound 10 to obtain ester amide 22, which is then globally deprotected to obtain compound of formula (VII).

[0256] Figure 4 shows the synthesis of compounds of formula (VIII), in which nitrile 28 is reacted with dimethyl carbonate 29 to give ester 30. Reduction of the nitrile and protection of the amine gives β-aminoester 31, which is deprotected to give amine salt 32. Reaction of amine salt 32 with compound 10 gives ester amide 33, which is globally deprotected to give compounds of formula (VIII).

[0257] Figure 5 shows an alternative synthesis of compound of formula (VIII), in which aryl halide 42 is cross-coupled with a transition metal compound to give compound 43, which is deprotected to give compound 44. Reaction of compound 44 with compound 10 gives ester amide 45, which is globally deprotected to give compound of formula (VIII).

[0258] Figure 6 illustrates the synthesis of amides and sulfonamides of formula (VIII), where reaction of free amine 51 under a variety of conditions can be used to provide amine, amide, urea, or sulfonamide 52, which is deprotected to provide amine salt 53. Reaction of amine salt 53 with compound 10 provides ester amide 45, which is globally deprotected to provide compounds of formula (VIII).

[0259] 7, compound 62 is then acylated or reductively alkylated with substituted piperidinyl ester 63 to give compound 64. Hydrolysis of compound 64 gives lithium salt 65, which is then reacted with ester 66 to give compound 67, which is globally deprotected to give compound 68.

[0260] Those skilled in the art will recognize that many other synthetic routes can be implemented to provide compounds of Formulae (I)-(VIII) and (Ia)-(IIIa), and therefore the methods set forth in Figures 1-7 should be considered representative rather than comprehensive.

[0261] How to use Provided is a method for treating, preventing or alleviating symptoms of medical disorders in patients who need such treatment, for example, idiopathic pulmonary fibrosis, systemic sclerosis-related interstitial lung disease, myositis-related interstitial lung disease, systemic lupus erythematosus-related interstitial lung disease, rheumatoid arthritis, related interstitial lung disease, diabetic nephropathy, focal segmental glomerulosclerosis, chronic kidney disease, nonalcoholic steatohepatitis, primary biliary cirrhosis, primary sclerosing cholangitis, solid tumor, hematological tumor, organ transplant, Alport syndrome, interstitial lung disease, radiation-induced fibrosis, bleomycin-induced fibrosis, asbestos-induced fibrosis, influenza-induced fibrosis, coagulation-induced fibrosis, vascular injury-induced fibrosis, aortic stenosis and cardiac fibrosis.When carrying out this method, a therapeutically effective amount of the compound of formula (I) and / or its pharmaceutical composition is administered to patients with the disorder or condition.

[0262] Examples of solid tumors (e.g., sarcomas, carcinomas, and lymphomas) that may be treated with the compounds of formula (I) and pharmaceutical compositions thereof include, for example, Ewing's sarcoma, rhabdomyosarcoma, osteosarcoma, myeloid sarcoma, chondrosarcoma, liposarcoma, leiomyosarcoma, soft tissue sarcoma, non-small cell lung cancer, small cell lung cancer, bronchial cancer, prostate cancer, breast cancer, pancreatic cancer, gastrointestinal cancer, colon cancer, rectal cancer, colon carcinoma, colorectal adenoma, thyroid cancer, liver cancer, intrahepatic bile duct cancer, hepatocellular carcinoma, adrenal gland cancer, gastric cancer, stomach cancer, glioma (e.g., adult, pediatric brainstem, pediatric brain astrocytoma, pediatric visual pathway and hypothalamus), glioblastoma, endometrial cancer, melanoma, kidney cancer, renal pelvis cancer, bladder cancer, uterine body, cervical cancer, vaginal cancer, ovarian cancer, multiple myeloma, esophageal cancer, brain cancer (e.g., brainstem glioma, cerebellar astrocytoma, tumors, brain astrocytoma / malignant glioma, ependymoma, medulloblastoma, cerebellar supratentorial primitive neuroectodermal tumor, visual pathway and hypothalamic glioma), lip and oral cavity and pharynx, larynx, small intestine, melanoma, villous colon adenoma, neoplasms, epithelial neoplasms, lymphomas (e.g., AIDS-related, Burkitt's, cutaneous T-cell, Hodgkin's, non-Hodgkin's and primary central nervous system), breast cancer, basal cell carcinoma, squamous cell carcinoma, actinic keratosis, oncological diseases including solid tumors, head and neck tumors, polycythemia vera, essential thrombocythemia, myelofibrosis with myeloid metaplasia, Waldenstrom's macroglobulinemia, adrenocortical carcinoma, AIDS-related cancers, childhood cerebellar astrocytoma, childhood cerebellar astrocytoma, basal cell carcinoma, extrahepatic bile duct carcinoma, malignant fibrous histiocytomaBone cancer, bronchial adenoma / carcinoid, carcinoid tumor, gastrointestinal carcinoid tumor, primary central nervous system, cerebellar astrocytoma, childhood cancer, ependymoma, extracranial germ cell tumor, extragonadal germ cell tumor, extrahepatic bile duct cancer, intraocular melanoma eye cancer, retinoblastoma eye cancer, gallbladder cancer, gastrointestinal carcinoid tumor, germ cell tumor (e.g., extracranial, extragonadal, and ovarian), gestational trophoblastic tumor, hepatocellular carcinoma, hypopharyngeal carcinoma, hypothalamic and optic pathway glioma, islet cell carcinoma (endocrine pancreas), laryngeal cancer, malignant fibrous histiocytoma / osteosarcoma of bone, medulloblastoma, mesothelioma, metastasis of unknown primary Includes squamous cell neck cancer, multiple endocrine neoplasia syndrome, multiple myeloma / plasma cell neoplasm, mycosis fungoides, nasal cavity and paranasal sinus cancer, nasopharyngeal carcinoma, neuroblastoma, oral cavity cancer, oropharyngeal carcinoma, ovarian epithelial cancer, ovarian germ cell tumor, ovarian low malignant potential tumor, islet cell pancreatic cancer, parathyroid carcinoma, pheochromocytoma, pineoblastoma, pituitary tumor, pleuropulmonary blastoma, ureteral transitional cell carcinoma, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, Sezary syndrome, non-melanoma skin cancer, Merkel cell carcinoma, squamous cell carcinoma, testicular cancer, thymoma, gestational trophoblastic tumor, and Wilms' tumor.

[0263] Examples of hematological tumors (e.g., sarcomas, carcinomas, and lymphomas) that can be treated with the compounds of formula (I) and pharmaceutical compositions thereof include, for example, acute lymphocytic leukemia, acute myeloid leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, Hodgkin's lymphoma, non-Hodgkin's lymphoma, and multiple myeloma.

[0264] Also provided herein is a method for inhibiting αβ integrin in a patient, wherein a therapeutically effective amount of a compound of formula (I) or a pharmaceutical composition thereof is administered to a patient having the disorder or condition.

[0265] Also provided herein is a method for inhibiting αβ integrin in a patient, wherein a therapeutically effective amount of a compound of formula (I) or a pharmaceutical composition thereof is administered to a patient having the disorder or condition.

[0266] Also provided herein is a method for inhibiting TGFβ activation in a cell, in which an effective amount of a compound of formula (I) or a pharmaceutical composition thereof is administered to a patient having the disorder or condition.

[0267] Compositions and Methods of Administration The compositions provided herein comprise a therapeutically effective amount of one or more compounds provided herein and a vehicle useful for treating, preventing, or alleviating symptoms of one or more of the diseases or disorders described herein. Vehicles suitable for administering the compounds provided herein include any carrier known to those skilled in the art to be suitable for the particular method of administration. In addition, the compounds may be formulated as the sole active ingredient in the composition or may be combined with other active ingredients.

[0268] The composition comprises one or more compounds provided herein. In some embodiments, the compound is formulated into a suitable formulation for oral administration solution, suspension, tablet, disintegrating tablet, pill, capsule, powder, sustained-release preparation or elixir, or sterile solution or suspension for parenteral administration, and topical administration, transdermal administration, and oral inhalation via nebulizer, pressurized metered dose inhaler and dry powder inhaler. In some embodiments, the compound is formulated into a composition using techniques and methods well known in the art (see, for example, Ansel, Introduction to Pharmaceutical Dosage Forms, Seventh Edition (1999)).

[0269] In the composition, an effective concentration of one or more compounds or derivatives thereof is mixed with a suitable vehicle. The compound may be derivatized into the corresponding salt, ester, enol ether or ester, acetal, ketal, orthoester, hemiacetal, hemiketal, acid, base, solvate, ion pair, hydrate, or prodrug before formulation, as described above. The concentration of the compound in the composition is effective to deliver an amount that, upon administration, will treat, prevent, or alleviate one or more symptoms of the diseases or disorders described herein. In some embodiments, the composition is formulated for single-dose administration. To formulate the composition, a weight fraction of the compound is dissolved, suspended, dispersed, or otherwise mixed in a selected vehicle at an effective concentration such that the condition being treated is alleviated, prevented, or one or more symptoms are alleviated.

[0270] The active compound is contained in the medium in an amount sufficient to exert therapeutically useful effects without causing undesirable side effects to treated patients.The therapeutically effective concentration can be empirically predicted by testing the compound in in vitro and in vivo systems well known to those skilled in the art, and then the dosage for humans is extrapolated from there.Then, the human dosage is typically fine-tuned in clinical trials and titrated to response.

[0271] The concentration of the active compound in the composition depends on the absorption, inactivation and excretion rate of the active compound, the physicochemical characteristics of the compound, the administration schedule and dosage, and other factors known to those skilled in the art. For example, the amount delivered is sufficient to alleviate one or more symptoms of the diseases or disorders described herein.

[0272] When the solubility of a compound is insufficient, methods for solubilizing the compound may be used, such as the use of liposomes, prodrugs, complexation / chelation, nanoparticles or emulsions, or tertiary templating. Such methods are known to those skilled in the art and include the use of cosolvents such as dimethyl sulfoxide (DMSO), Tween (登録商標)These include, but are not limited to, the use of surfactants or surface modifiers such as cyclodextrins, complexing agents such as cyclodextrins, or ionization-enhanced dissolution (i.e., dissolution in aqueous sodium bicarbonate). Derivatives of the compounds, such as prodrugs of the compounds, may also be used to formulate effective compositions.

[0273] After mixing or adding the compounds, the resulting mixture may be a solution, suspension, emulsion, etc. The form of the resulting mixture depends on several factors, including the intended method of administration and the solubility of the compound in the selected vehicle. The effective concentration is sufficient to alleviate the symptoms of the disease, disorder, or condition being treated and can be empirically determined.

[0274] The compositions are provided for administration to humans and animals in dosage forms appropriate for the indication, such as dry powder inhalers (DPIs), pressurized metered dose inhalers (pMDIs), nebulizers, tablets, capsules, pills, sublingual tapes / biodegradable strips, tablets or capsules, powders, granules, lozenges, lotions, ointments, suppositories, fast melts, transdermal patches or other transdermal application devices / formulations, sterile parenteral solutions or suspensions, oral solutions or suspensions, and oil-water emulsions, containing an appropriate amount of the compound or its derivatives. In some embodiments, the therapeutically active compounds and their derivatives are formulated and administered in unit dosage forms or multiple dosage forms. As used herein, unit dosage form refers to a physically separate unit suitable for human and animal subjects and individually packaged, as known in the art. Each unit dosage contains a predetermined amount of the therapeutically active compound sufficient to produce the desired therapeutic effect, together with the necessary vehicle. Examples of unit dosage forms include ampoules and syringes, and individually packaged tablets or capsules. A unit-dose form can be administered in a fraction or in multiples thereof. A multiple-dose form is a plurality of identical unit-dosage forms packaged in a single container, administered in separate unit-dose forms. Examples of multiple-dose forms include vials, bottles of tablets or capsules, or bottles of pints or gallons. Thus, a multiple-dose form is a plurality of unit doses in undivided packaging.

[0275] Liquid compositions can be prepared, for example, by dissolving, dispersing, or otherwise mixing the active compound(s) and any adjuvants defined above in a vehicle such as water, saline, aqueous dextrose, glycerol, glycol, ethanol, etc., thereby forming a solution or suspension, colloidal dispersion, emulsion, or liposomal preparation. If desired, the composition to be administered can also contain minor amounts of non-toxic auxiliary substances such as wetting agents, emulsifiers, solubilizing agents, pH buffering agents, and the like, for example, acetate, sodium citrate, cyclodextrin derivatives, sorbitan monolaurate, triethanolamine sodium acetate, triethanolamine oleate, and other such agents.

[0276] Actual methods for preparing such dosage forms will be known or apparent to those skilled in the art; see, for example, Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, Pa., 15th Edition, 1975 or subsequent editions thereof.

[0277] Dosage forms or compositions may be prepared containing active ingredient in the range of 0.005% to 100% with the remainder being vehicle or carrier. Methods for preparing these compositions are known to those skilled in the art. Contemplated compositions may contain 0.001% to 100% of the active ingredient, in some embodiments, 0.1 to 95%, and in other embodiments, 0.4 to 10%.

[0278] In some embodiments, the composition is a lactose-free composition containing additives well known in the art and described, for example, in the United States Pharmacopoeia (USP) 25-NF20 (2002). Generally, lactose-free compositions contain an active ingredient, a binder / filler, and a lubricant in equal amounts. A specific lactose-free dosage form contains an active ingredient, microcrystalline cellulose, pregelatinized starch, and magnesium stearate.

[0279] Also provided are anhydrous compositions and dosage forms containing active ingredients, because water can accelerate the decomposition of some compounds.For example, the addition of water (e.g., 5%) is widely accepted as a way to simulate long-term storage to determine characteristics such as shelf life or the stability of formulations over time.See, for example, Jens T. Carstensen, Drug Stability: Principles & Practice, 2d. Ed., Marcel Dekker, NY, NY, 1995, pp. 379-80.In effect, water and heat accelerate the decomposition of some compounds.Therefore, the effect of water on formulations can be significant, because moisture and / or humidity are commonly encountered during the production, handling, packaging, storage, transportation and use of formulations.

[0280] Anhydrous compositions and dosage forms provided herein can be prepared using anhydrous or low moisture containing ingredients and low moisture or low humidity conditions.

[0281] Anhydrous compositions are prepared and stored so as to maintain their anhydrous nature.Thus, anhydrous compositions are generally packaged using materials known to prevent exposure to water, so that they can be included in suitable formulation kits.Examples of suitable packaging include, but are not limited to, hermetically sealed foils, plastics, unit dose containers (e.g., vials), blister packs, and strip packs.

[0282] Oral dosage forms can be solid, gel, or liquid. Solid dosage forms include tablets, capsules, granules, and bulk powders. Types of oral tablets include compressed, chewable lozenges and tablets that may be enteric-coated, sugar-coated, or film-coated. Capsules can be hard or soft gelatin capsules, while granules and powders can be in non-effervescent form or effervescent form combined with other ingredients known to those skilled in the art.

[0283] In some embodiments, the formulation is in a solid dosage form, such as a capsule or tablet. Tablets, pills, capsules, lozenges, etc. may contain one or more of the following ingredients or compounds of similar nature: binders; lubricants; diluents; glidants; disintegrants; colorants; sweeteners; flavorings; wetting agents; enteric coatings; film coatings, and release modifiers. Examples of binders include microcrystalline cellulose, methylparaben, polyalkylene oxide, tragacanth gum, glucose solution, acacia mucilage, gelatin solution, sugar solution, polyvinylpyrrolidine, povidone, crospovidone, sucrose, and starch and starch derivatives. Lubricants include talc, starch, magnesium / calcium stearate, lycopodium and stearic acid. Diluents include, for example, lactose, sucrose, trehalose, lysine, leucine, lecithin, starch, kaolin, salt, mannitol, and dicalcium phosphate. Glidants include, but are not limited to, colloidal silicon dioxide. Disintegrants include croscarmellose sodium, sodium starch glycolate, alginic acid, corn starch, potato starch, bentonite, methylcellulose, agar, and carboxymethylcellulose. Coloring agents include, for example, approved certified water-soluble FD and C dyes, mixtures thereof, and water-insoluble FD and C dyes suspended in alumina hydrate, as well as high-performance or anti-counterfeit color / opaque additives known to those skilled in the art. Sweetening agents include sucrose, lactose, mannitol, and artificial sweeteners such as saccharin, as well as some spray-dried flavors. Flavoring agents include natural flavors extracted from plants such as fruits, and synthetic blends of compounds that provide a pleasant sensation or mask unpleasant tastes, such as, but not limited to, peppermint and methyl salicylate. Wetting agents include propylene glycol monostearate, sorbitan monooleate, diethylene glycol monolaurate, and polyoxyethylene lauryl ether. Enteric coatings include fatty acids, fats, waxes, shellac, ammoniated shellac, and cellulose acetate phthalate. Film coatings include hydroxyethylcellulose, sodium carboxymethylcellulose, polyethylene glycol 4000, and cellulose acetate phthalate.The release modifier is Eudragit. (登録商標) series and polymers such as cellulose esters.

[0284] The compound or its derivatives can be provided in a composition that protects it from the acidic environment of the stomach. For example, the composition can be formulated in an enteric coating that retains it intact in the stomach and releases the active compound in the intestine. The composition can also be formulated in combination with an acid-resistant or other such ingredient.

[0285] When the dosage unit is a capsule, it may contain, in addition to the above-mentioned materials, a liquid carrier such as fatty oil.Furthermore, the dosage unit may contain various other materials that modify the physical form of the dosage unit, such as sugar coating and other enteric agents.The compound may also be administered as a component of elixirs, suspensions, syrups, wafers, sprinkles, chewing gums, etc.Syrups may contain, in addition to the active compound, sucrose as a sweetener, preservatives, dyes, colorings, and flavoring agents.

[0286] The active material may also be mixed with other active materials that do not interfere with the desired action, or materials that supplement the desired action, such as antioxidants, H2 blockers, and diuretics. The active ingredient is a compound described herein or a derivative thereof. High concentrations of the active material, up to about 98% by weight, may be included.

[0287] In all embodiments, tablet and capsule formulations may be coated as known to those skilled in the art to modify or sustain dissolution of the active ingredient, for example, with conventional enteric, digestible coatings such as phenylsalicylate, waxes, and cellulose acetate phthalate.

[0288] Liquid oral dosage forms include aqueous solutions, emulsions, suspensions, solutions and / or suspensions reconstituted from non-effervescent granules, and effervescent preparations reconstituted from effervescent granules. Aqueous solutions include, for example, elixirs and syrups. Emulsions are oil-in-water or water-in-oil.

[0289] Elixirs are clear, sweetened, hydroalcoholic preparations. The vehicle used in elixirs includes a solvent. Syrups are concentrated aqueous solutions of a sugar, e.g., sucrose, and may contain a preservative. Emulsions are two-phase systems in which one liquid is dispersed in the form of small globules throughout another liquid. The carriers used in emulsions are non-aqueous liquids, emulsifiers, and preservatives. Suspensions use suspending agents and preservatives. Acceptable substances used in non-effervescent granules to be reconstituted into a liquid oral dosage form include diluents, sweeteners, and wetting agents. Acceptable substances used in effervescent granules to be reconstituted into a liquid oral dosage form include organic acids and a carbon dioxide source. Coloring and flavoring agents are used in all of the above dosage forms.

[0290] Solvents include glycerin, sorbitol, ethyl alcohol, and syrup. Examples of preservatives include glycerin, methyl and propylparaben, benzoic acid, sodium benzoate, and alcohol. Examples of non-aqueous liquids used in emulsions include mineral oil and cottonseed oil. Examples of emulsifying agents include gelatin, acacia, tragacanth, bentonite, and surfactants such as polyoxyethylene sorbitan monooleate. Suspending agents include sodium carboxymethylcellulose, pectin, tragacanth, Veegum, and acacia. Sweeteners include sucrose, syrup, glycerin, and artificial sweeteners such as saccharin. Wetting agents include propylene glycol monostearate, sorbitan monooleate, diethylene glycol monolaurate, and polyoxyethylene lauryl ether. Organic acids include citric acid and tartaric acid. Carbon dioxide sources include sodium bicarbonate and sodium carbonate. Coloring agents include any of the approved water-soluble FD and C dyes and mixtures thereof. Flavoring agents include natural flavors extracted from fruits and other plants and synthetic blends of compounds which provide a pleasant taste sensation.

[0291] For solid dosage forms, for example, solution or suspension in propylene carbonate, vegetable oil or triglyceride is encapsulated in gelatin capsule in some embodiments.Such solutions and formulations and encapsulation are disclosed in U.S. Patents 4,328,245; 4,409,239; and 4,410,545.For liquid dosage forms, for example, solution in polyethylene glycol can be diluted with a sufficient amount of liquid medium, for example, water, to facilitate measurement for administration.

[0292] Alternatively, liquid or semisolid oral formulations can be prepared by dissolving or dispersing the active compound or salt in vegetable oils, glycols, triglycerides, propylene glycol esters (e.g., propylene carbonate) and other such carriers, and encapsulating the resulting solution or suspension in a hard or soft gelatin capsule shell. Other useful formulations include those shown in U.S. Patents RE28,819 and 4,358,603. Briefly, such formulations include, but are not limited to, those containing a compound provided herein, dialkylated mono- or polyalkylene glycols, including, but not limited to, 1,2-dimethoxyethane, diglyme, triglyme, tetraglyme, polyethylene glycol-350-dimethyl ether, polyethylene glycol-550-dimethyl ether, polyethylene glycol-750-dimethyl ether (where 350, 550, and 750 refer to the approximate average molecular weight of the polyethylene glycol), and one or more antioxidants, such as butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), propyl gallate, vitamins, hydroquinone, hydroxycoumarin, ethanolamine, lecithin, cephalin, ascorbic acid, malic acid, sorbitol, phosphoric acid, thiodipropionic acid and its esters, and dithiocarbamates.

[0293] Other formulations include, but are not limited to, aqueous alcohol solutions containing acetals. The alcohols used in these formulations are any water-miscible solvents with one or more hydroxyl groups, including propylene glycol and ethanol. Acetals include, but are not limited to, di(lower alkyl) acetals of lower alkyl aldehydes, such as acetaldehyde diethyl acetal.

[0294] Parenteral administration, characterized in some embodiments by subcutaneous, intramuscular, or intravenous injection, is also contemplated herein. Injectables can be prepared in conventional forms, as liquid solutions or suspensions, solid forms suitable for dissolution or suspension in liquid prior to injection, or as emulsions. Injectables, solutions, and emulsions can also contain one or more additives. Suitable additives include, for example, water, saline, dextrose, glycerol, or ethanol. Furthermore, if desired, the compositions to be administered can also contain minor amounts of nontoxic auxiliary substances such as wetting or emulsifying agents, pH buffers, stabilizers, solubility enhancers, and other such agents, such as, for example, sodium acetate, sorbitan monolaurate, triethanolamine oleate, and cyclodextrins.

[0295] Implantation of a slow-release or sustained-release system, such that a constant level of dosage is maintained (see, eg, US Pat. No. 3,710,795) is also contemplated herein. Briefly, the compounds provided herein comprise a solid inner matrix that is insoluble in body fluids, e.g., a hydrophilic polymer such as polymethyl methacrylate, polybutyl methacrylate, plasticized or unplasticized polyvinyl chloride, plasticized nylon, plasticized polyethylene terephthalate, natural rubber, polyisoprene, polyisobutylene, polybutadiene, polyethylene, ethylene-vinyl acetate copolymer, silicone rubber, polydimethylsiloxane, silicone carbonate copolymer, hydrogels of esters of acrylic and methacrylic acid, collagen, cross-linked polyvinyl alcohol and cross-linked partially hydrolyzed polyvinyl acetate surrounded by an outer polymeric membrane, e.g., polyethylene, polypropylene, ethylene / propylene copolymer, ethylene / ethyl acrylic acid copolymer, ethylene / vinyl acetate copolymer, silicone rubber, polydimethylsiloxane, neoprene rubber, chlorinated polyethylene, polyvinyl chloride, vinyl chloride copolymer with vinyl acetate, vinylidene chloride, ethylene and propylene, ionomer polyethylene terephthalate, butyl rubber. The active compound is dispersed in epichlorohydrin rubber, ethylene / vinyl alcohol copolymer, ethylene / vinyl acetate / vinyl alcohol terpolymer, and ethylene / vinyloxyethanol copolymer. The compound diffuses through the polymer membrane in a release rate-controlling process. The percentage of active compound contained in such parenteral compositions is highly dependent on the specific nature and activity of the compound and the needs of the patient.

[0296] Parenteral administration of the composition includes intravenous, subcutaneous and intramuscular administration.The preparation for parenteral administration includes sterile solution for injection, sterile dry soluble product such as freeze-dried powder that is ready to be mixed with a solvent immediately before use, including subcutaneous tablets, sterile suspension that is ready to be injected, sterile dry insoluble product that is ready to be mixed with a vehicle immediately before use, and sterile emulsion.The solution can be aqueous or non-aqueous.

[0297] If administered intravenously, suitable carriers include physiological saline or phosphate buffered saline (PBS) and solutions containing thickening and solubilizing agents such as glucose, polyethylene glycol and polypropylene glycol, and mixtures thereof.

[0298] Vehicles used in parenteral formulations include aqueous vehicles, non-aqueous vehicles, antimicrobial agents, isotonic agents, buffers, antioxidants, local anesthetics, suspending and dispersing agents, emulsifying agents, sequestering or chelating agents and other substances.

[0299] Examples of aqueous vehicles include sodium chloride injection, Ringer's injection, isotonic dextrose injection, sterile water injection, dextrose and lactated Ringer's injection. Non-aqueous parenteral vehicles include fixed oils of vegetable origin, cottonseed oil, corn oil, sesame oil, and peanut oil. Antimicrobial agents in bacteriostatic or fungistatic concentrations must be added to parenteral formulations packaged in multi-dose containers and include phenol or cresol, mercurials, benzyl alcohol, chlorobutanol, methyl and propyl p-hydroxybenzoic acid esters, thimerosal, benzalkonium chloride, and benzethonium chloride. Isotonic agents include sodium chloride and dextrose. Buffers include phosphate and citric acid. Antioxidants include sodium bisulfate. Local anesthetics include procaine hydrochloride. Suspending and dispersing agents include sodium carboxymethylcellulose, hydroxypropyl methylcellulose, and polyvinylpyrrolidone. Emulsifying agents include polysorbate 80 (Tween 1). (登録商標) 80). Sequestering or chelating agents for metal ions include EDTA. Carriers also include ethyl alcohol, polyethylene glycol, and propylene glycol for water-miscible vehicles; and sodium hydroxide, hydrochloric acid, citric acid, or lactic acid for pH adjustment.

[0300] The concentration of the compound is adjusted so that an injection provides an effective amount to produce the desired pharmacological effect. The exact dose depends on the age, weight, body surface area and condition of the patient or animal, as is known in the art.

[0301] Unit dose parenteral formulations are packaged in ampoules, vials or syringes with needles. All formulations for parenteral administration must be sterile, as is known and practiced in the art.

[0302] By way of illustration, intravenous or intraarterial infusion of a sterile aqueous solution containing an active compound is an effective method of administration. Another embodiment is a sterile aqueous or oily solution or suspension containing the active material, injected as needed to produce the desired pharmacological effect.

[0303] Injectables are designed for local and systemic administration. In certain embodiments, a therapeutically effective dose is formulated to contain a concentration of at least about 0.01% w / w to about 90% w / w or more, in certain embodiments, greater than 0.1% w / w of the active compound in the treated tissue.

[0304] The compound can be suspended in micronized or other suitable form, or can be derivatized to produce a more soluble active product or prodrug. The form of the resulting mixture depends on several factors, including the intended method of administration and the solubility of the compound in the selected carrier or vehicle. The effective concentration is sufficient to ameliorate the symptoms of the condition and can be empirically determined.

[0305] The active ingredients provided herein can be administered by controlled-release means or delivery devices known to those skilled in the art. Examples include, but are not limited to, U.S. Patents 3,845,770; 3,916,899; 3,536,809; 3,598,123; 4,008,719; 5,674,533; 5,059,595; 5,591,767; 5,120,548; 5,073,543; 5,639,476; 5,354,556; 5,639,480; 5,733,566; 5,739,108; 5,891,474; 5,922,356; 5,9 72,891; 5,980,945; 5,993,855; 6,045,830; 6,087,324; 6,113,943; 6,197,350; 6,248,363; 6,264,970; 6,267,981; 6,376,461; 6,419,961; 6,589,548; 6,613,358; 6,699,500 and 6,740,634. Such dosage forms can be used to provide sustained or controlled release of one or more active ingredients, using, for example, hydroxypropyl methylcellulose, other polymer matrices, gels, permeable membranes, osmotic systems, multilayer coatings, microparticles, liposomes, microspheres, or combinations of such in various ratios to provide the desired release profile. Suitable controlled-release formulations known to those of ordinary skill in the art, including those described herein, can be readily selected for use with the active ingredients provided herein.

[0306] All controlled-release products share a common goal of improving drug therapy over that achieved by their non-controlled counterparts. Ideally, the use of an optimally designed controlled-release formulation in medical treatment is characterized by controlling a condition using a minimum amount of drug substance or for a minimum amount of time to cure. Advantages of controlled-release formulations include extended drug activity, reduced dosage frequency, and increased patient compliance. Furthermore, controlled-release formulations can be used to affect the time of onset of action or other characteristics, such as drug blood levels, and thus can affect the occurrence of side (e.g., adverse) effects.

[0307] Most controlled-release formulations are designed to initially release an amount of drug (active ingredient) that rapidly produces the desired therapeutic effect, and then gradually and sustainably release another amount of drug to maintain a level of therapeutic or prophylactic effect over an extended period of time. To maintain this constant level of drug in the body, the drug must be released from the dosage form at a rate that will replace the amount of drug being metabolized and excreted from the body. Controlled-release of an active ingredient can be stimulated by various conditions, including, but not limited to, pH, temperature, enzymes, water, or other physiological conditions or compounds.

[0308] In some embodiments, the agent may be administered using intravenous infusion, an implantable osmotic pump, a transdermal patch, liposomes, or other administration methods. In some embodiments, a pump may be used (see Sefton, CRC Crit. Ref. Biomed. Eng. 14:201 (1987); Buchwald et al., Surgery 88:507 (1980); Saudek et al., N. Engl. J. Med. 321:574 (1989)). In other embodiments, polymeric materials may be used. In other embodiments, the controlled release system may be placed near the therapeutic target, i.e., only a fraction of the systemic dose may be required (see, e.g., Goodson, Medical Applications of Controlled Release, vol. 2, pp. 115138 (1984)). In some embodiments, the controlled release device is introduced into the subject near the site of inappropriate immune activation or tumor. Other controlled-release systems are described in detail by Langer (Science 249:1527-1533 (1990)).The active ingredient is contained in a solid inner matrix that is insoluble in body fluids, e.g., a hydrophilic polymer such as polymethyl methacrylate, polybutyl methacrylate, plasticized or unplasticized polyvinyl chloride, plasticized nylon, plasticized polyethylene terephthalate, natural rubber, polyisoprene, polyisobutylene, polybutadiene, polyethylene, ethylene-vinyl acetate copolymer, silicone rubber, polydimethylsiloxane, silicone carbonate copolymer, hydrogels of esters of acrylic and methacrylic acid, collagen, cross-linked polyvinyl alcohol and cross-linked partially hydrolyzed polyvinyl acetate surrounded by an outer polymeric membrane, e.g., polyethylene, polypropylene, ethylene / propylene copolymer, ethylene / ethyl acrylic acid copolymer, ethylene / vinyl acetate copolymer, silicone rubber, polydimethylsiloxane, neoprene rubber, chlorinated polyethylene, polyvinyl chloride, vinyl chloride copolymer with vinyl acetate, vinylidene chloride, ethylene and propylene, ionomer polyethylene terephthalate, butyl rubber The active ingredient can be dispersed in epichlorohydrin rubber, ethylene / vinyl alcohol copolymer, ethylene / vinyl acetate / vinyl alcohol terpolymer and ethylene / vinyloxyethanol copolymer.The active ingredient then diffuses through the polymer membrane in a release rate-controlling process.The percentage of the active ingredient contained in such parenteral compositions highly depends on its specific nature and the needs of the patient.

[0309] Of interest herein are also lyophilized powders that can be reconstituted for administration as solutions, emulsions, and other mixtures. They can also be reconstituted and formulated as solids or gels.

[0310] Sterile, lyophilized powders are prepared by dissolving a compound provided herein or its derivative in a suitable solvent. The solvent may contain additives to improve stability or other pharmacological components of the powder or a reconstituted solution prepared from the powder. Additives that can be used include, but are not limited to, antioxidants, buffers, and bulking agents. In some embodiments, the additive is selected from dextrose, sorbitol, fructose, corn syrup, xylitol, glycerin, glucose, sucrose, and other suitable additives. The solvent contains a buffer solution, such as citric acid, sodium or potassium phosphate, or other such buffer, at approximately neutral pH. Subsequent sterile filtration of the solution followed by lyophilization under standard conditions known to those skilled in the art yields the desired formulation. In some embodiments, the resulting solution is dispensed into vials for lyophilization. Each vial contains a single or multiple doses of the compound. The lyophilized powder can be stored under appropriate conditions, such as at about 4°C to room temperature.

[0311] Reconstitution of this lyophilized powder with water for injection provides a formulation for use in parenteral administration. For reconstitution, the lyophilized powder is added to sterile water or other suitable carrier. The exact amount will depend on the selected compound. Such amounts can be determined empirically.

[0312] Topical mixtures are prepared as described for local and systemic administration. The resulting mixtures may be solutions, suspensions, emulsions, etc., and are formulated into creams, gels, ointments, emulsions, solutions, elixirs, lotions, suspensions, tinctures, pastes, foams, aerosols, douches, sprays, suppositories, bandages, skin patches, or any other formulation suitable for topical administration.

[0313] Compound or its derivative can be formulated into aerosol for local application such as by inhalation (see, for example, US Patent 4,044,126, 4,414,209 and 4,364,923, which describes the aerosol for delivering steroids useful for treating inflammatory diseases, especially asthma).These formulations for administration to the respiratory tract can be in the form of aerosol or solution for nebulizer or fine powder for insufflation, alone or in combination with inert carrier such as lactose.In such cases, the mass median geometric diameter of the formulation particles is less than 5 microns in some embodiments, and less than 10 microns in other embodiments.

[0314] Oral inhalation formulations of the compounds or derivatives suitable for inhalation include metered dose inhalers, dry powder inhalers, and liquid formulations administered from nebulizers or metered dose liquid delivery systems. For both metered dose inhalers and dry powder inhalers, a crystalline form of the compound or derivative is the preferred physical form of the drug to provide long-term product stability.

[0315] In addition to particle size reduction methods known to those skilled in the art, crystalline particles of a compound or derivative can be produced using supercritical fluid processing, which offers significant advantages in producing respirable particles of a desired size in a single step, thereby enabling the production of such particles for inhalation delivery (e.g., International Publication WO 2005 / 025506). The controlled particle size of the crystallites can be selected to ensure that a significant proportion of the compound or derivative is deposited in the lungs. In some embodiments, these particles have a mass median aerodynamic diameter of about 0.1 to about 10 microns, in other embodiments, about 1 to about 5 microns, and in yet other embodiments, about 1.2 to about 3 microns.

[0316] The inert and non-flammable HFA propellants are selected from HFA134a (1,1,1,2-tetrafluoroethane) and HFA227e (1,1,1,2,3,3,3-heptafluoropropane), provided alone or in a ratio to match the crystalline particles of the compound or derivative. The ratio is also selected so that the product suspension avoids harmful settling or creaming (which can be the precipitation of irreversible aggregates) and instead promotes a loosely cohesive system that disperses easily upon shaking. A loosely cohesive system is well believed to provide optimal stability in pMDI canisters. As a result of the nature of the formulation, it is ethanol-free and surfactant / stabilizer-free.

[0317] Compounds can be formulated in the form of gel, cream and lotion for topical or local application to mucous membranes such as skin and eyes, and for application to eyes or intravesical or intrathecal application.Topical administration is intended for transdermal delivery, and also for administration to eyes or mucous membranes or inhalation therapy.Nasal solutions of active compounds alone or in combination with other additives can also be administered.

[0318] For nasal administration, the formulation will contain the esterified phosphonic acid compound dissolved or suspended in a liquid carrier, particularly an aqueous carrier, for aerosol application. The carrier may contain solubilizing or suspending agents such as propylene glycol, surfactants, absorption enhancers such as lecithin or cyclodextrin, or preservatives. Solutions, particularly those intended for ophthalmic use, may be formulated as 0.01% to 10% isotonic solutions, pH about 5 to 7.4, with appropriate salts.

[0319] Other administration routes, such as transdermal patches and rectal administration, including iontophoretic and electrophoretic devices, are also contemplated herein.Transdermal patches, including iontophoretic and electrophoretic devices, are well known to those skilled in the art.For example, such patches are disclosed in U.S. Patents 6,267,983, 6,261,595, 6,256,533, 6,167,301, 6,024,975, 6,010715, 5,985,317, 5,983,134, 5,948,433 and 5,860,957.

[0320] For example, dosage forms for rectal administration include rectal suppositories, capsules, and tablets for systemic action. Rectal suppositories are used herein to mean solid objects inserted into the rectum that melt or soften at body temperature to release one or more pharmacologically or therapeutically active ingredients. The materials used in rectal suppositories are bases or vehicles and agents that raise the melting point. Examples of bases include cocoa butter (theobroma oil), glycerin-gelatin, carbowax (polyoxyethylene glycol), and appropriate mixtures of mono-, di-, and triglycerides of fatty acids. Combinations of various bases may be used. Agents for raising the melting point of suppositories include spermaceti and wax. Rectal suppositories can be produced by compression or molding. In some embodiments, the weight of a rectal suppository is approximately 2 to 3 gm. Tablets and capsules for rectal administration are produced using the same materials and in the same manner as formulations for oral administration.

[0321] The compounds provided herein or their derivatives can also be formulated to target specific tissues, receptors or other body regions of the subject to be treated.Many such targeting methods are well known to those skilled in the art.All such targeting methods are contemplated herein for use in the present compositions. For non-limiting examples of targeting methods, see, e.g., U.S. Patents 6,316,652, 6,274,552, 6,271,359, 6,253,872, 6,139,865, 6,131,570, 6,120,751, 6,071,495, 6,060,082, 6,048,736, 6,039,975, 6,004,534, 5,985,307, 5,972,366, 5,900,252, 5,840,674, 5,759,542, and 5,709,874.

[0322] In some embodiments, liposome suspensions, including tissue-targeted liposomes such as tumor-targeted liposomes, can also be suitable as carriers. These can be prepared by methods known to those skilled in the art. For example, liposome preparations can be prepared as described in U.S. Patent 4,522,811. Briefly, liposomes such as multilamellar vesicles (MLVs) can be formed by drying phosphatidylcholine and phosphatidylserine (7:3 molar ratio) inside a flask. A solution of the compound provided herein in phosphate-buffered saline (PBS) without divalent cations is added, and the flask is shaken until the lipid film is dispersed. The resulting vesicles are washed to remove unencapsulated compounds, pelleted by centrifugation, and then resuspended in PBS.

[0323] The compound or derivative thereof is packaged as a product comprising packaging, within the packaging, a compound or derivative thereof provided herein that is effective for the treatment, prevention, or amelioration of one or more symptoms of the disease or disorder, and a label indicating that the compound or composition or derivative thereof is used for the treatment, prevention, or amelioration of one or more symptoms of the disease or disorder.

[0324] The products provided herein include packaging materials. Packaging materials used to package products are well known to those skilled in the art. See, e.g., U.S. Patents 5,323,907, 5,052,558, and 5,033,252. Examples of packaging materials include, but are not limited to, blister packs, bottles, tubes, inhalers, pumps, bags, vials, containers, syringes, bottles, and any packaging suitable for the selected formulation and intended method of administration and treatment. A wide variety of formulations of the compounds and compositions provided herein are contemplated, as are various treatments for any of the diseases or disorders described herein.

[0325] Dosage For use in the treatment or prevention of disease, the compounds described herein or their pharmaceutical compositions are administered or applied in a therapeutically effective amount. In human treatment, the physician will determine the most appropriate dosage regimen, whether prophylactic or curative, depending on the age, weight, stage of disease, and other factors specific to the subject being treated. The amount of active ingredient in the formulations provided herein that is effective for the prevention or treatment of infectious diseases varies with the nature and severity of the disease or condition and the route by which the active ingredient is administered. The frequency and dosage also depend on the specific treatment (e.g., therapeutic or prophylactic agent) administered, the severity of the infection, the route of administration, and the subject's age, body size, weight, response, and past medical history, and vary according to factors specific to each subject.

[0326] Exemplary dosage formulations include milligram or microgram amounts of active compound per kilogram of subject (e.g., about 1 microgram / kilogram to about 50 milligrams / kilogram, about 10 micrograms / kilogram to about 30 milligrams / kilogram, about 100 micrograms / kilogram to about 10 milligrams / kilogram, or about 100 micrograms / kilogram to about 5 milligrams / kilogram).

[0327] In some embodiments, a therapeutically effective dosage should produce a serum concentration of the active ingredient of about 0.001 ng / ml to about 50-200 μg / ml. In other embodiments, the composition should provide a dosage of about 0.0001 mg to about 70 mg of compound per kilogram of body weight per day. Unit dosage forms are prepared to provide about 0.01 mg, 0.1 mg, or 1 mg to about 500 mg, 1000 mg, or 5000 mg of the active ingredient or combination of essential ingredients per unit dosage form, in some embodiments, about 10 mg to about 500 mg.

[0328] The active ingredient may be administered once or in several small doses at intervals of time.It is understood that the exact dosage and duration of treatment are a function of the disease to be treated and can be determined empirically using known test protocols or by extrapolating in vivo or in vitro test data or by subsequent clinical trials.It should be noted that concentration and dosage values ​​may also vary depending on the severity of the condition to be alleviated.For any specific subject, specific dosage regimens should be adjusted over time according to individual needs and the professional judgment of the person administering or supervising the administration of the composition, and it should be further understood that the concentration ranges provided herein are merely examples and are not intended to limit the scope or implementation of the composition of the present application.

[0329] As will be apparent to those skilled in the art, in some cases it may be necessary to use dosages of the active ingredients outside the ranges disclosed herein. Furthermore, the clinician or treating physician will know how and when to interrupt, adjust or terminate treatment in relation to the subject's response.

[0330] For systemic administration, a therapeutically effective dose can be estimated initially from in vitro assays. For example, a dose can be determined based on the IC 50 (i.e., the concentration of test compound that is lethal to 50% of the cell cultures) or IC determined in cell culture 100 (i.e., the concentration of the compound that is lethal in 100% of cell cultures). Such information can be used to more accurately determine useful doses in humans.

[0331] Initial dosages can also be estimated from in vivo data (e.g., animal models) using techniques well known in the art. Those skilled in the art can readily optimize human dosages based on animal data.

[0332] Alternatively, the initial dose may be determined by comparing the IC of a particular compound disclosed herein with a known compound. 50 , MIC and / or I 100 and adjusting the initial dose accordingly. Optimal doses can be obtained from these initial values ​​by routine optimization.

[0333] In cases of local administration or selective uptake, the effective local concentration of the compound used may not correlate to plasma concentration. One skilled in the art can optimize the therapeutically effective local dose without undue experimentation.

[0334] Ideally, a therapeutically effective dose of a compound described herein will provide therapeutic benefit without causing substantial toxicity. Compound toxicity can be assessed using standard techniques in cell cultures or experimental animals, e.g., LD 50 (the dose lethal to 50% of the population) or LD 100 The therapeutic index can be determined by determining the therapeutic dose (the dose lethal to 100% of the population). The dose ratio between toxic and therapeutic effects is the therapeutic index. Compounds that exhibit a high therapeutic index are preferred. Data obtained from these cell culture assays and animal studies can be used to formulate a non-toxic dosage range for use in subjects. The dosage of the compounds described herein is preferably within a range of circulating concentrations that includes the effective dose with little or no toxicity. Dosages can vary within this range depending on the dosage form used and the route of administration utilized. The exact formulation, route of administration, and dosage can be chosen by the individual physician in view of the patient's condition (e.g., Fingl et al., 1975, in The Pharmacological Basis of Therapeutics, Ch.1, p.1).

[0335] Treatment may be repeated intermittently. In some embodiments, administration of the same formulation provided herein may be repeated, and the administrations may be separated by at least 1 day, 2 days, 3 days, 5 days, 10 days, 15 days, 30 days, 45 days, 2 months, 75 days, 3 months, or 6 months.

[0336] Combination therapy The compounds of formula (I) and pharmaceutical compositions thereof disclosed herein may also be used in combination with one or more other active ingredients. In some embodiments, the compounds of formula (I) and pharmaceutical compositions thereof may be administered in combination with or sequentially with other therapeutic agents. Such other therapeutic agents include those known to treat, prevent, or ameliorate one or more symptoms associated with idiopathic pulmonary fibrosis, interstitial lung disease, systemic lupus erythematosus-related interstitial lung disease, rheumatoid arthritis, diabetic nephropathy, focal segmental glomerulosclerosis, chronic kidney disease, nonalcoholic steatohepatitis, primary biliary cirrhosis, primary sclerosing cholangitis, solid tumors, hematological tumors, organ transplantation, Alport syndrome, interstitial lung disease, radiation-induced fibrosis, bleomycin-induced fibrosis, asbestos-induced fibrosis, influenza-induced fibrosis, coagulation-induced fibrosis, vascular injury-induced fibrosis, aortic stenosis, and cardiac fibrosis.

[0337] Examples of therapeutic agents that may be used with the compounds of formula (I) and pharmaceutical compositions thereof include components and fragments of bee venom, pollen, milk, peanuts, CpG motifs, collagen, other components of the extracellular matrix, antihistamines (e.g., cetirizine, loratidine, acrivastine, fexofenadine, chlorphenamine, etc.), corticosteroids (e.g., fluticasone propionate, fluticasone furoate, beclomethasone dipropionate, budesonide, cyclohexim ... sonide, mometasone furoate, triamcinolone, flunisolide, prednisolone, hydrocortisone, etc.), NSAIDs (e.g., aspirin, ibuprofen, naproxen, etc.), leukotriene modulators (e.g., montelukast, zafirukast, pranlukast, etc.), iNOS inhibitors, tryptase inhibitors, p38 inhibitors (e.g., losmapimod, dilmapimod, etc.), elastase inhibitors, beta2 agonists, DP1 antagonists, DP2 antagonists, pl 3K delta inhibitors, lysophosphatidic acid inhibitors or 5-lipoxygenase-activating protein inhibitors (e.g., sodium 3-(3-(tert-butylthio)-1-(4-(6-ethoxypyridin-3-yl)benzyl)-5-((5-methylpyridin-2-yl)methoxy)-1H-indol-2-yl)-2,2-dimethylpropanoate, etc.), adenosine agonists (e.g., adenosine, regadenoson, etc.), chemokine antagonists (e.g., CCR3 antagonists, CCR4 antagonists, etc.), mediator release inhibitors, DMARDS (e.g., methotrexate, leflunomide, azathioprine, etc.), biopharmaceutical treatments (e.g., anti-lgE, anti-TNF, anti-interleukins (e.g., anti-IL-1, anti-IL-6, anti-IL-1), anti-IL-12, anti-IL-17, anti-IL-18, etc.), receptor therapy (e.g., etanercept), interferons, cytokines, chemokines, cytokine and chemokine receptor modulators, cytokine agonists or antagonists, TLR agonists, TGF synthesis inhibitors (e.g., pirfenidone), tyrosine kinase inhibitors targeting vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), ), fibroblast growth factor (FGF) receptor kinase, imatinib mesylate (i.e., Gleevec), endothelin receptor antagonists (e.g., ambrisentan or macitentan), antioxidants (e.g., N-acetylcysteine ​​(NAC), broad-spectrum antibiotics (e.g., cotrimoxazole, tetracycline, etc.), phosphodiesterase 5 inhibitors (e.g., sildenafil), anti-ανβχ antibodies and anti-ανββ monoclonal antibodies, bronchodilators (e.g., salbutamol), long-acting 2-agonists (e.g., salmeterol, formoterol, vilanterol, etc.), short-acting muscarinic antagonists (e.g., ipratropium bromide), long-acting muscarinic antagonists (e.g., tiotropium, umeclidinium), Lucentis®, and Avastin®.

[0338] It should be understood that any suitable combination of the compounds and compositions provided herein with one or more of the above therapeutic agents and, optionally, one or more additional pharmacologically active substances is considered within the scope of the present invention. In certain embodiments, the compounds and compositions provided herein are administered before or after one or more of the additional active ingredients.

[0339] Finally, it should be noted that there are alternative ways of practicing the invention. Accordingly, the present embodiments are to be construed as illustrative and not restrictive, and the invention is not to be limited to the details given herein, but may be modified within the scope of the appended claims and their equivalents. All publications and patents cited herein are incorporated by reference in their entirety.

[0340] The following examples are provided for illustrative purposes only and are not intended to limit the scope of the present invention. [Example]

[0341] [ka] FIG. 1, Scheme 1, illustrates the synthesis of key intermediate compound 10.

[0342] Preparation of Compound 3 To a solution of compound 1 (60.0 g, 4...

Claims

1. Formula (Ia) 【Chemistry 1】 {During the ceremony, q is 1, 2 or 3; R １ is independently halogen in each occurrence, C １－４ Alkyl, C １－４ Haloalkyl, -OR １１ , -SR １１ , -N(R １１ ) ２ , -C(O)N(R １１ ) ２ , -C(O)OR １１ , ═O, ═S and —CN; R ３ is independently halogen in each occurrence, C １－４ Alkyl and -C(O)N(R １１ ) ２ Selected from: m is 0; o is 0, 1 or 2; R ２ is independently halogen in each occurrence, C １－４ Alkyl, C １－４ Haloalkyl, -OR １２ , -SR １２ , -N(R １２ ) ２ , -CN and -NO ２ Selected from: n is 0; R ４ and R ５ is hydrogen; D is selected from a bond and -C(O)-; E is C １－４ is alkylene; XY is λ -C(O)N(R １４ )-, λ -N(R １４ ) C(O)-, λ -N(R １４ )C(O)CH ２ --, λ -N(R １４ )CH ２ --, λ -CH ２ N(R １４ )-, λ -O-, λ -OCH ２ - and λ -CH ２ O-; where R14 is in each case hydrogen and C １－４ alkyl; λ is from X-Y 【Chemistry 2】 means a bond to; R ６ and R ７ are each independently hydrogen, halogen, C １－４ Alkyl, C １－４ Haloalkyl, -OR １６ and -CN; A is (i) and (ii): (i) hydrogen, halogen and -CN or A and R ６ Let's unite and C ３－６ Forming a carbocyclic ring; (ii) C ３－１２ Carbocycles and 3- to 12-membered heterocycles, each of which is optionally: Halogen, -OR １７ , -N(R １７ ) ２ , -C(O)R １７ , -N(R １７ )C(O)R １７ , -N(R １７ )S(O) ２ (R １７ ), =O, =S and -CN; Optionally halogen, -OR １７ , -N(R １７ ) ２ , -N(R １７ )C(O)R １７ , -N(R １７ )S(O) ２ (R １７ ), -S(O)R １７ C substituted with one or more substituents independently selected from ═O and —CN １－６ Alkyl; and Each may optionally contain halogen, C １－４ Alkyl, C １－４ C substituted with one or more substituents independently selected from haloalkyl and ═O ３－１０ Carbocycles and 3- to 10-membered heterocycles and substituted with one or more substituents independently selected from Selected from: When A is selected from (ii), B is selected from (I); or When A is selected from (i) B is selected from (II): (I) Hydrogen, halogen and -CN, or B and R ７ Let's unite and C ３－６ Forming a carbocyclic ring or a 3- to 6-membered heterocyclic ring; (II)-N(R １８ ) ２ ,-N(R １８ )C(O)R １８ ,-N(R １８ )C(O)R １８ ,-N(R １８ )C(O)N(R １８ ) ２ and -N(R １８ )S(O) ２ (R １８ ); C ３－１２ Carbocycles and 3- to 12-membered heterocycles (each of which may optionally include: Halogen, -OR １８ , -N(R １８ ) ２ , -C(O)R １８ , ═O and —CN; C １－６ Alkyl (optionally: Halogen, -OR １８ , -SR １８ , -N(R １８ ) ２ , -C(O)R １８ , =O, -CN, C ３－６ Carbocyclic and 3- to 6-membered heterocyclic rings and is substituted with one or more substituents independently selected from Here, C ３－６ The carbocycle and the 3- to 6-membered heterocycle each optionally include halogen, C １－４ Alkyl, C １－４ substituted with one or more substituents independently selected from haloalkyl and ═O; R １１ , R １２ and R １６ are each independently hydrogen at each occurrence, C １－４ Alkyl and C １－４ haloalkyl; R １７ Independently in each case: hydrogen; Optionally halogen, -OR ２１ , -SR ２１ , -N(R ２１ ) ２ , -C(O)R ２１ , -C(O)OR ２１ , -OC(O)R ２１ , -OC(O)N(R ２１ ) ２ , -C(O)N(R ２１ ) ２ , -N(R ２１ )C(O)R ２１ , -NO ２ , =O, =S, =N(R ２１ ), -N ３ and -CN, １－６ Alkyl; and Each may optionally contain halogen, C １－４ Alkyl, C １－４ Haloalkyl, -OR ２１ , -SR ２１ , -N(R ２１ ) ２ , -C(O)R ２１ , -C(O)OR ２１ , -OC(O)R ２１ , -OC(O)N(R ２１ ) ２ , -C(O)N(R ２１ ) ２ , -N(R ２１ )C(O)R ２１ , -N(R ２１ )C(O)OR ２１ , -N(R ２１ )C(O)N(R ２１ ) ２ , -N(R ２１ ) C(S)N(R ２１ ) ２ , -N(R ２１ )S(O) ２ (R ２１ ), -S(O)R ２１ , -S(O) ２ R ２１ , -S(O) ２ N(R ２１ ) ２ , -NO ２ , =O, =S, =N(R ２１ ), -N ３ and -CN, ３－６ Carbocyclic and 3- to 6-membered heterocyclic rings Selected from: R １８ Independently in each case: hydrogen; C １－６ Alkyl (optionally: Halogen, -OR ２２ , -SR ２２ , -N(R ２２ ) ２ , -C(O)R ２２ , -C(O)OR ２２ , -OC(O)R ２２ , -OC(O)N(R ２２ ) ２ , -C(O)N(R ２２ ) ２ , -N(R ２２ )C(O)R ２２ , -NO ２ , =O, =S, =N(R ２２ ), -N ３ , -C.N., C. ３－１０ Carbocycles and 3- to 10-membered heterocycles and is substituted with one or more substituents independently selected from Here, C ３－１０ The carbocycle and the 3- to 10-membered heterocycle each optionally include halogen, C １－６ Alkyl, C １－６ Haloalkyl, -OR ２２ , -SR ２２ and -N(R ２２ ) ２ and C ３－１０ Carbocycles and 3- to 10-membered heterocycles, each of which is optionally: Halogen, C １－６ Alkyl, C １－６ Haloalkyl, -OR ２２ , -SR ２２ , -N(R ２２ ) ２ , -C(O)R ２２ , -C(O)OR ２２ , -OC(O)R ２２ , -OC(O)N(R ２２ ) ２ , -C(O)N(R ２２ ) ２ , -N(R ２２ )C(O)R ２２ , -N(R ２２ )C(O)OR ２２ , -N(R ２２ )C(O)N(R ２２ ) ２ , -N(R ２２ ) C(S)N(R ２２ ) ２ , -N(R ２２ )S(O) ２ (R ２２ ), -S(O)R ２２ , -S(O) ２ R ２２ , -S(O) ２ N(R ２２ ) ２ , -NO ２ , =O, =S, =N(R ２２ ), -N ３ , -C.N., C. ３－６ Carbocyclic and 3- to 6-membered heterocyclic rings and is substituted with one or more substituents independently selected from Here, C ３－６ The carbocycle and the 3- to 6-membered heterocycle each optionally include halogen, C １－４ Alkyl and C １－４ and substituted with one or more substituents independently selected from haloalkyl. Selected from: R ２１ and R ２２ are each independently in each case: hydrogen; Optionally, halogen, hydroxyl, C ３－６ C substituted with one or more substituents independently selected from a carbocycle and a 3- to 6-membered heterocycle １－４ Alkyl (wherein each C ３－６ Carbocyclic and 3- to 6-membered heterocyclic rings are optionally C １－４ Alkyl, -N(R ２３ ) ２ and -C(O)N(R ２３ ) ２ and C ３－６ Carbocyclic rings and 3- to 12-membered heterocyclic rings (each of which may optionally contain halogen, C １－４ Alkyl, C １－４ Haloalkyl, C １－４ substituted with one or more substituents independently selected from alkoxy and =O; is selected from; and R ２３ is independently hydrogen and C １－４ alkyl.} or a pharma- ceutically acceptable salt thereof.

2. 2. The compound or salt of claim 1, wherein q is 1 or 2.

3. X-Y is λ -C(O)N(R １４ )-, λ -N(R １４ )C(O)- and λ -OCH ２ -; and R １４ 2. The compound or salt of claim 1, wherein is hydrogen.

4. R １１ , R １２ , R １３ , R １４ , R １５ and R １６ 2. The compound or salt of claim 1, wherein each occurrence of is selected from hydrogen.

5. R ６ is selected from hydrogen and —OH or A and R ６ Together, C ３－６ forms a carbocyclic ring; and R ７ 2. The compound or salt of claim 1, wherein is selected from hydrogen and halogen.

6. R ６ and R ７ 2. The compound or salt of claim 1, wherein each is selected from hydrogen.

7. A is selected from hydrogen, halogen and -CN or A and R ６ Together, C ３－６ 2. The compound or salt of claim 1 which forms a carbocyclic ring.

8. 8. The compound or salt of claim 7, wherein A is hydrogen.

9. 2. The compound or salt of claim 1, wherein B is selected from hydrogen, halogen and -CN.

10. 10. The compound or salt of claim 9, wherein B is selected from hydrogen and halogen.

11. A is C ３－１２ 2. The compound or salt of claim 1, selected from a carbocycle and a 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents.

12. A of C ３－１２ 12. The compound or salt of claim 11, wherein the carbocycle and the 3- to 12-membered heterocycle are selected from phenyl; pyridine; indane; chroman; benzodioxole; 2,3-dihydrobenzofuran; quinoline; 1,2,3,4-tetrahydronaphthalene; naphthalene; quinoxaline; 2',3'-dihydrospiro[cyclopropane-1,1'-indene]; and pyrazole; each optionally substituted with one or more substituents.

13. One or more of the optional substituents of A is halogen, -OR １７ , C １－６ Alkyl, C １－６ Haloalkyl, C ３－１０ Carbocycles and 3- to 10-membered heterocycles, where C ３－１０ The carbocyclic ring and the 3- to 10-membered heterocyclic ring are each optionally １－４ Alkyl, C １－４ 13. The compound or salt of claim 12, wherein the alkyl group is selected from the group consisting of aryl, arylalkyl, arylsulfonyl ...

14. R １７ is independently hydrogen at each occurrence, C １－６ Alkyl, C ３－６ 2. The compound or salt of claim 1, which is selected from a carbocycle and a 3- to 6-membered heterocycle.

15. One or more optional substituents of A are halogen, hydroxyl, methoxy, trifluoromethyl, propyl, cyclopropyl, cyclopentyl, phenyl, phenoxy, 【Chemistry 3】 2. The compound or salt of claim 1, selected from:

16. A 【Chemistry 4】 【Chemistry 5】 2. The compound or salt of claim 1, selected from:

17. R １８ is independently hydrogen at each occurrence, C １－６ Alkyl, C ３－１０ carbocycle and 3- to 10-membered heterocycle, １－６ Alkyl, C ３－１０ 2. The compound or salt of claim 1, wherein the carbocyclic ring and the 3- to 10-membered heterocyclic ring are each optionally substituted with one or more substituents.

18. R １８ C ３－１０ 18. The compound or salt of claim 17, wherein the carbocycle and the 3- to 10-membered heterocycle are independently selected at each occurrence from pyrrolidine, piperidine, phenyl, indoline, bicyclo[2.2.2]octane, cyclohexane, tetrahydropyran, pyridine, oxadiazole, pyrimidine, quinazoline, naphthalene, quinoline, thieno[3,2-d]pyrimidine, thieno[2,3-d]pyrimidine, benzothiazole, indane, thieno[2,3-d]pyrimidine oxide and cyclopropyl, any of which is optionally substituted with one or more substituents.

19. R １８ C ３－１０ The carbocyclic ring and the 3- to 10-membered heterocyclic ring are each independently selected from halogen, C １－６ Alkyl, C １－６ Haloalkyl, -OR ２２ , -N(R ２２ ) ２ , -C(O)R ２２ , -C(O)N(R ２２ ) ２ , -N(R ２２ )C(O)R ２２ , -S(O) ２ R ２２ , =O, -CN, C ３－６ Carbocycles and 3- to 6-membered heterocycles, where C ３－６ The carbocyclic ring and the 3- to 6-membered heterocyclic ring each optionally include halogen, C １－４ Alkyl and C １－４ 20. The compound or salt of claim 17, optionally substituted with one or more substituents selected from haloalkyl.

20. R １８ C ３－１０ The carbocyclic ring and the 3- to 10-membered heterocyclic ring are each independently selected from halogen, C １－６ Alkyl, C １－６ Haloalkyl, -N(R ２２ ) ２ , -C(O)R ２２ , -C(O)N(R ２２ ) ２ , -S(O) ２ R ２２ , =O, C ３－６ Carbocycles and 3- to 6-membered heterocycles, where C ３－６ The carbocycle and the 3- to 6-membered heterocycle each optionally contain halogen and C １－４ 20. The compound or salt of claim 19, optionally substituted with one or more substituents selected from haloalkyl.

21. R ２２ is independently hydrogen at each occurrence, C １－４ Alkyl, C ３－６ carbocycle and 3- to 6-membered heterocycle, ３－６ The carbocyclic ring and the 3- to 6-membered heterocyclic ring are each optionally １－４ Alkyl and C １－４ 20. The compound or salt of claim 17, substituted with one or more substituents independently selected from alkoxy.

22. R １８ C ３－１０ The carbocycle and the 3- to 10-membered heterocycle each independently represent halogen, methyl, trifluoromethyl, cyclopropyl, phenyl, -NH ２ , = O, 【Chemistry 6】 18. The compound or salt of claim 17, optionally substituted with one or more substituents selected from:

23. B 【Chemistry 7】 【Chemistry 8】 2. The compound or salt of claim 1, selected from:

24. C of B ３－１２ 2. The compound or salt of claim 1, wherein the carbocycle and the 3- to 12-membered heterocycle are selected from phenyl; pyridinyl, naphthyl; 1,2,3,4-tetrahydronaphthalene; indane; 7-azaindole; indazole; and chroman, any of which is optionally substituted with one or more substituents.

25. C of B ３－１２ Carbocycle and 3- to 12-membered heterocycle are each optionally Halogen and -OR １８ ; Optionally halogen, OR １８ and C ３－６ C substituted with one or more substituents independently selected from carbocycles １－６ Alkyl; and C ３－１０ Carbocycles and 3- to 10-membered heterocycles, where C ３－１０ The carbocycle and the 3- to 10-membered heterocycle each optionally contain halogen and C １－４ substituted with one or more substituents independently selected from alkyl 25. The compound or salt of claim 24, substituted with one or more substituents independently selected from:

26. C of B ３－１２ The carbocycle and the 3- to 12-membered heterocycle each optionally include halogen, trifluoromethyl, cyclopropyl, phenyl, 【Chemistry 9】 25. The compound or salt of claim 24, substituted with one or more substituents independently selected from:

27. B 【Chemistry 10】 2. The compound or salt of claim 1, selected from:

28. The compound of formula (Ia) 【Chemistry 11】 【Chemistry 12】 【Chemistry 13】 【Chemistry 14】 【Chemistry 15】 【Chemistry 16】 【Chemistry 17】 【Chemistry 18】 【Chemistry 19】 【Chemistry 20】 【Chemistry 21】 【Chemical 22】 【Chemistry 23】 【Chemistry 24】 【Chemistry 25】 【Chemistry 26】 【Chemistry 27】 【Chemistry 28】 【Chemical Formula 29】 【Chemistry 30】 【Chemistry 31】 【Chemistry 32】 2. The compound or salt of claim 1, selected from:

29. A pharmaceutical composition comprising a pharma- ceutically acceptable excipient and a compound or salt of any of claims 1-28.

30. 30. An alpha V integrin modulating agent comprising a compound or salt of any one of claims 1 to 28.

31. The method of claim 30, wherein the alpha V integrin is alpha V beta 1 integrin.

32. The method of claim 30, wherein the alpha V integrin is alpha V beta 6 integrin.

33. A therapeutic agent for a disease or condition selected from idiopathic pulmonary fibrosis, systemic lupus erythematosus-associated interstitial lung disease, rheumatoid arthritis, diabetic nephropathy, focal segmental glomerulosclerosis, chronic kidney disease, nonalcoholic steatohepatitis, primary biliary cirrhosis, primary sclerosing cholangitis, solid tumors, blood tumors, organ transplantation, Alport syndrome, interstitial lung disease, radiation-induced fibrosis, bleomycin-induced fibrosis, asbestos-induced fibrosis, influenza-induced fibrosis, coagulation-induced fibrosis, vascular injury-induced fibrosis, aortic stenosis, and cardiac fibrosis, comprising a compound or salt according to any one of claims 1 to 28.

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