Bis-[N-((5-carbamoyl)-1H-benzo[d]imidazol-2-yl)-pyrazol-5-carboxamide] derivatives and related compounds as STING (Stimulator of Interferon Genes) agonists for the treatment of cancer

Abstract

The present disclosure relates to compounds of formula (IA') as STING (Stimulator of Interferon Genes) agonists for use in the treatment of e.g. cancer, obesity, liver injuries, sugar-lipid metabolism and virus infections. The present description discloses the synthesis and characterisation of exemplary compounds as well as pharmacological data thereof (e.g. pages 128 to 286; examples 1 to 54; tables 1, 2a, 2b and 3). An exemplary compounds is e.g. example 1: (E)-N-(5-carbamoyl- l-(4-(5-carbamoyl-2-(4-ethyl-2-methyloxazole-5-carboxamido)-7- (3-hydroxypropoxy)-1H-benzo[d]imidazol-1-yl)but-2-en-1-yl)-7- methoxy-1H-benzo[d]imidazol-2-yl)-4-ethyl-2-methyloxazote-5- carboxamide (compound 9).

Description

Related Applications

[001] This application claims priority to, and the benefit of, U.S. Provisional Application No. 62 / 882,081 filed August 2, 2019, U.S. Provisional Application No. 62 / 944,643 filed December 6, 2019, and U.S. Provisional Application No. 62 / 982,935 filed February 28, 2020. The contents of each of these applications are hereby incorporated by reference in their entireties. BACKGROUND

[002] Stimulator of Interferon Genes (STING) is a receptor in the endoplasmic reticulum that propagates innate immune sensing of cytosolic pathogen derived- and self-DNA. STING is a 378 amino acid protein, which mainly contains three structural domains: (i) N-terminal transmembrane domain (aa 1-154); (ii) central globular domain (aa 155-341); and (iii) C-terminal tail (aa 342-379). STING may form symmetrical dimers combined with its ligands in V-shaped conformation, while not completely covering the bound ligands. A STING agonist can bind into the pocket region of STING. However, the STING activation process is easily inhibited in some severe disease conditions, resulting in the inactivation of the STING pathway. Therefore, screening and designing potent STING agonists is of great importance for cancer immune therapy and other infectious diseases treatments, including, but not limited to, obesity, liver injury, sugar-lipid metabolism, and virus infection. Specific targeting of immune pathways presents opportunities for cancer therapy, potentially offering greater specificity than cell population-based therapeutic approaches.

[003] The compounds of this disclosure modulate the activity of STING, and accordingly, may provide a beneficial therapeutic impact in treatment of diseases, disorders and / or conditions in which modulation of STING (Stimulator of Interferon Genes) is beneficial, including, but not limited to, inflammation, allergic and autoimmune diseases, infectious diseases, cancer, pre-cancerous syndromes, and as vaccine adjuvants. SUMMARY [004 ] In some aspects, the present disclosure provides a compound of Formula (IA’) Ru (IA’) or a prodrug, solvate, pharmaceutically acceptable salt, or tautomer thereof, wherein: Wi. Xi, Yi, Zi, W2, X2, Y2, and Z2 are each independently 0, S, C, or N; X3 and X4 are each independently S or NRf; X5 is N or CRA2; X6isNorCRA!; X9 is N or CR4; r and s are each independently 0 or 1; p is I or 2; the total of r and s is 1 or 2; RA1 and RA2 are each independently H, halogen, ammo, amino(Ci-4 alkyl)-, hydroxy, -O-P(O)(OH)2, -O-P(O)(RIRn)2, -N(Re)(Rf), -CO2Rf, -N(Rf)CORb, -N(Rg)SO2(Ci-4 alkyl)-N(Re)(Rf), -N(R8)CO(Ci-4 alkyl)-N(Rh)(Rf), optionally substituted (Cue alkyl), optionally substituted (C1-6 alkyl)oxy-, optionally substituted (C1-6 alkyl)amino-, and optionally substituted (C1-6 alkyl)(Ci-4 alkyl)amino-, wherein the (Ci^ alkyl) of said optionally substituted (Ci-6 alkyl), optionally substituted (Ci-6 alkyl)oxy-, optionally substituted (C1-6 alkyl)amino- and optionally substituted (Cue alkyl)(Ci-4 alkyl)aniino- is optionally substituted by 1-4 substituents each independently selected from hydroxy, -O-P(O)(OH)2, -0^(0)^¾.1¼ Ci-4 alkoxy-, -N(Re)(Rf), -CO2(Rf), -C0N(Re)(Rf), optionally substituted phenyl, and optionally substituted 5-6 membered heteroaryl group, wherein said optionally substituted phenyl or 5-6 membered heteroaryl is optionally substituted by 1-4 substituents each independently selected from halogen, hydroxy, -O-P(O)(OH)2, -O-P(O)(RTRTI)2, amino, (Ci-6 alkyl)ammo-, (Ci-6 alkyl)(Ci-6 alkyl)ammo-, -(Cm alkyl)-NH2, halo(Ci-6 alkyl), hydroxy-(CM alkyl)-, -(C1.4 alkyl)-O-P(O)(OH)2, -(C1-4 alkyl)-O-P(O)(RTR1T)2, halo(Ci-4 alkoxy), Cm alkoxy-, hydroxy-(C2-4 alkoxy)-, -(C2-4 alkoxy)-O-P(O)(OH)2, -(C2-4 alkoxy)-O-P(O)(RJRII)2, -Cm alkyl-(Ci-4 alkoxy), and C1-4 alkoxy-(CM alkoxy)-; when r is 0, RBl and RB2 are each independently H, optionally substituted C1-6 alkyl, halo(Ci-6 alkyl), optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted C3-6 cycloalkyl, optionally substituted 4-6 membered heterocycloalkyl, optionally substituted phenyl, optionally substituted 5-6 membered heteroaryl, or optionally substituted 9-10 membered heteroaryl, wherein said optionally substituted Cm alkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted C3-6 cycloalkyl, optionally substituted 46 membered heterocycloalkyl, optionally substituted phenyl, optionally substituted 5-6 membered heteroaryl, or optionally substituted 9-10 membered heteroaryl is optionally substituted by 1-4 substituents each independently selected from halogen, nitro, ~RC, -OH, -O-P(O)(OH)2, -O-P(O)(RIRU)2 -ORC, -NHz, -NRCRC, -NRcRd, -OCORC, -CO2H, -CO2RC, -SORC, -SO2RC, -CONFR -CONRcRd, -SO2NH2, -SO2NRcRd, -OCONH2, -OCONRcRd, -NRdCORc, -NRdSORc, -NRdCO2Rc, and -NRdSO2Rc; when s is 0, RC1 is absent, H, halogen, or Cm alkyl and RC2 is absent or optionally substituted Cm alkyl, wherein said optionally substituted Cm alkyl group is optionally substituted by a substituent selected from -ORC, -NRcRd, -CO2RC, -CONRcRd, -SO2NRcRd, and -OCONRcRd; when r is 1, RB1 and R32 are each independently -CH2-, and B, taken together with R31 and R32, forms a linking group, wherein B is a bond or B is -halo(Cmo alkyl)-, optionally substituted -Cnioalkyl-, optionally substituted -C2-10 alkenyl-, optionally substituted -C2-10alkynyl-, optionally substituted -Cm alkyl-O-Ci-6 alkyl-, optionally substituted -Cm alkyl-NRa-CM alkyl, optionally substituted C3.6 cycloalkyl, optionally substituted phenyl, optionally substituted 4-6 membered heterocycloalkyl, optionally substituted 5-6 membered heteroaryl, optionally substituted -Cm alkyl-(C3-6 cycloalkyl)-CM alkyl-, optionally substituted -Cm alkyl-phenyl-CM alkyl-, optionally substituted -Cm alkyl-(4-6 membered heterocycloalkyl)-CM alkyl-, or optionally substituted -Cm alkyl-(5-6 membered heteroaryl)-Ci-4 alkyl-, wherein the alkyl moiety of said optionally substituted -Ci-io alkyl-, optionally substituted -C2-10 alkenyl-, optionally substituted -C2-10 alkynyl-, optionally substituted -C1-6 alkyl-O-Ci-6 alkyl-, optionally substituted -C1-6 alkyl-NRa-Ci-6 alkyl-, optionally substituted -Cm alkyl-(C3-6 cycloalkyl)-Ci-4 alkyl-, optionally substituted -Cm alkyl-phenyl-Ci-4 alkyl-, optionally substituted -Cm alkyl-(4-6 membered heterocycloalkyl)-CM alkyl-, or optionally substituted -Cm alkyl-(5-6 membered heteroaryl-Ci-4 alkyl)- is optionally substituted by 1 or 2 substituents each independently selected from halogen, halo(CM alkyl), -OH, -O-P(O)(OH)2, -O-P(O)(RTRn)2, -ORC, -NH2, -NRcRd, -OCORC, -CO2H, -CO2Rc, -SOR\ -SO2RC, -CONH2, •( ONR RC -SO2NH2, -SO2NRcRd, -OCONH2, -OCONRcRd, -NRdCORc, -NRdSORc, -NRdCO2Rc, and -NRdSO2Rc, and the C3-6 cycloalkyl, phenyl, 4-6 membered heterocycloalkyl, or 5-6 membered heteroaryl moiety of said optionally substituted C3-6 cycloalkyl, optionally substituted phenyl, optionally substituted 4-6 membered heterocycloalkyl, optionally substituted 5-6 membered heteroaryl, optionally substituted -Cm alkyl-(Cs-6 cycloalkyl)-Ci-4 alkyl-, optionally substituted -Cm alkylphenyl-Ci-4 alkyl-, optionally substituted -Cm alkyl-(4-6 membered heterocycloalkyl)-Ci-4 alkyl, or optionally substituted -Cm alkyl-(5-6 membered heteroaryl)-CM alkyl- is optionally substituted by 1-4 substituents each independently selected from halogen, hydroxy, -O-P(O)(OH)2, -O-P(O)(OR1R1I)2, amino, (Cm alkyl)amino~, (Cm alkyl)(Ci-4 alkyl)ammo-, Cm alkyl, halo(Ci-4 alkyl), halo(CM alkoxy)-, Cm alkoxy-, hydroxy-(C2-4 alkoxy)-, -(C2-4 alkoxy)-O-P(O)(OH)2, -(C2-4 alkoxy)-O-P(O)(RIRIi)2, and Cm alkoxy-(CM alkoxy)-; when s is 1, Wj and Z2 are each independently C or N, RCI and RC2 are each independently -CH2-, and D taken together with RC1 and RC2, forms a linking group, wherein D is -halo(Ct-j2 alkyl)-, optionally substituted -C1-12 alkyl-, optionally substituted -C2-12 alkenyl-, optionally-substituted -C2-12 alkynyl-, optionally substituted -Cm alkyl-O-CM alkyl-, optionally substituted -Cm alkyl-NRa-Ci-6 alkyl-, optionally substituted -Cm alkyl-(C3-6 cycloalkyl)-CM alkyl-, optionally substituted -Cm alkyl-phenyl-Ci-6 alkyl-, optionally substituted -Cm alkyl-(4-6 membered heterocycloalkyl)-Ci-6 alkyl-, or optionally substituted -Cm alkyl-(5-6 membered heteroaryl)-Ci-6 alkyl-, wherein the alkyl moiety of said optionally substituted -C1-12 alkyl-, optionally7 substituted -Cm alkenyl-, optionally7 substituted -C2-12 alkynyl-, optionally substituted -Cm alkyl-O-Ci-6 alkyl- , optionally substituted -Cue alkyl-NRa-Cu6 alkyl-, optionally substituted -Ci-6 alkyl-(C3-6 cycloalkyl)-Cu6 alkyl-, optionally substituted -Cue alkyl-phenyl-Ci-6 alkyl-, optionally substituted -Ci-6 alkyl-(4-6 membered heterocycloalkyl)-Cu6 alkyl-, or optionally substituted -Cue alkyl-(5-6 membered heteroaryl)Cue alkyl- is optionally substituted by 1 or 2 substituents each independently selected from halogen, halo(Ci-4 alkyl), -OH, -O-P(O)(OH)2, -O-P(O)(RTRIT)2, -ORC, -NH2, -NRcRd, -OCORC, -CO2H, -CO2Rc, -SORc, -SO2Rc, -CONH2, -CONRcRd, -SO2NH2, -SO2NRcRd, -OCONH2, -OCONRcRd, -NRdCORc, -NRdSORc, -NRdCO2Rc, and -NRdSO2Rc, and the C3-6 cycloalkyl, phenyl, 4-6 membered heterocycloalkyl, or 5-6 membered heteroaryl moiety of said optionally substituted -Cue alkyl-(C3-6 cycloalkyl)-Ci-6 alkyl-, optionally substituted -C1-6 alkyl-phenyl-Ci-6 alkyl-, optionally substituted -Cue alkyl-(4-6 membered heterocycloalkyl)-Cue alkyl-, or optionally substituted -Ci-6 alkyl-(5-6 membered heteroaryl)-Ci-6 alkyl- is optionally substituted by 1-4 substituents each independently selected from halogen, hydroxy, -O-P(O)(OH)2, O-P(O)(RiR1I)2, amino, (Ci-4 alkyl)amino-, (Ci-4 alkyl)(Ci-4 alkyljammo-, C1-4 alkyl, halo(Ci-4 alkyl), halo(Ci-4 alkoxy)-, Ci-4 alkoxy-, hydroxy-(C2-4 alkoxy)-, -(C2-4 alkoxy)-O-P(O)(OH)2, -(C2. 4 alkoxy)-O-P(O)(RIRI1)2, and C1-4 alkoxy-(Ci-4 alkoxy)-; R and R5 are each independently -CON(Rd)(Rf), -CH2N(Rd)(Rf), -N(Rd)(Rf), -N(Rd)CO(Rf), -CH2N(Rd)CO(R1), or one of R3 and R5 is -CON(Rd)(Rf), -CH2N(Rd)(Rf), -N(Rd)(Rf), -N(Rd)CO(Rf), or -CH2N(Rd)CO(Rf), and the other of R3 and R5 is H, COOH, or -CO2Rc; R4 and R6 are each independently selected from H, halogen, halo(Ci-6 alkyl), halo(Cj-6 alkoxy)-, hydroxy, -O-P(O)(OH)2, ()-P(())(RIRII)2, -NH2, -NRCRC, -NRcRd, -CORC, -CO2RC, -N(Rd)CORc, -N(Rd)SO2Rc, -N(Re)SO2(Cn2 alkyl)-N(Rh)(Rf), -N(Re)CO(Ct.2 alkyl)-N(Rh)(Rf), optionally substituted (Cj-e alkyl), optionally substituted (Cue, alkyl)oxy-, optionally substituted (Cue alkyl)amino-, and optionally substituted (Cue alkyl)(Ci-4 alkyl)amino-, wherein the (Cue alkyl) of said optionally substituted (Cue alkyl), optionally substituted (Ci-6 alkyl)oxy-, optionally substituted (Cue alkyl)amino- and optionally substituted (Cue alkyl)(Ci-4 alkyl)amino- is optionally substituted by 1-4 substituents each independently selected from -OH, -O-P(O)(OH)2, -O-P(O)(RiRu)2, -ORe, -NH2, -NRCRC, -NRcRd, -CO2H, -CO2RC, -OCORC, -CO2H, -CO2Rc, -S()Rc, -SO2Rc -CONH2, -CONRcRd, -SO2NH2, -SO2NRcRd, -OCONH2, -OCONRcRd, -NRdCORc, -NRdSORc, -NRdCO2Rc, -NRdSO2Rc, optionally substituted phenyl, optionally substituted 5-6 membered heterocycloalkyl, and optionally substituted 5-6 membered heteroaryl group, wherein said optionally substituted phenyl, 5-6 membered heterocycloalkyl, or 5-6 membered heteroaryl is optionally substituted by 1-4 substituents each independently selected from halogen, hydroxy, -O-P(O)(OH)2, -O-P(O)(RIR1I)2, ammo, (Ci-4 aikyl)amino-, (Ci-4 alkyl)(Ci-4 alkyl)amino-, Cn4 alkyl, halo(Ci-4 alkyl), hydroxy-(Ci-4 alkyl)-, -(Ci-4 alkyl)-O-P(O)(OH)2, -(Ci-4 alkyl)-O-P(0)(^^)2, halo(Ci-4 alkoxy)-, C1.4 alkoxy-, hydroxy-(C2-4 alkoxy)-, -(C2-4 alkoxy)-O-P(O)(OH)2, -(C2-4 alkoxy)-O-P(O)(RIRII)2, Cm alkoxy-(Ci-4 alkoxy)-, -CORd, -CON(Rd)(Rf), and -CO2Rd, R14 is absent, H, halogen, or optionally substituted C1.4 alkyl, wherein said optionally substituted Cm alkyl is optionally substituted by a substituent selected from halogen, -ORC, -NRcRd, -CO2RC, -CONRcRd, -SO2NRcRd, and -OCONRcRd; R16 is absent, H, halogen, or Cm alkyl; R15 and R17 are each independently absent, H, cyclopropyl, halogen or optionally-substituted Cm alkyl, wherein said optionally substituted C1-4 alkyl is optionally substituted by a substituent selected from halogen, -ORC, -NRcRd, -CO2RC, -CONRcRd, -SO2NRcRd, and -OCONRcRd; or R15 and R19 taken together with the atom or atoms through which they are connected, form a 5-6 membered ring; or R16 and R11 taken together with the atom or atoms through which they are connected, form a 5-6 membered ring; R18 and R19 are each independently absent, H, halogen, optionally substituted C1-4 alkyl, wherein said optionally substituted C1-4 alkyl is optionally substituted by a substituent selected from halogen, -ORC, -NRcRd, -CO2Rc, -C()NRcRd, -SO2NRcRd and -OCONRcRd; or R17 and R18 taken together with the atom or atoms through which they are connected, form a 5-6 membered ring; Ra is H, -Rc, -CORC, -CO2H, -CO2Rc, -SORC, -SO2Rc -CONH2, -CONRcRd, -SO2NH2, -CHz-CChRy or -SO2NRcRd; each RD is independently Cm alkyl, halo(Cj-4 alkyl), -(C1-4 alkyl)-OH, -(C1-4 alkyl)-O-P(O)(OH)2, -(Ci-4 alkyl)-O-P(O)(RIRn)2, -(Cm alkyl)-O-(Ci.4 alkyl), -(Cm alkyl)-N(Re)(Rf), -(Ci-4 alkyl)-O-CO(Ci-4 alkyl), or -(Cm alkyl)-CO-O-(Ci-4 alkyl); each Rc is independently H, Cm alkyl, halo(Ci-4 alkyl), -(Cm alkyl)-OH, -(Cm alkyl)-O-P(O)(OH)2, -(Ci-4 alkyl)-O-P(O)(RIRu)2, -(Cm alkyl)-O-(Ci-4 alkyl), -(Cm alkyl)-N(Re)(Rf), -(Cn 4 alkyl)-O-CO(Ci-4 alkyl), -(Cm alkyl)-CO-O-(Ci-4 alkyl), optionally substituted C3-6 cycloalkyl, optionally substituted phenyl, optionally substituted 4-6 membered heterocycloalkyl, optionally substituted 5-6 membered heteroaryl, optionally substituted 9-10 membered heteroaryl, optionally substituted -C1.4 alkyl-C3-6 cycloalkyl, optionally substituted -Cm alkyl-phenyl, optionally substituted -Cm alkyl-4-6 membered heterocycloalkyl, optionally substituted -Cm alkyl-5-6 membered heteroaryl, or optionally substituted -Cm alkyl-9-10 membered heteroaryl, wherein the C3-6 cycloalkyl, phenyl, 4-6 membered heterocycloalkyl, 5-6 membered heteroaryl or 9-10 membered heteroaryl moiety of said optionally substituted C3-6 cycloalkyl, optionally substituted phenyl, optionally substituted 4-6 membered heterocycloalkyl, optionally substituted 5-6 membered heteroaryl, optionally substituted 9-10 membered heteroaryl, optionally substituted -Cm alkyl-C3-6 cycloalkyl, optionally substituted -C1-4 alkyl-phenyl, optionally substituted -C1-4 alkyl-4-6 membered heterocycloalkyl, optionally substituted -Cm alkyl-5-6 membered heteroaryl, or optionally substituted -Cm alkyl-9-10 membered heteroaryl is optionally substituted by 1-4 substituents each independently selected from halogen, hydroxy, -O-P(O)(OH)2, -O-P(O)(RIR1I)2, amino, (C1-4 alkyl)amino-, (C1-4 alkyl)(Ci-4 alkyl)amino-, C1-4 alkyl, halo(Ci-4 alkyl), halo(Ci-4 alkoxy)-, Cm alkoxy-, hydroxy-(C2-4 alkoxy)-, -(C2-4 alkoxy)-O-P(O)(OH)2, -(C2-4 alkoxy)-O-P(O)(RIRn)2, Cm alkoxy-(Cw alkoxy)-, -CORd, -CON(Rd)(Rf), and -CO2Rd; each Rd is independently H, hydroxy, or C1-4 alkyl; each Re is independently H, (Cm alkyl), -C0(Cm alkyl), -0C0(Cm alkyl), -C02(Cm alkyl), -(Cm alkyl)amino, -(C1-4 alkyl)-Ci-4 alkoxy, -CO-(optionally substituted 5-6 membered heterocycloalkyl), -CO-(Ci-4 alkyl)-(optionally substituted 5-6 membered heterocycloalkyl), -CO-(optionally substituted 5-6 membered heteroaryl), -C0-(Cm alkyl)-(optionally substituted 5-6 membered heteroaryl), wherein the optionally substituted 5-6 membered heterocycloalkyl or optionally-substituted 5-6 membered heteroaryl is optionally substituted by 1-4 substituents each independently selected from halogen, hydroxy, -O-P(O)(OH)2, -O-PiOjfR’R1^., amino, (Cm alkyl)amino-, (Cm alkyl)(CM alkyl)amino-, Cm alkyl, halo(Ci-4 alkyl), halo(CM alkoxy)-, Cm alkoxy-, hydroxy-(C2-4 alkoxy)-, -(C2-4 alkoxy) O-P(O)(OH)2, -(C2-4 alkoxy)-O-P(O)(RiRI1)2, Cm alkoxy-(Ci-4 alkoxy)-, -CORd, -CON(Rd)(R1), and -CO2Rd; each Rf is independently H, hydroxy, or (Cm alkyl); Rg and Rn are each independently H or (Cm alkyl) or Rg and Rh, taken together with the atom or atoms through which they are connected, form a 5-6 membered ring; and each R1 and Rn are independently (C1-6 alkyl)oxy-; provided that at least one of (i), (ii), or (iii) applies: (i) when s is 0, r is I, (a) Zi, Z2, Yi and Y2 are each N, Wi, W2, Xi and X2 are each C; or (b) Wi, W2, Xi and X2 are each N, Zi, Z2, Yi and Y2 are each C; or (c) Zi and Yi are each N, Wi and Xi are each C; or (d) Z2 and Y2 are each N, W2 and X2 are each C; or (e) Wi and Xi are each N, Zi and Yi are each C; or (f) W2 and X2 are each N, Z2 and Y2 are each C, then at least one of X3 and X4 is S or X9 is N; or (ii) when s is 0, r is 1, (a) Zi, Z2, Yi and Y2 are each N, Wi, W2, Xi and X2 are each C; or (b) Wi, W2, Xi and X2 are each N, Zi, Z2, Yi and Y2 are each C, then R14 is a Cm alkyl substituted with halogen, -ORC, -NRcRd, -CO2RC, -CONRcRd, -SO2NRcRd, and -OCONRcRd wherein Rc is H; or (iii) when s is 0, r is 1, (a) Zi and Yi are each N, Wi and Xi are each C; or (b) Z2 and Y2 are each N, W2 and X2 are each C; or (c) Wi and Xi are each N, Zi and Yi are each C; or (d) W2 and X2 are each N, Z2 and Y2 are each C, then at least one of X5, X6, and X9 is N and RAl or RA2 is halogen, hydroxy, optionally substituted (C1-6 alkyl), substituted (C1-6 alkyl)oxy~, optionally substituted (Cm alkyl)amino-, or optionally substituted (Cue alkyl)(Ci-4 alkyl)amino-, wherein the (Cm alkyl) of said optionally substituted (Cm alkyl), substituted (C1-6 alkyl)oxy~, optionally substituted (Cue alkyl)amino-, or optionally substituted (Cm alkyl)(Ci-4 alkyljammo- is optionally substituted by 1-4 substituents each independently selected from hydroxy, -O-P(O)(OH)2, -O-P(O)(RIRII)2, -N(Re)(Rf), -CO2(Rf), -CON(Re)(Rf), optionally substituted phenyl, and optionally substituted 5-6 membered heteroaryl group, wherein said optionally substituted phenyl or 5-6 membered heteroaryl is optionally substituted by 1-4 substituents each independently selected from halogen, hydroxy, -O-P(O)(OH)2, -O-P(O)(R1Rlf)2, amino, (C1-6 alkyl)amino-, (Cue alkyl)(Cj-6 alkyl)amino-, -(Cue alkyl)-NH2, halo(Ci-6 alkyl), hydroxy-(CM alkyl)-, -(Ci-4 alkyl)-O-P(O)(OH)2, -(Cm alkyl)-O-P(O)(RIRu)2, halo(Cn4 alkoxy), Cm alkoxy-, hydroxy-(C2^ alkoxy)-, -(C2-4 alkoxy)-O-P(O)(OH)2, -(C2.4 alkoxy)-O-P(O)(RIR1I)2, -Cm alkyl-(Ci-4 alkoxy), and Cm alkoxy-(Ci-4 alkoxy.

[005] In some embodiments, the compound is of Formula (IA’), wherein the compound is Formula (IA): R14 (TA), or a prodrug, solvate, pharmaceutically acceptable salt, or tautomer thereof.

[006] In some embodiments, the compound is of Formula (V’): (V’) or a prodrug, solvate, pharmaceutically acceptable salt, or tautomer thereof, wherein: Yi, Y2, Zi and Z2 are each independently O, S, C or N; Xi, X2, Wi and W2 are each independently C or N; X3 and X4 are each independently S or NR1; X5 is N or CRA2; X6 is N or CRA \ X9 is N or CH; R3 and R5 are each independently -CON(Rd)(Rf), -CH2N(Rd)(Rf), -N(Rd)(Rf), -N(Rd)CO(Rt), -CH2N(Rd)CO(Rf) or one of R3 and R5 is -CON(Rd)(Rf), -CH2N(Rd)(Rf), -N(Rd)(Rf), -N(Rd)CO(Rf) or -CH2N(Rd)CO(Rf), and the other of R3 and R5 is H, -COOH, or -CO2Rc; Rc is Cm alkyl; RA2 and RAl are each independently H, halogen, amino, amino(Ci-4 alkyl)-, hydroxy, optionally substituted (Cue alkyl), or optionally substituted (Ci-6alkyl)oxy-, wherein Cue alkyl of said optionally substituted (Cue alkyl), or optionally substituted (Ci-6 alkyl)oxy- is optionally substituted with 1-4 substituents each independently selected from the group comprising hydroxy, Ci-4 alkoxyl, -N(Re)(Rf), -CO2(Rf), -CON(Re)(RI), and -COOH; each Rd is independently H, hydroxy, or Cm alkyl; Re is selected from H, (Cm alkyl), -C0(Cm alkyl), -0C0(Cm alkyl), and -C02(Cm alkyl); each Rf is independently H, hydroxy, or (Cm alkyl); R14 and Rc2 are each independently absent or Cm alkyl, wherein Cm alkyl is optionally substituted by a substituent selected from halogen, -ORC, -NRcRd, -CO2RC, -CONRcRd, -SO2NRcRd, and -OCONRcRd; R1D and RC1 are each independently absent, H or Cm alkyl; and R15, R17, R18, or R19 are each independently absent, H, or Cm alkyl, wherein Cm alkyl is optionally substituted by a substituent selected from halogen, -ORC, -NRcRd, -CO2RC, -CONRcRd, -SO2NRcRd, and -OCONRcRd; provided that at least one of (i), (ii), or (iii) applies: (i) when (a) Zi, Z2, Yj and Y2 are each N, Wj, W2, Xi and X2 are each C; or (b) Wi, W2, Xi and X2 are each N, Zi, Z2, Yj and Y2 are each C; or (c) Zj and Yi are each N, Wi and Xi are each C; or (d) Z2 and Y2 are each N, W2 and X2 are each C; or (e) Wi and Xi are each N, Zi and Yj are each C; or (f) W2 and X2 are each N, Z2 and Y2 are each C, then at least one of X? and X4 is S or X9 is N; or (ii) when (a) Zi, Z2, Yi and Y2 are each N, Ws, W2, Xi and X2 are each C; or (b) Wi, W2, Xi and X2 are each N, Zi, Z2, Yi and Y2 are each C, then R14 is a Ci .4 alkyl substituted with halogen, -ORC, -NRcRd, -CO2Rc, -C0NRRd, -SO2NRcRd, and -OCONRcRd wherein Rc is H; or (iii) when (a) Zi and Yi are each N, Wi and Xi are each C; or (b) Z2 and Y2 are each N, W2 and X2 are each C; or (c) Wi and Xi are each N, Zi and Yi are each C; or (d) W2 and X2 are each N, Z2 and Y2 are each C, then at least one of X5, Xe, and X9 is N and RA! or RA2 is halogen, hydroxy, optionally substituted (Cne alkyl), substituted (Ci-6 alkyl)oxy-, optionally substituted (Ci-6 alkyl)amino-, or optionally substituted (Cne alkyl)(Ci4 alkyi)amino-, wherein Ci 4 alkyl of said optionally substituted (Ci-6 alkyl), or substituted (Ci4alkyl)oxy-is optionally substituted with 1-4 substituents each independently selected from the group comprising hydroxy, C1-4 alkoxyl, -N(Re)(Rf), -CO2(Rf), -CON(Re)(Rf), and -COOH.

[007] In some embodiments, the compound is of Formula (V’), wherein the compound is of Formula (V): R14 (V), or a prodrug, solvate, pharmaceutically acceptable salt, or tautomer thereof.

[008] Unless otherwise defined, 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 disclosure belongs. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present disclosure, suitable methods and materials are described below. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety. In the case of conflict, the present specification, including definitions, will control. In addition, the materials, methods, and examples are illustrative only and are not intended to be limiting.

[009] Other features and advantages of the disclosure will be apparent from the following detailed description and claims. DETAILED DESCRIPTION

[010] It is to be understood that the references herein to compounds of any one or more of Formula (I’), (LA’), (IF), {HF), (IV’), or (V”), and salts thereof covers the compounds of Formula (F), (IA’), (IF), (IIF), (IV’), or (V’), as free bases, or as salts thereof, for example as pharmaceutically acceptable salts thereof. Thus, In some embodiments, the disclosure is directed to compounds of any one or more of Formula (F), (IA’), (IF), (IIF), (IV’), or (V’), as the free base. In some embodiments, the disclosure is directed to compounds of any one or more of Formula (I’), (IA’), (IF), (IIF), (IV’), or (V’), and salts thereof. In some embodiments, the disclosure is directed to compounds of any one or more of Formula (I’), (IA’), (IF), (IIF), (IV’), or (V’), and pharmaceutically acceptable salts thereof. [Oil] The compounds according to any one or more of Formula (I’), (IA’), (IF), (IIF), (IV’), or (V’), or salts, including pharmaceutically acceptable salts, thereof, are modulators of STING. Accordingly, this disclosure provides a compound of any one or more of Formula (I’), (IA’), (IF), (IIF), (TV’), or (V’), or a salt thereof, including a pharmaceutically acceptable salt thereof, for use in therapy. This disclosure provides for the use of a compound of any one or more of Formula (F), (IA’), (IF), (III’), (IV’), or (V’), or a pharmaceutically acceptable salt thereof, as an active therapeutic substance in the treatment of a STING-mediated disease or disorder. In some embodiments, a compound of any one or more of any one or more of Formula (F), (IA’), (IF), (IIF), (IV’), or (V’), or a salt thereof including a pharmaceutically acceptable salt thereof for use in the treatment of a disease mediated by agonism or antagonism of STING. The disclosure also provides a compound of any one or more of Formula (I’), (IA’), (IF), (IIF), (IV’), or (V’), or a salt thereof, including a pharmaceutically acceptable salt thereof, for use in the manufacture of a medicament for the treatment of a STING-mediated disease or disorder.

[012] The disclosure is further directed to a method of modulating STING, which method comprises contacting a cell with a compound according to any one or more of Formula (I’), (IA’), (IF), (III’), (IV’), or (V’), or a salt, including a pharmaceutically acceptable salt, thereof. The disclosure is further directed to a method of treating a STING-mediated disease or disorder which comprises administering a therapeutically effective amount of a compound according to any one or more of Formula (F), (IA’), (IF), (IIF), (IV’), or (V’), or a salt, including a pharmaceutically acceptable salt thereof, to a patient (a human or other mammal) in need thereof. Such STING-mediated diseases or disorders include inflammation, allergic and autoimmune diseases, infectious diseases, cancer, and pre-cancerous syndromes. In addition, modulators of STING may be useful as immunogenic composition or vaccine adjuvants.

[013] The present disclosure is further directed to a pharmaceutical composition comprising a compound according to any one or more of Formula (T), (IA’), (IF), (111’), (IV’), or (V’), or a salt, including a pharmaceutically acceptable salt, thereof and a pharmaceutically acceptable excipient. The disclosure is directed to a pharmaceutical composition for the treatment of a STING-mediated disease or disorder, where the composition comprises a compound according to any one or more of Formula (F), (IA’), (IF), (IIF), (IV’), or (V’), or a salt, including a pharmaceutically acceptable salt, thereof and a pharmaceutically acceptable excipient. Definitions

[014] The chemical names provided for the intermediate compounds and / or the compounds of this disclosure described herein may refer to any one of the tautomeric representations of such compounds (in some instances, such alternate names are provided with the experimental). It is to be understood that any reference to a named compound (an intermediate compound or a compound of the disclosure) or a structurally depicted compound (an intermediate compound or a compound of the disclosure) is intended to encompass all tautomeric forms including zwitterionic forms of such compounds and any mixture thereof.

[015] It is understood that in any one or more of Formula (F), (IA’), (IF), (IIF), (IV’), or (V’), when present, denotes Ring 1 which may be specified according to various embodiments described herein; and V / , when present, denotes Ring 2 which may be specified according to various embodiments described herein.

[016] It is to be understood that the embodiments for a compound of Formula (F), (IA’), (IF), (IIF), (IV’), or (V’), is intended to encompass Formula (F), (IA’), (IF), (111’), (IV’), and (V’) where applicable. [017 ] It is to be understood that the terms “In some embodiments”, “In some embodiments of the present disclosure”, and “In some embodiments of a compound of the present disclosure” may be used interchangeably where appropriate.

[018] The term "alkyl”, as used herein, represents a saturated, straight or branched hydrocarbon group having the specified number of carbon atoms. The term "Ci-4 alkyl" refers to a straight or branched alkyl moiety comprising from 1 to 4 carbon atoms. Exemplary alkyls include, but are not limited to methyl, ethyl, w-propyl, isopropyl, w-butyl, isobutyl, s-butyl, / -butyl, pentyl and hexyl.

[019] When a substituent term such as "alkyl" is used in combination with another substituent term, for example as in "hydroxy(Ci-4 alkyl)", the linking substituent term (e.g., alkyl) is intended to encompass a divalent moiety , wherein the point of attachment is through that linking substituent. Examples of "hydroxy(Ci-4 alkyl)" groups include, but are not limited to, hydroxy methyl, hydroxyethyl, and hydroxyisopropyl.

[020] The term "halo(alkyl)", as used herein, represents a saturated, straight or branched hydrocarbon group having the specified number (n) of carbon atoms and one or more (up to 2n+l) halogen atoms. For example, the term "halo(CM alkyl)" represents a group having one or more halogen atoms, which may be the same or different, at one or more carbon atoms of an alkyl moiety comprising from 1 to 4 carbon atoms. Examples of "halo(CM alkyl)" groups include, but are not limited to, -CF3 (trifluoromethyl), -CCh (trichloromethyl), 1,1 - difluoroethyl, 2,2,2-trifluoroethyl, and hexafluoroisopropyl.

[021] The term "Alkenyl", as used herein, refers to straight or branched hydrocarbon group having the specified number of carbon atoms and at least 1 and up to 3 carbon-carbon double bonds. Examples include ethenyl and propenyl.

[022] The term "Alkynyl", as used herein, refers to straight or branched hydrocarbon group having the specified number of carbon atoms and at least 1 and up to 3 carbon-carbon triple bonds. Examples include ethynyl and propynyl.

[023] The term "Alkoxy-” or "(alkyl)oxy-", as used herein, refers to an "alkyl-oxy-" group, comprising an alkyl moiety, having the specified number of carbon atoms, attached through an oxygen linking atom. For example, the term "Cm alkoxy-" represents a saturated, straight or branched hydrocarbon moiety having at least 1 and up to 4 carbon atoms attached through an oxygen linking atom. Exemplary "Cm alkoxy-" or "(Cm alkyl)oxy-" groups include, but are not limited to, methoxy, ethoxy, w-propoxy, isopropoxy, H-butoxy, s-butoxy, and / -butoxy.

[024] The term "halo(alkoxy)-", as used herein, represents a saturated, straight or branched hydrocarbon group having the specified number (n) of carbon atoms and one or more (up to 2n+l) halogen atoms, attached through an oxygen linking atom. For example, the term "halo(Ci-4 alkoxy)-” refers to a "haloalkyl-oxy-" group, comprising a "halo(Ci-4 alkyl)" moiety attached through an oxygen linking atom. Exemplary "halo(Ci-4 alkoxy)-" groups include, but are not limited to, -OCHF2 (difluoromethoxy), -OCF3 (trifluoromethoxy), -OCH2CF3 (trifluoroethoxy), and -OCH(CF3)2 (hexafluoroisopropoxy).

[025] The term “amino” as used herein refers to a substituent comprising at least one nitrogen atom. Specifically, -NH2, -NH(Ci-4 alkyl), alkylamino, or (C1-4 alkyl)amino- or (C1-4 alkyl)(Ci-4 alkyl)ammo- or dialkylamino, amide-, carbamide-, urea, and sulfamide substituents are included in the term “ammo”.

[026] The term “carbocyclic group or moiety” as used herein, refers to a cyclic group or moiety in which the ring members are carbon atoms, which may be saturated, partially unsaturated (nonaromatic) or fully unsaturated (aromatic).

[027] The term ’’cycloalkyl", as used herein, refers to a non-aromatic, saturated, hydrocarbon ring group comprising the specified number of carbon atoms in the ring. For example, the term "C3-6 cycloalkyl" refers to a cyclic group having from three to six ring carbon atoms. Exemplary "Cue cycloalkyl" groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[028] The term “heterocyclic group or moiety”, as used herein, refers to a cyclic group or moiety having, as ring members, atoms of at least two different elements, which cyclic group or moiety may be saturated, partially unsaturated (non-aromatic) or fully unsaturated (aromatic).

[029] The term "heteroatom", as used herein, refers to a nitrogen, sulfur, or oxygen atom, for example a nitrogen atom or an oxygen atom.

[030] The term "heterocycloalkyl", as used herein, refers to a non-aromatic, monocyclic or bicyclic group comprising 3-10 ring atoms and comprising one or more (generally one or two) heteroatom ring members independently selected from oxygen, sulfur, and nitrogen. The point of attachment of a heterocycloalkyl group may be by any suitable carbon or nitrogen atom. [031 ] Examples of "heterocycloalkyl" groups include, but are not limited to, aziridinyl, thiiranyl, oxiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, 1,3-dioxolanyl, piperidinyl, piperazinyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, 1,3-dioxanyl, 1,4-dioxanyl, 1,3-oxathiolanyl, 1,3-oxathianyl, 1,3-dithianyl, 1,4-oxathiolanyl, 1,4-oxathianyl, 1,4-dithianyl, morpholinyl, thiomorpholinyl, and hexahydro-11,4-diazepinyl.

[032] Examples of "4-membered heterocycloalkyl" groups include oxetanyl, thietanyl and azetidinyl.

[033] The term "5-6 membered heterocycloalkyl", as used herein, refers to a saturated, monocyclic group, comprising 5 or 6 ring atoms, which includes one or two heteroatoms selected independently from oxygen, sulfur, and nitrogen. Illustrative examples of 5-6 membered heterocycloalkyl groups include, but are not limited to pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, piperazinyl, morpholinyl, and thiomorpholinyl.

[034] The term "heteroaryl", as used herein, refers to an aromatic monocyclic or bicyclic group comprising 5 to 10 ring atoms, including 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur, wherein at least a portion of the group is aromatic. For example, this term encompasses bicyclic heterocyclic-aryl groups comprising either a phenyl ring fused to a heterocyclic moiety or a heteroaryl ring moiety fused to a carbocyclic moiety. The point of attachment of a heteroaryl group may be by any suitable carbon or nitrogen atom.

[035] The term "5-6 membered heteroaryl", as used herein refers to an aromatic monocyclic group comprising 5 or 6 ring atoms, including at least one carbon atom and 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur. Selected 5-membered heteroaryl groups contain one nitrogen, oxygen, or sulfur ring heteroatom, and optionally contain 1,2, or 3 additional nitrogen ring atoms. Selected 6-membered heteroaryl groups contain 1, 2, or 3 nitrogen ring heteroatoms. Examples of 5-membered heteroaryl groups include furyl (furanyl), thienyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, isothiazolyl, thiadiazolyl, oxazolyl, isoxazolyl, and oxadiazolyl. Selected 6-membered heteroaryl groups include pyridinyl (pyridyl), pyrazinyl, pyrimidinyl, pyridazinyl and triazinyl.

[036] The term "9-10 membered heteroaryl", as used herein, refers to an aromatic bicyclic group comprising 9 or 10 ring atoms, including 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur. Examples of 9-membered heteroaryl (6,5-fused heteroaryl) groups include benzothienyl, benzofuranyl, indolyl, mdolinyl (dihydroindolyl), isoindolyl, isoindolinyl, indazolyl, isobenzofuryl, 2,3-dihydrobenzofuryl, benzoxazolyl, benzoisoxazolyl, benzothiazolyl, benzoisothiazolyl, benzimidazolyl, benzoxadiazolyl, benzothiadiazolyl, benzotriazolyl, purinyl, imidazopyridinyl, pyrazolopyridinyl, triazolopyridinyl and 1,3-benzodi oxolyl.

[037] Examples of 10-membered heteroaryl (6,6-fused heteroaryl) groups include, but are not limited to, quinolinyl (quinolyl), isoquinolyl, phthalazmyl, naphthridinyl (1,5-naphthyridinyl, 1,6- naphthyridinyl, 1,7- naphthyridinyl, 1,8-naphthyridinyl), quinazolinyl, quinoxalinyl, 4H-quinolizinyl, 1,2,3,4- tetrahydroquinolinyl (tetrahydroquinolinyl), 1,2,3,4-tetrahydroisoquinolinyl (tetrahydroisoquinolinyl), cinnolinyl, pteridinyl, and 2,3-dihydrobenzo[b][l,4]dioxinyl.

[038] The terms "halogen" and "halo”, as used herein, refers to a halogen radical, for example, a fluoro, chloro, bromo, or iodo substituent.

[039] The term "oxo", as used herein, refers to a double-bonded oxygen moiety; for example, if attached directly to a carbon atom forms a carbonyl moiety (C = 0).

[040] The term "hydroxy" or "hydroxyl", as used herein, is intended to mean the radical -OH.

[041] The term "cyano", as used herein, refers to a nitrile group, -C=N.

[042] The term "optionally substituted", as used herein, indicates that a group (such as an alkyl, cycloalkyl, alkoxy, heterocycloalkyl, aryl, or heteroaryl group) or ring or moiety may be unsubstituted, or the group, ring or moiety may be substituted with one or more substituent(s) as defined in the substituent definitions (A, R3, etc,) provided herein. In the case where groups may be selected from a number of alternative groups, the selected groups may be the same or different.

[043] The term "independently", as used herein, means that where more than one substituent is selected from a number of possible substituents, those substituents may be the same or different.

[044] The term "pharmaceutically acceptable", as used herein, refers to those compounds, materials, compositions, and dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, or other problem or complication, commensurate with a. reasonable benefit / risk ratio.

[045] The length of the linking groups defined herein represents the lowest number of atoms in a direct chain composed of -RB1-B-RB2-and / or -RC1-D-RC2-. For example, when B is an optionally-substituted phenyl, the linking group -RB1-B-RB2- may be represented as -(CH2)-phenyl-(CH2)-. This linking group is characterized as a 4-membered linking group when the 2 -(CH2)- moi eties are located on adjacent carbon atoms of the phenyl ring (1,2 substituted phenyl).

[046] In some embodiments, this linking group is characterized as a 6-membered linking group when the 2 -(CH2)- moieties are substituted at para positions on the phenyl ring (1,4 substituted phenyl). It will be understood that any alkyl, alkenyl, or alkynyl group or moiety of B or D is a straight or branch ed-alkyl, alkenyl, or alkynyl group or moiety. For example, a -RB1-B-RB2- linking group, wherein B is -C1-10 alkyl- may contain an 8-membered linking group having a (C1.4 alkyl) branching group or 2-4 (C4.3 alkyl) branching groups, for example, 4 branching methyl groups (2 gem-dimethyl groups) or 2 branching methyl groups.

[047] The terms "compound(s) of the disclosure" or "compound(s) of this disclosure”, as used herein, mean a compound of Formula (I’), Formula (IA’), Formula (IF), Formula (IIF), Formula (IV’), and Formula (V’) as defined herein, in any form, i.e., any tautomeric form, any isomeric form, any salt or non-salt form (e.g., as a free acid or base form, or as a salt, particularly a pharmaceutically acceptable salt thereof) and any physical form thereof (e.g., including non-solid forms (e.g., liquid or semi-solid forms), and solid forms (e.g., amorphous or crystalline forms, specific polymorphic forms, solvate forms, including hydrate forms (e.g., mono-, di- and hemihydrates)), and mixtures of various forms.

[048] Accordingly, included within the present disclosure are the compounds of any one or more of Formula (I’), (IA’), (IF), (III’), (IV’), or (V’), as defined herein, in any salt or non-salt form and any physical form thereof, and mixtures of various forms. While such are included within the present disclosure, it will be understood that the compounds of any one or more of Formula (I’), (IA’), (IF), (IIF), (IV'), or (V’), as defined herein, in any salt or non-salt form, and in any physical form thereof, may have varying levels of activity, different bioavailabilities and different handling properties for formulation purposes. Compound of the Present Disclosure

[049] In some aspects, the present disclosure provides a compound of Formula (IA’) or a prodrug, solvate, pharmaceutically acceptable salt, or tautomer thereof, wherein: Wi. Xi, Yi, Zi, W2, X2, Y2, and Z2 are each independently 0, S, C, or N; X3 and X4 are each independently S or NRf; X5 is N or CRA2; XsisNorCRA!; X9 is N or CR4; r and s are each independently 0 or 1; p is 1 or 2; the total of r and s is 1 or 2; RA1 and RA2 are each independently H, halogen, ammo, amino(Ci-4 alkyl)-, hydroxy, -O-P(O)(OH)2, -0-P(0)(RIRn)2, -N(Re)(Rf), -CO2Rf, -N(Rf)C0Rb, -N(Rg)SO2(Ci-4 alkyl)-N(Re)(Rf), -N(R8)CO(Ci-4 alkyl)-N(Rh)(Rf), optionally substituted (C1-6 alkyl), optionally substituted (C1-6 alkyl)oxy~, optionally substituted (C1-6 alkyl)amino-, and optionally substituted (Ci-6 alkyl)(Ci-4 alkyl)amino-, wherein the (Ci^ alkyl) of said optionally substituted (Ci-6 alkyl), optionally substituted (Ci-6 alkyl)oxy-, optionally substituted (Ci-6 alkyl)amino- and optionally substituted (Cue alkyl)(Ci-4 alkyl)ammo- is optionally substituted by 1-4 substituents each independently selected from hydroxy, -O-P(O)(OH)2, -O~P(O)(RH)?. Ci-4 alkoxy-, -N(Re)(Rf), -CO2(Rf), -C0N(Re)(Rf), optionally substituted phenyl, and optionally substituted 5-6 membered heteroaryl group, wherein said optionally substituted phenyl or 5-6 membered heteroaryl is optionally substituted by 1-4 substituents each independently selected from halogen, hydroxy, -O-P(O)(OH)2, -O-P(O)(RIR1I)2, amino, (Ci-6 alkyl)amino-, (Ci-6 alkyl)(Ci-6 alkyl)amino-, -(Cj-6 alkyl)-NH2, halo(Ci^ alkyl), hydroxy-(Cn4 alkyl)-, -(Cm alkyl)-O-P(O)(OH)2, -(Cm alkyl)-O-P(O)(RIRn)2, halo(Ci-4 alkoxy), Ci-4 alkoxy-, hydroxy-(C2-4 alkoxy)-, -(C2.4 alkoxy)-O-P(O)(OH)2, -(CMalkoxyXO-PiOXR^R11^, -Cj-4 alkyl-(CM alkoxy), and Cn4 alkoxy-(Ci4 alkoxy)-; when r is 0, RB1 and R32 are each independently H, optionally substituted Ci-6 alkyl, halo(Ci-6 alkyl), optionally substituted C2-6 alkenyl, optionally substituted C2.e alkynyl, optionally substituted C3-6 cycloalkyl, optionally substituted 4-6 membered heterocycloalkyl, optionally substituted phenyl, optionally substituted 5-6 membered heteroaryl, or optionally substituted 9-10 membered heteroaryl, wherein said optionally substituted Ci-6 alkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6alkynyl, optionally substituted C3-6 cycloalkyl, optionally substituted 46 membered heterocycloalkyl, optionally substituted phenyl, optionally substituted 5-6 membered heteroaryl, or optionally substituted 9-10 membered heteroaryl is optionally substituted by 1-4 substituents each independently selected from halogen, nitro, -Rc, -OH, -O-P(O)(OH)2, -O-P(O)(RTRn)2 -ORC, -NH2, \R R\ -NRcRd, -OCORC, -CO2H, -CO2RC, -SORC, -SO2RC, -C0NH2, -C0NRcRd, -SO2NH2, -SO2NRcRd, -OCONH2, -OCONRcRd, -NRdC0Rc, -NRdSORc, -NRdC02Rc, and -NRdSO2Rc; when s is 0, R° is absent, H, halogen, or C1-4 alkyl and RC2 is absent or optionally substituted C1-4 alkyl, wherein said optionally substituted C1-4 alkyl group is optionally substituted by a substituent selected from -ORC, -NRcRd, -CO2RC, ~C0NRcRd, -SO2NRcRd, and -OCONRcRd; when r is 1, RBl and RB2 are each independently -CH2-, and B, taken together with RB1 and RB2, forms a linking group, wherein B is a bond or B is -halo(Ci-w alkyl)-, optionally substituted -C1-10alkyl-, optionally substituted -C2-10 alkenyl-, optionally substituted -C2-ioalkynyl-, optionally substituted -C1-6 alkyl-O-Ci-6 alkyl-, optionally substituted -C1-6 alkyl-NRa-Ci-6 alkyl, optionally substituted C3-6 cycloalkyl, optionally substituted phenyl, optionally substituted 4-6 membered heterocycloalkyl, optionally substituted 5-6 membered heteroaryl, optionally substituted -Cm alkyl-(C3-6 cycloalkyl)-Cn4 alkyl-, optionally substituted -Cm alkyl-phenyl-Cj-4 alkyl-, optionally substituted -Cm alkyl-(4-6 membered heterocycloalkyl)-Ci-4 alkyl-, or optionally substituted -Cm alkyl-(5-6 membered heteroaryl)-CM alkyl-, wherein the alkyl moiety of said optionally substituted -C1-10 alkyl-, optionally substituted -C2-10 alkenyl-, optionally substituted -C2-10 alkynyl-, optionally substituted -C1-6 alkyl-O-Cj-6 alkyl-, optionally substituted -Cm alkyl-NRa-Ci-6 alkyl-, optionally substituted -Cm alkyl-(C3-6 cycloalkyl)-CM alkyl-, optionally substituted -Cm alkyl-phenyl-CM alkyl-, optionally substituted -Cm alkyl-(4-6 membered heterocycloalkyl)-CM alkyl-, or optionally substituted -Cm alkyl-(5-6 membered heteroaryl-Ci-4 alkyl)- is optionally substituted by 1 or 2 substituents each independently selected from halogen, halo(Ci-4 alkyl), -OH, -O-P(O)(OH)2, -O-P(O)(R1RIi)2, -ORC, -NH2, -NR'Rd -OCORe, (OdI, -CO2RC, -S()RC, -SO2RC, -C0NH2, -CONRcRd, -SO2NH2, -SO2NRcRd, -0C0NH2, -OCONRcRd -NRdC0Re, -NRdSORc, -NRdC02Rc, and -NRdSO2Rc, and the C3-6 cycloalkyl, phenyl, 4-6 membered heterocycloalkyl, or 5-6 membered heteroaryl moiety of said optionally substituted C3-6 cycloalkyl, optionally substituted phenyl, optionally substituted 4-6 membered heterocycloalkyl, optionally substituted 5-6 membered heteroaryl, optionally substituted -Ci-4 alkyl-(C3-6 cycloalkyl)-CM alkyl-, optionally substituted -Cm alkylphenyl-Ci-4 alkyl-, optionally substituted -Cm alkyl-(4-6 membered heterocycloalkyl)-Ci-4 alkyl, or optionally substituted -Cm alkyl-(5-6 membered heteroaryl)-Ci-4 alkyl- is optionally substituted by 1-4 substituents each independently selected from halogen, hydroxy, -O-P(O)(OH)2, -O-P(O)(ORIRII)2, amino, (Cm aikyl)amino-, (Cm alkyl)(Ci-4 alkyl)ammo~, Cm alkyl, halo(Ci-4 alkyl), halo(Ci-4 alkoxy)-, Cm alkoxy-, hydroxy-(C2-4 alkoxy)-, -(C2-4 alkoxy)-O-P(O)(OH)2, -(C2-4 alkoxy)-O-P(O)(RIRI1)2, and Cm alkoxy-(Ci-4 alkoxy)-; when s is 1, Wi and Z2 are each independently C or N, RCI and RC2 are each independently -CH2-, and D taken together with RC1 and RC2, forms a linking group, wherein D is -halo(Ci-i2 alkyl)-, optionally substituted -Cni2 alkyl-, optionally substituted -C2-12 alkenyl-, optionally substituted -C2-12 alkynyl-, optionally substituted -Cm alkyl-O-Ci-6 alkyl-, optionally substituted -Cm alkyl-NRa-Ci-6 alkyl-, optionally substituted -C1-6 alkyl-(C3-6 cycloalkyl)-Ci-6 alkyl-, optionally substituted -C1-6 alkyl-phenyl-C 1-6 alkyl-, optionally substituted -Cm alkyl-(4-6 membered heterocycloalkyl)-CM alkyl-, or optionally substituted -Cm alkyl-(5-6 membered heteroaryl)-Ci-6 alkyl-, wherein the alkyl moiety of said optionally substituted -C1-12 alkyl-, optionally substituted -Cm alkenyl-, optionally substituted -C2-12 alkynyl-, optionally substituted -Cm alkyl-O-Ci-6 alkyl, optionally substituted -Cm alkyl-NRa-CM alkyl-, optionally substituted -Cm alkyl-(C3-6 cycloalkyl)-CM alkyl-, optionally substituted -Cm, alkyl-phenyl-CM alkyl-, optionally substituted -Cm alkyl-(4-6 membered heterocycloalkyl)-CM alkyl-, or optionally substituted -Cm, alkyl-(5-6 membered heteroaryl)Cj-6 alkyl- is optionally substituted by 1 or 2 substituents each independently-selected from halogen, halo(Ci.4 alkyl), -OH, -O-P(O)(OH)2, -O-P(O)(R1Rn)2, -ORC, -NH2, -NRcRd, -OCORC, -CO2H, -CO2Rc, -SORC, -SO2Rc, -CONH2, -C()NRcRd, -SO2NH2, -SO2NRcRd, -OCONH2, -OCONRcRd, -NRdC0Rc, -NRdSORe, -NRdC02Rc, and -NRdSO2Rc, and the C3-6 cycloalkyl, phenyl, 4-6 membered heterocycloalkyl, or 5-6 membered heteroaryl moiety of said optionally substituted -Cm alkyl-(C3-6 cycloalkyl)-CM alkyl-, optionally substituted -Cm alkyl-phenyl-Ci-6 alkyl-, optionally substituted -Cm alkyl-(4-6 membered heterocycloalkyl)-Cm alkyl-, or optionally substituted -Cm alkyl-(5-6 membered heteroaryl)-Ci-6 alkyl- is optionally substituted by 1-4 substituents each independently selected from halogen, hydroxy, -O-P(O)(OH)2, 0-P(0)(RiR1I)2, ammo, (Cm alkyl)amino-, (Cm alkyl)(Ci-4 alkyl)ammo-, Cm alkyl, halo(Ci-4 alkyl), halo(Ci-4 alkoxy)-, Cm alkoxy-, hydroxy-(C2-4 alkoxy)-, -(C24 alkoxy)-O-P(O)(OH)2, -(C2-4 alkoxy )-O-P(O)(RTRT1)2, and Cm alkoxy-(CM alkoxy)-; R3 and R5 are each independently -CON(Rd)(Rf), -CibMIHdC). -N(Rd)(Rf), -N(R^COiR1), -CH2N(Rd)CO(Rf), or one of R3 and R5 is -CON(Rd)(Rf), -CH2N(Rd)(Rf), -M Rd){ R1). -N(Rd)CO(Rf), or -CH2N(Rd)CO(Rf), and the other of R3 and R3 is H, COOH, or -CO2RC; R4 and R6 are each independently selected from H, halogen, halo(Ci-6 alkyl), halo(Ci-6 alkoxy)-, hydroxy, -O-P(O)(OH)2, O-P(O)(RIRII)2, -NH2, -NRCRC, -NRcRd, -CORC, -CO2RC, -N(Rd)CORc, -N(Rd)SO2Rc, -N(Rg)SO2(Cn2 alkyl)-N(Rh)(Rf), -N(Rg)CO(Ci-2 alkyl)-N(Rh)(Rf), optionally substituted (Cue alkyl), optionally substituted (C1-6 alkyl)oxy-, optionally substituted (Cue alkyl)amino-, and optionally substituted (Cue alkyl)(Ci-4 alkyl)ammo-, wherein the (Cm alkyl) of said optionally substituted (C1-6 alkyl), optionally substituted (Cm alkyl)oxy-, optionally substituted (Cm alkyljammo- and optionally substituted (Cw alkyl)(Ci-4 alkyl)amino- is optionally substituted by 1-4 substituents each independently selected from -OH, -O-P(O)(OH)2, -O-P(O)(RIRII)2, -ORC, -NH2, -NRCRC, -NRcRd, -CO2H, -CO2RC, -OCORC, -CO2H, -CO2Rc, -SORc, -SO2Rc -COMIx -CONRcRd, -SO2NH2, -SO2NRcRd, -OCONH2, -OCONRcRd, -NRdCORc, -NRdSORc, -NRdCO2Rc, -NRdSO?.Rc, optionally substituted phenyl, optionally substituted 5-6 membered heterocycloalkyl, and optionally substituted 5-6 membered heteroaryl group, wherein said optionally substituted phenyl, 5-6 membered heterocycloalkyl, or 5-6 membered heteroaryl is optionally substituted by 1 -4 substituents each independently selected from halogen, hydroxy, -O-P(O)(OH)2, -O-P(O)(RIRI1)2, amino, (C1-4 alkyl)amino-, (C1.4 alkyl)(CM alkyl)amino-, C1-4 alkyl, halo(Cj-4 alkyl), hydroxy-(Cj-4 alkyl)-, -(C1.4 alkyl)-O-P(O)(OH)2, -(C1-4 alkyl)-O-P(O)(RIR!l)2, halo(Cj-4 alkoxy)-, Cm alkoxy-, hydroxy-(C2-4alkoxy)-, -(Cm alkoxy)-O-P(O)(OH)2, -(Cm alkoxy)-O-P(O)(RIRiI)2, Cm alkoxy-(CM alkoxy)-, -CORd, -CON(Rd)(Rf), and -CO2Rd R14 is absent, H, halogen, or optionally substituted Cm alkyl, wherein said optionally substituted Cm alkyl is optionally substituted by a substituent selected from halogen, -ORC, -NRcRd, -CO2RC, -CONRcRd, -SO2NRcRd, and -OCONRcRd; Rlb is absent, H, halogen, or Cm alkyl; Ri5 and RiZ are each independently absent, H, cyclopropyl, halogen or optionally substituted Cm alkyl, wherein said optionally substituted Cm alkyl is optionally substituted by a substituent selected from halogen, -ORC, -NRcRd, -COiR', -CONRcRd, -SO2NRcRd, and -OCONRcRd; or Rl3 and R19 taken together with the atom or atoms through which they are connected, form a 5-6 membered ring; or Rl0 and Rl' taken together with the atom or atoms through which they are connected, form a 5-6 membered ring; Ri8 and R19 are each independently absent, H, halogen, optionally substituted Cm alkyl, wherein said optionally substituted C1-4 alkyl is optionally substituted by a substituent selected from halogen, -ORC, -NRcRd, -CO2Rc, -CONRcRd, -SO2NRcRd, and -OCONRcRd; or Ri7 and R1S taken together with the atom or atoms through which they are connected, form a 5-6 membered ring; Ra is H, -Rc, -CORC, -CO2H, -CO2Rc, -SORc, -SO2Rc -CONH2, -CONRcRd, -SO2NH2, -( H'-CO-R\ or -SO2NRcRd; each R° is independently Cm alkyl, halo(Ci-4 alkyl), -(Cm alkyl)-OH, -(C1-4 alkyl)-O-P(O)(OH)2, -(Cm alkyi)-()-lh())(^ -(Cm alkyl)-O-(CM alkyl), -(Ci-4 alkyl)-N(Re)(Rf), -(Cn 4 alkyl)-O-CO(Ci-4 alkyl), or -(C1-4 alkyl)-CO-O-(Ci-4 alkyl); each Rc is independently H, C1-4 alkyl, halo(Ci-4 alkyl), -(Cm alkyl)-OH, -(C1-4 alkyl)-O-P(O)(OH)2, -(Cm alkyl)-O-P(O)(RIRn)2, -(Cm alkyl)-O-(Ci-4 alkyl), -(Cm alkyl)-N(Re)(Rf), -(Cn 4 alkyl)-O-CO(Ci-4 alkyl), -(Cm alkyl)-CO-O-(Ci-4 alkyl), optionally substituted C3-6 cycloalkyl, optionally substituted phenyl, optionally substituted 4-6 membered heterocycloalkyl, optionally substituted 5-6 membered heteroaryl, optionally substituted 9-10 membered heteroaryl, optionally substituted -Cm alkyl-Cs-e cycloalkyl, optionally substituted -Ci-4 alkyl-phenyl, optionally-substituted -C1-4 alkyl-4-6 membered heterocycloalkyl, optionally substituted -Ci-4 alkyl-5-6 membered heteroaryl, or optionally substituted -Cm alkyl-9-10 membered heteroaryl, wherein the C3-6 cycloalkyl, phenyl, 4-6 membered heterocycloalkyl, 5-6 membered heteroaryl or 9-10 membered heteroaryl moiety of said optionally substituted C3-6 cycloalkyl, optionally substituted phenyl, optionally substituted 4-6 membered heterocycloalkyl, optionally substituted 5-6 membered heteroaryl, optionally substituted 9-10 membered heteroaryl, optionally substituted -Cm alkyl-C3-6 cycloalkyl, optionally substituted -Cm alkyl-phenyl, optionally substituted -Cm alkyl-4-6 membered heterocycloalkyl, optionally substituted -Cm alkyl-5-6 membered heteroaryl, or optionally substituted -Cm alkyl-9-10 membered heteroaryl is optionally substituted by 1-4 substituents each independently selected from halogen, hydroxy, -O-P(O)(OH)2, -O-P(O)(RiR1I)2, amino, (Cm alkyl)amino-, (Cm alkyl)(CM alkyl)amino-, Cm alkyl, halo(Ci-4 alkyl), halo(Ci-4 alkoxy)-, Cm alkoxy-, hydroxy-(C2-4 alkoxy)-, -(C2-4 alkoxy)-O-P(O)(OH)2, -(C2. 4 alkoxy )-O-P(O)(RTRn)2, C1.4 alkoxy-(CM alkoxy)-, -CORd, -CON(Rd)(Rf), and -CO2Rd; each Rd is independently H, hydroxy, or C1.4 alkyl; each Re is independently H, (C1-4 alkyl), -CO(Ci-4 alkyl), -OCO(Cm alkyl), -CO2(Ci-4 alkyl), -(Cm alkyl)amino, -(Cm alkyl)-Ci-4 alkoxy, -CO-(optionally substituted 5-6 membered heterocycloalkyl), -CO-(Ci-4 alkyl)-(optionally substituted 5-6 membered heterocycloalkyl), -CO-(optionally substituted 5-6 membered heteroaryl), -C0-(Cm alkyl)-(optionally substituted 5-6 membered heteroaryl), wherein the optionally substituted 5-6 membered heterocycloalkyl or optionally substituted 5-6 membered heteroaryl is optionally substituted by 1-4 substituents each independently selected from halogen, hydroxy, -O-P(O)(OH)2, -O~P(O)(R1RII)2, amino, (C1-4 alkyl)ammo-, (Cm alkyl)(Ci-4 alkyl)ammo-, C1-4 alkyl, halo(Ci-4 alkyl), halo(Ci-4 alkoxy)-, C1-4 alkoxy-, hydroxy-(C2-4 alkoxy)-, -(C2-4 alkoxy) O-P(O)(OH)2, -(C2^ alkoxy)-O-P(O)(R1RII)2, Cm alkoxy-(Ci-4 alkoxy)-, -CORd, -CON(Rd)(Rf), and -CO2Rd; each Rf is independently H, hydroxy, or (Cm alkyl); R8 and Rn are each independently H or (Cm alkyl) or Rg and Rh, taken together with the atom or atoms through which they are connected, form a 5-6 membered ring; and each R1 and Rn are independently (Cm alkyl)oxy-; provided that at least one of (i), (ii), or (Hi), applies: (1) when s is 0, r is 1, (a) Zi, Z2, Yj and Y2 are each N, Wi, W2, Xj and X2 are each C; or (b) Wi, W2, Xi and X2 are each N, Zi, Z2, Yj and Y2 are each C; or (c) Zj and Yi are each N, Wi and Xj are each C; or (d) Z2 and Y2 are each N, W2 and X2 are each C; or (e) Wj and Xi are each N, Zi and Yj are each C; or (f) W2 and X2 are each N, Z2 and Y2 are each C, then at least one of X3 and X4 is S or X9 is N; or (ii) when s is 0, r is 1, (a) Zj, Z2, Yi and Y2 are each N, Wi, W2, Xj and X2 are each C; or (b) Wi, W2, Xi and X2 are each N, Zi, Z2, Yi and Y2 are each C, then R34 is a Cm alkyl substituted with halogen, -ORC, -NR°Rd, -CO2RC, -CONRcRd, -SO2NRcRd, and -OCONRcRd wherein Rc is H; or (iii) when s is 0, r is 1, (a) Zi and Yi are each N, Wi and Xi are each C; or (b) Z2 and Y2 are each N, W2 and X2 are each C; or (c) Wi and Xi are each N, Zi and Yi are each C; or (d) W2 and X2 are each N, Z2 and Y2 are each C, then at least one of X5, Xe, and X9 is N and RAj or RA2 is halogen, hydroxy, optionally substituted (Ci-6 alkyl), substituted (Cue alkyl)oxy-, optionally-substituted (Ci-6 alkyl)amino-, or optionally substituted (Ci-6 alkyl)(Ci4 alkyl)amino-, wherein the (Cue alkyl) of said optionally substituted (Ci^ alkyl), substituted (Cue alkyl)oxy-, optionally7 substituted (Ci-6 alkyl)amino-, or optionally substituted (Ci-6 alkyl)(Ci-4 alkyl)ammo- is optionally substituted by 1-4 substituents each independently7 selected from hydroxy, -O-P(O)(OH)2, -O-P(O)(RTRn)2, -N(Re)(Rf), -CO2(Rf), -CON(Re)(Rf), optionally substituted phenyl, and optionally substituted 5-6 membered heteroaryl group, wherein said optionally substituted phenyl or 5-6 membered heteroaryl is optionally substituted by 1-4 substituents each independently selected from halogen, hydroxy, -O-P(O)(OH)2, -O-P(O)(R1Rn)2, amino, (Ci-6 alkyl)amino-, (Cue alkyl)(Ci-6 alkyl)amino-, -(Ci-6 alkyl)-NH2, halo(Ci-e alkyl), hydroxy~(Ci-4 alkyl)-, -(C1-4 alkyl)-O-P(O)(OH)2, -(C1-4 alkyl)-O-P(O)(R!R1I)2, halo(Ci-4 alkoxy), Ci-4 alkoxy-, hydroxy-(C2-4 alkoxy)-, -(C2-4 alkoxy)-O-P(O)(OH)2, -(CMalkoxy^-O-P^XR^11)}, -Ci-4 alkyl-(Ci-4 alkoxy), and Ci-4 arkoxy-iCiv alkoxy)-.

[050] In some embodiments, the compound is of Formula (IA’), wherein the compound is Formula (IA): Ru or a prodrug, solvate, pharmaceutically acceptable salt, or tautomer thereof..

[051] In some aspects, the present disclosure provides a compound of Formula (I’) R14 or a prodrug, solvate, pharmaceutically acceptable salt, or tautomer thereof, wherein: Wi, Xi, Yi, Zi, W2, X2, Y2, Z2, r, s, X3, X4, X5, X6, X9., R3, R5, Rf4, R\ Rb, Rc, Rd, Re, Rf, R1 and RI! are each independently as defined for Formula (IA’); when r is 0, RB! and R32 are each independently as defined for Formula (IA’); when s is 0, RC! is as defined for Formula (IA’); when r is 1, RB1 and RB2 are each independently -CH2-, and B, taken together with RB! and RB2, forms a linking group, wherein B is a bond or B is as defined for Formula (IA’); when s is 1, Wi and Z2 are each independently C or N, RC1 and RCz are each independently -CH2-, and D taken together with Rcl and RC2, forms a linking group, wherein D is as defined for Formula (IA’); R!6 is absent, H, halogen, or Ci-4 alkyl; R15 and R1'' are each independently absent, H, cyclopropyl, halogen or optionally substituted Cj-4 alkyl, wherein said optionally substituted Ct-4 alkyl is optionally substituted by a substituent selected from halogen, -ORC, -NRcRd, -CO2RC, -CONRcRd, -SO2NRcRd, and -OCONRcRd; or R13 and R19 taken together with the atom or atoms through which they are connected, form a 5-6 membered ring; R18 and R19 are each independently as defined for Formula (IA’); or R1' and R18 taken together with the atom or atoms through which they are connected, form a 5-6 membered ring; R8 and Rh are each independently as defined for Formula (IA’)or R8 and Rh, taken together with the atom or atoms through which they are connected, form a 5-6 membered ring; and provided that at least one of (i), (ii), or (iii) of Formula (IA’) applies.

[052] In some aspects, the present disclosure provides a compound of Formula (I’) or a prodrug, solvate, pharmaceutically acceptable salt, or tautomer thereof, provided that at least one of (i), (ii), or (iii) applies: (i) when s is 0, r is 1, (a) Zi, Z2, Yi and Y2 are each N, Wi, W2, Xi and X2 are each C; or (b) Wi, W2, Xi and X2 are each N, Zi, Z2, Yi and Y2 are each C; or (c) Zi and Yi are each N, Wi and Xi are each C; or (d) Z2 and Y2 are each N, W2 and X2 are each C; or (e) Wi and Xi are each N, Zi and Yi are each C; or (f) W2 and X2 are each N, Z2 and Y2 are each C, then at least one of X3 and X4 is S; or X9 is N; or (ii) when s is 0, r is 1, (a) Zi, Z2, Yi and Y2 are each N, Wi, W2, Xi and X2 are each C; or (b) Wi, W2, Xi and X2 are each N, Zi, Z2, Yi and Y2 are each C, then R14 is a Cm alkyl substituted with halogen, -ORC, -NRcRd, -CO2RC, -CONRcRd, -SO2NRcRd, and -OCONRcRd wherein Rc is H; or (iii) when s is 0, r is 1, (a) Zi and Yi are each N, Wi and Xi are each C; or (b) Z2 and y2 are each N, W2 and X2 are each C; or (c) Wi and Xi are each N, Zi and Yi are each C; or (d) W2 and X2 are each N, Z2 and Y2 are each C, then at least one of X5, Xe, and X9 is N and RA1 or RAz is hydroxy, substituted (C1-6 alkyl), substituted (C1-6 alkyl)oxy-, optionally substituted (C1-6 alkyl)amino-, and optionally substituted (Cue alkyl)(Ct-4 alkyljammo-, wherein the (C1-6 alkyl) of said substituted (C1-6 alkyl) and substituted (Ci-6 alkyl)oxy- is substituted by 1-4 substituents each independently selected from -O-P(O)(OH)2, -O-P(O)(RIRIi)2, - optionally substituted phenyl, and optionally substituted 5-6 membered heteroaryl group, wherein said optionally substituted phenyl or 5-6 membered heteroaryl is optionally substituted by 1-4 substituents each independently selected from halogen, hydroxy, -O-P(O)(OH)2, -O-P(O)(RIR1I)2, amino, (C1-6 alkyl)amino-, (C1-6 alkyl)(Ci-6 alkyl)amino-, -(Cj-6 alkyl)-NH2, halo(Ci^ alkyl), hydroxy-(CM alkyl)-, -(Cm alkyl)-O-P(O)(OH)2, -(Cn4 alkyl)-O-P(O)(RiRu)2, halo(Cu4 alkoxy), C1.4 alkoxy-, hydroxy-(C24 alkoxy)-, -(C2-4 alkoxy)-O-P(O)(OH)2, -(C2-4 alkoxy^O-P^XRW1^, -C1-4 alkyl-(Ci-4 alkoxy), and Ci-4 alkoxy-(Ci-4 alkoxy)-; and the (Ci^ alkyl) of said optionally substituted (C1-6 alkyl)amino- and optionally substituted (C1-6 alkyl)(Ci-4 alkyl)ammo- is optionally substituted by 1-4 substituents each independently selected from hydroxy, -O-P(O)(OH)2, -O-P(O)(RIRII)2, -N(Re)(Rt), -CO2(Rf), -CON(Re)(RI), optionally substituted phenyl, and optionally substituted 5-6 membered heteroaryl group, wherein said optionally substituted phenyl or 5-6 membered heteroaryl is optionally substituted by 1-4 substituents each independently selected from halogen, hydroxy, -O-P( O)(OH)2, -O-P(O)(RtRti)2, ammo, (Ci-6 alkyl)amino-, (Cue alkyl)(CM alkyl)ammo-, -(Ci-6 alkyl)-NH2, halo(Ci-6 alkyl), hydroxy-(Ci-4 alkyl)-, -(Ci-4 alkyl)-O-P(O)(OH)2, -(Ci-4 alkyl)-O-P(O)(RTRn)2, halo(Ci-4 alkoxy)-, C1.4 alkoxy-, hydroxy-(C2-4 alkoxy)-, -(C2-4 alkoxy)-O-P(O)(OH)2, -(€’2-4 alkoxy)-O-P(O)(R1R!1)2, -Cm alkyl-(Ci-4 alkoxy), and Cm alkoxy-(Ci-4 alkoxy)-.

[053] In some embodiments, the compound is of Formula (F), wherein the compound is Formula (I): or a prodrug, solvate, pharmaceutically acceptable salt, or tautomer thereof, wherein: W2, X2, Y2, Z2, r, s, X3, X4, X5, X6, XoR3, R4, R5, R6, Ra, Rb, Rc, Rd, Re, Rf, R1 and Rn are each independently as defined in Formula (IA’); when r is 0, RBj and RB2 are each independently as defined in Formula (IA’); when s is 0, RCi is as defined in Formula (IA’); when r is 1, RBt and RB2 are each independently -CH2-, and B, taken together with RB1 and R62, forms a linking group, wherein B is a bond or B is as defined in Formula (IA’); when s is 1, Z2 is C or N, RC1 and RC2 are each independently -CH2-, and D taken together with RCi and Ru, forms a linking group, wherein D is as defined in Formula (IA’); R16 is absent, H, halogen, or C1-4 alkyl; R1'' is absent, H, cyclopropyl, halogen or optionally substituted C1-4 alkyl, wherein said optionally substituted C1-4 alkyl is optionally substituted by a substituent selected from halogen, -ORC, -NRcRd, -CO2Rc, -CONRcRd, -SO2NRcRd, and -OCONRcRd; R18 is absent, H, halogen, optionally substituted Cm alkyl, wherein said optionally substituted Cm alkyl is optionally substituted by a substituent selected from halogen, -ORC, -NRcRd, -CO2RC, ~CONRcRd, -SO2NRcRd, and ~OCONRcRd; or R17 and R18 taken together with the atom or atoms through which they are connected, form a 5-6 membered ring; R19 is absent, H, halogen, optionally substituted Cm alkyl, wherein said optionally substituted Cm alkyl is optionally substituted by a substituent selected from halogen, -ORC, -NRcRd, -CO2RC, -CONRcRd, -SO2NRcRd, and -OCONRcRd; and Rg and Rn are each independently as defined in Formula (IA’)or Re and Rh, taken together with the atom or atoms through which they are connected, form a 5-6 membered ring.

[055] In some aspects, the present disclosure provides a compound of Formula (IF), or a prodrug, solvate, pharmaceutically acceptable salt, or tautomer thereof provided that when s is 0, r is 1, (a) Z2 and Y2 are each N, W2 and X2 are each C; or (b) W2 and X2 are each N, Z2 and Y2 are each C, then at least one of X5, Xe, and X9 is N and RA1 or R'v? is hydroxy, substituted (Cm alkyl), substituted (Cm alkyl)oxy-, optionally substituted (Cm alkyDammo-, and optionally substituted (Cm alkyl)(Ci-4 alkyl)amino-, wherein the (Cm alkyl) of said substituted (Cm alkyl) and substituted (Cm alkyl)oxy-, is optionally substituted by 1-4 substituents each independently selected from -O-P(O)(OH)2, -O-P(O)(RIRI1)2, - optionally substituted phenyl, and optionally substituted 5-6 membered heteroaryl group, wherein said optionally substituted phenyl or 5-6 membered heteroaryl is optionally substituted by 1-4 substituents each independently selected from halogen, hydroxy, -O-P( 0)(01¾ -O-P(O)(RtRti)2, ammo, (Ci-6 alkyl)amino-, (Cue alkyl)(CM alkyl)ammo-, -(Ci-6 alkyl)-NH2, halo(Ci-6 alkyl), hydroxy-(Ci-4 alkyl)-, -(Ci-4 alkyl)-O-P(O)(OH)2, -(Ci-4 alkyl)-O-P(O)(RTRn)2, halo(Ci-4 alkoxy)-, C1.4 alkoxy-, hydroxy-(C2-4 alkoxy)-, -(C2-4 alkoxy)-O-P(O)(OH)2, -(€’2-4 alkoxy)-O-P(O)(R1R!1)2, -Cm alkyl-(Ci-4 alkoxy), and Cm alkoxy-(Ci-4 alkoxy)-; and the (Cue alkyl) of said optionally substituted (Ci-6 alkyl)ammo~ and optionally substituted (Cm alkyl)(Ci-4 alkyl)ammo- is optionally substituted by 1-4 substituents each independently selected from hydroxy, -O-P(O)(OH)2, -O-P(O)(RIR1!)2, -N(Re)(Rf), -CO2(Rf), -CON(Re)(Rr), optionally substituted phenyl, and optionally substituted 5-6 membered heteroaryl group, wherein said optionally substituted phenyl or 5-6 membered heteroaryl is optionally substituted by 1-4 substituents each independently selected from halogen, hydroxy, -O-P(O)(OH)2, -O-P(O)(RiR1I)2, amino, (Ci-6 alkyl)amino-, (Cm alkyl)(CM alkyl)amino-, -(Cm alkyl)-NH2, halo(Ci-6 alkyl), hydroxy-(Ci-4 alkyl)-, -(Cm alkyl)-O-P(O)(OH)2, -(Cm alkyl)-O-P(O)(RIRI1)2, halo(Ci-4 alkoxy)-, Cm alkoxy-, hydroxy-(C2-4 alkoxy)-, -(C2-4 alkoxy)-O-P(O)(OH)2, -(C2-4 alkoxy)-O-P(O)(RIR11)2, -Cm alkyl-(Ci-4 alkoxy), and Cm alkoxy-(Ci-4 alkoxy)-.

[056] In some embodiments, the compound is of Formula (IF), wherein the compound is Formula (II): or a prodrug, solvate, pharmaceutically acceptable salt, or tautomer thereof.

[057] In some aspects, the present disclosure provides a compound of Formula (IIP) or a prodrug, solvate, pharmaceutically acceptable salt, or tautomer thereof, wherein: Wi, Xi, Yi, Zi, W2, X2, ¥2, Z2, s, X3, X4, X5, X6, X9. R3, R4 R5, R6, RJ4, Ra, Rb, Rc, Rd, Re, Rf, R1, and R11 are each independently as defined in Formula (IA’); when s is 0, RCl is as defined in Formula (IA’); when s is 1, Wi and Z2 are each independently C or N, RC1 and RC2 are each independently -CH2-, and D taken together with RC1 and RCz, forms a linking group, wherein D is as defined in Formula (IA’); R16 is absent, H, halogen, or C1-4 alkyl; R!3 and Rl / are each independently absent, H, cyclopropyl, halogen or optionally substituted C1-4 alkyl, wherein said optionally substituted C1-4 alkyl is optionally substituted by a substituent selected from halogen, -ORC, -NRcRd, -CO2RC, -CONRcRd, -SO2NRcRd, and -OCONRcRd; or R15 and R19 taken together with the atom or atoms through which they are connected, form a 5-6 membered ring; R18 and R19 are each independently as defined herein; or R1-' and R18 taken together with the atom or atoms through which they are connected, form a 5-6 membered ring; and Rg and Rh are each independently as defined in Formula (IA’)or Rg and Rn, taken together with the atom or atoms through which they are connected, form a 5-6 membered ring; and provided that at least one of (i), (ii), or (in) applies: (i) when (a) Zi, Z2, Yi and Y2 are each N, Wi, W2, Xi and X2 are each C; or (b) Wi, W2, Xi and X2 are each N, Zi, Z2, Yj and Y2 are each C; or (c) Zj and Yi are each N, Wi and Xi are each C; or (d) Z2 and Y2 are each N, W2 and X2 are each C; or (e) Wi and Xi are each N, Zi and Yi are each C; or (f) W2 and X2 are each N, Z2 and Y2 are each C, then at least one of X3 and X4 is S; or X9 is N; or (ii) when s is 0, (a) Zi, Z2, Yi and Y2 are each N, Wi, W2, Xi and X2 are each C; or (b) Wi, W2, Xi and X2 are each N, Zi, Z2, Yi and Y2 are each C, then R14 is a C1-4 alkyl substituted with halogen, -ORC, -NRcRd, -CO2RC, ~CONRcRd, -SO2NRcRd, and -OCONRcRd wherein Rc is H; or (iii) when s is 0, (a) Zi and Yi are each N, Wi and Xi are each C; or (b) Z2 and Y2 are each N, W2 and X2 are each C; or (c) Wi and Xi are each N, Zi and Yi are each C; or (d) W2 and X2 are each N, Z2 and Y2 are each C, then at least one of X5, Xe, and Xy is N and RAi or RA2 is halogen, hydroxy, optionally substituted (C1-6 alkyl), substituted (Cue alkyl)oxy-, optionally substituted (Ci-6 alkyl)amino-, or optionally substituted (Cue alkyl)(Ci-4 alkyl)amino-, wherein the (C1-6 alkyl) of said optionally substituted (C1-6 alkyl), substituted (Ci-6 alkyl)oxy-, optionally substituted (Ci-6 alkyl)amino-, or optionally substituted (Ci-6 alkyl)(Ci-4 alkyl)amino- is optionally substituted by 1-4 substituents each independently selected from hydroxy, -O-P(O)(OH)2, -O-P(O)(RIR1I)2, -N(Re)(RI), -CO2(Rf), -CON(Re)(Rf), optionally substituted phenyl, and optionally substituted 5-6 membered heteroaryl group, wherein said optionally substituted phenyl, or 5-6 membered heteroaryl is optionally substituted by 1-4 substituents each independently selected from halogen, hydroxy, -O-P(O)(OH)2, -O-P(O)(RiRn)2, amino, (Cu6alkyl)amino~, (Ci-6alkyl)(Ci-6 alkyl)amino-, -(Ci-6 alkyl)~NH2, halo(Ci-6 alkyl), hydroxy-(Ci-4 alkyl)-, -(C1-4 alkyl)-O-P(O)(OH)2, -(C1-4 alkyl)-O-P(O)(RIRn)2, halo(Cj-4 alkoxy)-, C4-4 alkoxy-, hydroxy-(C2-4 alkoxy)-, -(C2-4 alkoxy)-O-P(O)(OH)2, -(C2-4alkoxy)-O-P(O)(R!Rn)2, -C1.4 alkyl-(Ci-4 alkoxy), and C1-4 alkoxy-(Ci-4 alkoxy)-

[058] In some embodiments, the compound is of Formula (IIF), wherein the compound is Formula (III): R14 or a prodrug, solvate, pharmaceutically acceptable salt, or tautomer thereof.

[059] In some aspects, the present disclosure provides a compound of Formula (IV’) R14 or a prodrug, solvate, pharmaceutically acceptable salt, or tautomer thereof, wherein: Wi, Xi, Yi, Zi, W2, X2, Y2, Z2, r, s, X3, X4,X5, X6, X9. R3, R4 R5, R6,R14, R18, R19, Ra, Rb, Rc, Rd, Re, Rf, R1, and Rn are each independently when r is 0, RB1 and RBz are each independently as defined in Formula (IA’); when s is 0, RCl is as defined in Formula (IA’); when r is 1, RB ! and RB2 are each independently -CH2-> and B, taken together with RBi and RB2, forms a linking group, wherein B is a bond or B is as defined in Formula (IA’); when s is 1, Wi and Z2 are each independently C or N, RC1 and RC2 are each independently -CH2-, and D taken together with RC1 and RCz, forms a linking group, wherein D is as defined in Formula (IA’); R16 is absent, H, halogen, or Cm alkyl; R13 and R1' are each independently absent, H, cyclopropyl, halogen or optionally-substituted C1-4 alkyl, wherein said optionally substituted C1-4 alkyl is optionally substituted by a substituent selected from halogen, -ORC, -NRcRd, -CO2RC, -CONRcRd, -SChNRRl and -OCONRcRd; or R15 and R19 taken together with the atom or atoms through which they are connected, form a 5-6 membered ring; and Rg and Rh are each independently as defined in Formula (IA’)or Rg and R!!, taken together with the atom or atoms through which they are connected, form a 5-6 membered ring.

[060] In some embodiments, the compound is of Formula (IV’}, wherein the compound is Formula (IV): R14 or a prodrug, solvate, pharmaceutically acceptable salt, or tautomer thereof.

[061] In some embodiments, the compound is of Formula (V’): or a prodrug, solvate, pharmaceutically acceptable salt, or tautomer thereof, wherein: Yi, Y2, Zi and Z2 are each independently O, S, C or N; Xi, X2, Wi and W2 are each independently C or N; X3 and X4 are each independently S or NR1; X5 is N or CRA2; X6 is N or CR C X9 is N or CH; R3 and R5 are each independently -COX(Rd)(R). -CH2N(Rd)(Rf), -N(Rd)(Rf), -N(Rd)CO(Rf), -CH2N(Rd)CO(Rf) or one of R3 and R5 is -CON(Rd)(Rf), -CH2N(Rd)(Rf), -N(Rd)(Rf), -N(Rd)C0(Rf) or -CH2N(Rd)CO(Rf), and the other of R3 and R5 is H, -COOH, or -CO2Rc; Rc is Ci-4 alkyl; RA2 and RA1 are each independently H, halogen, amino, amino(Ci-4 alkyl)-, hydroxy, optionally substituted (Cj -6 alkyl), or optionally substituted (Ci-6alkyl)oxy-, wherein Ci-6 alkyl of said optionally substituted (Ci-6 alkyl), or optionally substituted (Cue alkyl)oxy- is optionally substituted with 1-4 substituents each independently selected from the group comprising hydroxy, C1-4 alkoxyl, -N(R®)(R1), -CO2(Rt), -CON(Re)(R‘), and -COOH; each Rd is independently H, hydroxy, or Ci-4 alkyl; R® is selected from H, (C1.4 alkyl), -CO(Ci-4 alkyl), -OCO(Ci4 alkyl), and -CO2(Ci4 alkyl); each R1 is independently H, hydroxy, or (C14 alkyl); R'14 and RC2 are each independently absent or C1.4 alkyl, wherein C1-4 alkyl is optionally substituted by a substituent selected from halogen, -ORC, -NRcRd, -CO2Rc, -CONRcRd, -SO2NRcRd, and -OCONRcRd; Rl6 and RC1 are each independently absent, H or C1-4 alkyl; and R13, Rn, R1S, or R19 are each independently absent, H, or C1-4 alkyl, wherein C1-4 alkyl is optionally substituted by a substituent selected from halogen, -ORC, -NRcRd, -CO2RC, -CONRcRd, -SO2NRcRd, and -OCONRcRd; provided that at least one of (i), (ii), or (iii) applies: (i) when (a) Zi, Z2, Yi and Y2 are each N, Wi, W2, Xi and X2 are each C; or (b) Wi, W2, Xi and X2 are each N, Zi, Z2, Yi and Y2 are each C; or (c) Zi and Yi are each N, Wi and Xi are each C; or (d) Z2 and Y2 are each N, W2 and X2 are each C; or (e) Wi and Xi are each N, Zi and Yi are each C; or (f) W2 and X2 are each N, Z2 and Y2 are each C, then at least one of X3 and X4 is S; or X9 is N; or (ii) when (a) Zi, Z2, Yi and Y2 are each N, Wi, W2, Xi and X2 are each C; or (b) Wi, W2, Xi and X2 are each N, Zi, Z2, Yi and Y2 are each C, then R14 is a Cm alkyl substituted with halogen, -ORC, -NRcRd, -CO2Rc, -CONRcRd, -SO2NRcRd, and -OCONRcRd wherein Rc is H; or (iii) when (a) Zi and Yi are each N, Wi and Xi are each C; or (b) Z2 and Y2 are each N, W2 and X2 are each C; or (c) Wi and Xi are each N, Zj and Yi are each C; or (d) W2 and X2 are each N, Z2 and Y2 are each C, then at least one of X5, X*, and X9 is N and RA1 or RAz is halogen, hydroxy, optionally substituted (C1-6 alkyl), substituted (Cm alkyl)oxy-, optionally substituted (Cj-6 alkyl)amino-, or optionally substituted (Cm alkyl)(Cj-4 alkyl)amino-, wherein Cj-6 alkyl of said optionally substituted (Cm alkyl) or substituted (Ci-6 alkyl)oxy-is optionally substituted with 1-4 substituents each independently selected from the group comprising hydroxy, Cm alkoxyl, -N(Re)(Rf), -CO2(Rf), -CON(Re)(Rf), and -COOH. [0621 In some embodiments, the compound is of Formula (V1), wherein the compound is of Formula (V): or a prodrug, solvate, pharmaceutically acceptable salt, or tautomer thereof.

[063] In some aspects, the present disclosure provides a compound of Formula (F), or a prodrug, solvate, pharmaceutically acceptable salt, or tautomer thereof, wherein: Yi, Y2, Zi, and Z2 are each independently O, S, C, or N; Xi, Xj, Wi, and W2 are each independently C or N; RA1 and RA2 are each independently H, halogen, hydroxy, -O-P(O)(OH)2, -04^0)^¾¾ -N(Re)(Rf), -CO?Rf, -N(Rf)C0Rb, -N(Rg)SO2(Ci-4 alkyl)-N(Re)(Rf), -N(Rg)CO(Cu4 alkyl)-N(Rh)(Rf), optionally substituted (C1-6 alkyl), optionally substituted (Ci^ alkyl)oxy~, optionally substituted (Cue alkyl)amino-, and optionally substituted (C1-6 alkyl)(Ci-4 alkyl)amino-, wherein the (Cue alkyl) of said optionally substituted (Cue alkyl), optionally substituted (Cue alkyl)oxy-, optionally substituted (Cue alkyl)amino- and optionally substituted (Cue alkyl)(Cu4 alkyl)amino- is optionally substituted by 1-4 substituents each independently selected from hydroxy, -O-P(O)(OH)2, -0-^0)(^¾ Cu4 alkoxy-, -N(Re)(Rf), -CO (Rf). -CON(Re)(Rf), optionally substituted phenyl, and optionally substituted 5-6 membered heteroaryl group, wherein said optionally substituted phenyl or 5-6 membered heteroaryl is optionally substituted by 1-4 substituents each independently selected from halogen, hydroxy, -O-P(O)(OH)2, -O-P(O)(R1Rlf)2, amino, (Cue alkyl)ammo-, (Cue alkyl)(Cue alkyl)amino-, -(Cue alkyl)-NH2, halo(Cue alkyl), hydroxy-(Cu4 alkyl)-, -(Cu4 alkyl)-O-P(O)(OH)2, -(C1-4 alkyl)-O-P(O)(RIRn)2, halo(Cu4 alkoxy), Cu4 alkoxy-, hydroxy-] C2.4 alkoxy)-, -(C2.4 alkoxy)-O-P(O)(OH)2, -(C2-4 alkoxy)-O-P(O)(RIR1I)2, and Cu4 alkoxy-(Cu4 alkoxy)-; and provided that at least one of (i), (ii), or (iii) applies: (i) when s is 0, r is 1, (a) Zi, Z2, Yi and Y2 are each N, Wi, W2, Xi and X2 are each C; or (b) Wi, W2, Xi and X2 are each N, Zi, Z2, Yi and Y2 are each C; or (c) Zi and Y- are each N, Wi and Xi are each C; or (d) Z2 and Y2 are each N, W2 and X2 are each C; or (e) Wi and Xi are each N, Zi and Yi are each C; or (f) W2 and X2 are each N, Z2 and Y2 are each C, then at least one of X3 and X4 is S; or X9 is N; or (ii) when s is 0, r is 1, (a) Zi, Z2, Yi and Y2 are each N, Wi, W2, Xi and X2 are each C; or (b) Wi, W2, Xi and X2 are each N, Zi, Z2, Yi and Y2 are each C, then R14 is a Cm alkyl substituted with halogen, -ORC, -NRcRd, -CO2Rc, -CONRcRd, -SO2NRcRd, and -OCOX ROY wherein Rc is H; or (iii) when s is 0, r is 1, (a) Zi and Yi are each N, Wi and Xi are each C; or (b) Z2 and Y2 are each N, W2 and X2 are each C; or (c) Wi and Xi are each N, Zi and Yi are each C; or (d) W2 and X2 are each N, Z2 and ¥2 are each C, then at least one of X5, Xe, and X9 is N and RA1 or RA2 is halogen, hydroxy, optionally substituted (Ci^ alkyl), substituted (Ci-6 alkyl)oxy-, optionally substituted (C1-6 alkyl)amino-, or optionally substituted (Ci^ alkyl)(Ci-4 alkyl)ammo-, wherein the (C1-6 alkyl) of said optionally substituted (C1-6 alkyl), substituted (C1-6 alkyl)oxy~, optionally substituted (C1-6 alkyl)amino-, or optionally substituted (C1-6 alkyl)(Ci-4 alkyl)amino- is optionally substituted by 1-4 substituents each independently selected from hydroxy, -O-P(O)(OH)2, -O-PfOXRR11)?, -N(Re)(Rf), -CO2(Rf), -CON(Re)(Rf), optionally substituted phenyl, and optionally substituted 5-6 membered heteroaryl group, wherein said optionally substituted phenyl or 5-6 membered heteroaryl is optionally substituted by 1-4 substituents each independently selected from halogen, hydroxy, -O-P(O)(OH)2, -O-P(O)(R!Rn)2, amino, (C1-6 alkyl)amino-, (Cj-6 alkyl)(Ct-6 alkyl)ammo-, -(Ct^ alkyl)-NH2, halo(Ci-6 alkyl), hydroxy-(Cj-4 alkyl)-, -(Cj-4 alkyl)-O-P(O)(OH)2, -(Cn4 alkyl)-O-P(O)(RIRu)2, halo(Cj-4 alkoxy)-, Cn4 alkoxy-, hydroxy-(C2-4 alkoxy)-, -(C2-4 alkoxy)-O-P(O)(OH)2, -(C2-4 alkoxy)-O-P(O)(RIRII)2, -Ct-4 alkyl-(Ci-4 alkoxy), and Cjm alkoxy-(C1-4 alkoxy)-.

[064] In some aspects, the present disclosure provides a compound of Formula (F ), or a prodrug, solvate, pharmaceutically acceptable salt, or tautomer thereof, wherein: RAl and RA2 are each independently H, halogen, hydroxy, -N(Re)(Rf), -CO2R1, -N(Rf)CORb, -N(Rg)S()2(Ci.4 alkyl)-N(Re)(Rf), -N(Rg)CO(Ci.4 alkyi)-N(Rh)(Rf), optionally substituted (C1-6 alkyl), optionally substituted (C1-6 alkyl)oxy-, optionally substituted (Cue alkyl)amino“, and optionally substituted (Cne alkyl)(Ci-4 alkyl)amino-, wherein the (C44 alkyl) of said optionally substituted (Ci-6 alkyl), optionally substituted (Ci-6 alkyl)oxy-, optionally substituted (Cue alkyl)amino- and optionally substituted (C1-6 alkyl)(Ci-4 alkyl)amino- is optionally substituted by 1-4 substituents each independently selected from hydroxy, Ci-4 alkoxy-, -N(Re)(Rf), -CO2(Rf), -CON(Re)(Rf), optionally substituted phenyl, and optionally substituted 5-6 membered heteroaryl group, wherein said optionally substituted phenyl or 5-6 membered heteroaryl is optionally substituted by 1-4 substituents each independently selected from halogen, hydroxy, amino, (C1-6 alkyl)amino-, (C1-6 alkyl)(Ci-6 alkyl)amino-, halo(Ci-6 alkyl), hydroxy-(Ci-4 alkyl)-, halo(Ci4 alkoxy)-, C1-4 alkoxy-, hydroxy-(C2-4 alkoxy)-, and C’1-4 alkoxy-(Ci-4 alkoxy)-; when r is 0, RB1 and RB2 are each independently H, optionally substituted C1-6 alkyl, halo(Ci-6 alkyl), optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted C3-6 cycloalkyl, optionally substituted 4-6 membered heterocycloalkyl, optionally substituted phenyl, optionally substituted 5-6 membered heteroaryl, or optionally substituted 9-10 membered heteroaryl, wherein said optionally substituted Ci^ alkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted C3-6 cycloalkyl, optionally substituted 46 membered heterocycloalkyl, optionally substituted phenyl, optionally substituted 5-6 membered heteroaryl, or optionally substituted 9-10 membered heteroaryl is optionally substituted by 1-4 substituents each independently selected from halogen, nitro, -Rc, -OH, -ORC, -NHz, -NRCRC, -NRcRd, -OCORC, -CO2H, -CO2Rc, -SORc, -SO2Rc, -CONHa, -CONRcRd, -SO2NH2, -SO2NRcRd, -OCONH2, -OCONRcRd, -NRdCORc, -NRdSORc, -NRdCO2Rc, and -NRdSO2Rc; when r is 1, RB! and RB2 are each independently -CH?.-, and B, taken together with RB1 and RB2, forms a linking group, wherein B is a bond or B is -halo(Ci-w alkyl)-, optionally substituted -Cuwalkyl-, optionally substituted -C2-10 alkenyl-, optionally substituted -C2-10alkynyl-, optionally-substituted -Cj-6 alkyl-O-Cnc, alkyl-, optionally substituted -Cue alkyl-NRa-Cj-6 alkyl-, optionally substituted C3.6 cycloalkyl, optionally substituted phenyl, optionally substituted 4-6 membered heterocycloalkyl, optionally substituted 5-6 membered heteroaryl, optionally substituted -C1-4 alkyl-(C3-6 cycloalkyl)-Ci-4 alkyl-, optionally substituted -C4-4 alkyl-phenyl-Ci-4 alkyl-, optionally substituted -C1.4 alkyl-(4-6 membered heterocycloalkyl)-Ci-4 alkyl-, or optionally substituted -Cn 4 alkyl-(5-6 membered heteroaryl)-Ci-4 alkyl-, wherein the alkyl moiety of said optionally substituted -Cmo alkyl-, optionally substituted -C2-10 alkenyl-, optionally substituted -C2.io alkynyl-, optionally substituted -Cm alkyl-O-Ci-6 alkyl-, optionally substituted -C1-6 alkyl-NRa-Ci-6 alkyl-, optionally substituted -Cm alkyl-(C3-6 cycloalkyl)-Ci-4 alkyl-, optionally substituted -Ci-4 alkyl-phenyl-Ci-4 alkyl-, optionally substituted -Cm alkyl-(4-6 membered heterocycloalkyl)-Ci-4 alkyl-, or optionally substituted -C1.4 alkyl-(5-6 membered heteroaryl-Ci-4 alkyl)- is optionally substituted by 1 or 2 substituents each independently selected from halogen, halo(Cu4 alkyl), -OH, -ORC, -NH2, -NRcRd, ~OCORC, -CO2H, -CO2RC, -SORc, -SO2Rc, -CONH2, -CONRcRd, -SO2NH2, -SO2NRcRd, -OCONH2, -OCONRcRd, -NRdCORc, -NRdSORc, -NRdCO2Rc, and -NRdSO2Rc, and the C3-6 cycloalkyl, phenyl, 4-6 membered heterocycloalkyl, or 5-6 membered heteroaryl moiety of said optionally substituted C3-6 cycloalkyl, optionally substituted phenyl, optionally substituted 4-6 membered heterocycloalkyl, optionally substituted 5-6 membered heteroaryl, optionally substituted -C1-4 alkyl-(C2-6 cycloalkyl)-Ci-4 alkyl-, optionally substituted -Cm alkylphenyl-Ci-4 alkyl-, optionally substituted -Cm alkyl-(4-6 membered heterocycloalkyl)-Ci-4 alkyl, or optionally substituted -Cm alkyl-(5-6 membered heteroaryl)-Ci-4 alkyl- is optionally substituted by 1-4 substituents each independently selected from halogen, hydroxy, ammo, (Cm alkyl)amino-, (Cm alkyl)(CM alkyl)amino-, Cm alkyl, halo(Ci-4 alkyl), halo(Ci-4 alkoxy)-, Cm alkoxy-, hydroxy-(C2-4 alkoxy)-, and Cm alkoxy-(Ci-4 alkoxy)-; when s is 1, Wi and Z2 are each independently C or N, RC1 and RC2 are each independently -CH2-, and D taken together with RC1 and RC2, forms a linking group, wherein D is -halo(Cni2 alkyl)-, optionally substituted -C1-12 alkyl-, optionally substituted -C2-12 alkenyl-, optionally substituted -C2-12 alkynyl-, optionally substituted -Cm alkyl-O-CM alkyl-, optionally substituted -Cm alkyl-NRa-CM> alkyl-, optionally substituted -Cue alkyl-(C3^ cycloalkyl)-Cm alkyl-, optionally substituted -Cm alkyl-phenyl-CM alkyl-, optionally substituted -Cm alkyl-(4-6 membered heterocycloalkyl)-Cj-6 alkyl-, or optionally substituted -Cm, alkyl-(5-6 membered heteroaryl)-Ci-6 alkyl-, wherein the alkyl moiety of said optionally substituted -C1.12 alkyl-, optionally substituted -Cm alkenyl-, optionally substituted -C2-12alkynyl-, optionally substituted -Cue alkyl-O-Ci-6 alkyl, optionally substituted -Cm alkyl-NRa-Ci-6 alkyl-, optionally substituted -Cue alkyl-(C3-6 cycloalkyl)-Ci-6 alkyl-, optionally substituted -Cm alkyl-phenyl-CM alkyl-, optionally substituted -Cm alkyl-(4-6 membered heterocycloalkyl)-Ci-6 alkyl-, or optionally substituted -Cm alkyl-(5-6 membered heteroaryl)Ci-6 alkyl- is optionally substituted by 1 or 2 substituents each independently selected from halogen, halo(Ci-4 alkyl), -OH, -ORC, -NH2, -NRcRd, -OCORC, -CO2H, -CO2RC, -SORC, -SO2Rc, -CONH2, -CONRcRd, -SO2NH2, -SO2NRcRd, -OCONH2, -OCONRcRd, -NRdCORc, -NRdSORc, -NRdCO2Rc, and -NRdSO2Rc, and the C3-6 cycloalkyl, phenyl, 4-6 membered heterocycloalkyl, or 5-6 membered heteroaryl moiety of said optionally substituted -Cm alkyl-(C3-6 cycloalkyl)-Ci-6 alkyl-, optionally substituted -C1-6 alkyl-phenyl-Ci-6 alkyl-, optionally substituted -Ci-6 alkyl-(4-6 membered heterocycloalkyl)-Ci-6 alkyl-, or optionally substituted -Ci-6 alkyl-(5-6 membered heteroaryl)-Ci-6 alkyl- is optionally substituted by 1-4 substituents each independently selected from halogen, hydroxy, ammo, (C1-4 alkyl)amino-, (C1-4 alkyl)(Ci-4 alkyl)amino-, C1-4 alkyl, halo(Ci-4 alkyl), halo(Ci-4 alkoxy)-, C1-4 alkoxy-, hydroxy-(C2.4 alkoxy)-, and C1-4 alkoxy-(Ci-4 alkoxy)-; R4 and R° are each independently selected from H, halogen, halo(Ci-6 alkyl), halo(Ci-6 alkoxy)-, hydroxy, -NH2, -NRCRC, -NRcRd, -CORC, -CO2RC, -N(Rd)CORc, -N(Rd)SO2Rc, -N(Rg)SO2(Ci-2 alkyl)-N(Rh)(Rf), -N(Rg)CO(Ci-2 alkyl)-N(Rh)(Rf), optionally substituted (C1-6 alkyl), optionally substituted (Ci-6 alkyl)oxy-, optionally substituted (Ci-6 alkyl)amino-, and optionally substituted (Cm alkyl)(CM alkyl)amino-, wherein the (Cm alkyl) of said optionally substituted (Ci-6 alkyl), optionally substituted (Cm alkyl)oxy-, optionally substituted (Cm alkyl)amino- and optionally substituted (Cj-6 alkyl)(Ci-4 alkyl)annno- is optionally substituted by 1-4 substituents each independently selected from -OH, -ORC, -NH2, -NRcRc, -NRcRd, -CO2H, -CO2RC, -OCORC, -CO2H, -CO2RC, -S()RC, -SO2Rc -CONH2, -CONRcRd, -SO2NH2, -SO2NRcRd, -OCONH2, -OCONRcRd, -NRdCORc, -NRdSORc, -NRdCO2Rc, -NRdSO2Rc, optionally substituted phenyl, optionally substituted 5-6 membered heterocycloalkyl, and optionally substituted 5-6 membered heteroaryl group, wherein said optionally substituted phenyl, 5-6 membered heterocycloalkyl, or 5-6 membered heteroaryl is optionally substituted by 1-4 substituents each independently selected from halogen, hydroxy, ammo, (C1-4 alkyl)ammo-, (C1-4 alkyl)(Ci-4 alkyl)ammo-, Cm alkyl, halo(CM alkyl), hydroxy-(Ci-4 alkyl)-, halo(Ci-4 alkoxy)-, Cm alkoxy-, hydroxy-(C2.4 alkoxy)-, Cm alkoxy-(Ci-4 alkoxy)-, -CORd, -CON(Rd)(Rf), and -CO2Rd; each RD is independently C1.4 alkyl, halo(Ci-4 alkyl), -(Cm alkyl)-OH, -(Ci-4 alkyl)-O-(Ci-4 alkyl), -(Ci-4 alkvl)-\(Rj(R). -(Cm alkyl)-O-CO(Ci-4 alkyl), or -(Cm alkyl)-CO-O-(Ci-4 alkyl); each Rc is independently H, Cm alkyl, halo(Ci..4 alkyl), -(Cm alkyl)-OH, -(Cm alkyl)-O-(C1-4 alkyl), -(Cm alkyl)-N(Re)(Rf), -(Cm alkyl)-O-CO(Ci.4 alkyl), -(Cm alkyl)-CO-O-(Ci-4 alkyl), optionally substituted C3-6 cycloalkyl, optionally substituted phenyl, optionally substituted 4-6 membered heterocycloalkyl, optionally substituted 5-6 membered heteroaryl, optionally substituted 9-10 membered heteroaryl, optionally substituted -Ci.4 alkyl-Cs -e cycloalkyl, optionally-substituted -Cm alkyl-phenyl, optionally substituted -Cm alkyl-4-6 membered heterocycloalkyl, optionally substituted -Cm alkyl-5-6 membered heteroaryl, or optionally substituted -Cm alkyl-9-10 membered heteroaryl, wherein the C3-6 cycloalkyl, phenyl, 4-6 membered heterocycloalkyl, 5-6 membered heteroaryl or 9-10 membered heteroaryl moiety of said optionally substituted C3-6 cycloalkyl, optionally substituted phenyl, optionally substituted 4-6 membered heterocycloalkyl, optionally substituted 5-6 membered heteroaryl, optionally substituted 9-10 membered heteroaryl, optionally-substituted -Cm alkyl-C3-6 cycloalkyl, optionally substituted -Cm alkyl-phenyl, optionally substituted -Cm alkyl-4-6 membered heterocycloalkyl, optionally substituted -Cm alkyl-5-6 membered heteroaryl, or optionally substituted -Cm alkyl-9-10 membered heteroaryl is optionally substituted by 1-4 substituents each independently selected from halogen, hydroxy, ammo, -(Cm alkyl)amino-, (Cm alkyl)(CM alkyl)amino-, Cm alkyl, halo(Ci-4 alkyl), halo(Ci-4 alkoxy)-, Cm alkoxy-, hydroxy-(C2-4 alkoxy)-, Cm alkoxy-(Ci-4 alkoxy)-, -COR“, -CON(Rd)(R!), and -CChRa; and each Re is independently H, (Cm alkyl), -C0(Cm alkyl), -0C0(Cm alkyl), -C02(Cm alkyl), -CO-(optionally substituted 5-6 membered heterocycloalkyl), -C0-(Cm alkyl)-(optionally substituted 5-6 membered heterocycloalkyl), -CO-(optionally substituted 5-6 membered heteroaryl), -C0-(Cm alkyl)-(optionahy substituted 5-6 membered heteroaryl), wherein the optionally substituted 5-6 membered heterocycloalkyl or optionally substituted 5-6 membered heteroaryl is optionally substituted by 1-4 substituents each independently selected from halogen, hydroxy, ammo, (Cm alkyl)ammo-, (Cm alkyB(('m alkyl)amino-, Cm alkyl, halo(Ci-4 alkyl), halo(Ci-4 alkoxy)-, Cm alkoxy-, hydroxy-(C2-4 alkoxy)-, Cm alkoxy-(Ci-4 alkoxy)-, -CORd, -CON(Rd)(Rf), and -CO2Rd; provided that at least one of (1), (ii), or (ih) applies: (i) when s is 0, r is 1, (a) Zi, Z2, Yi and Y2 are each N, Wi, W2, Xi and X2 are each C; or (b) Wi, W2, Xi and X2 are each N, Zi, Z2, Yi and Y2 are each C; or (c) Zi and Yi are each N, Wi and Xi are each C; or (d) Z2 and Y2 are each N, W2 and X2 are each C; or (e) Wi and Xi are each N, Zi and Yi are each C; or (f) W2 and X2 are each N, Z2 and Y2 are each C, then at least one of X3 and X4 is S; or X9 is N; or (n) when s is 0, r is 1, (a) Zi, Z2, Yi and Y2 are each N, Wi, W2, Xi and X2 are each C; or (b) Wi, W2, Xi and X2 are each N, Zi, Z2, Yi and Y2 are each C, then R14 is a Cm alkyl substituted with halogen, -ORC, -NRcRd, -CO2Rc, -CONRcRd, -SO2NRcRd, and -OCONRcRd wherein Rc is H; or (iii) when s is 0, r is 1, (a) Zi and Yi are each N, Wi and Xi are each C; or (b) Z2 and Y2 are each N, W2 and X2 are each C; or (c) Wi and Xi are each N, Zi and Yi are each C; or (d) W2 and X2 are each N, Z2 and Y2 are each C, then at ieast one of X5, Xe, and Xy is N and RA! or RA2 is halogen, hydroxy, optionally substituted (Cue alkyl), substituted (C1-6 alkyl)oxy-, optionally substituted (Cue alkyl)amino-, or optionally substituted (Cue alkyl)(Ci-4 alkyl)amino-, wherein the (Ci-6 alkyl) of said optionally substituted (C1-6 alkyl), substituted (Ci^ alkyl)oxy-, optionally substituted (C1-6 alkyl)amino- or optionally substituted (C1-6 alkyl)(Ci-4 alkyl)amino- is optionally substituted by 1-4 substituents each independently selected from hydroxy, -O-P(O)(OH)2, -O-P(O)(RIRI!)2, -N(Re)(Rf), -CO2.(Rf), -CON(Re)(RI), optionally substituted phenyl, and optionally substituted 5-6 membered heteroaryl group, wherein said optionally substituted phenyl or 5-6 membered heteroaryl is optionally substituted by 1-4 substituents each independently selected from halogen, hydroxy, -O-P(O)(OH)2, -O-P(O)(RIRIi)2, amino, (Cj-6 alkyl)amino-, (Cj-6 alkyl)(Ci-6 alkyl)amino-, -(C1-6 alkyl)-NH2, halo(Ci-6 alkyl), hydroxy-(Ci-4 alkyl)-, -(C1-4 alkyl)-O-P(O)(OH)2, -(Cj-4 alkyl)-O-P(O)(RIRl!)2, halo(Cj-4 alkoxy)-, C1-4 alkoxy-, hydroxy-(C2-4 alkoxy)-, -(C2-4 alkoxy)-O-P(O)(OH)2, -(( --4 alkoxy)-O-P(O)(RIRII)2, -C1-4 a Iky 1-((4.4 alkoxy), and Ci-4 alkoxy-(Ci-4 alkoxy)-.

[065] The alternative definitions for the various groups and substituent groups of Formula (I’), Formula (TA’), Formula (IF), Formula (III’), Formula (IV’), or Formula (V’) provided throughout the specification are intended to describe each compound species disclosed herein, individually, as well as groups of one or more compound species. The scope of this disclosure includes any combination of these group and substituent group definitions. The compounds of the disclosure are only those which are contemplated to be "chemically stable" as will be appreciated by those skilled in the art.

[066] It will be appreciated by those skilled in the art that the compounds of this disclosure may exist in other tautomeric forms including zwitterionic forms, or isomeric forms. All tautomeric (including zwitterionic forms) and isomeric forms of the formulas and compounds described herein are intended to be encompassed within the scope of the present disclosure.

[067] It will also be appreciated by those skilled in the art that the compounds of this disclosure may exist in tautomeric forms including, but not limited to, Formula (A), Formula (B), Formula (C), Formula (D) and / or Formula (E) or zwitterionic forms including, but not limited to, Formula (F), Formula (G) or Formula (H):

[068] In some embodiments, when r is 1 and s is 0 (the total of r and s is 1), the compound of the disclosure is a compound of Formula (I-B’) or Formula (I-b’): rM RB1 (I-B’) (I-b’) wherein X? and Xs are each independently CO or CH2. [069 ] In some embodiments, the compound of the disclosure is a compound of Formula (I-B’) or Formula (I-b’) wherein X9 is CR4

[070] In some embodiments, when r is 0 and s is 1 (the total of r and s is 1), Wi and Z2 are each independently C or N, the compound of the disclosure is a compound of Formula (I-D’) or Formula (I-d’): wherein X? and Xs are each independently CO or CH2.

[071] In some embodiments, the compound of the disclosure is a compound of Formula (I-D’) or Formula (I-d’) wherein X9 is CR4.

[072] In some embodiments, when r is 1 and s is 1 (the total of r and s is 2), Wi and Z2 are each independently C or N, the compound of the disclosure is a compound of Formula {1 -BI) ) or Formula (I-bd’): R14 R14 (I-BD)                                     (I-bd) wherein X7 and Xs are each independently 0=0 or CH2.

[073] In some embodiments, the compound of the disclosure is a compound of Formula (I-BD’) or Formula (I-bd’) wherein X9 is CR4

[074] It is to be understood that for a compound of Formula (I’), Formula (IA’), Formula (IF), Formula (IIP), Formula (IV’), or Formula (V’), where applicable:

[075] In some embodiments, Wi.Xi, Yi, Zi, W2, X2, Y2, and Z2 are each independently O, S, C, or N.

[076] In some embodiments, Wi, Xi, Yi, and Zi are each independently O, S, C, or N.

[077] In some embodiments, Wi, Xi, Yi, and Zi are each independently O, C, or N. In some embodiments, Wi.Xi, Yi, and Zi are each independently S, C, or N. In some embodiments, Wi, Xi, Yi, and Zi are each independently O, S, or C. In some embodiments, Wi. Xi, Yi, and Zi are each independently O, S, or N.

[078] In some embodiments, Wi is O, S, C, or N. In some embodiments, Wi is O. In some embodiments, Wi is S. In some embodiments, Wi is C. In some embodiments, Wi is N.

[079] In some embodiments, Xi is O, S, C, or N. In some embodiments, Xi is O. In some embodiments, Xi is S. In some embodiments, Xi is C. In some embodiments, Xi is N.

[080] In some embodiments, Yj is O, S, C, or N. In some embodiments, Yj is O. In some embodiments, Yi is S. In some embodiments, Yi is C. In some embodiments, Yl is N.

[081] In some embodiments, Zi is O, S, C, or N. In some embodiments, Zi is O. In some embodiments, Zi is S. In some embodiments, Zj is C. In some embodiments, Zj is N.

[082] In some embodiments, W2, X2, Y2, and Z2 are each independently 0, S, C, or N.

[083] In some embodiments, W2, X2, Y2, and Z2 are each independently 0, C, or N. In some embodiments, W2, X2, Y2, and Z2 are each independently S, C, or N. In some embodiments, W2, X2, Y2, and Z2 are each independently 0, S, or C. In some embodiments, W2, X2, Y2, and Z2 are each independently 0, S, or N.

[084] In some embodiments, W2 is 0, S, C, or N. In some embodiments, W2 is 0. In some embodiments, W2 is S. In some embodiments, W2 is C. In some embodiments, W2 is N.

[085] In some embodiments, X2 is 0, S, C, or N. In some embodiments, X2 is 0. In some embodiments, X2 is S. In some embodiments, X2 is C. In some embodiments, X2 is N.

[086] In some embodiments, Y2 is O, S, C, or N. In some embodiments, Y2 is O. In some embodiments, Y2 is S. In some embodiments, Y2 is C. In some embodiments, Y2 is N.

[087] In some embodiments, Z2 is O, S, C, or N. In some embodiments, Z2 is O. In some embodiments, Z2 is S. In some embodiments, Z2 is C. In some embodiments, Z2 is N.

[088] In some embodiments, X3 and X4 are each independently S or NRf

[089] In some embodiments, X3 and X4 are each independently S. In some embodiments, X3 and X4 are each independently NRf.

[090] In some embodiments, X3 is S or NRf In some embodiments, X3 is S. In some embodiments, X3 is NRf.

[091] In some embodiments, X4 is S or NRf In some embodiments, X4 is S. In some embodiments, X4 is NR1.

[092] In some embodiments, r is 0 or 1. In some embodiments, r is 0. In some embodiments, r is 1.

[093] In some embodiments, s is 0 or 1. In some embodiments, s is 0. In some embodiments, s is 1.

[094] In some embodiments, p is 1 or 2. In some embodiments, p is 1. In some embodiments, p is 2.

[095] In some embodiments, when r is 0, B is absent and RB1 and RB2 are not connected.

[096] In some embodiments, when s is 0, D is absent and RC1 and RC2 are not connected.

[097] In some embodiments of the compounds of the present disclosure, RA1 and RA2 are each independently H, halogen, hydroxy, -N(Re)(Rf), -CO2Rf, -N(Rf)CORb, ~N(Rg)SO2.(Ci-4 alkyl)-N^XR1), -N(Rg)CO(Ci-4 alkyl)-N(Rh)(R1), optionally substituted (Ci-6 alkyl), optionally-substituted (Ci-6 alkyl)oxy-, optionally substituted (Cue alkyl)ammo-, and optionally substituted (Ci-6 alkyl)(Ci-4 alkyl)amino-, wherein the (Cue alkyl) of said optionally substituted (Cj-6 alkyl), optionally substituted (C1-6 alkyl)oxy-, optionally substituted (Ci-6 alkyl)amino- and optionally substituted (Cue alkyl)(Ci-4 alkyl)amino- is optionally substituted by 1-4 substituents each independently selected from hydroxy, C1.4 alkoxy-, -N(Re)(Rf), -CO2(Rf), -CON(Re)(Rf), optionally substituted phenyl, and optionally substituted 5-6 membered heteroaryl group, wherein said optionally substituted phenyl or 5-6 membered heteroaryl is optionally substituted by 1-4 substituents each independently selected from halogen, hydroxy, ammo, (Ci-6 alkyl)amino-, (Ci-6 alkyl)(Ci-6 alkyl)ammo-, halo(Ci-6 alkyl), hydroxy-(Ci-4 alkyl)-, halo-(CM alkoxy)-, Cm alkoxy-, hydroxy-(C2-4 alkoxy)-, and Cm alkoxy-(Ci-4 alkoxy)-.

[098] In some embodiments of the compounds of the present disclosure, RAI and RA2 are each independently hydroxy, substituted (Cm alkyl), substituted (C1-6 alkyl)oxy-, optionally substituted (Cm alkyl)amino-, and optionally substituted (Cm alkyl)(Ci-4 alkyl)ammo-, wherein the (C1-6 alkyl) of said substituted (Ci-e alkyl) and substituted (Cm alkyl)oxy-, is optionally substituted by 1-4 substituents each independently selected from -O-P(O)(OH)2, -O-P(O)(RiRI1)2, - optionally substituted phenyl, and optionally substituted 5-6 membered heteroaryl group, wherein said optionally substituted phenyl or 5-6 membered heteroaryl is optionally substituted by 1-4 substituents each independently selected from halogen, hydroxy, -O-P(O)(OH)2, -O-P(O)(RiR!I)2, ammo, (Cue alkyl)amino-, (Cue alkyl)(Ci-6 alkyl)ammo-, -(C1-6 alkyl)-NH2, halo(Ci-6 alkyl), hydroxy-(Ci-4 alkyl)-, -(C1-4 alkyl)-O-P(O)(OH)2, -(Cm alkyl)-O-P(O)(RIRI1)2, halo(Ci-4 alkoxy)-, C1-4 alkoxy-, hydroxy-(C2-4 alkoxy)-, -(C2-4 alkoxy)-O-P(O)(OH)2, -(C2-4 alkoxy)-O-P(O)(RIRI1)2, -Cm alkyl-(Ci-4 alkoxy), and Cm alkoxy-(Ci-4 alkoxy)-; and the (Cm alkyl) of said optionally substituted (C1-6 alkyl)amino- and optionally substituted (C1-6 alkyl)(Ci-4 alkyl)amino- is optionally substituted by 1-4 substituents each independently selected from hydroxy, -O-P(O)(OH)2, -O-P(O)(RIRn)2, -N(Re)(Rf), -CO2(Rf), -CON(Re)(Rf), optionally substituted phenyl, and optionally substituted 5-6 membered heteroaryl group, wherein said optionally substituted phenyl or 5-6 membered heteroaryl is optionally substituted by 1-4 substituents each independently selected from halogen, hydroxy, -O-P(O)(OH)2, -O-P(O)(RIRiI)2, amino, (Cm alkyl)amino~, (Cm alkyl)(CM alkyl)amino-, -(Cm alkyl)-NH2, halo(CM alkyl), hydroxy-(Cj-4 alkyl)-, -(Cm alkyl)-O-P(O)(OH)2, -(Cm alkyl)-O-P(O)(R1RII)2, halo(Ct-4 alkoxy)-, Cm alkoxy-, hydroxy-(C2-4 alkoxy)-, -(C2-4 alkoxy)-O-P(O)(OH)2, -(C2-4 alkoxy)-O-P(O)(RIR11)2, -Cm alkyl-(CM alkoxy), and Cm alkoxy-(Ci-4 alkoxy)-.

[099] In some embodiments of the compounds of this present disclosure, RA1 and RA‘ are each independently H, halogen, hydroxy, -O-P(O)(OH)2, -0^(0)^¾1¾ -N(R®)(Rf), -CO2Rf, -N(Rf)C0Rb, -N(Rg)S()2(CM alkyl)-N(Re)(Rf), -N(RS)C0(Cm alkyi)-N(Rh)(Rf), optionally substituted (Cm alkyl), optionally substituted (Cm alkyl)oxy-, optionally substituted (Cm alkyl)amino-, and optionally substituted (Cm alkyl)(Ci-4 alkyl)amino-, wherein the (Cm alkyl) of said optionally substituted (Cm alkyl), optionally substituted (Cm alkyl)oxy-, optionally substituted (Cm alkyl)ammo- and optionally substituted (Cm alkyl)(CM alkyl)amino- is optionally substituted by 1-4 substituents each independently selected from hydroxy, -O-P(O)(OH)2, -O-P(O)(RIRII)2, Cm alkoxy-, -N( Re)( 1- -CO2(Rf), -CON(Re)(Rf), optionally substituted phenyl, and optionally substituted 5-6 membered heteroaryl group, wherein said optionally substituted phenyl or 5-6 membered heteroaryl is optionally substituted by 1-4 substituents each independently selected from halogen, hydroxy, -O-P(O)(OH)2, -O-P(O)(R1Rn)2, amino, (Ci-6 alkyl)ammo-, (Cue alkyl)(Ci-6 alkyl)ammo-, -(Ci-6 alkyl)-NH2, halo(Ci-6 alkyl), hydroxy~(Ci-4 alkyl)-, -(Cm alkyl)-O-P(O)(OH)2, -(C1-4 3^71)-0-1^0)^¾.¾ halo(Ci-4 alkoxy), Cm alkoxy-, hydroxy-(C2-4 alkoxy)-, -(Cm alkoxy)-O-P(O)(OH)2, -(Cm alkoxy)-O-P(O)(RIRl!)2, and Cm alkoxy-(Ci-4 alkoxy).

[100] In some embodiments of the compounds of the present disclosure, RA1 and RA2 are each independently H, halogen, hydroxy, amino, (C1-4 alkyl)amino-, (CMalkyl)(Ci-4alkyl)amino-, (Cn 4 alkyl), hydroxy(CM alkyl)-, amino(CM alkyl)-, (Cm alkyl)amino(CM alkyl)-, (Cm alkyl)(Ci-4 alkyl)amino(CM alkyl)-, Cm alkoxyl, hydroxy(C2-4 alkoxyl)-, amino(C2-4 alkoxy!)-. (Cm alkyl)amino(C2-4 alkoxyl)-, (Cm alkyl)(CM alkyl)amino(C2-4 alkoxyl)-, 6-membered heterocycloalkyl-(CM alkyl)-, phenyl(CM alkoxy)-, (Cm alkyl)OCONH(CM alkyl)-, hydroxy(Ci-4 alkyljammo-, (Cm alkyl)CONH-, (Cm alkyl)CON(CM alkyl)-, -CO2H, -C02(Cm alkyl), amino(CM alkyl)CONH-, (Cm alkyl)amino(CM alkyl)CONH-, (Cm alkyl)(CM alkyl)amino(CM alkyl)CONH-, amino(Ci-4 alkyl)C0N(Cm alkyl)-, (Cm alkyl)ammo(CM alkyl)CON(CM alkyl)-, hydroxy(Cm alkyl)CONH~, (Ci-4 alkyl)(Ci.4 alkyl)ammo(Ci-4 alkyl)CON(Ci.4 alkyl)-, hydroxy(Ci. 4 alkyl)CON(CM alkyl)-, H02C(Cm alkoxy)-, (Cm alkyl)OCO(CM alkoxy)-, H2NC0(Cm alkoxy)-, (Cm alkyl)HNCO(CM alkoxy)-, (Cm alkyl)(CM alkyl)NCO(CM alkoxy)-, and -NIISO4Cm alkyl)-.

[101] In some embodiments of the compounds of the present disclosure, RA1 and RA2 are each independently H, halogen, hydroxy, -O-P(O)(OH)2, -O-P(O)(R1Rn)2, amino, (Cm alkyl)amino-, (Cm alkyl)(CM alkyl)amino-, (Cm alkyl), hydroxy(Ci-4 alkyl)-, ammo(CM alkyl)-, (Cm alkyl)amino(CM alkyl)-, (Cm alkyl)(CM alkyl)amino(CM alkyl)-, Cm alkoxy-, hydroxy(C2-4 alkoxy)-, -(Cm alkoxy)-O-P(O)(OH)2, -(Cm alkoxy-O-P(O)(RIR1I)2, amino(C2-4 alkoxy)-, (Cm alkyl)ammo(C2-4 alkoxy)-, (Cm alkyl)(CM alkyl)ammo(C2-4 alkoxy)-, 6-membered heterocycloalkyl-(CM alkyl)-, phenyl(CM alkoxy)-, (Cm alkyl)OCONH(CM alkyl)-, hydroxy(Ci-4 alkyl)amino-, -amino(CM alkyl)-O-P(O)(OH)2, -amino(CM alkyl)-O-P(O)(R1RII)2, (Cm alkyl)CONH-, (Cm alkyl)CON(CM alkyl)-, -CO2H, -C02(Cm alkyl), ammo(CM alkyl)CONH-, (C1-4 alkyl)amino(Ci-4 alkyl)CONH-, (C1.4 alkyl)(Ci-4 alkyl)amino(Ci-4 alkyl)CONH-, ammo(Cj.4 alkyl)C0N(Ci-4 alkyl)", (C1-4 alkyl)amino(Ci-4 alkyl)C0N(Ci-4 alkyl)-, hydroxy(Ci-4 alkyl)CONH-, -M1CO(C:.4 alkyl)-O-P(O)(OH)2, -NHCO(Cm alkyl)-O-             (C1.4 alkyl)(Ci-4 alkyl)amino(Ci-4 alkyl)CON(Ci-4 alkyl)-, hydroxy(Ci-4 alkyl)CON(Ci-4 alkyl)-, -(C1-4 alk\ONCO(Ci 4 alkyl)-O-P(O)(OH)2, -(C1.4 alkyl)NC0(Ci.4 alkyl)-O-P(O)(RIRn)2, HO2C(Ci-4 alkoxy)-, (C1.4 alkyl)OCO(Ci-4 alkoxy)-, H2NCO(Ci-4 alkoxy)-, (C1-4 alkyl)HNCO(Ci-4 alkoxy)-, (Ci4 alkyl)(Ci-4 alkyl)NCO(Ci-4 alkoxy)-, and -NHSO2(Cw alkyl)-.

[102] In some embodiments, RA1 and RA2 are each independently H, halogen, (Ci-e alkyl)oxy-, hydroxy(C2-6 alkyl)oxy-, HO(O)C-(C2-6 alkyl)oxy-, ammo(C2-6 alkyl)oxy-, hydroxy, amino, or amino(Ci-4 alkyl)-.

[103] In some embodiments, RA1 and RA2 each independently H, halogen, hydroxy, (C1-6 alkyl)oxy-, hydroxy(C2-6 alkyl)oxy-, -(C2.4 alkoxy)-O-P(O)(OH)2, or -(C2.4 alkoxy)-O-P(O)(R'Ri:H

[104] In some embodiments, RA! and RA2 are each independently H. In some embodiments, RA1 and RA2 are each H. [ 105] In some embodiments, RA! and RAz are each independently halogen. In some embodiments, RA1 and RA2 are each halogen.

[106] In some embodiments, RA! and RA2 are each -OCH2CH2CH2NH2.

[107] In some embodiments, RA! and RA2 are independently H, halogen, hydroxy, -OCH2CH2CH2OH, -OG bCH-O I COOK -OCKCH-CHAl H -OCK. or -N(Re)(Rf).

[108] In some embodiments of RA! and RA2 is -OCH3 and the other ofRAi and RA2 is halogen, -OH, -OCH2CH2CH2OH, -OCH2CH2CH2COOH, -OCH2CH2CH2NH2, -OCH3, or -N(Re)(Rf).

[109] In some embodiments of RA1 and RA2 is Hand the other ofRA1 and RA2 is halogen, -OH, -OCH2CH2CH2OH, -OCKCH-CH COOH -OCKCKCKM b. -OCK. or -N(Re)(Rf).

[110] In some embodiments of RAl and RAz is -OCH3 and the other of RAs and RA‘ is -OCH2CH2CH2OH. [Ill] In some embodiments of RA1 and RA2 is -OCH3 and the other of RA1 and RA2 is -OCH2CH2CH2COOH.

[112] In some embodiments of RAl and RA2 is H and the other of RAs and RA2 is -OCH2CH2CH2OH.

[113] In some embodiments of RA1 and RA2 is -OCH3 and the other of RA1 and RA2 is -OCH2CH2CH2NH2.

[114] In some embodiments of RAI and RA2 is -OH and the other of RA1 and RA2 is -OCH2CH2CH2OH.

[115] In some embodiments of RAI and RA2 is -OH and the other of RA1 and RA2 is -OCH2CH2CH2COOH.

[116] In some embodiments of RAI and RA2 is -OH and the other of RAl and RA2 is -OCH2CH2CH2NH2.

[117] In some embodiments, RAI is H, halogen, amino, amino(Ci-4 alkyl)-, hydroxy, -O-P(O)(OH)2, -O-P(O)(RIRn)2, -N(Re)(Rf), -CO2Rf, -N(Rf)CORb, -N(R8)SO2(Ci-4 alkyl)-N(Re)(Rf), -N(Rg)CO(Cn4 alkyl)-N(Rh)(Rf), optionally substituted (Cw alkyl), optionally substituted (Cue alkyl)oxy-, optionally substituted (Ci-6 alkyl)amino-, and optionally substituted (Ci-6 alkyl)(Ci-4 alkyl)amino-, wherein the (Ci-6 alkyl) of said optionally substituted (Ci-6 alkyl), optionally substituted (Ci-6 alkyl)oxy-, optionally substituted (Ci-6 alkyl)ammo- and optionally substituted (Cw alkyl)(Ci-4 alkyl)amino- is optionally substituted by 1-4 substituents each independently selected from hydroxy, -O-P(O)(OH)2, -O-P(())(R'RHb. Cm alkoxy-, -N(Re)(Rf), -CO (Rf). -CON(Re)(Rf), optionally substituted phenyl and optionally substituted 5-6 membered heteroaryl group, wherein said optionally substituted phenyl or 5-6 membered heteroaryl is optionally substituted by 1-4 substituents each independently selected from halogen, hydroxy, -O-P(O)(OH)2, -O-P(O)(RIR1I)2, amino, (Cur, alkyl)amino-, (Ci-6 alkyl)(Cj-6 alkyl)amino-, -(Cue alkyl)-NH2, halo(Cne alkyl), hydroxy-(Cu4 alkyl)-, -(Ci-4 alkyl)-O-P(O)(OH)2, -(C1-4 alkyl)-O-P(O)(RIRu)2, halo(Cn4 alkoxy), Ci-4 alkoxy-, hydroxy-(C2^ alkoxy)-, -(C2-4 alkoxy)-O-P(O)(OH)2, -(C2.4 alkoxy)-O-P(O)(RIRu)2, -Cm alkyl-(Ci4 alkoxy), and C1.4 alkoxy-(CM alkoxy)-.

[118] In some embodiments, RA1 is H.

[119] In some embodiments, RA1 is halogen, ammo, ammo(Ci.4 alkyl)-, hydroxy, -O-P(O)(OH)2, -O-P(O)(RIRn)2, -N(Re)(Rf), -CO2Rf, -N(Rf)CORb, -N(Rg)SO2(Ci-4 alkylj-N^XR1), -N(Rg)CO(Ci-4 alkyl)-N(Rh)(Rf), optionally substituted (Cue alkyl), optionally substituted (Cue alkyl)oxy-, optionally substituted (Cue alkyljammo-, and optionally substituted (Cue alkyl)(Ci-4 alkyl)amino-. wherein the (C44 alkyl) of said optionally substituted (Cue alkyl), optionally substituted (C1-6 alkyl)oxy-, optionally substituted (Cue alkyl)amino- and optionally substituted (C1-6 alkyl)(Ci-4 alkyl)amino- is optionally substituted by 1-4 substituents each independently selected from hydroxy, -O-P(O)(OH)2, -O-P(O)(RIRII)2, Ci-4 alkoxy-, -N(Re)(Rf), -CO2(Rf), -CON(Re)(Rf), optionally substituted phenyl, and optionally substituted 5-6 membered heteroaryl group, wherein said optionally substituted phenyl or 5-6 membered heteroaryl is optionally substituted by 1-4 substituents each independently selected from halogen, hydroxy, -O-P(O)(OH)2, -O-P(O)(R1Rn)2, amino, (C1-6 alkyl)ammo-, (Cue alkyl)(Ci-6 alkyl)ammo-, -(Cue alkyl)-NH2, halo(Cue alkyl), hydroxy~(Cu4 alkyl)-, -(C1-4 alkyl)-O-P(O)(OH)2, -(Ci-4 alkyl)-O-P(O)(RTR11)2, halo(Cu4 alkoxy), C1-4 alkoxy-, hydroxy-(C2-4 alkoxy)-, -(C2-4 alkoxy)-O-P(O)(OH)2, -(C2-4 alkoxy)-O-P(O)(RIRl!)2, -Cm alkyl-(Ci-4 alkoxy), and Ci-4 alkoxy-(Ci4 alkoxy)-.

[120] In some embodiments, RA1 is halogen. In some embodiments, RAl is F, Cl, Br, or I. In some embodiments, RA1 is F, Cl, or Br. In some embodiments, RA1 is F. In some embodiments, RAl is Cl. In some embodiments, RA1 is Br.

[121] In some embodiments, RA1 is amino, amino(Ci-4 alkyl)-, hydroxy, -O-P(O)(OH)2, -O-PlOXR'Rbx -N(ReXRf), -CO2Rf, -N(Rf)CORb, -N(Rg)SO2(Ci-4 alkyl)-N(Re)(Rf), -N(Rg)CO(Ci-4 alkyl)-N(Rh)(R!), optionally substituted (Ci^ alkyl), optionally substituted (C1-6 alkyl)oxy-, optionally substituted (C1-6 alkyl)amino-, and optionally substituted (Cj -6 alkyl)(Ci-4 alkyl)amino- wherein the (C1-6 alkyl) of said optionally substituted (Cue alkyl), optionally substituted (Cue alkyl)oxy-, optionally substituted (Cue alkyl)amino- and optionally substituted (Cue alkyl)(Cu4 alkyl)amino- is optionally substituted by 1-4 substituents each independently selected from hydroxy, -O-P(O)(OH)2, -0-^0)(^¾ Cu4 alkoxy-, -N(Re)(Rf), -CO (Rf). -CON(Re)(Rf), optionally substituted phenyl, and optionally substituted 5-6 membered heteroaryl group, wherein said optionally substituted phenyl or 5-6 membered heteroaryl is optionally substituted by 1-4 substituents each independently selected from halogen, hydroxy, -O-P(O)(OH)2, -O-P(O)(R1RII)2, amino, (Cue alkyl)ammo-, (Cue alkyl)(Cue alkyl)amino-, -(Cue alkyl)-NH2, halo(Cue alkyl), hydroxy-(Cu4 alkyl)-, -(Cu4 alkyl)-O-P(O)(OH)2, -(C1-4 alkyl)-O-P(O)(RIRn)2, halo(Cu4 alkoxy), C1.4 alkoxy-, hydroxy-(C2-4 alkoxy)-, -(C2.4 alkoxy)-O-P(O)(OH)2, -(C2-4 alkoxyXO-PCOXRte11)^ -Cu4 alkyl-(Ci-4 alkoxy), and C1-4 alkoxy-(Cu4 alkoxy)-.

[122] In some embodiments, RA1 is ammo or amino(Ci.4 alkyl)-, wherein the (Ci-6 alkyl) of said optionally substituted (Ci^ alkyl)amino- is optionally substituted by 1-4 substituents each independently selected from hydroxy, -O-P(O)(OH)2, -0^(0)(^^)2, Ci-4 alkoxy-, -N(Re)(Rf), -CO2(Rf), -CON(Re)(Rf), optionally substituted phenyl, and optionally substituted 5-6 membered heteroaryl group, wherein said optionally substituted phenyl or 5-6 membered heteroaryl is optionally substituted by 1-4 substituents each independently selected from halogen, hydroxy, -O-P(O)(OH)2, -0-P(0)(RtR11)2, amino, (Cue alkyl)amino-, (Ci-6 alkyl)(Ci-6 alkyl)amino-, -(Cue alkyl)-NH2, halo(Cn6 alkyl), hydroxy-(C1-4 alkyl)-, -(C1-4 alkyl)-O-P(O)(OH)2, -(C1-4 alkyl)-O-P(0)(RtRit)2, halo(Ci-4 alkoxy)-, C1-4 alkoxy-, hydroxy-(C2-4 alkoxy)-, -(C2-4 alkoxy)-O-P(O)(OH)2, -(C2-4alkoxy)-O~P(O)(R1RII)2, -C1-4 alkyl-(Ci-4 alkoxy), and C1-4 alkoxy-(Ci-4 alkoxy)-

[123] In some embodiments, RA1 is hydroxy, -O-P(O)(OH)2, -O-PiOjfR^1^, -N(Re)(Rf), -CO2Rf, -N(Rf)C0Rb, -N(Rg)SO2(Cn4 aikyl)-X(R j(R=). -N(Rg)CO(Cn4 alkyl)-N(Rh)(Rf), optionally substituted (Ci-6 alkyl), optionally substituted (Ci-6 alkyl)oxy-, optionally substituted (Ci-6 alkyl)amino-, and optionally substituted (Ci-6 alkyl)(Ci-4 alkyl)amino-, wherein the (Ci-6 alkyl) of said optionally substituted (Ci-6 alkyl), optionally substituted (Ci-6 alkyl)oxy-, optionally substituted (Ci-6 alkyl)amino- and optionally substituted (Cw alkyl)(Cn4 alkyl)amino- is optionally substituted by 1-4 substituents each independently selected from hydroxy, -O-P(O)(OH)2, -O-P(O)(R'RHb. Cm alkoxy-, -N(Re)(Rf), -CO (Rf). -CON(Re)(Rf), optionally substituted phenyl, and optionally substituted 5-6 membered heteroaryl group, wherein said optionally substituted phenyl or 5-6 membered heteroaryl is optionally substituted by 1-4 substituents each independently selected from halogen, hydroxy, -O-P(O)(OH)2, -O-P(O)(R1Rlf)2, amino, (Cur, alkyl)amino-, (Cue alkyl)(Cj-6 alkyl)amino-, -(Cue alkyl)-NH2, halo(Ci-6 alkyl), hydroxy-(Cu4 alkyl)-, -(Ci-4 alkyl)-O-P(O)(OH)2, -(C1-4 alkyl)-O-P(O)(RIRu)2, halo(Cu4 alkoxy), Ch alkoxy-, hydroxy-(C2^ alkoxy)-, -(C2-4 alkoxy)-O-P(O)(OH)2, -(C2.4 alkoxy)-O-P(O)(RIR1I)2, -C1-4 alkyl-(Ci-4 alkoxy), and C1-4 alkoxy-(Ci-4 alkoxy)-.

[124] In some embodiments, RAs is optionally substituted (Cue alkyl)oxy-, wherein the (Ci-6 alkyl) of said optionally substituted (Cue alkyl)oxy- is optionally substituted by 1-4 substituents each independently selected from hydroxy, -O-P(O)(()H)2, -O-P(O)(RfRu)2, C1-4 alkoxy-, -N(Re)(Rr), -0()28^), -C0N(Re)(Rf), optionally substituted phenyl, and optionally substituted 5-6 membered heteroaryl group, wherein said optionally substituted phenyl or 5-6 membered heteroaryl is optionally substituted by 1-4 substituents each independently selected from halogen, hydroxy, -O-P(O)(OH)2, -O-P(O)(RTRn)2, amino, (Ci-6alkyl)amino-, (Cue alkyl)(Ci-6 alkyl)amino-, -(Ci-6 alkyl)-NH2, halo(Ci-6 alkyl), hydroxy-(Ci-4 alkyl)-, -(C4.4 alkyl)-O-P(O)(OH)2, -(Ci-4 alkyl)-O-P(O)(RIRII)2, halo(Ci-4 alkoxy)-, C1-4 alkoxy-, hydroxy-(C2-4 alkoxy)-, -(C2-4 alkoxy)-O-P(O)(OH)2, -(C2-4alkoxy)-O-P(O)(RTRIT)2, -Ci-4 alkyl-(Ci-4 alkoxy), and C1.4 alkoxy-(Ci-4 alkoxy)-

[125] In some embodiments, RAI is substituted (Cue alkyl)oxy-, wherein the (Ci-6 alkyl) of said substituted (Cue alkyl)oxy- is substituted by 1-4 substituents each independently selected from hydroxy, -O-P(O)(OH)2, -O-P(O)(RIRn)2, C1-4 alkoxy-, -N(Re)(Rf), -CO2(Rf), -CON(Re)(Rf), optionally substituted phenyl, and optionally substituted 5-6 membered heteroaryl group, wherein said optionally substituted phenyl or 5-6 membered heteroaryl is optionally substituted by 1-4 substituents each independently selected from halogen, hydroxy, -O-P(O)(OH)2, -O-P(O)(RIR1I)2, amino, (Ci-6 alkyl)ammo-, (Ci-6 alkyl)(Ci-6 alkyl)ammo-, -(C1-6 alkyl)-NH2, halo(Ci-6 alkyl), hydroxy-(Ci-4 alkyl)-, -(C1-4 alkyl)-O-P(O)(OH)2, -(C1-4 aIkyi)-O“P(O)(R:Rn)?., halo(Ci-4 alkoxy), Ci-4 alkoxy-, hydroxy-(C2-4 alkoxy)-, -(C2-4 alkoxy)-O-P(O)(OH)2, -(C2-4 alkoxy)-O-P(O)(RIRI1)2, -C1-4 alkyl-(Ci-4 alkoxy), and C1-4 alkoxy-(Ci-4 alkoxy)-.

[126] In some embodiments, RA1 is substituted (Ci-6 alkyl)oxy-, wherein the (C1-6 alkyl) of said substituted (Cj-6 alkyl)oxy- is substituted by hydroxy. In some embodiments, RA! is -OCH2CH2CH2OH.

[127] In some embodiments, RA1 is hydroxy(C2-6 alkyl)oxy-. In some embodiments, RA1 is HO(O)C-(C2-6 alkyl)oxy-. In some embodiments, RA! is -OCH2CH2CH2COOH.

[128] In some embodiments, RA1 is amino(C2-6 alkyl)oxy-. In some embodiments, Ra! is -OCH2CH2CH2NH2.

[129] In some embodiments, RAs is (C1-6 alkyl)oxy-. In some embodiments, RAs is (methyl)oxy-( / .e. methoxy).

[130] In some embodiments, RAs is -OH. In some embodiments, RA1 is amino.

[131] In some embodiments, RA1 is amino(Ci-4 alkyl)-.

[132] In some embodiments, RA2 and RA1 are each independently H, halogen, hydroxy, amino, amino(Ci-4 alkyl)-.optionally substituted (Cue alkyl), or optionally substituted (Cue alkyl)oxy-, wherein Ci-6 alkyl of said optionally substituted (Cue alkyl), or optionally substituted (Ci-6 alkyl)oxy- is optionally substituted with 1-4 substituents each independently selected from the group comprising hydroxy, -O-P(O)(OH)2, Cm alkoxyl, -N(Re)(Rf), -COOH, and optionally substituted phenyl, and each Re is independently selected from H, C1.4 alkyl, -C0(Cm alkyl), -OCO(Ci-4 alkyl), - (C1.4 alkyl)NH2, -(C1.4 alkyl)(Ci-4 alkoxy), and -C02(Cm alkyl). [133 ] In some embodiments, RA2 and RAJ are each independently H, halogen, hydroxy, amino, ammo(Cr.4 alkyl)-, optionally substituted (Cm alkyl), or optionally substituted (Cue alkyl)oxy-, and the C1-6 alkyl of said optionally substituted (Cm alkyl), optionally substituted (Ci-6 alkyl)oxy-is optionally substituted with 1-4 substituents each independently selected from the group comprising hydroxy, -O-P(O)(OH)2, -O-P(O)(RIRI1)2, -N(Re)(Rf), C1-4 alkoxyl, phenyl, and optionally substituted 5-6 membered heteroaryl comprising at least one nitrogen or oxygen as a member of the ring, and each Re is each independently selected from H, C1-4 alkyl, -(C1-4 alkyl)NH2, and -(C1.4 alkyl)Ci-4 alkoxy.

[134] In some embodiments, at least one of RA2 or RA1 are each independently H, hydroxy, halogen, amino, ammo(Ci-4 alkyl)-, optionally substituted (Cm alkyl), or optionally substituted (Cm alkyl)oxy-, and the Cm alkyl of said optionally substituted (Cm alkyl), optionally substituted (Cm alkyl)oxy- is optionally substituted with 1-4 substituents each independently selected from -N(Re)(R!), tetrahydropyran, pyrrolidinyl, piperazinyl, piperidyl and morpholinyl and each Re is each independently selected from H, Cm alkyl, -(Cm alkyl)NH2, and -(Cm alkyl)CM alkoxy.

[135] In some embodiments, at least one of RA2 or RA1 are each independently H, hydroxy, halogen, amino, amino(Ci-4 alkyl)-, optionally substituted (Cm alkyl), or optionally substituted (Cm alkyl)oxy-, and the Cm alkyl of said optionally substituted (Cm, alkyl), optionally substituted (Cm alkyl)oxy- is optionally substituted with 1-4 substituents each independently selected from tetrahydropyran, pyrrolidinyl, piperazinyl, piperidyl and morpholinyl, and each R® is each independently selected from H and Cm alkyl.

[136] In some embodiments, RA2 is H, halogen, amino, amino(Ci-4 alkyl)-, hydroxy, -O-P(O)(OH)2, -O-P(O)(RiR1i)2, -N(IV)(Rf), -CO2Rf, -N(Rf)CORb, -N(Rg)SO2(Ci-4 alky^-N^XR*), -N(Rg)CO(Ci-4 alkyl)-N(Rh)(R1), optionally substituted (Cm alkyl), optionally substituted (Cue alkyl)oxy-, optionally substituted (Cm alkyl)amino-, and optionally substituted (Cm alkyl)(Ci-4 alkyl)ammo-, wherein the (Cm alkyl) of said optionally substituted (Cm alkyl), optionally substituted (Cm alkyl)oxy-, optionally substituted (Cm alkyl)amino- and optionally substituted (Cm alkyl)(Ci-4 alkyl)amino- is optionally substituted by 1-4 substituents each independently selected from hydroxy, -O-P(O)(OH)2, 4)^(0)(11¾11^ C1.4 alkoxy-, -N(Re)(Rf), -CO2(Rf), -CON(Re)(Rf), optionally substituted phenyl, and optionally substituted 5-6 membered heteroaryl group, wherein said optionally substituted phenyl or 5-6 membered heteroaryl is optionally substituted by 1-4 substituents each independently selected from halogen, hydroxy, -O-P(O)(OH)2, -O-P(O)(RIR1I)2, ammo, (Cue alkyl)amino-, (Cm alkyl)(Ci..6 alkyl)amino-, -(Cue             halo(Ci-6 alkyl), hydroxy-(Ci.4 alkyl)-, -(Ci-4 alkyl)-O-P(O)(OH)2, -(Cm alkyl)-O~P(O)(R1Rn)2, halo(Ci-4 alkoxy), Cm. alkoxy-, hydroxy-(C2-4 alkoxy)-, -(C2-4 alkoxy)-O-P(O)(OH)2, -(C2-4 alkoxy)-O-P(O)(R1RI1)2, -C1-4 alkyl-(CM alkoxy), and Cm alkoxy-(Ci-4 alkoxy)-.

[137] In some embodiments, RA2 is H.

[138] In some embodiments, RA2 is halogen, amino, amino(Ci-4 alkyl)-, hydroxy, -O-P(O)(OH)2, -0^(0)(^^)2, -N(Re)(Rf), -CO2Rf, -N(Rf)CORb, -N(R8)SO2(Cn4 aikvIl-MOR'). -N(R8)C0(Cm alkyl)-N(Rh)(RI), optionally substituted (C1-6 alkyl), optionally substituted (Ci-e alkyl)oxy~, optionally substituted (C1-6 alkyl)amino-, and optionally substituted (Ci-6 alkyl)(Ci-4 alkyl)amino-, wherein the (Cm alkyl) of said optionally substituted (Ci-6 alkyl), optionally substituted (Cm alkyl)oxy-, optionally substituted (Cm alkyl)amino- and optionally substituted (Ci-e alkyl)(Ci-4 alkyl)ammo- is optionally substituted by 1-4 substituents each independently selected from hydroxy, -O-P(O)(OH)2, -O-P(O)(R;Rn)2, Ci-4 alkoxy-, -N(Re)(Rf), -CO2(Rf), -C0N(Re)(Rf), optionally substituted phenyl, and optionally substituted 5-6 membered heteroaryl group, wherein said optionally substituted phenyl or 5-6 membered heteroaryl is optionally substituted by 1-4 substituents each independently selected from halogen, hydroxy, -O-P(O)(OH)2, -O-P(O)(RIR1I)2, amino, (Ci-6 alkyl)amino-, (Ci-6 alkyl)(Ci-6 alkyl)amino-, -(Cj-6 alkyl)-NH2, halo(Ci-6 alkyl), hydroxy-(Ci-4 alkyl)-, -(Cm alkyl)-O-P(O)(OH)2, -(Cm alkyl)-O-P(O)(RIRn)2, halo(Cu4 alkoxy), Cm alkoxy-, hydroxy-(C2-4 alkoxy)-, -(C2-4 alkoxy)-O-P(O)(OH)2, -(C2-4alkoxy)-O-P(O)(R1RIi)2, -Cm alkyl-(CM alkoxy), and Cm alkoxy-(CM alkoxy)-.

[139] In some embodiments, RA2 is halogen. In some embodiments, RA2 is F, Cl, Br, or I. In some embodiments, RA‘ is F, Cl, or Br. In some embodiments, RA2 is F. In some embodiments, RA2 is Cl. In some embodiments, RA‘ is Br.

[140] In some embodiments, RA2 is amino, amino(Ci-4 alkyl)-, hydroxy, -O-P(O)(OH)2, -O-1^(0)(1^^^, -\(R}(R-). -CO2Rf, -N(Rf)C0Rb, -N(R8)SO2(Cm alkyl)-N(Re)(Rf), -N(R8)C0(Cm alkyl)-N(Rh)(RI), optionally substituted (Cue alkyl), optionally substituted (Cm alkyl)oxy-, optionally substituted (Ci-6 alkyl)amino-, and optionally substituted (Cm alkyl)(Ci-4 alkyl)amino- wherein the (Cm alkyl) of said optionally substituted (Ci-e alkyl), optionally substituted (Cm alkyl)oxy-, optionally substituted (Cue alkyl)ammo- and optionally substituted (Ci-6 alkyl)(Ci-4 alkyl)amino- is optionally substituted by 1-4 substituents each independently selected from hydroxy, -O-P(O)(OH)2, -O~P(O)(R1RIJ)2, Ci-4 alkoxy-, -N(Re)(Rf), -CO2(Rf), -CON(Re)(Rf), optionally substituted phenyl, and optionally substituted 5-6 membered heteroaryl group, wherein said optionally substituted phenyl or 5-6 membered heteroaryl is optionally substituted by 1-4 substituents each independently selected from halogen, hydroxy, -O-P(O)(OH)2, -O-P(O)(R1Rn)2, amino, (Ci-6 alkyl)ammo-, (Cue alkyl)(Ci-6 alkyl)ammo-, -(Cue alkyl)-NH2, halo(Ci-e alkyl), hydroxy~(Ci-4 alkyl)-, -(Cn4 alkyl)-O-P(O)(OH)2, -(Ci-4 alkyl)-O-P(O)(R!R1I)2, halo(Ci-4 alkoxy), Cm alkoxy-, hydroxy-(C2-4 alkoxy)-, -(C2-4 alkoxy)-O-P(O)(OH)2, -(C2-4 alkoxyXOJXOXR^11)}, -Cm alkyl-(Ci-4 alkoxy), and C1-4 alkoxy-(CM alkoxy)-.

[141] In some embodiments, RAz is amino or amino(Ci-4 alkyl)-, wherein the (Ci-6 alkyl) of said optionally substituted (Cm alkyl)amino- is optionally substituted by 1-4 substituents each independently selected from hydroxy, -O-P(O)(OH)2, -O-P(O)(R1R1I)2, Cm alkoxy-, -N(Re)(Rf), -CO2(Rf), -CON(Re)(Rf), optionally substituted phenyl, and optionally substituted 5-6 membered heteroaryl group, wherein said optionally substituted phenyl or 5-6 membered heteroaryl is optionally substituted by 1-4 substituents each independently selected from halogen, hydroxy, -O-P(O)(OH)2, -O-PfOXR^Xh, amino, (Cm, alkyl)amino-, (Cue, alkyl)(Ci-6 alkyl)amino-, -(Cm, alkyI)-NH2, halo(Ci-6 alkyl), hydroxy-(Cu4 alkyl)-, -(Cm alkyl)-O-P(O)(OH)2, -(Cm alkyl)-O-P(O)(RiRI1)2, halo(CM alkoxy)-, Cm alkoxy-, hydroxy-(C2-4 alkoxy)-, -(C2-4 alkoxy)-O-P(O)(OH)2, -(C2-4alkoxy)-O-P(O)(R!RII)2, -Cm alkyl-(CM alkoxy), and Cm alkoxy-(Ci-4 alkoxy)-

[142] In some embodiments, RA2 is optionally substituted (Cur, alkyl)oxy-, wherein the (Cur, alkyl) of said optionally substituted (Cue alkyl)oxy- is optionally substituted by 1-4 substituents each independently selected from hydroxy, -O-P(O)(OH)2, -O-P(O)(RfRu)2, Cm alkoxy-, -N(Re)(R1), -CO2(Rt), -CON(Re)(Rf), optionally substituted phenyl, and optionally substituted 5-6 membered heteroaryl group, wherein said optionally substituted phenyl or 5-6 membered heteroaryl is optionally substituted by 1-4 substituents each independently selected from halogen, hydroxy, -O-P(O)(OH)2, -O-P(O)(RTRn)2, amino, (Cu6alkyl)amino-, (Cm alkyl)(Ci-6 alkyl)amino- , -(Ci-6 alkyl)-NH2, halo(Ci-6 alkyl), hydroxy-((>M alkyl)-, -(Cm alkyl)-0-P(0)(0H)2, -(Cm alkyl)-0-P(0)(RIRII)2, halo(Ci-4 alkoxy)-, Cm alkoxy-, hydroxy-(C2-4 alkoxy)-, -(62-4 alkoxy)-O-P(O)(OH)2, -(C2-4 alkoxy)-O-P(O)(RTRn)2, -Cm alkyl-(CM alkoxy), and C1.4 alkoxy-(Ci-4 alkoxy)-

[143] In some embodiments, is substituted (Ci-6 alkyl)oxy-, wherein the (Ci-6 alkyl) of said substituted (Cm alkyl)oxy- is substituted by 1-4 substituents each independently selected from hydroxy, -O-P(O)(OH)2, -O-P(O)(RIRn)2, C1-4 alkoxy-, -N(Re)(Rf), -CO2(Rf), -CON(Re)(Rf), optionally substituted phenyl, and optionally substituted 5-6 membered heteroaryl group, wherein said optionally substituted phenyl or 5-6 membered heteroaryl is optionally substituted by 1-4 substituents each independently selected from halogen, hydroxy, -O-P(O)(OH)2, -O-P(O)(RIR1I)2, ammo, (Cue alkyl)amino-, (Ci-6 alkyl)(Ci-6 alkyl)amino-, -(Ci-6 alkyl)-NH2, halo(Ci-6 alkyl), hydroxy-(Ci-4 alkyl)-, -(C1-4 alkyl)-O-P(O)(OH)2, -(Cm alkylj-O-PfOXR^h, halo(Ci-4 alkoxy), Ci-4 alkoxy-, hydroxy-(C2-4 alkoxy)-, -(C2-4 alkoxy)-O-P(O)(OH)2, -(C2-4 alkoxy)-O-P(O)(RIRI1)2, -Cm alkyl-(CM alkoxy), and Cm alkoxy-(Ci-4 alkoxy)-.

[144] In some embodiments, RA2 is substituted (Cm alkyl)oxy-, wherein the (Cm alkyl) of said substituted (Cm alkyl)oxy- is substituted by hydroxy. In some embodiments, RA2 is -OCH2CH2CH2OH.

[145] In some embodiments, RA2 is hydroxy(C2-6 alkyl)oxy-. In some embodiments, RA2 is HO(O)C-(C2-6 alkyl)oxy-. In some embodiments, RA2 is -OCH2CH2CH2COOH.

[146] In some embodiments, RA2 is amino(C2-6 alkyl)oxy-. In some embodiments, RA2 is -OCH2CH2CH2NH2.

[147] In some embodiments, RA2 is (Cm alkyl)oxy-. In some embodiments, RA2 is (methyl)oxy-( / .e. methoxy).

[148] In some embodiments, RA2 is -OH, In some embodiments, RA2 is amino.

[149] In some embodiments, R,A2 is amino(Ci-4 alkyl)-.

[150] In some embodiments, r is 0 and RB1 and RB2 are each independently H, optionally substituted Cm alkyl, halo(Ci-6 alkyl), optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted C3-6 cycloalkyl, optionally substituted 4-6 membered heterocycloalkyl, optionally substituted phenyl, optionally substituted 5-6 membered heteroaryl, or optionally substituted 9-10 membered heteroary l, wherein said optionally substituted Cm alkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted C3-6cycloalkyl, optionally substituted 4-6 membered heterocycloalkyl, optionally substituted phenyl, optionally substituted 5-6 membered heteroaryl, or optionally substituted 9-10 membered heteroaryl is optionally substituted by 1-4 substituents each independently selected from halogen, nitro, -Rc, -OH, -ORC, -NH2, -NRtRc,-NRcRd, -OCORC, -CO2H, -CO2RC, -SORC, -SO2Rc, -CONH2, -CONRcRd, -SO2NH2, -SO2NRcRd, -OCONH2, -OCONRcRd, -NRdCORc, -NRdSORc, -NRdCO2Rc, and -NRdSO2Rc.

[151] In some embodiments, r is 0 and RBl and RB2 are each H.

[152] In some embodiments, r is 0 and RB! and RB2 are each independently H, optionally substituted Cue alkyl, halo(Ci-6 alkyl), optionally substituted C2-e alkenyl, optionally substituted C2-e alkynyl, optionally substituted C3-6 cycloalkyl, optionally substituted 4-6 membered heterocycloalkyl, optionally substituted 5-6 membered heteroaryl or optionally substituted 9 membered heteroaryl.

[153] In some embodiments, s is 0, Wi and Z2 are each independently C or N, and RC1 is absent, H, halogen, or Cm alkyl and RC2 is absent or an optionally substituted Cm alkyl, wherein said optionally substituted Cm alkyl group is optionally substituted by a substituent selected from -ORC, -NRcRd, -CO2Rc, -CONRcRd, -SO2NRcRd, and -OCONRcRd

[154] In some embodiments of the compounds of this disclosure, when s is 0, Wj and Z2 are each independently C or N, and RC1 and RC2 are each independently absent, H or Cm alkyl. In some embodiments, when s is 0, Wj is C, RC1 is Cm alkyl, specifically methyl. In some embodiments, when s is 0, Z2 is C or N, RC2 is Cm, alkyl, specifically methyl or ethyl. In some embodiments, when s is 0, Z2 is C or N, Rc‘ is ethyl.

[155] In some embodiments of the compounds of this disclosure, s is 0, Wi is C, Z2 is O or S, and RC1 is absent, H, halogen, or Cm alkyl and RC2 is absent.

[156] In some embodiments of the compounds of this disclosure, when s is 0, Wi is C, Z2 is O or S, and RCs is absent, H or Cm alkyl and RC2 is absent. In some embodiments, when s is 0, Wi is C, RC1 is Cm alkyl, specifically methyl. In some embodiments, when s is 0, Z2 is O or S, RC2 is Ci-3 alkyl, specifically methyl or ethyl. In some embodiments, when s is 0, Z2 is O or S, RC2 is ethyl.

[157] In some embodiments of the compounds of this disclosure, r is 1 and RB1 and R32 are each independently -CH2-, and B, taken together with RBJ and R32, forms a linking group, wherein B is a bond or B is -halo(Ci-io alkyl)-, optionally substituted -Ci.10 alkyl-, optionally substituted -C2-10 alkenyl-, optionally substituted -€2-10 alkynyl-, optionally substituted -Cm alkyl-O-Ci-6 alkyl-, optionally substituted -CMalkyl-NRa-Ci-6 alkyl-, optionally substituted C3-6 cycloalkyl, optionally substituted phenyl, optionally substituted 4-6 membered heterocycloalkyl, optionally substituted 5-6 membered heteroaryl, optionally substituted -Cm alkyl-(C3-6cycloalkly)-CM alkyl-, optionally substituted -Cm alkyl-phenyl-Ci-4 alkyl-, optionally substituted -Cm alkyl-(4-6 membered heterocycloalkyl)-Ci-4 alkyl-, or optionally substituted -Cm alkyl-(5-6 membered heteroaryl)-Ci-4 alkyl-, wherein the alkyl moiety of said optionally substituted -C1-10 alkyl-, optionally substituted -C2-10 alkenyl-, optionally substituted -C2-10 alkynyl-, optionally substituted -C1-6 alkyl-O-Ci-6 alkyl-, optionally substituted -Cm alkyl-NRa-Ci-6 alkyl-, optionally substituted -Cm alkyl-(C3-6 cycloalkyl)-Ci-4 alkyl-, optionally substituted -Cm alkyl-phenyl-CM alkyl-, optionally substituted -Cm alkyl-(4-6 membered heterocycloalkyl)-Ci-4 alkyl-, or optionally substituted -Cm alkyl-(5-6 membered heteroaryl-Ci-4 alkyl)- is optionally substituted by 1 or 2 substituents each independently selected from halogen, halo(Ci-4 alkyl), -OH, -ORC, -NH2, -NRcRd, -OCORC, -CO2H, -CO2RC, -SORc, -SO2Rc -CONH2, -CONRcRd, -SOAIK -SO2NRcRd -OCONH2, -OCONRcRd, -NRdCORc, -NRdSORc, -NRdCO2Rc, and -NRdSO2Rc, and the C3-6 cycloalkyl, phenyl, 4-6 membered heterocycloalkyl, or 5-6 membered heteroaryl moiety of said optionally substituted C3-6 cycloalkyl, optionally substituted phenyl, optionally substituted 4-6 membered heterocycloalkyl, optionally substituted 5-6 membered heteroaryl, optionally substituted -Cm alkyl-(C3-6 cycloalkyl)-CM alkyl-, optionally substituted -Cm alkyl-phenyl-Ci-4 alkyl-, optionally-substituted -Cm alkyl-(4-6 membered heterocycloalkyl)-CM alkyl-, or optionally substituted -Cu 4 alkyl-(5-6 membered heteroaryl)-Ci-4 alkyl- is optionally substituted by 1-4 substituents each independently selected from halogen, hydroxy, ammo, (Cm alkyl)amino-, (Cm alkyl)(CM alkyl)amino-, -Cm alkyl, halo(CM alkyl), halo(Ct-4 alkoxy)-, -Cm alkoxy-, hydroxy-(C2-4 alkoxy)-, and Cm alkoxy-(Ct-4 alkoxy)-.

[158] In some embodiments of the compounds of this disclosure, r is 1 and R31 and RB2 are each independently -CH2-, and B, taken together with R31 and RBz, forms a linking group, wherein B is a bond or B is -halo(Ci-ioalkyl)-, optionally substituted -C1-10 alkyl-, optionally substituted -C2-10 alkenyl-, optionally substituted -C2-10 alkynyl-, optionally substituted -Cm alkyl-O-Ci-6 alkyl-, optionally substituted -Cm alkyl-NRa-Ci-6 alkyl-, optionally substituted C3-6 cycloalkyl, optionally substituted phenyl, optionally substituted 4-6 membered heterocycloalkyl, optionally substituted 5-6 membered heteroaryl, optionally substituted -Cm aikd-fC-« cycloalkyl)-Ci-4 alkyl-, optionally substituted -C1.4 alkyl-phenyl-Ci-4 alkyl, optionally substituted -C1.4 alkyl-(4-6 membered heterocycloalkyl)-Ci-4 alkyl-, or optionally substituted -C1.4 alkyl-(5-6 membered heteroaryl) C1-4 alkyl-, wherein the alkyl moiety of said optionally substituted -C1-10 alkyl-, optionally substituted -C2-10 alkenyl-, optionally substituted -C2-10 alkynyl-, optionally substituted -C1-6 alkyl-O-Ci-6 alkyl-, optionally substituted -Cue alkyl-NRa-Ci-6 alkyl-, optionally substituted -Cm alkyl-(C3-6 cycloalkyl)-Ci-4 alkyl-, optionally substituted -Cm alkyl-phenyl-Ci-4 alkyl-, optionally substituted -Cm alkyl-(4-6 membered heterocycloalkyl)-CM alkyl-, or optionally substituted -Cm alkyl-(5-6 membered heteroaryl-Ci-4 alkyl)- is optionally substituted by 1 or 2 substituents each independently selected from halogen, halo(Ci-4 alkyl), -OH, -O-P(O)(OH)2, -O-P(O)(RIRI1)2,~ORC, -NH2, -NRcRd, -0C0Rc, -(WL -CO2RC, -SORC, -SO2RC, -CONH2, -CONRcRd, -SO2NH2, -SO2NRcRd, -OCONH2, -0C0NRcRd, -NRdC0Rc, -NRdSORc, -NRd, and NRdSO2Rc, and the C3-6 cycloalkyl, phenyl, 4-6 membered heterocycloalkyl, or 5-6 membered heteroaryl moiety of said optionally substituted C3-6 cycloalkyl, optionally substituted phenyl, optionally substituted 4-6 membered heterocycloalkyl, optionally substituted 5-6 membered heteroaryl, optionally substituted -Cm alkyl-(C3-6 cycloalkyl)-CM alkyl-, optionally substituted -Cm alkyl-phenyl-CM alkyl-, optionally substituted -Cm alkyl-(4-6 membered heterocycloalkyl)-CM alkyl-, or optionally substituted -Cm alkyl-(5-6 membered heteroaryl) Cm alkyl- is optionally substituted by 1-4 substituents each independently selected from halogen, hydroxy, -0-P(0)(0H)2, -O-P(O)(RIRl!)2, amino, (Cm alkyl)amino~, (Cm alkyl)(Ci-4 alkyl)amino-, -Cm alkyl, halo(Ct-4 alkyl), haIo(Cj-4 alkoxy)-, -Cm alkoxy-, hydroxy-(C2-4 alkoxy)-, and -Cm alkoxy-(Ci-4 alkoxy)-.

[159] In some embodiments of the compounds of this disclosure, r is 1, RB1 and R32 are each independently -CH2-, and B, taken together with R31 and R32, forms a 2-6 membered linking group. In a further embodiment, r is 1, RB1 and R32 are each independently -CH2-, and B, taken together with R31 and R32, forms a 3-6 membered linking group. In a still further embodiment, r is 1, RB1 and R32 are each independently -CH2-, and B, taken together with R31 and R32, forms a 4-5 membered linking group.

[160] In some embodiments, B is a bond.

[161] In some embodiments, r is I, RBI and RB2 are each independently -CH2-, and B is a substituted -Ci-10 alkyl- group or is an unsubstituted -C1-10 alkyl-, -C2-10 alkenyl-, -C2-10 alkynyl-, - Cm alkyl-O-Ci-6 alkyl-, or -Ci-6alkyl-NRa-Ci-6alkyl- group, wherein said substituted -Ciaoalkylgroup is substituted by 1-4 substituents each independently selected from halogen, hydroxy, ammo, (CMalkyl)amino-, (Ci-6alkyl)(Ci-6 alkyl)amino-, halo(Ci-6 alkyl), halo(Ci-4 alkoxy)-, -C1.4 alkoxy-, hydroxy-(C2-4 alkoxy)-, -Cm alkoxy-(CM alkoxy)-, -NHCO(Ci-4 alkyl), optionally substituted phenyl, optionally substituted 5-6 membered heterocycloalkyl, and optionally-substituted 5-6 membered heteroaryl, wherein said optionally substituted phenyl, 5-6 membered heterocycloalkyl, or 5-6 membered heteroaryl is optionally substituted by 1-4 substituents each independently selected from halogen, hydroxy, amino, (Cue alkyl)amino-, (Cue alkyl)(Ci-6 alkyl)amino-, halo(Ci-6 alkyl), halo(CM alkoxy)-, -Cm alkoxy-, hydroxy-(C2-4 alkoxy)-, and Cm alkoxy-(Ci-4 alkoxy)-.

[162] In some embodiments, r is 1, RBl and RB2 are each independently -CH2-, and B is a substituted -C1-10 alkyl- group or is an unsubstituted -Ci-w alkyl-, -C2-10 alkenyl-, -C2-10 alkynyl-, -Cm alkyl-O-Ci-6 alkyl-, or -Cm alkyl-NRa-Ci-6 alkyl- group, wherein said substituted -C1-10 alkylgroup is substituted by 1-4 substituents each independently selected from halogen, hydroxy, -O-P(O)(OH)2, -0^(0)^¾¾ ammo, (Cm alkyl)amino~, (C1-6 alkyl)(Ci-6 alkyl)amino-, halo(Ci-6 alkyl), halo(Ci-4 alkoxy)-, -Cm alkoxy-, hydroxy-(C2-4 alkoxy)-, Cm alkoxy-(Ci-4 alkoxy)-, -NHC0(Cm alkyl), optionally substituted phenyl, optionally substituted 5-6 membered heterocycloalkyl, and optionally substituted 5-6 membered heteroaryl, wherein said optionally-substituted phenyl, 5-6 membered heterocycloalkyl, or 5-6 membered heteroaryl is optionally substituted by 1-4 substituents each independently selected from halogen, hydroxy, -O-P(O)(OH)2, -O-P(O)(RIRn)2, amino, (Cm alkyl)ammo-, (Cm alkyl)(Ci-6 alkyljamino-, halo(CM alkyl), halo(CM alkoxy)-, Cm alkoxy-, hydroxy-(C2-4 alkoxy)-, and Cm alkoxy-(Ci-4 alkoxy)-.

[163] In some embodiments, r is 1, RB1 and RBz are each independently -CH2-, and B is a substituted -Ci-w alkyl- group or is an unsubstituted -C1-10 alkyl-, -C2-10 alkenyl-, -C2-J0 alkynyl-, -Cj-6 alkyl-O-Ci-6 alkyl-, or -Cm alkyl-NRa-Ci-6 alkyl- group, wherein said substituted -Ci-ioalkyl-group is substituted by 1-4 substituents each independently selected from halogen, hydroxy, amino, (Cm alkyl)amino-, (Cm alkyl)(Ci-4 alkyl)amino-, halo(Ci-4 alkyl), halo(Ci-4 alkoxy)-, and Cm alkoxy-.

[164] In some embodiments, r is 1, RB1 and RB2 are each independently -CH2-, and B is a substituted -Cnio alkyl- group or is an unsubstituted -Ci-io alkyl-, -C2-10 alkenyl-, -C2-10 aikynyl-, -Cm alkyl-O-CM alkyl-, or -Cm alkyl-NRa-CM alkyl- group, wherein said substituted -Ci-10 alkyl- group is substituted by 1-4 substituents each independently selected from halogen, hydroxy, -O-P(O)(OH)2, -O-P(O)(R1RII)2, amino, (C1.4 alkyl)ammo, (Cm alkyl)(Ci-4 alkyl)amino-, halo(Ci-4 alkyl), halo(C 1-4 alkoxy)-, and C1-4 alkoxy-.

[165] In some embodiments, r is I, RBI and RB2 are each independently -CH2-, and B is a substituted -Ci-8 alkyl- group or is an unsubstituted -C1-8 alkyl-, -C2-8 alkenyl-, -C2-8 aikynyl-, -Ci-4 alkyl-O-Ci-4 alkyl-, or -Cm alkyl-NRa~CM alkyl- group, wherein said substituted -Cns alkylgroup is substituted by 1-4 substituents each independently selected from halogen, hydroxy, ammo, (Cm alkyl)amino-, (Cm alkyl)(Ci-4 alkyl)amino-, halo(Ci-4 alkyl), halo(C 1-4 alkoxy)-, and Ci-4 alkoxy-.

[166] In some embodiments, r is 1, RBl and RB2 are each independently -CH2-, and B is a substituted -Cm alkyl- group or is an unsubstituted -Ci-salkyl-, -C2-8 alkenyl-,-C2-8 aikynyl-, -Cm alkyl-O-CM alkyl-, or -Cm alkyl-NRa-Ci-4alkyl- group, wherein said substituted -Cm alkyl- group is substituted by 1-4 substituents each independently selected from halogen, hydroxy, -O-P(O)(OH)2, -O-P(O)(RiR1I)2, amino, (Cm alkyl)amino~, (Cm alkyl)(CM alkyl)amino-, halo(Ci-4 alkyl), halo(Ci-4 alkoxy)-, and Cm alkoxy-.

[167] In some embodiments, r is 1, RB1 and RB2 are each independently -CH?.-, and B is a substituted -Cue alkyl- group or is an unsubstituted -Cue alkyl-, -C2-6 alkenyl-, -C2-6 aikynyl-, -Cm alkyl-O-C 1-2alkyl-, or -Cm alkyl-NRa-CM alkyl- group, wherein said substituted -Cuealkyl- group is substituted by 1-2 substituents each independently selected from halogen, hydroxy, amino, (Cj. 4 alkyl)amino-, (Cm alkyl)(CM alkyl)ammo-, halo(C 1.4 alkyl), halo(C 1-4 alkoxy)-, and CMalkoxy-

[168] In some embodiments, r is 1, Rb1 and RB2 are each independently -CH?.-, and B is a substituted -Cue alkyl- group or is an unsubstituted -Cue alkyl-, -C2-6 alkenyl-,-C2-6 aikynyl-, -Cm alkyl-O-CM alkyl-, or -Cm alkyl-NRa-CM alkyl- group, wherein said substituted -Cmalkyl- group is substituted by 1-2 substituents each independently selected from halogen, hydroxy, -O-P(O)(OH)2, ammo, (Cm alkyl)amino-, (Cm alkyl)(CM alkyl)amino-, halo(Ci-4 alkyl), halo(Ci-4 alkoxy)-, and Cm alkoxy-.

[169] In some embodiments, r is 1, RB1 and RB2 are each independently -CH?-, and B is a substituted -C2-4 alkyl- group or is an unsubstituted -Cm alkyl-, -C2-4 alkenyl-, -Cm aikynyl-, -Cm alkyl-O-Ci-4alkyl-, or -Cm alkyl-NR8-Cm alkyl- group, wherein said substituted -Cmalkyl- group is substituted by 1-2 substituents each independently selected from halogen, hydroxy, amino, (Ci-4 alkyl)amino-, (Cm alkyl)(Ci-4 alkyl)amino-, halo(Ci-4 alkyl), halo(Ci-4 alkoxy)-, and Ci.4alkoxy-

[170] In some embodiments, r is 1, RBj and RB2 are each independently -CH2-, and B is a substituted -C2-4 alkyl- group or is an unsubstituted -C2.4 alkyl-, -C2-4 alkenyl-,-Cm alkynyl-, -Ci alkyl-O-Ci alkyl-, or -Ci alkyl-NRa-Ci alkyl- group, wherein said substituted -Cm alkyl- group is substituted by 1-2 substituents each independently selected from halogen, hydroxy, -O-P(O)(OH)2, amino, (C1-4 alkyl)amino-, (Cm alkyl)(Ci-4 alkyl)amino-, halo(Ci-4 alkyl), halo(Ci-4 alkoxy)-, and Ci-4 alkoxy-.

[171] In some embodiments, r is 1, RB1 and R02 are each independently -CH2-, and B is -CH=CH-, -CH2CH2-, -CH(OH)CH(OH)-, or -CIIA (ClI3)CII2-. In some embodiments, r is 1, B, taken together with RB1 and RB2, form a -CH2CH=CHCH2-, -CH2CH2CH2CH2-, -CH2CH(OH)CH(OH)CH2-, or -CH2CH2N(CH3)CH2CH2- group. In some embodiments, r is 1, B, taken together with RB1 and RB2, form a -CH2CH=CHCH2-.

[172] In some embodiments of the compounds of this disclosure, when s is 1, Wi and Z2 are each independently C or N, RC1 and RC2 are each independently -CH2-, and I), taken together with RC1 and RC2, forms a linking group, wherein D is -halo(Ci-i2 alkyl)-, optionally substituted -C1-12 alkyl, optionally substituted -C2-12 alkenyl-, optionally substituted -C2-j2 alkynyl-, optionally substituted -Cm alkyl-O-Ci-6 alkyl-, optionally substituted -Cm alkyl-NRa-Ci-6 alkyl-, optionally substituted -Cm alkyl-(C3-6 cycloalkyl)-CM alkyl -, optionally substituted -Cm, alkyl-phenyl-Ci-6 alkyl-, optionally substituted -Cur, alkyl-(4-6 membered heterocycloalkyl)-Cj-6 alkyl-, or optionally substituted -Cm alkyl-(5-6 membered heteroaryl)-CM alkyl-, wherein the alkyl moiety of said optionally substituted -Cuj2 alkyl-, optionally substituted -C2.j2 alkenyl-, optionally substituted -C2-12 alkynyl-, optionally substituted -Cm, alkyl-O-Cj-6 alkyl-, optionally substituted -Cm, alkyl-NRa-Ct-6 alkyl-, optionally substituted -Cm alkyl-(-C3-6 cycloalkyl)-Ci-6alkyl-, optionally substituted -Cm alkyl-phenyl-Cne alkyl-, optionally substituted -Cm alkyl-(4-6 membered heterocycloalkyl)-Ci-6 alkyl-, or optionally substituted -Cue alkyl-(5-6 membered heteroaryl)-Ci-6 alkyl- is optionally substituted by 1 or 2 substituents each independently selected from halogen, halo(Ci-4 alkyl), -OH, -ORC, -NH2, -NReRd, -OCORe, -CO2H, -CO2RC, -SORc, -SO2Rc, CONH2, -CONRcRd, -SO2NH2, -SO2NRcRd, -OCONH2, -OCONRcRd, -NRdCORc, -NRdSORc, -NRdCO2Rc, and -NRdSO2Rc, and the Cm cycloalkyl, phenyl, 4-6 membered heterocycloalkyl, or 5-6 membered heteroaryl moiety of said optionally substituted -Cm alkyl-(C3-6 cycloalkyl)-CM alkyl-, optionally substituted -Cm alkyl-phenyl-Ci-6 alkyl-, optionally substituted -Ci-6 alkyl-(4-6 membered heterocycloalkyl)-Ci-6 alkyl-, or optionally substituted -Cue alkyl-(5-6 membered heteroaryl)-Ci-6 alkyl- is optionally substituted by 1-4 substituents each independently selected from halogen, hydroxy, ammo, (Cm alkyl)ammo-, (Cm alkyl)(CM alkyl)amino-, Cm alkyl, halo(C 1-4 alkyl), halo(C 1-4 alkoxy)-, Cm alkoxy-, hydroxy-(C2-4 alkoxy)-, and Cm alkoxy-(Ci-4 alkoxy)-.

[173] In some embodiments of the compounds of this disclosure, when s is 1, Wi and Z2 are each independently C or N, RC1 and RC2 are each independently -CH2-, and D, taken together with Ru and RCz, forms a linking group, wherein D is -halo(Cni2 alkyl)-, optionally substituted -C1-12 alkyl, optionally substituted -62-12 alkenyl-, optionally substituted -C2-12 alkynyl-, optionally substituted -Cm alkyl-O-CM alkyl-, optionally substituted -Cm alkyl-NRa-CM alkyl-, optionally substituted -Cm alkyl-(C3-6 cycloalkyl)-Ci-6 alkyl-, optionally substituted -Ci-6 alkyl-phenyl-C 1-6 alkyl-, optionally substituted -Cm alkyl-(4-6 membered heterocycloalkyl)-CM alkyl-, or optionally substituted -Cm alkyl-(5-6 membered heteroaryl)-Ci-6 alkyl-, wherein the alkyl moiety of said optionally substituted -C1-12 alkyl-, optionally substituted -C2-12 alkenyl-, optionally substituted -C2-12 alkynyl-, optionally substituted -Cm alkyl-O-Ci-6 alkyl-, optionally substituted -Cue alkyl-NRa-CM alkyl-, optionally substituted -Cm alkyl-(C3-6 cycloalkyl)-Ci-6 alkyl-, optionally substituted -Cm alkyl-phenyl-CM alkyl-, optionally substituted -Cm alkyl-(4-6 membered heterocycloalkyl)-Ci-6 alkyl-, or optionally substituted -Cm alkyl-(5-6 membered heteroaryl)-CM alkyl- is optionally substituted by 1 or 2 substituents each independently selected from halogen, halo(C 1-4 alkyl), -OH, -O-P(O)(OH)2, -O-P(O)(RIRn)2,-ORe, -NI-I2, -NRcRd, -OCORC, -CO2H, -CO2Rc, -SORc, -SO2Rc, -CONH2, -CONRcRd, -SO2NH2, -SO2NRcRd, -OCONH2, -OCONRcRd, -NRdCORe, -NRdSORc, -NRdCO2Rc, and -NRdSO2Rc, and the C3-6 cycloalkyl, phenyl, 4-6 membered heterocycloalkyl, or 5-6 membered heteroaryl moiety of said optionally substituted -Cm alkyl-(C3-6 cycloalkyl)-CM alkyl-, optionally substituted -Cm alkyl-phenyl-Ci-6 alkyl-, optionally substituted -Cm alkyl-(4-6 membered heterocycloalkyl)-Ci-6 alkyl-, or optionally substituted -Cm alkyl-(5-6 membered heteroaryl)-Ci-6 alkyl- is optionally substituted by 1-4 substituents each independently selected from halogen, hydroxy,-O-P(O)(OH)2, -O-P(O)(R1Rn)2, amino, (Cm alkyl)amino-, (Cm alkyl)(Ci-4 alkyl)amino-, Cm alkyl, halo(Ci-4 alkyl), halo(Ci-4 alkoxy)-. Cm alkoxy-, hydroxy-(C2-4 alkoxy)-, -(C2-4 alkoxy)-O-P(O)(OH)2, -(C2-4 alkoxy)-O-P(O)(R1RI1)2, and Cm alkoxy-(Ci-4 alkoxy)-.

[174] In some embodiments of the compounds of this disclosure, s is 1, Wi and Z2 are each independently C or N, Ru and RC2 are each independently -CH2-, and D, taken together with RCi and RC2, forms a 4-8 membered linking group. In a further embodiment, s is 1, Wi and Z2 are each independently C or N, and D, taken together with Ru and Ru, forms a 4-6 membered linking group. In a still further embodiment, s is 1 and D, taken together with RC1 and Rt2, forms a 5 membered linking group.

[175] In some embodiments, when s is 1, Wi and Z2 are each independently C or N, RCi and Rc2 are each independently -CH2-, and D is a substituted -C2-10 alkyl- group or is an unsubstituted -C2-10 alkyl-, -C2-10 alkenyl-, -C2-10 alkynyl-, -C1-4 alkyl-O-Ci-4 alkyl-, or -C1.4 alkyl-NRa-Ci-4 alkylgroup, wherein said substituted -C2-10 alkyl- group is substituted by 1-4 substituents each independently selected from halogen, hydroxy, amino, (C1-4 alkyl)amino~, (C1-4 alkyl)(Ci-4 alkyl)amino-, halo(Ci4 alkyl), halo(Ci-4 alkoxy)-, and C1-4 alkoxy-.

[176] In some embodiments, s is 1, Wi and Z2 are each independently C or N, RC1 and RC2 are each independently -CH2-, and D is a substituted -C2-10 alkyl- group or is an unsubstituted -C2-10 alkyl-, -C2-10 alkenyl-, -C2-10 alkynyl-, -C1-4 alkyl-O-Ci-4 alkyl-, or -Cm alkyl-NRa-Ci-4 alkylgroup, wherein said substituted -C2-10 alkyl- group is substituted by 1-4 substituents each independently selected from halogen, hydroxy, -O-P(O)(OH)2, -O-P(O)(R1RII)2, amino, (Cm alkyl)ammo-, (CMalkyl)(CMalkyl)amino-, halo(CM alkyl), halo(CM alkoxy)-, and Cm alkoxy-.

[177] In some embodiments, s is 1, Wi and Z2 are each independently C or N, RC1 and RC2 are each independently -CH2-, and D is a substituted -C2-8 alkyl- group or is an unsubstituted -C2-8 alkyl-, -C2-8 alkenyl-, -C2-8alkynyl-, -Cm alkyl-O-Ci-2alkyl-, or -Cm alkyl-NRa-Cj-2 alkyl- group, wherein said substituted -C2-8 alkyl- group is substituted by 1-2 substituents each independently-selected from halogen, hydroxy, amino, (CMalkyl)amino-, (Cm alkyl )(Cm alky l)amino-, halo(Cu 4 alkyl), halo(Ci-4 alkoxy)-, and Cm alkoxy-.

[178] In some embodiments, s is I, Wi and Z2 are each independently C or N, RC1 and Rc‘ are each independently -CH2-, and D is a substituted -C2-8 alkyl- group or is an unsubstituted -C2-8 alkyl-, -C2-8 alkenyl-, -€2-8 alkynyl-, -C1-2 alkyl-O-Ci .2 alkyl-, or -Cm alkyl-NRa-Ci-2 alkyl- group, wherein said substituted -C2-8 alkyl- group is substituted by 1-2 substituents each independently selected from halogen, hydroxy, -O-P(O)(OH)2, -04^(0)^¾1% ammo, (C1.4 alkyl)ammo-, (C1.4 alkyl)(Ci.4alkyl)ammo-, halo(Ci-4 alkyl), halo(Ci-4 alkoxy)-, and Cm alkoxy-.

[179] In some embodiments, s is 1, Wi and Z2 are each independently C or N, Ru and RC2 are each independently -CH2-, and D is a substituted -C2-6 alkyl- group or is an unsubstituted -C2-6 alkyl-, -C2-6 alkenyl-, -C2-6 alkynyl-, -C1-2 alkyl-O-Ci-2 alkyl -, or -Ci-2alkyl-NRa-Ci-2alkyl- group, wherein said substituted -C2-6 alkyl- group is substituted by 1-2 substituents each independently selected from halogen, hydroxy, amino, (Ci-4alkyl)amino-, (Ci-4alkyl)(Ci-4alkyl)amino-, halo(Cn 4 alkyl), halo(Ci-4 alkoxy)-, and Cm alkoxy-.

[180] In some embodiments, s is 1, Wi and Z2 are each independently C or N, RC: and RC2 are each independently -CH2-, and D is a substituted -C2-6 alkyl- group or is an unsubstituted -C2-6 alkyl-, -C2-6 alkenyl-, -C2-6 alkynyl-, C1-2 alkyl-O-Ci-2 alkyl ~, or -C1-2 alkyl-NRa-Ci-2 alkyl- group, wherein said substituted -C2-6 alkyl- group is substituted by 1-2 substituents each independently selected from halogen, hydroxy, -O-P(O)(OH)2, -O-P(O)(RIRI1)2, amino, (Cm alkyl)amino-, (Cm alkyl)(CMalkyl)amino-, halo(Ci-4 alkyl), halo(Ci-4 alkoxy)-, and Cm alkoxy-.

[181] In some embodiments, s is 1, Wi and Z2 are each independently C or N, RC1 and RC2 are each independently -CH2-, and D is a -C2-4 alkyl-, -C2-4 alkenyl-, or -C2-4 alkynyl- group.

[182] In some embodiments, s is 1, Wi and Z2 are each independently C or N, RC1 and RC2 are each independently -CH2-, and I) is -CH2CH2CH2-, wherein D, taken together with RC1 and RC2, form a -CH2CH2CH2CH2CH2- group.

[183] In some embodiments, R3 and R5 are each independently -CON(Rd)(Rf), -CH2N(Rd)(Rf), -N(Rd)(Rf), -N(Rd)CO(Rf), or -CH2N(Rd)CO(Rf).

[184] In some embodiments, one of R3 and R5 is -CON(Rd)(R1), -CH2N(Rd)(Rf), -N(Rd)(Rf), -N(Rd)CO(Rf) or -CH2N(Rd)CO(Rf), and the other of R3 and R5 is H, COOH or -CO2RC.

[185] In some embodiments, R and R5 are each independently -CON(Rd)(Rf), or one of R' and R5 is -CON(Rd)(Rf), and the other of R3 and R5 is H, COOH, or -CO2Rc. In some embodiments, R3 and R5 are each independently -CON(Rd)(Rf), or one of R3 and R5 is -CON(Rd)(Rf), and the other of R’ and R5 is H or -CO2Rc. In some embodiments, R3 and R’ are each independently -CON(Rd)(Rf). In some embodiments, one of R3 and R’ is -CON(Rd)(Rf) and the other of R3 and R5 is H. In some embodiments, one of R3 and R5 is -CON(Ra)(Rf) and the other of R3 and R5 is -CO2Rc In some embodiments, one of R3 and R' is -CON(Rd)(Rf) and the other of R3 and R5 is -CON(Rd)(Rf).

[186] In some embodiments, R3 and R3 are each independently -CH2N(Rd)(Rf) or one of R' and R5 is -CH2N(Rd)(Rf), and the other of R3 and R5 is H, COOH, or -CO2RR In some embodiments, R3 and R5 are each independently -CH2N(Rd)(Rf) or one of R3 and R5 is -CH2N(Ra)(Rf), and the other of R3 and R5 is H or -CO2Rc. In some embodiments, R3 and R3 are each independently -CH2N(Rd)(Rf). In some embodiments, one of R3 and R3 is -CH2N(Rd)(Rf) and the other of R3 and R5 is H. In some embodiments, one of R’ and R5 is -CH2N(RQ)(Rt) and the other of R3 and R3 is -CO2(Rc)- In some embodiments, one of R3 and R3 is -CH2N(Ra)(Rf) and the other of R3 and R3 is -CON(Rd)(Rf).

[187] In some embodiments, R3 and R3 are each independently -N(Rd)(Rf) or one of R3 and R3 is -N(Rd)(Rf), and the other of R3 and R3 is H, COOH, or -CO2(Rc). In some embodiments, R3 and R5 are each independently ~N(Rd)(R!) or one of R3 and R3 is -N(Rd)(Rf), and the other of R3 and R5 is H or -CO2Rc. In some embodiments, R3 and R5 are each independently -N(Rd)(Rf). In some embodiments, one of R3 and R5 is -N(Rd)(Rr) and the other of R3 and R5 is H. In some embodiments, one of R3 and R5 is -N(Rd)(Rf) and the other of R3 and R5 is -CO2Rc. In some embodiments, one of R3 and R5 is -N(Ra)(Rf) and the other of R3 and R5 is -CON(Rd)(Rf).

[188] In some embodiments, R3 and R5 are each independently -N(Rd)CO(Rf) or one of R3 and R3 is -N(Rd)CO(Rf), and the other of R3 and R5 is H, COOH, -CO2Rc or -CON(Rd)(R!). In some embodiments, R3 and R5 are each independently -N(Rd)CO(Rf) or one of R3 and R5 is -N(Rd)CO(Rf), and the other of R3 and R3 is H or -CO?Rc. In some embodiments, R3 and R3 are each independently -N(Ra)CO(Rf). In some embodiments, one of R3 and R5 is -N(Rd)CO(R!) and the other of R3 and R3 is H. In some embodiments, one of R3 and R5 is -N(R“)CO(R1) and the other of R3 and R3 is -CO?Rc In some embodiments, one of R3 and R3 is -N(Rd)CO(Rf) and the other of R3 and R5 is -CON(Rd)(Rf).

[189] In some embodiments, R3 and R3 are each independently -CH2N(Rd)CO(Rf) or one of R3 and R5 is -CH2N(Rd)CO(Rf), and the other of R3 and R5 is H, COOH, -CO2Rc or -CON(Rd)(Rf). In some embodiments, R3 and R5 are each independently -CH2N(Rd)CO(R1) or one of R3 and R5 is -CH2N(Ra)CO(Rf), and the other of R3 and R5 is H or -CO2Rc. In some embodiments, R3 and R5 are each independently -CH2N(Rd)CO(Rt). In some embodiments, one of R3 and R3 is -CH2N(Rd)CO(Rf), and the other of R3 and R3 is H. In some embodiments, one of R3 and R5 is -CH2N(Rd)CO(Rf), and the other of R3 and R5 is -CO2Rc. In some embodiments, one of R3 and R5 is -CH2N(Rd)CO(Rf) and the other of R3 and R3 is -CON(Rd)(Rf).

[190] In some embodiments, R3 and R5 are each -CONH2.

[191] In some embodiments, one ofR3 andR5 is -CH2NH2, and the other ofR3 andR3 is -CONH2. In some embodiments, one ofR3 and R5 is -CONH2, and the other ofR3 and R5 is -COOCH3. In some embodiments, one of R3 and R3 is -CH2N(CH3)2, and the other of R3 and R5 is -CONH2. In some embodiments, one ofR3 and R3 is -CH2NHC(O)CH3, and the other of R3 and R3 is -CONH2. In some embodiments, one of R3 and R3 is -NHC(O)CH3, and the other of R3 and R5 is -CONH2. In some embodiments, one of R3 and R5 is -NH2, and the other of R3 and R3 is -CONH2.

[192] In some embodiments, R4 and R6 are each independently H, halogen, halo C1-4 alkyl), halo(C 1-6 alkoxy)-, hydroxy, -NH2, -NRCRC, -NRcRd -CORe, -CO2RC, -N(Rd)CORe, -N(Rd)SO2Re, -N(Rg)SO2(Ci-2 alkyl)-N(Rh)(Rf), -N(Rg)CO2(Ci-2 aikyl)-N(R!!)(Rf), optionally substituted (C1-4 alkyl), optionally substituted (Cue alkyl)oxy-, optionally substituted (Cue alkyl)amino-, or optionally substituted (Ci^ alkyl)(Ci-4 alkyl)amino-, wherein the (Ci^ alkyl) of said optionally substituted (C1-6 alkyl), optionally substituted (Ci-6 alkyl)oxy~, optionally substituted (C1-6 alkyl)amino- and optionally substituted -(Ci-6 alkyl)(Ci-4 alkyl)amino- is optionally substituted by 1-4 substituents each independently selected from -OH, -ORC, Alb. -NRCRC, -NRcRd, -COJL -CO2RC, -OCORy -CO2Rd -SORC, -SO2RC, -CONH2, -CONRcRd, -SO2NH2, -SO2NRcRd, -OCONH2, -OCONRcRd, -NRdCORc, -NRdSORc, -NRdCO2Rc, -NRdSO2Rc, optionally substituted phenyl, optionally substituted 5-6 membered heterocycloalkyl, and optionally substituted 5-6 membered heteroaryl group, wherein said optionally substituted phenyl, 5-6 membered heterocycloalkyl, or 5-6 membered heteroaryl is optionally substituted by 1-4 substituents each independently selected from halogen, hydroxy, amino, (Cj-4alkyl)amino-, (Ci-4alkyl)(Ci-4alkyl)ammo-, C1-4alkyl, halo(Cj-4alkyl), hydroxy-(Cn 4 alkyl)-, halo(Cj-4 alkoxy)-, C1-4 alkoxy-, hydroxy-(C2-4 alkoxy)-, C1.4 alkoxy-Ci-4 alkoxy)-, -CORd -CON(Rd)(Rf), and -CO2Rd

[193] In some embodiments, R4 and R° are each independently H, halogen, halo(CM alkyl), halo(Ci.6 alkoxy)-, hydroxy, -O-P(O)(OH)2, -O-P(O)(RIR1I)2, -NH2, -NRCRC, -NRcRd -CORC, -CO2Rc, -N(Rd)CORc, -N(Rd)SO2Rc, -N(Rg)SO2(Ci-2 alkyl)-N(Rh)(R, -N(Rg)CO(Cr.2 alkyl)-N(Rh)(Rt), optionally substituted (Ci-6 alkyl), optionally substituted (C2-6 alkyl)oxy-, optionally substituted (Ci^alkyl)amino-, or optionally substituted (Cue alkyl)(Ci-4 alkyl)amino-, wherein the (Ci-6 alkyl) of said optionally substituted (C1-6 alkyl), optionally substituted (Ci-6 alkyl)oxy-, optionally substituted -Cue alkyl)amino- and optionally substituted (Ci-6 alkyl)(Ci-4 alkyl)amino- is optionally substituted by 1-4 substituents each independently selected from -OH, -O-P(O)(OH)2, -O-P(O)(RIRII)2, -ORC, -NH2, -NRCRC, -NRcRd, -CO2H, -CO2RC, OCORC, -CO2Rc, -SORc, -SO2Rc, -CONH2, -CONRcRd, -SO2NH2, -SO2NRcRd -OCONH2, -OCONRcRd, -NRdCORc, -NRdSORc, -NRdCO2Rc, -NRdSO2Rc, optionally substituted phenyl, optionally substituted 5-6 membered heterocycloalkyl, and optionally substituted 5-6 membered heteroaryl group, wherein said optionally substituted phenyl, 5-6 membered heterocycloalkyl, or 5-6 membered heteroaryl is optionally substituted by 1-4 substituents each independently selected from halogen, hydroxy, amino, (Cm alkyl)amino-, (Cm alkyl)(Ci-4 alkyl)ammo-, Cm alkyl, halo(Ci-4 alkyl), hydroxy-(CM alkyl)-, -(Cm alkyl)-O-P(O)(OH)2, -(Cm alkyl)-O-P(O)(R1RIi)2, halo(Ci-4 alkoxy)-, Cm alkoxy-, hydroxy-(C2-4 alkoxy)-, -(C2-4 alkoxy)-O-P(O)(OH)2, -(C2-4 alkoxy)-O-P(O)(RIRl!)2, Cm alkoxy-(Ci-4 alkoxy)-, -CORd, -CON(Rd)(Rf), and -CO2Rd [ 194] In some embodiments, R4 and R° are each H.

[195] In some embodiments, R4 and R° are each independently halogen, halo(Ci-4alkyl), halo(Ci-6 alkoxy)-, hydroxy, -O-P(O)(OH)2, -O-P(O)(RIRII)2, -Nik -NRCRC, -NRcRd, -CORC, -CO2RC, -N(Rd)CORc, -N(Rd)SO2Rc, -N(Rg)SO2(Ci-2 alkyl)-N(Rh)(R, -N(Rg)CO(Ci-2 alkyl)-N(RhXRf), optionally substituted (Ci-6 alkyl), optionally substituted (C2-6 alkyl)oxy-, optionally substituted (Cm alkyl)ammo-, or optionally substituted (CMalkyl)(CMalkyl)amino-, wherein the (Cm alkyl) of said optionally substituted (Cm alkyl), optionally substituted (Cm alkyl)oxy-, optionally substituted -Cm alkyl)amino- and optionally substituted (Cm alkyl)(CM alkyl)amino- is optionally substituted by 1-4 substituents each independently selected from -OH, -O-P(O)(OH)2, -O-P(O)(RIRII)2, -ORC, -NH2, -NRCRC, -NRcRd, -CO2H, -CO2RC, OCORC, -CO2Rc, -SORc, -SO2Rc, -COMP. -CONRcRd, -SO2NH2, -SO2NReRd, -OCONH2, -OCONRcRd, -NRdCORc, -NRdSORc, -NRdCO2Rc, -NRdSO2Rc, optionally substituted phenyl, optionally substituted 5-6 membered heterocycloalkyl and optionally substituted 5-6 membered heteroaryl group, wherein said optionally substituted phenyl, 5-6 membered heterocycloalkyl, or 5-6 membered heteroaryl is optionally substituted by I -4 substituents each independently selected from halogen, hydroxy, amino, (Cm alkyl)amino-, (Cm alkyl)(Ci-4 alkyl)ammo-, Cm alkyl, halo(Ci-4 alkyl), hydroxy-(Ci-4 alkyl)-, -(Cm alkyl)-O-P(O)(OH)2, -(Cm alkyl)-O-P(O)(R1RI1)2, halo(Ci-4 alkoxy)-, Cm alkoxy-, hydroxy-(C2-4 alkoxy)-, -(C2-4 alkoxy)-O-P(O)(OH)2, -(C2-4 alkoxy)-O-P(())(RJRn)2, Cm alkoxy-(Ci-4 alkoxy)-, -CORd, -CON(Rd)(Rf), and -CO2Rd

[196] In some embodiments, R4 is H.

[197] In some embodiments, R4 is halogen, halo(C 1.4 alkyl), halo(Ci-6 alkoxy)-, hydroxy, -O-P(O)(OH)2, -O-P(O)(RiRii)2, -NH2, -NRCRc, -NRcRd, -CORC, -CO2RC, -N(Rd)CORc, -N(Rd)SO2Rc, -N(Rg)SO2(Ci-2 alkyl)-N(Rh)(R, -N(Rg)CO(Ci-2 alkyl)-N(Rh)(Rf), optionally substituted (Ci-6 alkyl), optionally substituted (C2-6 alkyl)oxy-, optionally substituted (Cm alkyl)amino-, or optionally substituted (Cm alkyl)(Ci-4 alkyl)amino-, wherein the (Cue alkyl) of said optionally substituted (Cue alkyl), optionally substituted (Cue alkyl)oxy-, optionally substituted -Cm alkyl)amino- and optionally substituted (Cue alkyl)(Ci-4 alkyl)amino- is optionally substituted by 1-4 substituents each independently selected from -OH, -O-P(O)(OH)2, -O-P(O)(RTRIT)2, -ORC, -NH2, -NRCRC, -NRcRd, -CO2H, -CO2RC, OCORC, -CO2RC, -SORc, -SO2Rc, -CONH2, -CONRcRd, -SO2NH2, -SO2NRcRd, -OCONH2, -OCONRcRd, -NRaCORc, -NRdSORc, -NRaCO2Rc, ~NRdSO2Rc, optionally substituted phenyl, optionally substituted 5-6 membered heterocycloalkyl, and optionally substituted 5-6 membered heteroaryl group, wherein said optionally substituted phenyl, 5-6 membered heterocycloalkyl, or 5-6 membered heteroaryl is optionally substituted by 1 -4 substituents each independently selected from halogen, hydroxy, amino, (Cm alkyl)ammo~, (Cm alkyl)(CM alkyl)ammo-, Cm alkyl, halo(('M alkyl), hydroxy-(Ci-4 alkyl)-, -(Cm alkyl)-O-P(O)(OH)2, -(Cm alkyl)-O-P(O)(RIRII)2, halo(Ci-4 alkoxy)-, Cm alkoxy-, hydroxy-(C2-4 alkoxy)-, -(C2-4 alkoxy)-O-P(O)(OH)2, -(C2-4 alkoxy)-O-P(O)(RIR1I)2, Cm alkoxy-(C 1-4 alkoxy)-, -CORd, -CON(Rd)(Rf), and -CO2Rd

[198] In some embodiments, R6 is H.

[199] In some embodiments, R6 is halogen, halo(Ci-4 alkyl), halo(CM alkoxy)-, hydroxy, -O-P(O)(OH)2, -0-^0)(^1¾ -NH2, -NRcRc, -NRcRd, -CORC, -CO2RC, -N(Rd)CORc, -N(Rd)SO2Rc, -N(Rg)S02(CM alkyl)-N(Rh)(R, -N(Rg)CO(Cn2 alkyb-N(Rh)(Rf), optionally substituted (Cm alkyl), optionally substituted (C2-6 alkyl)oxy-, optionally substituted (Cm alkyl)amino-, or optionally substituted (Cm alkyl)(CM alkyl)amino-, wherein the (Cm alkyl) of said optionally substituted (Cj-e alkyl), optionally substituted (Cm alkyl)oxy-, optionally substituted -Cm alkyl)amino- and optionally substituted (Cm alkyl)(Ci-4 alkyl)amino- is optionally substituted by 1-4 substituents each independently selected from -OH, -O-P(O)(OH)2, -O-P(O)(R!Rfl)2, -ORC, -NH2, -NRCRC, -NRcRd, -CO2H, -CO2RC, OCORC, -CO2Rc, -SORc, -SO2Rc, -CONH2, -CONRcRd, -SO2NH2, -SO2NRcRd, -OCONH2, -0C0NRcRd, -NRdC0Rc, -NRdSORc, -NRdC02Rc, -NRdS()2Rc, optionally substituted phenyl, optionally substituted 5-6 membered heterocycloalkyl, and optionally substituted 5-6 membered heteroaryl group, wherein said optionally substituted phenyl, 5-6 membered heterocycloalkyl, or 5-6 membered heteroaryl is optionally substituted by 1-4 substituents each independently selected from halogen, hydroxy, amino, (C1.4 alkyl)amino-, (Ci-4 alkyl)(Ci-4 alkyl)amino-, Ci-4 alkyl, halo(Ci-4 alkyl), hydroxy-(Ci-4 alkyl)-, -(Cm alkyl)-O-P(O)(OH)2, -(Cm alkyl)-O-P(O)(RTRn)2, halo(Ci-4 alkoxy)-, Ci-4 alkoxy-, hydroxy-(C2-4 alkoxy)-, -(€2-4 alkoxy)-O-P(O)(OH)2, -(C2-4 alkoxy)-O-P(O)(R1R!1)2, Cm a!koxy-(C 1.4 alkoxy)-, -CORQ, -CON(Ra)(Rf), and -CO2Rd.

[200] In some embodiments, R14 is absent, H, halogen, or optionally substituted Cm alkyl, wherein said optionally substituted Cm alkyl is optionally substituted by a substituent selected from halogen, -ORC, -NRcRd, -CO2RC, -CONRcRd, -SO2NRcRd, and -OCONRcRd.

[201] In some embodiments, R14 is absent

[202] In some embodiments, R14 is H, halogen, or optionally substituted Cm alkyl, wherein said optionally substituted Cm alkyl is optionally substituted by a substituent selected from halogen, -ORC, -NRcRd, -CO2RC, -CONRcRd, -SO2NRcRd, and -OCONRcRd

[203] In some embodiments, R14 is H.

[204] In some embodiments, R14 is halogen or optionally substituted Cm alkyl, wherein said optionally substituted Cm alkyl is optionally substituted by a substituent selected from halogen, -ORC, -NRcRd, -CO2RC, -CONRcRd, -SO2NRcRd, and -OCONRcRd

[205] In some embodiments, R14 is halogen.

[206] In some embodiments, R14 is optionally substituted Cm alkyl, wherein said optionally substituted Cm alkyl is optionally substituted by a substituent selected from halogen, -ORC, -NRcRd, -CO2Rc, -CONRcRd, -SO2NRcRd, and -OCONRcRd

[207] In some embodiments, R14 is optionally substituted Cm alkyl, wherein said optionally-substituted Cm alkyl is optionally substituted by a. halogen.

[208] In some embodiments, R14 is optionally substituted Cm alkyl, wherein said optionally-substituted Cm alkyl is optionally substituted by a substituent selected from -ORC, -NRcRd, -CO2Re, -CONRcRd, -SO2NRcRd, and -OC()NRcRd.

[209] In some embodiments, R14 is substituted Cm alkyl, wherein said substituted Cm alkyl is substituted by a substituent selected from halogen, -ORC, -NRcRd, -CO2RC, -C()NRcRd, -SO2NRcRd, and -OCONRcRd.

[210] In some embodiments, R14 is Ci-4 alkyl. In some embodiments, R'14 is methyl or ethyl. In some embodiments, Ri4 is methyl. In some embodiments, Ri4 is ethyl. In some embodiments, Ri4 is substituted C1.4 alkyl, wherein said substituted C1-4 alkyl is substituted by a halogen.

[211] In some embodiments, R14 is substituted C1-4 alkyl, wherein said substituted C1-4 alkyl is substituted by a substituent selected from -ORC, -NRcRd, -CO2Rc, -CONRcRd, -SO2NRcRd, and -OCONRcRd

[212] In some embodiments, R14 is -CH2COOH.

[213] In some embodiments, R16 is H or absent. In some embodiments, R16 is H. In some embodiments, R16 is absent.

[214] In some embodiments, R16 is H, halogen, or C1-4 alkyl. In some embodiments, R!o halogen.

[215] In some embodiments, R16 is C1-4 alkyl. In some embodiments, R!t> is methyl or ethyl. In some embodiments, R16 is methyl. In some embodiments, R16 is ethyl.

[216] In some embodiments, R15 and R17 are each independently absent, H, cyclopropyl, halogen or optionally substituted C1-4 alkyl, wherein said optionally substituted C1-4 alkyl is optionally substituted by a substituent selected from halogen, -ORC, -NRcRd, -CO?.RC, -CONRcRd, -SO2NRcRd, and -OCONRcRd; or R13 and R19 taken together with the atom or atoms through which they are connected, form a 5-6 membered ring; or R16 and R1' taken together with the atom or atoms through which they are connected, form a 5-6 membered ring.

[217] In some embodiments, R15 and R17 are each independently absent, H, cyclopropyl, halogen or optionally substituted C1-4 alkyl, wherein said optionally substituted C1-4 alkyl is optionally substituted by a substituent selected from halogen, -ORC, -NRcRd, -CO?RC, -CONRcRd, -SO2NRcRd, and -OCONRcRd; or Rl3 and Retaken together with the atom or atoms through which they are connected, form a 5-6 membered ring.

[218] In some embodiments, R15 and R1' are each independently absent.

[219] In some embodiments, R15 and R17 are each independently H, cyclopropyl, halogen or optionally substituted C1.4 alkyl, wherein said optionally substituted C1-4 alkyl is optionally substituted by a substituent selected from halogen, -ORC, -NRcRd, -CO2RC, -CONReRd -SO2NRcRd, and -OCONRcRd; or Rl3 and R19 taken together with the atom or atoms through which they are connected, form a 5-6 membered ring.

[220] In some embodiments, R15 and R1' are each independently H.

[221] In some embodiments, Ri5 and R1' are each independently halo(Ci-4 alkyl).

[222] In some embodiments, R15 and R17 are each independently cyclopropyl, halogen or optionally substituted C1.4 alkyl, wherein said optionally substituted Cm alkyl is optionally substituted by a substituent selected from halogen, -ORC, -NRcRd, -CO2RC, -C()NRcRd, -SO2NRcRd, and -OCONRcRd; or Ri5 and Retaken together with the atom or atoms through which they are connected, form a 5-6 membered ring.

[223] In some embodiments, Rt3 and R1' are each independently cyclopropyl, halogen or optionally substituted C1-4 alkyl, wherein said optionally substituted Cm alkyl is optionally substituted by a substituent selected from halogen, ~ORC, -NRcRd, ~CO2Rc, -CONRcRd, -SO2NRcRd, and -OCONRcRd

[224] In some embodiments, R15 and R19 taken together with the atom or atoms through which they are connected, form a 5-6 membered ring.

[225] In some embodiments, R16 and R17 taken together with the atom or atoms through which they are connected, form a 5-6 membered ring.

[226] In some embodiments, R15 and R1'' are each independently absent, H, cyclopropyl, or C1-4 alkyl.

[227] In some embodiments, R15 and R1' are each methyl.

[228] In some embodiments, R15 is absent, H, cyclopropyl, halogen or optionally substituted Cn 4 alkyl, wherein said optionally substituted Cj-4 alkyl is optionally substituted by a substituent selected from halogen, -ORC, -NRcRd, -CO2Rc, -CONRcRd, -SO' \ RRd. and -OCONRcRd

[229] In some embodiments, R15 is absent.

[230] In some embodiments, R15 is II, cyclopropyl, halogen or optionally substituted Cm alkyl, wherein said optionally substituted Cm alkyl is optionally substituted by a substituent selected from halogen, -ORC, -NRcRd, -CO2RC, -CONRcRd, -SO2NRcRd, and -OCONRcRd. [231 ] In some embodiments, R15 is H.

[232] In some embodiments, R15 is halo(CM alkyl).

[233] In some embodiments, R1’ is cyclopropyl, halogen or optionally substituted Cm alkyl, wherein said optionally substituted Cm alkyl is optionally substituted by a substituent selected from halogen, -ORC, -NRcRd, -CO2RC, -CONReRd, -SO2NRcR\ and -OCONRcRd.

[234] In some embodiments, R15 is absent, H, cyclopropyl, or Cm alkyl. In some embodiments, R15 is cyclopropyl or Cm alkyl. In some embodiments, Rl5 is absent, H, cyclopropyl, or Cm alkyl. In some embodiments, R1’ is cyclopropyl. In some embodiments, R15 is absent, H, cyclopropyl, or Cm alkyl. In some embodiments, R15 is Cm alkyl.

[235] In some embodiments, R15 is each methyl.

[236] In some embodiments, Rf 7 is absent, H, cyclopropyl, halogen or optionally substituted Ci-4 alkyl, wherein said optionally substituted C1.4 alkyl is optionally substituted by a substituent selected from halogen, -ORC, -NRcRd, -CO2RC, -CONRcRd, -SO2NRcRd, and -OCONRcRd.

[237] In some embodiments, R11 is absent.

[238] In some embodiments, R17 is H, cyclopropyl, halogen or optionally substituted Cm alkyl, wherein said optionally substituted C1-4 alkyl is optionally substituted by a substituent selected from halogen, -ORC, -XRR\ -CO2RC, -CONRcRd, -SO2NRcRd, and -OCONRcRd.

[239] In some embodiments, R17 is H.

[240] In some embodiments, R17 is halo(Ci-4 alkyl).

[241] In some embodiments, R1' is cyclopropyl, halogen or optionally substituted C1-4 alkyl, wherein said optionally substituted C1-4 alkyl is optionally substituted by a substituent selected from halogen, -ORC, -NRcRd, -CO2Rc, -CONRcRd, -SO2NRcRd, and ~OCONRcRd

[242] In some embodiments, R17 is absent, H, cyclopropyl, or C1-4alkyl. In some embodiments, R17 is cyclopropyl or C1-4 alkyl. In some embodiments, R17 is absent, H, cyclopropyl, or C1-4 alkyl. In some embodiments, R17 is cyclopropyl. In some embodiments, R17 is absent, H, cyclopropyl, or Cm alkyl. In some embodiments, R1' is Cm alkyl.

[243] In some embodiments, R1' is each methyl.

[244] In some embodiments, R18 and R19 are each independently absent, H, halogen, or optionally substituted Cm alkyl, wherein said optionally substituted Cm alkyl is optionally substituted by a substituent selected from halogen, -ORC, -NRcRd, -CO2RC, -CONRcRd, -SO2NRcRd, and -OCONRcRd; or R17 and R18 taken together with the atom or atoms through which they are connected, form a 5-6 membered ring.

[245] In some embodiments, R18 and R19 are each independently absent.

[246] In some embodiments, R18 and R19 are each independently H, halogen, or optionally substituted Cm alkyl, wherein said optionally substituted Cm alkyl is optionally substituted by a substituent selected from halogen, -ORC, -NRcRd, -CO2RC, -CONRcRd, -S()2NRcRd, and -OCONRcRd; or R17 and R18 taken together with the atom or atoms through which they are connected, form a 5-6 membered ring.

[247] In some embodiments, R18 and R19 are each independently H.

[248] In some embodiments, Rl8 and R19 are each independently halogen or optionally substituted C1-4 alkyl, wherein said optionally substituted Ci-4 alkyl is optionally substituted by a substituent selected from halogen, -ORC, -NRcRd, -CO2Rc, -CONRcRd, -SO2NRcRd, and -OCONRcRd; or R17 and R1S taken together with the atom or atoms through which they are connected, form a 5-6 membered ring.

[249] In some embodiments, R1S and Ri9 are each independently halogen, or optionally substituted Cm alkyl, wherein said optionally substituted Ci-4 alkyl is optionally substituted by a substituent selected from halogen, -ORC, -NRcRd, -CO2RC, -CONRcRa, -SO2NRcRd, -CH2-CO2RC, and -OCONRcRd.

[250] In some embodiments, R17 and R!8 taken together with the atom or atoms through which they are connected, form a 5-6 membered ring.

[251] In some embodiments , R18 is absent, H, halogen, or optionally substituted Cm alkyl, wherein said optionally substituted Ci-4 alkyl is optionally substituted by a substituent selected from halogen, -ORC, -NRcRd, -CO2RC, -CONRcRd, -SO2NRcRd, and -OCONRcRd

[252] In some embodiments, R18 is absent.

[253] In some embodiments , R18 is H, halogen, or optionally substituted Cm alkyl, wherein said optionally substituted Cm alkyl is optionally substituted by a substituent selected from halogen, -ORC, -NRcRd, -CO2Rc, -CONRcRd, -SO2NRcRd, and -OCONRcRd

[254] In some embodiments, R18 is H.

[255] In some embodiments, R18 is halo(CM alkyl).

[256] In some embodiments, R18 is halogen or optionally substituted Cm alkyl, wherein said optionally substituted Cm alkyl is optionally substituted by a substituent selected from halogen, -ORC, -NRcRd, -CO2Rc, -CONRcRd, and -SO2NRcRd.

[257] In some embodiments, R18 is halogen, or optionally substituted Cm alkyl, wherein said optionally substituted Cm alkyl is optionally substituted by a substituent selected from halogen, -ORC, -NRcRd, -CO2Rc, -CONRcRd, -SO2NRcRd, and -OCONRcRd

[258] In some embodiments, R'19 is absent, II, halogen, or optionally substituted Cm alkyl, wherein said optionally substituted Cm alkyl is optionally substituted by a substituent selected from halogen, -ORC, -NRcRd, -COdC. -CONRcRd, -SO2NRcRd, and -OCONRcRd.

[259] In some embodiments, Ri9 is absent.

[260] In some embodiments, R19 is H, halogen, or optionally substituted Cm alkyl, wherein said optionally substituted C1.4 alkyl is optionally substituted by a substituent selected from halogen, -ORC, -NRcRd, -CO2Rc, -CONR' Rd. -SO2NRcRd, and -OCONRcRd

[261] In some embodiments, RJ9 is H.

[262] In some embodiments, R19 is halo(Ci-4 alkyl).

[263] In some embodiments, Ri9 is halogen or optionally substituted C1-4 alkyl, wherein said optionally substituted C1-4 alkyl is optionally substituted by a substituent selected from halogen, -ORC, -NRcRd, -CO2RC, -CONRcRd, and -SO2NRcRd

[264] In some embodiments, Rl9 is halogen, or optionally substituted C1-4 alkyl, wherein said optionally substituted C1-4 alkyl is optionally substituted by a substituent selected from halogen, -ORC, -NRcRd, -CO2Rc, -COX RuC. -SO2NRcRd, and -OCONRcRd

[265] In some embodiments, R15, R17, R18, or R19 are each independently absent, H, or Cm alkyl, wherein Cm alkyl is optionally substituted by a substituent selected from halogen, -ORC, -NRcRd, -CO R-. -CONRcRd, -SO2NRcRd, and -OCONRcRd

[266] In some embodiments, R15, R17, R18, or R19 are each independently absent, H, or Cm alkyl, wherein Cm alkyl is optionally substituted by a substituent selected from halogen.

[267] In some embodiments, R15, R1', R18, or R19 are each independently -ORC, -NRCRQ, -CO2RC, -CONRcRd, -SO2NRcRd, and -OCONRcRd

[268] In some embodiments, R13 is absent, H, or Cm alkyl, wherein Cm alkyl is optionally substituted by a substituent selected from halogen, -ORC, -NRcRd, -CO2RC, -CONRcRd, -SO2NRcRd, and -OCONRcRd

[269] In some embodiments, R15 is absent, H, or Cm alkyl, wherein Cm alkyl is optionally-substituted by a substituent selected from halogen.

[270] In some embodiments, R’15 is -ORC, -NRcRd, -CO2RC, -CONRcRd, -S()2NRcRd, and -OCONRcRd.

[271] In some embodiments, R17 is absent, H, or Cm alkyl, wherein Cm alkyl is optionally substituted by a substituent selected from halogen, -ORC, -NRcRd, -CO2RC, -CONReRd -SO2NRcRd, and -OCONRcRd.

[272] In some embodiments, Rlz is absent, H, or Cm alkyl, wherein Cm alkyl is optionally substituted by a substituent selected from halogen.

[273] In some embodiments, R37 is -ORC, -NRcRd, -CO2Rc, -CONRcRd, -SO2NRcRd, and -OCONRcRd

[274] In some embodiments, Ri8 is absent, H, or C1.4 alkyl, wherein Ci-4 alkyl is optionally substituted by a substituent selected from halogen, -ORC, -NRcRd, -CO2RC, -CONRcRd, -SO2NRcRd, and -OCONRcRd.

[275] In some embodiments, Rts is absent, H, or Cm alkyl, wherein C1-4 alkyl is optionally substituted by a substituent selected from halogen.

[276] In some embodiments, R18 is -ORC, -NRcRd, ~CO2RC, -CONRcRd, -SO2NRcRd, and -OCONRcRd

[277] In some embodiments, R19 is absent, H, or Cm alkyl, wherein C1-4 alkyl is optionally substituted by a substituent selected from halogen, -ORC, -NRcRd, -CO2RC, ~CONRcRd, -SO2NRcRd, and -OCONRR*

[278] In some embodiments, R19 is absent, H, or Cm alkyl, wherein Cm alkyl is optionally substituted by a substituent selected from halogen.

[279] In some embodiments, R19 is -ORC, -NRcRd, -CO2RC, -CONRcRd, -SO2NRcRd, and -OCONRcRd.

[280] In some embodiments, when Zi, Yi and Y2 are each independently C or N, R14, R18 and R19 are each independently absent or optionally substituted Cm alkyl, wherein said optionally substituted Cm alkyl is optionally substituted by a substituent selected from halogen -ORC, -NRcRd, -CO R(. -CONRcRd, -SO2NRcRd, and -OCONRcRd

[281] In some embodiments, R14, R15, R16, R1', R18 and R19 are each independently absent, H or Ci-4 alkyl.

[282] In some embodiments, R14, R15, R!6, R1R18 and R19 are each independently Cm alkyl.

[283] In some embodiments, R34, R15, R16, Rl / , R18 and R19 are each independently Cm alkyl, ( / .e., methyl or ethyl).

[284] In some embodiments, R14 is ethyl.

[285] In some embodiments, R34 is absent or Cm alkyl, wherein Cm alkyl is optionally substituted by a substituent selected from halogen, -ORC, -NRcRd, -CO2RC, -CONRcRd, -SO2NRcRd, and -OCONRcRd In some embodiments, R14 is absent or Cm alkyl, wherein Cm alkyl is optionally substituted by a substituent selected from halogen.

[286] In some embodiments, R14 is absent or Cm alkyl, wherein Cm alkyl is optionally substituted by a substituent selected from -ORC, -NRCR°, -CChR'k -CONRcRd, -SO2NRcRd, and -OCONRcRd

[287] In some embodiments, R14 is absent or Cm alkyl, wherein Cm alkyl is optionally substituted by a substituent selected from -ORC and -NRCRQ

[288] In some embodiments, R14 is absent or Cm alkyl, wherein Cm. alkyl is optionally substituted by a substituent selected from -CO2Rc, -CONRcRd, ~SO2NRcRa, and -OCONRcRd

[289] In some embodiments, R14 is absent or Cm alkyl, wherein Cm alkyl is optionally substituted by a substituent selected from -CO2H.

[290] In some embodiments, R14 is absent. Cm alkyl, or -CH2-CO2H.

[291] In some embodiments, RCz is absent or Cm alkyl, wherein Cm alkyl is optionally substituted by a substituent selected from halogen, -ORC, -NRcRd, -CO2RC, -CONRcRd, -SO2NRcRd, and -()( ONR:Rd.

[292] some embodiments, RC2 is absent or C1-4 alkyl, wherein Cm alkyl is optionally substituted by a substituent selected from halogen.

[293] In some embodiments, RC2 is absent or Cm alkyl, wherein Cm alkyl is optionally substituted by a substituent selected from -ORC, -NRcRa, -CO2Rc, -CONRcRd, -SO2NRcRd, and -OCONRcRd.

[294] In some embodiments, RCz is absent or Cm alkyl, wherein Cm alkyl is optionally substituted by a substituent selected from -ORC and -NRcRa

[295] In some embodiments, RCz is absent or Cm alkyl, wherein Cm alkyl is optionally substituted by a substituent selected from -COzR', -CONRcRd, -SO2NRcRa, and -OCONRcRd

[296] In some embodiments, RCz is absent or Cm alkyl, wherein Cm alkyl is optionally substituted by a substituent selected from -CO2H.

[297] In some embodiments, RC2 is absent, Cm alkyl, or -CH2-CO2H.

[298] In some embodiments, R19 is methyl.

[299] In some embodiments, R16 is ethyl.

[300] In some embodiments, R1S is methyl.

[301] In some embodiments, Ra is H, - Rc, -CORC, (Od I. -CO2RC, -SORC, -SO2RC, -CONH2, -CONRcRd, -SO2NH2, -SO2NRcRd or -CH2CO2RC.

[302] In some embodiments, Ra is H, Cm alkyl, -C0(Cm alkyl), -C0(Cm alkyl)-OH, -CO(Ci-4 alkyl)-O-(Ci-4 alkyl), -CO(Cm alkyl)-NH2, -CO(Cm alky1 )-NH(Ci.4 alkyl), or -CO(Ci-4 alkyl)-N(Ci-4 alkyl)(Ci-4 alkyl).

[303] In some embodiments, Ra is H.

[304] In some embodiments, Ra is -Rc, -CORC, -CO2H, -(O-K. -SORC, -SO2RC, -CONH2, -CONRcRd, -SO2NH2, -SO2NRcRd, or -CH2-CO2RC.

[305] In some embodiments, Ra is -Rc. In some embodiments, Ra is ~CORC. In some embodiments, Ra is -CO2H. In some embodiments, Ra is -CO2RC. In some embodiments, Ra is -SORC. In some embodiments, Ra is -SO2RC. In some embodiments, Ra is -CONH2. In some embodiments, Ra is -CONRcRd. In some embodiments, Ra is -SO2NH2. In some embodiments, Ra is -SO2NRcRd

[306] In some embodiments, Ra is -CH2-CO2Rc. In some embodiments, Ra is -CH2-CO2H.

[307] In some embodiments, each Rb is independently C1-4 alkyl, halo(Ci-4 alkyl), ~(Ci-4 alkyl)-OH, -(Cm alkyl)-O-P(O)(OH)2, -(Ci-4 alkyl)-O-P(O)(RIRII)2, -(Cm alkyl)-O-(Ci-4 alkyl), -(Cm alkyl)-N(Re)(Rf), -(Cm alkyl)-O-CO(('m alkyl), or -(Cm alkyl)-C()-O-(Cm alkyl).

[308] In some embodiments, each Rb is independently Cm alkyl.

[309] In some embodiments, each Rb is independently halo(Ci-4 alkyl), -(Cm alkyl)-OH, -(Cm alkyl)-O-P(O)(OH)2, -(Cm alkyl)-O-P(O)(RIRII)2, -(Cm alkyl)-O-(Ci-4 alkyl), -(Cm alkyl)-N(Re)(Rf), -(Cm alkyl)-O-CO(Ci-4 alkyl), or ~(Cim alkyl)-CO-O-(CM alkyl).

[310] In some embodiments, each Rc is independently H, Cm alkyl, halo(Ci-4 alkyl), -(Cm alkyl)-OH, -(Cm alkyl)-O-P(O)(OH)2, -(Cm alkyl)-O-P(O)(RIRII)2, -(Cm alkyl)-O-(CM alkyl), -(Cm alkyl)-N(Re)(Rf), -(C1-4 alkyl)-O-CO(CM alkyl), -(Cm alkyl)-CO-O-(CM alkyl), optionally substituted C3-6 cycloalkyl, optionally substituted phenyl, optionally substituted 4-6 membered heterocycloalkyl, optionally substituted 5-6 membered heteroaryl, optionally substituted 9-10 membered heteroaryl, optionally substituted -Cm alkyl-C3-6 cycloalkyl, optionally substituted -Cj. 4 alkyl-phenyl, optionally substituted -Cm alkyl-4-6 membered heterocycloalkyl, optionally substituted -Cm alkyl-5-6 membered heteroaryl, or optionally substituted -Cm alkyl-9-10 membered heteroaryl, wherein the C3-6 cycloalkyl, phenyl, 4-6 membered heterocycloalkyl, 5-6 membered heteroaryl or 9-10 membered heteroaryl moiety of said optionally substituted C3-6 cycloalkyl, optionally substituted phenyl, optionally substituted 4-6 membered heterocycloalkyl, optionally substituted 5-6 membered heteroaryl, optionally substituted 9-10 membered heteroaryl, optionally substituted -Cm alkyl-C3-6 cycloalkyl, optionally substituted -Cm alkyl-phenyl, optionally substituted -Cm alkyl-4-6 membered heterocycloalkyl, optionally substituted -Cm alkyl-5-6 membered heteroaryl, or optionally substituted -Cm alkyl-9-10 membered heteroaryl is optionally substituted by 1-4 substituents each independently selected from halogen, hydroxy, -O-P(O)(OH)2, -O-P(O)(RtRti)2, ammo, (Cm alkyl)amino-, (Cm alkyl)(CM alkyl)ammo-, Cm alkyl, halo(Ci-4 alkyl), halo(Ci-4 alkoxy)-, Cm alkoxy-, hydroxy-(C2-4alkoxy)-, -(C2-4alkoxy)-O-P(O)(OH)2, -(C2-4 alkoxy)-O-P(O)(RIRII)2, Cm alkoxy-(CM alkoxy)-, -CORd, -CON(Rd)(Rf), and -CO2Rd.

[311] In some embodiments, each Rc is independently H.

[312] In some embodiments, each Rc is independently Cm alkyl, halo(Ci-4 alkyl), -(Cm alkyl)-OH, -(Cm alkyl)-O-P(O)(OH)2, -(Cm. alkyl)-O-P(O)(RIRII)2, -(Cim alkyl)-O-(Ci-4 alkyl), -(Cm alkyl)~N(Re)(Rf), -(Cm alkyl)-O-CO(Ci-4 alkyl), -(Cm alkyl)-CO-O-(Ci-4 alkyl), optionally substituted C3-6 cycloalkyl, optionally substituted phenyl, optionally substituted 4-6 membered heterocycloalkyl, optionally substituted 5-6 membered heteroaryl, optionally substituted 9-10 membered heteroaryl, optionally substituted -Cm alkyl-Cs-6 cycloalkyl, optionally substituted -Cn 4 alkyl-phenyl, optionally substituted -Cm alkyl-4-6 membered heterocycloalkyl, optionally substituted -Cm alkyl-5-6 membered heteroaryl, or optionally substituted -Cm alkyl-9-10 membered heteroaryl, wherein the C3-6 cycloalkyl, phenyl, 4-6 membered heterocycloalkyl, 5-6 membered heteroaryl or 9-10 membered heteroaryl moiety of said optionally substituted Cm cycloalkyl, optionally substituted phenyl, optionally substituted 4-6 membered heterocycloalkyl, optionally-substituted 5-6 membered heteroaryl, optionally substituted 9-10 membered heteroaryl, optionally substituted -Cm alkyl-Cs-6 cycloalkyl, optionally substituted -Cm alkyl-phenyl, optionally-substituted -C1-4 alkyl-4-6 membered heterocycloalkyl, optionally substituted -Cm alkyl-5-6 membered heteroaryl, or optionally substituted -Cm alkyl-9-10 membered heteroaryl is optionally-substituted by I -4 substituents each independently selected from halogen, hydroxy, -O-P(O)(OH)2, -O-P(O)(R1Rii)2, ammo, (Cm alkyl)amino-, (Cm alkyl)(CM alkyl)amino-. Cm alkyl, halo(Ci-4 alkyl), halo(Ci-4 alkoxy)-, Cm alkoxy-, hydroxy-(C2.4 alkoxy)-, -(C24alkoxy)-O-P(O)(OH)2, -(C2-4alkoxy)-O-P(O)(RIRI1)2, Cm alkoxy-(Ci.4 alkoxy)-, -CORd, -CON(Rd)(Rf), and -CO2Rd

[313] In some embodiments, each Rd is independently H, hydroxy, or Cm alkyl. In some embodiments, each R° is independently H or Cm alkyl. In some embodiments, each Rd is independently H or hydroxy. In some embodiments, each Rd is independently hydroxy or Cm alkyl. In some embodiments, each Rd is independently H. In some embodiments, each Rd is independently C1.4 alkyl. In some embodiments, each Rd is independently hydroxy.

[314] In some embodiments, each Re is independently H, (C1.4 alkyl), -CO(Cm alkyl), -OCO(Ci-4 alkyl), -CO2(Cm alkyl), -(C1-4 alkyl)amino, -(C1-4 alkyl)-Ci4 alkoxy, -CO-(optionally substituted 5-6 membered heterocycloalkyl), -CO-(Ci-4 alkyl)-(optionally substituted 5-6 membered heterocycloalkyl), -CO-(optionally substituted 5-6 membered heteroaryl), -C0-(Cm alkyl)-(optionally substituted 5-6 membered heteroaryl), wherein the optionally substituted 5-6 membered heterocycloalkyl or optionally substituted 5-6 membered heteroaryl is optionally substituted by 1-4 substituents each independently selected from halogen, hydroxy, -O-P(O)(OH)2, -O-P(O)(RIRn)2, amino, (C1-4 alkyl)amino-, (Cm alkyl)(Ci-4 alkyl)amino-, C1-4 alkyl, halo(Ci-4 alkyl), halo(Ci-4 alkoxy)-, Cm alkoxy-, hydroxy-(C2-4alkoxy)-, -(C2-4 alkoxy) O-P(O)(OH)2, -(C2-4alkoxy)-O-P(O)(R1RII)2, Cm alkoxy-(Ci-4 alkoxy)-, -CORa, -CON(Rd)(Rf), and -CO2Rd

[315] In some embodiments, each Re is independently H.

[316] In some embodiments, each Re is independently (Cm alkyl), -C0(Cm alkyl), -0C0(Cm alkyl), -CO2(Ci-4 alkyl), -(Cm alkyl)amino, -(Cm alkyl)-CM alkoxy, -CO-(optionally substituted 5-6 membered heterocycloalkyl), -C0-(Cm alkyl)-(optionally substituted 5-6 membered heterocycloalkyl), -CO-(optionally substituted 5-6 membered heteroaryl), -C0~(Cm alkyl)-(optionally substituted 5-6 membered heteroaryl), wherein the optionally substituted 5-6 membered heterocycloalkyl or optionally substituted 5-6 membered heteroaryl is optionally substituted by 1-4 substituents each independently selected from halogen, hydroxy, -O-P(O)(OH)2, -O-P(O)(RIRn)2, ammo, (Cm alkyl)amino-, (Cm alkyl)(Cn 4 alkyl)ammo-, Cm alkyl, halo(CM alkyl), halo(CM alkoxy)-, Cm alkoxy-, hydroxy-(C2-4alkoxy)-, -(C2-4 alkoxy) O-P(O)(OH)2, -(C2-4 alkoxy)-O-P(O)(RIRI1)2, Cm alkoxy-(CM alkoxy)-, -CORd, -CON(Rd)(Rf), and -( O 'Rd

[317] In some embodiments, each Rf is independently H, hydroxy, or (Cm alkyl). In some embodiments, each R1 is independently H or (Cm alkyl). In some embodiments, each R1 is independently H or hydroxy. In some embodiments, each Rf is independently hydroxy or (Cm alkyl). In some embodiments, each Rf is independently H. In some embodiments, each R1 is independently (Cm alkyl). In some embodiments, each R1 is independently hydroxy.

[318] In some embodiments, each of R1 and R11 are independently (Ci-6 alkyl)oxy-. In some embodiments, each R1 is independently (Ci-6 alkyl)oxy-. In some embodiments, each R11 is independently (Ci-6 alkyl)oxy-.

[319] In some embodiments, Xs is N.

[320] In some embodiments, Xs is CRA2, wherein RA2 is selected from H, halogen, -OCH2CH2CH2OH, -OCH2CH2CH2COOH, -OCH2CH2CH2NH2, -OCB, and -N(Re)(Rf).

[321] In some embodiments, X5 is CRA2, wherein RA2 is selected from halogen, -OCH2CH2CH2OH, -OCH2CH2CH2COOH, -OCH2CH2CH2NH2, -OCH3, and -N(Re)(Rf).

[322] In some embodiments, X5 is CRA2, wherein R^ is selected from -OCH2CH2CH2OH, -OCH2CH2CH2COOH, -OCH2CH2CH2NH2, 0(1K and -N(Re)(Rf).

[323] In some embodiments, X5 is CRA2, wherein RA2 is selected from H, halogen, -OCH2CH2CH2OH, -OCH2CH2CH2COOH, -OCH2CH2CH2NH2, -OCH3, and -NH2.

[324] In some embodiments, X5 is CRA2, wherein RA2 is selected from halogen, -OCH2CH2CH2OH, -OCH2CH2CH2COOH, -OCH2CH2CH2NH2, -OCH3, and -NH2.

[325] In some embodiments, X5 is CRA2, wherein RAz is selected from -OCH2CH2CH2OH, -OCH2CH2CH2COOH, -OCH2CH2CH2NH2, -OCH3, and Alb

[326] In some embodiments, Xe is N.

[327] In some embodiments, Xe is CRA!, wherein RA! is selected from H, halogen, hydroxy, -OCH2CH2CH2OH, -OCH2CH2CH2COOH, -OCH2CH2CH2NH2, -OCH3, and -N(Re)(Rf).

[328] In some embodiments, Xc, is CRA1, wherein RA1 is selected from halogen, hydroxy, -OCH2CH2CH2OH, -OCH2CH2CH2COOH, -OCH2CH2CH2NH2, -OCH3, and -N(Re)(Rf).

[329] In some embodiments, Xe is CRA1, wherein RAs is selected from hydroxy, -OCH2CH2CH2OH, -OCH2CH2CH2COOH, -OCH2CH2CH2NH2, -OCH3, and -N(Re)(Rf).

[330] In some embodiments, Xe is CRA1, wherein Ra! is selected from -OCH2CH2CH2OH, -OCH2CH2CH2COOH, -OCH ( H'CH XH ■. -OCH3, and -X(Rj(R:)

[331] In some embodiments, Xe is CRA1, wherein RAs is selected from H, halogen, hydroxy, -OCH2CH2CH2OH, -OCH2CH2CH2COOH, -OCH2CH2CH2NH2, -OCH3, and -NH2.

[332] In some embodiments, Xe is CRA1, wherein RAl is selected from halogen, hydroxy, -OCH2CH2CH2OH, -OCH2CH2CH2COOH, -OCH2CH2CH2NH2, -OCH3, and -NH2.

[333] In some embodiments, Xe is CRA!, wherein RAi is selected from hydroxy, -OCH2CH2CH2OH, -OCH2CH2CH2COOH, -OCH2CH2CH2NH2, -OCH3, and -NH2.

[334] In some embodiments, Xe is CRA1, wherein RA1 is selected from -OCH2CH2CH2OH, - OCH2CH2CH2COOH, -OCH2CH2CH2NH2, -OCH3, and -MH

[335] In some embodiments, X5 is N and Xe is N.

[336] In some embodiments, X5 is CRA2 and Xe is CRAi. In some embodiments, X5 is CRA2 and Xe is N. In some embodiments, X5 is N and Xe is CRA1.

[337] In some embodiments, X5 is CRA2 and Xe is CRAi, wherein RAi is -OCH3 and RA2 is -OCH2CH2CH2OH.

[338] In some embodiments, X5 is CRA2 and Xe is CRA!, wherein RA1 is H and RA2 is - OCH2CH2CH2OH.

[339] In some embodiments, X5 is CRA2 and Xe is CRA1, wherein RA1 is -OH and RAz is - OCH2CH2CH2OH.

[340] In some embodiments, X5 is CRA2 and Xe is CRAi, wherein RA1 is -OCH3 and RA2 is -OCH2CH2CH2COOH.

[341] In some embodiments, X5 is CRA2 and Xe is CRA1, wherein RA1 is -OH and RAz is -OCH2CH2CH2COOH.

[342] In some embodiments, X5 is CRA2 and Xe is CRA1, wherein RA1 is -OCH3 and RA2 is -OCH2CH2CH2NH2.

[343] In some embodiments, X5 is CR42 and Xe is CRA1, wherein RA1 is -OH and RAz is -OCH2CH2CH2NH2.

[344] In some embodiments, Xe is N and X5 is CRA1, wherein RA1 is -OCH2CH2CH2OH.

[345] In some embodiments, Xe is N and X5 is CRA1, wherein RA! is -OCH2CH2CH2COOH.

[346] In some embodiments, Xe is N and X5 is CRAl, wherein RA! is -OCH2CH2CH2NH2.

[347] In some embodiments, Xe is N and X5 is CRA1, wherein RA! is halogen.

[348] In some embodiments, Xe is N and X5 is CRAl, wherein RA1 is -OCH3.

[349] In some embodiments, Xe is N and X5 is CRA1, wherein RAs is -OH.

[350] In some embodiments, X5 is CRA2 and Xe is CRA1, wherein RA1 is -OCH2CH2CH2NH2 and RA2 is -OCH2CH2CH2NH2.

[351] In some embodiments, RA1 and RA2 are independently H, halogen, hydroxy, -OCH2CH2CH2OH, -OCH2CH2CH2COOH, -OCH2CH2CH2NH2, OCI h. or -M R'}( Rd.

[352] In some embodiments, X3 and X4 are each independently S or NRf, wherein Rf is H

[353] In some embodiments, X3 is S and X4 is NRf, wherein Rf is H

[354] In some embodiments, X9 is N or CR4. In some embodiments, X9 is N. In some embodiments, X9 is CR4. In some embodiments, X9 is CH.

[355] In some embodiments, the disclosure is directed to a compound Formula (F), Formula (IA’), Formula (IF), Formula (IIF), Formula (IV’), or Formula (V’) wherein: the total of r and s is 1 or 2; X3 and X4 are each independently S or NR1; X5 is N or ( JR'\ X6 is N or CRA!; X9 is N or CH; RA1 and RA2 are independently selected from H, halogen, hydroxy, -OCH2CH2CH2OH, -OCH2CH2CH2COOH, -OCH2CH2CH2NH2, -OCH3 and -NReRf r is 0 and RB1 and RB2 are each H; or r is 1, RB1 and RB2 are each independently -CH2-, and B is -CH=CH-, -CH2CH2-, -CH(OH)CH(OH)~, or -CH2N(CH3)CH2-; s is 0, Yi, Y2, Zi and Z2 are each independently O or S; s is 0, Wi is C, RC1 is methyl; s is 0, Z2 is C, RCz is ethyl; s is 0, Wi is N, RC! is absent; s is 0, Z2 is N, RC2 is absent or ethyl; s is 1, Wi andZ2 are each independently C or N, RC1 and RC2 are each independently -CH2-, and D is -CH2CH2CH2-; R3 and R5 are each independently -CONH2, -CH2NH2, -NH2, -CH2N(CI-13)2, -CH2NIIC(O)CIh or -NHC(O)CH3; R4 and Rb are each FI; R!4 is absent, methyl or ethyl; R13 is absent, H or methyl; R16 is absent, H, methyl or ethyl; and R1! is absent or methyl, or a prodrug, solvate, pharmaceutically acceptable salt, or tautomer thereof.

[356] In some embodiments, the compound is of Formula (I-B ): R1< (I-B’) or a prodrug, solvate, pharmaceutically acceptable salt, or tautomer thereof, wherein: ¥1, Y?„ Zi, and Zj are each independently O, S, C, or N; Xj, X2, Wi, and W2 are each independently C or N; X3, X4.Xs, Xe, Xy R’, R3, Ra and Rf are each independently as defined in Formula (IA’); Rc is Ci-4 alkyl; Rdl and RB2 are each independently -CH2-; B is -halo(Ci-5 alkyl), unsubstituted -Cns alkyl, or unsubstituted -C2-5 alkenyl-; Ra2 and RA1 are each independently H, halogen, hydroxy, amino, amino(Ci4 alkyl)-, -O-P(O)(OH)2, -O-P(O)(RfRu)2, optionally substituted (Ci-6 alkyl), or optionally substituted (Cue aikyl)oxy-, wherein C44 alkyl of said optionally substituted (Cne alkyl), or optionally substituted (Cue alkyl)oxy- is optionally substituted with 1-4 substituents each independently selected from the group comprising hydroxy, -O-P(O)(OH)2, -O-P(O)(RTRn)2, Ci-4 alkoxyl, -N(Re)(Rf), -CO2(Rf), optionally substituted phenyl, and optionally substituted 5-6 membered heteroaryl; wherein said optionally substituted phenyl, or 5-6 membered heteroaryl is optionally substituted by 1-4 substituents each independently selected from halogen, hydroxy, -O-PO)(OH)2, -0-P(0)(RTRn)2, ammo, (Ci-6 alkyl)ammo-, (Ci-6alkyl)(Ci^alkyl)amino-, halo(Ci^ alkyl), hydroxy-(Ci-4 alkyl)-, -(C1-4 alkyl)-O-P(O)(OH)2, -(C1-4 alkyl)-O-P(O)(RIRII)2, halo(Ci-4 alkoxy)-, C1-4 alkoxy-, hydroxy-(C2-4 alkoxy)-, -(C2-4 alkoxy)-O-P(O)(OH)2, -(C2-4 alkoxy)-O-P(O)(RIRI1)2, -(Cue alkyl)-NH2, -Cn 4 alkyl-(Ci-4 alkoxy), and C1-4 alkoxy-(Ci-4 alkoxy)-; Re is selected from H, (C1.4 alkyl), -CO(Ci-4 alkyl), -OCO(Ci-4 alkyl), -(C1-4 alkyl)-NH2, -(Ci-4 alkyl)-Ci-4 alkoxy, and -CO2(Ci-4 alkyl); R4 and R6 are H; Rl4 and RC2 are each independently absent or C1-4 alkyl, wherein C1.4 alkyl is optionally substituted by a substituent selected from halogen, -ORC, -NRcRd, -CO2RC, -CONRcRd, -SO2NRcRd, and -OCONRcRd; R16 and Ru are each independently absent, H or C1-4 alkyl; and R13, Rn, R1S, or R19 are each independently absent, H, or C1-4 alkyl, wherein C1-4 alkyl is optionally substituted by a substituent selected from halogen, -ORC, -NRcRd, •■CO-RR, -CONRcRd, -SO2NRcRd and -OCONRcRd; and each R1 and R!I are independently (Cue alkyl)oxy-; provided that at least one of (i), (ii), or (iii) applies: (i) when (a) Zi, Z2, Yi and Y2 are each N, Wi, W2, Xi and X2 are each C; or (b) Wi, W2, Xi and X2 are each N, Zi, Z2, Yi and Y2 are each C; or (c) Zi and Yi are each N, Wi and Xi are each C; or (d) Z2 and Y2 are each N, W2 and X2 are each C; or (e) Wi and Xi are each N, Zi and Yi are each C; or (f) W2 and X2 are each N, Z2 and Y2 are each C, then at least one of X3 and X4 is S; or X9 is N; or (ii) when (a) Zi, Z2, Yi and Y2 are each N, Wi, W2, Xi and X2 are each C; or (b) Wi, W2, Xi and X2 are each N, Zi, Z2, Yi and Y2 are each C, then R14 is a Ci-4 alkyl substituted with halogen, -ORC, -NRcRd, -CO2Rc, -CONRcRd, -SO2NRcRd, and -OCONRcRd wherein Rc is H; or (iii) when (a) Zi and Yi are each N, Wi and Xi are each C; or (b) Z2 and Y2 are each N, W2 and X2 are each C; or (c) Wi and Xi are each N, Zi and Yi are each C; or (d) W2 and X2 are each N, Z2 and Y2 are each C, then at least one of X5, Xe, and X9 is N and RA1 or RA2 is halogen, hydroxy, optionally substituted (Cue alkyl), substituted (Ct-6 alkyl)oxy-, optionally substituted (Cu 6 alkyl)amino-, or optionally substituted (Cue alkyl)(Ci-4 alkyl)ammo-, wherein the (C1-6 alkyl) of said optionally substituted (Ct^ alkyl), substituted (Cue alkyl)oxy-, optionally substituted (Cur, alkyl)amino-, or optionally substituted (Cj-6 alkyl)(Cj-4 alkyl)amino- is optionally substituted by 1-4 substituents each independently selected from hydroxy, -O-P(O)(OH)2, -O-POiR^h, -N(ReXRf), -CO2(Rf), -CON(Re)(Rf), optionally substituted phenyl, and optionally substituted 5-6 membered heteroaryl group, wherein said optionally substituted phenyl or 5-6 membered heteroaryl is optionally substituted by 1-4 substituents each independently selected from halogen, hydroxy, -O-P(O)(OH)2, -O-P(O)(RIR1I)2, ammo, (Cue alkyl)amino-, (Cue alkyl)(Ci..6 alkyl)amino-, -(Cue alkyl)-NH2, halo(Ci-6 alkyl), hydroxy-(Cn4 alkyl)-, -(C1-4 alkyl)-O-P(O)(OH)2, -(Ci-4 alkyl)-O-P(O)(R1Rn)2, halo(Ci-4 alkoxy)- , C1-4 alkoxy-, hydroxy-(C2-4 alkoxy)-, -(C2-4 alkoxy)-O-P(O)(OH)2, -(C2-4 alkoxyXO-PfpXRW1^ -C1-4 alkyl-(Ci-4 alkoxy), and C1.4 alkoxy-(Ci-4 alkoxy)-.

[357] In some embodiments, the compound is of Formula (I-B’), wherein X9, is CR4 [358 ] In some embodiments, the compound is of Formula (II-B'): (n-B’) or a prodrug, solvate, pharmaceutically acceptable salt, or tautomer thereof, wherein: Y2 and Z2 are each independently O, S, C, or N; X2 and W2 are each independently C or N; X3, X4,X5, Xe, XyR3, R5, Ra and Rf are each independently as defined in Formula (IA’); Rc is Ci-4 alkyl; RB1 and RB2 are each independently -CH2-; B is -halo(Ci-5 alkyl), unsubstituted -C1-5 alkyl, or unsubstituted -C1-5 alkenyl-; RA2 and RA1 are each independently H, halogen, amino, amino(Ci-4 alkyl)-, hydroxy, -O-P(O)(OH)2, -O- P(O)(RIRn)2, optionally substituted (C1-6 alkyl), or optionally substituted (C1-6 alkyl)oxy-, wherein Ci^ alkyl of said optionally substituted (C1-6 alkyl), or optionally substituted (Ci-6 alkyl)oxy- is optionally substituted with 1-4 substituents each independently selected from the group comprising hydroxy, -O-P(O)(OH)2, -O-P(O)(RIRn)2,Ci-4 alkoxyl, -N(Re)(Rf), -CO2.(Rf), optionally substituted phenyl, and optionally substituted 5-6 membered heteroaryl; wherein said optionally substituted phenyl, or 5-6 membered heteroaryl is optionally substituted by 1-4 substituents each independently selected from halogen, hydroxy, -O-P(O)(OH)2, -O-P(O)(RIR1I)2, ammo, (Ci-6 alkyljammo-, (Cm alkyl)(CM alkyl)amino-, halo(Ci-6 alkyl), hydroxy-(CM alkyl)-, -(Cm alkyl)-0-P(0)(0H)2, -(Cm alkyl)-0-P(0)(RIRII)2, halo(Ci-4 alkoxy)-, Cm alkoxy-, hydroxy-(C2-4 alkoxy)-, -(C2-4 alkoxy)-O-P(O)(OH)2, -( C2-4 alkoxy )-O-P(O)(RTRT1)2, -(Ci-6alkyl)-NH2, and Cm alkoxy-(Ci-4 alkoxy)-; Re is selected from H, (C1-4 alkyl), -CO(Cm alkyl), -OCO(Ci-4 alkyl), -(Cm alkyl)-NH2, -(Cm alkyl)-Ci-4 alkoxy, and -CO2(Ci-4 alkyl), R4 and R6 are H; RC2 is absent, Cm alkyl or -CH2COOH; RH> and Ru are each independently absent, H or C1-4 alkyl; and R1', R1S, or R19 are each independently absent, H, C1-4 alkyl or halo(Ci-4 alkyl); and each R1 and R11 are independently (Cm alkyl)oxy-.

[359] In some embodiments, the compound is of Formula (II-B’), wherein X9, is CR4In some embodiments, the compound is of Formula (I-B'), or a prodrug, solvate, pharmaceutically acceptable salt, or tautomer thereof, wherein: RA2 and RA1 are each independently H, halogen, amino, amino(Ci-4 alkyl)-, hydroxy, -O-P(O)(OH)2, -O- P(O)(R1Rn)2, optionally substituted (Cm alkyl), or optionally substituted (Cm alkyl)oxy~, wherein Cm, alkyl of said optionally substituted (Cm, alkyl), or optionally substituted (Cue alkyl)oxy- is optionally substituted with 1-4 substituents each independently selected from the group comprising hydroxy, -O-P(O)(OH)2, -O-P(O)(RIRII)2,Ci-4 alkoxyl, -N(Re)(Rf), -CO2(Rf), optionally substituted phenyl, and optionally substituted 5-6 membered heteroaryl; wherein said optionally substituted phenyl, or 5-6 membered heteroaryl is optionally substituted by 1-4 substituents each independently selected from halogen, hydroxy, -O-P(O)(OH)2, -O-P(O)(RIR1I)2, amino, (Cm alkyl)amino~, (Cm, alkyl)(CM alkyl)ammo-, halo(CM> alkyl), hydroxy-(Cj-4 alkyl)-, -(Cm alkyl)-O-P(O)(OH)2, -(Cm alkyD-O-P^XR^h, halo(Cj-4 alkoxy)-, Cm alkoxy-, hydroxy-(C2-4 alkoxy)-, -(C2-4 alkoxy)-O-P(O)(OH)2, -( C2-4 alkoxy)-O-P(O)(R1RIi)2, -(Ci-6alkyl)-NH2, and Cm alkoxy-(Ci-4 alkoxy)-; provided that at least one of (i), (ii), or (iii) applies: (i) when (a) Zi, Z2, Yi and Y2 are each N, Wi, W2, Xi and X2 are each C; or (b) Wi, W2, Xi and X2 are each N, Zi, Z2, Y1 and Y2 are each C; or (c) Zi and Yi are each N, Wi and Xi are each C; or (d) Z2 and Y2 are each N, W2 and X2 are each C; or (e) Wi and Xi are each N, Zi and Yi are each C; or (f) W2 and X2 are each N, Z2 and Y2 are each C, then at least one of X3 and X4 is S; or X9 is N; or (li) when (a) Zi, Z2, Yi and Y2 are each N, Wi, W2, Xi and X2 are each C; or (b) Wi, W2, Xi and X2 are each N, Zi, Z2, Yi and Y2 are each C, then R14 is a C1-4 alkyl substituted with halogen, -ORC, -NRcRd, -CO2Rc, -C()NRcRd, -SO2NRcRd, and -OCONRcRd wherein Rc is H; or (iii) when (a) Zi and Yi are each N, Wi and Xi are each C; or (b) Z2 and Y2 are each N, W2 and X2 are each C; or (c) Wi and Xi are each N, Zi and Yi are each C; or (d) W2 and X2 are each N, Z2 and Y2 are each C, then at least one of X5, Xe, and X9 is N and RA1 or RA2 is halogen, hydroxy, optionally substituted (Cm alkyl), substituted (Ci-6 alkyl)oxy-, optionally substituted (Cn 6 alkyl)amino-, or optionally substituted (Ci-6 alkyl)(Ci-4 alkyl)amino-, wherein the (Cue alkyl) of said optionally substituted (Cm alkyl), substituted (Cue alkyl)oxy-, optionally substituted (Ci-6 alkyl)amino-, or optionally substituted (Cm alkyl)(Ci-4 alkyl)amino- is optionally substituted by 1-4 substituents each independently selected from hydroxy, -O-P(O)(OH)2, -0^(0)^¾1% -N(Re)(Rf), -COdR1). -CON(Re)(Rf), optionally-substituted phenyl, and optionally substituted 5-6 membered heteroaryl group, wherein said optionally substituted phenyl or 5-6 membered heteroaryl is optionally substituted by 1-4 substituents each independently selected from halogen, hydroxy, -O~P(O)(OH)2, -0-P(0)(RIRiI)2, ammo, (Ci-6 alkyl)amino-, (Cm alkyl)(Ci-6 alkyl)amino-, -(Cj-6 alkyl)-NH2, halo(Ci-6 alkyl), hydroxy-(Ci-4 alkyl)-, -(C1-4 alkyl)-O-P(O)(OH)2, -(Cm alkyl)-O-P(O)(RIRn)2, halo(Ci-4 alkoxy), Cm alkoxy-, hydroxy-(C2-4 alkoxy)-, -(C2-4 alkoxy)-O-P(O)(OH)2, -(C2-4alkoxy)-O-P(O)(RIRl!)2, -Cm alkyl-(CM alkoxy), and Cm alkoxy-(CM alkoxy)-.

[360] In some embodiments, the compound is of Formula (I-B'), or a prodrug, solvate, pharmaceutically acceptable salt, or tautomer thereof, wherein: Ra2 and RA1 are each independently H, halogen, amino, amino(Ci-4 alkyl)-, hydroxy, optionally substituted (Cm alkyl), or optionally substituted (CMalkyl)oxy-, wherein Cue alkyl of said optionally substituted (Cm alkyl), or optionally substituted (Cue alkyl)oxy- is optionally substituted with 1-4 substituents each independently selected from the group comprising hydroxyl, Cm alkoxyl, - N(Re)(R1), -CO2(Rf), optionally substituted phenyl, and optionally substituted 5- 6 membered heteroaryl; wherein said optionally substituted phenyl, or 56 membered heteroaryl is optionally substituted by 1-4 substituents each independently selected from halogen, hydroxy, -O-P(O)(OH)2, -O-P(O)(RTRn)2, amino, (Ci-6alkyl)amino-, (Cm alkyl)(Ci- 6 alkyl)amino-, halo(Ci-6 alkyl), hydroxy-(Ci4 alkyl)-, halo(Cu4 alkoxy)-, C1.4 alkoxy-, hydroxy-(C2-4 alkoxy)-, and C14 alkoxy-(Ci-4 alkoxy)-; and Re is selected from H, (C1.4 alkyl), -CO(Ci-4 alkyl), -OCO(Ci 4 alkyl), and -CO2(Ci4 alkyl); provided that at least one of (1), (ii), or (iii) applies: (i) when (a) Zi, Z2, Yi and Y2 are each N, Wi, W2, Xi and X2 are each C; or (b) Wi, W2, Xi and X2 are each N, Zi, Z2, Yi and Y2 are each C; or (c) Zi and Yi are each N, Wi and Xi are each C; or (d) Z2 and Y2 are each N, W2 and X2 are each C; or (e) Wi and Xi are each N, Zi and Yi are each C; or (f) W2 and X2 are each N, Z2 and Y2 are each C, then at least one of X3 and X4 is S; or X9 is N; or (ii) when (a) Zi, Z2, Yi and Y2 are each N, Wi, W2, Xi and X2 are each C; or (b) Wi, W2, Xi and X2 are each N, Zi, Z2, Yi and Y2 are each C, then R14 is a C14 alkyl substituted with halogen, -ORC, -NRcRd, -CO2Rc, -CONRcRd, -SO2NRcRd, and -OCONRcRd wherein Rc is H; or (iii) when (a) Zi and Yi are each N, Wi and Xi are each C; or (b) Z2 and Y2 are each N, W2 and X2 are each C; or (c) Wi and Xi are each N, Zi and Yi are each C; or (d) W2 and X2 are each N, Z2 and Y2 are each C, then at least one of X5, and Xe, and X9 is N and RA1 or RAz is halogen, hydroxy, optionally substituted (Ci^ alkyl), substituted (C1-6 alkyl)oxy-, optionally substituted (Cu 6 alkyl)amino-, or optionally substituted (C1-6 alkyl)(Ci4 alkyljammo-, wherein the (Cw alkyl) of said optionally substituted (Cj-6 alkyl), substituted (Cue alkyl)oxy-, optionally substituted (Cue alkyl)amino-, or optionally substituted (Ci^ alkyl)(Ci4 alkyl)amino- is optionally substituted by 1-4 substituents each independently selected from hydroxy, -O-P(O)(OH)2, -O-P(O)(RIRII)2, -N(Re)(Rf), -CO2(Rf), -CON(Re)(Rf), optionally substituted phenyl, and optionally substituted 5-6 membered heteroaryl group, wherein said optionally substituted phenyl or 5-6 membered heteroaryl is optionally substituted by 1-4 substituents each independently selected from halogen, hydroxy, -O-P(O)(OH)2, -O-P(O)(R1Rlf)2, amino, (Cur, alkyl)amino-, (Cue alkyl)(Cj-6 alkyl)amino-, -(Cue alkyl)-NH2, halo(Ci-6 alkyl), hydroxy-(Cu4 alkyl)-, -(C1.4 alkyl)-O-P(O)(OH)2, -(C1-4 alkyl)-O-P(O)(RIRn)2, halo(Ci4 alkoxy), Ci-4 alkoxy-, hydroxy-(C24 alkoxy)-, -(C24 alkoxy)-O-P(O)(OH)2, -(C2.4 alkoxy)-O-P(O)(RIRn)2, -Cm alkyl-(Ci4 alkoxy), and C1-4 alkoxy-(Ci-4 alkoxy)-.

[361] In some embodiments, the compound is of Formula (I-b’): R14 or a prodrug, solvate, pharmaceutically acceptable salt, or tautomer thereof, wherein: Yj, Y2, Zi, and Z2 are each independently O, S, C, or N; Xi, X2, Wi, and W2 are each independently C or N; X3, X4, X5, Xe, and X9 are each independently as defined in Formula (TA’);, B is -halo(Ci-5 alkyl), unsubstituted C1-5 alkyl, or unsubstituted -€2-5 alkenyl-; RA2 and RA! are each independently H, halogen, ammo, amino(Ci4 alkyl)-, hydroxy, -O-P(O)(OH)2, -O-P^XR’R11^, optionally substituted (Cue alkyl), or optionally substituted (C1-6 alkyl)oxy-, wherein C1-6 alkyl of said optionally substituted (Cue alkyl) or optionally substituted (C1-6 alkyl)oxy- is optionally substituted with 1-4 substituents each independently selected from the group comprising hydroxyl, C1-4 alkoxyl, -N(Re)(Rf), -CO2(Rf), optionally substituted phenyl, and optionally substituted 5- 6 membered heteroaryl, and wherein said optionally substituted phenyl or 5-6 membered heteroaryl is optionally substituted by 1-4 substituents each independently selected from halogen, hydroxy, -O-P(O)(OH)2, -0-P(0)(RTRn)2, ammo, (CnealkyBammo-, (C1-6 alkyl)(Ci-6alkyl)amino-, halo(Ci-6 alkyl), hydroxy-(Ci-4 alkyl)-, -(C1-4 alkyl)-O-P(O)(OH)2, -(C1-4 alkyl)-O-P(O)(RTRn)2, halo(Ci-4 alkoxy)-, C1-4 alkoxy-, hydroxy-(C2-4 alkoxy)-, -(C2-4 alkoxy)-O-P(O)(OH)2, -(C2-4 alkoxy)-O- P(O)(R!Rn)2, -(C1-6 alkyl)-NH2, -C1-4 alkyl-(Ci-4 alkoxy), and C1-4 alkoxy-(Ci-4 alkoxy)-; Re is selected from H, (C1-4 alkyl), -CO(Ci-4 alkyl), -OCO(Ci-4 alkyl), -(C1-4 alkyl)-NH2, -(C1-4 alkyl)-Ci-4 alkoxy, and -CO2(Ci-4 alkyl), each Rf is independently H, hydroxy, or (C1-4 alkyl); R4 and R6 are H; R'14 and RC2 are each independently absent or C1.4 alkyl, wherein C1-4 alkyl is optionally substituted by a substituent selected from halogen, -ORC, -NRcRd, -CO2Rc, -CONRcRd, -SO2NRcRd and -OCONRcRd; R16 and RCi are each independently absent, H or Ci-4 alkyl; Rl5, R1', R18, or Ri9 are each independently absent, H, or C1-4 alkyl, wherein C1-4 alkyl is optionally substituted by a substituent selected from halogen, -ORC, -NRcRa, -CO2Rc, -CONRcRd, -SO2NRcRd, and -OCONRcRd; and each RJ and R11 are independently (Ci^ alkyl)oxy-, provided that at least one of (i), (11), or (Hi) applies: (i) when (a) Zi, Z2, Yi and Y2 are each N, Wi, W2, Xi and X2 are each C; or (b) Wi, W2, Xi and X2 are each N, Zi, Z2, Yi and Y2 are each C; or (c) Zi and Yi are each N, Wi and Xi are each C; or (d) Z2 and Y2 are each N, W2 and X2 are each C; or (e) Wi and Xi are each N, Zi and Yi are each C; or (f) W2 and X2 are each N, Z2 and Y2 are each C, then at least one of X3 and X4 is S; or X9 is N; or (ii) when (a) Zi, Z2, Yi and Y2 are each N, Wi, W2, Xi and X?. are each C; or (b) Wi, W2, Xi and X2 are each N, Zi, Z2, Yi and Y2 are each C, then R14 is a Cm alkyl substituted with halogen, -ORC, A RcRd. -CO2Rc, -CONRcRd, -SO2NRcRd, and -OCONRcRd wherein Rc is H; or (iii) when (a) Zi and Yi are each N, Wi and Xi are each C; or (b) Z2 and Y2 are each N, W2 and X2 are each C; or (c) Wi and Xi are each N, Zj and Yi are each C; or (d) W2 and X2 are each N, Z2 and Y2 are each C, then at least one of X5, X*, and X9 is N and RA1 or RAz is halogen, hydroxy, optionally substituted (C1-6 alkyl), substituted (Cm alkyl)oxy-, optionally substituted (Cj-6 alkyl)amino-, or optionally substituted (Cm alkyl)(Cj-4 alkyl)amino-, wherein the (Cw alkyl) of said optionally substituted (Cj-6 alkyl), substituted (Cm alkyl)oxy-, optionally substituted (Cj-6 alkyl)amino-, or optionally substituted (Cm alkyl)(Ct-4 alkyl)amino- is optionally substituted by 1-4 substituents each independently selected from hydroxy, -O-P(O)(OH)2, -O-P(O)(R1RIi)2, -N(Re)(Rf), -CO2(Rf), -CON(Re)(Rf), optionally substituted phenyl, and optionally substituted 5-6 membered heteroaryl group, wherein said optionally substituted phenyl or 5-6 membered heteroaryl is optionally substituted by 1-4 substituents each independently selected from halogen, hydroxy, -O-P(O)(OH)2, -O-P(O)(R1RII)2, amino, (Cm alkyl)ammo-, (Cm alkyl)(Ci-6 alkyl)ammo-, -(Ci-6 alkyl)-NH2, halo(Ci-6 alkyl), hydroxy-(Ci-4 alkyl)-, -(C1.4 alkyl)-O-P(O)(OH)2, -(C1-4 alkyl)-O-P(O)(RTR1T)2, halo(Ci-4 alkoxy)- , C1-4 alkoxy-, hydroxy-(C2-4 alkoxy)-, -(C2-4 alkoxy)-O-P(O)(OH)2, -(C2-4 alkoxyXO-PfpXRW1^, -C1-4 alkyl-(Ci-4 alkoxy), and C1.4 alkoxy-(Ci-4 alkoxy)-.

[362] In some embodiments, the compound is of Formula (I-b’), or a prodrug, solvate, pharmaceutically acceptable salt, or tautomer thereof, wherein Xy is CR4.

[363] In some embodiments, the compound is of Formula (II-b'): or a prodrug, solvate, pharmaceutically acceptable salt, or tautomer thereof, wherein: Y2 and Z2 are each independently O, S, C or N; X2 and W2 are each independently C or N; X3, X4, X5, Xe, and X9 are each independently as defined herein;, B is -halo(Ci-5 alkyl), unsubstituted -C1.5 alkyl, or unsubstituted -C2-5 alkenyl-; RA2 and RA1 are each independently H, halogen, amino, amino(Ci-4 alkyl)-, hydroxy, -O-P(O)(OH)2, -O-P(O)(R{Rn)2, optionally substituted (C1-6 alkyl), or optionally substituted (C1-6 alkyl)oxy-, wherein Ci^ alkyl of said optionally substituted (Ci-6 alkyl), or optionally substituted (Cue alkyl)oxy- is optionally substituted with 1-4 substituents each independently selected from the group comprising hydroxyl, C1-4 alkoxyl, -N(Re)(Rf), -CO?.(Rf), optionally substituted phenyl, and optionally substituted 5 6 membered heteroaryl, and wherein said optionally substituted phenyl or 5-6 membered heteroaryl is optionally substituted by 1-4 substituents each independently selected from halogen, hydroxy, -O-P(O)(OH)2, -O-P(O)(RIRII)2, amino, (Ci-6alkyl)amino-, (Ci-6alkyl)(Cn 6 alkyl)amino-, halo(Ci-6alkyl), hydroxy-(Ci-4 alkyl)-, -(C1-4 alkyl)-O-P(O)(OH)2, -(C1-4 alkyl)-O-P(O)(RIR11)?., halo(Ci-4 alkoxy)-, C1-4 alkoxy-, hydroxy~(C2-4 alkoxy)-, -(C2-4 alkoxy)-O-P(O)(OH)2, -(C24 alkoxyj-O-PfOXRdlHh, -(C1-6 alkyl)-NH2, and C1-4 alkoxy-(Ci-4 alkoxy)-; R® is selected from H, (C4.4 alkyl), -CO(Cm alkyl), -0C0(Ci-4 alkyl), -(C1.4 alkyl)-NH2, -(Cm alkyl)-Ci-4 alkoxy, and -CO2(Ci-4 alkyl), each Rf is independently H, hydroxy, or (Ci-4 alkyl); R4 and R6 are H; RC2 is absent, Cm alkyl or -CH2COOH; Rl6 and RC1 are each independently absent, H or Cm alkyl; R!', R18, or R19 are each independently absent, H, Cm alkyl or halo(Ci-4 alkyl); and each R1 and R11 are independently (Cm alkyl)oxy-.

[364] In some embodiments, the compound is of Formula (II-b’), or a prodrug, solvate, pharmaceutically acceptable salt, or tautomer thereof, wherein Xy is CR4

[365] In some embodiments, the compound is of Formula (I-b!), or a prodrug, solvate, pharmaceutically acceptable salt, or tautomer thereof) wherein: RA2 and RA1 are each independently H, halogen, amino, amino(Ci-4 alkyl)-, hydroxy, -O-P(O)(OH)2, -O-P(O)(R1Rn)2, optionally substituted (C1-6 alkyl), or optionally substituted (C1-6 alkyl)oxy-, wherein Cm alkyl of said optionally substituted (C1-6 alkyl), or optionally substituted (C1-6 alkyl)oxy- is optionally substituted with 1-4 substituents each independently selected from the group comprising hydroxyl, Cm alkoxyl, -N(Re)(Rf), -CO2(Rf), optionally substituted phenyl, and optionally substituted 5 6 membered heteroaryl, and wherein said optionally substituted phenyl or 5-6 membered heteroaryl is optionally substituted by 1 -4 substituents each independently selected from halogen, hydroxy, -O-P(O)(OH)2, -O-P(O)(RIRn)2, amino, (CMalkyl)amino-, (CMalkyl)(Cu 6 alkyl)ammo-, halo(Ci-6alkyl), hydroxy-(Ci-4 alkyl)-, -(Cm alkyl)-O-P(O)(OH)2, -(Cm alkyl)-O-P(O)(RIRIi)2, halo(CM alkoxy)-, Cm alkoxy-, hydroxy-(C2-4 alkoxy)-, -(C2-4 alkoxy)-O-P(O)(OH)2, -(C2^alkoxy)-O-P(O)(RIRII)2, -(Cj-6alkyl)-NH2, and Cm alkoxy-(Ci-4 alkoxy)-; provided that at least one of (i), (11), or (ui) applies: (i) when (a) Zi, Z2, ¥1 and Y2 are each N, Wi, W2, Xi and X2 are each C; or (b) Wi, W2, Xi and X2 are each N, Zi, Z2, ¥1 and ¥2 are each C; or (c) Zi and Yi are each N, Wi and Xi are each C; or (d) Z2 and ¥2 are each N, W2 and X2 are each C; or (e) Wi and Xi are each N, Zi and Yi are each C; or (f) W2 and X2 are each N, Z2 and Y2 are each C, then at least one of X3 and X4 is S; or X9 is N; or (ii) when (a) Zi, Z2, Yi and Y2 are each N, Wi, W2, Xi and X2 are each C; or (b) Wi, W2, Xi and X2 are each N, Zi, Z2, Yi and Y2 are each C, then R14 is a Ci .4 alkyl substituted with halogen, -ORC, -NRcRd, -CO2Rc, -C()NRcRd, -SO2NRcRd, and -OCONRcRd wherein Rc is H; or (iii) when (a) Zi and Yi are each N, Wi and Xi are each C; or (b) Z2 and Y2 are each N, W2 and X2 are each C; or (c) Wi and Xi are each N, Zi and Yi are each C; or (d) W2 and X2 are each N, Z2 and Y2 are each C, then at least one of X5, Xe, and X9 is N and RA! or RA2 is halogen, hydroxy, optionally substituted (Ci-6 alkyl), substituted (Cw alkyl)oxy-, optionally substituted (Cue alkyl)amino-, or optionally substituted (Cm alkyl)(Ci-4 alkyl)amino-, wherein the (Cue alkyl) of said optionally substituted (Cm alkyl), substituted (Cue alkyl)oxy-, optionally substituted (Cue alkyl)amino-, or optionally substituted (Cm alkyl)(Ci-4 alkyl)ammo- is optionally substituted by 1-4 substituents each independently selected from hydroxy, -O-P(O)(OH)2, -0^(0)^¾1% -N(Re)(Rf), -CO2(Rf), -CON(Re)(Rf), optionally-substituted phenyl, and optionally substituted 5-6 membered heteroaryl group, wherein said optionally substituted phenyl or 5-6 membered heteroaryl is optionally substituted by 1-4 substituents each independently selected from halogen, hydroxy, -O-P(O)(OH)2, -0-P(0)(RIR1I)2, ammo, (Ci-6 alkyl)amino-, (Ci-6 alkyl)(Ci-6 alkyl)amino-, -(Ci-6 alkyl)-NH2, halo(Ci-6 alkyl), hydroxy-(Ci-4 alkyl)-, -(C1-4 alkyl)-O-P(O)(OH)2, -(C1-4 alkyl)-O-P(O)(RIRn)2, halo(Ci-4 alkoxy), C1-4 alkoxy-, hydroxy-(C2-4 alkoxy)-, -(C2-4 alkoxy)-O-P(O)(OH)2, -(C2-4 alkoxy)-O-P(O)(RIRl!)2, -C1-4 alkyl-(Ci-4 alkoxy), and C1-4 alkoxy-(Ci-4 alkoxy)-.

[366] In some embodiments, the compound of disclosure has Formula (I-b ), or a prodrug, solvate, pharmaceutically acceptable salt, or tautomer thereof, wherein: Ra2 and RA1 are each independently H, halogen, hydroxy, amino, amino(Ci-4 alkyl)-, optionally substituted (Cj -6 alkyl), or optionally substituted (Ci-6alkyl)oxy-, wherein Cm alkyl of said optionally substituted (Cm alkyl), or optionally substituted (Cue alkyl)oxy- is optionally substituted with 1-4 substituents each independently selected from the group comprising hydroxyl, C1-4 alkoxyl, -N(Re)(Rf), -CO2(Rt), optionally substituted phenyl, and optionally substituted 5- 6 membered heteroaryl, and wherein said optionally substituted phenyl or 5-6 membered heteroaryl is optionally substituted by 1-4 substituents each independently-selected from halogen, hydroxy, amino, (CMalkyl)amino-, (CMalkyl)(CMalkyl)amino-, halo(Cn 6 alkyl), hydroxy-(Ci-4 alkyl)-, halo(Ci-4 alkoxy)-, C4.4 alkoxy-, hydroxy-(C2 4 alkoxy)-, and C1.4 alkoxy-(Ci-4 alkoxy)-; and R® is H, (Ci-4 alkyl), -CO(Ci-4 alkyl), -OCO(Ci-4 alkyl), or -CO2(Ci-4 alkyl); provided that at least one of (i), (ii), or (iii) applies: (i) when (a) Zi, Z2, Yi and Y2 are each N, Wi, W2, Xi and X2 are each C; or (b) Wi, W2, Xi and X2 are each N, Zi, Z2, Yi and Y2 are each C; or (c) Zi and Yi are each N, Wi and Xi are each C; or (d) Z2 and Y2 are each N, W2 and X2 are each C; or (e) Wi and Xi are each N, Zi and Yi are each C; or (f) W2 and X2 are each N, Z2 and Y2 are each C, then at least one of X3 and X4 is S; or X9 is N; or (ii) when (a) Zi, Z2, Yi and Y2 are each N, Wi, W2, Xi and X2 are each C; or (b) Wi, W2, Xi and X2 are each N, Zi, Z2, Yi and Y2 are each C, then R14 is a Cn4 alkyl substituted with halogen, -OR®, -NRcRd, -COhV, -CONR®Rd, -SO2NRcRd, and -OCONRcRd wherein Rc is H; or (iii) when (a) Zi and Yi are each N, Wi and Xi are each C; or (b) Z2 and Y2 are each N, W2 and X2 are each C; or (c) Wi and Xi are each N, Zi and Yi are each C; or (d) W2 and X2 are each N, Z2 and Y2 are each C, then at least one of X5, X*, and X9 is N and RA1 or RAz is halogen, hydroxy, optionally substituted (C1-6 alkyl), substituted (C1-6 alkyl)oxy-, optionally substituted (Cue alkyl)amino~, or optionally substituted (C1-6 alkyl)(Ci-4 alkyl)amino-, wherein the (C1-6 alkyl) of said optionally substituted (Ci-6 alkyl), substituted (C1-6 alkyl)oxy-, optionally substituted (Cue alkyl)amino-, or optionally substituted (Cue alkyl)(Ci-4 alkyljammo- is optionally substituted by 1-4 substituents each independently selected from hydroxy, -O-P(O)(OH)2, -O-P(O)(RIRII)2, -N(R®)(Rf), -CO2(Rf), -CON(R®)(Rf), optionally substituted phenyl, and optionally substituted 5-6 membered heteroaryl group, wherein said optionally substituted phenyl, or 5-6 membered heteroaryl is optionally substituted by 1-4 substituents each independently selected from halogen, hydroxy, -O-P(O)(OH)2, -O-P(O)(R1Rlf)2, amino, (Cur, alkyljamino-, (Cne alkyl)(Cj-6 alkyljamino-, -(Cue alkyl)-NH2, halo(Cne alkyl), hydroxy-(Cn4 alkyl)-, -(Ci-4 alkyl)-O-P(O)(OH)2, -(Cn4 alkyl)-O-P(O)(RIRu)2, halo(Cn4 alkoxyj-, Cm alkoxy-, hydroxy-(C2-4alkoxy)-, -(C2.4alkoxy)-O-P(O)(OH)2, -(C2.4alkoxy)-O-P(O)(RIR1I)2, -Cn4 alkyl-(Ci-4 alkoxy), and C1-4 alkoxy-(Ci-4 alkoxy)-.

[367] In some embodiments, the compound is of Formula (I-B’), (II-B'), (I-b’), or (II-b’), or a prodrug, solvate, pharmaceutically acceptable salt, or tautomer thereof, wherein RA‘ and RAs are each independently H, halogen, hydroxy, ammo, amino(Ci-4 alkyl)-, optionally substituted (Cue alkyl), or optionally substituted (Cue alkyl)oxy-, and the Cue alkyl of said optionally substituted (Cue alkyl), optionally substituted (Cue alkyl)oxy- is optionally substituted with 1-4 substituents each independently selected from the group comprising hydroxyl, -O-P(O)(OH)2, -O-P(O)(R1RIi)2, -N(Re)(Rf), Cm alkoxyl, phenyl, and optionally substituted 5-6 membered heteroaryl comprising at least one nitrogen or oxygen as a member of the ring; each R® is independently selected from H, (Cm alkyl), -(Cm alkyl)-NH2, and -(Cm alkyl)-Ci-4 alkoxy; and each Rf is independently H, hydroxy, or (C1.4 alkyl).

[368] In some embodiments, the compound is of Formula (I-B’), (H-B'). (I-b’), or (II-b’), or a prodrug, solvate, pharmaceutically acceptable salt, or tautomer thereof, wherein RA? and RAl are each independently H, halogen, hydroxy, amino, amino(Ci-4 alkyl)-, optionally substituted (Ci-6 alkyl), or optionally substituted (Ci-6 alkyl)oxy-, and the Cue alkyl of said optionally substituted (Cue alkyl), optionally substituted (Cue alkyl)oxy- is optionally substituted with 1-4 substituents each independently selected from the group comprising hydroxyl, -N(R®)(RI), Cm alkoxyl, phenyl, and optionally substituted 5-6 membered heteroaryl comprising at least one nitrogen or oxygen as a member of the ring; each Re is independently H or (Cm alkyl); and each Rf is independently H, hydroxy, or (Cm alkyl).

[369] In some embodiments, the compound is of Formula (I-B’), (II-B'), (I-b’), or (II-b’), or a prodrug, solvate, pharmaceutically acceptable salt, or tautomer thereof, wherein Ra:’ and RA! are each independently H, halogen, hydroxy, amino, amino(CM alkyl)-, optionally substituted (Ci-6 alkyl), or optionally substituted (Cm alkyl)oxy-, and the Cm alkyl of said optionally substituted (Cm alkyl), optionally substituted (Cm alkyl)oxy- is optionally substituted with 1-4 substituents each independently selected from the group comprising hydroxyl, -N(Re)(Rf), Cm alkoxyl, phenyl, and optionally substituted 5-6 membered heteroaryl comprising at least one nitrogen or oxygen as a member of the ring; and R® and Rf are each independently H or (Cm alkyl).

[370] In some embodiments, the compound is of Formula (I-B’), (II-B'), (I-b’), or (II-b’), or a prodrug, solvate, pharmaceutically acceptable salt, or tautomer thereof, wherein at least one of RAz or Ra1 is independently H, halogen, hydroxy, ammo, amino(Ci-4 alkyl)-, optionally substituted (Ci-6 alkyl), or optionally substituted (Cm alkyl)oxy-, and the Cm alkyl of said optionally substituted (Cm alkyl), optionally substituted (Cm alkyl)oxy- is optionally substituted with 1-4 substituents each independently selected from -N(Re)(Rf), tetrahydropyran, pyrrolidmyl, piperazmyl, piperidyl, and morpholmyl; each R® is independently selected from H, (Cm alkyl), -(Cm alkylj-NFh, and -(Cm alkyl)-Ct-4 alkoxy; and each Rf is independently H, hydroxy, or (Cm alkyl).

[371] In some embodiments, the compound is of Formula (I-B'), (II-B'), (I-b’), or (II-b’), or a prodrug, solvate, pharmaceutically acceptable salt, or tautomer thereof, wherein at least one of RAz or RAI is independently H, halogen, hydroxy, amino, amino(Ci-4 alkyl)-, optionally substituted (Cu 6 alkyl), or optionally substituted (Ci-6 alkyl)oxy-, and the Ci-6 alkyl of said optionally substituted (Ci-6 alkyl), optionally substituted (Ci-6 alkyl)oxy- is optionally substituted with 1-4 substituents each independently selected from -N(Re)(Rf), tetrahydropyran, pyrrolidinyl, piperazinyl, piperidyl, and morpholinyl; each Re is independently H or (Cm alkyl); and each Rf is independently H, hydroxy, or (Cu4 alkyl).

[372] In some embodiments, the compound is of Formula (I-B'), (II-B1), (I-b’), or (II-b’), or a prodrug, solvate, pharmaceutically acceptable salt, or tautomer thereof, wherein at least one of RAz or RAl is independently H, halogen, hydroxy, amino, amino(Cu4 alkyl)-, optionally substituted (Cn 6 alkyl), or optionally substituted (Ci-6 alkyl)oxy-, and the Ci-6 alkyl of said optionally substituted (Ci-6 alkyl), optionally substituted (Ci-6 alkyl)oxy- is optionally substituted with 1-4 substituents each independently selected from -N(Re)(Rf), tetrahydropyran, pyrrolidinyl, piperazinyl, piperidyl, and morpholinyl; and Re and Rf are each independently H or (Ci-4 alkyl).

[373] In some embodiments, the compound is of Formula (I-B’), (II-B!), (I-b’), or (II-b’), or a prodrug, solvate, pharmaceutically acceptable salt, or tautomer thereof, wherein Yi, Y2, Zi and Zs are each independently O, S, C or N; Xi, X2, Wi and W2 are each independently C or N; X3 and X4 are each independently S or NRf; X5 is N or CRA2; X6 is N or CR 'Y B is unsubstituted -Cue alkyl, or unsubstituted -C2-5 alkenyl-; RA2 and RA1 are each independently H, halogen, hydroxy, amino, amino(Ci-4 alkyl)-, optionally substituted (Cue alkyl), or optionally substituted (Cu6alkyl)oxy-, wherein Cue alkyl of said optionally substituted (Cue alkyl), or optionally substituted (Cue alkyl)oxy- is optionally substituted with 1-2 substituents each independently selected from the group comprising hydroxyl, C1-4 alkoxyl, -N(Re)(Rf), -CO2(Rf), unsubstituted phenyl, and unsubstituted 5-6 membered heteroaryl; Re is H, (C1.4 alkyl), -CO(Ci-4 alkyl), -OCO(Ci-4 alkyl), or -CO2(Ci.4 alkyl); each occurrence of Rf is H, hydroxy, or (C1-4 alkyl); R'14 and RC2 are each independently absent or C1.4 alkyl, wherein C1-4 alkyl is optionally substituted by a substituent selected from halogen, -ORC, -NRcRd, -CO2Rc, -CONRcRd, -SO2NRcRd, and -OCONRcRd; R16 and RCi are each independently absent, H or Ci-4 alkyl; and Rl5, R1', R18, or Ri9 are each independently absent, H, or C1-4 alkyl, wherein C1-4 alkyl is optionally substituted by a substituent selected from halogen, -ORC, -NRcRa, -CO2Rc, -CONRcRd, -SO2NRcRd, and -OCONRcRd; provided that at least one of (i), (ii), or (iii) applies: (i) when (a) Zi, Z2, Yi and Y2 are each N, Wi, W2, Xi and X2 are each C; or (b) Wi, W2, Xi and X2 are each N, Zi, Z2, Yi and Y2 are each C; or (c) Zi and Yi are each N, Wi and Xi are each C; or (d) Z2 and Y2 are each N, W2 and X2 are each C; or (e) Wi and Xi are each N, Zi and Yi are each C; or (f) W2and X2 are each N, Z2 and Y2 are each C, then at least one of X3 and X4 is S; or X9 is N; or (ii) when (a) Zi, Z2, Yi and Y2 are each N, Wi, W2, Xi and X2 are each C; or (b) Wi, W2, Xi and X2 are each N, Zi, Z2, Yi and Y2 are each C, then R14 is a C1-4 alkyl substituted with halogen, -ORC, -NRcRd, -CO2Rc, -CONRcRd, -SO2NRcRd, and -OCONRcRd wherein Rc is H; or (iii) when (a) Zi and Yi are each N, Wi and Xi are each C; or (b) Z2 and Y2 are each N, W2 and X2 are each C; or (c) Wi and Xi are each N, Zi and Yi are each C; or (d) W2 and X2 are each N, Z2 and Y2 are each C, then at least one of X5, Xe, and X9 is N and RA1 or RA2 is halogen, hydroxy, optionally substituted (C1-6 alkyl), substituted (Cue alkyl)oxy-, optionally substituted (C1-6 alkyl)ammo-, or optionally substituted (Cue alkyl)(Ci-4 alkyl)amino-, wherein Cue alkyl of said optionally substituted (Cue alkyl) or substituted (Cue alkyl)oxy-is optionally substituted with 1-2 substituents each independently selected from the group comprising hydroxyl, Cj.4 alkoxy], -N(Re)(R!), -CO2(Rf), unsubstituted phenyl, and unsubstituted 5-6 membered heterocycloalkyl.

[374] In some embodiments, the compound is of Formula (I-b'), or a prodrug, solvate, pharmaceutically acceptable salt, or tautomer thereof, wherein Yi, Y2, Zi and Z2 are each independently O, S, C or N; Xi, X2, Wi and W2 are each independently C or N; X3, X4,Xs, Xe, and X9 are each independently as defined in Formula (IA’); B is unsubstituted -C2-5 alkenyl-; RA2 and RA1 are each independently H, hydroxy, optionally substituted (Ci-6 alkyl), optionally substituted (Ci-6 alkyl)oxy-, amino or amino(Ci-4 alkyl)-, wherein Ci-6 alkyl of said optionally substituted (C4-6 alkyl), or optionally substituted (Cue alkyl)oxy- is optionally substituted with 1 substituents each independently selected from the group comprising hydroxyl, Ci-4 alkoxyl, and unsubstituted 5-6 membered heteroaryl, Ri4 and RC2 are each independently absent or Ci-4 alkyl, wherein C1-4 alkyl is optionally substituted by a substituent selected from halogen, -ORC, -NRcRd, -CO2RC, ~CONRcRd, -SO2NRcRd, and -OCONRcRd; R and Ru are each independently absent, H or Ci-4 alkyl; R15, Rl / , R1S, or R19 are each independently absent, H, or Ci-4 alkyl, wherein C1-4 alkyl is optionally substituted by a substituent selected from halogen, -ORC, -NRcRa, -CO2RC, -CONRcRd, -SO2NRcRd, and -OCONRcRd; provided that at least one of (i), (ii), or (iii) applies: (i) when (a) Zi, Z2, Yi and Y2 are each N, Wi, W2, Xi and X2 are each C; or (b) Wi, W2, Xi and X2 are each N, Zi, Z2, Yi and Y2 are each C; or (c) Zi and Yi are each N, Wi and Xi are each C; or (d) Z2 and Y2 are each N, W2 and X2 are each C; or (e) Wi and Xi are each N, Zi and Yi are each C; or (f) W2 and X2 are each N, Z2 and Y2 are each C, then at least one of X3 and X4 is S; or X9 is N; or (ii) when (a) Zi, Z2, Yi and Y2 are each N, Wi, W2, Xi and X2 are each C; or (b) Wi, W2, Xi and X2 are each N, Zi, Z2, Yi and Y2 are each C, then R14 is a Cm alkyl substituted with halogen, -ORC, -NRcRd, -COdV -CONRcRd, -SO2NRcRd, and -OCONRcRd wherein Rc is H; or (iii) when (a) Zi and Yi are each N, Wi and Xi are each C; or (b) Z2 and Y2 are each N, W2 and X2 are each C; or (c) Wi and Xi are each N, Zi and Yi are each C; or (d) W2 and X2 are each N, Z2 and Y2 are each C, then at least one of X5, Xe, and X9 is N and RAs or R*2 is halogen, hydroxy, optionally substituted (Cue alkyl), substituted (Cue alkyl)oxy-, optionally substituted (Cue, alkyl)amino-, or optionally substituted (Cue alkyl)(Ci-4 alkyl)ammo-, wherein Ci-6 alkyl of said optionally substituted (Cue alkyl) or substituted (Ci-6alkyl)oxy-is optionally substituted with 1 substituents each independently selected from the group comprising hydroxyl, C4-4 alkoxyl, and unsubstituted 5-6 membered heteroaryl.

[375] In some embodiments, the compound is of Formula (I-b!), or a prodrug, solvate, pharmaceutically acceptable salt, or tautomer thereof, wherein Yi, Y2, Zi and Z2 are each independently O, S, C or N; Xi, X2, Wi and W2 are each independently C or N; X3, X4, X5, Xe, and X9 are each independently as defined in Formula (IA’); B is unsubstituted ethenyl; RA2 and RA! are each independently H, hydroxy, amino, ammo(Ci.4 alkyl)-, or optionally-substituted (C1-6 alkyl)oxy-, wherein Ci-6 alkyl of said optionally substituted (Ci-6 alkyl)oxy- is optionally substituted with hydroxyl; R14 and Rc2 are each independently absent or C1-4 alkyl, wherein C1-4 alkyl is optionally substituted by a substituent selected from halogen, -ORC, -NRcRd, -CO2RC, ~C0NRcRd, -SO2NRcRd, and -OCONRcRd; R10 and RC1 are each independently absent, H or C1-4 alkyl; and R!3, R1', R1S, or R19 are each independently absent, H, or C1-4 alkyl, wherein C1-4 alkyl is optionally substituted by a substituent selected from halogen, -ORC, -NRcRti, -CO2RC, -CONRcRd, -SO ARcRd. and -OCONRcRd; provided that at least one of (1), (ii), or (iii) applies: (i) when (a) Zi, Z2, Yi and Y2 are each N, Wi, W2, Xi and X2 are each C; or (b) Wi, W2, Xi and X2 are each N, Zi, Z2, Yi and Y2 are each C; or (c) Zi and Yi are each N, Wi and Xi are each C; or (d) Z2 and Y2 are each N, W2 and X2 are each C; or (e) Wi and Xi are each N, Zi and Yi are each C; or (f) W2 and X2 are each N, Z2 and Y2 are each C, then at least one of X3 and X4 is S; or X9 is N; or (ii) when (a) Zi, Z2, Yj and Y2 are each N, Wi, W2, Xi and X2 are each C; or (b) Wj, W2, Xi and X2 are eachN, Zi, Z2, Yi and Y2are each C, then R14 is a Cm alkyl substituted with halogen, -ORC, -NRcRd, -CO2Rc, -C()NRcRd, -SO2NRcRd, and -OCONReRd wherein Rc is H; or (iii) when (a) Zj and Yrj are each N, Wi and Xi are each C; or (b) Z? and Y? are each N, W2. and X2 are each C; or (c) Wi and Xi are each N, Zi and Yj are each C; or (d) W2 and X2 are each N, Z2 and Y2 are each C, then at least one of X5, Xe, and X9 is N and R^ and RA1 are each independently H, hydroxy, ammo, ammo(Ci..4 alkyl)-, or optionally substituted (Ci-6 alkyl)oxy-, wherein Ci-6 alkyl of said optionally substituted (Cue alkyl)oxy- is optionally substituted with hydroxyl.

[376] In some embodiments, the compound is of Formula (I-bd’): or a prodrug, solvate, pharmaceutically acceptable salt, or tautomer thereof, wherein: Yj, Y2, Zj and Z2 are each independently 0, S, C or N; Xi, X2, Wi and W2 are each independently C or N; X6 is N or CRA1; X9 is N or CR4; X3, X4, X9, Rd, and Rf are each independently as defined herein; RC1 and RC2 are each independently -CH2-, D is -halo(Ci-5 alkyl), unsubstituted -C1.5 alkyl, or unsubstituted -C1-5 alkenyl-; RB! and RB2 are each independently -CH2-; B is -halo(C 1-5 alkyl), unsubstituted -Ci-5 alkyl, or unsubstituted -C1.5 alkenyl-; RAz and RAi are each independently H, halogen, amino, ammo(Ci-4 alkyl)-, hydroxy, -O-P(O)(OH)2, -O-P(O)(RIRn)2, optionally substituted (C1-6 alkyl), or optionally substituted (C1-6 alkyl)oxy-, wherein C1-6 alkyl of said optionally substituted (C1-6 alkyl), or optionally substituted (Cue alkyl)oxy- is optionally substituted with 1-4 substituents each independently selected from the group comprising hydroxyl, -O-P(O)(OH)2, -0-P(0)(RTRI1)2, C1-4 alkoxyl, -N(Re)(Rf), -CO2(Rf), optionally substituted phenyl, and optionally substituted 5-6 membered heteroaryl; wherein said optionally substituted phenyl, or 5-6 membered heteroaryl is optionally substituted by 1-4 substituents each independently selected from halogen, hydroxy, -O-P(O)(OH)2, -O-P(O)(RIR1I)2, amino, (C1-6 alky)amino-, (C1-6 alkyl)(Ci-6 alkyl)amino-, halo(Ci-6 alkyl), hydroxy-(Ci-4 alkyl)-, -(Ci-4 alkyl)-O-P(O)(OH)2, -(Cm alkyl)-O-P(O)(RIRII)2, halo(Ci-4 alkoxy)-, C1-4 alkoxy-, hydroxy- (C2-4 alkoxy)-, -(C2-4 alkoxy)-O-P(O)(OH)2, -(C1.4 alkoxy)-O-P(O)(R1RIi)2„ -(Ci-6alkyl)-NH2, and Cm alkoxy-(Ci-4 alkoxy)-; Re is selected from H, (Cm alkyl), -CO(Cm alkyl), -OCO(Cm alkyl), -(Cm alkyl)-NH.2, -(Cm alkyl)-Ci-4 alkoxy, and -CO2(Ci-4 alkyl); R4 and R6 is H; R14 is absent or C1-4 alkyl, wherein Cm alkyl is optionally substituted by a substituent selected from halogen, -ORC, -NRcRd, -CO2RC, -CONRcRd, -SO2NRcRd, and -OCONRcRd; R16 is absent, H or Cm alkyl; R15, Ri?, RiS, or R19 are each independently absent, H, or Cm alkyl, wherein Cm alkyl is optionally substituted by a substituent selected from halogen, -ORC, -NRcRd, -CO2RC, -CONRcRd, -SO2NRcRd, and -OCONRcRd; and each R1 and R11 are independently (Cm alkyl)oxy-, provided that at least one of (i), (ii), or (lii) applies: (i) when (a) Zi, Z2, Yi and Y2 are each N, Wi, W2, Xi and X2 are each C; or (b) Wi, W2, Xi and X2 are each N, Zi, Z2, Yi and Y2 are each C; or (c) Zi and Yi are each N, Wi and Xi are each C; or (d) Z2 and Y2 are each N, W2 and X2 are each C; or (e) Wi and Xi are each N, Zi and Yi are each C; or (f) W2 and X2 are each N, Z2 and Y2 are each C, then at least one of X3 and X4 is S; or X9 is N; or (ii) when (a) Zi, Z2, Yi and Y2 are each N, Wi, W2, Xi and X2 are each C; or (b) Wi, W2, Xi and X2 are each N, Zi, Z2, Yi and Y2 are each C, then R14 is a Cm alkyl substituted with halogen, -ORC, -NRcRd, -CO2R4 -CONRcRd, -SO2NRcRd, and -OCONRcRd wherein Rc is H; or (lii) when (a) Zi and Yi are each N, Wi and Xi are each C; or (b) Z2 and ¥2 are each N, W2 and X2 are each C; or (c) Wi and Xi are each N, Zi and Yi are each C; or (d) W2 and X2 are each N, Z2 and Y2 are each C, then at least one of X5, Xe, and X9 is N and RA1 or R*2 is halogen, hydroxy, optionally substituted (Cue alkyl), substituted (Cm, alkyljoxy-, optionally substituted (Cm, alkyl)ammo-, or optionally substituted (Cm alkyl)(Ci-4 alkyl)ammo-, wherein the (Cm alkyl) of said optionally substituted (Cm alkyl), substituted (Cm alkyl)oxy-, optionally substituted (Cm alkyl)amino-, or optionally substituted (Cm alkyl)(Ci-4 alkyl)amino- is optionally substituted by 1-4 substituents each independently selected from hydroxy, -O-P(O)(OH)2, -O-P(O)(RJRn)2, -N(Re)(Rf), -CO2(Rf), -CON(Re)(Rf), optionally substituted phenyl, and optionally substituted 5-6 membered heteroaryl group, wherein said optionally substituted phenyl or 5-6 membered heteroaryl is optionally substituted by 1-4 substituents each independently selected from halogen, hydroxy, -O-P(O)(OH)2, -O-P(O)(RIR1I)2, ammo, (Cue alkyl)amino-, (Cne aik\ 1)((6 alkyl)amino-, -(Ci-6 aikdl-XIb. halo(Ci-6 alkyl), hydroxy-(Cn4 alkyl)-, -(Ci-4 alkyl)-O-P(O)(OH)2, -(Ci-4 alkyl)-O-P(O)(R1Rn)2, halo(Ci-4 alkoxy), Ci-4 alkoxy-, hydroxy-(C2-4 alkoxy)-, -(C2-4 alkoxy)-O-P(O)(OH)2, -(C24 alkoxy)-O-P(O)(R^ -C1-4 alkyl-(Ci-4 alkoxy), and C1-4 alkoxy-(Ci-4 alkoxy)-.

[377] In some embodiments, the compound is of Formula (I-bd’) or a prodrug, solvate, pharmaceutically acceptable salt, or tautomer thereof, wherein: Yi, Y2, Zi and Z2 are each independently O, S, C or N; Xi, X2, Wi and W2 are each independently C or N; X5 is N or CRA2; X6 is N or CR A X3, X4, X9, Rd, and Rf are each independently as defined in Formula (IA); RC1 and Rc2 are each independently -CH2-; D is -halo(Ci-5 alkyl), unsubstituted -C1-5 alkyl, or unsubstituted -C2-5 alkenyl-; Rbl and RB2 are each independently -CH2-; B is -halo(Ci-5 alkyl), unsubstituted -C1-5 alkyl, or unsubstituted -C2-5 alkenyl-; RA2 and RA1 are each independently H, halogen, amino, amino(Cj-4 alkyl)-, hydroxyl, optionally substituted (Cj-6 alkyl), or optionally substituted (CuealkyQoxy-, wherein C1-6 alkyl of said optionally substituted (C1-6 alkyl), or optionally substituted (Cue alkyl)oxy- is optionally substituted with 1-4 substituents each independently selected from the group comprising hydroxyl, C1-4 alkoxyl, - N(Re)(R1), -CO2(Rf), optionally substituted phenyl, and optionally substituted 5- 6 membered heteroaryl; wherein said optionally substituted phenyl, or 5- 6 membered heteroaryl is optionally substituted by 1-4 substituents each independently selected from halogen, hydroxy, amino, (Cm alkyl)amino-, (Ci-6 alkyl)(Ci-6 alkyl)amino-, halo(Ci-6 alkyl), hydroxy-(CM alkyl)-, halo(Ci4 alkoxy)-. Cm alkoxy-, hydroxy-(C2-4 alkoxy) and Cm alkoxy-(Ci-4 alkoxy)-, Re is selected from H, (Cm alkyl), -C0(Cm alkyl), -OCO(Ci 4 alkyl), and -CO2(Cm alkyl); R4 and R6 are H; R14 is absent or Cm alkyd, wherein Cm alkyl is optionally substituted by a substituent selected from halogen, -ORC, - W. -CO2Rc, -CONRcRd, -SO2NRcRd, and -OCONRcRd; RH> is independently absent, H or Cm alkyl; and R15, Rl / , R1S, or R19 are each independently absent, H, or Cm alkyl, wherein Cm alkyl is optionally substituted by a substituent selected from halogen, -ORC, -NRcRa, -CO2RC, -CONRcRd, -SO2NRcRd, and -OCONRcRd; provided that at least one of (i), (ii), or (iii) applies: (i) when (a) Zi, Z2, Yi and Y2 are each N, Wi, W2, Xi and X2 are each C; or (b) Wi, W2, Xi and X2 are each N, Zi, Z2, Yi and Y2 are each C; or (c) Zi and Yi are each N, Wi and Xi are each C; or (d) Z2 and Y2 are each N, W2 and X2 are each C; or (e) Wi and Xi are each N, Zi and Yi are each C; or (f) W2 and X2 are each N, Z2 and Y2 are each C, then at least one of X3 and X4 is S; or X9 is N; or (ii) when (a) Zi, Z2, Yi and Y2 are each N, Wi, W2, Xi and X2 are each C; or (b) Wi, W2, Xi and X2 are each N, Zi, Z2, Yi and Y2 are each C, then R14 is a Cm alkyl substituted with halogen, -ORC, -NRcRd, -(OdC -CONRcRd, -SO2NRcRd, and -OCONRcRd wherein Rc is H; or (iii) when (a) Zi and Yi are each N, Wi and Xi are each C; or (b) Z2 and Y2 are each N, W2 and X2 are each C; or (c) Wi and Xi are each N, Zi and Yi are each C; or (d) W2 and X2 are each N, Z2 and Y2 are each C, then at least one of X5, Xe, and X9 is N and RAs or R*2 is halogen, hydroxy, optionally substituted (C1-6 alkyl), substituted (Cm alkyl)oxy-, optionally substituted (Cm alkyl)ammo-, or optionally7 substituted (Cm alkyl)(Ci4 alkyl)amino-, wherein Cm alkyl of said optionally substituted (Cue alkyl) or substituted (Ci-6alkyl)oxy-is optionally substituted with 1-4 substituents each independently selected from the group comprising hydroxyl, Cm alkoxyl, - N(Re)(Rf), -CO2(R1), optionally substituted phenyl, and optionally substituted 5- 6 membered heteroaryl; wherein said optionally substituted phenyl, or 56 membered heteroaryl is optionally substituted by 1-4 substituents each independently selected from halogen, hydroxy, ammo, (Ci-6 alkyl)ammo-, (Cm alkyl)(Ci-6 alkylJammo-, halo(CM alkyl), hydroxy-(Ci-4 alkyl)-, halo(CM alkoxy)-, C1.4 alkoxy-, hydroxy-(C2-4 alkoxy) and C1.4 alkoxy-(Ci-4 alkoxy)-.

[378] In some embodiments, the compound is of Formula (I-bd’), or a prodrug, solvate, pharmaceutically acceptable salt, or tautomer thereof, wherein X9 is CR4

[379] In some embodiments, the compound is of Formula (I-bd’), or a prodrug, solvate, pharmaceutically acceptable salt, or tautomer thereof, wherein RA2 and RAI are each independently H, halogen, hydroxy, amino, ammo(Ci-4 alkyl)-, optionally substituted (Cue alkyl), or optionally substituted (Cue alkyl)oxy-, and the Cm alkyl of said optionally substituted (Cue alkyl), optionally substituted (Cue alkyl)oxy- is optionally substituted with 1-4 substituents each independently selected from the group comprising hydroxyl, -O-P(O)(OH)2, -O-P^XR’R^X, -N(Re)(Rf), Ci-6 alkoxyl, phenyl, and optionally substituted 5-6 membered heteroaryl comprising at least one nitrogen or oxygen as a member of the ring; each Re is independently selected from H, -(Cm alkyl)-NH2, and -(Cm alkyl)-CM alkoxy; and each Rf is independently H, hydroxy, or C1-4 alkyl.

[380] In some embodiments, the compound is of Formula (I-bd’), or a prodrug, solvate, pharmaceutically acceptable salt, or tautomer thereof, wherein RA2 and RA1 are each independently H, halogen, hydroxy, amino, amino(Ci-4 alkyl)-, optionally substituted (Cm alkyl), or optionally substituted (Cm> alkyl)oxy-, and the Cj-6 alkyl of said optionally substituted (Cue alkyl), optionally substituted (Cm alkyl)oxy- is optionally substituted with 1-4 substituents each independently selected from the group comprising hydroxyl, -N(Re)(Rf), C1.4 alkoxyl, phenyl, and optionally substituted 5-6 membered heteroaryl comprising at least one nitrogen or oxygen as a member of the ring; each R® is independently H or (Cm alkyl); and each R1 is independently H, hydroxy, or (Cm alkyl).

[381] In some embodiments, the compound is of Formula (I-bd’), or a prodrug, solvate, pharmaceutically acceptable salt, or tautomer thereof, wherein RA2 and RA1 are each independently H, halogen, hydroxy, ammo, amino(Ci-4 alkyl)-, optionally substituted (Cm alkyl), or optionally substituted (Cm alkyl)oxy-, and the Cm alkyl of said optionally substituted (Cm alkyl), optionally substituted (Cm alkyl)oxy- is optionally substituted with 1-4 substituents each independently selected from the group comprising hydroxyl, -N(Re)(Rf), Cm alkoxyl, phenyl, and optionally substituted 5-6 membered heteroaryl comprising at least one nitrogen or oxygen as a member of the ring; and Re and Rf are each independently H or (C1.4 alkyl).

[382] In some embodiments, the compound is of Formula (I-bd’), or a prodrug, solvate, pharmaceutically acceptable salt, or tautomer thereof, wherein at least one of RA2 or RAi is independently H, halogen, hydroxy, ammo, amino(Ci-4 alkyl)-, optionally substituted (Cue alkyl), or optionally substituted (Ci-6 alkyl)oxy-, and the Ci-6 alkyl of said optionally substituted (Ci-6 alkyl), optionally substituted (Ci-6 alkyl)oxy- is optionally substituted with 1-4 substituents each independently selected from -N(Re)(Rf), tetrahydropyran, pyrrolidinyl, piperazinyl, piperidyl, and morpholinyl; each Re is independently selected from H, (C1-4 alkyl), -(C1-4 alkyl)-NH2, and -(C1-4 alkyl)Ci4 alkoxy; and each Rf is independently H, hydroxy, or (C1-4 alkyl).

[383] In some embodiments, the compound is of Formula (I-bd’), or a prodrug, solvate, pharmaceutically acceptable salt, or tautomer thereof, wherein at least one of RA2 or RAi is independently H, halogen, hydroxy, amino, amino(Ci-4 alkyl)-, optionally substituted (Ci-6 alkyl), or optionally substituted (Ci-6 alkyDoxy-, and the Ci-6 alkyl of said optionally substituted (Cue alkyl), optionally substituted (Cm alkyl)oxy- is optionally substituted with 1-4 substituents each independently selected from -N(Re)(Rf), tetrahydropyran, pyrrolidinyl, piperazinyl, piperidyl, and morpholinyl; each Re is independently H or (C1-4 alkyl); and each R! is independently H, hydroxy, or (Ci-4 alkyl).

[384] In some embodiments, the compound is of Formula (I-bd’), or a prodrug, solvate, pharmaceutically acceptable salt, or tautomer thereof, wherein at least one of RA2 or RA1 is independently H, halogen, hydroxy, amino, ammo(Ct-4 alkyl)-, optionally substituted (Cm alkyl), or optionally substituted (Ci-6 alkyl)oxy-, and the Cm alkyl of said optionally substituted (Cj-6 alkyl), optionally substituted (Cm alkyl)oxy- is optionally substituted with 1-4 substituents each independently selected from -N(Re)(Rf), tetrahydropyran, pyrrolidinyl, piperazinyl, piperidyl, and morpholinyl; and Re and R1 are each independently H or (Cm alkyl).

[385] In some embodiments, the compound is of Formula (V’) is a compound of Formula (V-a), (V-b), (V-c), (V-d), (V-e), (V-el), (V-e2), (V-f), (V-fl), (V-£2), (V-f3), (V-f4), (V-f5), (V-f6), (V-f7), (V-g), (V-gl), (V-g2), (V-g3), (V-g4), (V-g5), (V-g6), (V-g7), (V-h), (V-hl), (V-h2), (V-h3), (V-h4), (V-h5), (V-h6), (V-h7), (V-i), (V-il), (V-i2), (V-i3), (V-i4), (V-i5), (V-i6), or (V-i7).

[386] In some embodiments, the compound is of Formula (V’), wherein the compound is Formula (V-a), Formula (V-b), Formula (V-c), Formula (V-d), Formula (V-e), Formula (V-el), or Formula (V-e2): R14 or a prodrug, solvate, pharmaceutically acceptable salt, or tautomer thereof, wherein: Yi, Y2, Zi, Z2, Xi, X2, Wi, W2, X5, X6, X9, X3, X4, RCI, RC2, R3, R5, R14, R16, R15, R17, R18, R19, Re, and R1 are each independently as defined in Formula (V’); and RA2 and RA1 when present, are each independently halogen, hydroxyl, optionally substituted (Ci-6 alkyl), substituted (Ci-6 alkyl)oxy-, optionally substituted (Cue alkyl)ammo-, or optionally substituted (Ci-6 alkyl)(Ci-4 alkyl)amino~, wherein Cj-6 alkyl of said optionally substituted (Cue, alkyl) or substituted (Cue, alkyl)oxy-is optionally substituted with 1-4 substituents each independently selected from the group comprising hydroxyl, Ci-4 alkoxyl, -N(R®)(R1), -CO2(R1), -CON(Re)(Rf), and -COOH.

[387] In some embodiments, the compound is of Formula (V-a), Formula (V-b), Formula (V-c), Formula (V-d), Formula (V-e), or Formula (V-e2), wherein X9 is CH.

[388] In some embodiments, the compound is of Formula (V’), wherein the compound is Formula (V-f), Formula (V-fl), Formula (V-f2), Formula (V-f3), Formula (V-f4), Formula (V-f5), Formula (V-f6), or Formula (V-f7): or a prodrug, solvate, pharmaceutically acceptable salt, or tautomer thereof, wherein: Y2 and Z2 are each independently O, S, C or N; X2 and W2 are each independently C or N; X3, X4, X5, Xe, X9, R16, RC1, Rc, R3, R3, R17, R18, R19, and Rd, are each independently as defined in Formula (V’); and RC2 are each independently absent or C1-4 alkyl, wherein Cm alkyl is optionally substituted by a substituent selected from halogen, -ORC, -NRcRd, -COtR0, -CONRcRd, -S()2NRcRd, and -OCONRcRd .

[389] In some embodiments, the compound is of Formula (V-f), Formula (V-fl), Formula (V-£2), Formula (V-f3), Formula (V-f4), Formula (V-f5), or Formula (V-f6), wherein X9 is CH.

[390] In some embodiments, the compound is of Formula (V’), wherein the compound is Formula (V-g), Formula (V-gl), Formula (V-g2), Formula (V-g3), Formula (V-g4), Formula (V-g5), Formula (V-g6), or Formula (V-f7): or a prodrug, solvate, pharmaceutically acceptable salt, or tautomer thereof, wherein: Y2 and Z2 are each independently O, S, C or N; X2 and W2 are each independently C or N; X3, X4, X5, Xe, X9, Rc, RC1, R3, R3, R16, R1', R18, R19, and Rd, are each independently as defined in Formula (V’); and RC2 is absent or Cm alkyl, wherein Cm alkyl is optionally substituted by a substituent selected from halogen, -ORC, -NRcRd, -CO2RC, -CONRcRd -SO2NRcRd, and -OCONRcRd

[391] In some embodiments, the compound is of Formula (V-g), Formula (V-gl), Formula (V-g2), Formula (V-g3), Formula (V-g4), Formula (V-g5), or Formula (V-g6), wherein X9 is CH.

[392] In some embodiments, the compound is of Formula (V’), wherein the compound is Formula (V-h), Formula (V-hl), Formula (V-h2), Formula (V-h3), Formula (V-h4), Formula (V-h5), (Formula (V-h6), or Formula (V-h7): or a prodrug, solvate, pharmaceutically acceptable salt, or tautomer thereof, wherein: Yi and Zi are each independently O, S, C or N; Xi and Wi are each independently C or N; X5, X6, X9, X3, X4, Rc, R\ R5, R16, R15, R18, R19, RC1, and Rd are each independently as defined in Formula (V’); and Rl4 is absent or C1.4 alkyl, wherein C1.4 alkyl is optionally substituted by a substituent selected from halogen, -ORC, -NRcRd, -CO2RC, -CONRcRd, -SO2NRcRd, and -OCONRcRd.

[393] In some embodiments, the compound is of Formula (V-h), Formula (V-hl), Formula (V-112), Formula (V-h3), Formula (V-h4), Formula (V-h5), or (Formula (V-h6), wherein X» is CH.

[394] In some embodiments, the compound is of Formula (V’), wherein the compound is Formula (V-i), Formula (V-il), Formula (V-12), Formula (V-i3), Formula (V-i4), Formula (V-i5), (Formula (V-i6), or Formula (V-i7): 2020324388  04 Jul 2024 (V-i4) (V-i5) (V-i6) (V-i7) or a prodrug, solvate, pharmaceutically acceptable salt, or tautomer thereof, wherein: X9, X3, X4, X5, X6, R3, R5, R16, R18, R19, and RC1 are each independently as defined in Formula (V’).

[395] In some embodiments, the compound is of Formula (V-i), Formula (V-i1), Formula (V-i2), Formula (V-i3), Formula (V-i4), Formula (V-i5), or Formula (V-i6), wherein X9 is CH.

[396] In some embodiments, when the compound of Formula (V’) is Formula (V-c), Formula (V-f), Formula (V-g), Formula (V-h), Formula or (V-i), at least one of X3 and X4 is S or at least one of X5, X6 and X9 is N.

[397] In some embodiments, when s is 0 and r is 1, then at least one of X3 and X4 is S or at least one of X5, X6 and X9 is N.

[398] In some embodiments, at least one of X3 and X4 is S or at least one of X5, X6 and X9 is N.

[399] In some embodiments, at least one of X3 and X4 is S.

[400] In some embodiments, at least one of X5, X6 and X9 is N.

[401] In some embodiments, X5, X6, and X9 are each CH and X3 and X4 are each N.

[402] In some embodiments, X5, Xe, and X9 are each CH; X3 is S; and X4 is N. [403 ] In some embodiments X5 and X9 are each CH and Xe, X-.. and X4 are each N.

[404] In some embodiments, X5 and X9 are each CH; Xe and X4 are each N; and X3 is S.

[405] In some embodiments, X5 and X9 are each CH; Xe and X3 are each N; and X4 is S.

[406] In some embodiments, X5 is CH; Xe, X4, and X9 are each N; and X3 is S.

[407] In some embodiments, the compound of the disclosure is not selected from:

[408] In some embodiments, the compound of the disclosure is not: (E)-N,N’-(but-2-ene-1,4-diylbis(5-carbamoyl-7-(2-hydroxyethoxy)- 1H-benzo[d]imidazole-l,2-diyl))bis(4-ethyl-2-methyloxazole-5-carboxamide); (E)-N,N’-(but-2-ene-l,4-diylbis(5-carbamoyl-7-hydroxy-lH-benzo[d]imidazole-l,2-diyl))bis(4-ethyl-2-methyloxazole-5-carboxamide); (E)-N-(5-carbamoyl-l-(4-(5-carbamoyl-2-(4-ethyl-2-methyloxazole-5-carboxamido)-7-hydroxy-lH-benzo[d]imidazol-l-yl)but-2-en-l-yl)-7-methoxy-lH-benzo[d]imidazol-2-yl)-4-ethyl-2-methyloxazole-5-carboxamide; N,N'-((((1 S,2S)-cyclopropane-l,2-diyl)bis(methylene))bis(5-carbamoyl-lH-benzo[d]imidazole-l,2-diyl))bis(4-ethyl-2-methyloxazole-5-carboxamide); (E)-l ,r-(but-2-ene-l,4-diyl)bis(2-(2,5-dimethylfuran-3-carboxamido)-7-methoxy-lH-ben zo [d] imi dazol e- 5 -carboxamide); (E)-N,N'-(hex-3-ene-l,6-diylbis(5-carbamoyl-lH-benzo[d]imidazole-l,2-diyl))bis(4-ethyl-2-methyloxazole-5-carboxamide); (E)-N-(5-carbamoyl-l-(4-(5-carbamoyl-2-(4-ethyl-2-methyloxazole-5-carboxamido)-lH-benzo[d]imidazol-l-yl)but-2-en-I-yl)-7-methyl-lH-benzo[d]imidazol-2-yl)-4-ethyl-2-methyloxazole-5 - carboxamide; (E)-N-(5-carbamoyl-1 -(4-(5-carbamoyl-2-(2,4-dimethyloxazole-5-carboxamido)-1H-benzofd] imidazol-1 -yl)but-2-en-1 -yl)-7-methyl-1 H-benzo[d ] imi dazol-2-y 1)-2,4-dimethyloxazole-5-carboxamide; (E)-N,N'-(but-2-ene-l,4-diylbis(5-carbamoyl-7-methoxy-lH-benzo[d] imidazole-1,2-diyl))bis(2,4-dimethyloxazole-5-carboxamide); (E)-N,N’-(but-2-ene-l,4-diylbis(5-carbamoyl-7-methoxy-lH-benzo[d] imidazole-1,2-diyl))bis(4-ethyl-2-methyloxazole-5-carboxamide); (E)-l,r-(but-2-ene-l,4-diyl)bis(2-(l-ethyl-lH-imidazole-5-carboxamido)-7-methoxy-lH-benzo[d]imidazole-5-carboxamide); (E)-l,r-(but-2-ene-l,4-diyl)bis(2-(l-ethyl-lH-imidazole-2-carboxamido)-7-methoxy-lH-benzo[d]imidazole-5-carboxamide); (Z)-4-carbamoyl-l,15-bis(4-ethyl-2-methyloxazole-5-carboxamido)-8,9,16,19-tetrahydro-7H-6,10-dioxa-2,14,15a, 19a-tetraazacyclopentadeca[3,2,1 -cd: 8,9,10-c'd'] diindene-12-carboxylic acid; (E)-l-(4-(5-carbamoyl-2-(furan-2-carboxamido)-lH-benzo[d]imidazol-l-yl)but-2-en-l-yl)-2-(furan-2-carboxamido)-7-methyl-1 H-benzo [d] imidazole-5-car boxamide; (E)-l-(4-(5-carbamoyl-2-(pyrazolo[l,5-a]pyridine-2-carboxamido)-lH- benzofd] imidazol-1 -yl)but-2-en-1 -yl)-7-methyl-2-(pyrazolo[ 1,5-a]pyridine-2-carboxamido)-lH-benzo[d]imidazole-5-carboxamide; (E)-l-(4-(5-carbamoyl-2-(l-methyl-lH-pyrrole-2-carboxamido)-lH-benzo[d]imidazol-l-yl)but-2-en-l-yl)-7-methyl-2-(l-methyl-lH-pyrrole-2-carboxamido)-lH-benzo[d]imidazole-5-carboxamide; (E)-l-(4-(5-carbanioyl-2-(lH-pyrrole-2-carboxamido)-lH-benzo[d]imidazol-l-yl)but-2-en-l-yl)-7-methyl-2-(lH-pyrrole-2-carboxamido)-lH-benzo[d]imidazole-5-carboxamide; (E)-l-(4-(5-carbamoyl-2-(l -methyl-lH-indole-2-carboxamido)-lH-benzo[d]imidazol-l-yl)but-2-en-l-yl)-7-methyl-2-(l-methyl-lH-indole-2-carboxamido)-lH-benzo[d]imidazole-5-carboxamide; (E)-N-(5-carbamoyl-l -(4-(5-carbamoyl-2-(4-ethyl-2-methyloxazole-5-carboxamido)-7-(3 -hydroxypropoxy)-1 H-benzo[d] imi dazol-1 -y l)but-2-en-1 -yl)-7-methoxy-1 H-benzo[d] imi dazol-2-yl)-4-ethyl-2-methyloxazole-5-carboxamide; (Z)-1,15-bis(4-ethyl-2-methyloxazole-5-carboxamido)-8,9,16,19-tetrahydro-7H-6,10-dioxa-2,14,15a, 19a-tetraazacyclopentadeca[3,2,1 -cd: 8,9,10-c'd’] diindene-4,12-dicarboxamide; N-(5-carbamoyl-l-(2-((lR,2R)-2-(2-(5-carbamoyl-2-(4-ethyl-2-methyloxazole-5-carboxamido)-1 H-benzo [d] imidazol -1 -yl)eth yl)cycl opropyl)ethy l)-7-m ethyl -1H-benzo[d]imidazol-2-yl)-4-ethyl-2-methyloxazole-5-carboxamide; (E)-N-(5-carbamoyl-l-(4-(5-carbamoyl-2-(4-ethyl-2-methyloxazole-5-carboxamido)-7-(2-hy droxyethoxy)- lH-benzo[d] imidazol-1 -yl)but-2-en-1 -yl)-7-methoxy-1 H-benzo[d] imidazol-2-yl)-4-ethyl-2-methyloxazole-5-carboxamide; (E)-2-((5-carbamoyl-l-(4-(5-carbamoyl-2-(4-ethyl-2-methyloxazole-5-carboxamido)-7-methoxy-1 H-benzo[d] imidazol-1 -yl)but-2-en-1 -yl)-2-(4-ethy 1-2-methy loxazole-5-carboxamido)-lH-benzo[d]imidazol-7-yl)oxy)acetic acid; (E)-2-((5-carbamoyl-l-(4-(5-carbamoyl-2-(4-ethyl-2-methyloxazole-5-carboxamido)-7-(2-hydroxyethoxy)-lH-benzo[d]imidazol-l-yl)but-2-en-l-yl)-2-(4-ethyl-2-methyloxazole-5-carboxamido)-lH-benzo[d]imidazol-7-yl)oxy)acetic acid; (E)-1,15-bis(4-ethyl-2-methyloxazole-5-carboxamido)-N-(2-hydroxyethyl)-8,9,16,19-tetrahydro-7H-6,10-dioxa-2,14,15a, 19a-tetraazacyclopentadeca[3,2,1 -cd: 8,9,10-c'd'] diindene-4,12-di carboxamide; (E)-N-(5-carbamoyl-l-(4-(5-carbamoyl-2-(4-ethyl-2-methyloxazole-5-carboxamido)-7-methoxy-1 H-benzo[d] imidazol-1 -yl)but-2-en-1 -yl)-7-(2-(dimethylamino)ethoxy)- 1H-benzo[d]imidazol-2-yl)-4-ethyl-2-methyloxazole-5-carboxamide; or (E)-l-(4-(5-carbamoyl-2-(l-(2-hydroxyethyl)-3-methyl-lH-pyrazole-5-carboxamido)-lH-benzo[d]imidazol-l-yl)but-2-en-l-yl)-2-(l-ethyl-3-methyl-lH-pyrazole-5-carboxamido)-lH-benzo[d]imidazole-5-carboxamide.

[409] Representative compounds of this disclosure include the compounds of the Examples. It will be appreciated that the present disclosure encompasses compounds of Formula (F), Formula (IA’), Formula (IF), Formula (HF). Formula (IV’), and Formula (V’) as the free base and as salts thereof, for example as a pharmaceutically acceptable salt thereof In some embodiments the disclosure relates to compounds of Formula (F), Formula (IA’), Formula (IF), Formula (O’), Formula (IV’), and Formula (V’) in the form of a free base. In some embodiments, the disclosure relates to compounds of Formula (F), Formula (IA’), Formula (IF), Formula (III’), Formula (IV’), and Formula (V’) in the form of a salt, particularly, a pharmaceutically acceptable salt. It will be further appreciated that, In some embodiments, the disclosure relates to compounds of the Examples in the form of a free base. In some embodiments, the disclosure relates to compounds of the Examples in the form of a salt, particularly, a pharmaceutically acceptable salt.

[410] In some embodiments, in the compound of Formula (I’), (IA’), (IIF), (IV’), (V’), (I-B’), (I-b’), (II-B’), (II-b’), (V-a), (V-b), (V-c), (V-d), (V-e), (V-el), (V-e2), (V-h), (V-hl), (V-h2), (V-h3), (V-h4), (V-h5), (V-h6), or (V-h7), Ring 1 is selected from any one of the following: (1) p19 O. x Al RC1         . 5 (2) R14 A? ? v\r15 (3) R‘4 s A-Rl9 RC1          . (4) R14 \    R19 । X-N' Rc^        . (5) Ru s 4¼ Ty4 RC1 • (6) R14 (7) R14 A Rc^        . (8) s R19 +A R-1         . 5 (9) -Ki rC1 ; (10) R14 . KA19 RC1         ; ZD vX   £ (12) sy--LRiS RC1          . (13) R14 . Ax-R'S 4x II XXr (14) R14 J9 S N-^rIS (15) R14 Ai" (16) s O-N 5 A»!5 rCI         . ¢17) R14 A-r" RC1          . (18) R14 1 # 0 i yAs RC1           . (19) R14 +tx >'  "R’5 RC1           . (20) R14 V R19 i N” ? yARls RC1           ■ (21) 1 y^R15 RC1         • 9 (22) < H'-O A^X RC1          . (23) AAx RC1          . (24) R14 A J N-^-r15 rC '         ; and (25) s N^R19 iy6 RCI wherein: R!4, R15, R19 and RC1 are each independently H, Cm alkyl, halogen or optionally substituted Cm alkyl wherein said Cm alkyl is optionally substituted Cm alkyl is substituent with a halogen or -COzH.

[411] In some embodiments, the Cm alkyl is methyl or ethyl.

[412] In some embodiments, the Cm alkyl is methyl substituted with -COOH.

[413] In some embodiments, in the compound of Formula (F), (IA’), (III’), (IV’), (V’), (I-B’), (I-b ), (II-B’), (II-b’), (V-a), (V-b), (V-c), (V-d), (V-e), (V-el), (V-e2), (V-f), (V-fl), (V-f2), (V- 6), (V-f4), (V-f5), (V-f6), (V47). (V-g), (V-gl), (V-g2), (V-g3), (V-g4), (V-g5), (V-g6), or (V-g7), Ring 2 is selected from any one of the following: CO (2) RC2 W (3) RC2 . (4) RC2 V^R18 T\^n R7®         . (5) RC2 / ¼ R16    . (6) rC2 s N--KR17 (7) RC2 \ R18 A R1B         . > (8) ■FC ft6        . (9) s ZS"N Wk V- R16        ; (10) RC2 . ^wR18 FcX y^R17 R16         . (11) TyARl7 R16         • (12) s R18 R16         . (13) RC2 . N R18 "K117 '•Ri? . (14) RC2 4< 1 s (15) RC2 wHR18 (IS) Jv°'N 5 (17) RC2 / -N lyU / R,z R16 (18) RC2 sy^Ri? R16       . 5 (19) RC2 4w 5 \ss=A.r17 ^16       . (20) RC2 K\   R18 i y-N*’ Cy*<Ri7 R16       . WXfW''      t-J1 )— co I        K) (23) Ri6         . (24) RC\ 1 # N 5 N^R17 p’16                  , ; and (25) w^R18 wherein: R'16, R1R18 and RC2 are each independently H, Ci-4 alkyl, halogen or optionally substituted Cj-4 alkyl wherein said is optionally substituted Cm alkyl is substituent with a halogen or -CO2H.

[414] In some embodiments, one or more of R16, R17, R18 and RC2 is methyl, ethyl, or methyl substituted with -COOH, provided that when r is 1, s is 0, Ring 1 is then at least one of X3 and X4 is S or at least one of X5. Xe, and X9 is N.

[415] In some embodiments, one or more of R16, Ri?, R18 and RC2 is methyl, ethyl, or methyl substituted with -COOH, R!4 provided that when r is 1, s is 0, Ring 1 is rC1 and Ring 2 is then at least one of X3 and X4 is S or at least one of Xs.Xe, and X9 is N

[416] In some embodiments, Ring 1 and Ring 2 are each independently selected from any one of the following: (1) ; ,, X (4) (5)              ; (6) -f / 'j (7)            ; \ 1 ^-0 (8) (9)hj , A-y / 5 , N \ s / ¼ “Ks 0 (12) N ; H (13)            ; ■kJ< (14)   'X, -K J] (15)    * ; & Z'-'N II (16) / N^; O A-OH (17 )77¾^ . X -¼¼ ij (18) N ; (19)"HJ; (20)”HJ ; S^Z ¢21) -7     , (22)          ; s^z (23)'^   ; (24) <, ZS-N (25) -X     ; (26) (27)           • (28) (29) XX ; (30)^-^   ; s ^Cf=3 (31)ZA>   ; (32)          ; J_#"S (33) W ; (35)^^^^: 0^ / (36)      /       ; (37)     /      ; H (38)            ; X'-Q (39)^^ ¾ ^'"S (40)          ; Jb-NH (41)            ; NQ 4O ¢42) \ ; —I—Z    1 (43) sV*; ^X-NH (44) (45) n-nx (46)            ; )47)“H1 (48)     /      ; -X? (49) (50)4V; 0 HO^ (51) V X; HO <5”) (52)        X ; HO X=O (53)^ , HO N (54) OH (55)-^. O HO..^ oz s     N iA h (56)   ^^X; (57) HO mX and HO ^0 0 (58)^

[417] In some embodiments, the compounds of the disclosure are selected from the compounds listed in Table 1, or a tautomer thereof, or a prodrug thereof, or a salt thereof, particularly a pharmaceutically acceptable salt thereof. Table 1 Example No Compound No. Structure LCMS (M + H)+ 4 12 z: I   o j                z'g Cp     Co 727.30 5 13 HznAtQ;^..... h2n 5         o 755.10 6 14 z T   O 6 A ..... / 799.20 Example No Compound No. Structure LCMS (M + H)+ / 15 9         o k .....153 —(7 781.40 8 16 9            O N. ^fvf3U HO'^\^XX'O / ' 3f          V.N 753.15 9 17 zu ZE     o M       \ Z    y °\   \      f=o (Vo Ty° zi M      T o T|                      O w                         T! w 867.05 Example No Compound No. Structure LCMS (M + H)+ 10 18 O       o 0, / HiN £; £ H2N-^ / / ^O   / 1 782.38 11 19 $       o o, / .....nLv hn £^££—nh o_ / 2 r^N 811.30 12 26 9          °x N-O .....nHa X^-NZ HO-^\ / xO / H N £ K / >"NH N-O 697.26 Example No Compound No. Structure LCMS (M + H)+ 13 27 T O ^V-O / X C'X 697.28 14 28 0= xAt               ! ox2z          5 ■ < T        ( o     T. z 669.22 15 36 o       o C .....MX YM-n / 1 H2Nx^0^ / ™Nr / O'M A        o V-N 782.15 Example No Compound No. Structure LCMS (M + H)+ 16 37 °         o Y       < / V-N 799.20 17 38 ..PMl i \ CM o I 798.30 18 39 HO^^^'O ^vvt^f'?SN / .....v\ 781.20 Example No Compound No. Structure LCMS (M + H)+ 19 40 °       o o. / HO-^-^O Z ^zOezt yy 799.30 20 41 zu ZC     O \      Vo V V" O \ / \ V( °""y^ A5 j    A° Y Y 795.30 21 42 °       0 VN H2nJ\Xa''^^ ) i V       A-oh W M 1 h / >“”NH N^kj 811.30 Example No Compound No. Structure LCMS (M + H)+ 25 53 °       0 CN .....yax h2n^jOQ““'^ Y       0 V-n 751.25 26 63 °         o H2N HOXX^ / X'O / 800.20 / 64 ?         o Y HO-^^^-O   / \ II >—NH \—Z o         o V- 772.20 Example No Compound No. Structure LCMS (M + H)+ 28 65 z zc     O X' 798.20 29 66 °         o x ° H JX-nh o_ / 828.20 30 67 O         O \ln X^ss^ N X H V-NH N^w H2Ny^^XX\ 797.30 Example No Compound No. Structure LCMS (M + H)+ 31 68 O          o k il                A / N / NS Ji \ h y_nh Vm 826.30 32 69 A = O'N HO-^^-O   / TH z>—nh ci / 799.30 33 70 °       o o^ / HzN hYW.....V r; \\ p iT Y-nh     / y-4 T Y     cyv*1 816.20 Example No Compound No. Structure LCMS (M + H)+ 34 71 zc     6 fo         \              zc °\_  \     x° / ” V- O       \ u % / / QyS      V° 799.30 35 72 1 , % / 'N ..... XX^ I IT X—NH O_ / 785.20 36 73 It T   O S-8    Xo ^X 799.30 Example No Compound No. Structure LCMS (M + H)+ 43 90 I ' X, l                z x) wz “""CX °\         \=o t 758.10 44 94 T   O Ck z              I i 1     /           ±v 752.30 45 95 T T   Q z o3     T \ I               ly 754.25 Example No Compound No. Structure LCMS (M + H)+ 116 O         q II                      \\ / N Ur H2N                     Jl 5     o n\ 798.33 117 I T   O r2>       \            m" Z^O U z / t          y=z 798.24 118 ^■Vy^..... HO'^S^XXO J       O 726.31 Example No Compound No. Structure LCMS (M + H)+ 125 I   O t          z__ /              T r / \    i \= ~Z.                         \__ i 766.34 126 9            o \ ( HO'^ / *XO / / ¼ 780.32 127 I I   o \         T ■ • / ■ r ° o 727.21 Example No Compound No. Structure LCMS (M + H)+ ) 128 769.28 I o Aln 129 ( 694.28 / I          1 ya 1 Ad V# ^4 H zll O-^Z zxz o ==^ 130 811.28 H N JkjL X”N.H P-- / \— / Example No Compound No. Structure LCMS (M + H)+ 131 H          O T T II I __nh y-"N ° ___ / H m X jC T P'S 2Y^n / "V 797.27 132 P / I                                          04 722.31 133 ° HO-^x / ^o H N JLx. [C        P'^' \—<< 797.31 Example No Compound No. Structure LCMS (M + H)+ 134 O "'Vm V-4 q / 'O / 680.26 135 O n   V—4 y, II      \\_| / h VN 755.27 136 9          o ex / y—sNn   r __7 HO-^^^O .....cr 755.23 Example No Compound No. Structure LCMS (M + H)+ 140 O         o HO zx       Z ■y^o / u                     f 797.12 141 z O Z o=( o==\     \         )= o v v— O      / \ W” Ox.                          1 'V T           Z.zjO \            I \ /                  r W 843.10 142 9         o h2N'^y^Y'Syn^~V’^ HO'^ / XO H N XfX >”NxH 2         / --o 787.08 Example No Compound No. Structure LCMS (M + H)+ 50 146 9 o .....AM TT ' ___ / 771.30 147 I T   O M       \ )                  N> aj / .....r / 'z %zZ \ 1 ' 2=4                 \ / 769.13 50a 148 I T   O M      \         I \              IT VA A   K 770.13 Example No Compound No. Structure LCMS (M + H)+ 155 HO           7 An / v Y          y_N 799.11 51 167 °      o QX h2n^y VSW^ V® ( HO^^^O / ■ k um r । / vnh o^ / "-_rA" 772.25 52 181 O    On II                      / '■'N \  || \_ NH N-N 2 811.40

[418] In some embodiments, the compounds of the disclosure is compound: or a prodrug, solvate, pharmaceutically acceptable salt, or tautomer thereof.

[419] In some embodiments, the compounds of the disclosure is compound: or a prodrug, solvate, pharmaceutically acceptable salt, or tautomer thereof.

[420] In some embodiments, the compounds of the disclosure is compound: or a prodrug, solvate, pharmaceutically acceptable salt, or tautomer thereof.

[421] In some embodiments, the compound of the disclosure is Example No. 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 50a, 51, or 52 or Compound No. 111, 112, 113, 114, 115, 116, 117, 118, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 147, 149, 150, 151, 152, 153, 154, 155, or 182. In some embodiments, the compound of the disclosure is Example No. 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, or 49, or Compound No. Ill, 112, 113, 114, 115, 116, 117, 118, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138. In some embodiments, the compound of the disclosure is Compound No. 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152 or 153. In some embodiments, the compound of the disclosure is Compound No. 63, 95, 109, 135, 143, 144, 145, 146, or 148. In some embodiments, the compound of the disclosure is Compound No. 63, 95, 109, 135, 145, or 146. In some embodiments, the compound of the disclosure is Compound No. 143, 144, or 148.

[422] In some embodiments, the compound of the disclosure is Example No. 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 50a, 51, or 52 or Compound No. Ill, 112, 113, 114, 115, 116, 117, 118, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 140, 141, 142, 143, 144, 145, 147, 149, 150, 151, 152, 153, 154, 155, or 182. In some embodiments, the compound of the disclosure is Example No. 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, or 49, or Compound No. 111,112, 113, 114, 115, 116, 117, 118, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138. In some embodiments, the compound of the disclosure is Compound No. 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152 or 153.

[423] In some embodiments, the compound of the disclosure is Example No. 37 (i.e., Compound No. 74) or Compound No. 119.

[424] In some embodiments, the compound of the disclosure is Example No. 26 (i.e., Compound No. 63), Example No. 45 (i.e., Compound No. 95), Example No. 48 (i.e., Compound No. 109), or Example No. 50 (i.e.. Compound No. 146).

[425] In some embodiments, the compound of the disclosure is Example No. 45 (i.e., Compound No. 95) or Example No. 48 (i.e., Compound No. 109).

[426] In some embodiments, the compound of the disclosure is Example No. 26 (i.e., Compound No. 63).

[427] In some embodiments, the compound of the disclosure is Example No. 45 (i.e., Compound No. 95).

[428] In some embodiments, the compound of the disclosure is Example No. 48 (i.e., Compound No. 109).

[429] In some embodiments, the compound of the disclosure is Example No. 50 (i.e., Compound No. 146).

[430] The compounds of this disclosure may contain one or more asymmetric centers (also referred to as a chiral center), such as a chiral carbon, or a chiral -SO- moiety. Compounds of this disclosure comprising one or more chiral centers may be present as racemic mixtures, diastereomeric mixtures, enantiomerically enriched mixtures, diastereomerically enriched mixtures, or as enantiomerically or diastereomerically pure individual stereoisomers.

[431] The stereochemistry of the chiral center present in compounds of this disclosure are generally represented in the compound names and / or in the chemical structures illustrated herein. Where the stereochemistry of a chiral center present in a compound of this disclosure, or in any chemical structure illustrated herein, is not specified, the structure is intended to encompass any stereoisomer and all mixtures thereof. Accordingly, the present disclosure encompasses all isomers of the compounds of any one or more of Formula (F), (IA’), (IF), (IIF), (IV’) or (V’), and salts thereof, whether as individual isomers isolated such as to be substantially free of the other isomer (i.e. pure) or as mixtures (i.e. racemates and racemic mixtures). An individual isomer isolated such as to be substantially free of the other isomer (i.e. pure) may be isolated such that less than 10%, particularly less than about 1%, for example less than about 0.1% of the other isomer is present.

[432] Individual stereoisomers of a compound of this disclosure may be resolved (or mixtures of stereoisomers may be enriched) using methods known to those skilled in the art. For example, such resolution may be carried out (1) by formation of diastereoisomeric salts, complexes or other derivatives; (2) by selective reaction with a stereoisomer-specific reagent, for example by enzymatic oxidation or reduction; or (3) by gas-liquid or liquid chromatography in a chiral environment, for example, on a chiral support such as silica with a bound chiral ligand or in the presence of a chiral solvent. It will be appreciated that where the desired stereoisomer is converted into another chemical entity by one of the separation procedures described above, a further step is required to liberate the desired form. Alternatively, specific stereoisomers may be synthesized by asymmetric synthesis using optically active reagents, substrates, catalysts or solvents, or byconverting one enantiomer to the other by asymmetric transformation.

[433] The disclosure also includes various deuterated forms of the compounds of this disclosure. Each available hydrogen atom attached to a carbon atom may be independently replaced with a deuterium atom. A person of ordinary skill in the art will know' how to synthesize deuterated forms of the compounds of this disclosure. For example, a-deuterated a-amino acids are commercially available or may be prepared by conventional techniques (see for example: Elemes, Y. and Ragnarsson, U. J. Chern. Soc, Perkin Trans. 1, 1996, 6, 537-40). Employing such compounds may allow7 for the preparation of compounds in which the hydrogen atom at a chiral center is replaced with a deuterium atom. Other commercially available deuterated starting materials may be employed in the preparation of deuterated analogs of the compounds of this disclosure (see for example: methyl-ds-amme available from Aldrich Chemical Co., Milwaukee, Wl), or they may be synthesized using conventional techniques employing deuterated reagents (e.g. by reduction using lithium aluminum deuteride or sodium borodeuteride or by metal-halogen exchange followed by quenching with D2O or methanol-ds)

[434] Suitable pharmaceutically acceptable salts of the compounds of any one or more of Formula (F), (IA’), (IF), (III’), (IV’) or (V’), can include acid addition salts or base addition salts. For reviews of suitable pharmaceutically acceptable salts see Berge et al., J. Pharm. Sci., 66:1-19, (1977) and P. H. Stahl and C. G. Wermuth, Eds., Handbook of Pharmaceutical Salts: Properties, Selection and Use, Weinheim / Zurich :Wiley-VCH / VHCA (2002).

[435] Salts of the compounds of any one or more of Formula (F), (IA’), (IF), (IIF), (IV’) or (V’), comprising a basic amine or other basic functional group may be prepared by any suitable method known in the art, such as treatment of the free base with a suitable inorganic or organic acid. Examples of pharmaceutically acceptable salts so formed include acetate, adipate, ascorbate, aspartate, benzenesulfonate, benzoate, camphorate, camphor-sulfonate (camsylate), caprate (decanoate), caproate (hexanoate), caprylate (octanoate), carbonate, bicarbonate, cinnamate, citrate, cyclamate, dodecylsulfate (estolate), ethane- 1,2-disulfonate (edisylate), ethanesulfonate (esylate), formate, fumarate (hemi-fumarate, etc.), galactarate (mucate), gentisate (2,5-dihydroxybenzoate), glucoheptonate (gluceptate), gluconate, glucuronate, glutamate, glutarate, glycerophosphorate, glycolate, hippurate, hydrobromide, hydrochloride (dihydrochloride, etc.), hydroiodide, isobutyrate, lactate, lactobionate, laurate, maleate, malate, malonate, mandelate, methanesulfonate (mesylate), naphthalene-l,5-disulfonate (napadisylate), naphthalene-sulfonate (napsylate), nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, phosphate (diphosphate, etc.), proprionate, pyroglutamate, salicylate, sebacate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate (tosylate), undecylenate, l-hydroxy-2-naphthoate, 2,2-dichloroacetate, 2-hydroxyethanesulfonate (isethionate), 2-oxoglutarate, 4-acetamidobenzoate, and 4-aminosalicylate.

[436] Salts of the disclosed compounds comprising a carboxylic acid or other acidic functional group can be prepared by reacting with a suitable base. Such a pharmaceutically acceptable salt may be made with a base which affords a pharmaceutically acceptable cation, which includes alkali metal salts (especially sodium and potassium), alkaline earth metal salts (especially calcium and magnesium), aluminum salts and ammonium salts, as well as salts made from physiologically acceptable organic bases such as trimethylamine, triethylamine, morpholine, pyridine, piperidine, picoline, di cyclohexylamine, A).¥-dibenzyl ethylenediamine, 2-hydroxy ethylamine, bis-(2-hy droxy ethyl )amine,     tri-(2-     hydroxy ethyl)amine,     procaine, dibenzylpiperidine, dehydroabietylamine, N,N- bisdehydroabietylamine, glucamine, A-m ethyl glucamine, collidine, choline, quinine, quinoline, and basic ammo acids such as lysine and arginine.

[437] The disclosure includes within its scope all possible stoichiometric and non- stoichiometric forms of the salts (e.g., hydrobromide, dihydrobromide, fumarte, hemi- fumarate, etc) of the compounds of any one or more of Formula (F), (IA’), (IF), (IIF), (IV’) or (V’).

[438] When a disclosed compound or its salt is named or depicted by structure, it is to be understood that the compound or salt, including solvates (particularly, hydrates) thereof, may exist in crystalline forms, non-crystalline forms or a mixture thereof. The compound or salt, or solvates (particularly, hydrates) thereof, may also exhibit polymorphism (i.e. the capacity to occur in different crystalline forms). These different crystalline forms are typically known as "polymorphs." It is to be understood that the disclosure includes all polymorphs of any compound of this disclosure, e.g., all polymorphic forms of any compound named or depicted by structure herein, including any salts and / or solvates (particularly, hydrates) thereof.

[439] Polymorphs have the same chemical composition but differ in packing, geometrical arrangement, and other descriptive properties of the crystalline solid state. Polymorphs, therefore, may have different physical properties such as shape, density, hardness, deformability, stability, and dissolution properties. Polymorphs typically exhibit different melting points, IR spectra, and X-ray powder diffraction patterns, which may be used for identification. It will be appreciated that different polymorphs may be produced, for example, by changing or adjusting the conditions used in crystallizing / recrystallizing the compound. Polymorphic forms may be characterized and differentiated using a number of conventional analytical techniques, including, but not limited to, X-ray powder diffraction (XRPD) patterns, infrared (IR) spectra, Raman spectra, differential scanning calorimetry (DSC), thermogravimetric analysis (TGA) and solid state nuclear magnetic resonance (SSNMR).

[440] The skilled artisan will appreciate that pharmaceutically acceptable solvates (particularly, hydrates) of a compound of any one or more of Formula (F), (IA’), (IF), (IIF), (IV’) or (V’), including pharmaceutically acceptable solvates of a pharmaceutically acceptable salt of a compound of any one or more of Formula (I’), (IA’), (IF), (IIP), (IV’) or (V’), may be formed when solvent molecules are incorporated into the crystalline lattice during crystallization. Solvates may involve non-aqueous solvents such as ethanol, or they may involve water as the solvent that is incorporated into the crystalline lattice. Solvates wherein water is the solvent that is incorporated into the crystalline lattice are typically referred to as "hydrates."

[441] The present disclosure includes within its scope all possible stoichiometric and non-stoichiometric salt and / or hydrate forms.

[442] Salts and solvates (e.g. hydrates and hydrates of salts) of the compounds of the disclosure which are suitable for use in medicine are those wherein the counterion or associated solvent is pharmaceutically acceptable. Salts having non-pharmaceutically acceptable counterions are within the scope of the present disclosure, for example, for use as intermed iates in the preparation of other compounds of the disclosure.

[443] Typically, a pharmaceutically acceptable salt may be readily prepared by using a desired acid or base as appropriate. The resultant salt may crystallize or precipitate from solution, or form by trituration, and may be recovered by filtration, or by evaporation of the solvent.

[444] Because the compounds of this disclosure are intended for use m pharmaceutical compositions it will readily be understood that they are each preferably provided in substantially pure form, for example at least 60% pure, more suitably at least 75% pure and preferably at least 85%, especially at least 98% pure (% are on a weight for weight basis). Impure preparations of the compounds may be used for preparing the purer forms used in the pharmaceutical compositions,

[445] The disclosure encompasses all prodrugs of the compounds of this disclosure, which upon administration to the recipient are capable of providing (directly or indirectly) a compound of this disclosure, or an active metabolite or residue thereof. Such derivatives are recognizable to those skilled in the art, without undue experimentation. Nevertheless, reference is made to the teaching of Burger's Medicinal Chemistry and Drug Discovery, 5th Edition, Vol 1: Principles and Practice, which is incorporated herein by reference to the extent of teaching such derivatives.

[446] It is to be further understood that the present disclosure includes within its scope all tautomeric or isomer forms of any free base form of the compounds of this disclosure as well as all possible stoichiometric and non-stoichiometric salt forms. The compounds of the disclosure are useful in the treatment or prevention of diseases and disorders in which modulation of STING is beneficial. Such STING mediated diseases and disorders include inflammation, allergic and autoimmune diseases, infectious diseases, cancer and precancerous syndromes. The compounds of the disclosure are also useful as an immunogenic composition or vaccine adjuvant. Accordingly, this disclosure is directed to a method of modulating STING comprising contacting a cell with a compound of the disclosure. Methods of Use

[447] In some embodiments, this disclosure provides a compound for use in an antibody-STING agonist candidate. In some embodiments, the antibody-STING agonist conjugate contains a linker. The disclosure further provides an antibody-STING agonist conjugate for use in therapy. The disclosure further provides the use of an antibody-STING agonist conjugate indicated above for the manufacture of a medicament. In some embodiments, the STING agonist has, or is modified to include, a group reactive with a conjugation point on an antibody.

[448] One aspect of the disclosure provides methods of treatment or prevention of STING mediated diseases and disorders, in which agonizing STING is beneficial. Exemplary diseases / disorders include, but are not limited to, cancer, infectious disease (e.g., HIV, HBV, HCV, HPV, and influenza), vaccine adjuvant.

[449] In some embodiments, the STING pathway may induce anti-tumor immunity by upregulating IFNp and interferon (IFN)-stimulated genes (ISGs) in many cell types within tumors in response to agonistic, cytosolic nucleic acids.

[450] In some embodiments, this disclosure provides a compound of the disclosure for use in therapy. This disclosure also provides a compound of any one or more of Formula (F), (IA’), (IT), (HF). (IV’), or (V’), or a pharmaceutically acceptable salt thereof, for use in therapy. This disclosure particularly provides a compound of any one or more of Formula (F), (IA’), (IF), (IIF), (TV’), or (V’), or a pharmaceutically acceptable salt thereof, for use in the treatment of a STING-mediated disease or disorder.

[451] This disclosure also provides a compound of any one or more of Formula (F), (IA’), (II’), (IIF), (IV’), or (V’), or a pharmaceutically acceptable salt thereof, for use as a vaccine adjuvant. There is also therefore provided an immunogenic composition or vaccine adjuvant comprising a compound of any one or more of Formula (I’), (IA’), (IF), (III’), (IV’), or (V’), or a pharmaceutically acceptable salt thereof.

[452] In a further embodiment of the disclosure, there is provided a composition comprising a compound of any one or more of Formula (F), (IA’), (IF), (III’), (IV’), or (V’), or a pharmaceutically acceptable salt thereof, and one or more immunostimulatory agents. [453 ] In some embodiments, this disclosure provides a compound of the disclosure for use in the treatment of a STING-mediated disease or disorder and / or for use as an immunogenic composi tion or a vaccine adjuvant. In some embodiments, this disclosure provides a compound of any one or more of Formula (F), (IA’), (II’), (HF), (IV’), or (V’), or a pharmaceutically acceptable salt thereof, for use in the amelioration of organ injury or damage sustained as a result of a STING-mediated disease or disorder.

[454] The disclosure further provides for the use of a compound of the disclosure in the manufacture of a medicament for treatment of a STING-mediated disease or disorder. The disclosure further provides for the use of a compound of any one or more of Formula (F), (IA’), (IF), (III’), (IV), or (V’), or a salt thereof, particularly a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treatment of a STING-mediated disease or disorder, for example the diseases and disorders recited herein.

[455] The disclosure further provides for the use of a compound of any one or more of Formula (I’), (IA’), (IF), (IIF), (IV’), or (V’), or a salt thereof, particularly a pharmaceutically acceptable salt thereof, in the manufacture of a vaccine. There is further provided the use of a compound of any one or more of Formula (I’), (IA’), (IF), (IIF), (TV’), or (V’), or a pharmaceutically acceptable salt thereof, for the manufacture of an immunogenic composition or a vaccine composition comprising an antigen or antigenic composition, for the treatment or prevention of disease.

[456] In some embodiments, the disclosure is directed to a method of treating a STING-mediated disease or disorder comprising administering a therapeutically effective amount of a compound of any one or more of Formula (F), (IA’), (IF), (IIF), (TV), or (V’), or a salt, particularly a pharmaceutically acceptable salt thereof, to a human in need thereof.

[457] In some embodiments, the disclosure is directed to a method of treating or preventing disease comprising the administration to a human subject suffering from or susceptible to disease, an immunogenic composition or a vaccine composition comprising an antigen or antigenic composition and a compound of any one or more of Formula (I’), (IA’), (IF), (IIF), (IV’), or (V’), or a pharmaceutically acceptable salt thereof.

[458] In some embodiments, this disclosure is directed to a compound of any one or more of Formula (I’), (IA’), (11’), (111’), (IV’), or (V’), or a pharmaceutically acceptable salt thereof for use in the treatment of inflammation, an autoimmune disease, an allergic disease, an infectious disease, an HIV infection, an AIDS infection, an HCV infection, influenza or a human papillomavirus (HPV) infection. In a further aspect there is provided a method of treating inflammation, an autoimmune disease, an allergic disease, an infectious disease, an HIV infection, an AIDS infection, an HCV infection, influenza or a human papillomavirus (HPV) infection comprising administering to a human in need thereof a therapeutically effective amount of a compound of any one or more of Formula (F), (IA’), (IF), (IIF), (IV’), or (V’), or a pharmaceutically acceptable salt thereof. In a further aspect there is provided a compound of any one or more of Formula (I’), (IA’), (IF), (IIF), (IV’), or (V’), or a pharmaceutically acceptable salt thereof for use in the manufacture of a medicament for the treatment of inflammation, an autoimmune disease, an allergic disease, an infectious disease, an HIV infection, an AIDS infection, an HCV infection, influenza or human papillomavirus (HPV) infection.

[459] As used herein, the terms "cancer," "neoplasm," and "tumor" are used interchangeably and, in either the singular or plural form, refer to cells that have undergone a malignant transformation that makes them pathological to the host organism. Primary cancer cells can be readily distinguished from non-cancerous cells by well-established techniques, particularly histological examination. The definition of a cancer cell, as used herein, includes not only a primary cancer cell, but any cell derived from a cancer cell ancestor. This includes metastasized cancer cells, and in vitro cultures and cell lines derived from cancer cells. When referring to a type of cancer that normally manifests as a solid tumor, a "clinically detectable" tumor is one that is detectable on the basis of tumor mass; e.g., by procedures such as computed tomography (CT) scan, magnetic resonance imaging (MRI), X-ray, ultrasound or palpation on physical examination, and / or which is detectable because of the expression of one or more cancer-specific antigens in a sample obtainable from a patient. Tumors may be a hematopoietic (or hematologic or hematological or blood-related) cancer, for example, cancers derived from blood cells or immune cells, which may be referred to as "liquid tumors." Specific examples of clinical conditions based on hematologic tumors include leukemias such as chronic myelocytic leukemia, acute myelocytic leukemia, chronic lymphocytic leukemia and acute lymphocytic leukemia; plasma cell malignancies such as multiple myeloma, MGUS and Waldenstrom’s macroglobulinemia; lymphomas such as nonHodgkin's lymphoma, Hodgkin's lymphoma; and the like.

[460] The cancer may be any cancer in which an abnormal number of blast cells or unwanted cell proliferation is present or that is diagnosed as a hematological cancer, including both lymphoid and myeloid malignancies. Myeloid malignancies include, but are not limited to, acute myeloid (or myelocytic or myelogenous or myeloblasts) leukemia (undifferentiated or differentiated), acute promyeloid (or promyelocytic or promyelogenous or promyeloblastic) leukemia, acute myelomonocytic (or myelomonoblastic) leukemia, acute monocytic (or monoblastic) leukemia, erythroleukemia and megakaryocyte (or megakaryoblastic) leukemia. These leukemias may be referred together as acute myeloid (or myelocytic or myelogenous) leukemia (AML). Myeloid malignancies also include myeloproliferative disorders (MPD) which include, but are not limited to, chronic myelogenous (or myeloid) leukemia (CML), chronic myelomonocytic leukemia (CMML), essential thrombocythemia (or thrombocytosis), and polycythemia vera (PCV). Myeloid malignancies also include myelodysplasia (or myelodysplastic syndrome or MDS), which may be referred to as refractory anemia (RA), refractory anemia with excess blasts (RAEB), and refractory anemia with excess blasts in transformation (RAEBT); as well as myelofibrosis (MFS) with or without angiogenic myeloid metaplasia.

[461] Hematopoietic cancers also include lymphoid malignancies, which may affect the lymph nodes, spleens, bone marrow, peripheral blood, and / or extranidal sites. Lymphoid cancers include B-cell malignancies, which include, but are not limited to, B-cell non-Hodgkin's lymphomas (B-NHLs). B-NHLs may be indolent (or low-grade), intermediate-grade (or aggressive) or high-grade (very aggressive). Indolent B-cell lymphomas include follicular lymphoma (FL); small lymphocytic lymphoma (SLL); marginal zone lymphoma (MZL) including nodal MZL, extranidal MZL, splenic MZL and splenic MZL with villous lymphocytes; lymphoplasmacytic lymphoma (LPL); and mucosa-associated-lymphoid tissue (MALT or extranidal marginal zone) lymphoma. Intermediate-grade B-NHLs include mantle cell lymphoma (MCL) with or without leukemic involvement, diffuse large cell lymphoma (DLBCL), follicular large cell (or grade 3 or grade 3B) lymphoma, and primary mediastinal lymphoma (PML). High-grade B-NHLs include Burkitt's lymphoma (BL), Burkitt-like lymphoma, small non- cleaved cell lymphoma (SNCCL) and lymphoblastic lymphoma. Other B-NHLs include immunoblastic lymphoma (or immunocytoma), primary effusion lymphoma, HIV associated (or AIDS related) lymphomas, and post-transplant lymphoproliferative disorder (PTLD) or lymphoma. B-cell malignancies also include, but are not limited to, chronic lymphocytic leukemia (CLL), prolymphocytic leukemia (PLL), Waldenstrom's macroglobulinemia (WM), hairy cell leukemia (HCL), large granular lymphocyte (LGL) leukemia, acute lymphoid (or lymphocytic or lymphoblastic) leukemia, and Castleman's disease. NHL may also include T-cell non-Hodgkin's lymphoma s(T-NHLs), which include, but are not limited to T-cell non-Hodgkin's lymphoma not otherwise specified (NOS), peripheral T-cell lymphoma (PTCL), anaplastic large cell lymphoma (ALCL), angioimmunoblastic lymphoid disorder (AILD), nasal natural killer (NK) cell / T-cell lymphoma, gamma / delta lymphoma, cutaneous T cell lymphoma, mycosis fungoides, and Sezary syndrome.

[462] Hematopoietic cancers also include Hodgkin's lymphoma (or disease) including classical Hodgkin's lymphoma, nodular sclerosing Hodgkin's lymphoma, mixed cellularity Hodgkin's lymphoma, lymphocyte predominant (LP) Hodgkin's lymphoma, nodular LP Hodgkin's lymphoma, and lymphocyte depleted Hodgkin's lymphoma. Hematopoietic cancers also include plasma cell diseases or cancers such as multiple myeloma (MM) including smoldering MM, monoclonal gammopathy of undetermined (or unknown or unclear) significance (MGUS), plasmacytoma (bone, extramedullary, lymphoplasmacytic lymphoma (LPL), Waldenstrom's Macroglobulinemia, plasma cell leukemia, and primary amyloidosis (AL). Hematopoietic cancers may also include other cancers of additional hematopoietic cells, including polymorphonuclear leukocytes (or neutrophils), basophils, eosinophils, dendritic cells, platelets, erythrocytes and natural killer cells. Tissues which include hematopoietic cells referred herein to as "hematopoietic cell tissues" include bone marrow; peripheral blood; thymus; and peripheral lymphoid tissues, such as spleen, lymph nodes, lymphoid tissues associated with mucosa (such as the gut-associated lymphoid tissues), tonsils, Peyer's patches and appendix, and lymphoid tissues associated with other mucosa, for example, the bronchial linings,

[463] In some embodiments, this disclosure is directed to a compound of any one or more of Formula (F), (IA’), (IT), (III’), (IV’) or (V’), or a pharmaceutically acceptable salt thereof for use in the treatment of cancer and pre-cancerous syndromes. In a further aspect there is provided a method of treating cancer and pre-cancerous syndromes comprising administering to a human in need thereof a therapeutically effective amount of a compound of any one or more of Formula (I’ ), (IA’), (II’), (HI’), (IV’) or (V’), or a pharmaceutically acceptable salt thereof. In a further aspect there is provided a compound of any one or more of Formula (F), (IA’), (IT), (III’), (IV”) or (V’), or a pharmaceutically acceptable salt thereof for use in the manufacture of a medicament for the treatment of cancer and pre-cancerous syndromes.

[464] The compounds of this disclosure may be used to treat inflammation of any tissue and organs of the body, including musculoskeletal inflammation, vascular inflammation, neural inflammation, digestive system inflammation, ocular inflammation, inflammation of the reproductive system, and other inflammation.

[465] Examples of cancer diseases and conditions in which compounds of this disclosure may have potentially beneficial antitumor effects include, but are not limited to, cancers of the lung, bone, pancreas, skin, head, neck, uterus, ovaries, stomach, colon, breast, esophagus, small intestine, bowel, endocrine system, thyroid gland, parathyroid gland, adrenal gland, urethra, prostate, penis, testes, ureter, bladder, kidney or liver; rectal cancer; cancer of the anal region; carcinomas of the fallopian tubes, endometrium, cervix, vagina, vulva, renal pelvis, renal cell; sarcoma of soft tissue; myxoma; rhabdomyoma; fibroma; lipoma; teratoma; cholangiocarcinoma; hepatoblastoma; angiosarcoma; hemangioma; hepatoma; fibrosarcoma; chondrosarcoma; myeloma; chronic or acute leukemia; lymphocytic lymphomas; primary CNS lymphoma; neoplasms of the CNS; spinal axis tumors; squamous cell carcinomas; synovial sarcoma; malignant pleural mesotheliomas; brain stem glioma; pituitary adenoma; bronchial adenoma; chondromatous hamartoma; mesotheli oma; Hodgkin's Disease or a combination of one or more of the foregoing cancers.

[466] Suitably the present disclosure relates to a method for treating or lessening the severity of cancers. In some embodiments, the compounds of the present disclosure may be used to treat sarcoma, breast cancer, colorectal cancer, gastroesophageal cancer, melanoma, non-small cell lung cancer (NSCLC), clear cell renal cell carcinoma (RCC), lymphomas, squamous cell carcinoma of the head and neck (SCCHN), hepatocellular carcinoma (HCC), and Non Hodgkin lymphoma (NHL). Suitably the present disclosure relates to a method for treating or lessening the severity of pre-cancerous syndromes in a mammal, including a human,

[467] In one aspect the human has a solid tumor. In one aspect the tumor is selected from head and neck cancer, gastric cancer, melanoma, renal cell carcinoma (RCC), esophageal cancer, nonsmall cell lung carcinoma, prostate cancer, colorectal cancer, ovarian cancer and pancreatic cancer. In some embodiments, the human has a liquid tumor such as diffuse large B cell lymphoma (DLBCL), multiple myeloma, chronic lymphoblastic leukemia (CLL), follicular lymphoma, acute myeloid leukemia, and chronic myelogenous leukemia.

[468] In some embodiments, the compounds of the present disclosure may be useful for treatment of skin cancers (e.g., non-melanoma skin cancer, squamous cell carcinoma, basal cell carcinoma) or actinic keratosis. In addition to a field effect for clearing superficial skin cancers, the compounds of the present disclosure may prevent the development of subsequent skin cancers and pre-malignant actinic keratosis in treated patients.

[469] The compounds of the present disclosure may also be useful in the treatment of one or more diseases afflicting mammals which are characterized by cellular proliferation in the area of disorders associated with neo-vascularization and / or vascular permeability, fibrotic disorders, and metabolic disorders.

[470] The compounds of this disclosure may be used to treat neurodegenerative diseases. Exemplary neurodegenerative diseases includes, but are not limited to, multiple sclerosis, Huntington's disease, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis (AES).

[471] The compounds of this disclosure may be used to treat an infectious disease, which is any disease instigated by or coincident with an infection from a pathogen, derived from bacteria, derived from the DNA virus families, or RNA virus families.

[472] The compounds of this disclosure may be employed alone or in combination with other therapeutic agents. As modulators of the immune response, the compounds of this disclosure may also be used in monotherapy or used in combination with another therapeutic agent in the treatment of diseases and conditions in which modulation of STING is beneficial. Combination therapies according to the present disclosure thus comprise the administration of a compound of any one or more of Formula (F), (IA’), (IF), (IIF), (IV’), or (V’), or a pharmaceutically acceptable salt thereof, and at least one other therapeutically active agent. In some embodiments, combination therapies according to the present disclosure comprise the administration of at least one compound of any one or more of Formula (F), (IA’), (IF), (IIF), (IV’), or (V’), or a pharmaceutically acceptable salt thereof, and at least one other therapeutic agent. The compound(s) of any one or more of Formula (F), (IA’), (IF), (IIF), (IV’), or (V’), and pharmaceutically acceptable salts thereof, and the other therapeutic agent(s) may be administered together in a single pharmaceutical composition or separately and, when administered separately this may occur simultaneously or sequentially in any order. The amounts of the compound(s) of any one or more of Formula (F), (IA’), (IF), (III’), (IV’), or (V’), and pharmaceutically acceptable salts thereof, and the other therapeutic agent(s) and the relative timings of administration will be selected in order to achieve the desired combined therapeutic effect. Thus, in a further aspect, there is provided a combination comprising a compound of any one or more of Formula (I’), (IA’), (IF), (HF), (IV’), or (V”), or a pharmaceutically acceptable salt thereof, together with one or more other therapeutic agents.

[473] The compounds of any one or more of Formula (I’), (IA’), (IF), (IIF), (IV’), or (V’), and pharmaceutically acceptable salts thereof may be used in combination with one or more other therapeutic agents which may be useful in the prevention or treatment of allergic disease, inflammatory disease, or autoimmune disease, for example; antigen immunotherapy, antihistamines, steroids, NSAIDs, bronchodilators,, methotrexate, leukotriene modulators, monoclonal antibody therapy, receptor therapies, or antigen non-specific immunotherapies.

[474] The compounds of any one or more of Formula (I’), (IA’), (IF), (IIF), (IA”), or (V’), and pharmaceutically acceptable salts thereof may be used in combination with radiotherapy and / or surgery and / or at least one other therapeutic agent which may be useful in the treatment of cancer and pre-cancerous syndromes. Any anti-neoplastic agent,, anti-microtubule, anti-mitotic agent, hormone, hormonal analogues signal transduction pathway inhibitor, protein tyrosine kinase, or anti-angiogenic therapeutic agent, may be utilized in the combination.

[475] Agents used in immunotherapeutic regimens, therapeutic agents used in proapoptotic regimens, or cell cycle signaling inhibitors may also be useful in combination with the compounds of any one or more of Formula (F), (IA’), (IF), (III’), (IV’) or (A”)..

[476] In some embodiments, the combination of the present disclosure comprises a compound of any one or more of Formula (I’), (IA’), (IF), (IIF), (IV’), or (V’), or a salt, particularly a pharmaceutically acceptable salt thereof, and at least one anti-neoplastic agent, anti-microtubule, anti-mitotic agent, hormone, hormonal analogues signal transduction pathway inhibitor, protein tyrosine kinase, or anti-angiogenic therapeutic agent, or a combination thereof,

[477] Additional examples of other therapeutic agents (e.g., anti-neoplastic agent) for use in combination or co-administered with a compound of any one or more of Formula (I’ ), (IA’), (IF), (IIF), (IA”), or (V’), or a pharmaceutically acceptable salt thereof are immuno-modulators.

[478] As used herein "immuno-modulators” refer to any substance including monoclonal antibodies that affects the immune system. Im...

Claims

1. A compound of Formula (V-f1), Formula (V-f2), Formula (V-f3), Formula (V-f4), Formula (V-f5), Formula (V-f6), Formula (V-f7), Formula (V-h1), Formula (V-h2), Formula (V-h3), Formula (V-h4), Formula (V-h5), Formula (V-h6), or Formula (V-h7):(V-f1)(V-f2)(V-f3)(V-f4)(V-f5)2020324388   23 Jun 2026(V-f6)(V-f7)(V-h2)(V-h1)(V-h3)2020324388   23 Jun 2026R14(V-h4)(V-h5)(V-h6)(V-h7)or a solvate, pharmaceutically acceptable salt, or tautomer thereof, wherein:2020324388   23 Jun 2026Ring 1 or Ring 2 is selected fromand; orY1, Z1, Y2, and Z2 are each independently O, S, C, or N;X1, W1, X2, and W2 are each independently C or N;X3 and X4, when present, are each independently S or NRf;X5 is N or CRA2;X6, when present, is N or CRA1;X9, when present, is N or CH;R3 and R5 are each independently -CON(Rd)(Rf), -CH2N(Rd)(Rf), -N(Rd)(Rf), -N(Rd)CO(Rf), -CH2N(Rd)CO(Rf) or one of R3 and R5 is -CON(Rd)(Rf), -CH2N(Rd)(Rf), -N(Rd)(Rf), -N(Rd)CO(Rf), or -CH2N(Rd)CO(Rf), and the other of R3 and R5 is H, -COOH, or -CO2Rc;Rc is C1-4 alkyl;RA2 and RA1, when present, are each independently halogen, amino(C1-4 alkyl)-, hydroxy, optionally substituted (C1-6 alkyl), or optionally substituted (C1-6 alkyl)oxy-,wherein C1-6 alkyl of said optionally substituted (C1-6 alkyl), or optionally substituted (C1-6 alkyl)oxy- is optionally substituted with 1-4 substituents each independently selected from the group comprising hydroxy, C1-4 alkoxyl, -N(Re)(Rf), -CO2(Rf), -CON(Re)(Rf), and -COOH;2020324388   23 Jun 2026each Rd is independently H, hydroxy, or C1-4 alkyl;each Re is independently selected from H, (C1-4 alkyl), -CO(C1-4 alkyl), -OCO(C1-4 alkyl), and -CO2(C1-4 alkyl);each Rf is independently H, hydroxy, or (C1-4 alkyl);R14 and RC2 are each independently absent or C1-4 alkyl, wherein C1-4 alkyl is optionally substituted by a substituent selected from halogen, -ORc, -NRcRd, -CO2Rc, -CONRcRd, -SO2NRcRd, and -OCONRcRd;R16 and RC1 are each independently absent, H or C1-4 alkyl; andR15, R17, R18, or R19 are each independently absent, H, or C1-4 alkyl, wherein C1-4 alkyl is optionally substituted by a substituent selected from halogen, -ORc, -NRcRd, -CO2Rc, -CONRcRd, -SO2NRcRd, and -OCONRcRd.

2. The compound of claim 1, wherein the compound is of Formula (V’), wherein thecompound is Formula (V-i1), Formula (V-i2), Formula (V-i3), Formula (V-i4), Formula (V-i5), (Formula (V-i6), or Formula (V-i7):(V-i1)2020324388   23 Jun 2026(V-i2)(V-i3)(V-i4)(V-i5)(V-i6)(V-i7)or a solvate, pharmaceutically acceptable salt, or tautomer thereof.

3. The compound of any one of the preceding claims, wherein Ring 1 and Ring 2 are eachindependently selected from any one of the following:2020324388   23 Jun 2026(11)N II N.;(16)   '(2)(7) N ;(12)(21)(31)(36)(17)(22)0^ 4< il (3) 5 VN ;(8)(9)(13)H(10)“K ](15) N0OH(18)(23)(27) N ;(28)(29), S^CF: Hl(30)J (35)             ;(37)(42)(47)(43) ? VO;(44) N \;(45)-K J] (50)2020324388   23 Jun 20264. The compound of any one of the preceding claims, wherein the compound is selected fromany one of the following,:IJChICHN^2020324388   23 Jun 2026tautomer or pharmaceutically salt thereof.or a5. The compound of claim 1, wherein the compound is:or a solvate, pharmaceutically acceptable salt, or tautomer thereof.

6. The compound of claim 1, wherein the compound is:2020324388   23 Jun 2026or a solvate, pharmaceutically acceptable salt, or tautomer thereof.

7. A pharmaceutical composition comprising the compound of any one of the precedingclaims, and a pharmaceutically acceptable excipient.

8. A pharmaceutical  composition comprising the compound of claim  5,  and apharmaceutically acceptable excipient.

9. A pharmaceutical  composition comprising the compound of claim  6,  and apharmaceutically acceptable excipient.

10. A compound of any one of claims 1-6, for use in therapy.

11. A compound of any one of claims 1-6, for use in a method of treating a STING-mediateddisorder, wherein the disorder is cancer.

12. A method of treating a STING-mediated disorder, wherein the disorder is cancer, wherein the method comprises administering a compound of any one of claims 1-6, or a pharmaceutical composition of any one of claims 7-9.

13. Use of a compound of any one of claims 1-6, or a pharmaceutical composition of any one of claims 7-9, in the manufacture of a medicament for treating a STING-mediated disorder, wherein the disorder is cancer.2020324388   23 Jun 202614. The compound of claim 11, the method of claim 12 or the use of claim 13, wherein the cancer is breast cancer, head and neck cancer, gastric cancer, melanoma, renal cell carcinoma (RCC), esophageal cancer, non-small cell lung carcinoma, prostate cancer, colorectal cancer, ovarian cancer, or pancreatic cancer.