Protein kinase inhibitors and uses thereof

Abstract

Provided in part herein are protein kinase inhibitors having a structure according to specified Formulae and uses thereof.

Description

[0001] PROTEIN KINASE INHIBITORS AND USES THEREOF

[0002] Cross-Reference to Related Applications

[0003] This application claims priority to, and is a non-provisional of, U.S. provisional patent application 63 / 689,835 (filed September 2, 2024), the entirety of which is incorporated herein by reference.

[0004] Reference to a Sequence Listing

[0005] This application contains a Sequence Listing in computer readable form. The computer readable form is incorporated herein by reference. The computer readable file is named Seqeuence.xml and was created on August 30, 2025 (19 kB).

[0006] Field

[0007] The technology relates in part to compounds that contain a quinazolinyl group and an amine- linked phenyl group. Compounds herein can inhibit one or more protein kinases (PKs), and the technology relates in part to uses of compounds herein.

[0008] Background

[0009] Protein kinases (PKs) are a category of proteins that catalyze phosphorylation of different protein substrates. Each PK typically is referred to by the three or four letter code afforded to the gene that encodes the PK protein. PKs are categorized into PK families according to polypeptide sequence and / or function. Dysregulation of PK genes and their encoded PKs are associated with certain cancers. The ABL1 protooncogene, for example, which also is known as ABL, JTK7, p150, c-ABL, CHDSKM, C-ABL1 , encodes an ABL1 PK implicated in processes of cell differentiation, cell division, cell adhesion, and stress response. Activity of the ABL1 PK is negatively regulated by its SH3 polypeptide domain. Modification to the ABL1 protooncogene, such as deletion of the SH3 domain-encoding portion and fusion with another protein, for example, can turn it into an oncogene. Translocation and head-to-tail fusion of the BCR and ABL1 genes is present in cases of chronic myeloid leukemia (CML) and in a subset of acute lymphoblastic leukemia (i.e., Philadelphia chromosome-positive ALL). Genes encoding other PKs, which can phosphorylate protein targets different than those of ABL1 , can be dysregulated in certain cancers and other medical conditions.

[0010] Summary

[0011] Provided are compounds that inhibit one or more particular PKs, including ABL, BTK, AURK, JAK, TRK, RET, EPH, TNK, PLK, IRAK, ROS, and TYK family PKs, and may be used for treating cancers and other medical conditions. Compounds herein contain a quinazolinyl group, an amine-linked phenyl group and substituents that can afford PK inhibitory activity. Compounds herein can inhibit multiple PKs in certain embodiments. Compounds herein can selectively inhibit at least one PK in certain instances. Compounds that inhibit one or more particular protein kinases (PKs) can be used to treat cancers and other medical conditions. Brief Description of the Drawings

[0012] The drawings illustrate certain embodiments of the technology and are not limiting. For clarity and ease of illustration, the drawings are not made to scale, and, in some instances, various aspects may be shown exaggerated or enlarged to facilitate an understanding of particular embodiments. FIG. 1 illustrates processes of a protein kinase (PK) labeled peptide cleavage assay. FIG. 2 illustrates amino acid substitutions identified in certain ABL1 variants. FIG. 3 shows ABL1 inhibition by CmpdI O and Cmpd11 determined by a labeled peptide cleavage assay. FIG. 4A to FIG. 11 C show PK inhibition by compounds determined by peptide cleavage and tracer displacement assays. FIG. 4A and FIG. 4B shows inhibition of ABL family PKs. FIG.

[0013] 5 shows inhibition of BTK family PKs. FIG. 6 shows inhibition of AURK family PKs. FIG. 7A and 7B show inhibition of JAK family PKs. FIG. 8 shows inhibition of TRK family PKs. FIG. 9 shows inhibition of RET family PKs. FIG. 10A shows inhibition of EPH family PKs. FIG. 10B shows inhibition of TNK family, PLK family and IRAK family PKs. FIG. 10C shows inhibition of SRC and DDR family PKs. FIG. 10D shows inhibition of ABL2 and PTK2B PKs. FIG. 11 A shows inhibition of ABL and BTK family PKs. FIG. 11 B shows inhibition of ABL and AURK family PKs. FIG. 11 C shows inhibition of ABL, BTK and AURK family PKs. The legend at the bottom of FIG. 4B is applicable to charts in FIG. 5 to FIG. 11 C. FIG. 12A and FIG. 12B show observed cytotoxicity responses to compounds for K562 LD50and NALM-21 cells, respectively. FIG. 13A, FIG. 13B and FIG. 13C show observed IL-6 reduction responses to compounds. FIG. 14 illustrates a dose escalation study overview.

[0014] Detailed Description

[0015] Compounds herein can inhibit one or more protein kinases (PKs) and can be used for treatment of medical conditions including cancers. Development of PK inhibitor cancer treatments is challenging. PK inhibitor drugs can present issues including ineffectiveness in a patient subgroup, loss of therapeutic effect during treatment for a patient subgroup, and triggering a serious adverse event in a patient subgroup. For example, an amino acid substitution in the ABL1 kinase domain occurring in a patient can impart resistance to cancer treatment. An ABL1 variant containing a threonine 315 to isoleucine (T315I) amino acid substitution can result in resistance to cancer treatment, for example. It has been reported that developing inhibitors against this variant is challenging because inhibitor candidates often bind to the PK at or near the site of the amino acid substitution. Despite this challenge, certain compounds herein can effectively inhibit the ABL1 (T315I) variant. Certain compounds herein can effectively inhibit other PKs, can effectively inhibit multiple PKs in different PK families and / or can selectively inhibit a PK.

[0016] Compounds

[0017] In certain aspects, provided is a compound of Formula A1 or Formula A2: or a pharmaceutically acceptable salt, amide or ester thereof, where:

[0018] R1, R2, R3and R4each independently is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkoxy, optionally substituted heteroalkyl, optionally substituted haloalkyl, optionally substituted deuteroalkyl, optionally substituted alkylthio, optionally substituted alkylamino, optionally substituted hydroxyalkyl, optionally substituted mercaptoalkyl, optionally substituted aminoalkyl, -C(O)RZ, - ORU, -B(OH)2, hydroxy, halo, cyano, nitro, amino or amido; )-RY, -C(O)N(Rb)-RYA, -N(Rb)-CH2-RY; -CH2-N(Rb)RY, -N(Ra)C(O)-Rv-N(Rb)RY, - RY, -N(Ra)Rbor of Formula F: Formula F;

[0019] Rais hydrogen, optionally substituted alkyl, optionally substituted alkynyl or of Formula F;

[0020] Rbis hydrogen or optionally substituted alkyl;

[0021] Rvis an optionally substituted alkylene;

[0022] RYis hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkoxy, optionally substituted heteroalkyl, optionally substituted haloalkyl, optionally substituted deuteroalkyl, optionally substituted hydroxyalkyl, optionally substituted mercaptoalkyl, optionally substituted aminoalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocycloalkylalkyl, optionally substituted aryl, optionally substituted arylaminoalkyl, optionally substituted aryloxyalkyl, optionally substituted arylthioalkyl or optionally substituted arylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylaminoalkyl, optionally substituted heteroaryloxyalkyl, optionally substituted heteroarylthioalkyl, optionally substituted heteroarylalkyl or is of Formula F; RYAis an optionally substituted aryl, optionally substituted arylaminoalkyl, optionally substituted aryloxyalkyl, optionally substituted arylthioalkyl or optionally substituted arylalkyl, optionally substituted heteroaryl, optionally substituted heteroarylaminoalkyl, optionally substituted heteroaryloxyalkyl, optionally substituted heteroarylthioalkyl or optionally substituted heteroarylalkyl;

[0023] Z1is an optionally substituted heterocycloalkyl, Xais C(R43)R43A; Xbis C(R44)R44A; Xcis C(R45)R45A, N-R45B, O, S, S(O) or SO2; Xdis C(R46)R46A; and Xeis C(R47)R47A; and R43, R44, R45, R46, R47, R43A, R44A, R45A, R46A, R47Aand R45Beach independently is hydrogen, optionally substituted C1 -C6 alkyl, optionally substituted C1 -C6 alkoxy, optionally substituted C1 -C6 heteroalkyl, optionally substituted C1 -C6 haloalkyl, optionally substituted C1 -C6 deuteroalkyl, optionally substituted C1-C6 alkylthio, optionally substituted C1 -C6 alkylamino, optionally substituted C1 -C6 hydroxyalkyl, optionally substituted C1 -C6 mercaptoalkyl, optionally substituted C1 -C6 aminoalkyl;

[0024] R10, R11, R12and R13each independently is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkoxy, optionally substituted heteroalkyl, optionally substituted haloalkyl, optionally substituted deuteroalkyl, optionally substituted alkylthio, optionally substituted alkylamino, optionally substituted hydroxyalkyl, optionally substituted mercaptoalkyl, optionally substituted aminoalkyl, -C(O)RZ, - C(O)OH, -C(O)ORU, -B(OH)2, hydroxy, halo, cyano, nitro, amino, amido, Rwor -W-Rw;

[0025] Rwis an optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocycloalkyl, optionally substituted heterocycloalkylalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted arylaminoalkyl, optionally substituted aryloxyalkyl, optionally substituted arylthioalkyl, optionally substituted heteroarylaminoalkyl, optionally substituted heteroaryloxyalkyl, optionally substituted heteroarylthioalkyl, optionally substituted arylalkyl or optionally substituted heteroarylalkyl;

[0026] W is an optionally substituted alkylene, optionally substituted alkynyl, amino, amido, -O-, -S-, - S(O)- or -SO2-;

[0027] Rzis hydrogen or Ru; and

[0028] Ruis an optionally substituted alkyl, optionally substituted hydroxyalkyl, optionally substituted mercaptoalkyl, optionally substituted aminoalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted arylaminoalkyl, optionally substituted aryloxyalkyl, optionally substituted arylthioalkyl, optionally substituted heteroarylaminoalkyl, optionally substituted heteroaryloxyalkyl, optionally substituted heteroarylthioalkyl, optionally substituted arylalkyl or optionally substituted heteroarylalkyl.

[0029] A substituent having a structure according to Formula F is referred to herein as a “Formula F group.” Z1, and Z2, Z3, Z4, Z5, Z2a, Z3a, Z4a, Z5a, Z2b, Z3b, Z4band Z5bdesignations herein, each designates a ring structure (e.g., monocyclic or multicyclic ring structure) and is not an atom, and the designated ring structure may be substituted or unsubstituted.

[0030] A compound herein is with the proviso that it is not of Formula X1 , not of Formula X2, not of Formula X3 and not of Formula X4:

[0031] Formula X4 where: R2X, R3Xand R4Xeach independently is hydrogen, optionally substituted C1 -C4 alkyl or optionally substituted C1-C4 alkoxy; R14X, R15X, R16Xand R17Xeach independently is hydrogen, optionally substituted C1-C4 alkyl, optionally substituted C1 -C4 alkoxy, or halo; R19X, R21Xand R22Xeach independently is hydrogen or optionally substituted C1 -C6 alkyl; m is an integer of 1 or 2; RYXis methyl or n is an integer of 1 to 10; and RYXXis hydrogen, optionally substituted alkyl or optionally substituted amidoalkyl. Compounds of Formula X1 , Formula X2, Formula X3 and Formula X4 as defined are excluded. In certain aspects pertaining to a compound of Formula A1 or Formula A2, Y is -N(Rb)C(O)-RYor -C(O)N(Rb)-RYA, and RYand RYAeach is an optionally substituted phenyl. In certain aspects, provided is a compound of Formula A1 -1 , Formula A1 -2 or Formula A2-1 : or a pharmaceutically acceptable salt, amide or ester thereof, where:

[0032] Y’ is -N(Rb)C(O)- or -C(O)N(Rb)-;

[0033] Rb, R1, R2, R3, R4, R10, R11, R12and R13each is as defined for a compound of Formula A1 and Formula A2; R5, R6, R7, R8, and R9each independently is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkoxy, optionally substituted heteroalkyl, optionally substituted haloalkyl, optionally substituted deuteroalkyl, optionally substituted alkylthio, optionally substituted alkylamino, optionally substituted hydroxyalkyl, optionally substituted mercaptoalkyl, optionally substituted aminoalkyl, -B(OH)2, - C(O)RZ, -C(O)OH, -C(O)ORU, hydroxy, halo, cyano, nitro, amino, amido, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocycloalkyl, optionally substituted heterocycloalkylalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted arylaminoalkyl, optionally substituted aryloxyalkyl, optionally substituted arylthioalkyl, optionally substituted heteroarylaminoalkyl, optionally substituted heteroaryloxyalkyl, optionally substituted heteroarylthioalkyl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl or a Formula F group; and Rzand Rueach is as defined for Formula A1 and Formula A2.

[0034] In certain aspects pertaining to a compound of Formula A1 , Formula A1 -1 , Formula A1 -2, Formula A2 or Formula A2-1 , R10is Rwand Rwis an optionally substituted phenyl or optionally substituted pyrazolyl. In certain aspects, provided is a compound of Formula A1 -3, Formula A1 - 4, Formula A1 -5, Formula A1 -6, Formula A2-2 or Formula A2-3:

[0035] or a pharmaceutically acceptable salt, amide or ester thereof, where:

[0036] Y, R1, R2, R3, R4, R5, R6, R7, R8, R9, R11, R12and R13each is as defined for a compound of

[0037] Formula A1 , Formula A1 -1 , Formula A1 -2, Formula A2 or Formula A2-1 ;

[0038] R14, R15, R16, R17, R18, R19B, R21and R22each independently is hydrogen optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkoxy, optionally substituted heteroalkyl, optionally substituted haloalkyl, optionally substituted deuteroalkyl, optionally substituted alkylthio, optionally substituted alkylamino, optionally substituted hydroxyalkyl, optionally substituted mercaptoalkyl, optionally substituted aminoalkyl, -C(O)RZ, -C(O)OH, -C(O)ORU, hydroxy, halo, cyano, nitro, amino, amido, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted arylaminoalkyl, optionally substituted aryloxyalkyl, optionally substituted arylthioalkyl, optionally substituted heteroarylaminoalkyl, optionally substituted heteroaryloxyalkyl, optionally substituted heteroarylthioalkyl, optionally substituted arylalkyl or optionally substituted heteroarylalkyl; and Rzand Rueach is as defined for Formula A1 and Formula A2.

[0039] In certain aspects pertaining to a compound of Formula A1 or Formula A1 -2, R10is -W-Rw, W is -CEC-, and Rwis an optionally substituted phenyl..

[0040] In certain aspects, a compound herein is provided as a hydrochloride salt.

[0041] Certain features of compounds of Formula A1 , Formula A1 -1 , Formula A1 -2, Formula A1 -3, Formula A1 -4, Formula A1 -5, Formula A1 -6, Formula A2, Formula A2-1 , Formula A2-2 and Formula A2-3 are described hereafter.

[0042] Y substituents

[0043] In certain embodiments, RYand RYAeach is an optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl or optionally substituted heteroarylalkyl. An optionally substituted arylalkyl typically contains an optionally substituted alkylene (for example, an optionally substituted C1-C6 alkylene) linked to an optionally substituted aryl. An optionally substituted heteroarylalkyl typically contains an optionally substituted alkylene (for example, an optionally substituted C1-C6 alkylene) linked to an optionally substituted heteroaryl. In certain embodiments, RYand RYAeach contains or is an optionally substituted aryl or optionally substituted heteroaryl of Formula B1 : Formula B1 where: Z2is aryl or heteroaryl; X1independently is C or N; X2independently is C-R5, N-R5Bor N; X3independently is C-R6, N-R5Bor N; X4independently is C-R7, N-R7Bor N; X5independently is C-R8, N-R8Bor N; and X6independently is C-R9, N-R9Bor N; R6, R7, R8, R9, R6B, R7B, R8Band R9Bare as defined herein; and optionally two adjacent R6, R7, R8, R9, R6B, R7B, R8Band R9Bare linked in an optionally substituted aryl or optionally substituted heteroaryl. In certain embodiments pertaining to Formula B1 , Z2is an optionally substituted pyridinyl, optionally substituted pyrimidinyl, optionally substituted pyrazinyl, optionally substituted pyridazinyl or optionally substituted triazinyl. In certain embodiments pertaining to Formula B1 , X1is C, X2is C-R5, X3is C-R6, X4is C-R7, X5is C-R8, and X6is C-R9. In certain embodiments pertaining to Formula B1 , X1is C, X2is C-R5, X3is N, X4is C-R7, X5is C-R8, and X6is C-R9. In certain embodiments pertaining to Formula B1 , X1is C, X2is N, X3is C-R6, X4is N, X5is C-R8, and X6is C-R9. In certain embodiments pertaining to Formula B1 , X1is C, X2is C-R5, X3is N, X4is C-R7, X5is N, and X6is C-R9. In certain embodiments pertaining to Formula B1 , X1is C, X2is C-R5, X3is C-R6, X4is N, X7is C-R8and X6is C-R9.

[0044] In certain embodiments, RYand RYAeach contains or is an optionally substituted aryl or optionally substituted heteroaryl of Formula C1 : X I7

[0045] X11„ X8

[0046] \

[0047] AX10-zYA9Formu Ila C1 where:

[0048] Z3is aryl or heteroaryl; X7independently is C or N; X8independently is C-R5, N- R5B, N, O, S, S(O) or SO2; X9independently is C-R6, N- R6B, N, O, S, S(O) or SO2; X10independently is C-R7, N- R7B, N, O, S, S(O) or SO2; and X11independently is C-R8, N- R8B, N, O, S, S(O) or SO2; R5, R6, R7, R8, R5B, R6B, R7Band R8Bare as defined herein; and optionally two adjacent R5, R6, R7, R8, R5B, R6B, R7Band R8Bare linked in an optionally substituted aryl or optionally substituted heteroaryl. In certain embodiments pertaining to Formula C1 , Z3is an optionally substituted pyrrolyl, optionally substituted imidazolyl, optionally substituted pyrazolyl, optionally substituted puranyl, optionally substituted thiophenyl, optionally substituted oxazolyl, optionally substituted thiazolyl, optionally substituted isoxazolyl or optionally substituted isothiazolyl. In certain embodiments pertaining to Formula C1 :

[0049] X7is C; X8is N or N-R5B; X9is N or N-R6B; X10is C-R7; and X11is C-R8;

[0050] X7is C; X8is N or N-R5A; X9is C-R6; X10is C-R7; and X11is C-R8;

[0051] X7is C; X8is N or N- R5B; X9is C-R6; X10is C-R7; and X11is N or N- R8B;

[0052] X7is C; X8is N; X9is C-R6; X10is C-R7; and X11is S;

[0053] X7is C; X8is N; X9is C-R6; X10is C-R7; and X11is O; or

[0054] X7is C; X8is N; X9is C-R6; X10is O; and X11is C-R8.

[0055] In certain embodiments, RYis an optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocycloalkyl or an optionally substituted heterocycloalkylalkyl. In certain embodiments, RYis an optionally substituted cycloalkylalkyl comprising an optionally substituted alkylene, for example an optionally substituted C1 -C6 alkylene, linked to an optionally substituted cycloalkyl. In certain embodiments, RYis an optionally substituted heterocycloalkylalkyl comprising an optionally substituted alkylene, for example an optionally substituted C1 -C6 alkylene, linked to an optionally substituted heterocycloalkyl.

[0056] In certain embodiments, RYis an optionally substituted heterocycloalkyl or an optionally substituted heterocycloalkylalkyl, and the optionally substituted heterocycloalkyl contains 4, 5 or 6 ring atoms. In certain instances, RYcontains or is an optionally substituted piperidinyl, optionally substituted piperazinyl, optionally substituted tetrahydropyran, or optionally substituted morpholinyl, optionally substituted pyrrolidinyl, optionally substituted imidazolidinyl, optionally substituted pyrazolidinyl or optionally substituted azetidinyl. In certain instances, RYcontains or is a substituted heterocycloalkyl containing 4, 5 or 6 ring atoms, which sometimes is a C1 -C6 alkyl substituted heterocycloalkyl, a methyl substituted heterocycloalkyl or a monomethyl substituted heterocycloalkyl.

[0057] In certain embodiments, RYis an optionally substituted cycloalkyl or optionally substituted heterocycloalkyl of Formula D1 , or an optionally substituted cycloalkylalkyl or optionally substituted heterocycloalkylalkyl containing the optionally substituted cycloalkyl or optionally substituted heterocycloalkyl of Formula D1 : Formula D1 where: Z4is cycloalkyl or heterocycloalkyl; X12is C-RaA, C or N; X13independently is C(R5)R5A, C-R5, N-R5B, N, O, S, S(O) or SO2; X14independently is C(R6)R6A, C-R6, N-R6B, N, O, S, S(O) or SO2; X15independently is C(R7)R7A, C-R7, N-R7B, N, O, S, S(O) or SO2; X16independently is C(R8)R8A, C-R8, N-R8B, N, O, S, S(O) or SO2; and X17independently is C(R9)R9A, C-R9, N-R9B, N, O, S, S(O) or SO2; and optionally two adjacent R5, R5A, R6, R6A, R7, R7A, R8, R8A, R9and R9Aare linked in an optionally substituted cycloalkyl or optionally substituted heterocycloalkyl. In certain instances pertaining to Formula D1 , Z4is an optionally substituted piperidinyl, optionally substituted piperazinyl, optionally substituted morpholinyl or optionally substituted tetrahydropyranyl. In certain instances pertaining to Formula D1 , X12is C-RaA; X13is C-R5; X14is C(R6)R6A; X15is N-R7B; X16is C(R8)R8A; and X17is C(R9)R9A. In certain instances pertaining to Formula D1 , X12is N; X13is C(R5)R5A; X14is C(R6)R6A; X15is N-R7B, X16is C(R8)R8A, and X17is C(R9)R9A. In certain instances pertaining to Formula D1 , X12is N; X13is C(R5)R5A; X14is C(R6)R6A; X15is C(R7)R7A, X16is C(R8)R8A, and X17is C(R9)R9A. In certain instances pertaining to Formula D1 , X12is C-R37'; X13is C(R5)R5A; X14is C(R6)R6A; X15is N-R7B; X16is C(R8)R8A; and X17is C(R9)R9A. In certain instances pertaining to Formula D1 , X12is C-R37'; X13is C(R5)R5A; X14is C(R6)R6A; X15is O; X16is C(R8)R8A; and X17is C(R9)R9A.

[0058] In certain embodiments, RYcontains or is an optionally substituted cycloalkyl or optionally substituted heterocycloalkyl of Formula E1 : Formula E1 where: Z5is cycloalkyl or heterocycloalkyl; X18is C-RaA, C or N; X19independently is C(R5)R5A, C-R5, N-R5B, N, O, S, S(O) or SO2; X20independently is C(R6)R6A, C-R6, N-R6B, N, O, S, S(O) or SO2; X21independently is C(R7)R7A, C-R7, N-R7B, N, O, S, S(O) or SO2; and X22independently is C(R8)R8A, C-R8, N-R8B, N, O, S, S(O) or SO2; and optionally two adjacent R5, R5A, R6, R6A, R7, R7A, R8, R8A, R5B, R6B, R7Band R8Bare linked in an optionally substituted cycloalkyl or optionally substituted hetero heterocycloalkyl. In certain embodiments pertaining to Formula E1 , Z5is an optionally substituted pyrrolidinyl, optionally substituted pyrazolidinyl, optionally substituted imidazolidinyl or optionally substituted pyrazolidinyl. In certain embodiments pertaining to Formula E1 , X18is C-RaA, X19is N-R5B, X20is C(R6)R6A, X21is C(R7)R7Aand X22is C(R8)R8A.

[0059] In certain embodiments, Y is -N(Rb)C(O)-RYor -N(Rb)C(O)-Rv-RY, and Rb, Rvand RYeach is as defined for Formula A1 and Formula A2.

[0060] In certain embodiments, RaA, R5, R5A, R6, R6A, R7, R7A, R8, R8A, R9and R9Aeach independently is hydrogen optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkoxy, optionally substituted heteroalkyl, optionally substituted haloalkyl, optionally substituted deuteroalkyl, optionally substituted alkylthio, optionally substituted alkylamino, optionally substituted hydroxyalkyl, optionally substituted mercaptoalkyl, optionally substituted aminoalkyl, -C(O)RZ, -C(O)OH, -C(O)ORU, hydroxy, halo, cyano, nitro, amino, amido, optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocycloalkyl, optionally substituted heterocycloalkylalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted arylaminoalkyl, optionally substituted aryloxyalkyl, optionally substituted arylthioalkyl, optionally substituted heteroarylaminoalkyl, optionally substituted heteroaryloxyalkyl, optionally substituted heteroarylthioalkyl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl; Ruis as defined for Formula A1 ; and RSB, R6B, R7B RSBANC| R9Beach independently is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted haloalkyl, optionally substituted deuteroalkyl, optionally substituted hydroxyalkyl, optionally substituted mercaptoalkyl, optionally substituted aminoalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted arylaminoalkyl, optionally substituted aryloxyalkyl, optionally substituted arylthioalkyl, optionally substituted heteroarylaminoalkyl, optionally substituted heteroaryloxyalkyl, optionally substituted heteroarylthioalkyl, optionally substituted arylalkyl, or optionally substituted heteroarylalkyl; and

[0061] In certain embodiments, RaA, R5, R5A, R6, R6A, R7, R7A, R8, R8A, R9and R9Aeach independently is hydrogen, optionally substituted C1 -C6 alkyl, optionally substituted C1-C6 alkoxy, optionally substituted C1 -C6 heteroalkyl, optionally substituted C1 -C6 haloalkyl, optionally substituted C1 - C6 deuteroalkyl, optionally substituted C1 -C6 alkylthio, optionally substituted C1 -C6 alkylamino, optionally substituted C1-C6 hydroxyalkyl, optionally substituted C1 -C6 mercaptoalkyl, optionally substituted C1-C6 aminoalkyl, RcC(O)N(Rd)-, -C(O)N(RcRd), -NReRf, -C(O)RZ, - C(O)OH, -C(O)ORU, hydroxy, halo, cyano, nitro, optionally substituted C5-C6 cycloalkyl, optionally substituted heterocycloalkyl containing 5 or 6 ring member atoms; where Rc, Rd, Reand Rfeach independently is hydrogen or optionally substituted C1-C6 alkyl. In certain instances, an optionally substituted C1 -C6 haloalkyl is an optionally substituted C1 -C4 haloalkyl, or trifluoromethyl. In certain instances, Rc, Rd, Reand Rfeach independently is hydrogen or methyl. In certain instances, Ruis an optionally substituted C1 -C4 alkyl, butyl, tert-butyl, isobutyl, propyl, iso-propyl, ethyl or methyl. In certain instances pertaining to Formula B1 , Formula C1 , Formula D1 and Formula E1 , RaA, R5, R5A, R6, R6A, R7, R7A, R8, R8A, R9and R9Aeach independently is hydrogen, unsubstituted C1 -C4 alkyl, Cl, F, CF3, CD3, unsubstituted C1 -C4 alkoxy, methoxy, isopropyloxy or dimethylamino.

[0062] In certain embodiments, R5B, R6B, R7B, R8B, and R9Beach independently is hydrogen, optionally substituted C1 -C6 alkyl, optionally substituted C1 -C6 heteroalkyl, optionally substituted C1 -C6 haloalkyl, optionally substituted C1 -C6 deuteroalkyl, optionally substituted C1 -C6 hydroxyalkyl, optionally substituted C1-C6 mercaptoalkyl, optionally substituted C1 -C6 aminoalkyl, optionally substituted C5-C6 cycloalkyl, optionally substituted heterocycloalkyl containing 5 or 6 ring member atoms, or -C(O)ORU. In certain instances, Ruis an optionally substituted C1 -C4 alkyl, butyl, tert-butyl, iso-butyl, propyl, iso-propyl, ethyl or methyl. In certain instances pertaining to Formula B1 , Formula C1 , Formula D1 and Formula E1 , R5B, R6B, R7B, R8B, and R9Beach independently is hydrogen, optionally substituted C1 -C4 alkyl, butyl, tert-butyl, iso-butyl, propyl, iso-propyl, ethyl or methyl.

[0063] In certain embodiments, Y contains a heterocycloalkyl of Formula D1 and is:

[0064] In certain embodiments for which Y contains an optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl or optionally substituted heterocycloalkyl of Formula B1 , C1 , D1 or E1 , one or more of R^, R5, R5A, R6, R6A, R7, R7A, R8, R8A, R9and R9Ais -C(O)N(RcRd) where Rcand Rdeach independently is hydrogen or optionally substituted C1- C4 alkyl. In certain embodiments, at least R7is -C(O)N(RcRd) and Rcand Rdeach independently is hydrogen or optionally substituted C1 -C4 alkyl. In certain instances, R° and Rdeach independently is unsubstituted C1 -C4 alkyl. In certain instances, at least R7is -C(O)N(CH3)CH3, -C(O)N(H)CH3or -C(O)NH2.

[0065] In certain embodiments for which Y contains an optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl or optionally substituted heterocycloalkyl of Formula B1 , C1 , D1 or E1 , one or more of R^, R5, R5A, R6, R6A, R7, R7A, R8, R8A, R9and R9Ais -C(O)OH or -C(O)ORUand in certain instances at least R7is -C(O)OH or -C(O)ORU, where Ruis an optionally substituted C1-C4 alkyl, butyl, tert-butyl, iso-butyl, propyl, iso-propyl, ethyl or methyl. In certain embodiments, one or more of RaA, R5, R5A, R6, R6A, R7, R7A, R8, R8A, R9and R9Ais - C(O)OH and in certain instances at least R7is -C(O)OH.

[0066] In certain embodiments for which Y contains an optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl or optionally substituted heterocycloalkyl of Formula B1 , C1 , D1 or E1 , one or more of R^, R5, R5A, R6, R6A, R7, R7A, R8, R8A, R9and R9Ais an optionally substituted C1-C4 haloalkyl, or a trifluoromethyl. In certain instances, one or two of R6, R7and R8each is, or R8is, an optionally substituted C1-C4 haloalkyl, or a trifluoromethyl.

[0067] In certain embodiments for which Y contains an optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl or optionally substituted heterocycloalkyl of Formula B1 , C1 , D1 or E1 , one or more of R^, R5, R5A, R6, R6A, R7, R7A, R8, R8A, R9and R9Ais an optionally substituted C1-C4 hydroxyalkyl or hydroxymethyleneyl. In certain instances, one or two of R6, R7and R8each is an optionally substituted C1 -C4 hydroxyalkyl or hydroxymethyleneyl.

[0068] In certain embodiments, one of RaA, R5, R5A, R6, R6A, R7, R7A, R8, R8A, R9and R9Ais a substituted heterocycloalkyl, substituted heterocycloalkylalkyl, unsubstituted heterocycloalkyl or unsubstituted heterocycloalkylalkyl. In certain instances, one of R3*, R5, R5A, R6, R6A, R7, R7A, R8, R8A, R9and R9Ais a substituted heterocycloalkylalkyl containing 5 or 6 ring atoms. In certain instances, one of R^, R5, R5A, R6, R6A, R7, R7A, R8, R8A, R9and R9Ais a substituted heterocycloalkylalkyl containing 6 ring atoms and the alkyl attached to the heterocycloalkyl group is an unsubstituted C1 -C4 alkylene, ethylene or methylene. In certain instances, one of RaA, R5, R5A, R6, R6A, R7, R7A, R8, R8A, R9and R9Acontains a substituted piperazinyl or piperidinyl and the alkyl attached to the heterocycloalkyl group is an unsubstituted ethylene or methylene. In certain instances, one of RaA, R5, R5A, R6, R6A, R7, R7A, R8, R8A, R9and R9Ais, or R7is:

[0069] In certain embodiments, one of RaA, R5, R5A, R6, R6A, R7, R7A, R8, R8A, R9and R9Ais a substituted heteroaryl, substituted heteroarylalkyl, unsubstituted heteroaryl or unsubstituted heteroarylalkyl. In certain instances, one of RaA, R5, R5A, R6, R6A, R7, R7A, R8, R8A, R9and R9Ais a substituted heteroaryl or unsubstituted heteroaryl each containing 5 or 6 ring atoms. In certain instances, one of R^, R5, R5A, R6, R6A, R7, R7A, R8, R8A, R9and R9Ais a substituted heteroaryl containing 5 ring atoms. In certain instances, one of RaA, R5, R5A, R6, R6A, R7, R7A, R8, R8A, R9and R9Ais a substituted pyrrolyl, substituted imidazolyl, or substituted pyrazolyl. In certain instances, one of R^, R5, R5A, R6, R6A, R7, R7A, R8, R8A, R9and R9Ais, or R6is:

[0070] In certain embodiments pertaining to a compound of Formula A1 -1 , Formula A1 -2, Formula A1 - 5, Formula A1 -6, Formula A2-1 or Formula A2-3, one, two, three or four of R5, R6, R8and R9each is hydrogen.

[0071] In certain embodiments for which Y contains an optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl or optionally substituted heterocycloalkyl of Formula B1 , C1 , D1 or E1 , one or more of R5, R5A, R6, R6A, R7, R7A, R8, R8A, R9and R9Ais a Formula F group defined for Formula A1 and Formula A2. In certain embodiments, R7is a Formula F group defined for Formula A1 and Formula A2.

[0072] In certain embodiments, Y is a Formula F group defined for a compound of Formula A1 and Formula A2. In certain embodiments, Y is -N(Rb)-CH2-RYand RYis a Formula F group defined for Formula A1 and Formula A2. In certain embodiments, Y is -N(Ra)Rb, Rais a Formula F group and Rbis hydrogen, optionally substituted C1 -C6 alkyl, optionally substituted C1 -C4 alkyl, butyl, tert-butyl, iso-butyl, propyl, iso-propyl, ethyl or methyl. In certain embodiments, Y is -N(Rb)C(O)- RV-RYand RYis a Formula F group defined for Formula A1 and Formula A2. In certain instances, Rvis an optionally substituted C1 -C4 alkylene, -CH2CH2- or -CH2-. In certain instances, Rbis hydrogen, optionally substituted C1 -C4 alkyl, butyl, tert-butyl, iso-butyl, propyl, iso-propyl, ethyl or methyl.

[0073] In certain embodiments pertaining to a compound that contains a Formula F group:

[0074] Z1is an optionally substituted piperidinyl, optionally substituted piperazinyl or optionally substituted morpholinyl;

[0075] Z1is an unsubstituted piperidinyl, unsubstituted piperazinyl or unsubstituted morpholinyl;

[0076] Z1is a substituted piperidinyl, substituted piperazinyl or substituted morpholinyl containing one or more C1-C6 alkyl substituents, or containing one or more C1 -C4 alkyl substituents, or containing one or more ethyl or methyl substituents, or containing one methyl substituent;

[0077] Xais C(R43)R43A; Xbis C(R44)R44A; Xcis N-R45B; Xdis C(R46)R46A; and Xeis C(R47)R47A;

[0078] Xais C(R43)R43A; Xbis C(R44)R44A; Xcis O; Xdis C(R46)R46A; and Xeis C(R47)R47A;

[0079] Xais C(R43)R43A; Xbis C(R44)R44A; Xcis C(R45)R45A; Xdis C(R46)R46A; and Xeis C(R47)R47A; R43, R44, R45, R46, R47, R43A, R44A, R45A, R46Aand R47Aeach independently is hydrogen, optionally substituted C1 -C6 alkyl, optionally substituted C1 -C6 alkoxy, optionally substituted C1 -C6 heteroalkyl, optionally substituted C1 -C6 haloalkyl, optionally substituted C1 -C6 deuteroalkyl, optionally substituted C1-C6 alkylthio, optionally substituted C1 -C6 alkylamino, optionally substituted C1 -C6 hydroxyalkyl, optionally substituted C1 -C6 mercaptoalkyl, optionally substituted C1 -C6 aminoalkyl;

[0080] R45Bis hydrogen, optionally substituted C1 -C6 alkyl, optionally substituted C1 -C6 heteroalkyl, optionally substituted C1-C6 haloalkyl, optionally substituted C1 -C6 deuteroalkyl, optionally substituted C1 -C6 hydroxyalkyl, optionally substituted C1 -C6 mercaptoalkyl, optionally substituted C1 -C6 aminoalkyl;

[0081] R43, R44, R45, R46, R47, R43A, R44A, R45A, R46Aand R47Aeach independently is hydrogen, unsubstituted C1 -C4 alkyl, Cl, F, CF3, CD3, unsubstituted C1 -C4 alkoxy, methoxy, isopropyloxy or dimethylamino;

[0082] R43, R44, R45, R46, R47, R43A, R44A, R45A, R46A, R47Aand R45Beach independently is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1 -C4 alkyl, ethyl or methyl;

[0083] R43, R44, R45, R46, R47, R43A, R44A, R46Aand R47Aeach is hydrogen and R45Aand R45Beach is hydrogen or optionally substituted C1 -C6 alkyl, optionally substituted C1 -C4 alkyl, ethyl or methyl;

[0084] R43, R44, R45, R46, R47, R43A, R44A, R4SAand R47Aeach is hydrogen and R45Aand R45Bis methyl; and / or the Formula F group is:

[0085] In certain embodiments, Y is -N(Rb)C(O)-RYor -N(Rb)C(O)-Rv-RYand RYis hydrogen, optionally substituted alkyl, optionally substituted alkynyl, optionally substituted alkoxy, optionally substituted heteroalkyl, optionally substituted haloalkyl, optionally substituted deuteroalkyl, optionally substituted hydroxyalkyl, optionally substituted mercaptoalkyl or optionally substituted aminoalkyl, and Rvand Rbare as defined for Formula A1 and Formula A2. In certain instances, Rvis an optionally substituted C1 -C4 alkylene, -CH2CH2- or -CH2-. In certain instances, Rbis hydrogen or optionally substituted C1 -C4 alkyl, ethyl or methyl. In certain instances, RYis an optionally substituted C1-C6 alkyl, optionally substituted C1 -C4 alkyl, butyl, tert-butyl, iso-butyl, propyl, iso-propyl, ethyl or methyl. In certain instances, RYis an optionally substituted C1 -C6 alkynyl, optionally substituted C1 -C4 alkynyl or -C=CH.

[0086] In certain embodiments, Y is -N(Rb)C(O)-RYor -N(Rb)C(O)-Rv-RY, RYis an optionally substituted alkenyl, and Rvand Rbare as defined for Formula A1 and Formula A2. In certain instances RYis -CH=CH2, and optionally is subject to a limitation defined herein. In certain embodiments, Y is -N(Ra)C(O)-Rv-N(Rb)RY; Ra, Rband Rvare as defined for Formula A1 and Formula A2, and RYis hydrogen or optionally substituted alkyl. In certain instances, RYis hydrogen, substituted C1 -C4 alkyl, unsubstituted C1 -C4 alkyl, butyl, tert-butyl, iso-butyl, propyl, iso-propyl, ethyl or methyl. In certain instances, Rvis an optionally substituted C1 -C4 alkylene, optionally substituted C1-C3 alkylene, -CH2CH2- or -CH2-. In certain instances, Rbis hydrogen or optionally substituted C1 -C4 alkyl, butyl, tert-butyl, iso-butyl, propyl, iso-propyl, ethyl or methyl.

[0087] In certain embodiments, Y is -N(Ra)Rband Raand Rbeach is hydrogen.

[0088] R10, R11, R12and R13substituents

[0089] In certain embodiments, at least one of, or one of, R10, R11, R12and R13is Rwor -W-Rw, and Rwis as defined for Formula A1 and Formula A2. In certain embodiments, R10is Rwor -W-Rwand R11, R12and R13each is not Rwor -W-Rw; or R11is Rwor -W-Rwand R10, R12and R13each is not Rwor -W-Rw; or R12is Rwor -W-Rwand R10, R11and R13each is not Rwor -W-Rw; or R13is Rwor -W-Rwand R10, R11and R12each is not Rwor -W-Rw. In certain instances, none of R10, R11, R12and R13is Rwor -W-Rw.

[0090] For embodiments in which R10, R11, R12or R13is not Rwor -W-Rw, the R10, R11, R12and R13that is not Rwor -W-Rweach independently can be hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkoxy, optionally substituted heteroalkyl, optionally substituted haloalkyl, optionally substituted deuteroalkyl, optionally substituted alkylthio, optionally substituted alkylamino, optionally substituted hydroxyalkyl, optionally substituted mercaptoalkyl, optionally substituted aminoalkyl, -C(O)RZ, - C(O)OH, -C(O)ORU, -B(OH)2, hydroxy, halo, cyano, nitro, amino or amido.

[0091] For embodiments in which R10, R11, R12or R13is not Rwor -W-Rw, the R10, R11, R12and R13that is not Rwor -W-Rweach independently can be hydrogen, optionally substituted C1 -C6 alkyl, optionally substituted C1-C6 alkoxy, optionally substituted C1 -C6 heteroalkyl, optionally substituted C1 -C6 haloalkyl, optionally substituted C1 -C6 deuteroalkyl, optionally substituted C1 -C6 alkylthio, optionally substituted C1 -C6 alkylamino, optionally substituted C1 -C6 hydroxyalkyl, optionally substituted C1 -C6 mercaptoalkyl, optionally substituted C1 -C6 aminoalkyl, R9C(O)N(Rh)-, -C(O)N(R9Rh), -NRRk, -C(O)RZ, -C(O)OH, -C(O)ORU, hydroxy, halo, cyano or nitro; and R9, Rh, R and Rkeach independently is hydrogen or optionally substituted C1 -C6 alkyl. In certain instances, R9, Rh, R' and Rkeach independently is hydrogen, optionally substituted C1 -C4 alkyl, butyl, iso-butyl, tert-butyl, propyl, isopropyl, ethyl or methyl. In certain embodiments, Ruis an optionally substituted C1 -C4 alkyl, butyl, iso-butyl, tert-butyl, propyl, isopropyl, ethyl or methyl.

[0092] For embodiments in which R10, R11, R12or R13is not Rwor -W-Rw, the R10, R11, R12and R13that is not Rwor -W-Rweach independently can be hydrogen, optionally substituted C1 -C4 alkyl, optionally substituted C1-C4 alkoxy, ethyl, ethoxy, methyl, methoxy, chloro, fluoro, bromo, iodo, CFs or CDs. In certain instances, one of R10, R11, R12and R13is Rwor -W-Rw, and one, two or three of R10, R11, R12and R13that is not Rwor -W-Rweach is hydrogen.

[0093] In certain embodiments, W is -CH2-, -C=C-, -NH(R’)-, -O-, -S-, -S(O)- or -SO2-, and R* is hydrogen or optionally substituted C1 -C6 alkyl, optionally substituted C1 -C4 alkyl, ethyl or methyl, and Rwis as defined herein for a compound of Formula A1 and Formula A2.

[0094] In certain embodiments, at least one of, or one of, R10, R11, R12and R13is Rwor -W-Rw, and Rwcontains or is an optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl or optionally substituted heteroarylalkyl. In certain instances, an optionally substituted arylalkyl comprises an optionally substituted alkylene (for example, an optionally substituted C1 - C6 alkylene), linked to an optionally substituted aryl. In certain embodiments, an optionally substituted heteroarylalkyl comprises an optionally substituted alkylene (for example, an optionally substituted C1-C6 alkylene), linked to an optionally substituted heteroaryl. In certain instances, Rwcontains an optionally substituted aryl or optionally substituted heteroaryl according to Formula B2: Formula B2 where: Z2ais aryl or heteroaryl; X1aindependently is C or N; X2aindependently is C-R14, N-R14Bor N; X3aindependently is C-R15, N-R15Bor N; X4aindependently is C-R16, N-R16Bor N; X5aindependently is C-R17, N-R17Bor N; and X6aindependently is C-R18, N-R18Bor N; and optionally two adjacent R14, R15, R16, R17, R18, R14B, R15B, R16B, R17Band R18Bare linked in an optionally substituted aryl or optionally substituted heteroaryl.

[0095] In certain embodiments pertaining to Formula B2, Z2ais an optionally substituted pyridinyl, optionally substituted pyrimidinyl, optionally substituted pyrazinyl, optionally substituted pyridazinyl or optionally substituted triazinyl. In certain embodiments pertaining to Formula B2, X1ais C, X2ais C-R14, X3ais C-R15, X4ais C-R16, X5ais C-R17and X6ais C-R18. In certain embodiments pertaining to Formula B2, X1ais C, X2ais C-R14, X3ais N, X4ais C-R16, X5ais C-R17, and X6ais C-R18. In certain embodiments pertaining to Formula B2, X1ais C, X2ais N, X3ais C- R15, X4ais N, X5ais C-R17, and X6ais C-R18. In certain embodiments pertaining to Formula B2, X1ais C, X2ais C-R14, X3ais N, X4ais C-R16, X5ais N, and X6ais C-R18. In certain embodiments pertaining to Formula B2, X1ais C, X2ais C-R14, X3ais C-R15, X4ais N, X5ais C-R17and X6ais C- R18.

[0096] In certain embodiments pertaining to Formula B2, X1ais C, X2ais C-R14, X3ais C-R15, X4ais C- R16, X5ais C-R17and X6ais C-R18, and R16and R17together are joined as a fused optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl or optionally substituted heterocycloalkyl containing five ring member atoms. In certain embodiments pertaining to Formula B2, X1ais C, X2ais C-R14, X3ais N, X4ais C-R16, X5ais C-R17, and X6ais C- R18, where the X3anitrogen and R16together are joined as a fused optionally substituted aryl or optionally substituted heteroaryl containing five ring member atoms. In certain instances, the fused ring is an optionally substituted heteroaryl containing five ring atoms, and in certain instances, the fused ring is an optionally substituted pyrrolyl or oxazolyl. In certain embodiments, Rwis an optionally substituted benzo-oxazolyl group or an optionally substituted benzo[d]oxazol-5-yl group. In certain instances,

[0097] Rwis an optionally substituted indolyl group or optionally substituted 1 H-indol-5-yl group. In certain instances, Rwis an optionally substituted imidazo-pyridinyl group or an optionally substituted imidazo[1 ,2-a]pyridin-6-yl group. In certain instances, a compound includes a Rwsubstituent of Cmpd 34, Cmpd 38 or Cmpd 40 illustrated in Table A.

[0098] In certain embodiments, at least one of, or one of, R10, R11, R12and R13is Rwor -W-Rw, and Rwcontains or is an optionally substituted aryl or optionally substituted heteroaryl according to Formula B3: Formula B3 where: Z2bis aryl or heteroaryl; X1b, X2b, X3b, X4b, Xaand X6beach independently is C or N; R14, R15, R16, R17, and R18each are as defined herein; and optionally two adjacent R14, R15, R16, R17, and R18are linked in an optionally substituted aryl or optionally substituted heteroaryl. In certain embodiments pertaining to Formula B3, one of X1b, X2b, X3b, X4b, X5band X6bis N; or two of X1b, X2b, X3b, X4b, X5band X6bare N; or three of X1b, X23, X3b, X4b, X5band X6bare N; or four of X1b, X2b, X3b, X4b, X5band X6bare N. In certain instances pertaining to Formula B3, Z2bis aryl and each of X1b, X2b, X3b, X4b, X5band X6bis C.

[0099] In certain embodiments, at least one of, or one of, R10, R11, R12and R13is Rwor -W-Rw, and Rwcontains or is an optionally substituted aryl or optionally substituted heteroaryl according to Formula C2: where: Z3ais aryl or heteroaryl; X7aindependently is C or N; X8aindependently is C-R19, N-R19B, N, O, S, S(O) or SO2; X9aindependently is C-R20, N- R20B, N, O, S, S(O) or SO2; X10aindependently is C-R21, N- R21 B, N, O, S, S(O) or SO2; and X11 aindependently is C-R22, N- R22B, N, O, S, S(O) or SO2; and optionally two adjacent R19, R20, R21, R22, R19B, R20B, R21 Band R22Bare linked in an optionally substituted aryl or optionally substituted heteroaryl.

[0100] In certain embodiments pertaining to Formula C2, Z3ais an optionally substituted pyrrolyl, optionally substituted imidazolyl, optionally substituted pyrazolyl, optionally substituted puranyl, optionally substituted thiophenyl, optionally substituted oxazolyl, optionally substituted thiazolyl, optionally substituted isoxazolyl or optionally substituted isothiazolyl. In certain embodiments pertaining to Formula C2, X7ais C; X8ais N or N-R19B; X9ais N or N-R20B; X10ais C-R21; and X11ais C-R22. In certain embodiments pertaining to Formula C2, X7ais C; X8ais N or N-R19B; X9ais C- R2°. x10ais C-R21; and X11ais C-R22. In certain embodiments pertaining to Formula C2, X7ais C; X8ais N or N- R19B; X9ais C-R20; X10ais C-R21; and X11ais N or N- R22B. In certain embodiments pertaining to Formula C2, X7ais C; X8ais N; X9ais C-R20; X10ais C-R21; and X11ais S. In certain embodiments pertaining to Formula C2, X7ais C; X8ais N; X9ais C-R20; X10ais O; and X11ais C- R22.

[0101] In certain embodiments pertaining to Formula C2, X7ais C; X8ais N or N-R19B; X9ais C-R20; X10ais C-R21; and X11ais C-R22and R20and R21together are joined as a fused optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl or optionally substituted heterocycloalkyl containing six ring member atoms. In certain instances, the fused ring is an optionally substituted heteroaryl containing five ring atoms, and in certain instances, the fused ring is an optionally substituted aryl or heteroaryl containing six ring atoms. In certain instances, the fused ring is an optionally substituted phenyl. In certain embodiments, Rwis an optionally substituted indolyl group or an optionally substituted 1 H-indol-2-yl group. In certain instances, a compound includes a Rwsubstituent of Cmpd 33 illustrated in Table A.

[0102] In certain embodiments, at least one of, or one of, R10, R11, R12and R13is Rwor -W-Rw, and Rwcontains or is an optionally substituted aryl or optionally substituted heteroaryl according to Formula C3: Formula C3 where: Z3bis aryl or heteroaryl; X7b, X8b, X9b, X10band X11beach independently is C, N, O or S;

[0103] R19, R20, R21and R22each is as defined herein; and optionally two adjacent R19, R20, R21and R22are linked in an optionally substituted aryl or optionally substituted heteroaryl. In Formula C3, each of R19, R20, R21and R22optionally is present and presence or absence is determined by the associated ring member atom X8b, X9b, X10band X11b. For embodiments in which ring member atom X8b, X9b, X10bor X11bis C or N, the R group shown in Formula C3 as bonded to the ring member atom is present or optionally present or not present. For example, where X8bis C or N, R19can be present; where X9bis C or N, R20can be present; where X10bis C or N, R21can be present; and where X11bis C or N, R22can be present. In certain embodiments, one of X7b, X8b, X9b, X10band X11 bis N; or two of X7b, X8b, X9b, X10band X11bare N; or three of X713, X8b, X9b, X10band X11bare N; or four of X7b, X8b, X9b, X10band X11bare N. In certain embodiments, one of X7b, X8b, X9b, X10band X11bis N and the others are C; or two of X7b, X8b, X9b, X10band X11 bare N and the others are C; or three of X7b, X8b, X9b, X10band X, 1bare N and the others are C; or four of X7b, X8b, X9b, X10band X11bare N and the other is C. For embodiments in which ring member atom X8b, X9b, X10bor X11bis O or S, the R group shown in Formula C3 as bonded to the ring member atom can be absent. For example, where X8bis O or S, R19can be absent; where X9bis O or S, R20can be absent; where X10bis O or S, R21bcan be absent; and where X11 bis O or S, R22can be absent. For embodiments in which ring member atom X8b, X9b, X10bor X11 bis S, the S may be in a reduced state (S) or an oxidized state (S(O) or SO2). In certain embodiments, one of X8b, X9b, X10band X11bis O or S; or two of X8b, X9b, X10band X11bare O or S; or three of X8b, X9b, X10band X11bare O or S. In certain embodiments, one of X8b, X9b, X10band X11bis O or S and the others are C; or two of X8b, X9b, X10band X11bare O or S and the others are C; or three of X8b, X9b, X10band X11bare O or S and the other is C. In certain embodiments, zero, one or two of X7b, X8b, X9b, X10band X11bis N and X7b, X8b, X9b, X10band X11bthat are not N are C. In certain instances, Z3bis heteroaryl; X7b, X10band X11beach is C, and one of X8band X9bis N and the other is C. In certain embodiments, X8band X9beach is N.

[0104] In certain embodiments, at least one of, or one of, R10, R11, R12and R13is Rwor -W-Rw, and Rwcontains or is an optionally substituted cycloalkyl, optionally substituted cycloalkylalkyl, optionally substituted heterocycloalkyl or an optionally substituted heterocycloalkylalkyl. In certain embodiments, Rwis an optionally substituted cycloalkylalkyl comprising an optionally substituted alkylene, for example an optionally substituted C1 -C6 alkylene, linked to an optionally substituted cycloalkyl. In certain embodiments, Rwis an optionally substituted heterocycloalkylalkyl comprising an optionally substituted alkylene, for example an optionally substituted C1 -C6 alkylene, linked to an optionally substituted heterocycloalkyl. In certain embodiments, Rwcontains an optionally substituted cycloalkyl or optionally substituted heterocycloalkyl according to Formula D2: Formula D2 where: Z4ais cycloalkyl or heterocycloalkyl; X12ais C-RaB, C or N; X13aindependently is C(R14)R14A, C-R14, N-R14B, N, O, S, S(O) or SO2; X14aindependently is C(R15)R15A, C-R15, N-R15B, N, O, S, S(O) or SO2; X15aindependently is C(R16)R16A, C-R16, N-R16B, N, O, S, S(O) or SO2; X16a independently is C(R17)R17A, C-R17, N-R17B, N, O, S, S(O) or SO2; and X17aindependently is C(R18)R18A, C-R18, N-R18B, N, O, S, S(O) or SO2; R14, R15, R16, R17, R18, R14A, R15A, R16A, R17A, Ri5Bj RBJ R17Banc|R18Bare asdef jnec| herein; and optionally two adjacent R14, R15, R16, R17, R18, R14A, R15A, R16A, R17A, R18A, R14B, R15B, R16B, R17Band R18Bare linked and joined in an optionally substituted cycloalkyl or optionally substituted heterocycloalkyl. In certain embodiments, Rwis an optionally substituted heterocycloalkyl or an optionally substituted heterocycloalkylalkyl of which the optionally substituted heterocycloalkyl contains 4, 5 or 6 ring atoms. In certain instances, Rwcontains an optionally substituted piperidinyl, optionally substituted piperazinyl, optionally substituted tetrahydropyran, or optionally substituted morpholinyl, optionally substituted pyrrolidinyl, optionally substituted imidazolidinyl, optionally substituted pyrazolidinyl or optionally substituted azetidinyl. In certain instances, Rwcontains a substituted heterocycloalkyl containing 4, 5 or 6 ring atoms, which sometimes is a C1 -C6 alkyl substituted heterocycloalkyl, a methyl substituted heterocycloalkyl or a mono-methyl substituted heterocycloalkyl.

[0105] In certain instances pertaining to Formula D2, Z4ais an optionally substituted piperidinyl, optionally substituted piperazinyl, optionally substituted morpholinyl or optionally substituted tetrahydropyridinyl. In certain instances pertaining to Formula D2, X12ais C; X13ais C-R14; X14ais C(R15)R15A; X15ais N-R16B; X16ais C(R17)R17A; and X17ais C(R18)R18A. In certain instances pertaining to Formula D2, X12ais N; X13ais C(R14)R14A; X14ais C(R15)R15A; X15ais N-R16B; X16ais C(R17)R17A; and X17ais C(R18)R18A. In certain instances pertaining to Formula D2, X12ais N; X13ais C(R14)R14A; X14ais C(R15)R15A; X15ais C(R16)R16A; X16ais C(R17)R17A; and X17ais C(R18)R18A. In certain embodiments pertaining to Formula D2, X12ais C-RaB; X13ais C(R14)R14A; X14ais C(R15)R15A; X15ais N-R16B; X16ais C(R17)R17Aand X17ais C(R18)R18A. In certain instances pertaining to Formula D2, X12ais C-RaB; X13ais C(R14)R14A; X14ais C(R15)R15A; X15ais O; X16ais C(R17)R17A; and X17ais C(R18)R18A.

[0106] In certain embodiments, at least one of, or one of, R10, R11, R12and R13is Rwor -W-Rw, and Rwcontains or is an optionally substituted cycloalkyl or optionally substituted heterocycloalkyl according to Formula D3: Formula D3 where: Z4bis cycloalkyl or heterocycloalkyl; X12bis C or N; X13b, X14b, X15b, X16band X17beach independently is C, N, O or S; R14, R15, R16, R17, R18, R14A, R15A, R16A, R17Aand R18Aare as defined herein; and optionally and optionally two adjacent R14, R15, R16, R17, R18, R14A, R15A, R16A, R17Aand R18Aare linked and joined in an optionally substituted cycloalkyl or optionally substituted heterocycloalkyl. In Formula D3, each of RaB, R14, R15, R16, R17, R18, R14A, R15A, R16A, R17Aand R18Ais an optionally present and presence or absence is determined by the associated ring member atom X12b, X13b, X14b, X15b, X16band X17b. For embodiments in which ring member atom X12b, X13b, X14b, X15b, X16band X17bis C, R groups shown in Formula D3 as bonded to the ring member atom may be present (e.g., both are present when ring Z4bis a saturated ring). For example, where X12bis C, RaBmay be present; where X13bis C, R14and R14Amay be present; where X14bis C, R15and R15Amay be present; where X15bis C, R16and R16Amay be present; where X16bis C, R17and R17Amay be present; or where X17bis C, R18and R18Amay be present. For embodiments in which ring member atom X12b, X13b, X14b, X15b, X16bor X17bis N, an R group shown in Formula D3 as bonded to the ring member atom may be absent. For example, where X12bis N, RaBmay be absent; X13bis N, R14or R14Amay be absent; where X14bis N, R15or R15Amay be absent; where X15bis N, R16or R16Amay be absent; where X16bis N, R17or R17Amay be absent; or where X17bis N, R18or R18Amay be absent. In certain embodiments, one of X12b, X13b, X14b, X15b, X16band X17bis N; or two of X12b, X13b, X14b, X15b, X16band X17bare N; or three of X12b, X13b, x14b, X15b, X16band X17bare N; or four of X12b, X13b, X14b, X15b, X16band X17bare N. In certain embodiments, one of X12b, X13b, X14b, X15b, X16band X17bis N and the others are C; or two of X12b, X13b, x14b, X15b, X16band X17bare N and the others are C; or three of X12b, X13b, X14b, X15b, X16band X17bare N and the others are C; or four of X12b, X13b, X14b, X15b, X16band X17bare N and the others are C. For embodiments in which ring member atom X13b, X14b, X15b, X16bor X17bis O or S, both R groups shown in Formula D3 as bonded to the ring member atom may be absent. For example, where X13bis O or S, R14and R14Amay be absent; where X14bis O or S, R15and R15Amay be absent; where X15bis O or S, R16and R16Amay be absent; where X16bis O or S, R17and R17Amay be absent; and where X17bis O or S, R18and R18Amay be absent. For embodiments in which ring member atom X13b, X14b, X15b, X16band X17bis S, the S may be in a reduced state (S) or an oxidized state (S(O) or SO2). In certain embodiments, one of X13b, X14b, X15b, X16band X17bis O or S; or two of X13b, X14b, X15b, X16band X17bare or S; or three of X13b, X14b, X15b, X16band X17bare O or S; or four of X13b, X14b, X15b, X16band X17bare O or S. In certain embodiments, one of X13b, X14b, X15b, X16band X17bis O or S and the others are C; or two of X13b, X14b, X15b, X16band X17bare O or S and the others are C; or three of X13b, X14b, X15b, X16band X17bare O or S and the others are C; or four of X13b, X14b, X15b, X16band X17bare O or S and the others are C. In certain embodiments, zero, one or two of X12b, X13b, X14b, X15b, X16band X17bin Formula D3 is N and X12b, X13b, X14b, X15b, X16band X17bthat are not N are C. In certain instances, Z3is cycloalkyl and each of X12b, X13b, X14b, X15b, X16band X17bis C.

[0107] In certain embodiments, at least one of, or one of, R10, R11, R12and R13is Rwor -W-Rw, and Rwcontains or is an optionally substituted cycloalkyl or optionally substituted heterocycloalkyl of Formula E2: Formula E2 where: Z5ais cycloalkyl or heterocycloalkyl; X18ais C-RaB, C or N; X19aindependently is C(R19)R19A, C-R19, N-R19B, N, O, S, S(O) or SO2; X20aindependently is C(R20)R20A, C-R20, N-R20B, N, O, S, S(O) or SO2; X21 aindependently is C(R21)R21 A, C-R21, N-R21 B, N, O, S, S(O) or SO2; and X22aindependently is C(R22)R22A, C-R22, N-R22B, N, O, S, S(O) or SO2; RaB, R19, R19A, R20, R20A, R21, R21 A, R22, R22A, R19B, R20B, R21 Band R22Bare as defined herein; and optionally two adjacent RaB, R19, R19A, R20, R20A, R21, R21A, R22, R22A, R19B, R20B, R21 Band R22Bare linked in an optionally substituted cycloalkyl or optionally substituted heterocycloalkyl. In certain embodiments pertaining to Formula E2, Z5ais an optionally substituted pyrazolidinyl, optionally substituted imidazolidinyl or optionally substituted pyrazolidinyl. In certain embodiments pertaining to Formula E2, X18ais C-RaB; X19ais N-R, 9B; X20ais C(R20)R20A; X21 ais C(R21)R21A; and X22ais C(R22)R22A.

[0108] In certain embodiments, at least one of, or one of, R10, R11, R12and R13is Rwor -W-Rw, and Rwcontains or is an optionally substituted cycloalkyl or optionally substituted heterocycloalkyl of Formula E3: Formula E3 where: Z5bis cycloalkyl or heterocycloalkyl; X18bis C or N; X19b, X20b, X21 band X22beach independently is C, N, O or S; RaB, R19, R19A, R20, R20A, R21, R21A, R22and R22Aare as defined herein; and optionally two adjacent RaB, R19, R19A, R20, R20*, R21, R21 A, R22and R22Aare linked in an optionally substituted cycloalkyl or optionally substituted heterocycloalkyl. In Formula E3, each of RaB, R19, R19A, R20, R20A, R21, R21 A, R22and R22Aoptionally is present and presence or absence is determined by the associated ring member atom X18b, X19b, X20b, X21 band X22b. For embodiments in which ring member atom X18b, X19b, X20b, X21 bor X22bis C, R groups shown in Formula E3 as bonded to the ring member atom may be present (e.g., both are present when ring Z5bis a saturated ring). For example, where X18bis C, RaBmay be present; where X19bis C, R19and R19Amay be present; where X20bis C, R20and R20Amay be present; where X21 bis C, R21and R21 Amay be present; or where X22bis N, R22and R22Amay be present. For embodiments in which ring member atom X18b, X19b, X20b, X21 bor X22bis N, an R group shown in Formula E as bonded to the ring member atom may be absent. For example, where X18bis N, RaBmay be absent; where X19bis N, R19or R19Amay be absent; where X20bis N, R20or R20Amay be absent; where X21bis N, R21or R21Amay be absent; or where X22bis N, R22or R22Amay be absent. In certain embodiments, one of X18b, X19b, X20b, X21band X22bis N; or two of X18b, X19b, X20b, X21band X22bare N; or three of X18b, X19b, X20b, X21band X22bare N; or four of X18b, X19b, X20b, X21band X22bare N. In certain embodiments, one of X18b, X19b, X20b, X21band X22bis N and the others are

[0109] C; or two of X18b, X19b, X20b, X21band X22bare N and the others are C; or three of X18b, X19b, X20b,

[0110] X21 band X22bare N and the others are C; or four of X18b, X19b, X20b, X21band X22bare N and the others are C. For embodiments in which ring member atom X18b, X19b, X20b, X21bor X22bis O or

[0111] S, R groups shown in Formula E3 as bonded to the ring member atom may be absent. For example, where X19bis O or S, R19and R19Amay be absent; where X20bis O or S, R20and R20Amay be absent; where X21bis O or S, R21and R21Amay be absent; or where X22bis O or S, R22and R22Amay be absent. For embodiments in which ring member atom X19b, X20b, X21bor X22bis

[0112] S, the S may be in a reduced state (S) or an oxidized state (i.e., S(O) or SO2). In certain embodiments, one of X19b, X20b, X21band X22bis O or S; or two of X19b, X20b, X21band X22bare O or S; or three of X19b, X20b, X21band X22bare O or S. In certain embodiments, one of X19b, X20b,

[0113] X21 band X22bis O or S and the others are C; or two of X19b, X20b, X21band X22bare O or S and the others are C; or three of X19b, X20b, X21band X22bare O or S and the others are C. In certain embodiments, zero, one or two of X18b, X19b, X20b, X21band X22bin Formula E3 is N and X18b,

[0114] X19b, X20b, X21band X22bthat are not N are C. In certain instances, Z5bis an optionally substituted cycloalkyl and X18b, X19b, X20b, X21band X22beach is C.

[0115] In certain embodiments, a compound contains a Rwgroup according to Formula B2, Formula C2, Formula D2, Formula E2, Formula B3, Formula C3, Formula D3 or Formula E3, and R14, each independently is hydrogen optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alky nyl, optionally substituted alkoxy, optionally substituted heteroalkyl, optionally substituted haloalkyl, optionally substituted deuteroalkyl, optionally substituted alkylthio, optionally substituted alkylamino, optionally substituted hydroxyalkyl, optionally substituted mercaptoalkyl, optionally substituted aminoalkyl, -C(O)RZ, -C(O)OH, -C(O)ORU, hydroxy, halo, cyano, nitro, amino, amido, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted arylaminoalkyl, optionally substituted aryloxyalkyl, optionally substituted arylthioalkyl, optionally substituted heteroarylaminoalkyl, optionally substituted heteroaryloxyalkyl, optionally substituted heteroarylthioalkyl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl; and

[0116] R14B, RISB, R16B pi7B, piss p>i 9B, R2OB, R2I Banc| R22Beach independently is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heteroalkyl, optionally substituted haloalkyl, optionally substituted deuteroalkyl, optionally substituted hydroxyalkyl, optionally substituted mercaptoalkyl, optionally substituted aminoalkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted arylaminoalkyl, optionally substituted aryloxyalkyl, optionally substituted arylthioalkyl, optionally substituted heteroarylaminoalkyl, optionally substituted heteroaryloxyalkyl, optionally substituted heteroarylthioalkyl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, or - C(O)ORU, where Ruis defined for Formula A1 .

[0117] In certain embodiments, a compound contains a Rwgroup according to Formula B2, Formula C2, Formula D2, Formula E2, Formula B3, Formula C3, Formula D3 or Formula E3, and R14, each independently is hydrogen, optionally substituted C1 -C6 alkyl, optionally substituted C1 - C6 alkoxy, optionally substituted C1 -C6 heteroalkyl, optionally substituted C1 -C6 haloalkyl, optionally substituted C1-C6 deuteroalkyl, optionally substituted C1 -C6 alkylthio, optionally substituted C1 -C6 alkylamino, optionally substituted C1 -C6 hydroxyalkyl, optionally substituted C1 -C6 mercaptoalkyl, optionally substituted C1 -C6 aminoalkyl, R9C(O)N(Rh)-, -C(O)N(R9Rh), - NRjRk, -C(O)RZ, -C(O)OH, -C(O)ORU, hydroxy, halo, cyano, nitro, optionally substituted C5-C6 cycloalkyl, optionally substituted heterocycloalkyl containing 5 or 6 ring member atoms; where R9, Rh, Rjand Rkeach independently is hydrogen or optionally substituted C1 -C6 alkyl. In certain instances, R9, Rh, R1and Rkeach independently is hydrogen, optionally substituted C1 - C4 alkyl, butyl, iso-butyl, tert-butyl, propyl, isopropyl, ethyl or methyl. In certain instances, Ruis an optionally substituted C1 -C4 alkyl, butyl, iso-butyl, tert-butyl, propyl, isopropyl, ethyl or methyl.

[0118] In certain embodiments, a compound contains a Rwgroup according to Formula B2, Formula C2, Formula D2, Formula E2, Formula B3, Formula C3, Formula D3 or Formula E3, and R14, R15 FR16 R17 R18 R14A R15A R16A R17A R18A aB R19 R19A p20 R20A p21 R21 A fR22 g|-|(j R22A each independently is hydrogen, optionally substituted C1 -C4 alkylamine, optionally substituted C1 -C4 hydroxyalkylamine, HO-CH2CH2-N(H)-, halo, fluoro, chloro, optionally substituted C1 -C4 alkyl, butyl, tert-butyl, iso-butyl, propyl, iso-propyl, ethyl, methyl, optionally substituted C1 -C4 alkoxy, substituted C1 -C4 alkoxy, unsubstituted benzyloxy, isopropyloxy, ethoxy, methoxy, nitro, -C(O)RZ, -C(O)ORUor -C(O)OH, where Rucan be optionally substituted C1-C6 alkyl, optionally substituted C1 -C4 alkyl, butyl, tert-butyl, iso-butyl, propyl, iso-propyl, ethyl or methyl. In certain instances, a compound contains a Rwgroup, the Rwgroup is an optionally substituted aryl or optionally substituted heteroaryl of Formula B2, and: R16is an optionally substituted C1 -C4 alkylamine, optionally substituted C1 -C4 hydroxyalkylamine, or HO-CH2CH2-N(H)-; R15or R16is halo, fluoro or chloro; one, two or three of R14, R16and R18is an optionally substituted C1 -C4 alkyl, ethyl, methyl, optionally substituted C1 -C4 alkoxy, isopropyloxy, ethoxy or methoxy; R16is hydroxy; R14is -C(O)H; R14is -C(O)RZ; R16is an optionally substituted C1 -C4 alkoxy, substituted C1 -C4 alkoxy, or unsubstituted benzyloxy; R15is nitro; and / or R17is -C(O)OH. In certain embodiments, a compound contains a Rwgroup according to Formula B2, Formula C2, Formula D2, Formula E2, Formula B3, Formula C3, Formula D3 or Formula E3, and R14, each independently is hydrogen, unsubstituted C1 -C4 alkyl, Cl, F, CF3, CD3, unsubstituted C1 - C4 alkoxy, methoxy, isopropyloxy or dimethylamino.

[0119] In certain embodiments, a compound contains a Rwgroup according to Formula B2, Formula C2, Formula D2, Formula E2, Formula B3, Formula C3, Formula D3 or Formula E3, and R14B, Ri se p>i 6B R17B piss R19B R2OB, p2i Banc| p>22B independently is hydrogen, optionally substituted C1 -C6 alkyl, optionally substituted C1 -C6 heteroalkyl, optionally substituted C1 -C6 haloalkyl, optionally substituted C1 -C6 deuteroalkyl, optionally substituted C1 -C6 hydroxyalkyl, optionally substituted C1-C6 mercaptoalkyl, optionally substituted C1 -C6 aminoalkyl, optionally substituted C5-C6 cycloalkyl, optionally substituted heterocycloalkyl containing 5 or 6 ring member atoms, or -C(O)ORU, where Ruis an optionally substituted C1 -C6 alkyl, optionally substituted C1 -C4 alkyl, butyl, tert-butyl, iso-butyl, propyl, iso-propyl, ethyl or methyl. In certain embodiments, a compound contains a Rwgroup according to Formula B2, Formula C2, Formula D2, Formula E2, Formula B3, Formula C3, Formula D3 or Formula E3, and R14B, R15B, R16B, RI7B, RISE p>i9B, R2OB R2I BANC| R22Beac|-| independently is hydrogen, optionally substituted C1 -C6 alkyl, optionally substituted C1 -C4 alkyl, butyl, tert-butyl, iso-butyl, propyl, iso-propyl, ethyl or methyl.

[0120] In certain embodiments, (i) one, two, three or four of R10, R11, R12and R13each is hydrogen, (ii) one, two or three of R15, R17and R18each is hydrogen, (iii) one or two of R14and R16each is hydrogen, and / or (iv) one or both of R21and R22each is hydrogen.

[0121] R1, R2, R3and R4substituents and other positions

[0122] In certain embodiments, R1, R2, R3and R4each independently is hydrogen, optionally substituted C1 -C6 alkyl, optionally substituted C1 -C6 alkoxy, optionally substituted C1 -C6 heteroalkyl, optionally substituted C1 -C6 haloalkyl, optionally substituted C1 -C6 deuteroalkyl, optionally substituted C1-C6 alkylthio, optionally substituted C1 -C6 alkylamino, optionally substituted C1 -C6 hydroxyalkyl, optionally substituted C1 -C6 mercaptoalkyl, optionally substituted C1 -C6 aminoalkyl, RPC(O)N(Rq)-, -C(O)N(RPRq), -NRrRs, -C(O)RZ, -C(O)OH, - C(O)ORU, hydroxy, halo, cyano or nitro; and Rp, Rq, Rrand Rseach independently is hydrogen or optionally substituted C1 -C6 alkyl. In certain instances, Rp, Rq, Rrand Rseach independently is hydrogen, optionally substituted C1 -C4 alkyl, butyl, iso-butyl, tert-butyl, propyl, isopropyl, ethyl or methyl. In certain embodiments, Ruis an optionally substituted C1 -C4 alkyl, butyl, iso-butyl, tert-butyl, propyl, isopropyl, ethyl or methyl. In certain embodiments, R1, R2, R3and R4each independently is hydrogen, optionally substituted C1 -C4 alkyl, optionally substituted C1 -C4 alkoxy, ethyl, ethoxy, methyl, methoxy, Cl, F, CF3or CD3. In certain instances, R1is hydrogen. In certain instances, one of R2, R3and R4is an optionally substituted C1 -C4 alkyl, optionally substituted C1 -C4 alkoxy, ethyl, ethoxy, methyl, methoxy, Cl, F, CF3or CD3, and the other two of R2, Ft3and R4are hydrogen.

[0123] In certain embodiments, R2is hydrogen, optionally substituted C1 -C4 alkyl, optionally substituted C1 -C4 deuteroalkyl, optionally substituted C1 -C4 haloalkyl, optionally substituted C1 -C4 alkylamino, halo or optionally substituted C1 -C4 alkoxy; or R2is hydrogen, unsubstituted C1 -C4 alkyl, unsubstituted C1 -C4 deuteroalkyl, unsubstituted C1 -C4 haloalkyl, unsubstituted C1 -C4 alkylamino, or halo; or R2is unsubstituted C1 -C4 alkoxy; or R2is hydrogen, unsubstituted C1 -C4 alkyl, Cl, F, CF3, CD3, unsubstituted C1 -C4 alkoxy, methoxy, isopropyloxy or dimethylamino; or R2is unsubstituted C1 -C4 alkyl, ethyl or methyl.

[0124] In certain instances, two, three or four of R1, R2, R3and R4are hydrogen. In certain instances, R2is methyl, ethyl, methoxy or ethoxy, and R1, R3and R4each is hydrogen. In certain instances, R3is methyl, ethyl, methoxy or ethoxy, and R1, R2and R4each is hydrogen. In certain instances, R4is methyl, ethyl, methoxy or ethoxy, and R1, R2and R3each is hydrogen.

[0125] Subgroups

[0126] In certain aspects, provided is a compound of the following Subgroup 1 , Subgroup 2, Subgroup 3, Subgroup 4, Subgroup 5, Subgroup 6, Subgroup 7, Subgroup 8, Subgroup 9, Subgroup 10, Subgroup 11 , Subgroup 12, Subgroup 13, Subgroup 14, Subgroup 15, Subgroup 16, Subgroup 17 and Subgroup 18.

[0127] Subgroup 1 : certain Formula A1-3 compounds

[0128] Provided in certain aspects is a compound of Formula A1 -3: Formula A1 -3 or a pharmaceutically acceptable salt, amide or ester thereof, where:

[0129] R1, R2, R3, R4, R11, R12, R13, R14, R15, R16, R17and R18each independently is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1 -C6 alkoxy, optionally substituted C1 -C6 heteroalkyl, optionally substituted C1 -C6 haloalkyl, optionally substituted C1 -C6 deuteroalkyl, optionally substituted C1 -C6 alkylthio, optionally substituted C1 -C6 alkylamino, optionally substituted C1-C6 hydroxyalkyl, optionally substituted C1 -C6 mercaptoalkyl, optionally substituted C1-C6 aminoalkyl, RpC(O)N(Rq)-, -C(O)N(RpRq), -NRrRs, -C(O)RZ, - C(O)OH, -C(O)ORU, -B(OH)2, hydroxy, halo, nitro or cyano;

[0130] Y is -N(Rb)C(O)-RYor -N(Rb)C(O)-Rv-RY; RYis an optionally substituted heterocycloalkyl containing six ring atoms;

[0131] Rvis a substituted C1 -C4 alkylene or unsubstituted C1 -C4 alkylene;

[0132] Rb, Rp, Rq, Rrand Rseach independently is hydrogen or optionally substituted C1 -C6 alkyl;

[0133] Rzis hydrogen or Ru; and

[0134] Ruis an optionally substituted C1 -C6 alkyl.

[0135] In certain embodiments, R1, R2, R3, R4, R11, R12, R13, R14, R15, R16, R17and R18each independently is hydrogen, optionally substituted C1 -C4 alkyl, optionally substituted C1 -C4 deuteroalkyl, optionally substituted C1 -C4 haloalkyl; optionally substituted C1 -C4 alkylamino, halo or optionally substituted C1 -C4 alkoxy. In certain embodiments, R1, R2, R3, R4, R11, R12, R13, R14, R15, R16, R17and R18each independently is hydrogen, unsubstituted C1 -C4 alkyl, Cl, F, CF3, CD3, unsubstituted C1 -C4 alkoxy, methoxy, isopropyloxy or dimethylamino.

[0136] In certain embodiments, (i) R14and R16each independently is hydrogen, C1 -C4 alkyl, Cl, F, CF3, CD3, C1 -C4 alkoxy, methoxy, isopropyloxy or dimethylamino; (ii) R14is C1 -C4 alkoxy; (iii) R14is methoxy or isopropyloxy; (iv) R16is chloro or fluoro; and / or (v) R16is fluoro. In certain embodiments, R1, R11, R12and R13each independently is hydrogen; R15, R17and R18each independently is hydrogen; R3and R4each independently is hydrogen; and / or Rbis hydrogen. In certain embodiments, R2is methyl, ethyl, methoxy or ethoxy, and R1, R3and R4each is hydrogen. In certain embodiments, Rvis unsubstituted ethylene or unsubstituted methylene. In certain embodiments, Rp, Rq, Rrand Rseach independently is hydrogen or methyl. In certain embodiments, Ruis ethyl or methyl.

[0137] In certain embodiments, RYis an optionally substituted piperidinyl, optionally substituted piperazinyl or optionally substituted morpholinyl. In certain instances, RYis a substituted piperidinyl or substituted piperazinyl, which sometimes is substituted by an optionally substituted C1 -C6 alkyl, ethyl or methyl at one, two or three ring atoms. In certain instances, RYis an unsubstituted morpholinyl. In certain embodiments, Y is - In certain embodiments, RYis of Formula D1 and X12is N; X13is C(R5)R X15is N-R7B, X16is C(R8)R8A, and X17is C(R9)R9A. In certain embodiments, . In certain instances, RYis of Formula D1 and X12is C-RaA; X13is C(R5)R X15is N-R7B; X16is C(R8)R8A; and X17is C(R9)R9A. In certain embodiments, A, R8, R8A, R9and R9Aeach independently is hydrogen, optionally substituted C1 -C6 alkyl, optionally substituted C1 -C6 alkoxy, optionally substituted C1 -C6 heteroalkyl, optionally substituted C1 -C6 haloalkyl, optionally substituted C1 -C6 deuteroalkyl, optionally substituted C1 -C6 alkylthio, optionally substituted C1-C6 alkylamino, optionally substituted C1 -C6 hydroxyalkyl, optionally substituted C1 -C6 mercaptoalkyl, optionally substituted C1 -C6 aminoalkyl, R9C(O)N(Rh)-, -C(O)N(R9Rh), -NRkR, -C(O)RZ, -C(O)OH, -C(O)ORU, -B(OH)2, hydroxy, halo, nitro or cyano; where R9, Rh, Rkand Ri each independently is hydrogen or optionally substituted C1 -C6 alkyl; and Ruis an optionally substituted C1 -C6 alkyl. In certain embodiments, R7Bis hydrogen, optionally substituted C1 -C6 alkyl, optionally substituted C1 -C6 heteroalkyl, optionally substituted C1 -C6 haloalkyl, optionally substituted C1 -C6 deuteroalkyl, optionally substituted C1 -C6 hydroxyalkyl, optionally substituted C1 -C6 mercaptoalkyl, optionally substituted C1 -C6 aminoalkyl, optionally substituted C5-C6 cycloalkyl, optionally substituted heterocycloalkyl containing 5 or 6 ring member atoms, or -C(O)ORU. In certain embodiments, (i) RaA, R5, R5A, R6, R6A, R7B, R8, R8A, R9and R9Aeach independently is hydrogen or optionally substituted C1 -C4 alkyl; (ii) Ruis an optionally substituted C1 -C4 alkyl; (iii) R9, Rh, Rkand Rjeach independently is hydrogen or optionally substituted C1 -C4 alkyl; (iv) the optionally substituted C1 - (ii) or (iii) is an unsubstituted C1 -C4 alkyl; and / or (v) the unsubstituted C1-C4 alk butyl, tert-butyl, iso-butyl, propyl, isopropyl, ethyl or methyl. In certain instances, R6, R6A, R7B, R8, R8A, R9and R9Aeach independently is hydrogen or optionally su C4 alkyl. In certain instances, RaA, R5, R5A, R6, R6A, R8, R8A, R9and R9Aeach is hydrogen and R7Bis methyl.

[0138] In certain embodiments, Y is:

[0139] A representative Subgroup 1 compound is:

[0140] N-(5-((8-(4-fluoro-2-isopropoxyphenyl)quinazolin-2-yl)amino)-2-methylphenyl)-1 - methylpiperidine-4-carboxamide; or

[0141] (S)-N-(5-((8-(4-fluoro-2-isopropoxyphenyl)quinazolin-2-yl)amino)-2-methylphenyl)-1 - methylpyrrolidine-2-carboxamide; or

[0142] N-(5-((8-(4-fluoro-2-isopropoxyphenyl)quinazolin-2-yl)amino)-2-methylphenyl)-1 - methylazetidine-3-carboxamide; or

[0143] N-(5-((8-(4-fluoro-2-isopropoxyphenyl)quinazolin-2-yl)amino)-2-methylphenyl)tetrahydro-2H- pyran-4-carboxamide; or

[0144] (R)-N-(5-((8-(4-fluoro-2-isopropoxyphenyl)quinazolin-2-yl)amino)-2-methylphenyl)-1 - methylpyrrolidine-2-carboxamide; or

[0145] N-(5-((8-(4-fluoro-2-isopropoxyphenyl)quinazolin-2-yl)amino)-2-methylphenyl)-2-(4- methylpiperazin-1 -yl)acetamide; or

[0146] N-(5-((8-(4-fluoro-2-isopropoxyphenyl)quinazolin-2-yl)amino)-2-methylphenyl)-4- methylpiperazine-1 -carboxamide; or or a pharmaceutically acceptable salt thereof.

[0147] Subgroup 2: certain Formula A1-3 compounds

[0148] Provided in certain aspects is a compound of Formula A1 -3:

[0149] Formula A1 -3 or a pharmaceutically acceptable salt, amide or ester thereof, where:

[0150] R1, R2, R3, R4, R11, R12, R13, R14, R15, R16, R17and R18each independently is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1 -C6 alkoxy, optionally substituted C1 -C6 heteroalkyl, optionally substituted C1 -C6 haloalkyl, optionally substituted C1 -C6 deuteroalkyl, optionally substituted C1 -C6 alkylthio, optionally substituted C1 -C6 alkylamino, optionally substituted C1-C6 hydroxyalkyl, optionally substituted C1 -C6 mercaptoalkyl, optionally substituted C1-C6 aminoalkyl, RPC(O)N(Rq)-, -C(O)N(RpRq), -NRrRs, -C(O)RZ, - C(O)OH, -C(O)ORU, -B(OH)2, hydroxy, halo, nitro or cyano;

[0151] Y is -N(Ra)Rb;

[0152] Ra, Rb, Rp, Rq, Rrand Rseach independently is hydrogen or optionally substituted C1 -C6 alkyl;

[0153] Rzis hydrogen or Ru; and

[0154] Ruis or optionally substituted C1 -C6 alkyl.

[0155] In certain embodiments, R1, R2, R3, R4, R11, R12, R13, R14, R15, R16, R17and R18each independently is hydrogen, optionally substituted C1 -C4 alkyl, optionally substituted C1 -C4 deuteroalkyl, optionally substituted C1 -C4 haloalkyl, optionally substituted C1 -C4 alkylamino, halo or optionally substituted C1 -C4 alkoxy. In certain embodiments, R1, R2, R3, R4, R11, R12, R13, R14, R15, R16, R17and R18each independently is hydrogen, unsubstituted C1 -C4 alkyl, Cl, F, CF3, CD3, unsubstituted C1 -C4 alkoxy, methoxy, isopropyloxy or dimethylamino. In certain embodiments, (i) R14and R1Seach independently is hydrogen, C1 -C4 alkyl, Cl, F, CF3, CD3, C1 - C4 alkoxy, methoxy, isopropyloxy or dimethylamino; (ii) R14is C1 -C4 alkoxy; (iii) R14is methoxy or isopropyloxy; (iv) R16is chloro or fluoro; and / or (v) R16is fluoro.

[0156] In certain embodiments, R2is an optionally substituted C1 -C4 alkoxy, optionally substituted C1 - C4 alkyl or methyl. In certain embodiments, R1, R11, R12and R13each is hydrogen. In certain instances, R2is methyl, ethyl, methoxy or ethoxy, and R1, R3and R4each is hydrogen. In certain embodiments, R15, R17and R18each is hydrogen. In certain embodiments, R3and R4each is hydrogen. In certain embodiments, R2is hydrogen. In certain embodiments, Rp, Rq, Rrand Rseach independently is hydrogen, ethyl or methyl. In certain embodiments, Raand Rbeach independently is hydrogen or C1 -C4 alkyl, ethyl or methyl. In certain embodiments, Raand Rbeach is hydrogen. In certain embodiments, Raand Rbare not joined and do not form an unsubstituted heterocycloalkyl or substituted heterocycloalkyl.

[0157] A representative Subgroup 2 compound is: or a pharmaceutically acceptable salt thereof.

[0158] Subgroup 3: certain Formula A1-3 compounds

[0159] Provided in certain aspects is a compound of Formula A1 -3: Formula A1 -3 or a pharmaceutically acceptable salt, amide or ester thereof, where:

[0160] R1, R3, R4, R11, R12, R13, R14, R15, R1S, R17and R18each independently is hydrogen, optionally substituted C1 -C6 alkyl, optionally substituted C1 -C6 alkoxy, optionally substituted C1 -C6 heteroalkyl, optionally substituted C1 -C6 haloalkyl, optionally substituted C1 -C6 deuteroalkyl, optionally substituted C1-C6 alkylthio, optionally substituted C1 -C6 alkylamino, optionally substituted C1 -C6 hydroxyalkyl, optionally substituted C1 -C6 mercaptoalkyl, optionally substituted C1 -C6 aminoalkyl, RqC(O)N(Rh)-, -C(O)N(RqRh), -NR'Rk, -C(O)RZ, -C(O)OH, - C(O)ORU, -B(OH)2, hydroxy, halo, nitro or cyano;

[0161] Y is -N(Rb)C(O)-RY;

[0162] RYis an optionally substituted alkenyl;

[0163] R2is hydrogen, optionally substituted C1 -C6 alkyl, unsubstituted C1 -C6 alkoxy, optionally substituted C1 -C6 heteroalkyl, optionally substituted C1 -C6 haloalkyl, optionally substituted C1 - C6 deuteroalkyl, optionally substituted C1 -C6 alkylthio, optionally substituted C1 -C6 alkylamino, optionally substituted C1-C6 hydroxyalkyl, optionally substituted C1 -C6 mercaptoalkyl, optionally substituted C1-C6 aminoalkyl, RpC(O)N(Rq)-, -C(O)N(RpRq), -NRrRs, -N(H)Rr, -NH2, - C(O)RZ, -C(O)OH, -C(O)ORU, -B(OH)2, hydroxy, halo, nitro or cyano; Rb, R9, Rh, Rj, Rk, Rpand Rqeach independently is hydrogen or optionally substituted C1 -C6 alkyl;

[0164] Rrand Rseach independently is hydrogen or unsubstituted C1 -C6 alkyl;

[0165] Rzis hydrogen or Ru; and

[0166] Ruis an optionally substituted C1 -C6 alkyl.

[0167] In certain embodiments, RYis an optionally substituted C2-C4 alkenyl. In certain embodiments, RYis -CH=CH2. In certain embodiments, R1, R3, R4, R11, R12, R13, R14, R15, R16, R17and R18each independently is hydrogen, optionally substituted C1 -C4 alkyl, optionally substituted C1 -C4 deuteroalkyl, optionally substituted C1 -C4 haloalkyl, optionally substituted C1 -C4 alkylamino, halo or optionally substituted C1 -C4 alkoxy. In certain embodiments, R1, R3, R4, R11, R12, R13, R14, R15, R16, R17and R18each independently is hydrogen, unsubstituted C1 -C4 alkyl, Cl, F, CF3, CD3, unsubstituted C1 -C4 alkoxy, methoxy, isopropyloxy or dimethylamino. In certain embodiments, (i) R14and R16each independently is hydrogen, C1 -C4 alkyl, Cl, F, CF3, CD3, C1 - C4 alkoxy, methoxy, isopropyloxy or dimethylamino; (ii) R14is C1 -C4 alkoxy; (iii) R14is methoxy or isopropyloxy; (iv) R16is chloro or fluoro; and / or (v) R16is fluoro.

[0168] In certain embodiments, R2is hydrogen, C1 -C4 alkyl, C1 -C4 deuteroalkyl, C1 -C4 haloalkyl, C1 - C4 alkylamino or halo. In certain embodiments, R2is hydrogen, unsubstituted C1 -C4 alkyl, unsubstituted C1 -C4 deuteroalkyl, unsubstituted C1 -C4 haloalkyl, unsubstituted C1 -C4 alkylamino or halo. In certain embodiments, R2is hydrogen, unsubstituted C1 -C4 alkyl, Cl, F, CF3, CD3, or dimethylamino. In certain embodiments, R2is unsubstituted C1 -C4 alkoxy, ethoxy or methoxy. In certain embodiments, R2is unsubstituted C1 -C4 alkyl, ethyl or methyl. In certain instances, R2is methyl or ethyl, and R1, R3and R4each is hydrogen. In certain instances, R2is methoxy or ethoxy, and R1, R3and R4each is hydrogen. In certain embodiments, R1, R11, R12and R13each independently is hydrogen. In certain embodiments, R15, R17and R18each independently is hydrogen. In certain embodiments, R3and R4each independently is hydrogen. In certain embodiments, R2is hydrogen. In certain embodiments, Rbis hydrogen. In certain embodiments, Rb, Rk, Rm, Rpand Rqeach independently is hydrogen or methyl. In certain embodiments, Rband RYare not joined and do not form an unsubstituted heterocycloalkyl or substituted heterocycloalkyl.

[0169] A representative Subgroup 3 compound is or a pharmaceutically acceptable salt thereof.

[0170] Subgroup 4: certain Formula A1-5 compounds Provided in certain aspects is a compound of Formula A1 -5: Formula A1 -5 or a pharmaceutically acceptable salt, amide or ester thereof, where:

[0171] R7is -C(O)N(RcRd) or is a Formula F group;

[0172] R1, R2, R3, R4, R5, R6, R8, R9, R11, R12, R13, R14, R15, R16, R17and R18each independently is hydrogen, optionally substituted C1 -C6 alkyl, optionally substituted C1 -C6 alkoxy, optionally substituted C1 -C6 heteroalkyl, optionally substituted C1 -C6 haloalkyl, optionally substituted C1 - C6 deuteroalkyl, optionally substituted C1 -C6 alkylthio, optionally substituted C1 -C6 alkylamino, optionally substituted C1-C6 hydroxyalkyl, optionally substituted C1 -C6 mercaptoalkyl, optionally substituted C1-C6 aminoalkyl, RPC(O)N(Rq)-, -C(O)N(RPRC'), -NRrRs, -C(O)RZ, - C(O)OH, -C(O)ORU, -B(OH)2, hydroxy, halo, nitro or cyano;

[0173] Z1is an optionally substituted heterocycloalkyl; Xais C(R43)R43A; Xbis C(R44)R44A; Xcis C(R45)R45A N-R45BQ s S(0) or SQ2.xdisc(R46)R46A; and Xeis C(R47)R47A;

[0174] R43, R44, R45, R46, R47, R43A, R44A, R45A, R46A, R47Aand R45Beach independently is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1 -C6 alkoxy, optionally substituted C1 -C6 heteroalkyl, optionally substituted C1 -C6 haloalkyl, optionally substituted C1 -C6 deuteroalkyl, optionally substituted C1 -C6 alkylthio, optionally substituted C1 -C6 alkylamino, optionally substituted C1-C6 hydroxyalkyl, optionally substituted C1 -C6 mercaptoalkyl, optionally substituted C1-C6 aminoalkyl;

[0175] Rc, Rd, Rp, Rq, Rrand Rseach independently is hydrogen or optionally substituted C1 -C6 alkyl;

[0176] Rzis hydrogen or Ru; and

[0177] Ruis an optionally substituted C1 -C6 alkyl.

[0178] In certain embodiments, R1, R2, R3, R4, R5, R6, R8, R9, R11, R12, R13, R14, R15, R16, R17and R18each independently is hydrogen, optionally substituted C1 -C4 alkyl, optionally substituted C1 - C4 deuteroalkyl, optionally substituted C1 -C4 haloalkyl; optionally substituted C1 -C4 alkylamino, halo or optionally substituted C1 -C4 alkoxy. In certain embodiments, R1, R2, R3, R4, R5, R6, R8, R9, R11, R12, R13, R14, R15, R16, R17and R18each independently is hydrogen, unsubstituted C1 -C4 alkyl, Cl, F, CF3, CD3, unsubstituted C1 -C4 alkoxy, methoxy, isopropyloxy or dimethylamino.

[0179] In certain embodiments, R1, R11, R12and R13each is hydrogen. In certain embodiments, R15, R17and R18each is hydrogen. In certain embodiments, R3and R4each is hydrogen. In certain embodiments, R2is hydrogen. In certain embodiments, R5, R6, R8and R9each is hydrogen. In certain embodiments, R2is an optionally substituted C1 -C4 alkoxy, optionally substituted C1 -C4 alkyl or methyl. In certain instances, R2is methyl, ethyl, methoxy or ethoxy, and R1, R3and R4each is hydrogen.

[0180] In certain embodiments, R7is -C(O)N(RcRd) and Rcand Rdeach independently is hydrogen or optionally substituted C1-C4 alkyl; or Rcand Rdeach independently is hydrogen or unsubstituted C1 -C4 alkyl; or Rcand Rdeach is unsubstituted C1 -C4 alkyl. In certain embodiments, R7is -C(O)N(CH3)CH3, -C(O)N(H)CH3or -C(O)NH2.

[0181] In certain embodiments, R7is a Formula F group. In certain embodiments, Xais C(R43)R43A; Xbis C(R44)R44A; Xcis N-R45B; Xdis C(R46)R46A; and Xeis C(R47)R47A. In certain embodiments, R43, R44, R45, R46, R47, R43A, R44A, R45A, R46A, R47Aand R45Beach independently is hydrogen, optionally substituted C1-C6 alkyl, ethyl or methyl. In certain embodiments, R43, R44, R45, R46, R47, p>43A R44A p>46Aanc| R47Aeac|q jshydrogen and R45Aand R45Beach is hydrogen, optionally substituted C1 -C6 alkyl, ethyl or methyl. In certain embodiments, R43, R44, R45, R46, R47, R43A, R44A, R46Aanc| R47Aeacjshydrogen and R45Aand R45Bis methyl. In certain embodiments, R7is:

[0182] In certain embodiments, Ruis an optionally substituted C1 -C4 alkyl, butyl, tert-butyl, iso-butyl, propyl, isopropyl, ethyl or methyl. In certain embodiments, Rp, Rq, Rrand Rseach independently is hydrogen or methyl. In certain embodiments: (i) R14and R16each independently is hydrogen, unsubstituted C1 -C4 alkyl, Cl, F, CF3, CD3, unsubstituted C1 -C4 alkoxy, methoxy, isopropyloxy or dimethylamino; (ii) R14is unsubstituted C1 -C4 alkoxy; (Hi) R14is methoxy or isopropyloxy; (iv) R16is hydrogen, chloro or fluoro; and / or (v) R16is fluoro.

[0183] A representative Subgroup 4 compound is:

[0184] N-(5-((8-(4-fluoro-2-isopropoxyphenyl)quinazolin-2-yl)amino)-2-methylphenyl)terephthalamide; or

[0185] N1 -(5-((8-(4-fluoro-2-isopropoxyphenyl)quinazolin-2-yl)amino)-2-methylphenyl)-N4- methylterephthalamide; or

[0186] N1 -(5-((8-(4-fluoro-2-isopropoxyphenyl)quinazolin-2-yl)amino)-2-methylphenyl)-N4,N4- dimethylterephthalamide; or

[0187] N-(5-((8-(4-fluoro-2-isopropoxyphenyl)quinazolin-2-yl)amino)-2-methylphenyl)-4-(4- methylpiperazine-1-carbonyl)benzamide; or

[0188] N-(5-((8-(4-fluoro-2-isopropoxyphenyl)quinazolin-2-yl)amino)-2-methylphenyl)-4-(morpholine-4- carbonyl)benzamide; or or a pharmaceutically acceptable amide, ester or salt thereof.

[0189] Subgroup 5: certain Formula A1-3 compounds In certain aspects, provided is a compound of Formula A1 -3: or a pharmaceutically acceptable salt, amide or ester thereof, where:

[0190] R1, R2, R3, R4, R11, R12, R13, R14, R15, R16, R,7and R18each independently is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1 -C6 alkoxy, optionally substituted C1 -C6 heteroalkyl, optionally substituted C1 -C6 haloalkyl, optionally substituted C1 -C6 deuteroalkyl, optionally substituted C1 -C6 alkylthio, optionally substituted C1 -C6 alkylamino, optionally substituted C1-C6 hydroxyalkyl, optionally substituted C1 -C6 mercaptoalkyl, optionally substituted C1-C6 aminoalkyl, RpC(O)N(Rq)-, -C(O)N(RpRq), -NRrRs, -C(O)RZ, - C(O)OH, -C(O)ORU, -B(OH)2, hydroxy, halo, nitro or cyano;

[0191] Y is -N(Rb)C(O)-RY;

[0192] RYis an unsubstituted C1 -C6 alkyl or unsubstituted C1 -C6 deuteroalkyl;

[0193] Rb, Rp, Rq, Rrand Rseach independently is hydrogen or optionally substituted C1 -C6 alkyl;

[0194] Rzis hydrogen or Ru; and

[0195] Ruis an optionally substituted C1 -C6 alkyl.

[0196] In certain embodiments, R1, R2, R3, R4, R5, R6, R8, R9, R11, R12, R13, R14, R15, R16, R17and R18each independently is hydrogen, optionally substituted C1 -C4 alkyl, optionally substituted C1 - C4 deuteroalkyl, optionally substituted C1 -C4 haloalkyl; optionally substituted C1 -C4 alkylamino, halo or optionally substituted C1 -C4 alkoxy. In certain instances, R1, R2, R3, R4, R5, R6, R8, R9, R11, R12, R13, R14, R15, R1S, R17and R18each independently is hydrogen, unsubstituted C1 -C4 alkyl, Cl, F, CF3, CD3, unsubstituted C1 -C4 alkoxy, methoxy, isopropyloxy or dimethylamino.

[0197] In certain embodiments, (i) R14and R16each independently is hydrogen, unsubstituted C1 -C4 alkyl, Cl, F, CF3, CD3, unsubstituted C1 -C4 alkoxy, methoxy, isopropyloxy or dimethylamino; (ii) R14is unsubstituted C1 -C4 alkoxy; (iii) R14is methoxy or isopropyloxy; (iv) R16is chloro or fluoro; and / or (v) R16is fluoro. In certain instances, one, two, three or four of R1, R11, R12and R13each is hydrogen. In certain embodiments, one, two or three of R15, R17and R18each is hydrogen. In certain embodiments, one or two of R3and R4each is hydrogen. In certain embodiments, Rbis hydrogen. In certain instances, R2is methyl, ethyl, methoxy or ethoxy, and R1, R3and R4each is hydrogen. In certain embodiments, (i) Rvis unsubstituted ethylene or unsubstituted methylene; (ii) Rp, Rq, Rrand Rseach independently is hydrogen or methyl; and / or (iii) Ruis ethyl or methyl. In certain instances, RYis methyl or ethyl. In certain embodiments, RYis methyl.

[0198] In certain embodiments, provided is a compound of formula:

[0199] N-(5-((8-(4-fluoro-2-isopropoxyphenyl)quinazolin-2-yl)amino)-2-methylphenyl)acetamide; or N-(5-((8-(4-fluoro-2-isopropoxyphenyl)quinazolin-2-yl)amino)-2-methoxyphenyl)acetamide; or or a pharmaceutically acceptable salt thereof.

[0200] Subgroup 6: certain Formula A1-6 compounds

[0201] Provided in certain aspects compound of Formula A1 -6: Formula A1 -6 or a pharmaceutically acceptable salt, amide or ester thereof, where:

[0202] R1, R2, R3, R4, R11, R12, R13, R21and R22each independently is hydrogen, optionally substituted C1 -C6 alkyl, optionally substituted C1 -C6 alkoxy, optionally substituted C1 -C6 heteroalkyl, optionally substituted C1-C6 haloalkyl, optionally substituted C1 -C6 deuteroalkyl, optionally substituted C1 -C6 alkylthio, optionally substituted C1 -C6 alkylamino, optionally substituted C1 - C6 hydroxyalkyl, optionally substituted C1-C6 mercaptoalkyl, optionally substituted C1 -C6 aminoalkyl, R9C(O)N(Rh)-, -C(O)N(R9Rh), -NRRk, -C(O)RZ, -C(O)OH, -C(O)ORU, -B(OH)2, hydroxy, halo, nitro or cyano;

[0203] R5, R6, R8and R9each independently is hydrogen, optionally substituted C1 -C6 alkyl, optionally substituted C1 -C6 alkoxy, optionally substituted C1 -C6 heteroalkyl, optionally substituted C1 -C6 haloalkyl, optionally substituted C1 -C6 deuteroalkyl, optionally substituted C1 -C6 alkylthio, optionally substituted C1-C6 alkylamino, optionally substituted C1 -C6 hydroxyalkyl, optionally substituted C1 -C6 mercaptoalkyl, optionally substituted C1 -C6 aminoalkyl,

[0204] RpC(O)N(Rq)-, -C(O)N(RpRq), -NRrRs, -C(O)RZ, -C(O)OH, -C(O)ORU, -B(OH)2, hydroxy, halo, nitro or cyano;

[0205] R7is RcC(O)N(Rd)- or -C(O)N(RcRd);

[0206] R19Bis hydrogen, optionally substituted C1 -C6 alkyl, optionally substituted C1 -C4 alkyl, butyl, tert-butyl, iso-butyl, propyl, iso-propyl, ethyl or methyl;

[0207] Rc, Rd, R9, Rh, Ri, Rk, Rp, Rq, Rrand Rseach independently is hydrogen or optionally substituted C1 -C6 alkyl;

[0208] Rzis hydrogen or Ru; and

[0209] Ruis an optionally substituted C1 -C6 alkyl. In certain embodiments, R1, R2, R3, R4, R5, R6, R8, R9, R11, R12, R13, R21and R22each independently is hydrogen, optionally substituted C1 -C4 alkyl, optionally substituted C1 -C4 deuteroalkyl, optionally substituted C1 -C4 haloalkyl; optionally substituted C1 -C4 alkylamino, halo or optionally substituted C1 -C4 alkoxy. In certain instances, R1, R2, R3, R4, R5, R6, R8, R9, R11, R12, R13, R21and R22each independently is hydrogen, unsubstituted C1 -C4 alkyl, Cl, F, CF3, CD3, unsubstituted C1 -C4 alkoxy, methoxy, isopropyloxy or dimethylamino.

[0210] In certain embodiments, one, two, three or four of R1, R11, R12and R13each is hydrogen. In certain embodiments, one, two of three of R19B, R21and R22each is hydrogen. In certain embodiments, one or two of R3and R4each is hydrogen. In certain embodiments, one, two, three or four of R5, R6, R8and R9each is hydrogen. In certain embodiments, R2is hydrogen. In certain instances, R2is methyl, ethyl, methoxy or ethoxy, and R1, R3and R4each is hydrogen. In certain embodiments, Rcand Rdeach independently is hydrogen or unsubstituted C1 -C4 alkyl; or Rcand Rdeach independently is hydrogen or methyl; or Rcis hydrogen and Rdis unsubstituted C1 -C4 alkyl; or Rcis hydrogen and Rdis methyl; or Rcand Rdeach is unsubstituted C1 -C4 alkyl; or Rcand Rdeach is methyl. In certain instances, R7is - C(O)N(CH3)CH3, -C(O)N(H)CH3or -C(O)NH2. In certain embodiments, R7is -C(O)N(H)CH3. In certain embodiments, R9, Rh, R1, Rk, Rrand Rseach independently is hydrogen or methyl. In certain instances: (i) R21and R22each independently is hydrogen, unsubstituted C1 -C4 alkyl, Cl, F, CF3, CD3, unsubstituted C1 -C4 alkoxy, methoxy, isopropyloxy or dimethylamino; (ii) one or two of R21and R22each is hydrogen; (iii) R19Bis an optionally substituted C1 -C6 alkyl; (iv) R19Bis unsubstituted C1 -C6 alkyl; and / or (v) R19Bis butyl, iso-butyl, tert-butyl, propyl, iso-propyl, ethyl or methyl.

[0211] In certain embodiments, provided is a compound of formula:

[0212] N1 -(5-((5-( 1 - isobutyl- 1 H-pyrazol-5-yl)quinazolin-2-yl)amino)-2-methylphenyl)-N4- methylterephthalamide; or

[0213] N1 -(5-((8-( 1 - isobutyl- 1 H-pyrazol-5-yl)quinazolin-2-yl)amino)-2-methylphenyl)-N4,N4- dimethylterephthalamide; or or a pharmaceutically acceptable amide, ester or salt thereof.

[0214] Subgroup 7: certain Formula A1-3 compounds

[0215] Provided in certain aspects is a compound of Formula A1 -3:

[0216] Formula A1 -3 or a pharmaceutically acceptable salt, amide or ester thereof, where:

[0217] R1, R2, R3, R4, R11, R12, R13, R14, R15, R16, R17and R18each independently is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1 -C6 alkoxy, optionally substituted C1 -C6 heteroalkyl, optionally substituted C1 -C6 haloalkyl, optionally substituted C1 -C6 deuteroalkyl, optionally substituted C1 -C6 alkylthio, optionally substituted C1 -C6 alkylamino, optionally substituted C1-C6 hydroxyalkyl, optionally substituted C1 -C6 mercaptoalkyl, optionally substituted C1-C6 aminoalkyl, RpC(O)N(Rq)-, -C(O)N(RpRq), -NRrRs, -C(O)RZ, - C(O)OH, -C(O)ORU, -B(OH)2, hydroxy, halo, nitro or cyano;

[0218] Y is of Formula F:

[0219] Z1is an optionally substituted heterocycloalkyl; Xais C(R43)R43A; Xbis C(R44)R44A; Xcis C(R45)R45A, N-R45B, O, S, S(O) or SO2; Xdis C(R46)R46A; and Xeis C(R47)R47A;

[0220] R43, R44, R45, R46, R47, R43A, R44A, R45A, R46A, R47Aand R45Beach independently is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1 -C6 alkoxy, optionally substituted C1 -C6 heteroalkyl, optionally substituted C1 -C6 haloalkyl, optionally substituted C1 -C6 deuteroalkyl, optionally substituted C1 -C6 alkylthio, optionally substituted C1 -C6 alkylamino, optionally substituted C1-C6 hydroxyalkyl, optionally substituted C1 -C6 mercaptoalkyl, optionally substituted C1-C6 aminoalkyl;

[0221] Rp, Rq, Rrand Rseach independently is hydrogen or optionally substituted C1 -C6 alkyl;

[0222] Rzis hydrogen or Ru; and

[0223] Ruis or optionally substituted C1 -C6 alkyl.

[0224] In certain embodiments, R1, R2, R3, R4, R11, R12, R13, R14, R15, R16, R17and R18each independently is hydrogen, optionally substituted C1 -C4 alkyl, optionally substituted C1 -C4 deuteroalkyl, optionally substituted C1 -C4 haloalkyl, optionally substituted C1 -C4 alkylamino, halo or optionally substituted C1 -C4 alkoxy. In certain instances, R1, R2, R3, R4, R11, R12, R13, R14, R15, R16, R17and R18each independently is hydrogen, unsubstituted C1 -C4 alkyl, Cl, F, CF3, CD3, unsubstituted C1 -C4 alkoxy, methoxy, isopropyloxy or dimethylamino.

[0225] In certain instances, (i) R14and R16each independently is hydrogen, unsubstituted C1 -C4 alkyl, Cl, F, CF3, CD3, unsubstituted C1 -C4 alkoxy, methoxy, isopropyloxy or dimethylamino; (ii) R14is unsubstituted C1 -C4 alkoxy; (iii) R14is methoxy or isopropyloxy; (iv) R16is chloro or fluoro; and / or (v) R16is fluoro. In certain embodiments, R2is an optionally substituted C1 -C4 alkoxy, methoxy, optionally substituted C1-C4 alkyl or methyl. In certain instances, R2is methyl, ethyl, methoxy or ethoxy, and R1, R3and R4each is hydrogen. In certain instances, one, two three or four of R1, R11, R12and R13each is hydrogen. In certain embodiments, one, two or three of R15, R17and R18each is hydrogen. In certain embodiments, one or two of R3and R4each is hydrogen. In certain embodiments, R2is hydrogen. In certain embodiments, Rp, Rq, Rrand Rseach independently is hydrogen, ethyl or methyl.

[0226] In certain instances, Y is of Formula F and Xais C(R43)R43A; Xbis C(R44)R44A; Xcis N-R45B; Xdis C(R46)R46A; and Xeis C(R47)R47A. In certain embodiments, Y is of Formula F and R43, R44, R45, R46, R47, R43A, R44A, R45A, R46A, R47Aand R45Beach independently is hydrogen, optionally substituted C1 -C6 alkyl, ethyl or methyl. In certain embodiments, Y is of Formula F and R43, R44, R45, R46, R47, R43A, R44A, R46Aand R47Aeach is hydrogen and R45Aand R45Beach is hydrogen, optionally substituted C1-C6 alkyl, ethyl or methyl. In certain embodiments, Y is Formula F and R43, R44, R45, R46, R47, R43A, R44A, R46Aand R47Aeach is hydrogen and R45Aand R45Bis methyl. In certain embodiments, Y is:

[0227] In certain instances, provided is a compound of formula: or a pharmaceutically acceptable salt thereof.

[0228] Subgroup 8: certain Formula A1-2 compounds

[0229] Provided in certain aspects is a compound of Formula A1 -2: Formula A1 -2 or a pharmaceutically acceptable salt, amide or ester thereof, where:

[0230] R10is of Formula B2: Formula B2;

[0231] Z2ais heteroaryl; and (i) X1ais C, X2ais C-R14, X3ais N, X4ais C-R16, X5ais N, and X6ais C-R18; or (ii) X1ais C, X2ais C-R14, X3ais N, X4ais C-R16, X5ais C-R17, and X6ais C-R18, and the X3anitrogen and R16together are joined as a fused optionally substituted heteroaryl containing five ring atoms;

[0232] R1, R2, R3, R4, R5, R6, R7, R8, R9, R11, R12, R13, R14, R15, R17and R18each independently is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy, optionally substituted C1-C6 heteroalkyl, optionally substituted C1-C6 haloalkyl, optionally substituted C1- C6 deuteroalkyl, optionally substituted C1-C6 alkylthio, optionally substituted C1-C6 alkylamino, optionally substituted C1-C6 hydroxyalkyl, optionally substituted C1-C6 mercaptoalkyl, optionally substituted C1-C6 aminoalkyl, RpC(O)N(Rq)-, -C(O)N(RpRq), -NRrRs, -C(O)RZ, - C(O)OH, -C(O)ORU, -B(OH)2, hydroxy, halo, nitro or cyano;

[0233] Rp, Rq, Rrand Rseach independently is hydrogen or optionally substituted C1-C6 alkyl;

[0234] Rzis hydrogen or Ru; and

[0235] Ruis an optionally substituted C1-C6 alkyl.

[0236] In certain embodiments, R1, R2, R3, R4, R5, R6, R8, R9, R11, R12, R13, R14, R16, R17and R18each independently is hydrogen, optionally substituted C1-C4 alkyl, optionally substituted C1-C4 deuteroalkyl, optionally substituted C1-C4 haloalkyl; optionally substituted C1-C4 alkylamino, halo or optionally substituted C1-C4 alkoxy. In certain instances, R1, R2, R3, R4, R5, R6, R8, R9, R11, R12, R13, R14, R16, R17and R18each independently is hydrogen, unsubstituted C1-C4 alkyl, Cl, F, CF3, CD3, unsubstituted C1-C4 alkoxy, methoxy, isopropyloxy or dimethylamino.

[0237] In certain embodiments, one, two, three or four of R1, R11, R12and R13each is hydrogen. In certain embodiments, one or two of R17and R18each is hydrogen. In certain embodiments, one or two of R3and R4each is hydrogen. In certain embodiments, R2is hydrogen. In certain embodiments, one, two, three or four of R5, R6, R8and R9each is hydrogen. In certain embodiments, R2is methyl, ethyl, methoxy or ethoxy, and R1, R3and R4each is hydrogen. In certain instances, R7is -C(O)OH or -C(O)ORU. In certain instances, R7is -C(O)OH. In certain embodiments, R7is -C(O)N(RcRd) and Rcand Rdeach independently is hydrogen or optionally substituted C1 -C4 alkyl. In certain instances, Rcand Rdeach independently is hydrogen or unsubstituted C1 -C4 alkyl; or Rcand Rdeach independently is hydrogen or methyl; or Rcand Rdeach is unsubstituted C1 -C4 alkyl; or Rcand Rdeach is methyl. In certain embodiments, R7is - C(O)N(CH3)CH3, -C(O)N(H)CH3or -C(O)NH2.

[0238] In certain instances, Ruis an optionally substituted C1 -C4 alkyl, butyl, tert-butyl, iso-butyl, propyl, isopropyl, ethyl or methyl. In certain embodiments, Rp, Rq, Rrand Rseach independently is hydrogen, ethyl or methyl.

[0239] In certain instances, X1ais C, X2ais C-R14, X3ais N, X4ais C-R16, X5ais N, and X6ais C-R18. In certain embodiments: (i) R14and R16each independently is hydrogen, unsubstituted C1 -C4 alkyl, Cl, F, CF3, CD3, unsubstituted C1 -C4 alkoxy, methoxy, isopropyloxy or dimethylamino; (ii) R14and R16each independently is hydrogen or unsubstituted C1 -C4 alkoxy; (iii) R14and R16each independently is hydrogen or methoxy; (iv) R14and R16each is methoxy; and / or (v) R18is hydrogen. In certain embodiments, R10is:

[0240] In certain instances, X1ais C, X2ais C-R14, X3ais N, X4ais C-R16, X5ais C-R17, and X6ais C-R18, and the X3anitrogen and R16together are joined as a fused optionally substituted pyrrolyl. In certain embodiments, X1ais C, X2ais C-R14, X3ais N, X4ais C-R16, X5ais C-R17, and X6ais C-R18, and the X3anitrogen and R16together are joined as a fused unsubstituted pyrrolyl. In certain instances, one, two or three of R14, R17or R18each is hydrogen. In certain embodiments, R10is:

[0241] In certain embodiments, provided is a compound of formula: or a pharmaceutically acceptable amide, ester or salt thereof.

[0242] Subgroup 9: certain Formula A1-2 compounds Provided in certain aspects is a compound of Formula A1-2: or a pharmaceutically acceptable salt, amide or ester thereof, where:

[0243] R11is of Formula C2: Formula C2; Z3ais heteroaryl; and X7ais C; X8ais N or N-R19B; X9ais N or N-R20B; X10ais C-R21; and X11 ais C- R22;

[0244] R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R12, R13, R21and R22each independently is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy, optionally substituted C1-C6 heteroalkyl, optionally substituted C1-C6 haloalkyl, optionally substituted C1-C6 deuteroalkyl, optionally substituted C1-C6 alkylthio, optionally substituted C1-C6 alkylamino, optionally substituted C1-C6 hydroxyalkyl, optionally substituted C1-C6 mercaptoalkyl, optionally substituted C1-C6 aminoalkyl, RpC(O)N(Rq)-, -C(O)N(RpRq), -NRrRs, -C(O)RZ, - C(O)OH, -C(O)ORLI, -B(OH)2, hydroxy, halo, nitro or cyano; R19Band R20Beach independently is hydrogen, optionally substituted C1 -C6 alkyl, optionally substituted C1 -C6 heteroalkyl, optionally substituted C1 -C6 haloalkyl, optionally substituted C1 - C6 deuteroalkyl, optionally substituted C1 -C6 hydroxyalkyl, optionally substituted C1 -C6 mercaptoalkyl, optionally substituted C1 -C6 aminoalkyl, RpC(O)N(Rq)-, -C(O)N(RpRq), -NRrRs, - C(O)RZ, -C(O)OH or -C(0)ORu;

[0245] Rp, Rq, Rrand Rseach independently is hydrogen or optionally substituted C1 -C6 alkyl;

[0246] Rzis hydrogen or Ru; and

[0247] Ruis an optionally substituted C1 -C6 alkyl.

[0248] In certain embodiments, R1, R2, R3, R4, R5, R6, R8, R9, R10, R12, R13, R21and R22each independently is hydrogen, optionally substituted C1 -C4 alkyl, optionally substituted C1 -C4 deuteroalkyl, optionally substituted C1 -C4 haloalkyl; optionally substituted C1 -C4 alkylamino, halo or optionally substituted C1 -C4 alkoxy. In certain embodiments, R1, R2, R3, R4, R5, R6, R8, R9, R10, R12, R13, R21and R22each independently is hydrogen, unsubstituted C1 -C4 alkyl, Cl, F, CF3, CD3, unsubstituted C1 -C4 alkoxy, methoxy, isopropyloxy or dimethylamino;

[0249] In certain embodiments, one, two, three or four of R1, R11, R12and R13each is hydrogen. In certain embodiments, one, two, three or four of R19B, R20B, R21and R22each is hydrogen. In certain embodiments, one or two of R3and R4each is hydrogen. In certain embodiments, R2is hydrogen. In certain embodiments, one, two, three or four of R5, R6, R8and R9each is hydrogen. In certain embodiments, R2is methyl, ethyl, methoxy or ethoxy, and R1, R3and R4each is hydrogen.

[0250] In certain embodiments, R7is -C(O)OH or -C(O)ORU. In certain embodiments, R7is -C(O)OH. In certain embodiments, R7is -C(O)N(RcRd) and Rcand Rdeach independently is hydrogen or optionally substituted C1-C4 alkyl. In certain embodiments, Rcand Rdeach independently is hydrogen or unsubstituted C1 -C4 alkyl; or Rcand Rdeach independently is hydrogen or methyl; or R° and Rdeach is unsubstituted C1 -C4 alkyl; or R° and Rdeach is methyl. In certain embodiments, R7is -C(O)N(CH3)CH3, -C(O)N(H)CH3or -C(O)NH2.

[0251] In certain embodiments, Ruis an optionally substituted C1 -C4 alkyl, butyl, tert-butyl, iso-butyl, propyl, isopropyl, ethyl or methyl. In certain embodiments, Rp, Rq, Rrand Rseach independently is hydrogen, ethyl or methyl.

[0252] In certain embodiments, R19Band R20Beach independently is hydrogen, optionally substituted C1 -C4 alkyl, optionally substituted C1 -C4 deuteroalkyl, optionally substituted C1 -C4 haloalkyl or optionally substituted C1-C4 alkylamino. In certain embodiments, (i) X8ais N and X9ais N-R20B;

[0253] (ii) R19Band R20Beach independently is hydrogen, unsubstituted C1 -C4 alkyl, ethyl or methyl;

[0254] (iii) R21and R22each independently is hydrogen, unsubstituted C1 -C4 alkyl, ethyl or methyl; (iv) R19Band R20Beach is hydrogen; and / or (v) R21and R22each is hydrogen. In certain embodiments, R11is In certain embodiments, provided is a compound of formula: or a pharmaceutically acceptable amide, ester or salt thereof.

[0255] A composition containing a compound of Subgroup 1 , Subgroup 2, Subgroup 3, Subgroup 4, Subgroup 5, Subgroup 6, Subgroup 7, Subgroup 8, Subgroup 9, Subgroup 10, Subgroup 11 , Subgroup 12, Subgroup 13, Subgroup 14, Subgroup 15, Subgroup 16, Subgroup 17 or Subgroup 18 sometimes is formulated for oral administration, topical administration (a cream, for example) or administration by injection or infusion.

[0256] In certain embodiments, a compound of Formula A1 , Formula A1-1 , Formula A1 -2, Formula A1 - 3, Formula A1 -4, Formula A1 -5, Formula A1 -6, Formula A2, Formula A2-1 , Formula A2-2 or Formula A2-3 is provided with one or more of the following applicable provisos.

[0257] In certain embodiments, a compound is provided with the proviso that R7is not -C(O)OH.

[0258] In certain embodiments, a compound is provided with the proviso that R2and R3, or optionally R3and R4, are not joined as an imidazolyl group. In certain embodiments, a compound is provided with the proviso that R2and R3, or optionally R3and R4, are not joined as: (i) an imidazolyl moiety fused to the phenyl group on which R2, R3and R4are substituents; (ii) an indolyl group; (iii) a five-membered ring; (iv) a five-membered ring fused to the phenyl group on which R2, R3and R4are substituents; (v) unsubstituted heteroaryl containing 5 ring atoms; and / or (vi) substituted heteroaryl containing 5 ring atoms.

[0259] In certain embodiments, a compound is provided with the proviso that R10and / or optionally one, two or three of R11, R12or R13, is not: methyl; substituted alkyl or unsubstituted alkyl; methoxy; substituted alkoxy or unsubstituted alkoxy; and / or unsubstituted phenyl. In certain embodiments, a compound is provided with the proviso that R11and R12each is not methoxy. In certain embodiments, a compound is provided, where R10, R11, R12or R13is -W-Rw, with the proviso that Rwis not a phenyl substituted with -C=CH3and W is not amino.

[0260] In certain embodiments, a compound is provided with the proviso that R2and R9do not form a bond (i.e. , R2and R9are not a bond). In certain embodiments, a compound is provided with the proviso that (i) the amino group joined by a covalent bond to the carbon ring atom in the quinazolinyl group, which carbon ring atom is positioned between the two nitrogen ring atoms of the quinazolinyl group, and (ii) R1, do not participate in a five-membered ring, and / or do not join in an indolyl group.

[0261] In certain embodiments, a compound is provided where Y is -NRaRb, -N(Rb)-CH2-RYor -CH2- N(Rb)RY, with the proviso that: (i) R16is not methoxy; (ii) R15or R16each independently is not

[0262] (iii) R15or R16each independently is not where R49Xis methyl, ethyl, methoxy, -C(O)CH3, -CH2CH2OH, -CH2CH2OCH3, -CH2CH(OH)CH3, -CH2C(OH)(CH3)CH3, or -CH2CH2F; (iv) Raand Rb, or RYand Rb, are not joined as an unsubstituted morpholino or where R49Xis methyl, ethyl, methoxy, -C(O)CH3, -CH2CH2OH, -CH2CH2OCH3, -CH2CH(OH)CH3, -CH2C(OH)(CH3)CH3, or -CH2CH2F; (v) Raand Rb, or RYand Rb, are not joined as an unsubstituted piperazinyl, or substituted piperazinyl, or unsubstituted morpholinyl or substituted morpholinyl; (vi) Raand Rb, or RYand Rb, are not joined as a group containing an unsubstituted piperazinyl, or substituted piperazinyl, or unsubstituted morpholinyl or substituted morpholinyl; (vii) Raand Rb, or RYand Rb, are not joined as an unsubstituted heterocycloalkyl or substituted heterocycloalkyl; (viii) Raand Rb, or RYand Rb, are not joined as a group containing an unsubstituted heterocycloalkyl or substituted heterocycloalkyl; (ix) R2is not unsubstituted morpholino or where R49Xis methyl, ethyl, methoxy, -C(O)CH3, -CH2CH2OH, -CH2CH2OCH3, -CH2CH(OH)CH3-CH2C(OH)(CH3)CH3, or -CH2CH2F; (x) R2is not a substituted alkyl substituted by a group defined in (ix); (xi) R2is not (a) an unsubstituted piperazinyl, or substituted piperazinyl, or unsubstituted morpholinyl or substituted morpholinyl; or (b) an alkyl substituted by a group defined in (xi)(a); (xii) R2is not a group containing an unsubstituted piperazinyl, or substituted piperazinyl, or unsubstituted morpholinyl or substituted morpholinyl; (xiii) R2is not an unsubstituted heterocycloalkyl or substituted heterocycloalkyl; (xiv) R2is not a group containing an unsubstituted heterocycloalkyl or substituted heterocycloalkyl; (xv) Rbin -CH2-N(Rb)RYis hydrogen and RYis not methyl or is not where n is an integer of 1 to 10; and RYXXis hydrogen, optionally substituted alkyl or optionally substituted amidoalkyl; (xvi) for -CH2-N(Rb)RY, Rband RYeach is not methyl; (xvii) for -N(Ra)Rb, Raand Rbeach is not methyl; (xviii) for -N(Ra)Rb, Rbis not unsubstituted C1 -C4 alkyl or is not substituted C1 -C4 alkyl; and / or (xix) RYis not an unsubstituted phenyl or substituted phenyl. In certain embodiments, a compound is provided with the proviso that (i) Y or R2each independently is not

[0263] (ii) Y or R2each independently is not -C(O)N(H)R50X, where R50Xis hydrogen, unsubstituted alkyl, substituted alkyl, unsubstituted heterocycloalkylalkyl or substituted heterocycloalkyl; (iii) Y or R2each independently is not hydrogen; (iv) Y or R2each independently is not chloro; (v) Y or R2each independently is not fluoro; (vi) Y or R2each independently is not halo; (vii) Y or R2each independently is not methoxy; (viii) Y or R2each independently is not unsubstituted alkoxy; (ix) Y or R2each independently is not cyano; (x) R1is not fluoro; (xi) R1is not halo; (xii) R4is not fluoro; (xiii) R4is not halo; (xiv) R3is not fluoro; and / or (xvi) R3is not halo.

[0264] In certain embodiments, a compound is provided with the proviso that: (i) R2is not an unsubstituted piperazinyl, or substituted piperazinyl, or unsubstituted morpholinyl or substituted morpholinyl; (ii) R2is not an unsubstituted heterocycloalkyl or substituted heterocycloalkyl; (iii) R2does not contain an unsubstituted heterocycloalkyl or substituted heterocycloalkyl; and / or (iv) R2is hydrogen, unsubstituted C1 -C4 alkyl, ethyl or methyl.

[0265] In certain embodiments, a compound is provided where Y is -N(Rb)C(O)-RYor -N(Rb)C(O)-Rv- RYand RYis an optionally substituted alkenyl, with the proviso that (i) Y, R1, R2, R3or R4each independently is not one of the following designated Group A electrophilic groups:

[0266] or (ii) Y, R1, R2, R3or R4each independently is not one of the following designated Group B electrophilic groups: or (iii) Y, R1, R2, R3or R4each independently is not an electrophilic group capable of forming a covalent bond with a cysteine of a protein.

[0267] In certain embodiments, a compound is provided, where Y is -N(Rb)C(O)-RYor -N(Rb)C(O)-Rv- RY, and RYis -CH=CH2, or Y, R1, R3or R4is one of the designated Group A electrophilic groups, one of the designated Group B electrophilic groups, or an electrophilic group capable of forming a covalent bond with a cysteine of a protein, with the proviso that: (i) R2is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C1 -C6 haloalkyl, optionally substituted C1 -C6 deuteroalkyl, optionally substituted C1 -C6 alkylthio, optionally substituted C1 -C6 mercaptoalkyl, RcC(O)N(Rd)-, -C(O)N(RcRd), - C(O)RZ, -C(O)OH, -C(O)ORU, -B(OH)2, hydroxy, halo, nitro or cyano, where Rc, Rdand Rueach independently is hydrogen or optionally substituted C1 -C6 alkyl, optionally substituted C1 -C4 alkyl, butyl, tert-butyl, iso-butyl, propyl, iso-propyl, ethyl or methyl and where Ruis an optionally substituted C1 -C6 alkyl, optionally substituted C1 -C4 alkyl, butyl, tert-butyl, iso-butyl, propyl, isopropyl, ethyl or methyl; (ii) R2is hydrogen, optionally substituted C1 -C4 alkyl, optionally substituted C1 -C4 deuteroalkyl, optionally substituted C1 -C4 haloalkyl, optionally substituted C1 -C4 alkylamino or halo; (iii) R2is hydrogen, unsubstituted C1 -C4 alkyl, unsubstituted C1 -C4 deuteroalkyl, unsubstituted C1 -C4 haloalkyl, or halo; (iv) R2is unsubstituted C1 -C4 alkoxy, ethoxy or methoxy; and / or (v) R2is unsubstituted C1 -C4 alkyl or methyl.

[0268] In certain embodiments, a compound is provided where Y is -N(Rb)C(O)-RYor -N(Rb)C(O)-Rv- RY, and RYis -CH=CH2, or Y, R1, R3or R4is one of the designated Group A electrophilic groups, one of the designated Group B electrophilic groups, or an electrophilic group capable of forming a covalent bond with a cysteine of a protein, with the proviso that: (i) R2is not -NRaRb, where Raand Rbare joined as an unsubstituted morpholino, substituted piperazinyl or substituted azetidinyl; (ii) R2is not -NRaRb, where Raand Rbare joined as a substituted heterocycloalkyl or unsubstituted heterocycloalkyl; (iii) R2is not -NRaRb, where Rais - CH2CH2N(CH3)CH3and Rbis hydrogen or methyl; (iv) R2is not -NRaRb, where Rais unsubstituted aminoalkyl or substituted aminoalkyl and Rbis hydrogen or unsubstituted alkyl; (v) R2is not -O-R51X, where R51Xis -CH2CH2N(CH3)CH3, -CH2CH2OCH3, substituted piperidinyl, substituted pyrrolidinyl or substituted azetidinyl; (vi) R2is not -O-R51X, where R51Xis unsubstituted aminoalkyl or substituted aminoalkyl, unsubstituted alkoxyalkyl or substituted alkoxyalkyl, unsubstituted heterocycloalkyl or substituted hetercycloalkyl; (vii) R4is not methoxy or fluoro; (viii) R4is not unsubstituted alkoxy or halo; (ix) R17and R18are not fluoro or chloro; and / or (x) R17and R18are not halo.

[0269] In certain embodiments, a compound is provided, where R1, R2, R3or R4is one of the designated Group A electrophilic groups, one of the designated Group B electrophilic groups, or an electrophilic group capable of forming a covalent bond with a cysteine of a protein, with the proviso that: (i) where Y is -NRaRb, Raand Rbare not joined as an unsubstituted morpholino, substituted piperazinyl or substituted azetidinyl; (ii) where Y is -NRaRb, where Raand Rbare not joined as a substituted heterocycloalkyl or unsubstituted heterocycloalkyl; (iii) where Y is - NRaRb, Rais not -CH2CH2N(CH3)CH3and Rbis not hydrogen or methyl; (iv) where Y is -NRaRb, Rais not unsubstituted aminoalkyl or substituted aminoalkyl and Rbis not hydrogen or unsubstituted alkyl; (v) Y is not -O-R51X, where R51Xis -CH2CH2N(CH3)CH3, -CH2CH2OCH3, substituted piperidinyl, substituted pyrrolidinyl or substituted azetidinyl; (vi) Y is not -O-R51X, where R51Xis unsubstituted aminoalkyl or substituted aminoalkyl, unsubstituted alkoxyalkyl or substituted alkoxyalkyl, or unsubstituted heterocycloalkyl or substituted heterocycloalkyl; (vii) R4 is not methoxy or fluoro; (viii) R4is not unsubstituted alkoxy or halo; (ix) R17and R18are not fluoro or chloro; and / or (x) R17and R18are not halo.

[0270] In certain embodiments, a compound is provided, where at least one of R10, R11, R12or R13is Rwor -W-Rw, with the proviso that R14, R15, R16, R17, R18, R14A, R15A, R16A, R17A, R18A, RaB, R19,

[0271] (ii) not one of the designated Group A electrophilic groups, (iii) not one of the designated Group B electrophilic groups, and / or (iv) not an electrophilic group capable of forming a covalent bond with a cysteine of a protein.

[0272] In the context of a chemical structure, a reference to a chemical structure, or a structure provided as part of a synthetic scheme, a number or letter normally designated as a superscript, for example, the “1 ” in R1, or the “L” in RL, may be referred to as a subscript, for example, Ri or or without any modification of script, such as, for example, R1 or RL.

[0273] Subgroup 10: certain Formula A1 compounds

[0274] In some embodiments, the compound has a structure of Formula A1 -10 wherein R2, R3and R4are defined elsewhere in this specification. In certain embodiments, R2, R3and R4are independently selected from H, F, Cl, OH, OCH3, CO2CH3, CH2CH2, CH(CH3)2, CF3and CH3. In certain embodiments, R2is CH3and R3and R4are H. In certain embodiments, R2and R3are H and R4is CH3.

[0275] R13is defined elsewhere in this specification. In certain embodiments, R13is hydrogen or an optionally substituted alkylamino such as methylamine, ethylamine, propylamine or isopropylamine.

[0276] R14is defined elsewhere in this specification. In certain embodiments, R14is selected from:

[0277] R15is defined elsewhere in this specification. In certain embodiments, R15is selected from:

[0278] R17is defined elsewhere in this specification. In certain embodiments, R17is selected from: and Y is defined elsewhere in this specification. In certain embodiments, Y is selected from

[0279] Y1and Y2may be independently selected from H, F, =0, OH. Y3may be independently selected from CH3, SO2CH3 and H. Y4, Y5, Y6, Y7and Y8are independently selected from H, Cl,

[0280] F, CN, OCHF2 and OCF3. Y9is selected from F, CO2H and CO2CH3. Y10is selected from H and F. Y11is selected from H, CH3, SO2CH3, SO2c-Pr where c-Pr is cyclopropyl, SO2CH2F,

[0281] SO2CHF2, SO2CF3, SO2NH2, COCH3, COi-Pr where i-Pr is isopropyl, CH2CCH, COCHCH2and CN. One of Y12, Y13, Y14’ Y15and Y16is NH or NCH3with the others being CH2. One of Y17, Y18and Y19is NY20and the others are CH2. Y20is H, CH3or SO2CH3.

[0282] Exemplary embodiments are depicted in Table C. Subgroup 11 : certain Formula A1 compounds

[0283] In some embodiments, the compound has a structure of Formula A1 -11 wherein R2and R4are defined elsewhere in this specification. In certain embodiments, R2and R4are independently selected from H and CH3;

[0284] R14is defined elsewhere in this specification. In certain embodiments, R14is selected from:

[0285] R17is defined elsewhere in this specification. In certain embodiments, R17is H or F. Y is defined elsewhere in this specification. In certain embodiments, Y is selected from

[0286] Exemplary embodiments are depicted in Table C.

[0287] Subgroup 12: certain Formula A1 compounds In some embodiments, the compound has a structure of Formula A1 -12 wherein R2and R4are defined elsewhere in this specification. In certain embodiments, R2and R4are independently selected from H and CH3;

[0288] R14is defined elsewhere in this specification. In certain embodiments, R14is selected from:

[0289] R15is defined elsewhere in this specification. In certain embodiments, R15is selected from:

[0290] R16is defined elsewhere in this specification. In certain embodiments, R16is selected from:

[0291] R18is defined elsewhere in this specification. In certain embodiments, R18is selected from: and Y is defined elsewhere in this specification. In certain embodiments, Y is selected from

[0292] Y21is CH3or H.

[0293] Exemplary embodiments are depicted in Table C.

[0294] Subgroup 13: certain Formula A1 compounds

[0295] In some embodiments, the compound has a structure of Formula A1 -13 wherein R2and R4are defined elsewhere in this specification. In certain embodiments, R2and R4are independently selected from H and CH3;

[0296] R16is defined elsewhere in this specification. In certain embodiments, R16is selected from: and Y is defined elsewhere in this specification. In certain embodiments Y is selected from

[0297] Exemplary embodiments are depicted in Table C. Subgroup 14: certain Formula A1 compounds

[0298] In some embodiments, the compound has a structure of Formula A1 -14 wherein R2and R4are defined elsewhere in this specification. In certain embodiments, R2and R4are independently selected from H and CH3; R10is defined elsewhere in this specification. In certain embodiments, R10is selected from: wherein R52is CH(CH3)2, CH2CH(CH3)2, CH2CH2CH(CH3)2or cyclopentyl and R53is H or CF3.

[0299] Y is defined elsewhere in this specification. In certain embodiments, Y is selected from

[0300] Exemplary embodiments are depicted in Table C.

[0301] Subgroup 15:

[0302] In some embodiments, the compound has a structure of:

[0303] R2and R4are defined elsewhere in this specification. In certain embodiments, R2and R4are independently selected from H and CH3.

[0304] X23, X24, X25, X26and X27are independently selected from N, CH, CR54. In some embodiments, two non-consecutive nitrogen atoms are present. R54is CH3, CN, Cl or OCH(CH3)2.

[0305] Y is defined elsewhere in this specification. In certain embodiments, Y is:

[0306] Exemplary embodiments are depicted in Table C. Subgroup 16:

[0307] R2and R4are defined elsewhere in this specification. In certain embodiments, R2and R4are independently selected from H and CH3.

[0308] X28is selected from H, F, CH3and OCH3.

[0309] Y is defined elsewhere in this specification. In certain embodiments, Y is:

[0310] Exemplary embodiments are depicted in Table C.

[0311] Subgroup 17:

[0312] In some embodiments, the compound has a structure of:

[0313] R2and R4are defined elsewhere in this specification. In certain embodiments, R2and R4are independently selected from H and CH3.

[0314] X29and X30are independently selected from H, CH2Ph, CH(CH3)2, OCH2CH3, cyclopropyl or a substituted arene. In one embodiment, the substituted arene has a structure of: wherein R55, R56, R57, R58and R59are independently selected from H, OCH3and F.

[0315] Y is defined elsewhere in this specification. In certain embodiments, Y is:

[0316] Exemplary embodiments are depicted in Table C.

[0317] Subgroup 18:

[0318] In some embodiments, the compound has a structure of:

[0319] R2and R4are defined elsewhere in this specification. In certain embodiments, R2and R4are independently selected from H and CH3.

[0320] X31is a tetrazole that attaches at the 5-position. The nitrogen at the 2-position of the tetrazole has a CH3 or H.

[0321] Y is defined elsewhere in this specification. In certain embodiments, Y is:

[0322] Exemplary embodiments are depicted in Table C.

[0323] Any definition herein may be used in combination with any other definition to describe a composite structural group. By convention, the trailing element of any such definition is that which attaches to a parent moiety. The composite group alkylamido, for example, would represent an alkyl group attached to a parent molecule through an amido group, the term amidoalkyl would represent an amido group attached to a parent molecule through an alkyl group, the term alkylalkoxy would represent an alkyl group attached to a parent molecule through an alkoxy group, and the term alkoxyalkyl would represent an alkoxy group attached to a parent molecule through an alkyl group, for example.

[0324] When a group is defined to be “null,” the group is absent. The term “optionally substituted” means the anteceding group may be substituted or unsubstituted. The term “substituted,” as used herein, refers, without limitation, to one or more substituents that can include, for example, substituents independently selected from the following groups or a particular designated set of groups, alone or in combination: lower alkyl, lower alkenyl, lower alkynyl, lower alkanoyl, lower heteroalkyl, lower aryl, lower cycloalkyl, lower heteroaryl, lower heterocycloalkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, lower haloalky I, lower haloalkenyl, lower haloalkynyl, lower perhaloalkyl, lower perhaloalkoxy, phenyl, aryloxy, lower hydroxyalkyl, lower mercaptoalkyl, lower aminoalkyl, lower arylaminoalkyl, aryloxyalkyl, lower aryloxyalkyl, arylthioalkyl, lower arylthioalkyl, heteroarylaminoalkyl, heteroaryloxyalkyl, heteroarylthioalkyl, arylalkyl, lower arylalkyl, heteroarylalkyl, lower heteroarylalkyl, lower alkoxy, lower haloalkoxy, oxo, lower acyloxy, carbonyl, carboxyl, lower alkylcarbonyl, lower carboxyester, lower carboxamido, cyano, hydrogen, halogen, hydroxy, amino, lower alkylamino, arylamino, amido, nitro, thiol, lower alkylthio, lower haloalkylthio, lower perhaloalkylthio, arylthio, sulfonate, sulfonic acid, trisubstituted silyl, N3, SH, SCH3, C(O)CH3, CO2CH3, CO2H, B(OH)2, pyridinyl, thiophene, furanyl, lower carbamate, and lower urea. Two substituents may be joined together to form a fused five-, six-, or seven-membered carbocyclic, heterocyclic aryl, or heteroaryl ring system having zero to three heteroatoms, for example, forming methylenedioxy or ethylenedioxy. An optionally substituted group may contain a deuterium in place of one or more hydrogen atoms (for example, -CD3instead of -CH3). An optionally substituted group may be unsubstituted (for example, -CH2CH3), fully substituted (for example, -CF2CF3), monosubstituted (for example, - CH2CH2F) or substituted at a level anywhere in-between fully substituted and monosubstituted (for example, -CH2CF3). Where substituents are recited without qualification as to substitution, both substituted and unsubstituted forms are encompassed. Where a substituent is qualified as “substituted,” the substituted form is specifically intended. Additionally, different sets of optional substituents to a particular moiety may be defined as needed. An optional substitution often is as defined, sometimes immediately following the phrase, “optionally substituted with.” The term R or the term R’, appearing by itself and without a number designation, unless otherwise defined, refers to a moiety chosen from hydrogen (H), alkyl, cycloalkyl, heteroalkyl, aryl, heteroaryl and heterocycloalkyl, any of which may be optionally substituted. Such R and R' groups should be understood to be optionally substituted as defined herein. Whether an R group has a number designation or not, every R group, including R, R’ and Rnwhere n = (1 , 2, 3, ... n), every substituent, and every term should be understood to be independent of every other in terms of selection from a group. Should any variable, substituent, or term (for example aryl, heterocycle, R, etc.) occur more than one time in a formula or generic structure, its definition at each occurrence is independent of the definition at every other occurrence. Certain groups may be attached to a parent molecule or may occupy a position in a chain of elements from either end as written. Thus, by way of example only, an asymmetrical group such as - C(O)N(R)- may be attached to a parent moiety at either the carbon or the nitrogen.

[0325] In embodiments, the term ‘substituted’ and ‘substituent group’, as used herein, means a group selected from the following moieties:

[0326] (A) oxo, halogen, -CCI3, -CBr3, -CF3, -Cl3, -CHCI2, -CHBr2, -CHF2, -CHI2, -CH2CI, -CH2Br, -CH2F, -CH2I, -0CCI3, -OCF3, -OCBr3, -OCI3, -OCHCI2, -OCHBr2, -0CHI2, -OCHF2, -OCH2CI, -OCH2Br, -OCH2I, -OCH2F, -CN, -OH, -NH2, -COOH, -CONH2, -N02, -SH, -SO3H, -OSO3H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, - NHC(NH)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -N3,

[0327] -SF5, unsubstituted alkyl (for example, Ci-C8alkyl, Ci-C6alkyl, or C1-C4 alkyl), unsubstituted heteroalkyl (for example, 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), unsubstituted cycloalkyl (for example, C3-C8cycloalkyl, C3-C6cycloalkyl, or C5-C6cycloalkyl), unsubstituted heterocycloalkyl (for example, 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), unsubstituted aryl (for example, Ce-C aryl, Cw aryl, or phenyl), or unsubstituted heteroaryl (for example, 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl), and

[0328] (B) alkyl (for example, Ci-C8alkyl, Ci-C6alkyl, or C1-C4 alkyl), heteroalkyl (for example, 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), cycloalkyl (for example, C3-C8cycloalkyl, C3-C6cycloalkyl, or C5-C6cycloalkyl), heterocycloalkyl (for example, 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), aryl (for example, C6-Ci0aryl, C aryl, or phenyl), heteroaryl (for example, 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl), substituted with at least one substituent selected from:

[0329] (i) oxo, halogen, -CCI3, -CBr3, -CF3, -Cl3, -CHCI2, -CHBr2, -CHF2, -CHI2, -CH2CI, -CH2Br, -CH2F, -CH2I, -OCCI3, -OCF3, -OCBr3, -OCI3, -OCHCI2, -OCHBr2, -OCHI2, -OCHF2, -OCH2CI, -OCH2Br, -OCH2I, -OCH2F, -CN, -OH, -NH2, -COOH, -CONH2,

[0330] -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, - NHC(NH)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -N3,

[0331] -SF5, unsubstituted alkyl (for example, Ci-C8alkyl, Ci-C6alkyl, or C1-C4 alkyl), unsubstituted heteroalkyl (for example, 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), unsubstituted cycloalkyl (for example, C3-C8cycloalkyl, C3-C8cycloalkyl, or C5-C6cycloalkyl), unsubstituted heterocycloalkyl (for example, 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), unsubstituted aryl (for example, C3-C aryl, C aryl, or phenyl), or unsubstituted heteroaryl (for example, 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl), and

[0332] (ii) alkyl (for example, Ci-C8alkyl, Ci-C8alkyl, or C1-C4 alkyl), heteroalkyl (for example, 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), cycloalkyl (for example, C3-C8cycloalkyl, C3-C6cycloalkyl, or C5-C6cycloalkyl), heterocycloalkyl (for example, 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), aryl (for example, C6-Cw aryl, Cw aryl, or phenyl), heteroaryl (for example, 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl), substituted with at least one substituent selected from: (a) oxo, halogen, -CCI3, -CBr3, -CF3, -Cl3, -CHCI2, -CHBr2, -CHF2, -CHI2, -CH2CI,

[0333] -CH2Br, -CH2F, -CH2I, -OCCI3, -OCF3, -OCBr3, -OCI3, -OCHCI2, -OCHBr2, -OCHI2, -OCHF2, -OC H2CI, -OCH2Br, -OCH2I, -OCH2F, -CN, -OH, -NH2, -COOH, -CONH2, -N02, -SH, -SO3H, - OSO3H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -

[0334] NHC(NH)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -N3,

[0335] -SF5, unsubstituted alkyl (for example, Ci-C8alkyl, Ci-C6alkyl, or C1-C4 alkyl), unsubstituted heteroalkyl (for example, 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), unsubstituted cycloalkyl (for example, C3-C8cycloalkyl, C3-C6 cycloalkyl, or C5-C6cycloalkyl), unsubstituted heterocycloalkyl (for example, 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), unsubstituted aryl (for example, C6-C aryl, Cw aryl, or phenyl), or unsubstituted heteroaryl (for example, 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl), and

[0336] (b) alkyl (for example, Ci-C8alkyl, Ci-Cs alkyl, or C1-C4 alkyl), heteroalkyl (for example, 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), cycloalkyl (for example, C3-C8cycloalkyl, C3-C6cycloalkyl, or C5-C6cycloalkyl), heterocycloalkyl (for example, 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), aryl (for example, Ce-C aryl, C10 aryl, or phenyl), heteroaryl (for example, 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl), substituted with at least one substituent selected from: oxo, halogen, -CCI3, -CBr3, -CF3, -Cl3, -CHCI2, -CHBr2,

[0337] -CHF2, -CHI2, -CH2CI, -CH2Br, -CH2F, -CH2I, -OCCI3, -OCF3, -OCBr3, -OCI3,

[0338] -OCHCI2, -OCHBr2, -OCHI2, -OCHF2, -OCH2CI, -OCH2Br, -OCH2I, -OCH2F, -CN,

[0339] -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, -NHNH2, -ONH2, -NHC(O)NHNH2, -NHC(O)NH2, -NHC(NH)NH2, -NHSO2H, -NHC(O)H,

[0340] -NHC(O)OH, -NHOH, -N3, -SF5, unsubstituted alkyl (for example, Ci-C8alkyl, Ci-C6alkyl, or Ci- 04 alkyl), unsubstituted heteroalkyl (for example, 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), unsubstituted cycloalkyl (for example, C3-C8cycloalkyl, C3-C6cycloalkyl, or C5-C6cycloalkyl), unsubstituted heterocycloalkyl (for example, 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), unsubstituted aryl (for example, C6-C aryl, C aryl, or phenyl), or unsubstituted heteroaryl (for example, 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl).

[0341] A “size-limited substituent” or “size-limited substituent group,” as used herein, means a group selected from all of the substituents described above for a “substituent group,” wherein each substituted or unsubstituted alkyl is a substituted or unsubstituted Ci-C2o alkyl, each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2 to 20 membered heteroalkyl, each substituted or unsubstituted cycloalkyl is a substituted or unsubstituted C3-C8cycloalkyl, each substituted or unsubstituted heterocycloalkyl is a substituted or unsubstituted 3 to 8 membered heterocycloalkyl, each substituted or unsubstituted aryl is a substituted or unsubstituted C6-Ci0aryl, and each substituted or unsubstituted heteroaryl is a substituted or unsubstituted 5 to 10 membered heteroaryl.

[0342] A “lower substituent” or “lower substituent group,” as used herein, means a group selected from all of the substituents described above for a “substituent group,” wherein each substituted or unsubstituted alkyl is a substituted or unsubstituted Ci-Cs alkyl, each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2 to 8 membered heteroalkyl, each substituted or unsubstituted cycloalkyl is a substituted or unsubstituted C3-C7 cycloalkyl, each substituted or unsubstituted heterocycloalkyl is a substituted or unsubstituted 3 to 7 membered heterocycloalkyl, each substituted or unsubstituted aryl is a substituted or unsubstituted phenyl, and each substituted or unsubstituted heteroaryl is a substituted or unsubstituted 5 to 6 membered heteroaryl.

[0343] In some embodiments, each substituted group described in the compounds herein is substituted with at least one substituent group. More specifically, in some embodiments, each substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, substituted heteroaryl, substituted alkylene, substituted heteroalkylene, substituted cycloalkylene, substituted heterocycloalkylene, substituted arylene, and / or substituted heteroarylene described in the compounds herein are substituted with at least one substituent group. In some embodiments, at least one or all of these groups are substituted with at least one size-limited substituent group. In some embodiments, at least one or all of these groups are substituted with at least one lower substituent group.

[0344] In some embodiments of the compounds herein, each substituted or unsubstituted alkyl may be a substituted or unsubstituted C1-C20 alkyl, each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2 to 20 membered heteroalkyl, each substituted or unsubstituted cycloalkyl is a substituted or unsubstituted C3-C8 cycloalkyl, each substituted or unsubstituted heterocycloalkyl is a substituted or unsubstituted 3 to 8 membered heterocycloalkyl, each substituted or unsubstituted aryl is a substituted or unsubstituted C6-Ci0aryl, and / or each substituted or unsubstituted heteroaryl is a substituted or unsubstituted 5 to 10 membered heteroaryl. In some embodiments of the compounds herein, each substituted or unsubstituted alkylene is a substituted or unsubstituted C1-C20 alkylene, each substituted or unsubstituted heteroalkylene is a substituted or unsubstituted 2 to 20 membered heteroalkylene, each substituted or unsubstituted cycloalkylene is a substituted or unsubstituted C3-C8cycloalkylene, each substituted or unsubstituted heterocycloalkylene is a substituted or unsubstituted 3 to 8 membered heterocycloalkylene, each substituted or unsubstituted arylene is a substituted or unsubstituted Ce-C arylene, and / or each substituted or unsubstituted heteroarylene is a substituted or unsubstituted 5 to 10 membered heteroarylene. In some embodiments, each substituted or unsubstituted alkyl is a substituted or unsubstituted Ci-C8alkyl, each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2 to 8 membered heteroalkyl, each substituted or unsubstituted cycloalkyl is a substituted or unsubstituted C3-C7 cycloalkyl, each substituted or unsubstituted heterocycloalkyl is a substituted or unsubstituted 3 to 7 membered heterocycloalkyl, each substituted or unsubstituted aryl is a substituted or unsubstituted C6-C aryl, and / or each substituted or unsubstituted heteroaryl is a substituted or unsubstituted 5 to 9 membered heteroaryl. In some embodiments, each substituted or unsubstituted alkylene is a substituted or unsubstituted Ci-C8alkylene, each substituted or unsubstituted heteroalkylene is a substituted or unsubstituted 2 to 8 membered heteroalkylene, each substituted or unsubstituted cycloalkylene is a substituted or unsubstituted C3-C7 cycloalkylene, each substituted or unsubstituted heterocycloalkylene is a substituted or unsubstituted 3 to 7 membered heterocycloalkylene, each substituted or unsubstituted arylene is a substituted or unsubstituted C6-Ci0arylene, and / or each substituted or unsubstituted heteroarylene is a substituted or unsubstituted 5 to 9 membered heteroarylene. In some embodiments, the compound is a chemical species set forth in the Examples section, figures, or tables below.

[0345] In embodiments, a substituted or unsubstituted moiety (for example, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, and / or substituted or unsubstituted heteroarylene) is unsubstituted (for example, is an unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, unsubstituted heteroaryl, unsubstituted alkylene, unsubstituted heteroalkylene, unsubstituted cycloalkylene, unsubstituted heterocycloalkylene, unsubstituted arylene, and / or unsubstituted heteroarylene, respectively). In embodiments, a substituted or unsubstituted moiety (for example, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, and / or substituted or unsubstituted heteroarylene) is substituted (for example, is a substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, substituted heteroaryl, substituted alkylene, substituted heteroalkylene, substituted cycloalkylene, substituted heterocycloalkylene, substituted arylene, and / or substituted heteroarylene, respectively). In embodiments, a substituted moiety (for example, substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, substituted heteroaryl, substituted alkylene, substituted heteroalkylene, substituted cycloalkylene, substituted heterocycloalkylene, substituted arylene, and / or substituted heteroarylene) is substituted with at least one substituent group, wherein if the substituted moiety is substituted with a plurality of substituent groups, each substituent group may optionally be different. In embodiments, if the substituted moiety is substituted with a plurality of substituent groups, each substituent group is different.

[0346] In embodiments, a substituted moiety (for example, substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, substituted heteroaryl, substituted alkylene, substituted heteroalkylene, substituted cycloalkylene, substituted heterocycloalkylene, substituted arylene, and / or substituted heteroarylene) is substituted with at least one size-limited substituent group, wherein if the substituted moiety is substituted with a plurality of size-limited substituent groups, each size-limited substituent group may optionally be different. In embodiments, if the substituted moiety is substituted with a plurality of size-limited substituent groups, each size-limited substituent group is different.

[0347] In embodiments, a substituted moiety (for example, substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, substituted heteroaryl, substituted alkylene, substituted heteroalkylene, substituted cycloalkylene, substituted heterocycloalkylene, substituted arylene, and / or substituted heteroarylene) is substituted with at least one lower substituent group, wherein if the substituted moiety is substituted with a plurality of lower substituent groups, each lower substituent group may optionally be different. In embodiments, if the substituted moiety is substituted with a plurality of lower substituent groups, each lower substituent group is different.

[0348] In embodiments, a substituted moiety (for example, substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, substituted heteroaryl, substituted alkylene, substituted heteroalkylene, substituted cycloalkylene, substituted heterocycloalkylene, substituted arylene, and / or substituted heteroarylene) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted moiety is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, sizelimited substituent group, and / or lower substituent group may optionally be different. In embodiments, if the substituted moiety is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and / or lower substituent group is different. The term “acyl,” as used herein, alone or in combination, refers to a carbonyl attached to an alkenyl, alkyl, aryl, cycloalkyl, heteroaryl, heterocycle, or any other moiety where the atom attached to the carbonyl is carbon. Non-limiting examples of acyl groups include formyl, alkanoyl and aroyl.

[0349] An “acetyl” group refers to a -C(O)CH3group.

[0350] The term “aliphatic,” as used herein, refers to saturated and partially unsaturated, nonaromatic, straight chain (i.e., unbranched), branched and cyclic (including bicyclic and polycyclic) hydrocarbons which may be optionally substituted with one or more functional groups. In certain embodiments, an aliphatic group contains 1 to 20 carbon atoms, 1 to 10 carbon atoms, 1 to 8 carbon atoms, 1 to 6 carbon atoms or 1 to 3 carbon atoms.

[0351] An “alkylcarbonyl” or “alkanoyl” group refers to an alkyl group attached to a parent molecular moiety through a carbonyl group. Non-limiting examples of such groups include methylcarbonyl and ethylcarbonyl.

[0352] The term “alkenyl,” as used herein, alone or in combination, refers to a straight-chain or branched-chain hydrocarbon radical having one or more double bonds and containing from 2 to 20 carbon atoms. In certain embodiments, an alkenyl includes 2 to 6 carbon atoms. The term “alkenylene” refers to a carbon-carbon double bond system attached at two or more positions such as ethenylene [(-CH=CH-),(-C::C-)]. Non-limiting examples of alkenyl radicals include ethenyl, propenyl, 2-methylpropenyl, 1 ,4-butadienyl and the like. Unless otherwise specified, the term “alkenyl” may include “alkenylene” groups. An alkene functionality is not directly bonded to a nitrogen. An alkenyl group containing an alkene functionality and alkyl portion, such as an allyl group, for example, can be bonded to a nitrogen such that the alkene functionality is not directly bonded to the nitrogen.

[0353] The term “alkoxy,” as used herein, alone or in combination, refers to an alkyl ether radical, where the term alkyl is as defined below. Non-limiting examples of alkyl ether radicals include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy, and the like.

[0354] The term “alkyl,” as used herein, alone or in combination, refers to a saturated straight-chain or branched-chain hydrocarbon radical containing from 1 to 20 carbon atoms. The term “straightchain alkyl” refers to a saturated straight-chain hydrocarbon radical. The term “branched-chain alkyl” refers to a saturated branched-chain hydrocarbon radical. In certain embodiments, an alkyl includes 1 to 10 carbon atoms (C1 -C10 alkyl), 1 to 8 carbon atoms (C1 -C8 alkyl), 1 to 6 carbon atoms (C1 -C6 alkyl) or 1 to 3 carbon atoms (C1-C3 alkyl). Alkyl groups may be optionally substituted as defined herein. Non-limiting examples of alkyl radicals include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, iso-amyl, hexyl, octyl, nonyl and the like.

[0355] The term “alkylene,” as used herein, alone or in combination, refers to a saturated aliphatic group derived from a straight or branched chain saturated hydrocarbon attached at two or more positions, such as methylene (-CH2-). Unless otherwise specified, the term “alkyl” may include “alkylene” groups. The term “alkylamino,” as used herein, alone or in combination, refers to an alkyl group attached to a parent molecular moiety through an amino group. Alkylamino groups include monoalkylated groups (monoalkylamino) or dialkylated groups (dialkylamino), non-limiting examples of which include N-methylamino, N-ethylamino, N,N-dimethylamino, N,N- ethylmethylamino and the like.

[0356] The term “alkylidene,” as used herein, alone or in combination, refers to an alkenyl group in which one carbon atom of the carbon-carbon double bond belongs to the moiety to which the alkenyl group is attached.

[0357] The term “alkylthio,” as used herein, alone or in combination, refers to an alkyl thioether (R-S-) radical where the term alkyl is as defined above and where the sulfur may be singly or doubly oxidized. Non-limiting examples of alkyl thioether radicals include methylthio, ethylthio, n- propylthio, isopropylthio, n-butylthio, iso-butylthio, sec-butylthio, tert-butylthio, methanesulfonyl, ethanesulfinyl, and the like.

[0358] The term “alkynyl,” as used herein, alone or in combination, refers to a straight-chain or branched chain hydrocarbon radical having one or more triple bonds and containing from 2 to 20 carbon atoms. In certain embodiments, an alkynyl includes 2 to 6 carbon atoms. In some embodiments, an alkynyl includes 2 to 4 carbon atoms. The term “alkynylene” refers to a carbon-carbon triple bond attached at two positions such as ethynylene (-C:::C-, -C=C-). Nonlimiting examples of alkynyl radicals include ethynyl, propynyl, hydroxypropynyl, butyn-1-yl, butyn-2-yl, pentyn-1 -yl, 3-methylbutyn-1-yl, hexyn-2-yl, and the like. Unless otherwise specified, the term “alkynyl” may include “alkynylene” groups. An alkyne functionality is not directly bonded to nitrogen. An alkynyl group containing an alkyne functionality and an alkyl portion, such as a propargyl group, for example, can be bonded to a nitrogen such that the alkyne functionality is not directly bonded to the nitrogen.

[0359] The terms “amido” and “carbamoyl,” as used herein, alone or in combination, refer to an amino group as described below attached to a parent molecular moiety through a carbonyl group, or vice versa. The term “C-amido” as used herein, alone or in combination, refers to a -C(O)N(RFT) group with R and R’ as defined herein or as defined by the specifically enumerated “R” groups designated. The term “N-amido” as used herein, alone or in combination, refers to a RC(O)N(R’)- group, with R and R’ as defined herein or as defined by the specifically enumerated “R” groups designated.

[0360] The term "acylamino" as used herein, alone or in combination, includes an acyl group attached to a parent moiety through an amino group. A non-limiting example of an "acylamino" group is acetylamino (CH3C(O)NH-).

[0361] The term “amino,” as used herein, alone or in combination, refers to -NRR’, where R and R’ are independently chosen from hydrogen, alkyl, alkenyl, alkynyl, acyl, heteroalkyl, aryl, cycloalkyl, heteroaryl, and heterocycloalkyl, any of which may themselves be optionally substituted. Additionally, R and R’ may combine to form heterocycloalkyl or heteroaryl, either of which may be optionally substituted.

[0362] The term "aminoalkyl," as used herein, refers to an amino group attached to a parent molecule through an alkyl group (N(R)(R')-alkyl-) , where R and R' are defined herein. The term "lower aminoalkyl," as used herein, refers to an amino group attached to a parent molecule through a lower alkyl group (N(R)(R')-lower alkyl-), where "lower alkyl," R and R' are defined herein. The term "aryl," as used herein, alone or in combination, refers to an aromatic cyclic ring system, or aromatic hydrocarbon ring system, in which all of the atoms that form the covalent structure of the one or more aromatic rings are carbon (referred to herein as an "aryl ring”). The aryl ring may be optionally substituted as defined herein. The ring system may be monocyclic or fused polycyclic, for example, bicyclic or tricylic (containing two or three rings fused together). In certain embodiments, the monocyclic aryl ring is C4-C10, or C5-C9, or C5-C8, or C5-C7, or, in certain embodiments, C5-C6, where these carbon numbers refer to the number of carbon ring member atoms that form the ring system. In some embodiments, the polycyclic ring system is a bicyclic aryl group, where the bicyclic aryl group in some embodiments is C8-C12, or, for example, C9-C10. In some embodiments, the polycyclic ring system is a tricyclic aryl group, where the tricyclic aryl group is C11 -C18, or, for example, C12-C16. Non-limiting examples of aryl ring systems include phenyl (monocyclic, C6), naphthyl (bicyclic, C10), anthracenyl (tricyclic, C14) and phenanthryl (tricyclic, C14).

[0363] The term “arylalkenyl” or “aralkenyl,” as used herein, alone or in combination, refers to an aryl group attached to a parent molecular moiety through an alkenyl group.

[0364] The term “arylalkoxy” or “aralkoxy,” as used herein, alone or in combination, refers to an aryl group attached to a parent molecular moiety through an alkoxy group.

[0365] The term “arylalkyl” or “aralkyl,” as used herein, alone or in combination, refers to an aryl group attached to a parent molecular moiety through an alkyl group. The term “lower arylalkyl” or “lower aralkyl,” as used herein, alone or in combination, refers to a lower aryl group attached to a parent molecular moiety through a lower alkyl group, where "lower aryl" and "lower alkyl" are as defined herein.

[0366] The term “arylalkynyl” or “aralkynyl,” as used herein, alone or in combination, refers to an aryl group attached to a parent molecular moiety through an alkynyl group.

[0367] The term “arylalkanoyl” or “aralkanoyl” or "aroyl,” as used herein, alone or in combination, refers to an acyl radical derived from an aryl-substituted alkanecarboxylic acid, non-limiting examples of which include benzoyl, napthoyl, phenylacetyl, 3-phenylpropionyl (hydrocinnamoyl), 4- phenylbutyryl, (2-naphthyl)acetyl, 4-chlorohydrocinnamoyl, and the like.

[0368] The term "arylaminoalkyl" as used herein refers to an aryl group attached to a parent molecule through an aminoalkyl group (aryl-N(R)-alkyl-), where R is as defined herein. The term "lower arylaminoalkyl" as used herein refers to a lower aryl group attached to a parent molecule through a lower aminoalkyl group (lower aryl-N(R)-lower alkyl-), where "lower aryl," "lower aminoalkyl" and R are as defined herein.

[0369] The term “aryloxy” as used herein, alone or in combination, refers to an aryl group attached to a parent molecular moiety through an oxygen atom.

[0370] The term "aryloxyalkyl" as used herein refers to an aryl group attached to a parent molecule through an alkyl ether group (aryl-O-alkyl-). The term "lower aryloxyalkyl" as used herein refers to a lower aryl group attached to a parent molecule through a lower alkyl ether group (lower aryl-O-lower alkyl-), where "lower aryl" and "lower alkyl" are defined herein.

[0371] The term "arylthioalkyl" as used herein refers to an aryl group attached to a parent molecule through a thioalkyl group (aryl-S-alkyl-). The term "lower arylthioalkyl" as used herein refers to a lower aryl group attached to a parent molecule through a lower thioalkyl group (lower aryl-S- lower alkyl-) where "lower aryl" and "lower alkyl" are defined herein.

[0372] The terms “benzo” and “benz,” as used herein, alone or in combination, refer to the divalent radical C6H4= derived from benzene. Non-limiting examples include benzothiophene and benzimidazole.

[0373] The term "boronic acid" as used herein refers to a -B(OH)2group.

[0374] The term “carbamate,” as used herein, alone or in combination, refers to an ester of carbamic acid (-NHCOO-) which may be attached to a parent molecular moiety from either the nitrogen or acid end, and which may be optionally substituted as defined herein.

[0375] The term “O-carbamyl” as used herein, alone or in combination, refers to a -OC(O)NRR’ group where R and R’ are as defined herein.

[0376] The term “N-carbamyl” as used herein, alone or in combination, refers to a ROC(O)NR’- group, where R and R’ are defined herein.

[0377] The term “carbonyl,” as used herein, when alone includes formyl [-C(O)H] and in combination includes a -C(O)- group.

[0378] The term “carboxyl” or “carboxy,” as used herein, refers to -C(O)OH or the corresponding “carboxylate” anion (for example, in a carboxylic acid salt). An “O-carboxy” group refers to a RC(O)O- group, where R is as defined herein. A “C-carboxy” group refers to a -C(O)OR group where R is as defined herein.

[0379] The term “cyano,” as used herein, alone or in combination, refers to -CN.

[0380] The terms “cycloalkyl,” and, interchangeably, “carbocycle,” as used herein, alone or in combination, refers to a ring system in which all of the ring member atoms are carbon and at least one of the rings is a saturated or partially unsaturated aliphatic cyclic ring moiety (referred to herein as a “cycloalkyl ring” or “carbocycle ring”). In some embodiments, each cyclic moiety contains from 3 to 12 carbon ring member atoms which may be optionally substituted as defined herein. In some embodiments, a cycloalkyl group contains 3 to 10 carbon ring member atoms. In certain embodiments, a cycloalkyl includes 5 to 7 carbon atoms. In certain embodiments, a cycloalkyl includes 5 to 6 carbon atoms. A cycloalkyl can be a monocyclic or polycyclic, for example, bicyclic or tricyclic, ring system in which at least one cyclic ring is a cycloalkyl ring. In certain embodiments, the monocyclic cycloalkyl ring is C3-C10, or C5-C9, or C5-C8, or C5-C7, or, in certain embodiments, C5-C6, where these carbon numbers refer to the number of carbon ring member atoms that form the ring system. Polycyclic cycloalkyl ring systems include fused, bridged and spiro-fused rings. Polycyclic cycloalkyl ring systems as defined herein, include ring systems in which one or more cycloalkyl rings is / are fused to one or more aryl rings (benzofused cycloalkyl ring systems) and / or other cycloalkyl rings. In some embodiments, all of the rings in a polycyclic cycloalkyl ring system are cycloalkyl rings. In some embodiments, the polycyclic ring system is a bicyclic cycloalkyl group, where the bicyclic cycloalkyl group in some embodiments is C8-C12, or, for example, C9-C10. In some embodiments, the polycyclic ring system is a tricyclic cycloalkyl group, where the tricyclic cycloalkyl group is C11 -C18, or, for example, C12-C16. Non-limiting examples of such cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, octahydronaphthalene, decahydronaphthalene, bicyclo[1 ,1 ,1]pentane and the like. Examples of aryl-fused cyclolalkyl ring systems include a benzene ring fused to hydrogenated or partially hydrogenated ring systems, non-limiting examples of which include dihydronaphthalene, tetrahydronaphthalene and indanyl. In polycyclic systems in which a cycloalkyl is fused to an aryl, attachment of the polycycle to the indicated point of attachment on the parent molecule may be through any ring atom of the polycycle rings. In some embodiments of polycyclic cycloalkyls, the polycycle is attached to the indicated point of attachment through a ring member atom of a cycloalkyl ring. In some embodiments of polycyclic cycloalkyls, the polycycle is attached to the indicated point of attachment through a ring member atom of a ring that is not a cycloalkyl ring, for example, an aryl ring.

[0381] The term “carbocycle-alkyl” or “cycloalkylalkyl” as used herein, alone or in combination, refers to a carbocycle group attached to a parent molecular moiety through an alkyl group.

[0382] The term “deuteroalkyl,” as used herein, alone or in combination, refers to an alkyl radical having the meaning as defined herein where one or more or all hydrogens are replaced with a deuterium. Specifically included are monodeuteroalkyl, dideuteroalkyl, trideuteroalkyl and polydeuteroalkyl radicals. A "lower deuteroalkyl" group is a C1 -C6, C1 -C5, C1 -C4, C1 -C3 or C1- C2 alkyl in which one or more hydrogens are replaced with a deuterium. A non-limiting example of a lower deuteroalkyl group is the trideuteroalkyl -CD3, in which the three hydrogens of -CH3are replaced by deuterium.

[0383] The term “ester,” as used herein, alone or in combination, refers to a carboxy group bridging two moieties linked at carbon atoms.

[0384] The term “ether,” as used herein, alone or in combination, refers to an oxy group bridging two moieties linked at carbon atoms.

[0385] The term “halo,” or “halogen,” as used herein, alone or in combination, refers to fluorine, chlorine, bromine, or iodine. The term “haloalkoxy,” as used herein, alone or in combination, refers to a haloalkyl group attached to a parent molecular moiety through an oxygen atom.

[0386] The term “haloalkyl,” as used herein, alone or in combination, refers to an alkyl radical having the meaning as defined above where one or more hydrogens are replaced with a halogen. Specifically included are monohaloalkyl, dihaloalkyl and polyhaloalkyl radicals. A monohaloalkyl radical, for example, sometimes include an iodo, bromo, chloro or fluoro atom within the radical. Dihalo and polyhaloalkyl radicals sometimes include two or more of the same halo atoms or a combination of different halo radicals. Non-limiting examples of haloalkyl radicals include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl and dichloropropyl. “Haloalkylene” refers to a haloalkyl group attached at two or more positions. Non-limiting examples include fluoromethylene (-CFH-), difluoromethylene (-CF2-), chloromethylene (-CHCI-) and the like.

[0387] The term “heteroaliphatic,” as used herein, refers to an aliphatic moiety, as defined herein, that contains one or more heteroatoms, such as, for example, oxygen, nitrogen, sulfur, phosphorous and / or silicon, for example, in place of a carbon atom or between carbon atoms. In some embodiments, a heteroaliphatic group contains from one to three heteroatoms chosen from O, N, and S, and where the nitrogen and sulfur atoms may optionally be oxidized and the nitrogen heteroatom may optionally be quaternized. In certain embodiments, the heteroatom(s) may be placed at any interior position of the heteroaliphatic group. In some embodiments, up to two heteroatoms may be consecutive. In certain embodiments, a heteroaliphatic group includes 2 to 20 carbon atoms, 2 to 10 carbon atoms, 2 to 8 carbon atoms or 2 to 6 carbon atoms. The term "heteroalkyl," as used herein, alone or in combination, refers to a saturated or unsaturated, stable straight or branched hydrocarbon chain having the stated number of carbon atoms and one or more heteroatoms, such as, for example, oxygen, nitrogen, sulfur, phosphorous and / or silicon, for example, in place of a carbon atom. In some embodiments, a heteroalkyl contains from one to three heteroatoms chosen from O, N, and S, and where the nitrogen and sulfur atoms may optionally be oxidized and the nitrogen heteroatom may optionally be quaternized. In certain embodiments, the heteroatom(s) may be placed at any interior position of the heteroalkyl group. In some embodiments, up to two heteroatoms may be consecutive, such as, for example, -CH2-NH-OCH3. In certain embodiments, a heteroalkyl includes 2 to 20 carbon atoms, 2 to 10 carbon atoms, 2 to 8 carbon atoms or 2 to 6 carbon atoms. In some instances, a heteroalkyl contains from 1 to 3 degrees of unsaturation. Heteroalkyl groups may be optionally substituted as defined herein.

[0388] The term “heteroalkenyl,” as used herein, alone or in combination, refers to an alkenyl moiety, as defined herein, that contains one or more heteroatoms, such as, for example, oxygen, nitrogen, sulfur, phosphorous and / or silicon, for example, in place of a carbon atom or between carbon atoms. In some embodiments, a heteroalkenyl contains from one to three heteroatoms chosen from O, N, and S, and where the nitrogen and sulfur atoms may optionally be oxidized and the nitrogen heteroatom may optionally be quaternized. In certain embodiments, the heteroatom(s) may be placed at any interior position of the heteroalkenyl group. In some embodiments, up to two heteroatoms may be consecutive. In certain embodiments, a heteroalkenyl includes 2 to 20 carbon atoms, 2 to 10 carbon atoms, 2 to 8 carbon atoms or 2 to 6 carbon atoms.

[0389] The term “heteroalkynyl,” as used herein, alone or in combination, refers to an alkynyl moiety, as defined herein, that contains one or more heteroatoms, such as, for example, oxygen, nitrogen, sulfur, phosphorous and / or silicon, for example, in place of a carbon atom or between carbon atoms. In some embodiments, a heteroalkynyl contains from one to three heteroatoms chosen from O, N, and S, and where the nitrogen and sulfur atoms may optionally be oxidized and the nitrogen heteroatom may optionally be quaternized. In certain embodiments, the heteroatom(s) may be placed at any interior position of the heteroalkynyl group. In some embodiments, up to two heteroatoms may be consecutive. In certain embodiments, a heteroalkynyl includes 2 to 20 carbon atoms, 2 to 10 carbon atoms, 2 to 8 carbon atoms or 2 to 6 carbon atoms.

[0390] The term "heteroaryl," as used herein, alone or in combination, refers to a cyclic ring system in which at least one of the rings is an aromatic ring in which all ring member atoms are carbon, except for at least one heteroatom (referred to herein as a “heteroaryl ring”), such as, for example, nitrogen, oxygen and sulfur. The heteroaryl ring may be optionally substituted as defined herein. A heteroaryl can be a monocyclic or a fused polycyclic, for example, bicyclic or tricyclic, ring system in which at least one cyclic ring is an aromatic heteroaryl ring. Polycyclic, for example, bicyclic and tricyclic, fused heteroaryl ring systems as defined herein include heteroaryl ring systems in which one or more heteroaryl rings is / are fused to one or more aryl rings (which are referred to herein as aryl-fused heteroaryl rings), one or more cycloalkyl rings and / or one or more other heteroaryl rings. In some embodiments, all of the rings in a polycyclic heteroaryl ring system are heteroaryl rings. In certain embodiments, a heteroaryl ring contains at least one atom chosen from O, S, and N. In certain embodiments, a heteroaryl ring is a 3 to 15 membered monocyclic ring. In certain embodiments, a monocyclic heteroaryl group may contain from 4 to 10 ring member atoms, and may have, for example, 1 to 4 heteroatoms in the ring, where the remaining ring member atoms are carbon. In some embodiments, a bicyclic heteroaryl ring may contain from 8 to 15 ring member atoms, and have from 1 to 8 heteroatoms, where the remaining ring member atoms are carbon. In some embodiments, a tricyclic heteroaryl ring may contain from 11 to 18 ring member atoms, and have from 1 to 10 heteroatoms, where the remaining ring member atoms are carbon. Non-limiting examples of heteroaryls include pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, tetrazinyl, triazolyl, tetrazolyl, furyl, thienyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, thiadiazolyl, isothiazolyl, indolyl, isoindolyl, indolizinyl, benzimidazolyl, quinolyl, isoquinolyl, quinoxalinyl, quinazolinyl, indazolyl, benzotriazolyl, thienopyridinyl, furopyridinyl, pyrrolopyridinyl and the like. Exemplary bicyclic and tricyclic heteroaryl groups include phenanthrolinyl, dibenzofuranyl, acridinyl, phenanthridinyl, dihydro[1 ,3]oxazolo[4,5-b]pyridinyl, benzothiazolyl, and the like. In polycyclic systems in which a heteroaryl is fused to one or more rings that are not heteroaryl, attachment of the polycycle to the indicated point of attachment on the parent molecule may be through any ring member atom of the polycycle rings. In some embodiments of polycyclic heteroaryls, the polycycle is attached to the indicated point of attachment through a ring member atom of a heteroaryl ring. In some embodiments of monocyclic or polycyclic heteroaryls, the monocyle or polycycle is attached to the indicated point of attachment through a ring member heteroatom of a heteroaryl ring. In some embodiments of polycyclic heteroaryls, the polycycle is attached to the indicated point of attachment through a ring member atom of a ring that is not a heteroaryl ring, for example, an aryl ring or a cycloalkyl ring. “Heteroaryl” includes sulfones, sulfoxides, N-oxides of tertiary nitrogen ring member atoms, and carbocyclic fused and benzo-fused ring systems. Non-limiting examples of a heteroaryl group may be referred to as an aryl group having one or more carbon atoms substituted with O, NRn, S, SO, SO2, where “n” denotes any positive integer.

[0391] The term “heteroarylalkyl” as used herein, alone or in combination, refers to an unsubstituted or substituted heteroaryl group attached to a parent molecular moiety through an alkyl group. The term “lower heteroarylalkyl” as used herein, alone or in combination, refers to an unsubstituted or substituted lower heteroaryl group attached to a parent molecular moiety through a lower alkyl group where "lower heteroaryl" and "lower alkyl" are as defined herein.

[0392] The term "heteroarylaminoalkyl" as used herein refers to a heteroaryl group attached to a parent molecule through an aminoalkyl group (heteroaryl-N(R)-alkyl-), where R is as defined herein. The term "lower heteroarylaminoalkyl" as used herein refers to a lower heteroaryl group attached to a parent molecule through a lower aminoalkyl group (lower heteroaryl-N(R)-lower alkyl-), where "lower heteroaryl," "lower alkyl" and R are as defined herein.

[0393] The term "heteroaryloxyalkyl" as used herein refers to a heteroaryl group attached to a parent molecule through an alkyl ether group (heteroaryl-O-alkyl-). The term " lower heteroaryloxyalkyl" as used herein refers to a lower heteroaryl group attached to a parent molecule through a lower alkyl ether group (lower heteroaryl-O-lower alkyl-), where "lower heteroaryl" and "lower alkyl" are defined herein.

[0394] The term "heteroarylthioalkyl" as used herein refers to a heteroaryl group attached to a parent molecule through a thioalkyl group (heteroaryl-S-alkyl-). The term "lower heteroarylthioalkyl" as used herein refers to a lower heteroaryl group attached to a parent molecule through a lower thioalkyl group (lower heteroaryl-S-lower alkyl-), where "lower heteroaryl" and "lower alkyl" are defined herein.

[0395] The term “heterocycle-alkyl” as used herein, alone or in combination, refers to a substituted or unsubstituted heterocycle group attached to a parent molecular moiety through an alkyl group. The terms “heterocycloalkyl” and, interchangeably, “heterocycle,” or “heterocyclic” as used herein, alone or in combination, each refer to a ring system in which at least one of the rings is a saturated or partially unsaturated, heteroaliphatic, nonaromatic cyclic ring moiety in which all of the ring member atoms are carbon, except for at least one heteroatom (referred to herein as a “heterocycloalkyl ring,” “heterocycle ring” or “heterocyclic ring”). The one or more heteroatoms that can be in the ring include, for example, nitrogen, oxygen, sulfur, phosphorous and / or silicon. In some embodiments, the ring heteroatom or heteroatoms is selected from nitrogen, oxygen and sulfur. The heterocycloalkyl ring may be optionally substituted as defined herein. A heterocycloalkyl is a monocyclic or polycyclic, for example, bicyclic or tricyclic, ring system in which at least one cyclic ring is a heterocycloalkyl ring. Polycyclic heterocycloalkyl ring systems include fused, bridged and spiro-fused rings. Polycyclic heterocycloalkyl ring systems as defined herein, include ring systems in which one or more heterocycloalkyl rings is / are fused to one or more cycloalkyl, aryl, heteroaryl and / or heterocycloalkyl rings. In some embodiments, all of the rings in a polycyclic heterocycloalkyl ring system are heterocycloalkyl rings. In certain embodiments, a heterocycloalkyl includes 1 to 4 heteroatoms as ring member atoms. In some embodiments, a heterocycloalkyl moiety includes 1 to 2 heteroatoms as ring member atoms. In certain embodiments, a heterocycloalkyl moiety includes 3 to 8 ring member atoms in each ring. In some embodiments, a heterocycloalkyl moiety includes 3 to 7 ring member atoms in each ring. In yet some embodiments, a heterocycloalkyl moiety includes 5 to 6 ring member atoms in each ring. In some embodiments, a heterocycloalkyl can be a 3 to 15 membered nonaromatic ring, or a fused bicyclic, or tricyclic non-aromatic ring, which contains at least one atom chosen from O, S, and N. In certain embodiments, a monocyclic heterocycloalkyl or heterocycle group may contain from 4 to 10 ring member atoms, and may have, for example, 1 to 4 heteroatoms in the ring, where the remaining ring member atoms are carbon. In some embodiments, a bicyclic heterocycloalkyl or heterocycle group may contain from 8 to 15 ring member atoms, and have from 1 to 8 heteroatoms, where the remaining ring member atoms are carbon. In some embodiments, a tricyclic heterocycloalkyl or heterocycle group may contain from 11 to 18 ring member atoms, and have from 1 to 10 heteroatoms, where the remaining ring member atoms are carbon. The term also includes fused polycyclic groups where one or more heterocyclic rings are fused with one or more cycloalkyl rings, aryl, heteroaryl and / or other heterocyclic groups. In polycyclic systems in which a heterocycloalkyl ring is fused to one or more rings that are not heterocycloalkyl, attachment of the polycycle to the indicated point of attachment on the parent molecule may be through any ring member atom of the polycycle rings. In some embodiments of polycyclic heterocycloalkyls, the polycycle is attached to the indicated point of attachment through a ring member atom of a heterocycloalkyl ring. In some embodiments of monocyclic or polycyclic heterocycloalkyls, the monocyle or polycycle is attached to the indicated point of attachment through a ring member heteroatom of a heterocycloalkyl ring. In some embodiments of polycyclic heterocycloalkyls, the polycycle is attached to the indicated point of attachment through a ring member atom of a ring that is not a heterocycloalkyl ring, for example, an aryl ring, heteroaryl ring or a cycloalkyl ring. “Heterocycloalkyl” and “heterocycle” include sulfones, sulfoxides and N-oxides of tertiary nitrogen ring member atoms. Non-limiting examples of heterocycle groups include aziridinyl, azetidinyl, 1 ,3-dioxanyl, 1 ,4-dioxanyl, 1 ,3- dioxolanyl, morpholinyl, piperazinyl, pyrrolidinyl, piperidinyl, thiomorpholinyl, pyranyl, dihydropyridinyl, tetrahydropyridinyl, carabazolyl, xanthenyl, 1 ,3-benzodioxolyl, dihydroisoquinolinyl, dihydrocinnolinyl, dihydrobenzodioxinyl, isoindolinyl, dihydroisoindolyl and dihydroindolyl, and the like. The heterocycle groups may be optionally substituted unless specifically prohibited. Non-limiting examples of heterocycloalkyl groups may be referred to as cycloalkyl group having one or more carbon atoms substituted with O, NRn, S, SO, SO2, where n denotes any positive integer.

[0396] The term “hydrazinyl” as used herein, alone or in combination, refers to two amino groups joined by a single bond, i.e., -HN-NH-.

[0397] The term “hydroxy,” as used herein, alone or in combination, refers to -OH.

[0398] The term “hydroxyalkyl,” as used herein, alone or in combination, refers to a hydroxy group attached to a parent molecular moiety through an alkyl group. The term “lower hydroxyalkyl,” as used herein, alone or in combination, refers to a hydroxy group attached to a parent molecular moiety through a lower alkyl group, where "lower alkyl" is as defined herein.

[0399] The term “imino,” as used herein, alone or in combination, refers to =N-

[0400] The term “iminohydroxy,” as used herein, alone or in combination, refers to =N(OH) and =N-O-

[0401] The phrase “in the main chain” refers to the longest contiguous or adjacent chain of carbon atoms starting at the point of attachment of a group to the compounds of any one of the formulas disclosed herein.

[0402] The term “isocyanato” refers to a -NCO group.

[0403] The term “isothiocyanate” refers to a -NCS group.

[0404] The phrase “linear chain of atoms” refers to the longest straight chain of atoms independently selected from carbon, nitrogen, oxygen and sulfur.

[0405] The term “lower,” as used herein, alone or in a combination, where not otherwise specifically defined, means a moiety containing from 1 to and including 6 carbon atoms. A "lower alkyl," for example, refers to an alkyl containing 1 to 6 carbon atoms (C1 -C6), 1 to 5 carbon atoms (C1 - C5), 1 to 4 carbon atoms (C1 -C4), 1 to 3 carbon atoms (C1-C3), or 1 to 2 carbon atoms (C1-C2) (for example, an alkyl containing 1 , 2, 3, 4, 5 or 6 carbon atoms; a C1 , C2, C3, C4, C5 or C6 alkyl).

[0406] The term “lower aryl,” as used herein, alone or in combination, means a C4-C6 aryl group, for example, a C5-C6 aryl group. A lower aryl group sometimes is a C4-C6 aryl ring group, or C5- C6 aryl ring group for example, including without limitation, phenyl. The term may also refer to a C8-C10 bicyclic ring aryl group, for example, including without limitation, napthyl. Lower aryl groups, including phenyl or napthyl, may be optionally substituted as provided.

[0407] The term “lower heteroaryl,” as used herein, alone or in combination, means a four-membered, five-membered, or six-membered heteroaryl group. A lower heteroaryl group sometimes is (1 ) a monocyclic heteroaryl ring comprising five or six ring member atoms, of which between one and four of the ring member atoms may be heteroatoms chosen from O, S, and N, or (2) a bicyclic heteroaryl ring, where each of the fused rings comprises five or six ring member atoms, comprising between them one to four heteroatoms chosen from O, S, and N. Lower heteroaryl groups may be optionally substituted as provided.

[0408] The term “lower cycloalkyl,” as used herein, alone or in combination, means a monocyclic cycloalkyl having between three and six ring member atoms. Non-limiting examples of lower cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Lower cycloalkyl groups may be optionally substituted as provided.

[0409] The term “lower heterocycloalkyl,” as used herein, alone or in combination, means a monocyclic heterocycloalkyl having between three and six ring member atoms, of which between one and four may be heteroatoms chosen from O, S, and N. Non-limiting examples of lower heterocycloalkyls include pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl, piperazinyl, and morpholinyl. Lower heterocycloalkyl groups may be optionally substituted as provided.

[0410] The term “lower amino,” as used herein, alone or in combination, refers to -NRR’, where R and R’ are independently chosen from hydrogen, lower alkyl, and lower heteroalkyl, any of which may be optionally substituted. Additionally, the R and R’ of a lower amino group may combine to form a five- or six-membered heterocycloalkyl, either of which may be optionally substituted.

[0411] The term "mercaptoalkyl," as used herein, refers to a mercaptan or mercaptyl group attached to a parent molecule through an alkyl group (-alkyl-SH), where R is defined herein. The term "lower mercaptoalkyl," as used herein, refers to a mercaptan or mercaptyl group attached to a parent molecule through a lower alkyl group, (-lower alkyl-SR), where "lower alkyl" and R are defined herein.

[0412] The terms “mercaptyl” or “mercaptan” as used herein, alone or in combination, refers to an -SH group.

[0413] The term “menthol,” as used herein, refers to 2-isopropyl-5-methylcyclohexanol. Menthol contains 3 chiral carbons and the term “menthol” encompasses all stereoisomers of the molecule unless specifically stated otherwise herein. For example, isomers of menthol include the (-)-menthol isomer ((1 R, 2S, 5R)-2-isopropyl-5-methylcyclohexanol), (+)-menthol isomer ((1 S, 2R, 5S)-2-isopropyl-5-methylcyclohexanol), (-)-isomenthol isomer ((1 R, 2S, 5S)-2- isopropyl-5-methylcyclohexanol), (+)-isomenthol isomer ((1S, 2R, 5R)-2-isopropyl-5- methylcyclohexanol), (-)-neomenthol isomer ((1 R, 2R, 5S)-2-isopropyl-5-methylcyclohexanol), (+)-neomenthol isomer ((1 S, 2S, 5R)-2-isopropyl-5-methylcyclohexanol), (-)-neoisomenthol isomer ((1 S, 2S, 5S)-2-isopropyl-5-methylcyclohexanol) and (+)-neoisomenthol isomer ((1 R, 2R, 5R)-2-isopropyl-5-methylcyclohexanol).

[0414] The term “menthyl,” as used herein, refers to a radical derived from menthol. Typically, a menthyl radical can be linked to another chemical group through the oxygen atom of the menthyl group.

[0415] The term “nitro,” as used herein, alone or in combination, refers to -NO2.

[0416] The terms “oxy” or “oxa,” as used herein, alone or in combination, refer to -O-.

[0417] The term “oxo,” as used herein, alone or in combination, refers to =0.

[0418] The term “partially unsaturated,” as used herein, alone or in combination, refers to a straightchain, branched-chain or ring moiety that includes at least one double or triple bond and that is not fully saturated. The term “partially unsaturated” when used in reference to a ring moiety means a ring having one or multiple sites of unsaturation but does not include aryl rings or heteroaryl rings as defined herein.

[0419] The term “perhaloalkoxy” refers to an alkoxy group where all of the hydrogen atoms are replaced by halogen atoms.

[0420] The term “perhaloalkyl” as used herein, alone or in combination, refers to an alkyl group where all of the hydrogen atoms are replaced by halogen atoms.

[0421] The term “piperitol,” as used herein, refers to p-menth-1-en-3-ol. Piperitol contains 2 chiral carbons and the term “piperitol” encompasses all stereoisomers of the molecule unless specifically stated otherwise herein. For example, isomers of piperitol include (3R, 4R)-piperitol (also referred to as trans-piperitol) and (3S, 4R)-piperitol (also referred to as cis-piperitol).

[0422] The term “ring member atoms,” as used herein, refers to all of the atoms that form the covalent structure of a cyclic ring structure.

[0423] By “saturated” is meant that the carbon-containing group contains no carbon-carbon double or triple bonds.

[0424] The terms “sulfonate,” “sulfonic acid,” and “sulfonic,” as used herein, alone or in combination, refer the -SO3H group and its anion as the sulfonic acid is used in salt formation.

[0425] The term “sulfanyl,” as used herein, alone or in combination, refers to -S-.

[0426] The term “sulfinyl,” as used herein, alone or in combination, refers to -S(0)-.

[0427] The term “sulfonyl,” as used herein, alone or in combination, refers to -S(O)z-.

[0428] The term “N-sulfonamido” refers to a RS(=0)2NR’- group with R and R' as defined herein.

[0429] The term “S-sulfonamido” refers to a -S(=0)2NRR’, group, with R and R’ as defined herein.

[0430] The terms “thia” and “thio,” as used herein, alone or in combination, refer to a -S- group or an ether where the oxygen is replaced with sulfur. The oxidized derivatives of the thio group, namely sulfinyl and sulfonyl, are included in the definition of thia and thio.

[0431] The terms “thiol” and “mercapto”, as used herein, alone or in combination, refers to an -SH group. The term “thiocarbonyl,” as used herein, when alone includes thioformyl -C(S)H and in combination is a -C(S)- group.

[0432] The term “N-thiocarbamyl” refers to an ROC(S)NFT- group, with R and R’ as defined herein. The term “O-thiocarbamyl” refers to a -OC(S)NRR’, group with R and R’ as defined herein. The term “thiocyanate” refers to a -CNS group.

[0433] The term “trihalomethanesulfonamido” refers to a X3CS(O)2NR- group with X is a halogen and R as defined herein.

[0434] The term “trihalomethanesulfonyl” refers to a X3CS(O)2- group where X is a halogen.

[0435] The term “trihalomethoxy” refers to a X3CO- group where X is a halogen. The term “trisubstituted silyl,” as used herein, alone or in combination, refers to a silicone group substituted at its three free valences with groups as listed herein under the definition of substituted amino. Non-limiting examples include trimethylsilyl, tert-butyldimethylsilyl, triphenylsilyl and the like.

[0436] The term “ureido,” as used herein, alone or in combination, refers to the univalent radical NH2CONH- derived from urea. Non-limiting examples include ureidoproprionate and ureidosuccinate.

[0437] Non-limiting examples of compounds are provided in the following Tables A, B, C, and D.

[0438] Table A

[0439]

[0440]

[0441]

[0442]

[0443] Table B

[0444] Table C

[0445]

[0446]

[0447]

[0448]

[0449]

[0450]

[0451]

[0452]

[0453]

[0454]

[0455]

[0456]

[0457]

[0458]

[0459]

[0460] Compounds in Tables A, B, C, or D may be provided as a pharmaceutically acceptable salt, such as a hydrochloride salt for example. In Table A, the following compound designations are not included and are held in reserve: Cmpd22, Cmpd23, Cmpd35, Cmpd41 , Cmpd56, Cmpd64 and Cmpd75.

[0461] Table D

[0462] Inhibition was measured by exposing the select compounds to a variety of targets at a concentration of 100 nM. Inhibitory data is presented in Table E.

[0463] Table E

[0464] Compositions

[0465] A composition can contain a compound herein. A compound in a composition can inhibit an activity of a protein kinase (PK; for example, a PK polypeptide). A PK activity can include a PK binding activity (for example, binding of a PK to a substrate that the PK phosphorylates and / or binding of a PK to a binding partner polypeptide that the PK does not phosphorylate) and / or PK catalytic activity (for example, PK substrate phosphorylation activity). In certain instances a compound herein is capable of effectively inhibiting, moderately inhibiting and / or selectively inhibiting a PK activity. A composition containing a compound herein can be for inhibition of a PK activity, inhibition of an activity of two or more PKs, preparation of a medicament and / or for preparation of a treatment of a PK-associated condition. In certain embodiments, a compound in a composition is or has been isolated (for example, isolated from other types of molecules). A compound sometimes is at least about 80% pure, by weight, in a composition and sometime is at least about 85% pure, at least about 90% pure, at least about 95% pure, at least about 99% pure, or at least about 99.5% pure. A compound n that is x% pure, by weight, in a composition includes x% by weight of the compound and y% of components other than the compound, where y% = 100% - x%, by weight. For example, a compound that is 90% pure in a composition contains 90% by weight of the compound and 10% by weight of components other than the compound.

[0466] A composition containing a compound herein can be a pharmaceutical composition. A pharmaceutical composition can include a compound herein as an active ingredient and one or more pharmaceutically acceptable additives, including one or more pharmaceutically acceptable excipients. One or more pharmaceutically acceptable excipients in a pharmaceutical composition typically form a carrier for the active ingredient. Non-limiting examples of excipient additives include a pharmaceutically acceptable solvent, diluent, isotonic agent, buffering agent, stabilizer, preservative, antioxidant, vasoconstrictive agent, antibacterial agent, antifungal agent, adsorption delaying agent, sustained release agent (for example, for example, U.S. Patent No. 5,624,677), and the like. One or more additives can be combined with an active ingredient for the manufacture of a pharmaceutical composition by a method known in the art. A pharmaceutical composition sometimes is prepared as a solid (for example, powder) or liquid (for example, aqueous solution, emulsion (for example, micro-emulsion, nano-emulsion)). Non-limiting examples of solvents and diluents include water, saline, dextrose, ethanol, glycerol, oil, water-miscible organic cosolvents such as acetone or dimethyl sulfoxide (DMSO), and the like. Non-limiting examples of isotonic agents include sodium chloride, dextrose, mannitol, glucose, sucrose, sorbitol, lactose, and the like. Non-limiting examples of buffering agents include bicarbonate, phosphate, and the like. Phosphate-buffered saline (PBS), which may be buffered to provide a neutral pH, or in certain embodiments an acidic pH, sometimes is utilized. Non-limiting examples of stabilizers include gelatin, albumin, and the like. Non-limiting examples of a preservatives include gentamicin, merthiolate, chlorocresol and the like.

[0467] Water or saline, when used for preparing a pharmaceutical composition, may be buffered or not buffered. Non-limiting examples of saline solutions that can be used to prepare a pharmaceutical composition include lactated Ringer's solution, acetated Ringer's solution, intravenous sugar solutions (for example, 5% dextrose in normal saline (D5NS), 10% dextrose in normal saline (D10NS), 5% dextrose in half-normal saline (D5HNS) and 10% dextrose in halfnormal saline (D10HNS)). Non-limiting example of buffered saline solutions and related solutions include phosphate buffered saline (PBS), TRIS-buffered saline (TBS), Hank's balanced salt solution (HBSS), Earle's balanced salt solution (EBSS), standard saline citrate (SSC), HEPES-buffered saline (HBS), and Gey's balanced salt solution (GBSS). In certain implementations, an additive enhances solubility and / or bioavailability of an active ingredient. A solubility-enhancing additive may include one or more of: a lipid, polyethylene glycol (PEG), polysorbate, glycerol, glycerin, dimethylacetamide, triacetin, an oil (for example, a vegetable oil), or combination thereof. In certain instances, solubility of an active ingredient is characterized by a particular amount of excipient that confers solubility to the active ingredient. Any suitable antioxidant can be included in a pharmaceutical composition, non-limiting examples of which include (1 ) butylated hydroxytoluene (BHT), (2) butylated hydroxyanisole (BHA), (3) DL-alpha-tocopherol, (4) ascorbyl palmitate and (5) propyl gallate. A pharmaceutical composition can include a mixture of two, three, four or five antioxidants.

[0468] A concentration of an active ingredient in a liquid composition sometimes is from about 0.1 wt% to about 35 wt%, or sometimes from about 0.5 wt% to about 10 wt%. The concentration in a semi-solid or solid composition such as a gel or a powder sometimes is about 0.1 wt% to about 5 wt%, or sometimes about 0.5 wt% to about 2.5 wt%. Higher concentrations are also appropriate for some solid or semi-solid compositions and may include amounts up to about 25 wt% or up to about 50 wt% or more.

[0469] A pharmaceutical composition may be prepared according to conventional techniques known in the pharmaceutical industry. In general terms, such techniques include bringing an active ingredient into association with on or more pharmaceutical carrier(s) and / or excipient(s) in liquid form or finely divided solid form, or both, and then shaping the product if required.

[0470] A pharmaceutical composition may be incorporated into a suitable dosage form (for example, unit dosage form), non-limiting examples of which include a tablet, capsule, gel capsule, liquid syrup, soft gel, suppository, enema, dressing or device (for example, in a syringe (for example, auto-injection device) or microneedle device). A pharmaceutical composition may be formulated as a suspension in aqueous, non-aqueous, or mixed media. Aqueous suspensions may further contain substances that increase viscosity, including for example, sodium carboxymethylcellulose, sorbitol, and / or dextran. A suspension may also contain one or more stabilizers. An amount of active ingredient required for use in treatment will vary not only with the particular form selected (for example, the salt selected) but also with route of administration, the nature of the condition being treated and the age and condition of the patient and ultimately will be at the discretion of the attendant physician or clinician. Any additive and material used in preparing a unit dosage form typically is pharmaceutically acceptable and substantially nontoxic in the amounts employed.

[0471] A composition can include a pharmaceutically acceptable ester or amide of a compound herein. In certain implementations, a composition includes a pharmaceutically acceptable salt of a compound herein. Non-limiting examples of pharmaceutically acceptable salts include carboxylate salts, amino acid addition salts and zwitterionic forms thereof, which are known to those skilled in the art as suitable for use with humans and animals. (See, for example, Berge, S. M., et al, "Pharmaceutical Salts," Pharm. Sci. (1977) 66:1 -19). In cases where a compound is sufficiently basic or acidic to form a stable nontoxic acid or base salt, a composition includes a pharmaceutically acceptable salt of the compound. Non-limiting examples of pharmaceutically acceptable salts are organic acid addition salts formed with acids that form a physiological acceptable anion, non-limiting examples of which include tosylate, methanesulfonate, acetate, citrate, malonate, tartarate, succinate, benzoate, ascorbate, [alpha]-ketoglutarate, and [alpha]- glycerophosphate. Suitable inorganic salts may also be formed, including hydrochloride, sulfate, nitrate, bicarbonate, and carbonate salts. Pharmaceutically acceptable salts are obtained using standard procedures known in the art. For example, pharmaceutically acceptable salts may be obtained by reacting a sufficiently basic compound with a suitable acid affording a physiologically acceptable anion. Alkali metal (for example, sodium, potassium or lithium) or alkaline earth metal (for example, calcium, magnesium) salts of carboxylic acids and other anionic groups in molecules within a pharmaceutical composition also are contemplated.

[0472] A composition can include an isomer of a compound herein. Non-limiting examples of isomers are stereoisomers (e.g., diastereomers and enantiomers) and structural isomers such as tautomers. A composition can include a mixture containing two or more isomers of a compound herein. In certain instances, a mixture can include an isomer that predominates over one or more other isomers of a compound herein (e.g., the molar amount of one isomer may represent about 55% or more of all isomers of the compound (e.g., about 60% or more, about 65% or more, about 70% or more, about 75% or more, about 80% or more, about 85% or more)). A composition can include an isomerically pure form of a compound herein, in which the molar amount of one isomer can represent about 95% or more (e.g., about 96% or more, about 97% or more, about 98% or more, about 99% or more or about 99.5% or more) of all isomers of the compound.

[0473] Non-limiting examples of pharmaceutical compositions are provided hereafter.

[0474] Pharmaceutical composition for oral administration

[0475] A pharmaceutical composition may be provided as a tablet (for example, ingestible tablet, buccal tablet), troche, capsule (for example, hard- or soft-shell gelatin capsule), drink, elixir, suspension, syrup, wafer, and the like, and / or may be incorporated directly in food or drink that is part of a subject’s diet. Such compositions and preparations sometimes contain at least 0.1% of active ingredient. The percentage of the compositions and preparations may be varied and sometimes are about 2% to about 60% of the weight of a given unit dosage form. The amount of active ingredient in a pharmaceutical composition is such that an effective dosage level can be obtained.

[0476] Tablets, troches, pills, capsules, and the like may contain one or more of the following: a binder such as gum tragacanth, acacia, corn starch or gelatin; an excipient such as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch, alginic acid and the like; a lubricant such as magnesium stearate; a sweetening agent such as sucrose, fructose, lactose or aspartame; a flavoring agent such as peppermint, oil of Wintergreen, or cherry flavoring. When the unit dosage form is a capsule, it may contain, in addition to materials described above, a liquid carrier, such as a vegetable oil or a polyethylene glycol. Various other materials may be present as coatings or to otherwise modify the physical form of the solid unit dosage form. For instance, tablets, pills, or capsules may be coated with gelatin, wax, shellac or sugar and the like. A syrup or elixir may contain the active compound, sucrose or fructose as a sweetening agent, methyl and propylparabens as preservatives, a dye and flavoring such as cherry or orange flavor.

[0477] Pharmaceutical composition for topical administration

[0478] For topical administration, a compound herein may be applied in liquid form. A compound herein may be combined with a dermatologically acceptable carrier, which may be a solid or a liquid. A compound herein may be formulated with a solid carrier, which include finely divided solids such as talc, clay, microcrystalline cellulose, silica, alumina and the like. Useful liquid carriers include water, alcohols or glycols or water-alcohol / glycol blends, or phospholipids in propylene glycol / ethylene glycol, in which the a compound herein can be dissolved or dispersed at an effective level, optionally with the aid of non-toxic surfactants. A composition sometimes includes a diluent and sometimes a carrier (for example, assimilable, editable), buffer, preservative and the like. Additives such as fragrances and additional antimicrobial agents can be added to optimize the properties for a given use. A liquid composition can be applied from an absorbent pad, used to impregnate a bandage or other dressing, or sprayed onto the affected area using a pump-type or aerosol sprayer. A thickener, such as a synthetic polymer, fatty acid, fatty acid salt and / or ester, fatty alcohol, modified cellulose or modified mineral material, can also be employed with a liquid carrier to form a spreadable cream, paste, gel, ointment, soap, and the like, for application directly to the skin of a subject.

[0479] Pharmaceutical composition for administration by injection

[0480] A pharmaceutical composition suitable for injection (for example, subcutaneous, intramuscular, intravenous administration) can include a sterile aqueous solution or dispersion or sterile powder for the extemporaneous preparation of a sterile injectable solution or dispersion. An injectable formulation often is sterile and often is fluid. It typically is stable under the conditions of manufacture and storage and typically is preserved against contaminating microorganisms, such as bacteria and fungi. A pharmaceutical composition can be delivered to a subject via any suitable injection device, including without limitation, a syringe, needle or microneedle (for example, including a syringe device for self-administration; auto-injection device).

[0481] An injectable formulation sometimes includes a carrier, which can be a solvent, excipient, or dispersion medium. A liquid carrier or vehicle can be a solvent or liquid dispersion medium including, for example, water, ethanol, a polyol (for example, glycerol, propylene glycol, liquid polyethylene glycols, and the like), vegetable oil, nontoxic glyceryl ester, or suitable mixture thereof. Fluidity of an injectable formulation can be maintained, for example, by the use of a coating, such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of a surfactant. Prevention of the action of microorganisms can be affected by an antibacterial and / or antifungal agent, for example, paraben, chlorobutanol, phenol, sorbic acid, thimerosal, and the like. In certain instances, an isotonic agent may be included, for example, a sugar or sodium chloride. Prolonged absorption of an injectable composition can be affected by use of an absorption delaying agent, for example, aluminum monostearate and / or gelatin. A pharmaceutical composition may include a co-polymer such as, for example, a co-polymer selected from polyjvinyl alcohol), poly(vinyl pyrrolidone), and hypromellose acetate succinate.

[0482] A sterile injectable solution can be prepared by incorporating an active ingredient in the required amount in the appropriate solvent with one or more other ingredients, as required, followed by filter sterilization. In the case of a sterile powder for the preparation of a sterile injectable solution, methods of preparation include vacuum drying and freeze-drying techniques, which yield a powder including the active ingredient and any additional desired ingredient present in the previously sterile-filtered solution.

[0483] Protein kinase inhibition

[0484] A compound can be an inhibitor of one or more protein kinases (PKs), and can be used to inhibit one or more PKs. A compound that inhibits a PK can bind to a PK, inhibit PK substrate phosphorylation activity and / or inhibit binding activity of a PK to another entity (for example, a polypeptide to which the PK binds).

[0485] A compound that is an inhibitor of one or more PKs sometimes is an effective inhibitor, moderate inhibitor, mild inhibitor and / or ineffective inhibitor of one or more PKs. A compound is designated as an “effective inhibitor” when (i) the compound at a concentration of 100 nM inhibits PK activity by greater than 90%; and / or (ii) the compound inhibits PK activity at a measured IC50 value of less than 20 nM. A compound is designated as a “moderate inhibitor” when (i) the compound at a concentration of 100 nM inhibits PK activity by 70% to 90%; and / or (ii) the compound inhibits PK activity at a measured IC50 value between 20 nM and 40 nM. A compound is designated as a “mild inhibitor” when (i) the compound at a concentration of 100 nM inhibits PK activity by 30% to 70%; and / or (ii) the compound inhibits PK activity at a measured IC50 value between 40 nM and 200 nM. A compound is designated as an “ineffective inhibitor” when (i) the compound at a concentration of 100 nM inhibits PK activity by less than 30%; and / or (ii) the compound inhibits PK phosphorylation at a measured IC50 value of greater than 200 nM. An “effective inhibitor” can be used to effectively inhibit a PK, a “moderate inhibitor” can be used to moderately inhibit a PK, a “mild inhibitor” can be used to mildly inhibit a PK, and an “ineffective inhibitor” can be used to ineffectively inhibit or not inhibit a PK. An IC50 value or percent activity can be measured by a suitable assay, such as an in vitro assay that assesses PK phosphorylation activity or PK ligand binding, for example. In certain embodiments, PK inhibition is assessed according to an IC50 value or percent activity measured by a peptide cleavage assay, tracer displacement assay, solid phase inhibitor competition assay, ADP formation assay, as described herein (described in Example 17), for example. In certain embodiments, a compound that contains a quinazolinyl group and an amine-linked phenyl group can be used to inhibit one or more of, or two or more of, or three or more of, or four or more of, or five or more of, or six or more of, or seven or more of, or eight or more of, or nine or more of, or ten or more of, or eleven or more of, or twelve or more of, or thirteen or more of, or each of: an ABL family PK, a BTK family PK, a AURK family PK, a JAK family PK, a TRK family PK, a RET PK, an EPH family PK, a TNK family PK, a PLK family PK, an IRAK family PK, a SRC family PK, a LCK family PK, a DDR family PK, a ROS family PK, and / or a PTK family PK.

[0486] In certain embodiments, a compound that contains a quinazolinyl group and an amine-linked phenyl group can selectively inhibit a JAK2 PK. In certain instances, the compound effectively inhibits or moderately inhibits a JAK2(wt) PK and does not effectively inhibit and does not moderately inhibit a JAK1 (wt) PK (for example, the compound mildly inhibits or ineffectively inhibits a JAK1 PK). In certain instances, the compound inhibits JAK3(wt) PK, and optionally effectively inhibits JAK3(wt) PK, or optionally moderately inhibits a JAK3(wt) PK. In certain instances, the compound inhibits, and optionally effectively inhibits, one or more of, or two or more of, or three or more of, or four or more of, or five or more of, or six or more of, or seven or more of, or eight or more of, or nine or more of, or ten or more of, or eleven or more of, or twelve or more of, or each of: an ABL family PK, a BTK family PK, a AURK family PK, a TRK family PK, a RET PK, an EPH family PK, a TNK family PK, a PLK family PK, an IRAK family PK, a SRC family PK, a LCK family PK, a DDR family PK, a ROS family PK, and / or a PTK family PK.

[0487] In certain instances, a compound effectively inhibits two or more of, or three or more of, or four or more of, or five or more of, or six or more of, or seven or more of, or eight or more of, or each of: an ABL family PK, a BTK family PK, a AURK family PK, a JAK family PK, a TRK family PK, a RET PK, an EPH family PK, a TNK family PK, a PLK family PK, an IRAK family PK, SRC family PK, DDR family PK, a ROS family PK, and / or PTK family PK. In certain instances, the compound moderately inhibits two or more of, or three or more of, or four or more of, or five or more of, or six or more of, or seven or more of, or eight or more of, or each of: an ABL family PK, a BTK family PK, a AURK family PK, a JAK family PK, a TRK family PK, a RET PK, an EPH family PK, a TNK family PK, a PLK family PK, an IRAK family PK, a SRC family PK, a LCK family PK, a DDR family PK, a ROS family PK, and / or a PTK family PK.

[0488] In certain embodiments, a compound that effectively inhibits and / or optionally moderately inhibits a PK in one or more of the foregoing PK families, does not effectively inhibit, and / or does not moderately inhibit, one or more of, or two or more of, or three or more of, or four or more of, or five or more of, or six or more of, or seven or more of, or eight or more of, or nine or more of, or ten or more of, or eleven or more of, or twelve or more of: an ABL family PK, a BTK family PK, a AURK family PK, a JAK family PK, a TRK family PK, a RET PK, an EPH family PK, a TNK family PK, a PLK family PK, an IRAK family PK, a SRC family PK, a LCK family PK, a DDR family PK, a ROS family PK, and / or a PTK family PK.

[0489] In certain embodiments, a compound used to inhibit a PK is a compound herein (in Tables A, B, C, or D for example). In certain instances, a composition used to inhibit a PK contains a compound herein (in Tables A, B, C, or D for example). In certain instances, a composition used to inhibit a PK contains a compound of Subgroup 1 , Subgroup 2, Subgroup 3, Subgroup 4, Subgroup 5, Subgroup 6, Subgroup 7, Subgroup 8, Subgroup 9, Subgroup 10, Subgroup 11 , Subgroup 12, Subgroup 13, Subgroup 14, Subgroup 15, Subgroup 16, Subgroup 17 or Subgroup 18.

[0490] A compound can be an effective inhibitor or moderate inhibitor of, and can be used to inhibit, an ABL family PK, including an ABL1 PK, including ABL1 (wt) and / or one or more ABL1 variants; and / or an ABL2 PK, including ABL2(wt) and / or one or more ABL2 variants. An ABL1 variant can include one or more of the following amino acid substitutions (relative to ABL1 (wt)): T315I, G250E, Q252H, Y253F, E255K, F317L, M351T and H396P, and / or other ABL1 amino acid substitution described herein. An ABL2 PK also is referred to as an ARG PK.

[0491] A compound can be an effective inhibitor or moderate inhibitor of, and can be used to inhibit, a BTK family PK. A BTK family PK can include: a BTK PK, including BTK(wt) and / or one or more BTK variants; a BMX PK, including BMX(wt) and / or one or more BMX variants; an ITK PK, including ITK(wt) and / or one or more ITK variants; a TEC PK, including TEC(wt) and / or one or more TEC variants; and a TXK PK, including TXK(wt) and / or one or more TXK variants. BMX is referred to also as ETK, ITK is referred to also as EMT and TXK is referred to also as RLK. In certain embodiments, a compound is an effective inhibitor or moderate inhibitor of TXK(wt) and / or one or more TXK variants, and sometimes is a compound of Subgroup 7.

[0492] A compound can be an effective inhibitor or moderate inhibitor of, and can be used to inhibit, an Aurora (AURK) family PK. An AURK family PK can include: an AURKA PK, including AURKA(wt) and / or one or more AURKA variants; an AURKB PK, including AURKB(wt) and / or one or more AURKB variants; and an AURKC PK, including AURKC(wt) and / or one or more AURKC variants.

[0493] A compound can be an effective inhibitor or moderate inhibitor of, and can be used to inhibit, a JAK family PK. A JAK family PK can include: a JAK1 PK, including JAK1 (wt) and / or one or more JAK1 variants; a JAK2 PK, including JAK2(wt) and / or one or more JAK2 variants; a JAK3 PK including JAK3(wt) and / or one or more JAK3 variants; and a TYK family PK. ATYK family PK can be a TYK2 family PK, including TYK2(wt) and / or one or more TYK2 variants. A JAK2 PK variant can include the amino acid substitution V617F, relative to JAK2(wt).

[0494] In certain embodiments, a compound is an effective inhibitor or moderate inhibitor of, and can be used to inhibit, a TYK family PK. In certain instances, a compound is an effective inhibitor or moderate inhibitor of, and can be used to inhibit, TYK2(wt). In certain embodiments, a compound may inhibit TYK2 through a JH1 kinase domain and / or by binding to a JH2 pseudokinase domain. In certain embodiments, a compound may bind to and thereby stabilize the JH2 pseudokinase domain. In certain embodiments, a compound may bind to and thereby stabilize the TYK2 JH2 pseudokinase domain. In certain embodiments, a compound may inhibit the JH1 kinase domain and also bind to and stabilize the JH2 pseudokinase domain. In certain embodiments, the compound does not effectively inhibit one or more of, or two or more of, or each of JAK1 (wt), JAK2(wt) and JAK3(wt), and optionally does not moderately inhibit one or more of, or two or more of, or each of JAK1 (wt), JAK2(wt) and / or JAK3(wt). In certain embodiments the compound is a compound of Subgroup 9.

[0495] In certain embodiments, a compound is an effective inhibitor or moderate inhibitor of JAK2(wt) and optionally one or more JAK2 variants. In certain instances, a compound is an effective inhibitor or moderate inhibitor of JAK3(wt) and optionally one or more JAK3 variants. In certain embodiments, a compound is a selective inhibitor of a JAK2 PK and does not effectively inhibit JAK1 (wt). In certain embodiments, a compound is a selective inhibitor of a JAK2 PK and does not moderately inhibit JAK1 (wt). In certain instances, a compound: does not effectively inhibit or moderately inhibit one or more JAK1 variants; does not effectively inhibit ABL1 (wt) and / or ABL1(T315I); mildly inhibits ABL1 (wt) and / or ABL1 (T315I); ineffectively inhibits ABL1 (wt) and / or ABL1(T315I); effectively inhibits ABL1(wt) and effectively inhibiting ABL1(T315I); moderately inhibits ABL1(wt); does not effectively inhibit, or optionally does not moderately inhibit, one or more of, or two or more of, or three or more of, or four or more of or five, or more of: an ABL family PK, a BTK family PK, a AURK family PK, a TRK family PK, a RET PK, an EPH family PK, a TNK family PK, a PLK family PK, an IRAK family PK, a SRC family PK, a LCK family PK, a DDR family PK, and / or a PTK family PK. In certain embodiments, a compound used to selective inhibit a JAK2 PK is a compound of Subgroup 2, Subgroup 3, Subgroup 5, Subgroup 6 or Subgroup 7. In certain embodiments, a compound inhibits, and optionally effectively inhibits or moderately inhibits, JAK2(wt) and a JAK2 variant comprising the V617F substitution, and in certain instances, the compound is a compound of Subgroup 3 or Subgroup 6.

[0496] A compound sometimes is an effective inhibitor or moderate inhibitor of, and can be used to inhibit, a TRK family PK. ATRK family PK can include: a TRKA PK, including TRKA(wt) and / or one or more TRKA variants; a TRKB PK, including TRKB(wt) and / or one or more TRKB variants; a TRKC PK, including TRKC(wt) and / or one or more TRKC variants; and a ROS1 PK, including ROS1 (wt) and / or one or more ROS1 variants. TRKA is referred to also as NTRK1 , TRKB is referred to also as NTRK2, and TRKC is referred to also as NTRK3.

[0497] A compound sometimes is an effective inhibitor or moderate inhibitor of, and can be used to inhibit, a RET family PK. A RET family PK can include: a RET PK, including RET(wt) and / or one or more RET variants. A RET variant can include one or more of the following amino acid substitutions, relative to RET(wt): A883F, G691 S, M918T, S891A, V804E, V804L, V804M and Y791 F. A compound sometimes is an effective inhibitor or moderate inhibitor of, and can be used to inhibit, an EPH family PK. An EPH family PK can include an EPHA1 PK, including EPHA1 (wt) and / or one or more EPHA1 variants; an EPHA2 PK, including EPHA2(wt) and / or one or more EPHA2 variants; an EPHA5 PK, including EPHA5(wt) and / or one or more EPHA5 variants; an EPHA8 PK, including EPHA8(wt) and / or one or more EPHA8 variants; an EPHB1 PK, including EPHB1 (wt) and / or one or more EPHB1 variants; and / or an EPHB2 PK, including EPHB2(wt) and / or one or more EPHB2 variants.

[0498] A compound sometimes is an effective inhibitor or moderate inhibitor of, and can be used to inhibit, a TNK family PK. A TNK family PK can include a TNK1 PK, including TNK1 (wt) and / or one or more TNK1 variants; and / or a TNK2 PK, including TNK2(wt) and / or one or more TNK2 variants. A TNK2 PK sometimes is referred to as an ACK PK.

[0499] A compound sometimes is an effective inhibitor or moderate inhibitor of, and can be used to inhibit, a PTK family PK. A PTK family PK can include a PTK2B PK, including PTK2B(wt) and / or one or more PTK2B variants. A PTK2B PK can be referred to as a FAK2 PK.

[0500] A compound sometimes is an effective inhibitor or moderate inhibitor of, and can be used to inhibit, a SRC family PK. A SRC family PK can include a SRC(wt) and / or one or more SRC variants, and a SRC-N1 (wt) and / or one or more SRC-N1 variants. A compound sometimes is an effective inhibitor or moderate inhibitor of, and can be used to inhibit, a LCK family PK. A LCK family PK can include a LCK(wt) and / or one or more LCK variants.

[0501] A compound sometimes is an effective inhibitor or moderate inhibitor of, and can be used to inhibit, a DDR family PK. A DDR family PK can include a DDR2 PK, including DDR2(wt) and / or one or more DDR2 variants. A DDR variant PK can include a T654M and / or N456S amino acid substitution.

[0502] A compound sometimes is an effective inhibitor or moderate inhibitor of, and can be used to inhibit, a PLK family PK. A PLK family PK can include PLK4(wt) and / or one or more PLK4 variants. A compound sometimes is an effective inhibitor or moderate inhibitor of, and can be used to inhibit, an IRAK family PK. An IRAK family PK can include an IRAKI PK, including IRAKI (wt) and / or one or more IRAKI variants; and / or an IRAK3 PK, including IRAK3(wt) and / or one or more IRAK3 variants. In certain embodiments, a compound used to inhibit a PLK PK and / or IRAK PK is a compound of Subgroup 8.

[0503] A compound sometimes is an effective inhibitor or moderate inhibitor of, and can be used to inhibit, a ROS family PK. A ROS family PK can include ROS1 (wt) and / or one or more ROS1 variants. In certain embodiments, a compound used to inhibit a ROS family PK is a compound of Subgroup 1 . A compound sometimes is an effective inhibitor or moderate inhibitor of, and can be used to inhibit, one or more, or two or more, variants of a PK. In certain embodiments, a compound is an effective inhibitor or moderate inhibitor of, and can be used to inhibit, one or more of the following PK variants: (i) an ABL1 variant optionally containing one or more of the following amino acid substitutions relative to ABL1 (wt): T315I, G250E, Q252H, Y253F, E255K, F317L, M351T and H396P; (ii) a JAK2 PK variant optionally containing the amino acid substitution V617F relative to JAK2(wt); (iii) a RET variant optionally containing one or more of the following amino acid substitutions relative to RET(wt): A883F, G691 S, M918T, S891 A, V804E, V804L, V804M and Y791 F; and / or (iv) a DDR2 variant optionally containing the amino acid substitution T654M relative to DDR2(wt) and / or the amino acid substitution N456S relative to DDR2(wt). A PK variant can be referred to with the PK name as a prefix and an amino acid substation as a suffix, where the amino acid substation suffix is separated from the PK name prefix by a hyphen (for example, ABL1 -T315I or DDR2-N456S) or by parentheses (for example, ABL1 (T315I) or DDR2(N456S)).

[0504] A compound can be an effective inhibitor of, and can be used to inhibit, two or more of: an ABL family PK, a BTK family PK, a AURK family PK, a JAK family PK, a TRK family PK, a RET PK, an EPH family PK, a TNK family PK, a PLK family PK, an IRAK family PK, a SRC family PK, a LCK family PK, a DDR family PK, a ROS family PK, and / or a PTK family PK. A compound can be an effective inhibitor of, and can be used to inhibit, an ABL family PK and a BTK family PK (for example, a BTK(wt) PK). A compound can be an effective inhibitor of, and can be used to inhibit, an ABL family PK and a AURK family PK. A compound can be an effective inhibitor of, and can be used to inhibit, an ABL family PK and a JAK family PK (for example, JAK2(wt) and / or JAK2(V617F)).

[0505] A compound can be an effective inhibitor of, and can be used to inhibit, three or more of: an ABL family PK, a BTK family PK, a AURK family PK, a JAK family PK, a TRK family PK, a RET PK, an EPH family PK, a TNK family PK, a PLK family PK, an IRAK family PK, a SRC family PK, a LCK family PK, a DDR family PK, a ROS family PK, and / or a PTK family PK. A compound can be an effective inhibitor of an ABL family PK (for example, ABL1 (wt) and / or ABL1 (T315I)), a BTK family PK (for example, a BTK(wt) PK) and a AURK family PK, for example.

[0506] A compound can be an effective inhibitor of, and can be used to inhibit, four or more of: an ABL family PK, a BTK family PK, a AURK family PK, a JAK family PK, a TRK family PK, a RET PK, an EPH family PK, a TNK family PK, a PLK family PK, an IRAK family PK, a SRC family PK, a LCK family PK, a DDR family PK, a ROS family PK, and / or a PTK family PK. A compound can be an effective inhibitor of: an ABL family PK (for example, ABL1 (wt) and / or ABL1 (T315I)), a BTK family PK (for example, a BTK(wt) PK), a AURK family PK, and a JAK family PK. A compound can be an effective inhibitor of: an ABL family PK (for example, ABL1 (wt) and / or ABL1 (T315I)), a BTK family PK (for example, a BTK(wt) PK), a AURK family PK, a JAK family PK (for example, JAK2(wt) PK and / or JAK2 variant PK containing a V617F amino acid substitution), and a TRK family PK.

[0507] A compound can be an effective inhibitor of, and can be used to inhibit, five of, or six of, or seven of, or eight of, or nine of, or ten of, or eleven of, or twelve of, or thirteen of or all of: an ABL family PK, a BTK family PK, a AURK family PK, a JAK family PK, a TRK family PK, a RET PK, an EPH family PK, a TNK family PK, a PLK family PK, an IRAK family PK, a SRC family PK, a LCK family PK, a DDR family PK, a ROS family PK, and / or a PTK family PK.

[0508] A compound can be an effective Inhibitor or moderate inhibitor of ABL1 , ABL1 -T315I, AURKA, and JAK2. The compound can be an effective inhibitor or moderate inhibitor of AURKB. The compound can be an effective inhibitor or moderate inhibitor of BTK. The compound can be an effective inhibitor of JAK3. The compound can be an effective inhibitor or moderate inhibitor of JAK1 , or the compound can be a mild inhibitor or ineffective inhibitor of JAK1 . The compound can be an effective inhibitor or moderate inhibitor of one or more or all of TYK2, a TRK family PK, ROS1 , TXK, an EPH family PK, IRAK3, PLK4, TNK1 , RET and JAK2-V617F. The compound can be an effective inhibitor or moderate inhibitor of one or more or all of TRKA,

[0509] TRKB, TRKC, ROS1 , EPHA1 and EPHB1. The compound can be an effective inhibitor or moderate inhibitor of a SRC family PK and / or a DDR family PK. The compound can be an effective inhibitor of or moderate inhibitor of a DDR2 PK and optionally a DDR2 variant PK (for example, a DDR2 variant PK containing a T654M and / or N456S amino acid substitution). In certain embodiments the compound is an effective inhibitor of SRC(wt), SRC-N1 (wt), and a DDR2 variant (DDR2-T654M for example). In certain instances the compound is a mild inhibitor of SRC(wt), a moderate inhibitor of SRC-N1 (wt), and an effective inhibitor of a DDR2 variant (DDR2-T654M for example). The compound can be an effective inhibitor or moderate inhibitor of ABL2. The compound can be an effective inhibitor or moderate inhibitor of PTK2B. The compound can be an effective inhibitor or moderate inhibitor of ABL1 , ABL1 -T315I, ABL2, TYK2, JAK2, TRKC and PTK2B. The compound can be an effective inhibitor or moderate inhibitor of ABL1 , ABL1 -T315I, BTK, AURKA, JAK2, NTRK3, PTK2B, TYK2 and ABL2. In certain instances, the NTRK3 is a ETV6-NTRK3 fusion. The compound can be an effective inhibitor or moderate inhibitor of LCK. In certain instances, the compound is a Subgroup 1 or Subgroup 4 compound. A compound of Subgroup 1 and / or Subgroup 4 can be an effective inhibitor of, or optionally a moderate inhibitor of, and can be used to inhibit, multiple PTKs, including ten or more of, or eleven or more of, or twelve or more of, or thirteen or more of, or all of an ABL family PK, a BTK family PK, an AURK family PK, a JAK family PK, a TRK family PK, a RET PK, an EPH family PK, a TNK family PK, a PLK family PK, an IRAK family PK, a SRC family PK, a LCK family PK, a DDR family PK, a ROS family PK, and / or a PTK family PK.

[0510] A compound can be an effective inhibitor of JAK2, JAK3, JAK2-V617F and a mild inhibitor of JAK1 . The compound can be an effective inhibitor of or a moderate inhibitor of one or more or all of ABL1 , TRKA, TRKB, TRKC, ROS1 , AURKA, IRAK3, TNK1 . In certain instances, the compound is a Subgroup 5 compound.

[0511] A compound can be an effective inhibitor of JAK2, an ineffective inhibitor of or a mild inhibitor of JAK1 , and optionally: a moderate inhibitor of JAK3 and / or a mild inhibitor of JAK2-V617F. The compound can be an effective inhibitor of or a moderate inhibitor of one or more or all of TRKB,

[0512] TRKC, AURKA, IRAK3 and PLK4. A compound can be an effective inhibitor of JAK2, an ineffective inhibitor of or a mild inhibitor of JAK1 , and optionally: a moderate inhibitor of JAK3 and / or JAK2-V617F. The compound can be an effective inhibitor of or a moderate inhibitor of one or more or all of TXK, JAK2-V617F, TRKB, TRKC, ROS1 , AURKA, IRAK3 and TNK1 . In certain instances, the compound is a Subgroup 2 compound.

[0513] A compound can be an effective inhibitor of JAK2, an ineffective inhibitor of or a mild inhibitor of JAK1 , and optionally: an effective inhibitor of JAK3 and / or JAK2-V617F. In certain instances, the compound is a Subgroup 3 compound.

[0514] A compound can be an effective inhibitor of JAK2, a moderate inhibitor of JAK1 , and optionally: a moderate inhibitor of JAK3 and / or a moderate inhibitor of or an effective inhibitor of JAK2- V617F. In certain instances, the compound is a Subgroup 6 compound.

[0515] A compound can be an effective inhibitor of or a moderate inhibitor of TYK2. The compound can be an effective inhibitor of or a moderate inhibitor of JAK3. The compound can be a mild inhibitor of or an ineffective inhibitor of JAK1 and / or JAK2. The compound can be an effective inhibitor of or a moderate inhibitor of one or more or all of ABL1-T315I, AURKA, PLK4 and IRAK3. In certain instances, the compound is a Subgroup 9 compound.

[0516] A compound can be an effective inhibitor of or a moderate inhibitor of TXK. The compound can be an effective inhibitor of JAK2, an ineffective inhibitor of or a mild inhibitor of JAK1 , and optionally: for an effective inhibitor of or a moderate inhibitor of JAK3 and / or JAK2-V617F. In certain instances, the compound is a Subgroup 7 compound.

[0517] A compound can be an effective inhibitor of or a moderate inhibitor of IRAK3. A compound can be an effective inhibitor of or a moderate inhibitor of PLK4. In certain instances, the compound is a Subgroup 8 compound.

[0518] A compound can inhibit a homo sapiens PK or viral PK. A polypeptide of each of the foregoing wild type (wt) homo sapiens PKs is accessible in (i) a public database (World Wide Web URL ncbi.nlm.nih.gov / protein / ) according to the corresponding accession number having a “NP” or “AA” prefix, and (ii) a public database (World Wide Web URL uniprot.org / uniprotkb / ) according to the corresponding accession number having a “P” prefix, in Table 4 of Example 17. A polypeptide of a corresponding PK variant can be determined according to the wt polypeptide accessed from the database and the position of one or more amino acid substitutions designated.

[0519] JAK1 (wt), JAK2(wt) and JAK3(wt) are receptor PKs. The JAK1 (wt) catalytic domain includes amino acids 866-1154 of the JAK1 (wt) polypeptide accessed by the accession number in Table 4 of Example 17, which can be utilized in assays. The JAK2(wt) catalytic domain includes amino acids 808-1132 of the JAK2(wt) polypeptide accessed by the accession number in Table 4 of Example 17, which can be utilized in assays. The JAK3(wt) catalytic domain includes amino acids 781-1124 of the JAK3(wt) polypeptide accessed by the accession number in Table 4 of Example 17, which can be utilized in assays. TRKA(wt), TRKB(wt) and TRKC(wt) also are receptor PKs. The TRKA(wt) catalytic domain includes amino acids 441 -796 of the TRKA(wt) polypeptide accessed by the accession number in Table 4 of Example 17, which can be utilized in assays. The TRKB(wt) catalytic domain includes amino acids 526-838 of the TRKB(wt) polypeptide accessed by the accession number in Table 4 of Example 17, which can be utilized in assays. The TRKC(wt) catalytic domain includes amino acids 510-825 of the TRKC(wt) polypeptide accessed by the accession number in Table 4 of Example 17, which can be utilized in assays. RET(wt) also is a receptor PK and the catalytic domain includes amino acids 658-1114 of the polypeptide accessed by the accession number in Table 4 of Example 17, which can be utilized in assays.

[0520] EPHA1(wt), EPHA2(wt), EPHA5(wt), EPHA8(wt), EPHB1 (wt) and EPHB2(wt) PKs also are receptor PKs. The EPHA1 (wt) catalytic domain includes amino acids 568-976 of the EPHA1 (wt) polypeptide accessed by the accession number in Table 4 of Example 17, which can be utilized in assays. The EPHA2(wt) catalytic domain includes amino acids 560-976 of the EPHA2(wt) polypeptide accessed by the accession number in Table 4 of Example 17, which can be utilized in assays. The EPHA5(wt) catalytic domain includes amino acids 595-1037 of the EPHA5(wt) polypeptide accessed by the accession number in Table 4 of Example 17, which can be utilized in assays. The EPHA8(wt) catalytic domain includes amino acids 565-1005 of the EPHA8(wt) polypeptide accessed by the accession number in Table 4 of Example 17, which can be utilized in assays. The EPHB1 (wt) catalytic domain includes amino acids 612-887 of the EPHB1 (wt) polypeptide accessed by the accession number in Table 4 of Example 17, which can be utilized in assays. The EPHB2(wt) catalytic domain includes amino acids 616-884 of the EPHB2(wt) polypeptide accessed by the accession number in Table 4 of Example 17, which can be utilized in assays.

[0521] TYK2(wt) also is a receptor PK and the catalytic domain includes amino acids 833-1187 of the polypeptide accessed by the accession number in Table 4 of Example 17, which can be utilized in assays. TNK2(wt), which also is referred to as ACK, also is a receptor PK and the catalytic domain includes amino acids 110-476 of the polypeptide accessed by the accession number in Table 4 of Example 17, which can be utilized in assays. IRAKI (wt) also is a receptor PK and the catalytic domain includes amino acids 194-712 of the polypeptide accessed by the accession number in Table 4 of Example 17, which can be utilized in assays. DDR2 also is a receptor PK and the catalytic domain includes amino acids 422-855 of the polypeptide accessed by the accession number in Table 4 of Example 17, which can be utilized in assays.

[0522] The SRC(wt) polypeptide can be accessed by either of the accession numbers shown in Table 4 of Example 17. The SRC-N1 (wt) polypeptide is nearly identical to the SRC(wt) polypeptide but includes a 6-amino acid polypeptide insertion in the SH3 domain of the SRC(wt) polypeptide. The T at position 117 in the SRC(wt) polypeptide is replaced by TRKVDVR in the SRC-N1 (wt) polypeptide. A PK referred to herein as ABL1, ABL2, AURKA, AURKB, AURK3, BTK, BMX, ITK, TEC, TXK, JAK1 , JAK2, JAK3, TYK2, R0S1 , EPHA1 , EPHA2, EPHA5, EPHA8, EPHB1 , EPHB2, IRAKI , IRAK3, PLK4, TNK1 , TNK2, RET, TRKA, TRKB, TRKC, NTRK1 , NTRK2, NTRK3, SRC, SRC- N1 , LCK, DDR2 or PTK2B, without an indication of an amino acid substitution, typically contains the polypeptide of ABL1(wt), ABL2(wt), AURKA(wt), AURKB(wt), AURK3(wt), BTK(wt), BMX(wt), ITK(wt), TEC(wt), TXK(wt), JAK1 (wt), JAK2(wt), JAK3(wt), TYK2(wt), ROS1(wt), EPHA1(wt), EPHA2(wt), EPHA5(wt), EPHA8(wt), EPHB1 (wt), EPHB2(wt), IRAKI (wt), IRAK3(wt), PLK4(wt), TNK1 (wt), TNK2(wt), RET(wt), TRKA(wt), TRKB(wt), TRKC(wt), NTRK1(wt), NTRK2(wt), NTRK3(wt), SRC(wt), SRC-N1(wt), LCK(wt), DDR2(wt) or PTK2B(wt), respectively, or a portion thereof containing (i) a catalytic domain or (ii) a fragment of a catalytic domain having phosphoryl-transfer activity (for example, in vitro phosphoryl-transfer activity). A PK referred to as having an amino acid substitution herein (for example DDR2-N456S and / or DDR2-T654M) typically includes the designated amino acid substitution at the designated position in the polypeptide accessed by the accession number referenced in Table 4 of Example 17, and can be the length of the accessed polypeptide, or a portion thereof containing (i) a catalytic domain or (ii) a fragment of a catalytic domain having phosphoryl-transfer activity (for example, in vitro phosphoryl-transfer activity).

[0523] ABL1 inhibition

[0524] In certain embodiments, a compound is an effective inhibitor or moderate inhibitor of one or more, or two or more, ABL1 variant polypeptides. Such a compound can be an effective inhibitor or moderate inhibitor of ABL1 (wt). A compound that is an effective inhibitor or two or more ABL1 variant polypeptides can be considered a pan-ABL1 inhibitor. In certain embodiments, a compound is an effective inhibitor of two or more ABL1 variant polypeptides containing one or more of M244V, G250E, Q252H, Y253F, Y253H, E255K, E255V, V299L, F311 L, T315A, T315I, F317L, F317V, M351T, E355G, F359V, V379I, L387M, H396P and / or H396R. A compound sometimes is an effective inhibitor of ABL1 (T315I) and an effective inhibitor of one or more other ABL1 variant polypeptides (for example, two or more other ABL1 variant polypeptides, three or more other ABL1 variant polypeptides, or four or more other ABL1 variant polypeptides). A compound sometimes is an effective inhibitor of ABL1 (T315I) and an effective inhibitor of one or more of ABL1 (G250E), ABL1 (Y253F), ABL1 (E255K) and ABL1 (F317L). A compound sometimes is an effective inhibitor of ABL1 (T315I) and an effective inhibitor of two or more of ABL1 (G250E), ABL1 (Y253F), ABL1 (E255K) and ABL1 (F317L). A compound sometimes is an effective inhibitor of ABL1 (T315I) and an effective inhibitor of three or more of ABL1 (G250E), ABL1 (Y253F), ABL1 (E255K) and ABL1 (F317L). A compound sometimes is an effective inhibitor of ABL1 (T315I), an effective inhibitor one or more other ABL1 variant polypeptides, and a moderate inhibitor of one or more other ABL1 variant polypeptides. A compound sometimes is an effective inhibitor of ABL1 (T315I), an effective inhibitor of one or more of ABL1 (G250E), ABL1 (Y253F), ABL1 (E255K) and ABL1(F317L), and a moderate inhibitor of one or more of ABL1 (G250E), ABL1 (Y253F), ABL1 (E255K) and ABL1 (F317L). A compound sometimes is an effective inhibitor of ABL1 (T315I), ABL1 (G250E), ABL1 (Y253F) and ABL1 (E255K), and a moderate inhibitor of ABL1 (F317L).

[0525] ABL1 (wt) and ABL1 variant polypeptides are described in greater detail hereafter. Two common alternatively spliced isoforms of the homo sapiens ABL1 PTK are referred to herein as "isoform a" and "isoform b." The following is the ABL1 "isoform a" polypeptide (SEQ ID NO: 1 ).

[0526] MLE ICLKLVGCKSKKGLSSSSSCYLEEALQRPVASDFEPQGLSEAARWNSKENLLAGPSENDPNLFV ALYDFVASGDNTLS ITKGEKLRVLGYNHNGEWCEAQTKNGOGWVPSNYITPVNSLEKHSWYHGPVSR NAAEYLLSSGINGSFLVRESESSPGQRSISLRYEGRVYHYRINTASDGKLYVSSESRFNTLAELVHH HSTVADGLITTLHYPAPKRNKPTVYGVSPNYDKWEMERTD I TMKHKLGGGQYGEVYEGVWKKYSLTV AVKTLKEDTMEVEEFLKEAAVMKEIKHPNLVQLLGVCTREPPFYIITEFMTYGNLLDYLRECNRQEV NAWLLYMATQISSAMEYLEKKNFIHRDLAARNCLVGENHLVKVADFGLSRLMTGDTYTAHAGAKFP IKWTAPESLAYNKFSIKSDVWAFGVLLWEIATYGMSPYPGIDLSQVYELLEKDYRMERPEGCPEKVY

[0527] The following is the ABL1 "isoform b" polypeptide (SEQ ID NO: 2).

[0528] MGQQPGKVLGDQRRPSLPALHFIKGAGKKESSRHGGPHCNVFVEHEALORPVASDFEPOGLSEAARW NSKENLLAGPSENDPNLFVALYDFVASGDNTLS ITKGEKLRVLGYNHNGEWCEAOTKNGOGWVPSNY ITPVNSLEKHSWYHGPVSRNAAEYLLSSGINGSFLVRESESSPGQRS I SLRYEGRVYHYRINTASDG KLYVSSESRFNTLAELVHHHSTVADGLITTLHYPAPKRNKPTVYGVSPNYDKWEMERTDITMKHKLG GGQYGEVYEGVWKKYSLTVAVKTLKEDTMEVEEFLKEAAVMKEIKHPNLVQLLGVCTREPPFYIITE

[0529] FMT YGNLLDYLRECNRQEVNAWLLYMATQ I S S AMEYLEKKNF I HRDLAARNCLVGENHLVKVADFG LSRLMTGDTYTAHAGAKFPIKWTAPESLAYNKFSIKSDVWAFGVLLWEIATYGMSPYPGIDLSQVYE LLEKDYRMERPEGCPEKVYELMRACWQWNP SDRP SFAE IHQAFETMFQES S ISDEVEKELGKQGVRG yySAtPQPPPPAIKTRTSRjy\AEHRpTJJpVPEMPHyjpGQGESpP_LDHEPAyS_P_LLPRKERGPPEGGL PPPyApLPKDKJ^TNLFSALJJ<KKKKTAPjrPPKRSS_S_FREMpGQPE_RRGAGEEE_GRpi SNGALAFTPL P JAPAPP P P KPSN G A GV P N_G ALRE S G GSGF R S P H L WKK S S T LT_S_S_RL ATGE _E_E_G G GS S S KRF L R SOS AS CVP HGAKD TE_WRSVT LPRD pQ S TGRQFDS S TF GGHKS E KPA_L_P_RKRAGE y_RS DQV TRGT VTP P PR LyKjg^EEAApEjy^Kp iMESyj^GSSPPNyjrPKPLRRQyTyAPASGJ^PHKEEAyKGSALGTPAAAEPyT PPP_KAG S GAP G_G T S K GP Ap_E_PPYPPPAH_S S E S P GRDKGK L S RLKPAP P P P P AA S AGKAGGKP S Q S P S QpyApE AV LGAKTKAT S LVDAVN S D AAKP S QP GE G_LAPPY PPAAJA Q P AKPSGTP I p PAAAP PPP VKEJJSD LVQR

[0530] In each of the ABL1 "isoform a" polypeptide and ABL1 "isoform b" polypeptide depicted above, an N-terminal region is underlined with single-underlining, followed by an adjacent downstream region underlined with double-underlining, followed by a catalytic domain highlighted in bold text, followed by a C-terminal region underlined with hatched underlining. The ABL1 "isoform a" polypeptide N-terminal region underlined above by single underlining differs from the ABL1 "isoform b" polypeptide N-terminal region underlined above by single underlining. The adjacent, downstream polypeptide region in each of the ABL1 "isoform a" polypeptide and ABL1 "isoform b" polypeptide, which is not underlined with single underlining, and which starts from the end of the N-terminal region underlined by single underlining and ends at the C-terminus, is identical (the "identical portion"). The common catalytic domain (also referred to as a "kinase domain") highlighted in bold text in the ABL1 "isoform a" polypeptide and ABL1 "isoform b" polypeptide above is reproduced below (SEQ ID NO: 3).

[0531] SPNYDKWEMERTD LTMKHKLGGGQYGEVYEGVWKKYSLTVAVKTLKEDTMEVEEFLKEAAVMKE LKH PNLVQLLGVCTREPPFYL LTEFMTYGNLLDYLRECNRQEVNAWLLYMATQL S SAMEYLEKKNF L HR DLAARNCLVGENHLVKVADFGLSRLMTGDTYTAHAGAKFP LKWTAPE SLAYNKF S LKSDVWAFGVLL WE LATYGMSPYPGLDLSQVYELLEKDYRMERPEGCPEKVYELMRACWQWNP SDRP SFAE LHQAFETM FQE SS L SDEVEKELGK

[0532] The amino acid highlighted in bold text and underlined in the catalytic domain above (SEQ ID NO: 3) is addressed hereafter.

[0533] An ABL1 polypeptide referred to as an "ABL1 wild type" polypeptide ("ABL1 (wt)") can (1) contain the polypeptide of SEQ ID NO: 3; or (2) contain the polypeptide of SEQ ID NO: 1 ; or (3) contain the polypeptide of SEQ ID NO: 2; or (4) contain the polypeptide of SEQ ID NO: 3 and: (i) an adjacent N-terminal region containing 2 or more contiguous amino acids in the doubleunderlined region and / or single underlined region shown above in SEQ ID NO: 1 or SEQ ID NO: 2, or (ii) an adjacent C-terminal region containing 2 or more contiguous amino acids in the hatched-underlined region shown above in SEQ ID NO: 1 and SEQ ID NO: 2, or a combination of (i) and (ii); or (5) contain a fragment of (1 ), (2), (3) or (4) containing 25 or more contiguous amino acids or 1100 or fewer contiguous amino acids; or (6) contain an ABL1 polypeptide portion containing a polypeptide of (1 ), (2), (3), (4) or (5) and a non-ABL1 polypeptide portion. An ABL1 (wt) polypeptide typically does not include a substitution of an amino acid in the identical portion, i.e. , the portion of the ABL1 "isoform a" and "isoform b" polypeptides above not underlined by single-underlining. An ABL1 (wt) polypeptide typically includes no amino acid insertion or amino acid deletion relative to the polypeptide of SEQ ID NO: 1 , SEQ ID NO: 2 or SEQ ID NO: 3. A fragment sometimes includes 25 or more contiguous amino acids of the polypeptide of SEQ ID NO: 1 , SEQ ID NO: 2 or SEQ ID NO: 3 (for example, 30 or more, 35 or more, 40 or more, 45 or more, 50 or more, 55 or more, 60 or more, 65 or more, 70 or more, 75 or more, 80 or more, 85 or more, 90 or more, 95 or more, 100 or more, 110 or more, 120 or more, 130 or more, 140 or more, 150 or more, 160 or more, 170 or more, 180 or more, 190 or more, 200 or more, 225 or more, 250 or more, 275 or more, 300 or more, 325 or more, 350 or more, 375 or more, 400 or more, 425 or more, 450 or more, 475 or more, 500 or more, 525 or more, 550 or more, 575 or more, 600 or more, 625 or more, 650 or more, 675 or more, 700 or more, 725 or more, 750 or more, 775 or more, 800 or more, 825 or more, 850 or more, 875 or more, 900 or more, 925 or more, 950 or more, 975 or more, 1000 or more, 1025 or more, 1050 or more, 1075 or more, or 1100 or more contiguous amino acids of the polypeptide of SEQ ID NO: 1 , SEQ ID NO: 2 or SEQ ID NO: 3). A fragment sometimes includes 1100 or fewer contiguous amino acids of the polypeptide of SEQ ID NO: 1 , SEQ ID NO: 2 or SEQ ID NO: 3 (for example, 50 or fewer, 55 or fewer, 60 or fewer, 65 or fewer, 70 or fewer, 75 or fewer, 80 or fewer, 85 or fewer, 90 or fewer, 95 or fewer, 100 or fewer, 110 or fewer, 120 or fewer, 130 or fewer, 140 or fewer, 150 or fewer, 160 or fewer, 170 or fewer, 180 or fewer, 190 or fewer, 200 or fewer, 225 or fewer, 250 or fewer, 275 or fewer, 300 or fewer, 325 or fewer, 350 or fewer, 375 or fewer, 400 or fewer, 425 or fewer, 450 or fewer, 475 or fewer, 500 or fewer, 525 or fewer, 550 or fewer, 575 or fewer, 600 or fewer, 625 or fewer, 650 or fewer, 675 or fewer, 700 or fewer, 725 or fewer, 750 or fewer, 775 or fewer, 800 or fewer, 825 or fewer, 850 or fewer, 875 or fewer, 900 or fewer, 925 or fewer, 950 or fewer, 975 or fewer, 1000 or fewer, 1025 or fewer, 1050 or fewer, or 1075 or fewer contiguous amino acids of the polypeptide of SEQ ID NO: 1 , SEQ ID NO: 2 or SEQ ID NO: 3).

[0534] A non-ABL1 polypeptide portion present in an ABL1 (wt) polypeptide sometime is (i) an N- terminal portion, or is located closer to the N-terminus of the ABL1 (wt) polypeptide than the ABL1 polypeptide portion; or (ii) a C-terminal portion, or is located closer to the C-terminus of the ABL1 (wt) polypeptide than the ABL1 polypeptide portion; or (iii) a combination of (i) and (ii) where there are multiple non-ABL1 polypeptide portions. A non-ABL1 polypeptide portion present in an ABL1 (wt) polypeptide sometimes contains a BCR portion (for example, a BCR portion of a BCR-ABL1 fusion polypeptide identified in cancer patients). A BCR portion present in an ABL1 (wt) polypeptide can be an N-terminal portion, or can be located closer to the N- terminus of the ABL1 (wt) polypeptide than the ABL1 polypeptide portion.

[0535] An ABL1 (wt) polypeptide can be modified with one or more components that facilitate use of the polypeptide, including without limitation one or more of separating, purifying, isolating and detecting an ABL1 polypeptide, and measuring an activity of an ABL1 polypeptide (for example, binding activity of an ABL1 polypeptide to a test compound and / or binding agent; phosphorylation activity of an ABL1 polypeptide). In certain embodiments, an ABL1 (wt) polypeptide can be modified to include a binding pair member (for example, biotin / avidin (or streptavidin), antibody / antigen), a luminescence molecule (for example, bioluminescence molecule; luciferase or portion thereof; nano-luciferase), fluorophore (for example, member or members of a fluorescence resonance energy transfer (FRET) pair), dye, particle (for example, nanoparticle), and the like, for example. For embodiments in which the component is a polypeptide, the polypeptide may be a non-ABL polypeptide portion referenced herein. In certain instances, a non-ABL1 polypeptide portion is an N-terminal or C-terminal portion useful to immobilizing the ABL1 polypeptide to a solid phase. In certain embodiments, a non-ABL polypeptide portion contains a poly-histidine peptide portion (for example, a peptide containing 5-20, or 6-10, consecutive histidine amino acids) capable of associating with a transition metalcontaining solid phase (for example, a solid phase containing Mn, Fe, Co, Ni or Cu). A non- ABL1 polypeptide portion sometimes contains one or both of a linker polypeptide portion and a cleavage recognition polypeptide portion. Multiple linker polypeptide portions are known and can be selected. Multiple cleavage recognition polypeptide portions also are known and can be selected for cleavage of an N-terminal portion or C-terminal portion from an ABL1 polypeptide under suitable cleavage conditions.

[0536] A non-limiting example of an ABL1 (wt) polypeptide containing the "isoform a" polypeptide of SEQ ID NO: 1 and a non-ABL1 C-terminal portion (highlighted in bold text) containing a polyhistidine peptide portion and linker portion, referred to herein as "isoahABLI (wt)," is as follows (SEQ ID NO: 4): MLE ICLKLVGCKSKKGLSS S SSCYLEEALQRPVASDFEPQGLSEAARWNSKENLLAGP SENDPNLFV ALYDFVASGDNTLS I TKGEKLRVLGYNHNGEWCEAQTKNGQGWVP SNYITPVNSLEKHSWYHGPVSR NAAEYLLS SGINGSFLVRE SESSPGQRS I SLRYEGRVYHYRINTASDGKLYVS SE SRFNTLAELVHH HSTVADGLITTLHYPAPKRNKPTVYGVSPNYDKWEMERTD I TMKHKLGGGQYGEVYEGVWKKYSLTV AVKTLKEDTMEVEEFLKEAAVMKE IKHPNLVQLLGVCTREPPFYI I TEFMTYGNLLDYLRECNRQEV NAWLLYMATQI S SAMEYLEKKNF IHRDLAARNCLVGENHLVKVADFGLSRLMTGDTYTAHAGAKFP IKWTAPE SLAYNKF S IKSDVWAFGVLLWE IATYGMSPYP GIDLSQVYELLEKDYRMERPEGCPEKVY ELMRACWQWNP SDRP SFAE IHQAFETMFQE S S I SDEVEKELGKQGVRGAVSTLLQAPELPTKTRTSR RAAEHRDTTDVPEMPHSKGQGESDPLDHEPAVSPLLPRKERGPPEGGLNEDERLLPKDKKTNLF SAL IKKKKKTAPTPPKRS SSFREMDGQPERRGAGEEEGRD I SNGALAFTPLDTADPAKSPKP SNGAGVPN GALRE SGGSGFRSPHLWKKS STLTSSRLATGEEEGGGS S SKRFLRSCSASCVPHGAKDTEWRSVTLP RDLQSTGRQFDS STFGGHKSEKPALPRKRAGENRSDQVTRGTVTPPPRLVKKNEEAADEVFKD IMES SPGSSPPNLTPKPLRRQVTVAPASGLPHKEEAGKGSALGTPAAAEPVTPTSKAGSGAPGGTSKGPAE ESRVRRHKHS SE SPGRDKGKLSRLKPAPPPPPAASAGKAGGKP SQSP SQEAAGEAVLGAKTKATSLV DAVNSDAAKP SQPGEGLKKPVLPATPKPQSAKP SGTP I SPAPVP STLP SAS SALAGDQP S STAF IPL I STRVSLRKTRQPPERIASGAITKGWLDSTEALCLAI SRNSEQMASHSAVLEAGKNLYTFCVSYVD S IQQMRNKFAFREAINKLENNLRELQI CPATAGSGPAATQDFSKLLS SVKE I SD IVQRLEACQLGTD DYDIPTTHHHHHH

[0537] A non-limiting example of an ABL1 (wt) polypeptide containing the "isoform b" polypeptide of SEQ ID NO: 2 and a non-ABL1 N-terminal portion (highlighted in bold text) containing a nano- luciferase portion and linker portion, referred to herein as "isoblABLI (wt)," is as follows (SEQ ID NO: 5):

[0538] MVFTLEDFVGDWRQTAGYNLDQVLEQGGVSSLFQNLGVSVTPIQRIVLSGENGLKIDIHVIIPYEGL SGDQMGQIEKIFKVVYPVDDHHFKVILHYGTLVIDGVTPNMIDYFGRPYEGIAVFDGKKITVTGTLW NGNKIIDERLINPDGSLLFRVTINGVTGWRLCERILAGGSGGGGSGGGSSGGAIAMGQQPGKVLGDQ

[0539] RRPSLPALHF IKGAGKKESSRHGGPHCNVFVEHEALQRPVASDFEPQGLSEAARWNSKENLLAGPSE NEPNEEVALYDEVASGDN'rESl'rKGEKLRVEGYNHNGEWCEAQTKNGQGWVPSNY lTPVNSEEKHSW YHGPVSRNAAEYLLSSGINGSFLVRESESSPGQRSISLRYEGRVYHYRINTASDGKLYVSSESRFNT LAELVHHHSTVADGLITTLHYPAPKRNKPTVYGVSPNYDKWEMERTD ITMKHKLGGGQYGEVYEGVW KKYSLTVAVKTLKEDTMEVEEFLKEAAVMKE IKHPNLVQLLGVCTREPPFYI ITEFMTYGNLLDYLR ECNRQEVNAWLLYMATQI SSAMEYLEKKNF IHRDLAARNCLVGENHLVKVADFGLSRLMTGDTYTA HAGAKFP IKWTAPESLAYNKFSIKSDVWAFGVLLWEIATYGMSPYPGIDLSQVYELLEKDYRMERPE GCPEKVYELMRACWQWNPSDRPSFAE IHQAFETMFQESS I SDEVEKELGKQGVRGAVSTLLQAPELP TKTRTSRRAAEHRDTTDVPEMPHSKGQGESDPLDHEPAVSPLLPRKERGPPEGGLNEDERLLPKDKK TNLFSALIKKKKKTAPTPPKRSSSFREMDGQPERRGAGEEEGRD ISNGALAFTPLDTADPAKSPKPS NGAGVPNGALRESGGSGFRSPHLWKKSSTLTSSRLATGEEEGGGSSSKRFLRSCSASCVPHGAKDTE WRSVTLPRDLQSTGRQFDSSTFGGHKSEKPALPRKRAGENRSDQVTRGTVTPPPRLVKKNEEAADEV FKD IMESSPGSSPPNLTPKPLRRQVTVAPASGLPHKEEAGKGSALGTPAAAEPVTPTSKAGSGAPGG TSKGPAEESRVRRHKHSSESPGRDKGKLSRLKPAPPPPPAASAGKAGGKPSQSPSQEAAGEAVLGAK TKATSLVDAVNSDAAKPSQPGEGLKKPVLPATPKPQSAKPSGTP ISPAPVPSTLPSASSALAGDQPS STAFIPLI STRVSLRKTRQPPERIASGAITKGWLDSTEALCLAISRNSEQMASHSAVLEAGKNLYT FCVSYVDSIQQMRNKFAFREAINKLENNLRELQICPATAGSGPAATQDFSKLLSSVKE ISD IVQR

[0540] The "isoahABLI (wt)" polypeptide can be utilized in a labeled peptide cleavage assay (for example, assay described in Example 17). The "isoblABLI (wt)" polypeptide can be utilized in a labeled peptide competition assay, such as a bioluminescence resonance energy transfer (BRET) intracellular assay (for example, Machleidt et al., ACS Chem. Biol. 10:1797-1804 (2015)), for example.

[0541] An ABL1 polypeptide referred to herein as an "ABL1 variant polypeptide" typically includes one or more amino acid substitutions relative to an ABL1 (wt) polypeptide. An ABL1 variant polypeptide may include a structure described herein for an ABL1 (wt) polypeptide, with the exception that the variant polypeptide includes one or more amino acid substitutions relative to the ABL1 (wt) polypeptide. An ABL1 variant polypeptide sometimes includes up to ten amino acid substitutions relative to an ABL1 (wt) polypeptide (for example, substitution of 1 , 2, 3, 4, 5, 6, 7, 8, 9 or 10 amino acids relative to an ABL1 (wt) polypeptide).

[0542] An amino acid substitution in an ABL1 variant polypeptide is defined herein relative to a position in SEQ ID NO: 1 , by the following notation utilizing the one-letter amino acid code: amino acid in SEQ ID NO: 1 - at position in SEQ ID NO: 1 - corresponding substituted amino acid in ABL1 variant polypeptide. For example, the amino acid substitution notated as "T315I" refers to the threonine at position 315 in SEQ ID NO: 1 substituted by isoleucine in an ABL1 variant ("ABL1 (T315I)"). An ABL1 variant polypeptide can include an amino acid substitution corresponding to a position in SEQ ID NO: 1 in instances where the ABL1 variant polypeptide includes the same number, or does not include the same number, of amino acids of the polypeptide of SEQ ID NO: 1 . A corresponding amino acid position of an amino acid substitution can be readily determined for a particular ABL1 variant polypeptide as known in the art. A corresponding amino acid position in an ABL1 variant polypeptide can be determined by aligning the ABL1 variant polypeptide to the polypeptide of SEQ ID NO: 1 , as known in the art, and determining the position of the substituted amino acid in the ABL1 variant polypeptide corresponding to the amino acid position of SEQ ID NO: 1 in the alignment (for example, World Wide Web Uniform Resource Locator (URL) Hypertext Transfer Protocol Secure: blast.ncbi.nlm.nih.gov / Blast. cgi?PAGE=Proteins). For example, the threonine highlighted in bold text and underlined in the catalytic domain polypeptide shown herein (SEQ ID NO: 3) corresponds to threonine 315 in SEQ ID NO: 1 . An ABL1 variant polypeptide often includes no amino acid insertion or amino acid deletion relative to the polypeptide of SEQ ID NO: 1 , SEQ ID NO: 2 or SEQ ID NO: 3. An ABL1 variant polypeptide can, in certain instances, include (i) an amino acid insertion within the polypeptide of SEQ ID NO: 1 , SEQ ID NO: 2 or SEQ ID NO: 3 containing 1 , 2 or 3 contiguous amino acids; or (ii) an amino acid deletion of 1 , 2 or 3 contiguous amino acids in the polypeptide of SEQ ID NO: 1 , SEQ ID NO: 2 or SEQ ID NO: 3; or a combination of (i) and (ii).

[0543] An ABL1 variant polypeptide may include an amino acid substitution in a particular portion of the polypeptide, non-limiting examples of which include a p-loop portion, SH3 contact portion, SH2 contact portion and A-loop portion. Non-limiting examples of amino acid substitutions, any one or more of which may be present in an ABL1 variant polypeptide, are illustrated in FIG. 2 (Soverini et al., Blood 118(5):1208-1215 (2011 )). An ABL1 variant may include one or more of the following amino acid substitutions: M237V, I242T, M244V, K247R, L248V, G250E, G250R, Q252R, Q252H, Y253F, Y253H, E255K, E255V, E258D, W261 L, L273M, E275K, E275Q, D276G, T277A, E279K, V280A, V289A, V289I, E292V, E292Q, I293V, L298V, V299L, F311 L, F311 I, T315A, T315I, F317L, F317V, F317I, F317C, Y320C, L324Q, Y342H, M343T, A344V, A350V, M351T, E355D, E355G, E355A, F359V, F359I, F359C, F359L, D363Y, L364I, A365V, A366G, L370P, V371A, E373K, V379I, A380T, F382L, L384M, L387M, L387F, L387V, M388L, Y393C, H396P, H396R, H396A, A397P, S417F, S417Y, 1418S, 1418V, A433T, S438C, E450K, E450G, E450A, E450V, E453G, E453K, E453V, E453Q, E459K, E459V, E459G, E459Q, M472I, P480L, F486S and E507G. The foregoing amino acid substitutions have been reported to confer imatinib therapy resistance in CML patients. Substitutions F317L and V299L have been reported to impart dasatinib therapy resistance and substitutions Y253H, E255K, E255V, F359V and F359C have been reported to impart nilotinib therapy resistance. The substitution T315I has been reported to impart resistance to imatinib, dasatinib and nilotinib therapy. Non-limiting examples of ABL1 variant polypeptides are referred to herein as ABL1(M237V), ABL1(I242T), ABL1(M244V), ABL1(K247R), ABL1(L248V), ABL1(G250E), ABL1(G250R), ABL1(Q252R), ABL1(Q252H), ABL1(Y253F), ABL1(Y253H), ABL1(E255K), ABL1(E255V), ABL1(E258D), ABL1(W261L), ABL1 (L273M), ABL1(E275K), ABL1(E275Q), ABL1(D276G), ABL1(T277A), ABL1(E279K), ABL1(V280A), ABL1(V289A), ABL1(V289I), ABL1(E292V), ABL1 (E292Q), ABL1 (I293V), ABL1 (L298V), ABL1 (V299L), ABL1 (F311 L), ABL1 (F3111), ABL1(T315A), ABL1(T315I), ABL1(F317L), ABL1(F317V), ABL1 (F317I), ABL1(F317C), ABL1(Y320C), ABL1(L324Q), ABL1(Y342H), ABL1(M343T), ABL1(A344V), ABL1(A350V), ABL1(M351T), ABL1(E355D), ABL1(E355G), ABL1(E355A), ABL1(F359V), ABL1(F359I), ABL1(F359C), ABL1(F359L), ABL1(D363Y), ABL1(L364I), ABL1(A365V), ABL1(A366G), ABL1(L370P), ABL1(V371A), ABL1(E373K), ABL1 (V379I), ABL1(A380T), ABL1(F382L), ABL1(L384M), ABL1(L387M), ABL1(L387F), ABL1(L387V), ABL1(M388L), ABL1(Y393C), ABL1(H396P), ABL1(H396R), ABL1(H396A), ABL1(A397P), ABL1(S417F), ABL1(S417Y), ABL1(I418S), ABL1 (1418V), ABL1(A433T), ABL1(S438C), ABL1(E450K), ABL1(E450G), ABL1(E450A), ABL1(E450V), ABL1(E453G), ABL1(E453K), ABL1(E453V), ABL1(E453Q), ABL1(E459K), ABL1(E459V), ABL1(E459G), ABL1(E459Q), ABL1(M472I), ABL1(P480L), ABL1 (F486S) or ABL1 (E507G).

[0544] A non-limiting example of an ABL1 variant polypeptide contains the polypeptide of SEQ ID NO: 3 with one or more of the following modifications: (i) the threonine highlighted in bold text and underlined in the polypeptide of SEQ ID NO: 3 herein is substituted to isoleucine, (ii) a polyhistidine tag containing ten consecutive histidine amino acids is appended at the N- terminus along with an adjacent 3’ linker sequence (SSGVDLGT) followed by a “TEV” cleavage site (ENLYFQ / S), and (iii) an initial “MG” sequence. An example of an ABL1 variant polypeptide containing the foregoing modifications is referred to as "catABL1(T315l)" herein and contains the following polypeptide (SEQ ID NO: 6).

[0545] MGHHHHHHHHHHSSGVDLGTENLYFQ / SSPNYDKWEMERTDITMKHKLGGGQYGEVYEGVWKKYSLT VAVKTLKEDTMEVEEFLKEAAVMKEIKHPNLVQLLGVCTREPPFYI I IEFMTYGNLLDYLRECNRQE VNAWLLYMATQISSAMEYLEKKNFIHRDLAARNCLVGENHLVKVADFGLSRLMTGDTYTAHAGAKF PIKWTAPESLAYNKFSIKSDVWAFGVLLWEIATYGMSPYPGIDLSQVYELLEKDYRMERPEGCPEKV YELMRACWQWNPSDRPSFAEIHQAFETMFQESSISDEVEKELGK

[0546] In the polypeptide of SEQ ID NO: 6 depicted above, the forward slash designates the TEV cleavage site and does not designate an amino acid (i.e. , the Q and S immediately flanking the forward slash are contiguous).

[0547] An ABL1 variant polypeptide can have the same or about the same substrate phosphorylation activity of an ABL1(wt) polypeptide containing the polypeptide of SEQ ID NO: 1 under phosphorylation conditions, when the polypeptide is not contacted by a test compound. An ABL1 variant polypeptide can have a substrate phosphorylation activity lower than the phosphorylation activity of an ABL1 (wt) polypeptide containing the polypeptide of SEQ ID NO: 1 under phosphorylation conditions, when the polypeptide is not contacted by a test compound (for example, a substrate phosphorylation activity within about 10-fold, or 9-fold, or 8-fold, or 7- fold, or 6-fold, or 5-fold, or 4-fold, or 3-fold, or 2-fold, lower than the substrate phosphorylation activity of the ABL1 (wt) polypeptide). An ABL1 variant polypeptide can have a substrate phosphorylation activity greater than the phosphorylation activity of an ABL1 (wt) polypeptide containing the polypeptide of SEQ ID NO: 1 under phosphorylation conditions, when the polypeptide is not contacted by a test compound (for example, a substrate phosphorylation activity within about 10-fold, or 9-fold, or 8-fold, or 7-fold, or 6-fold, or 5-fold, or 4-fold, or 3-fold, or 2-fold, greater than the substrate phosphorylation activity of the ABL1 (wt) polypeptide). Phosphorylation activity of an ABL1 variant polypeptide can be determined by a suitable assay, which can be an in vitro assay (for example, a labeled peptide cleavage assay described herein), for example.

[0548] R0S1 inhibition

[0549] In certain embodiments, a compound is an effective inhibitor or moderate inhibitor of one or more, or two or more, ROS1 variant polypeptides. Such a compound can be an effective inhibitor or moderate inhibitor of ROS1 (wt). A compound that is an effective inhibitor or two or more ROS1 variant polypeptides can be considered a pan-ROS1 inhibitor. In certain embodiments, a compound is an effective inhibitor of two or more ROS1 variant polypeptides containing one or more of G2032R, L2086F, S1986F, F2004C, F2004V, F2004I, L2026M, L2000V, D2033N, G2101A. A compound sometimes is an effective inhibitor of ROS1 (L2086F) and an effective inhibitor of one or more other ROS1 variant polypeptides (for example, two or more other ROS1 variant polypeptides, three or more other ROS1 variant polypeptides, or four or more other ROS1 variant polypeptides). A compound sometimes is an effective inhibitor of ROS1 (L2086F) and an effective inhibitor of one or more of ROS1 (G2032R), ROS1 (S1986F), and ROS1 (F2004C). A compound sometimes is an effective inhibitor of ROS1 (L2086F) and an effective inhibitor of two or more of ROS1 (G2032R), ROS1 (S1986F), and ROS1 (F2004C). A compound sometimes is an effective inhibitor of ROS1 (L2086F) and an effective inhibitor of three or more of ROS1 (G2032R), ROS1 (S1986F), and ROS1 (F2004C). A compound sometimes is an effective inhibitor of ROS1 (L2086F), an effective inhibitor one or more other ROS1 variant polypeptides, and a moderate inhibitor of one or more other ROS1 variant polypeptides. A compound sometimes is an effective inhibitor of ROS1(L2086F), an effective inhibitor of one or more of ROS1 (G2032R), ROS1 (S1986F), and ROS1 (F2004C), and a moderate inhibitor of one or more of ROS1 (G2032R), ROS1 (S1986F), and ROS1 (F2004C). ROS1 (wt) and ROS1 variant polypeptides are described in greater detail hereafter. The following is the ROS1 (wt) polypeptide (SEQ ID NO: 8).

[0550] MKNIYCLIPKLVNFATLGCLWISWQCTVLNSCLKSCVTNLGQQLDLGTPHNLSEPCIQGCHFWNSVDQK NCALKCRESCEVGCSSAEGAYEEEVLENADLPTAPFASS IGSHNMTLRWKSANFSGVKYI IQWKYAQLLG SWTYTKTVSRPSYWKPLHPFTEYIFRWWIFTAQLQLYSPPSPSYRTHPHGVPETAPLIRNIESSSPDT VEVSWDPPQFPGGP ILGYNLRLI SKNQKLDAGTQRTSFQFYSTLPNTIYRFSIAAVNEVGEGPEAESS IT TSSSAVQQEEQWLFLSRKTSLRKRSLKHLVDEAHCLRLDAIYHNITGI SVDVHQQIVYFSEGTLIWAKKA ANMSDVSDLRIFYRGSGLI SSIS IDWLYQRMYF IMDELVCVCDLENCSNIEEITPPS I SAPQKIVADSYN GYVFYLLRDGI YRADLPVPSGRCAEAVRIVESCTLKDFAIKPQAKRI I YFNDTAQVFMSTFLDGSASHLI LPRIPFADVKSFACENNDFLVTDGKVIFQQDALSFNEF IVGCDLSHIEEFGFGNLVIFGSSSQLHPLPGR PQELSVLFGSHQALVQWKPPALAIGANVILI SD I IELFELGPSAWQNWTYEVKVSTQDPPEVTHIFLNIS GTMLNVPELQSAMKYKVSVRASSPKRPGPWSEPSVGTTLVPASEPPF IMAVKEDGLWSKPLNSFGPGEFL SSD IGNVSDMDWYNNSLYYSDTKGDVFVWLLNGTDISENYHLPS IAGAGALAFEWLGHFLYWAGKTYVIQ RQSVLTGHTD IVTHVKLLVNDMWDSVGGYLYWTTLYSVESTRLNGESSLVLQTQPWFSGKKVIALTLDL SDGLLYWLVQDSQCIHLYTAVLRGQSTGDTTITEFAAWSTSEI SQNALMYYSGRLFWINGFRI ITTQE IG QKTSVSVLEPARFNQFTI IQTSLKPLPGNFSFTPKVIPDSVQESSFRIEGNASSFQILWNGPPAVDWGW FYSVEFSAHSKFLASEQHSLPVFTVEGLEPYALFNLSVTPYTYWGKGPKTSLSLRAPETVPSAPENPRIF ILPSGKCCNKNEVWEFRWNKPKHENGVLTKFE IFYNI SNQSITNKTCEDWIAVNVTPSVMSFQLEGMSP RCF IAFQVRAFTSKGPGPYADWKSTTSEINPFPHLITLLGNKIVFLDMDQNQWWTFSAERVI SAVCYT ADNEMGYYAEGDSLFLLHLHNRSSSELFQDSLVFDITVITIDWI SRHLYFALKESQNGMQVFDVDLEHKV KYPREVKIHNRNSTI ISFSVYPLLSRLYWTEVSNFGYQMFYYS I ISHTLHRILQPTATNQQNKRNQCSCN VTEFELSGAMAIDTSNLEKPLIYFAKAQEIWAMDLEGCQCWRVITVPAMLAGKTLVSLTVDGDLI YWI IT AKDSTQIYQAKKGNGAIVSQVKALRSRHILAYSSVMQPFPDKAFLSLASDTVEPTILNATNTSLTIRLPL AKTNLTWYGITSPTPTYLVYYAEVNDRKNSSDLKYRILEFQDS IALIEDLQPFSTYMIQIAVKNYYSDPL EHLPPGKEIWGKTKNGVPEAVQLINTTVRSDTSLI ISWRESHKPNGPKESVRYQLAI SHLALIPETPLRQ SEFPNGRLTLLVTRLSGGNIYVLKVLACHSEEMWCTESHPVTVEMFNTPEKPYSLVPENTSLQFNWKAPL NVNLIRFWVELQKWKYNEFYHVKTSCSQGPAYVCNITNLQPYTSYNVRWWYKTGENSTSLPESFKTKA GVPNKPGIPKLLEGSKNSIQWEKAEDNGCRITYYILE IRKSTSNNLQNQNLRWKMTFNGSCSSVCTWKSK NLKGIFQFRWAANNLGFGEYSGI SENI ILVGDDFWIPETSFILTI IVGIFLWTIPLTFVWHRRLKNQK SAKEGVTVLINEDKELAELRGLAAGVGLANACYAIHTLPTQEE IENLPAFPREKLTLRLLLGSGAFGEVY EGTAVD ILGVGSGE IKVAVKTLKKGSTDQEKIEFLKEAHLMSKFNHPNILKQLGVCLLNEPQYI ILELME GGDLLTYLRKARMATFYGPLLTLVDLVDLCVDI SKGCVYLERMHF IHRDLAARNCLVSVKDYTSPRIVKI GDFGLARDIYKNDYYRKRGEGLLPVRWMAPESLMDGIFTTQSDVWSFGILIWE ILTLGHQPYPAHSNLDV LNYVQTGGRLEPPRNCPDDLWNLMTQCWAQEPDQRPTFHRIQDQLQLFRNFFLNS IYKSRDEANNSGVIN ESFEGEDGDVICLNSDD IMPVALMETKNREGLNYMVLATECGQGEEKSEGPLGSQESESCGLRKEEKEPH ADKDFCQEKQVAYCPSGKPEGLNYACLTHSGYGDGSD

[0551] The following is the ROS1 L2086F polypeptide (SEQ ID NO: 9).

[0552] MKNIYCLIPKLVNFATLGCLWISVVQCTVLNSCLKSCVTNLGQQLDLGTPHNLSEPCIQGCHFWNSVDQK NCALKCRESCEVGCSSAEGAYEEEVLENADLPTAPFASS IGSHNMTLRWKSANFSGVKYI IQWKYAQLLG SWTYTKTVSRPSYWKPLHPFTEYIFRWWIFTAQLQLYSPPSPSYRTHPHGVPETAPLIRNIESSSPDT VEVSWDPPQFPGGP ILGYNLRLI SKNQKLDAGTQRTSFQFYSTLPNTIYRF SIAAVNEVGEGPEAESS IT TSSSAVQQEEQWLFLSRKTSLRKRSLKHLVDEAHCLRLDAIYHNITGI SVDVHQQIVYFSEGTLIWAKKA ANMSDVSDLRIFYRGSGLI SSIS IDWLYQRMYF IMDELVCVCDLENCSNIEEITPPS I SAPQKIVADSYN GYVFYLLRDGIYRADLPVPSGRCAEAVRIVESCTLKDFAIKPQAKRI I YFNDTAQVFMSTFLDGSASHLI LPRIPFADVKSFACENNDFLVTDGKVIFQQDALSFNEF IVGCDLSHIEEFGFGNLVIFGSSSQLHPLPGR PQELSVLFGSHQALVQWKPPALAIGANVILI SD I IELFELGPSAWQNWTYEVKVSTQDPPEVTHIFLNIS GTMLNVPELQSAMKYKVSVRASSPKRPGPWSEPSVGTTLVPASEPPF IMAVKEDGLWSKPLNSFGPGEFL SSD IGNVSDMDWYNNSLYYSDTKGDVFVWLLNGTDISENYHLPS IAGAGALAFEWLGHFLYWAGKTYVIQ RQSVLTGHTD IVTHVKLLVNDMWDSVGGYLYWTTLYSVESTRLNGESSLVLQTQPWFSGKKVIALTLDL SDGLLYWLVQDSQCIHLYTAVLRGQSTGDTTITEFAAWSTSEI SQNALMYYSGRLFWINGFRI ITTQE IG QKTSVSVLEPARFNQFTI IQTSLKPLPGNFSFTPKVIPDSVQESSFRIEGNASSFQILWNGPPAVDWGW FYSVEFSAHSKFLASEQHSLPVFTVEGLEPYALFNLSVTPYTYWGKGPKTSLSLRAPETVPSAPENPRIF ILPSGKCCNKNEVWEFRWNKPKHENGVLTKFE IFYNI SNQSITNKTCEDWIAVNVTPSVMSFQLEGMSP RCF IAFQVRAFTSKGPGP YADWKSTTSEINPFPHLITLLGNKIVFLDMDQNQWWTFSAERVI SAVCYT ADNEMGYYAEGDSLFLLHLHNRSSSELFQDSLVFDITVITIDWI SRHLYFALKESQNGMQVFDVDLEHKV KYPREVKIHNRNSTI ISFSVYPLLSRLYWTEVSNFGYQMFYYS I ISHTLHRILQPTATNQQNKRNQCSCN VTEFELSGAMAIDTSNLEKPLIYFAKAQEIWAMDLEGCQCWRVITVPAMLAGKTLVSLTVDGDLI YWI IT AKDSTQIYQAKKGNGAIVSQVKALRSRHILAYSSVMQPFPDKAFLSLASDTVEPTILNATNTSLTIRLPL AKTNLTWYGITSPTPTYLVYYAEVNDRKNSSDLKYRILEFQDS IALIEDLQPFSTYMIQIAVKNYYSDPL EHLPPGKEIWGKTKNGVPEAVQLINTTVRSDTSLI ISWRESHKPNGPKESVRYQLAI SHLALIPETPLRQ SEFPNGRLTLLVTRLSGGNIYVLKVLACHSEEMWCTESHPVTVEMFNTPEKPYSLVPENTSLQFNWKAPL NVNLIRFWVELQKWKYNEFYHVKTSCSQGPAYVCNITNLQPYTSYNVRWWYKTGENSTSLPESFKTKA GVPNKPGIPKLLEGSKNSIQWEKAEDNGCRITYYILE IRKSTSNNLQNQNLRWKMTFNGSCSSVCTWKSK NLKGIFQFRWAANNLGFGEYSGI SENI ILVGDDFWIPETSFILTI IVGIFLWTIPLTFVWHRRLKNQK SAKEGVTVLINEDKELAELRGLAAGVGLANACYAIHTLPTQEE IENLPAFPREKLTLRLLLGSGAFGEVY EGTAVD ILGVGSGE IKVAVKTLKKGSTDQEKIEFLKEAHLMSKFNHPNILKQLGVCLLNEPQYI ILELME GGDLLTYLRKARMATFYGPLLTLVDLVDLCVDI SKGCVYLERMHF IHRDLAARNCFVSVKDYTSPRIVKI GDFGLARDIYKNDYYRKRGEGLLPVRWMAPESLMDGIFTTQSDVWSFGILIWE ILTLGHQPYPAHSNLDV LNYVQTGGRLEPPRNCPDDLWNLMTQCWAQEPDQRPTFHRIQDQLQLFRNFFLNS IYKSRDEANNSGVIN ESFEGEDGDVICLNSDD IMPVALMETKNREGLNYMVLATECGQGEEKSEGPLGSQESESCGLRKEEKEPH

[0553] ADKDFCQEKQVAYCPSGKPEGLNYACLTHSGYGDGSD

[0554] Protein kinase inhibitor assessment

[0555] A compound herein can inhibit a protein kinase (PK) activity. A compound can be assessed as a test compound in a suitable assay or system to determine PK inhibitor activity. A test compound assessed by an assay for PK inhibitor activity sometimes is a compound herein and / or sometimes is another compound, such as a clinically approved PK inhibitor, for example. An assay sometimes is conducted in vitro or in vivo.

[0556] An in vitro assay sometimes quantifies substrate phosphorylation activity catalyzed by a PK polypeptide under phosphorylation conditions in the presence or absence of a test compound that can bind to the PK and potentially inhibit the PK phosphorylation activity. A suitable substrate can be utilized in an assay, such as a polypeptide or peptide substrate, for example. A peptide substrate for assessing ABL1 inhibitor activity can contain the amino acid sequence EAIYAAPFAKKK (SEQ ID NO: 7), for example. An assay for quantifying substrate phosphorylation activity inhibition sometimes outputs one or more of an IC50 value, Ki value, Kd value, KOff value and Konvalue as a quantification of PK inhibition and / or binding.

[0557] A non-limiting example of an assay for quantifying substrate phosphorylation activity inhibition analyzes a peptide substrate capable of being phosphorylated by a PK polypeptide, referred to herein as an "PK peptide substrate." A PK peptide substrate sometimes is labeled with one or more detectable labels (for example, a fluorescent agent). Fluorescence from a PK peptide substrate labeled with a fluorescent agent sometimes is assessed in an assay. In certain embodiments, a PK peptide substrate end-labelled with a distinct donor fluorophore on one end and a distinct acceptor fluorophore on the other end is utilized. In certain instances, the donor and the acceptor fluorophores are a Fluorescence Resonance Energy Transfer (FRET) pair. In certain embodiments, the donor fluorophore is coumarin and the acceptor fluorophore is fluorescein. In certain instances, a PK peptide substrate is cleaved in an assay after the peptide is exposed to phosphorylation conditions. An assay in which a PK peptide substrate is labeled with one or more detection agents and exposed to cleavage conditions is referred to as a "labeled peptide cleavage assay" and “peptide cleavage assay.”

[0558] In certain embodiments, a labeled peptide cleavage assay includes: (1) contacting an unphosphorylated peptide, labeled at each end with a FRET pair fluorophore, with a test compound and a PK polypeptide having a PK phosphorylation activity, under phosphorylation conditions, thereby generating a phosphorylated peptide; (2) exposing the peptide, after (1 ), to phosphorylation state-dependent cleavage conditions, thereby generating cleaved peptide; and (3) measuring and analyzing, after (2) a fluorescent emission signal from one or both fluorophores. A non-limiting example of a labeled peptide cleavage assay is described in Example 17 (Z’LYTE™ assay).

[0559] Under phosphorylation conditions, a PK polypeptide typically is capable of transferring a phosphate from a provided cofactor (for example, adenosine triphosphate (ATP)) to the substrate (for example, peptide or protein substrate), where presence of a PK inhibitor compound reduces the amount of substrate phosphorylation compared to conditions in which the compound is not present. Under phosphorylation state-dependent cleavage conditions, (i) the phosphorylated substrate, but not the unphosphorylated substrate, is capable of being cleaved, or (ii) the phosphorylated substrate is preferentially cleaved relative to the unphosphorylated substrate, or (iii) the unphosphorylated substrate, but not the phosphorylated substrate, is capable of being cleaved, or (iv) the unphosphorylated substrate is preferentially cleaved relative to the phosphorylated substrate. The substrate typically is exposed to cleavage conditions after the substrate is contacted with a PK polypeptide under phosphorylation conditions. The substrate can be cleaved by a peptidase or protease enzyme under cleavage conditions. After the substrate is exposed to phosphorylation conditions and cleavage conditions, a fluorescent signal from cleaved substrate can be measured. In certain embodiments for a substrate containing a donor and acceptor FRET pair, a ratio of donor emission to acceptor emission (or a ratio of acceptor emission to donor emission) after excitation of the donor can be determined to assess the degree of peptide cleavage and thereby degree of peptide phosphorylation. An IC5o value can be determined from such a ratio as known in the art. Another type of assay involving FRET is a tracer displacement assay, a non-limiting example of which is described in Example 17 (LanthaScreen™ Eu Kinase Binding Assay). A tracer binding assay measures test compound binding to a PK. In a tracer displacement assay, a PK is contacted with (i) a tracer ligand, labeled with a FRET pair fluorophore, that binds to the PK under binding conditions; (ii) a test molecule that displaces the tracer ligand when the test molecule binds to the PK under the binding conditions; and (iii) an antibody, conjugated to another FRET pair fluorophore, that binds to the PK. Binding of the antibody and tracer ligand to the PK results in a FRET signal, and displacement of tracer ligand from the PK by a test molecule that competes with the tracer ligand for binding to the PK results in a reduction of the FRET signal.

[0560] Another type of assay that can be utilized to quantify phosphorylation activity inhibition is an adenosine diphosphate (ADP) formation assay. The assay can be used to quantify ATP hydrolysis, including the intrinsic ATPase activity of a PK that transfers a terminal phosphate from ATP to water (and not a peptide substrate), thereby generating ADP from ATP. A nonlimiting example of an ADP formation assay is described in Kashem et al., J. Biomol. Screen. 12:70-83 (2007) and is described in Example 17 (Adapta™ Assay).

[0561] Another type of assay that can be utilized to quantify binding of a test compound to a PK is a solid phase inhibitor competition assay. The assay can be used to quantify binding of a test compound to a PK tagged with a nucleic acid detection tag in competition with a solid phase- associated PK inhibitor. The amount of the PK associated with the solid phase, assessed by PCR quantification of the detection tag, determines the level of PK binding to the test compound. A non-limiting example of a solid phase inhibitor competition assay is a KINOMEscan™ assay (EuroFins Discovery, described in Fabian et al., Nat. Biotechnol. 23: 329-336 (2005) for example).

[0562] Uses of compounds

[0563] A compound can be used in a variety of applications. A compound can be used to (i) inhibit one or more PKs in vitro, ex vivo, or in vivo, (ii) inhibit one or more PKs in cells, organs and / or tissues administered a composition containing a compound; and / or (iii) inhibit one or more PKs in a subject administered a composition containing the compound. A compound can be utilized in studies, including, for example: (i) studies of PK inhibitors (for example, in vitro assay studies); (ii) pre-clinical in vivo animal studies, including xenograft studies in mice and pharmacokinetic studies in higher animals (for example, rats, dogs and / or monkeys); and (iii) human clinical studies. A compound herein can be utilized as a reference compound in a study of other compounds (for example, negative control or positive control), such as in an in vitro assay study, pre-clinical study and / or clinical study, for example.

[0564] A compound herein can be (i) for treatment of a medical condition; (ii) prepared as a composition (for example, pharmaceutical composition) or medicament for treatment of a medical condition; and / or (iii) utilized in a method for treating a medical condition in which a compound is administered to a subject in need thereof in an amount sufficient to treat the medical condition (an effective amount). For embodiments in which a subject is treated, the subject can be human (homo sapiens) and can be an adult or pediatric patient. A medical condition sometimes is a PK-associated condition, such as a medical condition associated with a PK aberration and / or dysregulation of a PK (for example, dysregulation of a PK gene). A PK aberration can be a PK modification, which, for example, can be a nucleic acid translocation or other modification associated with a PK gene A PK modification can be outside of a PK gene coding region and result in dysregulation of the PK gene. A PK modification can be an addition, deletion or substitution of one or more amino acids in the PK encoded by a PK gene. A PK translocation can be within a PK gene coding region and result in a PK gene truncation and / or translocation of a PK gene or portion thereof to a different chromosome or different location of the same chromosome. A PK translocation can result in a fusion of a PK gene or portion thereof with another nucleic acid portion from a different chromosome or different location of the same chromosome. A PK aberration can result in an altered PK activity relative to the PK activity when the aberration is not present. An altered activity can be (i) altered binding affinity to an inhibitor, (ii) altered binding activity to a native binding partner, and / or (iii) increased phosphorylation activity due to PK overexpression or increased intrinsic activity, for example. A PK-associated medical condition can be caused by an aberration of (for example, dysregulation and / or modification of) one or more of: an ABL family PK, a BTK family PK, a AURK family PK, a JAK family PK, a TRK family PK, a RET PK, an EPH family PK, a TNK family PK, a PLK family PK, an IRAK family PK, a SRC family PK, a LCK family PK, a DDR family PK, and / or a PTK family PK.

[0565] A medical condition sometimes is a cell proliferative condition such as a cancer for example, and a compound can be used to treat a cancer condition. A compound can be used to treat a cancer condition associated with one or more PK modifications, including modification of one or more of: an ABL family PK, a BTK family PK, a AURK family PK, a JAK family PK, a TRK family PK, a RET PK, an EPH family PK, a TNK family PK, a PLK family PK, an IRAK family PK, a SRC family PK, a LCK family PK, a DDR family PK, and / or a PTK family PK. Non-limiting examples of cancers include lymphomas, thymomas, leukemias, carcinomas, gliomas, sarcomas (including liposarcoma), adenocarcinomas, adenosarcomas, and adenomas. Nonlimiting examples of cancers are cancers occurring in lymph nodes, blood, thymus, breast, heart, lung, small intestine, colon, rectum, spleen, kidney, bladder, head, neck, esophagus, ovary, prostate, brain, pancreas, skin, bone, bone marrow, uterus, testicles, cervix and liver. Cancers include leukemia or lymphoid malignancies, hematologic malignancies, such as Hodgkin's lymphoma; non-Hodgkin's lymphomas, including Burkitt's lymphoma, small lymphocytic lymphoma / chronic lymphocytic leukemia, mycosis fungoides, mantle cell lymphoma, follicular lymphoma, diffuse large B-cell lymphoma, marginal zone lymphoma, hairy cell leukemia and lymphoplasmacytic leukemia; tumors of lymphocyte precursor cells, including B-cell acute lymphoblastic leukemia / lymphoma and T-cell acute lymphoblastic leukemia / lymphoma; thymoma; tumors of the mature T and NK cells, including peripheral T-cell leukemias, adult T-cell leukemia / T-cell lymphomas and large granular lymphocytic leukemia; Langerhans cell histocytosis; a myeloid neoplasia including acute myelogenous leukemia (AML), AML with maturation, AML without differentiation, acute promyelocytic leukemia, acute myelomonocytic leukemia, and acute monocytic leukemias; myelodysplastic syndromes; and chronic myeloproliferative disorders, including chronic myelogenous leukemia.

[0566] Cancers include colorectal and head and neck tumors; squamous cell carcinoma of the head and neck; brain tumors such as glioblastomas; tumors of the lung, breast, pancreas, esophagus, bladder, kidney, ovary, cervix, and prostate; central nervous system neoplasms; neuroblastomas; capillary hemangioblastomas; meningiomas and cerebral metastases; melanoma; gastrointestinal and renal carcinomas and sarcomas; rhabdomyosarcoma; glioblastoma, including glioblastoma multiforme; leiomyosarcoma; lymphoma; blastoma; neuroendocrine tumors; mesothelioma; schwannoma; meningioma; tumors of the central nervous system, including glioma, glioblastoma, neuroblastoma, astrocytoma, medulloblastoma, ependymoma, and retinoblastoma; solid tumors of the head and neck, including nasopharyngeal cancer, salivary gland carcinoma, and esophageal cancer; a lung cancer including small-cell lung cancer, non-small cell lung cancer (NSCLC), adenocarcinoma of the lung and squamous carcinoma of the lung; a digestive system cancer, gastric cancer or stomach cancer, including gastrointestinal cancer, cancer of the bile duct or biliary tract, colon cancer, colon adenocarcinoma, rectal cancer, colorectal cancer, and anal carcinoma; a reproductive system cancer including testicular, penile, or prostate cancer, uterine, vaginal, vulval, cervical, ovarian, and endometrial cancer; thyroid cancer, including medullary thyroid cancer (MTC), thyroid gland medullary carcinoma, papillary thyroid cancer (PTC); skin cancer, including melanoma, cutaneous carcinoma, basal cell carcinoma, squamous cell cancer, actinic keratosis; liver cancer, including hepatic carcinoma, hepatocellular cancer, and hepatoma; bone cancer, including osteoclastoma, and osteolytic bone cancers; cancer of additional tissues and organs, including pancreatic cancer, bladder cancer, kidney or renal cancer, breast cancer, cancer of the peritoneum, and Kaposi's sarcoma; tumors of the vascular system, including angiosarcoma and hemangiopericytoma; and blood cancers including leukemia, myelodysplastic syndrome (MDS), myelofibrosis, polycythemia vera and essential thrombocythemia. A cancer can be treated with a composition containing a compound herein as an active ingredient. In certain embodiments a composition used to treat a cancer contains a compound of Subgroup 1 or Subgroup 4.

[0567] Particular blood cancers include leukemias, and leukemias include chronic myeloid leukemia (CML) and acute lymphoblastic leukemia (ALL). A CML that can be treated includes chronic phase CML (CML-CP), acute phase CML (CML-AP) and blast phase CML (CML-BP). An ALL that can be treated includes a relapsed and / or refractory ALL (R / R ALL), Philadelphia chromosome-positive ALL, and other forms of ALL described herein (for example, Philadelphia chromosome-positive-like-ALL, B-ALL, T-ALL).

[0568] A leukemia sometimes is associated with an ABL family PK aberration, and sometimes an ABL1 PK aberration. A compound that inhibits an ABL family PK (for example, an ABL1 PK) can be used to treat a leukemia (for example, CML and / or an ALL such as Philadelphia chromosomepositive ALL). A compound that effectively inhibits or moderately inhibits ABL1 , ABL1-T315I, BTK, AURKA, JAK2 and JAK3, and optionally JAK1 , can be used to treat a leukemia (for example, a CML and / or an ALL such as Philadelphia chromosome-positive ALL). A compound that effectively inhibits or moderately inhibits ABL1 , ABL1-T315I, BTK, AURKA, JAK2 and JAK3, and optionally mildly inhibits or ineffectively inhibits JAK1 , can be used to treat a leukemia (for example, a CML and / or an ALL). A compound that effectively inhibits or moderately inhibits one or more of all of TYK2, a TRK family PK, ROS1 , TXK, an EPH family PK, IRAK3, PLK4, TNK1 , RET and JAK2-V617F can be used to treat a leukemia (for example, a CML and / or an ALL such as Philadelphia chromosome-positive ALL).

[0569] A leukemia, such as CML and / or an ALL for example, can be treated with a compound of Subgroup 1 or Subgroup 4. For example, a Philadelphia chromosome-positive ALL and / or R / R Philadelphia chromosome-positive ALL, can be treated with a compound of Subgroup 1 or Subgroup 4.

[0570] A leukemia can be a Philadelphia chromosome-positive-like ALL, which has been associated with a rearrangement involving ABL1 , ABL2, CRLF2, CSF1 R, EPOR, JAK2, NTRK3, PDGFRB, PTK2B, TSLP and / or TYK2 and / or a sequence mutations involving FLT3, IL7R and / or SH2B3 (see, for example, Roberts et al., N Engl J Med 371 (11 ): 1005-1015 (2014)). A compound that effectively inhibits or moderately inhibits ABL2, TYK2, TRKC and PTK2B, can be used to treat a Philadelphia chromosome-positive-like ALL. A compound that effectively inhibits or moderately inhibits ABL1 , ABL1 -T315I, BTK, AURKA, JAK2 and JAK3, and optionally JAK1 , can be used to treat a Philadelphia chromosome-positive-like ALL. A compound that effectively inhibits or moderately inhibits ABL1 , ABL1 -T315I, BTK, AURKA, JAK2 and JAK3, and optionally mildly inhibits or ineffectively inhibits JAK1 , can be used to treat a Philadelphia chromosome-positive- like ALL. Acompound that effectively inhibits or moderately inhibits one or more of all of TYK2, a TRK family PK, ROS1. TXK, an EPH family PK, IRAK3, PLK4, TNK1 , RET and JAK2-V617F can be used to treat a Philadelphia chromosome-positive-like ALL. A Philadelphia chromosome- positive-like ALL can be treated with a compound of Subgroup 1 or Subgroup 4.

[0571] A leukemia can be a B-cell acute lymphoblastic leukemia (B-ALL). A B-ALL can be a TCF3- HLF-positive B-ALL, which can be a TCF3-HLF-positive acute B-ALL. A TCF3-HLF-positive B- ALL typically is a B-ALL harboring a t(17;19)(q22;p13) translocation, producing an aberrant TCF3-HLF fusion (see, for example, Leonard et al., Haematologica 106(11 ): 2990-2994 (2021)). A TCF3-HLF-positive B-ALL can be associated with an AURKA aberration, and a compound that effectively inhibits or moderately inhibits an AURKA PK can be used to treat a B-ALL, such as a TCF3-HLF-positive B-ALL for example. A compound that effectively inhibits or moderately inhibits ABL1 , ABL1 -T315I, BTK, AURKA, JAK2 and JAK3, and optionally JAK1 , can be used to treat a B-ALL, such as a TCF3-HLF-positive B-ALL for example. A compound that effectively inhibits or moderately inhibits ABL1 , ABL1-T315I, BTK, AURKA, JAK2 and JAK3, and optionally mildly inhibits or ineffectively inhibits JAK1 , can be used to treat a B-ALL, such as a TCF3-HLF- positive B-ALL for example. A compound that effectively inhibits or moderately inhibits ABL1 , ABL1-T315I, BTK, AURKA, JAK2, NTRK3 (for example, a ETV6-NTRK3 fusion), PTK2B, TYK2 and ABL2 can be used to treat a B-ALL, such as a TCF3-HLF-positive B-ALL for example, where the compound optionally can effectively inhibit or moderately inhibit JAK1 or the compound optionally can mildly inhibit or ineffectively inhibit JAK1 . A compound that effectively inhibits or moderately inhibits one or more of all of TYK2, a TRK family PK, ROS1 , TXK, an EPH family PK, IRAK3, PLK4, TNK1 , RET and JAK2-V617F can be used to treat a B-ALL, such as a TCF3-HLF-positive B-ALL for example. A B-ALL, including a TCF3-HLF-positive B-ALL for example, can be treated with a compound of Subgroup 1 or Subgroup 4.

[0572] A subject identified as having an ABL1-T315I variant can be treated with a compound herein (for example, for treatment of a leukemia such as a CML and / or an ALL such as Philadelphia chromosome-positive ALL). A subject not identified as having an ABL1 -T315I variant or identified as not having an ABL1-T315I variant, and is resistant and / or intolerant to at least two PK inhibitors, can treated with a compound herein (for example, for treatment of a leukemia such as a CML and / or ALL such as Philadelphia chromosome-positive ALL). A subject having no available protein kinase inhibitor options can be administered a compound herein to treat CML.

[0573] A leukemia can be a T-cell acute lymphoblastic leukemia (T-ALL), which can be a R / R T-ALL. A T-ALL can be associated with a LCK family PK aberration, and a compound that effectively inhibits or moderately inhibits a LCK family PK (for example, LCK(wt)) can be used to treat a T- ALL, including R / R T-ALL. A compound that effectively inhibits or moderately inhibits ABL1 , ABL1-T315I, BTK, AURKA, JAK2 and JAK3, and optionally JAK1 , can be used to treat a T-ALL, including R / R T-ALL for example. A compound that effectively inhibits or moderately inhibits ABL1 , ABL1 -T315I, BTK, AURKA, JAK2 and JAK3, and optionally mildly inhibits or ineffectively inhibits JAK1 , can be used to treat a T-ALL, including R / R T-ALL for example. A compound that effectively inhibits or moderately inhibits one or more of all of TYK2, a TRK family PK, ROS1 , TXK, an EPH family PK, IRAK3, PLK4, TNK1 , RET and JAK2-V617F can be used to treat a T- ALL, including R / R T-ALL for example. A T-ALL, including R / R T-ALL for example, can be treated with a compound of Subgroup 1 or Subgroup 4.

[0574] A cancer can be a solid cancer, such as a colon cancer, lung cancer (for example, a lung carcinoma), breast cancer, blood cancer or ovarian cancer. A solid cancer can be associated with a LCK family PK aberration, and a compound that effectively inhibits or moderately inhibits a LCK family PK (for example, LCK(wt)) can be used to treat a solid cancer. Non-limiting examples of solid tumor blood cancers include peripheral T-cell lymphoma (PTCL), PTCL-NOS (not otherwise specified) and PTCL and PTCL-NOS associated with a KHDRBS1 -LCK gene fusion (for example, Debackere et al., Nat Comm 12:3705, World Wide Web address URL doi.org / 10.1038 / s41467-021 -24037-4 (2021)). A compound that effectively inhibits or moderately inhibits a LCK family PK can also can be used to treat atherosclerotic coronary vascular disease (ASCVD). A compound that effectively inhibits or moderately inhibits ABL1 , ABL1-T315I, BTK, AURKA, JAK2 and JAK3, and optionally JAK1 , can be used to treat a solid cancer or ASCVD. A compound that effectively inhibits or moderately inhibits ABL1 , ABL1 - T315I, BTK, AURKA, JAK2 and JAK3, and optionally mildly inhibits or ineffectively inhibits JAK1 , can be used to treat a solid cancer or ASCVD. A compound that effectively inhibits or moderately inhibits one or more of all of TYK2, a TRK family PK, ROS1 , TXK, an EPH family PK, IRAK3, PLK4, TNK1 , RET and JAK2-V617F can be used to treat a solid cancer or ASCVD. A solid cancer or ASCVD can be treated with a compound of Subgroup 1 or Subgroup 4.

[0575] A cancer can be a lung cancer, such as non-small cell lung cancer (NSCLC). In certain instances, the lung cancer is associated with a ROS family PK aberration. In certain instances the ROS family PK aberration is a G2032R and / or a L2086F mutation. In certain instances, the lung cancer is associated with a DDR family PK aberration and / or a SRC family PK aberration. In certain instances, the DDR family PK aberration is a DDR2 variant PK aberration. The DDR2 variant PK contains a T654M and / or N456S amino acid substitution in certain instances. A compound that inhibits a SRC family PK or DDR family PK is used to treat a lung cancer (for example NSCLC) in certain embodiments. In certain embodiments, a compound that effectively inhibits or moderately inhibits SRC(wt), SCR-N1 , DDR2(wt) and / or a DDR2 variant containing a T654M and / or N456S amino acid substitution is used to treat a lung cancer, such as NSCLC for example. A compound that effectively inhibits or moderately inhibits ABL1 , ABL1-T315I, BTK, AURKA, JAK2 and JAK3, and optionally JAK1 , can be used to treat a lung cancer (for example NSCLC) in certain embodiments. A compound that effectively inhibits or moderately inhibits one or more or all of ABL1 , ABL1-T315I, BTK, AURKA, JAK2 and JAK3, and optionally mildly inhibits or ineffectively inhibits JAK1 , can be used to treat a lung cancer (for example NSCLC). A compound that effectively inhibits or moderately inhibits one or more of all of TYK2, a TRK family PK, ROS1 , TXK, an EPH family PK, IRAK3, PLK4, TNK1 , RET and JAK2-V617F can be used to treat a lung cancer (for example NSCLC). A lung cancer, such as NSCLC for example, can be treated with a compound of Subgroup 1 or Subgroup 4.

[0576] A compound that inhibits a TRK family PK can be utilized to treat a cancer associated with a TRK family PK aberration. A cancer sometime is a cancer positive for a TRK family PK fusion. In certain instances, the cancer is a solid tumor positive for a TRK family PK fusion, and optionally where the TRK portion of the fusion does not contain a known acquired resistance amino acid substitution.

[0577] A compound that inhibits a ROS family PK can be utilized to treat a cancer associated with a ROS family PK aberration. In certain instances, the cancer is a ROS1 positive lung cancer, including without limitation a solid tumor and / or a lung cancer. A ROS1 positive lung cancer can be a lung nodule cancer, non-small cell lung cancer, small cell lung cancer or mesothelioma. A compound that inhibits an EPH family PK can be utilized to treat a cancer associated with an EPH family PK aberration. In certain instances, the cancer is associated with an EPHA1 aberration, EPHA2 aberration and / or an EPHB1 aberration, non-limiting examples of which include a breast cancer, lung cancer, brain cancer, spinal cancer, gastric cancer, or skin cancer, and optionally a solid tumor cancer. In certain instances, the lung cancer is non-small cell lung cancer (NSCLC); the skin cancer is myeloma; and the brain cancer or spinal cancer is a glioblastoma.

[0578] A compound that inhibits a TNK family PK can be utilized to treat a cancer associated with a TNK family PK aberration. In certain instances, a cancer is associated with a TNK1 PK aberration, such as a cancer deficient in LKB1 , for example. In certain instances, a cancer associated with a TNK1 aberration is a cancer associated with a TNK1 variant to which binding of a 14-3-3 protein is weaker than to TNK1 (wt), a non-limiting example of which is Hodgkin lymphoma, for which the Hodgkin lymphoma cell line L540 can be representative.

[0579] A compound that inhibits a RET family PK can be utilized to treat a cancer associated with a RET family PK aberration (for example, a cancer associated with a RET family PK fusion). In certain instances, a cancer associated with a RET family PK is lung cancer, including non-small cell lung cancer (NSCLC) and / or lung adenocarcinoma; a thyroid cancer, including medullary thyroid cancer (MTC), thyroid gland medullary carcinoma and / or papillary thyroid cancer (PTC); a colon cancer, including colon adenocarcinoma; and / or a skin cancer including melanoma and / or cutaneous melanoma.

[0580] A compound that inhibits a PLK4 family PK can be utilized to treat a cancer associated with a PLK family PK aberration. In certain instances, a cancer is associated with a PLK4 aberration, non-limiting examples of which include liver cancer, breast cancer and AML. A compound that inhibits an IRAK family PK can be utilized to treat a cancer associated with an IRAK family PK aberration. In certain instances a cancer is associated with an IRAK3 aberration. In certain instances, a compound of Subgroup 8 is used to treat a cancer associated with a PLK4 aberration or an IRAK3 aberration. In certain instances, a compound herein used to treat a cancer associated with an IRAK3 aberration is used in combination with an immune checkpoint blockade (ICB) therapeutic, examples of which are known.

[0581] A compound that inhibits a JAK family PK can be utilized to treat a medical condition associated with a JAK family PK aberration (a JAK-associated medical condition). A JAK-associated medical condition sometimes is a JAK2-associated medical condition, and compound that selectively inhibits a JAK2 PK is used to treat the medical condition. In certain instances, a compound of Subgroup 2, Subgroup 3, Subgroup 5, Subgroup 6 or Subgroup 7 is utilized to treat a JAK2-associated medical condition.

[0582] In certain embodiments, a JAK2-associated medical condition is a cancer, including without limitation, a lung cancer, breast cancer, head cancer or neck cancer. In certain embodiments, a JAK2-associated medical condition is a blood cancer, including without limitation, myelodysplastic syndrome (MDS), myelofibrosis, polycythemia vera or essential thrombocythemia. In certain instances, a JAK2-associated cancer is positive for a JAK2 variant containing a V617F substitution. In certain instances, a compound used to treat a cancer positive for a JAK2 variant containing a V617F substitution is of Subgroup 3 or Subgroup 6. A compound can be used to treat minimum residual disease (MRD) associated with a cancer condition, and can be a compound that inhibits a JAK family PK. A compound that is an effective inhibitor, or optionally a moderate inhibitor, of a JAK PK can be used to treat a cancer condition with potentially higher efficacy, as compared to treatment of the condition with a compound that is not an effective inhibitor or not a moderate inhibitor of a JAK PK. A compound that is an effective inhibitor of, or moderate inhibitor of, a JAK family PK, and an effective inhibitor of or moderate inhibitor of one or more other family PKs, can be used to treat, with potentially high efficacy, a cancer associated with the one or more other family PKs. For example, a compound that is an effective inhibitor of a JAK family PK and of an ABL family PK can be used to treat an ABL1 -associated blood cancer, including CML and Philadelphia chromosome-positive ALL, for example, with potentially higher efficacy than a compound that effectively inhibits the ABL family PK but not the JAK family PK.

[0583] In certain embodiments, a compound is used to treat an inflammation condition, autoimmune condition and / or skin condition. In certain instances, the inflammation condition is a chronic inflammation condition and / or senescent cell chronic inflammation condition such as a senescence-associated secretory phenotype (SASP) condition, for example. In certain instances, the autoimmune condition is atopic dermatitis, non-segmental vitiligo or rheumatoid arthritis. In certain instances, the rheumatoid arthritis is intolerant to one or more tumor necrosis factor (TNF) blockers. In certain instances, the skin condition is atopic dermatitis, non- segmental vitiligo, psoriasis (for example, plaque psoriasis), ultraviolet (UV) damaged skin, severely UV damaged skin or aged skin. A topical cream containing a compound can be used to treat a inflammation condition, autoimmune condition or skin condition. A compound can reduce an amount of a cytokine associated with an inflammation condition, autoimmune condition and / or skin condition, such as interleukin-6 (IL-6) for example, sometimes with subnanomolar efficacy.

[0584] In certain embodiments, a compound is used to treat a medical condition associated with a TYK family PK aberration, such as a medical condition associated with a TYK2 PK aberration. In certain embodiments, a compound is used to treat psoriasis, which can be moderate to severe psoriasis. In certain embodiments, a compound is used to treat plaque psoriasis, which can be moderate to severe plaque psoriasis. In certain instances, a compound is used to treat a subject who is a candidate for systemic therapy or phototherapy. In certain embodiments, the compound inhibits a TYK family PK, and in certain instances, the compound inhibits TYK2(wt). In certain embodiments, the compound is a Subgroup 9 compound.

[0585] In certain embodiments, an inflammation condition, autoimmune condition and / or skin condition is treated with a compound that effectively inhibits and selectively inhibits a JAK2 PK. An example of a compound that effectively inhibits and selective inhibits a JAK2 PK is a compound that effectively inhibits JAK2(wt) PK, does not effectively inhibit JAK1 (wt) PK, and optionally effectively inhibits or moderately inhibits JAK3(wt) PK. In certain instances, a skin condition such as atopic dermatitis or non-segmental vitiligo, for example, is treated with a compound of Subgroup 2 or Subgroup 3. In certain embodiments, an autoimmune condition such as moderate to severe rheumatoid arthritis (for example, rheumatoid arthritis intolerant to a TNF inhibitor), for example, is treated with a compound of Subgroup 5, Subgroup 6 or Subgroup 7. A compound that is an effective inhibitor and selective inhibitor of a JAK2 PK can be used to treat a condition with a potentially lower incidence of a serious adverse event, as compared to treatment of the condition with a compound that is not a selective inhibitor of a JAK2 PK. Nonlimiting examples of compounds that are not selective inhibitors of JAK2 PK are tofacitinib or ruxolitinib. A serious adverse event can be a malignancy, serious adverse cardiovascular event and / or blood clot, mortality or infection. In certain embodiments, a compound that is an effective inhibitor and selective inhibitor of a JAK2 PK can be utilized to treat a condition in a subject having a prior history of heart disease, and to whom a compound that is not a selective inhibitor of JAK2 would not be administered.

[0586] A moderate to severe form of a medical condition can be treated. For example, moderate to severe rheumatoid arthritis or moderate to severe plaque psoriasis can be treated. A stage III or stage IV cancer condition can be treated (for example, a stage IV ROS1 positive lung cancer), for example.

[0587] A medical condition associated with a particular variant PK can be treated. In certain instances, a blood cancer, such as myelofibrosis, MDS, polycythemia vera or essential thrombocytopenia, for example, can be treated in subjects from which a sample was assessed as having a JAK2 containing a V617F variation. Such subjects can be treated with a compound that effectively inhibits a JAK2 variant containing the V617F variation (a compound of Subgroup 3 or Subgroup 6, for example). In certain instances, a leukemia, such as CML or Philadelphia chromosome- positive ALL, for example, can be treated in subjects from which a sample was assessed as having an ABL1 variant containing a T315I substitution. Such subjects can be treated with a compound that effectively inhibits an ABL1 variant containing a T315I substitution, such as a compound of Subgroup 1 or Subgroup 4, for example.

[0588] In certain embodiments, it is determined whether a PK having a particular variation (a PK variant) is present or absent in a sample from a subject, and if the PK variant is identified as being present in the sample, then a particular medical condition associated with the PK variant is treated. In certain instances, presence or absence of a JAK2 variant containing a V617F substitution is screened in a sample from a subject, and if the variant is present in the sample, the subject may be treated for a particular medical condition associated with the variant (for example, a blood cancer such as myelofibrosis, MDS, polycythemia vera or essential thrombocytopenia, for example). In certain instances, presence or absence of an ABL1 variant containing a T315I substitution is screened in a sample from a subject, and if the variant is present in the sample, the subject may be treated for a particular medical condition associated with the variant (for example, a leukemia such as CML or Philadelphia chromosome-positive ALL, for example). In certain instances, presence or absence of a DDR2 variant containing N456S and / or T654M substitution is screened in a sample from a subject, and if the variant is present in the sample, the subject may be treated for a particular medical condition associated with the variant (for example, a lung cancer such as non-small cell lung cancer (NSCLC)). In certain instances, presence or absence of a RET variant containing one or more of A883F, G691 S, M918T, S891 A, V804E, V804L, V804M and Y791 F is screened in a sample from a subject, and if the variant is present in the sample, the subject may be treated for a particular medical condition associated with the variant (for example, a lung cancer (NSCLC) or thyroid cancer (medullary thyroid cancer (MTC), papillary thyroid cancer (PTC) or thyroid gland medullary carcinoma, for example)).

[0589] A compound typically is utilized in an amount sufficient to inhibit a PK activity (an effective amount). An “effective amount” often is a dosage sufficient to affect a beneficial or desired result. Non-limiting examples of desired results include reducing a PK activity (e.g., test compound binding activity; substrate phosphorylation activity); decreasing, attenuating and / or stabilizing one or more symptoms associated with a condition; increasing quality of life of a subject suffering from a condition; decreasing the dose of other medications required to treat the condition; enhancing the effect of another medication; delaying the progression of the condition; and / or prolonging survival of a subject. Non-limiting examples of symptoms associated with cancer include presence and / or proliferation of cancer cells; presence and / or growth of one or more tumors; cancer metastases and the like. An effective amount can be an amount sufficient to: kill cancer cells; reduce the rate of cancer cell proliferation; and / or eliminate, reduce and / or delay metastasis from a primary site of cancer. An effective amount may be in conjunction with another therapeutic agent. An effective amount may be considered in the context of administering a compound described herein without another therapeutic agent or with another therapeutic agent. An optimal range of an effective amount of each component can be determined.

[0590] An effective amount can be determined by standard clinical techniques and can be a technique for determining dosage. An effective amount often depends on the route of administration and the seriousness of the...

Claims

What is claimed is:1 . A composition of matter comprising a compound, or a pharmaceutically acceptable salt, amide or ester thereof, with a formula of:wherein R14is H, OCH2CH3 or OCH(CH3)2;RI6is H or F; and Y is selected from:wherein Y1is H or OH, Y2is H or OH, Y3is H or CH3, Y11is H, C(O)CHCH2or CH32. The composition of matter as recited in claim 1 , wherein R2is CH3, R4is H, R14is OCH(CH3)2and R1Sis F.

3. The composition of matter as recited in claim 2, wherein Y is, wherein Y11is H, CH3or C(O)CHCH2.

4. The composition of matter as recited in claim 2, wherein Y is5. The composition of matter as recited in claim 2, wherein Y isand Y11is CH3or H.

6. The composition of matter as recited in claim 2, wherein Y isand Y11is CH3or H.

7. The composition of matter as recited in claim 2, wherein Y is8. The composition of matter as recited in claim 1 , wherein R2is H, R4is CH3, R14isOCH(CH3)2and R16is F.

9. The composition of matter as recited in claim 8, wherein Y isand Y11is H or CH3.

10. The composition of matter as recited in claim 8, wherein Y isand Y11is H or CH3.The composition of matter as recited in claim 8, wherein Y iswherein Y1is H or OH, Y2is H or OH and Y3is H or CH3.

12. The composition of matter as recited in claim 1 , wherein R2is H, R4is CH3, R14is H and R16is H.

13. The composition of matter as recited in claim 12, wherein Y iswherein Y11is H or CH3.The composition of matter as recited in claim 12, wherein Y iswherein Y3is H or CH3.

15. The composition of matter as recited in claim 1 , wherein R2is CH3, R4is H, R14is OCH2CH3 or OCH(CH3)2and R16is H.

16. The composition of matter as recited in claim 15, wherein Y isand Y11is H or CH3.

17. The composition of matter as recited in claim 1 , wherein R2is H, R4is CH3, R14is OCH(CH3)2and R16is H and Y iswherein Y3is H or CH3.

18. A composition of matter comprising a compound, or a pharmaceutically acceptable salt, amide or ester thereof, with a formula of:wherein R14is H or OCH(CH3)2; and Y iswherein Y1is H or OH, Y2is H or OH, Y3is H or CH3.

19. A method of treating cancer in a subject in need thereof, the method comprising: administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of a composition of matter having a formula as recited in claim 1 .

20. The method as recited in claim 19, wherein the cancer is lung carcinoma.21 . The method as recited in claim 20, wherein the cancer is non-small cell lung cancer(NSCLC).

22. The method as recited in claim 19, wherein the cancer is a solid tumor.

23. The method as recited in claim 22, wherein the cancer is bladder cancer, breast cancer, colon cancer, liver carcinoma or prostate cancer.

24. A method of treating cancer in a subject in need thereof, the method comprising: administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of a composition of matter having a formula as recited in claim 18.

25. The method as recited in claim 24, wherein the cancer is lung carcinoma.

26. The method as recited in claim 25, wherein the cancer is non-small cell lung cancer (NSCLC).

27. The method as recited in claim 24, wherein the cancer is a solid tumor.

28. The method as recited in claim 27, wherein the cancer is bladder cancer, breast cancer, colon cancer, liver carcinoma or prostate cancer.

29. A method of treating cancer in a subject in need thereof, the method comprising: administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of a composition of matter having a formula as recited in any of claims 1 -18.

30. The method as recited in claim 29, wherein the cancer is lung carcinoma.31 . The method as recited in claim 30, wherein the cancer is non-small cell lung cancer(NSCLC).

32. The method as recited in claim 29, wherein the cancer is a solid tumor.

33. The method as recited in claim 32, wherein the cancer is bladder cancer, breast cancer, colon cancer, liver carcinoma or prostate cancer.

Images