Pharmaceutical combinations of OMA1 activators with BH3 mimetics

Abstract

Provided are pharmaceutical combinations, pharmaceutical compositions, and methods of treatment of cancer using combinations of BH3 mimetics such as venetoclax and navitoclax with 0MA1 activators such as BTM-3566.

Description

[0001] PHARMACEUTICAL COMBINATIONS OF OMA1 ACTIVATORS WITH BH3 MIMETICS CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] [1] The present application claims the benefit of priority of U. S. Provisional Patent Application no. 63 / 744,061, filed January 10, 2025, which is hereby incorporated herein by reference in its entirety.

[0003] BACKGROUND OF THE DISCLOSURE

[0004] Field

[0005] [2] This disclosure relates to the treatment of cancer. This disclosure relates more particularly to pharmaceutical combinations, compositions including such pharmaceutical combinations, and treatment of cancers with such combinations.

[0006] Technical Background

[0007] [3] In the United States over 1,500,000 new cases of cancer are diagnosed annually with an estimated 500,000 deaths per year related to cancer. There are more than 200 different histopathological types of cancer largely classified into solid tumor and hematopoietic cancers. Current cancer therapies vary depending upon the localization and stage of the cancer but generally include a combination of surgery, systemic therapy, radiation therapy, and chemotherapy.

[0008] [4] Apoptosis, colloquially referred to as “programmed cell death,” is a key mechanism of cancer cell death. Cancer cells are often resistant to apoptosis, and so it is a common target for development of anti-cancer therapy. Pharmacological control of apoptosis can be achieved by altering the activity of pro- and anti-apoptotic BH3 containing proteins. Several classes of drugs have been developed to interfere with the activity of anti-apoptotic BH3 containing proteins, thus promoting mitochondrial outer membrane polarization, an important event in apoptosis. These include marketed drugs such as venetoclax, a BH3 mimetic that specifically blocks the activity of BCL2, which itself blocks apoptosis. Other compounds, such as navitoclax, are more broadly acting, inhibiting the activity of a BH3 proteins including BCL-xL, Bcl-W. A variety of other compounds are known to target additional BH3 proteins such as MCL1 or XIAP binding partners.

[0009] [5] While these BH3 mimetic drugs hold significant promise, further improvements to efficacy are needed.SUMMARY

[0010] [6] The present inventors have determined that 0MA1 activators, such as the compounds described herein, can improve the efficacy of BH3 mimetics such as venetoclax and navitoclax.

[0011] [7] Accordingly, one aspect of the disclosure is a pharmaceutical combination comprising

[0012] a BH3 mimetic (e.g., venetoclax or navitoclax); and

[0013] an 0MA1 activator (e.g., a compound of Formula I as described herein).

[0014] [8] Another aspect of the disclosure is a pharmaceutical composition comprising:

[0015] a BH3 mimetic (e.g., venetoclax or navitoclax); and

[0016] an 0MA1 activator (e.g., a compound of Formula I as described herein).

[0017] [9] Another aspect of the disclosure is a method for treating cancer in a patient in need thereof, the method comprising administering to the patient

[0018] an effective amount of a BH3 mimetic (e.g., venetoclax or navitoclax); and

[0019] an effective amount of an 0MA1 activator (e.g., a compound of Formula I as described herein).

[0020]

[0010] Another aspect of the disclosure is a method for improving the efficacy of treatment in a patient being treated with a BH3 mimetic for cancer, the method comprising administering to the patient an effective amount of an OMA1 activator.

[0021]

[0011] Other aspects of the disclosure will be apparent to the person of ordinary skill in the art based on the disclosure herein.

[0022] BRIEF DESCRIPTION OF THE FIGURES

[0023]

[0012] FIG. 1 is a graph of raw fluorescence assay data for BTM-3566 in various cancer cell lines.

[0024]

[0013] FIG. 2 is a graph of raw fluorescence assay data for coadministration of BTM-3566 and navitoclax in renal carcinoma cell line 769-P.

[0025]

[0014] FIG. 3A is a graph showing the estimated contribution to IC50 in cell line 769-P for navitoclax at a variety of concentrations of BTM-3566.

[0026]

[0015] FIG. 3B is a graph showing the estimated contribution to IC50 in cell line 769-P for BTM-3566 at a variety of concentrations of navitoclax.

[0027]

[0016] FIG. 4A is graph showing luminescence assay data for activation Caspase 3 / 7 in 769-P cells for BTM-3566 at various concentrations of navitoclax.

[0017] FIG. 4B is a graph showing the calculated ICsofor navitoclax-mediated induction of Caspase 3 / 7 in 769-P cells as a function of BTM-3566 concentration.

[0028]

[0018] FIG. 5 is a graph of relative growth inhibition caused by BTM-3566 in Jekol or Toledo cell lines. The graph depicts BTM-3566 as the x-axis with each dose level of BH-3 mimetic depicted as an individual curve. The IC50 of BTM-3566 at each dose level of BH3 mimetic is calculated.

[0029]

[0019] FIG. 6 is a graph of relative growth inhibition caused by the BH-3 mimetic navitoclax or venetoclax in Jekol or Toledo cell lines. The graph depicts each BH-3 mimetic concentration as the x-axis with each dose level of BTM-3566 depicted as an individual curve. The IC50 of each BH3 mimetic at each dose level of BTM-3566 is calculated.

[0030]

[0020] Figure 7 is a graph of the SynergyFinder Plus scoring output for the combination of BTM-3566 and the BH3 mimetics navitoclax or venetoclax in a venetoclax-resistant cell line (Jekol) and a venetoclax-sensitive cell line (Toledo). The x-axis represents the concentration of BH-3 mimetic in nanomolar, the y-axis the concentration of BTM-3566 in nanomolar. Each dose pair is assigned a synergy score and plotted as a heat map.

[0031] DETAILED DESCRIPTION

[0032]

[0021] As noted above, BH3 mimetics such as venetoclax and navitoclax can be used to promote apoptosis in various cancers by reducing the activity of various apoptosis-blocking proteins such as BLC2.

[0033]

[0022] Control of apoptosis may also be effected by altering the levels of BH3 proteins themselves. In eukaryotic cells, phosphorylation of the protein synthesis initiation factor elF2alpha leads to a reduction in the efficiency of specific messenger RNA translation of proteins involved in cell survival, including various BH3-containing proteins. Persistent elF2alpha phosphorylation leads to activation of the ATF4 integrated stress response, in which proteins that promote apoptosis such as DDIT4, TRIB3 and others are expressed. Compounds that persistently activate the ATF4 integrated stress response may therefore promote apoptosis in specific circumstances.

[0034]

[0023] Mitochondria are central to the control of the intrinsic apoptotic cell death pathway. Activation of the intrinsic apoptotic pathway is correlated with and requires mitochondrial outer membrane permeabilization (MOMP) to release pro-apoptotic proteins cytochrome c and SMAC / Diablo. MOMP occurs when the proapoptotic BH3 containing proteins BAK and BAX form oligomers on the outer membrane of mitochondria resulting in pore formation. Anti-apoptotic BH3 proteins including BCL2, BCL-xL and MCL1 bind to BAX and BAK, sequestering these proteins or otherwise preventing oligomerization and thus preventing MOMP.

[0035]

[0024] Movement of mitochondrial proteins cytochrome c and SMAC / DIABLO to the cytosol is considered to be a necessary requirement for apoptosis. Cytochrome c is enriched and retained in the cristae structures of the inner mitochondrial membrane. The integrity of mitochondrial cristae is essential to maintaining cell viability. 0PA1, a dynamin like protein, is responsible for maintaining tight cristae structure and limiting movement of cytochrome c to the mitochondrial inner membrane space. When 0PA1 is cleaved the cristae complex "opens" and in so doing presents cytochrome c to the mitochondrial inter membrane space. This mobilization of cytochrome c, in conjunction with MOMP opening by BTM-3566, induced loss of BH3 proteins or presence of BH3 mimetics, causes the release of cytochrome c into the cytosol where it activates caspase 3 / 7.

[0036]

[0025] The activity of OPA1 is tightly controlled by the mitochondrial protease 0MA1.

[0037] Activation of 0MA1 results in cleavage of OPA1 to a short form that is associated with fragmentation of mitochondria. Persistent activation of 0MA1 has been associated with cell death in specific model systems. The present inventors suggest, without intending to be bound by theory, that activators of 0MA1 may therefore be used to elicit or augment cell death in sensitive cell types by reducing influencing 0PA1 activity through cleavage of 0PA1.

[0038]

[0026] BTM-3566 (Compound 1 ) is one of a class of 1 -th iazol-2-yl-N-3-alkyl-1 H-pyrozole-5-carboxylic acid derivatives that have been found to have anti-tumor properties. See A. B.

[0039] Cooper et al., “1-Thiazol-2-yl-N-3-methyl-1 H-pyrozole-5-carboxylic acid derivatives as antitumor agents,” Bioorg Med Chem Lett. 27:4471-7 (2017), which is hereby incorporated herein by reference in its entirety for all purposes. A variety of other compounds are described in U. S. Patent Applications Publications nos. 2018 / 0311218 and 2019 / 0345152, each of which is hereby incorporated herein by reference in its entirety for all purposes, and especially for their description of other compounds useful as OMA1 activators. The mechanism of action of this class of compounds has been found to require changes in mitochondrial morphology and function via activation of the mitochondrial quality control protease OMA1. BTM-3566 has been found to be a potent inducer of apoptosis in B-cell lymphomas, an event correlated with activation of OMA1, cleavage of OPA1 and activation of the ATF4 integrated stress response. See, e.g., A. Schwarzer et al., “Targeting Aggressive B-cell Lymphomas through Pharmacological Activation of the Mitochondrial Protease OMA1,” Mol Cancer Ther. 22:1290-303 (2023). In sensitive tumor cell lines (for example, Diffuse Large B-cell Lymphoma) there is a reduction in the amount of the anti-apoptotic BH3 protein MCL-1 which is known to beimportant for survival of B-cell lymphoma. Without intending to be bound by theory, the present inventors surmise that apoptosis in these cell lines is the result of a cascade of events leading to rapid MOMP formation and cell death.

[0040]

[0027] The present inventors have unexpectedly found that combinations of the 0MA1 activator BTM-3566 with the BH3 mimetics venetoclax and navitoclax exhibited synergistic anticancer activity. Given the nature of the mechanism by which BTM-3566 regulates mitochondrial function and activates the ATF4 integrated stress response, the present inventors submit that combinations of 0MA1 activators more generally (such as BTM-3566 and other compounds of Formula I as described herein) with BH3 mimetics (such as venetoclax and navitoclax) would be useful therapeutics, across a variety of cancer types.

[0041]

[0028] Accordingly, one aspect of the disclosure is a pharmaceutical combination comprising

[0042] a BH3 mimetic (e.g., venetoclax or navitoclax); and

[0043] an 0MA1 activator (e.g., a compound of Formula I as described herein).

[0044]

[0029] Another aspect of the disclosure is a pharmaceutical composition comprising:

[0045] a BH3 mimetic (e.g., venetoclax or navitoclax); and

[0046] an 0MA1 activator (e.g., a compound of Formula I as described herein).

[0047]

[0030] Another aspect of the disclosure is a method for treating cancer in a patient in need thereof, the method comprising administering to the patient

[0048] an effective amount of a BH3 mimetic (e.g., venetoclax or navitoclax); and

[0049] an effective amount of an OMA1 activator (e.g., a compound of Formula I as described herein).

[0050]

[0031] Another aspect of the disclosure is a method for improving the efficacy of treatment in a patient being treated with a BH3 mimetic for cancer, the method comprising administering to the patient an effective amount of an OMA1 activator.

[0051]

[0032] A variety of BH3 mimetics are contemplated for the use in the combinations, compositions and therapeutic methods of the disclosure. Generally, as used herein, a BH3 mimetic is a compound that target, decrease, or inhibit antiapoptotic proteins from the BCL-2 family. For example, the data discussed herein demonstrate synergistic improvement of efficacy of venetoclax and navitoclax.

[0052]

[0033] Accordingly, in various embodiments, the BH3 mimetic is venetoclax. In various embodiments, the BH3 mimetic is navitoclax. Other BH3 mimetics are described in U. S. Patent Application Publication no. 2007 / 0072860, which describes navitoclax (also known as ABT-263); and U. S. Patent Application Publication no. 2010 / 0305122, which describes venetoclax(also known as ABT-199); each of these publications is hereby incorporated herein by reference in their entirety for their teachings of BH3 mimetic analogs of navitoclax and venetoclax suitable for use in the combinations, compositions and therapeutic methods of the disclosure.

[0053]

[0034] Other BH3 mimetics contemplated for use in the combinations, compositions and therapeutic methods of the disclosure include, without limitation, ABT-737 (Abbott / Abbvie), S55746 (Servier); sonrotoclax (Beigene), AZD4320 (AstraZeneca), and Obatoclax (Gemin X / Teva), which target BCL2.

[0054]

[0035] Other BH3 mimetics contemplated for use in the combinations, compositions and therapeutic methods of the disclosure include, without limitation, S63845 (Servier), AZD5991 (AstraZeneca), A-1210477 (Abbvie), murizatoclax (AMG-397, Amgen), and tapotoclax (AMG-176, Amgen), which target MCL1.

[0055]

[0036] Other BH3 mimetics contemplated for use in the combinations, compositions and therapeutic methods of the disclosure include, without limitation, xevinapant (DebioPharma), which targets IAP, and LCL161 (Novartis), which targets XIAP and clAP.

[0056]

[0037] Other BH3 mimetics contemplated for use in the combinations, compositions and therapeutic methods of the disclosure include, without limitation, A-1155463, which targets BCL-XL, and A-1331852, which targets BFL-1 / MCL-1.

[0057]

[0038] Other BH3 mimetics contemplated for use in the combinations, compositions and therapeutic methods of the disclosure include, without limitation, BGB-11417, LP-108, S65487, AT-101, APG-1252, APG2575, and BCL-201.

[0058]

[0039] Similarly, a variety of 0MA1 activators are contemplated for use in the combinations, compositions and therapeutic methods of the disclosure.

[0059]

[0040] In various desirable embodiments, the OMA1 activator is BTM-3566. BTM-3566 has been demonstrated to itself be effective against a variety of cancers; here it is demonstrated to synergistically improve the anti-cancer performance of BH3 mimetics such as navitoclax and venetoclax. The BTM-3566 base compound is 4-(3-fluorophenyl)-1-(5-(isopropylthio)-4-(4-(trifluoromethyl)cyclohex-1-en-1-yl)thiazol-2-yl)-3-methyl-1 H-pyrazole-5-carboxylic acid. As used herein, “BTM-3566” contemplates not only the base compound but also any pharmaceutically-acceptable salt of the base compound, either. Methods of synthesis of BTM-3566 and various pharmaceutical forms of BTM-3566 are described, respectively, in U. S. Patent Application Publications nos. 2022 / 0267314 and 2022 / 0162204, each of which is hereby incorporated by reference in its entirety for teachings with respect to forms of BTM-3566 suitable for use in the combinations, compositions and therapeutic methods of the disclosure.

[0041] A variety of other suitable 0MA1 compounds are described in U. S. Patent Applications Publications nos. 2018 / 0311218 and 2019 / 0345152, each of which is hereby incorporated herein by reference in its entirety for its teachings with respect to compounds, which are contemplated for use in combinations, compositions and therapeutic methods of the disclosure.

[0060]

[0042] For example, in various embodiments, the OMA1 activator is a compound of Formula

[0061] R4— L4

[0062] N

[0063] \

[0064] N

[0065] S

[0066]

[0067] or a pharmaceutically-acceptable salt thereof, wherein

[0068] L1is a -S-, -O-, -S(O)-, -S(O)2- or a bond;

[0069] R1is unsubstituted or fluorinated Ci-Cs alkyl, unsubstituted or fluorinated Ci-Cs alkenyl, unsubstituted or fluorinated C-i-Cs alkynyl, or phenyl optionally substituted with 1-5 R1E, in which

[0070] each R1Eis independently selected from oxo, optionally-substituted C1-C4 alkyl, C1-C4 fluoroalkyl, halogen, -CN, SF5, -N3, -C(O)R1F, -SR1F, -S(O)i.2R1F, -OR1F, - (OCH2CH2O)n-R1Gin which n is 1-4, -N(R1G)C(O)CH2-O-(CH2CH2O)nR1Gin which n is 0-3, -C(O)NR1G(CH2CH2O)nR1G, -NR1GR1Fand -C(O)R1F;

[0071] each R1Fis independently selected from H, C1-C3 alkyl and C1-C3 fluoroalkyl and each R1Gis independently selected from H and C1-C3 alkyl;

[0072] L2is a bond or -CH2-;

[0073] Q is -COOH or -C(O)O(Ci-C3alkyl);

[0074] L3is a bond, -C(O)-, -S-, -S(O)i-2-, -O-, -NR6-, -CH2-, -CH(CH3)(OH)- or -CH(OH)-;

[0075] R3is phenyl or monocyclic heteroaryl each (i) optionally substituted with a single substituent selected from -l_3C-(phenyl optionally substituted with 1-5 R3D), -l_3C-(monocyclic heteroaryl optionally substituted with 1-5 R3D), -l_3C-(monocyclic C3-C6 cycloalkyl optionally substituted with 1-5 R3E), -l_3C-(monocyclic C4-C6 heterocycloalkyl optionally substituted with 1-5 R3E) and (ii) optionally substituted with 1-5 R3E, in which

[0076] each L3Cis a bond, methylene, ethylene, -C(O)-, -S-, -S(O)i.2-, -O- or -NR3G-;each R3Dis independently selected from optionally-substituted C1-C4 alkyl, C1-C4 fluoroalkyl, halogen, -CN, SF5, -N3, -C(O)R3F, -SR3F, -S(O)I.2R3F,

[0077] -OR3F, -NR3GR3F, -C(O)R3F, -C(O)NR3GR3F, -NR3GC(O)R3F, -C(S)NR3GR3F, -NR3GC(S)R3F, -C(O)OR3F, -OC(O)R3F, -C(O)SR3F, -SC(O)R3F, -C(S)OR3F, -OC(S)R3F, -C(S)SR3F, -SC(S)R3F, -S(O)I-2OR3F, -OS(O)I-2R3F, -S(O)I-2NR3GR3Fand -NR3GS(O)I-2R3F;

[0078] each R3Eis independently selected from oxo, optionally-substituted C1-C4 alkyl, C1-C4 fluoroalkyl, halogen, -CN, SF5, -N3, -C(O)R3F, -SR3F,

[0079] -S(O)I-2R3F, -OR3F, -NR3GR3F, -C(O)R3F, -C(O)NR3GR3F, -NR3GC(O)R3F, -C(S)NR3GR3F, -NR3GC(S)R3F, -C(O)OR3F, -OC(O)R3F, -C(O)SR3F, -SC(O)R3F, -C(S)OR3F, -OC(S)R3F, -C(S)SR3F, -SC(S)R3F, -S(O)I-2OR3F, -OS(O)I-2R3F, -S(O)I-2NR3GR3F, -NR3GS(O)I-2R3F;

[0080] each R3Fis independently selected from H, Ci-C3alkyl and Ci-C3fluoroalkyl and each R3Gis independently selected from H and Ci-C3alkyl, Ci-C3fluoroalkyl;

[0081] L4is selected from the group consisting of a bond, -C(O)-, -S-, -S(O)i-2-, -O- and -NR6-; R4is selected from the group consisting of unsubstituted, hydroxylated, C1-C4 alkoxylated or fluorinated Ci-Cs alkyl, unsubstituted or fluorinated Ci-Cs alkenyl and unsubstituted or fluorinated C-i-Cs alkynyl;

[0082] L5is a bond, -C(O)-, -S-, -S(O)i.2-, -O- or -NR6-;

[0083] R5is phenyl, monocyclic heteroaryl, monocyclic heterocycloalkyl or monocyclic cycloalkyl each optionally substituted with 1-5 R5E, in which

[0084] each R5Eis independently selected from oxo, optionally-substituted C1-C4 alkyl, C1-C4 fluoroalkyl, halogen, -CN, -SF5, -N3, -C(O)R5F, -SR5F, -S(O)i-2R5F, -OR5F, -NR5GR5F, -C(O)R5F, -C(O)NR5GR5F, -NR5GC(O)R5F, -C(S)NR5GR5F, -NR1GC(S)R5F, -C(O)OR5F, -OC(O)R5F, -C(O)SR5F, -SC(O)R5F, -C(S)OR5F, -OC(S)R5F, -C(S)SR5F, -SC(S)R5F, -S(O)I-2OR5F, -OS(O)I-2R5F, -S(O)I-2NR5GR5Fand -NR5GS(O)I-2R5F;

[0085] each R5Fis independently selected from H, Ci-C3alkyl and Ci-C3fluoroalkyl and each R5Gis independently selected from H and Ci-C3alkyl;

[0086] wherein

[0087] each R6is selected from the group consisting of hydrogen, Ci-C3alkyl and -C(O)(Ci-C3alkyl);

[0088] each monocyclic cycloalkyl has 3-7 ring carbons and is saturated or partially unsaturated;each monocyclic heterocycloalkyl has 3-7 ring members and 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur and is saturated or partially unsaturated; each monocyclic heteroaryl is a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0089]

[0043] In various embodiments, L1is -S-. In various other embodiments,

[0090] L1is a bond.

[0091]

[0044] In various embodiments, R1is unsubstituted Ci-Cs alkyl. In various embodiments, R1is unsubstituted or fluorinated C1-C4 alkyl, e.g., unsubstituted C1-C4 alkyl. For example, in various embodiments, R1is isopropyl.

[0092]

[0045] In various embodiments, R1is phenyl optionally substituted with 1-5 R1E. For example, in various embodiments, the R1phenyl is substituted with 1-5 R1E, e.g., 1-4 R1E, or 1-3 R1E. In various embodiments, the R1phenyl is substituted with 1-2 R1E, e.g., 1 R1E. In various embodiments, the R1phenyl is unsubstituted.

[0093]

[0046] In various embodiments, L5is a bond.

[0094]

[0047] In various embodiments, R5is cycloalkyl or heterocycloalkyl, each optionally substituted with 1-5 R5E. For example, in various embodiments, R5is cyclohexenyl or cyclohexyl, each optionally substituted with 1-5 R5E. In various embodiments, R5is piperidinyl, piperazinyl, morpholinyl or pyrrolidinyl, each optionally substituted with 1-5 R5E. In various embodiments, R5is C5-C6 cycloalkyl orC5-C6 heterocycloalkyl, each optionally substituted with 1-5 R5E.

[0095]

[0048] In various embodiments, R5is phenyl, optionally substituted with 1-5 R5E.

[0096]

[0049] In various embodiments, R5is monocyclic heteroaryl, optionally substituted with 1-5 R5E. For example, in various embodiments, R5is isoxazolyl, a pyridyl, an imidazopyridyl, a pyrazolyl, optionally substituted with 1-5 R5E.

[0097]

[0050] In various embodiments, the R5group is substituted with 1-5 R5E, e.g., 1-4 R5E, or 1-3 R5E. In various embodiments, the R5group is substituted with 1-2 R5E, e.g., 1 R5E. In various embodiments, the R5group is unsubstituted.

[0098]

[0051] In various embodiments,

[0099] L1is selected from the group consisting of a bond, -S-, -S(O)i-2-, and -O- (e.g., as further described in any consistent embodiment above)

[0100] R1is selected from Ci-Cs alkyl and Ci-Cs alkenyl, each unsubstituted or fluorinated (e.g., as further described in any consistent embodiment above),L5is a bond, and

[0101] R5is cycloalkyl or heterocycloalkyl, each optionally substituted with 1-5 R5E(e.g., as further described in any consistent embodiment above).

[0102]

[0052] In various embodiments,

[0103] L1is a bond,

[0104] R1is selected from the group consisting of phenyl and monocyclic heteroaryl, each optionally substituted with 1-5 R1E(e.g., as further described in any consistent embodiment above);

[0105] L5is a bond, and

[0106] R5is phenyl, monocyclic heteroaryl, cycloalkyl or heterocycloalkyl, each optionally substituted with 1-5 R5E(e.g., as further described in any consistent embodiment above).

[0107]

[0053] In various embodiments, L2is a bond.

[0108]

[0054] In various embodiments, Q is -C(O)OH.

[0109]

[0055] In various embodiments, L3is a bond.

[0110]

[0056] In various embodiments, R3is phenyl substituted with 0-5 R3E.

[0111]

[0057] In various embodiments, R3is monocyclic heteroaryl substituted with 0-5 R3E.

[0112]

[0058] In various embodiments, R3is isothiazolyl, pyridonyl, thiadiazolyl, pyrazinyl, imidazolyl, pyridinyl, pyrazolyl, isoxazolyl, thienyl, furanyl or pyrimidinyl, each substituted with 0-5 R3E.

[0113]

[0059] In various embodiments, the R3group is substituted with 1-5 R3E, e.g., 1-4 R3E, or 1-3 R3E. In various embodiments, the R3group is substituted with 1-2 R3E, e.g., 1 R3E. In various embodiments, the R3group is unsubstituted.

[0114]

[0060] In various embodiments, R4is hydrogen or unsubstituted Ci-Ce alkyl. In various embodiments, R4is unsubstituted C1-C4 alkyl. In various embodiments, R4is methyl.

[0115]

[0061] In various embodiments, the OMA1 activator is one of the compounds of the compound Table 1 below, optionally provided as a pharmaceutically-acceptable salt, and optionally provided as an N-oxide, and / or a solvate or hydrate of the compound or salt. BJAB cell proliferation data is presented in the table; “A” indicates a measured EC50 less than or equal to 1 pM; “B” indicates a measured EC50 greater than 1 pM and less than or equal to 5 pM; “C” indicates a measured EC50 greater than 5 pM and less than or equal to 10 pM; “D” indicates a measured EC50 greater than 10 pM and less than or equal to 25 pM; “E” indicates a measuredECso greater than 25 pM and less than or equal to 50 pM; “F” indicates a measured ECso greater than 50 pM and less than or equal to 100 pM; “G” indicates that in the experiments performed there was no measured ECso less than or equal to 80 pM; “H” indicates that in the experiments performed there was no measured ECso less than or equal to 50 pM; “I” indicates that in the experiments performed there was no measured ECso less than or equal to 40 pM; “J” indicates that in the experiments performed there was no measured ECso less than or equal to 25 pM; and “K” indicates that in the experiments performed there was no measured ECso less than or equal to 20 pM. In various embodiments, the OMA1 activator is a compound having an activity as “A,” “B” or “C” in Compound Table 1 below. In certain embodiments, the OMA1 activator is a compound having an activity as “A” or “B” in Compound Table 1 below. In certain embodiments, the OMA1 activator is a compound having an activity as “A” in Compound Table 1 below.

[0116] Compound Table 1

[0117] Cpd Name ECso methyl 1-(4-(3,4-dichlorophenyl)thiazol-2-yl)-3-methyl-4-(2-nitrobenzyl)- A1 H

[0118] 1 H-pyrazole-5-carboxylate

[0119] 1-(4-(3,4-dichlorophenyl)thiazol-2-yl)-3-methyl-4-(2-nitrobenzyl)-1 H- A2 H pyrazole-5-carboxylic acid

[0120] methyl 1-(4-(3,4-dichlorophenyl)-5-(ethylthio)thiazol-2-yl)-3-methyl-4-(2- A3 G nitrobenzyl)-1 H-pyrazole-5-carboxylate

[0121] 1-(4-(3,4-dichlorophenyl)-5-(ethylthio)thiazol-2-yl)-3-methyl-4-(2- A4 F nitrobenzyl)-1 H-pyrazole-5-carboxylic acid

[0122] methyl 1-(4-(3,4-dichlorophenyl)-5-(isopropylthio)thiazol-2-yl)-3-methyl-4- A5 G (2-nitrobenzyl)-1 H-pyrazole-5-carboxylate

[0123] 1-(4-(3,4-dichlorophenyl)-5-(isopropylthio)thiazol-2-yl)-3-methyl-4-(2- A6 E nitrobenzyl)-1 H-pyrazole-5-carboxylic acid

[0124] methyl 1 -(4-(3,4-dichlorophenyl)thiazol-2-yl)-3-methyl-4-(2- A7 G (methylsulfonamido)benzyl)-1 H-pyrazole-5-carboxylate

[0125] 1-(4-(3,4-dichlorophenyl)thiazol-2-yl)-3-methyl-4-(2- A8 G (methylsulfonamido)benzyl)-1 H-pyrazole-5-carboxylic acid

[0126] methyl 1-(4-(3,4-dichlorophenyl)-5-(propylthio)thiazol-2-yl)-3-methyl-4-(2- A9 G nitrobenzyl)-1 H-pyrazole-5-carboxylate

[0127] 1-(4-(3,4-dichlorophenyl)-5-(propylthio)thiazol-2-yl)-3-methyl-4-(2- A10 E nitrobenzyl)-1 H-pyrazole-5-carboxylic acid

[0128]

[0129] Cpd Name ECso methyl 1-(5-(butylthio)-4-(3,4-dichlorophenyl)thiazol-2-yl)-3-methyl-4-(2- A11 G nitrobenzyl)-1H-pyrazole-5-carboxylate

[0130] 1-(5-(butylthio)-4-(3,4-dichlorophenyl)thiazol-2-yl)-3-methyl-4-(2- A12 G nitrobenzyl)-1 H-pyrazole-5-carboxylic acid

[0131] 1-(4-(3,4-dichlorophenyl)-5-(propylthio)thiazol-2-yl)-3-methyl-4-(2- A13 E (methylsulfonamido)benzyl)-1 H-pyrazole-5-carboxylic acid N-(2-((5-(4-(aminomethyl)piperidine-1-carbonyl)-1-(4-(3,4- D A14 dichlorophenyl)-5-(propylthio)thiazol-2-yl)-3-methyl-1 H-pyrazol-4- yl)methyl)phenyl)methanesulfonamide

[0132] 4-bromo-1-(4-(3,4-dichlorophenyl)-5-(isopropylthio)thiazol-2-yl)-3-methyl- A15 D 1 H-pyrazole-5-carboxylic acid

[0133] 1-(4-(3,4-dichlorophenyl)-5-(isopropylthio)thiazol-2-yl)-3-methyl-1 H- F A16

[0134] pyrazole-5-carboxylic acid

[0135] 1-(4-(3,4-dichlorophenyl)-5-(isopropylthio)thiazol-2-yl)-4-(imidazo[1,2- D A17

[0136] a]pyridin-6-yl)-3-methyl-1 H-pyrazole-5-carboxylic acid 1-(4-(3,4-dichlorophenyl)-5-(isopropylthio)thiazol-2-yl)-3-methyl-4-phenyl- A18 B 1 H-pyrazole-5-carboxylic acid

[0137] 1-(5-(cyclohexylthio)-4-(3,4-dichlorophenyl)thiazol-2-yl)-3-methyl-4-(2- D A19

[0138] nitrobenzyl)-1 H-pyrazole-5-carboxylic acid

[0139] 4-(benzofuran-2-yl)-1-(4-(3,4-dichlorophenyl)-5-(isopropylthio)thiazol-2- A20 C yl)-3-methyl-1 H-pyrazole-5-carboxylic acid

[0140] 1-(4-(3,4-dichlorophenyl)-5-(isopropylthio)thiazol-2-yl)-4-(2-fluoropyridin- C A21

[0141] 4-yl)-3-methyl-1 H-pyrazole-5-carboxylic acid

[0142] 2-(4-(3,4-dichlorophenyl)-5-(isopropylthio)thiazol-2-yl)-2',5,5'-trimethyl- A22 D 4,4'-bi(2H-pyrazole)-3-carboxylic acid

[0143] 1-(4-(3,4-dichlorophenyl)-5-(isopropylthio)thiazol-2-yl)-4-(2,6- A23 A dimethylpyridin-4-yl )-3-methyl- 1 H-pyrazole-5-carboxylic acid 1-(4-(3,4-dichlorophenyl)-5-(isopropylthio)thiazol-2-yl)-4-(3,5- A24 B difluorophenyl)-3-methyl-1 H-pyrazole-5-carboxylic acid 1-(4-(5-chloro-2-fluorophenyl)-5-(isopropylthio)thiazol-2-yl)-4-(3,5- A25 B dichlorophenyl)-3-methyl-1 H-pyrazole-5-carboxylic acid

[0144]

[0145] Cpd Name EC50 1-(4-(5-chloro-2-fluorophenyl)-5-(isopropylthio)thiazol-2-yl)-4-(2,6- A26 C dimethylpyridin-4-yl)-3-methyl-1 H-pyrazole-5-carboxylic acid 4-(3,5-dichlorophenyl)-1-(4-(3,5-dimethylisoxazol-4-yl)-5- A27 J (isopropylthio)thiazol-2-yl)-3-methyl-1 H-pyrazole-5-carboxylic acid 4-(3,5-dichlorophenyl)-1-(5-(isopropylthio)-4-(1-methyl-1H-pyrazol-4- A28 J yl)thiazol-2-yl)-3-methyl-1 H-pyrazole-5-carboxylic acid 4-(3,5-dichlorophenyl)-1-(5-(isopropylthio)-4-(pyridin-4-yl)thiazol-2-yl)-3- A29 J methyl-1 H-pyrazole-5-carboxylic acid

[0146] 4-(3,5-dichlorophenyl)-1-(5-(isopropylthio)-4-(pyridin-3-yl)thiazol-2-yl)-3- A30 J methyl-1 H-pyrazole-5-carboxylic acid

[0147] 4-(3,5-dichlorophenyl)-1 -(4-(imidazo[1,2-a] pyrid i n-6-y I )-5- A31 J (isopropylthio)thiazol-2-yl)-3-methyl-1 H-pyrazole-5-carboxylic acid methyl 1-(5-(sec-butylthio)-4-(3,4-dichlorophenyl)thiazol-2-yl)-4-(3,5- A32a dichlorophenyl)-3-methyl-1 H-pyrazole-5-carboxylate J

[0148] 1-(5-(sec-butylthio)-4-(3,4-dichlorophenyl)thiazol-2-yl)-4-(3,5- B A32b

[0149] dichlorophenyl)-3-methyl-1 H-pyrazole-5-carboxylic acid methyl 1-(5-(sec-butylthio)-4-(3,4-dichlorophenyl)thiazol-2-yl)-4-(2,6- A33a J dimethylpyridin-4-yl)-3-methyl-1H-pyrazole-5-carboxylate 1-(5-(sec-butylthio)-4-(3,4-dichlorophenyl)thiazol-2-yl)-4-(2,6- A A33b

[0150] dimethylpyridin-4-yl)-3-methyl-1 H-pyrazole-5-carboxylic acid

[0151] 4-(2,6-dimethylpyridin-4-yl)-1-(5-(isopropylthio)-4-(2- C A34

[0152] methoxyphenyl)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylic acid 4-(2,6-dimethylpyridin-4-yl)-1-(5-(isopropylthio)-4-(3- A35 B methoxyphenyl)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylic acid 4-(2,6-dimethylpyridin-4-yl)-1-(5-(isopropylthio)-4-(4- A36 D methoxyphenyl)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylic acid 4-(2,6-dimethylpyridin-4-yl)-1-(5-(isopropylthio)-4-phenylthiazol-2-yl)-3- A37 C methyl-1 H-pyrazole-5-carboxylic acid

[0153] 1-(4-(3,4-dichlorophenyl)-5-(isopropylthio)thiazol-2-yl)-4-(3- A38 (hydroxymethyl)-5-methylisoxazol-4-yl)-3-methyl-1 H-pyrazole-5- H carboxylic acid

[0154]

[0155] Cpd Name EC50 1-(4-(3,4-dichlorophenyl)-5-(isopropylthio)thiazol-2-yl)-4-(3- A39 (methoxymethyl)-5-methylisoxazol-4-yl)-3-methyl-1H-pyrazole-5- D carboxylic acid

[0156] 4-(2,6-dimethylpyridin-4-yl)-1-(5-(isopropylthio)-4-p-tolylthiazol-2-yl)-3- A40 B methyl-1 H-pyrazole-5-carboxylic acid

[0157] 4-(2,6-dimethylpyridin-4-yl)-1-(5-(isopropylthio)-4-m-tolylthiazol-2-yl)-3- A41 C methyl-1 H-pyrazole-5-carboxylic acid

[0158] 4-(2,6-dimethylpyridin-4-yl)-1 -(5-(isopropylthio)-4-o-tolylthiazol-2-yl)-3- A42 methyl-1 H-pyrazole-5-carboxylic acid B

[0159] 4-(2,6-dimethylpyridin-4-yl)-1-(5-(isopropylthio)-4-(phenylethynyl)thiazol- C A43

[0160] 2-yl)-3-methyl-1 H-pyrazole-5-carboxylic acid

[0161] 1-(4-(3,4-dichlorophenyl)-5-(isopropylthio)thiazol-2-yl)-3-methyl-4- A44 D (pyridin-3-yl)-1 H-pyrazole-5-carboxylic acid

[0162] 1-(4-(3,4-dichlorophenyl)-5-(methylthio)thiazol-2-yl)-3-methyl-4-(2- A45 E nitrobenzyl)-1 H-pyrazole-5-carboxylic acid

[0163] 1-(4-(3,4-dichlorophenyl)-5-(isopropylthio)thiazol-2-yl)-4-(3- A46 D (hydroxymethyl)phenyl)-3-methyl-1 H-pyrazole-5-carboxylic acid 1-(4-(3,4-dichlorophenyl)-5-(isopropylthio)thiazol-2-yl)-3-methyl-4- A47 C (pyridin-4-yl)-1 H-pyrazole-5-carboxylic acid

[0164] 4-(3-(aminomethyl)phenyl)-1-(4-(3,4-dichlorophenyl)-5- A48 E (isopropylthio)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylic acid

[0165] 1-(4-(3,4-dichlorophenyl)-5-(isopropylthio)thiazol-2-yl)-4-(4- A49 H (hydroxymethyl)phenyl)-3-methyl-1 H-pyrazole-5-carboxylic acid 1-(4-(3,4-dichlorophenyl)-5-(isopropylthio)thiazol-2-yl)-3-methyl-4-(2- A50 C (trifluoromethyl)phenyl)-1 H-pyrazole-5-carboxylic acid 1-(4-(3,4-dichlorophenyl)-5-(isopropylthio)thiazol-2-yl)-3-methyl-4-(3- A51 B (trifluoromethyl)phenyl)-1 H-pyrazole-5-carboxylic acid 1-(4-(3,4-dichlorophenyl)-5-(isopropylthio)thiazol-2-yl)-3-methyl-4-(4- A52 D (trifluoromethyl)phenyl)-1 H-pyrazole-5-carboxylic acid 1-(4-(3,4-dichlorophenyl)-5-(isopropylthio)thiazol-2-yl)-4- A53 H (hydroxy(phenyl)methyl)-3-methyl-1 H-pyrazole-5-carboxylic acid

[0166]

[0167] Cpd Name EC50 1-(4-(3,4-dichlorophenyl)-5-(isopropylsulfinyl)thiazol-2-yl)-3-methyl-4-(2- A54 E nitrobenzyl)-1 H-pyrazole-5-carboxylic acid

[0168] 1-(4-(3,4-dichlorophenyl)-5-(isopropylsulfonyl)thiazol-2-yl)-3-methyl-4-(2- D A55

[0169] nitrobenzyl)-1 H-pyrazole-5-carboxylic acid

[0170] 4-([1,2,4]triazolo[4,3-a]pyridin-3-yl)-1-(4-(3,4-dichlorophenyl)-5- A56 H (isopropylthio)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylic acid 1-(4-(3,4-dichlorophenyl)-5-(isopropylthio)thiazol-2-yl)-4-(3,5- A57 D dimethylisoxazol-4-yl)-3-methyl-1 H-pyrazole-5-carboxylic acid 4-(1H-benzo[d]imidazol-2-yl)-1-(4-(3,4-dichlorophenyl)-5- A58 E (isopropylthio)thiazol-2-yl)-3-methyl-1 H-pyrazole-5-carboxylic acid

[0171] 4-(3-chloro-2-methylphenyl)-1-(4-(3,4-dichlorophenyl)-5- C A59

[0172] (isopropylthio)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylic acid 4-(3,5-bis(trifluoromethyl)phenyl)-1-(4-(3,4-dichlorophenyl)-5- A60 B (isopropylthio)thiazol-2-yl)-3-methyl-1 H-pyrazole-5-carboxylic acid

[0173] 1-(4-(3,4-dichlorophenyl)-5-(isopropylthio)thiazol-2-yl)-4-(3- A61 B isopropylphenyl)-3-methyl-1 H-pyrazole-5-carboxylic acid 1-(4-(3,4-dichlorophenyl)-5-(isopropylthio)thiazol-2-yl)-4-(2-methoxy-5- A62 C methylphenyl)-3-methyl-1 H-pyrazole-5-carboxylic acid 1-(4-(3,4-dichlorophenyl)-5-(isopropylthio)thiazol-2-yl)-4-(1 H-imidazol-2- A63 D yl)-3-methyl-1 H-pyrazole-5-carboxylic acid

[0174] 1-(4-(3,4-dichlorophenyl)-5-(isopropylthio)thiazol-2-yl)-3-methyl-4- A64 D (pyrazolo[1,5-a]pyrid in-3-yl)-1 H-pyrazole-5-carboxylic acid 1-(4-(3,4-dichlorophenyl)-5-(isopropylthio)thiazol-2-yl)-3-methyl-4- E A65

[0175] (pyrazolo[1,5-a]pyrimidin-3-yl)-1 H-pyrazole-5-carboxylic acid 2-(4-(3,4-dichlorophenyl)-5-(isopropylthio)thiazol-2-yl)-2',5-dimethyl-4,4'- A66 C bi(2H-pyrazole)-3-carboxylic acid

[0176] 2-(4-(3,4-dichlorophenyl)-5-(isopropylsulfonyl)thiazol-2-yl)-2',5-dimethyl- A67 E 4,4'-bi(2H-pyrazole)-3-carboxylic acid

[0177] 1-(4-(3,4-dichlorophenyl)-5-(isopropylthio)thiazol-2-yl)-3-methyl-4-(1- A68 H methyl-1 H-benzo[d]imidazol-2-yl)-1 H-pyrazole-5-carboxylic acid 4-(5-cyanopyridin-3-yl)-1-(4-(3,4-dichlorophenyl)-5-(isopropylthio)thiazol- A69 D 2-yl)-3-methyl-1 H-pyrazole-5-carboxylic acid

[0178]

[0179] Cpd Name EC50 1-(4-(3,4-dichlorophenyl)-5-(isopropylthio)thiazol-2-yl)-4-(2-ethoxypyridin- A70 D 3-yl)-3-methyl-1 H-pyrazole-5-carboxylic acid

[0180] 2'-(4-(3,4-dichlorophenyl)-5-(isopropylthio)thiazol-2-yl)-2,5,5'-trimethyl- D A71

[0181] 3,4'-bi(2H-pyrazole)-3'-carboxylic acid

[0182] 1-(4-(3,4-dichlorophenyl)-5-(isopropylthio)thiazol-2-yl)-3-methyl-4- A72 D (pyrimidin-5-yl)- 1 H-pyrazole-5-carboxylic acid

[0183] 4-(3,5-bis(trifluoromethyl)phenyl)-1-(4-(3,4-dichlorophenyl)-5-A73 I(isopropylthio)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxamide 1-(4-(3,4-dichlorophenyl)-5-(isopropylthio)thiazol-2-yl)-4-(4,6- A74 E dimethylpyrimidin-2-yl)-3-methyl-1 H-pyrazole-5-carboxylic acid 4-(3,5-bis(trifluoromethyl)phenyl)-1-(4-(3,4-dichlorophenyl)-5- A75 (isopropylthio)thiazol-2-yl)-3-methyl-N-(pyridin-2-ylmethyl)-1H-pyrazole-5- I carboxamide

[0184] 4-(3,5-bis(trifluoromethyl)phenyl)-1-(4-(3,4-dichlorophenyl)-5- A76 (isopropylthio)thiazol-2-yl)-N-(2-hydroxyethyl)-N,3-dimethyl-1 H-pyrazole- I 5-carboxamide

[0185] 4-(3,5-bis(trifluoromethyl)phenyl)-1-(4-(3,4-dichlorophenyl)-5- A77 (isopropylthio)thiazol-2-yl)-N,3-dimethyl-N-(5-(trifluoromethyl)-1,3,4- I thiadiazol-2-yl)-1 H-pyrazole-5-carboxamide

[0186] (4-(3,5-bis(trifluoromethyl)phenyl)-1-(4-(3,4-dichlorophenyl)-5- A78 (isopropylthio)thiazol-2-yl)-3-methyl-1 H-pyrazol-5-yl)(3- I (diethylamino)pyrrolidin-1-yl)methanone

[0187] 1-(4-(3,4-dichlorophenyl)-5-(isopropylthio)thiazol-2-yl)-3-methyl-4- A79 D (pyrazin-2-yl)-1 H-pyrazole-5-carboxylic acid

[0188] 4-(3-cyano-5-methylphenyl)-1-(4-(3,4-dichlorophenyl)-5- A80 B (isopropylthio)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylic acid 4-(3,5-bis(trifluoromethyl)phenyl)-1-(4-(3,4-dichlorophenyl)-5-A81 (isopropylthio)thiazol-2-yl)-3-methyl-N-(1 H-tetrazol-5-yl)-1H-pyrazole-5- I carboxamide

[0189] 1-(4-(3,4-dichlorophenyl)-5-(isopropylthio)thiazol-2-yl)-3-methyl-4-(5- A82 I methyl-1,3,4-th iad iazol-2-yl)-1 H-pyrazole-5-carboxylic acid 4-(3-cyano-5-methoxyphenyl)-1-(4-(3,4-dichlorophenyl)-5- A83 C (isopropylthio)thiazol-2-yl)-3-methyl-1 H-pyrazole-5-carboxylic acid

[0190]

[0191] Cpd Name EC50 4-(3-cyano-5-(trifluoromethyl)phenyl)-1-(4-(3,4-dichlorophenyl)-5- A84 B (isopropylthio)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylic acid

[0192] 1-(4-(3,4-dichlorophenyl)-5-(isopropylthio)thiazol-2-yl)-4-(3- A85 C (methoxymethyl)phenyl)-3-methyl-1 H-pyrazole-5-carboxylic acid 4-(3-benzyl-5-methylisoxazol-4-yl)-1-(4-(3,4-dichlorophenyl)-5- B A86

[0193] (isopropylthio)thiazol-2-yl)-3-methyl-1 H-pyrazole-5-carboxylic acid

[0194] 1-(4-(3,4-dichlorophenyl)-5-(isopropylthio)thiazol-2-yl)-4-(3- A87 J ((dimethylamino)methyl)phenyl)-3-methyl-1 H-pyrazole-5-carboxylic acid

[0195] (1-(4-(3,4-dichlorophenyl)-5-(isopropylthio)thiazol-2-yl)-3-methyl-4- A88 J phenyl-1 H-pyrazol-5-yl)MeOH

[0196] 4-(benzo[d][1,3]dioxol-5-yl)-1-(4-(3,4-dichlorophenyl)-5- A89 C (isopropylthio)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylic acid

[0197] 1-(4-(3,4-dichlorophenyl)-5-(isopropylthio)thiazol-2-yl)-4-(4- A90 J methoxypyrimidin-2-yl)-3-methyl-1 H-pyrazole-5-carboxylic acid 1-(4-(3,4-dichlorophenyl)-5-(isopropylthio)thiazol-2-yl)-4-(isothiazol-4-yl)- A91 c 3-methyl-1 H-pyrazole-5-carboxylic acid

[0198] 1-(4-(3,4-dichlorophenyl)-5-(isopropylthio)thiazol-2-yl)-3-methyl-4-(3- A92 B methylisothiazol-5-yl)-1 H-pyrazole-5-carboxylic acid 1-(4-(3,4-dichlorophenyl)-5-(isopropylthio)thiazol-2-yl)-3-methyl-4-(1- A93 J methyl-2-oxo-1,2-d ihydropyridin-4-yl)-1 H-pyrazole-5-carboxylic acid 1-(4-(3,4-dichlorophenyl)-5-(isopropylthio)thiazol-2-yl)-4-(1,5-dimethyl-6- J A94

[0199] oxo-1,6-d ihydropyridin-3-yl)-3-methyl-1 H-pyrazole-5-carboxylic acid 1-(4-(3,4-dichlorophenyl)-5-(isopropylthio)thiazol-2-yl)-4-(3-fluoro-5- A95 B methylphenyl)-3-methyl-1 H-pyrazole-5-carboxylic acid 1-(4-(3,4-dichlorophenyl)-5-(isopropylthio)thiazol-2-yl)-4-(3-hydroxy-5- A96 J methylphenyl)-3-methyl-1 H-pyrazole-5-carboxylic acid 1-(4-(3,4-dichlorophenyl)-5-(isopropylthio)thiazol-2-yl)-4-(3-isopropoxy-5- A97 B methylphenyl)-3-methyl-1 H-pyrazole-5-carboxylic acid 1-(4-(3,4-dichlorophenyl)-5-(isopropylthio)thiazol-2-yl)-3-methyl-4-(3- A98 B methyl-5-(oxetan-3-yloxy)phenyl)-1 H-pyrazole-5-carboxylic acid 1-(4-(3,4-dichlorophenyl)-5-(isopropylthio)thiazol-2-yl)-4-(3- A99 C (dimethylamino)-5-methylphenyl)-3-methyl-1 H-pyrazole-5-carboxylic acid

[0200]

[0201] Cpd Name EC50 4-(3-(1H-imidazol-1-yl)-5-methylphenyl)-1-(4-(3,4-dichlorophenyl)-5- A100 B (isopropylthio)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylic acid 4-(2-(azetidin-1-yl)-6-methylpyridin-4-yl)-1-(4-(3,4-dichlorophenyl)-5- A101 B (isopropylthio)thiazol-2-yl)-3-methyl-1 H-pyrazole-5-carboxylic acid 1-(4-(3,4-dichlorophenyl)-5-(isopropylthio)thiazol-2-yl)-3-methyl-4-(2- A102 C methyl-6-morpholinopyridin-4-yl)-1 H-pyrazole-5-carboxylic acid 1-(5-(isopropylthio)-4-(3-methoxyphenyl)thiazol-2-yl)-3-methyl-4-(2- A103 G nitrobenzyl)-1 H-pyrazole-5-carboxylic acid

[0202] 1-(4-(3,4-dichlorophenyl)-5-(isopentylthio)thiazol-2-yl)-3-methyl-4-(2- E A104

[0203] nitrobenzyl)-1 H-pyrazole-5-carboxylic acid

[0204] 1-(5-(isopropylthio)-4-(3-methoxyphenyl)thiazol-2-yl)-3-methyl-4-(2- G A105

[0205] (methylsulfonamido)benzyl)-1 H-pyrazole-5-carboxylic acid 1-(5-(sec-butylthio)-4-(3,4-dichlorophenyl)thiazol-2-yl)-3-methyl-4-(2- A106 D nitrobenzyl)-1 H-pyrazole-5-carboxylic acid

[0206] 1-(4-(3,4-dichlorophenyl)-5-(isopropylthio)thiazol-2-yl)-4-(1H-indol-6-yl)-3- E A107

[0207] methyl-1 H-pyrazole-5-carboxylic acid

[0208] 1-(4-(3,4-dichlorophenyl)-5-(isopropylthio)thiazol-2-yl)-3-methyl-4-(3- A108 C nitrophenyl)-1 H-pyrazole-5-carboxylic acid

[0209] 2-(4-(3,4-dichlorophenyl)-5-(isopropylthio)thiazol-2-yl)-5-methyl-4,4'- E A109

[0210] bi(2H-pyrazole)-3-carboxylic acid

[0211] 1-(4-(3,4-dichlorophenyl)-5-(isopropylthio)thiazol-2-yl)-4-(1H-indol-3-yl)-3- A110 D methyl-1 H-pyrazole-5-carboxylic acid

[0212] 4-(2-chlorophenyl)-1-(4-(3,4-dichlorophenyl)-5-(isopropylthio)thiazol-2-yl)- D A111

[0213] 3-methyl-1 H-pyrazole-5-carboxylic acid

[0214] 4-(3-chlorophenyl)-1-(4-(3,4-dichlorophenyl)-5-(isopropylthio)thiazol-2-yl)- A112 B 3-methyl-1 H-pyrazole-5-carboxylic acid

[0215] 4-(4-chlorophenyl)-1-(4-(3,4-dichlorophenyl)-5-(isopropylthio)thiazol-2-yl)- A113 D 3-methyl-1 H-pyrazole-5-carboxylic acid

[0216] 1-(4-(3,4-dichlorophenyl)-5-(isopropylthio)thiazol-2-yl)-4-(2- A114 D methoxyphenyl)-3-methyl-1 H-pyrazole-5-carboxylic acid 1-(4-(3,4-dichlorophenyl)-5-(isopropylthio)thiazol-2-yl)-4-(3- A115 B methoxyphenyl)-3-methyl-1 H-pyrazole-5-carboxylic acid

[0217]

[0218] Cpd Name ECso 1-(4-(3,4-dichlorophenyl)-5-(isopropylthio)thiazol-2-yl)-4-(4- A116 D methoxyphenyl)-3-methyl-1 H-pyrazole-5-carboxylic acid 1-(4-(3,4-dichlorophenyl)-5-(isopropylthio)thiazol-2-yl)-3-methyl-4-o-tolyl- A117 C 1 H-pyrazole-5-carboxylic acid

[0219] 1-(4-(3,4-dichlorophenyl)-5-(isopropylthio)thiazol-2-yl)-3-methyl-4-m-tolyl- A118 B 1 H-pyrazole-5-carboxylic acid

[0220] 1-(4-(3,4-dichlorophenyl)-5-(isopropylthio)thiazol-2-yl)-3-methyl-4-p-tolyl- A119 D 1 H-pyrazole-5-carboxylic acid

[0221] 4-(4-acetamidophenyl)-1-(4-(3,4-dichlorophenyl)-5-(isopropylthio)thiazol- A120 H 2-yl)-3-methyl-1 H-pyrazole-5-carboxylic acid

[0222] 1-(4-(3,4-dichlorophenyl)-5-(isopropylthio)thiazol-2-yl)-3-methyl-4-(2- A121 H (methylsulfonamido)benzyl)-1 H-pyrazole-5-carboxylic acid 1-(4-(3,4-dichlorophenyl)-5-(isopropylthio)thiazol-2-yl)-4-(2-(N, N- A122 D dimethylsulfamoylamino)benzyl)-3-methyl-1 H-pyrazole-5-carboxylic acid

[0223] 4-(4-aminophenyl)-1-(4-(3,4-dichlorophenyl)-5-(isopropylthio)thiazol-2-yl)- A123 E 3-methyl-1 H-pyrazole-5-carboxylic acid

[0224] 1-(4-(3,4-dichlorophenyl)-5-(isopropylthio)thiazol-2-yl)-3-methyl-4-(4- A124 H (methylsulfonamido)phenyl)-1 H-pyrazole-5-carboxylic acid 1-(4-(3,4-dichlorophenyl)-5-(isopropylthio)thiazol-2-yl)-3-methyl-4-(3- A125 H (methylsulfonamido)phenyl)-1 H-pyrazole-5-carboxylic acid 2-(4-(3,4-dichlorophenyl)-5-(isopropylthio)thiazol-2-yl)-2'-(2- A126 D methoxyethyl)-5-methyl-4,4'-bi(2H-pyrazole)-3-carboxylic acid 1-(4-(3,4-dichlorophenyl)-5-(isopropylthio)thiazol-2-yl)-4-(1H-indol-7-yl)-3- A127 C methyl-1 H-pyrazole-5-carboxylic acid

[0225] 2-(4-(1 H-indol-7-yl)-3-methyl-1 H-pyrazol-1 -yl)-4-(3,4-dichlorophenyl)-5- A128 D (isopropylthio)thiazole

[0226] 2-(4-(3,4-dichlorophenyl)-5-(isopropylthio)thiazol-2-yl)-2'-ethyl-5-methyl- A129 C 4,4'-bi(2H-pyrazole)-3-carboxylic acid

[0227] 1-(4-(3,4-dichlorophenyl)-5-(isopropylthio)thiazol-2-yl)-N-(2- A130 H methoxyethyl)-3-methyl-4-m-tolyl-1H-pyrazole-5-carboxamide (4-(aminomethyl)piperidin-1-yl)(1-(4-(3,4-dichlorophenyl)-5- A131 B (isopropylthio)thiazol-2-yl)-3-methyl-4-o-tolyl-1 H-pyrazol-5-yl)methanone

[0228]

[0229] Cpd Name EC50 1-(4-(3,4-dichlorophenyl)-5-(isopropylthio)thiazol-2-yl)-4-(5- A132 D methoxypyridin-3-yl)-3-methyl-1 H-pyrazole-5-carboxylic acid 2-(4-(3,4-dichlorophenyl)-5-(isopropylthio)thiazol-2-yl)-2'-isobutyl-5- A133 D methyl-4,4'-bi(2H-pyrazole)-3-carboxylic acid

[0230] 1-(4-(3,4-dichlorophenyl)-5-(isopropylthio)thiazol-2-yl)-3-methyl-4-(2- A134 D (methylamino)pyridin-4-yl)-1 H-pyrazole-5-carboxylic acid 1-(4-(3,4-dichlorophenyl)-5-(isopropylthio)thiazol-2-yl)-1'- A135 E (dimethylcarbamoyl)-3-methyl-1 H,1'H-[4,4'-bipyrazole]-5-carboxylic acid

[0231] (4-(aminomethyl)piperidin-1-yl)(4-(3,5-bis(trifluoromethyl)phenyl)-1-(4- A136 (3,4-dichlorophenyl)-5-(isopropylthio)thiazol-2-yl)-3-methyl-1 H-pyrazol-5- B yl)methanone

[0232] N-(2-aminoethyl)-4-(3,5-bis(trifluoromethyl)phenyl)-1-(4-(3,4- A137 dichlorophenyl)-5-(isopropylthio)thiazol-2-yl)-N,3-dimethyl-1 H-pyrazole-5- B carboxamide

[0233] (3-aminoazetidin-1-yl)(4-(3,5-bis(trifluoromethyl)phenyl)-1-(4-(3,4- A138 dichlorophenyl)-5-(isopropylthio)thiazol-2-yl)-3-methyl-1H-pyrazol-5- D yl)methanone

[0234] (4-(3,5-bis(trifluoromethyl)phenyl)-1-(4-(3,4-dichlorophenyl)-5- A139 (isopropylthio)thiazol-2-yl)-3-methyl-1H-pyrazol-5- D yl)(morpholino)methanone

[0235] 4-(3,5-bis(trifluoromethyl)phenyl)-1-(4-(3,4-dichlorophenyl)-5- A140 I (isopropylthio)thiazol-2-yl)-N, N,3-trimethyl-1H-pyrazole-5-carboxamide (4-(3,5-bis(trifluoromethyl)phenyl)-1-(4-(3,4-dichlorophenyl)-5- A141 (isopropylthio)thiazol-2-yl)-3-methyl-1 H-pyrazol-5-yl)(4- I (hydroxymethyl)piperidin-1-yl)methanone

[0236] 1-(4-(3,4-dichlorophenyl)-5-isobutylthiazol-2-yl)-1',3-dimethyl-1 H,1'H- A142 B [4,4'-bipyrazole]-5-carboxylic acid

[0237] 1-(4-(3,4-dichlorophenyl)-5-(isopropylthio)thiazol-2-yl)-4-(3,5- A143 B dimethylphenyl)-3-methyl-1 H-pyrazole-5-carboxylic acid 4-(3,5-dichlorophenyl)-1-(4-(3,4-dichlorophenyl)-5-(isopropylthio)thiazol- A144 A 2-yl)-3-methyl-1 H-pyrazole-5-carboxylic acid

[0238] 4-(3-chloro-5-methoxyphenyl)-1-(4-(3,4-dichlorophenyl)-5- B A145

[0239] (isopropylthio)thiazol-2-yl)-3-methyl-1 H-pyrazole-5-carboxylic acid

[0240]

[0241] Cpd Name ECso 1-(4-(3,4-dichlorophenyl)-5-(isopropylthio)thiazol-2-yl)-4-(3-methoxy-5- B A146

[0242] (trifluoromethyl)phenyl)-3-methyl-1H-pyrazole-5-carboxylic acid

[0243] 4-(3-chloro-5-methylphenyl)-1-(4-(3,4-dichlorophenyl)-5- A 147

[0244] (isopropylthio)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylic acid 4-(3,5-bis(trifluoromethyl)phenyl)-1-(4-(3,4-dichlorophenyl)-5- A148 (isopropylthio)thiazol-2-yl)-3-methyl-N-(methylsulfonyl)-1 H-pyrazole-5- I carboxamide

[0245] 1-(4-(3,4-dichlorophenyl)-5-(isopropylthio)thiazol-2-yl)-4-(imidazo[1,2- A149 C a]pyridin-3-yl)-3-methyl-1 H-pyrazole-5-carboxylic acid 4-(3,5-dichlorophenyl)-1-(4-(3,5-dichlorophenyl)-5-(isopropylthio)thiazol- A150 B 2-yl)-3-methyl-1 H-pyrazole-5-carboxylic acid

[0246] 1-(4-(3,4-dichlorophenyl)-5-(isopropylthio)thiazol-2-yl)-4-(3-fluorophenyl)- A151 A, B 3-methyl-1 H-pyrazole-5-carboxylic acid

[0247] 1-(4-(3,4-dichlorophenyl)-5-(isopropylthio)thiazol-2-yl)-4-(3-fluoro-5- A152 C hydroxyphenyl)-3-methyl-1 H-pyrazole-5-carboxylic acid 4-(3-amino-5-methylphenyl)-1-(4-(3,4-dichlorophenyl)-5- A153 J (isopropylthio)thiazol-2-yl)-3-methyl-1 H-pyrazole-5-carboxylic acid

[0248] 4-(3-chloro-5-hydroxyphenyl)-1-(4-(3,4-dichlorophenyl)-5- A154 D (isopropylthio)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylic acid 1-(4-(3,4-dichlorophenyl)-5-(isopropylthio)thiazol-2-yl)-3-methyl-4-(1- A155 C methyl-1 H-indol-7-yl)- 1 H-pyrazole-5-carboxylic acid

[0249] J

[0250] A156 4-(3,4-dichlorophenyl)-5-(isopropylthio)-2-(1H-pyrazol-1-yl)thiazole

[0251] 1-(4-(2 -chlorophenyl)- 5-(isopropylthio)thiazol-2-yl)-4-(2,6-dimethylpyridin- A157 B 4-yl)-3-methyl-1 H-pyrazole-5-carboxylic acid

[0252] 1-(4-(3-chlorophenyl)-5-(isopropylthio)thiazol-2-yl)-4-(2,6-dimethylpyridin- A158 C 4-yl)-3-methyl-1 H-pyrazole-5-carboxylic acid

[0253] 1-(4-(4-chlorophenyl)-5-(isopropylthio)thiazol-2-yl)-4-(2,6-dimethylpyridin- A159 A 4-yl)-3-methyl-1 H-pyrazole-5-carboxylic acid

[0254] 1-(4-(2,4-dichlorophenyl)-5-(isopropylthio)thiazol-2-yl)-4-(2,6- A160 A dimethylpyridin-4-yl)-3-methyl-1 H-pyrazole-5-carboxylic acid

[0255]

[0256] Cpd Name EC50 1-(4-(2,5-dichlorophenyl)-5-(isopropylthio)thiazol-2-yl)-4-(2,6- A161 C dimethylpyridin-4-yl)-3-methyl-1 H-pyrazole-5-carboxylic acid 4-(2,6-dimethylpyridin-4-yl)-1-(5-(isopropylthio)-4-(phenylethynyl)thiazol- A162 C 2-yl)-3-methyl-1 H-pyrazole-5-carboxylic acid

[0257] 1-(4-benzyl-5-(isopropylthio)thiazol-2-yl)-4-(2,6-dimethylpyridin-4-yl)-3- A163 D methyl-1 H-pyrazole-5-carboxylic acid

[0258] 1-(4-(3,4-dichlorophenyl)-5-(isopropylthio)thiazol-2-yl)-4-(3-fluoro-5- A164 B methoxyphenyl)-3-methyl-1 H-pyrazole-5-carboxylic acid 1-(4-(3,4-dichlorophenyl)-5-(isopropylthio)thiazol-2-yl)-4-(3-methoxy-5- A165 B methylphenyl)-3-methyl-1 H-pyrazole-5-carboxylic acid 1-(4-(3,4-dichlorophenyl)-5-(isopropylthio)thiazol-2-yl)-4-(2- A166 C methoxypyridin-4-yl)-3-methyl-1 H-pyrazole-5-carboxylic acid 1-(4-(3,4-dichlorophenyl)-5-(isopropylthio)thiazol-2-yl)-3-methyl-4-(2- A167 B methyl pyrid in-4-yl)-1 H-pyrazole-5-carboxylic acid 1-(4-(1 H-indol-4-yl)-5-(isopropylthio)thiazol-2-yl)-4-(3-fluorophenyl)-3- A168 J methyl-1 H-pyrazole-5-carboxylic acid

[0259] 1-(4-(3-fluorophenyl)-5-(isopropylthio)thiazol-2-yl)-4-(1H-indol-4-yl)-3- A169 J methyl-1 H-pyrazole-5-carboxylic acid

[0260] 1-(4-(1H-indol-5-yl)-5-(isopropylthio)thiazol-2-yl)-4-(3-fluorophenyl)-3- A170 J methyl-1 H-pyrazole-5-carboxylic acid

[0261] 1-(4-(cyclopropylethynyl)-5-(isopropylthio)thiazol-2-yl)-4-(3-fluorophenyl)- A171 J 3-methyl-1 H-pyrazole-5-carboxylic acid

[0262] 4-cyclopropyl-1-(4-cyclopropyl-5-(isopropylthio)thiazol-2-yl)-3-methyl-1H- A172 J pyrazole-5-carboxylic acid

[0263] 4-cyclopropyl-1-(4-(3,4-dichlorophenyl)-5-(isopropylthio)thiazol-2-yl)-3- A173 D methyl-1 H-pyrazole-5-carboxylic acid

[0264] 4-(3-chloro-5-isopropoxyphenyl)-1-(4-(3,4-dichlorophenyl)-5- A174 B (isopropylthio)thiazol-2-yl)-3-methyl-1 H-pyrazole-5-carboxylic acid 4-(3-chloro-5-(2-methoxyethoxy)phenyl)-1-(4-(3,4-dichlorophenyl)-5- A175 B (isopropylthio)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylic acid 1-(4-(3-chlorophenyl)-5-(isopropylthio)thiazol-2-yl)-4-(3-fluorophenyl)-3- A176 C methyl-1 H-pyrazole-5-carboxylic acid

[0265]

[0266] Cpd Name EC50 1-(4-(4-chlorophenyl)-5-(isopropylthio)thiazol-2-yl)-4-(3-fluorophenyl)-3- A177 A methyl-1 H-pyrazole-5-carboxylic acid

[0267] 1-(4-(2,4-dichlorophenyl)-5-(isopropylthio)thiazol-2-yl)-4-(3-fluorophenyl)- A178 B 3-methyl-1 H-pyrazole-5-carboxylic acid

[0268] 4-bromo-1-(4-(6-(3-fluorophenyl)pyridin-3-yl)-5-(isopropylthio)thiazol-2- A179 E yl)-3-methyl-1 H-pyrazole-5-carboxylic acid

[0269] (R)-1-(4-(3,4-dichlorophenyl)-5-(isopropylthio)thiazol-2-yl)-3-methyl-4-(2- A180 methyl-6-((tetrahydrofuran-3-yl)oxy)pyridin-4-yl)-1 H-pyrazole-5-carboxylic D acid

[0270] 1-(4-(3,4-dichlorophenyl)-5-(isopropylthio)thiazol-2-yl)-4-(2-(2- A181 methoxyethoxy)-6-methylpyridin-4-yl)-3-methyl-1H-pyrazole-5-carboxylic D acid

[0271] (S)-1-(4-(3,4-dichlorophenyl)-5-(isopropylthio)thiazol-2-yl)-3-methyl-4-(2- A182 methyl-6-((tetrahydrofuran-3-yl)oxy)pyridin-4-yl)-1 H-pyrazole-5-carboxylic D acid

[0272] 1-(4-(cyclohex-1-en-1-yl)-5-(isopropylthio)thiazol-2-yl)-4-(3-fluorophenyl)- A183 C 3-methyl-1 H-pyrazole-5-carboxylic acid

[0273] 1-(4-(cyclopent-1-en-1-yl)-5-(isopropylthio)thiazol-2-yl)-4-(3-fluorophenyl)- A184 D 3-methyl-1 H-pyrazole-5-carboxylic acid

[0274] 4-(3-chloro-5-methoxyphenyl)-1-(5-(isopropylthio)-4-phenylthiazol-2-yl)-3- A185 D methyl-1 H-pyrazole-5-carboxylic acid

[0275] 4-(3-fluorophenyl)-1-(4-(4-fluorophenyl)-5-(isopropylthio)thiazol-2-yl)-3- A186 B methyl-1 H-pyrazole-5-carboxylic acid

[0276] 4-(3-fluorophenyl)-1-(5-(isopropylthio)-4-(4-methoxyphenyl)thiazol-2-yl)-3- A187 D methyl-1 H-pyrazole-5-carboxylic acid

[0277] 4-(3-fluorophenyl)-1-(5-(isopropylthio)-4-(4- A188 (methylsulfonyl)phenyl)thiazol-2-yl)-3-methyl-1 H-pyrazole-5-carboxylic I acid

[0278] 1-(4-(4-fluoro-3-methoxyphenyl)-5-(isopropylthio)thiazol-2-yl)-4-(3- A189 D fluorophenyl)-3-methyl-1 H-pyrazole-5-carboxylic acid 1-(4-(4-chloro-3-methylphenyl)-5-(isopropylthio)thiazol-2-yl)-4-(2,6- A190 B dimethylpyridin-4-yl)-3-methyl- 1 H-pyrazole-5-carboxylic acid 1-(4-(4-chloro-3-methylphenyl)-5-(isopropylthio)thiazol-2-yl)-4-(3- A191 B fluorophenyl)-3-methyl-1 H-pyrazole-5-carboxylic acid

[0279]

[0280] Cpd Name EC50 1-(4-(4-chloro-3,5-difluorophenyl)-5-(isopropylthio)thiazol-2-yl)-4-(2,6- A192 B dimethylpyridin-4-yl)-3-methyl-1 H-pyrazole-5-carboxylic acid 1-(4-(4-chloro-3,5-difluorophenyl)-5-(isopropylthio)thiazol-2-yl)-4-(3- A193 fluorophenyl)-3-methyl-1 H-pyrazole-5-carboxylic acid B

[0281] 1-(4-(4-chloro-3-methoxyphenyl)-5-(isopropylthio)thiazol-2-yl)-4-(2,6- A194 B dimethylpyridin-4-yl)-3-methyl-1 H-pyrazole-5-carboxylic acid 1-(4-(4-chloro-3-methoxyphenyl)-5-(isopropylthio)thiazol-2-yl)-4-(3- A195 C fluorophenyl)-3-methyl-1 H-pyrazole-5-carboxylic acid 4-(2,6-dimethylpyridin-4-yl)-1-(5-(isopropylthio)-4-(4- A196 (trifluoromethyl)phenyl)thiazol-2-yl)-3-methyl-1 H-pyrazole-5-carboxylic B acid

[0282] 4-(3-fluorophenyl)-1-(5-(isopropylthio)-4-(4-(trifluoromethyl)phenyl)thiazol- A197 A 2-yl)-3-methyl-1 H-pyrazole-5-carboxylic acid

[0283] 1-(4-(3,4-dichlorophenyl)-5-(isopropylthio)thiazol-2-yl)-3-methyl-4-(3- A198 B methyl-5-(oxetan-3-yloxy)phenyl)-1 H-pyrazole-5-carboxylic acid 1-(4-(3,4-dichlorophenyl)-5-(isopropylthio)thiazol-2-yl)-4-(2-methoxy-6- A199 B methylpyridin-4-yl)-3-methyl-1 H-pyrazole-5-carboxylic acid 1-(4-(3,4-dichlorophenyl)-5-(isopropylthio)thiazol-2-yl)-4-(3-fluoro-5- A200 B (oxetan-3-yloxy)phenyl)-3-methyl-1 H-pyrazole-5-carboxylic acid A201 4-(3-fluorophenyl)-1-(4-(3-fluorophenyl)-5-(isopropylthio)thiazol-2-yl)-3- E

[0284] a methyl-1 H-pyrazole-5-carboxylic acid

[0285] A201 1-(4-(benzofuran-2-yl)-5-(isopropylthio)thiazol-2-yl)-4-(3-fluorophenyl)-3- D

[0286] b methyl-1 H-pyrazole-5-carboxylic acid

[0287] 4-(3-fluorophenyl)-1-(5-(isopropylthio)-4-phenylthiazol-2-yl)-3-methyl-1 H- A202 D pyrazole-5-carboxylic acid

[0288] 1-(5-(isopropylthio)-4-phenylthiazol-2-yl)-1',3-dimethyl-1 H,1'H-[4,4'- A203 I bipyrazole]-5-carboxylic acid

[0289] 4-(2,6-dimethylpyridin-4-yl)-1-(4-(4-fluorophenyl)-5-(isopropylthio)thiazol- A204 B 2-yl)-3-methyl-1 H-pyrazole-5-carboxylic acid

[0290] 1-(4-(4-chloro-2-methoxyphenyl)-5-(isopropylthio)thiazol-2-yl)-4-(3- A205 B fluorophenyl)-3-methyl-1 H-pyrazole-5-carboxylic acid

[0291]

[0292] Cpd Name EC50 1-(4-(4-chloro-2-methoxyphenyl)-5-(isopropylthio)thiazol-2-yl)-4-(2,6- A206 B dimethylpyridin-4-yl)-3-methyl-1 H-pyrazole-5-carboxylic acid 1-(4-(3-chloro-4-methylphenyl)-5-(isopropylthio)thiazol-2-yl)-4-(3- A207 C fluorophenyl)-3-methyl-1 H-pyrazole-5-carboxylic acid 1-(4-(1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-yl)-5-(isopropylthio)thiazol- A208 I 2-yl)-4-(3-fluorophenyl)-3-methyl-1 H-pyrazole-5-carboxylic acid 1-(4-(2-chloro-5-(trifluoromethoxy)phenyl)-5-(isopropylthio)thiazol-2-yl)-4- A209 D (3-fluorophenyl)-3-methyl-1 H-pyrazole-5-carboxylic acid 1-(4-(5-cyanopyridin-3-yl)-5-(isopropylthio)thiazol-2-yl)-4-(3-fluorophenyl)- A210 I 3-methyl-1 H-pyrazole-5-carboxylic acid

[0293] 1-(4-(1,3-dimethyl-1H-pyrazol-5-yl)-5-(isopropylthio)thiazol-2-yl)-4-(3- A211 I fluorophenyl)-3-methyl-1H-pyrazole-5-carboxylic acid 4-(3-fluorophenyl)-1-(5-(isopropylthio)-4-(pyrimidin-5-yl)thiazol-2-yl)-3- A212 I methyl-1 H-pyrazole-5-carboxylic acid

[0294] 1-(4-(4-cyanophenyl)-5-(isopropylthio)thiazol-2-yl)-4-(3-fluorophenyl)-3- A213 C- methyl-1 H-pyrazole-5-carboxylic acid

[0295] 1-(4-(3-fluoro-4-methylphenyl)-5-(isopropylthio)thiazol-2-yl)-4-(3- A214 B fluorophenyl)-3-methyl-1 H-pyrazole-5-carboxylic acid 1-(4-(2-cyanophenyl)-5-(isopropylthio)thiazol-2-yl)-4-(3-fluorophenyl)-3- A215 E methyl-1 H-pyrazole-5-carboxylic acid

[0296] 1-(4-(4-chloro-2-methylphenyl)-5-(isopropylthio)thiazol-2-yl)-4-(3- A216 A fluorophenyl)-3-methyl-1 H-pyrazole-5-carboxylic acid 4-(3-fluorophenyl)-1-(5-(isopropylthio)-4-(2-methyl-4- A217 (trifluoromethyl)phenyl)thiazol-2-yl)-3-methyl-1 H-pyrazole-5-carboxylic A acid

[0297] 1-(4-(4-chloro-3-cyanophenyl)-5-(isopropylthio)thiazol-2-yl)-4-(3- A218 C fluorophenyl)-3-methyl-1 H-pyrazole-5-carboxylic acid 4-(3,5-dichlorophenyl)-1-(5-(isopropylthio)-4-(4- A219 (trifluoromethyl)phenyl)thiazol-2-yl)-3-methyl-1 H-pyrazole-5-carboxylic A acid

[0298] 4-(3-fluorophenyl)-1-(5-(isopropylthio)-4-(4-((2- A220 methoxyethyl)carbamoyl)phenyl)thiazol-2-yl)-3-methyl-1 H-pyrazole-5- I carboxylic acid

[0299]

[0300] Cpd Name EC50 1-(4-(4-(dimethylcarbamoyl)phenyl)-5-(isopropylthio)thiazol-2-yl)-4-(3- A221 I fluorophenyl)-3-methyl-1 H-pyrazole-5-carboxylic acid 4-(3-chloro-5-methoxyphenyl)-1-(5-(isopropylthio)-4-(4- A222 (trifluoromethyl)phenyl)thiazol-2-yl)-3-methyl-1 H-pyrazole-5-carboxylic A acid

[0301] 4-(3-fluorophenyl)-1-(5-(isopropylthio)-4-(4- A223 (trifluoromethoxy)phenyl)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylic B acid

[0302] 4-(3-fluorophenyl)-1-(5-(isopropylthio)-4-(2-methyl-4- A224 (trifluoromethoxy)phenyl)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylic A acid

[0303] 4-(3-chloro-5-fluorophenyl)-1-(4-(3,4-dichlorophenyl)-5- A225 A (isopropylthio)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylic acid 1-(4-(4-cyano-3-methylphenyl)-5-(isopropylthio)thiazol-2-yl)-4-(3- A226 C fluorophenyl)-3-methyl-1 H-pyrazole-5-carboxylic acid 1-(4-(3,4-dichlorophenyl)-5-fluorothiazol-2-yl)-4-(3-fluorophenyl)-3- A227 D methyl-1 H-pyrazole-5-carboxylic acid

[0304] 1-(4-(3,4-dichlorophenyl)-5-(isopropylthio)thiazol-2-yl)-4-(3-fluorophenyl)- A228 B 3-isopropyl-1 H-pyrazole-5-carboxylic acid

[0305] 1-(4-(4-(difluoromethyl)phenyl)-5-(isopropylthio)thiazol-2-yl)-4-(3- A229 B fluorophenyl)-3-methyl-1 H-pyrazole-5-carboxylic acid 1-(4-(3,4-dichlorophenyl)-5-isopropoxythiazol-2-yl)-4-(3-fluorophenyl)-3- A230 methyl-1 H-pyrazole-5- C carboxylic acid

[0306] 1-(4-(4-ethylphenyl)-5-(isopropylthio)thiazol-2-yl)-4-(3-fluorophenyl)-3- A231 B methyl-1 H-pyrazole-5-carboxylic acid

[0307] 2-(4-(2,6-dimethylpyridin-4-yl)-3,5-dimethyl-1 H-pyrazol-1-yl)-5- A232 E (isopropylthio)-4-(4-(trifluoromethyl)phenyl)thiazole 4-(3-fluorophenyl)-1-(4-(5-fluoropyridin-3-yl)-5-(isopropylthio)thiazol-2-yl)- A233 I 3-methyl-1 H-pyrazole-5-carboxylic acid

[0308] 1-(4-(benzofuran-3-yl)-5-(isopropylthio)thiazol-2-yl)-4-(3-fluorophenyl)-3- A234 I methyl-1 H-pyrazole-5-carboxylic acid

[0309]

[0310] Cpd Name EC50 4-(3,4-difluorophenyl)-1-(5-(isopropylthio)-4-(4- A235 (trifluoromethyl)phenyl)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylic A acid

[0311] 4-(4-fluoro-3-methylphenyl)-1-(5-(isopropylthio)-4-(4- A236 (trifluoromethyl)phenyl)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylic B acid

[0312] 4-(4-fluorophenyl)-1-(5-(isopropylthio)-4-(4-(trifluoromethyl)phenyl)thiazol- A237 B 2-yl)-3-methyl-1 H-pyrazole-5-carboxylic acid

[0313] 4-(4-fluoro-3-methoxyphenyl)-1-(5-(isopropylthio)-4-(4- A238 (trifluoromethyl)phenyl)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylic B acid

[0314] 1-(4-(4-chloro-2,6-dimethylphenyl)-5-(isopropylthio)thiazol-2-yl)-4-(3- A239 C fluorophenyl)-3-methyl-1 H-pyrazole-5-carboxylic acid 1-(4-(4-(1,1-difluoroethyl)phenyl)-5-(isopropylthio)thiazol-2-yl)-4-(3- A240 B fluorophenyl)-3-methyl-1 H-pyrazole-5-carboxylic acid 4-(4-fluoro-3,5-dimethylphenyl)-1-(5-(isopropylthio)-4-(4- A241 (trifluoromethyl)phenyl)thiazol-2-yl)-3-methyl-1 H-pyrazole-5-carboxylic A acid

[0315] 4-(3-fluorophenyl)-1-(5-(isopropylthio)-4-(2-(trifluoromethyl)pyrimidin-5- A242 C yl)thiazol-2-yl)-3-methyl-1 H-pyrazole-5-carboxylic acid 1-(4-(4-chloro-3-(ethylcarbamoyl)phenyl)-5-(isopropylthio)thiazol-2-yl)-4- A243 I (3-fluorophenyl)-3-methyl-1 H-pyrazole-5-carboxylic acid 1-(4-(2-amino-4-(trifluoromethyl)phenyl)-5-(isopropylthio)thiazol-2-yl)-4- A244 B (3-fluorophenyl)-3-methyl-1 H-pyrazole-5-carboxylic acid

[0316] 4-(3-fluorophenyl)-1-(5-(isopropylthio)-4-((4- A245 (trifluoromethyl)phenyl)ethynyl)thiazol-2-yl)-3-methyl-1 H-pyrazole-5- D carboxylic acid

[0317] 4-(3-fluorophenyl)-1-(5-(isopropylthio)-4-(5-(trifluoromethyl)pyrimidin-2- A246 D yl)thiazol-2-yl )-3-methyl-1 H-pyrazole-5-carboxylic acid 4-(3-fluorophenyl)-3-methyl-1-(4-(4-(trifluoromethyl)phenyl)thiazol-2-yl)- A247 D 1 H-pyrazole-5-carboxylic acid

[0318] 4-(3-fluorophenyl)-1-(5-(isopropylthio)-4-(4-(trifluoromethyl)phenyl)thiazol- A248 K 2-yl)-N-(2-methoxyethyl)-N,3-dimethyl-1 H-pyrazole-5-carboxamide

[0319]

[0320] Cpd Name EC50 N-(2-(2-(2-(2-azidoethoxy)ethoxy)ethoxy)ethyl)-4-(3-fluorophenyl)-1-(5- A249 (isopropylthio)-4-(4-(trifluoromethyl)phenyl)thiazol-2-yl)-3-methyl-1 H- K pyrazole-5-carboxamide

[0321] 4-(3-fluorophenyl)-1-(5-(isopropylthio)-4-(4-(trifluoromethyl)phenyl)thiazol- A250 D

[0322] 2-yl)-N-(2-methoxyethyl)-3-methyl-1H-pyrazole-5-carboxamide

[0323] 4-(3-fluorophenyl)-1-(5-(isopropylthio)-4-(4-(trifluoromethyl)phenyl)thiazol- A251 K

[0324] 2-yl)-3-methyl-N-(propylsulfonyl)-1H-pyrazole-5-carboxamide

[0325] 4-(3-fluorophenyl)-1-(5-(isopropylthio)-4-(2-(trifluoromethyl)phenyl)thiazol- A252 D

[0326] 2-yl)-3-methyl-1 H-pyrazole-5-carboxylic acid

[0327] 4-(3-fluorophenyl)-1-(5-(isopropylthio)-4-(3-(trifluoromethyl)phenyl)thiazol- A253 C

[0328] 2-yl)-3-methyl-1 H-pyrazole-5-carboxylic acid

[0329] 4-(3-fluorophenyl)-1-(5-(isopropylamino)-4-(4- A254 (trifluoromethyl)phenyl)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylic C acid

[0330] 4-(3-fluorophenyl)-1-(5-(isopropylthio)-4-(4-(pentafluoro-A6- A255 A sulfaneyl)phenyl)thiazol-2-yl)-3-methyl-1 H-pyrazole-5-carboxylic acid

[0331] 4-(3-fluorophenyl)-1-(5-(isopropylthio)-4-(4-(trifluoromethyl)phenyl)thiazol- A256 D

[0332] 2-yl)-N-methoxy-3-methyl-1 H-pyrazole-5-carboxamide

[0333] 4-(3-fluorophenyl)-1-(5-(isopropylthio)-4-(4-(2,2,2- A257 B trifluoroethyl)phenyl)thiazol-2-yl)-3-methyl-1 H-pyrazole-5-carboxylic acid

[0334] 4-(3-fluorophenyl)-1-(5-(isopropylthio)-4-(6-(trifluoromethyl)pyridin-3- A258 B yl)thiazol-2-yl)-3-methyl-1 H-pyrazole-5-carboxylic acid

[0335] 4-(3-fluorophenyl)-1-(5-(isopropylthio)-4-(1-(2,2,2-trifluoroethyl)-1H- A259 D pyrazol-4-yl)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylic acid

[0336]

[0337]

[0062] In various embodiments, the 0MA1 activator is one of the compounds of Compound Table 2 below, optionally provided as a pharmaceutically-acceptable salt, and optionally provided as an N-oxide, and / or a solvate or hydrate of the compound or salt. BJAB (malignant human B-cell-line) cell proliferation data is presented in the table; “A” indicates a measured EC50 less than or equal to 1 pM; “B” indicates a measured EC50 greater than 1 pM and less than or equal to 5 pM; “C” indicates a measured EC50 greater than 5 pM and less than or equal to 10 pM; “D” indicates a measured EC50 greater than 10 pM and less than or equal to 25 pM; “E” indicates a measured EC50 greater than 25 pM and less than or equal to 50 pM; “F” indicates ameasured EC50 greater than 50 pM and less than or equal to 100 pM; “G” indicates that in the experiments performed there was no measured EC50 less than or equal to 80 pM; “H” indicates that in the experiments performed there was no measured EC50 less than or equal to 50 pM; “I” indicates that in the experiments performed there was no measured EC50 less than or equal to 40 pM; “J” indicates that in the experiments performed there was no measured EC50 less than or equal to 25 pM; “K” indicates that in the experiments performed there was no measured EC50 less than or equal to 20 pM; and “L” indicates that in the experiments performed there was no measured EC50 less than or equal to 5 pM. In certain embodiments, the OMA1 activator is a compound having an activity as “A,” “B” or “C” in Compound Table 2 below. In certain embodiments, the OMA1 activator is a compound having an activity as “A” or “B” in Compound Table 2 below. In certain embodiments, the OMA1 activator is a compound having an activity as “A” in Compound Table 2 below.

[0338] Compound Table 2

[0339] Cpd Name BJAB

[0340] 1-(4-(4-chloro-2-(oxetan-3-yloxy)phenyl)-5-(isopropylthio)thiazol-2- B1 I

[0341] yl)-3-methyl-1 H-pyrazole-5-carboxylic acid

[0342] 1-(4-(4-chloro-3-(oxetan-3-yloxy)phenyl)-5-(isopropylthio)thiazol-2- B2 I

[0343] yl)-3-methyl-1 H-pyrazole-5-carboxylic acid

[0344] 4-(3-fluorophenyl)-1 -(5-(isopropylthio)-4-(4-(5-methyl-1,3,4- B3 oxadiazol-2-yl)phenyl)thiazol-2-yl)-3-methyl-1 H-pyrazole-5- E carboxylic acid

[0345] 4-(3-fluorophenyl)-1-(5-(isopropylthio)-4-(4-methyl cyclohex-1 -en-1- B4 B yl)thiazol-2-yl)-3-methyl-1 H-pyrazole-5-carboxylic acid

[0346] 4-(3-fluorophenyl)-1-(5-(isopropylthio)-4-(4- B5 (trifluoromethyl)cyclohex-1-en-1-yl)thiazol-2-yl)-3-methyl-1H- A pyrazole-5-carboxylic acid

[0347] 1-(4-(4,4-dimethylcyclohex-1-en-1-yl)-5-(isopropylthio)thiazol-2-yl)- B6 A

[0348] 4-(3-fluorophenyl)-3-methyl-1 H-pyrazole-5-carboxylic acid

[0349] 4-(3-fluorophenyl)-1-(5-(isopropylthio)-4-(1,4-dioxaspiro[4.5]dec-7- B7 E

[0350] en-8-yl)thiazol-2-yl)-3-methyl-1 H-pyrazole-5-carboxylic acid

[0351] 1-(4-(4-chloro-3-(morpholine-4-carbonyl)phenyl)-5- B8 (isopropylthio)thiazol-2-yl)-4-(3-fluorophenyl)-3-methyl-1H-pyrazole- I

[0352] 5-carboxylic acid

[0353] 4-(3,4-dichlorophenyl)-2-(4-(2,6-dimethylpyridin-4-yl)-3-methyl-1 H- B9 A, C, L pyrazol-1-yl)-5-(isopropylthio)thiazole

[0354] 2-(4-(3-fluorophenyl)-3,5-dimethyl-1 H-pyrazol-1-yl)-5- B10 I (isopropylthio)-4-(4-(trifluoromethyl)phenyl)thiazole

[0355] 4-(3-fluorophenyl)-1-(5-(isopropylthio)-4-(piperidin-1-yl)thiazol-2-yl)- B11 D

[0356] 3-methyl-1 H-pyrazole-5-carboxylic acid

[0357] 4-(3-fluorophenyl)-1-(5-(isopropylthio)-4-(4- B12 (trifluoromethyl)piperidin-1-yl)thiazol-2-yl)-3-methyl-1H-pyrazole-5- A

[0358]

[0359] carboxylic acidCpd Name BJAB 4-(3-fluorophenyl)-1-(5-(isopropylthio)-4-(4- B13 (trifluoromethyl)phenyl)thiazol-2-yl)-3-methoxy-1H-pyrazole-5- B carboxylic acid

[0360] 4-(3-fluorophenyl)-1-(5-(isopropylthio)-4-morpholinothiazol-2-yl)-3- B14 I methyl-1 H-pyrazole-5-carboxylic acid

[0361] 4-(3-fluorophenyl)-3-hydroxy-1-(5-(isopropylthio)-4-(4- B15 K (trifluoromethyl)phenyl)thiazol-2-yl)-1 H-pyrazole-5-carboxylic acid 1-(5-(3,4-dichlorophenyl)-1-isobutyl-1H-1,2,4-triazol-3-yl)-4-(3- B16 K fluorophenyl)-3-methyl-1 H-pyrazole-5-carboxylic acid 1-(3-(3,4-dichlorophenyl)-1-isobutyl-1H-1,2,4-triazol-5-yl)-4-(3- B17 K fiuorophenyl)-3-methyl-1 H-pyrazole-5-carboxylic acid 1 -(4-(4,4-difluoropiperidin-1 -yl)-5-(isopropylthio)thiazol-2-yl)-4-(3- B18 B fluorophenyl)-3-methyl-1 H-pyrazole-5-carboxylic acid methyl 4-(3-fluorophenyl)-1-(5-(isopropylthio)-4-(4- B19 (trifluoromethyl)cyclohex-1-en-1-yl)thiazol-2-yl)-3-methyl-1H- A pyrazole-5-carboxylate (enantiopure - unknown stereochemistry) methyl 4-(3-fluorophenyl)-1-(5-(isopropylthio)-4-(4- B20 (trifluoromethyl)cyclohex-1-en-1-yl)thiazol-2-yl)-3-methyl-1H- A pyrazole-5-carboxylate (enantiopure - unknown stereochemistry)

[0362] 4-(3-fluorophenyl)-3-methyl-1-(4-(4- B21 (trifluoromethyl)cyclohexyl)thiazol-2-yl)-1H-pyrazole-5-carboxylic K acid

[0363] 4-(3-fluorophenyl)-1-(5-isobutyl-4-(4-(trifluoromethyl)phenyl)thiazol- B22 A 2-yl)-3-methyl-1 H-pyrazole-5-carboxylic acid

[0364] 4-(3-fluorophenyl)-1-(5-(isopropylthio)-4-(4-(2,2,2- B23 trifluoroethyl)piperazin-1-yl)thiazol-2-yl)-3-methyl-1 H-pyrazole-5- C carboxylic acid

[0365] 1-(4-(4-cyanopiperidin-1-yl)-5-(isopropylthio)thiazol-2-yl)-4-(3- B24 D fluorophenyl)-3-methyl-1 H-pyrazole-5-carboxylic acid 1-(4-(4-cyclopropylpiperazin-1-yl)-5-(isopropylthio)thiazol-2-yl)-4-(3- B25 C fluorophenyl)-3-methyl-1 H-pyrazole-5-carboxylic acid 1-(4-(4-ethylpiperazin-1-yl)-5-(isopropylthio)thiazol-2-yl)-4-(3- B26 K fluorophenyl)-3-methyl-1 H-pyrazole-5-carboxylic acid 1-(4-(4-acetylpiperazin-1-yl)-5-(isopropylthio)thiazol-2-yl)-4-(3- B27 K fluorophenyl)-3-methyl-1 H-pyrazole-5-carboxylic acid 4-(3-fluorophenyl)-1-(5-(isopropylthio)-4-(4-methylpiperidin-1- B28 B yl)thiazol-2-yl)-3-methyl-1 H-pyrazole-5-carboxylic acid 4-(3-fluorophenyl)-1-(5-(isopropylthio)-4-(4-methylpiperazin-1- B29 yl)thiazol-2-yl)-3-methyl-1 H-pyrazole-5-carboxylic acid

[0366] 4-(3-fluorophenyl)-3-methyl-1-(5-(4-(trifluoromethyl)phenyl)-1,3,4- B30 K thiadiazol-2-yl)-1H-pyrazole-5-carboxylic acid

[0367] 4-(3-fluorophenyl)-1-(5-((2-methoxyethyl)(methyl)amino)-4-(4- B31 (trifluoromethyl)phenyl)thiazol-2-yl)-3-methyl-1 H-pyrazole-5- B carboxylic acid

[0368] 1-(4-(4,4-dimethylpiperidin-1-yl)-5-(isopropylthio)thiazol-2-yl)-4-(3- B32 fluorophenyl)-3-methyl-1 H-pyrazole-5-carboxylic acid A

[0369]

[0370] Cpd Name BJAB 1-(4-(4-(tert-butoxycarbonyl)piperazin-1-yl)-5-(isopropylthio)thiazol- B33 K 2-yl)-4-(3-fluorophenyl)-3-methyl-1H-pyrazole-5-carboxylic acid

[0371] 4-(3-fluorophenyl)-1-(5-(isopropylthio)-4-(3- B34 (trifluoromethyl)pyrrolidin-l -yl)thiazol-2-yl)-3-methyl-1 H-pyrazole-5- B carboxylic acid

[0372] 4-(3-fluorophenyl)-1-(5-(isopropylthio)-4-(piperazin-1-yl)thiazol-2-yl)- B35 K 3-methyl-1 H-pyrazole-5-carboxylic acid hydrochloric acid salt 4-(3-fluorophenyl)-3-methyl-1 -(5-(2-methylprop-1 -en-1 -y I )-4-(4- B36 A (trifluoromethyl)phenyl)thiazol-2-yl)-1 H-pyrazole-5-carboxylic acid 4-(3-fluorophenyl)-3-methyl-1 -(4-(2-methylprop-1 -en-1 -yl)-5-(4- B37 D (trifluoromethyl)phenyl)thiazol-2-yl)-1 H-pyrazole-5-carboxylic acid 1-(4,5-bis(4-(trifluoromethyl)phenyl)thiazol-2-yl)-4-(3-fluorophenyl)- B38 A 3-methyl-1 H-pyrazole-5-carboxylic acid

[0373] 2-(4-(3-fluorophenyl)-3-methyl-1 H-pyrazol-1 -yl )-4, 5-bis(4- B39 K (trifluoromethyl)phenyl)thiazole

[0374] 1-(4-(4-(tert-butyl)piperidin-1-yl)-5-(isopropylthio)thiazol-2-yl)-4-(3- B40 A fluorophenyl)-3-methyl-1 H-pyrazole-5-carboxylic acid 4-(3-fluorophenyl)-1-(5-(isopropylthio)-4-(6-azaspiro[2.5]octan-6- B41 B yl)thiazol-2-yl)-3-methyl-1 H-pyrazole-5-carboxylic acid 4-(3-fluorophenyl)-1-(5-(isopropylthio)-4-(4-methoxy-4- B42 (trifluoromethyl)piperidin-1-yl)thiazol-2-yl)-3-methyl-1H-pyrazole-5- A carboxylic acid

[0375] 4-(3-fluorophenyl)-1-(4-(4-methoxyphenyl)-5-(4- B43 (trifluoromethyl)phenyl)thiazol-2-yl)-3-methyl-1 H-pyrazole-5- B carboxylic acid

[0376] 1-(4,5-bis(4-methoxyphenyl)thiazol-2-yl)-4-(3-fluorophenyl)-3- B44 D methyl-1 H-pyrazole-5-carboxylic acid

[0377] 4-(3-fluorophenyl)-1-(5-(4-methoxyphenyl)-4-(4- B45 (trifluoromethyl)phenyl)thiazol-2-yl)-3-methyl-1 H-pyrazole-5- A carboxylic acid

[0378] 1-(4-(4-(tert-butyl)-3-oxopiperazin-1-yl)-5-(isopropylthio)thiazol-2-yl)- B46 K 4-(3-fluorophenyl)-3-methyl-1 H-pyrazole-5-carboxylic acid 4-(3-fluorophenyl)-3-methyl-1-(5-(3-(methylamino)-3-oxopropyl)-4- B47 (4-(trifluoromethyl)phenyl)thiazol-2-yl)-1H-pyrazole-5-carboxylic K acid

[0379] 4-(3-fluorophenyl)-1-(5-(isopropylthio)-4-(4-(2-methoxyethoxy)-4- B48 (trifluoromethyl)piperidin-1-yl)thiazol-2-yl)-3-methyl-1 H-pyrazole-5- B carboxylic acid

[0380] 4-(3-fluorophenyl)-1-(5-(4-((2-methoxyethyl)carbamoyl)phenyl)-4-(4- B49 (trifluoromethyl)phenyl)thiazol-2-yl)-3-methyl-1 H-pyrazole-5- K carboxylic acid

[0381] 4-(3-fluorophenyl)-1 -(5-(4-((2- methoxyethyl)(methyl)carbamoyl)phenyl)-4-(4- B50 K (trifluoromethyl)phenyl)thiazol-2-yl)-3-methyl-1 H-pyrazole-5- carboxylic acid

[0382] 4-(3-fluorophenyl)-1-(5-(4-(2-methoxyacetamido)phenyl)-4-(4- B51 (trifluoromethyl)phenyl)thiazol-2-yl)-3-methyl-1 H-pyrazole-5- D

[0383]

[0384] carboxylic acidCpd Name BJAB 4-(3-fluorophenyl)-1-(5-(4-(2-(2-methoxyethoxy)acetamido)phenyl)- B52 4-(4-(trifluoromethyl)phenyl)thiazol-2-yl)-3-methyl-1H-pyrazole-5- D carboxylic acid

[0385] 4-(3-fluorophenyl)-1-(5-(3-((2-methoxyethyl)amino)-3-oxopropyl)-4- B53 (4-(trifluoromethyl)phenyl)thiazol-2-yl)-3-methyl-1 H-pyrazole-5- K carboxylic acid

[0386] 4-(3-fluorophenyl)-1-(5-(3-((2-methoxyethyl)(methyl)amino)-3- B54 oxopropyl)-4-(4-(trifluoromethyl)phenyl)thiazol-2-yl)-3-methyl-1H- K pyrazole-5-carboxylic acid

[0387] 4-(3-fluorophenyl)-1-(5-(4-(2-methoxy-N-methylacetamido)phenyl)- B55 4-(4-(trifluoromethyl)phenyl)thiazol-2-yl)-3-methyl-1H-pyrazole-5- K carboxylic acid

[0388] 4-(3-fluorophenyl)-1-(5-(4-(2-(2-methoxyethoxy)-N- B56 methylacetamido)phenyl)-4-(4-(trifluoromethyl)phenyl)thiazol-2-yl)- K 3-methyl-1 H-pyrazole-5-carboxylic acid

[0389] 4-(3-fluorophenyl)-1-(5-(methoxymethyl)-4-(4- B57 (trifluoromethyl)phenyl)thiazol-2-yl)-3-methyl-1 H-pyrazole-5- C carboxylic acid

[0390] 1-(5-(4-(2-(2-ethoxyethoxy)ethoxy)phenyl)-4-(4- B58 (trifluoromethyl)phenyl)thiazol-2-yl)-4-(3-fluorophenyl)-3-methyl-1 H- B pyrazole-5-carboxylic acid

[0391] 4-(3-fluorophenyl)-1-(5-(3-fluorophenyl)-4-(4- B59 (trifluoromethyl)phenyl)thiazol-2-yl)-3-methyl-1 H-pyrazole-5- A carboxylic acid

[0392] 4-(3-fluorophenyl)-1-(5-(hydroxymethyl)-4-(4- B60 (trifluoromethyl)phenyl)thiazol-2-yl)-3-methyl-1 H-pyrazole-5- K carboxylic acid

[0393] 4-(3-fluorophenyl)-3-methyl-1-(5-(4-(trifluoromethyl)phenyl)-4-(4- B61 (trifluoromethyl)piperidin-1-yl)thiazol-2-yl)-1H-pyrazole-5-carboxylic A acid

[0394] 4-(3-fluorophenyl)-1-(4-(3-fluorophenyl)-5-(4- B62 (trifluoromethyl)phenyl)thiazol-2-yl)-3-methyl-1 H-pyrazole-5- C carboxylic acid

[0395] 4-(3-fluorophenyl)-1-(5-(1-hydroxyethyl)-4-(4- B63 (trifluoromethyl)phenyl)thiazol-2-yl)-3-methyl-1 H-pyrazole-5- K carboxylic acid

[0396] 4-(3-fluorophenyl)-1-(5-(2-hydroxyethyl)-4-(4- B64 (trifluoromethyl)phenyl)thiazol-2-yl)-3-methyl-1 H-pyrazole-5- K carboxylic acid

[0397] 4-(3-fluorophenyl)-1-(5-(4-(2-methoxyethoxy)phenyl)-4-(4- B65 (trifluoromethyl)phenyl)thiazol-2-yl)-3-methyl-1 H-pyrazole-5- B carboxylic acid

[0398] 4-(3-fluorophenyl)-1 -(5-(1 -methoxyethyl)-4-(4- B66 (trifluoromethyl)phenyl)thiazol-2-yl)-3-methyl-1 H-pyrazole-5- C carboxylic acid

[0399] 4-(3-fluorophenyl)-1-(4-(4-isopropylpiperidin-1-yl)-5- B67 B

[0400]

[0401] (isopropylthio)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylic acidCpd Name BJAB 4-(3-fluorophenyl)-1-(5-(isopropylthio)-4-(3-methoxy-3- B68 (trifluoromethyl)-8-azabicyclo[3.2.1]octan-8-yl)thiazol-2-yl)-3-methyl- -

[0402]

[0403] 1 H-pyrazole-5-carboxylic acid

[0404]

[0063] In various embodiments as otherwise described herein, the 0MA1 activator is a compound of Formula I

[0405] R4— L4

[0406]

[0407] or a pharmaceutically-acceptable salt thereof, wherein

[0408] L1is -S- or a bond;

[0409] R1is selected from the group consisting of C-i-Cs alkyl, Ci-Cs alkenyl and C-i-Cs alkynyl, each unsubstituted or fluorinated,

[0410] L2is a bond or -CH2-;

[0411] Q is -C(O)OH, -C(O)OR2A, of-C(O)NR2BR2A, in which

[0412] each R2Ais independently selected from H and C1-C3 alkyl, and

[0413] each R2Bis independently selected from H and C1-C3 alkyl;

[0414] L3is a bond;

[0415] R3is phenyl or monocyclic heteroaryl, optionally substituted with 1-5 R3E, in which each R3Eis independently selected from oxo, optionally-substituted C1-C4 alkyl, C1-C4 fluoroalkyl, halogen, -CN, SF5, -N3, -C(O)R3F, -SR3F,

[0416] -S(O)I-2R3F, -OR3F, -NR3GR3F, -C(O)R3F, -C(O)NR3GR3F, -NR3GC(O)R3F, -C(S)NR3GR3F, -NR3GC(S)R3F, -C(O)OR3F, -OC(O)R3F, -C(O)SR3F, -SC(O)R3F, -C(S)OR3F, -OC(S)R3F, -C(S)SR3F, -SC(S)R3F, -S(O)I-2OR3F, -OS(O)I-2R3F, -S(O)I-2NR3GR3F, -NR3GS(O)I-2R3F;

[0417] each R3Fis independently selected from H, C1-C3 alkyl and C1-C3 fluoroalkyl and each R3Gis independently selected from H and C1-C3 alkyl, C1-C3 fluoroalkyl;

[0418] L4is a bond,

[0419] R4is selected from the group consisting of hydrogen, optionally substituted C-i-Cs alkyl, optionally-substituted Ci-Cs alkenyl and optionally substituted Ci-Cs alkynyl;

[0420] L5is a bond,R5is cycloalkyl or heterocycloalkyl, each optionally substituted with 1-5 R5E, in which each R5Eis independently selected from oxo, optionally-substituted C1-C4 alkyl, C1-C4 fluoroalkyl, halogen, -CN, -SF5, -N3, -C(O)R5F, -SR5F, -S(O)I-2R5F, -OR5F, -NR5GR5F, -C(O)R5F, -C(O)NR5GR5F, -NR5GC(O)R5F, -C(S)NR5GR5F, -NR1GC(S)R5F, -C(O)OR5F, -OC(O)R5F, -C(O)SR5F, -SC(O)R5F, -C(S)OR5F, -OC(S)R5F, -C(S)SR5F, -

[0421]

[0422] SC(S)R5F, -S(O)I-2OR5F, -OS(O)I-2R5F, -S(O)I-2NR5GR5Fand -NR5GS(O)I-2R5F; each R5Fis independently selected from H, C1-C3 alkyl and C1-C3 fluoroalkyl and each R5Gis independently selected from H and C1-C3 alkyl;

[0423] wherein

[0424] each optionally substituted alkyl, alkenyl and alkynyl is unsubstituted, fluorinated or substituted with one or two hydroxyl groups;

[0425] each cycloalkyl has 3-10 ring carbons and is saturated or partially unsaturated, and optionally includes one or two fused cycloalkyl rings, each fused ring having 3-8 ring members;

[0426] each heterocylcloalkyl has 3-10 ring members and 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur and is saturated or partially unsaturated, and optionally includes one or two fused cycloalkyl rings, each having 3-8 ring members; each monocyclic heteroaryl is a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0427]

[0064] In various such embodiments, L1is -S-.

[0428]

[0065] In various such embodiments, R1is unsubstituted.

[0429]

[0066] In various such embodiments, R1is Ci-Cs alkyl.

[0430]

[0067] In various such embodiments, R1is propyl, butyl or butenyl.

[0431]

[0068] In various such embodiments, L2is a bond.

[0432]

[0069] In various such embodiments, Q is -C(O)OH,

[0433]

[0070] In various such embodiments, Q is -C(O)O(Ci-C3alkyl).

[0434]

[0071] In various such embodiments, R3is phenyl optionally substituted with 1-5 R3E.

[0435]

[0072] In various such embodiments, R4is unsubstituted C1-C3 alkyl.

[0436]

[0073] In various such embodiments, R5is heterocycloalkyl optionally substituted with 1-5 R5E.

[0437]

[0074] In various such embodiments, the heterocycloalkyl is a monocyclic nitrogencontaining heterocycloalkyl, attached to the -L5- through a nitrogen atom.

[0438]

[0075] In various such embodiments, R3is cycioalkyl optionally substituted with 1-5 R5E. In various such embodiments, the R3cycloalkyl is monocyclic and is partially unsaturated.

[0076] In various such embodiments, each optionally substituted alkyl, alkenyl and alkynyl is unsubstituted or fluorinated.

[0439]

[0077] In various such embodiments,

[0440] L1is -S-.

[0441] R1is propyl, butyl or butenyl;

[0442] L2 is a bond;

[0443] Q is -C(O)OH;

[0444] R3is phenyl optionally substituted with 1-5 R3E;

[0445] R4is unsubstituted C1-C3 alkyl; and

[0446] each optionally substituted alkyl, alkenyl and alkynyl is unsubstituted or fluorinated.

[0447]

[0078] In various such embodiments, R5is monocyclic heterocycloalkyl optionally substituted with 1-5 R5E, the monocyclic heterocycloalkyl being attached to the -L5- through a nitrogen atom.

[0448]

[0079] In various such embodiments, R5is monocyclic cycloalkyl optionally substituted with 1-5 R5E.

[0449]

[0080] In various such embodiments, R" monocyclic cycloalkyl is partially unsaturated.

[0450]

[0081] In various such embodiments, the compound is

[0451] 4-(3-fluorophenyl)-1-(5-(isopropylthio)-4-(4-methyl cyclohex-1 -en-1 -yl)thiazol-2-yl)-3- methyl-1 H-pyrazole-5-carboxylic acid;

[0452] 4-(3-fluorophenyl)-1-(5-(isopropylthio)-4-(4-(trifluoromethyl)cyclohex-1-en-1-yl)thiazol-2- yl)-3-methyl-1 H-pyrazole-5-carboxylic acid;

[0453] 1 -(4-(4,4-dimethyl cyclohex-1 -en-1 -yl)-5-(isopropylthio)thiazol-2-yl)-4-(3-fluorophenyl)-3- methyl-1 H-pyrazole-5-carboxylic acid;

[0454] 4-(3-fluorophenyl)-1-(5-(isopropylthio)-4-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)thiazol-2-yl)-3- methyl-1 H-pyrazole-5-carboxylic acid;

[0455] 4-(3-fluorophenyl)-1-(5-(isopropylthio)-4-(piperidin-1-yl)thiazol-2-yl)-3-methyl-1H- pyrazole-5-carboxylic acid;

[0456] 4-(3-fluorophenyl)-1-(5-(isopropylthio)-4-(4-(trifluoromethyl)piperidin-1-yl)thiazol-2-yl)-3- methyl-1 H-pyrazole-5-carboxylic acid;

[0457] 4-(3-fluorophenyl)-1-(5-(isopropylthio)-4-morpholinothiazol-2-yl)-3-methyl-1H-pyrazole-5- carboxylic acid;

[0458] 1-(4-(4,4-difluoropiperidin-1-yl)-5-(isopropylthio)thiazol-2-yl)-4-(3-fluorophenyl)-3-methyl- 1 H-pyrazole-5-carboxylic acid;methyl 4-(3-fluorophenyl)-1-(5-(isopropylthio)-4-(4-(trifluoromethyl)cyclohex-1-en-1- yl)thiazol-2-yl)-3-methyl-1 H-pyrazole-5-carboxylate;

[0459] 4-(3-fluorophenyl)-1-(5-isobutyl-4-(4-(trifluoromethyl)phenyl)thiazol-2-yl)-3-methyl-1 H- pyrazole-5-carboxylic acid;

[0460] 4-(3-fluorophenyl)-1-(5-(isopropylthio)-4-(4-(2,2,2-trifluoroethyl)piperazin-1-yl)thiazol-2- yl)-3-methyl-1 H-pyrazole-5-carboxylic acid;

[0461] 1-(4-(4-cyanopiperidin-1-yl)-5-(isopropylthio)thiazol-2-yl)-4-(3-fluorophenyl)-3-methyl-1H- pyrazole-5-carboxylic acid;

[0462] 1-(4-(4-cyclopropylpiperazin-1-yl)-5-(isopropylthio)thiazol-2-yl)-4-(3-fluorophenyl)-3- methyl-1 H-pyrazole-5-carboxylic acid;

[0463] 1-(4-(4-ethylpiperazin-1-yl)-5-(isopropylthio)thiazol-2-yl)-4-(3-fluorophenyl)-3-methyl-1 H- pyrazole-5-carboxylic acid;

[0464] 1-(4-(4-acetylpi perazin-1 -yl)-5-(isopropylthio)thiazol-2-yl)-4-(3-fluorophenyl)-3-methyl- 1 H-pyrazole-5-carboxylic acid;

[0465] 4-(3-fluorophenyl)-1-(5-(isopropylthio)-4-(4-methylpiperidin-1-yl)thiazol-2-yl)-3-methyl- 1 H-pyrazole-5-carboxylic acid;

[0466] 4-(3-fluorophenyl)-1-(5-(isopropylthio)-4-(4-methylpiperazin-1-yl)thiazol-2-yl)-3-methyl- 1 H-pyrazole-5-carboxylic acid;

[0467] 1-(4-(4,4-dimethylpiperidin-1-yl)-5-(isopropylthio)thiazol-2-yl)-4-(3-fluorophenyl)-3- methyl-1 H-pyrazole-5-carboxylic acid;

[0468] 4-(3-fluorophenyl)-1-(5-(isopropylthio)-4-(3-(trifluoromethyl)pyrrolidin-1-yl)thiazol-2-yl)-3- methyl-1 H-pyrazole-5-carboxylic acid;

[0469] 1-(4-(4-(tert-butyl)piperidin-1-yl)-5-(isopropylthio)thiazol-2-yl)-4-(3-fluorophenyl)-3- methyl-1 H-pyrazole-5-carboxylic acid;

[0470] 4-(3-fluorophenyl)-1-(5-(isopropylthio)-4-(6-azaspiro[2.5]octan-6-yl)thiazol-2-yl)-3-methyl- 1 H-pyrazole-5-carboxylic acid;

[0471] 4-(3-fluorophenyl)-1-(5-(isopropylthio)-4-(4-methoxy-4-(trifluoromethyl)piperidin-1- yl)thiazol-2-yl)-3-methyl-1 H-pyrazole-5-carboxylic acid; or

[0472] 4-(3-fluorophenyl)-1-(4-(4-isopropylpiperidin-1-yl)-5-(isopropylthio)thiazol-2-yl)-3-methyl- 1 H-pyrazole-5-carboxylic acid,

[0473] optionally in the form of a pharmaceutically acceptable salt or N-oxide, and / or a solvate or hydrate.

[0474]

[0082] Terms used herein may be preceded and / or followed by a single dash, or a double dash, to indicate the bond order of the bond between the named substituent and itsparent moiety; a single dash indicates a single bond and a double dash indicates a double bond or a pair of single bonds in the case of a spiro-substituent. In the absence of a single or double dash it is understood that a single bond is formed between the substituent and its parent moiety; further, substituents are intended to be read “left to right” with reference to the chemical structure referred to unless a dash indicates otherwise. For example, arylalkyl, arylalkyl-, and -alkylaryl indicate the same functionality.

[0475]

[0083] For simplicity, chemical moieties are defined and referred to throughout primarily as univalent chemical moieties (e.g., alkyl, aryl, etc.). Nevertheless, such terms are also used to convey corresponding multivalent moieties under the appropriate structural circumstances clear to those skilled in the art. For example, while an “alkyl” moiety can refer to a monovalent radical (e.g. CH3-CH2-), in some circumstances a bivalent linking moiety can be “alkyl,” in which case those skilled in the art will understand the alkyl to be a divalent radical (e.g., -CH2-CH2-), which is equivalent to the term “alkylene.” (Similarly, in circumstances in which a divalent moiety is required and is stated as being “aryl,” those skilled in the art will understand that the term “aryl” refers to the corresponding divalent moiety, arylene). All atoms are understood to have their normal number of valences for bond formation ( / .e., 4 for carbon, 3 for N, 2 for O, and 2, 4, or 6 for S, depending on the oxidation state of the S). Nitrogens in the presently disclosed compounds can be hypervalent, e.g., an N-oxide or tetrasubstituted ammonium salt. On occasion a moiety may be defined, for example, as -B-(A)a, wherein a is 0 or 1. In such instances, when a is 0 the moiety is -B and when a is 1 the moiety is -B-A.

[0476]

[0084] As used herein, the term “alkyl” includes a saturated hydrocarbon having a designed number of carbon atoms, such as 1 to 10 carbons ( / .e., inclusive of 1 and 10), 1 to 8 carbons, 1 to 6 carbons, 1 to 3 carbons, or 1, 2, 3, 4, 5 or 6. Alkyl group may be straight or branched and depending on context, may be a monovalent radical or a divalent radical ( / .e., an alkylene group). For example, the moiety “-(Ci-CealkyQ-O-” signifies connection of an oxygen through an alkylene bridge having from 1 to 6 carbons and Ci-Csalkyl represents methyl, ethyl, and propyl moieties. Examples of “alkyl” include, for example, methyl, ethyl, propyl, isopropyl, butyl, iso-, sec- and tert-butyl, pentyl, and hexyl.

[0477]

[0085] The term “alkoxy” represents an alkyl group of indicated number of carbon atoms attached to the parent molecular moiety through an oxygen bridge. Examples of “alkoxy” include, for example, methoxy, ethoxy, propoxy, and isopropoxy.

[0478]

[0086] The term “alkenyl” as used herein, unsaturated hydrocarbon containing from 2 to 10 carbons ( / .e., inclusive of 2 and 10), 2 to 8 carbons, 2 to 6 carbons, or 2, 3, 4, 5 or 6, unless otherwise specified, and containing at least one carbon-carbon double bond. Alkenyl group maybe straight or branched and depending on context, may be a monovalent radical or a divalent radical ( / .e., an alkenylene group). For example, the moiety “-(C2-C6alkenyl)-O-” signifies connection of an oxygen through an alkenylene bridge having from 2 to 6 carbons.

[0479] Representative examples of alkenyl include, but are not limited to, ethenyl, 2-propenyl, 2-methyl-2-propenyl, 3-butenyl, 4-pentenyl, 5-hexenyl, 2-heptenyl, 2-methyl-1 -heptenyl, 3-decenyl, and 3,7-dimethylocta-2,6-dienyl.

[0480]

[0087] The term “alkynyl” as used herein, unsaturated hydrocarbon containing from 2 to 10 carbons ( / .e., inclusive of 2 and 10), 2 to 8 carbons, 2 to 6 carbons, or 2, 3, 4, 5 or 6 unless otherwise specified, and containing at least one carbon-carbon triple bond. Alkynyl group may be straight or branched and depending on context, may be a monovalent radical or a divalent radical ( / .e., an alkynylene group). For example, the moiety “-(C2-C6 alkynyl)-O-” signifies connection of an oxygen through an alkynylene bridge having from 2 to 6 carbons.

[0481] Representative examples of alkynyl include, but are not limited to, acetylenyl, 1-propynyl, 2-propynyl, 3-butynyl, 2-pentynyl, and 1-butynyL

[0482]

[0088] The terms “halogen” or "halo" indicate fluorine, chlorine, bromine, and iodine. In certain embodiments of each and every embodiment described herein, the term “halogen” or “halo” refers to fluorine or chlorine. In certain embodiments of each and every embodiment described herein, the term “halogen” or “halo” refers to fluorine.

[0483]

[0089] The term “heteroaryl” refers to an aromatic ring system containing at least one aromatic heteroatom selected from nitrogen, oxygen and sulfur in an aromatic ring. Most commonly, the heteroaryl groups will have 1, 2, 3, or 4 heteroatoms. The heteroaryl may be fused to one or more non-aromatic rings, for example, cycloalkyl or heterocycloalkyl rings, wherein the cycloalkyl and heterocycloalkyl rings are described herein. In one embodiment of the present compounds the heteroaryl group is bonded to the remainder of the structure through an atom in a heteroaryl group aromatic ring. In another embodiment, the heteroaryl group is bonded to the remainder of the structure through a non-aromatic ring atom. Examples of heteroaryl groups include, for example, pyridyl, pyrimidinyl, quinolinyl, benzothienyl, indolyl, indolinyl, pyridazinyl, pyrazinyl, isoindolyl, isoquinolyl, quinazolinyl, quinoxalinyl, phthalazinyl, imidazolyl, isoxazolyl, pyrazolyl, oxazolyl, thiazolyl, indolizinyl, indazolyl, benzothiazolyl, benzimidazolyl, benzofuranyl, furanyl, thienyl, pyrrolyl, oxadiazolyl, thiadiazolyl, benzo[1,4]oxazinyl, triazolyl, tetrazolyl, isothiazolyl, naphthyridinyl, isochromanyl, chromanyl, isoindolinyl, isobenzothienyl, benzoxazolyl, pyridopyridinyl, purinyl, benzodioxolyl, triazinyl, pteridinyl, benzothiazolyl, imidazopyridinyl, imidazothiazolyl, benzisoxazinyl, benzoxazinyl, benzopyranyl, benzothiopyranyl, chromonyl, chromanonyl, pyridinyl-A / -oxide, isoindolinonyl,benzodioxanyl, benzoxazolinonyl, pyrrolyl / V-oxide, pyrimidinyl / V-oxide, pyridazinyl / V-oxide, pyrazinyl / V-oxide, quinolinyl / V-oxide, indolyl / V-oxide, indolinyl / V-oxide, isoquinolyl / V-oxide, quinazolinyl / V-oxide, quinoxalinyl / V-oxide, phthalazinyl / V-oxide, imidazolyl / V-oxide, isoxazolyl / V-oxide, oxazolyl / V-oxide, thiazolyl / V-oxide, indolizinyl / V-oxide, indazolyl / V-oxide, benzothiazolyl / V-oxide, benzimidazolyl / V-oxide, pyrrolyl / V-oxide, oxadiazolyl / V-oxide, thiadiazolyl / V-oxide, triazolyl / V-oxide, tetrazolyl / V-oxide, benzothiopyranyl S-oxide, benzothiopyranyl S, S-dioxide. Preferred heteroaryl groups include pyridyl, pyrimidyl, quinolinyl, indolyl, pyrrolyl, furanyl, thienyl and imidazolyl, pyrazolyl, indazolyl, thiazolyl and benzothiazolyl. In certain embodiments, each heteroaryl is selected from pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, imidazolyl, isoxazolyl, pyrazolyl, oxazolyl, thiazolyl, furanyl, thienyl, pyrrolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, isothiazolyl, pyridinyl- / V-oxide, pyrrolyl / V-oxide, pyrimidinyl / V-oxide, pyridazinyl / V-oxide, pyrazinyl / V-oxide, imidazolyl / V-oxide, isoxazolyl / V-oxide, oxazolyl / V-oxide, thiazolyl / V-oxide, pyrrolyl / V-oxide, oxadiazolyl / V-oxide, thiadiazolyl N-oxide, triazolyl / V-oxide, and tetrazolyl / V-oxide. Preferred heteroaryl groups include pyridyl, pyrimidyl, quinolinyl, indolyl, pyrrolyl, furanyl, thienyl, imidazolyl, pyrazolyl, indazolyl, thiazolyl and benzothiazolyl. The heteroaryl groups herein are unsubstituted or, when specified as “optionally substituted”, can unless stated otherwise be substituted in one or more substitutable positions with various groups, as indicated.

[0484]

[0090] The term “heterocycloalkyl” refers to a non-aromatic ring or ring system containing at least one heteroatom that is preferably selected from nitrogen, oxygen and sulfur, wherein said heteroatom is in a non-aromatic ring. The heterocycloalkyl may have 1, 2, 3 or 4 heteroatoms. The heterocycloalkyl may be saturated ( / .e., a heterocycloalkanyl) or partially unsaturated ( / .e., a heterocycloalkenyl). Heterocycloalkyl includes monocyclic groups of three to eight annular atoms as well as bicyclic and polycyclic ring systems, including bridged and fused systems, wherein each ring includes three to eight annular atoms. The heterocycloalkyl ring is optionally fused to other heterocycloalkyl rings and / or non-aromatic hydrocarbon rings. In certain embodiments, the heterocycloalkyl groups have from 3 to 7 members in a single ring. In other embodiments, heterocycloalkyl groups have 5 or 6 members in a single ring. In some embodiments, the heterocycloalkyl groups have 3, 4, 5, 6 or 7 members in a single ring.

[0485] Examples of heterocycloalkyl groups include, for example, azabicyclo[2.2.2]octyl (in each case also “quinuclidinyl” or a quinuclidine derivative), azabicyclo[3.2.1]octyl, 2,5-diazabicyclo[2.2.1]heptyl, morpholinyl, thiomorpholinyl, thiomorpholinyl S-oxide, thiomorpholinyl S, S-dioxide, 2-oxazolidonyl, piperazinyl, homopiperazinyl, piperazinonyl, pyrrolidinyl, azepanyl, azetidinyl, pyrrolinyl, tetrahydropyranyl, piperidinyl, tetrahydrofuranyl, tetrahydrothienyl, 3,4-dihydroisoquinolin-2(1 / - / )-yl, isoindolindionyl, homopiperidinyl, homomorpholinyl, homothiomorpholinyl, homothiomorpholinyl S, S-dioxide, oxazolidinonyl, dihydropyrazolyl, dihydropyrrolyl, dihydropyrazinyl, dihydropyridinyl, dihydropyrimidinyl, dihydrofuryl, dihydropyranyl, imidazolidonyl, tetrahydrothienyl S-oxide, tetrahydrothienyl S, S-dioxide and homothiomorpholinyl S-oxide. Especially desirable heterocycloalkyl groups include morpholinyl, 3,4-dihydroisoquinolin-2(1H)-yl, tetrahydropyranyl, piperidinyl, aza-bicyclo[2.2.2]octyl, y-butyrolactonyl ( / .e., an oxo-substituted tetrahydrofuranyl), y-butryolactamyl ( / .e., an oxo-substituted pyrrolidine), pyrrolidinyl, piperazinyl, azepanyl, azetidinyl, thiomorpholinyl, thiomorpholinyl S, S-dioxide, 2-oxazolidonyl, imidazolidonyl, isoindolindionyl, piperazinonyl. The heterocycloalkyl groups herein are unsubstituted or, when specified as “optionally substituted”, can unless stated otherwise be substituted in one or more substitutable positions with various groups, as indicated.

[0486]

[0091] The term “cycloalkyl” refers to a non-aromatic carbocyclic ring or ring system, which may be saturated ( / .e., a cycloalkanyl) or partially unsaturated ( / .e., a cycloalkenyl). The cycloalkyl ring optionally fused to or otherwise attached (e.g., bridged systems) to other cycloalkyl rings. Certain examples of cycloalkyl groups present in the disclosed compounds have from 3 to 7 members in a single ring, such as having 5 or 6 members in a single ring. In some embodiments, the cycloalkyl groups have 3, 4, 5, 6 or 7 members in a single ring.

[0487] Examples of cycloalkyl groups include, for example, cyclohexyl, cyclopentyl, cyclobutyl, cyclopropyl, tetrahydronaphthyl and bicyclo[2.2.1]heptane. The cycloalkyl groups herein are unsubstituted or, when specified as “optionally substituted”, may be substituted in one or more substitutable positions with various groups, as indicated.

[0488]

[0092] The term “ring system” encompasses monocycles, as well as fused and / or bridged polycycles.

[0489]

[0093] The term “oxo” means a doubly bonded oxygen, sometimes designated as =0 or for example in describing a carbonyl “C(0)” may be used to show an oxo substituted carbon.

[0490]

[0094] The term “substituted,” when used to modify a specified group or radical, means that one or more hydrogen atoms of the specified group or radical are each, independently of one another, replaced with the same or different substituent groups as defined below, unless specified otherwise.

[0491]

[0095] As used herein, the phrase “pharmaceutically acceptable salt” refers to both pharmaceutically acceptable acid and base addition salts and solvates. Such pharmaceutically acceptable salts include salts of acids such as hydrochloric, phosphoric, hydrobromic, sulfuric, sulfinic, formic, toluenesulfonic, methanesulfonic, nitric, benzoic, citric, tartaric, maleic,hydroiodic, alkanoic such as acetic, HOOC-(CH2)n-COOH where n is 0-4, and the like. Non-toxic pharmaceutical base addition salts include salts of bases such as sodium, potassium, calcium, ammonium, and the like. Those skilled in the art will recognize a wide variety of non-toxic pharmaceutically acceptable addition salts.

[0492]

[0096] One of ordinary skill in the art of medicinal chemistry also will appreciate that the disclosed structures are intended to include isotopically enriched forms of the present compounds. As used herein “isotopes” includes those atoms having the same atomic number but different mass numbers. As is known to those of skill in the art, certain atoms, such as hydrogen occur in different isotopic forms. For example, hydrogen includes three isotopic forms, protium, deuterium and tritium. As will be apparent to those of skill in the art upon consideration of the present compounds, certain compounds can be enriched at a given position with a particular isotope of the atom at that position. For example, compounds having a fluorine atom, may be synthesized in a form enriched in the radioactive fluorine isotope18F. Similarly, compounds may be enriched in the heavy isotopes of hydrogen: deuterium and tritium; and similarly can be enriched in a radioactive isotope of carbon, such as13C. Such isotopic variant compounds undergo different metabolic pathways and can be useful, for example, in studying the ubiquitination pathway and its role in disease. Of course, in certain embodiments, the compound has substantially the same isotopic character as naturally-occuring materials.

[0493]

[0097] As used herein, the term “cell” is meant to refer to a cell that is in vitro, ex vivo or in vivo. In some embodiments, an ex vivo cell can be part of a tissue sample excised from an organism such as a mammal. In some embodiments, an in vitro cell can be a cell in a cell culture. In some embodiments, an in vivo cell is a cell living in an organism such as a mammal.

[0494]

[0098] As used herein, the terms “individual,” “patient,” or “subject” are used interchangeably, refers to any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses, or primates, and most preferably humans.

[0495]

[0099] As used herein, the phrase “therapeutically effective amount” or “effective amount” refers to the amount of active compound or pharmaceutical agent that elicits the biological or medicinal response that is being sought in a tissue, system, animal, individual or human by a researcher, veterinarian, medical doctor or other clinician.

[0496]

[0100] In certain embodiments, a therapeutically effective amount can be an amount suitable for

[0497] (1 ) preventing the disease; for example, preventing a disease, condition or disorder in an individual who may be predisposed or otherwise susceptible to the disease, condition or disorder but does not yet experience or display the pathology or symptomatology of the disease;(2) inhibiting the disease; for example, inhibiting a disease, condition or disorder in an individual who is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder;

[0498] (3) ameliorating the disease (including a symptom thereof); for example, ameliorating a disease, condition or disorder in an individual who is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder ( / .e., reversing the pathology and / or symptomatology) such as decreasing the severity of disease; or

[0499] (4) eliciting a referenced biological effect, e.g., inhibiting the initiation of translation. Such biological effect need not be complete, i.e., an inhibition of the initiation of translation need not be complete inhibition in order for the amount of compound administered to be therapeutically effective.

[0500]

[0101] As used here, the terms “treatment” and “treating” means (i) ameliorating the referenced disease state, condition, or disorder (or a symptom thereof), such as, for example, ameliorating a disease, condition or disorder in an individual who is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder (i.e., reversing or improving the pathology and / or symptomatology) such as decreasing the severity of disease or symptom thereof; or (ii) eliciting the referenced biological effect (e.g., inhibiting the initiation of translation).

[0501]

[0102] The compounds of the disclosure can be administered, for example, orally, topically, parenterally, by inhalation or spray or rectally in dosage unit formulations containing one or more pharmaceutically acceptable carriers, diluents or excipients. The term parenteral as used herein includes percutaneous, subcutaneous, intravascular (e.g., intravenous), intramuscular, or intrathecal injection or infusion techniques and the like.

[0502]

[0103] Pharmaceutical compositions can be made using the presently disclosed compounds. For example, in one embodiment, a pharmaceutical composition includes a pharmaceutically acceptable carrier, diluent or excipient, and compound as described above with reference to any one of structural formulae.

[0503]

[0104] In the pharmaceutical compositions disclosed herein, one or more compounds of the disclosure may be present in association with one or more pharmaceutically acceptable carriers, diluents or excipients, and, if desired, other active ingredients. The pharmaceutical compositions containing compounds of the disclosure may be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsion, hard or soft capsules, or syrups or elixirs.

[0105] Compositions intended for oral use can be prepared according to any suitable method for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preservative agents in order to provide pharmaceutically elegant and palatable preparations. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients that are suitable for the manufacture of tablets. These excipients can be for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; binding agents, for example starch, gelatin or acacia, and lubricating agents, for example magnesium stearate, stearic acid or talc. The tablets can be uncoated or they can be coated by known techniques. In some cases such coatings can be prepared by suitable techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate can be employed.

[0504]

[0106] Formulations for oral use can also be presented as hard gelatin capsules, wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin, or olive oil.

[0505]

[0107] Formulations for oral use can also be presented as lozenges.

[0506]

[0108] Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients can be suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydropropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents such as a naturally-occurring phosphatide, for example, lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate. The aqueous suspensions may also contain one or more preservatives, for example ethyl, or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose or saccharin.

[0109] Oily suspensions can be formulated by suspending the active ingredients in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. The oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents and flavoring agents may be added to provide palatable oral preparations. These compositions may be preserved by the addition of an antioxidant such as ascorbic acid.

[0507]

[0110] Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents or suspending agents are exemplified by those already mentioned above. Additional excipients, for example sweetening, flavoring and coloring agents, can also be present.

[0508]

[0111] Pharmaceutical compositions can also be in the form of oil-in-water emulsions. The oily phase can be a vegetable oil or a mineral oil or mixtures of these. Suitable emulsifying agents can be naturally-occurring gums, for example gum acacia or gum tragacanth, naturally-occurring phosphatides, for example soy bean, lecithin, and esters or partial esters derived from fatty acids and hexitol, anhydrides, for example sorbitan monooleate, and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate. The emulsions can also contain sweetening and flavoring agents.

[0509]

[0112] In some embodiments, the pharmaceutically acceptable carrier, diluent, or excipient is not water. In other embodiments, the water comprises less than 50% of the composition. In some embodiments, compositions comprising less than 50% water have at least 1%, 2%, 3%, 4% or 5% water. In other embodiments, the water content is present in the composition in a trace amount.

[0510]

[0113] In some embodiments, the pharmaceutically acceptable carrier, diluent, or excipient is not alcohol. In other embodiments, the alcohol comprises less than 50% of the composition. In some embodiments, compositions comprising less than 50% alcohol have at least 1%, 2%, 3%, 4% or 5% alcohol. In other embodiments, the alcohol content is present in the composition in a trace amount.

[0511]

[0114] Syrups and elixirs can be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol, glucose or sucrose. Such formulations can also contain a demulcent, a preservative, flavoring, and coloring agents. The pharmaceutical compositions can be in the form of a sterile injectable aqueous or oleaginous suspension. This suspension can be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents that have been mentioned above. The sterile injectable preparation can alsobe a sterile injectable solution or suspension in a non-toxic parentally acceptable diluent or solvent, for example as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that can be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils can be employed as a solvent or suspending medium. For this purpose, any bland fixed oil can be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables.

[0512]

[0115] Compounds of the disclosure can also be administered in the form of suppositories, e.g., for rectal administration of the drug. These compositions can be prepared by mixing the compound with a suitable non-irritating excipient that is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Such materials include cocoa butter and polyethylene glycols.

[0513]

[0116] Compounds of the disclosure can also be administered parenterally in a sterile medium. The drug, depending on the vehicle and concentration used, can either be suspended or dissolved in the vehicle. Advantageously, adjuvants such as local anesthetics, preservatives and buffering agents can be dissolved in the vehicle.

[0514]

[0117] The compositions can be formulated in a unit dosage form of the active ingredient. The term “unit dosage forms” refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient.

[0515]

[0118] The active compound can be effective over a wide dosage range and is generally administered in a pharmaceutically effective amount. It will be understood, however, that the amount of the compound actually administered will usually be determined by a physician, according to the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound administered, the age, weight, and response of the individual patient, the severity of the patient's symptoms, and the like.

[0516]

[0119] For preparing solid compositions such as tablets, the principal active ingredient is mixed with a pharmaceutical excipient to form a solid preformulation composition containing a homogeneous mixture of a compound described herein. When referring to these preformulation compositions as homogeneous, the active ingredient is typically dispersed evenly throughout the composition so that the composition can be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules. This solid preformulation is then subdivided into unit dosage forms of the type described above containing from, for example, 0.1 to about 500 mg of the active ingredient of a compound described herein.

[0120] The tablets or pills can be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action. For example, the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former. The two components can be separated by an enteric layer which serves to resist disintegration in the stomach and permit the inner component to pass intact into the duodenum or to be delayed in release. A variety of materials can be used for such enteric layers or coatings, such materials including a number of polymeric acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol, and cellulose acetate.

[0517]

[0121] The amount of compound or composition administered to a patient will vary depending upon what is being administered, the purpose of the administration, such as prophylaxis or therapy, the state of the patient, the manner of administration, and the like. In therapeutic applications, compositions can be administered to a patient already suffering from a disease in an amount sufficient to cure or at least partially arrest the symptoms of the disease and its complications. Effective doses will depend on the disease condition being treated as well as by the judgment of the attending clinician depending upon factors such as the severity of the disease, the age, weight and general condition of the patient, and the like.

[0518]

[0122] The compositions administered to a patient can be in the form of pharmaceutical compositions described above. These compositions can be sterilized by conventional sterilization techniques or may be sterile filtered. Aqueous solutions can be packaged for use as is, or lyophilized, the lyophilized preparation being combined with a sterile aqueous carrier prior to administration. The pH of the compound preparations typically will be between 3 and 11, more preferably from 5 to 9 and most preferably from 7 to 8. It will be understood that use of certain of the foregoing excipients, carriers, or stabilizers will result in the formation of pharmaceutical salts.

[0519]

[0123] The therapeutic dosage of the compounds can vary according to, for example, the particular use for which the treatment is made, the manner of administration of the compound, the health and condition of the patient, and the judgment of the prescribing physician. The proportion or concentration of a compound described herein in a pharmaceutical composition can vary depending upon a number of factors including dosage, chemical characteristics (e.g., hydrophobicity), and the route of administration. For example, the compounds described herein can be provided in an aqueous physiological buffer solution containing about 0.1 to about 10% w / v of the compound for parenteral administration. Some typical dose ranges are from about 1 pg / kg to about 1 g / kg of body weight per day. In some embodiments, the dose range is from about 0.01 mg / kg to about 100 mg / kg of body weight per day. The dosage is likely to depend onsuch variables as the type and extent of progression of the disease or disorder, the overall health status of the particular patient, the relative biological efficacy of the compound selected, formulation of the excipient, and its route of administration. Effective doses can be extrapolated from dose-response curves derived from in vitro or animal model test systems.

[0520]

[0124] The compounds described herein can also be formulated in combination with one or more additional active ingredients which can include any pharmaceutical agent such as anti-viral agents, vaccines, antibodies, immune enhancers, immune suppressants,

[0521] anti-inflammatory agents and the like.

[0522]

[0125] The person of ordinary skill in the art will formulate a compound as described into pharmaceutical formulations herein, for example, based on the physicochemical properties of the compound, the amount of the compound needed for a pharmaceutically effective amount, and the desired route of administration.

[0523]

[0126] Overexpression of Bcl-2 proteins correlates with resistance to chemotherapy, clinical outcome, disease progression, overall prognosis or a combination thereof in various cancers; it is contemplated that the combinations, compositions and methods of the disclosure will be useful against various such cancers. It is contemplated that the combinations, compositions and methods of the disclosure will be useful against various cancers including, but not limited to, hematologic and solid tumor types such as acoustic neuroma, acute leukemia, acute lymphoblastic leukemia, acute myelogenous leukemia (monocytic, myeloblastic, adenocarcinoma, angiosarcoma, astrocytoma, myelomonocytic and promyelocytic), acute t-cell leukemia, basal cell carcinoma, bile duct carcinoma, bladder cancer, brain cancer, breast cancer (including estrogen-receptor positive breast cancer), bronchogenic carcinoma, Burkitt's lymphoma, cervical cancer, chondrosarcoma, chordoma, choriocarcinoma, chronic leukemia, chronic lymphocytic leukemia, chronic myelocytic (granulocytic) leukemia, chronic myelogenous leukemia, colon cancer, colorectal cancer, craniopharyngioma, cystadenocarcinoma, dysproliferative changes (dysplasias and metaplasias), embryonal carcinoma, endometrial cancer, endotheliosarcoma, ependymoma, epithelial carcinoma, erythroleukemia, esophageal cancer, estrogen-receptor positive breast cancer, essential thrombocythemia, Ewing's tumor, fibrosarcoma, gastric carcinoma, germ cell testicular cancer, gestational trophoblastic disease, glioblastoma, head and neck cancer, heavy chain disease, hemangioblastoma, hepatoma, hepatocellular cancer, hormone insensitive prostate cancer, leiomyosarcoma, liposarcoma, lung cancer (including small cell lung cancer and non-small cell lung cancer), lymphangioendothelio-sarcoma, lymphangiosarcoma, lymphoblastic leukemia, lymphoma (lymphoma, including diffuse large B-cell lymphoma, follicular lymphoma, Hodgkin's lymphoma and non-Hodgkin'slymphoma), malignancies and hyperproliferative disorders of the bladder, breast, colon, lung, ovaries, pancreas, prostate, skin and uterus, lymphoid malignancies of T-cell or B-cell origin, leukemia, medullary carcinoma, medulloblastoma, melanoma, meningioma, mesothelioma, multiple myeloma, myelogenous leukemia, myeloma, myosarcoma, neuroblastoma, oligodendroglioma, oral cancer, osteogenic sarcoma, ovarian cancer, pancreatic cancer, papillary adenocarcinomas, papillary carcinoma, peripheral T-cell lymphoma, pinealoma, polycythemia vera, prostate cancer (including hormone-insensitive (refractory) prostate cancer), rectal cancer, renal cell carcinoma, retinoblastoma, rhabdomyosarcoma, sarcoma, sebaceous gland carcinoma, seminoma, skin cancer, small cell lung carcinoma, solid tumors (carcinomas and sarcomas), stomach cancer, squamous cell carcinoma, synovioma, sweat gland carcinoma, testicular cancer (including germ cell testicular cancer), thyroid cancer, Waldenstrom's macroglobulinemia, testicular tumors, uterine cancer, and Wilms' tumor.

[0524]

[0127] In various embodiments, the cancer is a solid tumor cancer. In various embodiments, the cancer is a carcinoma, such as a renal carcinoma or a colon carcinoma.

[0525]

[0128] In various embodiments, the cancer is a hematological cancer, such as a lymphoma.

[0526]

[0129] In various embodiments, the 0MA1 activator alone does not substantially induce apoptosis in the cancer.

[0527]

[0130] In various embodiments, the BH3 mimetic alone does not substantially induce apoptosis in the cancer.

[0528]

[0131] In various embodiments, neither the BH3 mimetic nor the OMA1 activator alone substantially induces apoptosis in the cancer.

[0529] EXAMPLES

[0530]

[0132] A variety of tumor cell lines were selected based on their intrinsic responsiveness to BTM-3566 alone in cellular assays.Cell Line Type Tissue Tumor Type Response to BTM- 3566 IC50(pM) A498 Solid Renal Carcinoma 0.86

[0531] 786-0 Solid Renal Clear Cell Carcinoma 1.15

[0532] 769-P Solid Renal Clear Cell Carcinoma 1.04

[0533] HCT-116 Solid Colon Carcinoma 0.92

[0534] Jeko Hema Blood Mantle Cell Lymphoma 0.79 Toledo Hema Blood Diffuse Large Cell 1.45

[0535] Lymphoma

[0536]

[0537]

[0133] All cells were grown as per repository (ATCC) instructions. Response to drug in solid tumor lines was assessed using an image-based method that determined cell number and viability. Briefly, cells were seeded into 96 well optical quality plastic tissue culture plates. The cells were dosed first with the indicated concentration of BTM-3566 and incubated for 30 minutes. This was followed in some experiments by addition of the BH3 mimetic navitoclax at indicated concentrations. To measure cell viability an impermeant fluorescent nuclear label (YOYO-1) was added to each well of the plate. The treatment plates were placed into an Incucyte Zoom automated imaging apparatus. Four sectors of each well were imaged by phase contrast brightfield and fluorescent microscopy. Images were captured every 8 hours with a total incubation time of -144 hours. Images were evaluated using Zoom software where a readout for confluence in both the brightfield and fluorescent channels were determined. The raw data for each well is then plotted and the area under the curve (AUC) determined for each growth curve. A score for viability was captured by calculating the ratio AUC(Green Fluorescence) / AUC(Phase) at t=24 hours. Data for each dose pair was then plotted and the effective potency of BTM-3566 and navitoclax determined.

[0538]

[0134] FIG. 1 provides a set of graphs estimating well confluence for each channel of data (Green and Phase) in cell lines 769-P, 786-0, A498 and HCT-116, treated with BTM-3566 alone. The AUC was calculated for each linear fraction of the growth curve (max t=80 hours).

[0539]

[0135] Data for navitoclax in combination with BTM-3566 in the renal tumor cell lines 769-P are presented in FIG. 2, which presents navitoclax dose response in the presence of a dose of BTM-3566. All data pare presented as a ratio of AUC(green fluorescence channel) / AUC(brightfield). The data indicate that the ability of navitoclax to induce cell death in 769-P cells is augmented with increasing concentrations of BTM-3566.

[0136] FIG. 2 shows the titration curves for inhibition of cell growth (reduction in cell area) with navitoclax at any input concentration of BTM-3566. The data in FIG. 2 can be plotted as the estimated contribution to IC50 for navitoclax at any input concentration of BTM-3566.

[0540] Likewise, the estimated contribution to IC50 of BTM-3566 can be evaluated at any input dose of navitoclax. The results of this exercise are provided in FIG. 3A and FIG. 3B, respectively. The plot of FIG. 3A indicates that the estimated contribution to IC50 of navitoclax decreases significantly with increasing concentration of BTM-3566. Conversely, as shown in FIG. 3B, the estimated contribution to IC50 of BTM-3566 is not significantly altered in the presence of navitoclax. Accordingly, the data demonstrate that BTM-3566 significantly and synergistically increases the potency of navitoclax in the renal clear cell carcinoma cell line 769-P.

[0541]

[0137] Of course, based on these data alone, it is unclear as to whether the ability of navitoclax to induce cell death in 769-P cells is related to an increase in the activity of the intrinsic apoptosis pathway. To determine whether cell death is owing to increased apoptosis, a similar study was performed using Caspase 3 / 7 activation as an endpoint. Compound treatments were repeated as above, and Caspase 3 / 7 activity was assessed at t=24 hours after dosing (a point with the maximum peak intensity of nuclear labeling).

[0542]

[0138] Results are shown in FIGS. 4A and 4B, which respectively show activation of Caspase 3 / 7 in 769-P cells as determined by luminescence assay for BTM-3566 at different concentrations of navitoclax; and the calculated IC50 for navitoclax-mediated induction of Caspase 3 / 7 in 769-P cells as a function of BTM-3566 concentration. The data demonstrate that caspase activity was increased in a dose-dependent manner by navitoclax in 769-P cells. Navitoclax activated caspase 3 / 7 with an IC50 of -0.52 pM in the absence of BTM-3566. At the highest tested concentration of 5 pM BTM-3566, the IC50 for navitoclax-induced induction of caspase 3 / 7 was reduced to -0.045 pM.

[0543]

[0139] Thus, the activation of caspase 3 / 7 is similarly augmented. Since BTM-3566 does not increase caspase activity in this cellular context on its own, its ability to augment the action of navitoclax to activate caspase 3 / 7 is synergistic in nature.

[0544]

[0140] Response to the drug combination in two hematological tumor lines was assessed Briefly, cells were seeded into white, opaque 96 well plastic tissue culture plates. The cells were dosed first with the indicated concentration of BTM-3566 and incubated for 30 minutes. This was followed by the addition of the second compound (venetoclax or navitoclax) at indicated concentrations. The cells were then incubated for 72 hrs in a 37 °C, 5% CO2 incubator. Cellular ATP was used as a surrogate for cell number and was determined using Cell-Titre Gio Reagent. Luminescence measurements were performed within 30 minutesfollowing addition of reagent. Collected luminescence data were then processed using software that determines the synergy score for each dose pair combination. (Synergy FinderPlus, see S. Zheng et al., “SynergyFinder Plus: Toward Better Interpretation and Annotation of Drug Combination Screening Datasets. Genomics Proteomics Bioinformatics,” 20:587-96 (2022)).

[0545]

[0141] The Table below provides a calculation of IC50 for BTM-3566 at each dose level of BH3 mimetic as calculated from the data plotted in FIG. 5.

[0546] BH3 mimetic concentration, nM

[0547] BH3 Mimetic 0 1.4 4.1 12.3 37 111 333.3 1000 3000 Cell line

[0548] Navitoclax 337.0 363.3 317.5 266.1 225.6 221.9 281.6 328.8 144.7 Jeko-1

[0549] Navitoclax 661.1 895.0 754.5 613.3 513.5 342.0 1144.1 171.3 NA Toledo

[0550] Venetoclax 369.3 339.6 304.3 281.3 263.0 244.6 232.0 223.5 224.1 Jeko-1

[0551] Venetoclax 913.1 828.5 575.6 463.1 434.8 379.0 360.9 316.8 188.4 Toledo

[0552]

[0553]

[0142] The Table below provides a calculation of IC50 for BH3 mimetic at each dose level of BTM-3566, as calculated from the data plotted in FIG. 6. Data are not presented for a combination of Venetoclax with Jeko-1

[0554] BTM-3566, nM

[0555] Compound 0 39.1 78.1 156.3 312.5 625 1250 2500 5000 Cell line

[0556] Navitoclax 37.07 38.70 33.44 7.78 7.06 3.28 3.03 3.28 2.64 Jeko-1

[0557] Navitoclax 46.61 33.57 40.81 40.59 34.82 11.82 8.82 5.67 5.40 Toledo

[0558] Venetoclax 27.99 18.58 25.06 24.90 12.68 3.43 2.75 3.18 3.34 Toledo

[0559]

[0560]

[0143] The output of the analysis is conveniently displayed as a heat map, shown in FIG. 7.

[0561]

[0144] The analysis displayed in FIG. 7 demonstrates that BTM-3566 synergizes with either Navitoclax or Venetoclax in the mantle cell lymphoma cell line Jekol. This synergy occurs evenin Jekol cells, which are notably resistant to venetoclax as a single agent. Likewise there is significant synergy in the venetoclax-sensitive DLBCL line Toledo.

[0562]

[0145] In summary, these data support the hypothesis that BTM-3566 and other 0AM1 activators (and especially the 1-thiazol-2-yl-N-3-alkyl-1H-pyrazole-5-carboxylic acid derivatives described herein) can synergize with BH3 mimetics (especially venetoclax and navitoclax) to induce cell death and apoptosis in tumors.

[0563]

[0146] The disclosure further provides the following enumerated embedments, which can be combined in any number and in any fashion not technically or logically inconsistent to form other embodiments of the disclosure.

[0564] Embodiment 1. A pharmaceutical combination comprising

[0565] a BH3 mimetic (e.g., venetoclax or navitoclax); and

[0566] an 0MA1 activator (e.g., a compound of Formula I as described herein).

[0567] Embodiment 2. A pharmaceutical composition comprising:

[0568] a BH3 mimetic (e.g., venetoclax or navitoclax); and

[0569] an 0MA1 activator (e.g., a compound of Formula I as described herein).

[0570] Embodiment 3. A method for treating cancer in a patient in need thereof, the method comprising administering to the patient

[0571] an effective amount of a BH3 mimetic (e.g., venetoclax or navitoclax); and

[0572] an effective amount of an 0MA1 activator (e.g., a compound of Formula I as described herein).

[0573] Embodiment 4. A method for improving the efficacy of treatment in a patient being treated with a BH3 mimetic for cancer, the method comprising administering to the patient an effective amount of an 0MA1 activator (e.g., a compound of Formula I as described herein).

[0574] Embodiment 5. The combination, composition or method of any of Embodiments 1-4, wherein the BH3 mimetic is venetoclax.

[0575] Embodiment 6. The combination, composition or method of any of Embodiments 1-4, wherein the BH3 mimetic is navitoclax.Embodiment 7. The combination, composition or method of any of Embodiments 1-4, wherein the BH3 mimetic is any active compound described in U. S. Patent Application Publication no. 2007 / 0072860.

[0576] Embodiment 8. The combination, composition or method of any of Embodiments 1-4, wherein the BH3 mimetic is any active compound described in U. S. Patent Application Publication no. 2010 / 0305122, which describes venetoclax.

[0577] Embodiment 9. The combination, composition or method of any of Embodiments 1-4, wherein the BH3 mimetic is ABT-737 (Abbott / Abbvie), S55746 (Servier), sonrotoclax (Beigene), AZD4320 (AstraZeneca), or Obatoclax (Gemin X / Teva).

[0578] Embodiment 10. The combination, composition or method of any of Embodiments 1-4, wherein the BH3 mimetic is S63845 (Servier), AZD5991 (AstraZeneca), A-1210477 (Abbvie), murizatoclax (AMG-397, Amgen), or tapotoclax (AMG-176, Amgen).

[0579] Embodiment 11. The combination, composition or method of any of Embodiments 1-4, wherein the BH3 mimetic is xevinapant (DebioPharma), or LCL161 (Novartis).

[0580] Embodiment 12. The combination, composition or method of any of Embodiments 1-4, wherein the BH3 mimetic is A-1155463 or A-1331852.

[0581] Embodiment 13. The combination, composition or method of any of Embodiments 1-4, wherein the BH3 mimetic is BGB-11417, LP-108, S65487, AT-101, APG-1252, APG2575, and BCL-201.

[0582] Embodiment 14. The combination, composition or method of any of Embodiments 1-13, wherein the OMA1 activator is BTM-3566 (i.e., 4-(3-fluorophenyl)-1-(5-(isopropylthio)-4-(4-(trifluoromethyl)cyclohex-1-en-1-yl)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylic acid or a pharmaceutically-acceptable salt thereof.Embodiment 15. The combination, composition, or method of any of Embodiments 1-13, wherein the 0MA1 activator is in a form as described in U. S. Patent Application Publications no.

[0583] 2022 / 0162204.

[0584] Embodiment 16. The combination, composition, or method of any of Embodiments 1-13, wherein the OMA1 activator is an active compound described in U. S. Patent Application Publication no. 2018 / 0311218.

[0585] Embodiment 17. The combination, composition, or method of any of Embodiments 1-13, wherein the OMA1 activator is an active compound described in U. S. Patent Application Publication no. 2019 / 0345152.

[0586] Embodiment 18. The combination, composition, or method of any of Embodiments 1-13, wherein the OMA1 activator is a compound of Formula I

[0587]

[0588] or a pharmaceutically-acceptable salt thereof, wherein

[0589] L1is a -S-, -O-, -S(O)-, -S(O)2- or a bond;

[0590] R1is unsubstituted or fluorinated Ci-Cs alkyl, unsubstituted or fluorinated C-i-Cs alkenyl, unsubstituted or fluorinated C-i-Cs alkynyl, or phenyl optionally substituted with 1-5 R1E, in which

[0591] each R1Eis independently selected from oxo, optionally-substituted C1-C4 alkyl, C1-C4 fluoroalkyl, halogen, -CN, SF5, -N3, -C(O)R1F, -SR1F, -S(O)i-2R1F, -OR1F, - (OCH2CH2O)n-R1Gin which n is 1-4, -N(R1G)C(O)CH2-O-(CH2CH2O)nR1Gin which n is 0-3, -C(O)NR1G(CH2CH2O)nR1G, -NR1GR1Fand -C(O)R1F;

[0592] each R1Fis independently selected from H, C1-C3 alkyl and C1-C3 fluoroalkyl and each R1Gis independently selected from H and C1-C3 alkyl;

[0593] L2is a bond or-CH2-;

[0594] Q is -COOH or -C(O)O(Ci-C3alkyl);

[0595] L3is a bond, -C(O)-, -S-, -S(O)i-2-, -O-, -NR6-, -CH2-, -CH(CH3)(OH)- or -CH(OH)-;R3is phenyl or monocyclic heteroaryl each (i) optionally substituted with a single substituent selected from -L3C-(phenyl optionally substituted with 1-5 R3D), -L3C-(monocyclic heteroaryl optionally substituted with 1-5 R3D), -l_3C-(monocyclic C3-C6 cycloalkyl optionally substituted with 1-5 R3E), -l_3C-(monocyclic C4-C6 heterocycloalkyl optionally substituted with 1-5 R3E) and (ii) optionally substituted with 1-5 R3E, in which

[0596] each L3Cis a bond, methylene, ethylene, -C(O)-, -S-, -S(O)i-2-, -O- or -N3G-; each R3Dis independently selected from optionally-substituted C1-C4 alkyl, C1-C4 fluoroalkyl, halogen, -CN, SF5, -N3, -C(O)R3F, -SR3F, -S(O)I-23F,

[0597] -OR3F, -NR3GR3F, -C(O)R3F, -C(O)NR3GR3F, -NR3GC(O)R3F, -C(S)NR3GR3F, -NR3GC(S)R3F, -C(O)OR3F, -OC(O)R3F, -C(O)SR3F, -SC(O)R3F, -C(S)OR3F, -OC(S)R3F, -C(S)SR3F, -SC(S)R3F, -S(O)I-2O3F, -OS(O)I-23F, -S(O)I-2N3G 3Fand -N3GS(O)I-23F;

[0598] each R3Eis independently selected from oxo, optionally-substituted C1-C4 alkyl, C1-C4 fluoroalkyl, halogen, -CN, SF5, -N3, -C(O)R3F, -SR3F,

[0599] -S(O)I-2R3F, -OR3F, -NR3GR3F, -C(O)R3F, -C(O)NR3GR3F, -NR3GC(O)R3F, -C(S)NR3GR3F, -NR3GC(S)R3F, -C(O)OR3F, -OC(O)R3F, -C(O)SR3F, -SC(O)R3F, -C(S)OR3F, -OC(S)R3F, -C(S)SR3F, -SC(S)R3F, -S(O)I-2OR3F, -OS(O)I-2R3F, -

[0600]

[0601] S(O)I-2NR3GR3F, -NR3GS(O)I-2R3F; each R3Fis independently selected from H, Ci-C3alkyl and Ci-C3fluoroalkyl and each R3Gis independently selected from H and Ci-C3alkyl, Ci-C3fluoroalkyl;

[0602] L4is selected from the group consisting of a bond, -C(O)-, -S-, -S(O)i-2-, -O- and -NR6-; R4is selected from the group consisting of unsubstituted, hydroxylated, C1-C4 alkoxylated or fluorinated Ci-Cs alkyl, unsubstituted or fluorinated Ci-Cs alkenyl and unsubstituted or fluorinated C-i-Cs alkynyl;

[0603] L5is a bond, -C(O)-, -S-, -S(O)i.2-, -O- or -NR6-;

[0604] R5is phenyl, monocyclic heteroaryl, monocyclic heterocycloalkyl or monocyclic cycloalkyl each optionally substituted with 1-5 R5E, in which

[0605] each R5Eis independently selected from oxo, optionally-substituted C1-C4 alkyl, C1-C4 fluoroalkyl, halogen, -CN, -SF5, -N3, -C(O)R5F, -SR5F, -S(O)I-2R5F, -OR5F, -NR5GR5F, -C(O)R5F, -C(O)NR5GR5F, -NR5GC(O)R5F, -C(S)NR5GR5F, -NR1 GC(S)R5F, -C(O)OR5F, -OC(O)R5F, -C(O)SR5F, -SC(O)R5F, -C(S)OR5F, -OC(S)R5F, -C(S)SR5F, -SC(S)R5F, -S(O)I-2OR5F, -OS(O)I-2R5F, -S(O)I-2NR5GR5Fand -NR5GS(O)I-2R5F;

[0606] each R5Fis independently selected from H, Ci-C3alkyl and C1-C3 fluoroalkyl andeach R5Gis independently selected from H and C1-C3 alkyl;

[0607] wherein

[0608] each R6is selected from the group consisting of hydrogen, C1-C3 alkyl and -C(0)(Ci-C3 alkyl);

[0609] each monocyclic cycloalkyl has 3-7 ring carbons and is saturated or partially unsaturated; each monocyclic heterocycloalkyl has 3-7 ring members and 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur and is saturated or partially unsaturated; each monocyclic heteroaryl is a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0610] Embodiment 19. The combination, composition, or method of Embodiment 18, wherein L1is -S-.

[0611] Embodiment 20. The combination, composition, or method of Embodiment 18, wherein L1is a bond.

[0612] Embodiment 21. The combination, composition, or method of any of Embodiments 18-20, wherein R1is unsubstituted Ci-Cs alkyl.

[0613] Embodiment 22. The combination, composition, or method of any of Embodiments 18-20, wherein R1is unsubstituted or fluorinated C1-C4 alkyl, e.g., unsubstituted C1-C4 alkyl.

[0614] Embodiment 23. The combination, composition, or method of any of Embodiments 18-20, wherein R1is isopropyl.

[0615] Embodiment 24. The combination, composition, or method of any of Embodiments 18-20, wherein R1is phenyl optionally substituted with 1-5 R1E.

[0616] Embodiment 25. The combination, composition, or method of Embodiment 24, wherein the R1phenyl is substituted with 1-5 R1E, e.g., 1-4 R1E, or 1-3 R1E.

[0617] Embodiment 26. The combination, composition, or method of Embodiment 24, wherein the R1phenyl is substituted with 1-2 R1E, e.g., 1 R1E.Embodiment 27. The combination, composition, or method of Embodiment 24, wherein the R1phenyl is unsubstituted.

[0618] Embodiment 28. The combination, composition, or method of any of Embodiments 18-27, wherein L5is a bond.

[0619] Embodiment 29. The combination, composition, or method of any of Embodiments 18-28, wherein R5is cycloalkyl or heterocycloalkyl, each optionally substituted with 1-5 R5E.

[0620] Embodiment 30. The combination, composition, or method of any of Embodiments 18-28, wherein R5is cyclohexenyl or cyclohexyl, each optionally substituted with 1-5 R5E.

[0621] Embodiment 31. The combination, composition, or method of any of Embodiments 18-28, wherein R5is piperidinyl, piperazinyl, morpholinyl or pyrrolidinyl, each optionally substituted with 1-5 R5E.

[0622] Embodiment 32. The combination, composition, or method of any of Embodiments 18-28, wherein R5is C5-C6 cycloalkyl or C5-C6 heterocycloalkyl, each optionally substituted with 1-5 R5E.

[0623] Embodiment 33. The combination, composition, or method of any of Embodiments 18-28, wherein R5is phenyl, optionally substituted with 1-5 R5E.

[0624] Embodiment 34. The combination, composition, or method of any of Embodiments 18-28, wherein R5is monocyclic heteroaryl, optionally substituted with 1-5 R5E.

[0625] Embodiment 35. The combination, composition, or method of any of Embodiments 18-28, wherein R5is isoxazolyl, a pyridyl, an imidazopyridyl, a pyrazolyl, optionally substituted with 1-5 R5E.

[0626] Embodiment 36. The combination, composition or method of any of Embodiments 29-35, wherein the R5group is substituted with 1-5 R5E, e.g., 1-4 R5E, or 1-3 R5E.Embodiment 37. The combination, composition or method of any of Embodiments 29-35, wherein the R5group is substituted with 1-2 R5E, e.g., 1 R5E.

[0627] Embodiment 38. The combination, composition or method of any of Embodiments 29-35, wherein the R5group is unsubstituted.

[0628] Embodiment 39. The combination, composition, or method of any of Embodiments 18-23, 28-32, and 36-38, wherein

[0629] L1is selected from the group consisting of a bond, -S-, -S(O)i-2-, and -O- (e.g., as further described in any consistent Embodiment above)

[0630] R1is selected from C-i-Cs alkyl and Ci-Cs alkenyl, each unsubstituted or fluorinated (e.g., as further described in any consistent Embodiment above),

[0631] L5is a bond, and

[0632] R5is cycloalkyl or heterocycloalkyl, each optionally substituted with 1-5 R5E(e.g., as further described in any consistent Embodiment above).

[0633] Embodiment 40. The combination, composition, or method of any of Embodiments 18, 24-28, and 33-38, wherein

[0634] L1is a bond,

[0635] R1is selected from the group consisting of phenyl and monocyclic heteroaryl, each optionally substituted with 1-5 R1E(e.g., as further described in any consistent Embodiment above);

[0636] L5is a bond, and

[0637] R5is phenyl, monocyclic heteroaryl, cycloalkyl or heterocycloalkyl, each optionally substituted with 1-5 R5E(e.g., as further described in any consistent Embodiment above).

[0638] Embodiment 41. The combination, composition, or method of any of Embodiments 18-40, wherein L2is a bond.

[0639] Embodiment 42. The combination, composition, or method of any of Embodiments 18-41, wherein Q is -C(O)OH.

[0640] Embodiment 43. The combination, composition, or method of any of Embodiments 18-42, wherein L3is a bond.Embodiment 44. The combination, composition, or method of any of Embodiments 18-42, wherein R3is phenyl substituted with 0-5 R3E.

[0641] Embodiment 45. The combination, composition, or method of any of Embodiments 18-42, wherein R3is monocyclic heteroaryl substituted with 0-5 R3E.

[0642] Embodiment 46. The combination, composition, or method of any of Embodiments 18-42, wherein R3is isothiazolyl, pyridonyl, thiadiazolyl, pyrazinyl, imidazolyl, pyridinyl, pyrazolyl, isoxazolyl, thienyl, furanyl or pyrimidinyl, each substituted with 0-5 R3E.

[0643] Embodiment 47. The combination, composition, or method of any of Embodiments 18-46, wherein the R3group is substituted with 1-5 R3E, e.g., 1-4 R3E, or 1-3 R3E.

[0644] Embodiment 48. The combination, composition, or method of any of Embodiments 18-46, wherein the R3group is substituted with 1-2 R3E, e.g., 1 R3E.

[0645] Embodiment 49. The combination, composition, or method of any of Embodiments 18-46, wherein the R3group is unsubstituted.

[0646] Embodiment 50. The combination, composition, or method of any of Embodiments 18-49, wherein R4is hydrogen or unsubstituted C-i-Ce alkyl.

[0647] Embodiment 51. The combination, composition, or method of any of Embodiments 18-49, wherein R4is unsubstituted C1-C4 alkyl.

[0648] Embodiment 52. The combination, composition, or method of any of Embodiments 18-49, wherein R4is methyl.

[0649] Embodiment 53. The combination, composition, or method of any of Embodiments 1-13, wherein the OMA1 activator is a compound of Compound Table 1.Embodiment 54. The combination, composition, or method of any of Embodiments 1-13, wherein the 0MA1 activator is a compound having an activity as “A,” “B” or “C” in Compound Table 1.

[0650] Embodiment 55. The combination, composition, or method of any of Embodiments 1-13, wherein the 0MA1 activator is a compound having an activity as “A,” or “B” in Compound Table 1.

[0651] Embodiment 56. The combination, composition, or method of any of Embodiments 1-13, wherein the 0MA1 activator is a compound having an activity as “A” in Compound Table 1.

[0652] Embodiment 57. The combination, composition, or method of any of Embodiments 1-13, wherein the 0MA1 activator is a compound of Compound Table 2.

[0653] Embodiment 58. The combination, composition, or method of any of Embodiments 1-13, wherein the 0MA1 activator is a compound having an activity as “A,” “B” or “C” in Compound Table 2.

[0654] Embodiment 59. The combination, composition, or method of any of Embodiments 1-13, wherein the 0MA1 activator is a compound having an activity as “A,” or “B” in Compound Table 2.

[0655] Embodiment 60. The combination, composition, or method of any of Embodiments 1-13, wherein the OMA1 activator is a compound having an activity as “A” in Compound Table 2.

[0656] Embodiment 61. The combination, composition, or method of any of Embodiments 1-13, wherein the 0MA1 activator is a compound of Formula I

[0657] R4— L4

[0658]

[0659]

[0147] or a pharmaceutically-acceptable salt thereof, whereinL1is -S- or a bond;

[0660] R1is selected from the group consisting of Ci-Cs alkyl, Ci-Cs alkenyl and Ci-Cs alkynyl, each unsubstituted or fluorinated,

[0661] L2is a bond or -CH2-;

[0662] Q is -C(O)OH, -C(O)OR2A, of-C(O)NR2BR2A, in which

[0663] each R2Ais independently selected from H and C1-C3 alkyl, and

[0664] each R2Bis independently selected from H and C1-C3 alkyl;

[0665] L3is a bond;

[0666] R3is phenyl or monocyclic heteroaryl, optionally substituted with 1-5 R3E, in which each R3Eis independently selected from oxo, optionally-substituted C1-C4 alkyl, C1-C4 fluoroalkyl, halogen, -CN, SF5, -N3, -C(O)R3F, -SR3F,

[0667] -S(O)I-2R3F, -OR3F, -NR3GR3F, -C(O)R3F, -C(O)NR3GR3F, -NR3GC(O)R3F, -C(S)NR3GR3F, -NR3GC(S)R3F, -C(O)OR3F, -OC(O)R3F, -C(O)SR3F, -SC(O)R3F, -C(S)OR3F, -OC(S)R3F, -C(S)SR3F, -SC(S)R3F, -S(O)I-2OR3F, -OS(O)I-2R3F, -S(O)I-2NR3GR3F, -NR3GS(O)I-2R3F;

[0668] each R3Fis independently selected from H, C1-C3 alkyl and C1-C3 fluoroalkyl and each R3Gis independently selected from H and C1-C3 alkyl, C1-C3 fluoroalkyl; L4is a bond,

[0669] R4is selected from the group consisting of hydrogen, optionally substituted Ci-Cs alkyl, optionally-substituted Ci-Cs alkenyl and optionally substituted Ci-Cs alkynyl;

[0670] L5is a bond,

[0671] R5is cycloalkyl or heterocycloalkyl, each optionally substituted with 1-5 R5E, in which each R5Eis independently selected from oxo, optionally-substituted C1-C4 alkyl, C1-C4 fluoroalkyl, halogen, -CN, -SF5, -N3, -C(O)R5F, -SR5F, -S(O)I-2R5F, -OR5F, -NR5GR5F, -C(O)R5F, -C(O)NR5GR5F, -NR5GC(O)R5F, -C(S)NR5GR5F, -NR1GC(S)R5F, -C(O)OR5F, -OC(O)R5F, -C(O)SR5F, -SC(O)R5F, -C(S)OR5F, -OC(S)R5F, -C(S)SR5F, -SC(S)R5F, -S(O)I-2OR5F, -OS(O)I-2R5F, -S(O)I-2NR5GR5Fand -NR5GS(O)I-2R5F; each R5Fis independently selected from H, C1-C3 alkyl and C1-C3 fluoroalkyl and each R5Gis independently selected from H and C1-C3 alkyl;

[0672] wherein

[0673] each optionally substituted alkyl, alkenyl and alkynyl is unsubstituted, fluorinated or substituted with one or two hydroxyl groups;each cycloalkyl has 3-10 ring carbons and is saturated or partially unsaturated, and optionally includes one or two fused cycloalkyl rings, each fused ring having 3-8 ring members;

[0674] each heterocylcloalkyl has 3-10 ring members and 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur and is saturated or partially unsaturated, and optionally includes one or two fused cycloalkyl rings, each having 3-8 ring members;

[0675] each monocyclic heteroaryl is a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur.

[0676] Embodiment 62. The combination, composition, or method of Embodiment 61, wherein L1is -S-

[0677] Embodiment 63. The combination, composition, or method of Embodiment 61 or Embodiment 62, wherein R1is unsubstituted.

[0678] Embodiment 64. The combination, composition, or method of any of Embodiments 61-63, wherein R1is Ci-Cs alkyl.

[0679] Embodiment 65. The combination, composition, or method of any of Embodiments 61-63, wherein R1is propyl (e.g., isopropyl), butyl or butenyl.

[0680] Embodiment 66. The combination, composition, or method of any of Embodiments 61-65, wherein L2is a bond.

[0681] Embodiment 67. The combination, composition, or method of any of Embodiments 61-66, wherein Q is -C(O)OH,

[0682] Embodiment 68. The combination, composition, or method of any of Embodiments 61-67, wherein Q is -C(O)O(Ci-C3 alkyl).

[0683] Embodiment 69. The combination, composition, or method of any of Embodiments 61-68, wherein R3is phenyl optionally substituted with 1-5 R3E.Embodiment 70. The combination, composition, or method of any of Embodiments 61-69, wherein R4is unsubstituted C1-C3 alkyl.

[0684] Embodiment 71. The combination, composition, or method of any of Embodiments 61-70, wherein R5is heterocycloalkyl optionally substituted with 1-5 R5t.

[0685] Embodiment 72. The combination, composition, or method of Embodiment 71, wherein the heterocycloalkyl is a monocyclic nitrogen-containing heterocycloalkyl, attached to the -L?-through a nitrogen atom.

[0686] Embodiment 73. The combination, composition, or method of any of Embodiments 61-72, wherein Rbis cycloalkyl optionally substituted with 1-5 R5t:.

[0687] Embodiment 74. The combination, composition, or method of Embodiment 73, wherein the R5cycloalkyl is monocyclic and is partially unsaturated.

[0688] Embodiment 73. The combination, composition, or method of any of Embodiments 61-74, wherein each optionally substituted alkyl, alkenyl and alkynyl is unsubstituted or fluorinated.

[0689] Embodiment 74. The combination, composition, or method of Embodiment 61, wherein

[0690] L1is -S-.

[0691] R1is propyl, butyl or butenyl;

[0692] L2 is a bond;

[0693] Q is -C(O)OH;

[0694] R3is phenyl optionally substituted with 1-5 R3E;

[0695] R4is unsubstituted C1-C3 alkyl; and

[0696] each optionally substituted alkyl, alkenyl and alkynyl is unsubstituted or fluorinated^

[0697] Embodiment 75. The combination, composition, or method of Embodiment 74, wherein Rbis monocyclic heterocycloalkyl optionally substituted with 1-5 R5E, the monocyclic heterocycloalkyl being attached to the -Lb- through a nitrogen atom.

[0698] Embodiment 76. The combination, composition, or method of Embodiment 74, wherein Rbis monocyclic cycloalkyl optionally substituted with 1-5 R5E.Embodiment 77. The combination, composition, or method of Embodiment 76, wherein the R5monocyclic cycloalkyl is partially unsaturated.

[0699] Embodiment 78. The combination, composition, or method of any of Embodiments 1-13, wherein the compound is

[0700] 4-(3-fluorophenyl)-1-(5-(isopropylthio)-4-(4-methyl cyclohex-1 -en-1 -yl)thiazol-2-yl)-3- methyl-1 H-pyrazole-5-carboxylic acid;

[0701] 4-(3-fluorophenyl)-1-(5-(isopropylthio)-4-(4-(trifluoromethyl)cyclohex-1-en-1-yl)thiazol-2- yl)-3-methyl-1 H-pyrazole-5-carboxylic acid;

[0702] 1 -(4-(4,4-dimethyl cyclohex-1 -en-1 -yl)-5-(isopropylthio)thiazol-2-yl)-4-(3-fluorophenyl)-3- methyl-1 H-pyrazole-5-carboxylic acid;

[0703] 4-(3-fluorophenyl)-1-(5-(isopropylthio)-4-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)thiazol-2-yl)-3- methyl-1 H-pyrazole-5-carboxylic acid;

[0704] 4-(3-fluorophenyl)-1-(5-(isopropylthio)-4-(piperidin-1-yl)thiazol-2-yl)-3-methyl-1H- pyrazole-5-carboxylic acid;

[0705] 4-(3-fluorophenyl)-1-(5-(isopropylthio)-4-(4-(trifluoromethyl)piperidin-1-yl)thiazol-2-yl)-3- methyl-1 H-pyrazole-5-carboxylic acid;

[0706] 4-(3-fluorophenyl)-1-(5-(isopropylthio)-4-morpholinothiazol-2-yl)-3-methyl-1H-pyrazole-5- carboxylic acid;

[0707] 1-(4-(4,4-difluoropiperidin-1-yl)-5-(isopropylthio)thiazol-2-yl)-4-(3-fluorophenyl)-3-methyl- 1 H-pyrazole-5-carboxylic acid;

[0708] methyl 4-(3-fluorophenyl)-1-(5-(isopropylthio)-4-(4-(trifluoromethyl)cyclohex-1-en-1- yl)thiazol-2-yl)-3-methyl-1H-pyrazole-5-carboxylate;

[0709] 4-(3-fluorophenyl)-1-(5-isobutyl-4-(4-(trifluoromethyl)phenyl)thiazol-2-yl)-3-methyl-1H- pyrazole-5-carboxylic acid;

[0710] 4-(3-fluorophenyl)-1-(5-(isopropylthio)-4-(4-(2,2,2-trifluoroethyl)piperazin-1-yl)thiazol-2- yl)-3-methyl-1 H-pyrazole-5-carboxylic acid;

[0711] 1-(4-(4-cyanopiperidin-1-yl)-5-(isopropylthio)thiazol-2-yl)-4-(3-fluorophenyl)-3-methyl-1H- pyrazole-5-carboxylic acid;

[0712] 1-(4-(4-cyclopropylpiperazin-1-yl)-5-(isopropylthio)thiazol-2-yl)-4-(3-fluorophenyl)-3- methyl-1 H-pyrazole-5-carboxylic acid;

[0713] 1-(4-(4-ethylpiperazin-1-yl)-5-(isopropylthio)thiazol-2-yl)-4-(3-fluorophenyl)-3-methyl-1 H- pyrazole-5-carboxylic acid;1-(4-(4-acetylpi perazin-1 -yl)-5-(isopropylthio)thiazol-2-yl)-4-(3-fluorophenyl)-3-methyl- 1 H-pyrazole-5-carboxylic acid;

[0714] 4-(3-fluorophenyl)-1-(5-(isopropylthio)-4-(4-methylpiperidin-1-yl)thiazol-2-yl)-3-methyl- 1 H-pyrazole-5-carboxylic acid;

[0715] 4-(3-fluorophenyl)-1-(5-(isopropylthio)-4-(4-methylpiperazin-1-yl)thiazol-2-yl)-3-methyl- 1 H-pyrazole-5-carboxylic acid;

[0716] 1 -(4-(4,4-dimethylpiperidin-1 -yl)-5-(isopropylthio)thiazol-2-yl)-4-(3-fluorophenyl)-3- methyl-1 H-pyrazole-5-carboxylic acid;

[0717] 4-(3-fluorophenyl)-1-(5-(isopropylthio)-4-(3-(trifluoromethyl)pyrrolidin-1-yl)thiazol-2-yl)-3- methyl-1 H-pyrazole-5-carboxylic acid;

[0718] 1-(4-(4-(tert-butyl)piperidin-1-yl)-5-(isopropylthio)thiazol-2-yl)-4-(3-fluorophenyl)-3- methyl-1 H-pyrazole-5-carboxylic acid;

[0719] 4-(3-fluorophenyl)-1-(5-(isopropylthio)-4-(6-azaspiro[2.5]octan-6-yl)thiazol-2-yl)-3-methyl- 1 H-pyrazole-5-carboxylic acid;

[0720] 4-(3-fluorophenyl)-1-(5-(isopropylthio)-4-(4-methoxy-4-(trifluoromethyl)piperidin-1- yl)thiazol-2-yl)-3-methyl-1 H-pyrazole-5-carboxylic acid; or

[0721] 4-(3-fluorophenyl)-1-(4-(4-isopropylpiperidin-1-yl)-5-(isopropylthio)thiazol-2-yl)-3-methyl- 1 H-pyrazole-5-carboxylic acid,

[0722] optionally in the form of a pharmaceutically acceptable salt or N-oxide, and / or a solvate or hydrate.

[0723] Embodiment 79. The combination, composition, or method of any of Embodiments 3-78, wherein the cancer a solid tumor cancer.

[0724] Embodiment 80. The combination, composition, or method of any of Embodiments 3-78, wherein the cancer is a carcinoma, such as a renal carcinoma or a colon carcinoma.

[0725] Embodiment 81. The combination, composition, or method of any of Embodiments 3-78, wherein the cancer is a hematological cancer, such as a lymphoma.

[0726] Embodiment 82. The combination, composition, or method of any of Embodiments 3-78, wherein the cancer is selected from acoustic neuroma, acute leukemia, acute lymphoblastic leukemia, acute myelogenous leukemia (monocytic, myeloblastic, adenocarcinoma, angiosarcoma, astrocytoma, myelomonocytic and promyelocytic), acute t-cell leukemia, basalcell carcinoma, bile duct carcinoma, bladder cancer, brain cancer, breast cancer (including estrogen-receptor positive breast cancer), bronchogenic carcinoma, Burkitt's lymphoma, cervical cancer, chondrosarcoma, chordoma, choriocarcinoma, chronic leukemia, chronic lymphocytic leukemia, chronic myelocytic (granulocytic) leukemia, chronic myelogenous leukemia, colon cancer, colorectal cancer, craniopharyngioma, cystadenocarcinoma, dysproliferative changes (dysplasias and metaplasias), embryonal carcinoma, endometrial cancer, endotheliosarcoma, ependymoma, epithelial carcinoma, erythroleukemia, esophageal cancer, estrogen-receptor positive breast cancer, essential thrombocythemia, Ewing's tumor, fibrosarcoma, gastric carcinoma, germ cell testicular cancer, gestational trophoblastic disease, glioblastoma, head and neck cancer, heavy chain disease, hemangioblastoma, hepatoma, hepatocellular cancer, hormone insensitive prostate cancer, leiomyosarcoma, liposarcoma, lung cancer (including small cell lung cancer and non-small cell lung cancer), lymphangioendothelio-sarcoma, lymphangiosarcoma, lymphoblastic leukemia, lymphoma (lymphoma, including diffuse large B-cell lymphoma, follicular lymphoma, Hodgkin's lymphoma and non-Hodgkin's lymphoma), malignancies and hyperproliferative disorders of the bladder, breast, colon, lung, ovaries, pancreas, prostate, skin and uterus, lymphoid malignancies of T-cell or B-cell origin, leukemia, medullary carcinoma, medulloblastoma, melanoma, meningioma, mesothelioma, multiple myeloma, myelogenous leukemia, myeloma, myxosarcoma, neuroblastoma, oligodendroglioma, oral cancer, osteogenic sarcoma, ovarian cancer, pancreatic cancer, papillary adenocarcinomas, papillary carcinoma, peripheral T-cell lymphoma, pinealoma, polycythemia vera, prostate cancer (including hormone-insensitive (refractory) prostate cancer), rectal cancer, renal cell carcinoma, retinoblastoma, rhabdomyosarcoma, sarcoma, sebaceous gland carcinoma, seminoma, skin cancer, small cell lung carcinoma, solid tumors (carcinomas and sarcomas), stomach cancer, squamous cell carcinoma, synovioma, sweat gland carcinoma, testicular cancer (including germ cell testicular cancer), thyroid cancer, Waldenstrom's macroglobulinemia, testicular tumors, uterine cancer, and Wilms' tumor.

[0727] Embodiment 83. The combination, composition, or method of any of Embodiments 3-82, wherein the 0MA1 activator alone does not substantially induce apoptosis in the cancer.

[0728] Embodiment 84. The combination, composition, or method of any of Embodiments 3-82, wherein the BH3 mimetic alone does not substantially induce apoptosis in the cancer.Embodiment 85. The combination, composition, or method of any of Embodiments 3-82, wherein neither the BH3 mimetic nor the 0MA1 activator alone substantially induces apoptosis in the cancer.

Claims

What is claimed is:

1. A pharmaceutical combination comprisinga BH3 mimetic (e.g., venetoclax or navitoclax); andan 0MA1 activator (e.g., a compound of Formula I as described herein).

2. A pharmaceutical composition comprising:a BH3 mimetic (e.g., venetoclax or navitoclax); andan 0MA1 activator (e.g., a compound of Formula I as described herein).

3. A method for treating cancer in a patient in need thereof, the method comprising administering to the patientan effective amount of a BH3 mimetic (e.g., venetoclax or navitoclax); andan effective amount of an 0MA1 activator (e.g., a compound of Formula I as described herein).

4. A method for improving the efficacy of treatment in a patient being treated with a BH3 mimetic for cancer, the method comprising administering to the patient an effective amount of an 0MA1 activator (e.g., a compound of Formula I as described herein).

5. The combination, composition or method of any of claims 1-4, wherein the BH3 mimetic is venetoclax.

6. The combination, composition or method of any of claims 1-4, wherein the BH3 mimetic is navitoclax.

7. The combination, composition or method of any of claims 1-4, wherein the BH3 mimetic is ABT-737 (Abbott / Abbvie), S55746 (Servier), sonrotoclax (Beigene), AZD4320 (AstraZeneca), Obatoclax (Gemin X / Teva) is S63845 (Servier), AZD5991 (AstraZeneca), A-1210477 (Abbvie), murizatoclax (AMG-397, Amgen), tapotoclax (AMG-176, Amgen), xevinapant (DebioPharma), or LCL161 (Novartis), A-1155463, A-1331852, BGB-11417, LP-108, S65487, AT-101, APG-1252, APG2575, and BCL-201.

8. The combination, composition or method of any of claims 1-7, wherein the 0MA1 activator is BTM-3566 (i.e., 4-(3-fluorophenyl)-1-(5-(isopropylthio)-4-(4-(trifluoromethyl)cyclohex-1-en-1-yl)thiazol-2-yl)-3-methyl-1 H-pyrazole-5-carboxylic acid or a pharmaceutically-acceptable salt thereof.

9. The combination, composition, or method of any of claims 1-8, wherein the 0MA1 activator is a compound of Formula IR4— L4or a pharmaceutically-acceptable salt thereof, whereinL1is -S- or a bond;R1is selected from the group consisting of Ci-Cs alkyl, Ci-Cs alkenyl and Ci-Cs alkynyl, each unsubstituted or fluorinated,L2is a bond or -CH2-;Q is -C(O)OH, -C(O)OR2A, of-C(O)NR2BR2A, in whicheach R2Ais independently selected from H and C1-C3 alkyl, andeach R2Bis independently selected from H and C1-C3 alkyl;L3is a bond;R3is phenyl or monocyclic heteroaryl, optionally substituted with 1-5 R3E, in whicheach R3Eis independently selected from oxo, optionally-substituted C1-C4 alkyl, C1-C4 fluoroalkyl, halogen, -CN, SF5, -N3, -C(O)R3F, -SR3F,-S(O)I-2R3F, -OR3F, -NR3GR3F, -C(O)R3F, -C(O)NR3GR3F, -NR3GC(O)R3F, -C(S)NR3GR3F, -NR3GC(S)R3F, -C(O)OR3F, -OC(O)R3F, -C(O)SR3F, -SC(O)R3F, -C(S)OR3F, -OC(S)R3F, -C(S)SR3F, -SC(S)R3F, -S(O)I-2OR3F, -OS(O)I-2R3F, -S(O)I-2NR3GR3F, -NR3GS(O)I-2R3F;each R3Fis independently selected from H, C1-C3 alkyl and C1-C3 fluoroalkyl and each R3Gis independently selected from H and C1-C3 alkyl, C1-C3 fluoroalkyl;L4is a bond,R4is selected from the group consisting of hydrogen, optionally substituted Ci-Cs alkyl, optionally-substituted Ci-Cs alkenyl and optionally substituted Ci-Cs alkynyl;L5is a bond,R5is cycloalkyl or heterocycloalkyl, each optionally substituted with 1-5 R5E, in which each R5Eis independently selected from oxo, optionally-substituted C1-C4 alkyl, C1-C4 fluoroalkyl, halogen, -CN, -SF5, -N3, -C(O)R5F, -SR5F, -S(O)I-2R5F, -OR5F, -NR5GR5F, -C(O)R5F, -C(O)NR5GR5F, -NR5GC(O)R5F, -C(S)NR5GR5F, -NR1GC(S)R5F, -C(O)OR5F, -OC(O)R5F, -C(O)SR5F, -SC(O)R5F, -C(S)OR5F, -OC(S)R5F, -C(S)SR5F, -SC(S)R5F, -S(O)I-2OR5F, -OS(O)I-2R5F, -S(O)I-2NR5GR5Fand -NR5GS(O)I-2R5F; each R5Fis independently selected from H, C1-C3 alkyl and C1-C3 fluoroalkyl and each R5Gis independently selected from H and Ci-C3alkyl;whereineach optionally substituted alkyl, alkenyl and alkynyl is unsubstituted, fluorinated or substituted with one or two hydroxyl groups;each cycloalkyl has 3-10 ring carbons and is saturated or partially unsaturated, and optionally includes one or two fused cycloalkyl rings, each fused ring having 3-8 ring members;each heterocylcloalkyl has 3-10 ring members and 1-3 heteroatoms independently selected from nitrogen, oxygen and sulfur and is saturated or partially unsaturated, and optionally includes one or two fused cycloalkyl rings, each having 3-8 ring members;each monocyclic heteroaryl is a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen and sulfur.

10. The combination, composition, or method of claim 9, wherein L1is-S-.

11. The combination, composition, or method of claim 9 or claim 10, wherein R1is propyl (e.g., isopropyl), butyl or butenyl.

12. The combination, composition, or method of any of claims 9-11, wherein L2is a bond.

13. The combination, composition, or method of any of claims 9-12, wherein Q is -C(O)OH,14. The combination, composition, or method of any of claims 9-13, wherein Q is -C(O)O(Ci-C3alkyl).

15. The combination, composition, or method of any of claims 9-14, wherein R3is phenyl optionally substituted with 1-5 R3E.

16. The combination, composition, or method of any of claims 9-15, wherein R4is unsubstituted C1-C3 alkyl.

17. The combination, composition, or method of any of claims 9-16, wherein R5is cycloalkyl optionally substituted with 1-5 R5E.

18. The combination, composition, or method of claim 17, wherein the R5cycloalkyl is monocyclic and is partially unsaturated.

19. The combination, composition, or method of any of claims 9-16, wherein R5is heterocycloalkyl optionally substituted with 1-5 R5E.

20. The combination, composition, or method of claim 19, wherein the heterocycloalkyl is a monocyclic nitrogen-containing heterocycloalkyl, attached to the -L5- through a nitrogen atom.

21. The combination, composition, or method of any of claims 9-20, wherein each optionally substituted alkyl, alkenyl and alkynyl is unsubstituted or fluorinated.

22. The combination, composition, or method of claim 9, whereinL1is -S-.R1is propyl, butyl or butenyl;L2is a bond;Q is -C(O)OH;R3is phenyl optionally substituted with 1-5 R3E;R4is unsubstituted C1-C3 alkyl; andeach optionally substituted alkyl, alkenyl and alkynyl is unsubstituted or fluorinated^23. The combination, composition, or method of claim 22, wherein R5is monocyclic cycloalkyl optionally substituted with 1-5 R5E.

24. The combination, composition, or method of claim 23, wherein the R5monocyclic cycloalkyl is partially unsaturated,25. The combination, composition, or method of claim 22, wherein R5is monocyclic heterocycloalkyl optionally substituted with 1-5 R5E, the monocyclic heterocycloalkyl being attached to the -L5- through a nitrogen atom,26. The combination, composition, or method of any of claims 3-25, wherein the cancer a solid tumor cancer.

27. The combination, composition, or method of any of claims 3-25, wherein the cancer is a carcinoma, such as a renal carcinoma or a colon carcinoma.

28. The combination, composition, or method of any of claims 3-25, wherein the cancer is a hematological cancer, such as a lymphoma.

29. The combination, composition, or method of any of claims 3-25, wherein the cancer is selected from acoustic neuroma, acute leukemia, acute lymphoblastic leukemia, acute myelogenous leukemia (monocytic, myeloblastic, adenocarcinoma, angiosarcoma, astrocytoma, myelomonocytic and promyelocytic), acute t-cell leukemia, basal cell carcinoma, bile duct carcinoma, bladder cancer, brain cancer, breast cancer (including estrogen-receptor positive breast cancer), bronchogenic carcinoma, Burkitt's lymphoma, cervical cancer, chondrosarcoma, chordoma, choriocarcinoma, chronic leukemia, chronic lymphocytic leukemia, chronic myelocytic (granulocytic) leukemia, chronic myelogenous leukemia, colon cancer, colorectal cancer, craniopharyngioma, cystadenocarcinoma, dysproliferative changes (dysplasias and metaplasias), embryonal carcinoma, endometrial cancer, endotheliosarcoma, ependymoma, epithelial carcinoma, erythroleukemia, esophageal cancer, estrogen-receptor positive breast cancer, essential thrombocythemia, Ewing's tumor, fibrosarcoma, gastric carcinoma, germ cell testicular cancer, gestational trophoblastic disease, glioblastoma, head and neck cancer, heavy chain disease, hemangioblastoma, hepatoma, hepatocellular cancer, hormone insensitive prostate cancer, leiomyosarcoma, liposarcoma, lung cancer (including small cell lung cancer and non-small cell lung cancer), lymphangioendothelio-sarcoma, lymphangiosarcoma, lymphoblastic leukemia, lymphoma (lymphoma, including diffuse large B-cell lymphoma, follicular lymphoma, Hodgkin's lymphoma and non-Hodgkin's lymphoma), malignancies andhyperproliferative disorders of the bladder, breast, colon, lung, ovaries, pancreas, prostate, skin and uterus, lymphoid malignancies of T-cell or B-cell origin, leukemia, medullary carcinoma, medulloblastoma, melanoma, meningioma, mesothelioma, multiple myeloma, myelogenous leukemia, myeloma, myxosarcoma, neuroblastoma, oligodendroglioma, oral cancer, osteogenic sarcoma, ovarian cancer, pancreatic cancer, papillary adenocarcinomas, papillary carcinoma, peripheral T-cell lymphoma, pinealoma, polycythemia vera, prostate cancer (including hormoneinsensitive (refractory) prostate cancer), rectal cancer, renal cell carcinoma, retinoblastoma, rhabdomyosarcoma, sarcoma, sebaceous gland carcinoma, seminoma, skin cancer, small cell lung carcinoma, solid tumors (carcinomas and sarcomas), stomach cancer, squamous cell carcinoma, synovioma, sweat gland carcinoma, testicular cancer (including germ cell testicular cancer), thyroid cancer, Waldenstrom's macroglobulinemia, testicular tumors, uterine cancer, and Wilms' tumor.

30. The combination, composition, or method of any of claims 3-25, wherein neither the BH3 mimetic nor the OMA1 activator alone substantially induces apoptosis in the cancer.

Images