WO2019040511A1

WO2019040511A1 - Dual inhibitors of the bcl-2 and hdm2 families through co-mimicry of the bh3 and p53-alpha-helices

Info

Publication number: WO2019040511A1
Application number: PCT/US2018/047351
Authority: WO
Inventors: Steven Fletcher; Brandon J. DRENNEN; Ivie L. CONLON; Maryanna E. LANNING
Original assignee: University Of Maryland Batimore
Priority date: 2017-08-22
Filing date: 2018-08-21
Publication date: 2019-02-28

Abstract

The invention relates to dual HDM2/Bcl-2 inhibitors, providing a synergistic effect to help promote apoptosis in tumorigenic cells.

Description

Dual Inhibitors of the BCL-2 and HDM2 Families Through Co-Mimicry of the BH3 and P53-Alpha-Helices

FIELD OF THE INVENTION

[001] The invention described herein relates generally to inhibition of BCL-2 and HDM2, and more particularly, but not exclusively, to dual inhibition of BCL-2 and HDM2.

BACKGROUND OF THE INVENTION

[002] The human body undergoes a continuous process of self-renewal, whereby older cells tissues die and are replaced by new cells. In order to maintain a relatively constant number of cells in a particular tissue, it is important that the number of dying cells in a tissue is equivalent to the number of newly produced cells. This homeostasis is maintained by committing the cells in self-renewing tissues to a process of programmed cell death. The morphological features of cells undergoing this form of cell death have been termed

"apoptosis." Defects in the process of apoptosis occur in various pathological conditions. For example, in cancer, a defect in apoptosis results in cancer cells surviving longer than their normal cell counterparts. As a result, the increased number of surviving cancer cells can cause an increase in the mass of a tumor. In viral infections, induction of apoptosis can figure prominently in the pathophysiology of the disease process.

[003] The BCL-2 protein plays a central role in the process of programmed cell death by blocking apoptosis. For example, when BCL-2 levels in a cell are elevated, apoptosis is blocked. Conversely, when BCL-2 levels in a cell are lowered, the rate of cell death is accelerated. The presence of BCL-2 in a cell also renders the cell highly resistant to various chemical and physical agents. In particular, BCL-2 renders cancer cells more resistant to chemotherapeutic agents.

[004] The human p53 transcription factor induces cell cycle arrest and apoptosis in response to DNA damage and cellular stress, playing a critical role in protecting cells from malignant transformation. The HDM2 protein, an E3 ubiquitin ligase, controls p53 levels through a direct binding interaction that neutralizes p53 transactivation activity, exports nuclear p53, and targets it for degradation. Loss of p53 activity, either by deletion, mutation, or HDM2 overexpression, is one of the most common defects in human cancer. Tumors with preserved expression of wild type p53 are rendered vulnerable by pharmacologic approaches that stabilize native p53. Targeting HDM2 has therefore emerged as a validated approach to restore p53 activity and resensitize cancer cells to apoptosis. SUMMARY OF THE INVENTION

[005] In some embodiments, the invention relates to compounds of Formulas AA-AD:

Formula AA Formula AB Formula AC Formula AD

[006] wherein in Formulas AA-AD:

[007] each R is independently hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, fluoroalkyl, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilanyl, -OR^a, -SR^a, -OC(0)R^a, -N(R^a)R^b, -C(0)R^a, -C(0)OR^a, -OC(0)N(R^a)R^b, -C(0)N(R^a)R^b, -N(R^a)C(0)OR^a, - N(R^a)C(0)R^a, -N(R^a)C(0)N(R^a)R^b, - N(R^a)C(NR^a)N(R^a)R^b, -N(R^a)S(0)_tR^a, -C(0)N(R^a)S(0)_tR^a, - S(0)tOR^a, -S(0)tN(R^a)R^b, -S(0)tN(R^a)C(0)R^b, or -P(0)(OR^a)(OR^b);

[008] R^a and R^b are each independently selected from the group consisting of hydrogen, alkyl, fluoroalkyl, cycloalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, heteroarylalkyl, halogen, -O-alkyl, -O-aryl, cyano, nitro, - OH, -NH₂, -NH-alkyl, and -NH-aryl; and t is 1 or 2.

[009] In some embodiments, the invention relates to compounds of Formulas BA-BM:

Formula BA Formula BB Formula BC Formula BD

Formula BE Formula BF Formula BG Formula BH

Formula BI Formula BJ Formula BK Formula BL

Formula BM

[0010] wherein in Formulas BA-BM:

[0011] each R is independently hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, fluoroalkyl, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilanyl, -OR^a, -SR^a, -OC(0)R^a,

-N(R^a)R^b, -C(0)R^a, -C(0)OR^a, -OC(0)N(R^a)R^b, -C(0)N(R^a)R^b, -N(R^a)C(0)OR^a, -

N(R^a)C(0)R^a, -N(R^a)C(0)N(R^a)R^b, -

N(R^a)C(NR^a)N(R^a)R^b, -N(R^a)S(0)_tR^a, -C(0)N(R^a)S(0)_tR^a, -

S(0)tOR^a, -S(0)tN(R^a)R^b, -S(0)tN(R^a)C(0)R^b, or -P(0)(OR^a)(OR^b);

[0012] R' is hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, fluoroalkyl, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilanyl, -OR^a, -SR^a, -OC(0)R^a, -

N(R^a)R^b, -C(0)R^a, -C(0)OR^a, -OC(0)N(R^a)R^b, -C(0)N(R^a)R^b, -N(R^a)C(0)OR^a, - N(R^a)C(0)R^a, -N(R^a)C(0)N(R^a)R^b, -N(R^a)C(NR^a)N(R^a)R^b, -N(R^a)S(0)tR^a, - S(0)tOR^a, -S(0)tN(R^a)R^b, -S(0)tN(R^a)C(0)R^b, or -P(0)(OR^a)(OR^b);

[001] L is a linker selected from a bond, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, fluoroalkyl, -OC(O)-, -NR^a- , -C(O)-, -C(0)0-, -OC(0)N(R^a)-, -C(0)N(R^a)-, -C(0)N(R^a)S(0)t-, -N(R^a)C(0)0-, - N(R^a)C(0)-, -N(R^a)C(0)N(R^a)-, -N(R^a)C(NR^a)N(R^a)-, -N(R^a)S(0)t-, -S(0)tO-, -S(0)tN(R^a)- , -S(0)_tN(R^a)C(0)-, -P(0)(OR^a)0-, -OP(0)(OR^a)0-, -(CR^aR^b)_n-, -0-, -S-, and -S(0)t-;

[002] R^a and R^b are each independently selected from the group consisting of hydrogen, alkyl, fluoroalkyl, cycloalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, heteroarylalkyl, halogen, -O-alkyl, -O-aryl, cyano, nitro, - OH, -NH₂, -NH-alkyl, and -NH-aryl;

[003] n is a positive integer, and t is 1 or 2.

[004] In some embodiments, the invention relates to compounds of Formulas CA-CZ:

Formula CA Formula CB Formula CC Formula CD

Formula CI Formula CJ Formula CK Formula CL

Formula CM Formula CN Formula CO Formula CP

Formula CQ Formula CR Formula CS Formula CT

Formula CU Formula CV Formula CW Formula CX

Formula CY Formula CZ

[005] wherein in Formulas CA-CZ:

[006] each R is independently hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, fluoroalkyl, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilanyl, -OR^a, -SR^a, -OC(0)R^a, -N(R^a)R^b, -C(0)R^a, -C(0)OR^a, -OC(0)N(R^a)R^b, -C(0)N(R^a)R^b, -N(R^a)C(0)OR^a, -

N(R^a)C(0)R^a, -N(R^a)C(0)N(R^a)R^b, -

N(R^a)C(NR^a)N(R^a)R^b, -N(R^a)S(0)_tR^a, -C(0)N(R^a)S(0)_tR^a, -

S(0)tOR^a, -S(0)tN(R^a)R^b, -S(0)tN(R^a)C(0)R^b, or -P(0)(OR^a)(OR^b);

[007] R' is hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, fluoroalkyl, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilanyl, -OR^a, -SR^a, -OC(0)R^a, -

N(R^a)R^b, -C(0)R^a, -C(0)OR^a, -OC(0)N(R^a)R^b, -C(0)N(R^a)R^b, -N(R^a)C(0)OR^a, -

N(R^a)C(0)R^a, -N(R^a)C(0)N(R^a)R^b, -N(R^a)C(NR^a)N(R^a)R^b, -N(R^a)S(0)tR^a, -

S(0)tOR^a, -S(0)tN(R^a)R^b, -S(0)tN(R^a)C(0)R^b, or -P(0)(OR^a)(OR^b);

[008] X is alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, fluoroalkyl, -(CR^aR^b)_n-, -0-, -S-, -SO-, -SO2-, or -NR^a-;

[009] R^a and R^b are each independently selected from the group consisting of hydrogen, alkyl, fluoroalkyl, cycloalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, heteroarylalkyl, halogen, -O-alkyl, -O-aryl, cyano, nitro, -

OH, -NH2, -NH-alkyl, and -NH-aryl;

[0010] n is a positive integer, and t is 1 or 2.

[0011] In some embodiments, the invention relates to compounds of Formulas 1-27:

Formula 1 Formula 2 Formula 3 Formula 4

Formula 5 Formula 6 Formula 7 Formula 8

Formula 9 Formula 10 Formula 11 Formula 12

Formula 13 Formula 14 Formula 15 Formula 16

Formula 17 Formula 18 Formula 19 Formula 20

Formula 21 Formula 22 Formula 23 Formula 24

Formula 25 Formula 26 Formula 27

[0012] wherein in Formulas 1-27:

[0013] An and An are each independently an aryl or heteroaryl group, optionally substituted with one or more substituents such as alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilanyl, -OR^a, -SR^a, -OC(0)R^a, - N(R^a)R^b, -C(0)R^a, -C(0)OR^a, -OC(0)N(R^a)R^b, -C(0)N(R^a)R^b, -N(R^a)C(0)OR^a, - N(R^a)C(0)R^a, -N(R^a)C(0)N(R^a)R^b, -N(R^a)C(NR^a)N(R^a)R^b, -N(R^a)S(0)tR^a, - S(0)tOR^a, -S(0)tN(R^a)R^b, or -P(0)(OR^a)(OR^b);

[0014] Ri, and R2 are each independently hydrogen, alkyl, fluoroalkyl, -OR^a, -SR^a, - OC(0)R^a, -N(R^a)R^b, -OC(0)N(R^a)R^b, -N(R^a)C(0)OR^a, -N(R^a)C(0)R^a, -N(R^a)C(0)N(R^a)R^b, - N(R^a)C(NR^a)N(R^a)R^b, -N(R^a)S(0)_tR^a, -S(0)tOR^a, -S(0)tN(R^a)C(0)R^b, or -S(0)tN(R^a)R^b;

[0015] L is a linker selected from a bond, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, fluoroalkyl, -OC(O)-, -NR^a- , -C(O)-, -C(0)0-, -OC(0)N(R^a)-, -C(0)N(R^a)-, -C(0)N(R^a)S(0)t-, -N(R^a)C(0)0-, - N(R^a)C(0)-, -N(R^a)C(0)N(R^a)-, -N(R^a)C(NR^a)N(R^a)-, -N(R^a)S(0)t-, -S(0)tO-, -S(0)tN(R^a)- , -S(0)_tN(R^a)C(0)R^b, -P(0)(OR^a)0-, -OP(0)(OR^a)0-, -(CR^aR^b)_n-, -0-, -S-, and -S(0)t-;

[0016] R^a and R^b are each independently selected from the group consisting of hydrogen, alkyl, fluoroalkyl, cycloalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, heteroarylalkyl, halogen, -O-alkyl, -O-aryl, cyano, nitro, - OH, -NH2, -NH-alkyl, and -NH-aryl;

[0017] n is a positive integer, and t is 1 or 2.

[0018] In some embodiments, the invention relates to compounds of Formulas 101-154:

Formula 101 Formula 102 Formula 103 Formula 104

Formula 105 Formula 106 Formula 107 Formula 108

Formula 109 Formula 110 Formula 111 Formula 112

Formula 113 Formula 114 Formula 115 Formula 116

Formula 117 Formula 118 Formula 119 Formula 120

Formula 121 Formula 122 Formula 123 Formula 124

Formula 125 Formula 126 Formula 127 Formula 128

Formula 129 Formula 130 Formula 131 Formula 132

Formula 133 Formula 134 Formula 135 Formula 136

Formula 137 Formula 138 Formula 139 Formula 140

Formula 141 Formula 142 Formula 143 Formula 144

Formula 145 Formula 146 Formula 147 Formula 148

Formula 149 Formula 150 Formula 151 Formula 152

Formula 153 Formula 154

[0019] wherein in Formulas 101-154:

[0020] An and An are each independently an aryl or heteroaryl group, optionally substituted with one or more substituents such as alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilanyl, -OR^a, -SR^a, -OC(0)R^a, - N(R^a)R^b, -C(0)R^a, -C(0)OR^a, -OC(0)N(R^a)R^b, -C(0)N(R^a)R^b, -N(R^a)C(0)OR^a, - N(R^a)C(0)R^a, -N(R^a)C(0)N(R^a)R^b, -N(R^a)C(NR^a)N(R^a)R^b, -N(R^a)S(0)tR^a, - S(0)tOR^a, -S(0)tN(R^a)R^b, -S(0)tN(R^a)C(0)R^b, or -P(0)(OR^a)(OR^b);

[0021] Ri, R2, and R3 are each independently hydrogen, alkyl, fluoroalkyl, -OR^a, -SR^a, - OC(0)R^a, -N(R^a)R^b, -OC(0)N(R^a)R^b, -N(R^a)C(0)OR^a, -N(R^a)C(0)R^a, -N(R^a)C(0)N(R^a)R^b, - N(R^a)C(NR^a)N(R^a)R^b, -N(R^a)S(0)_tR^a, -S(0)tOR^a, -S(0)tN(R^a)C(0)R^b, or -S(0)tN(R^a)R^b;

[0022] X is alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, fluoroalkyl, -(CR^aR^b)_n-, -OR³-, -S-, -SO-, -SO2-, or - NR^a-;

[0023] R^a and R^b are each independently selected from the group consisting of hydrogen, alkyl, fluoroalkyl, cycloalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, heteroarylalkyl, halogen, -O-alkyl, -O-aryl, cyano, nitro, - OH, -NH2, -NH-alkyl, and -NH-aryl; [0024] n is a positive integer, and t is 1 or 2.

[0025] In some embodiments, the invention relates to compounds of Formulas 201-224:

Formula 201 Formula 202

Formula 204 Formula 205

Formula 207 Formula 208 Formula 209

Formula 211

Formula 215

Formula 216 Formula 217 Formula 218

Formula 220 Formula 221

Formula 222 Formula 224

[0026] wherein in Formulas 201-224:

[0027] each R is independently selected from the group consisting of alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilanyl, -OR^a, -SR^a OC(0)R^a, -N(R^a)R^b, -C(0)R^a, -C(0)OR^a, -OC(0)N(R^a)R^b, -C(0)N(R^a)R^b, -N(R^a)C(0)OR^a N(R^a)C(0)R^a, -N(R^a)C(0)N(R^a)R^b, -N(R^a)C(NR^a)N(R^a)R^b, -N(R^a)S(0)tR^a, - S(0)tOR^a, -S(0)tN(R^a)R^b, -S(0)tN(R^a)C(0)R^b, or -P(0)(OR^a)(OR^b);

[0028] each R2 is independently selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, isopropyl, or trifluoromethyl;

[0029] R₃ is -OH, -ORa, -NHRa, -NR_aRb, optionally substituted alkyl, or optionally substituted aryl;

[0030] R^a and R^b are each independently selected from the group consisting of hydrogen, alkyl, fluoroalkyl, cycloalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, heteroarylalkyl, halogen, -O-alkyl, -O-aryl, cyano, nitro, -

OH, -NH2, -NH-alkyl, and -NH-aryl; n is 0, 1, 2, 3, 4, 5, or 6; and t is 1 or 2.

[0031] In some embodiments, the invention relates to compounds of Formulas 301-333:

Formula 307 Formula 308 Formula 309

Formula 319 Formula 320 Formula 321

Formula 322 Formula 324

Formula 327

Formula 328 Formula 329 Formula 330

Formula 331 Formula 332 Formula 333 wherein in Formulas 301-333, each R is a substituent such as alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilanyl, -OR^a, -SR^a, - OC(0)R^a, -N(R^a)R^b, -C(0)R^a, -C(0)OR^a, -OC(0)N(R^a)R^b, -C(0)N(R^a)R^b, -N(R^a)C(0)OR^a, - N(R^a)C(0)R^a, -N(R^a)C(0)N(R^a)R^b, -N(R^a)C(NR^a)N(R^a)R^b, -N(R^a)S(0)tR^a, - S(0)tOR^a, -S(0)tN(R^a)R^b, -S(0)tN(R^a)C(0)R^b, or -P(0)(OR^a)(OR^b); R^a and R^b are each independently hydrogen, alkyl, fiuoroalkyl, cycloalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, heteroarylalkyl, halogen, -O-alkyl, -O-aryl, cyano, nitro, -OH, -NH2, -NH-alkyl, or -NH-aryl; n is 0, 1, 2, 3, 4, 5, or 6; and t is 1 or 2.

[0032] In some embodiments, the invention relates to compounds of Formulas 401-448, wherein n is 0, 1 , 2, 3, 4, 5, or 6 where applicable:

Formula 401 Formula 402 Formula 403

Formula 404 Formula 405 Formula 406

Formula 413 Formula 414 Formula 415

Formula 431

Formula 444 Formula 445

Formula 443

Formula 446 Formula 447 Formula 448

[0033] In some embodiments, the invention relates to BCL-2 inhibitors of Formulas AA- AD, BA-BM, CA-CZ, 1-27, 101-154, 201-224, 301-333, and 401-448. In some

embodiments, the invention relates to MDM2 inhibitors of Formulas AA-AD, BA-BM, CA- CZ, 1-27, 101-154, 201-224, 301-333, and 401-448. In some embodiments, the invention relates to dual BCL-2/MDM2 inhibitors of Formulas AA-AD, BA-BM, CA-CZ, 1-27, 101- 154, 201-224, 301-333, and 401-448.

[0034] In some embodiments, the invention relates to a pharmaceutical composition including one or more compounds of Formulas AA-AD, BA-BM, CA-CZ, 1-27, 101-154, 201-224, 301-333, and 401-448, or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or prodrug thereof, and a physiologically compatible carrier medium.

[0035] In some embodiments, the invention relates to a method of treating a disease alleviated by inhibiting BCL-2 in a patient in need thereof, including administering to the patient a therapeutically effective amount of one or more compounds of Formulas AA-AD, BA-BM, CA-CZ, 1-27, 101-154, 201-224, 301-333, and 401-448, or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or prodrug thereof.

[0036] In some embodiments, the invention relates to a method of treating a disease alleviated by inhibiting MDM2 in a patient in need thereof, including administering to the patient a therapeutically effective amount of one or more compounds of Formulas AA-AD, BA-BM, CA-CZ, 1-27, 101-154, 201-224, 301-333, and 401-448, or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or prodrug thereof.

[0037] In some embodiments, the invention relates to a method of treating a disease alleviated by inhibiting BCL-2 and MDM2 in a patient in need thereof, including

administering to the patient a therapeutically effective amount of one or more compounds of Formulas AA-AD, BA-BM, CA-CZ, 1-27, 101-154, 201-224, 301-333, and 401-448, or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or prodrug thereof.

[0038] In some embodiments, the invention relates to a method of treating a disease alleviated by inhibiting BCL-2, MDM2, or BCL-2 and MDM2, in a patient in need thereof, including administering to the patient dosage unit form including a therapeutically effective amount of one or more compounds of Formulas AA-AD, BA-BM, CA-CZ, 1-27, 101-154, 201-224, 301-333, and 401-448, or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or prodrug thereof. In some embodiments, the dosage unit form includes a physiologically compatible carrier medium.

[0039] In some embodiments, the invention relates to a method of treating a cancer alleviated by inhibiting BCL-2, MDM2, or BCL-2 and MDM2, in a patient in need thereof, including administering to the patient a therapeutically effective amount of one or more compounds of Formulas AA-AD, BA-BM, CA-CZ, 1-27, 101-154, 201-224, 301-333, and 401-448, or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or prodrug thereof. In some embodiments, the cancer can be bladder cancer, squamous cell carcinoma including head and neck cancer, pancreatic ductal adenocarcinoma (PDA), pancreatic cancer, colon carcinoma, mammary carcinoma, breast cancer, fibrosarcoma, mesothelioma, renal cell carcinoma, lung carcinoma, thymoma, prostate cancer, colorectal cancer, ovarian cancer, acute myeloid leukemia, thymus cancer, brain cancer, squamous cell cancer, skin cancer, eye cancer, retinoblastoma, melanoma, intraocular melanoma, oral cavity and oropharyngeal cancers, gastric cancer, stomach cancer, cervical cancer, renal cancer, kidney cancer, liver cancer, ovarian cancer, esophageal cancer, testicular cancer, gynecological cancer, thyroid cancer, acquired immune deficiency syndrome (AIDS)-related cancers (e.g. , lymphoma and Kaposi's sarcoma), viral-induced cancer, glioblastoma, esophageal tumors, hematological neoplasms, non-small-cell lung cancer, chronic myelocytic leukemia, diffuse large B-cell lymphoma, esophagus tumor, follicle center lymphoma, head and neck tumor, hepatitis C virus induced cancer, hepatocellular carcinoma, Hodgkin's disease, metastatic colon cancer, multiple myeloma, non-Hodgkin's lymphoma, indolent non-Hodgkin's lymphoma, ovary tumor, pancreas tumor, renal cell carcinoma, small-cell lung cancer, stage IV melanoma, chronic lymphocytic leukemia, B-cell acute lymphoblastic leukemia (ALL), mature B-cell ALL, follicular lymphoma, mantle cell lymphoma, and Burkitt's lymphoma.

BRIEF DESCRIPTION OF THE DRAWINGS

[0040] The foregoing summary, as well as the following detailed description of the invention, will be better understood when read in conjunction with the appended drawings.

[0041] FIG. 1 A illustrates the structure of Mcl-1-Bim-BH3 (PDB ID: 4HW4); Mcl-1 coloured by atom type: carbon - grey; nitrogen - blue; oxygen - red; sulfur - yellow; Bim- BH3 a-helix coloured in green; key residues and binding pockets on Mcl-1 shown in black.

[0042] FIG. IB illustrates the key residues of the Bim-BH3 a-helix.

[0043] FIG. 2 illustrates the cross-talk between the Bcl-2 and HDM2 families.

[0044] FIG. 3 illustrates the crystal structure of HDM2 in complex with a p53 peptide (PDB ID: 1YCR).

[0045] FIG. 4 illustrates the similarities between the p53 and BH3 a-helical domains.

[0046] FIG. 5 is a schematic illustrating the concept of a dual inhibitor allowing both the displacement of pro-apoptotic Bcl-2 proteins from their anti-apoptotic counterparts, as well as aiding in their transcription due to elevated levels of free p53 protein, which are also likewise displaced from HDM2, and the synergistic effect promoting apoptosis in tumorigenic cells.

[0047] FIG. 6 illustrates pyrazole-based a-helix mimetic dual inhibitors towards

HDM2/Bcl-2 family.

[0048] FIG. 7 illustrates the synthesis of pyrazole-based HDM2/Bcl-2 family inhibitors; (a) NaN02, hydrochloric acid, SnCh, 0 °C, 4 h; (b) dimethyl oxalate, potassium tert-butoxide, THF, 0 °C to room temp, 16 h, 76-87%; (c) phenylhydrazine hydrochloride, MeOH, 65 °C, 3 h, 49-62%; (d) KOH, MeOH, 60 °C, 4 h, 87-96%.

[0049] FIG. 8 illustrates the synthesis of pyrazole-based HDM2/Bcl-2 family inhibitors; (a) N2O3, MeOH, room temp, 2 h; (b) phenylhydrazine hydrochloride, MeOH, argon

atmosphere, 6 h, Na2S406, 21-25% over two steps; (c) 4-R3-benzoyl chloride, triethylamine, THF, 0 °C, 76-86%; (d) NaOH, 0 °C, THF:H₂0 = 2: 1, 85-95%.

[0050] FIG. 9 illustrates an inhibitor with enhanced HDM2/BCL-2 family affinity, including a "flexible linker" between the core and the R³ position improving binding affinity due to its ability to simulate the p53TAD.

[0051] FIG. 10 illustrates known pyrazole-based a-helix mimetics 5g and 6e. DETAILED DESCRIPTION OF THE INVENTION

[0052] The invention relates generally to a dual HDM2/Bcl-2 family inhibitor. In one embodiment, a dual inhibitor allows both the displacement of pro-apoptotic Bcl-2 proteins from their anti-apoptotic counterparts, as well as aid in their transcription due to elevated levels of free p53 protein, which will also likewise be displaced from HDM2. A synergistic effect to help promote apoptosis in tumorigenic cells is thus provided.

[0053] Dysregulation of BH3 and p53 protein-protein interaction contributes to a variety of human cancers, including multiple myeloma and acute myeloid leukemia. The small- molecule inhibitors disclosed herein mimic both the BH3 and p53 a-helices, thereby disrupting their native protein-protein interaction. The invention exploits the tools of polypharmacology to inhibit multiple families of proteins whose overexpression are observed in the same cancers. Moreover, the BCL-2 and HDM2 families engage in cross-talk with one another, providing further rationale to their dual inhibition with single molecules, i.e., the dual inhibitors disclosed herein.

[0054] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of skill in the art to which this invention belongs. All patents and publications referred to herein are incorporated by reference in their entireties.

Definitions

[0055] The term "dual inhibitor" as used herein refers to a compound capable of inhibiting at least two distinct biological targets. Without wishing to be bound by any particular theory, a dual inhibitor may act as such due to the presence of structural similarities between the two targets.

[0056] The term vivo" refers to an event that takes place in a subject's body.

[0057] The term vitro" refers to an event that takes places outside of a subject's body.

In vitro assays encompass cell-based assays in which cells alive or dead are employed and may also encompass a cell-free assay in which no intact cells are employed.

[0058] The term "effective amount" or "therapeutically effective amount" refers to that amount of a compound or combination of compounds as described herein that is sufficient to effect the intended application including, but not limited to, disease treatment. A

therapeutically effective amount may vary depending upon the intended application (in vitro or in vivo), or the subject and disease condition being treated (e.g. , the weight, age and gender of the subject), the severity of the disease condition, the manner of administration, etc. which can readily be determined by one of ordinary skill in the art. The term also applies to a dose that will induce a particular response in target cells (e.g. , the reduction of platelet adhesion and/or cell migration). The specific dose will vary depending on the particular compounds chosen, the dosing regimen to be followed, whether the compound is administered in combination with other compounds, timing of administration, the tissue to which it is administered, and the physical delivery system in which the compound is carried.

[0059] A "therapeutic effect" as that term is used herein, encompasses a therapeutic benefit and/or a prophylactic benefit. A prophylactic effect includes delaying or eliminating the appearance of a disease or condition, delaying or eliminating the onset of symptoms of a disease or condition, slowing, halting, or reversing the progression of a disease or condition, or any combination thereof.

[0001] As used herein, the terms "treat," "treatment," and/or "treating" may refer to the management of a disease, disorder, or pathological condition, or symptom thereof with the intent to cure, ameliorate, stabilize, prevent, and/or control the disease, disorder, pathological condition or symptom thereof. Regarding control of the disease, disorder, or pathological condition more specifically, "control" may include the absence of condition progression, as assessed by the response to the methods recited herein, where such response may be complete (e.g. , placing the disease in remission) or partial (e.g. , lessening or ameliorating any symptoms associated with the condition).

[0060] The terms "QD," "qd," or "q.d." mean quaque die, once a day, or once daily. The terms "BID," "bid," or "b.i.d." mean bis in die, twice a day, or twice daily. The terms "TID," "tid," or "t.i.d." mean ter in die, three times a day, or three times daily. The terms "QID," "qid," or "q.i.d." mean quater in die, four times a day, or four times daily.

[0061] The term "pharmaceutically acceptable salt" refers to salts derived from a variety of organic and inorganic counter ions known in the art. Pharmaceutically acceptable acid addition salts can be formed with inorganic acids and organic acids. Preferred inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid and phosphoric acid. Preferred organic acids from which salts can be derived include, for example, acetic acid, propionic acid, gly colic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p- toluenesulfonic acid and salicylic acid. Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases. Inorganic bases from which salts can be derived include, for example, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese and aluminum. Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins. Specific examples include isopropylamine, trimethylamine, diethylamine, triethylamine,

tripropylamine, and ethanolamine. In some embodiments, the pharmaceutically acceptable base addition salt is chosen from ammonium, potassium, sodium, calcium, and magnesium salts. The term "cocrystal" refers to a molecular complex derived from a number of cocrystal formers known in the art. Unlike a salt, a cocrystal typically does not involve hydrogen transfer between the cocrystal and the drug, and instead involves intermolecular interactions, such as hydrogen bonding, aromatic ring stacking, or dispersive forces, between the cocrystal former and the drug in the crystal structure.

[0062] "Pharmaceutically acceptable carrier" or "pharmaceutically acceptable excipient" is intended to include any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and inert ingredients. The use of such pharmaceutically acceptable carriers or pharmaceutically acceptable excipients for active pharmaceutical ingredients is well known in the art. Except insofar as any conventional pharmaceutically acceptable carrier or pharmaceutically acceptable excipient is incompatible with the active pharmaceutical ingredient, its use in the therapeutic compositions of the invention is contemplated. Additional active pharmaceutical ingredients, such as other drugs, can also be incorporated into the described compositions and methods.

[0063] "Prodrug" is intended to describe a compound that may be converted under physiological conditions or by solvolysis to a biologically active compound described herein. Thus, the term "prodrug" refers to a precursor of a biologically active compound that is pharmaceutically acceptable. A prodrug may be inactive when administered to a subject, but is converted in vivo to an active compound, for example, by hydrolysis. The prodrug compound often offers the advantages of solubility, tissue compatibility or delayed release in a mammalian organism (see, e.g. , Bundgaard, H., Design of Prodrugs (1985) (Elsevier, Amsterdam). The term "prodrug" is also intended to include any covalently bonded carriers, which release the active compound in vivo when administered to a subject. Prodrugs of an active compound, as described herein, may be prepared by modifying functional groups present in the active compound in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to yield the active parent compound. Prodrugs include, for example, compounds wherein a hydroxy, amino or mercapto group is bonded to any group that, when the prodrug of the active compound is administered to a mammalian subject, cleaves to form a free hydroxy, free amino or free mercapto group, respectively. Examples of prodrugs include, but are not limited to, acetates, formates and benzoate derivatives of an alcohol, various ester derivatives of a carboxylic acid, or acetamide, formamide and benzamide derivatives of an amine functional group in the active compound.

[0064] As used herein, the terms "programmed cell death" and "apoptosis" are used interchangeably.

[0065] Unless otherwise stated, the chemical structures depicted herein are intended to include compounds which differ only in the presence of one or more isotopically enriched atoms. For example, compounds where one or more hydrogen atoms is replaced by deuterium or tritium, or wherein one or more carbon atoms is replaced by ¹ C- or ¹⁴C-enriched carbons, are within the scope of this invention.

[0066] When ranges are used herein to describe, for example, physical or chemical properties such as molecular weight or chemical formulae, all combinations and

subcombinations of ranges and specific embodiments therein are intended to be included. Use of the term "about" when referring to a number or a numerical range means that the number or numerical range referred to is an approximation within experimental variability (or within statistical experimental error), and thus the number or numerical range may vary. The variation is typically from 0% to 15%, preferably from 0% to 10%, more preferably from 0% to 5% of the stated number or numerical range. The term "comprising" (and related terms such as "comprise" or "comprises" or "having" or "including") includes those embodiments such as, for example, an embodiment of any composition of matter, method or process that "consist of or "consist essentially of the described features.

[0067] "Alkyl" refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing no unsaturation, having from one to ten carbon atoms (e.g. , (Ci-io)alkyl or Ci-io alkyl). Whenever it appears herein, a numerical range such as "1 to 10" refers to each integer in the given range - e.g. , "1 to 10 carbon atoms" means that the alkyl group may consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc. , up to and including 10 carbon atoms, although the definition is also intended to cover the occurrence of the term "alkyl" where no numerical range is specifically designated. Typical alkyl groups include, but are in no way limited to, methyl, ethyl, propyl, isopropyl, w-butyl, isobutyl, sec- butyl isobutyl, tertiary butyl, pentyl, isopentyl, neopentyl, hexyl, septyl, octyl, nonyl and decyl. The alkyl moiety may be attached to the rest of the molecule by a single bond, such as for example, methyl (Me), ethyl (Et), ^-propyl (Pr), 1 -methylethyl (isopropyl), w-butyl, n- pentyl, 1,1-dimethylethyl (/-butyl) and 3-methylhexyl. Unless stated otherwise specifically in the specification, an alkyl group is optionally substituted by one or more of substituents which are independently heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl,

trifluoromethoxy, nitro, trimethylsilanyl, -OR^a, -SR^a, -OC(0)-R^a, -N(R^a)₂, - C(0)R^a, -C(0)OR^a, -OC(0)N(R^a)₂, -C(0)N(R^a)₂, -N(R^a)C(0)OR^a, - N(R^a)C(0)R^a, -N(R^a)C(0)N(R^a)₂, N(R^a)C(NR^a)N(R^a)₂, -N(R^a)S(0)tR^a (where t is 1 or 2), - S(0)tOR^a (where t is 1 or 2), -S(0)tN(R^a)₂ (where t is 1 or 2), -S(0)tN(R^a)C(0)R^b (where t is 1 or 2), or PCb(R^a)₂ where each R^a is independently hydrogen, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl.

[0068] "Alkylaryl" refers to an -(alkyl)aryl radical where aryl and alkyl are as disclosed herein and which are optionally substituted by one or more of the substituents described as suitable substituents for aryl and alkyl respectively.

[0069] "Alkylhetaryl" refers to an -(alkyl)hetaryl radical where hetaryl and alkyl are as disclosed herein and which are optionally substituted by one or more of the substituents described as suitable substituents for aryl and alkyl respectively.

[0070] "Alkylheterocycloalkyl" refers to an -(alkyl) heterocyclyl radical where alkyl and heterocycloalkyl are as disclosed herein and which are optionally substituted by one or more of the substituents described as suitable substituents for heterocycloalkyl and alkyl respectively.

[0071] An "alkene" moiety refers to a group consisting of at least two carbon atoms and at least one carbon-carbon double bond, and an "alkyne" moiety refers to a group consisting of at least two carbon atoms and at least one carbon-carbon triple bond. The alkyl moiety, whether saturated or unsaturated, may be branched, straight chain, or cyclic.

[0072] "Alkenyl" refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one double bond, and having from two to ten carbon atoms (i. e., (C₂-io)alkenyl or C₂-io alkenyl). Whenever it appears herein, a numerical range such as "2 to 10" refers to each integer in the given range - e.g. , "2 to 10 carbon atoms" means that the alkenyl group may consist of 2 carbon atoms, 3 carbon atoms, etc., up to and including 10 carbon atoms. The alkenyl moiety may be attached to the rest of the molecule by a single bond, such as for example, ethenyl (i. e., vinyl), prop-1- enyl (i. e., allyl), but-l -enyl, pent-l-enyl and penta-l,4-dienyl. Unless stated otherwise specifically in the specification, an alkenyl group is optionally substituted by one or more substituents which are independently alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilanyl, -OR^a, -SR^a, -OC(0)-R^a, -N(R^a)2, - C(0)R^a, -C(0)OR^a, -OC(0)N(R^a)₂, -C(0)N(R^a)₂, -N(R^a)C(0)OR^a, - N(R^a)C(0)R^a, -N(R^a)C(0)N(R^a)₂, N(R^a)C(NR^a)N(R^a)₂, -N(R^a)S(0)tR^a (where t is 1 or 2), - S(0)tOR^a (where t is 1 or 2), -S(0)tN(R^a)₂ (where t is 1 or 2), -S(0)tN(R^a)C(0)R^b (where t is 1 or 2), or PCb(R^a)₂, where each R^a is independently hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl.

[0073] "Alkenyl-cycloalkyl" refers to an -(alkenyl)cycloalkyl radical where alkenyl and cycloalkyl are as disclosed herein and which are optionally substituted by one or more of the substituents described as suitable substituents for alkenyl and cycloalkyl respectively.

[0074] "Alkynyl" refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one triple bond, having from two to ten carbon atoms (i.e., (C₂-io)alkynyl or C₂-io alkynyl). Whenever it appears herein, a numerical range such as "2 to 10" refers to each integer in the given range - e.g. , "2 to 10 carbon atoms" means that the alkynyl group may consist of 2 carbon atoms, 3 carbon atoms, etc., up to and including 10 carbon atoms. The alkynyl may be attached to the rest of the molecule by a single bond, for example, ethynyl, propynyl, butynyl, pentynyl and hexynyl. Unless stated otherwise specifically in the specification, an alkynyl group is optionally substituted by one or more substituents which independently are: alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl, trifluoromethoxy, nitro,

trimethylsilanyl, -OR^a, -SR^a, -OC(0)-R^a, -N(R^a)₂, -C(0)R^a, -C(0)OR^a, -OC(0)N(R^a)₂, - C(0)N(R^a)₂, -N(R^a)C(0)OR^a, -N(R^a)C(0)R^a, -N(R^a)C(0)N(R^a)₂, N(R^a)C(NR^a)N(R^a)₂, - N(R^a)S(0)tR^a (where t is 1 or 2), -S(0)tOR^a (where t is 1 or 2), -S(0)tN(R^a)₂ (where t is 1 or 2), -S(0)tN(R^a)C(0)R^b (where t is 1 or 2), or P0₃(R^a)₂, where each R^a is independently hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl.

[0075] "Alkynyl-cycloalkyl" refers to an -(alkynyl)cycloalkyl radical where alkynyl and cycloalkyl are as disclosed herein and which are optionally substituted by one or more of the substituents described as suitable substituents for alkynyl and cycloalkyl respectively.

[0076] "Carboxaldehyde" refers to a -(C=0)H radical.

[0077] "Carboxyl" refers to a -(C=0)OH radical.

[0078] "Cyano" refers to a -CN radical. [0079] "Cycloalkyl" refers to a monocyclic or poly cyclic radical that contains only carbon and hydrogen, and may be saturated, or partially unsaturated. Cycloalkyl groups include groups having from 3 to 10 ring atoms (i. e. (C3-io)cycloalkyl or C3-10 cycloalkyl). Whenever it appears herein, a numerical range such as "3 to 10" refers to each integer in the given range - e.g. , "3 to 10 carbon atoms" means that the cycloalkyl group may consist of 3 carbon atoms, etc., up to and including 10 carbon atoms. Illustrative examples of cycloalkyl groups include, but are not limited to the following moieties: cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, norbornyl, and the like. Unless stated otherwise specifically in the specification, a cycloalkyl group is optionally substituted by one or more substituents which independently are: alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl, trifiuoromethoxy, nitro,

trimethylsilanyl, -OR^a, -SR^a, -OC(0)-R^a, -N(R^a)₂, -C(0)R^a, -C(0)OR^a, - OC(0)N(R^a)₂, -C(0)N(R^a)₂, -N(R^a)C(0)OR^a, -N(R^a)C(0)R^a, -N(R^a)C(0)N(R^a)₂,

N(R^a)C(NR^a)N(R^a)₂, -N(R^a)S(0)tR^a (where t is 1 or 2), -S(0)tOR^a (where t is 1 or

2), -S(0)tN(R^a)₂ (where t is 1 or 2), -S(0)tN(R^a)C(0)R^b (where t is 1 or 2), or P0₃(R^a)₂, where each R^a is independently hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl.

[0080] "Cycloalkyl-alkenyl" refers to a -(cycloalkyl)alkenyl radical where cycloalkyl and alkenyl are as disclosed herein and which are optionally substituted by one or more of the substituents described as suitable substituents for cycloalkyl and alkenyl, respectively.

[0081] "Cycloalkyl-heterocycloalkyl" refers to a -(cycloalkyl)heterocycloalkyl radical where cycloalkyl and heterocycloalkyl are as disclosed herein and which are optionally substituted by one or more of the substituents described as suitable substituents for cycloalkyl and heterocycloalkyl, respectively.

[0082] "Cycloalkyl-heteroaryl" refers to a -(cycloalkyl)heteroaryl radical where cycloalkyl and heteroaryl are as disclosed herein and which are optionally substituted by one or more of the substituents described as suitable substituents for cycloalkyl and heteroaryl, respectively.

[0083] The term "alkoxy" refers to the group -O-alkyl, including from 1 to 8 carbon atoms of a straight, branched, cyclic configuration and combinations thereof attached to the parent structure through an oxygen. Examples include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, cyclopropyloxy and cyclohexyloxy. "Lower alkoxy" refers to alkoxy groups containing one to six carbons. [0084] The term "substituted alkoxy" refers to alkoxy wherein the alkyl constituent is substituted (i.e., -0-(substituted alkyl)). Unless stated otherwise specifically in the specification, the alkyl moiety of an alkoxy group is optionally substituted by one or more substituents which independently are: alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilanyl, -OR^a, -SR^a, -OC(0)-R^a, - N(R^a)₂, -C(0)R^a, -C(0)OR^a, -OC(0)N(R^a)₂, -C(0)N(R^a)₂, -N(R^a)C(0)OR^a, - N(R^a)C(0)R^a, -N(R^a)C(0)N(R^a)₂, N(R^a)C(NR^a)N(R^a)₂, -N(R^a)S(0)tR^a (where t is 1 or 2), - S(0)tOR^a (where t is 1 or 2), -S(0)tN(R^a)₂ (where t is 1 or 2), -S(0)tN(R^a)C(0)R^b (where t is 1 or 2), or PCb(R^a)₂, where each R^a is independently hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl.

[0085] The term "alkoxy carbonyl" refers to a group of the formula (alkoxy)(C=0)- attached through the carbonyl carbon wherein the alkoxy group has the indicated number of carbon atoms. Thus a (Ci-6)alkoxy carbonyl group is an alkoxy group having from 1 to 6 carbon atoms attached through its oxygen to a carbonyl linker. "Lower alkoxy carbonyl" refers to an alkoxy carbonyl group wherein the alkoxy group is a lower alkoxy group.

[0086] The term "substituted alkoxy carbonyl" refers to the group (substituted alkyl)-0- C(O)- wherein the group is attached to the parent structure through the carbonyl functionality. Unless stated otherwise specifically in the specification, the alkyl moiety of an

alkoxy carbonyl group is optionally substituted by one or more substituents which

independently are: alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl,

trifluoromethoxy, nitro, trimethylsilanyl, -OR^a, -SR^a, -OC(0)-R^a, - N(R^a)₂, -C(0)R^a, -C(0)OR^a, -OC(0)N(R^a)₂, -C(0)N(R^a)₂, -N(R^a)C(0)OR^a, - N(R^a)C(0)R^a, -N(R^a)C(0)N(R^a)₂, N(R^a)C(NR^a)N(R^a)₂, -N(R^a)S(0)tR^a (where t is 1 or 2), - S(0)tOR^a (where t is 1 or 2), -S(0)tN(R^a)₂ (where t is 1 or 2), -S(0)tN(R^a)C(0)R^b (where t is 1 or 2), or PCb(R^a)₂, where each R^a is independently hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl.

[0087] "Acyl" refers to the groups (alkyl)-C(O)-, (aryl)-C(O)-, (heteroaryl)-C(O)-, (heteroalkyl)-C(O)- and (heterocycloalkyl)-C(O)-, wherein the group is attached to the parent structure through the carbonyl functionality. If the R radical is heteroaryl or heterocycloalkyl, the hetero ring or chain atoms contribute to the total number of chain or ring atoms. Unless stated otherwise specifically in the specification, the alkyl, aryl or heteroaryl moiety of the acyl group is optionally substituted by one or more substituents which are independently alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl, trifluoromethoxy, nitro,

[0088] "Acyloxy" refers to a R(C=0)0- radical wherein R is alkyl, aryl, heteroaryl, heteroalkyl or heterocycloalkyl, which are as described herein. If the R radical is heteroaryl or heterocycloalkyl, the hetero ring or chain atoms contribute to the total number of chain or ring atoms. Unless stated otherwise specifically in the specification, the R of an acyloxy group is optionally substituted by one or more substituents which independently are: alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl, trifluoromethoxy, nitro,

[0089] "Amino" or "amine" refers to a -N(R^a)₂ radical group, where each R^a is

independently hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl, unless stated otherwise specifically in the specification. When a -N(R^a)₂ group has two R^a substituents other than hydrogen, they can be combined with the nitrogen atom to form a 4-, 5-, 6- or 7-membered ring. For example, -N(R^a)₂ is intended to include, but is not limited to, 1-pyrrolidinyl and 4- morpholinyl. Unless stated otherwise specifically in the specification, an amino group is optionally substituted by one or more substituents which independently are: alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl, trifluoromethoxy, nitro,

2), -S(0)tN(R^a)₂ (where t is 1 or 2), -S(0)tN(R^a)C(0)R^b (where t is 1 or

2), -S(0)tN(R^a)C(0)R^b (where t is 1 or 2), or PCb(R^a)₂, where each R^a is independently hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl.

[0090] The term "substituted amino" also refers to N-oxides of the groups -NHR^d, and NR^dR^d each as described above. N-oxides can be prepared by treatment of the corresponding amino group with, for example, hydrogen peroxide or m-chloroperoxybenzoic acid.

[0091] "Amide" or "amido" refers to a chemical moiety with formula -C(0)N(R)₂ or -NHC(0)R, where R is selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, heteroaryl (bonded through a ring carbon) and heteroalicyclic (bonded through a ring carbon), each of which moiety may itself be optionally substituted. The R₂ of -N(R)₂ of the amide may optionally be taken together with the nitrogen to which it is attached to form a 4-, 5-, 6- or 7-membered ring. Unless stated otherwise specifically in the specification, an amido group is optionally substituted independently by one or more of the substituents as described herein for alkyl, cycloalkyl, aryl, heteroaryl, or heterocycloalkyl. An amide may be an amino acid or a peptide molecule attached to a compound disclosed herein, thereby forming a prodrug. The procedures and specific groups to make such amides are known to those of skill in the art and can readily be found in seminal sources such as Greene and Wuts, Protective Groups in Organic Synthesis, 3^rd Ed., John Wiley & Sons, New York, N.Y., 1999, which is incorporated herein by reference in its entirety.

[0092] "Aromatic" or "aryl" or "Ar" refers to an aromatic radical with six to ten ring atoms (e.g. , C6-C10 aromatic or C6-C10 aryl) which has at least one ring having a conjugated pi electron system which is carbocyclic (e.g. , phenyl, fluorenyl, and naphthyl). Bivalent radicals formed from substituted benzene derivatives and having the free valences at ring atoms are named as substituted phenylene radicals. Bivalent radicals derived from univalent poly cyclic hydrocarbon radicals whose names end in "-yl" by removal of one hydrogen atom from the carbon atom with the free valence are named by adding "-idene" to the name of the corresponding univalent radical, e.g., a naphthyl group with two points of attachment is termed naphthylidene. Whenever it appears herein, a numerical range such as "6 to 10" refers to each integer in the given range; e.g. , "6 to 10 ring atoms" means that the aryl group may consist of 6 ring atoms, 7 ring atoms, etc., up to and including 10 ring atoms. The term includes monocyclic or fused-ring poly cyclic (i.e., rings which share adjacent pairs of ring atoms) groups. Unless stated otherwise specifically in the specification, an aryl moiety is optionally substituted by one or more substituents which are independently alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilanyl, -OR^a, -SR^a, - OC(0)-R^a, -N(R^a)₂, -C(0)R^a, -C(0)OR^a, -OC(0)N(R^a)₂, -C(0)N(R^a)₂, -N(R^a)C(0)OR^a, - N(R^a)C(0)R^a, -N(R^a)C(0)N(R^a)₂, N(R^a)C(NR^a)N(R^a)₂, -N(R^a)S(0)tR^a (where t is 1 or 2), - S(0)tOR^a (where t is 1 or 2), -S(0)tN(R^a)₂ (where t is 1 or 2), -S(0)tN(R^a)C(0)R^b (where t is 1 or 2), or PCb(R^a)₂, where each R^a is independently hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl.

[0093] The term "aryloxy" refers to the group -0-aryl.

[0094] The term "substituted aryloxy" refers to aryloxy wherein the aryl substituent is substituted (i.e., -0-(substituted aryl)). Unless stated otherwise specifically in the

specification, the aryl moiety of an aryloxy group is optionally substituted by one or more substituents which independently are: alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilanyl, -OR^a, -SR^a, -OC(0)-R^a, - N(R^a)₂, -C(0)R^a, -C(0)OR^a, -OC(0)N(R^a)₂, -C(0)N(R^a)₂, -N(R^a)C(0)OR^a, - N(R^a)C(0)R^a, -N(R^a)C(0)N(R^a)₂, N(R^a)C(NR^a)N(R^a)₂, -N(R^a)S(0)tR^a (where t is 1 or 2), - S(0)tOR^a (where t is 1 or 2), -S(0)tN(R^a)₂ (where t is 1 or 2), -S(0)tN(R^a)C(0)R^b (where t is 1 or 2), or PCb(R^a)₂, where each R^a is independently hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl.

[0095] "Aralkyl" or "arylalkyl" refers to an (aryl)alkyl-radical where aryl and alkyl are as disclosed herein and which are optionally substituted by one or more of the substituents described as suitable substituents for aryl and alkyl respectively.

[0096] "Ester" refers to a chemical radical of formula -COOR, where R is selected from the group consisting of alkyl, cycloalkyl, aryl, heteroaryl (bonded through a ring carbon) and heteroalicyclic (bonded through a ring carbon). The procedures and specific groups to make esters are known to those of skill in the art and can readily be found in seminal sources such as Greene and Wuts, Protective Groups in Organic Synthesis, 3^rd Ed., John Wiley & Sons, New York, N.Y., 1999, which is incorporated herein by reference in its entirety. Unless stated otherwise specifically in the specification, an ester group is optionally substituted by one or more substituents which independently are: alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilanyl, -OR^a, -SR^a, -OC(O)- R^a, -N(R^a)₂, -C(0)R^a, -C(0)OR^a, -OC(0)N(R^a)₂, -C(0)N(R^a)₂, -N(R^a)C(0)OR^a, - N(R^a)C(0)R^a, -N(R^a)C(0)N(R^a)₂, N(R^a)C(NR^a)N(R^a)₂, -N(R^a)S(0)tR^a (where t is 1 or 2), - S(0)tOR^a (where t is 1 or 2), -S(0)tN(R^a)₂ (where t is 1 or 2), -S(0)tN(R^a)C(0)R^b (where t is 1 or 2), or PCb(R^a)₂, where each R^a is independently hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl.

[0097] "Fluoroalkyl" refers to an alkyl radical, as defined above, that is substituted by one or more fluoro radicals, as defined above, for example, trifluoromethyl, difluoromethyl, 2,2,2-trifluoroethyl, 1 -fluoromethyl-2-fluoroethyl, and the like. The alkyl part of the fluoroalkyl radical may be optionally substituted as defined above for an alkyl group.

[0098] "Halo," "halide," or, alternatively, "halogen" is intended to mean fluoro, chloro, bromo or iodo. The terms "haloalkyl," "haloalkenyl," "haloalkynyl," and "haloalkoxy" include alkyl, alkenyl, alkynyl and alkoxy structures that are substituted with one or more halo groups or with combinations thereof. For example, the terms "fluoroalkyl" and

"fluoroalkoxy" include haloalkyl and haloalkoxy groups, respectively, in which the halo is fluorine.

[0099] "Heteroalkyl," "heteroalkenyl," and "heteroalkynyl" refer to optionally substituted alkyl, alkenyl and alkynyl radicals and which have one or more skeletal chain atoms selected from an atom other than carbon, e.g., oxygen, nitrogen, sulfur, phosphorus or combinations thereof. A numerical range may be given - e.g., C1-C4 heteroalkyl which refers to the chain length in total, which in this example is 4 atoms long. A heteroalkyl group may be substituted with one or more substituents which independently are: alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, nitro, oxo, thioxo, trimethylsilanyl, -OR^a, -SR^a, -OC(0)-R^a, - N(R^a)₂, -C(0)R^a, -C(0)OR^a, -OC(0)N(R^a)₂, -C(0)N(R^a)₂, -N(R^a)C(0)OR^a, - N(R^a)C(0)R^a, -N(R^a)C(0)N(R^a)₂, N(R^a)C(NR^a)N(R^a)₂, -N(R^a)S(0)tR^a (where t is 1 or 2), - S(0)tOR^a (where t is 1 or 2), -S(0)tN(R^a)₂ (where t is 1 or 2), -S(0)tN(R^a)C(0)R^b (where t is 1 or 2), or PCb(R^a)₂, where each R^a is independently hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl. [00100] "Heteroalkylaryl" refers to an -(heteroalkyl)aryl radical where heteroalkyl and aryl are as disclosed herein and which are optionally substituted by one or more of the substituents described as suitable substituents for heteroalkyl and aryl, respectively.

[00101] "Heteroalkylheteroaryl" refers to an -(heteroalkyl)heteroaryl radical where heteroalkyl and heteroaryl are as disclosed herein and which are optionally substituted by one or more of the substituents described as suitable substituents for heteroalkyl and heteroaryl, respectively.

[00102] "Heteroalkylheterocycloalkyl" refers to an -(heteroalkyl)heterocycloalkyl radical where heteroalkyl and heterocycloalkyl are as disclosed herein and which are optionally substituted by one or more of the substituents described as suitable substituents for heteroalkyl and heterocycloalkyl, respectively.

[00103] "Heteroalkylcycloalkyl" refers to an -(heteroalkyl)cycloalkyl radical where heteroalkyl and cycloalkyl are as disclosed herein and which are optionally substituted by one or more of the substituents described as suitable substituents for heteroalkyl and cycloalkyl, respectively.

[00104] "Heteroaryl" or "heteroaromatic" or "HetAr" refers to a 5- to 18-membered aromatic radical (e.g. , C5-C 13 heteroaryl) that includes one or more ring heteroatoms selected from nitrogen, oxygen and sulfur, and which may be a monocyclic, bicyclic, tricyclic or tetracyclic ring system. Whenever it appears herein, a numerical range such as "5 to 18" refers to each integer in the given range - e.g. , "5 to 18 ring atoms" means that the heteroaryl group may consist of 5 ring atoms, 6 ring atoms, etc., up to and including 18 ring atoms. Bivalent radicals derived from univalent heteroaryl radicals whose names end in "-yl" by removal of one hydrogen atom from the atom with the free valence are named by adding "- idene" to the name of the corresponding univalent radical - e.g. , a pyridyl group with two points of attachment is a pyridylidene. A N-containing "heteroaromatic" or "heteroaryl" moiety refers to an aromatic group in which at least one of the skeletal atoms of the ring is a nitrogen atom. The polycyclic heteroaryl group may be fused or non-fused. The

heteroatom(s) in the heteroaryl radical are optionally oxidized. One or more nitrogen atoms, if present, are optionally quatemized. The heteroaryl may be attached to the rest of the molecule through any atom of the ring(s). Examples of heteroaryls include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzindolyl, 1,3-benzodioxolyl, benzofuranyl, benzooxazolyl, benzo[cf]thiazolyl, benzothiadiazolyl, benzo[Z>] [l,4]dioxepinyl,

benzo[Z>] [l,4]oxazinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl,

benzodioxolyl, benzodioxinyl, benzoxazolyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzofurazanyl, benzothiazolyl, benzothienyl(benzothiophenyl), benzothieno[3,2-cf|pyrimidinyl, benzotriazolyl, benzo [4,6] imidazo[l,2-a] pyridinyl, carbazolyl, cinnolinyl, cyclopenta[cf|pyrimidinyl, 6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3- <f] pyrimidinyl, 5,6-dihydrobenzo[ 2]quinazolinyl, 5, 6-dihydrobenzo[ 2] cinnolinyl, 6,7- dihydro-5H-benzo[6,7]cyclohepta[l ,2-c]pyridazinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furazanyl, furanonyl, furo[3,2-c]pyridinyl, 5,6,7,8,9,10- hexahydrocycloocta[cf]pyrimidinyl, 5,6,7,8,9,10-hexahydrocycloocta[cf]pyridazinyl,

5,6,7,8,9,10-hexahydrocycloocta[cf]pyridinyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl, 5,8- methano-5,6,7,8-tetrahydroquinazolinyl, naphthyridinyl, 1,6-naphthyridinonyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl, 5,6,6a,7,8,9,10,10a-octahydrobenzo[ 2]quinazolinyl, 1- phenyl-lH-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyranyl, pyrrolyl, pyrazolyl, pyrazolo[3,4-d]pyrimidinyl, pyridinyl, pyrido[3,2- <f] pyrimidinyl, pyrido[3,4-cf]pyrimidinyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl, quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, 5,6,7,8- tetrahydroquinazolinyl, 5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidinyl, 6,7,8,9- tetrahydro-5H-cyclohepta[4,5]thieno[2,3-cf]pyrirnidinyl, 5,6,7,8-tetrahydropyrido[4,5- c] pyridazinyl, thiazolyl, thiadiazolyl, thiapyranyl, triazolyl, tetrazolyl, triazinyl, thieno[2,3- d\ pyrimidinyl, thieno[3,2-cf]pyrimidinyl, thieno[2,3-c]pyridinyl, and thiophenyl (i.e. , thienyl). Unless stated otherwise specifically in the specification, a heteroaryl moiety is optionally substituted by one or more substituents which are independently: alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, nitro, oxo, thioxo, trimethylsilanyl, -OR^a, -SR^a, -OC(0)-R^a, - N(R^a)₂, -C(0)R^a, -C(0)OR^a, -OC(0)N(R^a)₂, -C(0)N(R^a)₂, -N(R^a)C(0)OR^a, - N(R^a)C(0)R^a, -N(R^a)C(0)N(R^a)₂, N(R^a)C(NR^a)N(R^a)₂, -N(R^a)S(0)tR^a (where t is 1 or 2), - S(0)tOR^a (where t is 1 or 2), -S(0)tN(R^a)₂ (where t is 1 or 2), -S(0)tN(R^a)C(0)R^b (where t is 1 or 2), or PCb(R^a)₂, where each R^a is independently hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl.

[00105] Substituted heteroaryl also includes ring systems substituted with one or more oxide (-0-) substituents, such as, for example, pyridinyl N-oxides.

[00106] "Heteroarylalkyl" refers to a moiety having an aryl moiety, as described herein, connected to an alkylene moiety, as described herein, wherein the connection to the remainder of the molecule is through the alkylene group. [00107] "Heterocycloalkyl" refers to a stable 3- to 18-membered non-aromatic ring radical that comprises two to twelve carbon atoms and from one to six heteroatoms selected from nitrogen, oxygen and sulfur. Whenever it appears herein, a numerical range such as "3 to 18" refers to each integer in the given range - e.g. , "3 to 18 ring atoms" means that the heterocycloalkyl group may consist of 3 ring atoms, 4 ring atoms, etc., up to and including 18 ring atoms. Unless stated otherwise specifically in the specification, the heterocycloalkyl radical is a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may include fused or bridged ring systems. The heteroatoms in the heterocycloalkyl radical may be optionally oxidized. One or more nitrogen atoms, if present, are optionally quaternized. The heterocycloalkyl radical is partially or fully saturated. The heterocycloalkyl may be attached to the rest of the molecule through any atom of the ring(s). Examples of such

heterocycloalkyl radicals include, but are not limited to, dioxolanyl, thienyl[l,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2- oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, and 1,1-dioxo-thiomorpholinyl. Unless stated otherwise specifically in the specification, a heterocycloalkyl moiety is optionally substituted by one or more substituents which independently are: alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, nitro, oxo, thioxo, trimethylsilanyl, -OR^a, - SR^a, -OC(0)-R^a, -N(R^a)₂, -C(0)R^a, -C(0)OR^a, -OC(0)N(R^a)₂, -C(0)N(R^a)₂, - N(R^a)C(0)OR^a, -N(R^a)C(0)R^a, -N(R^a)C(0)N(R^a)₂, N(R^a)C(NR^a)N(R^a)₂, -N(R^a)S(0)tR^a (where t is 1 or 2), -S(0)tOR^a (where t is 1 or 2), -S(0)tN(R^a)₂ (where t is 1 or

2), -S(0)tN(R^a)C(0)R^b (where t is 1 or 2), or P0₃(R^a)₂, where each R^a is independently hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl.

[00108] "Heterocycloalkyl" also includes bicyclic ring systems wherein one non-aromatic ring, usually with 3 to 7 ring atoms, contains at least 2 carbon atoms in addition to 1-3 heteroatoms independently selected from oxygen, sulfur, and nitrogen, as well as combinations comprising at least one of the foregoing heteroatoms; and the other ring, usually with 3 to 7 ring atoms, optionally contains 1-3 heteroatoms independently selected from oxygen, sulfur, and nitrogen and is not aromatic.

[00109] "Nitro" refers to the -N0₂ radical. [00110] "Oxa" refers to the -O- radical.

[00111] "Oxo" refers to the =0 radical.

[00112] "Isomers" are different compounds that have the same molecular formula.

"Stereoisomers" are isomers that differ only in the way the atoms are arranged in space - i.e., having a different stereochemical configuration. "Enantiomers" are a pair of stereoisomers that are non-superimposable mirror images of each other. A 1 : 1 mixture of a pair of enantiomers is a "racemic" mixture. The term "(±)" is used to designate a racemic mixture where appropriate. "Diastereoisomers" are stereoisomers that have at least two asymmetric atoms, but which are not mirror-images of each other. The absolute stereochemistry is specified according to the Cahn-Ingold-Prelog R-S system. When a compound is a pure enantiomer the stereochemistry at each chiral carbon can be specified by either (R) or (S). Resolved compounds whose absolute configuration is unknown can be designated (+) or (-) depending on the direction (dextro- or levorotatory) which they rotate plane polarized light at the wavelength of the sodium D line. Certain of the compounds described herein contain one or more asymmetric centers and can thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that can be defined, in terms of absolute stereochemistry, as (R) or (S). The present chemical entities, pharmaceutical compositions and methods are meant to include all such possible isomers, including racemic mixtures, optically pure forms and intermediate mixtures. Optically active (R)- and (<S)-isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, and unless specified otherwise, it is intended that the compounds include both E and Z geometric isomers.

[00113] "Enantiomeric purity" as used herein refers to the relative amounts, expressed as a percentage, of the presence of a specific enantiomer relative to the other enantiomer. For example, if a compound, which may potentially have an (R)- or an (^-isomeric

configuration, is present as a racemic mixture, the enantiomeric purity is about 50% with respect to either the (R)- or (^-isomer. If that compound has one isomeric form predominant over the other, for example, 80% (^-isomer and 20% (i?)-isomer, the enantiomeric purity of the compound with respect to the (<S)-isomeric form is 80%. The enantiomeric purity of a compound can be determined in a number of ways known in the art, including but not limited to chromatography using a chiral support, polarimetric measurement of the rotation of polarized light, nuclear magnetic resonance spectroscopy using chiral shift reagents which include but are not limited to lanthanide containing chiral complexes or Pirkle's reagents, or derivatization of a compounds using a chiral compound such as Mosher's acid followed by chromatography or nuclear magnetic resonance spectroscopy.

[00114] In preferred embodiments, the enantiomerically enriched composition has a higher potency with respect to therapeutic utility per unit mass than does the racemic mixture of that composition. Enantiomers can be isolated from mixtures by methods known to those skilled in the art, including chiral high pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or preferred enantiomers can be prepared by asymmetric syntheses. See, for example, Jacques, et ai, Enantiomers, Racemates and Resolutions, Wiley Interscience, New York (1981); E. L. Eliel, Stereochemistry of Carbon Compounds, McGraw-Hill, New York (1962); and E. L. Eliel and S. H. Wilen, Stereochemistry of Organic Compounds, Wiley-Interscience, New York (1994).

[00115] The terms "enantiomerically enriched" and "non-racemic," as used herein, refer to compositions in which the percent by weight of one enantiomer is greater than the amount of that one enantiomer in a control mixture of the racemic composition (e.g., greater than 1 : 1 by weight). For example, an enantiomerically enriched preparation of the (<S)-enantiomer, means a preparation of the compound having greater than 50% by weight of the (<S)-enantiomer relative to the (i?)-enantiomer, such as at least 75% by weight, or such as at least 80% by weight. In some embodiments, the enrichment can be significantly greater than 80% by weight, providing a "substantially enantiomerically enriched" or a "substantially non- racemic" preparation, which refers to preparations of compositions which have at least 85% by weight of one enantiomer relative to other enantiomer, such as at least 90% by weight, or such as at least 95% by weight. The terms "enantiomerically pure" or "substantially enantiomerically pure" refers to a composition that comprises at least 98% of a single enantiomer and less than 2% of the opposite enantiomer.

[00116] "Moiety" refers to a specific segment or functional group of a molecule. Chemical moieties are often recognized chemical entities embedded in or appended to a molecule.

[00117] "Tautomers" are structurally distinct isomers that interconvert by tautomerization. "Tautomerization" is a form of isomerization and includes prototropic or proton-shift tautomerization, which is considered a subset of acid-base chemistry. "Prototropic tautomerization" or "proton-shift tautomerization" involves the migration of a proton accompanied by changes in bond order, often the interchange of a single bond with an adjacent double bond. Where tautomerization is possible (e.g., in solution), a chemical equilibrium of tautomers can be reached. An example of tautomerization is keto-enol tautomerization. A specific example of keto-enol tautomerization is the interconversion of pentane-2,4-dione and 4-hydroxypent-3-en-2-one tautomers. Another example of

tautomerization is phenol-keto tautomerization. A specific example of phenol-keto tautomerization is the interconversion of pyridin-4-ol and pyridin-4(lH)-one tautomers.

[00118] A "leaving group or atom" is any group or atom that will, under selected reaction conditions, cleave from the starting material, thus promoting reaction at a specified site. Examples of such groups, unless otherwise specified, include halogen atoms and mesyloxy, p-nitrobenzensulphonyloxy and tosyloxy groups.

[00119] "Protecting group" is intended to mean a group that selectively blocks one or more reactive sites in a multifunctional compound such that a chemical reaction can be carried out selectively on another unprotected reactive site and the group can then be readily removed or deprotected after the selective reaction is complete. A variety of protecting groups are disclosed, for example, in T. Η. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, Third Edition, John Wiley & Sons, New York (1999).

[00120] "Solvate" refers to a compound in physical association with one or more molecules of a pharmaceutically acceptable solvent.

[00121] "Substituted" means that the referenced group may have attached one or more additional groups, radicals or moieties individually and independently selected from, for example, acyl, alkyl, alkylaryl, cycloalkyl, aralkyl, aryl, carbohydrate, carbonate, heteroaryl, heterocycloalkyl, hydroxy, alkoxy, aryloxy, mercapto, alkylthio, arylthio, cyano, halo, carbonyl, ester, thiocarbonyl, isocyanato, thiocyanato, isothiocyanato, nitro, oxo,

perhaloalkyl, perfluoroalkyl, phosphate, silyl, sulfinyl, sulfonyl, sulfonamidyl, sulfoxyl, sulfonate, urea, and amino, including mono- and di-substituted amino groups, and protected derivatives thereof. The substituents themselves may be substituted, for example, a cycloalkyl substituent may itself have a halide substituent at one or more of its ring carbons. The term "optionally substituted" means optional substitution with the specified groups, radicals or moieties.

[00122] "Sulfanyl" refers to groups that include -S -(optionally substituted alkyl), -S- (optionally substituted aryl), -S-(optionally substituted heteroaryl) and -S -(optionally substituted heterocycloalkyl).

[00123] "Sulfinyl" refers to groups that include -S(0)-H, -S(0)-(optionally substituted alkyl), -S(0)-(optionally substituted amino), -S(0)-(optionally substituted aryl), -S(O)- (optionally substituted heteroaryl) and -S(0)-(optionally substituted heterocycloalkyl). [00124] "Sulfonyl" refers to groups that include -S(0₂)-H, -S(02)-(optionally substituted alkyl), -S(02)-(optionally substituted amino), -S(02)-(optionally substituted aryl), -S(C )- (optionally substituted heteroaryl), and -S(02)-(optionally substituted heterocycloalkyl).

[00125] "Sulfonamidyl" or "sulfonamido" refers to a -S(=0)2-NRR radical, where each R is selected independently from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, heteroaryl (bonded through a ring carbon) and heteroalicyclic (bonded through a ring carbon). The R groups in -NRR of the -S(=0)2-NRR radical may be taken together with the nitrogen to which it is attached to form a 4-, 5-, 6- or 7-membered ring. A sulfonamido group is optionally substituted by one or more of the substituents described for alkyl, cycloalkyl, aryl, heteroaryl, respectively.

[00126] "Sulfoxyl" refers to a -S(=0)₂OH radical.

[00127] "Sulfonate" refers to a -S(=0)2-OR radical, where R is selected from the group consisting of alkyl, cycloalkyl, aryl, heteroaryl (bonded through a ring carbon) and heteroalicyclic (bonded through a ring carbon). A sulfonate group is optionally substituted on R by one or more of the substituents described for alkyl, cycloalkyl, aryl, heteroaryl, respectively.

[00128] Compounds of the invention also include crystalline and amorphous forms of those compounds, including, for example, polymorphs, pseudopolymorphs, solvates, hydrates, unsolvated polymorphs (including anhydrates), conformational polymorphs, and amorphous forms of the compounds, as well as mixtures thereof. "Crystalline form" and "polymorph" are intended to include all crystalline and amorphous forms of the compound, including, for example, polymorphs, pseudopolymorphs, solvates, hydrates, unsolvated polymorphs (including anhydrates), conformational polymorphs, and amorphous forms, as well as mixtures thereof, unless a particular crystalline or amorphous form is referred to.

[00129] The term "hematological malignancy" refers to mammalian cancers and tumors of the hematopoietic and lymphoid tissues, including but not limited to tissues of the blood, bone marrow, lymph nodes, and lymphatic system. Hematological malignancies are also referred to as "liquid tumors." Hematological malignancies include, but are not limited to, ALL, CLL, SLL, acute myelogenous leukemia (AML), chronic myelogenous leukemia (CML), acute monocytic leukemia (AMoL), Hodgkin's lymphoma, and non-Hodgkin's lymphomas. The term "B cell hematological malignancy" refers to hematological malignancies that affect B cells.

[00130] The term "solid tumor" refers to an abnormal mass of tissue that usually does not contain cysts or liquid areas. Solid tumors may be benign or malignant. The term "solid tumor cancer" refers to malignant, neoplastic, or cancerous solid tumors. Solid tumor cancers include, but are not limited to, sarcomas, carcinomas, and lymphomas, such as cancers of the lung, breast, prostate, colon, rectum, and bladder. The tissue structure of solid tumors includes interdependent tissue compartments including the parenchyma (cancer cells) and the supporting stromal cells in which the cancer cells are dispersed and which may provide a supporting microenvironment.

[00131] For the avoidance of doubt, it is intended herein that particular features (for example integers, characteristics, values, uses, diseases, formulae, compounds or groups) described in conjunction with a particular aspect, embodiment or example of the invention are to be understood as applicable to any other aspect, embodiment or example described herein unless incompatible therewith. Thus such features may be used where appropriate in conjunction with any of the definition, claims or embodiments defined herein. All of the features disclosed in this specification (including any accompanying claims, abstract and drawings), and/or all of the steps of any method or process so disclosed, may be combined in any combination, except combinations where at least some of the features and/or steps are mutually exclusive. The invention is not restricted to any details of any disclosed

embodiments. The invention extends to any novel one, or novel combination, of the features disclosed in this specification (including any accompanying claims, abstract and drawings), or to any novel one, or any novel combination, of the steps of any method or process so disclosed.

The BCL-2 Family in Tumorigenesis

[00132] Apoptosis, or cell suicide, is caused by either oxidative stress or DNA damage. One of the key regulators of apoptosis is the Bcl-2 family of proteins, which contains both pro- apoptotic (Bak, Bim, Bax) and anti-apoptotic (Bcl-2, Bcl-xL, Mcl-1) members. The Bcl-2 proteins regulate each other to control apoptosis via a helix mediated protein - protein interaction between the a-helical BH3 domain (pro-apoptotic proteins) and hydrophobic binding grooves (anti-apoptotic proteins). Under apoptotic conditions, BH3 activators release the pro-apoptotic proteins from the anti-apoptotic proteins, initiating apoptosis. During tumorigenesis, the anti-apoptotic Bcl-2 proteins are upregulated, which capture the BH3 activators before they can properly function, thus inhibiting apoptosis and promoting tumorigenesis.

[00133] Mechanism of Action (FIGS. 1 A and IB): under homeostatic conditions, the Bcl-2 anti-apoptotic proteins are able to block apoptosis by binding to their pro-apoptotic proteins' a-helical amphipathic BH3 domains via their hydrophobic binding surface grooves. The hydrophobic binding grooves contain four hydrophobic pockets (pl-p4) which accommodate conserved hydrophobic residues on the BH3 domain.

Cross-talk Between the Bcl-2 and HDM2 Families

[00134] The tumor repressor gene p53 encodes a transcription factor that aids in the expression of various anti-tumorigenic proteins (FIG. 2). p53 has been shown to directly interact with members of the Bcl-2 family in initiating apoptosis, along with upregulating the transcription of pro-apoptotic Bcl-2 proteins. p53 is negatively controlled by HDM2, a protein ubiquitin ligase, causing its degradation via the ubiquitin-proteasome pathway. p53 interacts with HDM2 via a similar mechanism observed within the Bcl-2 protein family (FIG. 3). Additionally, HDM2 is often upregulated in conjugation with anti-apoptotic Bcl-2 proteins in many cancers.

Similarities Between the p53 and BH3 q-Helical Domains

[00135] Both the BH3 domain of pro-apoptotic Bcl-2 proteins and the transactivation domain (TAD) of p53 share an a-helical structure (FIG. 4). Also, both a-helices contain similar hydrophobic residues on one face of their helix that bind into their binding partners hydrophobic groove at the i, i + 3/4 and the i + 7 residues. Additionally, both a-helical domains contain a conserved aspartate residue on one side of the a-helix (FIG. 4). However, the aspartate residue in the BH3 domain is responsible for mediating protein binding via formation of a salt bridge, whereas the aspartate residue in the p53TAD aids in promoting the α-helical structure of the domain, not its binding to HDM2. In contrast to the BH3 domain, the p53TAD is slightly unfolded at one end of the helix.

HDM2(MDM2VBCL-2 dual inhibitors

[00136] The invention relates to HDM2/Bcl-2 dual inhibitors exploiting the similarities between the p53 and BH3 α-helical domains. In one embodiment, a dual inhibitor allows both the displacement of pro-apoptotic Bcl-2 proteins from their anti-apoptotic counterparts, as well as aid in their transcription due to elevated levels of free p53 protein, which is also likewise displaced from HDM2. The invention thus provides a synergistic effect for promoting apoptosis in tumorigenic cells.

[00137] Pyrazole-based a-helix mimetic dual inhibitors towards the HDM2/Bcl-2 family are known in the art, and due to the structural similarities between the pyrazole inhibitors and the α-helical domains, these compounds were pursued and evaluated for their affinity against HDM2/Bcl-2 family. Both the p53TAD and BH3 a-helix have similar pyramidal structure and angles, although the p53TAD is taller due to its partial unfolding. Pyrazole-based a-helix mimetics demonstrate similar geometric structure to the p53TAD and BH3 a-helical domains after energy minimalization simulations (FIG. 10). Compound 6 more accurately mimics the structure of both the p53TAD and BH3 domain since it has a flexible amide bond that can protrude an additional residue, allowing three hydrophobic groups on one face of the a-helix mimetic (FIG. 10).

[00138] Enhancing heterocyclic based compounds affinity toward the HDM2/Bcl-2 family is achieved through various medicinal chemistry approaches. In some embodiments, replacing the pyrazole core with various other heterocycles improves binding affinity. In some embodiments, the heterocycles used are five member ring heterocycles. In some

embodiments, various R¹, R², and R³ substituents are used (FIG. 9). In some embodiments, the Ri, R2, and R3 substituents (FIG. 9), are functional groups that mimic the i, i+3/4, and i+7 residues on both the BH3/p53TAD helices. Furthermore, the incorporation of a "flexible linker" between the core and the R³ position improves binding affinity due to its ability to simulate the p53TAD. Variation of the heterocyclic core allows for examination of the effect that the substitution pattern has on binding affinity.

[0013] In some embodiments, the invention relates to compounds of Formulas AA-AD:

Formula AA Formula AB Formula AC Formula AD

[0014] wherein in Formulas AA-AD:

[0015] each R is independently hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, fluoroalkyl, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilanyl, -OR^a, -SR^a, -OC(0)R^a, -N(R^a)R^b, -C(0)R^a, -C(0)OR^a, -OC(0)N(R^a)R^b, -C(0)N(R^a)R^b, -N(R^a)C(0)OR^a, - N(R^a)C(0)R^a, -N(R^a)C(0)N(R^a)R^b, - N(R^a)C(NR^a)N(R^a)R^b, -N(R^a)S(0)_tR^a, -C(0)N(R^a)S(0)_tR^a, - S(0)tOR^a, -S(0)tN(R^a)R^b, -S(0)tN(R^a)C(0)R^b, or -P(0)(OR^a)(OR^b);

[0016] R^a and R^b are each independently selected from the group consisting of hydrogen, alkyl, fluoroalkyl, cycloalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, heteroarylalkyl, halogen, -O-alkyl, -O-aryl, cyano, nitro, OH, -NH₂, -NH-alkyl, and -NH-aryl; and t is 1 or 2.

[0017] In some embodiments, the invention relates to compounds of Formulas BA-BM:

Fo

rmula BA Formula BB Formula BC

Formula BE Formula BF Formula BG Formula BH

Formula BI Formula BJ Formula BK Formula BL

Formula BM

[0018] wherein in Formulas BA-BM:

[0019] each R is independently hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, fluoroalkyl, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilanyl, -OR^a, -SR^a, -OC(0)R^a,

N(R^a)C(0)R^a, -N(R^a)C(0)N(R^a)R^b, -

N(R^a)C(NR^a)N(R^a)R^b, -N(R^a)S(0)tR^a, -C(0)N(R^a)S(0)tR^a, -

S(0)tOR^a, -S(0)tN(R^a)R^b, -S(0)tN(R^a)C(0)R^b, or -P(0)(OR^a)(OR^b);

[0020] R' is hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, fluoroalkyl, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilanyl, -OR^a, -SR^a, -OC(0)R^a, -

S(0)tOR^a, -S(0)tN(R^a)R^b, -S(0)tN(R^a)C(0)R^b, or -P(0)(OR^a)(OR^b);

[00139] L is a linker selected from a bond, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, fluoroalkyl, -OC(O)-, -NR^a-

, -C(O)-, -C(0)0-, -OC(0)N(R^a)-, -C(0)N(R^a)-, -C(0)N(R^a)S(0)t-, -N(R^a)C(0)0-, -

N(R^a)C(0)-, -N(R^a)C(0)N(R^a)-, -N(R^a)C(NR^a)N(R^a)-, -N(R^a)S(0)t-, -S(0)tO-, -S(0)tN(R^a)-

, -S(0)_tN(R^a)C(0)-, -P(0)(OR^a)0-, -OP(0)(OR^a)0-, -(CR^aR^b)_n-, -0-, -S-, and -S(0)t-;

[00140] R^a and R^b are each independently selected from the group consisting of hydrogen, alkyl, fluoroalkyl, cycloalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, heteroarylalkyl, halogen, -O-alkyl, -O-aryl, cyano, nitro, -

OH, -NH₂, -NH-alkyl, and -NH-aryl;

[00141] n is a positive integer, and t is 1 or 2.

[00142] In some embodiments, the invention relates to compounds of Formulas CA-CZ:

Formula CA Formula CB Formula CC Formula CD

Formula CE Formula CF Formula CG

Formula CI Formula CJ Formula CK Formula CL

Formula CM Formula CN Formula CO Formula CP

Formula CQ Formula CR Formula CS Formula CT

Formula CU Formula CV Formula CW Formula CX

Formula CY Formula CZ

[00143] wherein in Formulas CA-CZ:

[00144] each R is independently hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, fluoroalkyl, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilanyl, -OR^a, -SR^a, -OC(0)R^a,

N(R^a)C(0)R^a, -N(R^a)C(0)N(R^a)R^b, -

N(R^a)C(NR^a)N(R^a)R^b, -N(R^a)S(0)_tR^a, -C(0)N(R^a)S(0)_tR^a, -

S(0)tOR^a, -S(0)tN(R^a)R^b, -S(0)tN(R^a)C(0)R^b, or -P(0)(OR^a)(OR^b);

[00145] R' is hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, fluoroalkyl, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilanyl, -OR^a, -SR^a, -OC(0)R^a, -

S(0)tOR^a, -S(0)tN(R^a)R^b, -S(0)tN(R^a)C(0)R^b, or -P(0)(OR^a)(OR^b);

[00146] X is alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, fluoroalkyl, -(CR^aR^b)_n-, -0-, -S-, -SO-, -SO2-, or -NR^a-;

[00147] R^a and R^b are each independently selected from the group consisting of hydrogen, alkyl, fluoroalkyl, cycloalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, heteroarylalkyl, halogen, -O-alkyl, -O-aryl, cyano, nitro, - OH, -NH₂, -NH-alkyl, and -NH-aryl;

[00148] n is a positive integer, and t is 1 or 2.

[00149] In some embodiments, the invention relates to compounds of Formulas 1 -27:

Formula 1 Formula 2 Formula 3 Formula 4

Formula 5 Formula 6 Formula 7 Formula 8

Formula 9 Formula 10 Formula 1 1 Formula 12

Formula 13 Formula 14 Formula 15 Formula 16

Formula 17 Formula 18 Formula 19 Formula 20

Formula 21 Formula 22 Formula 23 Formula 24

Formula 25 Formula 26 Formula 27

[00150] wherein in Formulas 1 -27:

[00151] An and An are each independently an aryl or heteroaryl group, optionally substituted with one or more substituents such as alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl, trifiuoromethoxy, nitro, trimethylsilanyl, -OR^a, -SR^a, -OC(0)R^a, - N(R^a)R^b, -C(0)R^a, -C(0)OR^a, -OC(0)N(R^a)R^b, -C(0)N(R^a)R^b, -N(R^a)C(0)OR^a, - N(R^a)C(0)R^a, -N(R^a)C(0)N(R^a)R^b, -N(R^a)C(NR^a)N(R^a)R^b, -N(R^a)S(0)tR^a, - S(0)tOR^a, -S(0)tN(R^a)R^b, -S(0)tN(R^a)C(0)R^b, or -P(0)(OR^a)(OR^b);

[00152] Ri, and R2 are each independently hydrogen, alkyl, fluoroalkyl, -OR^a, -SR^a, - OC(0)R^a, -N(R^a)R^b, -OC(0)N(R^a)R^b, -N(R^a)C(0)OR^a, -N(R^a)C(0)R^a, -N(R^a)C(0)N(R^a)R^b, - N(R^a)C(NR^a)N(R^a)R^b, -N(R^a)S(0)_tR^a, -S(0)tOR^a, -S(0)tN(R^a)C(0)R^b, or -S(0)tN(R^a)R^b;

[00153] L is a linker selected from a bond, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, fluoroalkyl, -OC(O)-, -NR^a- , -C(O)-, -C(0)0-, -OC(0)N(R^a)-, -C(0)N(R^a)-, -C(0)N(R^a)S(0)t-, -N(R^a)C(0)0-, - N(R^a)C(0)-, -N(R^a)C(0)N(R^a)-, -N(R^a)C(NR^a)N(R^a)-, -N(R^a)S(0)t-, -S(0)tO-, -S(0)tN(R^a)- , -S(0)_tN(R^a)C(0)-, -P(0)(OR^a)0-, -OP(0)(OR^a)0-, -(CR^aR^b)_n-, -0-, -S-, and -S(0)t-;

[00154] R^a and R^b are each independently selected from the group consisting of hydrogen, alkyl, fluoroalkyl, cycloalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, heteroarylalkyl, halogen, -O-alkyl, -O-aryl, cyano, nitro, - OH, -NH2, -NH-alkyl, and -NH-aryl; [00155] n is a positive integer, and t is 1 or 2.

[00156] In some embodiments, the invention relates to compounds of Formula 101-154:

Formula 105 Formula 106 Formula 107 Formula 108

Formula 109 Formula 111 Formula

Formula 113 Formula 114 Formula 115 Formula 116

Formula 117 Formula 118 Formula 119 Formula 120

Formula 121 Formula 122 Formula 123 Formula 124

Formula 125 Formula 126 Formula 127 Formula 128

Formula 129 Formula 130 Formula 131 Formula 132

Formula 133 Formula 134 Formula 135 Formula 136

Formula 137 Formula 138 Formula 139 Formula 140

Formula 141 Formula 142 Formula 143 Formula 144

Formula 145 Formula 146 Formula 147 Formula 148

Formula 149 Formula 150 Formula 151 Formula 152

Formula 153 Formula 154

[00157] wherein in Formulas 101 -154:

[00158] An and An are each independently an aryl or heteroaryl group, optionally substituted with one or more substituents such as alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilanyl, -OR^a, -SR^a, -OC(0)R^a, - N(R^a)R^b, -C(0)R^a, -C(0)OR^a, -OC(0)N(R^a)R^b, -C(0)N(R^a)R^b, -N(R^a)C(0)OR^a, - N(R^a)C(0)R^a, -N(R^a)C(0)N(R^a)R^b, -N(R^a)C(NR^a)N(R^a)R^b, -N(R^a)S(0)tR^a, - S(0)tOR^a, -S(0)tN(R^a)R^b, -S(0)tN(R^a)C(0)R^b, or -P(0)(OR^a)(OR^b);

[00159] Ri, R2, and R3 are each independently hydrogen, alkyl, fluoroalkyl, -OR^a, -SR^a, - OC(0)R^a, -N(R^a)R^b, -OC(0)N(R^a)R^b, -N(R^a)C(0)OR^a, -N(R^a)C(0)R^a, -N(R^a)C(0)N(R^a)R^b, - N(R^a)C(NR^a)N(R^a)R^b, -N(R^a)S(0)_tR^a, -S(0)tOR^a, -S(0)tN(R^a)C(0)R^b, or -S(0)tN(R^a)R^b;

[00160] X is alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, fluoroalkyl, -(CR^aR^b)_n-, -OR³-, -S-, -SO-, -SO2-, or - NR^a-;

[00161] R^a and R^b are each independently selected from the group consisting of hydrogen, alkyl, fluoroalkyl, cycloalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, heteroarylalkyl, halogen, -O-alkyl, -O-aryl, cyano, nitro, - OH, -NH2, -NH-alkyl, and -NH-aryl;

[00162] n is a positive integer, and t is 1 or 2.

[00163] In some embodiments, the invention relates to compounds of Formulas 201-224:

Formula 201 Formula 202 Formula 203

Formula 204 Formula 205 Formula 206

Formula 208 Formula 209

Formula 211

Formula 216 Formula 217 Formula 218

Formula 220 Formula 221

Formula 222 Formula 223 Formula 224

[00164] wherein in Formulas 201-224:

[00165] each R is independently selected from the group consisting of alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilanyl, -OR^a, -SR^a, - OC(0)R^a, -N(R^a)R^b, -C(0)R^a, -C(0)OR^a, -OC(0)N(R^a)R^b, -C(0)N(R^a)R^b, -N(R^a)C(0)OR^a, - N(R^a)C(0)R^a, -N(R^a)C(0)N(R^a)R^b, -N(R^a)C(NR^a)N(R^a)R^b, -N(R^a)S(0)tR^a, - S(0)tOR^a, -S(0)tN(R^a)R^b, -S(0)tN(R^a)C(0)R^b, or -P(0)(OR^a)(OR^b);

[00166] each R2 is independently selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, isopropyl, or trifluoromethyl;

[00167] R₃ is -OH, -OR_a, -NHRa, -NR_aRb, optionally substituted alkyl, or optionally substituted aryl;

[00168] R^a and R^b are each independently selected from the group consisting of hydrogen, alkyl, fluoroalkyl, cycloalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, heteroarylalkyl, halogen, -O-alkyl, -O-aryl, cyano, nitro, - OH, -NH2, -NH-alkyl, and -NH-aryl;

[00169] n is 0, 1, 2, 3, 4, 5, or 6; and t is 1 or 2.

[00170] In some embodiments, the invention relates to compounds of Formulas 301-333:

Formula 301 Formula 302 Formula 303

Formula 304 Formula 305 Formula 306

Formula 310 Formula 311 Formula 312

Formula 313 Formula 314 Formula 315 Formula 316 Formula 317

Formula 322 Formula 323 Formula 324

Formula 325 Formula 326 Formula 327

[00171] wherein in Formulas 301-333, each R is a substituent such as alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilanyl, -OR^a, -SR^a, - OC(0)R^a, -N(R^a)R^b, -C(0)R^a, -C(0)OR^a, -OC(0)N(R^a)R^b, -C(0)N(R^a)R^b, -N(R^a)C(0)OR^a, - N(R^a)C(0)R^a, -N(R^a)C(0)N(R^a)R^b, -N(R^a)C(NR^a)N(R^a)R^b, -N(R^a)S(0)tR^a, - S(0)tOR^a, -S(0)tN(R^a)R^b, -S(0)tN(R^a)C(0)R^b, or -P(0)(OR^a)(OR^b);

[00172] R^a and R^b are each independently hydrogen, alkyl, fluoroalkyl, cycloalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, heteroarylalkyl, halogen, -O-alkyl, -O-aryl, cyano, nitro, -OH, -NH2, -NH-alkyl, or -NH-aryl; n is 0, 1, 2, 3, 4, 5, or 6; and t is 1 or 2.

[00173] In some embodiments, the invention relates to compounds of Formulas 401-448, wherein n is 0, 1, 2, 3, 4, 5, or 6, where applicable:

Formula 402

Formula 404 Formula 405

Formula 407 Formula 408 Formula 409

Formula 416 Formula 417 Formula 418

Formula 440 Formula 442

Formula 444 Formula 445

Formula 446 Formula 447 Formula 448

[00174] In some embodiments, the invention relates to BCL-2 inhibitors of Formulas AA- AD, BA-BM, CA-CZ, 1-27, 101 -154, 201-224, 301 -333, and 401-448. In some embodiments, the invention relates to MDM2 inhibitors of Formulas AA-AD, BA-BM, CA- CZ, 1-27, 101-154, 201-224, 301-333, and 401-448. In some embodiments, the invention relates to dual BCL-2/MDM2 inhibitors of Formulas AA-AD, BA-BM, CA-CZ, 1-27, 101- 154, 201-224, 301-333, and 401-448.

Pharmaceutical Compositions

[00175] In one embodiment, the invention provides a pharmaceutical composition for use in the treatment of the diseases and conditions described herein. In a preferred embodiment, the invention provides pharmaceutical compositions, including those described below, for use in the treatment of a hyperproliferative disease. In a preferred embodiment, the invention provides pharmaceutical compositions, including those described below, for use in the treatment of cancer.

[00176] In some embodiments, the invention relates to a pharmaceutical composition including one or more compounds of Formulas AA-AD, BA-BM, CA-CZ, 1-27, 101-154, 201-224, 301-333, and 401-448, or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or prodrug thereof, and a physiologically compatible carrier medium.

[00177] In some embodiments, the invention relates to a pharmaceutical composition including one or more BCL-2 inhibitors of Formulas AA-AD, BA-BM, CA-CZ, 1-27, 101- 154, 201-224, 301-333, and 401-448, or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or prodrug thereof, and a physiologically compatible carrier medium.

[00178] In some embodiments, the invention relates to a pharmaceutical composition including one or more MDM2 inhibitors of Formulas AA-AD, BA-BM, CA-CZ, 1-27, 101- 154, 201-224, 301-333, and 401-448, or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or prodrug thereof, and a physiologically compatible carrier medium.

[00179] In some embodiments, the invention relates to a pharmaceutical composition including one or more dual BCL-2 and MDM2 inhibitors of Formulas AA-AD, BA-BM, CA- CZ, 1-27, 101-154, 201-224, 301-333, and 401-448, or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or prodrug thereof, and a physiologically compatible carrier medium.

[00180] In some embodiments, the invention provides pharmaceutical compositions for treating a disease alleviated by inhibiting BCL-2 in a patient in need thereof, the composition including a therapeutically effective amount of one or more compounds of Formulas AA-AD, BA-BM, CA-CZ, 1-27, 101-154, 201-224, 301-333, and 401-448, or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or prodrug thereof. [00181] In some embodiments, the invention provides pharmaceutical compositions for treating a disease alleviated by inhibiting MDM2 in a patient in need thereof, the composition including a therapeutically effective amount of one or more compounds of Formulas AA-AD, BA-BM, CA-CZ, 1-27, 101-154, 201-224, 301-333, and 401-448, or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or prodrug thereof.

[00182] In some embodiments, the invention provides pharmaceutical compositions for treating a disease alleviated by inhibiting BCL-2 and MDM2 in a patient in need thereof, the composition including a therapeutically effective amount of one or more compounds of Formulas AA-AD, BA-BM, CA-CZ, 1-27, 101-154, 201-224, 301-333, and 401-448, or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or prodrug thereof.

[00183] The pharmaceutical compositions are typically formulated to provide a

therapeutically effective amount of a BCL-2 inhibitor, a MDM2 inhibitor, and/or a dual BCL- 2 and MDM2 inhibitor, or a fragment, derivative, conjugate, variant, radioisotope-labeled complex, or biosimilar thereof, or pharmaceutically acceptable salts, prodrugs, solvates, or hydrates thereof, as the active ingredients. Where desired, the pharmaceutical compositions contain a pharmaceutically acceptable salt and/or coordination complex of one or more of the active ingredients. Typically, the pharmaceutical compositions also comprise one or more pharmaceutically acceptable excipients, carriers, including inert solid diluents and fillers, diluents, including sterile aqueous solution and various organic solvents, permeation enhancers, solubilizers and adjuvants.

[00184] The pharmaceutical compositions described above are preferably for use in the treatment of the diseases and conditions described below. In a preferred embodiment, the pharmaceutical compositions are for use in the treatment of cancer. In one embodiment, the pharmaceutical compositions of the present invention are for use in the treatment of a cancer selected from the group consisting of bladder cancer, squamous cell carcinoma including head and neck cancer, pancreatic ductal adenocarcinoma (PDA), pancreatic cancer, colon carcinoma, mammary carcinoma, breast cancer, fibrosarcoma, mesothelioma, renal cell carcinoma, lung carcinoma, thymoma, prostate cancer, colorectal cancer, ovarian cancer, acute myeloid leukemia, thymus cancer, brain cancer, squamous cell cancer, skin cancer, eye cancer, retinoblastoma, melanoma, intraocular melanoma, oral cavity and oropharyngeal cancers, gastric cancer, stomach cancer, cervical cancer, renal cancer, kidney cancer, liver cancer, ovarian cancer, esophageal cancer, testicular cancer, gynecological cancer, thyroid cancer, acquired immune deficiency syndrome (AIDS)-related cancers (e.g. , lymphoma and Kaposi's sarcoma), viral-induced cancer, glioblastoma, esophageal tumors, hematological neoplasms, non-small-cell lung cancer, chronic myelocytic leukemia, diffuse large B-cell lymphoma, esophagus tumor, follicle center lymphoma, head and neck tumor, hepatitis C virus related cancer, hepatocellular carcinoma, Hodgkin's disease, metastatic colon cancer, multiple myeloma, non-Hodgkin's lymphoma, indolent non-Hodgkin's lymphoma, ovary tumor, pancreas tumor, renal cell carcinoma, small-cell lung cancer, stage IV melanoma, chronic lymphocytic leukemia, B-cell acute lymphoblastic leukemia (ALL), mature B-cell ALL, follicular lymphoma, mantle cell lymphoma, and Burkitt's lymphoma.

[00185] Where desired, other active pharmaceutical ingredient(s) may be mixed into a preparation or two or more components of the combination may be formulated into separate preparations for use in combination separately or at the same time. A kit containing the components of the combination, formulated into separate preparations for said use, is also provided by the invention.

[00186] In some embodiments, the concentration of any one BCL-2 inhibitor, MDM2 inhibitor, or dual BCL-2/MDM2 inhibitor, provided in a pharmaceutical composition of the invention, is independently less than, for example, 100%, 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11 %, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1 %, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.09%, 0.08%, 0.07%, 0.06%, 0.05%, 0.04%, 0.03%, 0.02%, 0.01 %, 0.009%, 0.008%, 0.007%, 0.006%, 0.005%, 0.004%, 0.003%, 0.002%, 0.001%, 0.0009%, 0.0008%, 0.0007%, 0.0006%, 0.0005%, 0.0004%, 0.0003%, 0.0002%, or 0.0001% w/w, w/v, or v/v of the pharmaceutical composition.

[00187] In some embodiments, the concentration of any one BCL-2 inhibitor, MDM2 inhibitor, or dual BCL-2/MDM2 inhibitor, provided in a pharmaceutical composition of the invention, is independently greater than 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 19.75%, 19.50%, 19.25% 19%, 18.75%, 18.50%, 18.25% 18%, 17.75%, 17.50%, 17.25% 17%, 16.75%, 16.50%, 16.25% 16%, 15.75%, 15.50%, 15.25% 15%, 14.75%, 14.50%, 14.25% 14%, 13.75%, 13.50%, 13.25% 13%, 12.75%, 12.50%, 12.25% 12%, 1 1.75%, 11.50%, 1 1.25% 1 1%, 10.75%, 10.50%, 10.25% 10%, 9.75%, 9.50%, 9.25% 9%, 8.75%, 8.50%, 8.25% 8%, 7.75%, 7.50%, 7.25% 7%, 6.75%, 6.50%, 6.25% 6%, 5.75%, 5.50%, 5.25% 5%, 4.75%, 4.50%, 4.25%, 4%, 3.75%, 3.50%, 3.25%, 3%, 2.75%, 2.50%, 2.25%, 2%, 1.75%, 1.50%, 125%, 1 %, 0.5%, 0.4%, 0.3%, 0.2%, 0.1 %, 0.09%, 0.08%, 0.07%, 0.06%, 0.05%, 0.04%, 0.03%, 0.02%, 0.01%, 0.009%, 0.008%, 0.007%, 0.006%, 0.005%, 0.004%, 0.003%, 0.002%, 0.001%, 0.0009%, 0.0008%, 0.0007%, 0.0006%, 0.0005%, 0.0004%, 0.0003%, 0.0002%, or 0.0001% w/w, w/v, or v/v of the pharmaceutical composition. [00188] In some embodiments, the concentration of any one BCL-2 inhibitor, MDM2 inhibitor, or dual BCL-2/MDM2 inhibitor, provided in a pharmaceutical composition of the invention, is independently in the range from about 0.0001% to about 50%, from about 0.001% to about 40%, from about 0.01% to about 30%, from about 0.02% to about 29%, from about 0.03% to about 28%, from about 0.04% to about 27%, from about 0.05% to about 26%, from about 0.06% to about 25%, from about 0.07% to about 24%, from about 0.08% to about 23%, from about 0.09% to about 22%, from about 0.1% to about 21%, from about 0.2% to about 20%, from about 0.3% to about 19%, from about 0.4% to about 18%, from about 0.5% to about 17%, from about 0.6% to about 16%, from about 0.7% to about 15%, from about 0.8% to about 14%, from about 0.9% to about 12%, or from about 1% to about 10% w/w, w/v, or v/v of the pharmaceutical composition.

[00189] In some embodiments, the concentration of any one BCL-2 inhibitor, MDM2 inhibitor, or dual BCL-2/MDM2 inhibitor, provided in a pharmaceutical composition of the invention, is independently in the range from about 0.001% to about 10%, from about 0.01% to about 5%, from about 0.02% to about 4.5%, from about 0.03% to about 4%, from about 0.04% to about 3.5%, from about 0.05% to about 3%, from about 0.06% to about 2.5%, from about 0.07% to about 2%, from about 0.08% to about 1.5%, from about 0.09% to about 1%, from about 0.1% to about 0.9% w/w, w/v, or v/v of the pharmaceutical composition.

[00190] In some embodiments, the concentration of any one BCL-2 inhibitor, MDM2 inhibitor, or dual BCL-2/MDM2 inhibitor, provided in a pharmaceutical composition of the invention, is independently equal to or less than about 10 g, about 9.5 g, about 9.0 g, about 8.5 g, about 8.0 g, about 7.5 g, about 7.0 g, about 6.5 g, about 6.0 g, about 5.5 g, about 5.0 g, about 4.5 g, about 4.0 g, about 3.5 g, about 3.0 g, about 2.5 g, about 2.0 g, about 1.5 g, about 1.0 g, about 0.95 g, about 0.9 g, about 0.85 g, about 0.8 g, about 0.75 g, about 0.7 g, about 0.65 g, about 0.6 g, about 0.55 g, about 0.5 g, about 0.45 g, about 0.4 g, about 0.35 g, about 0.3 g, about 0.25 g, about 0.2 g, about 0.15 g, about 0.1 g, about 0.09 g, about 0.08 g, about 0.07 g, about 0.06 g, about 0.05 g, about 0.04 g, about 0.03 g, about 0.02 g, about 0.01 g, about 0.009 g, about 0.008 g, about 0.007 g, about 0.006 g, about 0.005 g, about 0.004 g, about 0.003 g, about 0.002 g, about 0.001 g, about 0.0009 g, about 0.0008 g, about 0.0007 g, about 0.0006 g, about 0.0005 g, about 0.0004 g, about 0.0003 g, about 0.0002 g, or about 0.0001 g.

[00191] In some embodiments, the concentration of any one BCL-2 inhibitor, MDM2 inhibitor, or dual BCL-2/MDM2 inhibitor, provided in a pharmaceutical composition of the invention, is independently more than about 0.0001 g, about 0.0002 g, about 0.0003 g, about 0.0004 g, about 0.0005 g, about 0.0006 g, about 0.0007 g, about 0.0008 g, about 0.0009 g, about 0.001 g, about 0.0015 g, about 0.002 g, about 0.0025 g, about 0.003 g, about 0.0035 g, about 0.004 g, about 0.0045 g, about 0.005 g, about 0.0055 g, about 0.006 g, about 0.0065 g, about 0.007 g, about 0.0075 g, about 0.008 g, about 0.0085 g, about 0.009 g, about 0.0095 g, about 0.01 g, about 0.015 g, about 0.02 g, about 0.025 g, about 0.03 g, about 0.035 g, about 0.04 g, about 0.045 g, about 0.05 g, about 0.055 g, about 0.06 g, about 0.065 g, about 0.07 g, about 0.075 g, about 0.08 g, about 0.085 g, about 0.09 g, about 0.095 g, about 0.1 g, about 0.15 g, about 0.2 g, about 0.25 g, about 0.3 g, about 0.35 g, about 0.4 g, about 0.45 g, about 0.5 g, about 0.55 g, about 0.6 g, about 0.65 g, about 0.7 g, about 0.75 g, about 0.8 g, about 0.85 g, about 0.9 g, about 0.95 g, about 1 g, about 1.5 g, about 2 g, about 2.5, about 3 g, about 3.5, about 4 g, about 4.5 g, about 5 g, about 5.5 g, about 6 g, about 6.5 g, about 7 g, about 7.5 g, about 8 g, about 8.5 g, about 9 g, about 9.5 g, or about 10 g.

[00192] Each of the BCL-2 inhibitor, MDM2 inhibitor, or dual BCL-2/MDM2 inhibitor according to the invention is effective over a wide dosage range. For example, in the treatment of adult humans, dosages independently ranging from about 0.01 to about 1000 mg, from about 0.5 to about 100 mg, from about 1 to about 50 mg per day, and from about 5 to about 40 mg per day are examples of dosages that may be used. The exact dosage will depend upon the route of administration, the form in which the compound is administered, the gender and age of the subject to be treated, the body weight of the subject to be treated, and the preference and experience of the attending physician.

[00193] Described below are non-limiting pharmaceutical compositions and methods for preparing the same.

Pharmaceutical Compositions for Oral Administration

[00194] In preferred embodiments, the invention provides a pharmaceutical composition for oral administration containing one or more of a BCL-2 inhibitor, an MDM2 inhibitor, and/or a dual BCL-2/MDM2 inhibitor according to the invention, and a pharmaceutical excipient suitable for administration. In other embodiments, the invention provides a pharmaceutical composition for oral administration containing one or more of a BCL-2 inhibitor, an MDM2 inhibitor, or a dual BCL-2/MDM2 inhibitor according to the invention, a pharmaceutical excipient suitable for administration, and one or more additional active pharmaceutical ingredient.

[00195] In some embodiments, the pharmaceutical composition may be a solid

pharmaceutical composition suitable for oral consumption. In some embodiments, the pharmaceutical composition may be a liquid pharmaceutical composition suitable for oral consumption.

[00196] Pharmaceutical compositions of the invention suitable for oral administration can be presented as discrete dosage forms, such as capsules, sachets, tablets, liquids, or aerosol sprays each containing a predetermined amount of an active ingredient as a powder or in granules, a solution, or a suspension in an aqueous or non-aqueous liquid, an oil-in-water emulsion, a water-in-oil liquid emulsion, powders for reconstitution, powders for oral consumptions, bottles (including powders or liquids in a bottle), orally dissolving films, lozenges, pastes, tubes, gums, and packs. Such dosage forms can be prepared by any of the methods of pharmacy, but all methods include the step of bringing the active ingredient(s) into association with the carrier, which constitutes one or more necessary ingredients. In general, the compositions are prepared by uniformly and intimately admixing the active ingredient(s) with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product into the desired presentation. For example, a tablet can be prepared by compression or molding, optionally with one or more accessory ingredients. Compressed tablets can be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as powder or granules, optionally mixed with an excipient such as, but not limited to, a binder, a lubricant, an inert diluent, and/or a surface active or dispersing agent. Molded tablets can be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.

[00197] The invention further encompasses anhydrous pharmaceutical compositions and dosage forms since water can facilitate the degradation of some compounds. For example, water may be added (e.g. , 5%) in the pharmaceutical arts as a means of simulating long-term storage in order to determine characteristics such as shelf-life or the stability of formulations over time. Anhydrous pharmaceutical compositions and dosage forms of the invention can be prepared using anhydrous or low moisture containing ingredients and low moisture or low humidity conditions. Pharmaceutical compositions and dosage forms of the invention which contain lactose can be made anhydrous if substantial contact with moisture and/or humidity during manufacturing, packaging, and/or storage is expected. An anhydrous pharmaceutical composition may be prepared and stored such that its anhydrous nature is maintained.

Accordingly, anhydrous compositions may be packaged using materials known to prevent exposure to water such that they can be included in suitable formulary kits. Examples of suitable packaging include, but are not limited to, hermetically sealed foils, plastic or the like, unit dose containers, blister packs, and strip packs. [00198] Each of the BCL-2 inhibitor, MDM2 inhibitor, and/or a dual BCL-2/MDM2 inhibitor according to the invention, used as active ingredients can be combined in an intimate admixture with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques. The carrier can take a wide variety of forms depending on the form of preparation desired for administration. In preparing the compositions for an oral dosage form, any of the usual pharmaceutical media can be employed as carriers, such as, for example, water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents, and the like in the case of oral liquid preparations (such as suspensions, solutions, and elixirs) or aerosols; or carriers such as starches, sugars, micro-crystalline cellulose, diluents, granulating agents, lubricants, binders, and disintegrating agents can be used in the case of oral solid preparations, in some embodiments without employing the use of lactose. For example, suitable carriers include powders, capsules, and tablets, with the solid oral preparations. If desired, tablets can be coated by standard aqueous or nonaqueous techniques.

[00199] Binders suitable for use in pharmaceutical compositions and dosage forms include, but are not limited to, com starch, potato starch, or other starches, gelatin, natural and synthetic gums such as acacia, sodium alginate, alginic acid, other alginates, powdered tragacanth, guar gum, cellulose and its derivatives (e.g. , ethyl cellulose, cellulose acetate, carboxymethyl cellulose calcium, sodium carboxymethyl cellulose), polyvinyl pyrrolidone, methyl cellulose, pre-gelatinized starch, hydroxypropyl methyl cellulose, microcrystalline cellulose, and mixtures thereof.

[00200] Examples of suitable fillers for use in the pharmaceutical compositions and dosage forms disclosed herein include, but are not limited to, talc, calcium carbonate (e.g., granules or powder), microcrystalline cellulose, powdered cellulose, dextrates, kaolin, mannitol, silicic acid, sorbitol, starch, pre-gelatinized starch, and mixtures thereof.

[00201] Disintegrants may be used in the compositions of the invention to provide tablets that disintegrate when exposed to an aqueous environment. Too much of a disintegrant may produce tablets which disintegrate in the bottle. Too little may be insufficient for

disintegration to occur, thus altering the rate and extent of release of the active ingredients from the dosage form. Thus, a sufficient amount of disintegrant that is neither too little nor too much to detrimentally alter the release of the active ingredient(s) may be used to form the dosage forms of the compounds disclosed herein. The amount of disintegrant used may vary based upon the type of formulation and mode of administration, and may be readily discernible to those of ordinary skill in the art. About 0.5 to about 15 weight percent of disintegrant, or about 1 to about 5 weight percent of disintegrant, may be used in the pharmaceutical composition. Disintegrants that can be used to form pharmaceutical compositions and dosage forms of the invention include, but are not limited to, agar-agar, alginic acid, calcium carbonate, microcrystalline cellulose, croscarmellose sodium, crospovidone, polacrilin potassium, sodium starch glycolate, potato or tapioca starch, other starches, pre-gelatinized starch, other starches, clays, other algins, other celluloses, gums or mixtures thereof.

[00202] Lubricants which can be used to form pharmaceutical compositions and dosage forms of the invention include, but are not limited to, calcium stearate, magnesium stearate, sodium stearyl fumarate, mineral oil, light mineral oil, glycerin, sorbitol, mannitol, polyethylene glycol, other glycols, stearic acid, sodium lauryl sulfate, talc, hydrogenated vegetable oil (e.g., peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, and soybean oil), zinc stearate, ethyl oleate, ethylaureate, agar, or mixtures thereof. Additional lubricants include, for example, a syloid silica gel, a coagulated aerosol of synthetic silica, silicified microcrystalline cellulose, or mixtures thereof. A lubricant can optionally be added in an amount of less than about 0.5% or less than about 1% (by weight) of the pharmaceutical composition.

[00203] When aqueous suspensions and/or elixirs are desired for oral administration, the active pharmaceutical ingredient(s) may be combined with various sweetening or flavoring agents, coloring matter or dyes and, if so desired, emulsifying and/or suspending agents, together with such diluents as water, ethanol, propylene glycol, glycerin and various combinations thereof.

[00204] The tablets can be uncoated or coated by known 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. 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.

[00205] Surfactants which can be used to form pharmaceutical compositions and dosage forms of the invention include, but are not limited to, hydrophilic surfactants, lipophilic surfactants, and mixtures thereof. That is, a mixture of hydrophilic surfactants may be employed, a mixture of lipophilic surfactants may be employed, or a mixture of at least one hydrophilic surfactant and at least one lipophilic surfactant may be employed. [00206] A suitable hydrophilic surfactant may generally have an HLB value of at least 10, while suitable lipophilic surfactants may generally have an HLB value of or less than about 10. An empirical parameter used to characterize the relative hydrophilicity and

hydrophobicity of non-ionic amphiphilic compounds is the hydrophilic-lipophilic balance ("HLB" value). Surfactants with lower HLB values are more lipophilic or hydrophobic, and have greater solubility in oils, while surfactants with higher HLB values are more hydrophilic, and have greater solubility in aqueous solutions. Hydrophilic surfactants are generally considered to be those compounds having an HLB value greater than about 10, as well as anionic, cationic, or zwitterionic compounds for which the HLB scale is not generally applicable. Similarly, lipophilic (i.e. , hydrophobic) surfactants are compounds having an HLB value equal to or less than about 10. However, HLB value of a surfactant is merely a rough guide generally used to enable formulation of industrial, pharmaceutical and cosmetic emulsions.

[00207] Hydrophilic surfactants may be either ionic or non-ionic. Suitable ionic surfactants include, but are not limited to, alkylammonium salts; fusidic acid salts; fatty acid derivatives of amino acids, oligopeptides, and polypeptides; glyceride derivatives of amino acids, oligopeptides, and polypeptides; lecithins and hydrogenated lecithins; lysolecithins and hydrogenated lysolecithins; phospholipids and derivatives thereof; lysophospholipids and derivatives thereof; carnitine fatty acid ester salts; salts of alkylsulfates; fatty acid salts; sodium docusate; acyllactylates; mono- and di-acetylated tartaric acid esters of mono- and di- glycerides; succinylated mono- and di-glycerides; citric acid esters of mono- and di- glycerides; and mixtures thereof.

[00208] Within the aforementioned group, ionic surfactants include, by way of example: lecithins, lysolecithin, phospholipids, lysophospholipids and derivatives thereof; carnitine fatty acid ester salts; salts of alkylsulfates; fatty acid salts; sodium docusate; acyllactylates; mono- and di-acetylated tartaric acid esters of mono- and di-glycerides; succinylated mono- and di-glycerides; citric acid esters of mono- and di-glycerides; and mixtures thereof.

[00209] Ionic surfactants may be the ionized forms of lecithin, lysolecithin,

phosphatidylcholine, phosphatidylethanolamine, phosphatidylglycerol, phosphatidic acid, phosphatidylserine, lysophosphatidylcholine, lysophosphatidylethanolamine,

lysophosphatidylglycerol, lysophosphatidic acid, lysophosphatidylserine, PEG- phosphatidylethanolamine, PVP-phosphatidylethanolamine, lactylic esters of fatty acids, stearoyl-2-lactylate, stearoyl lactylate, succinylated monoglycerides, mono/diacetylated tartaric acid esters of mono/diglycerides, citric acid esters of mono/diglycerides, cholylsarcosine, caproate, caprylate, caprate, laurate, myristate, palmitate, oleate, ricinoleate, linoleate, linolenate, stearate, lauryl sulfate, teracecyl sulfate, docusate, lauroyl carnitines, palmitoyl carnitines, myristoyl carnitines, and salts and mixtures thereof.

[00210] Hydrophilic non-ionic surfactants may include, but not limited to, alkylglucosides; alkylmaltosides; alkylthioglucosides; lauryl macrogolglycerides; polyoxyalkylene alkyl ethers such as polyethylene glycol alkyl ethers; polyoxyalkylene alkylphenols such as polyethylene glycol alkyl phenols; polyoxyalkylene alkyl phenol fatty acid esters such as polyethylene glycol fatty acids monoesters and polyethylene glycol fatty acids diesters;

polyethylene glycol glycerol fatty acid esters; polyglycerol fatty acid esters; polyoxyalkylene sorbitan fatty acid esters such as polyethylene glycol sorbitan fatty acid esters; hydrophilic transesterification products of a polyol with at least one member of the group consisting of glycerides, vegetable oils, hydrogenated vegetable oils, fatty acids, and sterols;

polyoxyethylene sterols, derivatives, and analogues thereof; polyoxyethylated vitamins and derivatives thereof; polyoxyethylene-polyoxypropylene block copolymers; and mixtures thereof; polyethylene glycol sorbitan fatty acid esters and hydrophilic transesterification products of a polyol with at least one member of the group consisting of triglycerides, vegetable oils, and hydrogenated vegetable oils. The polyol may be glycerol, ethylene glycol, polyethylene glycol, sorbitol, propylene glycol, pentaerythritol, or a saccharide.

[00211] Other hydrophilic-non-ionic surfactants include, without limitation, PEG-10 laurate, PEG- 12 laurate, PEG-20 laurate, PEG-32 laurate, PEG-32 dilaurate, PEG- 12 oleate, PEG- 15 oleate, PEG-20 oleate, PEG-20 dioleate, PEG-32 oleate, PEG-200 oleate, PEG-400 oleate, PEG- 15 stearate, PEG-32 distearate, PEG-40 stearate, PEG- 100 stearate, PEG-20 dilaurate, PEG-25 glyceryl trioleate, PEG-32 dioleate, PEG-20 glyceryl laurate, PEG-30 glyceryl laurate, PEG-20 glyceryl stearate, PEG-20 glyceryl oleate, PEG-30 glyceryl oleate, PEG-30 glyceryl laurate, PEG-40 glyceryl laurate, PEG-40 palm kernel oil, PEG-50 hydrogenated castor oil, PEG-40 castor oil, PEG-35 castor oil, PEG-60 castor oil, PEG-40 hydrogenated castor oil, PEG-60 hydrogenated castor oil, PEG-60 corn oil, PEG-6 caprate/caprylate glycerides, PEG-8 caprate/caprylate glycerides, poly glyceryl- 10 laurate, PEG-30 cholesterol, PEG-25 phyto sterol, PEG-30 soya sterol, PEG-20 trioleate, PEG-40 sorbitan oleate, PEG-80 sorbitan laurate, polysorbate 20, polysorbate 80, POE-9 lauryl ether, POE-23 lauryl ether, POE-10 oleyl ether, POE-20 oleyl ether, POE-20 stearyl ether, tocopheryl PEG-100 succinate, PEG-24 cholesterol, polyglyceryl-10 oleate, Tween 40, Tween 60, sucrose monostearate, sucrose monolaurate, sucrose monopalmitate, PEG 10-100 nonyl phenol series, PEG 15-100 octyl phenol series, and poloxamers. [00212] Suitable lipophilic surfactants include, by way of example only: fatty alcohols; glycerol fatty acid esters; acetylated glycerol fatty acid esters; lower alcohol fatty acids esters; propylene glycol fatty acid esters; sorbitan fatty acid esters; polyethylene glycol sorbitan fatty acid esters; sterols and sterol derivatives; polyoxyethylated sterols and sterol derivatives; polyethylene glycol alkyl ethers; sugar esters; sugar ethers; lactic acid derivatives of mono- and di-glycerides; hydrophobic transesterification products of a polyol with at least one member of the group consisting of glycerides, vegetable oils, hydrogenated vegetable oils, fatty acids and sterols; oil-soluble vitamins/vitamin derivatives; and mixtures thereof. Within this group, preferred lipophilic surfactants include glycerol fatty acid esters, propylene glycol fatty acid esters, and mixtures thereof, or are hydrophobic transesterification products of a polyol with at least one member of the group consisting of vegetable oils, hydrogenated vegetable oils, and triglycerides.

[00213] In an embodiment, the composition may include a solubilizer to ensure good solubilization and/or dissolution of the compound of the present invention and to minimize precipitation of the compound of the present invention. This can be especially important for compositions for non-oral use - e.g. , compositions for injection. A solubilizer may also be added to increase the solubility of the hydrophilic drug and/or other components, such as surfactants, or to maintain the composition as a stable or homogeneous solution or dispersion.

[00214] Examples of suitable solubilizers include, but are not limited to, the following: alcohols and polyols, such as ethanol, isopropanol, butanol, benzyl alcohol, ethylene glycol, propylene glycol, butanediols and isomers thereof, glycerol, pentaerythritol, sorbitol, mannitol, transcutol, dimethyl isosorbide, polyethylene glycol, polypropylene glycol, polyvinylalcohol, hydroxypropyl methylcellulose and other cellulose derivatives, cyclodextrins and cyclodextrin derivatives; ethers of polyethylene glycols having an average molecular weight of about 200 to about 6000, such as tetrahydrofurfuryl alcohol PEG ether (glycofurol) or methoxy PEG; amides and other nitrogen-containing compounds such as 2- pyrrolidone, 2-piperidone, £-caprolactam, N-alkylpyrrolidone, N-hydroxyalkylpyrrolidone, N-alkylpiperidone, N-alkylcaprolactam, dimethylacetamide and polyvinylpyrrolidone; esters such as ethyl propionate, tributylcitrate, acetyl triethylcitrate, acetyl tributyl citrate, triethylcitrate, ethyl oleate, ethyl caprylate, ethyl butyrate, triacetin, propylene glycol monoacetate, propylene glycol diacetate, .epsilon.-caprolactone and isomers thereof, δ- valerolactone and isomers thereof, β-butyrolactone and isomers thereof; and other solubilizers known in the art, such as dimethyl acetamide, dimethyl isosorbide, N-methyl pyrrolidones, monooctanoin, diethylene glycol monoethyl ether, and water. [00215] Mixtures of solubilizers may also be used. Examples include, but not limited to, triacetin, triethylcitrate, ethyl oleate, ethyl caprylate, dimethylacetamide, N- methylpyrrolidone, N-hydroxyethylpyrrolidone, polyvinylpyrrolidone, hydroxypropyl methylcellulose, hydroxypropyl cyclodextrins, ethanol, polyethylene glycol 200-100, glycofurol, transcutol, propylene glycol, and dimethyl isosorbide. Particularly preferred solubilizers include sorbitol, glycerol, triacetin, ethyl alcohol, PEG-400, glycofurol and propylene glycol.

[00216] The amount of solubilizer that can be included is not particularly limited. The amount of a given solubilizer may be limited to a bioacceptable amount, which may be readily determined by one of skill in the art. In some circumstances, it may be advantageous to include amounts of solubilizers far in excess of bioacceptable amounts, for example to maximize the concentration of the drug, with excess solubilizer removed prior to providing the composition to a patient using conventional techniques, such as distillation or

evaporation. Thus, if present, the solubilizer can be in a weight ratio of about 10%, about 25%, about 50%, about 100%, or up to about 200% by weight, based on the combined weight of the drug, and other excipients. If desired, very small amounts of solubilizer may also be used, such as about 5%, about 2%, about 1% or even less. Typically, the solubilizer may be present in an amount of about 1% to about 100%, more typically about 5% to about 25% by weight.

[00217] The composition can further include one or more pharmaceutically acceptable additives and excipients. Such additives and excipients include, without limitation, detackifiers, anti-foaming agents, buffering agents, polymers, antioxidants, preservatives, chelating agents, viscomodulators, tonicifiers, flavorants, colorants, odorants, opacifiers, suspending agents, binders, fillers, plasticizers, lubricants, and mixtures thereof.

[00218] In addition, an acid or a base may be incorporated into the composition to facilitate processing, to enhance stability, or for other reasons. Examples of pharmaceutically acceptable bases include amino acids, amino acid esters, ammonium hydroxide, potassium hydroxide, sodium hydroxide, sodium hydrogen carbonate, aluminum hydroxide, calcium carbonate, magnesium hydroxide, magnesium aluminum silicate, synthetic aluminum silicate, synthetic hydrocalcite, magnesium aluminum hydroxide, diisopropylethylamine,

ethanolamine, ethylenediamine, triethanolamine, triethylamine, triisopropanolamine, trimethylamine, tris(hydroxymethyl)aminomethane (TRIS) and the like. Also suitable are bases that are salts of a pharmaceutically acceptable acid, such as acetic acid, acrylic acid, adipic acid, alginic acid, alkanesulfonic acid, amino acids, ascorbic acid, benzoic acid, boric acid, butyric acid, carbonic acid, citric acid, fatty acids, formic acid, fumaric acid, gluconic acid, hydroquinosulfonic acid, isoascorbic acid, lactic acid, maleic acid, oxalic acid, para- bromophenylsulfonic acid, propionic acid, p-toluenesulfonic acid, salicylic acid, stearic acid, succinic acid, tannic acid, tartaric acid, thiogly colic acid, toluenesulfonic acid, uric acid, and the like. Salts of polyprotic acids, such as sodium phosphate, disodium hydrogen phosphate, and sodium dihydrogen phosphate can also be used. When the base is a salt, the cation can be any convenient and pharmaceutically acceptable cation, such as ammonium, alkali metals and alkaline earth metals. Example may include, but not be limited to, sodium, potassium, lithium, magnesium, calcium, and/or ammonium.

[00219] Suitable acids are pharmaceutically acceptable organic or inorganic acids. Examples of suitable inorganic acids include hydrochloric acid, hydrobromic acid, hydriodic acid, sulfuric acid, nitric acid, boric acid, phosphoric acid, and the like. Examples of suitable organic acids include acetic acid, acrylic acid, adipic acid, alginic acid, alkanesulfonic acids, amino acids, ascorbic acid, benzoic acid, boric acid, butyric acid, carbonic acid, citric acid, fatty acids, formic acid, fumaric acid, gluconic acid, hydroquinosulfonic acid, isoascorbic acid, lactic acid, maleic acid, methanesulfonic acid, oxalic acid, para-bromophenylsulfonic acid, propionic acid, p-toluenesulfonic acid, salicylic acid, stearic acid, succinic acid, tannic acid, tartaric acid, thiogly colic acid, toluenesulfonic acid and uric acid.

Pharmaceutical Compositions for Injection

[00220] In preferred embodiments, the invention provides a pharmaceutical composition for injection containing a BCL-2 inhibitor, an MDM2 inhibitor, or a dual BCL-2/MDM2 inhibitor according to the invention, and a pharmaceutical excipient suitable for injection. Components and amounts of agents in the compositions are as described herein.

[00221] The forms in which the compositions of the present invention may be incorporated for administration by injection include aqueous or oil suspensions, or emulsions, with sesame oil, corn oil, cottonseed oil, or peanut oil, as well as elixirs, mannitol, dextrose, or a sterile aqueous solution, and similar pharmaceutical vehicles.

[00222] Aqueous solutions in saline are also conventionally used for injection. Ethanol, glycerol, propylene glycol and liquid polyethylene glycol (and suitable mixtures thereof), cyclodextrin derivatives, and vegetable oils may also be employed. The proper fluidity can be maintained, for example, by the use of a coating, such as lecithin, for the maintenance of the required particle size in the case of dispersion and by the use of surfactants. The prevention of the action of microorganisms can be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, and thimerosal. [00223] Sterile injectable solutions are prepared by incorporating a BCL-2 inhibitor, an MDM2 inhibitor, or a dual BCL-2/MDM2 inhibitor according to the invention, in the required amounts in the appropriate solvent with various other ingredients as enumerated above, as required, followed by filtered sterilization. Generally, dispersions are prepared by incorporating the various sterilized active ingredients into a sterile vehicle which contains the basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, certain desirable methods of preparation are vacuum-drying and freeze-drying techniques which yield a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof.

Pharmaceutical Compositions for Topical Delivery

[00224] In some embodiments, the invention provides a pharmaceutical composition for transdermal delivery containing a BCL-2 inhibitor, an MDM2 inhibitor, or a dual BCL- 2/MDM2 inhibitor according to the invention, and a pharmaceutical excipient suitable for transdermal delivery.

[00225] Compositions of the present invention can be formulated into preparations in solid, semi-solid, or liquid forms suitable for local or topical administration, such as gels, water soluble jellies, creams, lotions, suspensions, foams, powders, slurries, ointments, solutions, oils, pastes, suppositories, sprays, emulsions, saline solutions, dimethylsulfoxide (DMSO)- based solutions. In general, carriers with higher densities are capable of providing an area with a prolonged exposure to the active ingredients. In contrast, a solution formulation may provide more immediate exposure of the active ingredient to the chosen area.

[00226] The pharmaceutical compositions also may comprise suitable solid or gel phase carriers or excipients, which are compounds that allow increased penetration of, or assist in the delivery of, therapeutic molecules across the stratum corneum permeability barrier of the skin. There are many of these penetration-enhancing molecules known to those trained in the art of topical formulation. Examples of such carriers and excipients include, but are not limited to, humectants (e.g. , urea), glycols (e.g. , propylene glycol), alcohols (e.g. , ethanol), fatty acids (e.g., oleic acid), surfactants (e.g., isopropyl myristate and sodium lauryl sulfate), pyrrolidones, glycerol monolaurate, sulfoxides, terpenes (e.g. , menthol), amines, amides, alkanes, alkanols, water, calcium carbonate, calcium phosphate, various sugars, starches, cellulose derivatives, gelatin, and polymers such as polyethylene glycols.

[00227] Another exemplary formulation for use in the methods of the present invention employs transdermal delivery devices ("patches"). Such transdermal patches may be used to provide continuous or discontinuous infusion of the compounds of the invention, either with or without another active pharmaceutical ingredient.

[00228] The construction and use of transdermal patches for the delivery of pharmaceutical agents is well known in the art. See, e.g. , U.S. Patent Nos. 5,023,252; 4,992,445 and 5,001,139. Such patches may be constructed for continuous, pulsatile, or on demand delivery of pharmaceutical agents.

Pharmaceutical Compositions for Inhalation

[00229] In some embodiments, the invention provides a pharmaceutical composition for inhalation or insufflation delivery containing a BCL-2 inhibitor, an MDM2 inhibitor, or a dual BCL-2/MDM2 inhibitor according to the invention. Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable, aqueous or organic solvents, or mixtures thereof, and powders. The liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described supra. Preferably the compositions are administered by the oral or nasal respiratory route for local or systemic effect. Compositions in preferably pharmaceutically acceptable solvents may be nebulized by use of inert gases. Nebulized solutions may be inhaled directly from the nebulizing device or the nebulizing device may be attached to a face mask tent, or intermittent positive pressure breathing machine. Solution, suspension, or powder compositions may be administered, preferably orally or nasally, from devices that deliver the formulation in an appropriate manner. Dry powder inhalers may also be used to provide inhaled delivery of the compositions.

Other Pharmaceutical Compositions

[00230] Pharmaceutical compositions may also be prepared from compositions described herein and one or more pharmaceutically acceptable excipients suitable for sublingual, buccal, rectal, intraosseous, intraocular, intranasal, epidural, or intraspinal administration. Preparations for such pharmaceutical compositions are well-known in the art. See, e.g., Anderson, et al , eds., Handbook of Clinical Drug Data, Tenth Edition, McGraw-Hill, 2002; and Pratt and Taylor, eds., Principles of Drug Action, Third Edition, Churchill Livingston, N.Y., 1990, each of which is incorporated by reference herein in its entirety.

[00231] Administration of BCL-2 inhibitors, MDM2 inhibitors, or dual BCL-2/MDM2 inhibitors according to the invention, or pharmaceutical compositions of these compounds, can be effected by any method that enables delivery of the compounds to the site of action. These methods include oral routes, intraduodenal routes, parenteral injection (including intravenous, intraarterial, subcutaneous, intramuscular, intravascular, intraperitoneal or infusion), topical (e.g. , transdermal application), rectal administration, via local delivery by catheter or stent or through inhalation. The compounds or compositions thereof can also be administered intraadiposally or intrathecally.

[00232] Exemplary parenteral administration forms include solutions or suspensions of active compound in sterile aqueous solutions, for example, aqueous propylene glycol or dextrose solutions. Such dosage forms can be suitably buffered, if desired.

[00233] The invention also provides kits. The kits include each of a BCL-2 inhibitor, an MDM2 inhibitor, or a dual BCL-2/MDM2 inhibitor according to the invention, or pharmaceutical compositions thereof, either alone or in combination in suitable packaging, and written material that can include instructions for use, discussion of clinical studies and listing of side effects. Such kits may also include information, such as scientific literature references, package insert materials, clinical trial results, and/or summaries of these and the like, which indicate or establish the activities and/or advantages of the composition, and/or which describe dosing, administration, side effects, drug interactions, or other information useful to the health care provider. Such information may be based on the results of various studies, for example, studies using experimental animals involving in vivo models and studies based on human clinical trials. The kit may further contain another active pharmaceutical ingredient.

[00234] Suitable packaging and additional articles for use (e.g., measuring cup for liquid preparations, foil wrapping to minimize exposure to air, and the like) are known in the art and may be included in the kit. Kits described herein can be provided, marketed and/or promoted to health providers, including physicians, nurses, pharmacists, formulary officials, and the like. Kits may also, in some embodiments, be marketed directly to the consumer.

[00235] In some embodiments, the invention provides a kit comprising a composition comprising a therapeutically effective amount of a BCL-2 inhibitor, an MDM2 inhibitor, or a dual BCL-2/MDM2 inhibitor according to the invention, or a fragment, derivative, conjugate, variant, radioisotope-labeled complex, biosimilar, pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or prodrug thereof. These compositions are typically pharmaceutical compositions.

[00236] The kits described above are preferably for use in the treatment of the diseases and conditions described herein. In a preferred embodiment, the kits are for use in the treatment of cancer. In some embodiments, the kits are for use in treating solid tumor cancers, lymphomas and leukemias. [00237] In some embodiments, the kits of the present invention are for use in the treatment of a cancer selected from the group consisting of bladder cancer, squamous cell carcinoma including head and neck cancer, pancreatic ductal adenocarcinoma (PDA), pancreatic cancer, colon carcinoma, mammary carcinoma, breast cancer, fibrosarcoma, mesothelioma, renal cell carcinoma, lung carcinoma, thymoma, prostate cancer, colorectal cancer, ovarian cancer, acute myeloid leukemia, thymus cancer, brain cancer, squamous cell cancer, skin cancer, eye cancer, retinoblastoma, melanoma, intraocular melanoma, oral cavity and oropharyngeal cancers, gastric cancer, stomach cancer, cervical cancer, renal cancer, kidney cancer, liver cancer, ovarian cancer, esophageal cancer, testicular cancer, gynecological cancer, thyroid cancer, acquired immune deficiency syndrome (AIDS)-related cancers (e.g. , lymphoma and Kaposi's sarcoma), viral-induced cancer, glioblastoma, esophageal tumors, hematological neoplasms, non-small-cell lung cancer, chronic myelocytic leukemia, diffuse large B-cell lymphoma, esophagus tumor, follicle center lymphoma, head and neck tumor, hepatitis C virus related cancer, hepatocellular carcinoma, Hodgkin's disease, metastatic colon cancer, multiple myeloma, non-Hodgkin's lymphoma, indolent non-Hodgkin's lymphoma, ovary tumor, pancreas tumor, renal cell carcinoma, small-cell lung cancer, stage IV melanoma, chronic lymphocytic leukemia, B-cell acute lymphoblastic leukemia (ALL), mature B-cell ALL, follicular lymphoma, mantle cell lymphoma, and Burkitt's lymphoma.

Dosages and Dosing Regimens

[00238] The amounts of BCL-2 inhibitor, MDM2 inhibitor, or dual BCL-2/MDM2 inhibitor administered will be dependent on the human or mammal being treated, the severity of the disorder or condition, the rate of administration, the disposition of the compounds and the discretion of the prescribing physician. However, an effective dosage of each is in the range of about 0.001 to about 100 mg per kg body weight per day, such as about 1 to about 35 mg/kg/day, in single or divided doses. For a 70 kg human, this would amount to about 0.05 to 7 g/day, such as about 0.05 to about 2.5 g/day. In some instances, dosage levels below the lower limit of the aforesaid range may be more than adequate, while in other cases still larger doses may be employed without causing any harmful side effect, e.g. , by dividing such larger doses into several small doses for administration throughout the day. The dosage of BCL-2 inhibitor, MDM2 inhibitor, or dual BCL-2/MDM2 inhibitor may be provided in units of mg/kg of body mass, or in mg/m² of body surface area.

[00239] In some embodiments, the BCL-2 inhibitor, MDM2 inhibitor, or dual BCL- 2/MDM2 inhibitor is administered in a single dose. Such administration may be by injection, e.g., intravenous injection, in order to introduce the BCL-2 inhibitor, MDM2 inhibitor, or dual BCL-2/MDM2 inhibitor quickly. However, other routes, including the preferred oral route, may be used as appropriate. A single dose of BCL-2 inhibitor, MDM2 inhibitor, or dual BCL-2/MDM2 inhibitor may also be used for treatment of an acute condition.

[00240] In some embodiments, the BCL-2 inhibitor, MDM2 inhibitor, or dual BCL- 2/MDM2 inhibitor is administered in multiple doses. In a preferred embodiment, the BCL-2 inhibitor, MDM2 inhibitor, or dual BCL-2/MDM2 inhibitor is administered in multiple doses. Dosing may be once, twice, three times, four times, five times, six times, or more than six times per day. Dosing may be once a month, once every two weeks, once a week, or once every other day. In other embodiments, the BCL-2 inhibitor, MDM2 inhibitor, or dual BCL- 2/MDM2 inhibitor is administered about once per day to about 6 times per day. In some embodiments, the BCL-2 inhibitor, MDM2 inhibitor, or dual BCL-2/MDM2 inhibitor is administered once daily, while in other embodiments, the BCL-2 inhibitor, MDM2 inhibitor, or dual BCL-2/MDM2 inhibitor is administered twice daily, and in other embodiments the BCL-2 inhibitor, MDM2 inhibitor, or dual BCL-2/MDM2 inhibitor is administered three times daily.

[00241] Administration of the active pharmaceutical ingredients of the invention may continue as long as necessary. In some embodiments, the BCL-2 inhibitor, MDM2 inhibitor, or dual BCL-2/MDM2 inhibitor is administered for more than 1, 2, 3, 4, 5, 6, 7, 14, or 28 days. In some embodiments, the BCL-2 inhibitor, MDM2 inhibitor, or dual BCL-2/MDM2 inhibitor is administered for less than 28, 14, 7, 6, 5, 4, 3, 2, or 1 day. In some embodiments, the BCL-2 inhibitor, MDM2 inhibitor, or dual BCL-2/MDM2 inhibitor is administered chronically on an ongoing basis, e.g., for the treatment of chronic effects. In another embodiment the administration of the BCL-2 inhibitor, MDM2 inhibitor, or dual BCL- 2/MDM2 inhibitor continues for less than about 7 days. In yet another embodiment the administration continues for more than about 6, 10, 14, 28 days, two months, six months, or one year. In some cases, continuous dosing is achieved and maintained as long as necessary.

[00242] In some embodiments, an effective dosage of a BCL-2 inhibitor, MDM2 inhibitor, or dual BCL-2/MDM2 inhibitor disclosed herein is in the range of about 1 mg to about 50 mg, about 5 mg to about 45 mg, about 10 mg to about 40 mg, about 15 mg to about 35 mg, about 20 mg to about 30 mg, about 23 mg to about 28 mg, about 1 mg to about 500 mg, about 10 mg to about 300 mg, about 20 mg to about 250 mg, about 25 mg to about 200 mg, about 10 mg to about 200 mg, about 20 mg to about 150 mg, about 30 mg to about 120 mg, about 10 mg to about 90 mg, about 20 mg to about 80 mg, about 30 mg to about 70 mg, about 40 mg to about 60 mg, about 45 mg to about 55 mg, about 48 mg to about 52 mg, about 50 mg to about 150 mg, about 60 mg to about 140 mg, about 70 mg to about 130 mg, about 80 mg to about 120 mg, about 90 mg to about 110 mg, about 95 mg to about 105 mg, about 98 mg to about 102 mg, about 150 mg to about 250 mg, about 160 mg to about 240 mg, about 170 mg to about 230 mg, about 180 mg to about 220 mg, about 190 mg to about 210 mg, about 195 mg to about 205 mg, about 198 to about 202 mg, or about 198 to about 207 mg.

[00243] In some embodiments, an effective dosage of a BCL-2 inhibitor, MDM2 inhibitor, or dual BCL-2/MDM2 inhibitor disclosed herein is about 25 mg, about 50 mg, about 75 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, or about 250 mg.

[00244] In some embodiments, an effective dosage of a BCL-2 inhibitor, MDM2 inhibitor, or dual BCL-2/MDM2 inhibitor disclosed herein is in the range of about 0.01 mg/kg to about 0.7 mg/kg, about 0.07 mg/kg to about 0.65 mg/kg, about 0.15 mg/kg to about 0.6 mg/kg, about 0.2 mg/kg to about 0.5 mg/kg, about 0.3 mg/kg to about 0.45 mg/kg, about 0.3 mg/kg to about 0.4 mg/kg, about 0.7 mg/kg to about 2.15 mg/kg, about 0.85 mg/kg to about 2 mg/kg, about 1 mg/kg to about 1.85 mg/kg, about 1.15 mg/kg to about 1.7 mg/kg, about 1.3 mg/kg to about 1.6 mg/kg, about 1.35 mg/kg to about 1.5 mg/kg, about 1.4 mg/kg to about 1.45 mg/kg, about 0.01 mg/kg to about 4.3 mg/kg, about 0.15 mg/kg to about 3.6 mg/kg, about 0.3 mg/kg to about 3.2 mg/kg, about 0.35 mg/kg to about 2.85 mg/kg, about 0.15 mg/kg to about 2.85 mg/kg, about 0.3 mg to about 2.15 mg/kg, about 0.45 mg/kg to about 1.7 mg/kg, about 0.15 mg/kg to about 1.3 mg/kg, about 0.3 mg/kg to about 1.15 mg/kg, about 0.45 mg/kg to about 1 mg/kg, about 0.55 mg/kg to about 0.85 mg/kg, about 0.65 mg/kg to about 0.8 mg/kg, about 0.7 mg/kg to about 0.75 mg/kg, about 0.7 mg/kg to about 2.15 mg/kg, about 0.85 mg/kg to about 2 mg/kg, about 1 mg/kg to about 1.85 mg/kg, about 1.15 mg/kg to about 1.7 mg/kg, about 1.3 mg/kg mg to about 1.6 mg/kg, about 1.35 mg/kg to about 1.5 mg/kg, about 2.15 mg/kg to about 3.6 mg/kg, about 2.3 mg/kg to about 3.4 mg/kg, about 2.4 mg/kg to about 3.3 mg/kg, about 2.6 mg/kg to about 3.15 mg/kg, about 2.7 mg/kg to about 3 mg/kg, about 2.8 mg/kg to about 3 mg/kg, or about 2.85 mg/kg to about 2.95 mg/kg.

[00245] In some embodiments, an effective dosage of a BCL-2 inhibitor, MDM2 inhibitor, or dual BCL-2/MDM2 inhibitor disclosed herein is about 0.35 mg/kg, about 0.4 mg/kg, about 0.7 mg/kg, about 1 mg/kg, about 1.4 mg/kg, about 1.8 mg/kg, about 2.1 mg/kg, about 2.5 mg/kg, about 2.85 mg/kg, about 3.2 mg/kg, or about 3.6 mg/kg.

[00246] In some instances, dosage levels below the lower limit of the aforesaid ranges may be more than adequate, while in other cases still larger doses may be employed without causing any harmful side effect - e.g. , by dividing such larger doses into several small doses for administration throughout the day.

[00247] An effective amount of the combination of a BCL-2 inhibitor, MDM2 inhibitor, or dual BCL-2/MDM2 inhibitor may be administered in either single or multiple doses by any of the accepted modes of administration of agents having similar utilities, including rectal, buccal, intranasal and transdermal routes, by intra-arterial injection, intravenously, intraperitoneally, parenterally, intramuscularly, subcutaneously, orally, topically, or as an inhalant.

Methods of Treating Solid Tumor Cancers. Hematological Malignancies. Inflammation. Immune and Autoimmune Disorders, and Other Diseases

[00248] In some embodiments, the invention relates to a method of treating a disease alleviated by inhibiting BCL-2 in a patient in need thereof, including administering to the patient a therapeutically effective amount of one or more compounds of Formulas AA-AD, BA-BM, CA-CZ, 1-27, 101-154, 201-224, 301-333, and 401-448, or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or prodrug thereof.

[00249] In some embodiments, the invention relates to a method of treating a disease alleviated by inhibiting MDM2 in a patient in need thereof, including administering to the patient a therapeutically effective amount of one or more compounds of Formulas AA-AD, BA-BM, CA-CZ, 1-27, 101-154, 201-224, 301-333, and 401-448, or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or prodrug thereof.

[00250] In some embodiments, the invention relates to a method of treating a disease alleviated by inhibiting BCL-2 and MDM2 in a patient in need thereof, including administering to the patient a therapeutically effective amount of one or more compounds of Formulas AA-AD, BA-BM, CA-CZ, 1-27, 101-154, 201-224, 301-333, and 401-448, or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or prodrug thereof.

[00251] In a preferred embodiment, the patient or subject is a mammal, such as a human. In an embodiment, the patient or subject is a human. In an embodiment, the patient or subject is a companion animal. In an embodiment, the patient or subject is a canine, feline, or equine.

[00252] In some embodiments, the invention relates to a method of treating a disease alleviated by inhibiting BCL-2, MDM2, or BCL-2 and MDM2, in a patient in need thereof, including administering to the patient dosage unit form including a therapeutically effective amount of one or more compounds of Formulas AA-AD, BA-BM, CA-CZ, 1-27, 101-154, 201-224, 301-333, and 401-448, or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or prodrug thereof. In some embodiments, the dosage unit form includes a physiologically compatible carrier medium.

[00253] In some embodiments, the invention relates to a method of treating a cancer alleviated by inhibiting BCL-2, MDM2, or BCL-2 and MDM2, in a patient in need thereof, including administering to the patient a therapeutically effective amount of one or more compounds of Formulas AA-AD, BA-BM, CA-CZ, 1-27, 101-154, 201-224, 301-333, and 401-448, or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or prodrug thereof.

[00254] In some embodiments, the cancer can be bladder cancer, squamous cell carcinoma including head and neck cancer, pancreatic ductal adenocarcinoma (PDA), pancreatic cancer, colon carcinoma, mammary carcinoma, breast cancer, fibrosarcoma, mesothelioma, renal cell carcinoma, lung carcinoma, thymoma, prostate cancer, colorectal cancer, ovarian cancer, acute myeloid leukemia, thymus cancer, brain cancer, squamous cell cancer, skin cancer, eye cancer, retinoblastoma, melanoma, intraocular melanoma, oral cavity and oropharyngeal cancers, gastric cancer, stomach cancer, cervical cancer, renal cancer, kidney cancer, liver cancer, ovarian cancer, esophageal cancer, testicular cancer, gynecological cancer, thyroid cancer, acquired immune deficiency syndrome (AIDS)-related cancers (e.g. , lymphoma and Kaposi's sarcoma), viral-induced cancer, glioblastoma, esophageal tumors, hematological neoplasms, non-small-cell lung cancer, chronic myelocytic leukemia, diffuse large B-cell lymphoma, esophagus tumor, follicle center lymphoma, head and neck tumor, hepatitis C virus induced cancer, hepatocellular carcinoma, Hodgkin's disease, metastatic colon cancer, multiple myeloma, non-Hodgkin's lymphoma, indolent non-Hodgkin's lymphoma, ovary tumor, pancreas tumor, renal cell carcinoma, small-cell lung cancer, stage IV melanoma, chronic lymphocytic leukemia, B-cell acute lymphoblastic leukemia (ALL), mature B-cell ALL, follicular lymphoma, mantle cell lymphoma, and Burkitt's lymphoma.

[00255] In some embodiments, the invention relates to a method of treating a

hyperproliferative disorder alleviated by inhibiting BCL-2, MDM2, or BCL-2 and MDM2, in a patient in need thereof, including administering to the patient a therapeutically effective amount of one or more compounds of Formulas AA-AD, BA-BM, CA-CZ, 1-27, 101-154, 201-224, 301-333, and 401-448, or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or prodrug thereof.

[00256] Efficacy of the methods, compounds, and combinations of compounds described herein in treating, preventing and/or managing the indicated diseases or disorders can be tested using various animal models known in the art. Efficacy in treating, preventing and/or managing asthma can be assessed using the ova induced asthma model described, for example, in Lee, et al. , J. Allergy Clin. Immunol. 2006, 118, 403-9. Efficacy in treating, preventing and/or managing arthritis (e.g., rheumatoid or psoriatic arthritis) can be assessed using the autoimmune animal models described in, for example, Williams, et al, Chem. Biol. 2010, 17, 123-34, WO 2009/088986, WO 2009/088880, and WO 2011/008302. Efficacy in treating, preventing and/or managing psoriasis can be assessed using transgenic or knockout mouse model with targeted mutations in epidermis, vasculature or immune cells, mouse model resulting from spontaneous mutations, and immuno-deficient mouse model with xenotransplantation of human skin or immune cells, all of which are described, for example, in Boehncke, et al, Clinics in Dermatology, 2007, 25, 596-605. Efficacy in treating, preventing and/or managing fibrosis or fibrotic conditions can be assessed using the unilateral ureteral obstruction model of renal fibrosis, which is described, for example, in Chevalier, et al. , Kidney International 2009, 75, 1145-1152; the bleomycin induced model of pulmonary fibrosis described in, for example, Moore, et al. , Am. J. Physiol. Lung. Cell. Mol. Physiol. 2008, 294, L152-L160; a variety of liver/biliary fibrosis models described in, for example, Chuang, et al, Clin. Liver Dis. 2008, 12, 333-347 and Omenetti, et al, Laboratory

Investigation, 2007, 87, 499-514 (biliary duct-ligated model); or any of a number of myelofibrosis mouse models such as described in Varicchio, et al., Expert Rev. Hematol. 2009, 2(3), 315-334. Efficacy in treating, preventing and/or managing scleroderma can be assessed using a mouse model induced by repeated local injections of bleomycin described, for example, in Yamamoto, et al., J. Invest. Dermatol. 1999, 112, 456-462. Efficacy in treating, preventing and/or managing dermatomyositis can be assessed using a myositis mouse model induced by immunization with rabbit myosin as described, for example, in Phyanagi, et al., Arthritis & Rheumatism, 2009, 60(10), 3118-3127. Efficacy in treating, preventing and/or managing lupus can be assessed using various animal models described, for example, in Ghoreishi, et al, Lupus, 2009, 19, 1029-1035; Ohl, et al., J. Biomed.

Biotechnol , 2011, Article ID 432595; Xia, et al, Rheumatology, 2011, 50, 2187-2196; Pau, et al, PLoS ONE, 2012, 7(5), e36761; Mustafa, et al, Toxicology, 2011, 290, 156-168;

Ichikawa, et al, Arthritis & Rheumatism, 2012, 62(2), 493-503; Rankin, et al., J.

Immunology, 2012, 188, 1656-1667. Efficacy in treating, preventing and/or managing Sjogren's syndrome can be assessed using various mouse models described, for example, in Chiorini, et al. , J. Autoimmunity, 2009, 33, 190-196. Models for determining efficacy of treatments for pancreatic cancer are described in Herreros-Villanueva, et al , World J.

Gastroenterol. 2012, 18, 1286-1294. Models for determining efficacy of treatments for breast cancer are described, e.g. , in Fantozzi, Breast Cancer Res. 2006, 8, 212. Models for determining efficacy of treatments for ovarian cancer are described, e.g. , in Mullany, et al, Endocrinology 2012, 153, 1585-92; and Fong, et al. , J. Ovarian Res. 2009, 2, 12. Models for determining efficacy of treatments for melanoma are described, e.g., in Damsky, et al , Pigment Cell & Melanoma Res. 2010, 23, 853-859. Models for determining efficacy of treatments for lung cancer are described, e.g., in Meuwissen, et al , Genes & Development, 2005, 19, 643-664. Models for determining efficacy of treatments for lung cancer are described, e.g. , in Kim, Clin. Exp. Otorhinolaryngol. 2009, 2, 55-60; and Sano, Head Neck Oncol. 2009, 1, 32. Models for determining efficacy of treatments for colorectal cancer, including the CT26 model, are described in Castle, et al. , BMC Genomics, 2013, 15, 190; Endo, et al, Cancer Gene Therapy, 2002, 9, 142-148; Roth et al , Adv. Immunol. 1994, 57, 281-351; Fearon, et al, Cancer Res. 1988, 48, 2975-2980. Efficacy in DLBCL may be assessed using the PiBCLl murine model and BALB/c (haplotype H-2^d) mice. Illidge, et al, Cancer Biother. & Radiopharm. 2000, 15, 571-80. Efficacy in NHL may be assessed using the 38C13 murine model with C3H/HeN (haplotype 2-H^k) mice or alternatively the 38C13 Her2/neu model. Timmerman, et al , Blood, 2001, 97, 1370-77; Penichet, et al, Cancer Immunolog. Immunother. 2000, 49, 649-662. Efficacy in CLL may be assessed using the BCL1 model using BALB/c (haplotype H-2^d) mice. Dutt, et al , Blood, 2011, 117, 3230-29. Combinations of BCL-2 Inhibitors. MDM2 Inhibitors, and/or dual BCL-2/MDM2 Inhibitors with Chemotherapeutic Active Pharmaceutical Ingredients

[00257] BCL-2 inhibitors, MDM2 inhibitors, or dual BCL-2/MDM2 inhibitors described herein can also be co-administered with additional chemotherapeutic active pharmaceutical ingredients, for example gemcitabine, albumin-bound paclitaxel (nab-paclitaxel), and bendamustine or bendamustine hydrochloride. In a preferred embodiment, the invention provides a method of treating a hematological malignancy or a solid tumor cancer in a human including the step of administering to said human a BCL-2 inhibitor, a MDM2 inhibitor, or a dual BCL-2/MDM2 inhibitor, and further including the step of administering a

therapeutically-effective amount of gemcitabine, or a pharmaceutically acceptable salt, prodrug, cocrystal, solvate or hydrate thereof. In an embodiment, the invention provides a method of treating a hematological malignancy or a solid tumor cancer in a human including the step of administering to said human a BCL-2 inhibitor, a MDM2 inhibitor, or a dual BCL- 2/MDM2 inhibitor described herein, or a pharmaceutically acceptable salt, prodrug, cocrystal, solvate or hydrate thereof, and further including the step of administering a therapeutically- effective amount of gemcitabine, or a pharmaceutically acceptable salt, prodrug, cocrystal, solvate or hydrate thereof. In an embodiment, the solid tumor cancer in any of the foregoing embodiments is pancreatic cancer.

[00258] In any of the foregoing embodiments, the chemotherapeutic active pharmaceutical ingredient or combinations thereof may be administered before, concurrently, or after administration of the BCL-2 inhibitor, MDM2 inhibitor, or dual BCL-2/MDM2 inhibitor described herein.

[00259] While preferred embodiments of the invention are shown and described herein, such embodiments are provided by way of example only and are not intended to otherwise limit the scope of the invention. Various alternatives to the described embodiments of the invention may be employed in practicing the invention.

EXAMPLES

[00260] The embodiments encompassed herein are now described with reference to the following examples. These examples are provided for the purpose of illustration only and the disclosure encompassed herein should in no way be construed as being limited to these examples, but rather should be construed to encompass any and all variations which become evident as a result of the teachings provided herein.

[00261 Example 1 : Isoxazole Exemplary Synthetic Scheme (I)

[00262] A substituted aryl oxime (1 eq, 2.81 mmol) was reacted with N-chlorosuccinimide (1.2 eq, 3.37 mmol) in DMF (0.1 M) stirring at room temperature for four hours, at which time the reaction was confirmed completed by TLC (2: 1 Hexane/EtOAc). Then, a substituted methyl azidoacrylate (1 eq, 2.81 mmol) was added in 1 mL DMF, followed by TEA (1 eq, 2.81 mmol) stirring overnight at 90 °C. A TLC in 4: 1 Hexane/EtOAc indicated the reaction was complete. EtOAc (30 mL) was added to the reaction and washed with H2O (50 mL x 5) and brine (50 mL), dried over Na2S04, filtered, and concentrated. Flash chromatography separation (Isolera, 4: 1 Hex/EtOAc), followed by in vacuo solvent removal, afforded the 3,4- substituted isoxazole compound with a 29% yield.

[00263] Next, the 3,4-disubstituted isoxazole (1 eq, 0.68 mmol) was reacted with LiOH H2O (4 eq, 2.72 mmol) in 3: 1 : 1 THF/FhO/MeOH (0.1 M) at room temperature overnight. A TLC in 92:7: 1 CFhCh/MeOH/ Acetic acid indicated the reaction was complete. EtOAc (30 mL) was added to the reaction, washed with 1 M HC1 (50 mL x 3), dried over Na2S04, filtered, and concentrated in vacuo. The crude product was separated by flash chromatography (92:7: 1 CFhCh/MeOH/ Acetic acid), and concentrated in vacuo to afford the 3,4-disubstituted isoxazole carboxylic acid with a 55% yield.

[00264] The 3,4- disubstituted isoxazole carboxylic acid (1 eq, 0.16 mmol) was dissolved in THF (0.1 M), brought to -10 °C, when isobutylchloroformate (1.1 eq, 0.18 mmol) followed by NMM (1.1 eq, 0.18 mmol) was added. The reaction stirred for 1 hr at -10 °C. Then, at 0 °C, a substituted sulfonamide (1.5 eq, 0.24 mmol) was added, followed by NaH (3 eq, 0.48 mmol). Then, the reaction was warmed up to room temperature and stirred overnight. A TLC in 79:9: 1 CFhCh/MeOH/FhO showed the reaction was complete. EtOAc (15 mL) was added to the reaction, washed with 1 M HC1 (30 mL x 3), dried with Na2S04, filtered, and concentrated in vacuo. The crude product was flash chromatographed in 79:9: 1

CFhCh/MeOH/FhO, concentrated in vacuo to afford a 3,4,5-trisubstituted isoxazole with a 75% yield.

[00265] Example 2: Isoxazole Exemplary Synthetic Scheme (II)

[00266] A substituted ethyl 2,4-dioxo-4-phenylbutanoate (1 eq, 6.92 mmol) was reacted with NH2OH HCI (3 eq, 20.76 mmol) in EtOH (0.1 M) refluxing overnight. A TLC in 4: 1 Hex/EtOAc showed the reaction completed. CH2CI2 (50 mL) was added and the reaction mixture was washed with H2O (100 mL x 3), dried with Na2S04, filtered, and concentrated in vacuo. The crude product was flash chromatographed (Isolera, 4: 1 Hexane/EtOAc), and concentrated to afford the 3-substituted isoxazole with a 57% yield.

[00267] Next, the 3- substituted isoxazole (1 eq, 3.46 mmol) was reacted with N- iodosuccinimide (1.5 eq, 5.19 mmol) in TFA (0.2 M), stirring overnight at room temperature. A TLC in 4: 1 Hexane/EtOAc showed the reaction was completed. The solvent was concentrated in vacuo, and flash chromatographed (Isolera, 4: 1 Hexane/EtOAc). The fractions were concentrated to produce the 4-iodo-3 -substituted isoxazole with an 86% yield.

[00268] The 4-iodo 3-substituted isoxazole (1 eq, 0.24 mmol) was reacted with a substituted aromatic boronic acid (2 eq, 0.48 mmol), NaHC0₃, and PdCl₂(PPh₂)2 in 6: 1 DMF/H2O (0.1 M) overnight at 80 °C. A TLC in 4: 1 Hexane/EtOAc showed the reaction was complete. The reaction was extracted into EtOAc (15 mL x 2), washed with H2O (30 mL x 5) and brine (30 mL), dried with Na2S04, filtered, and concentrated in vacuo. The crude product was flash chromatographed (Isolera, 4: 1 Hexane/EtOAc), concentrated to produce the 3,4-substituted isoxazole with a 63% yield.

[00269] Next, the 3,4-substituted isoxazole (1 eq, 0.68 mmol) was reacted with LiOH LhO (4 eq, 2.72 mmol) in 3: 1 : 1 THF/H₂0/MeOH (0.1 M) at room temperature overnight. A TLC in 92:7: 1 CLhCh/MeOH/ Acetic acid indicated the reaction was complete. EtOAc (30 mL) was added to the reaction, washed with 1 M HC1 (50 mL x 3), dried with Na2S04, filtered, and concentrated in vacuo. The crude product was columned in 92:7: 1 CLhCh/MeOH/ Acetic acid, concentrated in vacuo to afford the 3,4-disubstituted isoxazole carboxylic acid with a 95% yield.

[00270] The 3,4-disubstituted isoxazole carboxylic acid (1 eq, 0.16 mmol) was dissolved in THF (0.1 M), brought to -10 °C, when isobutylchloroformate (1.1 eq, 0.18 mmol) followed by NMM (1.1 eq, 0.18 mmol) was added. The reaction stirred for 1 hr at -10 °C. Then, at 0 °C, a substituted sulfonamide (1.5 eq, 0.24 mmol) was added, followed by NaH (3 eq, 0.48 mmol). Then, the reaction warmed up to room temperature and stirred overnight. A TLC in 79:9: 1 CH2Ch/MeOH/H20 showed the reaction was complete. EtOAc (15 mL) was added to the reaction, washed with 1 M HC1 (30 mL x 3), dried with Na2S04, filtered, and concentrated in vacuo. The crude product was flash chromatographed with 79:9: 1

CLhCh/MeOH/LhO, concentrated in vacuo to afford a 3,4,5-trisubstituted isoxazole with a 75% yield.

[00271] Example 3: Imidazole Exemplary Synthetic Scheme

[00272] General Procedure A: A halogenated aryl cyanide (1.0 eq.) is placed into a reaction flask and solubilized in DMSO (0.1 M). Potassium carbonate (2.0 eq.) is then added to the reaction, followed by heating the reaction to 100 °C overnight. Reaction completion is monitored by TLC (9: 1 Hexanes/Ethyl Acetate). After completion, the reaction is partitioned between Ethyl Acetate and H2O. The organic layer is isolated, dried with sodium sulfate, filtered, and concentrated down. The crude product is then purified via flash chromatography on silica using a gradient of hexanes and ethyl acetate (9: 1) to provide the substituted aryl cyanide. The isolated product is azeotroped with chloroform 3 times to remove residual solvent.

[00273] General Procedure B: A substituted aniline (1.0 eq.) is added to a cooled reaction flask at 0 °C. The aniline is solubilized in dry toluene (0.1 M) and IVfeAl (1.3 eq.) is then added to the reaction slowly. The reaction is warmed to R.T. and stirred for 3.5 hours. The substituted aryl cyanide for General Procedure A (1.3 eq.) is then added to the reaction. The reaction is then warmed to 70 °C and stirred overnight. Reaction completion is monitored by TLC (DCM/MeOH/NLUOH 92:7: 1). After completion, the reaction is cooled to R.T. Silica gel in a mixture of chloroform/MeOH (2: 1) is added to the reaction until a slurry is formed. The slurry is filtered and the precipitate is washed with a mixture of DCM/MeOH (2: 1). The filtrates then combined, concentrated down, and then triturated with a mixture of hexanes and ether (1 : 1). The precipitate is filtered off and placed in a vacuum oven to dry yielding the imine intermediate.

[00274] General Procedure C: The imine intermediate from General Procedure B (1.0 eq.) is added to a reaction flask and solubilized in isopropanol (0.1 M). NaHCCb (2.0 eq.) is added to the reaction, followed by placing the reaction on heat at 40 °C. Ethyl-bromopyruvate (1.4 eq.) is slowly added to the reaction. The reaction is then heated to 70 °C and stirred overnight. The reaction is then warmed to 70 °C and stirred overnight. Reaction completion is monitored by TLC (DCM/MeOH/ LtOH 92:7: 1). After completion, the reaction is partitioned between Ethyl Acetate and H2O. The organic layer is isolated, dried with sodium sulfate, filtered, and concentrated down. The crude product is then purified via flash chromatography on silica using a gradient of hexanes and ethyl acetate (1 : 1) to provide the ethyl ester imidazole. The isolated product is azeotroped with chloroform 3 times to remove residual solvent.

[00275] General Procedure D: The ethyl ester imidazole from General Procedure C (1.0 eq.) is added to a reaction flask and solubilized in a mixture of THF/LhO/MeOH (3: 1 : 1). NaOH (3.0 eq.) is then added to the reaction. The reaction stirred at R.T overnight. Reaction completion is monitored by TLC (D CM/MeOH/ AcOH 92:7: 1). After completion, the reaction is partitioned between Ethyl Acetate and 1 M HC1. The organic layer is isolated, dried with sodium sulfate, filtered, and concentrated down. The isolated imidazole acid is azeotroped with chloroform 3 times to remove residual solvent.

[00276] General Procedure E: The imidazole acid from General Procedure D (1.0 eq.) is added to a dry flask and solubilized in SOCh (0.1 M). The reaction is heated to reflux and stirred for 2 hrs. Formation of acid chloride is determined via TLC (92/7/1

DCM:MeOH: AcOH) by performing a mini-workup in MeOH. After formation of the acid chloride, the SOCh is vacuumed off and the reaction mixture is placed on a high vacuum system for 1.5 hours. Then, the reaction mixture is solubilized in DCE (0.1 M). DMAP (0.5 eq.) and a sulfonamide (5.0 eq.) are then added to the reaction mixture. The reaction is heated to reflux and stirred overnight. Reaction completion is monitored by TLC (DCM/MeOH/FhO 92:7: 1). After completion, the DCE is vacuumed off. The crude product is then dry loaded onto silica and purified via flash chromatography (92:7: 1 DCM/MeOH/FhO) to provide the acyl sulfonamide imidazole. The isolated product is azeotroped with chloroform 3 times to remove residual solvent.

[00277] Example 4: Pyrazole Exemplary Synthetic Scheme

[00278] Step 1.) A substituted aryl-nitro (1 eq.) is placed in a reaction flask and solubilized in ethyl acetate (0.1 M). Tin (II) chloride dihydrate (3 eq.) is added and the reaction ran overnight at 50 °C. The reaction is then subjected to a basic aqueous wash and extracted with ethyl acetate. The organic layer is isolated, dried with sodium sulfate, filtered, and concentrated down. The crude product is then purified via flash chromatography on silica using a gradient of hexanes and ethyl acetate to provide the substituted anilines. The isolated product is azeotroped with chloroform 3 times.

[00279] Step 2.) The substituted aniline from the previous step (1 eq.) is placed in a reaction flask followed by 12 M HCI (0.2 M) and water (0.1 M). The reaction is stirred vigorously to solubilize the resulting hydrochloric acid salt. The reaction is cooled to -5 °C and a mixture of sodium nitrite (1.05 eq.) in water is added slowly to the reaction mixture. The reaction is stirred for 30 mins and then a mixture of tin (II) chloride (4 eq.) in water is added. The reaction is warmed to room temperature and stirred for 3 hours. The resulting precipitate is vacuum filtered and washed with hexanes and ether to provide the substituted aryl-hydrazine.

[00280] Step 3.) Under an inert atmosphere, a substituted aryl-aldehyde (1 eq.) is placed in a reaction flask followed by dry THF (0.1 M). Diethyl oxalate (1.2 eq.) is added to the reaction then the reaction placed on ice. After cooling the reaction, sodium hydride (2 eq.) is added slowly and the reaction stirred overnight at room temperature. The reaction is quenched with water and extracted into ethyl acetate. The organic layer is isolated, dried with sodium sulfate, filtered, and concentrated down. The crude product is then purified via flash chromatography on silica using a gradient of hexanes and ethyl acetate to provide the resulting adduct. The isolated product is azeotroped with chloroform 3 times.

[00281] Step 4.) The adduct from the previous step (1.2 eq.) is added to a reaction flask followed by the substituted aryl hydrazine from Step 2 (1 eq.). Acetic acid (0.1 M) is added to the reaction and it is refluxed overnight. The acetic acid is concentrated off and the crude product is subjected to an aqueous workup with ethyl acetate. The organic layer is isolated, dried with sodium sulfate, filtered, and concentrated down. The crude product is then purified via flash chromatography on silica using a gradient of hexanes and ethyl acetate to provide the substituted ester-pyrazole. The isolated product is azeotroped with chloroform 3 times.

[00282] Step 5.) The substituted ester-pyrazole from the previous step (1 eq.) is added to a reaction flask followed by a mixture of tetrahydrofuran, water, and methanol in a 3: 1 : 1 ratio (0.1 M). Lithium hydroxide monohydrate (3 eq.) is added to the reaction and the reaction stirred overnight at room temperature. The reaction is then subjected to an acidic aqueous workup with ethyl acetate. The organic layer is isolated, dried with sodium sulfate, filtered, and concentrated down. The product is azeotroped with chloroform 3 times to yield the pyrazole acid.

[00283] Step 6.) The pyrazole acid from the previous step (1 eq.) is added to a reaction flask followed by dichloromethane (0.1 M). The reaction is cooled to 0 °C and then l-Ethyl-3-(3- dimethylaminopropyl)carbodiirnide (1.3 eq.) with 4-Dimethylaminopyridine (1.4 eq.) is added. The reaction stirred for 30 minutes and then a substituted sulfonamide (1.2 eq.) is added. The reaction stirred overnight at room temperature. The dichloromethane is concentrated off the reaction. The crude product is then purified using flash chromatography on silica with a gradient of dichloromethane, methanol, and water to yield the acyl- sulfonamide pyrazole final molecule. The product is azeotroped 3 times with chloroform.

[00284] Example 5: Thiazole Exemplary Synthetic Scheme

o.n.

[00285] Ethyl 2-amino-5-chlorothiazole-4-carboxylate: Ethyl-2-aminothiazole-4- carboxylate (1 eq, 23.2 mmol) was chlorinated using N-chlorosuccinimide (1.1 eq, 25.3 mmol) in acetonitrile (50 mL, 0.5 M) stirring at 80 °C overnight. A TLC in 2: 1 Hex/EtOAc indicated completion of the reaction. The reaction was concentrated in vacuo, taken up in NaHCCb, and extracted with EtOAc (50 mL x 3). The organics were collected and washed with brine (100 mL), dried with Na2S04, filtered and concentrated to give the title compound in quantitative yield.

[00286] Ethyl 2-bromo-5-chlorothiazole-4-carboxylate: Tert-butyl nitrite (1.5 eq, 34.8 mmol) and copper (II) bromide (1.5 eq, 34.8) were dissolved in acetonitrile (180 mL). Ethyl 2-amino-5-chlorothiazole-4-carboxylate (1 eq, 23.2 mmol) in acetonitrile (60 mL) was added by dropping funnel over 45 min and upon complete addition the reaction stirred at 80 °C overnight. The reaction was determined to be complete by TLC (4: 1 Hex/EtOAc). The reaction was concentrated in vacuo, taken up in NaHCCb, and extracted with EtOAc (50 mL x 3). The organics were collected and washed with brine (100 mL), dried with Na2S04, filtered and concentrated to give the title compound in quantitative yield.

[00287] Ethyl 2,5-bis(4-substituted-phenyl)thiazole-4-carboxylate: Ethyl 2-bromo-5- chlorothiazole-4-carboxylate (1 eq, 1 mmol) was dissolved in a 2: 1 mixture of DME/MeOH (14 mL/6 mL, 0.05 M). Substituted phenylboronic acid (3 eq, 3 mmol) and cesium fluoride (3 eq, 3 mmol) were added. Nitrogen was bubbled through the solution for 10 mins and then tetrakis(triphenylphosphine)palladium (10 mol%, 0.10 mmol) was added. The reaction stirred overnight at reflux. Completion of the reaction was determined by TLC (1: 1 Hex/EtOAc). The reaction mixture was diluted with EtOAc (50 mL) and washed with deionized water (100 mL x 2), and brine (100 mL). The organics were dried with Na2S04, filtered and

concentrated. The crude product was purified by flash column chromatography (1 : 1

Hex/EtOAc) to give the title compound in 70% yield.

[00288] 2,5-bis(4-substituted-phenyl)thiazole-4-carboxylic acid: Ethyl 2,5-bis(4- substituted-phenyl)thiazole-4-carboxylate (1 eq, 0.2 mmol) was dissolved in a 3: 1 mixture of THF/H2O (1.5 mL/0.5 mL, 0.1 M) and lithium hydroxide monohydrate (4 eq, 0.8 mmol) was added. The reaction was stirred at room temperature overnight. The reaction was determined to be complete by TLC in CI^Ch/MeOH/AcOH (92:7:1). The reaction was quenched with 1 M HC1 (50 mL) and partitioned with EtOAc (25 mL x 3). The organics were collected and washed with brine, dried with Na2S04, filtered, concentrated, and azeotroped with CHCb (100 mL x 3). This afforded the title compound in 93% yield

[00289] Acyl sulfonamide: 2,5-bis(4-substituted-phenyl)thiazole-4-carboxylic acid (1 eq, 0.23 mmol) was dissolved in THF (3 mL, 0.1 M) and cooled to -10 °C. N-methylmorpholine (1.1 eq, 0.25) and i-butyl chloroformate (1.1 eq, 0.25 mmol) were added dropwise. The reaction stirred for 1 h and then NaH (3 eq, 0.68 mmol) and requisite sulfonamide (1.5 eq, 0.34 mmol) were added. The reaction stirred overnight warming up to room temperature. The reaction was determined complete by TLC in CftCh/MeOH/LhO (79:9: 1). The reaction was quenched with brine and extracted with EtOAc (50 mL). The organics were dried with Na2S04, filtered, and concentrated. The crude product was purified by gravity column chromatography (CH₂Cl2/MeOH/H₂0 (79:9: 1)) to give the title compound in 40-75% yield.

[00290] Example 6: Compound Characterization

[00291] Compound 414: ¾ NMR (400 MHz, DMSO): δ 7.19 (d, J = 8.8 Hz, 2H), 7.12 (d, J = 8.4 Hz, 2H), 6.93 (d, J = 8.4 Hz, 2H), 6.87 (d, J = 8.4 Hz, 2H), 6.71 (s, 1H), 4.66-4.58 (m, 2H), 1.26 (t, J = 7 Hz, 12H).

[00292] Compound 410: ¾ NMR (400 MHz, CDCb): δ 9.43 (s, 1H), 8.23 (d, J = 8.8 Hz, 2H), 7.37 (d, J = 8.8 Hz, 2H), 7.17 (d, J = 9.6 Hz, 2H), 7.06 (d, J = 8.4 Hz, 2H), 6.92 (s, 1H), 6.87 (d, J = 9.2 Hz, 2H), 6.78 (d, J = 8.4 Hz, 2H), 4.58-4.51 (m, 2H), 1.34 (q, Ji = 14.8 Hz, h = 6.0 Hz, 12H).

[00293] Compound 430: ¾ NMR (400 MHz, DMSO): δ 7.90 (s, 1H), 7.42 (t, J = 7.4 Hz, 2H), 7.35 (d, J = 8.4 Hz, 2H), 7.26 (d, J = 8.8 Hz, 2H), 7.19 (t, J = 7.0 Hz, 1H), 7.05 (d, J = 8.0 Hz, 2H), 7.00 (d, J = 8.8 Hz, 2H), 6.92 (d, J = 8.4 Hz, 2H), 4.68-4.65 (m, 1H), 1.28 (d, J = 6.4 Hz, 6H). [00294] Compound 428: ¾ NMR (400 MHz, DMSO): δ 7.42 (t, J = 7.8 Hz, 2H), 7.24-7.16 (m, 5H), 7.05 (d, J = 7.6 Hz, 2H), 6.95-6.93 (m, 4H), 6.74 (s. IH), 4.66-4.60 (m, IH), 1.27 (d, J = 5.2 Hz, 6H).

[00295] Compound 427: ¾ NMR (400 MHz, DMSO): δ 12.33 (s, IH), 8.01 (d, J = 8.8 Hz, 2H), 7.49 (t, J = 7.8 Hz, 2H), 7.42 (d, J = 8.0 Hz, 2H), 7.30-7.23 (m, 5H), 7.16 (t, J = 8.6 Hz, 4H), 7.07 (t, J = 10.2 Hz, 3H), 6.97 (t, J = 10.2 Hz, 4H), 4.68-4.64 (m, IH), 1.28 (d, J = 6.4 Hz, 6H).

[00296] Compound 426: ¾ NMR (400 MHz, CDCh): δ 9.41 (s, IH), 8.23 (d, J = 8.8 Hz. 2H), 7.36 (t, J = 7.8 Hz, 4H), 7.17 (t, J = 7.0 Hz, 3H), 7.11 (d. J = 8.4 Hz, 2H), 7.02 (d, J = 8.4 Hz, 2H), 6.95 (s, IH), 6.90-6.87 (m, 4H), 4.58-4.56 (m, IH), 1.36 (d, J = 6.0 Hz, 6H).

[00297] Compound 425: ¾ NMR (400 MHz, DMSO): δ 8.15 (d, J = 8.8 Hz, 2H), 7.96 (d, J = 8.8 Hz, IH), 7.67 (d, J = 7.6 Hz, 2H), 7.60 (d, J = 8.8 Hz, 2H), 7.51 (s, IH), 7.42 (t, J = 7.8 Hz, 2H), 7.28-7.17 (m, 5H), 7.10-7.04 (m, 3H), 7.02-6.94 (m, 4H), 4.68-4.64 (m, IH), 1.28 (d, J = 5.6 Hz, 6H).

[00298] Compound 429: ¾ NMR (400 MHz, CDCh): δ 8.75 (s, IH), 8.10 (d, J = 8.8 Hz. IH), 8.01 (d, J = 8.0 Hz, IH). 7.95 (d, J = 7.6 Hz, IH), 7.88 (d, J = 7.2 Hz, IH), 7.70 (s, IH), 7.65-7.57 (m, 2H), 7.35 (d, J = 7.6 Hz, 4H), 7.15 (t, J = 7.0 Hz, IH), 7.08-7.01 (m, 4H), 6.94- 6.86 (m, 5H), 4.56-4.53 (m, IH), 1.35 (d, J = 6.4 Hz, 6H).

[00299] Compound 431: ¾ NMR (400 MHz, CDCh): δ 8.12 (t, J = 7.0 Hz, 2H), 7.73 (s, IH), 7.42-7.31 (m, 6H), 7.22 (t, J = 7.2 Hz, IH), 7.15 (t, J = 7.0 Hz, IH), 7.08-7.03 (m, 8H), 7.01-6.86 (m, 4H), 4.58-4.54 (m, IH), 1.36 (d, J = 5.2 Hz. 6H).

[00300] Compound 432: ¾ NMR (400 MHz, DMSO): δ 11.67 (s, IH), 7.79 (d, J = 2.4 Hz. IH), 7.66 (d, J = 8.4 Hz, IH). 7.50 (d, J = 1.6 Hz, IH), 7.40 (d, J = 2.4 Hz, IH), 7.35-7.28 (m, 2H), 7.02 (t, J = 4.6 Hz, 2H).

[00301] Compound 433: ¾ NMR (400 MHz, DMSO): δ 11.68 (s, IH), 8.04 (d, J = 8.8 Hz, 2H), 7.91 (d, J = 2.4 Hz, IH), 7.77 (d, J = 8.8 Hz, 2H), 7.67 (d, J = 8.4 Hz, IH), 7.51 (s, IH), 7.36-7.30 (m, 3H), 7.15 (s, IH), 7.04 (d, J = 8.8 Hz, IH).

[00302] Compound 437: ¾ NMR (400 MHz, CDCh): δ 7.43 (d, J = 7.6 Hz, IH). 7.37 (d. J = 1.6 Hz, IH), 7.31 (t, J = 8.0 Hz. 3H), 7.14 (d, J = 5.6 Hz. 2H), 7.07-7.02 (m, 4H), 6.92 (d. J = 8.4 Hz, IH).

[00303] Compound 436: ¾ NMR (400 MHz, CDCh): δ 9.47 (s, IH), 8.11 (d, J = 8.8 Hz, 2H), 7.52 (d, J = 8.4 Hz, 2H), 7.40 (d, J = 8.8 Hz, IH), 7.33-7.24 (m, 5H), 7.15 (d, J = 8.0 Hz, IH), 7.05-6.98 (m, 5H), 6.94 (d, J = 8.0 Hz, IH). [00304] Compound 435: ¾ NMR (400 MHz, CDCh): δ 9.00 (s, IH), 8.93 (s, IH), 8.18 (d, J = 9.2 Hz, IH), 7.40 (d, J = 8.0 Hz, IH), 7.33-7.24 (m, 5H), 7.15 (d, J = 7.6 Hz, IH), 7.05 (d, J = 8.8 Hz, 3H), 7.00-6.93 (m, 4H), 3.78 (br s, 4H), 3.47 (br s, 2H), 2.79 (br s, 2H), 2.58 (br s, 4H).

[00305] Compound 434: ¾ NMR (400 MHz, CDCh): δ 9.03 (s, IH), 8.96 (s, IH), 8.47 (s, IH), 8.20 (dd, Ji = 9.6 Hz, h = 1.6 Hz, IH), 7.59 (s, IH), 7.40 (d, J = 12.0 Hz, 2H), 7.25 (s, 4H), 7.15 (dd, Ji = 8.4 Hz, h = 6.0 Hz, IH), 7.10 (dd, Ji = 8.4 Hz, h = 1.2 Hz, IH), 7.05 (s, IH), 6.97 (s, IH), 6.92 (d, J = 9.2 Hz, IH), 3.76 (t, J = 4.2 Hz, 4H), 3.44-3.40 (m, 2H), 2.75 (t, J = 5.8 Hz, 2H), 2.54 (br s, 4H).

[00306] Compound 401 : 5H (400 MHz, DMSO-de) 7.23 (d, 2H, Ar, J= 8.8 Hz), 7.15 (d, 2H, Ar, J= 7.6 Hz), 6.90-6.84 (m, 4H, Ar), 4.64-4.59 (m, 2H, CH(CH₃)₂), 1.28-1.24 (m, 12H, CH(CH₃)₃)

[00307] Compound 403: 5H (400 MHz, DMSO-de) 7.83 (d, 2H, Ar, J= 8.4 Hz), 7.39 (d, 2H, Ar, J= 8.4 Hz), 7.19 (d, 2H, Ar, J = 8.4 Hz), 7.03 (d, 2H, Ar, J= 8.8 Hz), 6.87 (d, 2H, Ar, J = 8.4 Hz), 6.79(d, 2H, Ar, J= 8.4 Hz), 4.63-4.55 (m, 2H, CH(CH₃)₂), 1.27-1.23 (m, 12H, CH(CH₃)₃)

[00308] Compound 402: 5H (400 MHz, CDCh-de) 7.35 (d, 4H, Ar, J= 6.8 Hz), 7.14 (t, 3H, Ar, J= 14 Hz), 7.03 (d, 2H, Ar, J= 8 Hz), 6.9 (t, 4H, Ar, J= 21 Hz), 4.56 (s, IH, CH(CH₃)₂), 1.34 (s, 6H, CH(CH₃)₃); 5c (400 MHz, DMSO-de) 160.6, 159.1, 158.3, 149.3, 131.5, 130.1, 129.8, 128.8, 124.1, 124.0, 122.2, 1 19.7, 119.6, 1 18.5, 118.0, 115.4, 69.8, 22.0

[00309] Compound 404: 5H (400 MHz, DMSO-de) 7.86 (d, 2H, Ar, J= 8.8 Hz), 7.42 (s, 4H, Ar), 7.30 (d, 2H, Ar, J = 8.8 Hz), 7.19 (t, IH, Ar, J= 1 1.6 Hz), 7.06 (t, 4H, Ar, J = 14 Hz), 6.96 (d, 2H, Ar, J= 8.4 Hz), 6.81 (d, 2H, Ar, J = 8 Hz), 4.61-4.58 (m, IH, CH(CH₃)₂), 1.26 (d, 6H, CH(CH₃)₃, J = 6 Hz)

[00310] Compound 405: 5H (400 MHz, DMSO-de) 7.80 (d, 2H, Ar, J= 8.4 Hz), 7.47-7.40 (m, 4H, Ar), 7.31 (d, 2H, Ar, J = 8.8 Hz), 7.23-7.19 (m, 2H, Ar), 7.11 (d, 2H, Ar, J = 7.6 Hz), 7.07 (d, 4H, Ar, J= 8.4 Hz), 7.02 (d, 2H, Ar, J = 8.4 Hz), 6.97 (d, 2H, Ar, J = 8.4 Hz), 6.83 (d, 2H, Ar, J= 8.4 Hz), 4.62-4.59 (m, IH, CH(CH₃)₂), 1.26 (d, 6H, CH(CH₃)₃, J= 5.2 Hz)

[00311] Compound 406: 5H (400 MHz, DMSO-de) 8.43 (s, IH, Ar), 8.11 (d, IH, Ar, J = 6.8 Hz), 8.01 (t, 2H, Ar, J = 7.6 Hz), 7.84 (d, IH, Ar, J= 8.4 Hz), 7.67-7.62 (m, 2H, Ar), 7.39 (t, 2H, Ar, J= 7.8 Hz), 7.30 (d, 2H, Ar, J = 8.4 Hz), 7.19 (t, IH, Ar, J= 7.4 Hz), 7.06 (d, 2H, Ar, J= 7.6 Hz), 7.01 (d, 2H, Ar, J = 8.4 Hz), 6.96 (d, 2H, Ar, J= 8.4 Hz), 6.73 (d, 2H, Ar, J = 8.4 Hz), 4.53-4.50(m, IH, CH(CH₃)₂), 1.24 (d, 6H, CH(CH₃)₃, J = 6.4 Hz) [00312] Compound 446: δ_Η (400 MHz, CDCh-de) 8.68 (s, 1H, Ar), 8.18 (d, 1H, Ar, J= 8.8 Hz), 7.52 (s, 1H, Ar), 7.35 (s, 1H, Ar), 7.32 (s, 1H, Ar), 7.30 (s, 1H, Ar), 7.16 (t, 2H, Ar, J = 10.6 Hz), 6.98 (s, 1H, Ar)

[00313] Compound 447: 5H (400 MHz, CDCh-de) 8.67 (s, 1H, Ar), 8.18 (d, 1H, Ar, J= 8.8 Hz), 7.56 (s, 1H, Ar), 7.52 (d, 1H, Ar, J= 8.4 Hz), 7.38-7.31 (m, 3H, Ar), 7.16 (t, 2H, Ar, J = 8.6 Hz), 6.98 (s, 1H, Ar)

[00314] Compound 441 : δ_Η (400 MHz, CDCh-de) 8.42 (s, 1H, Ar), 8.04 (d, 2H, Ar, J= 8.8 Hz), 7.94 (br s, 1H, Ar), 7.51 (d, 1H, Ar, J= 6.4 Hz), 7.48 (s, 1H, Ar), 7.33-7.28 (m, 2H, Ar), 7.10 (br s, 3H, Ar), 6.98 (d, 1H, Ar, J = 8.8 Hz), 6.79 (s, 1H, Ar)

[00315] Compound 440: δ_Η (400 MHz, CDCh-de) 8.38 (s, 1H, Ar), 8.05 (d, 2H, Ar, J= 8 Hz), 7.86 (d, 1H, Ar, J= 8 Hz), 7.49 (s, 1H, Ar), 7.29 (d, 2H, Ar, J = 9.2 Hz), 7.21 (t, 2H, Ar, J= 9 Hz), 7.10 (d, 1H, Ar, J= 8.4 Hz), 7.03 (br s, 2H, Ar), 6.92 (d, 1H, Ar, J = 8.4 Hz), 6.75 (br s, 1H, Ar)

[00316] Compound 448: 5H (400 MHz, CDCh-de) 7.68 (s, 1H, Ar), 7.40 (d, 2H, Ar, J= 8.8 Hz), 7.30 (d, 1H, Ar, J= 8.4 Hz), 7.21 (d, 2H, Ar, J = 8.8 Hz), 6.94 (d, 2H, Ar, J = 8 Hz), 4.61 (m, 1H, CH(CH₃)₃), 2.77 (d, 6H, CH(CH₃)₃, J= 5.6 Hz)

[00317] Compound 442: 5H (400 MHz, DMSO-de) 7.84 (d, 2H, Ar, J= 8.4 Hz), 7.71 (d, 1H, Ar, J= 8.8 Hz), 7.67 (s, 1H, Ar), 7.41 (br s, 3H, Ar), 7.09 (d, 2H, Ar, J= 8.8 Hz), 6.81 (d, 2H, Ar, J= 8.8 Hz), 4.62-4.10 (m, 1H, CH(CH₃)₃), 1.28 (d, 6H, CH(CH₃)₃, J= 6.4 Hz)

[00318] Compound 445 δ_Η (400 MHz, CDCh-de) 7.98 (s, 1H, Ar), 7.73 (s, 1H, Ar), 7.62 (br s, 1H, Ar), 7.24 (s, 2H, Ar), 6.89 (s, 2H, Ar), 2.41 (s, 3H, CH₃), 1.63 (s, 9H, OC(CH₃)₃)

[00319] Compound 443: δ_Η (400 MHz, CDCh-de) 7.74 (t, 3H, Ar, J= 7.8 Hz), 7.61 (d, 1H, Ar, J= 8.4 Hz), 7.42 (s, 1H, Ar), 7.40 (s, 1H, Ar), 7.32 (d, 2H, Ar, J = 8 Hz), 6.72 (d, 1H, Ar, J= 8 Hz), 6.67 (d, 1H, Ar, J= 8 Hz), 2.37 (s, 3H, CH₃)

[00320] Example 7: Biological Data: Fluorescence Polarization Competition Assay

[00321] Fluorescence polarization analyses were done using a PHERAstar FS multimode microplate reader (BMG LabTech) equipped with two photomultiplier tubes for simultaneous measurements of the perpendicular and parallel fluorescence emissions. For the fluorescence polarization competition assay (FPCA), inhibitors were titrated into a solution of Mcl-1^172"327, or Bcl-XL^2"212, and the fiuorescently-labeled Bak-BH3 peptide FITC-Ahx- GQVGRQLAIIGDDINR-CONH2 (hereafter "FITC-Bak"), where FITC = fluorescein isocyanate, Ahx = 6-aminohexanoyl linker. Origin (OriginLab, Northampton, USA) was used to execute the regression analysis to fit the data to the Hill equation to determine the initial binding affinities (Kd) and the IC50S in the FPCA. Kd values for the FITC-Bak peptide to Mcl- 1 and Bcl-xL were 33.8 ± 0.5 nM and 6.67 ± 0.05 nM, respectively. For the FPC titrations, the Nikolovska-Coleska equation was utilized to calculate Ki values from the IC50 data. All experiments were run in three biological replicates, each performed in triplicate. Similarly, the affinity of TAMRA-p53^15"29 was determined by the titration of MDM2^1"115 into 10 nM TAMRA-p53^15-29 peptide in PBS with 0.01 % Triton X-100 and 5% DMSO at room temperature with a 544 nm excitation and 590 nm emission filters. The fluorescence polarization assays (FPCA) were performed using 10 μΜ MDM2^1"115 in the same buffer (PBS with 0.01% Triton X-100 and 5% DMSO) with varying concentrations of unlabeled p53^15"29 peptide or experimental compounds.

Table 1

ND: not determined;

NA: no activity (precipitation).

[00322] Example 8: CellTitre-Blue Cell Viability Assay

[00323] Cells were incubated with compounds in 96-well plates for 48-72 h at 37 °C, then treated with CellTitre-Blue reagent for 4 h. Fluorescence (560Ex/590Em) was recorded in a fluorimeter, and is a measure of the metabolic activity of the cell (reduction of CellTitre-Blue reagent resazurin to resorufin) and hence the cell viability. ED50 is the dose of compound required for 50% reduction of resazurin, where the DMSO vehicle control is taken to be 100% reduction of resazurin.

[00324] All cell lines are acute myeloid leukemia cells.

• HL60: elevated levels of BCL-2 and BC1-XL, low Mcl-1, mutant p53;

• U937: elevated levels of BCL-2 and Mcl-1, low BC1-XL, p53 null;

• OCI-AML: elevated levels of BCL-2 and Mcl-1, low BC1-XL, wild-type p53.

Table 2

417 48.6 ± 6.2 35.5 ± 4.0 52.7 ± 9.8

418 22.6 ± 2.8 12.3 ± 2.5 13.4 ± 5.3

419 50.8 ± 7.9 28.2 ± 5.0 84.6 ± 20.4

420 33.3 ± 2.8 23.4 ± 5.5 53.3 ± 10.3

ND: not determined.

[00325] Example 9: Mcl-1 Binding Data

Table 3

REFERENCES

[00326] Each reference cited below is hereby incorporated in its entirety as if fully set forth herein.

1. Cao, X., Yap, J. L., Fletcher, S. et al. Molecular Cancer. 2013, 12:42

2. Akgul, C, Cell. Mol. Life Sci. 2009, 1326-1336

3. Thomas, L.W., Lam, C, Edwards, S.W., FEBS Letters 2010, 584, 2981-2989 4. Hemman, M.T. and Lowe, S.W., Cell Death and Differentiation 2006, 13, 1256- 1259

5. Polsky, D. et al, J. Natl. Cancer Inst. 2002, 94 (23): 1803-1806

6. Perfettini, J. et al., Nat. Cell Biol. 2004. 6. 386 - 388

7. Plante J.P. et al., Chem. Commun. (Camb.) 2009, 34,5091 -3.

8. Joerger A.C. and Fersht, A.R., Cold Spring Harb. Perspect. Biol. 2010, 6

9. Drennen, B.J. et al, ChemMedChem. 2016. 11 , 8, 827-833.

10. Wang Z., Zhang Z., et al. J. Med. Chem. 2016, 59(7):3152-62.

Claims

1. A compound of any one of Formulas 1-27:

Formula 1 Formula 2 Formula 3 Formula 4

Formula 5 Formula 6 Formula 7 Formula 8

Formula 9 Formula 10 Formula 1 1 Formula 12

Formula 13 Formula 14 Formula 15 Formula 16

Formula 17 Formula 18 Formula 19 Formula 20

Formula 25 Formula 26 Formula 27

wherein in Formulas 1-27:

An and An are each independently an aryl or heteroaryl group, optionally substituted with one or more substituents such as alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilanyl, -OR^a, -SR^a, -OC(0)R^a, - N(R^a)R^b, -C(0)R^a, -C(0)OR^a, -OC(0)N(R^a)R^b, -C(0)N(R^a)R^b, -N(R^a)C(0)OR^a, - N(R^a)C(0)R^a, -N(R^a)C(0)N(R^a)R^b, -N(R^a)C(NR^a)N(R^a)R^b, -N(R^a)S(0)tR^a, - S(0)tOR^a, -S(0)tN(R^a)R^b, -S(0)tN(R^a)C(0)R^b, or -P(0)(OR^a)(OR^b);

Ri, and R2 are each independently hydrogen, alkyl, fluoroalkyl, -OR^a, -SR^a, - OC(0)R^a, -N(R^a)R^b, -OC(0)N(R^a)R^b, -N(R^a)C(0)OR^a, -N(R^a)C(0)R^a, -N(R^a)C(0)N(R^a)R^b, - N(R^a)C(NR^a)N(R^a)R^b, -N(R^a)S(0)_tR^a, -S(0)tOR^a, -S(0)tN(R^a)C(0)R^b, or -S(0)tN(R^a)R^b;

L is a linker selected from a bond, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, fluoroalkyl, -OC(O)-, -NR^a- , -C(O)-, -C(0)0-, -OC(0)N(R^a)-, -C(0)N(R^a)-, -C(0)N(R^a)S(0)t-, -N(R^a)C(0)0-, - N(R^a)C(0)-, -N(R^a)C(0)N(R^a)-, -N(R^a)C(NR^a)N(R^a)-, -N(R^a)S(0)t-, -S(0)tO-, -S(0)tN(R^a)- , -S(0)_tN(R^a)C(0)-, -P(0)(OR^a)0-, -OP(0)(OR^a)0-, -(CR^aR^b)_n-, -0-, -S-, and -S(0)t-;

R^a and R^b are each independently selected from the group consisting of hydrogen, alkyl, fluoroalkyl, cycloalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, heteroarylalkyl, halogen, -O-alkyl, -O-aryl, cyano, nitro, - OH, -NH2, -NH-alkyl, and -NH-aryl; n is a positive integer, and t is 1 or 2.

2. The compound of claim 1, wherein the compound is of any one of Formulas 101-

154:

F

ormula 101 Formula 102 Formula 104

Formula 105 Formula 106 Formula 107 Formula 108

Formula 109 Formula 110 Formula 111 Formula 112

Formula 113 Formula 114 Formula 115 Formula 116

Formula 117 Formula 118 Formula 119 Formula 120

Formula 121 Formula 122 Formula 123 Formula 124

Formula 125 Formula 126 Formula 127 Formula 128

Formula 129 Formula 130 Formula 131 Formula 132

Formula 133 Formula 134 Formula 135 Formula 136

Formula 137 Formula 138 Formula 139 Formula 140

Formula 141 Formula 142 Formula 143 Formula 144

Formula 145 Formula 146 Formula 147 Formula 148

Formula 149 Formula 150 Formula 151 Formula 152

Formula 153 Formula 154

wherein in Formulas 101 -154:

Ri, R2, and R3 are each independently hydrogen, alkyl, fluoroalkyl, -OR^a, -SR^a, - OC(0)R^a, -N(R^a)R^b, -OC(0)N(R^a)R^b, -N(R^a)C(0)OR^a, -N(R^a)C(0)R^a, -N(R^a)C(0)N(R^a)R^b, - N(R^a)C(NR^a)N(R^a)R^b, -N(R^a)S(0)_tR^a, -S(0)tOR^a, -S(0)tN(R^a)C(0)R^b, or -S(0)tN(R^a)R^b;

R^a and R^b are each independently selected from the group consisting of hydrogen, alkyl, fluoroalkyl, cycloalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, heteroarylalkyl, halogen, -O-alkyl, -O-aryl, cyano, nitro, - OH, -NH2, -NH-alkyl, and -NH-aryl;

X is alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, fluoroalkyl, -(CR^aR^b)_n-, -OR³-, -S-, -SO-, -SO2-, or - NR^a-;

n is a positive integer, and t is 1 or 2.

3. The compound of claim 1, wherein the compound is of any one of Formulas 201-

224:

Formula 201 Formula 202 Formula 203

Formula 204 Formula 205 Formula 206

Formula 208 Formula 209

Formula 211

Formula 216 Formula 217 Formula 218

Formula 220 Formula 221

wherein:

each R is independently selected from the group consisting of alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilanyl, -OR^a, -SR^a, - OC(0)R^a, -N(R^a)R^b, -C(0)R^a, -C(0)OR^a, -OC(0)N(R^a)R^b, -C(0)N(R^a)R^b, -N(R^a)C(0)OR^a, - N(R^a)C(0)R^a, -N(R^a)C(0)N(R^a)R^b, -N(R^a)C(NR^a)N(R^a)R^b, -N(R^a)S(0)tR^a, - S(0)tOR^a, -S(0)tN(R^a)R^b, -S(0)tN(R^a)C(0)R^b, or -P(0)(OR^a)(OR^b);

each R2 is independently selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, isopropyl, or trifluoromethyl;

R3 is -OH, -ORa, -NHRa, -NR_aRt>, optionally substituted alkyl, or optionally substituted aryl;

n is 0, 1, 2, 3, 4, 5, or 6; and

t is 1 or 2.

4. The compound of 1, wherein the compound i one of Formulas 301-

333:

Formula 310 Formula 311 Formula 312

Formula 313 Formula 314 Formula 315

Formula 316 Formula 317

Formula 322 Formula 323 Formula 324

wherein:

each R is independently a substituent such as alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilanyl, -OR^a, -SR^a, -OC(0)R^a, - N(R^a)R^b, -C(0)R^a, -C(0)OR^a, -OC(0)N(R^a)R^b, -C(0)N(R^a)R^b, -N(R^a)C(0)OR^a, - N(R^a)C(0)R^a, -N(R^a)C(0)N(R^a)R^b, -N(R^a)C(NR^a)N(R^a)R^b, -N(R^a)S(0)tR^a, - S(0)tOR^a, -S(0)tN(R^a)R^b, -S(0)tN(R^a)C(0)R^b, or -P(0)(OR^a)(OR^b);

R^a and R^b are each independently hydrogen, alkyl, fluoroalkyl, cycloalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, heteroarylalkyl, halogen, -O-alkyl, -O-aryl, cyano, nitro, -OH, -NH2, -NH-alkyl, or -NH-aryl;

n is 0, 1, 2, 3, 4, 5, or 6; and t is 1 or 2.

5. The compound of claim 1, wherein the compound is of any one of Formulas 401- 448, wherein n is 0, 1 , 2, 3, 4, 5, or 6 where applicable:

Formula 407 Formula 408 Formula 409

Formula 416 Formula 417 Formula 418

120

Formula 440 Formula 442

Formula 444 Formula 445

Formula 446 Formula 447 Formula 448

6. The compound of any one of claims 1 to 5, wherein the compound is a BCL-2 inhibitor.

7. The compound of any one of claims 1 to 5, wherein the compound is an MDM2 inhibitor.

8. The compound of any one of claims 1 to 5, wherein the compound is a dual BCL-2 and MDM2 inhibitor.

9. A pharmaceutical composition comprising a compound of any one of claims 1 to 8, or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or prodrug thereof, and a physiologically compatible carrier medium.

10. A method of treating a disease alleviated by inhibiting BCL-2 in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of any one of claims 1 to 5, or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or prodrug thereof.

11. A method of treating a disease alleviated by inhibiting MDM2 in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of any one of claims 1 to 5, or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or prodrug thereof.

12. A method of treating a disease alleviated by inhibiting BCL-2 and MDM2 in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of any one of claims 1 to 5, or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or prodrug thereof.

13. The method of any one of claims 10 to 12, wherein the compound, or

pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or prodrug thereof, is administered in a dosage unit form.

14. The method of claim 13, wherein the dosage unit form comprises a

physiologically compatible carrier medium.

15. The method of any one of claims 10 to 14, wherein the disease is cancer.

16. The method of claim 15, wherein the cancer is selected from the group consisting of bladder cancer, squamous cell carcinoma including head and neck cancer, pancreatic ductal adenocarcinoma (PDA), pancreatic cancer, colon carcinoma, mammary carcinoma, breast cancer, fibrosarcoma, mesothelioma, renal cell carcinoma, lung carcinoma, thymoma, prostate cancer, colorectal cancer, ovarian cancer, acute myeloid leukemia, thymus cancer, brain cancer, squamous cell cancer, skin cancer, eye cancer, retinoblastoma, melanoma, intraocular melanoma, oral cavity and oropharyngeal cancers, gastric cancer, stomach cancer, cervical cancer, renal cancer, kidney cancer, liver cancer, ovarian cancer, esophageal cancer, testicular cancer, gynecological cancer, thyroid cancer, acquired immune deficiency syndrome (AIDS)-related cancers (e.g., lymphoma and Kaposi's sarcoma), viral-induced cancer, glioblastoma, esophageal tumors, hematological neoplasms, non-small-cell lung cancer, chronic myelocytic leukemia, diffuse large B-cell lymphoma, esophagus tumor, follicle center lymphoma, head and neck tumor, hepatitis C virus induced cancer, hepatocellular carcinoma, Hodgkin's disease, metastatic colon cancer, multiple myeloma, non-Hodgkin's lymphoma, indolent non-Hodgkin's lymphoma, ovary tumor, pancreas tumor, renal cell carcinoma, small-cell lung cancer, stage IV melanoma, chronic lymphocytic leukemia, B-cell acute lymphoblastic leukemia (ALL), mature B-cell ALL, follicular lymphoma, mantle cell lymphoma, and Burkitt's lymphoma.