Car activator agents for cyclophosphamide-based treatments of cancer

1. A compound of Formula (II), or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or prodrug thereof:

wherein in Formula (II):

Z is O or S;

Y is C, R 4 is H or C 1-6 -alkyl;

R 1 is selected from the group consisting of

X is a linker moiety selected from the group consisting of —C(O)—R 8 —, —CH 2 —NH—C(O)—, —CH═N—,—R 10 —NH—, —R 10 —NR 11 —, and —NH—C(O)—;

R 2 is selected from the group consisting of a bond, —C(O)—, C 1-6 -alkyl, and C 3-8 -heterocycloalkylamine;

R 3 is selected from the group consisting of aryl, heteroaryl, C 3-8 -cycloalkyl, and C 3-8 -heterocycloalkyl, wherein R 3 is optionally substituted with one or more substituents selected from the group consisting of non-substituted aryl, hydroxy, halo, cyano, trifluoromethyl, trifluoromethoxy, nitro, oxo, trimethylsilanyl, —OR a , —SR a , —OC(O)R a , —N(R a )R b , —C(O)R a , —C(O)OR a , —OC(O)N(R a )R b , —C(O)N(R a )R b , —N(R a )C(O)OR a , —N(R a )C(O)R a , —N(R a )C(O)N(R a )R b , —N(R a )C(NR a )N(R a )R b , —N(R a )S(O) t R a , —S(O) t OR a , —S(O) t N(R a )R b , or —P(O)(OR a )(OR b );

R 5 is selected from the group consisting of hydrogen, halogen, C 1-6 -alkyl, —C(O)R a , —C(O)OR a , and —C(O)N(R a )R b ;

R 8 is selected from the group consisting of a bond, C 1-3 -alkenyl, O, —NH—, and —NH—O—;

R 10 is non-substituted C 1-3 -alkyl or substituted or non-substituted C 2-3 -alkenyl;

R 11 is substituted or non-substituted C 1-3 -alkyl or C 2-3 -alkenyl;

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, —NH 2 , —NH-alkyl, and —NH-aryl;

and

t is 1 or 2.

2. The compound of Formula (II), or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or prodrug thereof, according to claim 1 , wherein Z is O, Y is C, and R 4 is H.

3. The compound of Formula (II), or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or prodrug thereof, according to claim 1 , wherein Z is S, Y is C, and R 4 is H.

4. The compound of Formula (II), or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or prodrug thereof, according to claim 1 , wherein X is —CH═N—, —CH 2 —NH—, —C(O)—, —C(O)—NH—, or —NH—C(O)—.

5. The compound of Formula (II), or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or prodrug thereof, according to claim 1 , wherein —R 2 -R 3 is selected from the group consisting of:

6. The compound of Formula (II), or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or prodrug thereof, according to claim 1 , wherein the compound is selected from:

Compound

Chemical Name

N-((6-(naphthalen-2-yl)imidazo[2,1- b]oxazol-5-yl)methyl)-2,3-dihydro- 1H-inden-2-amine

N-((6-(naphthalen-1-yl)imidazo[2,1- b]thiazol-5-yl)methyl)-2,3-dihydro- 1H-inden-2-amine

N-((6-(naphthalen-1-yl)imididazo[2,1- b]thiazol-5-yl)methyl)-2,3-dihydro- 1H-inden-2-amine

N-((6-(naphthalen-2-yl)imidazo[2,1- b]thiazol-5-yl)methyl)-2- phenylpropan-1-amine

N-((6-(4-chlorophenyl)imidazo[2,1- b]oxazol-5-yl)methyl)-2,3-dihydro- 1H-inden-2-amine

N-((2,3-dihydro-1H-inden-2- yl)methyl)-6-(naphthalen-2- yl)imidazo[2,1-b]oxazole-5- carboxamide

6-(naphthalen-2-yl)-N-(3- phenylpropyl)imidazo[2,1- b]oxazole- 5-carboxamide

N-((3,4-dichlorobenzyl)oxy)-6- (naphthalen-2-yl)imidazo[2,1- b]oxazole-5-carboxamide

N-(benzyloxy)-6-(naphthalen-2- yl)imidazo[2,1-b]oxazole-5- carboxamide

(6-(naphthalen-2-yl)imidazo[2,1- b]oxazol-5-yl)(4-phenylpiperazin-1- yl)methanone

6-(naphthalen-2-yl)-N-(1- phenylazetidin-3-yl)imidazo[2,1- b]oxazole-5-carboxamide

N-(3,4-dichlorophenethyl)-6- (naphthalen-2-yl)imidazo[2,1- b]oxazole-5-carboxamide

6-(2,4-difluorophenyl)-N-(2,3- dihydro-1H-inden-2-yl)imidazo[2,1- b]oxazole-5-carboxamide

6-(4-chlorophenyl)-N-(3,4- dichlorophenethyl)imidazo[2,1- b]oxazole-5-carboxamide

6-(2,4-difluorophenyl)-N-((2,3- dihydro-1H-inden-2- yl)methyl)imidazo[2,1- b]oxazole-5- carboxamide

N-(2,3-dihydro-1H-inden-2-yl)-6-(4- fluorophenyl)imidazo[2,1- b]oxazole- 5-carboxamide

N-(3,4-dichlorophenethyl)-6-(4- fluorophenyl)imidazo[2,1- b]oxazole- 5-carboxamide

6-(4-chlorophenyl)-N-(2,3-dihydro- 1H-inden-2-yl)imidazo[2,1- b]oxazole- 5-carboxamide

6-(4-chlorophenyl)-N-((2,3-dihydro- 1H-inden-2-yl)methyl)imidazo[2,1- b]oxazole-5-carboxamide

2-(2-(6-naphthalen-2-yl)imidazo[2,1- b]oxazol-5-yl)-2-oxoethyl)isoindoline- 1,3-dione

(E)-N-(isoindolin-2-yl)-1-(6- (naphthalen-2-yl)imidazo[2,1- b]oxazol-5-yl)methanimine

(E)-1-(6-(4-chlorophenyl)imidazo[2,1- b]thiazol-5-yl)-N-(3,4- dichlorophenethyl)methanimine

N-((6-(4-chlorophenyl)imidazo[2,1- b]thiazol-5-yl)methyl)-2-(3,4- dichlorophenyl)ethan-1-amine

N-((6-(4-chlorophenyl)imidzo[2,1- b]thiazol-5-yl)methyl)-2-(3,4- dichlorophenyl)ethan-1-amine hydrochloride

6-(4-chlorophenyl)-N-(3,4- dichlorophenethyl)imidazo[2,1- b]thiazole-5-carboxamide

2-(3-chlorophenyl)-N-((6-(4- chlorophenyl)imidazo[2,1-b]thiazol-5- yl)methyl)ethan-1-amine

2-(4-chlorophenyl)-N-((6-(4- chlorophenyl)imidazo[2,1-b]thiazol-5- yl)methyl)ethan-1-amine

2-(4-bromophenyl)-N-((6-(4- chlorophenyl)imidazo[2,1-b]thiazol-5- yl)methyl)ethan-1-amine

2-(3-bromo-4-chlorophenyl)-N-((6-(4- chlorophenyl)imidazo[2,1-b]thiazol-5- yl)methyl)ethan-1-amine

2-(3-chloro-4- (trifluoromethyl)phenyl)-N-((6-(4- chlorophenyl)imidazo[2,1-b]thiazol-5- yl)methyl)ethan-1-amine

2-(3-bromophenyl)-N-((6-(4- chlorophenyl)imidazo[2,1-b]thiazol-5- yl)methyl)ethan-1-amine

N-((6-(4-chlorophenyl)imidazo[2,1- b]thiazol-5-yl)methyl)-2-phenylethan- 1-amine

N-((6-(4-chlorophenyl)imidazo[2,1- b]thiazol-5-yl)methyl)-2-(4- fluorophenyl)ethan-1-amine

4-(2-((6-(4- chlorophenyl)imidazo[2,1-b]thiazol-5- yl)methyl)amino)ethyl)phenol

N-((6-(4-chlorophenyl)imidazo[2,1- b]thiazol-5-yl)methyl)-2-(1H-indol-3- yl)ethan-1-amine

N-((6-(4-chlorophenyl)imidazo[2,1- b]thiazol-5-yl)methyl)-2,3-dihydro- 1H-inden-2-amine

N-((6-(4-chlorophenyl)imidazo[2,1- b]thiazol-5-yl)methyl)naphthalen-2- amine

N-benzyl-1-(6-(4- chlorophenyl)imidazo[2,1-b]thiazol-5- yl)methanamine

N-((6-(4-chlorophenyl)imidazo[2,1- b]thiazol-5-yl)methyl)-2-(3,4- dichlorophenyl)-N-methylethan-1- amine

N-((6-(4-chlorophenyl)imidazo[2,1- b]thiazol-5-yl)methyl)-2-(3,4- dichlorophenyl)-N-ethylethan-1-amine

N-benzyl-N-((6-(4- chlorophenyl)imidazo[2,1-b]thiazol-5- yl)methyl)-2-(3,4- dichlorophenyl)ethan-1-amine

2-(3,4-dichlorophenyl)-N-((6-(4- methoxyphenyl)imidazo[2,1-b]thiazol- 5-yl)methyl)ethan-1-amine

N-((6-(3-chlorophenyl)imidazo[2,1- b]thiazol-5-yl)methyl)-2-(3,4- dichlorophenyl)ethan-1-amine

N-((6-(4-bromophenyl)imidazo[2,1- b]thiazol-5-yl)methyl)-2-(3,4- dichlorophenyl)ethan-1-amine

2-(3,4-dichlorophenyl)-N-((6-(4- isocyanophenyl)imidazo[2,1- b]thiazol-5-yl)methyl)ethan-1-amine

2-(3,4-dichlorophenyl)-N-((6- (naphthalen-2-yl)imidazo[2,1- b]thiazol-5-yl)methyl)ethan-1-amine

N-((6-(4-(tert- butyl)phenyl)imidazo[2,1-b]thiazol-5- yl)methyl)-2-(3,4- dichlorophenyl)ethan-1-amine

2-(3,4-dichlorophenyl)-N-((6-(4- fluorophenyl)imidazo[2,1-b]thiazol-5- yl)methyl)ethan-1-amine

2-(3,4-dichlorophenyl)-N-((6-(4- (trifluoromethyl)phenyl)imidazo[2,1- b]thiazol-5-yl)methyl)ethan-1-amine

2-(3,4-dichlorophenyl)-N-((6- ethylimidazo[2,1-b]thiazol-5- yl)methyl)ethan-1-amine

6-(4-chlorophenyl)-N-(3,4- dichlorophenethyl)imidazo[2,1- b]thiazole-5-carboxamide

N-(3-bromo-4-chlorophenethyl)-6-(4- chlorophenyl)imidazo[2,1-b]thiazole- 5-carboxamide

N-(2,3-dihydro-1H-inden-2-yl)-6- (naphthalen-2-yl)imidazo[2,1- b]thiazole-5-carboxamide

N-((6-(naphthalen-2-yl)imidazo[2,1- b]thiazol-5-yl)methyl)-2,3-dihydro- 1H-inden-2-amine

N-((6-(4-chlorophenyl)-2- methylimidazo[2,1-b]thiazol-5- yl)methyl)-2-(3,4- dichlorophenyl)ethan-1-amine

N-((6-(4-chlorophenyl)imidazo[2,1- b]oxazol-5-yl)methyl)-2-(3,4- dichlorophenyl)ethan-1-amine

1-(2,3-dihydro-1H-inden-2-yl)-N-((6- (naphthalen-2-yl)imidazo[2,1- b]oxazol-5-yl)methyl)methanamine

N-((6-(naphthalen-2-yl)imidazo[2,1- b]thiazol-5-yl)methyl)-2,3-dihydro- 1H-inden-2-amine

N-((6-(4-chlorophenyl)imidazo[2,1- b]thiazol-5-yl)methyl)-2-(3,4- dichlorophenyl)ethan-1-amine

N-((6-(naphthalen-2-yl)imidazo[2,1- b]oxazol-5-yl)methyl)-2,3-dihydro- 1H-indene-2-carboxamide

(6-(naphthalen-2-yl)imidazo[2,1- b]oxazol-5-yl)(4-phenylpiperazin-1- yl)methanone

N-(2,3-dihydro-1H-inden-2-yl)-6-(4- fluorophenyl)imidazo[2,1-b]oxazole- 5-carboxamide

N-((3,4-dichlorobenzyl)oxy)-6- (naphthalen-2-yl)imidazo[2,1- b]oxazole-5-carboxamide

N-(3,4-dichlorophenethyl)-6-(4- fluorophenyl)imidazo[2,1-b]oxazole- 5-carboxamide

N-(benzyloxy)-6-(naphthalen-2- yl)imidazo[2,1-b]oxazole-5- carboxamide

6-(naphthalen-2-yl)-N-(1- phenylazetidin-3-yl)imidazo[2,1- b]oxazole-5-carboxamide

6-(4-chlorophenyl)-N-((2,3-dihydro- 1H-inden-2-yl)methyl)imidazo[2,1- b]oxazole-5-carboxamide

N-((2,3-dihydro-1H-inden-2- yl)methyl)-6-(naphthalen-2- yl)imidazo[2,1-b]oxazole-5- carboxamide

6-(2,4-difluorophenyl)-N-((2,3- dihydro-1H-inden-2- yl)methyl)imidazo[2,1-b]oxazole-5- carboxamide

6-(naphthalen-2-yl)-N-(3- phenylpropyl)imidazo[2,1-b]oxazole- 5-carboxamide

6-(4-chlorophenyl)-N-(2,3-dihydro- 1H-inden-2-yl)imidazo[2,1-b]oxazole- 5-carboxamide

6-(2,4-difluorophenyl)-N-(2,3- dihydro-1H-inden-2-yl)imidazo[2,1- b]oxazole-5-carboxamide

N-(3,4-dichlorophenethyl)-6- (naphthalen-2-yl)imidazo[2,1- b]oxazole-5-carboxamide

2-(isoindolin-2-yl)-1-(6-(naphthalen- 2-yl)imidazo[2,1-b]oxazol-5-yl)ethan- 1-one

2,3-dihydro-1H-inden-2-yl 6- (naphthalen-2-yl)imidazo[2,1- b]oxazole-5-carboxylate

N-(2,3-dihydro-1H-inden-2-yl)-6- (naphthalen-2-yl)imidazo[2,1- b]oxazole-5-carboxamide

N-((2,3-dihydro-1H-inden-2-yl)oxy)- 6-(naphthalen-2-yl)imidazo[2,1- b]oxazole-5-carboxamide

2-(3,4-dichlorophenyl)-N-((6-(3,4- dimethoxyphenyl)imidazo[2,1- b]thiazol-5-yl)methyl)ethan-1-amine

2-(3,4-dichlorophenyl)-N-((6-(3,4- dichlorophenyl)imidazo[2,1-b]thiazol- 5-yl)methyl)ethan-1-amine

2-(3,4-dichlorophenyl)-N-((6-(4- nitrophenyl)imidazo[2,1-b]thiazol-5- yl)methyl)ethan-1-amine

2-(3,4-dichlorophenyl)-N-((6-(4- (methylsulfonyl)phenyl)imidazo[2,1- b]thiazol-5-yl)methyl)ethan-1-amine

N-((6-(naphthalen-2-yl)imidazo[2,1- b]thiazol-5-yl)methyl)-2-phenylethan- 1-amine

N-(2,3-dihydro-1H-inden-2-yl)-6- (naphthalen-2-yl)imidazo[2,1- b]oxazole-5-carboxamide

7. The compound of Formula (II), or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or prodrug thereof, according to claim 1 , wherein the compound is formulated in a physiologically compatible carrier medium.

8. A method of controlling a disease alleviated by activating hCAR in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of a compound of Formula (II), or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or prodrug thereof, according to claim 1 .

9. A method of controlling a disease alleviated by selective induction of CYP2B6 in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of a compound of Formula (II), or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or prodrug thereof, according to claim 1 .

10. The method of claim 9 , wherein CYP2B6 is selectively induced over CYP3A4.

11. The method of claim 8 , the method further comprising co-administering to the patient a therapeutically effective amount of cyclophosphamide (CPA), or a pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or prodrug thereof.

12. The method of claim 11 , wherein CPA is administered as part of the CHOP regimen (CPA, doxorubicin, vincristine, and prednisone).

13. The method of claim 11 , wherein the co-administration promotes the formation of therapeutically active CPA metabolite 4-OH-CPA.

14. The method of claim 8 , wherein the compound of Formula (II), or pharmaceutically acceptable salt, solvate, hydrate, cocrystal, or prodrug thereof, is administered in a dosage unit form.

15. The method of claim 14 , wherein the dosage unit form comprises a physiologically compatible carrier medium.

16. The method of claim 8 , wherein the disease is cancer.

17. The method of claim 16 , wherein the cancer is selected from the group consisting of bladder cancer, squamous cell carcinoma, 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, esophageal cancer, testicular cancer, gynecological cancer, thyroid cancer, acquired immune deficiency syndrome (AIDS)-related cancers, lymphoma, 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, 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.