Compounds and compositions for inhibition of FASN
10995078 · 2021-05-04
Assignee
Inventors
- Kenneth W. Bair (Wellesley, MA)
- David R. Lancia, Jr. (Boston, MA)
- Hongbin Li (Watertown, MA, US)
- James Loch (Watertown, MA, US)
- Wei Lu (Newton, MA)
- Matthew W. Martin (Arlington, MA)
- David S. Millan (Watertown, MA)
- Shawn E. R. Schiller (Watertown, MA, US)
- Mark J. Tebbe (Arlington, MA)
Cpc classification
A61K31/495
HUMAN NECESSITIES
C07D305/08
CHEMISTRY; METALLURGY
A61K2300/00
HUMAN NECESSITIES
A61K2300/00
HUMAN NECESSITIES
A61K31/4985
HUMAN NECESSITIES
C07D209/08
CHEMISTRY; METALLURGY
A61P35/00
HUMAN NECESSITIES
C07D209/18
CHEMISTRY; METALLURGY
C07D405/12
CHEMISTRY; METALLURGY
A61K45/06
HUMAN NECESSITIES
C07D231/12
CHEMISTRY; METALLURGY
C07D271/12
CHEMISTRY; METALLURGY
C07D417/12
CHEMISTRY; METALLURGY
C07D277/66
CHEMISTRY; METALLURGY
C07D235/08
CHEMISTRY; METALLURGY
A61K31/5025
HUMAN NECESSITIES
C07D403/04
CHEMISTRY; METALLURGY
C07D231/56
CHEMISTRY; METALLURGY
A61K31/496
HUMAN NECESSITIES
A61K31/506
HUMAN NECESSITIES
C07D491/048
CHEMISTRY; METALLURGY
C07D413/12
CHEMISTRY; METALLURGY
C07D401/04
CHEMISTRY; METALLURGY
C07D417/04
CHEMISTRY; METALLURGY
International classification
C07D277/66
CHEMISTRY; METALLURGY
C07D305/08
CHEMISTRY; METALLURGY
A61K31/495
HUMAN NECESSITIES
A61K31/496
HUMAN NECESSITIES
A61K31/4985
HUMAN NECESSITIES
A61K31/5025
HUMAN NECESSITIES
A61K31/506
HUMAN NECESSITIES
C07D209/08
CHEMISTRY; METALLURGY
C07D231/12
CHEMISTRY; METALLURGY
C07D235/08
CHEMISTRY; METALLURGY
C07D417/04
CHEMISTRY; METALLURGY
C07D209/18
CHEMISTRY; METALLURGY
C07D271/12
CHEMISTRY; METALLURGY
C07D491/048
CHEMISTRY; METALLURGY
C07D417/12
CHEMISTRY; METALLURGY
C07D231/56
CHEMISTRY; METALLURGY
A61K45/06
HUMAN NECESSITIES
A61P35/00
HUMAN NECESSITIES
C07D413/12
CHEMISTRY; METALLURGY
C07D405/12
CHEMISTRY; METALLURGY
C07D403/04
CHEMISTRY; METALLURGY
C07D401/04
CHEMISTRY; METALLURGY
Abstract
The present invention relates to compounds and composition for inhibition of FASN, their synthesis, applications, and antidotes. An illustrative compound of the invention is shown below: ##STR00001##
Claims
1. A compound selected from the group consisting of: TABLE-US-00008 NAME Structure 1-({4-[(4- phenylphenyl)carbonyl]piperazin-1- yl}carbonyl)cyclopropan-1-ol
2. A pharmaceutical composition comprising therapeutically effective amounts of at least one compound of claim 1, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.
Description
DESCRIPTION OF THE PREFERRED EMBODIMENTS
(1) An aspect of the present invention concerns compounds disclosed herein.
(2) An aspect of the present invention concerns compounds which are or can be inhibitors of FASN.
(3) An aspect of the present invention concerns the use of an inhibitor of FASN for the preparation of a medicament used in the treatment, prevention, inhibition or elimination of tumors.
(4) An aspect of the present invention concerns the use of an inhibitor of FASN for the preparation of a medicament used in the treatment, prevention, inhibition or elimination of cancer.
(5) An aspect of the present invention concerns the use of an inhibitor of FASN for the preparation of a medicament used in the treatment, prevention, inhibition or elimination of cancer, where the cancer is selected from leukemia, lymphoma, ovarian cancer, breast cancer, uterine cancer, colon cancer, cervical cancer, lung cancer, prostate cancer, skin cancer, CNS cancer, bladder cancer, pancreatic cancer and Hodgkin's disease.
(6) An aspect of the present invention concerns the use of an inhibitor of FASN for the preparation of a medicament used in the treatment, prevention, inhibition or elimination of diabetes.
(7) An aspect of the present invention concerns the use of an inhibitor of FASN for the preparation of a medicament used in the treatment, prevention, inhibition or elimination of viral infectious diseases.
(8) An aspect of the present invention concerns the use of an inhibitor of FASN for the preparation of a medicament used in the treatment, prevention, inhibition or elimination of overweight or obesity.
(9) An aspect of the present invention concerns the use of an inhibitor of FASN for the preparation of a medicament used in the treatment, prevention, inhibition or elimination of uterine leiomyomata.
(10) The present invention also describes one or more methods of synthesizing the compounds of the present invention.
(11) The invention also describes one or more uses of the compounds of the present invention.
(12) The invention also describes one or more uses of the compounds of the present invention with an adjunctive agent such as use with TNF, GCSF, or other chemotherapeutic agents
(13) The invention also describes one or more uses of the pharmaceutical compositions of the present invention.
(14) An aspect of the present invention concerns the use as an inhibitor of FASN for the preparation of a medicament used in the treatment of inflammatory diseases.
(15) An aspect of the present invention concerns the use as an inhibitor of FASN for the preparation of a medicament used in the treatment of inflammatory diseases, such as Irritable Bowel Syndrome or Inflammatory Bowel Disease.
(16) An aspect of the present invention concerns the use as an inhibitor of FASN for the preparation of a medicament used in the treatment of disease of the bone such as osteoporosis.
(17) An aspect of the present invention concerns the use as an inhibitor of FASN for the preparation of a medicament used in the treatment of disease of the cardiovascular system, such as atherosclerosis.
(18) An aspect of the present invention concerns the use as an inhibitor of FASN for the preparation of a medicament used in the treatment of disease or a condition caused by an elevated level of FASN.
(19) Such disease or condition is one or more selected from the group consisting of cancer, ovarian cancer, breast cancer, uterine cancer, colon cancer, cervical cancer, lung cancer, prostate cancer, skin cancer, bladder cancer, pancreatic cancer, leukemia, lymphoma, Hodgkin's disease, viral infections, Human Immunodeficiency Virus, hepatitis virus, herpes virus, herpes simplex, inflammatory disorders, irritable bowel syndrome, inflammatory bowel disease, rheumatoid arthritis, asthma, chronic obstructive pulmonary disease, osteoarthritis, osteoporosis, dermatitis, atoptic dermatitis, psoriasis, systemic lupus erythematosis, multiple sclerosis, psoriatic arthritis, ankylosing spondylitis, graft-versus-host disease, cerebrovascular accident, atherosclerosis, diabetes, glomerulonephiritis, metabolic syndrome, non-small cell lung cancer, small cell lung cancer, multiple myeloma, lymphomas, squamous cell cancers, kidney cancer, urethral and bladder cancers, cancers of head and neck, cancers of the brain and central nervous system (CNS).
(20) The inventive compounds of can be useful in the therapy of proliferative diseases such as cancer, autoimmune diseases, viral diseases, fungal diseases, neurological/neurodegenerative disorders, arthritis, inflammation, anti-proliferative (e.g., ocular retinopathy), neuronal, alopecia and cardiovascular disease. Many of these diseases and disorders are listed in U.S. Pat. No. 6,413,974, incorporated by reference herein.
(21) More specifically, the compounds can be useful in the treatment of a variety of cancers, including (but not limited to) the following: carcinoma, including that of the bladder, breast, colon, kidney, liver, lung, including small cell lung cancer, non-small cell lung cancer, head and neck, esophagus, gall bladder, ovary, pancreas, stomach, cervix, thyroid, prostate, and skin, including squamous cell carcinoma; hematopoietic tumors of lymphoid lineage, including leukemia, acute lymphocytic leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T-cell lymphoma, Hodgkins lymphoma, non-Hodgkins lymphoma, hairy cell lymphoma, mantle cell lymphoma, myeloma, and Burkett's lymphoma; hematopoietic tumors of myeloid lineage, including acute and chronic myelogenous leukemias, myelodysplastic syndrome and promyelocytic leukemia; tumors of mesenchymal origin, including fibrosarcoma and rhabdomyosarcoma; tumors of the central and peripheral nervous system, including astrocytoma, neuroblastoma, glioma and schwannomas; and other tumors, including melanoma, seminoma, teratocarcinoma, osteosarcoma, xenoderoma pigmentosum, keratoctanthoma, thyroid follicular cancer and Kaposi's sarcoma.
(22) The compounds of the invention may induce or inhibit apoptosis.
(23) The compounds of the invention may also be useful in the chemoprevention of cancer. Chemoprevention is defined as inhibiting the development of invasive cancer by either blocking the initiating mutagenic event or by blocking the progression of pre-malignant cells that have already suffered an insult or inhibiting tumor relapse.
(24) A further aspect of the invention is a method of inhibiting FASN in an animal, said method comprising administering to said animal a pharmaceutically acceptable amount of a compound of the invention to an animal in need thereof.
(25) A further aspect of the invention is a pharmaceutical formulation comprising a compound of the invention.
(26) Another embodiment of the invention comprises a pharmaceutical formulation of the invention, wherein the pharmaceutical formulation, upon administration to a human, results in a decrease in tumor burden.
(27) Still another embodiment of the invention is a pharmaceutical formulation, further comprising one or more of an antineoplastic agent, a chemotherapeutic agent, or an adjunctive chemotherapeutic agent.
(28) The pharmaceutical formulations of the invention may further comprise a therapeutic effective amount of an adjunctive chemotherapeutic agent.
(29) The adjunctive chemotherapeutic agent may be an agent which modifies blood cell growth and maturation. Non-limiting examples of adjunctive chemotherapeutic agent are filgrastim, pegfilgrastim and erythropoietin.
(30) The invention is also directed to a method of treating or preventing a disorder associated with excessive rate of growth of cells in a mammal comprising administering to the mammal an effective amount of the pharmaceutical formulation of the invention. Non-limiting examples of disorder include cancer or metastasis from malignant tumors.
(31) Another aspect of the invention is a method of inhibiting tumor cell growth and rate of division in a mammal with cancer, or other disorder associated with abnormally dividing cells comprising administering to the mammal an effective amount of the pharmaceutical formulation of this invention.
(32) Another embodiment of the invention is a method of treating bone pain due to excessive growth of a tumor or metastasis to bone in a mammal in need thereof comprising administering to the mammal an effective amount of the pharmaceutical formulation of this invention.
(33) Still another embodiment of the invention is a method for administering an FASN-inhibitor-containing compound to a mammal in need thereof comprising administering to the mammal the pharmaceutical formulation of the invention. In one embodiment, the mammal is a human.
(34) A further embodiment of the invention is a method of preparing a pharmaceutical formulation comprising mixing at least one pharmaceutically acceptable compound of the present invention, and, optionally, one or more pharmaceutically acceptable excipients or additives.
(35) The invention is also directed to methods of synthesizing compounds of the present invention.
Compounds of the Invention
(36) The present invention relates to particular molecules and pharmaceutically acceptable salts or isomers thereof. The invention further relates to molecules which are useful in inhibiting the enzyme fatty acid synthase (FASN) and pharmaceutically acceptable salts or isomers thereof.
(37) The invention is directed to compounds as described herein and pharmaceutically acceptable salts or isomers thereof, and pharmaceutical compositions comprising one or more compounds as described herein and pharmaceutically acceptable salts or isomers thereof. One aspect of this invention is the provision of compounds, compositions, and kits for FASN inhibition comprising a compound of formula I
(38) ##STR00036##
wherein R.sub.1 is a C.sub.1-C.sub.3 hydroxyl-alkyl either unsubstituted or substituted with —CH.sub.3 or —CH.sub.zF.sub.3-z, 5 membered cycloalkyl either unsubstituted or substituted with substituents selected from the group consisting of deuterium, —R.sub.p, —OR.sub.p, —NHR.sub.p, and —NR.sub.pR.sub.p1, or 3 or 4 membered cycloalkyl or heterocycloalkyl wherein (i) the heteroatom ring member of the 3 or 4 membered heterocycloalkyl is independently selected from O, S, or N, and (ii) each of said 3 or 4 membered cycloalkyl or heterocycloalkyl is either unsubstituted or optionally substituted with substituents selected from the group consisting of deuterium, —R.sub.a, —OR.sub.a, —NHR.sub.a, and —NR.sub.aR.sub.a1; L is a 5-10 membered monocyclic or bicyclic alkyl or heteroalkyl wherein (i) the heteroatom ring members of the 5-10 membered monocyclic or bicyclic heteroalkyl are independently selected from O, S, or N, and (ii) each of the 5-10 membered monocyclic or bicyclic alkyl or heteroalkyl is either unsubstituted or optionally substituted with substituents selected from the group consisting of deuterium and —R.sub.b; A and B are independently O or S; Ar.sub.1 is a 4-10 membered monocyclic or bicyclic aryl, heteroaryl or heterocycloalkyl, wherein (i) said 4-10 membered monocyclic or bicyclic heteroaryl or heterocycloalkyl have 1, 2, 3, or 4 heteroatoms which are independently selected from N, S or O, and (ii) each of said 4-10 membered monocyclic or bicyclic aryl, heteroaryl, or heterocycloalkyl is either unsubstituted or optionally independently substituted with 1 or more substituents which can be the same or different and are independently selected from the group consisting of deuterium, halo, alkyl, —CH.sub.zF.sub.3-z, cyano, hydroxyl, hydroxylalkyl, amino, aminoalkyl-, (amino)alkoxy-, —CONH.sub.2, —C(O)NH(alkyl), —C(O)N(alkyl).sub.2, —C(O)NH(aryl), —C(O)N(aryl).sub.2, —OCH.sub.zF.sub.3-z, -alkyl, -alkenyl, -alkynyl, -alkoxy or (alkoxyalkyl)amino-, —N(R.sub.c)—C(O)-alkyl, —N(Re)—C(O)-aryl, -cycloalkyl, -heterocycloalkyl, -aryl, and -heteroaryl, with the proviso that no two adjacent ring heteroatoms are both S or both O; R.sub.2 is H or a 4-15 membered monocyclic, bicyclic, or tricyclic aryl, heteroaryl, cycloalkyl, or heterocycloalkyl, (i) the 4-15 membered monocyclic, bicyclic, or tricyclic heteroaryl or heterocycloalkyl has 1, 2, 3, 4, 5, 6, 7, or 8 heteroatoms which are independently selected from N, S or O, and (ii) wherein each of said aryl, heteroaryl, cycloalkyl, and heterocycloalkyl is either unsubstituted or optionally substituted with 1 or more substituents which can be the same or different and are independently selected from the group consisting of deuterium, halo, cyano, hydroxyl, hydroxyl-alkyl-, hydroxylcycoalkyl-, hydroxyl-heterocycloalkyl-, hydroxyl-aryl-, hydroxyl-heteroaryl-, amino, aminoalkyl, (amino)alkoxy-, —CONH.sub.2, —C(O)NH(alkyl), —C(O)N(alkyl).sub.2, —C(O)NH(aryl), —C(O)N(aryl).sub.2, —CH.sub.zF.sub.3-z, —OCH.sub.zF.sub.3-z, -alkyl, alkoxy-, -alkenyl, -alkynyl, aryloxy-, (alkoxyalkyl)amino-, -cycloalkyl, -heterocycloalkyl, (heterocycloalkyl)alkyl-, -aryl, -heteroaryl, —O(alkyl), —O(cycloalkyl), —O(heterocycloalkyl), —O(aryl), —O(heteroaryl), ONH.sub.2, —C(O)NH(alkyl), —C(O)N(aryl).sub.2, —C(O)NH(cycloalkyl), —NH(CO)cycloalkyl, —NH(SO.sub.2), —NH(SO.sub.2)alkyl, —NH(SO.sub.2)aryl, —NH(SO.sub.2)heteroaryl, —N(SO.sub.2)cycolalkyl, —C(O)N(alkyl).sub.2, (aryl)alkyl-, -heteroaryl, (heteroaryl)alkyl-, —S(O).sub.2-alkyl, —S(O).sub.2-aryl, —S(O).sub.2-cycloalkyl, —C(O)N(alkyl).sub.2, —C(O)alkyl, —NH—C(O)-alkyl, —NH—C(O)-cycloalkyl, NH—C(O)-heterocycloalkyl, NH—C(O)-heterocycloalkyl-R.sub.d, —NH—C(O)—R.sub.d—(O)alkyl, —NH—C(O)-aryl, —NH—C(O)—NH-alkyl, NH—C(O)—NH-cycloalkyl, NH.sub.2(CO)cycloalkyl-, NH—C(O)—NH-aryl, —NH—C(O)—O-alkyl, NH—C(O)—NH-cycloalkyl, —NH—C(O)—O-cycloalkyl, —NH(R.sub.a)—C(O)-alkyl, —NH(R.sub.a)—C(O)-aryl, —NH(R.sub.a)—S(O.sub.2)cycloalkyl, —S(O.sub.2)NH.sub.2, —S(O.sub.2)NH(alkyl), —S(O.sub.2)N(R.sub.a)cycloalkyl, —S(O.sub.2)N(alkyl).sub.2, —C(O)N(H)(alkyl), —C(O)N(R.sub.d) (cycloalkyl), methylenedioxy, —CH.sub.zF.sub.3-z, —OCH.sub.zF.sub.3-z, and -alkoxy; R.sub.p and R.sub.p1 are independently H, halo, C.sub.1-C.sub.4 alkyl, or C.sub.3-C.sub.4 cycloalkyl; R.sub.a and R.sub.a1 are independently H, halo, C.sub.1-C.sub.4 alkyl, or C.sub.3-C.sub.4 cycloalkyl; R.sub.b is H, halo, C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.3 hydroxyl-alkyl, or C.sub.3-C.sub.4 cycloalkyl; R.sub.c is H, halo, C.sub.1-C.sub.4 alkyl, or C.sub.3-C.sub.4 cycloalkyl; R.sub.d is H, halo, C.sub.1-C.sub.4 alkyl, or C.sub.3-C.sub.4 cycloalkyl; and z is 0, 1 or 2;
and pharmaceutically acceptable salts, solvates, esters, prodrugs and isomers thereof.
(39) In another embodiment, the compound of Formula I is represented by the compound of Formula I-A:
(40) ##STR00037##
wherein: R.sub.1 is a C.sub.1-C.sub.3 hydroxyl-alkyl either unsubstituted or substituted with —CH.sub.3 or —CH.sub.zF.sub.3-z, 5 membered cycloalkyl either unsubstituted or substituted with substituents selected from the group consisting of deuterium, —R.sub.p, —OR.sub.p, —NHR.sub.p, and —NR.sub.pR.sub.p1, or 3 or 4 membered cycloalkyl or heterocycloalkyl wherein (i) the heteroatom ring member of the 3 or 4 membered heterocycloalkyl is independently selected from O, S, or N, and (ii) each of said 3 or 4 membered cycloalkyl or heterocycloalkyl is either unsubstituted or optionally substituted with substituents selected from the group consisting of deuterium, —R.sub.a, —OR.sub.a, —NHR.sub.a, and —NR.sub.aR.sub.a1; Ar.sub.1 is a 4-10 membered monocyclic or bicyclic aryl, heteroaryl or heterocycloalkyl, wherein (i) said 4-10 membered monocyclic or bicyclic heteroaryl or heterocycloalkyl have 1, 2, 3, or 4 heteroatoms which are independently selected from N, S or O, and (ii) each of said 4-10 membered monocyclic or bicyclic aryl, heteroaryl, or heterocycloalkyl is either unsubstituted or optionally independently substituted with 1 or more substituents which can be the same or different and are independently selected from the group consisting of deuterium, halo, alkyl, —CH.sub.zF.sub.3-z, cyano, hydroxyl, hydroxylalkyl, amino, aminoalkyl-, (amino)alkoxy-, —CONH.sub.2, —C(O)NH(alkyl), —C(O)N(alkyl).sub.2, —C(O)NH(aryl), —C(O)N(aryl).sub.2, —OCH.sub.zF.sub.3-z, -alkyl, -alkenyl, -alkynyl, -alkoxy or (alkoxyalkyl)amino-, —N(R.sub.c)—C(O)-alkyl, —N(Re)—C(O)-aryl, -cycloalkyl, -heterocycloalkyl, -aryl, and -heteroaryl, with the proviso that no two adjacent ring heteroatoms are both S or both O; R.sub.2 is H or a 4-15 membered monocyclic, bicyclic, or tricyclic aryl, heteroaryl, cycloalkyl, or heterocycloalkyl, (i) the 4-15 membered monocyclic, bicyclic, or tricyclic heteroaryl or heterocycloalkyl has 1, 2, 3, 4, 5, 6, 7, or 8 heteroatoms which are independently selected from N, S or O, and (ii) wherein each of said aryl, heteroaryl, cycloalkyl, and heterocycloalkyl is either unsubstituted or optionally substituted with 1 or more substituents which can be the same or different and are independently selected from the group consisting of deuterium, halo, cyano, hydroxyl, hydroxyl-alkyl-, hydroxylcycoalkyl-, hydroxyl-heterocycloalkyl-, hydroxyl-aryl-, hydroxyl-heteroaryl-, amino, aminoalkyl, (amino)alkoxy-, —CONH.sub.2, —C(O)NH(alkyl), —C(O)N(alkyl).sub.2, —C(O)NH(aryl), —C(O)N(aryl).sub.2, —CH.sub.zF.sub.3-z, —OCH.sub.zF.sub.3-z, -alkyl, alkoxy-, -alkenyl, -alkynyl, aryloxy-, (alkoxyalkyl)amino-, -cycloalkyl, -heterocycloalkyl, (heterocycloalkyl)alkyl-, -aryl, -heteroaryl, —O(alkyl), —O(cycloalkyl), —O(heterocycloalkyl), —O(aryl), —O(heteroaryl), ONH.sub.2, —C(O)NH(alkyl), —C(O)N(aryl).sub.2, —C(O)NH(cycloalkyl), —NH(CO)cycloalkyl, —NH(SO.sub.2), —NH(SO.sub.2)alkyl, —NH(SO.sub.2)aryl, —NH(SO.sub.2)heteroaryl, —N(SO.sub.2)cycolalkyl, —C(O)N(alkyl).sub.2, (aryl)alkyl-, -heteroaryl, (heteroaryl)alkyl-, —S(O).sub.2-alkyl, —S(O).sub.2-aryl, —S(O).sub.2-cycloalkyl, —C(O)N(alkyl).sub.2, —C(O)alkyl, —NH—C(O)-alkyl, —NH—C(O)-cycloalkyl, NH—C(O)-heterocycloalkyl, NH—C(O)-heterocycloalkyl-R.sub.d, —NH—C(O)—R.sub.d—(O)alkyl, —NH—C(O)-aryl, —NH—C(O)—NH-alkyl, NH—C(O)—NH-cycloalkyl, NH.sub.2(CO)cycloalkyl-, NH—C(O)—NH-aryl, —NH—C(O)—O-alkyl, NH—C(O)—NH-cycloalkyl, —NH—C(O)—O-cycloalkyl, —NH(R.sub.a)—C(O)-alkyl, —NH(R.sub.a)—C(O)-aryl, —NH(R.sub.a)—S(O.sub.2)cycloalkyl, —S(O.sub.2)NH.sub.2, —S(O.sub.2)NH(alkyl), —S(O.sub.2)N(R.sub.a)cycloalkyl, —S(O.sub.2)N(alkyl).sub.2, —C(O)N(H)(alkyl), —C(O)N(R.sub.d) (cycloalkyl), methylenedioxy, —CH.sub.zF.sub.3-z, —OCH.sub.zF.sub.3-z, and -alkoxy; R.sub.p and R.sub.p1 are independently H, halo, C.sub.1-C.sub.4 alkyl, or C.sub.3-C.sub.4 cycloalkyl; R.sub.a and R.sub.a1 are independently H, halo, C.sub.1-C.sub.4 alkyl, or C.sub.3-C.sub.4 cycloalkyl; R.sub.c is H, halo, C.sub.1-C.sub.4 alkyl, or C.sub.3-C.sub.4 cycloalkyl; R.sub.d is H, halo, C.sub.1-C.sub.4 alkyl, or C.sub.3-C.sub.4 cycloalkyl; and z is 0, 1 or 2;
and pharmaceutically acceptable salts, solvates, esters, prodrugs and isomers thereof.
(41) In another embodiment, the compound of Formula I is represented by the compound of Formula I-B:
(42) ##STR00038##
Wherein: Ar.sub.1 is a 4-10 membered monocyclic or bicyclic aryl, heteroaryl or heterocycloalkyl, wherein (i) said 4-10 membered monocyclic or bicyclic heteroaryl or heterocycloalkyl have 1, 2, 3, or 4 heteroatoms which are independently selected from N, S or O, and (ii) each of said 4-10 membered monocyclic or bicyclic aryl, heteroaryl, or heterocycloalkyl is either unsubstituted or optionally independently substituted with 1 or more substituents which can be the same or different and are independently selected from the group consisting of deuterium, halo, alkyl, —CH.sub.zF.sub.3-z, cyano, hydroxyl, hydroxylalkyl, amino, aminoalkyl-, (amino)alkoxy-, —CONH.sub.2, —C(O)NH(alkyl), —C(O)N(alkyl).sub.2, —C(O)NH(aryl), —C(O)N(aryl).sub.2, —OCH.sub.zF.sub.3-z, -alkyl, -alkenyl, -alkynyl, -alkoxy or (alkoxyalkyl)amino-, —N(R.sub.c)—C(O)-alkyl, —N(Re)—C(O)-aryl, -cycloalkyl, -heterocycloalkyl, -aryl, and -heteroaryl, with the proviso that no two adjacent ring heteroatoms are both S or both O; R.sub.2 is H or a 4-15 membered monocyclic, bicyclic, or tricyclic aryl, heteroaryl, cycloalkyl, or heterocycloalkyl, (i) the 4-15 membered monocyclic, bicyclic, or tricyclic heteroaryl or heterocycloalkyl has 1, 2, 3, 4, 5, 6, 7, or 8 heteroatoms which are independently selected from N, S or O, and (ii) wherein each of said aryl, heteroaryl, cycloalkyl, and heterocycloalkyl is either unsubstituted or optionally substituted with 1 or more substituents which can be the same or different and are independently selected from the group consisting of deuterium, halo, cyano, hydroxyl, hydroxyl-alkyl-, hydroxylcycoalkyl-, hydroxyl-heterocycloalkyl-, hydroxyl-aryl-, hydroxyl-heteroaryl-, amino, aminoalkyl, (amino)alkoxy-, —CONH.sub.2, —C(O)NH(alkyl), —C(O)N(alkyl).sub.2, —C(O)NH(aryl), —C(O)N(aryl).sub.2, —CH.sub.zF.sub.3-z, —OCH.sub.zF.sub.3-z, -alkyl, alkoxy-, -alkenyl, -alkynyl, aryloxy-, (alkoxyalkyl)amino-, -cycloalkyl, -heterocycloalkyl, (heterocycloalkyl)alkyl-, -aryl, -heteroaryl, —O(alkyl), —O(cycloalkyl), —O(heterocycloalkyl), —O(aryl), —O(heteroaryl), ONH.sub.2, —C(O)NH(alkyl), —C(O)N(aryl).sub.2, —C(O)NH(cycloalkyl), —NH(CO)cycloalkyl, —NH(SO.sub.2), —NH(SO.sub.2)alkyl, —NH(SO.sub.2)aryl, —NH(SO.sub.2)heteroaryl, —N(SO.sub.2)cycolalkyl, —C(O)N(alkyl).sub.2, (aryl)alkyl-, -heteroaryl, (heteroaryl)alkyl-, —S(O).sub.2-alkyl, —S(O).sub.2-aryl, —S(O).sub.2-cycloalkyl, —C(O)N(alkyl).sub.2, —C(O)alkyl, —NH—C(O)-alkyl, —NH—C(O)-cycloalkyl, NH—C(O)-heterocycloalkyl, NH—C(O)-heterocycloalkyl-R.sub.d, —NH—C(O)—R.sub.d—(O)alkyl, —NH—C(O)-aryl, —NH—C(O)—NH-alkyl, NH—C(O)—NH-cycloalkyl, NH.sub.2(CO)cycloalkyl-, NH—C(O)—NH-aryl, —NH—C(O)—O-alkyl, NH—C(O)—NH-cycloalkyl, —NH—C(O)—O-cycloalkyl, —NH(R.sub.a)—C(O)-alkyl, —NH(R.sub.a)—C(O)-aryl, —NH(R.sub.a)—S(O.sub.2)cycloalkyl, —S(O.sub.2)NH.sub.2, —S(O.sub.2)NH(alkyl), —S(O.sub.2)N(R.sub.a)cycloalkyl, —S(O.sub.2)N(alkyl).sub.2, —C(O)N(H)(alkyl), —C(O)N(R.sub.d) (cycloalkyl), methylenedioxy, —CH.sub.zF.sub.3-z, —OCH.sub.zF.sub.3-z, and -alkoxy; R.sub.c is H, halo, C.sub.1-C.sub.4 alkyl, or C.sub.3-C.sub.4 cycloalkyl; R.sub.d is H, halo, C.sub.1-C.sub.4 alkyl, or C.sub.3-C.sub.4 cycloalkyl; and z is 0, 1 or 2;
and pharmaceutically acceptable salts, solvates, esters, prodrugs and isomers thereof.
(43) In another embodiment, the compound of Formula I is represented by the compound of Formula I-C:
(44) ##STR00039##
wherein: R.sub.1 is a C.sub.1-C.sub.3 hydroxyl-alkyl either unsubstituted or substituted with —CH.sub.3 or —CH.sub.zF.sub.3-z, 5 membered cycloalkyl either unsubstituted or substituted with substituents selected from the group consisting of deuterium, —R.sub.p, —OR.sub.p, —NHR.sub.p, and —NR.sub.pR.sub.p1, or 3 or 4 membered cycloalkyl or heterocycloalkyl wherein (i) the heteroatom ring member of the 3 or 4 membered heterocycloalkyl is independently selected from O, S, or N, and (ii) each of said 3 or 4 membered cycloalkyl or heterocycloalkyl is either unsubstituted or optionally substituted with substituents selected from the group consisting of deuterium, —R.sub.a, —OR.sub.a, —NHR.sub.a, and —NR.sub.aR.sub.a1; R.sub.2 is H or a 4-15 membered monocyclic, bicyclic, or tricyclic aryl, heteroaryl, cycloalkyl, or heterocycloalkyl, (i) the 4-15 membered monocyclic, bicyclic, or tricyclic heteroaryl or heterocycloalkyl has 1, 2, 3, 4, 5, 6, 7, or 8 heteroatoms which are independently selected from N, S or O, and (ii) wherein each of said aryl, heteroaryl, cycloalkyl, and heterocycloalkyl is either unsubstituted or optionally substituted with 1 or more substituents which can be the same or different and are independently selected from the group consisting of deuterium, halo, cyano, hydroxyl, hydroxyl-alkyl-, hydroxylcycoalkyl-, hydroxyl-heterocycloalkyl-, hydroxyl-aryl-, hydroxyl-heteroaryl-, amino, aminoalkyl, (amino)alkoxy-, —CONH.sub.2, —C(O)NH(alkyl), —C(O)N(alkyl).sub.2, —C(O)NH(aryl), —C(O)N(aryl).sub.2, —CH.sub.zF.sub.3-z, —OCH.sub.zF.sub.3-z, -alkyl, alkoxy-, -alkenyl, -alkynyl, aryloxy-, (alkoxyalkyl)amino-, -cycloalkyl, -heterocycloalkyl, (heterocycloalkyl)alkyl-, -aryl, -heteroaryl, —O(alkyl), —O(cycloalkyl), —O(heterocycloalkyl), —O(aryl), —O(heteroaryl), ONH.sub.2, —C(O)NH(alkyl), —C(O)N(aryl).sub.2, —C(O)NH(cycloalkyl), —NH(CO)cycloalkyl, —NH(SO.sub.2), —NH(SO.sub.2)alkyl, —NH(SO.sub.2)aryl, —NH(SO.sub.2)heteroaryl, —N(SO.sub.2)cycolalkyl, —C(O)N(alkyl).sub.2, (aryl)alkyl-, -heteroaryl, (heteroaryl)alkyl-, —S(O).sub.2-alkyl, —S(O).sub.2-aryl, —S(O).sub.2-cycloalkyl, —C(O)N(alkyl).sub.2, —C(O)alkyl, —NH—C(O)-alkyl, —NH—C(O)-cycloalkyl, NH—C(O)-heterocycloalkyl, NH—C(O)-heterocycloalkyl-R.sub.d, —NH—C(O)—R.sub.d—(O)alkyl, —NH—C(O)-aryl, —NH—C(O)—NH-alkyl, NH—C(O)—NH-cycloalkyl, NH.sub.2(CO)cycloalkyl-, NH—C(O)—NH-aryl, —NH—C(O)—O-alkyl, NH—C(O)—NH-cycloalkyl, —NH—C(O)—O-cycloalkyl, —NH(R.sub.a)—C(O)-alkyl, —NH(R.sub.a)—C(O)-aryl, —NH(R.sub.a)—S(O.sub.2)cycloalkyl, —S(O.sub.2)NH.sub.2, —S(O.sub.2)NH(alkyl), —S(O.sub.2)N(R.sub.a)cycloalkyl, —S(O.sub.2)N(alkyl).sub.2, —C(O)N(H)(alkyl), —C(O)N(R.sub.d) (cycloalkyl), methylenedioxy, —CH.sub.zF.sub.3-z, —OCH.sub.zF.sub.3-z, and -alkoxy; R.sub.p and R.sub.p1 are independently H, halo, C.sub.1-C.sub.4 alkyl, or C.sub.3-C.sub.4 cycloalkyl; R.sub.a and R.sub.a1 are independently H, halo, C.sub.1-C.sub.4 alkyl, or C.sub.3-C.sub.4 cycloalkyl; R.sub.d is H, halo, C.sub.1-C.sub.4 alkyl, or C.sub.3-C.sub.4 cycloalkyl; R.sub.q is H, halo, C.sub.1-C.sub.4 alkyl, or C.sub.3-C.sub.4 cycloalkyl; and z is 0, 1 or 2;
and pharmaceutically acceptable salts, solvates, esters, prodrugs and isomers thereof.
(45) In another embodiment, the compound of Formula I is represented by the compound of Formula I-D:
(46) ##STR00040##
wherein: R.sub.1′ is OH or NH.sub.2; R.sub.2 is H or a 4-15 membered monocyclic, bicyclic, or tricyclic aryl, heteroaryl, cycloalkyl, or heterocycloalkyl, (i) the 4-15 membered monocyclic, bicyclic, or tricyclic heteroaryl or heterocycloalkyl has 1, 2, 3, 4, 5, 6, 7, or 8 heteroatoms which are independently selected from N, S or O, and (ii) wherein each of said aryl, heteroaryl, cycloalkyl, and heterocycloalkyl is either unsubstituted or optionally substituted with 1 or more substituents which can be the same or different and are independently selected from the group consisting of deuterium, halo, cyano, hydroxyl, hydroxyl-alkyl-, hydroxylcycoalkyl-, hydroxyl-heterocycloalkyl-, hydroxyl-aryl-, hydroxyl-heteroaryl-, amino, aminoalkyl, (amino)alkoxy-, —CONH.sub.2, —C(O)NH(alkyl), —C(O)N(alkyl).sub.2, —C(O)NH(aryl), —C(O)N(aryl).sub.2, —CH.sub.zF.sub.3-z, —OCH.sub.zF.sub.3-z, -alkyl, alkoxy-, -alkenyl, -alkynyl, aryloxy-, (alkoxyalkyl)amino-, -cycloalkyl, -heterocycloalkyl, (heterocycloalkyl)alkyl-, -aryl, -heteroaryl, —O(alkyl), —O(cycloalkyl), —O(heterocycloalkyl), —O(aryl), —O(heteroaryl), ONH.sub.2, —C(O)NH(alkyl), —C(O)N(aryl).sub.2, —C(O)NH(cycloalkyl), —NH(CO)cycloalkyl, —NH(SO.sub.2), —NH(SO.sub.2)alkyl, —NH(SO.sub.2)aryl, —NH(SO.sub.2)heteroaryl, —N(SO.sub.2)cycolalkyl, —C(O)N(alkyl).sub.2, (aryl)alkyl-, -heteroaryl, (heteroaryl)alkyl-, —S(O).sub.2-alkyl, —S(O).sub.2-aryl, —S(O).sub.2-cycloalkyl, —C(O)N(alkyl).sub.2, —C(O)alkyl, —NH—C(O)-alkyl, —NH—C(O)-cycloalkyl, NH—C(O)-heterocycloalkyl, NH—C(O)-heterocycloalkyl-R.sub.d, —NH—C(O)—R.sub.d—(O)alkyl, —NH—C(O)-aryl, —NH—C(O)—NH-alkyl, NH—C(O)—NH-cycloalkyl, NH.sub.2(CO)cycloalkyl-, NH—C(O)—NH-aryl, —NH—C(O)—O-alkyl, NH—C(O)—NH-cycloalkyl, —NH—C(O)—O-cycloalkyl, —NH(R.sub.a)—C(O)-alkyl, —NH(R.sub.a)—C(O)-aryl, —NH(R.sub.a)—S(O.sub.2)cycloalkyl, —S(O.sub.2)NH.sub.2, —S(O.sub.2)NH(alkyl), —S(O.sub.2)N(R.sub.a)cycloalkyl, —S(O.sub.2)N(alkyl).sub.2, —C(O)N(H)(alkyl), —C(O)N(R.sub.d) (cycloalkyl), methylenedioxy, —CH.sub.zF.sub.3-z, —OCH.sub.zF.sub.3-z, and -alkoxy; R.sub.d is H, halo, C.sub.1-C.sub.4 alkyl, or C.sub.3-C.sub.4 cycloalkyl; and z is 0, 1 or 2;
and pharmaceutically acceptable salts, solvates, esters, prodrugs and isomers thereof.
(47) In the compounds of Formulas I, I-A, I-B, I-C and I-D, the various moieties are independently selected.
(48) The following embodiments are directed to Formulas I, I-A, I-B, I-C and I-D, as applicable. For any moieties that are not specifically defined, the previous definitions control. Further, the moieties aryl, heteroaryl, and heterocycloalkyl in these embodiments can be independently unsubstituted or optionally substituted or optionally fused as described earlier.
(49) An embodiment of the invention is the provision of a compound, where the various moieties are independently selected, R.sub.1 is C.sub.1-C.sub.3 hydroxyl-alkyl either unsubstituted or substituted with —CH.sub.3 or —CH.sub.zF.sub.3-z, and A, B, L, Ar.sub.1, R.sub.2, R.sub.p, R.sub.p1, R.sub.a, R.sub.a1, R.sub.b, R.sub.c, R.sub.d, R.sub.q and z are as defined.
(50) An embodiment of the invention is the provision of a compound, where the various moieties are independently selected, R.sub.1 is a 5 membered cycloalkyl either unsubstituted or substituted with hydroxyl, and A, B, L, Ar.sub.1, R.sub.2, R.sub.p, R.sub.p1, R.sub.a, R.sub.a1, R.sub.b, R.sub.c, R.sub.d, R.sub.q and z are as defined.
(51) An embodiment of the invention is the provision of a compound, where the various moieties are independently selected, R.sub.1 is a 3 or 4 membered cycloalkyl, and A, B, L, Ar.sub.1, R.sub.2, R.sub.p, R.sub.p1, R.sub.a, R.sub.a1, R.sub.b, R.sub.c, R.sub.d, R.sub.q and z are as defined.
(52) An embodiment of the invention is the provision of a compound, where the various moieties are independently selected, R.sub.1 is a 3 or 4 membered heterocycloalkyl, and A, B, L, Ar.sub.1, R.sub.2, R.sub.p, R.sub.p1, R.sub.a, R.sub.a1, R.sub.b, R.sub.c, R.sub.d, R.sub.q and z are as defined.
(53) An embodiment of the invention is the provision of a compound, where the various moieties are independently selected, R.sub.1 is
(54) ##STR00041##
(55) and A, B, L, Ar.sub.1, R.sub.2, R.sub.p, R.sub.p1, R.sub.a, R.sub.a1, R.sub.b, R.sub.c, R.sub.d, R.sub.q and z are as defined.
(56) An embodiment of the invention is the provision of a compound, where the various moieties are independently selected, R.sub.1 is
(57) ##STR00042##
(58) and A, B, L, Ar.sub.1, R.sub.2, R.sub.p, R.sub.p1, R.sub.a, R.sub.a1, R.sub.b, R.sub.c, R.sub.d, R.sub.q and z are as defined.
(59) An embodiment of the invention is the provision of a compound, where the various moieties are independently selected, R.sub.1 is
(60) ##STR00043##
and A, B, L, Ar.sub.1, R.sub.2, R.sub.p, R.sub.p1, R.sub.a, R.sub.a1, R.sub.b, R.sub.c, R.sub.d, R.sub.q and z are as defined.
(61) An embodiment of the invention is the provision of a compound, where the various moieties are independently selected, R.sub.1 is
(62) ##STR00044##
and A, B, L, Ar.sub.1, R.sub.2, R.sub.p, R.sub.p1, R.sub.a, R.sub.a1, R.sub.b, R.sub.c, R.sub.d, R.sub.q and z are as defined.
(63) An embodiment of the invention is the provision of a compound, where the various moieties are independently selected, A and B are O, and R.sub.1, L, Ar.sub.1, R.sub.2, R.sub.p, R.sub.p1, R.sub.a, R.sub.a1, R.sub.b, R.sub.c, R.sub.d, R.sub.q and z are as defined.
(64) An embodiment of the invention is the provision of a compound, where the various moieties are independently selected, A and B are S, and R.sub.1, L, Ar.sub.1, R.sub.2, R.sub.p, R.sub.p1, R.sub.a, R.sub.a1, R.sub.b, R.sub.c, R.sub.d, R.sub.q and z are as defined.
(65) An embodiment of the invention is the provision of a compound, where the various moieties are independently selected, either A or B is O, the other is S, and R.sub.1, L, Ar.sub.1, R.sub.2, R.sub.p, R.sub.p1, R.sub.a, R.sub.a1, R.sub.b, R.sub.c, R.sub.d, R.sub.q and z are as defined.
(66) An embodiment of the invention is the provision of a compound, where the various moieties are independently selected, L is a 5-10 membered monocyclic alkyl, and A, B, R.sub.1, Ar.sub.1, R.sub.2, R.sub.p, R.sub.p1, R.sub.a, R.sub.a1, R.sub.b, R.sub.c, R.sub.d, R.sub.q and z are as defined.
(67) An embodiment of the invention is the provision of a compound, where the various moieties are independently selected, L is a 5-10 membered bicyclic alkyl, and A, B, R.sub.1, Ar.sub.1, R.sub.2, R.sub.p, R.sub.p1, R.sub.a, R.sub.a1, R.sub.b, R.sub.c, R.sub.d, R.sub.q and z are as defined.
(68) An embodiment of the invention is the provision of a compound, where the various moieties are independently selected, L is a 5-10 membered monocyclic heteroalkyl, and A, B, R.sub.1, Ar.sub.1, R.sub.2, R.sub.p, R.sub.p1, R.sub.a, R.sub.a1, R.sub.b, R.sub.c, R.sub.d, R.sub.q and z are as defined.
(69) An embodiment of the invention is the provision of a compound, where the various moieties are independently selected, L is a 5-10 membered bicyclic hetroalkyl, and A, B, R.sub.1, Ar.sub.1, R.sub.2, R.sub.p, R.sub.p1, R.sub.a, R.sub.a1, R.sub.b, R.sub.c, R.sub.d, R.sub.q and z are as defined.
(70) An embodiment of the invention is the provision of a compound, where the various moieties are independently selected, L is
(71) ##STR00045##
m is 1, 2, or 3, n is 0, 1, 2, or 3, and A, B, R.sub.1, Ar.sub.1, R.sub.2, R.sub.p, R.sub.p1, R.sub.a, R.sub.a1, R.sub.b, R.sub.c, R.sub.d, R.sub.q and z are as defined.
(72) An embodiment of the invention is the provision of a compound, where the various moieties are independently selected, L is
(73) ##STR00046##
and A, B, R.sub.1, Ar.sub.1, R.sub.2, R.sub.p, R.sub.p1, R.sub.a, R.sub.a1, R.sub.b, R.sub.c, R.sub.d, R.sub.q and z are as defined.
(74) An embodiment of the invention is the provision of a compound, where the various moieties are independently selected, L is
(75) ##STR00047##
and A, B, R.sub.1, Ar.sub.1, R.sub.2, R.sub.p, R.sub.p1, R.sub.a, R.sub.a1, R.sub.b, R.sub.c, R.sub.d, R.sub.q and z are as defined.
(76) An embodiment of the invention is the provision of a compound, where the various moieties are independently selected, Ar.sub.1 is an aryl, and A, B, R.sub.1, L, R.sub.2, R.sub.p, R.sub.p1, R.sub.a, R.sub.a1, R.sub.b, R.sub.c, R.sub.d, R.sub.q and z are as defined.
(77) An embodiment of the invention is the provision of a compound, where the various moieties are independently selected, Ar.sub.1 is a heteroaryl, and A, B, R.sub.1, L, R.sub.2, R.sub.p, R.sub.p1, R.sub.a, R.sub.a1, R.sub.b, R.sub.c, R.sub.d, R.sub.q and z are as defined.
(78) An embodiment of the invention is the provision of a compound, where the various moieties are independently selected, Ar.sub.1 is a 5-10 membered monocyclic aryl, and A, B, R.sub.1, L, R.sub.2, R.sub.p, R.sub.p1, R.sub.a, R.sub.a1, R.sub.b, R.sub.c, R.sub.d, R.sub.q and z are as defined.
(79) An embodiment of the invention is the provision of a compound, where the various moieties are independently selected, Ar.sub.1 is a 5-10 membered bicyclic aryl, and A, B, R.sub.1, L, R.sub.2, R.sub.p, R.sub.p1, R.sub.a, R.sub.a1, R.sub.b, R.sub.c, R.sub.d, R.sub.q and z are as defined.
(80) An embodiment of the invention is the provision of a compound, where the various moieties are independently selected, Ar.sub.1 is a 5-10 membered monocyclic heteroaryl, and A, B, R.sub.1, L, R.sub.2, R.sub.p, R.sub.p1, R.sub.a, R.sub.a1, R.sub.b, R.sub.c, R.sub.d, R.sub.q and z are as defined.
(81) An embodiment of the invention is the provision of a compound, where the various moieties are independently selected, Ar.sub.1 is a 5-10 membered bicyclic heteroaryl, and A, B, R.sub.1, L, R.sub.2, R.sub.p, R.sub.p1, R.sub.a, R.sub.a1, R.sub.b, R.sub.c, R.sub.d, R.sub.q and z are as defined.
(82) An embodiment of the invention is the provision of a compound, where the various moieties are independently selected, Ar.sub.1 is a substituted or unsubstituted 5 membered monocyclic aryl or heteroaryl and said heteroaryl has 1 or 2 heteroatoms which are independently S or N, and A, B, R.sub.1, L, R.sub.2, R.sub.p, R.sub.p1, R.sub.a, R.sub.a1, R.sub.b, R.sub.c, R.sub.d, R.sub.q and z are as defined.
(83) An embodiment of the invention is the provision of a compound, where the various moieties are independently selected, Ar.sub.1 is a substituted or unsubstituted form of
(84) ##STR00048##
and A, B, R.sub.1, L, R.sub.2, R.sub.p, R.sub.p1, R.sub.a, R.sub.a1, R.sub.b, R.sub.c, R.sub.d, R.sub.q and z are as defined.
(85) An embodiment of the invention is the provision of a compound, where the various moieties are independently selected, Ar.sub.1 is a substituted or unsubstituted 6 membered monocyclic aryl or heteroaryl and said heteroaryl has 1 or 2 heteroatoms which are N, and A, B, R.sub.1, L, R.sub.2, R.sub.p, R.sub.p1, R.sub.a, R.sub.a1, R.sub.b, R.sub.c, R.sub.d, R.sub.q and z are as defined.
(86) An embodiment of the invention is the provision of a compound, where the various moieties are independently selected, Ar.sub.1 is a substituted or unsubstituted form of
(87) ##STR00049##
Ph.sub.1 is phenyl, pyridinyl, pyrazinyl, or pyrimidinyl, R.sub.c is H, halo, or C.sub.1-C.sub.3 alkyl, and A, B, R.sub.1, L, R.sub.2, R.sub.p, R.sub.p1, R.sub.a, R.sub.a1, R.sub.b, R.sub.c, R.sub.d, R.sub.q and z are as defined.
(88) An embodiment of the invention is the provision of a compound, where the various moieties are independently selected, Ar.sub.1 is a substituted or unsubstituted form of
(89) ##STR00050##
and A, B, R.sub.1, L, R.sub.2, R.sub.p, R.sub.p1, R.sub.a, R.sub.a1, R.sub.b, R.sub.c, R.sub.d, R.sub.q and z are as defined.
(90) An embodiment of the invention is the provision of a compound, where the various moieties are independently selected, Ar.sub.1 is a substituted or unsubstituted 6 membered monocyclic aryl, and A, B, R.sub.1, L, R.sub.2, R.sub.p, R.sub.p1, R.sub.a, R.sub.a1, R.sub.b, R.sub.c, R.sub.d, R.sub.q and z are as defined.
(91) An embodiment of the invention is the provision of a compound, where the various moieties are independently selected, Ar.sub.1 is
(92) ##STR00051##
R.sub.e is H, halo, or C.sub.1-C.sub.3 alkyl, and A, B, R.sub.1, L, R.sub.2, R.sub.p, R.sub.p1, R.sub.a, R.sub.a1, R.sub.b, R.sub.c, R.sub.d, R.sub.q and z are as defined.
(93) An embodiment of the invention is the provision of a compound, where the various moieties are independently selected, Ar.sub.1 is
(94) ##STR00052##
and A, B, R.sub.1, L, R.sub.2, R.sub.p, R.sub.p1, R.sub.a, R.sub.a1, R.sub.b, R.sub.c, R.sub.d, R.sub.q and z are as defined.
(95) An embodiment of the invention is the provision of a compound, where the various moieties are independently selected, Ar.sub.1 is a substituted or unsubstituted 9 membered 6,5-bicyclic heteroaryl and and said heteroaryl has 1, 2, or 3 heteroatoms which are independently O, S or N, and A, B, R.sub.1, L, R.sub.2, R.sub.p, R.sub.p1, R.sub.a, R.sub.a1, R.sub.b, R.sub.c, R.sub.d, R.sub.q and z are as defined.
(96) An embodiment of the invention is the provision of a compound, where the various moieties are independently selected, Ar.sub.1 is a substituted or unsubstituted form of
(97) ##STR00053##
and said heteroaryl has 1, 2, or 3 heteroatoms which are independently S or N, and A, B, R.sub.1, L, R.sub.2, R.sub.p, R.sub.p1, R.sub.a, R.sub.a1, R.sub.b, R.sub.c, R.sub.d, R.sub.q and z are as defined.
(98) An embodiment of the invention is the provision of a compound, where the various moieties are independently selected, R.sub.2 is a substituted or unsubstituted aryl, and A, B, R.sub.1, L, Ar.sub.1, R.sub.p, R.sub.p1, R.sub.a, R.sub.a1, R.sub.b, R.sub.c, R.sub.d, R.sub.q and z are as defined.
(99) An embodiment of the invention is the provision of a compound, where the various moieties are independently selected, R.sub.2 is a substituted or unsubstituted heteroaryl, and A, B, R.sub.1, L, Ar.sub.1, R.sub.p, R.sub.p1, R.sub.a, R.sub.a1, R.sub.b, R.sub.c, R.sub.d, R.sub.q and z are as defined.
(100) An embodiment of the invention is the provision of a compound, where the various moieties are independently selected, R.sub.2 is a substituted or unsubstituted cycloalkyl, and A, B, R.sub.1, L, Ar.sub.1, R.sub.p, R.sub.p1, R.sub.a, R.sub.a1, R.sub.b, R.sub.c, R.sub.d, R.sub.q and z are as defined.
(101) An embodiment of the invention is the provision of a compound, where the various moieties are independently selected, R.sub.2 is a substituted or unsubstituted heterocycloalkyl, and A, B, R.sub.1, L, Ar.sub.1, R.sub.p, R.sub.p1, R.sub.a, R.sub.a1, R.sub.b, R.sub.c, R.sub.d, R.sub.q and z are as defined.
(102) An embodiment of the invention is the provision of a compound, where the various moieties are independently selected, R.sub.2 is a substituted or unsubstituted monocyclic or bicyclic 5-10 membered aryl or heteroaryl, and A, B, R.sub.1, L, Ar.sub.1, R.sub.p, R.sub.p1, R.sub.a, R.sub.a1, R.sub.b, R.sub.c, R.sub.d, R.sub.q and z are as defined.
(103) An embodiment of the invention is the provision of a compound, where the various moieties are independently selected, R.sub.2 is a unsubstituted or substituted monocyclic 6 membered aryl, and A, B, R.sub.1, L, Ar.sub.1, R.sub.p, R.sub.p1, R.sub.a, R.sub.a1, R.sub.b, R.sub.c, R.sub.d, R.sub.q and z are as defined.
(104) An embodiment of the invention is the provision of a compound, where the various moieties are independently selected, R.sub.2 is
(105) ##STR00054## ##STR00055## ##STR00056##
R.sub.1, L, Ar.sub.1, R.sub.p, R.sub.p1, R.sub.a, R.sub.a1, R.sub.b, R.sub.c, R.sub.d, R.sub.q and z are as defined.
(106) An embodiment of the invention is the provision of a compound, where the various moieties are independently selected, R.sub.2 is a substituted or unsubstituted bicyclic 8-10 membered aryl or 8-10 membered heteroaryl, and A, B, R.sub.1, L, Ar.sub.1, R.sub.p, R.sub.p1, R.sub.a, R.sub.a1, R.sub.b, R.sub.c, R.sub.d, R.sub.q and z are as defined.
(107) An embodiment of the invention is the provision of a compound, where the various moieties are independently selected, R.sub.2 is a substituted or unsubstituted 8 membered 5,5 bicyclic heteroaryl and said heteroaryl has 1, 2, 3, or 4 heteroatoms and said heteroatoms are independently O, S, or N, and A, B, R.sub.1, L, Ar.sub.1, R.sub.p, R.sub.p1, R.sub.a, R.sub.a1, R.sub.b, R.sub.c, R.sub.d, R.sub.q and z are as defined.
(108) An embodiment of the invention is the provision of a compound, where the various moieties are independently selected, R.sub.2 is a substituted or unsubstituted form of
(109) ##STR00057##
and A, B, R.sub.1, L, Ar.sub.1, R.sub.p, R.sub.p1, R.sub.a, R.sub.a1, R.sub.b, R.sub.c, R.sub.d, R.sub.q and z are as defined.
(110) An embodiment of the invention is the provision of a compound, where the various moieties are independently selected, R.sub.2 is a substituted or unsubstituted 9 membered 6,5 bicyclic heteroaryl and said heteroaryl has 1, 2, 3, or 4 heteroatoms and said heteroatoms are independently O, S, or N, and A, B, R.sub.1, L, Ar.sub.1, R.sub.p, R.sub.p1, R.sub.a, R.sub.a1, R.sub.b, R.sub.c, R.sub.d, R.sub.q and z are as defined.
(111) An embodiment of the invention is the provision of a compound, where the various moieties are independently selected, R.sub.2 is a substituted or unsubstituted form
(112) ##STR00058## ##STR00059##
and A, B, R.sub.1, L, Ar.sub.1, R.sub.p, R.sub.p1, R.sub.a, R.sub.a1, R.sub.b, R.sub.c, R.sub.d and z are as defined.
(113) An embodiment of the invention is the provision of a compound, where the various moieties are independently selected, R.sub.2 is a substituted or unsubstituted 10 membered 6,6 bicyclic aryl or heteroaryl and said heteroaryl has 1, 2, 3, or 4 heteroatoms and said heteroatoms are O, S, or N, and A, B, R.sub.1, L, Ar.sub.1, R.sub.p, R.sub.p1, R.sub.a, R.sub.a1, R.sub.b, R.sub.c, R.sub.d, R.sub.q and z are as defined.
(114) An embodiment of the invention is the provision of a compound, where the various moieties are independently selected, R.sub.2 is a substituted or unsubstituted form of
(115) ##STR00060##
and A, B, R.sub.1, L, Ar.sub.1, R.sub.p, R.sub.p1, R.sub.a, R.sub.a1, R.sub.b, R.sub.c, R.sub.d, R.sub.q and z are as defined.
(116) An embodiment of the invention is the provision of a compound, where the various moieties are independently selected, R.sub.p is H, and A, B, R.sub.1, L, Ar.sub.1, R.sub.2, R.sub.p1, R.sub.a, R.sub.a1, R.sub.b, R.sub.c, R.sub.d, R.sub.q and z are as defined.
(117) An embodiment of the invention is the provision of a compound, where the various moieties are independently selected, R.sub.p is halo, and A, B, R.sub.1, L, Ar.sub.1, R.sub.2, R.sub.p1, R.sub.a, R.sub.a1, R.sub.b, R.sub.c, R.sub.d, R.sub.q and z are as defined.
(118) An embodiment of the invention is the provision of a compound, where the various moieties are independently selected, R.sub.p is C.sub.1-C.sub.4 alkyl, and A, B, R.sub.1, L, Ar.sub.1, R.sub.2, R.sub.p1, R.sub.a, R.sub.a1, R.sub.b, R.sub.c, R.sub.d, R.sub.q and z are as defined.
(119) An embodiment of the invention is the provision of a compound, where the various moieties are independently selected, R.sub.p is C.sub.3-C.sub.4 cycloalkyl, and A, B, R.sub.1, L, Ar.sub.1, R.sub.2, R.sub.p1, R.sub.a, R.sub.a1, R.sub.b, R.sub.c, R.sub.d, R.sub.q and z are as defined.
(120) An embodiment of the invention is the provision of a compound, where the various moieties are independently selected, R.sub.p1 is H, and A, B, R.sub.1, L, Ar.sub.1, R.sub.2, R.sub.p, R.sub.a, R.sub.a1, R.sub.b, R.sub.c, R.sub.d, R.sub.q and z are as defined.
(121) An embodiment of the invention is the provision of a compound, where the various moieties are independently selected, R.sub.p1 is halo, and A, B, R.sub.1, L, Ar.sub.1, R.sub.2, R.sub.p, R.sub.a, R.sub.a1, R.sub.b, R.sub.c, R.sub.d, R.sub.q and z are as defined.
(122) An embodiment of the invention is the provision of a compound, where the various moieties are independently selected, R.sub.p1 is C.sub.1-C.sub.4 alkyl, and A, B, R.sub.1, L, Ar.sub.1, R.sub.2, R.sub.p, R.sub.a, R.sub.a1, R.sub.b, R.sub.c, R.sub.d, R.sub.q and z are as defined.
(123) An embodiment of the invention is the provision of a compound, where the various moieties are independently selected, R.sub.p1 is C.sub.3-C.sub.4 cycloalkyl, and A, B, R.sub.1, L, Ar.sub.1, R.sub.2, R.sub.p, R.sub.a, R.sub.a1, R.sub.b, R.sub.c, R.sub.d, R.sub.q and z are as defined.
(124) An embodiment of the invention is the provision of a compound, where the various moieties are independently selected, R.sub.a is H, and A, B, R.sub.1, L, Ar.sub.1, R.sub.2, R.sub.p, R.sub.p1, R.sub.a1, R.sub.b, R.sub.c, R.sub.d, R.sub.q and z are as defined.
(125) An embodiment of the invention is the provision of a compound, where the various moieties are independently selected, R.sub.a is halo, and A, B, R.sub.1, L, Ar.sub.1, R.sub.2, R.sub.p, R.sub.p1, R.sub.a1, R.sub.b, R.sub.c, R.sub.d, R.sub.q and z are as defined.
(126) An embodiment of the invention is the provision of a compound, where the various moieties are independently selected, R.sub.a is C.sub.1-C.sub.4 alkyl, and A, B, R.sub.1, L, Ar.sub.1, R.sub.2, R.sub.p, R.sub.p1, R.sub.a1, R.sub.b, R.sub.c, R.sub.d, R.sub.q and z are as defined.
(127) An embodiment of the invention is the provision of a compound, where the various moieties are independently selected, R.sub.a is C.sub.3-C.sub.4 cycloalkyl, and A, B, R.sub.1, L, Ar.sub.1, R.sub.2, R.sub.p, R.sub.p1, R.sub.a1, R.sub.b, R.sub.c, R.sub.d, R.sub.q and z are as defined.
(128) An embodiment of the invention is the provision of a compound, where the various moieties are independently selected, R.sub.a1 is H, and A, B, R.sub.1, L, Ar.sub.1, R.sub.2, R.sub.p, R.sub.p1, R.sub.a, R.sub.b, R.sub.c, R.sub.d, R.sub.q and z are as defined.
(129) An embodiment of the invention is the provision of a compound, where the various moieties are independently selected, R.sub.a1 is halo, and A, B, R.sub.1, L, Ar.sub.1, R.sub.2, R.sub.p, R.sub.p1, R.sub.a, R.sub.b, R.sub.c, R.sub.d, R.sub.q and z are as defined.
(130) An embodiment of the invention is the provision of a compound, where the various moieties are independently selected, R.sub.a1 is C.sub.1-C.sub.4 alkyl, and A, B, R.sub.1, L, Ar.sub.1, R.sub.2, R.sub.p, R.sub.p1, R.sub.a, R.sub.b, R.sub.c, R.sub.d, R.sub.q and z are as defined.
(131) An embodiment of the invention is the provision of a compound, where the various moieties are independently selected, R.sub.a1 is C.sub.3-C.sub.4 cycloalkyl, and A, B, R.sub.1, L, Ar.sub.1, R.sub.2, R.sub.p, R.sub.p1, R.sub.a, R.sub.b, R.sub.c, R.sub.d, R.sub.q and z are as defined.
(132) An embodiment of the invention is the provision of a compound, where the various moieties are independently selected, R.sub.b is H, and A, B, R.sub.1, L, Ar.sub.1, R.sub.2, R.sub.p, R.sub.p1, R.sub.a, R.sub.a1, R.sub.c, R.sub.d, R.sub.q and z are as defined.
(133) An embodiment of the invention is the provision of a compound, where the various moieties are independently selected, R.sub.b is halo, and A, B, R.sub.1, L, Ar.sub.1, R.sub.2, R.sub.p, R.sub.p1, R.sub.a, R.sub.a1, R.sub.c, R.sub.d, R.sub.q and z are as defined.
(134) An embodiment of the invention is the provision of a compound, where the various moieties are independently selected, R.sub.b is C.sub.1-C.sub.4 alkyl, and A, B, R.sub.1, L, Ar.sub.1, R.sub.2, R.sub.p, R.sub.p1, R.sub.a, R.sub.a1, R.sub.c, R.sub.d, R.sub.q and z are as defined.
(135) An embodiment of the invention is the provision of a compound, where the various moieties are independently selected, R.sub.b is C.sub.1-C.sub.3 hydroxyl-alkyl, and A, B, R.sub.1, L, Ar.sub.1, R.sub.2, R.sub.p, R.sub.p1, R.sub.a, R.sub.a1, R.sub.c, R.sub.d, R.sub.q and z are as defined.
(136) An embodiment of the invention is the provision of a compound, where the various moieties are independently selected, R.sub.b is C.sub.3-C.sub.4 cycloalkyl, and A, B, R.sub.1, L, Ar.sub.1, R.sub.2, R.sub.p, R.sub.p1, R.sub.a, R.sub.a1, R.sub.c, R.sub.d, R.sub.q and z are as defined.
(137) An embodiment of the invention is the provision of a compound, where the various moieties are independently selected, R.sub.c is H, and A, B, R.sub.1, L, Ar.sub.1, R.sub.2, R.sub.p, R.sub.p1, R.sub.a, R.sub.a1, R.sub.b, R.sub.d, R.sub.q and z are as defined.
(138) An embodiment of the invention is the provision of a compound, where the various moieties are independently selected, Re is halo, and A, B, R.sub.1, L, Ar.sub.1, R.sub.2, R.sub.p, R.sub.p1, R.sub.a, R.sub.a1, R.sub.b, R.sub.d, R.sub.q and z are as defined.
(139) An embodiment of the invention is the provision of a compound, where the various moieties are independently selected, Re is C.sub.1-C.sub.4 alkyl, and A, B, R.sub.1, L, Ar.sub.1, R.sub.2, R.sub.p, R.sub.p1, R.sub.a, R.sub.a1, R.sub.b, R.sub.d, R.sub.q and z are as defined.
(140) An embodiment of the invention is the provision of a compound, where the various moieties are independently selected, Re is C.sub.3-C.sub.4 cycloalkyl, and A, B, R.sub.1, L, Ar.sub.1, R.sub.2, R.sub.p, R.sub.p1, R.sub.a, R.sub.a1, R.sub.b, R.sub.d, R.sub.q and z are as defined.
(141) An embodiment of the invention is the provision of a compound, where the various moieties are independently selected, R is H, and A, B, R.sub.1, L, Ar.sub.1, R.sub.2, R.sub.p, R.sub.p1, R.sub.a, R.sub.a1, R.sub.b, R.sub.c, R.sub.q and z are as defined.
(142) An embodiment of the invention is the provision of a compound, where the various moieties are independently selected, R is halo, and A, B, R.sub.1, L, Ar.sub.1, R.sub.2, R.sub.p, R.sub.p1, R.sub.a, R.sub.a1, R.sub.b, R.sub.c, R.sub.q and z are as defined.
(143) An embodiment of the invention is the provision of a compound, where the various moieties are independently selected, R is C.sub.1-C.sub.4 alkyl, and A, B, R.sub.1, L, Ar.sub.1, R.sub.2, R.sub.p, R.sub.p1, R.sub.a, R.sub.a1, R.sub.b, R.sub.c, R.sub.q and z are as defined.
(144) An embodiment of the invention is the provision of a compound, where the various moieties are independently selected, R.sub.d is C.sub.3-C.sub.4 cycloalkyl, and A, B, R.sub.1, L, Ar.sub.1, R.sub.2, R.sub.p, R.sub.p1, R.sub.a, R.sub.a1, R.sub.b, R.sub.c, R.sub.q and z are as defined.
(145) An embodiment of the invention is the provision of a compound, where the various moieties are independently selected, R.sub.q is H, and A, B, R.sub.1, L, Ar.sub.1, R.sub.2, R.sub.p, R.sub.p1, R.sub.a, R.sub.a1, R.sub.b, R.sub.c, R.sub.d and z are as defined.
(146) An embodiment of the invention is the provision of a compound, where the various moieties are independently selected, R.sub.q is halo, and A, B, R.sub.1, L, Ar.sub.1, R.sub.2, R.sub.p, R.sub.p1, R.sub.a, R.sub.a1, R.sub.b, R.sub.c, R.sub.d and z are as defined.
(147) An embodiment of the invention is the provision of a compound, where the various moieties are independently selected, R.sub.q is C.sub.1-C.sub.4 alkyl, and A, B, R.sub.1, L, Ar.sub.1, R.sub.2, R.sub.p, R.sub.p1, R.sub.a, R.sub.a1, R.sub.b, R.sub.c, R.sub.d and z are as defined.
(148) An embodiment of the invention is the provision of a compound, where the various moieties are independently selected, R.sub.q is C.sub.3-C.sub.4 cycloalkyl, and A, B, R.sub.1, L, Ar.sub.1, R.sub.2, R.sub.p, R.sub.p1, R.sub.a, R.sub.a1, R.sub.b, R.sub.c, R.sub.d and z are as defined.
(149) An embodiment of the invention is the provision of a compound, where the various moieties are independently selected, z is 0, and A, B, R.sub.1, L, Ar.sub.1, R.sub.2, R.sub.p, R.sub.p1, R.sub.a, R.sub.a1, R.sub.b, R.sub.c, R.sub.d and R.sub.q are as defined.
(150) An embodiment of the invention is the provision of a compound, where the various moieties are independently selected, z is 1 and A, B, R.sub.1, L, Ar.sub.1, R.sub.2, R.sub.p, R.sub.p1, R.sub.a, R.sub.a1, R.sub.b, R.sub.c, R.sub.d and R.sub.q are as defined.
(151) An embodiment of the invention is the provision of a compound, where the various moieties are independently selected, z is 2 and A, B, R.sub.1, L, Ar.sub.1, R.sub.2, R.sub.p, R.sub.p1, R.sub.a, R.sub.a1, R.sub.b, R.sub.c, R.sub.d and R.sub.q are as defined.
(152) An embodiment of the invention is the provision of a compound as described in Formulas I, I-A, I-B, I-C or I-D wherein R.sub.2 is not a substituted or unsubstituted form of
(153) ##STR00061##
where X is N or CH.
(154) An embodiment of the invention is the provision of a compound as described in Formulas I, I-A, I-B, I-C or I-D wherein when Ar.sub.1 is
(155) ##STR00062##
connected to
(156) ##STR00063##
at position 1, and X.sub.1 and X.sub.2 are independently N or C—R.sub.z, and R.sub.y and R.sub.z are any substituent, then Rx does not include alkynyl, alkenyl, aryl, 5-14 membered heterocyclic, 5-14 membered heteroaromatic, or 4-9 membered carbocyclic.
(157) An embodiment of the invention is the provision of a compound as described in Formulas I, I-A, I-B, I-C, or I-D wherein when R.sub.2 is
(158) ##STR00064##
Ar.sub.1 is not a substituted or unsubstituted form of
(159) ##STR00065##
(160) An embodiment of the invention is the provision of a compound as described in Formulas I, I-A, I-B, I-C, or I-D wherein when Ar.sub.1 is a substituted or unsubstituted form of a 5 membered heteroaryl, Ar.sub.1 is
(161) ##STR00066##
In another embodiment, the invention is further illustrated by the compounds shown in Table 1, which lists the IUPAC names and the structures of the compounds.
(162) TABLE-US-00001 TABLE 1 IUPAC Name Compound Structure 1-({4-[(4- phenylphenyl)carbonyl]piperazin-1- yl}carbonyl)cyclopropan-1-ol
EXAMPLES
(163) The following are illustrative, but non-limiting, examples of certain embodiments of the present invention. The synthetic schemes are presented for the synthesis of certain compounds herein disclosed. The process and results for the assays testing FASN inhibition and effects on cancer cell line proliferation are also described.
(164) Definitions used in the following Schemes and elsewhere herein are:
(165) Ar—B(OH).sub.2 aryl boronic acid Ar—B(OR).sub.2 aryl boronic ester Ar—X aryl halide Atm atmosphere BOP ammonium 4-(3-(pyridin-3-1methyl)ureido)benzenesulfinate δ chemical shift (ppm) CbzCl benzyl chloroformate DCM dichloromethane or methylene chloride DDQ 2,3-Dichloro-5,6-dicyano-p-benzoquinone DIEA N,N-diisopropylethylamine DMA N,N-dimethylacetamide DMF N,N-dimethylformamide DMSO dimethylsulfoxide EDC N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride ES electrospray Et.sub.3N triethylamine EtOAc ethyl acetate EtOH ethanol EtN(i-Pr)2 diisopropylethyl amine equiv equivalents FCC flash column chromatography GF/F glass microfiber filter .sup.1H NMR proton nuclear magnetic resonance HCl hydrogen chloride HOAc acetic acid HATU 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate HBTU O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate HOBt 1H-benzo[d][1,2,3]triazol-1-ol hydrate HPLC high pressure liquid chromatography i-PrOH isopropanol (i-Pr.sub.2)NEt N,N-Diisopropylethylamine LC-MS liquid chromatography/mass spectrometry LiOH lithium hydroxide (M+1) mass+1 m/z mass to charge ratio MS mass spectrometry or molecular sieves N.sub.2 nitrogen NaH sodium hydride nm nanometer NaOH sodium hydroxide NaHCO.sub.3 sodium bicarbonate MeI methyl iodide MeOH methanol MeSO.sub.3H methane sulfonic acid MgSO.sub.4 magnesium sulfate mmol millimoles μwave microwave Pd(PPh.sub.3).sub.4 Tetrakis(triphenylphosphine)palladium Pd.sub.2(dba).sub.3 tris(dibenzylideneacetone)dipalladium Pd(dppf)Cl.sub.2 [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) PTLC preparative thin layer chromatography RCO.sub.2H 1-hydroxycyclopropanecarboxylic acid r.t. or RT room temperature SOCl.sub.2 thionyl chloride TEA triethylamine TFA trifluoroacetic acid THE tetrahydrofuran TLC thin layer chromatography UV ultraviolet X-Phos 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl
Materials
(166) Unless otherwise noted, all materials were obtained from commercial suppliers and were used without further purification. Anhydrous solvents were obtained from Sigma-Aldrich (Milwaukee, Wis.) and used directly. All reactions involving air- or moisture-sensitive reagents were performed under a nitrogen atmosphere. Purity and low resolution mass spectral data were measured using either: (1) Waters Acquity ultra performance liquid chromatography (UPLC) system (Waters Acquity UPLC with Sample Organizer and Waters Micromass ZQ Mass Spectrometer) with UV detection at 220 nm and a low resonance electrospray positive ion mode (ESI) (Column: Acquity UPLC BEH Cis 1.7 μm 2.1×50 mm; gradient: 5-100% Solvent B (95/5/0.09%: Acetonitrile/Water/Formic Acid) in Solvent A (95/5/0.1%: 10 mM Ammonium Formate/Acetonitrile/Formic Acid) for 2.2 min then 100-5% Solvent B in Solvent A for 0.01 min then hold at 5% Solvent B in Solvent A for 0.29 min) or (2) Waters H T2790 Alliance high performance liquid chromatography (HPLC) system (Waters 996 PDA and Waters Z Q Single Quad Mass Spectrometer) with UV detection at 220 nm and 254 nm and a low resonance electrospray ionization (positive/negative) mode (ESI) (Column: XBridge Phenyl or C18, 5 μm 4.6×50 mm; gradient: 5-95% Solvent B (95% methanol/5% water with 0.1% Formic Acid) in Solvent A (95% water/5% methanol with 0.1% Formic Acid) for 2.5 min then hold at 95% Solvent B in Solvent A for 1 min).
(167) General Methods for Compound Synthesis:
(168) Method 1.
(169) ##STR00731##
Step 1. tert-butyl 4-(4-bromobenzoyl)piperazine-1-carboxylate (Intermediate 1)
(170) N,N-Diisopropylethylamine (28.6 mL, 164 mmol) was added to a 0° C. solution of tert-butyl piperazine-1-carboxylate (10.18 g, 54.7 mmol) and 4-bromobenzoyl chloride (12.0 g, 54.7 mmol) in DMF (80 mL), and the reaction mixture stirred at rt for 6 h. Water was added and the resulting mixture was stirred overnight and then filtered and dried to afford tert-butyl 4-(4-bromobenzoyl)piperazine-1-carboxylate (19.388 g, 52.5 mmol, 96% yield) as an off-white solid. MS (ESI, pos. ion) m/z: 369, 371 (M+1).
Step 2. tert-butyl 4-(4′-chloro-2′-fluorobiphenylcarbonyl)piperazine-1-carboxylate
(171) Tetrakis(triphenylphosphine)palladium (0) (1.565 g, 1.354 mmol) was added to a mixture of tert-butyl 4-(4-bromobenzoyl)piperazine-1-carboxylate (5.00 g, 13.54 mmol), 4-chloro-2-fluorophenylboronic acid (2.95 g, 16.93 mmol), and sodium carbonate (5.74 g, 54.2 mmol) in 1,4-dioxane (50 mL) and water (10 mL). The mixture stirred at 70° C. for 5 h. The reaction mixture was filtered through Celite and concentrated to afford an orange oil. This material was purified via column chromatography on silica gel (Biotage 100 g column, gradient elution with 0-50% ethyl acetate-hexane) to afford tert-butyl 4-(4′-chloro-2′-fluorobiphenylcarbonyl)piperazine-1-carboxylate (5.508 g, 13.15 mmol, 97% yield) as a tan solid. MS (ESI, pos. ion) m/z: 419 (M+1).
Step 3. (4′-chloro-2′-fluorobiphenyl-4-yl)(piperazin-1-yl)methanone 2,2,2-trifluoroacetate
(172) Trifluoroacetic acid (20.0 mL, 260 mmol) was added to a solution of tert-butyl 4-(4′-chloro-2′-fluorobiphenylcarbonyl)piperazine-1-carboxylate (11.35 g, 27.1 mmol) in dichloromethane (100 mL) and the solution stirred at rt for 1.5 h. The reaction mixture was concentrated and the residue was triturated with diethyl ether to afford (4′-chloro-2′-fluorobiphenyl-4-yl)(piperazin-1-yl)methanone 2,2,2-trifluoroacetate (12.02 g, 27.8 mmol, 100% yield) as a tan solid. MS (ESI, pos. ion) m/z: 319 (M+1).
Step 4. (4′-chloro-2′-fluorobiphenyl-4-yl)(4-(1-hydroxycyclopropanecarbonyl)piperazin-1-yl)methanone
(173) N,N-Diisopropylethylamine (9.12 mL, 52.2 mmol) was added to a solution of (4′-chloro-2′-fluorobiphenyl-4-yl)(piperazin-1-yl)methanone 2,2,2-trifluoroacetate (5.647 g, 13.05 mmol), 1-hydroxycyclopropanecarboxylic acid (1.332 g, 13.05 mmol), and O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (7.42 g, 19.57 mmol) in DMF (50.0 mL), and the reaction mixture stirred at rt for 18 h. The reaction mixture was partitioned between ethyl acetate and water. The organic phase was washed with water and brine, dried over anhydrous sodium sulfate, filtered, and concentrated to afford a yellow oil. This material was purified via column chromatography on silica gel (Biotage 100 g column, gradient elution with 0-5% methanol-ethyl acetate) to afford an off-white solid which was further purified via column chromatography on silica gel (Biotage 100 g column, gradient elution with 0-10% methanol-dichloromethane) to afford (4′-chloro-2′-fluorobiphenyl-4-yl)(4-(1-hydroxycyclopropanecarbonyl)piperazin-1-yl)methanone (1.554 g, 3.86 mmol, 30% yield) as a white solid. MS (ESI, pos. ion) m/z: 403 (M+1).
(174) Method 2.
(175) ##STR00732##
Step 1. (4-bromophenyl)(piperazin-1-yl)methanone 2,2,2-trifluoroacetate
(176) Trifluoroacetic acid (5.0 mL, 64.9 mmol) was added to a solution of tert-butyl 4-(4-bromobenzoyl)piperazine-1-carboxylate (2.00 g, 5.42 mmol) in dichloromethane (25.0 mL), and the solution stirred at rt for 2 h. The reaction mixture was concentrated and the residue was triturated with diethyl ether to afford (4-bromophenyl)(piperazin-1-yl)methanone 2,2,2-trifluoroacetate. (1.992 g, 5.20 mmol, 96% yield) as a white solid. MS (ESI, pos. ion) m/z: 269, 271 (M+1).
Step 2. (4-(4-bromobenzoyl)piperazin-1-yl)(1-hydroxycyclopropyl)methanone
(177) N,N-Diisopropylethylamine (0.46 mL, 2.6 mmol) was added to a solution of (4-bromophenyl)(piperazin-1-yl)methanone 2,2,2-trifluoroacetate (0.250 g, 0.652 mmol), 1-hydroxycyclopropanecarboxylic acid (0.067 g, 0.652 mmol), and O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.371 g, 0.979 mmol) in DMF (5.0 mL), and the reaction mixture stirred at rt for 18 h. The reaction mixture was partitioned between ethyl acetate and water. The organic phase was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated to afford an orange oil. This material was purified via column chromatography on silica gel (Biotage 25 g column, gradient elution with 0-5% methanol-dichloromethane) to afford (4-(4-bromobenzoyl)piperazin-1-yl)(1-hydroxycyclopropyl)methanone (0.195 g, 0.552 mmol, 85% yield) as a light orange solid. MS (ESI, pos. ion) m/z: 353, 355 (M+1).
Step 3. (4-(4-(benzo[d]thiazol-5-yl)benzoyl)piperazin-1-yl)(1-hydroxycyclopropyl)methanone
(178) Tetrakis(triphenylphosphine)palladium(0) (0.016 g, 0.014 mmol) was added to a mixture of (4-(4-bromobenzoyl)piperazin-1-yl)(1-hydroxycyclopropyl)methanone (0.050 g, 0.142 mmol), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]thiazole (0.055 g, 0.212 mmol), and sodium carbonate (0.060 g, 0.566 mmol) in dioxane (1.5 mL) and water (0.30 mL). The mixture stirred in the microwave at 50° C. for 1 h. The reaction mixture was filtered through Celite and concentrated to afford a yellow oil. This material was purified via column chromatography on silica gel (Biotage 25 g column, gradient elution with 0-5% methanol-ethyl acetate) to afford (4-(4-(benzo[d]thiazol-5-yl)benzoyl)piperazin-1-yl)(1-hydroxycyclopropyl)methanone (0.020 g, 0.049 mmol, 35% yield) as an off-white solid. MS (ESI, pos. ion) m/z: 408 (M+1).
(179) Method 3.
(180) ##STR00733##
Step 1. tert-butyl 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoyl)piperazine-1-carboxylate
(181) A mixture of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid (15 g, 60.5 mmol), tert-butyl piperazine-1-carboxylate (11.26 g, 60.5 mmol), 1H-benzo[d][1,2,3]triazol-1-ol hydrate (4.63 g, 30.2 mmol), N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (12.75 g, 66.5 mmol), and triethylamine (33.7 mL, 242 mmol) in dichloromethane (180 mL) was stirred at room temperature overnight. The reaction mixture was washed with saturated aqueous sodium bicarbonate solution (75 mL), 0.5 M HCl solution (75 mL), and again with saturated aqueous sodium bicarbonate solution (75 mL). The combined organic phases were concentrated and the resulting solid was slurried in a solution of 1:1 methyl tert-butyl ether/hexane (200 mL). The material was filtered and dried to afford tert-butyl 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoyl)piperazine-1-carboxylate (20.03 g, 48.1 mmol, 80%). MS (ESI, pos. ion) m/z: 417 (M+1).
Step 2 (Pd(PPh.SUB.3.).SUB.4.). tert-butyl 4-(4-(1H-benzo[d]imidazol-2-yl)benzoyl)piperazine-1-carboxylate
(182) Tetrakis(triphenylphosphine)palladium(0) (0.028 g, 0.024 mmol) was added to a mixture of tert-butyl 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoyl)piperazine-1-carboxylate (0.050 g, 0.120 mmol), 2-bromo-1H-benzo[d]imidazole (0.035 g, 0.180 mmol), and sodium carbonate (0.051 g, 0.480 mmol) in dioxane (1.5 mL) and water (0.30 mL). The mixture stirred in the microwave at 50° C. for 3 h. The reaction mixture was filtered through Celite and concentrated. The residue was purified via column chromatography on silica gel (Biotage 10 g column, gradient elution with 0-50% ethyl acetate-hexane) to afford tert-butyl 4-(4-(1H-benzo[d]imidazol-2-yl)benzoyl)piperazine-1-carboxylate (0.027 g, 0.066 mmol, 55% yield) as an off-white solid. MS (ESI, pos. ion) m/z: 407 (M+1).
Step 2 (X-Phos). tert-butyl 4-(4-(pyrazolo[1,5-a]pyridin-2-yl)benzoyl)piperazine-1-carboxylate
(183) A mixture of tert-butyl 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoyl)piperazine-1-carboxylate (0.100 g, 0.240 mmol), 2-chloropyrazolo[1,5-a]pyridine (0.046 g, 0.300 mmol), tris(dibenzylideneacetone)dipalladium (0.011 g, 0.012 mmol), 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (X-Phos, 0.011 g, 0.024 mmol), and cesium carbonate (0.235 g, 0.721 mmol) in dioxane (2.5 mL) and water (0.50 mL) was stirred in the microwave at 80° C. for 1 h. The reaction mixture was filtered through Celite and concentrated to afford a yellow-brown oil. This material was purified via column chromatography on silica gel (Biotage 25 g column, gradient elution with 0-50-100% ethyl acetate-hexane) to afford tert-butyl 4-(4-(pyrazolo[1,5-a]pyridin-2-yl)benzoyl)piperazine-1-carboxylate (0.056 g, 0.138 mmol, 57% yield) as an off-white solid. MS (ESI, pos. ion) m/z: 407 (M+1).
Step 3. (4-(1H-benzo[d]imidazol-2-yl)phenyl)(piperazin-1-yl)methanone 2,2,2-trifluoroacetate (Intermediate 2)
(184) Trifluoroacetic acid (1.0 mL, 12.98 mmol) was added to a solution of tert-butyl 4-(4-(1H-benzo[d]imidazol-2-yl)benzoyl)piperazine-1-carboxylate (0.027 g, 0.066 mmol) in dichloromethane (3.0 mL), and the solution stirred at rt for 1.5 h. The reaction mixture was concentrated and the residue was triturated with diethyl ether and filtered to afford (4-(1H-benzo[d]imidazol-2-yl)phenyl)(piperazin-1-yl)methanone 2,2,2-trifluoroacetate (0.028 g, 0.067 mmol, 100% yield) as a brown film. MS (ESI, pos. ion) m/z: 307 (M+1).
Step 4. (4-(4-(1H-benzo[d]imidazol-2-yl)benzoyl)piperazin-1-yl)(1-hydroxycyclopropyl)methanone
(185) DIEA (0.047 mL, 0.266 mmol) was added to a solution of (4-(1H-benzo[d]imidazol-2-yl)phenyl)(piperazin-1-yl)methanone 2,2,2-trifluoroacetate (0.028 g, 0.067 mmol), 1-hydroxycyclopropanecarboxylic acid (7.14 mg, 0.070 mmol), and O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.038 g, 0.100 mmol) in DMF (1.0 mL), and the reaction mixture stirred at rt for 20 h. Water was added and the mixture was partitioned between ethyl acetate and water. The aqueous phase was separated and extracted with dichloromethane. The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, and filtered to afford a brown oil. This material was purified via column chromatography on silica gel (Biotage 10 g column, gradient elution with 0-5% methanol-ethyl acetate) to afford (4-(4-(1H-benzo[d]imidazol-2-yl)benzoyl)piperazin-1-yl)(1-hydroxycyclopropyl)methanone (0.004 g, 10.24 μmol, 15% yield) as a white solid. MS (ESI, pos. ion) m/z: 391 (M+1).
(186) Method 4.
(187) ##STR00734##
Step 1. Methyl 4-(benzo[d]oxazol-2-yl)benzoate
(188) Thionyl chloride (10 mL, 137 mmol) was added to mono-methyl terephthalate (5.00 g, 27.8 mmol). A drop of DMF was added, and the mixture was heated at 80° C. for 2 h. The excess thionyl chloride was removed, and the residue was treated with 2-aminophenol (3.03 g, 27.8 mmol) and dioxane (60 mL). Methanesulfonic acid (5.59 mL, 86 mmol) was added and the reaction mixture was heated at reflux for 18 h. The solution was concentrated and the residue was partitioned between dichloromethane and satd. aq. sodium bicarbonate solution. The aqueous phase was separated and washed with dichloromethane and the combined organic phases were washed with brine, filtered, and concentrated to afford a brown solid. This material was triturated with methanol, filtered, and dried to afford methyl 4-(benzo[d]oxazol-2-yl)benzoate (4.827 g, 19.06 mmol, 69% yield) as an off-white solid. MS (ESI, pos. ion) m/z: 254 (M+1).
Step 2 (LiOH). 4-(Benzo[d]oxazol-2-yl)benzoic acid
(189) Lithium hydroxide (0.894 g, 37.3 mmol) was added to a solution of methyl 4-(benzo[d]oxazol-2-yl)benzoate (4.728 g, 18.67 mmol) in THE (25 mL), Methanol (25 mL), and Water (25 mL), and the mixture stirred at rt for 18 h. The reaction mixture was concentrated and the aqueous solution was acidified to pH=5-6 with 1 N aq HCl solution. The resulting off-white precipitate was filtered and dried to afford 4-(benzo[d]oxazol-2-yl)benzoic acid (3.846 g, 16.08 mmol, 86% yield) as an off-white solid. MS (ESI, pos. ion) m/z: 240 (M+1).
Step 2 (NaOH). 4-(5-cyanobenzo[d]oxazol-2-yl)benzoic acid
(190) Sodium hydroxide (0.067 g, 1.675 mmol) was added to a solution of methyl 4-(5-cyanobenzo[d]oxazol-2-yl)benzoate (0.233 g, 0.837 mmol) in THE (4.0 mL) and water (2.00 mL), and the mixture stirred at rt for 18 h. The reaction mixture was concentrated and the aqueous solution was acidified to pH=5-6 with 1 N aq HCl solution. The resulting off-white precipitate was filtered and dried to afford 4-(5-cyanobenzo[d]oxazol-2-yl)benzoic acid (0.176 g, 0.666 mmol, 80% yield) as an off-white solid. MS (ESI, pos. ion) m/z: 265 (M+1).
Step 3. tert-Butyl 4-(4-(benzo[d]oxazol-2-yl)benzoyl)piperazine-1-carboxylate
(191) Thionyl chloride (25.0 mL, 343 mmol) was added to 4-(benzo[d]oxazol-2-yl)benzoic acid (3.5 g, 14.63 mmol). A drop of DMF was added and the mixture was heated at 80° C. for 1 h. The excess thionyl chloride was removed and DMF (40 mL) was added. tert-Butyl piperazine-1-carboxylate (2.72 g, 14.63 mmol) and N,N-diisopropylethylamine (7.67 mL, 43.9 mmol) were added, and the reaction mixture stirred at rt for 1.5 h. Water was added and the resulting mixture was stirred and then filtered and dried to afford tert-butyl 4-(4-(benzo[d]oxazol-2-yl)benzoyl)piperazine-1-carboxylate (5.006 g, 12.29 mmol, 84% yield) as a light tan solid. MS (ESI, pos. ion) m/z: 408 (M+1).
Step 4. (4-(Benzo[d]oxazol-2-yl)phenyl)(piperazin-1-yl)methanone 2,2,2-trifluoroacetate
(192) Trifluoroacetic acid (10.0 mL, 130 mmol) was added to a solution of tert-butyl 4-(4-(benzo[d]oxazol-2-yl)benzoyl)piperazine-1-carboxylate (5.006 g, 12.29 mmol) in dichloromethane (50 mL), and the solution stirred at rt for 5 h. The reaction mixture was concentrated and the residue was triturated with diethyl ether and filtered to afford (4-(benzo[d]oxazol-2-yl)phenyl)(piperazin-1-yl)methanone 2,2,2-trifluoroacetate (5.501 g, 13.06 mmol, 100% yield) as an off-white solid. MS (ESI, pos. ion) m/z: 308 (M+1).
Step 5 (acid chloride coupling). (4-(4-(Benzo[d]oxazol-2-yl)benzoyl)piperazin-1-yl)(1-hydroxycyclopropyl)methanone
(193) Thionyl chloride (2.0 mL, 27.4 mmol) was added to 1-hydroxycyclopropanecarboxylic acid (0.115 g, 1.123 mmol). A drop of DMF was added and the mixture was heated at 80° C. for 1 h. The excess thionyl chloride was removed to afford a brown oil. This material was added to a solution of (4-(benzo[d]oxazol-2-yl)phenyl)(piperazin-1-yl)methanone 2,2,2-trifluoroacetate (0.338 g, 0.802 mmol) and N,N-diisopropylethylamine (0.70 mL, 4.01 mmol) in dichloromethane (3.0 mL). The reaction mixture stirred at rt for 2 h. The mixture was concentrated and the residue was purified via column chromatography on silica gel (Biotage 25 g column, gradient elution with 0-5% methanol-ethyl acetate) to afford (4-(4-(benzo[d]oxazol-2-yl)benzoyl)piperazin-1-yl)(1-hydroxycyclopropyl)-methanone (0.208 g, 0.531 mmol, 66% yield) as a pink solid. MS (ESI, pos. ion) m/z: 392 (M+1).
Step 5 (HBTU coupling). (4-(4-(5-Chlorobenzo[d]oxazol-2-yl)benzoyl)piperazin-1-yl)(1-hydroxycyclopropyl)methanone
(194) N,N-Diisopropylethylamine (0.376 mL, 2.150 mmol) was added to a solution of (4-(5-chlorobenzo[d]oxazol-2-yl)phenyl)(piperazin-1-yl)methanone 2,2,2-trifluoroacetate (0.245 g, 0.537 mmol), 1-hydroxycyclopropanecarboxylic acid (0.058 g, 0.564 mmol), and O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HBTU, 0.306 g, 0.806 mmol) in DMF (5.0 mL), and the reaction mixture stirred at rt for 20 h. Water was added and the resulting precipitate was filtered and dried. This material was purified via column chromatography on silica gel (Biotage 50 g column, gradient elution with 0-5% methanol-ethyl acetate) to afford (4-(4-(5-chlorobenzo[d]oxazol-2-yl)benzoyl)piperazin-1-yl)(1-hydroxycyclopropyl)methanone (0.136 g, 0.319 mmol, 59% yield) as an off-white solid. MS (ESI, pos. ion) m/z: 426 (M+1).
(195) Method 5.
(196) ##STR00735##
Preparation of (4-(2-chloro-4-(quinolin-6-yl)benzoyl)piperazin-1-yl)(1-hydroxycyclopropyl)methanone
(197) 4-Bromo-2-chlorobenzoic acid (0.2 M in 1,4-dioxane, 180 μL, 0.036 mmol) was added to a solution of tert-butyl piperazine-1-carboxylate (0.2 M solution in 1,4-dioxane with 5% N,N-diisopropylethylamine, 150 μL, 0.03 mmol). (Benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophophate (BOP, 0.5 M solution in 1,2-dichloroethane, 72 μL, 0.036 mmol) was added, and the resulting mixture was put on a shaker at rt for 2 hour. Quinolin-6-ylboronic acid (0.2 M solution in 1,4-dioxane, 225 μL, 0.045 mmoL) and potassium phosphate (1 M aqueous, 150 μL, 0.15 mmol) were added. Tetrakis(triphenylphosphine)palladium (0) solution (0.02 M toluene, 75 μL, 1.5 μmol) was then added under a nitrogen atmosphere, and the resulting mixture was put on shaker in a glove box under nitrogen atmosphere and heated at 80° C. overnight. After being cooled to rt, the mixture was diluted with brine (0.30 mL) and ethyl acetate (0.5 mL). The organic layer was separated and the aqueous layer was extracted again with ethyl acetate (0.6 mL). The combined organic layers were dried down and the residue was re-dissolved in methanol (400 μL). HCl solution (4 N in 1,4-dioxane, 75 μL, 0.2 mmol) was added, and the mixture was heated on a shaker at 50° C. for 1 hour. The reaction mixture was dried down in vacuo and the residue was re-dissolved in a solution of 10% N,N-diisopropylethylamine in dimethylacetamide (200 μL). 1-Hydroxycyclopropanecarboxylic acid (0.2 M in 1,4-dioxane, 225 μL, 0.045 mmol) was added followed by BOP solution (0.5 M in 1,2-DCE, 90 μL, 0.045 mmol). The mixture was put on a shaker at rt for 2 hour. The reaction mixture was then diluted with sodium hydroxide solution (1 N in brine, 0.45 mL) and ethyl acetate (0.5 mL). The organic layer was separated and the aqueous layer was extracted with ethyl acetate (0.6 mL). The combined organic layers were concentrated and the residue was purified by high performance liquid chromatography (Waters Autopurification MS-directed HPLC prep fraction collection with the following conditions: Column: Waters XBridge OBD C18, 5 μm, 19×50 mm; flow rate 20 mL/min; mobile phase, water with 0.1% ammonium hydroxide (A) and methanol with 0.1% ammonium hydroxide (B) running the following gradient 0 to 2 mins (15% B), 2 to 6 mins (15-100% B); Detector ZQ Mass Detector in electrospray ionization mode) to afford (4-(2-chloro-4-(quinolin-6-yl)benzoyl)piperazin-1-yl)(1-hydroxycyclopropyl)methanone (5.9 mg, 14 μmol, 45% yield). MS (ESI, pos. ion) m/z: 436 (M+1).
(198) ##STR00736##
Method 6.
Step 1. tert-butyl 4-(4-(benzo[d]thiazol-2-yl)benzoyl)piperazine-1-carboxylate
(199) Tetrakis(triphenylphosphine)palladium(0) (0.313 g, 0.271 mmol) was added to a mixture of tert-butyl 4-(4-bromobenzoyl)piperazine-1-carboxylate (1.00 g, 2.71 mmol), 2-(tributylstannyl)benzo[d]thiazole (1.00 mL, 2.84 mmol), lithium chloride (0.230 g, 5.42 mmol), and copper(I) iodide (0.026 g, 0.135 mmol) in DMF (25 mL). The mixture stirred at 80° C. for 2 h and then at 90° C. for 8 h. The reaction mixture was filtered through Celite and the filtrate was partitioned between dichloromethane and water. The organic phase was separated and washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated to afford an orange oil. This material was purified via column chromatography on silica gel (Biotage 50 g column, gradient elution with 0-50% ethyl acetate-hexane) to afford tert-butyl 4-(4-(benzo[d]thiazol-2-yl)benzoyl)piperazine-1-carboxylate (0.586 g, 1.384 mmol, 51% yield) as a brown solid. MS (ESI, pos. ion) m/z: 424 (M+1).
Step 2. (4-(benzo[d]thiazol-2-yl)phenyl)(piperazin-1-yl)methanone 2,2,2-trifluoroacetate
(200) Trifluoroacetic acid (1.00 mL, 13.0 mmol) was added to a solution of tert-butyl 4-(4-(benzo[d]thiazol-2-yl)benzoyl)piperazine-1-carboxylate (0.586 g, 1.38 mmol) in dichloromethane (5.0 mL), and the solution stirred at rt for 3 h. The reaction mixture was concentrated and the residue was triturated with diethyl ether and filtered to afford (4-(benzo[d]thiazol-2-yl)phenyl)(piperazin-1-yl)methanone 2,2,2-trifluoroacetate (0.542 g, 1.239 mmol, 90% yield) as a tan solid. MS (ESI, pos. ion) m/z: 324 (M+1).
Step 3. (4-(4-(benzo[d]thiazol-2-yl)benzoyl)piperazin-1-yl)(1-hydroxycyclopropyl)methanone
(201) N,N-Diisopropylethylamine (0.87 mL, 5.0 mmol) was added to a solution of (4-(benzo[d]thiazol-2-yl)phenyl)(piperazin-1-yl)methanone 2,2,2-trifluoroacetate (0.542 g, 1.239 mmol), 1-hydroxycyclopropanecarboxylic acid (0.133 g, 1.301 mmol), and 0-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.705 g, 1.859 mmol) in DMF (5.0 mL), and the reaction mixture stirred at rt for 16 h. Water was added and the resulting precipitate was filtered and dried. This material was purified via column chromatography on silica gel (Biotage 50 g column, gradient elution with 0-5% methanol-ethyl acetate) to afford (4-(4-(benzo[d]thiazol-2-yl)benzoyl)piperazin-1-yl)(1-hydroxycyclopropyl)methanone (0.235 g, 0.577 mmol, 47% yield) as an off-white solid. MS (ESI, pos. ion) m/z: 408 (M+1).
(202) Method 7.
(203) ##STR00737##
Preparation of 5-(4-(4-(1-hydroxycyclopropanecarbonyl)piperazine-1-carbonyl)phenyl)-1H-indole-3-carbonitrile
(204) To a solution of tert-butyl 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoyl)piperazine-1-carboxylate (0.2 M in 1,4-dioxane, 100 μL, 0.02 mmol), was added 5-bromo-1H-indole-3-carbonitrile (0.2 M in 1,4-dioxane, 100 μL, 0.02 mmol) and potassium phosphate solution (1 M aqueous, 100 μL, 0.1 mmol). The mixture was bubbled with nitrogen and tetrakis(triphenylphosphine)palladium (0) (0.02 M in toluene, 50 μL, 1 μmol) was added. The resulting mixture was put on a shaker in a glove box under nitrogen atmosphere and heated at 80° C. overnight. After being cooled to rt, the mixture was diluted with 0.35 mL of brine and 0.5 mL of ethyl acetate. The organic layer was separated and the aqueous layer was extracted again with ethyl acetate (0.6 mL). The combined organic layers were concentrated and the residue was dissolved in 200 μL of methanol. HCl solution (50 μL, 4 N in 1,4-dioxane, 0.2 mmol) was added. The mixture was put on a shaker at 50° C. for 1 hour. The reaction mixture was concentrated in vacuo and the residue was dissolved in a solution of 10% N,N-diisopropylethylamine in dimethylacetamide (200 μL). 1-Hydroxycyclopropanecarboxylic acid (0.2 M in 1,4-dioxane, 120 μL, 0.024 mmol) was added, followed by BOP solution (0.5 M in 1,2-dichloroethane, 48 μL, 0.024 mmol). The mixture was put on a shaker at rt for 2 hour. The reaction mixture was then diluted with 0.45 mL of 1N NaOH in brine and 0.5 mL of ethyl acetate. The organic layer was separated and the aqueous layer was extracted again with ethyl acetate (0.6 mL). The combined organic layers were concentrated and the residue was purified by HPLC: Water Autopurification MS-directed HPLC prep fraction collection with the following conditions Column, Waters XBridge OBD C18, 5 μm, 19×50 mm; flow rate 20 ml/min; mobile phase, water with 0.1% ammonium hydroxide (A) and methanol with 0.1% ammonium hydroxide (B) running the following gradient 0 to 2 mins (15% B), 2 to 6 mins (15-100% B); Detector ZQ Mass Detector in electrospray ionization mode. 5-(4-(4-(1-Hydroxycyclopropanecarbonyl)piperazine-1-carbonyl)phenyl)-1H-indole-3-carbonitrile (3.5 mg, 8.4 μmol, 42% yield) was obtained. MS (ESI, pos. ion) m/z: 415 (M+1).
(205) Method 8.
(206) ##STR00738##
1-(4-(biphenylcarbonyl)piperazin-1-yl)-2-methoxy-2-methylpropan-1-one
(207) Sodium hydride (9.08 mg, 0.227 mmol) was added to a solution of 1-(4-(biphenylcarbonyl)piperazin-1-yl)-2-hydroxy-2-methylpropan-1-one (32 mg, 0.091 mmol) in DMF (4 mL). After stirring at rt for 30 min, methyl iodide (0.028 mL, 0.454 mmol) was added. The mixture was stirred at rt overnight. The mixture was concentrated and the residue was purified via preparative reversed phase HPLC (20 mL/min, 10 min gradient 15%-85% CH.sub.3CN, 0.01% HCO.sub.2H on an XTerra Prep MS C18 OBD 5 μM, 19×100 mm column) to afford 1-(4-(biphenylcarbonyl)piperazin-1-yl)-2-methoxy-2-methylpropan-1-one (12.2 mg, 37%). MS (ESI, pos. ion) m/z: 367 (M+1).
(208) Method 9.
(209) ##STR00739##
Preparation of (4-(2-chloro-4-(quinolin-6-yl)benzoyl)piperazin-1-yl)(1-hydroxycyclopropyl)methanone
(210) To a solution of tert-butyl piperazine-1-carboxylate (0.2 M 1,4-dioxane with 5% N,N-diisopropylethylamine, 150 μL, 0.03 mmol), was added 4-phenoxybenzoic acid (0.2 M 1,4-dioxane, 150 μL, 0.03 mmol), followed by (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophophate solution (BOP, 0.5 M in 1,2-dichloroethane, 66 μL, 0.033 mmol). The resulting mixture was put on a shaker at room temperature for 2 hours. Hydrochloric acid solution (4 N in 1,4-dioxane, 75 μL) was added and the mixture was put on a shaker at 50° C. for 1 hour. After being cooled to room temperature, the mixture was concentrated, and the residue was re-dissolved in a solution of 10% diisopropylethyl amine in dimethylacetamide (200 μL). 1-Hydroxycyclopropanecarboxylic acid (0.2 M 1,4-dioxane, 180 μL, 0.036 mmol) was added to the mixture, followed by BOP solution (0.5 M in 1,2-dichloroethane, 72 μL, 0.036 mmol). The mixture was put on a shaker at room temperature for 2 hours. The reaction mixture was then diluted with sodium hydroxide solution (1 N in brine, 0.45 mL) and ethyl acetate (0.5 mL). The organic layer was separated and the aqueous layer was extracted with ethyl acetate (0.6 mL). The combined organic layers were concentrated and the residue was purified by high performance liquid chromatography (Waters Autopurification MS-directed HPLC prep fraction collection with the following conditions: Column: Waters XBridge OBD C18, 5 μm, 19×50 mm; flow rate 20 mL/min; mobile phase, water with 0.1% ammonium hydroxide (A) and methanol with 0.1% ammonium hydroxide (B) running the following gradient 0 to 2 mins (15% B), 2 to 6 mins (15-100% B); Detector ZQ Mass Detector in electrospray ionization mode) to afford (4-(2-chloro-4-(quinolin-6-yl)benzoyl)piperazin-1-yl)(1-hydroxycyclopropyl)methanone (4.1 mg, 11 μmol, 37% yield). MS (ESI, pos. ion) m/z: 367 (M+1).
(211) Method 10.
(212) ##STR00740##
Step 1. tert-Butyl 4-(3-chloro-4-(1H-indol-5-yl)benzoyl)piperazine-1-carboxylate
(213) To a solution of tert-butyl 4-(4-bromo-3-chlorobenzoyl)piperazine-1-carboxylate (505 mg, 1.25 mmol) in 1,4-dioxane (9 mL) was added 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole (365 mg, 1.5 mmol), potassium phosphate (1.06 g, 5 mmol) and water (3 mL). The mixture was bubbled with nitrogen and tetrakis(triphenylphosphine)palladium (0) (72.2 mg, 0.063 mmol) was added. The mixture was sealed and heated at 80° C. overnight. After being cooled to rt, the mixture was diluted with water (10 mL) and ethyl acetate (20 mL). The organic layer was separated and the aqueous layer was extracted with ethyl acetate (20 mL). The combined organic layers were concentrated to yield tert-butyl 4-(3-chloro-4-(1H-indol-5-yl)benzoyl)piperazine-1-carboxylate (578 mg, 1.31 mmol, 100% yield). The crude product was used without further purification. MS (ESI, pos. ion) m/z: 440 (M+1).
Step 2. (4-(3-chloro-4-(1-isopropyl-1H-indol-5-yl)benzoyl)piperazin-1-yl)(1-hydroxycyclopropyl)methanone
(214) To a vial charged with sodium hydride (60% in mineral oil, 1.6 mg, 0.040 mmol) and DMF (0.1 mL), was added tert-butyl 4-(3-chloro-4-(1H-indol-5-yl)benzoyl)piperazine-1-carboxylate (0.2 M in DMF, 0.1 mL, 0.02 mmol), followed by 2-iodopropane (0.2 M in DMF, 0.2 mL, 0.04 mmol). The resulting mixture was put on a shaker for 30 min. at room temperature. The mixture was then diluted with water and ethyl acetate. The organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were concentrated in vacuo. The residue was dissolved in methanol (0.3 mL) and HCl solution (4 N 1,4-dioxane, 50 μL) was added. The mixture was put on a shaker at 50° C. for 1 hour. After being cooled to room temperature, the mixture was concentrated. The residue was dissolved in a solution of 5% N,N-diisopropylethylamine in dimethylacetamide (0.2 mL) and 1-hydroxycyclopropanecarboxylic acid (0.2 M 1,4-dioxane, 120 μL, 0.024 mmol) was added, followed by BOP solution (0.5 M in 1,2-dichloroethane, 48 μL, 0.024 mmol). The mixture was put on a shaker at room temperature for 2 hours. The reaction mixture was diluted with sodium hydroxide solution (1 N in brine, 0.45 mL) and ethyl acetate (0.5 mL). The organic layer was separated and the aqueous layer was extracted with ethyl acetate (0.6 mL). The combined organic layers were concentrated and the residue was purified by high performance liquid chromatography (Waters Autopurification MS-directed HPLC prep fraction collection with the following conditions: Column: Waters XBridge OBD C18, 5 μm, 19×50 mm; flow rate 20 mL/min; mobile phase, water with 0.1% ammonium hydroxide (A) and methanol with 0.1% ammonium hydroxide (B) running the following gradient 0 to 2 mins (15% B), 2 to 6 mins (15-100% B); Detector ZQ Mass Detector in electrospray ionization mode) to afford (4-(3-chloro-4-(1-isopropyl-1H-indol-5-yl)benzoyl)piperazin-1-yl)(1-hydroxycyclopropyl)methanone (2.2 mg, 4.7 μmol, 24% yield). MS (ESI, pos. ion) m/z: 466 (M+1).
(215) ##STR00741##
Method 11.
Step 1. tert-Butyl 4-(3′-amino-[1,1′-biphenyl]-4-carbonyl)piperazine-1-carboxylate
(216) To a solution of tert-butyl piperazine-1-carboxylate (745 mg, 4 mmol) in DMF (20 mL) was added N,N-diisopropylethylamine (1.43 mL, 8 mmol), followed by 3′-aminobiphenyl-4-carboxylic acid (853 mg, 4 mmol) and (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophophate (BOP, 2.12 g, 4.8 mmol). The resulting mixture was stirred at room temperature for 1 hour. The mixture was then poured into ice-water (40 mL) with stirring. The precipitate was filtered off, washed with water and air-dried to afford tert-butyl 4-(3′-aminobiphenylcarbonyl)piperazine-1-carboxylate (1.2 g, 3.15 mmol, 79% yield). The product was used for next step without further purification. MS (ESI, pos. ion) m/z: 382 (M+1).
Step 2. N-(4′-(4-(1-Hydroxycyclopropanecarbonyl)piperazine-1-carbonyl)-[1,1′-biphenyl]-3-yl)benzenesulfonamide or ethyl (4′-(4-(1-hydroxycyclopropane-1-carbonyl)piperazine-1-carbonyl)-[1,1′-biphenyl]-3-yl)carbamate
(217) To a solution of tert-butyl 4-(3′-aminobiphenylcarbonyl)piperazine-1-carboxylate (0.2 M 1,4-dioxane, 150 μL, 0.03 mmol) was added pyridine (9.7 μL, 0.12 mmol) followed by benzenesulfonyl chloride (0.2 M in 1,4-dioxane, 300 μL, 0.06 mmol) or ethyl carbonochloridate (0.2 M in 1,4-dioxane, 300 μL, 0.06 mmol). The resulting mixture was put on a shaker at 80° C. overnight. The reaction mixture was diluted with sodium hydroxide solution (1 N in brine, 0.45 mL) and ethyl acetate (0.6 mL). The organic layer was separated and the aqueous layer was extracted with ethyl acetate (0.6 mL). The combined organic layers were concentrated. The residue was dissolved in methanol (200 μL) and HCl solution (4 N in 1,4-dioxane, 75 μL) was added. The mixture was put on a shaker at 50° C. for 1 hour. The reaction mixture was concentrated in vacuo and the residue was dissolved in a solution of dimethylacetamide with 10% N,N-diisopropylethylamine (200 μL). 1-Hydroxycyclopropanecarboxylic acid (0.2 M in 1,4-dioxane, 180 μL, 0.036 mmol) was added followed by BOP solution (0.5 M in 1,2-dichloroethane, 72 μL, 0.036 mmol). The mixture was put on a shaker at rt for 2 hours. The reaction mixture was then diluted with sodium hydroxide solution (1 N in brine, 0.45 mL) and ethyl acetate (0.5 mL). The organic layer was separated and the aqueous layer was extracted with ethyl acetate (0.6 mL). The combined organic layers were concentrated and the residue was purified by high performance liquid chromatography (Waters Autopurification MS-directed HPLC prep fraction collection with the following conditions: Column: Waters XBridge OBD C18, 5 μm, 19×50 mm; flow rate 20 mL/min; mobile phase, water with 0.1% ammonium hydroxide (A) and methanol with 0.1% ammonium hydroxide (B) running the following gradient 0 to 2 mins (15% B), 2 to 6 mins (15-100% B); Detector ZQ Mass Detector in electrospray ionization mode) to afford N-(4′-(4-(1-hydroxycyclopropanecarbonyl)piperazine-1-carbonyl)biphenyl-3-yl)benzenesulfonamide (7.8 mg, 15 μmol, 51% yield). MS (ESI, pos. ion) m/z: 506 (M+1).
(218) ##STR00742##
Preparation of N-(4′-(4-(1-hydroxycyclopropanecarbonyl)piperazine-1-carbonyl)biphenyl-3-yl)oxetane-3-carboxamide
(219) (3′-Aminobiphenyl-4-yl)(4-(1-hydroxycyclopropanecarbonyl)piperazin-1-yl)methanone (0.168 g, 0.460 mmol), N,N-diisopropylethylamine (0.241 mL, 1.379 mmol) and oxetane-3-carboxylic acid (0.055 g, 0.506 mmol) were combined in DMF (5 mL). 0-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.244 g, 0.644 mmol) was added to give a light yellow solution. This was stirred for 18 h. N,N-Diisopropylethyl amine (0.120 mL, 0.687 mmol), 0-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.18 g, 0.474 mmol), and oxetane-3-carboxylic acid (0.025 g, 0.244 mmol) were added. Stirring was continued for 5 h. The reaction was diluted with 10 mL of water and stirred. Another 15 mL of water was added and the aqueous emulsion was extracted with 50 mL of dichloromethane and then 20 mL of dichloromethane. The combined organic layers were washed with 20 mL of water and then with 20 mL of brine, dried over MgSO.sub.4 and concentrated. The material was purified via column chromatography on silica gel (Biotage 25 g column, gradient elution with 0-6% methanol/dichloromethane). The material obtained was repurified on a second silica gel column (Biotage 25 g column, 4-6.5% methanol/dichloromethane). Concentration of the fractions afforded a yellow film. This material was taken up in 40 mL of dichloromethane and washed twice with 5 mL of dilute NaHCO.sub.3 and once with 5 mL of brine. The solution was dried over MgSO.sub.4 and concentrated to afford a yellow oil. This oil was taken up in dichloromethane and triturated with hexanes. Filtration afforded N-(4′-(4-(1-hydroxycyclopropanecarbonyl)piperazine-1-carbonyl)biphenyl-3-yl)oxetane-3-carboxamide (0.036 g, 0.076 mmol, 17%) as a yellow solid. MS (ESI, pos. ion) m/z: 450 (M+1).
(220) Method 13.
(221) ##STR00743## ##STR00744##
Step 1. 6-fluorobenzo[d]oxazole-2(3H)-thione
(222) Into a 250-mL round-bottom flask, was placed 2-amino-5-fluorophenol (8 g, 62.93 mmol, 1.00 equiv), ethoxy(potassiosulfanyl)methanethione (11.1 g, 69.25 mmol, 1.10 equiv), ethanol (150 mL). The resulting solution was heated to reflux overnight in an oil bath. The reaction mixture was cooled to room temperature with a water bath and then concentrated under vacuum. The resulting slurry was diluted with 150 mL of water and its pH value was adjusted to 5 with acetic acid and precipitation formed. The solids were collected by filtration and dried in an oven. This resulted in 9.2 g (86%) of the title compound as a gray solid. LC-MS (ES, m/z) 170 [M+H].sup.+
Step 2. 2-chloro-6-fluorobenzo[d]oxazole
(223) Into a 500-mL round-bottom flask, was placed 6-fluoro-2,3-dihydro-1,3-benzoxazole-2-thione (9.2 g, 54.38 mmol, 1.00 equiv), thionyl chloride (200 mL) and DMF (0.5 mL). The resulting solution was stirred for 6 h at 80° C. in an oil bath. After reaction, the excess of SOCl.sub.2 was removed under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (0/100˜7/93). The fractions were collected and concentrated under vacuum. This resulted in 3.5 g (38%) of the title compound as brown oil. LC-MS (ES, m/z) 172 [M+H].sup.+
Step 3. 4-bromo-2-fluorobenzoyl chloride
(224) Into a 250-mL round-bottom flask, was placed 4-bromo-2-fluorobenzoic acid (10 g, 45.66 mmol), thionyl chloride (50 mL) and N,N-dimethylformamide (0.1 mL). The resulting mixture was stirred for 2 h at 80° C. After cooling to room temperature, the solution concentrated under vacuum. This resulted in 10 g (92%) of the title compound as light yellow oil. The product was used in the next step directly without further purification.
Step 4. tert-butyl 4-(4-bromo-2-fluorobenzoyl)piperazine-1-carboxylate
(225) Into a 250-mL round-bottom flask, was placed a solution of 4-bromo-2-fluorobenzoyl chloride (10 g, 42.11 mmol, 1.00 equiv) in N,N-dimethylformamide (100 mL). This was followed by the addition of tert-butyl piperazine-1-carboxylate (7.88 g, 42.31 mmol, 1.00 equiv) in several portions. Then DIEA (16.25 g, 125.74 mmol, 2.99 equiv) was added in. The resulting solution was stirred overnight at room temperature. The product was precipitated by the addition of 400 mL of H.sub.2O. The solids were collected by filtration and dried in an oven. This resulted in 14 g (86%) of the title compound as a white solid. LC-MS (ES, m/z) 387,389 [M+H].sup.+
Step 5. tert-butyl 4-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoyl)piperazine-1-carboxylate (Intermediate 3)
(226) Into a 2000-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of tert-butyl 4-[(4-bromo-2-fluorophenyl)carbonyl]piperazine-1-carboxylate (57 g, 147.19 mmol, 1.00 equiv) in N,N-dimethylformamide (800 mL), 4,4,5,5-tetramethyl-2-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (76.2 g, 300.07 mmol, 2.01 equiv), PdCl.sub.2(dppf) (11 g, 15.03 mmol, 0.10 equiv), KOAc (44.1 g, 449.36 mmol, 3.00 equiv). The resulting mixture was stirred overnight at 70° C. After cooling to room temperature, the mixture was poured into 3 L of H.sub.2O. The solids were collected by filtration, further purified by a silica gel column with ethyl acetate/petroleum ether (3:7). The collected fractions were combined and concentrated under vacuum. This resulted in 30 g (47%) of the title compound as a light brown solid. LC-MS (ES, m/z) 435 [M+H].sup.+
Step 6. tert-butyl 4-(2-fluoro-4-(6-fluorobenzo[d]oxazol-2-yl)benzoyl)piperazine-1-carboxylate
(227) Into a 100-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of tert-butyl 4-[[2-fluoro-4-(tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]carbonyl]piperazine-1-carboxylate (1.26 g, 2.90 mmol, 1.00 equiv) in toluene (24 mL), 2-chloro-6-fluoro-1,3-benzoxazole (500 mg, 2.91 mmol, 1.00 equiv), Pd(PPh.sub.3).sub.4 (336 mg, 0.29 mmol, 0.10 equiv), sodium carbonate (12 mL, 2M), ethanol (3.3 mL). The resulting mixture was stirred overnight at 95° C. After cooling to room temperature, the resulting solution was diluted with 30 ml of water and extracted with 2×30 mL of ethyl acetate. The organic layers were combined and dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with EA/DCM (3/10). This resulted in 1.1 g (86%) of the title compound as a gray solid. LC-MS (ES, m/z) 444 [M+H].sup.+
Step 7. (2-fluoro-4-(6-fluorobenzo[d]oxazol-2-yl)phenyl)(piperazin-1-yl)methanone
(228) Into a 250-mL round-bottom flask, was placed a solution of tert-butyl 4-[[2-fluoro-4-(6-fluoro-1,3-benzoxazol-2-yl)phenyl]carbonyl]piperazine-1-carboxylate (1.1 g, 2.48 mmol, 1.00 equiv) in dichloromethane (100 mL). To the above hydrogen chloride gas was introduced in. The resulting solution was stirred for 1 h at room temperature. The solids were collected by filtration and then dissolved in water, then adjusted to pH 6-7 with sodium bicarbonate. Then the solids were collected by filtration and dried in oven. This resulted in 700 mg (82%) of the title compound as a gray solid. LC-MS (ES, m/z) 344 [M+H].sup.+
Step 8. (4-(2-fluoro-4-(6-fluorobenzo[d]oxazol-2-yl)benzoyl)piperazin-1-yl)(1-hydroxycyclopropyl)methanone
(229) Into a 50-mL round-bottom flask, was placed a solution of 6-fluoro-2-[3-fluoro-4-[(piperazin-1-yl)carbonyl]phenyl]-1,3-benzoxazole (538 mg, 1.57 mmol, 1.00 equiv) in N,N-dimethylformamide (15 mL), 1-hydroxycyclopropane-1-carboxylic acid (160 mg, 1.57 mmol, 1.00 equiv), HBTU (891 mg, 2.35 mmol, 1.50 equiv), DIEA (809 mg, 6.26 mmol, 4.00 equiv). The resulting solution was stirred overnight at room temperature. The reaction mixture was then diluted with 30 mL of water. The resulting solution was extracted with 2×20 mL of dichloromethane and the organic layers combined and dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (7:1). The fraction was collected and concentrated. This product was re-crystallized from EA/PE in the ratio of 10/1. This resulted in 206.7 mg (30%) of the title compound as an off-white solid. LC-MS (ES, m/z) 428 [M+H].sup.+
(230) Method 14.
(231) ##STR00745##
Step 1. tert-butyl 4-(4-(1-methyl-1H-benzo[d]imidazol-5-yl)benzoyl)piperazine-1-carboxylate
(232) Into a 100-mL round-bottom flask, was placed tert-butyl 4-[[4-(tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]carbonyl]piperazine-1-carboxylate (832 mg, 2.00 mmol, 1.00 equiv), 5-bromo-1-methyl-1H-1,3-benzodiazole (422 mg, 2.00 mmol, 1.00 equiv), Pd(PPh.sub.3).sub.4 (232 mg, 0.20 mmol, 0.10 equiv), sodium carbonate (2N, 5 mL), toluene (10 mL), ethanol (3 mL). The resulting mixture was stirred overnight at 95° C. in an oil bath. After cooled to room temperature, the resulting solution was diluted with 10 mL of water, extracted with 3×20 mL of ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (0/100˜100/0). The collected fractions were combined and concentrated under vacuum. This resulted in 800 mg (95%) of the title compound as a light yellow solid. LC-MS (ES, m/z): 421 [M+H].sup.+
Step 2. (4-(1-methyl-1H-benzo[d]imidazol-5-yl)phenyl)(piperazin-1-yl)methanone hydrochloride
(233) Into a 100-mL round-bottom flask, was placed tert-butyl 4-[[4-(1-methyl-1H-1,3-benzodiazol-5-yl)phenyl]carbonyl]piperazine-1-carboxylate (800 mg, 1.90 mmol, 1.00 equiv), dichloromethane (20 mL). Then HCl gas was introduced in. The resulting solution was stirred for 1.5 h at room temperature. The solids were collected by filtration and dried under vacuum. This resulted in 580 mg (95%) of the title compound as an off-white solid. LC-MS (ES, m/z): 321 [M+H].sup.+
Step 3. tert-butyl (1-(4-(4-(1-methyl-1H-benzo[d]imidazol-5-yl)benzoyl)piperazine-1-carbonyl)cyclopropyl)carbamate
(234) Into a 50-mL round-bottom flask, was placed 1-methyl-5-[4-[(piperazin-1-yl)carbonyl]phenyl]-1H-1,3-benzodiazole hydrochloride (580 mg, 1.63 mmol, 1.00 equiv), 1-[[(tert-butoxy)carbonyl]amino]cyclopropane-1-carboxylic acid (360 mg, 1.79 mmol, 1.10 equiv), HBTU (927 mg, 2.44 mmol, 1.50 equiv), DIEA (841 mg, 6.51 mmol, 4.00 equiv), N,N-dimethylformamide (10 mL). The mixture was stirred overnight at room temperature for overnight. The resulting solution was diluted with 60 mL of water, extracted with 3×60 mL of dichloromethane. The organic layers were combined, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with dichloromethane/methanol (80/20). The collected fractions were combined and concentrated under vacuum. This resulted in 800 mg (quantitative) of the title compound as colorless oil. LC-MS (ES, m/z): 504 [M+H].sup.+
Step 4. (4-(1-aminocyclopropane-1-carbonyl)piperazin-1-yl)(4-(1-methyl-1H-benzo[d]imidazol-5-yl)phenyl)methanone
(235) Into a 100-mL round-bottom flask, was placed tert-butyl N-[1-[(4-[[4-(1-methyl-1H-1,3-benzodiazol-5-yl)phenyl]carbonyl]piperazin-1-yl)carbonyl]cyclopropyl]carbamate (800 mg, 1.59 mmol, 1.00 equiv), dichloromethane (50 mL). Then HCl gas was bubbled in for 1.5 h at room temperature. The solids were collected by filtration and washed with DCM (50 mL). Then the solids were dissolved in 5 mL of water. The pH value of the solution was adjusted to 8 with potassium carbonate (2M). The resulting mixture was extracted with 2×50 mL of dichloromethane and the organic layers combined and concentrated under vacuum. The crude product was purified by Prep-HPLC with the following conditions (Waters III): Column, Xbridge RP18 19*150; mobile phase, water (0.05% NH.sub.4HCO.sub.3) and MeCN (15% CH.sub.3CN up to 75% in 10 min); Detector, UV 220&254 nm. This resulted in 93.1 mg (15%) of the title compound as a white solid. LC-MS (ES, m/z) 404[M+H].sup.+
(236) Method 15.
(237) ##STR00746##
Step 1. 4-bromo-2-fluorobenzoyl chloride
(238) Into a 250-mL round-bottom flask, was placed 4-bromo-2-fluorobenzoic acid (10 g, 45.66 mmol, 1.00 equiv), thionyl chloride (50 mL), N,N-dimethylformamide (0.1 mL). The resulting solution was stirred for 2 h at 80° C. After cooled to room temperature, the resulting mixture was concentrated under vacuum. This resulted in 10 g (92%) of the title compound as light yellow oil. The product was used in the next step directly without further purification.
Step 2. tert-butyl 4-(4-bromo-2-fluorobenzoyl)piperazine-1-carboxylate
(239) Into a 250-mL round-bottom flask, was placed a solution of 4-bromo-2-fluorobenzoyl chloride (10 g, 42.11 mmol, 1.00 equiv) in N,N-dimethylformamide (100 mL). This was followed by the addition of tert-butyl piperazine-1-carboxylate (7.88 g, 42.31 mmol, 1.00 equiv) in several portions. Then to this was added DIEA (16.25 g, 125.74 mmol, 2.99 equiv). The resulting mixture was stirred overnight at room temperature. The mixture was poured into 300 mL water. The solids were collected by filtration and dried under vacuum. This resulted in 14 g (86%) of the title compound as a white solid. LC-MS (ES, m/z): 387, 389[M+H].sup.+
Step 3. tert-butyl 4-(4′-chloro-2′,3-difluoro-[1,1′-biphenyl]-4-carbonyl)piperazine-1-carboxylate
(240) Into a 100-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of tert-butyl 4-(4-bromo-2-fluorobenzoyl)piperazine-1-carboxylate (1 g, 2.58 mmol, 1.00 equiv) in toluene (10 mL), (4-chloro-2-fluorophenyl)boronic acid (540 mg, 3.10 mmol, 1.20 equiv), Pd(PPh.sub.3).sub.4 (358 mg, 0.31 mmol, 0.12 equiv), sodium carbonate (2 M in water, 5 mL), ethanol (1.4 mL). The resulting mixture was stirred overnight at 105° C. After cooled to room temperature, the resulting solution was diluted with 20 mL of H.sub.2O and extracted with 3×20 mL of ethyl acetate. The organic layers were combined, washed with 3×20 mL of brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (3:7). The collected fractions were combined and concentrated under vacuum. This resulted in 1 g (89%) of the title compound as a light yellow solid. LC-MS (ES, m/z): 437[M+H].sup.+
Step 4. (4′-chloro-2′,3-difluoro-[1,1′-biphenyl]-4-yl)(piperazin-1-yl)methanone hydrochloride
(241) Into a 100-mL round-bottom flask, was placed tert-butyl 4-(4′-chloro-2′,3-difluoro-[1,1′-biphenyl]-4-carbonyl)piperazine-1-carboxylate (1 g, 2.28 mmol, 1.00 equiv), hydrochloric acid in 1,4-dioxane (4 M, 30 mL). The resulting solution was stirred for 30 min at room temperature. The resulting mixture was concentrated under vacuum. This resulted in 600 mg (78%) of the title compound as an off-white solid. LC-MS (ES, m/z): 337[M+H].sup.+
Step 5. (4-(4′-chloro-2′,3-difluoro-[1,1′-biphenyl]-4-carbonyl)piperazin-1-yl)(1-hydroxycyclopropyl)methanone
(242) Into a 100-mL round-bottom flask, was placed a solution of (4′-chloro-2′,3-difluoro-[1,1′-biphenyl]-4-yl)(piperazin-1-yl)methanone hydrochloride (500 mg, 1.48 mmol, 1.00 equiv), N,N-dimethylformamide (20 mL), 1-hydroxycyclopropane-1-carboxylic acid (166 mg, 1.63 mmol, 1.10 equiv), HBTU (841 mg, 2.22 mmol, 1.49 equiv), DIEA (764 mg, 5.91 mmol, 3.98 equiv). The resulting solution was stirred overnight at room temperature. The mixture was poured into 80 mL of water and precipitation was formed. The solids were collected by filtration and applied onto a silica gel column with ethyl acetate/hexane (3:2). The collected fractions were combined and concentrated under vacuum. This resulted in 260 mg (42%) of the title compound as an off-white solid. LC-MS (ES, m/z): 421[M+H].sup.+
(243) Method 16.
(244) ##STR00747##
Step 1. 5-bromo-N-methyl-2H-benzo[d][1,2,3]triazole
(245) Into a 100-mL round-bottom flask, was placed a solution of 6-bromo-H-1,2,3-benzotriazole (600 mg, 3.03 mmol, 1.00 equiv) in N,N-dimethylformamide (10 mL). This was followed by the addition of sodium hydride (60% in oil, 303 mg, 7.58 mmol, 2.50 equiv) in portions at 0° C. After stirring for 30 min at 0° C., CH.sub.3I (650 mg, 4.58 mmol, 1.50 equiv) was added in drop wise. The resulting solution was allowed to react, with stirring, for an additional 18 h at 20° C. The reaction mixture was then diluted with 10 mL of ice/water, extracted with 3×20 mL of ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with PE:EA (200:1-3:1). This resulted in 700 mg (crude) of a mixture of the title compounds as a yellow oil. LC-MS (ES, m/z): 212, 214 [M+H].sup.+
Step 2. tert-butyl 4-(4-(N-methyl-2H-benzo[d][1,2,3]triazol-5-yl)benzoyl)piperazine-1-carboxylate
(246) Into a 100-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed tert-butyl 4-[[4-(tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]carbonyl]piperazine-1-carboxylate (1.51 g, 3.63 mmol, 1.10 equiv), the mixture of 5-bromo-N-methyl-2H-benzo[d][1,2,3]triazoles (700 mg, 3.30 mmol, 1.00 equiv), Pd(PPh.sub.3).sub.4 (382 mg, 0.33 mmol, 0.10 equiv) and toluene/EtOH (30/4.5 mL), sodium carbonate (15 mL, 2M). The resulting mixture was stirred for 18 h at 90° C. After cooled to room temperature, the reaction mixture was diluted with 50 mL of water, extracted with 3×30 mL of ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with dichloromethane/methanol (200/1˜20/1). This resulted in 1.2 g (crude) of a mixture of the title compounds as a light yellow solid. LC-MS (ES, m/z): 422 [M+H].sup.+
Step 3. (4-(N-methyl-2H-benzo[d][1,2,3]triazol-5-yl)phenyl)(piperazin-1-yl)methanone hydrochloride
(247) Into a 100-mL round-bottom flask, was placed the mixture of tert-butyl 4-(4-(N-methyl-2H-benzo[d][1,2,3]triazol-5-yl)benzoyl)piperazine-1-carboxylate (1.2 g, 2.85 mmol, 1.00 equiv) and dichloromethane (50 mL). Then hydrogen chloride (gas) was introduced in. The resulting solution was stirred for 30 min at 20° C. The resulting solids were collected by filtration and dried under reduced pressure. This resulted in 800 mg (79%) of a mixture of the title compounds as a light yellow solid. LC-MS (ES, m/z): 322 [M+H].sup.+
Step 4. (4-(1-hydroxycyclopropane-1-carbonyl)piperazin-1-yl)(4-(2-methyl-2H-benzo[d][1,2,3]triazol-5-yl)phenyl)methanone
(248) Into a 100-mL round-bottom flask, was placed a solution of 1-hydroxycyclopropane-1-carboxylic acid (240 mg, 2.35 mmol, 1.10 equiv) in N,N-dimethylformamide (10 mL), the mixture of (4-(N-methyl-2H-benzo[d][1,2,3]triazol-5-yl)phenyl)(piperazin-1-yl)methanone hydrochloride (766 mg, 2.14 mmol, 1.00 equiv, 98%), HBTU (1.22 g, 3.22 mmol, 1.50 equiv), DIEA (1.11 g, 8.59 mmol, 4.00 equiv). The resulting solution was stirred for 18 h at 20° C. The reaction mixture was diluted with 20 mL of water, extracted with 3×20 mL of ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by Prep-HPLC with the following conditions (Waters III): Column, XBridge Prep Cis OBD Column, 5 um, 19*150 mm; mobile phase, water with 0.03% NH.sub.3H.sub.2O and MeCN (16% MeCN up to 34% in 8 min); Detector, 254&220 nm. This resulted in 90 mg (10%) of the title compound as a light yellow solid. LC-MS (ES, m/z) 406[M+H].sup.+
(249) Method 17.
(250) ##STR00748##
Step 1. (4-(4-(tert-butoxycarbonyl)piperazine-1-carbonyl)phenyl)boronic acid
(251) Into a 1 L round-bottom flask was placed Intermediate 3 (12.5 g, 30.03 mmol, 1.00 eqiv) a solution of sodium periodate (32.1 g, 150.00 mmol, 5.00 eqiv) in acetone (300 mL), ammonium acetate (150 mL, 5.00 eqiv, 1M). The resulting solution was stirred for 18 h at RT. The resulting solution was diluted with 300 mL of water and extracted with 3×100 mL of ethyl acetate. The organic layers were combined and dried over sodium sulfate. The solids were filtered out and the solution was concentrated in vacuo. This afforded the title compound (10.1 g, 96%) as a light yellow solid. LC-MS (ES, m/z) 335[M+H].sup.+
Step 2. tert-butyl 4-(4-(2-methyl-1H-benzo[d]imidazol-1-yl)benzoyl)piperazine-1-carboxylate
(252) Into a 250-mL round-bottom flask, was placed a solution of (4-(4-(tert-butoxycarbonyl)piperazine-1-carbonyl)phenyl)boronic acid (3.34 g, 9.05 mmol, 2.00 equiv) in dichloromethane (50 mL), 2-methyl-1H-benzo[d]imidazole (660 mg, 4.99 mmol, 1.00 equiv), Cu(OAc).sub.2 (1.23 mg, 1.50 equiv), pyridine (790 mg, 9.99 mmol, 2.00 equiv), 4A molecular sieves (3 g). The resulting mixture was stirred for 18 h at 20° C. The solids were filtered out. The filtrate was concentrated under vacuum. The residue was applied onto a silica gel column with DCM/MeOH (200/1˜20/1). This resulted in 1 g (27%) of the title compound as yellow oil. LC-MS (ES, m/z): 421[M+H].sup.+
Step 3. (4-(2-methyl-1H-benzo[d]imidazol-1-yl)phenyl)(piperazin-1-yl)methanone hydrochloride
(253) Into a 100-mL round-bottom flask, was placed tert-butyl 4-(4-(2-methyl-1H-benzo[d]imidazol-1-yl)benzoyl)piperazine-1-carboxylate (960 mg, 2.28 mmol, 1.00 equiv), DCM (30 mL), THE (30 mL). Then hydrogen chloride (gas) was introduced in. The resulting solution was stirred for 30 min at 20° C. The solids were collected by filtration and dried under vacuum. This resulted in 600 mg of the title compound as a light yellow solid. LC-MS (ES, m/z): 321[M+H].sup.+
Step 4. (4-(1-hydroxycyclopropane-1-carbonyl)piperazin-1-yl)(4-(2-methyl-1H-benzo[d]imidazol-1-yl)phenyl)methanone
(254) Into a 100-mL round-bottom flask, was placed 1-hydroxycyclopropane-1-carboxylic acid (190 mg, 1.86 mmol, 1.10 equiv), (4-(2-methyl-1H-benzo[d]imidazol-1-yl)phenyl)(piperazin-1-yl)methanone hydrochloride (600 mg, 1.68 mmol, 1.00 equiv), HBTU (955 mg, 2.52 mmol, 1.50 equiv), N,N-dimethylformamide (10 mL), DIEA (867 mg, 6.71 mmol, 4.00 equiv). The resulting solution was stirred for 18 h at 20° C. The reaction mixture was diluted with 20 mL of water, extracted with 3×20 mL of ethyl acetate. All the organic layers were combined, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by Prep-HPLC with the following conditions (Waters I): Column, Xbridge Prep C18 OBD column, 5 um, 19*150 mm; mobile phase, Water (0.05% NH.sub.4HCO.sub.3) and CH.sub.3CN (16% CH.sub.3CN up to 34% in 10 min); Detector, UV 220&254 nm. This resulted in 130 mg (19%) of the title compound as a white solid. LC-MS (ES, m/z): 405[M+H].sup.+
(255) Method 18.
(256) ##STR00749##
Step 1. tert-butyl 4-(4-(2-methyl-1H-indol-1-yl)benzoyl)piperazine-1-carboxylate
(257) Into a 250-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of tert-butyl 4-[(4-bromophenyl)carbonyl]piperazine-1-carboxylate (Intermediate 1 (X=H), 1.69 g, 4.58 mmol, 1.00 equiv) in toluene (50 mL), 2-methyl-1H-indole (600 mg, 4.57 mmol, 1.00 equiv), CuI (87 mg, 0.46 mmol, 0.10 equiv), potassium carbonate (1.9 g, 13.75 mmol, 3.00 equiv), (1R,2R)-1-N,2-N-dimethylcyclohexane-1,2-diamine (130 mg, 0.91 mmol, 0.20 equiv). The resulting mixture was stirred overnight at 120° C. After cooled to room temperature, the reaction mixture was diluted with 50 mL of H.sub.2O, extracted with 3×50 mL of ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:1). The collected fractions were combined and concentrated under vacuum. This resulted in 1.4 g (73%) of the title compound as a red solid. LC-MS (ES, m/z): 420[M+H].sup.+
Step 2. (4-(2-methyl-1H-indol-1-yl)phenyl)(piperazin-1-yl)methanone hydrochloride (Intermediate 4)
(258) Into a 100-mL round-bottom flask, was placed a solution of tert-butyl 4-(4-(2-methyl-1H-indol-1-yl)benzoyl)piperazine-1-carboxylate (1.4 g, 3.34 mmol) in dichloromethane (30 mL). To the above HCl gas was introduced in. The resulting solution was stirred for 30 min at room temperature. The resulting mixture was concentrated under vacuum. This resulted in 1.4 g (59%) of the title compound as a red solid. LC-MS (ES, m/z): 320[M+H].sup.+
Step 3. (4-(1-hydroxycyclopropane-1-carbonyl)piperazin-1-yl)(4-(2-methyl-1H-indol-1-yl)phenyl)methanone
(259) Into a 100-mL round-bottom flask, was placed a solution of (4-(2-methyl-1H-indol-1-yl)phenyl)(piperazin-1-yl)methanone hydrochloride (658 mg, 1.85 mmol, 1.00 equiv) in N,N-dimethylformamide (20 mL), 1-hydroxycyclopropane-1-carboxylic acid (189 mg, 1.85 mmol, 1.00 equiv), HBTU (1.05 g, 2.77 mmol, 1.50 equiv), DIEA (955 mg, 7.39 mmol, 4.00 equiv). The resulting solution was stirred overnight at room temperature. The reaction mixture was diluted with 30 mL of water and extracted with 3×30 mL of ethyl acetate. The organic layers were combined, dried over sodium sulfate anhydrous and concentrated under vacuum. The residue was applied onto a silica gel column with dichloromethane/methanol (10:1). The collected fractions were combined and concentrated under vacuum. This resulted in 112.3 mg (15%) of the title compound as a light brown solid. LC-MS (ES, m/z): 404[M+H].sup.+
(260) Method 19.
(261) ##STR00750##
Step 1. tert-butyl 4-(4-(indolin-1-yl)benzoyl)piperazine-1-carboxylate
(262) Into a 100-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 2,3-dihydro-1H-indole (390 mg, 3.27 mmol, 1.00 equiv), tert-butyl 4-[(4-bromophenyl)carbonyl]piperazine-1-carboxylate (Intermediate 1 (R═H), 1.5 g, 3.60 mmol, 1.10 equiv), Cs.sub.2CO.sub.3 (3.74 g, 11.48 mmol, 3.51 equiv), toluene (50 mL), RuPhos palladium(II) biphenyl-2-amine mesylate (276 mg). The resulting mixture was stirred overnight at 85° C. After cooled to room temperature, the resulting mixture was concentrated under vacuum and re-dissolved with 200 mL of EA. The resulting mixture was washed with 3×50 mL of brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (50:50). This resulted in 1 g (75%) of the title compound as a yellow solid. LC-MS (ES, m/z): 408[M+H].sup.+
Step 2. (4-(indolin-1-yl)phenyl)(piperazin-1-yl)methanone hydrochloride
(263) Into a 100-mL round-bottom flask, was placed tert-butyl 4-(4-(indolin-1-yl)benzoyl)piperazine-1-carboxylate (1 g, 2.45 mmol, 1.00 equiv), a solution of hydrogen chloride in 1,4-dioxane (4M, 20 mL). The resulting solution was stirred for 1 h at room temperature. The solids were collected by filtration and dried under vacuum. This resulted in 800 mg (95%) of the title compound as a yellow solid. LC-MS (ES, m/z): 308[M+H].sup.+
Step 3. (4-(1-hydroxycyclopropane-1-carbonyl)piperazin-1-yl)(4-(indolin-1-yl)phenyl)methanone
(264) Into a 100-mL round-bottom flask, was placed (4-(indolin-1-yl)phenyl)(piperazin-1-yl)methanone hydrochloride (540 mg, 1.57 mmol, 1.00 equiv), 1-hydroxycyclopropane-1-carboxylic acid (160 mg, 1.57 mmol, 1.00 equiv), N,N-dimethylformamide (20 mL), HBTU (892 mg, 2.35 mmol, 1.50 equiv), DIEA (810 mg, 6.27 mmol, 3.99 equiv). The resulting solution was stirred overnight at room temperature. The reaction mixture was diluted with 50 mL of EA, washed with 3×30 mL of brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by Prep-HPLC with the following conditions (Waters I): Column, SunFire Prep C18, 5 um, 19*100 mm; mobile phase, Water (0.05% NH.sub.4HCO.sub.3) and CH.sub.3CN (50% CH.sub.3CN up to 100% in 10 min); Detector, UV 220&254 nm. This resulted in 63.8 mg (10%) of the title compound as an off-white solid. LC-MS (ES, m/z): 392[M+H].sup.+
(265) Method 20.
(266) ##STR00751##
Step 1. tert-butyl 4-(4-(3,4-dihydroquinolin-1(2H)-yl)benzoyl)piperazine-1-carboxylate
(267) Into a 100-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed Pd.sub.2(dba).sub.4 (305 mg), DavePhos (627 mg), toluene (50 mL). The mixture was stirred at room temperature for 30 min. Then 1,2,3,4-tetrahydroquinoline (700 mg, 5.26 mmol, 1.00 equiv), tert-butyl 4-[(4-bromophenyl)carbonyl]piperazine-1-carboxylate (Intermediate 1, 1.94 g, 5.25 mmol, 1.00 equiv), t-BuOK (1.18 g, 10.52 mmol, 2.00 equiv) were added in. The system was evacuated and back-filled with N2 for 5 times. The resulting mixture was stirred for 18 h at 120° C. in an oil bath. After cooled to room temperature, the resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (0/100˜45/55). The collected fractions were combined and concentrated under vacuum. This resulted in 540 mg (24%) of the title compound as a yellow solid. LC-MS (ES, m/z): 422 [M+H].sup.+
Step 2. (4-(3,4-dihydroquinolin-1(2H)-yl)phenyl)(piperazin-1-yl)methanone hydrochloride
(268) Into a 100-mL round-bottom flask, was placed tert-butyl 4-(4-(3,4-dihydroquinolin-1(2H)-yl)benzoyl)piperazine-1-carboxylate (540 mg, 1.28 mmol, 1.00 equiv), dichloromethane (40 mL). Then hydrogen chloride gas was bubbled in. The resulting solution was stirred for 2 h at room temperature. The resulting mixture was concentrated under vacuum. This resulted in 635 mg (quantitative) of the title compound as a yellow solid. LC-MS (ES, m/z): 322 [M+H].sup.+
Step 3. (4-(4-(3,4-dihydroquinolin-1(2H)-yl)benzoyl)piperazin-1-yl)(1-hydroxycyclopropyl)methanone
(269) Into a 100-mL round-bottom flask, was placed 1-hydroxycyclopropane-1-carboxylic acid (635 mg, 6.22 mmol, 1.00 equiv), (4-(3,4-dihydroquinolin-1(2H)-yl)phenyl)(piperazin-1-yl)methanone hydrochloride (181 mg, 0.51 mmol, 0.08 equiv), HBTU (1.34 g, 3.53 mmol, 0.57 equiv), N,N-dimethylformamide (15 mL), DIEA (457 mg, 3.54 mmol, 0.57 equiv). The resulting solution was stirred overnight at room temperature. The reaction mixture was diluted with 60 mL of EA, washed with 4×20 mL of water and 1×20 mL of brine. The organic phase was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (0/100-100/0). The resulting crude product was further purified by Prep-HPLC with the following conditions (Waters III): Column, Xbridge RP18 19*150; mobile phase, water (0.05% NH.sub.4HCO.sub.3) and MeCN (15% CH.sub.3CN up to 75% in 10 min); Detector, UV 220&254 nm. This resulted in 66.3 mg (3%) of the title compound as a purple solid. LC-MS (ES, m/z): 406 [M+H].sup.+
(270) Method 21.
(271) ##STR00752##
Step 1. tert-butyl 4-(4-(1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-1H-benzo[d]imidazol-5 and 6-yl)benzoyl)piperazine-1-carboxylate
(272) Into a 250-mL round-bottom flask, was placed tert-butyl 4-(4-(1H-benzo[d]imidazol-5-yl)benzoyl)piperazine-1-carboxylate (1 g, 2.46 mmol, 1.00 equiv), (2-bromoethoxy)(tert-butyl)dimethylsilane (883 mg, 3.69 mmol, 1.50 equiv), N,N-dimethylformamide (50 mL), Cs.sub.2CO.sub.3 (2.41 g, 7.40 mmol, 3.01 equiv). The resulting mixture was stirred overnight at 70° C. After cooled to room temperature, the reaction mixture was diluted with 100 mL of EA, washed with 3×50 mL of water and 50 mL of brine. The organic phase was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by Prep-HPLC with the following conditions (Waters I): Column, SunFire Prep C18, 5 um, 19*100 mm; mobile phase, Water (0.05% NH.sub.4HCO.sub.3) and CH.sub.3CN (55% CH.sub.3CN up to 75% in 7 min); Detector, UV 220&254 nm. This resulted in 380 mg (27%) of tert-butyl 4-(4-(1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-1H-benzo[d]imidazol-5-yl)benzoyl)piperazine-1-carboxylate as a yellow solid and 390 mg (28%) tert-butyl 4-(4-(1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-1H-benzo[d]imidazol-6-yl)benzoyl)piperazine-1-carboxylate as a yellow solid. LC-MS (ES, m/z): 565[M+H].sup.+
Step 2. (4-(1-(2-hydroxyethyl)-1H-benzo[d]imidazol-6-yl)phenyl)(piperazin-1-yl)methanone hydrochloride
(273) Into a 100-mL round-bottom flask, was placed tert-butyl 4-(4-(1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-1H-benzo[d]imidazol-6-yl)benzoyl)piperazine-1-carboxylate (380 mg, 0.67 mmol, 1.00 equiv) and dioxane (40 mL). Then HCl gas was introduced in. The resulting solution was stirred for 1 h at room temperature. The resulting mixture was concentrated under vacuum. This resulted in 250 mg (96%) of the title compound as a yellow solid. LC-MS (ES, m/z): 351[M+H].sup.+
Step 3. (4-(1-hydroxycyclopropane-1-carbonyl)piperazin-1-yl)(4-(1-(2-hydroxyethyl)-1H-benzo[d]imidazol-5-yl)phenyl)methanone
(274) Into a 100-mL round-bottom flask, was placed (4-(1-(2-hydroxyethyl)-1H-benzo[d]imidazol-6-yl)phenyl)(piperazin-1-yl)methanone hydrochloride (250 mg, 0.65 mmol, 1.00 equiv), 1-hydroxycyclopropane-1-carboxylic acid (66 mg, 0.65 mmol, 1.00 equiv), N,N-dimethylformamide (20 mL), HBTU (367 mg, 0.97 mmol, 1.50 equiv), DIEA (333 mg, 2.58 mmol, 3.99 equiv). The resulting solution was stirred overnight at room temperature. The reaction mixture was washed with water, dried over Na.sub.2SO.sub.4 and concentrated under vacuum. The residue was purified by Prep-HPLC with the following conditions (Waters I): Column, SunFire Prep C18, 5 um, 19*100 mm; mobile phase, Water (0.05% NH.sub.4HCO.sub.3) and CH.sub.3CN (55% CH.sub.3CN up to 75% in 7 min); Detector, UV 220&254 nm. This resulted in 75 mg (27%) of the title compound as an off-white solid. LC-MS (ES, m/z): 435[M+H].sup.+
(275) Method 22.
(276) ##STR00753##
Step 1. tert-butyl (3-(3-bromophenyl)isoxazol-5-yl)carbamate
(277) Into a 250-mL round-bottom flask, was placed a solution of 3-(3-bromophenyl)-1, 2-oxazol-5-amine (1 g, 4.18 mmol, 1.00 equiv) in dichloromethane (40 mL), Boc.sub.2O (1.83 g, 8.38 mmol, 2.00 equiv), triethylamine (1.27 g, 12.55 mmol, 3.00 equiv), 4-dimethylaminopyridine (51.24 mg, 0.42 mmol, 0.10 equiv). The resulting solution was stirred for 1 h at room temperature. The resulting mixture was washed with 2×20 mL of hydrochloric acid (0.5M), dried over anhydrous sodium sulfate, concentrated under vacuum. This resulted in 1.42 g (crude) of the title compound as an off-white solid. LC-MS (ES, m/z): 339[M+H].sup.+
Step 2. benzyl 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoyl)piperazine-1-carboxylate (Intermediate 5)
(278) Into a 1 L round-bottom flask was placed benzyl piperazine-1-carboxylate (15 g, 68.10 mmol, 1.00 equiv), 4-(tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid (16.9 g, 68.12 mmol, 1.00 equiv), EDC (14.4 g, 75.12 mmol, 1.10 equiv), HOBt (5.8 g, 42.92 mmol, 0.50 equiv), and triethylamine (27.6 g 272.75 mmol, 4.00 equiv) in dichloromethane (300 mL). The resulting solution was stirred for 18 h at RT. The mixture was then washed with 0.5M sodium carbonate (aq, 75 mL). The resulting mixture was then washed with 0.5M HCl (aq, 75 mL) followed by 0.5M sodium carbonate (aq, 75 mL). The solution was concentrated in vacuo and the crude product was recrystallized from tBME/hexane (1:1). This afforded the title compound (26 g, 84%) as a white solid. LC-MS (ES, m/z): 451[M+H].sup.+
Step 3. benzyl 4-(3′-(5-((tert-butoxycarbonyl)amino)isoxazol-3-yl)-[1,1′-biphenyl]-4-carbonyl)piperazine-1-carboxylate
(279) Into a 250-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of tert-butyl (3-(3-bromophenyl)isoxazol-5-yl)carbamate (1.42 g, 4.19 mmol, 1.00 equiv) in 1,4-dioxane (30 mL), benzyl 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoyl)piperazine-1-carboxylate (1.89 g, 4.20 mmol, 1.00 equiv), Pd(dppf)Cl.sub.2.CH.sub.2Cl.sub.2 (410 mg, 0.50 mmol, 0.12 equiv), Cs.sub.2CO.sub.3 (4.11 g, 12.61 mmol, 3.01 equiv), water (10 mL). The resulting solution was stirred overnight at 60° C. After cooled to room temperature, the reaction mixture was diluted with 30 mL of H.sub.2O, extracted with 3×30 mL of ethyl acetate. The organic layers were combined, washed with 30 mL of brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:1). The collected fractions were combined and concentrated under vacuum. This resulted in 780 mg (32%) of the title compound as an off-white solid. LC-MS (ES, m/z): 583[M+H].sup.+
Step 4. tert-butyl (3-(4′-(piperazine-1-carbonyl)-[1,1′-biphenyl]-3-yl)isoxazol-5-yl)carbamate
(280) Into a 100-mL round-bottom flask, was placed benzyl 4-(3′-(5-((tert-butoxycarbonyl)amino)isoxazol-3-yl)-[1,1′-biphenyl]-4-carbonyl)piperazine-1-carboxylate (1.8 g, 3.09 mmol, 1.00 equiv), methanol (40 mL) and Lindlar catalyst (1.8 g). The flask was evacuated and back-filled with hydrogen for 6 times. The resulting solution was stirred overnight at room temperature. The solids were filtered out. The filtrate was concentrated under vacuum. The residue was applied onto a silica gel column with dichloromethane/methanol (90:10). The collected fractions were combined and concentrated under vacuum. This resulted in 850 mg (61%) of the title compound as a light yellow solid. LC-MS (ES, m/z): 449[M+H].sup.+
Step 5. tert-butyl (3-(4′-(4-(1-hydroxycyclopropane-1-carbonyl)piperazine-1-carbonyl)-[1,1′-biphenyl]-3-yl)isoxazol-5-yl)carbamate
(281) Into a 100-mL round-bottom flask, was placed a solution of tert-butyl (3-(4′-(piperazine-1-carbonyl)-[1,1′-biphenyl]-3-yl)isoxazol-5-yl)carbamate (850 mg, 1.90 mmol, 1.00 equiv) in N,N-dimethylformamide (20 mL), 1-hydroxycyclopropane-1-carboxylic acid (194 mg, 1.90 mmol, 1.00 equiv), HBTU (1.08 g, 2.85 mmol, 1.50 equiv), DIEA (980 mg, 7.58 mmol, 4.00 equiv). The resulting solution was stirred overnight at room temperature. The reaction mixture was diluted with 30 mL of EA, washed with 3×30 mL of brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with dichloromethane/methanol (90:10). The collected fractions were combined and concentrated under vacuum. This resulted in 600 mg (59%) of the title compound as a brown solid. LC-MS (ES, m/z): 533[M+H].sup.+
Step 6. (4-(3′-(5-aminoisoxazol-3-yl)-[1,1′-biphenyl]-4-carbonyl)piperazin-1-yl)(1-hydroxycyclopropyl)methanone
(282) Into a 100-mL round-bottom flask, was placed tert-butyl (3-(4′-(4-(1-hydroxycyclopropane-1-carbonyl)piperazine-1-carbonyl)-[1,1′-biphenyl]-3-yl)isoxazol-5-yl)carbamate (600 mg, 1.13 mmol, 1.00 equiv), dichloromethane (30 mL). To the above HCl gas was introduced in. The resulting solution was stirred for 1 h at room temperature. The mixture was concentrated and dissolved in 5 mL methanol. The pH value of the solution was adjusted to 8 with saturated sodium bicarbonate solution. The resulting solution was extracted with 2×30 mL of dichloromethane. The organic layers were combined, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by Prep-HPLC with the following conditions (Waters I): Column, Xbridge Prep C18 OBD column, 5 um, 19*150 mm; mobile phase, Water (0.05% NH.sub.4HCO.sub.3) and CH.sub.3CN (30% CH.sub.3CN up to 70% in 9 min); Detector, UV 220&254 nm. This resulted in 107.4 mg (22%) of the title compound as a white solid. LC-MS (ES, m/z): 433[M+H].sup.+
(283) Method 23.
(284) ##STR00754##
Step 1. 4-(1-methyl-1H-benzo[d]imidazol-5-yl)benzoic acid
(285) Into a 250-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of 4-(tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid (2.35 g, 9.47 mmol, 1.00 equiv) in CH.sub.3CN/toluene (70/12 mL), 5-bromo-1-methyl-1H-benzo[d]imidazole (2 g, 9.48 mmol, 1.00 equiv), Pd(PPh.sub.3).sub.4 (548 mg, 0.47 mmol, 0.05 equiv), sodium carbonate (0.4M, 50 mL, 2.00 equiv). The resulting solution was stirred for 18 h at 90° C. After cooled to room temperature, the reaction mixture was poured into 50 ml of water. The mixture was washed with 2×100 mL of ethyl acetate and the aqueous layer was collected. The pH value of the solution was adjusted to 4 with hydrochloric acid (1N). The solids were collected by filtration and dried under vacuum. This resulted in 2 g (84%) of the title compound as a white solid, which was dried under vacuum. LC-MS (ES, m/z): 253 [M+H].sup.+
Step 2. tert-butyl (R)-2-methyl-4-(4-(1-methyl-1H-benzo[d]imidazol-5-yl)benzoyl)piperazine-1-carboxylate
(286) Into a 50-mL round-bottom flask, was placed a solution of 4-(1-methyl-1H-benzo[d]imidazol-5-yl)benzoic acid (600 mg, 2.38 mmol, 1.00 equiv) in N,N-dimethylformamide (15 mL), tert-butyl (2R)-2-methylpiperazine-1-carboxylate (476 mg, 2.38 mmol, 1.00 equiv), HBTU (1.35 g, 3.56 mmol, 1.50 equiv), DIEA (1.22 g, 9.44 mmol, 4.00 equiv). The resulting solution was stirred overnight at room temperature. The reaction mixture was poured into 100 mL of water, extracted with 3×100 mL of dichloromethane. The organic layers were combined, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1/15). This resulted in 650 mg (63%) of the title compound as red oil. LC-MS (ES, m/z): 435 [M+H].sup.+
Step 3. (R)-(4-(1-methyl-1H-benzo[d]imidazol-5-yl)phenyl)(3-methylpiperazin-1-yl)methanone hydrochloride
(287) Into a 50-mL round-bottom flask, was placed a solution of tert-butyl (R)-2-methyl-4-(4-(1-methyl-1H-benzo[d]imidazol-5-yl)benzoyl)piperazine-1-carboxylate (650 mg, 1.50 mmol, 1.00 equiv) in dichloromethane (20 mL). To the above hydrogen chloride (gas) was introduced in. The resulting solution was stirred for 0.5 h at room temperature. The resulting mixture was concentrated under vacuum. The residue was triturated with 2×100 mL of ether. The solids were collected by filtration and dried under vacuum. This resulted in 500 mg (90%) of the title compound as a red solid. LC-MS (ES, m/z): 335 [M+H].sup.+
Step 4. (R)-(4-(1-hydroxycyclopropane-1-carbonyl)-3-methylpiperazin-1-yl)(4-(1-methyl-1H-benzo[d]imidazol-5-yl)phenyl)methanone
(288) Into a 50-mL round-bottom flask, was placed a solution of (R)-(4-(1-methyl-1H-benzo[d]imidazol-5-yl)phenyl)(3-methylpiperazin-1-yl)methanone hydrochloride (500 mg, 1.35 mmol, 1.00 equiv) in N,N-dimethylformamide (15 mL), 1-hydroxycyclopropane-1-carboxylic acid (137 mg, 1.34 mmol, 1.00 equiv), HBTU (766 mg, 2.02 mmol, 1.50 equiv), DIEA (695 mg, 5.38 mmol, 4.00 equiv). The resulting solution was stirred for overnight at room temperature. The reaction mixture was poured into 100 mL of water, extracted with 3×50 mL of dichloromethane. The organic layers were combined, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by Prep-HPLC with the following conditions (IntelFlash-1): Column, Cis silica gel; mobile phase, CH.sub.3CN/water with 0.05% NH.sub.4HCO.sub.3=20% increasing to CH.sub.3CN/water with 0.05% NH.sub.4HCO.sub.3=60% within 30 min; Detector, UV 254&220 nm. This resulted in 200.3 mg (36%) of the title compound as a white solid. LC-MS (ES, m/z): 419 [M+H]
(289) Method 24.
(290) ##STR00755##
Step 1. 7-benzyl 4-(tert-butyl) 4,7-diazaspiro[2.5]octane-4,7-dicarboxylate
(291) Into a 100-mL round-bottom flask, was placed a solution of tert-butyl 4, 7-diazaspiro[2.5]octane-4-carboxylate (3 g, 14.13 mmol, 1.00 equiv) and TEA (4.25 g, 42.00 mmol, 2.97 equiv) in dichloromethane (30 mL). This was followed by the addition of CbzCl (2.88 g, 16.88 mmol, 1.19 equiv) dropwise with stirring at 0° C. The resulting solution was stirred for 3 h at 25° C. The reaction mixture was diluted with 50 mL of water, extracted with 3×50 mL of dichloromethane. The organic layers were combined, washed with 2×100 mL of sodium carbonate solution (2M), dried over Na.sub.2SO.sub.4, and concentrated under vacuum. This resulted in 4 g (82%) of the title compound as yellow oil. LC-MS (ES, m/z) 347 [M+H].sup.+
Step 2. benzyl 4,7-diazaspiro[2.5]octane-7-carboxylate hydrochloride
(292) Into a 100-mL round-bottom flask, was placed a solution of 7-benzyl 4-tert-butyl 4, 7-diazaspiro[2.5]octane-4,7-dicarboxylate (4 g, 11.55 mmol, 1.00 equiv) in dichloromethane/tetrahydrofuran (20/20 mL). To the above solution, hydrogen chloride (gas) was introduced in. The resulting solution was stirred for 3 h at 25° C. The solids were collected by filtration. This resulted in 3 g (crude) of the title compound as a yellow oil. LC-MS (ES, m/z) 247 [M+H].sup.+
Step 3. benzyl 4-(4-(6-fluorobenzo[d]oxazol-2-yl)benzoyl)-4,7-diazaspiro[2.5]octane-7-carboxylate
(293) Into a 100-mL round-bottom flask, was placed HATU (1.55 g, 4.08 mmol, 1.00 equiv), 4-(6-fluoro-1,3-benzoxazol-2-yl)benzoic acid (951 mg, 3.70 mmol, 0.91 equiv), benzyl 4,7-diazaspiro[2.5]octane-7-carboxylate hydrogen chloride salt (1 g, 4.06 mmol, 1.00 equiv), DIEA (955 mg, 7.39 mmol, 1.82 equiv) and N,N-dimethylformamide (30 mL). The resulting solution was stirred for 18 h at 25° C. The mixture was then diluted with 50 mL of EA, washed with 2×50 mL of water, dried over Na.sub.2SO.sub.4 and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (10%-90%). This resulted in 1.2 g (crude) of the title compound as yellow oil. LC-MS (ES, m/z): 486 [M+H].sup.+
Step 4. (4-(6-fluorobenzo[d]oxazol-2-yl)phenyl)(4,7-diazaspiro[2.5]octan-4-yl)methanone
(294) Into a 100-mL round-bottom flask, was placed benzyl 4-[[4-(6-fluoro-1,3-benzoxazol-2-yl)phenyl]carbonyl]-4,7-diazaspiro[2.5]octane-7-carboxylate (Intermediate 2, 1.2 g, 2.47 mmol, 1.00 equiv), palladium on active carbon (1.2 g) and methanol (30 mL). Then the flask was evacuated and back-filled with hydrogen for three times. The resulting solution was stirred for 3 h at 25° C. The solids were filtered out. The filtrate was concentrated under vacuum. This resulted in 700 mg (crude) of the title compound as a light yellow solid. LC-MS (ES, m/z): 352 [M+H].sup.+
Step 5. (4-(4-(6-fluorobenzo[d]oxazol-2-yl)benzoyl)-4,7-diazaspiro[2.5]octan-7-yl)(1-hydroxycyclopropyl)methanone
(295) Into a 100-mL round-bottom flask, was placed HATU (658 mg, 1.73 mmol, 1.00 equiv), 1-hydroxycyclopropane-1-carboxylic acid (160 mg, 1.57 mmol, 0.91 equiv), 2-[4-([4,7-diazaspiro[2.5]octan-4-yl]carbonyl)phenyl]-6-fluoro-1,3-benzoxazole (608 mg, 1.73 mmol, 1.00 equiv), DIEA (406 mg, 3.14 mmol, 1.82 equiv) and N,N-dimethylformamide (15 mL). The resulting solution was stirred for 18 h at 25° C. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (10%-90%). The crude product was purified by Prep-HPLC with the following conditions (Waters I): Column, Xbridge Prep C18 OBD column, 5 um, 19*150 mm; mobile phase, Water (0.05% NH.sub.4HCO.sub.3) and CH.sub.3CN (10% CH.sub.3CN up to 40% in 9 min); Detector, UV 220&254 nm. This resulted in 171.6 mg (23%) of the title compound as a white solid. LC-MS (ES, m/z): 436 [M+H].sup.+
(296) Method 25.
(297) ##STR00756## ##STR00757##
Step 1. benzyl 4-(3′-(5-((tert-butoxycarbonyl)amino)-1H-pyrazol-3-yl)-[1,1′-biphenyl]-4-carbonyl)piperazine-1-carboxylate
(298) Into a 100-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of benzyl 4-[[4-(tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]carbonyl]piperazine-1-carboxylate (Intermediate 5, 710 mg, 1.58 mmol, 1.00 equiv) in 1,4-dioxane (20 mL), tert-butyl N-[3-(3-bromophenyl)-1H-pyrazol-5-yl]carbamate (533.2 mg, 1.58 mmol, 1.00 equiv), Pd(dppf)Cl2 (115.5 mg, 0.16 mmol, 0.10 equiv), sodium carbonate (2M, 5 mL). The resulting mixture was stirred overnight at 85° C. After cooled to room temperature, the reaction mixture was diluted with 30 mL of water, extracted with 2×100 mL of ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (4/1). This resulted in 300 mg (33%) of the title compound as a yellow solid. LC-MS (ES, m/z): 582[M+H].sup.+
Step 2. tert-butyl (3-(4′-(piperazine-1-carbonyl)-[1,1′-biphenyl]-3-yl)-1H-pyrazol-5-yl)carbamate
(299) Into a 50-mL round-bottom flask, was placed a solution of benzyl 4-(3′-(5-((tert-butoxycarbonyl)amino)-1H-pyrazol-3-yl)-[1,1′-biphenyl]-4-carbonyl)piperazine-1-carboxylate (670 mg, 1.15 mmol, 1.00 equiv) in methanol (20 mL). This was followed by the addition of Palladium carbon (670 mg). To the above hydrogen was introduced in. The resulting solution was stirred for 5 h at room temperature. The solids were filtered out. The filtrate was concentrated under vacuum. This resulted in 515.7 mg (100%) of the title compound as an orange solid. LC-MS (ES, m/z): 448[M+H].sup.+
Step 3. tert-butyl (3-(4′-(4-(1-hydroxycyclopropane-1-carbonyl)piperazine-1-carbonyl)-[1,1′-biphenyl]-3-yl)-1H-pyrazol-5-yl)carbamate
(300) Into a 250-mL round-bottom flask, was placed a solution of tert-butyl (3-(4′-(piperazine-1-carbonyl)-[1,1′-biphenyl]-3-yl)-1H-pyrazol-5-yl)carbamate (515.7 mg, 1.15 mmol, 1.00 equiv) in N,N-dimethylformamide (50 mL), 1-hydroxycyclopropane-1-carboxylic acid (117 mg, 1.15 mmol, 1.00 equiv), HBTU (654 mg, 1.72 mmol, 1.50 equiv), DIEA (445.5 mg, 3.45 mmol, 3.00 equiv). The resulting solution was stirred overnight at room temperature. The reaction mixture was then diluted with 50 mL of water, extracted with 2×150 mL of dichloromethane. The organic layers were combined, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (2/1). This resulted in 400 mg (65%) of the title compound as a brown solid. LC-MS (ES, m/z): 532[M+H].sup.+
Step 4. (4-(3′-(5-amino-1H-pyrazol-3-yl)-[1,1′-biphenyl]-4-carbonyl)piperazin-1-yl)(1-hydroxycyclopropyl)methanone
(301) Into a 100-mL round-bottom flask, was placed a solution of tert-butyl (3-(4′-(4-(1-hydroxycyclopropane-1-carbonyl)piperazine-1-carbonyl)-[1,1′-biphenyl]-3-yl)-1H-pyrazol-5-yl)carbamate (400 mg, 0.75 mmol, 1.00 equiv) in dichloromethane (30 mL). To the above HCl gas was introduced in. The resulting solution was stirred for 1 h at room temperature. The solids were collected by filtration and dissolved in 10 mL of water. The pH value was adjusted to 6-7 with saturated sodium bicarbonate solution. The solids were collected by filtration. The residue was purified by Flash-Prep-HPLC with the following conditions (IntelFlash-1): Column, Cis silica gel; mobile phase, CH.sub.3CN/water with 0.1% NH.sub.4HCO.sub.3=1/5 increasing to CH.sub.3CN/water with 0.1% NH.sub.4HCO.sub.3=3/2 within 20 min; Detector, UV 254&220 nm. This resulted in 102.9 mg (32%) of the title compound as a white solid. LC-MS (ES, m/z): 432[M+H].sup.+
(302) Method 26.
(303) ##STR00758## ##STR00759##
Step 1. N-(4-bromophenyl)-3-methyl-4,5,6,7-tetrahydro-1 and 2H-indazole
(304) Into a 250-mL round-bottom flask (1 atm) purged and maintained with an inert atmosphere of nitrogen, was placed 2-acetylcyclohexan-1-one (4.08 g, 29.11 mmol, 1.00 equiv), (4-bromophenyl)hydrazine hydrochloride (6.5 g, 29.08 mmol, 1.00 equiv), TsOH (500 mg, 2.90 mmol, 0.10 equiv), ethane-1,2-diol (100 mL). The resulting solution was stirred for 2 days at 105° C. in an oil bath. The resulting mixture was concentrated under vacuum. The crude product (4 g) was purified by Flash-Prep-HPLC with the following conditions (IntelFlash-1): Column, C18 silica gel; mobile phase, 0.05% NH.sub.4HCO.sub.3 solution, MeCN=95/5 increasing to 0.05% NH4HCO3 solution, MeCN=0/100 within 60 min; Detector, UV 254 nm. 1.5 g product was obtained. This resulted in 1.5 g (18%) of 2-(4-bromophenyl)-3-methyl-4,5,6,7-tetrahydro-2H-indazole as a light yellow solid and 0.8 g (9%) of 1-(4-bromophenyl)-3-methyl-4,5,6,7-tetrahydro-2H-indazole as a light yellow solid. LC-MS (ES, m/z): 292 [M+H].sup.+
Step 2. 1-(4-bromophenyl)-3-methyl-1H-indazole
(305) Into a 250-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 1-(4-bromophenyl)-3-methyl-4,5,6,7-tetrahydro-1H-indazole (3.5 g, 12.02 mmol, 1.00 equiv), benzene (100 mL), DDQ (10.9 g, 48.02 mmol, 3.99 equiv). The resulting solution was stirred for 22 h at 85° C. in an oil bath. After cooled to room temperature, the resulting mixture was concentrated under vacuum and diluted with 200 mL of EA and washed with 1×250 mL of water and 3×100 mL of brine. The organic phase was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (0/100-10/90). This resulted in 800 mg (23%) of the title compound as a white solid. LC-MS (ES, m/z) 287,289 [M+H].sup.+
Step 3. tert-butyl 4-(4-(3-methyl-1H-indazol-1-yl)benzoyl)piperazine-1-carboxylate
(306) Into a 250-mL pressure tank, was placed 1-(4-bromophenyl)-3-methyl-1H-indazole (800 mg, 2.79 mmol, 1.00 equiv), tert-butyl piperazine-1-carboxylate (770 mg, 4.13 mmol, 1.48 equiv), Pd(dppf)Cl.sub.2.CH.sub.2Cl.sub.2 (113 mg, 0.14 mmol, 0.05 equiv), toluene (120 mL), triethylamine (837 mg, 8.27 mmol, 2.97 equiv). Then the reactor was evacuated and back-filled with CO for three times. The resulting mixture was stirred for 24 h at 130° C. under CO pressure of 20 atm. After cooled to room temperature, the resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (0/100˜25/75). This resulted in 1.0 g (85%) of the title compound as a light yellow solid. LC-MS (ES, m/z) 421 [M+H].sup.+
Step 4. (4-(3-methyl-1H-indazol-1-yl)phenyl)(piperazin-1-yl)methanone hydrochloride
(307) Into a 250-mL round-bottom flask, was placed tert-butyl 4-(4-(3-methyl-1H-indazol-1-yl)benzoyl)piperazine-1-carboxylate (1 g, 2.38 mmol, 1.00 equiv), dichloromethane (100 mL). Then hydrogen chloride (gas) was introduced in. The resulting solution was stirred for 2 h at room temperature. The solids were collected by filtration. This resulted in 930 mg (crude) of the title compound as a light yellow solid. LC-MS (ES, m/z) 321 [M+H].sup.+
Step 5. (4-(1-hydroxycyclopropane-1-carbonyl)piperazin-1-yl)(4-(3-methyl-1H-indazol-1-yl)phenyl)methanone
(308) Into a 100-mL round-bottom flask, was placed 1-hydroxycyclopropane-1-carboxylic acid (265 mg, 2.60 mmol, 1.00 equiv), HBTU (1.086 g, 2.86 mmol, 1.10 equiv), N,N-dimethylformamide (20 mL), (4-(3-methyl-H-indazol-1-yl)phenyl)(piperazin-1-yl)methanone hydrochloride (930 mg, 2.61 mmol, 1.00 equiv), DIEA (1.68 g, 13.00 mmol, 5.01 equiv). The resulting solution was stirred overnight at room temperature. The resulting solution was diluted with 100 mL of EA, washed with 3×20 mL of water and 1×20 mL of brine. The organic phase was dried over anhydrous sodium sulfate and concentrate under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (0/100˜100/0). The collected fractions were combined and concentrated under vacuum. The resulting solid was stirred in 2×20 mL of MeCN, collected by filtration and dried under reduced pressure. This resulted in 228.5 mg (22%) of the title compound as an off-white solid. LC-MS (ES, m/z) 405 [M+H].sup.+
(309) Method 27.
(310) ##STR00760##
Step 1. (S)-(4-(4-(tert-butoxycarbonyl)-3-methylpiperazine-1-carbonyl)-3-fluorophenyl)boronic acid
(311) Into a 250 mL round-bottom flash was placed a solution of 4-(dihydroxyboranyl)-2-fluorobenzoic acid (1.84 g, 10.00 mmol, 1.00 equiv) in DMF (30 mL). HBTU (15.16 g, 39.97 mmol, 4.00 equiv) was added followed by DIEA (1.94 g, 15.01 mmol, 1.50 equiv). The resulting solution was stirred for 10 min. at RT, then a solution of tert-butyl (2R)-2-methylpiperazine-1-carboxylate (2 g, 9.99 mmol, 1.00 equiv) in DMF (5 mL) was added. The resulting solution was allowed to stir overnight. The solution was then diluted with EtOAc (50 mL) and washed with brine (3×50 mL). The organic layer was then dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by FCC eluting with dichloromethane/methanol (90:10). This afforded the title compound (3.5 g, 96%) as a brown solid. LC-MS (ES, m/z) 367 [M+H].sup.+
Step 2. tert-butyl (S)-4-(2-fluoro-4-(1-methyl-1H-benzo[d]imidazol-5-yl)benzoyl)-2-methylpiperazine-1-carboxylate
(312) Into a 100-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of (S)-(4-(4-(tert-butoxycarbonyl)-3-methylpiperazine-1-carbonyl)-3-fluorophenyl)boronic acid (837 mg, 2.29 mmol, 1.00 equiv) in toluene (20 mL), 5-bromo-1-methyl-1H-1,3-benzodiazole (400 mg, 1.90 mmol, 0.83 equiv), Pd(PPh.sub.3).sub.4 (264 mg, 0.23 mmol, 0.10 equiv), sodium carbonate (2M, 10 mL), ethanol (2.8 mL). The resulting mixture was stirred overnight at 95° C. After cooled to room temperature, the resulting solution was diluted with 20 mL of H.sub.2O, extracted with 3×30 mL of ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with dichloromethane/methanol (90:10). The collected fractions were combined and concentrated under vacuum. This resulted in 800 mg (77%) of the title compound as a brown solid. LC-MS (ES, m/z) 453 [M+H].sup.+
Step 3. (S)-(2-fluoro-4-(1-methyl-1H-benzo[d]imidazol-5-yl)phenyl)(3-methylpiperazin-1-yl)methanone hydrochloride
(313) Into a 100-mL round-bottom flask, was placed a solution of tert-butyl (S)-4-(2-fluoro-4-(1-methyl-1H-benzo[d]imidazol-5-yl)benzoyl)-2-methylpiperazine-1-carboxylate (800 mg, 1.77 mmol, 1.00 equiv) in dichloromethane (30 mL). To the above HCl (gas) was introduced in. The resulting solution was stirred for 2 h at room temperature. The solids were collected by filtration. This resulted in 650 mg (95%) of the title compound as a brown solid. LC-MS (ES, m/z) 353 [M+H].sup.+
Step 4. (S)-(4-(2-fluoro-4-(1-methyl-1H-benzo[d]imidazol-5-yl)benzoyl)-2-methylpiperazin-1-yl)(1-hydroxycyclopropyl)methanone
(314) Into a 100-mL round-bottom flask, was placed a solution of (S)-(2-fluoro-4-(1-methyl-1H-benzo[d]imidazol-5-yl)phenyl)(3-methylpiperazin-1-yl)methanone hydrochloride (650 mg, 1.67 mmol, 1.00 equiv) in N,N-dimethylformamide (20 mL), 1-hydroxycyclopropane-1-carboxylic acid (180 mg, 1.76 mmol, 1.05 equiv), HBTU (734 mg, 1.94 mmol, 1.16 equiv), DIEA (908 mg, 7.03 mmol, 4.20 equiv). The resulting solution was stirred overnight at room temperature. The reaction mixture was diluted with 30 mL of EA, washed with 3×30 mL of water and 30 mL of brine. The organic phase was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with dichloromethane/methanol (90:10). The crude product was further purified by Prep-HPLC with the following conditions (Waters III): Column, Xbridge RP18 5 um, 19*150; mobile phase, water (0.05% NH.sub.4HCO.sub.3) and MeCN (10% CH.sub.3CN up to 70% in 9 min); Detector, UV 220&254 nm. This resulted in 203.1 mg (28%) of the title compound as a white solid. LC-MS (ES, m/z) 437 [M+H].sup.+
(315) Method 28.
(316) ##STR00761##
Step 1. tert-butyl (S)-(1-(4-(4-(6-fluorobenzo[d]oxazol-2-yl)benzoyl)-2-methylpiperazine-1-carbonyl)cyclopropyl)carbamate
(317) Into a 100-mL round-bottom flask, was placed 1-[(tert-butoxy)carbonyl]aminocyclopropane-1-carboxylic acid (Intermediate 2, 400 mg, 1.99 mmol, 0.90 equiv), HBTU (830 mg, 2.19 mmol, 1.0 equiv), N,N-dimethylformide (30 mL), (S)-(4-(6-fluorobenzo[d]oxazol-2-yl)phenyl)(3-methylpiperazin-1-yl)methanone hydrochloride (750 mg, 2.21 mmol, 1.00 equiv) and DIEA (514 mg, 3.98 mmol, 1.80 equiv). The resulting solution was stirred for 18 h at 25° C. The resulting solution was diluted with 50 mL of EA and washed with 2×50 mL of water. The organic layer dried over Na.sub.2SO.sub.4 and concentrated under vacuum. This resulted in 800 mg (crude) of the title compound as a yellow solid. LC-MS (ES, m/z): 523 [M+H].sup.+
Step 2. (S)-(4-(1-aminocyclopropane-1-carbonyl)-3-methylpiperazin-1-yl)(4-(6-fluorobenzo[d]oxazol-2-yl)phenyl)methanone
(318) Into a 100-mL round-bottom flask, was placed tert-butyl (S)-(1-(4-(4-(6-fluorobenzo[d]oxazol-2-yl)benzoyl)-2-methylpiperazine-1-carbonyl)cyclopropyl)carbamate (800 mg, 1.53 mmol, 1.00 equiv), dichloromethane (20 mL), tetrahydrofuran (20 mL). Then hydrogen chloride (gas) was bubbled into the mixture. The resulting solution was stirred for 3 h at 25° C. The resulting mixture was concentrated under vacuum and dissolved in 10 mL of water. The pH value of the solution was adjusted to 8 with saturated sodium carbonate solution. The solids were collected by filtration. The crude product was purified by Prep-HPLC with the following conditions (Waters I): Column, Xbridge Prep C18 OBD column, 5 um, 19*150 mm; mobile phase, Water (0.05% NH.sub.4HCO.sub.3) and CH.sub.3CN (7% CH.sub.3CN up to 35% in 10 min); Detector, UV 220&254 nm. This resulted in 163.6 mg (25%) of the title compound as a white solid. LC-MS (ES, m/z): 423 [M+H].sup.+
(319) Method 29.
(320) ##STR00762## ##STR00763##
Step 1. tert-butyl 4-(4-(3-aminobenzo[d]isoxazol-6-yl)benzoyl)piperazine-1-carboxylate
(321) Into a 250-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of tert-butyl 4-[[4-(tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]carbonyl]piperazine-1-carboxylate (Intermediate 3, 1.9 g, 4.56 mmol, 1.00 equiv) in dioxane (100 mL), 6-bromo-1,2-benzoxazol-3-amine (1 g, 4.69 mmol, 1.00 equiv), Pd(dppf)Cl.sub.2 (344 mg, 0.47 mmol, 0.10 equiv), sodium carbonate (20 mL, 2M). The resulting solution was stirred overnight at 80° C. After cooled to room temperature, the resulting mixture was diluted with DCM, washed with water and concentrated under vacuum. The residue was applied onto a silica gel column with dichloromethane/methanol (10/1). This resulted in 1.6 g (83%) of the title compound as a gray solid. LC-MS (ES, m/z) 423 [M+H].sup.+
Step 2. tert-butyl 4-(4-(3-(cyclopropanecarboxamido)benzo[d]isoxazol-6-yl)benzoyl)piperazine-1-carboxylate
(322) Into a 100 mL round-bottom flask, was placed a solution of tert-butyl 4-[[4-(3-amino-1,2-benzoxazol-6-yl)phenyl]carbonyl]piperazine-1-carboxylate (800 mg, 1.89 mmol, 1.00 equiv) in pyridine (20 mL), cyclopropanecarbonyl chloride (199 mg, 1.90 mmol, 1.00 equiv). The resulting solution was stirred for 2 h at 70° C. After cooled to room temperature, the reaction mixture was diluted with EtOAc, washed with water and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1/1). This resulted in 535 mg (58%) of the title compound as a white solid. LC-MS (ES, m/z): 491[M+H].sup.+
Step 3. N-(6-(4-(piperazine-1-carbonyl)phenyl)benzo[d]isoxazol-3-yl)cyclopropanecarboxamide hydrochloride
(323) Into a 100-mL round-bottom flask, was placed a solution of tert-butyl 4-[[4-(3-cyclopropaneamido-1,2-benzoxazol-6-yl)phenyl]carbonyl]piperazine-1-carboxylate (535 mg, 1.09 mmol, 1.00 equiv) in dichloromethane (30 mL). To the above hydrogen chloride (g) was introduced in. The resulting solution was stirred for 1 h at room temperature. The resulting mixture was concentrated under vacuum. This resulted in 466 mg (quantitative) of the title compound as a white solid. LC-MS (ES, m/z): 391[M+H].sup.+
Step 4. N-(6-(4-(4-(1-hydroxycyclopropane-1-carbonyl)piperazine-1-carbonyl)phenyl)benzo[d]isoxazol-3-yl)cyclopropanecarboxamide
(324) Into a 50-mL round-bottom flask, was placed a solution of 1-hydroxycyclopropane-1-carboxylic acid (111 mg, 1.09 mmol, 1.00 equiv) in N,N-dimethylformamide (20 mL), HBTU (620 mg, 1.63 mmol, 1.50 equiv), DIEA (563 mg, 4.36 mmol, 4.00 equiv). The above mixture was stirred for 1 h at room temperature. To this was added N-(6-[4-[(piperazin-1-yl)carbonyl]phenyl]-1,2-benzoxazol-3-yl)cyclopropanecarboxamide hydrochloride (466 mg, 1.09 mmol, 1.00 equiv). The resulting mixture was stirred overnight at room temperature. The reaction mixture was diluted with DCM, washed with water and concentrated under vacuum. The residue was applied onto a silica gel column with dichloromethane/methanol (10/1), and further purified by Prep-HPLC with the following conditions (IntelFlash-1): Column, Cis silica gel; mobile phase, CH.sub.3CN/water with 0.05% NH.sub.4HCO.sub.3=40% increasing to CH.sub.3CN/water with 0.05% NH.sub.4HCO.sub.3=60% within 15 min; Detector, UV 254&220 nm. This resulted in 123.9 mg (24%) of the title compound as a white solid. LC-MS (ES, m/z): 475[M+H].sup.+
(325) Method 30.
(326) ##STR00764##
Step 1. tert-butyl 4-(3′-amino-[1,1′-biphenyl]-4-carbonyl)piperazine-1-carboxylate
(327) To a 100 mL flask was added tert-butyl piperazine-1-carboxylate (1.310 g, 7.03 mmol), 3′-aminobiphenyl-4-carboxylic acid (1.5 g, 7.03 mmol) and DIEA (2.457 ml, 14.07 mmol) in DMF (25 ml) followed by HBTU (3.20 g, 8.44 mmol) to give a brown suspension. This was stirred at RT for 8 hrs. Water (50 mL) was added and the reaction was extracted twice with methylene chloride (2×100 mL). The organic layers were combined and washed with water (25 mL) and brine (25 mL). The organic layer was then dried over magnesium sulfate, filtered and concentrated in vacuo. The crude residue was purified by FCC (04% MeOH/CH.sub.2Cl.sub.2) affording the title compound (1.70 g, 63%) as a yellow solid. LC-MS (ES, m/z): 382[M+H].sup.+
Step 2 (RCOCl). tert-butyl 4-(3′-(cyclopentanecarboxamido)-[1,1′-biphenyl]-4-carbonyl)piperazine-1-carboxylate
(328) In a 20 mL scintillation vial was added tert-butyl 4-(3′-aminobiphenylcarbonyl)piperazine-1-carboxylate (150 mg, 0.393 mmol), pyridine (0.095 ml, 1.180 mmol), and cyclopentanecarbonyl chloride (0.057 ml, 0.472 mmol) in THF (9 ml) to give an light yellow suspension. This was stirred at RT for 2 hours. The reaction was taken up in 75 mls of methylene chloride. The organic solution was washed twice with dilute sodium bicarbonate solution (aq, 35 mL) and once with brine (15 mL). The organic layer was then dried over magnesium sulfate, filtered and concentrated in vacuo. The crude product was purified by FCC (0-60% EtOAc/hexanes) affording the title compound (116 mg, 62%). LC-MS (ES, m/z): 478[M+H].sup.+
Step 2 (RCO.SUB.2.H). tert-Butyl 4-(3′-(3,3-difluorocyclobutanecarboxamido)biphenylcarbonyl)piperazine-1-carboxylate
(329) In a 20 mL scintillation vial was added tert-butyl 4-(3′-aminobiphenylcarbonyl)piperazine-1-carboxylate (200 mg, 0.524 mmol), 3,3-difluorocyclobutanecarboxylic acid (86 mg, 0.629 mmol) and Hunig's Base (0.275 ml, 1.573 mmol) in DMF (5 ml) followed by HBTU (239 mg, 0.629 mmol) to give a brown suspension. This was stirred at RT overnight and then the reaction was diluted with water (20 mL). The reaction mixture was then extracted with methylene chloride (2×40 mL). The combined organic layers were washed with water (20 mL) and brine (20 mL). The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. The crude product was purified by FCC (0-60% EtOAc/hexanes) affording the title compound as a foamy glass. LC-MS (ES, m/z): 500[M+H].sup.+
Step 3. N-(4′-(piperazine-1-carbonyl)-[1,1′-biphenyl]-3-yl)cyclopentanecarboxamide 2,2,2-trifluoroacetate
(330) In a 100 mL round-bottomed flask was added tert-butyl 4-(3′-(cyclopentanecarboxamido)biphenylcarbonyl)piperazine-1-carboxylate (114 mg, 0.239 mmol) in methylene chloride (15 ml) to give a yellow suspension. Trifluoroacetic acid (0.552 mls, 7.16 mmol) was added gradually by syringe. The solution was stirred at RT for 2.5 hours. The solution was concentrate and the crude product was triturated with ether and then decanted. The resulting solid was dried in vacuo affording the title compound (117 mg, 100%) as a foamy solid. LC-MS (ES, m/z): 378[M+H].sup.+
Step 4. N-(4′-(4-(1-hydroxycyclopropane-1-carbonyl)piperazine-1-carbonyl)-[1,1′-biphenyl]-3-yl)cyclopentanecarboxamide
(331) In a 100 mL round-bottomed flask was added N-(4′-(piperazine-1-carbonyl)biphenyl-3-yl)cyclopentanecarboxamide 2,2,2-trifluoroacetate (118 mg, 0.24 mmol), 1-hydroxycyclopropanecarboxylic acid (19.60 mg, 0.192 mmol) and pyridine (0.058 ml, 0.720 mmol) in DMF (5 ml) followed by HBTU (127 mg, 0.336 mmol) to give a yellow suspension. This was stirred at RT for 4.5 hours. Hunig's base was added (0.021 mL, 0.12 mmols) and the stirring was continued. After 18 hours additional Hunig's base (0.063 mL, 0.36 mmols) was added and the reaction solution was stirred overnight. The reaction was diluted with water (20 mL) and extracted with methylene chloride (2×50 mL). The organic layers were combined and washed with water (10 mL) and brine (10 mL). The solvent was dried over magnesium sulfate, filtered and concentrated in vacuo. The crude product was purified by FCC (0-7% MeOH/CH.sub.2Cl.sub.2) affording the title compound (35.5 mg, 29%) as an off-white solid. LC-MS (ES, m/z): 462[M+H].sup.+
(332) Method 31.
(333) ##STR00765##
Step 1. tert-Butyl 4-(4′-bromo-[1,1′-biphenyl]-4-carbonyl)piperazine-1-carboxylate
(334) To a suspension of 4′-bromo-[1,1′-biphenyl]-4-carboxylic acid (1.5 g, 5.4 mmol) in DMF (35 mL) was added TEA (1.21 mL, 8.6 mmol), followed by tert-butyl piperazine-1-carboxylate (1.11 g, 6.0 mmol) and HATU (2.6 g, 6.8 mmol). The reaction mixture was stirred at room temperature overnight then diluted with water and extracted with EtOAc. Organic phase was washed with water, 5% acetic acid, saturated NaHCO.sub.3, brine, dried over Na.sub.2SO.sub.4 and concentrated under reduced pressure. The crude material was chromatographed on a silica gel column eluting with a gradient of EtOAc in CH.sub.2Cl.sub.2 to afford 2.0 g (83% yield) of the title compound.
Step 2. tert-Butyl 4-(4′-(1H-pyrazol-4-yl)-[1,1′-biphenyl]-4-carbonyl)piperazine-1-carboxylate
(335) tert-Butyl 4-(4′-bromo-[1,1′-biphenyl]-4-carbonyl)piperazine-1-carboxylate (1.0 g, 2.3 mmol), (1H-pyrazol-4-yl)boronic acid (as HCl salt, 0.67 g, 4.5 mmol) and 2M K.sub.3PO.sub.4 (aq) (4.5 mL, 9.0 mmol) were mixed with 30 mL of DMF in a microwave tube. The resulting mixture was vacuumed several times and refilled with argon before adding Pd(PPh.sub.3).sub.4 (0.39 g, 0.3 mmol). The reaction mixture was microwaved for 35 min at 150° C. After cooling to room temperature, the reaction mixture was diluted with water and saturated NaHCO.sub.3 and extracted with MeOH/CHCl.sub.3 mixture of solvents. Organic phase was dried over Na.sub.2SO.sub.4 and concentrated under reduced pressure. The crude was purified twice by ISCO (24 g silica gel column) eluting with a gradient of 0.7 N NH.sub.3/MeOH in CHCl.sub.3 to afford 160 mg (17% yield) of the desired product.
Step 3. (4′-(1H-pyrazol-4-yl)-[1,1′-biphenyl]-4-yl)(piperazin-1-yl)methanone, HCl salt
(336) tert-Butyl 4-(4′-(1H-pyrazol-4-yl)-[1,1′-biphenyl]-4-carbonyl)piperazine-1-carboxylate (160 mg, 0.37 mmol) was dissolved in 18 mL of anhydrous MeOH saturated with HCl (gas) at 0° C. and was stirred at room temperature for 3 h. The resulting solution was concentrated to dryness under reduced pressure. The residue was triturated with 2% MeOH in Et.sub.2O followed by Et.sub.2O and pentane to afford 150 mg (quant. yield) of the title compound as the hydrochloride salt which was used in the next step without further purification.
Step 4. (4-(4′-(1H-pyrazol-4-yl)-[1,1′-biphenyl]-4-carbonyl)piperazin-1-yl)(1-hydroxycyclopropyl) methanone
(337) To a solution of (4′-(1H-pyrazol-4-yl)-[1,1′-biphenyl]-4-yl)(piperazin-1-yl)methanone, HCl salt (150 mg, 0.37 mol) and 1-hydroxycyclopropane-1-carboxylic acid (69 mg, 0.56 mmol) in 3 mL of DMF was added HBTU (230 mg, 0.6 mmol), followed by addition of DIEA (0.33 mL, 1.8 mmol). The resulting solution was stirred overnight at room temperature. The the reaction mixture was diluted with water and saturated NaHCO.sub.3 and extracted several times with with EtOAc/MeOH and MeOH/CHCl.sub.3 mixture of solvents. The organic layers were combined, washed with water, brine, dried over Na.sub.2SO.sub.4 and concentrated under reduced pressure. The crude was purified by ISCO twice (24 g silica gel gold column) eluting with a gradient of 0.7 N NH.sub.3/MeOH in EtOAc and 0.7 N NH.sub.3/MeOH in CHCl.sub.3. The product obtained after chromatography was triturated in Et.sub.2O to afford 110 mg (71% yield) of the pure target compound. LC-MS (ES, m/z): 417[M+H].sup.+
(338) Method 32.
(339) ##STR00766##
Step 1. tert-Butyl 4-(4-bromo-2,6-difluorobenzoyl)piperazine-1-carboxylate
(340) To a solution of 4-bromo-2,6-difluorobenzoic acid (1.00 g, 4.22 mmol), tert-butyl piperazine-1-carboxylate (0.786 g, 4.22 mmol), and HBTU (1.925 g, 5.06 mmol) in DMF (10.0 ml) was added DIEA (2.95 ml, 16.88 mmol). The reaction was stirred at room temperature overnight. Saturated sodium bicarbonate (aqueous, 10 mL) was added followed by water (10 mL). The reaction solution was then extracted several times with EtOAc (3×20 mL). The organic extracts were pooled and washed with water (2×20 mL) and brine (20 mL). The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo providing the crude product as an orange oil. The crude product was subjected to FCC (Biotage SNAP 25; eluent: 15%-25% EtOAc in hexanes over 10 CV). This afforded the title compound (1.44 g, 86%) as an off-white solid. LC-MS (ES, m/z): 405[M+H].sup.+
Step 2. tert-Butyl 4-(2,6-difluoro-4-(1-methyl-1H-indazol-6-yl)benzoyl)piperazine-1-carboxylate
(341) tert-Butyl 4-(4-bromo-2,6-difluorobenzoyl)piperazine-1-carboxylate (383.2 mg, 0.946 mmol), 1-methyl-1H-indazol-6-ylboronic acid (166 mg, 0.946 mmol) and potassium phosphate (1.00 g, 4.73 mmol) were suspended in a nitrogen purged solution of Dioxane (6.0 ml) and Water (1.2 ml). The reaction mixture was further purged with nitrogen for 5 minutes. Palladium Tetrakis (109 mg, 0.095 mmol) was added and the reaction solution was purged with nitrogen for 5 more minutes. The mixture was subjected to microwave irradiation at 130° C. for 30 minutes resulting in a yellow biphasic solution. The organic layer (top) was removed, filtered through celite and concentrated in vacuo to afford the crude product as a light red powder. The crude product was subjected to FCC (Biotage SNAP 25; Gradient Eluent: 0-20% MeOH in in EtOAc with 0.5% triethylamine over 15 CV). This afforded the title compound (327 mg, 76%) as a light beige powder. LC-MS (ES, m/z): 421[M+H].sup.+
Step 3. (2,6-difluoro-4-(1-methyl-1H-indazol-6-yl)phenyl)(piperazin-1-yl)methanone hydrochloride
(342) HCl (4N in 1,4-dioxane) (0.106 ml, 3.51 mmol) was added to a solution of tert-butyl 4-(2,6-difluoro-4-(1-methyl-1H-indazol-6-yl)benzoyl)piperazine-1-carboxylate (320.0 mg, 0.701 mmol) in Dioxane (4.0 ml). The reaction solution was stirred at room temperature for 2 hours resulting in the formation of a white precipitate. Ether (10 mL) was added to the reaction and the precipitate was then collected by filtration. The precipitate was further washed with ether (10 mL), collected and dried in vacuo affording the title compound (275 mg, 100%) as a white powder. LC-MS (ES, m/z): 356[M+H].sup.+
Step 4. (4-(2,6-difluoro-4-(1-methyl-1H-indazol-6-yl)benzoyl)piperazin-1-yl)(1-hydroxycyclopropyl)methanone
(343) To a solution of (2,6-difluoro-4-(1-methyl-H-indazol-6-yl)phenyl)(piperazin-1-yl)methanone hydrochloride (218.3 mg, 0.556 mmol), 1-hydroxycyclopropanecarboxylic acid (56.7 mg, 0.556 mmol), and HBTU (254 mg, 0.667 mmol) in DMF (4.0 ml) was added DIEA (0.388 ml, 2.223 mmol). The reaction was stirred at room temperature overnight. Saturated sodium bicarbonate (aqueous, 10 mL) was added followed by water (10 mL). The reaction solution was then extracted several times with EtOAc (3×20 mL). The organic extracts were pooled and washed with water (2×20 mL) and brine (20 mL). The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo providing the crude product as an orange oil. The crude product was subjected to FCC (Biotage SNAP 25; eluent: 20-10% hexanes in EtOAc over 10 CV). The product was then subjected to an additional purification via FCC (Biotage SNAP 25; gradient eluent: 5-15% MeOH in methylene chloride). This afforded the title compound (105.2 mg, 43%) as a white powder. LC-MS (ES, m/z): 441[M+H].sup.+
(344) Method 33.
(345) ##STR00767##
Step 1. tert-Butyl 4-(3′-nitrobiphenylcarbonyl)piperazine-1-carboxylate
(346) To a solution of tert-butyl 4-(4-bromobenzoyl)piperazine-1-carboxylate (1.00 g, 2.71 mmol), 3-nitrophenylboronic acid (0.452 g, 2.71 mmol) and potassium phosphate (2.87 g, 13.54 mmol) in nitrogen bubbled dioxane (10.0 ml) and nitrogen bubbled Water (2.0 ml) was added palladium tetrakis (0.313 g, 0.271 mmol). The reaction solution was further bubbled with a stream of nitrogen for 15 minutes. The reaction was then run overnight at 80° C. The reaction was cooled to room temperature resulting in a yellow precipitate. The precipitate was collected via filtration. The precipitate was then washed with methanol (20 mL) and ether (10 mL). This afforded the title compound (1.0 g, 92%) as a light yellow powder. LC-MS (ES, m/z): 412[M+H].sup.+
Step 2. tert-Butyl 4-(3′-aminobiphenylcarbonyl)piperazine-1-carboxylate
(347) A mixture of tert-butyl 4-(3′-nitrobiphenylcarbonyl)piperazine-1-carboxylate (1.00 g, 2.430 mmol) and palladium hydroxide on activated carbon (0.341 g, 2.430 mmol) was suspended in MeOH (30 ml). The bomb was placed on a Parr Shaker and charged with hydrogen gas at 30 psi. The reaction was allowed to shake for 3 hours. The reaction was then vented with nitrogen, filtered through celite and concentrated in vacuo affording the title compound (924 mg, 100%) as a light brown solid. LC-MS (ES, m/z): 382[M+H].sup.+
Step 3. tert-Butyl 4-(3′-(cyclobutanesulfonamido)biphenylcarbonyl)piperazine-1-carboxylate
(348) To a solution of tert-butyl 4-(3′-aminobiphenylcarbonyl)piperazine-1-carboxylate (500.0 mg, 1.311 mmol) in anhydrous pyridine (6.5 ml) was added cyclobutanesulfonyl chloride (203 mg, 1.311 mmol) at 40° C. The reaction solution (red color) was stirred at 40° C. for 2 days. The reaction solution was cooled to room temperature and diluted with water (10 mL). The solution was then extracted several times with EtOAc (3×20 mL). The organic extracts were pooled and washed with 1M citric acid (aqueous, 20 mL), water (20 mL) and brine (20 mL). The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was subjected to FCC (Biotage SNAP 50; gradient eluent: 40-50% EtOAc in hexanes over 15 CV). This afforded the title compound (173 mg, 26.3%) as a white powder. LC-MS (ES, m/z): 500[M+H].sup.+
Step 4. N-(4′-(piperazine-1-carbonyl)biphenyl-3-yl)cyclobutanesulfonamide hydrochloride
(349) Hydrogen chloride (4.0N in 1,4-dioxane) (0.438 ml, 1.751 mmol) was added to a solution of tert-butyl 4-(3′-(cyclobutanesulfonamido)biphenylcarbonyl)piperazine-1-carboxylate (175.0 mg, 0.350 mmol) in Dioxane (2.0 ml). The reaction solution was stirred at room temperature for 3 hours resulting in the formation of a off-white precipitate. Ether (10 mL) was added to the reaction and the precipitate was then collected by filtration. The precipitate was further washed with ether (10 mL), collected and dried in vacuo affording the title compound (153 mg, 100%) as an off-white powder. LC-MS (ES, m/z): 400[M+H].sup.+
Step 5. N-(4′-(4-(1-hydroxycyclopropanecarbonyl)piperazine-1-carbonyl)biphenyl-3-yl)cyclobutanesulfonamide
(350) To a solution of N-(4′-(piperazine-1-carbonyl)biphenyl-3-yl)cyclobutanesulfonamide hydrochloride (164.5 mg, 0.377 mmol), 1-hydroxycyclopropanecarboxylic acid (38.5 mg, 0.377 mmol), and HBTU (172 mg, 0.453 mmol) in DMF (2.0 ml) was added DIEA (0.264 ml, 1.509 mmol). The reaction was stirred at room temperature overnight. Saturated sodium bicarbonate (aqueous, 10 mL) was added followed by water (10 mL). The reaction solution was then extracted several times with EtOAc (3×20 mL). The organic extracts were pooled and washed with water (2×20 mL) and brine (20 mL). The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo providing the crude product as an orange oil. The crude product was subjected to FCC (Biotage SNAP 25; eluent: 100% EtOAc over 10 CV) followed by an additional FCC purification (Biotage SNAP 25; gradient eluent: 0-5% MeOH in methylene chloride). This afforded the title compound (55 mg, 30.3%) as a glassy clear solid. LC-MS (ES, m/z): 484[M+H].sup.+
(351) Method 34.
(352) ##STR00768##
Step 1. tert-Butyl 4-(3′-(cyclobutylmethylsulfonamido)-[1,1′-biphenyl]-4-carbonyl)piperazine-1-carboxylate
(353) To an ice-cold solution of tert-butyl 4-(3′-amino-[1,1′-biphenyl]-4-carbonyl)piperazine-1-carboxylate (300 mg, 0.79 mmol) in pyridine (4 mL) cyclobutylmethanesulfonyl chloride (200 mg, 1.2 mmol) was added dropwise. The resulting mixture was allowed to warm up to room temperature over 4 h then concentrated and kept on a high vacuum line overnight. The residue was dissolved in EtOAc, washed with water, 5% acetic acid, saturated NaHCO.sub.3, brine, dried over Na.sub.2SO.sub.4 and concentrated under reduced pressure. The crude material was chromatographed on a silica gel column eluting with a gradient of EtOAc in CH.sub.2Cl.sub.2 to obtain 295 mg (73% yield) of the title compound.
Step 2 (HCl). 1-cyclobutyl-N-(4′-(piperazine-1-carbonyl)-[1,1′-biphenyl]-3-yl)methanesulfonamide hydrogen chloride
(354) tert-Butyl 4-(3′-(cyclobutylmethylsulfonamido)-[1,1′-biphenyl]-4-carbonyl)piperazine-1-carboxylate (295 mg, 0.57 mmol) was dissolved in 18 mL of anhydrous MeOH saturated with HCl (gas) and stirred at room temperature for 3 h. The resulting solution was concentrated to dryness under reduced pressure. The residue was triturated with 2% MeOH in Et.sub.2O followed by trituration with Et.sub.2O and dried to afford 200 mg (78% yield) of the title compound as the hydrochloride salt which was used for the next step without further purification.
Step 2 (TFA). N-(4′-(Piperazine-1-carbonyl)-[1,1′-biphenyl]-3-yl)tetrahydro-2H-pyran-4-sulfonamide trifluoroacetate
(355) To a solution of tert-butyl 4-(3′-(tetrahydro-2H-pyran-4-sulfonamido)-[1,1′-biphenyl]-4-carbonyl)-piperazine-1-carboxylate (70 mg, 0.13 mmol) in DCM (3 mL) was added TFA (0.5 mL). The mixture was stirred at room temperature for 2 hours. After removal of solvents under reduced pressure, the crude title compound (69 mg, 100%) was used directly in the next step without further purification.
Step 3. 1-cyclobutyl-N-(4′-(4-(1-hydroxycyclopropanecarbonyl)piperazine-1-carbonyl)-[1,1′-biphenyl]-3-yl)methanesulfonamide
(356) To a solution of 1-cyclobutyl-N-(4′-(piperazine-1-carbonyl)-[1,1′-biphenyl]-3-yl)methanesulfonamide hydrogen chloride (295 mg, 0.45 mol) and 1-hydroxycyclopropane-1-carboxylic acid (77 mg, 0.76 mmol) in 3 mL of DMF was added HBTU (300 mg, 0.81 mmol) followed by an addition of DIEA (0.42 mL, 2.4 mmol). The resulting solution was stirred at room temperature overnight. The reaction mixture was diluted with water and satu. NaHCO.sub.3 and extracted several times with CH.sub.2Cl.sub.2 and MeOH/CHCl.sub.3 mixture of solvents. The organic layers were combined, washed with water, brine, dried over Na.sub.2SO.sub.4 and concentrated under reduced pressure. The crude material was twice purified by ISCO (40 g silica gel gold column) eluting with a gradient of MeOH in CH.sub.2Cl.sub.2 and then triturated in 2-3% MeOH in Et.sub.2O to afford 129 mg (58% yield) of the title compound. LC-MS (ES, m/z): 498[M+H].sup.+
(357) Method 35.
(358) ##STR00769##
Step 1. tert-butyl (1-(4-(2-fluoro-4-(2-methyl-1H-indol-1-yl)benzoyl)piperazine-1-carbonyl)cyclopropyl)carbamate
(359) Into a 100-mL round-bottom flask was placed 1-[3-fluoro-4-[(piperazin-1-yl)carbonyl]phenyl]-2-methyl-H-indole hydrochloride (Intermediate 4, 600 mg, 1.60 mmol, 1.00 equiv), 1-[[(tert-butoxy)carbonyl]amino]cyclopropane-1-carboxylic acid (322 mg, 1.60 mmol, 1.00 equiv), N,N-dimethylformamide (40 mL), HBTU (729 mg, 1.92 mmol, 1.20 equiv), DIEA (828 mg, 6.41 mmol, 3.99 equiv). The resulting solution was stirred overnight at room temperature. The reaction mixture was diluted with 50 mL of EA, washed with 3×50 mL of water and 50 mL of brine. The organic phase was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (70:30). This resulted in 300 mg (36%) of the title compound as a yellow solid. LC-MS (ES, m/z): 521[M+H].sup.+
Step 2. (4-(1-aminocyclopropane-1-carbonyl)piperazin-1-yl)(2-fluoro-4-(2-methyl-1H-indol-1-yl)phenyl)methanone
(360) Into a 100-mL round-bottom flask, was placed tert-butyl N-[1-[(4-[[2-fluoro-4-(2-methyl-1H-indol-1-yl)phenyl]carbonyl]piperazin-1-yl)carbonyl]cyclopropyl]carbamate (300 mg, 0.58 mmol, 1.00 equiv), dichloromethane (20 mL), trifluoroacetic acid (5 mL). The resulting solution was stirred overnight at room temperature. The resulting mixture was concentrated under vacuum. The residue was purified by Prep-HPLC with the following conditions (Waters I): Column, SunFire Prep C18, 5 um, 19*100 mm; mobile phase, Water (0.05% NH.sub.4HCO.sub.3) and CH.sub.3CN (65% CH.sub.3CN up to 85% in 7 min); Detector, UV 220&254 nm. This resulted in 73.3 mg (30%) of the title compound as a white solid. LC-MS (ES, m/z): 421[M+H].sup.+
(361) Method 36.
(362) ##STR00770## ##STR00771##
Step 1. tert-butyl 4-(6-hydroxynaphthalen-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate
(363) Into a 250 mL round bottom flash was placed 6-bromonaphthalen-2-ol (2 g, 8.97 mmol, 1.00 equiv), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (2.7 g, 8.70 mmol, 1.00 equiv), potassium carbonate (3.6 g, 26.05 mmol, 3.00 equiv), and Pd(dppf)Cl.sub.2 (100 mg, 0.14 mmol, 0.01 equiv) in 1,4-dioxane (30 mL) and water (10 mL). The resulting solution was stirred overnight at 110° C. in an oil bath. The reaction mixture was cooled, diluted with EtOAc (120 mL) and washed with brine (2×100 mL). The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by silica gel chromatography eluting with dichloromethane/methanol (50:1). This resulted in 1.9 g (65%) of the title compound as a yellow solid. LC-MS (ES, m/z): 326[M+H].sup.+
Step 2. tert-butyl 4-(6-hydroxynaphthalen-2-yl)piperidine-1-carboxylate
(364) Into a 250 mL round bottom flask was placed tert-butyl 4-(6-hydroxynaphthalen-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (1.9 g, 5.84 mmol, 1.00 equiv), ethanol (50 mL), and 10% palladium on carbon (0.5 g). To this suspension was charged in hydrogen gas. The resulting solution was stirred for 2 hours at r.t. The solids were filtered out and the solution was concentrated in vacuo affording the title compound (1.9 g, 99%) as a light yellow solid. LC-MS (ES, m/z): 328[M+H].sup.+
Step 3. tert-butyl 4-(6-(((trifluoromethyl)sulfonyl)oxy)naphthalen-2-yl)piperidine-1-carboxylate
(365) Into a 100 mL round bottom flask was placed tert-butyl 4-(6-hydroxynaphthalen-2-yl)piperidine-1-carboxylate (1.9 g, 5.79 mmol, 1.00 equiv), dichloromethane (20 mL), 2,6-lutidine (3.4 mL, 3.00 equiv) and triflic anhydride (1.5 mL, 1.50 equiv). The resulting solution was stirred at −40° C. for 10 minutes and then slowly warmed to r.t. over 2 hours. The reaction was quenched via the addition of water (100 mL). The organic layer was then washed with brine (2×100 mL) and 5% hydrochloric acid (2×50 mL). The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by silica gel chromatography eluting with EtOAc/petroleum ether (1:5). This resulted in 2.1 g (79%) of the title compound as a white solid. LC-MS (ES, m/z): 461[M+H].sup.+
Step 4. tert-butyl 4-(6-cyanonaphthalen-2-yl)piperidine-1-carboxylate
(366) Into a 30 mL vial was placed tert-butyl 4-(6-(((trifluoromethyl)sulfonyl)oxy)naphthalen-2-yl)piperidine-1-carboxylate (1.5 g, 3.26 mmol, 1.00 equiv), zinc cyanide (840 mg, 7.15 mmol, 2.20 equiv), and Pd(dppf)Cl.sub.2 (100 mg, 0.14 mmol, 0.04 equiv) in DMF (10 mL). The resulting solution was subjected to microwave irradiation at 160° C. for 15 minutes. The reaction was cooled, diluted with 100 mL of EtOAc and washed with water (2×100 mL) and brine (2×50 mL). The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by silica gel chromatography eluting with EtOAc/petroleum ether (1:10). This resulted in 1.0 g (91%) of the title compound as a white solid. LC-MS (ES, m/z): 337[M+H].sup.+
Step 5. 6-(piperidin-4-yl)-2-naphthonitrile hydrochloride
(367) Into a 100 mL round bottom flask was placed tert-butyl 4-(6-cyanonaphthalen-2-yl)piperidine-1-carboxylate (1.0 g, 2.97 mmol, 1.00 equiv) in dichloromethane (20 mL). HCl (g) was bubbled into the reaction solution and stirred for 30 minutes at r.t. resulting in a precipitate. The solid was collected and dried in vacuo affording the title compound (0.7 g, 100%) as a white solid. LC-MS (ES, m/z): 237[M+H].sup.+
Step 6. tert-butyl 4-(4-(6-cyanonaphthalen-2-yl)piperidine-1-carbonyl)piperazine-1-carboxylate
(368) Into a 100 mL round bottom flask was placed 6-(piperidin-4-yl)-2-naphthonitrile hydrochloride, triphosgene (1.0 g, 3.37 mmol, 1.10 equiv), Et.sub.3N (1.8 mL, 4.80 equiv) in dichloromethane (20 mL). The reaction was stirred for 2 hours and then pyridine (0.35 mL, 1.50 equiv) and tert-butyl piperazine-1-carboxylate (700 mg, 3.76 mmol, 1.20 equiv) were added. The resulting solution was stirred overnight at r.t. The reaction mixture was then washed with water (2×100 mL) and brine (2×50 mL). The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo affording the title compound (0.8 g, 60%) as a yellow solid. LC-MS (ES, m/z): 449[M+H].sup.+
Step 7. 6-(1-(piperazine-1-carbonyl)piperidin-4-yl)-2-naphthonitrile hydrochloride
(369) Into a 100 mL round bottom flask was placed tert-butyl 4-(4-(6-cyanonaphthalen-2-yl)piperidine-1-carbonyl)piperazine-1-carboxylate (800 mg, 1.78 mmol, 1.00 equiv) in dichloromethane (15 mL). HCl (g) was bubbled into the reaction solution and stirred for 2 hours at r.t. The reaction solution was concentrated in vacuo affording the title compound (0.6 g, 97%) as a white solid. LC-MS (ES, m/z): 349[M+H].sup.+
Step 8. 6-(1-(4-(1-hydroxycyclopropane-1-carbonyl)piperazine-1-carbonyl)piperidin-4-yl)-2-naphthonitrile
(370) Into a 100 mL round bottom flask was placed 1-hydroxycyclopropane-1-carboxylic acid (180 mg, 1.76 mmol, 1.00 equiv), HBTU (900 mg, 2.37 mmol, 2.30 equiv), and 6-(1-(piperazine-1-carbonyl)piperidin-4-yl)-2-naphthonitrile hydrochloride (600 mg, 1.72 mmol, 1.00 equiv) in DMF (15 mL). DIEA (0.8 mL, 5.00 equiv) was added and the resulting solution was stirred overnight at r.t. The reaction solution was then diluted with 100 mL of EtOAc and washed with water (2×100 mL) and brine (2×50 mL). The organic layer was then dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by silica gel chromatography eluting with dichloromethane/methanol (20:1) and then subjected to Prep-HPLC with the following conditions conditions (Waters I): Column, Xbridge Prep C18 OBD column, 5 um, 19*150 mm; mobile phase, Water (0.05% NH.sub.4HCO.sub.3) and CH.sub.3CN (33% CH.sub.3CN up to 38% in 12 min). This resulted in 106.9 mg (14%) of the title compound as a white solid. LC-MS (ES, m/z): 433 [M+H].sup.+
(371) Intermediates
(372) ##STR00772##
tert-Butyl 4-(4-(2-oxo-1,2-dihydroquinolin-3-yl)benzoyl)piperazine-1-carboxylate
(373) Tetrakis(triphenylphosphine)palladium(0) (0.078 g, 0.068 mmol) was added to a mixture of tert-butyl 4-(4-bromobenzoyl)piperazine-1-carboxylate (0.250 g, 0.677 mmol), 2-fluoroquinolin-3-ylboronic acid (0.129 g, 0.677 mmol), and sodium carbonate (0.287 g, 2.71 mmol) in dioxane (5.0 mL) and water (1.0 mL). The mixture stirred in the microwave at 60° C. for 1.5 h. The reaction mixture was filtered and concentrated to afford a yellow oil. This material was purified via column chromatography on silica gel (Biotage 25 g column, gradient elution with 50-100% ethyl acetate-hexane) to afford tert-butyl 4-(4-(2-oxo-1,2-dihydroquinolin-3-yl)benzoyl)piperazine-1-carboxylate (0.228 g, 0.526 mmol, 78% yield) as a white solid. MS (ESI, pos. ion) m/z: 434 (M+1).
(374) ##STR00773##
5-bromopicolinoyl chloride
(375) Thionyl chloride (10 ml, 137 mmol) was added to 5-bromopicolinic acid (5.00 g, 24.75 mmol). A drop of DMF was added, and the mixture was heated at 80° C. for 2 h. The excess thionyl chloride was removed to afford 5-bromopicolinoyl chloride (5.413 g, 24.55 mmol, 99% yield) as a pale yellow solid. An aliquot was quenched with methanol to afford methyl 5-bromopicolinate. MS (ESI, pos. ion) m/z: 216, 218 (M+1).
(376) ##STR00774##
5-bromo-1H-indole-2-carbonitrile
Step 1. 5-bromo-1H-indole-2-carboxamide
(377) 5-bromo-1H-indole-2-carboxylic acid (0.75 g, 3.12 mmol) was added to dichloromethane (10 mL) to give a suspension. Thionyl chloride (0.616 mL, 8.44 mmol) was added gradually by syringe. A drop of DMF was added and the suspension was heated at reflux for 2.5 h. The mixture was cooled to rrom temperature and then poured with stirring into 5 N ammonium hydroxide (20 mL, 100 mmol) in 18 mL of ice. The precipitate was stirred for 2 h. The aqueous emulsion was diluted and then extracted twice with ethyl acetate. Drying over MgSO.sub.4 and concentrating yielded a yellow crude solid. This was triturated with hexanes, filtered, washed with hexanes, and dried to afford 5-bromo-1H-indole-2-carboxamide (0.81 g, 3.15 mmol, 93% yield) as a tan solid. MS (ESI, pos. ion) m/z: 239, 241 (M+1)
Step 2. 5-bromo-1H-indole-2-carbonitrile
(378) 5-bromo-1H-indole-2-carboxamide (0.68 mg, 2.84 mmol) was added to toluene (20 mL) to give a suspension. Phosphorus oxychloride (1.326 mL, 14.22 mmol) was added gradually by syringe. The suspension was heated at reflux for 1.5 h. The reaction was poured into saturated NaHCO.sub.3 and allowed to quench. The layers were extracted twice with 50 mL of dichloromethane. The combined layers were washed with 20 mL of brine, dried over MgSO.sub.4, and concentrated to yield the crude product. This material was purified via column chromatography on silica gel (Biotage 25 g column, gradient elution with 0-5% ethyl acetate/dichloromethane) to afford 5-bromo-1H-indole-2-carbonitrile (0.408 g, 1.85 mmol, 65%) as a tan solid. MS (ESI, neg. ion) m/z 219/221
(379) ##STR00775##
tert-butyl 4-(5-bromopyrimidine-2-carbonyl)piperazine-1-carboxylate
Step 1. 5-bromopyrimidine-2-carbonyl chloride
(380) Thionyl chloride (3.96 mL, 54.2 mmol) was added to 5-bromopyrimidine-2-carboxylic acid (2.0 g, 9.85 mmol). A drop of DMF was added, and the mixture was heated at 80° C. for 2 hours. The excess thionyl chloride was removed in vacuo to afford 5-bromopyrimidine-2-carbonyl chloride as a pale yellow solid. The material was used without purification in the next step.
Step 2. tert-butyl 4-(5-bromopyrimidine-2-carbonyl)piperazine-1-carboxylate
(381) 5-Bromopyrimidine-2-carbonyl chloride (2.181 g, 9.85 mmol) and N,N-diisopropylethylamine (5.16 mL, 29.6 mmol) were taken up solution in DMF (30 mL). tert-Butyl piperazine-1-carboxylate was added and the reaction mixture stirred for 1.25 h. Water (100 mL) was added and the mixture was stirred. The aqueous mixture was then extracted twice with 100 mL of ethyl acetate. The second was an emulsion but saturating with NaCl separated the phases. The combined organic phases were washed once with brine, dried over MgSO.sub.4, and concentrated. The crude was purified via column chromatography on silica gel (Biotage, gradient elution with 0-10% methanol/dichloromethane) to afford tert-butyl 4-(5-bromopyrimidine-2-carbonyl)piperazine-1-carboxylate (3.1 g, 7.93 mmol, 81%) as a light tan solid. MS (ESI, pos. ion) m/z: 371/373 (M+1)
(382) ##STR00776##
2-chloro-4-(5-(cyclopropanesulfonamido)pyridin-3-yl)benzoic acid
Step 1. N-(5-bromopyridin-3-yl)cyclopropanesulfonamide
(383) 5-Bromopyridin-3-amine (0.304 mL, 3.0 mmol) and pyridine (0.534 mL, 1.1 mmol) were combined in dichloromethane (15 ml) to give a brown solution. Cyclopropanesulfonyl chloride (0.973 mL, 9.00 mmol) was added gradually by syringe. This was stirred at rt for 1 day. Additional pyridine (3.0 mmol) and 1 equivalent of cyclopropanesulfonyl chloride (3.00 mmol) were added. After an additional 1 day the reaction was complete. The reaction was diluted with 75 mL of dichloromethane and washed with 40 mL of saturated NaHCO.sub.3. The aqueous layer was extracted with 10 mL of dichloromethane and the combined organic phases were washed with 20 mL of brine. The solvent was then dried with MgSO.sub.4 and concentrated. The crude product was purified via column chromatography on silica gel (Biotage 100 g column, gradient elution with 0-50% ethyl acetate/hexanes) to afford N-(5-bromopyridin-3-yl)cyclopropanesulfonamide (0.81 mgs, 2.92 mmol, 73%) as a peach colored solid. MS (ESI, pos. ion) m/z: 277, 279 (M+1).
Step 2. 2-chloro-4-(5-(cyclopropanesulfonamido)pyridin-3-yl)benzoic acid
(384) N-(5-bromopyridin-3-yl)cyclopropanesulfonamide (0.810 g, 2.92 mmol), sodium carbonate (1.24 g, 11.69 mmol) and 2-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid (0.991 g, 3.51 mmol) were combined in 1,4-dioxane (32 mL) and water (6.4 mL) followed by tetrakis(triphenylphosphine)palladium (0) (0.34 g, 0.292 mmol) to give a light yellow suspension. The suspension was placed under nitrogen and heated for 16 h at 80° C. The reaction was filtered through Celite and the solids washed with 1,4-dioxane followed by ethyl acetate. Concentrating the solvents obtained a pale yellow sticky solid. This was suspended in 50 mL of water and basified with 1 N NaOH solution until the pH was 12. The basic layer was washed once with 25 mL of ethyl acetate. After a back-extraction of the organic phase with 20 mL of water at pH=12, the combined basic phases were acidified with 1 N HCl until pH=5 was reached. After standing overnight the precipitate was collected and dried to afford 2-chloro-4-(5-(cyclopropanesulfon-amido)pyridin-3-yl)benzoic acid (0.438 g, 1.24 mmol, 35%) as an off-white solid. MS (ESI, pos. ion) m/z: 353, 355 (M+1).
(385) ##STR00777##
N-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)cyclobutanecarboxamide
(386) 3-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (0.50 g, 2.28 mmol) and N,N-diisopropylethylamine (1.20 ml, 6.85 mmol), were combined in dichloromethane (5 mL) to give a light yellow solution. Cyclobutanecarbonyl chloride (0.260 mL, 2.282 mmol) was added gradually by syringe. The mixture was stirred for 2.5 h. The reaction was diluted with 70 mL of dichloromethane and then was washed twice with 20 mL of water. The organic layer was then washed with 20 mL of brine and dried over MgSO.sub.4. Concentrating gave a white solid which was purified via column chromatography on silica gel (Biotage 50 g column, gradient elution with 0-40% ethyl acetate/hexanes) to afford N-(4′-(4-(1-hydroxycyclopropanecarbonyl)piperazine-1-carbonyl)biphenyl-3-yl)oxetane-3-carboxamide as a waxy white solid. MS (ESI, pos. ion) m/z 302 (M+1).
(387) ##STR00778##
1 N-(5-bromopyridin-3-yl)cyclopropanecarboxamide
(388) 5-Bromopyridin-3-amine (0.292 mL, 2.89 mmol) and N,N-diisopropylethylamine (0.757 mL, 4.33 mmol) were combined in dichloromethane (15 mL) to give a light yellow solution. Cyclopropanecarbonyl chloride (0.263 mL, 2.89 mmol) was added gradually by syringe. The reaction was stirred at rt for 1.5 h. The reaction was diluted with 50 mL of dichloromethane and washed with 25 mL of saturated NaHCO.sub.3. After extracting the aqueous layer with 20 mL of dichloromethane the combined organic layers were washed with 20 mL NaHCO.sub.3, 20 mL of brine, and dried over MgSO.sub.4. The solvent was concentrated leaving a brown semi-solid. The residue was purified via column chromatography on silica gel (Biotage 50 g column, gradient elution with 04% methanol/dichloromethane) to afford N-(5-bromopyridin-3-yl)cyclopropanecarboxamide (0.603 g, 2.50 mmol, 87%) as a light tan solid. MS (ESI, pos. ion) m/z: 241,243 (M+1).
(389) ##STR00779##
N-(3-bromophenyl)ethanesulfonamide
(390) 3-Bromoaniline (0.158 mL, 1.453 mmol), and pyridine (0.118 mL, 1.453 mmoles) were combined in water (10 mL) to give a tan solution and ethanesulfonyl chloride (0.138 mL, 1.453 mmol) was added gradually by syringe. After 1 h additional ethanesulfonyl chloride (0.138 ml, 1.453 mmol) was added and the stirring was continued another 1 h. The reaction was extracted with twice with 15 mL of ethyl acetate and the combined organic layers were washed with 10 mL of brine and dried over MgSO.sub.4. The solvent was concentrated to afford a pale red oil. This material was purified via column chromatography on silica gel (Biotage 25 g column, gradient elution with 0-30% ethyl acetate/hexanes) to afford N-(3-bromophenyl)ethanesulfonamide (0.345 g, 1.24 mmol, 85%) as a colorless viscous film that partially solidified on standing. MS (ESI neg. ion) m/z 262,264 (M−1).
(391) ##STR00780##
(3′-aminobiphenyl-4-yl)(4-(1-hydroxycyclopropanecarbonyl)piperazin-1-yl)methanone
(392) (4-(1-Hydroxycyclopropanecarbonyl)piperazin-1-yl)(3′-nitrobiphenyl-4-yl)methanone (0.263 g, 0.665 mmol, prepared according to General Method B) was suspended in ethanol (6 mL) and water (2 mL). Iron powder (0.371 g, 6.65 mmol) and ammonium chloride (8.89 mg, 0.166 mmol) were added and the suspension was heated at 80° C. for 2 h. The suspension was diluted with methanol and filtered through Celite. The filtrate was concentrated and 50 mL of chloroform was added. The solution was washed with 30 mL of saturated NaHCO.sub.3 and the aqueous phase was separated and washed with 20 mL chloroform. The combined organic layers were washed with 20 mL of brine and dried over MgSO.sub.4. The mixture was concentrated and the residue was purified via column chromatography on silica gel (Biotage 25 g column, gradient elution with 0-6% methanol/chloroform) to afford an amber film. This was taken up in dichloromethane and triturated with hexanes to afford (3′-aminobiphenyl-4-yl)(4-(1-hydroxycyclopropanecarbonyl)-piperazin-1-yl)methanone (0.152 g, 0.345 mmol, 52%) as a foamy solid. MS (ESI, pos. ion) m/z 366 (M+1).
(393) ##STR00781##
tert-butyl 4-(2-chloro-4-(5-(cyclopropanesulfonamido)pyridin-3-yl)benzoyl)piperazine-1-carboxylate
(394) tert-Butyl piperazine-1-carboxylate (0.139 g, 0.748 mmol), 2-chloro-4-(5-(cyclopropanesulfonamido)-pyridin-3-yl)benzoic acid (0.240 g, 0.680 mmol) and N,N-diisopropylethylamine (0.131 mL, 0.748 mmol) were combined in DMF (5 mL), and O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.387 g, 1.020 mmol) was added to give a brown solution. This was stirred for 1 d.
(395) The reaction was diluted with 30 mL of water and stirred. The mixture was extracted with 60 mL dichloromethane and then with 15 mL of dichloromethane. The combined organic layers were washed with 20 mL of water and 20 mL of brine, and concentrated. The residue was purified via column chromatography on silica gel (Biotage 50 g column, gradient elution with 04% methanol/dichloromethane) to afford tert-butyl 4-(2-chloro-4-(5-(cyclopropanesulfonamido)pyridin-3-yl)benzoyl)piperazine-1-carboxylate (0.252 g, 71% yield) as an amber glassy film. MS (ESI, pos. ion) m/z: 521/523.
(396) ##STR00782##
tert-butyl 4-(2-chloro-4-(5-(cyclopropanecarboxamido)pyridin-3-yl)benzoyl)piperazine-1-carboxylate
(397) tert-Butyl piperazine-1-carboxylate (0.137 g, 0.736 mmol), 2-chloro-4-(5-(cyclopropanecarboxamido)-pyridin-3-yl)benzoic acid (0.212 g, 0.669 mmol), and N,N-diisopropylethylamine (0.129 mL, 0.736 mmol) were combined in DMF (5 mL) followed by O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.381 mg, 1.004 mmol) to give a brown solution. This was stirred for 1 d. Water (10 mL) was added and the reaction was stirred. The suspension was diluted with 60 mL of dichloromethane and 20 mL of water. The aqueous phase was separated and extracted with 15 mL of dichloromethane. The combined organic layers were washed with 20 mL of water and 20 mL of brine, dried over anhydrous magnesium sulfate, filtered, and concentrated. The crude product was purified via column chromatography on silica gel (Biotage 50 g column, gradient elution with 04% methanol/dichloromethane) to afford tert-butyl 4-(2-chloro-4-(5-(cyclopropanecarboxamido)-pyridin-3-yl)benzoyl)piperazine-1-carboxylate (0.454 g, 140%) as an amber glass. MS (ESI, pos. ion) m/z: 485/487.
(398) ##STR00783##
tert-butyl 5-bromo-3-methyl-1H-pyrazolo[3,4-b]pyridine-1-carboxylate
(399) Into a 100-mL round-bottom flask, was placed 5-bromo-3-methyl-H-pyrazolo[3,4-b]pyridine (800 mg, 3.77 mmol, 1.00 equiv), Boc.sub.2O (1.22 g, 5.59 mmol, 1.50 equiv), 4-dimethylaminopyridine (55 mg, 0.45 mmol, 0.12 equiv), TEA (756 mg, 7.47 mmol, 2.00 equiv) and tetrahydrofuran (20 mL). The resulting solution was stirred for 18 h at 20° C. The resulting solution was diluted with 50 mL of H.sub.2O, extracted with 3×20 mL of ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate and concentrated under vacuum. This resulted in 1.18 g (95%) of the title compound as a white solid. LC-MS (ES, m/z): 312, 314 [M+H].sup.+
(400) ##STR00784##
tert-butyl 5-bromo-2-(((tert-butoxycarbonyl)oxy)methyl)-1H-benzo[d]imidazole-1-carboxylate
(401) Into a 50-mL round-bottom flask, was placed (5-bromo-1H-1,3-benzodiazol-2-yl)methanol (600 mg, 2.64 mmol, 1.00 equiv), dichloromethane (20 mL), Boc.sub.2O (1 g, 4.58 mmol, 1.73 equiv), TEA (800 mg, 7.91 mmol, 2.99 equiv), 4-dimethylaminopyridine (32 mg, 0.26 mmol, 0.10 equiv). The resulting solution was stirred for 4 h at 25° C. The mixture was diluted with 20 mL of dichloromethane, washed with 3*30 mL of water and 30 mL of brine. The organic phase was dried over anhydrous sodium sulfate and concentrated under vacuum. This resulted in 600 mg (crude) of the title compound as yellow oil. LC-MS (ES, m/z) 429,427[M+H].sup.+
(402) ##STR00785##
tert-butyl (3-(3-bromophenyl)-1H-pyrazol-5-yl)carbamate
(403) Into a 50-mL round-bottom flask, was placed a solution of 3-(3-bromophenyl)-1H-pyrazol-5-amine (500 mg, 2.10 mmol, 1.00 equiv) in dichloromethane (20 mL), (Boc).sub.2O (916 mg, 4.20 mmol, 2.00 equiv), 4-dimethylaminopyridine (25.6 mg, 0.21 mmol, 0.10 equiv), TEA (636.5 mg, 6.29 mmol, 3.00 equiv). The resulting solution was stirred for 1 h at room temperature. The reaction mixture was then poured into 100 mL of water, extracted with 2×100 mL of dichloromethane. The organic layers were combined, dried over anhydrous sodium sulfate and concentrated under vacuum. This resulted in 710 mg (100%) of tert-butyl N-[3-(3-bromophenyl)-1H-pyrazol-5-yl]carbamate as brown oil. LC-MS (ES, m/z): 338[M+H].sup.+
(404) ##STR00786##
tert-butyl 3-bromo-7-fluoro-1H-indazole-1-carboxylate
(405) Into a 50-mL round-bottom flask, was placed 3-bromo-7-fluoro-1H-indazole (700 mg, 3.26 mmol, 1.00 equiv), dichloromethane (20 mL), Boc.sub.2O (1.5 g, 6.87 mmol, 2.11 equiv), TEA (1 g, 9.88 mmol, 3.04 equiv), 4-dimethylaminopyridine (40 mg, 0.33 mmol, 0.10 equiv). The resulting solution was stirred for 4 h at 25° C. The resulting mixture was poured into 50 ml of water, extracted and concentrated under vacuum. This resulted in 1 g (crude) of the title compound as red oil. LC-MS (ES, m/z): 315, 317[M+H].sup.+
(406) ##STR00787##
tert-butyl (5-bromobenzo[d]isoxazol-3-yl)carbamate
(407) Into a 50-mL round-bottom flask, was placed 5-bromo-1,2-benzoxazol-3-amine (1 g, 4.69 mmol, 1.00 equiv), dichloromethane (20 mL), Boc.sub.2O (2.1 g, 9.62 mmol, 2.05 equiv), 4-dimethylaminopyridine (57 mg, 0.47 mmol, 0.10 equiv), TEA (1.4 g, 13.84 mmol, 2.95 equiv). The reaction mixture was stirred for 3 h at 25° C. The resulting mixture was washed with 30 ml of water, 3×30 mL of brine, dried over anhydrous sodium sulfate and concentrated under vacuum. This resulted in 650 mg (crude) of the title compound as yellow oil. LC-MS (ES, m/z): 313, 315[M+H].sup.+
(408) ##STR00788##
2-chloro-6-fluoroquinazoline
(409) Into a 100-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 2,4-dichloro-6-fluoroquinazoline (1 g, 4.61 mmol, 1.00 equiv), brine (23 mL), dichloromethane (25 mL), ammonia hydrate (2 ml), Zn (0.9 g, 13.8 mmol, 3.0 equiv). The resulting mixture was stirred for overnight at 50° C. in an oil bath. The reaction mixture was cooled to room temperature and diluted with 50 mL of H.sub.2O, extracted with 2×100 mL of dichloromethane. The organic layers were combined and concentrated under vacuum. The residue was purified by Combi-Flash with the following conditions (IntelFlash-1): Column, silica gel; mobile phase, EA:PE=100% increasing to EA:PE=60% within 40 min; Detector, UV 254 nm. This resulted in 0.35 g (35%) of the title compound as a yellow solid. LC-MS (ES, m/z) 183 [M+H].sup.+
(410) ##STR00789##
6-bromo-1-methyl-1H-indazol-3-ol
(411) Into a 5-mL sealed tube, was placed methyl 4-bromo-2-fluorobenzoate (300 mg, 1.29 mmol, 1.00 equiv), methylhydrazine (71.4 mg, 1.55 mmol, 1.20 equiv), DMA (2 mL). The resulting solution was stirred overnight at 150° C. in a sand bath. After cooled to room temperature, the reaction mixture was diluted with 10 mL of ethyl acetate, washed with 3×10 mL of H.sub.2O and 1×20 mL of brine. The organic phase was concentrated under vacuum. This resulted in 225 mg (77%) of 6-bromo-1-methyl-1H-indazol-3-ol as an off-white solid. LC-MS (ES, m/z): 227, 229 [M+H].sup.+
(412) ##STR00790##
6-bromo-1-(methylsulfonyl)-1H-indole
(413) To a solution of 6-bromoindole (2.94 g, 15 mmol, 1 eq.) in anhydrous DMF (45 mL) cooled in an ice-water bath was added NaH (0.72 g, 18 mmol, 1.2 eq.) portionwise under N2. The mixture was stirred for additional 20 min. and MeSO.sub.2Cl (1.4 mL, 18 mmol, 1.2 eq.) was then added dropwise. The reaction mixture was allowed to warm to room temperature and stirred for 1 hour before being quenched with ice and diluted with EtOAc. The organic layer was washed with water (2×) and brine (2×), dried over Na.sub.2SO.sub.4 and concentrated in vacuum. The crude residue was purified by flash chromatography (silica gel) eluting with EtOAc/hexanes (0˜20%) to give the title compound as a white solid (0.94 g, 23%).
(414) Enzymatic Assay for FASN Inhibitors
(415) Assays were performed in a 384-well black plate to measure the inhibition of FASN activities by individual compounds herein disclosed. An aliquot of 250 nL of compound was incubated with 10 L of 40 nM FASN enzyme in assay buffer (50 mM HEPES pH=7.3, 0.5 mM EDTA, 1 mM Ascorbate, 100 mM NaCl and 0.04% TritonX-100) in each well at 25° C. for 60 minutes. After the plate was centrifuged briefly, 10 μL of substrate mix (20 M Acetyl-CoA, 60 M Malonyl-CoA, and 100 M NADPH in assay buffer) was added to each well. The reaction was maintained at 25° C. for 90 minutes. The reaction was then quenched by adding 10 L of 90 M 7-Diethylamino-3-(4′-Maleimidylpheynyl)-4-Methylcoumarin in 50/50 Ethanol/H.sub.2O solution. The assay plate was incubated at 25° C. for 15 minutes, and read on a plate reader with excitation and emission wavelength at 360 nm and 530 nm, respectively. The IC50 of a given compound was calculated by fitting the dose response curve with a four parameter logistic equation.
(416) Results
(417) Table 2-1 lists the compounds having an IC 50<0.5 μM.
(418) Table 2-2 lists the compounds having an IC 50≥0.5 M and <5.0 μM.
(419) Table 2-3 lists the compounds having an IC 50≥5.0 μM.
(420) In addition, the Molecular Weight, Mass Ion Spectrometry Results, HPLC retention time, and the Method used to synthesize the compound are also listed.
(421) TABLE-US-00002 TABLE 2-1 HPLC Mass reten- Ion tion Mol. Ob- time Meth- IC50 (uM) < 0.5 Weight served (min) od 5-[4-({4-[(1-hydroxy- 456.54 457.16 1.29 10 cyclopropyl)carbonyl]piperazin-1- yl}carbonyl)phenyl]-1-(propan-2-yl)- 1H-indole-3-carbonitrile 1-[(4-{[4-(4-chloro-3- 402.85 403.10 1.37 1 fluorophenyl)phenyl]car- bonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol 1-[(4-{[4-(6-methoxy-4- 445.51 446.16 1.16 7 methylquinolin-2- yl)phenyl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol 1-[(4-{[3-methyl-4-(quinolin-6- 415.48 416.21 0.92 5 yl)phenyl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol 1-[(4-{[4-(1-methyl-1H-indol-2- 403.47 404.25 1.56 5 yl)phenyl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol 1-[(4-{[4-(2-methoxyquinolin-6- 431.18 432.08 2.28 2 yl)phenyl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol 1-({4-[(4-{imidazo[1,2-a]pyridin-2- 390.44 391.19 0.61 3 yl}phenyl)carbonyl]piperazin-1- yl}carbonyl)cyclopropan-1-ol 1-{[4-({3-chloro-4-[1- 491.89 492.03 1.3 10 (trifluoromethyl)-1H-indol- 5-yl]phenyl}carbonyl)piperazin-1- yl]carbonyl}cyclopropan-1-ol 1-[(4-{[5-(1-methyl-1H- 405.45 406.22 1.09 5 indol-5-yl)pyrazin-2- yl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol 1-[(4-{[4-[1,3-benzothiazol-5-yl)-2- 441.93 442.11 1.14 5 chlorophenyl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol 3-[3-fluoro-4-({4-[(1- 435.45 436.13 0.96 5 hydroxycyclopropyl)car- bonyl]piperazin-1- yl}carbonyl)phenyl]quinolin-2-ol 5-[4-({4-[(1- 414.46 415.15 1.09 2 hydroxycyclopropyl)car- bonyl]piperazin-1- yl}carbonyl)phenyl]-1H- indole-2-carbonitrile 1-[(4-{[4-(5-chloro-1,3-benzoxazol-2- 425.87 426.13 1.31 4 yl)phenyl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol 1-[(4-{[4-(2,4- 419.30 419.12 1.47, 5 dichlorophenyl)phenyl]car- 1.68 bonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol 1-[(4-{[4-(quinolin-3- 401.46 402.14 0.99 1 yl)phenyl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol 3-[4-({4-[(oxetan-2-yl)car- 401.46 402.14 0.95 2 bonyl]piperazin-1- yl}carbonyl)phenyl]quinoline 1-[(4-{[4-[1,3-benzoxazol-2- 391.42 392.16 1.14 4 yl)phenyl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol 1-[(4-{[2-chloro-4-(quinolin-3- 435.90 436.16 1.11 5 yl)phenyl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol 1-[(4-{[4-(1-methyl-1H- 404.46 405.08 0.68 7 1,3-benzodiazol-5- yl)phenyl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol 1-[(4-{[4-(1H-indazol-3- 390.44 391.12 0.98 7 yl)phenyl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol 1-[(4-{[4-(1-methyl-1H-indol-5- 403.47 404.12 1.26 2 yl)phenyl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol 1-[(4-{[4-(1-benzofuran-5- 390.16 391.01 2.43 2 yl)phenyl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol 1-[(4-{[4-(1H-1,3-benzodiazol-5- 390.44 391.20 0.6 2 yl)phenyl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol 1-[(4-{[4-[1,3-dimethyl-1H-indazol-5- 418.49 419.09 1.07 7 yl)phenyl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol 1-[(4-{[4-(2,1,3-benzothiadiazol-4- 408.47 409.11 1.17 7 yl)phenyl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol 1-[(4-{[4-(6-methoxyquinolin-2- 431.48 432.20 1.16 5 yl)phenyl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol 1-({4-[(2-phenyl-1,3-benzothiazol-6- 407.49 408.09 1.22 5 yl)carbonyl]piperazin-1- yl}carbonyl)cyclopropan-1-ol 1-[(4-{[4-[1,3-benzothiazol-5- 407.49 408.13 1.04 2 yl)phenyl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol 1-[(4-{[3-methyl-4-(quinolin-3- 415.48 416.21 1.07 5 yl)phenyl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol 1-[(4-{[2-fluoro-4-(quinolin-6- 419.45 420.19 0.91 5 yl)phenyl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol 1-[(4-{[4-(6-fluoroquinolin-2- 419.45 420.16 1.24 5 yl)phenyl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol 1-[(4-{[2-chloro-4-(1- 437.92 438.15 1.32 5 methyl-1H-indol-5- yl)phenyl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol 1-[(4-{[4-(1H-1,3-benzodiazol-4- 390.44 391.14 0.7 7 yl)phenyl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol 1-[(4-{[4-[1,3-benzothiazol-5-yl)-3- 421.51 422.16 1.13 5 methylphenyl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol 1-[(4-{[4-[1,3-benzothiazol-6- 407.49 408.14 1 2 yl)phenyl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol 1-[(4-{[4-(4- 384.86 385.13 1.35 1 chlorophenyl)phenyl]car- bonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol 1-[(4-{[4-(6-chloro-1,3-benzoxazol-2- 425.87 426.11 1.33 4 yl)phenyl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol 1-[(4-{[4-(4-chloro-2- 402.85 403.12 1.36 1 fluorophenyl)phenyl]car- bonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol 1-[(4-{[4-[1,3-benzothiazol-5-yl)-3- 441.93 442.12 1.16 5 chlorophenyl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol 1-[(4-{[2-fluoro-4-(7-fluoro-1H-indol- 425.43 426.04 1.16 5 5-yl)phenyl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol 1-[(4-{[4-[1,3-benzothiazol-2- 407.49 408.09 1.24 6 yl)phenyl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol 1-[(4-{[4-(4-chloroquinolin-3- 435.90 436.11 1.19 7 yl)phenyl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol 1-[(4-{[4-(isoquinolin-1- 401.46 402.20 0.9 7 yl)phenyl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol 1-[(4-{[4-(5-chloro-1H-1,3- 424.88 425.08 1.01 7 benzodiazol-2- yl)phenyl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol 1-[(4-{[4-(1,3-benzoxazol-5- 391.42 392.16 0.97 2 yl)phenyl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol 1-[(4-{[4-[1,3-benzoxazol-4- 391.42 392.16 1.1 7 yl)phenyl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol 1-[(4-{[3-fluoro-4-(quinolin-6- 419.45 420.18 0.91 5 yl)phenyl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol 1-[(4-{[4-(3,4- 419.30 419.03 1.45 2 dichlorophenyl)phenyl]car- bonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol 1-[(4-{[6-(1-methyl-1H- 404.46 405.21 1.04 5 indol-5-yl)pyridin-3- yl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol 1-[(4-{[4-(2,1,3-benzothiadiazol-5- 408.47 409.11 1.17 3 yl)phenyl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol 1-[(4-{[2-fluoro-4-(quinolin-3- 419.45 420.18 1.07 5 yl)phenyl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol 5-[4-({4-[(1- 432.47 433.15 0.81 3 hydroxycyclopropyl)car- bonyl]piperazin-1- yl}carbonyl)phenyl]-1H- indole-2-carboxamide 1-[(4-{[4-(2-methyl-2H-indazol-6- 404.46 405.08 0.94 5 yl)phenyl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol 3-[4-({4-[(1- 417.46 418.15 0.93 1 hydroxycyclopropyl)car- bonyl]piperazin-1- yl}carbonyl)phenyl]-1,2- dihydroquinolin-2-one 1-[(4-{[4-(3-chloro-4- 402.85 403.11 1.36 1 fluorophenyl)phenyl]car- bonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol 1-{[4-({4-[2-methoxy-4- 446.50 447.23 1.19 5 (1H-pyrazol-1- yl)phenyl]phenyl}carbonyl)piperazin- 1-yl]carbonyl]cyclopropan-1-ol 1-[(4-{[2-chloro-4-(quinolin-6- 435.90 436.14 0.96 5 yl)phenyl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol 1-[(4-{[4-(2-methyl-2H-indazol-5- 404.46 405.17 0.88 7 yl)phenyl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol 1-[(4-{[4-(5-chloro-2- 402.85 403.10 1.33 1 fluorophenyl)phenyl]car- bonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol 5-[4-({4-[(1-hydroxycyclo- 414.46 415.17 0.97 1 propyl)carbonyl]piperazin-1- yl}carbonyl)phenyl]-1H- indole-3-carbonitrile 5-[4-({4-[(oxetan-2- 389.45 389.18 1.03 2 yl)carbonyl]piperazin-1- yl}carbonyl)phenyl]-1H-indole 5-[2-chloro-4-({4-[(1- 448.90 449.10 1.06 5 hydroxycyclopropyl)car- bonyl]piperazin-1- yl}carbonyl)phenyl]-1H- indole-3-carbonitrile 1-[(4-{[4-(quinolin-5- 401.46 402.17 0.84 7 yl)phenyl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol N-{3-[4-({4-[(1- 443.52 444.17 0.93 11 hydroxycyclopropyl)car- bonyl]piperazin-1- yl}carbonyl)phenyl]phenyl}methane- sulfonamide 1-[(4-{[5-(1-methyl-1H- 404.46 405.28 1.1 5 indol-5-yl)pyridin-2- yl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol 1-[(4-{[2-fluoro-4-(2- 449.47 450.17 1.39 5 methoxyquinolin-3- yl)phenyl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol 1-({4-[(4-phenylphenyl)car- 350.41 351.20 1.2 5 bonyl]piperazin-1- yl}carbonyl)cyclopropan-1-ol 1-[(4-{[4-(7-fluoro-1H-indol-5- 407.44 408.12 1.11 5 yl)phenyl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol 1-[(4-{[2,3-difluoro-4-(6- 467.46 468.16 1.28 7 methoxyquinolin-2- yl)phenyl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol N-{3-[4-({4-[(1- 469.55 470.08 1.04 11 hydroxycyclopropyl)car- bonyl]piperazin-1- yl}carbonyl)phenyl]phenyl}cyclo- propanesulfonamide 1-[(4-{[3-methyl-4-(1-methyl- 417.50 418.25 1.3 5 1H-indol-5- yl)phenyl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol 1-[(4-{[4-(3- 406.47 407.08 1.37 7 cyclopropoxyphenyl)phenyl]car- bonyl}piperazin- 1-yl)carbonyl]cyclopropan-1-ol 1-[(4-{[4-(2,5- 419.30 419.13 1.43 5 dichlorophenyl)phenyl]car- bonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol 1-[(4-{[3-chloro-4-(1-methyl- 437.92 438.18 1.33 5 1H-indol-5- yl)phenyl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol 5-[3-chloro-4-({4-[(1- 448.90 449.10 1.06 5 hydroxycyclopropyl)car- bonyl]piperazin-1- yl}carbonyl)phenyl]-1H- indole-3-carbonitrile 1-[(4-{[4-(2H-1,2,3-benzotriazol-5- 391.42 392.14 0.79 3 yl)phenyl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol 1-[(4-{[4-(3-chloro-2- 414.88 415.15 1.34 5 methoxyphenyl)phenyl]car- bonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol 1-[(4-{[2,3-difluoro-4-(quinolin-2- 437.44 438.15 1.27 7 yl)phenyl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol 1-[(4-{[4-(1H-indol-2- 389.45 390.12 1.24 2 yl)phenyl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol 3-[3-chloro-4-({4-[(1-hydroxy- 504.00 504.05 1.15 3 cyclopropyl)carbonyl]piperazin-1- yl}carbonyl)phenyl]-N- cyclopropylbenzene-1- sulfonamide 1-[(4-{[3-chloro-4-(quinolin-6- 435.90 436.16 0.99 5 yl)phenyl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol 1-[(4-{[4-(5-fluoro-1,3-benzoxazol-2- 409.41 410.14 1.18 4 yl)phenyl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol 1-[(4-{[4-(1-methyl-1H-indol-5-yl)-2- 471.47 472.22 1.39 5 (trifluoromethyl)phenyl]car- bonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol 1-[(4-{[4-(1-methyl-1H-indazol-6- 404.46 405.09 1.05 5 yl)phenyl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol N-cyclopropyl-3-[4-({4-[(1-hydroxy- 433.50 434.13 0.95 7 cyclopropyl)carbonyl]piperazin-1- yl}carbonyl)phenyl]benzamide 1-[(4-{[4-(4-chloro-2- 414.88 415.17 1.37 5 methoxyphenyl)phenyl]car- bonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol 1-[(4-{[4-(1-methyl-1H-indazol-5- 404.46 405.11 1.01 7 yl)phenyl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol 1-[(4-{[2-fluoro-4-(6-fluoroquinolin- 437.44 438.16 1.32 5 2-yl)phenyl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol 1-[(4-{[4-(isoquinolin-6- 401.46 402.02 1.48 1 yl)phenyl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol 1-{[4-({4-[3-(cyclopropyl- 420.50 421.16 1.4 5 methoxy)phenyl]phenyl}carbonyl) piperazin-1- yl]carbonyl}cyclopropan-1-ol 2-[4-({4-[(1- 416.43 417.14 1.07 4 hydroxycyclopropyl)car- bonyl]piperazin-1- yl}carbonyl)phenyl]-1,3- benzoxazole-5-carbonitrile 1-({4-[(4-{imidazo[1,2-b]pyridazin- 391.42 392.10 0.69 7 6-yl}phenyl)carbonyl]piperazin-1- yl}carbonyl)cyclopropan-1-ol 1-({4-[(4-[1H-pyrrolo[3,2-b]pyridin- 390.44 391.14 0.58 3 5-yl}phenyl)carbonyl]piperazin-1- yl}carbonyl)cyclopropan-1-ol 1-[(4-{[3-fluoro-4-(quinolin-3- 419.45 420.20 1.08 5 yl)phenyl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol 1-[(4-{[2-fluoro-4-(6- 449.47 450.15 1.25 5 methoxyquinolin-2- yl)phenyl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol 1-[(4-{[4-(2,3- 419.30 419.08 1.38 2 dichlorophenyl)phenyl]car- bonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol 1-[(4-{[2,3-difluoro-4-(6- 455.43 456.14 1.33 7 fluoroquinolin-2- yl)phenyl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol N-cyclopropyl-3-[4-({4-[(1-hydroxy- 469.55 470.13 1.05 11 cyclopropyl)carbonyl]piperazin-1- yl}carbonyl)phenyl]benzene- 1-sulfonamide 1-({4-[(4-{furo[3,2-b]pyridin-5- 391.42 392.08 0.97 7 yl}phenyl)carbonyl]piperazin-1- yl}carbonyl)cyclopropan-1-ol 1-({4-[(4-{3-chloroimidazo[1,2- 424.88 425.06 0.98 3 a]pyridin-2- yl}phenyl)carbonyl]piperazin-1- yl}carbonyl)cyclopropan-1-ol 1-[(4-{[4-[1,3-benzothiazol-5-yl)-3- 425.48 426.12 1.1 5 fluorophenyl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol N-{3-[4-({4-[(1-hydroxycyclo- 471.57 472.19 1.08 11 propyl)carbonyl]piperazin-1- yl}carbonyl)phenyl]phenyl}propane- 2-sulfonamide 6-[4-({4-[(oxetan-2- 401.17 402.02 1.46 2 yl)carbonyl]piperazin-1- yl}carbonyl)phenyl]isoquinoline N-{3-[4-({4-[(1-hydroxycyclo- 505.59 506.10 1.18 11 propyl)carbonyl]piperazin-1- yl}carbonyl)phenyl]phenyl}benzene- sulfonamide 1-{[4-({4-[2-methoxy-5- 464.43 465.17 1.43 5 (trifluoromethoxy)phenyl]phenyl}car- bonyl)piperazin- 1-yl]carbonyl}cyclopropan-1-ol 1-[(4-{[4-(2-chloro-4-fluoro- 402.85 403.17 1.33 5 phenyl)phenyl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol 1-[(4-{[4-(3-chloro- 384.86 385.06 1.33 1 phenyl)phenyl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol 1-[(4-{[4-(quinolin-3- 415.48 416.04 2.13 1 yl)phenyl]carbonyl}piperazin-1- yl)carbonyl]cyclobutan-1-ol 1-({4-[(2-chloro-4- 424.88 425.11 0.71 3 {imidazo[1,2-a]pyridin-2- yl}phenyl)carbonyl]piperazin-1- yl}carbonyl)cyclopropan-1-ol 1-[(4-{[4-(1H-indol-5- 389.17 390.06 2.11 2 yl)phenyl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol 1-[(4-{[4-(isoquinolin-6- 415.48 416.04 1.61 1 yl)phenyl]carbonyl}piperazin-1- yl)carbonyl]cyclobutan-1-ol 1-[(4-{[2-fluoro-4-(1-methyl- 421.46 422.22 1.29 5 1H-indol-5- yl)phenyl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol 1-[(4-{[4-(6-fluoro-1,3-benzoxazol- 409.41 410.14 1.2 4 2-yl)phenyl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol N-{3-[4-({4-[(1-hydroxycyclo- 433.50 434.13 1.06 5 propyl)carbonyl]piperazin-1- yl}carbonyl)phenyl]phenyl}cyclo- propanecarboxamide 1-({4-[(4-{pyrazolo[1,5-a]pyridin-2- 390.44 391.15 0.95 3 yl}phenyl)carbonyl]piperazin-1- yl)carbonyl)cyclopropan-1-ol 1-[(4-{[3-chloro-4-(quinolin-3- 435.90 436.15 1.14 5 yl)phenyl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol 1-[(4-{[4-(quinolin-2- 401.46 402.16 1.14 7 yl)phenyl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol 1-[(4-{[4-(1H-indol-4- 389.45 390.18 1.06 7 yl)phenyl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol 6-[4-({4-[(1-hydroxycyclo- 417.46 418.13 0.76 3 propyl)carbonyl]piperazin-1- yl}carbonyl)phenyl]-1,2- dihydroquinolin-2-one 2-[4-({4-[(1-hydroxycyclo- 416.43 417.15 1.06 4 propyl)carbonyl]piperazin-1- yl}carbonyl)phenyl]-1,3-benzoxazole- 6-carbonitrile 1-{[4-({3-chloro-4-[1-(propan-2- 465.97 466.05 1.5 10 yl)-1H-indol-5- yl]phenyl}carbonyl)piperazin-1- yl]carbonyl}cyclopropan-1-ol 1-[(4-{[4-(6-methoxynaphthalen-2- 430.50 431.12 1.36 5 yl)phenyl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol N-(3-{4-[4-(1- 461.23 462.15 1.23 30 hydroxycyclopropane- carbonyl)piperazine-1- carbonyl]phenyl}phenyl)cyclo- pentanecarboxamide 1-(4-{4-[4-(1H-pyrazol-4- 416.18 417.05 0.93 31 yl)phenyl]benzoyl}piperazine-1- carbonyl)cyclopropan-1-ol 1-{4-[4-(1,2,3,4- 405.21 406.15 1.25 20 tetrahydroisoquinolin-2- yl)benzoyl]piperazine-1- carbonyl}cyclopropan-1-ol 1-{4-[4-(1,3-dimethyl-1H- 435.21 436.27 0.88 14 indazol-5-yl)-2- fluorobenzoyl]piperazine-1- carbonyl}cyclopropan-1-amine 1-(4-{4-[4-(1-methyl-1H-pyrazol-4- 430.20 431.06 1.03 31 yl)phenyl]benzoyl}piperazine-1- carbonyl)cyclopropan-1-ol 1-[(2S)-4-[2-fluoro-4-(1- 436.19 437.20 0.74 27 methyl-1H-1,3- benzodiazol-5-yl)benzoyl]-2- methylpiperazine-1- carbonyl]cyclopropan-1-ol 1-{4-[3-chloro-4-(1-methyl- 438.15 439.11 1.11 13 1H-indazol-6- yl)benzoyl]piperazine-1- carbonyl}cyclopropan-1-ol 1-{4-[2-fluoro-4-(1-methyl-1H-1,3- 422.18 423.17 0.70 13 benzodiazol-5-yl)benzoyl]piperazine- 1-carbonyl}cyclopropan-1-ol 1-{4-[3-chloro-4-(1-methyl-1H-1,3- 438.15 439.09 0.74 13 benzodiazol-5-yl)benzoyl]piperazine- 1-carbonyl}cyclopropan-1-ol 1-[4-(4-{pyrazolo[1,5-a]pyridin-6- 390.17 391.11 0.97 13 yl}benzoyl)piperazine-1- carbonyl]cyclopropan-1-ol 1-{4-[4-(4-fluoro-2,3-dihydro- 409.18 410.23 1.34 19 1H-indol-1- yl)benzoyl]piperazine-1- carbonyl}cyclopropan-1-ol 1-{4-[4-(3-methyl-1H-indazol-6- 404.18 405.15 0.95 13 yl)benzoyl]piperazine-1- carbonyl}cyclopropan-1-ol 1-{4-[2-fluoro-4-(3-methyl- 422.18 423.16 1.11 13 1H-indazol-7- yl)benzoyl]piperazine-1- carbonyl}cyclopropan-1-ol 1-[(2S)-2-methyl-4-[4-(1-methyl-1H- 418.20 419.25 1.06 3 indazol-6-yl)benzoyl]piperazine-1- carbonyl]cyclopropan-1-ol 1-{4-[3-chloro-4-(2-methyl-2H- 438.15 439.10 1.00 13 indazol-6-yl)benzoyl]piperazine-1- carbonyl}cyclopropan-1-ol 3,3,3-trifluoro-N-(3-{4-[4-(1- 525.15 526.06 1.20 11 hydroxycyclopropane- carbonyl)piperazine-1- carbonyl]phenyl}phenyl)propane- 1-sulfonamide 1-{4-[2-fluoro-4-(1-methyl- 422.18 423.11 1.06 13 1H-indazol-6- yl)benzoyl]piperazine-1- carbonyl}cyclopropan-1-ol 1-{3,3-dimethyl-4-[4- 432.22 433.20 0.75 24 (1-methyl-1H-1,3-benzodiazol- 5-yl)benzoyl]piperazine-1- carbonyl}cyclopropan-1-ol 1-{4-[2,6-difluoro-4-(1-methyl-1H- 440.17 441.17 0.75 32 1,3-benzodiazol-5-yl)benzoyl] piperazine-1-carbonyl} cyclopropan-1-ol 1-{4-[2-fluoro-4-(1-methyl- 435.21 436.27 0.88 14 1H-indazol-6- yl)benzoyl]piperazine-1- carbonyl}cyclobutan-1-amine 1-{4-[3-chloro-4-(6-chloro- 459.08 460.02 1.40 13 1,3-benzoxazol-2- yl)benzoyl]piperazine-1- carbonyl}cyclopropan-1-ol 1-{4-[4-(1,3-dimethyl-1H-indazol- 436.19 437.16 1.08 13 5-yl)-2-fluorobenzoyl]piperazine-1- carbonyl}cyclopropan-1-ol N-(3-{4-[4-(1-hydroxycyclo- 483.18 484.16 1.07 33 propanecarbonyl)piperazine-1- carbonyl]phenyl}phenyl)cyclo- butanesulfonamide 1-{4-[4-(2,3-dihydro-1H-indol-1- 391.19 392.18 1.24 19 yl)benzoyl]piperazine-1- carbonyl}cyclopropan-1-ol 1-{4-[3-chloro-4-(1,3-dimethyl- 452.16 453.10 1.13 13 1H-indazol-5- yl)benzoyl]piperazine-1- carbonyl}cyclopropan-1-ol 1-[(2S)-2-methyl-4-[4- 418.20 419.26 0.70 23 (1-methyl-1H-1,3- benzodiazol-5-yl)benzoyl]piperazine- 1-carbonyl]cyclopropan-1-ol 1-{4-[2,6-difluoro-4-(2- 440.17 441.16 0.97 32 methyl-2H-indazol-6- yl)benzoyl]piperazine-1- carbonyl}cyclopropan-1-ol 1-(4-{4-[3-(5-amino-1,2- 450.17 451.12 1.02 13 oxazol-3-yl)phenyl]-2- fluorobenzoyl}piperazine-1- carbonyl)cyclopropan-1-ol 1-[(2S)-2-methyl-4-[4-(2-methyl-2H- 418.20 419.23 0.95 3 indazol-6-yl)benzoyl]piperazine-1- carbonyl]cyclopropan-1-ol 1-cyclobutyl-N-(3-{4-[4-(1- 497.20 498.10 1.21 34 hydroxycyclopropane- carbonyl)piperazine-1- carbonyl]phenyl}phenyl)methane- sulfonamide 1-{4-[2-fluoro-4-(7-fluoro- 426.15 427.12 1.07 13 1H-indazol-3- yl)benzoyl]piperazine-1- carbonyl}cyclopropan-1-ol 1-[(2S)-4-[4-(6-chloro-1,3- 439.13 440.18 1.39 23 benzoxazol-2- yl)benzoyl]-2-methylpiperazine-1- carbonyl]cyclopropan-1-ol 1-{4-[4-(1H-indol-1- 389.17 390.06 1.30 18 yl)benzoyl]piperazine-1- carbonyl}cyclopropan-1-ol 1-{4-[4-(7-fluoro-1H-indazol-3- 408.16 409.08 0.99 3 yl)benzoyl]piperazine-1- carbonyl}cyclopropan-1-ol 1-{4-[4-(7-fluoro-1,2,3,4- 423.20 424.20 1.28 19 tetrahydroisoquinolin-2- yl)benzoyl]piperazine-1- carbonyl}cyclopropan-1-ol 1-{4-[2-fluoro-4-(2-methyl-2H- 422.18 423.14 0.94 13 indazol-6-yl)benzoyl]piperazine-1- carbonyl}cyclopropan-1-ol 1-{4-[4-(3-amino-1H-indazol-6- 405.18 406.17 0.71 13 yl)benzoyl]piperazine-1- carbonyl}cyclopropan-1-ol 1-{4-[4-(3-amino-1,2-benzoxazol-5- 406.16 407.11 0.86 3 yl)benzoyl]piperazine-1- carbonyl}cyclopropan-1-ol 1-{4-[4-(1,3-dimethyl-1H-indazol-5- 449.22 450.29 0.89 14 yl)-2-fluorobenzoyl]piperazine-1- carbonyl}cyclobutan-1-amine 1-{4-[2-fluoro-4-(3-methyl-1H- 422.18 423.24 1.03 13 indazol-6-yl)benzoyl]piperazine-1- carbonyl}cyclopropan-1-ol ethyl N-(3-{4-[4-(1-hydroxycyclo- 437.20 438.13 1.12 11 propanecarbonyl)piperazine-1- carbonyl]phenyl}phenyl)carbamate 1-{4-[4-(5-chloro-2-methyl- 438.15 439.09 0.83 13 1H-1,3-benzodiazol-7- yl)benzoyl]piperazine-1- carbonyl}cyclopropan-1-ol 1-[4-(4-{1H,2H,3H,4H,9H- 444.22 445.17 1.26 19 pyrido[3,4-b]indol-2- yl}benzoyl)piperazine-1- carbonyl]cyclopropan-1-ol 1-[(2R,6S)-2,6-dimethyl- 432.22 433.20 0.73 23 4-[4-(1-methyl-1H-1,3- benzodiazol-5-yl)benzoyl]piperazine- 1-carbonyl]cyclopropan-1-ol 1-[4-(2-chloro-4-{3- 458.09 459.06 1.07 13 chloroimidazo[1,2-a]pyridin- 2-yl}benzoyl)piperazine-1- carbonyl]cyclopropan-1-ol 1-{4-[4-(4-chloro-2- 430.15 431.14 1.47 24 fluorophenyl)benzoyl]-3,3- dimethylpiperazine-1- carbonyl}cyclopropan-1-ol 1-{4-[2-chloro-4-(1-methyl- 438.15 439.10 1.10 13 1H-indazol-6- yl)benzoyl]piperazine-1- carbonyl}cyclopropan-1-ol 1-[(2S)-4-[4-(4-chloro-2- 416.13 417.14 1.40 23 fluorophenyl)benzoyl]-2- methylpiperazine-1- carbonyl]cyclopropan-1-ol 1-[(2S)-4-[4-(1,3-dimethyl- 432.22 433.27 1.10 3 1H-indazol-5- yl)benzoyl]-2-methylpiperazine-1- carbonyl]cyclopropan-1-ol 1-(4-{4-[3-(5-amino-1,2-oxazol-3- 432.18 433.23 0.97 22 yl)phenyl]benzoyl}piperazine-1- carbonyl)cyclopropan-1-ol 2-(3-{4-[4-(1-hydroxycyclo- 389.17 390.12 1.06 13 propanecarbonyl)piperazine-1- carbonyl]phenyl}phenyl)acetonitrile N-(3-{4-[4-(1-hydroxycyclo- 497.20 498.16 1.14 33 propanecarbonyl)piperazine-1- carbonyl]phenyl}phenyl)cyclo- pentanesulfonamide 1-[(3S)-3-methyl-4-[4- 418.20 419.21 0.67 23 (1-methyl-1H-1,3- benzodiazol- 5-yl)benzoyl]piperazine-1- carbonyl]cyclopropan-1-ol 1-cyclopropyl-N-(3-{4-[4-(1- 483.18 484.05 1.13 34 hydroxycyclopropane- carbonyl)piperazine-1- carbonyl]phenyl}phenyl)methane- sulfonamide 1-{4-[3-chloro-4-(6-fluoro- 443.10 444.08 1.25 13 1,3-benzoxazol-2- yl)benzoyl]piperazine-1- carbonyl}cyclopropan-1-ol 1-{4-[2-chloro-4-(2-methyl- 438.15 439.09 0.98 13 2H-indazol-6- yl)benzoyl]piperazine-1- carbonyl}cyclopropan-1-ol 1-{4-[2,6-difluoro-4-(1- 440.17 441.14 1.10 32 methyl-1H-indazol-6- yl)benzoyl]piperazine-1- carbonyl}cyclopropan-1-ol 1-[(3R)-3-methyl-4-[4-(1- 418.20 419.25 0.69 23 methyl-1H-1,3-benzodiazol- 5-yl)benzoyl]piperazine-1- carbonyl]cyclopropan-1-ol N-(6-{4-[4-(1-hydroxycyclo- 474.19 475.15 1.01 29 propanecarbonyl)piperazine-1- carbonyl]phenyl}-1,2-benzoxazol-3- yl)cyclopropanecarboxamide 1-[(3R,5S)-3,5-dimethyl-4- 432.51 433.16 0.74 23 [4-(1-methyl-1H-1,3- benzodiazol-5-yl)benzoyl]piperazine- 1-carbonyl]cyclopropan-1-ol propan-2-yl N-(3-{4-[4-(1- 451.21 452.16 1.24 11 hydroxycyclo- propanecarbonyl)piperazine-1- carbonyl]phenyl}phenyl)carbamate 1-{4-[4-(3-amino-1H-indazol-5- 405.18 406.17 0.73 13 yl)benzoyl]piperazine-1- carbonyl}cyclopropan-1-ol 1-[(2R)-2-methyl-4-[4- 418.20 419.25 0.69 23 (1-methyl-1H-1,3- benzodiazol-5-yl)benzoyl]piperazine- 1-carbonyl]cyclopropan-1-ol 3,3-difluoro-N-(3-{4-[4- 483.20 484.14 1.19 30 (1-hydroxycyclo- propanecarbonyl)piperazine-1- carbonyl]phenyl}phenyl)cyclobutane- 1-carboxamide 1-[(2S,6R)-4-[4-(6-fluoro- 437.18 438.13 1.28 4 1,3-benzoxazol-2- yl)benzoyl]-2,6-dimethylpiperazine- 1-carbonyl]cyclopropan-1-ol 1-(4-{4-[1-(2-hydroxyethyl)- 434.20 435.19 0.59 21 1H-1,3-benzodiazol- 6-yl]benzoyl}piperazine-1- carbonyl)cyclopropan-1-ol 1-{4-[4-(1H-1,3-benzodiazol-4-yl)-2- 424.13 425.04 0.79 5 chlorobenzoyl]piperazine-1- carbonyl}cyclopropan-1-ol 1-{4-[4-(5-fluoro-2,3-dihydro- 409.18 410.17 1.28 19 1H-indol-1- yl)benzoyl]piperazine-1- carbonyl}cyclopropan-1-ol 1-[4-(4-{3-chloroimidazo[1,2- 442.12 443.12 1.00 13 a]pyridin-2-yl}-2- fluorobenzoyl)piperazine-1- carbonyl]cyclopropan-1-ol 1-{4-[4-(4-chloro-2-fluorophenyl)-2- 420.11 421.01 1.39 15 fluorobenzoyl]piperazine-1- carbonyl}cyclopropan-1-ol 1-{4-[3-chloro-4-(4-chloro-2- 436.08 437.04 1.44 15 fluorophenyl)benzoyl]piperazine-1- carbonyl}cyclopropan-1-ol 1-{4-[2-chloro-4-(6-chloro- 459.08 460.03 1.43 13 1,3-benzoxazol-2- yl)benzoyl]piperazine-1- carbonyl}cyclopropan-1- ol 1-{4-[4-(5-fluoro-2,3- 409.18 410.23 1.31 19 dihydro-1H-isoindol-2- yl)benzoyl]piperazine-1- carbonyl}cyclopropan-1-ol 1-{4-[4-(3-methyl-1H-indazol-4- 404.18 405.15 0.90 13 yl)benzoyl]piperazine-1- carbonyl}cyclopropan-1-ol 1-{4-[4-(6-methoxy-1,3-benzoxazol- 421.16 422.04 1.13 4 2-yl)benzoyl]piperazine-1- carbonyl}cyclopropan-1-ol 1-{4-[4-(3-methyl-1H-indazol-7- 404.18 405.13 1.05 13 yl)benzoyl]piperazine-1- carbonyl}cyclopropan-1-ol 1-[(2R)-4-[4-(4-chloro-2- 416.13 417.14 1.40 23 fluorophenyl)benzoyl]-2- methylpiperazine-1- carbonyl]cyclopropan-1-ol 1-(3-{4-[4-(1-hydroxycyclo- 429.21 430.20 1.23 13 propanecarbonyl)piperazine-1- carbonyl]phenyl}phenyl)cyclo- butane-1-carbonitrile 1-{4-[2-fluoro-4-(6-fluoro- 427.13 428.09 1.22 13 1,3-benzoxazol-2- yl)benzoyl]piperazine-1- carbonyl}cyclopropan-1-ol 1-[4-(4-{1H,2H,3H,4H,5H- 444.22 445.16 1.20 19 pyrido[4,3-b]indol-2- yl}benzoyl)piperazine-1- carbonyl]cyclopropan-1-ol 1-{4-[4-(2-methyl-1H-indol-1- 403.19 404.15 1.32 18 yl)benzoyl]piperazine-1- carbonyl}cyclopropan-1-ol 1-[(2S)-2-methyl-4-[4-(1- 417.22 418.23 0.54 28 methyl-1H-1,3-benzodiazol- 5-yl)benzoyl]piperazine-1- carbonyl]cyclopropan-1-amine 1-{4-[3-fluoro-4-(1-methyl- 422.18 423.14 0.68 13 1H-1,3-benzodiazol-5- yl)benzoyl]piperazine-1- carbonyl}cyclopropan-1-ol 1-{4-[2-fluoro-4-(1-methyl- 435.21 436.27 0.57 14 1H-1,3-benzodiazol-5- yl)benzoyl]piperazine-1- carbonyl}cyclobutan-1-amine 1-{4-[3-fluoro-4-(1-methyl-1H- 422.18 423.09 1.05 13 indazol-6-yl)benzoyl]piperazine-1- carbonyl}cyclopropan-1-ol 1-[(2S)-4-[4-(6-fluoro- 423.16 424.18 1.21 4 1,3-benzoxazol-2- yl)benzoyl]-2-methylpiperazine-1- carbonyl]cyclopropan-1-ol 1-{4-[4-(4-fluoro-2,3- 409.18 410.21 1.30 19 dihydro-1H-isoindol-2- yl)benzoyl]piperazine-1- carbonyl}cyclopropan-1-ol 1-(4-{3-chloro-4-[3- 488.12 489.07 1.10 13 (cyclopropanesulfonyl)phenyl]ben- zoyl}piperazine-1- carbonyl)cyclopropan-1-ol 1-{4-[4-(7-fluoro-2,3-dihydro-1H- 409.18 410.23 1.28 19 indol-1-yl)benzoyl]piperazine-1- carbonyl}cyclopropan-1-ol 1-{4-[4-(3-cyclopropyl-1H-indazol-6- 430.20 431.15 1.09 13 yl)benzoyl]piperazine-1- carbonyl}cyclopropan-1-ol 1-{4-[4-(6-fluoro-1,3- 437.18 438.19 1.28 24 benzoxazol-2-yl)benzoyl]- 3,3-dimethylpiperazine-1- carbonyl}cyclopropan-1-ol 1-{4-[4-(3-methyl-1H-indazol-1- 404.18 405.11 1.14 18 yl)benzoyl]piperazine-1- carbonyl}cyclopropan-1-ol 1-{4-[2-fluoro-4-(3-methyl- 421.19 422.20 0.91 14 1H-indazol-7- yl)benzoyl]piperazine-1- carbonyl}cyclopropan-1-amine 1-{4-[4-(1-methanesulfonyl- 467.15 468.03 1.20 3 1H-indol-6- yl)benzoyl]piperazine-1- carbonyl}cyclopropan-1-ol 1-{4-[4-(1-methyl-1H-1,3- 403.20 404.16 0.81 14 benzodiazol-5- yl)benzoyl]piperazine-1- carbonyl}cyclopropan-1-amine 1-{4-[4-(2-methyl-2,3-dihydro- 405.21 406.24 1.37 19 1H-indol-1- yl)benzoyl]piperazine-1- carbonyl}cyclopropan-1-ol 1-{4-[4-(5-fluoro-1H-1,2,3- 409.16 410.10 0.79 13 benzotriazol-6- yl)benzoyl]piperazine-1- carbonyl}cyclopropan-1-ol 1-{4-[3-chloro-4-(5-chloro-2- 436.08 436.98 1.40 13 fluorophenyl)benzoyl]piperazine-1- carbonyl}cyclopropan-1-ol 1-[(2S,6R)-4-[4-(4-chloro-2- 430.15 431.18 1.48 23 fluorophenyl)benzoyl]-2,6- dimethylpiperazine-1- carbonyl]cyclopropan-1-ol N-(3-{4-[4-(1-hydroxycyclo- 513.19 514.05 0.98 34 propanecarbonyl)piperazine-1- carbonyl]phenyl}phenyl)oxane- 4-sulfonamide 1-{4-[4-(1-methyl-1H-indazol-6- 403.20 404.15 0.79 14 yl)benzoyl]piperazine-1- carbonyl}cyclopropan-1- amine 1-{4-[4-(7-methoxy-1,2,3,4- 435.22 436.21 1.26 19 tetrahydroisoquinolin-2- yl)benzoyl]piperazine-1- carbonyl}cyclopropan-1-ol 1-(3-{3-fluoro-4-[4-(1-hydroxycyclo- 433.18 434.16 1.22 13 propanecarbonyl)piperazine-1- carbonyl]phenyl}phenyl)cyclo- propane-1-carbonitrile 1-{4-[2-fluoro-4-(2-methyl-1H-indol- 421.18 422.12 1.41 18 1-yl)benzoyl]piperazine-1- carbonyl}cyclopropan-1-ol 1-{4-[4-(1H-1,3-benzodiazol-1- 390.17 391.14 0.81 18 yl)benzoyl]piperazine-1- carbonyl}cyclopropan-1-ol 1-(3-{4-[4-(1-hydroxycyclo- 415.19 416.18 1.14 13 propanecarbonyl)piperazine-1- carbonyl]phenyl}phenyl)cyclo- propane-1-carbonitrile 1-[4-[2-fluoro-4-(3-methyl-1H- 422.18 423.09 1.25 18 indazol-1-yl)benzoyl]piperazine-1- carbonyl}cyclopropan-1-ol 1-{4-[2-fluoro-4-(1-methyl-1H- 421.19 422.20 0.86 14 indazol-6-yl)benzoyl]piperazine-1- carbonyl}cyclopropan-1-amine 2-{4-[4-(1-hydroxycyclo- 430.20 431.19 1.15 19 propanecarbonyl)piperazine-1- carbonyl]phenyl}-1,2,3,4- tetrahydroisoquinoline- 7-carbonitrile 1-(4-{4-[1-(2-hydroxyethyl)- 434.20 435.23 0.59 21 1H-1,3-benzodiazol- 5-yl]benzoyl}piperazine-1- carbonyl)cyclopropan-1-ol 1-[(2R)-4-[4-(6-fluoro-1,3- 423.16 424.18 1.20 4 benzoxazol-2- yl)benzoyl]-2-methylpiperazine-1- carbonyl]cyclopropan-1-ol 1-{4-[4-(1H-indazol-1- 390.17 391.10 1.08 18 yl)benzoyl]piperazine-1- carbonyl}cyclopropan-1-ol 1-{4-[2-chloro-4-(5-chloro-2- 436.08 437.00 1.40 13 fluorophenyl)benzoyl]piperazine-1- carbonyl}cyclopropan-1-ol 1-{4-[4-(1,3-dimethyl-1H-indazol-5- 436.19 437.12 1.07 13 yl)-3-fluorobenzoyl]piperazine-1- carbonyl}cyclopropan-1-ol 1-{4-[4-(4-chloro-2- 428.13 429.15 1.48 24 fluorophenyl)benzoyl]-4,7- diazaspiro[2.5]octane-7- carbonyl}cyclopropan-1-ol 1-{4-[2-fluoro-4-(7-fluoro- 425.17 426.10 0.87 14 1H-indazol-3- yl)benzoyl]piperazine-1- carbonyl}cyclopropan-1-amine 6-{1-[4-(1-hydroxycyclo- 432.22 433.17 1.25 36 propanecarbonyl)piperazine-1- carbonyl]piperidin-4-yl}naphthalene- 2-carbonitrile 1-(3-{4-[4-(1-hydroxycyclo- 434.20 435.24 0.91 13 propanecarbonyl)piperazine-1- carbonyl]phenyl}phenyl) imidazolidin-2-one 1-{4-[2,6-difluoro-4-(2- 439.18 440.19 0.80 14 methyl-2H-indazol-6- yl)benzoyl]piperazine-1- carbonyl}cyclopropan-1-amine 1,3-dimethyl-5-{4-[4-(oxetane-2- 418.20 419.16 1.00 13 carbonyl)piperazine-1- carbonyl]phenyl}-1H- indazole 1-{4-[2-fluoro-4-(2-methyl-2H- 421.19 422.26 0.78 14 indazol-6-yl)benzoyl]piperazine-1- carbonyl}cyclopropan-1-amine 1-(4-{4-[3-(5-amino-1H-1,2,4-triazol- 432.19 433.14 0.75 13 3-yl)phenyl]benzoyl}piperazine-1- carbonyl)cyclopropan-1-ol 1-{4-[4-(1-methyl-1H-1,3- 430.20 431.21 0.74 24 benzodiazol-5-yl)benzoyl]- 4,7-diazaspiro[2.5]octane-7- carbonyl}cyclopropan-1-ol 1-{4-[4-(2-methyl-1H-indol-3- 403.19 404.28 1.15 13 yl)benzoyl]piperazine-1- carbonyl}cyclopropan-1-ol 1-{4-[4-(2-methyl-1H-1,3- 404.18 405.14 0.59 13 benzodiazol-5- yl)benzoyl]piperazine-1- carbonyl}cyclopropan-1-ol 1-{4-[4-(6-fluoro-1,3- 435.16 436.17 1.28 24 benzoxazol-2-yl)benzoyl]- 4,7-diazaspiro[2.5]octane-7- carbonyl}cyclopropan-1-ol 1-{4-[4-(6-fluoro-1-methyl- 423.17 424.12 0.92 13 1H-1,2,3-benzotriazol- 5-yl)benzoyl]piperazine-1- carbonyl}cyclopropan-1-ol 1-{4-[4-(1-methyl-1H-1,3- 418.20 419.04 0.73 1 benzodiazol-5- yl)benzoyl]piperazine-1- carbonyl}cyclobutan-1-ol 6-chloro-4-{4-[4-(1-hydroxycyclo- 440.13 441.07 0.92 13 propanecarbonyl)piperazine-1- carbonyl]phenyl}-2,3-dihydro-1H- 1,3-benzodiazol-2-one 1-(4-{4-[2-(hydroxymethyl)- 420.18 421.13 0.57 13 1H-1,3-benzodiazol- 5-yl]benzoyl}piperazine-1- carbonyl)cyclopropan-1-ol 5-{4-[4-(1-aminocyclo- 405.18 406.18 0.70 14 propanecarbonyl)piperazine-1- carbonyl]phenyl}-1,2- benzoxazol-3-amine 1-{4-[4-(2-cyclopropyl-2H-indazol- 430.20 431.12 1.04 7 5-yl)benzoyl]piperazine-1- carbonyl}cyclopropan-1-ol 1-{4-[2-fluoro-4-(5,6,7,8- 424.19 425.15 0.84 19 tetrahydro-1,7-naphthyridin- 7-yl)benzoyl]piperazine-1- carbonyl}cyclopropan-1-ol 1-{4-[4-(3-methyl-1,2,3,4- 419.22 420.21 1.38 19 tetrahydroisoquinolin- 2-yl)benzoyl]piperazine-1- carbonyl}cyclopropan-1-ol 1-{4-[4-(2,3-dihydro-1H-isoindol-2- 391.19 392.18 1.22 19 yl)benzoyl]piperazine-1- carbonyl}cyclopropan-1-ol 1-[(3R)-4-[4-(4-chloro-2- 416.13 417.14 1.40 23 fluorophenyl)benzoyl]-3- methylpiperazine-1- carbonyl]cyclopropan-1-ol 1-[4-(4-{3-methyl-1H- 405.18 406.13 0.76 13 pyrazolo[3,4-b]pyridin-5- yl}benzoyl)piperazine-1- carbonyl]cyclopropan-1-ol 1-{4-[4-(3-methyl-1H-indazol-6- 403.20 404.26 0.80 14 yl)benzoyl]piperazine-1- carbonyl}cyclopropan-1-amine 1-{4-[2-fluoro-4-(1-methyl- 421.19 422.20 0.54 14 1H-1,3-benzodiazol-5- yl)benzoyl]piperazine-1- carbonyl}cyclopropan-1-amine 6-{4-[4-(1-hydroxycyclo- 420.18 421.11 0.78 13 propanecarbonyl)piperazine-1- carbonyl]phenyl}-1-methyl- 1H-indazol-3-ol 1-{4-[4-(1,2,3,4- 405.21 406.14 1.33 20 tetrahydroquinolin-1- yl)benzoyl]piperazine-1- carbonyl}cyclopropan-1-ol 1-{4-[4-(3-methyl-1H-indazol-7- 403.20 404.20 0.88 14 yl)benzoyl]piperazine-1- carbonyl}cyclopropan-1-amine 1-[4-(4-{4H,5H,6H,7H- 411.16 412.15 1.23 19 thieno[3,2-c]pyridin-5- yl}benzoyl)piperazine-1- carbonyl]cyclopropan-1-ol 1-{4-[4-(1-methyl-1H-indazol-6- 417.22 418.29 0.84 14 yl)benzoyl]piperazine-1- carbonyl}cyclobutan-1-amine 1-(4-{4-[3-(2-amino-1,3-thiazol-4- 448.16 449.14 0.97 13 yl)phenyl]benzoyl}piperazine-1- carbonyl)cyclopropan-1-ol 1-{4-[4-(1,3-dimethyl-1H-indazol-5- 431.23 432.31 0.86 14 yl)benzoyl]piperazine-1- carbonyl}cyclobutan-1-amine 1-(4-{4-[3- 472.15 473.13 1.05 13 (cyclopropanesulfonyl)phenyl]-2- fluorobenzoyl}piperazine-1- carbonyl)cyclopropan-1-ol 1-{4-[4-(6-fluoroquinazolin-2- 420.16 421.10 1.13 13 yl)benzoyl]piperazine-1- carbonyl}cyclopropan-1-ol N-(5-{4-[4-(1-hydroxycyclo- 474.19 475.15 1.00 29 propanecarbonyl)piperazine-1- carbonyl]phenyl}-1,2-benzoxazol-3- yl)cyclopropanecarboxamide 4-{4-[4-(1-hydroxycyclo- 419.18 420.13 0.94 13 propanecarbonyl)piperazine-1- carbonyl]phenyl}-1-methyl- 2,3-dihydro-1H-indol-2-one 1-[(3R)-4-[4-(6-fluoro-1,3- 423.16 424.18 1.20 4 benzoxazol-2- yl)benzoyl]-3-methylpiperazine-1- carbonyl]cyclopropan-1-ol 1-{4-[4-(2-methyl-1H-1,3- 404.18 405.17 0.71 17 benzodiazol-1- yl)benzoyl]piperazine-1- carbonyl}cyclopropan-1-ol 1-{4-[4-(5-chloro-2- 401.13 402.09 1.06 14 fluorophenyl)benzoyl]piperazine-1- carbonyl}cyclopropan-1-amine 1-{4-[3-fluoro-4-(2-methyl- 422.18 423.10 0.94 13 2H-indazol-6- yl)benzoyl]piperazine-1- carbonyl}cyclopropan-1-ol 3-{4-[4-(1-hydroxycyclo- 407.18 408.18 0.80 13 propanecarbonyl)piperazine-1- carbonyl]phenyl}-N- methylbenzamide 1-(4-{4-[3-(5-amino-1H-pyrazol-3- 431.20 432.18 0.79 25 yl)phenyl]benzoyl}piperazine-1- carbonyl)cyclopropan-1-ol 1-[(2S)-2-methyl-4-[4- 420.22 421.09 1.02 19 (5,6,7,8-tetrahydro-1,7- naphthyridin-7- yl)benzoyl]piperazine-1- carbonyl]cyclopropan-1-ol 1-[(3S)-4-[4-(4-chloro-2- 416.13 417.14 1.40 23 fluorophenyl)benzoyl]-3- methylpiperazine-1- carbonyl]cyclopropan-1-ol 2-(3-{4-[4-(1-hydroxycyclo- 437.20 438.19 0.86 13 propanecarbonyl)piperazine-1- carbonyl]phenyl}phenoxy)- N-methylacetamide 1-{4-[4-(1-cyclopropyl-1H-indazol- 430.20 431.12 1.15 7 5-yl)benzoyl]piperazine-1- carbonyl}cyclopropan-1-ol 1-methyl-5-{4-[4-(oxetane- 404.18 405.13 0.60 13 2-carbonyl)piperazine- 1-carbonyl]phenyl}-1H-1,3- benzodiazole (1-{4-[4-(1-methyl-1H-1,3- 418.20 419.19 0.60 1 benzodiazol-5- yl)benzoyl]piperazine-1- carbonyl}cyclopropyl)methanol 1-{4-[4-(1-methyl-1H- 417.22 418.23 0.53 14 1,3-benzodiazol-5- yl)benzoyl]piperazine-1- carbonyl}cyclobutan-1-amine 1-[4-(3-chloro-4-{3- 458.09 459.08 1.00 13 chloroimidazo[1,2-a]pyridin- 2-yl}benzoyl)piperazine-1- carbonyl]cyclopropan- 1-ol 1-[(2R)-2-(hydroxymethyl)-4- 434.20 435.25 0.60 23 [4-(1-methyl-1H-1,3- benzodiazol-5-yl)benzoyl]piperazine- 1-carbonyl]cyclopropan-1-ol 1-{4-[4-(2,3,4,5-tetrahydro- 419.22 420.28 1.35 19 1H-3-benzazepin-3- yl)benzoyl]piperazine-1- carbonyl}cyclopropan-1-ol 1-[(2S,6R)-4-[4-(6-fluoro- 436.19 437.23 1.06 28 1,3-benzoxazol-2- yl)benzoyl]-2,6-dimethylpiperazine- 1-carbonyl]cyclopropan-1-amine 1-[(2S)-4-[4-(6-fluoro-1,3- 422.18 423.16 0.99 28 benzoxazol-2- yl)benzoyl]-2-methylpiperazine-1- carbonyl]cyclopropan-1-amine 1-(4-{4-[3-(5-methyl-1,3,4- 448.16 449.14 1.01 13 thiadiazol-2- yl)phenyl]benzoyl}piperazine-1- carbonyl)cyclopropan-1-ol 1-{4-[4-(3-methyl-2H-indazol-2- 404.18 405.18 1.18 26 yl)benzoyl]piperazine-1- carbonyl}cyclopropan-1-ol 2-(3-{4-[4-(1-hydroxycyclo- 417.21 418.23 1.23 1 propanecarbonyl)piperazine-1- carbonyl]phenyl}phenyl)-2- methylpropanenitrile 1-[(2S)-4-{4-[3-(cyclopropane- 468.17 469.23 1.08 3 sulfonyl)phenyl]benzoyl}-2- methylpiperazine-1- carbonyl]cyclopropan-1-ol 1-(3-{4-[4-(1-hydroxycyclo- 433.20 434.18 0.95 13 propanecarbonyl)piperazine-1- carbonyl]phenyl}phenyl)pyrrolidin- 2-one 3-(3-{4-[4-(1-aminocyclo- 449.19 450.19 0.82 14 propanecarbonyl)piperazine-1- carbonyl]-3-fluorophenyl}phenyl)- 1,2-oxazol-5- amine 6-{4-[4-(1-hydroxycyclo- 408.18 409.14 0.80 3 propanecarbonyl)piperazine-1- carbonyl]phenyl}-N-methylpyridine- 2-carboxamide 1-[(3S)-4-[4-(6-fluoro-1,3- 423.16 424.18 1.20 4 benzoxazol-2- yl)benzoyl]-3-methylpiperazine-1- carbonyl]cyclopropan-1-ol 4-(3-{4-[4-(1-hydroxycyclo- 459.22 460.23 1.13 13 propanecarbonyl)piperazine-1- carbonyl]phenyl}phenyl)oxane- 4-carbonitrile 1-(4-{4-[3-(5-methyl-1,2,4-oxadiazol- 432.18 433.12 1.13 13 3-yl)phenyl]benzoyl}piperazine-1- carbonyl)cyclopropan-1-ol 5-(3-{4-[4-(1-hydroxycyclo- 462.19 463.22 0.81 13 propanecarbonyl)piperazine-1- carbonyl]phenyl}phenyl)- 5-methylimidazolidine- 2,4-dione 1-{4-[2-fluoro-4-(2-methyl-1H-indol- 420.20 421.16 1.15 35 1-yl)benzoyl]piperazine-1- carbonyl}cyclopropan-1-amine 1-{4-[4-(3-amino-1,2-benzoxazol-6- 406.16 407.16 0.91 13 yl)benzoyl]piperazine-1- carbonyl}cyclopropan-1-ol 1-{4-[2-fluoro-4-(2-methyl- 435.21 436.27 0.80 14 2H-indazol-6- yl)benzoyl]piperazine-1- carbonyl}cyclobutan-1-amine 2-(3-{4-[4-(1-hydroxycyclo- 469.17 470.13 0.98 13 propanecarbonyl)piperazine-1- carbonyl]phenyl}phenyl)-1λ.sup.6,2- thiazolidine-1,1-dione 1-{4-[4-(6-chloro-1,3- 443.10 444.05 1.30 13 benzoxazol-2-yl)-3- fluorobenzoyl]piperazine-1- carbonyl}cyclopropan-1-ol 1-{4-[4-(2,3,4,5-tetrahydro- 419.22 420.26 1.29 19 1H-2-benzazepin-2- yl)benzoyl]piperazine-1- carbonyl}cyclopropan-1-ol 1-[4-(4-{3-chloroimidazo[1,2- 442.12 443.07 0.98 13 a]pyridin-2-yl}-3- fluorobenzoyl)piperazine-1- carbonyl]cyclopropan-1-ol 1-(3-{4-[4-(1-aminocyclo- 414.21 415.16 0.97 14 propanecarbonyl)piperazine-1- carbonyl]phenyl}phenyl) cyclopropane-1-carbonitrile 1-{4-[3-fluoro-4-(6- 427.13 428.08 1.17 13 fluoro-1,3-benzoxazol-2- yl)benzoyl]piperazine-1- carbonyl}cyclopropan-1-ol 1-{4-[4-(2-methyl-2H-1,2,3- 405.18 406.13 0.95 16 benzotriazol-5- yl)benzoyl]piperazine-1- carbonyl}cyclopropan-1-ol 1-[(3S)-3-methyl-4-[4-(1- 417.22 418.23 0.54 28 methyl-1H-1,3-benzodiazol- 5-yl)benzoyl]piperazine-1- carbonyl]cyclopropan-1-amine
(422) TABLE-US-00003 TABLE 2-2 HPLC retention Mol. Mass Ion time IC50 (uM) ≥0.5 and <5.0 Weight Observed (min) Method 1-[(4-{[4-(2-fluoro-3- 398.43 399.20 1.19 5 methoxyphenyl)phenyl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol 1-{[4-({4-[2-fluoro-3- 452.40 453.16 1.43 5 (trifluoromethoxy)phenyl]phenyl}carbonyl)piperazin- 1-yl]carbonyl}cyclopropan-1-ol 1-({4-[(4-{6-chloroimidazo[1,2-a]pyridin-3 424.88 425.04 0.75 7 yl}phenyl)carbonyl]piperazin-1- yl}carbonyl)cyclopropan-1-ol 1-({4-[(4-{furo[3,2-c]pyridin-4-yl}phenyl)carbonyl] 391.42 392.15 0.77 7 piperazin-1-yl}carbonyl)cyclopropan-1-ol 1-[(4-{[4-methyl-2-(quinolin-3-yl)-1,3-thiazol-5- 422.50 423.13 1.01 5 yl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol 1-({4-[(4-{imidazo[1,2-a]pyrazin-6- 391.42 392.16 0.69 7 yl}phenyl)carbonyl]piperazin-1- yl}carbonyl)cyclopropan-1-ol 4-fluoro-3-[4-({4-[(1- 453.51 454.24 1.28 5 hydroxycyclopropyl)carbonyl]piperazin-1- yl}carbonyl)phenyl]-N-(propan-2-yl)benzamide 1-{[(3S)-4-{[4-(4-chloro-2- 432.87 433.13 1.28 1 fluorophenyl)phenyl]carbonyl}-3- (hydroxymethyl)piperazin-1-yl] carbonyl}cyclopropan-1-ol 1-{[4-({4-[1-(trifluoromethyl)-1H-indol-5- 457.45 458.12 1.22 10 yl]phenyl}carbonyl)piperazin-1- yl]carbonyl}cyclopropan-1-ol 1-{[4-({4-[2-(trifluoromethyl)imidazo[1,2-a] 458.43 459.14 1.09 7 pyridin-6-yl]phenyl}carbonyl)piperazin-1- yl]carbonyl}cyclopropan-1-ol 1-({4-[(4-{imidazo[1,2-a]pyrimidin-7- 391.42 392.16 0.55 7 yl}phenyl)carbonyl]piperazin-1- yl}carbonyl)cyclopropan-1-ol 1-[(4-{[2-methoxy-4-(quinolin-6-yl)phenyl]carbonyl} 431.48 432.20 0.86 5 piperazin-1-yl)carbonyl]cyclopropan-1-ol 1-[(4-{[4-(5-methoxy-1H-1,3-benzodiazol-2- 420.46 421.18 0.75 7 yl)phenyl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol 1-[(4-{[4-(4-chloro-1H-1,3-benzodiazol-2- 424.88 425.11 1 7 yl)phenyl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol 1-[(4-{[6-(2-methoxyquinolin-6-yl)pyridin-3- 432.47 433.17 1.16 5 yl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol 1-[(4-{[5-(2-methoxyquinolin-6-yl)pyridin-2- 432.47 433.17 1.17 5 yl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol 1-[(4-{[2-(4-fluorophenyl)-1,3-benzothiazol-6- 425.48 426.07 1.26 5 yl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol 1-[(4-{[4-(2-fluoro-5- 382.43 383.21 1.54 5 methylphenyl)phenyl]carbonyl]piperazin-1- yl)carbonyl]cyclopropan-1-ol 1-[(4-{[4-(1,3-benzothiazol-5-yl)-2- 437.51 438.17 1.06 5 methoxyphenyl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol 1-[(4-{[4-methyl-2-(1-methyl-1H-indol-5-yl)-1,3- 424.52 425.16 1.13 5 thiazol-5-yl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol 6-[4-({4-[(1-hydroxycyclopropyl)carbonyl] 407.42 408.14 0.84 7 piperazin-1-yl}carbonyl)phenyl]-2,3-dihydro- 1,3-benzoxazol-2-one 1-[(4-{[5-(4-chloro-2-fluorophenyl)pyridin-2- 403.84 404.16 1.23 1 yl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol 1-[(4-{[4-(1H-1,3-benzodiazol-2- 390.44 391.14 0.73 3 yl)phenyl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol 1-{[4-({4-[2-chloro-5- 452.85 453.12 1.47 5 (trifluoromethyl)phenyl]phenyl}carbonyl)piperazin- 1-yl]carbonyl]cyclopropan-1-ol 1-[(4-{[5-(quinolin-6-yl)pyrazin-2-yl]carbonyl}- 403.43 404.19 0.79 5 piperazin-1yl)carbonyl]cyclopropan-1-ol 1-[(4-{[6-(quinolin-6-yl)pyridin-3-yl]carbonyl} 402.45 403.17 0.73 5 piperazin-1-yl)carbonyl]cyclopropan-1-ol 1-{[4-({4-[2-fluoro-3- 436.40 437.19 1.38 5 (trifluoromethyl)phenyl]phenyl}carbonyl)piperazin- 1-yl]carbonyl]cyclopropan-1-ol 1-[(4-{[4-(quinolin-6-yl)-2- 469.46 470.19 1.06 5 (trifluoromethyl)phenyl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol 1-{[4-({4-[3-fluoro-5- 436.40 437.17 1.43 5 (trifluoromethyl)phenyl]phenyl}carbonyl)piperazin- 1-yl]carbonyl]cyclopropan-1-ol 1-[(4-{[4-(5-fluoro-1H-1,3-benzodiazol-2- 408.43 409.09 0.86 5 yl)phenyl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol 4-fluoro-3-[4-({4-[(1- 425.45 426.19 1.1 5 hydroxycyclopropyl)carbonyl]piperazin-1- yl}carbonyl)phenyl]-N-methylbenzamide 1-[(4-{{4-(3-methyl-1,2-benzoxazol-6- 405.45 406.17 1.01 7 yl)phenyl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol 5-[4-({4-[(1-hydroxycyclopropyl)carbonyl] 407.42 408.15 0.91 7 piperazin-1-yl}carbonyl)phenyl]-2,3-dihydro- 1,3-benzoxazol-2-one 1-({4-[(4-{[1,2,4]triazolo[4,3-b]pyridazin-6- 392.41 393.13 0.65 7 yl}phenyl)carbonyl]piperazin-1- yl}carbonyl)cyclopropan-1-ol 1-{[4-({4-[7-(trifluoromethyl)quinolin-4- 469.46 470.09 1.28 7 yl]phenyl}carbonyl)piperazin-1- yl]carbonyl}cyclopropan-1-ol 1-{[4-({4-[4-chloro-2- 452.85 453.15 1.5 5 (trifluoromethyl)phenyl]phenyl}carbonyl)piperazin- 1-yl]carbonyl]cyclopropan-1-ol 1-{[4-({4-[1-(propan-2-yl)-1H-indazol-5- 432.51 433.24 1.23 3 yl]phenyl}carbonyl)piperazin-1- yl]carbonyl}cyclopropan-1-ol 1-[(4-{[5-(quinolin-3-yl)pyrazin-2-yl]carbonyl} 403.43 404.22 0.92 5 piperazin-1-yl)carbonyl]cyclopropan-1-ol 1-{(4-{{3-methoxy-4-(quinolin-6- 431.48 432.20 0.86 5 yl)phenyl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol 1-[(4-{[4-(5,6-difluoro-1H-1,3-benzodiazol-2- 426.42 427.15 0.99 7 yl)phenyl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol 1-[(4-{[4-(1-methyl-1H-1,3-benzodiazol-2- 404.46 405.11 0.73 3 yl)phenyl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol 1-[(4-{[4-(2-fluoro-3- 382.43 383.22 1.54 5 methylphenyl)phenyl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol 1-({4-[(4-{6-methoxyimidazo[1,2-a]pyridin-2- 420.46 421.19 0.69 3 yl}phenyl)carbonyl]piperazin-1- yl}carbonyl)cyclopropan-1-ol 1-[(4-{[4-(2-fluoro-4- 398.43 399.20 1.45 5 methoxyphenyl)phenyl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol 1-[(4-{[5-(quinolin-6-yl)pyrimidin-2-yl]carbonyl} 403.43 404.21 0.7 5 piperazin-1-yl)carbonyl]cyclopropan-1-ol 1-({4-[(4-{imidazo[1,2-a]pyridin-6- 390.44 391.21 0.55 5 yl}phenyl)carbonyl]piperazin-1- yl}carbonyl)cyclopropan-1-ol 1-({4-[(4-phenylphenyl)carbonyl]piperazin-1- 364.44 365.17 1.29 1 yl}carbonyl)cyclobutan-1-ol 1-{[4-({4-[4-fluoro-2- 436.40 437.20 1.38 5 (trifluoromethyl)phenyl]phenyl}carbonyl)piperazin- 1-yl]carbonyl}cyclopropan-1-ol 1-[(4-{[4-(3-fluoro-4- 382.43 383.22 1.55 5 methylphenyl)phenyl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol 1-[(4-{[4-(2,1,3-benzoxadiazol-5-yl)phenyl] 392.41 393.16 1.17 3 carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-ol 1-[(4-{[2-methoxy-4-(quinolin-3- 431.48 432.20 1.01 5 yl)phenyl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol 1-[(4-{[5-(4-chloro-2-fluorophenyl)pyrimidin-2- 404.82 405.16 1.12 1 yl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol
(423) TABLE-US-00004 TABLE 2-3 HPLC retention Mol. Mass Ion time IC50 (uM) ≥5.0 Weight Observed (min) Method 1-{[4-({4-[6-(trifluoromethyl)pyridin-3- 419.40 420.18 1.37 5 yl]phenyl}carbonyl)piperazin-1- yl]carbonyl}cyclopropan-1-ol 1-{[4-({4-[2-fluoro-3-(propan-2- 426.48 427.21 1.58 5 yloxy)phenyl]phenyl}carbonyl)piperazin-1- yl]carbonyl}cyclopropan-1-ol 1-({4-[(4-[6-fluoroimidazo[1,2-a]pyridin-2- 408.43 409.18 0.65 3 yl}phenyl)carbonyl]piperazin-1- yl}carbonyl)cyclopropan-1-ol 1-[(4-{[6-(4-fluorophenyl)imidazo[1,2-a]pyridin-2- 408.43 409.11 1.08 5 yl]carbonyl}piperazin-1-yl)carbonyl]cyclopropan- 1-ol 1-[(4-{[4-(2-chloro-5- 402.85 403.13 1.52 5 fluorophenyl)phenyl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol 1-[(4-{{4-[2,3- 386.39 387.18 1.45 5 difluorophenyl)phenyl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol 1-[(4-{[4-(3-fluoro-2- 398.43 399.20 1.46 5 methoxyphenyl)phenyl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol 1-[(4-{[4-(1,5-naphthyridin-3- 402.45 403.19 0.8 2 yl)phenyl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol 1-[(4-{[4-(2-fluoro-5- 398.43 399.21 1.44 5 methoxyphenyl)phenyl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol 1-{[(2S,5R)-4-{[4-(isoquinolin-6- 429.51 430.18 0.79 9 yl)pheny]carbonyl}-2,5-dimethylpiperazin-1- yl]carbonyl}cyclopropan-1-ol 1-{[4-({6-phenylimidazo[1,2-a]pyridin-2- 390.44 391.16 1.04 5 yl}carbonyl)piperazin-1-yl]carbonyl}cyclopropan- 1-ol 1-[(4-{[4-(4,5-difluoro-2- 416.42 417.18 1.49 5 methoxyphenyl)phenyl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol 1-{[(2S)-4-{[4-(4-chloro-2-fluorophenyl)phenyl] 432.87 433.04 1.29 1 carbonyl}-2-(hydroxymethyl)piperazin-1-yl] carbonyl}cyclopropan-1-ol 1-({4-[(4-phenoxyphenyl)carbonyl]piperazin-1- 366.41 367.12 1.21 9 yl}carbonyl)cyclopropan-1-ol 5-fluoro-2-[4-({4-[(1- 393.41 394.17 1.15 5 hydroxycyclopropyl)carbonyl]piperazin-1- yl}carbonyl)phenyl]benzonitrile 2-methoxy-2-methyl-1-{4-[(4-phenylphenyl) 366.45 367.15 1.44 8 carbonyl]piperazin-1-yl}propan-1-one 3,3,3-trifluoro-2-hydroxy-2-methyl-1-{4-[(4- 406.40 407.13 1.43 1 phenylphenyl)carbonyl]piperazin-1-yl}propan-1- one 1-[(4-{[4-(2-chloro-4- 414.88 415.17 1.52 5 methoxyphenyl)phenyl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol 2-hydroxy-2-methyl-1-{4-[(4-phenylphenyl) 352.43 353.14 1.24 1 carbonyl]piperazin-1-yl}propan-1-one 1-[(4-{[4-(4-methylphenyl)phenyl] 364.44 365.25 1.53 5 carbonyl}piperazin-1-yl)carbonyl] cyclopropan-1-ol 1-{[4-({4-[2-chloro-5-(hydroxymethyl) 414.88 415.17 1.22 5 phenyl]phenyl}carbonyl)piperazin-1-yl] carbonyl}cyclopropan-1-ol 1-[(4-{[2-(1,3-benzothiazol-5-yl)-4-methyl-1,3- 428.53 429.13 0.97 5 thiazol-5-yl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol 1-({4-[(3-phenoxyphenyl)carbonyl]piperazin-1- 366.41 367.09 1.19 9 yl}carbonyl)cyclopropan-1-ol 1-[(4-{[4-(3-methylphenyl)phenyl] 364.44 365.22 1.53 5 carbonyl}piperazin-1-yl)carbonyl] cyclopropan-1-ol 1-{(4-{[4-(3-methoxypyridin-4-yl)phenyl]carbonyl} 381.43 382.24 0.64 5 piperazin-1-yl)carbonyl]cyclopropan-1-ol 1-({4-[(4-phenylphenyl)carbonyl]piperazin-1- 378.46 379.25 1.37 5 yl}carbonyl)cyclopentan-1-ol 1-[(4-{[4-(1-methyl-1H-indazol-7- 404.46 405.21 1.3 5 yl)phenyl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol 1-[(4-{[4-(6-methylpyridin-3- 365.43 366.23 0.58 5 yl)phenyl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol (2S)-2-hydroxy-1-{4-[(4-phenylphenyl) 338.40 339.14 1.17 1 carbonyl]piperazin-1-yl}propan-1-one 1-{[4-([4-[5-chioro-2-(propan-2- 442.94 443.20 1.74 5 yloxy)phenyl]phenyl}carbonyl)piperazin-1- yl]carbonyl}cyclopropan-1-ol 1-[(4-{[6-(4-chloro-2-fluorophenyl)pyridin-3-yl] 403.84 404.14 1.22 1 carbonyl}piperazin-1-yl)carbonyl]cyclopropan-1-ol 1-[(4-{[4-(5-fluoropyridin-3- 369.39 370.17 1.11 5 yl)phenyl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol 1-[(4-{[4-(2,5- 386.39 387.18 1.46 5 difluorophenyl)phenyl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol 2-hydroxy-1-{4-[(4- 324.37 325.16 1.1 5 phenylphenyl)carbonyl]piperazin-1-yl}ethan-1-one 1-[(4-{[4-(2-fluoro-4- 382.43 383.17 1.55 5 methylphenyl)phenyl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol 1-[(4-{[4-(2,6-dimethoxypyridin-3- 411.45 412.18 1.48 5 yl)phenyl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol 1-[(4-{[4-(2,4-dichloro-3- 449.33 449.15 1.62 5 methoxyphenyl)phenyl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol 1-[(4-{[4-(5-fluoro-2- 382.43 383.20 1.53 5 methylphenyl)phenyl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol
Cell Proliferation Assays for FASN Inhibitors
(424) The effects of the FASN inhibitors on cultured cancer cell proliferation were studies with cell proliferation assays. PC3 cells were maintained at standard culture media (F12K media supplemented with 10% fetal bovine serum, 1×MEM nonessential amino acid and 1× penicillin/streptomycin). 2000-3000 cells/100 L/well was seeded in a 96-well clear culture plate. The cells were incubated overnight in 5% CO.sub.2 at 37° C. for attachment. Cell media were removed and replaced with F12K media containing 10% lipid reduced serum and compound. The final DMSO concentration is 0.1%. The cells were maintained in 5% CO.sub.2 at 37° C. for 4 days. The viability of cells was determined by MTT assays. The IC50 of a given compound was calculated by fitting the dose response curve with a four parameter logistic equation.
(425) Results
(426) Table 3-1 lists the compounds having an IC50≤0.5 μM.
(427) Table 3-2 lists the compounds having an IC50≥0.5 μM.
(428) In addition, the Molecular Weight, Mass Ion Spectrometry Results, HPLC retention time, and the Method used to synthesize the compound are also listed.
(429) TABLE-US-00005 TABLE 3-1 HPLC retention Mol. Mass Ion time IC50 (uM) <0.5 Weight Observed (min) Method 1-[(4-{[2-fluoro-4-(1-methyl-1H-indol-5- 421.46 422.22 1.29 5 yl)phenyl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol 1-[(4-{[4-(isoquinolin-6- 401.17 402.02 1.48 1 yl)phenyl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol 1-[(4-{[3-chloro-4-(quinolin-3- 435.90 436.15 1.14 5 yl)phenyl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol 5-[2-chloro-4-({4-[(1- 448.90 449.10 1.06 5 hydroxycyclopropyl)carbonyl]piperazin-1- yl}carbonyl)phenyl]-1H-indole-3-carbonitrile 1-[(4-{[4-(quinolin-2- 401.46 402.16 1.14 7 yl)phenyl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol 1-[(4-{[3-chloro-4-(1-methyl-1H-indol-5- 437.92 438.18 1.33 5 yl)phenyl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol 1-[(4-{[2-chloro-4-(1-methyl-1H-indol-5- 437.92 438.15 1.32 5 yl)phenyl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol 1-[(4-{[4-(1H-indol-4- 389.45 390.18 1.06 7 yl)phenyl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol 1-[(4-{[3-methyl-4-(1-methyl-1H-indol-5- 417.50 418.25 1.3 5 yl)phenyl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol 1-[(4-{[4-(1-benzofuran-5- 390.16 391.01 2.43 2 yl)phenyl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol 5-[4-({4-[(1- 414.46 415.15 1.09 3 hydroxycyclopropyl)carbonyl]piperazin-1- yl}carbonyl)phenyl]-1H-indole-2-carbonitrile 1-({4-[(4-{imidazo[1,2-b]pyridazin-6- 391.42 392.10 0.69 7 yl}phenyl)carbonyl]piperazin-1- yl}carbonyl)cyclopropan-1-ol 1-[(4-{[4-(1H-indol-5- 389.17 390.06 2.11 2 yl)phenyl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol 1-[(4-{[4-(1-methyl-1H-1,3-benzodiazol-5- 404.46 405.08 0.68 7 yl)phenyl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol 5-[4-({4-[(1- 414.46 415.17 0.97 7 hydroxycyclopropyl)carbonyl]piperazin-1- yl}carbonyl)phenyl]-1H-indole-3-carbonitrile 1-[(4-{[4-(1,3-benzothiazol-5-yl)-3- 441.93 442.12 1.16 5 chlorophenyl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol 1-[(4-{[2-fluoro-4-(6-methoxyquinolin-2- 449.47 450.15 1.25 5 yl)phenyl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol 1-[(4-{[2-chloro-4-(quinolin-3- 435.90 436.16 1.11 5 yl)phenyl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol 1-[(4-{[3-methyl-4-(quinolin-3- 415.48 416.21 1.07 5 yl)phenyl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol 1-[(4-{[2-fluoro-4-(quinolin-3- 419.45 420.18 1.07 5 yl)phenyl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol 1-[(4-{[3-chloro-4-(quinolin-6- 435.90 436.16 0.99 5 yl)phenyl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol 1-[(4-{[4-(6-methoxynaphthalen-2-yl) 430.50 431.12 1.36 5 phenyl]carbonyl}piperazin-1-yl) carbonyl]cyclopropan-1-ol 1-[(4-{[2-fluoro-4-(7-fluoro-1H-indol-5- 425.43 426.04 1.16 5 yl)phenyl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol 1-({4-[(4-{pyrazolo[1,5-a]pyridin-2-yl} 390.44 391.15 0.95 3 phenyl)carbonyl]piperazin-1- yl}carbonyl)cyclopropan-1-ol 1-[(4-{[3-fluoro-4-(quinolin-3- 419.45 420.20 1.08 5 yl)phenyl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol 1-[(4-{[4-(1-methyl-1H-indazol-6- 404.46 405.09 1.05 5 yl)phenyl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol 1-[(4-{[2-fluoro-4-(quinolin-6- 419.45 420.19 0.91 5 yl)phenyl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol 1-[(4-{[4-(2-methyl-2H-indazol-6-yl)phenyl] 404.46 405.08 0.94 5 carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol 1-[(4-{[4-(quinolin-5- 401.46 402.17 0.84 7 yl)phenyl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol 2-[4-({4-[(1- 416.43 417.15 1.06 4 hydroxycyclopropyl)carbonyl]piperazin-1- yl}carbonyl)phenyl]-1,3-benzoxazole-6- carbonitrile 1-[(4-{[4-(1,3-benzothiazol-6- 407.49 408.14 1 2 yl)phenyl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol 1-[(4-{[4-(1,3-benzothiazol-5- 407.49 408.13 1.04 2 yl)phenyl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol N-{3-[4-({4-[(1- 469.55 470.08 1.04 11 hydroxycyclopropyl)carbonyl]piperazin-1- yl}carbonyl)phenyl]phenyl} cyclopropanesulfonamide 1-({4-[(4-{1H-pyrrolo[3,2-b]pyridin-5- 390.44 391.14 0.58 2 yl}phenyl)carbonyl]piperazin-1- yl}carbonyl)cyclopropan-1-ol 1-[(4-{[4-(1H-indazol-3- 390.44 391.12 0.98 7 yl)phenyl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol 1-[(4-{[2-fluoro-4-(2-methoxyquinolin-3- 449.47 450.17 1.39 5 yl)phenyl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol 1-{[4-({3-chloro-4-[1-(trifluoromethyl)-1H-indol- 491.89 492.03 1.3 10 5-yl]phenyl}carbonyl)piperazin-1- yl]carbonyl}cyclopropan-1-ol 1-[(4-{[2,3-difluoro-4-(quinolin-2-yl)phenyl] 437.44 438.15 1.27 7 yl)phenyl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol 1-[(4-{[4-(1,3-dimethyl-1H-indazol-5- 421.51 422.16 1.13 2 methylphenyl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol 1-[(4-{[4-(1,3-dimethyl-1H-indazol-5- 418.49 419.09 1.07 7 yl)phenyl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol 1-[(4-{[3-methyl-4-(quinolin-6- 415.48 416.21 0.92 5 yl)phenyl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol 1-[(4-{[4-(1-methyl-1H-indol-2- 403.47 404.25 1.56 5 yl)phenyl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol 1-{[4-({4-[1-(trifluoromethyl)-1H-indol-5- 457.45 458.12 1.22 10 yl]phenyl}carbonyl)piperazin-1- yl]carbonyl}cyclopropan-1-ol 1-[(4-{[4-(6-chloro-1,3-benzoxazol-2- 425.87 426.11 1.33 4 yl)phenyl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol 1-[(4-{[4-(6-methoxyquinolin-2- 431.48 432.20 1.16 5 yl)phenyl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol N-{3-[4-(({4-[(1- 505.59 506.10 1.18 11 hydroxycyclopropyl)carbonyl]piperazin-1- yl}carbonyl)phenyl]phenyl}benzenesulfonamide 1-{{4-({4-[2-methoxy-5- 464.43 465.17 1.43 5 (trifluoromethoxy)phenyl]phenyl}carbonyl) piperazin-1-yl]carbonyl}cyclopropan-1-ol 1-[(4-{[4-(6-fluoro-1,3-benzoxazol-2-yl)phenyl] 409.41 410.14 1.2 4 carbonyl}piperazin-1-yl)carbonyl] cyclopropan-1-ol N-{3-[4-({4-[(1- 471.57 472.19 1.08 11 hydroxycyclopropyl)carbonyl]piperazin-1- yl}carbonyl)phenyl]phenyl}propane-2- sulfonamide 1-[(4-{[4-(isoquinolin-6- 415.19 416.04 1.61 1 yl)phenyl]carbonyl}piperazin-1- yl)carbonyl]cyclobutan-1-ol 1-[(4-{[4-(2,1,3-benzothiadiazol-5-yl)phenyl] 408.47 409.11 1.17 3 carbonyl}piperazin-1-yl)carbonyl] cyclopropan-1-ol 1-[(4-{[4-(1,3-benzoxazol-2-yl)phenyl] 391.42 392.16 1.14 4 carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol 1-[(4-{[4-[2-methyl-2H-indazol-5-yl)phenyl] 404.46 405.17 0.88 7 carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol 5-[3-chloro-4-({4-[(1- 448.90 449.10 1.06 5 hydroxycyclopropyl)carbonyl]piperazin-1- yl}carbonyl)phenyl]-1H-indole-3-carbonitrile 1-[(4-{[4-(1,3-benzothiazol-5-yl)-3- 425.48 426.12 1.1 5 fluorophenyl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol 1-[(4-{[4-(5-fluoro-1,3-benzoxazol-2-yl)phenyl] 409.41 410.14 1.18 4 carbonyl}piperazin-1-yl)carbonyl] cyclopropan-1-ol 1-[(4-{[4-(5-chloro-1,3-benzoxazol-2- 425.87 426.13 1.31 4 yl)phenyl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol 1-[(4-{[4-(1,3-benzothiazol-5-yl)-2- 441.93 442.11 1.14 5 chlorophenyl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol 1-[(4-{[4-(3-chloro-2- 414.88 415.15 1.34 5 methoxyphenyl)phenyl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol 1-[(4-{[4-(6-methoxy-4-methylquinolin-2- 445.51 446.16 1.16 7 yl)phenyl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol 1-[(4-{[4-(2-methoxyquinolin-6-yl)phenyl] 431.18 432.08 2.28 2 carbonyl}piperazin-1-yl)carbonyl] cyclopropan-1-ol 1-[(4-{[4-(1H-1,3-benzodiazol-5-yl)phenyl] 390.44 391.20 0.6 2 carbonyl}piperazin-1-yl)carbonyl] cyclopropan-1-ol 1-({4-[(2-chloro-4-{imidazo[1,2-a]pyridin-2- 424.88 425.11 0.71 3 yl}phenyl)carbonyl]piperazin-1- yl}carbonyl)cyclopropan-1-ol 1-[(4-{[5-(1-methyl-1H-indol-5-yl)pyridin-2- 404.46 405.28 1.1 5 yl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol 6-[4-({4-[(oxetan-2-yl)carbonyl]piperazin-1- 401.17 402.02 1.46 2 yl}carbonyl)phenyl]isoquinoline 1-({4-[(4-{imidazo[1,2-a]pyridin-2- 390.44 391.19 0.61 3 yl}phenyl)carbonyl]piperazin-1- yl}carbonyl)cyclopropan-1-ol 1-[(4-{[4-(quinolin-3- 415.19 416.04 2.13 1 yl)phenyl]carbonyl}piperazin-1- yl)carbonyl]cyclobutan-1-ol 1-[(4-{[4-(isoquinolin-1- 401.46 402.20 0.9 7 yl)phenyl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol 1-({4-[(4-{furo[3,2-b]pyridin-5-yl}phenyl) 391.42 392.08 0.97 7 carbonyl]piperazin-1-yl}carbonyl) cyclopropan-1-ol 1-[(4-{[4-(4-chloro-2- 402.85 403.12 1.36 1 fluorophenyl)phenyl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol 1-[(4-{[4-(5-chloro-2- 402.85 403.10 1.33 1 fluorophenyl)phenyl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol 1-[(4-{[4-(1,3-benzoxazol-5- 391.42 392.16 0.97 2 yl)phenyl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol 1-[(4-{[4-(1H-1,3-benzodiazol-4- 390.44 391.14 0.7 7 yl)phenyl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol 1-[(4-{[4-(2H-1,2,3-benzotriazol-5-yl)phenyl] 391.42 392.14 0.79 3 carbonyl}piperazin-1-yl)carbonyl] cyclopropan-1-ol 1-[(4-{[4-(4-chloroquinolin-3- 435.90 436.11 1.19 7 yl)phenyl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol 3-[3-fluoro-4-({4-[(1- 435.45 436.13 0.96 5 hydroxycyclopropyl)carbonyl]piperazin-1- yl}carbonyl)phenyl]quinolin-2-ol 3-[4-({4-[(1- 417.46 418.15 0.93 1 hydroxycyclopropyl)carbonyl]piperazin-1- yl}carbonyl)phenyl]-1,2-dihydroquinolin-2-one N-{3-[4-({4-[(1- 443.52 444.17 0.93 11 hydroxycyclopropyl)carbonyl]piperazin-1- yl}carbonyl)phenyl]phenyl}methanesulfonamide 6-[4-({4-[(1- 417.46 418.13 0.76 3 hydroxycyclopropyl)carbonyl]piperazin-1- yl}carbonyl)phenyl]-1,2-dihydroquinolin-2-one 1-[(4-{[4-(1-methyl-1H-indol-5-yl)-2- 471.47 472.22 1.39 5 (trifluoromethyl)phenyl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol 1-[(4-{[4-(1,3-benzothiazol-2-yl)phenyl 407.49 408.09 1.24 6 carbonyl}piperazin-1-yl)carbonyl] cyclopropan-1-ol 5-[4-({4-[(1- 456.54 457.16 1.29 10 hydroxycyclopropyl)carbonyl]piperazin-1- yl}carbonyl)phenyl]-1-(propan-2-yl)-1H-indole- 3-carbonitrile 1-[(4-{[2-chloro-4-(quinolin-6- 435.90 436.14 0.96 5 yl)phenyl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol 1-({4-[(2-phenyl-1,3-benzothiazol-6- 407.49 408.09 1.22 5 yl)carbonyl]piperazin-1- yl}carbonyl)cyclopropan-1-ol 1-[(4-{[4-(1H-1,3-benzodiazol-2- 390.44 391.14 0.73 3 yl)phenyl]carbonyl}piperazin-1- yl)carbonyl]cyclopropan-1-ol
(430) TABLE-US-00006 TABLE 3-2 HPLC Mass reten- Ion tion MOL. Ob- time Meth- IC50 (uM) ≥0.5 Weight served (min) od 1-{[4-({3-chloro-4-[1-(propan-2-yl)- 465.97 466.05 1.5 10 1H-indol-5- yl]phenyl}carbonyl)piperazin-1- yl]carbonyl}cyclopropan-1-ol 1-{[4-({4-[2-methoxy-4-(1H-pyrazol-1- 446.50 447.23 1.19 5 yl)phenyl]phenyl}carbonyl)piperazin-1- yl]carbonyl}cyclopropan-1-ol 5-[4-({4-[(oxetan-2-yl)carbonyl]piperazin- 389.45 389.18 1.03 2 1-yl}carbonyl)phenyl]-1H-indole 3 -[4-({4-[(oxetan-2-yl)carbonyl]piperazin- 401.46 402.14 0.95 2 1-yl}carbonyl)phenyl]quinoline 1-[(4-{[4-(2,4- 419.30 419.12 1.47, 5 dichlorophenyl)phenyl]carbonyl}piperazin- 1.68 1-yl)carbonyl]cyclopropan-1-ol
ENUMERATED EMBODIMENTS
(431) The present disclosure also relates to the following enumerated embodiments: 1. A fatty acid synthase inhibitor comprising the structure of formula I:
(432) ##STR00791##
wherein: R.sub.1 is a C.sub.1-C.sub.3 hydroxyl-alkyl either unsubstituted or substituted with —CH.sub.3 or —CH.sub.zF.sub.3-z, 5 membered cycloalkyl either unsubstituted or substituted with substituents selected from the group consisting of deuterium, —R.sub.p, —OR.sub.p, —NHR.sub.p, and —NR.sub.pR.sub.p1, or 3 or 4 membered cycloalkyl or heterocycloalkyl wherein (i) the heteroatom ring member of the 3 or 4 membered heterocycloalkyl is independently selected from O, S, or N, and (ii) each of said 3 or 4 membered cycloalkyl or heterocycloalkyl is either unsubstituted or optionally substituted with substituents selected from the group consisting of deuterium, —R.sub.a, —OR.sub.a, —NHR.sub.a, and —NR.sub.aR.sub.a1; L is a 5-10 membered monocyclic or bicyclic alkyl or heteroalkyl wherein (i) the heteroatom ring members of the 5-10 membered monocyclic or bicyclic heteroalkyl are independently selected from O, S, or N, and (ii) each of the 5-10 membered monocyclic or bicyclic alkyl or heteroalkyl is either unsubstituted or optionally substituted with substituents selected from the group consisting of deuterium and —R.sub.b; A and B are independently O or S; Ar.sub.1 is a 4-10 membered monocyclic or bicyclic aryl, heteroaryl or heterocycloalkyl, wherein (i) said 4-10 membered monocyclic or bicyclic heteroaryl or heterocycloalkyl have 1, 2, 3, or 4 heteroatoms which are independently selected from N, S or O, and (ii) each of said 4-10 membered monocyclic or bicyclic aryl, heteroaryl, or heterocycloalkyl is either unsubstituted or optionally independently substituted with 1 or more substituents which can be the same or different and are independently selected from the group consisting of deuterium, halo, alkyl, —CH.sub.zF.sub.3-z, cyano, hydroxyl, hydroxylalkyl, amino, aminoalkyl-, (amino)alkoxy-, —CONH.sub.2, —C(O)NH(alkyl), —C(O)N(alkyl).sub.2, —C(O)NH(aryl), —C(O)N(aryl).sub.2, —OCH.sub.zF.sub.3-z, -alkyl, -alkenyl, -alkynyl, -alkoxy (alkoxyalkyl)amino-, —N(Re)—C(O)-alkyl, —N(R.sub.c)—C(O)-aryl, -cycloalkyl, -heterocycloalkyl, -aryl, and -heteroaryl, with the proviso that no two adjacent ring heteroatoms are both S or both O; R.sub.2 is H or a 4-15 membered monocyclic, bicyclic or tricyclic aryl, heteroaryl, cycloalkyl, or heterocycloalkyl, (i) the 4-15 membered monocyclic, bicyclic or tricyclic heteroaryl or heterocycloalkyl has 1, 2, 3, 4, 5, 6, 7 or 8 heteroatoms that are independently selected from N, S or O, and (ii) wherein each of said aryl, heteroaryl, cycloalkyl, or heterocycloalkyl is either unsubstituted or optionally substituted with 1 or more substituents which can be the same or different and are independently selected from the group consisting of deuterium, halo, cyano, hydroxyl, hydroxyl-alkyl-, hydroxylcycloalkyl-, hydroxyl-heterocycloalkyl-, hydroxyl-aryl-, hydroxyl-heteroaryl-, amino, aminoalkyl, (amino)alkoxy-, —CONH.sub.2, —C(O)NH(alkyl), —C(O)N(alkyl).sub.2, —C(O)NH(aryl), —C(O)N(aryl).sub.2, —CH.sub.zF.sub.3-z, —OCH.sub.zF.sub.3-z, -alkyl, alkoxy-, -alkenyl, -alkynyl, aryloxy-, (alkoxyalkyl)amino-, -cycloalkyl, -heterocycloalkyl, (heterocycloalkyl)alkyl-, -aryl, -heteroaryl, —O(alkyl), —O(cycloalkyl), —O(heterocycloalkyl), —O(aryl), —O(heteroaryl), ONH.sub.2, —C(O)NH(alkyl), —C(O)N(aryl).sub.2, —C(O)NH(cycloalkyl), —NH(CO)cycloalkyl, —NH(SO.sub.2), —NH(SO.sub.2)alkyl, —NH(SO.sub.2)aryl, —NH(SO.sub.2)heteroaryl, —N(SO.sub.2)cycloalkyl, —C(O)N(alkyl).sub.2, (aryl)alkyl-, -heteroaryl, (heteroaryl)alkyl-, —S(O).sub.2-alkyl, —S(O).sub.2-aryl, —S(O).sub.2-cycloalkyl, —C(O)N(alkyl).sub.2, —C(O)alkyl, —NH—C(O)-alkyl, —NH—C(O)-cycloalkyl, NH—C(O)-heterocycloalkyl, NH—C(O)-heterocycloalkyl-R.sub.d, —NH—C(O)—R.sub.d—(O)alkyl, —NH—C(O)-aryl, —NH—C(O)—NH-alkyl, NH—C(O)—NH-cycloalkyl, NH.sub.2(CO)cycloalkyl-, NH—C(O)—NH-aryl, —NH—C(O)—O-alkyl, NH—C(O)—NH-cycloalkyl, —NH—C(O)—O-cycloalkyl, —NH(R.sub.a)—C(O)-alkyl, —NH(R.sub.a)—C(O)-aryl, —NH(R.sub.a)—S(O.sub.2)cycloalkyl, —S(O.sub.2)NH.sub.2, —S(O.sub.2)NH(alkyl), —S(O.sub.2)N(R.sub.a)cycloalkyl, —S(O.sub.2)N(alkyl).sub.2, —C(O)N(H)(alkyl), —C(O)N(R.sub.a)(cycloalkyl), methylenedioxy, —CH.sub.zF.sub.3-z, —OCH.sub.zF.sub.3-z, and -alkoxy; R.sub.p and R.sub.p1 are independently H, halo, C.sub.1-C.sub.4 alkyl, or C.sub.3-C.sub.4 cycloalkyl; R.sub.a and R.sub.a1 are independently H, halo, C.sub.1-C.sub.4 alkyl, or C.sub.3-C.sub.4 cycloalkyl; R.sub.b is H, halo, C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.3 hydroxyl-alkyl, or C.sub.3-C.sub.4 cycloalkyl; R.sub.c is H, halo, C.sub.1-C.sub.4 alkyl, or C.sub.3-C.sub.4 cycloalkyl; R.sub.d is H, halo, C.sub.1-C.sub.4 alkyl, or C.sub.3-C.sub.4 cycloalkyl; and z is 0, 1 or 2;
and pharmaceutically acceptable salts thereof. 2. A Compound of formula I:
(433) ##STR00792##
wherein: R.sub.1 is a C.sub.1-C.sub.3 hydroxyl-alkyl either unsubstituted or substituted with —CH.sub.3 or —CH.sub.zF.sub.3-z, 5 membered cycloalkyl either unsubstituted or substituted with substituents selected from the group consisting of deuterium, —R.sub.p, —OR.sub.p, —NHR.sub.p, and —NR.sub.pR.sub.p1, or 3 or 4 membered cycloalkyl or heterocycloalkyl wherein (i) the heteroatom ring member of the 3 or 4 membered heterocycloalkyl is independently selected from O, S, or N, and (ii) each of said 3 or 4 membered cycloalkyl or heterocycloalkyl is either unsubstituted or optionally substituted with substituents selected from the group consisting of deuterium, —R.sub.a, —OR.sub.a, —NHR.sub.a, and —NR.sub.aR.sub.a1; L is a 5-10 membered monocyclic or bicyclic alkyl or heteroalkyl wherein (i) the heteroatom ring members of the 5-10 membered monocyclic or bicyclic heteroalkyl are independently selected from O, S, or N, and (ii) each of the 5-10 membered monocyclic or bicyclic alkyl or heteroalkyl is either unsubstituted or optionally substituted with substituents selected from the group consisting of deuterium and —R.sub.b; A and B are independently O or S; Ar.sub.1 is a 4-10 membered monocyclic or bicyclic aryl, heteroaryl or heterocycloalkyl, wherein (i) said 4-10 membered monocyclic or bicyclic heteroaryl or heterocycloalkyl have 1, 2, 3, or 4 heteroatoms which are independently selected from N, S or O, and (ii) each of said 4-10 membered monocyclic or bicyclic aryl, heteroaryl, or heterocycloalkyl is either unsubstituted or optionally independently substituted with 1 or more substituents which can be the same or different and are independently selected from the group consisting of deuterium, halo, alkyl, —CH.sub.zF.sub.3-z, cyano, hydroxyl, hydroxylalkyl, amino, aminoalkyl-, (amino)alkoxy-, —CONH.sub.2, —C(O)NH(alkyl), —C(O)N(alkyl).sub.2, —C(O)NH(aryl), —C(O)N(aryl).sub.2, —OCH.sub.zF.sub.3-z, -alkyl, -alkenyl, -alkynyl, -alkoxy or (alkoxyalkyl)amino-, —N(R.sub.c)—C(O)-alkyl, —N(Re)—C(O)-aryl, -cycloalkyl, -heterocycloalkyl, -aryl, and -heteroaryl, with the proviso that no two adjacent ring heteroatoms are both S or both O; R.sub.2 is H or a 4-15 membered monocyclic, bicyclic, or tricyclic aryl, heteroaryl, cycloalkyl, or heterocycloalkyl, (i) the 4-15 membered monocyclic, bicyclic, or tricyclic heteroaryl or heterocycloalkyl has 1, 2, 3, 4, 5, 6, 7, or 8 heteroatoms that are independently selected from N, S or O, and (ii) wherein each of said aryl, heteroaryl, cycloalkyl, and heterocycloalkyl is either unsubstituted or optionally substituted with 1 or more substituents which can be the same or different and are independently selected from the group consisting of deuterium, halo, cyano, hydroxyl, hydroxyl-alkyl-, hydroxylcycloalkyl-, hydroxyl-heterocycloalkyl-, hydroxyl-aryl-, hydroxyl-heteroaryl-, amino, aminoalkyl, (amino)alkoxy-, —CONH.sub.2, —C(O)NH(alkyl), —C(O)N(alkyl).sub.2, —C(O)NH(aryl), —C(O)N(aryl).sub.2, —CH.sub.zF.sub.3-z, —OCH.sub.zF.sub.3-z, -alkyl, alkoxy-, -alkenyl, -alkynyl, aryloxy-, (alkoxyalkyl)amino-, -cycloalkyl, -heterocycloalkyl, (heterocycloalkyl)alkyl-, -aryl, -heteroaryl, —O(alkyl), —O(cycloalkyl), —O(heterocycloalkyl), —O(aryl), —O(heteroaryl), ONH.sub.2, —C(O)NH(alkyl), —C(O)N(aryl).sub.2, —C(O)NH(cycloalkyl), —NH(CO)cycloalkyl, —NH(SO.sub.2), —NH(SO.sub.2)alkyl, —NH(SO.sub.2)aryl, —NH(SO.sub.2)heteroaryl, —N(SO.sub.2)cycloalkyl, —C(O)N(alkyl).sub.2, (aryl)alkyl-, -heteroaryl, (heteroaryl)alkyl-, —S(O).sub.2-alkyl, —S(O).sub.2-aryl, —S(O).sub.2-cycloalkyl, —C(O)N(alkyl).sub.2, —C(O)alkyl, —NH—C(O)-alkyl, —NH—C(O)-cycloalkyl, NH—C(O)-heterocycloalkyl, NH—C(O)-heterocycloalkyl-R.sub.d, —NH—C(O)—R.sub.d—(O)alkyl, —NH—C(O)-aryl, —NH—C(O)—NH-alkyl, NH—C(O)—NH-cycloalkyl, NH.sub.2(CO)cycloalkyl-, NH—C(O)—NH-aryl, —NH—C(O)—O-alkyl, NH—C(O)—NH-cycloalkyl, —NH—C(O)—O-cycloalkyl, —NH(R.sub.a)—C(O)-alkyl, —NH(R.sub.a)—C(O)-aryl, —NH(R.sub.a)—S(O.sub.2)cycloalkyl, —S(O.sub.2)NH.sub.2, —S(O.sub.2)NH(alkyl), —S(O.sub.2)N(R.sub.a)cycloalkyl, —S(O.sub.2)N(alkyl).sub.2, —C(O)N(H)(alkyl), —C(O)N(R.sub.a)(cycloalkyl), methylenedioxy, —CH.sub.zF.sub.3-z, —OCH.sub.zF.sub.3-z, and -alkoxy; R.sub.p and R.sub.p1 are independently H, halo, C.sub.1-C.sub.4 alkyl, or C.sub.3-C.sub.4 cycloalkyl; R.sub.a and R.sub.a1 are independently H, halo, C.sub.1-C.sub.4 alkyl, or C.sub.3-C.sub.4 cycloalkyl; R.sub.b is H, halo, C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.3 hydroxyl-alkyl, or C.sub.3-C.sub.4 cycloalkyl; R.sub.c is H, halo, C.sub.1-C.sub.4 alkyl, or C.sub.3-C.sub.4 cycloalkyl; R.sub.d is H, halo, C.sub.1-C.sub.4 alkyl, or C.sub.3-C.sub.4 cycloalkyl;
and z is 0, 1 or 2; and pharmaceutically acceptable salts thereof.
further wherein:
R.sub.2 is not a
a substituted or unsubstituted form of
(434) ##STR00793##
where X is N or CH;
when R.sub.1 is
(435) ##STR00794##
connected to
(436) ##STR00795##
at position 1, and X.sub.1 and X.sub.2 are independently N or C—R.sub.z, and R.sub.y and R.sub.z are any substituent, then Rx does not include alkynyl, alkenyl, aryl, 5-14 membered heterocyclic, 5-14 membered heteroaromatic, or 4-9 membered carbocyclic;
when R.sub.2 is
(437) ##STR00796##
Ar.sub.1 is not a substituted or unsubstituted form of
(438) ##STR00797##
and when Ar.sub.1 is a substituted or unsubstituted form of a 5 membered heteroaryl, Ar.sub.1 is
(439) ##STR00798## 3. The compound of embodiment 1, wherein R.sub.1 is selected from the group consisting of:
(440) ##STR00799## 4. The compound of embodiment 2, wherein R.sub.1 is
(441) ##STR00800## 5. The compound of embodiment 2, wherein R.sub.1 is selected from the group consisting of:
(442) ##STR00801## 6. The compound of embodiment 2, wherein A and B are O. 7. The compound of embodiment 2, wherein L is:
(443) ##STR00802##
m is 1, 2, or 3 and
n is 0, 1, 2, or 3. 8. The compound of embodiment 7, wherein L is:
(444) ##STR00803## 9. The compound of embodiment 7, wherein L is:
(445) ##STR00804## 10. The compound of embodiment 2, wherein Ar.sub.1 is a substituted or unsubstituted 5-6 membered monocyclic aryl or heteroaryl. 11. The compound of embodiment 10, wherein Ar.sub.1 is a substituted or unsubstituted 5 membered monocyclic aryl or heteroaryl and said heteroaryl has 1 or 2 heteroatoms which are independently S or N. 12. The compound of embodiment 11, wherein Ar.sub.1 is a substituted or unsubstituted form of:
(446) ##STR00805## 13. The compound of embodiment 10, wherein Ar.sub.1 is a substituted or unsubstituted 6 membered monocyclic aryl or heteroaryl and said heteroaryl has 1 or 2 heteroatoms which are N. 14. The compound of embodiment 13, wherein Ar.sub.1 is
(447) ##STR00806## Ph.sub.1 is phenyl, pyridinyl, pyrazinyl, or pyrimidinyl, and R.sub.c is H, halo, or C.sub.1-C.sub.3 alkyl. 15. The compound of embodiment 14, wherein Ar.sub.1 is a substituted or unsubstituted form of:
(448) ##STR00807## 16. The compound of embodiment 14, wherein Ar.sub.1 is
(449) ##STR00808## 17. The compound of embodiment 16, wherein Ar.sub.1 is
(450) ##STR00809## 18. The compound of embodiment 2, wherein Ar.sub.1 is a substituted or unsubstituted 9 membered 6,5-bicyclic heteroaryl and said heteroaryl has 1, 2, or 3 heteroatoms which are independently O, S or N. 19. The compound of embodiment 18, wherein Ar.sub.1 is
(451) ##STR00810## 20. The compound of embodiment 2, wherein R.sub.2 is a substituted or unsubstituted monocyclic or bicyclic 5-10 membered aryl or heteroaryl. 21. The compound of embodiment 20, wherein R.sub.2 is a substituted or unsubstituted monocylic 6 membered aryl. 22. The compound of embodiment 21, wherein R.sub.2 is:
(452) ##STR00811## ##STR00812## ##STR00813## 23. The compound of embodiment 20, wherein R.sub.2 is a substituted or unsubstituted bicyclic 8-10 membered aryl or 8-10 membered heteroaryl. 24. The compound of embodiment 23, wherein R.sub.2 is a substituted or unsubstituted 8 membered 5,5 bicyclic heteroaryl and said heteroaryl has 1, 2, 3, or 4 heteroatoms and said heteroatoms are independently O, S, or N. 25. The compound of embodiment 24, wherein R.sub.2 is a substituted or unsubstituted form of:
(453) ##STR00814## 26. The compound of embodiment 20, wherein R.sub.2 is a substituted or unsubstituted 9 membered 6,5 bicyclic heteroaryl and said heteroaryl has 1, 2, 3, or 4 heteroatoms and said heteroatoms are independently O, S, or N. 27. The compound of embodiment 26, wherein R.sub.2 is a substituted or unsubstituted form of:
(454) ##STR00815## ##STR00816## 28. The compound of embodiment 20, wherein R.sub.2 is a substituted or unsubstituted 10 membered 6,6 bicyclic aryl or heteroaryl and said heteroaryl has 1, 2, 3, or 4 heteroatoms and said heteroatoms are O, S, or N. 29. The compound of embodiment 28, wherein R.sub.2 is a substituted or unsubstituted form of:
(455) ##STR00817## 30. A Compound of formula I-A:
(456) ##STR00818##
wherein: R.sub.1 is a C.sub.1-C.sub.3 hydroxyl-alkyl either unsubstituted or substituted with —CH.sub.3 or —CH.sub.zF.sub.3-z, 5 membered cycloalkyl either unsubstituted or substituted with substituents selected from the group consisting of deuterium, —R.sub.p, —OR.sub.p, —NHR.sub.p, and —NR.sub.pR.sub.p1, or 3 or 4 membered cycloalkyl or heterocycloalkyl wherein (i) the heteroatom ring member of the 3 or 4 membered heterocycloalkyl is independently selected from O, S, or N, and (ii) each of said 3 or 4 membered cycloalkyl or heterocycloalkyl is either unsubstituted or optionally substituted with substituents selected from the group consisting of deuterium, —R.sub.a, —OR.sub.a, —NHR.sub.a, and —NR.sub.aR.sub.a1; Ar.sub.1 is a 4-10 membered monocyclic or bicyclic aryl, heteroaryl, or heterocycloalkyl, wherein (i) said 4-10 membered monocyclic, bicyclic heteroaryl, or heterocycloalkyl have 1, 2, 3, or 4 heteroatoms which are independently selected from N, S or O, and (ii) each of said 4-10 membered monocyclic or bicyclic aryl or heteroaryl is either unsubstituted or optionally independently substituted with 1 or more substituents which can be the same or different and are independently selected from the group consisting of deuterium, halo, alkyl, —CH.sub.zF.sub.3-z, cyano, hydroxyl, hydroxylalkyl, amino, aminoalkyl-, (amino)alkoxy-, —CONH.sub.2, —C(O)NH(alkyl), —C(O)N(alkyl).sub.2, —C(O)NH(aryl), —C(O)N(aryl).sub.2, —OCH.sub.zF.sub.3-z, -alkyl, -alkenyl, -alkynyl, -alkoxy or (alkoxyalkyl)amino-, —N(R)—C(O)-alkyl, —N(R)—C(O)-aryl, -cycloalkyl, -heterocycloalkyl, -aryl, and -heteroaryl, with the proviso that no two adjacent ring heteroatoms are both S or both O; R.sub.2 is H or a 4-15 membered monocyclic, bicyclic, or tricyclic aryl, heteroaryl, cycloalkyl, or heterocycloalkyl, (i) the 4-15 membered monocyclic, bicyclic, or tricyclic heteroaryl or heterocycloalkyl has 1, 2, 3, 4, 5, 6, 7, or 8 heteroatoms which are independently selected from N, S or O, and (ii) wherein each of said aryl, heteroaryl, cycloalkyl, and heterocycloalkyl is either unsubstituted or optionally substituted with 1 or more substituents which can be the same or different and are independently selected from the group consisting of deuterium, halo, cyano, hydroxyl, hydroxyl-alkyl-, hydroxylcycloalkyl-, hydroxyl-heterocycloalkyl-, hydroxyl-aryl-, hydroxyl-heteroaryl-, amino, aminoalkyl, (amino)alkoxy-, —CONH.sub.2, —C(O)NH(alkyl), —C(O)N(alkyl).sub.2, —C(O)NH(aryl), —C(O)N(aryl).sub.2, —CH.sub.zF.sub.3-z, —OCH.sub.zF.sub.3-z, -alkyl, alkoxy-, -alkenyl, -alkynyl, aryloxy-, (alkoxyalkyl)amino-, -cycloalkyl, -heterocycloalkyl, (heterocycloalkyl)alkyl-, -aryl, -heteroaryl, —O(alkyl), —O(cycloalkyl), —O(heterocycloalkyl), —O(aryl), —O(heteroaryl), ONH.sub.2, —C(O)NH(alkyl), —C(O)N(aryl).sub.2, —C(O)NH(cycloalkyl), —NH(CO)cycloalkyl, —NH(SO.sub.2), —NH(SO.sub.2)alkyl, —NH(SO.sub.2)aryl, —NH(SO.sub.2)heteroaryl, —N(SO.sub.2)cycloalkyl, —C(O)N(alkyl).sub.2, (aryl)alkyl-, -heteroaryl, (heteroaryl)alkyl-, —S(O).sub.2-alkyl, —S(O).sub.2-aryl, —S(O).sub.2-cycloalkyl, —C(O)N(alkyl).sub.2, —C(O)alkyl, —NH—C(O)-alkyl, —NH—C(O)-cycloalkyl, NH—C(O)-heterocycloalkyl, NH—C(O)-heterocycloalkyl-R.sub.d, —NH—C(O)—R.sub.d—(O)alkyl, —NH—C(O)-aryl, —NH—C(O)—NH-alkyl, NH—C(O)—NH-cycloalkyl, NH.sub.2(CO)cycloalkyl-, NH—C(O)—NH-aryl, —NH—C(O)—O-alkyl, NH—C(O)—NH-cycloalkyl, —NH—C(O)—O-cycloalkyl, —NH(R.sub.a)—C(O)-alkyl, —NH(R.sub.a)—C(O)-aryl, —NH(R.sub.a)—S(O.sub.2)cycloalkyl, —S(O.sub.2)NH.sub.2, —S(O.sub.2)NH(alkyl), —S(O.sub.2)N(R.sub.a)cycloalkyl, —S(O.sub.2)N(alkyl).sub.2, —C(O)N(H)(alkyl), —C(O)N(R.sub.a)(cycloalkyl), methylenedioxy, —CH.sub.zF.sub.3-z, —OCH.sub.zF.sub.3-z, and -alkoxy; R.sub.p and R.sub.p1 are independently H, halo, C.sub.1-C.sub.4 alkyl, or C.sub.3-C.sub.4 cycloalkyl; R.sub.a and R.sub.a1 are independently H, halo, C.sub.1-C.sub.4 alkyl, or C.sub.3-C.sub.4 cycloalkyl; R.sub.c is H, halo, C.sub.1-C.sub.4 alkyl, or C.sub.3-C.sub.4 cycloalkyl; R.sub.d is H, halo, C.sub.1-C.sub.4 alkyl, or C.sub.3-C.sub.4 cycloalkyl; and z is 0, 1 or 2;
and pharmaceutically acceptable salts thereof. 31. The compound of embodiment 30, wherein R.sub.1 is
(457) ##STR00819## 32. A Compound of formula I-B:
(458) ##STR00820##
wherein: Ar.sub.1 is a 4-10 membered monocyclic or bicyclic aryl, heteroaryl, or heterocycloalkyl, wherein (i) said 4-10 membered monocyclic or bicyclic heteroaryl or heterocycloalkyl have 1, 2, 3, or 4 heteroatoms which are independently selected from N, S, or O, and (ii) each of said 4-10 membered monocyclic or bicyclic aryl or heteroaryl is either unsubstituted or optionally independently substituted with 1 or more substituents which can be the same or different and are independently selected from the group consisting of deuterium, halo, alkyl, —CH.sub.zF.sub.3-z, cyano, hydroxyl, hydroxylalkyl, amino, aminoalkyl-, (amino)alkoxy-, —CONH.sub.2, —C(O)NH(alkyl), —C(O)N(alkyl).sub.2, —C(O)NH(aryl), —C(O)N(aryl).sub.2, —OCH.sub.zF.sub.3-z, -alkyl, -alkenyl, -alkynyl, -alkoxy or (alkoxyalkyl)amino-, —N(R.sub.c)—C(O)-alkyl, —N(R)—C(O)-aryl, -cycloalkyl, -heterocycloalkyl, -aryl, and -heteroaryl, with the proviso that no two adjacent ring heteroatoms are both S or both 0; R.sub.2 is H or a 4-15 membered monocyclic, bicyclic, or tricyclic aryl, heteroaryl, cycloalkyl, or heterocycloalkyl, (i) the 4-15 membered monocyclic, bicyclic, tricyclic heteroaryl or heterocycloalkyl has 1, 2, 3, 4, 5, 6, 7, or 8 heteroatoms which are independently selected from N, S, or O, and (ii) wherein each of said aryl, heteroaryl, cycloalkyl, and heterocycloalkyl is either unsubstituted or optionally substituted with 1 or more substituents which can be the same or different and are independently selected from the group consisting of deuterium, halo, cyano, hydroxyl, hydroxyl-alkyl-, hydroxylcycloalkyl-, hydroxyl-heterocycloalkyl-, hydroxyl-aryl-, hydroxyl-heteroaryl-, amino, aminoalkyl, (amino)alkoxy-, —CONH.sub.2, —C(O)NH(alkyl), —C(O)N(alkyl).sub.2, —C(O)NH(aryl), —C(O)N(aryl).sub.2, —CH.sub.zF.sub.3-z, —OCH.sub.zF.sub.3-z, -alkyl, alkoxy-, -alkenyl, -alkynyl, aryloxy-, (alkoxyalkyl)amino-, -cycloalkyl, -heterocycloalkyl, (heterocycloalkyl)alkyl-, -aryl, -heteroaryl, —O(alkyl), —O(cycloalkyl), —O(heterocycloalkyl), —O(aryl), —O(heteroaryl), ONH.sub.2, —C(O)NH(alkyl), —C(O)N(aryl).sub.2, —C(O)NH(cycloalkyl), —NH(CO)cycloalkyl, —NH(SO.sub.2), —NH(SO.sub.2)alkyl, —NH(SO.sub.2)aryl, —NH(SO.sub.2)heteroaryl,—N(SO.sub.2)cycloalkyl, —C(O)N(alkyl).sub.2, (aryl)alkyl-, -heteroaryl, (heteroaryl)alkyl-, —S(O).sub.2-alkyl, —S(O).sub.2-aryl, —S(O).sub.2-cycloalkyl, —C(O)N(alkyl).sub.2, —C(O)alkyl, —NH—C(O)-alkyl, —NH—C(O)-cycloalkyl, NH—C(O)-heterocycloalkyl, NH—C(O)-heterocycloalkyl-R.sub.d, —NH—C(O)—R.sub.d—(O)alkyl, —NH—C(O)-aryl, —NH—C(O)—NH-alkyl, NH—C(O)—NH-cycloalkyl, NH.sub.2(CO)cycloalkyl-, NH—C(O)—NH-aryl, —NH—C(O)—O-alkyl, NH—C(O)—NH-cycloalkyl, —NH—C(O)—O-cycloalkyl, —NH(R.sub.a)—C(O)-alkyl, —NH(R.sub.a)—C(O)-aryl, —NH(R.sub.a)—S(O.sub.2)cycloalkyl, —S(O.sub.2)NH.sub.2, —S(O.sub.2)NH(alkyl), —S(O.sub.2)N(R.sub.a)cycloalkyl, —S(O.sub.2)N(alkyl).sub.2, —C(O)N(H)(alkyl), —C(O)N(R.sub.a)(cycloalkyl), methylenedioxy, —CH.sub.zF.sub.3-z, —OCH.sub.zF.sub.3-z, and -alkoxy; R.sub.c is H, halo, C.sub.1-C.sub.4 alkyl, or C.sub.3-C.sub.4 cycloalkyl; R.sub.d is H, halo, C.sub.1-C.sub.4 alkyl, or C.sub.3-C.sub.4 cycloalkyl; and z is 0, 1 or 2;
and pharmaceutically acceptable salts thereof. 33. A Compound of formula I-C:
(459) ##STR00821##
wherein: R.sub.1 is a C.sub.1-C.sub.3 hydroxyl-alkyl either unsubstituted or substituted with —CH.sub.3 or —CH.sub.zF.sub.3-z, 5 membered cycloalkyl either unsubstituted or substituted with substituents selected from the group consisting of deuterium, —R.sub.p, —OR.sub.p, —NHR.sub.p, and —NR.sub.pR.sub.p1, or 3 or 4 membered cycloalkyl or heterocycloalkyl wherein (i) the heteroatom ring member of the 3 or 4 membered heterocycloalkyl is independently selected from O, S, or N, and (ii) each of said 3 or 4 membered cycloalkyl or heterocycloalkyl is either unsubstituted or optionally substituted with substituents selected from the group consisting of deuterium, —R.sub.a, —OR.sub.a, —NHR.sub.a, and —NR.sub.aR.sub.a1; R.sub.2 is H or a 4-15 membered monocyclic, bicyclic, or tricyclic aryl, heteroaryl, cycloalkyl, or heterocycloalkyl, (i) the 4-15 membered monocyclic, bicyclic, or tricyclic heteroaryl or heterocycloalkyl has 1, 2, 3, 4, 5, 6, 7, or 8 heteroatoms which are independently selected from N, S or O, and (ii) wherein each of said aryl, heteroaryl, cycloalkyl, and heterocycloalkyl is either unsubstituted or optionally substituted with 1 or more substituents which can be the same or different and are independently selected from the group consisting of deuterium, halo, cyano, hydroxyl, hydroxyl-alkyl-, hydroxylcycloalkyl-, hydroxyl-heterocycloalkyl-, hydroxyl-aryl-, hydroxyl-heteroaryl-, amino, aminoalkyl, (amino)alkoxy-, —CONH.sub.2, —C(O)NH(alkyl), —C(O)N(alkyl).sub.2, —C(O)NH(aryl), —C(O)N(aryl).sub.2, —CH.sub.zF.sub.3-z, —OCH.sub.zF.sub.3-z, -alkyl, alkoxy-, -alkenyl, -alkynyl, aryloxy-, (alkoxyalkyl)amino-, -cycloalkyl, -heterocycloalkyl, (heterocycloalkyl)alkyl-, -aryl, -heteroaryl, —O(alkyl), —O(cycloalkyl), —O(heterocycloalkyl), —O(aryl), —O(heteroaryl), ONH.sub.2, —C(O)NH(alkyl), —C(O)N(aryl).sub.2, —C(O)NH(cycloalkyl), NH.sub.2(CO)cycloalkyl-, —NH(CO)cycloalkyl, —NH(SO.sub.2), —NH(SO.sub.2)alkyl, —NH(SO.sub.2)aryl, —NH(SO.sub.2)heteroaryl, —N(SO.sub.2)cycloalkyl, —C(O)N(alkyl).sub.2, (aryl)alkyl-, -heteroaryl, (heteroaryl)alkyl-, —S(O).sub.2-alkyl, —S(O).sub.2-aryl, —S(O).sub.2-cycloalkyl, —C(O)N(alkyl).sub.2, —C(O)alkyl, —NH—C(O)-alkyl, —NH—C(O)-cycloalkyl, NH—C(O)-heterocycloalkyl, NH—C(O)-heterocycloalkyl-R.sub.d, —NH—C(O)—R.sub.d—(O)alkyl, —NH—C(O)-aryl, —NH—C(O)—NH-alkyl, NH—C(O)—NH-cycloalkyl, NH—C(O)—NH-aryl, —NH—C(O)—O-alkyl, NH—C(O)—NH-cycloalkyl, —NH—C(O)—O— cycloalkyl, —NH(R.sub.a)—C(O)-alkyl, —NH(R.sub.a)—C(O)-aryl, —NH(R.sub.a)—S(O.sub.2)cycloalkyl, —S(O.sub.2)NH.sub.2, —S(O.sub.2)NH(alkyl), —S(O.sub.2)N(R.sub.a)cycloalkyl, —S(O.sub.2)N(alkyl).sub.2, —C(O)N(H)(alkyl), —C(O)N(R.sub.d)(cycloalkyl), methylenedioxy, —CH.sub.zF.sub.3-z, —OCH.sub.zF.sub.3-z, and -alkoxy; R.sub.p and R.sub.p1 are independently H, halo, C.sub.1-C.sub.4 alkyl, or C.sub.3-C.sub.4 cycloalkyl; R.sub.a and R.sub.a1 are independently H, halo, C.sub.1-C.sub.4 alkyl, or C.sub.3-C.sub.4 cycloalkyl; R.sub.d is H, halo, C.sub.1-C.sub.4 alkyl, or C.sub.3-C.sub.4 cycloalkyl; R.sub.q is H, halo, C.sub.1-C.sub.4 alkyl, or C.sub.3-C.sub.4 cycloalkyl; and z is 0, 1 or 2;
and pharmaceutically acceptable salts thereof. 34. The compound of embodiment 33, wherein R.sub.1 is
(460) ##STR00822## 35. A compound of formula I-D:
(461) ##STR00823##
wherein: R.sub.1′ is OH or NH.sub.2; R.sub.2 is H or a 4-15 membered monocyclic, bicyclic, or tricyclic aryl, heteroaryl, cycloalkyl, or heterocycloalkyl, (i) the 4-15 membered monocyclic, bicyclic, or tricyclic heteroaryl or heterocycloalkyl has 1, 2, 3, 4, 5, 6, 7, or 8 heteroatoms which are independently selected from N, S or O, and (ii) wherein each of said aryl, heteroaryl, cycloalkyl, and heterocycloalkyl is either unsubstituted or optionally substituted with 1 or more substituents which can be the same or different and are independently selected from the group consisting of deuterium, halo, cyano, hydroxyl, hydroxyl-alkyl-, hydroxylcycloalkyl-, hydroxyl-heterocycloalkyl-, hydroxyl-aryl-, hydroxyl-heteroaryl-, amino, aminoalkyl, (amino)alkoxy-, —CONH.sub.2, —C(O)NH(alkyl), —C(O)N(alkyl).sub.2, —C(O)NH(aryl), —C(O)N(aryl).sub.2, —CH.sub.zF.sub.3-z, —OCH.sub.zF.sub.3-z, -alkyl, alkoxy-, -alkenyl, -alkynyl, aryloxy-, (alkoxyalkyl)amino-, -cycloalkyl, -heterocycloalkyl, (heterocycloalkyl)alkyl-, -aryl, -heteroaryl, —O(alkyl), —O(cycloalkyl), —O(heterocycloalkyl), —O(aryl), —O(heteroaryl), ONH.sub.2, —C(O)NH(alkyl), —C(O)N(aryl).sub.2, —C(O)NH(cycloalkyl), NH.sub.2(CO)cycloalkyl-, —NH(CO)cycloalkyl, —NH(SO.sub.2), —NH(SO.sub.2)alkyl, —NH(SO.sub.2)aryl, —NH(SO.sub.2)heteroaryl, —N(SO.sub.2)cycloalkyl, —C(O)N(alkyl).sub.2, (aryl)alkyl-, -heteroaryl, (heteroaryl)alkyl-, —S(O).sub.2-alkyl, —S(O).sub.2-aryl, —S(O).sub.2-cycloalkyl, —C(O)N(alkyl).sub.2, —C(O)alkyl, —NH—C(O)-alkyl, —NH—C(O)-cycloalkyl, NH—C(O)-heterocycloalkyl, NH—C(O)-heterocycloalkyl-R.sub.d, —NH—C(O)—R.sub.d—(O)alkyl, —NH—C(O)-aryl, —NH—C(O)—NH-alkyl, NH—C(O)—NH-cycloalkyl, NH—C(O)—NH-aryl, —NH—C(O)—O-alkyl, NH—C(O)—NH-cycloalkyl, —NH—C(O)—O— cycloalkyl, —NH(R.sub.a)—C(O)-alkyl, —NH(R.sub.a)—C(O)-aryl, —NH(R.sub.a)—S(O.sub.2)cycloalkyl, —S(O.sub.2)NH.sub.2, —S(O.sub.2)NH(alkyl), —S(O.sub.2)N(R.sub.a)cycloalkyl, —S(O.sub.2)N(alkyl).sub.2, —C(O)N(H)(alkyl), —C(O)N(R.sub.a)(cycloalkyl), methylenedioxy, —CH.sub.zF.sub.3-z, —OCH.sub.zF.sub.3-z, and -alkoxy; R.sub.d is H, halo, C.sub.1-C.sub.4 alkyl, or C.sub.3-C.sub.4 cycloalkyl; R.sub.q is H, halo, C.sub.1-C.sub.4 alkyl, or C.sub.3-C.sub.4 cycloalkyl; and z is 0, 1 or 2;
and pharmaceutically acceptable salts thereof. 36. The compounds of embodiment 35, wherein R.sub.2 is a: 6 membered aryl either unsubstituted or optionally substituted with 1 or more substituents which can be the same or different and are independently selected from the group consisting of deuterium, halo, cyano, alkyl, aryl, —S(O).sub.2-alkyl, —S(O).sub.2-aryl, —S(O).sub.2-cycloalkyl, —NH—C(O)-alkyl, —NH—C(O)-cycloalkyl, NH—C(O)-heterocycloalkyl, NH—C(O)-heterocycloalkyl-R.sub.d, —NH—C(O)—R.sub.d—(O)alkyl, —NH—C(O)-aryl, —NH—C(O)—NH-alkyl, NH—C(O)—NH-cycloalkyl, NH.sub.2(CO)cycloalkyl-, NH—C(O)—NH-aryl, —NH—C(O)—O-alkyl, NH—C(O)—NH-cycloalkyl, —NH—C(O)—O-cycloalkyl, —NH(R.sub.a)—C(O)-alkyl, —NH(R.sub.a)—C(O)-aryl, —NH(R.sub.a)—S(O.sub.2)cycloalkyl, —S(O.sub.2)NH.sub.2, —S(O.sub.2)NH(alkyl), —S(O.sub.2)N(R.sub.a)cycloalkyl, —S(O.sub.2)N(alkyl).sub.2, —C(O)N(H)(alkyl), and —C(O)N(R.sub.a)(cycloalkyl); or 9 membered bicyclic heteroaryl having 1, 2, or 3 or 4 heteroatoms which are independently selected from N, S or O, and wherein each of said heteroaryl, is either unsubstituted or optionally substituted with 1 or more substituents which can be the same or different and are independently selected from the group consisting of deuterium, halo, cyano, alkyl, aryl, —S(O).sub.2-alkyl, —S(O).sub.2-aryl, —S(O).sub.2-cycloalkyl, —NH—C(O)-alkyl, —NH—C(O)-cycloalkyl, NH—C(O)-heterocycloalkyl, NH—C(O)-heterocycloalkyl-R.sub.d, —NH—C(O)—R.sub.d—(O)alkyl, —NH—C(O)-aryl, —NH—C(O)—NH-alkyl, NH—C(O)—NH-cycloalkyl, NH.sub.2(CO)cycloalkyl-, NH—C(O)—NH-aryl, —NH—C(O)—O-alkyl, NH—C(O)—NH-cycloalkyl, —NH—C(O)—O-cycloalkyl, —NH(R.sub.a)—C(O)-alkyl, —NH(R.sub.a)—C(O)-aryl, —NH(R.sub.a)—S(O.sub.2)cycloalkyl, —S(O.sub.2)NH.sub.2, —S(O.sub.2)NH(alkyl), —S(O.sub.2)N(R.sub.a)cycloalkyl, —S(O.sub.2)N(alkyl).sub.2, —C(O)N(H)(alkyl), and —C(O)N(R.sub.a)(cycloalkyl). 37. A compound selected from:
(462) TABLE-US-00007 IUPAC Name Compound Structure 1-({4-[(4- phenylphenyl)carbonyl]piperazin-1- yl}carbonyl)cyclopropan-1-ol
(463) While the present invention has been described in conjunction with the specific embodiments set forth above, many alternatives, modifications and other variations thereof will be apparent to those of ordinary skill in the art. All such alternatives, modifications and variations are intended to fall within the spirit and scope of the present invention.