Piperidine derivatives and compositions for the inhibition of nicotinamide phosphoribosyltransferase (NAMPT)
11479564 · 2022-10-25
Assignee
Inventors
- Kenneth W. Bair (Wellesley, MA)
- Timm R. Baumeister (Cambridge, MA)
- Alexandre J. Buckmelter (Acton, MA)
- Karl H. Clodfelter (Brighton, MA)
- Bingsong Han (Westwood, MA)
- Judith D. Kuntz (Watertown, MA)
- Jian Lin (Acton, MA)
- Dominic J. Reynolds (Stoneham, MA)
- Chase C. Smith (Rutland, MA)
- Zhongguo Wang (Lexington, MA)
- Xiaozhang Zheng (Lexington, MA)
Cpc classification
A61P29/00
HUMAN NECESSITIES
A61P9/10
HUMAN NECESSITIES
A61P43/00
HUMAN NECESSITIES
A61K31/4709
HUMAN NECESSITIES
A61K31/5377
HUMAN NECESSITIES
A61P35/00
HUMAN NECESSITIES
A61K31/4545
HUMAN NECESSITIES
A61K45/06
HUMAN NECESSITIES
A61K31/437
HUMAN NECESSITIES
A61P1/00
HUMAN NECESSITIES
A61P25/28
HUMAN NECESSITIES
C07D215/48
CHEMISTRY; METALLURGY
International classification
C07D519/00
CHEMISTRY; METALLURGY
A61K45/06
HUMAN NECESSITIES
A61K31/4709
HUMAN NECESSITIES
A61K31/437
HUMAN NECESSITIES
A61K31/5377
HUMAN NECESSITIES
A61K31/4545
HUMAN NECESSITIES
Abstract
The present invention relates to compounds and compositions for the inhibition of NAMPT, their synthesis, applications and antidotes. An illustrative compound of the invention is shown below: Formula (I) ##STR00001##
Claims
1. A process for preparing a compound of Formula II: ##STR00370## or a pharmaceutically acceptable salt thereof, wherein: W is —C(O)—; R is aryl or bicyclic heteroaryl; wherein said heteroaryl contains 1, 2, or 3 heteroatoms independently selected from N, S, and O, with the proviso that no two adjacent ring heteroatoms are both S or both O; and each of said aryl or heteroaryl is optionally substituted with one or more substituents which can be the same or different and are independently selected from the group consisting of deuterium, halo, cyano, 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, —CF.sub.3, —CHF.sub.2, —CH.sub.2F, -alkyl, alkoxy, hydroxyl, hydroxyalkyl, (alkoxyalkyl) amino, —N(R.sup.3)—C(O)-alkyl, —N(R.sup.3)—C(O)-aryl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, with the proviso that no two adjacent ring heteroatoms are both S or both O; G is aryl, heteroaryl, cycloalkyl, heterocycloalkyl, or —NR.sup.1R.sup.2; wherein each of said aryl, heteroaryl, heterocycloalkyl and cycloalkyl is either unsubstituted or substituted with 1, 2, 3, or 4 substituents which can be the same or different and are independently selected from the group consisting of deuterium, halo, cyano, 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, —CF.sub.3, —CHF.sub.2, —CH.sub.2F, alkyl, alkenyl, alkynyl, alkoxy, hydroxyl, hydroxyalkyl, aryloxy, (alkoxyalkyl)amino, —N(R.sup.3)—C(O)-alkyl, —N(R.sup.3)—C(O)-aryl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl; R.sup.1 and R.sup.2 are the same or they are different, and are independently selected from H, C.sub.1 to C.sub.7 alkyl, C.sub.1 to C.sub.7 alkoxy, C.sub.1 to C.sub.4 hydroxyalkyl, aryl, heteroaryl, heterocycloalkyl and cycloalkyl, and wherein heteroatoms of said heteroaryl and heterocycloalkyl are independently selected from one or more of N, O and S, with the proviso that no two adjacent ring heteroatoms are both S or both O; and wherein R.sup.1 and R.sup.2 are each unsubstituted or substituted with one or more substituents which can be the same or different and are independently selected from the group consisting of deuterium, halo, cyano, 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, —CF.sub.3, —CHF.sub.2, —CH.sub.2F, alkyl, hydroxyalkyl, alkoxy, hydroxyl, hydroxyalkyl, carboxy, (alkoxyalkyl)amino, alkylamine, aminocarbonyl, —CHO, —N(R.sup.3)—C(O)-alkyl, —N(R.sup.3)—C(O)-aryl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl; R.sup.3 is H; and n is 4, 5, or 6; wherein the process comprises a step of treating an acid: ##STR00371## with an amine: ##STR00372## in the presence of a base.
2. The process of claim 1, wherein the acid is: ##STR00373##
3. The process of claim 2, wherein the process of obtaining the compound of Formula II further comprises addition of a coupling agent.
4. The process of claim 3, wherein the coupling agent is EDCI, HATU, or HOBt.
5. The process of claim 3, wherein the base is K.sub.2CO.sub.3, Cs.sub.2CO.sub.3, DIEA, NaOH, or KOH.
6. The process of claim 1, wherein the acid is: ##STR00374##
7. The process of claim 6, wherein the base is TEA.
Description
DESCRIPTION OF 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 the formation of nicotinamide phosphoribosyltransferase.
(3) An aspect of the present invention concerns the use of an inhibitor of the formation of nicotinamide phosphoribosyltransferase 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 the formation of nicotinamide phosphoribosyltransferase 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 the formation of nicotinamide phosphoribosyltransferase 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) The present invention also describes one or more methods of synthesizing the compounds of the present invention.
(7) The invention also describes one or more uses of the compounds of the present invention.
(8) 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.
(9) The invention also describes one or more uses of the pharmaceutical compositions of the present invention.
(10) An aspect of the present invention concerns the use as an inhibitor of the formation of nicotinamide phosphoribosyltransferase for the preparation of a medicament used in the treatment of inflammatory diseases.
(11) An aspect of the present invention concerns the use as an inhibitor of the formation of nicotinamide phosphoribosyltransferase for the preparation of a medicament used in the treatment of inflammatory diseases, such as Irritable Bowel Syndrome or Inflammatory Bowel Disease.
(12) An aspect of the present invention concerns the use as an inhibitor of the formation of nicotinamide phosphoribosyltransferase for the preparation of a medicament used in the treatment of disease of the bone such as osteoporosis.
(13) An aspect of the present invention concerns the use as an inhibitor of the formation of nicotinamide phosphoribosyltransferase for the preparation of a medicament used in the treatment of disease of the cardiovascular system, such as atherosclerosis.
(14) An aspect of the present invention concerns the use as an inhibitor of the formation of nicotinamide phosphoribosyltransferase for the preparation of a medicament used in the treatment of disease or a condition caused by an elevated level of NAMPT.
(15) 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 spodylitis, graft-versus-host disease, Alzheimer's disease, cerebrovascular accident, atherosclerosis, diabetes, glomerulonephiritis, metabolic syndrome, non-small cell lung cancer, small cell lung cancer, multiple myeloma, leukemias, lymphomas, squamous cell cancers, kidney cancer, ureteral and bladder cancers, cancers of head and neck, cancers of the brain and central nervous system (CNS).
(16) 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.
(17) 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.
(18) The compounds of the invention may induce or inhibit apoptosis.
(19) 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.
(20) A further aspect of the invention is a method of inhibiting a NAMPT pathway 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.
(21) A further aspect of the invention is a pharmaceutical formulation comprising a compound of the invention.
(22) 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.
(23) 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.
(24) The pharmaceutical formulations of the invention may further comprise a therapeutic effective amount of an adjunctive chemotherapeutic agent.
(25) 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.
(26) 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.
(27) 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.
(28) 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.
(29) Still another embodiment of the invention is a method for administering a NAMPT-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.
(30) 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.
(31) Another aspect of the invention relates to a pharmaceutical composition comprising a compound of the invention and a cell rescuing agent. In an embodiment of the invention, the cell rescuing agent can be selected from the group consisting of nicotinamide, nicotinic acid and nicotinamide mononucleotide.
(32) The invention is also directed to methods of synthesizing compounds of the present invention.
Compounds of the Invention
(33) 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 nicotinamide phosphoribosyltransferase (NAMPT) and pharmaceutically acceptable salts, solvates, esters, prodrugs or isomers thereof.
(34) The invention is directed to compounds as described herein and pharmaceutically acceptable salts, solvates, esters, prodrugs 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, kits, and antidotes for the NAMPT pathway in mammals having a compound of the Formula I:
(35) ##STR00036##
wherein R is an aryl, heteroaryl, C.sub.3-C.sub.8 cycloalkyl, C.sub.3-C.sub.8 cycloalkenyl, heterocycloalkyl, arylalkyl-, (heteroaryl)alkyl-, (C.sub.3-C.sub.8 cycloalkyl)alkyl-, (C.sub.3-C.sub.8 cycloalkenyl)alkyl-, (heterocycloalkyl)alkyl-, (aryloxy)alkyl-, (heteroaryloxy)alkyl-, (C.sub.3-C.sub.8 cycloalkyloxy)alkyl-, (C.sub.3-C.sub.8 cycloalkenyloxy)alkyl- or (heterocycloalkyloxy)alkyl-, wherein the heteroatom of each of said heteroaryl and heterocycloalkyl numbers 1, 2 or 3, and is independently selected from N, S or O, further wherein each of said aryl, heteroaryl and heterocycloalkyl may independently be either substituted or fused with an aryl or heteroaryl, still further wherein any of said aryl, heteroaryl and heterocycloalkyl is either unsubstituted or optionally independently substituted with one or more substituents which can be the same or different and are independently selected from the group consisting of deuterium, halo, cyano, 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, -alkenyl, -alkynyl, -alkoxy, hydroxyl, alkyl hydroxy, hydroxyl, alkyl hydroxy, or (alkoxyalkyl) amino-, —N(R.sup.3)—C(O)-alkyl, —N(R.sup.3)—C(O)-aryl, -cycloalkyl, -heterocycloalkyl, -aryl, and heteroaryl, with the proviso that no two adjacent ring heteroatoms are both S or both O; G is aryl, heteroaryl, cycloalkyl, heterocycloalkyl or
(36) ##STR00037##
with each of said aryl, heteroaryl, heterocycloalkyl and cycloalkyl being either unsubstituted or optionally independently substituted with 1, 2, 3 or 4 substituents which can be the same or different and are independently selected from the group consisting of deuterium, halo, cyano, 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, -alkenyl, -alkynyl, -alkoxy, hydroxyl, -alkyl hydroxyl, aryloxy-, (alkoxyalkyl)amino-, —N(R.sup.3)—C(O)-alkyl, —N(R.sup.3)—C(O)-aryl, -cycloalkyl, -heterocycloalkyl, -aryl, and -heteroaryl; R.sup.1 and R.sup.2 are the same or they are different, and are independently selected from H, a straight or branched C.sub.1 to C.sub.7 alkyl, straight or branched C.sub.1 to C.sub.7 alkoxy, straight or branched C.sub.1 to C.sub.4 hydroxyalkyl, aryl, heteroaryl, heterocycloalkyl and cycloalkyl, and wherein heteroatoms of said heteroaryl and heterocycloalkyl are independently selected from one or more N, O and S, with the proviso that no two adjacent ring heteroatoms are both S or both O, further wherein R.sup.1 and R.sup.2 can be either unsubstituted or optionally independently substituted with one or more substituents which can be the same or different and are independently selected from the group consisting of deuterium, halo, cyano, 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, -alkenyl, -alkynyl, hydroxyalkyl-, -alkoxy, hydroxyl, alkyl hydroxy, hydroxyl, alkyl hydroxy, carboxy, (alkoxyalkyl) amino-, -alkylamine, aminocarbonyl-, —CHO, —N(R.sup.3)—C(O)-alkyl, —N(R.sup.3)—C(O)-aryl, -cycloalkyl, -heterocycloalkyl, -aryl, and heteroaryl; R.sup.3 is H, alkyl or arylalkyl-; A is aryl, heteroaryl, heterocycloalkyl or C.sub.3 to C.sub.8 cycloalkyl, with each of said aryl, heteroaryl, heterocycloalkyl and cycloalkyl being either unsubstituted or optionally independently substituted with 1, 2, 3 or 4 substituents which can be the same or different and are independently selected from the group consisting of deuterium, halo, cyano, 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, -alkenyl, -alkynyl, -alkoxy, hydroxyl, -alkyl hydroxyl, aryloxy-, (alkoxyalkyl)amino-, —N(R.sup.3)—C(O)-alkyl, —N(R.sup.3)—C(O)-aryl, -cycloalkyl, -heterocycloalkyl, -aryl, and -heteroaryl; Q is C(O), S(O), S(O).sub.2, —CH.sub.2—C(O)— —N(H)—C(O)—, —S(O.sub.2)—NH—, or —N(H)—S(O.sub.2)—; n is 0, 1, 2, 3, 4, 5 or 6; z is 0, 1 or 2; m is 0 or 1; s is 0 or 1; and
t is 0 or 1;
and pharmaceutically acceptable salts, solvates, esters, prodrugs or isomers thereof.
(37) In another embodiment, the compound of Formula I, wherein m=0 and s=1, is the compound of Formula IA:
(38) ##STR00038##
wherein R is an aryl, heteroaryl, C.sub.3-C.sub.8 cycloalkyl, C.sub.3-C.sub.8 cycloalkenyl, heterocycloalkyl, arylalkyl-, (heteroaryl)alkyl-, (C.sub.3-C.sub.8 cycloalkyl)alkyl-, (C.sub.3-C.sub.8 cycloalkenyl)alkyl-, (heterocycloalkyl)alkyl-, (aryloxy)alkyl-, (heteroaryloxy)alkyl-, (C.sub.3-C.sub.8 cycloalkyloxy)alkyl-, (C.sub.3-C.sub.8 cycloalkenyloxy)alkyl- or (heterocycloalkyloxy)alkyl-, wherein the heteroatom of each of said heteroaryl and heterocycloalkyl numbers 1, 2 or 3, and is independently selected from N, S or O, further wherein each of said aryl, heteroaryl and heterocycloalkyl may independently be either substituted or fused with an aryl or heteroaryl, still further wherein any of said aryl, heteroaryl and heterocycloalkyl is either unsubstituted or optionally independently substituted with one or more substituents which can be the same or different and are independently selected from the group consisting of deuterium, halo, cyano, 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, -alkenyl, -alkynyl, -alkoxy, hydroxyl, alkyl hydroxy, hydroxyl, alkyl hydroxy, or (alkoxyalkyl) amino-, —N(R.sup.3)—C(O)-alkyl, —N(R.sup.3)—C(O)-aryl, -cycloalkyl, -heterocycloalkyl, -aryl, and heteroaryl, with the proviso that no two adjacent ring heteroatoms are both S or both O; G is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl with each of said aryl, heteroaryl, heterocycloalkyl and cycloalkyl being either unsubstituted or optionally independently substituted with 1, 2, 3 or 4 substituents which can be the same or different and are independently selected from the group consisting of deuterium, halo, cyano, 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, -alkenyl, -alkynyl, -alkoxy, hydroxyl, -alkyl hydroxyl, aryloxy-, (alkoxyalkyl)amino-, —N(R.sup.3)—C(O)-alkyl, —N(R.sup.3)—C(O)-aryl, -cycloalkyl, -heterocycloalkyl, -aryl, and -heteroaryl; R.sup.3 is H, alkyl or arylalkyl-; A is aryl, heteroaryl, heterocycloalkyl or C.sub.3 to C.sub.8 cycloalkyl, with each of said aryl, heteroaryl, heterocycloalkyl and cycloalkyl being either unsubstituted or optionally independently substituted with 1, 2, 3 or 4 substituents which can be the same or different and are independently selected from the group consisting of deuterium, halo, cyano, 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, -alkenyl, -alkynyl, -alkoxy, hydroxyl, -alkyl hydroxyl, aryloxy-, (alkoxyalkyl)amino-, —N(R.sup.3)—C(O)-alkyl, —N(R.sup.3)—C(O)-aryl, -cycloalkyl, -heterocycloalkyl, -aryl, and -heteroaryl; Q is C(O), S(O), S(O).sub.2, —N(H)—C(O)—, —S(O.sub.2)—NH—, or —N(H)—S(O.sub.2)—; n is 0, 1, 2, 3, 4, 5 or 6; z is 0, 1 or 2; and t is 0 or 1;
and pharmaceutically acceptable salts, solvates, esters, prodrugs or isomers thereof.
(39) Another embodiment, the compound of Formula I, wherein m=0, t=1 and s=1, is the compound of Formula IB:
(40) ##STR00039##
Wherein R is an aryl, heteroaryl, C.sub.3-C.sub.8 cycloalkyl, C.sub.3-C.sub.8 cycloalkenyl, heterocycloalkyl, arylalkyl-, (heteroaryl)alkyl-, (C.sub.3-C.sub.8 cycloalkyl)alkyl-, (C.sub.3-C.sub.8 cycloalkenyl)alkyl-, (heterocycloalkyl)alkyl-, (aryloxy)alkyl-, (heteroaryloxy)alkyl-, (C.sub.3-C.sub.8 cycloalkyloxy)alkyl-, (C.sub.3-C.sub.8 cycloalkenyloxy)alkyl- or (heterocycloalkyloxy)alkyl-, wherein the heteroatom of each of said heteroaryl and heterocycloalkyl numbers 1, 2 or 3, and is independently selected from N, S or O, further wherein each of said aryl, heteroaryl and heterocycloalkyl may independently be either substituted or fused with an aryl or heteroaryl, still further wherein any of said aryl, heteroaryl and heterocycloalkyl is cither unsubstituted or optionally independently substituted with one or more substituents which can be the same or different and are independently selected from the group consisting of deuterium, halo, cyano, 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, -alkenyl, -alkynyl. -alkoxy, hydroxyl, alkyl hydroxy, hydroxyl, alkyl hydroxy, or (alkoxyalkyl) amino-, —N(R.sup.3)—C(O)-alkyl, —N(R.sup.3)—C(O)-aryl, -cycloalkyl, -heterocycloalkyl, -aryl, and heteroaryl, with the proviso that no two adjacent ring heteroatoms are both S or both O; n=0, 1, 2, 3, 4, 5 or 6; A is aryl, heteroaryl, heterocycloalkyl or C.sub.3 to C.sub.8 cycloalkyl, with each of said aryl, heteroaryl, heterocycloalkyl and cycloalkyl being either unsubstituted or optionally independently substituted with 1, 2, 3 or 4 substituents which can be the same or different and are independently selected from the group consisting of deuterium, halo, cyano, 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, -alkenyl, -alkynyl, -alkoxy, hydroxyl, -alkyl hydroxyl, aryloxy-, (alkoxyalkyl)amino-, —N(R.sup.3)—C(O)-alkyl, —N(R.sup.3)—C(O)-aryl, -cycloalkyl, -heterocycloalkyl, -aryl, and -heteroaryl; Q is C(O), S(O), S(O).sub.2, or —CH.sub.2—C(O); G is G is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl with each of said aryl, heteroaryl, heterocycloalkyl and cycloalkyl being either unsubstituted or optionally independently substituted with 1, 2, 3 or 4 substituents which can be the same or different and are independently selected from the group consisting of deuterium, halo, cyano, 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, -alkenyl, -alkynyl, -alkoxy, hydroxyl, -alkyl hydroxyl, aryloxy-, (alkoxyalkyl)amino-, —N(R.sup.3)—C(O)-alkyl, —N(R.sup.3)—C(O)-aryl, -cycloalkyl, -heterocycloalkyl, -aryl, and -heteroaryl; And z is 0, 1 or 2.
(41) Yet another embodiment, the compound of Formula I, wherein n=4, m=0, t=1 and s=1, is the compound of Formula IC:
(42) ##STR00040##
Wherein R is an aryl, heteroaryl, C.sub.3-C.sub.8 cycloalkyl, C.sub.3-C.sub.8 cycloalkenyl, heterocycloalkyl, arylalkyl-, (heteroaryl)alkyl-, (C.sub.3-C.sub.8 cycloalkyl)alkyl-, (C.sub.3-C.sub.8 cycloalkenyl)alkyl-, (heterocycloalkyl)alkyl-, (aryloxy)alkyl-, (heteroaryloxy)alkyl-, (C.sub.3-C.sub.8 cycloalkyloxy)alkyl-, (C.sub.3-C.sub.8 cycloalkenyloxy)alkyl- or (heterocycloalkyloxy)alkyl-, wherein the heteroatom of each of said heteroaryl and heterocycloalkyl numbers 1, 2 or 3, and is independently selected from N, S or O, further wherein each of said aryl, heteroaryl and heterocycloalkyl may independently be either substituted or fused with an aryl or heteroaryl, still further wherein any of said aryl, heteroaryl and heterocycloalkyl is either unsubstituted or optionally independently substituted with one or more substituents which can be the same or different and are independently selected from the group consisting of deuterium, halo, cyano, 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, -alkenyl, -alkynyl, -alkoxy, hydroxyl, alkyl hydroxy, hydroxyl, alkyl hydroxy, or (alkoxyalkyl) amino-, —N(R.sup.3)—C(O)-alkyl, —N(R.sup.3)—C(O)-aryl, -cycloalkyl, -heterocycloalkyl, -aryl, and heteroaryl, with the proviso that no two adjacent ring heteroatoms are both S or both O; A is
(43) ##STR00041## Q is C(O), S(O).sub.2, or —CH.sub.2—C(O); G is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl with each of said aryl, heteroaryl, heterocycloalkyl and cycloalkyl being either unsubstituted or optionally independently substituted with 1, 2, 3 or 4 substituents which can be the same or different and are independently selected from the group consisting of deuterium, halo, cyano, 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, -alkenyl, -alkynyl.-alkoxy, hydroxyl, -alkyl hydroxyl, aryloxy-, (alkoxyalkyl)amino-, —N(R.sup.3)—C(O)-alkyl, —N(R.sup.3)—C(O)-aryl, -cycloalkyl, -heterocycloalkyl, -aryl, and -heteroaryl; And z is 0, 1 or 2.
(44) In a further embodiment, compounds of the invention have the general Formula II,
(45) ##STR00042##
wherein, W is —C(O)—, —S(O)— or —S(O).sub.2—; R is an aryl or bicyclic heteroaryl wherein the heteroatoms of each of said heteroaryl numbers 1, 2 or 3, and are independently selected from N, S or O, wherein each of said aryl, heteroaryl is optionally substituted with one or more substituents which can be the same or different and are independently selected from the group consisting of deuterium, halo, cyano, 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, —CF.sub.3, —CHF.sub.2, —CH.sub.2F, -alkyl, alkoxy, hydroxyl, hydroxyalkyl, (alkoxyalkyl) amino, —N(R.sup.3)—C(O)-alkyl, —N(R.sup.3)—C(O)-aryl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, with the proviso that no two adjacent ring heteroatoms are both S or both O; G is aryl, heteroaryl, cycloalkyl, heterocycloalkyl or —NR.sup.1R.sup.2, with each of said aryl, heteroaryl, heterocycloalkyl and cycloalkyl being either unsubstituted or independently substituted with 1, 2, 3 or 4 substituents which can be the same or different and are independently selected from the group consisting of deuterium, halo, cyano, 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, —CF.sub.3, —CHF.sub.2, —CH.sub.2F, alkyl, alkenyl, alkynyl, alkoxy, hydroxyl, hydroxy alkyl, aryloxy, (alkoxyalkyl)amino, —N(R.sup.3)—C(O)-alkyl, —N(R.sup.3)—C(O)-aryl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl; R.sup.1 and R.sup.2 are the same or they are different, and are independently selected from H, C.sub.1 to C.sub.7 alkyl, C.sub.1 to C.sub.7 alkoxy, C.sub.1 to C.sub.4 hydroxyalkyl, aryl, heteroaryl, heterocycloalkyl and cycloalkyl, and wherein heteroatoms of said heteroaryl and heterocycloalkyl are independently selected from one or more N, O and S, with the proviso that no two adjacent ring heteroatoms are both S or both O, further wherein R.sup.1 and R.sup.2 can be either unsubstituted or optionally independently substituted with one or more substituents which can be the same or different and are independently selected from the group consisting of deuterium, halo, cyano, 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, —CF.sub.3, —CHF.sub.2, —CH.sub.2F, alkyl, hydroxyalkyl, -alkoxy, hydroxyl, hydroxyalkyl, carboxy, (alkoxyalkyl) amino, -alkylamine, aminocarbonyl, —CHO, —N(R.sup.3)—C(O)-alkyl, —N(R.sup.3)—C(O)-aryl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl; R.sup.3 is H, alkyl or arylalkyl; n is 4, 5 or 6; or a pharmaceutically acceptable salt thereof.
(46) In an embodiment in which compounds have the general Formula II, W is —C(O)—. In another embodiment W is —S(O).sub.2—.
(47) In an embodiment in which compounds have the general Formula II, 11 is 4. In another embodiment, n is 5. In another embodiment, n is 6. In another embodiment, n is 7.
(48) In an embodiment in which compounds have the general Formula II, R.sup.3 is H. In another embodiment, R.sup.3 is Me.
(49) In an embodiment in which compounds have the general Formula II, R is selected from the group consisting of optionally substituted thienopyridine, 1H-pyrrolopyidine, pyrrolopyidine, imidazopyridine, pyrazolopyridine, quinoline and furopyridine. In an embodiment, R is 1H-pyrrolopyidine. In an embodiment, R is 1H-pyrrolo[3,2-c]pyidin-2-yl. In an embodiment, R is pyrrolopyidine. In an embodiment, R is 1H-pyrrolo[3,2-c]pyidin-2-yl. In an embodiment, R is imidazopyridine. In an embodiment, R is thieno[2,3-c]pyridin-2-yl. In an embodiment, R is pyrazolopyridine. In an embodiment, R is pyrazolo[3,4-b]pyridin-5-yl. In an embodiment, R is quinoline. In an embodiment, R is quinolin-6-yl. In an embodiment, R is furopyridine. In an embodiment, R is furo[2,3-c]pyridin-2-yl. In an embodiment R is substituted with 1 to 3 halo, hydroxyl, amino, alkyl, haloalkyl, alkoxy or haloalkyl groups. In an embodiment, R is unsubstituted.
(50) In an embodiment in which compounds have the general Formula II, G is selected from the group consisting of aryl, heteroaryl, cycloalkyl, heterocycloalkyl optionally substituted with 1 to 3 substituents selected from the group consisting of halo, amino, cyano, hydroxyl, alkyl, haloalkyl, alkoxy, acyl, haloalkoxy, aryl, heteroaryl, alkoxyalkyl and mercapto. In an embodiment, G is phenyl, thiazol-4-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, indol-2-yl, indol-6-yl, imidazol-2-yl, imidazol-4-yl, piperidin-4-yl, furan-3-yl, oxazol-4-yl, pyridin-2-yl, cyclohexyl, benzodioxolane, benzothiophene, benzothiazole, imidazol[1,2-a]pyridin-6-yl or 1H-pyrrolo[3,2-c]pyridin-2-yl optionally substituted with 1 to 3 substituents selected from the group consisting of halo, amino, cyano, hydroxyl, alkyl, haloalkyl, alkoxy, acyl, haloalkoxy, aryl, heteroaryl, alkoxyalkyl and mercapto. In an embodiment G is imidazo[1,2-a]pyridine-6-yl. In an embodiment G is 1H-pyrrolo[3,2-c]pyridin-2-yl. In an embodiment G is thieno[2,3-c]pyridin-2-yl. In an embodiment G is furo[2,3-c]pyridin-2-yl. In an embodiment, G is phenyl substituted with 1 to 3 substituents selected from the group consisting of Cl, F, MeO, EtO, CF3O, CHF.sub.2O, CF.sub.3, Me, iPr-O and pyrazol-1-yl. In an embodiment, G is thiazol-4-yl substituted with 1 to 3 substituents selected from the group consisting of Me, phenyl, CF.sub.3 and pyridin-3-yl. In an embodiment, G is pyridin-2-yl, pyridin-3-yl or pyridin-4-yl substituted with 1 to 3 substituents selected from the group consisting of Me, methoxymethyl, CF.sub.3O— and mercapto.
(51) In an embodiment in which compounds have the general Formula II, R is thieno[2,3-c]pyridin-2-yl, 1H-pyrrolo[3,2-c]pyidin-2-yl, 1H-pyrrolo[3,2-c]pyidin-2-yl, imidazo[1,2-a]pyridin-6-yl or pyrazolo[3,4-b]pyridin-5-yl and G is phenyl, thiazol-4-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, indol-2-yl, indol-6-yl, imidazol-2-yl, imidazol-4-yl, piperidin-4-yl, furan-3-yl, oxazol-4-yl, pyridin-2-yl, cyclohexyl, benzodioxolane, benzothiophene, benzothiazole, imidazol[1,2-a]pyridin-6-yl or 1H-pyrrolo[3,2-c]pyidin-2-yl optionally substituted with 1-4 substituents selected from the group consisting of halo, amino, cyano, hydroxyl, alkyl, haloalkyl, alkoxy, acyl, haloalkoxy, aryl, heteroaryl, alkoxyalkyl and mercapto.
(52) In the compounds of Formulas I, IA, IB, IC and II the various moieties are independently selected.
(53) The following embodiments are directed to Formulas I, IA, IB, and IC. For any moieties that are not specifically defined, the previous definitions control. Further, the moieties aryl, heteroaryl, heterocycloalkyl, cycloalkyl, cycloalkenyl and heterocycloalkenyl in these embodiments can be independently unsubstituted or optionally substituted or optionally fused as described earlier. Any one or more embodiments listed here may be combined with other embodiments to create new embodiments.
(54) An embodiment of the invention is the provision of a compound, where the various moieties are independently selected, R is aryl, and n, m, t, s, X, A, Q and G are as defined.
(55) Another embodiment of the invention is the provision of a compound, where the various moieties are independently selected, R is heteroaryl, and n, m, t, s, X, A, Q and G are as defined.
(56) Another embodiment of the invention is the provision of a compound, where the various moieties are independently selected, R is C.sub.3-C.sub.8 cycloalkyl, and n, m, t, s, X, A, Q and G are as defined.
(57) Another embodiment of the invention is the provision of a compound, where the various moieties are independently selected, R is C.sub.4-C.sub.8 cycloalkcnyl, and n, m, t, s, X, A, Q and G are as defined.
(58) Another embodiment of the invention is the provision of a compound, where the various moieties are independently selected, R is heterocycloalkyl, and n, m, t, s, X, A, Q and G are as defined.
(59) Another embodiment of the invention is the provision of a compound, where the various moieties are independently selected, R is arylalkyl, and n, m, t, s, X, A, Q and G are as defined.
(60) Another embodiment of the invention is the provision of a compound, where the various moieties are independently selected, R is (heteroaryl)alkyl, and n, m, t, s, X, A, Q and G are as defined.
(61) Another embodiment of the invention is the provision of a compound, where the various moieties are independently selected, R is (C.sub.3-C.sub.8 cycloalkyl)alkyl, and n, m, t, s, X, A, Q and G are as defined.
(62) Another embodiment of the invention is the provision of a compound, where the various moieties are independently selected, R is (C.sub.3-C.sub.8 cycloalkenyl)alkyl, and n, m, s, t, X, A, Q and G are as defined.
(63) Another embodiment of the invention is the provision of a compound, where the various moieties are independently selected, R is (heterocycloalkyl)alkyl, and n, m, s, t, X, A, Q and G are as defined.
(64) Another embodiment of the invention is the provision of a compound, where the various moieties are independently selected, R is (aryloxy)alkyl, and n, m, s, t, X, A, Q and G are as defined.
(65) Another embodiment of the invention is the provision of a compound, where the various moieties are independently selected, R is (heteroaryloxy)alkyl, and n, m, s, t, X, A, Q and G are as defined.
(66) Another embodiment of the invention is the provision of a compound, where the various moieties are independently selected, R is (C.sub.3-C.sub.8 cycloalkyloxy)alkyl, and n, m, s, t, X, A, Q and G are as defined.
(67) Another embodiment of the invention is the provision of a compound, where the various moieties are independently selected, R is (C.sub.3-C.sub.8 cycloalkenyloxy)alkyl, and n, m, s, t, X, A, Q and G are as defined.
(68) Another embodiment of the invention is the provision of a compound, where the various moieties are independently selected, R is (heterocycloalkyloxy)alkyl, and n, m, s, t, X, A, Q and G are as defined.
(69) Another embodiment of the invention is the provision of a compound, where the various moieties are independently selected, R, n, m, s, X, Q and G are as defined, t=1 and A is aryl.
(70) Another embodiment of the invention is the provision of a compound, where the various moieties are independently selected, R, n, m, s, X, Q and G are as defined, t=1 and A is heteroaryl.
(71) Another embodiment of the invention is the provision of a compound, where the various moieties are independently selected, R, n, m, s, X, Q and G are as defined, t=1 and A is heterocycloalkyl.
(72) Another embodiment of the invention is the provision of a compound, where the various moieties are independently selected, R, n, m, s, X, Q and G are as defined, t=1 and A is C.sub.3-C.sub.8 cycloalkyl.
(73) Another embodiment of the invention is the provision of a compound, where the various moieties are independently selected, R, m, s, t, X, A, Q and G are as defined and n is 0.
(74) Another embodiment of the invention is the provision of a compound, where the various moieties are independently selected, R, m, s, t, X, A, Q and G are as defined and n is 1.
(75) Another embodiment of the invention is the provision of a compound, where the various moieties are independently selected, R, m, s, t, X, A, Q and G are as defined and n is 2.
(76) Another embodiment of the invention is the provision of a compound, where the various moieties are independently selected, R, m, s, t, X, A, Q and G are as defined and n is 3.
(77) Another embodiment of the invention is the provision of a compound, where the various moieties are independently selected, R, m, s, t, X, A, Q and G are as defined and n is 4.
(78) Another embodiment of the invention is the provision of a compound, where the various moieties are independently selected, R, m, s, t, X, A, Q and G are as defined and n is 5.
(79) Another embodiment of the invention is the provision of a compound, where the various moieties are independently selected, R, m, s, t, X, A, Q and G are as defined and n is 6.
(80) Another embodiment of the invention is the provision of a compound, where the various moieties are independently selected, R, n, s, t, A, Q and G are as defined and m is 0.
(81) Another embodiment of the invention is the provision of a compound, where the various moieties are independently selected, R, X, A, n, m, t and G are as defined, s=1 and Q is C(O).
(82) Another embodiment of the invention is the provision of a compound, where the various moieties are independently selected, R, X, A, n, m, t and G are as defined, s=1 and Q is S(O).
(83) Another embodiment of the invention is the provision of a compound, where the various moieties are independently selected, R, X, A, n, m, t and G are as defined, s=1 and Q is S(O.sub.2).
(84) Another embodiment of the invention is the provision of a compound, where the various moieties are independently selected, R, X, A, n, m, t and G are as defined, s=1 and Q is —N(H)—S(O.sub.2)—.
(85) Another embodiment of the invention is the provision of a compound, where the various moieties are independently selected, R, X, A, n, m, t and G are as defined, s=1 and Q is —S(O.sub.2)—N(H)—.
(86) Another embodiment of the invention is the provision of a compound, where the various moieties are independently selected, R, X, A, n, m, t and G are as defined, s=1 and Q is —N(H)—C(O)—
(87) Another embodiment of the invention is the provision of a compound, where the various moieties are independently selected, R, n, m, t, A, X and G are as defined and s is 0.
(88) Another embodiment of the invention is the provision of a compound, where the various moieties are independently selected, R, X, A, n, m and Q are as defined and G is aryl.
(89) Another embodiment of the invention is the provision of a compound, where the various moieties are independently selected, R, X, A, n, m, s, t and t and Q are as defined and G is heteroaryl.
(90) Another embodiment of the invention is the provision of a compound, where the various moieties are independently selected, R, X, A, n, m, s, t and Q are as defined and G is cycloalkyl.
(91) Another embodiment of the invention is the provision of a compound, where the various moieties are independently selected, R, X, A, n, m, s, t and Q are as defined and G is heterocycloalkyl.
(92) Another embodiment of the invention is the provision of a compound, where the various moieties are independently selected, R, X, A, n, m, s, t and Q are as defined and G is —N(R.sup.1R.sup.2).
(93) An embodiment of the invention is the provision of a compound, where the various moieties are independently selected, R is phenyl, and n, m, s, t, X, A, Q and G are as defined.
(94) An embodiment of the invention is the provision of a compound, where the various moieties are independently selected, R is naphthyl, and n, m, s, t, X, A, Q and G are as defined.
(95) An embodiment of the invention is the provision of a compound, where the various moieties are independently selected, R is pyridyl, and n, m, s, t, X, A, Q and G are as defined.
(96) An embodiment of the invention is the provision of a compound, where the various moieties are independently selected, R is a pyrrolopyridinyl group, and n, m, s, t, X, A, Q and G are as defined.
(97) An embodiment of the invention is the provision of a compound, where the various moieties are independently selected, R is a thienopyridinyl group, and n, m, s, t, X, A, Q and G are as defined.
(98) An embodiment of the invention is the provision of a compound, where the various moieties are independently selected, R is an indazolyl group, and n, m, s, t, X, A, Q and G are as defined.
(99) An embodiment of the invention is the provision of a compound, where the various moieties are independently selected, R is a pyrazolopyridinyl group, and n, m, s, t, X, A, Q and G are as defined.
(100) An embodiment of the invention is the provision of a compound, where the various moieties are independently selected, R is an imidazopyridinyl group, and n, m, s, t, X, A, Q and G are as defined.
(101) An embodiment of the invention is the provision of a compound, where the various moieties are independently selected, R is an imidazopyrazolyl group, and n, m, s, t, X, A, Q and G are as defined.
(102) An embodiment of the invention is the provision of a compound, where the various moieties are independently selected, R is a tetrazolopyridinyl group, and n, m, s, t, X, A, Q and G are as defined.
(103) An embodiment of the invention is the provision of a compound, where the various moieties are independently selected, R is a naphthyridinyl group, and n, m, s, t, X, A, Q and G are as defined.
(104) An embodiment of the invention is the provision of a compound, where the various moieties are independently selected, R is a benzodiazolyl group, and n, m, s, t, X, A, Q and G are as defined.
(105) An embodiment of the invention is the provision of a compound, where the various moieties are independently selected, R is a benzothiazolyl group, and n, m, s, t, X, A, Q and G are as defined.
(106) An embodiment of the invention is the provision of a compound, where the various moieties are independently selected, R is a furopyridinyl group, and n, m, s, t, X, A, Q and G are as defined.
(107) An embodiment of the invention is the provision of a compound, where the various moieties are independently selected, R is a (pyridmyloxy)methy 1 group, and n, m, s, t, X, A, Q and G are as defined.
(108) Another embodiment of the invention is the provision of a compound, where the various moieties are independently selected, R is (pyridinyl)alkyl, and n, m, s, t, X, A, Q and G are as defined.
(109) Another embodiment of the invention is the provision of a compound, where the various moieties are independently selected, R is (pyridinyl)ethyl, and n, m, s, t, X, A, Q and G are as defined.
(110) Another embodiment of the invention is the provision of a compound, where the various moieties are independently selected, R is (pyrrolopyridinyl)methyl, and n, m, s, t, X, A, Q and G are as defined.
(111) Another embodiment of the invention is the provision of a compound, where the various moieties are independently selected, R, n, m, s, t, X, Q and G are as defined and A is phenyl.
(112) Another embodiment of the invention is the provision of a compound, where the various moieties are independently selected, R, n, m, s, t X, Q and G are as defined and A is piperidinyl.
(113) Another embodiment of the invention is the provision of a compound, where the various moieties are independently selected, R, n, m, s, X, Q and G are as defined and t is 0.
(114) Another embodiment of the invention is the provision of a compound, where the various moieties are independently selected, R, X, A, n, m, t, s and Q are as defined and G is phenyl, with said phenyl being substituted or unsubstituted as defined earlier.
(115) Another embodiment of the invention is the provision of a compound, where the various moieties are independently selected, R, X, A, n, m, t, s and Q are as defined and G is tetrahydronaphthalinyl, with said phenyl being substituted or unsubstituted as defined earlier.
(116) Another embodiment of the invention is the provision of a compound, where the various moieties are independently selected, R, X, A, n, m, s, t, R.sup.2, and Q are as defined, G is —N(R.sup.1R.sup.2), and R.sup.1 is H.
(117) Another embodiment of the invention is the provision of a compound, where the various moieties are independently selected, R, A, n, R.sup.1, and Q are as defined, G is —N(R.sup.1R.sup.2), and —R.sup.2 is piperidinyl.
(118) Another embodiment of the invention is the provision of a compound, where the various moieties are independently selected, R, A, n, R.sup.1, and Q are as defined, G is —N(R.sup.1R.sup.2), and —R.sup.2 is quinolinyl.
(119) Another embodiment of the invention is the provision of a compound, where the various moieties are independently selected, R, A, n, R.sup.1, and Q are as defined, G is —N(R.sup.1R.sup.2), R.sup.1 is H and —R.sup.2 is morpholinyl.
(120) Another embodiment of the invention is the provision of a compound, where the various moieties are independently selected, R, A, n, R.sup.1, and Q are as defined, G is —N(R.sup.1R.sup.2), R.sup.1 is H and —R.sup.2 is piperidinyl.
(121) Another embodiment of the invention is the provision of a compound, where the various moieties are independently selected, R, A, n, R.sup.1, and Q are as defined, G is —N(R.sup.1R.sup.2), R.sup.1 is H and —R.sup.2 is quinolinyl.
(122) Another embodiment of the invention is the provision of a compound, where the various moieties are independently selected, R, A, n, R.sup.1, and Q are as defined, G is —N(R.sup.1R.sup.2), and —R.sup.2 is morpholinyl.
(123) Another embodiment of the invention is the provision of a compound, where the various moieties are independently selected, R, X, A, n, m, s, t and Q are as defined and G is piperidinyl.
(124) Another embodiment of the invention is the provision of a compound, where the various moieties are independently selected, R, X, A, n, m, s, t, and Q are as defined and G is 8-oxa-3-azabicyclooctanyl.
(125) Another embodiment of the invention is the provision of a compound, where the various moieties are independently selected, R, X, A, n, m, s, t, and Q are as defined, G is dihydrobenzodioxinyl.
(126) Another embodiment of the invention is the provision of a compound where the various moieties are independently selected, R, X, A, n, m, s, t, and Q are as defined, G is indazolyl.
(127) Another embodiment of the invention is the provision of a compound, where the various moieties are independently selected, R, X, A, n, m, s, t, and Q are as defined, G is 1-oxo-isochromenyl.
(128) Another embodiment of the invention is the provision of a compound, where the various moieties are independently selected, n, m, s, X, G, and Q are as defined, t=1, and both A and R are aryl.
(129) Another embodiment of the invention is the provision of a compound, where the various moieties are independently selected, n, m, s, X, G, and Q are as defined, t=1, and both A and R are heteroaryl.
(130) Another embodiment of the invention is the provision of a compound, where the various moieties are independently selected, n, m, s, X, G, and Q are as defined, R is heteroaryl, t=1, and A is aryl.
(131) Another embodiment of the invention is the provision of a compound, where the various moieties are independently selected, n, m, s, X, G, and Q are as defined, R is (heteroaryl)alkyl, t=1, and A is aryl.
(132) Another embodiment of the invention is the provision of a compound, where the various moieties are independently selected, n, m, s, X, G, and Q are as defined, R is (heteroaryloxy)alkyl t=1, and A is aryl.
(133) Another embodiment of the invention is the provision of a compound, where the various moieties are independently selected, n, m, s, X, G, and Q are as defined, R is aryl, t=1, and A is heteroaryl.
(134) Another embodiment of the invention is the provision of a compound, where the various moieties are independently selected, n, m, X, and G are as defined, t=1, both A and R are aryl, s=1 and Q is S(O.sub.2).
(135) Another embodiment of the invention is the provision of a compound, where the various moieties are independently selected, n, m, X, and G are as defined, t=1, both A and R are heteroaryl, s=1 and Q is S(O.sub.2).
(136) Another embodiment of the invention is the provision of a compound, where the various moieties are independently selected, n, m, X, and G are as defined, t=1, A is aryl, R is heteroaryl, s=1 and Q is S(O.sub.2).
(137) Another embodiment of the invention is the provision of a compound, where the various moieties are independently selected, n, m, X, and G are as defined, t=1, A is aryl, R is (heteroaryl)alkyl, s=1 and Q is S(O.sub.2).
(138) Another embodiment of the invention is the provision of a compound, where the various moieties are independently selected, n, m, X, and G are as defined, t=1, A is aryl, R is (heteroaryloxy)alkyl, s=1 and Q is S(O.sub.2).
(139) Another embodiment of the invention is the provision of a compound, where the various moieties are independently selected, n, m, and X, are as defined, t=1, A is aryl, R is (heteroaryloxy)alkyl, s=1, Q is S(O.sub.2) and G is aryl.
(140) Another embodiment of the invention is the provision of a compound, where the various moieties are independently selected, n, m, and X are as defined, t=1, A is aryl, R is (heteroaryloxy)alkyl, s=1, Q is S(O.sub.2) and G is heteroaryl.
(141) Another embodiment of the invention is the provision of a compound, where the various moieties are independently selected, n, m, and X are as defined, t=1, A is aryl, R is (heteroaryloxy)alkyl, s=1, Q is S(O.sub.2) and G is heterocycloalkyl.
(142) Another embodiment of the invention is the provision of a compound, where the various moieties are independently selected, n, m, and X are as defined, t=1, A is aryl, R is heteroaryl, s=1, Q is S(O.sub.2) and G is aryl.
(143) Another embodiment of the invention is the provision of a compound, where the various moieties are independently selected, n, m, and X are as defined, t=1, A is aryl, R is heteroaryl, s=1, Q is S(O.sub.2) and G is heteroaryl.
(144) Another embodiment of the invention is the provision of a compound, where the various moieties are independently selected, n, m, and X are as defined, t=1, A is aryl, R is heteroaryl, s=1, Q is S(O.sub.2) and G is heterocycloalkyl.
(145) Another embodiment of the invention is the provision of a compound, where the various moieties are independently selected, n, m, and X are as defined, t=1, A is aryl, R is (heteroaryl)alkyl, s=1, Q is S(O.sub.2) and G is aryl.
(146) Another embodiment of the invention is the provision of a compound, where the various moieties are independently selected, n, m, and X are as defined, t=1, A is aryl, R is (heteroaryl)alkyl, s=1, Q is S(O.sub.2) and G is heteroaryl. Another embodiment of the invention is the provision of a compound, where the various moieties are independently selected, n, m, and X are as defined, t=1, A is aryl, R is (heteroaryl)alkyl, s=1, Q is S(O.sub.2) and G is heterocycloalkyl.
(147) Another embodiment of the invention is the provision of a compound, where the various moities are independently selected, s, t, R, X, A and G are as defined, m=1, and n=3.
(148) Another embodiment of the invention is the provision of a compound, where re the various moities are independently selected, R, X, and G are as defined, and m=1, t=0, s=0 and n=6.
(149) In another embodiment, the invention is further illustrated by the compounds shown in Table 2:
(150) TABLE-US-00002 TABLE 2 Structure Chemical Name
EXAMPLES
(151) The following are illustrative, but non-limiting, examples of certain embodiments of the present invention.
(152) Definitions used in the following Schemes and elsewhere herein are:
(153) BOP ammonium 4-(3-(pyridin-3-methyl)ureido)benzenesulfinate CDCl.sub.3 deuterated chloroform δ chemical shift (ppm) DCM dichloromethane or methylene chloride DIEA N,N-diisopropylethylamine DMA N,N-dimethylacetamide DMF N,N-dimethylformamide DMSO dimethylsulfoxide DMSO-d.sub.6 deuterated dimethylsulfoxide EDCI N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride EtOAc ethyl acetate EtOH ethanol GF/F glass microfiber filter .sup.1H NMR proton nuclear magnetic resonance HOAc acetic acid HATU 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate HOBT 1H-benzo[d][1,2,3]triazol-1-ol hydrate HPLC high pressure liquid chromatography MHz megahertz KOAc potassium acetate i-PrOH isopropanol LC-MS liquid chromatography/mass spectrometry (M+1) mass+1 m-CPBA m-chloroperbenzoic acid MeOH methanol N.sub.2 nitrogen NaHCO.sub.3 sodium bicarbonate MgSO.sub.4 magnesium sulfate PTLC preparative thin layer chromatography TEA triethylamine THE tetrahydrofuran TLC thin layer chromatography
Preparation of Compounds
(154) The compounds of the present invention can be prepared in a number of ways well known to those skilled in the art of organic synthesis. By way of example, compounds of the present invention can be synthesized using the methods described below, together with synthetic methods known in the art of synthetic organic chemistry, or variations thereon as appreciated by those skilled in the art. Preferred methods include but are not limited to those methods described below. Compounds of the present invention amide-sulfonamide (III) can be synthesized by following the steps outlined in Scheme 1.
(155) ##STR00338##
(156) Compound III can be obtained by treating I with II (X═OH) in the presence of a coupling reagent such as EDCI, HATU, or HOBt, and a base (eg: K.sub.2CO.sub.3, Cs.sub.2CO.sub.3, NR.sub.1R.sub.2R.sub.3, NaOR, KOR) in an inert solvent such as dichloromethane, N,N-dialkylformamide, N,N-dialkylacetamide, dialkylethers, cyclic ethers, DMSO, N-methyl-2-pyrrolidinone at temperatures ranging from −78° C. to 200° C. Alternatively, compound I can be treated with II (X═Cl) in the presence of base such as TEA in an inert solvent (such as dichloromethane) at temperatures ranging from −78° C. to 200° C.
(157) Compounds (III) can also be synthesized by following the steps outlined in Scheme 2.
(158) ##STR00339##
(159) Compound V can be obtained by treating I with II (X═OH) in the presence of a coupling reagent such as EDCI, HATU, or HOBt, and a base (eg: K.sub.2CO.sub.3, Cs.sub.2CO.sub.3, NR.sub.1R.sub.2R.sub.3, NaOR, KOR) in an inert solvent such as dichloromethane, N,N-dialkylformamide, N,N-dialkylacetamide, dialkylethers, cyclic ethers, DMSO, N-methyl-2-pyrrolidinone at temperatures ranging from −78° C. to 200° C. Alternatively, compound I can be treated with II (X═Cl) in the presence of base such as TEA in an inert solvent (such as dichloromethane) at temperatures ranging from −78° C. to 200° C. Removing the protecting group of compound V with acid such as TFA or HCl following with reacting with VI in the presence of base such as TEA in an inert solvent (such as dichloromethane) at temperatures ranging from −78° C. to 200° C. afford the desired compound III.
(160) The disclosures in this application of all articles and references, including patents, are incorporated herein by reference.
(161) The invention is illustrated further by the following examples, which are not to be construed as limiting the invention in scope or spirit to the specific procedures described in them. Those having skill in the art will recognize that the starting materials may be varied and additional steps employed to produce compounds encompassed by the present inventions, as demonstrated by the following examples. Unless otherwise specified, all reagents and solvents were of standard commercial grade and were used without further purification. In some cases, protection of certain reactive functionalities may be necessary to achieve some of the above transformations. In general, such need for protecting groups, as well as the conditions necessary to attach and remove such groups, will be apparent to those skilled in the art of organic synthesis.
(162) Preparation of Representative Amide Analogues
(163) These examples illustrate the preparation of representative substituted urea-sulfonamide analogues.
Example 1
N-(4-(1-benzoylpiperidin-4-yl)butyl)-1H-pyrrolo[3,2-c]pyridine-2-carboxamide
(164) ##STR00340##
(165) In a 25 mL round-bottomed flask was added 1-H-pyrrolo[3,2-c]pyridine-2-carboxylic acid (100 mg, 0.617 mmol) and (4-(4-aminobutyl)piperidin-1-yl)(phenyl)methanone (161 mg, 0.617 mmol; prepared according to Galli U.; Ercolano, E.; Carraro, L.; Blasi Roman, C. R.; Sorba, G.; Canonico, P. L.; Genazzani, A. A.; Tron, G. C.; Billington, R. A. Synthesis and biological evaluation of isosteric analogues of FK866, an inhibitor of NAD salvage. ChemMedChem 2008, 3, 771-779) in dimethylformamide (5.0 ml) to give a light yellow suspension. O-(7-azabenzotriazol-1-yl)-N,N,N′,N′,-tetramethyluronium hexafluorphosphate (HATU) (220 mg, 0.577 mmol) and diisopropylethylamine (0.089 ml, 0.510 mmol) were added sequentially and the suspension was allowed to stir at room temperature overnight. The reaction was then poured in to a separatory funnel containing water and ethyl acetate. The aqueous phase was separated and extracted three times with ethyl acetate. The combined organic phase was dried over sodium sulfate, filtered and concentrated in vacuo. The resulting residue was purified by preparative HPLC to afford the title compound (76 mg, 31%).
(166) 1H NMR: (d6-DMSO, 300 MHz) δ.sub.H 11.94 (s, 1H), 8.88 (s, 1H), 8.59 (t, 1H), 8.19 (d, 2H), 7.39 (m, 3H), 7.31 (m, 3H), 7.20 (s, 1H), 4.43 (m, 1H), 3.51 (m, 1H), 3.26 (m, 2H), 2.96 (m, 1H), 2.70 (m, 1H), 1.70 (m, 2H), 1.51 (m, 3H) 1.29 (m, 4H) and 1.05 (m, 2H).
(167) LCMS: 405.2 (MH.sup.+)
Example 2
N-(4-(1-benzoylazetidin-3-yl)butyl)-1H-pyrrolo[3,2-c]pyridin-2-carboxamide
(168) ##STR00341##
A. tert-butyl 4-(1-benzoylazetidin-3-ylbutylcarbamate
(169) ##STR00342##
(170) In a 250 mL round-bottomed flask was added tert-butyl 4-(azetidin-3-yl)butylcarbamate (1 g, 4.38 mmol) and triethylamine (1.343 mL, 9.64 mmol) in dichloromethane (Volume: 50 mL) followed by dropwise addition of benzoyl chloride (0.508 mL, 4.38 mmol). The reaction was monitored by TLC and when complete, the reaction was diluted with methylene chloride and poured into a separatory funnel. The organic layer was washed with saturated, aqueous sodium bicarbonate, water, and saturated, aqueous sodium chloride. The organic was separated and concentrated under reduced pressure and purified on the Biotage to give 1.178 g of crude product. Material purified again on the Biotage to give 381 mg of product (26% yield).
(171) .sup.1H NMR (300 MHz, DMSO-d6): δ 7.59 (m, 2H), 7.45 (m, 3H), 6.77 (t, 1H), 4.43 (t, 1H), 4.09 (t, 1H), 3.89 (dd, 1H), 3.64 (dd, 1H), 2.89 (q, 2H), 2.58 (m, 11), 1.55 (m, 2H), 1.35 (m, 11H), 1.18 (m, 2H).
(172) LC-MS (ESI): 355 (M+Na).
B. (3-(4-aminobutyl)azetidin-1-yl)(phenyl)methanone
(173) ##STR00343##
(174) In a 100 mL round-bottomed flask was added tert-butyl 4-(1-benzoylazetidin-3-yl)butylcarbamate (381 mg, 1.146 mmol) in dichloromethane (Ratio: 1.000, Volume: 12.00 mL)/TFA (Ratio: 1.000, Volume: 12.00 mL) which was stirred at room temperature overnight. The solvent was removed under vacuum and the residue re-diluted with methylene chloride and concentrated again. The residue was then diluted with methylene chloride and poured into a separatory funnel. The organic layer was washed with saturated, aqueous sodium bicarbonate and saturated, aqueous sodium chloride. The bottom was separated, dried with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give 261 mg of crude product which was used without further purification (98% yield).
(175) .sup.1H NMR (300 MHz, DMSO-d6): δ 7.59 (m, 2H), 7.45 (m, 3H), 4.33 (t, 1H), 4.09 (t, 1H), 3.89 (dd, 1H), 3.64 (dd, 1H), 3.39 (br.s, 2H), 2.58 (m, 3H), 1.53 (m, 2H), 1.35 (m 4H).
(176) LC-MS (ESI): 233 (M+1).
C. N-(4-(1-benzoylazetidin-3-yl)butyl)-1H-pyrrolo[3,2-c]pyridine-2-carboxamide
(177) ##STR00344##
(178) In a 100 mL round-bottomed flask was added (3-(4-aminobutyl)azetidin-1-yl)(phenyl)methanone (260 mg, 1.119 mmol), 1H-pyrrolo[3,2-c]pyridine-2-carboxylic acid (181 mg, 1.119 mmol) and HATU (638 mg, 1.679 mmol) in DMF (Volume: 10 mL) followed by DIEA (0.430 mL, 2.462 mmol). The reaction was stirred overnight at room temperature and then concentrated under reduced pressure. The residue was diluted with methylene chloride and poured into a separatory funnel. The organic layer was washed with aqueous 2M NaOH. The bottom was separated, concentrated under reduced pressure and purified on the Biotage to give 258.9 mg of product (62% yield).
(179) .sup.1H NMR (300 MHz, DMSO-d6): δ 12.01 (s, 1H), 8.94 (s, 1H), 8.63 (t, 1H), 8.22 (d, 1H), 7.62 (m, 2H), 7.44 (m, 4H), 7.25 (s, 1H), 4.35 (t, 1H), 4.12 (t, 1H), 3.90 (dd, 1H), 3.67 (dd, 1H), 3.30 (m, 2H), 2.60 (m, 1H), 1.59 (m, 4H), 1.28 (2H).
(180) LC-MS (ESI): 377 (M+1).
Example 3
N(4-(1-benzoylpyrrolidin-3-ylbutyl)-1H-pyrrolo[3,2-c]pyridine-2-carboxamide
(181) ##STR00345##
(182) STEP A: To a solution of tert-butyl 4-(pyrrolidin-3-yl)butylcarbamate (0.993 g, 4.10 mmol) and triethylamine (1.343 mL, 9.64 mmol) in DCM (50 mL) at 0° C. was added dropwise benzoyl chloride (0.476 mL, 4.10 mmol). The reaction was allowed to warm slowly to ambient temperature over 16 h. The mixture was diluted with water and DCM and the layers separated. The organic layer was washed successively with saturated aqueous NaHCO.sub.3 and brine, and dried over MgSO.sub.4. The residue was purified by Biotage (EtOAc/hexane gradient) to afford tert-butyl (4-(1-benzoylpyrrolidin-3-yl)butyl)carbamate (474 mg, 33%) as a colorless oil.
(183) STEP B: To a solution of tert-butyl 4-(1-benzoylpyrrolidin-3-yl)butylcarbamate (474 mg, 1.368 mmol) in DCM (10 mL) was added TFA (10 mL). The mixture was stirred at ambient temperature for 16 h, and then was concentrated under reduced pressure. The residue was diluted with methylene chloride and washed successively with saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride. The organic layer was separated, dried with MgSO.sub.4, filtered, and concentrated under reduced pressure to afford (3-(4-aminobutyl)pyrrolidin-1-yl)(phenyl)methanone (64 mg, 19%).
(184) STEP C: To a mixture of (3-(4-aminobutyl)pyrrolidin-1-yl)(phenyl)methanone (64 mg, 0.260 mmol), 1H-pyrrolo[3,2-c]pyridine-2-carboxylic acid (42.1 mg, 0.260 mmol) and HATU (148 mg, 0.390 mmol) in DMF (5 mL) was added DIEA (0.100 mL, 0.572 mmol). The mixture was stirred for 16 hours at ambient temperature and was then concentrated under reduced pressure. The residue was diluted with ethyl acetate and washed with aqeuous 1N NaOH (2×) and dried (MgSO4). The crude mixture was purified by Biotage (DCM/MeOH gradient) to afford N-(4-(1-benzoylpyrrolidin-3-yl)butyl)-1H-pyrrolo[3,2-c]pyridine-2-carboxamide as a white solid (75 mg, 74%).
(185) .sup.1H NMR (DMSO-d.sub.6): δ 12.05 (br s, 1H), 8.94 (d, 1H), 8.63 (dt, 1H), 8.21 (d, 1H), 7.49-7.36 (m, 6H), 7.25 (d, 1H), 3.68-3.21 (m, 5H), 3.08-2.99 (m, 1), 2.17-1.89 (m, 2H), 1.61-1.20 (m, 7H).
(186) LC-MS (ESI): 391.17 (M+1).
Example 4
N-(6-(4-chlorophenoxy)hexyl)quinoline-6-carboxamide
(187) ##STR00346##
(188) In a 25 ml round-bottomed flask was added quinoline-6-carboxylic acid (100 mg, 0.577 mmol) and 6-(4-chlorophenoxy)hexan-1-amine (132 mg, 0.577 mmol) in dimethylformamide (5.8 ml) to give a light yellow suspension. O-(7-azabenzotriazol-1-yl)-N,N,N′,N′,-tetramethyluronium hexafluorphosphate (HATU) (220 mg, 0.577 mmol) and diisopropylethylamine (0.089 ml, 0.510 mmol) were added sequentially and the suspension was allowed to stir at room temperature overnight before being concentrated in vacuo. The resulting residue was purified by flash column chromatography (eluting with ethyl acetate) to afford the title compound (125 mg, 57%).
(189) 1H NMR: (d6-DMSO, 300 MHz) δ.sub.H 8.98 (d, 1H), 8.70 (t, 1H), 8.48 (m, 2H), 8.16 (dd, 1H), 8.07 (d, 1H), 7.61 (dd, 1H), 7.28 (d, 2H), 6.93 (d, 2H), 3.96 (t, 2H), 3.33 (m, 2H), 1.72 (m, 2H), 1.58 (m, 2H) and 1.42 (m, 4H).
(190) LCMS: 383.0 (MH.sup.+)
Example 5
N-(2-(biphenyl-4-ylethyl)-1H-pyrrolo[3,2-c]pyridine-2-carboxamide
(191) ##STR00347##
(192) In a 50 mL round-bottomed flask was added 1H-pyrrolo[3,2-c]pyridine-2-carboxylic acid (200 mg, 1.233 mmol), 2-(biphenyl-4-yl)ethanamine (243 mg, 1.233 mmol), and HATU (469 mg, 1.233 mmol) in DMF (Volume: 10 mL) along with DIEA (0.431 mL, 2.467 mmol). The reaction was stirred overnight, concentrated under reduced pressure and purified directly on the Biotage to give 273 mg of product with a small amount of impurities. Run through Biotage again to give 215.9 mg of product which was clean except for some DIEA salts. Diluted material in 10% MeOH/CH.sub.2Cl.sub.2 and washed with aq. sodium bicarbonate. Material formed emulsion. Drained methylene chloride and then added EtOAc. Emulsion again. Managed to separate organic layers and then combined and concentrated to give 159.6 mg of clean product (37% yield).
(193) .sup.1H NMR (DMSO-d6): δ 12.08 (br. s, 1H), 9.24 (t, 1H), 8.94 (s, 1H), 8.21 (d, 1H), 7.63 (m, 4H), 7.31-7.46 (m, 7H), 4.55 (d, 2H).
(194) LC-MS (ESI): 328 (M+1).
Example 6
N-(4-(benzyloxy) phenethyl)-1H-pyrrolo [3, 2-c]pyridine-2-carboxamide
(195) ##STR00348##
(196) To a 100 ml flask as added 1H-pyrrolo[3,2-c]pyridine-2-carboxylic acid (100 mg and 0.617 mmol) 2-(4-(benzyloxy)phenyl)ethanamine HCl (195 mg, 0.740 mmol) in DMF (10 ml) to give a light yellow suspension. HATU (352 mg, 0.925 mmol) and DIEA (319 mg, 2.467 mmol) were added. The mixture was stirred at RT for 16 hours. Added water and extracted with ethyl acetate (3×20 mL). The organic layers were combined and washed with water (3×20 mL). The organic was separated, dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure The Biotage purification afforded 140 mg of the product (61%). .sup.1H NMR (DMSO-d.sub.6). δ 13.00 (s, 1H), 9.30 (s, 1H), 9.00 (m, 1H), 8.37 (d, H), 7.78 (d, 1H), 7.52 (s, 1H), 7.30-7.47 (m, 5H), 7.18 (d, 2H), 6.90 (d, 2H), 5.02 (s, 2H), 3.37 (m, 2H0, 2.80 (m, 2H). LC-MS: 472.25 (M+1)
Example 7
N-(3-(1-benzoylpiperidin-4-yl)propyl)-1H-pyrrolo[3,2-c]pyridine-2-carboxamide
(197) ##STR00349##
A. tert-butyl 4-(3-(1H-pyrrolo[3,2-c]pyridine-2-carboxamido)propyl)piperidine carboxylate
(198) ##STR00350##
(199) To a 100 ml of flask added tert-butyl 4-(3-aminopropyl)piperidine-1-carboxylate (250 mg, 1.032 mmol) and 1H-pyrrolo[3,2-c]pyridine-2-carboxylic acid (167 mg, 1.032 mmol) in DMF (10 ml). HATU (510 mg, 1.341 mmol) and DIPEA (0.721 ml, 4.13 mmol) were added. The mixture was stirred at RT for 16 hours. The mixture was diluted with water and extracted with ethyl acetate (3×20 mL).
(200) The organic layers were combined and washed with water (3×20 mL). The organic was separated, dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the crude product which was purified by the Biotage to afford 300 mg of product (75%).
(201) .sup.1H NMR (DMSO-d.sub.6) δ: 12.35 (s, 1H), 9.08 (s, 1H), 8.75 (m, 1H), 3.87-3.91 (m, 2H), 3.23-3.30 (m, 4H), 1.49-1.63 (m, 5H), 1.32 (s, 9H), 1.20-1.24 (m, 2H), 0.90-0.98 (m, 2H).
(202) LC-MS: 387.22 (M+1)
B. N-(3-(piperidin-4-yl)propyl)-1H-pyrrolo[3,2-c]pyridine-2-carboxamide, TFA salt
(203) ##STR00351##
(204) To a 100 ml flask was added tert-butyl 4-(3-(1H-pyrrolo[3,2-c]pyridine-2-carboxamido)propyl) piperidine-1-carboxylate (300 mg, 0.776 mmol) and 30 ml of 1:1 TFA/DCM. The mixture was stirred at RT for overnight, removed solvent, added ether, filtered and dried to afford 300 mg of crude product (97%).
(205) .sup.1H NMR (DMSO-d.sub.6). δ 13.27 (s, 1H), 9.44 (s, 1H), 9.05 (m, 1H), 8.45 (d, 1H), 7.88 (d, 1H), 7.64 (s, 1H), 3.21-3.33 (m, 4H), 2.83 (m, 2H), 1.78 (m, 2H), 1.54 (m, 3H), 1.26 (m, 4H).
(206) LC-MS: 287.14 (M+1)
C. N-(3-(1-benzoylpiperidin-4-yl)propyl)-1H-pyrrolo[3,2-c]pyridine-2-carboxamide
(207) ##STR00352##
(208) To a solution of N-(3-(piperidin-4-yl)propyl)-1H-pyrrolo[3,2-c]pyridine-2-carboxamide, TFA, and pyridine (20 mL) in 20 ml of DCM was added benzoyl chloride (211 mg. 1.499 mmol). The mixture was stirred at RT for overnight. Removed solvents, added EtOAc, washed with water, brine, dried and concentrated. The Biotage purification afforded 37 mg of product (13%).
(209) .sup.1H NMR (CDCl.sub.3). δ 9.03 (s, 1H), 8.40 (d, 1H), 7.42 (d, 1H), 7.40 (s, 1H), 7.22 (m, 5H), 7.10 (s, 1H), 6.64 (s, 1H), 4.52 (m, 1H), 4.00 (m, 1H), 3.45 (m, 2H), 3.10 (m, 1H), 2.75 (m, 4H), 1.82 (m, 5H), 1.75 (m, 4H). LC-MS: 391.17 (M+1)
Example 8
N-(4-(4-Benzoylpiperazin-1-yl)butyl)-1H-pyrrolo[3,2-c]pyridine-2-carboxamide
(210) ##STR00353##
A. tert-Butyl 4-(4-(1,3-dioxoisoindolin-2-yl)butyl)piperazine-1-carboxylate
(211) ##STR00354##
(212) A mixture of 2-(4-bromobutyl)isoindoline-1,3-dione (3.33 g, 11.8 mmol), tert-butyl piperazine-1-carboxylate (2.2 g, 11.8 mmol) and Et.sub.3N (4.9 nil, 35.4 mmol) in CH.sub.3CN (50 mL) is heated at reflux for 16 h. The mixture is cooled and the solvent is evaporated. The residue is partitioned between EtOAc (70 mL) and water (70 mL). The organic layer is washed with brine (40 mL), dried (Na.sub.2SO.sub.4) and evaporated. The residue is purified by flash column with 1:1 Hexane/EtOAc gives colorless oil (3.91 g, 85%).
(213) .sup.1HNMR (CDCl.sub.3) δ: 7.83 (dd, 2H), 7.71 (dd, 2H), 3.71 (t, 2H), 3.41 (t, 4H), 2.34-2.38 (m, 6H), 1.67-1.70 (m, 2H), 1.50-1.56 (m, 2H), 1.45 (s, 9H).
(214) LC-MS M+1: 388.12;
B. tert-Butyl 4-(4-aminobutyl)piperazine-1-carboxylate
(215) ##STR00355##
(216) To a solution of tert-butyl 4-(4-(1,3-dioxoisoindolin-2-yl)butyl)piperazine-1-carboxylate (3.91 g, 10.1 mmol) in EtOH (60 mL) is added anhydrous hydrazine (3.23 mL, 100 mmol) and the mixture is stirred at ambient temperature for 24 h. The solvent is removed and to the solid is added EtOAc (40 mL) and Hexane (40 mL) and the suspension is stirred at RT for 2 h. The mixture is filtered and the solid is washed with 1:1 Hexane/EtOAc (20 mL). The filtrate is evaporated to gives a light yellow oil (2.41 g, 93%).
(217) .sup.1HNMR (CDCl.sub.3, δ): 3.42 (t, 4H), 3.25 (s, 2H, broad), 2.69 (t, 2H), 2.32-2.38 (m, 6H), 1.41-1.48 (m, 13H). LC-MS M+1: 258.19.
C. tert-Butyl 4-(4-(1H-pyrrolo[3,2-c]pyridine-2-carboxamido)butyl)piperazine-1-carboxylate
(218) ##STR00356##
(219) To a solution of tert-butyl 4-(4-aminobutyl)piperazine-1-carboxylate (258 mg, 1 mol), Et.sub.3N (0.42 mL, 3 mol) and 1H-pyrrolo[3,2-c]pyridine-2-carboxylic acid (163 mg, 1 mmol) in DCM (20 mL) and DMSO (4 mL) is add HBTU (380 mg, 1 mmol). The mixture is stirred at ambient temperature overnight and the solvent is evaporated. To the residue is added NaHCO.sub.3 (30 mL) and EtOAc (30 mL). The layers are separated and the organic layer is washed with water (30 mL), brine (30 mL) then dried and evaporated. The residue is purified by flash column with 100:8:0.8 DCM/MeOH/NH.sub.4OH to give the titled compounds as a white solid to give a light yellow solid (272 mg, 68%).
(220) .sup.1HNMR (CDCl.sub.3, δ): 8.94 (s, 1H), 8.33 (d, 1H), 7.38 (d, 1H), 7.29 (t, 1H), 7.02 (s, 1H), 3.53 (q, 2H), 3.36-3.41 (m, 4H), 3.14 (q, 1H), 2.30-2.37 (m, 6H), 1.54-1.72 (m, 4H), 1.43 (s, 9H). LC-MS M+1: 402.22.
D. N-(4-(Piperazin-1-yl)butyl)-1H-pyrrolo[3,2-c]pyridine-2-carboxamide trihydrochloride
(221) ##STR00357##
(222) To a solution of tert-butyl 4-(4-(1H-pyrrolo[3,2-c]pyridine-2-carboxamido)butyl)piperazine-1-carboxylate (272 mg, 0.68 mmol) in MeOH (10 mL) is added 4N HCl in dioxane (2 mL, 8 mmol) and the mixture is heated at 50° C. for 3 h then cooled to RT. The solvent is removed under vacuum and the residue is washed with ether to give a light yellow solid (216 mg, 94%). .sup.1HNMR (D.sub.2O, δ): 9.02 (s, 1H), 8.20 (d, 1H), 7.82 (d, 1H), 7.39 (s, 1H), 3.40-3.60 (m, 8H), 3.34 (t, 2H), 3.2 (t, 2H), 2.80 (s, 1H), 1.69-1.76 (m, 2H), 1.55-1.63 (m, 2H). LC-MS M+1: 302.24.
E. N-(4-(4-Benzoylpiperazin-1-yl)butyl)-1-pyrrolo[3,2-c]pyridine-2-carboxamide
(223) ##STR00358##
(224) To a solution of N-(4-(piperazin-1-yl)butyl)-1H-pyrrolo[3,2-c]pyridine-2-carboxamide trihydrochloride (82 mg, 0.2 mmol), benzoic acid (25 mg, 0.2 mmol) and Et.sub.3N (0.14 ml, 1 mmol) in 5:1 dioxane and DMA (6 mL) is added HBTU (76 mg, 0.2 mmol) in CH.sub.3CN (2 ml) and the mixture is stirred at RT overnight. The solvent is removed under vacuum and the residue is partitioned between EtOAc (10 mL) and water (10 mL). The organic layer is dried (Na.sub.2SO.sub.4) then concentrated and the residue is purified by preparative TLC with 100:7:0.7 DCM/MeOH/NH.sub.4OH to give the titled compounds as a white solid (47 mg, 58%).
(225) .sup.1HNMR (DMSO-d.sub.6, δ): 11.97 (s, broad, 1H), 8.90 (s, 1H), 8.61 (t, 1H), 8.19 (d, 1H), 7.33-7.43 (m, 5H), 7.23 (s, 1H), 3.26-3.58 (m, 9H), 2.30-2.38 (m, 5H), 1.48-1.55 (m, 3H). LC-MS M+1: 406.17.
Example 9
N-(4-(1-((4-Chlorophenyl)sulfonyl)piperidin-4-yl)butyl)-1H-pyrrolo[3,2-c]pyridine-2-carboxamide
(226) ##STR00359##
A. tert-Butyl 4-(3-((methylsulfonyl)oxy)propyl)piperidine-1-carboxylate
(227) ##STR00360##
(228) A solution of tert-butyl 4-(3-hydroxypropyl)piperidine-1-carboxylate (4.86 g, 20 mmol) and Et.sub.3N (6.7 mL, 48 mmol) in DCM (80 mL) is cooled to 0° C. by an ice bath. MeSO.sub.2Cl (2.75 g, 24 mmol) is added dropwise while maintaining the internal temperature below 10° C. The mixture is stirred at 0° C. for another 2 h then quenched with water (40 mL). The mixture is transferred to a separatory funnel and layers are separated. The organic layer is washed with NaHCO.sub.3 (30 mL) and brine (30 mL) then dried (Na.sub.2SO.sub.4) and concentrated. The light yellow oil (6.17 g, 96%) is used to next step without further purification.
(229) .sup.1HNMR (CDCl.sub.3, δ): 4.22 (t, 2H), 4.09 (t, 2H), 3.00 (s, 3H), 2.57 (t, 2H), 1.74-1.81 (m, 2H), 1.52-1.66 (m, 2H), 1.45 (s, 9H), 1.29-1.43 (m, 3H), 1.05-1.14 (m, 2H).
B. tert-Butyl 4-(3-cyanopropyl)piperidine-1-carboxylate
(230) ##STR00361##
(231) To a solution of tert-butyl 4-(3-((methylsulfonyl)oxy)propyl)piperidine-1-carboxylate (6.17 g, 19.2 mmol) in DMF (100 ml) is added solid KCN (1.56 g, 24 mmol) and the mixture is heated at 85° C. overnight. The solvent is removed under vacuum and the residue is partitioned between EtOAc (80 mL) and water (80 mL). The layers are separated and the organic layer is washed with water (40 mL) and brine (40 mL). The organic solution is dried over Na.sub.2SO.sub.4 and concentrated. The residue is purified by flash column with 1:1 EtOAc/hexane to give the titled compound as colorless oil (3.61 g, 74%).
(232) .sup.1HNMR (CDC.sub.3, δ): 4.09 (m, 2H), 2.68 (t, 2H), 2.34 (t, 2H), 1.60-1.72 (m, 4H), 1.45 (s, 9H), 1.36-1.42 (m, 3H), 1.06-1.15 (m, 2H).
C. tert-Butyl 4-(4-aminobutyl)piperidine-1-carboxylate
(233) ##STR00362##
(234) To a solution of tert-butyl 4-(3-cyanopropyl)piperidine-1-carboxylate (12 g, 4.76 mmol) in 2M NH3 in MeOH (30 mL) is add Raney Ni (0.5 mL, 50% in water). The mixture is hydrogenated at 50 psi for 4 h. The suspension is filtered through Celite and the filtrate is evaporated to give the titled compound as colorless oil (12 g, 100%).
(235) .sup.1HNMR (CDCl.sub.3), δ: 4.07 (m, 2H), 2.66 (t, 2H), 1.58-1.72 (m, 4H), 1.45 (s, 9H), 1.22-1.44 (m, 7H), 1.01-1.15 (m, 2H). LC-MS M+1: 257.20
D. tert-Butyl 4-(4-(1H-pyrrolo[3,2-c]pyridine-2-carboxamido)butyl)piperidine-1-carboxylate
(236) ##STR00363##
(237) To a solution of tert-butyl 4-(4-aminobutyl)piperidine-1-carboxylate (677 mg, 2.64 mmol) in dioxane (12 ml) is added 1H-pyrrolo[3,2-c]pyridine-2-carboxylic acid (430 mg, 2.64 mmol) in 8:2 DMSO/Et.sub.3N (6 mL) and the mixture is stirred at RT for 5 min. A solution of HBTU (1.0 g, 2.64 mmol) in CH.sub.3CN (10 mL) is added slowly and the mixture is stirred at RT overnight. The solvent is removed under vacuum and the residue is partitioned between EtOAc (20 mL) and water (20 mL). The organic layer is concentrated and the residue is purified by flash column with 100:7:0.7 DCM/MeOH/NH40H to give the titled compounds as a while solid (706 mg, 67%).
(238) .sup.1HNMR (CDCl.sub.3, δ): 9.62 (s, broad, 1H), 9.00 (d, 1H), 8.39 (d, 1H), 7.36 (dd, 1H), 6.92 (s, 1H), 6.29 (s, broad, 1H), 4.06 (m, 2H), 3.51 (q, 2H), 2.66 (t, 2H), 1.61-1.68 (m, 4H), 1.45 (s, 9H), 1.25-1.44 (m, 5H), 1.02-1.12 (m, 2H). LC-MS M+1: 401.23.
E. N-(4-(Piperidin-4-yl)butyl)-1H-pyrrolo[3,2-c]pyridine-2-carboxamide dihydrochloride
(239) ##STR00364##
(240) To a solution of tert-butyl 4-(4-(1H-pyrrolo[3,2-c]pyridine-2-carboxamido)butyl)piperidine-1-carboxylate (706 mg, 1.76 mmol) in MeOH (12 mL) is added 4N HCl in dioxane (4.5 mL, 18 mmol) and the mixture is heated at 50° C. for 3 h then cooled to RT. The solvent is removed under vacuum and the residue is washed with ether to give a light yellow solid (580 mg, 98%).
(241) .sup.1HNMR (DMSO-d.sub.6, δ): 9.46 (s, 1H), 9.17 (t, 1H), 8.97 (s, broad, 1H), 8.76 (s, broad, 1H), 8.43 (d, 1H), 7.87 (d, 1H), 7.71 (s, 1H), 4.35 (s, broad, 1H), 3.63-3.71 (m, 2H), 3.42-3.49 (m, 2H), 3.31 (q, 2H), 3.16-3.19 (m, 2H), 2.88 (s, broad, 1H), 2.77 (t, 2H), 1.74 (d, 2H), 1.48-1.56 (m, 2H), 1.22-1.33 (m, 3H). LC-MS M+1: 301.25.
F. N-(4-(1-((4-Chlorophenyl)sulfonyl)piperidin-4-yl)butyl)-1H-pyrrolo[3,2-c]pyridine-2-carboxamide
(242) ##STR00365##
(243) To a solution of N-(4-(piperidin-4-yl)butyl)-1H-pyrrolo[3,2-c]pyridine-2-carboxamide dihydrochloride (75 mg, 0.2 mmol), and Et.sub.3N (0.11 mL, 0.8 mmol) in 5:1 dioxane and DMA (6 mL) is added 4-chlorobenzenesulfonyl chloride (42 mg, 0.2 mmol) in DCM (2 mL) and the mixture is stirred at RT overnight. The solvent is removed under vacuum and the residue is partitioned between EtOAc (10 mL) and water (10 mL). The organic layer is dried (Na.sub.2SO.sub.4) then concentrated and the residue is purified by preparative TLC with 100:7:0.7 DCM/MeOH/NH40H to give the titled compounds as a white solid (71 mg, 75%).
(244) .sup.1HNMR (DMSO-d.sub.6, δ): 11.93 (s, broad, 1H), 8.88 (s, 1H), 8.56 (t, 1H), 8.18 (d, 1H), 7.70 (d, 4H), 7.32 (d, 1H), 7.19 (s, 1H), 3.59 (d, 2H), 3.24 (q, 2H), 2.18 (t, 2H), 1.68 (d, 2H), 1.47 (t, 2H), 1.08-1.27 (m, 7H). LC-MS M+1: 475.21.
Example 10
N-(3-((1-(2-fluorobenzoyl)piperidin-4-yl)oxy)propyl)-1H-pyrrolo[3,2-c]pyridine-2-carboxamide
(245) ##STR00366##
A: tert-butyl 4-(3-(1H-pyrrolo[3,2-c]pyridine-2-carboxamido)propoxy)piperidine-1-carboxylate
(246) ##STR00367##
(247) To a mixture of 1H-pyrrolo[3,2-c]pyridine-2-carboxylic acid (62.8 mg, 0.387 mmol), tert-butyl 4-(3-aminopropoxy)piperidine-1-carboxylate (100 mg, 0.387 mmol) in DMF (8 mL) was added BOP (188 mg, 0.426 mmol), followed by DIEA (0.081 mL, 0.464 mmol) to give a light yellow solution. The reaction was stirred at RT overnight. Crude LCMS shows major product (75%). Reaction mixture was concentrated in vacuo to remove the DMF. The residue was diluted with EtOAc and washed with 5% AcOH. The layers were separated. The aqueous layer was back-extracted with EtOAc. The combined EtOAc extracts were washed with saturated NaHCO.sub.3, water, brine, dried over Na.sub.2SO.sub.4 and concentrated to afford off-white solids (200 mg, 86% yield, HPLC purity >95%). The crude was used for next reaction without further purification. LC-MS: 403.14 (M+H).
B: N-(3-(piperidin-4-yloxy)propyl)-1H-pyrrolo[3,2-c]pyridine-2-carboxamide 2,2,2-trifluoroacetate
(248) ##STR00368##
(249) N-(3-(piperidin-4-yloxy)propyl)-1H-pyrrolo[3,2-c]pyridine-2-carboxamide 2,2,2-trifluoro-acetate (200 mg, 0.5 mmol) was dissolved in 8 mL of DCM, followed by addition of trifluoroacetic acid (2 mL). The reaction mixture was stirred for 3 h at room temperature. LC-MS analysis indicated that the reaction was completed. The solvent was removed via vacuo. The residual was taken up in a mixture of DCM/MeOH and continued to dry under reduced pressure to yield a desired product (235 mg).
(250) .sup.1H NMR (300 MHz, DMSO-d.sub.6): δ 13.28 (s, 1H), 9.46 (s, 1H), 9.05 (s, 1H), 8.45 (d, 1H), 7.87 (d, 1H), 7.64 (s, 1H), 3.49-3.38 (m, 5H), 3.13 (s, 2H), 2.96 (s, 2H), 1.90-1.65 (m, 6H). LC-MS: 302.04 (M+H).
C: N-(3-((1-(2-fluorobenzoyl)piperidin-4-yl)oxy)propyl)-1H-pyrrolo[3,2-c]pyridine-2-carboxamide
(251) ##STR00369##
(252) To a mixture of N-(3-(piperidin-4-yloxy)propyl)-1H-pyrrolo[3,2-c]pyridine-2-carboxamide, TFA salt (100 mg, 0.240 mmol) and triethylamine (0.134 mL, 0.961 mmol) in DCM (7 mL) was added 2-fluorobenzoyl chloride (38.1 mg, 0.240 mmol) to give a light yellow solution. The reaction mixture was stirred at RT overnight. LC-MS showed the major peak was the desired product. The reaction mixture was diluted with DCM and washed with only water and brine, then dried over Na.sub.2SO.sub.4, filtered and concentrated. The residue was dissolved in DMSO and purified on reversed phase HPLC to afford the desired product (12.2 mg, 12% yield)
(253) .sup.1H NMR (300 MHz, CDCl.sub.3): δ 9.00 (s, 1H), 8.52 (s, 1H), 8.31 (d, 1H), 7.74 (s, 1H), 7.54 (d, 1H), 7.40-7.32 (m, 2H), 7.21-7.08 (m, 2H), 4.15 (s, 1H), 3.66-3.50 (m, 7H), 3.13 (s, 1H), 2.00-1.66 (m, 6H). LCMS: 425.16 (M+H).
(254) Assays:
Assay Example 1
(255) Biochemical Inhibition Assay
(256) NAMPT Protein Purification
(257) Recombinant His-tagged NAMPT was produced in E. coli cells, purified over a Ni column, and further purified over a size-exclusion column by XTAL Biostructures.
(258) The NAMPT Enzymatic Reaction
(259) The NAMPT enzymatic reactions were carried out in Buffer A (50 mM Hepes pH 7.5, 50 mM NaCl, 5 mM MgCl.sub.2, and 1 mM THP) in 96-well V-bottom plates. The compound titrations were performed in a separate dilution plate by serially diluting the compounds in DMSO to make a 100× stock. Buffer A (89 μL) containing 33 nM of NAMPT protein was added to 1 μL of 100× compound plate containing controls (e.g. DMSO or blank). The compound and enzyme mix was incubated for 15 minutes at room temperature, then 10 μL of 10× substrate and co-factors in Buffer A were added to the test well to make a final concentration of 1 μM NAM, 100 μM 5-Phospho-D-ribose 1-diphosphate (PRPP), and 2.5 mM Adenosine 5′-triphosphate (ATP). The reaction was allowed to proceed for 30 minutes at room temperature, then was quenched with the addition of 11 μL of a solution of formic acid and 1-Cystathionine to make a final concentration of 1% formic acid and 10 μM L-Cystathionine. Background and signal strength was determined by addition (or non-addition) of a serial dilution of NMN to a pre-quenched enzyme and cofactor mix.
(260) Quantification of NMN
(261) A mass spectrometry-based assay was used to measure the Nampt reaction product (NMN) and the internal control (L-Cystathionine). NMN and L-Cystathionine were detected using the services of Biocius Lifesciences with the RapidFire system. In short, the NMN and L-Cystathionine are bound to a graphitic carbon cartridge in 0.1% formic acid, eluted in 30% acetonitrile buffer, and injected into a Sciex 4000 mass spectrometer. The components of the sample were ionized with electrospray ionization and the positive ions were detected. The Q1 (parent ion) and Q3 (fragment ion) masses of NMN were 334.2 and 123.2, respectively. The Q1 and Q3 for L-Cystathionine were 223.1 and 134.1, respectively. The fragments are quantified and the analyzed by the following method.
(262) % Inhibitions are Determined Using this Method.
(263) First the NMN signal is normalized to the L-Cystathionine signal by dividing the NMN signal by the L-Cystathionine signal for each well. The signal from the background wells are averaged and subtracted from the test plates. The compound treated cells re then assayed for % inhibition by using this formula.
% Inh=100−100*x/y
Wherein x denotes the average signal of the compound treated wells and y denotes the average signal of the DMSO treated wells.
IC50s are determined using Excel and this formula
IC50=10{circumflex over ( )}(LOG 10(X)+(((50−% Inh at Cmpd Concentration 1)/(XX−YY)*(LOG 10(X)−LOG 10(Y))))
Wherein X denotes the compound concentration 1, Y denotes the compound concentration 2, XX denotes the % inhibition at compound concentration 1 (X), and YY denotes the % inhibition at compound concentration 2 (Y). NAMPT inhibiting compounds of this invention have IC50 values below 1μ, more preferably below 0.1 μM and most preferably below 0.01 μM. Results for the compounds are provided in Table 3 below.
Assay Example 2
(264) In-Vitro Cell Proliferation Assay
(265) A2780 cells were seeded in 96-well plates at 1×10.sup.3 cells/well in 180 μL of culture medium (10% FBS, 1% Pen/Strep Amphoteericin B, RPMI-1640) with and without the addition of either β-nicotinamide mononucleotide (NMN) or nicotinamide (NAM). After overnight incubation at 37° C. and 5% CO.sub.2, the compound titrations were performed in a separate dilution plate by serially diluting the compounds in DMSO to make a 1000× stock. The compounds were then further diluted to 10× final concentration in culture media, whereupon 20 μL of each dilution was added to the plated cells with controls (e.g. DMSO and blank) to make a final volume of 200 μL. The final DMSO concentration in each well was 0.1%. The plates were then incubated for 72 hours at 37° C. in a 5% CO.sub.2 incubator. The number of viable cells was then assessed using sulforhodamine B (SRB) assay. Cells were fixed at 4° C. for 1 hour with the addition of 50 μL 30% trichloroacetic acid (TCA) to make a final concentration of 6% TCA. The plates were washed four times with H.sub.2O and allowed to dry for at least 1 hour, whereupon 100 μL of a 4% SRB in 1% acetic acid solution was added to each well and incubated at room temperature for at least 30 minutes. The plates were then washed three times with 1% acetic acid, dried, and treated with 100 μL of 10 mM Tris-Base solution. The plates were then read in a microplate reader at an absorbance of 570 nm. Background was generated on a separate plate with media only.
(266) Method for Determining % Inhibition
(267) First, the signals from the background plate are averaged, then the background was subtracted from the test plates. The compound-treated cells were then assayed for % inhibition by using the following formula:
% Inh=100−100*x/y
wherein x denotes the average signal of the compound-treated cells and y denotes the average signal of the DMSO-treated cells.
Formula for determining IC.sub.50 values:
IC50=10{circumflex over ( )}(LOG 10(X)+(((50−% Inh at Cmpd Concentration 1)/(XX−YY)*(LOG 10(X)−LOG 10(Y))))
wherein X denotes the compound concentration 1, Y denotes the compound concentration 2, XX denotes the % inhibition at compound concentration 1 (X), and YY denotes the % inhibition at compound concentration 2 (Y).
Specificity of Cytotoxicity.
(268) Inhibition of NAMPT could be reversed by the addition of NAM or NMN. The specificity of the compounds were determined via cell viability assay in the presence of the compound and either NAM or NMN. Percent inhibitions were determined using the method given above.
(269) NAMPT-inhibiting compounds of this invention have IC50-values below 1 μM, preferably below 0.1 μM and most preferably below 0.01 μM. Results of for the compounds are provided below in Table 3.
(270) TABLE-US-00003 TABLE 3 Biochem A2780 IUPAC Name IC50 uM IC50 uM N-[2-(4-phenylphenyl)ethyl]-1H-pyrrolo[3,2-c]pyridine- 0.126 3.98 2-carboxamide N-[2-(1-benzoylpiperidin-4-yl)ethyl]-1H-pyrrolo[3,2- 10 20 c]pyridine-2-carboxamide N-{2-[1-(benzenesulfonyl)piperidin-4-yl]ethyl}-1H- 0.0509 1.03 pyrrolo[3,2-c]pyridine-2-carboxamide N-[4-(1-benzoylpiperidin-4-yl)butyl]-1H-pyrrolo[3,2- 0.0081 0.0014 c]pyridine-2-carboxamide N-[6-(4-chlorophenoxy)hexyl]quinoline-6-carboxamide 0.0259 9.89 N-(4-{4-[(3-methoxyphenyl)carbonyl]piperazin-1- 0.436 0.855 yl}butyl)-1H-pyrrolo[3,2-c]pyridine-2-carboxamide N-[4-(1-cyclohexanecarbonylpiperidin-4-yl)butyl]-1H- 0.18 0.0155 pyrrolo[3,2-c]pyridine-2-carboxamide N-(4-{4-[(3-chlorophenyl)carbonyl]piperazin-1-yl}butyl)- 0.106 0.347 1H-pyrrolo[3,2-c]pyridine-2-carboxamide N-[4-(1-{[2-(pyridin-3-yl)-1,3-thiazol-4- 0.0811 0.0149 yl]carbonyl}piperidin-4-yl)butyl]-1H-pyrrolo[3,2- c]pyridine-2-carboxamide N-[4-(4-benzoylpiperazin-1-yl)butyl]-1H-pyrrolo[3,2- 0.016 0.0947 c]pyridine-2-carboxamide N-{4-[1-({1H-pyrrolo[3,2-c]pyridin-2- 0.0209 0.0113 yl}carbonyl)piperidin-4-yl]butyl}-1H-pyrrolo[3,2- c]pyridine-2-carboxamide N-(4-{1-[(4-methoxyphenyl)carbonyl]piperidin-4- 0.0797 0.0163 yl}butyl)-1H-pyrrolo[3,2-c]pyridine-2-carboxamide N-(4-{1-[(4-fluorophenyl)carbonyl]piperidin-4-yl}butyl)- 0.0598 0.0147 1H-pyrrolo[3,2-c]pyridine-2-carboxamide N-[4-(1-{[4-(difluoromethoxy)phenyl]carbonyl}piperidin-4- 0.183 0.0314 yl)butyl]-1H-pyrrolo[3,2-c]pyridine-2-carboxamide N-(4-{1-[(2H-1,3-benzodioxol-5-yl)carbonyl]piperidin-4- 0.0783 0.014 yl}butyl)-1H-pyrrolo[3,2-c]pyridine-2-carboxamide N-(4-{1-[(2,5-difluorophenyl)carbonyl]piperidin-4- 0.0103 0.0015 yl}butyl)-1H-pyrrolo[3,2-c]pyridine-2-carboxamide N-(4-{1-[(2-methoxyphenyl)carbonyl]piperidin-4- 0.0144 0.0019 yl}butyl)-1H-pyrrolo[3,2-c]pyridine-2-carboxamide N-(4-{1-[(pyridin-4-yl)carbonyl]piperidin-4-yl}butyl)-1H- 0.0097 0.0044 pyrrolo[3,2-c]pyridine-2-carboxamide N-[4-(1-{[6-(morpholin-4-yl)pyridin-3- 0.0647 0.0034 yl]carbonyl}piperidin-4-yl)butyl]-1H-pyrrolo[3,2- c]pyridine-2-carboxamide N-[4-(1-{[5-(propan-2-yl)pyridin-2-yl]carbonyl}piperidin-4- 0.163 0.0141 yl)butyl]-1H-pyrrolo[3,2-c]pyridine-2-carboxamide N-(4-{1-[(1H-indol-2-yl)carbonyl]piperidin-4-yl}butyl)- 0.125 0.0603 1H-pyrrolo[3,2-c]pyridine-2-carboxamide N-(4-{1-[(2-methyl-1,3-thiazol-4-yl)carbonyl]piperidin-4- 0.0695 0.025 yl}butyl)-1H-pyrrolo[3,2-c]pyridine-2-carboxamide N-(4-{1-[(1-acetylpiperidin-4-yl)carbonyl]piperidin-4- 0.134 0.0239 yl}butyl)-1H-pyrrolo[3,2-c]pyridine-2-carboxamide N-(4-{1-[(3-methoxyphenyl)carbonyl]piperidin-4- 0.0248 0.0038 yl}butyl)-1H-pyrrolo[3,2-c]pyridine-2-carboxamide N-[4-(1-{[4-(difluoromethoxy)phenyl]carbonyl}piperidin-4- 0.183 0.0314 yl)butyl]-1H-pyrrolo[3,2-c]pyridine-2-carboxamide N-[4-(1-{[4-(trifluoromethyl)phenyl]carbonyl}piperidin-4- 0.164 0.0381 yl)butyl]-1H-pyrrolo[3,2-c]pyridine-2-carboxamide N-(4-{1-[(3-ethoxyphenyl)carbonyl]piperidin-4-yl}butyl)- 0.0851 0.011 1H-pyrrolo[3,2-c]pyridine-2-carboxamide N-(4-{1-[(1H-indol-5-yl)carbonyl]piperidin-4-yl}butyl)- 0.0394 0.0135 1H-pyrrolo[3,2-c]pyridine-2-carboxamide N-(4-{1-[(3-fluoro-4-methoxyphenyl)carbonyl]piperidin-4- 0.0631 0.021 yl}butyl)-1H-pyrrolo[3,2-c]pyridine-2-carboxamide N-[4-(1-{[4-(trifluoromethoxy)phenyl]carbonyl}piperidin-4- 0.145 0.0127 yl)butyl]-1H-pyrrolo[3,2-c]pyridine-2-carboxamide N-(4-{1-[(3,4-dimethoxyphenyl)carbonyl]piperidin-4- 0.0686 0.003 yl}butyl)-1H-pyrrolo[3,2-c]pyridine-2-carboxamide N-[4-(1-{[4-(propan-2-yloxy)phenyl]carbonyl}piperidin-4- 0.0937 0.0131 yl)butyl]-1H-pyrrolo[3,2-c]pyridine-2-carboxamide N-(4-{1-[(3,5-dimethoxyphenyl)carbonyl]piperidin-4- 0.0741 0.0026 yl}butyl)-1H-pyrrolo[3,2-c]pyridine-2-carboxamide N-(4-{1-[(3-fluorophenyl)carbonyl]piperidin-4-yl}butyl)- 0.0164 0.0033 1H-pyrrolo[3,2-c]pyridine-2-carboxamide N-(4-{1-[(2-fluorophenyl)carbonyl]piperidin-4-yl}butyl)- 0.0075 0.0005 1H-pyrrolo[3,2-c]pyridine-2-carboxamide N-(4-{1-[(3-chlorophenyl)carbonyl]piperidin-4-yl}butyl)- 0.0217 0.0119 1H-pyrrolo[3,2-c]pyridine-2-carboxamide N-(4-{1-[(4-chlorophenyl)carbonyl]piperidin-4-yl}butyl)- 0.114 0.0657 1H-pyrrolo[3,2-c]pyridine-2-carboxamide N-(4-{1-[(2-fluoro-3-methylphenyl)carbonyl]piperidin-4- 0.0475 0.0069 yl}butyl)-1H-pyrrolo[3,2-c]pyridine-2-carboxamide N-(4-{1-[(2,6-difluorophenyl)carbonyl]piperidin-4- 0.0073 0.0014 yl}butyl)-1H-pyrrolo[3,2-c]pyridine-2-carboxamide N-(4-{1-[(3,4-difluorophenyl)carbonyl]piperidin-4- 0.056 0.0206 yl}butyl)-1H-pyrrolo[3,2-c]pyridine-2-carboxamide N-(4-{1-[(2,4-difluorophenyl)carbonyl]piperidin-4- 0.0393 0.0081 yl}butyl)-1H-pyrrolo[3,2-c]pyridine-2-carboxamide N-(4-{1-[(3,4-dichlorophenyl)carbonyl]piperidin-4- 0.093 0.058 yl}butyl)-1H-pyrrolo[3,2-c]pyridine-2-carboxamide N-(4-{1-[(1-benzothiophen-2-yl)carbonyl]piperidin-4- 0.124 0.0699 yl}butyl)-1H-pyrrolo[3,2-c]pyridine-2-carboxamide N-(4-{1-[(3,5-dichlorophenyl)carbonyl]piperidin-4- 0.0813 0.013 yl}butyl)-1H-pyrrolo[3,2-c]pyridine-2-carboxamide N-[4-(1-{[2-(trifluoromethoxy)phenyl]carbonyl}piperidin-4- 0.0205 0.0013 yl)butyl]-1H-pyrrolo[3,2-c]pyridine-2-carboxamide N-(4-{1-[(5-chloro-2-methoxyphenyl)carbonyl]piperidin-4- 0.0338 0.0033 yl}butyl)-1H-pyrrolo[3,2-c]pyridine-2-carboxamide N-(4-{1-[(2,6-dimethoxyphenyl)carbonyl]piperidin-4- 0.0215 0.0014 yl}butyl)-1H-pyrrolo[3,2-c]pyridine-2-carboxamide N-[4-(1-{[4-(trifluoromethyl)pyridin-3-yl]carbonyl}piperidin-4- 0.0398 0.0029 yl)butyl]-1H-pyrrolo[3,2-c]pyridine-2-carboxamide N-(4-{1-[(2,3-dimethoxyphenyl)carbonyl]piperidin-4- 0.0208 0.0019 yl}butyl)-1H-pyrrolo[3,2-c]pyridine-2-carboxamide N-(4-{1-[(2,5-dimethoxyphenyl)carbonyl]piperidin-4- 0.0155 0.0022 yl}butyl)-1H-pyrrolo[3,2-c]pyridine-2-carboxamide N-(4-{1-[(2,4-dimethoxyphenyl)carbonyl]piperidin-4- 0.0671 0.0033 yl}butyl)-1H-pyrrolo[3,2-c]pyridine-2-carboxamide N-(4-{1-[(2-chlorophenyl)carbonyl]piperidin-4-yl}butyl)- 0.0158 0.0015 1H-pyrrolo[3,2-c]pyridine-2-carboxamide N-(4-{1-[(2,3-dichlorophenyl)carbonyl]piperidin-4- 0.0312 0.0032 yl}butyl)-1H-pyrrolo[3,2-c]pyridine-2-carboxamide N-(4-{1-[(4-methoxyphenyl)carbonyl]piperidin-4- 0.0522 0.0803 yl}butyl)thieno[2,3-c]pyridine-2-carboxamide N-(4-{1-[(2,5-dichlorophenyl)carbonyl]piperidin-4- 0.0513 0.0061 yl}butyl)-1H-pyrrolo[3,2-c]pyridine-2-carboxamide N-(4-{1-[(1-methyl-1H-indol-2-yl)carbonyl]piperidin-4- 0.134 0.0238 yl}butyl)-1H-pyrrolo[3,2-c]pyridine-2-carboxamide N-[4-(1-{[5-(trifluoromethyl)pyridin-2- 0.137 0.0596 yl]carbonyl}piperidin-4-yl)butyl]-1H-pyrrolo[3,2- c]pyridine-2-carboxamide N-(4-{1-[(4-chloro-2-methoxyphenyl)carbonyl]piperidin-4- 0.0621 0.0061 yl}butyl)-1H-pyrrolo[3,2-c]pyridine-2-carboxamide N-(4-{1-[(pyridin-3-yl)carbonyl]piperidin-4-yl}butyl)-1H- 0.0986 0.0231 pyrrolo[3,2-c]pyridine-2-carboxamide N-(4-{1-[(2-methylpyridin-3-yl)carbonyl]piperidin-4- 0.0215 0.0017 yl}butyl)-1H-pyrrolo[3,2-c]pyridine-2-carboxamide N-(4-{1-[(5-methylpyrazin-2-yl)carbonyl]piperidin-4- 0.115 0.0238 yl}butyl)-1H-pyrrolo[3,2-c]pyridine-2-carboxamide N-(4-{1-[(pyridin-2-yl)carbonyl]piperidin-4-yl}butyl)-1H- 0.0306 0.0063 pyrrolo[3,2-c]pyridine-2-carboxamide N-(4-{1-[(dimethyl-1,3-thiazol-5-yl)carbonyl]piperidin-4- 0.0621 0.0057 yl}butyl)-1H-pyrrolo[3,2-c]pyridine-2-carboxamide N-[4-(1-{[2-(methylsulfanyl)pyridin-3- 0.0083 0.0007 yl]carbonyl}piperidin-4-yl)butyl]-1H-pyrrolo[3,2- c]pyridine-2-carboxamide N-(4-{1-[(2-ethoxypyridin-3-yl)carbonyl]piperidin-4- 0.0206 0.0006 yl}butyl)-1H-pyrrolo[3,2-c]pyridine-2-carboxamide N-(4-{1-[(5-chloro-2-methoxypyridin-3-yl)carbonyl]piperidin-4- 0.0303 0.0033 yl}butyl)-1H-pyrrolo[3,2-c]pyridine-2-carboxamide N-(4-{1-[(1-methyl-1H-imidazol-4-yl)carbonyl]piperidin-4- 0.0937 0.055 yl}butyl)-1H-pyrrolo[3,2-c]pyridine-2-carboxamide N-(4-{1-[(2-ethoxyphenyl)carbonyl]piperidin-4-yl}butyl)- 0.0305 0.0005 1H-pyrrolo[3,2-c]pyridine-2-carboxamide N-(4-{1-[(4-methyl-1,3-thiazol-5-yl)carbonyl]piperidin-4- 0.0054 0.001 yl}butyl)-1H-pyrrolo[3,2-c]pyridine-2-carboxamide N-(4-{1-[(1H-indol-6-yl)carbonyl]piperidin-4-yl}butyl)- 0.0529 0.0134 1H-pyrrolo[3,2-c]pyridine-2-carboxamide N-[4-(1-{[2-(trifluoromethyl)-1,3-thiazol-4- 0.0685 0.0222 yl]carbonyl}piperidin-4-yl)butyl]-1H-pyrrolo[3,2- c]pyridine-2-carboxamide N-[4-(1-{[6-(trifluoromethyl)pyridin-3- 0.278 0.0476 yl]carbonyl}piperidin-4-yl)butyl]-1H-pyrrolo[3,2- c]pyridine-2-carboxamide N-(4-{1-[(6-methylpyridin-3-yl)carbonyl]piperidin-4- 0.0651 0.0213 yl}butyl)-1H-pyrrolo[3,2-c]pyridine-2-carboxamide N-[4-(1-{[2-(trifluoromethyl)pyrimidin-5- 0.242 0.1-1 yl]carbonyl}piperidin-4-yl)butyl]-1H-pyrrolo[3,2- c]pyridine-2-carboxamide N-[4-(1-{[5-(methoxymethyl)pyridin-2- 0.0311 0.0142 yl]carbonyl}piperidin-4-yl)butyl]-1H-pyrrolo[3,2- c]pyridine-2-carboxamide N-(4-{1-[(5-fluoropyridin-2-yl)carbonyl]piperidin-4- 0.0572 0.014 yl}butyl)-1H-pyrrolo[3,2-c]pyridine-2-carboxamide N-(4-{1-[(5-fluoro-2-methylphenyl)carbonyl]piperidin-4- 0.0142 0.0023 yl}butyl)-1H-pyrrolo[3,2-c]pyridine-2-carboxamide N-(4-{1-[2-(2-methyl-1,3-thiazol-4-yl)acetyl]piperidin-4- 0.0494 0.0139 yl}butyl)-1H-pyrrolo[3,2-c]pyridine-2-carboxamide N-(4-{1-[(5-fluoro-1H-indol-2-yl)carbonyl]piperidin-4- 0.0971 0.1-1 yl}butyl)-1H-pyrrolo[3,2-c]pyridine-2-carboxamide N-(4-{1-[2-(1-methyl-1H-indol-3-yl)acetyl]piperidin-4- 0.0091 0.0112 yl}butyl)-1H-pyrrolo[3,2-c]pyridine-2-carboxamide N-[4-(1-{[4-(propan-2-yl)-1,3-oxazol-5- 0.0304 0.0053 yl]carbonyl}piperidin-4-yl)butyl]-1H-pyrrolo[3,2- c]pyridine-2-carboxamide N-(4-{1-[(2-phenyl-1,3-thiazol-4-yl)carbonyl]piperidin-4- 0.11 0.0725 yl}butyl)-1H-pyrrolo[3,2-c]pyridine-2-carboxamide N-(4-{1-[(3-fluoro-4-methylphenyl)carbonyl]piperidin-4- 0.0771 0.0224 yl}butyl)-1H-pyrrolo[3,2-c]pyridine-2-carboxamide N-(4-{1-[(3-fluoro-2-methylphenyl)carbonyl]piperidin-4- 0.0205 0.0031 yl}butyl)-1H-pyrrolo[3,2-c]pyridine-2-carboxamide N-(4-{1-[(1,3-benzothiazol-6-yl)carbonyl]piperidin-4- 0.0727 0.0126 yl}butyl)-1H-pyrrolo[3,2-c]pyridine-2-carboxamide N-(4-{1-[(2,3-difluorophenyl)carbonyl]piperidin-4- 0.0121 0.0034 yl}butyl)-1H-pyrrolo[3,2-c]pyridine-2-carboxamide N-{4-[1-({imidazo[1,2-a]pyridin-6-yl}carbonyl)piperidin-4- 0.0077 0.0138 yl]butyl}-1H-pyrrolo[3,2-c]pyridine-2-carboxamide N-(4-{1-[(furan-3-yl)carbonyl]piperidin-4-yl}butyl)-1H- 0.0091 0.0101 pyrrolo[3,2-c]pyridine-2-carboxamide N-[4-(1-benzoylpiperidin-4-yl)butyl]thieno[2,3- 0.0063 0.0012 c]pyridine-2-carboxamide N-[4-(1-{[2-(pyridin-3-yl)-1,3-thiazol-4- 0.0706 0.0853 yl]carbonyl}piperidin-4-yl)butyl]thieno[2,3-c]pyridine-2- carboxamide N-{4-[1-({1H-pyrrolo[3,2-c]pyridin-2- 0.0069 0.0137 yl}carbonyl)piperidin-4-yl]butyl}thieno[2,3-c]pyridine-2- carboxamide N-[4-(1-cyclohexanecarbonylpiperidin-4- 0.0779 0.0727 yl)butyl]thieno[2,3-c]pyridine-2-carboxamide N-[4-(1-{[4-(1H-pyrazol-1-yl)phenyl]carbonyl}piperidin-4- 0.0507 0.0136 yl)butyl]-1H-pyrrolo[3,2-c]pyridine-2-carboxamide N-(4-{1-[(4-fluorophenyl)carbonyl]piperidin-4- 0.0518 0.1-1 yl}butyl)thieno[2,3-c]pyridine-2-carboxamide N-[4-(1-{[4-(trifluoromethyl)phenyl]carbonyl}piperidin-4- 0.305 1 yl)butyl]thieno[2,3-c]pyridine-2-carboxamide N-(4-{1-[(2H-1,3-benzodioxol-5-yl)carbonyl]piperidin-4- 0.0211 0.1-1 yl}butyl)thieno[2,3-c]pyridine-2-carboxamide N-(4-{1-[(2-methoxyphenyl)carbonyl]piperidin-4- 0.0077 0.0033 yl}butyl)thieno[2,3-c]pyridine-2-carboxamide N-[4-(1-{[6-(morpholin-4-yl)pyridin-3-yl]carbonyl}piperidin-4- 0.0301 0.0131 yl)butyl]thieno[2,3-c]pyridine-2-carboxamide N-(4-{1-[(2-methyl-1,3-thiazol-4-yl)carbonyl]piperidin-4- 0.0224 0.1-1 yl}butyl)thieno[2,3-c]pyridine-2-carboxamide N-(4-{1-[(2,5-dichlorophenyl)carbonyl]piperidin-4- 0.016 0.0071 yl}butyl)thieno[2,3-c]pyridine-2-carboxamide N-[4-(1-{[6-(propan-2-yl)pyridin-3-yl]carbonyl}piperidin-4- 0.138 0.1-1 yl)butyl]thieno[2,3-c]pyridine-2-carboxamide N-(4-{1-[(1H-indol-2-yl)carbonyl]piperidin-4- 0.0335 0.1-1 yl}butyl)thieno[2,3-c]pyridine-2-carboxamide N-(4-{1-[(3-methoxyphenyl)carbonyl]piperidin-4- 0.0261 0.011 yl}butyl)thieno[2,3-c]pyridine-2-carboxamide N-[4-(1-{[4-(difluoromethoxy)phenyl]carbonyl}piperidin-4- 0.0774 0.1-1 yl)butyl]thieno[2,3-c]pyridine-2-carboxamide N-(4-{1-[(3-ethoxyphenyl)carbonyl]piperidin-4- 0.0391 0.0765 yl}butyl)thieno[2,3-c]pyridine-2-carboxamide N-(4-{1-[(1H-indol-5-yl)carbonyl]piperidin-4- 0.0427 0.0711 yl}butyl)thieno[2,3-c]pyridine-2-carboxamide N-(4-{1-[(3-fluoro-4-methoxyphenyl)carbonyl]piperidin-4- 0.0714 0.1-1 yl}butyl)thieno[2,3-c]pyridine-2-carboxamide N-(4-{1-[(2,5-difluorophenyl)carbonyl]piperidin-4- 0.0076 0.0016 yl}butyl)thieno[2,3-c]pyridine-2-carboxamide N-[4-(1-{[4-(trifluoromethoxy)phenyl]carbonyl}piperidin-4- 0.166 0.1-1 yl)butyl]thieno[2,3-c]pyridine-2-carboxamide N-(4-{1-[(3,4-dimethoxyphenyl)carbonyl]piperidin-4- 0.0326 0.0069 yl}butyl)thieno[2,3-c]pyridine-2-carboxamide N-[4-(1-{[4-(propan-2-yloxy)phenyl]carbonyl}piperidin-4- 0.04 0.1-1 yl)butyl]thieno[2,3-c]pyridine-2-carboxamide N-(4-{1-[(3,5-dimethoxyphenyl)carbonyl]piperidin-4- 0.0571 0.0202 yl}butyl)thieno[2,3-c]pyridine-2-carboxamide N-(4-{1-[(3-fluorophenyl)carbonyl]piperidin-4- 0.0077 0.0074 yl}butyl)thieno[2,3-c]pyridine-2-carboxamide N-(4-{1-[(2-fluorophenyl)carbonyl]piperidin-4- 0.0088 0.0006 yl}butyl)thieno[2,3-c]pyridine-2-carboxamide N-(4-{1-[(3-chlorophenyl)carbonyl]piperidin-4- 0.0334 0.0455 yl}butyl)thieno[2,3-c]pyridine-2-carboxamide N-(4-{1-[(4-chlorophenyl)carbonyl]piperidin-4- 0.0228 1-10 yl}butyl)thieno[2,3-c]pyridine-2-carboxamide N-(4-{1-[(1-methyl-1H-imidazol-2-yl)carbonyl]piperidin-4- 0.0765 0.0236 yl}butyl)-1H-pyrrolo[3,2-c]pyridine-2-carboxamide N-(4-{1-[(2-fluoro-3-methylphenyl)carbonyl]piperidin-4- 0.0212 0.0126 yl}butyl)thieno[2,3-c]pyridine-2-carboxamide N-(4-{1-[(2,6-difluorophenyl)carbonyl]piperidin-4- 0.0043 0.0008 yl}butyl)thieno[2,3-c]pyridine-2-carboxamide N-(4-{1-[(3,4-difluorophenyl)carbonyl]piperidin-4- 0.0229 0.1-1 yl}butyl)thieno[2,3-c]pyridine-2-carboxamide N-(4-{1-[(2,4-difluorophenyl)carbonyl]piperidin-4- 0.0128 0.0135 yl}butyl)thieno[2,3-c]pyridine-2-carboxamide N-(4-{1-[(2,6-dimethoxyphenyl)carbonyl]piperidin-4- 0.0056 0.0012 yl}butyl)thieno[2,3-c]pyridine-2-carboxamide N-(4-{1-[(3,4-dichlorophenyl)carbonyl]piperidin-4- 0.0345 0.1-1 yl}butyl)thieno[2,3-c]pyridine-2-carboxamide N-(4-{1-[(1-benzothiophen-2-yl)carbonyl]piperidin-4- 0.0177 0.1-1 yl}butyl)thieno[2,3-c]pyridine-2-carboxamide N-(4-{1-[(3,5-dichlorophenyl)carbonyl]piperidin-4- 0.03 0.0513 yl}butyl)thieno[2,3-c]pyridine-2-carboxamide N-[4-(1-{[2- 0.0104 0.0031 (trifluoromethoxy)phenyl]carbonyl}piperidin-4- yl)butyl]thieno[2,3-c]pyridine-2-carboxamide N-(4-{1-[(2-ethoxyphenyl)carbonyl]piperidin-4- 0.004 0.0006 yl}butyl)thieno[2,3-c]pyridine-2-carboxamide N-(4-{1-[(5-chloro-2-methoxyphenyl)carbonyl]piperidin-4- 0.0141 0.0033 yl}butyl)thieno[2,3-c]pyridine-2-carboxamide N-(4-{1-[(4-chloro-2-methoxyphenyl)carbonyl]piperidin-4- 0.0155 0.013 yl}butyl)thieno[2,3-c]pyridine-2-carboxamide N-(4-{1-[(2,5-dimethoxyphenyl)carbonyl]piperidin-4- 0.0055 0.0029 yl}butyl)thieno[2,3-c]pyridine-2-carboxamide N-[4-(1-{[6-(trifluoromethyl)pyridin-3- 0.0903 0.414 yl]carbonyl}piperidin-4-yl)butyl]thieno[2,3-c]pyridine-2- carboxamide N-(4-{1-[(2,4-dimethoxyphenyl)carbonyl]piperidin-4- 0.0157 0.0069 yl}butyl)thieno[2,3-c]pyridine-2-carboxamide N-(4-{1-[(2-chlorophenyl)carbonyl]piperidin-4- 0.0083 0.0017 yl}butyl)thieno[2,3-c]pyridine-2-carboxamide N-(4-{1-[(2,3-dichlorophenyl)carbonyl]piperidin-4- 0.0201 0.0067 yl}butyl)thieno[2,3-c]pyridine-2-carboxamide N-(4-{1-[(2,4-dichlorophenyl)carbonyl]piperidin-4- 0.041 0.0861 yl}butyl)thieno[2,3-c]pyridine-2-carboxamide N-(4-{1-[(1-methyl-1H-indol-2-yl)carbonyl]piperidin-4- 0.065 0.1-1 yl}butyl)thieno[2,3-c]pyridine-2-carboxamide N-(4-{1-[(2,4-dichlorophenyl)carbonyl]piperidin-4- 0.07 0.012 yl}butyl)-1H-pyrrolo[3,2-c]pyridine-2-carboxamide N-[4-(1-{[4-(trifluoromethyl)pyridin-3-yl]carbonyl}piperidin-4- 0.0099 0.0069 yl)butyl]thieno[2,3-c]pyridine-2-carboxamide N-(4-{1-[(pyridin-3-yl)carbonyl]piperidin-4- 0.0111 0.0274 yl}butyl)thieno[2,3-c]pyridine-2-carboxamide N-(4-{1-[(5-methylpyrazin-2-yl)carbonyl]piperidin-4- 0.0685 0.1-1 yl}butyl)thieno[2,3-c]pyridine-2-carboxamide N-(4-{1-[(dimethyl-1,3-thiazol-5-yl)carbonyl]piperidin-4- 0.0355 0.013 yl}butyl)thieno[2,3-c]pyridine-2-carboxamide N-[4-(1-{[2-(methylsulfanyl)pyridin-3-yl]carbonyl}piperidin-4- 0.0101 0.0014 yl)butyl]thieno[2,3-c]pyridine-2-carboxamide N-(4-{1-[(2-ethoxypyridin-3-yl)carbonyl]piperidin-4- 0.0056 0.0015 yl}butyl)thieno[2,3-c]pyridine-2-carboxamide N-(4-{1-[(5-chloro-2-methoxypyridin-3-yl)carbonyl]piperidin-4- 0.017 0.0071 yl}butyl)thieno[2,3-c]pyridine-2-carboxamide N-(4-{1-[(4-methyl-1,3-thiazol-5-yl)carbonyl]piperidin-4- 0.0053 0.0008 yl}butyl)thieno[2,3-c]pyridine-2-carboxamide N-[4-(1-{[4-(1H-pyrazol-1-yl)phenyl]carbonyl}piperidin-4- 0.0481 0.1-1 yl)butyl]thieno[2,3-c]pyridine-2-carboxamide N-(4-{1-[(1H-indol-6-yl)carbonyl]piperidin-4- 0.0361 0.0703 yl}butyl)thieno[2,3-c]pyridine-2-carboxamide N-[4-(1-{[2-(trifluoromethyl)-1,3-thiazol-4- 0.094 0.1-1 yl]carbonyl}piperidin-4-yl)butyl]thieno[2,3-c]pyridine-2- carboxamide N-(4-{1-[(6-methylpyridin-3-yl)carbonyl]piperidin-4- 0.0697 0.1-1 yl}butyl)thieno[2,3-c]pyridine-2-carboxamide N-[4-(1-{[5-(trifluoromethyl)pyridin-2- 0.0918 0.1-1 yl]carbonyl}piperidin-4-yl)butyl]thieno[2,3-c]pyridine-2- carboxamide N-[4-(1-{[2-(trifluoromethyl)pyrimidin-5- 0.158 0.1-1 yl]carbonyl}piperidin-4-yl)butyl]thieno[2,3-c]pyridine-2- carboxamide N-[4-(1-{[5-(methoxymethyl)pyridin-2- 0.0183 0.0302 yl]carbonyl}piperidin-4-yl)butyl]thieno[2,3-c]pyridine-2- carboxamide N-(4-{1-[(5-fluoropyridin-2-yl)carbonyl]piperidin-4- 0.0265 0.1-1 yl}butyl)thieno[2,3-c]pyridine-2-carboxamide N-(4-{1-[2-(2-methyl-1,3-thiazol-4-yl)acetyl]piperidin-4- 0.0135 0.0282 yl}butyl)thieno[2,3-c]pyridine-2-carboxamide N-[4-(1-{[5-(propan-2-yl)pyridin-2-yl]carbonyl}piperidin-4- 0.0898 0.1-1 yl)butyl]thieno[2,3-c]pyridine-2-carboxamide N-(4-{1-[(5-fluoro-1H-indol-2-yl)carbonyl]piperidin-4- 0.0304 1-10 yl}butyl)thieno[2,3-c]pyridine-2-carboxamide N-(4-{1-[2-(1-methyl-1H-indol-3-yl)acetyl]piperidin-4- 0.0116 0.024 yl}butyl)thieno[2,3-c]pyridine-2-carboxamide N-[4-(1-{[4-(propan-2-yl)-1,3-oxazol-5-yl]carbonyl}piperidin-4- 0.0074 0.0076 yl)butyl]thieno[2,3-c]pyridine-2-carboxamide N-(4-{1-[(2-phenyl-1,3-thiazol-4-yl)carbonyl]piperidin-4- 0.0131 0.0762 yl}butyl)thieno[2,3-c]pyridine-2-carboxamide N-(4-{1-[(3-fluoro-4-methylphenyl)carbonyl]piperidin-4- 0.0417 0.1-1 yl}butyl)thieno[2,3-c]pyridine-2-carboxamide N-(4-{1-[(5-fluoro-2-methylphenyl)carbonyl]piperidin-4- 0.0045 0.0018 yl}butyl)thieno[2,3-c]pyridine-2-carboxamide N-(4-{1-[(1,3-benzothiazol-6-yl)carbonyl]piperidin-4- 0.0323 0.0354 yl}butyl)thieno[2,3-c]pyridine-2-carboxamide N-(4-{1-[(2,3-difluorophenyl)carbonyl]piperidin-4- 0.0068 0.0045 yl}butyl)thieno[2,3-c]pyridine-2-carboxamide N-{4-[1-({thieno[2,3-c]pyridin-2-yl}carbonyl)piperidin-4- 0.0152 0.1-1 yl]butyl}thieno[2,3-c]pyridine-2-carboxamide N-(4-{1-[(furan-3-yl)carbonyl]piperidin-4- 0.004 0.006 yl}butyl)thieno[2,3-c]pyridine-2-carboxamide N-[4-(1-benzoylpiperidin-4-yl)butyl]imidazo[1,2- 0.0055 0.0057 a]pyridine-6-carboxamide N-[4-(1-{[2-(pyridin-3-yl)-1,3-thiazol-4- 0.0611 0.067 yl]carbonyl}piperidin-4-yl)butyl]imidazo[1,2-a]pyridine- 6-carboxamide N-(4-{1-[(2,3-dimethoxyphenyl)carbonyl]piperidin-4- 0.0169 0.0056 yl}butyl)thieno[2,3-c]pyridine-2-carboxamide N-{4-[1-({1H-pyrrolo[3,2-c]pyridin-2-yl}carbonyl)piperidin-4- 0.0086 0.0131 yl]butyl}imidazo[1,2-a]pyridine-6-carboxamide N-[4-(1-{[4-(trifluoromethyl)phenyl]carbonyl}piperidin-4- 0.152 0.1-1 yl)butyl]imidazo[1,2-a]pyridine-6-carboxamide N-[4-(1-cyclohexanecarbonylpiperidin-4- 0.0181 0.0009 yl)butyl]imidazo[1,2-a]pyridine-6-carboxamide N-(4-{1-[(3,4-difluorophenyl)carbonyl]piperidin-4- 0.019 0.0662 yl}butyl)imidazo[1,2-a]pyridine-6-carboxamide N-(4-{1-[(4-methoxyphenyl)carbonyl]piperidin-4- 0.0232 0.0576 yl}butyl)imidazo[1,2-a]pyridine-6-carboxamide N-(4-{1-[(4-fluorophenyl)carbonyl]piperidin-4- 0.012 0.0262 yl}butyl)imidazo[1,2-a]pyridine-6-carboxamide N-(4-{1-[(2H-1,3-benzodioxol-5-yl)carbonyl]piperidin-4- 0.0213 0.0292 yl}butyl)imidazo[1,2-a]pyridine-6-carboxamide N-[4-(1-{[6-(morpholin-4-yl)pyridin-3-yl]carbonyl}piperidin-4- 0.0129 0.0059 yl)butyl]imidazo[1,2-a]pyridine-6-carboxamide N-(4-{1-[(2-methyl-1,3-thiazol-4-yl)carbonyl]piperidin-4- 0.0314 0.0611 yl}butyl)imidazo[1,2-a]pyridine-6-carboxamide N-[4-(1-{[5-(propan-2-yl)pyridin-2-yl]carbonyl}piperidin-4- 0.0567 0.0529 yl)butyl]imidazo[1,2-a]pyridine-6-carboxamide N-[4-(1-{[6-(propan-2-yl)pyridin-3-yl]carbonyl}piperidin-4- 0.0387 0.0261 yl)butyl]imidazo[1,2-a]pyridine-6-carboxamide N-(4-{1-[(1H-indol-2-yl)carbonyl]piperidin-4- 0.0616 0.1-1 yl}butyl)imidazo[1,2-a]pyridine-6-carboxamide N-(4-{1-[(1-acetylpiperidin-4-yl)carbonyl]piperidin-4- 0.0396 0.0278 yl}butyl)imidazo[1,2-a]pyridine-6-carboxamide N-(4-{1-[(3-methoxyphenyl)carbonyl]piperidin-4- 0.0212 0.0066 yl}butyl)imidazo[1,2-a]pyridine-6-carboxamide N-[4-(1-{[4- 0.0427 0.101 (difluoromethoxy)phenyl]carbonyl}piperidin-4- yl)butyl]imidazo[1,2-a]pyridine-6-carboxamide N-(4-{1-[(3-ethoxyphenyl)carbonyl]piperidin-4- 0.0102 0.0132 yl}butyl)imidazo[1,2-a]pyridine-6-carboxamide N-(4-{1-[(1H-indol-5-yl)carbonyl]piperidin-4- 0.0195 0.0185 yl}butyl)imidazo[1,2-a]pyridine-6-carboxamide N-(4-{1-[(3-fluoro-4-methoxyphenyl)carbonyl]piperidin-4- 0.0202 0.0652 yl}butyl)imidazo[1,2-a]pyridine-6-carboxamide N-[4-(1-{[4- 0.091 0.1-1 (trifluoromethoxy)phenyl]carbonyl}piperidin-4- yl)butyl]imidazo[1,2-a]pyridine-6-carboxamide N-(4-{1-[(3,4-dimethoxyphenyl)carbonyl]piperidin-4- 0.0385 0.0029 yl}butyl)imidazo[1,2-a]pyridine-6-carboxamide N-[4-(1-{[4-(propan-2-yloxy)phenyl]carbonyl}piperidin-4- 0.0552 0.0209 yl)butyl]imidazo[1,2-a]pyridine-6-carboxamide N-(4-{1-[(3-fluorophenyl)carbonyl]piperidin-4- 0.0092 0.0103 yl}butyl)imidazo[1,2-a]pyridine-6-carboxamide N-(3-(1-benzoylpiperidin-4-yl)butyl)-1H-pyrrolo[3,2- 0.028 0.0175 c]pyridine-2-carboxamide N-(4-{1-[(2-fluorophenyl)carbonyl]piperidin-4- 0.0038 0.0005 yl}butyl)imidazo[1,2-a]pyridine-6-carboxamide N-(4-{1-[(3-chlorophenyl)carbonyl]piperidin-4- 0.0171 0.0223 yl}butyl)imidazo[1,2-a]pyridine-6-carboxamide N-(4-{1-[(4-chlorophenyl)carbonyl]piperidin-4- 0.0846 0.1-1 yl}butyl)imidazo[1,2-a]pyridine-6-carboxamide N-(4-{1-[(3-fluoro-2-methylphenyl)carbonyl]piperidin-4- 0.0068 0.0032 yl}butyl)thieno[2,3-c]pyridine-2-carboxamide N-(4-{1-[(2-fluoro-3-methylphenyl)carbonyl]piperidin-4- 0.0226 0.0127 yl}butyl)imidazo[1,2-a]pyridine-6-carboxamide N-(4-{1-[(2,6-difluorophenyl)carbonyl]piperidin-4- 0.0047 0.0012 yl}butyl)imidazo[1,2-a]pyridine-6-carboxamide N-(4-{1-[(2,4-difluorophenyl)carbonyl]piperidin-4- 0.0071 0.0256 yl}butyl)imidazo[1,2-a]pyridine-6-carboxamide N-(4-{1-[(3,4-dichlorophenyl)carbonyl]piperidin-4- 0.049 0.1-1 yl}butyl)imidazo[1,2-a]pyridine-6-carboxamide N-(4-{1-[(2,3-dimethoxyphenyl)carbonyl]piperidin-4- 0.0191 0.0029 yl}butyl)imidazo[1,2-a]pyridine-6-carboxamide N-[4-(1-{[6-(propan-2-yl)pyridin-3-yl]carbonyl}piperidin-4- 0.0867 0.0132 yl)butyl]-1H-pyrrolo[3,2-c]pyridine-2-carboxamide N-(4-{1-[(1-benzothiophen-2-yl)carbonyl]piperidin-4- 0.0258 0.0718 yl}butyl)imidazo[1,2-a]pyridine-6-carboxamide N-(4-{1-[(3,5-dichlorophenyl)carbonyl]piperidin-4- 0.0616 0.0329 yl}butyl)imidazo[1,2-a]pyridine-6-carboxamide N-[4-(1-{[2-(trifluoromethoxy)phenyl]carbonyl}piperidin-4- 0.0025 0.0019 yl)butyl]imidazo[1,2-a]pyridine-6-carboxamide N-(4-{1-[(2-ethoxyphenyl)carbonyl]piperidin-4- 0.0052 0.0007 yl}butyl)imidazo[1,2-a]pyridine-6-carboxamide N-(4-{1-[(5-chloro-2-methoxyphenyl)carbonyl]piperidin-4- 0.0105 0.0031 yl}butyl)imidazo[1,2-a]pyridine-6-carboxamide N-(4-{1-[(4-chloro-2-methoxyphenyl)carbonyl]piperidin-4- 0.0806 0.027 yl}butyl)imidazo[1,2-a]pyridine-6-carboxamide N-(4-{1-[(2,6-dimethoxyphenyl)carbonyl]piperidin-4- 0.0286 0.001 yl}butyl)imidazo[1,2-a]pyridine-6-carboxamide N-(4-{1-[(2,5-dimethoxyphenyl)carbonyl]piperidin-4- 0.0429 0.0019 yl}butyl)imidazo[1,2-a]pyridine-6-carboxamide N-(4-{1-[(2,4-dimethoxyphenyl)carbonyl]piperidin-4- 0.0222 0.0033 yl}butyl)imidazo[1,2-a]pyridine-6-carboxamide N-(4-{1-[(2-chlorophenyl)carbonyl]piperidin-4- 0.005 0.0015 yl}butyl)imidazo[1,2-a]pyridine-6-carboxamide N-(4-{1-[(2,4-dichlorophenyl)carbonyl]piperidin-4- 0.0357 0.0144 yl}butyl)imidazo[1,2-a]pyridine-6-carboxamide N-(4-{1-[(3,5-dimethoxyphenyl)carbonyl]piperidin-4- 0.0225 0.0028 yl}butyl)imidazo[1,2-a]pyridine-6-carboxamide N-(4-{1-[(1-methyl-1H-indol-2-yl)carbonyl]piperidin-4- 0.124 0.0551 yl}butyl)imidazo[1,2-a]pyridine-6-carboxamide N-[4-(1-{[4-(trifluoromethyl)pyridin-3-yl]carbonyl}piperidin-4- 0.0156 0.0038 yl)butyl]imidazo[1,2-a]pyridine-6-carboxamide N-(4-{1-[(pyridin-3-yl)carbonyl]piperidin-4- 0.0127 0.0274 yl}butyl)imidazo[1,2-a]pyridine-6-carboxamide N-(4-{1-[(3-fluoro-4-methylphenyl)carbonyl]piperidin-4- 0.0394 yl}butyl)imidazo[1,2-a]pyridine-6-carboxamide N-(4-{1-[(2-methylpyridin-3-yl)carbonyl]piperidin-4- 0.0098 0.0018 yl}butyl)imidazo[1,2-a]pyridine-6-carboxamide N-[4-(1-{[6-(trifluoromethyl)pyridin-3-yl]carbonyl}piperidin-4- 0.0919 0.093 yl)butyl]imidazo[1,2-a]pyridine-6-carboxamide N-(4-{1-[(5-methylpyrazin-2-yl)carbonyl]piperidin-4- 0.0109 0.0667 yl}butyl)imidazo[1,2-a]pyridine-6-carboxamide N-(4-{1-[(pyridin-2-yl)carbonyl]piperidin-4- 0.0364 0.0135 yl}butyl)imidazo[1,2-a]pyridine-6-carboxamide N-(4-{1-[(dimethyl-1,3-thiazol-5-yl)carbonyl]piperidin-4- 0.0241 0.0066 yl}butyl)imidazo[1,2-a]pyridine-6-carboxamide N-[4-(1-{[2-(methylsulfanyl)pyridin-3-yl]carbonyl}piperidin-4- 0.0055 0.0007 yl)butyl]imidazo[1,2-a]pyridine-6-carboxamide N-(4-{1-[(2-ethoxypyridin-3-yl)carbonyl]piperidin-4- 0.0092 0.0005 yl}butyl)imidazo[1,2-a]pyridine-6-carboxamide N-(4-{1-[(5-chloro-2-methoxypyridin-3-yl)carbonyl]piperidin-4- 0.0123 0.0033 yl}butyl)imidazo[1,2-a]pyridine-6-carboxamide N-(4-{1-[(2,5-dichlorophenyl)carbonyl]piperidin-4- 0.0102 0.0055 yl}butyl)imidazo[1,2-a]pyridine-6-carboxamide N-(4-{1-[(1-methyl-1H-imidazol-4-yl)carbonyl]piperidin-4- 0.0567 0.107 yl}butyl)imidazo[1,2-a]pyridine-6-carboxamide N-(4-{1-[(4-methyl-1,3-thiazol-5-yl)carbonyl]piperidin-4- 0.0029 0.0008 yl}butyl)imidazo[1,2-a]pyridine-6-carboxamide N-[4-(1-{[4-(1H-pyrazol-1-yl)phenyl]carbonyl}piperidin-4- 0.0307 0.0671 yl)butyl]imidazo[1,2-a]pyridine-6-carboxamide N-(4-{1-[(2,5-difluorophenyl)carbonyl]piperidin-4- 0.005 0.005 yl}butyl)imidazo[1,2-a]pyridine-6-carboxamide N-(4-{1-[(1H-indol-6-yl)carbonyl]piperidin-4- 0.0298 0.0149 yl}butyl)imidazo[1,2-a]pyridine-6-carboxamide N-[4-(1-{[2-(trifluoromethyl)-1,3-thiazol-4-yl]carbonyl}piperidin-4- 0.0743 0.074 yl)butyl]imidazo[1,2-a]pyridine-6-carboxamide N-(4-{1-[(6-methylpyridin-3-yl)carbonyl]piperidin-4- 0.0238 0.0736 yl}butyl)imidazo[1,2-a]pyridine-6-carboxamide N-[4-(1-{[5-(trifluoromethyl)pyridin-2-yl]carbonyl}piperidin-4- 0.0823 yl)butyl]imidazo[1,2-a]pyridine-6-carboxamide N-[4-(1-{[5-(methoxymethyl)pyridin-2-yl]carbonyl}piperidin-4- 0.0574 0.0671 yl)butyl]imidazo[1,2-a]pyridine-6-carboxamide N-(4-{1-[(5-fluoropyridin-2-yl)carbonyl]piperidin-4- 0.074 0.0679 yl}butyl)imidazo[1,2-a]pyridine-6-carboxamide N-(4-{1-[2-(2-methyl-1,3-thiazol-4-yl)acetyl]piperidin-4- 0.0189 0.028 yl}butyl)imidazo[1,2-a]pyridine-6-carboxamide N-(4-{1-[(5-fluoro-1H-indol-2-yl)carbonyl]piperidin-4- 0.0713 yl}butyl)imidazo[1,2-a]pyridine-6-carboxamide N-(4-{1-[2-(1-methyl-1H-indol-3-yl)acetyl]piperidin-4- 0.0295 0.0213 yl}butyl)imidazo[1,2-a]pyridine-6-carboxamide N-[4-(1-{[4-(propan-2-yl)-1,3-oxazol-5-yl]carbonyl}piperidin-4- 0.0275 0.0082 yl)butyl]imidazo[1,2-a]pyridine-6-carboxamide N-(4-{1-[(2-phenyl-1,3-thiazol-4-yl)carbonyl]piperidin-4- 0.0523 yl}butyl)imidazo[1,2-a]pyridine-6-carboxamide N-(3-(1-benzoylpiperidin-4-yl)propyl)-1H-pyrrolo[3,2- 0.126 0.4316 c]pyridine-2-carboxamide N-(4-{1-[(3-fluoro-2-methylphenyl)carbonyl]piperidin-4- 0.0131 0.0035 yl}butyl)imidazo[1,2-a]pyridine-6-carboxamide N-(4-{1-[(4-fluoro-3-methylbenzene)sulfonyl]piperidin-4- 0.0696 0.0147 yl}butyl)-1H-pyrrolo[3,2-c]pyridine-2-carboxamide N-(4-{1-[(1,3-benzothiazol-6-yl)carbonyl]piperidin-4- 0.0237 0.0393 yl}butyl)imidazo[1,2-a]pyridine-6-carboxamide N-(4-{1-[(2,3-difluorophenyl)carbonyl]piperidin-4- 0.0079 0.0101 yl}butyl)imidazo[1,2-a]pyridine-6-carboxamide N-{4-[1-({imidazo[1,2-a]pyridin-6-yl}carbonyl)piperidin-4- 0.0085 yl]butyl}imidazo[1,2-a]pyridine-6-carboxamide N-(4-{1-[(furan-3-yl)carbonyl]piperidin-4- 0.0062 0.0256 yl}butyl)imidazo[1,2-a]pyridine-6-carboxamide N-(4-{1-[(3,4-dimethoxybenzene)sulfonyl]piperidin-4- 0.0276 0.0032 yl}butyl)-1H-pyrrolo[3,2-c]pyridine-2-carboxamide N-(4-{1-[(2-fluorobenzene)sulfonyl]piperidin-4-yl}butyl)- 0.0076 0.0063 1H-pyrrolo[3,2-c]pyridine-2-carboxamide N-{4-[1-(benzenesulfonyl)piperidin-4-yl]butyl}-1H- 0.0249 0.0067 pyrrolo[3,2-c]pyridine-2-carboxamide N-{4-[1-(5-methyl-1,2-oxazole-4-sulfonyl)piperidin-4- 0.0367 yl]butyl}-1H-pyrrolo[3,2-c]pyridine-2-carboxamide N-{4-[1-(1-methyl-1H-pyrazole-3-sulfonyl)piperidin-4- 0.0495 0.0068 yl]butyl}-1H-pyrrolo[3,2-c]pyridine-2-carboxamide N-{4-[1-(pyridine-3-sulfonyl)piperidin-4-yl]butyl}-1H- 0.0161 0.0139 pyrrolo[3,2-c]pyridine-2-carboxamide N-(4-{1-[(5-fluoro-2-methylphenyl)carbonyl]piperidin-4- 0.0109 0.0039 yl}butyl)imidazo[1,2-a]pyridine-6-carboxamide N-(4-{1-[(2,5-dimethoxybenzene)sulfonyl]piperidin-4- 0.0284 0.0018 yl}butyl)-1H-pyrrolo[3,2-c]pyridine-2-carboxamide N-(4-{1-[(4-cyanobenzene)sulfonyl]piperidin-4-yl}butyl)- 0.0496 0.0127 1H-pyrrolo[3,2-c]pyridine-2-carboxamide N-(4-{1-[(4-fluorobenzene)sulfonyl]piperidin-4-yl}butyl)- 0.0489 0.0176 1H-pyrrolo[3,2-c]pyridine-2-carboxamide N-(4-{1-[(2-methylbenzene)sulfonyl]piperidin-4- 0.036 0.0067 yl}butyl)-1H-pyrrolo[3,2-c]pyridine-2-carboxamide N-(4-{1-[(4-chlorobenzene)sulfonyl]piperidin-4- 0.0499 0.0275 yl}butyl)-1H-pyrrolo[3,2-c]pyridine-2-carboxamide N-(4-{1-[(4-methoxybenzene)sulfonyl]piperidin-4- 0.0338 0.0071 yl}butyl)-1H-pyrrolo[3,2-c]pyridine-2-carboxamide N-[4-(1-{[4-(trifluoromethyl)benzene]sulfonyl}piperidin-4- 0.0748 0.0233 yl)butyl]-1H-pyrrolo[3,2-c]pyridine-2-carboxamide N-[4-(1-{[4-(trifluoromethoxy)benzene]sulfonyl}piperidin-4- 0.076 0.0272 yl)butyl]-1H-pyrrolo[3,2-c]pyridine-2-carboxamide N-[4-(1-{[4-(propan-2-yloxy)benzene]sulfonyl}piperidin-4- 0.0193 0.0019 yl)butyl]-1H-pyrrolo[3,2-c]pyridine-2-carboxamide N-(4-{1-[(4-methylbenzene)sulfonyl]piperidin-4- 0.0302 0.0099 yl}butyl)-1H-pyrrolo[3,2-c]pyridine-2-carboxamide N-[4-(1-{[2-(trifluoromethyl)benzene]sulfonyl}piperidin-4- 0.0245 0.005 yl)butyl]-1H-pyrrolo[3,2-c]pyridine-2-carboxamide N-(3-((1-(2-fluorobenzoyl)piperidin-4-yl)oxy)propyl)-1H- 0.035 0.1771 pyrrolo[3,2-c]pyridine-2-carboxamide N-[4-(1-{[2-(trifluoromethoxy)benzene]sulfonyl}piperidin-4- 0.0226 0.0033 yl)butyl]-1H-pyrrolo[3,2-c]pyridine-2-carboxamide N-(4-{1-[(3-cyanobenzene)sulfonyl]piperidin-4-yl}butyl)- 0.015 0.0276 1H-pyrrolo[3,2-c]pyridine-2-carboxamide N-(4-{1-[(4-fluoro-2-methylbenzene)sulfonyl]piperidin-4- 0.0152 0.0076 yl}butyl)-1H-pyrrolo[3,2-c]pyridine-2-carboxamide N-(4-{1-[(3-methoxybenzene)sulfonyl]piperidin-4- 0.0353 0.0107 yl}butyl)-1H-pyrrolo[3,2-c]pyridine-2-carboxamide N-(4-{1-[(3-chlorobenzene)sulfonyl]piperidin-4- 0.0388 0.0277 yl}butyl)-1H-pyrrolo[3,2-c]pyridine-2-carboxamide N-[4-(1-{[3-(trifluoromethyl)benzene]sulfonyl}piperidin-4- 0.0769 0.0623 yl)butyl]-1H-pyrrolo[3,2-c]pyridine-2-carboxamide N-[4-(1-{[3-(trifluoromethoxy)benzene]sulfonyl}piperidin-4- 0.0778 0.0187 yl)butyl]-1H-pyrrolo[3,2-c]pyridine-2-carboxamide N-(4-{1-[(3-fluorobenzene)sulfonyl]piperidin-4-yl}butyl)- 0.0217 0.0129 1H-pyrrolo[3,2-c]pyridine-2-carboxamide N-(4-{1-[(2,5-difluorobenzene)sulfonyl]piperidin-4- 0.0111 0.0058 yl}butyl)-1H-pyrrolo[3,2-c]pyridine-2-carboxamide N-(4-{1-[(2-fluoro-5-methylbenzene)sulfonyl]piperidin-4- 0.0268 0.0067 yl}butyl)-1H-pyrrolo[3,2-c]pyridine-2-carboxamide N-(4-{1-[(2,4-dimethoxybenzene)sulfonyl]piperidin-4- 0.0191 0.0017 yl}butyl)-1H-pyrrolo[3,2-c]pyridine-2-carboxamide N-(4-{1-[(3-fluoro-4-methylbenzene)sulfonyl]piperidin-4- 0.0307 0.0156 yl}butyl)-1H-pyrrolo[3,2-c]pyridine-2-carboxamide N-(4-{1-[(3-chloro-4-fluorobenzene)sulfonyl]piperidin-4- 0.0598 0.0685 yl}butyl)-1H-pyrrolo[3,2-c]pyridine-2-carboxamide N-(4-{1-[(3-fluoro-4-methoxybenzene)sulfonyl]piperidin-4- 0.0248 0.0075 yl}butyl)-1H-pyrrolo[3,2-c]pyridine-2-carboxamide N-(4-{1-[(2-methoxy-5-methylbenzene)sulfonyl]piperidin-4- 0.0273 0.0017 yl}butyl)-1H-pyrrolo[3,2-c]pyridine-2-carboxamide N-(4-{1-[(3,5-difluorobenzene)sulfonyl]piperidin-4- 0.0225 0.0069 yl}butyl)-1H-pyrrolo[3,2-c]pyridine-2-carboxamide N-{[4-({4-[(pyrrolidin-1- 0.0015 0.0014 yl)carbonyl]benzene}sulfonyl)phenyl]methyl}furo[2,3- c]pyridine-2-carboxamide N-(4-{1-[(5-fluoro-2-methoxybenzene)sulfonyl]piperidin-4- 0.0232 0.0015 yl}butyl)-1H-pyrrolo[3,2-c]pyridine-2-carboxamide N-(4-{1-[(3-chloro-4-methoxybenzene)sulfonyl]piperidin-4- 0.0293 0.0137 yl}butyl)-1H-pyrrolo[3,2-c]pyridine-2-carboxamide N-(4-{1-[6-(trifluoromethyl)pyridine-3-sulfonyl]piperidin-4- 0.0815 0.0298 yl}butyl)-1H-pyrrolo[3,2-c]pyridine-2-carboxamide N-(4-{1-[(3-fluoro-2-methylbenzene)sulfonyl]piperidin-4- 0.0255 0.0129 yl}butyl)-1H-pyrrolo[3,2-c]pyridine-2-carboxamide N-(4-{1-[(2-chlorobenzene)sulfonyl]piperidin-4- 0.0212 0.0071 yl}butyl)-1H-pyrrolo[3,2-c]pyridine-2-carboxamide N-{4-[1-(propane-2-sulfonyl)piperidin-4-yl]butyl}-1H- 0.0306 0.023 pyrrolo[3,2-c]pyridine-2-carboxamide N-(4-{1-[(3,4-difluorobenzene)sulfonyl]piperidin-4- 0.0346 0.0228 yl}butyl)-1H-pyrrolo[3,2-c]pyridine-2-carboxamide N-(4-{1-[(4-methoxy-3-methylbenzene)sulfonyl]piperidin-4- 0.0216 0.007 yl}butyl)-1H-pyrrolo[3,2-c]pyridine-2-carboxamide N-{[4-({4-[(pyrrolidin-1- 0.0037 0.0017 yl)carbonyl]benzene}sulfonyl)phenyl]methyl}thieno[2,3- c]pyridine-2-carboxamide N-{[4-({4-[(pyrrolidin-1- 0.0158 0.0093 yl)carbonyl]benzene}sulfonyl)phenyl]methyl}-1H- pyrazolo[3,4-b]pyridine-5-carboxamide N-(4-(benzyloxy) phenethyl)-1H-pyrrolo [3,2-c] 2.0 pyridine-2-carboxamide N-[4-(1-benzoylazetidin-3-yl)butyl]-1H-pyrrolo[3,2- 0.0232 0.0769 c]pyridine-2-carboxamide