WO2014141110A2 - Aminonitriles as kynurenine pathway inhibitors - Google Patents

Aminonitriles as kynurenine pathway inhibitors Download PDF

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WO2014141110A2
WO2014141110A2 PCT/IB2014/059705 IB2014059705W WO2014141110A2 WO 2014141110 A2 WO2014141110 A2 WO 2014141110A2 IB 2014059705 W IB2014059705 W IB 2014059705W WO 2014141110 A2 WO2014141110 A2 WO 2014141110A2
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chloro
phenyl
amino
fluorophenyl
acetonitrile
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PCT/IB2014/059705
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WO2014141110A3 (en
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Monali BANERJEE
Sandip MIDDYA
Ritesh SHRIVASTAVA
Sushil Raina
Arjun SURYA
Veejendra K YADAV
Kishore Kamal KAPOOR
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Curadev Pharma Pvt. Ltd.
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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K45/00Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/21Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/22Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
    • A61K31/222Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin with compounds having aromatic groups, e.g. dipivefrine, ibopamine
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/275Nitriles; Isonitriles
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/38Heterocyclic compounds having sulfur as a ring hetero atom
    • A61K31/381Heterocyclic compounds having sulfur as a ring hetero atom having five-membered rings
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins
    • A61K31/40Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins
    • A61K31/435Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44Non condensed pyridines; Hydrogenated derivatives thereof
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins
    • A61K31/435Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4425Pyridinium derivatives, e.g. pralidoxime, pyridostigmine
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins
    • A61K31/435Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47Quinolines; Isoquinolines
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins
    • A61K31/495Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4965Non-condensed pyrazines
    • YGENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02ATECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection
    • Y02A50/30Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
    • Y02A50/38Medical treatment of vector-borne diseases characterised by the agent
    • Y02A50/408Medical treatment of vector-borne diseases characterised by the agent the vector-borne disease being caused by a protozoa
    • Y02A50/409Medical treatment of vector-borne diseases characterised by the agent the vector-borne disease being caused by a protozoa of the genus Leishmania i.e. Leishmaniasis, Sand-fly fever, phlebotomus fever, kala-azar, black fever or Dumdum fever
    • YGENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02ATECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection
    • Y02A50/30Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
    • Y02A50/38Medical treatment of vector-borne diseases characterised by the agent
    • Y02A50/408Medical treatment of vector-borne diseases characterised by the agent the vector-borne disease being caused by a protozoa
    • Y02A50/411Medical treatment of vector-borne diseases characterised by the agent the vector-borne disease being caused by a protozoa of the genus Plasmodium, i.e. Malaria

Abstract

The present application provides novel kynurenine pathway inhibitors and pharmaceutically acceptable salts and prodrugs thereof. Also provided are methods for preparing these compounds. These compounds are useful in regulating the kynurenine pathway and the activity of indoleamine 2,3-dioxygenase and/or tryptophan 2,3-dioxygenase by administering a therapeutically effective amount of one or more of the compounds of formula (I) to a patient. By doing so, these compounds are effective in treating conditions associated with the dysregulation of the kynurenine pathway. A variety of conditions can be treated using these compounds and include diseases which are characterized by immunosuppression, abnormal cellular proliferation and/or inflammation. In one embodiment, the disease is cancer. In another embodiment, the disease is a viral infection. In a further embodiment, the disease is depression.

Description

AMINONITRILES AS KYNURENINE PATHWAY INHIBITORS

CROSS REFERENCE TO RELATED APPLICATIONS

This non-provisional application claims the benefit of U.S. Provisional Application Serial Number 61782503, filed on March 14, 2013, which is incorporated by reference in its entirety.

FIELD OF INVENTION

The present invention is directed to Aminonitrile derivatives which are inhibitors of the kynurenine pathway and 2,3-dioxygenase and are useful in the treatment of cancer, immunosupppression, and other diseases.

BACKGROUND

The essential amino acid Tryptophan is catabolized through the kynurenine pathway. The initial, rate-limiting step in the kynurenine pathway is performed by heme -containing oxidoreductase enzymes, including tryptophan 2,3-dioxygenase (TDO) and indoleamine 2,3-dioxygenase (IDO). IDO and TDO activity alter local tryptophan concentration and the build-up of kynurenin pathway metabolites can lead to numerous conditions associated with immune suppression.

Multiple publications implicate IDO in the maintenance of

immunosuppressive conditions associated with the persistence of tumor resistance, chronic infection, HIV infection, as well as in the normal phenomenon of increased immunological tolerance to prevent fetal rejection in utero. It is thought that therapeutic agents that inhibit IDO activity can be used to modulate regulatory T cells and activate cytotoxic T cells in immunosuppressive conditions associated with cancer and viral infection (e.g. HIV-AIDS, HCV). Inhibition of IDO may also be an important treatment strategy for patients with neurological or neuropsychiatric disease or disorders such as depression. The local immunosuppressive properties of the kynurenine pathway and specifically IDO and TDO have been implicated in cancer. A large proportion of primary cancer cells have been shown to overexpress IDO. In addition, TDO has recently been implicated in human brain tumors.

The earliest experiments proposed an anti -microbial role for IDO, and suggested that localized depletion of tryptophan by IDO led to microbial death (Yoshida et al, (1978) Proc. Natl. Acad. Sci. (USA): 75: 3998-4000). Subsequent research led to the discovery of a more complex role for IDO in immune suppression, best exemplified in the case of maternal tolerance towards the allogeneic fetus where IDO plays an immunosuppressive role in preventing fetal rejection from the uterus. Pregnant mice dosed with a specific IDO inhibitor rapidly reject allogeneic fetuses through induction of T cells (Munn et al, Science, 1998; 281(5380): 1191-3). Studies since then have established IDO as a regulator of certain disorders of the immune system and have discovered that it plays a role in the ability of transplanted tissues to survive in new hosts (Radu et al, Plast. Reconstr. Surg. 2007 Jun; 119(7): 2023-8). It is believed that increased IDO activity resulting in elevated kynurenine pathway metabolites causes peripheral and, ultimately, systemic immune tolerance. In-vitro studies suggest that the proliferation and function of lymphocytes are exquisitely sensitive to kynurenines (Cell Death and Differentiation: 9: 1069-1077 (2002)). The expression of IDO by activated dendritic cells suppresses immune response by mechanisms that include inducing cell cycle arrest in T lymphocytes, down regulation of the T lymphocyte cell receptor (TCR) and activation of regulatory T cells (T-regs) (J. Exp. Med.: 196 : 447-457 (2002); J. Immunol.: 176: 6752-6761 (2006)).

There is evidence that IDO is induced chronically by HIV infection and increases regulatory T cells leading to immunosuppression in patients (Sci. Transl. Med., 2010; 2). It has been recently shown that IDO inhibition can enhance the level of virus specific T cells and concomitantly reduce the number of virus infected macrophages in a mouse model of HIV (Blood : 106 : 2382-2390 (2005). Thus, inhibition of Kynurenine pathway and IDO activity appears to reduce immune suppression by reducing T-cell mediated immunity.

Kynurenine pathway and IDO are also believed to play a role in maternal tolerance and immunosuppressive process to prevent fetal rejection in utero (Science: 281 : 1191-1193 (1998)). Pregnant mice dosed with a specific IDO inhibitor rapidly reject allogeneic fetuses through suppression of T cells activity (Munn et al, Science. 1998; 281 (5380): 1191-3)). Studies since then have established IDO as a regulator of immune-mediated disorders and suggest that it plays a role in the ability of transplanted tissues to survive in new hosts (Radu et al., Plast Reconstr Surg. 2007 Jun; 119(7):2023-8).

The local immunosuppressive properties of the kynurenine pathway and specifically IDO and TDO have been implicated in cancer. A large proportion of primary cancer cells overexpress IDO. Several studies have focused on the ability of tumors to create a tolerogenic environment suitable for survival, growth and metastasis by activating IDO (Prendergast, Nature. 2011; 478: 192-4.). Increase in the number of T-regs and suppression of cytotoxic T cell responses associated with dysregulation of the Kynurenine pathway by overexpression of IDO appears to result in tumor resistance and promote tumor tolerance.

Data from both clinical and animal studies suggest that inhibiting IDO activity could be beneficial for cancer patients and may slow or prevent tumor metastases

(Nature Medicine : 11 : 3: 312- 319 (2005); Cell Cycle : 8: 1930-1934 (2009); Journal of the American College of Surgeons: 206: 849-854 (2008)). Genetic ablation of the IDO gene in mice (Ido-/-) resulted in decreased incidence of DMBA-induced premalignant skin papillomas (PNAS: 17073-17078 (2008)). Silencing of IDO expression by siRNA or a pharmacological IDO inhibitor 1 -methyl tryptophan enhanced tumor-specific killing (Clin Cancer Res: 15(2) (2009)). In addition, inhibiting IDO in tumor-bearing hosts improved the outcome of conventional chemotherapy at reduced doses (Clin Cancer Res: 15(2) (2009)). Clinically, the pronounced expression of IDO found in several human tumor types has been correlated with negative prognosis and poor survival rate (Nature Rev. Cancer: 5 :

263-274 (2005); Immunol. Lett.: I l l : 69-75 (2007)). Serum from cancer patients has higher kynurenine/tryptophan ratio, a higher number of circulating T-regs, and increased effector T cell apoptosis when compared to serum from healthy volunteers (Lung cancer : 67 : 361-365 (2010)). Thus, decreasing the rate of kynurenine production by inhibiting IDO may be beneficial to cancer patients. Kynurenine pathway dysregulation and IDO play an important role in the brain tumors and are implicated in inflammatory response in several

neurodegenerative disorders including multiple sclerosis, Parkinson's disease, Alzheimer's disease, stroke, amyotrophic lateral sclerosis, dementia (J Clin Invest. 122(8):2940-2954 (2012); Journal of Neuroinflammation 8: 17 (2011); Parkinson's Disease, Volume 2011 (2011)). Circulating T-reg levels were found to be decreased in patient with glioblastoma treated with anti -viral agent inhibitors of IDO (Soderlund, et al. J. of Neuroinflammation, 7:44 (2010))

Neuropsychiatric diseases and mood disorders such as depression and schizophrenia also said to have IDO and Kynurenine dysregulation. Several studies have found Kynurenine pathway metabolites to be neuroactive and neurotoxic.

Neurotoxic kynurenine metabolites are known to increase in the spinal cord of rats with experimental allergic encephalomyelitis (Neuroscience. 2001;102(3):687-95.

The neurotoxic effects of Kynurenine metabolites are exacerbated by increased plasma glucose levels. Additionally, changes in the relative or absolute concentrations of the kynurenines have been found in several neurodegenerative disorders, such as

Huntington's disease and Parkinson's disease, stroke and epilepsy (Central Nervous

System Agents in Medicinal Chemistry, 2007, 7, 45-56).

Kynurenine pathway dysregulation and IDO activity also correlates with cardiovascular risk factors, and kynurenines and IDO are markers for Atherosclerosis and other cardiovascular heart diseases (Science 310 (5749): 850-5 (2005)) in addition to kidney disease. The kynurenines are associated with oxidative stress, inflammation and the prevalence of cardiovascular disease in patients with end-stage renal disease (Atherosclerosis, (204)1, 309-314 (2009). Studies show that kynurenine pathway metabolites are associated with endothelial dysfunction markers in the patients with chronic kidney disease (Advances in Medical Sciences, 55(2), 196-203(2010).

There is a need in the art for compounds that are inhibitors of kynurenine pathway including indoleamine 2,3-dioxygenase or tryptophan 2,3-dioxygenase enzymes, as well as for methods for treating conditions that can benefit from such inhibition. SUMMARY OF THE INVENTION

In one aspect, the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt or prodrug thereof, wherein X!-X5, R!-R4, m and n are defined herein.

Figure imgf000007_0001

(I)

In another aspect, compounds of formulae (I-A) and (I-AA), are provided, wherein X!-X5, R!-R3, m and n are defined herein.

Figure imgf000007_0002

(I-A) (I-AA)

In another aspect, compounds of formulae (I-B), (I-BB), (I-BBB), and (I- BBBB), are provided, wherein X!-X5, R!-R3, and m are defined herein.

Figure imgf000007_0003

(I-B) (I-BB)

Figure imgf000008_0001

(I-BBB) (I-BBBB)

In another aspect, compounds of formulae (I-C), (I-CC), (I-D), (I-DD), (I-E), (I-EE), (I-F), (I-FF), (I-G), (I-GG), (I-GGG), (I-H), (I-I), (I-II), (I-J) and (I-JJ) are provided, wherein R1, and R5-Rn are defined herein

Figure imgf000008_0002

(I-C) (I-CC) (I-D) (I-DD)

Figure imgf000008_0003

(I-E) (I-EE) (I-F) (I-FF)

Figure imgf000008_0004

(I-G) (I-GG) (I-GGG) (I-H)

Figure imgf000009_0001

In a further aspect, a composition comprising a compound or prodrug thereof as described herein and a pharmaceutically acceptable carrier is provided.

In another aspect, a composition comprising a compound as described herein wherein the compound can regulate kynurenine pathway.

In yet another aspect, a kit comprising a compound or prodrug thereof described herein is provided.

In a further aspect, a method of regulating kynurenine pathway is provided comprising administering a compound or prodrug thereof as described herein to a subject in need thereof.

In still a further aspect, a method of regulating the kynurenine pathway by inhibiting indoleamine 2,3-dioxygenase or tryptophan 2,3-dioxygenase pathway or both is provided comprising administering a compound or prodrug thereof as described herein to a subject in need thereof. In another aspect, a method for treating a condition treatable by inhibiting the kynurenine pathway is provided comprising administering a compound or prodrug thereof described herein to a subject in need thereof.

In a further aspect, a method for treating a disease characterized by immunosuppression resulting from a dysregulated kynurenine pathway is provided comprising administering a compound or prodrug thereof described herein to a subject in need thereof. In yet a further aspect, a method for treating a disease characterized by an abnormal cellular proliferation associated with a dysregulated kynurenine pathway is provided comprising administering a compound or prodrug thereof described herein to a subject in need thereof.

In still a further aspect, a method for treating a disease characterized by inflammation associated with a dysregulated kynurenine pathway is provided comprising administering a compound or prodrug thereof described herein to a subject in need thereof.

In another aspect, a method for treating a condition treatable by inhibiting the indoleamine 2,3-dioxygenase or tryptophan 2,3-dioxygenase or both is provided comprising administering a compound or prodrug thereof described herein to a subject in need thereof.

In yet another aspect, a method of treating cancer, viral infection, bacterial infection parasitic infection, a neurodegenerative disorder, organ transplant rejection, an inflammatory disease, cardiovascular disease, a mood disorder, an autoimmune disease in a patient comprising administering to said patient a therapeutically effective amount of a compound of Formula I or prodrug thereof, or a pharmaceutically acceptable salt thereof. In one embodiment, the disease is characterized by immunosuppression. In another embodiment, the disease is characterized by inflammation. In yet another embodiment, the disease is characterized by abnormal cell proliferation. In another embodiment, the disease is associated with dysregulation of kynurenine pathway.

In still another aspect, a method of reducing or eliminating an immune- mediated disorder is provided comprising administering a compound or prodrug thereof described herein to a patient.

In still another aspect, a method of reducing or eliminating

immunosuppression is provided comprising administering a compound or prodrug thereof described herein to a patient. In one embodiment the immunosuppression is induced by dysregulation of kynurenine pathway. In a further aspect, a method of treating a viral infection is provided comprising administering a compound or prodrug thereof described herein to a patient.

In another aspect, a method of treating inflammatory disorder is provided comprising administering a compound or prodrug thereof described herein to a patient.

In another aspect, a method of treating tumor resistance is provided comprising administering a compound or prodrug thereof described herein to a patient.

Other aspects and advantages of the invention will be readily apparent from the following detailed description of the invention.

DETAILED DESCRIPTION OF THE INVENTION

The invention provides compounds or prodrugs thereof and pharmaceutical composition thereof, which are capable of reducing or eliminating immune mediated disorders as standalone therapy (monotherapy) or in combination with conventional chemotherapy or in combination with anti -cancer vaccines or in combination with hormonal therapy to slow or prevent tumor growth. The invention further provides compounds and compositions which function by decreasing levels of kynurenine in plasma and/or tissues through the inhibition of the indoleamine 2,3-dioxygenase (IDO) and/or tryptophan 2,3-dioxygenase (TDO) enzymes.

DEFINITIONS

The following definitions are used in connection with the compounds of the present invention unless the context indicates otherwise. Throughout the description and the claims of this specification the word "comprise" and other forms of the word, such as "comprising" and "comprises," means including but not limited to, and is not intended to exclude for example, other additives, components, integers, or steps.

As used in the description and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "a composition" includes mixtures of two or more such compositions.

"Optional" or "optionally" means that the subsequently described event or circumstances can or cannot occur, and that the description includes instances where the event or circumstance occurs and instances where it does not.

In general, the number of carbon atoms present in a given group is designated "Cx-Cy", where x and y are the lower and upper limits, respectively. For example, a group designated as "d-Ce" contains from 1 to 6 carbon atoms. The carbon number as used in the definitions herein refers to carbon backbone and carbon branching, but does not include carbon atoms of the substituents, such as alkoxy substitutions and the like. Unless indicated otherwise, the nomenclature of substituents that are not explicitly defined herein are arrived at by naming from left to right the terminal portion of the functionality followed by the adjacent functionality toward the point of attachment. For example, the substituent "arylalkyloxycarbonyl" refers to the group (C6-C14 aryl)-(Ci-C6 alkyl)-O-C(O)-. The term optionally substituted refers to replacing a hydrogen atom of a group with an alkyl, alkoxy, aryl, monocyclic or bicyclic cycloalkyl, mono or bicyclic heterocyclylalkyl, (aryl)alkyl, (alkoxy)carbonyl, (alkyl)amido, (alkyl)amino, -NH2, aminoalkyl, alkylcarboxyl, (alkyl)carboxyamido, (aryl)amino, haloalkyl, heteroaryl, heterocyclyl, heteroaryl(alkyl), mono, di or perfluoroalkyl, halogen, CN, C(0)OH, amide, amide formed from a primary or secondary amine, NO2, OH, mono-fluoroalkoxy, di-fluoroalkoxy, trifluoroalkoxy, and hydroxyalkyl. Terms not defined herein have the meaning commonly attributed to them by those skilled in the art.

"Alkyl" refers to a hydrocarbon chain that may be a straight chain or branched chain, containing the indicated number of carbon atoms, for example, a C1-C12 alkyl group may have from 1 to 12 (inclusive) carbon atoms in it. Examples of C\-C alkyl groups include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, neopentyl, and isohexyl. Examples of C1-C8 alkyl groups include, but are not limited to, methyl, propyl, pentyl, hexyl, heptyl, 3-methylhex-l-yl, 2,3-dimethylpent-2-yl, 3-ethylpent- l-yl, octyl, 2- methylhept-2-yl, 2,3-dimethylhex-l-yl, and 2,3,3-trimethylpent-l-yl. An alkyl group can be unsubstituted or substituted with one or more of halogen, NH2, (alkyl)NH, (alkyl)(alkyl)N-, -N(alkyl)C(0)(alkyl), -NHC(0)(alkyl), -NHC(0)H, -C(0)NH2, -C(0)NH(alkyl), -C(0)N(alkyl)(alkyl), CN, OH, alkoxy, alkyl, C(0)OH,

-C(0)0(alkyl), -C(0)(alkyl), aryl, heteroaryl, heterocyclyl, cycloalkyl, haloalkyl, aminoalkyl-, -OC(0)(alkyl), carboxyamidoalkyl-, NO2, and alkyl-CN.

"Alkoxy" refers to the group R-O- where R is an alkyl group, as defined above. Exemplary C1-C6 alkoxy groups include but are not limited to methoxy, ethoxy, n-propoxy, 1-propoxy, n-butoxy and t-butoxy. An alkoxy group can be unsubstituted or substituted with one or more of halogen, OH, alkoxy, NH2,

(alkyl)amino-, di(alkyl)amino-, (alkyl)C(0)N(Ci-C3 alkyl)-, (alkyl)carboxyamido-, HC(0)NH-, H2NC(0)-, (alkyl)NHC(O)-, di(alkyl)NC(0)-, CN, C(0)OH,

(alkoxy)carbonyl-, (alkyl)C(O)-, aryl, heteroaryl, cycloalkyl, haloalkyl, amino(Ci-C6 alkyl)-, (alkyl)carboxyl-, or carboxyamidoalkyl-.

Aryl refers to an aromatic 6 to 14 membered hydrocarbon group. Examples of a C6-C14 aryl group include, but are not limited to, phenyl, a-naphthyl, β-naphthyl, biphenyl, anthryl, tetrahydronaphthyl, fluorenyl, indanyl, biphenylenyl, and acenanaphthyl. Examples of a C6-C10 aryl group include, but are not limited to, phenyl, a-naphthyl, β-naphthyl, biphenyl, and tetrahydronaphthyl. An aryl group can be unsubstituted or substituted with one or more of alkyl, halogen, haloalkyl, alkoxy, haloalkoxy, OH, hydroxyalkyl, O(hydroxyalkyl), -0(alkyl)C(0)OH,

-(alkyl)(alkoxy)halogen, NH2, aminoalkyl-, dialkylamino-, C(0)OH, -C(0)0(alkyl), -OC(0)(alkyl), -0(alkyl)N(alkyl)(alkyl), N-alkylamido-, -C(0)NH2, (alkyl)amido-, N02, (aryl)alkyl, alkoxy, aryloxy, heteroaryloxy, (aryl)amino, (alkoxy)carbonyl-, (alkyl)amido-, (alkyl)amino, aminoalkyl-, alkylcarboxyl-, (alkyl)carboxyamido-, (aryl)alkyl-, (aryl)amino-, cycloalkenyl, di(alkyl)amino-, heteroaryl,

(heteroaryl)alkyl-, heterocyclyl, -O(heterocyclyl), heterocyclyl(alkyl)-,

(hydroxyalkyl)NH-, (hydroxyalkyl)2N, -S02(alkyl), -NHC(0)(aryl), -C(0)NH(aryl), -NHC(0)(heteroaryl), -C(0)NH(heteroaryl) or a spiro substituent.

The term "bicycle" or "bicyclic" as used herein refers to a molecule that features two fused rings, which rings are a cycloalkyl, heterocyclyl, or heteroaryl. In one embodiment, the rings are fused across a bond between two atoms. The bicyclic moiety formed therefrom shares a bond between the rings. In another embodiment, the bicyclic moiety is formed by the fusion of two rings across a sequence of atoms of the rings to form a bridgehead. Similarly, a "bridge" is an unbranched chain of one or more atoms connecting two bridgeheads in a polycyclic compound. In another embodiment, the bicyclic molecule is a "spiro" or "spirocyclic" moiety. The spirocyclic group is a carbocyclic or heterocyclic ring which bound through a single carbon atom of the spirocyclic moiety to a single carbon atom of a carbocyclic or heterocyclic moiety. In one embodiment, the spirocyclic group is a cycloalkyl and is bound to another cycloalkyl. In another embodiment, the spirocyclic group is a cycloalkyl and is bound to a heterocyclyl. In a further embodiment, the spirocyclic group is a heterocyclyl and is bound to another heterocyclyl. In still another embodiment, the spirocyclic group is a heterocyclyl and is bound to a cycloalkyl.

"(Aryl)alkyl" refers to an alkyl group, as defined above, wherein one or more of the alkyl group's hydrogen atoms has been replaced with an aryl group as defined above. (C6-C14 aryl)alkyl- moieties include benzyl, benzhydryl, 1-phenylethyl, 2- phenylethyl, 3-phenylpropyl, 2-phenylpropyl, 1-naphthylmethyl, 2-naphthylmethyl and the like. An (aryl)alkyl group can be unsubstituted or substituted with one or more of halogen, CN, NH2, OH, (alkyl)amino-, di(alkyl)amino-, (alkyl)C(0)N(alkyl)- , (alkyl)carboxyamido-, HC(0)NH-, H2NC(0)-, (alkyl)NHC(O)-, di(alkyl)NC(0)-, CN, OH, alkoxy, alkyl, C(0)OH, (alkoxy)carbonyl-, (alkyl)C(O)-, aryl, heteroaryl, cycloalkyl, haloalkyl, amino(alkyl)-, (alkyl)carboxyl-, carboxyamidoalkyl-, or N02.

"(Alkoxy)carbonyl-" refers to the group alkyl-O-C(O)-. Exemplary (C1-C6 alkoxy)carbonyl- groups include but are not limited to methoxy, ethoxy, n-propoxy, 1-propoxy, n-butoxy and t-butoxy. An (alkoxy)carbonyl group can be unsubstituted or substituted with one or more of halogen, OH, NH2, (alkyl)amino-, di(alkyl)amino-, (alkyl)C(0)N(alkyl)-, (alkyl)carboxyamido-, HC(0)NH-, H2NC(0)-,

(alkyl)NHC(O)-, di(alkyl)NC(0)-, CN, alkoxy, C(0)OH, (alkoxy)carbonyl-,

(alkyl)C(O)-, aryl, heteroaryl, cycloalkyl, haloalkyl, amino(alkyl)-, (alkyl)carboxyl-, carboxyamidoalkyl-, or N02.

"(Alkyl)amido-" refers to a -C(0)NH- group in which the nitrogen atom of said group is attached to a C1-C6 alkyl group, as defined above. Representative examples of a (C1-C6 alkyl)amido- group include, but are not limited to,

-C(0)NHCH3, -C(0)NHCH2CH3, -C(0)NHCH2CH2CH3, -C(0)NHCH2CH2CH2CH3, -C(0)NHCH2CH2CH2CH2CH3, -C(0)NHCH(CH3)2, -C(0)NHCH2CH(CH3)2, -C(0)NHCH(CH3)CH2CH3, -C(0)NH-C(CH3)3 and -C(0)NHCH2C(CH3)3.

"(Alkyl)amino-" refers to an -NH group, the nitrogen atom of said group being attached to a alkyl group, as defined above. Representative examples of an (C1-C6 alkyl)amino- group include, but are not limited to CH3NH-, CH3CH2NH-,

CH3CH2CH2NH-, CH3CH2CH2CH2NH-, (CH3)2CHNH-, (CH3)2CHCH2NH-, CH3CH2CH(CH3)NH- and (CH3)3CNH-. An (alkyl)amino group can be unsubstituted or substituted on the alkyl moiety with one or more of halogen, NH2, (alkyl)amino-, di(alkyl)amino-, (alkyl)C(0)N(alkyl)-, (alkyl)carboxyamido-, HC(0)NH-, H2NC(0)-, (alkyl)NHC(O)-, di(alkyl)NC(0)-, CN, OH, alkoxy, alkyl, C(0)OH,

(alkoxy)carbonyl-, (alkyl)C(O)-, aryl, heteroaryl, cycloalkyl, haloalkyl, amino(alkyl)-, (alkyl)carboxyl-, carboxyamidoalkyl-, or N02.

" Aminoalkyl-" refers to an alkyl group, as defined above, wherein one or more of the alkyl group's hydrogen atoms has been replaced with -NH2; one or both H of the NH2 may be replaced by a substituent.

" Alkylcarboxyl-" refers to an alkyl group, defined above that is attached to the parent structure through the oxygen atom of a carboxyl (C(O)-O-) functionality. Examples of (Ci-C6 alkyl)carboxyl- include acetoxy, propionoxy, propylcarboxyl, and isopentylcarboxyl.

"(Alkyl)carboxyamido-" refers to a -NHC(O)- group in which the carbonyl carbon atom of said group is attached to a C1-C6 alkyl group, as defined above.

Representative examples of a (Ci-C6 alkyl)carboxyamido- group include, but are not limited to, -NHC(0)CH3, -NHC(0)CH2CH3, -NHC(0)CH2CH2CH3,

-NHC(0)CH2CH2CH2CH3, -NHC(0)CH2CH2CH2CH2CH3, -NHC(0)CH(CH3)2, NHC(0)CH2CH(CH3)2, -NHC(0)CH(CH3)CH2CH3, -NHC(0)-C(CH3)3 and

-NHC(0)CH2C(CH3)3.

"(Aryl)amino" refers to a radical of formula (aryl)-NH-, wherein aryl is as defined above. "(Aryl)oxy" refers to the group Ar-O- where Ar is an aryl group, as defined above. "Cycloalkyl" refers to a non-aromatic, saturated, partially saturated, monocyclic, bicyclic or polycyclic hydrocarbon 3 to 12 membered ring system. Representative examples of a C3-C12 cycloalkyl include, but are not limited to, cyclopropyl, cyclopentyl, cycloheptyl, cyclooctyl, decahydronaphthalen-l-yl, octahydro-lH-inden-2-yl, decahydro-lH-benzo[7]annulen-2-yl, and dodecahydros- indacen-4-yl. Representative examples of a C3-C10 cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, decahydronaphthalen-l-yl, and octahydro-lH-inden-2-yl. Representative examples of a C3-C8 cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and octahydropentalen-2-yl. A cycloalkyl can be unsubstituted or substituted with one or more of halogen, NH2, (alkyl)NH, (alkyl)(alkyl)N-, -N(alkyl)C(0)(alkyl), -NHC(0)(alkyl), -NHC(0)H,

-C(0)NH2, -C(0)NH(alkyl), -C(0)N(alkyl)(alkyl), CN, OH, alkoxy, alkyl, C(0)OH, -C(0)0(alkyl), -C(O) alkyl), aryl, heteroaryl, cycloalkyl, haloalkyl, aminoalkyl-, -OC(0)(alkyl), carboxyamidoalkyl-, and NO2. Additionally, each of any two hydrogen atoms on the same carbon atom of the carbocyclic ring can be replaced by an oxygen atom to form an oxo (=0) substituent.

"Halo" or "halogen" refers to -F, -CI, -Br and -I.

"C1-C6 haloalkyl" refers to a C1-C6 alkyl group, as defined above, wherein one or more of the C1-C6 alkyl group's hydrogen atoms has been replaced with F, CI, Br, or I. Each substitution can be independently selected from F, CI, Br, or I.

Representative examples of an C1-C6 haloalkyl- group include, but are not limited to, -CH2F, -CCI3, -CF3, CH2CF3, -CH2CI, -CH2CH2Br, -CH2CH2I, -CH2CH2CH2F,

-CH2CH2CH2C1, -CH2CH2CH2CH2Br, -CH2CH2CH2CH2I, -CH2CH2CH2CH2CH2Br, -CH2CH2CH2CH2CH2I, -CH2CH(Br)CH3, -CH2CH(C1)CH2CH3, -CH(F)CH2CH3 and -C(CH3)2(CH2C1).

"Heteroaryl" refers to a monocyclic, bicyclic, or polycyclic aromatic ring system containing at least one ring atom selected from the heteroatoms oxygen, sulfur and nitrogen. Examples of C1-C9 heteroaryl groups include furan, thiophene, indole, azaindole, oxazole, thiazole, isoxazole, isothiazole, imidazole, N-methylimidazole, pyridine, pyrimidine, pyrazine, pyrrole, N-methylpyrrole, pyrazole, N- methylpyrazole, 1,3,4-oxadiazole, 1,2,4-triazole, 1 -methyl- 1,2,4-triazole, 1H- tetrazole, 1-methyltetrazole, benzoxazole, benzothiazole, benzoiuran, benzisoxazole, benzimidazole, N-methylbenzimidazole, azabenzimidazole, indazole, quinazoline, quinoline, and isoquinoline. Bicyclic C1-C9 heteroaryl groups include those where a phenyl, pyridine, pyrimidine or pyridazine ring is fused to a 5 or 6-membered monocyclic heteroaryl ring having one or two nitrogen atoms in the ring, one nitrogen atom together with either one oxygen or one sulfur atom in the ring, or one O or S ring atom. Examples of monocyclic C1-C4 heteroaryl groups include 2H-tetrazole, 3H- 1,2,4-triazole, furan, thiophene, oxazole, thiazole, isoxazole, isothiazole, imidazole, and pyrrole. A heteroaryl group can be unsubstituted or substituted with one or more of Ci-C6 alkyl, halogen, haloalkyl, OH, CN, hydroxyalkyl, NH2, aminoalkyl-, dialkylamino-, C(0)OH, -C(0)0-(alkyl), -OC(0)(alkyl), N-alkylamido-, -C(0)NH2, (alkyl)amido-, -NO2, (aryl)alkyl, alkoxy, aryloxy, heteroaryloxy, (aryl)amino, (alkoxy)carbonyl-, (alkyl)amido-, (alkyl)amino, aminoalkyl-, alkylcarboxyl-, (alkyl)carboxyamido-, (aryl)alkyl-, (aryl)amino-, cycloalkenyl, di(alkyl)amino-, heteroaryl, (heteroaryl)alkyl-, heterocyclyl, heterocyclyl(alkyl)-, (hydroxyalkyl)NH-, (hydroxyalkyl)2N, -NHC(0)aryl, -C(0)NHaryl, -NHC(0)heteroaryl,

-C(0)NH(heteroaryl), or a spiro substituent.

"Heterocycle" or "heterocyclyl" refers to monocyclic, bicyclic, polycyclic, or bridged head molecules in which at least one ring atom is a heteroatom. A heterocycle may be saturated or partially saturated. Exemplary C1-C9 heterocyclyl groups include but are not limited to aziridine, oxirane, oxirene, thiirane, pyrroline, pyrrolidine, dihydrofuran, tetrahydrofuran, dihydrothiophene, tetrahydrothiophene, dithiolane, piperidine, 1,2,3,6-tetrahydropyridine-l-yl, tetrahydropyran, pyran, thiane, thiine, piperazine, azepane, diazepane, oxazine, 5,6-dihydro-4H-l,3-oxazin-2-yl, 2,5- diazabicyclo[2.2.1]heptane, 2,5-diazabicyclo[2.2.2]octane, 3,6- diazabicyclo[3.1. l]heptane, 3,8-diazabicyclo[3.2. l]octane, 6-oxa-3,8- diazabicyclo[3.2. l]octane, 7-oxa-2,5-diazabicyclo[2.2.2]octane, 2,7-dioxa-5- azabicyclo[2.2.2]octane, 2-oxa-5-azabicyclo[2.2.1] heptane -5 -yl, 2-oxa-5- azabicyclo[2.2.2]octane, 3,6-dioxa-8-azabicyclo[3.2. l]octane, 3-oxa-6- azabicyclo[3.1. l]heptane, 3-oxa-8-azabicyclo[3.2.1]octan-8-yl, 5,7-dioxa-2- azabicyclo[2.2.2]octane, 6,8-dioxa-3-azabicyclo[3.2. l]octane, 6-oxa-3- azabicyclo [3.1.1] heptane , 8 -oxa-3 -azabicyclo [3.2.1] octan-3 -yl , 2 -methyl -2,5 - diazabicyclo[2.2. l]heptane-5-yl, l,3,3-trimethyl-6-azabicyclo[3.2. l]oct-6-yl, 3- hydroxy-8-azabicyclo[3.2. l]octan-8-yl-, 7-methyl-3-oxa-7,9- diazabicyclo[3.3. l]nonan-9-yl, 9-oxa-3 -azabicyclo [3.3. l]nonan-3-yl, 3-oxa-9- azabicyclo[3.3.1]nonan-9-yl, 3,7-dioxa-9-azabicyclo[3.3.1]nonan-9-yl, 4-methyl-3,4- dihydro-2H-l,4-benzoxazin-7-yl, thiazine, dithiane, and dioxane. The contemplated heterocycle rings or ring systems have a minimum of 3 members. Therefore, for example, Ci heterocyclyl radicals would include but are not limited to oxaziranyl, diaziridinyl, and diazirinyl, C2 heterocyclyl radicals include but are not limited to aziridinyl, oxiranyl, and diazetidinyl, C9 heterocyclyl radicals include but are not limited to azecanyl, tetrahydroquinolinyl, and perhydroisoquinolinyl. A heterocyclyl group can be unsubstituted or substituted with one or more of alkyl, halogen, alkoxy, haloalkyl, OH, hydroxyalkyl, -C(0)-(hydroxyalkyl), NH2, aminoalkyl-, dialkylamino- , C(0)OH, -C(0)0-(alkyl), -OC(0)(alkyl), N-alkylamido-, -C(0)NH2, (alkyl)amido-, -C(0)-(alkyl)-CN, (alkyl)-CN, or N02.

"Heterocyclyl(alkyl)-" refers to an alkyl group, as defined above, wherein one or more of the alkyl group's hydrogen atoms has been replaced with a heterocycle group as defined above. Heterocyclyl(Ci-C6 alkyl)- moieties include 1- piperazinylethyl, 4-morpholinylpropyl, 6-piperazinylhexyl, and the like. A heterocyclyl(alkyl) group can be unsubstituted or substituted with one or more of halogen, NH2, (alkyl)amino-, di(alkyl)amino-, (alkyl)C(0)N(alkyl)-,

(alkyl)carboxyamido-, HC(0)NH-, H2NC(0)-, (alkyl)NHC(O)-, di(alkyl)NC(0)-, CN, OH, alkoxy, alkyl, C(0)OH, (alkoxy)carbonyl-, (alkyl)C(O)-, 4- to 7-membered monocyclic heterocycle, aryl, heteroaryl, or cycloalkyl.

"Heteroaryl(alkyl)" refers to a heteroaryl which is attached to an alkyl group and the heteroaryl is defined above.

"Hydroxyalkyl" refers to a alkyl group, as defined above, wherein one or more of the alkyl group's hydrogen atoms has been replaced with OH groups. Examples of C1-C6 hydroxyalkyl moieties include, for example, -CH2OH, -CH2CH2OH, -CH2CH2CH2OH, -CH2CH(OH)CH2OH, -CH2CH(OH)CH3, -CH(CH3)CH2OH and higher homologs.

"Perfluoroalkyl-" refers to alkyl group, defined above, having two or more fluorine atoms. Examples of a C\-C perfluoroalkyl- group include CF3, CH2CF3, CF2CF3 and CH(CF3)2. This may also be referred to as mono or difluorine substituted alkyl group such as CHF2 or CH2F.

A "subject" is a mammal, e.g. , a human, mouse, rat, guinea pig, dog, cat, horse, cow, pig, or non-human primate, such as a monkey, chimpanzee, baboon or gorilla. In certain embodiments, the subject is a human. In certain embodiments, the subject is a non-human animal. The terms "human," "individual," "patient," and "subject" are used interchangeably herein.

The present invention also includes salts of the compounds described herein. As used herein, "salts" refers to derivatives of the disclosed compounds wherein the parent compound is modified by converting an existing acid or base moiety to its salt form. Examples of salts include, but are not limited to mineral acid (such as HC1, HBr, H2SO4) or organic acid (such as acetic acid, benzoic acid, trifluoroacetic acid) salts of basic residues such as amines; alkali (such as Li, Na, K, Mg, Ca) or organic (such as trialkyammonium) salts of acidic residues such as carboxylic acids; and the like. The salts of the present invention can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods.

Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amounts of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, non-aqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile (CAN) are preferred.

The phrase "pharmaceutically acceptable" indicates approval by a regulatory agency of the Federal or a state government or listed in the U.S. Pharmacopeia or other generally recognized pharmacopeia for use in animals, and more particularly in humans.

Representative "pharmaceutically acceptable salts" include but are not limited to those of an acid or base which are non-toxic salts of the parent compound formed, for example from non-toxic inorganic or organic acids. Lists of suitable salts are found in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, p 1418 and Journal of Pharmaceutical Science, 66, 2 (1977), each of which is incorporated in its entirety. In one embodiment, the pharmaceutical salt is selected from among water-soluble and water-insoluble salts, such as the acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, bromide, butyrate, calcium, chloride, choline, citrate, edisylate, camphorsulfonate, fumarate, gluconate, glucuronate, glutamate, hydrobromide, hydrochloride, lauryl sulfate, malate, maleate, mandelate, mesylate, palmitate, pantothenate, phosphate, potassium, propionate, p- toluenesulfonate, salicylate, sodium, stearate, succinate, and sulfate salts.

"Effective amount" means the amount of a compound that when administered to a subject, tissue, cell, living organism, is sufficient to inhibit the kynurenine pathway or activity of IDO and/or TDO. Throughout the present disclosure, the terms "effective amount" and "inhibiting amount" are used interchangeably. "Therapeutically effective amount" means the amount of a compound that, when administered to a subject for treating a disease, is sufficient to effect such treatment for the disease. The "therapeutically effective amount" can vary depending on the compound, the disease and its severity, and the age, weight, etc., of the subject to be treated.

As used herein, the term "isotopic variant" refers to a compound that contains unnatural proportions of isotopes at one or more of the atoms that constitute such compound. For example, an "isotopic variant" of a compound can contain one or more non-radioactive isotopes, such as for example, deuterium (2H or D), carbon- 13 (13C), nitrogen-15 (15N), or the like. It will be understood that, in a compound where such isotopic substitution is made, the following atoms, where present, may vary, so that for example, any hydrogen may be 2H/D, any carbon may be 13C, or any nitrogen may be 15N, and that the presence and placement of such atoms may be determined within the skill of the art. Likewise, the invention may include the preparation of isotopic variants with radioisotopes, in the instance for example, where the resulting compounds may be used for drug and/or substrate tissue distribution studies. The radioactive isotopes tritium, i.e., 3H, and carbon-14, i.e., 14C, are particularly useful for this purpose in view of their ease of incorporation and ready means of detection. Further, compounds may be prepared that are substituted with positron emitting

11 18 15 13

isotopes, such as C, F, O and N, and would be useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy. All isotopic variants of the compounds provided herein, radioactive or not, are intended to be encompassed within the scope of the invention.

The following abbreviations are used and have the indicated definitions:

Figure imgf000021_0001

NOVEL COMPOUNDS EXHIBITING KYNURENINE PATHWAY REGULATING ACTIVITY

In accordance with the instant invention, novel compounds are provided which are capable of regulating kynurenine pathway. In one embodiment, the compound is of formula (I) or a pharmaceutically acceptable salt or prodrug thereof.

Figure imgf000022_0001

(I)

In this compound, X1 is C, N or NO, O, S or SO or S02; X2 is C, N or NO, O, S or SO or S02; X3 is C, N or NO, O, S or SO or S02; X4 is C, N or NO, O, S or SO or SO2; X5 is C, N or NO, O, S or SO or SO2. In one embodiment, one or two of X1, X2, X3, X4 and X5 is N or O or S.

In one embodiment X1 and X2 or X2 and X3 or X3 and X4 or X4 and X5 form a fused five or six membered aryl or heteroaryl ring.. m is 0, 1, 2, 3, 4, 5, 6, or 7; and n is 0 or 1.

R3 is R5, R6, R7, R8, R9, R10, or R

R^ R^ I^ and i^ - R11 are independently selected from a group of H, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, C1-C6 alkoxy, mono or bicyclic optionally substituted C - Ci4 aryl, mono or bicyclic optionally substituted heteroaryl, optionally substituted (aryl)alkyl, (alkoxy)carbonyl, (alkyl)amido, (alkyl)amino, optionally substituted mono or bicyclic cycloalkyl, optionally substituted mono or bicyclic heterocyclyl, aminoalkyl, alkylcarboxyl, (alkyl)carboxyamido, optionally substituted (aryl)amino, halogen, Ci-C6 haloalkyl, optionally substituted heterocyclyl(alkyl)-, optionally substituted heteroaryl(alkyl), hydroxyalkyl, perfluoroalkyl, optionally substituted aryloxy, optionally substituted heteroaryloxy, optionally substituted C3-C6 cycloalkoxy, OR12, SR12, N(R12)2, CN, N02, C02H, CONRARB, and optionally substituted heterocyclyloxy having 1 to 2 heteroatoms selected from the group consisting of O, S, SO, S02, and NR12.

R is H, C1-C6 alkyl, mono or bicyclic C6-C14 aryl, mono or bicyclic heteroaryl, (aryl)alkyl, (alkyl)carbonyl, (alkoxy)carbonyl, (alkyl)amido, (alkyl)amino, mono or bicyclic cycloalkyl, mono or bicyclic heterocyclyl, alkylcarboxyl, heterocyclyl(alkyl), heteroaryl(alkyl), hydroxyalkyl, perfluoroalkyl, having 1 to 2 heteroatoms selected from the group consisting of O, S, SO, SO2, and NRC. RA and RB are independently selected from among H, optionally substituted C1-C6 alkyl, optionally substituted mono or bicyclic C6-C14 aryl, optionally substituted mono or bicyclic heteroaryl, optionally substituted (aryl)alkyl, optionally substituted mono or bicyclic C3-C8 cycloalkyl, optionally substituted mono or bicyclic heterocyclyl, C1-C6 haloalkyl, optionally substituted heterocyclyl(alkyl), optionally substituted heteroaryl(alkyl), hydroxyalkyl, and perfluoroalkyl. Rc is H, C1-Q5 alkyl, mono or bicyclic C6-C14 aryl, mono or bicyclic heteroaryl, (aryl)alkyl, (alkoxy)carbonyl, (alkyl)amido, (alkyl)amino, mono or bicyclic cycloalkyl, mono or bicyclic heterocyclyl, alkylcarboxyl, heterocyclyl(alkyl), heteroaryl(alkyl), hydroxyalkyl, perfluoroalkyl, aryloxy, heteroaryloxy, C3-C6 cycloalkoxy, or heterocyclyloxy. In an embodiment, wherein X1 and X2 or X2 and X3 or X3 and X4 or X4 and X5 do not form fused five or six membered aryl or heteroaryl ring, m is 0, 1, 2, 3, 4, or 5;

1 2 2 3 3 4 and n is 0 or 1. In another embodiment, wherein X and X or X and X or X and X or X4 and X5 form a fused ring, m is 0, 1, 2, 3, 4, 5, 6, or 7; n is 0 or 1 ; and R3 is R5, R6, R7, R8, R9, R10, or R11 as described herein. In one embodiment, R1 and R2 are independently selected from among H, optionally substituted C1-C6 alkyl, C1-C6 acyl, optionally substituted mono or bicyclic C6-C14 aryl, optionally substituted mono or bicyclic heteroaryl, optionally substituted (aryl)alkyl, optionally substituted mono or bicyclic cycloalkyl, optionally substituted mono or bicyclic heterocyclyl, C1-C6 haloalkyl, optionally substituted

heterocyclyl(alkyl), optionally substituted heteroaryl(alkyl), hydroxyalkyl, and perfluoroalkyl. In one embodiment, R1 or R2 is optionally substituted phenyl.

1 2 D

In another embodiment, R or R is of the following structure, wherein, R to RH are independently selected from among H, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, heterocycle, optionally substituted C1-C6 alkyl, C3-C8 cycloalkyl, CN, - O(aryl), C2-C6 alkynyl, C(0)Ci-C6 alkyl, -O-C1-C6 haloalkyl, and optionally substituted aryl.

Figure imgf000024_0001

In a further embodiment, R1 or R2 is of the following structure, wherein, RD to RH are independently selected from among H, halogen, CHF2, C(CH3)F2, OCF3, OCH3, OCH(CH3)2, moφholine, piperidine, CH3, C(CH3)3, CH2CH3, CH(CH3)2, cyclopropyl, cyclohexyl, CH2-cyclopropyl, CH2-cyclobutyl, benzyl, CN, phenoxy, ethynyl, C(0)CH3, and phenyl.

Figure imgf000024_0002
In yet another embodiment, R1 or R2 is of the following structure, wherein, R1 to RH are independently selected from the group consisting of H and optionally substituted aryl. In one embodiment, RD to RH are independently selected from among H and aryl substituted with halogen. In another embodiment, RD to RH are independently selected from among H and aryl substituted with one or more CI or F.

In still a

Figure imgf000024_0003
2-Cl-phenyl, 3-Cl-phenyl, 3- I-phenyl, 3-F-phenyl, 4-F-phenyl, 4-Br-phenyl, 4-Cl-phenyl, 2-Br-4-F-phenyl, 2-C1-4- F-phenyl, 2,3-di-Cl-4-F-phenyl, 2,4-di-Cl-phenyl, 2,4-di-F-3-Cl-phenyl, 2,4-di-F-5- Cl-phenyl, 2,5-di-Cl-phenyl, 3-Cl-4-F-phenyl, 3-Cl-4-I-phenyl, 3,4-di-F-phenyl, 2,4,5 -tri-F-phenyl, 2,3,4-tri-Cl-phenyl, 3-Br-4,5-di-F-phenyl, 3-F-4-Cl-phenyl, 3-Br-

4- F-phenyl, 3,5-di-Cl-4-F-phenyl, 4-F-5 -Cl-phenyl, 4-CF3 -phenyl, 3-CF3-phenyl, 4-F-

5- CF3-phenyl, 3-CF3-4-F-phenyl, 3-CHF2-phenyl, 3-C(CH3)F2-phenyl, 3-OCH3-4-Cl- phenyl, 2-OCH3 -5 -Cl-phenyl, 4-morpholinyl -phenyl, 2-piperidinyl -phenyl, 3-CH3- phenyl, 3-lBu-phenyl, 4-CH3-phenyl, 3-CH2CH3-phenyl, 3-cyclopropyl-phenyl, 3- cyclohexyl-phenyl, 3-CH(CH3)2-phenyl, 3,4-di-CH3-phenyl, 3,5-di-CH3-phenyl, 3,5- di-lBu-phenyl, 4-di-CH3-phenyl, CH2-cyclopropyl-phenyl, CH2-cyclobutyl-phenyl, 4- benzyl-phenyl, 3-benzyl-phenyl, 3-CH3-4-F-phenyl, 3 -CH3-4-Cl -phenyl, 3-Cl-4-CH3- phenyl, 3-Br-4-CH3-phenyl, 3-Cl-5-CH3-phenyl, 2-F-3-CN-phenyl, 4-CN-phenyl, 4- phenoxy-phenyl, 2,4-di-OCH3 -phenyl, 3-OCH(CH3)2-phenyl, 3,5-di-OCH3-phenyl, 3- ethynyl-phenyl, 4-ethynyl-phenyl, 4-C(0)CH3 -phenyl, 4-OCF3-phenyl, 3-OCF3-4-F- phenyl, or 3 -phenyl-phenyl.

In yet another embodiment, R1 or R2 is optionally substituted heteroaryl. In a further embodiment, R1 or R2 is pyridine optionally substituted with halogen.

In another embodiment, R1 or R2 is benzo[d]dioxolane.

1 2

In yet a further embodiment, R or R is tetrahydronaphthalene.

In another embodiment, R4 is selected from among H, CN, optionally substituted C1-C6 alkyl, C1-C6 acyl, optionally substituted mono or bicyclic C6-C14 aryl, optionally substituted mono or bicyclic heteroaryl, optionally substituted (aryl)alkyl, optionally substituted mono or bicyclic cycloalkyl, optionally substituted mono or bicyclic heterocyclyl, Ci-Ce haloalkyl, optionally substituted

heterocyclyl(alkyl), optionally substituted heteroaryl(alkyl), hydroxyalkyl, and perfluoroalkyl.

In another embodiment, the compound is of formula (I-A), wherein X!-X5, R1- R3, m and n are defined herein.

Figure imgf000026_0001

(I-A)

In another embodiment, the compound is of formula (I-AA), wherein X!-X5,

R1, R3, m and n are defined herein.

Figure imgf000026_0002

(I-AA)

In another embodiment, the compound is of formula (I-B), wherein X!-X4, R1

R\ and m is defined herein.

Figure imgf000026_0003

(I-B)

In a further embodiment, the compound is of formula (I-BB), wherein X 1 - vX4

R!,R3, and m is defined herein.

Figure imgf000026_0004

(I-BB) In another embodiment, the compound is of formula (I-BBB), wherein X!-X5,

R!-R3, and m is defined herein.

Figure imgf000027_0001

(I-BBB)

In a further embodiment, the compound is of formula (I-BBBB), wherein X X5, R1, R3, and m is defined herein.

Figure imgf000027_0002

(I-BBBB)

In yet another embodiment, the compound is of formula (I-C), wherein R and R5-R7 are defined herein.

Figure imgf000027_0003

(I-C)

In still a further embodiment, the compound is of formula (I-CC), wherein R and R5-R7 are defined herein.

Figure imgf000028_0001

(I CC)

In another embodiment, the compound is of formula (I-D), wherein R1 and R5 defined herein.

Figure imgf000028_0002

(I-D)

In yet a further embodiment, the compound is of formula (I-DD), wherein R1 and R5-R7 are defined herein.

Figure imgf000028_0003

(I-DD)

In still another embodiment, the compound is of formula (I-E), wherein R1, R5 R6 are defined herein.

Figure imgf000028_0004
In a further embodiment, the compound is of formula (I-EE), wherein R1 and

R5-R8 are defined herein.

Figure imgf000029_0001

(I-EE)

In yet another embodiment, the compound is of formula (I-F), wherein R1 and -R7 are defined herein.

Figure imgf000029_0002

(I-F)

In still a further embodiment, the compound is of formula (I-FF), wherein R and R -R are defined herein.

Figure imgf000029_0003

(I-FF)

In another embodiment, the compound is of formula (I-G), wherein R1 and R' R8 are defined herein.

Figure imgf000029_0004
(I-G)

In a further embodiment, the compound is of formula (I-GG), wherein R and are defined herein.

Figure imgf000030_0001

(I-GG)

In still another embodiment, the compound is of formula (I-GGG), wherein

5 8

R -R are defined herein.

Figure imgf000030_0002

(I-GGG)

In yet a further embodiment, the compound is of formula (I-H), wherein R are defined herein.

Figure imgf000030_0003

(I-H)

In another embodiment, the compound is of formula (I-I), wherein R and R R are defined herein.

Figure imgf000031_0001

(I-I)

In still a further aspect, the compound is of formula (I-II), wherein R1 and R5 defined herein.

Figure imgf000031_0002

(i n)

In another embodiment, the compound is of formula (I-J), wherein R1 and R5 defined herein.

Figure imgf000031_0003

(I-J)

In still a further aspect, the compound is of formula (I-JJ), wherein R1 and R5 are defined herein.

Figure imgf000031_0004

(i-JJ) At various places in the present specification, substituents of compounds of the invention may be disclosed in groups. It is specifically intended that the invention include each and every individual subcombination of the members of such groups.

It is further appreciated that certain features of the invention, which are, for clarity, described in the context of separate embodiments, can also be provided in combination in a single embodiment. Conversely various features of the invention which are, for brevity, described in the context of a single embodiment can also be provided separately or in any suitable subcombination.

Some compounds within the present invention possess one or more chiral centers, and the present invention includes each separate enantiomer of such compounds as well as mixtures of the enantiomers. Where multiple chiral centers exist in compounds of the present invention, the invention includes each possible combination of chiral centers within a compound, as well as all possible enantiomeric and diastereomeric mixtures thereof. All chiral, diastereomeric, and racemic forms of a structure are intended, unless the specific stereochemistry or isomeric form is specifically indicated. It is well known in the art how to prepare optically active forms, such as by resolution of racemic forms or by synthesis from optically active starting materials. Compounds of the invention also include tautomeric forms.

Tautomeric forms result from the swapping of a single bond with an adjacent double bond together the concomitant migration of a proton. For example, enols and ketones are tautomers because they are rapidly interconverted by treatment with either acid or base. Another example of tautomerism is the aci- and nitro- forms of

phenylnitromethane, which are likewise formed by treatment with acid or base. Tautomeric forms may be relevant to the attainment of the optimal chemical reactivity and biological activity of a compound of interest.

For the purposes of the present disclosure, the terms "compound," "analog," and "composition of matter" stand equally well for kynurenine pathway and/or the IDO- and/or TDO inhibitors described herein including all enantiomeric forms, diastereomeric forms, racemic forms, tautomeric forms, salts, and the like and the terms "compound," "analog," and "composition of the matter" are used

interchangeably throughout the present specification.

For the purposes of the present disclosure, the terms "disease," "condition," and "disorder" stand equally well for conditions where a subject may benefit from regulation of kynurenine pathway and may be used interchangeably throughout the present specification.

METHODS OF SYNTHESIS

Methods useful for making the compounds of formula (I) are set forth in the Examples below and generalized in Schemes 1-12. One of skill in the art will recognize that Schemes 1-12 can be adapted to produce the other compounds of formula (I) and pharmaceutically acceptable salts of compounds of formula (I) according to the present invention.

Scheme 1

Figure imgf000033_0001

1 -A (l-BB)

Scheme 1 provides compounds of formula I-BB. The compound 1-A was treated R'-substituted aniline resulting in to the formation of imine intermediate which underwent Strecker reaction with alkylsilyl cyanide, alkali metal cyanide, zinc cyanide in the presence of a catalyst in acetonitrile to afford aminonitrile compound of formula 1-BB. In one embodiment the alkylsilyl cyanide was TMSCN. In yet another embodiment the catalyst was iodine. Scheme 1A

Figure imgf000034_0001

Scheme 1A provides compounds of formula 1-B. The commercially available furan-2-carbaldehyde 1-1 was treated with R'-substituted aniline resulting in to the formation of imine intermediate which underwent Strecker reaction with

trimethylsilyl cyanide in the presence of a catalyst in acetonitrile to afford aminonitrile compound of formula 1-B.

Scheme IB

Figure imgf000034_0002

Scheme IB depicts a synthesis of 2-((3-chloro-4-fluorophenyl)amino)-2- (furan-2-yl)acetonitrile 1-2. The commercially available furan-2-carbaldehyde 1-1 was treated with 3-chloro-4-fluoro-aniline resulting in to the formation of imine intermediate which underwent Strecker reaction with trimethylsilyl cyanide in the presence of a catalyst in acetonitrile to afford 2-(furan-2-yl)-2-

(phenylamino)acetonitrile 1-2 as light brown powder. In one embodiment the catalyst used was iodine to provide 2-(furan-2-yl)-2-(phenylamino)acetonitrile 1-2 as light brown powder. Scheme 2

Figure imgf000035_0001

1 -A

Scheme 2 provides compounds of formula I-BB. The compound 1-A was treated R'-substituted aniline resulting in to the formation of imine intermediate which underwent Strecker reaction with alkylsilyl cyanide, alkali metal cyanide, zinc cyanide in trifluoroethanol to afford aminonitrile compound of formula 1-BB. In one embodiment the alkylsilyl cyanide was TMSCN.

Scheme 2A

Figure imgf000035_0002

2-1 2-A

Scheme 2A provides compounds of formula 2-A. The commercially available thiophene-3-carbaldehyde 2-1 was treated with R'-substituted aniline resulting in to the formation of imine intermediate which underwent Strecker reaction with trimethylsilyl cyanide in trifluoroethanol to afford aminonitrile compound of formula

Scheme 2B

Figure imgf000035_0003

2-1

2-2 Scheme 2B depicts a synthesis of 2-((3-chloro-4-fluorophenyl)amino)-2- (thiophen-3-yl)acetonitrile 2-2. The commercially available thiophene-3-carbaldehyde 2-1 was treated with 3-chloro-4-fluoro-aniline resulting in to the formation of imine intermediate which underwent Strecker reaction with trimethylsilyl cyanide in trifluoroethanol to afford 2-((3-chloro-4-fluorophenyl)amino)-2-(thiophen-3- yl)acetonitrile 2-2 as light tan powder.

Scheme 3

Figure imgf000036_0001

3-D Scheme 3 provides compounds of formula 3-C and 3-D. A mixture of R1- substituted aniline and a compound of formula 3-A in an alcoholic solvent was stirred under inert atmosphere resulting in the formation of imine intermediate 3-B. In one embodiment the solvent was ethanol or methanol. The formed imine was either isolated by filtration or used directly in the same pot for formation of aminonitrile. After the completion of imine formation, alkylsilyl cyanide or sodium or potassium cyanide or zinc cyanide and a catalyst were added into the solution of 3-B in a mixture of solvents acetonitrile, trifluoroethane and dichloromethane and the resulting reaction mixture was stirred at room temperature to afford compound of formula 3-C. In one embodiment the catalyst used was iodine. In yet another embodiment the catalyst used was guanidine HCl. The compound of formula 3-C was acylated with an acylating reagent in presence of a base to afford compound of formula 3-D. In one embodiment the acylating reagent was acetyl chloride. In another embodiment the base used was triethylamine.

Scheme 3A

Figure imgf000037_0001

Scheme 3A provides compounds of formula 3-E and 3-F. A mixture of R'-substituted aniline and 5-chlorosalicylaldehyde 3-1 in ethanol was stirred under inert atmosphere resulting in the formation of imine intermediate 3-D. The formed imine was either isolated by filtration or used directly in the same pot for formation of aminonitrile. After the completion of imine formation, TMSCN and a catalyst were added into the solution of 3-D in a mixture of solvents acetonitrile, trifluoroethane and dichloromethane and the resulting reaction mixture was stirred at room temperature to afford compound of formula 3-E. In one embodiment the catalyst used was iodine. In yet another embodiment the catalyst used was guanidine HCl. The compound 3-E was acetylated with acetyl chloride in presence of a base such as triethylamine to give the compound of formula 3-F.

Scheme 3B

Figure imgf000038_0001

Scheme 3B depicts the synthesis of 2-(5-chloro-2-hydroxyphenyl)-2- ((3-chloro-4-fluorophenyl)amino)acetonitrile 3-3. A mixture of 3-chloro-4- fluoroaniline and 5-chlorosalicylaldehyde 3-1 in ethanol was stirred under inert atmosphere resulting in the formation of imine intermediate 3-2. The formed imine was either isolated by filtration or used directly in the same pot for formation of aminonitrile. After the completion of imine formation, TMSCN and a catalyst were added into the solution of 3-2 in a mixture of solvents acetonitrile, trifluoroethane and dichloromethane and the resulting reaction mixture was stirred at room temperature to afford 2-(5 -chloro-2-hydroxyphenyl)-2-((3 -chloro-4-fluorophenyl)amino)acetonitrile 3-3 as beige powder. In one embodiment the catalyst used was iodine. In yet another embodiment the catalyst used was guanidine HC1. The compound 3-3 was treated with acetyl chloride in the presence of triethylamine in DCM to afford 4-chloro-2- (((3-chloro-4-fluorophenyl)amino)(cyano)methyl)phenyl acetate 3-4 as yellow powder. Scheme 4

Figure imgf000039_0001

Scheme 4 describes the synthesis of compound 4-C. The synthesis started with the preparation of 4-B from R1 -substituted aniline 4-A by the amide formation and reduction processes. In one embodiment the amide formation was formylation. Then 2-hydroxy aromatic aldehyde was reacted with 4-B to give an imine intermediate which in turn was allowed to react in situ with alkylsilyl cyanide or sodium or potassium cyanide or zinc cyanide in presence of catalyst to afford the Strecker product 4-C. In one embodiment the catalyst used was iodine. In yet another embodiment the catalyst used was guanidine HC1. In yet another embodiment the solvents used were acetonitrile and trifluoroethanol.

Scheme 4A

Figure imgf000039_0002

Scheme 4A describes the synthesis of compound 4-E. The synthesis started with the preparation of 4-D from R'-substituted aniline 4-A by the formylation and reduction processes. Then 5-chloro-2-hydroxybenzaldehyde was reacted with 4-D to give an imine intermediate which in turn was allowed to react in situ with TMSCN in presence of catalyst in acetonitrile and trifluoroethanol to afford the Strecker product 4-E. In one embodiment the catalyst was iodine. Scheme 4B

Figure imgf000040_0001

Scheme 4B describes the synthesis of 2-(5-chloro-2-hydroxyphenyl)-2-((3- chloro-4-fluorophenyl)(methyl)amino)acetonitrile 4-3. The synthesis started with the preparation of 3-chloro-4-fluoro-N-methylaniline 4-2 from 3-chloro-4-fluoroaniline 4- 1 by the formylation and reduction processes. Then 5-chloro-2-hydroxybenzaldehyde was reacted with 4-2 to give an imine intermediate which in turn was allowed to react in situ with TMSCN in presence of catalyst in acetonitrile and trifluoroethanol to afford the Strecker product 2-(5-chloro-2-hydroxyphenyl)-2-((3-chloro-4- fluorophenyl)(methyl)amino)acetonitrile 4-3 as violet colored solid. In one embodiment the catalyst was iodine.

Scheme 5

Figure imgf000040_0002
Scheme 5 describe the synthesis of compound of formula 5-E. Compound 5-A was protected as a suitable substituted benzyl group. In one embodiment the protecting group was 4-methoxybenzyl group. The protected compound 5-B was treated with R1 -substituted aniline to furnish the imine intermediate which then reacted with alkylsilyl cyanide or sodium or potassium cyanide or zinc cyanide to afford the Strecker product 5-C. In one embodiment the alkylsilyl cyanide was TMSCN. The 5-C was acetylated with an acylating reagent in presence of a base to furnish compound of formula 5-D. In one embodiment the acylating reagent was acetyl chloride. In another embodiment the base was DIPEA. Finally deprotection was done on 5-D with a deprotecting reagent in acetonitrile or THF or DCM or DMF to afford compound of formula 5-H. In one embodiment, when the protecting group was alkoxy substituted benzyl group, the deprotecting reagent was monohydrate cerium chloride and sodium iodide.

Scheme 5A

Figure imgf000041_0001

Scheme 5A describe the synthesis of compound 5-H. 5-Chlorosalicylaldehyde 5-1 was protected with 4-methoxybenzyl group to give 5-chloro-2-((4- methoxybenzyl)oxy)benzaldehyde 5-2. The 5-2 was treated with R1 -substituted aniline to furnish the imine intermediate which then reacted with TMSCN to afford compound of formula 5-F. The 5-F was acetylated with acetyl chloride in the presence of DIPEA to furnish compound of formula 5-G. Finally debenzylation was done on 5-G with monohydrate cerium chloride and sodium iodide in acetonitrile to afford compound of formula 5-H.

Scheme

Figure imgf000042_0001

Scheme 5B describe the synthesis of N-((5-chloro-2- hydroxyphenyl)(cyano)methyl)-N-(3-chloro-4-fluorophenyl)acetamide 5-5. 5- Chlorosalicylaldehyde 5-1 was protected with 4-methoxybenzyl group to give 5- chloro-2-((4-methoxybenzyl)oxy)benzaldehyde 5-2. The 5-2 was treated with 3- chloro-4-fluorophenylamine to furnish the imine intermediate which then reacted with TMSCN to afford 2-(5-chloro-2-((4-methoxybenzyl)oxy)phenyl)-2-((3-chloro-4- fluorophenyl)amino)acetonitrile 5-3. The 5-3 was acetylated with acetyl chloride in the presence of DIPEA to furnish N-((5-chloro-2-((4- methoxybenzyl)oxy)phenyl)(cyano)methyl)-N-(3-chloro-4-fluorophenyl)acetamide 5- 4. Finally debenzylation was done on 5-4 with monohydrate cerium chloride and sodium iodide in acetonitrile to afford N-((5-chloro-2-hydroxyphenyl)(cyano)methyl)- N-(3 -chloro-4-fluorophenyl)acetamide 5-5. Scheme 6

Figure imgf000043_0001

Scheme 6 describes the synthesis of compound of formula 6-D. Compound 6- A was brominated to provide compound of formula 6-B. In one embodiment the brominating reagent was bromine. The compound 6-B was formylated with dimethylformamide in the presence of a base at low temperature to afford compound of formula 6-C. In one embodiment the base used was n-BuLi or LDA or LHMDS or t-BuLi. The resulting aldehyde 6-C was coupled with R1 -substituted aniline to yield imine intermediate which in situ underwent Strecker reaction in the presence of alkylsilyl cyanide or sodium or potassium cyanide or zinc cyanide in acetonitrile and TFE to provide compound of formula 6-D.

Scheme 6A

Figure imgf000043_0002

Scheme 6A describes the synthesis of compound of formula 6-E. 5-Chloro-2- hydroxypyridine 6-1 was brominated with bromine in acetic acid to give 3-Bromo-5- chloropyridin-2-ol 6-2. The 6-2 was formylated with dimethylformamide in the presence of n-BuLi at low temperature to afford 5-chloro-2-hydroxynicotinaldehyde 6-3. The resulting aldehyde was coupled with R'-substituted aniline to yield imine intermediate which in situ underwent Strecker reaction in the presence of TMSCN in acetonitrile and TFE to provide compound of formula 6-E.

Scheme 6B

Figure imgf000044_0001

Scheme 6B describes the synthesis of 2-(5-chloro-2-hydroxypyridin-3-yl)-2- ((3-chloro-4-fluorophenyl)amino)acetonitrile 6-4. 5-Chloro-2-hydroxypyridine 6-1 was brominated with bromine in acetic acid to give 3-Bromo-5-chloropyridin-2-ol 6- 2. The 6-2 was formylated with dimethylformamide in the presence of n-BuLi at low temperature to afford 5-chloro-2-hydroxynicotinaldehyde 6-3. The resulting aldehyde was coupled with 3-chloro-4-fluorophenylamine to yield imine intermediate which in situ underwent Strecker reaction in the presence of TMSCN in acetonitrile and TFE to provide 2-(5-chloro-2-hydroxypyridin-3-yl)-2-((3-chloro-4- fluorophenyl)amino)acetonitrile 6-4.

Scheme 7 R10 R11 D9 1 I p5

Figure imgf000044_0002
Scheme 7 depicts the synthesis of compound of formula 7-F. Compound of formula 7-A was protected as a MOM-ether with MOMCl in the presence of sodium hydride in DMF to afford 7-B. In one embodiment the base used was potassium or sodium tert butoxide, potassium or sodium carbonate. The protected compound 7-B was formylated to corresponding aldehyde 7-C in the presence of TMEDA, n-BuLi and DMF. In one embodiment, the formylating agent was N,N-diphenylformamide. In another embodiment the formylating agent was dichloromethyl methyl ether. The compound 7-C was deprotected using TMSC1 and sodium iodide to provide 7-D. In one embodiment the deprotecting reagent was HC1. The compound 7-D was acetylated with acetyl chloride in the presence of DMAP in DCM to afford the compound 7-E. The 7-E was treated with R'-substituted anilines to give an imine intermediate which in situ was converted to aminonitrile 7-F in the presence of trialkylsilyl cyanide such as TMSCN.

Scheme 7A

Figure imgf000045_0001

Scheme 7A depicts the synthesis of compound of formula 7-G. Commercially available 1-naphthol 7-1 was protected as a MOM-ether with MOMCl in the presence of sodium hydride in DMF to afford 7-2. The l-(methoxymethoxy)naphthalene 7-2 was formylated to corresponding aldehyde 7-3 in the presence of TMEDA, n-BuLi and DMF. The l-(methoxymethoxy)-2-naphthaldehyde 7-3 was deprotected with

TMSC1 and sodium iodide to provide 7-4 which was acetylated with acetyl chloride in the presence of DMAP in DCM to afford 2-formylnaphthalen-l-yl acetate 7-5. The 7- 5 was treated with R -substituted aniline to give an imine intermediate which in situ was converted to aminonitrile 7-G in the presence of TMSCN.

Scheme 7B

Figure imgf000046_0001

7-5 7-6

Scheme 7B depicts the synthesis of 2-((3-chloro-4- fluorophenyl)carbamoyl)naphthalen-l-yl acetate 7-6. Commercially available 1- naphthol 7-1 was protected as a MOM-ether with MOMCl in the presence of sodium hydride in DMF to afford 7-2. The l-(methoxymethoxy)naphthalene 7-2 was formylated to corresponding aldehyde 7-3 in the presence of TMEDA, n-BuLi and DMF. The l-(methoxymethoxy)-2-naphthaldehyde 7-3 was deprotected with TMSC1 and sodium iodide to provide 8-4 which was acetylated with acetyl chloride in the presence of DMAP in DCM to afford 2-formylnaphthalen-l-yl acetate 7-5. The 7-5 was treated with 3-chloro-4-fluorophenylamine to give imine intermediate which in situ converted in to aminonitrile 7-6 in the presence of TMSCN.

Scheme 8

Figure imgf000047_0001

8-B 8-C

Scheme 8 describes the synthesis of compound of formula 8-C. Compound of formula 8-B was prepared from compound of formula 8-A with the reaction of cyclopropanecarbonyl chloride in the presence of triethylamine and DMAP in DCM, which was then coupled with R1 -substituted aniline to give imine intermediate which in turn underwent the Strecker reaction with TMSCN to afford the compound 8-C.

Scheme 8A

Figure imgf000047_0002

8-1 8-2 8-D Scheme 8A describes the synthesis of compound of formula 8-D. 4-Chloro-2- formylphenyl cyclopropanecarboxylate 8-2 was prepared from 5- chlorosalicylaldehyde 8-1 with the reaction of cyclopropanecarbonyl chloride in the presence of triethylamine and DMAP in DCM, which was then coupled with R1- substituted aniline to give imine intermediate which in turn underwent the Strecker reaction with TMSCN to afford the compound 8-D. Scheme 8B

Figure imgf000048_0001

Scheme 8B describes the synthesis of 4-chloro-2-(((3-chloro-4- fluorophenyl)amino)(cyano)methyl)phenyl cyclopropanecarboxylate 8-3. 4-Chloro-2- formylphenyl cyclopropanecarboxylate 8-2 was prepared from 5- chlorosalicylaldehyde 8-1 with the reaction of cyclopropanecarbonyl chloride in the presence of triethyl amine and DMAP in DCM, which was then coupled with 3- chloro-4-fluorophenylamine to give imine intermediate which in turn underwent the Strecker reaction with TMSCN to afford the target 4-chloro-2-(((3-chloro-4- fluorophenyl)amino)(cyano)methyl)phenyl cyclopropanecarboxylate 8-3.

Scheme 9

Figure imgf000048_0002

9-A 9-B 9-C

Scheme 9 describes the synthesis of compound of formula 9-C. The synthesis started with compound of formula 9-A which was treated an oxidizing agent to afford the corresponding aldehyde 9-B. In one embodiment the oxidizing agent was Dess- Martin periodinane. In another embodiment the oxidizing agent was manganese dioxide. In yet another embodiment the oxidizing agent was selenium dioxide. In one embodiment the reaction was done in DCM. The aldehyde 9-B was reacted with R1- substituted aniline to give an imine intermediate which underwent Strecker reaction with trialkylsilyl cyanide such as TMSCN in the mixture of acetonitrile, TFE and dichloromethane to afford compound of formula 9-C.

Scheme 9A

Figure imgf000049_0001
Scheme 9A describes the synthesis of compound of formula 9-D. The synthesis started with pyrazine-methyl alcohol 9-1 which was treated with Dess- Martin periodinane reagent in DCM to afford the corresponding aldehyde 9-2. The pyrazine-2-carbaldehyde 9-2 was reacted with R1 -substituted aniline to give an imine intermediate which underwent Strecker reaction with TMSCN in the mixture of acetonitrile, TFE and dichloromethane to afford 2-((3-chloro-4-fluorophenyl)amino)- 2-(pyrazin-2-yl)acetonitrile 9-D.

Scheme 9B

Figure imgf000049_0002

Scheme 9B describes the synthesis of 2-((3-chloro-4-fluorophenyl)amino)-2- (pyrazin-2-yl)acetonitrile 9-3. The synthesis started with pyrazine-methyl alcohol 9-1 which was treated with Dess-Martin periodinane reagent in DCM to afford the corresponding aldehyde 9-2. The pyrazine-2-carbaldehyde 9-2 was reacted with 3- chloro-4-fluorophenylamine to give imine intermediate which underwent Strecker reaction with TMSCN in the mixture of acetonitrile, TFE and dichloromethane to afford 2-((3-chloro-4-fluorophenyl)amino)-2-(pyrazin-2-yl)acetonitrile 9-3. Scheme 10

Figure imgf000050_0001

10-A 10-B

Figure imgf000050_0002

Scheme 10 describes the synthesis of compound of formula 10-D. The compound 10-A was oxidized to the N-oxide product 10-B. In one embodiment the oxidizing agent was MCPBA in DCM. The compound 10-B was further oxidized to compound 10-C. In one embodiment the oxidizing reagent was manganese or selenium oxide. The compound 10-C underwent coupling reaction with R'-substitute aniline followed by Strecker reaction with trialkylsilyl cyanide such as TMSCN to give the product 10-E.

Scheme 10A

Figure imgf000050_0003

Scheme 10A describes the synthesis of compound of formula 10-E. The pyridine-2-ylmethanol 10-1 was treated with MCPBA in DCM to give the N-oxide product 10-2. The 2-(hydroxymethyl)pyridine-l -oxide underwent oxidation with Dess-Martin periodinane to afford 2-formylpyridine-l -oxide 10-3. The 10-3 underwent coupling reaction with R -substitute aniline followed by Strecker reaction with TMSCN to give the product 10-E.

Scheme 10B

Figure imgf000051_0001

Scheme 10B describes the synthesis of 2-(((3-chloro-4- fluorophenyl)amino)(cyano)methyl)pyridine-l -oxide 10-4. The pyridine-2-ylmethanol 10-1 was treated with m-CPBA in DCM to give the N-oxide product 10-2. The 2- (hydroxymethyl)pyridine-l -oxide underwent oxidation with Dess-Martin periodinane to afford 2-formylpyridine-l -oxide 10-3. The 10-3 underwent coupling reaction with 3-chloro-4-fluorophenylamine followed by Strecker reaction with TMSCN to give the desired product 2-(((3-chloro-4-fluorophenyl)amino)(cyano)methyl)pyridine-l-oxide 10-4.

Scheme 11

Figure imgf000051_0002

11-E 1 1 -F 11-G

Scheme 11 describes the synthesis of compound of formula 11-G. The compound of formula 11-A was treated with MOMC1 in the presence of potassium tert-butoxide in THF/DMF to give MOM protected compound 11-B which underwent methoxylation with sodium methoxide to afford 2-methoxy-3- (methoxymethoxy)pyridine 11-C. In one embodiment the base used in the above transformation was sodium hydride or potassium/sodium carbonate. The compound 11-C was formylated with DMF in the presence of n-BuLi and TMEDA resulting in the formation of 11-D. The aldehyde 11-D was deprotected using an acid to give 11- E. In one embodiment the acid was HC1. The aldehyde 11-E was coupled with R1- substituted aniline to give imine intermediate 11-F which was converted to the product 11-G under Strecker reaction condition using trialkylsilyl cyanide such as TMSCN in acetonitrile and dichloromethane.

Scheme 11A

Figure imgf000052_0001

11 -5 11 -1

Scheme 11A describes the synthesis of compound of formula 11-1. The compound 2-chloro-3-hydroxypyridine 11-1 was treated with MOMCl in the presence of potassium tert-butoxide in THF/DMF to give MOM protected compound 11-2 which underwent methoxylation with sodium methoxide to afford 2-methoxy-3- (methoxymethoxy)pyridine 11-3. The 11-3 was formylated with DMF in the presence of n-BuLi and TMEDA resulting in the formation of 11-4. The 3-Hydroxy-2- methoxyisonicotinaldehyde 11-4 was deprotected using 3N HC1 to give 11-5. The 3- hydroxy-2-methoxyisonicotinaldehyde 11-5 was coupled with R1 -substituted aniline to give imine intermediate 11-H which was converted to the product 11-1 under Strecker reaction condition using TMSCN in acetonitrile and dichloromethane. Scheme 11B

Figure imgf000053_0001

11-5 11-7

11-6

Scheme 11B describes the synthesis of 2-((3-chloro-4-fluorophenyl)amino)-2- (2-methoxypyridin-4-yl)acetonitrile 11-7. 2-chloro-3-hydroxypyridine 11-1 was treated with MOMCl in the presence of potassium tert-butoxide in THF/DMF to give MOM protected compound 11-2 which underwent methoxylation with sodium methoxide to afford 2-methoxy-3-(methoxymethoxy)pyridine 11-3. The 11-3 was formylated with DMF in the presence of n-BuLi and TMEDA resulting in the formation of 11-4. The 3-Hydroxy-2-methoxyisonicotinaldehyde 11-4 was deprotected using 3N HC1 to give 11-5. The 3-hydroxy-2-methoxyisonicotinaldehyde 11-5 was coupled with 3-chloro-4-fluorophenyl amine to give imine intermediate 11-6 which was converted to the desired product 2-((3-chloro-4-fluorophenyl)amino)-2-(2- methoxypyridin-4-yl)acetonitrile 11-7 under Strecker reaction condition using TMSCN in acetonitrile and dichloromethane.

Scheme-12

Figure imgf000054_0001

Scheme 12 describes the synthesis of compound of formula 12-F. Compound of formula 12-A was treated with MOMC1 in the presence of potassium tert-butoxide in THF/DMF to give MOM protected compound 12-B. In one embodiment the base used was sodium or potassium hydride. In another embodiment the base was sodium or potassium carbonate. In yet another embodiment the base used was butyl lithium or other related bases known to those skilled in the art. The compound 12-B was converted to the acyl product 12-D via the intermediate 12-C. Treatment of 12-B with acetaldehyde in the presence of n-BuLi and TMEDA or HMPA resulting in the formation of 12-C. In one embodiment the base used was tert butyl lithium. In another embodiment the base used was LDA. The compound 12-C was oxidized with Dess Martin Periodenane to afford the ketone 12-D which was deprotected using an acid. In one embodiment the acid used was dilute HC1 to give 12-E. The compound 12-E was coupled with R1 -substituted aniline in DCM to give imine intermediate which in-situ reacted with trialkylsilyl cyanide such as TMSCN and a catalyst such as TMSOTf to give the compound of formula 12-F under Strecker reaction conditions. Scheme-12A

Figure imgf000055_0001

Scheme 12A describes the synthesis of compound of formula 12-G. 3- Hydroxypyridine 12-1 was treated with MOMC1 in the presence of potassium tert- butoxide in THF/DMF to give MOM protected compound 12-2. The 12-2 was reacted with acetaldehyde in the presence of n-BuLi and TMEDA resulting in the formation of 12-3. The l-(3-(methoxymethoxy)pyridin-4-yl)ethanol 12-3 was oxidized with Dess Martin Periodenane to afford 12-4 which was deprotected using 3N HCl to give 12-5. The l-(3-hydroxypyridin-4-yl)ethanone 11-5 was coupled with R'-substituted aniline in DCM to give imine intermediate which in-situ reacted with TMSCN in the presence of TMSOTf to give the compound of formula 12-G under Strecker reaction condition.

Scheme-12B

Figure imgf000055_0002

12-1 12-2 12-3 12-4

Figure imgf000055_0003
Scheme 12B describes the synthesis of 2-((3-chloro-4-fluorophenyl)amino)-2- (3-hydroxypyridin-4-yl)propanenitrile 12-6. 3-Hydroxypyridine 12-1 was treated with MOMC1 in the presence of potassium tert-butoxide in THF/DMF to give MOM protected compound 12-2. The 12-2 was reacted with acetaldehyde in the presence of n-BuLi and TMEDA resulting in the formation of 12-3. The l-(3-

(methoxymethoxy)pyridin-4-yl)ethanol 12-3 was oxidized with Dess Martin

Periodenane to afford 12-4 which was deprotected using 3N HC1 to give 12-5. The 1- (3-hydroxypyridin-4-yl)ethanone 11-5 was coupled with 3-chloro-4-fluorophenyl amine in DCM to give imine intermediate which in situ reacted with TMSCN in the presence of TMSOTf to give the desired product 2-((3-chloro-4-fluorophenyl)amino)- 2-(3-hydroxypyridin-4-yl)propanenitrile 12-6 under Strecker reaction condition.

PRODRUGS

One aspect of the invention is directed to prodrugs of aminonitriles. In a further embodiment, a compound of the invention may be a prodrug of a compound of formula (I). In one embodiment, the prodrug is an acetylated compound of formula (I). In another embodiment, the prodrug is a carbamate and/or carbonate of the compound of formula (I). In a further embodiment, the prodrug contains one carbamate or carbonate group. In yet another embodiment, the prodrug contains a carbamate and a carbonate groups. In still a further embodiment, the carbamate or carbonate group is selected from the following:

Figure imgf000056_0001
wherein Y is defined as N or O and Z is defined as alkyl, arylalkyl, and suitably substituted alkoxyalkyl.

Prodrugs of compounds of formula (I) may be prepared and used as a means to modulate the pharmacokinetic properties, using various methods known to those skilled in the art. See, e.g., Rautio, Nature Reviews Drug Discovery, 7:255-270 (2008) and Ettmayer, J. Med. Chem., 47:2393-2404 (2004), which are hereby incorporated by reference. In the case of drugs containing a hydroxy moiety, acetyl and other ester analogs are contemplated for use as prodrugs. See, e.g. , Beaumont, Current Drug Metabolism, 4:461-485 (2003), which is hereby incorporated by reference. In the case of drugs containing an amine moiety, prodrugs containing amides and carbamates are contemplated. See, e.g. , Simplicio, Molecules, 13 :519- 547 (2008), which is hereby incorporated by reference. As specific examples, (alkoxycarbonyloxy)alkyl carbamates, (acyloxy)alkyl carbamates, and

(oxodioxolenyl)alkyl carbamates and corresponding carbonates may be utilized as effective prodrug strategies for amines. See, e.g. , Li, Bioorg. Med. Chem. Lett., 7:2909-2912 (1997); Alexander, J. Med. Chem., 34:78-81 (1991); Alexander, J. Med. Chem., 31 :318-322 (1988); and Alexander, J. Med. Chem., 39:480-486 (1996), all of which are incorporated by reference herein.

Acetyl, carbamate, carbonate and ester prodrugs of compounds of Formula (I) may be prepared using the methods described herein. In one embodiment, a compound of Formula (I) may be reacted with an acyl chloride. In yet another embodiment, a compound of Formula (I) may be reacted with an alkyl or substituted alkyl chloroformates. In another embodiment, the acyl chloride may be RZC(0)C1, where Rz is C -Ce optionally substituted alkyl, C6-C10 optionally substituted aryl, or heteroaryl. In a further embodiment, the reaction may be performed in the presence of a base such as potassium tert-butoxide, to provide a prodrug of compound (I). Acetyl, amide, carbamate or carbonate prodrugs of compounds of Formula (I) may be prepared by using the methods described herein. In one embodiment, compounds of Formula (I) are reacted with an acyl chloride. In another embodiment, the acyl chloride is RZC(0)C1, wherein Rz is defined above. In a further embodiment, the reaction may be performed in the presence of a base such as pyridine. As well, acetyl amide prodrugs of compounds of formula (I) may be prepared by reaction of a compound of Formula (I) with MeCN. In one embodiment, the reaction is performed under acidic conditions.

PHARMACEUTICAL COMPOSITIONS

Pharmaceutical compositions useful herein contain a compound of formula (I) in a pharmaceutically acceptable carrier optionally with other pharmaceutically inert or inactive ingredients. In another embodiment, a compound of formula (I) is present in a single composition. In a further embodiment, a compound of formula (I) is combined with one or more excipients and/or other therapeutic agents as described below. The pharmaceutical compositions of the invention comprise an amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof that is effective for regulating the kynurenine pathway in a subject. The pharmaceutical compositions of the invention comprise an amount of a compound of formula (I) or

pharmaceutically acceptable salt there of that is effective for regulating indoleamine 2,3-dioxygenase and/or tryptophan 2,3-dioxygenase activity in a subject. Specifically, the dosage of the compound of formula (I) to achieve a therapeutic effect will depend on the formulation, age, weight and sex of the patient and route of delivery. It is also contemplated that the treatment and dosage of the compound of formula (I) may be administered in unit dosage form and that one skilled in the art would adjust the unit dosage form accordingly to reflect the relative level of activity. The decision as to the particular dosage to be employed (and the number of times to be administered per day) is within the discretion of the ordinarily-skilled physician, and may be varied by titration of the dosage to the particular circumstances to produce the desired therapeutic effect. In one embodiment, the therapeutically effective amount is about 0.01 mg/kg to 10 mg/kg body weight. In another embodiment, the therapeutically effective amount is less than about 5 mg/kg, about 500 mg/kg, about 400 mg/kg, about 300 mg/kg, about 200 mg/kg, about 100 mg/kg, about 50 mg/kg, about 25 mg/kg, about 10 mg/kg, about 1 mg/kg, about 0.5 mg/kg, about 0.25 mg/kg, about 0.1 mg/kg, about 100 μg/kg, about 75 μg/kg, about 50 μg/kg, about 25 μg/kg, about 10 μg kg, or about 1 μg/kg. However, the therapeutically effective amount of the compound of formula (I) can be determined by the attending physician and depends on the condition treated, the compound administered, the route of delivery, the age, weight, severity of the patient's symptoms and response pattern of the patient.

The therapeutically effective amounts may be provided on regular schedule, /'. e. , daily, weekly, monthly, or yearly basis or on an irregular schedule with varying administration days, weeks, months, etc. Alternatively, the therapeutically effective amount to be administered may vary. In one embodiment, the therapeutically effective amount for the first dose is higher than the therapeutically effective amount for one or more of the subsequent doses. In another embodiment, the therapeutically effective amount for the first dose is lower than the therapeutically effective amount for one or more of the subsequent doses. Equivalent dosages may be administered over various time periods including, but not limited to, about every 2 hours, about every 6 hours, about every 8 hours, about every 12 hours, about every 24 hours, about every 36 hours, about every 48 hours, about every 72 hours, about every week, about every two weeks, about every three weeks, about every month, about every two months and twice a year. The number and frequency of dosages corresponding to a completed course of therapy will be determined according to the judgment of a health-care practitioner. The therapeutically effective amounts described herein refer to total amounts administered for a given time period; that is, if more than one compound of formula (I) or a pharmaceutically acceptable salt thereof is

administered, the therapeutically effective amounts correspond to the total amount administered.

The pharmaceutical compositions containing a compound of formula (I) may be formulated neat or with one or more pharmaceutical carriers for administration. The amount of the pharmaceutical carrier(s) is determined by the solubility and chemical nature of the compound of formula (I), chosen route of administration and standard pharmacological practice. The pharmaceutical carrier(s) may be solid or liquid and may incorporate both solid and liquid carriers. A variety of suitable liquid carriers are known and may be readily selected by one of skill in the art. Such carriers may include, e.g., DMSO, saline, buffered saline, hydroxypropylcyclodextrin, and mixtures thereof. Similarly, a variety of solid carriers and excipients are known to those of skill in the art. The compounds of formula (I) may be administered by any route, taking into consideration the specific condition for which it has been selected. The compounds of formula (I) may, be delivered orally, by injection, inhalation (including orally, intranasally and intratracheally), ocularly, transdermally, intravascularly, subcutaneously, intramuscularly, sublingually, intracranially, epidurally, rectally, and vaginally, among others. Although the compound of formula (I) may be administered alone, it may also be administered in the presence of one or more pharmaceutical carriers that are physiologically compatible. The carriers may be in dry or liquid form and must be pharmaceutically acceptable. Liquid pharmaceutical compositions are typically sterile solutions or suspensions. When liquid carriers are utilized for parenteral administration, they are desirably sterile liquids. Liquid carriers are typically utilized in preparing solutions, suspensions, emulsions, syrups and elixirs. In one

embodiment, the compound of formula (I) is dissolved a liquid carrier. In another embodiment, the compound of formula (I) is suspended in a liquid carrier. One of skill in the art of formulations would be able to select a suitable liquid carrier, depending on the route of administration. The compound of formula (I) may alternatively be formulated in a solid carrier. In one embodiment, the composition may be compacted into a unit dose form, i.e. , tablet or caplet. In another embodiment, the composition may be added to unit dose form, i.e., a capsule. In a further embodiment, the composition may be formulated for administration as a powder. The solid carrier may perform a variety of functions, /'. e. , may perform the functions of two or more of the excipients described below. For example, solid carrier may also act as a flavoring agent, lubricant, solubilizer, suspending agent, filler, glidant, compression aid, binder, disintegrant, or encapsulating material. The composition may also be sub-divided to contain appropriate quantities of the compound of formula (I). For example, the unit dosage can be packaged compositions, e.g., packeted powders, vials, ampoules, prefilled syringes or sachets containing liquids.

Examples of excipients which may be combined with one or more compound of formula (I) include, without limitation, adjuvants, antioxidants, binders, buffers, coatings, coloring agents, compression aids, diluents, disintegrants, emulsifiers, emollients, encapsulating materials, fillers, flavoring agents, glidants, granulating agents, lubricants, metal chelators, osmo-regulators, pH adjusters, preservatives, solubilizers, sorbents, stabilizers, sweeteners, surfactants, suspending agents, syrups, thickening agents, or viscosity regulators. See, for example, the excipients described in the "Handbook of Pharmaceutical Excipients", 5th Edition, Eds.: Rowe, Sheskey, and Owen, APhA Publications (Washington, DC), December 14, 2005, which is incorporated herein by reference.

In one embodiment, the compositions may be utilized as inhalants. For this route of administration, compositions may be prepared as fluid unit doses using a compound of formula (I) and a vehicle for delivery by an atomizing spray pump or by dry powder for insufflation.

In another embodiment, the compositions may be utilized as aerosols, i.e. , oral or intranasal. For this route of administration, the compositions are formulated for use in a pressurized aerosol container together with a gaseous or liquefied propellant, e.g., dichlorodifluoromethane, carbon dioxide, nitrogen, propane, and the like. Also provided is the delivery of a metered dose in one or more actuations.

In another embodiment, the compositions may be administered by a sustained delivery device. "Sustained delivery" as used herein refers to delivery of a compound of formula (I) which is delayed or otherwise controlled. Those of skill in the art know suitable sustained delivery devices. For use in such sustained delivery devices, the compound of formula (I) is formulated as described herein.

TREATMENT METHODS UTILIZING THE COMPOUNDS OF THE INVENTION

The compounds described herein are useful in regulating diseases which are associated with increased immune suppression resulting from dysregulation of the kynurenine pathway due to activation of indoleamine 2,3-dioxygenase and/or tryptophan 2,3-dioxygenase. In one embodiment, such a disease is associated with abnormal cellular proliferation. The term "abnormal cellular proliferation" refers to the uncontrolled growth of cells which are naturally present in a mammalian body. In one embodiment, a disease which is characterized by abnormal cellular proliferation is cancer, including, without limitation, cancer of the prostate, head, neck, eye, mouth, throat, esophagus, bronchus, larynx, pharynx, chest, bone, lung, colon, rectum, stomach, bladder, uterus, cervix, breast, ovaries, vagina, testicles, skin, thyroid, blood, lymph nodes, kidney, liver, intestines, pancreas, brain, central nervous system, adrenal gland, or skin or a leukemia. The term "regulation" or variations thereof as used herein refers to the ability of a compound of formula (I) to inhibit one or more components of a biological pathway. In one embodiment, "regulation" refers to a decrease in plasma or tissue concentrations of kynurenine. In another embodiment, "regulation" refers to inhibition of indoleamine 2,3-dioxygenase activity. In another embodiment, "regulation" refers to inhibition of or tryptophan 2,3-dioxygenase activity. In a further embodiment, regulation refers to dual inhibition of indoleamine 2,3- dioxygenase and tryptophan 2,3-dioxygenase activity.

The compounds of the present invention inhibit the production of kynurenine pathway metabolites. The compounds of the present invention can also inhibit the activity of enzymes indoleamine-2-3-dioxygenase (IDO) or tryptophan 2,3- dioxygenase (TDO) or both. As a non-limiting example, the compounds of the invention can be used to inhibit activity of IDO in cell-free systems, cells, tissues, or in an individual in need of regulation of the enzyme by administering an inhibiting amount or effective amount of a compound of the invention. The utility of the compounds of formula (I) can be illustrated, as an example, by their activity in the in vitro cell-free and cell based assays described in Examples 13 and 14 below.

The present invention further provides methods of inhibiting degradation of tryptophan in a system containing cells expressing IDO such as a tissue, living organism, serum, or cell culture. For a non-limiting example, see Example 14. In some embodiments, the present invention provides methods for altering extracelllar tryptophan levels in a mammal by administering an effective amount of a compound of composition provided herein. Methods of measuring tryptophan levels and tryptophan catabolites or degradation products are routine in the art.

The compounds of the present invention are used as therapeutic agents for the treatment of conditions in mammals. Specifically these compounds can be used for the treatment of disease, disorder, or condition directly or indirectly related to kynurenine pathway. The compounds of the invention can also be used to inhibit the activity of indoleamine 2,3-dioxygenase (IDO) or tryptophan 2,3-dioxygenase (TDO) or both. The present invention provides methods of treating conditions or diseases associated with dysregulated kynurenine pathway. The present invention further provides methods of treating disease associated with activity of, including abnormal activity of IDO or TDO or both in an individual by administering to the individual in need of such treatment a therapeutically effective amount or dose of a compound of the present invention or a pharmaceutical composition thereof. Kynurenine pathway related disease or an IDO- or TDO-related disease can be any disease, disorder or condition that can be prevented, ameliorated or cured by regulating enzyme activity.

In one embodiment, methods for regulating kynurenine pathway are provided, said method comprising administering a compound of formula (I) to a patient in need thereof. In another embodiment, methods for inhibiting kynurenine pathway are provided, said method comprising administering a compound of formula (I) to a patient in need thereof. In yet another embodiment, methods for inhibiting the activity of indoleamine 2,3-dioxygenase or tryptophan 2,3-dioxygenase or both are provided comprising administering a compound of formula (I) to a patient in need thereof.

In one embodiment, methods for treating a condition associated with dysregulated kynurenine pathway are provided, said method comprising

administering a compound of formula (I) to a patient in need thereof. In one embodiment, such a condition is immunosuppression. The terms "immune suppression" used throughout the present disclosure refers to suppression of the body's immune system and its ability to fight infections and other diseases. The suppression of the immune system may be partial or complete. Immunosuppression may result from certain diseases such as chronic infections, for example AIDS, or cancer such as lymphoma. In addition, immunosuppression may result from disease treatment, for example, from treatment with anticancer drugs. The compounds of formula (I) regulate kynurenine pathway in which indoleamine 2,3-dioxygenase or tryptophan 2,3-dioxygenase or both play a role and therefore can be utilized to inhibit immunosuppression. Thus, the compounds of formula (I) are effective in the treatment of diseases, disorders or conditions with which immunosuppressive actions of dysregulated activity of indoleamine 2,3-dioxygenase or tryptophan 2,3- dioxygenase or both are associated, such as infection and cancer. In one embodiment, methods of treating a disease characterized by immunosuppression associated with dysregulated kynurenine pathway are provided, said methods comprising administering a compound of formula (I) to a patient in need thereof. In another embodiment, methods for reducing immunosuppression associated with dysregulated kynurenine pathway are provided. The present invention further provides methods of inhibiting immunosuppression, such as IDO- and/or TDO- mediated immunosuppression, in a patient in need thereof by administering to the patient an effective amount of a compound or composition of invention. Dysregulated Kynurenine pathway and IDO-associated immunosuppression have been observed in patients with cancers, tumor growth, metastasis, viral infection, bacterial infection etc. In one embodiment, the disease is a viral infection. In another embodiment, the viral infection is HIV infection.

Where immunosuppression is desired for treatment of a condition or disease or for a procedure such as preparation for bone marrow or other organ transplantation, immunosuppression is induced with drugs to prevent rejection of the donor tissue. The present invention also provides methods to induce faster recovery from immunosuppression after bone marrow treatment or other organ transplantation to fight infection post-procedure. One of skill in the art would understand that there is an established link between kynurenine pathway metabolites and immunosuppression in the clinical setting.

In yet a further aspect, a method for treating a disease characterized by an abnormal cellular proliferation associated with a dysregulated kynurenine pathway is provided comprising administering a compound described herein to a subject in need thereof. The term "abnormal cellular proliferation" refers to the uncontrolled growth of cells which are naturally present in a mammalian body. In one embodiment, a disease which is characterized by abnormal cellular proliferation is cancer, including, without limitation, cancer of the prostate, head, neck, eye, mouth, throat, esophagus, bronchus, larynx, pharynx, chest, bone, lung, colon, rectum, stomach, bladder, uterus, cervix, breast, ovaries, vagina, testicles, skin, thyroid, blood, lymph nodes, kidney, liver, intestines, pancreas, brain, central nervous system, adrenal gland, or skin or a leukemia. In one embodiment, the disease characterized by abnormal cellular proliferation is cancer.

The compounds of formula (I) exhibit indoleamine 2,3-dioxygenase or tryptophan 2,3-dioxygenase inhibitory activity, and therefore can be utilized in order to inhibit immunosuppression associated with abnormal cellular proliferation in which indoleamine 2,3-dioxygenase or tryptophan 2,3-dioxygenase or both play a role. Thus, the compounds of formula (I) are effective in the treatment of disorders with which immunosuppressive actions of indoleamine 2,3-dioxygenase or tryptophan 2,3- dioxygenase or both are associated, such as cancer. One of skill in the art would understand that there is an established link between decreased kynurenine pathway metabolites and anti-tumor activity in the clinical setting. One of skill in the art would further understand that there is established link between kynurenine pathway metabolites and inflammation in the clinical setting.

In another embodiment, methods for treating a disease characterized by an abnormal cellular proliferation resulting from a dysregulated indoleamine 2,3- dioxygenase or tryptophan 2,3-dioxygenase pathway are provided and include administering of a compound of formula (I) to a patient in need thereof.

In still a further aspect, a method for treating a disease characterized by inflammation associated with a dysregulated kynurenine pathway is provided comprising administering a compound described herein to a subject in need thereof.

In one embodiment, such a disease, disorder or condition is an inflammatory disorder. Accordingly, the compounds and pharmaceutical compositions provided herein find use as therapeutics for preventing and/or treating diseases associated with kynurenine pathway dysregulation. The compounds and pharmaceutical compositions also find use as therapeutics for preventing and/or treating IDO- and/or TDO-related diseases that include cancer, bacterial infection, viral infection like HIV infection, HCV infection, parasitic diseases, diseases of Central and Peripheral Nervous System, neurodegenerative diseases, autoimmune disorders neuropsychiatric diseases such as depression, cardiovascular diseases, metabolic syndrome, inflammatory diseases, immune-related diseases, and T-cell mediated immune diseases. In yet another aspect, the present invention provides methods of treating cancer, viral infection, bacterial infection parasitic infection, a neurodegenerative disorder, organ transplant rejection, an inflammatory disease, cardiovascular disease, a mood disorder, an autoimmune disease, immune-mediated disorders in a patient comprising administering to said patient a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt or prodrug thereof. In one embodiment, the disease is cancer.

In yet a further embodiment, methods for reducing or eliminating an immune mediated disorder are provided and include administering a compound of formula (I) to a patient in need thereof.

As described herein, a therapeutically effective amount of a compound when used for the treatment of cancer is an amount which may reduce the number of cancer cells, reduce tumor size, inhibit metastasis, inhibit tumor growth and/or ameliorate one or more of the symptoms of the cancer. For cancer therapy, efficacy can be measured for example, by assessing the time to disease progression and/or determining the response rate.

Thus, and as stated earlier, the present invention includes within its scope, and extends to, the recited methods of treatment, as well as to the compounds for such methods, and to the use of such compounds for the preparation of medicaments useful for such methods.

The details of the various diseases or conditions are given below:

Cancer: Examples of cancers treatable by methods herein include but are not restricted to melanoma, colon cancer, pancreatic cancer, breast cancer, prostate cancer, lung cancer, leukemia, brain tumors, lymphoma, sarcoma, ovarian cancer, and Kaposi's sarcoma. Other cancers and tumors that may be targeted include adrenocortico-cancer, basal cell carcinoma, bladder cancer, bowel cancer, brain and CNS tumors, breast cancers, B-cell lymphoma, carcinoid tumors, cervical cancers, childhood cancers, chondrosarcomas, chronic myeloid leukemia, rectal cancer, endocrine cancers, endometrial cancers, esophageal cancer, Ewing's sarcoma, eye cancer, gastric cancer or carcinoma, gastrointestinal cancers, genitourinary cancers, glioma, gynecological cancers, head and neck cancers, hepatocellular cancers, Hodgkin's disease, hypo pharynx cancer, islet cell cancer, kidney cancer, laryngeal cancer, liver cancer, lung cancer (include small cell lung carcinoma and non-small cell lung carcinoma), lymphoma, male breast cancer, melanoma, mesothelioma, multiple myeloma, nasopharyngeal cancer, neuroblastoma, non-Hodgkin's lymphoma, non-melanoma skin cancer, osteosarcoma, ovarian cancer, pancreases cancer pituitary cancer, prostate cancer, renal cell carcinoma, retinoblastoma, rhabdomyosarcoma, sarcoma, skin cancer, squamous cell carcinoma, stomach cancer, testicular cancer or seminoma, thymus cancer, thyroid cancer, transitional cell cancer, trophoblastic cancer, uterine cancer, vaginal cancer, Waldenstrom's

macroglobulinemia and Wilm's tumors, colorectal, cervical, endometrium, ovarian cancer, testicular cancer, cancer of mesothelial lining, cancers of white blood cells (including lymphoma and leukemia), esophagus, muscle, connective tissue, adrenal gland, bone, glioblastoma, and cutaneous basocellular carcinoma.

Bacterial infections: Examples of bacterial infections treatable by methods herein include chlamydia psittaci infection and streptococcus pyrogens infection. Particular intracellular bacterial infections may be selected from the group consisting of Mycobacterium leprae, Mycobacterium tuberculosis, Listeria monocytogens and Toxplasma gondii.

Viral infections: Examples of viral infections treatable by methods herein include HIV, Hepatitis C, Hepatitis B, influenza, SARS, and cytomegalo virus.

Parasitic diseases: Examples of parasitic diseases treatable by methods herein include Leishmania donovani, Leishmania tropica, Leishmania major, Leishmania aethiopica, Leishmania maxicana, Plasmodium facciparum, Plasmodium vivax, Plasmodium ovale and Plasmodium malariae.

Autoimmune disorders: Examples of autoimmune disorders treatable by methods herein include multiple sclerosis, rheumatoid arthritis, asthma, systemic lupus erythromatosis, psoriasis, inflammatory bowel disease. In one embodiment, the disease is rheumatoid arthritis. In another embodiment, the disease is lupus erythromatosis. In yet another embodiment, the disease is multiple sclerosis. Diseases of the central and peripheral nervous system: Examples of diseases of central and peripheral nervous system treatable by methods herein include

Alzheimer's disease, Huntington's disease, Parkinson's disease, Lyme

neuroborreliosis, late Lyme encephalopathy, Tourette's syndrome, systemic sclerosis, multiple sclerosis, Amyotrophic lateral sclerosis, Guillain-Barre syndrome, and muscular dystrophy. Examples of diseases also include neuropsychiatric diseases, including mood disorders. In one embodiment, disease is multiple sclerosis. In another embodiment, the disease is depression.

Inflammatory diseases: Examples of inflammatory disorders or conditions include Atherosclerosis, Irritable bowel syndrome, Crohn's disease, inflammation- associated arthritis, allergic airway disease, asthma, macrophage-mediated inflammatory diseases and stroke.

Transplantation and Immune Tolerance: Examples include Allogeneic hematopoietic stem cell transplantation (HSCT), graft-versus-host disease (GvHD), organ transplant, pregnancy-related fetal rejection.

The compounds may also be used as adjuvants to bone marrow transplantation or peripheral blood stem cells transplantation and in immunotherapy by adoptive transfer.

Kynurenine pathway inhibitors and IDO and/or TDO inhibitors can be administered in an amount effective to increase the delayed type hypersensitivity reaction to tumor antigen, delay the time of relapse of post- transplant malignancy, increase relapse free survival time post-transplant, and/or increase long term post- transplant survival.

As a further aspect there is provided the present compounds for use as a pharmaceutical especially in the treatment or prevention of the aforementioned conditions and diseases. Also provided is the use of the present compounds in the manufacture of a medicament for the treatment or prevention of one of the aforementioned conditions and diseases.

Injection dose levels range from about 0.1 mg/kg/hour to at least

10 mg/kg/hour, all for from about 1 to about 120 hours and especially 24 to 96 hours. A preloading bolus of from about 0.1 mg/kg to about 10 mg/kg or more may also be administered to achieve adequate steady state levels. The maximum total dose is not expected to exceed about 2 g/day for a 40 to 80 kg human patient.

For the prevention and/or treatment of long-term conditions, such as neurodegenerative and autoimmune conditions, the regimen for treatment usually stretches over many months or years so oral dosing is preferred for patient convenience and tolerance. With oral dosing, one to five and especially two to four and typically three oral doses per day are representative regimens. Using these dosing patterns, each dose provides from about 0.01 to about 20 mg/kg of the compound provided herein, with preferred doses each providing from about 0.1 to about 10 mg/kg and especially about 1 to about 5 mg/kg.

Transdermal doses are generally selected to provide similar or lower blood levels than are achieved using injection doses.

When used to prevent the onset of a neurodegenerative, autoimmune or inflammatory condition, the compounds provided herein will be administered to a patient at risk for developing the condition, typically on the advice and under the supervision of a physician, at the dosage levels described above. Patients at risk for developing a particular condition generally include those that have a family history of the condition, or those who have been identified by genetic testing or screening to be particularly susceptible to developing the condition.

The compounds provided herein can be administered as the sole active agent or they can be administered in combination with other agents, including other active amines and derivatives. Administration in combination can proceed by any technique apparent to those of skill in the art including, for example, separate, sequential, concurrent and alternating administration.

COMBINATION THERAPY

The present invention also provides methods of treating diseases associated with dysregulated kynurenine pathway or with activity of, including abnormal activity, of IDO and/or TDO in an subject by administering to the subject in need of such treatment a therapeutically effective amount of amount or dose of a compound of the present invention or a pharmaceutical composition thereof, in combination with one or more additional medications or therapeutic agents or treatment methods such as, for example, anti-viral agents, chemotherapeutics or other anti -cancer agents, immune enhancers, immunosuppressants, radiation therapy, anti-tumor and anti-viral vaccines, cytokine therapy, (e.g., IL2, GM-CSF etc.), stem cells, and dendritic cells. Therapeutically effective amounts of the additional medication(s) or therapeutic agents are well known to those skilled in the art. However, it is well within the attending physician to determine the amount of other medication to be delivered.

Combination therapy for the treatment of Cancer

In one embodiment, the additional medication is a chemotherapeutic.

Examples of chemotherapeutics include those recited in the "Physician's Desk Reference", 64th Edition, Thomson Reuters, 2010, which is hereby incorporated by reference. In one aspect, the chemotherapeutic includes doxorubicin, paclitaxel or derivative thereof, 5-FU, and carboplatin or a derivative thereof.

Suitable antineoplastic chemotherapeutic agents can be dosed in combination with the compounds of invention can include, for example without limitation, alkylating agents (including without limitation, nitrogen mustards, ethylenimine derivatives, alkyl sulfonates, nitrosoureas, and triazine) such as uracil mustard, cyclophosphamide (Cytoxan™), chlormethine, ifosfamide, melphala, chlorambucil, pipobroman, triethylene melamine, triethylenethiophosphoramine, busulfan, carmustine, lomustine, streptozocin, dacarbazine, temozoloide, and combinations thereof.

Other chemotherapeutic or anti -cancer agents include, for example without limitation, antimetabolites (including without limitation, folic acid antagonists, pyrimidine analogs, purine analogs, and adenosine deaminase inhibitors) such as methotrexate, fluorouracil, gemcitabine, and combinations thereof. Suitable chemotherapeutic or anti-cancer agents further include certain natural products and their derivatives, for example without limitation, vinca alkaloids, anti-tumor antibiotics, enzymes, lymphokines, and epipodohyllotoxins) such as vinblastine, doxorubicin, vincristine, vindesine, bleomycin, dactinomycin, daunorubicin, epirubicin, idarubicin, ara-C, paclitaxel (TAXOL ), deoxycoformycin, mitomycin- C, mithramycin, L-asparagine, interferons (particulary IFN-a) etoposide, and teniposide and combinations thereof.

The present invention also contemplates that compounds of invention may be used in combination with other anti-cancer agents such as antibody therapeutics. In one embodiment, the additional medication is a targeted antibody, /'. e. , an antibody which targets a specific tumor type. The term "antibody" is used in the broadest sense and specifically covers intact monoclonal antibodies, polyclonal antibodies, chimeric antibodies, humanized antibodies, multispecific antibodies (e.g. bispecific antibodies) formed from at least two intact antibodies, and antibody fragments so long as they exhibit the desired biological activity. The term "Antibody fragments" comprise a portion of an intact antibody, preferably the antigen binding or variable region of the intact antibody. Examples of antibody fragments include Fab, Fab', F(ab')2, and Fv fragments; diabodies; linear antibodies (Zapata et al. Protein Eng. 8(10): 1057-1062, 1995); single-chain antibody molecules; and multispecific antibodies formed from antibody fragments. The targeted antibody may be selected from those described in Pasquetto et al., "Targeted Drug Delivery Using Immunoconjugates: Principles and Applications", J. Immunother., 34(9):611-628 (Nov-Dec 2011), which is hereby incorporated by reference. In one aspect, the targeted antibody is nimotuxumab, trastuzumab (Herceptin™), Alemtuzumab (CAMPATH™), Bevacizumab

(Avastin™), Brentuximab vedotin (Adcetris™), Cetuximab (Erbitux), Gemtuzumab (Mylotarg), Ipilimumab (MDX-101 and also known as Yervoy), Ofatumumab (Arzerra), Panitumumab (Vectibix), Rituximab (Rituxin, Mabthera), Tositumomab (Bexxar), among others. In another embodiment, an additional medication includes antibodies to immune co-stimulatory molecules such as CTLA-4, 4- IBB and PD-1, antibodies to cytokines and chemokine receptors, among others. In yet another embodiment, the additional medication is a targeted drug. The term "targeted drug" as used herein refers to a medication that blocks cancer cell growth by interfering the specific "targeted" molecules which are required for tumor growth. See, Pasquetto cited above, which is hereby incorporated by reference. In one aspect, the targeted drug includes, without limitation, dasatnib, imatinib, nilotinib, bosutnib, lestaurtinib, ruxolitinib, crizotinib, vandetabib, cabozantinib, afibercept, adipotide, denileukin diftitox, everolimus, and temosirolimus, among others.

Other chemotherapeutic or anti -cancer agents include, for example, cytotoxic agents such as platinum coordination agents (for e.g., cisplastin, and carboplatin), antineoplastic enzymes, topoisomerase inhibitors, biological response modifiers, growth inhibitors, hematopoetic growth factors, chemokines, cytokines (for example a granulocyte -macrophage colony stimulating factor (GM-CSF) or FLT3-ligand), cell migration blockers, and inhibitors of angiogenesis. Angiogenesis inhibitors include, but are not limited to, angiostatin, endostatin, thrombospondin, platelet factor 4, Cartilage-derived inhibitor (CDI), retinoids, Interleukin-12, tissue inhibitor of metalloproteinase 1, 2 and 3 (ΉΜΡ-1, TIMP-2, and T1MP-3) and proteins that block the angiogenesis signaling cascade, such as anti-VEGF (Vascular Endothelial Growth Factor) and IFN-alpha.

Alternatively, the compounds may be used to augment the effects of radiation therapy, which may be delivered locally to the tumor or to the whole body.

The compounds may be used to augment the effects of therapeutic vaccination against various tumors. When the compounds are used in combination, then at least one additional therapeutic agent may be a vaccine, for example, an antiviral vaccine, a vaccine against FflV, a vaccine against tuberculosis, a vaccine against malaria. The vaccine may also be a tumor vaccine or a melanoma vaccine. Preferably, the tumor vaccine comprises genetically modified tumors cells or genetically modified tumors cell lines. In such cases, preferably the genetically modified tumors cells or genetically modified cell lines has been transfected to express granulocyte- macrophage stimulating factor (GM-CSF). Alternatively, the vaccine may comprise one or more immunogenic peptides, preferably immunogenic peptides of cancer testis antigen (CTAgs). Such CTAgs and immunogenic peptides thereof are well known in the art. CTAgs protein include MAGE, BAGE, GAGE, SSX, NY-ESO-1, LAGE, SCP, CTSP, CT7, CT8, CT9, CT10, CT11, SAGE, OY-TES-1, NY-SAR-35 and NY- BPv-1. Several MAGe proteins are known, including MAGE-Al, A3, A4, A5, A6, A8, A10,A12, B l, B2, B2, B4, CI, C2 and C3 proteins. Several SSX proteins exist, including SSX1 and SSX2, SSX3 and SSX5. Vaccine may comprise one of more DNA vaccines and recombinant viruses. Further the tumor vaccine may comprise dendritic cells. In another embodiment, the additional medication is a cancer vaccine. In one aspect, the cancer vaccine is the Provenge® vaccine (Dendreon Corp).

In yet another embodiment, the additional medication is hormonal therapy. The term "hormonal therapy " as used herein refers to a medication that blocks cancer cell growth by interfering with the activity of specific hormones such as estrogen, testosterone, dihydrotestosterone.

Methods for the safe and effective administration of most of these chemotherapeutic agents are known to those skilled in the art. In addition, their administration is described in the standard literature. For example, the administration of many chemotherapeutic agents is described in "Physician's Desk Reference" (PDR, e.g., 2010 edition, PDR Network, Montvale, N.J.), the disclosure of which is incorporated by reference as if set forth in its entirety.

The compounds of formula (I) and/or other medication(s) or therapeutic agent(s) may be administered in a single composition. However, the present invention is not so limited. The present compounds of the formula (I) and/or other medications or therapeutic agents may be administered sequentially, consecutively or in any manner a physician deems appropriate. In other embodiments, the compounds of formula (I) may be administered in one or more separate formulations from other compounds of formula (I), chemotherapeutic agents, cancer vaccine, targeted drug, targeted antibody, hormonal therapy, or other agents as is desired.

Combination Therapy for Viral Infections

Suitable antiviral agents contemplated for use in combination with the compounds of the present invention comprise nucleoside and nucleotide reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors

(NNRTIs), protease inhibitors, and other anti-viral drugs. Examples of NRTIs include zidovuine (AZT); didanosine (ddl); zalcitabine (ddC); stavudine (d4T); lamivudine (3TC); abacavir (1592U89); adefovir diplovixil [bis(POM)-PMEA]; lobucavir (BMS- 180194); BCH- 10652; emitricitabine [(-)-FTC]; beta-L-FD4 (also known as beta-L- D4C and beta-L-2',3'dicleoxy-5-fuoro-cytidene); DAPD, ((-)0beta-D-2,6,-diamino- purine dioxolane,); and lodenosine (FddA). Typical suitable NNRTIs include nevirpine (BI-RG-587); delaviradine (BHAP, U-90152); efavirnz (DP-266); PNU- 142721 ; AG-1549; MKC-442 (l-(ethoxy-methyl)-5-(l-methylethyl)-6- (phyenylmethyl)-2,4( lH,3H)-pyrimedinedione); and (+)-calanolide A(NSC-675451) and B. Typical suitable protease inhibitors include saquinavir (Ro 31-8959); ritonavir (ABT-538); indinavir (MK-639); nelfnavir (AG-1343); amprenavir (141W94);

lasinavir (BMS-234475); DMP-450; BMS-2322623; ABT-378; and AG-1 549. Other antiviral agents include hydroxyurea, ribavarin, IL-2, IL12, perntasufide and Yissum Project No. 1 1607.

KITS AND PACKAGING

Also provided herein are kits or packages of pharmaceutical formulations containing the compounds of formula (I) or compositions described herein. The kits may be organized to indicate a single formulation or combination of formulations to be taken at each desired time.

Suitably, the kit contains packaging or a container with the compound of formula (I) formulated for the desired delivery route. Suitably, the kit contains instructions on dosing and an insert regarding the active agent. Optionally, the kit may further contain instructions for monitoring circulating levels of product and materials for performing such assays including, e.g. , reagents, well plates, containers, markers or labels, and the like. Such kits are readily packaged in a manner suitable for treatment of a desired indication. For example, the kit may also contain instructions for use of a spray pump or other delivery device. Other suitable components to include in such kits will be readily apparent to one of skill in the art, taking into consideration the desired indication and the delivery route.

The compounds of formula (I) or compositions described herein can be a single dose or for continuous or periodic discontinuous administration. For continuous administration, a package or kit can include the compound of formula (I) in each dosage unit (e.g., solution, lotion, tablet, pill, or other unit described above or utilized in drug delivery), and optionally instructions for administering the doses daily, weekly, or monthly, for a predetermined length of time or as prescribed. When the compound of formula (I) is to be delivered periodically in a discontinuous fashion, a package or kit can include placebos during periods when the compound of formula (I) is not delivered. When varying concentrations of a composition, of the components of the composition, or the relative ratios of the compounds of formula (I) or agents within a composition over time is desired, a package or kit may contain a sequence of dosage units which provide the desired variability.

A number of packages or kits are known in the art for dispensing

pharmaceutical agents for periodic oral use. In one embodiment, the package has indicators for each period. In another embodiment, the package is a labeled blister package, dial dispenser package, or bottle.

The packaging means of a kit may itself be geared for administration, such as an inhalant, syringe, pipette, eye dropper, or other such apparatus, from which the formulation may be applied to an affected area of the body, such as the lungs, injected into a subject, or even applied to and mixed with the other components of the kit. The compositions of these kits also may be provided in dried or lyophilized forms. When reagents or components are provided as a dried form, reconstitution generally is by the addition of a suitable solvent. It is envisioned that the solvent also may be provided in another package.

The kits of the present invention also will typically include a means for containing the vials in close confinement for commercial sale such as, e.g. , injection or blow-molded plastic containers into which the desired vials are retained.

Irrespective of the number or type of packages and as discussed above, the kits also may include, or be packaged with a separate instrument for assisting with the injection/administration or placement of the composition within the body of an animal. Such an instrument may be an inhalant, syringe, pipette, forceps, measuring spoon, eye dropper or any such medically approved delivery means.

In one embodiment, a kit is provided and contains a compound of formula (I). The compound of formula (I) may be in the presence or absence of one or more of the carriers or excipients described above. The kit may optionally contain instructions for administering the medication and the compound of formula (I) to a subject having a disease characterized by the dysregulation of the kynurenine pathway and of the activity of indoleamine 2,3-dioxygenase and/or tryptophan 2,3-dioxygenase.

In a further embodiment, a kit is provided and contains a compound of formula (I) in a second dosage unit, and one or more of the carriers or excipients described above in a third dosage unit. The kit may optionally contain instructions for administering the medication and the compound of formula (I) to a subject having a disease characterized by the dysregulation of the kynurenine pathway and of the activity of indoleamine 2,3-dioxygenase and/or tryptophan 2,3-dioxygenase.

BIOMARKERS AND DIAGNOSTICS

Kynurenine pathway metabolites and indoleamine 2,3-dioxygenase and/or tryptophan 2,3-dioxygenase are potential biomarkers of a variety of kynurenine pathway associated conditions including inflammatory disorders and have utility as predictive markers for diagnosing, predicting and tracking treatment responsiveness, development and prognosis of diseases such as atherosclerosis, stroke, Parkinson's disease, parasitic infections such as visceral leishmaniasis, cancers like ovarian cancer, graft-versus-host disease and transplant rejections, and tuberculosis. The compounds of the present invention therefore have diagnostic and prognostic utility in diagnosing the kynurenine pathway associated conditions as well as tracking the progression or amelioration of diseases. The compounds of the present invention therefore have diagnostic and prognostic utility for IDO- and/or TDO-associated conditions. The present invention includes the use of the compounds of the invention to detect, measure, quantify kynurenine metabolites and kynurenine pathway activity in subject samples including serum, plasma, urine etc. Another aspect of the present invention related to fluorescent dyes, spin label, heavy metal or radio-labeled compounds of the invention that would be useful not only in imaging but also assays, both in vitro and in vivo, for localizing and quantitating kynurenine pathway activity and metabolites in serum, plasma, urine, tissues samples including whole body, and for identifying kynurenine pathway enzyme ligands by inhibiting binding of a labeled compound. Accordingly, the present invention includes kynurenine pathway and IDO enzyme assays that contain such labeled compounds. Non-limiting examples of such assays include immunohistochemistry (IHC), fluorescence activated cell sorting (FACS), ELISA, RIA, and fluorescent in situ hybridization (FISH). The present invention provides for the use of the compounds of the present invention with serum and plasma samples from subjects. The present invention further includes isotopically labeled compounds of formula (I). It is understood that a "radio-labeled" or "labeled-compound" is a compound that has incorporated at least one radionuclide. In some embodiments, the

3 14 125 35 82 radionuclide is selected from the group consisting of H, C, I, S and Br. It is further understood that the radionuclide that is incorporated in the instant radio- labeled compounds will depend on the specific application of that radio-labeled compound. For example, for in vitro IDO enzyme labeling and competition assays,

3 14 125 35 82

compounds that incorporate H, C, I, S and Br will generally be most useful. For radio-imaging applications, nC, 18F, 1251, 123I, 124I, 1311, 76Br, or 77Br will generally be most useful. Synthetic methods of incorporating radio-isotopes into organic compounds are applicable to compounds of the invention and are well known in the art.

A radio-labeled compound of the invention can be used in a screening assay to identify/evaluate compounds. In general terms, a newly synthesized or identified compound (i.e., test compound) can be evaluated for its ability to reduce binding of the radio-labeled compound of the invention to the IDO and/or TDO enzyme.

Accordingly, the ability of a test compound to compete with the radio-labeled compound for binding to the IDO and/or TDO directly correlates to its binding affinity.

The following examples are illustrative only and are not intended to limit the present invention. EXAMPLES

Figure imgf000078_0002

Figure imgf000078_0003

Example 1

Preparation of 2-((3-chloro-4-fluorophenyl)amino)-2-(furan-2-yl)acetonitrile

Figure imgf000078_0001

Procedure A:

A mixture of furan-2-carbaldehyde (0.5 g, 5.20 mmol, 1.0 eq.), 3-chloro-4- fluoroaniline (0. 754 g, 5.20 mmol 1.0 eq.), TMSCN (0.774 g, 0.976 mL, 7.80 mmol, 1.5 eq.) and iodine (0.132 g, 0.52 mmol, 0.1 eq.) in acetonitrile (5 mL) was stirred at room temperature under N2 for overnight. After completion of reaction the reaction mass was diluted with ethyl acetate (25 mL), washed with brine, dried over sodium sulfate and concentrated under reduced pressure to give crude product which was purified by column chromatography on silica gel using mixture of ethyl acetate and heptane as eluent to afforded 2-((3-chloro-4-fluorophenyl)amino)-2-(furan-2- yl)acetonitrile (0.125 g, 0.50 mmol, 9.7%) as light brown powder.

Example 2

Preparation of 2-((3-chloro-4-fluorophenyl)amino)-2-(thiophen-3-yl)acetonitrile

(Molecule 18)

Figure imgf000079_0001

Procedure B:

Thiophene-3-carbaldehyde (0.25 g, 2.23 mmol, 1.0 eq.) and 3-chloro-4-fluoroaniline (0.325 g, 2.23 mmol, 1.0 eq.) was added in trifluoroethanol (2 mL) under N2 at room temperature and stirred the reaction mass for 2hr. TMSCN (0.332 g, 3.35 mmol, 1.5 eq.) was added dropwise in to the reaction mass and stirred for 5hr. The reaction mixture was quenched in water, extracted with ethyl acetate, washed with brine, dried over sodium sulfate and concentrated under reduced pressure to give crude product which was purified by column chromatography on silica gel using 15% ethyl acetate and heptane mixture as eluent to afforded 2-((3-chloro-4-fluorophenyl)amino)-2- (thiophen-3-yl)acetonitrile (0.15 g, 0.562 mmol, 25.2 %) as light tan powder.

Example 3

Preparation of 4-chloro-2-(((3-chloro-4- fluorophenyl)amino)(cyano)methyl)phenyl acetate (Molecule 86)

Figure imgf000079_0002

Step-1 : 4-Chloro-2-(((3-chloro-4-fluorophenyl)imino)methyl)phenol

Figure imgf000080_0001

A mixture of 3-chloro-4-fluoroaniline (9.30 g, 63.85 mmol) and 5- chlorosalicylaldehyde (10.0 g, 63.85 mmol) in ethanol (500 mL) was stirred under inert atmosphere for 16 hrs (formation of imine was monitored by TLC). Solvent was evaporated under reduced pressure to afford the imine 4-chloro-2-(((3-chloro-4- fluorophenyl)imino)methyl)phenol (14.0 g, 77 %) as yellow solid. !H NMR (400 MHz, CDC13): δ 12.70 (bs, 1H), 8.44 (s, 1H), 7.31-7.26 (m, 3H), 7.16-7.08 (m, 2H), 6.91 (d, J= 8.8 Hz, 1H) Step-2 : 2-(5-chloro-2-hydroxyphenyl)-2-((3-chloro-4-fluorophenyl)amino) acetonitrile

Figure imgf000080_0002

Procedure C:

The imine 4-chloro-2-(((3-chloro-4-fluorophenyl)imino)methyl)phenol (5.0 g, 17.67 mmol) was dissolved in MeCN-DCM-TFE (1 : 1 : 1) under N2 atmosphere and TMSCN (5.26 g, 53.00 mmol) was added dropwise to the reaction mixture. The mixture was stirred at room temperature for 50 hrs, (monitored by TLC). After completion of the reaction, quenched with saturated NaHCC>3 in cold condition and extracted with EtOAc (100 mL X 2). The combined organic layer was washed with water, brine and dried over NaiSOzt. The amorphous solid was dissolved in 10 mL EtOAc and precipitated by adding hexane in cold condition. The solid precipitate was filtered off and washed with pentane (50 mL X 2) to yield the aminonitrile 2-(5-chloro-2- hydroxyphenyl)-2-((3-chloro-4-fluorophenyl)amino)acetonitrile (3.80 g, 69 %). as beige powder. !H NMR (400 MHz, DMSO-d6): δ 10.56 (bs, 1H), 7.45 (d, J= 2.8 Hz, 1H), 7.30 (dd, J' = 9.0 Hz, J" = 2.8 1H), 7.22 (t, J= 9.2 Hz, 1H), 6.99 (dd, J' = 6.4 Hz, J" = 2.8, 1H), 6.93 (d, J= 8.8 Hz, 1H), 6.79 (td, J' = 9.2 Hz, J" = 3.6 Hz, 1H), 6.69 (d, J= 9.2 Hz, 1H), 5.85 (d, J= 5.6 Hz, 1H)

Step-3: 4-chloro-2-(((3-chloro-4-fluorophenyl)amino)(cyano)methyl)phenyl acetate

Figure imgf000081_0001

Procedure D:

To stir solution of 2-(5-chloro-2-hydroxyphenyl)-2-((3-chloro-4-fluorophenyl)amino)- acetonitrile (100 mg, 0.32 mmol) in DCM (3 inL) was added TEA (0.065 g, 0.64 mmol) at RT in an inert atmosphere and cooled to 0 °C and was added acetyl chloride (0.020 g, 0.264 mmol). Reaction mixture was stirred for 2h at RT. After complete consumption of starting material, reaction mixture was concentrated under reduced pressure. Crude compound was purified by column chromatography using 100-200 mesh silica gel and 3% ethyl acetate in hexane as eluent to afford 4-chloro-2-(((3- chloro-4-fluorophenyl)amino)(cyano)-methyl)phenyl acetate (25 mg) as yellow powder. IH-NMR (400 MHz, CDC13): 2.16 (s, 3H), 3.91 (d, J= 8.3 Hz, 1H), 5.35 (d, 1H, J = 8.0 Hz), 6.56-6.60 (m, 1H), 6.77-6.79 (m, 1H), 7.06 (t, J = 8.6 Hz, IH), 7.15 (d, J = 8.6 Hz, IH), 7.46 (dd, J' = 8.6 Hz, J" = 2.3 Hz, IH), 7.66 (d, J = 2.4 Hz, IH); [M-H] : 350.9.

Example 4

Preparation of 2-(5-chloro-2-hydroxyphenyl)-2-((3-chloro-4- fluorophenyl)(methyl)amino)acetonitrile (Molecular 33)

Figure imgf000082_0001

Step-1 : 3-chloro-4-fluoro-N-methylaniline

Figure imgf000082_0002

A solution of acetic anhydride (10.19 g, 109.65 mmol) and formic acid (37.83g, 822.03 mmol) was stirred at room temperature for 10 minutes. 3-Chloro-4-fluoro- phenylamine (3 g, 20.68 mmol) was added and resulting mass was stirred at 60 °C for 1.5 h. Reaction mass was concentrated, residue was diluted with NaHC03 solution (50 mL) and extracted with dichloromethane (3 x 100 mL). Combined organic layer was dried over sodium sulphate and concentrated under reduced pressure to afford N- (3-chloro-4-fluoro-phenyl)-formamide as white solid (3.4 g). To the stirred suspension of LAH (3.2 g, 37.95 mmol) in dry tetrahydrofuran (10 mL) was added N- (3-Chloro-4-fluoro-phenyl)-formamide (3.4 g, 19.65 mmol, taken in 20 ml THF) drop wise at 0 °C. Resulting reaction mixture was stirred at room temperature for 2 h. Reaction was cooled to 0 °C and quenched with water (50 mL) and aqueous NaOH solution (2 mL). Aqueous layer was extracted with ethyl acetate (3 x 100 mL).

Combined organic layer was dried over sodium sulphate and evaporated under reduced pressure to afford 3-chloro-4-fluoro-N-methylaniline (2.36 g) as brown liquid. Step-2 : 2-(5-chloro-2-hydroxyphenyl)-2-((3-chloro-4-fluorophenyl)(methyl) amino)acetonitrile

Figure imgf000082_0003

Procedure A: To a stirred solution of 5-chloro-2-hydroxy-benzaldehyde (250 mg, 1.60 mmol) in ACN: TFE (1 : 1, 8 mL) was added 3-chloro-4-fluoro-N-methylaniline (254 mg, 1.60 mmol) and stirred for 2 hrs at room temperature. TMSCN (824 mg, 8.33 mmol) and iodine (40.7 mg, 0.16 mmol) were added under inert atmosphere and the resulting mixture was stirred 18 hrs at room temperature. Reaction mass was concentrated in vacuum to afford brown crude material which was purified by column

chromatography using 100-200 mesh silica gel and 7% EtOAc in hexane as eluent to afford 2-(5-chloro-2-hydroxyphenyl)-2-((3-chloro-4- fluorophenyl)(methyl)amino)acetonitrile (127 mg) as violet colored solid.

Example 5

Preparation of 7V-((5-chloro-2-hydroxyphenyl)(cyano)methyl)-N-(3-chloro-4- fluorophenyl)acetamide (Molecule 102)

Figure imgf000083_0001

Step-1 : 5-Chloro-2-((4-methoxybenzyl)oxy)benzaldehyde

Figure imgf000083_0002

To a stirred solution of 5-chloro-salicylaldehyde (2.0 g, 12.773 mmol) in DMF (20 mL) was added p-methoxybenzyl chloride (2.25 mL, 16.605 mmol) at 0 °C followed by the addition of K2CO3 (5.296 g, 38.321 mmol). After stirring the reaction mixture for 1 h at 0 °C and 4 h at 25 °C, it was poured into ice-water, extracted with diethyl ether, washed with brine and dried over Na2S04 and was evaporated. The crude material was purified by triturating with hexane/pentane to afford 5-chloro-2- (4-methoxy-benzyloxy)-benzaldehyde (2.9 g) as colorless solid. Step-2: 2-(5-Chloro-2-((4-methoxybenzyl)oxy)phenyl)-2-((3-chloro-4- fluorophenyl)amino)acetonitrile

Figure imgf000084_0001

To a stirred solution of 5-chloro-2-(4-methoxy-benzyloxy)-benzaldehyde (1.0 g, 3.623 mmol) in a mixed solvent (MeCN: TFE: DCM; 6 mL: 6 mL: 3 mL) was added 3-chloro-4-fluoroaniline (0.527 g, 3.623 mmol) and the mixture was stirred for 3 h at 25 °C. To that TMSCN (2.35 mL, 18.84 mmol) was added and allowed to stir for another 3 h at 25 °C. The solid precipitate obtained was filtered to afford (3- Chloro-4-fluoro-phenylamino)-[5-chloro-2-(4-methoxy-benzyloxy)-phenyl]- acetonitrile (1.0 g) as white solid. LCMS: [M-H] 429.

Step-3: 7V-((5-Chloro-2-((4-methoxybenzyl)oxy)phenyl)(cyano)methyl)-N-(3- chloro-4-fluorophenyl)acetamide

Figure imgf000084_0002

To a stirred solution of (3-chloro-4-fluoro-phenylamino)-[5-chloro-2-(4- methoxy-benzyloxy)-phenyl]-acetonitrile (0.25 g, 0.581 mmol) in DCM (3 mL) was added pyridine (0.36 mL, 4.42 mmol) followed by the addition of acetyl chloride (0.31 mL, 4.360 mmol) at 0 °C. After stirring the reaction mixture for 2 h at 25 °C, the volatiles were removed. To the residue ice-water was added and was stirred for 30 minutes. The white solid precipitate obtained was filtered and isolated N-(3-chloro-4- fluoro-phenyl)-N- { [5 -chloro-2-(4-methoxy-benzyloxy)-phenyl] -cyano-methyl } - acetamide (0.25 g) as white solid. LCMS: [M+H] 473.2.

Step-4: 7V-((5-Chloro-2-hydroxyphenyl)(cyano)methyl)-7V-(3-chloro-4- fluorophenyl)acetamide

Figure imgf000085_0001

To a stirred solution of N-(3-chloro-4-fluoro-phenyl)-N-{[5-chloro-2-(4- methoxy-benzyloxy)-phenyl]-cyano-methyl}-acetamide (0.25 g, 0.529 mmol) in MeCN (7 mL) was added CeCl3.7H20 (0.295 g, 0.794 mmol) and sodium iodide (0.0793 g, 0.105 mmol) at 25 °C. The reaction mixture was refluxed for 16 h. After cooling down to room temperature, it was filtered through Celite® bed. The filtrate was evaporated and the crude material obtained was purified by silica gel column chromatography using ethyl acetate/hexane as eluent to afford N-(3 -chloro-4-fluoro- phenyl)-N-[(5-chloro-2-hydroxy-phenyl)-cyano-methyl]-acetamide (0.04 g) as pale yellow colored solid. !H-NMR (400 MHz, CDC13): δ 7.43 (dd, J' = 6.4 Hz, J" = 2.5 Hz, 1H), 7.23-7.22 (m, 1H), 7.18 (d, J= 8.6 Hz, 1H), 7.09 (t, J= 8.6 Hz, 1H), 7.03 (d, J= 7.6 Hz, 1H), 4.50 (s, 2H), 2.10 (s, 3H). LCMS: [M-H] 351.2.

Example 6

Preparation of 2-(5-chloro-2-hydroxypyridin-3-yl)-2-((3-chloro-4- fluorophenyl)amino)acetonitrile (Molecule 56)

Figure imgf000085_0002

Step-1 : 3-Bromo-5-chloropyridin-2-ol

Figure imgf000085_0003

To a stirred solution of 5-chloropyridin-2-ol (4 g, 31 mmol) in acetic acid (35 mL) at room temperature was added bromine (2.55 mL, 49.6 mmol) dropwise. After stirring the reaction mixture for overnight at room temperature, water was added and the mixture was extracted twice with ethyl acetate (2 x 150 mL). The organic layer was washed with water, dried over anhydrous sodium sulfate and was concentrated under reduced pressure to afford crude product. The crude product was purified by column chromatography by using silica (100-200 mesh) using 22% EtOAc-hexane as eluent to afford the 3-bromo-5-chloropyridin-2-ol (4.4 g) as yellow solid.

Step-2 : 5-Chloro-2-hydroxynicotinaldehyde

Figure imgf000086_0001

To a suspension of NaH (423 mg, 60% dispersion in oil, 10.51 mmol) in anhydrous THF (40 mL) under organ atmosphere was added the 3-bromo-5- chloropyridin-2-ol (2 g, 9.61 mmol) at 0 °C. After stirring the reaction mixture for 30 minutes, it was cooled to -78 °C and n-butyl lithium (7.6 mL, 10.5 mmol, 1.38 M) was added drop wise at -78 °C. After stirring the mixture for 15 mins, DMF was added drop wise at -78 °C and the reaction mixture was allowed to reach to room

temperature (25 °C), then the pH was adjusted to ~5 using IN HCL and extracted twice with ethyl acetate (2 x 150 ml). The organic layer was washed with brine and dried over sodium sulfate and was concentrated to afford 5-chloro-2- hydroxynicotinaldehyde (1 g) crude solid which was used in next step without further purification.

Step-3: 2-(5-chloro-2-hydroxypyridin-3-yl)-2-((3-chloro-4-fluorophenyl)amino) acetonitrile

Figure imgf000086_0002

Procedure C: To stirred solution of 5-chloro-2-hydroxynicotinaldehyde (100 mg, 0.63 mmol) in acetonitrile (2 mL), trifluoroethanol (2 mL) was added 3-chloro-4- fluoroaniline (92.7 mg, 0. 63 mmol) at room temperature in an inert atmosphere. The reaction mixture was stirred for 1 hr, imine formation was observed by TLC. To that trimethylsilyl cyanide (0.4 mL, 3.33 mmol) was added and stirred for 18 hrs at room temperature. After completion of the reaction, reaction mixture was concentrated under reduced pressure to get the crude compound which was purified by column chromatography using silica (100-200 mesh) and 40% EtOAc-hexane as eluent to afford 2-(5-chloro-2-hydroxypyridin-3-yl)-2-((3-chloro-4- fluorophenyl)amino)acetonitrile (75 mg) as orange solid. 'H-NMR-^OO MHZ,

DMSO-d6): δ 12.4 (bs, lH), 7.78 (bs, 1H), 7.71 (bs, 1H), 7.14(t, J= 9.1 Hz, 1H), 7.03- 7.01 (m, 1H), 6.82-6.79 (m, lH), 6.65 (d, J= 9.7 Hz, 1H), 5.74 (d, J= 9.7 Hz, 1H); [M-H] : 310

Example 7 Preparation of 2-((3-chloro-4-fluorophenyl)carbamoyl)naphthalen-l-yl acetate

(Molecule 49)

Figure imgf000087_0001

Step-1 : l-(Methoxymethoxy)naphthalene

Figure imgf000087_0002
To a suspension of NaH (1.63 g, 41.61 mmol) in dry DMF (20 mL) the naphthol-1 (5 g, 34.68 mmol) in DMF (30 mL) was added at 0 °C. After stirring the reaction mixture for 30 minutes, MOM-Cl (2.9 mL, 38.14 mmol) in ether was added to the reaction mixture at °C. After stirring the reaction mixture for 6 hrs, it was poured into ice-water, extracted twice with ether (2 x 150 mL). The organic layer was dried over sodium sulphate and concentrated under reduced pressure to give crude material which was purified by column chromatography over silica gel (100-200 mesh) using 5% EtOAc-hexane as eluent to afford l-(methoxymethoxy)naphthalene (4.2 g) as off white solid.

Step-2: l-(Methoxymethoxy)-2-naphthaldehyde

Figure imgf000088_0001

To a stirred solution of l-(methoxymethoxy)naphthalene (8.7 g, 46.27 mmol) in dry THF (27 mL) was added TMEDA (9.7 mL, 64.78 mmol). The resulting reaction mixture was cooled to -78 °C and n-butyl lithium (43 mL, 60.15 mmol, 1.38 M) was added drop wise and stirred for 90 minutes at -78 °C. DMF (4.65 mL, 60.159 mmol) was added to it and stirred for 30 mins. Temperature of the reaction mixture was slowly raised to 0 °C and quenched with saturated ammonium chloride solution. Reaction mixture was extracted with diethyl ether (200 mL X 4). Combined the organic layer was washed with brine, dried over sodium sulfate and concentrated under reduced pressure to afford crude compound which was purified by column chromatography using silica (100-200 mesh) and 5% EtOAc-hexane as eluent to afford l-(methoxymethoxy)-2-naphthaldehyde (2.5 g) as yellow solid. Step-3: l-Hydroxy-2-naphthaldehyde

Figure imgf000088_0002

To a stirred solution of l-(methoxymethoxy)naphthalene (2.2 g, 10.185 mmol) in acetonitrile (15 mL) was added sodium iodide (3.05 g, 20.370 mmol) at room temperature. Resulting mixture was cooled to 0 °C, TMSC1 (1.93 mL, 15.277 mmol) was added drop wise and stirred for 3 hrs at room temperature. Reaction mixture was concentrated under reduced pressure and dissolved in DCM (250 mL). The organic layer was washed with brine solution, dried over sodium sulfate and was concentrated under reduced pressure to afford crude product which was purified by column chromatography using silica (100-200 mesh) and EtOAc-hexane as eluent to afford 1- hydroxy-2-naphthaldehyde (650 mg) of as off white solid.

Step-4: 2-Formylnaphthalen-l-yl acetate

Figure imgf000089_0001

To a stirred solution of l-hydroxy-2-naphthaldehyde (1.89 g, 10.46 mmol) in DCM (15 inL) was added triethylamine (1.89 mL, 13.60 mmol) at room temperature. The resulting mixture was cooled to 0 °C and acetyl chloride (1.26 mL, 17.79 mmol) was added followed by the addition of DMAP (127 mg, 1.0 mmol) and stirred for 1 hr at room temperature. Reaction mixture was diluted with DCM (200 mL), washed with water, followed by brine, dried over sodium sulfate and was concentrated under reduced pressure to afford crude which was purified by column chromatography using silica (100-200 mesh) and EtOAc-hexane as eluent to afford 2-formylnaphthalen-l-yl acetate (900 mg) as yellow solid.

Step-5: 2-((3-Chloro-4-fluorophenyl)carbamoyl)naphthalen-l-yl acetate

Figure imgf000089_0002

Procedure C:

To a stirred solution of 2-formylnaphthalen-l-yl acetate (60 mg, 0.27 mmol) in DCM (2 mL) was added 3-chloro-4-fluoro-phenylamine (44 mg, 0.30 mmol) at room temperature. Reaction mixture was stirred for 1 hr, imine formation was observed by TLC. To the mixture trifluoroethanol (1 mL) and acetonitrile (1 mL) were added followed by the addition of trimethylsilylcyanide (0.17 mL, 1.3 mmol). Reaction mixture was stirred at room temperature for 18 hrs and was concentrated under reduced pressure. The crude material obtained was subjected to purification by preparative HPLC to afford 2-((3-chloro-4-fluorophenyl)carbamoyl)naphthalen-l-yl acetate (1.8 mg) as off white solid. 1H-NMR(400 MHz, CDC13): δ 8.10 (d, J= 8.2 Hz, 1H), 7.87 (d, J= 8.2 Hz, lH), 7.64 (m, 1H), 7.56-7.50 (m, 2H), 7.39 (t, J= 7.5 Hz, 1H), 7.3-7.28 (m, 2H), 7.08 (t, J= 8.4 Hz, 1H), 4.39 (s, 2H), 2.15 (s, 3H); [M-H] : 367

Example 8

Preparation of 4-chloro-2-(((3-chloro-4-fluorophenyl)amino)

(cyano)methyl)phenyl cyclopropanecarboxylate (Molecule 47)

Figure imgf000090_0001

Step-1 : 4-Chloro-2-formylphenyl cyclopropanecarboxylate

Figure imgf000090_0002

To a stirred solution of 5-chloro-2-hydroxybenzaldehyde (500 mg, 3.19 mmol) in DCM (10 mL) at 0 °C was added triethylamine (0.57 mL, 4.15 mmol) followed by the addition of cyclopropyl carbonyl chloride (0.37 mL, 4.15 mmol) and DMAP (38.9 mg, 0.3193 mmol). The reaction mixture was stirred for 1 h at 0 °C. Water was added to the reaction mixture and was extracted with DCM. The DCM layer was washed with water, dried over anhydrous sodium sulfate and was evaporated to afford 4- chloro-2-formylphenyl cyclopropanecarboxylate (550 mg). Step-2; 4-Chloro-2-(((3-chloro-4-fluorophenyl)amino)(cyano)methyl)phenyl cyclopropanecarboxylate

Figure imgf000091_0001

Procedure C:

To a stirred solution of 4-chloro-2-formylphenyl cyclopropanecarboxylate

(200 mg, 0.89 mmol) in MeCN (2 mL) and TFE (2 mL) was added 3-chloro-4- fluoroaniline (130 mg, 0.89 mmol). The reaction mixture was stirred for 1 h at rt. Imine formation was observed in TLC. To the mixture TMSCN (0.56 mL, 4.64 mmol) was added. After stirring the mixture for 16 h at rt, white solid precipitate was observed which was filtered out to give 4-chloro-2-(((3-chloro-4- fluorophenyl)amino)(cyano)methyl)phenyl cyclopropanecarboxylate ( 150 mg) as white solid. 'H-NMR^OO MHZ, CDCI3): δ 7.67 (d, J= 2.3 Hz, 1H), 7.46-7.43 (m, 1H), 7.14 (d, J= 8.7 Hz, lH), 7.05 (t, J= 8.7 Hz, lH), 6.79-6.77 (m, 1H), 6.60-6.56 (m, 1H), 5.35 (d, J= 7.8 Hz, 1H), 3.92 (d, J= 7.8 Hz, 1H), 1.74-1.70 (m, 1H), 1.09- 1.06 (m, 1H), 1.00-0.86 (m, 3H); [M-H] : 377

Example 9

Preparation of 2-((3-chloro-4-fluorophenyl)amino)-2-(pyrazin-2-yl)acetonitrile

(Molecule 51)

Figure imgf000091_0002

Step-1 : Pyrazine-2-carbaldehyde

Figure imgf000092_0001

To a stirred solution pyrazin-2-ylmethanol (500 mg, 4.545 mmol) in DCM (20 ml) was added Dess-martin periodinane (2.89 g, 6.818 mmol) and stirred for 1 hr at RT. Reaction mass was diluted with DCM (100 ml) washed with saturated sodium bicarbonate solution (50 ml X 2) twice. DCM part was separated, dried over sodium sulfate, evaporated to dryness to get 300 mg crude, which was purified by column chromatography using 100-200 silica and 20% EtOAc in hexane as eluent to afford pyrazine-2-carbaldehyde (100 mg) as brown liquid.

Step-2: 2-((3-Chloro-4-fluorophenyl)amino)-2-(pyrazin-2-yl)acetonitrile

Figure imgf000092_0002

Procedure C:

To a stirred solution pyrazine-2-carbaldehyde (100 mg, 0.925 mmol) in CH3CN:DCM :Trifluoroethanol (1 : 1 : 1) (10 ml) was added 3-chloro-4-fluoroaniline (130 mg, 0.893 mmol) and stirred for 30 minutes at RT. TLC indicated a new spot (imine) formation. TMSCN (0.45 g, 4.54 mmol) was added to it drop wise and stirred for 2hrs. Reaction mass was concentrated to afford crude material which was purified by column chromatography (100-200 silica, eluent: 10% EtO Ac-Hex) to give 2-((3- chloro-4-fluorophenyl)amino)-2-(pyrazin-2-yl)acetonitrile (25 mg) as a pale brown liquid. !H-NMR (400 MHz, CDC13): δ 8.83 (s, 1H), 8.71-8.67 (m, 2H), 7.07 (t, J= 8.6

Hz, 1H), 6.88 (dd, J' = 5.9 Hz, J" = 2.9 Hz, 1H), 6.69 (dt, J' = 8.8 Hz, J

1H), 5.47 (d, J= 8.6 Hz, lH), 4.90 (d, J= 8.5 Hz, 1H); MS: [M-H] 261.

Example 10 Preparation of 2-(((3-chloro-4-fluorophenyl)amino)(cyano)methyl)pyridine-l- oxide (Molecule 52)

Figure imgf000093_0001

Step-1 : 2-(Hydroxymethyl)pyridine-l-oxide

Figure imgf000093_0002

To a stirred solution of pyridin-2-ylmethanol (500 mg, 4.58 mmol) in CHC13 (6 mL) was added m- P A (949 g, 5.5 mmol) at 0 °C. Reaction mixture was allowed to stir at RT for 12 hrs. Reaction mixture was concentrated and the crude was triturated with ether thrice. After vacuum drying to give crude 2- (hydroxymethyl)pyridine 1 -oxide (700 mg) which was directly forwarded to the next step.

Step-2: 2-Formylpyridine-l-oxide

Figure imgf000093_0003

To a stirred solution of crude 2-(hydroxymethyl)pyridine 1-oxide (500 mg, 4.0 mmol) in dioxane:DCM (1 : 1) was added DessMartin periodinane (2.5 g, 5.89 mmol) at 0 °C. Resulting reaction mass was stirred at RT for lhr. Reaction mass was concentrated and the crude purified by column chromatography using 100-200 silica using MeOH/EtOAc (20:80) as an eluent to give 2-formylpyridine- 1-oxide (250 mg) as white solid. Step-3 : 2-(((3-Chloro-4-fluorophenyl)amino)(cyano)methyl)pyridine-l-oxide

Figure imgf000094_0001

To a stirred solution of 2-formylpyridine-l-oxide (200 mg, 1.63 mmol) in DCM:TFE:MeCN (4mL: 2mL: 2mL) was added 3-chloro-4-fluoroaniline (280 mg, 1.95 mmol) and the reaction was stirred for 2 hrs at RT. TMSCN (810 mg, 8.13 mmol) was then added to it and the reaction was allowed to stir at RT for 16 hrs. Reaction mass was concentrated, crystallization/precipitation from DCM/pentane afford 2-(((3-chloro-4-fluorophenyl)amino)(cyano)methyl)pyridine-l-oxide (120 mg). !H-NMR (400 MHz, DMSO-d6): δ 8.70 (d, J= 4.6 Hz, lH), 8. 14 (d, J= 8.0 Hz, 1H), 8.00-7.96 (m, 2H), 7.70 (bs, 1H), 7.59-7.56 (m, 1H), 7.42 (t, J= 9.0 Hz, 1H), 7.20 (dd, J' = 6.6 Hz, J" = 2.4 Hz, 1H), 7.01 (dt, J' = 8.5 Hz, J" = 4.0 Hz, 1H); MS: [M- H] 276.2

Example 11

Preparation of 2-((3-chloro-4-fluorophenyl)amino)-2-(2-methoxypyridin-4- yl)acetonitrile (Molecule 109)

Figure imgf000094_0002

Step-1 : 2-Chloro-3-(methoxymethoxy)pyridine

Figure imgf000094_0003

To a stirred solution of 2-chloro-3-hydroxy-pyridine (5.0 g, 38.59 mmol) in THF: DMF (10:25 mL) at 0 °C was added t-BuOK (4.763 g, 42.45 mmol) portion wise. After stirring the reaction mixture for 15 mins, Methoxy methyl Chloride (3.062 mL, 40.5 mmol) was added to it at 0 °C and the resulting mixture was stirred for 1 hr at 25 C. Reaction mixture was diluted with water and extracted with ethyl acetate (3 x 150 mL). Combined organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure to afford crude product which was purified by column chromatography using silica (100-200 mesh) and 10% EtOAc-hexane as eluent to afford 2-chloro-3-methoxymethoxy-pyridine (5.4 g) as pale Brown liquid. LCMS: 174 (M+H).

Step-2 : 2-Methoxy-3-(methoxymethoxy)pyridine

Figure imgf000095_0001

To a stirred solution of 2-chloro-3-methoxymethoxy-pyridine (2.5 g, 14.45 mmol) in MeOH (10 mL) was added sodium methoxide (1.95 g, 36.125 mmol) at 0 °C. Reaction mass was refluxed overnight, little product formation was observed, major SM remained. Reaction mass was transferred to sealed tube and sodium methoxide (0.78 g, 14.45 mmol) was further added to it at 0 °C and the resulting mixture was heated at 100 C for 16 hrs. Reaction mass was concentrated, residue was dissolved in DCM and filtered. Filtrate was evaporated and the afforded crude product which was purified by column chromatography to afford 2-methoxy-3- methoxymethoxy-pyridine (1.0 g). LCMS: 170 (M+H).

Step-3 : 2-Methoxy-3-(methoxymethoxy)isonicotinaldehyde

Figure imgf000095_0002

To a stirred solution of 2-methoxy-3-methoxymethoxy-pyridine (700 mg, 4.14 mmol) in anhydrous THF (7 mL) was added TMEDA (0.7 mL, 4.55 mmol) at 25 °C. The reaction mixture was cooled to -78 °C, n-BuLi (2.09 mL, 4.55 mmol, 2.17 M in hexane) was added drop wise maintaining the temperature -78 °C. After stirring for 2 hrs at -78 °C, DMF (0.5 mL, 6.21 mmol) was added to it and stirred for 1 hr at -78 C and slowly raised the temperature to 25 °C. Reaction mixture was quenched with saturated ammonium chloride solution, extracted with ethyl acetate (50 mL X 2), EtOAc part was washed with water followed by brine, dried over sodium sulfate and concentrated under reduced pressure to afford crude material which was passed through a pad of silica (100-200 mesh) using 10% EtOAc -hexane as eluent to afford 2-methoxy-3-methoxymethoxy-pyridine-4-carbaldehyde (450 mg) as pale yellow liquid. GCMS: 197(m/z).

Step-4 : 3-Hydroxy-2-methoxyisonicotinaldehyde

Figure imgf000096_0001

To a stirred solution of 2-methoxy-3-methoxymethoxy-pyridine-4- carbaldehyde (450 mg, 2.28 mmol) in THF (2 mL) was added 3N HC1 (5 mL) and stirred at 60 °C for 2hr. Reaction mixture was cooled under ice bath and pH was adjusted to 7 with solid K2CO3. Resulting mixture was extracted with EtOAc (20 mL X 2). Organic layer was dried over sodium sulfate, concentrated under reduced pressure to afford crude which was purified by column chromatography using silica gel (100-200mesh) and 23% EtOAc/Hexane as eluent to afford 3-hydroxy-2- methoxy-pyridine-4-carbaldehyde (250 mg). GCMS: 153 (m/z).

Step-5: (E)-4-(((3-chloro-4-fluorophenyl)imino)methyl)-2-methoxypyridin-3-ol

Figure imgf000096_0002

3-Hydroxy-2-methoxy-pyridine-4-carbaldehyde (100 mg, 0.653 mmol) was taken in mixed solvent [TFE (1 mL):MeCN(l mL)] and 4-fluoro-3-chloro phenyl amine (95 mg, 0.653 mmol) was added to it at 25 °C, resulting mixture was stirred at this temperature for 2 hr. Reaction mass was concentrated and purified by triturating with n-pentane to afford 4-{ [3-chloro-4-fluoro-phenylimino]-methyl}-2-methoxy- pyridin-3-ol (110 mg). LCMS: 281[M+H].

Step-6: 2-((3-Chloro-4-fluorophenyl)amino)-2-(2-methoxypyridin-4- yl)acetonitrile

Figure imgf000097_0001

Procedure C:

To a stirred solution of 4-{ [3-chloro-4-fluoro-phenylimino]-methyl}-2- methoxy-pyridin-3-ol (100 mg, 0.35 mmol) in mixed solvent [DCM (1 mL): TFE (1 mL)] was added TMSCN (0.16 mL, 1.24 mmol) at 25 °C. Reaction mixture was stirred for 4 hrs at 25 °C, and concentrated, crude material was triturated with acetonitrile/ pentane to get (3-chloro-4-fluoro-phenylamino)-(3-hydroxy-2-methoxy- pyridin-4-yl)-acetonitrile (30 mg) as white solid. !H-NMR (400 MHz, DMSO-d6): δ 9.99 (s, 1H), 7.71 (d, J= 5.0 Hz, 1H), 7.22 (t, J= 9.0 Hz, 1H), 7.06 (d, J= 4.9 Hz, 1H), 6.98 (d, J= 3.8 Hz, lH), 6.77 (d, J= 8.5 Hz, 2H), 5.94 (d, J= 8.8 Hz, 1H), 3.92 (s, 3H). LCMS 305.8 [M-H] .

Example 12 Preparation of 2-((3-chloro-4-fluorophenyl)amino)-2-(3-hydroxypyridin-4- yl)propanenitrile (Molecule 117)

Figure imgf000097_0002

Step-1 : 3-(methoxymethoxy)pyridine

Figure imgf000097_0003

To a stirred solution of 3-hydroxy pyridine (1) (25 g, 276.24 mmol) in THF: DMF (50: 100 mL) at 0 °C was added t-BuOK (34.09 g, 303.86 mmol) portion wise. After stirring the reaction mixture for 15 mins, methoxymethyl chloride (22.03 mL, 290.05 mmol) was added to it at 0 °C and the resulting mixture was stirred for 1 hr at 25 °C. Reaction mixture was diluted with water and extracted with ethyl acetate (4 x 300 ml). Organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure to afford the crude which was purified by column chromatography using silica (100-200 mesh) and 10% EtOAc-hexane as eluent to afford 3- methoxymethoxypyridine (24 g) as pale Brown liquid. LCMS: 140 (M+H).

Step-2 : l-(3-(methoxymethoxy)pyridin-4-yl)ethanol

Figure imgf000098_0001

To a solution of 3-methoxymethoxypyridine (2.0 g, 14.4 mmol) in dry THF (130 mL) under Ar was added TMEDA (3.3 mL, 21.6 mmol) and the mixture was cooled to -78 °C. n-BuLi (1.6 M, 13.3 mL, 21.6 mmol) solution was added to this and allowed to stir for 1 h at the same temperature. A THF solution of acetaldehyde (1.9 g, 43.2 mmol in 10 mL of THF) was added to the reaction mixture and stirred at -78 °C for additional 15 min and then warmed to RT. TLC monitoring showed product along with traces of SM. The reaction mixture was quenched with water, extracted with ethyl acetate, dried over NaiSO/t, and concentrated. The crude residue was purified by column chromatography (S1O2, 100-200 mesh) using 10-50% ethyl acetate in hexanes to afford l-(3-methoxymethoxy-pyridin-4-yl)-ethanol (1.3 g) an off-white solid. LCMS: 184 (M+H).

Step-3 : l-(3-(methoxymethoxy)pyridin-4-yl)ethanone

Figure imgf000098_0002

To a solution of l-(3-methoxymethoxy-pyridin-4-yl)-ethanol (0.500 g, 2.73 mmol) in DCM (15 mL) was added Dess-Martin periodinane (3.94 g, 9.29 mmol) in multiple portions, followed by the addition of NaHC03 (0.689 g, 8.20 mmol). After stirring the reaction mixture at 25 °C for 16 h, it was quenched with water and DCM was added to that. Organic layer was separated and aqueous layer was extracted with DCM a few times after pH was adjusted to 7. The organic layers were combined, dried over NaiS04 and concentrated. The crude residue was purified by column chromatography (S1O2, 100-200 mesh) using 10-30% ethyl acetate in hexanes to afford l-(3-Methoxymethoxy-pyridin-4-yl)-ethanone (0.4 g) as yellow liquid. LCMS: 182 (M+H). Step-4: l-(3-hydroxypyridin-4-yl)ethanone

Figure imgf000099_0001

To a solution of l-(3-Methoxymethoxy-pyridin-4-yl)-ethanone (0.500 g, 2.76 mmol) in THF (10 ml) was added 3N HC1 (15 ml) and then warmed to 50-60 °C for 3h. TLC and LCMS monitoring during this period indicated completion of the reaction. Reaction mixture was cooled to RT and then quenched with solid K2CO3, water was added followed by ethyl acetate. The organic layer was separated and the aqueous layer was saturated with NaCl, which was then extracted with ethyl acetate a few times. The combined organic layers were dried over Na2S04 and concentrated. The crude residue was purified by column chromatography (S1O2, 100-200 mesh) using 30-50% ethyl acetate in hexanes to afford l-(3-Hydroxy-pyridin-4-yl)-ethanone (0.250 g) as reddish solid. LCMS: 138 (M+H).

Step-5: 2-((3-chloro-4-fluorophenyl)amino)-2-(3-hydroxypyridin-4- yl)propanenitrile

Figure imgf000099_0002
To a solution of l-(3-Hydroxy-pyridin-4-yl)-ethanone (0.100 g, 0.73 mmol) in DCM (2 mL) was added 3-chloro-4-fluoroaniline (0.106 g, 0.73 mmol), followed by TMSCN (0.5 mL, 3.80 mmol) and TMSOTf (0.03 mL, 0.15 mmol) and stirred for 5 h at RT. TLC monitoring as well as LCMS showed the reaction was not completed at that point and so it was left overnight stirring at rt. Next day the reaction was stirred for another 4h with addition of another 2 equiv of TMSCN (0.2 mL, 1.46 mmol) and one drop of TMSOTf (0.02 mL). The reaction mixture was diluted with DCM (5 mL). The organic layer was washed with water, dried over Na2S04 and concentrated to afford an off-white solid, which was washed with pentane and ether subsequently. The residual solid was then subjected to lyophilisation to obtain desired 2-(3-Chloro- 4-fluoro-phenylamino)-2-(3-hydroxy-pyridin-4-yl)-propionitrile (0.045 g) as off- white solid. !H-NMR (DMSO, 400MHz): δ 10.70 (s, lH), 8.23 (bs, lH), 8.03 (d, lH), 7.18 (t,lH), 7.09 -7.07 (m, 2H), 6.64-6.62 (m, lH), 6.45-6.42 (m, 1H), 1.90 (s, 3H). LCMS: 292 (M+H).

Table-1: IUPAC and Procedure Type

Figure imgf000100_0001
Figure imgf000101_0001

Figure imgf000102_0001
Figure imgf000103_0001
Figure imgf000104_0001
Figure imgf000105_0001
Figure imgf000106_0001
Figure imgf000107_0001

Figure imgf000108_0001
Figure imgf000109_0001
Figure imgf000110_0001
Figure imgf000111_0001
Figure imgf000112_0001
Figure imgf000113_0001
Figure imgf000114_0001
Figure imgf000115_0001
Figure imgf000116_0001

Figure imgf000117_0001

Figure imgf000118_0001
Figure imgf000119_0001
Figure imgf000120_0001

The following compounds are prepared using the methods and reagents described herein for Examples 1-17, Procedures A-D and Schemes 1-13:

Table-2: NMR and LCMS data

Figure imgf000120_0002

Figure imgf000121_0001
Figure imgf000122_0001
Figure imgf000123_0001

Figure imgf000124_0001
Figure imgf000125_0001

Figure imgf000126_0001

Figure imgf000127_0001
Figure imgf000128_0001

Figure imgf000129_0001
Figure imgf000130_0001
Figure imgf000131_0001

Figure imgf000132_0001

Figure imgf000133_0001
Figure imgf000134_0001
Figure imgf000135_0001
Figure imgf000136_0001
Figure imgf000137_0001
Figure imgf000138_0001

Figure imgf000139_0001
Figure imgf000140_0001
Figure imgf000141_0001

Figure imgf000142_0001

Figure imgf000143_0001

Figure imgf000144_0001

Figure imgf000145_0001

Example 13. In-vitro IDO Enzyme (2,3-dioxygenase) Assay

Human 2,3-dioxygenase (hIDO) catalyzes the oxidative cleavage of the pyrrole ring of the indole nucleus of tryptophan to yield N-formylkynurenine (kyn). hIDO with an N-terminal hexa-Histidine tag expressed and purified from E.coli (Enzo Life Sciences, NY, US). All other materials were procured from Sigma. The assay monitoring the conversion of L-tryptophan to kyn by hIDO was carried out as follows. hIDO (50-100 ng) was incubated with tryptophan (30 μΜ) in the presence of ascorbic acid (20 mM), methylene blue (10 μΜ) and catalase (100 μg/mL) in potassium phosphate buffer (50 mM; pH 6.5) at 37°C for 30 min. The reaction was terminated with 30% trichloro acetic acid (TCA) and further incubated at 65°C for 15 min to convert N-formylkynurenine to kynurenine. The reaction mixture was then centrifuged to remove sediments and the supernatant was monitored by UV- visible absorption spectroscopy at 360 nm using a Waters HPLC system fitted with a C-18 column. See, Sono, 1980, J. Bio. Chem., 255: 1339-1345, which is herein incorporated by reference.

Percent inhibition at each concentration of test compounds was determined by estimating the decrease in kyn. Data were analyzed using nonlinear regression to generate IC5o values using Graph Pad Prism® 5. Example 14. HeLa Cell Based IDO (2,3-dioxygenase)Assay

HeLa cells were obtained from ATCC and maintained in DMEM

supplemented with sodium bicarbonate (2.1 g/L), HEPES (4.1 g/L), L-glutamine (2 mM), non-essential amino acid (84 mg/L) and fetal bovine serum (10%) at 5% CO2 and maintained at 95% humidity and 5% C02 in a 37°C incubator. All materials were procured from Sigma.

Upon incubation with gamma-interferon (IFNy), HeLa cells induced IDO expression which catalyzed the formation of N-formylkynurenine from Tryptophan present in growth medium. The assay was performed as follows:

Cells were plated in medium (300 μί) at a density of 0.1 million per well of a 48 well plate and IDO was induced by overnight treatment with ΙΚΝγ (50 ng/mL). The following day, cells were washed to remove IFNy. Cells were incubated with specific concentrations of test compounds (final volume 300 μί). Following incubation, supernatant (150 μί) was transferred to a 96 well plate into which TCA (30μί) was added and the contents further incubated at 65°C for 15 min to convert N- formylkynurenine to kynurenine. The reaction mixture was then centrifuged to remove sediments and the supernatant was monitored by UV-visible absorption spectroscopy at 360 nm using a Waters HPLC system fitted with a C-18 column. Sono described above.

Percent inhibition at each concentration of test compounds was determined by estimating the decrease in kyn. Data were analyzed using nonlinear regression to generate IC50 values using Graph Pad Prism® 5.

Table-3: IC50 Ranges

(A: IC50 < 200 nM; B: IC50 = 200-1000 nM; C: IC50 > 1000 nM)

Figure imgf000147_0001


Figure imgf000148_0001


Figure imgf000149_0001


Figure imgf000150_0001


Figure imgf000151_0001
150

Figure imgf000152_0001
151

Figure imgf000153_0001

Figure imgf000154_0001
ı53

Figure imgf000155_0001

Figure imgf000156_0001
ı55

Figure imgf000157_0001

Figure imgf000158_0001


Figure imgf000159_0001


Figure imgf000160_0001


Figure imgf000161_0001
160

Figure imgf000162_0001
161

Figure imgf000163_0001
ı62

Figure imgf000164_0001

Figure imgf000165_0001

Example 15. Drug Metabolism and Pharmacokinetics: HERG assay:

HEK 293 cells which stably express the HERG potassium channel are used for electrophysiological study. The methodology for stable transfection of this channel in HEK cells can be found elsewhere (Zhou et al., Biophys. J. 74:230-41, 1998). Before the day of experimentation, the cells are harvested from culture flasks and plated onto glass coverslips in a standard Minimum Essential Medium (MEM) medium with 10% Fetal Calf Serum (FCS). The plated cells are stored in an incubator at 37 °C maintained in an atmosphere of 95%Oi/5%C02. Cells are studied between 15-28 hrs after harvest.

HERG currents are studied using standard patch clamp techniques in the whole-cell mode. During the experiment the cells are superfused with a standard external solution of the following composition (mM); NaCl, 130; KC1, 4; CaC^, 2; MgCl2, 1; Glucose, 10; HEPES, 5; pH 7.4 with NaOH. Whole-cell recordings are made using a patch clamp amplifier and patch pipettes which have a resistance of 1-3 MOhm when filled with the standard internal solution of the following composition (mM); KC1, 130; MgATP, 5; MgCl2, 1.0; HEPES, 10; EGTA 5, pH 7.2 with KOH. Only those cells with access resistances below 15 MOhm and seal resistances

>lGOhm are accepted for further experimentation. Series resistance compensation is applied up to a maximum of 80%. No leak subtraction is done. However, acceptable access resistance depends on the size of the recorded currents and the level of series resistance compensation that can safely be used. Following the achievement of whole cell configuration and sufficient time for cell dialysis with pipette solution (>5 min), a standard voltage protocol is applied to the cell to evoke membrane currents. The voltage protocol is as follows. The membrane is depolarized from a holding potential of -80 mV to +40 mV for 1000ms. This is followed by a descending voltage ramp (rate 0.5 mV msec-1) back to the holding potential. The voltage protocol is applied to a cell continuously throughout the experiment every 4 seconds (0.25 Hz). The amplitude of the peak current elicited around -40mV during the ramp is measured. Once stable evoked current responses are obtained in the external solution, vehicle (0.5% DMSO in the standard external solution) is applied for 10-20 min by a peristaltic pump. Provided there are minimal changes in the amplitude of the evoked current response in the vehicle control condition, the test compound of either 0.3, 1, 3, or 10 mM is applied for a 10 min period. The 10 min period includes the time which supplying solution is passing through the tube from solution reservoir to the recording chamber via the pump. Exposing time of cells to the compound solution is more than 5 min after the drug concentration in the chamber well reached the attempting concentration. There is a subsequent wash period of a 10-20 min to assess reversibility. Finally, the cells is exposed to high dose of dofetilide (5 mM), a specific IKr blocker, to evaluate the insensitive endogenous current. All experiments are performed at room temperature (23 ± 1°C). Evoked membrane currents are recorded on-line on a computer, filtered at 500-1 KHz (Bessel -3dB) and sampled at 1-2 KHz using the patch clamp amplifier and a specific data analyzing software. Peak current amplitude, which occurred at around -40 mV, is measured off line on the computer.

The arithmetic mean of the ten values of amplitude is calculated under vehicle control conditions and in the presence of drug. Percent decrease of IN in each experiment is obtained by the normalized current value using the following formula: IN = (1- ID/IC)xl00, where ID is the mean current value in the presence of drug and IC is the mean current value under control conditions. Separate experiments are performed for each drug concentration or time-matched control, and arithmetic mean in each experiment is defined as the result of the study.

Example 16. Drug Metabolism and Pharmacokinetics: Half-life in human liver microsomes (HLM):

Test compounds (1 μΜ) are incubated with 3.3 mM MgCl2 and 0.78 mg/mL HLM (HL101) in 100 mM potassium phosphate buffer (pH 7.4) at 37°C on the 96- deep well plate. The reaction mixture is split into two groups, a non-P450 and a P450 group. NADPH is only added to the reaction mixture of the P450 group. An aliquot of samples of P450 group is collected at 0, 10, 30, and 60 min time point, where 0 min time point indicates the time when NADPH is added into the reaction mixture of P450 group. An aliquot of samples of non-P450 group is collected at -10 and 65 min time point. Collected aliquots are extracted with acetonitrile solution containing an internal standard. The precipitated protein is spun down in centrifuge (2000 rpm, 15 min). The compound concentration in supernatant is measured by LC/MS/MS system. The half-life value is obtained by plotting the natural logarithm of the peak area ratio of compounds/ internal standard versus time. The slope of the line of best fit through the points yields the rate of metabolism (k). This is converted to a half-life value using following equation:

Half-life = In 2 / k. Example 17. In Vivo efficacy assay

Reduction of LPS induced plasma Kynurenine levels in C57BL/6 mice by Test Compounds

Inflammatory mediators such as Lipopolysaccharides (LPS) and Interferon- gamma (IFNg) are well-established inducers of IDO expression. Intraperitoneal (i.p.) administration of bacterial lipopolysaccharide (LPS) induces peak IDO activity in a variety of tissues within one day after LPS administration resulting in the production and release of kynurenine into the bloodstream (Takikawa, O., et al. (1986) J. Biol. Chem. 261:3648-53; Yoshida, H., et al. (1998) Cell 94:739-750) and has been used as a model to study IDO 1 expression and activity.

Following is a non-limiting example. Six fed Balb/C mice (age 7-8 weeks, weight: about 20-22 g) were injected intrapritoneally with bacterial

lipopolysaccharide (LPS; 0127: B8 Sigma) at a concentration of 15 mg/kg. Animals were then housed in normal condition for 20 hours at which time the test compound 38 was administered subcutaneously in formulation containing 67% polyethylene glycol 400 (PEG 400) and 33% propylene glycol (PG). Blood was drawn through retrorbital bleeds into a tube containing 100 mM EDTA for plasma collection at the following times: just prior to LPS treatment, just prior to test compound dosing (0 hr) and then at 2 hr and 4 hr post-test compound dosing. Plasma KYN were determined by LC/MS/MS using an API4000 mass spectrometer (Applied Biosystems) coupled to a Shimadzu Prominence LC system fitted with a C 18 column.

Compound 38 decreased plasma KYN levels by -40% at 2 hrs post dosing as compared with the plasma KYN levels at time of test compound dosing at 0 hr. The synthetic and biological examples described in this application are offered to illustrate the compounds, pharmaceutical compositions and methods provided herein and are not to be construed in any way as limiting their scope. In the examples, all temperatures are in degrees Celsius (unless otherwise indicated).

Compounds that can be prepared in accordance with the methods provided herein along with their biological activity data are presented in tables. The syntheses of these representative compounds can be carried out in accordance with the methods set forth above.

All publications cited in this specification are incorporated herein by reference. While the invention has been described with reference to particular embodiments, it will be appreciated that modifications can be made without departing from the spirit of the invention. Such modifications are intended to fall within the scope of the appended claims.

Claims

CLAIMS WHAT IS CLAIMED IS:
1. A compound of formula (I)
Figure imgf000170_0001
or a pharmaceutically acceptable salt or prodrug thereof, wherein:
X1 is C, N or NO, O, S or SO or S02;
X2 is C, N or NO, O, S or SO or S02;
X3 is C, N or NO, O, S or SO or S02;
X4 is C, N or NO, O, S or SO or S02;
X5 is C, N or NO, O, S or SO or S02;
1 2 2 3 3 4 4 5
X and X or X and X or X and X or X and X or none form a fused five or six membered aryl or heteroaryl ring; m is 0, 1, 2, 3, 4, 5, 6, or 7; n is 0 or 1 ;
R3 is R5, R6, R7, R8, R9, R10, or R11;
R1, R2, R4, and R5-Rn are independently selected from H, optionally substituted Ci-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, Ci-C6 alkoxy, mono or bicyclic optionally substituted C6-Ci4 aryl, mono or bicyclic optionally substituted heteroaryl, optionally substituted (aryl)alkyl, (alkoxy)carbonyl, (alkyl)amido, (alkyl)amino, optionally substituted mono or bicyclic cycloalkyl, optionally substituted mono or bicyclic heterocyclyl, aminoalkyl, alkylcarboxyl, (alkyl)carboxyamido, optionally substituted (aryl)amino, halogen, Ci-Ce haloalkyl, optionally substituted heterocyclyl(alkyl)-, optionally substituted heteroaryl(alkyl), hydroxyalkyl, perfluoroalkyl, optionally substituted aryloxy, optionally substituted heteroaryloxy, optionally substituted C3-C6 cycloalkoxy, OR12, SR12, N(R12)2, CN, N02, C02H, CONRARB, and optionally substituted heterocyclyloxy having 1 to 2 heteroatoms selected from the group consisting of O, S, SO, S02, and NR12;
12
R is H, Ci-C6 alkyl, mono or bicyclic C6-Ci4 aryl, mono or bicyclic heteroaryl, (aryl)alkyl, (alkyl)carbonyl, (alkoxy)carbonyl, (alkyl)amido, (alkyl)amino, mono or bicyclic cycloalkyl, mono or bicyclic heterocyclyl, alkylcarboxyl, heterocyclyl(alkyl), heteroaryl(alkyl), hydroxyalkyl, perfluoroalkyl, having 1 to 2 heteroatoms selected from the group consisting of O, S, SO, S02, and NRC;
RA and RB are independently selected from H, optionally substituted Ci-C6 alkyl, optionally substituted mono or bicyclic C6-Ci4 aryl, optionally substituted mono or bicyclic heteroaryl, optionally substituted (aryl)alkyl, optionally substituted mono or bicyclic C3-C8 cycloalkyl, optionally substituted mono or bicyclic heterocyclyl, Ci-Ce haloalkyl, optionally substituted heterocyclyl(alkyl), optionally substituted heteroaryl(alkyl), hydroxyalkyl, and perfluoroalkyl; and
R^ is H, Ci-C6 alkyl, mono or bicyclic C6-Ci4 aryl, mono or bicyclic heteroaryl,
(aryl)alkyl, (alkoxy)carbonyl, (alkyl)amido, (alkyl)amino, mono or bicyclic cycloalkyl, mono or bicyclic heterocyclyl, alkylcarboxyl, heterocyclyl(alkyl), heteroaryl(alkyl), hydroxyalkyl, perfluoroalkyl, aryloxy, heteroaryloxy, C3-C6 cycloalkoxy, or heterocyclyloxy.
2. The compound according to claim 1, wherein X1, X2, X3, X4 and X5 are C.
3. The compound according to claim 1, wherein one or two of X1, X2, X3, X4 and X5 are
independently selected from the group consisting of N, O, or S.
4. The compound according to claim 1 having formula (I- A):
Figure imgf000172_0001
5. The compound according to claim 1 having formula (I-AA):
Figure imgf000172_0002
6. The compound according to claim 1 having formula (I-B):
Figure imgf000172_0003
7. The compound according to claim 1 having formula (I-BB):
Figure imgf000172_0004
8. The compound according to claim 1 having formula (I-BBB):
Figure imgf000172_0005
9. The compound according to claim 1 having formula (I-BBBB):
Figure imgf000173_0001
10. The compound according to claim 1 having formula (I-C):
Figure imgf000173_0002
11. The compound according to claim 1 having formula (I-CC):
Figure imgf000173_0003
12. The compound according to claim 1 having formula (I-D):
Figure imgf000173_0004
13. The compound according to claim 1 having formula (I-DD):
Figure imgf000173_0005
14. The compound according to claim 1 having formula (I-E):
Figure imgf000173_0006
15. The compound according to claim 1 having formula (I-EE):
Figure imgf000174_0001
16. The compound according to claim 1 having formula (I-F):
Figure imgf000174_0002
17. The compound according to claim 1 having formula (I-FF):
Figure imgf000174_0003
18. The compound according to claim 1 having formula (I-G):
Figure imgf000174_0004
19. The compound according to claim 1 having formula (I-GG):
Figure imgf000174_0005
20. The compound according to claim 1 having formula (I-GGG):
Figure imgf000174_0006
21. The compound according to claim 1 having formula (I-H):
Figure imgf000175_0001
22. The compound according to claim 1 having formula I-I :
Figure imgf000175_0002
23. The compound according to claim 1 having formula (I-II):
Figure imgf000175_0003
24. The compound according to claim 1 having formula (I- J):
Figure imgf000175_0004
25. The compound according to claim 1 having formula (I-JJ):
Figure imgf000175_0005
26. The compound according to claim 1, wherein R1 or R2 is optionally substituted phenyl.
27. The compound according to claim 26, wherein R 1 or R 2 is:
Figure imgf000176_0001
wherein, RD to RH are independently selected from among H, halogen, Ci-C6 haloalkyl, Ci-C6 alkoxy, heterocycle, optionally substituted Ci-C6 alkyl, C3-C8 cycloalkyl, CN, -O(aryl), C2-C6 alkynyl, C(0)Ci-C6 alkyl, -0-Ci-C6 haloalkyl, and optionally substituted aryl.
28. The compound according to claim 25, wherein R 1 or R 2 is:
Figure imgf000176_0002
wherein, RD to RH are independently selected from among H, halogen, CHF2, C(CH3)F2, OCF3, OCH3, OCH(CH3)2, morpholine, pipendine, CH3, C(CH3)3, CH2CH3, CH(CH3)2, cyclopropyl, cyclohexyl, CH2-cyclopropyl, CH2-cyclobutyl, benzyl, CN, phenoxy, ethynyl, C(0)CH3, and phenyl.
29. The compound according to claim 26, R 1 or R 2 is:
Figure imgf000176_0003
wherein, R D to R H are independently selected from the group consisting of H and optionally substituted aryl.
30. The compound according to claim 30, wherein RD to RH are independently selected from a group consisting of H and aryl substituted with halogen.
31. The compound according to claim 31, RD to RH are independently selected from a group consisting of H and aryl substituted with one or more CI or F.
32. The compound according to claim 26, wherein R1 or R2 is phenyl, 2-Cl-phenyl, 3-Cl-phenyl, 3-I-phenyl, 3-F-phenyl, 4-F-phenyl, 4-Br-phenyl, 4-Cl-phenyl, 2-Br-4-F-phenyl, 2-C1-4-F- phenyl, 2,3-di-Cl-4-F-phenyl, 2,4-di-Cl-phenyl, 2,4-di-F-3-Cl-phenyl, 2,4-di-F-5-Cl-phenyl, 2,5-di-Cl-phenyl, 3-Cl-4-F-phenyl, 3-Cl-4-I-phenyl, 3,4-di-F-phenyl, 2,4,5-tri-F-phenyl, 2,3,4-tri-Cl-phenyl, 3-Br-4,5-di-F-phenyl, 3-F-4-Cl-phenyl, 3-Br-4-F-phenyl, 3,5-di-Cl-4-F- phenyl, 4-F-5-Cl-phenyl, 4-CF3-phenyl, 3-CF3-phenyl, 4-F-5-CF3-phenyl, 3-CF3-4-F-phenyl, 3-CHF2-phenyl, 3-C(CH3)F2-phenyl, 3-OCH3-4-Cl-phenyl, 2-OCH3-5-Cl-phenyl, 4- morpholinyl-phenyl, 2-piperidinyl-phenyl, 3-CH3-phenyl, S-Tiu-phenyl, 4-CH3-phenyl, 3- CH2CH3 -phenyl, 3-cyclopropyl-phenyl, 3-cyclohexyl-phenyl, 3-CH(CH3)2-phenyl, 3,4-di- CH3-phenyl, 3,5-di-CH3-phenyl, S^-di-Tiu-phenyl, 4-di-CH3 -phenyl, CH2-cyclopropyl- phenyl, CH2-cyclobutyl-phenyl, 4-benzyl-phenyl, 3-benzyl-phenyl, 3 -CH3 -4-F-phenyl, 3- CH3-4-Cl-phenyl, 3 -Cl-4-CH3 -phenyl, 3-Br-4-CH3-phenyl, 3-Cl-5-CH3-phenyl, 2-F-3-CN- phenyl, 4-CN-phenyl, 4-phenoxy-phenyl, 2,4-di-OCH3-phenyl, 3-OCH(CH3)2-phenyl, 3,5-di- OCH3-phenyl, 3-ethynyl-phenyl, 4-ethynyl-phenyl, 4-C(0)CH3-phenyl, 4-OCF3-phenyl, 3- OCF3-4-F-phenyl, or 3 -phenyl-phenyl.
33. The compound according to claim 1, wherein R4 is H, optionally substituted Ci-C6 alkyl, optionally substituted aryl or heteroaryl.
34. The compound according to claim 33, wherein R4 is H or Me.
35. The compound according to claim 34, wherein R4 is H.
36. The compound according to claim 1, wherein R1 or R2 is optionally substituted heteroaryl.
37. The compound according to claim 36, wherein R1 or R2 is pyridine optionally substituted with halogens.
38. The compound according to claim 36, wherein R1 or R2 is optionally substituted
tetrahydronaphthalene.
39. The compound according to claim 36, wherein R1 or R2 is optionally substituted benzo [d] dioxolane.
40. The compound according to claim 1, wherein R1 or R2 is optionally substituted cycloalkyl.
41. The compound according to claim 1, wherein R1 or R2 is optionally substituted cyclohexyl.
42. The compound according to claim 1, which is selected from the group consisting of :
2-(Furan-2-yl)-2-(phenylamino)acetonitrile,
[(3 -Chloro-4-fluorophenyl)amino] (furan-2-yl)acetonitrile,
[(3 -Chloro-4-fluorophenyl)amino] (furan-3 -yl)acetonitrile,
[(3 -Chlorophenyl)amino] (furan-3 -yl)acetonitrile,
[(4-Chlorophenyl)amino] (furan-3 -yl)acetonitrile,
[(4-Chlorophenyl)amino](furan-2-yl)acetonitrile,
[(3 -Chlorophenyl)amino] (furan-2-yl)acetonitrile,
Furan-3-yl(phenylamino)acetonitrile,
[(2-Chlorophenyl)amino](furan-2-yl)acetonitrile,
[(2-Chlorophenyl)amino] (furan-3 -yl)acetonitrile,
[(3 -Chloro-4-fluorophenyl)amino] (thiophen-2-yl)acetonitrile,
(Phenylamino)(thiophen-2-yl)acetonitrile,
(Phenylamino)(thiophen-3-yl)acetonitrile,
[(3-chloro-4-fluorophenyl)amino](5-chlorothiophen-2-yl)acetonitrile,
[(3-Chloro-4-fluorophenyl)amino](4-phenylthiophen-2-yl)acetonitrile,
(5-Chlorothiophen-2-yl)(phenylamino)acetonitrile,
(Phenylamino)(4-phenylthiophen-2-yl)acetonitrile,
[(3 -Chloro-4-fluorophenyl)amino] (thiophen-3 -yl)acetonitrile,
(Phenylamino)(l,3-thiazol-2-yl)acetonitrile,
[(3 -Chloro-4-fluorophenyl)amino] ( 1 ,3 -thiazol-2-yl)acetonitrile,
[(3 -Chloro-4-fluorophenyl)amino] ( 1 -methyl- 1 H-pyrrol-2-yl)acetonitrile,
( 1 -Methyl- 1 H-pyrrol-2-yl)(phenylamino)acetonitrile,
( 1 -Methyl- 1 H-imidazol- 5-yl)(phenylamino)acetonitrile,
[(3 -Chloro-4-fluorophenyl)amino] ( 1 -methyl- 1 H-imidazol-5-yl)acetonitrile, [(3-Chloro-4-fluorophenyl)amino][6-(thiophen-2-yl)pyridin-2-yl]acetonitrile,
(Phenylamino)[6-(thiophen-2-yl)pyridin-2-yl]acetonitrile,
(Phenylamino)(quinolin-3-yl)acetonitrile,
[(3 -Chloro-4-fluorophenyl)amino] (quinolin-3 -yl)acetonitrile,
(Phenylamino)(quinolin-4-yl)acetonitrile,
2-[(5-Phloro-2-hydroxyphenyl)-2-((3-chloro-4-fluorophenyl)amino]acetonitrile,
2- [(3 -Chloro-4-fluorophenyl)amino] -2-(2-hydroxyphenyl)acetonitrile,
2-[(3-Chloro-4-fluorophenyl)amino]-2-(2-hydroxy-5-methylphenyl)acetonitrile,
2-(5-Chloro-2-hydroxyphenyl)-2-[(3-chloro-4-fluorophenyl)(methyl)amino]acetonitrile,
2-(2-Amino-5-chlorophenyl)-2-[(3-chloro-4-fluorophenyl)amino]acetonitrile,
2-(2-amino-5-chlorophenyl)-2-[(3-chloro-4-fluorophenyl)(methyl)amino]acetonitrile,
2-[(3-Chloro-4-fluorophenyl)amino]-2-(2-hydroxy-5-iodophenyl)acetonitrile,
2-[(3-Chloro-4-fluorophenyl)amino]-2-(2-hydroxy-5-(trifluoromethyl)phenyl)acetonitrile,
2- [(3 -Chloro-4-fluorophenyl)amino] -2-(5 -fluoro-2-hydroxyphenyl)acetonitrile,
4-Chloro-2-(((3-chloro-4-fluorophenyl)amino)(cyano)methyl)phenyl acetate,
2-((3-Chloro-4-fluorophenyl)amino)-2-(3,4-difluoro-2-hydroxyphenyl)acetonitrile,
2-(5-Bromo-2-hydroxy-3-methoxyphenyl)-2-((3-chloro-4-fluorophenyl)amino)acetonitrile,
2-((3-Chloro-4-fluorophenyl)amino)-2-(2-hydroxy-5-methoxyphenyl)acetonitrile,
4-Chloro-2-(((3-chloro-4-fluorophenyl)amino)(cyano)methyl)phenyl benzoate,
4-Chloro-2-(((3-chloro-4-fluorophenyl)amino)(cyano)methyl)phenyl propionate,
4-Chloro-2-(((3-chloro-4-fluorophenyl)amino)(cyano)methyl)phenyl isobutyrate,
4-Chloro-2-(((3-chloro-4-fluorophenyl)amino)(cyano)methyl)phenyl pivalate,
4-Chloro-2-(((3-chloro-4-fluorophenyl)amino)(cyano)methyl)phenyl
cyclopropanecarboxylate,
4-Chloro-2-(((4-chloro-3-methoxyphenyl)amino)(cyano)methyl)phenyl acetate,
2-(((3 -Chloro-4-fluorophenyl)amino)(cyano)methyl)naphthalen- 1 -yl acetate,
4-Chloro-2-(((3-chloro-4-methoxyphenyl)amino)(cyano)methyl)phenyl acetate,
2-((3-Chloro-4-fluorophenyl)amino)-2-(pyrazin-2-yl)acetonitrile,
2-(((3 -Chloro-4-fluorophenyl)amino)(cyano)methyl)pyridine 1 -oxide,
2-((3-Chloro-4-fluorophenyl)amino)-2-(pyridin-3-yl)acetonitrile,
2-((3-Chloro-4-fluorophenyl)amino)-2-(pyridin-2-yl)acetonitrile, [(3 -Chloro-4-fluorophenyl)amino] ( 1 H-indazol-7-yl)acetonitrile,
2-(5-Chloro-2-hydroxypyridin-3-yl)-2-((3-chloro-4-fluorophenyl)amino)acetonitrile,
3 -(((3 -Chloro-4-fluorophenyl)amino)(cyano)methyl)benzonitrile,
2-((3-Chloro-4-fluorophenyl)amino)-2-(3,4,5-trimethoxyphenyl)acetonitrile,
2-((3-Chloro-4-fluorophenyl)amino)-2-(3-hydroxyphenyl)acetonitrile,
2-((3-Chloro-4-fluorophenyl)amino)-2-(4-(heptyloxy)phenyl)acetonitrile,
2-((3-Chloro-4-fluorophenyl)amino)-2-(2-(difluoromethoxy)phenyl)acetonitrile,
2-(2-Bromo-5-hydroxyphenyl)-2-((3-chloro-4-fluorophenyl)amino)acetonitrile, tert-Butyl 4-(4-(((3-chloro-4-fluorophenyl)amino)(cyano)methyl)phenyl)piperazine-l- carboxylate,
2-(3-Bromo-4-methoxyphenyl)-2-((3-chloro-4-fluorophenyl)amino)acetonitrile, 2-((3 -Chloro-4-fluorophenyl)amino)-2-(4-(4-methylpiperazin- 1 -yl)phenyl)acetonitrile, 2-((3-Chloro-4-fluorophenyl)amino)-2-(2-morpholinophenyl)acetonitrile,
2-((3 -Chloro-4-fluorophenyl)amino)-2-(4-(piperidin- 1 -yl)phenyl)acetonitrile,
2-((3-Chloro-4-fluorophenyl)amino)-2-(4-morpholinophenyl)acetonitrile,
2-(2-(lH-l,2,4-Triazol-l-yl)phenyl)-2-((3-chloro-4-fluorophenyl)amino)acetonitrile, tert-Butyl 4-(2-(((3-chloro-4-fluorophenyl)amino)(cyano)methyl)phenyl)piperazine-l- carboxylate,
2-((3-Chloro-4-fluorophenyl)amino)-2-(4-(pyrimidin-5-yl)phenyl)acetonitrile,
2-((3-Chloro-4-fluorophenyl)amino)-2-(2-(2-hydroxyethoxy)phenyl)acetonitrile,
2-((3-Chloro-4-fluorophenyl)amino)-2-(4-(2-hydroxyethoxy)phenyl)acetonitrile,
4-(((3-Chloro-4-fluorophenyl)amino)(cyano)methyl)benzonitrile,
2-((3-Chloro-4-fluorophenyl)amino)-2-(3-(2-hydroxyethoxy)phenyl)acetonitrile,
2-((3 -Chloro-4-fluorophenyl)amino)-2-(2-(4-hydroxypiperidin- 1 -yl)phenyl)acetonitrile,
2-(4-Chloro-3-nitrophenyl)-2-((3-chloro-4-fluorophenyl)amino)acetonitrile,
N-(4-Chloro-2-(((3-chloro-4-fluorophenyl)amino)(cyano)methyl)phenyl)acetamide,
2-(5-Chloro-2-nitrophenyl)-2-((3-chloro-4-fluorophenyl)amino)acetonitrile,
2-(((3-Chloro-4-fluorophenyl)amino)(cyano)methyl)benzonitrile,
2-((3-Chloro-4-fluorophenyl)amino)-2-(2-hydroxycyclohexyl)acetonitrile,
2-(5-Chloro-2-hydroxyphenyl)-2-((4-fluorophenyl)amino)acetonitrile,
2-((3-Chloro-4-fluorophenyl)amino)-2-(3-methoxynaphthalen-2-yl)acetonitrile, 2-(5-Chloro-2-methoxy-3-(trifluoromethyl)phenyl)-2-((3-chloro-4- fluorophenyl)amino)acetonitrile,
(2-(5-Chloro-2-hydroxyphenyl)-2-(cyclohexylamino)acetonitrile,
4-Chloro-2-(((3-chloro-4-fluorophenyl)amino)(cyano)methyl)phenyl acetate,
4-Chloro-2-((N-(3-chloro-4-fluorophenyl)acetamido)(cyano)methyl)phenyl acetate, N-(4-Chloro-2-(((3-chloro-4-fluorophenyl)amino)(cyano)methyl)phenyl)-4- methylbenzenesulfonamide,
N-(4-Chloro-2-(((3-chloro-4-fluorophenyl)amino)(cyano)methyl)phenyl)-N- (methylsulfonyl)methanesulfonamide,
4-Chloro-2-(((3-chloro-4-fluorophenyl)amino)(cyano)methyl)phenyl propionate, 4-Chloro-2-(((3-chloro-4-fluorophenyl)amino)(cyano)methyl)phenyl butyrate,
4-Chloro-2-(cyano((2,4-dichlorophenyl)amino)methyl)phenyl propionate,
4-Chloro-2-(cyano((3,4-dichlorophenyl)amino)methyl)phenyl propionate,
4-Chloro-2-(((2-chlorophenyl)amino)(cyano)methyl)phenyl propionate,
4-Chloro-2-(((4-chlorophenyl)amino)(cyano)methyl)phenyl propionate,
4-Chloro-2-(cyano((3,5-dichlorophenyl)amino)methyl)phenyl propionate,
4-Chloro-2-(((4-(4-chlorophenoxy)phenyl)amino)(cyano)methyl)phenyl propionate, 4-Chloro-2-(((3-chlorophenyl)amino)(cyano)methyl)phenyl propionate,
4-Chloro-2-(((3-chloro-4-methoxyphenyl)amino)(cyano)methyl)phenyl propionate, 4-Chloro-2-(cyano(naphthalen-2-ylamino)methyl)phenyl propionate,
4-Chloro-2-(cyano((3,5-dimethoxyphenyl)amino)methyl)phenyl propionate,
N-((5-Chloro-2-hydroxyphenyl)(cyano)methyl)-N-(3-chloro-4-fluorophenyl)acetamide, 4-Chloro-2-(cyano(phenylamino)methyl)phenyl propionate,
4-Chloro-2-(cyano(pyridin-3 -ylamino)methyl)phenyl propionate,
2,4-Dichloro-6-(((3-chloro-4-fluorophenyl)amino)(cyano)methyl)phenyl propionate, 4-Chloro-2-(((3 -chloro-4-fluorophenyl)amino)(cyano)methyl)phenyl methyl carbonate, 2-((3-Chloro-4-fluorophenyl)amino)-2-(3-hydroxypyridin-2-yl)acetonitrile,
2-(((3-Chloro-4-fluorophenyl)amino)(cyano)methyl)-4-fluorophenyl propionate, 2-((3-Chloro-4-fluorophenyl)amino)-2-(3-hydroxy-2-methoxypyridin-4-yl)acetonitrile, 2-((3-Chloro-4-fluorophenyl)amino)-2-(2-ethoxy-3-hydroxypyridin-4-yl)acetonitrile, 2-((3-Chloro-4-fluorophenyl)amino)-2-(3-hydroxy-2-isopropoxypyridin-4-yl)acetonitrile, 4-(((3-Chloro-4-fluorophenyl)amino)(cyano)methyl)-3-hydroxybenzamide, 4-(((3 -Chloro-4-fluorophenyl)amino)(cyano)methyl)-3 -hydroxybenzoic acid,
2- (2-(Benzylthio)phenyl)-2-((3-chloro-4-fluorophenyl)amino)acetonitrile,
3 -(((3 -Chloro-4-fluorophenyl)amino)(cyano)methyl)-4-hydroxybenzonitrile, and
3- (((3-Chloro-4-fluorophenyl)amino)(cyano)methyl)-2-hydroxybenzonitrile.
43. The compound according to any one of claims 1 to 42, which is an acetylated prodrug.
44. The compound according to any one of claims 1 to 42, which is a carbonate prodrug.
45. The compound according to any one of claims 1 to 42, which is a carbamate prodrug.
46. The compound according to any one of claims 1 to 45, is a salt of an acid or a base.
47. A composition comprising a compound of any one of claims 1 to 46 and a pharmaceutically acceptable carrier.
48. A kit comprising a compound of any one of claims 1 to 47.
49. The kit according to claim 48, further comprising a chemotherapeutic.
50. A method of regulating a kynurenine pathway, said method comprising administering a compound of any one of claims 1 to 47 to a subject in need thereof.
51. The method according to claim 50, wherein said regulating comprises inhibition of said pathway.
52. A method of regulating a kynurenine pathway by inhibiting the activity of indoleamine 2,3- di oxygenase or tryptophan 2,3-dioxygenase activity or both, said method comprising administering a compound of any one of claims 1 to 47 to a subject in need thereof.
53. A method for treating a condition treatable by regulating a kynurenine pathway, said method comprises administering a compound of any one of claims 1 to 47 to a subject in need thereof.
54. A method according to claim 53, wherein said regulating comprises inhibition of said pathway.
55. A method according to claim 54, wherein said inhibition of said pathway results from
inhibition of the activity of indoleamine 2,3-dioxygenase or tryptophan 2,3-dioxygenase activity or both.
56. A method for treating a condition associated with dysregulated kynurenine pathway, said method comprising administering a compound of any one of claims 1 to 47 to a subject in need thereof.
57. The method according to claim 56, wherein said condition is abnormal cellular proliferation.
58. The method according to claim 56, wherein said condition is immunosuppression.
59. The method according to claim 56, wherein said condition is selected from a group
consisting of cancer, viral infection, bacterial infection parasitic infection, a
neurodegenerative disorder, an immune-mediated disorder, an inflammatory disease, cardiovascular disease, a mood disorder, and an autoimmune disease.
60. The method according to claim 59, wherein said mood disorder is depression.
61. The method according to claim 59, wherein said viral infection is HIV infection.
62. The method according to claim 59, wherein the neurodegenerative disorder is multiple
sclerosis.
63. The method according to claim 59, wherein said inflammatory disease is rheumatoid arthritis.
64. A method for treating a disease characterized by immunosuppression resulting from a
dysregulated kynurenine pathway, said method comprising administering a compound of any one of claims 1 to 47 to a subject in need thereof.
65. A method for treating a disease characterized by an abnormal cellular proliferation associated with a dysregulated kynurenine pathway, said method comprising administering a compound of any one of claims 1 to 47 to a subject in need thereof.
66. A method for treating a disease characterized by inflammation associated with a dysregulated kynurenine pathway, said method comprising administering a compound of any one of claims 1 to 47 to a subject in need thereof.
67. A method for treating a disease characterized by immunosuppression resulting from a
dysregulated indoleamine 2,3 -di oxygenase or tryptophan 2,3-dioxygenase pathway, said method comprising administering a compound of any one of claims 1 to 47 to a subject in need thereof.
68. The method according to claim 61, further comprising administering a chemotherapeutic, cancer vaccine, a targeted drug, or a targeted antibody.
69. The method according to claim 69, wherein said chemotherapeutic is selected from the group consisting of doxorubicin, paclitaxel or derivative thereof, 5-FU, and carbop latin or a derivative thereof.
70. A method of reducing or eliminating an immune mediated disorder, said method comprising administering a compound of any one of claims 1 to 47 to a patient.
PCT/IB2014/059705 2013-03-14 2014-03-13 Aminonitriles as kynurenine pathway inhibitors WO2014141110A2 (en)

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