The present invention relates to novel 2,3-dihydro-lH-indole compounds that inhibit the conversion of tryptophan to kynurenine, certain of which have been confirmed 5 to bind to indoleamine 2,3-dioxygenase (IDOl). The present invention also relates to pharmaceutical compositions comprising these compounds and methods of using these compounds to treat physiological disorders, more particularly for the treatment of cancer such as melanoma, acute myeloid leukemia, chronic lymphocytic leukemia, colorectal cancer, renal cell carcinoma, breast cancer, lung cancer, ovarian cancer, 10 fallopian tube carcinoma, primary peritoneal carcinoma, cervical cancer, gastric cancer, liver cancer, pancreatic cancer, thyroid cancer, glioma, non-Hodgkin's lymphoma, and Hodgkin's lymphoma.
Tryptophan is an essential amino acid required for protein biosynthesis, cellular growth, the generation of neuroactive metabolites such as serotonin (5- 15 hydroxytryptamine), melatonin, and the co-enzyme nicotinamide adenine dinucleotide (NAD). Tryptophan is catabolized by indoleamine 2,3-dioxygenase (IDOl), a heme- dependent enzyme that catalyzes the first and rate-limiting step in tryptophan catabolism to N-formyl-kynurenine, which is then deformylated to generate kynurenine. During infection, the expression of IDOl is induced by interferon gamma to locally deplete 20 tryptophan, which inhibits the growth of tryptophan-dependent intracellular pathogens such as Chlamydia trachomatis, Toxoplasma gondii, and viruses. Additionally, IDOl plays a role in preventing oxidative damage in cells, several neuropathologies, regulation of the immune system, and cancer. Although IDOl activity is a critical component of the immune response to pathogens, prolonged activity results in the depletion of extracellular

25 tryptophan with the concomitant production of kynurenine, both of which are

immunosuppressive. IDOl expression in cancer is well documented and occurs through both intrinsic activation of IDOl gene expression and/or through the activation of the IFN-y-to-IDOl axis, a result of immune cell activation. Additionally, innate immune cells such as dendritic cells, monocytes and macrophages, which are recruited to sites of

30 inflammation and the tumor microenvironment, are immunosuppressive when they

express IDOl. Together the IDOl -dependent depletion of tryptophan and production of kynurenine have been linked to suppression of T-cell activation and proliferation and NK cell function. Furthermore depletion of tryptophan and production of kynurenine are critical for the formation of regulatory T cells (Treg) and myeloid-derived suppressor cells (MDSCs), which function to dampen immune cell activation. These IDOl dependent immunosuppressive mechanisms are components that allow tumors to circumvent the immune system.

Potential inhibitors of kynurenine production through IDOl inhibition are already known in the literature. See for example, WO2010005958, WO2012142237 and WO2014150646 and Journal of Medicinal Chemistry (2016), 59(1), 419-430. Certain 2,3-dihydro-lH-indole compounds are known in the art. See for example, CAS registry numbers 1359420-19-1, 1358912-57-8, 1358648-68-6, 1357815-05-4, 1359035-89-4, and 1359002-77-9.

There is a need for new cancer treatments. In particular there is a need for new cancer treatments for melanoma, acute myeloid leukemia, chronic lymphocytic leukemia, colorectal cancer, renal cell carcinoma, breast cancer, lung cancer, ovarian cancer, fallopian tube carcinoma, primary peritoneal carcinoma, cervical cancer, gastric cancer, liver cancer, pancreatic cancer, thyroid cancer, glioma, non-Hodgkin's lymphoma, and Hodgkin's lymphoma. There remains a need to provide alternative kynurenine production inhibitors useful in the treatment of cancer. Preferably such compounds have properties that enable optimal dosing required for maximal inhibition of tumor cell growth while having acceptable tolerability for the patient. Preferably such compounds would also be orally bioavailable. Preferably such compounds would also have the ability to cross the blood brain barrier and thus have brain exposure. Preferably such compounds would also have the ability to potentially overcome resistance to existing kynurenine inhibitors by having an alternate mechanism of action.

The present invention provides certain novel 2,3-dihydro-lH-indole compounds that are inhibitors of kynurenine production. The skilled person will appreciate that inhibitors of kynurenine production may have clinical utility as a single agent or in combination with other anti-cancer agents for the treatment of different types of cancers and in particular melanoma, acute myeloid leukemia, chronic lymphocytic leukemia, colorectal cancer, renal cell carcinoma, breast cancer, lung cancer, ovarian cancer, fallopian tube carcinoma, primary peritoneal carcinoma, cervical cancer, gastric cancer, liver cancer, pancreatic cancer, thyroid cancer, glioma, non-Hodgkin's lymphoma, and Hodgkin's lymphoma.

The present invention also provides a compound of the formula:

wherein:

Rla is hydrogen, methyl, ethenyl, cyano, fluoro, chloro, fluoromethyl, or difluoromethyl;

Rib is hydrogen, fluoro, or chloro;

Rlc is hydrogen, hydroxy, fluoro, benzyloxy, or hydroxyethylamino;

R2 is hydrogen or methyl;

R2a is hydrogen or methyl; and

R3a is tetrahydropyranyl.

The present invention rovides a compound of the formula:

The present invention also provides a compound of the formula:

The present invention also provides a compound of the formula:

The present invention also provides a compound which is 4-fluoro-N-{(lR)-l-[l-(tetrahydro-2H-pyran-4-ylcarbonyl)-2 -dihydro-lH-indol-5-yl]ethyl}benzamide.

Preferably the compound is 4-fluoro-N-{(lR)-l-[l-(tetrahydro-2H-pyran-4-ylcarbonyl)-2,3-dihydro-lH-indol-5-yl]ethyl}benzamide in a crystalline form. Preferably the compound is crystalline 4-fluoro-N-{(lR)-l-[l-(tetrahydro-2H-pyran-4-ylcarbonyl)-2,3-dihydro-lH-indol-5-yl]ethyl}benzamide characterized by an X-ray powder diffraction pattern (Cu radiation, λ-1.54060 A) comprising at least one peak at 17.38° in combination with one or more peaks selected from the group consisting of 12.51°, 15.65°, 16.37°, 17.56°, 21.48° and 25.23° (2Θ+ 0.2°).

The present invention also provides an intermediate or salt thereof of the formula:

useful in the method of making certain compounds of the present invention.

The present invention also provides an intermediate or salt thereof of the formula:

useful in the method of making certain compounds of the present invention.

The present invention also provides an intermediate or salt thereof of the formula:

useful in the method of making certain compounds of the present invention.

The present invention also provides an intermediate of the formula:

in the method of making certain compounds of the present invention.

The present invention also provides an intermediate of the formula:

useful in the method of making certain compounds of the present invention.

The present invention also provides an intermediate of the formula:

useful in the method of making certain compounds of the present invention.

The present invention also provides a pharmaceutical composition comprising a compound of the present invention with a pharmaceutically acceptable excipient, carrier, or diluent. Preferably the compound is 4-fluoro-N-{(lR)-l-[l-(tetrahydro-2H-pyran-4-ylcarbonyl)-2,3-dihydro-lH-indol-5-yl]ethyl}benzamide.

The present invention provides a method of treating a patient with a cancer selected from the group consisting of melanoma, acute myeloid leukemia, chronic lymphocytic leukemia, colorectal cancer, renal cell carcinoma, breast cancer, lung cancer, ovarian cancer, fallopian tube carcinoma, primary peritoneal carcinoma, cervical cancer, gastric cancer, liver cancer, pancreatic cancer, thyroid cancer, glioma, non-Hodgkin' s lymphoma, and Hodgkin's lymphoma comprising administering to the patient an effective amount of a compound of the present invention. Preferably the cancer is melanoma. Preferably the cancer is colorectal cancer. Preferably the cancer is renal cell carcinoma. Preferably the cancer is breast cancer. Preferably the cancer is lung cancer, in particular non-small cell lung cancer. Preferably the cancer is ovarian cancer.

Preferably the cancer is glioma. Preferably the compound is 4-fluoro-N-{(lR)-l-[l-(tetrahydro-2H-pyran-4-ylcarbonyl)-2 -dihydro-lH-indol-5-yl]ethyl}benzamide.

This invention also provides a compound of the present invention for use in therapy. Additionally, this invention provides a compound of the present invention for use in the treatment of a cancer selected from the group consisting of melanoma, acute myeloid leukemia, chronic lymphocytic leukemia, colorectal cancer, renal cell carcinoma, breast cancer, lung cancer, ovarian cancer, fallopian tube carcinoma, primary

peritoneal carcinoma, cervical cancer, gastric cancer, liver cancer, pancreatic cancer, thyroid cancer, glioma, non-Hodgkin' s lymphoma, and Hodgkin' s lymphoma. Preferably the cancer is melanoma. Preferably the cancer is colorectal cancer. Preferably the cancer is renal cell carcinoma, Preferably the cancer is breast cancer. Preferably the cancer is lung cancer, in particular non-small cell lung cancer. Preferably the cancer is ovarian cancer. Preferably the cancer is glioma. Preferably the compound is 4-fluoro-N-{(lR)-l-[l-(tetrahydro-2H-pyran-4-ylcarbonyl)-2,3-dihydro-lH-indol-5-yl]ethyl}benzamide. Preferably the compound is 4-fluoro-N-{(lR)-l-[l-(tetrahydro-2H-pyran-4-ylcarbonyl)-2,3-dihydro-lH-indol-5-yl]ethyl}benzamide.

This invention also provides a combination comprising a compound of the present invention and LY3300054 for simultaneous, separate, or sequential use in the treatment of a cancer selected from the group consisting of non-small cell lung cancer and colon cancer. Preferably the cancer is non-small cell lung cancer. Preferably the cancer is colon cancer. Preferably the compound is 4-fluoro-N-{(lR)-l-[l-(tetrahydro-2H-pyran-4-ylcarbonyl)-2,3-dihydro-lH-indol-5-yl]ethyl}benzamide. Preferably the compound is 4-fluoro-N-{(lR)-l-[l-(tetrahydro-2H-pyran-4-ylcarbonyl)-2,3-dihydro-lH-indol-5-yl] ethyl }benzamide and the cancer is non-small cell lung cancer. Preferably the compound is 4-fluoro-N-{(lR)-l-[l-(tetrahydro-2H-pyran-4-ylcarbonyl)-2,3-dihydro-lH-indol-5-yl]ethyl}benzamide and the cancer is colon cancer.

The following paragraphs describe preferred classes of Formula I:

a) Rlais hydrogen, methyl, cyano, fluoro, or chloro;

b) Rib is hydrogen, fluoro, or chloro;

c) Rlc is hydrogen or hydroxy;

d) R2 is hydrogen or methyl;

e) R2a is hydrogen or methyl;

f) R3a is tetrahydropyranyl; and

g) Rla is fluoro, Rib is hydrogen, Rlc is hydrogen, R2 is hydrogen, R2a is hydrogen, and R3 is tetrahydropyranyl.

Certain of the compounds of the present invention are crystalline. It is well known in the crystallography art that, for any given crystal form, the relative intensities of the diffraction peaks may vary due to preferred orientation resulting from factors such as crystal morphology and habit. Where the effects of preferred orientation are present, peak intensities are altered, but the characteristic peak positions of the polymorph are unchanged. See, e.g. The U. S. Pharmacopeia 38 - National Formulary 35 Chapter <941> Characterization of crystalline and partially crystalline solids by X-ray powder diffraction (XRPD) Official May 1, 2015. Furthermore, it is also well known in the crystallography art that for any given crystal form the angular peak positions may vary slightly. For example, peak positions can shift due to a variation in the temperature or humidity at which a sample is analyzed, sample displacement, or the presence or absence of an internal standard. In the present case, a peak position variability of + 0.2 in 2Θ will take into account these potential variations without hindering the unequivocal identification of the indicated crystal form. Confirmation of a crystal form may be made based on any unique combination of distinguishing peaks (in units of 0 2Θ), typically the more prominent peaks. The crystal form diffraction patterns, collected at ambient temperature and relative humidity, were adjusted based on NIST 675 standard peaks at 8.85 and 26.77 degrees 2-theta.

As used herein, "treat", "treating" or "treatment" refers to restraining, slowing, stopping, or reversing the progression or severity of an existing symptom or disorder.

As used herein, the term "patient" refers to a warm blooded animal such as a mammal, in particular a human, which is afflicted with a particular disease, disorder, or condition.

One of ordinary skill in the art will appreciate that compounds and certain intermediates of the invention can exist in tautomeric forms. When any reference in this application to one of the specific tautomers of the compounds of the invention is given, it is understood to encompass both tautomeric forms and all mixtures thereof.

Some intermediates or compounds of the present invention disclosed herein may have one or more chiral or stereogenic centers. All individual stereoisomers, enantiomers and diastereomers, as well as mixtures of the enantiomers and diastereomers of all of these aforementioned compounds or intermediates of the present invention are contemplated including racemates. It is preferred that compounds or intermediates of the present invention disclosed herein containing at least one chiral center exist as single enantiomers or diastereomers. The single enantiomer or diastereomer may be prepared beginning with chiral reagents or by stereoselective or stereospecific synthetic techniques (as illustrated in the preparations and examples). Alternatively, the single enantiomer or diastereomers may be isolated from mixtures by standard chiral chromatographic (as illustrated in the preparations and examples) or crystallization techniques. The skilled artisan will appreciate that in some circumstances the elution order of enantiomers or diastereomers may be different due to different chromatographic columns and mobile phases.

The designation of "Isomer 1" in a compound name represents that the corresponding intermediate or compound of the present invention is the first of two eluting enantiomers when a mixture of a pair of enantiomers is separated by chiral chromatography. The designation of "Isomer 2" in a compound name represents that the corresponding intermediate or compound of the present invention is the second of two eluting enantiomers when the mixture of a pair of enantiomers is separated by chiral chromatography.

The designation of "Isomer A" in a compound name represents that the corresponding intermediate or compound of the present invention is a single isomer from a chiral synthesis of unknown absolute configuration.

As used herein, "LY3300054" is an antibody that binds human PD-L1 (SEQ ID NO: 1), comprising a light chain (LC) and a heavy chain (HC), wherein the light chain comprises a light chain variable region (LCVR) and the heavy chain comprises a heavy chain variable region (HCVR), and wherein the LCVR comprises light chain

complementarity determining regions LCDR1, LCDR2, and LCDR3, where the amino acid sequence of LCDR1 is SGSSSNIGSNTVN (SEQ ID NO: 5), the amino acid sequence of LCDR2 is YGNSNRPS (SEQ ID NO: 6), and the amino acid sequence of LCDR3 is QSYDSSLSGSV (SEQ ID NO: 7), and wherein the HCVR comprises heavy chain complementarity determining regions HCDR1, HCDR2, and HCDR3, where the amino acid sequence of HCDR1 is KASGGTFS S YAIS (SEQ ID NO: 2), the amino acid

WE CLAIM:

1. A compound of the formula:

wherein:

Rlais hydrogen, methyl, ethenyl, cyano, fluoro, chloro, fluoromethyl, or difluoromethyl;

Rib is hydrogen, fluoro, or chloro;

Rlc is hydrogen, hydroxy, fluoro, benzyloxy, or hydroxyethylamino; R2 is hydrogen or methyl;

R2a is hydrogen or methyl; and

R3a is tetrahydropyranyl.

2. The compound accordin to claim 1 which is:

The compound according to either claim 1 or claim 2 which

4. The compound according to either claim 1 or claim 2 which is

5. The compound according to any one of claims 1-3 which is crystalline 4-fluoro-N-{(lR)-l-[l-(tetrahydro-2H-pyran-4-ylcarbonyl)-2,3-dihydro-lH-indol-5-yl]ethyl}benzamide.

6. The compound according to claim 5 which is crystalline 4-fluoro-N-{(lR)- 1 - [ 1 -(tetrahydro-2H-pyran-4-ylcarbonyl)-2,3 -dihydro- 1 H-indol-5 -yljethyl } benzamide characterized by an X-ray powder diffraction pattern (Cu radiation, λ- 1.54060 A) comprising at least one peak at 17.38° in combination with one or more peaks selected from the group consisting of 12.51°, 15.65°, 16.37°, 17.56°, 21.48° and 25.23° (2Θ+ 0.2°).

7. A pharmaceutical composition comprising a compound according to any one of claims 1-6 with one or more pharmaceutically acceptable excipients, carriers or diluents.

8. A method of treating a patient with a cancer selected from the group consisting of melanoma, acute myeloid leukemia, chronic lymphocytic leukemia, colorectal cancer, renal cell carcinoma, breast cancer, lung cancer, ovarian cancer, fallopian tube carcinoma, primary peritoneal carcinoma, cervical cancer, gastric cancer, liver cancer, pancreatic cancer, thyroid cancer, glioma, non-Hodgkin's lymphoma, and Hodgkin's lymphoma comprising administering to the patient an effective amount of a compound according to any one of claims 1-6.

9. A compound according to any one of claims 1-6 for use in therapy.

10. A compound according to any one of claims 1-6 for use in cancer.

11. A compound according to claim 10 wherein the cancer is selected from the group consisting of melanoma, acute myeloid leukemia, chronic lymphocytic leukemia, colorectal cancer, renal cell carcinoma, breast cancer, lung cancer, ovarian cancer, fallopian tube carcinoma, primary peritoneal carcinoma, cervical cancer, gastric cancer, liver cancer, pancreatic cancer, thyroid cancer, glioma, non-Hodgkin's lymphoma, and Hodgkin's lymphoma.