EA038517B1 - Compositions and methods for inhibiting arginase activity - Google Patents

Abstract

The invention provides a series of compounds suitable for the inhibition of arginase, that is useful in treating cancer. The invention provides a compound that (a) has a structure of formula (I*)or (b) is a pharmaceutically acceptable salt thereof; whrein R1 is methyl; and R4 is H or (C1-C6)alkyl.

Description

Prior art

Cancer is characterized by uncontrolled cell growth in the body, leading to invasion of vital organs and often death. Originally, the pharmacological treatment of cancer used nonspecific cytotoxic agents to target all rapidly dividing cells, including normal cells. These nonspecific cytotoxic agents have antitumor effects, but their use is often limited by severe toxicity. As the understanding of proteins and the pathways that allow cancer cells to grow has developed, new, more targeted agents have been developed that block specific proteins that are activated in cancer cells.

A new area for the development of therapeutic agents that addresses the challenges posed by cancer treatment is immuno-oncology, also called tumor immunology. Several types of tumors have developed mechanisms to avoid being destroyed by the body's immune system. Immunology of tumors is a therapeutic area aimed at activating the body's own immune system to attack and destroy tumors. The natural amino acid arginine is involved in tumor immunology as it is important for the activation, growth and survival of the body's cancer-fighting cytotoxic T cells. However, arginine levels are depleted in the tumor microenvironment by arginase, an enzyme produced and secreted by neutrophils and myeloid suppressor cells (MDSCs) that accumulate in cancer patients with multiple histotypes. In fact, elevated levels of the enzyme arginase have been observed in the plasma of patients with renal cell carcinoma, breast cancer, chronic myelogenous leukemia, esophageal cancer, prostate cancer, non-small cell lung cancer, glioblastoma, and acute myeloid leukemia. Therefore, there is a need for the development of arginase inhibitors that restore arginine levels in the tumor microenvironment, thereby promoting tumor-killing cytotoxic T cell activity.

Summary of the invention

In some embodiments, the invention provides a variety of compounds useful for inhibiting arginase. The proposed invention provides a compound that (a) has the structure of formula (I *)

or (b) is a pharmaceutically acceptable salt thereof;

where R ¹ is methyl and

R ⁴ is H or (C ₁ -C ₆ ) α-alkyl.

In some embodiments, the invention also provides pharmaceutical compositions comprising a compound of the present invention and a pharmaceutically acceptable carrier.

In some embodiments, the compounds of the present invention are for use in methods of treating cancer comprising administering to a subject in need thereof a therapeutically effective amount of a compound of the invention.

In some embodiments, the compounds of the present invention are for use in methods of treating cancer comprising administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition of the invention.

The compounds of the present invention may also be intended for use in methods of treating cancer comprising co-administering to a subject in need thereof an arginase inhibitor of the present invention and one or more additional chemotherapeutic agents.

In specific embodiments, the compounds of the present invention are for use in methods of treating or preventing cancer, comprising co-administering to a subject in need thereof an arginase inhibitor of the present invention and an indoleamine 2,3 dioxygenase (IDO) inhibitor. The IDO inhibitor can be a compound disclosed in the invention or a compound having the structure of any of the formulas disclosed herein. In specific embodiments, the IDO inhibitor is epacadostat.

Also described herein are compounds of formula (I)

or a pharmaceutically acceptable salt thereof;

- 1 038517 where R ^b , X, R ¹ , R ² , R ³ and R ^{4 are} defined as set forth in the detailed discussion of the description section below.

In some embodiments, the structure

in the compounds of formula (I) may represent an alpha-amino acid residue, where X = O and the terminal amine is optionally substituted with R ³ . In such compounds, the R ¹ group is the alpha amino acid side chain. Suitable amino acid side chains include natural and unnatural amino acid chains. For example, in some embodiments, R ¹ is an amino acid side chain from Arg, His, Liz, Asp, Glu, Ser, Tre, Asn, Gln, Cis, Sec (selenocysteine), Gly, Ala, Val, Ile, Leu, Met , Fen, Tyr or Trp, in particular Gli, Ser or Ala. In some compounds, R ¹ is an amino acid side chain from Gly, Ala or Ser. In such connections, R ¹ may take on the R or S configuration.

Brief Description of Drawings

FIG. 1 shows the structure of compound 10e obtained by X-ray diffraction with 50% probability levels of a thermal ellipsoid. Most hydrogen atoms have been omitted for clarity.

FIG. 2 shows NMR spectra (in D ₂ O) showing the conversion of compound 10 (designated as compound A in the figure) to compound 10e (designated as compound B in the figure) and back to compound 10 (designated as compound C in the figure).

FIG. 3 is a graph showing tumor volume over time. Compound 10, which inhibits arginase, administered as a single agent, slowed tumor growth compared to controls in C57BL / 6 mice implanted with Lewis lung carcinoma cells.

FIG. 4 is a graph showing tumor volume over time. Madison 109 lung carcinoma cells were implanted in BALB / c mice, and the mice were orally dosed with vehicle or arginase inhibitor 10 compound twice daily (N = 10 per group).

FIG. 5 is a graph showing tumor volume over time. B16F10 murine melanoma cells were implanted in C57BL / 6 mice, and the mice were orally dosed with vehicle or arginase inhibitor compound 10 twice daily (N = 10 per group).

FIG. 6A and 6B show the growth of 4T1 breast carcinoma cells orthotopically implanted in female BALB / c mice treated with vehicle Compound 10 (100 mg / kg orally); anti-CTLA-4 (5 mg / kg ip on days 2, 5, 8) plus anti-PD-1 (5 mg / kg ip on days 3, 6 and 9); or a combination of compound 10 with anti-CTLA-4 and anti-PD-1 (N = 10 per group;

* P <0.05; *** P <0.001, **** P <0.0001, compared to vehicle).

FIG. 7 is a graph of the sorption isotherm of compound 10e.

Detailed description of the invention

The present invention relates to compounds and compositions useful for inhibiting arginase, as well as to their various therapeutic uses. Previous research by the inventors has focused on a class of small molecules having (i) an amino acid moiety and (ii) a boronic acid type moiety, such as compounds generally represented by Formula A below. The compounds of Formula A have been found to be useful for inhibiting arginase.

Surprisingly, the inventors found that when the free base of the compound of formula A was treated with anhydrous alcohol, the cyclic alkoxylated compound of formula (I) could be isolated. Unlike many prodrugs, such cyclic alkoxylated compounds of formula (I) do not require an enzymatic process to identify the main arginase inhibitor compounds; rather, treatment of a compound of formula (I) with water or an aqueous medium (eg, when administered orally) will result in the formation of an underlying arginase inhibitor, eg, a compound of formula (A). Typically, these cyclic alkoxylated compounds of formula (I) exhibit improved manufacturing and processing properties, higher purity and better stability than their non-cyclized counterparts.

Compounds of the invention

Also disclosed herein is a compound having the structure of formula (I)

- 2 038517

or a pharmaceutically acceptable salt thereof;

where the definitions of R ^b , X, R ¹ , R ² , R ³ and R4 are given below.

Certain compounds of formula (I) have the structure of formula (I ')

or a pharmaceutically acceptable salt thereof;

wherein

R ^{b is} selected from H, alkyl, alkenyl, alkynyl, acyl, —C (O) O (αalkyl) and —C (O) O (aryl);

X is O or S;

R ¹ and R ² are each independently selected from H, alkyl, —CH 2 OH, alkenyl, alkynyl, cycloalkyl, (cycloalkyl) alkyl, heterocycloalkyl, (heterocycloalkyl) alkyl, aryl, heteroaryl, aralkyl, and hetero aralkyl; or

R ¹ and R ² taken together with intermediate atoms form a 3-7 membered ring and

R ³ represents H or alkyl;

or R ¹ and R ³ taken together with intermediate atoms form a 5-7 membered ring; and

R4 is H or (C ₁ -C ₆ ) α-alkyl.

In some compounds of Formula I, R ² is H.

In some compounds of Formula I, R ^b is H or alkyl.

In specific compounds, R ^b is H.

In some compounds of Formula I, 'X is O.

In some compounds of Formula I ', if R ¹ is H then R ^{3 is} not benzyl.

In some compounds of Formula I, R ¹ is H. In some such compounds, R ² is H.

In some compounds of Formula I ', if R ¹ is benzyl then R ^{3 is} not methyl.

In some compounds of Formula I, R ¹ is aralkyl, heteroaralkyl, (cycloalkyl) alkyl, or (heterocycloalkyl) alkyl.

In some compounds of Formula I, R ¹ is aralkyl or heteroaralkyl.

In some compounds of Formula I, R ¹ is benzyl.

In some compounds of formula I, R ^{1 is} not benzyl substituted with —CF ₃ .

In some compounds of Formula I, R ¹ is heteroaralkyl. In certain compounds, R ¹ is —CH ₂ - (1H-imidazol-4-yl).

In some compounds of Formula I, R ¹ is alkyl, alkenyl, or alkynyl.

In some compounds of Formula I, R ¹ is (C ₁ -C ₄ ) alkyl. In some such compounds, R ² is H.

In some compounds of Formula I, R ¹ is methyl. In some such compounds, R ² is H.

In some compounds of Formula I, R ^{1 is} selected from cycloalkyl, heterocycloalkyl, aryl, and heteroaryl.

In some compounds of Formula I, R ¹ is —CH 2 OH. In some such compounds, R ² is H.

In some compounds, both R ¹ and R ² are hydrogen.

In some compounds of Formula I ', R ¹ and R ² are taken together with the intermediate atoms to form a 5-7 membered ring.

In some compounds of Formula I, R ³ is H.

In some compounds of formula I ', R ¹ and R ³ are taken together with the intermediate atoms to form a 5-membered ring.

In some compounds of formula I ', R ¹ and R ³ , taken together with the intermediate atoms, do not form a 5-membered ring.

- 3 038517

R ³ , taken together with intermediate atoms, form

In some compounds of Formula I, R is ¹ and a 6- or 7-membered ring.

In some compounds of formula I 'R ¹ and

R ³ taken together with intermediate atoms do not form a tetrahydroisoquinolinyl ring, for example

In some compounds of Formula I, R ⁴ is (C ₁ -C ₄ ) α-alkyl. In specific compounds, the lower alkyl group is selected from methyl, ethyl, propyl, isopropyl, and isobutyl. In certain compounds, R ⁴ is ethyl. In other specific embodiments, R ⁴ is isopropyl.

Certain compounds of formula (I) have the structure of formula (I ″)

or a pharmaceutically acceptable salt thereof;

wherein

R ^b is H or is selected from optionally substituted alkyl, alkenyl, alkynyl, acyl, —C (O) O (alkyl) and —C (O) O (aryl);

X is O or S;

R ¹ and R ² are each independently selected from H and optionally substituted alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl) alkyl, heterocycloalkyl, (heterocycloalkyl) alkyl, aryl, heteroaryl, aralkyl, and heteroaralkyl;

or R ¹ and R ² , taken together with intermediate atoms, form an optionally substituted 3-7 membered ring; and

R ³ is H or optionally substituted alkyl;

or R ¹ and R ³ , taken together with intermediate atoms, form an optionally substituted 5-7 membered ring; and

R ⁴ is H or (C ₁ -C ₆ ) alkyl.

Certain compounds of formula (I) have the structure of formula (I ″ ″)

or a pharmaceutically acceptable salt thereof;

wherein

R ^b represents H or a group selected from alkyl, alkenyl, alkynyl, acyl, —C (O) O (alkyl) and —C (O) O (aryl), wherein said group is optionally substituted with one or more substituents selected from hydroxy, halogen, haloalkyl, alkoxy, -SH, -S- (alkyl), -SeH, -Se- (alkyl), aryl, heteroaryl, cycloalkyl, heterocycloalkyl, amino, carboxylic acid, ester, guanidino and amido;

X is O or S;

R ¹ and R ² are each independently selected from H or a group selected from alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl) alkyl, heterocycloalkyl, (heterocycloalkyl) alkyl, aryl, heteroaryl, aralkyl and heteroaralkyl, where said group is optionally substituted by one or more substituents selected from hydroxy, halogen, haloalkyl, alkoxy, -SH, -S- (alkyla), -SeH, -Se (alkyl), aryl, heteroaryl, cycloalkyl, heterocycloalkyl, amino, carboxylic acid, ester , guanidino and amido; or

R ¹ and R ² , taken together with intermediate atoms, form a 3-7 membered ring, where the 3-7 membered ring is optionally substituted with one or more substituents selected from hydroxy, halogen, haloalkyl, alkoxy, -SH, -S - (alkyl), -SeH, -Se- (alkyl), aryl, heteroaryl, cycloalkyl, heterocycloalkyl, amino, carboxylic acid, ester, guanidino and amido; and

R ³ is H or alkyl, optionally substituted with one or more substituents selected from hydroxy, halogen, haloalkyl, alkoxy, -SH, -S- (alkyl), -SeH, -Se (alkyl), aryl , heteroaryl, cycloalkyl, heterocycloalkyl, amino, carboxylic acid, ester, guanidino and amido;

or R ¹ and R ³ taken together with intermediate atoms form a 5-7 membered ring, where the 5-7 membered ring is optionally substituted with one or more substituents selected from hydroxy, halogen, haloalkyl, alkoxy, -SH, -S- (alkyl), -SeH, -Se- (alkyl), aryl, heteroaryl, cycloalkyl, heterocycloalkyl, amino, carboxylic acid, ester, guanidino and amido; and

R ⁴ is H or (C ₁ -C ₆ ) alkyl.

In some compounds of Formula I, ″ ″ R ² is H.

In some compounds of Formula I, "" R ^b is H or alkyl. In specific compounds, R ^b is H.

In some compounds of Formula I, ″ ″ X is O.

In some compounds of formula I ″ ″, if R ¹ is H, then R ^{3 is} not benzyl.

In some compounds of Formula I ″ ″, R ¹ is H. In some such compounds, R ² is H.

In some compounds of Formula I ″ ″, if R ¹ is benzyl, then R ^{3 is} not methyl.

In some compounds of Formula I, "" R ¹ is aralkyl, heteroaralkyl, (cycloalkyl) alkyl, or (heterocycloalkyl) alkyl.

In some compounds of Formula I, "" R ¹ is aralkyl or heteroaralkyl.

In some compounds of Formula I, "" R ¹ is benzyl.

In some compounds of Formula I, "" R ^{1 is} not benzyl substituted with —CF ₃ .

In some compounds of Formula I, "" R ¹ is heteroaralkyl. In specific embodiments, R ¹ is —CH ₂ - (1H-imidazol-4-yl).

In some compounds of Formula I, "" R ¹ is alkyl, alkenyl, or alkynyl.

In some compounds of Formula I, "" R ¹ is alkyl, optionally substituted with one or more substituents independently selected from hydroxy, alkoxy, haloalkyl, and —S— (alkyl).

In some compounds of Formula I, "" R ¹ is (C ₁ -C ₄ ) alkyl. In some such compounds, R ² is H.

In some compounds of Formula I, "" R ¹ is methyl. In some such compounds, R ² is H.

In some compounds of Formula I, R ¹ is —CH 2 OH. In some such compounds, R ² is H.

In some compounds of Formula I, "" R ^{1 is} selected from cycloalkyl, heterocycloalkyl, aryl, and heteroaryl. In some such compounds, the cycloalkyl, heterocycloalkyl, aryl or heteroaryl group is optionally substituted with one or more groups selected from hydroxy, halogen, haloalkyl, alkoxy, SH, and —S— (alkyl).

In some compounds of Formula I, "" R ¹ is —CH ₂ OH. In some such compounds, R ² is H.

In some compounds of formula I '''R ¹ is an amino acid side chain from Arg, His, Liz, Asp, Glu, Ser, Tre, Asn, Gln, Cis, Sec, Gli, Ala, Val, Ile, Leu, Met, Hairdryer, Shooting Range or Trp.

In some compounds of formula I ″ ″, R ¹ and R ² are taken together with the intermediate atoms to form a 5-7 membered ring.

In some compounds of Formula I, ″ ″ R ³ is H.

In some compounds of formula I ″ ″, R ¹ and R ³ are taken together with the intermediate atoms to form a 5-membered ring.

In some compounds of Formula I ″ ″, R ¹ and R ³ , taken together with the intermediate atoms, do not form a 5-membered ring.

In some compounds of formula I ″ ″, R ¹ and R ³ are taken together with the intermediate atoms to form a 6- or 7-membered ring.

In some compounds of formula I ″ ″ R ¹ and R ³ , taken together with intermediate atoms, do not form a tetrahydroisoquinolinyl ring, for example

In some compounds of Formula I, "" R ⁴ is (C ₁ -C ₄ ) alkyl. In specific compounds, the lower alkyl group is selected from methyl, ethyl, propyl, isopropyl, and isobutyl. In certain compounds, R ⁴ is ethyl. In other specific compounds, R ⁴ is

- 5 038517 isopropyl.

The proposed invention relates to a compound having the structure of the formula (I *)

or a pharmaceutically acceptable salt thereof;

wherein

R ¹ is methyl and

R ⁴ is H or (C ₁ -C ₆ ) alkyl.

In some embodiments of the compound of Formula I * R ⁴ is (C ₁ -C ₄ ) alkyl. In specific embodiments, the lower alkyl group is selected from methyl, ethyl, propyl, isopropyl, and isobutyl. In certain embodiments, R ⁴ is ethyl. In other specific embodiments, R ⁴ is isopropyl.

In a specific embodiment, the compound of Formula I * has the following structure:

The compound can be a free base or can be ionized to form a pharmaceutically acceptable salt thereof.

In another specific embodiment, the compound of Formula I * has the following structure

The compound can be a free base or can be ionized to form a pharmaceutically acceptable salt thereof. A compound of formula (I) may have the structure of formula (Ia)

A compound of formula (I) may have the structure of formula (Ib)

A compound of formula (I) may have the structure of formula (Ic)

- 6 038517

The compound of formula (I) may have the structure of formula (Id)

A compound of formula (I) may have the structure of formula (Ie)

The compound of formula (I) may have the structure of formula (If)

A compound of formula (I) may have the structure of formula (Ig)

The compound of formula (I) may have the structure of formula (Ih)

For compounds of formulas (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig) and (Ih) the variables R ^b , X, R ¹ , R ² , R ³ and R ⁴ are as described above for the various formulas described by formula (I).

It will be understood that any recitation of a compound of formula (I) in the disclosure below includes compounds of formulas (I '), (I), (I'), (I *), (Ia), (Ib), (Ic), (Id ), (Ie), (If), (Ig) and (Ih).

Related arginase inhibitors are described in US Patent Application Publication Nos. 2014/0343019, 2012/0083469, 2014/0371175, 2012/0129806, 2015/0080341 and PCT Application Publication Nos. WO 99/19295, WO 2010/085797 and WO 2012/091757. Such related arginase inhibitors are expected to form cyclic alkoxylated compounds analogous to the compounds of the invention when treated with anhydrous alcohol. In some embodiments, the aqueous alcohol contains 1-5% water, preferably <1% water, most preferably <0.5% water.

For example, U.S. Patent Application Publication No. 2012/0129806 discloses an arginase inhibitor of Formula J

- 7 038517

wherein

R ^{2 is} selected from H, linear or branched (C1-C6) alkyl and (C1-C6) alkyl-C (O) -;

W, X, Y and Z are each independently selected from -C (R ') (R') -, -C (R '' ') 2-, -CR'-, -NR'-, -N-, -O-, -C (O) - and -S-, where no more than three of W, X, Y and Z simultaneously represent a bond; at least one of W, X, Y or Z is selected from -NR'-, -N-, -O- and -S- and no two adjacent members of W, X, Y and Z are simultaneously -O-, - S-, -N- or -NR'-;

l, m, n and p are each independently 0 or 1 or 2;

optionally represents one or more double bonds;

D is selected from linear or branched _(C3-C5) alkylene;

R ', R and R' are each independently selected from H, OH, S (O) R ^d , S (O) 2R ^d , (C1-C8) alkyl, (C3-C6) aryl, -NH2, -NH (C1-C ₆₎ alkyl, -N [(C1-C ₆₎ alkyl] ^{2, -C (O) NR d R} e, -C (O) (C _r Sa) alkyl, -C (O) (Cs -C14) aryl, -C (O) O (C1-C ₆ ) alkyl, -C (O) O (C ₃ -C ₁₄ ) aryl, (C ₃ -C ₆ ) cycloalkyl, (C ₃ -C ₁₄ ) heterocycloalkyl, C (O) (C ₃ C ₁₄ ) heterocycloalkyl, (C ₃ -C ₁₄ ) heteroaryl, (C ₃ -C ₁₄ ) aryl- (C ₁ -C ₆ ) alkylene-, -C (O) (C ₃ -C ₁₄ ) aryl- (C1-C ₆ ) alkylene-, -C (O) (C ₃ -C ₁₄ ) aryl, (C ₃ -C ₆ ) cycloalkyl- (C ₁ -C ₆ ) alkylene-, (C ₃ - From ₁₄₎ heteroaryl- _(C1-C6) alkylene (C ₃ -C _14), heterocycle- (C ₁ -C ₆₎ alkylene-;

where any alkyl, alkylene, aryl, heteroaryl, cycloalkyl or heterocycloalkyl is optionally substituted with one or more members selected from halogen, oxo, -COOH, -CN, -NO ₂ , -OH, -NR ^d R ^e , -NR ^g S (O) 2R ^h, (C1-C6) alkoxy, (C ₃ -C ₁₄₎ aryl, (C ₁ -C ₆₎ -haloalkyl and (C ₃ -C ₁₄₎ aryloxy;

where each of R ^d , R ^e , R ^g and R ^{h is} independently selected from H, unbranched or branched (C1C ₆ ) alkyl, optionally substituted (C ₃ -C ₁₄ ) aryl (C ₁ -C ₆ ) alkylene-, with optionally substituted (C ₃ -C ₁₄ ) aryl, (C1-C ₆ ) hydroxyalkyl, (C1-C ₆ ) aminoalkyl, H ₂ N (C ₁ -C ₆ ) alkylene, optionally substituted (C ₃ -C ₆ ) cycloalkyl, optionally substituted (C ₃ -C ₁₄ ) heterocycloalkyl, optionally substituted (C ₃ -C ₁₄ ) heteroaryl, optionally substituted (C ₃ -C ₁₄ ) aryl- (C1C ₆ ) alkylene-, NR'RC (O ) -, and (C ₃ -C ₆ ) aryl- (C ₃ -C ₁₄ ) -cycloalkylene-.

After treatment with anhydrous alcohol, a compound of Formula J can be cyclized to form a compound of Formula B

X / ml

Formula B wherein R ⁵ is H or lower alkyl and the remaining variables are as defined for Formula J.

In some compounds of Formula B, R ⁵ is lower alkyl, preferably methyl, ethyl, propyl or isopropyl. Most preferably R ⁵ is ethyl.

In some compounds, D is propylene.

A compound of the present invention may have a prodrug modification, for example, at the R ¹ position. For example, compounds of Formula I may have an R ¹ equivalent to an amino acid side chain such as Arg or Lys. In some such compounds, the guanidino or amino group of such a side chain can be protected, for example, with an amide. Alternatively, in compounds in which R ¹ is a side chain from a serine residue, the hydroxyl group in the parent compound may be in the form of an ester or carbonate. In other compounds in which R ¹ is a side chain of a glutamic acid residue, the carboxylic acid group present in the parent compound may be in the form of an ester. In some such compounds, the prodrug is metabolized to the active parent compound in vivo (eg, the amide is hydrolyzed to the corresponding amino or guanidine group, the ester or carbonate is hydrolyzed to hydroxyl, or the ester is hydrolyzed to the carboxylic acid).

In some embodiments, the compounds of the present invention may be racemic. In some embodiments, the implementation of the compounds of the present invention can be enriched in one enantiomer. For example, a compound of the present invention may have more than 30% ee, 40% ee, 50% ee, 60% ee, 70% ee, 80% ee. , 90% e.o. or even 95% or more e.o.

- 8 038517

The compounds of the present invention have more than one stereocenter. Accordingly, the compounds of the invention can be enriched in one or more diastereomers. For example, a compound of the present invention may have greater than 30% doo, 40% doo, 50% doo, 60% doo, 70% doo, 80% doo. , 90% d.d. or even 95% or more doo. In some embodiments, the compounds of the present invention have substantially one isomeric configuration at one or more stereogenic centers, and have multiple isomeric configurations at the remaining stereogenic centers.

In some embodiments, the enantiomeric excess of the stereocenter carrying R ¹ is at least 40% ee, 50% ee, 60% ee, 70% ee, 80% ee. , 90% e.d., 92% e.d., 94% e.d., 95% e.d., 96% e.d., 98% e.d. or more e.o.

Used in this application, simple bonds, drawn without stereochemistry, do not indicate the stereochemistry of the compound. The compound of the formula (I) is an example of a compound for which the stereochemistry is not indicated.

As used in this application, non-wedge bonds directed from the observer or to the observer indicate a relative, but not absolute stereochemical configuration (for example, do not distinguish between the enantiomers of a given diastereomer). For example, in formula (Ia)

non-wedge-shaped bonds directed towards the observer indicate that the -CO ₂ R ^a group and the (CH2) 3B (OR ^c ) 2 group are configured to be cis-bonded to each other, but non-wedge-shaped bonds directed towards the observer do not represent absolute ( i.e. R or S) connection configuration.

Used in this document directed from the observer or to the observer, wedge-shaped bonds indicate the absolute stereochemical configuration. For example, in formula (Ic)

a wedge-shaped bond directed towards the observer indicates the absolute configuration of the stereocenter to which it is attached, while a non-wedge-shaped bond directed towards the observer indicates that the -CO ₂ R ^a group and the (CH2) 3B (OR ^c ) 2 group have such a configuration to be cis to each other, but do not indicate the absolute configuration of these stereocenters. Therefore, the compound of formula (Ic) has only two isomers:

In some embodiments, a therapeutic agent from a compound of the present invention can be enriched to produce predominantly one enantiomer of the compound. The enantiomerically enriched mixture may contain, for example, at least 60 mol% of one enantiomer, or more preferably at least 75, 90, 95 or even 99 mol%. In some embodiments, a compound enriched in one enantiomer is substantially free of the other enantiomer, wherein substantially free means that the substance in question is less than 10%, or less than 5%, or less than 4%, or less than 3%, or less than 2%, or less than 1%, compared to the amount of the other enantiomer, for example, in a composition or mixture of compounds. For example, if a composition or mixture of compounds contains 98 g of the first enantiomer and 2 g of the second enantiomer, it can be said to contain 98 mol% of the first enantiomer and only 2% of the second enantiomer.

In some embodiments, a therapeutic agent can be enriched to provide predominantly one diastereomer of a compound of the present invention. The diastereomerically enriched mixture may contain, for example, at least 60 mol% of one diastereomer, or more preferably at least 75, 90, 95 or even 99 mol%.

- 9 038517

In some embodiments, a formulation of a compound of the present invention may contain at least 50 mol%, at least 60 mol%, at least 70 mol%, at least 80 mol%, at least 90 mol% or at least 95 mol% of the cyclic alkoxylated compounds of the invention. In some such embodiments, the drug residue is a non-cyclized free boronic acid ester analog or a cyclized but non-esterified boronic acid (eg, Formula I, R ⁴ = H; Scheme 1).

In some embodiments, the compounds of the present invention exhibit an improved pharmacokinetic profile over existing arginase inhibitors. In one embodiment, cyclic alkoxylated compounds of the invention, when administered to a subject or a number of subjects, provide an increased (or decreased) Tmax value over that obtained with the administration of a noncyclized free boronic acid ester analog as described herein by at least about 10 %, or at least about 20%, or at least about 30%, or at least about 40%, or at least about 50%, and under similar conditions and when administered at similar dosages. In one embodiment, cyclic alkoxylated compounds of the present invention, when administered to a subject or a number of subjects, provide an increased (or decreased) Cmax value over that obtained when a non-cyclized free boronic acid ester analog as described herein is administered, at least about 10%, or at least about 20%, or at least about 30%, or at least about 40%, or at least about 50%, and under similar conditions and when administered at similar dosages.

In some embodiments, the compounds of the present invention exhibit improved bioavailability over existing arginase inhibitors. In one embodiment, the cyclic alkoxylated compounds of the invention, when administered to a subject or a number of subjects, provide increased bioavailability over that obtained by administering a non-cyclized free boronic acid ester analog (e.g., compounds of Formula J described herein) by at least about 20 %, or at least about 25%, or at least about 30%, or at least about 35%, or at least about 40%, or at least about 45%, or at least at least about 50%, or at least about 55%, or at least about 60%, for example, at least 65%, wherein bioavailability is defined as AUC (0-infinity) and under similar conditions and when administered similar dosages.

The cyclic alkoxylated compounds of the present invention are generally less hygroscopic than their free boronic acid ester counterparts (eg, the compounds of formula J described herein). For example, compound 10e, shown in the examples, has a low water content and is resistant to water absorption up to a relative humidity of about 60%, while its free boric acid analog, compound 10, has a higher water content and absorbs more water as an increase in moisture, which leads to a less clear definition of the composition.

The cyclic alkoxylated compounds of the present invention may be about 50, 45, 40, 35, 30, 25, 20, 15, 10, or 5% less hygroscopic than their free boronic acid ester counterparts when measured by standard methods such as thermogravimetric analysis (TGA) or dynamic vapor sorption (DSP). These values can be used to define a range, for example, about 40 to 20%.

In some embodiments, the cyclic alkoxylated compounds of the invention are crystalline. Cyclic alkoxylated compounds of the invention generally have a higher degree of crystallinity than their free boronic acid ester counterparts (eg, the compounds of formula J described herein). For example, compound 10e also shows certain peaks on powder X-ray diffraction that are not visible for its free boric acid analog, compound 10, which is amorphous.

In some embodiments, the cyclic alkoxylated compounds of the invention are greater than 96, 97, or 98% pure. In some embodiments, the cyclic alkoxylated compounds of the present invention are greater than 99% pure. In some embodiments, the cyclic alkoxylated compounds of the present invention are greater than 99.5% pure. In some embodiments, the cyclic alkoxylated compounds of the present invention are greater than 99.8% pure.

As a result, the cyclic alkoxylated compounds of the present invention may have the beneficial properties of more stable compositions exhibiting better processing properties during manufacture, and may ultimately lead to compositions having higher purity and stability. In some embodiments, a pharmaceutical composition comprising a cyclic alkoxylated compound of the invention, when exposed to an environment with at least 50% humidity for at least 24 hours, absorbs less than 50% (preferably less than 25% or even less than 10 or 5%) of water, which the corresponding composition of the non-cyclized analog of the free boronic acid ester of the compound absorbs under identical conditions.

In some embodiments, cyclic alkoxylated compounds of the present invention exhibit improved stability, such as improved storage stability, with respect to structurally related compounds that have a free and uncyclized boronic acid group (e.g., compounds of Formula J described herein). For example, the present compounds or pharmaceutical compositions can exhibit improved storage stability, exhibiting less than about 10, 7, 5, 4, 3, 2, 1, or 0.5% by weight of impurities after storage under stress conditions. Stress conditions include storage for at least one, two, three, four, five or six months at 25 ° C and 60% RH, 30 ° C and 65% RH, or 40 ° C and 75% RH ... Such compounds or compositions can be considered storage stable. In some embodiments, the impurities are associated with the degradation or degradation of the compound in question. Determination of the amount of impurities present in a sample of the present compounds or pharmaceutical compositions that have been subjected to stressful conditions can be performed using typical analytical methods known in the art, such as HPLC or NMR analysis.

In some embodiments, the present compounds or pharmaceutical compositions exhibit improved storage stability, exhibiting little or no change in the purity profile after exposure to stressful conditions as defined herein. For example, after exposure to stressful conditions, cyclic alkoxylated compounds of the invention or pharmaceutical compositions containing cyclic alkoxylated compounds of the invention may exhibit a decrease in purity of about 10, 7, 5, 4, 3, 2, 1, or 0.5% or less ( for example, a decrease in purity from 98% to 97% would be a decrease of 1% or less).

Treatment methods

Several specific approaches to T cell activation have recently shown significant promise in the treatment of tumors. One such approach involves the activation of T cells by blocking the CTLA-4 antigen on the surface of T cells with the antibody ipilimumab. A second approach is to prevent the activation of immune checkpoints by blocking the interaction of programmed cell death protein 1, or PD-1, expressed on T cells, and its ligand, PD-L1, found in many tumors. A third approach is to activate the T cell receptor by supplying key stimulants or nutrients such as tryptophan.

Indoleamine dioxygenase inhibitors, or IDOs, have been shown to reduce extracellular tryptophan, without which the T cell receptor cannot become active. Arginine, like tryptophan, is an amino acid that is fundamental to the function of cytotoxic T cells. Without arginine, tumor-specific cytotoxic T cells are unable to express a functional T cell receptor on their surface and, as a result, are unable to activate, proliferate, or induce an effective antitumor response. In response to factors secreted by the tumor, myeloid suppressor cells or MDSCs accumulate around the tumor and secrete the enzyme arginase, which leads to depletion of arginine from the tumor microenvironment.

Arginine depletion due to elevated arginase levels is observed in renal cell carcinoma and acute myeloid leukemia. In addition, significant MDSC infiltrates have been observed in tumors of the pancreas, breast, and other types of tumors. Certain embodiments of the present invention provide a method for treating cancer by increasing levels of arginine in the tumor microenvironment, thereby activating cytotoxic T cells in the body.

One of the ways to increase the level of arginine in the tumor microenvironment is by inhibiting arginase. Arginase inhibitors, such as the compounds of the present invention, can stimulate an anti-tumor immune response by restoring arginine levels to activate the body's cytotoxic T cells.

Accordingly, in some embodiments, the compounds of the present invention are useful in methods of treating or preventing cancer, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I *) or a pharmaceutical composition containing said compound.

In some embodiments, the cancer treated by the methods of the present invention is acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), adrenocortical carcinoma, anal cancer, appendix cancer, atypical teratoid / rhabdoid tumor, basal cell carcinoma, bile duct carcinoma , bladder cancer, bone cancer, brain tumor, astrocytoma, brain and spinal cord tumors, brainstem glioma, atypical teratoid / rhabdoid tumors of the central nervous system, embryonic tumors of the central nervous system, breast cancer, bronchial tumors, Burkitt's lymphoma, carcinoid tumor, carcinoma without an identified primary focus, cancer of the central nervous system, cervical cancer 11 038517 ki, childhood cancer, chordoma, chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), chronic myeloproliferative diseases, colon cancer, colorectal cancer, craniopharyngioma, cutaneous T-cell lymph mu, ductal carcinoma in situ (DCIS), embryonic tumors, endometrial cancer, ependymoblastoma, ependymoma, esophageal cancer, esthesioneuroblastoma, Ewing's sarcoma, extracranial germ cell tumor, extragonadal germ cell tumor, extrahepatic bile duct cancer, eye cancer, biliary fibrosis bladder cancer, gastric cancer, gastrointestinal carcinoid tumor, gastrointestinal stromal tumor (GIST), germ cell tumor, extracranial germ cell tumor, extragonadal germ cell tumor, ebryonic ovarian cell tumor, gestational trophoblastic hair tumor, head and neck cancer hepatic cell carcinoma, histiocytosis, Langerhans cell cancer, Hodgkin's lymphoma, hypopharyngeal cancer, intraocular melanoma, insulinoma, Kaposi's sarcoma, kidney cancer, Langerhans cell histiocytosis, laryngeal cancer, leukemia, oral and lip cancer, liver cancer, lobular carcinoma ), lung cancer, whether mfoma, AIDS-associated lymphoma, macroglobulinemia, breast cancer in men, medulloblastoma, medulloepithelioma, melanoma, Merkel cell carcinoma, malignant mesothelioma, metastatic squamous cell carcinoma of the neck with a hidden primary focus, median carcinoma with NUT-regrouping, syndrome multiple endocrine neoplasia, multiple myeloma / plasma cell tumor, fungal mycosis, myelodysplastic syndrome, myelodysplastic / myeloproliferative neoplasm, chronic myelogenous leukemia (CML), acute myeloid leukemia (AML), cancer, cancer, multiple myeloplastic disease sinus, nasopharyngeal cancer, neuroblastoma, non-Hodgkin's lymphoma, non-small cell lung cancer, oral cancer, oral cancer, lip cancer, oropharyngeal cancer, osteosarcoma, ovarian cancer, pancreatic cancer, papillomatosis, paraganglioma, paranasal sinus cancer, nasal cancer, parathyroid cancer Noah gland, penile cancer, pharyngeal cancer, pheochromocytoma, parenchymal tumors of the pineal gland of intermediate differentiation, pineoblastoma, pituitary tumor, plasma cell tumor, pleuropulmonary blastoma, breast cancer, primary central nervous system (CNS) lymphoma, prostate cancer, rectal cancer , renal cell carcinoma, renal pelvis cancer, ureter cancer, transitional cell carcinoma, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, sarcoma, Sesari's syndrome, skin cancer, small cell lung cancer, small intestine cancer, soft tissue sarcoma, squamous cell carcinoma, latent squamous cell carcinoma primary focus, stomach cancer, supratentorial primitive neuroectodermal tumors, T-cell lymphoma, testicular cancer, throat cancer, thymoma, thymus cancer, thyroid cancer, transitional cell carcinoma of the renal pelvis and ureter, gestational trophoblastic tumor, atypical cancer with unknown in children, urethral cancer, uterine cancer, uterine sarcoma , Waldenstrom's macroglobulinemia or Wilms' tumor.

In some embodiments, the cancer treated by the methods of the invention is a subset of acute myeloid leukemia (AML), breast cancer, colorectal cancer, chronic myelogenous leukemia (CML), esophageal cancer, stomach cancer, lung cancer, melanoma, non-small cell lung cancer (NSCLC), pancreatic cancer, prostate cancer, or kidney cancer.

In some embodiments, the cancer is selected from bladder cancer, breast cancer (including triple negative breast cancer), cervical cancer, colorectal cancer, chronic lymphocytic leukemia (CML), diffuse large B cell lymphoma (DLBCL), esophageal adenocarcinoma, glioblastoma, head and neck cancer, leukemia (acute and chronic), low-grade glioma, lung cancer (including adenocarcinoma, non-small cell lung cancer and squamous cell carcinoma), Hodgkin's lymphoma, non-Hodgkin's lymphoma (NHL), melanoma, multiple myeloma (MM), ovarian cancer, pancreatic cancer, prostate cancer, kidney cancer (including renal cell carcinoma and papillary kidney cancer), and stomach cancer.

Combination therapy is an important treatment for many conditions, such as cancer. Recent scientific advances have expanded our understanding of the pathophysiological processes underlying these and other complex diseases. This increased awareness has spurred the development of new therapeutic approaches using drug combinations targeting multiple therapeutic targets to improve response to treatment, minimize the development of resistance, or minimize side effects. In an environment where combination therapy offers significant therapeutic benefits, there is growing interest in the development of combinations with new investigational drugs, such as arginase inhibitors.

When considering the introduction of several therapeutic agents in combination, one should think about what type of drug interactions will be observed. This effect may be positive (when the effect of the drug is increased) or antagonistic (when the effect of the drug is diminished), or a new side effect may occur that does not appear when used alone.

When an interaction causes an increase in the effects of one or both drugs, the extent to which the final effect of the combination drugs is greater than with any drug administration can be calculated, resulting in a so-called combination index. (CI) (Chou and Talalay, 1984). A composite index at or near 1 is considered additive; whereas a value greater than 1 is considered synergistic.

The present invention relates to methods of combination therapy for the treatment or prevention of cancer, comprising an arginase inhibitor (eg, a compound of the present invention) and one or more additional chemotherapeutic agents.

Certain embodiments of the invention relate to cancer treatment comprising co-administering a chemotherapeutic agent and a compound of the invention.

In some embodiments, the implementation of the chemotherapeutic agent is an immunostimulating agent. For example, an immunostimulatory agent can be a pro-inflammatory agent.

A chemotherapeutic agent that can be co-administered with the arginase inhibitors described herein in the disclosure methods include AVT-263, afatinib dimaleate, aminoglutethimide, amsacrine, anastrozole, asparaginase, axitinib, bacillus Calmette-Guerin vaccine (bcg), bevacizumab 35 bleomycin, bortezomib, buserelin, busulfan, cabozantinib, campothecin, capecitabine, carboplatin, carfilzomib, carmustine, ceritinib, chlorambucil, chloroquine, cisplatins, cladribine, clodronate, cobimetinib, crizlobidinacirubin, cycloprotein demetoksiviridin, dexamethasone, dichloroacetate, dienestrol, diethylstilbestrol, docetaxel, doxorubicin, epirubicin, eribulin, erlotinib, estradiol, estramustine, etoposide, everolimus, exemestane, filgrastim, fludarabine, fludrocortisone, fluorouracil and 5ftoruratsil, fluoxymesterone, flutamide, gefitinib, gemcitabine, genistein, goserelin, GSK1120212, hydroxyurea, idarubicin, ifosfamide, imatinib, interferon, irinotecan, ixabepilone, lenalidomide, letrozole, leucovorin, leuprolide, levamisole, lomustine, lonidamine, mechlorethamine, medroxyprogesterone, megestrol, melphalan, mercaptopurin, mesna, metformin, miltehotrexinitom, mittetroxin, mc nocodazole, octreotide, olaparib, oxaliplatin, paclitaxel, pamidronate, pazopanib, pemetrexed, pentostatin, perifosin, PF-04691502, plikamycin, pomalidomide, porfimer, procarbazine, raltitrexed, rutubosimabus, rutubocelemabus, rutubosimabus sunitinib, suramin, thalazoparib, tamoxifen, temozolomide, temsirolimus, teniposide, testosterone, thalidomide, thioguanine, thiotepa, titanocene dichloride, topotecan, trametinib, trastuzumab, tretinoin, veliparib, vinristine.

In some embodiments, a chemotherapeutic agent that can be administered with the arginase inhibitors described herein in the methods of the invention includes abagovomab, adekatumumab, afutuzumab, alemtuzumab, anatumomab mafenatox, apolizumab, atezolizumab, blinatumomab, epacwalax-9365omab epratuzumab, indoximod, inotuzumab ozogamicin, intelumumab, ipilimumab, isatuximab, lambrolizumab, MED14736, MGA012, MPDL3280A, nivolumab, obinutuzumab, okaratuzumab, ofatumumab, rimatulysimabelimabel.

In some embodiments, the chemotherapeutic agent is ipilimumab, MGA012, nivolumab, pembrolizumab, or pidilizumab.

Many combination therapies have been developed to treat cancer. In some embodiments, the compounds of the present invention may be co-administered with combination therapy. Examples of combination therapy with which the compounds of the invention can be co-administered are included in Table II. 1.

Table 1. Exemplary combination therapies for cancer treatment.

Name Therapeutic agents ABV Doxorubicin, Bleomycin, Vinblastine ABVD Doxorubicin, Bleomycin, Vinblastine, Dacarbazine

- 13 038517

AC (Breast Cancer) Doxorubicin, Cyclophosphamide AS (Sarcoma) Doxorubicin, Cisplatin AS (Neuroblastoma) Cyclophosphamide, Doxorubicin ACE Cyclophosphamide, Doxorubicin, Etoposide Ace Cyclophosphamide, Doxorubicin AD Doxorubicin, Dacarbazine AR Doxorubicin, Cisplatin ARAC-DNR Cytarabine, Daunorubicin B-CAVe Bleomycin, Lomustine, Doxorubicin, Vinblastine BCVPP Carmustine, Cyclophosphamide, Vinblastine, Procarbazine, Prednisone VEASORR Bleomycin, Etoposide, Doxorubicin, Cyclophosphamide, Vincristine, Procarbazine, Prednisone, Filgrastim BEP Bleomycin, Etoposide, Cisplatin BIP Bleomycin, Cisplatin, Ifosfamide, Mesna WOMP Bleomycin, Vincristine, Cisplatin, Mitomycin CA Cytarabine, Asparaginase SAVO Cisplatin, Methotrexate, Bleomycin, Vincristine CAF Cyclophosphamide, Doxorubicin, Fluorouracil CAL-G Cyclophosphamide, Daunorubicin, Vincristine, Prednisone, Asparaginase CAMP Cyclophosphamide, Doxorubicin, Methotrexate, Procarbazine SAR Cyclophosphamide, Doxorubicin, Cisplatin CaT Carboplatin, Paclitaxel CAV Cyclophosphamide, Doxorubicin, Vincristine CAVE ADD CAV and Etoposide CA-VP16 Cyclophosphamide, Doxorubicin, Etoposide SS Cyclophosphamide, Carboplatin CDDP / VP-16 Cisplatin, Etoposide CEF Cyclophosphamide, Epirubicin, Fluorouracil

- 14 038517

CEPP (B) Cyclophosphamide, Etoposide, Prednisone, with or without bleomycin CEV Cyclophosphamide, Etoposide, Vincristine CF Cisplatin, Fluorouracil or Carboplatin, Fluorouracil CHAP Cyclophosphamide or Cyclophosphamide, Altretamin, Doxorubicin, Cisplatin ChlVPP Chlorambucil, Vinblastine, Procarbazine, Prednisone CHOP Cyclophosphamide, Doxorubicin, Vincristine, Prednisone CHOP-BLEO Adding Bleomycin to CHOP CISCA Cyclophosphamide, Doxorubicin, Cisplatin CLD-BOMP Bleomycin, Cisplatin, Vincristine, Mitomycin CMF Methotrexate, Fluorouracil, Cyclophosphamide CMFP Cyclophosphamide, Methotrexate, Fluorouracil, Prednisone CMF VP Cyclophosphamide, Methotrexate, Fluorouracil, Vincristine, Prednisone CMV Cisplatin, Methotrexate, Vinblastine CNF Cyclophosphamide, Mitoxantrone, Fluorouracil CNOP Cyclophosphamide, Mitoxantrone, Vincristine, Prednisone COB Cisplatin, Vincristine, Bleomycin CODE Cisplatin, Vincristine, Doxorubicin, Etoposide COMLA Cyclophosphamide, Vincristine, Methotrexate, Leucovorin, Cytarabine COMP Cyclophosphamide, Vincristine, Methotrexate, Prednisone Cooper Mode Cyclophosphamide, Methotrexate, Fluorouracil, Vincristine, Prednisone COP Cyclophosphamide, Vincristine, Prednisone COPE Cyclophosphamide, Vincristine, Cisplatin, Etoposide COPP Cyclophosphamide, Vincristine, Procarbazine,

- 15 038517

Prednisone CP (Chronic Lymphocytic Leukemia) Chlorambucil, Prednisone SR (Ovarian cancer) Cyclophosphamide, Cisplatin ST Cisplatin, Paclitaxel CVD Cisplatin, Vinblastine, Dacarbazine CVI Carboplatin, Etoposide, Ifosfamide, Mesna CVP Cyclophosphamide, Vincristine, Prednisone CVPP Lomustine, Procarbazine, Prednisone CYVADIC Cyclophosphamide, Vincristine, Doxorubicin, Dacarbazine DA Daunorubicin, Cytarabine DAT Daunorubicin, Cytarabine, Thio Guanine DAV Daunorubicin, Cytarabine, Etoposide DCT Daunorubicin, Cytarabine, Thio Guanine DHAP Cisplatin, Cytarabine, Dexamethasone DI Doxorubicin, Ifosfamide DTIC / T amoxifen Dacarbazine, Tamoxifen DVP Daunorubicin, Vincristine, Prednisone EAP Etoposide, Doxorubicin, Cisplatin EC Etoposide, Carboplatin EFP Etoposide, Fluorouracil, Cisplatin ELF Etoposide, Leucovorin, Fluorouracil EMA 86 Mitoxantrone, Etoposide, Cytarabine EP Etoposide, Cisplatin EVA Etoposide, Vinblastine FAC Fluorouracil, Doxorubicin, Cyclophosphamide FAM Fluorouracil, Doxorubicin, Mitomycin FAMTX Methotrexate, Leucovorin, Doxorubicin FAP Fluorouracil, Doxorubicin, Cisplatin F-CL Fluorouracil, Leucovorin FEC Fluorouracil, Cyclophosphamide, Epirubicin

- 16 038517

FED Fluorouracil, Etoposide, Cisplatin FL Flutamide, Leiprolide FZ Flutamide, Goserelin acetate implant HDMTX Methotrexate, Leucovorin Hexa-CAF Altretamine, Cyclophosphamide, Methotrexate, Fluorouracil ICE-T Ifosfamide, Carboplatin, Etoposide, Paclitaxel, Mesna IDMTX / 6-MP Methotrexate, Mercaptopurine, Leucovorin IE Ifosfamide, Etoposide, Mesna Ifo VP Ifosfamide, Etoposide, Mesna IPA Ifosfamide, Cisplatin, Doxorubicin M-2 Vincristine, Carmustine, Cyclophosphamide, Prednisone, Melphalan MAC-III Methotrexate, Leucovorin, Dactinomycin, Cyclophosphamide MASS Methotrexate, Doxorubicin, Cyclophosphamide, Lomu STIN MACOP-B Methotrexate, Leucovorin, Doxorubicin, Cyclophosphamide, Vincristine, Bleomycin, Prednisone MAID Mesna, Doxorubicin, Ifosfamide, Dacarbazine m-BACOD Bleomycin, Doxorubicin, Cyclophosphamide, Vincristine, Dexamethasone, Methotrexate, Leucovorin MBC Methotrexate, Bleomycin, Cisplatin MC Mitoxantrone, Cytarabine MF Methotrexate, Fluorouracil, Leucovorin MICE Ifosfamide, Carboplatin, Etoposide, Mesna MINE Mesna, Ifosfamide, Mitoxantrone, Etoposide mini-BEAM Carmustine, Etoposide, Cytarabine, Melphalan MOBP Bleomycin, Vincristine, Cisplatin, Mitomycin MOP Mechlorethamine, Vincristine, Procarbazine MOPP Mechlorethamine, Vincristine, Procarbazine, Prednisone MOPP / ABV Mechlorethamine, Vincristine, Procarbazine, Prednisone,

- 17 038517

Doxorubicin, Bleomycin, Vinblastine MR (multiple myeloma) Melphalan, Prednisone MR (prostate cancer) Mitoxantrone, Prednisone MTX / 6-MO Methotrexate, Mercaptopurine MTX / 6-MP / VP Methotrexate, Mercaptopurine, Vincristine, Prednisone MTX-CDDPAdr Methotrexate, Leucovorin, Cisplatin, Doxorubicin MV (breast cancer) Mitomycin, Vinblastine MV (acute myelocytic leukemia) Mitoxantrone, Etoposide M-VAC Methotrexate Vinblastine, Doxorubicin, Cisplatin MVP Mitomycin Vinblastine, Cisplatin MVPP Mechlorethamine, Vinblastine, Procarbazine, Prednisone NFL Mitoxantrone, Fluorouracil, Leucovorin NOVP Mitoxantrone, Vinblastine, Vincristine OPA Vincristine, Prednisone, Doxorubicin ORRA Adding Procarbazine to OPA. RAS Cisplatin, Doxorubicin PAC-1 Cisplatin, Doxorubicin, Cyclophosphamide PA-CI Cisplatin, Doxorubicin PC Paclitaxel, Carboplatin or Paclitaxel, Cisplatin PCV Lomustine, Procarbazine, Vincristine PE Paclitaxel, Estramustine PFL Cisplatin, Fluorouracil, Leucovorin RUS Prednisone, Vincristine, Lomustine ProMACE Prednisone, Methotrexate, Leucovorin, Doxorubicin, Cyclophosphamide, Etoposide ProMACE / cytaBOM Prednisone, Doxorubicin, Cyclophosphamide, Etoposide, Cytarabine, Bleomycin, Vincristine,

- 18 038517

Methotrexate, Leucovorin, Cotrimoxazole PRoMACE / MOPP Prednisone, Doxorubicin, Cyclophosphamide, Etoposide, Mechlorethamine, Vincristine, Procarbazine, Methotrexate, Leucovorin Pt / VM Cisplatin, Teniposide PVA Prednisone, Vincristine, Asparaginase PVB Cisplatin, Vinblastine, Bleomycin PVDA Prednisone, Vincristine, Daunorubicin, Asparaginase SMF Streptozocin, Mitomycin, Fluorouracil TAD Mechlorethamine, Doxorubicin, Vinblastine, Vincristine, Bleomycin, Etoposide, Prednisone TCF Paclitaxel, Cisplatin, Fluorouracil TIP Paclitaxel, Ifosfamide, Mesna, Cisplatin TTT Methotrexate, Cytarabine, Hydrocortisone Topo / CTX Cyclophosphamide, Topotecan, Mesna VAB-6 Cyclophosphamide, Dactinomycin, Vinblastine, Cisplatin, Bleomycin VAC Vincristine, Dactinomycin, Cyclophosphamide VACAdr Vincristine, Cyclophosphamide, Doxorubicin, Dactinomycin, Vincristine VAD Vincristine, Doxorubicin, Dexamethasone VATH Vinblastine, Doxorubicin, Tiotepa, Fluoxymesterone VBAP Vincristine, Carmustine, Doxorubicin, Prednisone VBCMP Vincristine, Carmustine, Melphalan, Cyclophosphamide, Prednisone VC Vinorelbine, Cisplatin VCAP Vincristine, Cyclophosphamide, Doxorubicin, Prednisone VD Vinorelbine, Doxorubicin VelP Vinblastine, Cisplatin, Ifosfamide, Mesna VIP Etoposide, Cisplatin, Ifosfamide, Mesna VM Mitomycin, Vinblastine VMCP Vincristine, Melphalan, Cyclophosphamide, Prednisone VP Etoposide, Cisplatin V-TAD Etoposide, Thio Guanine, Daunorubicin, Cytarabine 5 + 2 Cytarabine, Daunorubicin, Mitoxantrone 7 + 3 Cytarabine with / Daunorubicin or Idarubicin or Mitoxantrone 8 in 1 Methylprednisolone, Vincristine, Lomustine, Procarbazine, Hydroxyurea, Cisplatin, Cytarabine, Dacarbazine

In some embodiments, the co-administered chemotherapeutic agent is selected from a metabolic inhibitor of an enzyme such as glucose transporters, hexokinase, pyruvate kinase M2, lactate dehydrogenase 1 or 2, pyruvate dehydrogenase kinase, fatty acid synthase, and glutaminase. In some variations, the inhibitor inhibits lactate dehydrogenase 1 or 2 or glutaminase. In some embodiments, the inhibitor is CB-839.

In some embodiments, the co-administered chemotherapeutic agent is an immuno-oncological therapeutic agent, such as a CTLA-4, indoleamine-2,3-dioxygenase, and / or PD-1 / PD-L1 inhibitor. In some embodiments, the immuno-oncological therapeutic agent is abagomab, adekatumumab, afutuzumab, anatumomab mafena

- 19 038517 tox, apolizumab, atezolizumab, blinatumomab, catumaxomab, durvalumab, epacadostat, epratuzumab, indoximod, inotuzumab ozogamicin, intelumumab, ipilimumab, isatuximab, lambrolizumab, okolatumabulumabulumab, or nivolumabulumabu In some embodiments, the immuno-oncological agent is indoximod, ipilimumab, nivolumab, pembrolizumab, or pidilizumab. In some embodiments, the immuno-oncological therapeutic agent is ipilimumab.

Typical immuno-oncological agents are described in Adams, J.L. et al. Big Opportunities for Small Molecules in Immuno-Oncology Nature Reviews Drug Discovery 2015, 14, page 603-621.

In some embodiments, the co-administered chemotherapeutic agent is a pro-inflammatory agent. In some embodiments, the pro-inflammatory agent administered with the arginase inhibitors of the invention is a cytokine or chemokine.

Proinflammatory cytokines are produced predominantly by activated macrophages and are involved in the activation of inflammatory responses. Typical pro-inflammatory cytokines include, but are not limited to, IL-1, β-1β, IL-6, IL-8, TNF-α, and IFN-γ.

Chemokines are a group of small cytokines. Proinflammatory chemokines stimulate the recruitment and activation of multiple leukocyte lines (eg, lymphocytes, macrophages). Chemokines are linked by their primary structure and share several conserved amino acid residues. In particular, chemokines typically include two or four cysteine residues that contribute to the three-dimensional structure through the formation of disulfide bonds. Chemokines can be classified into one of four groups: CC chemokines, CXC chemokines, C chemokines, and CX ₃ C chemokines. The CXC chemokines include a number of potent chemoattractants and neutrophil activators such as interleukin 8 (IL-8), PF4, and neutrophil activating peptide-2 (NAP-2). Chemokines C-C include, for example, RANTES (regulated upon activation, normal T-expressed and secreted), inflammatory macrophage proteins 1-alpha and 1-beta (MIP-1a and MIP-1e), eotaxin, and human monocytic chemotactic proteins 1- 3 (MCP-1, MCP-2, MCP-3), which have been characterized as chemoattractants and activators of monocytes or lymphocytes. Accordingly, typical pro-inflammatory chemokines include MIP-1a, MIP-1e, MIP-1y, MPC-1, MCP-2, MCP-3, IL-8, PF4, NAP-2, RANTES, CCL2, CCL3, CCL4, CCL5, CCL11, CXCL2, CXCL8 and CXCL10.

In some embodiments, the method for treating or preventing cancer further comprises using one or more non-chemical methods for treating cancer, such as radiation therapy, surgery, thermal ablation, focused ultrasound therapy, cryotherapy, or a combination of the above.

Cellular pathways function more like networks than superhighways. There are several redundancies or alternative routes that are activated in response to pathway inhibition. This redundancy promotes the emergence of resistant cells or organisms under the selective pressure of the target agent, which leads to drug resistance and clinical relapse.

In some embodiments, the chemotherapeutic agent is administered concurrently with an arginase inhibitor. In some embodiments, the chemotherapeutic agent is administered from about 5 minutes to about 168 hours before or after the arginase inhibitor.

The present invention provides a combination therapy comprising an immuno-oncological agent selected from CTLA-4, indoleamine-2,3-dioxygenase and PD-1 / PD-L1 inhibitors and an arginase inhibitor of formula (I). In some embodiments, the combination therapy treats or prevents cancer, immunological disorder, or chronic infection.

The present invention provides a combination therapy comprising an immuno-oncological agent selected from indolamine-2,3-dioxygenase and PD-1 / PD-L1 inhibitors and an arginase inhibitor of formula (I), such as combinations with epacadostat and nivolumab, epacadostat and pembrolizumab, and See also epacadostat and MGA012. In some of the methods discussed here, combination therapy treats or prevents cancer, immunological disorder, or chronic infection.

Also discussed herein are methods of treating or preventing an immunological disease comprising administering to a subject in need thereof a therapeutically effective amount of a compound of the present invention (e.g., a compound of formula (I) or a pharmaceutical composition containing said compound.

The immunologic disease can be selected from ankylosing spondylitis, Crohn's disease, erythema nodosum (ENL), graft versus host disease (GVHD), HIV wasting syndrome, systemic lupus erythematosus, organ transplant rejection, post-polycythemia, psoriasis, psoriatic arthritis, recurrent , rheumatoid arthritis (RA), severe recurrent aphthous stomatitis, systemic sclerosis and tuberous sclerosis.

The method of treating or preventing an immunological disease may further comprise co-administering an immuno-oncological therapeutic agent as described above.

Also discussed herein are methods of treating or preventing chronic

- 20,038517 infections, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of the present invention (eg, a compound of formula (I)) or a pharmaceutical composition containing said compound.

Chronic infection can be selected from bladder infection, chronic fatigue syndrome, cytomegalovirus / Epstein-Barr virus, fibromyalgia, hepatitis B virus (HBV), hepatitis C virus (HCV), HIV / AIDS virus, mycoplasma infection, and urinary tract infection.

The method for treating or preventing a chronic infection may further comprise co-administration of an immuno-oncological therapeutic agent as described above.

Also discussed herein is a method of treating or preventing a disease or condition associated with the expression or activity of arginase I, arginase II, or a combination thereof in a subject, comprising administering to the subject a therapeutically effective amount of at least one of Formula (I), or a pharmaceutically acceptable salt thereof or a stereoisomer.

The disease or condition can be selected from cardiovascular disorders, sexual disorders, wound healing disorders, gastrointestinal disorders, autoimmune disorders, immune disorders, infections, pulmonary disorders, and hemolytic disorders.

The disease or condition can be a cardiovascular disorder selected from systemic hypertension, pulmonary arterial hypertension (PAH), high-altitude pulmonary arterial hypertension, ischemic reperfusion (IR) injury, myocardial infarction, and atherosclerosis.

The disease or condition may be pulmonary arterial hypertension (PAH).

The disease or condition can be myocardial infarction or atherosclerosis.

The disease or condition can be a pulmonary disorder selected from chemically induced pulmonary fibrosis, idiopathic pulmonary fibrosis, cystic fibrosis, chronic obstructive pulmonary disease (COPD), and asthma.

The disease or condition may be an autoimmune disorder selected from encephalomyelitis, multiple sclerosis, antiphospholipid syndrome 1, autoimmune hemolytic anemia, chronic inflammatory demyelinating polyradiculoneuropathy, herpetiformis dermatitis, dermatomyelitis, sclerosis type 1, myphematoid arthritis syndrome spondylitis, paroxysmal nocturnal hemoglobinuria (PNH), paroxysmal cold hemoglobinuria, severe idiopathic autoimmune hemolytic anemia, and Goodpasture's syndrome.

The disease or condition may be an immune disorder selected from myeloid suppressor cell (MDSC) mediated T cell dysfunction, human immunodeficiency virus (HIV), autoimmune encephalomyelitis, and an ABO error transfusion reaction.

The disease or condition may be myeloid suppressor cell (MDSC) mediated T cell dysfunction.

The disease or condition may be a hemolytic disorder selected from sickle cell anemia, thalassemia, hereditary spherocytosis, stomatocytosis, microangiopathic hemolytic anemia; deficiency of pyruvate kinase; anemia caused by infection; anemia caused by cardiopulmonary bypass and mechanical heart valve; and chemically induced anemia.

The disease or condition can be a gastrointestinal disorder selected from gastrointestinal motility disorders, stomach cancer, inflammatory bowel disease, Crohn's disease, ulcerative colitis, and gastric ulcer.

The disease or condition can be a sexual disorder selected from Peyronie's disease and erectile dysfunction.

The disease or condition can be ischemia / reperfusion (RR) injury selected from liver IR, renal IR, and myocardial IR.

The disease or condition can be selected from kidney inflammation, psoriasis, leishmaniasis, neurodegenerative diseases, wound healing, human immunodeficiency virus (HIV), hepatitis B virus (HBV), H. pylori infections, fibrotic disorders, arthritis, candidiasis, periodontal disease, keloids, adenotonsillar disease, African sleeping sickness and Chagas disease.

The disease or condition can be a wound healing disorder selected from the healing of infected and uninfected wounds.

A combination therapy regimen is more effective than an arginase inhibitor regimen as a single agent or a regimen of therapy with an additional chemotherapeutic agent as a single agent.

Combinations of arginase inhibitors of the invention with IDO inhibitors

The invention provides methods for treating or preventing cancer in a subject comprising co-administering to a subject in need thereof an arginase inhibitor of formula (I *) and an IDO inhibitor. The IDO inhibitor can be a compound disclosed in the invention or a compound having the structure of any of the formulas disclosed herein. In some embodiments

- 21 038517 methods further comprise co-administration of one or more additional chemotherapeutic agents.

In some embodiments, the implementation of the subject is a human.

The invention further provides pharmaceutical kits comprising an IDO inhibitor, an arginase inhibitor of formula (I *) and, if necessary, instructions on how to administer the IDO inhibitor and an arginase inhibitor.

In some embodiments, the IDO inhibitor is epacadostat, norharman, rosmarinic acid, 1-methyltryptophan, a tryptophan derivative, indoximod, or NLG919, or pharmaceutically acceptable salts thereof. In some embodiments, the IDO inhibitor is epacadostat. In some embodiments, the IDO inhibitor has the structure of any of the formulas disclosed herein. In some embodiments, the IDO inhibitor is a compound of any of the formulas disclosed herein.

Suitable IDO inhibitors for use in the compositions and methods disclosed herein are described in U.S. Patent Application Publication Nos. 20160158353, US 2015353546, US 2015291632, US 2015218186, US 2015291557, US 2015246898, US 2016002242, US 2016015712, US 2016166574, US 20150; US Patent Nos. 8748461, 9309273, 8809378, 8883797, 8669274, 8389543, 9447073, 9150527, 9056855, 8987315, 9409914, 9120804, 9073944, 9320735, 9023851; PCT Application Publications No. WO 2016059412, WO 2016051181, WO 2016057986, WO 2016196890 and European Patent Publications No. EP 2804858, EP 2563771.

In some embodiments, suitable IDO inhibitors for use in the compositions and methods disclosed herein are the IDO inhibitors described in US Pat. No. 7,767,675. In some embodiments, the IDO inhibitor is a compound of formula (II), or a pharmaceutically acceptable salt thereof:

^R ' ^N ' Formula (II).

In some embodiments, the IDO inhibitor is a compound selected from one of the following formulas, or a pharmaceutically acceptable salt thereof:

L ¹ -Cy ¹

Formula (Pa);

Formula (Pb);

- 22 038517

Variable definitions, embodiments and compound structures are as described in US Pat. No. 7,767,675.

In some embodiments, suitable IDO inhibitors for use in the compositions and methods disclosed herein are the IDO inhibitors described in US Pat. No. 8,088,803. In some embodiments, the IDO inhibitor is a compound of Formula (III), or a pharmaceutically acceptable salt thereof

R '

and ²

Formula (III).

In some embodiments, the IDO inhibitor is a compound selected from formulas F15, F19, and F28, or a pharmaceutically acceptable salt thereof:

R '

Rn

Formula F15;

R /

R '.

Formula Fl9; and ¹¹⁴ Formula F28.

Variable definitions, embodiments and compound structures are as described in US Pat. No. 8,088,803.

In some embodiments, suitable IDO inhibitors for use in the compositions and methods disclosed herein are the IDO inhibitors described in US Patent No. 8377976. In some embodiments, the IDO inhibitor is a compound of formula (IV), or a pharmaceutically acceptable salt thereof:

- 23 038517

Q

R ²

Formula (IV).

In some embodiments, the IDO inhibitor is a compound selected from one of the following formulas, or a pharmaceutically acceptable salt thereof:

Formula (IVa);

Formula (IVb); and

Formula (IVc).

Variable definitions, embodiments and compound structures are as described in US Pat. No. 8,377,976.

In some embodiments, suitable IDO inhibitors for use in the compositions and methods disclosed herein are the IDO inhibitors described in US Pat. No. 8,507,541. In some embodiments, the IDO inhibitor is a compound of Formula (V), or a pharmaceutically acceptable salt thereof

Formula (V).

In some embodiments, the IDO inhibitor is a compound selected from one of the following formulas, or a pharmaceutically acceptable salt thereof:

Formula (Vb);

Formula (Vc); and

Formula (Vd).

^ Formula (Va);

Variable definitions, embodiments and compound structures are as described in US Pat. No. 8,507,541.

In some embodiments, suitable IDO inhibitors for use in the compositions and methods disclosed herein are the IDO inhibitors described in US Patent No. 9321755. In some embodiments, the IDO inhibitor is a compound of formula (VI) or a pharmaceutically acceptable salt he _

Η, Ν

Formula (VI).

In some embodiments, the IDO inhibitor is a compound selected from formulas F5, F8, F10, F15, F16, F17, F18, F19, and F20, or a pharmaceutically acceptable salt thereof:

- 25 038517

Formula Fl6;

Br

Formula Fl8;

F17;

F19; and 'Formula F20.

Variable definitions, embodiments, and compound structures are as described in US Pat. No. 9,321,755.

In some embodiments, suitable IDO inhibitors for use in the compositions and methods disclosed herein are the IDO inhibitors described in US Pat. No. 8,748,469. In some embodiments, the IDO inhibitor is a compound of Formula (VII), Formula (VIII), or its pharmaceutically acceptable salt to ¹

Ν

R ^{5 r4} Formula (VII); or

R ⁵

Formula (VIII).

In some embodiments, the IDO inhibitor is a compound selected from one of the following formulas, or a pharmaceutically acceptable salt thereof

- 26 038517

- 27 038517

- 28 038517

- 29 038517

- 30 038517

Formula (IXau);

Formula (IXav);

Formula (IXaw);

Formula (IXax);

Formula (IXay); and —N Formula (IXaz).

Variable definitions, embodiments and compound structures are as described in US Pat. No. 8,748,469.

In some embodiments, suitable IDO inhibitors for use in the compositions and methods disclosed herein are the IDO inhibitors described in US Pat. No. 9,260,434. In some embodiments, the IDO inhibitor is a compound of formula (X), or a pharmaceutically acceptable salt thereof

- 31 038517

In some embodiments, the IDO inhibitor is a compound selected from one of the following formulas, or a pharmaceutically acceptable salt thereof

- 32 038517

Variable definitions, embodiments and compound structures are as described in US Pat. No. 9,260,434.

In some embodiments, suitable IDO inhibitors for use in the compositions and methods disclosed herein are the IDO inhibitors described in US Pat. No. 9,120,804. In some embodiments, the IDO inhibitor is a compound of Formula (XI), or a pharmaceutically acceptable salt thereof. N Η

^r2 Formula (XI).

Variable definitions, embodiments and compound structures are as described in US Pat. No. 9,120,804.

In some embodiments, suitable IDO inhibitors for use in the compositions and methods disclosed herein are the IDO inhibitors described in US Patent Publication No. 2008/0146624. In some embodiments, the IDO inhibitor is a compound of formula (XII), (XIII), or a pharmaceutically acceptable salt thereof:

RO

i; or

Formula (XIII).

In some embodiments, the IDO inhibitor is a compound selected from one of the following formulas, or a pharmaceutically acceptable salt thereof

- 33 038517

- 34 038517

^N Formula (XIVi);

Formula (XIVj);

Formula (XIVk);

Formula (XIVI);

Formula (XIVm);

Formula (XlVn):

Formula (XIVo);

Formula (XIVp);

^N Formula (XlVq); and

Formula (XlVr),

Variable definitions, embodiments and connection structures are as follows

35,038517 is described in US Patent Publication No. 2008/0146624.

In some embodiments, suitable IDO inhibitors for use in the compositions and methods disclosed herein are the IDO inhibitors described in US Patent Publication No. 2008/0182882. In some embodiments, the IDO inhibitor is a compound of Formula (XV), or a pharmaceutically acceptable salt thereof ^v Formula (XV).

In some embodiments, the IDO inhibitor is a compound of formula (XVa), formula (XVb), or a pharmaceutically acceptable salt thereof

OR

Formula (XVa); or

Formula (XVb).

Variable definitions, embodiments and connection structures are as described in US Patent Publication No. 2008/0182882.

In some embodiments, suitable IDO inhibitors for use in the compositions and methods disclosed herein are the IDO inhibitors described in US Patent Publication No. 2007/0203140. In some embodiments, the IDO inhibitor is a compound of formula (XVI), or a pharmaceutically acceptable salt thereof

Formula (XVI).

Variable definitions, embodiments and compound structures are as described in US Patent Publication No. 2007/0203140.

In some embodiments, suitable IDO inhibitors for use in the compositions and methods disclosed herein are the IDO inhibitors described in US Patent Publication No. 2008/0119491. In some embodiments, the IDO inhibitor is a compound of formula (XVII), or a pharmaceutically acceptable salt thereof

Formula (XVII).

In some embodiments, the IDO inhibitor is a compound selected from one of the following formulas, or a pharmaceutically acceptable salt thereof

Formula (XVIIa);

- 36 038517

^N Formula (XVIId);

Formula (XVIIf);

Formula (XVIIg);

Formula (XVIIh):

Formula (XVIIk);

Formula (XVIII); and

- 37 038517

Variable definitions, embodiments and compound structures are as described in US Patent Publication No. 2008/0119491.

In some embodiments, suitable IDO inhibitors for use in the compositions and methods disclosed herein are the IDO inhibitors described in US Patent Publication No. 2016/0289238. In some embodiments, the IDO inhibitor is a compound of formula (XVIII), or a pharmaceutically acceptable salt thereof

In some embodiments, the IDO inhibitor is a compound selected from one of the following formulas, or a pharmaceutically acceptable salt thereof

- 38 038517

Variable definitions, embodiments and connection structures are as described in US Patent Publication No. 2016/0289238.

In some embodiments, suitable IDO inhibitors for use in compositions and methods disclosed herein are IDO inhibitors disclosed in

39038517 of US Patent Publication No. 2016/0229843. In some embodiments, the IDO inhibitor is a compound of formula (XIX), or a pharmaceutically acceptable salt thereof

R "

W

R ⁴

Formula (XIX).

In some embodiments, the IDO inhibitor is a compound selected from one of the following formulas, or a pharmaceutically acceptable salt thereof

Formula (XlXb):

Formula (XIXc);

Formula (ΧΙΧα):

Formula (XIXe):

Formula (XIXi);

Formula (XIXa);

- 40 038517

Variable definitions, embodiments and connection structures are as follows

41 038517 is described in US Patent Publication No. 2016/0229843.

In some embodiments, suitable IDO inhibitors for use in the compositions and methods disclosed herein are the IDO inhibitors described in US Patent Publication No. 2016/0046596. In some embodiments, the IDO inhibitor is a compound of Formula (XX), or a pharmaceutically acceptable salt thereof z

nh ₂

Formula (XX).

In some embodiments, the IDO inhibitor is a compound selected from one of the following formulas, or a pharmaceutically acceptable salt thereof b

NH,

Formula (XXa);

- 42 038517

- 43 038517

Variable definitions, embodiments and connection structures are as described in US Patent Publication No. 2016/0046596.

In some embodiments, suitable IDO inhibitors for use in the compositions and methods disclosed herein are the IDO inhibitors described in US Patent Publication No. 2011/0053941 or 2013/0289083. In some embodiments, the IDO inhibitor is a compound of Formula (XXI), Formula (XXII), or a pharmaceutically acceptable salt thereof:

Formula (XXII)

In some embodiments, the IDO inhibitor is a compound selected from one of the following formulas, or a pharmaceutically acceptable salt thereof

- 44 038517

- 45 038517

- 46 038517

- 47 038517

- 48 038517

- 50 038517

- 51 038517

- 52 038517

- 53 038517

- 54 038517

- 55 038517

Formula (XXVIIIax);

Formula (XXVIIIay);

Formula (XXVIIIaz);

Formula (XXVIIIba); and

Formula (XXVIIIbb).

Variable definitions, embodiments and connection structures are as described in US Patent Publication No. 2011/0053941 or 2013/0289083.

In some embodiments, suitable IDO inhibitors for use in the compositions and methods disclosed herein are the IDO inhibitors described in US Patent Publication No. 2016/0060266. In some embodiments, the IDO inhibitor is a compound of formula (XXIX), or a pharmaceutically acceptable salt thereof

Formula (XXIX).

In some embodiments, the IDO inhibitor is a compound selected from the following formulas, or a pharmaceutically acceptable salt thereof

- 56 038517

- 57 038517

- 58 038517

Variable definitions, embodiments and connection structures are as described in US Patent Publication No. 2016/0060266.

In some embodiments, suitable IDO inhibitors for use in the compositions and methods disclosed herein are the IDO inhibitors described in US Patent Publication No. 2016/075711. In some embodiments, the IDO inhibitor is a compound of formula (XXX), or a pharmaceutically acceptable salt thereof

^lR Formula (XXX).

In some embodiments, the IDO inhibitor is a compound selected from a compound of the following formulas, or a pharmaceutically acceptable salt thereof

- 59 038517

- 60 038517

- 61 038517

- 62 038517

- 63 038517, (R

Formula (XXXz); and (XXXy);

Formula (XXXab).

Variable definitions, embodiments and connection structures are as described in US Patent Publication No. 2016/075711.

In some embodiments, suitable IDO inhibitors for use in the compositions and methods disclosed herein are the IDO inhibitors described in US Patent Publication No. 2016/0022619. In some embodiments, the IDO inhibitor is a compound of formula (XXXI), a compound of formula (XXXII), or a pharmaceutically acceptable salt thereof

R “

R ¹

Formula (XXXI); or

Formula (XXXII).

Variable definitions, embodiments and connection structures are as described in US Patent Publication No. 2016/0022619.

In some embodiments, suitable IDO inhibitors for use in the compositions and methods disclosed herein are the IDO inhibitors described in US Patent Publication No. 2016/0060237. In some embodiments, the IDO inhibitor is a compound of formula (XXXIII), a compound of formula (XXXIV), or a pharmaceutically acceptable salt thereof

R '

Formula (XXXIII); or —R ^s

Formula (XXXIV).

Variable definitions, embodiments and connection structures are as described in US Patent Publication No. 2016/0060237.

In some embodiments, suitable IDO inhibitors for use in the compositions and methods disclosed herein are the IDO inhibitors described in US Patent Publication No. 2016/0137595. In some embodiments, the IDO inhibitor is a compound of formula (XXXV), a compound of formula (XXXVI), or a pharmaceutically acceptable salt thereof

Variable definitions, embodiments and connection structures are as described in US Patent Publication No. 2016/0137595.

In some embodiments, suitable IDO inhibitors for use in the compositions and methods disclosed herein are the IDO inhibitors described in US Patent Publication No. 2016/0143870. In some embodiments, the IDO inhibitor is a compound of formula (XXXVII), a compound of formula (XXXVIII), or a pharmaceutically acceptable salt thereof

Variable definitions, embodiments and connection structures are as described in US Patent Publication No. 2016/0143870.

In some embodiments, suitable IDO inhibitors for use in the compositions and methods disclosed herein are the IDO inhibitors described in US Patent Publication No. 2016/0200674. In some embodiments, the IDO inhibitor is a compound of formula (XXXIX), a compound of formula (XL), or a pharmaceutically acceptable salt thereof

Variable definitions, embodiments and connection structures are as described in US Patent Publication No. 2016/0200674.

In some embodiments, suitable IDO inhibitors for use in the compositions and methods disclosed herein are the IDO inhibitors described in US Patent Publication No. 2016/0289171. In some embodiments, the IDO inhibitor is a compound of formula (XLI), a compound of formula (XLII), or a pharmaceutically acceptable salt thereof

- 65 038517

Variable definitions, embodiments and connection structures are as described in US Patent Publication No. 2016/0289171.

In some embodiments, suitable IDO inhibitors for use in the compositions and methods disclosed herein are the IDO inhibitors described in US Patent Publication No. 2016/0137652. In some embodiments, the IDO inhibitor is a compound of formula (XLIII), or a pharmaceutically acceptable salt thereof

In some embodiments, the IDO inhibitor is a compound selected from one of the following formulas, or a pharmaceutically acceptable salt thereof

- 66 038517

- 67 038517

- 68 038517

- 69 038517

- 70 038517

- 71 038517

Variable definitions, embodiments and connection structures are as described in US Patent Publication No. 2016/0137652.

In some embodiments, suitable IDO inhibitors for use in the compositions and methods disclosed herein are the IDO inhibitors described in US Patent Publication No. 2016/0137653. In some embodiments, the IDO inhibitor is a compound of formula (XLIV), or a pharmaceutically acceptable salt thereof

Formula (XLIV).

In some embodiments, the IDO inhibitor is a compound selected from one of the following formulas, or a pharmaceutically acceptable salt thereof

- 72 038517

- 73 038517

- 74 038517

Variable definitions, embodiments and connection structures are as described in US Patent Publication No. 2016/0137653.

In some embodiments, suitable IDO inhibitors for use in the compositions and methods disclosed herein are the IDO inhibitors described in PCT Application Publication No. WO 2014141110. In some embodiments, the IDO inhibitor is a compound of formula (XLV), or a pharmaceutically acceptable salt

In some embodiments, the IDO inhibitor is a compound selected from one of the following formulas, or a pharmaceutically acceptable salt thereof

- 75 038517

- 76 038517

- 77 038517

Variable definitions, embodiments and connection structures are as described in PCT Application Publication No. WO 2014141110.

In some embodiments, suitable IDO inhibitors for use in the compositions and methods disclosed herein are the IDO inhibitors described in PCT Application Publication No. WO 2016027241. In some embodiments, the IDO inhibitor is a compound of formula (XLVI), or a pharmaceutically acceptable salt

- 78 038517

In some embodiments, the IDO inhibitor is a compound selected from one of the following formulas, or a pharmaceutically acceptable salt thereof

Formula (XLVic);

Formula (XLVie); and

Formula (XLVIf)

Variable definitions, embodiments and connection structures are as described in PCT Application Publication No. WO 2016027241.

In some embodiments, suitable IDO inhibitors for use in the compositions and methods disclosed herein are the IDO inhibitors described in PCT Application Publication No. WO 2016181348. In some embodiments, the IDO inhibitor is a compound of formula (XLVII), or a pharmaceutically acceptable salt

In some embodiments, the IDO inhibitor is a compound selected from one of the following formulas, or a pharmaceutically acceptable salt thereof

- 79 038517

Variable definitions, embodiments and connection structures are as described in PCT Application Publication No. WO 2016181348.

In some embodiments, suitable IDO inhibitors for use in the compositions and methods disclosed herein are the IDO inhibitors described in PCT Application Publication No. WO 2016051181. In some embodiments, the IDO inhibitor is a compound of formula (XLIX), or a pharmaceutically acceptable salt

In some embodiments, the IDO inhibitor is a compound selected from one of the following formulas, or a pharmaceutically acceptable salt thereof

- 80 038517

Formula (XLIXb);

Formula (XLIXc);

Formula (XLIXd):

Formula (XLIXi); and

Formula (XLIXj)

Variable definitions, embodiments and connection structures are as described in PCT Application Publication No. WO 2016051181.

In some embodiments, suitable IDO inhibitors for use in the compositions and methods disclosed herein are the IDO inhibitors described in PCT Application Publication No. WO 2016059412. In some embodiments, the IDO inhibitor is a compound of Formula (L), or a pharmaceutically acceptable salt

- 81 038517

In some embodiments, the IDO inhibitor is a compound selected

of the following formulas, or a pharmaceutically acceptable salt thereof

Formula (Lf);

Formula (Lg);

Formula (Lh);

- 82 038517

Variable definitions, embodiments and connection structures are as described in PCT Application Publication No. WO 2016059412.

In some embodiments, suitable IDO inhibitors for use in the compositions and methods disclosed herein are the IDO inhibitors described in PCT Application Publication No. WO 2015119944, which corresponds to European Patent Publication Number EP 3102237. In some embodiments, the IDO inhibitor is is a compound of formula (LI) or a pharmaceutically acceptable salt thereof.

OO _n N ^N N _s _N ^N

Formula (LI).

In some embodiments, the IDO inhibitor is a compound selected from Formula (LII) and Formula (LIII), or a pharmaceutically acceptable salt thereof

I h ₂ n ^z '

R ² 'O'

Formula (LII); and he %? N

X η ₂ ν n ", Ν О

R ³ Formula (LIII).

Variable definitions, embodiments and connection structures are as described in PCT Application Publication No. WO 2015119944.

In some embodiments, suitable IDO inhibitors for use in the compositions and methods disclosed herein are the IDO inhibitors described in PCT Application Publication No. WO 2016073738. In some embodiments, the IDO inhibitor is a compound of Formula (LIV), or a pharmaceutically acceptable salt:

R ²

E ^η ζ Formula (LIV).

In some embodiments, the IDO inhibitor is a compound selected from one of the following formulas, or a pharmaceutically acceptable salt thereof

- 83 038517

- 84 038517

- 85 038517

- 86 038517

Variable definitions, embodiments and connection structures are as described in PCT Application Publication No. WO 2016073738.

In some embodiments, suitable IDO inhibitors for use in the compositions and methods disclosed herein are the IDO inhibitors described in PCT Application Publication No. WO 2015188085. In some embodiments, the IDO inhibitor is a compound of Formula (LV), or a pharmaceutically acceptable salt

In some embodiments, the IDO inhibitor is a compound selected from one of the following formulas, or a pharmaceutically acceptable salt thereof

- 87 038517

Variable definitions, embodiments and connection structures are as described in PCT Application Publication No. WO 2015188085.

Also discussed herein are methods of treating cancer by administering to a subject an epacadostat and an arginase inhibitor having one of the following structures, or a pharmaceutically acceptable salt thereof

The epacadostat and the arginase inhibitor depicted in the above diagram can be provided in a single pharmaceutical composition. Alternatively, the epacadostat and arginase inhibitor depicted in the scheme above can be administered in separate pharmaceutical compositions.

Definitions.

The term acyl is recognized in the art and refers to a group represented by the general formula hydrocarbyl-C (O) -, preferably α-alkyl-C (O) -.

The term acylamino is known in the art and refers to an amino group substituted with an acyl group and may be represented, for example, by the formula hydrocarbyl-C (O) NH-.

The term acyloxy is recognized in the art and refers to a group represented by the general formula hydrocarbyl-C (O) O-, preferably α-alkyl-C (O) O-.

The term alkoxy refers to an alkyl group, preferably a lower alkyl group, to which oxygen is attached. Typical alkoxy groups include methoxy, ethoxy, propoxy, tert-butoxy, and the like.

The term alkoxyalkyl refers to an alkyl group substituted with an alkoxy group and may be represented by the general formula alkyl-O-alkyl.

Used in this application, the term alkenyl refers to an aliphatic group containing at least one double bond.

An alkyl group or alkane is a non-aromatic hydrocarbon with a straight or

- 88 038517 branched chain, which is fully saturated. Typically, a straight or branched chain alkyl group has from 1 to about 20 carbon atoms, preferably from 1 to about 10, unless otherwise indicated. Examples of linear and branched alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, t-butyl, pentyl, hexyl, pentyl, and octyl. A straight or branched C1-C6 alkyl group is also referred to as a lower alkyl group.

The term Cx.y when used in combination with a chemical moiety such as acyl, acyloxy, alkyl, alkenyl, alkynyl, or alkoxy is intended to include groups that contain from x to y carbon atoms in the chain. For example, the term Cx.y-alkyl refers to substituted or unsubstituted saturated hydrocarbon groups, including straight or branched chain alkyl groups, which contain from x to y carbon atoms in the chain, including haloalkyl groups such as trifluoromethyl and 2,2,2 -trifluoroethyl, etc. C ₀ -alkyl denotes hydrogen, where the group is in the terminal position if the bond is internal. The terms C ₂ - _y -alkenyl and C ₂ - _y -alkilnil refer to unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but which contain at least one double or triple bond, respectively.

As used herein, the term alkylamino refers to an amino group substituted with at least one alkyl group.

As used herein, the term alkylthio refers to a thiol group substituted with an alkyl group and may be represented by the general formula alkyl-S-.

As used herein, the term alkynyl refers to an aliphatic group containing at least one triple bond and is intended to include both unsubstituted alkynyls and substituted alkynyls, the latter of which refers to alkynyl groups having substituents substituting hydrogen on one or more atoms alkynyl carbon. Such substituents can occur on one or more carbon atoms, which are included or not included in one or more triple bonds. In addition, such substituents include all substituents that are provided for alkyl groups as discussed above, unless this interferes with stability. For example, substitution of alkynyl groups with one or more alkyl, carbocyclyl, aryl, heterocyclyl, or heteroaryl groups is contemplated.

The term amide, as used herein, refers to the group o

where each R _{10 is} independently hydrogen or a hydrocarbyl group, or two R ₁₀ taken together with the N atom to which they are attached complete a heterocycle having 4 to 8 atoms in the ring structure.

The terms amine and amino are generally recognized in the art and refer to both unsubstituted and substituted amines and their salts, for example, the portion that may be represented by

R ¹⁰ R ¹⁰ | —g / N * —R ¹⁰

R ¹⁰ or R ^{10 wherein each R 10 is} independently hydrogen or a hydrocarbyl group, or the two R 10 taken together with the N atom to which they are attached constitute a heterocycle having 4 to 8 atoms in a ring structure.

The term aminoalkyl as used herein refers to an alkyl group substituted with an amino group.

As used herein, the term aralkyl refers to an alkyl group substituted with an aryl group.

As used herein, the term aryl includes substituted or unsubstituted single ring aromatic groups in which each ring atom is carbon. Preferably the ring is a 5-7 membered ring, more preferably a 6 membered ring. The term aryl also includes polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjacent rings, where at least one of the rings is aromatic, for example, the other cyclic rings may be cycloalkyls, cycloalkenyls, cycloalkynyls , aryl, heteroaryl and / or heterocyclyl. Accordingly, the term aryl may include (C ₅ -C ₁₀ ) and (C ₆ -C ₁₀ ) aryl groups. Aryl groups include benzene, naphthalene, phenanthrene, phenol, aniline, and the like.

The term carbamate is recognized in the art and refers to the group ' ^R1 ° or A _n A _o ^{. R 10}

R ⁹ R *

89 038517 wherein R ⁹ and R ¹⁰ independently represent hydrogen or a hydrocarbyl group such as an alkyl group, or R ⁹ and R ¹⁰ taken together with the intermediate atom (s) complete a heterocycle having 4 to 8 atoms in the ring structure.

As used herein, the terms carbocycle and carbocyclic refer to a saturated or unsaturated ring in which each ring atom is carbon. The term carbocycle includes both aromatic carbocycles and non-aromatic carbocycles. Non-aromatic carbocycles include both cycloalkane rings, in which all carbon atoms are saturated, and cycloalkene rings, which contain at least one double bond. The carbocycle includes 5-7 membered monocyclic and 8-12 membered bicyclic rings. Each ring of the bicyclic carbocycle can be selected from saturated, unsaturated, and aromatic rings. A carbocycle includes bicyclic molecules in which one, two, or three or more atoms are distributed between two rings. The term fused carbocycle refers to a bicyclic carbocycle in which each of the rings has two adjacent atoms to the other ring. Each fused carbocycle ring can be selected from saturated, unsaturated, and aromatic rings. In an exemplary embodiment, an aromatic ring, such as phenyl, may be fused with a saturated or unsaturated ring, such as cyclohexane, cyclopentane, or cyclohexene. Any combination of saturated, unsaturated and aromatic bicyclic rings, if the valence permits, is included in the definition of a carbocycle. Exemplary carbocycles include cyclopentane, cyclohexane, bicyclo [2.2.1] heptane, 1,5-cyclooctadiene, 1,2,3,4tetrahydronaphthalene, bicyclo [4.2.0] oct-3-ene, naphthalene, and adamantane. Typical fused carbocycles include decalin, naphthalene, 1,2,3,4-tetrahydronaphthalene, bicyclo [4.2.0] octane, 4,5,6,7tetrahydro-III-indene, and bicyclo [4.1.0] hept-3-ene. Carbocycles can be substituted at any one or more positions capable of carrying a hydrogen atom.

A cycloalkyl group is a cyclic hydrocarbon that is fully saturated. Cycloalkyl includes monocyclic and bicyclic rings. Typically, a monocyclic cycloalkyl group has from 3 to about 10 carbon atoms, more typically from 3 to 8 carbon atoms, unless otherwise indicated. The second ring of the bicyclic cycloalkyl can be selected from saturated, unsaturated, and aromatic rings. Cycloalkyl includes bicyclic molecules in which one, two, or three or more atoms are distributed between two rings. The term fused cycloalkyl refers to a bicyclic cycloalkyl in which each of the rings has two adjacent atoms to the other ring. The second ring of the fused bicyclic cycloalkyl can be selected from saturated, unsaturated, and aromatic rings. A cycloalkenyl group is a cyclic hydrocarbon containing one or more double bonds.

As used herein, the term (cycloalkyl) alkyl refers to an alkyl group substituted with a cycloalkyl group.

The term carbonate is known in the art and refers to the group —OCO ₂ —R ¹⁰ , where R ¹⁰ is a hydrocarbyl group.

As used herein, the term carboxy refers to a group represented by the formula —CO ₂ H.

As used herein, the term ester refers to a —C (O) OR ¹⁰ group, where R ¹⁰ is a hydrocarbyl group.

As used herein, the term “ether” refers to a hydrocarbyl group linked through oxygen to another hydrocarbyl group. Accordingly, the ether substituent of the hydrocarbyl group may be hydrocarbyl-O-. Ethers can be symmetrical or unbalanced. Examples of ethers include, but are not limited to, heterocycle-O-heterocycle and aryl-O-heterocycle. Ethers include alkoxyalkyl groups, which may be represented by the general formula alkyl-O-alkyl.

The terms halo and halogen, as used herein, mean halogen and include chlorine, fluorine, bromine and iodine.

As used herein, the term heteroaralkyl refers to an alkyl group substituted with a heteroaryl group.

The term heteroalkyl, as used herein, refers to a saturated or unsaturated chain of carbon atoms and at least one heteroatom, where there are no two adjacent heteroatoms.

The term heteroaryl includes substituted or unsubstituted aromatic single ring structures, preferably 5-7 membered rings, more preferably 5-6 membered rings, whose ring structures include at least one heteroatom, preferably one to four heteroatoms, more preferably one or two heteroatoms ... The terms heteroaryl also include polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjacent rings, where at least one of the rings is heteroaromatic, for example, the other cyclic rings may be cycloalkyls, cycloalkenyls, cycloalkynyls , aryl, heteroaryl and / or heterocyclyl. Accordingly, the term heteroaryl 90 038517 may include (C ₂ -C ₁₀ ) and (C ₂ -C ₁₀ ) heteroaryl groups. Heteroaryl groups include, for example, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, pyrazole, pyridine, pyrazine, pyridazine, and pyrimidine, and the like.

Used in this application, the term heteroatom means an atom of any element other than carbon or hydrogen. Preferred heteroatoms are nitrogen, oxygen and sulfur.

The terms heterocycloalkyl, heterocycle, and heterocyclic refer to substituted or unsubstituted non-aromatic ring structures, preferably having 3 to 10 membered rings, more preferably 3 to 7 membered rings, whose ring structures include at least one heteroatom, preferably one to four heteroatoms, more preferably one or two heteroatoms. The terms heterocycloalkyl and heterocyclic also include polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjacent rings, where at least one of the rings is heterocyclic, for example, the other cyclic rings may be cycloalkyls, cycloalkenyls , cycloalkynyl, aryl, heteroaryl and / or heterocyclyl. Heterocycloalkyl groups include, for example, piperidine, piperazine, pyrrolidine, morpholine, lactones, lactams, and the like.

As used herein, the term (heterocycloalkyl) alkyl refers to an alkyl group substituted with a heterocycloalkyl group.

Used in this application, the term hydrocarbyl refers to a group that is linked through a carbon atom, which has no substituent = O or = S, and usually has at least one carbon-hydrogen bond and mainly a carbon chain, but if necessary may include heteroatoms. Thus, groups such as methyl, ethoxyethyl, 2-pyridyl and trifluoromethyl are considered hydrocarbyl for the purposes of this application, and substituents such as acetyl (which has an = O substituent on the linking carbon) and ethoxy (which is linked through oxygen, not carbon) - no. Hydrocarbyl groups include, but are not limited to, aryl, heteroaryl, carbocycle, heterocyclyl, alkyl, alkenyl, alkynyl, and combinations thereof.

As used herein, the term hydroxyalkyl refers to an alkyl group substituted with a hydroxy group.

The term lower when used in combination with a chemical moiety such as acyl, acyloxy, alkyl, alkenyl, alkynyl, or alkoxy is intended to include groups where the substituent has ten or fewer non-hydrogen atoms, preferably six or fewer. Lower alkyl, for example, refers to an alkyl group that contains ten or fewer carbon atoms, preferably six or fewer. In certain embodiments, acyl, acyloxy, alkyl, alkenyl, alkynyl, or alkoxy substituents as defined herein are, respectively, lower acyl, lower acyloxy, lower alkyl, lower alkenyl, lower alkynyl, or lower alkoxy, whether or not they appear alone or in combination with other substituents such as in the descriptions of hydroxyalkyl and aralkyl (in which case, for example, the atoms in the aryl group are not counted when calculating the carbon atoms in the alkyl substituent).

The terms polycyclyl, polycyclic, and polycyclic refer to two or more rings (eg, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, and / or heterocyclyl) in which two or more atoms are common to two adjacent rings; for example, the rings are condensed rings. Each of the rings of the polycycle can be substituted or unsubstituted. In certain embodiments, each ring of the polycycle contains from 3 to 10 ring atoms, preferably from 5 to 7.

The term silyl refers to a silicon moiety with three hydrocarbyl moieties attached thereto.

The term “substituted” refers to moieties having substituents substituting for hydrogen on one or more carbon atoms of the main chain. It is understood that substitution or substituted includes the implicit condition that such substitution corresponds to the permissible valence of the substituted atom and substituent, and that the substitution leads to a stable compound, for example, which does not undergo spontaneous transformation, such as rearrangement, cyclization, elimination, etc. ... Used in this application, the term substituted is intended to include all permissible substituents of organic compounds. In a broad aspect, permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic, organic substituents. Permissible substituents can be one or more and the same or different for the respective organic compounds. For the purposes of the present invention, heteroatoms such as nitrogen may have hydrogen substituents and / or any permissible substituents of organic compounds described herein that satisfy the valence of the heteroatoms. Substituents can include any substituents described herein, for example, halogen, hydroxyl, carbonyl (such as carboxyl, alkoxycarbonyl, formyl, or acyl), thiocarbonyl (such as thioether, thioacetate or thioformate), alkoxyl, phosphoryl, phosphate, phosphonate, phosphinate , amino, amido, amidine, imine, cyano, nitro, azido, sulf-91 038517 hydryl, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, heterocyclyl, aralkyl or aromatic or heteroaromatic fragment.

Those of ordinary skill in the art will appreciate that the substituents themselves may be substituted as needed. Unless specifically indicated that they are unsubstituted, references to chemical fragments in this description are understood to include substituted variants. For example, reference to an aryl group or moiety implicitly includes both substituted and unsubstituted variants.

The term sulfate is known in the art and refers to the group —OSO3H or a pharmaceutically acceptable salt thereof.

The term sulfonamide is known in the art and refers to the group represented by the general formulas □ 10 <i R ¹⁰ o./h'V m where R ⁹ and R ^{10 are} independently hydrogen or hydrocarbyl such as alkyl, or R ⁹ and R ¹⁰ , taken together with the intermediate atom (s), complete a heterocycle having 4 to 8 atoms in the ring structure.

The term sulfoxide is known in the art and refers to the group —S (O) —R ¹⁰ , where R ¹⁰ is hydrocarbyl.

The term sulfonate is known in the art and refers to the group SO3H or a pharmaceutically acceptable salt thereof.

The term sulfone is known in the art and refers to the group —S (O) 2 —R ¹⁰ , where R ¹⁰ is hydrocarbyl.

Used in this application, the term thioalkyl refers to an alkyl group substituted with a thiol group.

As used herein, the term thioether refers to the group —C (O) SR ¹⁰ or —SC (O) R ¹⁰ , where R ¹⁰ is hydrocarbyl.

Used in this application, the term thioether is equivalent to ether, in which oxygen is replaced by sulfur.

The term urea is known in the art and can be represented by the general formula o

Α, Α-κ ’”

R ⁹ R ⁹ wherein R ⁹ and R ^{10 are} independently hydrogen or hydrocarbyl such as alkyl, or any of R ⁹ present, taken together with R ¹⁰ , and the intermediate atom (s) terminate a heterocycle having 4 to 8 atoms in ring structure.

The term bioavailability refers to the fraction of an administered drug that reaches the systemic circulation, one of the main pharmacokinetic properties of drugs. When the drug is administered intravenously, its bioavailability is 100%. When a drug is administered by other routes (eg, oral), its bioavailability usually decreases due to incomplete absorption and first-pass metabolism, or may vary from patient to patient. Bioavailability is a term that refers to the measurement of the total amount of a drug that reaches the total blood flow from an administered pharmaceutical composition, for example from oral or intravenous administration of a pharmaceutical composition, in a single or multiple dosage. It is often expressed in%, i.e. area under the pharmacokinetic curve AUC (0 to infinity) or AUC (0 to 48 or 72 h) of a single dose of a drug when administered, for example, orally, in serum, blood or plasma compared to AUC (0 to infinity) or AUC (0 to 48 or 72 hours) of a single dose of the same amount of drug when injected, i.e. AUC (oral) / AUC (when injected) is expressed in%. In addition, Tmax denotes the time to reach the maximum plasma concentration (Cmax) after administration.

A protecting group refers to a group of atoms that, when attached to a reactive functional group in a molecule, masks, reduces, or prevents the reactivity of the functional group. Typically, the protecting group can be selectively removed as desired during synthesis. Examples of protecting groups can be found in Greene and Wuts, Protective Groups in Organic Chemistry, 3rd Ed., 1999, John Wiley & Sons, NY and Harrison et al., Compendium of Synthetic Organic Methods, Vols. 1-8, 1971-1996, John Wiley & Sons, NY. Typical nitrogen protecting groups include formyl, acetyl, trifluoroacetyl, benzyl, benzyloxycarbonyl (CBZ), tert-butoxycarbonyl (Boc), trimethylsilyl (TMS), 2-trimethylsilyl ethanesulfonyl (TES), trityl and substituted trityl groups, allyloxycarbonylmethyloxy (FMOC), nitroveratryloxycarbonyl (NVOC), and the like, but are not limited to them. Typical hydroxyl protecting groups include those where the hydroxyl group is either acylated (esterified) or alkylated, such as benzyl and trityl ethers, as well as alkyl ethers, tetrahydropyranyl ethers, trialkylsilyl ethers (e.g. TMS or TIPS groups), glycol ethers such as, but not limited to, ethylene glycol and propylene glycol derivatives and allyl ethers.

As used herein, a therapeutic agent that prevents a disorder or disease refers to a compound that, in a statistical sample, reduces the occurrence of a disorder or disease in a treated sample as compared to an untreated control sample, or delays the onset or reduces the severity of one or more symptoms of the disorder, or disease compared to an untreated control.

The term treatment includes prophylactic and / or therapeutic treatment. The term prophylactic or therapeutic treatment is recognized in the art and includes the introduction into the body of one or more of the contemplated compositions. If the treatment is applied before the clinical manifestation of the undesirable condition (for example, a disease or other undesirable condition of the host animal), then the treatment is prophylactic (i.e., it protects the host from developing the undesirable condition), whereas if it is administered after the appearance of the undesirable condition, the treatment is therapeutic (that is, it is intended to reduce, alleviate or stabilize an existing undesirable condition or its side effects).

The term prodrug is intended to encompass compounds that under physiological conditions are converted to therapeutically active agents, such as compounds of Formula A or Formula B. molecules. In other embodiments, the prodrug is converted by the enzymatic activity of the host animal. For example, esters or carbonates (eg esters or carbonates of alcohols or carboxylic acids) are preferred prodrugs of the present invention. Alternatively, amides (eg, amino group amide) can be prodrugs of the invention. Some or all of the compounds of formula I in the formulation above may be replaced with an appropriate suitable prodrug, for example, where the hydroxyl in the parent compound is present as an ester or carbonate, or the carboxylic acid present in the parent compound is present as an ester.

One or more constituent atoms of the compounds provided herein can be substituted or substituted with isotopes of atoms in natural or unnatural abundance. In some embodiments, the compound comprises at least one hydrogen that is enriched in deuterium atoms, that is, the compound contains deuterium atoms in excess of the natural level of deuterium on Earth. For example, one or more hydrogen atoms in the compound provided herein may be enriched with deuterium (e.g., one or more atoms of protium C _1- 6alkilnoy groups may be replaced by deuterium atoms, such as -CD3, replacing more widespread -C (1H) ₃ methyl group). In some embodiments, the compound is enriched in two or more deuterium atoms. In some embodiments, the connection includes 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22 23 or 24 deuterium atoms. In some embodiments, all of the hydrogen atoms in the compound may be enriched in deuterium atoms instead of protium atoms.

Synthetic methods for incorporating isotopes into organic compounds are known in the art (Deuterium Labeling in Organic Chemistry by Alan F. Thomas (New York, NY, Appleton Century-Crofts, 1971; The Renaissance of H / D Exchange by Jens Atzrodt, Volker Derdau, Thorsten Fey and Jochen Zimmermann, Angew. Chem. Int. Ed. 2007, 7744-7765; The Organic Chemistry of Isotopic Labeling by James R. Hanson, Royal Society of Chemistry, 2011) Isotopically labeled compounds can be used in a variety of studies such as such as NMR spectroscopy, metabolism experiments and / or quantitative analyzes.

Substitution with heavier isotopes such as deuterium for protium may provide certain therapeutic benefits due to greater metabolic stability, such as increased in vivo half-life or reduced dosage requirements, and therefore may be preferable in some circumstances (see, for example , A. Kerekes et al. J. Med. Chem. 2011, 54, 201-210; R. Xu et al. J. Label Compd. Radiopharm. 2015, 58, 308-312).

The radionuclide that is included in the present radiolabeled compounds will depend on the particular application of that radiolabeled compound. For radioactive imaging applications, ⁿ C, ¹⁸ F, ¹²⁵ 1, ¹²³ 1, ¹²⁴ 1, ¹³¹ I, ⁷⁵ Br, ⁷⁶ Br, or ⁷⁷ Br may be useful.

It is understood that a radiolabeled or labeled compound is one that contains at least one radionuclide. In some embodiments, the radionuclide is selected from ³ H, ¹⁴ C, ¹²⁵ I, ³⁵ S, and ⁸² Br.

The present invention may further include synthetic methods for incorporating radioisotopes into compounds of the invention. Synthetic methods for incorporating radioisotopes into organic compounds are well known in the art and those of skill in the art

- 93 038517 will readily understand the methods applicable to the disclosed compounds.

Pharmaceutical compositions

In some embodiments, the invention relates to a solid pharmaceutical composition comprising a compound of the present invention, such as a compound of formula (I *), or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier.

In certain embodiments, the present invention provides a pharmaceutical preparation suitable for use in a human patient, comprising any compound of the present invention (eg, a compound of formula (I *)) and one or more pharmaceutically acceptable excipients. In certain embodiments, pharmaceutical preparations can be used to treat or prevent a condition or disease as described herein. In certain embodiments, the pharmaceutical preparations have sufficiently low pyrogenic activity to be suitable for use in a human patient.

In one embodiment, the present invention provides a pharmaceutical kit containing a compound of the present invention, such as a compound of formula (I *), or a pharmaceutically acceptable salt thereof, and, if necessary, instructions on how to use the compound.

The compositions and methods of the present invention can be used to treat an individual in need thereof. In certain embodiments, the individual is a mammal, such as a human, or a non-human mammal. When used in an animal, such as a human, the composition or compound is preferably administered as a pharmaceutical composition containing, for example, a compound of the invention and a pharmaceutically acceptable carrier. Pharmaceutically acceptable carriers are well known in the art and include, for example, non-aqueous carriers such as glycols, glycerol, oils such as olive oil, or injectable organic esters. Excipients can be selected, for example, to effect sustained release of the agent or to selectively target one or more cells, tissues, or organs. The pharmaceutical composition may be in the form of a unit dose such as a tablet, capsule (including an openable capsule and a gelatin capsule), granule, lyophilized reconstitute, powder, suppository, or the like. The composition can also be present in a transdermal delivery system such as a skin patch.

A pharmaceutically acceptable carrier may contain physiologically acceptable agents that act, for example, to stabilize, increase solubility, or increase absorption of a compound, such as a compound of the present invention. Such physiologically acceptable agents include, for example, carbohydrates such as glucose, sucrose or dextrans; antioxidants such as ascorbic acid or glutathione; chelating agents, low molecular weight proteins or other stabilizers or excipients. The choice of a pharmaceutically acceptable carrier, including a physiologically acceptable agent, depends, for example, on the route of administration of the composition. The drug or pharmaceutical composition can be a self-emulsifying drug delivery system or a self-microemulsifying drug delivery system. The pharmaceutical composition (preparation) may also be a liposome or other polymer matrix, which may include, for example, a compound of the present invention. For example, liposomes that contain phospholipids or other lipids are non-toxic, physiologically acceptable and metabolizable carriers that are relatively easy to manufacture and use.

The term pharmaceutically acceptable is used in this application to refer to those compounds, materials, compositions and / or dosage forms that, within the framework of medical common sense, are suitable for use in contact with tissues of humans and animals without undue toxicity, irritation, allergic reaction, or other problems or complications commensurate with a reasonable benefit / risk ratio.

The term “pharmaceutically acceptable carrier” as used herein means a pharmaceutically acceptable material, composition, or solvent, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material. Each carrier must be acceptable in the sense of being compatible with the other ingredients of the formulation and not causing harm to the patient. Some examples of materials that can serve as pharmaceutically acceptable carriers include: (1) sugars such as lactose, glucose, and sucrose; (2) starches such as corn starch and potato starch; (3) cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) powdered gum tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients such as cocoa butter and suppository waxes; (9) oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; (10) glycols such as propylene glycol; (11) polyols such as glycerin, sorbitol, mannitol, and polyethylene glycol; (12) esters such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) ethyl alcohol; and (17) other non-toxic compatible substances used in pharmaceutical formulations.

The pharmaceutical composition (preparation) can be administered to a subject by any of a number of modes of administration, including, for example, oral administration (e.g., drops, as in non-aqueous solutions or suspensions, tablets, capsules (including openable capsules and gelatin capsules), boluses, powders, granules, pastes for application on the tongue); absorption through the oral mucosa (eg, sublingual); anal, rectal, or vaginal (for example, as a pessary, cream, or foam); parenteral administration (including intramuscular, intravenous, subcutaneous, or intrathecal, such as by means of a sterile solution or suspension); intranasal, intraperitoneal, subcutaneous, transdermal administration (for example, using a patch applied to the skin), and topical (for example, using a cream, ointment or spray applied to the skin, or in the form of eye drops). The compound can also be formulated for inhalation. Details of suitable routes of administration and suitable compositions therefor can be found, for example, in US Pat. Nos. 6,110,973, 5,763,493, 5,731,000, 5,541,231, 5,427,798, 5358970 and 4,172,896, as well as the patents cited therein.

The compositions can conveniently be presented in unit dosage form and can be prepared by any means well known in the pharmaceutical art. The amount of active ingredient that can be combined with a carrier material to form a unit dosage form will vary depending on the host being treated and the particular route of administration. The amount of active ingredient that can be combined with a carrier material to produce a unit dosage form will generally be that amount of the compound that will have a therapeutic effect. Typically, out of one hundred percent, this amount will be from about 1 to 99% of the active ingredient, preferably from about 5 to 70%, most preferably from about 10 to 30%.

Methods for preparing these compositions or compositions include the step of bringing into association an active compound, such as a compound of the invention, with a carrier and, if necessary, with one or more accessory ingredients. Typically, the compositions are prepared by uniformly and intimately combining a compound of the present invention with liquid carriers or finely divided solid carriers, or both, and then, if necessary, shaping the product.

Compositions of the invention suitable for oral administration may be in the form of capsules (including openable capsules and gelatin capsules), cachets, pills, tablets, troches (using a flavored base, usually sucrose and gum arabic or gum tragacanth), lyophilized substances, powders , granules, or in the form of a solution or suspension in a non-aqueous liquid, or in the form of lozenges (using an inert base such as gelatin and glycerin, or sucrose and gum arabic) and the like, where each of the forms contains a predetermined amount of a compound from the present invention as an active ingredient. The compositions or compounds can also be administered as a bolus, electuary, or paste.

For the preparation of solid dosage forms for oral administration (capsules (including openable capsules and gelatin capsules), tablets, pills, dragees, powders, granules and the like), the active ingredient is mixed with one or more pharmaceutically acceptable carriers such as sodium citrate or dicalcium phosphate and / or any of the following: (1) fillers or diluents such as starches, lactose, sucrose, glucose, mannitol and / or silicic acid; (2) binding agents such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and / or gum arabic; (3) humectants such as glycerin; (4) disintegrants such as agar agar, calcium carbonate, potato starch or tapioca starch, alginic acid, some silicates and sodium carbonate; (5) retarding dissolution agents such as paraffin; (6) absorption accelerators such as quaternary ammonium compounds; (7) wetting agents such as, for example, cetyl alcohol and glycerol monostearate; (8) absorbents such as kaolin and bentonite clay; (9) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof; (10) complexing agents such as modified and unmodified cyclodextrins; and (11) colorants. In the case of capsules (including openable capsules and gelatin capsules), tablets and pills, the pharmaceutical compositions may also contain buffering agents. Solid compositions of a similar type can also be used as fillers in soft and hard gelatin capsules using excipients such as lactose or milk sugars as well as high molecular weight polyethylene glycols and the like.

The tablet can be made by compression or molding, if necessary with one or more additional ingredients. Compressed tablets can be prepared using a binder (eg gelatin or hydroxypropyl methylcellulose), lubricant, inert diluent, preservative, disintegrant (eg sodium starch glycolate or crosslinked sodium carboxymethylcellulose), surfactant, or dispersing agent. Molded tablets can be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.

- 95 038517

Tablets and other solid dosage forms of pharmaceutical compositions, such as dragees, capsules (including openable capsules and gelatin capsules), pills and granules, can be optionally provided with a break line or prepared with coatings and shells such as enteric coatings and other coatings, well famous in the field of pharmaceuticals. They can also be formulated to provide slow or controlled release of the active ingredient therein using, for example, hydroxypropyl methylcellulose in varying proportions to provide the desired release profile, other polymer matrices, liposomes and / or microspheres. They can be sterilized, for example, by filtration through a bacteria-retaining filter or by the inclusion of sterilizing agents in the form of sterile solid compositions that can be dissolved in sterile water or some other sterile injection medium immediately prior to use. These compositions may also optionally contain opacifying agents and may be a composition in which they release the active ingredient (s) only or preferably in a certain part of the gastrointestinal tract, optionally with a delay. Examples of embedding compositions that can be used include polymeric substances and waxes. The active ingredient can also be in microencapsulated form, if necessary, with one or more of the above-described auxiliary substances.

Formulations of pharmaceutical compositions for rectal, vaginal or urethral administration can be presented in the form of a suppository, which can be prepared by mixing one or more active compounds with one or more suitable non-irritating excipients or carriers, including, for example, cocoa butter, polyethylene glycol, wax for a suppository or salicylate that is solid at room temperature but liquid at body temperature and therefore will melt in the rectum or vaginal cavity and release the active compound.

Alternatively or additionally, the compositions can be formulated for delivery via a catheter, stent, wire, or other intraluminal device. Delivery through such devices can be particularly useful for delivery to the bladder, urethra, ureter, rectum, or intestines.

Compositions that are suitable for vaginal administration also include pessaries, tampons, creams, gels, pastes, foams, or aerosol compositions containing such carriers known in the art to be suitable for this purpose.

Dosage forms for topical or transdermal administration include powders, aerosols, ointments, pastes, creams, lotions, gels, solutions, patches, and inhalable forms. The active compound can be mixed under sterile conditions with a pharmaceutically acceptable carrier and with any preservatives, buffers or propellants that may be required.

Ointments, pastes, creams and gels may contain, in addition to the active compound, excipients such as animal and vegetable fats, oils, waxes, paraffins, starch, gum tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and oxide zinc or mixtures thereof.

Powders and sprays may contain, in addition to the active compound, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances. Sprays may additionally contain conventional propellants such as chlorofluorocarbons and volatile unsubstituted hydrocarbons such as butane and propane.

Transdermal patches have the additional advantage of providing controlled delivery of a compound of the present invention to the body. Such dosage forms can be prepared by dissolving or dispersing the active compound in a suitable medium. Absorption enhancers can also be used to increase skin penetration of a compound. The rate of such permeation can be controlled either by providing a rate-controlling membrane or by dispersing the compound in a polymer matrix or gel.

Ophthalmic formulations, ophthalmic ointments, powders, solutions and the like are also contemplated as being within the scope of this invention. Typical ophthalmic formulations are described in US Publication Nos. 2005/0080056, 2005/0059744, 2005/0031697 and 2005/004074 and US Pat. No. 6,583,124. Optionally, liquid ophthalmic formulations have properties similar to those of lacrimal fluids, aqueous humor or vitreous humor, or compatible with such fluids. The preferred route of administration is local administration (eg, topical application, such as with eye drops, or through an implant).

The terms parenteral and parenteral as used herein mean modes of administration other than enteral and topical administration, usually by injection, and include intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, subcutaneous , subcuticular, intra-articular, subcapsular, subarachnoid, intraspinal and intrasternal administration and infusion, but are not limited to them. Pharmaceutical

- 96 038517 compositions suitable for parenteral administration contain one or more active compounds in combination with one or more pharmaceutically acceptable sterile isotonic non-aqueous solutions, dispersions, suspensions or emulsions or sterile powders, which can be converted into sterile injectable solutions or dispersions immediately prior to uses which may contain antioxidants, buffers, bacteriostatic agents, solutes that render the formulation isotonic with the blood of the intended recipient, or suspending or thickening agents.

Examples of suitable non-aqueous carriers that can be used in the pharmaceutical compositions of the invention include ethanol, polyols (such as glycerin, propylene glycol, polyethylene glycol, and the like) and suitable mixtures thereof, vegetable oils such as olive oil, and injectable organic complex ethers such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of coating materials such as lecithin, by maintaining the desired particle size in the case of dispersions, and by the use of surfactants.

These compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents, and dispersing agents. Prevention of the action of microorganisms can be ensured by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenolsorbic acid, and the like. It may also be necessary to include isotonic agents such as sugars, sodium chloride and the like in the compositions. In addition, prolonged absorption of the injectable pharmaceutical form can be brought about by the inclusion of agents that delay absorption, such as aluminum monostearate and gelatin.

In some cases, in order to prolong the effect of the drug, it is desirable to slow down the absorption of the drug by subcutaneous or intramuscular injection. This can be achieved by using a liquid suspension of crystalline or amorphous material having poor water solubility. The rate of absorption of the drug is then dependent on its rate of dissolution, which in turn may be dependent on the size of the crystal and the crystalline form. Alternatively, delayed absorption of a parenterally administered dosage form is achieved by dissolving or suspending the drug in an oil vehicle.

Depot injectables are prepared by forming microencapsulated matrices of the compounds of interest in biodegradable polymers such as polylactide polyglycolide. Depending on the ratio of drug to polymer and the nature of the particular polymer used, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly (orthoesters) and poly (anhydrides). Depot injectables are also prepared by introducing the drug into liposomes or microemulsions that are compatible with body tissues.

For use in the methods of this invention, the active compounds can be provided by themselves or in the form of a pharmaceutical composition containing, for example, 0.1 to 99.5% (more preferably 0.5 to 90%) of the active ingredient in combination with a pharmaceutically acceptable medium.

Routes of administration can also be provided with rechargeable or biodegradable devices. In recent years, various slow release polymer devices for controlled drug delivery, including protein biopharmaceuticals, have been developed and tested in vivo. Various biocompatible polymers (including hydrogels), including both biodegradable and non-degradable polymers, can be used to form an implant for sustained release of a compound at a specific target site.

Actual dosage levels of active ingredients in pharmaceutical compositions can be varied to provide an amount of active ingredient that is effective to achieve the desired therapeutic response for a particular patient, composition and route of administration, without toxicity to the patient.

The selected dosage level will depend on many factors, including the activity of the particular compound or combination of compounds or an ester, salt or amide thereof, route of administration, time of administration, clearance rate of the particular compound (s) used, duration of treatment, other drugs , compounds and / or materials used in combination with specific compound (s), age, sex, body weight, condition, general health and previous medical history of the patient being treated, and similar factors well known in the medical field ...

A physician or veterinarian of ordinary skill in the art can readily determine and prescribe a therapeutically effective amount of the pharmaceutical composition required. For example, a physician or veterinarian may start dosing of the pharmaceutical composition or compound at levels lower than that required to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved. By a therapeutically effective amount is meant a concentration of a compound sufficient to achieve the desired therapeutic effect. It is generally believed that an effective amount of a compound will be

- 97 038517 vary with body weight, gender, age and medical history of the subject. Other factors that affect the effective amount may include, but are not limited to, the severity of the patient's condition, the disorder being treated, the stability of the compound, and, if necessary, another type of therapeutic agent administered with the compound of the invention. A large total dose can be delivered by multiple administration of the agent. Methods for determining efficacy and dosage are known to those skilled in the art (Isselbacher et al. (1996), Harrison's Principles of Internal Medicine 13 ed., 1814-1882).

In general, a suitable daily dose of active compound used in the compositions and methods of the invention will be that amount of the compound that is the lowest effective dose to produce a therapeutic effect. This effective dose usually depends on the factors described above.

If necessary, an effective daily dose of the active compound can be administered as one, two, three, four, five, six or more sub-doses administered separately at appropriate intervals throughout the day, in unit dosage forms as needed. In certain embodiments of the present invention, the active compound may be administered two or three times a day. In preferred embodiments, the active compound will be administered once a day.

A patient receiving such treatment is any animal in need, including primates, in particular humans, and other mammals such as horses, cattle, pigs and sheep; and poultry and domestic animals in general.

In certain embodiments, the compounds of the present invention can be used alone or in conjunction with another type of therapeutic agent. As used herein, the expression co-administration refers to any form of administration of two or more different therapeutic compounds such that the second compound is administered while the previously administered therapeutic compound is still effective in the body (for example, two compounds are simultaneously effective in a patient, which may include the synergistic action of the two compounds). For example, different therapeutic compounds can be administered either in the same composition or in a separate composition, either simultaneously or sequentially. In certain embodiments, the various therapeutic compounds may be administered within 1, 12, 24, 36, 48, 72 hours, or weeks apart. Thus, an individual who receives such treatment can benefit from the combined action of various therapeutic compounds.

In certain embodiments, co-administration of compounds of the invention with one or more additional therapeutic agents (e.g., one or more additional chemotherapeutic agents) provides improved efficacy with respect to each individual administration of a compound of the present invention (e.g., a compound of formula (I *)) or one or more several additional therapeutic agents. In some such embodiments, co-administration provides an additive effect, wherein the additive effect refers to the sum of each of the effects of the individual administration of a compound of the present invention and one or more additional therapeutic agents.

This invention includes the use of pharmaceutically acceptable salts of the compounds of the invention in the compositions and methods of the present invention. Used in this application, the term pharmaceutically acceptable salt includes salts derived from inorganic or organic acids, including, for example, hydrochloric, hydrobromic, sulfuric, nitric, perchloric, phosphoric, formic, acetic, lactic, maleic, fumaric, succinic, tartaric, glycolic, salicylic, citric, methanesulfonic, benzenesulfonic, benzoic, malonic, trifluoroacetic, trichloroacetic, naphthalene-2-sulfonic, oxalic, mandelic and other acids. Pharmaceutically acceptable salt forms may include forms in which the ratio of the molecules making up the salt is not 1: 1. For example, a salt can contain more than one inorganic or organic acid molecule per base molecule, for example two hydrochloric acid molecules per compound of formula (I *). As another example, a salt may contain less than one inorganic or organic acid molecule per base molecule, for example two molecules of a compound of formula (I *) per tartaric acid molecule.

In additional embodiments, the implementation of contemplated salts of the present invention include, but are not limited to, alkyl-, dialkyl-, trialkyl-, or tetraalkylammonium salts. In certain embodiments, contemplated salts of the invention include salts of L-arginine, benentamine, benzathine, betaine, calcium hydroxide, choline, deanol, diethanolamine, diethylamine, 2 (diethylamino) ethanol, ethanolamine, ethylenediamine, N-methylglucamine, hydrabamine, 1H-imidazole , lithium, L-lysine, magnesium, 4- (2-hydroxyethyl) morpholine, piperazine, potassium, 1- (2-hydroxyethyl) pyrrolidine, sodium, triethanolamine, tromethamine, and zinc. In certain embodiments, contemplated salts of the present invention include, but are not limited to, salts of Na, Ca, K, Mg, Zn, or other metals.

Pharmaceutically acceptable acid addition salts can also exist as various personal solvates such as methanol, ethanol, dimethylformamide and the like. Mixtures of such solvates can also be prepared. The source of such a solvate may be a solvent from crystallization, typical of the solvent for preparation or crystallization, or incidental to such a solvent.

Wetting agents, emulsifiers and lubricants such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, anti-adhesive agents, coating agents, sweeteners, fragrances and perfumes, preservatives and antioxidants can also be present in the compositions.

Examples of pharmaceutically acceptable antioxidants include: (1) water-soluble antioxidants such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite and the like; (2) oil-soluble antioxidants such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, alpha-tocopherol, and the like; and (3) metal chelating agents such as citric acid, ethylenediaminetetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, and the like.

The invention, now described as a whole, will be more easily understood with reference to the following examples, which are included only for the purpose of illustrating certain aspects and embodiments of the present invention and are not intended to limit the invention.

Examples of

Examples outside the scope of the claims are for reference purposes only.

Abbreviations:

ACN = acetonitrile

Boc = tert-butyloxycarbonyl

Bn = benzyl

Cbz or Z = benzyloxycarbonyl

COD = cyclooctadiene

DCM = methylene chloride or dichloromethane

DMAP = 4- (dimethylamino) pyridine

DMF = dimethylformamide dppe = ethylenebis (diphenylphosphine)

EDC or EDCI = N- (3-dimethylaminopropyl) -N'-ethylcarbodiimide

EtOAc = ethyl acetate iso-BuB (OH) ₂ = isobutylboronic acid

LiHMDS - lithium bis (trimethylsilyl) amide

OSu = N-hydroxysuccinimide

TBAF = tetrabutylammonium fluoride hydrate

TFA = trifluoroacetic acid

THF = tetrahydrofuran

TMS = trimethylsilane

Z-Ala-OSu = benzyloxycarbonyl-L-αlanine hydroxysuccinimide ester

Z-OSu = N- (benzyloxycarbonyloxy) succinimide

Pin = pinacol

Example 1. General method for the formation of an alcoholic complex

Boronic acid amino acid (200 mg) was suspended in anhydrous alcohol (20 ml). The suspension was stirred at 70 ° C for 14 h, which led to the complete dissolution of the compound. The reflux heater was replaced with a small distillation head and the reaction mixture was distilled (at atmospheric pressure (with a drier tube attached with Drierite® to remove moisture) until the hot solution became cloudy (about half of the alcohol was collected during distillation). Anhydrous was added. alcohol (10 ml) and then the reaction mixture was heated to 80 ° C and stirred at 80 ° C for another 4 h. The distillation process was repeated until the solution became cloudy again (~ 10 ml of distillate collected) Anhydrous alcohol was added again (10 ml) and then the reaction mixture was heated to 80 ° C and stirred at 80 ° C for another 2 hours. Distillation process

- 99 038517 was repeated until the solution became cloudy (collected - 15 ml of distillate). The remaining solution was allowed to cool to room temperature and then filtered and quickly dried under vacuum, and then further dried under high vacuum (38 mTorr) at room temperature for at least 2 hours to obtain the product as an almost white or pale yellow powder.

Example 2. An Exemplary Method for Synthesizing an Arginase Inhibitor

Synthesis of (6aS, 9aR) -8- (L-αlanyl) -9a-amino-3-ethoxyoctahydro- [1,2] oxaborocino [6,7-c] pyrrol1 (3H) -one (10e).

Starting material compound 21 (racemic) was prepared as described in WO2 012/58065 on pages 48-50. Separation was performed using chiral chromatography. Racemic compound 21 was separated on a chiral stationary phase CHIRALPAK® 1B column (Daicel Chiral Technologies) using heptane-ethanol as eluent to give the resolved enantiomer of compound 21.

Iridium catalyzed hydroboration to give 22

A 10 L reaction flask with dichloromethane (5 L) was vacuumed to approximately 250 mbar and the pressure was released with nitrogen. The procedure was repeated twice and the reaction was carried out under a nitrogen atmosphere. Bis (1,5-cyclooctadiene) diyridium (I) dichloride (26.00 g, 38.7 mmol, 0.03 eq.) And ethylene bis (diphenylphosphine) (30.85 g, 77.4 mmol, 0.06 eq.), and the mixture was stirred at 13-15 ° C until a clear solution was formed. Compound 21 (separated, 466.3 g, 1.269 mol) was added and the mixture was stirred at 15-17 ° C for 30 minutes. The resulting dark red solution was cooled to 0 ° C and 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (224.0 g, 1.750 mol, 1.38 eq.) Was added at a temperature from -2 to + 2 ° C for 1 h. The reaction mixture was stirred at a temperature from -2 to + 2 ° C for 2 h and HPLC showed a conversion of 90.7%. After further stirring for 14 hours at 18-22 ° C, HPLC showed a conversion of 98.9%.

Acetonitrile (2.2 L) was added to the reaction mixture. The mixture was heated for distillation at 30-35 ° C under reduced pressure (470 mbar) and 2.7 liters were distilled off. Acetonitrile (2.2 L) was added to the residue. The mixture was heated for distillation at 35-38 ° C under reduced pressure (350-250 mbar) and 2.2 L was distilled off. Acetonitrile (2.2 L) was added to the residue. The mixture was heated for distillation at 55-40 ° C under reduced pressure (240-155 mbar) and 3.7 liters were distilled off.

The residual suspension (-1300 ml) was stirred at 20-23 ° C overnight and the precipitate was isolated by filtration. The filter cake was washed with cold (0-10 ° C) acetonitrile (1.5 L) and dried to constant weight at 40 ° C in a drying oven with air ventilation. The obtained yield of compound 22: 466.5 g (74%).

Getting a connection 26.

48% HBr (aqueous solution, 500 ml) and compound 22 (250 g, 505 mmol) were added to a 2 L three neck round bottom flask. The mixture was heated for distillation and distillation was continued until an internal temperature of 120 ° C was reached. The mixture was stirred at 120 ° C for an additional 2 h. The mixture was given

- 100 038517 cool to room temperature. Water (0.5 L) was added and the reaction mixture was extracted with toluene (1 L). The atmosphere was changed to nitrogen, and the aqueous mixture was cooled to 0 ° C, and the aqueous solution of compound 23 was left overnight. The pH of the mixture was adjusted to 9.7 with NaOH (27.65%, 460 ml) followed by the addition of acetonitrile (750 ml). Z-Ala-OSu (323 g, 1009 mmol, 2 eq.) Was added and the pH was continuously adjusted to 9.5-10.0 with NaOH (27.65%, 175 ml). After 1.5 h, the conversion was> 98% (TLC). The pH was adjusted to 3.3 with 48% HBr (aq, 207 ml) and the reaction mixture was allowed to warm to room temperature. The mixture was extracted with toluene (1.14 L) and twice with ethyl acetate (2 x 1.14 L). The two ethyl acetate phases were extracted twice with water (2x225 ml). The combined aqueous phases containing compound 24 were kept under nitrogen at 0 ° C overnight.

The pH of the mixture was adjusted to 10.4 with NaOH (27.65%, 207 ml) and the temperature was allowed to rise to 10-20 ° C. Acetonitrile (750 ml) was added followed by Z-OSu (176 g, 707 mmol, 1.4 eq.) And the pH of the mixture was continuously adjusted to 10.0-10.5 with NaOH (27.65%, 112 ml) ... The reaction was allowed to continue for 3 h until a conversion of> 95% was observed (HPLC vs. standard). The pH was adjusted to 3.2 with 48% HBr (aq, 300 ml). Ethyl acetate (1.14 L) was added and the mixture was stirred vigorously. The phases were separated and the organic phases were combined to give compound 25, which was stored in a freezer overnight.

An ethyl acetate solution of compound 25 was evaporated under reduced pressure at a water bath temperature of 50 ° C to dryness. Acetonitrile (200 ml) was added and the evaporation was continued until dry. The residue was dissolved in acetonitrile (3.63 L) at 40 ° C and isopropanol (225 ml) was added. Diethanolamine (95.9 g, 912 mmol) was dissolved in isopropanol (150 ml) and acetonitrile (150 ml). The diethanolamine solution was added to a solution of compound 25 in acetonitrile / isopropanol at 40 ° C over 10 min. The solution was seeded with compound 26 and cooled to room temperature. The settling was very slow and had to be left overnight to get a thick slurry. The suspension was filtered slowly and the filter cake was washed with 2 L of 10% isopropanol / acetonitrile. A portion of the filter cake was dried to give 83% yield (276.2 g).

The main part (271.6 g) of the material was re-precipitated by suspending it in isopropanol (400 ml) and acetonitrile (900 ml). The solid was dissolved at reflux temperature. Acetonitrile (2.7 L) was added and the solution was allowed to cool to room temperature. No precipitation was observed at 45 ° C. After 5 hours, the thick slurry was filtered and the filter cake washed with 1.5 L of 10% isopropanol / acetonitrile. The solid was dried overnight under vacuum at 25 ° C to give 239.2 g of compound 26 (88% recovery, 72% overall yield).

Getting compound 10e.

Water (2.4 L) and 36% HCl (aqueous solution, 75 g) were added to a 5 L three neck round bottom flask. Ethyl acetate (2.45 L) was added followed by compound 26 (250 g, 343 mmol). The mixture was stirred until the solid dissolved. The phases were separated and the aqueous phase was extracted with ethyl acetate (1.22 L). The combined organic phases were dried over magnesium sulfate (190 g). The suspension was filtered and the filter cake was washed with ethyl acetate (560 ml). The filtrate and wash were evaporated under reduced pressure in a water bath temperature of 50 ° C to give crude compound 25 as a white foam. Ethanol (2.4 L) and water (100 ml) were added and the mixture was stirred until a solution was obtained. The system was vacuum treated to <180 mbar and the vacuum was vented with nitrogen three times. 10% Pd / C (wet, 57.7% water, 35.9 g) was added. The system was evacuated to <180 mbar and the vacuum was released with nitrogen once and hydrogen three times. Hydrogenation was continued overnight at room temperature, then the atmosphere was changed to nitrogen and another portion of 10% Pd / C (wet, 57.7% water, 4.5 g) was added. The atmosphere was changed to hydrogen and hydration continued overnight. The suspension was filtered through celite (83 g) and the filter cake was washed with a mixture of ethanol (400 ml) and water (16.7 ml) to give a crude solution 10. The filtrate was evaporated under reduced pressure in portions at a water bath temperature of 50 ° C to a volume of 350 ° C. 400 ml. Ethanol (600 ml) was added and the solution was seeded with compound 10e. The fine suspension was concentrated to the same volume under reduced pressure and a water bath temperature of 50 ° C. The suspension was kept at -15 ° C for three days. The suspension was allowed to warm to approximately 0 ° C and then filtered (GF-A). The filter cake was washed with ethanol (3x100 ml). The solid was dried at 50 ° C in vacuo overnight to obtain 82.8 g of compound 10e. This material can be further refined as described below.

Compound 10e (77.5 g) was suspended in ethanol (1.1 L) and heated to 60-62 ° C for 6 hours and 15 minutes. The suspension was cooled to 2 ° C and stirred overnight. The suspension was filtered and the filter cake was washed with ethanol (400 ml). The solid was dried at 50 ° C in vacuo overnight,

- 101 038517 to obtain 71.5 g of compound 10e as a white solid.

An analytical sample or 10e was prepared as follows: 2 g of 10e was suspended in a sufficient amount of anhydrous ethanol (~ 70 ml) to completely dissolve the material at 80 ° C. This solution was heated at 80 ° C for 2 hours under a dry nitrogen atmosphere. The reflux heater was replaced with a small reflux condenser and the reaction mixture was distilled (at atmospheric pressure, with a drying tube attached to remove moisture) until the hot solution became cloudy (approximately 40 ml of ethanol was collected during distillation). This procedure was repeated two more times, the remaining solution was allowed to cool to room temperature, then filtered and quickly dried under vacuum, and then further dried in a high vacuum (40 mTorr) at room temperature for 2 h, obtaining analytical sample 10е in the form of a white powder ...

Compound 10e. 400 MHz, d ₆ -DMSO: (3: 2 population of rotamers) d 7.01-6.80 (2H, br m, exch); 3.81 (1H, d, J = 12.8Hz); 3.68 (0.6H, dd, J = 9.8, 7.5Hz); 3.62 (0.4H, dd, J = 11.3, 7.8Hz); 3.53 (0.4H, d, J = 10.4Hz); 3.48-3.35 (3H, m); 3.20 (0.6 H, d, J = 12.5 Hz); 3.13 (0.6H, dd, J = 11.7, 9.7Hz); 2.81 (0.4H, t, J = 11.6Hz); 2.42 (0.6H, m) and 2.30 (0.4H, m); 1.83-1.70 (2H, m); 1.62 (2H, br s, exch); 1.44-1.37 (1H, m); 1.09-1.04 (6H, m, CH3CH2 and CH3CHN); 0.98 (1H, dd, J = 15, 12.4Hz); 0.65 (1H, dd, J = 14.7, 5.6Hz) and 0.42 (1H, m).

^P B-NMR (400 MHz, DMSO) δ: 7.85 cpm. FTIR (powder diffraction) (cm ^-1 ): 2905 (w), 1722 (s), 1646 (s), 1623 (s), 1271 (s), 1119 (s), 1067 (m), 658 (m) and 562 (m).

800 mg of analytical sample 10e was dissolved in a minimum amount of ethanol (~ 30 ml) at room temperature. This solution was left at room temperature and pressure in a desiccator equipped with a DRIERITE® drying tube to remove moisture to allow the ethanol to slowly evaporate causing small crystals to slowly form over 10 days. The crystals were isolated by vacuum filtration, washed quickly with cold (5 ° C) ethanol, and then dried under high vacuum (40 mTorr) at room temperature for 14 hours to give the product (386 mg) as white crystals suitable for crystallography.

X-ray structure determination

Low-temperature diffraction data (ω-scans) were collected on a Rigaku MicroMax007HF diffractometer connected to a Saturn994 + CCD detector with Cu Κα (λ = 1.54178 A) for structure 10e. Diffraction images were processed and scaled using Rigaku CrystalClear software (CrystalClear and CrystalStructure; Rigaku / MSC: Te Woodlands, TX, 2005). The structure was determined using SHELXT and refined by F2 for all data by a full matrix least squares method using SHELXL (Sheldrick, G.M. Acta Cryst. 2008, A64, 112-122). All non-hydrogen atoms were refined anisotropically. Hydrogen atoms were included in the model in geometrically calculated positions and refined using the rider model. The parameters of the isotropic displacement of all hydrogen atoms were recorded 1.2 times higher than the value of U of the atoms with which they are bound (1.5 times for the methyl groups). All hydrogen atoms associated with nitrogen atoms were found in the difference map. The N-H distances were limited to 0.92 (2) as shown in the difference map. The parameters of atomic displacements were set for free refinement. The hydrogen atom associated with ethanol was geometrically located and confined. All hydrogen atoms involved in hydrogen bonds were identified, and the corresponding donor / acceptor metrics were refined.

The X-ray diffraction structure 10e is shown in FIG. 1 at 50% thermal ellipsoid probability levels. This structure is consistent with the drawings for 10e shown in the text. Some data on crystals and structure refinement for 10e are given in Table. 2.

- 102 038517

Table 2. Crystal data and structure refinement for 10e

Empirical formula C14 H26 B N3 04.50 Mass according to the formula 319.19 Temperature 93 (2) K Wavelength 1.54178 A Crystal system Orthorhombic Space group P212121 Unit cell dimensions a = 9.7668 (7) A a = 90 °. B = 11.6068 (8) A β = 90 °. c = 29.707 (2) A γ = 90 °. Volume 3367.6 (4) AZ Z eight Density (calculated) 1.259 mg / m ³ Absorption coefficient 0.761 mm ' ¹ F (000) 1376 Crystal size 0.200 x 0.200 x 0.010 mm ³ Theta range for data collection 4.089-66.565 °. Index ranges -1 l <= h <= l 1, -13 <= k <= 13, -35 <= 1 <= 35 Collected reflections 111128 Independent reflections 5944 [R (int) = 0.1161] Completeness to theta = 66.565 ° 99.9% Takeover correction Semi-empirical equivalents Maximum and min. transmissions 1,000 and 0.727 Refinement method Full-matrix least squares on F2 Data / restrictions / parameters 5944/8/444 F2 goodness test 1.171

Final indices R [1> 2sigma (1)] RI = 0.0642, wR2 = 0.1681

R indices (all data) RI = 0.0739, wR2 = 0.1741

Absolute structural parameter -0.10 (8) The largest diff, peak and hole 0.330 and -0.227 e.A3

Conversion of compound 10 to compound 10e is an equilibrium and the composition of the mixture depends on the composition of the solvent. The formation of 10e occurs when compound 10 is treated with anhydrous ethanol. This conversion appears to occur via intermediates B and / or C as shown in Scheme 1. Compound 10e is the predominant material formed by treating 10 with absolute ethanol and removing water by distillation or resuspending the material with hot absolute ethanol. Samples from 10, which underwent less intensive treatment (in ethanol) to remove water, contain mixtures of 10e and intermediate products A, B, or C (Scheme 1).

Scheme 1. Interconversion of compounds 10 and 10e.

The isolated ethanolate (compound 10e) is rapidly hydrolyzed under physiological conditions or under any other aqueous conditions to the open form of free boronic acid, compound 10, which can exist in the equilibrium between open form A and closed form B. It should be understood that in these depicted structures, each of NH ₂ groups exist in equilibrium between protonated (saline) and non-protonated (free base) forms, and the above images are not intended to represent a fixed form for either of these groups. The presence of other acids and / or bases in solution will affect these equilibria, as will be appreciated by those skilled in the art.

The rapid conversion of compound 10е to compound 10 in water is confirmed by the similarity of spectrum 10е in D2O with spectrum 10 in D2O. When a sample of compound 10e was dissolved in D2O and the spectra were immediately

- 103 038517 were recorded (elapsed time <5 min), the spectra observed were identical to those of compound 10 (free boronic acid) plus ethanol (1: 1 ratio). The spectrum of 10e in D2O was the same after 5 min and one hour after sample preparation, indicating a fast and complete conversion after a few minutes.

FIG. 2 shows the conversion of 10e to 10 in D2O. The NMR (D2O) spectra designated A are compound 10 (free base) prepared from 11 as described in Example 2. The NMR (D2O) spectra designated B are an analytical sample of compound 10e prepared as described above. The NMR (D ₂ O) spectra labeled C represent a sample from spectra B that was lyophilized and redissolved in D 2 O. The spectra in FIG. 2 demonstrate that 10e undergoes hydrolysis in water, and the spectra of 10e in D ₂ O are identical to 10, except for the presence of ethanol, which is released during hydrolysis.

After dissolution in 1: 1 water / acetonitrile and immediate injection into the HPLC system, only one peak is observed. The mass of this peak corresponds to compound 10. No mass was found for intact compound 10e.

Compound 10 is hygroscopic, with constant absorption of water with increasing humidity. The observed moisture absorption is over 70% at 90% relative humidity (RH). Sorption and desorption isotherms show minimal hysteresis for compound 10. Compound 10e is not particularly hygroscopic below 60% relative humidity. The sorption isotherm suggests that compound 10е absorbs water up to 40 wt% at a relative humidity of 60–90%. The isotherm also indicates significant hysteresis. This hysteresis is consistent with the rapid hydrolysis of ethanolate to the corresponding form of boronic acid, which has bound water in the solid state when released from aqueous solutions.

Example 3. Alternative synthesis of a typical arginase inhibitor (3R, 4S) -3-amino-1 - ((S) -2aminopropanoyl) -4- (3-boronopropyl) -yl) pyrrolidine-3-carboxylate.

Trans-4-allyl-3-azido-1- (tert-butoxycarbonyl) pyrrolidine-3-carboxylic acid (4, racemic)

N ₃ CO ₂ H

IN— 'Vos' 4

A solution of chloroform (26.86 ml, 333 mmol) and TMS-Cl (32.86 ml, 257.1 mmol) in anhydrous THF (300 ml) was cooled to -78 ° C. After stirring for 10 min, LiHMDS (1M in THF, 249 ml, 249 mmol) was added at a rate that kept the temperature below -60 ° C (approximately 30 min). After additional stirring for 30 min at a temperature of -60 to -70 ° C (the reaction mixture became cloudy), the solution was heated to -20 ° C (the reaction mixture became transparent) and treated with tert-butyl-3-allyl-4-oxopyrrolidine-1 -carboxylate (3.30 g, 133.2 mmol) in DMF (90 ml) and tetrabutylammonium acetate (3.69 g, 12.24 mmol) in DMF (90 ml) at a rate at which the internal reaction temperature remained below - 20 ° C (the reaction became cloudy). After the addition was complete, the reaction mixture was warmed to room temperature with stirring until the ketone starting material was consumed (by TLC), then poured into saturated aqueous NH ₄ Cl and extracted with EtOAc (3x100 mL). The combined organic layers were washed sequentially with saturated aqueous NH4Cl and saturated aqueous NaCl (2x80 ml), dried over MgSO ₄ , filtered and concentrated.

Under nitrogen conditions, the crude intermediate protected by TMS was dissolved in dry THF (300 ml), cooled to 0 ° C and carefully treated with acetic acid (7.5 ml, 130.9 mmol) and TBAF (1M in THF, 133, 2 ml, 133.2 mmol) dropwise. After the addition was complete, the reaction mixture was stirred for an additional 10 min at 0 ° C, then poured into saturated aqueous NaHCO ₃ and extracted with EtOAc (3x100 ml). The combined organic layers were washed with saturated aqueous NaCl, dried over MgSO4, filtered and concentrated to give the crude alcohol intermediate.

The crude alcohol was dissolved in dioxane (200 ml), cooled to 0 ° C and treated with a pre-cooled (0 ° C) sodium azide solution (14.04 g, 399.5 mmol) and NaOH (15.98 g, 399.5 mmol ) in water (200 ml) dropwise. The resulting reaction mixture was allowed to warm to room temperature with stirring overnight, then quenched with saturated aqueous NH ₄ Cl and extracted with EtOAc (500 mL). The aqueous layer was separated and extracted with EtOAc (2x300 ml). The combined organic layers were washed with water and saturated aqueous NaCl, dried over MgSO ₄ , filtered and concentrated to give crude trans-4-allyl-3-azido-1- (tert-butoxycarbonyl) pyrrolidine-3 carboxylic acid (4, crude compound, 45 d), which was used without further purification.

1 H-NMR (CDCl 3, 400 MHz): δ H: 5.80 (1H, m); 5.06 (2H, m); 4.05 (1H, dd, J = 9.9; 4.9Hz); 3.59 (2H, m); 3.22 (1H, dd, J = 11.6; 4.4Hz); 3.08 (1H, dd, J = 11.0; 5.2 Hz); 2.24-2.04 (2H, m); 1.65 (1H, br s, OH) and 1.45 (9H, s).

Trans-3-benzyl-1 - (tert-butyl) -4-allyl-3-azidopyrrolidine-1,3-dicarboxylate

Vos Vos

5a

A solution of crude trans-4-allyl-3-azido-1- (tert-butoxycarbonyl) pyrrolidine-3-carboxylic acid (4, 39.5 g, 133 mmol - calculated amount assuming 100% yield from the previous steps) and K ₂ CO ₃ (92.04 g, 666 mmol) in acetonitrile (317 ml) was cooled to 0 ° C and treated with benzyl bromide (17.52 ml, 146.5 mmol). After stirring overnight at room temperature, the solution was concentrated, dissolved in EtOAc (600 ml), washed with saturated aqueous NaCl, dried over MgSO4, filtered and concentrated. Purification by silica gel chromatography (10 to 30% EtOAc in hexane) gave trans-3-benzyl-1- (tert-butyl) -4-allyl-3-azidopyrrolidine-1,3-dicarboxylate as a yellow liquid (5, 40 d, yield 78%).

The product was separated into its enantiomers using a Chiral Technologies Chiralpak ADH column with isopropyl alcohol and hexane (2:98) as eluent. Analysis of the separated enantiomers using a Chiralpak ADH analytical column (4.6x250 mm) with the same eluent and a flow rate of 1.0 ml / min and UV detection (210 nm) gave the required enantiomer (3-benzyl-1- (tert-butyl) ( 3R, 4S) -4-allyl-3-azidopyrrolidine-1,3-dicarboxylate, 5а) with a retention time of 13.5 min and an undesirable enantiomer (3-benzyl-1- (tert-butyl) (3S, 4R) -4 α-allyl-3-azidopyrrolidine-1,3 dicarboxylate, 5b) with a time of 10.3 minutes, each with an enantiomeric excess of about 98%.

1 H-NMR (CDCl ₃ , 400 MHz): 6H: 7.37 (5H, s); 5.62 (1H, m); 5.25 (2H, m); 5.00 (2H, m); 3.88 (1H, dd, J = 37.2; 12.0 Hz); 3.58 (1H, ddd, J = 37.2; 11.0; 7.0 Hz); 3.42 (1H, dd, J = 21.4; 12.0 Hz); 3.28 (1H, ddd, J = 28.3; 11.0; 5.4 Hz); 2.41 (1H, m); 2.11 (1H, m); 1.80 (1H, m) and 1.44 (9H, s).

(3 R, 4S) -3-benzyl-1-tert-butyl-3-azido-4- (3 - (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) propyl ) pyrrolidine-1,3-dicarboxylate (6)

Stirred solution of 3-benzyl-1- (tert-butyl) (3R, 4S) -4-allyl-3-azidopyrrolidine-1,3-dicarboxylate (5а, 16.4 g, 42.4 mmol) in anhydrous methylene chloride (130 ml) in a nitrogen atmosphere were treated with bis (1,5-cyclooctadiene) diiridium (I) dichloride (0.75 g; 1.12 mmol) and 1.2bis (diphenylphosphino) ethane (0.894 g, 2.24 mmol), and the reaction mixture was stirred for 30 min at room temperature and then cooled to -25 ° C. 4,4,5,5-tetramethyl [1,3,2] dioxaborolane (9.83 ml; 67.75 mmol) was added dropwise and then the reaction mixture was allowed to slowly warm to room temperature and stirred for 20 h. Water was added (60 ml) and the reaction mixture was stirred for 10 min and then the methylene chloride was removed under reduced pressure. The remaining aqueous phase was extracted with ethyl acetate (3x100 ml). The combined organic phase was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The remaining solid was passed through a small pad of silica gel eluting with 15-30% ethyl acetate in hexane to give (3R, 4S) -3-benzyl-1-tert-butyl-3-azido-4- (3- (4.4, 5,5-tetramethyl-1,3,2-dioxaborolan2-yl) propyl) pyrrolidine-1,3-dicarboxylate (6; 12.5 g, 57%).

1H-NMR (CDCl3, 400 MHz): 6H: 7.35 (5H, m); 5.23 (2H, m); 3.85 (1H, dd, J = 39.3; 11.8 Hz); 3.60 (1H, m); 3.37 (1H, dd, J = 24.3; 11.8 Hz); 3.25 (1H, ddd, J = 40; 10.6; 6.6 Hz); 2.33 (1H, m); 1.43 (9H, s); 1.39-1.26 (3H, m); 1.21 (12H, s); 1.07 (1H, m) and 0.68 (2H, m).

(3R, 4S) -3-Benzyl-3-azido-4- (3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) propyl) pyrrolidine-3-carboxylate, trifluoroacetic salt acid (7).

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A solution of (3R, 4S) -3-benzyl-1-tert-butyl-3-azido-4- (3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2yl) propyl) pyrrolidine -1,3-dicarboxylate (6; 10.2 g, 19.8 mmol) was dissolved in anhydrous methylene chloride (160 ml), cooled to 0 ° C and treated with trifluoroacetic acid (40 ml). Then, the reaction mixture was allowed to warm, stirred at room temperature for 4 hours, and then concentrated under reduced pressure to give a viscous oil. The resulting oil was subjected to azeotropic distillation with dry toluene (3x100 ml) to remove residual trifluoroacetic acid and then dried under high vacuum to give (3R, 4S) -3-benzyl-3-azido-4- (3- (4,4,5 , 5-tetramethyl-1,3,2-dioxaborolan-2-yl) propyl) pyrrolidine-3-carboxylate, trifluoroacetic acid salt (7) as a very viscous oil (10.56 g), which slowly turns to glass.

1H-NMR (CDCl3, 400 MHz): δΗ: 9.7 (1H, br m (exch), NH); 7.55 (1H, br s (exch), NH); 7.38 (5H, m); 5.31 (1H, d, J = 11.7Hz); 5.26 (1H, d, J = 11.7Hz); 3.77 (1H, d, J = 12.5Hz); 3.65 (1H, dd, J = 11.8; 7.8 Hz); 3.32 (1H, d, J = 12.4Hz); 3.18 (1H, m); 2.54 (1H, m); 1.45-1.26 (3H, m); 1.22 (12H, s); 1.02 (1H, m) and 0.63 (2H, t, J = 7.4Hz).

(3R, 4S) -benzyl-3-azido-1 - ((S) -2 - ((tert-butoxycarbonyl) amino) propanoyl) -4- (3- (4,4,5,5-tetramethyl-1, 3,2-dioxaborolan-2-yl) propyl) pyrrolidine-3-carboxylate (8)

A solution of the salt of TFA (3R, 4S) -benzyl-3-azido-4- (3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2yl) propyl) pyrrolidine-3-carboxylate (7 ) (31.43 g, 59.48 mmol) in anhydrous dichloromethane (400 ml) was stirred at room temperature under a dry nitrogen atmosphere. Triethylamine (33.1 ml, 237.9 mmol), DMAP (200 mg; 1.64 mmol) and HOBt (200 mg; 1.49 mmol) were added and then the reaction mixture was cooled to 0 ° C. Boc-L-alanine (16.88 g, 89.22 mmol) was added as a solid in one portion, and then EDCI (17.1 g, 89.22 mmol) was added in 3 portions at 0 ° C. The reaction mixture was stirred at 0 ° C for 1 h and then allowed to warm to room temperature and stirred overnight at this temperature.

The reaction mixture is poured into 300 ml of saturated ammonium chloride solution, separated, and then the aqueous phase (3x100 ml) was extracted with dichloromethane. The combined organic phase was washed with water (200 ml), brine (2x200 ml), dried over magnesium sulfate, filtered and concentrated in vacuo to give a pale yellow oil. The reaction mixture was purified on silica gel eluting with a gradient of ethyl acetate (20-50%) in hexane to afford the title compound (8) as a colorless oil (30.10 g, 51.41 mmol, 86%) as a mixture of rotamers.

1 H-NMR (400 MHz, CDCl 3), δ: 7.30 (5H, s); 5.35 (1H, dd, J = 13.5, 8Hz, NH); 5.25 (2H, m); 4.35 (1H, m); 4.12-3.30 (4H, m); 2.42 (1H, m); 1.45 (9H, s); 1.37-1.18 (18H including (3H, d, J = 6.5 Hz) and 1.22 (12H, s)), 1.07 (1H, m) and 0.68 (2H, m ). LCMS (ESI + ve) C ₂₉ H44BN ₅ O ₇ m / z calcd 585.33, found 586.5 (MH +); 530.5 (MH ⁺ -iBu); 486.5 (MH ⁺ -Boc).

(3R, 4S) -benzyl-1 - ((S) -2-aminopropanoyl) -3-azido-4- (3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2yl) propyl) pyrrolidine-3-carboxylate, TFA salt (9).

A solution of (3R, 4S) -benzyl-3-azido-1 - ((S) -2 - ((tert-butoxycarbonyl) amino) propanoyl) -4- (3- (4,4,5,5tetramethyl) -1, 3,2-dioxaborolan-2-yl) propyl) pyrrolidine-3-carboxylate (8) (30.04 g, 51.31 mmol) in anhydrous dichloromethane (250 ml) was cooled to 0 ° C and then the TFA solution (50 ml )) in dichloromethane (50 ml) was added dropwise over 10 min. The solution was allowed to warm to room temperature and then stirred at this temperature for 3 hours until TLC showed complete consumption of starting material. The reaction mixture was concentrated in vacuo to give a pale yellow oil. This oil was dissolved in toluene (100 ml) and concentrated. The azeotropic procedure was repeated three times to give the product as a TFA salt (30.85 g) as a pale yellow oil.

1 H-NMR (400 MHz, D ₄ -MeOH) δ: 7.39 (4H, m); 7.15 (1H, m); 5.29 (2H, dd, J = 14.12Hz); 4.25-3.20 (5H,

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m); 2.51 (1H, m); 1.50-1.25 (6H, including 1.47 (1.5H, d, J = 7.0 Hz) and 1.31 (1.5H, d, J = 6.9 Hz (alanine rotamers)) ); 1.20 (12H, s)); 1.07 (1H, m) and 0.65 (2H, m). LCMS (ESI + ve) C ₂₄ H ₃₆ BN ₅ O ₅ m / z calculated 485.3;

established 486.2 (MH +).

(3 - ((3 S, 4R) -1 - ((S) -2-aminopropanoyl) -4-azido-4 - ((benzyloxy) carbonyl) pyrrolodin-3-yl) propyl) boronic acid, hydrochloride salt (11 HCl).

(3R, 4S) -benzyl-1 - ((S) -2-aminopropanoyl) -3-azido-4- (3- (4,4,5,5-tetramethyl-1,3,2-) dioxaborolane TFA salt -2-yl) propyl) pyrrolidine-3-carboxylate (9) (30.76 g, 51.31 mmol) was dissolved in a biphasic mixture of methanol (200 ml) and hexane (400 ml). Isobutylboronic acid (18.31 g, 179.6 mmol) was added followed by 2N hydrochloric acid (50.85 mL, 101.7 mmol). The reaction mixture was vigorously stirred at room temperature for 16 hours. The methanol phase was separated and washed with hexane (5x100 ml) and then concentrated in vacuo to give boronic acid (11 HCl) as the hydrochloride salt as an off-white foam.

1 H-NMR (400 MHz, D2 O) δ: 7.48-7.42 (5H, m); 5.31 (2H, m); 4.22 (1H, dd, J = 13; 6.5Hz); 3.95-3.10 (4H, m); 2.71-2.51 (1H, m); 1.40-1.25 (3H, m); 1.25-0.98 (4H, m including 1.20 (1.5H, d, J = 6.9 Hz) and 1.07 (1.5H, d, J = 6.9 Hz (alanine rotamers) )) and 0.69 (2H, m). LCMS (ESI + ve) C ₁₈ H ₂₆ BN ₅ O ₅ m / z calculated 403.2; installed 404.2 (MH +).

(3 - ((3 S, 4R) -1 - ((S) -2-aminopropanoyl) -4-azido-4 - ((benzyloxy) carbonyl) pyrrolodin-3-yl) propyl) boronic acid (11).

(3 - ((3 S, 4R) -1 - ((S) -2-aminopropanoyl) -4-azido-4 - ((benzyloxy) carbonyl) pyrrolodin-3-yl) propyl) boronic acid hydrochloride salt (11 HCl) from the previous step was dissolved in 30 ml of water, and then the pH of the solution was brought to 9 by the careful addition of solid potassium carbonate. The resulting solution was saturated by the addition of solid sodium chloride and then extracted with dichloromethane (5x100 ml). The combined dichloromethane phase was dried over magnesium sulfate, filtered and concentrated in vacuo to give product 11 as its free base as a white foamy solid (19.4 g, 48.11 mmol, 94%).

'H-NMR (400 MHz, Pd-MeOH); δ: 7.44-7.36 (5H, m); 5.31 (1H, d, J = 1.8Hz); 5.27 (1H, d, J = 1.8Hz); 4.05 (1H, dd, J = 12.5 Hz); 3.80 (1H, m); 3.69-3.55 (2H, m); 3.45-3.30 (1H, m); 2.51 (1H, m; 1.40-1.05 (7H, m, including 1.22 (1.5H, d, J = 6.8 Hz) and 1.07 (1.5H, d, J = 6.8 Hz (alanine rotamers))) and 0.63 (2H, m) LCMS (ESI + ve): C ₁₈ H ₂₆ BN ₅ O ₅ m / z calculated 403.2; found 404.7 (MH +).

(3R, 4S) -3-amino-1 - ((S) -2-aminopropanoyl) -4- (3-boronopropyl) -yl) pyrrolidine-3-carboxylate (10)

(3 - ((3 S, 4R) -1 - ((S) -2-aminopropanoyl) -4-azido-4 - ((benzyloxy) carbonyl) pyrrolodin-3-yl) propyl) boronic acid azidobenzyl ester 11 (9 , 70 g, 24.06 mmol) was suspended in a mixture of water (300 ml) and ethyl acetate (30 ml) and stirred vigorously. Added 10% palladium-carbon (2.6 g, 0.1 eq.) And then the stirred mixture was evacuated in a weak vacuum and purged with hydrogen. The evacuation / washing procedure was repeated 3 times to remove air and replace it with hydrogen, and then the reaction mixture was stirred vigorously overnight at room temperature under a hydrogen balloon, after which LC-MS analysis of the filtered aliquot showed complete reduction of the azide and benzyl ether groups. The reaction mixture was placed under vacuum to remove hydrogen and then purged with nitrogen, filtered through a pad of celite (with 3 washes with water) and then the solution was concentrated in vacuo to approximately 50 ml. The resulting aqueous solution was filtered through a 4 micron filter (to remove traces of Pd) and then concentrated in vacuo to give the title compound 10 as a white powder (6.45 g, 93%).

'H-NMR (400 MHz, D2O) δ: 4.12 (1H, m); 4.05 (1H, m); 3.92 (1H, m); 3.60-3.22 (2H, m); 2.47-2.18 (1H,

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m); 1.58-1.31 (6H, m including 1.46 (3H, d, J = 6.9Hz)); 1.24-1.19 (1H, m) and 0.79 (2H, m). LCMS (ESI + ve):

C11H20BN3O5 m / z calcd 287.2; found 269.9 (MH + -H2O); 251.9 (MH + -2H2O) and (ESI-ve):

C ₁₁ H ₂₀ BN ₃ O ₅ m / z calculated 287.2; established 267.7 (M-H-H2O).

Conversion of 10 to ethanolate 10e is as described in Example 1 above.

(3R, 4S) -3-amino-1 - ((S) -2-aminoacetyl) -4- (3-boropropyl) -yl) pyrrolidine-3-carboxylate (12) and (6aS, 9aR) -8- ( 2-aminoacetyl) -9а-amino-3-ethoxyoctahydro- [1,2] oxaborocino [6,7-c] pyrrol-1 (3H) -one 12е

Compound 12 was prepared as described for 10 in Example 2 using Boc glycine as a binding partner with 7. Compound 12 (1.0 g, 3.7 mmol) was suspended in sufficient anhydrous ethanol (-40 ml) to completely dissolve material at 80 ° C. This solution was heated at 80 ° C for 2 hours under a dry nitrogen atmosphere. The reflux heater was replaced with a small reflux condenser and the reaction mixture was distilled (at atmospheric pressure with a DRIERITE® drying tube attached to remove moisture) until the hot solution became cloudy (approximately 20 ml ethanol was collected during distillation). Anhydrous ethanol (20 ml) was added, and then the reaction mixture was heated to 80 ° C and stirred at 80 ° C for another 4 h. The distillation process was repeated until the solution became cloudy (–20 ml of distillate was collected). This was repeated once more and the suspension was allowed to cool to room temperature. The solid was collected by filtration and quickly dried under vacuum and then further dried under high vacuum (38 mTorr) at room temperature for 2 hours to give the product as an off-white powder (986 mg) as a 2: 1 mixture of rotamers.

¹ H-NMR (400 MHz, (16-DMSO (rotamer population 2: 1)) δ: 6.73-7.31 (4H; exch); 3.84 (1H; m); 3.573.71 (3H; m); 3.48-3.21 (3H; m); 3.05 (0.67 H; dd; J = 11.8; 9.7 Hz); 2.88 (0.33H; t; J = 11.5 Hz); 2.48-2.35 (1H; m); 1.67-1.83 (2H; m); 1.52-1.41 (1H; m); 1.09- 1.03 (3H; m); 0.97 (1H; m); 0.67 (1H; dd; J = 14.9; 5.6Hz; BCHH) and 0.42 (1H; m; BCHH) ,

11B-NMR (400 MHz; DMSO) δ: 7.78 cpm, FTIR (powder diffraction) (cm ^-1 ): 2912 (w); 1720 (s); 1645 (s); 1463 (s); 1269 (s); 1102 (s); 1063 (m); 1037 (m); 660 (s) and 573 (s).

Example 4. Typical Cyclic Alcoholates

The following compounds were prepared as in Example 1 (i.e. conversion from 10 to 10e) by heating with an appropriate anhydrous alcohol under conditions that removed water, such as azeotropic distillation

Example 5. Synthesis of selected compounds of the invention (6aS, 9aR) -9a-amino-8 - ((S) -2-amino-3-hydroxypropanoyl) -3-ethoxyoctahydro- [1,2] oxaborocino {6,7-c } pyrrole-1 {3Chone (R1 = CH ₂ OH, R ₂ = Et).

(6aS, 9aR) -9a-amino-8 - ((S) -2-amino-hydroxypropanoyl) -3-ethoxyoctahydro- [1,2] oxaborocino {6,7c} pyrrole-1 {3CHon (R1 = CH ₂ OH , R ₂ = Et) was prepared according to the general procedure using serine-108 038517 mid (3R, 4S) -3-amino-1 - ((S) -2-amino-3-hydroxypropanoyl) -4- (3- boronopropyl) yl) pyrrolidine-3-carboxylate as a starting material and ethanol as an alcoholic solvent, and was isolated as a pale yellow powder;

¹ H-NMR (400 MHz, d ₆ -DMSO (3: 2 rotamer population)) δ: 6.86-6.97 (2H; exch); 3.84 (2H; m); 3.603.68 (1H; m); 3.48-3.35 (4H; m); 3.22 (1H; m); 3.11 (0.6H; dd; J = 11.2; 10.4Hz) and 2.80 (0.4H; t; J = 11.6Hz); 2.36 (0.6H; m) and 2.31 (0.4H; m); 1.83-1.65 (2H; m); 1.48-1.36 (1H; m); 1.08-1.03 (3H; m; CH ₃ CH ₂ O); 0.96 (1H; m); 0.64 (1H; dd; J = 14.0; 4.5 Hz; BCHH) and 0.41 (1H; m; BCHH), ¹¹ B-NMR (400 MHz; DMSO) δ: 7.62 counts. / min, FTIR (powder diffraction) (cm ^-1 ): 1627 (s); 1459 (m); 1365 (m); 1063 (s); 589 (m).

(6aS, 9aR) -9a-amino-8 - ((S) -2-aminopropanoyl) -3-isopropoxyoctahydro- [1,2] oxaborocino {6,7c} pyrrole-1 {3H} one (R ₁ = Me; R ₂ = i-Pr).

(6aS, 9aR) -9a-amino-8 - ((S) -2-aminopropanoyl) -3-isopropoxyoctahydro- [1,2] oxaborocino {6,7c} pyrrole-1 {3H} one (R | Me; R2 = Et) was prepared according to the general procedure using alaninamide (3R, 4S) -3-amino-1 - ((S) -2-aminopropanoyl) -4- (3-boronopropyl) -yl) pyrrolidine-3-carboxylate in as starting material and 2-propanol as alcoholic solvent, and was isolated as a pale yellow powder, ¹ H-NMR (400 MHz, d ₆ -DMSO (3: 2 rotamer population)) δ: 6.64-6.87 (2H ; exch); 3.73-3.81 (1H; m); 3.56-3.66 (1H; m); 3.37-3.49 (2H; m); 3.16 (1H; d; J = 12.9Hz); 3.10 (0.6H; dd; J = 10.8; 9.6Hz) and 2.78 (0.4H; t; J = 11.6Hz); 2.43 (0.6H; m) and 2.31 (0.4H; m); 1.69 (2H; m); 1.40 (1H; m); 1.07 (3H; d; J = 6.9Hz; CH3CHO); 1.02 (3H; m); 1.00 (3H; d; J = 6.1Hz; CH3CHO); 0.95 (1H; m); 0.55 (1H; dd; J = 14.7; 5.6 Hz; BCHH) and 0.38 (1H; m; BCHH), ^p B-NMR (400 MHz; DMSO) δ: 8.24 counts. / min, FTIR (powder diffraction) (cm ^-1 ): 1723 (s); 1618 (s); 1459 (s); 1269 (s); 1129 (s); 1074 (m); 653 (m) and 579 (m).

(6aS, 9aR) -9a-amino-8 - ((S) -2-aminopropanoyl) -3-propoxyoctahydro- [1,2] oxaborocino {6,7-c} pyrrole-1 {3H} one (R ₁ = Me, R ₂ = n-Pr).

(6aS, 9aR) -9a-amino-8 - ((S) -2-aminopropanoyl) -3-propoxyoctahydro- [1,2] oxaborocino {6,7-c} pyrrole-1 {3H} one (R ₁ = Me, R2 n-Pr) was prepared according to the general procedure using alaninamide (3R, 4S) -3-amino-1 - ((S) -2-aminopropanoyl) -4- (3-boropropyl) -yl) pyrrolidine- 3-carboxylate as starting material and 1-propanol as alcohol solvent, and isolated as a pale yellow powder, ¹ H-NMR (400 MHz, d ₆ -DMSO (3: 2 rotamer population)) δ: 6.85-6 , 92 (2H; exch); 3.81 (1H; dd; J = 11.5; 6.3 Hz); 3.67 (0.6H; dd; J = 9.6; 6.3 Hz) and 3.61 (0.4H; dd; J = 11.3; 7.8 Hz); 3.51 (1H; m); 3.42-3.32 (2H; m) 3.20 (1H; d; J = 12.6Hz); 3.12 (0.6H; dd; J = 11.7; 9.8 Hz) and 2.79 (0.4H; t; J = 11.6 Hz); 2.40 (0.6H; m) and 2.31 (0.4H; m); 1.82-1.69 (2H; m); 1.48-1.36 (3H; m); 1.08 (3H; m; CH3CHN); 0.96 (1H; m); 0.85-0.80 (3H; m); 0.63 (1H; dd; J = 14.6; 5.4 Hz; BCHH) and 0.41 (1H; m; BCHH).

Example 6. Studies of Oral Bioavailability and Enzymatic Activity

Dosing solutions of compounds were prepared at concentrations of 2.5 and 5 mg / ml in water. Female C57BL / 6 mice (16-20 g) from Charles River Laboratories (Hollister, Calif.) Were caged for at least 3 days prior to dosing. The diet for irradiated rodents, PicoLab 5053, was provided ad libitum throughout the study. The compounds were administered once by gavage to the appropriate animals at a dose of 25 or 50 mg / kg (10 ml / kg). Blood samples were collected (from 3 animals at each time point) 30 minutes and 1, 2, 4, 8 hours after dosing for 25 mg / kg studies and 1 hour for 50 mg / kg studies. Blood samples were kept on wet ice and then centrifuged for 10 min in a refrigerated centrifuge. The resulting plasma was separated, transferred to labeled polypropylene tubes and stored frozen in a freezer set to maintain at -70 ° C until analysis.

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Plasma samples were analyzed using an LC-MS system. 50 μl of plasma sample was mixed with

100 μl acetonitrile / water (80:20) with 0.1% TFA containing 100 ng / ml internal standard. The mixture was shaken and centrifuged. 30 μl of the supernatant was transferred to a 96-well plate containing 90 μl of water with 0.1% formic acid. 20 μl of the resulting solution was injected into the system

SCIEX QTRAP4000 LC / MS / MS equipped with electrospray ionization source for quantitative determination.

Oral pharmacokinetic parameters were calculated by non-compartmental analysis of concentration-time data using Phoenix WinNonLin 6.3 software (Pharsight, Mountain View, CA). The area under the concentration-time curve (AUC) was estimated using the linear-logarithmic trapezoidal method, calculated from the time of dose administration to the last measured concentration.

Inhibition of human arginase-1 was determined using the assay described in Van Zandt et al., J Med. Chem. 2013, 56, 2586-2580, with the following modifications: Human recombinant arginase I was purchased from Enzo Life Sciences and tested at a final concentration of 80 ng / ml in a total reaction volume of 25 μl. The reaction buffer was phosphate buffered saline supplemented with 0.01% Tx-100, 0.5 mM DTT, 0.1 mM CaCl ₂ and 0.49 mM MgCl ₂ . After the addition of the diluted inhibitor compounds, reactions were initiated by adding the substrate L-arginine to a final concentration of 20 mM, followed by incubation at 37 ° C for 30 min. Reactions were stopped and urea production was measured by adding 150 μl of a urea developer solution from BioAssay Systems.

The AUC and IC ₅₀ values of arginase-1 inhibition for typical compounds are shown below:

Compared to proline, trifluoromethylphenylalanine and compounds - derivatives of N methylphenylalanine, oral exposure for derivatives of alanine, valine and serine is more pleasant.

Example 7. Pharmacokinetic studies

The pharmacokinetics of the compounds of the present invention were studied after administration of a single dose (50 mg / kg) at one time point (1 hour) to mice. Plasma concentrations were determined as described in Example 4. Results for representative compounds are shown below. IC _{50 of} arginase-1 are given for selected compounds. For these cases, the active isomer was prepared and used to determine the IC ₅₀ .

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- 111 038517

Example 8 Antitumor Activity of a Single Agent of Compound 10.

Lewis Lung Carcinoma Efficacy Study

Female C57.B1 / 6 mice (n = 40) were subcutaneously implanted with 1x106 Lewis lung carcinoma cells suspended in PBS. On the day after implantation, mice were randomly assigned to 4 groups of n = 10 mice to receive the following treatments, when administered orally twice daily until the end of the study: (1) vehicle (water); (2) Compound 10 at a concentration of 50 mg / kg in water; (3) Compound 10 at a concentration of 100 mg / kg in water; or (4) Compound 10 at a concentration of 200 mg / kg in water. Tumors were measured three times per week using digital calipers and tumor volumes were calculated using the following formula: tumor volume (mm ³⁾ = (axb ^2/2), where b - diameter of the smallest and a largest diameter perpendicular. *** P-value <0.001, ^^ P-value <0.0001 (two-sided T-test). The results are shown in FIG. 3.

Efficiency study on the Madison109 model

Female balb / c mice (n = 20) were subcutaneously implanted with 5x104 Madison109 mouse lung carcinoma cells suspended in PBS. On the day after implantation, mice were randomly assigned to 2 groups of n = 10 mice to receive the following treatments, when administered orally twice daily until the end of the study: (1) Vehicle (water); or (2) Compound 10 at a dose of 100 mg / kg formulated in water. Tumors were measured three times per week using digital calipers and tumor volumes were calculated using the following formula: tumor volume (mm ³⁾ = (axb ^2/2), where b - the smallest diameter, and a - the greatest perpendicular diameter. * P-value <0.05 (two-sided Ttest). The results are shown in FIG. 4.

Efficiency study on the B16 model

Female C57.B1 / 6 mice (n = 20) were subcutaneously implanted with 2x106 B16F10 murine melanoma cells suspended in PBS. On the day after implantation, mice were randomly assigned to 2 groups of n = 10 mice to receive the following treatments, when administered orally twice daily until the end of the study: (1) Vehicle (water); or (2) Compound 10 at a dose of 100 mg / kg formulated in water. Tumors were measured three times per week using digital calipers and tumor volumes were calculated using the following formula: tumor volume (mm ³⁾ = (axb ^2/2), where b - the smallest diameter, and a - the greatest perpendicular diameter. *** P-value <0.001 (two-sided T test). The results are shown in FIG. 5.

Example 9. Studies of 4T1 Combination Therapy

Female balb / c mice (n = 40) were implanted in the mammary fat pad with 1x105 4T1 mouse mammary carcinoma cells suspended in PBS. On the day after implantation, mice were randomly assigned to 4 groups of n = 10 mice each to receive the following treatments: (1) vehicle (water) administered orally twice daily until the end of the study; (2) Compound 10 at a dose of 100 mg / kg in water, administered orally twice a day until the end of the study; (3) Combination of anti-PD-1 (clone RMPI-14) administered intraperitoneally at a dose of 5 mg / kg on days 3, 6 and 9 after implantation plus anti-CTLA-4 (clone 9H10) administered intraperitoneally at a dose of 5 mg / kg on days 2, 5, and 8 post-dose; or (4) a triple combination of Compound 10 plus anti-PD-1 plus anti-CTLA4 in their respective treatment regimens. Tumors were measured three times a week using digital calipers, and tumor volumes were calculated using the following formula: tumor volume

- 112 038517 (mm ³⁾ = (ahb ^2/2), where b - the smallest diameter, and a - the greatest perpendicular diameter.

*** P-value <0.001 (two-tailed T-test). On the 25th day, mice were sacrificed and the lungs were perfused with Indian ink (25% in PBS), then collected and fixed in a mixture of 100% ethanol: 10% neutral buffered formalin: acetic acid in a ratio of 10: 1: 0.5. The number of lung metastases was manually counted in a blind manner. The results are shown in FIG. 6.

Example 10. Study by thermogravimetric analysis (TGA) for compound 10e.

In a TGA study, a weighed amount of compound 10e was treated with an increasing amount of water vapor (increased humidity) and the effect of humidity on the sample weight was evaluated. FIG. 7 shows an adsorption isotherm (top line) and a desorption isotherm (bottom line) for compound 10e. As shown in FIG. 7, the TGA graph of compound 10e shows that the compound resists water absorption up to about 60% relative humidity. The low moisture absorption of compound 10e greatly facilitates the manufacture of the compound and the preparation of pharmaceutical compositions containing the compound.

In the event of a conflict between this application and any publication mentioned herein, this application, including any definitions in this document, will prevail.

Claims (38)

CLAIM 1. A compound having the structure of formula (I *) or a pharmaceutically acceptable salt thereof; wherein R ¹ is methyl and R4 is H or (C ₁ -C ₆ ) alkyl. 2. A compound having the structure of formula (Ie) cr ^R4 o'U 0 = / \ R ^b HN4? ^X C) - NH R ¹ R ³ (Ie); or a pharmaceutically acceptable salt thereof; wherein X is O; R1 is methyl; R ⁴ is H or (C ₁ -C ₆ ) alkyl; R ^b represents H and R ³ represents H. 3. A compound according to claim 1 or 2, wherein R ⁴ is H. 4. A compound according to claim 1 or 2, wherein R ⁴ is (C ₁ -C ₆ ) α-alkyl. 5. A compound according to claim 4 wherein R ⁴ is methyl. 6. A compound according to claim 4 wherein R ⁴ is ethyl. 7. A compound according to claim 4 wherein R ⁴ is propyl. 8. A compound according to claim 4 wherein R ⁴ is isopropyl. 9. A compound having the structure of formula (Ie) o ' ^R4 oX 0 = / \ R ^b HN4? ^χ = (y — NH R ¹ R ³ (Ie); or a pharmaceutically acceptable salt thereof; wherein - 113 038517 X is O; R ¹ is methyl; R4 is ethyl; R ^b represents H and R ³ represents H. 10. A compound having the structure of formula (Ie) or a pharmaceutically acceptable salt thereof; wherein X is O; R ¹ is methyl; R4 is isopropyl; R ^b represents H and R ³ represents H. 11. A pharmaceutical composition comprising a compound according to any one of claims 1-10 and a pharmaceutically acceptable carrier. 12. Use of a compound according to any one of claims 1-10 for the treatment of cancer. 13. Use of a pharmaceutical composition according to claim 11 for the treatment of cancer. 14. Use according to claim 12 or 13, wherein the cancer is selected from acute myeloid leukemia (AML), adrenocortical carcinoma, bladder cancer, breast cancer, colorectal cancer, chronic myelogenous leukemia (CML), esophageal cancer, stomach cancer, lung cancer , melanoma, mesothelioma, non-small cell lung cancer (NSCLC), ovarian cancer, pancreatic cancer, prostate cancer, kidney cancer, skin cancer, bile duct cancer, multiple myeloma, adrenal cancer, head and neck cancer, and endometrial cancer. 15. Use according to claim 14, wherein the cancer is selected from bladder cancer, colorectal cancer, esophageal cancer, stomach cancer, lung cancer, melanoma, mesothelioma, non-small cell lung cancer (NSCLC), ovarian cancer, kidney cancer, bile duct cancer, multiple myeloma, adrenocortical carcinoma, head and neck cancer, and endometrial cancer. 16. Use according to claim 15, wherein the cancer is bladder cancer. 17. Use according to claim 15, wherein the cancer is colorectal cancer. 18. Use according to claim 15, wherein the cancer is esophageal cancer. 19. Use according to claim 15, wherein the cancer is stomach cancer. 20. Use according to claim 15, wherein the cancer is lung cancer. 21. Use according to claim 15, wherein the cancer is melanoma. 22. Use according to claim 15, wherein the cancer is mesothelioma. 23. The use of claim 15, wherein the cancer is non-small cell lung cancer (NSCLC). 24. The use of claim 15, wherein the cancer is ovarian cancer. 25. Use according to claim 15, wherein the cancer is kidney cancer. 26. Use according to claim 15, wherein the cancer is bile duct cancer. 27. The use of claim 15, wherein the cancer is multiple myeloma. 28. Use according to claim 15, wherein the cancer is adrenocortical carcinoma. 29. Use according to claim 15, wherein the cancer is head and neck cancer. 30. Use according to claim 15, wherein the cancer is endometrial cancer. 31. A method of treating cancer, comprising co-administration of a compound according to any one of claims 1 to 10 with one or more additional chemotherapeutic agents selected from aminoglutethimide, amsacrine, anastrozole, asparaginase, AZD5363, axitinib, bacillus Calmet Guerin vaccine (bcg), bicalutamide, bleomicycin , bortezomib, buserelin, busulfan, campothecin, capecitabine, carboplatin, carfilzomib, carmustine, chlorambucil, chloroquine, cisplatin, cladribine, clodronate, cobimetinib, colchicine, cyclophosphamide, cyproterone, dystarabioxenomide, dystarabauetine, dystarabazetinamide, cyproterone, dystarabazuetinamide, dystarabazi , diethylstilbestrol, docetaxel, doxorubicin, epirubicin, erlotinib, estradiol, estramustine, etoposide, everolimus, exemestane, filgrastim, fludarabine, fludrocortisone, fluorouracil, fluoxymesterone, gemoferinamidecine, ibuprinamide, ibuproferin, ibuproferine, ibuproferin , lenalidomi yes, letrozole, leucovorin, leuprolide, levamisole, lomustine, lonidamine, mechlorethamine, medroxyprogesterone, megestrol, melphalan, mercapto- - 114 038517 purine, mesna, metformin, methotrexate, miltefosine, mitomycin, mitotane, mitoxantrone, MK2206, nilutamide, nocodazole, octreotide, olaparib, oxaliplatin, paclitaxel, pamidronate, pazopanicamid, perifosidin, pentostatalidomite , rituximab, rukaparib, selumetinib, sorafenib, streptozocin, sunitinib, suramin, thalazoparib, tamoxifen, temozolomide, temsirolimus, teniposide, testosterone, thalidomide, thioguanine, thiotep, tretanocene dichloride, viniloparine, tiotep, tretanocene dichloride, vindesine or vinorelbine. 32. The method of claim 31, wherein the one or more additional chemotherapeutic agents comprises gemcitabine. 33. The method of claim 31, wherein the one or more additional chemotherapeutic agents comprises abagovomab, adekatumumab, afutuzumab, alemtuzumab, anatumomab mafenatox, apolizumab, atezolizumab, avelumab, blinatumomab, BMS-936559, catumaxomab, epoxuma-durvaluma , ozogamicin, intelumumab, ipilimumab, isatuximab, lambrolizumab, MED14736, MPDL3280A, nivolumab, okaratuzumab, ofatumumab, olatatumab, pembrolizumab, pidilizumab, rituximab, talicillimumab, or. 34. The method of claim 31, wherein one or more additional chemotherapeutic agents comprises abagomab, adekatumumab, afutuzumab, anatumomab, mafenatox, apolizumab, blinatumomab, catumaxomab, durvalumab, epratuzumab, isotuzumab, ozogamicin, andpilumumumabiz, isotuzumab, ozogamicin andpilumumumabiz okaratuzumab, olatatumab, pembrolizumab, pidilizumab, ticilimumab, samalizumab, or tremelimumab. 35. The method of claim 31, wherein the one or more additional chemotherapeutic agents comprises ipilimumab, nivolumab, pembrolizumab, pidilizumab, or epacadoostat. 36. The method of claim 35, wherein the additional chemotherapeutic agent is epacadostat. 37. The method of any one of claims 12 to 36, wherein the method for treating cancer further comprises using one or more non-chemical methods for treating cancer. 38. The method of claim 37, wherein the one or more non-chemical cancer treatments are selected from radiation therapy, surgery, thermal ablation, focused ultrasound therapy, cryotherapy, or a combination thereof.