RU2841732C2 - Indanes as pd-l1 inhibitors - Google Patents

Abstract

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula (I) or (II) wherein Y and Y' are each independently selected from the group consisting of O and NH; R¹ is C_1-4 alkyl; each R^2a and R^2a' is independently selected from a group consisting of H, halogen, R^a, and OR^b, where each R^b is C_1-8 alkyl; and each R^a is C_1-8 alkyl; each R^2b, R^2c, R^2b' and R^2c' is independently H; R³ and R^3' each independently selected from a group consisting of -NR^dR^e and 4–6 membered monocyclic non-aromatic ring containing 1 N heteroatom, or 8–9 membered spirocyclic non-aromatic heterocyclic ring containing 1–3 N heteroatoms, optionally substituted with 1–2 substitutes R^3a; where R^d is selected from the group consisting of H and C_1-8 alkyl; R^e is selected from H, -C_1-8 alkyl, X²-CONHSO₂R^g, X²-SO₃R^g, C_3-10 cycloalkyl, C_4-6 heterocyclyl, containing 1 N heteroatom, and X²-C_4-6 heterocyclyl, containing 1 N heteroatom; wherein the alkyl or alkylene part R^e is optionally further substituted with 1-3 substituents independently selected from OH, COOH, CONH₂, and COO-C_1-8 alkyl; and C_4-6 heterocyclyl and C_3-10 cycloalkyl fragments R^e optionally substituted with 1 substitute R^w; each R^3a is independently selected from a group consisting of an oxo group, -R^f, and OC(O)R^g, X² is C_1-6 alkylene and optionally further has a substituent OH; each R^g is independently selected from a hydrogen atom, C_1-8 alkyl, optionally substituted with 1–2 substituents selected from NH₂; each R^f is independently selected from the group consisting of -OH and C_1-8 alkyl; each R^w is independently selected from OH, and oxo group; R⁴ and R^4' each is independently selected from a group consisting of OC_1-8 alkyl, -OC_1-4 alkyl-C₆aryl, and -OC_1-4 alkyl-C₆ heteroaryl containing 1 N heteroatom, each of which optionally has 1–2 substituents R^4a; each R^4a is independently selected from the group consisting of CN; where each n is independently equal to 0; R^6a and R^6a' each is independently selected from H; each m is independently 0 or 1; and each R^6b and R^6b' is independently selected from F. Invention also relates to a pharmaceutical composition for inhibiting PD-L1, containing a compound of formula (I) or (II).

EFFECT: compounds of formula (I) or (II) possessing PD-L1 inhibition for treating PD-L1 mediated diseases.

20 cl, 1 tbl, 1 ex

Description

Prior art

Programmed cell death protein 1 (PD-1) is a member of the CD28 superfamily that mediates negative signals when interacting with its two ligands, PD-L1 or PD-L2. PD-1 and its ligands are widely expressed and perform a number of immunoregulatory functions in T cell activation and tolerance. PD-1 and its ligands are involved in the attenuation of immunity to infections and immunity to tumors, and contribute to the development of chronic infections and tumor progression.

Modulation of the PD-1 signaling pathway has therapeutic potential in a variety of human diseases (Hyun-Tak Jin et al., Curr Top Microbiol Immunol. (2011); 350:17–37). Blockade of the PD-1 signaling pathway has emerged as an attractive target in cancer therapy. Therapeutic antibodies that block the immune checkpoint protein programmed cell death-1 (PD-1) prevent the decline in T cell production and promote an immune response against cancer. Several PD-1 pathway inhibitors have shown potent activity in different phases of clinical trials (RD Harvey, Clinical Pharmacology and Therapeutics (2014); 96(2), 214–223).

There is a need for agents that block the interaction of PD-L1 with PD-1 or CD80. Several antibodies have been developed and marketed. Several patent applications have been published disclosing non-peptide small molecules (WO 2015/160641, WO 2015/034820, and WO 2017/066227 and WO2018/009505 by Bristol-Myers Squibb; WO 2015/033299 and WO 2015/033301 by Aurigene; WO 2017/070089, US 2017/0145025, WO 2017/106634, US2017/0174679, WO2017/192961, WO2017/222976, WO2017/205464, WO2017/112730, WO2017/041899 and WO2018/013789 by Incyte, WO2018/006795 by Maxinovel and WO2018/005374 by ChemoCentryx). However, there is still a need for alternative compounds, such as small molecules, as PD-L1 inhibitors that have improved characteristics in terms of oral administration, stability, bioavailability, therapeutic index and toxicity.

Brief description of the invention

In one aspect, the present invention provides compounds having formula (I) or (II):

or a pharmaceutically acceptable salt, prodrug, or bioisostere thereof; where R¹, R^2a, R^2b, R^2c, R³, R⁴, R⁵, R^6a, R^6b, R^2a', R^2b', R^2c', R^3', R^4', R^5', R^6a', R^6b', Y, Y’ subscripts m and n have the meanings indicated in this text.

1. In addition to the compounds described herein, the present invention also includes pharmaceutical compositions comprising one or more of these compounds, as well as methods related to the preparation and use of these compounds. In some embodiments, the compounds described herein are used in therapeutic methods for the treatment of diseases associated with the PD-1/PD-L1 pathway.

Detailed description of the invention

Abbreviations and definitions

As used in the present text, the use of the singular covers not only single-representative aspects but also multi-representative aspects. For example, singular forms may refer to multiple representatives unless the context clearly indicates otherwise. Thus, for example, the word “cell” includes instances of multiple cells, and “agent” may refer to one or more agents known in the art, etc.

2. The terms “about” and “approximately” generally mean an acceptable degree of error for a measured value, taking into account the nature and precision of the measurement made. Typical examples of degrees of error are in the range of 20 percent (%), preferably in the range of 10%, and more preferably in the range of 5%, of the stated value or range of values. Alternatively, and particularly in biological systems, the terms “about” and “approximately” may mean values within one order of magnitude, preferably within 5 times, and more preferably within 2 times, the stated value. Numerical values given in this text are approximate unless otherwise stated, which means that the term “about” or “approximately” may be implied where it is not explicitly used.

_The term "alkyl", by itself or as part of another substituent, means, unless otherwise specified, a linear or branched hydrocarbon group having the designated number of carbon atoms (e.g., C _1-8 means 1-8 carbon atoms). Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like. The term "alkenyl" means an unsaturated alkyl group containing one or more double bonds. Similarly, the term "alkynyl" means an unsaturated alkyl group containing one or more triple bonds. Examples of alkenyl groups include vinyl, 2-propenyl, crotyl, 2-isopentenyl, 2-(butadienyl), 2,4-pentadienyl, 3-(1,4-pentadienyl). Examples of alkynyl groups include ethynyl, 1- and 3-propynyl, 3-butynyl and their higher homologues and isomers.

The term "cycloalkyl" refers to a hydrocarbon ring or rings having the stated number of ring atoms (e.g., C _3-6 cycloalkyl) that are fully saturated or contain no more than one double bond between ring members. The term "cycloalkyl" refers to bicyclic and polycyclic hydrocarbon rings such as, for example, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, etc. Bicyclic or polycyclic rings may be fused, bridged, spiro, or combinations thereof.

The term "heterocycloalkyl" or "heterocyclyl" refers to a cycloalkyl group containing 1-5 heteroatoms selected from N, O, and S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom(s) are optionally quaternized. Heterocycloalkyl may be a monocyclic, bicyclic, or polycyclic ring system. Bicyclic or polycyclic rings may be fused, bridged, spiro, or combinations thereof. Reference to, for example, 'C _4-12 heterocyclyl' means a group containing from 4 to 12 ring members, wherein at least one of the ring members is a heteroatom. Non-limiting examples of heterocycloalkyl groups include pyrrolidine, imidazolidine, pyrazolidine, butyrolactam, valerolactam, imidazolidinone, tetrazolone, hydantoin, dioxolane, phthalimide, piperidine, 1,4-dioxane, morpholine, thiomorpholine, thiomorpholine-S-oxide, thiomorpholine-S,S-oxide, piperazine, pyran, pyridone, 3-pyrroline, thiopyran, pyrone, tetrahydrofuran, tetrahydrothiophene, quinuclidine, and the like. The heterocycloalkyl group can be attached to the rest of the molecule through a carbon atom in the ring or a heteroatom in the ring.

The term "alkylene" alone or as part of another substituent means a divalent group derived from an alkane, an example being -CH ₂ CH ₂ CH ₂ CH ₂ -. The alkylene group may be linear or branched. Examples of the latter are -CH ₂ C(CH ₃ ) ₂ CH ₂ -, -CH ₂ C(CH ₃ ) ₂ - or -CH(CH ₃ )CH ₂ CH ₂ -. Typically, an alkyl (or alkylene) group contains from 1 to 12 carbon atoms, with groups containing 8 or fewer carbon atoms being preferred in the present invention. Similarly, "alkenylene" and "alkynylene" mean unsaturated forms of "alkylene" containing double or triple bonds.

The terms "alkoxy,""alkylamino," and "alkylthio" (or thioalkoxy) are used in their ordinary sense and refer to alkyl groups attached to the rest of the molecule through an oxygen atom, an amino group, or a sulfur atom, respectively. Additionally, for dialkylamino groups, the alkyl moieties may be the same or different and may combine to form a 3- to 7-membered ring with the nitrogen atom to which they are attached. Accordingly, the group depicted as -NR ^a R ^b includes piperidinyl, pyrrolidinyl, morpholinyl, azetidinyl, etc.

The term "halogen" by itself or as part of another substituent means, unless otherwise specified, a fluorine, chlorine, bromine or iodine atom. In addition, terms such as "haloalkyl" include monohaloalkyl and polyhaloalkyl. For example, the term "C _1-4 haloalkyl" includes trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, etc.

The term “hydroxyalkyl” or “alkyl-OH” means an alkyl group as defined above in which at least one (and up to three) hydrogen atoms are replaced by a hydroxy group. With respect to the alkyl group, hydroxyalkyl groups may contain any suitable number of carbon atoms, for example, C _1-6 . Examples of hydroxyalkyl groups include, but are not limited to, hydroxymethyl, hydroxyethyl (where the hydroxy group is in the 1 or 2 position), hydroxypropyl (where the hydroxy group is in the 1, 2 or 3 position) and 2,3-dihydroxypropyl.

The term "aryl" means, unless otherwise specified, a polyunsaturated, typically aromatic, hydrocarbon group which may be a single ring or multiple rings (up to three rings) conjugated or covalently linked.

The term "heteroaryl" means a 5-10 membered aromatic ring (or rings) containing one to five heteroatoms each selected from N, O, and S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom(s) are optionally quaternized. A heteroaryl group may be attached to the rest of the molecule through a heteroatom. By "C _5-10 heteroaryl" is meant a heteroaryl moiety containing 5-10 ring members, wherein at least one of the ring members is a heteroatom. Non-limiting examples of aryl groups include phenyl, naphthyl, and biphenyl, and non-limiting examples of heteroaryl groups include pyridyl, pyridazinyl, pyrazinyl, pyrimidinyl, triazinyl, quinolinyl, quinoxalinyl, quinazolinyl, cinnolyl, phthalazinyl, benzotriazinyl, purinyl, benzoimidazolyl, benzopyrazolyl, benzotriazolyl, benzisoxazalyl, isobenzofuryl, isoindolyl, indolizinyl, benzotriazinyl, thienopyridinyl, thienopyrimidinyl, pyrazolopyrimidinyl, imidazopyridines, benzothiaxolyl, benzofuranyl, benzothienyl, indolyl, quinolyl, isoquinolyl, isothiazolyl, pyrazolyl, indazolyl, pteridinyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiadiazolyl, pyrrolyl, thiazolyl, furyl, thienyl, etc. The substituents in each of the above aryl or heteroaryl ring systems are selected from the group of acceptable substituents described below.

When any of the above terms (e.g., "alkyl," "aryl," and "heteroaryl") are prefixed with the word "substituted" without further description of the substituents, the substituted forms of the indicated groups will be as described below.

Substituents for alkyl groups (including groups often referred to as alkylene, alkenyl, alkynyl and cycloalkyl) may be various groups selected from the following:
-halogen, -OR', -NR'R”, -SR', -SiR'R”R”’, -OC(O)R’, -C(O)R’, -CO ₂ R’, -CONR’R”,
-OC(O)NR'R”, -NR”C(O)R’, -NR’-C(O)NR”R”’, -NR”C(O) ₂ R', -NH-C(NH ₂ )=NH,
-NR'C(NH ₂ )=NH, -NH-C(NH ₂ )=NR', -S(O)R', -S(O) ₂ R', -S(O) ₂ NR'R”, -NR'S(O) ₂ R”, -CN and
-NO ₂ , in an amount from zero to (2m'+1), where m' is the total number of carbon atoms in such group. R', R" and R"' each independently represent a hydrogen atom, an unsubstituted _{C 1-8 alkyl} , unsubstituted heteroalkyl, unsubstituted aryl, aryl substituted with _1-3 halogens, unsubstituted C _1-8 alkyl, C _1-8 alkoxy or _{C 1-8 thioalkoxy} groups, or unsubstituted aryl- _{C 1-4 alkyl} groups. When R' and R" are attached to the same nitrogen atom, they can combine with that nitrogen atom to form a 3-, 4-, 5-, 6-, or 7-membered ring. For example, -NR'R" includes 1-pyrrolidinyl and 4-morpholinyl. The term “acyl” when used alone or as part of another group means an alkyl group in which two substituents on the carbon atom nearest to the point of attachment of the group are replaced by an =O substituent (e.g., -C(O)CH ₃ , -C(O)CH ₂ CH ₂ OR', etc.).

3. Similarly, the substituents on the aryl and heteroaryl groups vary and are generally selected from the following: -halogen, -OR', -OC(O)R', -NR'R”, -SR', -R', -CN, -NO ₂ ,
-CO ₂ R', -CONR'R”, -C(O)R', -OC(O)NR'R”, -NR”C(O)R', -NR”C(O) ₂ R', -NR'-C(O)NR”R”', -NHC(NH ₂ )=NH, -NR'C(NH ₂ )=NH, -NH-C(NH ₂ )=NR', -S(O)R', -S(O) ₂ R', -S(O) ₂ NR'R”, -NR'S(O) ₂ R”, -N ₃ , perfluoro(C ₁ -C ₄ )alkoxy and perfluoro(C ₁ -C ₄ )alkyl, in an amount from zero to the total number of free valences in the aromatic system; and wherein R', R" and R"' are independently selected from hydrogen, _C1-8 alkyl, _C3-6 cycloalkyl, _C2-8 alkenyl, _C2-8 alkynyl, unsubstituted aryl and heteroaryl, (unsubstituted aryl) _-C1-4 alkyl and (unsubstituted aryloxy) _{-C1-4 alkyl} . Other suitable substituents include all of the above-described aryl substituents attached to a ring atom through an alkylene bridge containing _1-4 carbon atoms.

Two substituents on adjacent atoms in the aryl or heteroaryl ring may be optionally replaced by a substituent of the formula -TC(O)-(CH ₂ ) _q -U-, where T and U are independently -NH-, -O-, -CH ₂ -, or a single bond, and q is an integer from 0 to 2. Alternatively, two of the substituents on adjacent atoms in the aryl or heteroaryl ring may be optionally replaced by a substituent of the formula -A-(CH ₂ ) _r -B-, where A and B are independently -CH ₂ -, -O-, -NH-, -S-, -S(O)-, -S(O) ₂ -, -S(O) ₂ NR'-, or a single bond, and r is an integer from 1 to 3. One of the single bonds in the new ring thus formed may optionally be replaced by a double bond. Alternatively, two of the substituents on adjacent atoms in the aryl or heteroaryl ring may be optionally replaced by a substituent of the formula -( _CH2 ) _s -X-( _CH2 ) _t- , where s and t are independently integers from 0 to 3, and X is -O-, -NR'-, -S-, -S(O)-, -S(O) _2- , or -S(O) _2NR'- . The substituent R' in -NR'- and -S(O) _2NR'- is selected from a hydrogen atom or _{unsubstituted C1-6} alkyl.

As used in this text, the term "heteroatom" includes oxygen (O), nitrogen (N), sulfur (S), and silicon (Si).

The present disclosure also concerns prodrugs and bioisosteres. Suitable bioisosteres, for example, include replacements of carboxylates (phosphonic acids, phosphinic acids, sulfonic acids, sulfinic acids, and acidic heterocyclic groups such as tetrazoles). Suitable prodrugs include common groups that are known to hydrolyze and/or oxidize under physiological conditions to yield a compound of formula I.

The terms "patient" and "subject" include primates (especially humans), companion animals (such as dogs, cats, horses, etc.), and farm animals (such as cattle, pigs, sheep, etc.).

As used in this text, the term "treat" or "treatment" includes both disease-modifying treatment and symptomatic treatment, either of which may be prophylactic (i.e., before symptoms occur, to prevent, delay, or reduce the severity of symptoms) or therapeutic (i.e., after symptoms occur, to reduce the severity and/or duration of symptoms).

The term "pharmaceutically acceptable salts" includes salts of the compounds prepared with relatively non-toxic acids or bases, depending on the particular substituents on the compounds described herein. When the compounds of the present invention contain relatively acidic functional groups, base addition salts can be prepared by reacting the neutral form of such compounds with a sufficient amount of the desired base, even without a solvent or in a suitable inert solvent. Examples of salts derived from pharmaceutically acceptable inorganic bases include aluminum, ammonium, calcium, copper, iron (II), iron (III), lithium, magnesium, manganese, potassium, sodium, zinc, etc. Salts derived from pharmaceutically acceptable organic bases include salts of primary, secondary and tertiary amines, including substituted amines, cyclic amines, natural amines, etc., such as arginine, betaine, caffeine, choline, N,N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, etc. When the compounds of the present invention contain relatively basic functional groups, acid addition salts can be prepared by reacting the neutral form of such compounds with a sufficient amount of the desired acid, without a solvent or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include salts with inorganic acids such as hydrochloric, hydrobromic, nitric, carbonic, monohydrocarbonic, phosphoric, monohydrophosphoric, dihydrophosphoric, sulfuric, monohydrosulfuric, hydroiodic or phosphorous acid and the like, as well as salts with relatively non-toxic organic acids such as acetic, propionic, isobutyric, malonic, benzoic, succinic, suberic, fumaric, mandelic, phthalic, benzenesulfonic, p-toluenesulfonic, citric, tartaric, methanesulfonic and the like. Also included are salts with amino acids such as arginates and the like, and salts of organic acids such as glucuronic or galacturonic acids and the like (see, for example, Berge, S. M., et al, “Pharmaceutical Salts,” Journal of Pharmaceutical Science, 1977, 66, 1-19). Certain particular compounds of the present invention contain both basic and acidic functional groups, allowing such compounds to form both base addition and acid addition salts.

Neutral forms of the compounds can be regenerated by reacting the salt with a base or acid and isolating the parent compound in the usual manner. The parent form of the compound differs from the various salt forms in certain physical characteristics, such as solubility in polar solvents, but otherwise the salts are equivalent to the parent compounds for the purposes of the present invention.

Some compounds of the present invention may exist in unsolvated forms as well as solvated forms, including hydrated forms. In general, solvated forms are equivalent to unsolvated forms, and all are encompassed by the present invention. Some compounds of the present invention may exist in multiple crystalline or amorphous forms. In general, all physical forms are equivalent for the uses covered by the present invention and are within the scope of the present invention.

Some compounds of the present invention have asymmetric carbon atoms (optical centers) or double bonds; all racemates, diastereomers, geometric isomers, regioisomers, and individual isomers (e.g., individual enantiomers) are within the scope of the present invention. When stereochemical designations are shown, this refers to a compound that is one of the isomers and is substantially free of the other isomer. "Substantially free" of the other isomer means a ratio of the two isomers of at least 80/20, more preferably 90/10 or 95/5 or greater. In some embodiments, one of the isomers is present in an amount of at least 99%.

The compounds of the present invention may also have unnatural isotopic ratios of one or more of the atoms that make up the compounds. For example, the compounds may be radioactively labeled with radioactive isotopes such as, for example, tritium ( ^3H ), iodine-125 ( ^125I ), or carbon-14 ( ^14C ). All isotopic variations of the compounds of the present invention, radioactive and non-radioactive, are within the scope of the present invention. For example, the compounds may be prepared such that a number of carbon atoms are replaced by the isotope deuterium ( ^2H ). The compounds of the present invention may also have unnatural isotopic ratios of one or more of the atoms that make up the compounds. The unnatural isotope content may range from the natural content to 100%. For example, the compounds may contain radioactive isotopes such as, for example, tritium ( ^3H ), iodine-125 ( ^125I ), or carbon-14 ( ^14C ), or non-radioactive isotopes such as deuterium ( ^2H ) or carbon-13 ( ^13C ). Such isotopic variations may provide additional uses in addition to those already described herein. For example, isotopic variations of the compounds of the present invention may find additional uses, including (but not limited to) use as diagnostic and/or imaging reagents, or as cytostatic/radiotoxic therapeutic agents. In addition, isotopic variations of the compounds of the present invention may have altered pharmacokinetic and pharmacodynamic characteristics that may contribute to improved safety, tolerability, or efficacy in treatment therewith. All isotopic variations of the compounds of the present invention, both radioactive and non-radioactive, are within the scope of the present invention.

Connections

In one aspect, the present invention provides compounds having formula (I) or formula (II):

or a pharmaceutically acceptable salt, solvate or hydrate thereof, wherein

Y and Y' are each independently selected from the group consisting of O, NH and N(C _1-4 alkyl);

R ¹ is independently selected from the group consisting of H, halogen, CN, C _1-4 alkyl, C _1-4 haloalkyl, –OC _1-4 alkyl and –OC _1-4 haloalkyl;

each R ^2a , R ^2b , R ^2c , R ^2a' , R ^2b' and R ^2c' is independently selected from the group consisting of H, halogen, -CN, -R ^a , CO ₂ R ^b , -CONR ^b R ^c , -OC(O)NR ^b R ^c , -NR ^c C(O)R ^b , -NR ^c C(O) ₂ R ^a ,
-NR ^b -C(O)NR ^b R ^c , -NR ^b R ^c , -OR ^b , -X ¹ OR ^b , -X ¹ NR ^b R ^c , -X ¹ CO ₂ R ^b , -SF ₅ and -S(O) ₂ NR ^b R ^c , wherein each X ¹ is C _1-4 alkylene; each R ^b and R ^c is independently selected from a hydrogen atom, C _1-8 alkyl and C _1-8 haloalkyl, or, if attached to a single nitrogen atom, can combine with the nitrogen atom to form a 5- or 6-membered ring containing as ring members from 0 to 2 additional heteroatoms selected from N, O and S, and optionally substituted with an oxo group; each R ^a is independently selected from the group consisting of C _1-8 alkyl, C _2-8 alkenyl and C _1-8 haloalkyl;

R ³ and R ^3' are each independently selected from the group consisting of –NR ^d R ^e and a 4-12 membered monocyclic, bicyclic or spirocyclic non-aromatic heterocyclic ring optionally substituted with 1 to 6 R ^3a substituents; wherein

R ^d is selected from the group consisting of H, C _1-8 haloalkyl and C _1-8 alkyl;

R ^e is selected from H, -C _1-8 alkyl, C _1-8 haloalkyl, C _1-8 hydroxyalkyl, -X ² -CO ₂ R ^g ,
-X ² -CONR ^g R ^h and -X ² -CONHSO ₂ R ^g , -X ² -SO ₂ NR ^g R ^h , -X ² -SO ₃ R ^g , -X ² -B(OH) ₂ ,
-X ² -PO ₃ H ₂ , -X ² -C(O)NHOH, -X ² -NR ^g R ^h , -C(O)R ^g , C _3-10 cycloalkyl, -C _3-10 cycloalkyl-COOR ^g , -C _3-10 cycloalkyl-OR ^g , C _4-8 heterocyclyl, -C _4-8 heterocyclyl-COOR ^g , -C _4-8 heterocyclyl-OR ^g , -X ² -C _4-8 heterocyclyl, -C(=O)OX ² -C _4-8 heterocyclyl, -X ² -C _3-10 cycloalkyl, C _5-10 heteroaryl, X ² -C _5-10 heteroaryl,
X ² -C _6-10 aryl, X ² - (C=O)-C _6-10 aryl, -CO ₂ X ² -O ₂ CC _1-8 alkyl, X ² -NH(C=O)-C _2-8 alkenyl, X ² -NH(C=O)-C _1-8 alkyl, X ² -NH(C=O)-C _2-8 alkynyl, X ² - (C=O)-NHX ² -COOR ^g and X ² - (C=O)-NHX ² -OR ^g , optionally substituted with a CO ₂ H group; wherein the alkyl or alkylene portion of R ^e is optionally further substituted with 1 to 3 substituents independently selected from OH, COOH, SO ₂ NH ₂ , CONH ₂ , C(O)NHOH, COO-C _1-8 alkyl and PO ₃ H ₂ ; The C _5-10 heteroaryl and C _6-10 aryl moieties R ^e are optionally substituted with 1 to 3 substituents independently selected from OH, B(OH) ₂ , COOH, NH ₂ , SO ₂ NH ₂ , CONH ₂ , C(O)NHOH, PO ₃ H ₂ , COO-C _1-8 alkyl, C _1-4 alkyl, C _1-4 alkylene-OH, C _1-4 alkylene-SO ₂ NH ₂ , C _1-4 alkylene-CONH ₂ , C _1-4 alkylene-C(O)NHOH, C _1-4 alkylene-PO ₃ H ₂ and C _1-4 alkylene-COOH; and the C _4-8 heterocyclyl and C _3-10 cycloalkyl moieties R ^e are optionally substituted with 1 to 4 R ^w substituents;

or

R ^e in combination with the N to which it is attached is a mono-amino acid, di- or tripeptide comprising natural amino acids and unnatural amino acids, wherein the unnatural amino acids have at the alpha-carbon a substituent selected from the group consisting of C _2-4 hydroxyalkyl, C _1-3 alkyl-guanidinyl and C _1-4 alkyl-heteroaryl, and wherein the alpha-carbon in each natural or unnatural amino acid is optionally further substituted with a methyl group, and the terminal moiety of the mono-, di- or tripeptide is selected from the group consisting of C(O)OH, C(O)OC _1-6 alkyl, C(O)NH ₂ and PO ₃ H ₂ ;

each R ^3a is independently selected from the group consisting of a halogen atom, -CN, oxo group, -R ^f , -CO ₂ R ^g , -CONR ^g R ^h , -CONHC _1-6 alkyl-OH, -C(O)R ^g , -OC(O)R ^g , -OC(O)NR ^g R ^h , -NR ^g C(O)R ^h , -NR ^g C(O) ₂ R ^h , -CONHOH, -PO ₃ H ₂ , -NR ^g -X ² -C(O) ₂ R ^h ,
-NR ^g C(O)NR ^g R ^h , -NR ^g R ^h , -OR ^g , -S(O) ₂ NR ^g R ^h , -OX ² OR ^g , -OX ² NR ^g R ^h ,
-OX ² CO ₂ R ^g , -OX ² CONR ^g R ^h , -X ² OR ^g , -X ² NR ^g R ^h , -X ² CO ₂ R ^g , -X ² CONR ^g R ^h ,
-X ² - CONHSO ₂ R ^g and SF ₅ ; wherein X ² is C _1-6 alkylene and optionally further has a substituent of OH, NH ₂ , SO ₂ NH ₂ , CONH ₂ , C(O)NHOH, PO ₃ H ₂ , COO-C _1-8 alkyl or CO ₂ H, wherein each R ^g and R ^h is independently selected from a hydrogen atom, C _1-8 alkyl optionally substituted with 1-2 substituents selected from OH, NH ₂ , SO ₂ NH ₂ , CONH ₂ , C(O)NHOH, PO ₃ H ₂ , COO-C _1-8 alkyl and CO ₂ H, and C _1-8 haloalkyl is optionally substituted with 1-2 substituents selected from OH, NH ₂ , SO ₂ NH ₂ , CONH ₂ , C(O)NHOH, PO ₃ H ₂ , COO-C _1-8 alkyl and _CO2H , or, if attached to the same nitrogen atom, ^Rg and ^Rh may combine with the nitrogen atom to form a 5- or 6-membered ring containing as ring members from 0 to 2 additional heteroatoms selected from N, O or S, and optionally substituted with an oxo group; each ^Rf is independently selected _from the group consisting of -OH, _C1-8 alkyl, _C2-8 alkenyl and _C1-8 haloalkyl, each of which may optionally _be substituted with OH, _NH2 , _SO2NH2 , _CONH2 , C(O)NHOH, _PO3H2 , COO- _C1-8 alkyl or _CO2H ;

each substituent R ^w is independently selected from C _1-4 alkyl, C _1-4 alkylene-OH, C _1-4 alkylene-COOH, C _1-4 alkylene-SO ₂ NH ₂ , C _1-4 alkylene-CONH ₂ , C _1-4 alkylene-C(O)NHOH, C _1-4 alkylene-PO ₃ H, OH, COO-C _1-8 alkyl, COOH, SO ₂ NH ₂ , CONH ₂ , C(O)NHOH, PO ₃ H ₂ and an oxo group;

R ⁴ and R ^4' are each independently selected from the group consisting of -OC _1-8 alkyl, -OC _1-8 haloalkyl, -C _6-10 aryl, -C _5-10 heteroaryl, -OC _1-4 alkyl-C _4-7 heterocycloalkyl, -OC _1-4 alkyl-C _6-10 aryl and -OC _1-4 alkyl-C _5-10 heteroaryl, each of which optionally has 1 to 5 R ^4a substituents;

each R ^4a is independently selected from the group consisting of a halogen atom, -CN, -R ⁱ ,
-CO ₂ R ^j , -CONR ^j R ^k , -C(O)R ^j , -OC(O)NR ^j R ^k , -NR ^j C(O)R ^k , -NR ^j C(O) ₂ R ⁱ ,
-NR ^j -C(O)NR ^j R ^k , -NR ^j R ^k and -OR ^j ; Where

each R ⁱ is independently selected from the group consisting of C _1-8 alkyl, C _2-8 alkenyl and C _1-8 haloalkyl; and optionally, when the R ^4a substituents are on adjacent atoms, they combine to form a 5- or 6-membered carbocyclic or heterocyclic ring optionally substituted with an oxo group;

each R ^j and R ^k is independently selected from a hydrogen atom, C _1-8 alkyl and C _1-8 haloalkyl, or, if attached to a single nitrogen atom, they may combine with the nitrogen atom to form a 5- or 6-membered ring containing as ring members from 0 to 2 additional heteroatoms selected from N, O or S, and optionally substituted with an oxo group;

each n is independently equal to 0, 1, 2, or 3;

each R ⁵ and R ^5' is independently selected from the group consisting of a halogen atom, -CN, -R ^q , -CO ₂ R ^r , -CONR ^r R ^s , -C(O)R ^r , -NR ^r R ^s and -OR ^r , where

each R ^r and R ^s is independently selected from a hydrogen atom, C _1-4 alkyl and C _1-4 haloalkyl, or, if attached to a single nitrogen atom, they can combine with the nitrogen atom to form a 5- or 6-membered ring containing as ring members from 0 to 2 additional heteroatoms selected from N, O or S, and optionally substituted with an oxo group; each R ^q is independently selected from the group consisting of C _1-8 alkyl and C _1-8 haloalkyl;

R ^6a and R ^6a' are each independently selected from the group consisting of H, C _1-4 alkyl and C _1-4 haloalkyl;

each m is independently equal to 0, 1, 2, 3, or 4;

each R ^6b and R ^6b' is independently selected from the group consisting of F, C _1-4 alkyl and C _1-4 haloalkyl.

In one group of embodiments, the compounds of the present invention are represented by formula (I).

4. In one group of embodiments, the compounds of the present invention are represented by formula (II).

In one group of embodiments, the compounds of formula (I) or (II) are those wherein Y and Y' are each independently selected from the group consisting of O and NH.

In one group of embodiments, the compounds of formula (I) or (II) are those wherein Y and Y' are each O.

In some embodiments, the compounds of formula (I) or (II) are those wherein each subscript n is 0 or 1. In some embodiments, the compounds of formula (I) or (II) are those wherein each subscript m is 0 or 1. In some embodiments, the compounds of formula (I) or (II) are those wherein each subscript n is 0 or 1, and each subscript m is 0 or 1.

In some embodiments, the compounds of formula (I) or (II) are those wherein each R ³ and R ^3' is a 4-9 membered monocyclic or spirocyclic non-aromatic heterocyclic ring optionally substituted with 1-4 R ^3a substituents.

In some embodiments, the compounds of formula (I) or (II) are those wherein each R ³ and R ^3' is independently –NR ^d R ^e .

In some embodiments, the compounds of formula (I) or (II) are those wherein R ³ and R ^3' are each independently -NR ^d R ^e , and R ^e taken together with the N to which it is attached is a natural or non-natural amino acid, wherein the non-natural amino acids have at the alpha carbon a substituent selected from the group consisting of C _2-4 hydroxyalkyl and C _1-3 alkyl guanidinyl, and wherein the alpha carbon in each natural or non-natural amino acid is optionally further substituted with a methyl group, and the terminal moiety is selected from the group consisting of C(O)OH, C(O)OC _1-6 alkyl, and C(O)NH ₂ .

In some embodiments, the compounds of formula (I) or (II) are those wherein each R ³ and R ^3' is independently –NR ^d R ^e , and R ^e combined with the N to which it is attached is a natural or non-natural amino acid, wherein the non-natural amino acids comprise a C _2-4 hydroxyalkyl alpha carbon, wherein the alpha carbon in each natural or non-natural amino acid is further substituted with a methyl group, and the terminal moiety is selected from the group consisting of C(O)OH, C(O)OC _1-4 alkyl, and C(O)NH ₂ .

In some embodiments, the compounds of formula (I) or (II) are those wherein R ^2a , R ^2b , R ^2c , R ^2a' , R ^2b' and ^{R 2c'} are each independently selected from the group ^consisting of H ^, halogen, -CN, ^-Ra , _-CO2Rb , ^-CONRbRc , ^-NRbRc and ^-ORb ; wherein R ^b and ^Rc are each independently selected from hydrogen, C _1-8 alkyl and C _1-8 haloalkyl, or if attached to a single nitrogen atom, can combine with the nitrogen atom to form a 5- or 6-membered ring containing as ring members from 0 to 2 additional heteroatoms selected from N, O and S, and optionally substituted with an oxo group; each R ^a is independently selected from the group consisting of C _1-8 alkyl, C _2-8 alkenyl, and C _1-8 haloalkyl.

In some embodiments, the compounds of formula (I) or (II) are those wherein each R ⁴ and R ^4' is independently selected from the group consisting of -OC _1-8 alkyl, -OC _1-8 haloalkyl, -OC _1-4 alkyl-C _6-10 aryl, and -OC _1-4 alkyl-C _5-10 heteroaryl, each of which optionally has 1 to 5 R ^4a substituents.

In some embodiments, the compounds of formula (I) or (II) are those wherein each R ⁴ and R ^4' is independently selected from the group consisting of -OC _1-8 alkyl, -OC _1-4 alkyl-phenyl, and -OC _1-4 alkyl-pyridyl, each of which optionally has 1 to 3 R ^4a substituents.

In some embodiments, the compounds of formula (I) or (II) are those wherein R ^2a , R ^2b , R ^2c , R ^2a' , R ^2b' and ^{R 2c'} are each independently selected from the group ^consisting of H ^, halogen, -CN, ^-Ra , _-CO2Rb , ^-CONRbRc , ^-NRbRc and ^-ORb ; wherein R ^b and ^Rc are each independently selected from hydrogen, C _1-8 alkyl and C _1-8 haloalkyl, or if attached to a single nitrogen atom, can combine with the nitrogen atom to form a 5- or 6-membered ring containing as ring members from 0 to 2 additional heteroatoms selected from N, O and S, and optionally substituted with an oxo group; each R ^a is independently selected from the group consisting of C _1-8 alkyl, C _2-8 alkenyl and C _1-8 haloalkyl; each R ³ is a 4-9 membered monocyclic or spirocyclic non-aromatic heterocyclic ring optionally substituted with 1 to 4 R ^3a substituents; and each R ⁴ is selected from the group consisting of -OC _1-8 alkyl, -OC _1-4 alkyl-phenyl and -OC _1-4 alkyl-pyridyl, each of which optionally has 1 to 3 R ^4a substituents.

In some embodiments, the compounds of formula (I) or (II) are those wherein R ^2a , R ^2b , R ^2c , R ^2a' , R ^2b' and ^{R 2c'} are each independently selected from the group ^consisting of H ^, halogen, -CN, ^-Ra , _-CO2Rb , ^-CONRbRc , ^-NRbRc and ^-ORb ; wherein R ^b and ^Rc are each independently selected from hydrogen, C _1-8 alkyl and C _1-8 haloalkyl, or if attached to a single nitrogen atom, can combine with the nitrogen atom to form a 5- or 6-membered ring containing as ring members from 0 to 2 additional heteroatoms selected from N, O and S, and optionally substituted with an oxo group; each R ^a is independently selected from the group consisting of C _1-8 alkyl, C _2-8 alkenyl, and C _1-8 haloalkyl; each R ³ is –NR ^d R ^e , and R ^e taken together with the N to which it is attached is a natural or unnatural amino acid, wherein the unnatural amino acids have at the alpha carbon a substituent selected from the group consisting of C _2-4 hydroxyalkyl and C _1-3 alkyl guanidinyl, and wherein the alpha carbon in each natural or unnatural amino acid is optionally further substituted with a methyl group, and the terminal moiety is selected from the group consisting of C(O)OH, C(O)OC _1-6 alkyl, and C(O)NH ₂ ; and each R ⁴ is selected from the group consisting of -OC _1-8 alkyl, -OC _1-4 alkyl-phenyl and -OC _1-4 alkyl-pyridyl, each of which optionally has 1 to 3 R ^4a substituents.

In some embodiments, compounds of formula (II) are those wherein R ¹ is H, halogen, CN, or C _1-4 alkyl.

In some particular embodiments, including any of the embodiments listed above, additional embodiments include compounds of formula (I) or (II), wherein each R ³ and R ^3' is independently selected from the group consisting of

.

In some embodiments of each of formulas (I) and (II), and other particular embodiments described above, the compounds or pharmaceutically acceptable salts thereof are selected from Table 1 having an activity of ++ or +++.

In addition to the compounds described above, the present invention also encompasses pharmaceutically acceptable salts of these compounds. In some embodiments, the pharmaceutically acceptable salts are selected from ammonium, calcium, magnesium, potassium, sodium, zinc, arginine, betaine, caffeine, choline, N,N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, salts with hydrochloric acid, carbonic acid, from monohydrogen carbonates, salts with phosphoric acid, monohydrogen phosphates, dihydrogen phosphates, salts with acetic, propionic, isobutyric, malonic, benzoic, succinic, suberic, fumaric, mandelic, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, methanesulfonic acid, arginates, salts with glucuronic acid and galacturonic acid. In some embodiments, the pharmaceutically acceptable salts are selected from ammonium, calcium, magnesium, potassium, sodium salts, salts with hydrochloric, carbonic acids, monohydrogen carbonates, salts with phosphoric acid, monohydrogen phosphates, dihydrogen phosphates, salts with acetic, propionic, isobutyric, malonic, benzoic, succinic, suberic, fumaric, mandelic, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, methanesulfonic acid, arginates, salts with glucuronic acid and galacturonic acid. In some embodiments, the pharmaceutically acceptable salts are sodium salts or hydrochlorides.

In addition to salt forms, the present invention describes compounds in prodrug form. Prodrugs of the compounds described herein are compounds that readily undergo chemical changes under physiological conditions to yield the compounds of the present invention. In addition, prodrugs can be converted into the compounds of the present invention by chemical or biological methods under ex vivo conditions. For example, prodrugs can be slowly converted into the compounds of the present invention when placed in a transdermal patch reservoir with a suitable enzyme or chemical reagent.

The ester can be used as a prodrug for the corresponding carboxylic acid. C _1-10 alkyl ester or C _1-10 haloalkyl ester can be used as a prodrug for the corresponding carboxylic acid. The following esters can be used: tert-butyl ester, methyl ester, ethyl ester, isopropyl ester.

Pharmaceutical compositions

In addition to the compounds of the present invention, compositions of these compounds typically contain a pharmaceutically acceptable carrier or diluent.

The term "composition" as used herein includes a product containing the stated ingredients in the stated amounts, as well as any product formed, directly or indirectly, from the combination of the stated ingredients in the stated amounts. The term "pharmaceutically acceptable" means that the carrier, diluent or excipient must be compatible with the other ingredients of the preparation and not injurious to the patient.

In another embodiment, a pharmaceutical composition is described comprising a compound of the present invention, including a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

In some embodiments, the pharmaceutical composition further comprises one or more additional therapeutic agents. In some embodiments, said one or more additional therapeutic agents are selected from the group consisting of an antimicrobial agent, an antiviral agent, a cytotoxic agent, a gene expression modulating agent, a chemotherapeutic agent, an anticancer agent, an antiangiogenic agent, an immunotherapeutic agent, an antihormonal agent, an antifibrotic agent, a radiation therapy, an agent for radiation therapy, an antitumor agent, and an antiproliferative agent. In some embodiments, the one or more additional therapeutic agents is a chemokine and/or chemotactic receptor antagonist, which includes, but is not limited to, CCR1, CCR2, CCR3, CCR4, CCR5, CCR6, CCR7, CCR8, CCR9, CCR10, CCR11, CCR12, CXCR1, CXCR2, CXCR3, CXCR4, CXCR5, CXCR6, CXCR7, C3aR and/or C5aR. Chemokine and/or chemotactic receptor antagonists are known in the art and are described, for example, in WO2007/002667, WO2007/002293, WO/2003/105853, WO/2007/022257, WO/2007/059108, WO/2007/044804, WO2007/115232, WO2007/115231, WO2008/147815, WO2010/030815, WO2010/075257, WO2011/163640, WO2010/054006, WO2010/051561, WO2011/035332, WO2013/082490, WO2013/082429, WO2014/085490, WO2014/100735, WO2014/089495, WO2015/084842, WO2016/187393, WO2017/127409, WO2017/087607, WO2017/087610, WO2017/176620, WO2018/222598, WO2018/222601, WO2013/130811, WO2006/076644, WO2008/008431, WO2009/038847, WO2008/008375, WO2008/008374, WO2008/010934, WO2009/009740, WO2005/112925, WO2005/112916, WO2005/113513, WO2004/085384, WO2004/046092. Chemokine and/or chemotactic receptor antagonists also include CCX354, CCX9588, CCX140, CCX872, CCX598, CCX6239, CCX9664, CCX2553, CCX3587, CCX3624, CCX 2991, CCX282, CCX025, CCX507, CCX430, CCX765, CCX224, CCX662, CCX650, CCX832, CCX168, CCX168-M1, CCX3022 and/or CCX3384.

Pharmaceutical compositions for administering the compounds of the present invention may be in the form of unit dosage forms and may be prepared by any of the methods known in the art of pharmacology and drug administration. All methods include the step of combining the active substance with a carrier that contains one or more accessory ingredients. In general, pharmaceutical compositions are prepared by uniformly and intimately mixing the active substance with a liquid carrier or a finely divided solid carrier, or both, and then, if necessary, shaping the product into the desired preparation. In a pharmaceutical composition, the active substance is present in an amount sufficient to exert the desired effect on the disease or pathological condition.

The pharmaceutical compositions containing the active substance may be in a form suitable for oral administration, for example, they may be in the form of tablets, sachets, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions and self-emulsifying preparations as described in U.S. Patent Application 2002-0012680, hard or soft capsules, syrups, elixirs, solutions, buccal patches, oral gel, chewing gum, chewable tablets, effervescent powders and effervescent tablets. Compositions intended for oral administration can be prepared by any methods known in the art of producing pharmaceutical compositions. Such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents, antioxidants and preservatives, to create pharmaceutically attractive and palatable preparations. The tablets contain the active substance in a mixture with non-toxic pharmaceutically acceptable auxiliary substances suitable for the manufacture of tablets. Such auxiliary substances may be, for example, inert diluents such as cellulose, carbon dioxide, aluminum oxide, calcium carbonate, sodium carbonate, glucose, mannitol, sorbitol, lactose, calcium phosphate or sodium phosphate; granulating agents and agents accelerating the disintegration of tablets, for example, corn starch or alginic acid; binding agents, for example, polyvinylpyrrolidone, cellulose, starch, gelatin or acacia gum, and lubricants, for example, magnesium stearate, stearic acid or talc. The tablets may be uncoated or they may be enteric coated or have a coating applied in some other known way in order to slow down disintegration and absorption in the gastrointestinal tract, thereby providing a prolonged effect over a longer period of time. For example, disintegrating materials such as glyceryl monostearate or glyceryl distearate may be used. Tablets may also be coated by the methods described in U.S. Patents 4,256,108; 4,166,452; and 4,265,874 to form osmotic, sustained-release tablets.

Preparations intended for oral administration may also be in the form of hard gelatin capsules, where the active substance is mixed with an inert solid diluent, such as calcium carbonate, calcium phosphate or kaolin, polyethyleneglycol (PEG) with different average molecular sizes (e.g. PEG400, PEG4000), or in the form of soft gelatin capsules, where the active substance is mixed with an aqueous or oily medium, such as peanut oil, liquid paraffin or olive oil. In addition, emulsions can be prepared with water-insoluble ingredients, such as oils, and stabilized with surfactants, such as mono- or diglycerides, PEG esters, etc.

Aqueous suspensions contain the active substances in admixture with auxiliary substances suitable for the manufacture of aqueous suspensions. Such auxiliary substances are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth, and acacia; The dispersing or wetting agents may be natural phosphatides, such as lecithin, or condensation products of alkylene oxide with fatty acids, such as polyoxyethylene stearate, or condensation products of ethylene oxide with long-chain aliphatic alcohols, such as heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol, such as polyoxyethylene sorbitan monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, such as polyethylene sorbitan monooleate. The aqueous suspensions may also contain one or more preservatives, such as ethyl or n-propyl para-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose or saccharin.

Oily suspensions can be prepared by suspending the active substance in a vegetable oil, such as peanut oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. Oily suspensions may contain thickening agents, such as beeswax, solid paraffin or cetyl alcohols. Sweetening agents, such as those listed above, and coloring agents may be added to provide a palatable oral composition. Such compositions may be stabilized by the addition of an antioxidant, such as ascorbic acid.

Dispersible powders and granules suitable for the preparation of an aqueous suspension by adding water contain the active substance in a mixture with a dispersing or wetting agent, a suspending agent and one or more preservatives. Examples of dispersing or wetting agents, suspending agents are given above. Additional auxiliary substances, such as sweeteners, flavourings and colourings, may also be present.

The pharmaceutical compositions of the present invention may also be in the form of oil-in-water emulsions. The oil phase may be a vegetable oil, such as olive oil or peanut oil, or a mineral oil, such as liquid paraffin, or a mixture thereof. Suitable emulsifiers may be natural gums, such as acacia or tragacanth, natural phosphatides, such as soya oil, lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, such as sorbitan monooleate, and condensation products of these partial esters with ethylene oxide, such as polyoxyethylene sorbitan monooleate. The emulsion may also contain sweeteners and flavoring agents.

Syrups and elixirs may contain sweeteners such as glycerin, propylene glycol, sorbitol or sucrose. Such preparations may also contain demulcents, a preservative, flavorings and colorings. Oral solutions may be prepared in combination with, for example, cyclodextrin, PEG and surfactants.

The pharmaceutical compositions may be in the form of sterile injectable aqueous or oleaginous suspensions. Such a suspension may be prepared according to techniques known in the art using suitable dispersing or wetting agents and suspending agents as have been mentioned above. The sterile injectable preparations may also be sterile injectable solutions or suspensions in a nontoxic parenterally acceptable diluent or solvent, for example, they may be in the form of a solution in 1,3-butanediol. Among the suitable carriers and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile oils are often employed as a solvent or suspending medium. Any tasteless, fixed oil may be used for this purpose, including synthetic mono- and diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables.

The compounds described herein can also be administered in the form of suppositories for rectal administration of the drug. Such compositions can be prepared by mixing the drug with a suitable non-irritating excipient that is solid at room temperature but liquefies at body temperature and therefore melts in the rectum to release the drug. Such materials include cocoa butter and polyethylene glycols. In addition, the compounds can be administered in the form of eye preparations such as drops or ointments. In addition, transdermal administration of the compounds in question can be carried out by means of iontophoretic patches and the like. For topical application, creams, ointments, gels, solutions or suspensions containing the compounds of the present invention are used. In the context of the present invention, topical application also includes the use of mouth rinses and solutions.

The compounds of the present invention can also be combined with a carrier that is suitable polymers as targeted drug carriers. Such polymers can include polyvinylpyrrolidone, pyran copolymer, polyhydroxy-propyl-methacrylamide-phenol, polyhydroxyethyl-aspartamide-phenol or polyethyleneoxide-polylysine substituted with palmitoyl residues. In addition, the compounds of the present invention can be combined with a carrier that belongs to the class of biodegradable polymers that can be used to achieve controlled drug release, such as: polylactic acid, polyglycolic acid, copolymers of polylactic and polyglycolic acid, poly-epsilon-caprolactone, polyhydroxybutyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates and crosslinked or amphipathic hydrogel block copolymers. Polymers and semipermeable polymer matrices can be formed into articles such as valves, stents, tubes, prostheses, etc. In one embodiment of the present invention, a compound of the present invention is combined with a polymer or semipermeable polymer matrix formed into a stent or stent graft.

Methods of treating diseases and disorders

The compounds of the present invention can be used as immunomodulators. The compounds of the present invention can be used as agonists, antagonists, partial agonists, inverse agonists and inhibitors of PD-1 and/or PD-L1 in a variety of contexts, both in vitro and in vivo. In some embodiments, the compounds of the present invention can be used as inhibitors of PD-1/PD-L1 protein-protein interaction. In some embodiments, the compounds of the present invention can be used as inhibitors of PD-L1. In some embodiments, the compounds of the present invention can be used as inhibitors of CD80/PD-L1 protein-protein interaction. In some embodiments, the compounds of the present invention can be used to inhibit the interaction between PD-1 and PD-L1 and/or PD-1 and CD80 and/or PD-1 and PD-L2 in vitro or in vivo. In some embodiments, the compounds of the present invention can be used to inhibit VISTA and/or TIM-3. In some embodiments, the compounds of the present invention can be PD-1/PD-L1 protein-protein interaction inhibitors and VISTA and/or TIM-3 inhibitors. In some embodiments, in addition to functioning as PD-1/PD-L1 protein-protein interaction inhibitors, the compounds of the present invention can be CTLA-4 and/or BTLA and/or LAG-3 and/or KLRG-1 and/or 2B4 and/or CD160 and/or HVEM and/or CD48 and/or E-cadherin and/or MHC-II and/or galectin-9 and/or CD86 and/or PD-L2 and/or VISTA and/or TIM-3 and/or CD80 inhibitors.

The compounds of the present invention may be contacted with a receptor with which they interact in an aqueous solution and under conditions otherwise suitable for binding of the ligand to the receptor. The receptor may be in suspension (e.g., in an isolated membrane or in a cell preparation), in a cultured or isolated cell, or in a tissue or organ.

Preferably, the amount of the compounds of the present invention that contacts the receptor should be sufficient to inhibit PD-1/PD-L1 binding in vitro, as measured, for example, by ELISA. The receptor may be in a solution or suspension, in a preparation of cultured or isolated cells, or in the body of a patient.

In some embodiments, the compounds of the present invention can be used to restore and enhance T-cell activation. In some embodiments, the compounds of the present invention can be used to enhance the immune response in a patient. In some embodiments, the compounds of the present invention can be used to treat, prevent, or slow the progression of diseases or disorders in various therapeutic areas, such as cancer and infectious diseases.

In some embodiments, the compounds of the present invention can be used to treat patients suffering from pathological conditions responsive to modulation of PD-1/PD-L1 protein-protein interaction.

In some embodiments, a method of modulating an immune response in a subject mediated through the PD-1 signaling pathway is described, comprising administering to the subject a therapeutically effective amount of a compound of the present invention, including a compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof, or a composition comprising a compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof.

In some embodiments, a method is described for enhancing, stimulating, modulating and/or increasing an immune response in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the present invention, including a compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof, or a composition comprising a compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof.

In some embodiments, a method for inhibiting the growth, proliferation, or metastasis of cancer cells in a subject in need thereof is described, comprising administering to the subject a therapeutically effective amount of a compound of the present invention, including a compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof, or a composition of a compound of the present invention, including a compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof.

5. In some embodiments, a method of treating a subject in need thereof is described, comprising administering to the subject a therapeutically effective amount of a compound of the present invention, including a compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof, or a composition of a compound of the present invention, including a compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof.

In some embodiments, the subject suffers from a disease or disorder selected from the group consisting of an infectious disease, a bacterial infectious disease, a viral infectious disease, a fungal infectious disease, a solid tumor, a hematological malignancy, an immune disorder, an inflammatory disease, and cancer. In some embodiments, the disease or disorder is selected from the group consisting of: melanoma, glioblastoma, esophageal cancer, nasopharyngeal cancer, uveal melanoma, lymphoma, lymphocytic lymphoma, primary CNS lymphoma, T-cell lymphoma, diffuse large B-cell lymphoma, primary mediastinal large B-cell lymphoma, prostate cancer, castration-resistant prostate cancer, chronic myelocytic leukemia, Kaposi's sarcoma, fibrosarcoma, liposarcoma, chondrosarcoma, osteosarcoma, angiosarcoma, lymphangiosarcoma, synovioma, meningioma, leiomyosarcoma, rhabdomyosarcoma, soft tissue sarcoma, sarcoma, sepsis, gallbladder cancer, basal cell carcinoma, thymus cancer, thyroid cancer, parathyroid cancer, uterine cancer, adrenal cancer, liver infection, Merkel cell carcinoma, nervous system cancer, follicle center cell lymphoma, colon cancer, Hodgkin's lymphoma, non-Hodgkin's lymphoma, leukemia, chronic or acute leukemia including acute myeloid leukemia, chronic myeloid leukemia, acute lymphoblastic leukemia, chronic lymphoblastic leukemia, multiple myeloma, ovarian cancer, myelodysplastic syndrome, cutaneous or intraocular malignant melanoma, renal cell carcinoma, small cell lung cancer, lung cancer, mesothelioma, breast cancer, squamous cell non-small cell lung cancer, non-squamous cell non-small cell lung cancer, colorectal cancer, ovarian cancer, gastric cancer, hepatocellular cancer, pancreatic carcinoma, pancreatic cancer, pancreatic ductal adenocarcinoma, head and neck squamous cell carcinoma, head and neck cancer, gastrointestinal cancer, stomach cancer, HIV, hepatitis A, hepatitis B, hepatitis C, hepatitis D, herpes virus, human papillomavirus, influenza, bone cancer, skin cancer, rectal cancer, anal cancer, testicular cancer, fallopian tube cancer, endometrial cancer, cervical cancer, vaginal cancer, vulvar cancer, esophageal cancer, small bowel cancer, endocrine cancer, urethral cancer, penile cancer, bladder cancer, kidney cancer, urethral cancer, renal pelvis cancer, central nervous system (CNS) neoplasms, tumor angiogenesis, spinal axis cancer, brain stem glioma, pituitary adenoma, epidermoid cancer, asbestosis, carcinoma, adenocarcinoma, papillary carcinoma, cystadenocarcinoma, bronchogenic carcinoma, renal cell carcinoma, transitional cell carcinoma, choriocarcinoma, seminoma, embryonal carcinoma, Wilms tumor, pleomorphic adenoma, liver cell papilloma, renal tubular adenoma, cystadenoma, papilloma, adenoma, leiomyoma, rhabdomyoma, hemangioma, lymphangioma, osteoma, chondroma, lipoma and fibroma.

In some embodiments, the subject is further administered a therapeutically effective amount of one or more additional therapeutic agents. In some embodiments, the one or more additional therapeutic agents are selected from the group consisting of an antimicrobial agent, an antiviral agent, a cytotoxic agent, a gene expression modulating agent, a chemotherapeutic agent, an anticancer agent, an antiangiogenic agent, an immunotherapeutic agent, an antihormonal agent, an antifibrotic agent, a radiation therapy, an agent for radiation therapy, an antitumor agent, and an antiproliferative agent. In some embodiments, the one or more additional therapeutic agents is a chemokine and/or chemotactic receptor antagonist, which includes, but is not limited to, CCR1, CCR2, CCR3, CCR4, CCR5, CCR6, CCR7, CCR8, CCR9, CCR10, CCR11, CCR12, CXCR1, CXCR2, CXCR3, CXCR4, CXCR5, CXCR6, CXCR7, C3aR and/or C5aR. Chemokine and/or chemotactic receptor antagonists are known in the art and are described, for example, in WO2007/002667, WO2007/002293, WO/2003/105853, WO/2007/022257, WO/2007/059108, WO/2007/044804, WO2007/115232, WO2007/115231, WO2008/147815, WO2010/030815, WO2010/075257, WO2011/163640, WO2010/054006, WO2010/051561, WO2011/035332, WO2013/082490, WO2013/082429, WO2014/085490, WO2014/100735, WO2014/089495, WO2015/084842, WO2016/187393, WO2017/127409, WO2017/087607, WO2017/087610, WO2017/176620, WO2018/222598, WO2018/222601, WO2013/130811, WO2006/076644, WO2008/008431, WO2009/038847, WO2008/008375, WO2008/008374, WO2008/010934, WO2009/009740, WO2005/112925, WO2005/112916, WO2005/113513, WO2004/085384, WO2004/046092. Chemokine and/or chemotactic receptor antagonists also include CCX354, CCX9588, CCX140, CCX872, CCX598, CCX6239, CCX9664, CCX2553, CCX3587, CCX3624, CCX 2991, CCX282, CCX025, CCX507, CCX430, CCX765, CCX224, CCX662, CCX650, CCX832, CCX168, CCX168-M1, CCX3022 and/or CCX3384.

In some embodiments, the compounds of the present invention can be used to suppress an infectious disease. Infectious disease includes, but is not limited to, HIV, influenza, giardiasis, malaria, leishmaniasis, pathogenic infections caused by hepatitis virus (A, B, and C), herpes virus (e.g., VZV, HSV-I, HAV-6, HSV-II, and CMV, Epstein-Barr virus), adenovirus, influenza virus, flaviviruses, echovirus, rhinovirus, coxsackievirus, coronavirus, respiratory syncytial virus, mumps virus, rotavirus, measles virus, rubella virus, carvovirus, vaccinia virus, human T-lymphotropic virus, dengue virus, papillomavirus, molluscum virus, polio virus, rabies virus, John Cunningham virus, and arbovirus encephalitis virus, pathogenic bacterial infections caused by chlamydia, rickettsial bacteria, mycobacteria, staphylococci, streptococci, pneumococci, meningococci and gonococci, klebsiella, proteus, serratia, pseudomonas aeruginosa, Escherichia coli, legionella, diphtheria bacteria, salmonella, rod-shaped bacteria (bacilli), bacteria that cause cholera, tetanus, botulism, anthrax, plague, leptospirosis and Lyme disease, pathogenic infections caused by fungi of the genus Candida (albicans, krusei, glabrata, tropicalis, etc.), yeast fungi, fungi of the genus Aspergillus (fumigatus, niger, etc.), mold fungi (mucor, absidia, rhizophus), Sporothrix schenkii, Blastomyces dermatitidis, Paracoccidioides brasiliensis, Coccidioides immitis and Histoplasma capsulatum, and pathogenic infections caused by the parasites Entamoeba histolytica, Balantidium coli, Naegleriafowleri, Acanthamoeba sp., Giardia lambia, Cryptosporidium sp., Pneumocystis carinii, Plasmodium vivax, Babesia microti, Trypanosoma brucei, Trypanosoma cruzi, Leishmania donovani, Toxoplasma gondi, Nippostrongylus brasiliensis.

In some embodiments, the compounds of the present invention can be used to suppress HIV infection, slow the progression of AIDS, eradicate the HIV viral reservoir, or reduce the severity of symptoms of either HIV infection or AIDS.

The compounds of the present invention can be used to treat cancerous and precancerous conditions in a subject.

The methods of treatment described in the present invention include administering to a patient an effective amount of one or more compounds described herein. Suitable patients include patients suffering from or susceptible to (i.e., prophylactic treatment of) a disease or disorder described herein. Typical patients for the treatment described in the present invention include mammals, in particular primates, especially humans. Other suitable patients include companion animals such as dogs, cats, horses, etc., or farm animals such as cattle, pigs, sheep, etc.

In general, the methods of treatment described herein comprise administering to a patient an effective amount of one or more compounds described herein. In a preferred embodiment, the compound(s) of the present invention are preferably administered to the patient (e.g., a human) intravenously, orally, or topically. An effective amount can be an amount sufficient to modulate PD-1/PD-L1 interaction and/or an amount sufficient to reduce or ameliorate symptoms in the patient. Preferably, the amount administered is sufficient to provide a plasma concentration of the compound (or its active metabolite, if the compound is a prodrug) high enough to substantially modulate PD-1/PD-L1 interaction. Treatment regimens can vary depending on the compound employed and the particular condition being treated; for the treatment of most disorders, the preferred frequency of administration is 4 times daily or less. In general, twice daily administration is more preferred, and once daily administration is particularly preferred. It should be understood, however, that the specific dosage level and administration regimen for any particular patient will depend on a number of factors, including the activity of the particular compound, age, body weight, general health, sex, diet, time of administration, route of administration, rate of elimination, drug combinations (e.g., other drugs administered to the patient), and the severity of the particular disorder being treated, as well as the judgment of the treating physician. In general, it is preferable to use the minimum dosage sufficient to provide effective therapy. Therapeutic efficacy in patients may be monitored using medical or veterinary criteria appropriate to the particular disorder being treated.

Combinations

The combined preparation containing the compounds of the present invention and another drug can be administered as a combined preparation in which both components are contained in one finished form, or as separate preparations. The administration of separate preparations includes simultaneous administration and administration at certain time intervals. In the case of administration at certain time intervals, the compound of the present invention can be administered first, and then the other drug can be administered, or the other drug can be administered first, and then the compound of the present invention can be administered. The method of administration of the respective drugs can be the same or different.

The dosage of the other drug can be appropriately selected based on clinically applicable dosages. The ratio of the amount of the compound of the present invention and the other drug can be appropriately selected according to the age and body weight of the subject to be administered, the route of administration, the time of administration, the disease to be treated, its symptoms, and a combination thereof. For example, the other drug can be used in an amount of 0.01 to 100 parts by weight relative to 1 part by weight of the compound of the present invention. The other drug may be a combination of two or more kinds of independent drugs in a desired ratio.

The compounds of the present invention can be used or combined with one or more therapeutic agents such as an antimicrobial agent, an antiviral agent, a cytotoxic agent, a gene expression modulating agent, a chemotherapeutic agent, an anticancer agent, an antiangiogenic agent, an immunotherapeutic agent, an antihormonal agent, an antifibrotic agent, a radiation therapy agent, an antitumor agent, and an antiproliferative agent. These therapeutic agents can be in the form of compounds, antibodies, polypeptides, or polynucleotides.

6. The compounds of the present invention can be used or combined with one or more of the following: therapeutic antibodies, bispecific antibodies and “antibody-like” therapeutic proteins (such as DARTs®, Duobodies®, Bites®, XmAbs®, TandAbs®, Fab derivatives), antibody-drug conjugates, a virus, an oncolytic virus, gene modifiers or editors such as CRISPR (including CRISPR Cas9), zinc finger nucleases or synthetic nucleases (TALEN), chimeric antigen receptor T cell immunotherapy agents, or any combination thereof.

Examples of chemotherapeutic agents include alkylating agent, nitrosourea agent, antimetabolite, anticancer antibiotics, plant alkaloid, topoisomerase inhibitor, hormonal drug, hormone antagonist, aromatase inhibitor, P-glycoprotein inhibitor, platinum complex derivatives, other immunotherapeutic agents, and other anticancer drugs.

The compounds of the present invention can be used or combined with an adjuvant anticancer therapy agent such as a drug for treating leukopenia (neutropenia), a drug for treating thrombocytopenia, an antiemetic drug, and a drug for treating cancer pain, in the form of concomitant or combination therapy.

The compounds of the present invention may be used or combined with a kinase inhibitor.

In one embodiment, the compounds of the present invention can be used with another immunomodulator and/or stimulant in the form of concomitant or combination therapy. Examples of an immunomodulator include various cytokines, vaccines and adjuvants. Examples of such cytokines, vaccines and adjuvants that stimulate an immune response include, but are not limited to, GM-CSF, M-CSF, G-CSF, interferon-alpha, beta or gamma, IL-1, IL-2, IL-3, IL-12, Poly (I:C) and CPG. Stimulating agents include cyclophosphamide and cyclophosphamide analogs, anti-TGF and imatinib (Gleevac), a mitotic inhibitor such as paclitaxel, sunitinib (Sutent) or other antiangiogenic agents, an aromatase inhibitor such as letrozole, an A2a adenosine receptor (A2AR) antagonist, an angiogenesis inhibitor, anthracyclines, oxaliplatin, doxorubicin, TLR4 antagonists, and IL-18 antagonists.

In some embodiments, the compounds of the present invention may be used or combined with one or more modulators of CCR1, CCR2, CCR3, CCR4, CCR5, CCR6, CCR7, CCR8, CCR9, CCR10, CCR11, CXCR1, CXCR2, CXCR3, CXCR4, CXCR5, CXCR6, CXCR7, ChemR23, C5aR, C5a, and C5. In some embodiments, the modulator is an antagonist.

In some embodiments, the compounds of the present invention may be used or combined with one or more chemokine and/or chemotactic receptor antagonists described, for example, in WO2007/002667, WO2007/002293, WO/2003/105853, WO/2007/022257, WO/2007/059108, WO/2007/044804, WO2007/115232, WO2007/115231, WO2008/147815, WO2010/030815, WO2010/075257, WO2011/163640, WO2010/054006, WO2010/051561, WO2011/035332, WO2013/082490, WO2013/082429, WO2014/085490, WO2014/100735, WO2014/089495, WO2015/084842, WO2016/187393, WO2017/127409, WO 2017/087607, WO2017/087610, WO2017/176620, WO2018/222598, WO2018/222601, WO2013/130811, WO2006/076644, WO2008/008431, WO2009/038847, WO2008/008375, WO2008/008374, WO2008/010934, WO2009/009740, WO2005/112925, WO2005/112916, WO2005/113513, WO2004/085384, WO2004/046092. Chemokine and/or chemotactic receptor antagonists that can be used according to the present invention also include CCX354, CCX9588, CCX140, CCX872, CCX598, CCX6239, CCX9664, CCX2553, CCX3587, CCX3624, CCX 2991, CCX282, CCX025, CCX507, CCX430, CCX765, CCX224, CCX662, CCX650, CCX832, CCX168, CCX168-M1, CCX3022 and/or CCX3384.

Dosage

Dosages of about 0.1 mg to about 140 mg per kilogram of body weight per day may be used in the treatment or prophylaxis of conditions involving the PD-1/PD-L1 interaction (about 0.5 mg to about 7 g per person per day). The amount of active substance that can be combined with carriers to produce a single dosage form varies depending on the particular patient being treated and the route of administration used. Dosage formulations typically contain from about 1 mg to about 500 mg of active substance. For compounds administered orally, transdermally, intravenously or subcutaneously, it is preferred that a sufficient amount of the compound be administered to achieve a plasma concentration of 5 ng (nanogram)/mL to 10 μg (microgram)/mL of blood plasma, more preferably a sufficient amount of the compound to achieve a plasma concentration of 20 ng/mL to 1 μg/mL of blood plasma, most preferably a sufficient amount of the compound to achieve a plasma concentration of 50 ng/mL to 200 ng/mL of blood plasma. For direct administration into the synovium (for the treatment of arthritis), a sufficient amount of the compound should be administered to achieve a local concentration of about 1 micromolar.

The frequency of administration may also vary depending on the compound used and the specific condition being treated. However, for the treatment of most diseases, a regimen of 4 times daily, 3 times daily or less is preferred, with a regimen of once daily or twice daily being particularly preferred. It should be understood, however, that the specific dosage level for any particular patient will depend on a number of factors, including the potency of the particular compound, age, body weight, general health, sex, diet, time of administration, route of administration, rate of elimination, drug combinations (e.g., other drugs being administered to the patient), the severity of the specific condition being treated, and other factors, including the judgment of the treating physician.

In another aspect of the present invention, the compounds of the present invention can be used in various non-pharmaceutical in vitro and in vivo applications. The compounds of the present invention can also be used as positive controls in PD-1/PD-L1 interaction activity tests, i.e. as standards for determining the ability of a candidate to bind to PD-1 and/or PD-L1, or as radiotracers for positron emission tomography (PET) or single photon emission computed tomography (SPECT).

Also included within the scope of the present invention are kits containing a compound of the present invention or a pharmaceutically acceptable salt thereof and instructions for use. The kit may also contain at least one additional reagent. Kits typically include a label indicating the purpose of the contents of the kit. The term "label" includes any written or recorded materials on or within the package of the kit or otherwise accompanying the kit.

Examples

The following examples illustrate various methods for preparing compounds of the present invention, including compounds of formula (I) or (II). The following examples are provided for illustration and not to limit the scope of the present invention.

The reagents and solvents described below can be obtained from commercial sources such as Aldrich Chemical Co. (Milwaukee, Wisconsin, USA). ¹ H NMR spectra were recorded on a Varian Mercury 400 MHz NMR spectrometer. Chemical shifts are reported relative to tetramethylsilane (TMS) and are listed in the order of multiplicity (s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet) and proton number. Mass spectrometry data are reported as mass divided by charge. In the examples, one m/e value is given for each M+H (or MH, when indicated) ion containing the most abundant isotopes of the atoms. In all cases, the isotopic distribution is consistent with the expected formula. Electrospray ionization (ESI) mass spectrometry was performed on a Hewlett-Packard MSD electrospray ionization mass spectrometer equipped with an HP1100 HPLC for sample injection. Typically, the analyte was dissolved in methanol or _CH3CN at a concentration of 0.1 mg/mL, and 1 microliter of the resulting solution was injected into the mass spectrometer scanning ions in the range of 100 to 1000 daltons. All compounds were analyzed in ESI mode with positive or negative ion detection using acetonitrile/water with 1% formic acid as solvent.

In the Examples and throughout the rest of the application, the following abbreviations are used: TLC means Thin Layer Chromatography.

The compounds of the present invention can be synthesized as described below using a variety of reactions known to those skilled in the art. Those skilled in the art will also appreciate that alternative methods for synthesizing the target compounds can be used and that the approaches used herein are not exhaustive but provide workable and practical methods for preparing the compounds of the present invention.

Certain molecules claimed in this patent may exist in different enantiomeric and diastereomeric forms, and all such variations of the compounds are within the scope of the present invention unless a specific enantiomer is indicated.

The detailed descriptions of the experimental procedures used to synthesize the key compounds in this text lead to molecules that are described by identifying physical data and by chemical structure drawings that describe them.

Those skilled in the art will also appreciate that acids and bases are often used during standard processing techniques in organic chemistry. Salts of the parent compounds are sometimes formed if they possess the necessary intrinsic acidity or basicity during the experimental procedures described herein.

Example 1: Synthesis of ((2S,2'S)-2,2'-(((((1S,1'S)-2,2',3,3'-tetrahydro-1H,1'H-[4,4'-biindene]-1,1'-diyl)bis(oxy))bis(5-chloro-2-((5-cyanopyridine-3-yl)methoxy)-4,1-phenylene))bis(methylene))bis(azanediyl))bis(3-hydroxypropanoic acid)

Step a: A solution of (S)-5-((4-chloro-2-formyl-5-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-1-yl)oxy)phenoxy)methyl)nicotinonitrile (350 mg, 0.66 mmol), 5-[[5-[(1S)-4-bromoindan-1-yl]oxy-4-chloro-2-formyl-phenoxy]methyl]pyridine-3-carbonitrile (320 mg, 0.66 mmol), and 2 M aqueous K ₂ CO ₃ (1.0 mL, 2.0 mmol) in dioxane (13 mL) was degassed with nitrogen for 30 min, after which the complex was added [1,1′-bis(diphenylphosphino)ferrocene]-dichloropalladium(II) with dichloromethane (110 mg, 0.13 mmol). After additional degassing for 10 min, the solution was heated to 90ºC and left stirring at this temperature for 4 h. Water (20 ml) was then added to the reaction mixture and the mixture was extracted with 2:1 chloroform:isopropanol (20 ml x 3). The combined organic phases were dried over MgSO ₄ , filtered and evaporated in vacuo. Purification by flash chromatography ( _SiO2 , 50% EtOAc in hexanes to 100% EtOAc) gave 5,5'-((((((1S,1'S)-2,2',3,3'-tetrahydro-1H,1'H-[4,4'-biindene]-1,1'-diyl)bis(oxy))bis(4-chloro-6-formyl-3,1-phenylene))bis(oxy))bis(methylene))dinicotinonitrile.

Step b: A solution of 5,5'-((((((1S,1'S)-2,2',3,3'-tetrahydro-1H,1'H-[4,4'-biindene]-1,1'-diyl)bis(oxy))bis(4-chloro-6-formyl-3,1-phenylene))bis(oxy))bis(methylene))dinicotinonitrile (100 mg, 0.124 mmol) and L-serine (130 mg, 1.24 mmol) was stirred in DMF (4 mL) for 1 h, after which sodium triacetoxyborohydride (0.72 g, 3.4 mmol) was added in small portions over 10 min. The reaction mixture was stirred at room temperature overnight. Most of the DMF was evaporated in vacuo and the residue was purified by reversed-phase preparative HPLC (CH ₃ CN–H ₂ O with 0.1% NH ₄ CO ₃ H) to give ((2S,2'S)-2,2'-(((((1S,1'S)-2,2',3,3'-tetrahydro-1H,1'H-[4,4'-biindene]-1,1'-diyl)bis(oxy))bis(5-chloro-2-((5-cyanopyridine-3-yl)methoxy)-4,1-phenylene))bis(methylene))bis(azanediyl))bis(3-hydroxypropanoic acid). MS: (ES) m/z calculated for C ₅₂ H ₄₆ Cl ₂ N ₆ O ₁₀ [M+H] ⁺ 985.3, found 985.7. ¹ H-NMR (400 MHz, methanol-d ₄ ) δ 9.02 – 8.99 (m, 2H), 8.91 (d, J = 1.9 Hz, 2H), 8.46 (t, J = 1.9 Hz, 2H), 7.51 (s, 2H), 7.36 – 7.29 (m, 4H), 7.30 – 7.24 (m, 2H), 7.08 (s, 2H), 6.08 – 5.94 (m, 2H), 5.41 (s, 4H), 4.61 (s, 4H), 4.37 (d, J = 13.1 Hz, 2H), 4.25 (d, J = 13.0 Hz, 2H), 3.99 (dd, J = 11.9, 3.9 Hz, 2H), 3.84 (dd, J = 11.8, 7.1 Hz, 2H), 3.55 (dd, J = 7.0, 3.9 Hz, 2H), 3.09 – 2.93 (m, 2H), 2.83 – 2.69 (m, 2H), 2.60 – 2.44 (m, 2H), 2.18 – 2.04 (m, 2H).

Biological example: Enzyme-linked immunosorbent assay (ELISA)

96-well plates were coated with 1 μg/ml human PD-L1 (obtained from R&D) in phosphate-buffered saline (PBS) overnight at 4°C. Wells were then blocked with 2% BSA in PBS (w/v) with 0.05% TWEEN-20 for 1 h at 37°C. Plates were washed 3 times with PBS/0.05% TWEEN-20, compounds were serially diluted (1:5) in dilution medium, and added to the ELISA plates. Human PD-1 and 0.3 μg/ml biotin (ACRO Biosystems) were added and incubated for 1 h at 37°C, then washed 3 times with PBS/0.05% TWEEN-20. The second block was performed with 2% BSA in PBS (w/v)/0.05% TWEEN-20 for 10 min at 37°C and the plates were washed 3 times with PBS/0.05% TWEEN-20. Streptavidin-HRP was added for 1 h at 37°C, then the plates were washed 3 times with PBS/0.05% TWEEN-20. TMB substrate was added and the reaction was allowed to proceed for 20 min at 37°C. Stop solution (2 N aqueous _H2SO4 ) _was added. Absorbance was read at 450 nm using a microplate reader. The results are presented in Table 1: _IC50 values are listed as follows: 100 to 10,000 nM (+); less than 100 nM (++).

Table 1

Compound Structure ELISA IC50 (nM) 1.001 + 1.002 ++ 1.003 + 1.004 ++ 1.005 + 1.006 ++ 1.007 1.008 ++ 1.009 ++ 1.010 + 1.011 + 1.012 ++ 1.013 ++ 1.014 ++ 1.015 ++ 1.016 + 1.017 ++ 1.018 ++ 1.019 ++ 1.020 ++ 1.021 + 1.022 + 1.023 + 1.024 ++ 1.025 ++ 1.026 ++ 1.027 ++ 1.028 ++ 1.029 1.030 ++ 1.031 ++ 1.032 ++ 1.033 ++ 1.034 + 1.035 ++ 1.036 ++ 1.037 ++ 1.038 ++ 1.039 ++ 1.040 ++ 1.041 + 1.042 ++ 1.043 + 1.044 ++ 1.045 ++ 1.046 ++ 1.047 ++ 1.048 ++ 1.049 ++ 1.050 ++ 1.051 ++

The compounds from Table 1 were prepared using synthetic procedures similar to those described for Example 1.

7. In the present text, particular embodiments of the invention are described. Upon reading the above description, variations of the described embodiments may be obvious to those skilled in the art, and the skilled person is expected to be able to apply such variations properly. Accordingly, the present invention can be implemented in practice in a manner different from the particular embodiments described in the present text, and the present invention includes all modifications and equivalents of the subject matter of the invention, characterized in the appended claims, within the framework of the current legislation. In addition, any combination of the above-described elements in any possible variations thereof is included in the present invention, unless otherwise specifically indicated or clearly contradicted by the context.

All publications, patent publications, accession numbers and other references cited in this specification are herein incorporated by reference to the same extent as if each individual publication or patent publication was specifically and individually indicated to be incorporated by reference.

Claims (96)

1. A compound having formula (I) or formula (II): or a pharmaceutically acceptable salt thereof, where: Y and Y’ are each independently selected from the group consisting of O and NH; R ¹ is C _1-4 alkyl; each R ^2a and R ^2a' is independently selected from the group consisting of H, halogen, R ^a , and OR ^b wherein each R ^b is C _1-8 alkyl; and each R ^a is C _1-8 alkyl; each R ^2b , R ^2c , R ^2b' and R ^2c' independently represents H; R ³ and R ^3' are each independently selected from the group consisting of -NR ^d R ^e and a 4-6 membered monocyclic non-aromatic ring containing 1 N heteroatom, or an 8-9 membered spirocyclic non-aromatic heterocyclic ring containing 1-3 N heteroatoms, optionally substituted with 1-2 R ^3a substituents; wherein R ^d is selected from the group consisting of H and C _1-8 alkyl; R ^e is selected from H, -C _1-8 alkyl, X ² -CONHSO ₂ R ^g , X ² -SO ₃ R ^g , C _3-10 cycloalkyl, C _4-6 heterocyclyl containing 1 N heteroatom, and X ² -C _4-6 heterocyclyl containing 1 N heteroatom; wherein the alkyl or alkylene portions of R ^e are optionally further substituted with 1 to 3 substituents independently selected from OH, COOH, CONH ₂ , and COO-C _1-8 alkyl; and the C _4-6 heterocyclyl and C _3-10 cycloalkyl moieties of R ^e are optionally substituted with 1 R ^w substituent; each R ^3a is independently selected from the group consisting of oxo, -R ^f , and OC(O)R ^g , X ² is C _1-6 alkylene and optionally further has an OH substituent; each R ^g is independently selected from hydrogen, C _1-8 alkyl optionally substituted with 1-2 substituents selected from NH ₂ ; each R ^f is independently selected from the group consisting of –OH and C _1-8 alkyl; each R ^w is independently selected from OH, and oxo; R ⁴ and R ^4' are each independently selected from the group consisting of -OC _1-8 alkyl, -OC _1-4 alkyl-C ₆ aryl, and -OC _1-4 alkyl-C ₆ heteroaryl containing 1 N heteroatom, each of which optionally has 1-2 R ^4a substituents; each R ^4a is independently selected from the group consisting of CN; where each n is independently equal to 0; R ^6a and R ^6a' are each independently selected from H; each m is independently equal to 0 or 1; and each R ^6b and R ^6b' is independently selected from F. 2. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, having formula (I). 3. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, having formula (II). 4. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein Y and Y’ are each O. 5. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein each subscript m is equal to 1. 6. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein each R ³ and R ^3' independently represents a 4-6-membered monocyclic non-aromatic heterocyclic ring or an 8-9-membered spirocyclic non-aromatic heterocyclic ring, optionally substituted with 1-2 R ^3a substituents. 7. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein each R ³ and R ^3' is independently –NR ^d R ^e . 8. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein each R ^2a and R ^2a' is independently selected from halogen. 9. The compound according to claim 3, or a pharmaceutically acceptable salt thereof, wherein R ¹ is methyl. 10. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein each R ⁴ and R ^4' is independently OC _1-8 alkyl. 11. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein each R ⁴ and R ^4' is independently -OC _1-4 alkyl-pyridyl, each of which optionally has 1-2 R ^4a substituents. 12. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein each R ^2a and R ^2a' is independently halogen; each R ³ is a 4-6 membered monocyclic non-aromatic ring or an 8-9 membered spirocyclic non-aromatic heterocyclic ring optionally substituted with 1-2 R ^3a substituents; and each R ⁴ is selected from the group consisting of -OC _1-8 alkyl, -OC _1-4 alkyl-phenyl and -OC _1-4 alkyl-pyridyl, each of which optionally has 1-2 R ^4a substituents. 13. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein each R ^2a and R ^2a' is independently halogen; and each R ⁴ is selected from the group consisting of -OC _1-8 alkyl, -OC _1-4 alkyl-phenyl and -OC _1-4 alkyl-pyridyl, each of which optionally has 1-2 R ^4a substituents. 14. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein each R ³ and R ^3' is independently selected from the group consisting of . 15. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, Where: Y and Y’ each independently represents O or NH; R ¹ is methyl; each R ^2a and R ^2a' is independently selected from the group consisting of H, methyl, Cl, F and –O–methyl; each R ^2b , R ^2c , R ^2b' and R ^2c' independently represents H; R ³ and R ^3' are each independently selected from the group consisting of –NR ^d R ^e and a 4-6 membered monocyclic non-aromatic ring or an 8-9 membered spirocyclic non-aromatic heterocyclic ring optionally substituted with 1-2 R ^3a substituents; R ^d is selected from the group consisting of H and C _1-8 alkyl; R ^e is selected from H, -C _1-8 alkyl, -X ² -CONHSO ₂ R ^g , X ² -SO ₃ R ^g , C _3-10 cycloalkyl, C _4-6 heterocyclyl containing 1 N heteroatom, and -X ² -C _4-6 heterocyclyl containing 1 N heteroatom, wherein the alkyl or alkylene portions of R ^e are optionally further substituted with 1 to 2 substituents independently selected from OH, COOH, CONH ₂ and COO-C _1-8 alkyl, and the C _4-6 heterocyclyl and C _3-10 cycloalkyl portions of R ^e are optionally substituted with 1 R ^w substituent; X ² is C _1-6 alkylene and is optionally further substituted with OH; each R ^3a is independently selected from the group consisting of oxo, -R ^f and -OC(O)R ^g ; each R ^g is independently selected from H and C _1-8 alkyl optionally substituted with 1 NH ₂ ; each R ^f is independently selected from the group consisting of –OH and C _1-8 alkyl; each R ^w is independently selected from OH and oxo; R ⁴ and R ^4' are each independently selected from the group consisting of -O-ethyl, -O-CH ₂ -pyridyl optionally substituted with 1 R ^4a substituent, and -O-CH ₂ -phenyl optionally substituted with 2 R ^4a substituents; each R ^4a represents –CN; n is 0; R ^6a and R ^6a' each represent H; m is 0 or 1; and R ^6b and R ^6b' each represent F. 16. The compound according to claim 2, or a pharmaceutically acceptable salt thereof, Where: Y and Y' each independently represents O; each R ^2a and R ^2a' independently represents Cl; each R ^2b , R ^2c , R ^2b' and R ^2c' independently represents H; R ³ and R ^3' are each independently selected from the group consisting of –NR ^d R ^e and a 4-6 membered monocyclic non-aromatic ring or an 8-9 membered spirocyclic non-aromatic heterocyclic ring optionally substituted with 1-2 R ^3a substituents; R ^d is selected from the group consisting of H and C _1-8 alkyl; R ^e is selected from H, -C _1-8 alkyl, -X ² -CONHSO ₂ R ^g , C _3-10 cycloalkyl, C _4-6 heterocyclyl containing 1 N heteroatom, and -X ² -C _4-6 heterocyclyl containing 1 N heteroatom, wherein the alkyl or alkylene portions of R ^e are optionally further substituted with 1 to 2 substituents independently selected from OH, COOH, CONH ₂ and COO-C _1-8 alkyl, and the C _4-6 heterocyclyl and C _3-10 cycloalkyl portions of R ^e are optionally substituted with 1 R ^w substituent; X ² is C _1-6 alkylene and is optionally further substituted with OH; each R ^3a is independently selected from the group consisting of oxo and -R ^f ; each R ^g is C _1-8 alkyl; each R ^f is independently selected from the group consisting of –OH and C _1-8 alkyl; each R ^w is independently selected from OH and oxo; R ⁴ and R ^4' are each independently selected from the group consisting of -O-ethyl, -O-CH ₂ -pyridyl optionally substituted with 1 R ^4a substituent, and -O-CH ₂ -phenyl optionally substituted with 2 R ^4a substituents; each R ^4a represents –CN; n is 0; R ^6a and R ^6a' each represent H; and m is equal to 0. 17. The compound according to claim 3, or a pharmaceutically acceptable salt thereof, Where: Y and Y’ each independently represents O or NH; R ¹ is methyl; each R ^2a and R ^2a' is independently selected from the group consisting of H, methyl, Cl, F and –O–methyl; each R ^2b , R ^2c , R ^2b' and R ^2c' independently represents H; R ³ and R ^3' are each independently selected from the group consisting of –NR ^d R ^e and a 4-6 membered monocyclic non-aromatic ring or an 8-9 membered spirocyclic non-aromatic heterocyclic ring optionally substituted with 1-2 R ^3a substituents; R ^d is selected from the group consisting of H and C _1-8 alkyl; R ^e is selected from -C _1-8 alkyl and -X ² -SO ₃ R ^g , wherein the alkyl or alkylene portions of R ^e are optionally further substituted with 1-2 substituents independently selected from OH, COOH, and COO-C _1-8 alkyl; each R ^3a is independently selected from the group consisting of -R ^f and -OC(O)R ^g ; X ² is C _1-6 alkylene; each R ^g is independently selected from H and C _1-8 alkyl optionally substituted with 1-2 NH ₂ ; each R ^f represents –OH; each R ^w is independently selected from OH and oxo; R ⁴ and R ^4' each represent –O-ethyl; n is 0; R ^6a' represents H; m is 0 or 1; and R ^6b and R ^6b' each represent F. 18. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from Connection ID Structure 1.002 1.004 1.006 1.009 1.012 1.013 1.014 1.015 1.017 1.018 1.019 1.020 1.025 1.026 1.027 1.028 1.030 1.031 1.032 1.033 1.035 1.036 1.038 1.039 1.040 1.042 1.044 1.045 1.046 1.047 1.048 1.049 1.050 1.051 19. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is an optically pure or enriched isomer. 20. A pharmaceutical composition for inhibiting PD-L1, comprising a compound according to any one of claims 1-19, or a pharmaceutically acceptable salt thereof in an effective amount, and a pharmaceutically acceptable excipient.