WO2025085652A1 - Indole carboxamides useful as rac1 inhibitors - Google Patents

Abstract

Disclosed is a compound of Formula I, or a pharmaceutically acceptable salt thereof. The variables are defined herein. Also disclosed are pharmaceutical compositions comprising a compound of Formula I and their use for treating cancer.

Description

136280-00820 INDOLE CARBOXAMIDES USEFUL AS RAC1 INHIBITORS CROSS-REFERENCE TO RELATED APPLICATION [001] This application claims the benefit of U.S. Provisional Application No. 63/544,524, filed on October 17, 2023, the entire contents of which are incorporated herein by reference. BACKGROUND [002] The Rho GTPases Rac (Ras-related C3 botulinum toxin substrate) and Cdc42 (cell division control protein 42 homolog) regulate cell functions governing cancer malignancy, including cell polarity, migration, and cell cycle progression. The Rho family of GTPases in humans consists of 20 different members, and aberrant behavior in their regulatory activity has been implicated in cancer and other diseases. More than 70 guanine nucleotide exchange factors (GEFs) are known, which specifically activate one or more of the GTPases. In turn, the activated GTPases can specifically interact with over 60 downstream effectors. Dysregulation of one or more cellular processes can lead to release of malignant cells from their original locations, which subsequently can establish themselves in pre-metastatic niches in, for example, bone or lungs. It has been found that members of the Rho GTPase family, including Rac, Cdc42 and Rho, play key signaling roles in these processes. [003] Rho GTPases regulate migration and invasion, cytoskeletal organization, transcriptional regulation, cell cycle progression, apoptosis, vesicle trafficking, and cell-to- cell and cell-to-extracellular matrix adhesions. The Rho GTPases Rac and Cdc42 are potent inducers of actin polymerization and extension of actin structures at the leading edge of motile cells. In addition, Cdc42 plays a critical role in cell polarity, and thus, promotes directed and persistent migration. [004] Hyperactive Rac and Cdc42 are associated with increased cancer cell survival, proliferation, and invasion, as well in Ras and other oncogene-mediated transformation. Furthermore, oncogenic cell surface receptors, such as tyrosine kinase, cytokine, and G protein coupled receptors, activate Rac and Cdc42 via regulation of their upstream effector GEFs. [005] Despite the recognized role of Rac1 in promoting tumor progression, there are no approved drugs that target this signaling protein. Although a handful of Rac1 inhibitors have been reported, the reported inhibitors have not been suitable for clinical development due to 136280-00820 low potency or poor drug properties. [006] NSC23766 was identified as a small molecule that binds to a putative binding pocket in the surface groove of Racl that interacts with the Rac-specific GEFs Trio and Tiam1.

NSC23766 [007] NSC23766 has been shown to inhibit the anchorage-independent growth and invasion of human prostate cancer PC-3 cells as well as Rac activation and Rac-dependent aggregation of platelets stimulated by thrombin. It also inhibits Rac1 and Rac2 activities of hematopoietic stem/progenitor cells and migration from mouse bone marrow to peripheral blood. NSC23766 has also been shown to inhibit invasion of chronic myelogenous leukemia cells in vitro and in vivo in a mouse model. However, NSC23766 is a relatively weak Rac inhibitor, with a high IC₅₀ of 50-100 µM in fibroblasts. The weak activity of NSC23766 limits its potential use as a therapeutic agent. [008] US Patent 8,884,006 discloses a derivative of NSC23766, EHop-016, that is a more potent inhibitor of Rac1:

EHop-016 [009] EHop-016 is reported to be 100-fold more efficient than NSC23766 as an inhibitor of Rac activity. In MDA-MB-435 breast cancer cells, EHop-016 (<5 mM) inhibits the association of the Rac-GEF Vav2 with a nucleotide-free Rac I (G15A), which has a high affinity for activated GEFs. EHop-016 does not affect the association of the Rac-GEF Tiam- 1with Rac1 (G15A) at similar concentrations. EHop-0l6 also inhibits the Rac activity of 136280-00820 MDA-MB-231 metastatic breast cancer cells and reduces Rac-directed lamellipodia formation in both cell lines. Despite its improved potency, EHop-016 does not have a favorable in vivo pharmacokinetic profile, with low systemic exposure after oral administration in mice. Humphries-Bickley et al. J Chromatography B (2015), Volume 981- 982, 19-26. [0010] US Patent 1047235 and Molecular Cancer Therapeutics (2019), 18(5), 957-968 describes GYS32661:

GYS32661 [0011] GYS32661 shows very good activity against animal models of estrogen positive and HER2 positive breast cancer, prostate cancer, melanoma and colorectal cancer as a single agent and in combination with standard of care. GYS32661 is not orally bioavailable. [0012] While Rac and Cdc42 GTPases are hyperactive or overexpressed in many types of cancer, there are no drugs for these important targets. As there is a continuing need for new therapeutic agents to treat cancer and other hyperproliferative diseases, it is desirable to have new inhibitors of Rac and/or Cdc42 with improved activity and pharmacokinetic properties. SUMMARY OF THE INVENTION [0013] It has now been found that certain indole carboxamide compounds disclosed herein have potent activity against wild type Rac1 and certain genomic variants thereof such as Rac1b and Rac1 P29S. A number of these compounds are significantly more potent than the aforementioned prior art compounds with an IC50 inhibitory concentration versus wild type Rac1 below 1.0 µM in an AlphaLisa assay (see the section entitled “In Vitro Assays” below subsection 2 and Tables 1-4). By comparison, the reference standard Ehop-016 has an IC₅₀ of about 10 µM in the same assay. Based on this discovery, pharmaceutical compositions comprising the disclosed Rac1 inhibitors and methods of treating cancer with the disclosed Rac1 inhibitors are described herein. 136280-00820 [0014] One embodiment of the invention relates to a compound of Formula I:

or a pharmaceutically acceptable salt thereof, wherein R¹ is hydrogen, halo, or C1-3 alkyl; R² is hydrogen, halo, C1-5 alkyl, -OH, -OC(O)(C1-6 alkyl), C1-3 haloalkyl, C1-3 hydroxyalkyl, CONH₂, CONH(C_1-3 alkyl), CONH(C_1-3 alkyl)₂, CHO, CN, or C_1-4 alkoxy; R³ is hydrogen, halo, C_1-5 alkyl, -OH, -OC(O)(C_1-6 alkyl), C_1-3 haloalkyl, or C_1-4 alkoxy; R⁴ is hydrogen, halo, or C_1-3 alkyl; Q is -CO₂(C_1-4 alkyl), -CONH(C_1-4 alkyl), phenyl or 5-6 membered heteroaryl, wherein the phenyl or heteroaryl is optionally substituted by R⁵; R⁵ is C1-5 alkyl, -O(C1-4 alkyl), -C(O)(C1-4 alkyl), -CO2(C1-4 alkyl), -C(O)(C1-4 haloalkyl), C_1-3 hydroxyalkyl, -CONH(C_1-4 alkyl), -C(O)(C_1-4 haloalkyl), or -CO₂(C_1-4 haloalkyl); and provided that when each of R¹, R², R³ and R⁴ are hydrogen, Q is other than -CO₂CH₂CH₃. [0015] Another embodiment of the invention relates to a pharmaceutical composition comprising a compound of Formula I or pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient, carrier or diluent. The invention further provides a method of treating cancer in a patient comprising administering to the patient an effective amount of a pharmaceutical composition disclosed herein. Alternatively, the invention is a method of treating cancer in a patient comprising administering to the patient an effective amount of a Rac1 inhibitor disclosed herein or a pharmaceutically acceptable salt thereof. 136280-00820 [0016] Another embodiment of the invention is a disclosed Rac1 inhibitors in which one or more hydrogen atoms are replaced by deuterium. Also included are pharmaceutical compositions comprising the deuterated Rac1 inhibitors and methods of treating cancer in a patient by administering to the patient an effective amount of the deuterated Rac1 inhibitors or pharmaceutical compositions comprising the same. DETAILED DESCRIPTION OF THE INVENTION [0017] Disclosed herein are Rac1 inhibitors which can be used in the treatment of a variety of cancers and pharmaceutical compositions comprising the same and a pharmaceutically acceptable excipient, carrier or diluent. [0018] The Rac1 inhibitors used in the disclosed pharmaceutical compositions and methods of treatment are represented by Formula I above or a pharmaceutically acceptable salt thereof. One embodiment of the invention relates to a compound of Formula I or pharmaceutically acceptable salt thereof, wherein: R¹ is hydrogen, halo, or C_1-3 alkyl; R² is R² is hydrogen, halo, C1-5 alkyl, -OH, -OC(O)(C1-6 alkyl), C1-3 haloalkyl, C1-3 hydroxyalkyl, CONH2, CONH(C1-3 alkyl), CONH(C1-3 alkyl)2, CHO, CN, or C1-4 alkoxy; R³ is hydrogen, halo, C_1-5 alkyl, -OH, C_1-3 haloalkyl, or C_1-4 alkoxy; R⁴ is hydrogen, halo, or C_1-3 alkyl; Q is -CO₂(C_1-4 alkyl), -CONH(C_1-4 alkyl), phenyl or 5-6 membered heteroaryl, wherein the phenyl or heteroaryl is optionally substituted by R⁵; and R⁵ is C1-5 alkyl, -O(C1-4 alkyl), - C(O)(C1-4 alkyl), -CO2(C1-4 alkyl), -C(O)(C1-4 haloalkyl), -CONH(C1-4 alkyl), -C(O)(C1-4 haloalkyl), C_1-3 hydroxyalkyl, or -C(O₂)(C_1-4 haloalkyl); provided that when each of R¹, R², R³ and R⁴ are hydrogen, Q is other than -CO2CH2CH3. [0019] Another embodiment of the invention relates to a compound of Formula I or pharmaceutically acceptable salt thereof, wherein: R¹ is hydrogen, halo, or C_1-3 alkyl; R² is hydrogen, C1-3 hydroxyalkyl, halo, C1-5 alkyl, -OH, C1-3 haloalkyl, or C1-4 alkoxy; R³ is hydrogen, halo, C1-5 alkyl, -OH, C1-3 haloalkyl, or C1-4 alkoxy; R⁴ is hydrogen, halo, or C1-3 alkyl; Q is a phenyl or 5-6 membered heteroaryl, wherein the phenyl or heteroaryl is optionally substituted by R⁵; and R⁵ is C_1-5 alkyl, -O(C_1-4 alkyl), -C(O)(C_1-4 alkyl), -CO₂(C_1-4 alkyl), -C(O)(C1-4 haloalkyl), -CONH(C1-4 alkyl), -C(O)(C1-4 haloalkyl), or -CO2(C1-4 haloalkyl). In one aspect of this embodiment, R¹ is hydrogen or C1-3 alkyl and R⁴ is hydrogen or C_1-3 alkyl. In another aspect, R¹ is hydrogen or C_1-3 alkyl; R⁴ is hydrogen or C_1-3 alkyl; one of R³ and R⁴ is hydrogen, -OH or alkyl and the other of R³ and R⁴ is halo, C1-5 alkyl, -OH, C1- 136280-00820 3 haloalkyl, or C1-4 alkoxy. In another aspect, R¹ is hydrogen or C1-3 alkyl; R⁴ is hydrogen or C1-3 alkyl; one of R³ and R⁴ is hydrogen and the other of R³ and R⁴ is halo, C1-5 alkyl, -OH, C_1-3 haloalkyl, or C_1-4 alkoxy. In another aspect, R¹ is hydrogen or C_1-3 alkyl; R² is halo, C_1-5 alkyl, -OH, C1-3 haloalkyl, or C1-4 alkoxy R³ is hydrogen or C1-3 alkyl; and R⁴ is hydrogen or C1-3 alkyl. In another aspect R³ is -OH. [0020] One embodiment of this invention provides compounds of Formula I or pharmaceutically acceptable salt thereof, wherein R¹ and R⁴ are each hydrogen; R² is -OH, - OC(O)(C1-6 alkyl), C1-3 hydroxyalkyl, CONH2, CONH(C1-3 alkyl), CONH(C1-3 alkyl)2; R³ is hydrogen, halo, C1-5 alkyl, -OH, -OC(O)(C1-6 alkyl), C1-3 haloalkyl, or C1-4 alkoxy; Q is a 5-6 membered heteroaryl that is optionally substituted by R⁵; and R⁵ is C_1-5 alkyl or C_1-3 hydroxyalkyl. [0021] One embodiment relates to compounds of Formula I or pharmaceutically acceptable salt thereof, wherein Q is an optionally substituted 5- to 6-membered heteroaryl ring. Examples of Q include furanyl, pyridyl, thienyl, oxazolyl, pyrazolyl, pyrrolyl, isoxazolyl, and thiazolyl. In one embodiment, Q is 5-methyl-furan-2-yl, 2-methyl-oxazol-5-yl, oxaxol-5-yl, pyridin-3-yl, pyridin-2-yl, or thiazol-5-yl. Examples of optional R⁵ substituents of Q include methyl, ethyl, propyl, hydroxymethyl, C(O)CH₃, and C(O)CF₃. Another embodiment of this invention provides compounds of Formula I or pharmaceutically acceptable salt thereof, wherein R¹ is H; R² is OH, OCH3, F, CHO, CONH2, CONH(CH3)2, CONHCH3, CH2NH2, CHF₂, CN, CH₂OH or CH(OH)CH₃; R³ is H, OH, OCH₃ or CH₃; R⁴ is H or CH₃; and Q–R⁵ is CO2Me or CO2Et or furanyl, pyridyl, thienyl, oxazolyl, pyrazolyl, pyrrolyl, isoxazolyl or thiazolyl, each optionally substituted with CH3 or CH2CH3^. Table 1. Examples of Compounds of Formula I

Q Rings: 136280-00820

No. R¹ R² R³ R⁴ Activity 101 H OCH3 H H †† 102 H OH H H ††† 103 H H OH H ††† 104 H H OCH3 H †† 105 H F H H †† 106 H CHO H H †† 107 H F F H †† 108 H OH CH3 H ††† 109 H H OH CH₃ NA 110 H CONH2 H H ††† 111 H CONH(CH3)2 H H NA 112 H CONHCH₃ H H NA 113 H CH2NH2 H H NA 114 H CHF2 H H NA 115 H CN H H NA 116 H CH₂OH H H †† 136280-00820 No. R¹ R² R³ R⁴ Activity 117 H CH(OH)CH3 H H NA 118 H OH H H ††† 119 H OH H H ††† 120 H H H H 121 H H H H †† 122 H OH H H ††† 123 H OH H H ††† 124 H OH H H ††† 125 H OH H H NA 126 H OH H H ††† 127 H OH H CH3 ††† 128 H CONH2 H H ††† 129 H CHO H H 130 H OH H H 131 H H H H 132 H H H H 133 H OH H H 134 H OH H H 135 H H H H [0022] The IC50 values reported in Tables 1-6 were obtained from the Rac Activation AlphaScreen Assay (Racl AS) assay described in subsection 2 under the section entitled “In Vitro Assays”. “†” represents an IC₅₀ of greater than 50 uM; “††” represents an IC₅₀ of greater than 5 uM and less than 50 uM; and “†††” represents an IC₅₀ of less than 5 uM. 136280-00820 [0023] Another embodiment of the invention is a disclosed Rac1 inhibitor in which one or more hydrogen atoms are replaced by deuterium. When a hydrogen atom is replaced by deuterium at a particular position, the position is understood to have deuterium at an abundance that is at least 3000 times greater than the natural abundance of deuterium, which is 0.015% (i.e., at least 45% incorporation of deuterium). Alternatively, the deuterium incorporation is at least 52.5% at each designated position, at least 60% at each designated position, at least 67.5% at each designated position, at least 75% at each designated position, at least 82.5% at each designated position, at least 90% at each designated position, at least 95% at each designated position, at least 97% at each designated position, at least 99% at each designated position, or at least 99.5% at each designated position. [0024] In one aspect, each R group of the disclosed Rac1 inhibitors is independently deuterated when the R group is alkyl or alkoxy. In another aspect, the deuterated R group is perdeuterated, i.e., all of the hydrogen atoms are replaced with deuterium. [0025] In another aspect, each alkylene carbon of an R group is independently substituted with 0 or 2 deuterium. –(CH2)n- is an alkeylene group. In yet another aspect, each R group as just described in the preceding paragraph is perdeuterated or each alkylene carbon of an R group is independently substituted with 0 or 2 deuterium. [0026] When a position is designated specifically as “H” or “hydrogen”, the position is understood to have hydrogen at its natural abundance isotopic composition. When a position is designated specifically as “D” or “deuterium”, the position is understood to be enriched in deuterium, as described above. When there is no specific designation as to whether a position has hydrogen or deuterium, it is understood that the position has hydrogen at natural abundance. For example, the term “methyl”, unless there is a specific designation to the contrary, is understood to mean –CH3 with all three hydrogen atoms present at natural abundance, and the term “phenyl”, unless there is a specific designation to the contrary, means all five hydrogen atoms to be present at natural abundance. [0027] As used herein, "alkyl" refers to a fully saturated branched or unbranched hydrocarbon moiety. Unless otherwise specified, an alkyl comprises 1 to 4 carbon atoms. Representative examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, iso- propyl, n-butyl, sec-butyl, iso-butyl and tert-butyl. [0028] "Halogen" or "halo" may be fluoro, chloro, bromo or iodo. 136280-00820 [0029] As used herein, the term "heteroaryl" refers to an aromatic 5- to 6-membered monocyclic or a 7- to 10- membered bicyclic ring system, having 1 to 4 heteroatoms independently selected from O, N and S, and wherein N can be oxidized (e.g., N(O)) or quaternized, and S can be optionally oxidized to sulfoxide and sulfone. Examples of 5- to 6- membered monocyclic heteroaryls include, but are not limited to, pyrrolyl, furanyl, thiophenyl (or thienyl), imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, furazanyl, oxadiazolyl, thiadiazolyl, dithiazolyl, triazolyl, tetrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, tetrazinyl, and the like. Examples of 8- to 10-membered bicyclic heteroaryls include, but are not limited to, dihydropyrrolopyrrolyl, indolyl, isoindolyl, benzimidazolyl, benzothiazolyl, quinolinyl, isoquinolinyl, quinazolinyl and purinyl. [0030] In many cases, the compounds of the present invention are capable of forming acid and/or base salts by virtue of the presence of amino and/or carboxyl groups or groups similar thereto. As used herein, the terms “salt” or “salts” refers to an acid addition or base addition salt of a compound of the invention. “Salts” include in particular “pharmaceutical acceptable salts”. The term “pharmaceutically acceptable salts” refers to salts that retain the biological effectiveness and properties of the compounds of this invention and, which typically are not biologically or otherwise undesirable. [0031] Pharmaceutically acceptable acid addition salts can be formed with inorganic acids and organic acids, e.g., tosylate, methanesulfonate, acetate, citrate, malonate, tartarate, succinate, benzoate, hydrochloride, sulfate, nitrate, bicarbonate, phosphate and carbonate salts. . Lists of additional suitable salts can be found, e.g., in REMINGTON'S PHARMACEUTICAL SCIENCES, 20th ed., Mack Publishing Company, Easton, Pa., (1985); and in HANDBOOK OF PHARMACEUTICAL SALTS: PROPERTIES, SELECTION, AND USE, by Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002). [0032] As used herein, the term “pharmaceutically acceptable carrier” includes any and all solvents, dispersion media, coatings, surfactants, antioxidants, preservatives (e.g., antibacterial agents, antifungal agents), isotonic agents, absorption delaying agents, salts, preservatives, drug stabilizers, binders, excipients, disintegration agents, lubricants, sweetening agents, flavoring agents, dyes, and the like and combinations thereof, as would be known to those skilled in the art (see, for example, 136280-00820 REMINGTON'S PHARMACEUTICAL SCIENCES, 18th Ed. Mack Printing Company, 1990, pp. 1289-1329). Except insofar as any conventional carrier is incompatible with the active ingredient, its use in the therapeutic or pharmaceutical compositions is contemplated. [0033] The term “effective amount” (used interchangeably with “therapeutically effective amount”) of a compound of the present invention refers to an amount of the compound of the present invention that will elicit the biological or medical response of a subject, for example, reduction or inhibition of an enzyme or a protein activity, or ameliorate symptoms, alleviate conditions, slow or delay disease progression, or reduce the likelihood or delay reoccurrence of a disease, etc. In one non-limiting embodiment, the term “a therapeutically effective amount” refers to the amount of the compound of the present invention that, when administered to a subject, is effective to (1) at least partially alleviate, inhibit and/or ameliorate a condition, or a disorder or a disease (i) mediated by hyperactivation of Rac1 or (ii) associated with overexpression of Rac1, or (iii) characterized by activity (normal or abnormal) of Rac1. [0034] In another non-limiting embodiment, the term “a therapeutically effective amount” or “an effective amount” refers to the amount of the compound of the present invention that, when administered to a cell, or a tissue, or a non-cellular biological material, or a medium, is effective to at least partially reduce or inhibit the activity of Rac1, or at least partially reduce or inhibit the expression of Rac1. [0035] As used herein, the term “subject” refers to an animal. Typically, the animal is a mammal. A subject also refers to for example, primates (e.g., humans, male or female), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds and the like. In certain embodiments, the subject is a primate. In specific embodiments, the subject is a human. [0036] As used herein, the term “inhibit”, “inhibition” or “inhibiting” refers to the reduction or suppression of a given condition, activity, effect, symptom, or disorder, or disease, or a significant decrease in the baseline activity of a biological activity or process. [0037] As used herein, the term “treat”, “treating” or “treatment” of any disease or disorder refers in one embodiment, to ameliorating the disease or disorder (i.e., slowing or arresting or reducing the development of the disease or at least one of the clinical symptoms thereof). In another embodiment “treat”, “treating” or “treatment” refers to alleviating or ameliorating at 136280-00820 least one physical parameter including those which may not be discernible by the patient. In yet another embodiment, “treat”, “treating” or “treatment” refers to modulating the disease or disorder, either physically, (e.g., stabilization of a discernible symptom), physiologically, (e.g., stabilization of a physical parameter), or both. In yet another embodiment, “treat”, “treating” or “treatment” refers to delaying the progression of the disease or disorder. In another embodiment, “treat”, “treating” or “treatment” refers to reducing the likelihood or delaying reoccurrence of the disease or disorder after it has gone into remission. [0038] The pharmaceutical composition or combination of the present invention can be in unit dosage of about 1-2000 mg of active ingredient(s) for a subject of about 50-70 kg, of active ingredients. The therapeutically effective dosage of a compound, the pharmaceutical composition, or the combinations thereof, is dependent on the species of the subject, the body weight, age and individual condition, the disorder or disease being treated and the severity thereof. A physician, clinician or veterinarian of ordinary skill can readily determine the effective amount of each of the active ingredients necessary to prevent, treat or inhibit the progress of the disorder or disease. [0039] As indicated above, a further embodiment of the invention relates to a pharmaceutical composition comprising at least one compound of the invention and a pharmaceutically acceptable diluent, excipient, or carrier. [0040] The compounds of the invention are typically administered with suitable pharmaceutical diluents, excipients, or carriers (collectively referred to herein as pharmaceutically acceptable carriers). Suitable pharmaceutical diluents, excipients, and carriers include, but are not limited to, lubricants, solvents, binders, and stabilizers that are suitably selected with respect to the intended form of administration including solid and liquid forms, such as capsules, tablets, gels, solutions, syrups, suspensions, powders, aerosols, ointments, and the like. [0041] Diluents that may be used in the compositions of the invention include but are not limited to dicalcium phosphate, calcium sulfate, lactose, cellulose, kaolin, mannitol, sodium chloride, dry starch, powdered sugar and hydroxy propyl methyl cellulose (HPMC). The binders that may be used in the compositions of the invention include but are not limited to 136280-00820 starch and gelatin. Additionally, fillers such as sucrose, glucose, dextrose and lactose may also be used. [0042] Natural and synthetic gums that may be used in the compositions of the invention include but are not limited to sodium alginate, ghatti gum, carboxymethyl cellulose, methyl cellulose, polyvinyl pyrrolidone and veegum. Excipients that may be used in the compositions of the invention include but are not limited to microcrystalline cellulose, calcium sulfate, dicalcium phosphate, starch, magnesium stearate, lactose, and sucrose. Stabilizers that may be used in the compositions of the invention include but are not limited to polysaccharides such as acacia, agar, alginic acid, guar gum and tragacanth, amphotsics such as gelatin and synthetic and semi-synthetic polymers such as carbomer resins, cellulose ethers and carboxymethyl chitin. [0043] Solvents that may be used in the composition of the invention include but are not limited to Ringers solution, water, distilled water, dimethyl sulfoxide to 50% in water, propylene glycol (neat or in water), phosphate buffered saline, balanced salt solution, glycol and other conventional fluids. [0044] The dosages and dosage regimen in which the compounds of the invention are administered will vary according to the dosage form, mode of administration, the condition being treated and particulars of the patient being treated. Accordingly, optimal therapeutic concentrations will be best determined at the time and place through routine experimentation. [0045] The compounds according to the invention can also be used enterally. Orally, the compounds according to the invention are suitably administered at the rate of 10 µg to 300 mg per day per kg of body weight. The required dose can be administered in one or more portions. For oral administration, suitable forms are, for example, capsules, tablets, gels, aerosols, pills, dragees, syrups, suspensions, emulsions, solutions, powders and granules. A preferred method of administration consists of using a suitable form containing from 0.01 mg to about 500 mg of active substance. [0046] The compounds according to the invention can also be administered parenterally in the form of solutions or suspensions for intravenous, subcutaneous or intramuscular perfusions or injections. In that case, the compounds according to the invention are generally administered at the rate of about 10 µg to 10 mg per day per kg of body weight. A preferred 136280-00820 method of administration consists of using solutions or suspensions containing approximately from 0.01 mg to 1 mg of active substance per ml. [0047] The compounds may be administered according to various routes, typically by oral route or by injection, such as local or systemic injection(s). Intratumoral injections are preferred for treating existing cancers. However, other administration routes may be used as well, such as intramuscular, intravenous, intradermic, subcutaneous, etc. Furthermore, repeated injections may be performed, if needed, although it is believed that a limited number of injections will be needed in view of the efficacy of the compounds. [0048] The compounds of the invention can be used in a substantially similar manner to other known anti-tumor agents for treating (both chemopreventively and therapeutically) various tumors. The dose to be administered, whether a single dose, multiple dose, or a daily dose, will vary with the particular compound employed because of the varying potency of the compound, the chosen route of administration, the size of the recipient, the type of disease, and the nature of the patient's condition. The dosage to be administered is not subject to definite bounds, but it will usually be an effective amount, or the equivalent on a molar basis of the pharmacologically active free form produced from a dosage formulation upon the metabolic release of the active drug to achieve its desired pharmacological and physiological effects. An oncologist skilled in the art of cancer treatment or a doctor skilled in the art in treating kidney or heart disease will be able to ascertain, without undue experimentation, appropriate protocols for the effective administration of the compounds of this present invention. [0049] The compounds of the invention may also be administered in combination with other known therapies. For example, the compounds of the invention can be administered in combination with other known chemotherapy drugs. When co-administered with one or more other therapies, the compounds of the invention can be administered either simultaneously with the other treatment(s), or sequentially. If administered sequentially, the attending physician will decide on the appropriate sequence of administering the compounds of the invention in combination with the other therapy. Synthesis of Compounds 136280-00820 Compounds of Formula I can be prepared in a manner similar or analogous to that described in Scheme I below. Scheme I

Reagents and Conditions. (a) (Boc)₂O, Et₃N, CH₂Cl₂, 0^◦C →rt; (b) 3 is commercially available, TCFH, Me-imidazole, DMF, 70^◦C; (c) NIS, DMF, 0^◦C; (d) 6 is commercially available, Pd-118 (1,1′-Bis(di-tert-butylphosphino)ferrocene)dichloropalladium (II)), ^K2^PO4^{, dioxane, RT; (e) BBr}3^{, CH}2^Cl2^{, 0◦C, then aq. NaBHCO}3^{, HCl, ether.} 136280-00820 Synthetic Examples Step-1: Synthesis of 1-(tert-butoxycarbonyl)-5-methoxy-1H-indole-3-carboxylic acid [0050] To a stirred solution of 5-methoxy-1H-indole-3-carboxylic acid (1.000 g, 5.230 mmol) in DMF (10.00 mL) at 0 °C was added Et3N (1.590 g, 15.69 mmol), Boc anhydride (1.710 g, 7.845 mmol) and DMAP (0.064 g, 0.523 mmol) at 0 °C and it was stirred at room temperature for about 3 h. Reaction progress was monitored by TLC analysis. TLC (PE:EA=6:4) showed that the starting materials (Rf=0.1) was consumed and reaction mixture (Rf=0.5) was formed The reaction mass was filtered through celite bed, washed with EtOAc was evaporated under reduced pressure. The crude was purified by combiflash chromatography (Redsep, 12 g), eluted the product with 15-50% EtOAc: hexane to afford 1- (tert-butoxycarbonyl)-5-methoxy-1H-indole-3-carboxylic acid (3) (1.2 g, 4.12 mmol, yield: 78.8%) as pale Off-white solid. LC-MS:-ve mode (M-1) = 289.9 Step-2: Synthesis of tert-butyl 5-methoxy-3-(pyrazolo[1,5-a]pyridin-5-ylcarbamoyl)-1H- indole-1-carboxylate (4) [0051] To a solution of 1-(tert-butoxycarbonyl)-5-methoxy-1H-indole-3-carboxylic acid (1.0 g, 3.432 mmol) in DMF (15.0 mL) added TCFH (2.88 g 10.29 mmol), 1-methyl imidazole (1.492g 17.16 mmol) and it was stirred for about 10 minutes. Later added pyrazolo[1,5- a]pyridin-5-amine (0.457 g, 3.432 mmol) and stirred the reaction mixture at 70 °C for about 1 h. Reaction progress was monitored by TLC analysis. TLC (CH2Cl2:CH3OH=9:1) showed that the starting materials (Rf=0.25) was consumed and reaction mixture (Rf=0.45) was formed. Then the reaction mass was diluted with water and extracted twice with ethyl acetate (2x 50 ml), the collective organic layers were washed with water, saturated brine solution, and dried over sodium sulphate, filtered, and concentrated under vacuum. The crude was purified by combiflash chromatography (Redsep, 12 g), eluted the product with 5-15% CH3OH: CH2Cl2 to afford tert-butyl 5-methoxy-3-(pyrazolo[1,5-a]pyridin-5-ylcarbamoyl)- 1H-indole-1-carboxylate (3) (1.2 g, 4.12 mmol, yield: 78.8%) as pale yellow solid. LC-MS: (M+1) = 407.15 Step-3: Synthesis of tert-butyl 3-((3-iodopyrazolo[1,5-a]pyridin-5-yl)carbamoyl)-5- methoxy-1H-indole-1-carboxylate (5) 136280-00820 [0052] To a solution of tert-butyl 5-methoxy-3-(pyrazolo[1,5-a]pyridin-5-ylcarbamoyl)-1H- indole-1-carboxylate (0.900 g, 1.476 mmol) in DMF (10.0 ml) added NIS (0.498 g 1.476 mmol) at 0 °C and it was stirred at same temperature for 1 h. Reaction progress was monitored by TLC analysis. TLC (PE:EA=1:1) showed that the starting materials (Rf=0.2) was consumed and reaction mixture (Rf=0.4) was formed. The the reaction mass was diluted with water and extracted twice with ethyl acetate (2x50 mL). The collective organic layers were washed with water, saturated brine solution, and dried over sodium sulphate, filtered, and concentrated under vacuum. The crude was purified by combiflash chromatography (Redsep, 12 g), eluted the product with 25-60% EA: Hex to afford tert-butyl 3-((3- iodopyrazolo[1,5-a]pyridin-5-yl)carbamoyl)-5-methoxy-1H-indole-1-carboxylate (750 mg, 1.4 mmol) as pale yellow solid. LC-MS: (M+1) = 533.05 Step-4: Synthesis of tert-butyl 5-methoxy-3-((3-(5-methylfuran-2-yl)pyrazolo[1,5- a]pyridin-5-yl)carbamoyl)-1H-indole-1-carboxylate (7) APSL-01105-082-P1: [0053] To a stirred solution of tert-butyl 3-((3-iodopyrazolo[1,5-a] pyridin-5-yl) carbamoyl)- 5-methoxy-1H-indole-1-carboxylate (0.300 g, 0.563 mmol) in Dioxane: H2O (3.00mL) was added 4,4,5,5-tetramethyl-2-(5-methylfuran-2-yl)-1,3,2-dioxaborolane (0.140 g, 0.676 mmol) and K3PO4 (0.360 g, 1.689 mmol) and reaction mixture was degassed by passing the argon gas through the solution. After which added Pd-118 (0.036 g, 0.056 mmol) and repeated de- gassing process once again and the reaction mixture was stirred at room temperature for 12 h. Reaction progress was monitored by TLC analysis. TLC (PE:EA=4:6) showed that the starting materials (Rf=0.45) was consumed and reaction mixture (Rf=0.5) was formed. Then the reaction mass was filtered through celite bed, washed with EtOAc and it was distilled under reduced pressure. The crude was purified by combiflash chromatography (Redsep, 12 g), eluted the product with 25-60% EA: Hex to afford tert-butyl 5-methoxy-3-((3-(5- methylfuran-2-yl)pyrazolo[1,5-a]pyridin-5-yl)carbamoyl)-1H-indole-1-carboxylate (250 mg, 0.51 mmol, 90%) as pale yellow solid. LC-MS: (M+1) = 487.05 Step-5: Synthesis of 5-hydroxy-N-(3-(5-methylfuran-2-yl)pyrazolo[1,5-a]pyridin-5-yl)- 1H-indole-3-carboxamide (RP-0103913) APSL-01105-092-P1: [0054] To a solution of tert-butyl 5-methoxy-3-((3-(5-methylfuran-2-yl) pyrazolo[1,5-a] pyridin-5-yl) carbamoyl)-1H-indole-1-carboxylate (0.250 g, 0.513 mmol) in DCM (3.00 mL) added BBr3 (0.193 g, 0.770 mmol) at -78 °C and it was stirred at 0 °C for about 6 h. Reaction progress was monitored by TLC analysis. TLC (PE:EA=1:1) showed that the starting 136280-00820 materials (Rf=0.45) was consumed and reaction mixture (Rf=0.1) was formed. The reaction mass quenched by adding water and it was extracted twice with ethyl acetate. The collective organic layer was washed with water, saturated brine solution, and dried over sodium sulphate, filtered, and concentrated under vacuum. The crude compound was purified by prep HPLC, using column XBRIDGE (C18, 21.2mm X 150mm, Mobile Phase: A= 0.02% NH4OH IN WATER, B=ACN, Flow: 20mL/min, followed by lyophilization of the purified fractions to afford the compound and it was treated with 2N HCl in ether to obtain the product 5-hydroxy-N-(3-(5-methylfuran-2-yl)pyrazolo[1,5-a]pyridin-5-yl)-1H-indole-3- carboxamide as HCl salt (25 mg, HPLC: 97%) as pale yellow solid. 1H NMR (400 MHz, DMSO-d6): δ ppm 11.51 (s, 1 H), 9.94 (s, 1 H), 8.92 (brs, 1H), 8.63 (d, J = 10.4 Hz, 1 H), 8.49 (d, J = 1.4 Hz, 1 H), 8.24 (d, J = 4 Hz, 1 H), 8.16-8.15 (m, 2H), 7.61 (d, J = 4.2 Hz, 1 H) 7.33 - 7.26 (m, 2 H), 6.72 - 6.08 (m, 1H), 6.40 (d, J = 1.6 Hz, 1 H), 6.21 (brs, 1 H), 2.37 (s, 3 H); LC-MS: (ES+) m/z = 373.15 [M+H] [0055] The compounds of the invention are useful for treating cancers that show a dependence on Rac protein signaling for their growth and survival and, in particular, where the tumor progression is driven by dysregulation of Rac signaling. Specific examples include breast cancer, melanoma, ovarian cancer, head cancer, neck cancer, prostate cancer, colorectal cancer, pancreatic cancer, liver cancer, bladder cancer, non-Hodgkin's lymphoma, and leukemia (acute lymphoblastic leukemia, chronic myeloid leukemia, acute myeloid leukemia). Additionally, the compounds of the invention can be used to treat kidney disease and heart disease. [0056] The invention also provides a method to treat a condition characterized by excessive or undesired levels of activity of Rac1, wherein the method comprises administering to a subject in need of such treatment an effective amount of a compound of Formula (I) or any subgenus thereof as described herein, or a pharmaceutical composition comprising such compound. The subject can be a mammal, and is preferably a human, and is typically a subject diagnosed with a condition associated with excessive activity of Rac1. Conditions treatable by the compounds and methods described herein include various forms of cancer that are responsive to Rac1 inhibitors, such as solid tumors, adenoma, bladder cancer, brain cancer, breast cancer, cervical cancer, colorectal cancer, colon cancer, epidermal carcinoma, follicular carcinoma, genitourinary cancers, glioblastoma, head and neck cancers, Hodgkin's disease, non-Hodgkin's lymphoma, hepatoma, kidney cancer, lung 136280-00820 cancers such as small cell or non-small cell lung cancer, leukemias such as AML or CML, multiple myeloma, lymphoid disorders, skin cancers including melanoma, neuroblastoma, ovarian cancer, pancreatic cancer, prostate cancer, rectal cancer, sarcoma, testicular cancer, and thyroid cancer. [0057] The compounds are especially indicated for use to treat melanoma, ovarian cancer, thyroid cancer, colon cancer, breast cancer, and prostate cancer. Indications of special interest for use of the compounds of the invention include cancers that express Rac1b, a splice variant of Rac1, and the mutant forms Rac1 P29S and Rac1 A149V. Examples of breast cancer for use of the compounds include ER+ breast cancer that is resistant to ER targeted therapy and/or CDK 4/6 inhibitors; and HER2+ breast cancer that is resistant to HER2 targeted therapies. Examples of prostate cancer for use of the compounds include castrate resistant prostate cancer (CRPC) that resistant to androgen receptor inhibitors. Examples of ovarian cancer for use of the compounds include ovarian cancer that is platinum resistant and for patients who are HRD negative. [0058] In one aspect, the cancer is determined to exhibit a high expression level of Rac1 prior to treatment with a therapeutically effective amount of a Rac1 inhibitor. This determination can be made by routine diagnostic methods which obtain cancer cells from a patient. These methods include, but are not limited to, biopsy, blood tests, and other diagnostic methods which obtain samples of cancer cells such as tissue samples, circulating tumor cells, exosomes, or biomolecules characteristic of cancer such as circulating nucleic acids or proteins. The expression level of Rac1 in the cancer cells is then determined or inferred. Determining if the cancer exhibits a high expression level of Rac1 is by methodology known in the art, for example, by determining Rac1 expression levels in the isolated cancer cells by RNA sequencing (RNA-Seq), microarray, quantitative PCR, or NanoString™ gene expression panels, gene amplification by FISH, or Rac1 protein by immunohistochemistry, flow cytometry, immunocytochemistry or Western blot. See e.g., RT-qPCR analysis discussed below. In one embodiment, the methods disclosed herein further comprise a step of performing a biopsy of the patient’s cancer prior to treatment and determining from the cancer cells isolated from the biopsy if the cancer (cancer cells) exhibits a high expression level of Rac1. 136280-00820 [0059] In one embodiment, the Rac1 expression level is determined for Rac1 wild type (Rac1 wt). In another embodiment, the Rac1 expression level is determined for a genomic variant of Rac1, such as the Rac1b splice variant and the Rac1 P29S mutant. [0060] In another aspect, the invention is a method of treating a patient with a cancer comprising providing cancer cells from the cancer patient; determining the expression level of Rac1 in the cancer cells; and administering to the patient a therapeutically effective amount of a Rac1 inhibitor, if the patient’s cancer (cancer cells) exhibits a high expression level of Rac1. In one embodiment, the method further comprises excluding the patient from administration of a Rac1 inhibitor if the patient’s cancer (cancer cells) does not exhibit a high expression level of Rac1. The cancer cells used in the present invention can be obtained from a sample which is, but not limited to a sample of tissue, blood (including blood fractions), lymphatic fluid, sputum, feces, urine, bronchial lavage, or other body fluid. [0061] In another aspect, provided herein is a method of selecting a patient who is likely to respond to treatment with a Rac1 inhibitor, said method comprising determining the expression level of Rac1 of a cancer of the patient, wherein the patient is likely to respond to treatment if the expression level of Rac1 by the cancer is high. [0062] In another aspect, provided herein is a method of treating a patient with a cancer, comprising determining the expression level of Rac1 of the cancer and administering a therapeutically effective amount of a Rac1 inhibitor if the expression level of Rac1 by the cancer is high, and treating the patient with an anti-cancer therapy other than a Rac1 inhibitor if the patient’s cancer does not exhibit a high expression level of Rac1. [0063] In one aspect, the high expression level of Rac1 is characterized by an expression level falling within the top 50% of Rac1 expression levels of the cancer cells from the same cancer type in a random population of patients. The Rac1 expression level can be obtained from methods suitable for determining Rac1 expression levels, such as, e.g., expression levels derived from RNA- sequencing such as normalized read counts and TPM (Transcripts Per Million) or normalized cycle threshold (Ct) levels from RT-PCR measurements] for Rac1 robustly standardized (quantiles 2.5% and 97.5% set to -1 and +1, respectively). [0064] As used herein “high expression” means an expression level falling within the top 5%, 10%, 15%, 20%, 25%, 30%, 40%, 45%, or 50% of the expression levels. “Top 50%”, for example, can be obtained by collecting expression levels of Rac1 from the cancer cells (e.g., from tissue samples) of a random population of subjects, e.g., at least 25 subjects, at least 50 subjects, at least 100 subjects, at least 500 subjects, at least 1000 subjects or the like, having 136280-00820 the same cancers and then assessing whether the expression level of a new subject falls within the top 50% percentile. [0065] In an alternative, “high expression” refers to a level of Rac1 in the cancer from the patient above a defined reference level of 25%, 30%, 40%, 50%, 60%, 70%, 80%, 85%, 90%, 95%, 100%, 150%, 200%, 250% or greater, determined by the methods described herein, as compared to the reference level. [0066] “Reference level” refers to an average Rac1 expression level determined in cells of the same cell type as the cancer obtained from a population of healthy individuals without the cancer. In an alternative aspect, the reference level can be determined in non-cancerous cells of the same cell type as the cancer obtained from the patient. [0067] In one aspect, the reference level can be obtained by determining the average normalized Rac1 expression [which can be obtained from methods suitable for determining Rac1 expression levels, such as, e.g., expression levels derived from RNA- sequencing such as normalized read counts and TPM (Transcripts Per Million) or normalized cycle threshold (Ct) levels from RT-PCR measurements] for Rac1 robustly standardized (quantiles 2.5% and 97.5% set to -1 and +1, respectively). [0068] Some genomic variants of Rac1, such as Rac1 P29S, are only known to be expressed in cancerous cells. Thus, for such genomic variants, “high Rac1 expression” means a detectable level of such Rac1 genomic variant. Rac1 P29S is most prevalent in melanoma. Accordingly, one embodiment of this invention relates to a method of treating a cancer that expresses Rac1 P29S in a patient by administering to the patient an effective amount of a Rac1 P29S inhibitor of this invention. In one aspect, the cancer that expresses Rac1 P29S is melanoma. [0069] Another embodiment of this invention provides a method of treating a cancer that is characterized by high expression of Rac1b in a patient by administering to the patient an effective amount of a Rac1b inhibitor. In one aspect, the cancer that highly expresses Rac1b is colorectal, non-small cell lung, small cell lung, breast, prostate, thyroid, hepatocellular, ovarian, esophageal, gastric, or pancreatic cancer. [0070] Elevated levels of activated Rac1 or GTP-bound Rac1 are found in patients that have high expression levels of certain other proteins that activate Rac1 such as guanine nucleotide exchange factors (GEFs). At least 20 GEFs are involved in Rac1 activation. The GEFs Tiam1 and P-Rex1 are Rac1 specific. Accordingly, one embodiment of this invention relates to treating a cancer that is characterized by high expression levels of a GEF in a patient by 136280-00820 administering to the patient an effective amount of a Rac1 inhibitor. In one aspect, the cancer is characterized by high expression levels of Tiam1 or P-Rex1. Methods for determining the expression levels of the GEF are available to those skilled in the art in manners that are analogous to those described above for determining the expression levels of Rac1. [0071] Elevated levels of activated Rac1 or GTP-bound Rac1 are also found in patients that have low expression levels of proteins that are involved in the degradation of active Rac1. HACE-1 is an E3- ubiquitin ligase tumor suppressor that targets active Rac1 for degradation. Low levels of HACE-1 are associated with higher levels of active, GTP-bound Rac1. Accordingly, one embodiment of this invention relates to treating a cancer that is characterized by low expression levels of HACE-1 in a patient by administering to the patient an effective amount of a Rac1 inhibitor. Methods for determining the expression levels of HACE-1 are available to those skilled in the art in manners that are analogous to those described above for determining the expression levels of Rac1. [0072] In one aspect, the low expression level of HACE-1 is characterized by an expression level falling within the bottom 50% of HACE-1 expression levels of the cancer cells from the same cancer type in a random population of patients. The HACE-1 expression level can be obtained from methods suitable for determining HACE-1 expression levels, such as, e.g., expression levels derived from RNA- sequencing such as normalized read counts and TPM (Transcripts Per Million) or normalized cycle threshold (Ct) levels from RT-PCR measurements] for Rac1 robustly standardized (quantiles 2.5% and 97.5% set to -1 and +1, respectively). [0073] As used herein “low expression” means an expression level falling within the bottom 5%, 10%, 15%, 20%, 25%, 30%, 40%, 45%, or 50% of the expression levels. “Bottom 50%”, for example, can be obtained by collecting expression levels of HACE-1 from the cancer cells (e.g., from tissue samples) of a random population of subjects, e.g., at least 25 subjects, at least 50 subjects, at least 100 subjects, at least 500 subjects, at least 1000 subjects or the like, having the same cancers and then assessing whether the expression level of a new subject falls within the bottom 50% percentile. [0074] In an alternative, “low expression” refers to a level of HACE-1 in the cancer from the patient below a defined reference level by 25%, 30%, 40%, 50%, 60%, 70%, 80%, 85%, 90%, 95%, 100%, 150%, 200%, 250% or greater, determined by the methods described herein, as compared to the reference level. 136280-00820 [0075] Levels of HACE-1 may also be determined using known immunohistochemistry methods for the HACE-1 protein. See Da et al., Signal Transduction and Targeted Therapy 6, Article Number 399 (2021) and Anglesio et al., Human Molecular Genetics 13(18), pp 2061-2074 (2004). [0076] The invention is illustrated by the following examples, which are not intended to be limiting in any way. Pharmacology In Vitro Assays 1. Cell Viability Assay (MCF7) In order to determine a compound's effect on cell viability, PrestoBlue assays were performed as previously described by Kuhn et al. (2013) with modifications. MCF-7 human breast cancer and IGR-1 human melanoma cell lines were seeded into 96-well plates 24 hours prior to addition of drug. Cells are treated with 0 to 200 µΜ (concentrations) of compound solubilized in DMSO, adjusting the final concentration of DMSO to 1% in the well. Three days after drug treatment (unless another duration of time after treatment is specified), cell viability was measured by adding PrestoBlue (Life Technologies Ltd.; cat. No. A13262) reagent directly to wells containing media/drug to reach a final concentration of 10%. PrestoBlue is a modified molecule of the common Alamar Blue probe used to determine viability based on the ability of a cell to metabolize a nonfluorescent compound (resazurin) to a florescent molecule (resorufin). Following a 1-hour incubation period, total well fluorescence was measured using the microplate reader M1000 pro (Tecan) with excitation 560-5 nm and emission 590-5 nm. Data is analyzed using the GraphPad Prism software (GraphPad Software, Inc.), and IC50 (dose leading to 50% cell death) was calculated from the dose-response curves. The percentage of living cells was then computed by comparison with control wells. Kuhn, Jonas et al., Assay and Drug Development Technologies, March 2013, Label-Free Cytotoxicity Screening Assay by Digital Holographic Microscopy. 2. Rac Activation AlphaScreen Assay (Racl AS) AlphaScreen® assays were performed in 96-well microplates in a final reaction volume of 60 µL. Recombinant His-Racl, recombinant GST-PBD (PAK Binding Domain), donor and acceptor beads (PerkinElmer), and inhibitors were incubated in exchange buffer 136280-00820 (20 mM Tris pH 7.5, 50 mM NaCl, 1 mM MgCl2 , 1 mM EDTA, 500 nM GTPyS (guanosine 5'-[Y-thio]triphosphate)) at 37°C. Readings were performed on a Tecan M1000 pro microplate reader after 1 hour. Data was analyzed using the GraphPad Prism software (GraphPad Software, Inc.), and IC50 (dose leading to 50% disruption of complex) was calculated from the dose-response curves. 3. Cell Migration Assay An essential characteristic of malignant cells is their ability to migrate, invade host tissues and to produce metastases. In order to evaluate the capacity of one compound to affect the ability of tumoral cells to migrate, migration assays are performed using HUVEC cells. HUVECs (2.5xl04) are seeded onto uncoated filters in a 24-well transwell Boyden chamber (8-mm pore size; Costar) and allowed to migrate in the presence and absence of different doses of the Racl inhibitor test material (5, 6.25, 10, 12.5, 20, 25 µΜ). The cells that migrated to the underside of the filter are stained with crystal violet and counted under the bright field microscopy. 4. Cellular Proliferation Assay This assay measures the ability of the test material to inhibit the proliferation of HUVEC cells. 25,000 cells were seeded in 6-well plates. The next day, vehicle (DMSO) or test material were added to cells (Day 0). Cells were counted on days 0 through day 4 using a hemocytometer. 5. Western Blot Analysis Western blot analysis is used to identify specific proteins from a complex mixture of proteins extracted from cells. Equal amount of protein is run on the SDS-PAGE gel and after separating the protein mixture, it is transferred to a membrane. The transferred protein is then probed with a combination of antibodies: one antibody specific to the protein of interest (primary antibody) and another antibody specific to the host species of the primary antibody (secondary antibody). The secondary antibody is complexed with an enzyme, which when combined with an appropriate substrate, will produce a detectable signal. WM1158 cells are treated with increasing concentrations of test material for two hours. SDS-PAGE are conducted on cell lysates and Western Blot analysis are conducted on samples for total and phosphorylated AKT, MEK1/2, and ERK1/2

Claims

136280-00820 CLAIMS What is claimed is: 1. A compound of Formula I:

or a pharmaceutically acceptable salt thereof, wherein R¹ is hydrogen, halo, or C1-3 alkyl; R² is hydrogen, halo, C_1-5 alkyl, -OH, -OC(O)(C_1-6 alkyl), C_1-3 haloalkyl, C_1-3 hydroxyalkyl, CONH2, CONH(C1-3 alkyl), CONH(C1-3 alkyl)2, CHO, CN, or C1-4 alkoxy; R³ is hydrogen, halo, C1-5 alkyl, -OH, -OC(O)(C1-6 alkyl), C1-3 haloalkyl, or C1-4 alkoxy; R⁴ is hydrogen, halo, or C_1-3 alkyl; Q is -CO₂(C_1-4 alkyl), -CONH(C_1-4 alkyl), phenyl or 5-6 membered heteroaryl, wherein the phenyl or heteroaryl is optionally substituted by R⁵; R⁵ is C_1-5 alkyl, -O(C_1-4 alkyl), -C(O)(C_1-4 alkyl), -CO₂(C_1-4 alkyl), -C(O)(C_1-4 haloalkyl), C_1-3 hydroxyalkyl, -CONH(C_1-4 alkyl), -C(O)(C_1-4 haloalkyl), or -CO₂(C_1-4 haloalkyl); and provided that when each of R¹, R², R³ and R⁴ are hydrogen, Q is other than -CO₂CH₂CH₃. 2. The compound or pharmaceutically acceptable salt thereof of claim 1 wherein Q is a 5-6 membered heteroaryl ring optionally substituted with R⁵. 3. The compound or pharmaceutically acceptable salt thereof of claim 2 wherein R¹ and R⁴ are each hydrogen. 4. The compound or pharmaceutically acceptable salt thereof of claim 1 wherein: 136280-00820 R¹ and R⁴ are each hydrogen; R² is -OH, -OC(O)(C1-6 alkyl), C1-3 hydroxyalkyl, CONH2, CONH(C1-3 alkyl), CONH(C_1-3 alkyl)₂; R³ is hydrogen, halo, C1-5 alkyl, -OH, -OC(O)(C1-6 alkyl), C1-3 haloalkyl, or C1-4 alkoxy; Q is a 5-6 membered heteroaryl that is optionally substituted by R⁵; and R⁵ is C_1-5 alkyl or C_1-3 hydroxyalkyl. 5. The compound or pharmaceutically acceptable salt thereof of claim 4 wherein Q is 5- methyl-furan-2-yl, 2-methyl-oxazol-5-yl, oxaxol-5-yl, pyridin-3-yl, pyridin-2-yl, or thiazol-5- yl. 6. A pharmaceutical composition comprising a compound of any of claims 1-5 or pharmaceutically acceptable salt thereof and a pharmaceutical acceptable carrier. 7. A method of treating cancer in a patient comprising administering to the patient an effective amount of the pharmaceutical composition of claim 6. 8. The method of claim 7 wherein the cancer is characterized by overexpression of Rac1 or a genomic variant thereof. 9. The method of claim 8 wherein the Rac1 genomic variant is Rac1b or Rac1 P29S. 10. The method of any one of claims 7-9 wherein the cancer is selected from breast cancer, prostate cancer, ovarian cancer, melanoma, colorectal cancer, and renal cell carcinoma.