The term “pharmaceutically acceptable salt” refers to a salt of a compound that does not cause significant irritation to an organism to which it is administered and does not abrogate the biological activity and properties of the compound. In several embodiments, the salt is an acid addition salt of the compound. Pharmaceutical salts can be obtained by reacting a compound with inorganic acids such as hydrohalic acid (e.g., hydrochloric acid or hydrobromic acid), sulfuric acid, nitric acid and phosphoric acid. Pharmaceutical salts can also be obtained by reacting a compound with an organic acid such as aliphatic or aromatic carboxylic or sulfonic acids, for example formic, acetic, succinic, lactic, malic, tartaric, citric, ascorbic, nicotinic, methanesulfonic, ethanesulfonic, p-toluenesulfonic, salicylic or naphthalenesulfonic acid. Pharmaceutical salts can also be obtained by reacting a compound with a base to form a salt such as an ammonium salt, an alkali metal salt, such as a sodium or a potassium salt, an alkaline earth metal salt, such as a calcium or a magnesium salt, a salt of organic bases such as dicyclohexylamine, N-methyl-D-glucamine, tris(hydroxymethyl)methylamine, C₁-C₇alkylamine, cyclohexylamine, triethanolamine, ethylenediamine, and salts with amino acids such as arginine and lysine.

It is understood that, in any compound described herein having one or more chiral centers, if an absolute stereochemistry is not expressly indicated, then each center may independently be of R-configuration or S-configuration or a mixture thereof. Thus, the compounds provided herein may be enantiomerically pure, enantiomerically enriched, racemic mixture, diastereomerically pure, diastereomerically enriched, or a stereoisomeric mixture. In addition it is understood that, in any compound described herein having one or more double bond(s) generating geometrical isomers that can be defined as E or Z, each double bond may independently be E or Z a mixture thereof. It is understood that, in any compound described herein having one or more chiral centers, all possible diastereomers are also envisioned. It is understood that, in any compound described herein all tautomers are envisioned. It is also understood that, in any compound described herein, all isotopes of the included atoms are envisioned. For example, any instance of hydrogen, may include hydrogen-1 (protium), hydrogen-2 (deuterium), hydrogen-3 (tritium) or other isotopes; any instance of carbon may include carbon-12, carbon-13, carbon-14, or other isotopes; any instance of oxygen may include oxygen-16, oxygen-17, oxygen-18, or other isotopes; any instance of fluorine may include one or more of fluorine-18, fluorine-19, or other isotopes; any instance of sulfur may include one or more of sulfur-32, sulfur-34, sulfur-35, sulfur-36, or other isotopes.

The term “gatekeeper mutation” when used herein denotes mutations in a kinase enzyme that modulate the accessibility of the kinase ATP-binding pocket.

The term “target sequence” or “target nucleic acid sequence” shall be given its ordinary meaning and shall also include and also refer to the particular nucleotide sequence of the target nucleic acid to be detected (e.g., through amplification). The target sequence may include a probe-hybridizing region contained within the target molecule with which a probe will form a stable hybrid under desired conditions. The “target sequence” may also include the complexing sequences to which the oligonucleotide primers complex and be extended using the target sequence as a template. Where the target nucleic acid is originally single-stranded, the term “target sequence” also refers to the sequence complementary to the “target sequence” as present in the target nucleic acid. If the “target nucleic acid” is originally double-stranded, the term “target sequence” refers to both the plus (+) and minus (−) strands. Moreover, where sequences of a “target sequence” are provided herein, it is understood that the sequence may be either DNA or RNA. Thus where a DNA sequence is provided, the RNA sequence is also contemplated and is readily provided by substituting “T” of the DNA sequence with “U” to provide the RNA sequence. In several embodiments, the target sequence is one or more of the particular sequences for FGFR mutants provided herein (such as Tables 0.1 or 0.2).

As used herein, the term “kinase inhibitor” means any compound, molecule or composition that inhibits or reduces the activity of a kinase. The inhibition can be achieved by, for example, blocking phosphorylation of the kinase (e.g., competing with adenosine triphosphate (ATP), a phosphorylating entity), by binding to a site outside the active site, affecting its activity by a conformational change, or by depriving kinases of access to the molecular chaperoning systems on which they depend for their cellular stability, leading to their ubiquitylation and degradation.

As used herein, “subject,” “host,” “patient,” and “individual” are used interchangeably and shall be given its ordinary meaning and shall also refer to an organism that has FGFR proteins. This includes mammals, e.g., a human, a non-human primate, ungulates, canines, felines, equines, mice, rats, and the like. The term “mammal” includes both human and non-human mammals. In some aspects, the “subject,” “host,” “patient,” or “individual” is human.

“Diagnosis” as used herein shall be given its ordinary meaning and shall also include determination of a subject's susceptibility to a disease or disorder, determination as to whether a subject is presently affected by a disease or disorder, prognosis of a subject affected by a disease or disorder (e.g., identification of cancer or cancerous states, stages of cancer, or responsiveness of cancer to therapy), and use of therametrics (e.g., monitoring a subject's condition to provide information as to the effect or efficacy of therapy).

The term “sample” or “biological sample” shall be given its ordinary meaning and also encompasses a variety of sample types obtained from an organism and can be used in an imaging, a diagnostic, a prognostic, or a monitoring assay. The term encompasses blood and other liquid samples of biological origin, solid tissue samples, such as a biopsy specimen or tissue cultures or cells derived therefrom and the progeny thereof. The term encompasses samples that have been manipulated in any way after their procurement, such as by treatment with reagents, solubilization, or enrichment for certain components. The term encompasses a clinical sample, and also includes cells in cell culture, cell supernatants, cell lysates, serum, plasma, biological fluids, and tissue samples.

The terms “treatment,” “treating,” “treat” and the like shall be given its ordinary meaning and shall also include herein to generally refer to obtaining a desired pharmacologic and/or physiologic effect. The effect may be prophylactic in terms of completely or partially preventing a disease or symptom thereof and/or may be therapeutic in terms of a partial or complete stabilization or cure for a disease and/or adverse effect attributable to the disease. “Treatment” as used herein shall be given its ordinary meaning and shall also cover any treatment of a disease in a mammal, particularly a human, and includes: (a) preventing the disease or symptom from occurring in a subject which may be predisposed to the disease or symptom but has not yet been diagnosed as having it; (b) inhibiting the disease symptom, e.g., arresting its development; and/or (c) relieving the disease symptom, e.g., causing regression of the disease or symptom.

The terms “cancer,” “neoplasm,” and “tumor” are used interchangeably herein, shall be given its ordinary meaning and shall also refer to cells which exhibit relatively autonomous growth, so that they exhibit an aberrant growth phenotype characterized by a significant loss of control of cell proliferation. In general, cells of interest for detection or treatment in the present application include precursors, precancerous (e.g., benign), malignant, pre-metastatic, metastatic, and non-metastatic cells. As used herein, “FGFR related cancer” denotes those cancers that involve an increased activity in a mutant FGFR kinase, for example, the continued activation of FGFR.

“Cancerous phenotype” shall be given its ordinary meaning and shall also generally refer to any of a variety of biological phenomena that are characteristic of a cancerous cell, which phenomena can vary with the type of cancer. The cancerous phenotype is generally identified by abnormalities in, for example, cell growth or proliferation (e.g., uncontrolled growth or proliferation), regulation of the cell cycle, cell mobility, cell-cell interaction, or metastasis, etc. In several embodiments, a subject is identified as a potential recipient if they have a cancerous phenotype. In several embodiments, a subject is identified as a potential recipient if they exhibit a new cancerous phenotype when they are already on a cancer therapy (other than a compound as disclosed herein (e.g., Formula (I), as well as all subgenera disclosured herein)).

The term “control” refers shall be given its ordinary meaning and shall also include a sample or standard used for comparison with a sample which is being examined, processed, characterized, analyzed, etc. In several embodiments, the control is a sample obtained from a healthy patient or a non-tumor tissue sample obtained from a patient diagnosed with a tumor. In several embodiments, the control is a historical control or standard reference value or range of values. In several embodiments, the control is a comparison to a wild-type FGFR arrangement or scenario.

The section headings used herein are for organizational purposes only and are not to be construed as limiting the described subject matter in any way. All literature and similar materials cited in this application, including but not limited to, patents, patent applications, articles, books, treatises, and internet web pages are expressly incorporated by reference in their entirety for any purpose. When definitions of terms in incorporated references appear to differ from the definitions provided in the present teachings, the definition provided in the present teachings shall control. It will be appreciated that there is an implied “about” prior to the temperatures, concentrations, times, etc. discussed in the present teachings, such that slight and insubstantial deviations are within the scope of the present teachings herein. In this application, the use of the singular includes the plural unless specifically stated otherwise. Also, the use of “comprise”, “comprises”, “comprising”, “contain”, “contains”, “containing”, “include”, “includes”, and “including” are not intended to be limiting. It is to be understood that both the general description and the following detailed description are exemplary and explanatory only and are not restrictive. The term “and/or” denotes that the provided possibilities can be used together or be used in the alternative. Thus, the term “and/or” denotes that both options exist for that set of possibilities.

Terms and phrases used in this application, and variations thereof, especially in the appended claims, unless otherwise expressly stated, should be construed as open ended as opposed to limiting. As examples of the foregoing, the term “including” should be read to mean “including, without limitation,” “including but not limited to,” or the like; the term “comprising” as used herein is synonymous with “including,” “containing,” or “characterized by,” and is inclusive or open-ended and does not exclude additional, unrecited elements or method steps; the term “having” should be interpreted as “having at least;” the term “includes” should be interpreted as “includes but is not limited to;” the term “example” is used to provide exemplary instances of the item in discussion, not an exhaustive or limiting list thereof; and use of terms like “preferably,” “preferred,” “desired,” or “desirable,” and words of similar meaning should not be understood as implying that certain features are critical, essential, or even important to the structure or function of the invention, but instead as merely intended to highlight alternative or additional features that may or may not be utilized in a particular embodiment of the invention. In addition, the term “comprising” is to be interpreted synonymously with the phrases “having at least” or “including at least”. When used in the context of a process, the term “comprising” means that the process includes at least the recited steps, but may include additional steps. When used in the context of a compound, composition or device, the term “comprising” means that the compound, composition or device includes at least the recited features or components, but may also include additional features or components. Likewise, a group of items linked with the conjunction “and” should not be read as requiring that each and every one of those items be present in the grouping, but rather should be read as “and/or” unless expressly stated otherwise. Similarly, a group of items linked with the conjunction “or” should not be read as requiring mutual exclusivity among that group, but rather should be read as “and/or” unless expressly stated otherwise.

With respect to the use of substantially any plural and/or singular terms herein, those having skill in the art can translate from the plural to the singular and/or from the singular to the plural as is appropriate to the context and/or application. The various singular/plural permutations may be expressly set forth herein for sake of clarity. The indefinite article “a” or “an” does not exclude a plurality. The mere fact that certain measures are recited in mutually different dependent claims does not indicate that a combination of these measures cannot be used to advantage. Any reference signs in the claims should not be construed as limiting the scope.

Compounds of the Disclosure

Several embodiments pertain to indazolyl sulfoximine compounds. In several embodiments, the indazole sulfoximine is a compound having the structure of Formula (I) (or a pharmaceutically acceptable salt thereof):

[Image Omitted]

According to the disclosure, Y is —C(O)—NR⁸—, —NR⁸C(O)—, —CR¹═CR¹—, or Y is absent (e.g., Y is a single bond connecting Q and the indazole ring). In some aspects, Y is —C(O)—NR⁸—. In other aspects, Y is —NR⁸C(O)—. In these aspects, R⁸is H or C_1-6alkyl (e.g., methyl).

In some aspects, Y is —CR¹═CR¹—, wherein each R¹is independently selected from the group consisting —H, —F, —Cl, —C_1-6alkyl (e.g., methyl), C_1-6haloalkyl (e.g, CF₃), C_1-6alkoxy e.g., (OCH₃), or C_1-6hydroxyalkyl (e.g., CH₂CH₂OH). In some aspects, both R¹are H. In some aspects, one R¹is H and the other R¹is —F, —Cl, —C_1-6alkyl, C_1-6haloalkyl, C_1-6alkoxy, or C_1-6hydroxyalkyl. In some aspects, at least one R¹is F. In some aspects, at least one R¹is Cl. In some aspects, at least one R¹is C_1-6alkyl. In some aspects, at least one R¹is C_1-6haloalkyl. In some aspects, at least one R¹is C_1-6alkoxy. In some aspects, at least one R¹is C_1-6hydroxyalkyl.

In some aspects, Y is absent, that is, Y is a single bond connecting moiety Q to the indazolyl ring.

According to the disclosure R²is selected from the group consisting of —H, C₁-C₆alkyl (e.g., C₁-C₃alkyl), and substituted C₁-C₆alkyl (e.g., substituted C₁-C₃alkyl) When R²is not H, R²may be in the R or S configuration.

According to the disclosure, X¹is selected from the group consisting of CH, CR³, and N. In some aspects, X¹is CH. In other aspects X¹is N. In other aspects, X¹is CR³.

Other than for CR³, each instance of R³is located on any available carbon (e.g., one or more of positions 2, 3, 5, and/or 6) of Ring A (e.g., the terminal heterocyclyl ring). Also in these aspects, each instance of R³is independently selected from the group consisting of —F, —Cl, —Br, optionally substituted C₁-C₆-alkyl, C_1-6haloalkyl, C₃-C₆-cycloalkyl, and —OR⁹. In some aspects, one or more R³is independently F. In some aspects, one or more R³is independently Cl. In some aspects, one or more R³is independently —Br. In some aspects, one or more R³is independently C₁-C₃-alkyl. In some aspects, one or more R³is independently substituted C₁-C₃-alkyl. In some aspects, one or more R³is independently C₁-C₆haloalkyl. In some aspects, one or more R³is independently C₃-C₆-cycloalkyl. In some aspects, one or more R³is independently substituted C₃-C₆-cycloalkyl. In some aspects, one or more R³is independently C_1-6alkoxy. In some aspects, one or more R³is independently —OR⁹, wherein each R⁹is independently selected from the group consisting of H, C₁-C₃-alkyl, C_1-6haloalkyl and substituted C₁-C₃-alkyl. In some aspects, each R⁹is H. In some aspects, each R⁹is independently C₁-C₃-alkyl. In some aspects each R⁹is independently substituted C₁-C₃-alkyl. In some aspects, each R⁹is independently C_1-6haloalkyl.

According to the disclosure, Q is selected from the group consisting of optionally substituted phenyl, optionally substituted pyridine, optionally substituted pyrimidine, optionally substituted pyridazine, optionally substituted pyrazole, optionally substituted imidazole, optionally substituted thiazolyl, and optionally substituted pyrrolopyridinyl.

In some aspects Q is phenyl. In other aspects, Q is substituted phenyl.

In some aspects Q is pyridinyl. In other aspects, Q is substituted pyridinyl.

In some aspects Q is pyrimidinyl. In other aspects, Q is substituted pyrimidinyl.

In some aspects Q is pyridazinyl. In other aspects, Q is substituted pyridazinyl.

In some aspects Q is pyrazolyl. In other aspects, Q is substituted pyrazolyl.

In some aspects Q is imidazolyl. In other aspects, Q is substituted imidazolyl.

In some aspects Q is thiazolyl. In other aspects, Q is substituted thiazolyl.

In some aspects, Q is pyrrolopyridinyl. In some aspects, Q is substituted pyrrolopyridinyl.

According to the disclosure, R⁴is positioned at any available position of Q.

According to the disclosure, R⁴is selected from the group consisting of:

[Image Omitted]

wherein X is N or C—H. In some aspects, X is N. In other aspects, X is CH.

According to the disclosure, c is an integer equal to 1 or 2. In some aspects, c is 1. In some aspects, c is 2.

According to the disclosure, R⁵is selected from the group consisting of —H, optionally substituted C₁-C₆-alkyl, and optionally substituted C₃-C₆-cycloalkyl. In some aspects, R⁵is H. In some aspects, R⁵is C₁-C₆-alkyl. In some aspects, R⁵is substituted C₁-C₆-alkyl. In some aspects, R⁵is C₃-C₆-cycloalkyl. In some aspects, R⁵is substituted C₃-C₆-cycloalkyl.

According to the disclosure, each instance of R⁶is independently selected from optionally substituted C₁-C₆-alkyl, and optionally substituted C₃-C₆-cycloalkyl. In some aspects, at least one R⁶is independently C₁-C₆-alkyl. In some aspects, at least one R⁶is independently substituted C₁-C₆-alkyl. In some aspects, at least one R⁶is independently C₃-C₆-cycloalkyl. In some aspects, at least one R⁶is independently substituted C₃-C₆-cycloalkyl. In some aspects, two R⁶groups, together with the atoms to which they are attached, form a 4- to 7-membered ring.

According to the disclosure, W is selected from the group consisting

of —CH₂—, —C(O)—, CH(OH), and —N(R⁷)—. In some aspects, W is —CH₂—. In some aspects, W is —C(O)—. In some aspects, W is CH(OH). In some aspects, W is —N(R⁷)—.

In those aspects wherein W is —N(R⁷)—, R⁷is selected from the group consisting of —H, optionally substituted —C₁-C₆-alkyl, —C₁-C₆-alkenyl, and optionally substituted —C₃-C₆-cycloalkyl. In some aspects, R⁷is H. In some aspects, R⁷is —C₁-C₆-alkyl. In some aspects, R⁷is substituted —C₁-C₆-alkyl. In some aspects, R⁷is —C₁-C₆-alkenyl. In some aspects, R⁷is substituted —C₁-C₆-alkenyl. In some aspects, R⁷is —C₃-C₆-cycloalkyl. In some aspects, R⁷is substituted —C₃-C₆-cycloalkyl.

In some aspects, R⁴is