pyridine, pyrazine, and triazine compounds as allosteric shp2 inhibitors

专利摘要:
The present description is directed to SHP2 inhibitors and their use in the treatment of disease. Pharmaceutical compositions comprising the same are also described.
公开号:BR112020007058A2
申请号:R112020007058-0
申请日:2018-10-11
公开日:2020-10-06
发明作者:Jie Jack Li；James Joseph Cregg；Elena S. Koltun；Adrian Liam Gill；Andreas BUCKL；Walter Won；Naing Aay；Kevin MELLEM；Christos TZITZILONIS；Ashutosh JOGALEKAR
申请人:Revolution Medicines, Inc.；
IPC主号:

专利说明:

[2] [2] The present description relates to SHP2 protein tyrosine phosphatase inhibitors useful in the treatment of diseases or disorders. Specifically, this description is concerned with compounds and compositions that inhibit SHP2, methods of treating diseases associated with SHP2, and methods of synthesizing these compounds. BACKGROUND OF THE DESCRIPTION
[3] [3] Protein tyrosine phosphatase-2 containing the SH2 domain (SHP2) is a non-receptor tyrosine phosphatase protein encoded by the PTPN7171 gene that contributes to multiple cellular functions including proliferation, differentiation, cell cycle maintenance and migration. SHP2 is involved in signaling through the Ras-activated protein, the JAK-STAT or phosphoinositol 3-kinase-AKT pathways.
[4] [4] SHP2 has two N-terminal Src homology 2 domains (N-SH2 and C-SH2), a catalytic domain (PTP), and a C-terminal tail. The two SH2 domains control the subcellular location and functional regulation of SHP2. The molecule in an inactive, self-inhibited conformation stabilized by a bonding network that involves residues from both the N-SH2 and PTP domains. Stimulation, for example, by cytokines or growth factors induces exposure of the catalytic site resulting in the enzymatic activation of SHP2.
[5] [5] Mutations in the PTPN11 gene and subsequently in SHP2 have been identified in several human diseases, such as Noonan Syndrome, Leopard Syndrome, juvenile myelomonocytic leukemias, neuroblastoma, melanoma, acute myeloid leukemia and breast, lung and colon cancers. SHP2, therefore, represents a highly attractive target for the development of new therapies for the treatment of various diseases. The compounds of the present description meet the need for small molecules that inhibit SHP2 activity. DESCRIPTION SUMMARY DESCRIPTION
[6] [6] The present description refers to compounds capable of inhibiting SHP2 activity. The description also provides a process for the preparation of compounds described herein, pharmaceutical preparations comprising such compounds and methods of using such compounds and compositions in the control of diseases or disorders associated with abnormal SHP2 activity.
[7] [7] One aspect of the description concerns compounds of Formula la: NY Xi mt) NE x
[8] [8] One aspect of the description relates to compounds of Formula |: 1 1 ITA 2
[9] [9] One aspect of the description concerns compounds of Formula 1: CS NES
[10] [10] One aspect of the description relates to compounds of Formula Ilb: CS NES
[11] [11] One aspect of the description relates to compounds of Formula Ill:
[12] [12] One aspect of the description relates to compounds of Formula IV: 1 1 ISA,
[13] [13] One aspect of the description concerns compounds of Formula V: 1 1 ATA A; + RR (V) and pharmaceutically acceptable salts, prodrugs, hydrates, tautomers
[14] [14] One aspect of the description concerns the compounds of Formula VI: CS NES
[15] [15] Another aspect of the description relates to methods of treating a disease associated with modulation of SHP2 in an individual in need thereof, comprising administering to the individual an effective amount of one or more compounds described here (for example , compounds of Formula la, |, Ila, Ilb, III, IV, V, or VI, and pharmaceutically acceptable salts, prodrugs, hydrates, tautomers or isomers thereof).
[16] [16] Another aspect of the description concerns methods of inhibiting SHP2. The method comprises administering to a patient in need of it, an effective amount of one or more compounds described herein (for example, compounds of Formula la, |, la, Ilb, III, IV, V, or VI, and salts pharmaceutically acceptable products, prodrugs, hydrates, tautomers or isomers thereof).
[17] [17] Another aspect of the description is directed to pharmaceutical compositions that comprise one or more compounds described here (for example, compounds of Formula la, 1, lla, Ilb, III, IV, V, or VI, and salts pharmaceutically acceptable, prodrugs, hydrates, tautomers or isomers thereof), and a pharmaceutically acceptable carrier. The pharmaceutically acceptable carrier may also comprise an excipient, diluent or surfactant. The pharmaceutical composition can be effective for the treatment of a disease associated with SHP2 modulation in an individual in need of it.
[18] [18] Another aspect of the description relates to methods of treating a disease associated with modulation of SHP2 in an individual in need, comprising administering to the individual an effective amount of a pharmaceutical composition comprising one or more compounds described herein (for example, compounds of Formula la, 1, Ila, Ilb, III, IV, V, or VI, and pharmaceutically acceptable salts, prodrugs, hydrates, tautomers or isomers thereof).
[19] [19] Another aspect of the description relates to methods of inhibiting SHP2 which comprise administering to a patient in need of the same, an effective amount of a pharmaceutical composition comprising one or more compounds described herein (for example, for example, compounds of Formula 1, 1, 1, IIb, III, IV, V, or VI, and pharmaceutically acceptable salts, prodrugs, hydrates, tautomers or isomers thereof).
[20] [20] Another aspect of the description relates to one or more compounds described here (for example, compounds of Formula la, |, la, Ilb, III, IV, V, or VI, and pharmaceutically acceptable salts, prodrugs, hydrates, tautomers or isomers thereof), for use in the treatment or prevention of a disease associated with SHP2 modulation. One aspect of the description relates to pharmaceutical compositions that comprise one or more compounds described herein (for example, compounds of Formula la, |, 1a, Ilb, III, IV, V, or VI, and pharmaceutically acceptable salts, prodrugs , hydrates, tautomers or isomers thereof), and a pharmaceutically acceptable carrier, for use in the treatment of prevention of a disease associated with SHP2 modulation.
[21] [21] Another aspect of the description relates to the use of one or more compounds described herein (for example, compounds of Formula la, |, Ila, 1lb, 111, IV, V, or VI, and pharmaceutically acceptable salts, proparma- hydrates, tautomers or isomers thereof), in the manufacture of a medicine for the treatment or prevention of an associated disease
[22] [22] Another aspect of the description relates to one or more compounds described here (for example, compounds of Formula la, |, la, Ilb, III, IV, V, or VI, and pharmaceutically acceptable salts, prodrugs, hydrates, tautomers or isomers thereof), for use as medication. Another aspect of the description relates to pharmaceutical compositions comprising one or more compounds described herein (for example, compounds of Formula la, |, Ila, Ilb, III, IV, V or Vl, and pharmaceutically acceptable salts, prodrugs, hydrates, tautomers or isomers thereof), for use as a medicine. In some embodiments, the drug is used to treat or prevent a disease associated with SHP2 modulation.
[23] [23] The present description also provides compounds and pharmaceutical compositions that are useful in inhibiting SHP2. DETAILED DESCRIPTION OF THE DESCRIPTION
[24] [24] In a first aspect, compounds of Formula la are described: 1 1 To De. 2
[25] [25] In another aspect, compounds of Formula | are described: Yo xt 1 [2 (R ES x, RD nº R 1 RR), and pharmaceutically acceptable salts, prodrugs, hydrates, tautomers and isomers thereof, where A, Y ', R1, Rº, Rà, R4, X (, Xº, X%, and n are described as above.
[26] [26] In another aspect, compounds of Formula 1 are described: (RR); EX
[27] [27] In another aspect, compounds of Formula Ilb are described: (RR); NX
[28] [28] In another aspect, compounds of Formula Ill are described: 1 (Rs x Í [2
[29] [29] In another aspect, compounds of Formula IV are described: 1 1 CS Ex RA ”Rº Rº (IV), and pharmaceutically acceptable salts, prodrugs, hydrates, tautomers and isomers thereof, where A, R ', R2à, Rà, R4, XI, XX%, and n are described as above.
[30] [30] In another aspect, compounds of Formula V are described: O. xi Í 2
[31] [31] In another aspect, compounds of Formula VI are described: 1
[32] [32] The details of the description are set out in the accompanying description below. Although methods and materials similar or equivalent to those described here can be used in the practice or testing of the present description, illustrative methods and materials are now described. Other characteristics, objects and advantages of the description will be evident from the description and the claims. In the specification and in the appended claims, singular forms also include the plural, unless the context clearly indicates otherwise. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as is commonly understood by someone skilled in the technique to which this description belongs. All patents and publications cited in this specification are incorporated herein by reference in their entirety.
[33] [33] Each modality described here can be considered alone or in combination with any one or more other modalities. Terms
[34] [34] The articles “one, one (a)” and “one, one (an)” that are used in this description refer to one or more than one (that is, at least one) of the grammatical objectives of the article. For example, "an element" means an element or more than one element.
[35] [35] The term "and / or" is used in this description to mean either "and" or "or", unless otherwise indicated.
[36] [36] By "optional" or "optionally," it is understood that the subsequently described event or circumstance may or may not occur, and that the description includes cases where the event or circumstance occurs and cases where it does not. For example, "optionally substituted aryl" encompasses both "aryl" and "substituted aryl" as defined here. It will be understood by those skilled in the art, with respect to any group containing one or more substituents, that such groups are not intended to introduce any substitution or substitution patterns that are sterically impracticable, synthetically unfeasible and / or inherently unstable.
[37] [37] The term “optionally substituted” is understood to mean that a certain chemical moiety (for example, an alkyl group)
[38] [38] The term "alkyl" refers to a straight or branched chain saturated hydrocarbon. C1-Cs alkyl groups contain from 1 to 6 carbon atoms. Examples of a C1-Cs alkyl group include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, isopropyl, isobutyl, sec-butyl and tert-butyl, isopentyl and neopentyl.
[39] [39] The term "alkenyl" means a hydrocarbon group containing a carbon-carbon double bond and which can be linear or branched having about 2 to about 6 carbon atoms. Certain alkenyl groups have about 2 to about 4 carbon atoms in the chain. Branched means that one or more lower alkyl groups such as methyl, ethyl, or propyl are attached to a line-ar alkenyl chain. Exemplary alkenyl groups include ethylene, propenyl, n-butenyl, and i-butenyl. A C2-Cs alkenyl group is an alkenyl group containing between 2 and 6 carbon atoms.
[40] [40] The term "alkynyl" means an aliphatic hydrocarbon group containing a carbon-carbon triple bond and which can be | near or branched having from about 2 to about 6 carbon atoms in the chain. Certain alkynyl groups have 2 to about 4 carbon atoms in the chain. Branched means that one or more lower alkyl groups such as methyl, ethyl, or propyl are attached to a linear alkynyl chain. Exemplary alkynyl groups include ethynyl, propynyl, n-butynyl, 2-butynyl, 3-methylbutynyl, and n-pentynyl. A C2-Cs alkynyl group is an alkynyl group containing between 2 and 6 carbon atoms.
[41] [41] The term "cycloalkyl" refers to a simple saturated or partially unsaturated all-carbon ring having 3 to 20 ring carbon atoms (i.e., C3-C209 cycloalkyl), for example, 3 to 12 ring atoms, for example, from 3 to 10 ring atoms. The term "cycloalkyl" also includes fully condensed, saturated, and partially unsaturated, multi-ring systems (for example, ring systems comprising 2, 3 or 4 carocyclic rings). Consequently, cycloalkyl includes carbocycles such as bicyclic carbocycles (for example, bicyclic carbocycles having about 6 to 12 ring carbon atoms such as [3.1.0] hexane and [2.1.1] hexane), and polycyclic carbocycles (for example, tricyclic and tetracyclic carbocycles with up to about 20 ring carbon atoms). The rings of a condensed multi-ring system can be connected between sip or fused, spiro and bridged connection means, when permitted by valency requirements. Non-limiting examples of monocyclic cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl, cyclohexyl, 1-cyclohexyl-1 -enyl, 1-cyclohex-2-enyl and 1-cyclohex-3-enyl.
[42] [42] The term “cycloalkenyl” means monocyclic, non-aromatic, saturated carbon rings containing 4 to 18 carbon atoms. Examples of cycloalkenyl groups include, without limitation, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, and norborenyl. A C4-Cg cycloalkenyl is a cycloalkenyl group containing between 4 and 8 carbon atoms.
[43] [43] The term "aryl" as used here refers to a single fully carbon aromatic ring or a system of multiple fully carbon condensed rings, where at least one of the rings is aromatic. For example, in certain embodiments, an aryl group has 6 to 20 ring carbon atoms, 6 to 14 ring carbon atoms, or 6 to 12 ring carbon atoms. Arila includes a phenyl radical. Arila also includes condensed multi-ring systems (for example, ring systems comprising 2, 3 or 4 rings) having about 9 to 20 carbon atoms in which at least one ring is aromatic and in which the other rings can be aromatic or non-aromatic (ie carbocycle). Such condensed multiple ring systems are optionally substituted with one or more (for example, 1, 2 or 3) oxo groups on any carbocycle portion of the condensed multiple ring system. The rings of the condensed multi-ring system can be connected to each other by means of fused, spiral and bridge connections, when permitted by valency requirements. It is also understood that when reference is made to a certain aryl with members in the atom range (for example, 6 to 12 membered aryl), the atom range is for the total ring (ring) atoms of the aryl. For example, a 6-membered aryl would include phenyl and a 10-membered aryl would include naphthyl and 1, 2, 3, 4-tetrahydronaphthyl. Non-limiting examples of aryl groups include, but are not limited to, phenyl, indenyl, naphthyl, 1,2,3,4-tetrahydronaftyl, anthracenyl, and the like
[44] [44] The aryl group can be optionally substituted by one or more substituents, for example, 1 to 5 substituents, at any point of attachment. Exemplary substituents include, but are not limited to, -H, halogen, -O-C1-Cs alkyl, -C1-Cs alkyl, -OC2-Cs alkenyl, -OC2-Cs alkynyl, -C2-Cs alkenyl , -C2-Cs6 alkynyl, -OH, -OP (O) (OH) 2, -OC (O0) C1-Cs alkyl, -C (O) C1-Cs alkyl, -OC (0) OC71-Cs alkyl, = -NH2, - = NH (C1-Csalkyl), = N (C1-Cealkyl) 2, -S (0) 2-C1-Cs al-
[45] [45] The term "heteroaryl" as used here refers to a single aromatic ring that has at least one atom other than carbon in the ring, where the atom is selected from the group consisting of oxygen, nitrogen and sulfur; the term also includes multi-ring condensed systems that have at least one such aromatic ring, whose multi-ring condensed systems are also described below. Thus, the term includes simple aromatic rings of about 1 to 6 ring carbon atoms and about 1 to 4 ring hetero atoms selected from the group consisting of oxygen, nitrogen and sulfur in the rings. The sulfur and nitrogen atoms can also be present in an oxidized form, as long as the ring is aromatic. Such rings include, but are not limited to, pyridyl, pyrimidinyl, oxazolyl or furyl. The term also includes condensed multiple ring systems (for example, ring systems comprising 2, 3 or 4 rings), wherein a heteroaryl group, as defined above, can be condensed with one or more selected heteroaryl rings (to form , for example, a natphyridinyl such as 1,8-naphthyridinyl), heterocycloalkyls, (to form, for example, a 1,2,3,4-tetrahydronaphthyridinyl such as 1,2,3,4-tetrahydro- 1,8-naphthyridinyl), cycloalkyls (to form, for example, 5,6,7,8-tetrahydroquinolyl) and aryls (to form, for example, indazolyl) to form the condensed multiple ring systems . Thus, a heteroaryl (a single aromatic ring or multiple condensed ring system) has about 1 to 20 ring carbon atoms and about 1 to 6 ring hetero atoms. Such multi-ring condensed systems can optionally be replaced with one or more (for example, 1, 2, 3 or 4) oxo groups in the carbocycle or heterocycle portions of the condensed ring. The rings of the condensed multiple ring system can be
[46] [46] The terms "heterocycloalkyl", "heterocycle", or "heterocyclic" as used here refer to a single saturated or partially unsaturated non-aromatic ring or a multiple non-aromatic ring system that has at least one heteroatom in the ring (at least one ring heteroatom selected from oxygen, nitrogen and sulfur). Unless otherwise specified, a heterocycloalkyl group has 3 to about 20 ring atoms, for example, 5 to 20 ring atoms, for example, 5 to 14 ring atoms, for example, from a 10 ring atoms, for example, from 3 to 12 ring atoms. Thus, the term includes simple saturated or partially unsaturated rings (for example, 3, 4, 5, 6 or 7 ring members) having about 1 to 6 ring carbon atoms and about 1 to 3 hetero atoms rings selected from the group consisting of oxygen, nitrogen and
[47] [47] The terms "spirocycle" or "spirocyclic" mean carbogenic bicyclic ring systems with both rings connected through a single atom. The ring can be different in size and nature, or identical in size and nature. Examples include spiropentane, spirohexane, spiroheptane, spirooctane, spirononane, or spirochondane. One or both rings on a spirocycle can be fused to another ring and can be fused to another carbocyclic, heterocyclic, aromatic, or heteroaromatic ring. One or more of the carbon atoms in the spirocycle can be substituted with a hetero atom (for example, O, N, S, or P). A C5-C12 spirocycle is a spirocycle containing between 5 and 12 carbon atoms. In some embodiments, a Cs5-C12 spirocycle is a spirocycle containing 5 to 12 carbon atoms. One or more of the carbon atoms can be replaced with a hetero atom.
[48] [48] The term "spirocyclic heterocycle", "spiro-heterocyclic", or "spiro-heterocycle" is understood to mean a spirocycle in which at least one of the rings is a heterocycle (for example, at least one of the rings is furanyl, morpholinyl , or piperadinyl). A spirocyclic heterocycle can contain between 5 and 12 atoms, at least one of which is a heteroatom selected from N, O, Se P. In some modalities, a spirocyclic heterocycle can contain from 5 to 12 atoms, at least one of which is a heteroatom selected from N, O, Se P.
[49] [49] The term "halo" or "halogen" means a fluorine, chlorine, bromine, or iodine group.
[50] [50] The term "carbonyl" refers to a functional group that comprises a carbon atom with double bond to an oxygen atom. It can be abbreviated here as “oxo,” as C (O), or as C = O.
[51] [51] The description also includes pharmaceutical compositions that comprise an effective amount of one or more compounds described and a pharmaceutically acceptable carrier. As used herein, "pharmaceutically acceptable carrier, diluent or excipient" includes, without limitation, any adjuvant, carrier, excipient, glidant, sweetener, diluent, preservative, tincture / colorant, flavor enhancer, surfactant, wetting agent, dispersing agent , suspending agent, stabilizer, isotonic agent, solvent, surfactant or emulsifier that has been approved by the United States Food and Drug Administration as acceptable for use in humans or domestic animals.
[52] [52] The description includes pharmaceutically acceptable salts of the compounds described here. "Pharmaceutically acceptable" salts include, but are not limited to, for example, water-soluble and water-insoluble salts, such as the acetate, ansonate (4,4-diaminostilbene-2,2-disulfonate), benzenesulfonate salts , benzonate, bi-
[53] [53] "Pharmaceutically acceptable salt" also includes both acid and base addition salts. “Pharmaceutically acceptable acid addition salt” refers to those salts that maintain the biological efficacy and properties of the free bases, which are not biologically or otherwise undesirable, and which are formed with inorganic acids such as, but not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, and organic acids, such as, but not limited to, acetic acid, 2,2-dichloroacetic acid, adipic acid, alginic acid, ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, camphoric acid, camphor-10-sulfonic acid, capric acid, caproic acid, caprylic acid, carbonic acid, cinnamic acid, citric acid, acid cyclamic, dodecyl sulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, formic acid, fumaric acid, galactary acid, gentisic acid, glycoheptonic acid, glyconic acid, glucuronic acid, glutamic acid, glutaric acid, glutaric acid, 2-oxo-glutaric acid, glycerophos-
[54] [54] “Pharmaceutically acceptable base addition salt” refers to those salts that maintain the biological efficacy and properties of free acids, which are not biologically or otherwise undesirable. These salts are prepared by adding an inorganic base or an organic base to the free acid. Salts derived from inorganic bases include, but are not limited to, salts of sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum and the like. For example, inorganic salts include, but are not limited to, ammonium, sodium, potassium, calcium, and magnesium salts. Salts derived from organic bases include, but are not limited to, primary, secondary and tertiary amine salts, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as ammon resins - nioa, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, diethanolamine, ethanolamine, deanol, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, betaine, choline, choline, benzyme , benzathine, ethylenediamine, glucosamine, methylglucamine, theobromine, triethanolamine, tromethamine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine and the like.
[55] [55] The term “tautomers” refers to a group of compounds that have the same number and type of atoms, but differ in bonding connectivity and are in equilibrium with each other. A "tautomer" is a simple member of this group of compounds. Typically, a simple tautomer is extracted, but it is understood that this simple structure represents all possible tautomers that could exist. Examples include enol ketone tautomerism. When a ketone is extracted, it is understood that both the forms of enol and ketone are part of the description.
[56] [56] The description includes prodrugs of the compounds described here. The term "prodrug," as used in this description, means a compound that is convertible in vivo by metabolic means (for example, by hydrolysis) into a described compound. In addition, as used here, a prodrug is a drug that is inactive in the body, but is typically transformed into the cup during absorption or after absorption of the gastrointestinal into the active compound. The conversion of the prodrug into the active compound in the body can be done chemically or biologically (that is, using an enzyme).
[57] [57] The description includes solvates of the compounds described herein. The term "solvate" refers to a complex of variable stoichiometry formed by a solute and solvent. Such solvents for the purposes of the description may not interfere with the biological activity of the solute. Examples of suitable solvents include, but are not limited to, water, MeOH, EtOH and AcOH. Solvates in which water is the solvent molecule are typically referred to as hydrates. Hydrates include compositions containing stoichiometric amounts of water, as well as compositions containing varying amounts of water.
[58] [58] The description includes isomers of the compounds described here. The term "isomer" refers to compounds that have the same composition and molecular weight, but differ in physical and / or chemical properties. The structural difference may be in the constitution (geometric isomers) or in the ability to rotate the plane of polarized light (stereoisomers). With respect to stereoisomers, the compounds of the present description can have one or more asymmetric carbon atoms and can occur as racemates, racemic mixtures and as individual enantiomers or diastereomers.
[59] [59] The term “stereoisomers” refers to the group of compounds that have the same number and type of atoms and share the same bonding connectivity between those atoms, but differ in the three-dimensional structure. The term "stereoisomer" refers to any member of this group of compounds. For example, a stereoisomer can be an enantiomer or a diastereomer. The description includes stereoisomers of the compounds described here.
[60] [60] In addition, this description covers all geometric and positional isomers. For example, if a compound of the present description incorporates a double bond or a fused ring, both cis and trans forms, as well as mixtures, will be covered within the scope of this description. If the compound contains a double bond, the substituent may be in the e or Z configuration. If the compound contains a disubstituted cycloalkyl, the cycloalkyl substituent may have a cis or trans configuration.
[61] [61] The term "enantiomers" refers to a pair of stereoisomers that are reflected images not overlapping each other. The term "enantiomer" refers to a single member of this pair of stereoisomers. The term "racemic" refers to a 1: 1 mixture of a pair of enantiomers. The description includes enantiomers of the compounds described here. Each compound described here includes all enantiomers that conform to the general structure of the compound. The compounds can be in a racemic or enantiomerically pure form, or any other form in terms of stoichiometry. In some embodiments, the compounds are the (S) enantiomer. In other modalities, the compounds are the enantiomer (R). In still other modalities, the compounds are the (+) or (-) enantiomers.
[62] [62] In some embodiments, the compounds and compositions of the description can be enriched to provide predominantly an enantiomer of a compound described herein. An enantiomerically enriched mixture can comprise, for example, at least 60 mol% of an enantiomer, or more preferably at least 75, 80, 85, 90, 95, 96, 97, 98, 99, 99.5 or 100 mol percent. In some embodiments, the compound described here enriched in one enantiomer is substantially free of the other enantiomer, where substantially free means that the substance in question comprises less than 10%, or less than 5%, or less than 4%, or less than 3%, or less than 2%, or less than 1% as compared to the amount of the other enantiomer, for example, in the compound composition or mixture. For example, if a composition or compound mixture contains 98 grams of a first enantiomer and 2 grams of a second enantiomer, it will be said to contain 98 mole percent of the first enantiomer and only 2 mole percent of the second enantiomer. enantiomer.
[63] [63] The term “diastereomers” refers to the group of stereoisomers that cannot be overlapped by rotation around single bonds. For example, cis and trans double bonds, endo and exo- substitution in bicyclic ring systems and compounds containing multiple stereogenic centers with different related configurations are considered diastereomers. The term "diastereomer" refers to any member of this set of compounds. In some examples presented, the synthetic route can produce a single diastereomer or a mixture of diastereomers. The description includes diathereomers of the compounds described here.
[64] [64] In some embodiments, the compounds and compositions of the description can be enriched to provide predominantly a diastereomer of a compound described here. A diastereomerically enriched mixture can comprise, for example, at least 60 mol percent of a diastereomer, or more preferably at least 75, 85, 95, 96, 97, 98, 99, or even 100 percent in mol.
[65] [65] The compounds described here also include all pharmaceutically acceptable isotopically labeled compounds. An “isotopically” or “radio-labeled” compound is a compound in which one or more atoms are exchanged or replaced by an atom that has an atomic mass or mass number different from the atomic mass or mass number normally found in nature (ie is, naturally occurring). For example, in some modalities, in the compounds described here, the hydrogen atoms are exchanged or replaced with one or more deuterium or tritium. Certain isotopically labeled compounds of this description, for example, those that incorporate a radioactive isotope, are useful in studies of tissue distribution of drug and / or substrates. The radioactive isotopes tritium, that is, 3H, and carbon 14, that is, * C, are particularly useful for this purpose in view of their ease of incorporation and ready means of detection. Substitution with heavier isotopes such as deuterium, that is, 2H, can provide certain therapeutic advantages resulting from increased metabolic stability, for example, increased in vivo half-life or reduced dosage requirements and therefore can be preferred in some circumstances. Suitable isotopes that can be incorporated into the compounds described here include, but are not limited to H (also written as D for deuterium), H (also written as T for tritium), 'C, ºC, C, * N , * N, O, O, 189, 18FE, 358, 36C]; 82Br, 7SBr, 76Br, 7TBr, 1231, 124, 1251, and 131. The
[66] [66] An "effective amount" when used in connection with a compound is an effective amount for treating or preventing a disease in an individual as described here.
[67] [67] The term "vehicle," as used in this description, encompasses excipients and thinners and means a material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or packaging material, involved in the transport or conduction of a pharmaceutical agent from one organ, or part of the body, to another organ, or part of the body of an individual.
[68] [68] The term "treat" with respect to an individual, refers to the improvement of at least one symptom of the individual's disorder. Treating includes curing, improving or at least partially improving the disorder.
[69] [69] The term “prevent” or “preventing” with respect to an individual refers to withholding a disease or disorder that afflicts the individual. Prevention includes prophylactic treatment. For example, prevention may administer to the individual one or more compounds described here before an individual is afflicted with a disease and administration will preserve the individual from being afflicted with the disease.
[70] [70] The term “disorder” is used in this description to mean, and is used interchangeably with, the terms disease, condition, or illness, unless otherwise indicated.
[71] [71] The term "administer," "administering," or "administration" as used in this description refers to directly administering one or more described compounds or a pharmaceutically acceptable salt of one or more described compounds or a composition comprising a or more compounds described to an individual, or administer a prodrug derivative or compound analog or a pharmaceutical salt.
[72] [72] A "patient" or "individual" is a mammal, for example, a human, mouse, rat, guinea pig, dog, cat, horse, cow, pig, non-human primate, such as a monkey, chimpanzee, baboon OR rhesus. Description Compound
[73] [73] The present description provides compounds of Formula la: CS NES
[74] [74] This description provides compounds of Formula |, 1 1 ATA 2 The RR)
[75] [75] The present description provides compounds of Formula 1la, CS SS
[76] [76] The present description provides compounds of Formula Ilb, AS NOx
[77] [77] The present description provides compounds of Formula IV: NS EX
[78] [78] As described above for Formula la, |, and IV, Y * is -S- or a direct link. In certain embodiments, Y * is —-S-. In certain modalities, Y ' it is a direct link.
[79] [79] As described above, X * is N or CH. In certain modalities, X is N. In certain embodiments, X '* is CH.
[80] [80] As described above, X is N or CH. In certain modalities, X is N. In certain embodiments, X is CH.
[81] [81] As described above, X is N or CH. In certain modalities, Xº is N. In certain modalities, X is CH.
[82] [82] As described above, at least one of X ', X , or Xº is N. In certain modalities, X * is N. In certain modalities, Xº is N. In certain modalities, Xº is N. In certain modalities, X 'is Ne X2º is N. In certain modalities, X' is Ne Xº is N. In certain modalities, Xº is NexX is N. In certain embodiments, X 'E N; X is Ne Xº is N.
[83] [83] As described above, A is selected from the group consisting of 5 to 12-membered monocyclic or polycyclic cycloalkyl, monocyclic or polycyclic heterocycloalkyl, monocyclic or polycyclic aryl or monocyclic or polycyclic heteroaryl.
[84] [84] In certain embodiments, A is 5- to 12 monocyclic or polycyclic cycloalkyl members. In certain embodiments, A is 5- to 12 monocyclic or polycyclic heterocycloalkyl members. In certain modalities, A is 5- to 12-membered monocyclic or polycyclic aryl. In certain embodiments, A is 5- to 12-membered monocyclic or polycyclic heteroaryl.
[85] [85] In certain embodiments, A is a monocyclic heteroaryl. In certain embodiments, A is a monocyclic aryl. In certain modalities, A is a polycyclic heteroaryl. In certain embodiments, A is a polycyclic heterocycloalkyl.
[86] [86] In certain embodiments, A is selected from:
[87] [87] In certain embodiments, A is selected from: x
[88] [88] As described above for formula |, Ila, and Ilb, R 'is independently, in each occurrence, -H, —D, —C1-Cs alkyl, -—- C2-Cs alkenyl, —- Ca4-Cg cycloalkenyl, -—- C2-Cs alkynyl, -C3-Cg cycloalkyl, -OH, -OR $, halogen, -NO> 2, -CN, —NRºRº, —SR5, —S (O) .NRºRº, - S (O) 2R , -NRºS (O) NRºRº, —-NR $ S (O) 2Rº, -S (O) NRºRº, —S (O) R5, - NRÍS (O) NRºRº, -NRºS (O ) Rº, —C (O) R , -—- CO2R ”, -C (O) NR'Rô, or - NRºC (O) Rº, where each alkyl, alkenyl, cycloalkenyl, alkynyl, or cycloalkyl is optionally substituted with one or more -OH, halogen, —-NO ,, oxo, -CN, -Rº, -OR ”, —-NRºR6, -SR”, -S (O) .NR “R $, - S ( O) 2R , -NRºS (O) NRºRº, —NRºS (O) 2Rº, -S (O) NRºRº, —S (O) R5, - NRSS (O) NRºR86, —-NRºS (O) R $, heterocycle , aryl or heteroaryl.
[89] [89] In certain embodiments, each R 'is selected from the group consisting of -H, halogen, -C1-Cs alkyl, and -NRºRº. In certain modalities, Rº and R $ are H.
[90] [90] As described above for formula la and IV, R 'is independently, at each occurrence, -H, —D, —C1-Cs alkyl, -—- C2-Cs «alkenyl, —-C4 -Cg cycloalkenyl, -—- C2-Cs alkynyl, -C3-Cg cycloalkyl, - OH, -OR $, halogen, -NO> 2, -CN, —NRºRº, —SRº, —S (O) .NR “Rº , - S (O) 2R , -NRºS (O) NRºRº, —NRºS (O) 2Rº, -S (O) NRºRº, —S (O) R5, -
[91] [91] As described above, n is independently 0, 1,2,3,4, 5,6,7,8,9, or 10.
[92] [92] As described above, Rº and Rô are each independently, in each occurrence, selected from the group consisting of —H, —D, —C1-Cs alkyl, —-C2-Cs alkenyl, —C4-C ; cycloalkenyl, —-C2-C6 alkynyl, —-C3-Cg cycloalkyl, a 3- to 12-membered monocyclic or polycyclic heterocycle, -OR ”, —SR”, halogen, -NR / Rô, —NO ,, and —CN. In certain modalities, Rº and Rº are H.
[93] [93] In certain embodiments, A (shown with R ') is selected from:
[94] [94] As described above for the formula la, |, Ila, and Ilb, Rº is -H,
[95] [95] In certain embodiments, Rº is —-H, —D, or —-C1-Cs alkyl, where each alkyl is optionally substituted with one or more -OH, - NH>, halogen, or oxo. In certain embodiments, Rº is an optionally substituted C1-Cs alkyl. In certain embodiments, Rº is -C1-Ces alkyl substituted with -OH. In certain embodiments, Rº is -CH2-OH. In certain embodiments, Rº is -C1-Cs alkyl substituted with one or more halogen. In certain embodiments, Rº is -C1-Cs alkyl substituted with one or more fluorine. In certain modalities, Rº is -CHF>.
[96] [96] As described above for formula IV, Rº is -C1-Cs alkyl, —C1-Cehalo alkyl, —C1-C6 hydroxyalkyl -CF20H, -CHFOH, —NH- NHRº, -NH-OR ”, -O- NRºRº, —-NHR ”, -ORº, -NHC (OJ) RS, -— NHC (O) NHRS, -NHS (O) 2R5, -NHS (O) aNHRS5, -S (0) 2OH, -C (0 ) ORS, - NH (CH2)) OH, = C (O) NH (CH2)) OH, = C (O) NH (CH2)), RP, = C (O) Rº, —-NH>, —OH , —CN, —C (O) NRºRô, —S (O) / NRºR $ 6, C3-Czg cycloalkyl, aryl, heterocyclyl containing 1 to 5 heteroatoms selected from the group consisting of N, S, P, and O , or heteroaryl containing 1 to 5 heteroatoms selected from the group consisting of N, S, P, and O, where each cycloalkyl or heterocyclyl alkyl is optionally substituted with one or more -OH, - = NH> 2 , = OR º, halogen, or 0x0; where each aryl or heteroaryl is optionally substituted with one or more -OH, - NH> 2, or halogen. In certain embodiments, Rº is an optionally substituted C1-Cs alkyl. In certain embodiments, Rº is -C1-Cs alkyl substituted with -OH. In certain embodiments, Rº is -CH2-OH. In certain modalities, Rº is -—C1-Cs alkyl substituted with one or more halogen. In certain embodiments, Rº is -C1-Cs alkyl substituted with one or more fluorine. In certain modalities, Rº is -CHF>.
[97] [97] As described above, R and Rº are independently selected from the group consisting of —H, -D, -OH, —C1-Cs alkyl, a 3- to 12-membered monocyclic or polycyclic heterocycle, a 12-membered 5-spiroheterocycle, C3-Cg cycloalkyl, or - (CH2)) - Rº, where each alkyl, heterocycle, or cycloalkyl is optionally substituted with one or more —C1-Cs alkyl, -OH, —NH2, -ORº , -NHRº, - ( CH2)) OH, heterocyclyl, or spiroheterocyclyl. In certain modalities, R or Rº is - (CH2)) C (O) NRºRº.
[98] [98] As described above, can R $ be combined with R to form a 3- to 12-membered monocyclic or polycyclic heterocycle, or a 5 to 12-membered spiroheterocycle, where each hetero-cycle or spiro-heterocycle is optionally substituted with one or more —C1-Cs alkyl, halogen - OH, -ORP, —-NH2, - = - NHRº, heteroaryl, heterocyclic, - (CH2)) NHa, - (CH2)) OH, -COOR ”, -CONHRº, - CONH (CH2)). COOR !, - NHCOOR ", -—- CF3, —-CHF2, -CH2F, or = O. In certain embodiments, Rº can be combined with R To form an optionally substituted heteroaryl or an optionally substituted heterocyclyl, where heteroaryl and heterocyclyl are optionally substituted with -CN.
[99] [99] In certain modalities, can Rº be combined with R to form an optionally substituted 3-12 membered monocyclic heterocycle. In certain modalities, can Rº be combined with R
[100] [100] In certain modalities, can Rº be combined with R to form a 3- to 12-membered monocyclic or polycyclic heterocycle, where the heterocycle is optionally substituted with more than - C1-Cs alkyl, halogen -OH, —ORº, - = NH> 2, = -NHR , heteroaryl , heterocyclic, - (CH2)) NHa, - - (CH2) OH, —-COOR ”, -CONHR, -— CONH (CH2)). COOR !, -NHCOORP, -CF3, -CHF2, -CH2F, or = O.
[101] [101] In certain modalities, can R $ be combined with R to form a 3- to 12-membered monocyclic or polycyclic heterocycle, where the heterocycle is optionally substituted with —C1-Cs alkyl, = ORº, or -NH>.
[102] [102] In certain modalities, can Rº be combined with R to form a 5- to 12-membered spiro-heterocycle, where the spiro-heterocycle is optionally substituted with more than —C1-Cs alkyl, halogen -OH, -ORº, —NH2, —NHRº, heteroaryl, heterocyclyl, - (CH2 )) NH2, - (CH2)) OH, -COORº, -CONHR !, -CONH (CH2)). COORº, - NHCOOR , -CF3, -CHF2, -CH2F, or = O.
[103] [103] In certain modalities, can R $ be combined with R to form a 5 to 12-membered spiroheterocycle, where the spirocycle is optionally substituted with —C1-Cs alkyl, = ORº, or -NH>.
[104] [104] In certain modalities, can Rº be combined with R to form a selected portion of: * y NH> FR É. NH qe (OX, and o.
[105] [105] In certain modalities, can Rº be combined with R to form a selected portion of:
[106] [106] This description provides compounds of Formula III, Rº S HO x,
[107] [107] This description provides compounds of Formula V: CS EX
[108] [108] This description provides compounds of Formula VI: and A EX
[109] [109] As described above in Formula Ill, V, and VI, X 'is N or CH. In certain embodiments, X * is N. In certain embodiments, X 'is CH.
[110] [110] As described above in Formula III, V, and VI, X is N or CH. In certain modalities, X is N. In certain embodiments, X is CH.
[111] [111] As described above in Formula III, V, and VI, XP is N or CH. In certain modalities, X is N. In certain embodiments, X * is CH.
[112] [112] As described above in Formula Ill, V, and VI, at least one of X ', X , or X is N. In certain modalities, X * is N. In certain modalities, X is N. In certain embodiments, X is N. In certain modalities, X 'is Ne Xº is N. In certain modalities, X' is Ne Xº is N. In certain modalities, X is N and Xº is N. In certain embodiments, X * is N; XéN; eXºéN.
[113] [113] As described above in Formula Ill, V, and VI, A is selected
[114] [114] In certain embodiments, A is monocyclic or polycyclic cycloalkyl of 5 to 12 members. In certain embodiments, A is 5 to 12 membered monocyclic or polycyclic heterocycloalkyl. In certain modes, A is 5 to 12-membered monocyclic or polycyclic aryl. In certain embodiments, A is a 5- to 12-membered monocyclic or polycyclic heteroaryl.
[115] [115] In certain embodiments, A is a monocyclic heteroaryl. In certain embodiments, A is a monocyclic aryl. In certain modalities, A is a polycyclic heteroaryl. In certain embodiments, A is a polycyclic heterocycloalkyl.
[116] [116] In certain modalities, A is selected from: NS; ; NS; &S. "-) 8.
[117] [117] In certain modalities, A is selected from: o. and SS OO O, NZ 2H ON 2H; ; VOA, OA, TRA N CO LO,
[118] [118] As described above in Formula Ill, Rº is independently, in each occurrence, -H, —D, —C1-Cs alkyl, —C2-Cs alkenyl, - C4-Cg cycloalkenyl, —C2-Cs alkynyl, —-C3-Cs cycloalkyl, -OH, -ORS, halogen, —-NO> 2, —CN, —NRºRº, —SRº, —S (O) .NRºRº, —S (O) 2R5, - NRºS (O) 2NRºRº, —NRºS (O) 2R $, —S (O) NRºR $, —S (O) R ”, -
[119] [119] In certain embodiments, each R 'is selected from the group consisting of -H, halogen, -C1-Cs alkyl, and -NRºRº. In certain modalities, Rº and Rô are H.
[120] [120] As described above in Formula V and VI, R 'is independently, at each occurrence, -H, —D, —C1-Cs alkyl, —-C2-Cs alkenyl, —C4-Cs cycloalkenyl, —- C2-Cs alkynyl, —-C3-Cg cycloalkyl, -OH, -OR $, halogen, —NO> 2, —-CN, —NRºR6, —SR5 ”, —S (O) .NRºRº, —S (O) -R ”, - NRºS (O) 2NRºRº, —NRºS (O) 2R $, —-S (O) NRºR $, —-S (O) R”, - NRÍS (O) NRºRô, —NRºS (O) Rº , —C (OJ) Ró, -CO2R ”, -C (O) NRºRô, - NR5C (O) RS, or monocyclic or polycyclic heterocycle of 3 to 12 members, where each alkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkyl or heterocycle is optionally substituted with one or more -OH, halogen, —-NO ,, oxo, -CN, -R5, -ORº, —-NRºR $, -SRº, —S (O) aNR “ºRº, —S (O) 2Ró, -NRºS (O) aNRºRº, -NRºS (O) 2Rº, -S (O) NRRº, —S (O) R5, - NRSS (O) NR5Rº, —-NR5S (O) R $ , heterocycle, aryl or heteroaryl. In certain embodiments, each R 'is a 3 to 12 membered optionally substituted monocyclic or polycyclic heterocycle. In certain modalities, each R 'is a monocyclic or polycyclic heterocycle of 3 to 12 members substituted with heterocycle or -S (O) 2Rº. In certain embodiments, each R 'is selected from the group consisting of halogen, -C1-Cs6 alkyl, - ORô, -CN, —C (O) NRºR $, and -NRºRº. In certain modalities, Rº and Rº are H.
[121] [121] As described above in Formula Ill, V, and VI, n is independently O, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.
[122] [122] As described above in Formula III, V, and VI, Rº and Rº are each independently, in each occurrence, selected from the group consisting of —-H, —D, —C1-Cs alkyl, —-C2- Alkenyl Cs6, -Ca- cycloalkenyl, —-C2-Cs alkynyl, —-C3-Cg cycloalkyl, a 3- to 12-membered monocyclic or polycyclic heterocycle, -OR ” , -SR7, halogen, —NR'R3, - -NO ,, and -CN. In certain modalities, Rº and Rº are H.
[123] [123] In certain modalities, A (shown with R ') are selected from: e GR TER ç ER Ne CI Na AOS S&S, CH; Cc; CC! ; Cc; H ; CH; and
[124] [124] As described above in Formula III, Rº is -H, —D, or —C1-C6 alkyl, where each alkyl is optionally substituted with one or more -OH, —NH> z, halogen, or oxo. In certain embodiments, Rº is optionally substituted an -C1-Cs alkyl. In certain embodiments, Rº is -C1-Cs alkyl substituted with -OH. In certain modalities, Rº is - CH2-OH. In certain embodiments, Rº is —-C1-Cs alkyl substituted with one or more halogen. In certain embodiments, Rº is -C1-Cs alkyl substituted with one or more fluorine. In certain modalities, Rº is - CHF>.
[125] [125] As described above in Formula V and VI, Rº is -C1-Cs alkyl, where each alkyl is optionally substituted with one or more - OH, —NH>, halogen, or oxo. In certain embodiments, Rº is -C1-Cs alkyl substituted with -OH. In certain modalities, Rº is “CH2-OH. In certain embodiments, Rº is —-C1-Cs alkyl substituted with one or more halogen. In certain embodiments, Rº is —-C1-Cs alkyl substituted with one or more fluorine. In certain modalities, Rº is -CHF2.
[126] [126] As described above in Formula Ill and V, R2 and Rº are
[127] [127] As described above in Formula Ill, V, and VI, can R $ be combined with R to form a 3- to 12-membered monocyclic or polycyclic heterocycle, or a 5-to-12-membered spiroheterocycle, where each heterocycle or spiroheterocycle is optionally substituted with one or more alkyl-, C1-Cs, halogen —-OH, -ORº, —NH>, - NHRº, heteroaryl, heterocyclyl, - (CH2), NH2, - (CH2)) OH, -COORº, - CONHRº, = -CONH (CH2)). COOR , = -NHCOOR ", —CF3, = CHF2, -—CHoF, or = O. In certain embodiments, Rº can combine with R 'to form an optionally substituted heteroaryl or an optionally substituted heterocyclyl, where the heteroaryl and heterocyclyl are optionally substituted with -CN.
[128] [128] In certain modalities, can Rº be combined with R to form an optionally substituted 3-12 membered monocyclic heterocycle. In certain modalities, can Rº be combined with R to form an optionally substituted 3 to 12 membered polycyclic heterocycle. In certain embodiments, R $ can be combined with R º to form an optionally substituted 3 to 12 membered polycyclic spiroheterocycle.
[129] [129] In certain modalities, can Rº be combined with R to form a 3- to 12-membered monocyclic or polycyclic heterocycle, where the heterocycle is optionally substituted with more than - C1-Cs alkyl, halogen -OH, -ORº , —NN2, - = - NHRº, heteroaryl, heterocyclyl, - (CH2)) NHo, - - (CH2);) OH, - -COOR ”, —-CONHR !, -
[130] [130] In certain embodiments, can R3 be combined with R to form a 3- to 12-membered monocyclic or polycyclic heterocycle, where the heterocycle is optionally substituted with —C1-Ce alkyl, = ORº, or —-NH>.
[131] [131] In certain embodiments, can R3 be combined with R to form a 5 to 12-membered spiroheterocycle, where the spiroheterocycle is optionally substituted with more than —C1-C; s alkyl, halogen -OH, -ORº, —NH2, —NHRº, heteroaryl, heterocyclic, - (CH2)) NH2, - (CH2)) OH, -COORº, -CONHR !, -CONH (CH2) .COORº, - NHCOOR , -CF3, - = CHF2, -CH2F, or = O.
[132] [132] In certain modalities, can Rº be combined with R to form a 5- to 12-membered spiroheterocycle, where the spirocycle is optionally substituted with —C1-Cs alkyl, = ORº, or -NH,>.
[133] [133] In certain modalities, can Rº be combined with R to form a selected portion of: * y NHo * y NH, XD Que NX, ") o.
[134] [134] In certain modalities, can Rº be combined with R to form a selected portion of: * y Not É. NH XX ve OS “CH; ; "-) O .
[135] [135] The present description provides a compound of Formula la, 1, 1la, 1lb, III, IV, V, and VI having one, two, three, four or more of the following characteristics: a) X 'is CH; eX eXº are N; b) A is optionally substituted monocyclic or polycyclic heteroaryl; Cc) R 'is independently, in each occurrence, -H, -C1-Cs alkyl, halogen or -NH>; d) Can Rº be combined with R to form an optionally substituted 3 to 12 membered polycyclic spiroheterocycle; and e) Rº is -CH2-OH.
[136] [136] The present description provides a compound of Formula | a, 1, la, 1lb, III, IV, V, and VI, having one, two, three, four or more of the following characteristics: a) X 'is CH; eX EX are N; b) A is optionally substituted monocyclic or polycyclic heteroaryl; c) R 'is independently, in each occurrence, -H, -C1-Ces alkyl, halogen or -NH>; d) Can R3 be combined with R to form an optionally substituted monocyclic or polycyclic heterocycle of 3 to 12 members; and e) Rº is -CH2-OH.
[137] [137] The present description provides a compound of Formula | a, 1, la, 1lb, III, IV, V, and VI, having one, two, three, four or more of the following characteristics: a) X 'is CH; eX EXº are N; b) A is optionally substituted monocyclic or polycyclic aryl; c) R 'is independently, in each occurrence, -H, XC1-Cs alkyl, halogen or -NH>; d) R3 can be combined with R to form an optionally substituted 3 to 12 membered polycyclic spiroheterocycle; and e) Rº is -CH2-OH.
[138] [138] The present description provides a compound of Formula | a, 1, la, 1lb, III, IV, V, and VI, having one, two, three, four or more of the following characteristics:
[139] [139] The present description provides a compound of Formula la, 1, la, 1lb, III, IV, V, and VI, having one, two, three, four or more of the following characteristics: a) XéCH eX EX areN; b) A is optionally substituted monocyclic or polycyclic heteroaryl; Cc) R 'is independently, in each occurrence, -H, -C1-Ce alkyl, halogen or -NH>; d) R can be combined with R to form an optionally substituted 3 to 12 membered polycyclic spiroheterocycle; and e) Rº is -C1-Cs alkyl substituted with one or more halogen.
[140] [140] The present description provides a compound of Formula la, 1, la, 1lb, III, IV, V, and VI, having one, two, three, four or more of the following characteristics: a) X 'is CH ; eX eXº are N; b) A is optionally substituted monocyclic or polycyclic heteroaryl; Cc) R 'is independently, in each occurrence, -H, XC1-Cs alkyl, halogen or -NH>; d) Can R3 be combined with R to form an optionally substituted 3 to 12 membered monocyclic or polycyclic heterocycle
[141] [141] The present description provides a compound of Formula la, 1, la, 1lb, III, IV, V, and VI, having one, two, three, four or more of the following characteristics: a) X 'is CH eX eXº are N; b) A is optionally substituted monocyclic or polycyclic aryl; c) R 'is independently, in each occurrence, -H, -C1-Cs alkyl, halogen or -NH>; d) R can be combined with R to form an optionally substituted 3 to 12 membered polycyclic spiroheterocycle; and e) Rº is -C1-Cs alkyl substituted with one or more halogen.
[142] [142] The present description provides a compound of Formula | a, 1, la, 1lb, III, IV, V, and VI, having one, two, three, four or more of the following characteristics: a) X 'is CH; eX eX are N; b) A is optionally substituted monocyclic or polycyclic aryl; Cc) R 'is independently, in each occurrence, -H, -C1-Ces alkyl, halogen or -NH>; d) Can R3 be combined with R to form an optionally substituted monocyclic or polycyclic heterocycle of 3 to 12 members; and e) Rº is -C1-Cs alkyl substituted with one or more halogen.
[143] [143] The present description provides a compound of Formula la, 1, 1la, 1lb, III, IV, V, and VI having one, two, three, four or more of the following characteristics: a) X 'is CH and a X and Xº is N; b) A is optionally substituted monocyclic or polycyclic heteroaryl; c) R 'is independently, in each occurrence, -H, -C1-Ces alkyl, halogen or -NH>; d) Can R3 be combined with R to form an optionally substituted 3 to 12 membered polycyclic spiroheterocycle; and e) Rº is -CH2-OH or a -C1-Cs alkyl substituted with one or more halogen.
[144] [144] The present description provides a compound of Formula la, 1, la, 1lb, III, IV, V, and VI, having one, two, three, four or more of the following characteristics: a) X 'is CH eumde Xe Xº É N; b) A is optionally substituted monocyclic or polycyclic heteroaryl; c) R 'is independently, in each occurrence, -H, -C1-Cs alkyl, halogen or -NH>; d) Can Rº be combined with R to form an optionally substituted monocyclic or polycyclic heterocycle of 3 to 12 members; and e) Rº is -CH2-OH or a -C1-Cs alkyl substituted with one or more halogen.
[145] [145] The present description provides a compound of Formula la, 1, la, Ilb, III, IV, V, and VI, having one, two, three, four or more of the following characteristics: a) X 'is CH eumde X eXºéN; b) A is optionally substituted monocyclic or polycyclic aryl; Cc) R 'is independently, in each occurrence, -H, XC1-Cs alkyl, halogen or -NH>; d) Can R3 be combined with R to form an optionally substituted 3 to 12 membered polycyclic spiroheterocycle; and e) Rº is -CH2-OH or a -C1-Cs alkyl substituted with one or more halogen.
[146] [146] The present description provides a compound of Formula la, 1, la, 1lb, III, IV, V, and VI, having one, two, three, four or more of the following characteristics: a) X 'is CH e of X and Xº is N; b) A is optionally substituted monocyclic or polycyclic aryl; c) R 'is independently, in each occurrence, -H, -C1-Cs alkyl, halogen or -NH>; d) Can Rº be combined with R to form an optionally substituted monocyclic or polycyclic heterocycle of 3 to 12 members; and e) R is -CH2-OH or a -C1-Cs alkyl substituted with one or more halogen.
[147] [147] The present description provides a compound selected from: CI No. NH NH Cc NH NH O a. o O e, Que NH>: Que Ho (3), and Ho 4). and pharmaceutically acceptable salts, prodrugs, hydrates, tautomers or isomers thereof.
[148] [148] This description provides a compound selected from:
[149] [149] The present description provides a compound selected from: nO Air Pes Ps c Gives NH, [=] Ex NH a E AS AS 2) Dem (1) 2) (3) - ac NAN NAS NZ Ns NH and NA, No E TO SE SOS. ; (4) (6) 6 o on N AAA, LX, O, to NA, No. to NA, NH and NA) No. o o o (7) (8) (9) AS ue NS: on AS (10) (11) (12) to 7 a and TD TA, XT. Th to Air VAO (13) (14) (15)
[150] [150] The present description provides a compound selected from dd Is N Dl MEAN No, Cu: CHF, S CFH If o (34) (35)
[151] [151] The compounds of the present description can be prepared by a variety of methods, including standard chemistry. Suitable synthetic routines are described in the diagrams described below.
[152] [152] The compounds of any of the formulas described herein can be prepared by methods known in the art of organic synthesis as established in part by the following synthetic schemes and examples. In the schemes described below, it is well understood that protective groups for sensitive or active groups are deployed where necessary in accordance with general chemistry principles. Protection groups are manipulated according to standard methods of organic synthesis (T. W. Greene and P. G. M. Wuts, "Protective Groups in Organic Synthesis", Third Edition, Wiley, New York 1999). These groups are removed at a convenient stage of compound synthesis using methods that are easily evident to those skilled in the art. The selection processes, as well as the reaction conditions and order of their execution, must be consistent with the preparation of compounds of Formula |
[153] [153] Those skilled in the art will recognize whether a stereocenter exists in any of the compounds of the present description. Consequently, the present description includes both possible stereoisomers (unless specified in the synthesis) and includes not only racemic products, but also individual enantiomers and / or diastereomers. When a compound is desired as a single enantiomer or diastereomer, it can be obtained by stereospecific synthesis or by resolving the final product or any convenient intermediary. The resolution of the final product, an intermediate or a starting material can be affected by any suitable method known in the art. See, for example, "Stereochemistry of Organic Compounds" by E. L. Eliel, S. H. Wilen, and L. N. Mander (Wiley-Interscience, 1994). Preparation of Compounds
[154] [154] The compounds described here can be prepared from commercially available starting materials or synthesized using organic, inorganic and / or enzymatic processes.
[155] [155] The compounds of the present description can be prepared in a variety of ways well known to those skilled in the art of organic synthesis. By way of examples, the compounds of the description can be synthesized using the methods described below, together with the synthetic methods known in the art of synthetic organic chemistry, or variations thereon as appreciated by those skilled in the art. These methods include, but are not limited to, those described below. Scheme 1. General synthesis of (3-amino-6-phenylpyrazin-2-yl) methanol oe: e Po sector So no
[156] [156] The general synthesis of (3-amino-6-phenylpyrazin-2-yl) methane! is outlined in Scheme 1. 3-Chloro-6-phenylpyrazine-2-ethylcarboxylate can be coupled to a substituted aryl or boronic heteroaryl acid in the presence of a palladium catalyst (eg Pd (dppf) Cl2). The resulting biaryl intermediate can then be coupled to a substituted primary or secondary amine under SNAr conditions, followed by reduction to provide a (3-amino-6-phenylpyrazin-2-yl)] methanol. Additional deprotection and / or functionalization steps may be required to produce the final compound.
[157] [157] The general synthesis of (3- (amino) -6- (phenylthio) pyrazin-2-yl) methane] is outlined in Scheme 2.
[158] [158] 3-Chloro-6-phenylpyrazine-2-carboxylate can be coupled to primary or secondary amines under SNAr conditions. The resulting aminopyrazine ester can then be reduced to produce amino pyrazin-2-yl-netanol, following coupling to an appropriately substituted potassium (or sodium) salt of arylthiol or heteroarylthiol. Additional deprotection and / or functionalization steps may be required to produce the final compound. Methods of Use of the Compounds and Compositions Described Methods and Uses of the Description
[159] [159] Another aspect of the description relates to a method of treating a disease associated with SHP2 modulation in an individual in need of it. The method involves administering to a patient in need of treatment for diseases or disorders associated with SHP2 modulation an effective amount of one or more compounds of the present description (for example, compounds of Formula la, 1, Ila, Ilb, III, IV, V, or VI, and pharmaceutically acceptable salts, prodrugs, hydrates, tautomers or isomers thereof), or one or more pharmaceutical compositions of the present description. In some modalities, the disease can be, but it is not limited to Noonan Syndrome, Leopard Syndrome, juvenile myelomonocytic leukemias, neuroblastoma, melanoma, acute myeloid leukemia and cancers of the breast, lung and colon. SHP2 is an important signaling molecule downstream for a variety of receptor tyrosine kinases, including platelet-derived growth factor receptors (PDGF-R), fibroblast growth factor (FGF-R) and epidermal growth (EGF-R). SHP2 is also an important signaling molecule downstream for the activation of the mitogen-activated protein kinase (MAP) pathway, which can lead to cell transformation, a prerequisite for the development of cancer. The elimination of SHP2 significantly inhibited the cell growth of lung cancer cell lines with SHP2 mutation or EML4 / ALK translocations, as well as breast cancers amplified by EGFR and esophageal cancer. SHP2 is also activated downstream of oncogenes in gastric carcinoma, anaplastic large cell lymphoma and glioblastoma.
[160] [160] In addition, SHP2 plays a role in transduction signals that originate from immunological checkpoint molecules, including but not limited to programmed cell death protein 1 (PD-1) and protein 4 associated with T lymphocyte. cytotoxic (CTLA-4). In this context, modulation of the SHP2 function can induce immune activation, specifically anti-cancer immune responses.
[161] [161] Another aspect of the description is directed to a method of inhibiting SHP2. The method involves administering to an individual in need an effective amount of one or more compounds of the present description (for example, compounds of Formula la, 1, la, lb, III, IV, V, or VI, and salts pharmaceutically acceptable, prodrugs, hydrates, tautomers or isomers thereof), or one or more pharmaceutical compositions of the present description.
[162] [162] The present description relates to the compounds or compositions described here that are capable of modulating SHP2 activity (for example, inhibiting). The present description also relates to the therapeutic use of such compounds and compositions.
[163] [163] One or more of the compounds or compositions described can be administered in amounts effective to treat or prevent disorders and / or prevent the development of these in individuals. In some embodiments, SHP2 is inhibited after treatment with less than 1000 nM of a compound of the description. In some embodiments, SHP2 is inhibited after treatment with about 10 nM to about 100 nM of a compound of the description. In some embodiments, SHP 2 is inhibited after treatment with 10 nM to 100 nM of a compound of the description. In some embodiments, SHP2 is inhibited after treatment with less than 10 nM of a compound of the description.
[164] [164] Another aspect of the present description relates to one or more compounds of the present description (for example, compounds of Formula la, |, Ila, Ilb, III, IV, V, or VI, and pharmaceutically acceptable salts, crystals, prodrugs, solvates, hydrates, tautomers, or isomers thereof), or one or more compositions of the present description for use in the treatment or prevention of a disease associated with SHP2 modulation. In some modalities, the disease is Noonan's Syndrome, Leopard Syndrome, juvenile myelomonocytic leukemias, neuroblastoma, melanoma, acute myeloid leukemia and cancers of the breast, lung and colon. SHP2 is an important signaling molecule downstream for a variety of receptor tyrosine kinases, including platelet-derived growth factor receptors (PDGF-R), fibroblast growth factor (FGF-R) and epidermal growth (EGF-R). SHP2 is also an important signaling molecule downstream for the activation of the mitogen-activated protein kinase (MAP) pathway, which can lead to cell transformation, a prerequisite for the development of cancer. The elimination of SHP2 significantly inhibited cell growth of puimão cancer cell lines with SHP2 mutation or EMLA4 / ALK translocations, as well as breast cancer amplified by EGFR and esophageal cancer. SHP2 is also activated downstream of oncogenes in gastric carcinoma, anaplastic large cell lymphoma and glioblastome.
[165] [165] In another aspect, the present description relates to the use of one or more compounds of the present description (for example, compounds of Formula la, |, lla, Ilb, III, IV, V, or VI, and pharmaceutically acceptable salts, crystals, prodrugs, hydrates, solvates, hydrates, tautomers or isomers or the same), in the manufacture of a medicine for the treatment or prevention of diseases. In some modalities, the disease is associated with SHP2 modulation.
[166] [166] In another aspect, the present description relates to one or more compounds of the present description (for example, compounds of Formula la, |, Ila, Ilb, III, IV, V, or VI, and pharmaceutically acceptable salts crystals, prodrugs, hydrates, solvates, hydrates, tautomers or isomers or the same), for use as a medicine. In some modalities, the drug is used to treat or prevent a disease associated with SHP2 modulation.
[167] [167] In another, the present description relates to one or more compositions comprising one or more compounds of the present description (for example, compounds of Formula la, |, Ila, Ilb, III, IV, V, or Vl, and pharmaceutically acceptable salts, prodrugs, hydrates, tautomers or isomers thereof), for use as a medicine. In some embodiments, the drug is used to treat or prevent a disease associated with SHP2 modulation. Pharmaceutical Compositions and Administration Modes of the description
[168] [168] Another aspect of the present description relates to pharmaceutical compositions that comprise one or more compounds of the present description and a pharmaceutically acceptable carrier. Pharmaceutically acceptable vehicles can also include excipients such as diluent, surfactant, lipid, solvent. In certain modalities, there are one or more pharmaceutically acceptable vehicles or excipients.
[169] [169] Compositions can be prepared according to conventional methods of preparing the dosage forms that are applicable for different routes of administration, respectively. The present pharmaceutical compositions can contain from about 0.1% to about 99%, from about 5% to about 90%, or from about 1% to about 20% of the compound described by weight or volume.
[170] [170] Administration of the described compounds and pharmaceutical compositions can be carried out by any means of administration for therapeutic agents. These modes include systemic or local administration such as oral, nasal, parenteral, intravenous, transdermal, subcutaneous, vaginal, buccal, rectal or topical administration modes.
[171] [171] Depending on the intended mode of administration, the pharmaceutical compounds or compositions described may be in solid, semi-solid or liquid dosage form, such as, for example, injectables, capsules, tablets, pellets, suppositories, pills, forms of modified-release dosage, elixirs, tinctures, emulsions, syrups, powders, liquids, suspensions, plasters, or the like, sometimes in unit doses and consistent with conventional pharmaceutical practices. Likewise, they can also be administered in intravenous (bolus and infusion), intraperitoneal, subcutaneous or intramuscular, transdermal forms, and all using forms well known to those wearing the pharmaceutical techniques.
[172] [172] Illustrative pharmaceutical compositions are liquid and solid dosage forms, such as tablets and capsules, comprising one or more compounds of the present description and a pharmaceutically acceptable carrier, such as, but not limited to: a) a diluent, for example example, purified water, triglyceride oils, such as hydrogenated or partially hydrogenated vegetable oil, or mixtures thereof, corn oil, olive oil, sunflower oil, safflower oil, fish oils, such as EPA or DHA, or their esters or triglycerides or mixtures thereof, omega-3 fatty acids or derivatives thereof, lactose, dextrose, sucrose, mannitol, sorbite |, cellulose, sodium, saccharin, glucose and / or glycine; b) a lubricant, for example, silica, talc, stearic acid, its magnesium or calcium salt, sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and / or polyethylene glycol; for pills too; c) a binder, for example, magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, magnesium carbonate, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth or sodium alginate, waxes and / or polyvinylpyrrolidone, if desired; d) a disintegrant, for example, starches, agar, methyl cellulose, bentonite, xanthan gum, alginic acid or its sodium salt or effervescent mixtures; e) absorbent, color, flavor and sweetener; f) an emulsifier or dispersing agent, such as Tween 80, Labrasol, HPMC, DOSS, caproil 909, labrafac, labrafil, peceol, transcutol, MCM cap, PG-12 cap, cap 35, gelucir, vitamin and TGPS or another acceptable emulsifier; and / or g) an agent that enhances the absorption of the compound such as cyclodextrin, hydroxypropyl-cyclodextrin, PEG400, PEG200. In certain modalities, pharmaceutical compositions comprise HPMC. In certain embodiments, the pharmaceutical compositions comprise vegetarian type capsules (Vegi).
[173] [173] Liquid compositions, particularly injectable, can, for example, be prepared by dissolving, dispersing, lyophilizing. etc. For example, one or more compounds are dissolved or mixed with a pharmaceutically acceptable solvent, such as, for example, water, saline, aqueous dextrose, buffer, glycerol, ethanol, cyclodextrin, cremophor EL and the like, to form an injectable isotonic solution or suspension or lyophilized cake for reconstitution. Proteins such as albumin, chylomicron particles or serum proteins can be used to solubilize the described compounds.
[174] [174] One or more described compounds or compositions can also be formulated as a suppository that can be prepared from emulsions or fatty suspensions; using polyalkylene glycols such as propylene glycol, as the vehicle.
[175] [175] One or more of the compounds or compositions described can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles. Liposomes can be formed from a variety of phosphospholipids, containing cholesterol, stearylamine or phosphatidylcholines. In some embodiments, a film of lipid components is hydrated with an aqueous drug solution to form a lipid layer that encapsulates the drug, as described, for example, in U.S. Patent No.
[176] [176] One or more described compounds or compositions can also be released by using monoclonal antibodies as individual vehicles to which the described compounds are coupled. The described compounds can also be coupled with soluble polymers as targetable drug carriers. Such polymers can include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamide-phenol, polyhydroxyethylspanamide phenol or polyethylene oxide polylysine substituted with palmitoyl residues. In addition, one or more of the described compounds can be coupled to a class of biodegradable polymers useful in obtaining controlled release of a drug, for example, polylactic acid, polypsilon caprolactone, polyhydroxy butyric acid, polyoreaesters, polyeace - such, polyhydropyranes, polycyanoacrylates and copolymers of cross-linked amphipathic block hydrogels. In some embodiments, one or more of the compounds described are not covalently attached to a polymer, for example, a polycarboxylic acid polymer or a polyacrylate.
[177] [177] One or more described compounds or compositions can be released by parental administration. Injectable pa- rent administration is generally used for subcutaneous, intramuscular or intravenous injections and infusions. Injectables can be prepared in conventional forms, or as liquid solutions or suspensions or solid forms suitable for dissolving or dispersing in the liquid prior to injection. Description Dosage Regimes
[178] [178] The dosage regimen using the described compound is selected according to a variety of factors, including the patient's type, species, age, weight, sex and medical condition; the severity of the condition to be treated; the route of administration; the patient's renal or liver function; and the particular described compound employed. A doctor or veterinarian skilled in the art can easily determine and prescribe the effective amount of medication needed to prevent, combat or halt the progress of the disease.
[179] [179] The effective dosage amounts of the compounds described, when used for the indicated effects, range from about 0.5 mg to about 5000 mg of the described compound, as needed to treat the condition. Compositions for in vivo or in vitro use may contain about 0.5, 5, 20, 50, 75, 100, 150, 250, 500, 750, 1000, 1250, 2500, 3500 or 5000 mg of the compound described , or, in a range from one quantity to another quantity in the dose list. In some embodiments, the compositions are in the form of a tablet that can be marked.
[180] [180] If desired, the effective daily dose of one or more compounds or compositions of this description can be administered as one, two, three, four, five, six or more sub-doses administered separately.
[181] [181] In some embodiments, one or more compounds or compositions described herein can be used alone or together or administered together, or used in combination with another type of therapeutic agent. Joint administration or used in combination refers to any form of administration of two or more different compounds or therapeutic compositions, so that the second compound or composition is administered while the previously administered therapeutic compound or composition is still effective. on body. For example, the different compounds or therapeutic compositions can be administered in the same formulation or in a separate formulation, simultaneously, sequentially, or by separate dosage of the individual components of the treatment. In some embodiments, the different compounds or therapeutic compositions can be administered over a period of one hour, 12 hours, 24 hours, 36 hours, 48 hours, 72 hours or one week each. In this way, an individual who receives such a treatment can benefit from a combined effect of different therapeutic compounds or compositions. Kits
[182] [182] In some embodiments, this description also provides a kit or pharmaceutical package comprising one or more containers filled with at least one compound or composition of this description. Optionally, associated with such container (s) may be a notice in the form prescribed by a government agency that regulates
[183] [183] In some embodiments, the Kit includes additional materials to facilitate the release of individual compounds and compositions. For example, the Kkit may include one or more catheters, tubes, infusion bags, syringes and the like. In some embodiments, the compounds and compositions are packaged in a lyophilized form, and the Kit includes at least two containers: a container comprising the compounds or compositions and a container comprising an adequate amount of water, buffer or other suitable liquid to replenish the lyophilized material.
[184] [184] The foregoing apply to any of the compounds, compositions, methods and uses described here. This description specifically contemplates any combination of the characteristics of such compounds, compositions, methods and uses (alone or in combination) with the characteristics described for the various kits described in this section. Exemplary Modalities
[185] [185] Some modalities of this description are Modality |, as follows:
[186] [186] Mode | -1. A compound of Formula |: 1 1 ATA 2 The RR)
[187] [187] Mode | -2. A compound of Formula | 1: 1 o) Nx
[188] [188] Mode | -3. A compound of Formula Ill:
[189] [189] Mode | -4. The compound of any of Modalities | -1 to 1-3, where X 'is N.
[190] [190] Mode | -5. The compound of any of Modalities | -1 to | -3, where X 'is CH.
[191] [191] Mode | -6. The compound of any of Modalities | -1 to | -5, where XP is N.
[192] [192] Mode | -7. The compound of any of the | -1 to | -5 modalities, where X is CH.
[193] [193] Mode | -8. The compound of any of Modalities | -1 to | -7, where X is N.
[194] [194] Mode | -9. The compound of any of the | -1 to | -7 modalities, where X is CH.
[195] [195] Mode | -10. The compound of any of Modalities | -1 to | -9, where A is monocyclic or polycyclic aryl.
[196] [196] Mode | -11. The compound of any of Modalities | -1 to | -9, where A is monocyclic or polycyclic cycloalkyl.
[197] [197] Mode 1 | -12. The compound of any of Modalities | -1 to | -9, where A is monocyclic or polycyclic heterocycloalkyl.
[198] [198] Mode | -13. The compound of any of Modalities | -1 to | -9, where A is monocyclic or polycyclic heteroaryl.
[199] [199] Mode | -14. The compound of any of Modalities | -1 to 1-13, where each R 'is selected from the group consisting of -H, halogen, -C1-Cs alkyl, and -NRºRº.
[200] [200] Mode | -15. The modality compound | -14, where Rº and Rº are H.
[201] [201] Mode | -16. The compound of any of Modalities | -1 to | -15, in which Rº is an optionally substituted —C1-Ce alkyl.
[202] [202] Mode | -17. The compound of any of Modalities | -1 to | -16, where Rº is “CH2-OH.
[203] [203] Mode | -18. The compound of any of Modalities | -1 to | -17, in which R $ can be combined with R to form a 3- to 12-membered monocyclic or polycyclic heterocycle, where the heterocycle is optionally substituted with —C1-Cs alkyl, halogen -OH, -ORP, —-NH2, - = - NHRº, heteroaryl, heterocyclyl, - (CH2)) NH> z, - (CH2), OH, -COOR , -CONHRº ”, -CONH (CH2) ,. COORº, -NHCOOR , - CF3, - = CHF2, —-CH2F, or = O .
[204] [204] Modality | -19. The | -18 Modality compound, in which the heterocycle is unsubstituted or substituted with —C1-Cs alkyl, -ORº, or -NH,>.
[205] [205] Mode | -20. The compound of any of Modalities | -1 to | -17, in which Rô can be combined with R to form a 5 to 12-membered spiroheterocycle, where the spiroheterocycle is optionally substituted with —C1-Cs alkyl, halogen -OH, -—OR , —NH2, —NHRº, heteroaryl, heterocyclic, - (CH2 )) NH2, - (CH2)) OH, - COORP, -CONHRº, -CONH (CH2)). COORº, -NHCOOR, -CF3, —-CHF>, —CH2F, or = O.
[206] [206] Mode | -21. The Modality 1-20 compound, in which the spirocycle is unsubstituted or substituted with —C1-Cs alkyl, -OR , or -NH,>.
[207] [207] Mode | 1-22. A compound, or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, tautomer or isomer thereof, selected from the group consisting of
[208] [208] Mode | -23. A pharmaceutical composition comprising a compound of any of Modalities | -1 to 1-22, or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, tautomer or isomer thereof, and a pharmaceutically acceptable carrier.
[209] [209] Mode | -24. A method of treating a disease associated with SHP2 modulation in an individual in need thereof, comprising administering to the individual an effective amount of a compound of any one of Modalities | -1 to | - 22, or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, tautomer or isomer thereof.
[210] [210] Mode | -25. The | -24 Mode method, in which the disease is selected from Noonan Syndrome, Leopard Syndrome, juvenile myelomonocytic leukemias, neuroblastoma, melanoma, acute myeloid leukemia and cancers of the breast, lung and colon.
[211] [211] Mode | -26. A compound of any of Modes 1-1 to 1-22, or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, tautomer or isomer thereof, for use as a medicine.
[212] [212] Mode | -27. A compound of any of the Modalities | -1 to 1-22, or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, tautomer or isomer thereof, for use in the treatment
[213] [213] Mode | -28. Use of a compound of any of Modalities | -1 to | -22, or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, tautomer or isomer thereof, in the manufacture of a drug for the treatment or prevention of an associated disease with SHP2 modulation.
[214] [214] Mode | -29. A method of treating a disease associated with SHP2 modulation in an individual in need of it, comprising administering to the individual an effective amount of a pharmaceutical composition of Modality | - 23.
[215] [215] Mode 1-30. Method 1-29, in which the disease is selected from Noonan Syndrome, Leopard Syndrome, juvenile myelomonocytic leukemias, neuroblastoma, melanoma, acute myeloid leukemia and cancers of the breast, lung and colon.
[216] [216] Mode | -31. A pharmaceutical composition of Modality | -23 for use as a medicine.
[217] [217] Mode | -32. A pharmaceutical composition of Modality | -23 for use in the treatment or prevention of a disease associated with SHP2 modulation.
[218] [218] Mode 1-33. Use of a pharmaceutical composition of Modality 1-23 in the manufacture of a drug for the treatment or prevention of a disease associated with SHP2 modulation.
[219] [219] Some of the modalities of this description are from Modality II, as follows:
[220] [220] Mode I1 | -1. A compound of Formula |: 1 1 ATA 7
[221] [221] Mode 11-2. A compound of Formula 1: 1 1 e) NOx
[222] [222] Mode 11 | -3. A compound of Formula Ilb: 1 1 ATA,
[223] [223] Mode 11 | -4. A compound of Formula III:
[224] [224] Mode 1 | -5. The compound of any of Modalities I | -1 to 1 | -4, where X is N.
[225] [225] Mode 11 | -6. The compound of any of Modes Il-1 to 1I-4, where X 'is CH.
[226] [226] Mode 11 | -7. The compound of any of Modes Il-1 to 11-6, where X P is N.
[227] [227] Mode 11 | -8. The compound of any of Modalities I | -1 to 11-6, where X is CH.
[228] [228] Mode 1 | -9. The compound of any of the Modalities | 1l-1 to 11-8, where X is N.
[229] [229] Mode 11-10. The compound of any of Modes 11-1 to 11-8, where X is CH.
[230] [230] Mode 11-11. The compound of any of Modes 11-1 to 11-10, where A is monocyclic or polycyclic aryl.
[231] [231] Mode 11-12. The compound of any of the Fashion-
[232] [232] Mode 11-13. The compound of any of Modes 11-1 to 11-10, where A is monocyclic or polycyclic heterocycloalkyl.
[233] [233] Mode 11-14. The compound of any of Modes 11-1 to 11-10, where A is monocyclic or polycyclic heteroaryl.
[234] [234] Mode 11-15. The compound of any of Modes 11-1 to 11-14, where each R 'is selected from the group consisting of -H, halogen, -C1-Cs alkyl, and -NRºRº.
[235] [235] Mode 11-16. The compound of claim 14, wherein R and R are H.
[236] [236] Mode 11-17. The compound of any of Modes 11-1 to 11-16, where Rº is an optionally substituted —C1-C6s alkyl.
[237] [237] Mode 11-18. The compound of any of Modes 11-1 to 11-17, where Rº is -CH2-OH.
[238] [238] Mode 11-19. The compound of any of the Modes 11-1 to 11-18, in which R $ can be combined with R to form a 3- to 12-membered monocyclic or polycyclic heterocycle, where the heterocycle is optionally substituted with —C1-Cs alkyl, halogen -OH, -ORP, NH », —NHRº, heteroaryl, heterocyclic, - ( CH2)) NH2, - (CH2) »OH, -COORP, -CONHR , -CONH (CH2)). COOR , - NHCOOR , -CF3, —-CHF2, —-CH2F, or = O.
[239] [239] Mode 11-20. The compound of Modality 11-19, in which the heterocycle is unsubstituted or substituted with —C1-Cs alkyl, -OR ”, or -NH>.
[240] [240] Mode 11-21. The compound of any of the Modes 11-1 to 11-18, in which Rº can be combined with R to form a 5 to 12-membered spiroheterocycle, in which the spiroheterocycle is optionally substituted with —C1-Cs alkyl, halogen
[241] [241] Mode 11-22. The compound of Modality 11-21, in which the spirocycle is unsubstituted or substituted with —C1-Cs alkyl, - OR P, or -NH ,.
[242] [242] Mode 11-23. A compound, or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, tautomer or isomer thereof, selected from the group consisting of No. c fo NH2 Cc f NH Ho U) (9), Ho 8), Ps CO Qu NH 7 Que Ho (3), and Ho (4).
[243] [243] Mode 11-24. A compound, or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, tautomer or isomer thereof, selected from the group consisting of "O. -." DO SO q 7 ”NO No v 7 X and Os (5) and (5a).
[244] [244] Mode 11-25. A pharmaceutical composition comprising a compound of any of Modalities 11-1 to 11-24, or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, tautomer or isomer thereof, and a pharmaceutically acceptable carrier.
[245] [245] Mode 11-26. A method of treating a disease associated with modulation of SHP2 in an individual in need thereof, comprising administering to the individual an effective amount of a compound of any one of Modes 11-1 to 11-24, or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, tautomer or isomer thereof.
[246] [246] Mode 11-27. Method 11-26, in which the disease is selected from Noonan Syndrome, Leopard Syndrome, juvenile myelomonocytic leukemias, neuroblastoma, melanoma, acute myeloid leukemia and cancers of the breast, lung and colon.
[247] [247] Mode 11-28. A compound of any of Modes 11-1 to 11-24, or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, tautomer or isomer thereof, for use as a medicine.
[248] [248] Mode 11-29. A compound of any of Modes 1l | -1 to 11-24, or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, tautomer or isomer thereof, for use in the treatment or prevention of a disease associated with modulation of SHP2.
[249] [249] Mode 11-30. Use of a compound of any of Modalities 11 | -1 to 11-24, or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, tautomer or isomer thereof, in the manufacture of a drug for the treatment or prevention of a disease associated with SHP2 modulation.
[250] [250] Mode 11-31. A method of treating a disease associated with SHP2 modulation in an individual in need of it, comprising administering to the individual an effective amount of a pharmaceutical composition of Modality | l-
[251] [251] Mode 11-32. Method 11-31, in which the disease is selected from Noonan Syndrome, Leopard Syndrome, juvenile myelomonocytic leukemias, neuroblastoma, melanoma, acute myeloid leukemia and cancers of the breast, lung and colon.
[252] [252] Mode 11-33. A pharmaceutical composition of Fashion 11-25 for use as a medicine.
[253] [253] Mode 11-34. A pharmaceutical composition of Modality 11-25 for use in the treatment or prevention of a disease associated with modulation of SHP 2.
[254] [254] Mode 11-35. Use of a pharmaceutical composition of Modality 11-25 in the manufacture of a drug for the treatment or prevention of a disease associated with SHP2 modulation.
[255] [255] Some modalities of this description are of Ill Mode, as follows:
[256] [256] Mode 111-1. A compound of Formula | V: CS NES
[257] [257] Modality | 11-2. A compound of Formula V: AS Ex
[258] [258] Modality | 111-3. A compound of Formula VI: AS NE Se
[259] [259] Modality | 111-4. A compound of Formula |: 1 1 e) Ox
[260] [260] Mode 11I-5. The compound of any of Modes 111-1 to 111-4, where X is N.
[261] [261] Mode 11I-6. The compound of any of Modes IIl-1 to Ill-4, where X 'is CH.
[262] [262] Modality | 11-7. The compound of any of the
[263] [263] Mode 111-8. The compound of any of Modes 111-1 to 111-6, wherein X is CH.
[264] [264] Mode | 1l-9. The compound of any of Modes 111-1 to 111-8, where X º is N.
[265] [265] Mode 11-10. The compound of any of Modes 111-1 to 111-8, where X * is CH.
[266] [266] Mode 11-11. The compound of any of Modes 111-1 to 111 | -10, where A is monocyclic or polycyclic aryl.
[267] [267] Mode 11-12. The compound of any of Modes I11 | -1 to 111-10, where A is monocyclic or polycyclic cycloalkyl.
[268] [268] Mode 111-13. The compound of any of Modes I111-1 to 111 | -10, where A is monocyclic or polycyclic heterocycloalkyl.
[269] [269] Mode 11-14. The compound of any of the Modes I11 | -1 to 111 | -10, where A is monocyclic or polycyclic heteroaryl.
[270] [270] Mode 11-15. The compound of any of Modes 111-1 to 111-14, where each R 'is selected from the group consisting of -H, halogen, -C1-Cs alkyl, and -NRºRº.
[271] [271] Mode 111-16. The compound of Modality 11-14, where Rº and Rô are H.
[272] [272] Mode 11-17. The compound of any of Modes 111-1 to 111-16, where R is an optionally substituted C1-Cs alkyl.
[273] [273] Mode 111-18. The compound of any of Modes 111-1 to 111-17, where R is “CH2-OH.
[274] [274] Mode 11-19. The compound of any of the Modes 111-1 to 111-18, in which Rº can be combined with R to form a 3- to 12-membered monocyclic or polycyclic heterocycle, where the heterocycle is optionally substituted with —C1-Cs alkyl, ha-
[275] [275] Mode 111-20. The compound of Modality 111-19, in which the heterocycle is unsubstituted or substituted with —C1-Cs alkyl, —OR º, or -NH>.
[276] [276] Mode 111-21. The compound of any of the Modes 111-1 to 111-18, in which Rº can be combined with R to form a 5- to 12-membered spiroheterocycle, in which the spiroheterocycle is optionally substituted with —C1-Cs alkyl, halogen —OH, -—ORº, —-NH2, - = NHRº ”, heteroaryl, heterocyclyl , - (CH2)). NH2, - (CH2)) OH, -COORº, -CONHRº, -CONH (CH2) ,. COORº ”, -NHCOOR , - CF3, -CHF2, -CH2F, or = O.
[277] [277] Mode 111-22. The compound of Modality 111-21, where the spirocycle is unsubstituted or substituted with —C1-Cs alkyl, —ORº, or -NH>.
[278] [278] Mode 111-23. The compound of any of Modes 111-1 to 111-18, in which R º is combined R º to form a selected portion of: Yes. NA E * y NH N. * O os, o and o.
[279] [279] Mode 111-24. A compound, or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, tautomer or isomer thereof, selected from the group consisting of De and STE c (ON c SP NH2 Cc f NH a O (9), »O 2 .
[280] [280] Mode 111-25. A compound, or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, tautomer or isomer thereof, selected from the group consisting of E ANA "ç; DO CO o | ES NZ RS, (5) and (5a).
[281] [281] Mode 111-26. A compound, or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, tautomer or isomer thereof, selected from the group consisting of Ds AP, AP, AAA in E NA, 0Nº to NA, TOS TOS pbaom (1) (2) GS)
[282] [282] Mode 111-27. A pharmaceutical composition comprising a compound of any of Modes 111-1 to 11-26, or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, tautomer or isomer thereof, and a pharmaceutically acceptable carrier.
[283] [283] Mode 111-28. A method of treating a disease associated with SHP2 modulation in an individual in need thereof, comprising administering to the individual an effective amount of a compound of any one of Modes I111-1 to 111-26, or a pharmaceutically acceptable salt, prodrug, solvent, hydrate, tautomer or isomer thereof.
[284] [284] Mode 111-29. Method 111-28, in which the disease is selected from Noonan Syndrome, Leopard Syndrome, juvenile myelomonocytic leukemias, neuroblastoma, melanoma, acute myeloid leukemia and cancers of the breast, lung and colon.
[285] [285] Mode 1111-380. A compound of any of Modes II-1 to 111-26, or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, tautomer or isomer thereof, for use as a medicine.
[286] [286] Mode 111-31. A compound of any of Modes 11l-1 to 111-26, or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, tautomer or isomer thereof, for use in the treatment or prevention of a disease associated with modulation of SHP2.
[287] [287] Mode 111-32. Use of a compound of any of Modes 11I-1 to 111-26, or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, tautomer or isomer thereof, in the manufacture of a drug for the treatment or prevention of an associated disease with SHP2 modulation.
[288] [288] Mode 111-33. A method of treating a disease associated with SHP2 modulation in an individual in need of it, comprising administering to the individual an effective amount of a pharmaceutical composition of Modality |
[289] [289] Mode 111-34. Method 11-31, in which the disease is selected from Noonan Syndrome, Leopard Syndrome, juvenile myelomonocytic leukemias, neuroblastoma, melanoma, acute myeloid leukemia and cancers of the breast, lung and colon.
[290] [290] Mode 11-35. A pharmaceutical composition of Fashion 111-27, for use as a medicine.
[291] [291] Mode 111-36. A pharmaceutical composition of Fashion 111-27, for use in the treatment or prevention of a disease associated with SHP modulation 2.
[292] [292] Mode 111-37. Use of a pharmaceutical composition of Modality 111-27 in the manufacture of a drug for the treatment or prevention of a disease associated with modulation of SHP 2.
[293] [293] Some modalities of this description are Modality IV, as follows:
[294] [294] Mode IV-1. A compound of Formula | V: CS Ex
[295] [295] Mode IV-2. A compound of Formula V: NS EX
[296] [296] Mode IV-3. A compound of Formula VI: AS x
[297] [297] Mode IV-4. A compound of Formula |: 1 1 e) Ads
[298] [298] Mode IV-5. The compound of any of Modes IV-1 to IV-4, where X is N.
[299] [299] Mode IV-6. The compound of any of Modes I | V-1 to IV-4, where X 'is CH.
[300] [300] Mode IV-7. The compound of any of Modes IV-1 to IV-6, where X is N.
[301] [301] Mode IV-8. The compound of any of Modes I | V-1 to IV-6, where X is CH.
[302] [302] Mode IV-9. The compound of any of Modes IV-1 to IV-8, where X is N.
[303] [303] Mode IV-10. The compound of any of Modes IV-1 to IV-8, in which X is CH.
[304] [304] Mode IV-11. The compound of any of Modes IV-1 to IV-10, where A is monocyclic or polycyclic aryl.
[305] [305] Mode IV-12. The compound of any of Modes IV-1 to IV-10, where A is monocyclic or polycyclic cycloalkyl.
[306] [306] Mode IV-13. The compound of any of Modes IV-1 to IV-10, where A is monocyclic or polycyclic heterocycloalkyl.
[307] [307] Modality | IV-14. The compound of any of Modes IV-1 to IV-10, where A is monocyclic or polycyclic heteroaryl.
[308] [308] Mode IV-15. The compound of any of Modes IV-1 to IV-14, where each R 'is selected from the group consisting of -H, halogen, -C1-Cs alkyl, and -NRºRº.
[309] [309] Mode IV-16. The IV-15 modality compound, where R $ and R are H.
[310] [310] Mode IV-17. The compound of any of Modes IV-1 to IV-16, where Rº is an optionally substituted alkyl-C1-Cs.
[311] [311] Modality | V-18. The compound of any of Modes IV-1 to IV-17, where Rº is “CH2-OH.
[312] [312] Mode IV-19. The compound of any of Modes IV-1 to IV-17, where Rº is -C1-Cs alkyl substituted with one or more halogen.
[313] [313] Modality | V-20. The compound of any of Modes IV-1 to IV-19, in which R can be combined with R to form a 3- to 12-membered monocyclic or polycyclic heterocycle, where the heterocycle is optionally substituted with —C1-Cs alkyl, halogen -OH, -ORP, NH », —NHRº, heteroaryl, heterocyclic, - ( CH2)) NH2, - (CH2)) OH, -COORº , -CONHRº, -CONH (CH2) .COOR , - NHCOOR , -CF3, - = CHF2, —-CH2F, or = O.
[314] [314] Mode IV-21. The compound of Modality I1V-20, in which the heterocycle is unsubstituted or substituted with —C1-Cs alkyl, —ORº, or -NH>.
[315] [315] Modality | V-22. The compound of any of Modes IV-1 to IV-19, in which R can be combined with R to form a 5- to 12-membered spiroheterocycle, in which the spiroheterocycle is optionally substituted with —C1-Cs alkyl, OH halogen, -ORº, —-NH2, —NHRº, heteroaryl, heterocyclyl, - (CH2 )). NH2, - (CH2)) OH, -COOR !, -CONHRº ”, -CONH (CH2) ,. COORº, -NHCOOR , - CF3, -CHF2, —-CH2F, or = O.
[316] [316] Mode | 1V-23. The Modality compound | V-22, in which the spirocycle is unsubstituted or substituted with —C1-Cs alkyl, —ORº, or -NH>.
[317] [317] Modality | V-24. The compound of any of the Modes IV-1 to IV-19, in which R º is combined with R º to form a selected portion of: Yes. NH> z Is it * and NH N * Or the, and the.
[318] [318] Mode IV-25. A compound, or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, tautomer or isomer thereof, selected from the group consisting of
[319] [319] Modality | V-26. A compound, or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, tautomer or isomer thereof, selected from the group consisting of HN. S. S. H a CA
[320] [320] Mode IV-27. A compound, or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, tautomer or isomer thereof, selected from the group consisting of DA, Pes AP, tests ”& SE in A (1), (2), G), the oH 7 o o (6), (4), (5),
[321] [321] I1V-28 mode. A compound, or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, tautomer or isomer thereof, selected from the group consisting of cos cos (34) and * (35).
[322] [322] Mode | V-29. A pharmaceutical composition comprising a compound of any of Modalities | IV-1 to IV-28, or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, tautomer or isomer thereof, and a pharmaceutically acceptable carrier.
[323] [323] Mode IV-30. A method of treating a disease associated with SHP2 modulation in an individual in need thereof, comprising administering to the individual an effective amount of a compound of any of Modes IV-1 to IV-28, or a pharmaceutically acceptable salt, prodrug, solvent, hydrate, tautomer or isomer thereof.
[324] [324] Mode IV-31. The IV-30 method, in which the disease is selected from Noonan Syndrome, Leopard Syndrome, juvenile myelomonocytic leukemias, neuroblastoma, melanoma, acute myeloid leukemia and cancers of the breast, lung and colon.
[325] [325] Mode IV-32. A compound of any of Modes IV-1 to 1V-28, or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, tautomer or isomer thereof, for use as a medicine.
[326] [326] Mode IV-33. A compound from any of the
[327] [327] Mode IV-34. Use of a compound of any of Modalities IV-1 to 1V-28, or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, tautomer or isomer thereof, in the manufacture of a drug for the treatment or prevention of an associated disease with SHP2 modulation.
[328] [328] Mode IV-35. A method of treating a disease associated with SHP2 modulation in an individual in need of it, comprising administering to the individual an effective amount of a Modality IV- pharmaceutical composition.
[329] [329] Mode IV-36. Method IV-35, in which the disease is selected from Noonan Syndrome, Leopard Syndrome, juvenile myelomonocytic leukemias, neuroblastoma, melanoma, acute myeloid leukemia and cancers of the breast, lung and colon.
[330] [330] Mode IV-37. A pharmaceutical composition of Fashion IV-29, for use as a medicine.
[331] [331] 1V-38 mode. A pharmaceutical composition of Modality IV-29, for use in the treatment or prevention of a disease associated with SHP2 modulation.
[332] [332] Modality | IV-39. Use of a pharmaceutical composition of Modality | V-29, in the manufacture of a medication for the treatment or prevention of a disease associated with the modulation of SHP 2. Examples
[333] [333] The description is also illustrated by the examples and synthesis examples, which should not be interpreted as limiting this description in the scope or spirit of the specific procedures described here. It should be understood that the examples are provided to illustrate certain modalities and that no limitation on the scope of the description is understood in this way. It should also be understood that several other modalities, modifications, and equivalents of the same may be necessary that can be suggested to those skilled in the art without departing from the spirit of the present description and / or the scope of the attached claims.
[334] [334] The definitions used in the following examples and elsewhere here: CH2Cle, DOM - Methylene chloride, Dichloromethane CH3CN, MeCN Acetonitrile Cul copper lodide (1) DIPEA Diisopropylethyl amine DMF N N-dimethylformamide EtOAc Ethyl acetate Hr Hour H2O Water HCl! Hydrochloric acid K3PO, 4 Potassium phosphate (tribasic) MeOH Methanol Na2SO, s Sodium sulfate NMP N-methyl pyrrolidone Pd (dppf) Cl2 [1, 1'-bis (diphenylphosphine) ferrocene] dichloropalladium (! Il) Example 1 - Synthesis of (3 - [[(1R) -1-amino-8-aspasospiro [4,5] decan-8-i1] -6- (2,3-dichloropyridin-4-yl) pyrazin-2-yl) netanol ( Compound 1)
[335] [335] A mixture of 6-bromo-3-chloropyrazine-2-ethylcarboxylate (1 g, 3.97 mmol), boronic acid (2,3-dichloropyridin-4-yl) (0.93 g, 4.76 mmol) ), and potassium carbonate (2.18 g, 15.8 mmol) in 40 mL of acetonitrile was degassed, and Pd (dppf) CI2CH2CI2 (648 mg, 0.79 mmol) was added. The resulting mixture was allowed to stir under an inert atmosphere at 95 ° C for 1 hour. Concentration under reduced pressure, and purification by column chromatography (40% EtOAc / 60% heptane) resulted in 3-chloro-6- (2,3-dichloropyridin-4-yl) pyrazine-2-ethylcarboxylate ( 350 mg, 27% yield). Step-2: Synthesis of 6- (2,3-dichloropyridin-4-i1) -3 - ((R) -1 - ((R) -1,1-dimethylethylsulfinamido) -8-azospiro [4,5] decan -8-yl) pyrazine-2-ethylcarboxylate
[336] [336] To a solution of 3-chloro-6- (2,3-dichloropyridin-4-yl) pyrazine-2-ethylcarboxylate (350 mg, 1.835 mmol) and (R) -2-methyl-N - ((R ) -8- azaespiro [4,5] decan-1-yl) propane-2-sulfinamide (450 mg, 1.4 mmol) in DMA (2.5 mL) under an inert atmosphere DIPEA (233 uL, 1 , 4 mmol). The resulting mixture was allowed to stir at 50 ° C for 30 minutes. Ethyl acetate (20 ml) was added to the reaction mixture, and the resulting suspension was washed with water (20 ml), brine (10 ml), and dried over anhydrous magnesium sulfate. Filtration and concentration under reduced pressure resulted in 6- (2,3-dichloropyridin-4-yl) -3- ((R) -1 - ((R) -1,1-dimethylethylsulfinamido) -8-azospiro [4 , 5] decan-8-
[337] [337] To a solution of 6- (2,3-dichloropyridin-4-i1) -3 - ((R) -1 - ((R) - 1,1-dimethylethylsulfinamido) -8-azospiro [4,5] decan-8-yl) pyrazine-2-ethylcarboxylate (150 mg, 0.28 mmol) in DCM (3 mL) at -78 ° C, 1M solution of DIBAL-H and DCM (1.1 mL) was added dropwise , 1.1 mmol). The resulting mixture was allowed to stir at -78 ° C for 30 minutes, then heated to 0 ° C and left to stir for an additional 5 minutes. The reaction mixture was subsequently stirred to -78 ° C, followed by the addition of a saturated Rochelle salt solution (6 ml). And the resulting suspension was allowed to warm to RT under vigorous stirring for a period of 1 hour, followed by the addition of DCM (20 ml) and water (15 ml). The layers were separated and the aqueous phase was extracted with DCM (20 ml). The combined organic layers were dried over anhydrous magnesium sulfate. Filtration and concentration under reduced pressure resulted in the yellow oil. The resulting sample was dissolved in MeOH (2 ml), and HCI / MeOH (4 M, 0.5 ml) was added. The resulting mixture was stirred at 50 ° C for 1 hour, and concentrated under reduced pressure. Purification by preparative HPLC chromatography, followed by lyophilization resulted in (R) - (3- (1-amino-8-azaospiro [4,5] decan-8-yl) -6- (2,3-dichloropyridin-4- il) pyrazin-2- i) methane! (11 mg, 9.7% yield) as a white solid. * H NMR (500 MHz, methanol-d4) 5 8.62 (s, 1H), 8.56 (s, 1H), 8.40 (d, J = 5.0 Hz, 1H), 7.76 ( d, J = 5.0 Hz, 1H), 4.75 (s, 2H), 3.95 - 3.88 (m, 1H), 3.88 - 3.80 (m, 1H), 3.30 - 3.15 (m, 3H), 2.30 - 2.20 (m, 1H), 1.99 - 1.71 (m, 5H), 1.66 - 1.54 (m, 2H). LC-MS (ESI): m / z [M + H] Ci9H25CI2NsO calculated 408.13, found 408.30. Example 2 - Synthesis of (3 - [(1R) -1-amino-8-azospiro [4,5] decan-8-
[338] [338] (3 - [(1R) -1-amino-8-azospiro [4,5] decan-8-yl] -6- (2,3-dichlorophenyl) pyrazin-2-yl) methanol was synthesized in a manner similar to Example 1, except that (2,3-dichloropyridin-4-yl) boronic acid has been replaced by (2,3-dichlorophenyl) boronic acid. * H NMR (500 MHz, methanol-d4) 5 8.57 (s, 1H), 8.44 (d, J = 0.5 Hz, 1H), 7.64 (dd, J = 8.0, 1 , 6 Hz, 1H), 7.61 (dd, J = 7.8, 1.6 Hz, 1H), 7.44 (t, J = 7.9 Hz, 1H), 4.75 (d, J = 0.5 Hz, 2H), 3.74 (dd, J = 26.9, 13.3 Hz, 2H), 3.22 - 3.11 (m, 3H), 2.27 - 2.14 ( m, 1H), 2.01 - 1.75 (m, 6H), 1.74 - 1.63 (m, 1H), 1.56 (dd, J = 20.9, 13.0 Hz, 2H) . LOC-MS (ESI): m / z [M + H] CroH25CI2N1O calculated 407.13, found 407.31. Example 3 - Synthesis of [3- (4-amino-4-methylpiperidin-1-11) -6- (2,3-dichlorophenyl) pyrazin-2-illmethanol (Compound 3)
[339] [339] [3- (4-amino-4-methylpiperidin-1-yl) -6- (2,3-dichlorophenyl) pyrazin-2-illmethanol can be synthesized in a similar way to Example 1, except that (R ) Tert-Butyl 2-methyl-N - ((R) -8-azospiro [4,5] decan-1-yl) propane-2-sulfinamide was replaced by tert-butyl N- (4-methylpiperidin-4-yl) carbamate . * H NMR (500 MHz, methanol-d4) 5 8.55 (s, 1 H) 8.45 (s, 1 H) 7.60 (ddd, J = 14.36, 8.00, 1.75 Hz, 2 H) 7.39 - 7.46 (m, 1 H) 4.73 (s, 2 H) 3.72 (dt, J = 14.03, 4.17 Hz, 2 H) 3.32 - 3.39 (m, 2 H) 1.96 - 2.06 (m, 2 H) 1.86 - 1.95 (m, 2 H) 1.50 (s, 3 H). LC-MS (ESI): m / z [M + H] C17H21CI2N4O calculated 367.1, found 366.9.
[340] [340] A mixture of 6-bromo-3-chloropyrazine-2-methylcarboxylate (2 g, 7.95 mmol), tert-butyl N- (4-methylpiperidin-4-yl) carbamate (1.87 9, 8 , 74 mmol), N, N-diisopropylethylamine (6.57 mL, 39.7 mmol), and 40 mL of acetonitrile were allowed to stir in a sealed tube at 35 ° C for 2 hours, followed by concentration under reduced pressure. The residue was extracted with EtOAc / water, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting product was subjected to the next step without further purification. * H NMR (500 MHz, methanol-d4) d 8.27 (s, 1H), 3.95 (s, 3H), 3.68 - 3.59 (m, 2H), 3.32 - 3.27 (m, 2H), 2.14 (d, Jy = 13.9 Hz, 2H), 1.59 (ddd, J = 14.1, 10.8, 4.1 Hz, 2H), 1.46 ( s, 12H), 1.35 (s, 3H). LC-MS (ESI): m / z [M + H] Ci7H26BrN4O; calculated 429.12, found 429.3. Step-2: Synthesis of (3- (4-amino-4-methylpiperidin-1-yl) -6-bromopyrazin-2-yl)] methanol
[341] [341] Methyl 6-bromo-3- (4 - ((tert-butoxycarbonyl) amino) -4-methylpiperidin-1-yl) pyrazine-2-carboxylate (3.5 g, 8.15 mmol) was dissolved in DCM (81.5 ml). The resulting yellow solution was cooled to - 78 ° C and DIBAL-H (4.63 g, 32.6 mmol) was added dropwise, and the resulting mixture was allowed to stir for 1 hour at -78 ° C, heated to 0 ° C for 30 minutes. , cooled again to -78ºC, followed by the addition of saturated aqueous Rochelle salt solution (800 mL) at -78ºC. To the resulting suspension, 400 ml of DCM was added and the reaction was allowed to warm to RT while stirring vigorously. The resulting suspension was allowed to stir for 18 hours in RT, and the aqueous phase was extracted with DCM (2 x 400 ml). The combined organic extracts were dried over magnesium sulfate and concentrated under reduced pressure. The residue was dissolved in 20 ml of MeOH, and 2.0 ml of 4N HCI / 4N dioxane was added. The resulting mixture was allowed to stir at 50 ° C for 18 hours. Purification by preparative HPLC chromatography, followed by lyophilization resulted in (3- (4-amino-4-methylpiperidin-1-yl) -6-bromopyrazin-2-yl) methanol. * H NMR (500 MHz, methanol-d4) 5 8.55 (s, 1H), 8.29 - 8.25 (m, 1H), 4.64 (d, J = 0.5 Hz, 2H), 3.62 (dt, J = 14.0, 4.1 Hz, 2H), 3.27 (ddd, J = 13.5, 10.1, 3.2 Hz, 3H), 1.98 (ddd, J = 13.8, 10.0, 4.1 Hz, 2H), 1.93 - 1.85 (m, 2H), 1.49 (s, 3H). LC-MS (ESI): m / z [M + H] C11H17BrN4O calculated 301.06, found 301.2 Step-3: Synthesis of (6 - ((2-amino-3-chloropyridin-4-yl) uncle) -3- (4-amino-4-methylpiperidin-1-yl) pyrazin-2-yl) methane]
[342] [342] A solution of (3- (4-amino-4-methylpiperidin-1-yl) -6-bromopyrazin-2-yl) methanol (50 mg, 0.1660 mmol) 3-chloro-4- (potassiosulfanyl) pyridin-2-amine (49.4 mg, 0.2490 mmol), Pdadbaz (15.2 mg, 0.01660 mmol), and Xantphos (19.2 mg, 0.03320 mmol) in dioxane (1.66 mL ) was degassed, and N, N-diisopropylethylamine (57.8 µL, 0.332 mmol) was added. The resulting mixture was heated to 120 ° C under a microwave condition for 2 hours, allowed to cool to room temperature, filtered over celite, and concentrated under reduced pressure. Purification by preparative HPLC followed by lyophilization resulted in 7.60 mg (6 - ((2-amino-3-chloropyridin-4-yl) thio) -3- (4-amino-4-methylpiperidin-1-yl) pyrazin- 2-yl) methane! (12.0% of production). 1H NMR (400 MHz, methanol-d4) 5 8.43 (s, 2H), 8.32 (s, 1H), 7.62 (dd, J = 5.6, 0.7 Hz, 1H), 6 , 07 (dd, J = 5.6, 0.7 Hz, 1H), 4.68 (s, 2H), 3.83 (dt, J = 14.2, 4.5 Hz, 2H), 3, 37 (ddd, J = 13.7, 10.2, 3.2 Hz, 2H), 1.98 (ddd, J = 14.0, 10.1, 4.1 Hz, 2H), 1.90 ( dt, J = 13.4, 3.9 Hz, 2H), 1.50 (s, 3H).
[343] [343] To a solution of methyl 3-fluoropyridine-2-carboxylate (319 mg, 2.06 mmol) and (3S, 4S) -3-methyl-2-0xa-8-azospiro [4,5] decan- 4- amine (454 mg, 1.87 mmol, 2HCI salt) in DMF (3.8 mL) was added Cs2CO; (1.83 g, 5.61 mmol). The mixture was stirred at 100 ° C for 4 hours. The reaction mixture was quenched by the addition of H2O (3 ml) at 25 ° C and the resulting mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO, anhydrous, filtered and concentrated under reduced pressure to provide 3 - [(3S, 4S) -4-amino-3-methyl-2-0xa-8-azospiro [4, 5] methyl decan-8-illpyridine-2-carboxylate (2 g, raw) as a white oil. LCMS (ESI): m / z [M + H] calculated over Ci6H24N303: 306.2, found 306.3. Step 2.
[344] [344] To a solution of methyl 3 - [(3S / 4S) -4-amino-3-methyl-2-0xa-8-azospiro [4,5] decan-8-yl] pyridine-2-carboxylate ( 2 g, 6.55 mmol) in THF (20 mL) Boc2O (4.3 g, 19.65 mmol, 4.5 mL) was added. The reaction mixture was stirred at 25 ° C for 12 hours. The reaction mixture was extinguished by adding H2O (3 mL) at 25ºC. The reaction mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The remaining residue was purified by column chromatography to provide 3 - [(3S, 4S) -4- (tert-butoxycarbonylamino) -3-methyl-2-0xa-8-azospiro [4,5] decan-8 & -il] methyl pyridine-2-carboxylate (800 mg, 11% yield) as a white solid. * H NMR (400MHz, chloroform-d) 5 ppm 8.27 (d, J = 3.7 Hz, 1H), 7.44 - 7.38 (m, 1H), 7.36 - 7.30 (m , 1H), 5.31 (s, 2H), 4.59 (d, J = 10.8 Hz, 1H), 4.18 (d, J = 4.6 Hz, 1H), 4.02 (d , J = 4.4 Hz, 1H), 3.99 (s, 1H), 3.98 (s, 2H), 3.73 - 3.62 (m, 2H), 3.26 - 2.84 ( m, 5H), 1.99 - 1.77 (m, 3H), 1.71 (d, J = 4.4 Hz, 1H), 1.51 (s, 1H), 1.46 (s, 6H ), 1.24 - 1.18 (m, 3H). LCMS (ESI): m / z: [M + H] calculated over C21H32N30Os: 406.2, found 406.3. Step 3.
[345] [345] To a solution of 3 - [(3S, 4S) -4- (tert-butoxycarbonylamino) - 3-methyl-2-0xa-8-azospiro [4,5] decan-8-yl] pyridine-2- methyl carboxylate (250 mg, 616 umol) in CH3CN (5 ml) NBS (165 mg, 925 umol) was added. The mixture was stirred at 0 ° C for 5 minutes. The reaction mixture was quenched by the addition of H2O (3 mL) at 25ºC. The reaction mixture was extracted with EtOAc and the combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography to provide G6-bromo-3 - [(3S, 4S) -4- (tert-butoxycarbonylamino) -3-methyl-2-0xa-8-azaespiro [4,5] decan -8 & -yl] pyridine-2-carboxylate methyl (200 mg, 67% yield) as a white solid. * H NMR (400MHz, chloroform-d) at ppm 7.47 (d, J = 8.7 Hz, 1H), 7.29 (s, 1H), 4.59 (d, J = 11.0 Hz, 1H), 4.18 - 4.14 (m, 1H), 4.01 (s, 1H), 4.00 - 3.96 (m, 1H), 3.95 (s, 3H), 3.71 - 3.61 (m, 2H), 3.22 - 2.87 (m, 4H), 3.22 - 2.87 (m, 1H), 1.96 - 1.75 (m, 3H), 1 , 72 - 1.63 (m, 1H), 1.50 (s, 1H), 1.46 (s, 9H), 1.20 (d, J = 6.2 Hz, 3H). LCMS (ESI):
[346] [346] To a solution of 6-bromo-3 - [(3S, 4S) -4- (tert-butoxycarbonylamino) -3-methyl-2-0xa-8-azospiro [4,5] decan-8 & -il] methyl pyridine-2-carboxylate (184 mg, 380 umol) in 1,4-dioxane (2 ml) 2-amino-3-chloro-pyridine-4-thiol (73 mg, 456 umol), 1 , 10-phenanthroline (14 mg, 76 umol), Cul (7 mg, 38 umol) and K3PO. (161 mg, 760 umol) at 20 ° C, and the mixture was degassed with N2. The reaction mixture was heated to 140 ° C for 1 hour under N> 2. The reaction mixture was filtered and concentrated under reduced pressure. The resulting residue was purified by preparative HPLC to provide 6 - [(2-amino-3-chloro-4-pyridyl) sulfonyl] -3 - [(3S, 4S) -4- (tert-butoxycarbonylamino) - 3-methyl- 2-0xa-8-azaespiro [4,5] decan-8-yl] pyridine-2-carboxylate methyl (140 mg, 65% yield) as a white solid. LCMS (ESI): m / z: [M + H] calculated during CosH35CINsOsS: 564.2, found 564.3. Step 5.
[347] [347] To a solution of 6 - [(2-amino-3-chloro-4-pyridyl) sulfonyl] -3- [(3S, 4S) -4- (tert-butoxycarbonylamino) -3-methyl-2-0x Methyl azospiro [4,5] decan-8 & -ylJpiridine-2-carboxylate (90 mg, 159 umol) in THF (1 ml) LiBHa (10 mg, 479 umol) was added. The mixture was stirred at 50 ° C for 30 minutes. To the mixture, 0.2 ml of HCl was added and the mixture was stirred at 25 for 30 minutes. The mixture was adjusted to pH = 7 with NaHCO ;, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC to provide [6 - [(2-amino-3-chloro-4-pyridyl) sulfonyl] -3 - [(3S, 4S) -4-amino-3-methyl-2- 0xa-8-azaespiro [4,5] decan-8-yl] -2-pyridyl | methanol (6 mg, 9% yield) as a yellow solid. * H NMR (400MHz, methanol) δ ppm 8.49 (s, 1H), 7.69 - 7.56 (m, 2H), 7.53 - 7.47 (m, 1H),
[348] [348] To a solution of 1,3-benzodioxol (500 mg, 4.09 mmols, 1.0 eq) in MeCN (5 ml) was added TMSCI (44.48 mg, 409.43 umol) and NCS (1 , 20 g, 9.01 mmol). The mixture was stirred at 20 ° C for 2 hours and then quenched by the addition of aqueous Na2S2O; 3 (10 ml). After extraction with EtOAc, the combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude residue was purified by column chromatography to provide 5,6-dichloro-1,3-benzodioxol (620 mg, 3.25 mmol, 79% yield) as a white solid. * H NMR (400 MHz, methanol-da) at ppm 6.98 (s, 2 H) 6.02 (s, 2H). Step 2
[349] [349] n-BuLi (2.5 M, 500 µL) was added dropwise to a mixture of 5,6-dichloro-1,3-benzodioxol (200 mg, 1.1 mmol) in THF (5 mL) at -78ºC. After 30 minutes, B (OMe) 3 (163 mg, 1.6 mmol) was added at -78ºC. The reaction was allowed to warm to 20 ° C for more than 2 hours and 1N HCI was added. After extraction with EtOAc, the combined organic layers were washed with brine, dried
[350] [350] To a solution of [3 - [(3S, 4S) -4-amino-3-methyl-2-0xa-8-azaespiro [4,5] decan-8-yl] -6-bromo-pyrazin- 2-illmethanol (for synthesis, see Example 1, 100 mg, 280 umol) in DME (2 ml) and H2O (0.4 ml) acid (5,6-dichloro-1,3-benzodioxol-4-) was added il) boronic (79 mg, 336 umol), Na2CO; 3 (59 mg, 560 pumol) and Pd (PPh3) a (32 mg, 28 pmol, 0.1 equivalent). The mixture was heated to 110 ° C for 24 hours under N> 2. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure to provide a crude residue, which was purified by preparative HPLC to provide (3 - [(3S, 4S) -4-amino-3-methyl-2-0x- 8-aspasospiro [4,5] decan-8-yl] -6- (5,6-dichloro-2H-1,3-benzodioxol-4-yl) pyrazin-2-ylmethanol (6.5 mg, 13.3 umol, 5% production) as a white solid LCMS (ESI): m / z: [M + H] calculated during Ca1H24ClaN4O4: 467.1, found 467.2; * H NMR (400 MHz, DMSO- ds) 5 ppm 8.23 (s, 1 H) 7.28 (d, J = 1.71 Hz, 1 H) 6.11 (s, 2H) 4.94 (br s, 1 H) 4.60 (br s, 2 H) 3.73 (br d, J = 8.31 Hz, 1 H) 3.63 (br d, J = 13.20 Hz, 3 H) 3.56 (br d, J = 9.17 Hz, 1 H) 3.11 - 3.30 (m, 3 H) 1.89 (br d, J = 8.44 Hz, 1 H) 1.75 - 1.84 (m, 1 H ) 1.81 (br d, J = 14.18 Hz, 2H) 1.56 - 1.69 (m, 3 H) 1.14 (br d, J = 6.48 Hz, 3 H). Synthesis of (3 - [(3S, 4S) -4-amino-3-methyl-2-0xa-8-azospiro [4,5] decan-8-yl] -6- (2,3-dichloro-6 -methoxyphenyl) pyrazin-2-illmethanol. (Compound 7)
[351] [351] To a solution of 3,4-dichlorophenol (4 g, 24.5 mmol) in DMF (40 mL) was added NBS (4.4 g, 24.5 mmol) at 0 ° C. After stirring for 30 min at 0 ° C the solvent was removed under reduced pressure and the crude residue was purified by column chromatography to provide 2-bromo-3,4-dichloro-phenol (0.95 g, 4.0 mmols, 16% yield) as a white solid. * H NMR (400 MHz, DMSO-d6) 5 ppm 11.00 (s, 1 H) 7.46 (d, J = 9.04 Hz, 1 H) 6.95 (d, J = 8.82 Hz , 1 H). Step 2
[352] [352] To a solution of 2-bromo-3,4-dichloro-phenol (0.35 g, 1.5 mmol) in DMF (2 mL) was added K2CO3 (540 mg, 3.9 mmol) and CH3l ( 0.4 ml, 6.5 mmol) at 20 ° C. After 3 hours, the reaction was diluted with water and extracted with ethyl acetate. The combined organic layers were dried over magnesium sulfate. The solvent was removed under reduced pressure and the crude residue was purified by column chromatography to provide 3-bromo-1,2-dichloro-4-methoxy-benzene (0.3 g, 1.2 mmol, 81% yield) like a white solid. * H NMR (400 MHz, methanol-d4) at ppm 7.49 (d, J = 9.04 Hz, 1 H) 7.00 (d, J = 9.04 Hz, 1 H) 3.90 (s , 3 H). Step 3
[353] [353] To a solution of 3-bromo-1,2-dichloro-4-methoxy-benzene (0.25 g, 0.98 mmol) in dioxane (6 mL) was added 4,4,5,5-tetramethyl -2- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1,3,2-dioxaborolane (372 mg, 1.5 mmol), KOAc (192 mg, 1.9 mmol) and Pd (dppf) Cl2-CH2Cl2 (80 mg, 97.7 umol). The reaction mixture was stirred at 85 ° C for 5 hours under N2. Upon cooling to room temperature, the reaction was diluted with water and extracted with ethyl acetate. The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by column chromatography to provide 2- (2,3-dichloro-6-methoxy-phenyl) -4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.19 g 0.63 mmols, 64% yield) as a yellow solid. * H NMR (400 MHz, methanol-d4) 5 ppm 7.44 (d, J = 8.93 Hz, 1 H) 6.89 (d, J = 8.80 Hz, 1 H) 3.78 (s , 3 H) 1.37 (s, 12H). Step 4
[354] [354] To a solution of [3 - [(3S, 4S) 4-amino-3-methyl-2-0xa-8-azaespiro [4,5] decan-8-yl] -6-bromo-pyrazin-2 -illmethanol (for synthesis, see Example 1, 79 mg, 220 umol) in DME (2 ml) 2- (2,3-dichloro-6-methoxy-phenyl) -4,4,5,5-tetramethyl -1,3,2-dioxaborolane - (0.1 g, 330 umol), Na2CO; 3 (47 mg, 440 pmol), H2O (0.4 mL) and Pd (PPh3a) a (25 mg, 22 pmol) . The reaction was stirred at 85 ° C for 5 hours under N. After cooling to room temperature was filtered and the solvent was removed under reduced pressure and the crude residue was purified by preparative HPLC to provide (3 - [(3S, 4S) -4-amino-3-methyl-2-0x -8- azaespiro [4,5] decan-8-yl] -6- (2,3-dichloro-6-methoxyphenyl) pyrazin-2-unlimited (2.9 mg, 6 umol, 3% yield) as a white solid LCMS (ESI): m / z: [M + H] calculated over C21H27CI2N1403: 453.1, found 453.3; * H NMR (400 MHz, methanol-d4) 5 ppm 8.49 ( br s, 1 H) 8.10 - 8.07 (m, 1 H) 7.58 (d, J = 9.04 Hz, 1 H) 7.10 (d, J = 9.04 Hz, 1 H ) 4.71 (s, 2 H) 4.29 (dd, J = 6.51, 4.30 Hz, 1 H) 3.95 (d, J = 9.04 Hz, 1 H) 3.84 ( d, J = 9.04 Hz, 1 H) 3.75 (s, 3 H) 3.71 - 3.65 (m, 1 H) 3.39 (d, J = 4.19 Hz, 1 H) 3.16 - 3.01 (m, 2 H) 2.04 - 1.86 (m, 3 H) 1.74 (d, J = 12.57 Hz, 1 H) 1.30 (d, J = 6.62 Hz, 3 H) Example 8. Synthesis of 2- (5 - [(3S, 4S) -4-amino-3-methyl-2-0xa-8- azaespiro [4,5] decan-8- yl] -6- (hydroxymethyl) pyrazin-2-11) -3,4-
[355] [355] To a solution of methyl 3,6-dibromopyrazine-2-carboxylate (8.4 g, 28.3 mmol) in MeCN (142 mL) was added (3S, 4S) -3 bis-hydrochloride -methyl-2-0xa-8-azospiro [4,5] decan-4-amine (7.59 g, 31.2 mmol), DIEA (24.7 ml, 142 mmol). The reaction mixture was stirred at room temperature for 16 hours. The solvent was removed under reduced pressure and the residue was partitioned between water / NH.OH (10: 1) and EtOAc. The phases were separated and the aqueous phase was extracted with EtOAc. The combined organic phases were dried over anhydrous Na2SO4, filtered and concentrated to provide methyl 3 - [(3S, 4S) -4-amino-3-methyl-2-0xa-8-azospiro [4,5] decan-8-yl ] -6-bromo-pyrazine-2-carboxylate (12 g, raw), which was used without further purification. LCMS (ES): m / z: [M + H] calculated over C15H22BrNa403: 385.1, found 385.1. Step 2
[356] [356] To a solution of 3 - [(3S, 4S) 4-amino-3-methyl-2-0xa-8-azaespiro [4,5] decan-8-yl] -6-bromo-5-methyl- pyrazine-2-ethyl carboxylate (12 g, 29.0 mmol) in DCM (240 mL) at —78 ° C was added DIBAL-H (1 M, 116 mL) over 10 minutes. The reaction mixture was stirred at - 78 ° C for 1 hour and then heated to 0 ° C for 1 hour. The reaction was quenched by pouring it into a saturated aqueous Rochelle salt solution. EtOAc was added and the reaction was allowed to warm to
[357] [357] To a solution of 3,4-dichlorophenol (4 g, 24.54 mmol) in DMF (40 mL) was added NBS (4.37 g, 24.54 mmol) at 0 ° C and the reaction was stirred for 0.5 hour. The solvent was evaporated under reduced pressure and the crude residue was purified by column chromatography to provide 2-bromo-3,4-dichloro-phenol (0.95 g, 3.93 mmol, 16% yield) as a white solid. * H NMR (400 MHz, DMSO-ds) at ppm 11.00 (s, 1 H) 7.46 (d, J = 9.04 Hz, 1 H) 6.95 (d, J = 8.82 Hz , 1 H). Step 4
[358] [358] To a solution of 2-bromo-3,4-dichloro-phenol (0.3 g, 1.24 mmol) in dioxane (6 mL) was added [3 - [(3S, 4S) -4-amino -3-methyl-2-oxa-8-azospiro [4,5] decan-8-yl] -6-bromo-pyrazin-2-yl] methanol (443.1 mg, 1.24 mmol), KOAc (243 , 4 mg, 248 mmol), 4,4,5,5-tetramethyl-2- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1,3,2- dioxaborolane (472.4 mg, 1.86 mmol) and Pd (dppf) Cla-CH2Cl2 (101.3 mg, 124.0 umol) at 20 ° C under N>, the mixture was heated to 105 ° C for 2 hours. After cooling to room temperature and filtration the solvent was removed under reduced pressure and the crude residue was purified by preparative HPLC to provide 2- (5 - [(3S, 4S) -4-amino-3-methyl -2-0x-8-
[359] [359] 13 - [(38S, 4S) -4-amino-3-methyl-2-0xa-8-azospiro [4,5] decan-8-yl) -6- (5-chloroquinoxalin-6-yl) pyrazin-2-ilkmethanol was synthesized in a similar way to 2- (5 - [(3S, 4S) -4-amino-3-methyl-2-0xa-8-azospiro [4,5] decan-8-yl] -6- (hydroxymethyl) pyrazin-2-i1) -3,4-dichlorophenol, except that 2-bromo-3,4-dichloro-phenol has been replaced by 6-bromo-5-chloro-quinoxaline. LCMS (ESI): m / z: [M + H] calculated during C2o2H26CIN6O2: 441.2, found 440.9; * H NMR (400 MHz, methanol-d4) δ ppm 9.01 (br d, J = 13.23 Hz, 2 H) 8.71 (s, 1 H) 8.49 (br s, 1 H) 8.25 - 8.20 (m, 1 H) 8.18 - 8.13 (m, 1 H) 4.78 (s, 2 H) 4.34 - 4.26 (m, 1 H) 3.97 (d , J = 9.26 Hz, 1 H) 3.88 - 3.73 (m, 3 H) 3.40 (br d, J = 3.75 Hz, 1H) 3.23 - 3.06 (m, 2 H) 2.05 - 1.95 (m, 2 H) 1.94 - 1.87 (m, 1 H) 1.76 (br d, J = 13.45 Hz, 1 H) 1.31 ( d, J = 6.39 Hz, 3 H). Example 10. Synthesis of (43 - [(38.4S) 4-amino-3-methyl-2-0xa-8-azospiro [4,5] decan-8-yl] -6- (7-chloro-2, 3-dihydro-1-benzofuran-6-yl) pyrazin-2-yl) methanol. (Compound 10) nes Neo Sou PA (PPha) a (10 mol%) QD ne no ss “Me e. K2CO ;, 6: 1 DME / H, O, 120 ºC CS and
[360] [360] To a microwave vial was added (3 - [(3S, 4S) -
[361] [361] (3 - [(3S, 4S) -4-amino-3-methyl-2-0xa-8-azospiro [4,5] decan-8- i1) -6- (1H-indol-7-yl ) pyrazin-2-ilkmethanol was synthesized in a similar way to (3 - [(3S, 4S) -4-amino-3-methyl-2-0xa-8-azospiro [4,5] decan-8-11) - 6- (7-chloro-2,3-dihydro-1-benzofuran-6-yl) pyrazin-2-yl) methanol, except that (7-chloro-2,3-dihydro-1-benzofuran) -6-yl) boronic acid has been replaced by (1H-indol-7-yl) boronic acid. LCMS (ESI): m / z: [M + H] calculated during C22H27N5O> 2: 394.2, found 394.5; * "H NMR (500 MHz,
[362] [362] (3 - [(38S, 4S) -4-amino-3-methyl-2-0xa-8-azospiro [4,5] decan-8- iI] -6- (quinoxalin-6-yl) pyrazin -2-yl) methane! was synthesized in a similar way to (3 - [(3S, 4S) -4-amino-3-methyl-2-0xa-8-azospiro [4,5] decan-8- i1]) - 6- (7- chlorine-2,3-dihydro-1-benzofuran-6-yl) pyrazin-2-ylmethanol, except that (7-chloro-2,3-dihydro-1-benzofuran-6-yl) boronic acid was replaced by 6-quinoxalinyl-boronic acid. LCMS (ESI): m / z: [M + H] calculated during Co2H26N6O> 2: 407.2, found 407.5. * H NMR (500 MHz, methanol-da) 5 8.90 (dd, J = 18.4, 1.9 Hz, 2H), 8.82 (s, 1H), 8.71 (d, J = 1 , 9 Hz, 1H), 8.59 (dd, J = 8.9, 2.0 Hz, 1H), 8.16 (d, J = 8.9 Hz, 1H), 4.79 (s, 2H ), 3.99 (d, J = 9.1 Hz, 1H), 3.88 (d, J = 9.1 Hz, 1H), 3.50 (d, J = 4.1 Hz, 1H), 3.37 (s, 1H), 2.68 (s, 3H), 1.35 (d, J = 6.5 Hz, 3H). Example 13. Synthesis of (4 (3 - [(3S, 4S) -4-amino-3-methyl-2-0xa-8-azaospiro [4,5] decan-8-yl] -6- (4-chlorine -2H-indazol-6-yl) pyrazin-2-ylmethanol. (Compound 13)
[363] [363] (3 - [(38S, 4S) -4-amino-3-methyl-2-0xa-8-azospiro [4,5] decan-8- i1] -6- (4-chloro-2H-indazole -6-yl) pyrazin-2-yl) methanol was synthesized in a similar way to (3 - [(3S, 4S) -4-amino-3-methyl-2-0xa-8- azaespiro [4,5] decan -8-yl] -6- (7-chloro-2,3-dihydro-1-benzofuran-6- iNpyrazin-2-ylmethanol, except that (7-chloro-2,3-dihydro-1 acid - benzofuran-6-yl) boronic acid was replaced by acid (4-chloro-1H-indazole-
[364] [364] (3 - [(38S, 4S) -4-amino-3-methyl-2-0xa-8-aspasospiro [4,5] decan-8- i1] -6- (5-chloro-2H-indazole -6-yl) pyrazin-2-yl) methanol was synthesized in a similar way to (3 - [(3S, 4S) -4-amino-3-methyl-2-0xa-8- azaespiro [4,5] decan -8-yl] -6- (7-chloro-2,3-dihydro-1-benzofuran-6-yl) pyrazin-2-ylmethanol, except that (7-chloro-2,3-dihydro -1- benzofuran-6-yl) boronic acid was “replaced by S5-chloro-6- (4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl) -1H-indazole. LCMS ( ESI): m / z: [M + H] calculated during C21H26CINsO2: 429.2, found 429.0; * H NMR (400 MHz, DMSO-d6) 5 ppm 8.44 (s, 1 H) 8.23 (br s, 1 H) 8.13 (s, 1 H) 8.01 (s, 1 H) 7.79 (s, 1 H) 4.59 (s, 2 H) 4.08 - 4.16 (m, 1 H) 3.75 (br d, J = 8.38 Hz, 1 H) 3.54 - 3.67 (m, 3 H) 3.03 - 3.19 (m, 3 H) 1 , 76 - 1.93 (m, 2 H) 1.55 - 1.70 (m, 2 H) 1.14 (d, J = 6.39 Hz, 3 H) Example 15. Synthesis of (4 ( 3 - [(3S, 4S) -4-amino-3-methyl-2-o0xa-8- azospiro [4,5] decan-8-yl] -6- (1-methyl-1H-indol-2-yl ) pyrazin-2-illmethanol. (Compound 15)
[365] [365] 13 - [(38S 4S) -4-amino-3-methyl-2-0xa-8-azospiro [4,5] decan-8- i1) -6- (1-methyl-1H-indole-2 -yl) pyrazin-2-yl) methanol was synthesized in a similar way to (3 - [(3S, 4S) -4-amino-3-methyl-2-0xa-8- azaespiro [4,5] decan-8 -yl] -6- (7-chloro-2,3-dihydro-1-benzofuran-6-yl) pyrazin-2-yl) methanol, except that (7-chloro-2,3-dihydro acid -1-
[366] [366] (3 - [(3S, 4S) -4-amino-3-methyl-2-0xa-8-aspasospiro [4,5] decan-8- i1] -6- (8-chloro-3,4 -di-hydro-2H-1-benzopyran-7-yl) pyrazin-2-ylkmethanol - was synthesized in a similar way to (3 - [(3S, 4S) -4-amino-3-methyl-2-oxa- 8-azospiro [4,5] decan-8-yl] -6- (7-chloro-2,3-dihydro-1-benzofuran-6-iN) pyrazin-2-ylmethanol, except that acid (7- chlorine-2,3-dihydro-1-benzofuran-6-yl) boronic was replaced by (8-chloro-3,4-dihydro-2H-1-benzopyran-7-yl) boronic acid. ESI): m / z: [M + H] calculated for Ca1H26CIN; OS: 445.2, found 445.4; * H NMR (500 MHz, meta-ds) 5 8.36 (s, 1H ), 7.12— 7.01 (m, 2H), 4.69 (s, 2H), 4.29 - 4.26 (m, 3H), 3.93 (d, J = 9.2 Hz, 1H), 3.82 (d, J = 9.2 Hz, 1H), 3.72 - 3.59 (m, 1H), 3.41 (d, J = 4.1 Hz, 1H), 3, 03 (dddd, J = 31.9, 13.5, 11.1, 2.8 Hz, 2H), 2.85 (t, J = 6.5 Hz, 2H), 2.63 (s, 2H) , 2.05 - 1.91 (m, 3H), 1.87 (d, J = 13.4 Hz, 1H), 1.75— 1.67 (m, 1H), 1.28 (d, J = 6.5 Hz, 3H) Example 17. Synthesis of (3 - [(3S, 4S) -4-amino-3-methyl-2-0xa-8-azaespiro [4,5] decan-8-yl] - 6- (2-chloro-6-fluoro-3-methoxyphenyl) pyrazin-2-ylmethanol. (Compound 17)
[367] [367] (3 - [(3S, 4S) -4-amino-3-methyl-2-0xa-8-aspasospiro [4,5] decan-8-
[368] [368] (3 - [(3S, 4S) -4-amino-3-methyl-2-0xa-8-aspasospiro [4,5] decan-8-11) -6- (2,3,6-trichlorophenyl ) pyrazin-2-ylYmethanol was synthesized in a similar way to (3 - [(3S, 4S) -4-amino-3-methyl-2-0xa-8- azaespiro [4,5] decan-8-yl ] -6- (7-chloro-2,3-dihydro-1-benzofuran-6-yl) pyrazin-2-ylmethanol, except that (7-chloro-2,3-dihydro-1-benzofuran acid -6-il) boronic acid - was - * replaced - with boronic acid (2,3,6-trichlorophenyl) LOCMS (ESI): m / z: [M + H] calculated for CroH23CIaN4O2: 457.1, found 457, 2; * H NMR (500 MHz, methanol-d4) 5 8.69 - 8.50 (m, 1H), 8.50 (s, 1H), 7.72 (d, J = 2.5 Hz, 1H ), 7.70 (d, Jy = 2.5 Hz, 1H), 4.75 (s, 2H), 4.33 (qd, J = 6.5, 4.2 Hz, 1H), 3.99 (dd, J = 9.1, 0.8 Hz, 1H), 3.88 (dd, J = 9.2, 0.8 Hz, 1H), 3.82 (dtd, J = 13.4, 4 , 1, 1.6 Hz, 1H), 3.78 - 3.73 (m, 1H), 3.47 (d, J = 4.2 Hz, 1H), 3.16 (ddd, J = 13, 8, 11.1, 2.9 Hz, 1H), 3.09 (ddd, J = 13.6, 11.2, 2.7 Hz, 1H), 2.01 (ddd, J = 13.6, 8.4, 3.5 Hz, 2H), 1.95 - 1.89 (m, 1H), 1.82 - 1.71 (m, 1H), 1.35 (d, J = 6.5 Hz , 3H).
[369] [369] (3 - [(3S, 4S) -4-amino-3-methyl-2-0xa-8-azospiro [4,5] decan-8- i1] -6- (2H-indazol-5-yl ) pyrazin-2-ylYmethanol was synthesized in a similar way to (3 - [(3S, 4S) -4-amino-3-methyl-2-0xa-8-azospiro [4,5] decan-8- i1) - 6- (7-chloro-2,3-dihydro-1-benzofuran-6-yl) pyrazin-2-ylmethanol, except that (7-chloro-2,3-dihydro-1-benzofuran-6 acid -il) boronic acid was replaced by (1H-indazol-6-yl) boronic acid LCMS (ESI): m / z: [M + H] calculated for Ca1H26N6O> z: 395.2, found 395, 4; 'H NMR (500 MHz, methanol-da) 5 8.67 (s, 1H), 8.47 (dd, J = 1.7, 0.8 Hz, 1H), 8.18 - 8.12 (m, 2H), 7.65 (d, J = 8.8 Hz, 1H), 4.77 (s, 2H), 3.96 (d, J = 9.1 Hz, 1H), 3.85 (d, J = 9.1 Hz, 1H), 3.48 (d, J = 4.1 Hz, 1H), 3.37 (s, 3H), 2.68 (s, OH), 2.00 (s, 1H), 1.34 (d, J = 6.5 Hz, 3H) Example 20. Synthesis of (3 - [(3S, 4S) -4-amino-3-methyl-2-0x-8 - azospiro [4,5] decan-8-i1] -6- (2H-indazol-5-yl) pyrazin-2-yl) Ymethanol (Compound 20)
[370] [370] (3 - [(3S, 4S) -4-amino-3-methyl-2-0xa-8-aspasospiro [4,5] decan- 8-i1] -6- (2H-indazol-5-yl ) pyrazin-2-yl) methanol was synthesized in a similar way to (3 - [(38S, 4S) -4-amino-3-methyl-2-0xa-8- azaespiro [4,5] decan-8 -yl] -6- (7-chloro-2,3-dihydro-1-benzofuran-6-yl) pyrazin-2-yl) methanol, except that (7-chloro-2,3-dihydro acid -1- benzofuran-6-yl) boronic was replaced by 1H-indazol-6-yl boronic acid. LCMS (ESI): m / z: [M + H] calculated over C21H27N6O> 2: 395.2, found 395.4; * H NMR (400 MHz, DMSO-ds) 5 ppm 13.20 (s, 1 H) 8.78 (s, 1 H) 8.21 (s, 1 H) 8.10 (s, 1 H) 7 , 84 (s, 2 H) 5.39 (s, 1 H) 4.61 (s, 2 H) 4.12 - 4.06 (m, 1 H) 3.69 (d, J = 8.38 Hz, 1 H) 3.52 (d, J = 8.60 Hz, 2 H) 3.20 - 3.02 (m, 3 H) 2.96 (d, J = 5.29 Hz, 1 H) 1.76 - 1.74 (m, 2 H) 1.68 - 1.52 (m, 2 H) 1.10 (d, J = 6.62 Hz, 3 H). Example 21. Synthesis of (43 - [(3S8,4S) -4-amino-3-methyl-2-0xa-8-
[371] [371] (3 - [(3S, 4S) -4-amino-3-methyl-2-0xa-8-aspasospiro [4,5] decan-8- i1) -6- (2,3-dichlorophenyl) pyrazin -2-ilkmethanol was synthesized in a similar way to (3 - [(3S, 4S) -4-amino-3-methyl-2-0xa-8-azospiro [4,5] decan-8-yl] -6- (7-chloro-2,3-dihydro-1-benzofuran-6-yl) pyrazin-2-ylYmethanol, except that (7-chloro-2,3-dihydro-1-benzofuran-6-yl) ) boronic acid was replaced by 2,3-dichlorobenzoic acid LCMS (ESI): m / z: [M + H] calculated during CooH24ClaN4O>: 423.1, found 423.4; * 'H NMR (500 MHz, methanol-d4) 5 8.55 (s, 1H), 8.44 (d, J = 0.6 Hz, 1H), 7.66 - 7.57 (m, 2H), 7.43 (t, J = 7.9 Hz, 1H), 4.75 (d, J = 0.5 Hz, 2H), 4.31 (qd, J = 6.5, 4.3 Hz, 1H), 3.97 (dd , J = 9.0, 0.8 Hz, 1H), 3.85 (dd, J = 9.0, 0.8 Hz, 1H), 3.73 (ddtd, J = 26.7, 13.4 , 4.2, 1.6 Hz, 2H), 3.40 - 3.35 (m, 1H), 3.16 (ddd, J = 13.6, 10.9, 2.9 Hz, 1H), 3.09 (ddd, J = 13.5, 11.0, 2.8 Hz, 2H), 2.68 (s, 0H), 2.05 - 1.95 (m, 3H), 1.93 - 1.86 (m, 2H), 1.80 - 1.73 (m, 1H), 1.32 (d, J = 6.5 Hz, 3H) Example 22. Synthesis of 3 - ((5- [ (3S, 4 S) -4-amino-3-methyl-2-0xa-8- azaespiro [4,5] decan-8-yl] -6- (hydroxymethyl) pyrazin-2-yl) sulfonyl) -2-chlorobenzonitrile. (Compound 22) in the TZ "Step 1
[372] [372] To a mixture of 3-bromo-2-chloro-benzonitrile (0.5 g, 2.3 mmol) and 2-ethylhexyl 3-sulfonylpropanoate (656 mg, 3.0 mmol) in dioxane (4 mL) Xantphos (27 mg, 46 umol), DIEA (0.8 ml, 4.6 mmol) and Pd2 (dba); s (11 mg, 12 umol) were added. The mixture was stirred at
[373] [373] To a mixture of 2-ethylhexyl 3- (2-chloro-3-cyano-phenyl) sulfonylpropanoate (720 mg, 2.0 mmol) in THF (4 mL) was added t-BUOK (1 M in THF , 3.1 mmol, 3.1 mL) at -78 ° C under N>. The mixture was stirred at -78 ° C for 1 hour and then concentrated under reduced pressure. The crude residue was purified by column chromatography to provide 2-chloro-3-mercaptobenzonitrile (260 mg, 63% yield) as a brown solid. * H NMR (400MHz, methanol-da) 5 = 7.75 (dd, J = 1.1, 7.9 Hz, 1H), 7.56 (dd, J = 1.1, 7.7 Hz, 1H ), 7.32 (t, J = 7.9 Hz, 1H). Step 3
[374] [374] To a solution of 2-chloro-3-mercaptobenzonitrile (116 mg, 560 umol) and [3 - [(3S, 4S) -4-amino-3-methyl-2-0xa-8-azospiro [4, 5] decan-8-yl] -6-bromo-pyrazin-2-yl | methanol (100 mg, 280 umol) in 1,4-dioxane (2 ml) was added K3PO. (119 mg, 560 umol) 1,10-phenanthroline (10 mg, 56 umol) and Cul (5 mg, 27 umol). The mixture was degassed and then heated to 130 ° C for 12 hours. After cooling to room temperature and filtration, the solvent was removed under reduced pressure. The crude residue was purified by preparative HPLC to provide —3 - ((5 - [(3S, 4S) -4-amino-3-methyl-2-0xa-8-azospiro [4,5] decan-
[375] [375] 4 - ((5 - [(3S, 4S) -4-amino-3-methyl-2-0xa-8- azaospiro [4,5] decan-8-yl] -6- (hydroxymethyl) pyrazin- 2-yl) sulfonyl) -3-chloropyridine-2-carbonitrile was synthesized in a similar manner to 3- (15 - [(3S, 4S) -4-amino-3-methyl-2-0xa-8-azospiro [4 , 5] decan-8-yl] -6- (hydroxymethyl) pyrazin-2-yl) sulfonyl) -2-chlorobenzonitrile, except that 2-chloro-3-mercaptobenzonitrile has been replaced by 3-chloro-4-sulfonyl-pyridine- 2-carbonitrile. LCMS (ESI): m / z: [M + H] calculated during C2oH24CIN6O> 2S: 447.1, found 447.2; * 'H NMR (400MHz, methanol-da) 5 = 8.48 (br s, 1H), 8.36 (s, 1H), 8.30 (d, J = 5.3 Hz, 1H), 7, 13 (d, J = 5.3 Hz, 1H), 4.68 (s, 2H), 4.34 - 4.21 (m, 1H), 3.98 - 3.93 (m, 1H), 3 , 87 (br s, 1H), 3.84 (br d, J = 8.8 Hz, 1H), 3.36 (br d, J = 4.0 Hz, 1H), 3.27 - 3.09 (m, 3H), 2.01 - 1.81 (m, 3H), 1.73 (br d, J = 12.8 Hz, 1H), 1.30 (d, J = 6.6 Hz, 3H ).
[376] [376] 13 - [(8S 4S) -4-amino-3-methyl-2-0xa-8-azospiro [4,5] decan-8- i1] -6 - [(3-chloro-2-methoxypyridin- 4-yl) sulfonyl] pyrazin-2-ylYmethanol was synthesized in a similar way to 3 - ((5 - [(3S, 4S) -4-amino-3-methyl-2-0x-
[377] [377] (3 - [(38S, 4S) -4-amino-3-methyl-2-0xa-8-aspasospiro [4,5] decan-8- i1] -6 - [(2-chloro-3- methoxyphenyl) sulfonyl] pyrazin-2-ylkmethanol was synthesized in a similar way to 3 - ((5 - [(3S, 4S) -4-amino-3-methyl-2-0xa-8- azaespiro [4,5] decan -8-yl] -6- (hydroxymethyl) pyrazin-2-yl) sulfonyl) -2-chlorobenzonitrile, except that 2-chloro-3-mercaptobenzonitrile has been replaced by 2-chloro-3-methoxy-benzenethiol. ESI): m / z: [M + H] calculated during C21H28NC4SO3CI: 451.1, found 451.2; * H NMR (400MHz, methanol-da) 5 = 8.49 (br s, 1 H), 7.97 (s, 2H), 7.25 - 7.17 (m, 2 H), 7.04 (dd, J = 1.2, 8.3 Hz, 2 H), 6.86 (dd, J = 1.3, 7.9 Hz, 2 H), 4.63 (s, 4 H), 4.30 - 4.24 (m, 2 H), 3.95 - 3.88 (m, 8 H), 3.81 (d, J = 9.2 Hz, 2 H), 3.72 - 3.58 (m, 4 H), 3.37 (d, J = 4.2 Hz, 2 H) , 3.11 - 2.96 (m, 4 H), 1.98 - 1.82 (m, 6 H), 1.72 - 1.64 (m, 2 H), 1.29 (d, J = 6.5 Hz, 7 H) Example 26. Synthesis of (43 - [(3S, 4S) 4-amino-3-methyl-2-0x-8-azaospiro [4,5] decan-8-yl] -6 - ([3-chloro-2- (3-methanesulfonylazetidin-1-yl) pyridin-4-i] sulfon il) pyrazin-2-yl) methanol. (Compound 26) E) e. O. “The TX Meo Peti mild Í X Dr dioxane, 120ºC o
[378] [378] Dioxane (1.4 ml) was added to a mixture of (3- [(38S, 4S) -4-amino-3-methyl-2-0xa-8-azospiro [4,5] decan-8- yl] -6-bromopyrazin-2-ylkmethanol (50 mg, 139 umol)) 3-chloro-2- (3-methanesulfonylazetidin-1-yl) pyridine-4-thiol (56 mg, 201 umol), Xantphos (16 mg , 28 umol), tris (dibenzylidenoacetone) dipaladium (13 mg, 14 upmol). DIPEA (48 µL, 278 umol) was added. And the heterogeneous mixture was heated to 120ºC under N, for 1 hour. After cooling to room temperature and filtration, the solvent was removed under reduced pressure and the crude residue was purified by preparative HPLC to provide (3 - [(38S, 4S) -4-amino-3-methyl-2-0xa-8- azaespiro [4,5] decan-8-yl] -6 - ([3-chloro-2- (3-methanesulfonylazetidin-1-yl) pyridin-4-yl] sulfonyl) pyrazin-2-ilkmethanol (20.3 mg , 25% production) LCMS (ESI): m / z [M + H] calculated during C23H32CIN6O4S8S> 2: 555.2, found 555.3; 'H NMR (500 MHz, methanol-da) 5 8 , 55 (s, 1H), 8.32 (s, 1H), 7.81 (d, J = 5.5 Hz, 1H), 6.24 (d, J = 5.4 Hz, 1H), 4 , 69 (d, J = 0.4 Hz, 2H), 4.60 - 4.48 (m, 4H), 4.36 - 4.26 (m, 2H), 3.95 (d, J = 8 , 9 Hz, 1H), 3.91 - 3.77 (m, 3H), 3.32 (d, J = 4.5 Hz, 1H), 3.23 (ddd, J = 13.7, 10, 8, 3.1 Hz, 1H), 3.15 (ddd, J = 13.6, 10.9, 2.8 Hz, 1H), 3.03 (s, 3H), 2.01 - 1.91 (m, 2H), 1.90 - 1.83 (m, 1H), 1.78 - 1.70 (m, 1H), 1.31 (d, J = 6.5 Hz, 3H). Synthesis of (43 - [(3S, 4S) -4-amino-3-methyl-2-0xa-8-azospiro [4,5] decan-8-yl] -6 - (((3-chloro-2- [(oxan-4-yl) amino] pyridin-4- i llsulfonyl) pyrazin-2-ylmethanol. (Compound 27)
[379] [379] (3 - [(3S, 4S) -4-amino-3-methyl-2-0xa-8-aspasospiro [4,5] decan-8- i1) -6 - ((3-chloro-2- [(oxan-4-yl) amino] pyridin-4-yl) sulfonyl) pyrazin-2-ylmethane! was synthesized in a similar way to (3 - [(3S, 4S) -4-amino-3-methyl-2-0xa-8-azospiro [4,5] decan-8-yl] -6-f [3- chloro-2- (3-methanesulfonylazetidin-1-yl) pyridin-4-yl] sulfonyl) pyrazin-2-ylkmethane | 1, except 3-chloro-2- (3-methanesulfonylazetidin-1-yl) pyridine-4 -thiol was replaced by 3-chloro-2 - [(tetrahydro-2H-pyran-4-yl) amino] -4-pyridinatiol.
[380] [380] 3- (15 - [(3S, 4S8) -4-amino-3-methyl-2-0xa-8-azospiro [4,5] decan-8-yl] -6- (hydroxymethyl) pyrazin-2 -yl) sulfonyl) -2-chloro- N, N-dimethylbenzamide was synthesized in a similar way to (3- [(8S, 4S) -4-amino-3-methyl-2-0xa-8-azospiro [4, 5] decan-8-yl] -6 - ([3-chloro-2- (3-methanesulfonylazetidin-1-yl) pyridin-4-yl] sulfonyl) pyrazin-2-ylkmethane], except that 3-chloro-2 - (3-methanesulfonylazetidin-1-yl) pyridine-4-thiol was replaced by 2-chloro-N N-dimethyl-3-sulfonylbenzamide. LCMS (ESI): m / z [M + H] calculated during Co3H30oCIN5O3S: 492, 2, found 492.3; TH NMR (500 MHz, methanol-d4) 5 8.45 (s, 1H), 8.13 (s, 1H), 7.43 - 7.34 (m, 2H), 7 , 30 (dd, J = 6.9, 2.3 Hz, 1H), 4.65 (s, 2H), 4.31 (qd, J = 6.5, 4.1 Hz, 1H), 3, 96 (d, J = 9.1 Hz, 1H), 3.90 - 3.81 (m, 1H), 3.76 (d, J = 13.6 Hz, 1H), 3.72 - 3.65 (m, 1H), 3.44 (d, J = 4.2 Hz, 1H), 3.14 (s, 3H), 3.12 - 3.01 (m, 1H), 2.91 (s, 3H), 1.97 (td, J = 12.2, 11.3, 4.0 Hz, 2H), 1.89 (d, J = 13.5 Hz, 1H), 1.78 - 1.69 (m, 1H), 1.33 (d J = 6.5 Hz, 3H) Example 29 Synthesis of 1- [4 - ((5 - [(3S, 4S) -4-amino-3-methyl-2-0xa-8- azospiro [4,5] decan-8-yl] -6- (hydroxymethyl ) pyrazin-2-yl) sulfonyl) -3-chloropyridin-2-ylJazetidin-3-ol. (Compound 29)
[381] [381] 1- [4 - ((5 - [(3S, 4S) -4-amino-3-methyl-2-0xa-8- azospiro [4,5] decan-8-yl] -6- (hydroxymethyl ) pyrazin-2-yl) sulfonyl) -3-
[382] [382] 13 - [(8S8,4S) -4-amino-3-methyl-2-0xa-8-azospiro [4,5] decan-8- i1) -6 - [(2,3-dichlorophenyl) sulfonyl ] pyrazin-2-yl) methanol was synthesized in a similar way to (3 - [(38S, 4S) -4-amino-3-methyl-2-0xa-8-azospiro [4,5] decan-8-yl ] -6 - ([3-chloro-2- (3-methanesulfonylazetidin-1-yl) pyridin-4-yl] sulfonyl) pyrazin-2-ylkmethanol, except that 3-chloro-2- (3-methanesulfonylazetidin-1- il) pyridine-4-thiol was replaced by 2,3-dichlorobenzenethiol LCMS (ESI): m / z [M + H] calculated during C2oH24CIaN4028: 455.1, found 455.3; "H NMR (500 MHz, target - nol-d4) 5 8.49 (s, 1H), 8.12 (d, J = 0.5 Hz, 1H), 7.45 (ddd, JU = 7.9, 1.6, 0.5 Hz, 1H), 7.21 (td, J = 7.9, 0.5 Hz, 1H), 7.15 (ddd, J = 8.0, 1.6, 0.5 Hz, 1H), 4 , 64 (d, J = 0.5 Hz, 2H), 4.28 (qd, J = 6.5, 4.2 Hz, 1H), 3.94 (d, J = 9.1 Hz, 1H) , 3.83 (dd, J = 9.1, 0.8 Hz, 1H), 3.79 - 3.64 (m, 2H), 3.41 (d, J = 4.2 Hz, 1H), 3.10 (ddd, J = 13.8, 11.1, 2.9 Hz, 1H), 3.03 (ddd, J = 13.7, 11.2, 2.7 Hz, 1H), 2, 66 (d, J = 0.5 Hz, 3H), 1.95 (ddt, J =
[383] [383] 16 - [(2-amino-3-chloropyridin-4-yl) sulfonyl] -3 - [(3S, 4S) -4-amino-3-methyl-2-0xa-8-azospiro [4,5 ] decan-8 & -yl] pyrazin-2-ylkmethanol was synthesized in a similar way to (3 - [(3S, 4S) -4-amino-3-methyl-2-0xa-8- azaospiro [4,5 ] decan-8-yl] -6 - ([3-chloro-2- (3-methanesulfonylazetidin-1-yl) pyridin-4-yl] sulfonyl) pyrazin-2-ylmethanol, except that 3-chloro-2- ( 3-methanesulfonylazetidin-1-yl) pyridine-4-thiol was replaced by 2-amino-3-chloro-4-pyridinatiol LOCMS (ESI): m / z [M + H] calculated during C19H25CINC> 2S: 437.1 , found 437.4; * H NMR (500 MHz, methanol-d4) 5 8.50 (s, 2H), 8.31 (d, J = 2.1 Hz, 1H), 7.62 (dd, J = 5.7, 2.1 Hz, 1H), 6.07 (dd, J = 5.7, 2.1 Hz, 1H), 4.68 (d, J = 2.1 Hz, 2H), 4 , 33 - 4.26 (m, 1H), 3.96 (d, JU = 9.3 Hz, 1H), 3.91 - 3.77 (m, 4H), 3.40 - 3.34 (m , 1H), 3.24 - 3.09 (m, 2H), 1.95 (d, J = 12.5 Hz, 2H), 1.88 (d, J = 13.3 Hz, 1H), 1 , 74 (d, J = 13.2 Hz, 1H), 1.31 (dd, JU = 6.5, 2.1 Hz, 3H). Example 32. Synthesis of (3 - [(3S, 4S) - 4-amino-3-methyl-2-0xa-8- aspasospiro [4,5] dec an-8-yl] -6 - [(2-amino-5-chloropyridin-4-yl) sulfonyl] pyrazin-2-yl) methanol. (Compound 32)
[384] [384] 13 - [(38S8,4S) -4-amino-3-methyl-2-0xa-8-azospiro [4,5] decan-8- i1]) - 6 - [(2-amino-B5- chloropyridin-4-yl) sulfonyl] pyrazin-2-ylYmethanol was synthesized in a similar way to (3 - [(3S, 4S) -4-amino-3-methyl-2-0xa-8- azaospiro [4, 5] decan-8-yl] -6 - ([3-chloro-2- (3-methanesulfonylazetidin-1-yl) pyridin-4-yl] sulfonyl) pyrazin-2-yl) methanol, except that 3-chloro- 2- (3-methanesulfonylazetidin-1-yl) pyridine-4-thiol was replaced by 2-amino-5-chloro-4-pyridinatiol. LOCMS (ESI): m / z [M + H] calculated during C19H25CINsO> 2S: 437.1, found 437.5; * H NMR (500 MHz, methanol-d4) 5 8.39 (s, 1H), 8.33 (s, 1H), 7.81 (s, 1H), 6.07 (s, 1H), 4.71 (s,
[385] [385] To a solution of 2,4-dichloro-5-fluoro-pyrimidine (5 g, 30 mmol) in 1,4-dioxane (70 mL) was added tributyl (1-ethoxyvinyl) tin (9.73 g, 30 mmols, 9.10 ml), LiCI (3.89, 90 ml, 1.84 ml) and Pd (PPhs3) «(1.73 g, 1.5 mmol). The mixture was stirred at 85 ° C for 1.5 hours. The reaction mixture was concentrated under reduced pressure and the resulting residue was purified by column chromatography to provide 2-chloro-4- (1-ethoxyvinyl) -S-fluoro-pyrimidine (3.9 g, 19.2 mmols, 64% yield) as a white solid. * H NMR (400MHz, chloroform-d) 5 = 8.47 (d, J = 2.9 Hz, 1H), 5.31 (d, J = 3.1 Hz, 1H), 4.72 (d, J = 2.9 Hz, 1H), 3.96 (q, J = 7.0 Hz, 2H), 1.43 (t, J = 6.9 Hz, 3H). Step 2
[386] [386] To a solution of 2-chloro-4- (1-ethoxyvinyl) -5-fluoro-pyrimidine (3.7 g, 18.4 mmol) in 1,4-dioxane (260 mL) was added a solution tion of NalOa (7.90 g, 37 mmol) in H2O (130 mL). Solid KMnO4 (438 mg, 2.77 mmol) was then added to this solution. The mixture was stirred at 25 ° C for 1 hour. The reaction mixture was filtered and the resulting filtrate was diluted with EtOAc (50 ml), aqueous sodium bicarbonate (30 ml) and aqueous NaCl (30 ml). The resulting mixture was stirred for 5 minutes. The aqueous layer was extracted with EtOAc (50 ml x 2) and the combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by column chromatography to provide ethyl 2-chloro-5-fluoro-pyrimidine-4-carboxylate (2.7 g, 13 mois, 72% yield) as a colorless oil. * H NMR (400MHz, chloroform-d) ô = 8.70 (d, J = 1.8 Hz, 1H), 4.51 (q, J = 7.2 Hz, 2H), 1.44 ( t, J = 7.2 Hz, 3H).
[387] [387] To a solution of ethyl 2-chloro-5-fluoro-pyrimidine-4-carboxylate (547 mo, 27 mmol) and (3S4S) -3-methyl-2-0xa-8-azospiro [4,5] decan-4-amine (650 mg, 2.7 mmol) in i-PrOH (10 ml) DIPEA (6.91 9, 53.5 mmol, 9.3 ml) was added. The mixture was stirred at 0 ° C for 12 hours. The reaction mixture was used for the next step without purification. LCMS (ESI): m / z: [M + H] calculated during C1i6H24CIN103: 355.2, found 355.1.
[388] [388] To a solution of 5 - [(3S, 4S) -4-amino-3-methyl-2-0xa-8-azaspiro [4,5] decan-8-yl] -2-chloro-pyrimidine-4 -ethyl carboxylate (949 mg, 2.7 mmol) in i-PrOH (5 mL) Boc2O (2.92 9, 13.4 mmol, 3.1 mL) and DIPEA (6.9 g, 53, 5 mmols, 9.3 mL). The mixture was stirred at 0 ° C for 1 hour. The reaction mixture was concentrated under reduced pressure and the resulting residue was purified by preparative HPLC to provide 5 - [(3S, 4S) -4- (tert-butoxycarbonylamino) -3-methyl-2-0xa-8-azospiro [4, 5] ethyl decan-8-yl] -2-chloro-pyrimidine-4-carboxylate (600 mg, 1.3 mmol, 49% yield) as a yellow solid. LCMS (ESI): m / z: [M + H] calculated during C21H32CIN1Os:
[389] [389] To a solution of 2-amino-3-chloro-pyridine-4-thiol (159 mg, 0.99 mmol) and 5 - [(3S, 4S) -4- (tert-butoxycarbonylamino) -3-methyl -2-0xa-8- azaespiro [4,5] decan-8-yl] -2-chloro-pyrimidine-4-carboxylate (300 mg, 659 umol) in 1,4-dioxane (5 ml) were added 1.10- phenanthroline (24 mg, 132 umol), Cul (13 mg, 66 umol) and K3PO, a (420 mg, 2 mmol) under N> 2. The mixture was stirred at 130 ° C for 3 hours. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by preparative HPLC to provide 2 - [(2-amino-3-chloro-4-pyridyl) sulfonyl] -5 - [(3S, 4S) -4- (tert-butoxycarbonylamino) -3- ethyl methyl-2-0xa-8-azospiro [4,5] decan-8-illpyrimidine-4-carboxylate (180 mg, 311 umol, 47% production) as a yellow oil. LCMS (ESI): m / z: [M + H] calculated during CosH3asCINsOsS: 579.2, found 579.3. Step 6
[390] [390] To a solution of 2 - [(2-amino-3-chloro-4-pyridyl) sulfonyl] -5- [(3S, 4S) -4- (tert-butoxycarbonylamino) -3-methyl-2-0x -8- azaespiro [4,5] decan-8-yl | pyrimidine-4-carboxylate (80 mg, 138 umol) in THF (1 ml) DIBAL-H (1 M in toluene, 414.43 uL) was added ). The mixture was stirred at -78 ° C for 1 hour, and NaBH, (26 mg, 691 umol) in MeOH (1 ml) was then added to the reaction mixture. The reaction mixture was stirred at 25 ° C for 1 hour. The mixture was extinguished by the addition of H2O (2 ml). The mixture was filtered and the resulting filtrate was concentrated under reduced pressure. The remaining residue was purified by preparative HPLC to provide N - [(3S, 4S) -8- [2 - [(2-amino-3-chloro-4-pyridyl) sulfonyl] -4- (hydroxymethyl) pyrimidin- 5-i1] -3-methyl-2-0xa-8- azaespiro [4,5] decan-4-yl | tert-butyl carbamate (40 mg, 75 umol, 54% yield) as a white solid. LCMS (ESI): m / z: [M + H] calculated during C24H34CINsO48S: 537.2, found 537.3.
[391] [391] A solution of NH (3S4S) -8- [2 - [(2-amino-3-chloro-4-pyridyl) sulfonyl] -4- (hydroxymethyl) pyrimidin-5-yl] -3-methyl-2 -0xa-8- azaespiro [4,5] decan-4-yl | tert-butyl carbamate (27 mg, 50 umol) in HCI / MeOH (4M, 10 ml) was stirred at 0 ° C for 3 hours. The reaction mixture was concentrated under reduced pressure. The resulting residue was purified by preparative HPLC to provide [2 - [(2-amino-3-chloro-4-pyridyl) sulfonyl] -5 - [(3S, 4S) -4-amino-3-methyl-2-0x -8- azaespiro [4,5] decan-8-yl] pyrimidin-4-yl] methanol (2 mg, 4.6 umol, 9% yield) as a white solid. * H NMR (400MHz, methanol-da) 5 = 8.55 (d, J = 19.8 Hz, 1H), 8.35 (s, 1H), 7.83 (d, J = 5.4 Hz, 1H), 6.93 (d, J = 5.4 Hz, 1H), 4.68 (s, 2H), 4.33 - 4.22 (m, 1H), 3.92 (d, J = 9 , 2 Hz, 1H), 3.81 (d, J = 9.2 Hz, 1H), 3.40 (d, J = 4.2 Hz, 1H), 3.23 - 3.05 (m, 2H ), 2.96 - 2.77 (m, 2H), 2.04 - 1.83 (m, 3H), 1.73 (d, J = 12.7 Hz, 1H), 1.30 (d, J = 6.5 Hz, 3H). LOCMS (ESI): m / z: [M + H] calculated during C19H26CIN6O> 2S: 437.1, found 437.1. Example 34. Synthesis of (1R) -8- [5- (2,3-dichlorophenyl) -3- (difluoromethyl) pyrazin-2-yl] -8-azospiro [4,5] decan-1-amine Cove LE sos CE
[392] [392] To a solution of methyl 3,6-dibromopyrazine-2-carboxylate (583 mg, 1.97 mmol), and boronic acid (2,3-dichlorophenyl) (375 mg, 1.97 mmol) dioxane (40 ml) was added Cs2CO; 3 (1.93 g, 5.91 mmol) in H2O (10 ml) and PdCladppf (144 mg, 0.2 mmol). The reaction was refluxed for 20 minutes, allowed to cool to room temperature, and extracted with EtOAc. The combined organic layers were washed with brine and dried over MgSO2 .. The mixture was concentrated under reduced pressure. Purification by flash chromatography resulted in 370 mg (52%) of the desired product. * H NMR (500 MHz, CDCl3) 5 8.58 - 8.53 (m, 1H), 7.38 - 7.32 (m, 1H), 7.29 - 7.22 (m, 1H), 7 , 14 - 7.08 (m, 1H), 3.82 - 3.76 (m, 3H). Step 2.
[393] [393] To a solution of methyl 3-bromo-6- (2,3-dichlorophenyl) pyrazine-2-carboxylate (270 mg, 0.75 mmol) in THF (5 mL) at —78 ºC was added DIBAL- H (2.23 mL, 1 M, 2.23 mmol). The reaction was heated to rt and stirred for 2 hours. The reaction mixture was cooled to 0 ° C and quenched with methanol and Rochelle salt. Extraction with EtOAc, followed by drying over MgSO. provides (3-bromo-6- (2,3-dichlorophenyl) pyrazin-2-yl) methanol (108 mg, 43%) which was used without further purification in the next step. Step 3.
[394] [394] To a solution of (3-bromo-6- (2,3-dichlorophenyl) pyrazin-2-yl) methane! (224 mg, 0.67 mmol) in CH2Cl2 (5 mL) Dess-Martin reagent (222 mg, 1.0 mmol) was added. The reaction was stirred at room temperature for 1 hour and quenched by the addition of aqueous NaHSO; 3. The mixture was extracted with EtOAc, the organic layer was concentrated under reduced pressure, and the combined organic fractions were dried over MgSO .. The resulting solution was filtered through a pad of silica gel to provide 3-bromo-6- ( 2,3-dichlorophenyl) pyrazine-2-carbaldehyde (158 mg, 71%). Step 4.
[395] [395] To a solution of 3-bromo-6- (2,3-dichlorophenyl) pyrazine-2-carbaldehyde (70 mg, 0.21 mmol) in CH2Cl2 (5 mL) was added DAST (101 mg, 0.63 mmol) . The reaction was stirred at room temperature for 1 hour, concentrated under reduced pressure, and the resulting residue was purified by filtration through a plug of silica to provide 2-bromo-5- (2,3-dichlorophenyl) -3 - desired (difluoromethyl) pyrazine (53 mg, 76%). Step 5.
[396] [396] To a solution of 2-bromo-5- (2,3-dichlorophenyl) -3- (difluoromethyl) pyrazine (50 mg, 0.14 mmol) in DMA (5 mL) was added (S) - 2-methyl-N - ((R) -8-azospiro [4,5] decan-1-yl) propane-2-sulfinamide (72.8 mg, 0.28 mmol) and DIPEA (1 ml). The resulting solution was stirred under microwave conditions at 120 ° C for 2 hours. After cooling to room temperature, the solvent was removed under reduced pressure and the crude residue was purified by flash chromatography to provide (S) -N - ((R) -8- (5- (2,3-dichlorophenyl) -3- (difluoromethyl |) pyrazin-2-yl) -8-azospiro [4,5] decan-1-yl) -2-methylpropane-2-sulfinamide (44 mg, 59%). Step 6.
[397] [397] To a solution of (S) -N - ((R) -8- (5- (2,3-dichlorophenyl) -3- (difluoromethyl) pyrazin-2-yl) -8-azospiro [4,5 ] decan-1-yl) -2-methylpropane-2-sulfinamide (35 mg, 0.066 mmol) in methanol (5 ml) 1 ml of HCl in dioxane was added. The resulting solution was stirred at room temperature for 10 minutes. After removing all volatiles under reduced pressure, the crude residue was purified by preparative HPLC to provide (1R) -8- [5- (2,3-dichlorophenyl) -3- (difluoromethyl) pyrazin-2- il] - 8-azospiro [4,5] decan-1-amine as the formic acid salt (22 mg, 70%). 1H NMR (500 MHz, methanol-d4) 5 8.82 (t, J = 4.3 Hz, 1H), 8.06 - 7.50 (m, 3H), 7.44 - 6.82 (m, 1H), 4.36 - 3.70 (m, 5H), 2.79 - 1.06 (m, 10H). LOC-MS (ESI): m / z [M + H] CaoH22Cl2F2Na calculated 427.1, found 427.3. Example 35. Synthesis of (3S, 4S) -8- [5- (2,3-dichlorophenyl) -3- (difluoromethyl) pyrazin-2-yl] -3-methyl-2-0xa-8-azospiro [4, 5] decan-4-amine ci “and we Cc EO. O
[398] [398] To a solution of 2-bromo-5- (2,3-dichlorophenyl) -3- (difluoromethyl) pyrazine (123 mg, 0.347 mmols, Example 34) in DMA (5 ml) was added (1R, 2R) -2-methyl-8-azospiro [4,5] decan-1-amine (168 mg, 0.694 mmol) and DIPEA (1 ML) The resulting solution was stirred under microwave conditions at 120 ° C for 2 hours. After cooling to room temperature the resulting mixture was concentrated under reduced pressure and the residue was purified by preparative HPLC to provide (3S, 4S) -8- [5- (2,3-dichlorophenyl) -3- (difluoromethyl) pyrazine -2-yl] -3-methyl-2-0xa-8- azaespiro [4,5] decan-4-amine as the formate salt (30 mg, 18%). * H NMR (500 MHz, methanol-da) 8.63 (s, 1H), 7.65-7.42 (m, 3H), 6.93 (t J = 50 Hz, 1 hour, CF2H), 4 , 34 (m, 1H), 4.02-3.19 (m, 7H), 2.68-1.94 (4H), 1.36 (d, J = 5.0 Hz, 3H); LOC-MS (ES)): m / z [M + H] CroH22CI2F2N4O calculated 443.1, found 443.3. Biological Examples - SHP2 Allosteric Inhibition Assay
[399] [399] Without wishing to be bound by theory, SHP is allosterically activated through the binding of bis-tyrosyl phosphorylated peptides to these Src 2 (SH2) homology domains. The last activation step leads to the release of the SHP2 autoinhibitory interface, which, in turn, makes the SHP2 protein tyrosine phosphatase (PTP) active and available for substrate recognition and reaction catalysis. The catalytic activity of SHP2 was monitored using the substitute substrate DIFMUP in a ready-made fluorescence test format.
[400] [400] Phosphate reactions were carried out at room temperature on a 96-well, black, flat-bottomed polystyrene plate with a non-bonding surface (Corning, Cat f 3650) using a final reaction volume of 100 ul and the following assay buffer conditions: 50 mM HEPES, pH 7.2, 100 mM NaCl, 0.5 mM EDTA, 0.05% P-20, 1 mM DTT.
[401] [401] The inhibition of SHP2 by compounds of the present description (concentrations ranging from 0.00005 to 10 µM) was monitored using an assay in which 0.2 nM of SHP 2 was incubated with 0.5 µM of Activation of Peptide 1 (sequence: H2oN- LN (pY) IDLDLV (dPEG8) LST (pY) ASINFQK-amide) or Activation Peptide 2 (sequence: HIN-LN (pY) AQLWHA (dPEG8) LTI (pY) ATIRRF- amide ). After 30 to 60 minutes of incubation at 25 ºC, the substitute substrate DIFMUP (Invitrogen, Cat% & D6567) was added to the reaction and the activity was determined by a kinetic reading using a plate reader (Envision, Perkin-Elmer or Spectramax M5, Molecular Devices). The excitation and emission wavelengths were 340 nm and 450 nm, respectively. The initial rates were determined from a linear fit of the data, and the dose response curves of the inhibitor were analyzed using regression curve adjustment of normalized IC50 with control-based normalization.
[402] [402] Using the above protocol, SHP2 inhibition was measured as set out in Table 1. Table-1: SHP2 inhibition of tested compounds
[403] [403] Using the above protocol, SHP2 inhibition was measured as set out in Table 2. In the table below: “+++” refers to <= 50nM; “++ 'refers to> 50NM to <= 500nM; w “+” refers to> 500nM. Table 2: SHP2 Inhibition of Tested Compounds
[404] [404] In some embodiments, the compounds of the description tested in the assay described above demonstrated an activity less than 1000 nM. In some embodiments, the compounds of the description tested in the assay described above demonstrated an activity of about 10 nM to about 100 nM. In some embodiments, the compounds of the description tested in the assay described above demonstrated an activity from 10 nM to 100 nM. In some embodiments, the compounds of the description tested in the assay described above demonstrated an activity of less than 10 nM.
[405] [405] One or more described compounds or compositions can be administered in amounts effective to treat or prevent a disorder and / or prevent its development in individuals. In some embodiments, SHP2 is initiated after treatment with less than 1000 nM of a compound of the description. In some embodiments, SHP2 is initiated after treatment with about 1 nM to about 10 nM of a compound of the description. In some modalities, SHP2 is inhibited with treatment with about 10 nM to about 100 nM of a compound of the description. In some embodiments, SHP 2 is inhibited with treatment with about 100 nM to about 10 µM of a compound of the description. Equivalents
[406] [406] At the same time that the present description has been described together with the specific modalities set out above, many alternatives, modifications and other variations of them will be evident to those skilled in the art. All alternatives, modifications and variations are intended to be included in the spirit and scope of this description.

权利要求:
Claims (36)
[1]
1. Compound, characterized by the fact that it presents Formula | V:
NS EX
RA RR (IV) or a pharmaceutically acceptable salt, prodrug, hydrate, tautomer or isomer thereof, where: X 'is Nou CH; X 'is Nou CH; X is Nou CH; where at least one of X ', X , or Xº is N; Y1 is —S- or a direct bond, A is selected from the group consisting of 5 to 12-membered monocyclic or polycyclic cycloalkyl, monocyclic or polycyclic heterocycloalkyl, monocyclic or polycyclic aryl or monocyclic or polycyclic heteroaryl; R 'is independently, at each occurrence, -H, —D, —C1-Cs alkyl, —C2-Cs6 alkenyl, —-C4-C; g cycloalkenyl, —C2-Cs6 alkynyl, —C3-Cs cycloalkyl, —OH, —ORº, halogen, —NO>, CN, —NRºRº, —SRº, - S (O) ANRºRS, —S (O) 2R5, —-NR5S (O) aNRºRº, -NR $ S (O) 2R6 , —S (O) NRºR $, -S (O) R5, —NRºS (O) NRºRº, —NRºS (O) Rº, —C (OJ) JRó, COR, - C (O) INRºRº, -NRºC (O ) R $, or 3- to 12-membered monocyclic or polycyclic heterocycle, where each alkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkyl or heterocycle is optionally substituted with one or more -OH, halogen, -NO>, 0x0, - CN, -R5, -OR ”, —-NRºRº, -SRS $, —S (O) NRºR6, -“ - S (O) Rº, —NRÍS (O) NRºR, —NRºS (O) R $, -— S (O) NRºR6, -S (O) R5, -NR5S (O) NRºR $, -NR $ S (O) R $, heterocycle, aryl or heteroaryl; R º and Rº are independently selected from the group consisting of —H, -D, -OH, —C1-Cs alkyl, a 3-12 membered monocyclic or polycyclic heterocycle, a 5-12 membered spiroheterocycle, C3- Cg cycloalkyl, - (CH2)) - RP, or - (CH2)) C (O) NR “R $, in which each alkyl, heterocycle, or cycloalkyl is optionally substituted with one or more —C1-Cs alkyl, = OH, - = NH> 2, -ORº, -NHRb, - (CH2)), OH, heterocyclyl, or spiroheterocyclyl; or R3 can be combined with R to form a 3- to 12-membered monocyclic or polycyclic heterocycle, or a 5-12 membered spiroheterocycle, where each heterocycle or spiroheterocycle is optionally substituted with one or more alkyl-, C1-Cs, halogen -OH, - ORP, —-NH> 2, = -NHR , optionally substituted heteroaryl, optionally substituted heterocyclyl, - (CH2)) NH2, - (CH2)) OH, -COOR , - CONHRº, -CONH (CH2 )). COORº, -NHCOOR , -OC (O) -NR “Rô, —CF3, - CHF2, -CH2F, or = O; wherein the heteroaryl and heterocyclyl are optionally substituted with -CN; Rº is -C1-Cs alkyl, = C1-Cehalo alkyl, = C1-Cs6 hydroxyalkyl -CF2OH, —CHFOH, —-NH-NHR ”, -NH-OR”, -O-NRºRº, —NHR ”, -OR” , - NHC (O) Rº, -NHC (O) NHR5, -NHS (O) 2R5, -NHS (O) 2NHR ", —-S (O) 2OH, —C (0) ORS, —-NH (CH2 )); OH, —C (O) NH (CH2). OH, —C (O) NH (CH2), Rº, - C (O) Rº, —-NH2, = OH, —CN, —C (O ) NRºR6, -S (O) NR “Rº, C3-Cz cycloalkyl, aryl, heterocyclyl containing from 1 to 5 heteroatoms selected from the group consisting of N, S, P, and O, or heteroaryl containing from 1 to heteroatoms selected from the group consisting of N, S, P, and O, where each cycloalkyl or heterocyclyl alkyl is optionally substituted with one or more -OH, —-NH> 2, —OR , halogen, or 0x0; that each aryl or heteroaryl is optionally substituted with one or more —OH, -NH>, or halogen; Rº and Rô are each independently, in each occurrence, selected from the group consisting of —H, —D, —C1 -Cs alkyl, —-C2-Cs alkenyl, —Ca4-C; cycloalkenyl, —C2-Cs alkynyl, —-C3-Csa cycloalkyl, a monocyclic or polycyclic heterocycle I click from 3 to 12 members, -OR ”, —SR7, halogen, —-NR7Rô, —NO,», and —CN; R 'and R $ are independently, in each occurrence, -H, —D, —C1-Cs alkyl, —-C2-Cs alkenyl, -—- Ca-C; g cycloalkenyl, —-C2-Cs alkynyl, —C3 - Cycloalkyl Cs, a 3- to 12-membered monocyclic or polycyclic heterocycle, where each alkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkyl, or heterocycle is optionally substituted with one or more —OH, -SH, —-NH> 2 , —-NO>, or —-CN; Rº is independently —H, —-D, —C1-Cs alkyl, —-C1-Cs cycloalkyl, - C2-Cs6 alkenyl, - (CH> 2) »- aryl, heterocyclyl containing 1 to 5 heteroatoms selected from group consisting of N, S, P, or O, or heteroaryl containing 1 to 5 heteroatoms selected from the group consisting of N, S, P, and O; where each alkyl, cycloalkyl, alkenyl, heterocycle, heteroaryl, or - (CH2), - aryl is optionally substituted with one or more -OH, halogen, —-NO>, oxo, -CN, -R5, -—OR $ , - NRºRô, -SRº, —S (O) NRºRº, —S (O) R, —NRºS (O) NRºRô, - NR $ S (O) 2R6, —S (O) NR “R8, -S (O ) R ”, -NRºS (O) NR“ Rº, -NR $ S (O) Rº, - C (OINRRE-, - NRºR $ C (O) -, heterocycle, aryl, heteroaryl, - (CH2); OH, -C1-Cs alkyl, CF3, CHF2, or CH2F; en is independently O, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.
[2]
2. Compound, characterized by the fact that it has Formula V: 1 1 and RR V) or a pharmaceutically acceptable salt, prodrug, hydrate, tautomer or isomer thereof, where: X 'is Nou CH; X 'is Nou CH; X º is Nou CH;
where at least one of X ', X , or Xº is N; Y'1 is —S- or a direct bond, A is selected from the group consisting of 5- to 12-membered monocyclic or polycyclic cycloalkyl, monocyclic or polycyclic heterocycloalkyl, monocyclic or polycyclic aryl or monocyclic or polycyclic heteroaryl; R 'is independently, at each occurrence, -H, —D, —C1-Cs alkyl, —C2-Cs6 alkenyl, —-C4-C; g cycloalkenyl, —C2-Cs alkynyl, —C3-Ca cycloalkyl, -OH, —ORº, halogen, -NO2, CN, —NRºRº, —SR5, - S (O) NRSRô, —S (O) 2R5, —-NRºS (O) aNRºRº, —-NRºS (O) 2R6, - S (O) NRºR $, —S (O) Ró, —NRºS (O) NRºRº, —NRºS (O) Rº, —C (OJ) Rº, COR ”, - C (OINRºRô, -NRºC (O) R $ , or 3- to 12-membered monocyclic or polycyclic heterocycle, where each alkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkyl or heterocycle is optionally substituted with one or more -OH, halogen, -NO,>, oxo, -CN, -R5, -OR ”, —-NRºR6, -SR $, —S (O) NRºRº, -“ - S (O) R ”, —NRÍS (O) LNRºR, —NRºS (O) R, -— S ( O) NRºR6, -S (O) Ró, -NRºS (O) NRºRº, -NR $ S (O) R $, heterocycle, aryl or heteroaryl; R And R $ are independently selected from the group consisting of —H, -D, -OH, —C1-Cs alkyl, a 3- to 12-membered monocyclic or polycyclic heterocycle, a 5-membered 5-spiroheterocycle, C3- Cg cycloalkyl, (CH2)) - RP, or - (CH2 )) C (O) NR “R $, where each alkyl a, heterocycle, or cycloalkyl is optionally substituted with one or more —C1-Cs alkyl, - = OH, —-NH2, -ORº, -NHRP, - (CH2)) YOH, heterocycle, or spiro-heterocyclyl; or R3 can be combined with R to form a 3- to 12-membered monocyclic or polycyclic heterocycle, or a 5-12 membered spiroheterocycle, where each heterocycle or spiroheterocycle is optionally substituted with one or more -C1-Cs alkyl, halogen - OH, - ORP, —-NH> 2, = NHR , optionally substituted heteroaryl, optionally substituted heterocyclyl, - (CH2)) NH2, - (CH2)) ºOH, -COORº, - CONHRº, -CONH (CH2)). COOR !, -NHCOOR ", -OC (O) -NRºR $, —CF3, - CHF2, -CH2F, or = O; where heteroaryl and heterocyclic are optionally substituted with -CN; Rº is —C1-Cs alkyl, where each alkyl is optionally substituted with one or more -OH, -—- NH>, halogen, or 0x0; Rº and Rô are each independently, in each occurrence, selected from the group consisting of —H, —D, —C1-Cs alkyl, —C2-Cs alkenyl, —C4-C; g cycloalkenyl, —-C2-Cs alkynyl, —-C3-Cag cycloalkyl, a 3- to 12-membered monocyclic or polycyclic heterocycle, -OR ” , —SR, halogen, —-NR7Rô, —NO,», and —CN; R 'and R $ are independently , at each occurrence, -H, —D, —C1-Cs alkyl, —-C2-Cs alkenyl, -—- C4-Cg cycloalkenyl, —-C2-Cs alkynyl, —C3- Cs cycloalkyl, a monocyclic or polycyclic heterocycle 3 to 12 members, where each alkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkyl, or heterocycle is optionally substituted with one or more —OH, -SH, —-NH> 2, —YNO;>, or -CN ; Rº is independently —H, —D, —C1-Cs alkyl, —-C1-Cs cycloalkyl, - C2-Cs6 alkenyl, - (CH2), "- aryl, heterocyclyl containing 1 to 5 heteroatoms selected from the group that consists of N, S, P, or O, or heteroaryl containing 1 to 5 heteroatoms selected from the group consisting of N, S, P, and O; each alkyl, cycloalkyl, alkenyl, heterocycle, heteroaryl, or - (CH2), - aryl is optionally substituted with one or more -OH, halogen, —-NO>, oxo, -CN, -R5, -OR $, - NRºR, -SR5, —S (O) NRºRº, - -S (O) Ró, —NRºS (O) NRºRº, - NR $ ºS (O) 2R $, -S (O) NRºR8 $, -S (O) Rº, -NRºS (O) NRºRº, -NR $ S (O) R $, - C (OINRºRº-, - NR R $ C (O) -, heterocycle, aryl, heteroaryl, (CH2)) OH, -C1-Cs alkyl, CF3, CHF2, or CH2F; en is independently O, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.
[3]
3. Composite, characterized by the fact that it presents the
Formula VI:
CNS NES
RA RR (VI) or a pharmaceutically acceptable salt, prodrug, hydrate, tautomer or isomer thereof, where: X 'is Nou CH; X is N or CH; X is Nou CH; where at least one of X ', X , or Xº is N; Y1 is —S- or a direct bond, A is selected from the group consisting of 5- to 12-membered monocyclic or polycyclic cycloalkyl, monocyclic or polycyclic heterocycloalkyl, monocyclic or polycyclic aryl or monocyclic or polycyclic heteroaryl; R 'is independently, at each occurrence, -H, —D, —C1-Cs alkyl, —C2-Cs alkenyl, —-C4-C; g cycloalkenyl, —-C2-Cs alkynyl, —C3-Ca cycloalkyl , —OH, —ORº, halogen, —NO », CN, —NRºRº, —SRº, - S (O) ANR“ Rô, —S (O) 2R ”, —-NRºS (O) aNR“ Rº, —- NRºS (O) 2R6, -S (O) NRºR $, —S (O) Ró, —NRºS (O) NR * Rº, —NRºS (O) Rº, —C (OJ) Rº, —CO2R ”, - C (O) INRºRº, -NR5C (O) R $, or 3 to 12 membered monocyclic or polycyclic heterocycle, in which each alkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkyl or heterocycle is optionally substituted with one or more -—- OH, halogen, -NO;>, oxo, -CN, -R5, -OR ”, —-NRºRô, -SR $, —S (O) NRºRº, -“ - S (O) R ”, —NR'S (O ) LNR'ºR, —NRºS (O) R $, -— S (O) NRºRô, -S (O) Ró, -NRÍS (O) NRºRº, -NRºS (O) R $, heterocycle, aryl or heteroaryl; Can R3 be combined with R to form a 3- to 12-membered monocyclic or polycyclic heterocycle, or a 5-to-12-membered spiroheterocycle, where each heterocycle or spiroheterocycle is optionally
substituted with one or more —C1-Cs alkyl, halogen -OH, - OR, —-NH> 2, = -NHR , optionally substituted heteroaryl, optionally substituted heterocyclyl, - (CH2)) JNH2, —H (CH2) JºOH, -COORº ”, - CONHR , -CONH (CH2)). COORº, -NHCOOR" ”, -OC (O) -NRºRºô, —CF3, - CHF2, -CH2F, or = O; where heteroaryl and heterocyclyl are optionally substituted with -CN; Rº is —-C1-Cs alkyl, where each alkyl is optionally substituted with one or more -OH, -—- NH>, halogen, or 0x0; Rº and Rô are each independently, in each occurrence, selected from the group consisting of —H, —D, —C1-Cs alkyl, —-C2-Cs alkenyl, —-C4-C; g cycloalkenyl, —-C2-Cs alkynyl , —-C3-Cs cycloalkyl, a 3- to 12-membered monocyclic or polycyclic heterocycle, -OR ”, —SR”, halogen, -NR7Rô, —NO, », and —CN; R And Rô are independently, in each occurrence, —H, —D, —C1-Cs alkyl, —-C2-Cs6 alkenyl, -—- Ca-C; g cycloalkenyl, —-C2-Cs alkynyl, —C3a- Cs cycloalkyl, a monocyclic or polycyclic heterocycle 3 to 12 member group, where each alkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkyl, or heterocycle is optionally substituted with one or more —OH, -SH, —-NH> 2, —YNO;>, or - CN; Rº is independently —H, —D, -C1-Cs alkyl, -C1-Cs cycloalkyl, - C2-Cs6 alkenyl, - (CH>), "- aryl, heterocyclyl containing 1 to 5 heteroatoms selected from the group that consists of N, S, P, or O, or heteroaryl containing 1 to 5 heteroatoms selected from the group consisting of N, S, P, and O; each alkyl, cycloalkyl, alkenyl, heterocycle, heteroaryl, or - (CH>) n-aryl is optionally substituted with one or more -OH, halogen, —-NO>, oxo, -CN, -R5, -—ORS $, - NRºRô $, -SRº, —S (O) NRºRº, —S (O) R, —NRºS (O) NRºRº, - NRÍS (O) 2Rô, —S (O) NRºR $, -S (O) Ró, -NRS (O) NRºRº, —-NR $ S (O) RS $, - C (O) INRºR6-, - NR & R $ C (O) -, heterocycle, aryl, heteroaryl, - (CH2)); OH, -C1-Cs alkyl, CF3, CHF2, or CH2F; and n is independently O, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.
[4]
4. Compound, characterized by the fact that it has Formula |: 1 1 AT AA 2 and RR) or a pharmaceutically acceptable salt, prodrug, hydrate, tautomer or isomer thereof, where: X 'is Nou CH; X 'is Nou CH; X is Nou CH; where at least one of X ', X , or Xº is N; Y'1 is —S- or a direct bond, A is selected from the group consisting of 5- to 12-membered monocyclic or polycyclic cycloalkyl, monocyclic or polycyclic heterocycloalkyl, monocyclic or polycyclic aryl or monocyclic or polycyclic heteroaryl; R 'is independently, at each occurrence, -H, —D, —C1-Cs alkyl, —C2-C6 alkenyl, —-C4-C; g cycloalkenyl, —C2-Cs alkynyl, —C3-Ca cycloalkyl, -OH, —ORº, halogen, -NO2, CN, —NRºRº, —SR ”, - S (O) aNRºRS, —S (O) 2Ró, -NR5S (O) aNRºRº, -NR $ S (O) 2R6, - = S (O) NRºR $, —S (O) Ró, —NRºS (O) NRºRº, —NRºS (O) Rº, —C (OJ) Rº, —-COXR ”, - C (O) NRºRô, or -NRºC (O) Rô, where each alkyl, alkenyl, cycloalkenyl, alkynyl, or cycloalkyl is optionally substituted with one or more -OH, halogen, —-NO ,, 0x0, = CN, -R5, —-OR ”, —-NRºRº, -SRSº, —S (O) NRºRº, -“ - S (O) Rº, —NRSS (O) NRºR, —NRºS (O) R%, -— S (O) NRºRS, -S (O) RS, -NR5S (O) NRºR $, -NR $ S (O) R $, heterocycle, aryl or heteroaryl; R and R $ are independently selected from the group consisting of —H, -D, -OH, —C1-Cs alkyl, a monocyclic or polycyclic heterocycle
3 to 12 membered cyclic, a 5 12 membered spiroheterocycle, C3-Cs cycloalkyl, or - (CH2)) - R ', where each alkyl, heterocycle, or cycloalkyl is optionally substituted with one or more - -C1-Cs alkyl, OH, NH ', -ORº, -NHRºP, - (CH2)) OH, heterocyclic, or spiro-heterocyclyl; or R can be combined with R to form a 3- to 12-membered monocyclic or polycyclic heterocycle, or a 5-12 membered spiroheterocycle, where each heterocycle or spiroheterocycle is optionally substituted with one or more —C1-Cs alkyl, halogen - OH, - OR, -NH2, - = - NHRº, heteroaryl, heterocyclyl, - (CH2)) NH2, - (CH2) JOH, -COOR , -CONHRº, -—- CONH (CH2) ,. COOR ”, - NHCOOR " , —CF3, - CHF2, -CH2F, or = O; Rº is —H, —D, —C1-Cs alkyl, —C1-Cehalo alkyl, —-C1-Cs hydroxyalkyl - CF20H, -CHFOH, - NH-NHRS, - = - NH-OR5, = O-NRºR6, - = NHR5, —OR $, - NHC (O) Rº, -NHC (O) NHR5, -NHS (O) 2R5, -NHS (O) 2NHR ", —-S (0) 2OH, —C (0) ORS, -NH (CH2)); OH, —C (O) NH (CH2)) OH, —C (O) NH (CH2)) Rº, - C (O) Rº, —-NH2, -OH, —CN, —C (O) NRºR6, -S (O) NR “R $, C3-Cz cycloalkyl, aryl, heterocyclyl containing from 1 to 5 heteroatoms selected from the group consisting of N, S, P, and O, or heteroaryl containing from 1 to heteroatoms selected from group consisting of N, S, P, / and O, where each cycloalkyl or heterocyclyl alkyl is optionally substituted with one or more -OH, —-NH> 2, —OR , halogen, or 0x0; where each aryl or heteroaryl is optionally substituted with one or more —OH, —NN;>, or halogen; Rº and Rô are each independently, in each occurrence, selected from the group consisting of —H, —D, —C1-Cs alkyl, —C2-Cs alkenyl, —C4-C; g cycloalkenyl, —- C2-Cs alkynyl, —-C3-Ca cycloalkyl, a 3- to 12-membered monocyclic or polycyclic heterocycle, -OR ”, —SR”, halogen, -NR7Rô, —-NO, », and —-CN; R and R $ are independently, in each occurrence, —H, —D, —C1-Cs alkyl, —C2-Ce6 alkenyl, —C4a-C; g cycloalkenyl, —C2-Cs alkynyl, —C3- Cs cycloalkyl, a heterocycle 3- to 12-membered monocyclic or polycyclic, where each alkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkyl, or heterocycle is optionally substituted with one or more —OH, -SH, - = NH> 2, - = NO>, or —CN; Rº is independently —H, —-D, —- C1-Cs alkyl, —-C1-Cs cycloalkyl, - C2-Cs alkenyl, - (CH> 2), - aryl, heterocyclyl containing from 1 to 5 selected heteroatoms the group consisting of N, S, P, or O, or heteroaryl containing 1 to 5 heteroatoms selected from the group consisting of N, S, P, and O; where each alkyl, cycloalkyl, alkenyl, heterocycle, heteroaryl, or - (CH>) n-aryl is optionally substituted with one or more -OH, halogen, —-NO>, oxo, -CN, -R5, -—OR $, - NRºR6, -SRº, —S (O) NR'ºRº, —S (O) R5, —NRSS (O) NR'ºRº, -— NRÍS (O) 2Rô, = S (O) NRºR $, - S (O) Ró, = -NRºS (O) NRºRº, -NR $ S (O) RS $, - C (OINRºRô-, - NR R $ C (O) -, heterocycle, aryl, heteroaryl, - (CH2 )) OH, -C1-Cs alkyl, CF3, CHF2, or CH2F; and n is independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.
[5]
5. Compound according to any one of claims 1 to 4, characterized by the fact that Xº is N.
[6]
6. A compound, as defined in any one of claims 1 to 4, characterized by the fact that X 'is CH.
[7]
7. Compound, as defined in any of claims 1 to 6, characterized by the fact that X º is N.
[8]
8. A compound, as defined in any of claims 1 to 6, characterized by the fact that X is CH.
[9]
9. Compound, as defined in any one of claims 1 to 8, characterized by the fact that Xº is N.
[10]
10. Compound, as defined in any one of claims 1 to 8, characterized by the fact that X * is CH.
[11]
11. Compound, as defined in any of the claims
1 to 10, characterized by the fact that A is monocyclic or polycyclic aryl.
[12]
12. Compound, as defined in any one of claims 1 to 10, characterized by the fact that A is cycloalkyl monocyclic or polycyclic.
[13]
13. Compound, as defined in any one of claims 1 to 10, characterized by the fact that A is monocyclic or polycyclic heterocycloalkyl.
[14]
14. Compound, as defined in any one of claims 1 to 10, characterized by the fact that A is monocyclic or polycyclic heteroaryl.
[15]
15. Compound, as defined in any one of claims 1 to 14, characterized by the fact that each R 'is selected from the group consisting of -H, halogen, -C1-Cs alkyl, and -NRºRº.
[16]
16. Compound, according to claim 15, characterized by the fact that Rº and Rº are H.
[17]
17. Compound, as defined in any one of claims 1 to 16, characterized by the fact that Rº is optionally substituted an -C1-Cç alkyl.
[18]
18. Compound, as defined in any one of claims 1 to 17, characterized by the fact that Rº is “CH2-OH.
[19]
19. Compound, as defined in any one of claims 1 to 17, characterized by the fact that Rº is -C1-Cs alkyl substituted with one or more halogen.
[20]
20. Compound, as defined in any one of claims 1 to 19, characterized by the fact that Rº can be combined with R to form a 3- to 12-membered monocyclic or polycyclic heterocycle, where the heterocycle is optionally substituted with - C1-Cs alkyl, halogen -OH, -ORº, —-NH2, - = - NHRº, heteroaryl, heterocyclyl, - (CH2)) NHo, - - (CH2)) OH, - -COOR ”, - -CONHR !, —-—
CONH (CH2)), COORP, -NHCOORP, -CF3, = CHF2, —-CH2F, or = O.
[21]
21. A compound according to claim 20, characterized by the fact that the heterocycle is unsubstituted or substituted with —C1-Cs alkyl, -ORº, or —-NH>.
[22]
22. Compound, as defined in any one of claims 1 to 19, characterized by the fact that R3 can be combined with R to form a 5- to 12-membered spiroheterocycle, where the spiroheterocycle is optionally substituted with —C1-Cs alkyl, halogen -OH, -ORº, —-NH> 2, - = - NHRº, heteroaryl, heterocyclyl, - (CH2)) NH2, - (CH2)) OH, -COORº, -CONHR !, -CONH (CH2) .COORº, - NHCOOR , -CF3, - = CHF2, -CH2F, or = O.
[23]
23. A compound according to claim 22, characterized by the fact that the spirocycle is unsubstituted or substituted with —C1-Cs alkyl, - = ORº, or —-NH>.
[24]
24. Compound, as defined in any one of claims 1 to 19, characterized by the fact that Rº combines with R to form a selected portion of: * y No & * y NH> L Y; Let them, o and o.
[25]
25. Compound, or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, tautomer or isomer thereof, characterized by the fact that it is selected from the group consisting of No. Cc NH> was] PY NH Ho O (9), Ho U), QD DOS, and q À OX N ZD Qu NH s That Ho (3), and HO (4).
[26]
26. A compound, or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, tautomer or isomer thereof, characterized by the fact that it is selected from the group consisting of HA IS. 1 ADJUSTMENT TO "DO
Z Y NR and ADS »Dee (5) and (5a).
[27]
27. Compound, or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, tautomer or isomer thereof, characterized by the fact that it is selected from the group consisting of out AS> STD, o, (2) G) , POO. DB. STS: G) “e (4), 'SD, 8), (9),' (10), '(12), SAS» SAE | TS 3), (14), (15) x CA »COS» TOS: on AS ie a) on AS (16), '(18),
EA RACE pn SOS. WAISTBAND. on the NX. (19), (20), 21), If: Are AO IA mm O RNAÇ m NE RAR m (22), (23), (24), SC: “ão Sr E, NS COS. So * Pá "the NS im es. | 28), (27), (28), (29), (30), SE e and MNA, S & and CDS OF NH AA Me o (32), and in” Ts » (31), (33).
[28]
28. Compound, or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, tautomer or isomer thereof, characterized by the fact that it is selected from the group consisting of A, Q, Cc NA, nºs Cc NA, Nº , CHF, Ss FAO: (34) and (35).
[29]
29. A compound, as defined in any one of claims 1 to 28, or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, tautomer or isomer thereof, characterized by the fact that it is for use as a medicine.
[30]
30. A compound, as defined in any one of claims 1 to 28, or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, tautomer or isomer thereof, characterized by the fact that it is for use in the treatment or prevention of a disease associated with SHP2 modulation.
[31]
31. Pharmaceutical composition, characterized by the fact that it comprises the compound as defined in any one of claims 1 to 28, or a pharmaceutically acceptable salt, prophylactic, solvate, hydrate, tautomer or isomer thereof, and a pharmaceutically carrier acceptable.
[32]
32. Pharmaceutical composition, as defined in claim 31, characterized by the fact that it is for use as a medicine.
[33]
33. Pharmaceutical composition, as defined in claim 31, characterized by the fact that it is for use in the treatment or prevention of a disease associated with SHP2 modulation.
[34]
34. Use of a compound, as defined in any one of claims 1 to 28, or a pharmaceutically acceptable salt, prodrug, solvate, hydrate, tautomer or isomer thereof, characterized by the fact that it is in the manufacture of a medicament for treatment or preventing a disease associated with SHP2 modulation.
[35]
35. Use of a pharmaceutical composition, as defined in claim 31, characterized by the fact that it is in the manufacture of a drug for the treatment or prevention of a disease associated with SHP2 modulation.
[36]
36. Use according to claim 34 or 35, characterized by the fact that the disease is selected from Noano Syndrome, Leopard Syndrome, juvenile myelomonocytic leukemias, neuroblastoma, melanoma, acute myeloid leukemia and cancers of the myeloid breast, lung and colon.

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